PMID- 26413479 TI - Motor pathway degeneration in young ataxia telangiectasia patients: A diffusion tractography study. AB - BACKGROUND: Our understanding of the effect of ataxia-telangiectasia mutated gene mutations on brain structure and function is limited. In this study, white matter motor pathway integrity was investigated in ataxia telangiectasia patients using diffusion MRI and probabilistic tractography. METHODS: Diffusion MRI were obtained from 12 patients (age range: 7-22 years, mean: 12 years) and 12 typically developing age matched participants (age range 8-23 years, mean: 13 years). White matter fiber tracking and whole tract statistical analyses were used to assess quantitative fractional anisotropy and mean diffusivity differences along the cortico-ponto-cerebellar, cerebellar-thalamo-cortical, somatosensory and lateral corticospinal tract length in patients using a linear mixed effects model. White matter tract streamline number and apparent fiber density in patient and control tracts were also assessed. RESULTS: Reduced fractional anisotropy along all analyzed patient tracts were observed (p < 0.001). Mean diffusivity was significantly elevated in anterior tract locations but was reduced within cerebellar peduncle regions of all patient tracts (p < 0.001). Reduced tract streamline number and tract volume in the left and right corticospinal and somatosensory tracts were observed in patients (p < 0.006). In addition, reduced apparent fiber density in the left and right corticospinal and right somatosensory tracts (p < 0.006) occurred in patients. CONCLUSIONS: Whole tract analysis of the corticomotor, corticospinal and somatosensory pathways in ataxia telangiectasia showed significant white matter degeneration along the entire length of motor circuits, highlighting that ataxia-telangiectasia gene mutation impacts the cerebellum and multiple other motor circuits in young patients. PMID- 26413480 TI - Transcriptome profiling of sleeping, waking, and sleep deprived adult heterozygous Aldh1L1 - eGFP-L10a mice. AB - Transcriptomic studies revealed that hundreds of mRNAs show differential expression in the brains of sleeping relative to awake rats, mice, flies, and sparrows. Although these results have offered clues regarding the molecular consequences of sleep and sleep loss, their functional significance thus far has been limited. This is probably because the previous studies pooled transcripts from all brain cells, including neurons and glia. In Bellesi et al. 2015 [1], we used the translating ribosome affinity purification technology (TRAP) and microarray analysis to obtain a genome-wide mRNA profiling of astrocytes as a function of sleep and wake. We used bacterial artificial chromosome (BAC) transgenic mice expressing eGFP tagged ribosomal protein L10a under the promoter of the Aldh1L1 gene, a highly expressed astrocytic gene. Using this approach, we could extract only the astrocytic mRNAs, and only those already committed to be translated into proteins (L10a is part of the translational machinery). Here, we report a detailed description of the protocol used in the study [1]. Array data have been submitted to NCBI GEO under accession number (GSE69079). PMID- 26413481 TI - Endocrine hypertension: An overview on the current etiopathogenesis and management options. AB - Endocrine causes of secondary hypertension include primary aldosteronism, pheochromocytoma, cushing's syndrome, hyperparathyroidism and hypo- and hyperthyroidism. They comprise of the 5%-10% of the causes of secondary hypertension. Primary hyperaldosteronism, the most common of the endocrine cause of hypertension often presents with resistant or difficult to control hypertension associated with either normo-or hypokalemia. Pheochromocytoma, the great mimicker of many conditions, is associated with high morbidity and mortality if left untreated. A complete history including pertinent family history, physical examination along with a high index of suspicion with focused biochemical and radiological evaluation is important to diagnose and effectively treat these conditions. The cost effective targeted genetic screening for current known mutations associated with pheochromocytoma are important for early diagnosis and management in family members. The current review focuses on the most recent evidence regarding causes, clinical features, methods of diagnosis, and management of these conditions. A multidisciplinary approach involving internists, endocrinologists and surgeons is recommended in optimal management of these conditions. PMID- 26413482 TI - Hepatocyte selection medium eliminating induced pluripotent stem cells among primary human hepatocytes. AB - Hepatic insufficiency is a fatal liver disease with a significant decrease in functioning hepatocytes. If hepatocytes could be generated from human induced pluripotent stem (hiPS) cells and transplanted into patients with hepatic insufficiency, the disease may become curable. However, a major limitation to this therapeutic strategy is due to the tumorigenicity of hiPS cells and their ability to form cancer. Current methods for eliminating unwanted hiPS cells use genetic manipulation or reagents that are potentially hazardous for hepatocytes; therefore, revised methods are necessary and anticipated. Glucose and arginine are essential cell culture medium ingredients for the survival of most cells, including hiPS cells. However, hepatocytes can produce its own glucose and arginine through galactokinase and ornithine transcarbamylase, respectively. Therefore, it was hypothesized that unwanted hiPS cells could be eliminated in a medium without glucose and arginine, and supplemented with galactose and ornithine instead. This modified medium has been established as hepatocyte selection medium (HSM). So far, attempts to generate a pure colony of mature hepatocytes from hiPS cells have not been successful. After establishment of co culture in HSM, primary human hepatocytes survive while hiPS cells die within three days. Our latest results regarding a modification of HSM will be introduced in this manuscript. PMID- 26413483 TI - Metabolic bone disease in the preterm infant: Current state and future directions. AB - Neonatal osteopenia is an important area of interest for neonatologists due to continuing increased survival of preterm infants. It can occur in high-risk infants such as preterm infants, infants on long-term diuretics or corticosteroids, and those with neuromuscular disorders. Complications such as rickets, pathological fractures, impaired respiratory function and poor growth in childhood can develop and may be the first clinical evidence of the condition. It is important for neonatologists managing such high-risk patients to regularly monitor biochemical markers for evidence of abnormal bone turnover and inadequate mineral intake in order to detect the early phases of impaired bone mineralization. Dual-energy X-ray absorptiometry has become an increasingly used research tool for assessing bone mineral density in children and neonates, but more studies are still needed before it can be used as a useful clinical tool. Prevention and early detection of osteopenia are key to the successful management of this condition and oral phosphate supplements should be started as soon as is feasible. PMID- 26413484 TI - Methodological challenges to control for immortal time bias in addressing drug effects in type 2 diabetes. AB - There are multiple biases in using observational studies to examine treatment effects such as those from prevalent drug users, immortal time and drug indications. We used renin angiotensin system (RAS) inhibitors and statins as reference drugs with proven efficacies in randomized clinical trials (RCTs) and examined their effectiveness in the prospective Hong Kong Diabetes Registry using adjustment methods proposed in the literature. Using time-dependent exposures to drug treatments yielded greatly inflated hazard ratios (HR) regarding the treatment effects of these drugs for cardiovascular disease (CVD) in type 2 diabetes. These errors were probably due to changing indications to use these drugs during follow up periods, especially at the time of drug commencement making time-dependent analysis extremely problematic. Using time-fixed analysis with exclusion of immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of RAS inhibitors for CVD was comparable to that in RCT. The result supported the use of the Registry for performing pharmacoepidemiological analysis which revealed an attenuated low low-density lipoprotein cholesterol related cancer risk with RAS inhibitors. On the other hand, time-fixed analysis with including immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of statins for CVD was similar to that in the RCT. Our results highlight the complexity and difficulty in removing these biases. We call for validations of the methods to cope with immortal time and drug use indications before applying them to particular research questions, so to avoid making erroneous conclusions. PMID- 26413485 TI - Endoscopic management of adenomatous ampullary lesions. AB - Lesions of the ampulla of Vater represent an uncommon group of gastrointestinal malignancies. The majority of lesions of the ampulla of Vater are either adenomas or adenocarcinomas. Ampullary lesions are often incidental findings. Accurate preoperative diagnosis and staging of ampullary tumors is imperative for predicting prognosis and determining the most appropriate therapeutic approach. Endoscopic ampullectomy is a safe and efficacious therapeutic procedure that can obviate the need for potentially major surgical intervention. This review will provide the framework for the diagnosis and management of ampullary lesions from the perspective of the practicing gastroenterologist. Strategies for safe and successful endoscopic ampullectomy with a focus on accurate preoperative diagnosis and staging, resection technique, and management of complications are presented. PMID- 26413486 TI - "How many times must a man look up before he can really see the sky?" Rheumatic cardiovascular disease in the era of multimodality imaging. AB - Cardiovascular involvement in rheumatic diseases (RD) is the result of various pathophysiologic mechanisms including inflammation, accelerated atherosclerosis, myocardial ischemia, due to micro- or macro-vascular lesions and fibrosis. Noninvasive cardiovascular imaging, including echocardiography, nuclear techniques, cardiovascular computed tomography and cardiovascular magnetic resonance, represents the main diagnostic tool for early, non-invasive diagnosis of heart disease in RD. However, in the era of multimodality imaging and financial crisis there is an imperative need for rational use of imaging techniques in order to obtain the maximum benefit at the lowest possible cost for the health insurance system. The oligo-asymptomatic cardiovascular presentation and the high cardiovascular mortality of RD necessitate a reliable and reproducible diagnostic approach to catch early cardiovascular involvement. Echocardiography remains the routine cornerstone of cardiovascular evaluation. However, a normal echocardiogram can not always exclude cardiac involvement and/or identify heart disease acuity and pathophysiology. Therefore, cardiovascular magnetic resonance is a necessary adjunct complementary to echocardiography, especially in new onset heart failure and when there are conflicting data from clinical, electrocardiographic and echocardiographic evaluation of RD patients. PMID- 26413487 TI - Lamb's head: The model for novice education in endoscopic sinus surgery. AB - Structured training in endonasal endoscopic sinus surgery (EESS) and skull base surgery is essential considering serious potential complications. We have developed a detailed concept on training these surgical skills on the lamb's head. This simple and extremely cheap model offers the possibility of training even more demanding and advanced procedures in human endonasal endoscopic surgery such as: frontal sinus surgery, orbital decompression, cerebrospinal fluid-leak repair followed also by the naso-septal flap, etc. Unfortunately, the sphenoid sinus surgery cannot be practiced since quadrupeds do not have this sinus. Still, despite this anatomical limitation, it seems that the lamb's head can be very useful even for the surgeons already practicing EESS, but in a limited edition because of a lack of the experience and dexterity. Only after gaining the essential surgical skills of this demanding field it makes sense to go for the expensive trainings on the human cadaveric model. PMID- 26413488 TI - Refractory chronic cough due to gastroesophageal reflux: Definition, mechanism and management. AB - Refractory chronic cough due to gastroesophageal reflux is a troublesome condition unresponsive to the standard medical anti-reflux therapy. Its underlying mechanisms may include incomplete acid suppression, non-acid reflux, transient lower esophageal sphincter relaxations and esophageal hypersensitivity. The diagnosis of this disorder depends on both the findings of multi-channel intraluminal impedance-pH monitoring and the subsequent intensified anti-reflux therapy. The strategies of pharmacological treatment for refractory chronic cough due to reflux include the optimization of proton pump inhibitors and add-on therapies with histamine H2 receptor antagonists, baclofen and gabapentin. However, the further study is needed to satisfy its management. PMID- 26413489 TI - Early probiotics to prevent childhood metabolic syndrome: A systematic review. AB - AIM: To conduct a systematic review of studies on early probiotic supplementation to prevent childhood metabolic syndrome (MS). METHODS: Using the Cochrane systematic review strategy we searched PubMed, EMBASE, CENTRAL, CINAHL, and the conference proceedings of the Pediatric American Society meetings and trial registries in December 2014. Randomised controlled trials (RCTs) and non RCTs of probiotic supplementation to the mother and/or infant for a minimum duration of 4 wk were selected. Of these, studies that reported on MS or its components (obesity, raised blood pressure, hyperglycemia, dyslipidemia) in children between 2-19 years were to be eligible for inclusion in the review. Risk of bias (ROB) in selected RCTs and quality assessment of non-RCT studies were to be assessed by the Cochrane ROB assessment table and New Castle Ottawa scale. RESULTS: There were no studies on early probiotic administration for prevention of childhood MS (CMS). Follow up studies of two placebo controlled RCTs (n = 233) reported on the effects of early probiotics on one or more components of MS in children aged 2-19 years. Meta-analysis of those two studies could not be performed due to differences in the patient population, type of outcomes studied and the timing of their assessment. Assessment of childhood metabolic outcomes was not the primary objective of these studies. The first study that assessed the effects of prenatal and postnatal supplementation of Lactobacillus rhamnosus GG on body mass index till 10 years, did not report a significant benefit. In the second study, Lactobacillus paracasei 19 was supplemented to healthy term infants from 4-13 mo. No significant effect on body mass index, body composition or metabolic markers was detected. CONCLUSION: Current evidence on early probiotic administration to prevent CMS is inadequate. Gaps in knowledge need to be addressed before large RCTs can be planned. PMID- 26413491 TI - Aspirin as Primary Prevention of Acute Coronary Heart Disease Events. AB - BACKGROUND/OBJECTIVE: Aspirin for primary prophylaxis is controversial. This study evaluated associations between prophylactic aspirin use and incident acute coronary heart disease (CHD) events. METHODS AND RESULTS: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study was accessed for aspirin use examining black and white hazards for incident CHD, for men and women, each adjusting incrementally for sampling, sociodemographics, and CHD risk factors. Stratified models examined risks across strata of the Framingham risk score, and all-cause mortality. 23,949 participants (mean 64 yo), had 503 incident events over a 3.5 year follow-up. Prophylactic aspirin use was not associated with incident acute CHD, HR 1.05 (95% CI 0.86, 1.29). Modeling had little impact on the HR (1.09 {95% CI 0.89, 1.33) nor did the addition of risk factors (HR 1.00 {95% CI 0.81, 1.23). Aspirin use was not associated with incident CHD for any Framingham risk level. Findings were similar when including all aspirin users (not just those taking aspirin prophylactically), and when examining associations with all-cause mortality. There was no excess hospitalized bleeding in the aspirin users. CONCLUSION: Aspirin was not associated with lower risk for incident acute CHD overall, or within race, gender, or Framingham Risk Score. PMID- 26413490 TI - Prevalence of antibiotic resistance in Helicobacter pylori: A recent literature review. AB - AIM: To review previous studies (the last 6 years) about the Helicobacter pylori (H. pylori) antibiotic resistance in order to evaluate the trend in antibiotic resistance. METHODS: In this study, the PubMed, MEDLINE, Science Direct, Google Scholar and Scielo manuscripts were reviewed from 2009 to 2014. RESULTS: On the whole rates of H. pylori antibiotic resistance were 47.22% (30.5%-75.02%) for metronidazole, 19.74% (5.46%-30.8%) for clarithromycin, 18.94% (14.19%-25.28%) for levofloxacin, and 14.67% (2%-40.87%) for amoxicillin, 11.70% (0%-50%) for tetracycline, 11.5% (0%-23%) for furazolidon and 6.75% (1%-12.45%) for rifabutin. The frequency of tetracycline, metronidazole and amoxicillin resistance was higher in Africa, while clarithromycin and levofloxacin resistance was higher in North America and Asian, respectively. CONCLUSION: The most sensitive drug is rifabutin and the lowest sensitive drug is metronidazole in the world. The worldwide H. pylori antibiotic resistance to clarithromycin and levofloxacin has increased during the last 6 years. The present systematic review show alarming results and a novel plan is needed for eradication therapy of H. pylori infections. PMID- 26413492 TI - Effect of spent turmeric on kidney glycoconjugates in streptozotocin-induced diabetic rats. AB - BACKGROUND: Curcumin known to have number of medicinal use and masked the fiber containing ukonan like active polysaccharide in turmeric and its pharmacological effect will be addressed on diabetic nephropathy particularly the glycoconjugates of extracellular components viz., glycoproteins and glycosaminoglycans - heparan sulfate (HS). METHODS: Male Wistar rats were maintained on AIN-76 diet containing 10% spent turmeric and were grouped into control and STZ induced diabetes SFC/TFC and SFD/TFD, respectively. Diabetic status was monitored using blood and urine, and at the end, harvested kidneys were used to study the amelioration of glycoprotiens (collagen) and HS by enzymatic digestion, spectrophotometric, hydroxyproline and agarose electrophoretic methods. RESULTS: In the present study spent turmeric (10%) fed diabetic rats showed improved glomerular filtration rate (50%), kidney enlargement (60%) and other glycoconjugate metabolism in kidney. Increased collagen content in diabetic group was observed by hydroxyproline estimation (24%) and periodic acid-Schiff's (PAS) staining. Furthermore, elevated activities of enzymes involved in the synthesis and degradation of glycosaminoglycans (GAGs) were significantly lowered in spent turmeric fed diabetic group. Improvement in total GAGs (43%) and sulfate content (18%) followed by fractionation of GAGs using specific enzymes led to HS (28%) in the spent turmeric fed diabetic group, when compared to starch fed diabetic group and was further confirmed by electrophoresis of GAG. CONCLUSION: These results clearly indicate beneficial role of spent turmeric in controlling glycoconjugates such as glycoproteins and heparan sulfate related kidney complications during diabetes. PMID- 26413493 TI - Effects of CoQ10 Supplementation on Lipid Profiles and Glycemic Control in Patients with Type 2 Diabetes: a randomized, double blind, placebo-controlled trial. AB - BACKGROUND: Low grade inflammation and oxidative stress are the key factors in the pathogenesis and development of diabetes and its complications. Coenzyme Q10 (CoQ10) is known as an antioxidant and has a vital role in generation of cellular energy providing. This study was undertaken to evaluate the effects of CoQ10 supplementation on lipid profiles and glycemic controls in patients with diabetes. METHODS: Fifty patients with diabetes were randomly allocated into two groups to receive either 150 mg CoQ10 or placebo daily for 12 weeks. Before and after supplementation, fasting venous blood samples were collected and lipid profiles containing triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) and glycemic indices comprising of fasting plasma glucose (FPG), insulin and hemoglobin A1C (HbA1C) were measured. Insulin resistance was calculated using HOMA-IR index. RESULTS: Forty patients completed the study. After intervention FPG and HbA1C were significantly lower in the CoQ10 group compared to the placebo group, but there were no significant differences in serum insulin and HOMA-IR between the two groups. Although total cholesterol did not change in the Q10 group after supplementation, triglyceride and HDL-C significantly decreased and LDL-C significantly increased in the CoQ10 group. CONCLUSION: The present study showed that treatment with Q10 may improve glycemic control with no favorable effects on lipid profiles in type 2 patients with diabetes. TRIAL REGISTRATION: IRCT registry number: IRCT138806102394N1. PMID- 26413494 TI - Progress in Treatment Development for Neuropsychiatric Symptoms in Alzheimer's Disease: Focus on Agitation and Aggression. A Report from the EU/US/CTAD Task Force. AB - The management of neuropsychiatric symptoms (NPS) such as agitation and aggression is a major priority in caring for people with Alzheimer's disease (AD). Agitation and aggression (A/A) are among the most disruptive symptoms, and given their impact, they are increasingly an important target for development of effective treatments. Considerable progress has been made in the last years with a growing number of randomized controlled trials (RCTs) of drugs for NPS. The limited benefits reported in some RCTs may be accounted for by the absence of a biological link of the tested molecule to NPS and also by key methodological issues. In recent RCTs of A/A, a great heterogeneity design was found. Designing trials for dementia populations with NPS presents many challenges, including identification of appropriate participants for such trials, engagement and compliance of patients and caregivers in the trials and the choice of optimal outcome measures to demonstrate treatment effectiveness. The EU/US -CTAD Task Force, an international collaboration of investigators from academia, industry, non-profit foundations, and regulatory agencies met in Philadelphia on November 19, 2014 to address some of these challenges. Despite potential heterogeneity in clinical manifestations and neurobiology, agitation and aggression seems to be accepted as an entity for drug development. The field appears to be reaching a consensus in using both agitation and aggression (or other NPS)-specific quantitative measures plus a global rating of change for agitation outcomes based on clinician judgment as the main outcomes. PMID- 26413495 TI - Three-dimensional functional unit analysis of hemifacial microsomia mandible-a preliminary report. AB - BACKGROUND: The aim of this study was to present three-dimensional (3D) structural characteristics of the mandible in the hemifacial microsomia. The mandible has six distinct functional units, and its architecture is the sum of balanced growth of each functional unit and surrounding matrix. METHODS: In order to characterize the mandibular 3D architecture of hemifacial microsomia, we analyzed the mandibular functional units of four hemifacial microsomia patients using the 3D reconstructed computed tomography (CT) images. And we compared the functional unit size between affected and non-affected side. RESULTS: The length of condyle and angle showed significant differences between affected and non affected sides. However, the length of mandibular body showed insignificant differences. The size differences between affected and non-affected side were observed at the condyle, angle, and body in descending order. CONCLUSIONS: This preliminary study suggests that the main etiopathogenic units are condyle and angle in the hemifacial microsomia mandible. Further investigation with the increased number of subjects will be helpful to establish treatment modality by etiopathogenic targeting of hemifacial microsomia. PMID- 26413496 TI - Facial asymmetry: a case report of localized linear scleroderma patient with muscular strain and spasm. AB - Facial asymmetry is found in patients with or without cosmetic facial alterations. Some patients have facial asymmetry that manifests underlying skeletal problems, while others have only limited soft-tissue facial asymmetry. Orthognathic surgery brings about a dermatic change, as soft tissue covers underlying bones. Limited soft-tissue asymmetry, meanwhile, is difficult to correct. The treatment modalities for the creation or restoration of an esthetically pleasing appearance were autogenous fat grafts, cartilage graft, and silicon injections. A young female patient had right-side facial asymmetry. The clinical assessment involved visual inspection of the face and palpation to differentiate soft tissue and bone. Although the extra-oral examination found facial asymmetry with skin atrophy, the radiographic findings revealed no mandibular atrophy or deviation. She was diagnosed as localized scleroderma with muscle spasm. In conclusion, facial asymmetry patients with skeletal asymmetry can be esthetically satisfied by orthognathic surgery; however, facial atrophy patients with skin or subdermal tissue contraction need treatment by cosmetic dermatological surgery and orthodontic correction. PMID- 26413497 TI - Assessment of the proximity between the mandibular third molar and inferior alveolar canal using preoperative 3D-CT to prevent inferior alveolar nerve damage. AB - BACKGROUND: The inferior alveolar nerve (IAN) may be injured during extraction of the mandibular third molar, causing severe postoperative complications. Many methods have been described for evaluating the relative position between the mandibular third molar and the inferior alveolar canal (IAC) on panoramic radiography and computed tomography, but conventional radiography provides limited information on the proximity of these two structures. The present study assessed the benefits of three-dimensional computed tomography (3D-CT) prior to surgical extraction of the mandibular third molar, to prevent IAN damage. METHODS: This retrospective study included 4917 extractions in 3555 patients who presented for extraction of the mandibular third molars. The cases were classified into three groups, according to anatomical relationship between the mandibular third molars and the IAC on panoramic radiography and whether 3D-CT was performed. Symptoms of IAN damage were assessed using the touch-recognition test. Data were compared using the chi-square test and Fisher's exact test. RESULTS: Among the 32 cases of IAN damage, 6 cases were included in group I (0.35 %, n = 1735 cases), 23 cases in group II (1.1 %, n = 2063 cases), and 3 cases in group III (0.27 %, n = 1119 cases). The chi-square test showed a significant difference in the incidence of IAN damage between groups I and II. No significant difference was observed between groups I and III using Fisher's exact test. In the 6 cases of IAN damage in group I, the mandibular third molar roots were located lingual relative to the IAC in 3 cases and middle relative to the IAC in 3 cases. The overlap was >=2 mm in 3 of 6 cases and 0-2 mm in the remaining 3 cases. The mean distance between the mandibular third molar and IAC was 2.2 mm, the maximum distance 12 mm, and the minimum distance 0.5 mm. Greater than 80 % recovery was observed in 15 of 32 (46.8 %) cases of IAN damage. CONCLUSIONS: 3D CT may be a useful tool for assessing the three-dimensional anatomical relationship and proximity between the mandibular third molar and IAC in order to prevent IAN damage during extraction of mandibular third molars. PMID- 26413498 TI - Cannabinoid Receptor Type 2 (CB2) Dependent and Independent Effects of WIN55,212 2 on Atherosclerosis in Ldlr-null Mice. AB - PURPOSE: WIN55,212-2, a potent synthetic agonist of cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), reduces atherosclerosis in apolipoprotein E (ApoE) null mice. Although pharmacologic evidence suggests the anti-atherosclerotic effects of WIN55,212-2 are mediated via CB2, this remains to be confirmed by genetic studies. Therefore, in this study, we investigated the effects of WIN55,212-2 on development of atherosclerosis in low-density lipoprotein receptor (Ldlr) null mice with and without homozygous deletion of the CB2 gene. METHODS: After 6 weeks on an atherogenic diet, groups of CB2+/+ and CB2 /- Ldlr-null mice received a daily intraperitoneal injection of WIN55,212-2 or vehicle. After two weeks, plasma lipid levels and atherosclerosis in the aortic root were quantified. RESULTS: Plasma cholesterol and triglyceride levels did not differ between CB2+/+ and CB2-/- mice and WIN55,212-2 had no effect on total cholesterol levels in either genotype. However, triglyceride levels in both CB2+/+ and CB2-/- mice were significantly lowered by WIN55,212-2. The size of aortic root lesions did not differ significantly between CB2+/+ and CB2-/- mice with or without WIN55,212-2 treatment. However, WIN55,212-2 treatment significantly lowered lesional macrophage accumulation in CB2+/+ mice, and lesional smooth muscle content in both CB2+/+ and CB2-/- mice. Lesional apoptosis was also greater in CB2+/+ mice compared to CB2-/-mice, and only reduced by WIN55,212-2 in CB2+/+ mice. Collagen content and elastin fiber fragmentation were unaffected by genotype or WIN55,212-2. CONCLUSIONS: WIN55,212-2 treatment does not alter lesion size in Ldlr null-mice, but does modify lesion cellularity via CB2-dependent and CB2-independent mechanisms. PMID- 26413499 TI - Evaluation of Motor Neuron Excitability by CMAP Scanning with Electric Modulated Current. AB - Introduction. Compound Muscle Action Potential (CMAP) scan is a noninvasive promissory technique for neurodegenerative pathologies diagnosis. In this work new CMAP scan protocols were implemented to study the influence of electrical pulse waveform on peripheral nerve excitability. Methods. A total of 13 healthy subjects were tested. Stimulation was performed with an increasing intensities range from 4 to 30 mA. The procedure was repeated 4 times per subject, using a different single pulse stimulation waveform: monophasic square and triangular and quadratic and biphasic square. Results. Different waveforms elicit different intensity-response amplitude curves. The square pulse needs less current to generate the same response amplitude regarding the other waves and this effect is gradually decreasing for the triangular, quadratic, and biphasic pulse, respectively. Conclusion. The stimulation waveform has a direct influence on the stimulus-response slope and consequently on the motoneurons excitability. This can be a new prognostic parameter for neurodegenerative disorders. PMID- 26413500 TI - The Effect of Omega-3 Docosahexaenoic Acid Supplementation on Gestational Length: Randomized Trial of Supplementation Compared to Nutrition Education for Increasing n-3 Intake from Foods. AB - OBJECTIVE: DHA supplementation was compared to nutrition education to increase DHA consumption from fish and DHA fortified foods. DESIGN: This two-part intervention included a randomized double-blind placebo controlled DHA supplementation arm and a nutrition education arm designed to increase intake of DHA from dietary sources by 300 mg per day. SETTING: Denver Health Hospitals and Clinics, Denver, Colorado, USA. POPULATION: 871 pregnant women aged 18-40 were recruited between 16 and 20 weeks of gestation of whom 564 completed the study and complete delivery data was available in 505 women and infants. METHODS: Subjects received either 300 or 600 mg DHA or olive oil placebo or nutrition education. MAIN OUTCOME VARIABLE: Gestational length. RESULTS: Gestational length was significantly increased by 4.0-4.5 days in women supplemented with 600 mg DHA per day or provided with nutrition education. Each 1% increase in RBC DHA at delivery was associated with a 1.6-day increase in gestational length. No significant effects on birth weight, birth length, or head circumference were demonstrated. The rate of early preterm birth (1.7%) in those supplemented with DHA (combined 300 and 600 mg/day) was significantly lower than in controls. CONCLUSION: Nutrition education or supplementation with DHA can be effective in increasing gestational length. PMID- 26413501 TI - To Compare Time-Weighted Graphs to Evaluate the Inclination of the Acetabular Component of Patients Who Had Total Hip Replacement Surgery. AB - Time-weighted graphs are used to detect small shifts in statistical process control. The aim of this study is to evaluate the inclination of the acetabular component with CUmulative SUM (CUSUM) chart, Moving Average (MA) chart, and Exponentially Weighted Moving Average (EWMA) chart. The data were obtained directly from thirty patients who had undergone total hip replacement surgery at Ondokuz Mayis University, Faculty of Medicine. The inclination of the acetabular component of these people, after total hip replacement, was evaluated. CUSUM chart, Moving Average chart, and Exponentially Weighted Moving Average were used to evaluate the quality control process of acetabular component inclination. MINITAB Statistical Software 15.0 was used to generate these control charts. The assessment done with time-weighted charts revealed that the acetabular inclination angles were settled within control limits and the process was under control. It was determined that the change within the control limits had a random pattern. As a result of this study it has been obtained that time-weighted quality control charts which are used mostly in the field of industry can also be used in the field of medicine. It has provided us with a faster visual decision. PMID- 26413502 TI - Morphine Reduces Myocardial Infarct Size via Heat Shock Protein 90 in Rodents. AB - Opioids reduce injury from myocardial ischemia-reperfusion in humans. In experimental models, this mechanism involves GSK3beta inhibition. HSP90 regulates mitochondrial protein import, with GSK3beta inhibition increasing HSP90 mitochondrial content. Therefore, we determined whether morphine-induced cardioprotection is mediated by HSP90 and if the protective effect is downstream of GSK3beta inhibition. Male Sprague-Dawley rats, aged 8-10 weeks, were subjected to an in vivo myocardial ischemia-reperfusion injury protocol involving 30 minutes of ischemia followed by 2 hours of reperfusion. Hemodynamics were continually monitored and myocardial infarct size determined. Rats received morphine (0.3 mg/kg), the GSK3beta inhibitor, SB216763 (0.6 mg/kg), or saline, 10 minutes prior to ischemia. Some rats received selective HSP90 inhibitors, radicicol (0.3 mg/kg), or deoxyspergualin (DSG, 0.6 mg/kg) alone or 5 minutes prior to morphine or SB216763. Morphine reduced myocardial infarct size when compared to control (42 +/- 2% versus 60 +/- 1%). This protection was abolished by prior treatment of radicicol or DSG (59 +/- 1%, 56 +/- 2%). GSK3beta inhibition also reduced myocardial infarct size (41 +/- 2%) with HSP90 inhibition by radicicol or DSG partially inhibiting SB216763-induced infarct size reduction (54 +/- 3%, 47 +/- 1%, resp.). These data suggest that opioid-induced cardioprotection is mediated by HSP90. Part of this protection afforded by HSP90 is downstream of GSK3beta, potentially via the HSP-TOM mitochondrial import pathway. PMID- 26413503 TI - Compressed Sensing for fMRI: Feasibility Study on the Acceleration of Non-EPI fMRI at 9.4T. AB - Conventional functional magnetic resonance imaging (fMRI) technique known as gradient-recalled echo (GRE) echo-planar imaging (EPI) is sensitive to image distortion and degradation caused by local magnetic field inhomogeneity at high magnetic fields. Non-EPI sequences such as spoiled gradient echo and balanced steady-state free precession (bSSFP) have been proposed as an alternative high resolution fMRI technique; however, the temporal resolution of these sequences is lower than the typically used GRE-EPI fMRI. One potential approach to improve the temporal resolution is to use compressed sensing (CS). In this study, we tested the feasibility of k-t FOCUSS--one of the high performance CS algorithms for dynamic MRI--for non-EPI fMRI at 9.4 T using the model of rat somatosensory stimulation. To optimize the performance of CS reconstruction, different sampling patterns and k-t FOCUSS variations were investigated. Experimental results show that an optimized k-t FOCUSS algorithm with acceleration by a factor of 4 works well for non-EPI fMRI at high field under various statistical criteria, which confirms that a combination of CS and a non-EPI sequence may be a good solution for high-resolution fMRI at high fields. PMID- 26413504 TI - Dentin Morphology of Root Canal Surface: A Quantitative Evaluation Based on a Scanning Electronic Microscopy Study. AB - Dentin is a vital, hydrated composite tissue with structural components and properties that vary in the different topographic portions of the teeth. These variations have a significant implication for biomechanical teeth properties and for the adhesive systems utilized in conservative dentistry. The aim of this study is to analyse the root canal dentin going from coronal to apical zone to find the ratio between the intertubular dentin area and the surface occupied by dentin tubules varies. Observations were conducted on 30 healthy premolar teeth extracted for orthodontic reasons in patients aged between 10 and 14. A SEM analysis of the data obtained in different canal portions showed that, in the coronal zone, dentinal tubules had a greater diameter (4.32 MUm) than the middle zone (3.74 MUm) and the apical zone (1.73 MUm). The average number of dentinal tubules (in an area of 1 mm(2)) was similar in coronal zone (46,798 +/- 10,644) and apical zone (45,192 +/- 10,888), while in the middle zone they were lower in number (30,940 +/- 7,651). However, intertubular dentin area was bigger going from apical to coronal portion. The differences between the analysed areas must be considered for the choice of the adhesive system. PMID- 26413505 TI - Correction for Eddy Current-Induced Echo-Shifting Effect in Partial-Fourier Diffusion Tensor Imaging. AB - In most diffusion tensor imaging (DTI) studies, images are acquired with either a partial-Fourier or a parallel partial-Fourier echo-planar imaging (EPI) sequence, in order to shorten the echo time and increase the signal-to-noise ratio (SNR). However, eddy currents induced by the diffusion-sensitizing gradients can often lead to a shift of the echo in k-space, resulting in three distinct types of artifacts in partial-Fourier DTI. Here, we present an improved DTI acquisition and reconstruction scheme, capable of generating high-quality and high-SNR DTI data without eddy current-induced artifacts. This new scheme consists of three components, respectively, addressing the three distinct types of artifacts. First, a k-space energy-anchored DTI sequence is designed to recover eddy current induced signal loss (i.e., Type 1 artifact). Second, a multischeme partial Fourier reconstruction is used to eliminate artificial signal elevation (i.e., Type 2 artifact) associated with the conventional partial-Fourier reconstruction. Third, a signal intensity correction is applied to remove artificial signal modulations due to eddy current-induced erroneous T2(*) -weighting (i.e., Type 3 artifact). These systematic improvements will greatly increase the consistency and accuracy of DTI measurements, expanding the utility of DTI in translational applications where quantitative robustness is much needed. PMID- 26413506 TI - Adjunctive Pessary Therapy after Emergency Cervical Cerclage for Cervical Insufficiency with Protruding Fetal Membranes in the Second Trimester of Pregnancy: A Novel Modification of Treatment. AB - AIM: To evaluate the effectiveness of adjunctive pessary therapy after emergency cervical cerclage (ECC) in improving perinatal outcome in cervical insufficiency with fetal membranes protruding into the vagina. MATERIAL AND METHODS: A retrospective analysis of patients treated at the 1st Department of Obstetrics and Gynecology, Medical University of Warsaw, between 2008 and 2013. The study group consisted of 15 women treated with ECC and a pessary and the control group consisted of 17 patients treated with cerclage only. RESULTS: The mean gestational age at delivery was significantly higher in the study group (34.7 versus 29.7 weeks, p = 0.03). The period between cerclage insertion and delivery was significantly longer in the study group (82.9 versus 52.1 days, p = 0.045). The mean neonatal birthweight and neonatal "discharge alive" ratio were higher in the study group, although not statistically significant (2550 g versus 1883 g, p = 0.14, and 93.3% versus 70.5%, p = 0.18, resp.). NICU hospitalization rates were comparable (33.3% versus 35.3%, p = 0.9). CONCLUSIONS: Adjunctive pessary therapy allows delaying delivery in women treated with ECC due to cervical insufficiency with protruding fetal membranes. It also seems to improve neonatal outcome, although the differences are not statistically significant. Further prospective study is required to prove these findings. PMID- 26413507 TI - Automatic Tooth Segmentation of Dental Mesh Based on Harmonic Fields. AB - An important preprocess in computer-aided orthodontics is to segment teeth from the dental models accurately, which should involve manual interactions as few as possible. But fully automatic partition of all teeth is not a trivial task, since teeth occur in different shapes and their arrangements vary substantially from one individual to another. The difficulty is exacerbated when severe teeth malocclusion and crowding problems occur, which is a common occurrence in clinical cases. Most published methods in this area either are inaccurate or require lots of manual interactions. Motivated by the state-of-the-art general mesh segmentation methods that adopted the theory of harmonic field to detect partition boundaries, this paper proposes a novel, dental-targeted segmentation framework for dental meshes. With a specially designed weighting scheme and a strategy of a priori knowledge to guide the assignment of harmonic constraints, this method can identify teeth partition boundaries effectively. Extensive experiments and quantitative analysis demonstrate that the proposed method is able to partition high-quality teeth automatically with robustness and efficiency. PMID- 26413508 TI - Epigenomics of Neural Cells: REST-Induced Down- and Upregulation of Gene Expression in a Two-Clone PC12 Cell Model. AB - Cell epigenomics depends on the marks released by transcription factors operating via the assembly of complexes that induce focal changes of DNA and histone structure. Among these factors is REST, a repressor that, via its strong decrease, governs both neuronal and neural cell differentiation and specificity. REST operation on thousands of possible genes can occur directly or via indirect mechanisms including repression of other factors. In previous studies of gene down- and upregulation, processes had been only partially investigated in neural cells. PC12 are well-known neural cells sharing properties with neurons. In the widely used PC12 populations, low-REST cells coexist with few, spontaneous high REST PC12 cells. High- and low-REST PC12 clones were employed to investigate the role and the mechanisms of the repressor action. Among 15,500 expressed genes we identified 1,770 target and nontarget, REST-dependent genes. Functionally, these genes were found to operate in many pathways, from synaptic function to extracellular matrix. Mechanistically, downregulated genes were predominantly repressed directly by REST; upregulated genes were mostly governed indirectly. Among other factors, Polycomb complexes cooperated with REST for downregulation, and Smad3 and Myod1 participated in upregulation. In conclusion, we have highlighted that PC12 clones are a useful model to investigate REST, opening opportunities to development of epigenomic investigation. PMID- 26413509 TI - Resting-State fMRI in MS: General Concepts and Brief Overview of Its Application. AB - Brain functional connectivity (FC) is defined as the coherence in the activity between cerebral areas under a task or in the resting-state (RS). By applying functional magnetic resonance imaging (fMRI), RS FC shows several patterns which define RS brain networks (RSNs) involved in specific functions, because brain function is known to depend not only on the activity within individual regions, but also on the functional interaction of different areas across the whole brain. Region-of-interest analysis and independent component analysis are the two most commonly applied methods for RS investigation. Multiple sclerosis (MS) is characterized by multiple lesions mainly affecting the white matter, determining both structural and functional disconnection between various areas of the central nervous system. The study of RS FC in MS is mainly aimed at understanding alterations in the intrinsic functional architecture of the brain and their role in disease progression and clinical impairment. In this paper, we will examine the results obtained by the application of RS fMRI in different multiple sclerosis (MS) phenotypes and the correlations of FC changes with clinical features in this pathology. The knowledge of RS FC changes may represent a substantial step forward in the MS research field, both for clinical and therapeutic purposes. PMID- 26413510 TI - Tracking Transplanted Stem Cells Using Magnetic Resonance Imaging and the Nanoparticle Labeling Method in Urology. AB - A reliable in vivo imaging method to localize transplanted cells and monitor their viability would enable a systematic investigation of cell therapy. Most stem cell transplantation studies have used immunohistological staining, which does not provide information about the migration of transplanted cells in vivo in the same host. Molecular imaging visualizes targeted cells in a living host, which enables determining the biological processes occurring in transplanted stem cells. Molecular imaging with labeled nanoparticles provides the opportunity to monitor transplanted cells noninvasively without sacrifice and to repeatedly evaluate them. Among several molecular imaging techniques, magnetic resonance imaging (MRI) provides high resolution and sensitivity of transplanted cells. MRI is a powerful noninvasive imaging modality with excellent image resolution for studying cellular dynamics. Several types of nanoparticles including superparamagnetic iron oxide nanoparticles and magnetic nanoparticles have been used to magnetically label stem cells and monitor viability by MRI in the urologic field. This review focuses on the current role and limitations of MRI with labeled nanoparticles for tracking transplanted stem cells in urology. PMID- 26413511 TI - Evaluation of the Contribution of Signals Originating from Large Blood Vessels to Signals of Functionally Specific Brain Areas. AB - The fusiform face area (FFA) is known to play a pivotal role in face processing. The FFA is located in the ventral region, at the base of the brain, through which large blood vessels run. The location of the FFA via functional MRI (fMRI) may be influenced by these large blood vessels. Responses of large blood vessels may not exactly correspond to neuronal activity in a target area, because they may be diluted and influenced by inflow effects. In this study, we investigated the effects of large blood vessels in the FFA, that is, whether the FFA includes large blood vessels and/or whether inflow signals contribute to fMRI signals of the FFA. For this purpose, we used susceptibility-weighted imaging (SWI) sequences to visualize large blood vessels and dual-echo gradient-echo echo planar imaging (GE-EPI) to measure inflow effects. These results showed that the location and response signals of the FFA were not influenced by large blood vessels or inflow effects, although large blood vessels were located near the FFA. Therefore, the data from the FFA obtained by individual analysis were robust to large blood vessels but leaving a warning that the data obtained by group analysis may be prone to large blood vessels. PMID- 26413512 TI - Tropomyosin and Actin Identified as Major Allergens of the Carpet Clam (Paphia textile) and the Effect of Cooking on Their Allergenicity. AB - OBJECTIVES: To identify the major allergenic proteins of clam (Paphia textile) and to investigate the effect of different cooking methods on the allergenicity of these identified proteins. METHODS: Clam protein extracts were separated by denaturing polyacrylamide gel electrophoresis. IgE reactive proteins were then analyzed by immunoblotting with sera from patients with positive skin prick tests (SPT) to the raw clam extract. Mass spectrometry was used to identify the major allergenic proteins of this clam. RESULTS: Raw extract showed 12 protein bands (18-150 kDa). In contrast, fewer protein bands were seen in the boiled extract; those ranging from 40 to 150 kDa were denatured. The protein profiles were similarly altered by frying or roasting. The immunoblots of raw and boiled extracts yielded 10 and 2 IgE-binding proteins, respectively. The fried and roasted extracts showed only a single IgE-binding protein at 37 kDa. Mass spectrometry analysis of the 37 and 42 kDa major allergens indicated that these spots were tropomyosin and actin, respectively. CONCLUSION: The two major allergens of Paphia textile were identified as the thermostable tropomyosin and a new thermolabile allergen actin. PMID- 26413513 TI - Pretreatment Diffusion-Weighted MRI Can Predict the Response to Neoadjuvant Chemotherapy in Patients with Nasopharyngeal Carcinoma. AB - PURPOSE: To explore the potential of diffusion-weighted (DW) magnetic resonance imaging (MRI) using apparent diffusion coefficient (ADC) for predicting the response to neoadjuvant chemotherapy in nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: Ninety-two consecutive patients with NPC who underwent three cycles of neoadjuvant chemotherapy were retrospectively analyzed. DW and anatomical MRI were performed before and after neoadjuvant chemotherapy prior to radiotherapy. Pretreatment ADCs and percentage increases in ADC after chemotherapy were calculated for the primary lesions and metastatic adenopathies. Receiver operating characteristic curve analysis was used to select optimal pretreatment ADCs. RESULTS: Pretreatment mean ADCs were significantly lower for responders than for nonresponders (primary lesions, P = 0.012; metastatic adenopathies, P = 0.013). Mean percentage increases in ADC were higher for responders than for nonresponders (primary lesions, P = 0.008; metastatic adenopathies, P < 0.001). The optimal pretreatment primary lesion and metastatic adenopathy ADCs for differentiating responders from nonresponders were 0.897 * 10(-3) mm(2)/sec and 1.031 * 10(-3) mm(2)/sec, respectively. CONCLUSIONS: NPC patients with low pretreatment ADCs tend to respond better to neoadjuvant chemotherapy. Pretreatment ADCs could be used as a new pretreatment imaging biomarker of response to neoadjuvant chemotherapy. PMID- 26413514 TI - Epidemiological Scenario of Dengue in Brazil. AB - Dengue is the most important reemerging mosquito-borne viral disease worldwide. It is caused by any of four Dengue virus types or serotypes (DENV-1 to DENV-4) and is transmitted by mosquitoes from the genus Aedes. Ecological changes have favored the geographic expansion of the vector and, since the dengue pandemic in the Asian and Pacific regions, the infection became widely distributed worldwide, reaching Brazil in 1845. The incidence of dengue in Brazil has been frequently high, and the number of cases in the country has at some point in time represented up to 60% of the dengue reported cases worldwide. This review addresses vector distribution, dengue outbreaks, circulating serotypes and genotypes, and prevention approaches being utilized in Brazil. PMID- 26413515 TI - Developmental Changes in Morphology of the Middle and Posterior External Cranial Base in Modern Homo sapiens. AB - The basicranium has been described as phylogenetically informative, developmentally stable, and minimally affected by external factors and consequently plays an important role in cranial size and shape in subadult humans. Here basicranial variation of subadults from several modern human populations was investigated and the impact of genetic relatedness on basicranial morphological similarities was investigated. Three-dimensional landmark data were digitized from subadult basicrania from seven populations. Published molecular data on short tandem repeats were statistically compared to morphological data from three ontogenetic stages. Basicranial and temporal bone morphology both reflect genetic distances in childhood and adolescence (5-18 years), but not in infancy (<5 years). The occipital bone reflects genetic distances only in adolescence (13-18 years). The sphenoid bone does not reflect genetic distances at any ontogenetic stage but was the most diagnostic region evaluated, resulting in high rates of correct classification among populations. These results suggest that the ontogenetic processes driving basicranial development are complex and cannot be succinctly summarized across populations or basicranial regions. However, the fact that certain regions reflect genetic distances suggests that the morphology of these regions may be useful in reconstructing population history in specimens for which direct DNA evidence is unavailable, such as archaeological sites. PMID- 26413516 TI - Functional and Structural Details about the Fabella: What the Important Stabilizer Looks Like in the Central European Population. AB - The posterolateral corner of the knee accommodating the fabella complex is of importance in orthopaedic surgery. Unfortunately, there is a lack of data in literature for clinical routine. Therefore, we investigated the fabella's characteristics, biomechanical nature, and present histologic details. Of special interest were the fabella's occurrence and position, calcium concentration as long-term load intake indicator, and the histology. Within our analysis, fabellae were found in 30.0% of all datasets, located on the upper part of the posterolateral femoral condyle. The region of fabella contact on this condyle showed a significantly lower calcium concentration than its surroundings. Histologically, the fabella showed no articular cartilage but a clearly distinguishable fabellofibular ligament that consisted of two bundles: one, as already described in literature inserted at the fibular tip, and another part newly described on the top of the lateral meniscus. In its role of stabilizing the soft tissue structures of the posterolateral knee, the fabella seems to serve as suspension for the ligaments evolving from its base. Even though a joint formation of any kind is unlikely, the presence of a fabella needs to be kept in mind during knee examination and any surgical procedures. PMID- 26413517 TI - Quantitative Anatomy of the Growing Lungs in the Human Fetus. AB - Using anatomical, digital, and statistical methods we examined the three dimensional growth of the lungs in 67 human fetuses aged 16-25 weeks. The lung dimensions revealed no sex differences. The transverse and sagittal diameters and the base circumference were greater in the right lungs while the lengths of anterior and posterior margins and the lung height were greater in the left lungs. The best-fit curves for all the lung parameters were natural logarithmic models. The transverse-to-sagittal diameter ratio remained stable and averaged 0.56 +/- 0.08 and 0.52 +/- 0.08 for the right and left lungs, respectively. For the right and left lungs, the transverse diameter-to-height ratio significantly increased from 0.74 +/- 0.09 to 0.92 +/- 0.08 and from 0.56 +/- 0.07 to 0.79 +/- 0.09, respectively. The sagittal diameter-to-height ratio significantly increased from 1.41 +/- 0.23 to 1.66 +/- 0.18 in the right lung, and from 1.27 +/- 0.17 to 1.48 +/- 0.22 in the left lung. In the fetal lungs, their proportionate increase in transverse and sagittal diameters considerably accelerates with relation to the lung height. The lung dimensions in the fetus are relevant in the evaluation of the normative pulmonary growth and the diagnosis of pulmonary hypoplasia. PMID- 26413518 TI - Fast Imaging Technique for fMRI: Consecutive Multishot Echo Planar Imaging Accelerated with GRAPPA Technique. AB - This study was to evaluate the proposed consecutive multishot echo planar imaging (cmsEPI) combined with a parallel imaging technique in terms of signal-to-noise ratio (SNR) and acceleration for a functional imaging study. We developed cmsEPI sequence using both consecutively acquired multishot EPI segments and variable flip angles to minimize the delay between segments and to maximize the SNR, respectively. We also combined cmsEPI with the generalized autocalibrating partially parallel acquisitions (GRAPPA) method. Temporal SNRs were measured at different acceleration factors and number of segments for functional sensitivity evaluation. We also examined the geometric distortions, which inherently occurred in EPI sequence. The practical acceleration factors, R = 2 or R = 3, of the proposed technique improved the temporal SNR by maximally 18% in phantom test and by averagely 8.2% in in vivo experiment, compared to cmsEPI without parallel imaging. The data collection time was decreased in inverse proportion to the acceleration factor as well. The improved temporal SNR resulted in better statistical power when evaluated on the functional response of the brain. In this study, we demonstrated that the combination of cmsEPI with the parallel imaging technique could provide the improved functional sensitivity for functional imaging study, compensating for the lower SNR by cmsEPI. PMID- 26413519 TI - Anthropometric Measurements Usage in Medical Sciences. AB - Morphometry is introduced as quantitative approach to seek information concerning variations and changes in the forms of organisms that described the relationship between the human body and disease. Scientists of all civilization, who existed until today, examined the human body using anthropometric methods. For these reasons, anthropometric data are used in many contexts to screen for or monitor disease. Anthropometry, a branch of morphometry, is the study of the size and shape of the components of biological forms and their variations in populations. Morphometrics can also be defined as the quantitative analysis of biological forms. The field has developed rapidly over the last two decades to the extent that we now distinguish between traditional morphometrics and the more recent geometric morphometrics. Advances in imaging technology have resulted in the protection of a greater amount of morphological information and have permitted the analysis of this information. The oldest and most commonly used of these methods is radiography. With developments in this area, CT and MRI have also been started to be used in screening of the internal organs. Morphometric measurements that are used in medicine, are widely used in the diagnosis and the follow-up and the treatment of the disease, today. In addition, in cosmetology use of these new measurements is increasing every day. PMID- 26413520 TI - Preterm Birth: Pathophysiology, Prevention, Diagnosis, and Treatment. PMID- 26413521 TI - Disease Related Knowledge Summarization Based on Deep Graph Search. AB - The volume of published biomedical literature on disease related knowledge is expanding rapidly. Traditional information retrieval (IR) techniques, when applied to large databases such as PubMed, often return large, unmanageable lists of citations that do not fulfill the searcher's information needs. In this paper, we present an approach to automatically construct disease related knowledge summarization from biomedical literature. In this approach, firstly Kullback Leibler Divergence combined with mutual information metric is used to extract disease salient information. Then deep search based on depth first search (DFS) is applied to find hidden (indirect) relations between biomedical entities. Finally random walk algorithm is exploited to filter out the weak relations. The experimental results show that our approach achieves a precision of 60% and a recall of 61% on salient information extraction for Carcinoma of bladder and outperforms the method of Combo. PMID- 26413522 TI - Predictors for Early Identification of Hepatitis C Virus Infection. AB - Hepatitis C virus (HCV) infection can cause permanent liver damage and hepatocellular carcinoma, and deaths related to HCV deaths have recently increased. Chronic HCV infection is often undiagnosed such that the virus remains infective and transmissible. Identifying HCV infection early is essential for limiting its spread, but distinguishing individuals who require further HCV tests is very challenging. Besides identifying high-risk populations, an optimal subset of indices for routine examination is needed to identify HCV screening candidates. Therefore, this study analyzed data from 312 randomly chosen blood donors, including 144 anti-HCV-positive donors and 168 anti-HCV-negative donors. The HCV viral load in each sample was measured by real-time polymerase chain reaction method. Receiver operating characteristic curves were used to find the optimal cell blood counts and thrombopoietin measurements for screening purposes. Correlations with values for key indices and viral load were also determined. Strong predictors of HCV infection were found by using receiver operating characteristics curves to analyze the optimal subsets among red blood cells, monocytes, platelet counts, platelet large cell ratios, and mean corpuscular hemoglobin concentrations. Sensitivity, specificity, and area under the receiver operator characteristic curve (P < 0.0001) were 75.6%, 78.5%, and 0.859, respectively. PMID- 26413523 TI - Transarterial Embolization for Hepatocellular Carcinoma: A Comparison between Nonspherical PVA and Microspheres. AB - Transarterial chemoembolization (TACE) and transarterial embolization (TAE) have improved the survival rates of patients with unresectable hepatocellular carcinoma (HCC); however, the optimal TACE/TAE embolic agent has not yet been identified. The aim of this study was to compare the effect of two different embolic agents such as microspheres (ME) and polyvinyl alcohol (PVA) on survival, tumor response, and complications in patients with HCC submitted to transarterial embolization (TAE). Eighty HCC patients who underwent TAE between June 2008 and December 2012 at a single center were retrospectively studied. A total of 48 and 32 patients were treated with PVA and ME, respectively. There were no significant differences in survival (P = 0.679) or tumoral response (P = 0.369) between groups (PVA or ME). Overall survival rates at 12, 18, 24, 36, and 48 months were 97.9, 88.8, 78.9, 53.4, and 21.4% in the PVA-TAE group and 100, 92.9, 76.6, 58.8, and 58% in the ME-TAE group (P = 0.734). Patients submitted to TAE with ME presented postembolization syndrome more frequently when compared with the PVA group (P = 0.02). According to our cohort, the choice of ME or PVA as embolizing agent had no significant impact on overall survival. PMID- 26413525 TI - Comment on "Transmission Model of Hepatitis B Virus with the Migration Effect". AB - Some consequences of erroneous results concerning eigenvalues in the recent literature of mathematical biology are highlighted. Furthermore, an improved stability criterion and the true value of the basic reproduction number is presented. PMID- 26413524 TI - Psychobiobehavioral Model for Preterm Birth in Pregnant Women in Low- and Middle Income Countries. AB - Preterm birth (PTB) is a final common outcome resulting from many interrelated etiological pathways; of particular interest is antenatal psychosocial distress (i.e., stress, anxiety, and depression). In LMI countries, both exposure to severe life stressors and rate of PTB are on average greater when compared with high-income countries. In LMI countries women are exposed to some of the most extreme psychosocial stress worldwide (e.g., absolute poverty, limited social resources). High prevalence of antenatal stress and depression have been observed in some studies from LMI countries. We propose a psychosocial, biological, and behavioral model for investigating the complex multisystem interactions in stress responses leading to PTB and explain the basis of this approach. We discuss ethical considerations for a psychosocial, biological, and behavioral screening tool to predict PTB from a LMI country perspective. PMID- 26413526 TI - Lentivirus-Mediated siRNA Targeting ER-alpha Inhibits Tumorigenesis and Induces Apoptosis in Hepatocarcinoma Cells. AB - BACKGROUND AND OBJECTIVES: Estrogen receptor-alpha (ER-alpha) plays important roles in hepatocarcinogenesis. Recent studies have shown that ER-alpha could lead to cell cycle progression or inhibition of apoptosis. To better understand the role of ER-alpha, RNA interference (RNAi) was used to inhibit ER-alpha expression in the human hepatocellular carcinoma (HCC) cells. METHODS: Lentivirus-mediated ER-alpha small interfering RNA (siRNA) was transfected into HCC cells Hep3B. ER alpha expression was monitored by real-time polymerase chain reaction (PCR) and western blot. Cell proliferation, apoptosis, and invasion were examined by methyl thiazol tetrazolium (MTT), flow cytometry (FCM), and invasion assay, respectively. RESULTS: ER-alpha siRNA efficiently downregulated the expression of ER-alpha in Hep3B cells at both mRNA and protein levels in a time-dependent manner. ER-alpha siRNA also inhibited cell proliferation and reduced cell invasion (compared with other groups, P < 0.05, resp.). Furthermore, knockdown of ER-alpha slowed down the cell population at S phase and increased the rate of apoptosis (P < 0.05, resp.). CONCLUSION: ER-alpha knockdown suppressed the growth of HCC cells. Thus, ER-alpha may play a very important role in carcinogenesis of HCC and its knockdown may offer a new potential gene therapy approach for human liver cancer in the future. PMID- 26413527 TI - Predict Defibrillation Outcome Using Stepping Increment of Poincare Plot for Out of-Hospital Ventricular Fibrillation Cardiac Arrest. AB - Early cardiopulmonary resuscitation together with early defibrillation is a key point in the chain of survival for cardiac arrest. Optimizing the timing of defibrillation by predicting the possibility of successful electric shock can guide treatments between defibrillation and cardiopulmonary resuscitation and improve the rate of restoration of spontaneous circulation. Numerous methods have been proposed for predicting defibrillation success based on quantification of the ventricular fibrillation waveform during past decades. To date, however, no analytical technique has been widely accepted for clinical application. In the present study, we investigate whether median stepping increment that is calculated from the Euclidean distance of consecutive points in Poincare plot could be used to predict the likelihood of successful defibrillation. Electrocardiographic recordings of out-of-hospital cardiac arrest patients were obtained from the external defibrillators. The performance of the proposed method was evaluated by receiver operating characteristic curve and compared with the results of other established features. The results indicated that median stepping increment has comparable performance to the established methods in predicting the likelihood of successful defibrillation. PMID- 26413528 TI - MRI for Assessing Response to Neoadjuvant Therapy in Locally Advanced Rectal Cancer Using DCE-MR and DW-MR Data Sets: A Preliminary Report. AB - To evaluate MRI for neoadjuvant therapy response assessment in locally advanced rectal cancer (LARC) using dynamic contrast enhanced-MRI (DCE-MRI) and diffusion weighted imaging (DWI), we have compared magnetic resonance volumetry based on DCE-MRI (V(DCE)) and on DWI (V(DWI)) scans with conventional T2-weighted volumetry (V(C)) in LARC patients after neoadjuvant therapy. Twenty-nine patients with LARC underwent MR examination before and after neoadjuvant therapy. A manual segmentation was performed on DCE-MR postcontrast images, on DWI (b-value 800 s/mm(2)), and on conventional T2-weighted images by two radiologists. DCE-MRI, DWI, and T2-weigthed volumetric changes before and after treatment were evaluated. Nonparametric sample tests, interobserver agreement, and receiver operating characteristic curve (ROC) were performed. Diagnostic performance linked to DCE-MRI volumetric change was superior to T2-w and DW-MRI volumetric changes performance (specificity 86%, sensitivity 93%, and accuracy 93%). Area Under ROC (AUC) of V(DCE) was greater than AUCs of V(C) and V(DWI) resulting in an increase of 15.6% and 11.1%, respectively. Interobserver agreement between two radiologists was 0.977, 0.864, and 0.756 for V(C), V(DCE), and V(DWI), respectively. V(DCE) seems to be a promising tool for therapy response assessment in LARC. Further studies on large series of patients are needed to refine technique and evaluate its potential value. PMID- 26413529 TI - Evaluation of Nutritional Status of Patients with Depression. AB - AIMS AND OBJECTIVES: Our goal was to determine nutritional status, body composition, and biochemical parameters of patients diagnosed with depression based on DSM-IV-TR criteria. METHODS: A total of 59 individuals, aged 18-60 years admitted to Mental Health Centre of Kayseri Education and Research Hospital, were included in the study. The participants were randomly assigned to two groups; depression group (n = 29) and control group (n = 30). Anthropometric measurements, some biochemical parameters, demographic data, and 24-hour dietary recall were evaluated. RESULTS: 65.5% of depression and 60.0% of control group were female. Intake of vitamins A, thiamine, riboflavin, B6, folate, C, Na, K, Mg, Ca, P, Fe, Zn, and fibre (p < 0.05) were lower in depression group. Median levels of body weight, waist circumference, hip circumference, waist-to-hip ratio (p < 0.05) were significantly higher in depression group. Fasting blood glucose levels, serum vitamins B12, and folic acid (p < 0.05) in depression group were lower than controls. Serum insulin and HOMA levels of two groups were similar. CONCLUSION: Some vitamin B consumption and serum vitamin B12 and folic acid levels were low while signs of abdominal obesity were high among patients with depression. Future research exploring nutritional status of individuals with depression is warranted. PMID- 26413530 TI - A Prospective Randomized Study of Brain Tissue Oxygen Pressure-Guided Management in Moderate and Severe Traumatic Brain Injury Patients. AB - The purpose of this study was to compare the effect of PbtO2-guided therapy with traditional intracranial pressure- (ICP-) guided treatment on the management of cerebral variables, therapeutic interventions, survival rates, and neurological outcomes of moderate and severe traumatic brain injury (TBI) patients. From 2009 to 2010, TBI patients with a Glasgow coma scale <12 were recruited from 6 collaborative hospitals in northern Taiwan, excluding patients with severe systemic injuries, fixed and dilated pupils, and other major diseases. In total, 23 patients were treated with PbtO2-guided management (PbtO2 > 20 mmHg), and 27 patients were treated with ICP-guided therapy (ICP < 20 mmHg and CPP > 60 mmHg) in the neurosurgical intensive care unit (NICU); demographic characteristics were similar across groups. The survival rate in the PbtO2-guided group was also significantly increased at 3 and 6 months after injury. Moreover, there was a significant correlation between the PbtO2 signal and Glasgow outcome scale extended in patients from 1 to 6 months after injury. This finding demonstrates that therapy directed by PbtO2 monitoring is valuable for the treatment of patients with moderate and severe TBI and that increasing PaO2 to 150 mmHg may be efficacious for preventing cerebral hypoxic events after brain trauma. PMID- 26413531 TI - A Window into the Brain: Advances in Psychiatric fMRI. AB - Functional magnetic resonance imaging (fMRI) plays a key role in modern psychiatric research. It provides a means to assay differences in brain systems that underlie psychiatric illness, treatment response, and properties of brain structure and function that convey risk factor for mental diseases. Here we review recent advances in fMRI methods in general use and progress made in understanding the neural basis of mental illness. Drawing on concepts and findings from psychiatric fMRI, we propose that mental illness may not be associated with abnormalities in specific local regions but rather corresponds to variation in the overall organization of functional communication throughout the brain network. Future research may need to integrate neuroimaging information drawn from different analysis methods and delineate spatial and temporal patterns of brain responses that are specific to certain types of psychiatric disorders. PMID- 26413532 TI - Three-Dimensional Assessment of Bilateral Symmetry of the Scaphoid: An Anatomic Study. AB - Preoperative 3D CT imaging techniques provide displacement analysis of the distal scaphoid fragment in 3D space, using the matched opposite scaphoid as reference. Its accuracy depends on the presence of anatomical bilateral symmetry, which has not been investigated yet using similar techniques. Our purpose was to investigate symmetry by comparing the relative positions of distal and proximal poles between sides. We used bilateral CT scans of 19 adult healthy volunteers to obtain 3D scaphoid models. Left proximal and distal poles were matched to corresponding mirrored right sides. The left-to-right positional differences between poles were quantified in terms of three translational and three rotational parameters. The mean (SD) of ulnar, dorsal, and distal translational differences of distal poles relative to proximal poles was 0.1 (0.6); 0.4 (1.2); 0.2 (0.6) mm and that of palmar rotation, ulnar deviation, and pronation differences was -1.1 (4.9); -1.5 (3.3); 1.0 (3.7) degrees , respectively. These differences did not significantly differ from zero and thus were not biased to left or right side. We proved that, on average, the articular surfaces of scaphoid poles were symmetrically aligned in 3D space. This suggests that the contralateral scaphoid can serve as reference in corrective surgery. No level of evidence is available. PMID- 26413533 TI - Change in the Pathologic Supraspinatus: A Three-Dimensional Model of Fiber Bundle Architecture within Anterior and Posterior Regions. AB - Supraspinatus tendon tears are common and lead to changes in the muscle architecture. To date, these changes have not been investigated for the distinct regions and parts of the pathologic supraspinatus. The purpose of this study was to create a novel three-dimensional (3D) model of the muscle architecture throughout the supraspinatus and to compare the architecture between muscle regions and parts in relation to tear severity. Twelve cadaveric specimens with varying degrees of tendon tears were used. Three-dimensional coordinates of fiber bundles were collected in situ using serial dissection and digitization. Data were reconstructed and modeled in 3D using Maya. Fiber bundle length (FBL) and pennation angle (PA) were computed and analyzed. FBL was significantly shorter in specimens with large retracted tears compared to smaller tears, with the deeper fibers being significantly shorter than other parts in the anterior region. PA was significantly greater in specimens with large retracted tears, with the superficial fibers often demonstrating the largest PA. The posterior region was absent in two specimens with extensive tears. Architectural changes associated with tendon tears affect the regions and varying depths of supraspinatus differently. The results provide important insights on residual function of the pathologic muscle, and the 3D model includes detailed data that can be used in future modeling studies. PMID- 26413534 TI - Preliminary Observations on Sensitivity and Specificity of Magnetization Transfer Asymmetry for Imaging Myelin of Rat Brain at High Field. AB - Magnetization transfer ratio (MTR) has been often used for imaging myelination. Despite its high sensitivity, the specificity of MTR to myelination is not high because tissues with no myelin such as muscle can also show high MTR. In this study, we propose a new magnetization transfer (MT) indicator, MT asymmetry (MTA), as a new method of myelin imaging. The experiments were performed on rat brain at 9.4 T. MTA revealed high signals in white matter and significantly low signals in gray matter and muscle, indicating that MTA has higher specificity than MTR. Demyelination and remyelination studies demonstrated that the sensitivity of MTA to myelination was as high as that of MTR. These experimental results indicate that MTA can be a good biomarker for imaging myelination. In addition, MTA images can be efficiently acquired with an interslice MTA method, which may accelerate clinical application of myelin imaging. PMID- 26413535 TI - Effect of Bone Cement Implantation on Haemodynamics in Elderly Patients and Preventive Measure in Cemented Hemiarthroplasty. AB - This study was to investigate the influence of bone cement implantation on haemodynamics and the preventive effect of epinephrine hydrochloride on pulmonary embolism in elderly patients with cemented semihip replacement. 128 patients were retrospectively analyzed. The patients were treated with (group A, 64 cases) or without (group B, 64 cases) epinephrine hydrochloride saline. The monitoring indicators included systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), and pulse oxygen saturation (SPO2). The indicators of the two groups were compared before and 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 minutes after bone cement implantation. Analysis of variance and SNK-q test were used for the statistical analysis. Blood pressure and SPO2 of group B decreased with statistical difference (P < 0.05) and HR increased without statistical significance, comparing with those of group A. In group A, SBP, DBP, MAP, HR, and SPO2 after bone cement implantation did not change significantly at each time point comparing with before implantation (P > 0.05). Bone cement implantation has significant influence on hemodynamics in elderly patients with hemiarthroplasty. Flushing the bone marrow cavity with saline epinephrine hydrochloride is an effective measure to reduce the incidence of bone cement pulmonary embolism. PMID- 26413536 TI - Soluble and Endogenous Secretory Receptors for Advanced Glycation End Products in Threatened Preterm Labor and Preterm Premature Rupture of Fetal Membranes. AB - The aim of the study was to compare sRAGE and esRAGE plasma levels in pregnant women with (A) threatened premature labor (n = 41), (B) preterm premature rupture of membranes (n = 49), and (C) preterm rupture of membranes at term (n = 48). The relationship between these and classic intrauterine infection markers and the latent time from symptoms up to delivery depending on RAGE's concentration were investigated. In groups A and B, a positive correlation was found between plasma sRAGE and latent time (r = 0,422; p = 0,001; r = 0,413, p = 0,004, resp.). High prognostic values were found in both groups for plasma sRAGE concentration and the latent time from symptoms up to delivery. Groups B and C presented higher levels of esRAGE than group A (526,315 +/- 129,453 pg/mL and 576,212 +/- 136,237 pg/mL versus 485,918 +/- 133,127 pg/mL, p< 0,05). The conclusion is that sRAGE concentration can be a favorable prognostic factor in the presence of symptoms of threatened premature labor. Higher esRAGE plasma level in case of the rupture of membranes in mature and premature pregnancy suggests its participation in fetal membranes destruction. PMID- 26413537 TI - MRI Guided Brain Stimulation without the Use of a Neuronavigation System. AB - A key issue in the field of noninvasive brain stimulation (NIBS) is the accurate localization of scalp positions that correspond to targeted cortical areas. The current gold standard is to combine structural and functional brain imaging with a commercially available "neuronavigation" system. However, neuronavigation systems are not commonplace outside of specialized research environments. Here we describe a technique that allows for the use of participant-specific functional and structural MRI data to guide NIBS without a neuronavigation system. Surface mesh representations of the head were generated using Brain Voyager and vectors linking key anatomical landmarks were drawn on the mesh. Our technique was then used to calculate the precise distances on the scalp corresponding to these vectors. These calculations were verified using actual measurements of the head and the technique was used to identify a scalp position corresponding to a brain area localized using functional MRI. PMID- 26413538 TI - Volumetric MR-Guided High-Intensity Focused Ultrasound with Direct Skin Cooling for the Treatment of Symptomatic Uterine Fibroids: Proof-of-Concept Study. AB - OBJECTIVE: To prospectively assess the safety and technical feasibility of volumetric magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) ablation with direct skin cooling (DISC) during treatment of uterine fibroids. METHODS: In this proof-of-concept study, eight patients were consecutively selected for clinical MR-HIFU ablation of uterine fibroids with the use of an additional DISC device to maintain a constant temperature (T ~ 20 degrees C) at the interface between the HIFU table top and the skin. Technical feasibility was verified by successful completion of MR-HIFU ablation. Contrast-enhanced T1 weighted MRI was used to measure the treatment effect (nonperfused volume (NPV) ratio). Safety was evaluated by recording of adverse events (AEs) within 30 days' follow-up. RESULTS: All MR-HIFU treatments were successfully completed in an outpatient setting. The median NPV ratio was 0.56 (IQR [0.27-0.72]). Immediately after treatment, two patients experienced coldness related discomfort which resolved at the same day. No serious (device-related) AEs were reported. Specifically, no skin burns, cold injuries, or subcutaneous edema were observed. CONCLUSION: This study showed that it is safe and technically feasible to complete a volumetric MR-HIFU ablation with DISC. This technique may reduce the risk of thermal injury to the abdominal wall during MR-HIFU ablation of uterine fibroids. This trial is registered with NTR4189. PMID- 26413539 TI - Two-Dimensional Crystallization Procedure, from Protein Expression to Sample Preparation. AB - Membrane proteins play important roles for living cells. Structural studies of membrane proteins provide deeper understanding of their mechanisms and further aid in drug design. As compared to other methods, electron microscopy is uniquely suitable for analysis of a broad range of specimens, from small proteins to large complexes. Of various electron microscopic methods, electron crystallography is particularly well-suited to study membrane proteins which are reconstituted into two-dimensional crystals in lipid environments. In this review, we discuss the steps and parameters for obtaining large and well-ordered two-dimensional crystals. A general description of the principle in each step is provided since this information can also be applied to other biochemical and biophysical methods. The examples are taken from our own studies and published results with related proteins. Our purpose is to give readers a more general idea of electron crystallography and to share our experiences in obtaining suitable crystals for data collection. PMID- 26413540 TI - Morphometric Evaluation of Korean Femurs by Geometric Computation: Comparisons of the Sex and the Population. AB - We measured 28 parameters of 202 femurs from Koreans by an automated geometric computation program using 3D models generated from computed tomography images. The measurement parameters were selected with reference to physical and forensic anthropology studies as well as orthopedic implant design studies. All measurements were calculated using 3D reconstructions on a computer using scientific computation language. We also analyzed sex and population differences by comparison with data from previous studies. Most parameters were larger in males than in females. The height, head diameter, head center offset, and chord length of the diaphysis, most parameters in the distal femur, and the isthmic width of the medullary canal were smaller in Koreans than in other populations. However, the neck-shaft angle, subtense, and width of the intercondylar notch in the distal femur were larger than those in other populations. The results of this study will be useful as a reference for physical and forensic anthropology as well as the design of medical devices suitable for Koreans. PMID- 26413541 TI - The Association between Endometriomas and Ovarian Cancer: Preventive Effect of Inhibiting Ovulation and Menstruation during Reproductive Life. AB - Although endometriosis frequently involves multiple sites in the pelvis, malignancies associated with this disease are mostly confined to the ovaries, evolving from an endometrioma. Endometriomas present a 2-3-fold increased risk of transformation in clear-cell, endometrioid, and possibly low-grade serous ovarian cancers, but not in mucinous ovarian cancers. These last cancers are, in some aspects, different from the other epithelial ovarian cancers, as they do not appear to be decreased by the inhibition of ovulation and menstruation. The step by step process of transformation from typical endometrioma, through atypical endometrioma, finally to ovarian cancer seems mainly related to oxidative stress, inflammation, hyperestrogenism, and specific molecular alterations. Particularly, activation of oncogenic KRAS and PI3K pathways and inactivation of tumor suppressor genes PTEN and ARID1A are suggested as major pathogenic mechanisms for endometriosis associated clear-cell and endometrioid ovarian cancer. Both the risk for endometriomas and their associated ovarian cancers seems to be highly and similarly decreased by the inhibition of ovulation and retrograde menstruation, suggesting a common pathogenetic mechanism and common possible preventive strategies during reproductive life. PMID- 26413542 TI - Added Value of Assessing Adnexal Masses with Advanced MRI Techniques. AB - This review will present the added value of perfusion and diffusion MR sequences to characterize adnexal masses. These two functional MR techniques are readily available in routine clinical practice. We will describe the acquisition parameters and a method of analysis to optimize their added value compared with conventional images. We will then propose a model of interpretation that combines the anatomical and morphological information from conventional MRI sequences with the functional information provided by perfusion and diffusion weighted sequences. PMID- 26413544 TI - Using Magnetic Resonance for Predicting Femoral Strength: Added Value with respect to Bone Densitometry. AB - BACKGROUND AND PURPOSE: To evaluate the added value of MRI with respect to peripheral quantitative computed tomography (pQCT) and dual energy X-ray absorptiometry (DXA) for predicting femoral strength. MATERIAL AND METHODS: Bone mineral density (BMD) of eighteen femur specimens was assessed with pQCT, DXA, and MRI (using ultrashort echo times (UTE) and the MicroView software). Subsequently biomechanical testing was performed to assess failure load. Simple and multiple linear regression were used with failure load as the dependent variable. RESULTS: Simple linear regression allowed a prediction of failure load with either pQCT, DXA, or MRI in an r(2) range of 0.41-0.48. Multiple linear regression with pQCT, DXA, and MRI yielded the best prediction (r(2) = 0.68). CONCLUSIONS: The accuracy of MRI, using UTE and MicroView software, to predict femoral strength compares well with that of pQCT or DXA. Furthermore, the inclusion of MRI in a multiple-regression model yields the best prediction. PMID- 26413545 TI - Influence of the Weight of a School Backpack on Spinal Curvature in the Sagittal Plane of Seven-Year-Old Children. AB - The aim of the paper was to determine a correlation between the weight of a child's backpack, their body weight, and certain features of their body posture. MATERIAL AND METHODS: The study group consisted of 109 children, all aged seven years. The parameters of body posture were determined using the Zebris Ultrasonic System. RESULTS: The number of children carrying a school backpack in accordance with recommendations was 44 subjects (40.37%). Statistically significant changes were found in the total length of the spine (Z = 2.223, p = 0.026) and between backpack weight and changes in the following parameters: the total length of the spine (rs = -0.3999, p = 0.017), the length and the angle of the lumbar lordosis (rs = -0.3352, p = 0.049), the angle of the lumbar lordosis (rs = -0.5065, p = 0.002), and the sacral angle (rs = -0.4279, p = 0.010). CONCLUSIONS: Wearing a backpack heavier than 10% of one's body weight can cause shallowing of the lumbar lordosis and a tendency towards a vertical position of the sacrum. Monitoring the weight of children's school backpacks and enabling them to leave books and notebooks at school would probably be beneficial in reducing the daily burden put on children's spines. PMID- 26413543 TI - MRI for Crohn's Disease: Present and Future. AB - Crohn's disease (CD) is a chronic inflammatory condition with relapsing-remitting behavior, often causing strictures or penetrating bowel damage. Its lifelong clinical course necessitates frequent assessment of disease activity and complications. Computed tomography (CT) enterography has been used as primary imaging modality; however, the concern for radiation hazard limits its use especially in younger population. Magnetic resonance (MR) imaging has advantages of avoiding radiation exposure, lower incidence of adverse events, ability to obtain dynamic information, and good soft-tissue resolution. MR enterography (MRE) with oral contrast agent has been used as primary MR imaging modality of CD with high sensitivity, specificity, and interobserver agreement. The extent of inflammation as well as transmural ulcers and fibrostenotic diseases can be detected with MRE. Novel MR techniques such as diffusion-weighted MRI (DWI), motility study, PET-MRI, and molecular imaging are currently investigated for further improvement of diagnosis and management of CD. MR spectroscopy is a remarkable molecular imaging tool to analyze metabolic profile of CD with human samples such as plasma, urine, or feces, as well as colonic mucosa itself. PMID- 26413546 TI - Exploring Dynamic Brain Functional Networks Using Continuous "State-Related" Functional MRI. AB - We applied a "temporal decomposition" method, which decomposed a single brain functional network into several "modes"; each of them dominated a short temporal period, on a continuous, "state-" related, "finger-force feedback" functional magnetic resonance imaging experiment. With the hypothesis that attention and internal/external information processing interaction could be manipulated by different (real and sham) feedback conditions, we investigated functional network dynamics of the "default mode," "executive control," and sensorimotor networks. They were decomposed into several modes. During real feedback, the occurrence of "default mode-executive control competition-related" mode was higher than that during sham feedback (P = 0.0003); the "default mode-visual facilitation-related" mode more frequently appeared during sham than real feedback (P = 0.0004). However, the dynamics of the sensorimotor network did not change significantly between two conditions (P > 0.05). Our results indicated that the visual-guided motor feedback involves higher cognitive functional networks rather than primary motor network. The dynamics monitoring of inner and outside environment and multisensory integration could be the mechanisms. This study is an extension of our previous region-specific and static-styled study of our brain functional architecture. PMID- 26413547 TI - How to Quantify Penile Corpus Cavernosum Structures with Histomorphometry: Comparison of Two Methods. AB - The use of morphometrical tools in biomedical research permits the accurate comparison of specimens subjected to different conditions, and the surface density of structures is commonly used for this purpose. The traditional point counting method is reliable but time-consuming, with computer-aided methods being proposed as an alternative. The aim of this study was to compare the surface density data of penile corpus cavernosum trabecular smooth muscle in different groups of rats, measured by two observers using the point-counting or color-based segmentation method. Ten normotensive and 10 hypertensive male rats were used in this study. Rat penises were processed to obtain smooth muscle immunostained histological slices and photomicrographs captured for analysis. The smooth muscle surface density was measured in both groups by two different observers by the point-counting method and by the color-based segmentation method. Hypertensive rats showed an increase in smooth muscle surface density by the two methods, and no difference was found between the results of the two observers. However, surface density values were higher by the point-counting method. The use of either method did not influence the final interpretation of the results, and both proved to have adequate reproducibility. However, as differences were found between the two methods, results obtained by either method should not be compared. PMID- 26413548 TI - Tumour Relapse Prediction Using Multiparametric MR Data Recorded during Follow-Up of GBM Patients. AB - PURPOSE: We have focused on finding a classifier that best discriminates between tumour progression and regression based on multiparametric MR data retrieved from follow-up GBM patients. MATERIALS AND METHODS: Multiparametric MR data consisting of conventional and advanced MRI (perfusion, diffusion, and spectroscopy) were acquired from 29 GBM patients treated with adjuvant therapy after surgery over a period of several months. A 27-feature vector was built for each time point, although not all features could be obtained at all time points due to missing data or quality issues. We tested classifiers using LOPO method on complete and imputed data. We measure the performance by computing BER for each time point and wBER for all time points. RESULTS: If we train random forests, LogitBoost, or RobustBoost on data with complete features, we can differentiate between tumour progression and regression with 100% accuracy, one time point (i.e., about 1 month) earlier than the date when doctors had put a label (progressive or responsive) according to established radiological criteria. We obtain the same result when training the same classifiers solely on complete perfusion data. CONCLUSIONS: Our findings suggest that ensemble classifiers (i.e., random forests and boost classifiers) show promising results in predicting tumour progression earlier than established radiological criteria and should be further investigated. PMID- 26413549 TI - Increase in Preterm Birth during Demographic Transition in Chile from 1991 to 2012. AB - INTRODUCTION: Universally mothers at 35 years or more have had higher maternal and perinatal risks. This study analyzed the trend of this group in maternal population and determined their risk of having premature children, during the demographic transition period in Chile. MATERIALS AND METHODS: Epidemiological study conducted in the population of simple live births registered in the Chilean National Database Births of 1991-2012. Analyses were performed in three categories of maternal age: 35 or more, under 35, and 20 to 29 years. The risk of prematurity was measured by crude and Adjusted Odds Ratio from logistic regression model. RESULTS: Mothers aged 35 and older increased in population from 10.6% in 1991 to 16.7% in 2012 and presented an overall prevalence of preterm delivery of 6.7%, higher prevalence than 20-29 age group (4.7%). In aging mothers, the Odds Ratio for preterm birth adjusted for education, marital status, and parity was 1.68 (95% CI (1.66-1.70)) compared to mothers aged 20-29. All differences were significant (p < 0.001). CONCLUSIONS: During Chilean demographic transition, mothers aged 35 or older increased steadily and significantly maintaining higher risks of preterm births. Policies to prevent and monitor the late motherhood could contribute to stopping the current trend. PMID- 26413550 TI - Association of Aortic Diameters with Coronary Artery Disease Severity and Albumin Excretion. AB - INTRODUCTION: Aortic diameters, aortic distensibility, microalbuminuria, coronary artery disease which are all together related to vascular aging are investigated in this paper. METHODS: Eighty consecutive nondiabetic patients undergoing elective coronary angiography were enrolled into the study. Systolic and diastolic aortic diameters, aortic distensibility, CAD severity by angiogram with the use of Gensini scoring, and albumin excretion rates were determined. RESULTS: Cases with CAD had significantly larger systolic (30,72 +/- 3,21 mm versus 34,19 +/- 4,03 mm for cases without and with CAD, resp.) and diastolic aortic diameters measured 3 cm above aortic valve compared to patients without CAD (33,56 +/- 4,07 mm versus 29,75 +/- 3,12 mm). The systolic and diastolic diameters were significantly higher in albuminuria positive patients compared to albuminuria negative patients (p = 0.017 and 0.008, resp., for systolic and diastolic diameters). CONCLUSION: In conclusion aortic diameters are increased in patients with coronary artery disease and in patients with microalbuminuria. In CAD patients, systolic blood pressure, pulse pressure, aortic systolic and diastolic pressure, and albumin excretion rate were higher and aortic distensibility was lower. PMID- 26413552 TI - Ischemic Postconditioning and Subanesthetic S(+)-Ketamine Infusion: Effects on Renal Function and Histology in Rats. AB - BACKGROUND: Ischemic postconditioning (IP) in renal Ischemia reperfusion injury (IRI) models improves renal function after IRI. Ketamine affords significant benefits against IRI-induced acute kidney injury (AKI). The present study investigated the effects of IP and IP associated with subanesthetic S(+)-ketamine in ischemia-reperfusion-induced AKI. METHODS: Forty-one Wistar rats were randomized into four groups: CG (10), control; KG (10), S(+)-ketamine infusion; IPG (10), IP; and KIPG (11), S(+)-ketamine infusion + IP. All rats underwent right nephrectomy. IRI and IP were induced only in IPG and KIPG by left kidney arterial occlusion for 30 min followed by reperfusion for 24 h. Complete reperfusion was preceded by three cycles of 2 min of reocclusion followed by 2 min of reperfusion. Renal function was assessed by measuring serum neutrophil gelatinase-associated lipocalin (NGAL), creatinine, and blood urea nitrogen (BUN). Tubular damage was evaluated by renal histology. RESULTS: Creatinine and BUN were significantly increased. Severe tubular injury was only observed in the groups with IRI (IPG and KIPG), whereas no injury was observed in CG or KG. No significant differences were detected between IPG and KIPG. CONCLUSIONS: No synergic effect of the use of subanesthetic S(+)-ketamine and IP on AKI was observed in this rat model. PMID- 26413553 TI - Reexamination of Statistical Methods for Comparative Anatomy: Examples of Its Application and Comparisons with Other Parametric and Nonparametric Statistics. AB - Various statistical methods have been published for comparative anatomy. However, few studies compared parametric and nonparametric statistical methods. Moreover, some previous studies using statistical method for comparative anatomy (SMCA) proposed the formula for comparison of groups of anatomical structures (multiple structures) among different species. The present paper described the usage of SMCA and compared the results by SMCA with those by parametric test (t-test) and nonparametric analyses (cladistics) of anatomical data. In conclusion, the SMCA can offer a more exact and precise way to compare single and multiple anatomical structures across different species, which requires analyses of nominal features in comparative anatomy. PMID- 26413551 TI - Volumetric Growth of the Liver in the Human Fetus: An Anatomical, Hydrostatic, and Statistical Study. AB - Using anatomical, hydrostatic, and statistical methods, liver volumes were assessed in 69 human fetuses of both sexes aged 18-30 weeks. No sex differences were found. The median of liver volume achieved by hydrostatic measurements increased from 6.57 cm(3) at 18-21 weeks through 14.36 cm(3) at 22-25 weeks to 20.77 cm(3) at 26-30 weeks, according to the following regression: y = -26.95 + 1.74 * age +/- Z * (-3.15 + 0.27 * age). The median of liver volume calculated indirectly according to the formula liver volume = 0.55 * liver length * liver transverse diameter * liver sagittal diameter increased from 12.41 cm(3) at 18-21 weeks through 28.21 cm(3) at 22-25 weeks to 49.69 cm(3) at 26-30 weeks. There was a strong relationship (r = 0.91, p < 0.001) between the liver volumes achieved by hydrostatic (x) and indirect (y) methods, expressed by y = -0.05 + 2.16x +/- 7.26. The liver volume should be calculated as follows liver volume = 0.26 * liver length * liver transverse diameter * liver sagittal diameter. The age specific liver volumes are of great relevance in the evaluation of the normal hepatic growth and the early diagnosis of fetal micro- and macrosomias. PMID- 26413554 TI - Preterm Birth: A Prominent Risk Factor for Low Apgar Scores. AB - OBJECTIVE: To determine predictive risk factors for Apgar scores < 7 at 5 minutes at two hospitals providing tertiary care and secondary care, respectively. METHODS: A retrospective registry cohort study of 21126 births (2006-2010) using data from digital medical records. Risk factors were analyzed by logistic regression analyses. RESULTS: AS(5 min) < 7 was multivariately associated with the following: preterm birth; gestational week 32 + 0-36 + 6, OR = 3.9 (95% CI 2.9-5.3); week 28 + 0-31 + 6, OR = 8 (5-12); week < 28 + 0, OR = 15 (8-29); postterm birth, OR = 2.0 (1.7-2.3); multiple pregnancy, OR = 3.53 (1.79-6.96); previous cesarean section, OR = 3.67 (2.31-5.81); BMI 25-29, OR = 1.30 (1.09 1.55); BMI >= 30 OR = 1.70 (1.20-2.41); nonnormal CTG at admission, OR = 1.98 (1.48-2.66). >= 1-para was associated with a decreased risk for AS(5 min) < 7, OR = 0.34 (0.25-0.47). In the univariate logistic regression analysis AS(5 min) < 7 was associated with tertiary level care, OR = 1.48 (1.17-1.87); however, in the multivariate analysis there was no significant difference. CONCLUSION: A number of partially preventable risk factors were identified, preterm birth being the most evident. Further, no significant difference between the two hospital levels regarding the risk for low Apgar scores was detected. PMID- 26413556 TI - Axons take a dive: Specialized contacts of serotonergic axons with cells in the walls of the lateral ventricles in mice and humans. AB - In the walls of the lateral ventricles of the adult mammalian brain, neural stem cells (NSCs) and ependymal (E1) cells share the apical surface of the ventricular subventricular zone (V-SVZ). In a recent article, we show that supraependymal serotonergic (5HT) axons originating from the raphe nuclei in mice form an extensive plexus on the walls of the lateral ventricles where they contact E1 cells and NSCs. Here we further characterize the contacts between 5HT supraependymal axons and E1 cells in mice, and show that suprependymal axons tightly associated to E1 cells are also present in the walls of the human lateral ventricles. These observations raise interesting questions about the function of supraependymal axons in the regulation of E1 cells. PMID- 26413555 TI - Isolation and Purification of Satellite Cells for Skeletal Muscle Tissue Engineering. AB - Engineered skeletal muscle holds promise as a source of graft tissue for the repair of traumatic injuries such as volumetric muscle loss. The resident skeletal muscle stem cell, the satellite cell, has been identified as an ideal progenitor for tissue engineering due to its role as an essential player in the potent skeletal muscle regeneration mechanism. A significant challenge facing tissue engineers, however, is the isolation of sufficiently large satellite cell populations with high purity. The two common isolation techniques, single fiber explant culture and enzymatic dissociation, can yield either a highly pure satellite cell population or a suitably large number or cells but fail to do both simultaneously. As a result, it is often necessary to use a purification technique such as pre-plating or cell sorting to enrich the satellite cell population post-isolation. Furthermore, the absence of complex chemical and biophysical cues influencing the in vivo satellite cell "niche" complicates the culture of isolated satellite cells. Techniques under investigation to maximize myogenic proliferation and differentiation in vitro are described in this article, along with current methods for isolating and purifying satellite cells. PMID- 26413557 TI - Biomimetic Scaffolds for Osteogenesis. AB - Skeletal regenerative medicine emerged as a field of investigation to address large osseous deficiencies secondary to congenital, traumatic, and post-oncologic conditions. Although autologous bone grafts have been the gold standard for reconstruction of skeletal defects, donor site morbidity remains a significant limitation. To address these limitations, contemporary bone tissue engineering research aims to target delivery of osteogenic cells and growth factors in a defined three dimensional space using scaffolding material. Using bone as a template, biomimetic strategies in scaffold engineering unite organic and inorganic components in an optimal configuration to both support osteoinduction as well as osteoconduction. This article reviews the various structural and functional considerations behind the development of effective biomimetic scaffolds for osteogenesis and highlights strategies for enhancing osteogenesis. PMID- 26413558 TI - Breastfeeding after Anesthesia: A Review for Anesthesia Providers Regarding the Transfer of Medications into Breast Milk. AB - Doctors, nurses, and midwives often inform mothers to "pump and dump" their breast milk for 24 hours after receiving anesthesia to avoid passing medications to the infant. This advice, though cautious, is probably outdated. This review highlights the more recent literature regarding common anesthesia medications, their passage into breast milk, and medication effects observed in breastfed infants. We suggest continuing breastfeeding after anesthesia when the mother is awake, alert, and able to hold her infant. We recommend multiple types of medications for pain relief while minimizing sedating medications. Few medications can have sedating effects to the infant, but those medications are specifically outlined. For additional safety, anesthesia providers and patients may screen medications using the National Institute of Health' LactMed database. PMID- 26413559 TI - Utilizing Multidimensional Measures of Race in Education Research: The Case of Teacher Perceptions. AB - Education scholarship on race using quantitative data analysis consists largely of studies on the black-white dichotomy, and more recently, on the experiences of student within conventional racial/ethnic categories (white, Hispanic/Latina/o, Asian, black). Despite substantial shifts in the racial and ethnic composition of American children, studies continue to overlook the diverse racialized experiences for students of Asian and Latina/o descent, the racialization of immigration status, and the educational experiences of Native American students. This study provides one possible strategy for developing multidimensional measures of race using large-scale datasets and demonstrates the utility of multidimensional measures for examining educational inequality, using teacher perceptions of student behavior as a case in point. With data from the first grade wave of the Early Childhood Longitudinal Study, Kindergarten Cohort of 1998 1999, I examine differences in teacher ratings of Externalizing Problem Behaviors and Approaches to Learning across fourteen racialized subgroups at the intersections of race, ethnicity, and immigrant status. Results show substantial subgroup variation in teacher perceptions of problem and learning behaviors, while also highlighting key points of divergence and convergence within conventional racial/ethnic categories. PMID- 26413560 TI - Optical sectioning using a digital Fresnel incoherent-holography-based confocal imaging system. AB - We propose a new type of confocal microscope using Fresnel incoherent correlation holography (FINCH). Presented here is a confocal configuration of FINCH using a phase pinhole and point illumination that is able to suppress out-of-focus information from the recorded hologram and hence combine the super-resolution capabilities of FINCH with the sectioning capabilities of confocal microscopy. PMID- 26413562 TI - Oral glucose tolerance testing to modulate plasma amyloid levels: A novel biomarker. AB - INTRODUCTION: Plasma levels of amyloid-beta (Abeta) do not correlate well with different stages of Alzheimer's disease (AD) in cross-sectional studies. Measuring the changes in Abeta plasma levels with an acute intervention may be more sensitive to distinguishing individuals in earlier stages of AD (mild cognitive impairment; MCI) from normal controls. METHODS: 57 participants (18 with AD/MCI and 39 cognitively normal controls) underwent oral glucose tolerance testing (OGTT). Blood samples were obtained over a 2 hour time period. Changes in plasma Abeta40 and42 levels were measured from either baseline or 5 minutes to the 10 minute time point. RESULTS: Compared to normal controls, subjects with AD/MCI had significantly less change (Delta) in plasma levels for both Abeta40( 3.13(40.93)pg/ml vs. 41.34(57.16)pg/ml;p=0.002) and Abeta42(-0.15(3.77)pg/ml vs. 5.64(10.65)pg/ml; p=0.004). DISCUSSION: OGTT combined with measures of plasma Abeta40 and 42 is potentially useful in distinguishing aging individuals who are in different stages of AD. PMID- 26413563 TI - An Experimental Realization of a Chaos-Based Secure Communication Using Arduino Microcontrollers. AB - Security and secrecy are some of the important concerns in the communications world. In the last years, several encryption techniques have been proposed in order to improve the secrecy of the information transmitted. Chaos-based encryption techniques are being widely studied as part of the problem because of the highly unpredictable and random-look nature of the chaotic signals. In this paper we propose a digital-based communication system that uses the logistic map which is a mathematically simple model that is chaotic under certain conditions. The input message signal is modulated using a simple Delta modulator and encrypted using a logistic map. The key signal is also encrypted using the same logistic map with different initial conditions. In the receiver side, the binary coded message is decrypted using the encrypted key signal that is sent through one of the communication channels. The proposed scheme is experimentally tested using Arduino shields which are simple yet powerful development kits that allows for the implementation of the communication system for testing purposes. PMID- 26413561 TI - Outcomes after viral load rebound on first-line antiretroviraltreatment in children with HIV in the UK and Ireland: an observational cohort study. AB - BACKGROUND: About a third of children with HIV have virological failure within 2 years of beginning antiretroviral treatment (ART). We assessed the probability of switch to second-line ART or virological re-suppression without switch in children who had virological rebound on first-line ART in the UK and Ireland. METHODS: In this study, we used data reported to the Collaborative HIV Paediatric Study (CHIPS), a national multicentre observational cohort. We included children with virological rebound (confirmed viral load>400 copies per mL after suppression<400 copies per mL) on first-line ART. We did a competing-risk analysis to estimate the probability of switch to second-line treatment, confirmed resuppression (two consecutive viral load measurments<400 copies per mL) without switch, and continued viral load above 400 copies per mL without switch. We also assessed factors that predicted a faster time to switch. FINDINGS: Of the 900 children starting first-line ART who had a viral load below 400 copies per mL within a year of starting treatment, 170 (19%) had virological rebound by a median of 20.6 months (IQR 9.7-40.5). At rebound, median age was 10.6 years (5.6-13.4), median viral load was 3.6 log10 copies per mL (3.1-4.2), and median CD4% was 24% (17-32). 89 patients (52%) switched to second-line ART at a median of 4.9 months (1.7-13.4) after virological rebound, 53 (31%) resuppressed without switch (19 [61%] of 31 patients on a first-line regimen that included a protease inhibitor and 31 [24%] of 127 patients on a first-line regimen that included a non-nucleoside reverse transcriptase inhibitor; NNRTI), and 28 (16%) neither resuppressed nor switched. At 12 months after rebound, the estimated probability of switch was 38% (95% CI 30-45) and of resuppression was 27% (21-34). Faster time to switch was associated with a higher viral load (p<0.0001), later calendar year at virological rebound (p=0.02), and being on an NNRTI-based or triple nucleoside reverse transcriptase inhibitor-based versus protease-inhibitor-based first-line regimen (p=0.001). INTERPRETATION: A third of children with virological rebound resuppressed without switch. Clinicians should consider the possibility of resuppression with adherence support before switching treatment in children with HIV. FUNDING: NHS England (London Specialised Commissioning Group). PMID- 26413565 TI - Laminar Wall Jet Flow and Heat Transfer over a Shallow Cavity. AB - This paper presents the detailed simulation of two-dimensional incompressible laminar wall jet flow over a shallow cavity. The flow characteristics of wall jet with respect to aspect ratio (AR), step length (X u), and Reynolds number (Re) of the shallow cavity are expressed. For higher accuracy, third-order discretization is applied for momentum equation which is solved using QUICK scheme with SIMPLE algorithm for pressure-velocity coupling. Low Reynolds numbers 25, 50, 100, 200, 400, and 600 are assigned for simulation. Results are presented for streamline contour, velocity contour, and vorticity formation at wall and also velocity profiles are reported. The detailed study of vortex formation on shallow cavity region is presented for various AR, X u , and Re conditions which led to key findings as Re increases and vortex formation moves from leading edge to trailing edge of the wall. Distance between vortices increases when the step length (X u) increases. When Re increases, the maximum temperature contour distributions take place in shallow cavity region and highest convection heat transfer is obtained in heated walls. The finite volume code (FLUENT) is used for solving Navier Stokes equations and GAMBIT for modeling and meshing. PMID- 26413564 TI - Risk Factors for Depression in Children and Adolescents with High Functioning Autism Spectrum Disorders. AB - The objective of our study was to examine, discuss, and provide proposals on diagnostic comorbidity of depression in children and adolescents with high functioning autism spectrum disorder (HFASD) in the following aspects. (1) Prevalence. It was concluded that there are an elevated depression rate and the need for longitudinal studies to determine prevalence and incidence based on functioning level, autistic symptoms, gender, age, type of depression, prognosis, duration, and treatment. (2) Explicative Hypotheses and Vulnerability. The factors that present the greatest specific risk are higher cognitive functioning, self-awareness of deficit, capacity for introspection, stressful life events, adolescence, quality of social relationships, and alexithymia. (3) Risk of Suicide. The need for control and detection of suicidal tendencies and bullying is emphasised. (4) Depressive Symptoms. Indicators for early detection are proposed and their overlap with HFASD is analysed, examining the assessment techniques used and arguing that specific adapted tests are needed. PMID- 26413566 TI - Comparison of Subcuticular Suture Materials in Cesarean Skin Closure. AB - Aim. Comparison of the rate of wound complications, pain, and patient satisfaction based on used subcuticular suture material. Methods. A total of 250 consecutive women undergoing primary and repeat cesarean section with low transverse incision were prospectively included. The primary outcome was wound complication rate including infection, dehiscence, hematoma, and hypertrophic scar formation within a 6-week period after operation. Secondary outcomes were skin closure time, the need for use of additional analgesic agent, pain score on numeric rating scale, cosmetic score, and patient scar satisfaction scale. Results. Absorbable polyglactin was used in 108 patients and nonabsorbable polypropylene was used in 142 patients. Wound complication rates were similar in primary and repeat cesarean groups based on the type of suture material. Skin closure time is longer in nonabsorbable suture material group in both primary and repeat cesarean groups. There was no difference between groups in terms of postoperative pain, need for additional analgesic use, late phase pain, and itching at the scar. Although the cosmetic results tended to be better in the nonabsorbable group in primary surgery patients, there was no significant difference in the visual satisfaction of the patients. Conclusions. Absorbable and nonabsorbable suture materials are comparable in cesarean section operation skin closure. PMID- 26413567 TI - An Assessment of the Clinical and Economic Impact of Establishing Ileocolic Anastomoses in Right-Colon Resection Surgeries Using Mechanical Staplers Compared to Hand-Sewn Technique. AB - Purpose. To estimate and compare clinical outcomes and costs associated with mechanical stapling versus hand-sewn sutured technique in creation of ileocolic anastomoses after right sided colon surgery. Methods. A previously conducted meta analysis was updated for estimates of anastomotic leak rates and other clinical outcomes. A value analysis model was developed to estimate cost savings due to improved outcomes in a hypothetical cohort of 100 patients who underwent right colon surgery involving either mechanical stapling or hand-sewn anastomoses. Cost data were obtained from publicly available literature. Results. Findings from the updated meta-analysis reported that the mechanical stapling group had lower anastomotic leaks 2.4% (n = 11/457) compared to the hand-sewn group 6.1% leaks (n = 44/715). Utilizing this data, the value analysis model estimated total potential cost savings for a hospital to be around $1,130,656 for the 100-patient cohort using mechanical stapling instead of hand-sewn suturing, after accounting for incremental supplies cost of $49,400. These savings were attributed to lower index surgery costs, reduced OR time costs, and reduced reoperation costs driven by lower anastomotic leak rates associated with mechanical stapling. Conclusion. Mechanical stapling can be considered as a clinically and economically favorable option compared to suturing for establishing anastomoses in patients undergoing right colon surgery. PMID- 26413569 TI - Conducting Research with Vulnerable Populations: Cautions and Considerations in Interpreting Outliers in Disparities Research. AB - Addressing the needs of understudied and vulnerable populations first and foremost necessitate correct application and interpretation of research that is designed to understand sources of disparities in healthcare or health systems outcomes. In this brief research report, we discuss some important concerns and considerations in handling "outliers" when conducting disparities-related research. To illustrate these concerns, we use data from our recently completed study that investigated sources of disparities in cancer pain outcomes between African Americans and Whites with cancer-related pain. A choice-based conjoint (CBC) study was conducted to compare preferences for analgesic treatment for cancer pain between African Americans and Whites. Compared to Whites, African Americans were both disproportionately more likely to make pain treatment decisions based on analgesic side-effects and were more likely to have extreme values for the CBC-elicited utilities for analgesic "side-effects." Our findings raise conceptual and methodological consideration in handling extreme values when conducting disparities-related research. Extreme values or outliers can be caused by random variations, measurement errors, or true heterogeneity in a clinical phenomenon. The researchers should consider: 1) whether systematic patterns of extreme values exist and 2) if systematic patterns of extreme values are consistent with a clinical pattern (e.g., poor management of cancer pain and side effects in racial/ethnic subgroups as documented by many previous studies). As may be evident, these considerations are particularly important in health disparities research where extreme values may actually represent a clinical reality, such as unequal treatment or disproportionate burden of symptoms in certain subgroups. Approaches to handling outliers, such as non-parametric analyses, log transforming clinically important extreme values, or removing outliers may represent a missed opportunity in understanding a potentially targetable area of intervention. PMID- 26413568 TI - Porosome in Cystic Fibrosis. AB - Macromolecular structures embedded in the cell plasma membrane called 'porosomes', are involved in the regulated fractional release of intravesicular contents from cells during secretion. Porosomes range in size from 15 nm in neurons and astrocytes to 100-180 nm in the exocrine pancreas and neuroendocrine cells. Porosomes have been isolated from a number of cells, and their morphology, composition, and functional reconstitution well documented. The 3D contour map of the assembly of proteins within the porosome complex, and its native X-ray solution structure at sub-nm resolution has also advanced. This understanding now provides a platform to address diseases that may result from secretory defects. Water and ion binding to mucin impart hydration, critical for regulating viscosity of the mucus in the airways epithelia. Appropriate viscosity is required for the movement of mucus by the underlying cilia. Hence secretion of more viscous mucus prevents its proper transport, resulting in chronic and fatal airways disease such as cystic fibrosis (CF). CF is caused by the malfunction of CF transmembrane conductance regulator (CFTR), a chloride channel transporter, resulting in viscous mucus in the airways. Studies in mice lacking functional CFTR secrete highly viscous mucous that adhered to the epithelium. Since CFTR is known to interact with the t-SNARE protein syntaxin-1A, and with the chloride channel CLC-3, which are also components of the porosome complex, the interactions between CFTR and the porosome complex in the mucin-secreting human airway epithelial cell line Calu-3 was hypothesized and tested. Results from the study demonstrate the presence of approximately 100 nm in size porosome complex composed of 34 proteins at the cell plasma membrane in Calu-3 cells, and the association of CFTR with the complex. In comparison, the nuclear pore complex measures 120 nm and is comprised of over 500 protein molecules. The involvement of CFTR in porosome-mediated mucin secretion is hypothesized, and is currently being tested. PMID- 26413570 TI - Stem Cell Therapy for Sensorineural Hearing Loss, Still Alive? AB - In mammals, the auditory system, which includes the cochlea, has a very complex structure harboring many types of cells performing different functions. Among these cells are the auditory hair cells (HCs), which are terminally and well differentiated unique cells which have lost their regenerative potential after development. The auditory HCs are easily damaged by aging as well as during episodes of ototoxicity and acoustic trauma. HCs damages typically occur in the early stage of injury and can result a permanent hearing loss. Recently, there have been tremendous developments from stem cells (SCs) research involving sensorineural hearing loss, but several limitations and obstacles persist in allowing these developments from continuing onto clinical applications. This review discusses the recent advances in SC research in sensorineural hearing loss with the subsequent sections discussing the possible hurdles and limitations that currently preclude their clinical application. PMID- 26413571 TI - Test-Retest Reliability of Word Recognition Score Using Korean Standard Monosyllabic Word Lists for Adults as a Function of the Number of Test Words. AB - BACKGROUND AND OBJECTIVES: The purpose was to establish the test-retest reliability of word recognition score (WRS) using Korean standard monosyllabic word lists for adults (KS-MWL-A) recently developed based on the international standard for speech audiometry (ISO 8253-3:2012). SUBJECTS AND METHODS: Subjects consisted of 159 adults aged to 18 to 25 years with normal hearing sensitivity. WRSs were obtained in 2 dB steps from the level of speech recognition thresholds to the level of 86% correct responses or greater. After one or two weeks, retest was performed. Correlation, confidence interval (CI) and prediction interval (PI) were calculated for the reliability. RESULTS: Correlation coefficients were 0.88 for 50 test words, 0.76 for 25 and 0.61 for 10 words. Results also showed that 95% CIs and PIs were narrower for 25 and 50 test words than those for 10 test words. CONCLUSIONS: Korean WRS using the KS-MWL-A has high reliability for 25 and 50 test words, but relatively low for 10 words. It suggested that 95% CIs for each test words would be criteria for significant differences in WRS for groups and 95% PIs at each score of WRS could be utilized for a considerable difference for each individual at retest. PMID- 26413572 TI - Long-Term Outcomes of Acute Low-Tone Hearing Loss. AB - BACKGROUND AND OBJECTIVES: Although acute low-tone hearing loss has been associated with cochlear hydrops or early stage Meniere's disease, its prognosis in the short-term has been reported to be better than sudden hearing loss. However, recurrence of hearing loss and possible progression to Meniere's disease remain important concerns in the clinical setting. This study aims to investigate the long-term audiological outcomes of acute low-tone hearing loss. SUBJECTS AND METHODS: A retrospective review of patients presenting with a first attack of acute low-tone hearing loss was performed. Of the 77 patients, 33 were followed up for more than 3 months. Progression, recovery of hearing loss and recurrence of hearing loss were examined. Also, correlation between long-term outcomes and associated clinical factors were analyzed. RESULTS: Twenty-five patients (75.7%) had complete hearing recovery, five patients (15.1%) had partial recovery, two patients (6.0%) had no recovery, and one patient (3.0%) had progression of hearing loss 1 month after initial treatment. Thirty-three patients were followed up for more than 3 months (mean 22 months, range 3-79 months). Recurrences of acute low-tone hearing loss were observed in five patients (15.2%). All of the recurrences occurred during the first 12 months of follow-up. Long-term prognosis correlated with the initial therapy results (R(2)=0.693). CONCLUSIONS: Recurrences of hearing loss were documented in five patients (15.2%), and all of these cases occurred within one year of the first attack. Audiological outcomes after initial therapy may predict the recurrence of acute low-tone hearing loss. PMID- 26413573 TI - Measurement of Acceptable Noise Level with Background Music. AB - BACKGROUND AND OBJECTIVES: Acceptable noise level (ANL) is a measure of the maximum background noise level (BNL) that a person is willing to tolerate while following a target story. Although researchers have used various sources of target sound in ANL measures, a limited type of background noise has been used. Extending the previous study of Gordon-Hickey & Moore (2007), the current study determined the effect of music genre and tempo on ANLs as possible factors affecting ANLs. We also investigated the relationships between individual ANLs and the familiarity of music samples and between music ANLs and subjective preference. SUBJECTS AND METHODS: Forty-one participants were seperated into two groups according to their ANLs, 29 low-ANL listeners and 12 high-ANL listeners. Using Korean ANL material, the individual ANLs were measured based on the listeners' most comfortable listening level and BNL. The ANLs were measured in six conditions, with different music tempo (fast, slow) and genre (K-pop, pop, classical) in a counterbalanced order. RESULTS: Overall, ANLs did not differ by the tempo of background music, but music genre significantly affected individual ANLs. We observed relatively higher ANLs with K-pop music and relatively lower ANLs with classical music. This tendency was similar in both low-ANL and high-ANL groups. However, the subjective ratings of music familiarity and preference affected ANLs differently for low-ANL and high-ANL groups. In contrast to the low ANL listeners, the ANLs of the high-ANL listeners were significantly affected by music familiarity and preference. CONCLUSIONS: The genre of background music affected ANLs obtained using background music. The degree of music familiarity and preference appears to be associated with individual susceptibility to background music only for listeners who are greatly annoyed by background noise (high-ANL listeners). PMID- 26413575 TI - Hearing Thresholds for a Geriatric Population Composed of Korean Males and Females. AB - BACKGROUND AND OBJECTIVES: The purpose of the present study was to provide the hearing threshold levels in the elderly Korean population, and to compare Korean data with that in the International Organization for Standardization (ISO) 7029 (2000). SUBJECTS AND METHODS: Data were collected from a total of 526 ears from 112 males and 151 females aged 60-84 years. All participants were screened otologically by the procedure given in ISO 8253-1 (2010). RESULTS: Results showed that the pure-tone average was gradually elevated with increasing age. The amount of hearing loss was greater in males than in females, and the high frequency hearing thresholds were worse than the low frequency hearing thresholds in males and females. The hearing threshold levels were higher at low frequencies in males and at all frequencies in females than the norms of ISO 7029 (2000). CONCLUSIONS: Results from this study will be partly used for standardization of hearing thresholds as a function of age in Korea and for updating the ISO 7029. PMID- 26413574 TI - The Effect of Korean Red Ginseng on Symptoms and Quality of Life in Chronic Tinnitus: A Randomized, Open-Label Pilot Study. AB - BACKGROUND AND OBJECTIVES: The major mechanism of inner ear cell damage is the production of reactive oxygen species (ROS). Korean red ginseng (KRG) has an anti ROS effect; thus we hypothesized that KRG may be of use for the treatment of chronic idiopathic tinnitus. The aim of the study is to investigate clinical outcomes and health-related quality of life (QoL) in chronic tinnitus patients after taking KRG. SUBJECTS AND METHODS: This study was an open-label randomized controlled trial. Sixty-one patients with chronic tinnitus were enrolled and randomized to three groups. The control group was treated for 4 weeks with 160 mg/day Ginkgo biloba extract, and two other groups receiving 1500 mg/day or 3000 mg/day KRG for 4 weeks. Clinical assessments were performed using the tinnitus handicap inventory (THI), Visual Analogue Scale (VAS) and QoL was assessed by Short Form-36 Health Survey (SF-36) questionnaire. RESULTS: Fifty-nine patients completed the planned protocol. Significant improvements were observed between initial and post-treatment THI scores in patients receiving 3000 mg/day KRG. There was no statistically significant difference between initial and post treatment VAS scores in all groups. Treatment with 3000 mg/day KRG for 4 weeks significantly improved role emotional and mental health scores in the SF-36 survey. CONCLUSIONS: These results suggest that KRG may improve tinnitus symptoms and mental wellbeing in chronic tinnitus patients. PMID- 26413576 TI - The Dynamic Range for Korean Standard Sentence Material: A Gender Comparison in a Male and a Female Speakers. AB - BACKGROUND AND OBJECTIVES: The purpose of this study was to identify differences between the dynamic ranges (DRs) of male and female speakers using Korean standard sentence material. Consideration was especially given to effects within the predefined segmentalized frequency-bands. MATERIALS AND METHODS: We used Korean standard sentence lists for adults as stimuli. Each sentence was normalized to a root-mean-square of 65 dB sound pressure level. The sentences were then modified to ensure there were no pauses, and the modified sentences were passed through a filter bank in order to perform the frequency analysis. Finally, the DR was quantified using a histogram that showed the cumulative envelope distribution levels of the speech in each frequency band. RESULTS: In DRs that were averaged across all frequency bands, there were no significant differences between the male and the female speakers. However, when considering effects within the predefined frequency bands, there were significant differences in several frequency bands between the DRs of male speech and those of female speech. CONCLUSIONS: This study shows that the DR of speech for the male speaker differed from the female speaker in nine frequency bands among 21 frequency bands. These observed differences suggest that a standardized DR of male speech in the band-audibility function of the speech intelligibility index may differ from that of female speech derived in the same way. Further studies are required to derive standardized DRs for Korean speakers. PMID- 26413577 TI - Objective Tinnitus Concomitant with Eye Blinking: A Case Report. AB - Tinnitus is a common auditory phenomenon associated with many otological diseases, and is usually subjective. Objective tinnitus can be generated by para auditory structures, usually derived from vascular or myogenic sources, or the eustachian tube. We present a rare case of intermittent unilateral tinnitus associated with eye blinking. Otoendoscopic examination showed that the external auditory canals and tympanic membranes were normal; however, rhythmic movements of both tympanic membranes, concomitant with the tinnitus, were evident whenever the patient blinked. The tympanometry and stapedial reflexes measured via impedance audiometry exhibited saw-tooth patterns; movement of the tympanic membrane was associated with eyelid blinking. The patient was managed conservatively, with reassurance and medication, and the condition became well controlled. Here, we present this educational case and review the literature. PMID- 26413578 TI - Persistent Positional Vertigo in a Patient with Sudden Sensorineural Hearing Loss: A Case Report. AB - Because inner ear organs are interconnected through the endolymph and surrounding endolymphatic membrane, the patients with sudden sensorineural hearing loss (SSNHL) often complain of vertigo. In this study, we report a patient with SSNHL accompanied by persistent positional vertigo, and serial findings of head-roll tests are described. At acute stage, head-roll test showed persistent geotropic direction-changing positional nystagmus (DCPN), which led to a diagnosis of SSNHL and ipsilateral light cupula. Although vertigo symptom gradually improved, positional vertigo lasted for more than 3 weeks. At this chronic stage, persistent apogeotropic DCPN was observed in a head roll test, which led to a diagnosis of the heavy cupula. Although the mechanism for the conversion of nystagmus direction from geotropic to apogeotropic persistent DCPN is unclear, the change of specific gravity of the endolymph might be one of the plausible hypothetical explanations. PMID- 26413579 TI - Skin Flap Necrosis by Bone Marking with Methylene Blue in Cochlear Implantation. AB - One of surgical complications in cochlear implantation is the necrosis of the skin flap above the receiver-stimulator coil. We present a case of 55-year-old woman who underwent cochlear implantation and developed a bluish skin necrosis due to bone marking. The planned position for the receiver-stimulator was marked using methylene blue through skin to bone. She did not undergo skin flap thinning and underwent successful implantation with complete electrode insertion. Few weeks postoperatively, the patient developed bluish discoloration with progressive thick, blue eschar formation and skin flap necrosis. She subsequently underwent wound debridement and skin flap closure. Cochlear explantation was not necessary. Timely diagnosis and management about this complication is necessary to prevent further skin breakdown and subsequent device extrusion. This report identifies the marking using methylene blue as another possible source of skin flap necrosis in cochlear implantation, and surgeons should be aware of this potential complication. PMID- 26413580 TI - Understanding the Role of Medical Experts during a Public Health Crisis Digital Tools and Library Resources for Research on the 1918 Spanish Influenza. AB - Humanities scholars, particularly historians of health and disease, can benefit from digitized library collections and tools such as topic modeling. Using a case study from the 1918 Spanish Flu epidemic, this paper explores the application of a big humanities approach to understanding the impact of a public health official on the course of the disease and the response of the public, as documented through digitized newspapers and medical periodicals. PMID- 26413581 TI - Optimal kVp Selection for Contrast CT Imaging Based on a Projection-domain Method. AB - Computed Tomography (CT) has been in clinical use for several decades. The number of CT scans has increased significantly worldwide, which results in increased radiation dose delivered to the general population. Many technologies have been developed to minimize the dose from CT scans, including scanner hardware improvements, task-specific protocol design and advanced reconstruction algorithms. In this study, we focused on selection of X-ray tube voltage and filtration to achieve optimal dose efficiency given required image quality, more specifically the contrast to noise ratio. Our approach differs from previous studies in two aspects. Typically, Monte-Carlo simulation is used to estimate dose in simulations, but this is computationally costly. We instead use a projection-domain dose estimation method. No image reconstruction is required for the projection-domain method, which further simplifies the analysis. This study also includes tantalum, a new contrast agent, in addition to soft tissue (water), bone and iodine contrast. Optimal tube voltages and filtration are identified as a function of phantom size. The simulation analysis is confirmed with a limited phantom study. PMID- 26413582 TI - Weaving Clinical Expertise in Online Health Communities. AB - Many patients visit online health communities to receive support. In face-to-face support groups, health professionals facilitate peer-patients exchanging experience while adding their clinical expertise when necessary. However, the large scale of online health communities makes it challenging for such health professional moderators' involvement to happen. To address this challenge of delivering clinical expertise to where patients need them, we explore the idea of semi-automatically providing clinical expertise in online health communities. We interviewed 14 clinicians showing them example peer-patient conversation threads. From the interviews, we examined the ideal practice of clinicians providing expertise to patients. The clinicians continuously assessed when peer-patients were providing appropriate support, what kinds of clinical help they could give online, and when to defer to patients' healthcare providers. The findings inform requirements for building a semi-automated system delivering clinical expertise in online health communities. PMID- 26413583 TI - The Language Abilities of Resident Physicians. AB - PURPOSE: The Joint Commission mandates that health care systems provide culturally and linguistically appropriate care for patients. Similarly, the Accreditation Council for Graduate Medical Education (ACGME) requires that resident physicians learn to communicate effectively across cultures. The purpose of this study was to analyze residents' self-report of fluency in a second language and level of training in the use of interpreters to assess the institution's preparation of residents to meet mandates regarding the delivery of cross-cultural care. METHODS: Seven hundred and twenty two (722) surveys were analyzed from resident physicians in 62 different ACGME accredited programs. Language ability was measured with a survey question asking about comfort providing patient care in a language other than English. Knowledge of working with interpreters was measured by a survey question asking about amount of training received. Survey questions on gender, post-graduate year (PGY), specialty, and underrepresented minority (URM) status were examined using c2 and independent samples Mann-Whitney U test. Logistic regression was used to estimate the adjusted odds ratio by variable. RESULTS: Fifty-five percent of all of the resident physicians endorsed feeling comfortable providing patient care in a language other than English, and Spanish was the most common language (77%). Almost 20% percent of residents reported little or no training in the use of interpreters. In bivariate analysis, race-ethnicity was associated (P-value <.001) with comfort in providing patient care in a language other than English. Primary care resident physicians had a 1.67 adjusted odds ratio (95% confidence interval [CI] 1.18, 2.37; p value = 0.004) of feeling comfortable providing patient care in a language other than English compared to resident physicians from other specialties. CONCLUSIONS: Primary care resident physicians are more likely to report feeling comfortable in providing patient care in a language other than English. Most residents would benefit from additional education in working with interpreters. PMID- 26413584 TI - Epilepsy genetics in Africa: challenges and future perspectives. AB - Despite the diversity of the African population, genetic studies, of epilepsy in particular, have been limited, especially in sub-Saharan Africa. In recent years, with the regression of infectious diseases in developing countries, the focus has shifted more towards non communicable disorders. The prevalence of epilepsy in Africa is higher compared to other continents. Although this has been attributed to the high rate of infectious diseases, genetic contributions should not be ignored. Research in genetic epilepsy in Africa could well benefit from the decreasing cost of genetic analysis, and could contribute to further our knowledge on the spectrum of these diseases in Africa. The growing collaboration between African research institutions and those of developed countries offers a unique opportunity to boost research in Africa and improve our global understanding of human disease, thus leading to the development of better therapeutic approaches. PMID- 26413586 TI - The construction of a two-dimensional supramolecular organic framework with parallelogram pores and stepwise fluorescence enhancement. AB - A novel single-layer two-dimensional (2D) supramolecular organic framework (SOF) with parallelogram pores has been assembled to turn on the fluorescence emission of a non-emissive building block, and the emission could be further enhanced by the aggregation of the as-prepared 2D monolayers. PMID- 26413587 TI - On-tip photodetection: a simple and universal platform for optoelectronic screening. AB - A novel platform for transient photodetector component screening has been developed whereby an optical fiber tip serves as the counter electrode when placed in a variety of dielectric media, connected to a photoresponsive working electrode. The soft processing conditions allow for ubiquitous photodetection for organic and biological systems. PMID- 26413585 TI - Electronic communication of cells with a surface mediated by boronic acid saccharide interactions. AB - The fabrication of a molecularly tailored surface functionalised with a saccharide binding motif, a phenyl boronic acid derivative is reported. The functionalised surface facilitated the transfer of electrons, via unique electronic interactions mediated by the presence of the boronic acid, from a macrophage cell line. This is the first example of eukaryotic cellular-electrical communication mediated by the binding of cells via their cell-surface saccharide units. PMID- 26413588 TI - Chemoselective reduction of the phosphoryl bond of O-alkyl phosphinates and related compounds: an apparently impossible transformation. AB - A method is reported for the phosphoryl bond cleavage of O-alkyl phosphinates, phosphinothioates and certain phosphonamidates to furnish the corresponding P(III) borane adducts. The two-step procedure relies upon initial activation of the phosphoryl bond with an alkyl triflate, followed by reduction of the resulting intermediate using lithium borohydride. PMID- 26413589 TI - Tribute: John H. Laragh, MD. PMID- 26413590 TI - Animal moves reveal bigger picture. AB - As the performance of electronic tracking devices improves dramatically, their use opens up new areas of investigation. The movements of individuals can be linked to physiology, environmental conditions and group behaviour, report back on otherwise inaccessible parts of the biosphere, and warn us of disease spread and natural disasters. Michael Gross reports. PMID- 26413592 TI - Environmental hazards, air pollution, and noise as novel cardiovascular risk factors. PMID- 26413591 TI - Melissa Bateson. PMID- 26413593 TI - Reduce air pollution to reduce the burden of cardiovascular diseases! AB - The second highest environmental risk factor for years of lives lost annually. PMID- 26413594 TI - Stress and cardiovascular mortality: an evident but underestimated connection. PMID- 26413595 TI - Stress and the heart: the role of type D personality in personalized care. PMID- 26413596 TI - Music and the heart. AB - Emeritus Professor of Cardiology Peter Sleight discusses his observations on how music can affect heart rate variability and life expectancy. PMID- 26413597 TI - The Asklepios project in perspective: the population on its way to ageing. AB - Thierry Gillebert discusses an ambitious project that started in 2002 and is ongoing. PMID- 26413598 TI - European Heart for Children: a story of humanity and success. AB - Since its foundation in 2009 and the last publications, European Heart for Children has grown substantially. PMID- 26413599 TI - [Editorial]. PMID- 26413600 TI - Reply to A Macri. PMID- 26413601 TI - Removal of restrictions following primary THA with posterolateral approach does not increase the risk of early dislocation--reply. PMID- 26413602 TI - Cell-Penetrating Peptides. Preface. PMID- 26413603 TI - Google Trends (GT) related to influenza--the authors reply. PMID- 26413604 TI - Functionalized Gold Nanoparticles: Synthesis, Properties and Applications--A Review. AB - The past few decades have witnessed significant advances in the development of functionalized gold nanoparticles for applications in various fields such as chemistry, biology, pharmacy and physics. Although it has been more than 150 years since they were first synthesized, extensive research has recently been undertaken to improve or modify gold nanoparticles, thereby opening up opportunities to enhance and optimize their potential and breadth of their applicability. Recently developed methods have allowed a precise control of gold nanoparticle size and the modification of gold nanoparticles with suitable protecting and functionalizing agents, facilitate their applications in different areas such as chemical and biological sensing, imaging and biomedical applications. This review focuses on the recent developments in various methods for the size and shape controlled synthesis of gold nanoparticles, understanding of different properties of gold nanoparticles and their applications in various fields. Particular attention is given to the chemical and biological sensing applications of gold nanoparticles and on the advances in the controlled ordering of gold nanoparticles for creating nanostructures for diverse applications. PMID- 26413605 TI - Recent Advances in Nonpolar and Semipolar InGaN Light-Emitting Diodes (LEDs). AB - The III-nitrides have attracted much attention because of their applicability in optoelectronic devices, whose emission wavelengths range from green to ultraviolet light due to their wide band gap. However, conventional c-plane GaN based devices are influenced significantly by spontaneous and piezoelectric polarization effects, which could pose a limitation for increased luminous efficiency as a result of the quantum confined stark effect. Since the early 2000s, many groups have tried to solve these problems by examining the growth of GaN on non- or semipolar surface planes. High power non- and semipolar LEDs can be realized by the growth of a thick active layer. In addition, it is expected that it is possible to grow nonpolar InGaN LEDs with high quality p-GaN layers due to lower hole activation energy, and also long-wavelength semipolar InGaN LEDs because of the capacity for high indium incorporation in the quantum wells (QWs). However, non- and semipolar structures grown on sapphire substrate usually contain a high density of basal stacking faults and threading dislocations. For this reason, the growth of non- and semipolar GaN-based LEDs on a sapphire substrate has been attempted through the introduction of defect reduction techniques such as epitaxial lateral overgrowth, patterned sapphire substrate and re-growth techniques on a porous GaN layer, etc. Also, some researchers have grown high quality non- and semipolar GaN-based LEDs using non- and semipolar freestanding GaN substrates. In this review paper, we introduce and discuss recent progress in the development of non- and semipolar GaN-based LEDs and freestanding GaN substrates. PMID- 26413606 TI - Vibration Damping Materials and Their Applications in Nano/Micro-Electro Mechanical Systems: A Review. AB - The present review explores an overall view of the vibration damping materials ranging from traditionally used viscoelastic materials for macroscale damping to hybrid thin film heterostructures for micro-electro-mechanical systems (MEMS). Vibration damping materials like rubbers, polymers, metals, metal-matrix composites and smart materials are reviewed in terms of damping capacity, stiffness, mechanical strength and figure of merit. Nanoscale shape memory alloys, piezoelectric materials, carbon nanotubes, their composites and thin films are promising materials for future nanoscale damping devices. The main focus of this article is on our development of new vibration damping approach for MEMS structures comprising of ferroelastic/ferroelastic thin film heterostructures. For the first time, nanoindentation has been explored as an alternative tool to evaluate the damping capability of actual components (e.g., thin films for MEMS) where production of dynamic mechanical analyzer (DMA) test samples is not feasible. A comprehensive insight on the existing vibration damping materials and our new approach would definitely trigger some important applications in nano- and micro-electro-mechanical systems. PMID- 26413607 TI - Cancer Targeting: Responsive Polymers for Stimuli-Sensitive Drug Delivery. AB - Effective treatment of cancer is limited by the lack of delivery technology to specifically and efficiently deliver chemotherapeutic agents within the tumor vicinity. The tumor targeting based on ligand or antibody conjugation to therapeutics is limited by the chemistry, stability and scalability issues. Recently, functional polymers which are responsive to internal and external stimuli have been developed. Stimuli-responsive carriers show potential to overcome the limitations of cancer targeting. Internal stimuli localized to cancer tissue including pH, redox potential, extracellular enzyme expression can be utilized to target tumors. Furthermore, polymer responsiveness to external stimuli, including temperature, magnetic field, ultrasound and light can be utilized to localize the nanocarriers to specific tumor location after administration. The present review provides an overview of the current status of development of responsive polymers for various stimuli to target cancer. PMID- 26413608 TI - CRISPR/Cas: A Faster and More Efficient Gene Editing System. AB - Gene editing technology has been at its mature stage with the successful development of TALENs and CRISPR/Cas enzymes. The genetically modified endonucleases of ZFNs, TALENs, and CRISPR/Cas are widely used in the development of genetically modified cells or organisms. Among the enzymes that possess gene editing ability, CRISPR/Cas is the latest member with high efficiency in gene editing and simplicity in cloning. This review discusses the discovery of CRISPR, the development of the CRISPR/Cas system, and its applications as a new gene editing system. PMID- 26413609 TI - Multifunctional Drug Delivery Systems Using Inorganic Nanomaterials: A Review. AB - Targeted drug delivery with controlled rate is vital for therapeutic purpose especially for cancer therapy. Advanced biomaterials with the aid of nanotechnology have evolved as efficient drug delivery systems (DDS), providing a multi-functional platform for simultaneous therapeutic and diagnostic (theranostic) functions. This review discusses current advances in synthesis and applications of inorganic materials such as quantum dots, carbon nanotubes and graphene oxides for drug delivery. The strategies of surface-functionalization of these inorganic materials to render them biocompatible are also reviewed. The advantages and applications of these biomaterials as multi-functional moiety for bio-imaging, drug targeting and delivery have been discussed. The review concludes with discussion on challenges that limits the practical applications of some materials as a drug carrier for therapeutic use. These issues remain to be fully addressed for their maximum utilization for biomedical applications. PMID- 26413610 TI - Analysis of Carrier Transport of Organic Devices by Using Nonlinear Optical Polarization. AB - In this review, we discuss the Maxwell-Wagner (MW) effect model analysis of organic devices and time-resolved optical second harmonic generation (TR-EFISHG) measurement that is available for directly probing carrier motion in organic semiconductor devices. Using these, we show that organic field effect transistor as well organic double-layer device operation is analyzed well, and we can make clear the mechanism of these organic devices' operation. Finally, we conclude that the dielectric physics approach using the MW model analysis and the TR EFISHG experiment is useful to study carrier transport mechanism of organic devices. PMID- 26413611 TI - Recent Advances in Preparation, Structure, Properties and Applications of Graphite Oxide. AB - Graphite oxide, also referred as graphitic oxide or graphitic acid, is an oxidized bulk product of graphite with a variable composition. However, it did not receive immense attention until it was identified as an important and easily obtainable precursor for the preparation of graphene. This inspired many researchers to explore facts related to graphite oxide in exploiting its fascinating features. The present article culminates up-dated review on different preparative methods, morphology and characterization of physical/chemical properties of graphite oxide by XRD, XPS, FTIR, Raman, NMR, UV-visible, and DRIFT analyses. Finally, recent developments on intercalation and applications of GO in multifaceted areas of catalysis, sensor, supercapacitors, water purification, hydrogen storage and magnetic shielding etc. has also been reviewed. PMID- 26413612 TI - Flexible and Conductive Graphene-Poly (diallyldimethylammoniumchloride) Buckypaper. AB - This paper describes the fabrication and characterization of flexible, conductive reduced graphene oxide (rGO)-poly(diallyldimethylammoniumchloride) (PDDA) buckypaper (BP). PDDA acts as a reducing agent to prepare an rGO-PDDA nanosheet dispersion from graphite oxide. The incorporation of PDDA as a "glue" molecule successfully binds rGO nanosheets into BPs with strong interlayer binding. The resulting BPs were characterized by scanning electronic microscopy (SEM), Raman, energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), and resistivity measurements. The sp2 structure was greatly restored by the PDDA induced reduction. Moreover, rGO was chemically doped from the adsorbed PDDA, which causes the Raman G band to shift from ~1585 to ~1610 cm(-1). This chemical doping substantially increased the density of the free charge carriers in rGO and thereby further enhanced the electrical conductivity of the rGO-BP. Good inter layer connection in the rGO percolating network was obtained after thermal annealing at higher than ~250 degrees C. The resulting rGO-PDDA-BPs exhibited an isotropic sheet resistance as low as ~100 Omega/sq, which indicates a reduction by six orders of magnitude compared to the GO-BPs resistance before annealing. This PDDA-induced reduction with a low-temperature annealing process preserved the BPs' structural integrity and mechanical flexibility, thus overcoming the fragility problems with high-temperature annealing. PMID- 26413613 TI - Preparation and Characterization of Photosensitive and Magnetic Targeting Graphene Oxide Nanocomposite. AB - Hematoporphyrin-conjugated magnetic graphene oxide nanocomposite was designed and prepared as a novel promising model. Fe3O4 nanoparticles were dispersed on the surface and edges of the graphene oxide in a uniform size, and hematoporphyrin was effectively conjugated onto graphene oxide via hydrophobic interactions and pi-pi stacking. With the photosensitivity of hematoporphyrin and the magnetic properties of Fe3O4 nanoparticles, it can be applied for photodynamic therapy to increase the accumulation of hematoporphyrin in tumor cells. The cytotoxicity in vitro showed that hematoporphyrin conjugated magnetic graphene oxide nanocomposite irradiated at 671 nm generated cytotoxic singlet oxygen and exhibited a good inhibition to the human tumor cell HeLa (IC50 = 10.12 ug/ml), which suggested that the nanocomposite is potential for targeting photodynamic therapy as a promising drug delivery system. PMID- 26413614 TI - Ultrasonication-Assisted Controllable Self-Assembly of Graphene Oxide. AB - A facile, and cost-efficient ultrasonication-assisted exfoliation strategy is proposed to fabricate GO sheets with various sizes. Just by controlling the original GO sizes as basic building blocks in deionized water, various aligned architectures, such as films, microfibers, submicron rods, and nanorods, are self assembled at the water/air interface. The formation mechanisms are analyzed on the basis of the morphology evolutions of various aligned architectures. It is very interesting to note that various functional structures are generally aligned in a certain direction, which is probably attributed to the intrinsic lamellar orientation and the corresponding polarity of the GO sheets. This work provides a beneficial reference for controlling the assembling behaviors of GO in a broad range of applications. PMID- 26413615 TI - Facile and Effective Functionalization of Graphene Oxide by Boron-Oxygen Covalent or Bingel Cyclopropanation Reaction. AB - Functionalized graphene oxide (GO-BPh2), was obtained via one step reaction between triphenyl boron and oxygen-containing groups on graphene sheets. In addition, functionalized graphene oxide (GO-Carbene) was obtained via bingel cyclopropanation reaction of active double bands on graphene sheets. Both functionalized materials can be homogeneously distributed into ortho dichlorobenene. They were characterized by FTIR spectroscopy, UV Vis NIR spectroscopy, thermal gravimetric analysis, raman spectra, and X-ray photoelectron spectroscopy (XPS). FTIR, TGA and XPS results prove that phenyl boron has been successfully attached to the graphene sheets by covalent bonds. And the Raman spectra and XPS confirm that many carbon double bands changed into carbon single bands on graphene sheets after cyclopropanation reaction. PMID- 26413616 TI - Direct Ablation by Laser of Single Graphene Monolayer and Graphene/Photopolymer Double Layer. AB - A diode-pumped Q-switched neodymium-doped yttrium vanadate (Nd:YVO4, lambda = 1064 nm) laser was applied to obtain graphene patterns on a photopolymer layer by direct ablation. In the transfer process of the graphene layer, the photopolymer was employed as a graphene supporting layer and it was not removed for the simplification of the process. The laser ablation was carried out on graphene/photopolymer double layers for various beam conditions. The results showed that the laser-ablated widths on the graphene/photopolymer double layer were much greater than those on the graphene monolayer, especially at lower scanning speeds and at higher repetition rates. The photopolymer layer was not removed by the laser ablation, and the thermal energy was considered to have been dissipated in the lateral direction of graphene instead of being conducted vertically to the glass substrate. The Raman spectrum results showed that the graphene layer was clearly removed on the laser-ablated region of interest. PMID- 26413617 TI - Controllable and Reversible Dispersiblity of Graphene Materials by a Generic Organometallic Functionalization. AB - A general and reversible functionalization method has been developed for reduced graphene oxide (rGO) based on a simple reaction sequence. In this sequence, the chemical functionalization of reduced graphene oxide (rGO) was first carried out by a nucleophilic addition of n-butyllithium (n-BuLi) to rGO sheets, followed by a subsequent coupling step of intermediates (n-Bu-rGO)n-Li(n+) with alkyl halide, leading to functionalized rGO with controllable and reversible dispersiblity in either nonpolar or polar solvents depending on the functional groups. Next, the functional groups could be reversibly removed by solvothermal treatment to generate reduced graphene sheets. Then the reduced materials could be again functionalized using the same reaction sequence above with either the same or different functional groups to almost the same extent of the first functionalization cycle. PMID- 26413618 TI - Electrostatically Gated Graphene-Zinc Oxide Nanowire Heterojunction. AB - This paper presents an electrostatically gated graphene-ZnO nanowire (NW) heterojunction for the purpose of device applications for the first time. A sub nanometer-thick energy barrier width was formed between a monatomic graphene layer and electrochemically grown ZnO NWs. Because of the narrow energy barrier, electrons can tunnel through the barrier when a voltage is applied across the junction. A near-ohmic current-voltage (I-V) curve was obtained from the graphene electrochemically grown ZnO NW heterojunction. This near-ohmic contact changed to asymmetric I-V Schottky contact when the samples were exposed to an oxygen environment. It is believed that the adsorbed oxygen atoms or molecules on the ZnO NW surface capture free electrons of the ZnO NWs, thereby creating a depletion region in the ZnO NWs. Consequentially, the electron concentration in the ZnO NWs is dramatically reduced, and the energy barrier width of the graphene ZnO NW heterojunction increases greatly. This increased energy barrier width reduces the electron tunneling probability, resulting in a typical Schottky contact. By adjusting the back-gate voltage to control the graphene-ZnO NW Schottky energy barrier height, a large modulation on the junction current (on/off ratio of 10(3)) was achieved. PMID- 26413619 TI - Synthesis and Characterization of the Graphene-Fe3O4 Hybrid Composite. AB - Graphene and iron oxide composites have attracted huge attention in the fields of nanoelectronics and nanodevices due to their superior magnetic and electric characteristics. However, their synthesis methods are composed of many steps and use toxic chemical reactants. Accordingly, in this study, a GN-Fe3O4 NP hybrid composite was prepared using an eco-friendly and facile method. Its morphological and structural characteristics were then investigated by scanning electron microscopy, transmission electron microscopy, X-ray diffractometer and UV-visible spectroscopy. The results indicated that the GN structures as well as Fe3O4 NPs were significantly associated with the composite of GN-Fe3O4 NPs. PMID- 26413620 TI - Functionalized Graphene Oxide with Hepatocyte Targeting as Anti-Tumor Drug and Gene Intracellular Transporters. AB - In order to realize the hepatocyte-specific targeted delivery of anti-tumor drug and gene, lactosylated chitosan oligosaccharide (LCO) functionalized graphene oxides (GO-LCO) containing quaternary ammonium groups (GO-LCO+) were prepared. The formation and composition of GO-LCO+ were confirmed by FTIR, AFM, TGA and zeta-potential. The in vitro cells uptakes of this functionalized GO were investigated and the results showed that GO-LCO+ can deliver fluorescein FAM labeled DNA sequence (FAM-DNA) into human hepatic carcinoma cells (QGY-7703) with higher efficiency than positively charged chitosan oligosaccharide (CO) functionalized graphene oxides (GO-CO+) without Lactose acid modification. The loading efficiency of doxorubicin chloride (Dox) on GO-LCO+ with 477 ug/mg was obtained at the initial Dox concentration of 0.45 mg/ml and release of Dox on GO LCO+ showed strong pH dependence. The toxicity of GO-LCO+ before and after loading with Dox toward QGY-7703 cells was further investigated. Our results suggest the functionalized GO to be used as a nanocarrier for hepatocyte targeted co-delivery of anti-tumor drugs and genes with low cytotoxicity, promising for future applications in anticancer drug and gene combined therapy. PMID- 26413621 TI - Inhibition of Viability of the Respiratory Epithelial Cells Using Functionalized Graphene Oxide. AB - The viability of A549 cells, a human lung carcinoma epithelial cell line, was evaluated after exposure to graphene oxide (GO) and its derivatives (dodecylamine GO (DA-GO), reduced GO (rGO), and sodium dodecyl sulfate rGO (SDS-rGO)). A decrease in the relative amounts of C-OH bonds and an increase in the number of C C and C-N bonds in the C 1s spectra indicated that the reduction of GO to rGO and the surface functionalization of GO has taken place. The appearance of amine stretching bands, out-of-plane C-H stretching vibrations, and S = O stretching bands in the infrared spectra indicated the formation of DA-GO, rGO, and SDS-rGO, respectively. Low concentrations (3-25 ug/mL) of GO, rGO, and SDS-rGO were found to be mildly toxic, whereas DA-GO exhibited severe dose-dependent toxicity over the same concentration range. High concen- trations (50-400 ug/mL) of GO and all its derivatives resulted in severe toxicity to the A549 cells. It is believed that surface functionality strongly affects the viability of A549 cells. PMID- 26413622 TI - Three Arginine-Rich Cell-Penetrating Peptides Facilitate Cellular Internalization of Red-Emitting Quantum Dots. AB - Nanoparticles, such as semiconductor quantum dots (QDs), have been found increasing use in biomedical diagnosis and therapeutics because of their unique properties, including quantum confinement, surface plasmon resonance, and superparamagnetism. Cell-penetrating peptides (CPPs) represent an efficient mechanism to overcome plasma membrane barriers and deliver biologically active molecules into cells. In this study, we demonstrate that three arginine-rich CPPs (SR9, HR9, and PR9) can noncovalently complex with red light emitting QDs, dramatically increasing their deliv- ery into living cells. Zeta-potential and size analyses highlight the importance of electrostatic interactions between positive-charged CPP/QD complexes and negative-charged plasma membranes indicating the efficiency of transmembrane complex transport. Subcellular colocalization indicates associations of QD with early endosomes and lysosomes following PR9-mediated delivery. Our study demonstrates that nontoxic CPPs of varied composition provide an effective vehicle for the design of optimized drug delivery systems. PMID- 26413623 TI - The Effect of Hydrophobin Protein on Conductive Properties of Carbon Nanotube Field-Effect Transistors: First Study on Sensing Mechanism. AB - Hydrophobin is a surface active protein having both hydrophobic and hydrophilic functional domains which has previously been used for functionalization and solubilization of graphene and carbon nanotubes. In this work, field-effect transistors based on single nanotubes have been employed for electronic detection of hydrophobin protein in phosphate buffer solution. Individual nanotubes, single and multiwalled, are characterized by atomic force microscopy after being immersed in protein solution, showing a relatively dense coverage with hydrophobin. We have studied aspects such as nanotube length (0.3-1.2 um) and the hysteresis effect in the gate voltage dependent conduction. When measured in ambient condition after the exposure to hydrophobin, the resistance increase has a strong dependence on the nanotube length, which we ascribe to mobility degradation and localization effects. The change could be exceptionally large when measured in-situ in solution and at suitable gate voltage conditions, which is shown to relate to the different mechanism behind the hysteresis effect. PMID- 26413624 TI - Differential Expression of Mir-1 26 and Vascular Endothelial Growth Factor in Retinal Cells of Metabolic Acidosis-Induced Neonatal Rats. AB - In present study, we aimed at investigating the expression level of microRNA and the related gene which might be involved in retinopathy of prematurity. Neonatal SD rats were randomly divided into 2 groups, the first one having rats with NH4CI induced acidosis, as experimental group. We observed retinal vascular morphology and hyperplasia using microscope, for both experimental and control groups, in days 3, 5, 8, 10, 13 and 20 after birth. Total RNA from the retinal samples was obtained at each time point. MiR-126 and VEGF mRNA were measured by quantitative RT-PCR, while immunohistochemistry was applied to analyze the protein expression level of VEGF. Results showed significant differential expression of miR-126 in the acidosis-induced neonatal rats at day 8 when compared with control rats. The VEGF mRNA and protein quantitative results also demonstrated corresponding differential expression among the experimental and control groups. Results from this study revealed that VEGF mRNA and protein expression levels increased in day 10, while the expression of miR-126 was remarkably down-regulated. It is thus suggested that the miR-126 plays an important role in the development of acidosis induced retinopathy. PMID- 26413625 TI - Effect of Radix Trichosanthis and Trichosanthin on Hepatitis B Virus in HepG2.2.15 Cells. AB - Radix Trichosanthis is a Chinese herbal medicine that has great medical value and pharmacological actions. There is already a long history of using the plant Radix Trichosanthis as treatment for hepatitis B virus in China. This research mainly focused on investigating the therapeutic effect of different extracts from Radix Trichosanthis on hepatitis B virus, on a cellular level (ex vivo). Cell survival rate of HepG2.2.15 cells was detected by MTT assay. HBsAg and HBeAg in HepG 2.2.15 cell supernatant were evaluated by enzyme linked immunosorbent assay (ELISA). Results showed that water extract from Radix Trichosanthis had a stronger inhibitive effect on expression of HBsAg and HBeAg in HepG2.2.15 cells than the alcohol extract from the same plant. Considering that the most active component of Radix Trichosanthis was in its aqueous extract and this might be related to the active component Trichosanthin. Trichosanthin was further used for related experiments to confirm this hypothesis. The results showed that Trichosanthin, in the aqueous extract from Radix Trichosanthis, is likely the main component responsible for the anti-hepatitis B viral effect. PMID- 26413626 TI - Kinetics of Ultrasonic Drug Delivery from Targeted Micelles. AB - To minimize the adverse side effects of conventional chemotherapy, a targeted micellar drug carrier was investigated that retains hydrophobic drugs in its core and then releases the drug via ultrasonic activation. This paper compares the percent drug release from folated versus non-folated micelles by insonation at 70 kHz and different acoustic power densities. The encapsulated drug is Doxoru- bicin (Dox). A physical model of zero-order release with first-order re encapsulation was used to fit the experimental kinetic data. Additionally, the acoustic activation power density and Gibbs free energy were introduced and calculated for folated and non-targeted micelles. The data suggests an important role of inertial cavitation in drug release and the presence of a power density threshold for inertial cavitation. PMID- 26413628 TI - Atmospheric-Pressure Plasma Interaction with Soft Materials as Fundamental Processes in Plasma Medicine. AB - Molecular-structure variation of organic materials irradiated with atmospheric pressure He plasma jet have been investigated. Optical emission spectrum in the atmospheric-pressure He plasma jet has been measured. The spectrum shows considerable emissions of He lines, and the emission of O and N radicals attributed to air. Variation in molecular structure of Polyethylene terephthalate (PET) film surface irradiated with the atmospheric-pressure He plasma jet has been observed via X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FT-IR). These results via XPS and FT-IR indicate that the PET surface irradiated with the atmospheric-pressure He plasma jet was oxidized by chemical and/or physical effect due to irradiation of active species. PMID- 26413627 TI - Toxicity of Raw and Purified Single-Walled Carbon Nanotubes in Rat's Lung Epithelial and Cervical Cancer Cells. AB - The increased applications of carbon nanotubes in the field of drug delivery, bioimaging and biosensors demand nanotubes to be of highest purity, free from metallic impurities and amorphous carbon. All of these sectors require a profound investigation about the toxic effects on human and the environment. Many attempts have been made to purify and surface modify the carbon nanotubes, however a detailed study on the raw and purified material has yet to be conducted. Here we present the toxicity studies of raw and the purified single-walled carbon nanotubes in rat's lung epithelial cell and cervical cancer cells (HeLa). These cells were treated with increasing concentration of 0.5 ug/mL to 50 ug/mL and the various biocompatibility assays were performed. The results showed an increased cell death with purified single-walled carbon nanotubes followed by the depletion of antioxidant levels and activation of the caspase cascade at a rapid rate compared to raw single-walled carbon nanotubes. This suggests that purified single walled carbon nanotubes are more toxic to the cells and exhibit ultra-fine particulate matter like toxicity. PMID- 26413629 TI - Plasma Interaction with Organic Molecules in Liquid as Fundamental Processes in Plasma Medicine. AB - Investigation of plasma-organic materials interaction in aqueous solution with atmospheric pressure plasmas have been carried out. Degradation of methylene blue (MB) in aqueous solution via atmospheric pressure He plasma exposure through gas/liquid interface have been investigated. The optical emission spectrum shows considerable emissions of He lines and the emission of O, OH and N radicals attributed to dissociation of water (H2O) and air has been confirmed. Structure variation of MB in solution treated with the atmospheric-pressure He plasma has been measured by Fourier transform infrared spectroscopy (FT-IR). The results obtained from FT-IR analysis show degradation of MB in solution treated with the atmospheric-pressure He plasma. The pH effect of MB degradation was investigated using controlled pH solutions by an ultraviolet-visible (UV-Vis) spectroscopy and FT-IR. The results show no effect of MB degradation on pH. The results exhibit that the atmospheric pressure plasmas exposure has made it possible to degrade organic materials in solution due to irradiated radicals from plasma through plasma/liquid interface. PMID- 26413630 TI - Integration of Peptides for Enhanced Uptake of PEGylayed Gold Nanoparticles. AB - Polyethylene glycol (PEG) has promoted the prospective applications of nanoparticles (NPs) in cancer therapy. PEG is used to evade the immune system allowing NPs accumulation within the tumor using its leaky vasculature. However, the cellular uptake of PEG-coated (PEGylated) NPs is lower in comparison to non PEGylated NPs since PEG minimizes surface binding of ligands that mediate NP endocytosis. For improved outcome in therapeutic applications, it is necessary to enhance the uptake of PEGylated NPs. We added a peptide containing an integrin binding domain known as the RGD sequence to the NP surface in addition to PEG. We used gold NPs (GNPs) of sizes 14, 50, and 70 nm in this study. Our in vitro data for HeLa cells show enhanced uptake for NPs coated with both PEG and the peptide in comparison to PEGylated GNPs. NPs of size 50 nm had the highest uptake among the three sizes for all GNP surfaces. A similar size-dependent trend was observed for MDA-MB-231 cells for as-made GNPs with lower uptake in comparison to HeLa cells. However, only 14 nm peptide-modified PEGylated NPs had enhanced uptake. Hence, NP uptake was found dependent on cell type and NP surface properties. A properly designed NP system with both PEG and cell membrane targeting peptides can be used to protect it from the immune system and promote internalization by cells upon entry into tumor environment. PMID- 26413631 TI - Differentially Expressed miRNA in Inflammatory Mucosa of Chronic Rhinosinusitis. AB - Chronic sinusitis (chronic rhinosinusitis, CRS) is a chronic inflammatory disease of the nasal cavity and paranasal sinuses, pathogenesis of which is not yet completely elucidated. MicroRNA has been shown to extensively be involved in immune response. To analyze the differential expression of miRNAs in chronic sinusitis, with or without nasal polyps (nasal polyps, NP), seven miRNAs (miR- 181b, miR-26b, miR-155, miR-146a, miR-125b, miR-124 and miR-92a) that are associated with inflammation were selected to be quantifying by RT-qPCR in 40 clinical samples and 5 controls. When compared to the normal control group, results showed that, in all patients with CRS, miR- 125b, miR-155 and miR-146a were up-regulated (P < 0.05), while miR-92a, miR-26b and miR- 181b were down regulated (P < 0.05). MiR124 expression levels were not found to have significant changes. In relation to CRS without NP, miR-125b and miR-155 were significantly up-regulated while miR-92a, miR-26b, miR-181b were down-regulated in NP patients. Furthermore, the miR-92a and miR-26b expression levels were significantly reduced while miR-146a and miR124 expression levels had no significant changes in the NP samples. The RT-qPCR results indicate that the miRNAs were differentially expressed in CRS patients and various inflammation severities could lead to this difference. The results from this study may further reveal the relationship between miRNA expressions and inflammation. These results can also provide an important mechanism (primitive data) on the occurrence of chronic sinusitis and nasal polyps. PMID- 26413632 TI - Copper Oxide Nanoparticles Reduce Vasculogenesis in Transgenic Zebrafish Through Down-Regulation of Vascular Endothelial Growth Factor Expression and Induction of Apoptosis. AB - The present study investigated the effects of exposure to metal oxide nanoparticles on vasculogenesis/angiogenesis using transgenic zebrafish. The study also examined the potential mechanisms involved in those effects using human umbilical vein endothelial cells (HUVEC). TG (nacre/fli1:EGFP) zebrafish were exposed to nano-sized titanium dioxide (TiO2), silica dioxide (SiO2), and copper oxide (CuO) particles at 0.01, 1 and 100 ug/ml concentrations from 1 to 5 dpf (day-post-fertilization). Angiogenesis was evaluated morphologically at the end of exposure. Exposure to CuO nanoparticles reduced the number of transversely running subintestinal vessels in TG zebrafish. Exposure to CuO nanoparticles down regulated the expression of vascular endothelial growth factor (VEGF) and VEGF receptor in endothelial cells sorted by Fluorescence Activated Cell Sorter (FACS). Exposure of HUVEC to CuO nanoparticles reduced cell viability and increased apoptotic index in a dose-dependent manner. The results suggested that CuO nanoparticles inhibit vasculogenesis through reduction of VEGF expression and induction of apoptosis. PMID- 26413633 TI - Polyethylene Films Containing Silver Nanoparticles for Applications in Food Packaging: Characterization of Physico-Chemical and Anti-Microbial Properties. AB - This paper reports the antibacterial effect and physico-chemical characterization of films containing silver nanoparticles for use as food packaging. Two masterbatches (named PEN and PEC) con- taining silver nanoparticles embedded in distinct carriers (silica and titanium dioxide) were mixed with low-density polyethylene (LDPE) in different compositions and extruded to produce plain films. These films were characterized by Scanning Electron Microscopy (SEM), X ray diffraction (XRD), Differential Scanning Calorimetry (DSC), Thermogravimetric analysis (TGA) and Fourier Transform Infrared Spectroscopy (FTIR). The morphology of the films showed the formation of agglomerates of nanoparticles in both PEN and PEC composites. X-ray analyses confirmed the presence of SiO2 in PEN samples and TiO2 in PEC samples. Thermal analyses indicated an increase in thermal stability of the PEC compositions. The antimicrobial efficacy was determined by applying the test strain for Escherichia coli and Staphylococcus aureus, according to the Japanese Industrial Standard Method (JIS Z 2801:2000). The films analyzed showed antimicrobial properties against the tested microorganisms, presenting better activity against the S. aureus than E. Coli. These findings suggest that LDPE films with silver nanoparticles are promising to provide a significant contribution to the quality and safety of packaged food. PMID- 26413634 TI - Copper Phthalocyanine Functionalized Single-Walled Carbon Nanotubes: Thin Films for Optical Detection. AB - Thin films of non-covalently hybridized single-walled carbon nanotubes (SWCNT) and tetra-substituted copper phthalocyanine (CuPcR4) molecules have been produced from their solutions in dimethylformamide (DMF). FTIR spectra revealed the 7pi 7pi interaction between SWCNTs and CuPcR4 molecules. DC conductivity of films of acid-treated SWCNT/CuPcR4 hybrid has increased by more than three orders of.magnitude in comparison with conductivity of CuPcR4 films. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) measurements have shown that films obtained from the acid-treated SWCNTs/CuPcR4 hybrids demonstrated more homogenous surface which is ascribed to the highly improved solubility of the hybrid powder in DMF Using total internal reflection ellipsometry spectroscopy (TIRE), thin films of the new hybrid have been examined as an optical sensing membrane for the detection of benzo[a]pyrene in water to demonstrate the sensing properties of the hybrid. PMID- 26413635 TI - Subband Structure and Effective Mass in the Inversion Layer of a Strain Si-Based Alloy P-Type MOSFET. AB - In this paper, the subband structure and effective mass of an Si-based alloy inversion layer in a PMOSFET are studied theoretically. The strain condition considered in our calculations is the intrinsic strain resulting from growth of the silicon-carbon alloy on a (001) Si substrate and mechanical uniaxial stress. The quantum confinement effect resulting from the vertically effective electric field was incorporated into the k . p calculation. The distinct effective mass, such as the quantization effective mass and the density-of-states (DOS) effective mass, as well as the subband structure of the silicon-carbon alloy inversion layer for a PMOSFET under substrate strain and various effective electric field strengths, were all investigated. Ore results show that subband structure of relaxed silicon-carbon alloys with low carbon content are almost the same as silicon. We find that an external stress applied parallel to the channel direction can efficiently reduce the effective mass along the channel direction, thus producing hole mobility enhancement. PMID- 26413636 TI - A Resultant Stress Effect of Contact Etching Stop Layer and Geometrical Designs of Poly Gate on Nanoscaled nMOSFETs with a Si1-xGe(x) Channel. AB - In this research, an n-type metal-oxide-semiconductor field effect transistor (nMOSFET) device with a SiGe channel exerted by the combination of a contact etching stop layer (CESL) and silicon germanium (Si1-xGe(x)) channel stressors is proposed. To explore the foregoing mechanical effect on the stress distribution of nMOSFETs within the channel region, a process-oriented simulated technique is adopted for the concerned nMOSFET device. The loading sources are a 1.1 GPa tensile CESL (t-CESL) and a SiGe channel structure constructed with 0%, 22.5%, and 25%, germanium (Ge) mole fractions. The results of the simulation show that the stress components of the Si1-xGe(x) channel evidently increase when the Ge mole fraction within a Si1-xGe(x) layer is increased. A pulling force exerted on the protruding gate structure by the CESL layer that causes dominant bending deformation and channel stress variation behaviors is a major reason for this phenomenon. Therefore, the degree of bending effect caused by the protruding gate structure is concluded as being the key to determining the trends and stress magnitudes of the Si1-xGe(x) device channel. PMID- 26413637 TI - Structural Optimizations of Silicon Based NMOSFETs with a Sunken STI Pattern by Using a Robust Stress Simulation Methodology. AB - As the strained engineering technology of metal-oxide-semiconductor field effect transistors (MOSFET) is scaled beyond the 22 nm node critical dimension, shallow trench isolation (STI) becomes one of the most important resolutions for isolate devices to enhance the carrier mobility of advanced transistors. Several key design factors of n-type MOSFET (NMOSFET) under the resultant loadings of STI structures and contact etching stop layers are sensitively analyzed for silicon channel stress via finite element method-based simulations integrated with the use of design of experienmnts. NMOSFETs with 15 nm deep sunken STI have achieved a ~5% mobility enhancement as compared with a regular STI shape. By adopting simulation-based factorial designs, we have determined that the design factor of recess depth in STI is a critical factor influencing device performance. Moreover, a response surface curve on carrier mobility of NMOSFET under a consideration of combining the sunken STI and source/drain lengths is further presented in this research. PMID- 26413638 TI - Annealing Dependence of Solution-Processed Ultra-Thin ZrOx Films for Gate Dielectric Applications. AB - Ultra-thin ZrOx thin films on Si substrates were prepared by sol-gel technique and processed with different methods (baked on hot plate at 150 degrees C, annealed at 500 degrees C in furnace, and photo-annealed under UV light). The decomposition of the organic groups and the formation of Zr-O bonding in the ZrOx thin films were confirmed by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. It is found that the ZrOx thin film annealed under UV light shows decent characteristics, including an ultra-small surface roughness, a low leakage current density of 10(-9) A/cm2 at 1 MV/cm, a large breakdown electric field of 9.5 MV/cm, and a large areal capacitance of 775 nF/cm2. PMID- 26413639 TI - Atmospheric-Pressure Gas-Breakdown Characteristics with a Radio-Frequency Voltage. AB - We present He atmospheric-pressure gas-breakdown phenomena with radio frequency (RF) voltages in the frequency region from a few tens MHz to 100 MHz. The gas breakdown voltage for RF and very high frequency (VHF) discharges is considerably lower than that for the DC discharge, and the gas-breakdown voltage is effectively reduced to be as low as 160 V in VHF region. The discharge characteristics drastically change with increasing discharge-voltage frequency, and strong emisson is highly loclized in front of the power- and ground-electrode in the VHF discharges. The lowering gas-brakdown voltage and the localized emission-profile are well explained by the effect of the charged-particle confinement in a micro dishcarge-space. PMID- 26413640 TI - Effects of Annealing on the Microstructures and UV and Visible Light-Induced Photocatalytic Activities of Indium Hydroxide Nanocubes. AB - This work initiated a systematic study on the thermal treatment for In(OH)3 photocatalysts and its impact on their microstructures and photocatalytic properties. The phase transformation process from In(OH)3 to In2O3 was investigated by XRD, TG, DRS and ion etching XPS technologies. The results demonstrated that the formation of In2O3 phase occurred from surface to inside of bulk In(OH)3 and a heterojunction structure between In2O3 and In(OH)3 was formed. The variation of textural properties and the formation of heterojunction structure were crucial for the enhanced UV-light photocatalytic activities for RhB degradation, while the visible-light photocatalytic activity was mainly associated with the enhancement of the visible light absorbance capacity deriving from surfaced In2O3. The results may be extended to comprehend the structure property correlations of hydroxide-containing photocatalysts and help to explore highly efficient photocatalysts towards thermal decomposition. PMID- 26413641 TI - Effect of Blend Composition on Binary Organic Solar Cells Using a Low Band Gap Polymer. AB - This report investigates the influence of the solution blend composition of binary bulk heterojunction organic solar cells composed of poly(2,1,3 benzothiadiazole-4,7-diyl[4,4-bis(2-ethylhexyl)-4H- cyclopenta[2,1-b:3,4 b'dithiophene-2,6-diy]] (PCPDTBT) and [6,6]-phenyl C71 butyric acid methyl ester (PC71BM). The blend polymer:fullerene composition was varied from 1:1 (50 wt% PC71 BM) to 2:9 (82 wt% PC71 BM). Increasing the amount of polymer in the blend results in the greatest overall absorption, as the donor material PCPDTBT is the main contributor to absorption. However, high polymer content leads to poor photovoltaic performance. For this material combination, the optimum blend polymer:fullerene composition was found to be 2:7. Increasing the fullerene content in the blend led to a significant improvement in the internal quantum efficiency of devices. This was correlated with an increase of the electron mobility, as the fullerene content was increased. Improved electron transport, leading to more balanced transport between electrons and holes, significantly improved the short circuit current density (Jsc) and fill factor (FF). PMID- 26413642 TI - Fabrication and Characterization of Electronic and Optical Properties of Polyaniline Nanopatterns. AB - The authors conducted polyaniline (HA) polymerization on a micro-scale patterned Si water and nano-scale patterned Al surface. Polymerization was performed using a microliter solution droplet made of aniline, HCI and oxidation agent ammonium peroxodisulfate (APS). The droplet was dropped on a flat Si wafer, a micro patterned Si wafer and a nanostructured Al surface. The SEM image showed that PA was densely polymerized on the circle edge of the dropped 1 mm sized droplet on the flat Si wafer because of large surface tension due to the flat surface. On the other hand, a droplet was broken on a circular trench pattern of 100 um in diameter fabricated on a Si wafer. The width and depth of the trench were 1 um and 1 um, respectively. Tree-like polymer was intensively polymerized along the circular trench. Droplet was also dropped on a lattice trench pattern whose pitch was 10 um. The width and the depth of the trench were 1 um and 1 um, respectively. The SEM image showed that dots of PA were fabricated along the trenches. Far smaller dots of PA were also observed on the flat area of the lattice. Thus, micro-scale structure affects the shape and size of PA in polymerization. Nanoscopic polymerization of PA was conducted locally in a nanoscale highly-oriented line pattern with nanoscale trenches formed on an Al surface. One of the characteristic fabricated patterns was a highly conductive PA line pattern whose pitch was 100 nm. In this case, point-contact IV characteristic measurement, step-like curve was observed. PL spectra of the PA line-pattern exhibited significantly enhanced emission peaks at 380, 450 anc 550 nm due to PA which were overlapped by the rippled PL pattern due to the Al nanostructure. PMID- 26413643 TI - Numerical Study on the Particle Trajectory Tracking in a Micro-UV Bio Fluorescence Sensor. AB - A micro-UV bio-fluorescence sensor was developed to detect primary biological aerosols including bacteria, bacterial spores, fungal spores, pollens, viruses, algae, etc. In order to effectively detect the bio-particles in a micro-UV bio fluorescence sensor, numerical calculations were performed to adjust for appropriate flow conditions of the sensor by regulating the sample aerosols and sheath flow. In particular, a CFD-based model of hydrodynamic processes was developed by computing the trajectory of particles using commercially available ANSYS CFX-14 software and the Lagrangian tracking model. The established model was evaluated with regard to the variation of sheath flow rate and particle size. Results showed that the sheath flow was changed rapidly at the end of nozzle tip, but the sample particles moved near the center of aerosol jet for aerodynamic focusing with little deviation from the axis. PMID- 26413644 TI - Near Band Edge Emission by Free Exciton Decay and Intrinsic Ferromagnetic Ordering of Cu-Doped SnO2 Hollow Nanofibers. AB - High quality nanocrystalline pristine and Cu-doped SnO2 hollow nanofibers were successfully prepared through simple and effective electrospinning technique. Nanofibers calcined at 600 degrees C for 3 h were characterized with different analytical techniques such as X-ray diffraction (XRD), Transmission electron Microscope (TEM) and Vibrating sample magnetometer (VSM). Observed TEM images and XRD patterns were corroborate to the formation of tetragonal crystalline SnO2 hollow nanofibers with rutile phase. Excellent optical behaviour was observed for Cu-doped SnO2. Highly intense near band edge emission at 3.58 eV for Cu-doped SnO2 evidences the free exciton decay process in the hollow nanofibers. For the first time we have reported here the near band edge PL emission in Cu-doped SnO2 tubular hollow nanostructure. This study substantiates that material potential for UV-lasing application. In addition to the above, magnetic measurement ascribes that Cu-doped SnO2 exhibit the intrinsic room temperature ferromagnetism within the low field strength. The occurrence of ferromagnetism in Cu-doped SnO2 is directly related to the p-d ferromagnetic exchange coupling between the local magnetic moment of Cu2+ and the polarized valence electrons of surrounding oxygen. Over all this study provides the primary information about tunable multifunctionality of SnO2 hollow nanostructures by adding the non-magnetic Cu ions. PMID- 26413645 TI - Plasmonics Resonance Enhanced Active Photothermal Effects of Aluminum and Iron Nanoparticles. AB - Localized Surface Plasmonics Resonance (LSPR) enhanced active photothermal effects of both aluminum nanoparticles (Al NPs) and iron nanoparticles (Fe NPs) are experimentally observed. Photothermally activated motion and ignition by low energy xenon flash are quantitatively measured. For nanoparticles of comparable sizes, photothermally activated motion height of Fe NPs is about 60% lower than that of Al NPs, while photothermal Minimum Ignition Energy (MIE) of Fe NPs is about 50% lower than that of Al NPs. Joule heating by LSPR enhanced photothermal effects among nanoparticles and subsequently triggered oxidation reactions are found responsible for the motion and ignition of the nanoparticles. PMID- 26413646 TI - Boron Doped Nanocrystalline Film with Improved Work Function as a Buffer Layer in Thin Film Silicon Solar Cells. AB - We investigated thin film silicon solar cells with boron doped hydrogenated nanocrystalline silicon/ hydrogenated amorphous silicon oxide [p-type nc-Si:H/a SiOx:H] layer. First, we researched the bandgap engineering of diborane (B2H6) doped wide bandgap hydrogenated nanocryslline silicon (p-type nc-Si:H) films, which have excellent electrical properties of high dark conductivity, and low activation energy. The films prepared with lower doping ratio and higher hydrogen dilution ratio had higher optical gap (Eg), with higher dark conductivity (sigma(d)), and lower activation energy (Ea). We controlled Eg from 2.10 eV to 1.75 eV, with sigma(d) from 1.1 S/cm to 7.59 x 10(-3) S/cm, and Ea from 0.040 eV to 0.128 eV. Next, we focused on the fabrication of thin film silicon solar cells. By inserting p-type nc-Si:H film into the thin film silicon solar cells, we achieved a remarkable increase in the built-in potential from 0.803 eV to 0.901 eV. By forming p-type nc-Si:H film between SnO2:F/ZnO:Al (30 nm) and p-type a-SiOx:H layer, the solar cell properties of open circuit voltage (Voc), short circuit current density (Jsc), and efficiency (eta) were improved by 3.7%, 9.2%, and 9.8%, respectively. PMID- 26413647 TI - Investigation of Electrical and Optical Properties of Highly Transparent TCO/Ag/TCO Multilayer. AB - Transparent conductive oxides (TCOs) have been widely used as transparent electrodes for opto-electronic devices, such as solar cells, flat-panel displays, and light-emitting diodes, because of their unique characteristics of high optical transmittance and low electrical resistivity. Among various TCO materials, zinc oxide based films have recently received much attention because they have advantages over commonly used indium and tin-based oxide films. Most TCO films, however, exhibit valleys of transmittance in the wavelength range of 550-700 nm, lowering the average transmittance in the visible region and decreasing short-circuit current (Isc) of solar cells. A TCO/Ag/TCO multi-layer structure has emerged as an attractive alternative because it provides optical characteristics without the valley of transmittance compared with a 100-nm-thick single-layer TCO. In this article, we report the electrical, optical and surface properties of TCO/Ag/TCO. These multi-layers were deposited at room temperature with various Ag film thicknesses from 5 to 15 nm while the thickness of TCO thin film was fixed at 40 nm. The TCO/Ag/TCO multi-layer with a 10-nm-thick Ag film showed optimum transmittance in the visible (400-800 nm) wavelength region. These multi-layer structures have advantages over TCO layers of the same thickness. PMID- 26413648 TI - Synthesis and Electrochemical Properties of LiFePO4/C for Lithium Ion Batteries. AB - LiFePO4/C was prepared through a facile rheological phase reaction method by using Fe3(PO4)2, Li3PO4 . 8H2O, and glucose as reactants. The LiFePO4/C samples were characterized by X-ray diffraction, scanning electron microscopy, and thermogravimetric analysis. The electrochemical properties of the samples were investigated. The results show that the LiFePO4/C samples have single-phase olivine-type structure, and their particles feature a spherical shape. The carbon coating on the particles of LiFePO4 is about 1.8% of the LiFePO4/C by weight. The particle size was distributed from 0.2 to 1 um. The initial discharge capacity of LiFePO4/C reached 154 mA h/g at 0.1 C. The retained discharge capacity of LiFePO4/C was 152.9 mA h g(-1) after 50 cycles. The LiFePO4/C also showed better cycling performance than that of the bare LiPeO4 at a higher charge/discharge rate (1 C). The LIFePO4/C prepared in this way could be a promising cathode material for lithium ion battery application. PMID- 26413649 TI - Catalytic Performance of La0.8K0.2Fe0.7Mn0.3O3 with Pt-Substitution in B-Site for Removal of NOx and Soot. AB - Nanocrystalline, porous, perovskite La0.8K0.2Fe0.69Mn0.3Pt0.01O3, La0.8K0.2Fe0.67Mn0.3Pt0.03O3, La0.8K0.2Fe0.65Mn0.3Pt0.05O3 catalysts were prepared by the citrate-gel process. The optimized chemical composition La0.8K0.2Fe0.67Mn0.3Pt0.03O3 has a porous structure and it shows a good activity for soot combustion, with T20, T50 and T90 being 149, 367 and 409 degrees C, respectively. Furthermore, the La0.8K0.2Fe0.67Mn0.3Pt0.03O3-coated honeycomb ceramic device was prepared by the citrate-gel assisted dip-coating process and it has the effect of simultaneous removal of diesel soot and nitrogen oxides at the operational temperature range of 200 to 400 degrees C, with a NOx maximum conversion rate of 21.2%. It seems that the perovskite structure benefits the activity of low Pt content due to higher contribution of lattice oxygen and local changes in redox reaction. PMID- 26413650 TI - Synthesis and Characterization of Polyvinylpyrrolidone Silica Core-Shell Nanocomposite Particles. AB - In this work, a novel and facile strategy for making a new type of polymer/silica nanocomposte particle was proposed. Colloidally stable polyvinypyrrolidone (PVP)/silica core-shell nanocomposite particles have been successfully synthesized using an azo initiator via seed polymerization of N-vinyl-2 pyrrolidone (NVP) and VFSs (VFSs) that were derived from vinyl triethoxysilane (VTES). It was suggested from the FTIR and TGA analysis that the copolymerization reaction of NVP with VFSs has been thoroughly carried out. In addition, SEM images showed that PVP/silica nanocomposite particles have relatively rough surface due to surface polymerization in comparison with VFSs. Furthermore, TEM results proved that the size of VFSs had considerable effects on the appearance of PVP/silica nanocomposite particles. Generally, it presented that several silica nanoparticle cores with an average size of 78 nm mainly pack together within each nanocomposite particle after seed polymerization. Interestingly, the average shell thickness was 59 nm for most PVP/silica nanocomposite particles with cores about 242 nm. However, when the core size was large enough to about 504 nm, a series of PVP/silica nanocomposite particles with a relative thin shell were observed. PMID- 26413651 TI - Indium Tin Oxide Nanoparticles/Vaseline Nanocomposites: Preparation of Nanoelectrode Assembles with Tunable Dimensions. AB - In this paper, we describe a novel approach for fabricating tailor-made indium tin oxide nanoelectrode assembles (ITO-NEAs) based on indium tin oxide nanoparticles (ITONPs) as conducting materials and vaseline as insulating binder. ITO nanoelectrode assembles were formed on the surface of a glassy carbon electrode (GCE) by uniformly covering GCE with ITONPs/vaseline nanocomposite. Cyclic voltammetry (CV) studies demonstrated that the ITO-NEAs exhibit fast mass transport and low charging current, suggesting that the ITO-NEAs, fabricated with ITONPs and vaseline hybrid film coating, behave like a microelectrode array. Furthermore, electrochemical results show the as-prepared ITONPs electrodes have tunable dimensions, ranging from a conventional electrode to a nanoelectrode ensemble, depending on the amount of insulting vaseline dissolved in the ITO NPs/acetone dispersion. As novel kind of ITONPs-based film electrodes with tunable dimensions and good electrochemical activity, the ITO film electrodes are very attractive for potential application in fundamental and practical electrochemical studies. PMID- 26413652 TI - Field Emission from Zinc Oxide Nanobelts. AB - We report here, the in-situ field emission (FE) property measurement on the individual ZnO nanobelts inside a high resolution transmission electron microscope (TEM) using a special scanning tunneling microscopy (STM)-TEM system. The field emission properties were found to be size scale dependent. It was found that the threshold voltage decreases and the field enhancement factor increases with the decrease in the diameter of the tip of the nanobelt and increase in the sharpness of the tip. The field emission parameter was estimated following the Fowler-Nordheim (F-N) theory. The ZnO nanobelt with the sharp agave like tip structure (d = 10 nm) showed the highest value of the field enhancement factor, beta ~ 4562, and a high field emission current of ~ 502 uA. PMID- 26413653 TI - High-Temperature Cross-Linking of Carbon Nanotube Multi-Yarn Using Polyvinylpyrrolidone as a Binding Agent. AB - Carbon nanotube (CNT) multi-yarn was cross-linked together at elevated temperatures using a poly- mer, with the intent of improving their strength and electrical conductivity. They were functionalized using an acid treatment and immersed in a bath of different concentrations (0.5%, 0.1%, and 0.2%) of polyvinylpyrrolidone (PVP). Then they were placed in an oven at various temperatures (180 degrees C, 200 degrees C, and 220 degrees C) in order to cause cross-linking among the carbon nanotube yarns. The phys- ical, chemical, electrical, and mechanical properties of the cross-linked yarns were investigated. The yarns cross-linked at higher temperatures and greater concentrations of PVP had a greater increase in linear mass density, indicating that the cross-linking process had worked as expected. Yarns that were cross linked at lower temperatures had greater tensile strength and better spe- cific electrical conductivity. Those that were treated with a greater concentration of polymer had a greater ultimate tensile strength. All these results are encouraging first step, but still need further development if CNT yarn is to replace copper wire. PMID- 26413654 TI - Spectroscopic Characteristics of Three Dimensional Split-Ring Resonator Arrays at Terahertz Frequencies. AB - In this work, three-dimensional, stacked arrays of subwavelength, square, dual, concentric split ring resonators exhibiting characteristics at the Terahertz frequencies have been designed, simulated, and fabricated through a photolithographic lift-off process and electron beam evaporation metal deposition. Characterization of the split-ring resonator arrays was performed by transmission mode Terahertz time domain spectroscopy. The effects of the split ring resonator unit cell spatial dimensions on resonant absorption frequencies and relative absorption strength are investigated as well as effects from the addition of a dielectric spacing layer and additional split-ring resonator layer. The split-ring resonator arrays were seen to develop two distinct and switchable LC resonances as well as a dipole resonance by measuring the arrays at 0 degrees and 90 degrees in-plane rotations about the terahertz propagation vector. The dielectric spacing layer served to effectively lower the resonant frequencies of the split-ring resonantors while the dual split-ring resonator array was seen to have a slight modulating effect on the absorption strength at the resonant frequencies compared to that of the passivated array without the second layer. PMID- 26413655 TI - Crystalline Fraction and Doping Concentration Effect on Heterojunction Solar Cells n-Doped uc-Si:H Back Surface Field Layer. AB - The back surface field (BSF) plays a vital role for high efficiency in the Heterojunction Intrinsic Thin (HIT) film solar cell. This paper investigated the effect of crystalline volume fraction (Xc) and 1% hydrogen diluted phosphine (PH3) gas doping concentration of the n-type uc-Si:H back surface file (BSF) layer. Initially, the thickness of the n-type uc-Si:H BSF layer was optimized. With increase in Xc from 6% to 59%, the open circuit voltage (Voc) increased from 573 mV to 696 mV, and the fill factor (FF) also increased from 59% to 71%. In the long wavelengths region (>= 950 nm), the QE of the solar cells decreased over the optimized Xc of the n-doped micro BSF layer, due to the defects of a film. In the second part of this paper, the effect of high conductivity n-type uc-Si:H BSF layer with optimized thickness on the performance of HIT solar cells was investigated, by doping gas ratio variation. Even though Xc decreased, conductivity was increased, with increasing PH3 doping concentration. Under the optimized condition, a n-uc-Si:H BSF layer has a dark conductivity of 2.59 S/cm, activation energy of 0.0519 eV, and X, of 52%. The conversion efficiency of 18.9% was achieved with a Voc of 706 mV, fill factor of 72%, and short circuit current density of 37.1 mW.cm(-2). PMID- 26413656 TI - Microwave Band-Pass Filter with Aerosol-Deposited Al2O3-Polytetrafluoroethylene Composite Thick Films. AB - Fabrication of microwave band-pass filter with coplanar waveguide with ground structure was realized by employing Al2O3-polytetrafluoroethylene (Al2O3-PTFE) composite thick films for integrated substrates produced by aerosol deposition (AD). In order to predict the performance of the band-pass filter, 3-D electromagnetic simulations were performed by high-frequency structure analysis. The thick Al2O3-PTFE composite films prepared by the AD process had submicron sized Al2O3 crystallites due to the shock-absorbing effect of PTFE during the film growth. The thick films were characterized by X-ray diffraction and scanning electron microscopy. The Cu transmission lines with the thickness of 300 nm were deposited by electron-beam evaporation to form the band-pass filter. The fabricated band-pass filter showed similar characteristics to the simulation results. The insertion loss and resonance frequency were 9.5 dB and 2.3 GHz, respectively. PMID- 26413657 TI - Preparation and Phase Transfer of Hydrophobic CdSe-Based Quantum Dots. AB - Monodispersed CdTe(x)Se1-x and CdSe cores were synthesized via organic methods. The as-prepared cores were coated with a Cd(y)Zn1-yS shell by an epitaxial growth. Compared with the cores, an obvious red shift was observed in both the absorption and photoluminescence (PL) spectra of core-shell quantum dots (QDs) and the PL efficiency was improved. The CdSe-based core-shell QDs were transferred from oil to water phase by the encapsulation of amphiphilic polymers. The ligands of QDs, namely hexadecylamine (HDA) and oleic acid (OA), dramatically influenced the process of phase transfer. The process of phase transfer of HDA coated CdTe(x)Se1-x/CdyZn1-yS core-shell QDs was failed, however, the OA-coated CdSe/CdyZn1-yS core-shell QDs can be successfully transferred from oil to water phase. This is ascribed that the surface ligand HDA falls from CdTe(x)Se1 x/Cd(y)Zn1-yS core-shell QDs during the process of phase transfer, leading to non interaction between QDs and amphiphilic polymers. The effect of molecular weight of the poly(styrene-co-maleic anhydride) (PSMA) on the phase transfer was also investigated. For the QDs with the same size, the PSMA with high molecular weight exhibit a shorter time in the process of phase transfer compared with light molecular weight. Furthermore, the size of the QDs also affects the process of the phase transfer from oil to water phase. The smaller of the QDs, the shorter of the phase transfer time. PMID- 26413658 TI - Viscoelastic Properties of Poly[(butylene succinate)-co-adipate] Nanocomposites. AB - This article reports the viscoelastic properties of poly[(butylene succinate)-co adipate] (PBSA) nanocomposites. The nanocomposites of PBSA with various loadings of organically modified clay were prepared by melt-mixing in a batch-mixer. The solid and melt-state viscoelastic properties of neat PBSA and various nanocomposites were studied in detail. The dynamic mechanical studies demonstrated an increase in the storage modulus of PBSA matrix with organoclay loading. Melt-state rheological properties were found to be modified with organoclay loading changing from liquid-like, to gel-like and then viscoelastic solid-like. Such changes in viscoelastic properties along with the improvements in thermomechanical properties are expected to open opportunities for the use of PBSA extending its applications from the classical field of packaging to new niches such as tissue-engineering. PMID- 26413659 TI - Selective Laser Direct Patterning of Silver Nanowire Percolation Network Transparent Conductor for Capacitive Touch Panel. AB - We introduce a facile method to enhance the functionality of a patterned metallic transparent conductor through selective laser ablation of metal nanowire percolation network. By scanning focused nanosecond pulsed laser on silver nanowire percolation network, silver nanowires are selectively ablated and patterned without using any conventional chemical etching or photolithography steps. Various arbitrary patterns of silver nanowire transparent conductors are readily created on the percolation network by changing various laser parameters such as repetition rate and power. The macroscopic optical and electrical properties of the percolation network transparent conductor can be easily tuned by changing the conductor pattern design via digital selective laser ablation. Further investigation on the silver nanowire based electrode line prepared by the ablation process substantiates that the general relation for a conducting thin film fails at a narrow width, which should be considered for the applications that requires a high resolution patterns. Finally, as a proof of concept, a capacitive touch sensor with diamond patterns has been demonstrated by selective laser ablation of metal nanowire percolation network. PMID- 26413660 TI - Dynamic Properties of Helium Atmospheric Dielectric-Barrier-Discharge Plasma Jet. AB - We present here experiments on helium atmospheric dielectric-barrier discharge jet in open air. A long stable plasma plume is realized at high applied voltage and high gas flow rate. Optical emission measurements show that the plasma plume consists of two part: a plume head with high energy electrons and a tail part with low energy electrons. The plasma plume propagates away from the quartz-tube outlet with about 30-80 km/sec along the helium gas flow channel. The propagation velocity of plasma plume is in the time scale of electron drift velocity, and the electric field plays an important role as a driving force of the plasma plume propagation. PMID- 26413661 TI - Dielectric Properties of (Ca0.7Sr0.3)(Zr0.8Ti0.2)O3 Thin Films with Different Deposition Temperatures. AB - In this paper, (Ca0.7Sr0.3)(Zr0.8Ti0.2)O3 thin films were fabricated by RF sputtering at various deposition temperatures from 300 degrees C to 700 degrees C to determine the optimal deposition condition. The XRD data confirmed the successful fabrication of crystalline CSZT thin films. Based on the dielectric properties of the fabricated thin films, the optimal deposition temperature was 700 degrees C, which resulted in a film with a relatively high dielectric constant and low dielectric loss (28.4 and 0.006) (at 1 MHz). Moreover, the CSZT thin film deposited at 700 degrees C showed stable dielectric properties at microwave frequencies. With increasing deposition temperature, the roughness of the CSZT thin film increased but the leakage current of the CSZT thin film decreased, simultaneously. PMID- 26413662 TI - Microwave Sintering of Silver Nanoink for Radio Frequency Applications. AB - Microwave sintering is a promising method for low-temperature processes, as it provides advantages such as uniform, fast, and volumetric heating. In this study, we investigated the electrical characteristics of inkjet-printed silver (Ag) circuits sintered by microwaves. The microstructural evolutions of inkjet-printed Ag circuits sintered at various temperatures for different durations were observed with a field emission scanning electron microscope. The electrical properties of the inkjet-printed Ag circuits were analysed by electrical resistivity measurements and radio frequency properties including scattering parameters in the frequency range of 20 MHz to 20 GHz. The experimental results show that the signal losses of the Ag circuits sintered by microwave heating were lower than those sintered by conventional heating as microwave heating led to granular films which were nearly fully sintered without pores on the surfaces. When the inkjet-printed Ag circuits were sintered by microwaves at 300 degrees C for 4 min, their electrical resistivity was 5.1 uOmega cm, which is 3.2 times larger than that of bulk Ag. Furthermore, microwave sintering at 150 degrees C for 4 min achieved much lower signal losses (1.1 dB at 20 GHz) than conventional sintering under the same conditions. PMID- 26413663 TI - Effects of Mass Flow Rate on the Thermal-Flow Characteristics of Microwave CO2 Plasma. AB - In this study, the thermal-flow characteristics of atmospheric pressure microwave CO2 plasma were numerically investigated by simulation. The electric and gas flow fields in the reaction chamber with a microwave axial injection torch operated at 2.45 GHz were simulated. The microwave launcher had the standard rectangular waveguide WR340 geometry. The simulation was performed by using the COMSOL Multiphysics plasma model with various mass flow rates of CO2. The electric fields, temperature profiles and the density of electrons were graphically depicted for different CO2 inlet mass flow rates. PMID- 26413664 TI - RF Magnetron Sputtering Grown Cu2O Film Structural, Morphological, and Electrical Property Dependencies on Substrate Type. AB - We investigated the structural, morphological, and electrical properties of cuprous oxide (Cu2O) film dependency on substrate type. Thin films grown using RF magnetron sputtering were characterized by scanning electron microscopy, X-ray diffraction (XRD), and Hall effect measurements. Cu2O thin films were deposited onto sapphire (0001), Si (100), and MgO (110) substrates, and showed Cu2O single phase only, which was confirmed by XRD measurement. Relatively larger compressive strain existed in Cu2O film grown on sapphire and Si, while a smaller tensile strain appeared in Cu2O film grown on MgO. Cu2O thin film crystallite sizes showed a linear dependence on strain. Moreover, film carrier concentration and mobility increased with increasing strain, while resistivity decreased with decreasing strain. Cu2O film strain due to induced strain opens the possibility of controlling structural and electrical properties in device applications. PMID- 26413665 TI - Electrospun ZnO Nanofibers as a Photoelectrode in Dye-Sensitized Solar Cells. AB - A nanoparticle-based DSSC shows limited efficiency levels due to its disordered geometrical structure and interfacial interference during electron transport, whereas the use of nanofibers in a DSSC can increase the electron mobility at the interfacial area of the materials due to the reduced recombination of electrons before reaching the collecting electrode. In this study, we describe the fabrication and characteristics of a ZnO nanofiber electrode for DSSC. From the results of a thermogravimetric analysis, a stepped heat treatment was developed for the calcinations of the ZnO electrodes. The ZnO electrode morphology and crystalline structure were confirmed by scanning electron microscopy and the X ray diffraction patterns, respectively. The DSSC with the ZnO nanofiber photoelectrode (wire shaped) created by electrospinning showed an enhanced short circuit current density (37% enhancement) compared to that of a ZnO sphere particle-shaped photoelectrode under irradiation of AM 1.5 simulated sunlight (100 mW/cm2). Moreover, we have investigated the origin of the improved performance through electrochemical impedance spectroscopic (EIS) and open circuit voltage-decay (OCVD) measurements. PMID- 26413666 TI - Effect of Bulky and Hydroxyl Groups on Gas Separation Performance of Polyimide Membranes. AB - A series of polyimides were synthesized by a polycondensation reaction using various aromatic dianhydrides and diamines containing bulky cardo and hydroxyl groups. The imidization and chemical structure of the polyimides were confirmed by NMR and FT-IR. The thermal and gas properties of the polyimides were measured by time-lag, XRD, TGA, and DSC studies. The polyimides showed excellent solubility in common organic solvents and high thermal stability. The CO2 selectivity of HPI membrane was higher than traditional polyimides. In particular, the incorporation of hydroxyl groups improved the CO2 permeability of the polyimide due to increased carbon dioxide solubility. The HPI was thermally converted to polybenzoxazole (PBO) at 450 degrees C. PMID- 26413667 TI - Magnetocrystalline Anisotropy of d0-Magnetic Material NaN(001) Thin Films: A Density Functional Study. AB - A bulk d0 NaN of rocksalt or zinc-blende structure was predicted to be a ferromagnetic half metal and furthermore the half-metallicity would be retained in thin films. Such half metallicity of d0 ferromagnetic NaN is attractive for possible application in a spintronics device, such as a spin transfer torque magnetic random access memory. In this study, we carried out first-principles calculations on magnetocrystalline anisotropy rocksalt structured NaN thin films with different thicknesses, using Vienna Ab-initio Simulation Package code. It was found that the NaN(001) thin films have perpendicular magnetization with quite low magnetocrystalline anisotropy energies of order of 10 ueV, but capping of a 5d-transition metal Ta monolayer over the NaN(001) thin films enhances the perpendicular magnetocrystalline anisotropy energies significantly, more than 10 times. Furthermore, the 1 (Ta)/NaN(001) systems retain their half-metallicity except the NaN layer just below Ta. PMID- 26413668 TI - (Na, K)NbO3-Based Ceramics for Self-Powered Energy Harvesting Applications. AB - Self-powered energy harvesting technologies have been intensively investigated by employ- ing Pb-free piezoelectric materials. One such Pb-free piezoelectric material, the ceramic 0.97(Na0.5K0.5)NbO3-0.03(Bi0.5Na0.5)TiO3, was prepared by employing the conventional mixed oxide method. 0.97(Na0.5K0.5)NbO3 0.03(Bi0.5Na0.5)TiO3 ceramics were prepared and the effect of sintering temperature on the microstructure, piezoelectric and ferroelectric properties were system- atically investigated for energy harvesting applications. The crystal structure of 0.97(Na0.5K0.5)NbO3- 0.03(Bi0.5Na0.5) TiO3 Pb-free piezoelectric ceramics, sintered at temperatures between 1080 degrees C and 1160 degrees C, was examined by X-ray diffraction analysis. The dielectric properties of 0.97(Na0.5K0.5)NbO3-0.03(Bi0.5Na0.5)TiO3 ceramics were measured from 1 kHz to 1 MHz for the various sintering temperatures. We expect that optimization of sintering parameters can improve the piezoelectric and ferroelectric properties of 0.97 (Na0.5K0.5)NbO3-0.03(Bi0.5Na0.5)TiO3 ceramics for energy harvesting. PMID- 26413669 TI - Synthesis of Highly Monodispersed CdS/SiO2 Core-Shell Nanoparticles and Their Photocatalytic Activities. AB - Monodispersed CdS/SiO2 core-shell composite nanoparticles with effective photocatalytic activity were successfully synthesized. The structure and morphologies of composite nanoparticles were characterized by XRD, FTIR, TEM, and high-resolution transmission electron microscopy (HRTEM). Results showed that the CdS/SiO2 composite nanoparticles exhibited obvious core-shell structure, and that the thickness of the SiO2 shell could be reduced by either increasing the water/alcohol volume ratio or decreasing TEOS amount. The photocatalytic activity of the prepared composite nanoparticles was determined by degradation of methylene blue (MB) in aqueous solution. CdS/SiO2 showed a lower photocatalytic activity compared with CdS nanoparticles. However, the residual concentration of Cd2+ in aqueous solution after MB complete degradation was reduced by half. PMID- 26413670 TI - A Facile Approach to Monodisperse Au Nanoparticles on Fe3O4 Nanostructures with Surface Plasmon Resonance Amplification. AB - Composite magnetic nanoparticles, Fe3O4@Au, were synthesized in an aqueous phase via reducing gold chloride acid (HAuCl4) in-situ on (3-aminopropyl) triethoxysilane layer around Fe3O4 nanostructures. Connection between gold and Fe3O4 was confirmed by the magnetic separa- tion technique and X-ray diffraction (XRD). Transmission electron microscopy (TEM) observation revealed that the gold nanoparticles were dispersed on the surface of magnetic Fe3O4 nanoparticles. Significantly, aqueous dispersion of such composite nanoparticles exhibited surface plasmon of Au nanoparticles. The composite magnetic nanoparticles were then modified with 3-mercaptopropionic via an Au-S bond. These ligand-modified nanoparticles were facilely conjugated to anti-penicillin antibody. The resulting Fe3O4@Au-antibody conjugates were successfully used as a powerful sandwich element and an excellent amplification reagent for surface plasmon resonance based sandwich immunoassay. By the amplification effect of Fe3O4 @ Au-antibody conjugates, there was a nearly 30-fold increase in signal and penicillin in aqueous solution was detected at a lowest detection limit of 5 ng/ml. The biological properties of the Fe3O4@Au-antibody conjugates were investigated by Western Blotting. To our knowledge, this is the first report on the in-situ synthesis of monodisperse Au nanoparticles on Fe3O4 magnetic nanostructures in an aqueous solution with surface plasmon resonance amplification. PMID- 26413671 TI - Elemental and Microscopic Analysis of Naturally Occurring C-O-Si Hetero-Fullerene Like Structures. AB - Carbon exhibits an ability to form a wide range of structures in nature. Under favorable conditions, carbon condenses to form hollow, spheroid fullerenes in an inert atmosphere. Using high resolution FESEM, we have concealed the existence of giant hetero-fullerene like structures in the natural form. Clear, distinct features of connected hexagons and pentagons were observed. Energy dispersive X ray analysis depth-profile of natural fullerene structures indicates that Russian doll-like configurations composed of C, 0, and Si rings exist in nature. The analysis is based on an outstanding molecular feature found in the size fraction of aerosols having diameters 150 nm to 1.0 um. The fullerene like structures, which are ~ 150 nm in diameter, are observed in large numbers. To the best of our knowledge, this is the first direct detailed observation of natural fullerene like structures. This article reports inadvertent observation of naturally occurring hetero-fullerene-like structures in the Arctic. PMID- 26413672 TI - Large-Scale and Selective Synthesis of Carbon Nanofiber Bundles, Curved Carbon Nanofibers and Helical Carbon Nanofibers. AB - Through the pyrolysis of acetylene at 250 degrees C, large quantities of carbon nanofiber bundles (CNFBs), curved carbon nanofibers (CCNFs) and helical carbon nanofibers (HCNFs) can be synthesized selectively by controlling the Fe:Cu molar ratio of Fe-Cu nanoparticles. In this study, the systematic experimental results indicated that the Cu content in the Fe-Cu nanoparticles and pyrolysis temperature had great impact on the yield and structure of the final samples. Moreover, the transmission electron microscopic observation indicated that the catalyst nanoparticles were enwrapped tightly by graphite layers, and the obtained HCNFs show good magnetic property. Compared to the methods reported in the literature, the approach described herein has the advantages of being simple, low-cost, and environment-friendly. It is suitable for the controllable and mass production of CNFBs, CCNFs and HCNFs. PMID- 26413673 TI - Hollow Capsules Fabricated by Template Polymerization of N-Vinylcaprolactam. AB - We report the facile fabrication of polymer capsules based on the template polymerization of N-vinylcaprolactam (VCL) at the surface of silica particles. The modification of silica surfaces with methacrylate groups favors the polymerization of VCL leading to the formation of a homogenous PVCL layer. PVCL capsules approximately 200 nm in diameter were obtained after removal of the silica template. In contrast to most of other polymer capsules, the hollow morphology was maintained even in the dried state. The PVCL capsules, which possess smart properties based on thermal stimuli, should have wide potential applications in biological therapy. PMID- 26413674 TI - Production of Self-Assembled Fullerene (C60) Nanocrystals at Liquid-Liquid Interface. AB - Here we present self-assembled nanostructure of functional molecule fullerene (C60) at liquid-liquid interface. The nanostructured nanocrystals were grown at liquid-liquid interface of isopropyl alcohol (IPA) and C60 solution in butylbenzene under ambient condition of temperature and pressure, and characterized by Raman scattering, power X-ray diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The crystal formation mechanism is driven by supersaturation related to the low solubility of C60 in IPA. A slow diffusion of IPA towards the C60 solution causes unsaturation of C60 at the liquid-liquid interface and consequently small clusters of C60 is formed at the interface, which acts as the nucleation site. Further diffusion of IPA supplies the C60 molecules from bulk to the interface promoting the crystal growth. Based on SEM and TEM observation, the average size of the individual hexagonal bipyramid nanocrystal is found to be ca. 1.4 um and the average size of their assembly is found to be approximately 2 um. XRD measurements have shown that these materials are crystalline with mixed face-centered cubic (cell dimension: a = 1.352 nm, and V = 2.475 nm3) and hexagonal (cell dimension: a = 1.452 nm, c = 1.207 nm, c/a = 0.831, and V = 2.475 nm3) structures. Raman scattering measurements showed two Ag and six Hg vibration bands, which are similar to those obtained in the pristine C60. PMID- 26413675 TI - Characteristics of Carrier Collection of Nanopillar-Patterned Silicon Solar Cells. AB - Nanopillar-patterned Si solar cells were investigated. Ag nanoparticles were coated on a polished Si substrate as an etching mask. Reactive ion etching caused Si nanopillars to replicate in a reverse fashion on the Ag nanoparticles over a large area. The nanopillar structures efficiently reduced the light reflection on the surface and effectively drove the incident light into a Si absorber. This induced a significant enhancement of the photogenerated-current with an improved solar cell efficiency of 16.07%. The Si nanopillar-patterned solar cells showed improved carrier collection for long wavelengths; however, the surface-defect induced recombination degraded the quantum efficiency at short wavelengths. We suggest that the reduction of recombination loss should be considered for efficient nanostructure solar cells. PMID- 26413676 TI - Optimization of Semitransparent Anode Electrode for Flexible Green and Red Phosphorescent Organic Light-Emitting Diodes. AB - In this paper, we demonstrated thin film semitransparent anode electrode using Ni/Ag/Ni (3/6/3 nm) on green and red phosphorescent OLEDs, which have basically high efficiency and good optical characteristics. Moreover, we applied this semitransparent anode on flexible green and red phosphorescent OLEDs, which were then optimized for possible applications on flexible substrates. First, we studied optimization using various conditions of Ni/Ag/Ni electrodes via transmittance and sheet resistance. We then fabricated the devices on a glass substrate with ITO or Ni/Ag/Ni electrodes as well as on a flexible substrate with a Ni/Ag/Ni electrode for green and red phosphorescent OLEDs. Consequently, we could be proposed that the potential of our semitransparent anode electrode is demonstrated. Green phosphorescent OLEDs characteristics using ITO or Ni/Ag/Ni anode electrodes were coincided and those of the red phosphorescent OLEDs were improved by semitransparent electrodes at 10,000 cd/m2 criterion. Therefore, this research suggests for additional studies to be conducted on flexible and high performance phosphorescent OLED displays and light applications for ITO-free processes. PMID- 26413677 TI - YBa2Cu3O6+xSemiconductors Fabricated Using the Aerosol Deposition Method for IR Sensors. AB - In this study, YBa2Cu306+x (YBCO) thick films were investigated for their application in uncooled microbolometers. YBCO powders were prepared using the conventional mixed oxide method and were deposited on an SiO2/Si substrate using the aerosol deposition method (ADM) at room temperature. As a result of thermogravimetry and differential thermal analysis (TG-DTA) of YBCO powder, an endothermic peak was observed at approximately 820 degrees C. The powder was calcined at 880 degrees C. The deposited film were annealed at 600-750 degrees C (O2:Ar = 1:1, pO2) and their structural and electrical properties were investigated at varying annealing temperatures. From X-ray diffraction (XRD) results, all films displayed the typical XRD patterns of the tetragonal phase and the second phase was observed. The thickness of all the YBCO thick films was approximately 15.7 um. As a result of the temperature coefficient of resistance (TCR = 1/R * dR/dT), the YBCO thick films annealed at 700 degrees C showed the maximum value of -3.1%/ degrees C and all YBCO thick films showed typical NTCR (negative temperature coefficient of resistance) properties, displaying decreased electrical resistance with an increase in temperature. PMID- 26413678 TI - Laser Direct Ablation of Indium Tin Oxide Films on Both Sides of Various Substrates. AB - We demonstrate ablation of indium tin oxide (ITO) films onto both glass and polyethylene terephthalate (PET) substrates, using a Q-switched diode-pumped neodymium-doped yttrium vanadate laser (Nd:YVO4, lambda = 1064 nm) incident on both the front and back sides of the substrate. From scanning electron microscope (SEM) images and depth profile data, ITO patterns that were laser-ablated onto glass from the back side showed a larger abrupt change in the ablated line width than those ablated from the front. However, there were only slight differences in ablated line widths due to the direction of the incident laser beam. We provide a possible explanation in terms of several factors: dispersion of laser beam energy through the substrate, overlapping of each laser beam spot due to scanning speed, and the thickness of glass and PET substrates. PMID- 26413679 TI - Electrochemical Performances of Li2MnSiO4 Cathodes Synthesized by Mechanical Alloying Process. AB - We report the fabrication and electrochemical properties of Li2MnSiO4 powders produced by various solid-state reactions, such as ball-, attrition-, and bead milling. Li2MnSiO4 powders prepared by bead-milling had the smallest particle sizes (~100 nm) and the largest amount of surface carbon (~20 wt%), which were produced by adding sucrose during milling process. The surface carbon layer can improve electronic/ionic conductivity of Li2MnSiO4 as cathode material for lithium ion battery. As expected, the bead-milled Li2MnSiO4 powder electrode showed the best electrochemical performance of the electrode materials obtained by the various solid-state reactions. This is attributed to the small particle size and facile electronic transport through the conductive carbon layer on each Li2MnSiO4 particle. PMID- 26413680 TI - Electroless Cu Plating on Anodized Al Substrate for High Power LED. AB - Area-selective copper deposition on screen printed Ag pattern/anodized Al/Al substrate was attempted using a neutral electroless plating processes for printed circuit boards (PCBs), according to a range of variation of pH 6.5-pH 8 at 70 degrees C. The utilized basic electroless solution consisted of copper(II) sulfate pentahydrate, sodium phosphinate monohydrate, sodium citrate tribasic dihydrate, ammonium chloride, and nickel(II) sulfate hexahydrate. The pH of the copper plating solutions was adjusted from pH 6.5 to pH 8 using NH4OH. Using electroless plating in pH 6.5 and pH 7 baths, surface damage to the anodized Al layer hardly occurred; the structure of the plated Cu-rich films was a typical fcc-Cu, but a small Ni component was co-deposited. In electroless plating at pH 8, the surface of the anodized Al layer was damaged and the Cu film was composed of a lot of Ni and P which were co-deposited with Cu. Finally, in a pH 7 bath, we can make a selectively electroless plated Cu film on a PCB without any lithography and without surface damage to the anodized Al layer. PMID- 26413681 TI - Nanomechanical Analysis of a UV Treated Ag Thin Film Based on a Three-Step Oxidation Model. AB - Nanoindentation was used as the main method to measure the change in nanomechanical properties on the surface of an Ag thin film due to UV treatment. The 4-point probe method, X-ray diffraction (XRD), and atomic force microscopy (AFM) were used to measure the electrical, crystallographic, and morphological properties, respectively. During a UV treatment time of between 1 and 3 minutes, the sheet resistance increased dramatically to 0.55 Omega/sq. (the sheet resistance was 0.16 Omega/sq. prior to UV treatment) and these results were supported by a proportional decreased in XRD intensity. Thereafter, the sheet resistance decreased and the XRD intensity increased in response to increases in UV treatment time. These results were related to a change in crystal structure from Ag to AgOx, which could also have caused the change in sheet resistance. Based on these results, we propose a 3-step oxidation model of an Ag thin film according to UV treatment time. This proposal has been proven by nanoindentation testing. PMID- 26413682 TI - Effects of a Pretreatment on Al-Doped ZnO Thin Films Grown by Atomic Layer Deposition. AB - In this study, we investigated the electrical, structural, and optical properties of Al-doped ZnO (AZO) thin films approximately 50 nm thick grown by atomic layer deposition (ALD) on glass substrates at 200 degrees C. An H2O pretreatment was conducted for all AZO samples. The electrical properties of the AZO thin film were improved after the pretreatment process. The Al doping concentrations were controlled by inserting an Al2O3 cycle after every "n" ZnO cycles while varying n from 99 to 16. As the doping concentration increases, the resistivity decreases and the optical band gap increases. When the Al2O3 cycle ratio is 5%, the electrical resistivity showed the lowest value of 4.66 x 10(-3) Omega cm. A carrier concentration of 1.10 x 10(20) cm(-3), and the optical transmittance exceeding 90% were obtained in the visible and near-infrared region. The thin film was strongly textured along the (100) direction in the X-ray diffraction patterns. PMID- 26413683 TI - Structural and Electrical Properties of Lithium-Ion Rechargeable Battery Using the LiFePO4/Carbon Cathode Material. AB - LiFePO4/C composite powder as cathode material and graphite powder as anode material for Li-ion batteries were synthesized by using the sol-gel method. An electrochemical improvement of LiFePO4 materials has been achieved by adding polyvinyl alcohol as a carbon source into as-prepared materials. The samples were characterized by elemental analysis (EA), X-ray diffraction (XRD), and field emission scanning electron microscopy (FE-EM). The chemical composition of LiFePO4/C powders was in a good agreement with that of the starting solution. The capacity loss after 500 cycles of LiFePO4/C cell is 11.1% in room temperature. These superior electrochemical properties show that LiFePO4/C composite materials are promising candidates as cathode materials. PMID- 26413684 TI - Synthesis of Ordered Mesoporous Manganese Oxides with Various Oxidation States. AB - Ordered mesoporous MnO, MnO4, Mn2O3 and MnO2 materials with 3-D pore structure were suc- cessfully synthesized via a nano-replication method by using ordered mesoporous silica, KIT-6 (Cubic Ia3d space group mesostructure) as the template under specific oxidation and reduction conditions. Notably, ordered mesoporous MnO with a crystalline wall (rock salt structure) was syn- thesized for the first time, to the best of our knowledge. The synthesis of the ordered mesoporous MnO was achieved by reducing the ordered mesoporous Mn3O4 under an H2 atmosphere, while preserving the ordered mesostructure and crystalline wall throughout the solid/solid transformation. All of the ordered mesoporous manganese oxides with different crystal structures and oxidation states demonstrated almost the same spherical-like morphology with several hundred nanometers of particles. The synthesized ordered mesoporous manganese oxides had uniform dual mesopores (2-3 nm, and ~20 nm) and crystalline frameworks with large surface areas (86-140 m2/g) and pore volumes (0.27-0.33 cm3/g). PMID- 26413685 TI - Multifunctional Nanobiocomposite of Poly[(butylene succinate)-co-adipate] and Clay. AB - The processing and characterization of multifunctional nanobiocomposite of biodegradable poly[(butylene succinate)-co-adipate] (PBSA) and organically modified synthetic fluorine mica (OSFM) are reported. The nanobiocomposite of PBSA with OSFM was prepared using melt- blending, and the structure and morphology of the nanocomposite were characterized using X-ray diffraction and transmission electron microscopy. The mechanical and material properties measurements showed the concurrent improvement in temperature dependence storage modulus, tensile properties, gas barrier, and thermal stability of neat PBSA after nanocomposite formation. Such improved inherent properties along with the environmentally-friendly feature are expected to widen the use of PBSA for short term food-packaging applications. PMID- 26413686 TI - Chirality of 4,4'-Biphenylene Bridged Polybissilsesquioxane Nanotubes Using the Dipeptides Derived from Valine. AB - Four dipeptides with alkyl chains derived from L- and D-valines were synthesized, the handedness of their self-assemblies were controlled by the valine chirality at the terminals. The stacking of the carbonyl groups plays an important in the formation of chiral organic self-assemblies. Chiral 4,4'-biphenylene bridged polybissilsesquioxane nanotubes were prepared using the self-assemblies of these dipeptides as the templates. The chirality of the polysilsesquioxane nanotubes was mainly controlled by the valines at the terminals of the dipeptides, which was transferred from the valines at the terminals through electrostatic interaction. The valines near the alkyl chains could also affect the polysilsesquioxane chirality through hydrogen bonding. PMID- 26413687 TI - A Novel Sensitive Electrochemical Sensor for Podophyllotoxin Assay Based on the Molecularly Imprinted Poly-o-Phenylenediamine Film. AB - An electrochemical sensor for podophyllotoxin (PPT) based on the molecular imprinting polymer (MIP) membranes was constructed. The sensor was prepared by electropolymerizing o-phenylenediamine (o-PD) on a glassy carbon electrode (GCE) in the presence of PPT as template, and then removing the template by immersing the modified GCE in ethanol. Experimental parameters such as the types of monomer, scan cycles, concentration of o-PD and extraction condition were optimized. Under optimal conditions, the sensor exhibits a good selectivity and high sensitivity. A good linearity was obtained in the range of 4 x 10-8 mol . L( 1) to 3.2 x 10(-5) mol . L(-1) with an estimated detection limit of 4.8 x 10(-9) mol . L(-1). The sensor was applied to the determination of PPT in podophyllum hexandrum and human serum samples with satisfactory results. PMID- 26413688 TI - Palladium Decorated Graphene-Nanoribbon Network for Enhanced Gas Sensing. AB - The fabrication of large-scale graphene nanoribbon (GNR) network and its application for gas sensing are reported. A large area, nanoscale GNR network was produced by a facile approach of silver nanowires (Ag NWs) templated graphene masking and subsequent 02 plasma etching. GNR network shows significantly enhanced sensitivity to ammonia gas compared to pristine graphene layer. The gas detection sensitivity of the nanoscale GNR network is even further improved by decorating GNR network with palladium (Pd) or platinum (Pt) nanoparticles, which show a relative resistance response of 65% and 45%, respectively to 50 ppm (parts per million) of ammonia (NH3) in nitrogen (N2) at room temperature as well as good reversibility in air. PMID- 26413689 TI - Novel Gas Sensor Based on ZnO Nanorod Circular Arrays for C2H5OH Gas Detection. AB - Novel side-heating gas sensor based on ZnO nanorod circular arrays was firstly fabricated by hydrothermal treatment assisted with a kind of simple dip-coating technique. The structure and morphologies of ZnO nanorods were characterized by X ray diffraction (XRD), Scanning Electron Microscope (SEM), respectively. XRD result indicates that the obtained ZnO nanorods have good crystalline with the hexagonal wurtzite structure. SEM result indicates that ZnO nanorod arrays are vertically growth on the surface of ceramic tube of side-heating sensor with controlled diameter and length, narrow size distribution and high orientation. The gas sensing properties of ZnO nanorod circular arrays are also evaluated. Comparative to the sensor based on scattered ZnO nanorods responding to 25 ppm H2, CO, C6H5CH3 and C2H5OH gas, respectively, the sensing values of high orientation gas sensor are generally increased by 5%. This novel sensor has good application promising for the fabrication of cost effective and high performance gas sensors. PMID- 26413690 TI - Theoretica Study of Asymmetric Double D-pi-A Organic Sensitizers for Efficient Dye-Sensitized Solar Cells. AB - Three novel dye sensitizers that were based on asymmetric double D-pi-A chains with phenoxazine (POZ) and diphenylamine (DPA) as electron donors and cyanoacetic acid (CA) and 2-(1,1- dicyanomethylene) rhodanine (RD) as electron acceptors (DCPR, DRPC, DRPR) were designed, theoretically investigated, and compared with the reference dye based on asymmetric double D-pi-A chains (DCPC). Using density functional theory (DFT) and time-dependent density functional theory (TD-DFT) calculations, we gained insight into the factors responsible for the photovoltaic properties of the dye sensitizers. Due to the different HOMO levels of each donor and the different LUMO levels of each acceptor, the absorption spectrum of each dye showed different shapes. Among the dyes, DRPR showed a broader and more bathochromically shifted absorption band than the other dies. It also showed a higher molar extinction coefficient than that of the reference dye (DCPC). This work suggests optimizing the chain of electron donors and acceptors in dye sensitizers based on asymmetric double D-pi-A chains would produce good photovoltaic properties for dye-sensitized solar cells (DSSCs). PMID- 26413691 TI - Effect of an Ag Insertion Layer on the Optical and Electrical Properties of Ga Doped Zinc Oxide Films. AB - GZO/Ag/GZO films were investigated for use as high quality transparent conductive electrodes. The GZO and Ag films were deposited by RF sputtering and electron beam evaporation, respectively, at room temperature. The effects of Ag thickness and post heat treatment on the structural, electrical and optical properties of these multilayer films were investigated. The insertion of the Ag layer with optimized thickness between the GZO layers and the optimized annealing temperature improved the electrical and optical properties of the GZO/Ag/GZO film due to the very low resistivity and surface plasmon effect of the Ag layer. The best multilayer film exhibited a low resistivity of 2.2 x 10(-5) Omega . cm and a transmittance of 88.9%. PMID- 26413692 TI - Novel Ru(II) Complex with 1H-Benzo[d]lmidazole Derivative for Dye-Sensitized Solar Cell. AB - It was reported that ruthenium(II) complex CBTR with 1H-benzo[d]imidazole derivative for heteroleptic donor system exhibited an enhancement of the solar cell performance, compared to N3. We took a theoretical approach about the CBTR dye. Density functional theory (DFT) and time-dependent density functional theory (TD-DFT) calculations were used to gain insight into the factors responsible for the photovoltaic properties of the dye sensitizer. The values of the absorption spectrum of the CBTR dye with the 1 H-benzo[d]imidazole derivative were not improved compared to those of the N3 dye. The lack of improvement was attributed to the destabilization of the lowest unoccupied molecular orbital (LUMO) energy level of the CTBR dye. According to the molecular orbital analysis, the LUMO of the CBTR dye mainly localized on the dcbpy (dcbpy = 4,4'-dicarboxy-2,2' bipyridine) moiety. The highest occupied molecular orbitals (HOMOs) of N3 were localized on the Ru-NCS moiety, and the HOMOs of CBTR were also localized on Ru NCS. The introduction of the 1H-benzo[d]imidazole derivative to the heteroleptic donor system did not change the location of the HOMOs. The addition on of the NHC ligand to the CBTR dye seems to be an essential structural modification to enhance the efficiency of solar cells. PMID- 26413693 TI - Effect of Sulfurization Temperature on Solution-Processed Cu2ZnSnS4 Thin Films. AB - Cu2ZnSnS4 (CZTS) solar cells are attracting significant attention as an alternative to CIGS (Culn1-xGa(x)S2) solar cells because of the non-toxic and inexpensive constituent elements of CZTS. Recently, solution-based deposition methods are being developed because they have advantages such as suitability for use in large-area deposition, high-throughput manufacturing, and a very short energy payback time with drastically lower manufacturing costs. In this work, we fabricated solution-based CZTS thin films and investigated them in order to observe the effects of sulfurization temperature on CZTS thin films. We confirmed the grain size, morphology, chemical composition, crystallinity, and electrical properties of CZTS thin films depending on various sulfurization temperatures. PMID- 26413694 TI - Crystallization Behavior of Solution-Processed CIGSe Thin Film Semiconductor by Stepwise Annealing Process. AB - CuIn(x)Ga1-xSe2 (CIGS) thin films were prepared by a solution-based CuInGa (CIG) precursor- selenization process. First, we investigated the effect of selenization temperature on the formation of polycrystalline CIGS and grain growth. The CIG precursor films were selenized using a two-step process to investigate the reaction of Se and CIG precursors during the formation of CIGS thin films. Depending on the temperature in the 1st step of the selenization process, the CIG precursor forms a different intermediate phase between the single phase to ternary phase such as Cu, Se, CuSe, InSe, and CuInSe2. In addition, the intermediate phase exerts a significant influence on the final phase obtained after the 2nd step of the selenization process, particularly with regard to characteristics such as polycrystalline structure and grain growth in the CIGS films. The photoelectron conversion efficiency of devices prepared using CIGS thin films was approximately 1.59-2.75%. PMID- 26413695 TI - Surface Morphology and Structural Modification Induced by Femtosecond Pulses in Hydrogenated Amorphous Silicon Films. AB - This work investigates the modification, resulting from fs-laser irradiation (150 fs, 775 nm and 1 kHz), on the structure and surface morphology of hydrogenated amorphous silicon (a-Si:H) thin films. The sample morphology was studied by performing a statistical analyzes of atomic force microscopy images, using a specially developed software that identifies and characterizes the domains (spikes) produced by the laser irradiation. For a fluence of 3.1 MJ/m2, we observed formation of spikes with smaller average height distribution, centered at around 15 nm, while for fluencies higher than 3.7 MJ/m2 aggregation of the produced spikes dominates the sample morphology. On the other hand, Raman spectroscopy revealed that a higher crystalline fraction (73%) is obtained for higher fluences (> 3.1 MJ/m2), which is accompanied by a decrease in the size of the produced crystals. Therefore, such results indicate that there is a trade-off between the spike distribution, crystallization fraction and size of the nanocrystals attained by laser irradiation, which has to be taken into account when using such approach for the development of devices. PMID- 26413696 TI - An Alternative to Annealing TiO2 Nanotubes for Morphology Preservation: Atmospheric Pressure Plasma Jet Treatment. AB - Titanium oxide nanotube layer formed by plasma electrolytic oxidation (PEO) is known to be excellent in biomaterial applications. However, the annealing process which is commonly performed on the TiO2 nanotubes cause defects in the nanotubular structure. The purpose of this work was to apply a non-thermal atmospheric pressure plasma jet on diameter-controlled TiO2 nanotubes to mimic the effects of annealing while maintaining the tubular structure for use as biomaterial. Diameter-controlled nanotube samples fabricated by plasma electrolytic oxidation were dried and prepared under three different conditions: untreated, annealed at 450 degrees C for 1 h in air with a heating rate of 10 degrees C/min, and treated with an air-based non-thermal atmospheric pressure plasma jet for 5 minutes. The contact angle measurement was investigated to confirm the enhanced hydrophilicity of the TiO2 nanotubes. The chemical composition of the surface was studied using X-ray photoelectron spectroscopy, and the morphology of TiO2 nanotubes was examined by field emission scanning electron microscopy. For the viability of the cell, the attachment of the osteoblastic cell line MC3T3-E1 was determined using the water-soluble tetrazolium salt assay. We found that there are no morphological changes in the TiO2 nanotubular structure after the plasma treatment. Also, we investigated a change in the chemical composition and enhanced hydrophilicity which result in improved cell behavior. The results of this study indicated that the non-thermal atmospheric pressure plasma jet results in osteoblast functionality that is comparable to annealed samples while maintaining the tubular structure of the TiO2 nanotubes. Therefore, this study concluded that the use of a non-thermal atmospheric pressure plasma jet on nanotube surfaces may replace the annealing process following plasma electrolytic oxidation. PMID- 26413697 TI - Synthesis of Cerium-Doped Titania Nanoparticles and Nanotubes. AB - Cerium-doped titania nanoparticles and nanotubes were synthesized via hydrothermal processes. X-Ray Diffraction revealed that cerium-doped titania nanoparticles have an anatase crystal structure, while cerium-doped titania nanotubes have an H2Ti3O7-type structure. Scanning electron microscopy and high resolution transmission electron microscopy showed that both types of titania are well crystallized with relatively uniform size distribution. The photocatalytic degradation of methylthioninium chloride known as methylene blue dye was tested and both cerium-doped titania nanoparticles and nanotubes. The preliminary photocatalytic degradation of Methylene Blue data showed significantly improved visible light photocatalytic activities as compared to commercial titania powders. PMID- 26413698 TI - Synthesis of Polypropylene/Organoclay Nanocomposites via In Situ Polymerization with Improved Thermal and Dynamic-Mechanical Properties. AB - Preparation of polypropylene/clay nanocomposites via in situ polymerization is investigated. MgCl2/organophilic clay bi-supported Ziegler-Natta catalysts were used to prepare these nanocomposites. Three organophilic clays (Cloisite 30B, Cloisite 15A, and Claytone HY) were used as support and reinforcement agents. The nanostructure of the composites was characterized by X-ray diffraction. The results showed that the most active catalyst was that with clay having high inter layer spacing without functional OH groups. Moreover, the silica layers of the clays (Cloisite 15A and Claytone HY) in these polypropylene/clay nanocomposites were exfoliated and well dispersed in the polypropylene matrix. Differential scanning calorimetric was used to investigate both melting and crystallization temperatures, as well as the crystallinity of the nanocomposite samples. These results showed that Cloisite 15A and Claytone HY acted as nucleating agents in the process of crystallization of polypropylene. Thermogravimetric analysis showed that Cloisite 15A and Claytone HY promoted an increase in resistance to thermal degradation. Dynamic-mechanical analysis showed that nanocomposites presented an increase in the storage modulus. Furthermore, Cloisite 15A and Claytone HY promoted an increase in glass transition temperature. Small-angle X ray scattering analysis was used to determine how clay and its concentration influence the size of the polymer nanocrystals. PMID- 26413699 TI - Macroparticles Reduction Using Filter Free Cathodic Vacuum Arc Deposition Method in ZnO Thin Films. AB - We report a new method to reduce macroparticles in ZnO thin films using filter free cathodic vacuum arc deposition without using any cooling arrangements operated at low arc current. The detailed mechanism has been proposed to reduce macroparticles during thin film deposition. The successful reduction of macroparticles was confirmed employing FESEM-EDX studies. FESEM images of ZnO thin films deposited with cathode spot to substrate distance from 10 to 20 cm revealed that the population of the macroparticles were reduced with the increase of cathode spot to substrate distances at low arc current. The prepared ZnO films were characterised and showed good structural and optical properties. PMID- 26413700 TI - Superhydrophilic and Highly Transparent TiO2 Films Prepared by Dip Coating for Photocatalytic Degradation of Methylene Blue. AB - Nanocrystalline TiO2 films were prepared on slide glass by sol-gel and dip coating methods, and the samples were then annealed at 200 degrees C, 250 degrees C, 300 degrees C, 350 degrees C, 400 degrees C, 450 degrees C and 500 degrees C for 2 h. The samples' crystal structures, morphology, water contact angle, transmission spectra, and photocatalytic performance with respect to the degradation of methylene blue (MB) under UV light irradiation were characterized by X-ray diffraction spectroscopy, scanning electron microscopy, contact angle measurement, and UV-vis spectrophotometry. The results obtained indicate that all of the films were highly transparent to the visible spectrum, but with an increase in the annealing temperature, the optical band-gap and the water contact angle both reduced. Samples annealed at 450 degrees C and 500 degrees C exhibited superhydrophilic properties, with the hydrophilicity of the films remaining stable for at least 6 months without UV light irradiation. Among all the samples, the one annealed at 450 degrees C was found to have the highest maximum MB degradation rate of 71.1%. PMID- 26413701 TI - Chitosan-Polypyrrole Fiber for Strain Sensor. AB - A chitosan/polypyrrole composited fiber as bio-compatible materials for artificial muscles is investigated. The chitosan/polypyrrole fiber (CPF) is fabricated by in-situ chemical polymerization of pyrrole monomer solution using FeCl3 as an oxidant. The electrical resistivity of the fiber is changed according to the strain variation applied to the both ends of the specimen. The sensor built by using the CPF has a higher gauge factor (4) compared to conventional metal strain gauges (~2) indicating a suitable material for delicate force control in sensing work. PMID- 26413702 TI - Control of Size Uniformity of Cu Nanoparticle Array Produced by Plasma-Induced Dewetting. AB - The effects of plasma parameters such as plasma density, electron temperature, and sheath voltage on the uniformity of Cu nanoparticle arrays were investigated. These parameters were controlled by varying the pressure, RF power, and substrate bias voltage. A floating harmonic method was used to monitor the plasma parameters. Uniform nanoparticle arrays were produced when hole generation was increased by using a high ion.bombardment energy. As oppose to a low energy flux condition, where small and large nanoparticles coexisted due to a small number of holes, a larger number of holes was generated and distributed more uniformly during a high energy flux condition. PMID- 26413703 TI - CO2 Gas Transport Property of Sulfonated Poly(Arylenen Ether Sulfone) Copolymer Membrane. AB - The effect of functional groups such as sulfuric acid group and metal ions on the CO2 gas transport property of membranes was investigated. Sulfonated poly(arylene ether sulfone) (SPAES) was prepared by direct copolymerization with a non sulfonated monomer and sulfonated monomer. The sulfonation degree of SPAES was controlled from 0 to 50%. Metal ions such as lithium and sodium were substituted for the protons of the -SO3H group. The thermal properties, microstructure of polymer chains, and the permeability and selectivity of membranes were evaluated. The solubility coefficient of CO2 gas increased with an increase in sulfonation degree. But the diffusivity was largely decreased and the CO2/N2 selectivity of the membrane substituted for metal ions was increased. PMID- 26413704 TI - Biomimetic Deposition of Hydroxyapatite by Mixed Acid Treatment of Titanium Surfaces. AB - A simple chemical method was established for inducing bioactivity of Ti metal. In the present study, two kinds of mixed acid solutions were used to treat Ti specimens to induce Ca-P formation. Following a strong mixed acid activation process, Ca-P coatings successfully formed on the Ti surfaces in the simulated body fluid. Strong mixed acid etching was used to increase the roughness of the metal surface, because the porous and rough surfaces allow better adhesion between Ca-P coatings and substrate. Nano-scale modification of titanium surfaces can alter cellular and tissue responses, which may benefit osseointegration and dental implant therapy. Some specimens were treated with a 5 M NaOH aqueous solution, and then heat treated at 600 degrees C in order to form an amorphous sodium titanate layer on their surface. This treated titanium metal is believed to form a dense and uniform bone-like apatite layer on its surface in a simulated body fluid (SBF). This study proved that mixed acid treatment is not only important for surface passivation but is also another bioactive treatment for titanium surfaces, an alternative to alkali treatment. In addition, mixed acid treatment uses a lower temperature and shorter time period than alkali treatment. PMID- 26413705 TI - Monoethanolamine Impregnation of Titanosilicate Zeolite ETS-10. AB - ETS-10, a mixed octahedral/tetrahedral titanosilicate molecular sieve, has a unique architecture where its 0.8 nm pores are lined exclusively with silicon which imparts a high degree of chemical stability, yet the anionic framework can be modified by cation exchange. In this work, the hydrogen-exchanged form of ETS 10 was impregnated with monoethanolamine and the thermal stability and CO2 adsorption characteristics were analyzed. The surface area of the material was characterized by N2 physisorption, the thermal stability of the material assessed through TG-MS experiments, the CO2 capacity was measured via static volumetric adsorption experiments, and the influence of moisture as a carbamate promoter was investigated through a series of gravimetric CO2 adsorption/desorption cycling experiments. Several measurements converge on ~7 wt% monoethanolamine loading which occupies about half of the available pore volume of the sieve. The results suggest that the monoethanolamine is so effectively retained by the molecular sieve that, while the amine is effectively immobilized, under both humid and dry process streams the monoethanolamine is either chemically or sterically hindered and is unable to react measurable quantities of CO2. PMID- 26413706 TI - Sb-Doped SnO2 Nanoparticles Synthesized by Sonochemical-Assisted Precipitation Process. AB - Sb-doped SnO2 nanopowders were synthesized by sonochemical-assisted precipitation process using stannic chloride pentahydrate (SnCl4.5H2O) and antimony chloride (SbC3) as starting precursors. Effect of sonication and Sb doping concentrations on physical structures and electrical properties of Sb-doped SnO2 nanoparticles were investigated by X-ray diffraction, transmission electron microscope, X-ray photoelectron spectroscopy, Raman spectroscopy and two-point probe method. The results indicated that the good dispersion with less agglomeration of particles in SnO2 phase can be obtained by single step sonochemical-assisted process. Moreover, XRD results indicated that the crystallinity of Sb-doped SnO2 nanopowders deteriorated with increasing Sb content, suggesting that Sb dopant significantly prevent SnO2 crystallite growth. The XPS spectra of Sb-doped SnO2 obviously confirmed the existence of Sb ion incorporated into SnO2 matrix. These results revealed that incorporation of Sb ions into SnO2 lattice with specific concentration has significant influence on formation and crystallization and can dramatically enhance the conductivity of tin oxide. PMID- 26413707 TI - Application of 8YSZ Nanopowder Synthesized by the Modified Solvothermal Process for Anode Supported Solid Oxide Fuel Cells. AB - Thin electrolyte yttria-stabilized zirconia (8YSZ) films were coated on the porous solid oxide fuel cell (SOFC) anode substrates for the use at an intermediate temperature range. Nano-8YSZ powder with a particle size of about 5 nm was synthesized using the modified solvothermal process. The electrolyte suspension was prepared by dispersion the synthesized 8YSZ nanopowder in ethanol, with PVB and 1,3-propanediol as a binder and a charging agent respectively. The 8YSZ suspension was subsequently deposited on the pre-sintered NiO-YSZ porous substrates by the electrophoretic deposition (EPD) technique. In order to obtain high quality electrolyte films, preparation process was optimized through two strategic approaches; (i) adjustment of suspension's rheological property and (ii) compatibility of anode-electrolyte sintering shrinkage. Rheological property of the suspension was improved with an addition of 1,3-propanediol. The zeta potential of this suspension was increased and reached the value of +24 mV so the well-dispersed slurry was finally obtained. The second approach was achieved by using a proper composite anode powders. Dense and uniform 8YSZ electrolyte films with a thickness of about 1 thickness successfully be formed on the NiO-YSZ porous substrates after co-sintering at 1400 degrees C for 2 h. PMID- 26413708 TI - Behavior of Ultra Fine Particles in Electric Field. AB - The behavior of ultra fine particles in an electric field was measured in order to apply it to classification of fine particles. The sample particles used are spherical polystyrene particles with the average size of 0.03, 0.1, 1.0, 4.3 and 9.6 um. The forces acting the particles in an electric field are considered to be electrical force, friction force and some other forces like the asymmetric effect and electrophoretic retardation effect which appear in ionic behavior. We found that the moving velocity of particles depends on the particle size. When the particle size is less than 1 um, the velocity increases with increasing the particle size. On the other hand, the velocity deceases with an increase in the particle size, when the particle size is larger than 1 um. We can apply the behavior to classification of fine particles. The phenomena could be explained by various forces acting the fine particles in the electric field. PMID- 26413709 TI - Rapid Solidification and Magnetic Properties of (Fe,Co)-(Fe,Co)17Gd2 Pseudo Binary Eutectic Alloys. AB - The (Fe,Co)-(Fe,Co)17Gd2 pseudo-binary eutectic system has been determined by investigating phase compositions on the analysis of DSC, EDS and XRD. The rapid solidification of Gd7.3Fe30.56Co62.14, Gd9Fe30Co61 and Gd9.63Fe29.79Co60.58 ternary alloys is realized by single roller techniques. With a rising cooling rate, the equiaxed zone near the roller surface expands inwards. For Gd7.3Fe30.56Co62.14 hypoeutectic alloy ribbons, the feathery irregular eutectic zone shrinks and the grains (Fe,Co) near the free surface are refined. (Fe,Co) equiaxed dendrites plus the radial, irregular eutectic ultimately fill in the ribbon at the maximum cooling rate. For Gd9Fe30Co61 near-eutectic alloy ribbons, the growth direction of irregular eutectics near the free surface becomes more and more perpendicular to the surface, and finally the whole ribbons are occupied by the fine, irregular eutectic. The dendritic spacing of the (Fe,Co)17Gd2 phase which grows from the roller surface to the free surface in Gd9.63Fe29.79Co60.58 alloy ribbons becomes smaller. The grain size of the (Fe,Co)17Gd2 dendrite and the fraction of (Fe,Co) soft phase in alloy ribbons, which determine coercivity in the pseudo-binary eutectic system, vary with the increase of the cooling rate. Of the three alloys, the Gd9Fe30Co61 alloy has the best hard magnetic properties at Vr = 20 m/s; the maximum coercivity Hc is 431.34 Oe. PMID- 26413710 TI - Effects of Li4Ti5O12 Anode Electrode Thickness on the Cell Balancing of Hybrid Super Capacitor. AB - The hybrid super capacitor was prepared by controlling the anode electrode thickness to optimize cell balancing. With an increasing anode electrode thickness, the internal resistance increased, while the capacitance was not changed remarkably. The potential of the cathode increased and that of the anode was decreased with the working voltage. However, the potential variation of the cathode was larger than that of the anode due to the difference in the reaction mechanism of the cathode and anode. The discharge capacity retention as a function of the current rates increased and the cycle performance was improved with an increasing anode electrode thickness. The effects of the anode electrode thickness on the electrode potential are also discussed. PMID- 26413711 TI - Calvin Ross Scott, 1922-2015. PMID- 26413712 TI - Working toward Best Practice: Microbubble Filtration and Patient Safety During Extracorporeal Circulation. PMID- 26413713 TI - Response to Letter "Working toward Best Practice: Microbubble Filtration and Patient Safety during Extracorporeal Circulation" by Daniel P. Herbst. PMID- 26413714 TI - Prediction of telephone calls load using Echo State Network with exogenous variables. AB - We approach the problem of forecasting the load of incoming calls in a cell of a mobile network using Echo State Networks. With respect to previous approaches to the problem, we consider the inclusion of additional telephone records regarding the activity registered in the cell as exogenous variables, by investigating their usefulness in the forecasting task. Additionally, we analyze different methodologies for training the readout of the network, including two novel variants, namely nu-SVR and an elastic net penalty. Finally, we employ a genetic algorithm for both the tasks of tuning the parameters of the system and for selecting the optimal subset of most informative additional time-series to be considered as external inputs in the forecasting problem. We compare the performances with standard prediction models and we evaluate the results according to the specific properties of the considered time-series. PMID- 26413715 TI - Laser-Supported Dual Energy X-Ray Absorptiometry (DXL) Compared to Conventional Absorptiometry (DXA) and to FRAX as Tools for Fracture Risk Assessments. AB - Dual X-ray and Laser (DXL) adds a measure of the external thickness of the heel, measured by laser, to a conventional measurement of bone mineral density (BMD) of the calcaneus, using Dual energy X-ray Absorptiometry (DXA). The addition of heel thickness aims at a better separation of fatty tissue from bone than the standard method of DXA, which may mistake fatty tissue for bone and vice versa. The primary aim of this study was to evaluate whether DXL of the calcaneus can be used to assess the 10-year risk of fractures. Secondary aims were to compare the predictive ability of DXL with the two most established methods, Dual energy X ray Absorptiometry (DXA) of the hip and spine and the WHO fracture risk assessment tool, FRAX. In 1999 a cohort of 388 elderly Swedish women (mean age 73.2 years) was examined with all three methods. Prospective fracture data was collected in 2010 from health care registers. One SD decrease in BMD of the heel resulted in an age-adjusted Hazard Ratio (HR) of 1.47 for a hip fracture (95% CI 1.09-1.98). Harrell's C is the Cox regression counterpart of the Area Under Curve (AUC) of the Receiver Operating Characteristic (ROC) as a measure of predictive accuracy. Harrell's C for BMD of the calcaneus was 0.65 for prediction of hip fractures. These results were not significantly different from those for BMD of the femoral neck or for FRAX. The HR for a hip fracture, for one SD decrease in BMD at the femoral neck, was 1.72 (95% CI 1.21-2.44. Harrell's C was 0.67 for BMD at the femoral neck and 0.59 for FRAX. We conclude that DXL of the calcaneus could be a useful tool for fracture risk assessments. PMID- 26413717 TI - Diagnostic Utility of Unbiased Circulating Tumour Cell Capture through Negative Depletion of Peripheral Blood Cells. AB - OBJECTIVES: Cytological analysis of peripheral blood circulating tumour cells (CTCs) is a potential method of confirmatory clinical diagnosis of cancer. However, cell capture methods tend to be biased and captured cells are not usually portable resulting in difficulties in pathology reporting. We evaluated unbiased cell capture through depletion of unwanted normal cells and conventional clinical analyses of captured cells. METHODS: Blood was sampled from 29 patients who underwent surgery for suspected lung cancer. It was processed using two different depletion cocktails. After depletion of unwanted cells, the resultant cell pellet was processed onto glass slides or embedded into FFPE blocks and stained using standard haematoxylin and eosin staining followed by cytopathologic assessment. Two pathologists performed the assessment independently. RESULTS: The CTCs were identified in 38-45% of cases using CD45 depletion cocktail with the cell pellet processed on a glass slide, while other combinations of methods produced poorer results. Overall, there was a good concordance between the pathologists (up to 91.3%). The sensitivity of cancer diagnosis was 42% (95% CI 23-63%), while the specificity was 100% (95% CI 29-100%). CONCLUSION: Negative depletion can be used to isolate CTCs in standard clinical settings; however, more effective ways of detection are required to increase the sensitivity of the diagnosis. PMID- 26413716 TI - A GWAS Study on Liver Function Test Using eMERGE Network Participants. AB - INTRODUCTION: Liver enzyme levels and total serum bilirubin are under genetic control and in recent years genome-wide population-based association studies have identified different susceptibility loci for these traits. We conducted a genome wide association study in European ancestry participants from the Electronic Medical Records and Genomics (eMERGE) Network dataset of patient medical records with available genotyping data in order to identify genetic contributors to variability in serum bilirubin levels and other liver function tests and to compare the effects between adult and pediatric populations. METHODS: The process of whole genome imputation of eMERGE samples with standard quality control measures have been described previously. After removing missing data and outliers based on principal components (PC) analyses, 3294 samples from European ancestry were used for the GWAS study. The association between each single nucleotide polymorphism (SNP) and total serum bilirubin and other liver function tests was tested using linear regression, adjusting for age, gender, site, platform and ancestry principal components (PC). RESULTS: Consistent with previous results, a strong association signal has been detected for UGT1A gene cluster (best SNP rs887829, beta = 0.15, p = 1.30x10-118) for total serum bilirubin level. Indeed, in this region more than 176 SNPs (or indels) had p<10-8 spanning 150Kb on the long arm of chromosome 2q37.1. In addition, we found a similar level of magnitude in a pediatric group (p = 8.26x10-47, beta = 0.17). Further imputation using sequencing data as a reference panel revealed association of other markers including known TA7 repeat indels (rs8175347) (p = 9.78x10-117) and rs111741722 (p = 5.41x10-119) which were in proxy (r2 = 0.99) with rs887829. Among rare variants, two Asian subjects homozygous for coding SNP rs4148323 (G71R) were identified. Additional known effects for total serum bilirubin were also confirmed including organic anion transporters SLCO1B1-SLCO1B3, TDRP and ZMYND8 at FDR<0.05 with no gene-gene interaction effects. Phenome-wide association studies (PheWAS) suggest a protective effect of TA7 repeat against cerebrovascular disease in an adult cohort (OR = 0.75, p = 0.0008). Among other liver function tests, we also confirmed the previous effect of the ABO blood group locus for variation in serum alkaline phosphatase (rs579459, p = 9.44x10 15). CONCLUSIONS: Taken together, our data present interesting findings with strong confirmation of previous effects by simply using the eMERGE electronic health record phenotyping. In addition, our findings indicate that similar to the adult population, the UGT1A1 is the main locus responsible for normal variation of serum bilirubin in pediatric populations. PMID- 26413718 TI - The Effect of Post-Exercise Cryotherapy on Recovery Characteristics: A Systematic Review and Meta-Analysis. AB - The aim of this review and meta-analysis was to critically determine the possible effects of different cooling applications, compared to non-cooling, passive post exercise strategies, on recovery characteristics after various, exhaustive exercise protocols up to 96 hours (hrs). A total of n = 36 articles were processed in this study. To establish the research question, the PICO-model, according to the PRISMA guidelines was used. The Cochrane's risk of bias tool, which was used for the quality assessment, demonstrated a high risk of performance bias and detection bias. Meta-analyses of subjective characteristics, such as delayed-onset muscle soreness (DOMS) and ratings of perceived exertion (RPE) and objective characteristics like blood plasma markers and blood plasma cytokines, were performed. Pooled data from 27 articles revealed, that cooling and especially cold water immersions affected the symptoms of DOMS significantly, compared to the control conditions after 24 hrs recovery, with a standardized mean difference (Hedges' g) of -0.75 with a 95% confidence interval (CI) of -1.20 to -0.30. This effect remained significant after 48 hrs (Hedges' g: -0.73, 95% CI: -1.20 to -0.26) and 96 hrs (Hedges' g: -0.71, 95% CI: -1.10 to -0.33). A significant difference in lowering the symptoms of RPE could only be observed after 24 hrs of recovery, favouring cooling compared to the control conditions (Hedges' g: -0.95, 95% CI: -1.89 to -0.00). There was no evidence, that cooling affects any objective recovery variable in a significant way during a 96 hrs recovery period. PMID- 26413720 TI - Correction: Decrypting Financial Markets through E-Joint Attention Efforts: On Line Adaptive Networks of Investors in Periods of Market Uncertainty. PMID- 26413719 TI - Marital Status, Lifestyle and Dementia: A Nationwide Survey in Taiwan. AB - BACKGROUND: Evidence of an association between lifestyle and marital status and risk of dementia is limited in Asia. METHODS: In this nationwide population-based cross-sectional survey, participants were selected by computerized random sampling from all 19 counties in Taiwan. A total of 10432 residents were assessed by a door-to-door in-person survey, among whom 7035 were normal and 929 were diagnosed with dementia using the criteria recommended by National Institute on Aging-Alzheimer's Association. Premorbid lifestyle habits and demographic data including marital status were compared between normal subjects and participants with dementia. RESULTS: After adjustment for age, gender, education, body mass index, smoking, drinking, marital status, sleep habits, exercise, social engagement and co-morbidities including hypertension, diabetes and cerebrovascular diseases, an increased risk for dementia was found in people with widow or widower status (OR 1.42, 95% CI 1.15-1.77) and people who used to take a nap in the afternoon (OR 1.33, 95% CI 1.02-1.72). Decreased risk was found in people with the habit of regular exercise (OR 0.12, 95% CI 0.09-0.16), adequate night sleep (OR 0.55, 95% CI 0.39-0.76) and regular social engagement (OR 0.53, 95% CI 0.36-0.77). CONCLUSIONS: Our results provide preliminary evidence of possible risk-reduction effects for dementia, including regular exercise even in modest amounts, social engagement and adequate night sleep, whereas people with the widow/widower status or who used to take an afternoon nap might have increased risk of dementia. PMID- 26413721 TI - Correction to Aydin, Frohmader, and Akil (2015). PMID- 26413722 TI - Binaural cues provide for a release from informational masking. AB - Informational masking (IM) describes the insensitivity of detecting a change in sound features in a complex acoustical environment when such a change could easily be detected in the absence of distracting sounds. IM occurs because of the similarity between deviant sound and distracting sounds (so-called similarity based IM) and/or stimulus uncertainty stemming from trial-to-trial variability (so-called uncertainty-based IM). IM can be abolished if similarity-based or uncertainty-based IM are minimized. Here, we modulated similarity-based IM using binaural cues. Standard/deviant tones and distracting tones were presented sequentially, and level-increment thresholds were measured. Deviant tones differed from standard tones by a higher sound level. Distracting tones covered a wide range of levels. Standard/deviant tones and distracting tones were characterized by their interaural time difference (ITD), interaural level difference (ILD), or both ITD and ILD. The larger the ITD or ILD was, the better similarity-based IM was overcome. If both interaural differences were applied to standard/deviant tones, the release from IM was larger than when either interaural difference was used. The results show that binaural cues are potent cues to abolish similarity-based IM and that the auditory system makes use of multiple available cues. PMID- 26413723 TI - Age-related impairments in object-place associations are not due to hippocampal dysfunction. AB - Age-associated cognitive decline can reduce an individual's quality of life. As no single neurobiological deficit can account for the wide spectrum of behavioral impairments observed in old age, it is critical to develop an understanding of how interactions between different brain regions change over the life span. The performance of young and aged animals on behaviors that require the hippocampus and cortical regions to interact, however, has not been well characterized. Specifically, the ability to link a spatial location with specific features of a stimulus, such as object identity, relies on the hippocampus, perirhinal and prefrontal cortices. Although aging is associated with dysfunction in each of these brain regions, behavioral measures of functional change within the hippocampus, perirhinal and prefrontal cortices in individual animals are often not correlated. Thus, how dysfunction of a single brain region within this circuit, such as the hippocampus, impacts behaviors that require communication with the perirhinal and prefrontal cortices remains unknown. To address this question, young and aged rats were tested on the interregion dependent object place paired association task, as well as a hippocampal-dependent test of spatial reference memory. This particular cohort of aged rats did not show deficits on the hippocampal-dependent task, but were significantly impaired at acquiring object-place associations relative to young. These data suggest that behaviors requiring functional connectivity across different regions of the memory network may be particularly sensitive to aging, and can be used to develop models that will clarify the impact of systems-level dysfunction in the elderly. PMID- 26413724 TI - Mnemonic discrimination of similar face stimuli and a potential mechanism for the "other race" effect. AB - Face recognition is an important component of successful social interactions in humans. A large literature in social psychology has focused on the phenomenon termed the "other race" (ORE) effect, the tendency to be more proficient with face recognition within one's own ethnic group compared with other ethnic groups. Several potential hypotheses have been proposed for this effect, including perceptual expertise, social grouping, and holistic face processing. Recent work on mnemonic discrimination (i.e., the ability to resolve mnemonic interference among similar experiences) may provide a mechanistic account for the ORE. In the current study, we examined how discrimination and generalization in the presence of mnemonic interference may contribute to the ORE. We developed a database of computerized faces divided evenly among ethnic origins (Black, Caucasian, East Asian, South Asian), as well as morphed face stimuli that varied in the amount of similarity to the original stimuli (30%, 40%, 50%, and 60% morphs). Participants first examined the original unmorphed stimuli during study, then during test were asked to judge the prior occurrence of repetitions (targets), morphed stimuli (lures), and new stimuli (foils). We examined participants' ability to correctly reject similar morphed lures and found that it increased linearly as a function of face dissimilarity. We additionally found that Caucasian participants' mnemonic discrimination-generalization functions were sharply tuned for Caucasian faces but considerably less tuned for East Asian and Black faces. These results suggest that expertise plays an important role in resolving mnemonic interference, which may offer a mechanistic account for the ORE. PMID- 26413725 TI - 2-((Benzimidazol-2-yl)thio)-1-arylethan-1-ones: Synthesis, crystal study and cancer stem cells CD133 targeting potential. AB - In order to develop a potent anti-tumor agent that can target both cancer stem cells and the bulk of tumor cells, a series of 2-((benzimidazol-2-yl)thio)-1 arylethan-1-ones 5a-o was synthesized. All compounds were evaluated for their anti-proliferative activity towards colon HT-29 cancer cell line. In addition, their inhibitory effect against cell surface expression of CD133, a potent cancer stem cells (CSCs) marker, in the same cells was evaluated by flow cytometry at 10 MUM. Compound 5l emerged as the most active anti-proliferative analog against HT 29 (IC50 = 18.83 +/- 1.37 MUM), that almost equipotent as 5-fluorouracil (IC50 = 15.83 +/- 1.63 MUM) with 50.11 +/- 4.05% inhibition effect on CD133 expression, suggested dual targeted effect. Also, compounds 5h, 5j, 5k and 5m-o inhibited the expression of CD133 with more than 50%. The SAR study pointed out the significance of substitution of the pendent phenyl group with lipophilic electron donating groups or replacing it by 2-thienyl or 2-furyl groups. PMID- 26413727 TI - Novel techniques and future directions in molecular diagnosis of malaria in resource-limited settings. AB - Despite being preventable and treatable, malaria remains a global health concern with approximately 1.2 billion people at high risk of being infected, 90% of whom are in the resource-limited settings of sub-Saharan Africa. The continued decline in malaria cases globally has rekindled the possibility of elimination in certain regions. As humans constitute the main reservoir of malaria, prompt and accurate diagnosis by microscopy or rapid diagnostic tests is part not only of effective disease management but also of control measures. However, for malaria elimination, more sensitive diagnostic tools are needed to detect asymptomatic and sub-microscopic infections that contribute to transmission. Molecular techniques, which involve amplification of nucleic acids, are being developed and modified to suit this purpose. This report provides a summary of the nucleic acid amplification tests that are currently available for diagnosis of malaria, with current improvements and adaptations for use in resource-limited settings. PMID- 26413726 TI - H2O-mediated isatin spiro-epoxide ring opening with NaCN: Synthesis of novel 3 tetrazolylmethyl-3-hydroxy-oxindole hybrids and their anticancer evaluation. AB - A simple method for isatin spiro-epoxide ring-opening by sodium cyanide in water to obtain a variety of isatin hydroxy nitriles has been developed. Further, these intermediates have been converted into new 3-tetrazolylmethyl-3-hydroxy-oxindole hybrids via azide-nitrile cycloaddition reaction in a sealed tube. These compounds were evaluated for their in vitro anticancer activity on five human cancer cell lines i.e. breast (BT549 and MDA MB-231), prostate (PC-3 and DU-145) and ovarian (PA-1). The compounds 6d and 6r showed potent anticancer activity against DU-145 cell line with IC50 values in the range of 7.01 +/- 0.91 and 4.26 +/- 0.09 MUM respectively. The compounds 6d, 6g, 6q and 6r were also tested on human normal prostate epithelial (RWPE-1) cells and found to be safer with lesser cytotoxicity. The morphology and long term clonogenic survival of DU-145 cells were severely affected by compound 6r. Cell cycle analysis revealed that the compounds arrest the cells in G2/M phase. Acridine orange/ethidium bromide (AO/EB) staining, DAPI staining, annexin-V binding assay and DNA fragmentation analysis showed that cell proliferation was inhibited through induction of apoptosis. Moreover, one of the compounds 6r treatment led to collapse of the mitochondrial membrane potential (DPsim) and increased levels of reactive oxygen species (ROS) in DU-145 cells. PMID- 26413728 TI - Ab Initio Reaction Kinetics of CH3OC(?O) and CH2OC(?O)H Radicals. AB - The dissociation and isomerization kinetics of the methyl ester combustion intermediates methoxycarbonyl radical (CH3OC(?O)) and (formyloxy)methyl radical (CH2OC(?O)H) are investigated theoretically using high-level ab initio methods and Rice-Ramsperger-Kassel-Marcus (RRKM)/master equation (ME) theory. Geometries obtained at the hybrid density functional theory (DFT) and coupled cluster singles and doubles with perturbative triples correction (CCSD(T)) levels of theory are found to be similar. We employ high-level ab initio wave function methods to refine the potential energy surface: CCSD(T), multireference singles and doubles configuration interaction (MRSDCI) with the Davidson-Silver (DS) correction, and multireference averaged coupled-pair functional (MRACPF2) theory. MRSDCI+DS and MRACPF2 capture the multiconfigurational character of transition states (TSs) and predict lower barrier heights than CCSD(T). The temperature- and pressure-dependent rate coefficients are computed using RRKM/ME theory in the temperature range 300-2500 K and a pressure range of 0.01 atm to the high pressure limit, which are then fitted to modified Arrhenius expressions. Dissociation of CH3OC(?O) to CH3 and CO2 is predicted to be much faster than dissociating to CH3O and CO, consistent with its greater exothermicity. Isomerization between CH3OC(?O) and CH2OC(?O)H is predicted to be the slowest among the studied reactions and rarely happens even at high temperature and high pressure, suggesting the decomposition pathways of the two radicals are not strongly coupled. The predicted rate coefficients and branching fractions at finite pressures differ significantly from the corresponding high-pressure-limit results, especially at relatively high temperatures. Finally, because it is one of the most important CH3O removal mechanisms under atmospheric conditions, the reaction kinetics of CH3O + CO was also studied along the PES of CH3OC(?O); the resulting kinetics predictions are in remarkable agreement with experiments. PMID- 26413729 TI - Patient response to insurer-led intervention for medication adherence - a pilot study based on claims data in Korea. AB - OBJECTIVE: This study was designed to investigate patient responses to a medication counseling intervention program piloted by the National Health Insurance Service (NHIS), the national health insurer in Korea, to improve medication management in patients with hypertension, hyperlipidemia, or diabetes. METHODS AND MATERIALS: Interventions were conducted from July to September 2013 through direct mailing followed by two telephone-initiated counseling sessions for the medication discontinuation group (< 80% medication possession ratio (MPR) and >= 2 months of discontinuation) and the medication over-possession group (>= 150% MPR). The telephone intervention was applied through two models: model 1 (counseling by NHIS staff only) and model 2 (counseling by NHIS staff with contract-based working pharmacists in community pharmacies). Multivariate logistic regression analysis was performed to identify factors affecting favorable responses of patients to the telephone-initiated intervention. Patient responses to the telephone-initiated intervention were evaluated by a counselor. RESULTS: In all, 891 patients were counseledvia telephone. Patient responses to the telephone-initiated intervention were favorablein 57.6%, neutral in 17.4% and not favorable in 24.9% overall. Counseling by NHIS staff together with pharmacists (model 2) produced more favorable responses from patients than counseling by NHIS staff alone (model 1) (OR 2.73, 95% CI 1.97 - 3.77). CONCLUSION: Our findings of favorable responses to interventions support a personalized approach by the NHIS to improve patient behavior for medication adherence. PMID- 26413730 TI - Dealing with the high cost of biological therapies: developing and implementing a biological therapy prioritization protocol for ankylosing spondylitis patients in a tertiary hospital. AB - OBJECTIVE: In January 2011, a biological therapies commission was created in our hospital to fully address the management of biological drugs. A biological therapy prioritization protocol was developed for ankylosing spondylitis (AS) patients. Here, we describe it and report on its economic impact to illustrate how we are optimizing the use of these expensive new drugs. METHODS: The biological therapies commission established several procedures for the rational use of biological drugs such as cost-efficiency therapeutic protocols, pharmacovigilance, and therapeutic drug monitoring programs. The AS protocol was based on clinical and economic aspects. We estimated the economic impact of the protocol by comparing the cost of treating AS patients with biological drugs in the pre-commission (2009 - 2010) vs. post-commission period (2011 - 2013). AS patients treated with adalimumab (ADA), etanercept (ETN) or infliximab (IFX) for at least 6 months in the 2009 - 2013 period were included. RESULTS: 107 patients were included. In the pre-commission period, total expenses increased by +30,944 Euro (+4%). After protocol implementation, total expenses decreased by 11,441 Euro (-1%) during 2011, and by an additional 36,781 Euro (-4%) and 53,872 Euro ( 8%) in 2012 and 2013, respectively. In the 2010 - 2013 period the cost of biological therapy per patient-year decreased by 869A a?!, suggesting the positive effects of the biological therapy prioritization protocol instauration. CONCLUSION: We describe the establishment of a multidisciplinary biological therapy commission to optimize the use of biological therapies. We illustrate its work in developing a protocol for the management of AS patients with such therapies. We show that after 3-years of implementation, the biological therapy prioritization protocol allowed us to steadily decrease the direct cost of biological drug therapies per patient, up to 869 Euro. PMID- 26413731 TI - Pharmacokinetic and pharmacodynamic study of dexmedetomidine in elderly patients during spinal anesthesia. AB - OBJECTIVE: The application of dexmedetomidine in patient sedation is generally accepted, though its clinical application is limited because of the lack of information detailing the specific properties among diverse populations of patients. The aim of this study was to compare the pharmacokinetic and pharmacodynamic characteristics of dexmedetomidine between elderly and young patients during spinal anesthesia. METHODS: 34 subjects (elderly group: n = 15; young group: n = 19) with spinal anesthesia were enrolled in the present study following the inclusion/exclusion criteria detailed below. All subjects received intravenous infusion of dexmedetomidine with a loading dose of 0.5 ug x kg-1 for 10 minutes and a maintenance dose of 0.5 ug x kg-1 x h-1 for 50 minutes. Plasma concentrations of dexmedetomidine were detected by the HPLC-MS/MS method and pharmacokinetic parameters were calculated using WinNolin software. RESULTS: There was no significant difference between the elderly and young subjects in major pharmacokinetic parameters. There was a marked gender difference in the Cmax (peak plasma concentration) and tmax (time to reach Cmax) between genders in elderly subjects, though in this cohort the other pharmacokinetic parameters were not significantly different. In the young subjects there were no noteworthy variations between genders in pharmacokinetic parameters. There was no significant difference between the two groups in BISAUC(0-t) (the area under the bispectral index-time curve from time 0 to t hours), BISmin (the minimum value of the bispectral index after drug delivery), and or tmin-BIS (bispectral index for the minimum value of time). SBP (systolic blood pressure), DBP (diastolic blood pressure), HR (heart rate), and SpO2(pulse oxygen saturation) developed substantive differences in a time-dependent manner, but there were no statistically significant differences in these four indicators in the time*group at three time points (1 hour, 2 hours, and 3 hours after drug administration); while SBP was significantly different between the groups, this differential declined in a time-dependent manner, and there were no significant attendant differences in the D-value. The observed values and D-values of DBP and HR were similar in the groups, but the observed value and D-value of SpO2did differ. There were 14 drug-related adverse events in the young group, and 26 drug-related adverse events in the elderly group, a 46% differential. The percentage of patients who requiring intervention during surgery was 68.75% (11/16) in the elderly group and 36.84% (7/19) in the young group, with no significant difference between the two groups once age was factored in (p = 0.06). None of the pharmacodynamic indices, however, correlated with the key pharmacokinetic parameters (Cmax, AUC(0->t), AUC(0->infinity)) of dexmedetomidine. CONCLUSIONS: The clearance of dexmedetomidine in elderly patients showed a declining trend compared to young patients. Interventions in the elderly group were more frequent than in the young group, and the elderly group showed significant adverse effects. It is suggested that elderly patients who use dexmedetomidine may benefit from a different dose. However, further research with a larger population size is required to confirm these findings. PMID- 26413732 TI - Pharmacotherapeutic aspect of antibiotic therapy during acute community-acquired pneumonia in adults at the University Hospital of Cocody (Abidjan). AB - OBJECTIVE: Acute community-acquired pneumonia in Cote d'Ivoire, mainly in the pneumology units, is the second most common cause of hospitalization after tuberculosis. This study aimed to evaluate the compliance of antibiotic therapy during bacterial acute community-acquired pneumonia with international guidelines serving as frame of reference at the University Hospital of Cocody. MATERIALS AND METHODS: We carried out a descriptive retrospective and analytic study on 62 hospitalized patients from December 1, 2008 to November 30, 2010 in the Pneumophtisiology department at the University Hospital of Cocody (Abidjan). The prescription of antibiotics was compared with the recommendations of the 15th consensus conference on anti-infectious therapy by the Societe de Pathologie Infectieuse de Langue Francaise (SPILF) (French Speaking Society of Infectious Pathology) held in 2006. RESULTS: The main antibiotics prescribed were amoxicillin-clavulanic acid (42.27%), netilmicin (34.5%) and ciprofloxacin (6%). The antibiotic therapy diagrams were dominated by an antibiotic bitherapy; the association of amoxicillin-clavulanic acid+netilmicin was observed in 80.64% of the prescriptions. An antibiotic monotherapy was reported in 14.52% of the prescriptions. Apyrexia at 72 hours was obtained with 64% of the patients with nonstop antibiotic treatment, 24% of them presented a lack of apyrexia, and 12% of them died. The lack of apyrexia at 72 hours treatment correlated with concomitant administration of cotrimoxazole with prophylactic doses among HIV positive patients. The level of the compliance with the SPILF recommendations is low (3.6%). CONCLUSION: Thus, our results convey the necessity to draw up national recommendations because of the specific realities of countries with limited incomes. PMID- 26413733 TI - Oscar Marin: A Daughter's Perspective. PMID- 26413734 TI - Why I Honor Oscar Marin. PMID- 26413735 TI - Neurologist, Cognitive Neuroscientist, Inspirer of Psychologists, and Humanist: An Appreciation of Oscar Marin. PMID- 26413736 TI - The Marin Lab at the Dawn of Cognitive Neuropsychology. AB - This essay discusses the intellectual developments in psychology, linguistics, and behavioral neurology that shaped Oscar Marin's approach to disorders of high cortical function. As Chief of Neurology at Baltimore City Hospitals in the 1970s, Dr Marin teamed with biopsychologist Eleanor Saffran and the author in seminal studies of acquired language disorders (aphasia) centering on core processes of syntax and semantics, and rejecting premature reductionism. The philosophical and methodological principles that motivated these studies are traced through the author's personal recollections and the published writings of the Marin lab. These principles came to be associated with the cognitive neuropsychology school of research and have important linkages to contemporary work in the neuroscience of aphasia and related cognitive disorders. PMID- 26413737 TI - Oscar Marin: The Phenomenology of Mentoring. PMID- 26413738 TI - Oscar Marin and the Creation of a Cognitive Neuropsychology Laboratory. AB - During the 1980s, the Cognitive Neuropsychology Laboratory at Good Samaritan Hospital, Portland, Oregon, made important strides in the study of brain injury. Created and headed by Oscar Marin and the author, in affiliation with the University of Oregon, the lab brought together students, fellows, and visiting experts in neurology, psychology, psychiatry, neuropsychology, neurobiology, neurophysiology, and computation. Their patient-focused collaborations produced groundbreaking research in language and its disorders, bradyphrenia, neglect, cerebellar function and impairment, and the psychology of music. The lab hosted the meeting that they documented in the influential 1985 book Attention and Performance XI: Mechanisms of Attention. The lab's members have gone on to lead distinguished careers and continue making major contributions to cognitive neuroscience. PMID- 26413739 TI - What Oscar Marin Taught Me. PMID- 26413740 TI - A Visit with Oscar and Clara Marin. PMID- 26413741 TI - Revisiting the Single-Case Approach to Studying Reading Disorders. AB - Oscar Marin was a neurologist with a remarkably broad interest in the brain and its function. He was passionate about understanding how the brain processes language and about helping people with acquired language disorders through his science-based practice. Here we honor his memory by presenting a review and commentary charting the cycle of neuroscientific approaches to studying reading disorders over the past century. During this time, "best practices" have changed from individual case studies to group studies and mega-studies and back again to individual studies. We show how, across decades and almost unimaginable advances in neuroimaging technology, the individual approach taken by Oscar Marin has retained its importance. PMID- 26413743 TI - Neuropsychological Thoughts, Then and Now: A Tribute to Oscar Marin. AB - This brief paper, inspired by an invitation to acknowledge and celebrate Oscar Marin's great contributions to cognitive neurology and neuropsychology, reviews the case of a patient, T.P., who had significant deficits of naming, reading, and spelling. I first studied and reported this patient 35 years ago, in 1979, when I was significantly influenced by the work of Oscar Marin and his colleagues. I have recently had the unusual opportunity to do some brief reassessment of T.P.'s current (2015) cognitive abilities, and to reassess the interpretations that I had given to her pattern of impairment in the initial studies. I suggest that advances over the last decade or so-in theorizing about, and connectionist modeling of, reading and spelling disorders-enable a more coherent account of T.P.'s acquired anomia, dyslexia, and dysgraphia, and the relationships among them. PMID- 26413742 TI - Alzheimer Lesions in the Autopsied Brains of People 30 to 50 Years of Age. AB - OBJECTIVE: To test the hypothesis that asymptomatic Alzheimer disease lesions may appear before 50 years of age. BACKGROUND: Alzheimer disease has an asymptomatic stage during which people are cognitively intact despite having substantial pathologic changes in the brain. While this asymptomatic stage is common in older people, how early in life it may develop has been unknown. METHODS: We microscopically examined the postmortem brains of 154 people aged 30 to 39 years (n=59) and 40 to 50 years (n=95) for specific Alzheimer lesions: beta-amyloid plaques, neurofibrillary tangles, and tau-positive neurites. We genotyped DNA samples for the apolipoprotein E gene (APOE). RESULTS: We found beta-amyloid lesions in 13 brains, all of them from people aged 40 to 49 with no history of dementia. These plaques were of the diffuse type only and appeared throughout the neocortex. Among these 13 brains, five had very subtle tau lesions in the entorhinal cortex and/or hippocampus. All individuals with beta-amyloid deposits carried one or two APOE4 alleles. Among the individuals aged 40 to 50 with genotype APOE3/4, 10 (36%) had beta-amyloid deposits but 18 (64%) had none. CONCLUSIONS: Our study demonstrates that beta-amyloid deposits in the cerebral cortex appear as early as 40 years of age in APOE4 carriers, suggesting that these lesions may constitute a very early stage of Alzheimer disease. Future preventive and therapeutic measures for this disease may have to be stratified by risk factors like APOE genotype and may need to target people in their 40s or even earlier. PMID- 26413744 TI - Functional Mapping of the Human Auditory Cortex: fMRI Investigation of a Patient with Auditory Agnosia from Trauma to the Inferior Colliculus. AB - OBJECTIVE: To use functional magnetic resonance imaging to map the auditory cortical fields that are activated, or nonreactive, to sounds in patient M.L., who has auditory agnosia caused by trauma to the inferior colliculi. BACKGROUND: The patient cannot recognize speech or environmental sounds. Her discrimination is greatly facilitated by context and visibility of the speaker's facial movements, and under forced-choice testing. Her auditory temporal resolution is severely compromised. Her discrimination is more impaired for words differing in voice onset time than place of articulation. Words presented to her right ear are extinguished with dichotic presentation; auditory stimuli in the right hemifield are mislocalized to the left. METHODS: We used functional magnetic resonance imaging to examine cortical activations to different categories of meaningful sounds embedded in a block design. RESULTS: Sounds activated the caudal sub-area of M.L.'s primary auditory cortex (hA1) bilaterally and her right posterior superior temporal gyrus (auditory dorsal stream), but not the rostral sub-area (hR) of her primary auditory cortex or the anterior superior temporal gyrus in either hemisphere (auditory ventral stream). CONCLUSIONS: Auditory agnosia reflects dysfunction of the auditory ventral stream. The ventral and dorsal auditory streams are already segregated as early as the primary auditory cortex, with the ventral stream projecting from hR and the dorsal stream from hA1. M.L.'s leftward localization bias, preserved audiovisual integration, and phoneme perception are explained by preserved processing in her right auditory dorsal stream. PMID- 26413746 TI - The Use of Surrogate Data in Demographic Population Viability Analysis: A Case Study of California Sea Lions. AB - Reliable data necessary to parameterize population models are seldom available for imperiled species. As an alternative, data from populations of the same species or from ecologically similar species have been used to construct models. In this study, we evaluated the use of demographic data collected at one California sea lion colony (Los Islotes) to predict the population dynamics of the same species from two other colonies (San Jorge and Granito) in the Gulf of California, Mexico, for which demographic data are lacking. To do so, we developed a stochastic demographic age-structured matrix model and conducted a population viability analysis for each colony. For the Los Islotes colony we used site-specific pup, juvenile, and adult survival probabilities, as well as birth rates for older females. For the other colonies, we used site-specific pup and juvenile survival probabilities, but used surrogate data from Los Islotes for adult survival probabilities and birth rates. We assessed these models by comparing simulated retrospective population trajectories to observed population trends based on count data. The projected population trajectories approximated the observed trends when surrogate data were used for one colony but failed to match for a second colony. Our results indicate that species-specific and even region-specific surrogate data may lead to erroneous conservation decisions. These results highlight the importance of using population-specific demographic data in assessing extinction risk. When vital rates are not available and immediate management actions must be taken, in particular for imperiled species, we recommend the use of surrogate data only when the populations appear to have similar population trends. PMID- 26413745 TI - Plaque2.0-A High-Throughput Analysis Framework to Score Virus-Cell Transmission and Clonal Cell Expansion. AB - Classical plaque assay measures the propagation of infectious agents across a monolayer of cells. It is dependent on cell lysis, and limited by user-specific settings and low throughput. Here, we developed Plaque2.0, a broadly applicable, fluorescence microscopy-based high-throughput method to mine patho-biological clonal cell features. Plaque2.0 is an open source framework to extract information from chemically fixed cells by immuno-histochemistry or RNA in situ hybridization, or from live cells expressing GFP transgene. Multi-parametric measurements include infection density, intensity, area, shape or location information at single plaque or population levels. Plaque2.0 distinguishes lytic and non-lytic spread of a variety of DNA and RNA viruses, including vaccinia virus, adenovirus and rhinovirus, and can be used to visualize simultaneous plaque formation from co-infecting viruses. Plaque2.0 also analyzes clonal growth of cancer cells, which is relevant for cell migration and metastatic invasion studies. Plaque2.0 is suitable to quantitatively analyze virus infections, vector properties, or cancer cell phenotypes. PMID- 26413747 TI - Mutational Heterogeneity in p6 Gag Late Assembly (L) Domains in HIV-1 Subtype C Viruses from South Africa. AB - Contradictory results have been reported on the impact of duplications/insertions in the HIV-1 gag-p6 late assembly domains [TSG101-binding P(T/S)APP motif and ALIX-binding LYPxnLxxL motif] heterogeneity following therapy failure. However, most studies are limited to small numbers of patients and do not include samples from South Africa, which has the largest number of HIV-1C-infected patients (HIV 1CZA). In this study we compared the gag-p6 variability among HIV-1CZA-infected patients from a South African clinical cohort who experienced antiretroviral therapy (ART) failure (n = 845) with ART-naive HIV-1CZA sequences (n = 706) downloaded from the Los Alamos database. Partial (PTA/PTV/APP) or complete P(T/S)APP duplications were less frequent in HIV-1CZA with ART failure compared to therapy-naive ones (14% vs. 30%; p < 0.001). In contrast, the tetrapeptide PYxE insertion, recently described by us, occurred more frequently (5-fold) in therapy-failure patients (p < 0.001) and was associated with a higher number of reverse transcriptase inhibitor (RTI) mutations (p = 0.04) among patients failing ART. PMID- 26413748 TI - On the Inference of Functional Circadian Networks Using Granger Causality. AB - Being able to infer one way direct connections in an oscillatory network such as the suprachiastmatic nucleus (SCN) of the mammalian brain using time series data is difficult but crucial to understanding network dynamics. Although techniques have been developed for inferring networks from time series data, there have been no attempts to adapt these techniques to infer directional connections in oscillatory time series, while accurately distinguishing between direct and indirect connections. In this paper an adaptation of Granger Causality is proposed that allows for inference of circadian networks and oscillatory networks in general called Adaptive Frequency Granger Causality (AFGC). Additionally, an extension of this method is proposed to infer networks with large numbers of cells called LASSO AFGC. The method was validated using simulated data from several different networks. For the smaller networks the method was able to identify all one way direct connections without identifying connections that were not present. For larger networks of up to twenty cells the method shows excellent performance in identifying true and false connections; this is quantified by an area-under-the-curve (AUC) 96.88%. We note that this method like other Granger Causality-based methods, is based on the detection of high frequency signals propagating between cell traces. Thus it requires a relatively high sampling rate and a network that can propagate high frequency signals. PMID- 26413749 TI - Spironolactone for People Age 70 Years and Older With Osteoarthritic Knee Pain: A Proof-of-Concept Trial. AB - OBJECTIVE: To determine whether spironolactone could benefit older people with osteoarthritis (OA), based on a previous study showing that spironolactone improved quality of life. METHODS: This parallel-group, randomized, placebo controlled, double-blind trial randomized community-dwelling people ages >=70 years with symptomatic knee OA to 12 weeks of 25 mg daily oral spironolactone or matching placebo. The primary outcome was between-group difference in change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale scores. Secondary outcomes included WOMAC stiffness and physical function subscores, EuroQol 5-domain (EQ-5D) 3L score, and mechanistic markers. Analysis was by intent to treat, using mixed-model regression, adjusting for baseline values of test variables. RESULTS: A total of 421 people had eligibility assessed, and 86 were randomized. Mean +/- SD age was 77 +/- 5 years and 53 of 86 (62%) were women. Adherence to study medication was 99%, and all participants completed the 12-week assessment. No significant improvement was seen in the WOMAC pain score (adjusted treatment effect 0.5 points [95% confidence interval (95% CI) - 0.3, 1.3]; P = 0.19). No improvement was seen in WOMAC stiffness score (0.2 points [95% CI -0.6, 1.1]; P = 0.58), WOMAC physical function score (0.0 points [95% CI -0.7, 0.8]; P = 0.98), or EQ-5D 3L score (0.04 points [95% CI 0.04, 0.12]; P = 0.34). Cortisol, matrix metalloproteinase 3, and urinary C telopeptide of type II collagen were not significantly different between groups. More minor adverse events were noted in the spironolactone group (47 versus 32), but no increase in death or hospitalization was evident. CONCLUSION: Spironolactone did not improve symptoms, physical function, or health-related quality of life in older people with knee OA. PMID- 26413750 TI - LYAR promotes colorectal cancer cell mobility by activating galectin-1 expression. AB - Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. However, the molecular mechanisms of CRC pathogenesis are not fully understood. In this study, we report the characterization of LYAR (Ly-1 antibody reactive clone) as a key regulator of the migration and invasion of human CRC cells. Immunohistochemistry analysis demonstrated that LYAR is expressed at a higher level in metastatic CRC tissues. We found that LYAR promoted the migratory and invasive capabilities of CRC cells. Gene expression profile analysis of CRC cells showed that LGALS1, which encodes the galectin-1 protein, was a potential target of LYAR. The ChIP assay and gene reporter assays indicated that LYAR directly bound to the LGALS1 promoter. The ectopic expression of galectin-1 partially restored the mobile potential of LYAR knocked-down cells, which suggests that galectin-1 contributed to the LYAR-promoted cell migration and invasion of CRC cells. Thus, this study revealed a novel mechanism by which the transcription factor LYAR may promote tumor cell migration and invasion by upregulating galectin-1 gene expression in CRC. PMID- 26413751 TI - Application of mitochondrial pyruvate carrier blocker UK5099 creates metabolic reprogram and greater stem-like properties in LnCap prostate cancer cells in vitro. AB - Aerobic glycolysis is one of the important hallmarks of cancer cells and eukaryotic cells. In this study, we have investigated the relationship between blocking mitochondrial pyruvate carrier (MPC) with UK5099 and the metabolic alteration as well as stemness phenotype of prostatic cancer cells. It was found that blocking pyruvate transportation into mitochondrial attenuated mitochondrial oxidative phosphorylation (OXPHOS) and increased glycolysis. The UK5099 treated cells showed significantly higher proportion of side population (SP) fraction and expressed higher levels of stemness markers Oct3/4 and Nanog. Chemosensitivity examinations revealed that the UK5099 treated cells became more resistant to chemotherapy compared to the non-treated cells. These results demonstrate probably an intimate connection between metabolic reprogram and stem-like phenotype of LnCap cells in vitro. We propose that MPC blocker (UK5099) application may be an ideal model for Warburg effect studies, since it attenuates mitochondrial OXPHOS and increases aerobic glycolysis, a phenomenon typically reflected in the Warburg effect. We conclude that impaired mitochondrial OXPHOS and upregulated glycolysis are related with stem-like phenotype shift in prostatic cancer cells. PMID- 26413752 TI - Phased-array combination for MR spectroscopic imaging using a water reference. AB - PURPOSE: To evaluate methods for multichannel combination of three-dimensional MR spectroscopic imaging (MRSI) data with a focus on using information from a water reference spectroscopic image. METHODS: Volumetric MRSI data were acquired for a phantom and for human brain using 8- and 32-channel detection. Acquisition included a water-reference dataset that was used to determine the weights for several multichannel combination methods. Results were compared using the signal to-noise ratio (SNR) of the N-acetylaspartate resonance. RESULTS: Performance of all methods was very similar for the phantom study, with the whitened singular value decomposition (WSVD) and signal magnitude (S) weighting combination having a small advantage. For in vivo studies, the S weighting, SNR weighting and signal to noise squared (S/N(2) ) weighting were the three best methods and performed similarly. Example spectra and SNR maps indicated that the SVD and WSVD methods tend to fail for voxels at the outer edges of the brain that include strong lipid signal contributions. CONCLUSION: For data combination of MRSI data using water reference information, the S/N(2) weighting, SNR and S weighting were the best methods in terms of spectral quality SNR. These methods are also computationally efficient and easy to implement. Magn Reson Med 76:733-741, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26413754 TI - The Mechanics of Morality. PMID- 26413753 TI - Identification of ILK as a novel therapeutic target for acute and chronic myeloid leukemia. AB - Current treatment options as well as clinical efficacy are limited for chronic myelogenous leukemia (CML), Ph+ acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). In response to the pressing need for more efficacious treatment approaches and strategies to override drug resistance in advanced stage CML, Ph+ ALL, and AML, we investigated the effects of inhibition of ILK as a potentially novel and effective approach to treatment of these challenging malignancies. Using the small molecule ILK inhibitor, Cpd22, and ILK knockdown, we investigated the importance of ILK in the growth and viability of leukemia. Our results suggest that the ILK inhibition may be an effective treatment for CML, Ph+ ALL, and AML as a single therapy, with ILK expression levels positively correlating with the efficacy of ILK inhibition. The identification of ILK as a novel target for leukemia therapy warrants further investigation as a therapeutic approach that could be of potential clinical benefit in both acute and chronic myeloid leukemias. PMID- 26413755 TI - The Author Replies. PMID- 26413756 TI - Normalizing Aid-in-Dying within the Practice of Medicine. PMID- 26413757 TI - Giving Up My Naivete. PMID- 26413758 TI - Justice Roberts Gets It. PMID- 26413759 TI - Warm and Dead? PMID- 26413760 TI - Limits of Responsibility: Genome Editing, Asilomar, and the Politics of Deliberation. PMID- 26413761 TI - Why Training in Ecological Research Must Incorporate Ethics Education. PMID- 26413762 TI - Teaching Bioethics at the Secondary School Level. PMID- 26413763 TI - Bridging the Gap between Knowledge and Skill: Integrating Standardized Patients into Bioethics Education. PMID- 26413765 TI - Having Conversations about Organ Donation. PMID- 26413766 TI - Looking for experts (a call for essays). PMID- 26413767 TI - Predictors of Hypopituitarism in Patients with Traumatic Brain Injury. AB - Hypopituitarism may often occur in association with traumatic brain injury (TBI). Identification of reliable predictors of pituitary dysfunction is of importance in order to establish a rational testing approach. We searched the records of patients with TBI, who underwent neuroendocrine evaluation in our institution between 2007 and 2013. One hundred sixty-six adults (70% men) with TBI (median age: 41.6 years; range: 18-76) were evaluated at a median interval of 40.4 months (0.2-430.4).Of these, 31% had >=1 pituitary deficiency, including 29% of patients with mild TBI and 35% with moderate/severe TBI. Growth hormone deficiency was the most common deficiency (21%); when body mass index (BMI)-dependent cutpoints were used, this was reduced to 15%. Central hypoadrenalism occurred in10%, who were more likely to have suffered a motor vehicle accident (MVA, p = 0.04), experienced post-traumatic seizures (p = 0.04), demonstrated any intracranial hemorrhage (p = 0.05), petechial brain hemorrhages (p = 0.017), or focal cortical parenchymal contusions (p = 0.02). Central hypothyroidism occurred in 8% and central hypogonadism in 12%; the latter subgroup had higher BMI (p = 0.03), were less likely to be working after TBI (p = 0.002), and had lower Global Assessment of Functioning (GAF) scores (p = 0.03). Central diabetes insipidus (DI) occurred in 6%, who were more likely to have experienced MVA (p < 0.001) or sustained moderate/severe TBI (p < 0.001). Patients with MVA and those with post-traumatic seizures, intracranial hemorrhage, petechial brain hemorrhages, and/or focal cortical contusions are at particular risk for serious pituitary dysfunction, including adrenal insufficiency and DI, and should be referred for neuroendocrine testing. However, a substantial proportion of patients without these risk factors also developed hypopituitarism. PMID- 26413768 TI - Magnetoelectric Coupling Induced by Interfacial Orbital Reconstruction. AB - Reversible orbital reconstruction driven by ferroelectric polarization modulates the magnetic performance of model ferroelectric/ferromagnetic heterostructures without onerous limitations. Mn-d(x2-y2) orbital occupancy and related interfacial exotic magnetic states are enhanced and weakened by negative and positive electric fields, respectively, filling the missing member-orbital in the mechanism of magnetoelectric coupling and advancing the application of orbitals to microelectronics. PMID- 26413769 TI - Flexible goal attribution in early mindreading. AB - The 2-systems theory developed by Apperly and Butterfill (2009; Butterfill & Apperly, 2013) is an influential approach to explaining the success of infants and young children on implicit false-belief tasks. There is extensive empirical and theoretical work examining many aspects of this theory, but little attention has been paid to the way in which it characterizes goal attribution. We argue here that this aspect of the theory is inadequate. Butterfill and Apperly's characterization of goal attribution is designed to show how goals could be ascribed by infants without representing them as related to other psychological states, and the minimal mindreading system is supposed to operate without employing flexible semantic-executive cognitive processes. But research on infant goal attribution reveals that infants exhibit a high degree of situational awareness that is strongly suggestive of flexible semantic-executive cognitive processing, and infants appear moreover to be sensitive to interrelations between goals, preferences, and beliefs. Further, close attention to the structure of implicit mindreading tasks--for which the theory was specifically designed- indicates that flexible goal attribution is required to succeed. We conclude by suggesting 2 approaches to resolving these problems. PMID- 26413770 TI - Correction: Are Sex Drive and Hypersexuality Associated with Pedophilic Interest and Child Sexual Abuse in a Male Community Sample? PMID- 26413772 TI - Standardization of Free Thyroxine and Harmonization of Thyrotropin Measurements: A Request for Input from Endocrinologists and Other Physicians. PMID- 26413771 TI - Detecting acute mesenteric ischemia in CT of the acute abdomen is dependent on clinical suspicion: Review of 95 consecutive patients. AB - OBJECTIVES: (1) To evaluate the ability of emergency room radiologists to detect acute mesenteric ischemia (AMI) from computed tomography (CT) images in patients with acute abdominal pain. (2) To identify factors affecting radiologists' performance in the CT interpretation and patient outcome. MATERIALS AND METHODS: A retrospective study of 95 consecutive patients treated for 97 AMI events between 2009 and 2013 was carried out. The etiology of AMI was embolism in 24 (25%), atherosclerotic vascular disease (ASVD) in 39 (40%), non-obstructive mesenteric ischemia (NOMI) in 25 (26%), and mesenteric venous thrombosis (MVT) in nine (9%) cases. The protocols, referrals and initial radiology reports of the abdominal CTs were analyzed. The CT studies were further scrutinized for vascular and intestinal findings. RESULTS: The referring clinician had suspected AMI in 30 (31%) cases prior to imaging. The crucial findings of AMI had been stated in 97% of the radiology reports if the clinician had mentioned AMI suspicion in the referral; if not, the corresponding rate was 81% (p=0.04). Patients without suspicion of AMI prior to CT were more prone to undergo bowel resection. CT protocol was optimal for AMI (with contrast enhancement in arterial and venous phases) in only 34 (35%) cases. Intestinal findings were more difficult to detect than vascular findings. Vascular findings were retrospectively detectable in 92% of cases with embolism and 100% in ASVD and MVT. Some evidence of intestinal abnormality was retrospectively found in the CT findings in 92%, 100%, 100% and 67% of cases with embolism, ASVD, NOMI and MVT, respectively. CONCLUSIONS: AMI is underdiagnosed in the CT of the acute abdomen if there is no clinical suspicion. PMID- 26413774 TI - A randomised control trial of the cognitive effects of working in a seated as opposed to a standing position in office workers. AB - Sedentary behaviour is increasing and has been identified as a potential significant health risk, particularly for desk-based employees. The development of sit-stand workstations in the workplace is one approach to reduce sedentary behaviour. However, there is uncertainty about the effects of sit-stand workstations on cognitive functioning. A sample of 36 university staff participated in a within-subjects randomised control trial examining the effect of sitting vs. standing for one hour per day for five consecutive days on attention, information processing speed, short-term memory, working memory and task efficiency. The results of the study showed no statistically significant difference in cognitive performance or work efficiency between the sitting and standing conditions, with all effect sizes being small to very small (all ds < .2). This result suggests that the use of sit-stand workstations is not associated with a reduction in cognitive performance. Practitioner Summary: Although it has been reported that the use of sit-stand desks may help offset adverse health effects of prolonged sitting, there is scant evidence about changes in productivity. This randomised control study showed that there was no difference between sitting and standing for one hour on cognitive function or task efficiency in university staff. PMID- 26413773 TI - HIV-1 Tropism Determines Different Mutation Profiles in Proviral DNA. AB - In order to establish new infections HIV-1 particles need to attach to receptors expressed on the cellular surface. HIV-1 particles interact with a cell membrane receptor known as CD4 and subsequently with another cell membrane molecule known as a co-receptor. Two major different co-receptors have been identified: C-C chemokine Receptor type 5 (CCR5) and C-X-C chemokine Receptor type 4 (CXCR4) Previous reports have demonstrated cellular modifications upon HIV-1 binding to its co-receptors including gene expression modulations. Here we investigated the effect of viral binding to either CCR5 or CXCR4 co-receptors on viral diversity after a single round of reverse transcription. CCR5 and CXCR4 pseudotyped viruses were used to infect non-stimulated and stimulated PBMCs and purified CD4 positive cells. We adopted the SOLiD methodology to sequence virtually the entire proviral DNA from all experimental infections. Infections with CCR5 and CXCR4 pseudotyped virus resulted in different patterns of genetic diversification. CCR5 virus infections produced extensive proviral diversity while in CXCR4 infections a more localized substitution process was observed. In addition, we present pioneering results of a recently developed method for the analysis of SOLiD generated sequencing data applicable to the study of viral quasi-species. Our findings demonstrate the feasibility of viral quasi-species evaluation by NGS methodologies. We presented for the first time strong evidence for a host cell driving mechanism acting on the HIV-1 genetic variability under the control of co receptor stimulation. Additional investigations are needed to further clarify this question, which is relevant to viral diversification process and consequent disease progression. PMID- 26413775 TI - Expression of NY-ESO-1 in Triple-Negative Breast Cancer Is Associated with Tumor Infiltrating Lymphocytes and a Good Prognosis. AB - OBJECTIVES: Accumulating evidence suggests that immunotherapy has great potential for treating triple-negative breast cancer (TNBC). We analyzed the expression of NY-ESO-1, which is a potent immunogenic cancer testis antigen, and its association with clinicopathological factors in large cohorts of breast cancer patients. METHODS: A total of 623 consecutive breast cancer patients who underwent surgery between 1993 and 1998 and 612 TNBC patients who underwent surgery between 2004 and 2010 at Asan Medical Center were included. Immunohistochemical staining for NY-ESO-1 was performed using tissue microarrays. RESULTS: NY-ESO-1 was expressed in 2.6% of consecutive breast cancers, all of which were TNBC (p < 0.001). NY-ESO-1 expression was identified in 9.7% of the TNBC cohort and was significantly correlated with a higher level of tumor infiltrating lymphocytes (TIL; p = 0.026). In survival analyses, a lower level of TIL (all, p < 0.001) and the absence of NY-ESO-1 expression (p = 0.024) were significantly associated with poor disease-free survival. Additionally, positive NY-ESO-1 expression was an independent favorable prognostic factor in TNBC patients (p = 0.046). CONCLUSIONS: NY-ESO-1 is specifically expressed in TNBC, and NY-ESO-1 expression is an independent good prognostic factor in TNBC. Evaluation of NY-ESO-1 expression in TNBC might be useful for selecting patients who may benefit from vaccination therapy and also has a prognostic significance in TNBC. PMID- 26413777 TI - VEGF-A mRNA measurement in meningiomas using a new simplified approach: branched DNA and chemiluminescence. AB - For decades, the preferred and almost sole method for measurement of gene expression has been RT-qPCR. The method is robust, inexpensive, and well-studied; however, PCR is also quite laborious and vulnerable to contamination. As part of an investigation of VEGF-A gene expression in meningiomas, an alternative and less laborious method for gene expression analysis based on branched DNA hybridization and chemiluminescence (Lumistar) was tested. Albeit the two methods differ, in principle, cellular mRNA-concentration is measured with both. Because they both determine gene expression via the measurement of mRNA-concentration, they were expected to be comparable. The aim of the present study was to compare Lumistar to the traditional RT-qPCR approach in a routine laboratory setting, where there is emphasis on rapid analysis response. Meningioma (nA =A 10) and control brain tissue (nA =A 5) samples were collected and VEGF-A and GAPDH mRNA were quantified using both RT-qPCR and Lumistar. Furthermore, two dilution series of two of the meningioma samples were prepared in order to make quantitative analyses. Both Lumistar and RT-qPCR-results were found to follow concentration dependent linear paths when diluted (p < 0.0001 and p < 0.01). Finally, Lumistar and RT-qPCR analyses were performed with the inclusion of a reference gene (GAPDH), where similar results were obtained with the two methods (R2 = 0.48; p = 0.01). It is intriguing that in spite of the vast difference in handling and assay principles, gene expression results are similar. The preferred method depends on the variability of the samples, budget, and time. Lumistar was less time consuming, while RT-qPCR was less expensive and best suited for data sets with large sample variability. PMID- 26413776 TI - Intimate-Partner and Client-Initiated Violence among Female Street-Based Sex Workers in China: Does a Support Network Help? AB - BACKGROUND: Globally, female street-based sex workers are vulnerable to gender based violence. Previous research has shown having a peer social network can reduce sex workers' risks of victimization. However, mechanisms of how social network impacts violence among female street-based sex workers are still far from clear. METHODS: Our study was based on data abstracted from a paper-and-pencil survey administered among 218 female street-based sex workers in Shanghai, China. We focused on self-reported client-initiated violence and intimate-partner violence in emotional, physical, and sexual forms. Social networks were characterized by the size and sources of financial and psychosocial support (e.g. family, friends, and peers). Multi-variable logistic regression was used to estimate adjusted odds ratios (AOR) of each type of violence exposure by social network structure after the adjustment of age, education, and years in Shanghai. RESULTS: The street-based female sex workers in our study were primarily rural-to urban migrants (95.7%) with an average age of 41 years old. 24.3% and 62.8% of the sex workers reported intimate-partner violence and client-initiated violence respectively. Lack of financial support, as defined by having only one individual or none in her peer support system to help financially, was significantly associated with self-reported intimate-partner violence (AOR: 2.5; 95% CI: 1.1 5.9). Respondents who reported client-initiated violence, by contrast, were more likely to report lacked psychosocial support from family (AOR: 2.2, 95% CI: 1.0 4.6) and peers (AOR: 5.1, 95% CI: 2.2-11). CONCLUSION: This study is one of the first to systematically analyze the associations between social network and gender-based violence among street-based female sex worker. We reported a high prevalence of both types of gender-based violence and their complex associations with family, friends, and peer support network. Policies with goals to reduce violence against women may apply these findings to leverage social network in the interventions against gender-based violence. PMID- 26413778 TI - Pathology-confirmed cerebral arterial invasion and recurrent multiple brain metastasis from cardiac myxoma without evidence of disease after surgery and radiotherapy. PMID- 26413779 TI - Bipolar Versus Monopolar Transurethral Resection of Nonmuscle-Invasive Bladder Cancer: A Meta-Analysis. AB - BACKGROUND AND PURPOSE: Bipolar energy has recently been used as a common alternative to conventional monopolar transurethral resection of the bladder (TURB) while managing nonmuscle-invasive bladder cancer (NMIBC). We established a meta-analysis comparing the safety and efficacy of plasmakinetic bipolar and monopolar TURB for NMIBC. METHODS: A systematic search of PubMed, MEDLINE, Web of Science, and China National Knowledge Infrastructure was performed up to March 1, 2015. Outcomes of interest assessing the two techniques included demographic and clinical baseline characteristics, perioperative variables, and complications. RESULTS: Eight eligible trials evaluating bipolar TURB (bTURB) versus monopolar TURB (mTURB) for NMIBC were identified including six randomized controlled trials (RCTs), one prospective study, and one retrospective study. The bTURB was associated with shorter operative time (P = 0.002), shorter hospital stay (P < 0.001), less established blood loss (P < 0.001), and shorter catheterization time (P = 0.004). There were fewer complications such as obturator nerve reflex (P < 0.001) and bladder perforation (P = 0.003) in the bTURB group. The postoperative recurrence rate in 2 years also showed advantages of bTURB over mTURB. CONCLUSION: Our data showed that bTURB appeared to be a safe and efficient method and had presented several advantages when compared with conventional mTURB in the management of NMIBC. As a promising technique, bTURB may be used as a preferable choice instead of mTURB for superficial bladder tumor. PMID- 26413780 TI - Endogenous antigen processing drives the primary CD4+ T cell response to influenza. AB - By convention, CD4+ T lymphocytes recognize foreign and self peptides derived from internalized antigens in combination with major histocompatibility complex class II molecules. Alternative pathways of epitope production have been identified, but their contributions to host defense have not been established. We show here in a mouse infection model that the CD4+ T cell response to influenza, critical for durable protection from the virus, is driven principally by unconventional processing of antigen synthesized within the infected antigen presenting cell, not by classical processing of endocytosed virions or material from infected cells. Investigation of the cellular components involved, including the H2-M molecular chaperone, the proteasome and gamma-interferon-inducible lysosomal thiol reductase revealed considerable heterogeneity in the generation of individual epitopes, an arrangement that ensures peptide diversity and broad CD4+ T cell engagement. These results could fundamentally revise strategies for rational vaccine design and may lead to key insights into the induction of autoimmune and anti-tumor responses. PMID- 26413782 TI - Colon Necrosis Due to Sodium Polystyrene Sulfonate with and without Sorbitol: An Experimental Study in Rats. AB - INTRODUCTION: Based on a single rat study by Lillemoe et al, the consensus has been formed to implicate sorbitol rather than sodium polystyrene sulfonate (SPS) as the culprit for colon necrosis in humans treated with SPS and sorbitol. We tested the hypothesis that colon necrosis by sorbitol in the experiment was due to the high osmolality and volume of sorbitol rather than its chemical nature. METHODS: 26 rats underwent 5/6 nephrectomy. They were divided into 6 groups and given enema solutions under anesthesia (normal saline, 33% sorbitol, 33% mannitol, SPS in 33% sorbitol, SPS in normal saline, and SPS in distilled water). They were sacrificed after 48 hours of enema administration or earlier if they were very sick. The gross appearance of the colon was visually inspected, and then sliced colon tissues were examined under light microscopy. RESULTS: 1 rat from the sorbitol and 1 from the mannitol group had foci of ischemic colonic changes. The rats receiving SPS enema, in sorbitol, normal saline, distilled water, had crystal deposition with colonic necrosis and mucosal erosion. All the rats not given SPS survived until sacrificed at 48 h whereas 11 of 13 rats that received SPS in sorbitol, normal saline or distilled water died or were clearly dying and sacrificed sooner. There was no difference between sorbitol and mannitol when given without SPS. CONCLUSIONS: In a surgical uremic rat model, SPS enema given alone or with sorbitol or mannitol seemed to cause colon necrosis and high mortality rate, whereas 33% sorbitol without SPS did not. PMID- 26413781 TI - Clinical translation of a high-performance neural prosthesis. AB - Neural prostheses have the potential to improve the quality of life of individuals with paralysis by directly mapping neural activity to limb- and computer-control signals. We translated a neural prosthetic system previously developed in animal model studies for use by two individuals with amyotrophic lateral sclerosis who had intracortical microelectrode arrays placed in motor cortex. Measured more than 1 year after implant, the neural cursor-control system showed the highest published performance achieved by a person to date, more than double that of previous pilot clinical trial participants. PMID- 26413783 TI - Generation of human iPS cell line ihFib3.2 from dermal fibroblasts. AB - The human ihFib3.2 iPS cell line was generated from dermal fibroblasts obtained from a healthy donor. Lentiviral particles were produced with the polycistronic hSTEMCCA vector with Oct4, Sox2, cMyc and Klf4 as reprogramming factors. PMID- 26413784 TI - CD34 defines an osteoprogenitor cell population in mouse bone marrow stromal cells. AB - Bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) and their progenitors have been identified based on retrospective functional criteria. CD markers are employed to define cell populations with distinct functional characteristics. However, defining and prospective isolation of BMSCs and committed progenitors are lacking. Here, we compared the transcriptome profile of CD markers expressed at baseline and during the course of osteoblast and adipocyte differentiation of two well-characterized osteogenic committed murine BMSCs (mBMSC(Bone)) and adipogenic-committed mBMSCs (mBMSC(Adipo)), respectively. Bioinformatic analysis revealed the presence of a core set of canonical mBMSC CD markers with comparable expression levels in mBMSC(Bone) and mBMSC(Adipo) at baseline and during their differentiation. We identified 11 CD markers that are differentially expressed between mBMSC(Adipo) and mBMSC(Bone). Among these, we identified osteoprogenitor-associated CD markers expressed only in mBMSC(Bone): CD34, CD54, CD73, CD132, CD200, CD227 and adipoprogenitor-associated CD markers expressed only in mBMSC(Adipo): CD53, CD80, CD134, CD141 and CD212. FACS analysis confirmed these results. We selected CD34 for further analysis. CD34 was expressed at baseline of mouse stromal cell line ST2, primary mBMSCs, mBMSC(Bone) and its expression decreased during osteoblast differentiation. FACS-sorted CD34(+) primary mBMSCs exhibited higher expression of 70% osteoblast-associated genes, and formed significantly higher heterotopic bone in vivo when implanted subcutaneously in immune-deficient mice compared with CD34(-) primary mBMSCs. Our results demonstrate that a set of CD markers can distinguish osteoprogenitor versus adipoprogenitor populations of mBMSCs. CD34 is suitable for prospective isolation of mouse bone marrow osteoprogenitors. PMID- 26413785 TI - Amyotrophic lateral sclerosis models derived from human embryonic stem cells with different superoxide dismutase 1 mutations exhibit differential drug responses. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron (MN) disease. The gene encoding superoxide dismutase 1 (SOD1) is a causative element of familial ALS. Animal ALS models involving SOD1 gene mutations are widely used to study the underlying mechanisms of disease and facilitate drug discovery. Unfortunately, most drug candidates have failed in clinical trials, potentially due to species differences among rodents and humans. It is unclear, however, whether there are different responses to drugs among the causative genes of ALS or their associated mutations. In this study, to evaluate different SOD1 mutations, we generated SOD1-ALS models derived from human embryonic stem cells with identical genetic backgrounds, except for the overexpression of mutant variants of SOD1. The overexpression of mutant SOD1 did not affect pluripotency or MN differentiation. However, mutation-dependent reductions in neurite length were observed in MNs. Moreover, experiments investigating the effects of specific compounds revealed that each ALS model displayed different responses with respect to MN neurite length. These results suggest that SOD1 mutations could be classified based the response of MNs to drug treatment. This classification could be useful for the development of mutant-specific strategies for drug discovery and clinical trials. PMID- 26413786 TI - Establishment of leukemia inhibitory factor (LIF)-independent iPS cells with potentiated Oct4. AB - Leukemia inhibitory factor (LIF) is widely used to establish and maintain naive pluripotent stem cells, including mouse embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Although the combination of chemical inhibitors called 2i can establish mouse iPSCs without LIF from primed pluripotent stem cells, it has been difficult, if not impossible, to establish mouse iPSCs from differentiated somatic cells without LIF. We previously showed that the fusion gene of the transactivation domain of MyoD and the full-length Oct4 (M3O) increases the efficiency of making iPSCs when transduced into fibroblasts along with Sox2, Klf4, and c-Myc (M3O-SKM). Here, we report that M3O-SKM allows for establishment of iPSCs without exogenous LIF from mouse embryonic fibroblasts. The established iPSCs remained undifferentiated and maintained pluripotency over 90 days without LIF as long as M3O was expressed. The iPSCs upregulated miR-205 5p, which was potentially involved in the LIF-independence by suppressing the two signaling pathways inhibited by 2i. The result indicates that potentiated Oct4 can substitute for the LIF signaling pathway, providing a novel model to link Oct4 and LIF, two of the most significant players in naive pluripotency. PMID- 26413787 TI - E-Ras improves the efficiency of reprogramming by facilitating cell cycle progression through JNK-Sp1 pathway. AB - We have previously shown that pluripotent stem cells can be induced from adult somatic cells which were exposed to protein extracts isolated from mouse embryonic stem cells (mESC). Interestingly, generation of induced pluripotent stem (iPS) cells depended on the background of ES cell lines; possible by extracts from C57, but not from E14. Proteomic analysis of two different mES cell lines (C57 and E14) shows that embryonic Ras (E-Ras) is expressed differently in two mES cell lines; high level of E-Ras only in C57 mESC whose extracts allows iPS cells production from somatic cells. Here, we show that E-Ras augments the efficiency in reprogramming of fibroblast by promoting cell proliferation. We found that over-expression of E-Ras in fibroblast increased cell proliferation which was caused by specific up-regulation of cyclins D and E, not A or B, leading to the accelerated G1 to S phase transition. To figure out the common transcription factor of cyclins D and E, we used TRANSFAC database and selected SP1 as a candidate which was confirmed as enhancer of cyclins D and E by luciferase promoter assay using mutants. As downstream signaling pathways, E-Ras activated only c-Jun N-terminal kinases (JNK) but not ERK or p38. Inhibition of JNK prevented E-Ras-mediated induction of pSP1, cyclins D, E, and cell proliferation. Finally, E-Ras transduction to fibroblast enhanced the efficiency of iPS cell generation by 4 factors (Oct4/Klf4/Sox2/C-myc), which was prevented by JNK inhibitor. In conclusion, E-Ras stimulates JNK, enhances binding of Sp1 on the promoter of cyclins D and E, leading to cell proliferation. E-Ras/JNK axis is a critical mechanism to generate iPS cells by transduction of 4 factors or by treatment of mESC protein extracts. PMID- 26413788 TI - Improving Maternal Care through a State-Wide Health Insurance Program: A Cost and Cost-Effectiveness Study in Rural Nigeria. AB - BACKGROUND: While the Nigerian government has made progress towards the Millennium Development Goals, further investments are needed to achieve the targets of post-2015 Sustainable Development Goals, including Universal Health Coverage. Economic evaluations of innovative interventions can help inform investment decisions in resource-constrained settings. We aim to assess the cost and cost-effectiveness of maternal care provided within the new Kwara State Health Insurance program (KSHI) in rural Nigeria. METHODS AND FINDINGS: We used a decision analytic model to simulate a cohort of pregnant women. The primary outcome is the incremental cost effectiveness ratio (ICER) of the KSHI scenario compared to the current standard of care. Intervention cost from a healthcare provider perspective included service delivery costs and above-service level costs; these were evaluated in a participating hospital and using financial records from the managing organisations, respectively. Standard of care costs from a provider perspective were derived from the literature using an ingredient approach. We generated 95% credibility intervals around the primary outcome through probabilistic sensitivity analysis (PSA) based on a Monte Carlo simulation. We conducted one-way sensitivity analyses across key model parameters and assessed the sensitivity of our results to the performance of the base case separately through a scenario analysis. Finally, we assessed the sustainability and feasibility of this program's scale up within the State's healthcare financing structure through a budget impact analysis. The KSHI scenario results in a health benefit to patients at a higher cost compared to the base case. The mean ICER (US$46.4/disability-adjusted life year averted) is considered very cost effective compared to a willingness-to-pay threshold of one gross domestic product per capita (Nigeria, US$ 2012, 2,730). Our conclusion was robust to uncertainty in parameters estimates (PSA: median US$49.1, 95% credible interval 21.9-152.3), during one-way sensitivity analyses, and when cost, quality, cost and utilization parameters of the base case scenario were changed. The sustainability of this program's scale up by the State is dependent on further investments in healthcare. CONCLUSIONS: This study provides evidence that the investment made by the KSHI program in rural Nigeria is likely to have been cost effective; however, further healthcare investments are needed for this program to be successfully expanded within Kwara State. Policy makers should consider supporting financial initiatives to reduce maternal mortality tackling both supply and demand issues in the access to care. PMID- 26413789 TI - Evaluation of the long-term cost-effectiveness of liraglutide therapy for patients with type 2 diabetes in France. AB - OBJECTIVES: The present study aimed to compare the projected long-term clinical and cost implications associated with liraglutide, sitagliptin and glimepiride in patients with type 2 diabetes mellitus failing to achieve glycemic control on metformin monotherapy in France. METHODS: Clinical input data for the modeling analysis were taken from two randomized, controlled trials (LIRA-DPP4 and LEAD 2). Long-term (patient lifetime) projections of clinical outcomes and direct costs (2013 Euros; ?) were made using a validated computer simulation model of type 2 diabetes. Costs were taken from published France-specific sources. Future costs and clinical benefits were discounted at 3% annually. Sensitivity analyses were performed. RESULTS: Liraglutide was associated with an increase in quality adjusted life expectancy of 0.25 quality-adjusted life years (QALYs) and an increase in mean direct healthcare costs of ?2558 per patient compared with sitagliptin. In the comparison with glimepiride, liraglutide was associated with an increase in quality-adjusted life expectancy of 0.23 QALYs and an increase in direct costs of ?4695. Based on these estimates, liraglutide was associated with an incremental cost-effectiveness ratio (ICER) of ?10,275 per QALY gained vs sitagliptin and ?20,709 per QALY gained vs glimepiride in France. CONCLUSION: Calculated ICERs for both comparisons fell below the commonly quoted willingness to-pay threshold of ?30,000 per QALY gained. Therefore, liraglutide is likely to be cost-effective vs sitagliptin and glimepiride from a healthcare payer perspective in France. PMID- 26413790 TI - Erratum. AB - JUDY OU, SEBASTIEN HAIART, STEVEN GALLUCCIO, JULIAN WHITE, and SCOTT A. WEINSTEIN. (2015) An instructive case of presumed brown snake ( Pseudonaja spp.) Envenoming Clinical Toxicology, 53(08), pp. 834-839. http://dx.doi.org/10.3109/15563650.2015.1059947 When the above article was first published online, there was an inadvertent omission from the authors' Conflict of Interest statement. This unintentional omission is corrected below: The public teaching hospital that employs two of the authors (JW and SAW) has a long standing contract with CSL Ltd, the company that produces brown snake antivenom. The hospital provides advice to health practitioners pertaining to the diagnosis and management of envenoming and related toxinology diseases. The contract with CSL Ltd allows such queries to CSL to be addressed through our hospital service. Our department provides this service on behalf of the hospital. Dr. White occasionally receives travel support to attend toxinology meetings from CSL Ltd. However, neither he nor his family receives any financial remuneration or other compensation from CSL Ltd. CSL Ltd had no role or input into this work. PMID- 26413791 TI - Improvement of polypyrrole nanowire devices by plasmonic space charge generation: high photocurrent and wide spectral response by Ag nanoparticle decoration. AB - In this study, improvement of the opto-electronic properties of non-single crystallized nanowire devices with space charges generated by localized surface plasmon resonance (LSPR) is demonstrated. The photocurrent and spectral response of single polypyrrole (PPy) nanowire (NW) devices are increased by electrostatically attached Ag nanoparticles (Ag NPs). To take advantage of plasmon-exciton coupling in the photocurrent of the device, 80 nm of Ag NPs (454 nm = lambdamax) were chosen for matching the maximum absorption with PPy NWs (442 nm = lambdamax). The photocurrent density is remarkably improved, up to 25.3 times (2530%), by the Ag NP decoration onto the PPy NW (PPyAgNPs NW) under blue light (lambda = 425-475 nm) illumination. In addition, the PPyAgNPs NW shows a photocurrent decay time twice that of PPy NW, as well as an improved spectral response of the photocurrent. The improved photocurrent efficiency, decay time, and spectral response resulted from the space charges generated by the LSPR of Ag NPs. Furthermore, the increasing exponent (m) of the photocurrent (JPC ~ V(m)) and finite-differential time domain (FDTD) simulation straightforwardly indicate relatively large plasmonic space charge generation under blue light illumination. These results prove that the performance of non-single crystallized polymer nanowire devices can also be improved by plasmonic enhancement. PMID- 26413792 TI - Physicochemical and in vitro mucoadhesive properties of microparticles/discs of betamethasone for the management of oral lichen planus. AB - This study involved the preparation and evaluation of buccal-mucoadhesive microparticles/discs of bethamethasone disodium phosphate (BDSP). The microparticles were prepared using the emulsion solvent diffusion method. Microparticles were prepared and characterized by encapsulation efficiency particle size, Fourier Transform Infra Red (FTIR) spectrums, Differential Scanning Calorimetric (DSC) thermograms and mucoadhesive properties. FTIR studies reported that BDSP was changed to bethamethasone base molecule inside the intact microparticles. The best drug to polymers ratio in microparticles was F1 containing 50 mg drug, 50 mg HPMC (as non-ionic and hydrophilic polymer) and 50 mg carbomer 934p (an anionic mucoadhesive polymer). The production yield of F1 microparticles was calculated as 78.60% with loading efficiency of about 65.14% and the mean particle size was also measured as 281.84 MUm. It was proposed that during the microparticle preparation procedure, water soluble salt of the drug may be converted to the base which could be more effective in the buccal mucosa due to its higher partition coefficient and lipophilicity. The highest and lowest releases resulted from the discs prepared from F1 and F4, respectively, compared with the commercial tablet and untreated drug powder (p < 0.05). The data revealed that the discs exhibited good percentage of mucoadhesion (F1, 326 g/cm2). It may be concluded that drug loaded buccal-mucoadhesive microparticles are a suitable delivery system for BDSP, and may be used in the effective management of lichen planus. PMID- 26413794 TI - Clinical outcome after switching therapy from ranibizumab and/or bevacizumab to aflibercept in central retinal vein occlusion. AB - PURPOSE: After 48 months, unresolved macular edema secondary to central retinal vein occlusion (CRVO) is present in more than half of the patients treated with ranibizumab/bevacizumab. Switching therapy to aflibercept, a more recent vascular endothelial growth factor-A (VEGF-A) inhibitor, as well as VEGF-B and placental growth factor inhibitor, might improve the clinical outcome in patients with CRVO who respond insufficiently to ranibizumab/bevacizumab. METHODS: The presented study is a retrospective analysis of CRVO patients (n = 13) responding insufficiently to ranibizumab and/or bevacizumab (requiring treatment every 6 weeks or more frequently). Treatment in these patients was switched to aflibercept, which was administered based on a 'treat and extend' regime. The injection interval, relapse-free interval, central retinal thickness, central retinal volume, visual acuity, and intraocular pressure (IOP) were evaluated prior to switching to aflibercept and at month 6 and year 1 after switching therapy. RESULTS: From baseline to year 1 after switching therapy to aflibercept, the mean injection interval (primary end point) increased by 0.51 months (p = 0.023) and the relapse-free interval by 3.02 weeks (p = 0.003). The mean central retinal thickness decreased by 195.84 um and the mean central retinal volume (6 mm diameter) by -1.81 mm3 (p = 0.007). Correspondingly, the mean ETDRS score increased from 66.15 at baseline to 76.54 letters at year 1 after switching therapy to aflibercept (+10.38 letters, p = 0.021). The IOP was not statistically significantly affected (-1.2 mm Hg, p = 0.196). CONCLUSION: Switching therapy from intravitreal ranibizumab/bevacizumab to aflibercept in insufficiently responding macular edema secondary to CRVO elongates the injection interval and the relapse-free interval and provides an improved anatomical as well as functional outcome. PMID- 26413795 TI - Recent patents and technology transfer for molecular diagnosis of beta thalassemia and other hemoglobinopathies. AB - INTRODUCTION: Biological tests and genetic analyses for diagnosis and characterization of hematological diseases in health laboratories are designed with the aim of meeting the major medical needs of hospitals and pharmaceutical companies involved in this field of applied biomedicine. Genetic testing approaches to perform diagnosis consist of molecular techniques, which should be absolutely reproducible, fast, sensitive, cheap, and portable. AREAS COVERED: Biological tests analyzed involve adult/newborn subjects, whereas genetic analyses involve adult thalassemia patients, newborns, embryos/fetuses (including non-invasive prenatal diagnosis), pre-implantation embryos, and pre-fertilization oocytes. EXPERT OPINION: The most recent findings in the diagnostic approach for beta-thalassemias are related to three major fields of investigation: moving towards ultrasensitive methodologies for effective detection of the primary causative mutation of beta-thalassemia, including the development of polymerase chain reaction-free approaches and non-invasive prenatal diagnosis; comparing analyses of the genotype of beta-thalassemia patients to high-HbF-associated polymorphisms; introducing whole genome association assays and next-generation sequencing. All these issues should be considered and discussed in the context of several aspects, including regulatory, ethical and social issues. DNA sequence data aligned with the identification of genes central to the induction, development, progression, and outcome of beta-thalassemia will be a key point for directing personalized therapy. PMID- 26413793 TI - Ligament Tissue Engineering Using a Novel Porous Polycaprolactone Fumarate Scaffold and Adipose Tissue-Derived Mesenchymal Stem Cells Grown in Platelet Lysate. AB - PURPOSE: Surgical reconstruction of intra-articular ligament injuries is hampered by the poor regenerative potential of the tissue. We hypothesized that a novel composite polymer "neoligament" seeded with progenitor cells and growth factors would be effective in regenerating native ligamentous tissue. METHODS: We synthesized a fumarate-derivative of polycaprolactone fumarate (PCLF) to create macro-porous scaffolds to allow cell-cell communication and nutrient flow. Clinical grade human adipose tissue-derived human mesenchymal stem cells (AMSCs) were cultured in 5% human platelet lysate (PL) and seeded on scaffolds using a dynamic bioreactor. Cell growth, viability, and differentiation were examined using metabolic assays and immunostaining for ligament-related markers (e.g., glycosaminoglycans [GAGs], alkaline phosphatase [ALP], collagens, and tenascin C). RESULTS: AMSCs seeded on three-dimensional (3D) PCLF scaffolds remain viable for at least 2 weeks with proliferating cells filling the pores. AMSC proliferation rates increased in PL compared to fetal bovine serum (FBS) (p < 0.05). Cells had a low baseline expression of ALP and GAG, but increased expression of total collagen when induced by the ligament and tenogenic growth factor fibroblast growth factor 2 (FGF-2), especially when cultured in the presence of PL (p < 0.01) instead of FBS (p < 0.05). FGF-2 and PL also significantly increased immunostaining of tenascin-C and collagen at 2 and 4 weeks compared with human fibroblasts. SUMMARY: Our results demonstrate that AMSCs proliferate and eventually produce a collagen-rich extracellular matrix on porous PCLF scaffolds. This novel scaffold has potential in stem cell engineering and ligament regeneration. PMID- 26413796 TI - Ultraviolet light-emitting-diode irradiation inhibits TNF-alpha and IFN-gamma induced expression of ICAM-1 and STAT1 phosphorylation in human keratinocytes. AB - BACKGROUND AND OBJECTIVES: Ultraviolet light-emitting diodes (UV-LEDs) are a novel light source for phototherapy. This research investigated the in vitro safety and efficacy of UV-LEDs as a phototherapeutic device for atopic dermatitis (AD). STUDY DESIGN/MATERIALS AND METHODS: Human keratinocytes and fibroblasts were irradiated by UV-LEDs with a center wavelength of 310 and 340 nm. We examined the effects of UV-LED irradiation on the suppression of TNF-alpha/IFN gamma-induced activation of STAT1 and ICAM-1 and on NF-kappaB expression; we used the following methods: cell viability assay, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, Western blotting, and immunocytochemistry. RESULTS: We observed anti-inflammatory responses through the suppression of TNF-alpha/IFN-gamma-induced expression of TARC and MCP-1/CCL2, IL 1beta, IL-6, and sICAM-1 via blockage of ICAM-1 activation and subsequent activation of STAT1 and NF-kappaB. The results suggested that UV-LED irradiation inhibited ICAM expression by suppressing TNF-alpha/IFN-gamma-induced NF-kappaB activation in vitro. CONCLUSION: We concluded that novel UV-LED (310 and 340 nm) modalities were effective for the treatment of AD and may be promising for the treatment of inflammatory skin diseases. PMID- 26413797 TI - Berry Phenolic Compounds Increase Expression of Hepatocyte Nuclear Factor-1alpha (HNF-1alpha) in Caco-2 and Normal Colon Cells Due to High Affinities with Transcription and Dimerization Domains of HNF-1alpha. AB - Hepatocyte nuclear factor-1alpha (HNF-1alpha) is found in the kidneys, spleen, thymus, testis, skin, and throughout the digestive organs. It has been found to promote the transcription of various proteins involved in the management of type II diabetes, including dipeptidyl peptidase-IV (DPP-IV). Phenolic compounds from berries and citrus fruits are known to inhibit DPP-IV, but have not been tested for their interactions with wild-type HNF-1alpha. By studying the interactions of compounds from berries and citrus fruits have with HNF-1alpha, pre transcriptional mechanisms that inhibit the expression of proteins such as DPP-IV may be elucidated. In this study, the interactions of berry phenolic compounds and citrus flavonoids with the dimerization and transcriptional domains of HNF 1alpha were characterized using the molecular docking program AutoDock Vina. The anthocyanin delphinidin-3-O-arabinoside had the highest binding affinity for the dimerization domain as a homodimer (-7.2 kcal/mol) and transcription domain (-8.3 kcal/mol) of HNF-1alpha. Anthocyanins and anthocyanidins had relatively higher affinities than resveratrol and citrus flavonoids for both, the transcription domain and the dimerization domain as a homodimer. The flavonoid flavone had the highest affinity for a single unit of the dimerization domain (-6.5 kcal/mol). Nuclear expression of HNF-1alpha was measured in Caco-2 and human normal colon cells treated with blueberry and blackberry anthocyanin extracts. All extracts tested increased significantly (P < 0.05) the nuclear expression of HNF-1alpha in Caco-2 cells by 85.2 to 260% compared to a control. The extracts tested increased significantly (P < 0.02) the nuclear expression of HNF-1alpha in normal colon cells by 48.6 to 243%. It was confirmed that delphinidin-3-O-glucoside increased by 3-fold nuclear HNF-1alpha expression in Caco-2 cells (P < 0.05). Anthocyanins significantly increased nuclear HNF-1alpha expression, suggesting that these compounds might regulate the genes HNF-1alpha promotes. PMID- 26413798 TI - Correction: CD26 Expression on T Helper Populations and sCD26 Serum Levels in Patients with Rheumatoid Arthritis. PMID- 26413799 TI - Drug-Drug Molecular Salt Hydrate of an Anticancer Drug Gefitinib and a Loop Diuretic Drug Furosemide: An Alternative for Multidrug Treatment. AB - A 1:1 monohydrate salt containing gefitinib, an orally administrated chemotherapy treatment for lung and breast cancers and furosemide, a loop diuretic drug, commonly used in the treatment of hypertension and edema, has been prepared. The molecular salt crystallized in triclinic P-1 space group. The C-O bond lengths (~1.26 A) in the COOH group show that proton transfer has occurred from furosemide to morpholine moiety of the gefitinib suggesting cocrystal to be ionic. The morpholine moiety of the gefitinib showed significant conformational change because of its involvement in conformation dictating the strong N-H...O hydrogen bonding interaction. The strong hydrogen bonding interaction between gefitinib and furosemide places their benzene rings in stacking mode to facilitate the generation of pi-stack dimers. The neighboring dimers are bridged to each other via water molecule through N-H...O, C-H...O, O-H...N, and O-H...O interactions. The remarkable stability of the salt hydrate could be attributed to the strong hydrogen bonding interactions in the crystal structure. Interestingly, release of water from the lattice at 140 degrees C produced new anhydrous salt that has better solubility and dissolution rate than salt hydrate. The drug-drug molecular salt may have some bearing on the treatment of patient suffering from anticancer and hypertension. PMID- 26413800 TI - Eco-efficiency of agricultural water systems: Methodological approach and assessment at meso-level scale. AB - This study presents a methodological framework for the meso-level eco-efficiency assessment of agricultural water systems using a life-cycle system-based approach. The methodology was applied to the Sinistra Ofanto irrigation scheme, located in Southern Italy, where about 28,165 ha are under irrigation. The environmental performance of the system was evaluated through a set of selected mid-point environmental impact categories while the economic performance was measured using the total value added to the system's final products due to water use and the adopted management practices. Both economic performance and environmental performance were measured at different stages and for each stakeholder in the value chain. A distinction was made between foreground and background systems referring, respectively, to the processes that occurred inside the water system boundaries and those used for the production of supplementary resources. The analysis revealed that the major environmental burdens are: i) the freshwater resource depletion (i.e. excessive groundwater pumping), ii) climate change (i.e. direct emissions due to fertilizer use and diesel combustion), and iii) eutrophication (as a result of excessive application of N and P fertilizers). A considerable impact was observed on the background system where energy, fuel and agrochemicals were produced thereby confirming the prominent role of background processes in the comprehensive eco-efficiency assessment. The presented methodology aimed at the quantitative assessment of the eco-efficiency level rather than at the identification of the most affected environmental category. Hence, the results can be used to compare the performance of the system from one year to the next, among different stakeholders (water users) and/or to assess the impact of adopting innovative technologies and management practices. Moreover, the presented approach is useful for comparing the performance among different agricultural water systems and also in respect to other meso-level water systems in a cross-sectorial analysis. PMID- 26413801 TI - Residues of endosulfan in surface and subsurface agricultural soil and its bioremediation. AB - The persistence of many hydrophobic pesticides has been reported by various workers in various soil environments and its bioremediation is a major concern due to less bioavailability. In the present study, the pesticide residues in the surface and subsurface soil in an area of intense agricultural activity in Pakkam Village of Thiruvallur District, Tamilnadu, India, and its bioremediation using a novel bacterial consortium was investigated. Surface (0-15 cm) and subsurface soils (15-30 cm and 30-40 cm) were sampled, and pesticides in different layers of the soil were analyzed. Alpha endosulfan and beta endosulfan concentrations ranged from 1.42 to 3.4 mg/g and 1.28-3.1 mg/g in the surface soil, 0.6-1.4 mg/g and 0.3-0.6 mg/g in the subsurface soil (15-30 cm), and 0.9-1.5 mg/g and 0.34-1.3 mg/g in the subsurface soil (30-40 cm) respectively. Residues of other persistent pesticides were also detected in minor concentrations. These soil layers were subjected to bioremediation using a novel bacterial consortium under a simulated soil profile condition in a soil reactor. The complete removal of alpha and beta endosulfan was observed over 25 days. Residues of endosulfate were also detected during bioremediation, which was subsequently degraded on the 30th day. This study revealed the existence of endosulfan in the surface and subsurface soils and also proved that the removal of such a ubiquitous pesticide in the surface and subsurface environment can be achieved in the field by bioaugumenting a biosurfactant-producing bacterial consortium that degrades pesticides. PMID- 26413802 TI - Temporal trends of perfluoroalkyl substances in limed biosolids from a large municipal water resource recovery facility. AB - While the recycling of wastewater biosolids via land-application is a sustainable practice for nutrient recovery and soil reclamation that has become increasingly common worldwide, concerns remain that this practice may become a source of toxic, persistent organic pollutants to the environment. This study concentrates on assessing the presence and the temporal trends of 12 perfluoroalkyl substances (PFASs), pollutants of global consequence, in limed Class B biosolids from a municipal water resource recovery facility (WRRF), also know as a wastewater treatment plant. PFASs are of significant concern due to their extensive presence and persistence in environmental and biotic samples worldwide, most notably human blood samples. Class B biosolids were collected from the WRRF, prior to land application, approximately every two to three months, from 2005 to 2013. Overall, this study found that concentrations of the 7 detectable PFAS compounds remained unchanged over the 8-year period, a result that is consistent with other temporal studies of these compounds in sewage sludges. From these analyzed compounds, the highest mean concentrations observed over the study period were 25.1 ng/g dw, 23.5 ng/g dw, and 22.5 ng/g dw for perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), and perfluorooctanesulfonic acid (PFOS), respectively, and these compounds were detected at concentrations 2.5-5 times higher than the remaining, detectable PFASs. Furthermore, it was observed that PFOS, while demonstrating no overall change during the study, exhibited a visible spike in concentration from late 2006 to early 2007. This study indicates that concentrations of PFASs in WRRFs have been stagnant over time, despite regulation. This study also demonstrates that the use of glass jars with polytetrafluoroethylene-lined lids, a common storage method for environmental samples, will not influence PFOA and PFNA concentrations in archived biosolids samples. PMID- 26413803 TI - Degradation of enoxacin antibiotic by the electro-Fenton process: Optimization, biodegradability improvement and degradation mechanism. AB - This study aims to investigate the effectiveness of the electro-Fenton process on the removal of a second generation of fluoroquinolone, enoxacin. The electrochemical reactor involved a carbon-felt cathode and a platinum anode. The influence of some experimental parameters, namely the initial enoxacin concentration, the applied current intensity and the Fe(II) amount, was examined. The degradation of the target molecule was accompanied by an increase of the biodegradability, assessed from the BOD5 on COD ratio, which increased from 0 before treatment until 0.5 after 180 min of electrolysis at 50 mg L(-1) initial enoxacin concentration, 0.2 mmol L(-1) Fe(II) concentration and 300 mA applied current intensity. TOC and COD time-courses were also evaluated during electrolysis and reached maximum residual yields of 54% and 43% after 120 min of treatment, respectively. Moreover, a simultaneous generation of inorganic ions (fluorides, ammonium and nitrates) were observed and 3 short chain carboxylic acids (formic, acetic and oxalic acids) were identified and monitored during 180 min of electrolysis. By-products were identified according to UPLC-MS/MS results and a degradation pathway was proposed. PMID- 26413804 TI - The potential for tree planting strategies to reduce local and regional ecosystem impacts of agricultural ammonia emissions. AB - Trees are very effective at capturing both gaseous and particulate pollutants from the atmosphere. But while studies have often focussed on PM and NOx in the urban environment, little research has been carried out on the tree effect of capturing gaseous emissions of ammonia in the rural landscape. To examine the removal or scavenging of ammonia by trees a long-range atmospheric model (FRAME) was used to compare two strategies that could be used in emission reduction policies anywhere in the world where nitrogen pollution from agriculture is a problem. One strategy was to reduce the emission source strength of livestock management systems by implementing two 'tree-capture' systems scenarios - tree belts downwind of housing and managing livestock under trees. This emission reduction can be described as an 'on-farm' emission reduction policy, as ammonia is 'stopped' from dispersion outside the farm boundaries. The second strategy was to apply an afforestation policy targeting areas of high ammonia emission through two planting scenarios of increasing afforestation by 25% and 50%. Both strategies use trees with the aim of intercepting NH3 emissions to protect semi natural areas. Scenarios for on-farm emission reductions showed national reductions in nitrogen deposition to semi-natural areas of 0.14% (0.2 kt N-NHx) to 2.2% (3.15 kt N-NHx). Scenarios mitigating emissions from cattle and pig housing gave the highest reductions. The afforestation strategy showed national reductions of 6% (8.4 kt N-NHx) to 11% (15.7 kt N-NHx) for 25% and 50% afforestation scenarios respectively. Increased capture by the planted trees also showed an added benefit of reducing long range effects including a decrease in wet deposition up to 3.7 kt N-NHx (4.6%) and a decrease in export from the UK up to 8.3 kt N-NHx (6.8%). PMID- 26413805 TI - Simultaneous biosorption of selenium, arsenic and molybdenum with modified algal based biochars. AB - Ash disposal waters from coal-fired power stations present a challenging water treatment scenario as they contain high concentrations of the oxyanions Se, As and Mo which are difficult to remove through conventional techniques. In an innovative process, macroalgae can be treated with Fe and processed through slow pyrolysis into Fe-biochar which has a high affinity for oxyanions. However, the effect of production conditions on the efficacy of Fe-biochar is poorly understood. We produced Fe-biochar from two algal sources; "Gracilaria waste" (organic remnants after agar is extracted from cultivated Gracilaria) and the freshwater macroalgae Oedogonium. Pyrolysis experiments tested the effects of the concentration of Fe(3+) in pre-treatment, and pyrolysis temperatures, on the efficacy of the Fe-biochar. The efficacy of Fe-biochar increased with increasing concentrations of Fe(3+) in the pre-treatment solutions, and decreased with increasing pyrolysis temperatures. The optimized Fe-biochar for each biomass was produced by treatment with a 12.5% w/v Fe(3+) solution, followed by slow pyrolysis at 300 degrees C. The Fe-biochar produced in this way had higher a biosorption capacity for As and Mo (62.5-80.7 and 67.4-78.5 mg g(-1) respectively) than Se (14.9-38.8 mg g(-1)) in single-element mock effluents, and the Fe-biochar produced from Oedogonium had a higher capacity for all elements than the Fe-biochar produced from Gracilaria waste. Regardless, the optimal Fe biochars from both biomass sources were able to effectively treat Se, As and Mo simultaneously in an ash disposal effluent from a power station. The production of Fe-biochar from macroalgae is a promising technique for treatment of complex effluents containing oxyanions. PMID- 26413806 TI - Spatial Patterns and Risk Assessment of Heavy Metals in Soils in a Resource Exhausted City, Northeast China. AB - Northeast China is an intensive area of resource-exhausted city, which is facing the challenges of industry conversion and sustainable development. In order to evaluate the soil environmental quality influenced by mining activities over decades, the concentration and spatial distribution of arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), nickel (Ni), lead (Pb), and Zinc (Zn) in surface soils (0-20cm) of a typical resource-exhausted city were investigated by analyzing 306 soil samples. The results showed that the average concentrations in the samples were 6.17 mg/kg for As, 0.19 mg/kg for Cd, 51.08 mg/kg for Cr, 23.27 mg/kg for Cu, 31.15 mg/kg for Ni, 22.17 mg/kg for Pb, and 54.21 mg/kg for Zn. Metals distribution maps produced by using the inverse distance weighted interpolation method and results revealed that all investigated metals showed distinct geographical patterns, and the concentrations were higher in urban and industrial areas than in farmland. Pearson correlation and principal component analysis showed that there were significant positive correlations (p<0.05) between all of the metals, and As, Cd, Cr, Mn, Ni, Pb, and Zn were closely associated with the first principal component (PC1), which explained 39.81% of the total variance. Cu and As were mainly associated with the second component (PC2). Based on the calculated Nemerow pollution index, percentage for slightly polluted (1

90%. Employing small molecule- and decoy-peptide-based approaches we further affirm that complete remission of BCCs could only be achieved by combined inhibition of p50-NFkappaB/Bcl3 and Shh signaling. We posit that Ptch1+/-/SKH-1 mice are a novel and relevant animal model for NBCCS. Understanding mechanisms that govern genetic predisposition to BCCs should facilitate our ability to identify and treat NBCCS gene carriers, including those at risk for sporadic BCCs while accelerating development of novel therapeutic modalities for these patients. PMID- 26413812 TI - JAK2 tyrosine kinase mediates integrin activation induced by CXCL12 in B-cell chronic lymphocytic leukemia. AB - Chemokines participate to B-cell chronic lymphocytic leukemia (B-CLL) pathogenesis by promoting cell adhesion and survival in bone marrow stromal niches and mediating cell dissemination to secondary lymphoid organs. In this study we investigated the role of JAK protein tyrosine kinases (PTK) in adhesion triggering by the CXC chemokine CXCL12 in normal versus CLL B-lymphocytes. We demonstrate that CXCL12 activates JAK2 in normal as well as CLL B-lymphocytes, with kinetics consistent with rapid adhesion triggering. By using complementary methodologies of signal transduction interference, we found that JAK2 mediates CXCL12-triggered activation of lymphocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4) integrins. We also show that JAK2 mediates the activation of the small GTP-binding protein RhoA, in turn controlling LFA-1 affinity triggering by CXCL12. Importantly, comparative analysis of 41 B-CLL patients did not evidence JAK2 functional variability between subjects, thus suggesting that JAK2, differently from other signaling events involved in adhesion regulation in B-CLL, is a signaling molecule downstream to CXCR4 characterized by a conserved regulatory role. Our results reveal JAK2 as critical component of chemokine signaling in CLL B-lymphocytes and indicate JAK inhibition as a potentially useful new pharmacological approach to B-CLL treatment. PMID- 26413813 TI - GLI1 orchestrates CXCR4/CXCR7 signaling to enhance migration and metastasis of breast cancer cells. AB - The up-regulation of chemokine receptors CXCR4 and CXCR7 impacts on the distant metastasis and prognosis of breast cancer, though knowledge about the regulatory mechanism of their expressions is limited. Meanwhile, the GLI transcription factors of Hedgehog signaling have been reported to play a pivotal role in the development and progression of many types of human cancer. In breast cancer, the increased expression of GLI1 correlated with metastasis and unfavorable overall prognosis, though its molecular mechanism is also not fully understood. Based on our findings that GLI1 enhanced the lung metastasis of breast cancer cells in a mouse model system, we comprehensively screened for genes up-regulated by GLI1 in breast cancer cells, and as such identified CXCR4, CXCR7/ACKR3, and actin-binding protein LCP1/L-PLASTIN, all of which have been reported to be involved in CXCL12 stimulating signaling. In breast cancer cells, we found that GLI1 and GLI2 up regulated these expressions, while treatment with GLI-specific inhibitor GANT61 reduced the expressions. As for CXCR4, we confirmed it as a direct target of GLI1 through the reporter assay and the chromatin immunoprecipitation assay. We also found that GLI1 enhanced CXCL12-induced ERK phosphorylation and cell migration, both of which were blocked by either CXCR4-specific inhibitor or knockdown of CXCR7 or LCP1. These evidences suggest an indispensable role of GLI1 in the migration and metastasis of breast cancer cells through CXCL12/CXCR4 signaling enhancement. PMID- 26413814 TI - Valproic acid enhances the efficacy of radiation therapy by protecting normal hippocampal neurons and sensitizing malignant glioblastoma cells. AB - Neurocognitive deficits are serious sequelae that follow cranial irradiation used to treat patients with medulloblastoma and other brain neoplasms. Cranial irradiation causes apoptosis in the subgranular zone of the hippocampus leading to cognitive deficits. Valproic acid (VPA) treatment protected hippocampal neurons from radiation-induced damage in both cell culture and animal models. Radioprotection was observed in VPA-treated neuronal cells compared to cells treated with radiation alone. This protection is specific to normal neuronal cells and did not extend to cancer cells. In fact, VPA acted as a radiosensitizer in brain cancer cells. VPA treatment induced cell cycle arrest in cancer cells but not in normal neuronal cells. The level of anti-apoptotic protein Bcl-2 was increased and the pro-apoptotic protein Bax was reduced in VPA treated normal cells. VPA inhibited the activities of histone deacetylase (HDAC) and glycogen synthase kinase-3beta (GSK3beta), the latter of which is only inhibited in normal cells. The combination of VPA and radiation was most effective in inhibiting tumor growth in heterotopic brain tumor models. An intracranial orthotopic glioma tumor model was used to evaluate tumor growth by using dynamic contrast-enhanced magnetic resonance (DCE MRI) and mouse survival following treatment with VPA and radiation. VPA, in combination with radiation, significantly delayed tumor growth and improved mouse survival. Overall, VPA protects normal hippocampal neurons and not cancer cells from radiation-induced cytotoxicity both in vitro and in vivo. VPA treatment has the potential for attenuating neurocognitive deficits associated with cranial irradiation while enhancing the efficiency of glioma radiotherapy. PMID- 26413815 TI - Differential expression and biochemical activity of the immune receptor Tim-3 in healthy and malignant human myeloid cells. AB - The T cell immunoglobulin and mucin domain 3 (Tim-3) is a plasma membrane associated receptor which is involved in a variety of biological responses in human immune cells. It is highly expressed in most acute myeloid leukaemia (AML) cells and therefore may serve as a possible target for AML therapy. However, its biochemical activities in primary human AML cells remain unclear. We therefore analysed the total expression and surface presence of the Tim-3 receptor in primary human AML blasts and healthy primary human leukocytes isolated from human blood. We found that Tim-3 expression was significantly higher in primary AML cells compared to primary healthy leukocytes. Tim-3 receptor molecules were distributed largely on the surface of primary AML cells, whereas in healthy leukocytes Tim-3 protein was mainly expressed intracellularly. In primary human AML blasts, both Tim-3 agonistic antibody and galectin-9 (a Tim-3 natural ligand) significantly upregulated mTOR pathway activity. This was in line with increased accumulation of hypoxia-inducible factor 1 alpha (HIF-1alpha) and secretion of VEGF and TNF-alpha. Similar results were obtained in primary human healthy leukocytes. Importantly, in both types of primary cells, Tim-3-mediated effects were compared with those induced by lipopolysaccharide (LPS) and stem cell factor (SCF). Tim-3 induced comparatively moderate responses in both AML cells and healthy leukocytes. However, Tim-3, like LPS, mediated the release of both TNF alpha and VEGF, while SCF induced mostly VEGF secretion and did not upregulate TNF-alpha release. PMID- 26413817 TI - Relationship between self-focused attention, mindfulness and distress in individuals with auditory verbal hallucinations. AB - INTRODUCTION: The purpose of this study was to investigate the relationships among self-focused attention, mindfulness and distress caused by the voices in psychiatric patients. METHODS: Fifty-one individuals with a psychiatric diagnosis participated in this study. The Psychotic Symptom Rating Scale (PSYRATS) emotional factor was applied to measure the distress caused by the voices, the Self-Absorption Scale (SAS) was given for measuring the levels of self-focused attention, and the Mindful Attention Awareness Scale (MAAS) was used to measure mindfulness. RESULTS: The results showed that distress caused by the voices correlated positively with self-focused attention (private and public) and negatively with mindfulness. A negative correlation was also found between mindfulness and self-focused attention (private and public). Finally, multiple linear regression analysis showed that public self-focus was the only factor predicting distress caused by the voices. CONCLUSIONS: Intervention directed at diminishing public self-focused attention and increasing mindfulness could improve distress caused by the voices. PMID- 26413821 TI - Temporospatial and kinetic gait variables of Doberman Pinschers with and without cervical spondylomyelopathy. AB - OBJECTIVE: To characterize and compare gait variables in Doberman Pinschers with and without cervical spondylomyelopathy (CSM). ANIMALS: 18 Doberman Pinschers (9 clinically normal dogs and 9 CSM-affected dogs). PROCEDURES: A neurologic examination was performed on all dogs. The diagnosis of CSM was confirmed with MRI. Temporospatial and kinetic gait variables were measured by use of a pressure sensitive walkway. Temporospatial variables evaluated included stance phase duration, swing phase duration, gait cycle duration, stride length, and gait velocity. Kinetic variables evaluated included peak vertical force and vertical impulse. Random-effects linear regression was used to determine the difference between CSM-affected and clinically normal dogs for each of the 7 variables. RESULTS: Values for temporospatial variables were significantly smaller in the thoracic limbs of CSM-affected dogs, compared with values for the thoracic limbs of clinically normal dogs. For the kinetic variables, peak vertical force was significantly higher in the thoracic limbs than the pelvic limbs for all dogs. Vertical impulse values were higher in the thoracic limbs than the pelvic limbs. There were significant differences in mean vertical impulse between the thoracic and pelvic limbs for both groups. CONCLUSIONS AND CLINICAL RELEVANCE: In this study, significant differences in temporospatial variables were identified between the thoracic limbs of clinically normal and CSM-affected dogs, with the values being smaller for the CSM-affected dogs than for the clinically normal dogs. A pressure-sensitive walkway may provide a valid, practical option for rapid, objective assessment of gait and response to treatment in dogs with CSM. PMID- 26413816 TI - Chlamydia trachomatis immunoglobulin G3 seropositivity is a predictor of reproductive outcomes in infertile women with patent fallopian tubes. AB - OBJECTIVE: To determine if Chlamydia trachomatis (C. trachomatis) seropositivity, as detected by the C. trachomatis elementary body (EB)-based enzyme-linked immunosorbent assay [EB ELISA] predicts pregnancy and pregnancy outcome among infertile women with documented tubal patency. DESIGN: Cohort study. SETTING: Outpatient clinics. PATIENT(S): In all, 1,250 infertile women with documented tubal patency enrolled in 1 of 2 randomized controlled trials: Pregnancy in Polycystic Ovary Syndrome II; and the Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation. INTERVENTION(S): Sera were analyzed for anti C. trachomatis immunoglobulin G (IgG)1 and IgG3 antibodies, using a research C. trachomatis EB ELISA. The optical density (OD)405 readings of >= 0.35 and >= 0.1 were considered positive for IgG1 and IgG3, respectively. MAIN OUTCOME MEASURE(S): Primary outcomes included pregnancy, live birth, and ectopic pregnancy. Log-linear regression was used to determine the relative risk after adjusting for age, race, treatment medication, smoking status, and current alcohol use. RESULT(S): A total of 243 (19%) women were seropositive for anti-C. trachomatis IgG3. They tended to be nonwhite and smokers. Anti-C. trachomatis IgG3 seropositive women were significantly less likely to conceive (risk ratio [RR] 0.65, 95% confidence interval [CI] 0.52-0.83) or to have a live birth (RR 0.59, 95% CI 0.43-0.80); these associations were weakened after adjusting for number of hysterosalpingography-documented patent tubes (RR 0.73, 95% CI 0.56 0.97) and (RR 0.73, 95% CI 0.50-1.04), respectively. Anti-C. trachomatis IgG3 seropositive women who conceived had a *2.7 risk (95% CI 1.40-5.34) of ectopic pregnancy. CONCLUSION(S): Even in the presence of tubal patency, anti-C. trachomatis IgG3 seropositivity is associated with a lower likelihood of pregnancy. Anti-C. trachomatis IgG3 seropositive women have as high as 3 times the risk of ectopic pregnancy. CLINICAL TRIAL REGISTRATION NUMBER: PPCOSII: NCT00719186 and AMIGOS: NCT01044862. PMID- 26413818 TI - DNA Methylation Dynamics During Differentiation, Proliferation, and Tumorigenesis in the Intestinal Tract. AB - DNA methylation, an epigenetic control mechanism in mammals, is widely present in the intestinal tract during the differentiation and proliferation of epithelial cells. Cells in stem cell pools or villi have different patterns of DNA methylation. The process of DNA methylation is dynamic and occurs at many relevant regulatory elements during the rapid transition of stem cells into fully mature, differentiated epithelial cells. Changes in DNA methylation patterns most often take place in enhancer and promoter regions and are associated with transcription factor binding. During differentiation, enhancer regions associated with genes important to enterocyte differentiation are demethylated, activating gene expression. Abnormal patterns of DNA methylation during differentiation and proliferation in the intestinal tract can lead to the formation of aberrant crypt foci and destroy the barrier and absorptive functions of the intestinal epithelium. Accumulation of these epigenetic changes may even result in tumorigenesis. In the current review, we discuss recent findings on the association between DNA methylation and cell differentiation and proliferation in the small intestine and highlight the possible links between dysregulation of this process and tumorigenesis. PMID- 26413822 TI - Evaluation of the safety of long-term, daily oral administration of grapiprant, a novel drug for treatment of osteoarthritic pain and inflammation, in healthy dogs. AB - OBJECTIVE: To investigate the safety of daily oral administration of grapiprant to dogs. ANIMALS: Thirty-six 9-month-old Beagles of both sexes. PROCEDURES: Dogs were randomly assigned to groups that received grapiprant via oral gavage at 0, 1, 6, or 50 mg/kg (total volume, 5 mL/kg), q 24 h for 9 months. Each group contained 4 dogs of each sex (ie, 8 dogs/group), except for the 50 mg/kg group, which included 4 additional dogs that were monitored for an additional 30 days after treatment concluded (recovery period). All dogs received ophthalmologic, ECG, and laboratory evaluations before treatment began (baseline) and periodically afterward. All dogs were observed daily. Dogs were euthanized at the end of the study for necropsy and histologic evaluation. RESULTS: All dogs remained clinically normal during treatment, with no apparent changes in appetite or demeanor. Emesis and soft or mucoid feces that occasionally contained blood were observed in all groups, although these findings were more common in dogs that received grapiprant. In general, clinicopathologic findings remained within baseline ranges. Drug-related changes in serum total protein and albumin concentrations were detected, but differences were small and resolved during recovery. No drug-related gross or microscopic pathological changes were detected in tissue samples except mild mucosal regeneration in the ileum of 1 dog in the 50 mg/kg group. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested the safety of long-term oral administration of grapiprant to dogs. Efficacy of grapiprant in the treatment of dogs with osteoarthritis needs to be evaluated in other studies. PMID- 26413823 TI - Bactericidal effects of various concentrations of enrofloxacin, florfenicol, tilmicosin phosphate, and tulathromycin on clinical isolates of Mannheimia haemolytica. AB - OBJECTIVE: To determine bactericidal effects of enrofloxacin, florfenicol, tilmicosin, and tulathromycin on clinical isolates of Mannheimia haemolytica at various bacterial densities and drug concentrations. SAMPLE: 4 unique isolates of M haemolytica recovered from clinically infected cattle. PROCEDURES: Minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined for each drug and isolate. Mannheimia haemolytica suspensions (10(6) to 10(9) CFUs/mL) were exposed to the determined MIC and MPC and preestablished maximum serum and tissue concentrations of each drug. Log10 reduction in viable cells (percentage of cells killed) was measured at various points. RESULTS: Bacterial killing at the MIC was slow and incomplete. After 2 hours of isolate exposure to the MPC and maximum serum and tissue concentrations of the tested drugs, 91% to almost 100% cell killing was achieved with enrofloxacin, compared with 8% growth to 93% cell killing with florfenicol, 199% growth to 63% cell killing with tilmicosin, and 128% growth to 43% cell killing with tulathromycin over the range of inoculum tested. For all drugs, killing of viable organisms was evident at all bacterial densities tested; however, killing was more substantial at the MPC and maximum serum and tissue drug concentrations than at the MIC and increased with duration of drug exposure. Rank order of drugs by killing potency was enrofloxacin, florfenicol, tilmicosin, and tulathromycin. CONCLUSIONS AND CLINICAL RELEVANCE: Findings suggested that antimicrobial doses that equaled or exceeded the MPC provided rapid killing of M haemolytica by the tested drugs, decreasing opportunities for antimicrobial-resistant subpopulations of bacteria to develop during drug exposure. PMID- 26413824 TI - Development of a model to induce transient synovitis and lameness in the hip joint of dogs. AB - OBJECTIVE: To develop a model of hip joint synovitis on the basis of intra articular injection of a sodium urate suspension in dogs and to characterize associated gait changes. ANIMALS: 6 healthy adult dogs. PROCEDURES: Each dog was sedated, and synovitis was induced by injection of 1 mL of a sodium urate suspension (20 mg/mL) into the right hip joint under ultrasonographic guidance. Observational and instrumented gait analyses to determine temporospatial, kinetic, and kinematic variables were performed prior to and 4, 8, and 24 hours after sedation and synovitis induction. RESULTS: Injection of a sodium urate suspension into the hip joint of healthy dogs resulted in lameness of the ipsilateral pelvic limb as determined by observational and instrumented gait analyses. For all dogs, lameness was clinically detectable within 1.5 to 2 hours after injection, reached its maximum intensity at 4 hours after injection, and had subsided by 24 hours after injection. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that injection of a sodium urate suspension into the hip joint of healthy dogs reliably induced synovitis and signs of pain and lameness in the ipsilateral pelvic limb that lasted 24 hours. This model can be used in conjunction with instrumented gait analysis to provide information on gait changes associated with hip joint disease and might be useful for evaluating the efficacy of analgesics or other interventions for the treatment of hip joint disease in dogs. PMID- 26413825 TI - In vitro assessment of bacterial translocation during needle insertion through inoculated culture media as a model of arthrocentesis through cellulitic tissue. AB - OBJECTIVE: To determine by use of an in vitro model the potential for translocating sufficient numbers of bacteria into a joint during arthrocentesis through cellulitic tissue to cause sepsis. SAMPLE: Culture media containing 4 concentrations of Staphylococcus aureus and needles of 3 sizes. PROCEDURES: Needles (22, 20, and 19 gauge) were inserted through Mueller-Hinton agar that contained known concentrations of S aureus (10(3),10(4),10(5), and 10(6) CFUs/mL). After a needle exited through the medium, any agar plug within the needle bore was ejected into a sterile syringe and the contaminated portion of the needle was harvested. Sterile saline (0.9% NaCl) solution was used to emulsify the agar plug and wash the contaminated portion of the needle. The resulting solution was cultured to determine the number of bacterial CFUs that could be deposited into a joint during arthrocentesis through contaminated tissue. RESULTS: Needle gauge and bacterial concentration were both associated with the number of bacterial CFUs deposited after insertion through contaminated agar. Although all needle sizes were capable of bacterial translocation sufficient to cause septic arthritis, ORs for 20- and 22-gauge needles translocating > 33 CFUs of S aureus were significantly higher than the OR for a 19-gauge needle. The ORs for 20- or 22-gauge needles translocating > 33 CFUs of S aureus (the minimum population of S aureus known to cause joint sepsis) were 0.22. CONCLUSIONS AND CLINICAL RELEVANCE: Results for this in vitro model indicated that caution should be used when performing arthrocentesis through cellulitic tissue. PMID- 26413826 TI - Evaluation of serum amyloid A and haptoglobin concentrations as prognostic indicators for horses with inflammatory disease examined at a tertiary care hospital. AB - OBJECTIVE: To evaluate use of serum amyloid A (SAA) and haptoglobin concentrations as prognostic indicators for horses with inflammatory disease in regard to euthanasia, complications, and hospitalization duration and cost. ANIMALS: 20 clinically normal horses and 53 horses with inflammatory disease. PROCEDURES: Total WBC count, neutrophil count, and fibrinogen, SAA, and haptoglobin concentrations were determined for clinically normal horses and horses with suspected inflammatory disease. Clinicopathologic values at admission were compared to test the use of SAA and haptoglobin concentrations in predicting euthanasia, complications, and hospitalization duration and cost. Haptoglobin and SAA concentrations of 22 horses were monitored during hospitalization to test the use of serial measurements in predicting survival and complications. RESULTS: Neutrophil count and SAA and haptoglobin concentrations were significantly different at admission for horses with inflammatory disease, compared with those for clinically normal horses. Horses with colitis and peritonitis had significantly higher SAA and haptoglobin concentrations than clinically normal horses. A moderate positive correlation (r = 0.355) between hospitalization duration and haptoglobin concentration was identified. Horses with an increase in SAA concentration between 24 and 72 hours after admission, compared with admission SAA concentration, were significantly more likely (OR, 7.0; 95% confidence interval, 1.1 to 45.9) to be euthanized or develop complications. CONCLUSIONS AND CLINICAL RELEVANCE: Concentrations of SAA and haptoglobin at admission were not significantly correlated with outcome in horses with inflammatory conditions. Acute-phase proteins likely have more utility in serial analysis rather than testing at a single time point for horses with inflammatory conditions. PMID- 26413827 TI - Effects of a docosahexaenoic acid-rich microalgae nutritional product on insulin sensitivity after prolonged dexamethasone treatment in healthy mature horses. AB - OBJECTIVE: To determine effects of a microalgae nutritional product on insulin sensitivity in horses. ANIMALS: 8 healthy mature horses. PROCEDURES :Horses (n = 4/group) received a basal diet without (control diet) or with docosahexaenoic acid-rich microalgae meal (150 g/d) for 49 days (day 0 = first day of diet). On day 28, an isoglycemic hyperinsulinemic clamp procedure was performed. Horses then received dexamethasone (0.04 mg/kg/d) for 21 days. On day 49, the clamp procedure was repeated. After a 60-day washout, horses received the alternate diet, and procedures were repeated. Plasma fatty acid, glucose, and insulin concentrations and glucose and insulin dynamics during the clamp procedure were measured on days 28 and 49. Two estimates of insulin sensitivity (reciprocal of the square root of the insulin concentration and the modified insulin-to-glucose ratio for ponies) were calculated. RESULTS: Baseline glucose and insulin concentrations or measures of insulin sensitivity on day 28 did not differ between horses when fed the control diet or the basal diet plus microalgae meal. On day 49 (ie, after dexamethasone administration), the microalgae meal was associated with lower baseline insulin and glucose concentrations and an improved modified insulin-to-glucose ratio for ponies, compared with results for the control diet. CONCLUSIONS AND CLINICAL RELEVANCE: Although the microalgae meal had no effect on clamp variables following dexamethasone treatment, it was associated with improved plasma glucose and insulin concentrations and insulin sensitivity estimates. A role for microalgae in the nutritional management of insulin-resistant horses warrants investigation. PMID- 26413828 TI - Use of indocyanine green and sodium fluorescein for anterior segment angiography in ophthalmologically normal cats. AB - OBJECTIVE: To assess and compare results of anterior segment angiography of ophthalmologically normal cats following IV injection with indocyanine green and sodium fluorescein dyes. ANIMALS: 10 client-owned cats. PROCEDURES: Anterior segment angiography was performed in anesthetized cats following administration of 0.25% indocyanine green (1.0 mg/kg, IV) or 10% sodium fluorescein (20 mg/kg, IV) solution. All cats received both treatments. Imaging (1 eye/cat) was performed with a full-spectrum digital single-lens reflex camera equipped with an adaptor (1 image/s for 30 seconds) immediately following IV dye injection and 1, 2, 3, 4, and 5 minutes after injection. Onset and duration of arterial, capillary, and venous phases of iris vasculature were identified and compared statistically between treatments. Degree of iridal pigmentation, leakage of dye from iris vasculature, and image quality were subjectively assessed. RESULTS: No differences were found in onset or duration of vascular phases between treatments. Visibility of the iris vasculature was not impaired by poor or moderate iridal pigmentation with either method. Indocyanine green provided subjectively better vascular detail and image contrast than sodium fluorescein. No vascular dye leakage was observed following indocyanine green administration. Leakage of dye from blood vessels in the stroma (in 10 cats) and presence of dye in the anterior chamber (in 5 cats) were detected after sodium fluorescein administration. CONCLUSIONS AND CLINICAL RELEVANCE: Images obtained with either fluorescent dye were considered to be of diagnostic quality. Lack of leakage following indocyanine green administration suggested this treatment may have better diagnostic utility for anterior segment angiography. The photographic equipment used provided a cost-effective alternative to existing imaging systems. PMID- 26413829 TI - Effect of laser treatment on first-intention incisional wound healing in ball pythons (Python regius). AB - OBJECTIVE: To evaluate effects of laser treatment on incisional wound healing in ball pythons (Python regius). ANIMALS: 6 healthy adult ball pythons. PROCEDURES: Snakes were sedated, a skin biopsy specimen was collected for histologic examination, and eight 2-cm skin incisions were made in each snake; each incision was closed with staples (day 0). Gross evaluation of all incision sites was performed daily for 30 days, and a wound score was assigned. Four incisions of each snake were treated (5 J/cm(2) and a wavelength of 980 nm on a continuous wave sequence) by use of a class 4 laser once daily for 7 consecutive days; the other 4 incisions were not treated. Two excisional skin biopsy specimens (1 control and 1 treatment) were collected from each snake on days 2, 7, 14, and 30 and evaluated microscopically. Scores were assigned for total inflammation, degree of fibrosis, and collagen maturity. Generalized linear models were used to investigate the effect of treatment on each variable. RESULTS: Wound scores for laser-treated incisions were significantly better than scores for control incisions on day 2 but not at other time points. There were no significant differences in necrosis, fibroplasia, inflammation, granuloma formation, or bacterial contamination between control and treatment groups. Collagen maturity was significantly better for the laser-treated incisions on day 14. CONCLUSIONS AND CLINICAL RELEVANCE: Laser treatment resulted in a significant increase in collagen maturity at day 14 but did not otherwise significantly improve healing of skin incisions. PMID- 26413830 TI - Anti-bovine herpesvirus and anti-bovine viral diarrhea virus antibody responses in pregnant Holstein dairy cattle following administration of a multivalent killed virus vaccine. AB - OBJECTIVE: To determine the effect of a commercially available multivalent killed virus vaccine on serum neutralizing (SN) and colostrum neutralizing (CN) antibodies against bovine herpesvirus (BHV) type 1 and bovine viral diarrhea virus (BVDV) types 1 and 2 in pregnant dairy cattle. ANIMALS: 49 Holstein dairy cattle. PROCEDURES :25 cattle were vaccinated (IM injection) at least 60 days prior to calving (ie, at the end of the lactation period or according to the expected calving date for heifers) and again 5 weeks later. The remaining 24 cattle were not vaccinated (control group). Titers of SN antibodies were measured at the 5-week time point. Titers of SN and CN antibodies were measured at parturition. RESULTS: 5 weeks after initial vaccination, titers of SN antibodies against BHV-1 and BVDV types 1 and 2 were 1:512, 1:128, and 1:2,048, respectively, in vaccinates and 1:64, 1:128, and 1:64, respectively, in unvaccinated controls. Equivalent SN antibody titers at parturition were 1:256, 1:64, and 1:512, respectively, in vaccinates and 1:128, 1:128, and 1:64, respectively, in controls. Median titers of CN antibodies against BHV-1 and BVDV types 1 and 2 were 1:1,280, 1:10,240, and 1:20,480, respectively, in vaccinates and 1:80, 1:1,280, and 1:2,560, respectively, in controls. CONCLUSIONS AND CLINICAL RELEVANCE: Titers of antibodies against viral respiratory pathogens were significantly enhanced in both serum (BHV-1 and BVDV type 2) and colostrum (BHV-1 and BVDV types 1 and 2) in cattle receiving a killed virus vaccine (with no adverse reactions) before parturition. To maximize protection of bovine neonates, this method of vaccination should be considered. PMID- 26413831 TI - Preoperative Decision Making for Nephron-Sparing Procedure in the Renal Mass: Time for Using Standard Tools? AB - OBJECTIVE: To determine if the application of using standard tools on tumor complexity and comorbidity indexes may replace the traditional choice of nephron sparing procedure (NSP) based on clinical maximal tumor diameter (cMTD), age, and comorbidity. PATIENTS AND METHODS: Anatomic complexity scores (PADUA and RENAL) and Charlson comorbidity index (CCI) and CCI age-adjusted (CACI) were applied to 261 cases of either nephron-sparing surgery (NSS) or cryoablation (CA). Patient- and tumor-related preoperative variables, PADUA, RENAL, CCI, and CACI, were evaluated for their association and as treatment predictors in uni- and multivariate regression analysis. Discriminative ability of each of the models generated was compared for their receiver operating curve area under the curve (AUC). Survival analysis was performed using log rank tests. RESULTS: In total, 124 cases underwent partial nephrectomy and 137 cases CA. cMTD, RENAL, PADUA, age, and CACI were independently associated with the choice of NSS. Five models integrating a combination of age, cMTD, CACI, PADUA, and RENAL (scores and complexity groups) showed an AUC >0.72 to predict the odds of receiving NSS. The discriminative ability of these five models was not statistically significantly different. CONCLUSIONS: cMTD, RENAL, PADUA, age, and CACI are preoperative variables independently associated with the choice of NSP. Models incorporating tools on tumor anatomic complexity and CACI may replace the decision-making in the type of NSP based on cMTD and age. The use of these models can be of value for future standardization and comparison. PMID- 26413833 TI - Clinical Significance of Prenatal and Postnatal Heavily T2-Weighted Magnetic Resonance Images in Patients with Myelomeningocele. AB - PURPOSE: To compare the utility and limitations of prenatal magnetic resonance (MR) imaging using half-Fourier acquisition single-shot turbo spin-echo (HASTE) with postnatal heavily T2-weighted imaging (hT2WI) for the evaluation of central nervous system abnormalities associated with myelomeningocele (MMC). METHODS: Sixteen patients with MMC who had undergone pre- and postnatal MR imaging were included in this study. MR imaging, including HASTE, was undertaken in the 3rd trimester, and hT2WI was performed immediately after delivery. The precision with which each could distinguish MMC, hindbrain herniation and ventriculomegaly was compared retrospectively. RESULTS: The skin defects and MMC sacs were clearly visible on prenatal HASTE images, although it was difficult to identify precisely the level of MMC compared with postnatal hT2WI, in which the detailed anatomical relationships of the spinal cord, neural placode and ventral nerve roots were evident in every case. Hindbrain herniation could be visualized on prenatal HASTE images, although its severity was difficult to evaluate because of the small size of the structures and neck flexion; again, the resolution was superior on postnatal hT2WI. For hydrocephalus, there were no significant differences in the diagnostic precision and ability to grade the severity between pre- and postnatal imaging. CONCLUSION: Prenatal HASTE imaging permits the diagnosis and understanding of the gross anatomy of MMC and associated hindbrain herniation and ventriculomegaly, but postnatal hT2WI is superior for evaluating detailed anatomy. PMID- 26413834 TI - Control of Neuronal Network in Caenorhabditis elegans. AB - Caenorhabditis elegans, a soil dwelling nematode, is evolutionarily rudimentary and contains only ~ 300 neurons which are connected to each other via chemical synapses and gap junctions. This structural connectivity can be perceived as nodes and edges of a graph. Controlling complex networked systems (such as nervous system) has been an area of excitement for mankind. Various methods have been developed to identify specific brain regions, which when controlled by external input can lead to achievement of control over the state of the system. But in case of neuronal connectivity network the properties of neurons identified as driver nodes is of much importance because nervous system can produce a variety of states (behaviour of the animal). Hence to gain insight on the type of control achieved in nervous system we implemented the notion of structural control from graph theory to C. elegans neuronal network. We identified 'driver neurons' which can provide full control over the network. We studied phenotypic properties of these neurons which are referred to as 'phenoframe' as well as the 'genoframe' which represents their genetic correlates. We find that the driver neurons are primarily motor neurons located in the ventral nerve cord and contribute to biological reproduction of the animal. Identification of driver neurons and its characterization adds a new dimension in controllability of C. elegans neuronal network. This study suggests the importance of driver neurons and their utility to control the behaviour of the organism. PMID- 26413836 TI - Development and Validation of the Scan of Postgraduate Educational Environment Domains (SPEED): A Brief Instrument to Assess the Educational Environment in Postgraduate Medical Education. AB - INTRODUCTION: Current instruments to evaluate the postgraduate medical educational environment lack theoretical frameworks and are relatively long, which may reduce response rates. We aimed to develop and validate a brief instrument that, based on a solid theoretical framework for educational environments, solicits resident feedback to screen the postgraduate medical educational environment quality. METHODS: Stepwise, we developed a screening instrument, using existing instruments to assess educational environment quality and adopting a theoretical framework that defines three educational environment domains: content, atmosphere and organization. First, items from relevant existing instruments were collected and, after deleting duplicates and items not specifically addressing educational environment, grouped into the three domains. In a Delphi procedure, the item list was reduced to a set of items considered most important and comprehensively covering the three domains. These items were triangulated against the results of semi-structured interviews with 26 residents from three teaching hospitals to achieve face validity. This draft version of the Scan of Postgraduate Educational Environment Domains (SPEED) was administered to residents in a general and university hospital and further reduced and validated based on the data collected. RESULTS: Two hundred twenty-three residents completed the 43-item draft SPEED. We used half of the dataset for item reduction, and the other half for validating the resulting SPEED (15 items, 5 per domain). Internal consistencies were high. Correlations between domain scores in the draft and brief versions of SPEED were high (>0.85) and highly significant (p<0.001). Domain score variance of the draft instrument was explained for >=80% by the items representing the domains in the final SPEED. CONCLUSIONS: The SPEED comprehensively covers the three educational environment domains defined in the theoretical framework. Because of its validity and brevity, the SPEED is promising as useful and easily applicable tool to regularly screen educational environment quality in postgraduate medical education. PMID- 26413837 TI - Radiation-induced resistance oscillations in a 2D hole gas: a demonstration of a universal effect. AB - We report on a theoretical study about the microwave-induced resistance oscillations and zero resistance states when dealing with p-type semiconductors and holes instead of electrons. We consider a high-mobility two-dimensional hole gas hosted in a pure Ge/SiGe quantum well. Similarly to electrons we obtain radiation-induced resistance oscillations and zero resistance states. We analytically deduce a universal expression for the irradiated magnetoresistance, explaining the origin of the minima positions and their 1/4 cycle phase shift. The outcome is that these phenomena are universal and only depend on radiation and cyclotron frequencies. We also study the possibility of having simultaneously two different carriers driven by radiation: light and heavy holes. As a result the calculated magnetoresistance reveals an interference profile due to the different effective masses of the two types of carriers. PMID- 26413835 TI - The speed of swelling kinetics modulates cell volume regulation and calcium signaling in astrocytes: A different point of view on the role of aquaporins. AB - Regulatory volume decrease (RVD) is a process by which cells restore their original volume in response to swelling. In this study, we have focused on the role played by two different Aquaporins (AQPs), Aquaporin-4 (AQP4), and Aquaporin 1 (AQP1), in triggering RVD and in mediating calcium signaling in astrocytes under hypotonic stimulus. Using biophysical techniques to measure water flux through the plasma membrane of wild-type (WT) and AQP4 knockout (KO) astrocytes and of an astrocyte cell line (DI TNC1) transfected with AQP4 or AQP1, we here show that AQP-mediated fast swelling kinetics play a key role in triggering and accelerating RVD. Using calcium imaging, we show that AQP-mediated fast swelling kinetics also significantly increases the amplitude of calcium transients inhibited by Gadolinium and Ruthenium Red, two inhibitors of the transient receptor potential vanilloid 4 (TRPV4) channels, and prevented by removing extracellular calcium. Finally, inhibition of TRPV4 or removal of extracellular calcium does not affect RVD. All together our study provides evidence that (1) AQP influenced swelling kinetics is the main trigger for RVD and in mediating calcium signaling after hypotonic stimulus together with TRPV4, and (2) calcium influx from the extracellular space and/or TRPV4 are not essential for RVD to occur in astrocytes. PMID- 26413838 TI - Diminished Chondrogenesis and Enhanced Osteoclastogenesis in Leptin-Deficient Diabetic Mice (ob/ob) Impair Pathologic, Trauma-Induced Heterotopic Ossification. AB - Diabetic trauma patients exhibit delayed postsurgical wound, bony healing, and dysregulated bone development. However, the impact of diabetes on the pathologic development of ectopic bone or heterotopic ossification (HO) following trauma is unknown. In this study, we use leptin-deficient mice as a model for type 2 diabetes to understand how post-traumatic HO development may be affected by this disease process. Male leptin-deficient (ob/ob) or wild-type (C57BL/6 background) mice aged 6-8 weeks underwent 30% total body surface area burn injury with left hind limb Achilles tenotomy. Micro-CT (MUCT) imaging showed significantly lower HO volumes in diabetic mice compared with wild-type controls (0.70 vs. 7.02 mm(3), P < 0.01) 9 weeks after trauma. Ob/ob mice showed evidence of HO resorption between weeks 5 and 9. Quantitative real time PCR (qRT-PCR) demonstrated high Vegfa levels in ob/ob mice, which was followed by disorganized vessel growth at 7 weeks. We noted diminished chondrogenic gene expression (SOX9) and diminished cartilage formation at 5 days and 3 weeks, respectively. Tartrate resistant acid phosphatase stain showed increased osteoclast presence in normal native bone and pathologic ectopic bone in ob/ob mice. Our findings suggest that early diminished HO in ob/ob mice is related to diminished chondrogenic differentiation, while later bone resorption is related to osteoclast presence. PMID- 26413839 TI - Immune and Inflammatory Cell Composition of Human Lung Cancer Stroma. AB - Recent studies indicate that the abnormal microenvironment of tumors may play a critical role in carcinogenesis, including lung cancer. We comprehensively assessed the number of stromal cells, especially immune/inflammatory cells, in lung cancer and evaluated their infiltration in cancers of different stages, types and metastatic characteristics potential. Immunohistochemical analysis of lung cancer tissue arrays containing normal and lung cancer sections was performed. This analysis was combined with cyto-/histomorphological assessment and quantification of cells to classify/subclassify tumors accurately and to perform a high throughput analysis of stromal cell composition in different types of lung cancer. In human lung cancer sections we observed a significant elevation/infiltration of total-T lymphocytes (CD3+), cytotoxic-T cells (CD8+), T helper cells (CD4+), B cells (CD20+), macrophages (CD68+), mast cells (CD117+), mononuclear cells (CD11c+), plasma cells, activated-T cells (MUM1+), B cells, myeloid cells (PD1+) and neutrophilic granulocytes (myeloperoxidase+) compared with healthy donor specimens. We observed all of these immune cell markers in different types of lung cancers including squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma, small cell carcinoma, papillary adenocarcinoma, metastatic adenocarcinoma, and bronchioloalveolar carcinoma. The numbers of all tumor-associated immune cells (except MUM1+ cells) in stage III cancer specimens was significantly greater than those in stage I samples. We observed substantial stage-dependent immune cell infiltration in human lung tumors suggesting that the tumor microenvironment plays a critical role during lung carcinogenesis. Strategies for therapeutic interference with lung cancer microenvironment should consider the complexity of its immune cell composition. PMID- 26413841 TI - Right-to-try laws: hope, hype, and unintended consequences. PMID- 26413843 TI - Correction: Effects of Reducing Antimicrobial Use and Applying a Cleaning and Disinfection Program in Veal Calf Farming: Experiences from an Intervention Study to Control Livestock-Associated MRSA. PMID- 26413840 TI - The Impact of Midcervical Contusion Injury on Diaphragm Muscle Function. AB - Midcervical contusion injuries disrupt descending ipsilateral excitatory bulbospinal projections to phrenic motoneurons, compromising ventilation. We hypothesized that a unilateral contusion injury at C3 versus C5 would differentially impact phrenic activity reflecting more prominent disruption of ipsilateral descending excitatory drive to more caudal segments of the phrenic motor pool with more cranial injuries. Phrenic motoneuron counts and evidence of diaphragm muscle denervation at individual neuromuscular junctions (NMJ) were evaluated at 14 days post-injury after unilateral contusion injury (100 kDynes). Whole body plethysmography and chronic diaphragm EMG were measured before the injury and at 3, 7, and 14 days post-injury. Contusion injuries at either level resulted in a similarly sized cavity. C3 contusion resulted in loss of 39 +/- 13% of ipsilateral phrenic motoneurons compared with 13 +/- 21% after C5 contusion (p = 0.003). Cervical contusion injuries resulted in diaphragm muscle denervation (C3 contusion: 17 +/- 4%; C5 contusion: 7 +/- 4%; p = 0.047). The pattern of denervation revealed segmental innervation of the diaphragm muscle, with greater denervation ventrally after C3 contusion and dorsally after C5 contusion. Overall, diaphragm root mean square electromyography activity did not change ipsilaterally after C3 or C5 contusion, but increased contralaterally (~ 11%) after C3 contusion only on the first day post-injury (p = 0.026). Similarly, there were no significant changes in breathing parameters during eupnea or exposure to hypoxia (10% O2) - hypercapnia (5% CO2) at any time post-injury. Unilateral midcervical contusions minimally impair ventilatory behaviors despite phrenic motoneuron loss and diaphragm muscle denervation. PMID- 26413842 TI - Relation of Step Length to Magnetic Resonance Imaging-Detected Structural Damage in the Patellofemoral Joint: The Multicenter Osteoarthritis Study. AB - OBJECTIVE: To investigate the relationship of step length to the sex-specific prevalence and worsening of magnetic resonance imaging (MRI)-detected structural damage in the patellofemoral (PF) joint among a cohort of older women and men with or at risk of knee osteoarthritis (OA). METHODS: The Multicenter Osteoarthritis Study is a cohort study of persons ages 50-79 years with or at risk of knee OA. Step length was assessed using the GAITRite walkway (CIR Systems) at the 60-month visit, and cartilage damage and bone marrow lesions (BMLs) were graded on MRI at the 60- and 84-month visits. Step length was divided into sex-specific quintiles, and the relationship of step length to the prevalence and worsening of cartilage damage and BMLs in the PF joint was examined using logistic regression, adjusting for age, body mass index (BMI), leg length, and tibiofemoral joint structural damage. RESULTS: In 1,053 knees, 4,094 and 4,083 PF joint subregions were studied for the cartilage and BML analyses, respectively. Mean +/- SD age was 65.6 +/- 8.1 years and mean +/- SD BMI was 29.1 +/- 4.7 kg/m(2) ; 62% of participants were female. In women, compared to those with the shortest step length, those with the longest step length had 0.62 (95% confidence interval [95% CI] 0.43-0.88) and 0.59 (95% CI 0.40-0.87) times the odds of cartilage damage and BMLs, respectively. There was no cross-sectional association in men, and no longitudinal association in either sex. CONCLUSION: Women with PF joint structural damage may adapt their gait by shortening their step length, but this may not be sufficient to reduce the risk of worsening damage over time. PMID- 26413844 TI - Magnetotransport Properties of Epitaxial Ge/AlAs Heterostructures Integrated on GaAs and Silicon. AB - The magnetotransport properties of epitaxial Ge/AlAs heterostructures with different growth conditions and substrate architectures have been studied under +/-9 T magnetic field and at 390 mK temperature. Systematic mobility measurements of germanium (Ge) epilayers grown on GaAs substrates at growth temperatures from 350 to 450 degrees C allow us to extract a precise growth window for device quality Ge, corroborated by structural and morphological properties. Our results on Si substrate using a composite metamorphic AlAs/GaAs buffer at 400 degrees C Ge growth temperature, show that the Ge/AlAs system can be tailored to have a single carrier transport while keeping the charge solely in the Ge layer. Single carrier transport confined to the Ge layer is demonstrated by the weak localization quantum correction to the conductivity observed at low magnetic fields and 390 mK temperature. The weak localization effect points to a near absence of spin-orbit interaction for carriers in the electronically active layer and is used here for the first time to pinpoint Ge as this active layer. Thus, the epitaxial Ge grown on Si using AlAs/GaAs buffer architecture is a promising candidate for next-generation energy-efficient fin field-effect transistor applications. PMID- 26413845 TI - Systolic Anterior Motion of the Mitral Valve Triggered by the Intra-Aortic Balloon Pump. PMID- 26413847 TI - Brief Report: Prevalence of Latent Rheumatic Heart Disease Among HIV-Infected Children in Kampala, Uganda. AB - Rheumatic heart disease (RHD) remains highly prevalent in resource-constrained settings around the world, including countries with high rates of HIV/AIDS. Although both are immune-mediated diseases, it is unknown whether HIV modifies the risk or progression of RHD. We performed screening echocardiography to determine the prevalence of latent RHD in 488 HIV-infected children aged 5-18 in Kampala, Uganda. The overall prevalence of borderline/definite RHD was 0.82% (95% confidence interval: 0.26% to 2.23%), which is lower than the published prevalence rates of 1.5%-4% among Ugandan children. There may be protective factors that decrease the risk of RHD in HIV-infected children. PMID- 26413846 TI - Prevalence of Transmitted HIV Drug Resistance Among Recently Infected Persons in San Diego, CA 1996-2013. AB - BACKGROUND: Transmitted drug resistance (TDR) remains an important concern when initiating antiretroviral therapy (ART). Here, we describe the prevalence and phylogenetic relationships of TDR among ART-naive, HIV-infected individuals in San Diego from 1996 to 2013. METHODS: Data were analyzed from 496 participants of the San Diego Primary Infection Cohort who underwent genotypic resistance testing before initiating therapy. Mutations associated with drug resistance were identified according to the WHO-2009 surveillance list. Network and phylogenetic analyses of the HIV-1 pol sequences were used to evaluate the relationships of TDR within the context of the entire cohort. RESULTS: The overall prevalence of TDR was 13.5% (67/496), with an increasing trend over the study period (P = 0.005). TDR was predominantly toward nonnucleoside reverse transcriptase inhibitors (NNRTIs) [8.5% (42/496)], also increasing over the study period (P = 0.005). By contrast, TDR to protease inhibitors and nucleos(t)ide reverse transcriptase inhibitors were 4.4% (22/496) and 3.8% (19/496), respectively, and did not vary with time. TDR prevalence did not differ by age, gender, race/ethnicity, or risk factors. Using phylogenetic analysis, we identified 52 transmission clusters, including 8 with at least 2 individuals sharing the same mutation, accounting for 23.8% (16/67) of the individuals with TDR. CONCLUSIONS: Between 1996 and 2013, the prevalence of TDR significantly increased among recently infected ART-naive individuals in San Diego. Around one-fourth of TDR occurred within clusters of recently infected individuals. These findings highlight the importance of baseline resistance testing to guide selection of ART and for public health monitoring. PMID- 26413848 TI - Implementation and Operational Research: Programmatic Feasibility of Dried Blood Spots for the Virological Follow-up of Patients on Antiretroviral Treatment in Nord Kivu, Democratic Republic of the Congo. AB - BACKGROUND: As part of its policy to shift monitoring of antiretroviral therapy (ART) to primary health care (PHC) workers, the Ministry of Health of the Democratic Republic of Congo (DRC) tested the feasibility of using dried blood spots (DBS) for viral load (VL) quantification and genotypic drug resistance testing in off-site high-throughput laboratories. METHODS: DBS samples from adults on ART were collected in 13 decentralized PHC facilities in the Nord-Kivu province and shipped during program quarterly supervision to a reference laboratory 2000 km away, where VL was quantified with a commercial assay (m2000rt, Abbott). A second DBS was sent to a World Health Organization (WHO) accredited laboratory for repeat VL quantification on a subset of samples with a generic assay (Biocentric) and genotypic drug resistance testing when VL >1000 copies per milliliter. FINDINGS: Constraints arose because of an interruption in national laboratory funding rather than to technical or logistic problems. All samples were assessed by both VL assays to allow ART adjustment. Median DBS turnaround time was 37 days (interquartile range: 9-59). Assays performed unequally with DBS, impacting clinical decisions, quality assurance, and overall cost-effectiveness. Based on m2000rt or generic assay, 31.3% of patients were on virological failure (VF) and 14.8% presented resistance mutations versus 50.3% and 15.4%, respectively. CONCLUSION: This study confirms that current technologies involving DBS make virological monitoring of ART possible at PHC level, including in challenging environments, provided organizational issues are addressed. Adequate core funding of HIV laboratories and adapted choice of VL assays require urgent attention to control resistance to ART as coverage expands. PMID- 26413849 TI - Mucosal Topical Microbicide Candidates Exert Influence on the Subsequent SIV Infection and Survival by Regulating SIV-Specific T-Cell Immune Responses. AB - OBJECTIVE: To determine whether mucosal topical microbicides have any influence on disease progression during subsequent simian immunodeficiency virus (SIV) infection. DESIGN: A 2-phase study was performed in primate monkeys. The first phase mimicked microbicide efficacy studies; the second phase served to determine the disease progression in a productive infection model. METHODS: During the first phase, monkeys were intrarectally pretreated with tenofovir, sifuvirtide (SFT), or maraviroc-formulated microbicides and then challenged with low-dose SHIV-1157ipd3N4. Second, all monkeys were rechallenged with a single high dose of SIVmac239 to generate productive infections. The survival rate, viral loads, CD4(+) T-cell counts, and SIV-specific T-cell responses were determined during the 104-week following up. RESULTS: Repeated rectal challenges did not result in productive infection in all groups, evidenced by undetectable viral loads with occasional viral blips during the first phase of this study. All monkeys were productively infected after the high-dose rechallenge with SIVmac239. Two groups, including maraviroc-treated and tenofovir-treated groups, experienced 100% mortality during the 104-week following up. In contrast, the SFT-treated group showed significantly higher survival, and only 25% died at week 95. Interestingly, SIV-specific T-cell responses were also significantly higher in the SFT group. Transcriptomic analyses evidenced immune imprint in immune system among different microbicide-treated groups. CONCLUSIONS: This study provides preliminary but important evidence for the influence of prophylactically applied microbicides on disease progression of subsequent SIV infection and suggests that the long-term immune safety concern for microbicides should be also considered in the effort to develop effective microbicides. PMID- 26413851 TI - V1/V2 Neutralizing Epitope is Conserved in Divergent Non-M Groups of HIV-1. AB - BACKGROUND: Highly potent broadly neutralizing monoclonal antibodies (bNAbs) have been obtained from individuals infected by HIV-1 group M variants. We analyzed the cross-group neutralization potency of these bNAbs toward non-M primary isolates (PI). MATERIAL AND METHODS: The sensitivity to neutralization was analyzed in a neutralization assay using TZM-bl cells. Twenty-three bNAbs were used, including reagents targeting the CD4-binding site, the N160 glycan-V1/V2 site, the N332 glycan-V3 site, the membrane proximal external region of gp41, and complex epitopes spanning both env subunits. Two bispecific antibodies that combine the inhibitory activity of an anti-CD4 with that of PG9 or PG16 bNAbs were included in the study (PG9-iMab and PG16-iMab). RESULTS: Cross-group neutralization was observed only with the bNAbs targeting the N160 glycan-V1/V2 site. Four group O PIs, 1 group N PI, and the group P PI were neutralized by PG9 and/or PG16 or PGT145 at low concentrations (0.04-9.39 MUg/mL). None of the non-M PIs was neutralized by the bNAbs targeting other regions at the highest concentration tested, except 10E8 that neutralized weakly 2 group N PIs and 35O22 that neutralized 1 group O PI. The bispecific bNAbs neutralized very efficiently all the non-M PIs with IC50 below 1 MUg/mL, except 2 group O strains. CONCLUSION: The N160 glycan-V1/V2 site is the most conserved neutralizing site within the 4 groups of HIV-1. This makes it an interesting target for the development of HIV vaccine immunogens. The corresponding bNAbs may be useful for immunotherapeutic strategies in patients infected by non-M variants. PMID- 26413850 TI - Effect of Depot Medoxyprogesterone Acetate on Immune Functions and Inflammatory Markers of HIV-Infected Women. AB - OBJECTIVES: Depot medroxyprogesterone acetate (DMPA) was associated with increased HIV transmission and accelerated disease progression in untreated women. The potential underlying mechanisms include immune modulation. We evaluated the effect of a single DMPA injection on cell-mediated immunity (CMI), T-cell activation, T-cell regulation (Treg), and inflammation in HIV-infected women on combination antiretroviral regimen (cART). METHODS: Women with HIV plasma RNA <= 400 copies per milliliter on stable cART received DMPA and had immunologic and medroxyprogesterone acetate (MPA) measurements at baseline, 4 weeks [peak MPA concentration (Cmax)], and 12 weeks [highest MPA area under the concentration curve]. RESULTS: At baseline, among 24 women with median age of 32 years and 622 CD4(+) cells per microliter, >= 68% had HIV, varicella-zoster virus, phytohemagglutinin A and CD3/CD28 CMI measured by lymphocyte proliferation, and/or IFNgamma/IL2 dual-color fluorospot. CMI did not significantly change after DMPA administration except for a 1.4-fold increase in IL2/IFNgamma varicella-zoster virus fluorospot at week 12. T-cell activation decreased after DMPA administration, reaching statistical significance at week 12 for CD4(+)CD25+%. Treg behaved heterogeneously with an increase in CD8+FOXP3+% at week 4 and a decrease in CD4+IL35+% at week 12. There was a decrease in TGFbeta at week 12 and no other changes in plasma biomarkers. Correlation analyses showed that high MPA Cmax and/or area under the concentration curve were significantly associated with increases of IFNgamma HIV enzyme-linked ImmunoSpot, CD4+IL35+%, and CD4+TGFbeta+% Treg and decreases of plasma IL10 from baseline to weeks 4 and/or 12. CONCLUSIONS: A single dose of DMPA did not have immune-suppressive or pro-inflammatory effects in HIV-infected women on cART. Additional studies need to assess the effect of multiple doses. PMID- 26413852 TI - Lower HIV Risk Among Circumcised Men Who Have Sex With Men in China: Interaction With Anal Sex Role in a Cross-Sectional Study. AB - BACKGROUND: Voluntary medical male circumcision reduces the risk of HIV heterosexual transmission in men, but its effect on male-to-male sexual transmission is uncertain. METHODS: Circumcision status of men who have sex with men (MSM) in China was evaluated by genital examination and self-report; anal sexual role was assessed by questionnaire interview. Serostatus for HIV and syphilis was confirmed. RESULTS: Among 1155 participants (242 were seropositive and 913 with unknown HIV status at enrollment), the circumcision rate by self report (10.4%) was higher than confirmed by genital examination (8.2%). Male circumcision (by examination) was associated with 47% lower odds of being HIV seropositive [adjusted odds ratio (aOR): 0.53; 95% confidence interval (CI): 0.27 to 1.02] after adjusting for demographic covariates, number of lifetime male sexual partners, and anal sex role. Among MSM who predominantly practiced insertive anal sex, circumcised men had 62% lower odds of HIV infection than those who were uncircumcised (aOR: 0.38; 95% CI: 0.09 to 1.64). Among those whose anal sex position was predominantly receptive or versatile, circumcised men have 46% lower odds of HIV infection than did men who were not circumcised (aOR: 0.54; 95% CI: 0.25 to 1.14). Compared to uncircumcised men reporting versatile or predominantly receptive anal sex positioning, those who were circumcised and reported practicing insertive sex had an 85% lower risk (aOR: 0.15; 95% CI: 0.04 to 0.65). Circumcision was not associated clearly with lower syphilis risk (aOR: 0.91; 95% CI: 0.51 to 1.61). CONCLUSIONS: Circumcised MSM were less likely to have acquired HIV, most pronounced among men predominantly practicing insertive anal intercourse. A clinical trial is needed. PMID- 26413854 TI - Microbiota-Dependent Marker TMAO Is Elevated in Silent Ischemia but Is Not Associated With First-Time Myocardial Infarction in HIV Infection. AB - OBJECTIVES: HIV infection is associated with increased risk of coronary heart disease beyond that explained by traditional risk factors, and altered gut microbiota has been proposed as a potential trigger. Trimethylamine-N-oxide (TMAO) is a proatherogenic substance formed in the liver from trimethylamine, exclusively generated by gut microbiota from dietary phosphatidylcholine. We aimed to investigate whether TMAO is associated with subclinical and clinical coronary heart disease in HIV infection. METHODS: Two previously described cohorts were examined as follows: (1) cross-sectional cohort of HIV-infected persons and uninfected controls with known atherosclerotic plaque burden as assessed by myocardial perfusion scintigraphy, coronary artery calcium score, and intima-media thickness and (2) nested case-control study of HIV-infected persons with first-time myocardial infarction (MI) compared with HIV-infected persons without MI, assessed at 4 time points from before initiation of antiretroviral therapy (ART) to last sample before the case's MI (median: 51, range: 0-239 days). RESULTS: There was no difference in plasma TMAO when comparing HIV infected persons and uninfected controls. TMAO was elevated in HIV-infected persons with myocardial perfusion defects but was not associated with coronary artery calcium score, intima media thickness, or Framingham risk score. In the nested case control study, plasma TMAO was not associated with first-time MI. However, TMAO increased after ART introduction and was associated with the use of protease inhibitors in both cohorts. CONCLUSIONS: TMAO was elevated in HIV infected persons with myocardial perfusion defects, but was not associated with first-time MI. Our data question TMAO as a useful biomarker of cardiovascular risk in HIV infection, at least in ART-treated individuals. PMID- 26413853 TI - The Safety of Tenofovir-Emtricitabine for HIV Pre-Exposure Prophylaxis (PrEP) in Individuals With Active Hepatitis B. AB - BACKGROUND: Pre-exposure prophylaxis (PrEP) with daily oral emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) prevents HIV infection. The safety and feasibility of HIV PrEP in the setting of hepatitis B virus (HBV) infection were evaluated. METHODS: The Iniciativa Profilaxis Pre-Exposicion study randomized 2499 HIV-negative men and transgender women who have sex with men to once-daily oral FTC/TDF versus placebo. Hepatitis serologies and transaminases were obtained at screening and at the time PrEP was discontinued. HBV DNA was assessed by polymerase chain reaction, and drug resistance was assessed by population sequencing. Vaccination was offered to individuals susceptible to HBV infection. RESULTS: Of the 2499 participants, 12 (0.5%; including 6 randomized to FTC/TDF) had chronic HBV infection. After stopping FTC/TDF, 5 of the 6 participants in the active arm had liver function tests performed at follow-up. Liver function tests remained within normal limits at post-stop visits except for a grade 1 elevation in 1 participant at post-stop week 12 (alanine aminotransferase = 90, aspartate aminotransferase = 61). There was no evidence of hepatic flares. Polymerase chain reaction of stored samples showed that 2 participants in the active arm had evidence of acute HBV infection at enrollment. Both had evidence of grade 4 transaminase elevations with subsequent resolution. Overall, there was no evidence of TDF or FTC resistance among tested genotypes. Of 1633 eligible for vaccination, 1587 (97.2%) received at least 1 vaccine; 1383 (84.7%) completed the series. CONCLUSIONS: PrEP can be safely provided to individuals with HBV infection if there is no evidence of cirrhosis or substantial transaminase elevation. HBV vaccination rates at screening were low globally, despite recommendations for its use, yet uptake and efficacy were high when offered. PMID- 26413855 TI - Thiazyl Trifluoride (NSF3) Adducts and Imidodifluorosulfate (F2OSN-) Derivatives of Hg(OTeF5)2. AB - Reactions of Hg(OTeF5)2 with excess amounts of NSF3 at 0 degrees C result in the formation of NSF3 adducts having the compositions [Hg(OTeF5)2.N=SF3]infinity (1), [Hg(OTeF5)2.2N=SF3]2 (2), and Hg3(OTeF5)6.4N=SF3 (3). When the reactions are carried out at room temperature, oxygen/fluorine metatheses occur yielding the F2OSN- derivatives [Hg(OTeF5)(N?SOF2).N=SF3]infinity (4) and [Hg3(OTeF5)5(N?SOF2).2N=SF3]2 (5). The proposed reaction pathway leading to F2OSN group formation occurs by nucleophilic attack by a F5TeO- group at the sulfur(VI) atom of NSF3, followed by TeF6 elimination. Tellurium hexafluoride formation was confirmed by (19)F NMR spectroscopy. The NSF3 molecules are terminally N-coordinated to mercury, whereas the F2OSN- ligands are N-bridged to two mercury atoms. The compound series was characterized by low-temperature single-crystal X-ray diffraction and low-temperature Raman spectroscopy. Several structural motifs are observed within this structurally diverse series. These include the infinite chain structures of the related compounds, 1 and 4; 2, a dimeric structure which possesses an (HgO(MU))2 ring at its core; 3, a structure based on a cage comprised of a (HgO(MU))3 ring that is capped on each face by MU(3)-oxygen bridged F5TeO- groups; and 5, a dimeric structure possessing two distorted (Hg3O2N) rings that are formally derived from 3 by replacement of a F5TeO- group by a F2OSN- group in each ring. Quantum-chemical calculations were carried out to gain insight into the bonding of the MU(3)-oxygen bridged teflate groups observed in structure 3. Compounds 1-5 represent a novel class of neutral transition metal complexes with NSF3, providing the first examples of NSF3 coordination to mercury. Compounds 4 and 5 also provide the only examples of F2OSN- derivatives of mercury that have been characterized by single-crystal X ray diffraction. PMID- 26413857 TI - Curvature Softening and Negative Compressibility of Gel-Phase Lipid Membranes. AB - We show that gel-phase lipid membranes soften upon bending, leading to curvature localization and a negative compressibility. Using simulations of two very different lipid models to quantify shape and stress-strain relation of buckled membranes, we demonstrate that gel phase bilayers do not behave like Euler elastica and hence are not well described by a quadratic Helfrich Hamiltonian, much unlike their fluid-phase counterparts. We propose a theoretical framework which accounts for the observed softening through an energy density that smoothly crosses over from a quadratic to a linear curvature dependence beyond a critical new scale [Formula: see text](-1). This model captures both the shape and the stress-strain relation for our two sets of simulations and permits the extraction of bending moduli, which are found to be about an order of magnitude larger than the corresponding fluid phase values. We also find surprisingly large crossover lengths [Formula: see text], several times bigger than the bilayer thickness, rendering the exotic elasticity of gel-phase membranes more strongly pronounced than that of homogeneous compressible sheets and artificial metamaterials. We suggest that such membranes have unexpected potential as nanoscale systems with striking materials characteristics. PMID- 26413856 TI - Contribution of Raman spectroscopy in nephrology: a candidate technique to detect hydroxyethyl starch of third generation in osmotic renal lesions. AB - BACKGROUND AND OBJECTIVES: HydroxyEthyl Starch (HES) has been one of the most commonly used colloid volume expanders in intensive care units for over 50 years. The first and second generation HES, with a high molecular weight (>=200 kD) and a high degree of substitution (>=0.5), has been associated with both renal dysfunction and osmotic nephrosis-like lesions in histological studies. Recently, third generation HES (130 kD/<0.5) has also been shown to impair renal function in critically ill adult patients although tubular accumulation of HES has never been proven in the human kidney. Our objective was to demonstrate the potential of Raman micro-imaging to bring out the presence of third generation-HES in the kidney of patients having received the volume expander. DESIGN: Four biopsies presenting osmotic nephrosis-like lesions originated from HES-administrated patients with impaired renal function were compared with HES-negative biopsies (n = 10) by Raman microspectroscopy. RESULTS: The first step was dedicated to the identification of a specific vibration of HES permitting the detection of the cellular and tissue accumulation of the product. This specific vibration at 480 cm(-1) is assigned to a collective mode of the macromolecule; it is located in a spectral region with a limited contribution from biological materials. Based on this finding, HES distribution within tissue sections was investigated using Raman micro-imaging. Determination of HES positive pixels permitted us to clearly distinguish positive cases from HES-free biopsies (proportions of positive pixels from the total number of pixels: 23.48% +/- 28 vs. 0.87% +/- 1.2; p = 0.004). CONCLUSIONS: This study shows that Raman spectroscopy is a candidate technique to detect HES in kidney tissue samples currently manipulated in nephrology departments. In addition, on the clinical aspect, our approach suggests that renal impairment related to third generation HES administration is associated with osmotic nephrosis-like lesions and HES accumulation in the kidney. PMID- 26413858 TI - A Hybrid One-Way ANOVA Approach for the Robust and Efficient Estimation of Differential Gene Expression with Multiple Patterns. AB - BACKGROUND: Identifying genes that are differentially expressed (DE) between two or more conditions with multiple patterns of expression is one of the primary objectives of gene expression data analysis. Several statistical approaches, including one-way analysis of variance (ANOVA), are used to identify DE genes. However, most of these methods provide misleading results for two or more conditions with multiple patterns of expression in the presence of outlying genes. In this paper, an attempt is made to develop a hybrid one-way ANOVA approach that unifies the robustness and efficiency of estimation using the minimum beta-divergence method to overcome some problems that arise in the existing robust methods for both small- and large-sample cases with multiple patterns of expression. RESULTS: The proposed method relies on a beta-weight function, which produces values between 0 and 1. The beta-weight function with beta = 0.2 is used as a measure of outlier detection. It assigns smaller weights (>= 0) to outlying expressions and larger weights (<= 1) to typical expressions. The distribution of the beta-weights is used to calculate the cut-off point, which is compared to the observed beta-weight of an expression to determine whether that gene expression is an outlier. This weight function plays a key role in unifying the robustness and efficiency of estimation in one-way ANOVA. CONCLUSION: Analyses of simulated gene expression profiles revealed that all eight methods (ANOVA, SAM, LIMMA, EBarrays, eLNN, KW, robust BetaEB and proposed) perform almost identically for m = 2 conditions in the absence of outliers. However, the robust BetaEB method and the proposed method exhibited considerably better performance than the other six methods in the presence of outliers. In this case, the BetaEB method exhibited slightly better performance than the proposed method for the small-sample cases, but the the proposed method exhibited much better performance than the BetaEB method for both the small- and large sample cases in the presence of more than 50% outlying genes. The proposed method also exhibited better performance than the other methods for m > 2 conditions with multiple patterns of expression, where the BetaEB was not extended for this condition. Therefore, the proposed approach would be more suitable and reliable on average for the identification of DE genes between two or more conditions with multiple patterns of expression. PMID- 26413859 TI - 'I am a mother': young women's negotiation of femininity and risk in the transition to adulthood. AB - In studies of sexual risk behaviour among youth, the role of dominant conceptions of masculinity and femininity has received increasing attention. However, where research has sought to explore femininity, it has predominantly focused on adolescent girls. This paper departs from previous research by offering insights into how young women negotiate their femininity as they transition from adolescence to adulthood and encounter changing social contexts. Drawing on data from ethnographic enquiry, it argues that as young women transition out of school and into emerging adulthood, their options for negotiating different types of femininity become constrained, with consequences for engagement in sexual risk behaviours. This may to some extent explain why in some South African contexts older young women are more vulnerable to HIV infection than adolescent girls. The paper offer insights into future prospects for youth development programming seeking to reduce young women's vulnerability to risk. PMID- 26413861 TI - Alterations of Nonconserved Residues Affect Protein Stability and Folding Dynamics through Charge-Charge Interactions. AB - Charge-charge interactions play an important role in thermal stability of proteins. We employed an all-atom, native-topology-based model with non-native electrostatics to explore the interplay between folding dynamics and stability of TNfn3 (the third fibronectin type III domain from tenascin-C). Our study elucidates the role of charge-charge interactions in modulating the folding energy landscape. In particular, we found that incorporation of explicit charge charge interactions in the WT TNfn3 induces energetic frustration due to the presence of residual structure in the unfolded state. Moreover, optimization of the surface charge-charge interactions by altering the evolutionarily nonconserved residues not only increases the thermal stability (in agreement with previous experimental study) but also reduces the formation of residual structure and hence minimizes the energetic frustration along the folding route. We concluded that charge-charge interaction in the rationally designed TNfn3 plays an important role not only in enhancing the stability but also in assisting folding. PMID- 26413860 TI - Chronic inflammation and risk of colorectal and other obesity-related cancers: The health, aging and body composition study. AB - Evidence of the association between chronic inflammation and the risk of colorectal cancer (CRC) and other obesity-related cancers (OBRC) remains inconsistent, possibly due to a paucity of studies examining repeated measures of inflammation. In the Health ABC prospective study of 2,490 adults aged 70-79 years at baseline, we assessed whether circulating levels of three markers of systemic inflammation, IL-6, CRP and TNF-alpha, were associated with the risk of CRC and OBRC, a cluster including cancers of pancreas, prostate, breast and endometrium. Inflammatory markers were measured in stored fasting blood samples. While only baseline measures of TNF-alpha were available, IL-6 and CRP were additionally measured at Years 2, 4, 6 and 8. Multivariable Cox models were fit to determine whether tertiles and log-transformed baseline, updated and averaged measures of CRP and IL-6 and baseline measures of TNF-alpha were associated with the risk of incident cancer(s). During a median follow-up of 11.9 years, we observed 55 and 172 cases of CRC and OBRC, respectively. The hazard of CRC in the highest tertile of updated CRP was more than double that in the lowest tertile (HR = 2.29; 95% CI: 1.08-4.86). No significant associations were seen between colorectal cancer and IL-6 or TNF-alpha. Additionally, no significant associations were found between obesity-related cancers and the three inflammatory markers overall, but we observed a suggestion of effect modification by BMI and NSAID use. In summary, in this population, higher CRP levels were associated with increased risk of CRC, but not of OBRC. The findings provide new evidence that chronically elevated levels of CRP, as reflected by repeated measures of this marker, may play a role in colorectal carcinogenesis in older adults. PMID- 26413862 TI - Diversity in Compartmental Dynamics of Gene Regulatory Networks: The Immune Response in Primary Influenza A Infection in Mice. AB - Current approaches to study transcriptional profiles post influenza infection typically rely on tissue sampling from one or two sites at a few time points, such as spleen and lung in murine models. In this study, we infected female C57/BL6 mice intranasally with mouse-adapted H3N2/Hong Kong/X31 avian influenza A virus, and then analyzed the gene expression profiles in four different compartments (blood, lung, mediastinal lymph nodes, and spleen) over 11 consecutive days post infection. These data were analyzed by an advanced statistical procedure based on ordinary differential equation (ODE) modeling. Vastly different lists of significant genes were identified by the same statistical procedure in each compartment. Only 11 of them are significant in all four compartments. We classified significant genes in each compartment into co expressed modules based on temporal expression patterns. We then performed functional enrichment analysis on these co-expression modules and identified significant pathway and functional motifs. Finally, we used an ODE based model to reconstruct gene regulatory network (GRN) for each compartment and studied their network properties. PMID- 26413863 TI - Laser Photocoagulation Induces Transduction of Retinal Pigment Epithelial Cells by Intravitreally Administered Adeno-Associated Viral Vectors. AB - Retinal transduction by intravitreally administered adeno-associated viral (AAV) vector is previously known to be extremely limited to the neural retina except AAV2 capsid type. Recently, we showed that prior laser photocoagulation enhances retinal transduction of intravitreally administered AAV vectors, including the outer retina and retinal pigment epithelium (RPE). Here, by performing short pulse laser pretreatment on the mouse retina, we demonstrate RPE cells transduced by three different capsid types of AAV vectors, AAV2, AAV5, and AAV8, using RPE wholemounts. For all capsid types, laser pretreatment effectively induced the transduction of RPE cells in and around the laser site. PMID- 26413864 TI - Comparison of the effect of two Quillaja bark saponin extracts on DPPC and DPPC/cholesterol Langmuir monolayers. AB - The present study aims at comparing the effect of two commercially available Quillaja bark saponin (QBS) products on model Langmuir monolayers. Pure dipalmitoylphosphatidylcholine (DPPC) and mixed DPPC/cholesterol Langmuir monolayers were used as crude models of erythrocyte membranes in order to better understand a hemolytic activity of QBS. Both QBS products are mixtures of several saponins and non-saponin fractions, only few of which can be assigned an exact chemical structure, as shown by an HPLC analysis. Noticeable differences in the saponin profiles, and most importantly-in the content of non-saponin fractions (tannins and phenolic compounds) are probably responsible for their different adsorption behavior at the water/air interface. The lipids Langmuir monolayers were initially spread on pure water and compressed to surface pressure of 32.5 mN/m, which is believed to provide the lipid packing similar to that in real biological membranes. The water subphase was subsequently exchanged with the respective QBS solutions in the concentration range 5 * 10(-4) to 2 * 10(-1)wt%. In order to assess the resistance of the model lipid monolayers to QBS, a combination of surface pressure relaxation and surface dilatational rheology was employed. Both QBS are shown to penetrate the lipid layers without removing them, but their effect on the lipid layers' relaxation and viscoelastic dilational properties is different. The differences virtually disappear when cholesterol is present in the monolayer, especially for the DPPC/Cholesterol molar ratio between 10:9 and 4:1 (mol/mol). Despite several jumps of surface pressure, the lipid layers containing cholesterol can resist penetration of QBS. PMID- 26413865 TI - Magnesium oxide nanoparticles coated with glucose can silence important genes of Leishmania major at sub-toxic concentrations. AB - The aim of this study was to investigate the effect of magnesium oxide nanoparticles (MgO NPs) and MgO NPs coated with glucose (MONPCG) on Leishmania (L) major. First, the promastigotes of L. major were separately incubated with serial concentrations of MgO NPs and MONPCG for 24, 48, and 72 h at 37 degrees C. Then, the cell viability of promastigotes was evaluated by MTT assay. On the other hand, the relative expression of Cpb and GP63 genes was detected by quantitative-real time PCR. Based on results, the increase of concentration, both MgO NPs and MONPCG, and incubation time led to decrease of cell viability. Moreover, the expression of Cpb and GP63 genes was decreased with increase of concentration of MgO NPs and MONPCG. Also, the increase of incubation time led to decrease of their expression in MgO NPs treated promastogotes. But, in case of MONPCG treated promastogotes, the increase of incubation time did not change the expression of Cpb and GP63. Interestingly, MONPCG could silence Cpb and GP63 genes better than MgO NPs. Note, the capability was also seen at sub-toxic concentrations of MONPCG. PMID- 26413866 TI - Efficient Genotyping of KRAS Mutant Non-Small Cell Lung Cancer Using a Multiplexed Droplet Digital PCR Approach. AB - Droplet digital PCR (ddPCR) can be used to detect low frequency mutations in oncogene-driven lung cancer. The range of KRAS point mutations observed in NSCLC necessitates a multiplex approach to efficient mutation detection in circulating DNA. Here we report the design and optimisation of three discriminatory ddPCR multiplex assays investigating nine different KRAS mutations using PrimePCRTM ddPCRTM Mutation Assays and the Bio-Rad QX100 system. Together these mutations account for 95% of the nucleotide changes found in KRAS in human cancer. Multiplex reactions were optimised on genomic DNA extracted from KRAS mutant cell lines and tested on DNA extracted from fixed tumour tissue from a cohort of lung cancer patients without prior knowledge of the specific KRAS genotype. The multiplex ddPCR assays had a limit of detection of better than 1 mutant KRAS molecule in 2,000 wild-type KRAS molecules, which compared favourably with a limit of detection of 1 in 50 for next generation sequencing and 1 in 10 for Sanger sequencing. Multiplex ddPCR assays thus provide a highly efficient methodology to identify KRAS mutations in lung adenocarcinoma. PMID- 26413867 TI - Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasis. AB - Alterations in insulin granule exocytosis and endocytosis are paramount to pancreatic beta cell dysfunction in diabetes mellitus. Here, using temporally controlled gene ablation specifically in beta cells in mice, we identified an essential role of dynamin 2 GTPase in preserving normal biphasic insulin secretion and blood glucose homeostasis. Dynamin 2 deletion in beta cells caused glucose intolerance and substantial reduction of the second phase of glucose stimulated insulin secretion (GSIS); however, mutant beta cells still maintained abundant insulin granules, with no signs of cell surface expansion. Compared with control beta cells, real-time capacitance measurements demonstrated that exocytosis-endocytosis coupling was less efficient but not abolished; clathrin mediated endocytosis (CME) was severely impaired at the step of membrane fission, which resulted in accumulation of clathrin-coated endocytic intermediates on the plasma membrane. Moreover, dynamin 2 ablation in beta cells led to striking reorganization and enhancement of actin filaments, and insulin granule recruitment and mobilization were impaired at the later stage of GSIS. Together, our results demonstrate that dynamin 2 regulates insulin secretory capacity and dynamics in vivo through a mechanism depending on CME and F-actin remodeling. Moreover, this study indicates a potential pathophysiological link between endocytosis and diabetes mellitus. PMID- 26413868 TI - Dual-Affinity Re-Targeting proteins direct T cell-mediated cytolysis of latently HIV-infected cells. AB - Enhancement of HIV-specific immunity is likely required to eliminate latent HIV infection. Here, we have developed an immunotherapeutic modality aimed to improve T cell-mediated clearance of HIV-1-infected cells. Specifically, we employed Dual Affinity Re-Targeting (DART) proteins, which are bispecific, antibody-based molecules that can bind 2 distinct cell-surface molecules simultaneously. We designed DARTs with a monovalent HIV-1 envelope-binding (Env-binding) arm that was derived from broadly binding, antibody-dependent cellular cytotoxicity mediating antibodies known to bind to HIV-infected target cells coupled to a monovalent CD3 binding arm designed to engage cytolytic effector T cells (referred to as HIVxCD3 DARTs). Thus, these DARTs redirected polyclonal T cells to specifically engage with and kill Env-expressing cells, including CD4+ T cells infected with different HIV-1 subtypes, thereby obviating the requirement for HIV specific immunity. Using lymphocytes from patients on suppressive antiretroviral therapy (ART), we demonstrated that DARTs mediate CD8+ T cell clearance of CD4+ T cells that are superinfected with the HIV-1 strain JR-CSF or infected with autologous reservoir viruses isolated from HIV-infected-patient resting CD4+ T cells. Moreover, DARTs mediated CD8+ T cell clearance of HIV from resting CD4+ T cell cultures following induction of latent virus expression. Combined with HIV latency reversing agents, HIVxCD3 DARTs have the potential to be effective immunotherapeutic agents to clear latent HIV-1 reservoirs in HIV-infected individuals. PMID- 26413869 TI - LKB1 loss promotes endometrial cancer progression via CCL2-dependent macrophage recruitment. AB - Endometrial cancer is the most common gynecologic malignancy and the fourth most common malignancy in women. For most patients in whom the disease is confined to the uterus, treatment results in successful remission; however, there are no curative treatments for tumors that have progressed beyond the uterus. The serine/threonine kinase LKB1 has been identified as a potent suppressor of uterine cancer, but the biological modes of action of LKB1 in this context remain incompletely understood. Here, we have shown that LKB1 suppresses tumor progression by altering gene expression in the tumor microenvironment. We determined that LKB1 inactivation results in abnormal, cell-autonomous production of the inflammatory cytokine chemokine (C-C motif) ligand 2 (CCL2) within tumors, which leads to increased recruitment of macrophages with prominent tumor promoting activities. Inactivation of Ccl2 in an Lkb1-driven mouse model of endometrial cancer slowed tumor progression and increased survival. In human primary endometrial cancers, loss of LKB1 protein was strongly associated with increased CCL2 expression by tumor cells as well as increased macrophage density in the tumor microenvironment. These data demonstrate that CCL2 is a potent effector of LKB1 loss in endometrial cancer, creating potential avenues for therapeutic opportunities. PMID- 26413870 TI - Excess placental secreted frizzled-related protein 1 in maternal smokers impairs fetal growth. AB - Maternal cigarette smoking during pregnancy remains one of the most common and preventable causes of fetal growth restriction (FGR), a condition in which a fetus is unable to achieve its genetically determined potential size. Even though epidemiologic evidence clearly links maternal cigarette smoking with FGR, insight into the molecular mechanisms of cigarette smoke-induced FGR is lacking. Here, we performed transcriptional profiling of placentas obtained from smoking mothers who delivered growth-restricted infants and identified secreted frizzled-related protein 1 (sFRP1), an extracellular antagonist of endogenous WNT signaling, as a candidate molecule. sFRP1 mRNA and protein levels were markedly upregulated (~10 fold) in placentas from smoking mothers compared with those from nonsmokers. In pregnant mice, adenovirus-mediated overexpression of sFRP1 led to FGR, increased karyorrhexis in the junctional zone, and decreased proliferation of labyrinthine trophoblasts. Consistent with our hypothesis that placental WNT signaling is suppressed in maternal smokers, we found that exposure to carbon monoxide analogs led to reduced WNT signaling, increased SFRP1 mRNA expression, and decreased cellular proliferation in a trophoblast cell line. Moreover, administration of carbon monoxide analogs to pregnant mice in late gestation led to FGR. In summary, our results indicate that the increased placental expression of sFRP1 seen in smokers impairs fetal growth by inhibiting WNT signaling and trophoblast proliferation. PMID- 26413871 TI - IL-21R signaling is critical for induction of spontaneous experimental autoimmune encephalomyelitis. AB - IL-17-producing CD4+ T cells (Th17 cells) have well-described pathogenic roles in tissue inflammation and autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE); however, the involvement of IL-21 in these processes has remained controversial. While IL-21 is an essential autocrine amplification factor for differentiation of Th17 cells, the loss of IL-21 or IL-21 receptor (IL 21R) does not protect mice from actively induced EAE. Here, we utilized a transgenic EAE mouse model, in which T and B cells overexpress receptors for myelin oligodendrocyte glycoprotein (MOG) (referred to as 2D2xTH mice), and demonstrated that IL-21 is critical for the development of a variant form of spontaneous EAE in these animals. Il21r deletion in 2D2xTH mice reduced the incidence and severity of spontaneous EAE, which was associated with a defect in Th17 cell generation. Moreover, IL-21R deficiency limited IL-23R expression on Th17 cells and inhibited expression of key molecules involved in the generation of pathogenic Th17 cells. Conversely, loss of IL-23R in 2D2xTH mice resulted in complete resistance to the development of spontaneous EAE. Our data identify a previously unappreciated role for IL-21 in EAE and reveal that IL-21-mediated signaling supports generation and stabilization of pathogenic Th17 cells and development of spontaneous autoimmunity. PMID- 26413872 TI - TIGIT predominantly regulates the immune response via regulatory T cells. AB - Coinhibitory receptors are critical for the maintenance of immune homeostasis. Upregulation of these receptors on effector T cells terminates T cell responses, while their expression on Tregs promotes their suppressor function. Understanding the function of coinhibitory receptors in effector T cells and Tregs is crucial, as therapies that target coinhibitory receptors are currently at the forefront of treatment strategies for cancer and other chronic diseases. T cell Ig and ITIM domain (TIGIT) is a recently identified coinhibitory receptor that is found on the surface of a variety of lymphoid cells, and its role in immune regulation is just beginning to be elucidated. We examined TIGIT-mediated immune regulation in different murine cancer models and determined that TIGIT marks the most dysfunctional subset of CD8+ T cells in tumor tissue as well as tumor-tissue Tregs with a highly active and suppressive phenotype. We demonstrated that TIGIT signaling in Tregs directs their phenotype and that TIGIT primarily suppresses antitumor immunity via Tregs and not CD8+ T cells. Moreover, TIGIT+ Tregs upregulated expression of the coinhibitory receptor TIM-3 in tumor tissue, and TIM-3 and TIGIT synergized to suppress antitumor immune responses. Our findings provide mechanistic insight into how TIGIT regulates immune responses in chronic disease settings. PMID- 26413873 TI - A Pilot Study of IL2 in Drug-Resistant Idiopathic Nephrotic Syndrome. AB - Tregs infusion reverts proteinuria and reduces renal lesions in most animal models of nephrotic syndrome (i.e. Buffalo/Mna, Adriamycin, Promycin, LPS). IL2 up-regulates Tregs and may be an alternative to cell-therapy in this setting. To evaluate a potential role of IL2 as Tregs inducer and proteinuria lowering agent in human nephrotic syndrome we treated 5 nephrotic patients with 6 monthly cycles of low-dose IL2 (1x106 U/m2 first month, 1.5x106 U/m2 following months). The study cohort consisted of 5 children (all boys, 11-17 years) resistant to all the available treatments (i.e. steroids, calcineurin inhibitors, mycophenolate, Rituximab). Participants had Focal Segmental Glomerulosclerosis (3 cases) or Minimal Change Nephropathy (2 cases). IL2 was safe in all but one patient who had an acute asthma attack after the first IL2 dose and did not receive further doses. Circulating Tregs were stably increased (>10%) during the whole study period in 2 cases while were only partially modified in the other two children who started with very low levels and partially responded to single IL2 Proteinuria and renal function were not modified by IL2 at any phase of the study. We concluded that low-dose IL2 given in monthly pulses is safe and modifies the levels of circulating Tregs. This drug may not be able to lower proteinuria or affect renal function in children with idiopathic nephrotic syndrome. We were unable to reproduce in humans the effects of IL2 described in rats and mice reducing de facto the interest on this drug in nephrotic syndrome. TRIAL REGISTRATION: ClinicalTrials.gov NCT02455908. PMID- 26413874 TI - Oligomerization of p62 allows for selection of ubiquitinated cargo and isolation membrane during selective autophagy. AB - Autophagy is a major pathway for the clearance of harmful material from the cytoplasm. During autophagy, cytoplasmic material is delivered into the lysosomal system by organelles called autophagosomes. Autophagosomes form in a de novo manner and, in the course of their formation, isolate cargo material from the rest of the cytoplasm. Cargo specificity is conferred by autophagic cargo receptors that selectively link the cargo to the autophagosomal membrane decorated with ATG8 family proteins such as LC3B. Here we show that the human cargo receptor p62/SQSTM-1 employs oligomerization to stabilize its interaction with LC3B and linear ubiquitin when they are clustered on surfaces. Thus, oligomerization enables p62 to simultaneously select for the isolation membrane and the ubiquitinated cargo. We further show in a fully reconstituted system that the interaction of p62 with ubiquitin and LC3B is sufficient to bend the membrane around the cargo. PMID- 26413875 TI - Ultrasonographic Identification of the Anterolateral Ligament of the Knee. AB - PURPOSE: To determine ultrasonography's sensitivity for identifying the anterolateral ligament (ALL). METHODS: A descriptive study of 18 cadaveric knees was performed. Ultrasonography was used to locate any anterolateral structures at the knee that could correspond to the ALL. The structure's length and relation with other notable anatomic landmarks (fibular head, Gerdy tubercle, joint line, lateral femoral epicondyle, popliteus tendon insertion) were quantified. The ultrasonography measurements were validated by dissecting each knee. The sensitivity of ultrasonography for detecting the ALL and the agreement between the ultrasonographic and cadaveric measurements (Cohen kappa) were determined by statistical analysis. RESULTS: The ALL was found in all 18 cadaveric knees and corresponded anatomically to the ultrasonographic descriptions. Ultrasonography had 100% sensitivity for detecting the presence of the ALL. The ALL's insertion on the lateral femoral condyle was, on average, 12.08 mm (SD, 4 mm; range, 7 to 15 mm) proximal and posterior to the lateral femoral epicondyle and 20.5 mm (SD, 3 mm; range, 16 to 24 mm) proximal to the middle of the popliteus tendon insertion. The ALL inserted onto the tibia, midway between the Gerdy tubercle and the fibular head; the distance between the midpoint of the tibial insertion and middle of the Gerdy tubercle was 19.05 mm (SD, 2.1 mm; range, 15 to 25 mm), and the distance was 19.13 mm (SD, 2.3 mm; range, 14 to 23 mm) to the tip of the fibular head. The agreement between the ultrasonographic and cadaveric findings was excellent (Cohen kappa coefficient between 0.88 and 0.94). CONCLUSIONS: Ultrasound imaging is a suitable tool for identifying the ALL of the knee, and it allowed for a detailed analysis of the entire ALL in all 18 knees. However, its ability to evaluate any injuries to the ALL must still be shown. CLINICAL RELEVANCE: Ultrasonography can be used to confirm the integrity of the ALL. PMID- 26413877 TI - A Not-So-Subtle Bump on the Head. PMID- 26413876 TI - Preferential Extracellular Generation of the Active Parkinsonian Toxin MPP+ by Transporter-Independent Export of the Intermediate MPDP+. AB - AIMS: 1-Methyl-4-phenyl-tetrahydropyridine (MPTP) is among the most widely used neurotoxins for inducing experimental parkinsonism. MPTP causes parkinsonian symptoms in mice, primates, and humans by killing a subpopulation of dopaminergic neurons. Extrapolations of data obtained using MPTP-based parkinsonism models to human disease are common; however, the precise mechanism by which MPTP is converted into its active neurotoxic metabolite, 1-methyl-4-phenyl-pyridinium (MPP(+)), has not been fully elucidated. In this study, we aimed to address two unanswered questions related to MPTP toxicology: (1) Why are MPTP-converting astrocytes largely spared from toxicity? (2) How does MPP(+) reach the extracellular space? RESULTS: In MPTP-treated astrocytes, we discovered that the membrane-impermeable MPP(+), which is generally assumed to be formed inside astrocytes, is almost exclusively detected outside of these cells. Instead of a transporter-mediated export, we found that the intermediate, 1-methyl-4-phenyl 2,3-dihydropyridinium (MPDP(+)), and/or its uncharged conjugate base passively diffused across cell membranes and that MPP(+) was formed predominately by the extracellular oxidation of MPDP(+) into MPP(+). This nonenzymatic extracellular conversion of MPDP(+) was promoted by O2, a more alkaline pH, and dopamine autoxidation products. INNOVATION AND CONCLUSION: Our data indicate that MPTP metabolism is compartmentalized between intracellular and extracellular environments, explain the absence of toxicity in MPTP-converting astrocytes, and provide a rationale for the preferential formation of MPP(+) in the extracellular space. The mechanism of transporter-independent extracellular MPP(+) formation described here indicates that extracellular genesis of MPP(+) from MPDP is a necessary prerequisite for the selective uptake of this toxin by catecholaminergic neurons. PMID- 26413878 TI - A cholesterol-lowering VLP vaccine that targets PCSK9. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory protein that controls cholesterol homeostasis by enhancing endosomal and lysosomal degradation of the low-density lipoprotein receptor (LDL-R). Mutations that cause increased activity of PCSK9 are associated with hypercholesterolemia, atherosclerosis and early cardiovascular disease (CVD), whereas individuals with loss-of-function mutations in PCSK9 are apparently healthy but are hypocholesterolemic and have a dramatically decreased risk of CVD. In this study, we generated virus-like particle (VLP)-based vaccines targeting PCSK9. Mice and macaques vaccinated with bacteriophage VLPs displaying PCSK9-derived peptides developed high titer IgG antibodies that bound to circulating PCSK9. Vaccination was associated with significant reductions in total cholesterol, free cholesterol, phospholipids, and triglycerides. A vaccine targeting PCSK9 may, therefore, be an attractive alternative to monoclonal antibody-based therapies. PMID- 26413879 TI - A systematic review of adverse events following immunization during pregnancy and the newborn period. AB - In 2013, the WHO Strategic Advisory Group of Experts on Immunization (SAGE) requested WHO to develop a process and a plan to move the maternal immunization agenda forward in support of an increased alignment of data safety evidence, public health needs, and regulatory processes. A key challenge identified was the continued need for harmonization of maternal adverse event following immunization (AEFI) research and surveillance efforts within developing and developed country contexts. We conducted a systematic review as a preliminary step in the development of standardized AEFI definitions for use in maternal and neonatal clinical trials, post-licensure surveillance, and other vaccine studies. We documented the current extent and nature of variability in AEFI definitions and adverse event reporting among 74 maternal immunization studies, which reported a total of 240 different types of adverse events. Forty-nine studies provided explicit AEFI case definitions describing 35 separate types of AEFIs. We identified variability in how AEFIs were determined to be present, in how AEFI definitions were applied, and in the ways that AEFIs were reported. Definitions for key maternal/neonatal AEFIs differed on four discrete attributes: overall level of detail, physiological and temporal boundaries and cut-offs, severity strata, and standards used. Our findings suggest that investigators may proactively address these inconsistencies through comprehensive and consistent reporting of AEFI definitions and outcomes in future publications. In addition, efforts to develop standardized AEFI definitions should generate definitions of sufficient detail and consistency of language to avoid the ambiguities we identified in reviewed articles, while remaining practically applicable given the constraints of low-resource contexts such as limited diagnostic capacity and high patient throughput. PMID- 26413880 TI - Antigen-specific IgA titres after 23-valent pneumococcal vaccine indicate transient antibody deficiency disease in children. AB - Paediatric patients with antibody deficiency may either be delayed in development of humoral immunity or may be persistently deficient in antibody production. To differentiate between these entities, we examined the 23-valent pneumococcal polysaccharide (PnPS) vaccine-induced IgM-, IgG- and IgA antibody responses in a cohort of 66 children with recurrent respiratory tract infections. Individual serum titres against 11 pneumococcal serotypes were measured by Luminex. The cohort contained 33 antibody deficiency patients, 17 transient antibody deficiency patients and 16 patients without antibody deficiency diagnosis (control group). Transient antibody deficiency patients produced consistently higher levels of PnPS-specific IgA responses than antibody deficiency patients. Decreased IgA responses to serotypes 1, 5, 7F and 18C were most discriminative to stratify transient antibody deficiency patients from antibody deficiency patients with persistent disease. We conclude that measuring PnPS-specific IgA responses may predict the disease course in young children diagnosed with antibody deficiency and suggest confirmation of these data in a prospective setting. PMID- 26413881 TI - Will there ever be a new influenza pandemic and are we prepared? PMID- 26413882 TI - Isometrically invariant and allosterically aware description of deformable macromolecular surfaces: Application to the viral neuraminidase. AB - MOTIVATION: The macromolecular surfaces associated with proteins and macromolecules play a key role in determining their functionality and interactions, and are also of importance in structural analysis and classification. As a result of their interaction with their environment, the macromolecular surfaces experience random conformational deformations. Consequently, a realistic description of the molecular surface must be invariant under these deformations. Further, the motion associated with disconnected regions on the molecular surface may be correlated. This property is known as the allosteric effect. In this paper, we address these two requirements. To this end, we propose an approach based on discrete differential geometry and the fractional Fokker-Planck equation which provides an isometrically invariant and allosteric aware description of macromolecular surfaces. Our method is applied to the influenza neuraminidase. PMID- 26413883 TI - Bone marrow microenvironmental CD4 + and CD8 + lymphocyte infiltration patterns define overall- and progression free survival in standard risk multiple myeloma- an analysis from the Austrian Myeloma Registry. PMID- 26413884 TI - Anti-Aging and Tissue Regeneration Ability of Policosanol Along with Lipid Lowering Effect in Hyperlipidemic Zebrafish via Enhancement of High-Density Lipoprotein Functionality. AB - We investigated the tissue regeneration and lipid-lowering effects of policosanol (PCO) by employing a hyperlipidemic zebrafish model. A reconstituted high-density lipoprotein containing policosanol (PCO-rHDL) facilitated greater cell growth and replication with less apoptosis and reactive oxygen species (ROS) production in BV-2 microglial cell lines. From in vivo study, injection of rHDL containing apolipoprotein A-I (ApoA-I) caused 76 +/- 4% (p = 0.01) greater tissue regeneration activity than the phosphate-buffered saline (PBS) control, whereas PCO-rHDL caused 94 +/- 7% (p = 0.002) increased regeneration. PCO in ethanol (EtOH) showed lower cholesteryl ester transfer protein (CETP) inhibitory ability than did anacetrapib, whereas PCO-rHDL showed higher inhibitory ability than anacetrapib, suggesting a synergistic effect between PCO and rHDL. Following 9 weeks of PCO consumption, the PCO group (0.003% PCO in Tetrabit) showed the highest survivability (80%), whereas normal diet (ND) and high-cholesterol diet (HCD) control groups showed 67% and 70% survival rates, respectively. Supplementation with a HCD resulted in two-fold elevation of CETP activity along with 3- and 2.5-fold increases in serum total cholesterol (TC) and triglycerides (TGs) levels, respectively. Consumption of PCO for 9 weeks resulted in 40 +/- 5% (p = 0.01 vs. HCD) and 33 +/- 4% (p = 0.02 vs. HCD) reduction of TC and TGs levels, respectively. Serum high-density lipoprotein cholesterol (HDL-C) level increased up to 37 +/- 2 mg/dL (p = 0.004), whereas the percentage of HDL-C/TC increased up to 20 +/- 2% from 5 +/- 1% compared to the HCD control. The serum glucose level was reduced to 47 +/- 2% (p = 0.002) compared to the HCD control. Fatty liver change and hepatic inflammation levels were remarkably increased upon HCD consumption and were two-fold higher than that under ND. However, the PCO group showed 58 +/- 5% (p = 0.001) and 50 +/- 3% (p = 0.006) reduction of inflammation enzyme levels and lipid content in hepatic tissue under HCD. In conclusion, PCO supplementation showed lipid-lowering and HDL-C-elevating effects with ameliorating fatty liver change. These in vivo anti-atherosclerotic and anti diabetic effects of PCO are well associated with in vitro anti-apoptotic activities. PMID- 26413885 TI - A Single Dose of Intraoperative Antibiotics Is Sufficient to Prevent Urinary Tract Infection During Ureteroscopy. AB - BACKGROUND: American Urology Association (AUA) Best Practice Guidelines for ureteroscopic stone treatment recommend antibiotic coverage for <24 hours following the procedure. The purpose of this study was to evaluate if the addition of postoperative antibiotics reduces urinary tract infections (UTIs) following ureteroscopic stone treatment beyond the recommended preoperative dose. METHODS: A retrospective review was performed of consecutive patients at two institutions, University of British Columbia and Massachusetts General Hospital, Harvard. All patients received a single dose of antibiotics before ureteroscopic stone treatment. A subset of patients was also given postoperative antibiotics. The rate of UTI was compared in patients receiving only preoperative antibiotics (group 1) vs those who received pre- and postoperative antibiotics (group 2). RESULTS: Eighty-one patients underwent ureteroscopy for renal calculi. Mean time to follow up was 42 +/- 88 days. Eight (9.9%) patients in total (two from group 1 and six from group 2, p = 0.1457) developed UTIs postoperatively. In group 1, both patients presented with pyelonephritis (n = 2); those patients with infections in group 2 presented with urosepsis (n = 2) and cystitis (n = 2) and two patients had asymptomatic bacteriuria. Risk factors such as preoperative stenting, nephrostomy tubes, and foley catheters neither differed between groups nor did they predispose patients to postoperative infections. CONCLUSIONS: The postoperative UTI rate in this study (9.9%) is consistent with previous reports. Our data suggest that a single preoperative dose of antibiotics is sufficient, and additional postoperative antibiotics do not decrease infection rates after ureteroscopic stone treatment. Risk for selection bias is a potential limitation. PMID- 26413886 TI - Imbalance Between Bone Morphogenetic Protein 2 and Noggin Induces Abnormal Osteogenic Differentiation of Mesenchymal Stem Cells in Ankylosing Spondylitis. AB - OBJECTIVE: To study the osteogenic differentiation capacity of bone marrow derived mesenchymal stem cells (BM-MSCs) from patients with ankylosing spondylitis (AS) and to investigate the mechanisms of abnormal osteogenic differentiation of BM-MSCs in AS. METHODS: BM-MSCs from healthy donors (HD-MSCs) and patients with AS (AS-MSCs) were cultured in osteogenic differentiation medium for 0-21 days, after which their osteogenic differentiation capacity was determined using alizarin red S and alkaline phosphatase assays. Gene expression levels of osteoblastic markers and related cytokines were detected by high throughput quantitative reverse transcription-polymerase chain reaction. Enzyme linked immunosorbent assay was performed to detect protein levels of bone morphogenetic protein 2 (BMP-2) and Noggin in the cell culture supernatant. The activation of Smad1/5/8 and MAPK signaling pathways was measured by Western blotting. The balance between BMP-2 and Noggin expression was regulated using lentiviruses encoding short hairpin RNA and exogenous Noggin, respectively, which enabled evaluation of how this balance affected osteogenic differentiation of AS MSCs. RESULTS: AS-MSCs outperformed HD-MSCs in osteogenic differentiation capacity. During osteogenic differentiation, AS-MSCs secreted more BMP-2 but less Noggin, accompanied by an overactivation of Smad1/5/8 and ERK-1/2. When the Noggin concentration was increased or BMP-2 expression was inhibited, the abnormal osteogenic differentiation of AS-MSCs was rectified. In addition, the balance between BMP-2 and Noggin secretion was restored. CONCLUSION: The results of this study demonstrate that an imbalance between BMP-2 and Noggin secretion induces abnormal osteogenic differentiation of AS-MSCs. These findings reveal a mechanism of pathologic osteogenesis in AS and provide a new perspective on inhibiting pathologic osteogenesis by regulating the balance between BMP-2 and Noggin. PMID- 26413887 TI - Characterization of Streptomycin Resistance in Isolates of Erwinia amylovora in California. AB - In surveys from 2006 to 2014, streptomycin resistance in Erwinia amylovora from pear-growing areas in California declined from very high incidence in 2006 and 2007 to very low incidence in 2013 and 2014. The majority of resistant strains were designated as moderately resistant-low (MR-L), and were almost exclusively found in Sacramento County, whereas highly resistant (HR) strains were only recovered in Sutter-Yuba and San Joaquin counties. Resistance of HR strains was associated with a mutation in codon 43 of the chromosomal rpsL gene that results in a change from lysine to arginine, the same mutation that was originally reported for resistant strains from California in the mid-1970s. MR-L strains were found to harbor the strA-strB streptomycin resistance genes on transposon Tn5393a. This transposon lacks insertion sequence IS1133 that provides a promoter for efficient expression of strA-strB, resulting in lower minimum inhibitory concentrations of MR-L strains compared with those from other locations that harbor strA-strB on Tn5393::IS1133. In contrast to previously described plasmid mediated resistance where Tn5393 is inserted in pEa34, or pEA29, Tn5393a in MR-L strains was located on plasmid pEU30. This plasmid was first described in E. amylovora from the western United States but was not associated with streptomycin resistance determinants previously. We hypothesize that Tn5393a was introduced into an E. amylovora strain carrying pEU30 and transposed into that plasmid. This hypothesis was supported by clustered regularly interspaced short palindromic repeat (CRISPR) sequence analysis that showed that two MR-L strains share the same CRISPR1 pattern as a streptomycin-sensitive strain. With current low resistance levels in California growing regions, streptomycin could be successfully used again, but applications per season should be limited and the antibiotic should be mixed and rotated with different modes of action. PMID- 26413888 TI - Why is number word learning hard? Evidence from bilingual learners. AB - Young children typically take between 18 months and 2 years to learn the meanings of number words. In the present study, we investigated this developmental trajectory in bilingual preschoolers to examine the relative contributions of two factors in number word learning: (1) the construction of numerical concepts, and (2) the mapping of language specific words onto these concepts. We found that children learn the meanings of small number words (i.e., one, two, and three) independently in each language, indicating that observed delays in learning these words are attributable to difficulties in mapping words to concepts. In contrast, children generally learned to accurately count larger sets (i.e., five or greater) simultaneously in their two languages, suggesting that the difficulty in learning to count is not tied to a specific language. We also replicated previous studies that found that children learn the counting procedure before they learn its logic - i.e., that for any natural number, n, the successor of n in the count list denotes the cardinality n+1. Consistent with past studies, we found that children's knowledge of successors is first acquired incrementally. In bilinguals, we found that this knowledge exhibits item-specific transfer between languages, suggesting that the logic of the positive integers may not be stored in a language-specific format. We conclude that delays in learning the meanings of small number words are mainly due to language-specific processes of mapping words to concepts, whereas the logic and procedures of counting appear to be learned in a format that is independent of a particular language and thus transfers rapidly from one language to the other in development. PMID- 26413889 TI - The AINU Technique for Laparoscopic Vesico-Vaginal Fistula Repair: A Preliminary Report. AB - INTRODUCTION: With safe obstetric practices now globally available, most vesico vaginal fistulas (VVF) presenting in recent times are secondary to various gynecologic surgeries. Most of them are supra-trigonal in location. Laparoscopic repair of VVF is gaining ground as an alternative to open repair of VVF. In this study, we describe our initial experience with a novel technique of laparoscopic VVF repair involving a limited transverse cystotomy for access and a single layered barbed suture closure of bladder. MATERIALS AND METHODS: Twenty cases of supra-trigonal VVFs following gynecologic surgeries were taken up for repair by our novel technique. The mean age of the patients was 32 years and the mean VVF size was 1.5 cm. RESULTS: The mean operative time was 54 min. Estimated mean blood loss was 30 ml and the mean postoperative stay was 2.5 days. None of the patients had any recurrence with a mean follow-up of 14 months. CONCLUSION: The limited transverse cystotomy approach has advantages in decreasing the operative time, improving ease of laparoscopic suturing, allowing an automatic separation of suture lines and allowing for an easier anterior dissection of the bladder to reduce tension on the suture line if necessary. Further this approach provides excellent results in select patients of supra-trigonal VVF in terms of continence and postoperative bladder overactivity. PMID- 26413890 TI - Strategy use fully mediates the relationship between working memory capacity and performance on Raven's matrices. AB - Working memory capacity consistently correlates with fluid intelligence. It has been suggested that this relationship is partly attributable to strategy use: Participants with high working memory capacity would use more effective strategies, in turn leading to higher performance on fluid intelligence tasks. However, this idea has never been directly investigated. In 2 experiments, we tested this hypothesis by directly manipulating strategy use in a combined experimental-correlational approach (Experiment 1; N = 250) and by measuring strategy use with a self-report questionnaire (Experiment 2; N = 93). Inducing all participants to use an effective strategy in Raven's matrices decreased the correlation between working memory capacity and performance; the strategy use measure fully mediated the relationship between working memory capacity and performance on the matrices task. These findings indicate that individual differences in strategic behavior drive the predictive utility of working memory. We interpret the results within a theoretical framework integrating the multiple mediators of the relationship between working memory capacity and high-level cognition. PMID- 26413891 TI - Fast but not intuitive, slow but not reflective: Decision conflict drives reaction times in social dilemmas. AB - When people have the chance to help others at a cost to themselves, are cooperative decisions driven by intuition or reflection? To answer this question, recent studies have tested the relationship between reaction times (RTs) and cooperation, reporting both positive and negative correlations. To reconcile this apparent contradiction, we argue that decision conflict (rather than the use of intuition vs. reflection) drives response times, leading to an inverted-U shaped relationship between RT and cooperation. Studies 1 through 3 show that intermediate decisions take longer than both extremely selfish and extremely cooperative decisions. Studies 4 and 5 find that the conflict between self interested and cooperative motives explains individual differences in RTs. Manipulating conflictedness causes longer RTs and more intermediate decisions, and RTs mediate the relationship between conflict and intermediate decisions. Finally, Studies 6 and 7 demonstrate that conflict is distinct from reflection by manipulating the use of intuition (vs. reflection). Experimentally promoting reliance on intuition increases cooperation, but has no effects on decision extremity or feelings of conflictedness. In sum, we provide evidence that RTs should not be interpreted as a direct proxy for the use of intuitive or reflective processes, and dissociate the effects of conflict and reflection in social decision making. PMID- 26413892 TI - Compete, coordinate, and cooperate: How to exploit uncertain environments with social interaction. AB - Countless decisions, from the trivial to the crucial, are made in complex social contexts while facing uncertain consequences. Yet a large portion of decision making research focuses on either the effects of social interaction or the effects of environmental uncertainty by examining strategic games against others or individual games against nature. Drawing a connection between these approaches, the authors extend a standard individual choice paradigm to include social interaction with 1 other person. In this paradigm, 2 competing decision makers repeatedly select among 2 options, each offering a particular probability of a fixed payoff. When both players choose the same, correct option, the payoff is evenly split; when they choose different options, the player choosing the correct option receives the full payoff. The addition of this social dimension gives players an opportunity to fully exploit an uncertain environment via cooperation: By consistently choosing opposite options, two players can exploit the uncertain environment more effectively than a single player could. We present 2 experiments that manipulate environmental (Experiment 1) and social (Experiment 2) aspects of the paradigm. In Experiment 1, the outcome probabilities were either known or unknown to participants; in Experiment 2, participants' attention was drawn to individual or group gains by introducing either within- or between group competition. Efficient cooperation did not emerge spontaneously in Experiment 1. Instead, most people probability maximized, mirroring the behavior observed in individual choice. By contrast, between--group competition in Experiment 2 facilitated efficient-but not always equitable--exploitation of uncertain environments. This work links the concepts of individual risky choice and strategic decision making under both environmental and social uncertainty. PMID- 26413893 TI - Self-enhancement diminished. AB - Self-enhancement is a positive bias in self-perception, which may imply error. However, conventional measures of self-enhancement are difference scores that do not distinguish a positive bias from a self-enhancement error, that is, they fail to identify those individuals who hold an irrationally or inaccurately positive view of themselves. We propose 2 new measures to separate error from bias. In the domain of personality judgment, we estimate a defensible bias and an enhancement error from individuals' actual and perceived similarity with others. In the domain of performance, we adapt a decision-theoretic framework to distinguish those who falsely believe to be better than average from those who actually are better. We illustrate the properties of these measures in 3 empirical studies and computer simulations. Implausibly high majorities of people consider themselves to be above average on various dimensions. PMID- 26413895 TI - Sedation versus general anaesthesia for provision of dental treatment to patients younger than 18 years. AB - BACKGROUND: A significant proportion of children have caries requiring restorations or extractions, and some of these children will not accept this treatment under local anaesthetic. Historically this has been managed by the use of a general anaesthetic in children; however, use of sedation may lead to reduced morbidity and cost. The aim of this review was to compare the efficiency of sedation versus general anaesthesia (GA) for provision of dental treatment to children and adolescents younger than 18 years. This review was originally published in 2009 and was updated in 2012 and again in 2015. OBJECTIVES: We will evaluate morbidity and effectiveness of sedation versus GA for provision of dental treatment to patients younger than 18 years. If data become available, we will analyse the cost-effectiveness of different interventions. If data are not available, we will obtain crude estimates of cost.Morbidity can be defined as 'an undesired result or complication'. For the purposes of this review, 'postoperative morbidity' refers to undesired results or complications such as nausea following a procedure, once the patient had been restored to consciousness and could breathe unaided. 'Intraoperative morbidity' refers to any complications that occur during the procedure that may necessitate action by the anaesthetist or the sedationist, such as respiratory arrest. SEARCH METHODS: In this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 7); MEDLINE Ovid SP (1950 to July 2015); EMBASE Ovid SP (1974 to July 2015); System for Information on Grey Literature in Europe (SIGLE) (1980 to October July 2012); Latin American & Caribbean Health Sciences Literature (LILACS) (1982 to July 2015); and Institute for Scientific Information (ISI) Web of Science (1945 to July 2015).We also carried out handsearching of relevant journals to July 2015. We imposed no language restriction. SELECTION CRITERIA: We planned to include randomized controlled clinical trials that compared sedative agents versus general anaesthesia in children and adolescents up to 18 years of age undergoing dental treatment. We excluded complex surgical procedures and pseudo-randomized trials. DATA COLLECTION AND ANALYSIS: Two review authors assessed titles and abstracts for inclusion in the review. We recorded information relevant to objectives and outcome measures by using a specially designed 'data extraction form'. We will employ the Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE) approach to interpret findings. MAIN RESULTS: In our original review, we identified 16 studies for potential inclusion after searching available databases and screening titles and abstracts. After retrieving full-text studies, we found none to be eligible. We identified no additional studies in the updated search of July 2012. We identified two studies for possible inclusion in the updated search of July 2015; again we found these to be ineligible. AUTHORS' CONCLUSIONS: Randomized controlled studies comparing use of dental general anaesthesia versus sedation are needed to quantify differences such as morbidity and cost. PMID- 26413894 TI - The Ca2+-Regulation of the Mitochondrial External NADPH Dehydrogenase in Plants Is Controlled by Cytosolic pH. AB - NADPH is a key reductant carrier that maintains internal redox and antioxidant status, and that links biosynthetic, catabolic and signalling pathways. Plants have a mitochondrial external NADPH oxidation pathway, which depends on Ca2+ and pH in vitro, but concentrations of Ca2+ needed are not known. We have determined the K0.5(Ca2+) of the external NADPH dehydrogenase from Solanum tuberosum mitochondria and membranes of E. coli expressing Arabidopsis thaliana NDB1 over the physiological pH range using O2 and decylubiquinone as electron acceptors. The K0.5(Ca2+) of NADPH oxidation was generally higher than for NADH oxidation, and unlike the latter, it depended on pH. At pH 7.5, K0.5(Ca2+) for NADPH oxidation was high (~100 MUM), yet 20-fold lower K0.5(Ca2+) values were determined at pH 6.8. Lower K0.5(Ca2+) values were observed with decylubiquinone than with O2 as terminal electron acceptor. NADPH oxidation responded to changes in Ca2+ concentrations more rapidly than NADH oxidation did. Thus, cytosolic acidification is an important activator of external NADPH oxidation, by decreasing the Ca2+-requirements for NDB1. The results are discussed in relation to the present knowledge on how whole cell NADPH redox homeostasis is affected in plants modified for the NDB1 gene. PMID- 26413896 TI - Potential risk and control strategy of biofilm pretreatment process treating raw water. AB - An enhanced lab-scale biofilm pretreatment process treating raw water obtained from eutrophicated water bodies was established and started up with a novel strategy of low-level nutrients addition and effluent recirculation. Results showed that the startup strategy was useful for biofilm formation and pollutants removal, but it had the risks of increasing substrate affinity constant (Ks) and biofilm decay in treating raw water. Fortunately, the increased Ks value did not affected the NH4(+)-N removal performance via keeping the NH4(+)-N loading rate larger than 6.29 mg L(-1)d(-1). In addition, lower hydraulic retention time (HRT) favored the removal of organic matters, and the maximum TOC removal rate of 76.5 mg L(-1)d(-1) were achieved at HRT of 2h. After long-term acclimatization at oligotrophic niche, the decrease of Ks value and increase of biomass, extracellular polymeric substances, bioactivity were achieved. Finally, the stable operation of biofilm pretreatment process was realized in treating polluted raw water. PMID- 26413897 TI - A Ca-alginate particle co-immobilized with Phanerochaete chrysosporium cells and the combined cross-linked enzyme aggregates from Trametes versicolor. AB - For improving stability of immobilized white-rot fungus to treat various effluents, Phanerochaete chrysosporium cells and the combined cross-link enzyme aggregates (combi-CLEAs) prepared from Trametes versicolor were co-immobilized into the Ca-alginate gel particles in this paper. The activity yields of obtained combi-CLEAs were 42.7% for lignin peroxidases (LiPs), 31.4% for manganese peroxidases (MnPs) and 40.4% for laccase (Lac), respectively. And their specific activities were 30.2U/g as combi-CLEAs-LiPs, 9.5 U/g as combi-CLEAs-MnPs and 28.4 U/g as combi-CLEAs-Lac. Further, the present of the combi-CLEAs in the particles extremely improved their ability to degrade the dyes. Compared to the immobilized Ph. chrysosporium without the combi-CLEAs, the co-immobilized particles enhanced the decolorized rate of Acid Violet 7 (from 45.2% to 93.4%) and Basic Fuchsin (from 12.1% to 67.9%). In addition, the addition of the combi-CLEAs improved the adaptability of the white-rot fungal particles to adverse environmental conditions. PMID- 26413898 TI - Effectiveness of Training Clinicians' Communication Skills on Patients' Clinical Outcomes: A Systematic Review. AB - OBJECTIVE: The aim of this systematic review was to investigate the literature on the effectiveness of communication skills training for clinicians on patients' clinical outcomes in primary care and rehabilitation settings. METHODS: We systematically reviewed the literature for randomized controlled trials investigating the effectiveness of communication skills training for clinicians on patients' satisfaction with care and on pain and disability in primary care and rehabilitation settings. The search strategy was conducted using AMED, PsycINFO, MEDLINE, CINAHL, EMBASE, PEDro, and Cochrane Central Register of Controlled Trials through June 2015. Methodological quality of included trials was assessed by 2 independent investigators using the PEDro scale, and consensus was used to resolve disagreements. Data were extracted, and meta-analyses were performed. RESULTS: Nineteen randomized controlled trials were included. Of these, 16 investigated communication training for clinicians that emphasized patient participation (eg, shared decision-making approaches). Communication training had small effects on patients' satisfaction with care when compared to control (4.1 points on a 100-point scale, 95% confidence interval [CI], 1.1-7.0). Communication training also had small effects on pain and disability with pooled results showing weighted mean differences of -3.8 points (95% CI, -6.5 to -1.1) and -3.6 (95% CI, -5.4 to -1.7), respectively. CONCLUSIONS: Studies show that communication training for clinicians produces small effects in improving patients' satisfaction with care or reducing pain and disability in primary care and rehabilitation settings. PMID- 26413899 TI - Neuromechanical responses after biofeedback training in participants with chronic low back pain: an experimental cohort study. AB - OBJECTIVE: The objective of this study was to evaluate changes in neuromechanical responses and clinical outcomes in chronic low back pain participants after 4 sessions of biofeedback training. METHODS: Twenty-one participants took part in an electromyography biofeedback 4-session training program aimed at reducing lumbar paraspinal muscle activity during full trunk flexion. The sessions consisted of ~46 trunk flexion-extension divided into 5 blocks. The effects of training blocks and sessions on lumbar flexion-relaxation ratio and lumbopelvic ranges of motion were assessed. Changes in disability (Oswestry Disability Index), pain intensity (numerical rating scale), and fear of movement (Tampa Scale for Kinesiophobia) were also evaluated. RESULTS: Analyses of variance revealed a significant block effect for which an increase in the flexion relaxation ratio and the lumbar range of motion between block 1 and the other blocks for sessions 1 and 2 (P < .0001) was observed. However, no significant session or interaction effect was observed. Among clinical outcomes, only fear of movement significantly decreased between the baseline (mean [SD], 33.05 [7.18]) and the fourth session (29.80 [9.88]) (P = .02). There was no significant correlation between clinical outcomes and neuromechanical variables. CONCLUSION: Biofeedback training led to decreases in lumbar paraspinal muscle activity in full trunk flexion and increases in lumbopelvic range of motion in participants with chronic nonspecific low back pain. Although the neuromechanical changes were mostly observed at the early stage of the program, the presence of a decrease in the fear of movement suggests that the participants' initially limited ROMs may have been modulated by fear avoidance behaviors. PMID- 26413900 TI - Dose Response of MARV/Angola Infection in Cynomolgus Macaques following IM or Aerosol Exposure. AB - Marburg virus infection in humans causes a hemorrhagic disease with a high case fatality rate. Countermeasure development requires the use of well-characterized animal models that mimic human disease. To further characterize the cynomolgus macaque model of MARV/Angola, two independent dose response studies were performed using the intramuscular or aerosol routes of exposure. All animals succumbed at the lowest target dose; therefore, a dose effect could not be determined. For intramuscular-exposed animals, 100 PFU was the first target dose that was not significantly different than higher target doses in terms of time to disposition, clinical pathology, and histopathology. Although a significant difference was not observed between aerosol-exposed animals in the 10 PFU and 100 PFU target dose groups, 100 PFU was determined to be the lowest target dose that could be consistently obtained and accurately titrated in aerosol studies. PMID- 26413901 TI - Megacystis microcolon intestinal hypoperistalsis syndrome: A report of a nationwide survey in Japan. AB - BACKGROUND: Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a rare condition with a poor outcome. A nationwide survey was conducted to identify the clinical features and outcomes of MMIHS in Japan. METHODS: Data were collected via a questionnaire, which was sent to 353 pediatric/pediatric surgical departments in Japan. RESULTS: Of the 28 patients registered as having a certain diagnosis of MMIHS, 19 (male/female, 3/16) patients were analyzed. All of the patients developed functional bowel obstruction in the neonatal period and showed a distended bladder and microcolon in the radiological examination. A histopathology assessment of the full-thickness of intestinal specimens showed no pathological abnormalities in all patients. Although various medications were given, the patients did not show significant improvement. Drainage stomas were created in the jejunum (n=11) and colon (n=5). Sixteen patients were maintained by parenteral nutrition (PN). Nine patients died of sepsis or liver failure. The five- and ten-year survival rates were 63% and 57%, respectively. CONCLUSIONS: MMIHS patients developed severe functional intestinal obstruction in the neonatal period and had no specific therapeutic intervention. The majority of MMIHS patients required long-term PN. Small bowel or multivisceral transplantation may be necessary to improve the outcome of this condition. PMID- 26413902 TI - Cardiac fetal ultrasonographic parameters for predicting outcomes of isolated left-sided congenital diaphragmatic hernia. AB - BACKGROUND: The purpose of this study was to investigate fetal cardiac ultrasonographic parameters in relation to the outcomes of patients with isolated left-sided congenital diaphragmatic hernia (CDH). METHODS: Subjects comprised 33 fetuses with fetal CDH and 99 control fetuses without cardiac and lung anomalies. Three parameters, cardiothoracic area ratio (CTAR), the ratio of the diameter of the main pulmonary artery to that of the ascending aorta (MPA/AAo), and the ratio of the diameter of the tricuspid valve to that of the mitral valve (TV/MV) were compared between fetal CDH and control subjects and between survival (SG) and non survival (NSG) groups. RESULTS: All three parameters differed significantly between CDH and control fetuses. Significant differences between SG and NSG were observed in CTAR and TV/MV ratio, but not in MPA/AAo ratio before and after 32 gestational weeks. A significant increase in the TV/MV ratio was noted along with an increase in gestational age. A TV/MV ratio of >1.72 discriminated non survivors from survivors with better sensitivity and specificity. CONCLUSIONS: Fetal cardiac ultrasonography provides useful information for predicting the outcomes of isolated left-sided CDH. The TV/MV ratio was considered a reliable indicator that reflected outcomes of isolated left-sided CDH. PMID- 26413903 TI - The Association of Gender, Age, Efavirenz Use, and Hypovitaminosis D Among HIV Infected Adults Living in the Tropics. AB - Vitamin D, which is important for calcium homeostasis and bone metabolism, has several noncalcemic actions. Low vitamin D levels have been observed in HIV infected patients from high latitudes, with consequently reduced bone mineral density (BMD), but data from the tropics are scarce. We aimed to determine the prevalence of and risk factors for hypovitaminosis D among HIV-infected patients in the tropics. This was a cross-sectional study to determine serum 25 hydroxyvitamin D [25(OH)D] levels in HIV-infected patients who attended our HIV clinic in Bangkok, Thailand from July 2010 to June 2011. Hypovitaminosis D was defined as vitamin D insufficiency and deficiency [25(OH)D 20-30 ng/ml and <20 ng/ml, respectively]. Hypovitaminosis D prevalence was calculated and risk factors were determined using multivariate logistic regression. A total of 673 HIV-infected adults were included. The median age was 41 years and 47% were females. The median body mass index (BMI) was 21.9 kg/m(2) and 93% were using antiretroviral therapy (ART), with a median (IQR) duration of 8.9 (5.0-10.4) years. Thirty-one percent were using efavirenz (EFV). The prevalence of vitamin D insufficiency and deficiency was 40.6% and 29.9%, respectively. In multivariate analysis, female gender [odds ratio: OR (95% confidence interval: 95% CI) 1.7 (1.2-2.3), p = 0.005], age >37 years [OR (95% CI) 1.6 (1.1-2.4), p = 0.01], and EFV use [OR (95% CI) 2.0 (1.3-3.2), p = 0.004] were independent predictors of hypovitaminosis D. Even in tropical areas where the sun is abundant, hypovitaminosis D is highly prevalent. Thus, treatment of low vitamin D in HIV infected patients at high risk should not be ignored to prevent reductions in BMD and other hypovitaminosis D-related comorbidities. PMID- 26413904 TI - Effect of starting body fat content and genotype of laying hens on the changes in their live weight, body fat content, egg production and egg composition during the first egg-laying period. AB - A total 120 laying hens (60 TETRA BLANCA white egg layers and 60 TETRA SL brown egg layers) were selected from 250 TETRA BLANCA and 250 TETRA SL pullets based on their predicted body fat content by means of computed tomography (CT) at 16 weeks of age. Three groups of pullets were chosen for the investigation with the highest (n = 20), lowest (n = 20) and average (n = 20) body fat content. Changes in the live weight, body fat content, egg production and egg composition of the chosen animals were recorded at 32, 52 and 72 weeks of age. Based on the results, it was established that differences in starting body fat content of the hens remained the same during the experimental period. The differences between the two extreme groups were statistically significant at each age. The starting body fat content of the hens affected the rate of egg production, i.e. hens with high starting body fat content produced 11-14 eggs fewer than the hens with a low or average body fat content but had no effect on the composition of the eggs. Genotype affected almost all of the examined traits: TETRA BLANCA hens had lower live weight and higher body fat content during the experimental period and produced fewer eggs with lower albumen and higher yolk, dry matter and crude fat content than the TETRA SL hens. PMID- 26413905 TI - Serendipitous Meta-Transcriptomics: The Fungal Community of Norway Spruce (Picea abies). AB - After performing de novo transcript assembly of >1 billion RNA-Sequencing reads obtained from 22 samples of different Norway spruce (Picea abies) tissues that were not surface sterilized, we found that assembled sequences captured a mix of plant, lichen, and fungal transcripts. The latter were likely expressed by endophytic and epiphytic symbionts, indicating that these organisms were present, alive, and metabolically active. Here, we show that these serendipitously sequenced transcripts need not be considered merely as contamination, as is common, but that they provide insight into the plant's phyllosphere. Notably, we could classify these transcripts as originating predominantly from Dothideomycetes and Leotiomycetes species, with functional annotation of gene families indicating active growth and metabolism, with particular regards to glucose intake and processing, as well as gene regulation. PMID- 26413906 TI - UV-Visible and Plasmonic Nanospectroscopy of the CO2 Adsorption Energetics in a Microporous Polymer. AB - In the context of carbon capture and storage (CCS), micro- and mesoporous polymers have received significant attention due to their ability to selectively adsorb and separate CO2 from gas streams. The performance of such materials is critically dependent on the isosteric heat of adsorption (Qst) of CO2 directly related to the interaction strength between CO2 and the adsorbent. Here, we show using the microporous polymer PIM-1 as a model system that its Qst can be conveniently determined by in situ UV-vis optical transmission spectroscopy directly applied on the adsorbent or, with higher resolution, by indirect nanoplasmonic sensing based on localized surface plasmon resonance in metal nanoparticles. Taken all together, this study provides a general blueprint for efficient optical screening of micro- and mesoporous polymeric materials for CCS in terms of their CO2 adsorption energetics and kinetics. PMID- 26413907 TI - Novelties in the management of B-cell malignancies: B-cell receptor signaling inhibitors and lenalidomide. AB - B-cell lymphoproliferative disorders comprise 85% of Non-Hodgkin's lymphomas. Despite successful chemoimmunotherapy regimens, responses are not durable and the outcome is fatal in a considerable portion of patients. There is an inevitable need for less toxic and more potent therapeutic agents. Over the recent years, a plethora of agents including monoclonal antibodies, Bcl-2 antagonists, tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, mTOR inhibitors and immunomodulatory drugs have been developed in B-cell malignancies. The aim of this paper is to focus on B-cell receptor signaling inhibitors and lenalidomide as an immunomodulatory drug and to provide insight on how and when to incorporate these agents into the treatment algorithms. PMID- 26413909 TI - Crossed Molecular Beams and Quasiclassical Trajectory Surface Hopping Studies of the Multichannel Nonadiabatic O((3)P) + Ethylene Reaction at High Collision Energy. AB - The combustion relevant O((3)P) + C2H4 reaction stands out as a prototypical multichannel nonadiabatic reaction involving both triplet and singlet potential energy surfaces (PESs), which are strongly coupled. Crossed molecular beam (CMB) scattering experiments with universal soft electron ionization mass spectrometric detection have been used to characterize the dynamics of this reaction at the relatively high collision energy Ec of 13.7 kcal/mol, attained by crossing the reactant beams at an angle of 135 degrees . This work is a full report of the data at the highest Ec investigated for this reaction. From laboratory product angular and velocity distribution measurements, angular and translational energy distributions in the center-of-mass system have been obtained for the five observed exothermic competing reaction channels leading to H + CH2CHO, H + CH3CO, CH3 + HCO, CH2 + H2CO, and H2 + CH2CO. The product branching ratios (BRs) have been derived. The elucidation of the reaction dynamics is assisted by synergic full-dimensional quasiclassical trajectory surface-hopping calculations of the reactive differential cross sections on coupled ab initio triplet/singlet PESs. This joint experimental/theoretical study extends and complements our previous combined CMB and theoretical work at the lower collision energy of 8.4 kcal/mol. The theoretically derived BRs and extent of intersystem crossing (ISC) are compared with experimental results. In particular, the predictions of the QCT results for the three main channels (those leading to vinoxy + H, methyl + HCO and methylene + H2CO formation) are compared directly with the experimental data in the laboratory frame. Good overall agreement is noted between theory and experiment, although some small, yet significant shortcomings of the theoretical differential cross section are noted. Both experiment and theory find almost an equal contribution from the triplet and singlet surfaces to the reaction, with a clear tendency of the degree of ISC to decrease with increasing Ec and with theory slightly overestimating the extent of ISC. PMID- 26413908 TI - A Fluorinated Ligand Enables Room-Temperature and Regioselective Pd-Catalyzed Fluorination of Aryl Triflates and Bromides. AB - A new biaryl monophosphine ligand (AlPhos, L1) allows for the room-temperature Pd catalyzed fluorination of a variety of activated (hetero)aryl triflates. Furthermore, aryl triflates and bromides that are prone to give mixtures of regioisomeric aryl fluorides with Pd-catalysis can now be converted to the desired aryl fluorides with high regioselectivity. Analysis of the solid-state structures of several Pd(II) complexes, as well as density functional theory (DFT) calculations, shed light on the origin of the enhanced reactivity observed with L1. PMID- 26413910 TI - Neuroimaging Biomarkers of a History of Concussion Observed in Asymptomatic Young Athletes. AB - Participation in contact sports places athletes at elevated risk for repeated head injuries and is associated with negative mental health outcomes later in life. The current study identified changes observable on neuroimaging that persisted beyond the apparent resolution of acute symptoms of concussion. Sixteen young adult ice hockey players with a remote history of concussion but no subjective complaints were compared against 13 of their teammates with no history of concussion. Participants completed a detailed phenotypic assessment and a neuroimaging battery including diffusion kurtosis imaging and resting-state functional magnetic resonance imaging. Athletes with a history of concussion performed no differently from those without on phenotypic assessment, but showed significantly elevated fractional anisotropy (FA) in the left genu and anterior corona radiata relative to those without. Post hoc analyses revealed that elevated FA was associated with increased microstructural complexity perpendicular to the primary axon (radial kurtosis). Athletes with concussion history also showed significant differences in the organization of the default mode network (DMN) characterized by stronger temporal coherence in posterior DMN, decreased temporal coherence in anterior DMN, and increased functional connectivity outside the DMN. In the absence of deficits on detailed phenotypic assessment, athletes with a history of concussion displayed changes to the microstructural architecture of the cerebral white matter and to the functional connectivity of the brain at rest. Some of these changes are consistent with those previously associated with persisting deficits and complaints, but we also report novel, complementary changes that possibly represent compensatory mechanisms. PMID- 26413911 TI - Folate Receptor Alpha Immunohistochemistry in Cytology Specimens of Metastatic Breast Carcinoma. AB - BACKGROUND: Folate receptor alpha (FRA) is involved in folate accumulation and utilization, and is expressed in varying proportions in breast, ovary and parotid epithelial cells, among others. FRA overexpression by immunohistochemistry (IHC) has been shown in estrogen/progesterone receptor (ER/PR)-negative carcinoma (40 74%) and in triple-negative breast carcinoma (TNBC; 50-86%) in histological specimens of primary breast cancers. We assessed the feasibility of IHC in detecting FRA expression and its patterns and clinical significance in metastatic TNBC in fine-needle aspiration (FNA) cell blocks (CBs). MATERIALS AND METHODS: Metastatic breast ductal carcinoma cases were retrospectively immunostained with FRA IHC on FNA CBs. FRA staining was scored qualitatively (+/-), by intensity (0 3) and by staining area (0-100%). Of these metastatic cases, a subset of primary breast carcinoma cases was also immunostained with FRA. The results were correlated with ER, PR and human epidermal growth factor receptor 2 (Her2/Neu) performed by routine IHC. RESULTS: A total of 40 FNA CBs with metastatic disease were studied, including hormone (ER/PR) positive (n = 5), triple positive (n = 5), Her2/Neu-only positive (n = 5) and TNBC (n = 25). FRA IHC showed immunoreactivity with moderate positivity in only 1 (4%) TNBC. All the remaining 39 cases were negative for FRA expression. Five cases of primary TNBC were stained with FRA IHC and were negative for FRA expression. CONCLUSIONS: Our data suggest that FRA expression by IHC was rarely associated with ER/PR-negative tumors relative to ER/PR-positive tumors and, more importantly, with TNBC in FNA CBs. This finding may have a clinical significance and prognostic implications in metastatic breast carcinoma. Furthermore, 5 primary TNBC cases did not overexpress FRA by IHC. Hence, antifolate receptor therapies do not appear to be clinically relevant in TNBC based on immunostaining of FNA CBs of metastatic breast cancers. PMID- 26413912 TI - Fatty acid amide hydrolase inhibitors: a patent review (2009-2014). AB - INTRODUCTION: Fatty acid amide hydrolase (FAAH) is a key enzyme responsible for the degradation of the endocannabinoid anandamide. FAAH inactivation is emerging as a strategy to treat several CNS and peripheral diseases, including inflammation and pain. The search for effective FAAH inhibitors has thus become a key focus in present drug discovery. AREAS COVERED: Patents and patent applications published from 2009 to 2014 in which novel chemical classes are claimed to inhibit FAAH. EXPERT OPINION: FAAH is a promising target for treating many disease conditions including pain, inflammation and mood disorders. In the last few years, remarkable efforts have been made to develop new FAAH inhibitors (either reversible and irreversible) characterized by excellent potency and selectivity, to complete the arsenal of tools for modulating FAAH activity. The failure of PF-04457845 in a Phase II study on osteoarthritis pain has not flattened the interest in FAAH inhibitors. New clinical trials on 'classical' FAAH inhibitors are now ongoing, and new strategies based on compounds with peculiar in vivo distribution (e.g., peripheral) or with multiple pharmacological activities (e.g., FAAH and COX) are under investigation and could boost the therapeutic potential of this class in the next future. PMID- 26413920 TI - Rare case of external dental fistula of the submental region misdiagnosed as inverted follicular keratosis and thyroglossal duct cyst. AB - INTRODUCTION: Odontogenic cutaneous sinus tract is a relatively rare occurrence that can be complicated to diagnose. The presence of a cutaneous lesion is often not even partly associated with a dental etiology because of the less frequency of occurrence in the case of dental symptoms. Consequently, the underlying dental cause is often missed leading to inappropriate diagnosis and treatment. CASE PRESENTATION: Here, we report the case of a 45-year-old man who presented with a persistent lesion of the cervical region. At the time of presentation, the lesion had been present for approximately one year with a gradual increase in size but no specific symptoms. The patient had previously undergone punch resection under local anesthesia, which resulted in a histopathological diagnosis of inverted follicular keratosis. A diagnosis was made of an odontogenic cutaneous sinus tract secondary to chronic apical periodontitis of the left mandibular second molar. DISCUSSION: Cutaneous sinus tract in the face and neck is most likely to develop intraorally. Root canal treatment or surgical extractions are the common treatment choices. A previously reported review of 137 cases found that 106 (77%) were treated by extraction and 27 (20%) were treated by surgical or conservative nonsurgical endodontic therapy. CONCLUSION: Early diagnosis of cutaneous sinus tract using proper aid is responsible for shortening the treatment duration and avoiding unnecessary treatment. PMID- 26413921 TI - Huge hepatocellular carcinoma with multiple intrahepatic metastases: An aggressive multimodal treatment. AB - INTRODUCTION: Huge hepatocellular carcinoma (HCC) possesses a potential risk for spontaneous rupture, which leads to a life-threatening complication with a high mortality rate. In addition, a large HCC is frequently accompanied by intrahepatic metastases. PRESENTATION OF CASE: We describe, the case of a 74-year old woman with a huge extrahepatically expanding HCC with multiple intrahepatic metastases who was treated by liver resection with repeated transcatheter arterial chemoembolization (TACE). To prevent tumor rupture or bleeding, we performed right hepatectomy. After the operation, TACE was applied for multiple intrahepatic metastases in the remnant liver. Furthermore, the elevated protein induced vitamin K absence (PIVKA II) level had decreased to limits within the normal range. Three months after the first TACE, computed tomography revealed several recurrences in the liver. TACE was applied for the second and third time and the tumors were well controlled. DISCUSSION: Although, liver resection is occasionally performed for patients with huge HCC to avoid spontaneous tumor rupture, only surgical approach might not be sufficient for such advanced HCC. To achieve long-term survival, it is necessary to control the residual intrahepatic tumors. We could control multiple intrahepatic metastases with repeated TACEs after hepatectomy. CONCLUSION: Multimodal treatment involving hepatectomy and TACE might be a good treatment strategy for patients with huge HCC with multiple intrahepatic metastases if the tumors are localized in the liver without distant or peritoneal metastasis. PMID- 26413922 TI - Unusual presentation of a Meckel's diverticulum: A case report. AB - INTRODUCTION: Meckel's diverticulum (MD) is the most common congenital malformation of the gastrointestinal tract. Intestinal obstruction is the lead presenting symptom in the adult population due to multiple causes (intussusception, incarceration, adhesions, strictures and torsion). Our patient had a complicated MD with an unique combination of risk factors and findings. PRESENTATION OF CASE: We report an unusual case of an 18-year-old patient presenting with acute small bowel obstruction for several days, who developed focal peritoneal signs on right lower quadrant. On laparotomy, findings included a necrotic giant MD and a small bowel volvulus around a fibrous band that attached MD to the umbilicus. Segmental enterectomy with primary anastomosis was performed. DISCUSSION: Axial torsion and gangrene of MD is the rarest complication. Its pre-operative diagnosis remains elusive as it can be clinically indistinguishable from other intra-abdominal inflammatory conditions. The correct diagnosis of complicated MD before surgery is often difficult because this condition can mimic other acute abdominal pathologies. There are several risk factors that can point to an accurate and early diagnosis, especially when combined with the appropriate imaging techniques, such as computed tomography with oral and intravenous contrast. CONCLUSION: This complication remains underdiagnosed, often with delayed surgical intervention and sub-optimal treatment that leads to significant morbidity and mortality. PMID- 26413923 TI - The hanging manoeuver to complete liver resection for a locally advanced angiosarcoma: A case report. AB - INTRODUCTION: Angiosarcomas arising in the liver are rare tumours in the Western world. We report a case of a locally advanced primary hepatic angiosarcoma and also describe the manoeuvres used to achieve operative resection. PRESENTATION OF A CASE: A 52-year old woman presented with vague right upper quadrant pain. Abdominal imaging revealed a heterogenous tumour in the right liver measuring 15centimetres in maximal diameter. Although the tumour was deemed to be resectable, there was free fluid in the right paracolic gutter suggestive of rupture. Intra-operatively, the peritoneal cavity was noted to be free of metastatic disease. However, tumour was adherent to the diaphragm precluding traditional mobilization of the liver. Therefore, a modified hanging manoeuvre was performed using a nasogastric tube. This allowed controlled mobilization of the right liver, parenchymal transection and en-bloc resection of the diaphragm with good hemostasis. Histologic examination revealed a primary angiosarcoma with uninvolved margins. DISCUSSION: When they occur, primary hepatic angiosarcomas are most often locally advanced. Nevertheless, surgeons should be aggressive in the pursuit of complete resections because this is the only therapeutic modality that has been shown to have a survival advantage. CONCLUSION: Hepatobiliary surgeons should keep the hanging manoeuver in their armamentarium when performing complex liver resections for locally advanced angiosarcomas. PMID- 26413924 TI - Total laparoscopic subtotal gastrectomy with transvaginal specimen extraction is feasible in advanced gastric cancer. AB - PURPOSE: Natural orifice specimen extraction (NOSE) is an ever-evolving advanced laparoscopic technique. NOSE minimizes surgical injury, involving a low risk of wound complications, fewer incisional hernias, faster recovery and less postoperative pain. Laparoscopic gastrectomy combined with NOSE is a procedure that can potentiate the advantages of both minimal invasive techniques. We aim to demonstrate the feasibility of laparoscopic subtotal gastrectomy with transvaginal specimen extraction in advanced gastric cancer. CASE: A 72-year-old woman with a 2cm adenocarcinoma in gastric antrum was treated by laparoscopic subtotal gastrectomy and lymph node dissection. A totally laparoscopic Roux-en-Y gastrojejunostomy was constructed. Specimen was extracted through the posterior fornix of vagina without difficulty. Histopathology confirmed pT3pN0 tumor. After a 10-month follow-up the patient was asymptomatic and getting adjuvant chemoradiotherapy. CONCLUSIONS: Transvaginal specimen extraction after laparoscopic gastric resection for advanced gastric cancer is a feasible procedure. It is offered to selected patients and of course only to female patients. Natural orifice surgery may provide faster recovery and decrease the wound related complications which may cause a delay on postoperative adjuvant chemo-radio therapies. We have presented, as far as we know, the first human case of a transvaginal extraction of an advanced gastric cancer after laparoscopic gastrectomy. PMID- 26413925 TI - Relationship Between Disease Characteristics and Oral Radiologic Findings in Systemic Sclerosis: Results From a Canadian Oral Health Study. AB - OBJECTIVE: Systemic sclerosis (SSc; scleroderma) is associated with a wide periodontal ligament (PDL) and mandibular erosions. We investigated the clinical correlates of SSc with these radiologic abnormalities. METHODS: Subjects from the Canadian Scleroderma Research Group cohort underwent detailed radiologic examinations. Associations between radiologic abnormalities and clinical manifestations of SSc were examined with univariate and multivariate analyses. RESULTS: The study included 159 subjects; 90.6% were women, the mean +/- SD age was 56 +/- 10 years, diffuse disease was present in 28.3%, and mean +/- SD disease duration was 13.7 +/- 8.4 years. Widening of the PDL involving at least 1 tooth was present in 38% of subjects, and 14.5% had at least 1 site in the mandible with an erosion. In analyses adjusting for age, disease duration, sex, smoking, and education, we found significant associations between the number of teeth with widening of the PDL and disease severity assessed by the physician global assessment (PGA) (relative risk [RR] 1.19, 95% confidence interval [95% CI] 1.02-1.39, P = 0.028). Analyses replacing the PGA with the skin score, disease subset, or anti-topoisomerase I antibodies confirmed the relationship with indices of disease severity. There was no relationship between either the number of teeth with periodontal disease or the number of missing teeth, and the number of teeth with wide PDL. A smaller interdental distance (RR 0.89, 95% CI 0.82-0.97, P = 0.006), but not disease severity, facial skin score, or ischemia was associated with a larger number of erosions. CONCLUSION: In SSc, a wide PDL may reflect generalized overproduction of collagen, and mandibular erosions are related to local factors in the oral cavity. PMID- 26413926 TI - Topography-Guided Proliferation: Distinct Surface Microtopography Increases Proliferation of Chondrocytes In Vitro. AB - Chondrocyte-based cartilage repair techniques require control of articular chondrocyte expansion ex vivo. Articular chondrocytes have limited availability, and prolonged culturing to obtain a cell number sufficient for clinical use often results in phenotypic alterations and increased costs. In this study, we applied a screening library consisting of micrometer-sized topographical features, termed biosurface structure array (BSSA), to identify specific topographical microstructures affecting the proliferation of human chondrocytes in passage 1 (P1) or 2 (P2). The BSSA library comprised 10 patterns and 16 combinations of pillar size (X) and interpillar gap size (Y). Specific microstructures significantly increased the chondrocytes' proliferative responsiveness in term of patterns, X and Y for P2 compared with P1. The P1 and P2 chondrocytes responded independently to similar patterns after 4 days of culturing, whereas only chondrocytes at P2 responded to specific microstructures with Y = 1 MUm and X = 2, 4 MUm by a 2.3- and 4.4-fold increased proliferation, respectively. In conclusion, these findings indicate that specific surface topographies promote chondrocyte proliferation and may, indeed, be a tool to control the behavior of chondrocytes in vitro. PMID- 26413927 TI - A Pilot Study of In Vivo Confocal Laser Endomicroscopy of Upper Tract Urothelial Carcinoma. AB - PURPOSE: Tissue diagnosis of upper tract urothelial carcinoma (UTUC) is limited by variance in tumor sampling by standard ureteroscopic biopsy. Optical imaging technologies can potentially improve UTUC diagnosis, surveillance, and endoscopic treatment. We previously demonstrated in vivo optical biopsy of urothelial carcinoma of the bladder using confocal laser endomicroscopy (CLE). In this study, we evaluated a new 0.85-mm imaging probe in the upper urinary tract and demonstrated feasibility and compatibility with standard ureteroscopes to achieve in vivo optical biopsy of UTUC. MATERIALS AND METHODS: Fourteen patients scheduled for ureteroscopy of suspected upper tract lesions or surveillance of UTUC were recruited. After intravenous (IV) administration of fluorescein, CLE was performed using a 0.85-mm-diameter imaging probe inserted through the working channel of standard ureteroscopes. Acquired confocal video sequences were reviewed and analyzed. A mosaicing algorithm was used to compile a series of images into a single larger composite image. Processed CLE images were compared with standard histopathologic analysis. RESULTS: Optical biopsy of the UTUC using CLE was effectively achieved during standard ureteroscopy. There were no adverse events related to IV fluorescein administration or image acquisition. Confocal imaging of UTUC showed characteristic features similar to urothelial carcinoma of the bladder, including papillary structure, fibrovascular stalks, and pleomorphism. Lamina propria in normal areas of the renal pelvis and ureter was also identified. CONCLUSIONS: We report an initial feasibility of CLE of UTUC. Pending further clinical investigation, CLE may become a useful adjunct to ureteroscopic biopsy, endoscopic ablation, and surveillance of UTUC. PMID- 26413928 TI - Silent Atrial Fibrillation in Elderly Pacemaker Users: A Randomized Trial Using Home Monitoring. AB - BACKGROUND: Pacemaker with remote monitoring (PRM) may be useful for silent atrial fibrillation (AF) detection. The aims of this study were to evaluate the incidence of silent AF, the role of PRM, and to determine predictors of silent AF occurrence. METHODS: Three hundred elderly patients with permanent pacemaker (PPM) were randomly assigned to the remote group (RG) or control group (CG). All patients received PPM with remote monitoring capabilities. Primary end point was AF occurrence rate and the secondary end points were time to AF detection and number of days with AF. RESULTS: During the average follow-up of 15.7+/-7.7 months, AF episodes were detected in 21.6% (RG = 24% vs CG = 19.3%, P = 0.36]. There was no difference in the time to detect the first AF episode. However, the median time to detect AF recurrence in the RG was lower than that in the CG (54 days vs 100 days, P = 0.004). The average number of days with AF was 16.0 and 51.2 in the RG and CG, respectively (P = 0.028). Predictors of silent AF were left atrial diameter (odds ratio [OR] 1.2; 95% CI = 1.1-1.3; P < 0.001) and diastolic dysfunction (OR 4.8; 95% CI = 1.6-14.0; P = 0.005). CONCLUSIONS: The incidence of silent AF is high in elderly patients with pacemaker; left atrial diameter and diastolic dysfunction were predictors of its occurrence. AF monitoring by means of pacemaker is a valuable tool for silent AF detection and continuous remote monitoring allows early AF recurrence detection and reduces the number of days with AF. PMID- 26413929 TI - Phototherapy-Induced Antitumor Immunity: Long-Term Tumor Suppression Effects via Photoinactivation of Respiratory Chain Oxidase-Triggered Superoxide Anion Burst. AB - AIMS: Our previous studies have demonstrated that as a mitochondria-targeting cancer phototherapy, high-fluence, low-power laser irradiation (HF-LPLI) results in oxidative damage that induces tumor cell apoptosis. In this study, we focused on the immunological effects of HF-LPLI phototherapy and explored its antitumor immune regulatory mechanism. RESULTS: We found not only that HF-LPLI treatment induced tumor cell apoptosis but also that HF-LPLI-treated apoptotic tumor cells activated macrophages. Due to mitochondrial superoxide anion burst after HF-LPLI treatment, tumor cells displayed a high level of phosphatidylserine oxidation, which mediated the recognition and uptake by macrophages with the subsequent secretion of cytokines and generation of cytotoxic T lymphocytes. In addition, in vivo results showed that HF-LPLI treatment caused leukocyte infiltration into the tumor and efficaciously inhibited tumor growth in an EMT6 tumor model. These phenomena were absent in the respiration-deficient EMT6 tumor model, implying that the HF-LPLI-elicited immunological effects were dependent on the mitochondrial superoxide anion burst. INNOVATION: In this study, for the first time, we show that HF-LPLI mediates tumor-killing effects via targeting photoinactivation of respiratory chain oxidase to trigger a superoxide anion burst, leading to a high level of oxidatively modified moieties, which contributes to the phenotypic changes in macrophages and mediates the antitumor immune response. CONCLUSION: Our results suggest that HF-LPLI may be an effective cancer treatment modality that both eradicates the treated primary tumors and induces an antitumor immune response via photoinactivation of respiratory chain oxidase to trigger superoxide anion burst. PMID- 26413930 TI - A Solid Phase Vibrational Circular Dichroism Study of Polypeptide-Surfactant Interaction. AB - We studied the interaction of poly-l-lysine (PLL) and poly-l-arginine (PLAG) with sodium dodecyl sulfate (SDS) surfactant and the interaction of poly-l-glutamic acid (PLGA) and poly-l-aspartic acid (PLAA) with tetradecyltrimethylammonium bromide (TTAB) surfactant using vibrational circular dichroism (VCD) spectroscopy in the region of C-H stretching vibration and in the Amide I region both in solution and in mulls. A chirality transfer from polypeptides to achiral surfactants was observed in the C-H stretching region, where measurements in solution were impossible. This observation was enabled by a special sample treatment technique using lyophilization and the preparation of mulls. This technique demonstrated itself as an interesting and beneficial tool for VCD measurements. In addition, we observed that SDS changed the secondary structure of PLL to the beta-sheet and of PLAG to the alpha-helix. TTAB disrupted the PLGA and PLAA structure. These results were obtained in the mull but were confirmed by the VCD spectra measured in solution and by electronic circular dichroism. The chirality transfer from the polypeptides to SDS was caused by polypeptides ordered into a specific conformation during the interaction, while in the TTBA system it was induced primarily by the chirality of the amino acid residues. PMID- 26413931 TI - TEMPO-Oxidized Nanofibrillated Cellulose as a High Density Carrier for Bioactive Molecules. AB - Controlled and efficient immobilization of specific biomolecules is a key technology to introduce new, favorable functions to materials suitable for biomedical applications. Here, we describe an innovative and efficient, two-step methodology for the stable immobilization of various biomolecules, including small peptides and enzymes onto TEMPO oxidized nanofibrillated cellulose (TO NFC). The introduction of carboxylate groups to NFC by TEMPO oxidation provided a high surface density of negative charges able to drive the adsorption of biomolecules and take part in covalent cross-linking reactions with 1-ethyl-3-[3 (dimethylamino)propyl]carbodiimide (EDAC) and glutaraldehyde (Ga) chemistry. Up to 0.27 MUmol of different biomolecules per mg of TO-NFC could be reversibly immobilized by electrostatic interaction. An additional chemical cross-linking step prevented desorption of more than 80% of these molecules. Using the cysteine protease papain as model, a highly active papain-TO-NFC conjugate was achieved. Once papain was immobilized, 40% of the initial enzymatic activity was retained, with an increase in kcat from 213 to >700 s(-1) for the covalently immobilized enzymes. The methodology presented in this work expands the range of application for TO-NFC in the biomedical field by enabling well-defined hybrid biomaterials with a high density of functionalization. PMID- 26413932 TI - SIRT1 Overexpression Maintains Cell Phenotype and Function of Endothelial Cells Derived from Induced Pluripotent Stem Cells. AB - Endothelial cells (ECs) that are differentiated from induced pluripotent stem cells (iPSCs) can be used in establishing disease models for personalized drug discovery or developing patient-specific vascularized tissues or organoids. However, a number of technical challenges are often associated with iPSC-ECs in culture, including instability of the endothelial phenotype and limited cell proliferative capacity over time. Early senescence is believed to be the primary mechanism underlying these limitations. Sirtuin1 (SIRT1) is an NAD(+)-dependent deacetylase involved in the regulation of cell senescence, redox state, and inflammatory status. We hypothesize that overexpression of the SIRT1 gene in iPSC ECs will maintain EC phenotype, function, and proliferative capacity by overcoming early cell senescence. SIRT1 gene was packaged into a lentiviral vector (LV-SIRT1) and transduced into iPSC-ECs at passage 4. Beginning with passage 5, iPSC-ECs exhibited a fibroblast-like morphology, whereas iPSC-ECs overexpressing SIRT1 maintained EC cobblestone morphology. SIRT1 overexpressing iPSC-ECs also exhibited a higher percentage of canonical markers of endothelia (LV-SIRT1 61.8% CD31(+) vs. LV-empty 31.7% CD31(+), P < 0.001; LV-SIRT1 46.3% CD144(+) vs. LV-empty 20.5% CD144(+), P < 0.02), with a higher nitric oxide synthesis, lower beta-galactosidase production indicating decreased senescence (3.4% for LV-SIRT1 vs. 38.6% for LV-empty, P < 0.001), enhanced angiogenesis, increased deacetylation activity, and higher proliferation rate. SIRT1 overexpressing iPSC-ECs continued to proliferate through passage 9 with high purity of EC-like characteristics, while iPSC-ECs without SIRT1 overexpression became senescent after passage 5. Taken together, SIRT1 overexpression in iPSC ECs maintains EC phenotype, improves EC function, and extends cell lifespan, overcoming critical hurdles associated with the use of iPSC-ECs in translational research. PMID- 26413933 TI - Fever Control Management Is Preferable to Mild Therapeutic Hypothermia in Traumatic Brain Injury Patients with Abbreviated Injury Scale 3-4: A Multi Center, Randomized Controlled Trial. AB - In our prospective, multi-center, randomized controlled trial (RCT)-the Brain Hypothermia (B-HYPO) study-we could not show any difference on neurological outcomes in patients probably because of the heterogeneity in the severity of their traumatic condition. We therefore aimed to clarify and compare the effectiveness of the two therapeutic temperature management regimens in severe (Abbreviated Injury Scale [AIS] 3-4) or critical trauma patients (AIS 5). In the present post hoc B-HYPO study, we re-evaluated data based on the severity of trauma as AIS 3-4 or AIS 5 and compared Glasgow Outcome Scale score and mortality at 6 months by per-protocol analyses. Consequently, 135 patients were enrolled. Finally, 129 patients, that is, 47 and 31 patients with AIS 3-4 and 36 and 15 patients with AIS 5 were allocated to the mild therapeutic hypothermia (MTH) and fever control groups, respectively. No significant intergroup differences were observed with regard to age, gender, scores on head computed tomography (CT) scans, and surgical operation for traumatic brain injury (TBI), except for Injury Severity Score (ISS) in AIS 5. The fever control group demonstrated a significant reduction of TBI-related mortality compared with the MTH group (9.7% vs. 34.0%, p = 0.02) and an increase of favorable neurological outcomes (64.5% vs. 51.1%, p = 0.26) in patients with AIS 3-4, although the latter was not statistically significant. There was no difference in mortality or favorable outcome in patients with AIS 5. Fever control may be considered instead of MTH in patients with TBI (AIS 3-4). PMID- 26413935 TI - Correction: Clinical Utility of a Coronary Heart Disease Risk Prediction Gene Score in UK Healthy Middle Aged Men and in the Pakistani Population. PMID- 26413934 TI - A novel role for flotillin-1 in H-Ras-regulated breast cancer aggressiveness. AB - Elevated expression and aberrant activation of Ras have been implicated in breast cancer aggressiveness. H-Ras, but not N-Ras, induces breast cell invasion. A crucial link between lipid rafts and H-Ras function has been suggested. This study sought to identify the lipid raft protein(s) responsible for H-Ras-induced tumorigenicity and invasiveness of breast cancer. We conducted a comparative proteomic analysis of lipid raft proteins from invasive MCF10A human breast epithelial cells engineered to express active H-Ras and non-invasive cells expressing active N-Ras. Here, we identified a lipid raft protein flotillin-1 as an important regulator of H-Ras activation and breast cell invasion. Flotillin-1 was required for epidermal growth factor-induced activation of H-Ras, but not that of N-Ras, in MDA-MB-231 triple-negative breast cancer (TNBC) cells. Flotillin-1 knockdown inhibited the invasiveness of MDA-MB-231 and Hs578T TNBC cells in vitro and in vivo. In xenograft mouse tumor models of these TNBC cell lines, we showed that flotillin-1 played a critical role in tumor growth. Using human breast cancer samples, we provided clinical evidence for the metastatic potential of flotillin-1. Membrane staining of flotillin-1 was positively correlated with metastatic spread (p = 0.013) and inversely correlated with patient disease-free survival rates (p = 0.005). Expression of flotillin-1 was associated with H-Ras in breast cancer, especially in TNBC (p < 0.001). Our findings provide insight into the molecular basis of Ras isoform-specific interplay with flotillin-1, leading to tumorigenicity and aggressiveness of breast cancer. PMID- 26413936 TI - Effect of the laser pulse width on the field evaporation behavior of metals and oxides. AB - The laser assisted field-evaporation of metals and oxides strongly depends on the illumination conditions. Here we study the effect of laser pulse width using two different laser systems, with a pulse duration of a few tens of femtoseconds and a few tens of picoseconds, respectively. Adjusting the laser wavelength by nonlinear optical conversion systems, we study the evaporation behavior of FeCu and MgO samples. We prove that the laser pulse width does not affect the evaporation behavior, in the range of duration explored. These results are explained taking into account the absorption behavior of nanometric samples and their thermal properties. PMID- 26413937 TI - Self-adapting denoising, alignment and reconstruction in electron tomography in materials science. AB - An automatic procedure for electron tomography is presented. This procedure is adapted for specimens that can be fashioned into a needle-shaped sample and has been evaluated on inorganic samples. It consists of self-adapting denoising, automatic and accurate alignment including detection and correction of tilt axis, and 3D reconstruction. We propose the exploitation of a large amount of information of an electron tomography acquisition to achieve robust and automatic mixed Poisson-Gaussian noise parameter estimation and denoising using undecimated wavelet transforms. The alignment is made by mixing three techniques, namely (i) cross-correlations between neighboring projections, (ii) common line algorithm to get a precise shift correction in the direction of the tilt axis and (iii) intermediate reconstructions to precisely determine the tilt axis and shift correction in the direction perpendicular to that axis. Mixing alignment techniques turns out to be very efficient and fast. Significant improvements are highlighted in both simulations and real data reconstructions of porous silicon in high angle annular dark field mode and agglomerated silver nanoparticles in incoherent bright field mode. 3D reconstructions obtained with minimal user intervention present fewer artefacts and less noise, which permits easier and more reliable segmentation and quantitative analysis. After careful sample preparation and data acquisition, the denoising procedure, alignment and reconstruction can be achieved within an hour for a 3D volume of about a hundred million voxels, which is a step toward a more routine use of electron tomography. PMID- 26413938 TI - Recovery of Olfactory Function following Pediatric Traumatic Brain Injury: A Longitudinal Follow-Up. AB - There is increasing evidence that disruption of olfactory function after pediatric traumatic brain injury (TBI) is common. Olfactory dysfunction (OD) has been linked to significant functional implications in areas of health, safety, and quality of life, but longitudinal research investigating olfactory recovery is limited. This study aimed to investigate recovery trajectories for olfaction following pediatric TBI and explore predictors of early and late olfactory outcomes. The olfactory function of 37 children with TBI ages 8-16 years was assessed on average at 1.5, 8.0, and 18.0 months post-injury using the University of Pennsylvania Smell Identification Test. A significant improvement in olfactory performance was seen over time in those with acute OD, however, only 16% of those with the most severe OD showed recovery to normal olfactory function, with the remainder demonstrating ongoing olfactory impairment at the 18 month follow-up. Predictors of early (0-3 month) and late (18 month) olfactory outcomes varied with site of impact, a significant predictor of later olfactory performance. In summary, while there was evidence of recovery of OD over time in pediatric TBI, the majority of children with severe OD did not show any recovery. In light of limited recovery of function for more severely affected children, the importance of appropriate education and implementation of rehabilitation management strategies is highlighted. PMID- 26413939 TI - Biomechanical Evaluation of the Stabilizing Function of Three Atlantoaxial Implants Under Shear Loading: A Canine Cadaveric Study. AB - OBJECTIVE: To compare the biomechanical properties of a ventral transarticular lag screw fixation technique, a new dorsal atlantoaxial instability (AAI) clamp, and a new ventral AAI hook plate under sagittal shear loading after transection of the ligaments of the atlantoaxial joint. STUDY DESIGN: Cadaveric biomechanical study. ANIMALS: Canine cadavers (n = 10). MATERIALS AND METHODS: The occipitoatlantoaxial region of Beagles euthanatized for reasons unrelated to the study was prepared leaving only ligamentous structures and the joint capsules between the first 2 cervical vertebrae (C1 and C2). The atlanto-occipital joints were stabilized with 2 transarticular diverging positive threaded K-wires. The occipital bone and the caudal end of C2 were embedded in polymethylmethacrylate and loaded in shear to a force of 50 Newtons. The range of motion (ROM) and neutral zone (NZ) of the atlantoaxial joint were determined after 3 loading cycles with atlantoaxial ligaments intact, after ligament transection, and after fixation with each implant. The testing order of implants was randomly assigned. The implants tested last were subjected to failure testing. RESULTS: All stabilization procedures decreased the ROM and NZ of the atlantoaxial joint compared to transected ligament specimens. Only stabilization with transarticular lag screws and ventral plates produced a significant reduction of ROM compare to intact specimens. CONCLUSION: Fixation with transarticular lag screws and a ventral hook plate was biomechanically similar and provided more rigidity compared to dorsal clamp fixation. Further load cycling to failure tests and clinical studies are required before making clinical recommendations. PMID- 26413942 TI - The Trustworthiness Deficit in Postgenomic Research on Human Intelligence. AB - In the past, work on racial and ethnic variation in brain and behavior was marginalized within genetics. Against the backdrop of genetics' eugenic legacy, wide consensus held such research to be both ethically problematic and methodologically controversial. But today it is finding new opportunistic venues in a global, transdisciplinary, data-rich postgenomic research environment in which such a consensus is increasingly strained. The postgenomic sciences display worrisome deficits in their ability to govern and negotiate standards for making postgenomic claims in the transdisciplinary space between human population variation research, studies of intelligence, neuroscience, and evolutionary biology. Today some researchers are pursuing the genomics of intelligence on a newly grand scale. They are sequencing large numbers of whole genomes of people considered highly intelligent (by varying empirical and social measures) in the hope of finding gene variants predictive of intelligence. Troubling and at times outlandish futurist claims accompany this research. Scientists involved in this research have openly discussed the possibility of marketing prenatal tests for intelligence, of genetic engineering or selective embryo implantation to increase the likelihood of a high-IQ child, and of genotyping children to guide their education. In this permissive and contested environment, what would trustworthy research on the genomics of high intelligence look like? PMID- 26413943 TI - An Introduction to Thinking about Trustworthy Research into the Genetics of Intelligence. AB - The advent of new technologies has rekindled some hopes that it will be possible to identify genetic variants that will help to explain why individuals are different with respect to complex traits. At least one leader in the development of "whole genome sequencing"-the Chinese company BGI-has been quite public about its commitment to using the technique to investigate the genetics of intelligence in general and high intelligence in particular. Because one needs large samples to detect the small effects associated with small genetic differences in the sequence of those base pairs, to make headway with the new sequencing technologies, one also needs to enlist much larger numbers of study participants than geneticists have enrolled before. In an effort to increase the size of a sample, one team of researchers approached the Center for Talented Youth at Johns Hopkins University. They wanted to gain access to records concerning participants in CTY's ongoing Study of Exceptional Talent, and they wanted to approach those individuals to see if they would be willing to share samples of their DNA. We agreed that CTY's dilemma about whether to give the researchers access to those records raised larger questions about the ethics of research into the genetics of intelligence, and we decided to hold a workshop at The Hastings Center that could examine those questions. Our purpose was to create what, borrowing from Sarah Richardson, we came to call a "transformative conversation" about research into the genetics of general cognitive ability-a conversation that would take a wide and long view and would involve a diverse group of stakeholders, including both people who have been highly critical of the research and people who engage in it. This collection of essays, which grew out of that workshop, is intended to provide an introduction to and exploration of this complex and important area. PMID- 26413944 TI - General Intelligence (g): Overview of a Complex Construct and Its Implications for Genetics Research. AB - Current technology has dramatically increased the prevalence of studies to establish the genetic correlates of a wide variety of human characteristics, including not only the physical attributes that determine what we look like and the risk of physiological disease but also the psychological and cognitive characteristics that often define who we are as individuals. Perhaps one of the most deeply personal and often controversial characteristics is the concept of general intelligence, known in the psychological literature as "g." As with the genetic study of any complex trait, the first step in studying the genetics of g is to carefully define the characteristic of interest. For g, this entails establishing what intelligence means and providing a clear operational definition for how it will be measured. In this paper, we provide a brief historical and theoretical overview of the construct of general intelligence, describe its relationship to the contemporary measurement of intelligence, and discuss these concepts in light of the challenges associated with defining g as a characteristic in the study of genetics. PMID- 26413945 TI - Classical and Molecular Genetic Research on General Cognitive Ability. AB - Arguably, no psychological variable has received more attention from behavioral geneticists than what has been called "general cognitive ability" (as well as "general intelligence" or "g"), and for good reason. GCA has a rich correlational network, implying that it may play an important role in multiple domains of functioning. GCA is highly correlated with various indicators of educational attainment, yet its predictive utility is not limited to academic achievement. It is also correlated with work performance, navigating the complexities of everyday life, the absence of various social pathologies (such as criminal convictions), and even health and mortality. Although the causal basis for these associations is not always known, it is nonetheless the case that research on GCA has the potential to provide insights into the origins of a wide range of important social outcomes. In this essay, our discussion of why GCA is considered a fundamentally important dimension of behavior on which humans differ is followed by a look at behavioral genetics research on CGA. We summarize behavioral genetics research that has sought to identify and quantify the total contributions of genetic and environmental factors to individual differences in GCA as well as molecular genetic research that has sought to identify genetic variants that underlie inherited effects. PMID- 26413946 TI - Genetic Prediction. AB - The fundamental reason that the genetics of behavior has remained so controversial for so long is that the layer of theory between data and their interpretation is thicker and more opaque than in more established areas of science. The finding that variations in tiny snippets of DNA have small but detectable relations to variation in behavior surprises no one, at least no one who was paying attention to the twin studies. How such snippets of DNA are related to differences in behavior-known as the gene-to-behavior pathway-is the great theoretical problem of modern behavioral genetics. Given that intentional human breeding is a horrific prospect, what kind of technology might we want (or fear) out of human behavioral genetics? One possibility is a technology that could predict important behavioral characteristics of humans based on their genomes alone. A moment's thought suggests significant benefits and risks that might be associated with such a possibility, but for the moment, just consider how convincing it would be if on the day of a baby's birth we could make meaningful predictions about whether he or she would become a concert pianist or an alcoholic. This article will consider where we are right now as regards that possibility, using human height and intelligence as the primary examples. PMID- 26413947 TI - Can Genetics Research Benefit Educational Interventions for All? AB - Pretty much everyone knows that our genes have at least something to do with how able or how high achieving we are. Some believe that we should not speak of this common knowledge, nor inquire into how genetic influence works or what it might mean. If we do not keep an open mind to the fact of genetic influence on academic achievement, however, then we cannot explore its possible implications. And if we do not consider the implications, then we cannot, as a society, harness any potential benefits or avoid possible pitfalls. So that's what this essay is about exploring what behavioral genetics research might be able to offer to educational theory, policy, and practice. We cannot yet use biological information to make accurate predictions for all children. We do know, however, that academic achievement is heritable, which is to say that differences between individuals are influenced by differences in their DNA. If genes are part of the problem for some pupils (to take the negative spin on this), then it seems likely that studying them could be part of a solution. And that's what behavioral geneticists are trying to do-to chart and understand pathways from DNA to behavior and to identify interventions that can maximize outcomes for all. The fact is, though, that we have an awfully long way to go. PMID- 26413948 TI - What Does Behavioral Genetics Offer for Improving Educaton? AB - For much of its history, behavioral genetics, or research into the influence genetics has on human behavior, has been associated with a pessimistic view of educational reforms' potential to make much difference in improving educational outcomes or reducing inequality. Recently, however, some behavioral geneticists have begun to speak in more optimistic terms about the promise of genetically informed education to improve learning for all children, especially those who are socially or economically disadvantaged. This shift in emphasis should be welcome news for everyone interested in promoting educational improvement who worried that behavioral genetics offered support for the status quo. However, I think it amounts to little more than a shift in tone. Behavioral genetics, I will argue, does not advance educational reform: its proposed solutions are rooted in the limits, not the strength, of behavioral genetics knowledge; repeat the ideas of earlier U.S. educational reform efforts; and rely on a naive optimism about the power of choice and personalization. PMID- 26413949 TI - Can Research on the Genetics of Intelligence Be "Socially Neutral"? AB - The history of research on the genetics of intelligence is fraught with social bias. During the eugenics era, the hereditary theory of intelligence justified policies that encouraged the proliferation of favored races and coercively stemmed procreation by disfavored ones. In the 1970s, Berkeley psychologist Arthur Jensen argued that black students' innate cognitive inferiority limited the efficacy of federal education programs. The 1994 controversial bestseller The Bell Curve, by Richard J. Herrnstein and Charles Murray, rehashed the claim that race and class disparities stem from immutable differences in inherited intelligence, which could not be eliminated through social interventions. Today most scientists studying the genetics of intelligence distance themselves from this history of social bias by arguing that their research need not investigate intellectual differences between social groups. Rather, they argue, examining the heritability of intelligence can be socially neutral and may even help to reduce social inequities. I argue, however, that research on the genetics of intelligence cannot be socially neutral. Even if we divorce the heritability of intelligence from a eugenicist mission, measuring intelligence remains useful only as a gage of individuals' appropriate positions in society. Research into the genetics of intelligence ultimately helps to determine individuals' inherited capacity for particular social positions, even when researchers aim to modify the effects of inheritance. PMID- 26413950 TI - Taking a Stand: The Genetics Community's Responsibility for Intelligence Research. AB - There is a longstanding debate about genetics research into intelligence. Some scholars question the value of focusing on genetic contributions to intelligence in a society where social and environmental determinants powerfully influence cognitive ability and educational outcomes. Others warn that censoring certain research questions, such as inquiries about genetic differences in intellectual potential, compromises academic freedom. Still others view interest in this subject as a corollary to a long and troublesome history of eugenics research. The dawn of a new era in genome sequencing as a commodity will sustain scientific interest in the genetics of intelligence for the foreseeable future, but deep rooted challenges threaten the scientific merit of the research. The use of imprecise definitions of study populations, the difficult nature of studying the environment, and the potential of researcher bias are inextricably linked with concerns about the trustworthiness and utility of research in this area. Leadership by the genetics community is essential to ensure the value and trustworthiness of these studies. PMID- 26413951 TI - Trustworthy Research Institutions: The Challenging Case of Studying the Genetics of Intelligence. AB - It is simple enough to claim that academic research institutions ought to be trustworthy. Building the culture and taking the steps necessary to earn and preserve institutional trust are, however, complex processes. The experience motivating this special report--a request for the Center for Talented Youth at Johns Hopkins University to collaborate on research regarding the genetics of intelligence--illustrates how ensuring institutional trustworthiness can be in tension with a commitment to fostering research. In this essay, we explore the historical context for biomedical research institutions like Johns Hopkins that have worked to build local community trust. In so doing, we consider how the example under focus in this special report can lead to greater consideration of how research institutions balance fostering trust with their other commitments. PMID- 26413952 TI - Obligations and Concerns of an Organization Like the Center for Talented Youth. AB - There is another set of entities that needs to be brought into the conversation about the ethical, legal, and social implications of scientific conduct. This widely varied group includes not-for-profit educational, academic, public service, and philanthropic organizations other than the type mentioned above as well as for-profit businesses. Despite their major differences, these organizations may all be in a position to make decisions, directly or indirectly, about the conduct of scientific research. And those decisions may have a significant impact on the parties normally involved in thinking and talking about obligations and concerns-the researchers, the subjects, and the general public. Yet there are few if any conceptual frameworks to help organizations address the ethical, legal, and social issues related to conducting scientific research. There are also few resources to help organizations find and develop the expertise required to make responsible decisions or communicate those decisions in ways that could support and advance the ethical conduct of research. In what follows, we try to identify and explore the duties, rights, and interests of one such organization, the Center for Talented Youth at Johns Hopkins University, when asked to play a supporting role in research on the genetics of intelligence. As central agents in this case, we hope to demonstrate why organizations like CTY cannot be neglected in the broader effort to ensure trustworthy research into the genetics of intelligence. PMID- 26413953 TI - Why Is Studying the Genetics of Intelligence So Controversial? AB - From the very beginning, studies of the nature and nurture of intelligence have been closely associated with an interest in intervening, and those interventions have been surrounded by controversy. The nature of those controversies has not always been the same, however. Since the mid-nineteenth century, when Francis Galton imagined a science that would assess the extent to which a trait like "genius" was due to nature or due to nurture, science and technology have changed dramatically, and so have the interventions that have been envisioned in light of those developments. A scientist today can search for particular stretches of DNA and assess whether differences in those stretches are associated with differences in a human trait of interest; a genetic counselor today can genetically test an individual (be it an embryo, fetus, newborn, child, or adult) and provide information about what that genetic result means, allowing for interventions that can range from terminating a pregnancy to prescribing chemotherapy. So when one asks a question like, "Why is studying the genetics of intelligence controversial?," it is important to realize up front that the answer will be, "It can be controversial for a variety of different reasons, and those reasons have evolved over time." The purpose of this essay is to provide a survey of the controversies that surround genetic studies of intelligence. With the survey in place, I will then draw out several lessons both for scientists who study the genetics of intelligence as well as for science studies scholars (bioethicists, philosophers, historians, sociologists) who reflect and comment on the controversies surrounding that research. PMID- 26413954 TI - A critical review of low-carbohydrate diets in people with Type 2 diabetes. AB - AIMS: The efficacy of low-carbohydrate diets (LCD) in people with Type 2 diabetes has divided the nutrition community. This review seeks to re-examine the available data to clarify understanding. METHODS: A comprehensive search of databases was used to identify meta-analyses of LCD in Type 2 diabetes. To improve the quality of the studies analysed, the following inclusion criteria were applied: randomized control trials >= 4 weeks in people aged > 18 years with Type 2 diabetes; a carbohydrate intake <= 45% of total energy intake per day; and a dietary intake assessment at the end of the study. The resulting studies were subjected to a thematic analysis. RESULTS: Nine meta-analyses were identified containing 153 studies. Twelve studies met our amended inclusion criteria. There were no significant differences in metabolic markers, including glycaemic control, between the two diets, although weight loss with a LCD was greater in one study. Carbohydrate intake at 1 year in very LCD (< 50 g of carbohydrates) ranged from 132 to 162 g. In some studies, the difference between diets was as little as 8 g/day of carbohydrates. CONCLUSION: Total energy intake remains the dietary predictor of body weight. A LCD appears no different from a high carbohydrate diet in terms of metabolic markers and glycaemic control. Very LCDs may not be sustainable over a medium to longer term as carbohydrate intake in diets within studies often converged toward a more moderate level. The variable quality of studies included in earlier meta-analyses likely explains the previous inconsistent findings between meta-analyses. PMID- 26413957 TI - Comparison of Subciliary Approaches in Orbito-Zygomatic Fractures: Skin Flap Versus Skin-Muscle Flap. AB - BACKGROUND: Because of the complications of classical subciliary incision, some modified subciliary approaches have been described in recent literature. OBJECTIVES: The aim of this study was to compare 2 commonly used subciliary approaches according to development of postoperative complications (scar formation, and ectropion). MATERIALS AND METHODS: Ninety patients were included in this retrospective study. Subciliary skin flap technique (SF group) was performed to 39 patients, while the others were operated by using skin-muscle (stepped) flap technique (SMF group). Fitzpatrick skin types, genders, ages, scar scores, and ectropion scores of the patients also were recorded. RESULTS: The mean age of the patients was 39.3 (18-99) years, and the mean follow-up period was 2.1 (1-6) years. Fitzpatrick skin-type levels were between 2 and 4 (median = 3). No difference was found between 2 groups in terms of age, follow-up period, and Fitzpatrick skin-type levels. However, the scar values of the SMF group were significantly lower than the SF group statistically. Also, there was no significant difference between males and females in SF and SMF groups in terms of scar and ectropion formation. On the other hand, scar values were lower in SMF groups rather than SF group in males. Although ectropion values were not different between SF and SMF groups in females, ectropion values of SMF group were significantly lower than SF group in males statistically. CONCLUSION: Subciliary skin-muscle (stepped) flap technique can be more reliable than subciliary skin flap technique for approach to orbitozygomatic fractures. PMID- 26413958 TI - Cleft Patient-Reported Postoperative Donor Site Pain Following Alveolar Autologous Iliac Crest Bone Grafting: Comparing Two Minimally Invasive Harvesting Techniques. AB - BACKGROUND: Autologous bone grafting is still considered the standard method for alveolar cleft repair. However, donor site morbidities remain a relevant problem in cleft care. Thus, the authors assessed postoperative donor site pain in cleft patients who underwent alveolar cleft repair by iliac crest bone graft transferring through a prospective randomized study comparing 2 minimally invasive harvesting techniques. METHODS: Fifty-six consecutive patients with cleft lip and palate who underwent iliac crest bone grafting for alveolar cleft repair were randomly divided into 2 groups: bone graft harvested by minimally invasive techniques without (group 1) and with (group 2) periosteum elevation. Postoperative donor site pain was evaluated using a unidimensional numerical pain intensity rating scale (0, "no pain;" 10, "worst pain imaginable") at 1, 3, 6, 9, and 12 hours after the procedures and on the 3rd, 7th, 14th, 21st, and 28th days after surgeries. Intergroup comparisons were performed. RESULTS: The mean measurements of donor site pain revealed no significant differences (all P > 0.05) in any of the evaluated postoperative period comparisons between groups 1 and 2. There was a greater number (P < 0.05) of group 1 patients who reported "no pain" in the donor site compared with group 2, suggesting that periosteum elevation may play a role in pain intensity measurement. CONCLUSIONS: This prospective randomized study showed no difference in pain intensity among cleft patients who had postoperative pain. However, a greater number of patients in group 1 reported "no pain" in comparison to patients in group 2. PMID- 26413959 TI - Pseudomeningocele With Orbital Extension as a Complication of Fronto-Orbital Advancement and Remodeling in Craniosynostosis. AB - AIM: The authors present a series of patients who developed a pseudomeningocele following fronto-orbital advancement and remodeling (FOAR), describing clinical presentation, investigations, and management. Risk factors are identified and preventative strategies suggested. MATERIALS AND METHODS: From 2002 to 2012, all patients who underwent FOAR at our unit were identified. Those who developed a pseudomeningocele were selected and case notes, scan imaging and photographs were reviewed. RESULTS: Two hundred thirty-six FOAR operations were carried out over 12 consecutive years. Sixty-one of these patients were syndromic. A pseudomeningocele occurred in 6 patients. All affected cases were syndromic. Clinical features of presentation with orbital pseudomeningocele included orbital swelling, ptosis, proptosis, and/or hypoglobus. Raised intracranial pressure (ICP) was managed before pseudomeningocele repair in 2 patients, at the time of pseudomeningocele repair using an extra-ventricular drain (EVD) or lumbar drain in 4 patients. Decompression of the pseudomeningocele with excision and duraplsty was carried out in 5 patients, 1 patient required excision of gliotic brain and obliteration of dead space. Four patients had a calvarial graft to manage the bony defect and a further 2 had a titanium mesh. None of the patients had a recurrence of the pseudomeningocele or any long-term ocular or aesthetic complications. CONCLUSION: Pseudomeningocele has not previously been described in FOAR, but in a large series of consecutive patients, we have identified a 2.5% incidence. This incidence increases to 10% in the syndromic population of patients undergoing FOAR. The risk factors include a diagnosis of syndromic craniosynostosis, dural tear, hydrocephalus or raised ICP, infection, persistent cerebrospinal fluid (CSF) leak, or presence of dead space. Preventative strategies include CSF management before or post-FOAR. The ultimate treatment of the pseudomeningocele and growing fracture involves surgical decompression of the collection, a duraplasty, reconstruction of the orbital roof, and temporary CSF diversion. PMID- 26413960 TI - Analysis of Long-Term Prognosis and Prognostic Predictors in Severe Brain Injury Patients Undergoing Decompressive Craniectomy and Standard Care. AB - Decompressive craniectomy (DC) is widely used to treat acute subdural haematoma and hemispheric swelling following traumatic brain injury (TBI). The therapeutic effect of DC on severe TBI treatment is still controversial. The aim of our study was to evaluate effectiveness of DC treatment and seek some prognostic predictors. According to the therapy method, we divided the patients into 2 groups: DC group and standard care group. Between 2010 and 2014, a total number of 223 severe TBI patients, containing 112 patients undergoing DC and 111 patients undergoing standard care, were enrolled into the study according to Glasgow Coma Scale (GCS). The long-term prognosis was evaluated by Extended Glasgow Outcome Scale 12 months after discharging from hospital. We used univariate analysis and receiver operating characteristic curves to explore prognostic predictors. The results showed that patients in the DC group had a lower mortality, but there was no statistical significance in long-term prognosis between these 2 groups. It seemed that admission GCS, platelet, neutrophile granulocyte, total protein, and albumin were associated with long-term prognosis in DC group and reactivity of pupils in standard care group. Simultaneously, using the multivariable logistic regression model, we confirmed that admission GCS and albumin were independent prognostic predictors for patients undergoing DC, and reactivity of pupils for those undergoing standard care. Our data suggested that DC was an effective therapy for severe TBI patients in reducing mortality, but it failed to improve long-term prognosis. Through our study, we could comprehend the characteristics of the 2 treatments and provide more scientific individuation therapy for severe TBI patients. PMID- 26413961 TI - Clinical and Radiologic Characteristics of Inferior Rectus Muscle Sheath Entrapment in Orbital Blowout Fracture. AB - Blowout fracture is a common condition in the oculoplastics clinic. One of the indications for its repair is entrapment of the inferior rectus muscle within the fracture site. Herein, the authors present 3 patients of inferior rectus muscle sheath entrapment without entrapment of the muscle itself. The outcome of treatment was excellent in all patients. The aim of this report is to present the special clinical and radiologic findings in such patients. PMID- 26413962 TI - Comparison Between Continuous Buried Suture and Interrupted Buried Suture Methods for Double Eyelid Blepharoplasty. AB - PURPOSE: The objective of this study was to compare the surgical outcomes between interrupted and continuous buried suture methods in double eyelid blepharoplasty in Koreans. METHODS: Medical records of 204 patients (392 eyes) who underwent double eyelid operation by buried suture method and who were followed up for at least more than 3 months were reviewed. Patients were divided into 2 groups according to the buried suture method; an interrupted group (88 patients) and a continuous group (116 patients). RESULTS: The rate of loss of formed double eyelid is 19.3 % (17 of 88 patients) in interrupted buried method and 8.6 % (10 of 116 patients) in continuous group (P = 0.026). One patient experienced an exposure of suture knot in a continuous group, whereas 5 patients experienced an exposure of suture knot and 1 patient suffered from granuloma in an interrupted group (P = 0.021). CONCLUSIONS: The continuous buried suture method has a lower rate of the loss of double folds and less complication than the interrupted buried suture method for double fold formation in Koreans. PMID- 26413963 TI - Communications Between the Facial Nerve and the Vestibulocochlear Nerve, the Glossopharyngeal Nerve, and the Cervical Plexus. AB - The aim of this review is to elucidate the communications between the facial nerves or facial nerve and neighboring nerves: the vestibulocochlear nerve, the glossopharyngeal nerve, and the cervical plexus.In a PubMed search, 832 articles were searched using the terms "facial nerve and communication." Sixty-two abstracts were read and 16 full-text articles were reviewed. Among them, 8 articles were analyzed.The frequency of communication between the facial nerve and the vestibulocochlear nerve was the highest (82.3%) and the frequency of communication between the facial nerve and the glossopharyngeal nerve was the lowest (20%). The frequency of communication between the facial nerve and the cervical plexus was 65.2 +/- 43.5%. The frequency of communication between the cervical branch and the marginal mandibular branch of the facial nerve was 24.7 +/- 1.7%.Surgeons should be aware of the nerve communications, which are important during clinical examinations and surgical procedures of the facial nerves such as those communications involved in facial reconstructive surgery, neck dissection, and various nerve transfer procedures. PMID- 26413964 TI - Do Pharyngeal Surgeries for Snoring and Obstructive Sleep Apnea Have an Impact on Nasalance Scores? AB - OBJECTIVE: Most of the surgeries which are used in the treatment of habitual snoring and obstructive sleep apnea (OSA) mainly target velopharyngeal structures, which play an important role in voice characteristics such as nasalance. The aim of this study is to assess the effect of different types of such surgical procedures including expansion sphincter pharyngoplasty (ESP), lateral pharyngoplasty (LP), and anterior palatoplasty (AP) on nasalance scores. SUBJECTS AND METHODS: Forty-nine consecutive patients with primary snoring or OSA who underwent AP, LP, and ESP procedures were included in this study. All patients underwent a fully attended overnight polysomnography and detailed otolaryngologic examination. Nasalance studies were performed with Nasometer II instrument (model 6400; Kay Elemetrics, Lincoln Park, NJ) by reading 3 passages that were categorized according to the amount of nasal consonants (oral, oro nasal, and nasal passages), preoperatively, and 3 months after surgery. RESULTS: There was no statistically significant difference in either group between preoperative and postoperative assessments of nasalance scores for all 3 passages. Seven patients experienced nasal regurgitation symptoms for fluids for a short time after LP, 2 patients after AP, and 7 patients after ESP. None of these symptoms showed persistence and diminished approximately at 1-month follow up. CONCLUSION: Anterior palatoplasty, LP, and ESP seem not to have any impact on nasalance scores of males. PMID- 26413965 TI - Congenital Melanocytic Nevus of the Nose Removed Using Dermabrasion, Hydroquinone, and Serial Excision. AB - We report a child with a congenital pigmented nevus of the nose involving the left ala, sidewall, soft triangle, and tip. Removal of the lesion was performed using dermabrasion, topical hydroquinone, and serial excision to optimize the aesthetic outcome. The patient was left with a linear scar and did not require reconstruction with a skin graft or flap. PMID- 26413966 TI - Incidence and Features of Vertebral Fractures After Scalp Avulsion Injuries. AB - BACKGROUND: Scalp injuries are usually extensive and may have a deleterious impact for the patient. To date, little is known in the literature about simultaneous vertebral fractures. The aim of this study was to analyze the frequency, features and pathogenesis of vertebrae fractures after scalp avulsion injuries. METHODS: Between 2004 and 2014, 64 patients were retrospectively identified after scalp avulsion injuries. Patient records were reviewed for mechanism of trauma, clinical examination and neurological deficits. The features of vertebral fractures were evaluated by X-ray, computed tomography or magnetic resonance imaging, where necessary. Various treatment options were evaluated according to their injuries. RESULTS: Totally, 6 women (9.4%) with a mean age 37 +/- 6 years were identified with cervical fractures due to scalp avulsion injuries (mean size defect 808 +/- 56 cm). Clinical examination revealed neurological deficits in 3 patients. Five patients were diagnosed with different types of C2 fracture and 1 patient was diagnosed with C7 fracture. One patient had simultaneous fractures of T3/T4. Treatment for the scalp avulsion consisted in either composite graft in 5 patients or microsurgical replantation in 1 patient. The vertebral fractures were treated by collar protection (3), cervical traction (1), HALO fixation (1), and internal stabilization (1), respectively. CONCLUSIONS: Most vertebral fractures associated with scalp avulsion injuries are C2 fractures. Careful and appropriate examination is mandatory for patients with scalp avulsion injuries to exclude vertebral fractures which, if not recognized early, can have serious and devastating consequences. PMID- 26413967 TI - Recurrent Cricopharyngeal Achalasia in a Child With Williams-Beuren Syndrome. PMID- 26413968 TI - Isolated Congenital Partial Absence of the Lateral Crural Cartilage. PMID- 26413969 TI - Polymorphous Low-Grade Adenocarcinoma of the Oral Cavity. PMID- 26413970 TI - Solitary Neurofibroma Originating From the Nasal Septum. PMID- 26413971 TI - Complete Removal of External Nasal Neurofibroma by Endonasal Approach. AB - Although neurofibroma can develop in every possible anatomic location, neurofibroma originating from the external nose is extremely rare, and to our knowledge, only 2 cases have been reported so far in the English literature. In this report, the authors experienced a solitary neurofibroma originating from the external nose, which was successfully removed by endonasal approach (marginal incision). PMID- 26413972 TI - Tetrodotoxin detection and species identification of pufferfish in retail roasted fish fillet by DNA barcoding in China. AB - This study identifies the pufferfish species and detects tetrodotoxin (TTX) in roasted fish fillet samples collected in Beijing, Qingdao and Xiamen, China. The cytochrome c oxidase I (COI) gene was used as the target gene for identification of the pufferfish species in the samples. Enzyme-linked immunosorbent assay (ELISA) screened the TTX levels in samples that had been detected as containing pufferfish by DNA barcode. A total of 125 samples were identified by DNA barcodes; 32 (26%) samples contained pufferfish composition and, among them, 26 (81%) were the highly toxic species Lagocephalus lunaris. All 32 samples containing the pufferfish composition were positive for TTX with levels ranging from 100 to 63,800 ng g(-1). Most of the 32 samples contained the highly toxic L. lunaris. Based on the results, we suggest that the monitoring of roasted fish fillet should be strengthened and the processing procedures should be standardised to minimise TTX poisoning caused by pufferfish. PMID- 26413973 TI - An easy-to-prepare mini-scaffold for DNA origami. AB - The DNA origami strategy for assembling designed supramolecular complexes requires ssDNA as a scaffold strand. A system is described that was designed approximately one third the length of the M13 bacteriophage genome for ease of ssDNA production. Folding of the 2404-base ssDNA scaffold into a variety of origami shapes with high assembly yields is demonstrated. PMID- 26413974 TI - Straightforward Generation of Pillared, Microporous Graphene Frameworks for Use in Supercapacitors. AB - Microporous, pillared graphene-based frameworks are generated in a simple functionalization/coupling procedure starting from reduced graphene oxide. They are used for the fabrication of high-performance supercapacitor devices. PMID- 26413975 TI - Therapeutic application of mesenchymal stem cells in osteoarthritis. AB - INTRODUCTION: Osteoarthritis (OA) is a degenerative disease characterized by cartilage degradation and subchondral bone alterations. This disease represents a global public health problem whose prevalence is rapidly growing with the increasing aging of the population. With the discovery of mesenchymal stem cells (MSC) as possible therapeutic agents, their potential for repairing cartilage damage in OA is under investigation. AREAS COVERED: Characterization of MSCs and their functional properties are mentioned with an insight into their trophic function and secretory profile. We present a special focus on the types of extracellular vesicles (EVs) that are produced by MSCs and their role in the paracrine activity of MSCs. We then discuss the therapeutic approaches that have been evaluated in pre-clinical models of OA and the results coming out from the clinical trials in patients with OA. EXPERT OPINION: MSC-based therapy seems a promising approach for the treatment of patients with OA. Further research is still needed to demonstrate their efficacy in clinical trials using controlled, prospective studies. However, the emergence of MSC-derived EVs as possible therapeutic agents could be an alternative to cell-based therapy. PMID- 26413976 TI - Facile synthesis of nano-sized agarose based amino acid-Its pH-dependent protein like behavior and interactions with bovine serum albumin. AB - In a facile synthesis agarose was amphoterically functionalized to afford nano sized agarose amino acids, aminoagarose succinate half-esters (AAE) containing one pendant carboxyl group. Nano-sized AAEs (<10 nm; DLS) were characterized and they had three various degrees of substitution [overall DSs 0.88, 0.89 and 0.96], both the amino and half-ester groups were placed on C-6 positions of the 1,3 beta d-galactopyranose moieties of agarose backbone ((13)C NMR). AAEs performed like large protein molecules exhibiting pH-responsive structural variations (optical rotatory dispersion), presenting a mixed solubility pattern like random coil (soluble) and aggregate (precipitation) formations. Circular dichroism studies showed their pH-dependent associative interactions with bovine serum albumin, which indicated complexation at acidic and basic pHs, and decomplexation at pH 6.8 with AAE (DS 0.96). Thus, these nano-sized AAE based systems may be of potential utility in the domains demanding the merits of preferential protein bindings e.g. pH-responsive cationic/anionic drug carrier, separations or chiral sensing applications. PMID- 26413977 TI - Preameloblast-Derived Factors Mediate Osteoblast Differentiation of Human Bone Marrow Mesenchymal Stem Cells by Runx2-Osterix-BSP Signaling. AB - Epithelial-mesenchymal interaction occurs during development of various tissues, including teeth and bone. Recently, a preameloblast-conditioned medium (PA-CM) from mouse apical bud cells (ABCs), a type of dental epithelial cell, was found to induce odontogenic differentiation of dental pulp stem cells and promote dentin formation. The aims of the present study were to investigate the effects of PA-CM on human bone marrow mesenchymal stem cells (hBMSCs) in vitro, and to investigate the bone regenerative capacity in vivo through epithelial-mesenchymal interactions of developmental osteogenesis. Coculturing with ABCs and PA-CM treatment upregulated osteoblast differentiation markers of hBMSCs compared to cells cultured alone. PA-CM accelerated mineralized nodule formation and also increased bone sialoprotein promoter activity in hBMSCs. PA-CM facilitated the migration of hBMSCs, but did not significantly influence proliferation. PA-CM promoted bone formation of hBMSCs in vivo. Radiographic and histologic findings showed that PA-CM induced the bony regeneration at calvarial defects in rat. Taken together, these data show that PA-CM enhances the migration and osteogenic differentiation of hBMSCs in vitro and induces bone formation in vivo. PMID- 26413980 TI - Small-to-moderate decreases in cold hypersensitivity up to 3 years after severe hand injuries: A prospective cohort study. AB - BACKGROUND: The natural course and predictors for decreased cold hypersensitivity were studied in 85 patients with severe hand injuries involving nerve lesions. METHODS: Questionnaires including the McCabe Cold Sensitivity Severity scale (CSS 0-400) were collected after injury, and at 6-month, 12-month, 2-year, and 3-year follow-ups. RESULTS: Between the 12-month and 3-year follow-up, there was a small decrease in cold hypersensitivity as measured by the CSS (median = 24; Q1-Q3 = 11-75; n = 85). Five of the patients recovered from cold hypersensitivity, and ~ 40% of the patients were less affected by cold hypersensitivity in daily life. Little or no pain early after injury and higher CSS-scores 12 months after primary surgery were weakly associated with the reduced CSS-scores (R(2) = 0.20) at the 3-year follow-up. Six patients had changed work or did not work due to cold hypersensitivity, but the majority of the patients had kept their cold exposed work. CONCLUSION: Cold-hypersensitive patients may have a reasonable chance for decreased cold sensitivity and cold-associated activity limitations over time, although the majority of the patients will experience persistent problems. Tools to predict improvement remain insufficient. PMID- 26413979 TI - Development and Pilot Testing of an Encounter Tool for Shared Decision Making About the Treatment of Graves' Disease. AB - BACKGROUND: The best treatment option for patients with Graves' disease (GD) depends on each person's situation and how the differences between the treatment options matter to them in bringing resolution to their illness. The objective of this study was to develop and test an encounter decision tool (GD Choice) for patients and clinicians to engage in shared decision making about the treatment of GD. METHODS: GD Choice was developed using an iterative process based on the principles of interaction design and participatory action research. To evaluate the impact of the tool, a controlled before-after study was conducted, assessing the use of GD Choice versus usual care (UC). RESULTS: Sixty-eight patients were enrolled, 37 to UC and 31 to GD Choice. At baseline, the groups were similar. Treatment discussion length was similar in both arms. After their visit, patients in both groups had similar knowledge about the options, except for GD Choice patients knowing significantly more about the complications of treatment (correctly answered by 83% vs. 55%; p = 0.04). Compared with UC, patients in the GD Choice arm had greater involvement in decision making observed on video recordings of clinical encounters (mean OPTION scale score, 35% vs. 30%; p = 0.02), but reported similar levels of decisional comfort and participation in shared decision making. CONCLUSIONS: GD Choice increases engagement in the decision-making process and knowledge regarding intervention complications without increasing the length of consultation. These promising results support the conduct of a randomized trial of GD Choice versus UC in a large multicenter trial. PMID- 26413978 TI - Genetics of pancreatic neuroendocrine tumors: implications for the clinic. AB - Pancreatic neuroendocrine tumors (PanNETs) are a common and deadly neoplasm of the pancreas. Although the importance of genetic alterations in PanNETs has been known for many years, recent comprehensive sequencing studies have greatly expanded our knowledge of neuroendocrine tumorigenesis in the pancreas. These studies have identified specific cellular processes that are altered in PanNETs, highlighted alterations with prognostic implications, and pointed to pathways for targeted therapies. In this review, we will discuss the genetic alterations that play a key role in PanNET tumorigenesis, with a specific focus on those alterations with the potential to change the way patients with these neoplasms are diagnosed and treated. PMID- 26413981 TI - Re-examination of genetic and nutritional factors related to trichothecene biosynthesis in Fusarium graminearum. AB - Disruption of two Fusarium genes that negatively regulate trichothecene biosynthesis was reported to cause a drastic increase in trichothecene production. However, careful inspection of these genes revealed that neither was significantly related to trichothecene production. Agmatine medium maintained the expression of trichothecene genes at significant levels, resulting in a 2-3-fold increase in the final yield, as compared to glutamine medium. PMID- 26413983 TI - The effect of the pre-pregnancy weight of the mother and the gestational weight gain on the bilirubin level of term newborn. AB - OBJECTIVE: Jaundice is a problem in newborns. There are many maternal and infant related factors affecting neonatal jaundice. The maternal pre-pregnancy weight, maternal body mass index (BMI) and gestational weight gain may have an effect on the newborn bilirubin levels. We research the effect of the maternal pre pregnancy weight and gestational weight gain on the bilirubin levels of the newborn infants in the first 2 weeks prospectively. METHODS: Term and healthy infants who were born between 38 and 42 weeks in our clinic were included in the study. Maternal pre-pregnancy BMIs were calculated. Babies were divided into three groups according to their mothers' advised amount of gestational weight gain. Total serum bilirubin (TSB) values of the newborns were measured in the 2nd, 5th and 15th postnatal days. RESULTS: In our study, the 5th and 15th day capillary bilirubin level of the babies with mothers who gained more weight than the advised amount during pregnancy were found statistically significant higher compared to the other two groups (p < 0.05). Similarly, the hematocrit level of the babies with mothers who gained more weight than the advised amount were found statistically significant higher compared to the other two groups (p < 0.05). CONCLUSIONS: We conclude that the babies with mothers who gained more weight than the advised amount were under risk for newborn jaundice. Therefore, these babies should be monitored more closely for neonatal jaundice and prolonged jaundice. PMID- 26413982 TI - A phase II study of oxaliplatin and prednisone for patients with relapsed or refractory marginal zone lymphoma: Consortium for Improving Survival of Lymphoma trial. AB - Overall, more than 50% of marginal zone lymphoma (MZL) patients experience a relapse within 10 years. This phase II trial was conducted to assess the efficacy and safety of oxaliplatin-prednisone (Ox-P) chemotherapy for patients with relapsed or refractory MZL. Patients received oxaliplatin 130 mg/m(2) on day 1 and prednisone 100 mg/day on days 1-5 of each cycle. A total of 38 patients were enrolled. The median age of the 34 (16 males, 18 females) evaluated patients was 53 (range = 27-74) years. There were seven complete responses (20.6%) and 15 partial responses (44.1%) (Overall response rate = 64.7%). No treatment-related deaths occurred. The median progression-free survival was 14.2 months (95% CI = 2.1-26.3 months); 3-year overall survival rate was 77.7%. Thus, salvage Ox-P chemotherapy for patients with relapsed or refractory MZL at the stated dosage and schedule showed moderate clinical activity and was considerable in very few selected patients (NCT01068392). PMID- 26413984 TI - Architectured materials: Straining to expand entanglements. PMID- 26413985 TI - A sunblock based on bioadhesive nanoparticles. AB - The majority of commercial sunblock preparations use organic or inorganic ultraviolet (UV) filters. Despite protecting against cutaneous phototoxicity, direct cellular exposure to UV filters has raised a variety of health concerns. Here, we show that the encapsulation of padimate O (PO)--a model UV filter--in bioadhesive nanoparticles (BNPs) prevents epidermal cellular exposure to UV filters while enhancing UV protection. BNPs are readily suspended in water, facilitate adherence to the stratum corneum without subsequent intra-epidermal or follicular penetration, and their interaction with skin is water resistant yet the particles can be removed via active towel drying. Although the sunblock based on BNPs contained less than 5 wt% of the UV-filter concentration found in commercial standards, the anti-UV effect was comparable when tested in two murine models. Moreover, the BNP-based sunblock significantly reduced double-stranded DNA breaks when compared with a commercial sunscreen formulation. PMID- 26413986 TI - Nanoscale transport of charge-transfer states in organic donor-acceptor blends. AB - Charge-transfer (CT) states, bound combinations of an electron and a hole on separate molecules, play a crucial role in organic optoelectronic devices. We report direct nanoscale imaging of the transport of long-lived CT states in molecular organic donor-acceptor blends, which demonstrates that the bound electron-hole pairs that form the CT states move geminately over distances of 5 10 nm, driven by energetic disorder and diffusion to lower energy sites. Magnetic field dependence reveals a fluctuating exchange splitting, indicative of a variation in electron-hole spacing during diffusion. The results suggest that the electron-hole pair of the CT state undergoes a stretching transport mechanism analogous to an 'inchworm' motion, in contrast to conventional transport of Frenkel excitons. Given the short exciton lifetimes characteristic of bulk heterojunction organic solar cells, this work confirms the potential importance of CT state transport, suggesting that CT states are likely to diffuse farther than Frenkel excitons in many donor-acceptor blends. PMID- 26413987 TI - Plasmons in graphene moire superlattices. AB - Moire patterns are periodic superlattice structures that appear when two crystals with a minor lattice mismatch are superimposed. A prominent recent example is that of monolayer graphene placed on a crystal of hexagonal boron nitride. As a result of the moire pattern superlattice created by this stacking, the electronic band structure of graphene is radically altered, acquiring satellite sub-Dirac cones at the superlattice zone boundaries. To probe the dynamical response of the moire graphene, we use infrared (IR) nano-imaging to explore propagation of surface plasmons, collective oscillations of electrons coupled to IR light. We show that interband transitions associated with the superlattice mini-bands in concert with free electrons in the Dirac bands produce two additive contributions to composite IR plasmons in graphene moire superstructures. This novel form of collective modes is likely to be generic to other forms of moire-forming superlattices, including van der Waals heterostructures. PMID- 26413989 TI - Prenatal serum screening markers may not require adjustment in former smokers. PMID- 26413988 TI - Reversible dilatancy in entangled single-wire materials. AB - Designing structures that dilate rapidly in both tension and compression would benefit devices such as smart filters, actuators or fasteners. This property however requires an unusual Poisson ratio, or Poisson function at finite strains, which has to vary with applied strain and exceed the familiar bounds: less than 0 in tension and above 1/2 in compression. Here, by combining mechanical tests and discrete element simulations, we show that a simple three-dimensional architected material, made of a self-entangled single long coiled wire, behaves in between discrete and continuum media, with a large and reversible dilatancy in both tension and compression. This unusual behaviour arises from an interplay between the elongation of the coiled wire and rearrangements due to steric effects, which, unlike in traditional discrete media, are hysteretically reversible when the architecture is made of an elastic fibre. PMID- 26413991 TI - Hypercoagulability in Kidney Transplant Recipients. AB - Thrombosis remains an important complication after kidney transplantation. Outcomes for graft and deep vein thrombosis are not favorable. The majority of early kidney transplant failure in adults is due to allograft thrombosis. Risk stratification, early diagnosis, and appropriate intervention are critical to the management of thrombotic complications of transplant. In patients with end-stage renal disease, the prevalence of acquired risk factors for thrombosis is significantly high. Because of hereditary and acquired risk factors, renal transplant recipients manifest features of a chronic prothrombotic state. Identification of hereditary thrombotic risk factors before transplantation may be a useful tool for selecting appropriate candidates for thrombosis prophylaxis immediately after transplantation. Short-term anticoagulation may be appropriate for all patients after kidney transplantation. PMID- 26413992 TI - Glucose Effectiveness: The Mouse Trap in the Development of Novel beta-Cell Replacement Therapies. AB - BACKGROUND: Cure of diabetes and normalization of glucose disposal during intravenous glucose tolerance tests (IVGTT) remains critical for stringent evaluation of novel replacement therapies in type 1 diabetes. Glucose disposal during an IVGTT depends on a complex interaction of both insulin-dependent and independent mechanisms. Glucose effectiveness, that is, the function of glucose per se, independent of insulin, to stimulate its uptake and suppress endogenous glucose production is less recognized. METHODS: To unravel the relative importance of these pathways, rats were injected with streptozotocin to induce diabetes and implanted subcutaneously with slow-release devices of insulin. RESULTS: These animals demonstrated rapid normalization of blood glucose and perfectly normal glucose disposal during an IVGTT with no differences when compared with nondiabetic controls even though no active c-peptide secretion was detected in plasma and almost no remaining insulin-producing cells were present in the pancreas. CONCLUSIONS: The present study highlights that glucose is the predominant mediator of its own disposal in rodents having only basal and nonglucose-regulated plasma insulin levels. The herein presented results calls for a reassessment how results obtained in the most commonly used experimental models should be interpreted in the development of future replacement therapies in type 1 diabetes. PMID- 26413993 TI - Peritubular Capillary Basement Membrane Multilayering in Renal Allograft Biopsies of Patients With De Novo Donor-Specific Antibodies. AB - BACKGROUND: Severe peritubular capillary basement membrane multilayering (PTCBML) is part of the Banff definition of chronic antibody-mediated rejection. We retrospectively investigated whether assessment of the mean number of layers of basement membrane (BM) around peritubular capillaries (PTC) can be used in a cohort of patients with de novo donor-specific antibodies (dnDSA) as an early marker to predict long-term antibody-mediated injury. METHODS: This is a retrospective cohort study with 151 electron microscopy samples from 54 patients with dnDSA, assessed at around 1 year after transplantation, for a mean number of BM layers around PTC and in serial biopsies. Graft survival and time to transplant glomerulopathy (TG) development were estimated in survival analyses. RESULTS: We found that a mean PTCBML count greater than 2.5 layers assessed in a sample of 25 PTCs around 1 year after transplantation is indicative of the development of TG in patients with dnDSA (P = 0.001). In addition, in patients with serial biopsies available for electron microscopy analysis, we could distinguish 2 groups: patients with a mean PTCBML count of 2.5 or less on all biopsies, and patients who developed greater than 2.5 layers at any time after transplantation. The latter group reflected dnDSA patients at risk for TG development (P < 0.001). In patients with dnDSA, PTCBML score added significantly to the sensitivity and specificity of prediction of TG compared with microcirculation injury score alone. CONCLUSIONS: Our results highlight the potential value of assessing the mean number of BM in PTC for early prediction of progression to chronic antibody-mediated injury. PMID- 26413990 TI - Impact of Tacrolimus Compared With Cyclosporin on the Incidence of Acute Allograft Rejection in Human Immunodeficiency Virus-Positive Kidney Transplant Recipients. AB - BACKGROUND: Kidney transplantation (KT) of human immunodeficiency virus (HIV) positive patients has transformed the management of end-stage kidney disease in this population. Although favourable outcomes have been reported, patients experience high rates of acute allograft rejection (AR). We examined factors associated with AR in the first year after KT, with particular emphasis on the choice of calcineurin inhibitor (CNI) immunosuppressive therapy. METHODS: We conducted a national observational cohort study of HIV/KT in the United Kingdom. Patients were included if HIV positive at KT, transplanted in the United Kingdom between January 2005 and December 2013, and did not experience primary graft failure. Kaplan-Meier methods were used to estimate host/graft survival and cumulative incidence of biopsy proven AR. Logrank tests were used to compare survival, and Cox proportional hazard models to examine factors associated with AR. RESULTS: Our study analyzed the incidence of AR in the first year after KT in 78 HIV-positive patients of whom 31 initiated cyclosporin (CsA) and 47 tacrolimus (Tac) based immunosuppression. AR was observed in 28 patients (36%) after a median of 2.6 (interquartile range, 0.5-5.9) months. The cumulative incidence of AR at 1 year was 58% and 21% among patients on CsA and Tac, respectively (P =0.003). Choice of CNI was the only factor significantly associated with AR (hazard ratio for Tac vs CsA 0.25 [95% confidence interval, 0.11-0.57], P = 0.001). Subtherapeutic CNI concentrations were common in the first 12 weeks after KT. CONCLUSIONS: Our data suggest that Tac may be the preferred CNI for use in KT in people living with HIV. PMID- 26413994 TI - Engaging in Culturally Informed Nursing Care With Hmong Children and Their Families. AB - The Hmong are an ethnic hill tribe group originally from Southern China with concentrated populations throughout Southeast Asia, especially the mountains of northern Laos. Following the Vietnam War, the Hmong started immigrating to the United States in waves to escape prosecution for fighting communism alongside the United States. Today, the Hmong population in the United States is growing rapidly, with a median age of 20.4 years. As the Hmong move and redistribute themselves across the country to be with family or pursue new opportunities, it is more and more likely that nurses everywhere will interact with Hmong children and their families. Historically medically underserved, the Hmong community continues to face barriers to healthcare as a result of culture, language, and lack of access. Nurses who are informed about cultural values and norms of the Hmong and their family and social structures, as well as their spiritual and traditional practices, will be able to establish trust with their pediatric patients and their caregivers. Utilizing strategies including interpretive services, asking detailed social and physical histories, providing extra appointment time, asking open ended questions, and employing teach back methods can help improve communication as well as provide higher quality care that addresses the specific needs of this population. PMID- 26413995 TI - MET/HGF targeted drugs as potential therapeutic strategies in non-small cell lung cancer. PMID- 26413997 TI - Rotational Orientation Effects in NO(X) + Ar Inelastic Collisions. AB - Rotational angular momentum orientation effects in the rotationally inelastic collisions of NO(X) with Ar have been investigated both experimentally and theoretically at a collision energy of 530 cm(-1). The collision-induced orientation has been determined experimentally using a hexapole electric field to select the epsilon = -1 Lambda-doublet level of the NO(X) j = 1/2 initial state. Fully quantum state resolved polarization-dependent differential cross sections were recorded experimentally using a crossed molecular beam apparatus coupled with a (1 + 1') resonance-enhanced multiphoton ionization detection scheme and subsequent velocity-map imaging. To determine the NO sense of rotation, the probe radiation was circularly polarized. Experimental orientation polarization dependent differential cross sections are compared with those obtained from quantum mechanical scattering calculations and are found to be in good agreement. The origin of the collision-induced orientation has been investigated by means of close-coupled quantum mechanical, quantum mechanical hard shell, quasi-classical trajectory (QCT), and classical hard shell calculations at the same collision energy. Although there is evidence for the operation of limiting classical mechanisms, the rotational orientation cannot be accounted for by QCT calculations and is found to be strongly influenced by quantum mechanical effects. PMID- 26413996 TI - Challenges and Prospects for Alpha-1 Antitrypsin Deficiency Gene Therapy. AB - Alpha-1 antitrypsin (AAT) is a protease inhibitor belonging to the serpin family. A number of identified mutations in the SERPINA1 gene encoding this protein result in alpha-1 antitrypsin deficiency (AATD). A decrease in AAT serum concentration or reduced biological activity causes considerable risk of chronic respiratory and liver disorders. As a monogenic disease, AATD appears to be an attractive target for gene therapy, particularly for patients with pulmonary dysfunction, where augmentation of functional AAT levels in plasma might slow down respiratory disease development. The short AAT coding sequence and its activity in the extracellular matrix would enable an increase in systemic serum AAT production by cellular secretion. In vitro and in vivo experimental AAT gene transfer with gamma-retroviral, lentiviral, adenoviral, and adeno-associated viral (AAV) vectors has resulted in enhanced AAT serum levels and a promising safety profile. Human clinical trials using intramuscular viral transfer with AAV1 and AAV2 vectors of the AAT gene demonstrated its safety, but did not achieve a protective level of AAT >11 MUM in serum. This review provides an in depth critical analysis of current progress in AATD gene therapy based on viral gene transfer. The factors affecting transgene expression levels, such as site of administration, dose and type of vector, and activity of the immune system, are discussed further as crucial variables for optimizing the clinical effectiveness of gene therapy in AATD subjects. PMID- 26413999 TI - Genetically Programmed Clusters of Gold Nanoparticles for Cancer Cell-Targeted Photothermal Therapy. AB - Interpretations of the interactions of nanocarriers with biological cells are often complicated by complex synthesis of materials, broad size distribution, and heterogeneous surface chemistry. Herein, the major capsid proteins of an icosahedral T7 phage (55 nm in diameter) are genetically engineered to display a gold-binding peptide and a prostate cancer cell-binding peptide in a tandem sequence. The genetically modified phage attracts gold nanoparticles (AuNPs) to form a cluster of gold nanoparticles (about 70 nanoparticles per phage). The cluster of AuNPs maintains cell-targeting functionality and exhibits excellent dispersion stability in serum. Under a very low light irradiation (60 mW cm(-2)), only targeted AuNP clusters kill the prostate cancer cells in minutes (not in other cell types), whereas neither nontargeted AuNP clusters nor citrate stabilized AuNPs cause any significant cell death. The result suggests that the prostate cancer cell-targeted clusters of AuNPs are targeted to only prostate cancer cells and, when illuminated, generate local heating to more efficiently and selectively kill the targeted cancer cells. Our strategy can be generalized to target other types of cells and assemble other kinds of nanoparticles for a broad range of applications. PMID- 26413998 TI - Surfactant Effects on Particle Generation in Antibody Formulations in Pre-filled Syringes. AB - Protein aggregation and particle formation have been observed when protein solutions contact hydrophobic interfaces, and it has been suggested that this undesirable phenomenon may be initiated by interfacial adsorption and subsequent gelation of the protein. The addition of surfactants, such as polysorbate 20, to protein formulations has been proposed as a way to reduce protein adsorption at silicone oil-water interfaces and mitigate the production of aggregates and particles. In an accelerated stability study, monoclonal antibody formulations containing varying concentrations of polysorbate 20 were incubated and agitated in pre-filled glass syringes (PFS), exposing the protein to silicone oil-water interfaces at the siliconized syringe walls, air-water interfaces, and agitation stress. Following agitation in siliconized syringes that contained an air bubble, lower particle concentrations were measured in the surfactant-containing antibody formulations than in surfactant-free formulations. Polysorbate 20 reduced particle formation when added at concentrations above or below the critical micelle concentration (CMC). The ability of polysorbate 20 to decrease particle generation in PFS corresponded with its ability to inhibit gelation of the adsorbed protein layer, which was assessed by measuring the interfacial diffusion of individual antibody molecules at the silicone oil-water interface using total internal reflectance fluorescence (TIRF) microscopy with single-molecule tracking. PMID- 26414000 TI - Confinement of Surface Plasmon Polaritons by Heterostructures of Plasmonic Crystals. AB - Square lattice plasmonic crystals (SQ-PlCs) composed of silver pillars generate large bandgaps for surface plasmon polaritons (SPPs). SPP confinement is demonstrated using one- and two-dimensional heterostructures of SQ-PlCs comprised of cylindrical pillars with different diameters in a common square lattice. Two kinds of localized modes are observed to appear in the heterostructures by photon map imaging using cathodoluminescence (CL) technique combined with a scanning transmission electron microscopy (STEM). Angle-resolved CL spectroscopy reveals contrasting characteristics of the two localized modes in their emission distributions, indicating that they originate from the band-edge A and E modes of the matrix SQ-PlC. PMID- 26414001 TI - Nonosseous Tarsal Coalition of the Lateral Cuneocuboid Joint: A Case Report. AB - We describe a rare case of a nonosseous coalition of the lateral cuneocuboid joint with peroneal spasm that we successfully treated with resection. A 60-year old female had been experiencing constant pain in her right foot, particularly when walking and going up and down stairs. The pain had been present for approximately 1 year after she had experienced a minor injury. Her right ankle showed plantar flexion restrictions (right 20 degrees and left 40 degrees ) and was held in an antalgic valgus position. Sudden passive plantar flexion produced pain behind the lateral malleolus of the right ankle. Tenderness was detected in the right peroneus brevis tendon and the right sinus tarsi. On plain radiographs, the oblique view showed an irregularity in the articular surface of the lateral cuneocuboid joint in both feet. On computed tomography images, there was no osseous continuation in the lateral cuneocuboid joint, indicative of a nonosseous bridge between the lateral cuneiform and the cuboid. The nonosseous coalition between the lateral cuneiform and the cuboid was resected and the trabecular surfaces and cortical margins covered with a thin film of bone wax. The patient's recovery was unremarkable, and 1 year after surgery, she was able to walk without pain and was able to perform her usual activities and job. PMID- 26414002 TI - The role of mothers' and fathers' religiosity in African American adolescents' religious beliefs and practices. AB - OBJECTIVES: To advance understanding of youth religiosity in its sociocultural context, this study examined the associations between parents' and adolescents' religious beliefs and practices and tested the roles of parent and youth gender and youth ethnic identity in these linkages. METHOD: The sample included 130 two parent, African American families. Adolescents (49% female) averaged 14.43 years old. Mothers, fathers, and adolescents were interviewed in their homes about their family and personal characteristics, including their religious beliefs. In a series of 7 nightly phone calls, adolescents reported on their daily practices, including time spent in religious practices (e.g., attending services, prayer), and parents reported on their time spent in religious practices with their adolescents. RESULTS: Findings indicated that mothers' beliefs were linked to the beliefs of sons and daughters, but fathers' beliefs were only associated with the beliefs of sons. Mothers' practices were associated with youths' practices, but the link was stronger when mothers' held moderately strong religious beliefs. Fathers' practices were also linked to youth practices, but the association was stronger for daughters than for sons. CONCLUSIONS: Findings highlight the understudied role of fathers in African American families, the importance of examining religiosity as a multidimensional construct, and the utility of ethnic homogeneous designs for illuminating the implications of sociocultural factors in the development of African American youth. (PsycINFO Database Record PMID- 26414005 TI - Children's Interstitial and Diffuse Lung Disease. Progress and Future Horizons. AB - Children's interstitial and diffuse lung disease (chILD) is a term that encompasses a large and diverse group of rare pediatric diseases and disorders. Significant progress has been made over the last 2 decades in classification, clinical care, research, and organizational structure to enhance the care of children with these high-morbidity and -mortality diseases. New diseases have been defined clinically and genetically, classification systems developed and applied, organizations formed such as the chILD Research Network (chILDRN) and chILD Foundation, and basic and translational science expanded to focus on chILD diseases. Multidisciplinary collaborations and efforts to advance understanding and treatment of chILD have been extended worldwide. The future horizon holds great promise to expand scientific discoveries, collaborate more broadly, and bring new treatment to these children. An overview of key historical past developments, major clinical and research updates, and opportunities for the future in chILD is reviewed in this Perspective. PMID- 26414004 TI - Course of Magnetic Resonance Imaging-Detected Inflammation and Structural Lesions in the Sacroiliac Joints of Patients in the Randomized, Double-Blind, Placebo Controlled Danish Multicenter Study of Adalimumab in Spondyloarthritis, as Assessed by the Berlin and Spondyloarthritis Research Consortium of Canada Methods. AB - OBJECTIVE: To investigate changes in magnetic resonance imaging (MRI)-assessed inflammation and structural lesions in the sacroiliac (SI) joints during treatment with adalimumab versus placebo. METHODS: In a 48-week double-blind, placebo-controlled trial, 52 patients with spondyloarthritis were randomized to receive subcutaneous injections of either adalimumab 40 mg (n = 25) or placebo (n = 27) every other week for 12 weeks. Patients in the adalimumab group continued to receive and patients in the placebo group were switched to adalimumab 40 mg every other week for an additional 12 weeks. MRI of the SI joints was performed at weeks 0, 12, 24, and 48, and the images were assessed independently in a blinded manner using the modified Berlin and the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI scores for inflammation and structural lesions of the SI joints. RESULTS: At baseline, 56% of the adalimumab group and ~72% of the placebo group had an MRI-assessed inflammation score of >=1. Among the patients with inflammation at baseline, the mean percent reductions in MRI scores for inflammation from week 0 to 12 were greater in the adalimumab group compared with the placebo group (Berlin method, -62% versus -5%; SPARCC method, -58% versus -12% [both P < 0.04]). Furthermore, the mean SPARCC erosion score decreased (-0.6) and the SPARCC backfill score increased (+0.8) in the adalimumab group from week 0 to week 12. From week 12 to week 24, larger absolute reductions in the Berlin/SPARCC inflammation scores and the SPARCC erosion score and larger increases in the Berlin/SPARCC fatty lesion scores were seen in the placebo group compared with the adalimumab group. In univariate regression analyses (analysis of covariance) and multivariate stepwise regression analyses, treatment with adalimumab was independently associated with regression of the SPARCC erosion score from week 0 to 12 but not with changes in the other types of MRI lesions. CONCLUSION: Significant changes in the Berlin and SPARCC MRI-assessed inflammation scores and in the SPARCC MRI-assessed erosion scores occurred within 12 weeks after initiation of adalimumab. Tumor necrosis factor inhibitor treatment was associated with resolution of erosions and the development of backfill. PMID- 26414003 TI - Increased sphingosine 1-phosphate mediates inflammation and fibrosis in tubular injury in diabetic nephropathy. AB - Hyperglycemia induces all isoforms of transforming growth factor beta (TGFbeta), which in turn play key roles in inflammation and fibrosis that characterize diabetic nephropathy. Sphingosine 1-phosphate (S1P) is a signaling sphingolipid, derived from sphingosine by the action of sphingosine kinase (SK). S1P mediates many biological processes, which mimic TGFbeta signaling. To determine the role of SK1 and S1P in inducing fibrosis and inflammation, and the interaction with TGFbeta-1, 2 and 3 signalling in diabetic nephropathy, human proximal tubular cells (HK2 cells) were exposed to normal (5 mmol/L) or high (30 mmol/L) glucose or TGFbeta-1, -2, -3 +/- an SK inhibitor (SKI-II) or SK1 siRNA. Control and diabetic wild type (WT) and SK1(-/-) mice were studied. Fibrotic and inflammatory markers, and relevant downstream signalling pathways were assessed. SK1 mRNA and protein expression was increased in HK2 cells exposed to high glucose or TGFbeta1,-2,-3. All TGFbeta isoforms induced fibronectin, collagen IV and macrophage chemoattractant protein 1 (MCP1), which were reversed by both SKI-II and SK1 siRNA. Exposure to S1P increased phospho-p44/42 expression, AP-1 binding and NFkB phosphorylation. WT diabetic mice exhibited increased renal cortical S1P, fibronectin, collagen IV and MCP1 mRNA and protein expression compared to SK1(-/-) diabetic mice. In summary, this study demonstrates that inhibiting the formation of S1P reduces tubulointerstitial renal inflammation and fibrosis in diabetic nephropathy. PMID- 26414006 TI - The Effects of Thermal Radiation on an Unsteady MHD Axisymmetric Stagnation-Point Flow over a Shrinking Sheet in Presence of Temperature Dependent Thermal Conductivity with Navier Slip. AB - In this paper, the magnetohydrodynamic (MHD) axisymmetric stagnation-point flow of an unsteady and electrically conducting incompressible viscous fluid in with temperature dependent thermal conductivity, thermal radiation and Navier slip is investigated. The flow is due to a shrinking surface that is shrunk axisymmetrically in its own plane with a linear velocity. The magnetic field is imposed normally to the sheet. The model equations that describe this fluid flow are solved by using the spectral relaxation method. Here, heat transfer processes are discussed for two different types of wall heating; (a) a prescribed surface temperature and (b) a prescribed surface heat flux. We discuss and evaluate how the various parameters affect the fluid flow, heat transfer and the temperature field with the aid of different graphical presentations and tabulated results. PMID- 26414007 TI - Evidence-Based Guideline of the German Nutrition Society: Fat Intake and Prevention of Selected Nutrition-Related Diseases. AB - As nutrition-related chronic diseases have become more and more frequent, the importance of dietary prevention has also increased. Dietary fat plays a major role in human nutrition, and modification of fat and/or fatty acid intake could have a preventive potential. The aim of the guideline of the German Nutrition Society (DGE) was to systematically evaluate the evidence for the prevention of the widespread diseases obesity, type 2 diabetes mellitus, dyslipoproteinaemia, hypertension, metabolic syndrome, coronary heart disease (CHD), stroke, and cancer through the intake of fat or fatty acids. The main results can be summarized as follows: it was concluded with convincing evidence that a reduced intake of total and saturated fat as well as a larger intake of polyunsaturated fatty acids (PUFA) at the expense of saturated fatty acids (SFA) reduces the concentration of total and low-density lipoprotein cholesterol in plasma. Furthermore, there is convincing evidence that a high intake of trans fatty acids increases risk of dyslipoproteinaemia and that a high intake of long-chain polyunsaturated n-3 fatty acids reduces the triglyceride concentration in plasma. A high fat intake increases the risk of obesity with probable evidence when total energy intake is not controlled for (ad libitum diet). When energy intake is controlled for, there is probable evidence for no association between fat intake and risk of obesity. A larger intake of PUFA at the expense of SFA reduces risk of CHD with probable evidence. Furthermore, there is probable evidence that a high intake of long-chain polyunsaturated n-3 fatty acids reduces risk of hypertension and CHD. With probable evidence, a high trans fatty acid intake increases risk of CHD. The practical consequences for current dietary recommendations are described at the end of this article. PMID- 26414008 TI - Choosing Wisely in Daily Practice: An Intervention Study on Antinuclear Antibody Testing by Rheumatologists. AB - OBJECTIVE: To assess the effect of a simple intervention on antinuclear antibody (ANA) test overuse by rheumatologists. METHODS: This was an explorative, pragmatic, before-and-after, controlled implementation study among rheumatologists working at 3 rheumatology departments in secondary and tertiary care centers in The Netherlands. The intervention was given in all study centers separately and combined education with feedback. Six outcome measures describe the intervention effects: the ANA/new patient ratio (APR), difference with the target APR, percentage of positive ANA tests, percentage of repeated ANA testing, percentage of ANA-associated diseases, and APR variation between rheumatologists. Outcomes were compared between the pre- and postintervention period (both 12 months) using (multilevel) logistic regression or F testing. Results are reported together for centers 1 and 2, and separately for center 3, because ANA tests could not be linked to an individual rheumatologist in center 3. RESULTS: The APR decreased from 0.37 to 0.11 after the intervention in centers 1 and 2 (odds ratio [OR] 0.19, 95% confidence interval [95% CI] 0.17-0.22, P < 0.001) and from 0.45 to 0.30 in center 3 (OR 0.53, 95% CI 0.45-0.62, P < 0.001). The percentage of repeated ANA requests in all centers and the APR variation for centers 1 and 2 decreased significantly. Only in center 3 did the percentage of ANA-associated diseases increase significantly. CONCLUSION: A simple intervention resulted in a relevant and significant decrease in the numbers of ANA tests requested by rheumatologists, together with an improvement on 3 other outcome measures. PMID- 26414009 TI - Elucidation of Enzymatic Mechanism of Phenazine Biosynthetic Protein PhzF Using QM/MM and MD Simulations. AB - The phenazine biosynthetic pathway is of considerable importance for the pharmaceutical industry. The pathway produces two products: phenazine-1,6 dicarboxylic acid and phenazine-1-carboxylic acid. PhzF is an isomerase that catalyzes trans-2,3-dihydro-3-hydroxyanthranilic acid isomerization and plays an essential role in the phenazine biosynthetic pathway. Although the PhzF crystal structure has been determined recently, an understanding of the detailed catalytic mechanism and the roles of key catalytic residues are still lacking. In this study, a computational strategy using a combination of molecular modeling, molecular dynamics simulations, and quantum mechanics/molecular mechanics simulations was used to elucidate these important issues. The Apo enzyme, enzyme substrate complexes with negatively charged Glu45, enzyme-transition state analog inhibitor complexes with neutral Glu45, and enzyme-product complexes with negatively charged Glu45 structures were optimized and modeled using a 200 ns molecular dynamics simulation. Residues such as Gly73, His74, Asp208, Gly212, Ser213, and water, which play important roles in ligand binding and the isomerization reaction, were comprehensively investigated. Our results suggest that the Glu45 residue at the active site of PhzF acts as a general base/acid catalyst during proton transfer. This study provides new insights into the detailed catalytic mechanism of PhzF and the results have important implications for PhzF modification. PMID- 26414010 TI - Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated stress reduces cell death after blast-induced traumatic brain injury. AB - A total of 1.7 million traumatic brain injuries (TBIs) occur each year in the United States, but available pharmacologic options for the treatment of acute neurotrauma are limited. Oxidative stress is an important secondary mechanism of injury that can lead to neuronal apoptosis and subsequent behavioral changes. Using a clinically relevant and validated rodent blast model, we investigated how nicotinamide adenine dinucleotide phosphate oxidase (Nox) expression and associated oxidative stress contribute to cellular apoptosis after single and repeat blast injuries. Nox4 forms a complex with p22phox after injury, forming free radicals at neuronal membranes. Using immunohistochemical-staining methods, we found a visible increase in Nox4 after single blast injury in Sprague Dawley rats. Interestingly, Nox4 was also increased in postmortem human samples obtained from athletes diagnosed with chronic traumatic encephalopathy. Nox4 activity correlated with an increase in superoxide formation. Alpha-lipoic acid, an oxidative stress inhibitor, prevented the development of superoxide acutely and increased antiapoptotic markers B-cell lymphoma 2 (t = 3.079, P < 0.05) and heme oxygenase 1 (t = 8.169, P < 0.001) after single blast. Subacutely, alpha-lipoic acid treatment reduced proapoptotic markers Bax (t = 4.483, P < 0.05), caspase 12 (t = 6.157, P < 0.001), and caspase 3 (t = 4.573, P < 0.01) after repetitive blast, and reduced tau hyperphosphorylation indicated by decreased CP-13 and paired helical filament staining. Alpha-lipoic acid ameliorated impulsive-like behavior 7 days after repetitive blast injury (t = 3.573, P < 0.05) compared with blast exposed animals without treatment. TBI can cause debilitating symptoms and psychiatric disorders. Oxidative stress is an ideal target for neuropharmacologic intervention, and alpha-lipoic acid warrants further investigation as a therapeutic for prevention of chronic neurodegeneration. PMID- 26414011 TI - Microvesicles but Not Exosomes from Pathfinder Cells Stimulate Functional Recovery of the Pancreas in a Mouse Streptozotocin-Induced Diabetes Model. AB - Pathfinder cells (PCs), a novel cell type derived from the pancreas of adult rats, have been demonstrated to stimulate recovery of tissue structure and function in two animal models of acute tissue damage to date-streptozotocin (STZ) induced diabetes and ischemia-reperfusion damage to the kidney. In repaired tissue, PCs and their progeny typically represent only 0.02% of the repaired tissue, suggesting that they act via a paracrine mechanism on native cells in the damaged area. Extracellular vesicles are strong candidates for mediating such a paracrine effect. Therefore, we studied the effects of two PC-derived extracellular vesicle fractions on tissue repair in the STZ diabetes model, one containing primarily microvesicles and the second containing predominantly exosomes. Treatment of STZ-induced diabetic mice with the microvesicles preparation led to blood glucose, insulin, glucagon, and C-peptide levels similar to those found with PC treatment. Furthermore, analysis of the histopathology of the pancreas indicated islet regeneration. In contrast, the exosome fraction demonstrated no repair activity, and STZ diabetic mice treated with exosome preparations had blood glucose values that were indistinguishable from those of vehicle-only treated controls. Therefore, we conclude that exosomes play no part in PC action as detected by this assay, whereas microvesicles provide all or a large component of the paracrine activity of PCs. Because they act to stimulate repair of multiple tissues, PC-derived microvesicles may similarly have the potential to stimulate repair of many damaged tissues, identifying a very significant cell-free therapeutic opportunity in regenerative medicine. PMID- 26414012 TI - Isolated Primary Blast Inhibits Long-Term Potentiation in Organotypic Hippocampal Slice Cultures. AB - Over the last 13 years, traumatic brain injury (TBI) has affected over 230,000 U.S. service members through the conflicts in Iraq and Afghanistan, mostly as a result of exposure to blast events. Blast-induced TBI (bTBI) is multi-phasic, with the penetrating and inertia-driven phases having been extensively studied. The effects of primary blast injury, caused by the shockwave interacting with the brain, remain unclear. Earlier in vivo studies in mice and rats have reported mixed results for primary blast effects on behavior and memory. Using a previously developed shock tube and in vitro sample receiver, we investigated the effect of isolated primary blast on the electrophysiological function of rat organotypic hippocampal slice cultures (OHSC). We found that pure primary blast exposure inhibited long-term potentiation (LTP), the electrophysiological correlate of memory, with a threshold between 9 and 39 kPa.ms impulse. This deficit occurred well below a previously identified threshold for cell death (184 kPa.ms), supporting our previously published finding that primary blast can cause changes in brain function in the absence of cell death. Other functional measures such as spontaneous activity, network synchronization, stimulus-response curves, and paired-pulse ratios (PPRs) were less affected by primary blast exposure, as compared with LTP. This is the first study to identify a tissue-level tolerance threshold for electrophysiological changes in neuronal function to isolated primary blast. PMID- 26414013 TI - Single Molecule Cluster Analysis dissects splicing pathway conformational dynamics. AB - We report Single Molecule Cluster Analysis (SiMCAn), which utilizes hierarchical clustering of hidden Markov modeling-fitted single-molecule fluorescence resonance energy transfer (smFRET) trajectories to dissect the complex conformational dynamics of biomolecular machines. We used this method to study the conformational dynamics of a precursor mRNA during the splicing cycle as carried out by the spliceosome. By clustering common dynamic behaviors derived from selectively blocked splicing reactions, SiMCAn was able to identify the signature conformations and dynamic behaviors of multiple ATP-dependent intermediates. In addition, it identified an open conformation adopted late in splicing by a 3' splice-site mutant, invoking a mechanism for substrate proofreading. SiMCAn enables rapid interpretation of complex single-molecule behaviors and should prove useful for the comprehensive analysis of a plethora of dynamic cellular machines. PMID- 26414014 TI - Proteome-wide profiling of protein assemblies by cross-linking mass spectrometry. AB - We describe an integrated workflow that robustly identifies cross-links from endogenous protein complexes in human cellular lysates. Our approach is based on the application of mass spectrometry (MS)-cleavable cross-linkers, sequential collision-induced dissociation (CID)-tandem MS (MS/MS) and electron-transfer dissociation (ETD)-MS/MS acquisitions, and a dedicated search engine, XlinkX, which allows rapid cross-link identification against a complete human proteome database. This approach allowed us to detect 2,179 unique cross-links (1,665 intraprotein cross-links at a 5% false discovery rate (FDR) and 514 interprotein cross-links at 1% FDR) in HeLa cell lysates. We validated the confidence of our cross-linking results by using a target-decoy strategy and mapping the observed cross-link distances onto existing high-resolution structures. Our data provided new structural information about many protein assemblies and captured dynamic interactions of the ribosome in contact with different elongation factors. PMID- 26414015 TI - The costs and effectiveness of large Phase III pre-licensure vaccine clinical trials. AB - Prior to the 1980s, most vaccines were licensed based upon safety and effectiveness studies in several hundred individuals. Beginning with the evaluation of Haemophilus influenzae type b conjugate vaccines, much larger pre licensure trials became common. The pre-licensure trial for Haemophilus influenzae oligosaccharide conjugate vaccine had more than 60,000 children and that of the seven-valent pneumococcal conjugate vaccine included almost 38,000 children. Although trial sizes for both of these studies were driven by the sample size required to demonstrate efficacy, the sample size requirements for safety evaluations of other vaccines have subsequently increased. With the demonstration of an increased risk of intussusception following the Rotashield brand rotavirus vaccine, this trend has continued. However, routinely requiring safety studies of 20,000-50,000 or more participants has two major downsides. First, the cost of performing large safety trials routinely prior to licensure of a vaccine is very large, with some estimates as high at US$200 million euros for one vaccine. This high financial cost engenders an opportunity cost whereby the number of vaccines that a company is willing or able to develop to meet public health needs becomes limited by this financial barrier. The second downside is that in the pre-licensure setting, such studies are very time consuming and delay the availability of a beneficial vaccine substantially. One might argue that in some situations, this financial commitment is warranted such as for evaluations of the risk of intussusception following newer rotavirus vaccines. However, it must be noted that while an increased risk of intussusception was not identified in large pre-licensure studies, in post marketing evaluations an increased risk of this outcome has been identified. Thus, even the extensive pre-licensure evaluations conducted did not identify an associated risk. The limitations of large Phase III trials have also been demonstrated in efficacy trials. Notably, pre-licensure trials of pneumococcal conjugate severely underestimated their true effect and cost-effectiveness. In fact, in discussions prior to vaccine introduction in the USA for PCV7, the vaccine was said to be not cost-effective and some counseled against its introduction. In reality, following introduction, PCV7 has been shown to be highly cost-effective. In the last decade, new methods have been identified using large linked databases such as the Vaccine Safety Datalink in the USA that allow identification of an increased risk of an event within a few months of vaccine introduction and that can screen for unanticipated very rare events as well. In addition, the availability of electronic medical records and hospital discharge data in many settings allows for accurate assessment of vaccine effectiveness. Given the high financial and opportunity cost of requiring large pre-licensure safety studies, consideration could be given to 'conditional licensure' of vaccines whose delivery system is well characterized in a setting where sophisticated pharmacovigilance systems exist on the condition that such licensure would incorporate a requirement for rapid cycle and other real-time evaluations of safety and effectiveness following introduction. This would actually allow for a more complete and timely evaluation of vaccines, lower the financial barrier to development of new vaccines and thus allow a broader portfolio of vaccines to be developed and successfully introduced. PMID- 26414016 TI - Coated-Platelet Levels Increase with Number of Injuries in Patients with Mild Traumatic Brain Injury. AB - Coated-platelets are procoagulant platelets that are elevated in stroke and are associated with stroke recurrence. In a previous study, prompted by data showing an increased risk for stroke following traumatic brain injury (TBI), we found that coated-platelet levels are elevated in patients with combat-related mild TBI (mTBI) several years after the injury, compared with controls. We now investigate in an expanded patient population whether parameters commonly recorded in mTBI are related to increased coated-platelet potential. Coated-platelet levels were assayed in 120 mTBI patients at intervals ranging from 6 months to 10 years from the last injury. Correlations were calculated between coated-platelet levels and age, gender, race/ethnicity, loss of consciousness, alteration in consciousness, post-traumatic amnesia, number of injuries, mechanism of injury, time since first and last injury, smoking, medications that may influence coated-platelet levels, and pertinent comorbid conditions. Significant correlations were detected between coated-platelet levels and number of injuries (p = 0.026), gender (p = 0.01), and time since last injury (p = 0.04). A multi-variable linear model analysis, including these three parameters and an additional three parameters (race/ethnicity, smoking, and mechanism of injury) that reached a p value of <0.2, showed that the number of injuries were predictive of coated-platelet levels (p = 0.004). These results support a mechanistic link between increased coated-platelet levels and repeated injuries in mTBI. Long-term studies will be required to determine the impact of increased prothrombotic potential in mTBI patients. PMID- 26414018 TI - Image Generation Using Bidirectional Integral Features for Face Recognition with a Single Sample per Person. AB - In face recognition, most appearance-based methods require several images of each person to construct the feature space for recognition. However, in the real world it is difficult to collect multiple images per person, and in many cases there is only a single sample per person (SSPP). In this paper, we propose a method to generate new images with various illuminations from a single image taken under frontal illumination. Motivated by the integral image, which was developed for face detection, we extract the bidirectional integral feature (BIF) to obtain the characteristics of the illumination condition at the time of the picture being taken. The experimental results for various face databases show that the proposed method results in improved recognition performance under illumination variation. PMID- 26414017 TI - Impact of Hydroxychloroquine on Atherosclerosis and Vascular Stiffness in the Presence of Chronic Kidney Disease. AB - Cardiovascular disease is the largest cause of morbidity and mortality among patients with chronic kidney disease (CKD) and end-stage kidney disease, with nearly half of all deaths attributed to cardiovascular disease. Hydroxychloroquine (HCQ), an anti-inflammatory drug, has been shown to have multiple pleiotropic actions relevant to atherosclerosis. We conducted a proof-of efficacy study to evaluate the effects of hydroxychloroquine in an animal model of atherosclerosis in ApoE knockout mice with and without chronic kidney disease. Forty male, 6-week-old mice were divided into four groups in a 2 x 2 design: sham placebo group; sham treatment group; CKD placebo group; and CKD treatment group. CKD was induced by a two-step surgical procedure. All mice received a high-fat diet through the study duration and were sacrificed after 16 weeks of therapy. Mice were monitored with ante-mortem ultrasonic echography (AUE) for atherosclerosis and vascular stiffness and with post-mortem histology studies for atherosclerosis. Therapy with HCQ significantly reduced the severity of atherosclerosis in CKD mice and sham treated mice. HCQ reduced the area of aortic atherosclerosis on en face examination by approximately 60% in HCQ treated groups compared to the non-treated groups. Additionally, therapy with HCQ resulted in significant reduction in vascular endothelial dysfunction with improvement in vascular elasticity and flow patterns and better-preserved vascular wall thickness across multiple vascular beds. More importantly, we found that presence of CKD had no mitigating effect on HCQ's anti-atherosclerotic and vasculoprotective effects. These beneficial effects were not due to any significant effect of HCQ on inflammation, renal function, or lipid profile at the end of 16 weeks of therapy. This study, which demonstrates structural and functional protection against atherosclerosis by HCQ, provides a rationale to evaluate its use in CKD patients. Further studies are needed to define the exact mechanisms through which HCQ confers these benefits. PMID- 26414020 TI - Behavioral Programs for Type 1 Diabetes Mellitus: A Systematic Review and Meta analysis. AB - BACKGROUND: Whether behavioral approaches for self-management programs benefit individuals with type 1 diabetes mellitus is unclear. PURPOSE: To determine the effects of behavioral programs for patients with type 1 diabetes on behavioral, clinical, and health outcomes and to investigate factors that might moderate effect. DATA SOURCES: 6 electronic databases (1993 to June 2015), trial registries and conference proceedings (2011 to 2014), and reference lists. STUDY SELECTION: 36 prospective, controlled studies involving participants of any age group that compared behavioral programs with usual care, active controls, or other programs. DATA EXTRACTION: One reviewer extracted and another verified data. Two reviewers assessed quality and strength of evidence (SOE). DATA SYNTHESIS: Moderate SOE showed reduction in glycated hemoglobin (HbA1c) at 6 months after the intervention compared with usual care (mean difference, -0.29 [95% CI, -0.45 to -0.13] percentage points) and compared with active controls ( 0.44 [CI, -0.69 to -0.19] percentage points). At the end of the intervention and 12-month follow-up or longer, there were no statistically significant differences in HbA1c (low SOE) for comparisons with usual care or active control. Compared with usual care, generic quality of life at program completion did not differ (moderate SOE). Other outcomes had low or insufficient SOE. Adults appeared to benefit more for glycemic control at program completion (-0.28 [CI, -0.57 to 0.01] percentage points) than did youth (-0.12 [CI, -0.43 to 0.19] percentage points). Program intensity appeared not to influence effectiveness; some individual delivery appears beneficial. LIMITATIONS: All studies had medium or high risk of bias. There was scarce evidence for many outcomes. CONCLUSION: Behavioral programs for type 1 diabetes offer some benefit for glycemic control, at least at short-term follow-up, but improvement for other outcomes has not been shown. (PROSPERO registration number: CRD42014010515). PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERD registration number: CRD42014010515). PMID- 26414019 TI - Areca nut alkaloids induce irreparable DNA damage and senescence in fibroblasts and may create a favourable environment for tumour progression. AB - BACKGROUND: Oral submucous fibrosis (OSMF) is a pre-malignant condition that is strongly associated with the areca nut alkaloids, arecoline (ARC) and arecaidine (ARD). The condition is characterised by the presence of senescent fibroblasts in the subepithelial mesenchyme which have the potential to promote malignancy in the neighbouring epithelial cells. We tested the hypothesis that areca nut alkaloids induce senescence in oral fibroblasts and promote the secretion of invasion-promoting transforming growth factor beta (TGF-beta) and matrix metalloproteinase-2 (MMP-2). METHODS: Two oral fibroblast lines were treated for 48h with ARC and ARD. Senescence-associated beta-galactosidase (SA-betaGal) activity, Ki67 (cycling cells), large 53BP1 foci (irreparable DNA strand breaks) and p16(INK) (4A) (late senescence) were used as markers of cellular senescence and were quantified using indirect immunofluorescence and the ImageJ program. TGF beta and MMP-2 levels were measured using ELISA. Statistical analyses were performed with the two-tailed unpaired t-test where n = 3 and the Wilcoxon-Mann Whitney test where n = 6. RESULTS: ARC (100 and 300 MUM) and ARD (30 and 100 MUM) significantly (P < 0.05) induced fibroblast senescence, as determined by the increased expression of SA-betaGal, 53BP1 staining and CDKN2A/p16(INK) (4A) ; there was also a non-significant reduction in Ki67 staining. Treated cells also showed a three- fivefold increase in TGF-beta and a small non-significant increase in MMP-2. CONCLUSIONS: Areca nut alkaloids induce senescence in oral fibroblasts and promote increased secretion of TGF-beta and perhaps MMP-2 that may create a tissue environment thought to be critical in the progression of OSMF to malignancy. PMID- 26414021 TI - Curcumin raises lipid content by Wnt pathway in hepatic stellate cell. AB - BACKGROUND: Activation of hepatic stellate cells (HSCs) is a pivotal event in liver fibrosis, which is characterized by dramatic disappearance of lipid droplets. However, the underlying molecular mechanisms are largely unknown. We aimed to explore the role of Wnt/beta-catenin pathway in HSC lipogenesis and to examine the effects of curcumin in this molecular context. METHODS: Primary rat HSCs were cultured in vitro for experiments. The Wnt activator WAY-262611 and beta-catenin activator lithium chloride (LiCl) were used to activate the pathway at distinct levels in HSCs. Cell proliferation, fibrogenic markers, intracellular lipids and triglyceride, and adipogenic transcription factors were examined in HSCs. RESULTS: Both WAY-262611 and LiCl promoted proliferation and upregulated the expression of alpha-smooth muscle actin and alpha1(I) procollagen, but they decreased the contents of intracellular lipids and triglyceride in HSCs. Analyses of adipogenic transcription pattern showed that the two compounds reduced the expression of peroxisome proliferator-activated receptor gamma, CCAAT/enhancer binding protein alpha, retinoid X receptor-alpha, and retinoic acid receptor beta, four key transcription regulators of HSC adipogenic phenotype. Curcumin also reduced the expression of Frizzled and beta-catenin, upregulated the expression of adipogenic transcription factors, and restored lipid content in HSCs. However, both WAY-262611 and LiCl abrogated curcumin restoration of lipogenesis and inhibition of fibrogenic marker expression in HSCs. CONCLUSIONS: Wnt/beta-catenin pathway was a profibrogenic signaling and inhibited lipogenesis by suppressing adipogenic transcription pattern in HSCs. Blockade of this pathway was associated with curcumin stimulation of HSC lipogenesis. We revealed a novel mechanism underlying curcumin restoration of lipid droplets during HSC activation. PMID- 26414023 TI - Sensitive and rapid detection of pathogenic bacteria in small volumes using impedance spectroscopy technique. AB - We illustrate a novel impedance immunosensor which rapidly and sensitively detects typhoid-causing infectious bacteria Salmonella enterica serovar (Salmonella typhi) in 10 MUL of sample volume. The bacteria are tagged with gold nanoparticles (Au NPs) via high-affinity antigen-antibody interactions for enhanced signal amplification and selectivity. The cell-particle bioconjugates are then subjected to alternating current (AC) electric fields applied through interdigitated microelectrodes. The immunosensor performance is optimized with respect to electric field frequency, cell concentration, incubation times and the type of blocking agent to achieve a low limit of detection (LOD) of 100 CFU/mL. The approach is extendable to a wide spectrum of clinical diseases and offers an efficient and cost-effective solution for point-of-care diagnosis. PMID- 26414022 TI - Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial. AB - IMPORTANCE: Early identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms. OBJECTIVES: To assess the safety of the gamma-secretase inhibitor avagacestat in PDAD and to determine whether CSF biomarkers can identify this patient population prior to clinical diagnosis of dementia. DESIGN, SETTING, AND PARTICIPANTS: A randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated, nonrandomized observational cohort of CSF biomarker-negative participants was conducted May 26, 2009, to July 9, 2013, in a multicenter global population. Of 1358 outpatients screened, 263 met MCI and CSF biomarker criteria for randomization into the treatment phase. One hundred two observational cohort participants who met MCI criteria but were CSF biomarker-negative were observed during the same study period to evaluate biomarker assay sensitivity. INTERVENTIONS: Oral avagacestat or placebo daily. MAIN OUTCOMES AND MEASURE: Safety and tolerability of avagacestat. RESULTS: Of the 263 participants in the treatment phase, 132 were randomized to avagacestat and 131 to placebo; an additional 102 participants were observed in an untreated observational cohort. Avagacestat was relatively well tolerated with low discontinuation rates (19.6%) at a dose of 50 mg/d, whereas the dose of 125 mg/d had higher discontinuation rates (43%), primarily attributable to gastrointestinal tract adverse events. Increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects were observed with avagacestat. Serious adverse event rates were higher with avagacestat (49 participants [37.1%]) vs placebo (31 [23.7%]), attributable to the higher incidence of nonmelanoma skin cancer. At 2 years, progression to dementia was more frequent in the PDAD cohort (30.7%) vs the observational cohort (6.5%). Brain atrophy rate in PDAD participants was approximately double that of the observational cohort. Concordance between abnormal amyloid burden on positron emission tomography and pathologic CSF was approximately 87% (kappa = 0.68; 95% CI, 0.48-0.87). No significant treatment differences were observed in the avagacestat vs placebo arm in key clinical outcome measures. CONCLUSIONS AND RELEVANCE: Avagacestat did not demonstrate efficacy and was associated with adverse dose-limiting effects. This PDAD population receiving avagacestat or placebo had higher rates of clinical progression to dementia and greater brain atrophy compared with CSF biomarker negative participants. The CSF biomarkers and amyloid positron emission tomography imaging were correlated, suggesting that either modality could be used to confirm the presence of cerebral amyloidopathy and identify PDAD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00890890. PMID- 26414024 TI - Label-free DNA Y junction for bisphenol A monitoring using exonuclease III-based signal protection strategy. AB - A label-free DNA Y junction sensing platform for the amplified detection of bisphenol A (BPA) has been constructed by the ingenious combination of toehold mediated strand displacement and exonuclease III (Exo III)-based signal protection strategy. Three hairpin probes were utilized as the building blocks to fabricate the DNA Y junction with cascaded signal amplification via a series of toehold-mediated strand displacement reactions. Exo III was employed as a protecting agent for the first time to keep the Y-shaped molecular architecture intact, thereby greatly enhancing the fluorescence intensity of DNA intercalator SYBR Green I. The resulting biosensor exhibits ultrasensitivity towards BPA at low concentration (5 fM) without any labeling, modification, immobilization, or washing procedure. Our proposed sensing system also displays remarkable specificity to BPA against other possible interference molecules. Moreover, this DNA junction biosensor is robust and can be applied to the reliable monitoring of spiked BPA in environmental water samples with good recovery and accuracy. With the successful demonstration for BPA detection, the label-free DNA Y junction can be readily expanded to monitor other analytes in a simple, cost-effective, and ultrasensitive way by substituting the target-specific aptamer sequence. PMID- 26414025 TI - Leverage principle of retardation signal in titration of double protein via chip moving reaction boundary electrophoresis. AB - In the present work we address a simple, rapid and quantitative analytical method for detection of different proteins present in biological samples. For this, we proposed the model of titration of double protein (TDP) and its relevant leverage theory relied on the retardation signal of chip moving reaction boundary electrophoresis (MRBE). The leverage principle showed that the product of the first protein content and its absolute retardation signal is equal to that of the second protein content and its absolute one. To manifest the model, we achieved theoretical self-evidence for the demonstration of the leverage principle at first. Then relevant experiments were conducted on the TDP-MRBE chip. The results revealed that (i) there was a leverage principle of retardation signal within the TDP of two pure proteins, and (ii) a lever also existed within these two complex protein samples, evidently demonstrating the validity of TDP model and leverage theory in MRBE chip. It was also showed that the proposed technique could provide a rapid and simple quantitative analysis of two protein samples in a mixture. Finally, we successfully applied the developed technique for the quantification of soymilk in adulterated infant formula. The TDP-MRBE opens up a new window for the detection of adulteration ratio of the poor food (milk) in blended high quality one. PMID- 26414027 TI - [The changing face of public health in Quebec]. PMID- 26414026 TI - Highly selective and sensitive surface enhanced Raman scattering nanosensors for detection of hydrogen peroxide in living cells. AB - Determination of hydrogen peroxide (H2O2) with high sensitivity and selectivity in living cells is a challenge for evaluating the diverse roles of H2O2 in the physiological and pathological processes. In this work, we present novel surface enhanced Raman scattering (SERS) nanosensors, 4-carboxyphenylboronic acid (4-CA) modified gold nanoparticles (Au NPs/4-CA), for sensing H2O2 in living cells. The nanosensors are based on that the H2O2-triggered oxidation reaction with the arylboronate on Au NPs would liberate the phenol, thus causing changes of the SERS spectra of the nanosensors. The results show the nanosensors feature higher selectivity for H2O2 over other reactive oxygen species, abundant competing cellular thiols and biologically relevant species, as well as excellent sensitivity with a low detection limit of 80 nM, which fulfills the requirements for detection of H2O2 in a biological system. In addition, the SERS nanosensors exhibit long term stability against time and pH, and high biocompatibility. More importantly, the presented nanosensors can be successfully used for monitoring changes of H2O2 levels within living biological samples upon oxidative stress, which opens up new opportunities to study its cellular biochemistry. PMID- 26414028 TI - [Immunization educational game in general practice waiting rooms. A comparative study]. AB - INTRODUCTION: The general practitioner's (GP) waiting room is an ideal place to conduct health education actions. The use of tools in GP waiting rooms would appear to be a useful approach, but the available tools are not very efficient. The objective of this study was to study the efficacy of a game compared with two other health education strategies. METHODS: A comparative study was conducted in two general practices. 212 patients were divided into three groups using a paper game or a booklet or nothing in the waiting room, before a discussion about immunization with the practitioner. The capacity of the tool to encourage questions about immunization was estimated by the GP at the end of the consultation by a questionnaire. RESULTS: The use of a tool in the waiting room facilitated the discussion between patients and practitioners (34% vs 12%, p<0.01). The game induced longer discussions than the booklet (1 minute 32 seconds vs 1 minute 14 seconds, p<0.05) without more themes. The game and the booklet had a comparable acceptability. CONCLUSIONS: Using a multistep education strategy facilitated discussion between the patient and the practitioner. However, the GP is required to trigger the conversation. PMID- 26414029 TI - [Assessment of smoking cessation assistance in French pharmacies]. AB - INTRODUCTION: While smoking continues to kill 73,000 people each year in France, new legislation allows pharmacists to ensure public health actions. How do pharmacists contribute to smoking cessation? METHODS: This study described smoking cessation professional practices, the tests used and dispensing of nicotine replacement therapy based on an online questionnaire administered to a random sample of 220 pharmacists, selected from the "Ordre des pharmaciens" website. The questionnaire concerned the type of pharmacy, place of smoking cessation support, knowledge and application of tests, training, referral to the physician and dispensing of nicotine replacement therapy. RESULTS: Among the 133 respondent pharmacies, minimal intervention and the Fagerstrom test were two tools most commonly used and 82.7% of pharmacists advised nicotine replacement therapy. Practices complied with guidelines, although certain dispensing difficulties were identified, as well as somewhat approximate or even incorrect knowledge concerning the dispensing of nicotine replacement therapy for certain patients (coronary heart disease, pregnant and breastfeeding women, teenagers). DISCUSSION: Certain improvements can be proposed such as the use of a confidential place for private conversations, better patient follow-up, better training and improvement of good practices by young pharmacists. PMID- 26414030 TI - [Psychosocial work factors and self-reported health in the French national SUMER survey]. AB - INTRODUCTION: This study was designed to investigate the associations between psychosocial work factors, using well-known theoretical models and emerging concepts, and self-reported health in the national population of French employees. METHODS: This study was based on the data of the French national representative SUMER 2010 survey. The sample included 46,962 employees, 26,883 men and 20,079 women, with an 87% participation rate. Self-reported health was measured by means of a single question and was analysed as a binary variable. Psychosocial work factors included factors related to job strain and effort reward imbalance models, workplace violence and working hours. Associations between psychosocial work factors and self-reported health were studied using weighted logistic regression models adjusted for covariates (age, occupation, economic activity, and other types of occupational exposure). RESULTS: Low decision latitude (skill discretion and decision authority), high psychological demands, low social support (from supervisors for men), low reward (low esteem and low job promotion for both genders and job insecurity for men), bullying and verbal abuse for both genders were associated with self-reported health. CONCLUSIONS: This study emphasizes the role of psychosocial work factors as risk factors for poor self-reported health and suggests that the implementation of preventive measures to reduce exposure to psychosocial work factors should be an objective for the improvement of health at work. PMID- 26414031 TI - [From professional practice assessment to continuing professional development: hospital practitioners' involvement and opinion concerning professional practice assessment activities]. AB - INTRODUCTION: The aim of this study was to describe implementation of professional practice assessment (PPA) programmes and participation of physicians and pharmacists in these programmes in a French university hospital. METHODS: We conducted an observational study based on PPA programmes validated in Grenoble university hospital continuing education board between 2007 and 2011. Data were extracted from individual commitment forms filled in by professionals and programme validation forms. The main outcome was the proportion of full-time hospital practitioners who validated at least one PPA programme. RESULTS: Over a 5-year period, 64 PPA programmes and 509 individual commitments involving 366 professionals were validated. At study endpoint, 264 (47%) permanent professionals had validated their mandatory PPA programme. The main methods used in PPA programmes included mortality and morbidity reviews (23), multidisciplinary meetings (23), staff PPA (8) and experience feedback committees (6). The most commonly reported strengths of these programmes included team work (49%) and improvement of patient care (30%). The most commonly reported drawbacks were organizational issues (27%) and unavailability to participate (23%). CONCLUSION: Hospital practitioners and pharmacists adhered to team-based PPA programmes. Implementation of team-base continuing development programmes was the preferred modality during the study period. Implementation of continuing professional development should help support this dynamic. PMID- 26414032 TI - [Arduous working conditions for beginners: when workplace prevention becomes an economic risk]. AB - The French law of 20.01.2014 recently instituted an arduous working conditions allowance. This innovated legislation is designed to improve the status of workers subject to arduous working conditions either by allowing lighter work schedules or job reclassification or early retirement. The impact of arduous working conditions on health has been clearly established, but no consensual solution has yet been proposed. Life expectancy without disability can differ by as much as 9 years between higher executives and manual workers, but the proposed solutions comprise a multitude of perverse effects. Workers may benefit from maintaining their arduous working conditions in order to preserve their right to early retirement. Companies do not necessarily have the desire or the resources to invest in prevention, which is the only consensually accepted effective measure, if they are also required to finance both training and retirement. In particular, management of the arduous working conditions allowance is very complex and entirely financed by companies. Consequently, company productivity can be impacted, leading to transfers of company headquarters, outsourcing to interim workers, replacement of jobs by automation. Unemployment could be the big winner of this conflict. Politically, arduous working conditions allowance appears to be very difficult to put into practice and can be considered to be more a promise by the government to the left and to the trade unions. PMID- 26414033 TI - [Palliative care practices in residential facilities for the elderly requiring full-time care]. AB - AIMS: The purpose of this study was to assess palliative care practices for residents of Larmont residential facilities for the elderly requiring full-time care (Doubs, France) throughout their stay. METHODS: This was a healthcare peer review based on a retrospective clinical audit in compliance with the recommendations of the French Health Authority. The 252-bed Larmont residential care facilities for the elderly is a public institution, attached to the local Hospital. The 72 residents of the Larmont residential care facilities for the elderly who died during 2012 were included in the study. RESULTS: Death occurred on the premises for 95.8 percent of residents. The proposal to appoint a support person was recorded in 27.6 percent of audited cases. End-of-life instructions were recorded in 23.2 percent of cases. In 31.8 percent of cases, the medical record referred to a multidisciplinary procedure, which complied with regulations in less than one half of cases. The residents' pain at the end of their life was insufficiently assessed and managed. A discomfort other than pain was identified in 89.2 percent of cases. CONCLUSIONS: This healthcare peer review led to a quality improvement plan focusing on three areas : ensure that medical practices are in line with patients' rights, anticipate identification of the end of life and improve management of pain and suffering at the end of life. PMID- 26414034 TI - [Impact on professional practices of a care protocol implemented between usual hospital care and hospital at home]. AB - BACKGROUND: Implementation of a care protocol between usual hospital care and hospital at home (HAH) could improve the quality of care and decrease fragmentations of the French healthcare system. This study evaluated the impact on professional practices of a care protocol implemented between a surgery unit and hospital at home. METHODS: Twenty healthcare professionals (nurses, head nurses, physicians) from HAH and a Paris public hospital urology unit were interviewed by a public heath physician. Semistructured interviews were analyzed using the grounded theory. RESULTS: Professional practices were modified with better traceability of care, greater safety for professionals and for patients, standardization of practices and improved continuity of interventions between hospital and hospital at home. However, these changes in practices appeared to be limited to the protocol itself and indicated potential enhancement of technical aspects to the detriment of human contact. CONCLUSION: This care protocol has an encouraging impact on the quality of care. These results demonstrate the value of extending this approach to other wards to improve continuity of care between usual hospital care and hospital at home. PMID- 26414035 TI - [Organized or individual breast cancer screening: what motivates women?]. AB - OBJECTIVE: The breast cancer screening programme, proposed to all women between 50 and 69 years, consisting of two-view mammography screening every two years, has been generalized in France since 2004. The programme coexists with opportunistic mammography screening, provided outside official frameworks. This qualitative study was designed to identify the pros and cons of these two screening modes. METHODS: Three hundred and forty-five women were randomly selected from women who had participated in a previous quantitative study and who were invited to attend for breast cancer screening in 13 French departments between 2010 and 2011. These women were asked to participate in a face-to-face semistructured interview conducted by a sociologist. RESULTS: 48 women (17 from deprived areas) were interviewed. All chose to be screened for breast cancer either because they feared cancer, or because they wanted to control their own health. Twenty-seven women chose the organized screening programme, which they considered to be trustworthy, as negative mammograms are double checked by a second radiologist. Twenty-one women preferred individual screening, which they considered to be more reliable, less anonymous and providing them with more liberty to take control of their own health. CONCLUSION: Gynaecologists play an important role in women's decision to undergo individual breast cancer screening. They also have an important role to play in the promotion of organized breast cancer screening programme with this public. PMID- 26414036 TI - [Frequency and coding of psychiatric care of short-stay patients]. AB - INTRODUCTION: The objective of this study was to describe the frequency and coding of the psychiatric management of short-stay patients admitted to Nice University Hospital in 2013. METHODS: Various parameters were measured : percentage of outpatient psychiatric procedures or psychiatric diagnosis codes ; coding practice differences between the Programme de medicalisation des systemes d'information (Medical Information System Programme) for medicine, surgery and obstetrics and psychiatric medical data records, and the impact of coding on diagnosis-related groups. RESULTS: Twenty-four per cent of hospitalised patients received psychiatric management (either outpatient care or a psychiatric diagnosis) and 3.9% received both psychiatric management and a psychiatric diagnosis. Liaison psychiatrists more commonly used codes for neurotic and psychosomatic disorders (28% vs 16%), while somatic physicians more commonly used codes for psychoactive substance use-related disorders (26% vs 16%).The presence of psychiatric comorbidity had an impact on the DRG classification or the level of severity for 0.5% of standardized discharge summaries. CONCLUSION: This study illustrates the importance of the active involvement of psychiatry personnel in the management of short-stay patients. The importance of psychosomatic medicine in a short-stay institution could be improved by establishing a clearer definition of coding rules for these diseases and revising and identifying wards or beds devoted to psychosomatic disorders. PMID- 26414038 TI - [Health workers' involvement for data quality improvement in Benin]. AB - OBJECTIVE: In developing countries, the poor quality of data derived from Health Information Systems constitutes a problem that limits use of these data and contributes to the recurrent difficulties of health system management. The low level of involvement of health workers directly responsible for data may contribute to this poor quality. This study documents a Health Information System collection tool design experience by health workers and assesses its effect on data quality. METHODS: Eighty health workers responsible for clinical statistics in public health centres participated in this study. The two tools used for clinical data collection were modified by a group of 6 volunteer health workers. Monitoring indicators, data entry time, percentage exhaustiveness and quality of data were assessed before and after using the new tools. Data were compared by Wilcoxon's test for paired data and Mc Nemar's chi-square test. RESULTS: Between the two assessments, the data entry time increased from 28.7 to 22.5 seconds by reported case (p=0.153), the exhaustiveness of the reports increased from 16% to 89% (p<0.001) and the proportion of reports with sufficient data quality increased from 18.8% to 45.8% (p=0.002). CONCLUSION: The positive course of the indicators shows that increased involvement of health workers in key stages such as the design of data collection tools can help improve data quality. PMID- 26414037 TI - [Is there room for improvement in the field of dental ethics?]. AB - INTRODUCTION: Dental ethics, enforced by the Dental Board, are defined in the Code of Conduct for dentists included in the French Public Health Code. Dentist patient relationships are changing, while scientific progress advances more rapidly than dental ethics. Are dental ethics still adapted to the practice of dentistry? METHODS: This study was based on the Institut BVA "The French and patients' rights" survey conducted in September 2013, together with a systematic review of the literature using the Medline, Legifrance, Lexisnexis, and Elnet.fr databases and the Paris Descartes University medical library website. RESULTS: Five essential principles were identified and a total of 210 articles were included. The results indicate that there is room for improvement in pain management, respect of human dignity, information and consent concerning healthcare, and free choice of a practitioner. CONCLUSION: Dental ethics have evolved, but further improvement is required to adapt the dentist-patient relationship to scientific progress and the patients' expectations. To ensure a truly informed choice, this article shows that dental ethics cannot vary in response to surveys or fashions, as dental practice must remain essentially based on an ethical approach that cannot be rigidly defined in a code of professional conduct. PMID- 26414039 TI - [Antibiotic consumption at Antananarivo University Hospital: prevalence and strategic challenges]. AB - INTRODUCTION: Very few studies have been conducted on antibiotic consumption in Madagascar. The objective of this study was to describe antibiotic consumption in a tertiary university hospital in Antananarivo, Madagascar to more clearly define good antibiotic use strategies. MATERIALS AND METHOD: A one-day prevalence survey was conducted on 5 April 2011 in the 339-bed Befelatanana Hospital with a bed occupation rate of 65.5%. RESULTS: The prevalence of antibiotic therapy among the 222 patients hospitalised on the day of the survey was 57.2%. Almost one half (49.6%) of patients received a combination of at least two antibiotics. The classes of antibiotics most commonly prescribed were beta-lactam antibiotics (55.3%), imidazoles (14.9%), aminoglycosides (14.9%), quinolones (7.9%) and macrolides with 7% of prescriptions. Penicillins accounted for 55.5% of all beta lactam antibiotic prescriptions, followed by third-generation cephalosporins. Children under the age of 14 years (p<0.019) and patients with invasive devices (p<10(-6)) received more antibiotics. Antibiotic prescription in the Emergency Room-Intensive Care Unit was significantly higher than in the other wards (p<0.01). CONCLUSION: A high rate of antibiotic use was observed in Befelatanana University Hospital. Beta-lactam antibiotics were the agents most commonly prescribed and the Emergency Room-Intensive Care Unit was the leading antibiotic prescriber. It is essential to set up a good antibiotic use policy. PMID- 26414041 TI - [Evaluation of application of national guidelines for the management of malaria in Bobo-Dioulasso university hospital]. AB - INTRODUCTION: To evaluate compliance with national guidelines concerning the diagnosis and treatment of malaria at Souro Sanou university hospital in Bobo Dioulasso. METHODS: This was a cross-sectional descriptive study based on the medical records of patients hospitalised in the Medicine and Paediatrics departments in 2012. All cases labelled as "malaria" on admission and on discharge, for which the medical records were complete, were included in the study. RESULTS: Of the total of 1,722 cases collected, 1,674 cases (97.22%) were labelled as "severe malaria". The mean age of these patients was 2.65 years [95% CI: 2.41-2.90 years]; 87.63% of cases were under the age of 5 years. The sex ratio was 1.22. The diagnosis complied with guidelines in 13.82% of cases. The rate of compliance with the diagnosis did not differ according to the severity of the disease (p=0.78), but differed according to age-group: 13.12% in subjects under the age of 5 years versus 18.78% in subjects over the age of 5 years (p=0.02). Cases labelled as "severe malaria" (SM comprised 1.47% of cases of "uncomplicated malaria" (UCM); inversely, 4.17% cases of SM were identified among cases labelled as UCM. Overall, 242 cases (14.05%) were confirmed cases of malaria versus 1,480 cases (85.95%) of presumed malaria. Treatment complied with guidelines in 57.49% of cases. The adequate treatment rate was higher for cases of SM (58.90% versus 8.33%, p<0.01) and in children under the age of 5 years (58.71% versus 48.30%, p=0.02). CONCLUSION: This study demonstrated poor compliance with clinical practice guidelines concerning the management of malaria in Bobo-Dioulasso university hospital. Identification of factors responsible for poor compliance with these guidelines may help to identify appropriate measures to improve compliance and contribute to control of malaria in the country. PMID- 26414040 TI - [Quality of immunization data in children aged 0 to 11 months in Cote d'Ivoire]. AB - INTRODUCTION: In order to guide the decisions of programme managers, an immunization Data Quality Self-Assessment was performed in Cote d'Ivoire in 2012. This study was designed to assess the accuracy of immunization data and the quality of the immunization tracking system with this tool. METHODS: A descriptive cross-sectional study was conducted in 88 randomly selected immunization facilities from 30 health districts. These structures were included in the study based on the number of children aged 0-11 months who received three doses of vaccine against Diphtheria, Tetanus, Pertussis, Hepatitis B Viral and Haemophilus Influenzae b on the one hand and measles vaccine coverage on the other. This assessment focused on two criteria in particular: accuracy of immunization data measured by the verification factor (VF) and the quality of the immunization tracking system. RESULTS: The accuracy of immunization data was satisfactory at the district level (VF=95%), but not for the health centre level (VF=81%), as 73% of health districts and health centres obtained a satisfactory factor (>=95%).The number of children aged 0-11 months vaccinated differed from one level of the health system to another and from one document to another.The mean quality index was not satisfactory for both the district and health centre levels (64% vs 50%). Only one health district and one health centre obtained a quality index greater than 80%. Furthermore, 93% of health districts and 50% of health centres obtained quality indices ranging from 50% and 80%, respectively.The weakest components at both levels were "supervision and monitoring" and "analysis and use of data". CONCLUSION: The deficiencies in data reporting and the quality of the immunization monitoring system need to be improved by supportive supervision. PMID- 26414043 TI - Effect of Playing Video Games on Laparoscopic Skills Performance: A Systematic Review. AB - BACKGROUND AND PURPOSE: The advances in both video games and minimally invasive surgery have allowed many to consider the potential positive relationship between the two. This review aims to evaluate outcomes of studies that investigated the correlation between video game skills and performance in laparoscopic surgery. METHODS: A systematic search was conducted on PubMed/Medline and EMBASE databases for the MeSH terms and keywords including "video games and laparoscopy," "computer games and laparoscopy," "Xbox and laparoscopy," "Nintendo Wii and laparoscopy," and "PlayStation and laparoscopy." Cohort, case reports, letters, editorials, bulletins, and reviews were excluded. Studies in English, with task performance as primary outcome, were included. The search period for this review was 1950 to December 2014. RESULTS: There were 57 abstracts identified: 4 of these were found to be duplicates; 32 were found to be nonrelevant to the research question. Overall, 21 full texts were assessed; 15 were excluded according to the Medical Education Research Study Quality Instrument quality assessment criteria. The five studies included in this review were randomized controlled trials. Playing video games was found to reduce error in two studies (P 0.002 and P 0.045). For the same studies, however, several other metrics assessed were not significantly different between the control and intervention group. One study showed a decrease in the time for the group that played video games (P 0.037) for one of two laparoscopic tasks performed. In the same study, however, when the groups were reversed (initial control group became intervention and vice versa), a difference was not demonstrated (P for peg transfer 1 - 0.465, P for cobra robe - 0.185). Finally, two further studies found no statistical difference between the game playing group and the control group's performance. CONCLUSION: There is a very limited amount of evidence to support that the use of video games enhances surgical simulation performance. PMID- 26414045 TI - Building a Culture of Excellence: Learning From Our Successes. PMID- 26414044 TI - Targeting lipid metabolism for the treatment of anaplastic thyroid carcinoma. AB - INTRODUCTION: Anaplastic thyroid carcinoma (ATC) is the rarest subtype of thyroid cancer; however, it disproportionately accounts for a large percentage of all thyroid cancer-related deaths and is considered one of the most lethal solid tumors in humans, having a median survival of only a few months upon diagnosis. Although a variety of treatment options are available including surgery, radiation and targeted therapies, response rates are low, due in part to the drug resistant nature of this disease; therefore, new avenues for therapeutic intervention are surely needed. Recent investigation into the metabolic profile of ATC has revealed a tumor-specific dependency for increased de novo lipogenesis, offering new insight into the molecular mechanisms that govern disease initiation and progression. AREAS COVERED: Herein we summarize known oncogenic signaling pathways and current therapeutic strategies for the treatment of ATC. We further discuss the unique expression pattern of lipid metabolism constituents in this disease. Additionally, the current literature correlating aberrant lipogenesis with carcinogenesis is reviewed, and the implications of targeting this pathway as an innovative approach for treating ATC and other malignancies are discussed. As stearoyl-CoA desaturase (SCD) is the most differentially expressed constituent of lipid metabolism in ATC, an additional focus on this enzyme as a novel therapeutic target is applied. EXPERT OPINION: This section is used to summarize the current research efforts underway in defining the role of lipid metabolism specifically in thyroid carcinoma. Included is a brief summary of lipid metabolism factors for which inhibitors have been generated and are under current investigation as anti-cancer agents. Finally, research limitations regarding the use of these inhibitors against components of this pathway are discussed. PMID- 26414046 TI - Health Policy in Medical Education: A Renewed Look at a Timely and Achievable Imperative. PMID- 26414047 TI - In Reply to Kagan and Armstrong. PMID- 26414048 TI - Discordance Persists Between Trainers' and Trainees' Perceptions of Workplace Based Assessment. PMID- 26414049 TI - In Reply to Ali. PMID- 26414050 TI - Top or Flop: The Need to Improve Knowledge and Skills Achieved by Ultrasound Medical Curricula. PMID- 26414051 TI - Lifestyle Medicine Curricula: An Initiative to Include Lifestyle Medicine in Our Nation's Medical Schools. PMID- 26414052 TI - What's in a Name? The Necessary Transformation of the Academic Medical Center in the Era of Population Health and Accountable Care. AB - Academic medical centers (AMCs) and the physicians and other professionals who lead them need to recognize they are in a business that is making a transition from a system of "sickness" care to one of "health" care, accountable for the health of defined populations and for the value (quality divided by cost) of the services provided. This change has profound implications for how AMCs conceive themselves, how they function, and how they are paid for the work that they do. A failure to recognize how the disruption of the mission of AMCs is changing may impair them as irrevocably as other changes caused the demise of Kodak, once the world's leader in the manufacture and sale of photographic film and cameras. Leaders of academic medicine need to understand, respond to, and ultimately lead the transformation of our system of health. In this Commentary, the authors review the pressures driving these changes and potential responses to them-a process already under way. They summarize the issues in the question "Should the words 'health' and 'system' take the place of 'medical' and 'center' in our institutions' names and, more important, in how we conceive of what we do?" The authors propose the name "academic health system" to better identify primary objectives to measure success by the health of patients. PMID- 26414053 TI - Why We Need to Build a Culture of Health in the United States. AB - The United States spends $2.7 trillion a year on health care, more than any other country by far, and yet the U.S. population is not healthy. In fact, the United States loses $227 billion in productivity each year because of poor health. This is not sustainable-and it is the reason behind the Robert Wood Johnson Foundation's Culture of Health initiative. Culture of Health means so much more than simply not being sick. It means embracing a definition of health as outlined by the World Health Organization-a state of complete physical, mental, and social well-being. And it means shifting the values-and the actions-in the United States so that health becomes a part of everything we do. Health is the bedrock of personal fulfillment. It is the backbone of prosperity and the key to creating a strong and competitive nation. With health, children can grow up making the most of life's opportunities. Businesses can rely on the vitality of workers to stay competitive, and the military can perform at its highest level. But there is no single way to cultivate health. This Commentary explores the principles behind the Culture of Health initiative and examines the role of academic medicine in achieving this vision. Different communities must come up with the approaches that serve them best. Only by working toward a common goal in unique ways will a true Culture of Health be attainable in the United States. PMID- 26414055 TI - Artist's Statement: The Persistence of Clerkship Memory. PMID- 26414054 TI - Sustaining the Clinical and Translational Research Workforce: Training and Empowering the Next Generation of Investigators. AB - There is mounting concern that clinician-scientists are a vanishing species and that the pipeline for clinical and translational research (CTR) investigators is in jeopardy. For the majority of current junior CTR investigators, the career path involves first obtaining a National Institutes of Health (NIH)-funded K-type career development award, particularly K08 and K23, and subsequently an NIH R01. This transition, popularly referred to as K2R, is a major hurdle with a low success rate and gaps in funding. In this Perspective, the authors identify factors that facilitate K2R transition and important aspects of increasing and sustaining the pipeline of CTR investigators. They also highlight significant differences in success rates of women and those underrepresented in biomedical research. Early career exposure to research methodology, protected time, multidisciplinary mentoring, and institutional "culture shift" are important for fostering and rewarding team science. Mentoring is the single most important contributor to K2R success, and emerging evidence suggests that formal mentor training and team mentoring are effective. Leadership training can empower junior investigators to thrive as independent CTR investigators. Future research should focus on delineating the difference between essential and supplemental factors to achieve this transition, and mentoring methods that foster success, including those that promote K2R transition of women and those underrepresented in biomedical research. The Clinical and Translational Science Awards National Consortium is well positioned to test existing models aimed at shortening the time frame, increasing the rate of K2R transition, and identifying strategies that improve success. PMID- 26414056 TI - Commentary on Excerpts From Never Let Me Go. PMID- 26414057 TI - A Night on Trauma. PMID- 26414058 TI - Wise After the Fact. PMID- 26414059 TI - A paper-based detection method of cancer cells using the photo-thermal effect of nanocomposite. AB - A novel paper-based dot immune-graphene-gold filtration assay (DIGGFA) for the detection of breast cancer cells was developed based on the photo-thermal effect of graphene oxide (GO)-Au nanocomposite. Anti-EpCAM antibody which specific to the MCF-7 cell surface antigen, was immobilized on the nitrocellulose paper. The GO-Au-anti-EpCAM composite would interact with the MCF-7 cells captured on the nitrocellulose paper. After the test zone was irradiated by a laser, GO-Au nanocomposite could generate heat, temperature contrast was recorded and positive correlated with the cell number. Standard curve was prepared according to the temperature contrast and the cell number. Under optimal conditions, this method could detect a minimum of 600 MCF-7 cells with a near infrared laser and an infrared temperature gun within 15 min. This simple and rapid method could be applied to the clinical diagnosis in hospitals. PMID- 26414060 TI - High-throughput method for the determination of residues of beta-lactam antibiotics in bovine milk by LC-MS/MS. AB - This study describes the development and validation procedures for scope extension of a method for the determination of beta-lactam antibiotic residues (ampicillin, amoxicillin, penicillin G, penicillin V, oxacillin, cloxacillin, dicloxacillin, nafcillin, ceftiofur, cefquinome, cefoperazone, cephapirine, cefalexin and cephalonium) in bovine milk. Sample preparation was performed by liquid-liquid extraction (LLE) followed by two clean-up steps, including low temperature purification (LTP) and a solid phase dispersion clean-up. Extracts were analysed using a liquid chromatography-electrospray-tandem mass spectrometry system (LC-ESI-MS/MS). Chromatographic separation was performed in a C18 column, using methanol and water (both with 0.1% of formic acid) as mobile phase. Method validation was performed according to the criteria of Commission Decision 2002/657/EC. Main validation parameters such as linearity, limit of detection, decision limit (CCalpha), detection capability (CCbeta), accuracy, and repeatability were determined and were shown to be adequate. The method was applied to real samples (more than 250) and two milk samples had levels above maximum residues limits (MRLs) for cloxacillin - CLX and cefapirin - CFAP. PMID- 26414061 TI - [Robert Labauge (1922-2015)]. PMID- 26414062 TI - A New Approach to Evidence Synthesis in Traumatic Brain Injury: A Living Systematic Review. AB - Living systematic reviews (LSRs) are online summaries of health care research that are updated as new research becomes available. This new development in evidence synthesis is being trialled as part of the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) project. We will develop and sustain an international TBI knowledge community that maintains up-to-date, high quality LSRs of the current state of knowledge in the most important questions in TBI. Automatic search updates will be run three monthly, and newly identified studies incorporated into the review. Review teams will seek to publish journal updates at regular intervals, with abridged updates available more frequently online. Future project stages include the integration of LSR and other study findings into "living" clinical practice guidance. It is hoped these efforts will go some way to bridging current temporal disconnects between evidence, guidelines, and practice in TBI. PMID- 26414063 TI - MIIB: A Metric to Identify Top Influential Bloggers in a Community. AB - Social networking has revolutionized the use of conventional web and has converted World Wide Web into the social web as users can generate their own content. This change has been possible due to social web platforms like forums, wikis, and blogs. Blogs are more commonly being used as a form of virtual communication to express an opinion about an event, product or experience and can reach a large audience. Users can influence others to buy a product, have certain political or social views, etc. Therefore, identifying the most influential bloggers has become very significant as this can help us in the fields of commerce, advertisement and product knowledge searching. Existing approaches consider some basic features, but lack to consider some other features like the importance of the blog on which the post has been created. This paper presents a new metric, MIIB (Metric for Identification of Influential Bloggers), based on various features of bloggers' productivity and popularity. Productivity refers to bloggers' blogging activity and popularity measures bloggers' influence in the blogging community. The novel module of BlogRank depicts the importance of blog sites where bloggers create their posts. The MIIB has been evaluated against the standard model and existing metrics for finding the influential bloggers using dataset from the real-world blogosphere. The obtained results confirm that the MIIB is able to find the most influential bloggers in a more effective manner. PMID- 26414066 TI - Kinetics of Ion Transport in Perovskite Active Layers and Its Implications for Active Layer Stability. AB - Solar cells fabricated using alkyl ammonium metal halides as light absorbers have the right combination of high power conversion efficiency and ease of fabrication to realize inexpensive but efficient thin film solar cells. However, they degrade under prolonged exposure to sunlight. Herein, we show that this degradation is quasi-reversible, and that it can be greatly lessened by simple modifications of the solar cell operating conditions. We studied perovskite devices using electrochemical impedance spectroscopy (EIS) with methylammonium (MA)-, formamidinium (FA)-, and MA(x)FA(1-x) lead triiodide as active layers. From variable temperature EIS studies, we found that the diffusion coefficient using MA ions was greater than when using FA ions. Structural studies using powder X ray diffraction (PXRD) show that for MAPbI3 a structural change and lattice expansion occurs at device operating temperatures. On the basis of EIS and PXRD studies, we postulate that in MAPbI3 the predominant mechanism of accelerated device degradation under sunlight involves thermally activated fast ion transport coupled with a lattice-expanding phase transition, both of which are facilitated by absorption of the infrared component of the solar spectrum. Using these findings, we show that the devices show greatly improved operation lifetimes and stability under white-light emitting diodes, or under a solar simulator with an infrared cutoff filter or with cooling. PMID- 26414065 TI - Late Presentation into Care of HIV Disease and Its Associated Factors in Asia: Results of TAHOD. AB - Many HIV-infected individuals do not enter health care until late in the infection course. Despite encouraging earlier testing, this situation has continued for several years. We investigated the prevalence of late presenters and factors associated with late presentation among HIV-infected patients in an Asian regional cohort. This cohort study included HIV-infected patients with their first positive HIV test during 2003-2012 and CD4 count and clinical status data within 3 months of that test. Factors associated with late presentation into care (CD4 count <200 cells/MUl or an AIDS-defining event within +/-3 months of first positive HIV test) were analyzed in a random effects logistic regression model. Among 3,744 patients, 2,681 (72%) were late presenters. In the multivariable model, older patients were more likely to be late presenters than younger (<=30 years) patients [31-40, 41-50, and >=51 years: odds ratio (OR) = 1.57, 95% confidence interval (CI) 1.31-1.88; OR = 2.01, 95% CI 1.58-2.56; and OR = 1.69, 95% CI 1.23-2.31, respectively; all p <= 0.001]. Injecting drug users (IDU) were more likely (OR = 2.15, 95% CI 1.42-3.27, p < 0.001) and those with homosexual HIV exposure were less likely (OR = 0.45, 95% CI 0.35-0.58, p < 0.001) to be late presenters compared to those with heterosexual HIV exposure. Females were less likely to be late presenters (OR = 0.44, 95% CI 0.36-0.53, p < 0.001). The year of first positive HIV test was not associated with late presentation. Efforts to reduce the patients who first seek HIV care at the late stage are needed. The identified risk factors associated with late presentation should be utilized in formulating targeted public health intervention to improve earlier entry into HIV care. PMID- 26414067 TI - Evidence-Based Structural Model of the Staphylococcal Repressor Protein: Separation of Functions into Different Domains. AB - Horizontal transfer of mobile genetic elements within Staphylococci is of high biomedical significance as such elements are frequently responsible for virulence and toxic effects. Staphylococcus-encoded repressor proteins regulate the replication of these mobile genetic elements that are located within the so called pathogenicity islands. Here, we report structural and functional characterization of one such repressor protein, namely the Stl protein encoded by the pathogenicity island SaPIbov1. We create a 3D structural model and based on this prediction, we investigate the different functionalities of truncated and point mutant constructs. Results suggest that a helix-turn-helix motif governs the interaction of the Stl protein with its cognate DNA site: point mutations within this motif drastically decrease DNA-binding ability, whereas the interaction with the Stl-binding partner protein dUTPase is unperturbed by these point mutations. The 3D model also suggested the potential independent folding of a carboxy-terminal domain. This suggestion was fully verified by independent experiments revealing that the carboxy-terminal domain does not bind to DNA but is still capable of binding to and inhibiting dUTPase. A general model is proposed, which suggests that among the several structurally different repressor superfamilies Stl-like Staphylococcal repressor proteins belong to the helix-turn helix transcription factor group and the HTH motif is suggested to reside within N-terminal segment. PMID- 26414068 TI - Modelling cephalopod-inspired pulsed-jet locomotion for underwater soft robots. AB - Cephalopods (i.e., octopuses and squids) are being looked upon as a source of inspiration for the development of unmanned underwater vehicles. One kind of cephalopod-inspired soft-bodied vehicle developed by the authors entails a hollow, elastic shell capable of performing a routine of recursive ingestion and expulsion of discrete slugs of fluids which enable the vehicle to propel itself in water. The vehicle performances were found to depend largely on the elastic response of the shell to the actuation cycle, thus motivating the development of a coupled propulsion-elastodynamics model of such vehicles. The model is developed and validated against a set of experimental results performed with the existing cephalopod-inspired prototypes. A metric of the efficiency of the propulsion routine which accounts for the elastic energy contribution during the ingestion/expulsion phases of the actuation is formulated. Demonstration on the use of this model to estimate the efficiency of the propulsion routine for various pulsation frequencies and for different morphologies of the vehicles are provided. This metric of efficiency, employed in association with the present elastodynamics model, provides a useful tool for performing a priori energetic analysis which encompass both the design specifications and the actuation pattern of this new kind of underwater vehicle. PMID- 26414069 TI - Traditional Cardiovascular Disease Risk Factor Management in Rheumatoid Arthritis Compared to Matched Nonrheumatoid Arthritis in a US Managed Care Setting. AB - OBJECTIVE: To compare traditional cardiovascular (CV) risk factor management among patients with rheumatoid arthritis (RA) to that of matched non-RA controls within a large US managed care setting. METHODS: Adult patients with RA and age- and sex-matched general population (general controls) or osteoarthritis (OA) controls were identified between January 1, 2007 and December 31, 2011. We compared health care utilization, measurement, treatment, and treatment target achievement of traditional CV risk factors among subgroups of CV comorbidity during 1 year of followup between RA and controls. RESULTS: A total of 9,440 RA patients, 31,009 general controls, and 10,352 OA controls were included. The proportions with measurements (blood pressure [BP], low-density lipoprotein [LDL] cholesterol, or hemoglobin A1c ), treatment (antihypertensive, statin, or anti diabetes mellitus medications), and treatment target achievement were slightly higher in patients with RA compared with general controls. Controlling for other factors, RA patients were more likely to have a measurement of BP (odds ratio [OR] 16.77 [95% confidence interval (95% CI) 10.01-28.08]) or LDL cholesterol (OR 1.25 [95% CI 1.13-1.39]), and to receive antihypertensive (OR 1.84 [95% CI 1.47 2.30]) or anti-diabetic medications (OR 1.26 [95% CI 1.01-1.56]) compared to general controls. RA was not associated with receiving a statin (OR 1.01 [95% CI 0.92-1.12]); however, a target LDL level was more likely to be achieved in RA compared to general controls (OR 1.27 [95% CI 1.17-1.37]) as well as target levels of BP and hemoglobin A1c . These results were consistent with results for OA controls except for a lower probability of receiving a statin in RA compared to OA. CONCLUSION: Traditional CV risk factors in patients with RA were not less aggressively managed compared to non-RA controls. PMID- 26414070 TI - CXCR2 Inhibition Combined with Sorafenib Improved Antitumor and Antiangiogenic Response in Preclinical Models of Ovarian Cancer. AB - Antiangiogenic therapy is important for the treatment of gynecological cancer. However, the therapeutic benefit derived from these treatments is transient, predominantly due to the selective activation of compensatory proangiogenic pathways that lead to rapid development of resistance. We aimed to identify and target potential alternative signaling to anti-vascular endothelial growth factor (VEGF) therapy, with a view toward developing a combination of antiangiogenic agents to provide extended therapeutic benefits. We developed a preclinical in vivo phenotypic resistance model of ovarian cancer resistant to antiangiogenic therapy. We measured dynamic changes in secreted chemokines and angiogenic signaling in tumors and plasma in response to anti-VEGF treatment, as tumors advanced from the initial responsive phase to progressive disease. In tumors that progressed following sorafenib treatment, gene and protein expression levels of proangiogenic CXC chemokines and their receptors were significantly elevated, compared with responsive tumors. The chemokine (C-X-C motif) ligand 8 (CXCL8), also known as interleukin-8 (IL-8) increase was time-dependent and coincided with the dynamics of tumor progression. We used SB225002, a pharmacological inhibitor of chemokine (C-X-C motif) receptor 2 (CXCR2), to disrupt the CXC chemokine mediated functions of ovarian cancer cells in in vitro assays of cell growth inhibition, spheroid formation, and cell migration. The combination of CXCR2 inhibitor with sorafenib led to a synergistic inhibition of cell growth in vitro, and further stabilized tumor progression following sorafenib in vivo. Our results suggest that CXCR2-mediated chemokines may represent an important compensatory pathway that promotes resistance to antiangiogenic therapy in ovarian cancer. Thus, simultaneous blockage of this proangiogenic cytokine pathway using CXCR2 inhibitors and the VEGF receptor (VEGFR) pathway could improve the outcomes of antiangiogenic therapy. PMID- 26414072 TI - Prediction of Pulmonary Arterial Hypertension in Chronic Obstructive Lung Disease from Three-Dimensional Vectorcardiographic Parameters. AB - AIM: The objective of our study was to assess diagnostic value of three dimensional (3D) vectorcardiographic (VCG) parameters in detecting pulmonary arterial hypertension (PAH) in chronic obstructive lung disease (COLD) with and without right ventricular hypertrophy (RVH). METHODS: The study group of 62 patients with COPD was stratified on the basis of color Doppler echocardiographic findings into three subgroups: non-PAH (n = 23), PAH without RVH (n = 22), and PAH with RVH (n = 17). Pairwise differences between the subgroups were evaluated by one-way analysis of variance, and Pearson correlation analysis was used to evaluate the significance of the correlations between pulmonary arterial systolic pressure (PASP) and various VCG parameters. RESULTS: The azimuth of the QRS vector decreased from -24 degrees in the non-PAH group to -62 degrees in PAH without RVH and to -140 degrees in PAH with RVH (P < 0.01 for pairwise differences between all three groups). Similar significant decrease was observed for the azimuth of the ventricular gradient (VG) vector. Spatial QRS/T angle increased from 69 degrees in the non-PAH group to 115 degrees in PAH without RVH (P < 0.01). In the PAH group with RVH, QRS/T angle was 94 degrees (P < 0.05 for difference from the non-PAH group). There was a significant correlation between PASP and QRS/T angle (r = 0.89, P < 0.05) and between PASP and the azimuth of the VG vector (r = 0.86, P < 0.05). PASP increase from linear regression model was 0.8 mmHg for a QRS/T angle increase by 10 degrees and 1.3 mmHg for each 10 degrees increase in the azimuth of the VG vector. CONCLUSION: 3DVCG parameters are potentially useful for predicting PASP in COLD patients, and possibly also for differentiation between COLD patients with PAH and RVH from those without RVH. PMID- 26414071 TI - 2-Fluoro-L-Fucose Is a Metabolically Incorporated Inhibitor of Plant Cell Wall Polysaccharide Fucosylation. AB - The monosaccharide L-fucose (L-Fuc) is a common component of plant cell wall polysaccharides and other plant glycans, including the hemicellulose xyloglucan, pectic rhamnogalacturonan-I (RG-I) and rhamnogalacturonan-II (RG-II), arabinogalactan proteins, and N-linked glycans. Mutations compromising the biosynthesis of many plant cell wall polysaccharides are lethal, and as a result, small molecule inhibitors of plant cell wall polysaccharide biosynthesis have been developed because these molecules can be applied at defined concentrations and developmental stages. In this study, we characterize novel small molecule inhibitors of plant fucosylation. 2-fluoro-L-fucose (2F-Fuc) analogs caused severe growth phenotypes when applied to Arabidopsis seedlings, including reduced root growth and altered root morphology. These phenotypic defects were dependent upon the L-Fuc salvage pathway enzyme L-Fucose Kinase/ GDP-L-Fucose Pyrophosphorylase (FKGP), suggesting that 2F-Fuc is metabolically converted to the sugar nucleotide GDP-2F-Fuc, which serves as the active inhibitory molecule. The L-Fuc content of cell wall matrix polysaccharides was reduced in plants treated with 2F-Fuc, suggesting that this molecule inhibits the incorporation of L-Fuc into these polysaccharides. Additionally, phenotypic defects induced by 2F Fuc treatment could be partially relieved by the exogenous application of boric acid, suggesting that 2F-Fuc inhibits RG-II biosynthesis. Overall, the results presented here suggest that 2F-Fuc is a metabolically incorporated inhibitor of plant cellular fucosylation events, and potentially suggest that other 2 fluorinated monosaccharides could serve as useful chemical probes for the inhibition of cell wall polysaccharide biosynthesis. PMID- 26414074 TI - The influence of injection speed on pain during injection of local anaesthetic. AB - STUDY OBJECTIVE: To determine the influence of injection speed on pain during injection of local anaesthetics. METHODS: In a blinded randomised study with 36 healthy volunteers, each volunteer received three injections of 4.5 ml lidocaine subcutaneously on the abdomen. The injections were given during 15 seconds (0.3 ml/s), 30 seconds (0.15 ml/s), and 45 seconds (0.1 ml/s). The needle tip remained beneath the skin for 45 seconds during all three injections. Participants rated the pain experienced on a 100 mm visual analogue scale (VAS) immediately after each injection. After the last injection, they were asked which injections were the least and most painful. RESULTS: The mean VAS pain score for the 15 seconds injections was 26 (SD = 19), for the 30 seconds injections 24 (SD = 19), and for the 45 seconds injections also 24 (SD = 18) (ns). Eight subjects preferred the 15 seconds injection, 15 preferred the 30 seconds injection, and 10 preferred the 45 seconds injection (ns). CONCLUSION: It is concluded that varying the injection speed between 0.3 ml/s and 0.1 ml/s has no influence on the pain experienced during subcutaneous injection of 4.5 ml lidocaine. PMID- 26414073 TI - Genome Filtering for New DNA Biomarkers of Loa loa Infection Suitable for Loop Mediated Isothermal Amplification. AB - Loa loa infections have emerged as a serious public health problem in patients co infected with Onchocerca volvulus or Wuchereria bancrofti because of severe adverse neurological reactions after treatment with ivermectin. Accurate diagnostic tests are needed for careful mapping in regions where mass drug administration is underway. Loop-mediated isothermal amplification (LAMP) has become a widely adopted screening method because of its operational simplicity, rapidity and versatility of visual detection readout options. Here, we present a multi-step bioinformatic pipeline to generate diagnostic candidates suitable for LAMP and experimentally validate this approach using one of the identified candidates to develop a species-specific LAMP assay for L. loa. The pipeline identified ~140 new L. loa specific DNA repeat families as putative biomarkers of infection. The consensus sequence of one family, repeat family 4 (RF4), was compiled from ~ 350 sequences dispersed throughout the L. loa genome and maps to a L. loa-specific region of the long terminal repeats found at the boundaries of Bel/Pao retrotransposons. PCR and LAMP primer sets targeting RF4 specifically amplified L. loa but not W. bancrofti, O. volvulus, Brugia malayi, human or mosquito DNA. RF4 LAMP detects the DNA equivalent of one microfilaria (100 pg) in 25-30 minutes and as little as 0.060 pg of L. loa DNA (~1/1600th of a microfilaria) purified from spiked blood samples in approximately 50 minutes. In summary, we have successfully employed a bioinformatic approach to mine the L. loa genome for species-specific repeat families that can serve as new DNA biomarkers for LAMP. The RF4 LAMP assay shows promise as a field tool for the implementation and management of mass drug administration programs and warrants further testing on clinical samples as the next stage in development towards this goal. PMID- 26414076 TI - Fecal microbiota transplantation in gastrointestinal disease: 2015 update and the road ahead. AB - At its height, the Clostridium difficile infection epidemic caused approximately 7000 infections and 300 deaths per day in the USA. Fecal microbiota transplantation (FMT) has demonstrated extraordinary clinical resolution, C. difficile infection cure rates of over 90%, and low recurrence. In tandem with the rise of FMT, the gastrointestinal microbiome has emerged as a 'vital' organ armed with a wealth of microbe 'soldiers' more powerful than known antibiotics. FMTs' reputation has diffused into many new 'indications' yet these appear to be merely the tip of the iceberg when considering its potential applications. FMT as a therapeutic tool has evolved from the original format of blended donor stool and moved towards a refined product comprising a myriad of microbial components, presented aesthetically as encapsulated lyophilized powder. PMID- 26414079 TI - Systemic lupus erythematosus, bone health, and osteoporosis. AB - PURPOSE OF REVIEW: This manuscript will provide a review of recent publications, examining the correlation of systemic lupus erythematosus (SLE) with changes in bone health and associated osteoporosis, highlighting prevalence, etiology, diagnosis, and treatment. RECENT FINDINGS: Studies suggest that bone loss and fractures are associated with SLE, related not only to the disease itself, but also with low vitamin D and treatment side-effects. Understanding the mechanisms of glucocorticoids on bone and the immunologic relationship of vitamin D, as well as recognizing the role of chronic inflammation on bone, allows for better understanding of skeletal side-effects. Further awareness of the association of poor bone health has led to an increased need for prevention and treatment. New imaging and treatment are emerging, although not recommended currently. SUMMARY: Loss of bone density culminating in osteoporosis and fracture is a frequent comorbidity in SLE patients at any age and is multifactorial in etiology. Awareness and diagnosis is crucial because of its prevalence and morbidity. Prevention is safe and effective in this high-risk population where diagnostic measures and interventions are underutilized and guidelines are lacking. PMID- 26414077 TI - Middle East respiratory syndrome: current status and future prospects for vaccine development. AB - The outbreaks of Middle East respiratory syndrome (MERS) previously in Middle East and recently in South Korea have raised serious concerns worldwide, reinforcing the importance of developing effective and safe vaccines against MERS coronavirus (MERS-CoV). A number of vaccine candidates have been developed on the basis of viral vectors, recombinant proteins, DNAs, nanoparticles, and recombinant MERS-CoV, and some of them have shown efficacy in laboratory animals. However, the paucity of financial support has made it difficult to transfer effective candidates from the preclinical stage to clinical trials. Here, we summarize currently available MERS vaccine candidates and illustrate strategies for future development, with the aim of provoking government agencies and Big Pharma to invest more funds for developing efficacious and safe MERS vaccines. PMID- 26414080 TI - Vitamin D and anemia: insights into an emerging association. AB - PURPOSE OF REVIEW: The current review highlights recent findings in the emerging association between vitamin D and anemia through discussion of mechanistic studies, epidemiologic studies, and clinical trials. RECENT FINDINGS: Vitamin D has previously been found to be associated with anemia in various healthy and diseased populations. Recent studies indicate that the association may differ between race and ethnic groups and is likely specific to anemia of inflammation. The mechanism underlying this association involves the reduction of proinflammatory cytokines by vitamin D and the direct suppression of hepcidin mRNA transcription. There is also evidence that vitamin D may be protective against anemia by supporting erythropoiesis. Other calciotropic hormones including fibroblast growth factor 23, and parathyroid hormone have also been found to be associated with iron homeostasis and erythropoiesis. SUMMARY: Recent advances in our understanding of the association between vitamin D and anemia suggest that maintenance of sufficient vitamin D status may be important in preventing anemia, particularly in diseases characterized by inflammation. Early clinical trials have been promising, but further research is needed to define the efficacy of vitamin D as a future approach for the treatment of anemia. PMID- 26414081 TI - Bone loss in HIV: a contemporary review. AB - PURPOSE OF REVIEW: Because of antiretroviral therapy (ART), people are living with HIV infection longer than ever before. As this patient group ages, it is expected that medical comorbidities such as osteoporosis and fragility fractures will increase. The purpose of this review is to address the epidemiology and what is known regarding the pathogenesis of bone loss in people living with HIV infection with a focus on recently published literature. RECENT FINDINGS: HIV infected individuals are at increased risk for low bone mineral density and bone fractures. The cause of bone loss in HIV is multifactorial including traditional risk factors some of which disproportionately affect HIV-infected individuals and alterations in bone metabolism due to ART, HIV viral proteins and chronic inflammation. Lifestyle modification, changing ART, calcium and vitamin D supplementation and pharmacologic treatment for osteoporosis may all be employed to abrogate bone loss in this patient group. SUMMARY: Clinicians should be aware of the contributors to bone loss in people living with HIV in order to recognize high-risk individuals and to take appropriate steps to address modifiable risk factors to prevent future fracture. PMID- 26414082 TI - Skeletal muscle and pediatric bone development. AB - PURPOSE OF REVIEW: The purpose of this review is to summarize the recent clinical findings surrounding the muscle-bone relationships in children, while considering muscle adiposity, endocrine factors, and lifestyle influences (i.e., diet and exercise) involved in pediatric musculoskeletal development. RECENT FINDINGS: Positive relationships between cortical bone geometry and muscle mass, size and function have been reported. Prospective studies in particular have helped clarify some of the inconsistent relationships between muscle and cortical bone volumetric density. Muscle fat is associated with impaired glucose handling and muscular functionality, which may in turn have a downstream effect on cortical bone growth during adolescence. Lifestyle factors such as healthful diets and higher impact physical activities can promote optimal skeletal development by improving the muscular phenotype and endocrine profile. SUMMARY: Muscle and bone are two intricately-related tissue types; however, factors such as sex, maturation, study design, and outcome measures studied can modify this relationship. Further research is warranted to understand the impact of muscle adiposity on cardiometabolic health, muscle function and, subsequently, pediatric musculoskeletal development and fracture risk. Following age-specific diet and physical activity recommendations should be a major focus in obtaining optimal muscle and bone development throughout maturation. PMID- 26414083 TI - Self-Healing Supramolecular Self-Assembled Hydrogels Based on Poly(L-glutamic acid). AB - Self-healing polymeric hydrogels have the capability to recover their structures and functionalities upon injury, which are extremely attractive in emerging biomedical applications. This research reports a new kind of self-healing polypeptide hydrogels based on self-assembly between cholesterol (Chol)-modified triblock poly(L-glutamic acid)-block-poly(ethylene glycol)-block-poly(L-glutamic acid) ((PLGA-b-PEG-b-PLGA)-g-Chol) and beta-cyclodextrin (beta-CD)-modified poly(L-glutamic acid) (PLGA-g-beta-CD). The hydrogel formation relied on the host and guest linkage between beta-CD and Chol. This study demonstrates the influences of polymer concentration and beta-CD/Chol molar ratio on viscoelastic behavior of the hydrogels. The results showed that storage modulus was highest at polymer concentration of 15% w/v and beta-CD/Chol molar ratio of 1:1. The effect of the PLGA molecular weight in (PLGA-b-PEG-b-PLGA)-g-Chol on viscoelastic behavior, mechanical properties and in vitro degradation of the supramolecular hydrogels was also studied. The hydrogels showed outstanding self-healing capability and good cytocompatibility. The multilayer structure was constructed using hydrogels with self-healing ability. The developed hydrogels provide a fascinating glimpse for the applications in tissue engineering. PMID- 26414084 TI - Long-Term Function of Alginate-Encapsulated Islets. AB - Human trials have demonstrated the feasibility of alginate-encapsulated islet cells for the treatment of type 1 diabetes. Encapsulated islets can be protected from the host's immune system and remain viable and functional following transplantation. However, the long-term success of these therapies requires that alginate microcapsules maintain their immunoprotective capacity and stability in vivo for sustained periods. In part, as a consequence of different encapsulation strategies, islet encapsulation studies have produced inconsistent results in regard to graft functioning time, stability, and overall metabolic benefits. Alginate composition (proportion of M- and G-blocks), alginate purity, the cross linking ions (calcium or barium), and the presence or absence of additional polymer coating layers influence the success of cell encapsulation. This review summarizes the outcomes of long-term studies of alginate-encapsulated islet transplants in animals and humans and provides a critical discussion of the graft failure mechanisms, including issues with graft biocompatibility, transplantation site, and integrity of the encapsulated islet grafts. Strategies to improve the mechanical stability of alginate capsules and methods for monitoring graft survival and function in vivo are presented. PMID- 26414085 TI - The health benefits of reducing air pollution in Sydney, Australia. AB - Among industrialised countries, fine particle (PM2.5) and ozone levels in the Sydney metropolitan area of Australia are relatively low. Annual mean PM2.5 levels have historically remained below 8 MUg/m(3) while warm season (November March) ozone levels occasionally exceed the Australian guideline value of 0.10 ppm (daily 1 h max). Yet, these levels are still below those seen in the United States and Europe. This analysis focuses on two related questions: (1) what is the public health burden associated with air pollution in Sydney; and (2) to what extent would reducing air pollution reduce the number of hospital admissions, premature deaths and number of years of life lost (YLL)? We addressed these questions by applying a damage function approach to Sydney population, health, PM2.5 and ozone data for 2007 within the BenMAP-CE software tool to estimate health impacts and economic benefits. We found that 430 premature deaths (90% CI: 310-540) and 5800 YLL (95% CI: 3900-7600) are attributable to 2007 levels of PM2.5 (about 2% of total deaths and 1.8% of YLL in 2007). We also estimate about 630 (95% CI: 410-840) respiratory and cardiovascular hospital admissions attributable to 2007 PM2.5 and ozone exposures. Reducing air pollution levels by even a small amount will yield a range of health benefits. Reducing 2007 PM2.5 exposure in Sydney by 10% would, over 10 years, result in about 650 (95% CI: 430 850) fewer premature deaths, a gain of 3500 (95% CI: 2300-4600) life-years and about 700 (95% CI: 450-930) fewer respiratory and cardiovascular hospital visits. These results suggest that substantial health benefits are attainable in Sydney with even modest reductions in air pollution. PMID- 26414086 TI - Direct Comparison of Wharton's Jelly and Bone Marrow-Derived Mesenchymal Stromal Cells to Enhance Engraftment of Cord Blood CD34(+) Transplants. AB - Cotransplantation of CD34(+) hematopoietic stem and progenitor cells (HSPCs) with mesenchymal stromal cells (MSCs) enhances HSPC engraftment. For these applications, MSCs are mostly obtained from bone marrow (BM). However, MSCs can also be isolated from the Wharton's jelly (WJ) of the human umbilical cord. This source, regarded to be a waste product, enables a relatively low-cost MSC acquisition without any burden to the donor. In this study, we evaluated the ability of WJ MSCs to enhance HSPC engraftment. First, we compared cultured human WJ MSCs with human BM-derived MSCs (BM MSCs) for in vitro marker expression, immunomodulatory capacity, and differentiation into three mesenchymal lineages. Although we confirmed that WJ MSCs have a more restricted differentiation capacity, both WJ MSCs and BM MSCs expressed similar levels of surface markers and exhibited similar immune inhibitory capacities. Most importantly, cotransplantation of either WJ MSCs or BM MSCs with CB CD34(+) cells into NOD SCID mice showed similar enhanced recovery of human platelets and CD45(+) cells in the peripheral blood and a 3-fold higher engraftment in the BM, blood, and spleen 6 weeks after transplantation when compared to transplantation of CD34(+) cells alone. Upon coincubation, both MSC sources increased the expression of adhesion molecules on CD34(+) cells, although stromal cell-derived factor-1 (SDF 1)-induced migration of CD34(+) cells remained unaltered. Interestingly, there was an increase in CFU-GEMM when CB CD34(+) cells were cultured on monolayers of WJ MSCs in the presence of exogenous thrombopoietin, and an increase in BFU-E when BM MSCs replaced WJ MSCs in such cultures. Our results suggest that WJ MSC is likely to be a practical alternative for BM MSC to enhance CB CD34(+) cell engraftment. PMID- 26414087 TI - Societal costs of diabetes mellitus in Denmark. AB - AIM: To provide comprehensive real-world evidence on societal diabetes attributable costs in Denmark. METHODS: National register data are linked on an individual level through unique central personal registration numbers in Denmark. All patients in the Danish National Diabetes Register in 2011 (N = 318 729) were included in this study. Complication status was defined according to data from the Danish National Hospital Register. Diabetes-attributable costs were calculated as the difference between costs of patients with diabetes and the expected costs given the annual resource consumption of the diabetes-free population. RESULTS: Societal costs attributable to diabetes were estimated to be at least 4.27 billion EUR in 2011, corresponding to 14,349 EUR per patient-year. A twofold higher healthcare resource usage was found for patients with diabetes as compared with the diabetes-free population. Attributable costs, grouped according to different components, were 732 million EUR for primary and secondary care services, 153 million EUR for pharmaceutical drugs, 851 million EUR for nursing services, 1.77 billion EUR in lost productivity and 761 million EUR for additional costs. A steep increase in diabetes-attributable costs was found for patients with major complications compared with patients without complications across all cost components. For attributable healthcare costs this increase was estimated to be 6,992 EUR per person-year after controlling for potential confounders. CONCLUSIONS: Nearly half of the total costs of patients with diabetes can be attributed directly to their diabetes. The majority of costs are incurred among patients with major complications pointing to the importance of secondary preventive efforts among patients with diabetes. PMID- 26414088 TI - Halogenated quinolines discovered through reductive amination with potent eradication activities against MRSA, MRSE and VRE biofilms. AB - Small molecules capable of eradicating non-replicating bacterial biofilms are of great importance to human health as conventional antibiotics are ineffective against these surface-attached bacterial communities. Here, we report the discovery of several halogenated quinolines (HQs) identified through a reductive amination reaction that demonstrated potent eradication of MRSA (HQ-6; MBEC = 125 MUM), MRSE (HQ-3; MBEC = 3.0 MUM) and VRE (HQ-4, HQ-5 and HQ-6; MBEC = 1.0 MUM) biofilms. HQs were evaluated using the Calgary Biofilm Device (CBD) and demonstrated near equipotent killing activities against planktonic and biofilm cells based on MBC and MBEC values. When tested against red blood cells, these HQ analogues demonstrated low haemolytic activity (3 to 21% at 200 MUM) thus we conclude that these HQ analogues do not operate primarily through the destruction of bacterial membranes, typical of other biofilm-eradicating agents (i.e., antimicrobial peptides). HQ antibacterial agents are potent biofilm-eradicating compounds and could lead to useful treatments for biofilm-associated bacterial infections. PMID- 26414089 TI - Group Visits to Improve Pediatric Attention-Deficit Hyperactivity Disorder Chronic Care Management. AB - OBJECTIVE: Children with attention-deficit hyperactivity disorder (ADHD) may experience continued impairment at home and school even after medication initiation. Group visits offer a way for pediatricians to provide more time to address ongoing needs. A pilot study was undertaken to examine whether a group visit model improved ADHD management in the pediatric medical home. METHODS: Parents and children aged 6 to 18 years with ADHD were recruited and randomized to group visits or a usual care control. Data included attendance at ADHD follow up visits, parent-rated ADHD symptoms, adaptive functioning, and quality of life. Longitudinal linear mixed models (continuous variables) and generalized linear mixed models (binary outcomes) were used to compare groups. In our statistical models, child and family were random effects; study assignment was a fixed effect. RESULTS: Twenty families representing 29 children participated (intervention: 9 parents/13 children and control: 11 parents/16 children). Aside from race, baseline characteristics of participants were similar. None of the intervention families missed the expected 5 ADHD follow-up visits over 1 year; control families missed 1 or more visits over the same period. Intervention families reported an improved level of adaptive functioning at 12 months compared with control (mean severity score: 3.7 vs 4.4, p = .003). All families reported greater limitations and poorer quality of life compared with national norms. CONCLUSION: Group visits in the pediatric medical home can improve adherence, and preliminary results show a variety of improvements for the family. PMID- 26414090 TI - Examining Parents' Experiences and Information Needs Regarding Early Identification of Developmental Delays: Qualitative Research to Inform a Public Health Campaign. AB - OBJECTIVE: The purpose of this study was to assess the approach and materials of Centers for Disease Control and Prevention's "Learn the Signs. Act Early." (LTSAE) health education campaign, which aims to improve awareness of developmental milestones and early warning signs of developmental delay among parents of young children. METHODS: We conducted 2 phases of qualitative research. Focus groups assessed the campaign's objectives by exploring the experiences of parents with children who have developmental delays or disabilities to determine facilitators of and barriers to identification. In depth interviews were conducted with parents of typically developing children, who reviewed campaign materials and provided feedback on appropriateness, appeal, and clarity with regard to the campaign's objectives. RESULTS: Phase 1: Parents were typically the first to express concern about their child's development, and most talked with their child's health care provider. Two categories of health care providers emerged: those who proactively asked about a child's development, used tools to facilitate conversations, and made referrals, and those who did not ask about development, told parents to "wait and see," and did not provide information about services and supports. Few parents knew about special education services before identification. Phase 2: Participants found the campaign materials appealing, but were unclear about how to act early and why acting early was important. CONCLUSIONS: Results affirmed LTSAE's evidence-based approach to educating parents about child development. Additional campaign considerations include providing more information about how to act early and why acting early is important and enhancing outreach to providers to help them communicate with concerned parents. PMID- 26414091 TI - Bringing Innovation to Attention-Deficit Hyperactivity Disorder Care. PMID- 26414092 TI - Towards a Critical Reframing of Early Detection and Intervention for Developmental Concerns. PMID- 26414093 TI - Detection of Growth Hormone Deficiency in Adults with Chronic Traumatic Brain Injury. AB - This study examined the prevalence of growth hormone deficiency (GHD) in patients with traumatic brain injury (TBI) during the post-acute phase of recovery and whether GHD was associated with increased disability, decreased independence, and depression. A secondary objective was to determine the accuracy of insulin-like growth factor-1 (IGF-1) levels in predicting GHD in patients with TBI. Anterior pituitary function was assessed in 235 adult patients with TBI through evaluation of fasting morning hormone levels. GH levels were assessed through provocative testing, specifically the glucagon stimulation test. GHD was diagnosed in a significant number of patients, with 45% falling into the severe GHD (<=3 MUg/L) category. IGF-1 levels were not predictive of GHD. Patients with GHD were more disabled and less independent compared with those patients who were not GHD. Those patients with more severe GHD also showed decreased levels of cortisol and testosterone. Symptoms of depression were also more prevalent in this group. In addition, patients with severe GHD had delayed admission to post-acute rehabilitation. This study confirms the high prevalence of GHD in patients with TBI and the necessity to monitor clinical symptoms and perform provocative testing to definitively diagnose GHD. PMID- 26414094 TI - Subjective acceleration of time experience in everyday life across adulthood. AB - Most people believe that time seems to pass more quickly as they age. Building on assumptions of socioemotional selectivity theory, we investigated whether awareness that one's future lifetime is limited is associated with one's experience of time during everyday activities across adulthood in 3 studies. In the first 2 studies (Study 1: N = 608; Study 2: N = 398), participants completed a web-based version of the day reconstruction method. In Study 3 (N = 392) participants took part in a newly developed tomorrow construction method, a web based experimental method for assessing everyday life plans. Results confirmed that older adults' subjective interpretation of everyday episodes is that these episodes pass more quickly compared with younger adults. The subjective acceleration of time experience in old age was more pronounced during productive activities than during regenerative-consumptive activities. The age differences were partly related to limited time remaining in life. In addition, subjective acceleration of time experience was associated with positive evaluations of everyday activities. Findings suggest that subjective acceleration of time in older adults' daily lives reflects an adaptation to limitations in time remaining in life. (PsycINFO Database Record PMID- 26414095 TI - Figuring out function: Children's and adults' use of ownership information in judgments of artifact function. AB - Across 3 experiments, we found evidence that information about who owns an artifact influenced 5- to 10-year-old children's and adults' judgments about that artifact's primary function. Children's and adults' use of ownership information was underpinned by their inference that owners are typically familiar with owned artifacts and are therefore likely to know their primary functions. Accordingly, when this inference was undermined-when an artifact's owner was said to be unfamiliar with the owned artifact-ownership was no longer used as a privileged heuristic cue to artifact function. These experiments also revealed age-related differences in how ownership information was prioritized relative to another well studied source of information known to influence artifact cognition, namely, information about an artifact's original designer-intended function. Specifically, older children and adults were more likely than younger children to prioritize design information over ownership information. Our results suggest that children and adults differ in how they weight the relative importance of these 2 sources of function-relevant information-likely reflecting age-related changes in children's and adults' sensitivity to ownership and design information across development. (PsycINFO Database Record PMID- 26414096 TI - Longitudinal bidirectional relations between adolescents' sympathy and prosocial behavior. AB - Despite the importance of understanding sympathy and prosocial behaviors, research on the development of these tendencies in adolescence remains relatively sparse. In the present study, we examined age trends and bidirectional longitudinal relations in sympathy and prosocial behaviors across early to middle adolescents. Participants were 500 12-year-olds at Time 1 (52% girls, 70% European American) who completed measures of sympathy and prosocial behaviors at 5 different time points, each approximately 1 year apart. Results showed significant bidirectional relations between sympathy and prosocial behaviors across all time points, and an initial decrease of prosocial behaviors followed by an increase into middle adolescence. The implications for prosocial developmental theories and research are discussed. (PsycINFO Database Record PMID- 26414097 TI - Costs and benefits of children's physical and relational aggression trajectories on peer rejection, acceptance, and friendships: Variations by aggression subtypes, gender, and age. AB - This study examined the associations between children's co-occurring relational and physical aggression trajectories and their peer relations (i.e., peer rejection, peer acceptance, and reciprocated friendships) from late childhood (Grade 4; Mage = 10.0) to early adolescence (Grade 8; Mage = 13.9). Using a sample of 477 children (240 girls), the findings indicated there were multiple heterogeneous subgroups of children who followed distinct co-occurring aggression trajectories. For each of these subgroups, multiple indices of their relational development were assessed and findings revealed notable group differences. These results have implications about the potential costs and benefits of aggression, and how its associations with children's peer relationships may vary as a function of aggression subtype, developmental timing, and gender. PMID- 26414098 TI - Increased expression of E3 ubiquitin ligases targeting p53 in CLL patients with wild-type TP53 exhibits associations with clinical features of the disease. PMID- 26414099 TI - Bond-Selective and Mode-Specific Dissociation of CH3D and CH2D2 on Pt(111). AB - Infrared laser excitation of partially deuterated methanes (CH3D and CH2D2) in a molecular beam is used to control their dissociative chemisorption on a Pt(111) single crystal and to determine the quantum state-resolved dissociation probabilities. The exclusive detection of C-H cleavage products adsorbed on the Pt(111) surface by infrared absorption reflection spectroscopy indicates strong bond selectivity for both methane isotopologues upon C-H stretch excitation. Furthermore, the dissociative chemisorption of both methane isotopologues is observed to be mode-specific. Excitation of symmetric C-H stretch modes produces a stronger reactivity increase than excitation of the antisymmetric C-H stretch modes, whereas bend overtone excitation has a weaker effect on reactivity. The observed mode specificity and bond selectivity are rationalized by the sudden vector projection model in terms of the overlap of the reactant's normal mode vectors with the reaction coordinate at the transition state. PMID- 26414100 TI - Hepatitis B virus surface antibody titers in babies administered hepatitis B immune globulin both intravenously and intramuscularly after birth. AB - OBJECTIVE: High rates of vertical transmission of hepatitis B virus (HBV) infection from carrier mothers to their babies are observed in hepatitis B e antigen (HBeAg)-positive mothers under the existing protocol. The current status suggests that the existing protocol may be insufficient for the prevention of mother-to-child transmission (MTCT) in HBeAg-positive mothers. To achieve complete prevention of HBV vertical transmission, we designed a protocol implementing intravenous administration along with ordinary intramuscular administration of HBV immune globulin (HBIG) to the baby after birth. METHODS: We compared the HBV surface antibody (HBsAb) titer in babies who were simultaneously administered HBIG both intravenously and intramuscularly after birth with that in babies who received HBIG only intramuscularly. RESULTS: The HBsAb titer rose rapidly after administration in the combined administration group, and the elevated titer was maintained for approximately 2 months. Although the antibody titer at the peak was nearly 6 times greater in the combined administration group than in the intramuscular administration group, the combined administration of HBIG did not have any effect on total IgG antibody levels in the bloodstream. CONCLUSION: The combined protocol was demonstrated to be safe and superior to the protocol of only intramuscular HBIG administration with respect to rapid elevation of HBsAb in the bloodstream. It could be an effective method for the prevention of MTCT in HBeAg-positive mothers. PMID- 26414101 TI - Tissue-Engineered Microvasculature to Reperfuse Isolated Renal Glomeruli. AB - Kidney transplantation is often the most effective therapy for end-stage renal disease, but there are not enough donor organs to meet the rising demand. Tissue engineering of kidneys is a potential solution to this organ shortage. Achieving microvascular perfusion has been a major barrier to engineering tissues beyond thin muscularized sheets such as the bladder wall. Our laboratory has previously reported that human umbilical vein endothelial cells (ECs) transduced with the antiapoptotic protein Bcl-2 will spontaneously organize into perfused microvessels within type I collagen gels when implanted in immunodeficient mice. To test if this system can be used to perfuse more complex structures, we combined Bcl-2-transduced ECs (Bcl-2-ECs) with renal glomeruli, the specialized vascular filtration units of the kidney. Microdissected green fluorescent protein expressing rat glomeruli suspended in type I collagen gels were implanted within immunodeficient mice with or without the inclusion of Bcl-2-ECs. Survival of rat glomeruli was enhanced by coimplantation with Bcl-2-ECs. Intravital rhodamine dextran injections demonstrated that surviving glomeruli were perfused through Bcl-2-EC-derived microvessels. Perfused glomeruli maintained podocin staining, but transmission electron microscopy revealed endothelial swelling and podocyte foot process effacement. Anastomosis of microvessels derived from Bcl-2-ECs with glomerular capillaries provides proof of concept that self-assembled microvessels can perfuse specialized organ structures such as glomeruli, but that perfusion alone may be insufficient to maintain normal structure. PMID- 26414102 TI - Lyme borreliosis: reviewing potential vaccines, clinical aspects and health economics. AB - Lyme borreliosis (LB) is a multisystem infectious disease with a growing burden in many parts of North America, Asia and Europe. Persistent infection of LB can usually be treated effectively with antibiotic therapy, but it may be followed by post-treatment Lyme disease syndrome. Therefore, it is important to begin with treatment in the early phase of the disease. Vaccination shows potential as the most effective way of preventing LB and reducing its burden in these continents. It is concluded that there is a need for continuous effort in research from all perspectives on LB, especially regarding prevention with novel vaccines, their development, clinical efficacy and cost-effectiveness. This review may help to further develop (cost-) effective strategies for prevention and control of the disease to reduce its burden and achieve population-wide health benefits. PMID- 26414103 TI - Hemispheric specialization of impaired disengagement of attention in depression: a tachistoscopic method. AB - Difficulty shifting attention away from negative stimuli once engaged is a well established cognitive bias observed in depression. This study attempted to determine whether this impaired disengagement of attention is lateralized in the brain. Thirty depressed and 30 control participants performed an attention disengagement task wherein the valence of the stimulus and the visual field was presented. The depressed group had longer reaction times than the control group, indicative of the typical cognitive and psychomotor slowing seen in depression. The effect of visual field presentation on the ability to disengage attention however was different for controls as compared to the patients. In controls, a distinct right hemisphere advantage was seen for disengaging attention which is in line with research that has identified right hemisphere structures as the seat of behavioural inhibition. In the depressed group, however, this right hemisphere advantage was not observed. PMID- 26414104 TI - Controlled Directional Crystallization of Oligothiophenes Using Zone Annealing of Preseeded Thin Films. AB - We demonstrate a simple route to directionally grow crystals of oligothiophenes, based on 2,5-bis(3-alkylthiophen-2-yl)thieno[3,2-b]thiophene with degrees of polymerization of 2 (BTTT-2) and 4 (BTTT-4) via zone annealing (ZA) of preseeded films. ZA of spun-cast films of BTTT-2 does not yield highly aligned crystals. However, if the film is oven-annealed briefly prior to ZA, highly aligned crystals that are millimeters in length can be grown, whose length depends on the velocity of the ZA front. The precrystallized region provides existing nuclei that promote crystal growth and limit nucleation of new crystals in the melted region. Aligned crystals of BTTT-2 can be obtained even when the moving velocity for ZA is an order of magnitude greater than the crystal growth rate. The relative nucleation rate to the crystallization rate for BTTT-4 is greater than that for BTTT-2, which decreases the length over which BTTT-4 can be aligned to ~500 MUm for the conditions examined. The temperature gradient and moving velocity of ZA enable control of the length of the aligned crystalline structure at the macroscale. PMID- 26414105 TI - Antimicrobial use in swine production and its effect on the swine gut microbiota and antimicrobial resistance. AB - Antimicrobials have been used in swine production at subtherapeutic levels since the early 1950s to increase feed efficiency and promote growth. In North America, a number of antimicrobials are available for use in swine. However, the continuous administration of subtherapeutic, low concentrations of antimicrobials to pigs also provides selective pressure for antimicrobial-resistant bacteria and resistance determinants. For this reason, subtherapeutic antimicrobial use in livestock remains a source of controversy and concern. The swine gut microbiota demonstrates a number of changes in response to antimicrobial administration depending on the dosage, duration of treatment, age of the pigs, and gut location that is sampled. Both culture-independent and -dependent studies have also shown that the swine gut microbiota contains a large number of antimicrobial resistance determinants even in the absence of antimicrobial exposure. Heavy metals, such as zinc and copper, which are often added at relatively high doses to swine feed, may also play a role in maintaining antimicrobial resistance and in the stability of the swine gut microbiota. This review focuses on the use of antimicrobials in swine production, with an emphasis on the North American regulatory context, and their effect on the swine gut microbiota and on antimicrobial resistance determinants in the gut microbiota. PMID- 26414106 TI - Chemical Vapor Deposition of Large-Sized Hexagonal WSe2 Crystals on Dielectric Substrates. AB - High-quality large-sized hexagoal WSe2 crystals can be grown on dielectric substrates using atmospheric chemical vapor deposition in the presence of hydrogen gas. These hexagonal crystals (lateral width >160 um) have a carrier mobility of 100 cm(2) V(-1) s(-1) and a photoresponsivity of ~1100 mA W(-1), which is comparable to that of exfoliated flakes. PMID- 26414108 TI - Low-dose adjunctive cilostazol in patients with complex lesions undergoing percutaneous coronary intervention. AB - Patients with complex coronary lesions undergoing percutaneous coronary intervention (PCI) have more major adverse cardiac events (MACE) than do those with simpler cases. Therefore, intensive antiplatelet therapy might be needed in these patients. A total of 127 patients with complex lesions undergoing PCI in the Second Hospital of Tianjin Medical University from October 2012 to April 2014 were randomized to receive either dual (aspirin plus clopidogrel, DAPT, n = 66), or triple antiplatelet therapy (aspirin plus clopidogrel plus cilostazol; TAPT, n = 61). Patients in the TAPT group received low-dose cilostazol (100 mg loading, followed with 50 mg twice per day) for 3-6 months. The primary endpoint was composite MACE. The complex coronary target lesions were defined as at least one of the following: left main disease; severe 3-vessel disease; chronic total occlusion lesions; true bifurcation lesion; ostial lesions; severe calcified lesions; and highly thrombotic lesions. The two groups had similar baseline clinical and angiographic characteristics. One-year clinical outcomes showed that the TAPT group had significantly lower incidences of myocardial infarction (1.6% vs 13.6%, P = 0.018) and MACE (1.6% vs 16.7%, P = 0.004) than DAPT group. The DAPT group had two cases of stent thrombosis, while the TAPT group did not. Furthermore, adjunctive low-dose cilostazol didn't significantly increase the incidence of bleeding events (26.2% vs 19.7%, P = 0.381) regardless of major (4.9% vs 4.5%, P = 0.921) or minor (21.3% vs 15.2%, P = 0.368) bleeding events. In conclusion, low-dose adjunctive cilostazol seems superior to dual antiplatelet therapy in reducing recurrent ischemic events in patients with complex coronary lesions and the two test groups have a similar incidence of bleeding events. PMID- 26414107 TI - Prognostic value of pretherapy platelet elevation in oropharyngeal cancer patients treated with chemoradiation. AB - The purpose of this study is to evaluate potential associations between increased platelets and oncologic outcomes in oropharyngeal cancer patients receiving concurrent chemoradiation. A total of 433 oropharyngeal cancer patients (OPC) treated with intensity-modulated radiation therapy (IMRT) with concurrent chemotherapy between 2002 and 2012 were included under an approved IRB protocol. Complete blood count (CBC) data were extracted. Platelet and hemoglobin from the last phlebotomy (PLTpre-chemoRT, Hgbpre-chemoRT ) before start of treatment were identified. Patients were risk-stratified using Dahlstrom-Sturgis criteria and were tested for association with survival and disease-control outcomes. Locoregional control (LRC), freedom from distant metastasis (FDM) and overall survival (OS) were decreased (p < 0.03, p < 0.04 and p < 0.0001, respectively) for patients with PLTpre-chemoRT value of >=350 * 10(9) /L. Actuarial 5-year locoregional control (LRC) and FDM were 83 and 85% for non-thrombocythemic patients while patient with high platelets had 5-year LRC and FDM of 73 and 74%, respectively. Likewise, 5-year OS was better for patients with normal platelet counts by comparison (76 vs. 57%; p < 0.0001). Comparison of univariate parametric models demonstrated that PLTpre-chemoRT was better among tested models. Multivariate assessment demonstrated improved performance of models which included pretherapy platelet indices. On Bayesian information criteria analysis, the optimal prognostic model was then used to develop nomograms predicting 3-, 5- and 10-year OS. In conclusion, pretreatment platelet elevation is a promising predictor of prognosis, and further work should be done to elucidate the utility of antiplatelets in modifying risk in OPC patients. PMID- 26414110 TI - Insulin Dependence Increases the Risk of Failure After Total Knee Arthroplasty in Morbidly Obese Patients. AB - The aims of this study were to compare the outcomes between nondiabetic (n=1284), type II diabetic (n=530), and insulin-dependent type II diabetic (n=164) morbidly obese (body mass index >=40 kg/m(2)) patients undergoing primary total knee arthroplasty at 6-year follow-up. Patients with type II diabetes mellitus (DM) had similar outcomes when compared with non-DM patients. However, patients with insulin dependence had an increased risk of reoperation (hazard ratio [HR], 1.8; P=.005), revision (HR, 2; P=.02), and periprosthetic joint infection (HR, 2.1; P=.03), as well as decreased 10-year implant survivorship (84% vs 92%; P=.01) when compared to non-DM patients. Prospective studies should further evaluate outcomes and optimization measures within this population. LEVEL OF EVIDENCE: Level III-prognostic study. PMID- 26414109 TI - Thyroid Dysfunction in Patients with Metastatic Carcinoma Treated with Sunitinib: Is Thyroid Autoimmunity Involved? AB - BACKGROUND: Sunitinib is a tyrosine kinase inhibitor (TKI) inducing thyroid dysfunction, but the precise mechanism(s) involved remains to be explained, including the role of thyroid autoimmunity. The objective of this study was to evaluate thyroid function, parameters of autoimmunity, and thyroid ultrasound findings in patients with metastatic cancer and normal thyroid function/autoimmunity before the initiation of sunitinib therapy. This was a prospective, observational cohort study. METHODS: Twenty-seven patients with metastatic carcinomas at comparable tumor stages were evaluated over 12-18 months after initiating therapy with sunitinib given at a daily oral dose of 50 mg for four weeks (ON), followed by one to two weeks off therapy (OFF). Serum thyrotropin (TSH), free thyroxine (fT4), free triiodothyronine (fT3), and antithyroglobulin (TgAb), and antithyroid peroxidase (TPOAb) autoantibodies were measured in all cases. Thyroid morphology and volume were evaluated by echo-color Doppler ultrasound. RESULTS: A total of 16/27 patients (60%) became hypothyroid (TSH range 7-114 mIU/L) within 30-120 days of therapy. The thyroid volume decreased in 24/27 (89%) patients (from M = 14.6 mL, SD = 6.4 mL to M = 3.8 mL, SD = 2.6 mL after 12 months; p < 0.001), together with the appearance of mild to severe hypoechogenicity. TPOAb (40-3000 IU/mL) became detectable in 7/27 (25%) patients, and TPOAb-positive patients displayed a higher degree of hypothyroidism and volume reduction. The progression-free survival (PFS) was significantly longer in patients developing TPOAb (10.8 months) than in the other group of patients (5.8 months). CONCLUSIONS: These data confirm the thyroid inhibitory effect of sunitinib, in keeping with the key role of kinases in controlling thyroid function and growth. However, the novel appearance of TPOAb in a subgroup of patients with more severe hypothyroidism and longer survival indicates that sunitinib may also trigger/exacerbate thyroid autoimmunity contributing to thyroid failure. The development of TPOAb was associated with a longer PFS. PMID- 26414111 TI - The AMPK enzyme-complex: from the regulation of cellular energy homeostasis to a possible new molecular target in the management of chronic inflammatory disorders. AB - INTRODUCTION: Adenosine monophosphate-activated protein kinase (AMPK), known as an enzymatic complex that regulates the energetic metabolism, is emerging as a pivotal enzyme and enzymatic pathway involved in the regulation of immune homeostatic networks. It is also involved in the molecular mechanisms underlying the pathophysiology of chronic inflammatory diseases. AREAS COVERED: AMPK is expressed in several immune cell types including macrophages, lymphocytes, neutrophils and dendritic cells, and governs a broad array of cell functions, which include cytokine production, chemotaxis, cytotoxicity, apoptosis and proliferation. Based on its wide variety of immunoregulatory actions, the AMPK system has been targeted to reveal its impact on the course of immune-related diseases, such as atherosclerosis, psoriasis, joint inflammation and inflammatory bowel diseases. EXPERT OPINION: The identification of AMPK subunits responsible for specific anti-inflammatory actions and the understanding of the underlying molecular mechanisms will promote the generation of novel AMPK activators, endowed with improved pharmacodynamic and pharmacokinetic profiles. These new tools will aid us to utilize AMPK pathway activation in the management of acute and chronic inflammatory diseases, while minimizing potential adverse reactions related to the effects of AMPK on metabolic energy. PMID- 26414112 TI - The Effect of Renal Cysts on the Fragmentation of Renal Stones During Shockwave Lithotripsy: A Comparative In Vitro Study. AB - PURPOSE: To assess the potential effect of simple renal cysts (SRC) on stone fragmentation during shockwave lithotripsy (SWL) in an in vitro model. MATERIALS AND METHODS: The in vitro model was constructed using 10% ordnance gelatin (OG). Models were created to mimic four scenarios: Model A-with an air-filled cavity (suboptimal for stone fragmentation); model B-without a cavity (normal anatomy); model C-with a 3-cm serum filled cavity (to represent a small SRC); model D-with a 4-cm serum filled cavity (to represent a larger SRC). SWL was applied to 24 standardized phantom stones (weight of 2+/-0.1 g) in each model using a standardized protocol. Stone fragments were retrieved, then dried overnight at room air temperature. Fragmentation coefficient (FC) was calculated for each stone, for fragments<4 mm and <2 mm. RESULTS: The OG in vitro model was robust enough for the proposed research. There was no fragmentation evident in model A as expected. The mean FC was 29.7 (+/-20.5) and 39.7 (+/-23.7) for <4 mm fragments (P=0.069) and 7.6 (+/-4.1) and 10.6 (+/-6.7) for <2 mm fragments (P=0.047), for noncystic and cystic models, respectively. The mean FC was 29.7 (+/-20.5), 38.8 (+/-26.2) and 40.7 (+/-21.3) for <4 mm fragments (P=0.213) and 7.6 (+/-4.1), 11.1 (+/-8) and 10.2 (+/-5.3) for <2 mm fragments (P=0.138), for models B, C, and D, respectively. CONCLUSION: Our in vitro experiment confirms better stone fragmentation associated with SWL in the presence of adjacent SRC. PMID- 26414113 TI - Dissociating associative and motor aspects of action understanding: Processing of dual-ended tools by 16-month-old infants. AB - When learning about the functions of novel tools, it is possible that infants may use associative and motoric processes. This study investigated the ability of 16 month-olds to associate the orientation in which an actor held a dual-function tool with the actor's prior demonstrated interest in one of two target objects, and their use of the tool on that target. The actors' hand posture did not differ between conditions. The infants were shown stimuli in which two actors acted upon novel objects with a novel tool, each actor employing a different function of the tool. Using an eye-tracker, infants' looking time at images depicting the actors holding the tool in an orientation congruent or incongruent with the actor's goal was measured. Infants preferred to look at the specific part of the tool that was incongruent with the actor's goal. Results show that the association formed involves the specific part of the tool, the actor, and the object the actor acted upon, but not the orientation of the tool. The capacity to form such associations is demonstrated in this study in the absence of motor information that would allow 16-month-olds to generate a specific representation of how the tool should be held for each action via mirroring processes. PMID- 26414114 TI - Addition of Amino Acids to Further Stabilize Lyophilized Sucrose-Based Protein Formulations: I. Screening of 15 Amino Acids in Two Model Proteins. AB - In small amounts, the low molecular weight excipients-sorbitol and glycerol-have been shown to stabilize lyophilized sucrose-based protein formulations. The purpose of this study was to explore the use of amino acids as low molecular weight excipients to similarly enhance stability. Model proteins, recombinant human serum albumin and alpha-chymotrypsin, were formulated with sucrose in combination with one of 15 amino acid additives. Each formulation was lyophilized at 1:1:0.3 (w/w) protein-sucrose-amino acid. Percent total soluble aggregate was measured by size-exclusion chromatography before and after storage at 50 degrees C for 2 months. Classical thought might suggest that the addition of the amino acids to the sucrose-protein formulations would be destabilizing because of a decrease in the system's glass transition temperature. However, significant improvement in storage stability was observed for almost all formulations at the ratio of amino acid used. Weak correlations were found between the extent of stabilization and both amino acid molar volume and side-chain charge. The addition of amino acids at a modest level generally improves storage stability, often by more than a 50% increase, for lyophilized sucrose-based protein formulations. PMID- 26414115 TI - Asymptomatic Versus Symptomatic Ankle Joints in Rheumatoid Arthritis: A High Resolution B-Mode and Power Doppler Ultrasound Study. AB - OBJECTIVE: Ankle joints are frequently neglected in activity scoring systems, including the Disease Activity Score in 28 joints (DAS28). Only a few studies have assessed pathologies detected by ultrasonography of the ankles in symptomatic rheumatoid arthritis (RA) patients. We evaluated ankle joints in RA patients regardless of symptomatology, using musculoskeletal ultrasound (MSUS) as well as power Doppler ultrasound (PDUS). METHODS: A total of 160 ankle joints of 80 RA patients were examined using MSUS and PDUS, according to the European League Against Rheumatism MSUS guidelines. Additionally, the talonavicular joints (TNJs) and the medial and the lateral tendon compartments were examined. The visual analog scale (VAS) score was recorded for each patient. RESULTS: A total of 80 RA patients with a median age of 60 years and disease duration of 5 years were enrolled in our study. The median DAS28 score was 5. A total of 97 ankles were painful (VAS 1-10), whereas 63 ankles were asymptomatic (VAS 0). Overall, the predominant pathology was arthritis of the tibiotalar joint (TTJ) and/or TNJ in 124 ankles (77%), followed by tenosynovitis of the medial compartment tendons in 44 ankles (28%). Arthritis of the TTJ was present in 59% and synovitis of the TNJ in 35% of the symptomatic ankles. In asymptomatic ankles, TTJ synovitis was detected in 35%, whereas TNJ arthritis was observed in 18%. PDUS activity was higher in the subgroup of symptomatic ankles. CONCLUSION: The most frequent pathologies detected by MSUS were arthritis of the TTJ and TNJ, followed by tenosynovitis of the medial compartment tendons. Pathologic findings were more frequent in symptomatic but also common in asymptomatic patients, whereas PDUS activity was generally low and mainly observed in symptomatic patients. PMID- 26414116 TI - Interplay of Promoter Usage and Intragenic CpG Content: Impact on GFP Reporter Gene Expression. AB - Successful therapeutic protein production in vitro and in vivo requires efficient and long-term transgene expression supported by optimized vector and transgene cis-regulatory sequence elements. This study provides a comparative analysis of CpG-rich, highly expressed, versus CpG-depleted, poorly expressed green fluorescent protein (GFP) reporter transgenes, transcribed by various promoters in two different cell systems. Long-term GFP expression from a defined locus in stable Chinese hamster ovary cells was clearly influenced by the combination of transgene CpG content and promoter usage, as shown by differential silencing effects on selection pressure removal among the cytomegalovirus (CMV) promoter and elongation factor (EF)-1alpha promoter. Whereas a high intragenic CpG content promoted local DNA methylation, CpG depletion rather accelerated transgene loss and increased the local chromatin density. On lentiviral transfer of various expression modules into epigenetically sensitive P19 embryonic pluripotent carcinoma cells, CMV promoter usage led to rapid gene silencing irrespective of the intragenic CpG content. In contrast, EF-1alpha promoter-controlled constructs showed delayed silencing activity and high-level transgene expression, in particular when the CpG-rich GFP reporter was used. Notably, GFP silencing in P19 cells could be prevented completely by the bidirectional, dual divergently transcribed A2UCOE (ubiquitously acting chromatin-opening element derived from the human HNRPA2B1-CBX3 locus) promoter. Because the level of GFP expression by the A2UCOE promoter was entirely unaffected by the intragenic CpG level, we suggest that A2UCOE can overcome chromatin compaction resulting from intragenic CpG depletion due to its ascribed chromatin-opening abilities. Our analyses provide insights into the interplay of the intragenic CpG content with promoter sequences and regulatory sequence elements, thus contributing toward the design of therapeutic transgene expression cassettes for future gene therapy applications. PMID- 26414117 TI - Phenotypic plasticity and targeting of Siglec-F(high) CD11c(low) eosinophils to the airway in a murine model of asthma. AB - Eosinophil recruitment in asthma is a multistep process, involving both trans endothelial migration to the lung interstitium and trans-epithelial migration into the airways. While the trans-endothelial step is well studied, trans epithelial recruitment is less understood. To contrast eosinophil recruitment between these two compartments, we employed a murine kinetics model of asthma. Eosinophils were phenotyped by multicolor flow cytometry in digested lung tissue and bronchoalveolar lavage (BAL) simultaneously, 6 h after each ovalbumin (OVA) challenge. There was an early expansion of tissue eosinophils after OVA challenge followed by eosinophil buildup in both compartments and a shift in phenotype over the course of the asthma model. Gradual transition from a Siglec-F(med) CD11c(-) to a Siglec-F(high) CD11c(low) phenotype in lung tissue was associated with eosinophil recruitment to the airways, as all BAL eosinophils were of the latter phenotype. Secondary microarray analysis of tissue-activated eosinophils demonstrated upregulation of specific integrin and chemokine receptor signature suggesting interaction with the mucosa. Using adhesion assays, we demonstrated that integrin CD11c mediated adhesion of eosinophils to fibrinogen, a significant component of epithelial barrier repair and remodeling. To the best of our knowledge, this is the only report to date dissecting compartmentalization of eosinophil recruitment as it unfolds during allergic inflammation. By capturing the kinetics of eosinophil phenotypic change in both tissue and BAL using flow cytometry and sorting, we were able to demonstrate a previously undocumented association between phenotypic shift of tissue-recruited eosinophils and their trans-epithelial movement, which implicates the existence of a specific mechanism targeting these cells to mucosal airways. PMID- 26414119 TI - A combination of retinal morphology and visual electrophysiology testing increases diagnostic yield in Parkinson's disease. AB - BACKGROUND: Impaired vision and remodeled foveal pit have been demonstrated in Parkinson's disease (PD) patients using different techniques. METHODS: Ten PD (20 eyes) and eight healthy controls (HC) subjects (16 eyes) were enrolled. Subjects were evaluated for N70 and P100 latencies using two-channel VEP with pattern reversal and on/off pattern; Contrast sensitivity (CS) using Pelli-Robson chart; macular thickness measured using Zeiss-HD optical coherence tomography (OCT). RESULTS: PD patients had a significantly delayed N70 (reversal pattern) and P100 (on/off pattern), lower CS score, and decreased retinal thickness at temporal 1.5 2.5 mm from the foveola. N70 latency was negatively correlated with CS (R = 0.419, P = 0.01) and average GCL-IPL thickness (R = -0.529, P = 0.001). CS was positively correlated with parafoveal thickness (R = 0.490, P = 0.002). A combination of parafoveal thickness and CS score yielded an AUC of 0.784 for PD discrimination which increased to 0.844 when combined with N70 and P100 measures. CONCLUSION: A combination of pattern reversal VEP latency, CS score, and inner retinal foveal thickness measures has a high diagnostic yield for PD. PMID- 26414118 TI - Genetic susceptibility variants in parkinsonism. AB - Parkinsonism is an umbrella term for a group of disorders characterized by the clinical signs of tremor, bradykinesia, rigidity, and postural instability. On neuropathologic examination parkinsonism can display alternate protein pathologies (e.g. alpha-synucleinopathy or tauopathy) but the degeneration of nigral neurons is consistent. The main forms of parkinsonism are, Parkinson's disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). Genetic studies from candidate gene, to unbiased genome-wide approaches including association and next-generation sequencing have nominated a number of disease determinants. Within this review we will highlight the genetic loci that are associated with disease and discuss the implications and importance for a better understanding of the genes involved and thus the underlying pathophysiology of these disorders. PMID- 26414120 TI - Surface Coating Constraint Induced Self-Discharging of Silicon Nanoparticles as Anodes for Lithium Ion Batteries. AB - One of the key challenges of Si-based anodes for lithium ion batteries is the large volume change upon lithiation and delithiation, which commonly leads to electrochemi-mechanical degradation and subsequent fast capacity fading. Recent studies have shown that applying nanometer-thick coating layers on Si nanoparticle (SiNPs) enhances cyclability and capacity retention. However, it is far from clear how the coating layer function from the point of view of both surface chemistry and electrochemi-mechanical effect. Herein, we use in situ transmission electron microscopy to investigate the lithiation/delithiation kinetics of SiNPs coated with a conductive polymer, polypyrrole (PPy). We discovered that this coating layer can lead to "self-delithiation" or "self discharging" at different stages of lithiation. We rationalized that the self discharging is driven by the internal compressive stress generated inside the lithiated SiNPs due to the constraint effect of the coating layer. We also noticed that the critical size of lithiation-induced fracture of SiNPs is increased from ~150 nm for bare SiNPs to ~380 nm for the PPy-coated SiNPs, showing a mechanically protective role of the coating layer. These observations demonstrate both beneficial and detrimental roles of the surface coatings, shedding light on rational design of surface coatings for silicon to retain high power and high capacity as anode for lithium ion batteries. PMID- 26414121 TI - Restoration of impaired ecosystems: An ounce of prevention or a pound of cure? Introduction, overview, and key messages from a SETAC-SER workshop. AB - A workshop on Restoration of Impaired Ecosystems was held in Jackson, Wyoming, in June 2014. Experts from Australia, Canada, Mexico, the United Kingdom, and the United States in ecotoxicology, restoration, and related fields from both the Society of Environmental Toxicology and Chemistry and the Society for Ecological Restoration convened to advance the practice of restoring ecosystems that have been contaminated or impaired from industrial activities. The overall goal of this workshop was to provide a forum for ecotoxicologists and restoration ecologists to define the best scientific practices to achieve ecological restoration while addressing contaminant concerns. To meet this goal, participants addressed 5 areas: 1) links between ecological risk assessment and ecological restoration, 2) restoration goals, 3) restoration design, 4) monitoring for restoration effectiveness and 5) recognizing opportunities and challenges. Definitions are provided to establish a common language across the varied disciplines. The current practice for addressing restoration of impaired ecosystems tends to be done sequentially to remediate contaminants, then to restore ecological structure and function. A better approach would anticipate or plan for restoration throughout the process. By bringing goals to the forefront, we may avoid intrusive remediation activities that close off options for the desired restoration. Participants realized that perceived limitations in the site assessment process hinder consideration of restoration goals; contaminant presence will influence restoration goal choices; social, economic, and cultural concerns can factor into goal setting; restoration options and design should be considered early during site assessment and management; restoration of both structure and function is encouraged; creative solutions can overcome limitations; a regional focus is imperative; monitoring must occur throughout the restoration process; and reciprocal transfer of knowledge is needed among theorists, practitioners, and stakeholders and among varied disciplines. PMID- 26414123 TI - Single dose oral analgesics for acute postoperative pain in adults - an overview of Cochrane reviews. AB - BACKGROUND: This is an updated version of the original Cochrane overview published in Issue 9, 2011. That overview considered both efficacy and adverse events, but adverse events are now dealt with in a separate overview.Thirty-nine Cochrane reviews of randomised trials have examined the analgesic efficacy of individual drug interventions in acute postoperative pain. This overview brings together the results of those individual reviews and assesses the reliability of available data. OBJECTIVES: To summarise the efficacy of pharmaceutical interventions for acute pain in adults with at least moderate pain following surgery who have been given a single dose of oral analgesic. METHODS: We identified systematic reviews in the Cochrane Database of Systematic Reviews in The Cochrane Library through a simple search strategy. All reviews were overseen by a single review group, had a standard title, and had as their primary outcome the number of participants with at least 50% pain relief over four to six hours compared with placebo. For individual reviews, we extracted the number needed to treat for an additional beneficial outcome (NNT) for this outcome for each drug/dose combination, and also the percentage of participants achieving at least 50% maximum pain relief, the mean of mean or median time to remedication, and the percentage of participants remedicating by six, eight, 12, or 24 hours. Where there was adequate information for pairs of drug and dose (at least 200 participants, in at least two studies), we defined the addition of four comparisons of typical size (400 participants in total) with zero effect as making the result potentially subject to publication bias and therefore unreliable. MAIN RESULTS: The overview included 39 separate Cochrane Reviews with 41 analyses of single dose oral analgesics tested in acute postoperative pain models, with results from about 50,000 participants in approximately 460 individual studies. The individual reviews included only high-quality trials of standardised design, methods, and efficacy outcome reporting. No statistical comparison was undertaken.Reliable results (high quality information) were obtained for 53 pairs of drug and dose in painful postsurgical conditions; these included various fixed dose combinations, and fast acting formulations of some analgesics. NNTs varied from about 1.5 to 20 for at least 50% maximum pain relief over four to six hours compared with placebo. The proportion of participants achieving this level of benefit varied from about 30% to over 70%, and the time to remedication varied from two hours (placebo) to over 20 hours. Good (low) NNTs were obtained with ibuprofen 200 mg plus paracetamol (acetaminophen) 500 mg (NNT compared with placebo 1.6; 95% confidence interval 1.5 to 1.8), ibuprofen fast acting 200 mg (2.1; 1.9 to 2.3); ibuprofen 200 mg plus caffeine 100 mg (2.1; 1.9 to 3.1), diclofenac potassium 50 mg (2.1; 1.9 to 2.5), and etoricoxib 120 mg (1.8; 1.7 to 2.0). For comparison, ibuprofen acid 400 mg had an NNT of 2.5 (2.4 to 2.6). Not all participants had good pain relief and, for many pairs of drug and dose, 50% or more did not achieve at least 50% maximum pain relief over four to six hours.Long duration of action (eight hours or greater) was found for etoricoxib 120 mg, diflunisal 500 mg, paracetamol 650 mg plus oxycodone 10 mg, naproxen 500/550 mg, celecoxib 400 mg, and ibuprofen 400 mg plus paracetamol 1000 mg.There was no evidence of analgesic effect for aceclofenac 150 mg, aspirin 500 mg, and oxycodone 5 mg (low quality evidence). No trial data were available in reviews of acemetacin, meloxicam, nabumetone, nefopam, sulindac, tenoxicam, and tiaprofenic acid. Inadequate amounts of data were available for nine drugs and doses, and data potentially susceptible to publication bias for 13 drugs and doses (very low quality evidence). AUTHORS' CONCLUSIONS: There is a wealth of reliable evidence on the analgesic efficacy of single dose oral analgesics. Fast acting formulations and fixed dose combinations of analgesics can produce good and often long-lasting analgesia at relatively low doses. There is also important information on drugs for which there are no data, inadequate data, or where results are unreliable due to susceptibility to publication bias. This should inform choices by professionals and consumers. PMID- 26414122 TI - Higher Cognitive Function in Elderly Individuals with Previous Cataract Surgery: Cross-Sectional Association Independent of Visual Acuity in the HEIJO-KYO Cohort. AB - Cataract surgery improves visual acuity and drastically increases the capacity for light reception to the retina. Although previous studies suggested that both light exposure and visual acuity were associated with cognitive function, the relationships between cataract surgery, visual acuity, and cognitive function have not been evaluated in large populations. In this cross-sectional study, we measured cognitive function using the Mini-Mental State Examination and best corrected visual acuity in pseudophakic (previous cataract surgery) and phakic (no previous cataract surgery) elderly individuals. Of 945 participants (mean age 71.7 years), 166 (17.6%) had pseudophakia and 317 (33.5%) had impaired cognitive function (score <=26). The pseudophakic group showed significantly better visual acuity than the phakic group (p = 0.003) and lower age-adjusted odds ratio (ORs) for cognitive impairment (OR 0.66; p = 0.038). Consistently, in multivariate logistic regression models, after adjusting for confounding factors, including visual acuity and socioeconomic status, ORs for cognitive impairment were significantly lower in the pseudophakic group than in the phakic group (OR 0.64; 95% confidence interval 0.43-0.96; p = 0.031). This association remained significant in sensitivity analysis, excluding participants with low cognitive score <=23 (n = 36). In conclusion, in a general elderly population, prevalence of cognitive impairment was significantly lower in pseudophakic individuals independently of visual acuity. The association was also independent of several major causes of cognitive impairment such as aging, gender, obesity, socioeconomic status, hypertension, diabetes, sleep disturbances, depressive symptoms, and physical inactivity. PMID- 26414125 TI - Patterns of Coexisting Lesions Detected on Magnetic Resonance Imaging and Relationship to Incident Knee Osteoarthritis: The Multicenter Osteoarthritis Study. AB - OBJECTIVE: To identify patterns of coexisting lesions seen on magnetic resonance imaging (MRI) in knees that are free of radiographic osteoarthritis (OA) and to examine the relationship of these MRI-detected lesions to incident OA. METHODS: Study subjects were individuals enrolled in the Multicenter Osteoarthritis Study, a prospective cohort study. In each subject, 1 knee in which radiographic OA was absent in both the tibiofemoral and patellofemoral joints at baseline was selected for study, with followup for 84 months. We used a novel approach, latent class analysis, to group the constellation of MRI lesions in each joint, i.e., cartilage damage, bone marrow lesion, meniscal tear, meniscal extrusion, synovitis, and effusion, into a manageable number of subgroups. The association of these subgroups with incident radiographic OA in the same joint was assessed using logistic regression. RESULTS: Among 885 eligible knees (203 with incident disease in the tibiofemoral joint, 64 with incident disease in the patellofemoral joint), 4 latent subgroups in the tibiofemoral joint were identified (described briefly as minimal lesions, mild lesions, moderate lesions [but limited meniscal lesions], and severe lesions). The odds ratios of incident tibiofemoral joint OA in the latter 3 subgroups (compared to the knees with minimal lesions as the referent) were 5.6, 1.8, and 5.0, respectively. A similar set of 4 subgroups in the patellofemoral joint was identified, except that the fourth subgroup had limited meniscal lesions. The odds ratios of incident disease in the patellofemoral joint were 3.8, 5.1, and 13.7 in the subgroups with mild lesions, moderate lesions, and severe lesions, respectively. CONCLUSION: Different patterns of coexisting MRI lesions, which have different implications with regard to risk of knee OA, were identified. Meniscal damage seemed to play a different role in the development of incident disease in tibiofemoral versus patellofemoral joints. PMID- 26414124 TI - Distinct Phenotypes of Cigarette Smokers Identified by Cluster Analysis of Patients with Severe Asthma. AB - RATIONALE: Smoking may have multifactorial effects on asthma phenotypes, particularly in severe asthma. Cluster analysis has been applied to explore novel phenotypes, which are not based on any a priori hypotheses. OBJECTIVES: To explore novel severe asthma phenotypes by cluster analysis when including cigarette smokers. METHODS: We recruited a total of 127 subjects with severe asthma, including 59 current or ex-smokers, from our university hospital and its 29 affiliated hospitals/pulmonary clinics. Twelve clinical variables obtained during a 2-day hospital stay were used for cluster analysis. After clustering using clinical variables, the sputum levels of 14 molecules were measured to biologically characterize the clinical clusters. MEASUREMENTS AND MAIN RESULTS: Five clinical clusters were identified, including two characterized by high pack year exposure to cigarette smoking and low FEV1/FVC. There were marked differences between the two clusters of cigarette smokers. One had high levels of circulating eosinophils, high IgE levels, and a high sinus disease score. The other was characterized by low levels of the same parameters. Sputum analysis revealed increased levels of IL-5 in the former cluster and increased levels of IL-6 and osteopontin in the latter. The other three clusters were similar to those previously reported: young onset/atopic, nonsmoker/less eosinophilic, and female/obese. Key clinical variables were confirmed to be stable and consistent 1 year later. CONCLUSIONS: This study reveals two distinct phenotypes of severe asthma in current and former cigarette smokers with potentially different biological pathways contributing to fixed airflow limitation. Clinical trial registered with www.umin.ac.jp (000003254). PMID- 26414126 TI - An updated model to describe the neuroendocrine control of reproduction in chickens. AB - Since its first identification in quail 15 years ago, gonadotropin inhibitory hormone (GnIH) has become a central regulator of reproduction in avian species. In this review, we have revisited our original model published in 2009 to incorporate recent experimental evidence suggesting that GnIH acts as a molecular switch during the integration of multiple external and internal cues that allow sexual maturation to proceed in chickens. Furthermore, we discuss the regulation of a dual inhibitory/stimulatory control of the hypothalamo-pituitary-gonadal axis involving the interaction between GnIH and gonadotropin releasing hormone (GnRH). Finally, beyond seasonality, we also propose that GnIH along with this dual control may be responsible for the circadian control of ovulation in chickens, allowing eggs to be laid in a synchronized manner. PMID- 26414127 TI - Expression and localization of vascular endothelial growth factor A (VEGFA) and its two receptors (VEGFR1/FLT1 and VEGFR2/FLK1/KDR) in the canine corpus luteum and utero-placental compartments during pregnancy and at normal and induced parturition. AB - VEGFA is one of the most potent known inducers of angiogenesis. However, the function of angiogenic factors in the canine corpus luteum (CL) of pregnancy and in the pregnant uterus and placenta has not yet been elucidated. Therefore, here we investigated the expression and localization of VEGFA and its receptors (VEGFR1/FLT1 and VEGFR2/FLK1/KDR) in the canine CL and utero-placental compartments (ut-pl) throughout pregnancy until prepartum luteolysis. Antigestagen-mediated effects on expression of VEGF system in ut-pl were elucidated in mid-pregnant dogs. While displaying high individual variation, the luteal VEGFA was elevated during pre-implantation and post-implantation, followed by a decrease during mid-gestation, which was more pronounced at the mRNA level, and showed constant expression afterwards. Within the uterus, it increased following implantation and during mid-gestation in ut-pl compartments, but was downregulated at prepartum luteolysis. Luteal VEGFR1 expression resembled that of VEGFA; VEGFR2 remained unaffected throughout pregnancy. In ut-pl compartments, both receptors increased gradually towards mid-gestation; a prepartum decrease was observed for VEGFR1. Antigestagen-treatment resulted in decreased expression of ut-pl VEGFR1. In the CL, VEGFA stained in luteal cells. Uterine signals of VEGFA and its two receptors were observed in epithelial and vascular compartments, and in myometrium. In placental labyrinth, additionally, trophoblast stained positively. Luteal VEGFR1 was localized to the luteal cells and tunica media of blood vessels, whereas VEGFR2 stained only in capillary endothelial cells. The upregulation of luteal and the ut-pl VEGF system during early gestational stages supports the increased vascularization rate during this time. The diminishing effects of the prepartum endocrine milieu on VEGFA function seem to be more pronounced in the ut-pl units. PMID- 26414128 TI - Sialadenoma Papilliferum with Inverted Pattern in a Young Patient: A Case Report. AB - BACKGROUND: Sialadenoma papilliferum (SP) is a rare, benign neoplasm of salivary gland origin which manifests as an exophytic papillary excrescence of the mucosa. Indeed, SP is both an exophytic proliferation of papillary stratified squamous epithelium above the mucosal surface and an endophytic salivary ductal proliferation beneath the mucosa. It arises predominantly in minor salivary glands and usually affects patients in the age range of 32-87 years, with reports in young patients being exceedingly rare. CASE REPORT: We report the case of a previously healthy 20-year-old man diagnosed with a nodular mass in the upper lip buccal mucosa. The tumor was excised and submitted for microscopic examination. Histologic examination revealed a biphasic proliferation of papillary stratified squamous and salivary ductal epithelia, both underneath the mucosal surface. CONCLUSIONS: In this unique case, as the classical SP, the tumor had a biphasic proliferation of squamous and ductal epithelia. However, unlike the classical SP, both epithelia grew under the mucosal surface. As a result, it did not manifest as an exophytic proliferation, but as a nodule. We excluded squamous papilloma, inverted ductal papilloma, intraductal papilloma and mucoepidermoid carcinoma, the principal entities in the differential diagnosis of SP, and concluded it was an SP with inverted pattern. PMID- 26414129 TI - Radiotherapy after hyperbaric oxygenation in malignant gliomas. AB - OBJECTIVE: This review was to evaluate the efficacy and toxicity of radiation therapy (RT) administered immediately after hyperbaric oxygen (HBO) therapy in patients with high grade gliomas. RESEARCH DESIGN AND METHODS: PubMed, Embase, ISI Web of Knowledge, and Cochrane databases were searched using combinations of the following search terms: radiotherapy, hyperbaric oxygenation, chemotherapy, glioma, brain tumor. Selection was limited to prospective studies involving patients given HBO followed by RT for high-grade gliomas. Data extracted from studies included the clinical research phase of the study, number of study arms, number of patients, patient age and gender, glioma type and grade, pressure and length of HBO, protocol of radiation therapy, duration of follow-up, and the outcomes. MAIN OUTCOME MEASURES: Overall survival, time to progression, response rate, tumor regression, and toxic effects associated with HBO plus RT treatment. RESULTS: Literature search/screening yielded eight studies for analysis. Six of the studies were single-arm in design and enrolled a total of 203 patients, of whom 142 had grade IV gliomas and 61 had grade III gliomas. In these six studies, all patients received HBO then RT. Two studies were double-arm in design, with 24 patients treated with HBO followed by RT and 26 patients treated with RT alone. The findings from both the single- and double-arm studies indicated improved outcomes (survival rate, progression free survival, time to progression, response rate) with HBO and RT therapy. Reported toxicity included leucopenia, anemia, thrombocytopenia, fever, loss of appetite, constipation, nausea, vomiting, and liver dysfunction. The addition of HBO had minimal effect on toxicity or side effects; across the eight studies, only one patient with severe middle ear barotrauma had a complication directly related to HBO exposure. CONCLUSION: This systematic reviews suggests that the addition of HBO to RT is tolerated and may be beneficial in patients with high-grade gliomas. PMID- 26414130 TI - [Public health international research: research scientist-field worker partnership, interdisciplinarity and social role]. PMID- 26414131 TI - [Action-driven research and research-driven action: introduction to interventional cancer research in human and social sciences]. PMID- 26414132 TI - [How to understand and facilitate return to school of high school students treated for cancer: analysis of a sociology research-action project]. AB - Based on a sociology research-action project, this article analyses the specific issue of return to school of high school students with cancer. Three detailed cases, illustrating the global results of the study, are presented to highlight the academic trajectories of these students. This situation has a particular impact on juvenile sociability. Moreover, the education of these students does not comply with French educational standards and is very complex for professionals. Finally, social inequalities in education are reinforced by the experience of serious illness, as pedagogical negotiations are even more complex due to the fact that families are not familiar with school practices. PMID- 26414133 TI - [Knowledge co-production and local transfer to reduce inequalities of access to breast cancer screening]. AB - This paper describes a knowledge transfer experiment that has been conducted since September 2012 in Argenteuil (Val d'Oise, France). This experiment is part of an interventional research project called DeCL/C: "Knowledge translation on social and spatial inequalities: a tool to raise local awareness and mobilization to lessen cancer screening participation rate disparities': The project is carried out by health geographers from Paris Ouest University (UPO) and the National Association of Cities for Public Health (Elus, Sante Publique et Territoires, ESPT). It encompasses two main components: intervention designed to implement a knowledge co-production and transfer process among researchers, stakeholders and decision makers at various levels. This knowledge concerns social and spatial determinants of inequalities of access to breast cancer screening programmes in cities. The research is multidisciplinary (geography, sociology, political science, epistemology) and is designed to measure the impact of this knowledge co-production and transfer in terms of actions in the targeted cities (six cities in the Paris region) as well as the reduction of inequalities of access to breast cancer screening programmes. This article, based on knowledge transfer literature and an empirical experiment in Argenteuil, describes the ongoing knowledge transfer process. It also highlights Argenteuil stakeholders' and decision makers' interest in action and research. The analysis of the knowledge co-production, sharing and ownership process by local actors a e both "strategic" and "profound': PMID- 26414134 TI - [Contribution of intervention to research in the context of a serious disease]. AB - By placing in perspective two ongoing studies based on interventional research dynamics in the field of cancer, this article proposes a review of the specific effects of this type of research. Although this approach is often poorly regarded in the field of academic sociology, it is particularly adapted to the analysis of ongoing processes, providing access to certain phenomena that would be otherwise impossible to observe. The research worker's active involvement, the experience that he/she shares with the subjects studied and the partnerships formed with institutional bodies are the basis for the production of original scientific knowledge, but also sometimes uncomfortable configurations. PMID- 26414136 TI - [Cognitive dimensions of public health intervention: support for two primary healthcare projects in rural areas]. AB - Some public health interventions are designed to support transformation of primary health care services, by transforming an individual structure into a collective healthcare structure. These interventions can be considered to be knowledge-generating processes, as they help the actors involved in development of a healthcare project to objectify and collectively share a common position on the future supply of primary care. This shared vision helps them to adopt a project approach in that this shared knowledge provides meaning to their action. They can also help project stakeholders to know and recognize each other as primary care partners, thus initiating the development of a health care team. This approach helps to enhance and formalize coordination of existing practices and event new coordination practices. Collective knowledge is therefore generated by actors and capitalized by the third party. This knowledge can be used to objectify individual experiences and consequently facilitates reflexivity of the actors. Finally, the field response can be considered to be a dynamic conversion. PMID- 26414135 TI - [Nurse action research on the cancer announcement system. Experience feedback from the accompanying sociologist]. AB - This paper reports the action research conducted by a group of nurses working in various hospitals belonging to the Onconord-llede- France (Val d'Oise) network and involved in the setting-up of the paramedical cancer announcement system following the 2005 Cancer plan from the point of view of the sociologist who accompanied them. This analysis of the modalities and difficulties of implementation of the new system allowed these nurses to develop their own self assessment practice survey. They defined the best conaitions for setting up the announcement visit and also achieved a better understanding of their position. This research also opened up lines of reflection on the new organizational configurations and the consequences on professional autonomy. PMID- 26414137 TI - [Factors associated with drug prescription in general practice: a multicenter cross-sectional study]. AB - OBJECTIVE: Iatrogenic, environmental and economic consequences of drug prescription are public health issues. This study was designed to identify physician, patient and consultation characteristics that influence drug prescription in general practice. METHODS: A national multicentre cross-sectional study was conducted in general practice from December 2011 to Apri/2012. Bivariate analyses were performed, followed by multivariate analyses based on a mixed model. RESULTS: At least one drug was prescribed in 16,626 (80.7%) of 20,600 consultations conducted by 128 practitioner. Apart from the number of health problems managed (OR= 10.6 [8.8; 13.0] if :2 4), independent patient related factors were female gender (OR= 1.1 [1.0; 1.2]), extreme ages (OR= 1.3 [1.1; 1.5]younger than 4 years, OR= 1.5 [1.3; 1.8] from 5 to 14 years, and OR= 1.3 {1.2; 1.5] older than 60 years vs. between 15 to 29 years), new patients (OR= 0.8 {0. 7; 0.9]), work accident or occupational disease (OR= 0.3 {0.3; 0.4]). For the physician, drug prescription was linked to visits by pharmaceutical representatives (OR = 1.6 [1.2; 2.0] if :2 5 times a week) but not to visits by Public Health Insurance delegates or signature of the contract designed to improve individual practices (CAP/). CONCLUSIONS: Independently of health problems, patient and physician characteristics, including visits by pharmaceutical representatives, influence drug prescription. PMID- 26414138 TI - [Analysis of hospital outpatient care of a rare disease: cystic fibrosis]. AB - INTRODUCTION: Following the generalization of neonatal screening, the French CF Care Network has become structured around 45 qualified centres, the French CF Society, 2 national expertise centres, the Patient Registry and the National Protocol of CF Care in collaboration with the Vaincre Ia Mucoviscidose patient association. This organization and progress in treatment have resulted in the outpatient follow-up of a growing number of patients. Since 2010, the CF Network representatives have been conducting an assessment of outpatient follow-up to identify difficulties in complying with national and international clinical practice guidelines. METHODS: Two complementary quantitative and qualitative approaches were used to characterize and quantify the activities carried out by professionals in 8 centres both for outpatient visits and patient care coordination. RESULTS: Two thirds of the 1,4 75 patients followed in the centres were managed over the period, less than half (40%) of them attended outpatient visits, but all of them were concerned by care coordination activities, whether or not they were related to the visit. The core team (doctor, nurse, physio therapist) is not mobilized at each scheduled outpatient visit as recommended. Professionals devote 40% less time for follow-up in adult centres than in paediatric centres, all activities included. The multidisciplinary outpatient visit process is complicated by the lack of available resources and the unsuitability of certain premises. DISCUSSION: With a constantly growing number of patients, CF centres are struggling to comply with good clinical practice and meet the specific needs of adult patients and transplant recipients. An upgrade of professional resources and an update of the National Protocol appear to be necessary. PMID- 26414139 TI - [HIV infection. A chronic disease that redefines collaboration between general practitioners and specialists. A qualitative study on opportunities and obstacles to collaboration]. AB - PURPOSE: With the development of antiretroviral therapy, Human Immunodeficiency Virus [HIV) infection has become a chronic disease. In order to develop an efficient response to this new challenge, there is a need for closer collaboration between specialized units and general practitioners. This article identifies the opportunities for and the barriers to this collaboration. METHODS: Semi-structured interviews were conducted with patients living with HIV, general practitioners working in multidisciplinary group practice using the capitation system and infectiologists from one Belgian urban area. Interviews focused one xperiences and expectations in relation to diagnosis, follow-up and collaboration between general practitioners and infectiologists. RESULTS: Overall, infectiologists and general practitioners aspire to improved communication and collaboration. There are overlaps between general practitioner's and infectiologist's field of action. The general practitioner's intervention is sometimes restricted to common uncomplicated or psychosocial problems, in the context of unplanned and short contacts.Infectiologists prefer to focus on HIV problems, leaving general practitioners to take care of these patients' other health problems. The patient may be an obstacle to greater involvement of general practitioners due to fear of stigmatization from his family and social circle or lack of confidence in the general practitioner's skills. CONCLUSION: This research underlines the difficulties and gaps in the care of HIV patients and provides preliminary explanations for the lack of active cooperation between general practitioners and infectiologists. Overlaps between the areas of professional skills can result in uncovered aspects of care, which can have a negative impact on patients, but also on general practitioners and infectiologists. Collaboration between general practitioners and infectiologists should be based on a concerted decision, with clear allocation of tasks, taking into account the patient's expectations. PMID- 26414140 TI - [Use of medical and administrative databases to measure social health inequalities]. AB - OBJECTIVE: The ability to measure social health inequalities is a prerequisite to the implementation of local policies designed to reduce such inequalities. The absence of individual socioeconomic data in medical and administrative databases does not allow direct evaluation of those inequalities. The objective of this study is to propose a method of measurement of social health inequalities from national health insurance databases and a validated deprivation index. METHODS: 27 health care and prevention indicators were constructed to identify social health inequalities. Medical and administrative databases were cross-matched with the European Deprivation Index, completed by a potential spatial accessibility indicator in order to take into account the spatial distribution health care services. RESULTS: The study population comprised data devived from the three main health insurance schemes, and represents 89% of the population of the Midi Pyrenees region. 98% were able to be geographically coded. The 27 indicators were therefore calculated on a total of 2,574,310 individuals, i.e. 87% of the regional population. CONCLUSION: This study illustrates the value of using medical and administrative data to create databases allowing measurement of social health inequalities and their variations within a region. The proposed indicators could be used as decision-making tools for the selection of zones of intervention and to assess the impact of public policies designed to reduce social health inequalities. PMID- 26414141 TI - [Theoretical basis for health system performance assessment]. AB - In France, the search for improved performance in the public sector, considered to reflect optimization of public services, has undergone various phases since the second World War. Public policy assessment has also considerably developed since the 1990s. The various reforms and resulting programmes have contributed to changing the French public administration from a means-based approach to a results-based approach, an essential step to improve performance according to the New Public Management paradigm. Other theories have also been proposed concerning performance assessment in the public sector, especially the medical care sector. The primary objective of this article is to propose a theoretical framework for the concept of performance and performance assessment in the health sector. The authors also propose a reading grid of the main theories concerning application of performance assessment in the health care sector. PMID- 26414142 TI - [The non-uptake of prenatal care in Burkina Faso]. AB - INTRODUCTION: Despite the importance of prenatal care to decrease maternal and neonatal mortality, uptake remains suboptimal in Burkina Faso. This article documents the reasons for non-uptake of prenatal care, by focusing on women who either completely renounce or delay their access to prenatal care. METHODS: Qualitative data collection was performed in the rural town of Kokologho from October 2013 to january 2014. Different collection methods were used: participant observation, twenty-two individual semi-structured interviews with women who accessed prenatal care as a late option and eight informal interviews with key informants identified in the community. RESULTS: Thematic analysis revealed four barriers against the effective use of prenatal care by women: (1) lack of knowledge about the prenatal care schedule and purpose (2) perception of pregnancy and prenatal care (3) socioeconomic barriers: direct payment for prenatal care and the limited autonomy of women, and (4) perception of the quality of prenatal care. DISCUSSION: Based on these observations, non-uptake of prenatal care is discussed using different types of explanatory typologies adopted for this study: non-knowledge, non-claiming by choice or constraints and non-reception of care. This theoretical approach reveals that failures in healthcare services as well as the dichotomy between social representations and medical standards of pregnancy and prenatal care contribute to exclude some women from the prenatal care system. PMID- 26414143 TI - [Change management: An analysis of actors; perceptions about technical assistance in the Democratic Republic of Congo]. AB - INTRODUCTION: Technical assistance (TA) is a common component of health system strengthening interventions. This type of intervention is too often designed and evaluated according to a logic that fails to take into account social complexity. Actors' perceptions are one element of this complexity. This article presents a study conducted in the Democratic Republic of Congo designed to identify perceptions concerning two types of technical support providers for health system strengthening: long-term technical assistants (agents of development agencies) and provincial technical advisors (agents of the Ministry of Health). METHODS: Interviews were conducted with an innovative tool inspired by the principles of systems thinking. Interviewees were actors involved in a TA intervention in the province of Bandundu. Their expectations regarding TA providers were identified in terms of personal characteristics (knowledge, know-how and interpersonal skills), roles, and styles of interaction for capacity building ("interventionist/ prescriptive axes"). RESULTS AND DISCUSSION: Interviewees emphasized the importance of mutual learning and the quality of interactions, which depends on TA provider's interpersonal skills and mutual willingness. Perceptions of TA provider's characteristics tend to be similar, but several differences were observed concerning the expectations about the roles of TAs, and the style that should be adopted for capacity building. Ignoring these differences in expectations may be a threat to the effectiveness of TA. PMID- 26414144 TI - [Negotiation of a heath policy controversy: application of an indirect dialogue approach to performance-based financing in sub-Saharan Africa]. AB - OBJECTIVES: This article assesses the controversy around performance-based financing (PBF) and its contribution to the reform of health systems. It aims to reduce tensions between the different camps by restructuring the debate. METHODS: Our approach was to organize an indirect dialogue between critics and supporters of PBF, based on the framework developed by Norman Daniels. This analytical framework is non-partisan and uses clear and objective criteria. The interviews were carried out in two rounds (first the critics, then the supporters) and were then analyzed. Parts of answers were regrouped according to the most common sectoral themes while also highlighting major areas of disagreement. RESULTS: The interviews revealed some areas of convergence around PBF; the strategy is considered to be a complementary strategy to other strategies; such as those which aim to improving financial access to health care. The analysis also revealed disagreements based on misunderstandings of claims often ascribed to PBF, or lack of sufficient evidence, or asymmetrical information between experts. CONCLUSIONS: Several questions polarize PBF discussions. However, better structuring of convergent and divergent areas and arguments should facilitate a synthesis, at least to some extent. Experts need to adopt an objective approach with universally accepted criteria, for the benefit of all. PMID- 26414146 TI - A proof of concept study investigating the feasibility of combining iPAM robot assisted rehabilitation with functional electrical stimulation to deliver whole arm exercise in stroke survivors. AB - Rehabilitation robots can provide exercise for stroke survivors with weakness at the shoulder and elbow, but most do not facilitate hand movements. The aim was to combine robotics and functional electrical stimulation to facilitate exercise in stroke survivors with upper limb impairment. iPAM Mk II was used to assist active reaching in combination with an Odstock Pace stimulator to assist hand opening. The ABILHAND, Action Research Arm Test (ARAT) and the Stroke Impact Scale (SIS) were recorded at baseline and completion. Nine participants (eight males and one female; mean age = 58 years) were recruited; mean time since stroke was 16 months (range = 6-64). The ABILHAND at baseline was -2.73, improving to -1.45 at follow up (p = 0.038). The ARAT changed from 4.1 to 2.6 (p = 0.180), and the SIS from 49 to 60 (p = 0.019). This study demonstrates that it is possible to combine two technologies in stroke rehabilitation. PMID- 26414148 TI - COHORT EFFECTS OF SUICIDE MORTALITY ARE SEX SPECIFIC IN THE RAPIDLY DEVELOPED HONG KONG CHINESE POPULATION, 1976-2010. AB - BACKGROUND: To examine temporal variations of age, period, and cohort on suicide mortality rate in Hong Kong (HK) from 1976 to 2010, and speculate the macroenvironmental mechanisms of the observed trends. METHODS: Poisson age-period cohort modeling was used to delineate the effects of age, period, and cohort on suicide mortality. Analysis by sex was also conducted to examine if gender difference exists for suicidal behaviours. RESULTS: Age-cohort model provides the best fit to the mortality data, implying that the cohort effect is likely to explain more of the contributions to HK's suicide mortality pattern than the period effect. Risk of suicide mortality increases nonlinearly with age and accelerates after age 65-69 for both sexes. Moreover, the cohort effects differ between the sexes-risk of mortality increases continually for men born after 1961, but no change is observed for women since the 1941 cohort. CONCLUSIONS: With increased risk of suicide mortality in younger cohorts and the age effect of suicide mortality, we may see future increase in suicide mortality as these younger cohorts age. Further studies are needed to clarify plausible associations between broader sociohistorical changes in the population impacting psychological risk factors and suicidal behaviour to better inform suicide prevention strategies. PMID- 26414149 TI - Successful treatment of HCV-associated cryoglobulinemia with ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin: A case report. AB - Cryoglobulinemia is an important extrahepatic manifestation of chronic hepatitis C virus infection. Current treatments are suboptimal, resulting in relapse or refractoriness in 30-40% of patients. Hereby, we describe the case of a 40-year old man with severe hepatitis C virus-associated cryoglobulinemia, effectively treated with an interferon-free combination regimen. The patient was treated for 12 weeks with ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin. Rapid clinical and immunological response, i.e., the resolution of symptoms and disappearance of serum cryoglobulins, ensued as early as 4 weeks after initiating direct acting antiviral therapy. Our reported case directs the attention to the possible consequences and importance of new, effective, interferon-free antiviral treatments in devastating lymphoproliferative and immunological manifestations of chronic hepatitis C virus infection. PMID- 26414147 TI - Inefficiencies and High-Value Improvements in U.S. Cervical Cancer Screening Practice: A Cost-Effectiveness Analysis. AB - BACKGROUND: Studies suggest that cervical cancer screening practice in the United States is inefficient. The cost and health implications of nonadherence in the screening process compared with recommended guidelines are uncertain. OBJECTIVE: To estimate the benefits, costs, and cost-effectiveness of current cervical cancer screening practice and assess the value of screening improvements. DESIGN: Model-based cost-effectiveness analysis. DATA SOURCES: New Mexico HPV Pap Registry; medical literature. TARGET POPULATION: Cohort of women eligible for routine screening. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: Current cervical cancer screening practice; improved adherence to guidelines based screening interval, triage testing, diagnostic referrals, and precancer treatment referrals. OUTCOME MEASURES: Reductions in lifetime cervical cancer risk, quality-adjusted life-years (QALYs), lifetime costs, incremental cost effectiveness ratios, and incremental net monetary benefits (INMBs). RESULTS OF BASE-CASE ANALYSIS: Current screening practice was associated with lower health benefit and was not cost-effective relative to guidelines-based strategies. Improvements in the screening process were associated with higher QALYs and small changes in costs. Perfect adherence to screening every 3 years with cytologic testing and adherence to colposcopy/biopsy referrals were associated with the highest INMBs ($759 and $741, respectively, at a willingness-to-pay threshold of $100,000 per QALY gained); together, the INMB increased to $1645. RESULTS OF SENSITIVITY ANALYSIS: Current screening practice was inefficient in 100% of simulations. The rank ordering of screening improvements according to INMBs was stable over a range of screening inputs and willingness-to-pay thresholds. LIMITATION: The effect of human papillomavirus vaccination was not considered. CONCLUSIONS: The added health benefit of improving adherence to guidelines, especially the 3-year interval for cytologic screening and diagnostic follow-up, may justify additional investments in interventions to improve U.S. cervical cancer screening practice. PRIMARY FUNDING SOURCE: U.S. National Cancer Institute. PMID- 26414150 TI - The crisis in pediatric cardiac transplantation: How soon is now? PMID- 26414151 TI - Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis. AB - INTRODUCTION: The influence of human leukocyte antigen (HLA) mismatching on survival in adult and pediatric patients with cystic fibrosis (CF) after lung transplantation (LTx) is unknown. METHODS: The United Network for Organ Sharing database was queried from 1987 to 2013 to determine the influence of HLA mismatching on survival in adult and pediatric CF LTx recipients by assessing the association of HLA mismatching with survival in first-time adult (aged >= 18 years) and pediatric (aged <18 years) recipients. RESULTS: Of 3149 adult and 489 pediatric patients with CF, 3145 and 489 were used for univariate Cox analysis, 2687 and 363 for Kaplan-Meier survival analysis, and 2073 and 257 for multivariate Cox analysis, respectively. Univariate analyses in adult and pediatric patients with CF demonstrated conflicting associations between HLA mismatching and survival (adult hazard ratio [HR], 1.0; 95% confidence interval [CI], 0.97-1.1; P = .45 vs pediatric HR, 0.87; 95% CI, 0.77-0.99; P = .032). Multivariate Cox models including both pediatric and adult patients confirmed that HLA mismatching had an initially protective effect at young ages (HR, 0.85; 95% CI, 0.73-0.99; P = .044) and that this protective effect diminished at older ages and was no longer associated with survival at P < .05 beyond age 10 years. CONCLUSIONS: HLA mismatching has significantly different implications for survival after LTx in adult compared with pediatric patients with CF. PMID- 26414152 TI - Surgical resection of circumferential epicardial adipose tissue hypertrophy: Case report and systematic review of the literature. PMID- 26414153 TI - Cellular signaling pathways implicated in metastasis of colorectal cancer and the associated targeted agents. AB - Colorectal cancer (CRC) is the third leading cancer worldwide and CRC-related death is mainly attributed to metastasis. Many cellular signaling pathways have been demonstrated to be aberrant in colorectal tumors, and some of them lead to the acquisition of malignant phenotypes. Therefore, the evaluation of signaling pathways implicated in CRC metastasis is urgent for further understanding of CRC progression and pharmacotherapy. This review focuses on several novel cellular signaling pathways associated with CRC metastasis, including Wnt/beta-catenin, p53, COX, TGF-beta/Smad, NF-kappaB, Notch, VEGF and JAKs/STAT3 signaling pathways. Targeted agents developed based on these pathways are also briefly discussed. PMID- 26414154 TI - Assessment of strobilurin fungicides' content in soya-based drinks by liquid micro-extraction and liquid chromatography with tandem mass spectrometry. AB - Seven strobilurin fungicides were pre-concentrated from soya-based drinks using dispersive liquid-liquid micro-extraction (DLLME) with a prior protein precipitation step in acid medium. The enriched phase was analysed by liquid chromatography (LC) with dual detection, using diode array detection (DAD) and electrospray-ion trap tandem mass spectrometry (ESI-IT-MS/MS). After selecting 1 undecanol and methanol as the extractant and disperser solvents, respectively, for DLLME, the Taguchi experimental method, an orthogonal array design, was applied to select the optimal solvent volumes and salt concentration in the aqueous phase. The matrix effect was evaluated and quantification was carried out using external aqueous calibration for DAD and matrix-matched calibration method for MS/MS. Detection limits in the 4-130 and 0.8-4.5 ng g(-1) ranges were obtained for DAD and MS/MS, respectively. The DLLME-LC-DAD-MS method was applied to the analysis of 10 different samples, none of which was found to contain residues of the studied fungicides. PMID- 26414155 TI - Psychometric evaluation of the Concerns of Social Reprisal Scale: Further explicating the roots of fear of positive evaluation. AB - Fear of positive evaluation (FPE) has been proposed to be an important feature of social anxiety disorder (SAD) and to be rooted, at least partly, in concerns of social reprisal due to positive impressions. In order to formally test this hypothesis, the Concerns of Social Reprisal Scale (CSRS) was developed. The purpose of the present series of studies was to examine the psychometric profile of the CSRS across several independent samples including: a large (n=981) undergraduate sample; a clinical sample of individuals diagnosed with social anxiety disorder (n=27), and a demographically-matched subsample of healthy control participants (n=24). The factorial validity, internal consistency, and construct validity of the CSRS were examined. Results across both studies provided support for the psychometric profile of the CSRS. The implications of concerns of social reprisal for the assessment of social anxiety symptoms, theoretical models of fear of evaluation and SAD, and their potential clinical utility with regard to treating SAD are discussed. PMID- 26414156 TI - Economic analysis of athletic team coverage by an orthopedic practice. AB - OBJECTIVE: Coverage of high school football by orthopedic sports medicine specialists is considered standard of care in many localities. Determining the economic viability of this endeavor has never been investigated. The primary purpose of the present investigation was to perform an economic analysis of local high school sports coverage by an orthopedic sports medicine practice. METHODS: From January 2010 to June 2012, a prospective injury report database was used to collect sports injuries from five high school athletic programs covered by a single, private orthopedic sports medicine practice. Patients referred for orthopedic care were then tracked to determine expected cost of care (potential revenue). Evaluation and management codes and current procedure terminology codes were obtained to determine the value of physician visits and surgical care rendered. Overhead costs were calculated based on historical rates within our practice and incorporated to determine estimated profit. RESULTS: 19,165 athletic trainer contacts with athletes playing all sports, including both those 'on field' and in the training room, resulted in 473 (2.5%) physician referrals. The covering orthopedic practice handled 89 (27.9%) of the orthopedic referrals. Of orthopedic physician referrals, 26 (5.4%) required orthopedic surgical treatment. The covering team practice handled 17/26 (65%) surgical cases. The total revenue collected by the covering team practice was $26,226.14. The overhead cost of treatment was $9441.41. Overall estimated profit of orthopedic visits and treatment during this period for the covering practice was $16,784.73. CONCLUSIONS: The covering team practice handled 28% of the orthopedic referrals, 65% of the surgical cases and captured 59% of the potential profit. An increase in physician referrals could increase the benefit for orthopedic surgeons. PMID- 26414158 TI - Time Course of Coagulation and Fibrinolytic Parameters in Patients with Traumatic Brain Injury. AB - Traumatic brain injury (TBI) has long been associated with coagulopathy; however, the time course of coagulation/fibrinolytic parameters in the acute phase of TBI remains unclear. The purpose of the study was to analyze the time course of coagulation/fibrinolytic parameters in the acute phase of TBI and to elucidate parameter relationships to prognosis. We retrospectively evaluated 234 patients with severe isolated TBI with initial blood samples obtained no more than 1 h after injury. Platelet count, prothrombin time, activated partial thromboplastin time (aPTT), plasma levels of fibrinogen, and D-dimer were measured on arrival in the emergency department and 3, 6, and 12 h after injury. Multivariate logistic regression analysis was performed to identify risk factors for poor prognosis at each time point. From hospital admission to 12 h after injury, an elevated D dimer level was a significant negative prognostic indicator (admission: p < 0.0001; 3 h after injury: p = 0.0005; 6 h after injury: p = 0.005; 12 h after injury: p = 0.0009). An upward trend of aPTT on admission and 3 h after injury was also a significant negative prognostic indicator (admission: p = 0.0011; 3 h after injury: p = 0.013). On multivariate logistic regression analysis, which included all initial variables, independent risk factors for poor prognosis included older age (p = 0.0005), low Glasgow Coma Scale score (p < 0.0001), high Abbreviated Injury Score (p = 0.015), aPTT >30.2 sec (p = 0.019), and elevated D dimer level (p = 0.0005). We concluded that D-dimer is the best coagulation/fibrinolytic parameter to monitor for prediction of outcome. PMID- 26414157 TI - Nucleosome Repositioning: A Novel Mechanism for Nicotine- and Cocaine-Induced Epigenetic Changes. AB - Drugs of abuse modify behavior by altering gene expression in the brain. Gene expression can be regulated by changes in DNA methylation as well as by histone modifications, which alter chromatin structure, DNA compaction and DNA accessibility. In order to better understand the molecular mechanisms directing drug-induced changes in chromatin structure, we examined DNA-nucleosome interactions within promoter regions of 858 genes in human neuroblastoma cells (SH-SY5Y) exposed to nicotine or cocaine. Widespread, drug- and time-resolved repositioning of nucleosomes was identified at the transcription start site and promoter region of multiple genes. Nicotine and cocaine produced unique and shared changes in terms of the numbers and types of genes affected, as well as repositioning of nucleosomes at sites which could increase or decrease the probability of gene expression based on DNA accessibility. Half of the drug induced nucleosome positions approximated a theoretical model of nucleosome occupancy based on physical and chemical characteristics of the DNA sequence, whereas the basal or drug naive positions were generally DNA sequence independent. Thus we suggest that nucleosome repositioning represents an initial dynamic genome-wide alteration of the transcriptional landscape preceding more selective downstream transcriptional reprogramming, which ultimately characterizes the cell- and tissue-specific responses to drugs of abuse. PMID- 26414160 TI - Effect of bladder wall thickness on miniature pneumatic artificial muscle performance. AB - Pneumatic artificial muscles (PAMs) are actuators known for their high power to weight ratio, natural compliance and light weight. Due to these advantages, PAMs have been used for orthotic devices and robotic limbs. Small scale PAMs have the same advantages, as well as requiring greatly reduced volumes with potential application to prostheses and small scale robotics. The bladder of a PAM affects common actuator performance metrics, specifically: blocked force, free contraction, hysteresis, and dead-band pressure. This paper investigates the effect that bladder thickness has on static actuation performance of small scale PAMs. Miniature PAMs were fabricated with a range of bladder thicknesses to quantify the change in common actuator performance metrics specifically: blocked force, free contraction, and dead-band pressure. These PAMs were then experimentally characterized in quasi-static conditions, where results showed that increasing bladder wall thickness decreases blocked force and free contraction, while dead-band pressure increases. A nonlinear model was then applied to determine the structure of the stress-strain relationship that enables accurate modeling and the minimum number of terms. Two nonlinear models are compared and the identified parameters are analyzed to study the effect of the bladder thickness on the model. PMID- 26414159 TI - A 22-Year Follow-up Study of Long-term Cardiac Outcome and Predictors of Survival in Friedreich Ataxia. AB - IMPORTANCE: Friedreich ataxia (FRDA) is the most common genetic sensory ataxia, and myocardial involvement is a major determinant of survival. OBJECTIVE: To assess FRDA survival and cardiac outcome to adapt future therapeutic trials. DESIGN, SETTING, AND PARTICIPANTS: In a longitudinal follow-up study, all patients with genetically confirmed FRDA seen in the reference center and referred for cardiac evaluation (standard 12-lead electrocardiogram and transthoracic echocardiography) to the cardiology department were enrolled and followed up from April 27, 1990, to July 31, 2013. The setting was the French National Reference Center for Rare Diseases and the Department of Cardiology, Salpetriere University Hospital, Paris, France. In total, 138 patients with FRDA were followed up. Among 133 patients homozygous for expanded GAA repeats, the mean (SD) age was 31 (10) years (age range, 11-62 years), with a mean (SD) age at disease onset of 16 (8) years (age range, 3-50 years) and a mean (SD) age at first wheelchair use of 26 (9) years (age range, 11-64 years). Cardiac hypertrophy was present in 57.9% (77 of 133), and electrocardiography was normal in 6.8% (9 of 133). MAIN OUTCOMES AND MEASURES: Long-term cardiac outcome and predictors of survival in FRDA. RESULTS: After a mean (SD) follow-up of 10.5 (5.5) years (range, 0.6-23.0 years), the 10-year survival rate was 88.5%. In 80.0% of patients (12 of 15), death was due to cardiac causes. Predictors of survival were a shorter GAA repeat length on the smaller allele of the frataxin gene (hazard ratio [HR], 1.85; 95% CI, 1.28-2.69), left ventricular ejection fraction (HR, 0.42; 95% CI, 0.20-0.89), and left ventricular mass index (HR, 1.19; 95% CI, 1.04-1.36). Two cardiac evolutions were distinguished with a group based trajectory model, including a low-risk cardiac group (78.6% [81 of 103] with normal ejection fraction at baseline that declined slightly over time but remained within the normal range) and a high-risk cardiac group (21.4% [22 of 103] in which the ejection fraction progressively declined during follow-up). The patients with the worse cardiac evolution had longer GAA repeats. Neurological impairment was not predictive of cardiac change over time. CONCLUSIONS AND RELEVANCE: Survival in FRDA is determined by cardiac complications, which are dependent on the mutation (ie, the size of the expanded GAA repeat). Patients with progressive decline of the left ventricular ejection fraction had a worse prognosis. This finding demonstrates that cardiac follow-up is important in FRDA to identify individuals at risk for further cardiac complications. PMID- 26414161 TI - Steep Decline and Cessation in Seed Dispersal by Myrmica rubra Ants. AB - Myrmecochorous diaspores bear a nutrient-rich appendage, the elaiosome, attractive to ant workers that retrieve them into the nest, detach the elaiosome and reject the seed intact. While this interaction is beneficial for the plant partner by ensuring its seed dispersal, elaiosome consumption has various effects -positive, negative or none - on ants' demography and survival, depending on both the ant/plant species involved. In this context, the contribution of ants to seed dispersal strongly varies according to the ant/plant pairs considered. In this paper, we investigate whether the dynamics of myrmecochory also vary on a temporal scale, for a given pair of partners: Myrmica rubra ants and Viola odorata seeds. During their first encounter with seeds, ants collect all the diaspores and eat the majority of elaiosomes. Both the harvesting effort and the elaiosome consumption decline when seeds are offered on the next week and completely cease for the following weeks. This is related to a decrease in the number of foragers reaching the food source, as well as to a reduced probability for an ant contacting a seed to retrieve it. Seed retrieval is not reactivated after seven weeks without any encounter with V. odorata seeds. By contrast, naive ant colonies only fed with fruit flies do not show a decline of prey harvesting of which the speed of retrieval even increases over the successive weeks. Myrmecochory may thus be labile at the scale of a fruiting season due to the ability of ants to steeply tune and cease for several months the harvesting of these seemingly poorly rewarding items and to maintain cessation of seed exploitation. The present study emphasizes the importance of a long-lasting follow up of the myrmecochory process, to assess the stability of this ant-plant partnership and to identify mechanisms of adaptive harvesting in ants. PMID- 26414162 TI - Nonbiaryl and Heterobiaryl Atropisomers: Molecular Templates with Promise for Atropselective Chemical Transformations. PMID- 26414163 TI - Phylogeography of the Golden Jackal (Canis aureus) in India. AB - The golden jackal (Canis aureus) is one of the most common and widely distributed carnivores in India but phylogeographic studies on the species have been limited across its range. Recent studies have observed absence of mitochondrial (mt) DNA diversity in European populations while some North African populations of golden jackal were found to carry gray wolf (Canis lupus lupaster) mtDNA lineages. In the present study, we sequenced 440 basepairs (bp) of control region (CR) and 412 bp of cytochrome b (cyt b) gene of mtDNA from 62 golden jackals sampled from India (n = 55), Israel (n = 2) and Bulgaria (n = 5), to obtain a total of eighteen haplotypes, comprising sixteen from India and one each from Israel and Bulgaria. Except for three previously described haplotypes represented by one cyt b and one CR haplotype both from India, and one CR haplotype from Bulgaria, all haplotypes identified in this study are new. Genetic diversity was high in golden jackals compared to that reported for other canids in India. Unlike the paraphyletic status of African conspecifics with the gray wolf, the Indian (and other Eurasian) golden jackal clustered in a distinct but shallow monophyletic clade, displaying no evidence of admixture with sympatric and related gray wolf and domestic dog clades in the region. Phylogeographic analyses indicated no clear pattern of genetic structuring of the golden jackal haplotypes and the median joining network revealed a star-shaped polytomy indicative of recent expansion of the species from India. Indian haplotypes were observed to be interior and thus ancestral compared to haplotypes from Europe and Israel, which were peripheral and hence more derived. Molecular tests for demographic expansion confirmed a recent event of expansion of golden jackals in the Indian subcontinent, which can be traced back ~ 37,000 years ago during the late Pleistocene. Our results suggest that golden jackals have had a potentially longer evolutionary history in India than in other parts of the world, although further sampling from Africa, the Middle East and south-east Asia is needed to test this hypothesis. PMID- 26414164 TI - Impact of androgen and dietary advanced glycation end products on female rat liver. AB - BACKGROUND/AIMS: Advanced glycation end products (AGEs) have been related to a wide range of liver disorders including hyperandrogenic states such as the Polycystic Ovary Syndrome (PCOS). The aim of the present study is to evaluate the potential impact of dietary glycotoxins exposure and androgen excess on hepatic histology and biochemistry in an androgenized female rat model. METHODS: The study population consisted of 80 female Wistar rats, divided in 3 groups, a group of prepubertal (Group A, n=30) and adult rats (Group B, n=20) that were androgenized via subcutaneous implantation of dihydrotestosterone-containing pellets as well as a group of adult non-androgenized rodents (Group C, n=30). All groups were randomly assigned either to a high-AGE or low-AGE diet for 3 months. RESULTS: Rats fed with a high-AGE diet exhibited significantly elevated levels of gamma-glutamyl transferase (x03B3;GT) (p<=0.0002) and indices of AGE immunostaining in liver tissue (p<0.01) when compared to the respective low-AGE group, while aspartate aminotransferase (AST) levels were affected only in non androgenized animals (p=0.0002). Androgenization per se constitutes an aggravating factor as demonstrated by the elevated x03B3;GT levels in adult androgenized animals compared to non-androgenized, independent of diet content (p=0.0002) and by the elevated AST and alanine aminotransferase (ALT) levels in low-AGE subgroups (adult androgenized vs. non-androgenized, p=0.0002) followed by increased immunohistochemical AGE deposition in hepatocytes of the latter categories (p=0.0007). CONCLUSION: The present study suggests that androgens and glycotoxins may contribute synergistically to distort hepatic physiology and function as observed in hyperandrogenic conditions. PMID- 26414165 TI - Stem cells in clinical trials for treatment of retinal degeneration. AB - INTRODUCTION: After decades of basic science research involving the testing of regenerative strategies in animal models of retinal degenerative diseases, a number of clinical trials are now underway, with additional trials set to begin shortly. These efforts will evaluate the safety and preliminary efficacy of cell based products in the eyes of patients with a number of retinal conditions, notably including age-related macular degeneration, retinitis pigmentosa and Stargardt's disease. AREAS COVERED: This review considers the scientific work and early trials with fetal cells and tissues that set the stage for the current clinical investigatory work, as well the trials themselves, specifically those either now completed, underway or close to initiation. The cells of interest include retinal pigment epithelial cells derived from embryonic stem or induced pluripotent stem cells, undifferentiated neural or retinal progenitors or cells from the vascular/bone marrow compartment or umbilical cord tissue. EXPERT OPINION: Degenerative diseases of the retina represent a popular target for emerging cell-based therapeutics and initial data from early stage clinical trials suggest that short-term safety objectives can be met in at least some cases. The question of efficacy will require additional time and testing to be adequately resolved. PMID- 26414166 TI - Psychological distance reduces literal imitation: Evidence from an imitation learning paradigm. AB - The present experiments tested the hypothesis that observers engage in more literal imitation of a model when the model is psychologically near to (vs. distant from) the observer. Participants learned to fold a dog out of towels by watching a model performing this task. Temporal (Experiment 1) and spatial (Experiment 2) distance from the model were manipulated. As predicted, participants copied more of the model's specific movements when the model was near (vs. distant). Experiment 3 replicated this finding with a paper-folding task, suggesting that distance from a model also affects imitation of less complex tasks. Perceived task difficulty, motivation, and the quality of the end product were not affected by distance. We interpret the findings as reflecting different levels of construal of the model's performance: When the model is psychologically distant, social learners focus more on the model's goal and devise their own means for achieving the goal, and as a result show less literal imitation of the model. (PsycINFO Database Record PMID- 26414167 TI - Carrying a biological "backpack": Quasi-experimental effects of weight status and body fat change on perceived steepness. AB - The apparent steepness of hills and stairs is overestimated in explicit perception. These overestimations are malleable in that when physiological resources are compromised, apparent steepness is further overestimated. An alternative explanation of these experimental findings attributes them to demand characteristics. This article tests the relationship between estimated steepness and naturally occurring differences in body composition. A quasi-experimental field study revealed more exaggerated reports of staircase steepness in overweight than in healthy-weight participants in a situation where experimental demand would be an implausible explanation for any differences. A longitudinal follow-up study used dual X-ray absorptiometry to objectively measure participants' body composition at the beginning and end of a weight-loss program (N = 52). At baseline, higher levels of body fat were associated with steeper explicit estimates of staircase steepness. At follow-up, changes in body fat were associated with changes in estimated steepness such that a loss of fat mass co occurred with shallower estimates. Discussion focuses on the malleability of perceived steepness at an individual level and the implication of these findings for the debate surrounding "embodied" models of perception. (PsycINFO Database Record PMID- 26414168 TI - Automaticity and primacy of auditory streaming: Concurrent subjective and objective measures. AB - Two experiments used subjective and objective measures to study the automaticity and primacy of auditory streaming. Listeners heard sequences of "ABA-" triplets, where "A" and "B" were tones of different frequencies and "-" was a silent gap. Segregation was more frequently reported, and rhythmically deviant triplets less well detected, for a greater between-tone frequency separation and later in the sequence. In Experiment 1, performing a competing auditory task for the first part of the sequence led to a reduction in subsequent streaming compared to when the tones were attended throughout. This is consistent with focused attention promoting streaming, and/or with attention switches resetting it. However, the proportion of segregated reports increased more rapidly following a switch than at the start of a sequence, indicating that some streaming occurred automatically. Modeling ruled out a simple "covert attention" account of this finding. Experiment 2 required listeners to perform subjective and objective tasks concurrently. It revealed superior performance during integrated compared to segregated reports, beyond that explained by the codependence of the two measures on stimulus parameters. We argue that listeners have limited access to low-level stimulus representations once perceptual organization has occurred, and that subjective and objective streaming measures partly index the same processes. PMID- 26414170 TI - Graphitic Carbon Conformal Coating of Mesoporous TiO2 Hollow Spheres for High Performance Lithium Ion Battery Anodes. AB - Rational design and controllable synthesis of TiO2 based materials with unique microstructure, high reactivity, and excellent electrochemical performance for lithium ion batteries are crucially desired. In this paper, we developed a versatile route to synthesize hollow TiO2/graphitic carbon (H-TiO2/GC) spheres with superior electrochemical performance. The as-prepared mesoporous H-TiO2/GC hollow spheres present a high specific surface area (298 m(2) g(-1)), a high pore volume (0.31 cm(3) g(-1)), a large pore size (~5 nm), well-defined hollow structure (monodispersed size of 600 nm and inner diameter of ~400 nm, shell thickness of 100 nm), and small nanocrystals of anatase TiO2 (~8 nm) conformably encapsulated in ultrathin graphitic carbon layers. As a result, the H-TiO2/GC hollow spheres achieve excellent electrochemical reactivity and stability as an anode material for lithium ion batteries. A high specific capacity of 137 mAh g( 1) can be achieved up to 1000 cycles at a current density of 1 A g(-1) (5 C). We believe that the mesoporous H-TiO2/GC hollow spheres are expected to be applied as a high-performance electrode material for next generation lithium ion batteries. PMID- 26414169 TI - Higher Activation in CD4(+) T Cells But Similar Viral Control Among HIV/Hepatitis C Virus-Coinfected Patients on a Simplification Monotherapy. AB - The aim of this study was to assess whether hepatitis C virus (HCV) coinfection would affect the clinical and immunological outcome of HIV-infected patients following a simplification strategy. A prospective cohort of HIV-infected patients starting a ritonavir boosted darunavir monotherapy (mtDRV/rtv) was followed for 24 months. HCV infection was evaluated by HCV viremia and hepatic fibrosis. Immune activation was studied as HLA-DR CD38 coexpression on CD4(+) and CD8(+) T cells and also the quantification of plasma sCD14 levels. Microbial translocation was studied by the plasma levels of 16S rDNA and lipopolysaccharide (LPS). A total of 150 HIV-infected patients were enrolled in this study, including 46 individuals also infected with HCV (30.6%). HIV/HCV coinfection did not decrease mtDRV/rtv efficacy, since similar rates of HIV-1 intermittent viremia (HCV: 26.6% vs. no-HCV: 34.7%) and episodes of virological failure (HCV: 22.2% vs. no-HCV: 11.2%, p-value = 0.381) were found. No major differences were found between both groups at baseline, although higher HLA-DR(+)CD38(+)CD4(+) T cell counts were found in the coinfected group (HCV: 6.65% vs. no-HCV: 4.55%, p value = 0.032); this difference was maintained in the 24 months of follow-up. After the 24-month follow-up, both groups, HIV-monoinfected patients and HIV/HCV coinfected patients, presented similar immune activation and microbial translocation profiles. In conclusion, the use of a simplified mtDRV/rtv strategy compromises neither HIV nor HCV viremic control in coinfected patients, although a higher immune activation of CD4(+) T cells was found. PMID- 26414172 TI - Activation of FGF1B Promoter and FGF1 Are Involved in Cardiogenesis Through the Signaling of PKC, but Not MAPK. AB - Heart disease is the leading cause of human death in the 21st century. Heart transplantation is a promising way to treat this. Because donor resources are limited, cell-based therapy has been developed as an alternative. Therefore, genes that trigger cardiogenesis could have potential in the treatment of heart disease. Fibroblast growth factor 1 (FGF1) is reported to stimulate cardiomyocyte proliferation under conditions of myocardial infarction, but little is known about its function during cardiac differentiation. In this study, we established an in vitro cardiogenesis model through a reliable chemical induction protocol to determine whether FGF1 and its gene expression are involved in cardiogenesis. Oxytocin, not only a well-known hormone but also a cardiac differentiation inducer, was used in a mouse embryonic stem cell line, E14Tg2a, to achieve cardiac differentiation. After differentiation, beating cell clusters appeared and the expression of FGF1B mRNA was upregulated in the late differentiation stage (differentiation days 8-14). Interestingly, FGF1B expression patterns during cardiac differentiation were similar to those of a mature cardiomyocyte marker, troponin T2, cardiac. The blockage of FGF1-FGF receptor (FGFR) signaling reduced not only the appearance of beating cluster formation but also the expression levels of cardiomyocyte-associated genes. Moreover, by investigating FGF1 downstream signaling cascades, we observed that the efficiency of beating cluster formation was mainly regulated through the FGF1-FGFR-PKC signaling axis. Taken together, we provide evidence to support that FGF1 could regulate cardiogenesis primarily through the protein kinase C signaling, but not through the mitogen-activated protein kinase signaling, pathway. PMID- 26414173 TI - Surgical Treatment of Cor Triatriatum Sinister in a Cat Under Cardiopulmonary Bypass. AB - OBJECTIVE: To report the surgical repair of cor triatriatum sinister (CTS) incorporating heart-beating cardiopulmonary bypass (CPB) in a cat. STUDY DESIGN: Clinical case report. ANIMAL: Fourteen-month-old, 5.9-kg male castrated Maine Coon cat. MATERIALS AND METHODS: The cat had a 3 month history of inappetance, weight loss, and recurrent pulmonary edema. CTS with severe systolic pulmonary arterial (SPA) hypertension (124 mm Hg) was diagnosed by 2D echocardiography, color flow and continuous wave Doppler modes, and left atrial and pulmonary angiography. Surgery was performed through a left intercostal thoracotomy. CPB was initiated and the heart was kept beating. The left atrial appendage was opened and the intra-atrial membrane was excised. RESULTS: After 48 hours, the cat was doing well. Reduced SPA pressure (52 mm Hg) with decreased right heart enlargement was observed on ultrasound examination and the cat was discharged 6 days after surgery with oral antibiotics for 10 days, aspirin, and furosemide. Four months after surgery, the cat presented with increased activity and weight gain and was completely asymptomatic. Transthoracic echocardiography showed a marked improvement of all echo-Doppler variables with disappearance of SPA hypertension (24 mm Hg). Four years after surgery, the cat was still doing well with no recurrence of clinical signs despite the lack of medical treatment. CONCLUSION: CTS in the cat may be successfully treated by surgery facilitated by use of CPB leading to early and long-term substantial improvement in clinical status and cardiac function. CTS can safely be repaired under CPB in cats. PMID- 26414174 TI - Environmental Influences on Endothelial to Mesenchymal Transition in Developing Implanted Cardiovascular Tissue-Engineered Grafts. AB - Tissue-engineered grafts for cardiovascular structures experience biochemical stimuli and mechanical forces that influence tissue development after implantation such as the immunological response, oxidative stress, hemodynamic shear stress, and mechanical strain. Endothelial cells are a cell source of major interest in vascular tissue engineering because of their ability to form a luminal antithrombotic monolayer. In addition, through their ability to undergo endothelial to mesenchymal transition (EndMT), endothelial cells may yield a cell type capable of increased production and remodeling of the extracellular matrix (ECM). ECM is of major importance to the mechanical function of all cardiovascular structures. Tissue engineering approaches may employ EndMT to recapitulate, in part, the embryonic development of cardiovascular structures. Improved understanding of how the environment of an implanted graft could influence EndMT in endothelial cells may lead to novel tissue engineering strategies. This review presents an overview of biochemical and mechanical stimuli capable of influencing EndMT, discusses the influence of these stimuli as found in the direct environment of cardiovascular grafts, and discusses approaches to employ EndMT in tissue-engineered constructs. PMID- 26414175 TI - Facilitators and Barriers to Spinal Cord Injury Clinical Trial Participation: Multi-National Perspective of People Living with Spinal Cord Injury. AB - These are exciting times for the translation of promising interventions for spinal cord injury (SCI) into testing with clinical trials. These interventions include acute surgical decompression, neuroprotection, neural repair, cell replacement, activity-based rehabilitation, and medical devices, including devices requiring surgical implantation. By nature, clinical trials can have strict inclusion and exclusion criteria, which narrow down the pool of potential participants. Meeting enrollment numbers for properly powered trials is a daunting task. Therefore, it is important that trials are designed in a manner that facilitates participation. The purpose of this research study was to learn more about the factors that encourage or interfere with the decision to participate in clinical trials from the perspective of people living with SCI. A multi-national survey was conducted, primarily online, in which 802 participants with SCI ranked 32 factors as facilitators or barriers, using a Likert-type scale. There were 13 universal facilitators, five universal barriers, and three universally neutral factors. The number one facilitator was possible improvement in functionality and the number one barrier was possible decline in functionality -as may be expected. However, many unexpected facilitators and barriers were identified. There also were certain factors that were strong barriers or facilitators to certain sub-groups of people living with SCI. All of these factors should be taken into careful consideration when designing clinical trials so as to promote enrollment and enable adherence to different protocols. PMID- 26414177 TI - Influence of C-Trap Ion Accumulation Time on the Detectability of Analytes in IR MALDESI MSI. AB - Laser desorption followed by post electrospray ionization requires synchronized timing of the key events (sample desorption/ionization, mass spectrometry analysis, and sample translation) necessary to conduct mass spectrometry imaging (MSI) with adequate analyte sensitivity. In infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) MSI analyses, two laser pulses are used for analysis at each volumetric element, or voxel, of a biological sample and ion accumulation in the C-trap exceeding 100 ms is necessary to capture all sample-associated ions using an infrared laser with a 20 Hz repetition rate. When coupled to an Orbitrap-based mass spectrometer like the Q Exactive Plus, this time window for ion accumulation exceeds dynamically controlled trapping of samples with comparable ion flux by Automatic Gain Control (AGC), which cannot be used during MSI analysis. In this work, a next-generation IR-MALDESI source has been designed and constructed that incorporates a mid infrared OPO laser capable of operating at 100 Hz and allows requisite C-trap inject time during MSI to be reduced to 30 ms. Analyte detectability of the next generation IR-MALDESI integrated source has been evaluated as a function of laser repetition rate (100-20 Hz) with corresponding C-trap ion accumulation times (30 110 ms) in both untargeted and targeted analysis of biological samples. Reducing the C-trap ion accumulation time resulted in increased ion abundance by up to 3 orders of magnitude for analytes ranging from xenobiotics to endogenous lipids, and facilitated the reduction of voxel-to-voxel variability by more than 3-fold. PMID- 26414178 TI - The Complete Genome Phylogeny of Geographically Distinct Dengue Virus Serotype 2 Isolates (1944-2013) Supports Further Groupings within the Cosmopolitan Genotype. AB - Dengue virus serotype 2 (DENV-2) isolates have been implicated in deadly outbreaks of dengue fever (DF) and dengue hemorrhagic fever (DHF) in several regions of the world. Phylogenetic analysis of DENV-2 isolates collected from particular countries has been performed using partial or individual genes but only a few studies have examined complete whole-genome sequences collected worldwide. Herein, 50 complete genome sequences of DENV-2 isolates, reported over the past 70 years from 19 different countries, were downloaded from GenBank. Phylogenetic analysis was conducted and evolutionary distances of the 50 DENV-2 isolates were determined using maximum likelihood (ML) trees or Bayesian phylogenetic analysis created from complete genome nucleotide (nt) and amino acid (aa) sequences or individual gene sequences. The results showed that all DENV-2 isolates fell into seven main groups containing five previously defined genotypes. A Cosmopolitan genotype showed further division into three groups (C I, C-II, and C-III) with the C-I group containing two subgroups (C-IA and C-IB). Comparison of the aa sequences showed specific mutations among the various groups of DENV-2 isolates. A maximum number of aa mutations was observed in the NS5 gene, followed by the NS2A, NS3 and NS1 genes, while the smallest number of aa substitutions was recorded in the capsid gene, followed by the PrM/M, NS4A, and NS4B genes. Maximum evolutionary distances were found in the NS2A gene, followed by the NS4A and NS4B genes. Based on these results, we propose that genotyping of DENV-2 isolates in future studies should be performed on entire genome sequences in order to gain a complete understanding of the evolution of various isolates reported from different geographical locations around the world. PMID- 26414176 TI - Development of Preliminary Remission Criteria for Gout Using Delphi and 1000Minds Consensus Exercises. AB - OBJECTIVE: To establish consensus for potential remission criteria to use in clinical trials of gout. METHODS: Experts (n = 88) in gout from multiple countries were invited to participate in a web-based questionnaire study. Three rounds of Delphi consensus exercises were conducted using SurveyMonkey, followed by a discrete-choice experiment using 1000Minds software. The exercises focused on identifying domains, definitions for each domain, and the timeframe over which remission should be defined. RESULTS: There were 49 respondents (56% response) to the initial survey, with subsequent response rates ranging from 57% to 90%. Consensus was reached for the inclusion of serum urate (98% agreement), flares (96%), tophi (92%), pain (83%), and patient global assessment of disease activity (93%) as measurement domains in remission criteria. Consensus was also reached for domain definitions, including serum urate (<0.36 mm), pain (<2 on a 10-point scale), and patient global assessment (<2 on a 10-point scale), all of which should be measured at least twice over a set time interval. Consensus was not achieved in the Delphi exercise for the timeframe for remission, with equal responses for 6 months (51%) and 1 year (49%). In the discrete-choice experiment, there was a preference towards 12 months as a timeframe for remission. CONCLUSION: These consensus exercises have identified domains and provisional definitions for gout remission criteria. Based on the results of these exercises, preliminary remission criteria are proposed with domains of serum urate, acute flares, tophus, pain, and patient global assessment. These preliminary criteria now require testing in clinical data sets. PMID- 26414180 TI - An overview of imaging techniques for liver metastases management. AB - Evaluation of liver metastases is one of the most common indications for liver imaging. Imaging plays a key role in the of assessment liver metastases. A variety of imaging techniques, including ultrasonography, computed tomography, MRI and PET combined with CT scan are available for diagnosis, planning treatment, and follow-up treatment response. In this paper, the authors present the role of imaging for the assessment of liver metastases and the contribution of each of the different imaging techniques for their evaluation and management. Following recent developments in the field of oncology, the authors also present the importance of imaging for the assessment of liver metastases response to therapy. Finally, future perspectives on imaging of liver metastases are presented. PMID- 26414179 TI - Redesigning Recombinase Specificity for Safe Harbor Sites in the Human Genome. AB - Site-specific recombinases (SSRs) are valuable tools for genetic engineering due to their ability to manipulate DNA in a highly specific manner. Engineered zinc finger and TAL effector recombinases, in particular, are two classes of SSRs composed of custom-designed DNA-binding domains fused to a catalytic domain derived from the resolvase/invertase family of serine recombinases. While TAL effector and zinc-finger proteins can be assembled to recognize a wide range of possible DNA sequences, recombinase catalytic specificity has been constrained by inherent base requirements present within each enzyme. In order to further expand the targeted recombinase repertoire, we used a genetic screen to isolate enhanced mutants of the Bin and Tn21 recombinases that recognize target sites outside the scope of other engineered recombinases. We determined the specific base requirements for recombination by these enzymes and demonstrate their potential for genome engineering by selecting for variants capable of specifically recombining target sites present in the human CCR5 gene and the AAVS1 safe harbor locus. Taken together, these findings demonstrate that complementing functional characterization with protein engineering is a potentially powerful approach for generating recombinases with expanded targeting capabilities. PMID- 26414181 TI - Reconstructing the fractal dimension of granular aggregates from light intensity spectra. AB - There has been growing interest in using the fractal dimension to study the hierarchical structures of soft materials after realising that fractality is an important property of natural and engineered materials. This work presents a method to quantify the internal architecture and the space-filling capacity of granular fractal aggregates by reconstructing the three-dimensional capacity dimension from their two-dimensional optical projections. Use is made of the light intensity of the two-dimensional aggregate images to describe the aggregate surface asperities (quantified by the perimeter-based fractal dimension) and the internal architecture (quantified by the capacity dimension) within a mathematical framework. This method was tested on control aggregates of diffusion limited (DLA), cluster-cluster (CCA) and self-correlated (SCA) types, stereolithographically-fabricated aggregates, and experimentally-acquired natural sedimentary aggregates. Statistics of the reconstructed capacity dimension featured correlation coefficients R >= 98%, residuals NRMSE <= 10% and percent errors PE <= 4% as compared to controls, and improved earlier approaches by up to 50%. PMID- 26414182 TI - An Approach to Improve the Performance of PM Forecasters. AB - The particulate matter (PM) concentration has been one of the most relevant environmental concerns in recent decades due to its prejudicial effects on living beings and the earth's atmosphere. High PM concentration affects the human health in several ways leading to short and long term diseases. Thus, forecasting systems have been developed to support decisions of the organizations and governments to alert the population. Forecasting systems based on Artificial Neural Networks (ANNs) have been highlighted in the literature due to their performances. In general, three ANN-based approaches have been found for this task: ANN trained via learning algorithms, hybrid systems that combine search algorithms with ANNs, and hybrid systems that combine ANN with other forecasters. Independent of the approach, it is common to suppose that the residuals (error series), obtained from the difference between actual series and forecasting, have a white noise behavior. However, it is possible that this assumption is infringed due to: misspecification of the forecasting model, complexity of the time series or temporal patterns of the phenomenon not captured by the forecaster. This paper proposes an approach to improve the performance of PM forecasters from residuals modeling. The approach analyzes the remaining residuals recursively in search of temporal patterns. At each iteration, if there are temporal patterns in the residuals, the approach generates the forecasting of the residuals in order to improve the forecasting of the PM time series. The proposed approach can be used with either only one forecaster or by combining two or more forecasting models. In this study, the approach is used to improve the performance of a hybrid system (HS) composed by genetic algorithm (GA) and ANN from residuals modeling performed by two methods, namely, ANN and own hybrid system. Experiments were performed for PM2.5 and PM10 concentration series in Kallio and Vallila stations in Helsinki and evaluated from six metrics. Experimental results show that the proposed approach improves the accuracy of the forecasting method in terms of fitness function for all cases, when compared with the method without correction. The correction via HS obtained a superior performance, reaching the best results in terms of fitness function and in five out of six metrics. These results also were found when a sensitivity analysis was performed varying the proportions of the sets of training, validation and test. The proposed approach reached consistent results when compared with the forecasting method without correction, showing that it can be an interesting tool for correction of PM forecasters. PMID- 26414183 TI - Emergence of OXA-48-Producing Klebsiella pneumoniae in Taiwan. AB - The isolation of OXA-48-producing Enterobacteriaceae has increased dramatically in Mediterranean countries in the past 10 years, and has recently emerged in Asia. Between January 2012 and May 2014, a total of 760 carbapenem non susceptible Klebsiella pneumoniae (CnSKP) isolates were collected during a Taiwan national surveillance. Carbapenemases were detected in 210 CnSKP isolates (27.6%), including 162 KPC-2 (n = 1), KPC-3, KPC-17, and NDM-1 (n = 1 each), OXA 48 (n = 4), IMP-8 (n = 18), and VIM-1 (n = 24). The four blaOXA-48 CnSKP isolates were detected in late 2013. Herein we report the emergence OXA-48-producing K. pneumoniae isolates in Taiwan. PFGE analysis revealed that the four isolates belonged to three different pulsotypes. Three isolates harboured blaCTX-M genes and belonged to MLST type ST11. In addition, the plasmids belonged to the incompatibility group, IncA/C. One isolate belonged to ST116 and the plasmid incompatibility group was non-typeable. The sequence upstream of the blaOXA-48 gene in all four isolates was identical to pKPOXA-48N1, a blaOXA-48-carrying plasmid. This is the first report of OXA-48-producing Enterobacteriaceae in Taiwan and the second report to identify blaOXA-48 on an IncA/C plasmid in K. pneumoniae. Given that three isolates belong to the same pandemic clone (ST11) and possess the IncA/C plasmid and similar plasmid digestion profile that indicated the role of clonal spread or plasmid for dissemination of blaOXA-48 gene, the emergence of OXA-48-producing K. pneumoniae in Taiwan is of great concern. PMID- 26414185 TI - Platelet transfusion and respecting patient D type. AB - PURPOSE OF REVIEW: Current guidance allows transfusing D-mismatched platelets to D negative recipients when necessitated by logistic constraints. Although the D antigen is not expressed on the platelet membrane, platelet concentrates are still labeled by their D antigen status because the platelet concentrates contain a small quantity of red blood cells. D matching is currently recommended to prevent D alloimmunization based on frequencies of D alloimmunization after transfusing platelet concentrates obtained from whole blood collections of up to 18.7%. RECENT FINDINGS: The content of red blood cells is higher in pooled platelet concentrates prepared from whole blood collections (range: 0.036-0.59 ml) than in platelet concentrates obtained from apheresis devices (range: 0.00017 0.009 ml). Large retrospective studies with long follow-up suggest that it is not possible to rule out a secondary immunization in D negative patients who developed an alloanti-D within 4 weeks after receiving the first D-mismatched platelet transfusion, and the frequency of D alloimmunization after D-mismatched platelet transfusions ranges between 0 and 7.1%. SUMMARY: Based on the reported frequencies of D alloimmunization and data from some recent large studies, we recommend administering Rh Immune Globulin, if D-mismatched platelet concentrates prepared from whole blood collections are transfused to D negative females of childbearing potential. PMID- 26414186 TI - Neutrophil/granulocyte transfusions collected from G-CSF + dexamethasone stimulated donors. AB - PURPOSE OF REVIEW: The purpose of this review is to report a recently completed multicenter randomized controlled trial of neutrophil/granulocyte transfusions collected from G-CSF + dexamethasone donors to treat neutropenic infections in oncology and transplant patients, within the context of other historic and current clinical trials.The multicenter trial (RING Study) was funded by the NHLBI transfusion medicine/hemostasis clinical trials network. RECENT FINDINGS: There was no significant benefit of therapeutic neutrophil/granulocyte transfusions versus antibiotics per intention to treat analysis, but 32% of patients received substandard neutrophil doses. Separate analysis suggested patients given a higher neutrophil doses had better outcomes. SUMMARY: Efficacy of 'high-dose' therapeutic neutrophil/granulocyte transfusions remains unproven, but promising. PMID- 26414184 TI - The Viral Mimetic Polyinosinic:Polycytidylic Acid Alters the Growth Characteristics of Small Intestinal and Colonic Crypt Cultures. AB - BACKGROUND & AIMS: The intestinal epithelium is the first line of defense against enteric pathogens. We investigated the response of small intestinal and colonic crypt cultures to a panel of toll-like receptor ligands to assess the impact of microbial pattern recognition on epithelial growth. METHODS: Primary murine jejunal enteroids and colonoids were cultured with lipopeptide Pam3CSK4, lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (Poly I:C) for 4 to 6 days. Surface area, budding and survival were assessed. Proliferation and numbers of lysozyme positive cells were quantified by flow cytometry. Gene expression was assessed by Nanostring and qRT-PCR. RESULTS: Exposure to Pam3CSK4 and LPS had minimal impact on either enteroids or colonoids. In contrast, Poly I:C increased the surface area of enteroids, while colonoids demonstrated decreased budding. Survival was decreased by Poly I:C in enteroids but not in colonoids. Both enteroids and colonoids exhibited upregulated gene expression of chemokines, but these were increased in magnitude in enteroids. Decreases in gene expression associated with epithelial differentiation and lysozyme positive cells were more apparent in enteroids than in colonoids. Baseline gene expression between enteroids and colonoids differed markedly in levels of stem cell and inflammatory markers. The changes in morphology induced by Poly I:C were mediated by the toll like receptor adaptor molecule 1 (Ticam1) in enteroids but not in colonoids. CONCLUSIONS: Poly I:C alters the molecular program of epithelial cells and shifts from absorption and digestion towards defense and inflammation. Diversity of responses to microbial patterns in enteroids and colonoids may underlie differences in susceptibility to infection along the intestinal tract. PMID- 26414189 TI - Single nucleotide polymorphisms in TP53 but not KRAS or MDM2 are predictive of clinical outcome in multiple myeloma treated with high-dose melphalan and autologous stem cell support. PMID- 26414190 TI - Social power and recognition of emotional prosody: High power is associated with lower recognition accuracy than low power. AB - Listeners have to pay close attention to a speaker's tone of voice (prosody) during daily conversations. This is particularly important when trying to infer the emotional state of the speaker. Although a growing body of research has explored how emotions are processed from speech in general, little is known about how psychosocial factors such as social power can shape the perception of vocal emotional attributes. Thus, the present studies explored how social power affects emotional prosody recognition. In a correlational study (Study 1) and an experimental study (Study 2), we show that high power is associated with lower accuracy in emotional prosody recognition than low power. These results, for the first time, suggest that individuals experiencing high or low power perceive emotional tone of voice differently. PMID- 26414191 TI - The impact of affective contexts on working memory capacity in healthy populations and in individuals with PTSD. AB - Individual differences in working memory capacity (WMC) strongly predict variations in real-world cognitive functioning. However, little is known about how WMC is influenced by the ubiquitously present affective information in our everyday environments. Here, we present a series of 3 experiments investigating a novel WMC paradigm performed in affective (vs. neutral) contexts. The paradigm requires simultaneous performance of a visuospatial search and a verbal storage task. These tasks are performed in the presence of either neutral or negative emotional distractor images. Experiments 1 and 2 confirmed our prediction that WMC would be reduced in the context of emotional compared with neutral distractors in student and community samples. Experiment 3 extended these findings to a clinical sample. WMC in motor vehicle accident survivors with a history of posttraumatic stress disorder (PTSD) was selectively reduced in the presence of trauma-related emotional distraction compared with survivors without a history of PTSD. Implications of these findings for affective cognitive science are discussed. PMID- 26414193 TI - Metagenomic insights into the dynamics of microbial communities in food. AB - Metagenomics has proven to be a powerful tool in exploring a large diversity of natural environments such as air, soil, water, and plants, as well as various human microbiota (e.g. digestive tract, lungs, skin). DNA sequencing techniques are becoming increasingly popular and less and less expensive. Given that high throughput DNA sequencing approaches have only recently started to be used to decipher food microbial ecosystems, there is a significant growth potential for such technologies in the field of food microbiology. The aim of this review is to present a survey of recent food investigations via metagenomics and to illustrate how this approach can be a valuable tool in the better characterization of foods and their transformation, storage and safety. Traditional food in particular has been thoroughly explored by global approaches in order to provide information on multi-species and multi-organism communities. PMID- 26414192 TI - A New Acute Impact-Compression Lumbar Spinal Cord Injury Model in the Rodent. AB - Traumatic injury to the lumbar spinal cord results in complex central and peripheral nervous tissue damage causing significant neurobehavioral deficits and personal/social adversity. Although lumbar cord injuries are common in humans, there are few clinically relevant models of lumbar spinal cord injury (SCI). This article describes a novel lumbar SCI model in the rat. The effects of moderate (20 g), moderate-to-severe (26 g) and severe (35 g, and 56 g) clip impact compression injuries at the lumbar spinal cord level L1-L2 (vertebral level T11 T12) were assessed using several neurobehavioral, neuroanatomical, and electrophysiological outcome measures. Lesions were generated after meticulous anatomical landmarking using microCT, followed by laminectomy and extradural inclusion of central and radicular elements to generate a traumatic SCI. Clinically relevant outcomes, such as MR and ultrasound imaging, were paired with robust morphometry. Analysis of the lesional tissue demonstrated that pronounced tissue loss and cavitation occur throughout the acute to chronic phases of injury. Behavioral testing revealed significant deficits in locomotion, with no evidence of hindlimb weight-bearing or hindlimb-forelimb coordination in any injured group. Evaluation of sensory outcomes revealed highly pathological alterations including mechanical allodynia and thermal hyperalgesia indicated by increasing avoidance responses and decreasing latency in the tail-flick test. Deficits in spinal tracts were confirmed by electrophysiology showing increased latency and decreased amplitude of both sensory and motor evoked potentials (SEP/MEP), and increased plantar H-reflex indicating an increase in motor neuron excitability. This is a comprehensive lumbar SCI model and should be useful for evaluation of translationally oriented pre-clinical therapies. PMID- 26414195 TI - Optical rectennas: Nanotubes circumvent trade-offs. PMID- 26414194 TI - Infrared rectification in a nanoantenna-coupled metal-oxide-semiconductor tunnel diode. AB - Direct rectification of electromagnetic radiation is a well-established method for wireless power conversion in the microwave region of the spectrum, for which conversion efficiencies in excess of 84% have been demonstrated. Scaling to the infrared or optical part of the spectrum requires ultrafast rectification that can only be obtained by direct tunnelling. Many research groups have looked to plasmonics to overcome antenna-scaling limits and to increase the confinement. Recently, surface plasmons on heavily doped Si surfaces were investigated as a way of extending surface-mode confinement to the thermal infrared region. Here we combine a nanostructured metallic surface with a heavily doped Si infrared reflective ground plane designed to confine infrared radiation in an active electronic direct-conversion device. The interplay of strong infrared photon phonon coupling and electromagnetic confinement in nanoscale devices is demonstrated to have a large impact on ultrafast electronic tunnelling in metal oxide-semiconductor (MOS) structures. Infrared dispersion of SiO2 near a longitudinal optical (LO) phonon mode gives large transverse-field confinement in a nanometre-scale oxide-tunnel gap as the wavelength-dependent permittivity changes from 1 to 0, which leads to enhanced electromagnetic fields at material interfaces and a rectified displacement current that provides a direct conversion of infrared radiation into electric current. The spectral and electrical signatures of the nanoantenna-coupled tunnel diodes are examined under broadband blackbody and quantum-cascade laser (QCL) illumination. In the region near the LO phonon resonance, we obtained a measured photoresponsivity of 2.7 mA W(-1) cm(-2) at -0.1 V. PMID- 26414196 TI - Surface imaging beyond the diffraction limit with optically trapped spheres. AB - Optical traps play an increasing role in the bionanosciences because of their ability to apply forces flexibly on tiny structures in fluid environments. Combined with particle-tracking techniques, they allow the sensing of miniscule forces exerted on these structures. Similar to atomic force microscopy (AFM), but much more sensitive, an optically trapped probe can be scanned across a structured surface to measure the height profile from the displacements of the probe. Here we demonstrate that, by the combination of a time-shared twin-optical trap and nanometre-precise three-dimensional interferometric particle tracking, both reliable height profiling and surface imaging are possible with a spatial resolution below the diffraction limit. The technique exploits the high-energy thermal position fluctuations of the trapped probe, and leads to a sampling of the surface 5,000 times softer than in AFM. The measured height and force profiles from test structures and Helicobacter cells illustrate the potential to uncover specific properties of hard and soft surfaces. PMID- 26414198 TI - A carbon nanotube optical rectenna. AB - An optical rectenna--a device that directly converts free-propagating electromagnetic waves at optical frequencies to direct current--was first proposed over 40 years ago, yet this concept has not been demonstrated experimentally due to fabrication challenges at the nanoscale. Realizing an optical rectenna requires that an antenna be coupled to a diode that operates on the order of 1 PHz (switching speed on the order of 1 fs). Diodes operating at these frequencies are feasible if their capacitance is on the order of a few attofarads, but they remain extremely difficult to fabricate and to reliably couple to a nanoscale antenna. Here we demonstrate an optical rectenna by engineering metal-insulator-metal tunnel diodes, with a junction capacitance of ~2 aF, at the tip of vertically aligned multiwalled carbon nanotubes (~10 nm in diameter), which act as the antenna. Upon irradiation with visible and infrared light, we measure a d.c. open-circuit voltage and a short-circuit current that appear to be due to a rectification process (we account for a very small but quantifiable contribution from thermal effects). In contrast to recent reports of photodetection based on hot electron decay in a plasmonic nanoscale antenna, a coherent optical antenna field appears to be rectified directly in our devices, consistent with rectenna theory. Finally, power rectification is observed under simulated solar illumination, and there is no detectable change in diode performance after numerous current-voltage scans between 5 and 77 degrees C, indicating a potential for robust operation. PMID- 26414197 TI - Nanoscale cation motion in TaO(x), HfO(x) and TiO(x) memristive systems. AB - A detailed understanding of the resistive switching mechanisms that operate in redox-based resistive random-access memories (ReRAM) is key to controlling these memristive devices and formulating appropriate design rules. Based on distinct fundamental switching mechanisms, two types of ReRAM have emerged: electrochemical metallization memories, in which the mobile species is thought to be metal cations, and valence change memories, in which the mobile species is thought to be oxygen anions (or positively charged oxygen vacancies). Here we show, using scanning tunnelling microscopy and supported by potentiodynamic current-voltage measurements, that in three typical valence change memory materials (TaO(x), HfO(x) and TiO(x)) the host metal cations are mobile in films of 2 nm thickness. The cations can form metallic filaments and participate in the resistive switching process, illustrating that there is a bridge between the electrochemical metallization mechanism and the valence change mechanism. Reset/Set operations are, we suggest, driven by oxidation (passivation) and reduction reactions. For the Ta/Ta2O5 system, a rutile-type TaO2 film is believed to mediate switching, and we show that devices can be switched from a valence change mode to an electrochemical metallization mode by introducing an intermediate layer of amorphous carbon. PMID- 26414199 TI - HDAC4 stabilizes SIRT1 via sumoylation SIRT1 to delay cellular senescence. AB - The nicotinamide adenine dinucleotide-dependent protein deacetylase silent information regulator 2 (Sir2) regulates cellular lifespan in several organisms. Histone deacetylase 4 (HDAC4) belongs to the class IIa group of HDACs; this class of HDACs is composed of proteins that are important regulators of gene expression that control pleiotropic cellular functions. However, the role of HDAC4 in cellular senescence is still unknown. This study shows that the expression patterns of HDAC4 and Sirtuin 1 (SIRT1; the mammalian homolog of Sir2) are positively correlated during cellular senescence. Moreover, the overexpression of HDAC4 delays senescence, whereas the knockdown of HDAC4 leads to premature senescence in human fibroblasts. Furthermore, it is demonstrated that HDAC4 increases endogenous SIRT1 expression by enhancing its sumoylation modification levels, thereby stabilizing its protein levels. This study, therefore, provides a new molecular mechanism for the regulation of cellular senescence. PMID- 26414200 TI - Contrasting Solid-State Fluorescence of Diynes with Small and Large Aryl Substituents: Crystal Packing Dependence and Stimuli-Responsive Fluorescence Switching. AB - There has been a significant current interest in solid state luminescence of organic molecules and their stimuli responsive fluorescence switching behavior. Although small organic derivatives with olefinic, acetylenic, phenylenevinylenic, phenyleneethynylenic spacers are widely documented as solid state emitters in the literature, the solid state photophysics of organic derivatives with "butadiyne" spacer still remains unexplored. We provide detailed investigation on the solid state fluorescence properties of a series of butadiynyl fluorophores. Replacement of a phenyl ring, which is at periphery of the butadiyne bridge, with a large moiety such as pyrenyl group furnishes contrasting emissions in the solid state. While the butadiyne bridged phenyl derivatives show a blue shift of emission maxima in the solid powder with respect to monomer spectra in solution state, the butadiyne bridged pyrenyl derivatives exhibit a red shift in the solid state. The blue shift of the emission maxima of the butadiyne bridged phenyl derivatives in the solid powder is attributed to allowed excitonic transition in aggregates with nearly parallel transition dipoles. On the other hand, formation of pyrenyl excimer accounts for the red shift of the butadiyne bridged pyrenyl derivatives in the solid powder. In addition to that, the solid state fluorescence of the pyrenyl analogues is reversibly switched between two aggregate forms through external heating and rubbing stimuli. PMID- 26414201 TI - Enantioselective Synthesis of a Furan Lignan (+)-Sylvone. AB - A synthesis of natural tetrahydrofuran lignan (+)-sylvone is achieved starting from methyl allenoate in 5 steps. The synthesis begins from an enantioselective aldol reaction of methyl allenoate with 3,4-dimethoxybenzaldehyde to afford alpha addition aldol adduct. Key steps for the synthesis of sylvone include an oxacyclization of the alpha-hydroxy allenyl adduct followed by a Michael addition of a 1,3-dithiane derivative to establish a sylvone skeleton with suitable stereoselections. PMID- 26414202 TI - Functional electrical stimulation for the upper limb in tetraplegic spinal cord injury: a systematic review. AB - Technological advances have helped to improve functional ability in spinal cord injury survivors. The aim of this study is to systematically review the evidence for functional electrical stimulation (FES) on functional tasks involving the upper limb in people with spinal cord injuries. The authors systematically searched from September 2009 to September 2014 in relevant databases using a combination of keywords covering spinal cord injury and FES. Studies were selected using pre-determined criteria. The search yielded 144 studies. Only five studies met the inclusion criteria. All five reported improvements immediately and at follow-up in functional ability as a result of FES or FES combined with conventional therapy. There is some preliminary evidence that FES may reduce disability due to upper limb-related activity limitations in tetraplegic spinal cord injury. Further work needs to examine the role of FES in more detail and in combination with other treatments. PMID- 26414203 TI - Patterns of fetal lung growth in fetuses with isolated left-sided congenital diaphragmatic hernia. AB - OBJECTIVE: To evaluate right lung growth pattern in fetuses with isolated left sided congenital diaphragmatic hernia (iL-CDH) and to analyze the pattern according to postnatal outcome. METHODS: Lung-to-head ratio (LHR) and observed-to expected LHR (O/E LHR) were obtained in 58 cases. Correlation and regression analysis for the total number of measurements, general linear models for those cases with a least three serial measurements and linear mixed effect models were used to analyze the influence of gestational age on the right lung size. Cases expectantly managed and those with fetal endoscopic tracheal occlusion were analyzed separately. RESULTS: LHR, but not O/E LHR, increased significantly with gestational age (GA) (r = 0.43, p = 0.003 and r = -0.13, p = 0.30, respectively). According to neonatal mortality, in those fetuses that died, LHR remained unchanged and O/E LHR decreased significantly with GA (r = 0.07, p = 0.65 and r = -0.37, p = 0.02, respectively). In those cases with at least three serial measurements, the same two patterns were found. Similarly, in cases with expectant management, surviving fetuses showed a significantly higher weekly increase in LHR (p = 0.01) and a trend to a lower weekly decrease in O/E LHR (p = 0.17) than in those that died. CONCLUSIONS: Patterns of right lung growth in iL CDH differ according to postnatal survival. Serial measurements, but not a single one, might increase the prediction of neonatal death. PMID- 26414204 TI - Understanding sibling influence on adolescents' alcohol use: Social and cognitive pathways. AB - Research indicates that older siblings uniquely influence their younger brothers' and sisters' substance use behaviors during adolescence; however, the underlying mechanisms of socialization are rarely examined. The present study investigated whether social and/or cognitive pathways mediated the association between adolescent siblings' alcohol use and whether these pathways were moderated by the gender composition of the sibling dyad. Participants included one parent and two adolescent siblings (M age=14.52 and 17.17years) from 326 families. Data were collected via telephone interviews. Path analysis demonstrated that the association between older and younger siblings' alcohol use was mediated via social and cognitive pathways. Specifically, older siblings' drinking was positively related to the frequency of siblings' co-use as well as more positive expectations about alcohol, which in turn were positively associated with younger siblings' alcohol use. Identifying the ways in which siblings influence each other's substance use and health is critical because they are emerging and effective targets of intervention and prevention. PMID- 26414205 TI - Sexual revictimization, PTSD, and problem drinking in sexual assault survivors. AB - Posttraumatic stress disorder (PTSD) and problem drinking are common and often co occurring sequelae experienced by women survivors of adult sexual assault, yet revictimization may mediate risk of symptoms over time. Structural equation modeling was used to examine data from a 3-wave panel design with a large (N=1012), ethnically diverse sample of women assault survivors to examine whether repeated sexual victimization related to greater PTSD and problem drinking. Structural equation modeling revealed that child sexual abuse was associated with greater symptoms of PTSD and problem drinking and intervening sexual victimization was associated with greater symptoms of PTSD and problem drinking at both 1 and 2year follow-ups. We found no evidence, however, that PTSD directly influenced problem drinking over the long term or vice versa, although they were correlated at each timepoint. Revictimization during the study predicted survivors' prospective PTSD and problem drinking symptoms inconsistently. Implications and recommendations for future research are discussed. PMID- 26414206 TI - Developmental trajectories of adolescent cannabis use and their relationship to young adult social and behavioural adjustment: A longitudinal study of Australian youth. AB - This study aimed to identify distinct developmental trajectories (sub-groups of individuals who showed similar longitudinal patterns) of cannabis use among Australian adolescents, and to examine associations between trajectory group membership and measures of social and behavioural adjustment in young adulthood. Participants (n=852, 53% female) were part of the International Youth Development Study. Latent class growth analysis was used to identify distinct trajectories of cannabis use frequency from average ages 12 to 19, across 6 waves of data. Logistic regression analyses and analyses of covariance were used to examine relationships between trajectory group membership and young adult (average age: 21) adjustment, controlling for a range of covariates. Three trajectories were identified: abstainers (62%), early onset users (11%), and late onset occasional users (27%). The early onset users showed a higher frequency of antisocial behaviour, violence, cannabis use, cannabis-related harms, cigarette use, and alcohol harms, compared to the abstinent group in young adulthood. The late onset occasional users reported a higher frequency of cannabis use, cannabis-related harms, illicit drug use, and alcohol harms, compared to the abstinent group in young adulthood. There were no differences between the trajectory groups on measures of employment, school completion, post-secondary education, income, depression/anxiety, or alcohol use problems. In conclusion, early onset of cannabis use, even at relatively low frequency during adolescence, is associated with poorer adjustment in young adulthood. Prevention and intervention efforts to delay or prevent uptake of cannabis use should be particularly focussed on early adolescence prior to age 12. PMID- 26414207 TI - Pathogen Loading From Canada Geese Faeces in Freshwater: Potential Risks to Human Health Through Recreational Water Exposure. AB - Canada geese (Branta canadensis) faeces have been shown to contain pathogenic protozoa and bacteria in numerous studies over the past 15 years. Further, increases in both the Canada geese populations and their ideal habitat requirements in the United States (US) translate to a greater presence of these human pathogens in public areas, such as recreational freshwater beaches. Combining these factors, the potential health risk posed by Canada geese faeces at freshwater beaches presents an emerging public health issue that warrants further study. Here, literature concerning human pathogens in Canada geese faeces is reviewed and the potential impacts these pathogens may have on human health are discussed. Pathogens of potential concern include Campylobacter jejuni, Salmonella Typhimurium, Listeria monocytogenes, Helicobacter canadensis, Arcobacter spp., Enterohemorragic Escherichia coli pathogenic strains, Chlamydia psitacci, Cryptosporidium parvum and Giardia lamblia. Scenarios presenting potential exposure to pathogens eluted from faeces include bathers swimming in lakes, children playing with wet and dry sand impacted by geese droppings and other common recreational activities associated with public beaches. Recent recreational water-associated disease outbreaks in the US support the plausibility for some of these pathogens, including Cryptosporidium spp. and C. jejuni, to cause human illness in this setting. In view of these findings and the uncertainties associated with the real health risk posed by Canada geese faecal pathogens to users of freshwater lakes, it is recommended that beach managers use microbial source tracking and conduct a quantitative microbial risk assessment to analyse the local impact of Canada geese on microbial water quality during their decision-making process in beach and watershed management. PMID- 26414208 TI - The relationship between inflammation and neoangiogenesis of epicardial adipose tissue and coronary atherosclerosis based on computed tomography analysis. AB - OBJECTIVE: Previous studies indicate that epicardial adipose tissue (EAT) biologically contributes to the progression of coronary atherosclerosis. We evaluated the relationship between EAT pathology, represented by inflammation and neoangiogenesis, and coronary atherosclerosis on computed tomography (CT) images. METHODS: We performed CT examination in 45 patients scheduled for cardiac surgery (coronary artery bypass graft [CABG], n = 21; non-CABG, n = 24) to assess visceral adipose tissue (VAT) area, EAT volume, coronary calcium score (CCS), and presence of non-calcified coronary plaque (NCP) on CT angiography. Each patient was assessed with the numbers of CD68(+) individual macrophages and CD31(+) neovessels in six random high-power fields (400*) of EAT samples subsequently obtained during cardiac surgery. RESULTS: In three groups based on CCS (mild, 0 100; moderate, 101-400; severe, >400), the moderate group had the most extensive macrophage infiltration (p = 0.0025) and neoangiogenesis (p = 0.0036) in EAT. The patients with NCP had more extensive macrophage infiltration (p = 0.010) and neoangiogenesis (p = 0.0043) in EAT than those without. On multivariate analysis adjusted for age, sex, CABG versus. non-CABG, VAT area, and EAT volume, moderate CCS and the presence of NCP showed significant correlations with increased macrophage infiltration (beta = 0.65; p < 0.0001, and beta = 0.49; p = 0.0089, respectively) and neoangiogenesis (beta = 0.55; p = 0.0011, and beta = 0.53; p = 0.012, respectively) in EAT. CONCLUSION: Inflammation and neoangiogenesis in EAT independently correlate with moderate coronary calcification and presence of NCP, suggesting that these two factors may have a role in promoting coronary atherosclerosis. PMID- 26414209 TI - Association between serum gamma-glutamyltransferase and the progression of coronary artery calcification. AB - BACKGROUND: Elevated serum gamma-glutamyltransferase (GGT) has been demonstrated to be associated with coronary artery calcification (CAC). CAC progression is an important marker of atherosclerosis and correlates with future cardiovascular risk. However, there is a lack of research that directly examines the association between serum GGT and CAC progression. The aim of this study was to elucidate the association between serum GGT activity and CAC progression. METHODS: We enrolled 1246 asymptomatic participants who underwent repeated CAC score measurement during routine health examinations. To eliminate the dependence of the inter scan variability on the baseline CAC scores, square root-transformed CAC scores were used to analyze CAC progression. In addition, the annualized rate of change in CAC scores was computed. RESULTS: Serum GGT activities were significantly higher in "progressors" than "nonprogressors". The prevalence of progression increased with the GGT tertile (11.9%, 20.1% and 27.9% in the 1st, 2nd, and 3rd GGT tertiles, respectively; p < 0.001). In the multivariate logistic regression analysis, the odds ratio (95% confidence interval) for CAC score progression was 1.85 (1.14-3.00) in the highest GGT tertile group. By multivariate linear regression analysis, baseline serum GGT activity demonstrated a positive association with the annualized change in CAC score (beta = 0.002; p = 0.006) after adjusting for cardiovascular risk factors. CONCLUSION: Elevated serum GGT levels are independently associated with CAC progression. Serum GGT levels may be a potential biomarker of future coronary atherosclerosis and prognosis. PMID- 26414210 TI - A carotid extra-media thickness, PATIMA combined index and coronary artery disease: Comparison with well-established indexes of carotid artery and fat depots. AB - BACKGROUND: The clinical utility of traditional cardiovascular (CV) risk factors to predict coronary artery disease (CAD) is insufficient and limited. Our aim was to evaluate the association between a novel ultrasound index of periarterial fat and adventitia (carotid extra-media thickness; EMT) and the severity of CAD and to compare this with well-known vascular indexes in patients with high and very high CV risk. METHODS AND RESULTS: Four hundred twenty two patients scheduled for elective coronary angiography were included in the study (age: 61.3 +/- 7.4 years; males 65%). Several clinical parameters of obesity were obtained as well as the following ultrasound indexes: carotid EMT and intima-media thickness (IMT), epicardial and pericardial fat thickness (EFT and PFT), and intra abdominal fat thickness (IAT). These were then related to CAD severity in all individuals. Our study patients had a very high estimated CV risk (82%), and most (60%) fulfilled the MS criteria. Most individuals (71%) had CAD (>=50% stenosis) with equal rates of one, two, or three-vessel disease, and critical (>=70%) coronary stenosis was found in 40% of patients. Carotid EMT was significantly increased in patients with CAD (812 +/- 116 vs 746 +/- 131 MUm) and patients with critical coronary stenosis (829 +/- 119 vs 769 +/- 122 MUm) compared to the appropriate control groups. Moreover, carotid EMT was significantly associated with the severity of CAD. Carotid IMT and EFT (but not PFT and IAT) also revealed significant relations to the number of diseased vessels. Carotid EMT and the new proposed combined index (PATIMA = EMT/BMIx35 + IMT + EFTx60) were predictive for CAD (AUC: 686 +/- 304 and 755 +/- 260, sensitivity: 60 and 62%, specificity: 76 and 81% for 772 MUm and 2015u). CONCLUSIONS: We present the first study showing that the new vascular index (carotid EMT) and the proposed combined index PATIMA are associated with the presence and the severity of CAD. PMID- 26414211 TI - Mutations in CypA Binding Region of HIV-1 Capsid Affect Capsid Stability and Viral Replication in Primary Macrophages. AB - Mutations in the cyclophilin A (CypA) binding region in the HIV-1 capsid affect their dependency on the known HIV-1 cofactor CypA and allow escape from the HIV-1 restriction factor Trim5alpha in human and simian cells. Here we study the effect of these mutations in the CypA binding region of capsid on cofactor binding, capsid destabilization, and viral replication in primary cells. We showed that the viral capsid with mutations in the CypA binding region (CypA-BR) interacted efficiently with CypA, but had an increased stability upon infection as compared to the wild-type capsid. Interestingly, the wild-type virus was able to infect monocyte-derived macrophages (MDM) more efficiently as compared to the CypA-BR mutant variant. The lower infectivity of the CypA-BR mutant virus in MDM was associated with lower levels of reverse transcription products. Similar to the wild-type virus, the CypA-BR mutant variant was unable to induce a strong innate response in primary macrophages. These data demonstrate that mutations in the CypA binding site of the capsid resulted in higher capsid stability and hampered infectivity in macrophages. PMID- 26414213 TI - Stereotactic body radiotherapy for head and neck cancer: an addition to the armamentarium against head and neck cancer. AB - In the recent years, stereotactic body radiation therapy (SBRT) has emerged as a potential therapy for head and neck malignancies. Although early results appear to be promising, serious acute and late effects have been observed, mainly in patients who have had prior external beam radiotherapy. This review will discuss the radiobiology of SBRT, clinical rationale and outcomes for SBRT in head and neck cancers and focus on the benefits and potential limitations in both de novo and re-irradiation settings. PMID- 26414214 TI - Erratum: Big Data Bioinformatics by C. S. Greene, J. Tan, M. Ung, J. H. Moore, and C. Cheng. PMID- 26414212 TI - Time Course and Size of Blood-Brain Barrier Opening in a Mouse Model of Blast Induced Traumatic Brain Injury. AB - An increasing number of studies have reported blood-brain barrier (BBB) dysfunction after blast-induced traumatic brain injury (bTBI). Despite this evidence, there is limited quantitative understanding of the extent of BBB opening and the time course of damage after blast injury. In addition, many studies do not report kinematic parameters of head motion, making it difficult to separate contributions of primary and tertiary blast-loading. Detailed characterization of blast-induced BBB damage may hold important implications for serum constituents that may potentially cross the compromised barrier and contribute to neurotoxicity, neuroinflammation, and persistent neurologic deficits. Using an in vivo bTBI model, systemic administration of sodium fluorescein (NaFl; 376 Da), Evans blue (EB; 69 kDa when bound to serum albumin), and dextrans (3-500 kDa) was used to estimate the pore size of BBB opening and the time required for recovery. Exposure to blast with 272 +/- 6 kPa peak overpressure, 0.69 +/- 0.01 ms duration, and 65 +/- 1 kPa*ms impulse resulted in significant acute extravasation of NaFl, 3 kDa dextran, and EB. However, there was no significant acute extravasation of 70 kDa or 500 kDa dextrans, and minimal to no extravasation of NaFl, dextrans, or EB 1 day after exposure. This study presents a detailed analysis of the time course and pore size of BBB opening after bTBI, supported by a characterization of kinematic parameters associated with blast-induced head motion. PMID- 26414218 TI - 2-Arachidonylglycerol Protects Primary Astrocytes Exposed to Oxygen-Glucose Deprivation Through a Blockade of NDRG2 Signaling and STAT3 Phosphorylation. AB - The human N-Myc downstream-regulated gene 2 (NDRG2) is expressed in astrocytes, and may be involved in the modulation of gliacyte function in the central nervous system. Our previous study found suppression of NDRG2 up-regulation in reactive astrocytes in cerebral ischemic tolerance. 2-Arachidonylglycerol (2-AG) can induce cerebral ischemic tolerance. However, the underlying mechanism of NDRG2 in cytoprotection induced by 2-AG in primary astrocytesis still unknown. In this study, we investigated the role of NDRG2 in cerebral ischemic tolerance induced by 2-AG after oxygen-glucose deprivation (OGD) in primary astrocytes. The results showed that primary astrocytes exposed to OGD resulted in marked increase of lactate dehydrogenase (LDH) release and decrease of methyl thiazolyl tetrazolium (MTT) reduction activity in comparison to control cultures. The levels of NDRG2 and phospho-signal transducer and activator of transcription 3 (pSTAT3) in the OGD group were comparably higher than those in the control group, and the up regulation of NDRG2 and pSTAT3 was suppressed in NDRG2 siRNA group. The cell viability in the 2-AG group was higher than that in the OGD group, and transfecting the NDRG2 pSRL-CDH1-GFP vector reversed the protective effects of 2 AG. The levels of NDRG2 and pSTAT3 in the 2-AG group were lower than those in the OGD group. 2-AG suppressed STAT3 phosphorylation by decreased expression of NDRG2. In conclusion, 2-AG protects primary astrocytes exposed to oxygen-glucose deprivation through a blockade of NDRG2 signaling and STAT3 phosphorylation. These findings bring insight to the roles of NDRG2 in ischemic-hypoxic injury and provide novel potential targets for future potent clinical therapies on cerebral ischemia injury. PMID- 26414219 TI - Estimation of residue depletion of cyadox and its marker residue in edible tissues of pigs using physiologically based pharmacokinetic modelling. AB - Physiologically based pharmacokinetic (PBPK) models are powerful tools to predict tissue distribution and depletion of veterinary drugs in food animals. However, most models only simulate the pharmacokinetics of the parent drug without considering their metabolites. In this study, a PBPK model was developed to simultaneously describe the depletion in pigs of the food animal antimicrobial agent cyadox (CYA), and its marker residue 1,4-bisdesoxycyadox (BDCYA). The CYA and BDCYA sub-models included blood, liver, kidney, gastrointestinal tract, muscle, fat and other organ compartments. Extent of plasma-protein binding, renal clearance and tissue-plasma partition coefficients of BDCYA were measured experimentally. The model was calibrated with the reported pharmacokinetic and residue depletion data from pigs dosed by oral gavage with CYA for five consecutive days, and then extrapolated to exposure in feed for two months. The model was validated with 14 consecutive day feed administration data. This PBPK model accurately simulated CYA and BDCYA in four edible tissues at 24-120 h after both oral exposure and 2-month feed administration. There was only slight overestimation of CYA in muscle and BDCYA in kidney at earlier time points (6-12 h) when dosed in feed. Monte Carlo analysis revealed excellent agreement between the estimated concentration distributions and observed data. The present model could be used for tissue residue monitoring of CYA and BDCYA in food animals, and provides a foundation for developing PBPK models to predict residue depletion of both parent drugs and their metabolites in food animals. PMID- 26414220 TI - Denosumab-treated Giant Cell Tumor of Bone Exhibits Morphologic Overlap With Malignant Giant Cell Tumor of Bone. AB - Giant cell tumor (GCT) of bone is a locally aggressive benign neoplasm characterized by an abundance of osteoclastic giant cells that are induced by the neoplastic mononuclear cells; the latter express high levels of receptor activator of nuclear factor kappa-B ligand (RANKL). Denosumab, a RANKL inhibitor, which is clinically used to treat GCT, leads to a marked alteration in the histologic appearance of the tumor with giant cell depletion and new bone deposition, leading to substantial histologic overlap with other primary tumors of bone. Most significantly, denosumab-treated GCT (tGCT) with abundant bone deposition may mimic de novo osteosarcoma, or GCT that has undergone malignant transformation. To histologically characterize tGCT, we identified 9 cases of GCT biopsied or resected after denosumab treatment. tGCT cases included 16 specimens from 9 patients including 6 female and 3 male individuals aged 16 to 47 (median 32) years. Duration of treatment varied from 2 to 55 months. We compared these tumors with malignant neoplasms arising in GCTs (n=9). The histology of tGCT was variable but appeared to relate to the length of therapy. All tGCTs showed marked giant cell depletion. Early lesions were highly cellular, and the combination of cellularity, atypia, and haphazard bone deposition caused the lesion to resemble high-grade osteosarcoma. Unlike de novo high-grade osteosarcoma or malignancies arising in GCT, however, tGCT showed less severe atypia, reduced mitotic activity, and lack of infiltrative growth pattern. Tumor in patients on prolonged therapy showed decreased cellularity and abundant new bone, deposited as broad, rounded cords or long, curvilinear arrays. The latter morphology was reminiscent of low-grade central osteosarcoma, but, unlike low-grade central osteosarcoma, tGCT was negative for MDM2 and again lacked an infiltrative growth pattern. Overall, tGCT may have a wide range of morphologic appearances. Because the treated tumors bear little resemblance to their pretreatment counterparts, careful attention to the history of denosumab administration is crucial to avoid a misdiagnosis with an important impact on therapy. Unlike malignant GCTs, tGCTs lack significant nuclear atypia, mitotic activity, and infiltration of preexisting bone, but instead show a unique pattern of intralesional bone deposition. PMID- 26414221 TI - Eosinophilic, Solid, and Cystic Renal Cell Carcinoma: Clinicopathologic Study of 16 Unique, Sporadic Neoplasms Occurring in Women. AB - A unique renal neoplasm characterized by eosinophilic cytoplasm and solid and cystic growth was recently reported in patients with tuberous sclerosis complex (TSC). We searched multiple institutional archives and consult files in an attempt to identify a sporadic counterpart. We identified 16 morphologically identical cases, all in women, without clinical features of TSC. The median age was 57 years (range, 31 to 75 y). Macroscopically, tumors were tan and had a solid and macrocystic (12) or only solid appearance (4). Average tumor size was 50 mm (median, 38.5 mm; range, 15 to 135 mm). Microscopically, the tumors showed solid areas admixed with variably sized macrocysts and microcysts that were lined by cells with a pronounced hobnail arrangement. The cells had voluminous eosinophilic cytoplasm with prominent granular cytoplasmic stippling and round to oval nuclei with prominent nucleoli. Scattered histiocytes and lymphocytes were invariably present. Thirteen of 16 patients were stage pT1; 2 were pT2, and 1 was pT3a. The cells demonstrated a distinct immunoprofile: nuclear PAX8 expression, predominant CK20-positive/CK7-negative phenotype, patchy AMACR staining, but no CD117 reactivity. Thirteen of 14 patients with follow-up were alive and without disease progression after 2 to 138 months (mean: 53 mo; median: 37.5 mo); 1 patient died of other causes. Although similar to a subset of renal cell carcinomas (RCCs) seen in TSC, we propose that sporadic "eosinophilic, solid, and cystic RCC," which occurs predominantly in female individuals and is characterized by distinct morphologic features, predominant CK20-positive/CK7 negative immunophenotype, and indolent behavior, represents a novel subtype of RCC. PMID- 26414222 TI - Radiation-induced Sarcomas Occurring in Desmoid-type Fibromatosis Are Not Always Derived From the Primary Tumor. AB - Desmoid-type fibromatosis is a rare, highly infiltrative, locally destructive neoplasm that does not metastasize, but recurs often after primary surgery. Activation of the Wnt/beta-catenin pathway is the pathogenic mechanism, caused by an activating mutation in exon 3 of CTNNB1 (85% of the sporadic patients). Radiotherapy is a frequent treatment modality with a local control rate of approximately 80%. In very rare cases, this may result in the development of radiation-induced sarcoma. It is unclear whether these sarcomas develop from the primary tumor or arise de novo in normal tissue. In 4 tertiary referral centers for sarcoma, 6 cases of desmoid-type fibromatosis that subsequently developed sarcoma after radiotherapy were collected. The DNA sequence of CTNNB1 exon 3 in the desmoid-type fibromatosis and the subsequent postradiation sarcoma was determined. Sarcomas developed 5 to 21 years after the diagnosis of desmoid-type fibromatosis and included 2 osteosarcomas, 2 high-grade undifferentiated pleomorphic sarcomas, 1 fibrosarcoma, and 1 undifferentiated spindle cell sarcoma. Three patients showed a CTNNB1 hotspot mutation (T41A, S45F, or S45N) in both the desmoid-type fibromatosis and the radiation-induced sarcoma. The other 3 patients showed a CTNNB1 mutation in the original desmoid-type fibromatosis (2 with a T41A and 1 with an S45F mutation), which was absent in the sarcoma. In conclusion, postradiation sarcomas that occur in the treatment area of desmoid type fibromatosis are extremely rare and can arise through malignant transformation of CTNNB1-mutated desmoid fibromatosis cells, but may also originate from CTNNB1 wild-type normal cells lying in the radiation field. PMID- 26414223 TI - Nuclear Expression of CAMTA1 Distinguishes Epithelioid Hemangioendothelioma From Histologic Mimics. AB - Epithelioid hemangioendothelioma (EHE) is a malignant endothelial neoplasm characterized by recurrent translocations involving chromosomal regions 1p36.3 and 3q25, resulting in the formation of a WWTR1-CAMTA1 fusion gene in approximately 90% of cases; a small subset (<5%) have a YAP1-TFE3 fusion gene. The WWTR1-CAMTA1 fusion gene leads to overexpression of both genes. WWTR1 protein is expressed in many different cell types, whereas CAMTA1 expression is normally limited to the brain. A prior study using a polyclonal antibody directed against regions within the C-terminus of CAMTA1 reported widespread expression in both normal tissues and diverse tumor types. In contrast, a recent study using a different polyclonal antibody directed against the C-terminus of CAMTA1 suggested that this other antibody is a potentially useful diagnostic marker for EHE. Our study aimed to validate this finding in a large series of EHE cases and to determine whether CAMTA1 is expressed in other epithelioid mesenchymal tumors that may mimic EHE. Protein expression of CAMTA1 was evaluated in whole-tissue sections of 204 tumors using a polyclonal anti-CAMTA1 antibody: 59 EHE (48 conventional, 11 "malignant"; 4 with known TFE3 gene rearrangement); 70 other epithelioid vascular tumors; and 75 nonendothelial epithelioid mesenchymal neoplasms. In total, 51/59 cases (86%) of EHE showed diffuse nuclear staining for CAMTA1, including 44/48 cases (92%) with conventional histology and 7/11 cases (64%) with "malignant" histology. Of the 8 CAMTA1-negative tumors, 6 were positive for TFE3. With the exception of 1 case previously diagnosed as epithelioid angiosarcoma on core biopsy, all other tumor types examined were negative for CAMTA1. In conclusion, in keeping with the reported frequency of WWTR1-CAMTA1 in EHE, nuclear CAMTA1 expression is identified in the majority of EHE cases, whereas other epithelioid mesenchymal neoplasms are negative for CAMTA1. These findings support the diagnostic utility of immunohistochemistry for CAMTA1 in distinguishing EHE from histologic mimics, in particular benign epithelioid vascular tumors, epithelioid angiosarcoma, and epithelioid sarcoma, an important distinction given the differences in biological potential and clinical course. PMID- 26414224 TI - Combined "Infiltrating Astrocytoma/Pleomorphic Xanthoastrocytoma" Harboring IDH1 R132H and BRAF V600E Mutations. AB - Pleomorphic xanthoastrocytoma (PXA) has rarely been reported in combination with infiltrating glioma, historically interpreted as a "collision tumor." Isocitrate dehydrogenase 1 (IDH1) and BRAF V600E mutations are usually not concurrent. The former is typical of adult infiltrating gliomas, and the latter is identified in a variety of primary central nervous system neoplasms, including PXA, ganglioglioma, pilocytic astrocytoma, and rarely infiltrating gliomas. We report the case of a 56-year-old man presenting with seizures and headaches. Magnetic resonance imaging revealed a large right temporal lobe mass with low T1 and high T2/FLAIR signal and a discrete contrast-enhancing focus. Histologically, the tumor showed 2 distinct components: an infiltrating astrocytoma harboring 5 mitoses/10 high-power fields and a relatively circumscribed focus, resembling PXA with, at most, 2 mitoses/10 high-power fields. No microvascular proliferation or necrosis was present in either component. The infiltrating astrocytoma component contained numerous axons, whereas the PXA-like component had sparse axons, as demonstrated by the neurofilament immunostain. Both components were positive for the mutant IDH1 R132H and showed loss of ATRX expression, whereas BRAF V600E was restricted to the PXA-like component. On sequencing of the 2 components separately after microdissection, both showed identical IDH1 R132H and TP53 R273C point mutations, whereas the BRAF V600E mutation was limited to the PXA-like component. These findings are consistent with clonal expansion of a morphologically distinct focus, harboring a private BRAF V600E mutation within an IDH1-mutant glioma. Intratumoral heterogeneity and clonal evolution, as seems to have occurred here, suggest reevaluation of "collision tumors" as a concept. PMID- 26414225 TI - Neutropenic Enterocolitis: New Insights Into a Deadly Entity. AB - Neutropenic enterocolitis (NE) is a deadly ileocecal-based disease seen in patients with a recent history of chemotherapy. As histology is not included in the current diagnostic criteria, the pathologic features of NE are poorly understood. We undertook a multi-institutional study of NE, and report helpful clinical clues, such as immunosuppression (n=20/20), recent chemotherapy (n=17/18), neutropenia (n=16/18) gastrointestinal symptoms (n=19/19), abnormal imaging studies of the cecum/right colon (n=11/14), and positive microbiological studies (n=13/15). Fever (n=9/15) and sepsis (n=8/16) were also common. Pathologically, the cecum/right colon was always involved (n=17/17), but findings were identified in other bowel segments as well. NE lesions consisted of patchy necrosis (n=18/20), infiltrating organisms (n=17/20), hemorrhage (n=15/20), ulcer (n=15/19), edema (n=15/20), and depletion of inflammatory cells (n=15/20). Seventy-nine percent (n=15/19) of patients with histologically confirmed NE died: 47% (n=7/15) of these deaths were attributed to NE and the remainder to the patients' underlying conditions. Importantly, we observed a clinical diagnostic discordancy rate of 35% (n=9/26): 15% (n=3/20) of histologically confirmed NE were clinically unsuspected, and 26% (n=6/23) of clinically suspected NE represented a different disease process. Alternative diagnoses included unspecified colitis, infection, graft-versus-host disease, relapsed malignancy, mycophenolate injury, appendicitis, and ischemia. The causes of death in patients with NE mimics included unrecognized appendicitis and unrecognized graft-versus host disease. To improve diagnostic accuracy, we propose that histology be required for a diagnosis of "definitive NE," with other clinically suspicious cases reported as "suspicious for NE" until all other possible diagnoses have been reasonably excluded. PMID- 26414226 TI - Assessment of Stone Complexity for PCNL: A Systematic Review of the Literature, How Best Can We Record Stone Complexity in PCNL? AB - INTRODUCTION: This study aims to systematically review the literature reporting tools for scoring stone complexity and the stratification of outcomes by stone complexity. In doing so, we aim to determine whether the evidence favors uniform adoption of any one scoring system. METHODS: PubMed and Embase databases were systematically searched for relevant studies from 2004 to 2014. Reports selected according to predetermined inclusion and exclusion criteria were appraised in terms of methodologic quality and their findings summarized in structured tables. RESULTS: After review, 15 studies were considered suitable for inclusion. Four distinct scoring systems were identified and a further five studies that aimed to validate aspects of those scoring systems. Six studies reported the stratification of outcomes by stone complexity, without specifically defining a scoring system. All studies reported some correlation between stone complexity and stone clearance. Correlation with complications was less clearly established, where investigated. CONCLUSIONS: This review does not allow us to firmly recommend one scoring system over the other. However, the quality of evidence supporting validation of the Guy's Stone Score is marginally superior, according to the criteria applied in this study. Further evaluation of the interobserver reliability of this scoring system is required. PMID- 26414227 TI - Behavioral Programs for Type 2 Diabetes Mellitus: A Systematic Review and Network Meta-analysis. AB - BACKGROUND: Behavioral programs may improve outcomes for individuals with type 2 diabetes mellitus, but there is a large diversity of behavioral interventions and uncertainty about how to optimize the effectiveness of these programs. PURPOSE: To identify factors moderating the effectiveness of behavioral programs for adults with type 2 diabetes. DATA SOURCES: 6 databases (1993 to January 2015), conference proceedings (2011 to 2014), and reference lists. STUDY SELECTION: Duplicate screening and selection of 132 randomized, controlled trials evaluating behavioral programs compared with usual care, active controls, or other behavioral programs. DATA EXTRACTION: One reviewer extracted and another verified data. Two reviewers independently assessed risk of bias. DATA SYNTHESIS: Behavioral programs were grouped on the basis of program content and delivery methods. A Bayesian network meta-analysis showed that most lifestyle and diabetes self-management education and support programs (usually offering >= 11 contact hours) led to clinically important improvements in glycemic control (>= 0.4% reduction in hemoglobin A1c [HbA1c]), whereas most diabetes self-management education programs without added support-especially those offering 10 or fewer contact hours-provided little benefit. Programs with higher effect sizes were more often delivered in person than via technology. Lifestyle programs led to the greatest reductions in body mass index. Reductions in HbA1c seemed to be greater for participants with a baseline HbA1c level of 7.0% or greater, adults younger than 65 years, and minority persons (subgroups with >= 75% nonwhite participants). LIMITATIONS: All trials had medium or high risk of bias. Subgroup analyses were indirect, and therefore exploratory. Most outcomes were reported immediately after the interventions. CONCLUSION: Diabetes self-management education offering 10 or fewer hours of contact with delivery personnel provided little benefit. Behavioral programs seem to benefit persons with suboptimal or poor glycemic control more than those with good control. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO registration number: CRD42014010515). PMID- 26414228 TI - A biomimetic underwater vehicle actuated by waves with ionic polymer-metal composite soft sensors. AB - The ionic polymer-metal composite (IPMC) is a soft material based actuator and sensor and has a promising potential in underwater application. This paper describes a hybrid biomimetic underwater vehicle that uses IPMCs as sensors. Propelled by the energy of waves, this underwater vehicle does not need an additional energy source. A physical model based on the hydrodynamics of the vehicle was developed, and simulations were conducted. Using the Poisson-Nernst Planck system of equations, a physics model for the IPMC sensor was proposed. For this study, experimental apparatus was developed to conduct hydrodynamic experiments for both the underwater vehicle and the IPMC sensors. By comparing the experimental and theoretical results, the speed of the underwater vehicle and the output of the IPMC sensors were well predicted by the theoretical models. A maximum speed of 1.08 * 10(-1) m s(-1) was recorded experimentally at a wave frequency of 1.6 Hz. The peak output voltage of the IPMC sensor was 2.27 * 10(-4) V, recorded at 0.8 Hz. It was found that the speed of the underwater vehicle increased as the wave frequency increased and the IPMC output decreased as the wave frequency increased. Further, the energy harvesting capabilities of the underwater vehicle hosting the IPMCs were tested. A maximum power of 9.50 * 10( 10) W was recorded at 1.6 Hz. PMID- 26414229 TI - Responses to and Outcomes of Treatment of Autoimmune Cerebellar Ataxia in Adults. AB - IMPORTANCE: Classic Purkinje cell cytoplasmic antibody type 1 (PCA-1, or anti-Yo) paraneoplastic cerebellar ataxia has a poor prognosis, yet little has been published otherwise regarding treatment responses and outcomes among patients with autoimmune cerebellar ataxia. OBJECTIVES: To investigate treatment responses and outcomes in adults with autoimmune cerebellar ataxia. DESIGN, SETTING, AND PARTICIPANTS: A cohort study conducted at Mayo Clinic, Rochester, Minnesota, included 118 patients who had ataxia, were 18 years or older, were seropositive for at least 1 neural autoantibody, had received at least 1 immunotherapy or cancer therapy, and had neurologist-reported outcomes documented from January 1, 1989, through December 31, 2013. Data were collected from May 14, 2013, through August 9, 2014, and analyzed from August 9, 2014, through April 27, 2015. Responses to immunotherapy (corticosteroids, intravenous immunoglobulin, plasma exchange, and immunosuppressants) and ambulatory outcomes were compared between different subgroups. Subgroups were classified as paraneoplastic vs nonparaneoplastic disorders; neuronal nuclear and/or cytoplasmic (NNC) antibody positivity vs plasma membrane protein (PMP) antibody positivity; and glutamic acid decarboxylase 65-kDa isoform (GAD65) antibody positivity vs PMP antibody positivity. MAIN OUTCOMES AND MEASURES: Response to therapy and ambulatory ability, with univariate logistic regression and Kaplan-Meier analyses. RESULTS: Inclusion criteria were met by 118 patients. Median age at onset of neurologic symptoms was 58 (range, 27-83) years, and 87 patients (73.7%) were women. Median duration from symptom onset to last follow-up was 25 (range, 2-223) months. Sixty three patients had paraneoplastic and 55 patients had nonparaneoplastic ataxic disorders. Eighty-one patients were seropositive for NNC antibodies (most commonly PCA-1 [anti-Yo], antineuronal nuclear antibody type 1 [anti-Hu], and GAD65 antibody); 22 patients, for neural PMP receptor or ion channel antibodies (most commonly targeting P/Q- or N-type voltage-gated calcium channels); and 15 patients, for antibodies from both categories. Neurologic improvements occurred in 54 patients (with a robust change in ambulatory ability in 22) attributable to immunotherapy; univariate regression analysis revealed that improvements were significantly more common among patients with nonparaneoplastic disorders (P = .03) and those with exclusively PMP antibodies (P = .02). Kaplan-Meier analyses revealed that progression to wheelchair dependence occurred significantly faster among patients with NNC antibody positivity only (P = .02), although those with GAD65 autoimmunity progressed to wheelchair dependence at a rate similar to those with PMP autoimmunity (P = .92). CONCLUSIONS AND RELEVANCE: Although autoimmune ataxia is usually severe, treatment responses can be gratifying, particularly in patients with nonparaneoplastic disorders and in those harboring autoantibodies directed against GAD65 or neural PMPs. PMID- 26414231 TI - Comment on Accurate Data Process for Nanopore Analysis. PMID- 26414230 TI - Abnormal Expression of Urea Transporter Protein in a Rat Model of Hepatorenal Syndrome Induced by Succinylated Gelatin. AB - BACKGROUND: Hepatorenal syndrome (HRS) is a serious complication of advanced chronic liver disease. Abdominal compartment syndrome (ACS) occurs with dysfunction of multiple organs when abdominal pressure increases. Here, we report on a novel model of ACS with ascites and a model of HRS in rats to observe the urea transporter protein (UT) expression in the 2 models. MATERIAL AND METHODS: A liver cirrhosis model was induced by CCl4. After changes of liver histopathology were observed, rats were injected intraperitoneally with succinylated gelatin to establish a model of ACS and HRS. Then, changes in BUN, Cr, and renal histopathology were detected. Moreover, the UT in ACS and HRS were also quantified. RESULTS: The surfaces of liver in the cirrhotic group became coarse, with visible small nodules and became yellow and greasy. The normal structure of the hepatic lobules were destroyed, and hyperplasia of fibrotic tissue and pseudo lobe was observed. The levels of BUN and Cr were significantly increased in rats suffering from ACS and HRS, respectively, compared to their control groups. In addition, the mRNA levels of UT-A2 and UT-A3 decreased in rats with HRS compared to cirrhotic rats. However, there was no significant difference between the mRNA levels of UT-A2, UT-A3, and UT-B in rats with ACS vs. normal rats. CONCLUSIONS: It is feasible to model ACS in rats by injecting succinylated gelatin into the abdominal cavity. Increasing the intra-abdominal pressure by succinylated gelatin is also a novel approach for modeling HRS in cirrhotic rats. Compared with control rats, there is an abnormal mRNA expression of UT in ACS rats and HRS rats. PMID- 26414232 TI - Pituitary Apoplexy. AB - Pituitary apoplexy, a rare clinical syndrome secondary to abrupt hemorrhage or infarction, complicates 2%-12% of pituitary adenomas, especially nonfunctioning tumors. Headache of sudden and severe onset is the main symptom, sometimes associated with visual disturbances or ocular palsy. Signs of meningeal irritation or altered consciousness may complicate the diagnosis. Precipitating factors (increase in intracranial pressure, arterial hypertension, major surgery, anticoagulant therapy or dynamic testing, etc) may be identified. Corticotropic deficiency with adrenal insufficiency may be life threatening if left untreated. Computed tomography or magnetic resonance imaging confirms the diagnosis by revealing a pituitary tumor with hemorrhagic and/or necrotic components. Formerly considered a neurosurgical emergency, pituitary apoplexy always used to be treated surgically. Nowadays, conservative management is increasingly used in selected patients (those without important visual acuity or field defects and with normal consciousness), because successive publications give converging evidence that a wait-and-see approach may also provide excellent outcomes in terms of oculomotor palsy, pituitary function and subsequent tumor growth. However, it must be kept in mind that studies comparing surgical approach and conservative management were retrospective and not controlled. PMID- 26414234 TI - A Pilot Study of Safety and Efficacy of Cranial Electrotherapy Stimulation in Treatment of Bipolar II Depression. AB - This double-blind, sham-controlled study sought to investigate the effectiveness of cranial electrotherapy stimulation (CES) for the treatment of bipolar II depression (BD II). After randomization, the active group participants (n = 7) received 2 mA CES treatment for 20 minutes five days a week for 2 weeks, whereas the sham group (n = 9) had the CES device turned on and off. Symptom non remitters from both groups received an additional 2 weeks of open-label active treatment. Active CES treatment but not sham treatment was associated with a significant decrease in the Beck Depression Inventory (BDI) scores from baseline to the second week (p = 0.003) maintaining significance until week 4 (p = 0.002). There was no difference between the groups in side effects frequency. The results of this small study indicate that CES may be a safe and effective treatment for BD II suggesting that further studies on safety and efficacy of CES may be warranted. PMID- 26414235 TI - Protection afforded by quercetin against H2O2-induced apoptosis on PC12 cells via activating PI3K/Akt signal pathway. AB - Cell damage and apoptosis induced by oxidative stress have been involved in various neurodegenerative diseases. This study aims to explore the neuro protective effects of quercetin on PC12 cells apoptosis induced by hydrogen peroxide (H(2)O(2)) and the underlying mechanisms. The cell viability was detected, as well as the production of reactive oxygen species (ROS), lactate dehydrogenase (LDH) leakage, and the activities of glutathione peroxidase (GSH Px), superoxide dismutase (SOD) and malondialdehyde (MDA) of the cells in control, H(2)O(2) and quercetin groups. It finally turned out that quercetin might protect PC12 cells against the negative effect of H(2)O(2) by decreasing of LDH release, ROS concentration and MDA level and regaining the GSH-Px and SOD activities. To investigate the mechanism, LY294002 was introduced, the phosphatidylinositol-3-kinase (PI3K) inhibitor. Bax/Bcl-2 ratio and Akt phosphorylation (p-Akt) were examined by Western blot analysis. The data showed that LY294002 almost had the same effects with H(2)O(2), which was also significantly reversed by quercetin could enhance Bax/Bcl-2 ratio and adjust the p-Akt expression, which indicated quercetin might protect PC12 cells against the negative effect of H(2)O(2) via activating the PI3K/Akt signal pathway. PMID- 26414233 TI - Executive Summary to EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals. AB - This Executive Summary to the Endocrine Society's second Scientific Statement on environmental endocrine-disrupting chemicals (EDCs) provides a synthesis of the key points of the complete statement. The full Scientific Statement represents a comprehensive review of the literature on seven topics for which there is strong mechanistic, experimental, animal, and epidemiological evidence for endocrine disruption, namely: obesity and diabetes, female reproduction, male reproduction, hormone-sensitive cancers in females, prostate cancer, thyroid, and neurodevelopment and neuroendocrine systems. EDCs such as bisphenol A, phthalates, pesticides, persistent organic pollutants such as polychlorinated biphenyls, polybrominated diethyl ethers, and dioxins were emphasized because these chemicals had the greatest depth and breadth of available information. The Statement also included thorough coverage of studies of developmental exposures to EDCs, especially in the fetus and infant, because these are critical life stages during which perturbations of hormones can increase the probability of a disease or dysfunction later in life. A conclusion of the Statement is that publications over the past 5 years have led to a much fuller understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability. These findings will prove useful to researchers, physicians, and other healthcare providers in translating the science of endocrine disruption to improved public health. PMID- 26414236 TI - A randomized multicenter study of minilaparotomy cholecystectomy versus laparoscopic cholecystectomy with ultrasonic dissection in both groups. AB - OBJECTIVE: Ultrasonic dissection (UsD) has been used in laparoscopic cholecystectomy (LC), though it is not the golden standard technique. Applying UsD to cholecystectomy by minilaparotomy (MC) is less common and there are no prospective randomized trials comparing these two techniques. Therefore, we conducted the present study to investigate the use of the UsD in the MC versus the LC procedure. MATERIAL AND METHODS: Initially 104 patients with non complicated symptomatic gallstone disease were randomized into MC (n = 53) or LC (n = 51) groups, both groups using UsD, over a period of 2 years (2013-2015). The study groups were similar in terms of age and American Society of Anesthesiologists (ASA) physical status score. RESULTS: The demographic variables and the surgical data were similar in the study groups. Similar low postoperative pain scores were reported in the two study groups during the first four hours after surgery. The incidence of nausea/vomiting was similar between the two study groups, 47% in the MC group versus 42% in the LC group. However, the patients in the MC group were treated more frequently with antiemetics, the incidence being 39% in the MC group versus 21% in the LC group (p = 0.02). The pain at rest at 24h after the surgery was similar in the two study groups, but the LC patients reported less pain at the normal activity, the mean of numerical rating scale (NRS) of 0-10 score being 3.9 in the MC group versus 2.9 in the LC group (p = 0.05), and the pain at the quick movement/coughing, the mean NRS being 4.9 in the MC group versus 3.2 in the LC group (p = 0.005). The length of sick leave was 17.4 days in the MC group and 14.4 days in the LC group (p = 0.05). CONCLUSION: Our results suggest that both MC and LC are feasible and safe options for mini invasive cholecystectomy. A new finding with clinical relevance in the present work is a relatively similar short-term outcome in the MC and LC although the LC patients reported significantly lower pain score 24 hours postoperatively and a shorter convalescence. PMID- 26414237 TI - Application and Utility of iPads in Pediatric Tele-echocardiography. AB - BACKGROUND: Telemedicine is used with increasing frequency to improve patient care in remote areas. The interpretation of medical imaging on iPad((r)) (Apple, Cupertino, CA) tablets has been reported to be accurate. There are no studies on the use of iPads for interpretation of pediatric echocardiograms. We compared the quality of echo images, diagnostic accuracy, and review time using three different modalities: remote access on an iPad Air (iPad), remote access via a computer (Remote), and direct access on a computer linked through Ethernet to the server, the "gold standard" (Direct). MATERIALS AND METHODS: Fifty consecutive archived pediatric echocardiograms were interpreted using the three modalities. Studies were analyzed blindly by three pediatric cardiologists; review time, diagnostic accuracy, and image quality were documented. Diagnostic accuracy was assessed by comparing the study diagnoses with the official diagnosis in the patient's chart. Discrepancies between diagnoses were graded as major (more than one grade difference) or minor (one grade difference in severity of lesion). RESULTS: There were no significant differences in accuracy among the three modalities. There was one major discrepancy (size of patent ductus arteriosus); all others were minor, hemodynamically insignificant. Image quality ratings were better for iPad than Remote; Direct had the highest ratings. Review times (mean [standard deviation] minutes) were longest for iPad (5.89 [3.87]) and then Remote (4.72 [2.69]), with Direct having the shortest times (3.52 [1.42]) (p < 0.0001). CONCLUSIONS: Pediatric echocardiograms can be interpreted using convenient, portable devices while preserving accuracy and quality with slightly longer review times (1-2 min). These findings are important in the current era of increasing need for mobile health. PMID- 26414238 TI - Intra-Articular Transplantation of Allogeneic BMMSCs Rehabilitates Cartilage Injury of Antigen-Induced Arthritis. AB - Apart from the immunosuppressive property, which has been widely investigated in the treatment of various autoimmune diseases, bone marrow mesenchymal stem cells (BMMSCs) also exhibit the chondrogenic capacity. Recently, BMMSCs have attracted more and more attention in the remission of rheumatoid arthritis (RA) and the reconstruction of cartilage injury. In addition to the significant regulatory hurdles of systemic treatment by BMMSCs, the poor inhibitory efficiency on articular inflammatory reaction and the inferior result of preventing the persistent destruction of cartilage were observed. Herein, toward the ovalbumin (OVA)-induced arthritis in rabbits, the in situ transplantation of fibrin gel encapsulated BMMSCs to osteochondral defect was confirmed to result in the decreased levels of cytokines, such as interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, and anti-OVA antibody, in the serum. What is more, the implantation of BMMSCs also inhibited the proliferation of antigen-specific lymphocytes. Meanwhile, the fibrin gel-encapsulated BMMSCs performed outstanding capacity of cartilage repair, resulted in the remission of local joint inflammatory condition, and prevented further articular cartilage damage. The results demonstrated that the transplantation of BMMSCs in fibrin gel to osteochondral defect under arthritic condition could effectively stimulate BMMSCs to exhibit the immunosuppression and cartilage protection capability, as well as cartilage repair. This study provided a new therapeutic strategy for RA-induced cartilage injury through the local transplantation of BMMSCs. PMID- 26414239 TI - An anti-mosquito mixture for domestic use, combining a fertiliser and a chemical or biological larvicide. AB - BACKGROUND: Plant saucers are an important larval habitat for Aedes aegypti and Ae. albopictus in peridomestic situations. Because NPK fertilisers in plant containers tend to enhance the oviposition of these species, we investigated the effects of Bacillus thuringiensis var. israelensis, spinosad, pyriproxyfen and diflubenzuron larvicides in combination with fertiliser on the adult emergence and fecundity of the mosquitoes coming from plant saucers in controlled greenhouse experiments. NPK + larvicide (NPK-LAV) treatments were tested on Ae. aegypti. Each treatment was compared with water and with fertiliser alone on a total of five houseplants and their saucers. The fertilising treatment was renewed every 30-45 days. RESULTS: With less than 5% imaginal emergence, the NPK + spinosad 0.5% treatment remained effective for 30 days. Both NPK + pyriproxyfen 0.1% and NPK + diflubenzuron 0.25% were effective for 45 days. The average number of eggs laid in the three treatments was similar to the NPK treatment, indicating that spinosad, pyriproxyfen and diflubenzuron did not alter the attraction effect of the fertiliser on egg laying. NPK + pyriproxyfen and NPK + diflubenzuron also had ovicidal activity and an important impact on the fecundity of the Ae. aegypti female imagos and the fertility of their eggs. CONCLUSION: The addition of NPK fertiliser to insecticides can increase larval control of Aedes mosquitoes. This innovative measure for personal protection, which is harmless for both humans and animals, would be an additional support for the community-based actions led by the institutional services for vector control. (c) 2015 Society of Chemical Industry. PMID- 26414240 TI - Anti-Melanoma Differentiation-Associated Gene 5 Is Associated With Rapidly Progressive Lung Disease and Poor Survival in US Patients With Amyopathic and Myopathic Dermatomyositis. AB - OBJECTIVE: Clinically amyopathic dermatomyositis (CADM) is a subset of dermatomyositis (DM) presenting with the characteristic rash of DM without objective muscle weakness. Asian studies report that anti-melanoma differentiation-associated gene 5 (anti-MDA-5) autoantibody in CADM is associated with interstitial lung disease (ILD), particularly rapidly progressive ILD (RPILD). These associations have not been established in US myositis patients. The goal of our study was to determine the association of anti-MDA-5 autoantibody with ILD, RPILD, and survival in US patients with CADM and classic DM. METHODS: CADM patients were identified in the University of Pittsburgh Myositis Center Database and matched 1:1 (sex and age) to classic DM controls. Anti-MDA-5 was measured by serum enzyme-linked immunosorbent assay. Kaplan-Meier, log rank, and chi-square tests were used for analysis. RESULTS: We identified 61 CADM patients (62% women, mean age 48.2 years) and 61 classic DM controls (64% women, mean age 44.8 years). The frequencies of anti-MDA-5 positivity, ILD, and RPILD were similar in the 2 cohorts (MDA-5 positive: CADM 13.1% [8 of 61] and DM 13.1% [8 of 61], ILD positive: CADM 31.1% [19 of 61] and DM 26.2% [16 of 61], and RPILD positive: CADM 8.2% [5 of 61] and DM 5% [3 of 61]; P = 1, 0.55, and 0.46, respectively). Anti-MDA-5 positivity was significantly associated with ILD, since 50% of MDA-5-positive subjects (8 of 16) had ILD versus 25.5% of MDA-5-negative subjects (27 of 106; P = 0.04). Anti-MDA-5 was strongly associated with RPILD (P < 0.001). Anti-MDA-5-positive patients with ILD had worse baseline pulmonary function testing variables compared to anti-MDA-5-negative patients. Anti-MDA-5 positivity was significantly associated with poor survival (P = 0.007). CONCLUSION: Anti-MDA-5 antibody is significantly associated with ILD, RPILD, worse pulmonary outcome, and survival in US classic DM and CADM patients. PMID- 26414241 TI - Molecular dynamics simulations of the free and inhibitor-bound cruzain systems in aqueous solvent: insights on the inhibition mechanism in acidic pH. AB - The major cysteine protease of Trypanosoma cruzi, cruzain (CRZ), has been described as a therapeutic target for Chagas' disease, which affects millions of people worldwide. Thus, a series of CRZ inhibitors has been studied, including a new competitive inhibitor, Nequimed176 (NEQ176). Nevertheless, the structural and dynamic basis for CRZ inhibition remains unclear. Hoping to contribute to this ever-growing understanding of timescale dynamics in the CRZ inhibition mechanism, we have performed the first study using 100 ns of molecular dynamics (MD) simulations of two CRZ systems in an aqueous solvent under pH 5.5: CRZ in the apo form (ligand free) and CRZ complexed to NEQ176. According to the MD simulations, the enzyme adopts an open conformation in the apo form and a closed conformation in the NEQ176-CRZ complex. We also suggest that this closed conformation is related to the hydrogen-bonding interactions between NEQ176 and CRZ, which occurs through key residues, mainly Gly66, Met68, Asn69, and Leu160. In addition, the cross-correlation analysis shows evidence of the correlated motions among Ala110 Asp140, Leu160-Gly189, and Glu190-Gly215 subdomains, as well as, the movements related to Ala1-Thr59 and Asp60-Pro90 regions seem to be crucial for CRZ activity. PMID- 26414242 TI - Ultrafast Interfacial Electron and Hole Transfer from CsPbBr3 Perovskite Quantum Dots. AB - Recently reported colloidal lead halide perovskite quantum dots (QDs) with tunable photoluminescence (PL) wavelengths covering the whole visible spectrum and exceptionally high PL quantum yields (QYs, 50-90%) constitute a new family of functional materials with potential applications in light-harvesting and emitting devices. By transient absorption spectroscopy, we show that the high PL QYs (~79%) can be attributed to negligible electron or hole trapping pathways in CsPbBr3 QDs: ~94% of lowest excitonic states decayed with a single-exponential time constant of 4.5 +/- 0.2 ns. Furthermore, excitons in CsPbBr3 QDs can be efficiently dissociated in the presence of electron or hole acceptors. The half lives of electron transfer (ET) to benzoquinone and subsequent charge recombination are 65 +/- 5 ps and 2.6 +/- 0.4 ns, respectively. The half-lives for hole transfer (HT) to phenothiazine and the subsequent charge recombination are 49 +/- 6 ps and 1.0 +/- 0.2 ns, respectively. The lack of electron and hole traps and fast interfacial ET and HT rates are key properties that may enable the development of efficient lead halide perovskite QDs-based light-harvesting and emitting devices. PMID- 26414243 TI - Breg Cells Are Numerically Decreased and Functionally Impaired in Patients With Systemic Sclerosis. AB - OBJECTIVE: Breg cells, a regulatory cell subset that produces interleukin-10 (IL 10), play a significant role in suppressing autoimmune responses and preventing autoimmunity. This study was undertaken to examine the number and function of Breg cells in patients with systemic sclerosis (SSc), a disease with many autoantibodies. METHODS: Forty-five patients with SSc (12 with early SSc, 33 with established disease including 16 with SSc-associated pulmonary fibrosis [PF]), 12 healthy control subjects, and 10 patients with rheumatoid arthritis (RA) associated PF were studied. The phenotypes of immature/transitional Breg cells (CD19+CD24(high) CD38(high) ) and memory Breg cells (CD19+CD27+CD24(high) ) were evaluated by flow cytometry. The function of Breg cells was assessed by measuring the production of IL-10 after B cell activation. In addition, activation of p38 MAPK and STAT-3 was measured following stimulation of the cells with B cell receptor (BCR) and Toll-like receptor 9 (TLR-9). RESULTS: Percentages of memory Breg cells were decreased in patients with early SSc (mean +/- SEM 1.85 +/- 0.38%), those with established SSc (1.6 +/- 0.88%), those with SSc-associated PF (1.52 +/- 0.17%), and those with RA-associated PF (1.58 +/- 0.26%), compared to healthy controls (6.3 +/- 0.49%; each P < 0.001). Percentages of transitional Breg cells were also decreased. Expression of IL-10 by Breg cells after stimulation with TLR-9 was impaired in patients with SSc, particularly those with SSc-associated PF. Activation of STAT-3 and p38 MAPK was impaired in naive and memory B cells from patients with SSc after stimulation with BCR and TLR-9. Expression of the stimulatory CD19 receptor was increased in B cells and also increased, to a lesser extent, in Breg cells from patients with SSc compared to healthy controls. Percentages of memory B cells were decreased in patients with SSc, particularly in those with SSc-associated PF. CONCLUSION: This is the first study to demonstrate that Breg cells are phenotypically and functionally impaired in patients with SSc. Furthermore, in SSc, B cells exhibit impaired p38 MAPK and STAT-3 activation upon stimulation with BCR and TLR-9. The findings of decreased numbers of Breg cells along with increased expression of CD19 support the idea of B cell autoaggression acting as an immunopathogenic mediator in SSc. PMID- 26414245 TI - Hypothesis test of mediation effect in causal mediation model with high dimensional continuous mediators. AB - Causal mediation modeling has become a popular approach for studying the effect of an exposure on an outcome through a mediator. However, current methods are not applicable to the setting with a large number of mediators. We propose a testing procedure for mediation effects of high-dimensional continuous mediators. We characterize the marginal mediation effect, the multivariate component-wise mediation effects, and the L2 norm of the component-wise effects, and develop a Monte-Carlo procedure for evaluating their statistical significance. To accommodate the setting with a large number of mediators and a small sample size, we further propose a transformation model using the spectral decomposition. Under the transformation model, mediation effects can be estimated using a series of regression models with a univariate transformed mediator, and examined by our proposed testing procedure. Extensive simulation studies are conducted to assess the performance of our methods for continuous and dichotomous outcomes. We apply the methods to analyze genomic data investigating the effect of microRNA miR-223 on a dichotomous survival status of patients with glioblastoma multiforme (GBM). We identify nine gene ontology sets with expression values that significantly mediate the effect of miR-223 on GBM survival. PMID- 26414246 TI - Gene Transfer Strategies to Promote Chondrogenesis and Cartilage Regeneration. AB - Gene transfer has been used experimentally to promote chondrogenesis and cartilage regeneration. While it is controversial to apply gene therapy for nonlethal conditions such as cartilage defect, there is a possibility that the transfer of therapeutic transgenes may dramatically increase the effectiveness of cell therapy and reduce the quantity of cells that are needed to regenerate cartilage. Single or combination of growth factors and transcription factors has been transferred to mesenchymal stem cells or articular chondrocytes using both nonviral and viral approaches. The current challenge for the clinical applications of genetically modified cells is ensuring the safety of gene therapy while guaranteeing effectiveness. Viral gene delivery methods have been mainstays currently with enhanced safety features being recently refined. On the other hand, efficiency has been greatly improved in nonviral delivery. This review summarizes the history and recent update on the gene transfer to enhance chondrogenesis from stem cells or articular chondrocytes. PMID- 26414244 TI - Folic Acid Promotes Recycling of Tetrahydrobiopterin and Protects Against Hypoxia Induced Pulmonary Hypertension by Recoupling Endothelial Nitric Oxide Synthase. AB - AIMS: Nitric oxide (NO) derived from endothelial NO synthase (eNOS) has been implicated in the adaptive response to hypoxia. An imbalance between 5,6,7,8 tetrahydrobiopterin (BH4) and 7,8-dihydrobiopterin (BH2) can result in eNOS uncoupling and the generation of superoxide instead of NO. Dihydrofolate reductase (DHFR) can recycle BH2 to BH4, leading to eNOS recoupling. However, the role of DHFR and eNOS recoupling in the response to hypoxia is not well understood. We hypothesized that increasing the capacity to recycle BH4 from BH2 would improve NO bioavailability as well as pulmonary vascular remodeling (PVR) and right ventricular hypertrophy (RVH) as indicators of pulmonary hypertension (PH) under hypoxic conditions. RESULTS: In human pulmonary artery endothelial cells and murine pulmonary arteries exposed to hypoxia, eNOS was uncoupled as indicated by reduced superoxide production in the presence of the nitric oxide synthase inhibitor, L-(G)-nitro-L-arginine methyl ester (L-NAME). Concomitantly, NO levels, BH4 availability, and expression of DHFR were diminished under hypoxia. Application of folic acid (FA) restored DHFR levels, NO bioavailability, and BH4 levels under hypoxia. Importantly, FA prevented the development of hypoxia-induced PVR, right ventricular pressure increase, and RVH. INNOVATION: FA induced upregulation of DHFR recouples eNOS under hypoxia by improving BH4 recycling, thus preventing hypoxia-induced PH. CONCLUSION: FA might serve as a novel therapeutic option combating PH. PMID- 26414248 TI - The sadistic trait predicts minimization of intention and causal responsibility in moral judgment. AB - The present research tests the hypothesis that specific socially aversive traits subclinical sadism in particular-are associated with an impaired judgment of moral wrongness, guilt, and punishment in various moral scenarios manipulating intent, cause and consequence of harm. In three online studies (total N=1069), participants completed a battery of tests scaled to assess sadism and the Dark Triad constructs, then faced different situations involving moral issues (attempted harm, intentional harm, accidental harm). Study 1 revealed that a sadistic personality trait was associated with minimization of the importance of harmful intent in moral judgment. Study 2 showed that a sadistic personality trait predicted minimization of the importance of causal mechanisms to harmful consequences in moral judgment. Study 3 showed that these effects were mediated by enjoyment of cruelty, a characteristic unique to sadists. In the light of Cushman's (2008) two-process model of moral judgment, this set of studies provides the first evidence that deficits in the integration of the theory of mind and causality can be observed in personality traits. The independent predictive value of sadism highlights that features other than emotional deficits are essential in explaining impaired moral evaluations. PMID- 26414247 TI - Elevated carbon dioxide accelerates the spatial turnover of soil microbial communities. AB - Although elevated CO2 (eCO2 ) significantly affects the alpha-diversity, composition, function, interaction and dynamics of soil microbial communities at the local scale, little is known about eCO2 impacts on the geographic distribution of micro-organisms regionally or globally. Here, we examined the beta-diversity of 110 soil microbial communities across six free air CO2 enrichment (FACE) experimental sites using a high-throughput functional gene array. The beta-diversity of soil microbial communities was significantly (P < 0.05) correlated with geographic distance under both CO2 conditions, but declined significantly (P < 0.05) faster at eCO2 with a slope of -0.0250 than at ambient CO2 (aCO2 ) with a slope of -0.0231 although it varied within each individual site, indicating that the spatial turnover rate of soil microbial communities was accelerated under eCO2 at a larger geographic scale (e.g. regionally). Both distance and soil properties significantly (P < 0.05) contributed to the observed microbial beta-diversity. This study provides new hypotheses for further understanding their assembly mechanisms that may be especially important as global CO2 continues to increase. PMID- 26414250 TI - [In Process Citation]. PMID- 26414251 TI - [In Process Citation]. PMID- 26414252 TI - [In Process Citation]. PMID- 26414249 TI - Is there a domain-general cognitive structuring system? Evidence from structural priming across music, math, action descriptions, and language. AB - Cognitive processing in many domains (e.g., sentence comprehension, music listening, and math solving) requires sequential information to be organized into an integrational structure. There appears to be some overlap in integrational processing across domains, as shown by cross-domain interference effects when for example linguistic and musical stimuli are jointly presented (Koelsch, Gunter, Wittfoth, & Sammler, 2005; Slevc, Rosenberg, & Patel, 2009). These findings support theories of overlapping resources for integrational processing across domains (cfr. SSIRH Patel, 2003; SWM, Kljajevic, 2010). However, there are some limitations to the studies mentioned above, such as the frequent use of unnaturalistic integrational difficulties. In recent years, the idea has risen that evidence for domain-generality in structural processing might also be yielded though priming paradigms (cfr. Scheepers, 2003). The rationale behind this is that integrational processing across domains regularly requires the processing of dependencies across short or long distances in the sequence, involving respectively less or more syntactic working memory resources (cfr. SWM, Kljajevic, 2010), and such processing decisions might persist over time. However, whereas recent studies have shown suggestive priming of integrational structure between language and arithmetics (though often dependent on arithmetic performance, cfr. Scheepers et al., 2011; Scheepers & Sturt, 2014), it remains to be investigated to what extent we can also find evidence for priming in other domains, such as music and action (cfr. SWM, Kljajevic, 2010). Experiment 1a showed structural priming from the processing of musical sequences onto the position in the sentence structure (early or late) to which a relative clause was attached in subsequent sentence completion. Importantly, Experiment 1b showed that a similar structural manipulation based on non-hierarchically ordered color sequences did not yield any priming effect, suggesting that the priming effect is not based on linear order, but integrational dependency. Finally, Experiment 2 presented primes in four domains (relative clause sentences, music, mathematics, and structured descriptions of actions), and consistently showed priming within and across domains. These findings provide clear evidence for domain-general structural processing mechanisms. PMID- 26414253 TI - [In Process Citation]. PMID- 26414254 TI - [In Process Citation]. PMID- 26414255 TI - [In Process Citation]. PMID- 26414256 TI - [In Process Citation]. PMID- 26414257 TI - [In Process Citation]. PMID- 26414258 TI - [In Process Citation]. PMID- 26414259 TI - [In Process Citation]. PMID- 26414262 TI - [In Process Citation]. PMID- 26414261 TI - [In Process Citation]. PMID- 26414260 TI - [In Process Citation]. 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However, there is still a group of children with poor symptom control despite intensive treatment. The current review will provide an overview of a standardized approach to characterize this heterogeneous group of severely sick children. Factors that attenuate the effect of the prescribed treatment and make asthma difficult to treat are discussed. In addition, the usefulness of current methods of assessing asthma severity, pulmonary function, allergy and airway inflammation is also described. Finally, an overview of therapeutic options for children with severe asthma is provided. PMID- 26414276 TI - Microgravity Reduces the Differentiation and Regenerative Potential of Embryonic Stem Cells. AB - Mechanical unloading in microgravity is thought to induce tissue degeneration by various mechanisms, including inhibition of regenerative stem cell differentiation. To address this hypothesis, we investigated the effects of microgravity on early lineage commitment of mouse embryonic stem cells (mESCs) using the embryoid body (EB) model of tissue differentiation. We found that exposure to microgravity for 15 days inhibits mESC differentiation and expression of terminal germ layer lineage markers in EBs. Additionally, microgravity unloaded EBs retained stem cell self-renewal markers, suggesting that mechanical loading at Earth's gravity is required for normal differentiation of mESCs. Finally, cells recovered from microgravity-unloaded EBs and then cultured at Earth's gravity showed greater stemness, differentiating more readily into contractile cardiomyocyte colonies. These results indicate that mechanical unloading of stem cells in microgravity inhibits their differentiation and preserves stemness, possibly providing a cellular mechanistic basis for the inhibition of tissue regeneration in space and in disuse conditions on earth. PMID- 26414278 TI - Fabrication of Tunable, High-Refractive-Index Titanate-Silk Nanocomposites on the Micro- and Nanoscale. AB - The combination of water-based titanate nanosheets dispersion and silk fibroin solution allows the realization of a versatile nanocomposite. Different fabrication techniques can be easily applied on these nanocomposites to manipulate the end form of these materials on the micro- and nanoscale. Easy tunability of the refractive index from n = 1.55 up to n = 1.97 is achieved, making it attractive for flexible, biopolymer-based optical devices. PMID- 26414279 TI - "Keep your brain fit!" Effectiveness of a psychoeducational intervention on cognitive functioning in healthy adults: A randomised controlled trial. AB - A psychoeducational intervention (Keep your brain fit!) was designed for the middle-aged and older working population. The intervention focuses on increasing knowledge and awareness about cognitive ageing and teaching strategies to cope with cognitive changes. The primary aim of this study was to investigate the effectiveness of the e-health intervention in terms of subjective cognitive functioning. As secondary aims, objective cognitive functioning and psychological well-being were also measured. A randomised controlled trial that included people aged 40 to 65 years was conducted. A maximum of 4 weeks was allowed to complete the intervention. The outcome measures were obtained from an online test battery that was administered at baseline, post-test and at 4-week follow-up. A total of 376 participants completed the whole study. After the intervention, the experimental group reported more feelings of stability concerning memory functioning and perceived greater locus of control over memory compared to the control group. These effects were maintained at the 4-week follow-up. Taking into account the relatively low costs and easy accessibility of this e-health intervention, we consider the programme to be a valuable contribution to public healthcare interventions for middle-aged and older adults. PMID- 26414280 TI - Uterine artery embolization using progressively larger calibrated gelatin sponge particles. AB - PURPOSE: To assess the effectiveness and safety of uterine artery embolization (UAE) using progressively larger calibrated gelatin sponge particles for symptomatic uterine fibroids. MATERIAL AND METHODS: Thirty patients with symptomatic uterine fibroids underwent UAE. Calibrated gelatin sponge particles were used in all patients, beginning with 355-500 MUm particles, progressively increasing to 500-710 MUm and finally to 710-1000 MUm particles. Changes in tumor, uterine volume, and tumor infarction rate were assessed using pelvic magnetic resonance imaging (MRI). The level of complication, improvement of clinical symptoms, and Uterine Fibroid Symptom and Quality of Life (UFS-QOL) score were assessed. RESULTS: MR imaging revealed the mean largest tumor volume reduction was 56.23 +/- 16.25% at three months and 72.61 +/- 14.47% at 12 months after the procedure. 100% infarction of the dominant fibroids was 91.27 +/- 5.02% at three months and 96 +/- 5.20% at 12 months after the procedure. Menorrhagia improved markedly in all 23 patients. Bulk-related symptoms improved in 12 (92.30%) of 13 patients. The baseline UFS-QOL score was 43.13 and improved to 11.88 (p < 0.001). No major complications were observed. CONCLUSION: UAE using progressively larger calibrated gelatin sponge particles is an effective and safe treatment for symptomatic uterine fibroids. PMID- 26414281 TI - Comments on Auble et al. Regarding Hypopituitarism in Pediatric Survivors of Inflicted Traumatic Brain Injury. PMID- 26414282 TI - Survey of Attitudes and Ethical Concerns Related to Gene Therapy Among Medical Students and Postgraduates in China. AB - Gene therapy is becoming an important treatment modality for gravely ill patients, and today's medical students and postgraduates are both potential consumers and future providers of gene therapy. Therefore, their attitudes and concerns about gene therapy may directly influence its long-term development and implementation in the clinic. We performed a cross-sectional survey of medical students and postgraduates at West China Medical School of Sichuan University. A custom-designed questionnaire was distributed to 600 students, and 579 were valid (96.98% response). Most respondents (84.46%) indicated little prior knowledge about gene therapy. The proportion of respondents considering gene therapy as acceptable ranged from 63.73% for serious illness to 17.72% for genetic enhancement. Adverse side effects were the most frequent concern among respondents when asked to imagine that they would receive gene therapy to treat a severe brain-related illness. These results suggest that medical students in China consider gene therapy's acceptability to be rather low, and are most concerned about its adverse side effects. PMID- 26414283 TI - Comparative Evaluation of the Vector Competence of Four South American Populations of the Rhipicephalus sanguineus Group for the Bacterium Ehrlichia canis, the Agent of Canine Monocytic Ehrlichiosis. AB - This study compared the vector competence of four populations of Rhipicephalus sanguineus group ticks for the bacterium Ehrlichia canis, the agent of canine monocytic ehrlichiosis (CME). Ticks (larvae and nymphs) from the four populations one from Sao Paulo state, southeastern Brazil (BSP), one from Rio Grande do Sul state, southern Brazil (BRS), one from Argentina (ARG), and one from Uruguay (URU)-were exposed to E. canis infection by feeding on dogs that were experimentally infected with E. canis. Engorged ticks (larvae and nymphs) were allowed to molt to nymphs and adults, respectively, which were tested by molecular analysis (E. canis-specific PCR assay) and used to infest naive dogs. Through infestation of adult ticks on naive dogs, after nymphal acquisition feeding on E. canis-infected dogs, only the BSP population was shown to be competent vectors of E. canis, i.e., only the dogs infested with BSP adult ticks developed clinical illness, seroconverted to E. canis, and yielded E. canis DNA by PCR. This result, demonstrated by two independent replications, is congruent with epidemiological data, since BSP ticks were derived from Sao Paulo state, Brazil, where CME is highly endemic. On the other hand, BRS, ARG, and URU ticks were derived from a geographical region (South America southern cone) where CME has never been properly documented. Molecular analysis of unfed adults at 30 days post molting support these transmission results, since none of the BRS, ARG, and URU ticks were PCR positive, whereas 1% of the BSP nymphs and 31.8% of the BSP adults contained E. canis DNA. We conclude that the absence or scarcity of cases of CME due to E. canis in the South America southern cone is a result of vector incompetence of the R. sanguineus group ticks that prevail on dogs in this part of South America. PMID- 26414284 TI - Diagnosis and Treatment of Left-Sided Prosthetic Paravalvular Regurgitation. AB - Paravalvular leak (PVL) is a complication related to the surgical implantation of left-sided prosthetic valves. The prevalence of paravalvular regurgitation ranges between 5 and 20%. Left-sided prosthetic paravalvular regurgitation presents with a wide constellation of signs and symptoms ranging from asymptomatic murmur to heart failure, hemolysis and cardiac cachexia. Echocardiography plays a key role in imaging the PVL and can help in guiding the closure procedure with both transesophageal and intracardiac probes. Transcatheter closure of paravalvular regurgitations is an appealing prospect. PMID- 26414286 TI - A vegetable oil-based organogel for use in pH-mediated drug delivery. AB - Organogels prepared with vegetable oils as the liquid organic phase present an excellent platform for the controlled delivery of hydrophobic guest molecules. We disclose a graft copolymer comprised of a poly(L-serine) backbone linked to alkane side-chains by hydrolytically susceptible ester bonds, that is capable of gelating edible safflower oil. The thermoresponsive organogel formed, which is non-cytotoxic, is capable of withholding guest molecules before undergoing targeted disassembly upon incubation in solutions of acidic pH, permitting the directed release of payload molecules. The presented material offers an extremely promising candidate for the controlled delivery of hydrophobic agents within acidic environments, such as cancer tumour sites. PMID- 26414288 TI - Agreement between High School Athletes and Their Parents on Reporting Athletic Events and Concussion Symptoms. AB - An enhanced understanding of agreement levels between adolescents and parents for reporting athletic events and symptoms can help inform surveillance systems as well as clinical and epidemiological investigations of sports-related concussions. We sought to quantify agreement levels between high school athletes and parents for reporting: (1) number of games; (2) number of practices; (3) occurrence of an injury resulting in any concussion symptoms; and (4) presence of each specific symptom on the date of that injury among high school boys' football and girls' soccer athletes playing in Autumn 2012 in Washington State. There was substantial agreement on reporting the number of athletic events. Agreement levels were greater for games (kappa = 0.82; 95% confidence interval [CI]: 0.79 0.85 in boys' football; kappa = 0.75; 95% CI: 0.72-0.79 in girls' soccer) than for practices (kappa = 0.64; 95% CI: 0.62-0.67 in boys' football; kappa = 0.65; 95% CI: 0.62-0.67 in girls' soccer). There was moderate to substantial agreement on the occurrence of injury resulting in any concussion symptoms; however, agreement on the presence and severity of each symptom varied from poor to almost perfect. Overall, athletes reported greater severity of symptoms than parents did; notably, no difference in mean symptom scores was found when the athlete had a history of concussion. Agreement levels were greater when information was ascertained within 1 week of injury than when it was obtained later than 1 week. Including both athletes' and parents' reports of sports-related events and ascertaining information as soon as possible after injury are important considerations in designing injury surveillance systems. PMID- 26414290 TI - Application of the continual reassessment method to dose-finding studies in regional anesthesia: an estimate of the ED95 dose for 0.5% bupivacaine for ultrasound-guided supraclavicular block: erratum. PMID- 26414287 TI - Identification of Circulating Biomarker Candidates for Hepatocellular Carcinoma (HCC): An Integrated Prioritization Approach. AB - Hepatocellular carcinoma (HCC) is the world's third most widespread cancer. Currently available circulating biomarkers for this silently progressing malignancy are not sufficiently specific and sensitive to meet all clinical needs. There is an imminent and pressing need for the identification of novel circulating biomarkers to increase disease-free survival rate. In order to facilitate the selection of the most promising circulating protein biomarkers, we attempted to define an objective method likely to have a significant impact on the analysis of vast data generated from cutting-edge technologies. Current study exploits data available in seven publicly accessible gene and protein databases, unveiling 731 liver-specific proteins through initial enrichment analysis. Verification of expression profiles followed by integration of proteomic datasets, enriched for the cancer secretome, filtered out 20 proteins including 6 previously characterized circulating HCC biomarkers. Finally, interactome analysis of these proteins with midkine (MDK), dickkopf-1 (DKK-1), current standard HCC biomarker alpha-fetoprotein (AFP), its interacting partners in conjunction with HCC-specific circulating and liver deregulated miRNAs target filtration highlighted seven novel statistically significant putative biomarkers including complement component 8, alpha (C8A), mannose binding lectin (MBL2), antithrombin III (SERPINC1), 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1), alcohol dehydrogenase 6 (ADH6), beta-ureidopropionase (UPB1) and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6). Our proposed methodology provides a swift assortment process for biomarker prioritization that eventually reduces the economic burden of experimental evaluation. Further dedicated validation studies of potential putative biomarkers on HCC patient blood samples are warranted. We hope that the use of such integrative secretome, interactome and miRNAs target filtration approach will accelerate the selection of high-priority biomarkers for other diseases as well, that are more amenable to downstream clinical validation experiments. PMID- 26414289 TI - Differences in pteridine urinary levels in patients with malignant and benign ovarian tumors in comparison with healthy individuals. AB - Pteridines belong to a class of fluorescent metabolites that are excreted by humans in urine and their concentrations can reflect various pathophysiological states. We quantified the differences in urinary pteridine levels in patients with malignant and benign ovarian tumors and in healthy individuals. Urine samples were centrifuged and supernatants were oxidized by MnO2 before analysis. Levels of neopterin, biopterin, and pterin were assessed by fluorescence analysis of human urine after HPLC separation. We have revealed that the median neopterin levels were higher in urine samples from patients with malignant (0.226 MUmol/mmol creatinine) and benign ovarian tumors (0.150 MUmol/mmol creatinine) than in healthy subjects (0.056 MUmol/mmol creatinine). The median neopterin levels of patients with malignant tumors were higher (1.5-times) than in patients with benign tumors. The median biopterin level in urine of patients with benign ovarian tumors (0.268 MUmol/mmol creatinine) was found to be very close to the level in patients with malignant ovarian tumors (0.239 MUmol/mmol creatinine), and both were higher than in healthy samples (0.096 MUmol/mmol creatinine). The levels of urine pterin followed a pattern similar to neopterin levels for both ovarian tumors, but their concentrations were about three times lower than neopterin levels. PMID- 26414291 TI - Relativistic Force Field: Parametrization of (13)C-(1)H Nuclear Spin-Spin Coupling Constants. AB - Previously, we reported a reliable DU8 method for natural bond orbital (NBO) aided parametric scaling of Fermi contacts to achieve fast and accurate prediction of proton-proton spin-spin coupling constants (SSCC) in (1)H NMR. As sophisticated NMR experiments for precise measurements of carbon-proton SSCCs are becoming more user-friendly and broadly utilized by the organic chemistry community to guide and inform the process of structure determination of complex organic compounds, we have now developed a fast and accurate method for computing (13)C-(1)H SSCCs. Fermi contacts computed with the DU8 basis set are scaled using selected NBO parameters in conjunction with empirical scaling coefficients. The method is optimized for inexpensive B3LYP/6-31G(d) geometries. The parametric scaling is based on a carefully selected training set of 274 ((3)J), 193 ((2)J), and 143 ((1)J) experimental (13)C-(1)H spin-spin coupling constants reported in the literature. The DU8 basis set, optimized for computing Fermi contacts, which by design had evolved from optimization of a collection of inexpensive 3-21G*, 4 21G, and 6-31G(d) bases, offers very short computational (wall) times even for relatively large organic molecules containing 15-20 carbon atoms. The most informative SSCCs for structure determination, i.e., (3)J, were computed with an accuracy of 0.41 Hz (rmsd). The new unified approach for computing (1)H-(1)H and (13)C-(1)H SSCCs is termed "DU8c". PMID- 26414292 TI - Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. AB - RATIONALE: Reducing the global burden of sepsis, a recognized global health challenge, requires comprehensive data on the incidence and mortality on a global scale. OBJECTIVES: To estimate the worldwide incidence and mortality of sepsis and identify knowledge gaps based on available evidence from observational studies. METHODS: We systematically searched 15 international citation databases for population-level estimates of sepsis incidence rates and fatality in adult populations using consensus criteria and published in the last 36 years. MEASUREMENTS AND MAIN RESULTS: The search yielded 1,553 reports from 1979 to 2015, of which 45 met our criteria. A total of 27 studies from seven high-income countries provided data for metaanalysis. For these countries, the population incidence rate was 288 (95% confidence interval [CI], 215-386; tau = 0.55) for hospital-treated sepsis cases and 148 (95% CI, 98-226; tau = 0.99) for hospital treated severe sepsis cases per 100,000 person-years. Restricted to the last decade, the incidence rate was 437 (95% CI, 334-571; tau = 0.38) for sepsis and 270 (95% CI, 176-412; tau = 0.60) for severe sepsis cases per 100,000 person years. Hospital mortality was 17% for sepsis and 26% for severe sepsis during this period. There were no population-level sepsis incidence estimates from lower income countries, which limits the prediction of global cases and deaths. However, a tentative extrapolation from high-income country data suggests global estimates of 31.5 million sepsis and 19.4 million severe sepsis cases, with potentially 5.3 million deaths annually. CONCLUSIONS: Population-level epidemiologic data for sepsis are scarce and nonexistent for low- and middle income countries. Our analyses underline the urgent need to implement global strategies to measure sepsis morbidity and mortality, particularly in low- and middle-income countries. PMID- 26414294 TI - Comparison of Physician-Based and Patient-Based Criteria for the Diagnosis of Fibromyalgia. AB - OBJECTIVE: The American College of Rheumatology (ACR) 2010 preliminary fibromyalgia diagnostic criteria require symptom ascertainment by physicians. The 2011 survey or research modified ACR criteria use only patient self-report. We compared physician-based (MD) (2010) and patient-based (PT) (2011) criteria and criteria components to determine the degree of agreement between criteria methodology. METHODS: We studied prospectively collected, previously unreported rheumatology practice data from 514 patients and 30 physicians in the ACR 2010 study. We evaluated the widespread pain index, polysymptomatic distress (PSD) scale, tender point count (TPC), and fibromyalgia diagnosis using 2010 and 2011 rules. Bland-Altman 95% limits of agreement (LOA), kappa statistic, Lin's concordance coefficient, and the area under the receiver operating curve (ROC) were used to measure agreement and discrimination. RESULTS: MD and PT diagnostic agreement was substantial (83.4%, kappa = 0.67). PSD scores differed slightly (12.3 MD, 12.8 PT; P = 0.213). LOA for PSD were -8.5 and 7.7, with bias of -0.42. The TPC was strongly associated with both the MD (r = 0.779) and PT PSD scales (r = 0.702). CONCLUSION: There was good agreement in MD and PT fibromyalgia diagnosis and other measures among rheumatology patients. Low bias scores indicate consistent results for physician and patient measures, but large values for LOA indicate many widely discordant pairs. There is acceptable agreement in diagnosis and PSD for research, but insufficient agreement for clinical decisions and diagnosis. We suggest adjudication of symptom data by patients and physicians, as recommended by the 2010 ACR criteria. PMID- 26414295 TI - Semiconductor Behavior of a Three-Dimensional Strontium-Based Metal-Organic Framework. AB - The self-assembly of a three-dimensional strontium-based metal-organic framework [Sr(Hbtc)(H2O)]n (1) was achieved through the reaction of Sr(NO3)2 with a 1,2,4 benzenetricarboxylic acid (1,2,4-H3btc) ligand under hydrothermal conditions. This Sr-based metal-organic framework exhibits remarkable semiconducting behavior, as evidenced by theoretical calculations and experimental measurements. Temperature-dependent DC conductivity, near-room-temperature AC conductivity, diffuse reflection spectra, and photoluminescence spectra provide strong proof that compound 1 shows a band gap of 2.3 eV, which is comparable to that for other commonly available semiconducting materials (e.g., CdSe, CdTe, ZnTe, GaP, etc.). The optimized molecular structure and electronic properties (density of states and band gap energy) of 1 were calculated using density functional theory, and the results are consistent with experimental findings. This is the first report on the semiconducting properties of a strontium-based MOF, which will pave the way for further studies in semiconducting MOFs with interesting potential applications in optoelectronic devices. PMID- 26414296 TI - Investigation of denitrifying microbial communities within an agricultural drainage system fitted with low-grade weirs. AB - Enhancing wetland characteristics in agricultural drainage ditches with the use of low-grade weirs, has been identified as a best management practice (BMP) to mitigate nutrient runoff from agriculture landscapes. A major objective of utilizing low-grade weirs as a BMP includes fostering environments suitable for the biogeochemical removal of nitrogen via denitrification. This study examined the spatial resolution of microbial communities involved in denitrification in agricultural drainage systems fitted with low-grade weirs. Appropriate sampling scales of microbial communities were investigated using 16S rRNA and denitrification functional genes nosZ, nirS, and nirK via quantitative polymerase chain reaction (qPCR) and terminal-restriction fragment length polymorphism (T RFLP) analysis. Genes 16S rRNA, nosZ, and nirS were all successfully detected in soil samples, while nirK was below the detection limit throughout the study. Utilizing a combination of three sampling regimes (management, reach, catchment) was found to be effective in capturing microbial community patterns, as ANOVA results revealed nosZ gene abundance was significantly greater at the management rather than reach scale (p = 0.045; F = 3.311), although, no significant differences were observed in 16S rRNA or nirS between sampling scales (p > 0.05). A Pearson correlation matrix confirmed that 16S rRNA and nosZ gene abundances were positively correlated with soil carbon (C), nitrogen (N), and moisture, while nirS abundance was only positively correlated with soil C and soil moisture. This highlights the potential for wetland-like characteristics to be recovered in agricultural drainage systems, as weir proximity is observed to enhance soil moisture and conditions for N remediation. This study provides the basis for additional investigations of these unique environments in the Mississippi Alluvial Valley and a starting point for adaptive management to enhance agricultural drainage systems for microbial communities towards nutrient remediation goals. PMID- 26414297 TI - Surface analysis of pilot distribution system pipe autopsies: The relationship of organic and inorganic deposits to input water quality. AB - Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) surface analysis was conducted to characterise deposits in polyethylene pipes used in a novel pilot water distribution system (PDS). The system consisted of four (4) parallel distribution systems receiving water from different treatment processes, ranging from conventional coagulation through to an advanced membrane filtration system. After two years of operation, the distribution system was shut down and samples of pipe were collected for autopsy analysis. Inlet and outlet samples from each PDS were collected for purpose of comparison. ToF-SIMS was used to assess chemical differences in surface biofilm accumulation and particulate deposition, which resulted as a consequence of the treatment method and operational mode of each system. These data supplemented previously collected bacteriological and chemical water quality data. Results from the inorganic analysis of the pipes were consistent with corrosion and contamination events that occurred upstream in the corresponding treatment systems. Principal component analysis of data on organic constituents showed oxygen and nitrogen containing fragments were associated with the treatment inlet and outlet samples. These types of signals can often be ascribed to biofilm polysaccharides and proteins. A trend was observed when comparing samples from the same PDS, showing an association of lower molecular weight (MW) organic fragments with the inlet and higher MW organic fragments with the outlet samples. PMID- 26414293 TI - Perspective on Adeno-Associated Virus Capsid Modification for Duchenne Muscular Dystrophy Gene Therapy. AB - Duchenne muscular dystrophy (DMD) is a X-linked, progressive childhood myopathy caused by mutations in the dystrophin gene, one of the largest genes in the genome. It is characterized by skeletal and cardiac muscle degeneration and dysfunction leading to cardiac and/or respiratory failure. Adeno-associated virus (AAV) is a highly promising gene therapy vector. AAV gene therapy has resulted in unprecedented clinical success for treating several inherited diseases. However, AAV gene therapy for DMD remains a significant challenge. Hurdles for AAV mediated DMD gene therapy include the difficulty to package the full-length dystrophin coding sequence in an AAV vector, the necessity for whole-body gene delivery, the immune response to dystrophin and AAV capsid, and the species specific barriers to translate from animal models to human patients. Capsid engineering aims at improving viral vector properties by rational design and/or forced evolution. In this review, we discuss how to use the state-of-the-art AAV capsid engineering technologies to overcome hurdles in AAV-based DMD gene therapy. PMID- 26414298 TI - Effect of residual monomer from polyacrylamide on head lettuce grown in peat substrate. AB - The paper investigates the migration of the acrylamide monomer (AMD) to lettuce chosen as a test plant growing in an organic medium (peat substrate). Polyacrylamide (PAM)-based flocculant added to the growing medium contained no more than 1000 mg kg(-1) of AMD. Plants were grown with varied doses of PAM preparation (0.5-3.0 mg dm(-3) of peat substrate) to compare the results with the control sample. The determination of AMD content, chlorophyll content, weight of the lettuce head, and also analysis of macro- and micro-elements in lyophilised test material was made under the same analytical conditions. The results showed that lettuce plants absorb AMD to the leaves from the peat substrate. The AMD uptake has a negative impact on the growth of lettuce. It reduces the average fresh weight of heads and destabilises the mineral composition of the plant. Therefore, concern related to the transfer risk of the residual AMD from sludge used for organic fertilisation of edible plants still remains a crucial question from a food and consumer safety point of view. To ensure consumer safety, the fate of the AMD following the application of PAM to cropland should be carefully monitored in the whole food chain. PMID- 26414299 TI - Improving Diagnosis in Health Care: Highlights of a Report From the National Academies of Sciences, Engineering, and Medicine. PMID- 26414300 TI - A tale of two paralogs: human Transformer2 proteins with differential RNA-binding affinities. AB - The Transformer2 (Tra2) proteins in humans are homologues of the Drosophila Tra2 protein. One of the two RNA-binding paralogs, Tra2beta, has been very well studied over the past decade, but not much is known about Tra2alpha. It was very recently shown that the two proteins demonstrate the phenomenon of paralog compensation. Here, we provide a structural basis for this genetic backup circuit, using molecular modelling and dynamics studies. We show that the two proteins display similar binding specificities, but differential affinities to a short GAA-rich RNA stretch. Starting from the 6-nucleotide RNA in the solution structure, close to 4000 virtual mutations were modelled on RNA and the domain RNA interactions were studied after energy minimisation to convergence. Separately, another known 13-nucleotide stretch was docked and the domain-RNA interactions were observed through a 100-ns dynamics trajectory. We have also demonstrated the 'compensatory' mechanism at the level of domains in one of the domain repeat-containing RNA-binding proteins. PMID- 26414301 TI - Online interferometric study of viscoelastic rupture and necking deformation of as-spun (iPP) fibres due to creep process. AB - Creep deformation under constant load leads to rupture when the polymer chains can no longer separate and accommodate the load. This fracture phenomenon is investigated interferometrically. The creep behaviour of as-spun isotactic Polypropylene (iPP) fibres is studied at different stresses, different initial lengths and different radii. The creep rate, which defines the velocity of the creep deformation and the dimensional stability of the material, is studied. The failure time and stress of iPP due to creep process is determined. The necking deformation was in situ detected during creep process. The mean refractive indices (n(P) andn?) profiles of iPP fibres were determined at different positions along the fibre axis before and after necking. The relation between the creep behaviour and different optical and structural parameters is investigated. Microinterferograms are given for illustration. PMID- 26414302 TI - Conducting Polymers for Neural Prosthetic and Neural Interface Applications. AB - Neural-interfacing devices are an artificial mechanism for restoring or supplementing the function of the nervous system, lost as a result of injury or disease. Conducting polymers (CPs) are gaining significant attention due to their capacity to meet the performance criteria of a number of neuronal therapies including recording and stimulating neural activity, the regeneration of neural tissue and the delivery of bioactive molecules for mediating device-tissue interactions. CPs form a flexible platform technology that enables the development of tailored materials for a range of neuronal diagnostic and treatment therapies. In this review, the application of CPs for neural prostheses and other neural interfacing devices is discussed, with a specific focus on neural recording, neural stimulation, neural regeneration, and therapeutic drug delivery. PMID- 26414303 TI - Fabrication and characterization of artificial miniaturized insect compound eyes for imaging. AB - Polystyrene (PS) microspheres are synthesized by dispersion polymerization, and a close-packed two-dimensional (2D) array of the PS microspheres is formed by the self-assembly method through dip drawing under magnetic stirring. This array is then used to fabricate a 2D polydimethylsiloxane concave mold by soft lithography. The mold is employed to produce convex polymethylmethacrylate-based compound eye-replicating films of different hemispherical heights by thermopressing. The optical properties of the ommatidia on these biomimetic compound eye-replicating films are investigated, and the films are used with a charge-coupled device camera to construct a biomimetic visual system. The visual distance and field of view of this system are measured. The film with the greatest hemispherical height results in the biomimetic visual system with the highest visual distance and the widest field of view. In addition, it is found that the quality of the optical images is not dependent on the hemispherical height of the biomimetic films. The ability of the biomimetic visual system to detect moving object in real time is also studied. PMID- 26414304 TI - Ultrasound-Guided Renal Access for Percutaneous Nephrolithotomy: A Description of Three Novel Ultrasound-Guided Needle Techniques. AB - Ultrasound-guided renal access for percutaneous nephrolithotomy (PCNL) is a safe, effective, and low-cost procedure commonly performed worldwide, but a technique underutilized by urologists in the United States. The purpose of this article is to familiarize the practicing urologist with methods for ultrasound guidance for percutaneous renal access. We discuss two alternative techniques for gaining renal access for PCNL under ultrasound guidance. We also describe a novel technique of using the puncture needle to reposition residual stone fragments to avoid additional tract dilation. With appropriate training, ultrasound-guided renal access for PCNL can lead to reduced radiation exposure, accurate renal access, and excellent stone-free success rates and clinical outcomes. PMID- 26414305 TI - What automaticity deficit? Activation of lexical information by readers with dyslexia in a rapid automatized naming Stroop-switch task. AB - Reading fluency is often predicted by rapid automatized naming (RAN) speed, which as the name implies, measures the automaticity with which familiar stimuli (e.g., letters) can be retrieved and named. Readers with dyslexia are considered to have less "automatized" access to lexical information, reflected in longer RAN times compared with nondyslexic readers. We combined the RAN task with a Stroop-switch manipulation to test the automaticity of dyslexic and nondyslexic readers' lexical access directly within a fluency task. Participants named letters in 10 * 4 arrays while eye movements and speech responses were recorded. Upon fixation, specific letter font colors changed from black to a different color, whereupon the participant was required to rapidly switch from naming the letter to naming the letter color. We could therefore measure reading group differences on "automatic" lexical processing, insofar as it was task-irrelevant. Readers with dyslexia showed obligatory lexical processing and a timeline for recognition that was overall similar to typical readers, but a delay emerged in the output (naming) phase. Further delay was caused by visual-orthographic competition between neighboring stimuli. Our findings outline the specific processes involved when researchers speak of "impaired automaticity" in dyslexic readers' fluency, and are discussed in the context of the broader literature in this field. PMID- 26414306 TI - Molecular Catalysis of O2 Reduction by Iron Porphyrins in Water: Heterogeneous versus Homogeneous Pathways. AB - Despite decades of active attention, important problems remain pending in the catalysis of dioxygen reduction by iron porphyrins in water in terms of selectivity and mechanisms. This is what happens, for example, for the distinction between heterogeneous and homogeneous catalysis for soluble porphyrins, for the estimation of H2O2/H2O product selectivity, and for the determination of the reaction mechanism in the two situations. With water-soluble iron tetrakis(N-methyl-4-pyridyl)porphyrin as an example, procedures are described that allow one to operate this distinction and determine the H2O2/H2O product ratio in each case separately. It is noteworthy that, despite the weak adsorption of the iron(II) porphyrin on the glassy carbon electrode, the contribution of the adsorbed complex to catalysis rivals that of its solution counterpart. Depending on the electrode potential, two successive catalytic pathways have been identified and characterized in terms of current-potential responses and H2O2/H2O selectivity. These observations are interpreted in the framework of the commonly accepted mechanism for catalytic reduction of dioxygen by iron porphyrins, after checking its compatibility with a change of oxygen concentration and pH. The difference in intrinsic catalytic reactivity between the catalyst in the adsorbed state and in solution is also discussed. The role of heterogeneous catalysis with iron tetrakis(N-methyl-4-pyridyl)porphyrin has been overlooked in previous studies because of its water solubility. The main objective of the present contribution is therefore to call attention, by means of this emblematic example, to such possibilities to reach a correct identification of the catalyst, its performances, and reaction mechanism. This is a question of general interest, so that reduction of dioxygen remains a topic of high importance in the context of contemporary energy challenges. PMID- 26414308 TI - The Beginning Psychotherapist and Borderline Personality Disorder: Basic Treatment Principles and Clinical Foci. AB - Borderline personality disorder is a prevalent psychopathology; thus, most graduate students in psychology, residents in psychiatry, and early career clinicians will encounter patients with this disorder in the course of their training or initial professional practice. This paper provides clear and concise guidelines for conducting treatment geared toward the clinician's developmental level. It builds upon the knowledge and skills that are typically acquired during graduate education and training to provide an accessible framework for undertaking psychotherapy with patients who have borderline personality disorder. This paper draws upon common psychotherapeutic factors and existing evidence based treatments for the disorder to identify principals and interventions that are likely to contribute to therapeutic action. It uses behavioral, cognitive, and psychodynamic interventions to address the patient's multidimensional psychopathology. This approach offers a coherent and integrated treatment framework for the beginning psychotherapy practitioner. PMID- 26414309 TI - Intensive Individual and Group Cognitive Behavioural Therapy for Obsessive Compulsive Disorder. AB - Whilst there is good evidence to show intensive individual therapy can be effective for obsessive-compulsive disorder (OCD), this treatment can be challenging to deliver for therapists in the National Health Service (NHS). We report on a novel means of delivering intensive cognitive behavioural therapy (CBT) by combining it with group work, which allowed therapists to offer each other mutual support and permitted patients to gain the interpersonal benefits of working with others. This case study describes the combined intensive individual and group CBT programme for a 46-year-old woman with OCD. This treatment took place within a community mental health team within outer London. Following treatment, the client showed significant improvements in symptoms. This creative method for treating OCD as part of routine clinical practice may be beneficial for therapists to feel supported, for reduction in clinicians' time in treatment, and for clients to benefit from a group experience. PMID- 26414307 TI - The roles of oxidative stress, endoplasmic reticulum stress, and autophagy in aldosterone/mineralocorticoid receptor-induced podocyte injury. AB - Podocytes play an important role in the pathogenesis and progression of glomerulosclerosis. Recent studies indicate that aldosterone/mineralocorticoid receptor (MR) is a major contributor of chronic kidney disease (CKD) progression. Aldosterone/MR induces glomerular podocyte injury, causing the disruption of the glomerular filtration barrier and proteinuria. The present study investigated the mechanisms by which aldosterone/MR mediated podocyte injury, focusing on the involvement of oxidative stress, endoplasmic reticulum (ER) stress, and autophagy. We observed that aldosterone/MR induced ER stress and podocyte injury both in vivo and in vitro. Blockade of ER stress significantly reduced aldosterone/MR-induced podocyte injury. In addition, we found that ER stress induced podocyte injury was mediated by CCAAT/enhancer-binding protein (C/EBP) homologous protein (Chop). Interestingly, autophagy was also enhanced by aldosterone/MR. Pharmacological inhibition of autophagy resulted in increased apoptosis. Inhibition of ER stress significantly reduced aldosterone/MR-induced autophagy. In addition, the activation of ER stress increased the formation of autophagy, which protected podocytes from apoptosis. Moreover, we observed that the addition of ROS scavenger, N-acetyl cystein (NAC), blocked both ER stress and autophagy by aldosterone/MR. Collectively, these results suggest that oxidant stress-mediated aldosterone/MR-induced podocyte injury via activating ER stress, which then triggers both Chop-dependent apoptosis and autophagy to cope with the injury. These findings may guide us to therapeutic strategies for glomerular diseases. PMID- 26414310 TI - Coming Together to Move Apart: Family Therapy for Enhancing Adolescent Development. AB - An important goal of adolescent development is emotional separation from the family of origin. Differing views on how to accomplish this task exist, and these are reflected in the choice of treatment modality. It has been common practice in the treatment of adolescents for work with parents to be done separately from the adolescent. Since social, cultural, and economic factors have an impact on development, as society changes it is important to think creatively about effective ways to accomplish the process of becoming a functioning adult. It is in this context that authors have focused recently on the need for young adults to have a positive connection with their parents. This paper will address the role of involvement of family in the psychotherapy of adolescents either by inviting them to participate in some of the individual sessions or through conjoint family therapy to facilitate forward development. Clinical illustrations will demonstrate the issues of an adolescent with unresolved early traumatic separation, an adolescent who is fulfilling parental needs, an adolescent with too much power in the family, the importance of beginning treatment after assessing where everyone is emotionally, and the problem of premature disconnection by parents. PMID- 26414311 TI - Specific Techniques Vs. Common Factors? Psychotherapy Integration and its Role in Ethical Practice. AB - Important change in competent practice in psychological therapy is increasingly being influenced by evidence-based practice. This paper explores major issues related to the evidence-based literature with regard to specific techniques and common factors. Increasing evidence that support common factors provides validity for the psychotherapy integration movement. This movement is explored in relation to the three waves of behavior therapy that indicate an increasing integration of a wide range of therapies. The discussion concludes with implications for therapists who wish to adopt an ethical and evidence-based approach. PMID- 26414312 TI - Perfectionism and Personality Disorders as Predictors of Symptoms and Interpersonal Problems. AB - Maladaptive perfectionism is a common factor in many disorders and is correlated with some personality dysfunctions. Less clear is how dimensions, such as concern over mistakes, doubts about actions, and parental criticism, are linked to overall suffering. Additionally, correlations between perfectionism and personality disorders are poorly explored in clinical samples. In this study we compared a treatment seeking individuals (n=93) and a community sample (n=100) on dimensions of maladaptive perfectionism, personality disorders, symptoms, and interpersonal problems. Results in both samples revealed maladaptive perfectionism was strongly associated with general suffering, interpersonal problems, and a broad range of personality disordered traits. Excessive concern over one's errors, and to some extent doubts about actions, predicted unique additional variance beyond the presence of personality pathology in explaining symptoms and interpersonal problems. PMID- 26414313 TI - My Patient, My Stalker Empathy as a Dual-Edged Sword: A Cautionary Tale. AB - Success in psychotherapy is correlated with the "fit" between patient and therapist, a factor related to attachment. For psychotherapists of any orientation, empathy and building the bond of attachment is our stock-in-trade. When empathy builds the bond of attachment with someone starved for connection, a therapist may inadvertently set him- or herself up to become a victim of a stalker. Because individuals who stalk others suffer from severe attachment disorders, their hunger for attachment motivates them to shadow psychotherapists, which makes being stalked a very real occupational hazard for psychotherapists. This was a painful discovery for me. I was stalked for 11 months, leaving me with post-traumatic stress disorder. After recovering, I deconstructed the experience to understand how and why it happened, and discovered that it was my empathy and compassion that contributed to and maintained the stalking. What I learned from the forensic literature provided the knowledge and confidence needed to end the stalking. In this paper recommendations are made about how to prevent stalking and to halt it if it does happens. PMID- 26414314 TI - Validity of (Ultra-)Short Recordings for Heart Rate Variability Measurements. AB - OBJECTIVES: In order to investigate the applicability of routine 10s electrocardiogram (ECG) recordings for time-domain heart rate variability (HRV) calculation we explored to what extent these (ultra-)short recordings capture the "actual" HRV. METHODS: The standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive differences (RMSSD) were measured in 3,387 adults. SDNN and RMSSD were assessed from (ultra)short recordings of 10s(3x), 30s, and 120s and compared to 240s-300s (gold standard) measurements. Pearson's correlation coefficients (r), Bland-Altman 95% limits of agreement and Cohen's d statistics were used as agreement analysis techniques. RESULTS: Agreement between the separate 10s recordings and the 240s-300s recording was already substantial (r = 0.758-0.764/Bias = 0.398-0.416/d = 0.855-0.894 for SDNN; r = 0.853-0.862/Bias = 0.079-0.096/d = 0.150-0.171 for RMSSD), and improved further when three 10s periods were averaged (r = 0.863/Bias = 0.406/d = 0.874 for SDNN; r = 0.941/Bias = 0.088/d = 0.167 for RMSSD). Agreement increased with recording length and reached near perfect agreement at 120s (r = 0.956/Bias = 0.064/d = 0.137 for SDNN; r = 0.986/Bias = 0.014/d = 0.027 for RMSSD). For all recording lengths and agreement measures, RMSSD outperformed SDNN. CONCLUSIONS: Our results confirm that it is unnecessary to use recordings longer than 120s to obtain accurate measures of RMSSD and SDNN in the time domain. Even a single 10s (standard ECG) recording yields a valid RMSSD measurement, although an average over multiple 10s ECGs is preferable. For SDNN we would recommend either 30s or multiple 10s ECGs. Future research projects using time-domain HRV parameters, e.g. genetic epidemiological studies, could calculate HRV from (ultra-)short ECGs enabling such projects to be performed at a large scale. PMID- 26414316 TI - Remediation technologies for oil-contaminated sediments. AB - Oil-contaminated sediments pose serious environmental hazards for both aquatic and terrestrial ecosystems. Innovative and environmentally compatible technologies are urgently required to remove oil-contaminated sediments. In this paper, various physical, chemical and biological technologies are investigated for the remediation of oil-contaminated sediments such as flotation and washing, coal agglomeration, thermal desorption, ultrasonic desorption, bioremediation, chemical oxidation and extraction using ionic liquids. The basic principles of these technologies as well as their advantages and disadvantages for practical application have been discussed. A combination of two or more technologies is expected to provide an innovative solution that is economical, eco-friendly and adaptable. PMID- 26414315 TI - Cerebral Blood Flow Alterations in Acute Sport-Related Concussion. AB - Sport-related concussion (SRC) is a major health problem, affecting millions of athletes each year. While the clinical effects of SRC (e.g., symptoms and functional impairments) typically resolve within several days, increasing evidence suggests persistent neurophysiological abnormalities beyond the point of clinical recovery after injury. This study aimed to evaluate cerebral blood flow (CBF) changes in acute SRC, as measured using advanced arterial spin labeling (ASL) magnetic resonance imaging (MRI). We compared CBF maps assessed in 18 concussed football players (age, 17.8 +/- 1.5 years) obtained within 24 h and at 8 days after injury with a control group of 19 matched non-concussed football players. While the control group did not show any changes in CBF between the two time-points, concussed athletes demonstrated a significant decrease in CBF at 8 days relative to within 24 h. Scores on the clinical symptom (Sport Concussion Assessment Tool 3, SCAT3) and cognitive measures (Standardized Assessment of Concussion [SAC]) demonstrated significant impairment (vs. pre-season baseline levels) at 24 h (SCAT, p < 0.0001; SAC, p < 0.01) but returned to baseline levels at 8 days. Two additional computerized neurocognitive tests, the Automated Neuropsychological Assessment Metrics and Immediate Post-Concussion and Cognitive Testing, showed a similar pattern of changes. These data support the hypothesis that physiological changes persist beyond the point of clinical recovery after SRC. Our results also indicate that advanced ASL MRI methods might be useful for detecting and tracking the longitudinal course of underlying neurophysiological recovery from concussion. PMID- 26414318 TI - Heart Rate and VO2 Concordance in Continuous-Flow Left Ventricular Assist Devices. AB - The American College of Sports Medicine currently recommends the HR reserve (HRR) method to guide exercise in individuals who have heart failure with reduced ejection fraction. This recommendation is based on the known association between %HRR and percentage of VO2 reserve (%VO2R) in this population. However, to our knowledge, no studies exist regarding this relation in individuals with a left ventricular assist device (LVAD). PURPOSE: This article aimed to describe the relation between VO2 and surrogate markers of exercise intensity among patients with LVAD. METHODS: Patients with continuous-flow LVAD (n = 24, seven females) completed a symptom-limited graded exercise test on a treadmill. HR and VO2 were measured continuously and averaged every 20 s. Regression equations were determined using a generalized estimating equation to predict %VO2R from %HRR, Borg RPE, and LVAD flow, overall and stratified by presence of pacing. RESULTS: Although the association between %HRR and %VO2R was good (R = 0.75), the slope and y-intercept for %HRR versus %VO2R was different from the line of identity (P = 0.002). However, when paced subjects were excluded (n = 8) from the analysis, there was no significant difference between the slope and y-intercept (= 0.036 + 0.937 * %HRR; SEE, 2%; P = 0.052). RPE showed a strong association with %VO2R (R = 0.84), whereas LVAD flow showed a weak (albeit statistically significant) association (R = 0.05). Both had slopes and y-intercepts that were different from the line of identity (P < 0.05). CONCLUSIONS: In patients with LVAD who are not paced during exercise, the use of %HRR is a good predictor of %VO2R. However, for patients in this population who are also paced during exercise, RPE is a suitable surrogate measure of exercise intensity. PMID- 26414317 TI - Influence of the Metaboreflex on Pulmonary Vascular Capacitance in Heart Failure. AB - PURPOSE: An impaired metaboreflex is associated with abnormal ventilatory and peripheral vascular function in heart failure (HF), whereas its influence on cardiac function or pulmonary vascular pressure remains unclear. We aimed to assess whether metabolite-sensitive neural feedback (metaboreflex) from locomotor muscles via postexercise regional circulatory occlusion (RCO) attenuates pulmonary vascular capacitance (GXCAP) and/or circulatory power (CircP) in patients with HF. METHODS: Eleven patients with HF (NYHA class, I/II; ages, 51 +/ 15 yr; ejection fraction, 32% +/- 9%) and 11 age- and gender-matched controls (ages, 43 +/- 9 yr) completed three cycling sessions (4 min, 60% peak oxygen uptake (VO2)). Session 1 was a control trial including normal recovery (NR). Session 2 or 3 included bilateral upper thigh pressure tourniquets inflated suprasystolic at end of exercise (RCO) for 2-min recovery with or without inspired CO2 (RCO + CO2) (randomized). Mean arterial pressure, HR, and VO2 were continuously measured. Estimates of central hemodynamics; CircP = (VO2 * mean arterial pressure)/weight; oxygen pulse index (O2pulseI = (VO2/HR)/body surface area); and GXCAP = O2pulseI * end-tidal partial pressure CO2 were calculated. RESULTS: At rest and end of exercise, CircP and GXCAP were lower in HF versus those in controls (P < 0.05), with no differences between transients (P > 0.05). At 2-min recovery, GXCAP was lower during RCO versus that during NR in both groups (72 +/- 23 vs 98 +/- 20 and 73 +/- 34 vs 114 +/- 35 mL.beat.mm Hg.m, respectively; P < 0.05), whereas CircP did not differ between transients (P > 0.05). Differences (% and Delta) between baseline and 2-min recovery among transients suggest that metaboreflex attenuates GXCAP in HF. Differences (% and Delta) between baseline and 2-min recovery among transients suggest that metaboreflex may attenuate CircP in controls. CONCLUSIONS: The present observations suggest that locomotor muscle metaboreflex activation may influence CircP in controls but not in HF. However, metaboreflex activation may evoke decreases in GXCAP (increased pulmonary vascular pressures) in HF and controls. PMID- 26414319 TI - Cardiac Kinetophagy Coincides with Activation of Anabolic Signaling. AB - PURPOSE: Growing evidence has shown that endurance exercise is a strong inducer of autophagy in various tissues. Thus, we define here endurance exercise-induced autophagy as "kinetophagy" derived from the Greek terms "kineto" (movement), "auto" (self), and "phagy" (eating). Currently, the exact cellular mechanisms responsible for kinetophagy remain unclear; hence, we examined kinetophagy signaling transduction pathways occurring during acute endurance exercise (AEE). METHODS: C57BL/6 mice were randomly assigned to either AEE (n = 7) or control sedentary group (CON, n = 7). After 5 d of treadmill running acclimation, mice performed 60 min of a single bout of treadmill running at 12 m . min(-1) on a 0% grade. Hearts were excised immediately 1 h after exercise and homogenized for Western blot analyses. RESULTS: Our data showed that AEE promoted kinetophagy flux (an increase in LC3-II to LC3-I ratio and LC3-II levels and a reduction in p62 levels) with Beclin-1 levels suppressed but Atg7 levels elevated compared with those in the sedentary group. We also observed that AEE increased lysosome associated membrane protein and cathepsin L, linked to the termination process of autophagy, and that AEE augmented potent autophagy inducers (i.e., adenosine monophosphate kinase phosphorylation, BNIP3, and HSP70). Moreover, we found that exercise-mediated BNIP3 upregulation is associated with hypoxia-inducing factor 1alpha rather than FoxO3a. Intriguingly, we found for the first time that kinetophagy parallels with anabolic signaling activation (Akt and mammalian target of rapamycin). CONCLUSIONS: Our findings provide evidence that AEE results in kinetophagy without a time-associated elevation in Beclin-1 but with the presence of Akt-mTOR activation and that AEE-induced activation of anabolic signaling is not associated with kinetophagy promotion. PMID- 26414321 TI - Directional Energy Transfer in Mixed-Metallic Copper(I)-Silver(I) Coordination Polymers with Strong Luminescence. AB - Strongly luminescent mixed-metallic copper(I)-silver(I) coordination polymers with various Cu/Ag ratio were prepared by utilizing the isomorphous relationship of the luminescent parent homometallic coordination polymers (Phi(em) = 0.65 and 0.72 for the solid Cu and Ag polymers, respectively, at room temperature). The mixed-metallic polymer with the mole fraction of copper even as low as 0.005 exhibits a strong emission (Phi(em) = 0.75) from only the copper sites as the result of the efficient energy migration from the silver to the copper sites. The migration rates between the two sites were evaluated from the dependence of emission decays upon the mole fraction of copper. PMID- 26414320 TI - PeakForce Tapping resolves individual microvilli on living cells. AB - Microvilli are a common structure found on epithelial cells that increase the apical surface thus enhancing the transmembrane transport capacity and also serve as one of the cell's mechanosensors. These structures are composed of microfilaments and cytoplasm, covered by plasma membrane. Epithelial cell function is usually coupled to the density of microvilli and its individual size illustrated by diseases, in which microvilli degradation causes malabsorption and diarrhea. Atomic force microscopy (AFM) has been widely used to study the topography and morphology of living cells. Visualizing soft and flexible structures such as microvilli on the apical surface of a live cell has been very challenging because the native microvilli structures are displaced and deformed by the interaction with the probe. PeakForce Tapping(r) is an AFM imaging mode, which allows reducing tip-sample interactions in time (microseconds) and controlling force in the low pico-Newton range. Data acquisition of this mode was optimized by using a newly developed PeakForce QNM-Live Cell probe, having a short cantilever with a 17-um-long tip that minimizes hydrodynamic effects between the cantilever and the sample surface. In this paper, we have demonstrated for the first time the visualization of the microvilli on living kidney cells with AFM using PeakForce Tapping. The structures observed display a force dependence representing either the whole microvilli or just the tips of the microvilli layer. Together, PeakForce Tapping allows force control in the low pico-Newton range and enables the visualization of very soft and flexible structures on living cells under physiological conditions. PMID- 26414322 TI - The Prevalence and Long-Term Outcomes of Extreme Right versus Extreme Left Ventricular Hypertrophic Cardiomyopathy. AB - OBJECTIVES: Extreme left ventricular hypertrophy (LVH) is a known risk factor for sudden cardiac death in hypertrophic cardiomyopathy (HCM). Extreme right ventricular hypertrophy (RVH) is rare, and whether it is linked to a poor outcome is unknown. This study was designed to investigate differences between HCM patients with extreme RVH and those with extreme LVH. METHODS: Among 2,413 HCM patients, 31 with extreme RVH (maximum right ventricular wall thickness >= 10 mm) and 194 with extreme LVH (maximum left ventricular wall thickness >= 30 mm) were investigated. The main clinical features and natural history were compared between the 2 groups. RESULTS: The prevalence of extreme RVH and extreme LVH was 1.3 and 8.0%, respectively. Patients with extreme RVH tended to be younger and female (p < 0.01). Cardiovascular-related mortality and morbidity within 10 years were significantly greater in the extreme RVH group (p < 0.05). Multivariate analysis demonstrated 3 independent predictors for cardiovascular mortality - extreme RVH, left ventricular end-diastolic dimension >= 50 mm, and age <= 18 years at baseline - and 2 for morbidity - extreme RVH and presyncope. CONCLUSIONS: Compared with extreme LVH, extreme RVH was quite uncommon in HCM and had a worse prognosis. A right ventricle examination should be performed in routine HCM evaluation. PMID- 26414323 TI - A Molecular Phylogeny of the Lichen Genus Lecidella Focusing on Species from Mainland China. AB - The phylogeny of Lecidella species is studied, based on a 7-locus data set using ML and Bayesian analyses. Phylogenetic relationships among 43 individuals representing 11 Lecidella species, mainly from mainland China, were included in the analyses and phenotypical characters studied and mapped onto the phylogeny. The Lecidella species fall into three major clades, which are proposed here as three informal groups-Lecidella stigmatea group, L. elaeochroma group and L. enteroleucella group, each of them strongly supported. Our phylogenetic analyses support traditional species delimitation based on morphological and chemical traits in most but not all cases. Individuals considered as belonging to the same species based on phenotypic characters were found to be paraphyletic, indicating that cryptic species might be hidden under these names (e.g. L. carpathica and L. effugiens). Potentially undescribed species were found within the phenotypically circumscribed species L. elaeochroma and L. stigmatea. Additional sampling across a broader taxonomic and geographic scale will be crucial to fully resolving the taxonomy in this cosmopolitan genus. PMID- 26414324 TI - HIV-Specific Antibody Responses in HIV-Infected Patients: From a Monoclonal to a Polyclonal View. AB - HIV infections represent a major global health threat, affecting more than 35 million individuals worldwide. High infection rates and problems associated with lifelong antiretroviral treatment emphasize the need for the development of prophylactic and therapeutic immune intervention strategies. It is conceivable that insights for the design of new immunogens capable of eliciting protective immune responses may come from the analysis of HIV-specific antibody responses in infected patients. Using sophisticated technologies, several monoclonal neutralizing antibodies were isolated from HIV-infected individuals. However, the majority of polyclonal antibody responses found in infected patients are nonneutralizing. Comprehensive analyses of the molecular targets of HIV-specific antibody responses identified that during natural infection antibodies are mainly misdirected towards gp120 epitopes outside of the CD4-binding site and against regions and proteins that are not exposed on the surface of the virus. We therefore argue that vaccines aiming to induce protective responses should include engineered immunogens, which are capable of focusing the immune response towards protective epitopes. PMID- 26414325 TI - Pancreatic tuberculosis. AB - Pancreatic tuberculosis is very rare, but recently, there has been a spurt in the number of reports on pancreatic involvement by tuberculosis. It closely mimics pancreatic cancer, and before the advent of better imaging modalities it was often detected as a histological surprise in patients resected for a presumed pancreatic malignancy. The usual presentation involves abdominal pain, loss of appetite and weight, jaundice which can be associated with cholestasis, fever and night sweats, palpable abdominal lump, and peripheral lymphadenopathy. Computed tomography (CT) of the abdomen is an important tool for evaluation of patients with pancreatic tuberculosis. This CT imaging yields valuable information about the size and nature of tubercular lesions along with the presence of ascites and lymphadenopathy. However, there are no distinctive features on CT that distinguish it from pancreatic carcinoma. Endoscopic ultrasound provides high resolution images of the pancreatic lesions as well as an opportunity to sample these lesions for cytological confirmation. The presence of granulomas is the most common finding on histological/cytological examination with the presence of acid fast bacilli being observed only in minority of patients. As there are no randomized or comparative studies on treatment of pancreatic tuberculosis it is usually treated like other forms of tuberculosis. Excellent cure rates are reported with standard anti tubercular therapy given for 6-12 months. PMID- 26414327 TI - Long-term attraction and toxic effects of tephritid insecticide-bait mixtures by applying Torricelli's barometer principle in a trapping device. AB - BACKGROUND: The field activity of the mixtures of liquid baits and insecticides used in the control of tephritid pests is normally short, both when they are sprayed or when used in trapping or in attract-and-kill devices. A new lure-and kill device based on Torricelli's barometer principle was tested as a long lasting dispenser for two liquid hydrolysed protein baits mixed with insecticide, GF-120 and Captor 300 + malathion, against Anastrepha ludens (Loew) flies of laboratory origin. The dispensers were kept under field conditions for 42 days. Laboratory bioassays for insecticide properties and field cage studies for attraction capacity were carried out on a weekly basis after 22 and 42 days of weathering respectively. RESULTS: Our results demonstrated that both mixtures of insecticides and phagostimulant baits killed up to 80% of the tested flies when they were 42 days old. The attraction capacity of both weathering-exposed mixtures was even higher than fresh insecticidal-bait mixtures after the same period. CONCLUSION: The device is efficient when used with the liquid baits currently employed in the control of tephritid flies. It also offers a high potential for combining visual stimuli, such as shape and colour, and for improving trapping and bait station designs. Incorporating this new device in trapping and attract-and-kill methods could help to reduce the frequency of servicing of the traps and bait stations and lower their costs. (c) 2015 Society of Chemical Industry. PMID- 26414328 TI - Randomly and Non-Randomly Missing Renal Function Data in the Strong Heart Study: A Comparison of Imputation Methods. AB - Kidney and cardiovascular disease are widespread among populations with high prevalence of diabetes, such as American Indians participating in the Strong Heart Study (SHS). Studying these conditions simultaneously in longitudinal studies is challenging, because the morbidity and mortality associated with these diseases result in missing data, and these data are likely not missing at random. When such data are merely excluded, study findings may be compromised. In this article, a subset of 2264 participants with complete renal function data from Strong Heart Exams 1 (1989-1991), 2 (1993-1995), and 3 (1998-1999) was used to examine the performance of five methods used to impute missing data: listwise deletion, mean of serial measures, adjacent value, multiple imputation, and pattern-mixture. Three missing at random models and one non-missing at random model were used to compare the performance of the imputation techniques on randomly and non-randomly missing data. The pattern-mixture method was found to perform best for imputing renal function data that were not missing at random. Determining whether data are missing at random or not can help in choosing the imputation method that will provide the most accurate results. PMID- 26414334 TI - Representing scale: What should be special about the heritage of mass science? AB - This symposium marks the achievement of a transformation in the history of science. Whereas in the 1960s, the study of modern developments was marginal to the field, it has now become a key part of the discipline's central concerns. The contrast between this conference and a 1960 symposium is illuminating. The paper reflects on the tensions over the future direction of the discipline expressed at the 1974 semi-centenary conference of the History of Science Society. Today, genomics with its vast demand for resources and its challenges to traditional boundaries is not untypical of a wide range of scientific activities. Its study can serve as a pioneering case study interesting for itself and important for a wider understanding of science. Papers at this meeting show the implications for the understanding of methods, appropriate targets of study, the interpretation of images and the preservation of archives. PMID- 26414329 TI - Alterations in Daytime and Nighttime Activity in Piglets after Focal and Diffuse Brain Injury. AB - We have developed and implemented a noninvasive, objective neurofunctional assessment for evaluating the sustained effects of traumatic brain injury (TBI) in piglets with both diffuse and focal injury types. Derived from commercial actigraphy methods in humans, this assessment continuously monitors the day/night activity of piglets using close-fitting jackets equipped with tri-axial accelerometers to monitor movements of the thorax. Acceleration metrics were correlated (N = 7 naive piglets) with video images to define values associated with a range of activities, from recumbancy (rest) to running. Both focal (N = 8) and diffuse brain injury (N = 9) produced alterations in activity that were significant 4 days post-TBI. Compared to shams (N = 6) who acclimated to the animal facility 4 days after an anesthesia experience by blurring the distinction between day and night activity, post-TBI time-matched animals had larger fractions of inactive periods during the daytime than nighttime, and larger fractions of active time in the night were spent in high activity (e.g., constant walking, intermittent running) than during the day. These persistent disturbances in rest and activity are similar to those observed in human adults and children post-TBI, establishing actigraphy as a translational metric, used in both humans and large animals, for assessment of injury severity, progressions, and intervention. PMID- 26414335 TI - Infant outcomes following midtrimester emergency cerclage in the presence of fully dilated cervix and prolapsing amniotic membranes into the vagina. AB - OBJECTIVE: To investigate the morbidity of infants, whose delivery was prolonged by an emergency cervical cerclage (EC). METHODS: Ante- and postnatal data on subsequent EC procedures performed between 14 and 28 weeks of gestation for advanced cervical dilatation with prolapsing of amniotic membranes at a single institution within a 5-year-period were retrieved. RESULTS: We identified 21 fetuses from 18 pregnancies. Median gestational age [interquartile range, IQR] at EC and prolongation of pregnancy was 21.5 [15-26] weeks and 49.3 [24-92] days, respectively. There were 4 (19%) stillbirths, 3 (14%) neonatal deaths, and 1 (5%) infant death. Ten infants (59% of livebirths) were admitted to neonatal intensive care unit and hospitalized for a median period of 11 [6-66] d. Of the surviving fetuses (14/21, 66.7%), 9 (42.8%) were intact, whereas 3 (17.6% of livebirths) had cerebral palsy (CP), 1 was diagnosed with hypothyroidism, and another had growth failure at 12 months of follow-up. CONCLUSION: EC seems to be beneficial only in a subset of pregnancies presenting with full cervical dilatation accompanied by prolapsing amniotic membranes into the vagina, and there is a requirement for more objective selection criteria. Neonatal morbidity, especially neurodevelopmental disability should be discussed thoroughly prior to this procedure. PMID- 26414336 TI - Recurrence of hepatocellular carcinoma after liver transplantation: an update. AB - Liver transplantation is the only curative alternative for selected patients with hepatocellular carcinoma (HCC) who are not eligible for resection and/or with decompensated cirrhosis. According to Milan criteria the 5-year survival rate is 70-85%, with a recurrence-free survival of 75%. However, HCC recurrence rate after liver transplantation remains a significant problem in the clinical practice. The prognosis in patients with HCC recurrence is poor. The treatment of choice for HCC recurrence is surgery, but it seems that a systemic treatment based on combination of an mTOR inhibitor with sorafenib can be used. Data on safety and efficacy are limited, clinical monitoring is necessary. The aim of this review is to underline the main concerns, pitfalls and warnings for these patients. PMID- 26414337 TI - Varenicline for treatment of alcohol dependence: a randomized, placebo-controlled trial. AB - BACKGROUND: Alcohol dependence is a devastating illness affecting a large population, and new pharmacological treatments with good efficacy are greatly needed. One potential candidate is varenicline, a smoking cessation agent with partial agonist action at alpha4 beta2 nicotinic acetylcholine receptors. METHODS: A total of 160 subjects, 30 to 70 years of age, fulfilling DSM-IV criteria for alcohol dependence without any serious physical or mental disorders, were recruited through advertisement at 3 university clinics in Sweden during March 2009 to January 2011. After a 2-week placebo run-in period, subjects received 2 mg varenicline daily (titrated from 0.5 mg during first week) or placebo for 12 weeks in a double-blind manner. RESULTS: The primary outcome was the proportion of heavy drinking days, measured by self-reported alcohol consumption. Primary and secondary outcomes were calculated as a mean over the 10 week steady-state active treatment period. In the primary outcome analysis, no effect of varenicline over placebo was found (p = 0.73 for the intention to treat [ITT] and 0.92 for per protocol [PP]). Secondary outcome analysis found a significant reduction of specific alcohol marker phosphatidylethanol (PEth) in the blood in the varenicline group compared to placebo (p = 0.02 ITT). Craving (p = 0.048 PP) and Alcohol Use Disorders Identification Test (AUDIT) scores (p = 0.015 ITT) were also reduced in the active treatment group. PEth more strongly correlated with self-reported alcohol consumption than carbohydrate-deficient ttransferrin and gamma-glutamyl transferase, and correlation coefficients were higher in the varenicline group than in the placebo group for all markers. CONCLUSIONS: Although the results of the main outcome of this study did not support an effect of varenicline in alcohol-dependent individuals, the secondary analyses of PEth, craving and AUDIT score support an effect of varenicline on alcohol consumption. The disclosure of a treatment effect and the lack of a clear placebo effect when using PEth as outcome variable, together with a nonsymmetric bias associated with self-reported data, strongly argue for using the specific biomarker PEth in studies of treatments of alcohol dependence. PMID- 26414339 TI - In Situ, Simultaneous Irradiation and Monitoring of a Photocatalyzed Organic Oxidation Reaction in a TiO2-Coated NMR Tube. AB - The semiconductor photocatalyzed (SPC) oxidation of toluene is performed inside an NMR spectrometer and the reaction is monitored simultaneously in situ, using a fiber optic probe/diffuser to provide the UV light to activate the titania photocatalyst coating on the inside of the NMR tube. Such a system has great potential for the simple rapid screening of a wide range of SPC mediated organic reactions. PMID- 26414338 TI - Clotting factor product administration and same-day occurrence of thrombotic events, as recorded in a large healthcare database during 2008-2013. AB - BACKGROUND: Thrombotic events (TEs) are serious adverse events that can occur following administration of clotting factors (CFs). OBJECTIVES: To evaluate occurrence of same-day TEs for different CF products and potential risk factors. METHODS: A retrospective cohort study of individuals exposed to CF products during 2008-2013 was conducted using a large commercial insurance database. CF products were identified by procedure codes, and TEs were ascertained via diagnosis codes. Crude same-day TE rates (per 1000 persons exposed) were estimated overall and by congenital factor deficiency (CFD) status, CF products, age and gender. Multivariable logistic regression analyses were used to control for confounding. Laboratory analysis was used to compare the procoagulant activities of FIX products. RESULTS: Of 3801 individuals exposed to CFs, 117 (30.8 per 1000) had same-day TEs recorded. The crude same-day TE rate was higher for CF users without CFD, 70.2 (102 of 1452), as compared with those with CFD, 6.4 (15 of 2349) (RR, 11.0; 95% CI, 6.4-18.9). For individuals without CFD, a significantly increased same-day TE risk was identified for factor IX complex (OR, 6.92; 95% CI, 3.11-15.40), factor VIIa (OR, 9.42; 95% CI, 4.99-17.78) and other products when compared with fibrin sealant. An increased risk of a TE was found with older age (>= 45 years), history of TEs and underlying health conditions. The laboratory identified elevated procoagulant activity in Profilnine((r)) and Benefix((r)) . CONCLUSIONS: The study shows an increased same day TE risk for CF users without CFD and suggests substantial off-label CF use. The study findings also show elevated same-day TE rates for different CF products and suggest the importance of product properties and patient factors. PMID- 26414340 TI - Simultaneously modulated accelerated radiation therapy reduces severe oesophageal toxicity in concomitant chemoradiotherapy of locally advanced non-small-cell lung cancer. AB - OBJECTIVE: The aim of this study was to evaluate the potential of simultaneously modulated accelerated radiation therapy (SMART) to reduce the incidence of severe acute oesophagitis in the treatment of unresectable locally advanced non-small cell lung cancer (LANSCLC). METHODS: 21 patients were treated with SMART and concomitant platinum-based chemotherapy. The prescribed doses were limited to 54 Gy at 1.8 Gy per day to the zones of presumed microscopic extent while simultaneously maintaining doses of 66 Gy at 2.2 Gy per day to the macroscopic disease. The whole treatment was delivered over 30 fractions and 6 weeks. Dosimetric parameters of SMART and the standard technique of irradiation [intensity-modulated radiation therapy (IMRT)] were compared. Acute toxicity was prospectively recorded. RESULTS: The highest grade of oesophagitis was 62% (13 patients) grade 1, 33% (7 patients) grade 2 and 5% (1 patient) grade 3. Three (14%) patients experienced acute grade 2 pneumonitis. There was no grade 4 oesophageal or pulmonary toxicity. Doses to the organs at risk were significantly reduced in SMART compared with IMRT [oesophagus: V50Gy, 28.5 Gy vs 39.9 Gy (p = 0.003); V60Gy, 7.1 Gy vs 30.7 Gy (p = 0.003); lung: V20Gy, 27.4 Gy vs 30.1 Gy (p = 0,002); heart: V40Gy, 7.3 Gy vs 10.7 Gy (p = 0.006); spine: Dmax, 42.4 Gy vs 46.4 Gy (p = 0.003)]. With a median follow-up of 18 months (6-33 months), the 1 year local control rate was 70% and the disease-free survival rate was 47%. CONCLUSION: SMART reduces the incidence of severe oesophagitis and improves the whole dosimetric predictors of toxicity for the lung, heart and spine. ADVANCES IN KNOWLEDGE: Our study shows that SMART optimizes the therapeutic ratio in the treatment of LANSCLC, opening a window for dose intensification. PMID- 26414341 TI - Safety and tolerability of lacosamide as adjunctive therapy for adults with partial-onset seizures: Analysis of data pooled from three randomized, double blind, placebo-controlled clinical trials. AB - OBJECTIVE: The objective of this study was to describe a priori protocol-defined analyses to evaluate the safety and tolerability of adjunctive oral lacosamide (200-600 mg/day) in adults (ages 16-70 years) with partial-onset seizures (POS) using data pooled from three similarly designed randomized, double-blind, placebo controlled trials (SP667, SP754 [NCT00136019], SP755 [NCT00220415]). METHODS: Patients with POS (>=2 years' duration, >=2 previous antiepileptic drugs [AEDs]) uncontrolled by a stable dosing regimen of 1-3 concomitant AEDs were randomized to treatment with lacosamide at doses of 200 mg/day, 400 mg/day, or 600 mg/day, or placebo. Studies comprised a 4- to 6-week titration phase to target dose followed by a 12-week maintenance phase. Safety outcomes included treatment emergent adverse events (TEAEs) of particular relevance to patients with POS, overall TEAEs, and discontinuations due to TEAEs. Post hoc analyses included evaluation of TEAEs potentially related to cognition and TEAEs leading to discontinuation analyzed by concomitant AEDs. RESULTS: One thousand three hundred eight patients were randomized to and received treatment; 944 to lacosamide and 364 to placebo. Most patients (84.4%) were taking 2 or 3 concomitant AEDs. The most common drug-associated TEAEs (reported by >=5% of patients in any lacosamide dose group and with an incidence at least twice that reported for placebo during the treatment phase) were dizziness (30.6% for lacosamide vs 8.2% for placebo), nausea (11.4% vs 4.4%), and diplopia (10.5% vs 1.9%). Common drug-associated TEAEs generally appeared to be dose-related, and the incidence of each was lower during the 12-week maintenance phase than during the titration phase. Most TEAEs were either mild or moderate in intensity; severe TEAEs were predominantly observed with lacosamide 600 mg/day. No individual serious TEAE occurred in >=1% of all lacosamide-treated patients. Treatment-emergent adverse events led to discontinuation in 8.1%, 17.2%, and 28.6% of the lacosamide 200-, 400-, and 600 mg/day groups, respectively (vs 4.9% of placebo). Few TEAEs were related to rash, weight loss/gain, changes in clinical chemistry parameters, or psychiatric disturbances, or were seizure-related. The odds of reporting any potential cognition-related TEAE vs placebo increased with dose and were similar between lacosamide doses of 200 and 400mg/day and placebo (odds ratio 1.3, 95% confidence interval 0.7-2.4). Discontinuations due to TEAEs based on most commonly used AEDs taken in combination with lacosamide (all doses combined) were carbamazepine (15.3% [51/334] vs 3.9% [5/129] placebo), lamotrigine (19.2% [56/291] vs 4.3% [5/117]), and levetiracetam (10.1% [28/278] vs 3.9% [4/103]). CONCLUSIONS: The safety and tolerability profile of adjunctive lacosamide in this detailed evaluation was similar to that observed in the individual double-blind trials. Adjunctive lacosamide was associated with TEAEs related to the nervous system and gastrointestinal tract, predominantly during titration. PMID- 26414342 TI - Stigma and quality of life at long-term follow-up after surgery for epilepsy in Uganda. AB - Epilepsy is a worldwide health problem with a 10-fold greater prevalence in the developing world. Commonly, the seizure focus is in the temporal lobe, and seizures in about 30% of people with epilepsy are intractable to medication. For these individuals, surgery for intractable temporal lobe epilepsy (iTLE) is more effective than medication alone and may be the only option for cure. Intractable temporal lobe epilepsy is associated with elevated morbidity and mortality, reduced quality of life (QOL), and associated stigma particularly occurring in the developing world. Individuals with intractable epilepsy who participated in an earlier Uganda pilot study were selected for the current study based on their undergoing previous surgery for iTLE or having comparable seizure type who did not have surgery. At long-term follow-up, 10 who underwent surgery for iTLE in addition to 9 patients with focal dyscognitive type epilepsy who did not have surgery were evaluated in the current study. Tests were administered to look at various outcome parameters: seizure severity, QOL, stigma, and self-esteem. Stigma and self-esteem were additionally evaluated in the parent/caregiver. Seventy-percent of surgical resection patients were seizure-free at 8 years postsurgery. The QOLIE-31 scores were higher in surgical patients. Child/patient and parent/proxy surveys identified lower stigma in seizure-free patients. The results suggest that surgery for iTLE is an effective treatment for epilepsy in the developing world and provides an opportunity to reduce stigma and improve QOL. PMID- 26414343 TI - A randomized controlled multimodal behavioral intervention trial for improving antiepileptic drug adherence. AB - PURPOSE: Medication nonadherence is one of the most important reasons for treatment failure in patients with epilepsy. The present study investigated the effectiveness of a multicomponent intervention to improve adherence to antiepileptic drug (AED) medication in patients with epilepsy. METHODS: In a prospective, randomized multicenter trial, three sessions of face-to-face motivational interviewing (MI) in combination with complementary behavior change techniques were compared with standard care. Motivational interviewing prompted change talk and self-motivated statements from the patients, planning their own medication intake regimen and also identifying and overcoming barriers that may prevent adherence. Participants were provided with calendars to self-monitor their medication taking behavior. A family member and the health-care team were invited to attend the last session of MI in order to improve the collaboration and communication between patients, their caregiver or family member, and their health-care provider. At baseline and 6-month follow-up, psychosocial variables and medical adherence were assessed. RESULTS: In total, 275 participants were included in the study. Compared with the active control group, patients in the intervention group reported significantly higher medication adherence, as well as stronger intention and perceptions of control for taking medication regularly. The intervention group also reported higher levels of action planning, coping planning, self-monitoring, and lower medication concerns. CONCLUSIONS: This study shows that MI can be effective in clinical practice to improve medication adherence in patients with epilepsy. It also provides evidence that combining volitional interventions, including action planning, coping planning, and self monitoring with motivational interviewing can promote the effectiveness of the medical treatments for epilepsy by improving adherence. PMID- 26414344 TI - Personalities of patients with nonepileptic psychogenic status. AB - The purposes of this study were to determine whether personalities of patients with nonepileptic psychogenic status (NEPS) are different from those of patients with typical intermittent psychogenic nonepileptic seizures (iPNES) using the Personality Assessment Inventory (PAI) and to compare their PAI profiles with the population norms. We hypothesized that patients with NEPS have more psychopathology compared with patients with iPNES and that, as a group, patients with PNES (iPNES+NEPS) would have more psychopathology compared with healthy individuals. We first compared the PAI profiles of patients with iPNES and NEPS and then the profiles of patients with NEPS, iPNES, and PNES with population norms in order to assess which PAI specific scales differed between groups in order to better characterize the psychopathology of PNES. All patients admitted for diagnostic evaluation to the epilepsy monitoring unit (EMU) were prospectively approached for participation. All patient/family interviews were conducted by an epileptologist, and the diagnosis of iPNES or NEPS was confirmed in all cases through video/EEG and/or family interview. The population norms for PAI were obtained from the manual. Of the 224 approached patients, 130 completed the PAI, and included 43 iPNES and 11 with NEPS. There were no significant differences between the two groups in regard to demographic or PAI profiles. Comparison with population norms revealed the presence of abnormal personality profiles on all scales in patients with iPNES, NEPS, or PNES. We conclude that while the occurrence of NEPS is relatively common in patients with PNES, the demographic characteristics and personality profiles of patients with NEPS are not different from those of patients with iPNES. We also confirmed the presence of significant psychopathology in the group with PNES when compared with population norms. PMID- 26414345 TI - Association of knowledge about epilepsy with mood and self-efficacy in Korean people with epilepsy. AB - PURPOSE: We determined the level of knowledge about epilepsy in Korean people with epilepsy (PWE) and evaluated whether this is associated with self-efficacy, perceived stigma, anxiety, and depressive mood in these patients. METHODS: This was a cross-sectional multicenter study. A total of 530 PWE participated from 31 secondary or tertiary hospitals in Korea. Knowledge about epilepsy was assessed using 34 medical items (EKP-M) of the Epilepsy Knowledge Profile-General. Additional questionnaires included the Epilepsy Self-Efficacy Scale (ESES), Stigma Scale, and Hospital Anxiety and Depression Scale (HADS). Multiple linear regression analyses were used. RESULTS: The mean EKP-M score was 22.2 (SD: 4.1). By univariate analyses, the EKP-M was related to ESES (r=0.220, p<0.001) and HADS D (r=-0.154, p<0.001) scores but not to the Stigma Scale or HADS-A. By linear regression analyses, after adjusting for the confounding variables, the higher EKP-M scores were independently related to both higher ESES (p<0.001) and lower HADS-D scores (p<0.05). CONCLUSION: Korean PWE have a relatively low level of knowledge about their condition. Knowledge about epilepsy is associated with a high level of self-efficacy and less depressive symptoms in affected individuals. PMID- 26414346 TI - Activating therapy modalities in older individuals with chronic non-specific low back pain: a systematic review. AB - BACKGROUND: Although there are many special exercise-based therapy approaches for the working population suffering chronic low back pain, similar programmes for older individuals are rare. OBJECTIVES: To summarise all evaluated physical therapy approaches, and assess the effects on older people with chronic low back pain. DATA SOURCES: Medline, CINAHL, Cochrane, Embase, PEDro, PsychINFO and Psyndex. STUDY SELECTION/ELIGIBILITY: Age>=65 years, subacute or chronic non specific low back pain of >=6weeks' duration, and a physical therapy approach. STUDY APPRAISAL AND SYNTHESIS METHODS: Study selection, data extraction, and assessment of methodological quality and clinical relevance were performed independently by two reviewers. As there were only a few controlled trials and wide heterogeneity in observation periods and outcome measures, pooling of data was not feasible. Therefore, the results are presented descriptively. RESULTS: In total, nine studies were included; six related to mixed physiotherapy modalities, one related to strength training, and two related to endurance training. Low quality evidence suggests that physical therapy modalities are associated with a small-to-moderate reduction in pain and a small improvement in function. LIMITATIONS: The results must be interpreted with caution due to poor methodological quality. CONCLUSION AND IMPLICATIONS OF KEY FINDINGS: Few studies have been performed in this highly relevant and growing age group. It is not possible to recommend one particular modality or programme; as such, prescriptions should reflect patients' preferences and local conditions. Further research of higher methodological quality is needed urgently. PMID- 26414347 TI - The Structure of Plasmodium falciparum Blood-Stage 6-Cys Protein Pf41 Reveals an Unexpected Intra-Domain Insertion Required for Pf12 Coordination. AB - Plasmodium falciparum is an apicomplexan parasite and the etiological agent of severe human malaria. The complex P. falciparum life cycle is supported by a diverse repertoire of surface proteins including the family of 6-Cys s48/45 antigens. Of these, Pf41 is localized to the surface of the blood-stage merozoite through its interaction with the glycophosphatidylinositol-anchored Pf12. Our recent structural characterization of Pf12 revealed two juxtaposed 6-Cys domains (D1 and D2). Pf41, however, contains an additional segment of 120 residues predicted to form a large spacer separating its two 6-Cys domains. To gain insight into the assembly mechanism and overall architecture of the Pf12-Pf41 complex, we first determined the 2.45 A resolution crystal structure of Pf41 using zinc single-wavelength anomalous dispersion. Structural analysis revealed an unexpected domain organization where the Pf41 6-Cys domains are, in fact, intimately associated and the additional residues instead map predominately to an inserted domain-like region (ID) located between two beta-strands in D1. Notably, the ID is largely proteolyzed in the final structure suggesting inherent flexibility. To assess the contribution of the ID to complex formation, we engineered a form of Pf41 where the ID was replaced by a short glycine-serine linker and showed by isothermal titration calorimetry that binding to Pf12 was abrogated. Finally, protease protection assays showed that the proteolytic susceptibility of the ID was significantly reduced in the complex, consistent with the Pf41 ID directly engaging Pf12. Collectively, these data establish the architectural organization of Pf41 and define an essential role for the Pf41 ID in promoting assembly of the Pf12-Pf41 heterodimeric complex. PMID- 26414349 TI - Abstracts of Award-Winning Posters, 20th Annual Health Sciences Poster Conference, Faculty of Medicine, Health Sciences Centre, Kuwait University, Kuwait, May 5-7, 2015. PMID- 26414348 TI - The Inhibition of Heat Shock Protein 90 Facilitates the Degradation of Poly Alanine Expanded Poly (A) Binding Protein Nuclear 1 via the Carboxyl Terminus of Heat Shock Protein 70-Interacting Protein. AB - BACKGROUND: Since the identification of poly-alanine expanded poly(A) binding protein nuclear 1 (PABPN1) as the genetic cause of oculopharyngeal muscular dystrophy (OPMD), considerable progress has been made in our understanding of the pathogenesis of the disease. However, the molecular mechanisms that regulate the onset and progression of the disease remain unclear. RESULTS: In this study, we show that PABPN1 interacts with and is stabilized by heat shock protein 90 (HSP90). Treatment with the HSP90 inhibitor 17-AAG disrupted the interaction of mutant PABPN1 with HSP90 and reduced the formation of intranuclear inclusions (INIs). Furthermore, mutant PABPN1 was preferentially degraded in the presence of 17-AAG compared with wild-type PABPN1 in vitro and in vivo. The effect of 17-AAG was mediated through an increase in the interaction of PABPN1 with the carboxyl terminus of heat shock protein 70-interacting protein (CHIP). The overexpression of CHIP suppressed the aggregation of mutant PABPN1 in transfected cells. CONCLUSIONS: Our results demonstrate that the HSP90 molecular chaperone system plays a crucial role in the selective elimination of abnormal PABPN1 proteins and also suggest a potential therapeutic application of the HSP90 inhibitor 17-AAG for the treatment of OPMD. PMID- 26414352 TI - Epidermal growth factor receptor tyrosine kinase inhibitors in elderly patients with non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. At diagnosis, half of the patients are over 70 years of age, and most present with advanced disease, for which chemotherapy is recommended as first line treatment. However, the benefit from such therapy is modest and it is at times poorly tolerated. The discovery of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has significantly impacted the treatment of patients with EGFR mutation-positive advanced NSCLC. These novel agents demonstrate efficacy and a favorably mild toxicity profile. Despite limited data in elderly patients, the largest subpopulation in NSCLC, EGFR-TKIs are considered the standard of care therapy for advanced EGFR-positive disease in the elderly. In this review, we seek to compile the available data about the EGFR-TKIs use in elderly patients with advanced NSCLC, with the hope to better understand its role in this major yet, underrepresented, group of patients. PMID- 26414351 TI - Subangstrom single-molecule measurements of motor proteins using a nanopore. AB - Techniques for measuring the motion of single motor proteins, such as FRET and optical tweezers, are limited to a resolution of ~300 pm. We use ion current modulation through the protein nanopore MspA to observe translocation of helicase Hel308 on DNA with up to ~40 pm sensitivity. This approach should be applicable to any protein that translocates on DNA or RNA, including helicases, polymerases, recombinases and DNA repair enzymes. PMID- 26414350 TI - A catalog of the mouse gut metagenome. AB - We established a catalog of the mouse gut metagenome comprising ~2.6 million nonredundant genes by sequencing DNA from fecal samples of 184 mice. To secure high microbiome diversity, we used mouse strains of diverse genetic backgrounds, from different providers, kept in different housing laboratories and fed either a low-fat or high-fat diet. Similar to the human gut microbiome, >99% of the cataloged genes are bacterial. We identified 541 metagenomic species and defined a core set of 26 metagenomic species found in 95% of the mice. The mouse gut microbiome is functionally similar to its human counterpart, with 95.2% of its Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologous groups in common. However, only 4.0% of the mouse gut microbial genes were shared (95% identity, 90% coverage) with those of the human gut microbiome. This catalog provides a useful reference for future studies. PMID- 26414353 TI - Electroencephalographic Monitoring of Brain Wave Activity During Laparoscopic Surgical Simulation to Measure Surgeon Concentration and Stress: Can the Student Become the Master? AB - PURPOSE: To measure gamma and alpha brain wave activity as a measurement of concentration and stress levels during surgical simulator performance of laparoscopic tasks to determine if expert surgeons have different brain activity patterns compared with intermediate and novice surgeons. MATERIALS AND METHODS: After obtaining Institutional Review Board approval, 1st and 2nd year medical students, urology residents (PGY2-PGY5), and attending urologists from one institution were recruited. Participants were stratified by level of experience and performed laparoscopic tasks on the EDGE laparoscopic simulator. Subjects were evaluated for concentration and stress levels using the electroencephalography (EEG) data extracted from the MUSE(TM) headband. The MUSE software developer kit (SDK) allowed quantification of gamma and alpha waves during each task. An analysis of variance was used to compare concentration and stress levels between groups. RESULTS: A total of 19 participants were recruited for the study and stratified by surgical experience into novice, intermediate, and expert laparoscopy groups: 6 medical students, 9 urology residents, and 4 attending urologists, respectively. Concentration and stress were quantified by calculating the area under the curve of the gamma and alpha EEG wave tracings. Stress was significantly lower in the attending urologists compared with the residents and medical students during the laparoscopic suturing and trended toward significance in the peg transfer task (P = 0.0003, P = 0.069). Concentration was significantly higher in the expert group compared with the less experienced groups during both the peg and suture tasks (P = 0.036, P = 0.0039). CONCLUSIONS: EEG brain activity in more experienced surgeons reveals a significant increase in concentration levels with a decrease in stress during simulated laparoscopic tasks compared with novices. This information may correlate with increased proficiency as well as provide objective feedback of progress along the learning curve with the MUSE SDK. PMID- 26414354 TI - Link Between Increased Prevalence of Autism Spectrum Disorder Syndromes and Oxidative Stress, DNA Methylation, and Imprinting: The Impact of the Environment. PMID- 26414355 TI - An updated review on gastro-esophageal reflux in pediatrics. AB - Comprehensive guidelines for the diagnosis and management of gastro-esophageal reflux (GER) and GER disease (GERD) were developed by the European and North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition. GERD is reflux associated with troublesome symptoms or complications. The recognition of GER and GERD is relevant to implement best management practices. A conservative management is indicated in infants with uncomplicated physiologic reflux. Children with GERD may benefit from further evaluation and treatment. Since the publications of the European and North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition guidelines in 2009, no important novelties in drug treatment have been reported. Innovations are mainly restricted to the management of regurgitation in infants. During the last 5 years, pros and cons of multichannel intraluminal impedance have been highlighted. However, overall 'not much has changed' in the diagnosis and management of GER and GERD in infants and children. PMID- 26414356 TI - Visual Stimuli Evoked Action Potentials Trigger Rapidly Propagating Dendritic Calcium Transients in the Frog Optic Tectum Layer 6 Neurons. AB - The superior colliculus in mammals or the optic tectum in amphibians is a major visual information processing center responsible for generation of orientating responses such as saccades in monkeys or prey catching avoidance behavior in frogs. The conserved structure function of the superior colliculus the optic tectum across distant species such as frogs, birds monkeys permits to draw rather general conclusions after studying a single species. We chose the frog optic tectum because we are able to perform whole-cell voltage-clamp recordings fluorescence imaging of tectal neurons while they respond to a visual stimulus. In the optic tectum of amphibians most visual information is processed by pear shaped neurons possessing long dendritic branches, which receive the majority of synapses originating from the retinal ganglion cells. Since the first step of the retinal input integration is performed on these dendrites, it is important to know whether this integration is enhanced by active dendritic properties. We demonstrate that rapid calcium transients coinciding with the visual stimulus evoked action potentials in the somatic recordings can be readily detected up to the fine branches of these dendrites. These transients were blocked by calcium channel blockers nifedipine CdCl2 indicating that calcium entered dendrites via voltage-activated L-type calcium channels. The high speed of calcium transient propagation, >300 MUm in <10 ms, is consistent with the notion that action potentials, actively propagating along dendrites, open voltage-gated L-type calcium channels causing rapid calcium concentration transients in the dendrites. We conclude that such activation by somatic action potentials of the dendritic voltage gated calcium channels in the close vicinity to the synapses formed by axons of the retinal ganglion cells may facilitate visual information processing in the principal neurons of the frog optic tectum. PMID- 26414359 TI - Eyes wide open: reader and author responsibility in understanding the limits of peer review. AB - 'Medical science can only flourish in a free society and dies under totalitarian repression.' (1) Peer review post-publication is relatively easy to define: when the world decides the importance of publication. Peer review pre-publication is what the scientific community frequently means when using the term 'peer review'. But what it is it? Few will agree on an exact definition; generally speaking, it refers to an independent, third party scrutiny of a manuscript by scientific experts (called peers) who advise on its suitability for publication. Peer review is expensive; although reviewers are unpaid, the cost in time is enormous and it is slow. There is often little agreement among reviewers about whether an article should be published and peer review can be a lottery. Often referred to as a quality assurance process, there are many examples of when peer review failed. Many will be aware of Woo-Suk Hwang's shocking stem cell research misconduct at Seoul National University. (2) Science famously published two breakthrough articles that were found subsequently to be completely fabricated and this happened in spite of peer review. Science is not unique in making this error. However, love it or hate it, peer review, for the present time at least, is here to stay. In this article, Philippa Benson, Managing Editor of Science Advances (the first open access journal of the American Association for the Advancement of Science), discusses the merits of peer review. Dr Benson has extensive experience in the publishing world and was Executive Director of PJB Consulting, a not-for profit organisation supporting clients on issues related to converting to full electronic publishing workflows as well as challenges working with international authors and publishers. Her clients included the Public Library of Science journals, the American Society for Nutrition and the de Beaumont Foundation. She recently co-authored a book, What Editors Want: An Author's Guide to Scientific Journal Publishing (University of Chicago Press), which helps readers understand and navigate the publishing process in high impact science and technical journals. Her master's and doctorate degrees are from Carnegie Mellon University. JYOTI SHAH Commissioning Editor References 1. Eaton KK . Editorial: when is a peer review journal not a peer review journal? J Nutr Environ Med 1997 ; 7 : 139 144 . 2. van der Heyden MA , van de Ven T , Opthof T . Fraud and misconduct in science: the stem cell seduction . Neth Heart J 2009 ; 17 : 25 - 29 . PMID- 26414358 TI - Novel Food Supplement "CP1" Improves Motor Deficit, Cognitive Function, and Neurodegeneration in Animal Model of Parkinson's Disease. AB - Based on pivotal roles of oxidative stress, dopaminergic and cholinergic systems on the pathophysiology of Parkinson's disease (PD), the searching for functional food for patients attacked with PD from Cyperus rotundus and Zingiber officinale, the substances possessing antioxidant activity, and the suppression effects on monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE) have been considered. In this study, we aimed to determine the effect of the combined extract of C. rotundus and Z. officinale (CP1) to improve motor and memory deficits, neurodegeneration, oxidative stress, and functions of both cholinergic and dopaminergic systems in the animal model of PD induced by 6-hydroxydopamine hydrochloride (6-OHDA). Male Wistar rats, weighing 180-220 g, were induced unilateral lesion at right substantia nigra by 6-OHDA and were orally given CP1 at doses of 100, 200, and 300 mg/kg body weight for 14 days after 6-OHDA injection. The results showed that the 6-OHDA rats treated with CP1 increased spatial memory, but decreased neurodegeneration, malondialdehyde level, and AChE activity in hippocampus. The decreased motor disorder and neurodegeneration in substantia nigra together with the enhanced catalase activity, but decreased MAO B activity in striatum, were also observed. The memory enhancing effect of CP1 might occur through the improved oxidative stress and the enhanced cholinergic function, whereas the effect to improve motor disorder of CP1 might occur through the enhanced dopaminergic function in striatum by decreasing the degeneration of dopaminergic neurons and the suppression of MAO-B. Therefore, CP1 is the potential functional food against PD. However, further researches in clinical trial and drug interactions are essential. PMID- 26414360 TI - Retrospective cohort study of an enhanced recovery programme in oesophageal and gastric cancer surgery. AB - Introduction Enhanced recovery programmes have been established in some areas of elective surgery. This study applied enhanced recovery principles to elective oesophageal and gastric cancer surgery. Methods An enhanced recovery programme for patients undergoing open oesophagogastrectomy, total and subtotal gastrectomy for oesophageal and gastric malignancy was designed. A retrospective cohort study compared length of stay on the critical care unit (CCU), total length of inpatient stay, rates of complications and in-hospital mortality prior to (35 patients) and following (27 patients) implementation. Results In the cohort study, the median total length of stay was reduced by 3 days following oesophagogastrectomy and total gastrectomy. The median length of stay on the CCU remained the same for all patients. The rates of complications and mortality were the same. Conclusions The standardised protocol reduced the median overall length of stay but did not reduce CCU stay. Enhanced recovery principles can be applied to patients undergoing major oesophagogastrectomy and total gastrectomy as long as they have minimal or reversible co-morbidity. PMID- 26414362 TI - Effect of an independent-sector treatment centre on provision of elective orthopaedic surgery in east and north Hertfordshire. AB - Introduction Independent Sector Treatment Centres (ISTCs) were created to relieve pressure from Acute Hospital Trusts. In October 2011, an ISTC opened on the grounds of a hospital within the East and North Hertfordshire NHS Trust. Most elective orthopaedic procedures were transferred there. We investigated the effect on productivity of operating theatres working in the ISTC compared with those working in the Acute Hospital Trust (AHT). Methods A 3-month period of working at the AHT was compared with the same period 9-months later in the ISTC, which were termed 'pre-' and 'post-ISTC' opening, respectively. Data for upper limb (UL) as well as foot and ankle (F&A) surgery were collected. Differences in the number of lists and patients per list constituted usage analyses. Financial productivity was calculated from the latest Payment by Results (PbR) data. A two tailed Mann-Whitney U-test at a confidence level of 95% was employed to compare costs between groups. Results The UL surgeon undertook 18 lists in both years with 66 patients (pre-ISTC) and 32 (post-ISTC), eliciting a reduction in productivity of 51.5%. There were 13 lists for F&A surgery pre-ISTC with 67 procedures, and 20 lists with 49 patients post-ISTC. Allowing for the difference in the number of lists, a reduction of 52.5% was noted. PbR analyses confirmed productivity of L169,695 (pre-ISTC) and L95,760 (post-ISTC) at a loss of L73,935 for the UL surgeon. F&A data revealed L97,801 (pre-ISTC) and L91,960 (post-ISTC) at a loss of L54,742 when correcting for the difference in the number of lists. There was a combined reduction in potential financial productivity of L128,677 over 3 months or L514,708 over 1 year. Discussion Implementation of the ISTC was detrimental to departmental efficiency, with <50% of the number of patients being treated and a marked reduction in financial productivity. PMID- 26414361 TI - Injection of botulinum toxin for the treatment of post-laryngectomy pharyngoesophageal spasm-related disorders. AB - Introduction Pharyngoesophageal spasm (PES) can cause dysphagia, central valve leak (CVL), and dypshonia in post-laryngectomy patients. Botulinum toxin has been used effectively for the treatment of PES, but data regarding patient-reported outcomes and efficacy for CVL are limited. We evaluated the results of botox injection for PES spasm using subjective and objective measures. Methods Data were collected prospectively (February 2010 to August 2013) on 13 patients undergoing botox injection for PES as identified by video fluoroscopy. We collected digital voice recordings, air-pressure measurements (APMs) for speech, and quality of life (QoL) data before and after the procedure: University of Washington QoL questionnaire (UW-QoL), MD Anderson Swallowing Inventory (MDADI) and the Voice Handicap Index (VHI-30). Results APMs for a sustained vowel decreased by 18% after botox injection, whereas maximum phonatory times increased by 63% (mean increase, 8 to 13 seconds). Sustained vowel amplitude decreased (mean, 87db to 83db) with an associated reduction in sustained vowel frequency (117Hz to 77Hz). MDADI scores improved by 10.2% overall, and UW-QoL scores showed an improvement in score of 7.6%. Mean scores for VHI-30 deteriorated by 2% overall but, when considering only those patients experiencing dysphonia, an improvement of 9.4% was seen. There was an overall net reduction for the CVL cohort of 12 speech valves in the year after injection. Conclusions Our series confirm the safety and objective efficacy of botox injection for PES. QoL measurements were less convincing, and this disparity between subjective and objective measurements must be considered when treating such patients. PMID- 26414363 TI - Rectus sheath catheters provide equivalent analgesia to epidurals following laparotomy for colorectal surgery. AB - Introduction Rectus sheath catheters (RSCs) are increasingly being used to provide postoperative analgesia following laparotomy for colorectal surgery. Little is known about their efficacy in comparison with epidural infusion analgesia (EIA). They are potentially better as they avoid the recognised complications associated with EIA. This study compares these two methods of analgesia. Outcomes include average pain scores, time to mobilisation and length of stay. Methods This was a 33-month single centre observational study including all patients undergoing elective open or laparoscopic-converted-to-open colorectal resection for both benign and malignant disease. Patients received either EIA or RSCs. Data were collected prospectively and analysed retrospectively. Results A total of 95 patients were identified. Indications for surgery, operation and complications were recorded. The mean time to mobilisation was significantly shorter in patients who had RSCs compared with EIA patients (2.4 vs 3.5 days, p<0.05). There was no difference in postoperative pain scores or length of stay. Conclusions RSCs provide equivalent analgesia to EIA and avoid the recognised potential complications of EIA. They are associated with a shorter time to mobilisation. Their use should be adopted more widely. PMID- 26414365 TI - Reflections. PMID- 26414366 TI - Recent NICE guidance of interest to surgeons. PMID- 26414367 TI - Creating gelatine models for vascular access surgical courses. PMID- 26414368 TI - The Wessex wrap circumcision dressing. PMID- 26414369 TI - Femoral access for endovascular aneurysm repair in obese patients. PMID- 26414370 TI - A novel technique for harvesting fat for breast augmentation. PMID- 26414371 TI - Novel approach to drainage of a right subphrenic abscess using trans diaphragmatic laparoscopy. PMID- 26414372 TI - Doege-Potter Syndrome. AB - Doege-Potter syndrome is a rare paraneoplastic syndrome presenting as a hypoinsulinaemic hypoglycaemia from the ectopic secretion of a prohormone of insulin-like growth factor II (IGF-II) from a solitary fibrous tumour. Surgical resection is curative in the majority of cases. If, however, the diagnosis is not suspected and treatment is delayed, it can lead to hypoxic cerebral injury or death. The underlying tumour can be a benign or malignant pleural tumour but may be present in extrapleural sites. For a diagnosis of Doege-Potter syndrome, symptoms attributable to hypoglycaemia and low blood glucose levels should be present along with the secretion of prohormone IGF-II. We report a case of severe hypoglycaemia in a 76-year-old inpatient admitted for resection of a recurrent left-sided pleural tumour. Investigation revealed true hypoglycaemia and Doege Potter syndrome was diagnosed. The tumour was completely resected and the patient made a full recovery with no further hypoglycaemic episodes. PMID- 26414373 TI - Quantitative functional outcomes of the conservative management of partial segmental thrombosis of the corpus cavernosum. AB - The low incidence of partial segmental thrombosis of the corpus cavernosum (PSTCC) means its management is guided by isolated case reports. Erectile function is an important outcome that has not been described quantitatively in the literature. We present two cases of PSTCC managed conservatively. Although both patients reported resolution of local symptoms, formal analysis of sexual function at follow-up review has revealed that only one achieved complete recovery. PMID- 26414377 TI - An ALE-based finite element model of flagellar motion driven by beating waves: A parametric study. AB - A computational model of flagellar motility is presented using the finite element method. Two-dimensional traveling waves of finite amplitude are propagated down the flagellum and the swimmer is propelled through a viscous fluid according to Newto's second law of motion. Incompressible Navier-Stokes equations are solved on a triangular moving mesh and arbitrary Lagrangian-Eulerian formulation is employed to accommodate the deforming boundaries. The results from the present study are validated against the data available in the literature and close agreement with previous works is found. The effects of wave parameters as well as head morphology on the swimming characteristics are studied for different swimming conditions. We have found that the swimming velocities are linear functions of finite amplitudes and that the rate of work is independent of the channel height for large amplitudes. Furthermore, we have also demonstrated that for the range of wave parameters that are often encountered in human sperm motility studies, the propulsive velocity versus the wavelength exhibits dissimilar trends for different channel heights. Various head configurations were analyzed and it is also observed that wall proximity amplifies the effects induced by different head shapes. By taking non-Newtonian fluids into account, we present new efficiency analyzes through which we have found that the model microorganism swims much more efficiently in shear-thinning fluids. PMID- 26414376 TI - Excess Secretion of Gel-Forming Mucins and Associated Innate Defense Proteins with Defective Mucin Un-Packaging Underpin Gallbladder Mucocele Formation in Dogs. AB - Mucosal protection of the gallbladder is vital yet we know very little about the mechanisms involved. In domestic dogs, an emergent syndrome referred to as gallbladder mucocele formation is characterized by excessive secretion of abnormal mucus that results in obstruction and rupture of the gallbladder. The cause of gallbladder mucocele formation is unknown. In these first mechanistic studies of this disease, we investigated normal and mucocele-forming dog gallbladders to determine the source, identity, biophysical properties, and protein associates of the culprit mucins with aim to identify causes for abnormal mucus behavior. We established that mucocele formation involves an adoptive excess secretion of gel forming mucins with abnormal properties by the gallbladder epithelium. The mucus is characterized by a disproportionally significant increase in Muc5ac relative to Muc5b, defective mucin un-packaging, and mucin-interacting innate defense proteins that are capable of dramatically altering the physical and functional properties of mucus. These findings provide an explanation for abnormal mucus behavior and based on similarity to mucus observed in the airways of people with cystic fibrosis, suggest that abnormal mechanisms for maintenance of gallbladder epithelial hydration may be an instigating factor for mucocele formation in dogs. PMID- 26414378 TI - A similarity-based data warehousing environment for medical images. AB - A core issue of the decision-making process in the medical field is to support the execution of analytical (OLAP) similarity queries over images in data warehousing environments. In this paper, we focus on this issue. We propose imageDWE, a non-conventional data warehousing environment that enables the storage of intrinsic features taken from medical images in a data warehouse and supports OLAP similarity queries over them. To comply with this goal, we introduce the concept of perceptual layer, which is an abstraction used to represent an image dataset according to a given feature descriptor in order to enable similarity search. Based on this concept, we propose the imageDW, an extended data warehouse with dimension tables specifically designed to support one or more perceptual layers. We also detail how to build an imageDW and how to load image data into it. Furthermore, we show how to process OLAP similarity queries composed of a conventional predicate and a similarity search predicate that encompasses the specification of one or more perceptual layers. Moreover, we introduce an index technique to improve the OLAP query processing over images. We carried out performance tests over a data warehouse environment that consolidated medical images from exams of several modalities. The results demonstrated the feasibility and efficiency of our proposed imageDWE to manage images and to process OLAP similarity queries. The results also demonstrated that the use of the proposed index technique guaranteed a great improvement in query processing. PMID- 26414379 TI - Ex-Ante Economic Impact Assessment of Genetically Modified Banana Resistant to Xanthomonas Wilt in the Great Lakes Region of Africa. AB - BACKGROUND: Credible empirical evidence is scanty on the social implications of genetically modified (GM) crops in Africa, especially on vegetatively propagated crops. Little is known about the future success of introducing GM technologies into staple crops such as bananas, which are widely produced and consumed in the Great Lakes Region of Africa (GLA). GM banana has a potential to control the destructive banana Xanthomonas wilt disease. OBJECTIVE: To gain a better understanding of future adoption and consumption of GM banana in the GLA countries which are yet to permit the production of GM crops; specifically, to evaluate the potential economic impacts of GM cultivars resistant to banana Xanthomonas wilt disease. DATA SOURCES: The paper uses data collected from farmers, traders, agricultural extension agents and key informants in the GLA. ANALYSIS: We analyze the perceptions of the respondents about the adoption and consumption of GM crop. Economic surplus model is used to determine future economic benefits and costs of producing GM banana. RESULTS: On the release of GM banana for commercialization, the expected initial adoption rate ranges from 21 to 70%, while the ceiling adoption rate is up to 100%. Investment in the development of GM banana is economically viable. However, aggregate benefits vary substantially across the target countries ranging from US$ 20 million to 953 million, highest in countries where disease incidence and production losses are high, ranging from 51 to 83% of production. CONCLUSION: The findings support investment in the development of GM banana resistant to Xanthomonas wilt disease. The main beneficiaries of this technology development are farmers and consumers, although the latter benefit more than the former from reduced prices. Designing a participatory breeding program involving farmers and consumers signifies the successful adoption and consumption of GM banana in the target countries. PMID- 26414380 TI - Blood Pressure Response to Losartan and Continuous Positive Airway Pressure in Hypertension and Obstructive Sleep Apnea. AB - RATIONALE: Obstructive sleep apnea (OSA) is common in people with hypertension, particularly resistant hypertension. Treatment with an antihypertensive agent alone is often insufficient to control hypertension in patients with OSA. OBJECTIVES: To determine whether continuous positive airway pressure (CPAP) added to treatment with an antihypertensive agent has an impact on blood pressure (BP) levels. METHODS: During the initial 6-week, two-center, open, prospective, case control, parallel-design study (2:1; OSA/no-OSA), all patients began treatment with an angiotensin II receptor antagonist, losartan, 50 mg daily. In the second 6-week, sex-stratified, open, randomized, parallel-design study of the OSA group, all subjects continued to receive losartan and were randomly assigned to either nightly CPAP as add-on therapy or no CPAP. MEASUREMENTS AND MAIN RESULTS: Twenty four-hour BP monitoring included assessment every 15 minutes during daytime hours and every 20 minutes during the night. Ninety-one patients with untreated hypertension underwent a home sleep study (55 were found to have OSA; 36 were not). Losartan significantly reduced systolic, diastolic, and mean arterial BP in both groups (without OSA: 12.6, 7.2, and 9.0 mm Hg; with OSA: 9.8, 5.7, and 6.1 mm Hg). Add-on CPAP treatment had no significant changes in 24-hour BP values but did reduce nighttime systolic BP by 4.7 mm Hg. All 24-hour BP values were reduced significantly in the 13 patients with OSA who used CPAP at least 4 hours per night. CONCLUSIONS: Losartan reduced BP in OSA, but the reductions were less than in no-OSA. Add-on CPAP therapy resulted in no significant changes in 24-hour BP measures except in patients using CPAP efficiently. Clinical trial registered with www.clinicaltrials.gov (NCT00701428). PMID- 26414381 TI - Early events in hepatitis B virus infection: From the cell surface to the nucleus. AB - While most adults are able to clear acute hepatitis B virus (HBV) infection, chronic HBV infection is recalcitrant to current therapy because of the persistence of covalently closed circular DNA in the nucleus. Complete clearance of the virus in these patients is rare, and long-term therapy with interferon and/or nucleoside analogues may be required in an attempt to suppress viral replication and prevent progressive liver damage. The difficulty of establishing HBV infection in cell culture and experimental organisms has hindered efforts to elucidate details of the HBV life cycle, but it has also revealed the importance of the cellular microenvironment required for HBV binding and entry. Recent studies have demonstrated an essential role of sodium-taurocholate cotransporting polypeptide as a functional receptor in HBV infection, which has facilitated the development of novel infection systems and opened the way for more detailed understanding of the early steps of HBV infection as well as a potential new therapeutic target. However, many gaps remain in understanding of how HBV recognizes and attaches to hepatocytes prior to binding to sodium-taurocholate cotransporting polypeptide, as well as events that are triggered after binding, including entry into the cell, intracellular transport, and passage through the nuclear pore complex. This review summarizes current knowledge of the initial stages of HBV infection leading to the establishment of covalently closed circular DNA in the nucleus. PMID- 26414382 TI - Why does teaching research skills to family medicine trainees make sense? AB - There are only a few countries in Europe that have incorporated research skills training in specialty training programmes. In the eyes of most practising family physicians, research traditionally is a field reserved for colleagues with academic ambitions; an activity that often is not associated with the clinical practice of family medicine. However, residents became aware that research is essential to improving healthcare provision. Research in family medicine has a long tradition. Performing or taking part in research projects opens new horizons to present and future family physicians and provides support to increase their self-esteem. Consequently, this could foster future family medicine development. The authors urge the whole family physician community to raise the awareness every single family physician towards teaching and learning research skills in specialty training and basic medical education as a generic subject. PMID- 26414383 TI - Evidence in the Age of Social Media. PMID- 26414384 TI - Implications of Overdiagnosis: Impact on Screening Mammography Practices. AB - This review article explores the issue of overdiagnosis in screening mammography. Overdiagnosis is the screen detection of a breast cancer, histologically confirmed, that might not otherwise become clinically apparent during the lifetime of the patient. While screening mammography is an imperfect tool, it remains the best tool we have to diagnose breast cancer early, before a patient is symptomatic and at a time when chances of survival and options for treatment are most favorable. In 2015, an estimated 231,840 new cases of breast cancer (excluding ductal carcinoma in situ) will be diagnosed in the United States, and some 40,290 women will die. Despite these data, screening mammography for women ages 40-69 has contributed to a substantial reduction in breast cancer mortality, and organized screening programs have led to a shift from late-stage diagnosis to early-stage detection. Current estimates of overdiagnosis in screening mammography vary widely, from 0% to upwards of 30% of diagnosed cancers. This range reflects the fact that measuring overdiagnosis is not a straightforward calculation, but usually one based on different sets of assumptions and often biased by methodological flaws. The recent development of tomosynthesis, which creates high-resolution, three-dimensional images, has increased breast cancer detection while reducing false recalls. Because the greatest harm of overdiagnosis is overtreatment, the key goal should not be less diagnosis but better treatment decision tools. (Population Health Management 2015;18:S3-S11). PMID- 26414385 TI - Identification and quantification of lichenysin - a possible source of food poisoning. AB - Lichenysin produced by 53 different Bacillus licheniformis strains has been structurally examined with a qualitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) method using quadrupole-time-of-flight mass spectrometry. The same lichenysin isoforms are produced from all strains, indicating that the growth conditions have a stronger influence on the lipopeptide production than the genotype. A rapid method for the quantification of lichenysin from bacterial cell cultures with LC-MS/MS after a simple methanol extraction has been refined. For the first time commercially available lichenysin has been used as calibrant, making quantification more accurate. The trueness for C15-lichenysin has been improved to 94% using matrix-matched calibration with lichenysin compared with 30% using solvent calibration with surfactin. The quantitative method was fully validated based on Commission Decision 2002/657/EC. The LOD of the method was below 1 ug g(-1) and the repeatability ranged from 10% to 16%. PMID- 26414386 TI - Acute pain: a multifaceted challenge - the role of nimesulide. AB - BACKGROUND: This article summarizes the outcome from an international consensus meeting, which took place in Vienna on 4 November 2014. SCOPE: The aim of the meeting was to provide the state of the art on the pathophysiology and treatment of acute pain with special emphasis on nimesulide, a non-steroidal anti inflammatory drug (NSAID) indicated for the treatment of acute pain and primary dysmenorrhea. Besides the data on the mechanisms of acute inflammatory pain and on the efficacy and safety of nimesulide in patients affected by different forms of acute pain, the clinical experience of attending experts was discussed based on selected case reports. RESULTS: The members of this consensus group recognized that nimesulide is a NSAID highly effective in the treatment of several painful situations with an acute inflammatory component including primary dysmenorrhea. Although safety concerns regarding nimesulide have emerged in recent years, both robust new epidemiological data and clinical experience confirm a positive benefit/risk profile of nimesulide in the treatment of several forms of acute pain. CONCLUSIONS: The members of this international consensus group concluded that nimesulide, when used appropriately, remains a particularly valuable and safe option for the treatment of several conditions characterized by the presence of acute inflammatory pain because of the rapid onset of the analgesic action, and the positive evidence-based benefit/risk profile. PMID- 26414387 TI - Subdiffusion reflectance spectroscopy to measure tissue ultrastructure and microvasculature: model and inverse algorithm. AB - Reflectance measurements acquired from within the subdiffusion regime (i.e., lengthscales smaller than a transport mean free path) retain much of the original information about the shape of the scattering phase function. Given this sensitivity, many models of subdiffusion regime light propagation have focused on parametrizing the optical signal through various optical and empirical parameters. We argue, however, that a more useful and universal way to characterize such measurements is to focus instead on the fundamental physical properties, which give rise to the optical signal. This work presents the methodologies that used to model and extract tissue ultrastructural and microvascular properties from spatially resolved subdiffusion reflectance spectroscopy measurements. We demonstrate this approach using ex-vivo rat tissue samples measured by enhanced backscattering spectroscopy. PMID- 26414388 TI - Anthropometric Renal Anatomic Alterations Between Supine and Prone Positions in Percutaneous Renal Ablation for Renal Cortical Neoplasms. AB - OBJECTIVES: To establish patterns of anatomic changes relevant to the kidney and colon during positional change between the supine and prone positions as noted on CT scans performed during percutaneous cryoablation for renal cortical neoplasms (RCN). METHODS: Nineteen patients undergoing percutaneous cryoablation for RCN with abdominal CT scan in both the supine and prone positions were included in the study. We documented the anterior/posterior, medial/lateral, and cranial/caudal anatomic changes of the kidney, kidney rotation, and the proportion of the kidney whose access was limited by the liver, spleen, and lung. We also calculated the length of the percutaneous access tract and the distance between the colon and kidney in hilar position as well as the anterior/posterior location of the colon relative to the kidney. RESULTS: In the prone position, the kidney lies significantly more anteriorly on both sides: 4.7 cm vs 4.3 cm (L) and 4.4 cm vs 4.1 cm (R) (p = 0.02 and p = 0.03, respectively). On prone CT images, both kidneys are more cranial when compared with the supine position: 80.4 mm vs 60.8 mm (L) and 87.2 mm vs 57.4 mm (R) (p = 0.002 and p < 0.001, respectively). The skin to tumor distance is significantly shorter in the prone position (p < 0.0001 [L], p = 0.005 [R]). The colon lies closer to the hilum of the kidney and is more posteriorly located in the prone position: 1.21 cm vs 1.04 cm (L) and 0.80 cm vs 0.70 cm (R) (p = 0.005 and p = 0.005, respectively). In the prone position, the lung covers a significantly larger proportion of the right kidney (27.3 mm vs 6.05 mm, p = 0.0001). CONCLUSIONS: We documented clinically significant anatomic alterations between supine and prone CT imaging. The changes associated with the prone position modify percutaneous access, particularly for right upper pole tumors. Prone imaging before surgery may be helpful in selected cases. PMID- 26414389 TI - Genomic confirmation of nutrient-dependent mutability of mutators in Escherichia coli. AB - Mutators with increased mutation rates are prevalent in various environments and have important roles in accelerating adaptive evolution. Previous studies on mutator strains of microorganisms have shown that some mutators have constant mutation rates, whereas others exhibit switchable mutation rates depending on nutritional conditions. This suggests that the contributions of mutators on evolution vary with fluctuating nutritional conditions. However, such conditional mutability has been unclear at the genomic level. In addition, it is still unknown why mutation rates change with nutritional condition. Here, we used two mutator strains of Escherichia coli to explore the nutrient dependence of mutation rates at the genomic level. These strains were transferred repeatedly under different nutritional conditions for hundreds of generations to accumulate mutations. Whole-genome sequencing of the offspring showed that the nutrient dependence of the mutation rates was pervasive at the genomic scale. Neutrality in the mutation accumulation processes and constancy in the mutational bias suggested that nutrient dependence was not derived from conditional selective purges or from shifts of mutational bias. Some mutators could simply switch their mutation rates for both transitions and transversions in response to nutritional shifts. PMID- 26414396 TI - Electric Field Modulation of Semiconductor Quantum Dot Photoluminescence: Insights Into the Design of Robust Voltage-Sensitive Cellular Imaging Probes. AB - The intrinsic properties of quantum dots (QDs) and the growing ability to interface them controllably with living cells has far-reaching potential applications in probing cellular processes such as membrane action potential. We demonstrate that an electric field typical of those found in neuronal membranes results in suppression of the QD photoluminescence (PL) and, for the first time, that QD PL is able to track the action potential profile of a firing neuron with millisecond time resolution. This effect is shown to be connected with electric field-driven QD ionization and consequent QD PL quenching, in contradiction with conventional wisdom that suppression of the QD PL is attributable to the quantum confined Stark effect. PMID- 26414398 TI - Turning a New Leaf on Metal-TMC Chemistry: Ni(II)(TMC) Acetylides. AB - Novel [Ni(TMC)C=CY](+)-type compounds 1-4 [TMC = 1,4,8,11-tetramethyl-1,4,8,11 tetraazacyclotetradecane; Y = SiMe3 (1), Si(i)Pr3 (2), Ph (3), and C2H (4)] have been synthesized and characterized. Single-crystal X-ray diffraction studies revealed that these compounds adopt a distorted square-pyramidal geometry, with the acetylide ligand occupying the apical position and a RSRS isomer for the TMC ligand. The room temperature magnetic properties of 1-4 are consistent with an S = 1 ground state, as corroborated by CASSCF and density functional theory calculations, which indicate that the singly occupied molecular orbitals are d(z(2)) and d(x(2)-y(2)). PMID- 26414397 TI - Screening and Brief Alcohol Counseling of College Students and Persons Not in School. PMID- 26414399 TI - Growth arrest-specific 6 regulates thrombin-induced expression of vascular cell adhesion molecule-1 through forkhead box O1 in endothelial cells. AB - BACKGROUND: Growth arrest-specific 6 (Gas6)-deficient mice are protected against venous thromboembolism (VTE), suggesting a role for Gas6 in this disorder. We previously demonstrated that Gas6 induces forkhead box O1 (FoxO-1) phosphorylation through the phosphoinositide 3-kinase-Akt pathway. FoxO-1 regulates the expression of vascular cell adhesion molecule-1 (VCAM-1), a molecule that has been implicated in VTE. OBJECTIVES: To assess the role of FoxO 1 in Gas6-dependent VCAM-1 expression. METHODS: Thrombin was used to stimulate endothelial cells (ECs). Wild-type (WT) and Gas6(-/-) ECs were transfected with small interfering RNA targeting Axl or FoxO-1, a luciferase-coupled plasmid containing the FoxO-1 consensus sequence, and a phosphorylation-resistant FoxO-1 mutant, or treated with an Akt inhibitor. VCAM-1 mRNA expression was measured by real time-qPCR. VCAM-1 protein expression and FoxO-1 and Akt phosphorylation were assessed by western blot analysis. FoxO-1 localization was assessed by immunofluorescence. Adhesion of bone marrow mononuclear cells (BM-MCs) on ECs was assessed by fluorescence. RESULTS AND CONCLUSIONS: Thrombin induces both VCAM-1 expression and FoxO-1 phosphorylation and nuclear exclusion in WT ECs only. Silencing of FoxO-1 enhances VCAM-1 expression in both WT and Gas6(-/-) ECs. Inhibition of Akt or FoxO-1 phosphorylation prevents VCAM-1 expression in WT ECs. These data show that Gas6 induces FoxO-1 phosphorylation, leading to derepression of VCAM-1 expression. BM-MC-EC adhesion is increased by thrombin in WT ECs. BM-MC EC adhesion is further increased when FoxO-1 is silenced, but decreased when FoxO 1 phosphorylation is inhibited. These results demonstrate that the Gas6-FoxO-1 signaling axis plays an important role in VCAM-1 expression in the context of VTE by promoting BM-MC-EC adhesion. PMID- 26414400 TI - Behavior modulation of rats to a robotic rat in multi-rat interaction. AB - In this paper, we study the behavioral response of rats to a robotic rat during multi-rat interaction. Experiments are conducted in an open-field where a robotic rat called WR-5 is put together with three laboratory rats. WR-5 is following one rat (target), while avoiding the other two rats (outside observers) during interaction. The behavioral characteristics of each target rat is evaluated by scoring its locomotor activity and frequencies of performing rearing, body grooming and mounting actions. Additionally, the frequency of being mounted by other rats is also measured. Experimental results show that the target becomes more active after interaction. The rat species, with more active behavioral characteristics, is more susceptible to being adjusted by the robot. The increased time spent by the outside observers in the vicinity of the robot indicates that a biomimetic robot has the promise for modulating rat behavior even without direct interaction. Thus, this study provide a novel approach to shaping the sociality of animals living in groups. PMID- 26414401 TI - The Aryl Hydrocarbon Receptor Antagonist StemRegenin1 Improves In Vitro Generation of Highly Functional Natural Killer Cells from CD34(+) Hematopoietic Stem and Progenitor Cells. AB - Early natural killer (NK)-cell repopulation after allogeneic stem cell transplantation (allo-SCT) has been associated with reduced relapse rates without an increased risk of graft-versus-host disease, indicating that donor NK cells have specific antileukemic activity. Therefore, adoptive transfer of donor NK cells is an attractive strategy to reduce relapse rates after allo-SCT. Since NK cells of donor origin will not be rejected, multiple NK-cell infusions could be administered in this setting. However, isolation of high numbers of functional NK cells from transplant donors is challenging. Hence, we developed a cytokine-based ex vivo culture protocol to generate high numbers of functional NK cells from granulocyte colony-stimulating factor (G-CSF)-mobilized CD34(+) hematopoietic stem and progenitor cells (HSPCs). In this study, we demonstrate that addition of aryl hydrocarbon receptor antagonist StemRegenin1 (SR1) to our culture protocol potently enhances expansion of CD34(+) HSPCs and induces expression of NK-cell associated transcription factors promoting NK-cell differentiation. As a result, high numbers of NK cells with an active phenotype can be generated using this culture protocol. These SR1-generated NK cells exert efficient cytolytic activity and interferon-gamma production toward acute myeloid leukemia and multiple myeloma cells. Importantly, we observed that NK-cell proliferation and function are not inhibited by cyclosporin A, an immunosuppressive drug often used after allo-SCT. These findings demonstrate that SR1 can be exploited to generate high numbers of functional NK cells from G-CSF-mobilized CD34(+) HSPCs, providing great promise for effective NK-cell-based immunotherapy after allo-SCT. PMID- 26414402 TI - Complementary activities of TPX2 and chTOG constitute an efficient importin regulated microtubule nucleation module. AB - Spindle assembly and function require precise control of microtubule nucleation and dynamics. The chromatin-driven spindle assembly pathway exerts such control locally in the vicinity of chromosomes. One of the key targets of this pathway is TPX2. The molecular mechanism of how TPX2 stimulates microtubule nucleation is not understood. Using microscopy-based dynamic in vitro reconstitution assays with purified proteins, we find that human TPX2 directly stabilizes growing microtubule ends and stimulates microtubule nucleation by stabilizing early microtubule nucleation intermediates. Human microtubule polymerase chTOG (XMAP215/Msps/Stu2p/Dis1/Alp14 homologue) only weakly promotes nucleation, but acts synergistically with TPX2. Hence, a combination of distinct and complementary activities is sufficient for efficient microtubule formation in vitro. Importins control the efficiency of the microtubule nucleation by selectively blocking the interaction of TPX2 with microtubule nucleation intermediates. This in vitro reconstitution reveals the molecular mechanism of regulated microtubule formation by a minimal nucleation module essential for chromatin-dependent microtubule nucleation in cells. PMID- 26414403 TI - Competition for actin between two distinct F-actin networks defines a bistable switch for cell polarization. AB - Symmetry-breaking polarization enables functional plasticity of cells and tissues and is yet not well understood. Here we show that epithelial cells, hard-wired to maintain a static morphology and to preserve tissue organization, can spontaneously switch to a migratory polarized phenotype after relaxation of the actomyosin cytoskeleton. We find that myosin II engages actin in the formation of cortical actomyosin bundles and thus makes it unavailable for deployment in the process of dendritic growth normally driving cell motility. Under low contractility regimes, epithelial cells polarize in a front-back manner owing to the emergence of actin retrograde flows powered by dendritic polymerization of actin. Coupled to cell movement, the flows transport myosin II from the front to the back of the cell, where the motor locally 'locks' actin in contractile bundles. This polarization mechanism could be employed by embryonic and cancer epithelial cells in microenvironments where high-contractility-driven cell motion is inefficient. PMID- 26414404 TI - Lateral adhesion drives reintegration of misplaced cells into epithelial monolayers. AB - Cells in simple epithelia orient their mitotic spindles in the plane of the epithelium so that both daughter cells are born within the epithelial sheet. This is assumed to be important to maintain epithelial integrity and prevent hyperplasia, because misaligned divisions give rise to cells outside the epithelium. Here we test this assumption in three types of Drosophila epithelium; the cuboidal follicle epithelium, the columnar early embryonic ectoderm, and the pseudostratified neuroepithelium. Ectopic expression of Inscuteable in these tissues reorients mitotic spindles, resulting in one daughter cell being born outside the epithelial layer. Live imaging reveals that these misplaced cells reintegrate into the tissue. Reducing the levels of the lateral homophilic adhesion molecules Neuroglian or Fasciclin 2 disrupts reintegration, giving rise to extra-epithelial cells, whereas disruption of adherens junctions has no effect. Thus, the reinsertion of misplaced cells seems to be driven by lateral adhesion, which pulls cells born outside the epithelial layer back into it. Our findings reveal a robust mechanism that protects epithelia against the consequences of misoriented divisions. PMID- 26414405 TI - Depression-like behaviour in mice is associated with disrupted circadian rhythms in nucleus accumbens and periaqueductal grey. AB - An association between circadian rhythms and mood regulation is well established, and disturbed circadian clocks are believed to contribute to the development of mood disorders, including major depressive disorder. The circadian system is coordinated by the suprachiasmatic nucleus (SCN), the master pacemaker in the hypothalamus that receives light input from the retina and synchronizes circadian oscillators in other brain regions and peripheral tissues. Lacking the tight neuronal network that couples single-cell oscillators in the SCN, circadian clocks outside the SCN may be less stable and more susceptible to disturbances, for example by clock gene mutations or uncontrollable stress. However, non-SCN circadian clocks have not been studied extensively in rodent models of mood disorders. In the present study, it was hypothesized that disturbances of local circadian clocks in mood-regulating brain areas are associated with depression like behaviour in mice. Using the learned helplessness procedure, depression-like behaviour was evoked in mice bearing the PER2::LUC circadian reporter, and then circadian rhythms of PER2 expression were examined in brain slices from these mice using luminometry and bioluminescence imaging. It was found that helplessness is associated with absence of circadian rhythms in the nucleus accumbens and the periaqueductal grey, two of the most critical brain regions within the reward circuit. The current study provides evidence that susceptibility of mice to depression-like behaviour is associated with disturbed local circadian clocks in a subset of mood-regulating brain areas, but the direction of causality remains to be determined. PMID- 26414406 TI - The first reported outbreak of equine herpesvirus myeloencephalopathy in New Zealand. AB - CASE HISTORY AND CLINICAL FINDINGS: On 9 January 2014 (Day 0) a mare from a stud farm in the Waikato region presented with urinary incontinence without pyrexia. Over the following 33 days 15 mares were clinically affected with neurological signs. All but one mare had a foal at foot. The most commonly observed clinical signs were hind limb paresis and ataxia. In some cases recumbency occurred very early in the course of disease and seven mares were subject to euthanasia for humane reasons. LABORATORY FINDINGS: Equid herpesvirus (EHV) type 1 was detected using PCR in various tissues collected post mortem from two mares with neurological signs. DNA sequencing data from the DNA polymerase gene of the virus showed a nucleotide transition at position 2254, a mutation encoding amino acid D752 that is highly associated with the neuropathogenic genotype of EHV-1. In total 12/15 mares were confirmed positive for EHV-1 on PCR. Results from a virus neutralisation test and ELISA on paired serum samples, and PCR on whole blood and nasal swabs, indicated that of four paddocks in a high-risk area where a cluster of cases had occurred, 20/21 (95%) horses were likely to have been exposed or were confirmed infected with EHV-1. Subsequent to the outbreak two mares aborted, one at 9 months and one at 10 months of gestation. The cause of abortion was confirmed as EHV-1 with the same genotype as that involved in the outbreak. DIAGNOSIS: Equine herpesvirus myeloencephalopathy. CLINICAL RELEVANCE: The outbreak described shows the considerable impact that can occur in outbreaks of equine herpesvirus myeloencephalopathy in New Zealand. Early biosecurity controls not only reduced the effect on the farm but mitigated the potential for the virus to spread to other horse enterprises. PMID- 26414407 TI - Into the groove: instructive silk-polypyrrole films with topographical guidance cues direct DRG neurite outgrowth. AB - Instructive biomaterials capable of controlling the behaviour of the cells are particularly interesting scaffolds for tissue engineering and regenerative medicine. Novel biomaterials are particularly important in societies with rapidly aging populations, where demand for organ/tissue donations is greater than their supply. Herein we describe the preparation of electrically conductive silk film based nerve tissue scaffolds that are manufactured using all aqueous processing. Aqueous solutions of Bombyx mori silk were cast on flexible polydimethylsiloxane substrates with micrometer-scale grooves on their surfaces, allowed to dry, and annealed to impart beta-sheets to the silk which assures that the materials are stable for further processing in water. The silk films were rendered conductive by generating an interpenetrating network of polypyrrole and polystyrenesulfonate in the silk matrix. Films were incubated in an aqueous solution of pyrrole (monomer), polystyrenesulfonate (dopant) and iron chloride (initiator), after which they were thoroughly washed to remove low molecular weight components (monomers, initiators, and oligomers) and dried, yielding conductive films with sheet resistances of 124 +/- 23 kOmega square(-1). The micrometer-scale grooves that are present on the surface of the films are analogous to the natural topography in the extracellular matrix of various tissues (bone, muscle, nerve, skin) to which cells respond. Dorsal root ganglions (DRG) adhere to the films and the grooves in the surface of the films instruct the aligned growth of processes extending from the DRG. Such materials potentially enable the electrical stimulation (ES) of cells cultured on them, and future in vitro studies will focus on understanding the interplay between electrical and topographical cues on the behaviour of cells cultured on them. PMID- 26414408 TI - Intratympanic delivery of oligoarginine-conjugated nanoparticles as a gene (or drug) carrier to the inner ear. AB - A drug delivery system to the inner ear using nanoparticles consisting of oligoarginine peptide (Arg8) conjugated to poly(amino acid) (poly(2-hydroxyethyl L-aspartamide; PHEA) was investigated to determine whether the limitations of low drug transport levels across the round window membrane (RWM) and poor transport into inner ear target cells, including hair cells and spiral ganglion, could be overcome. Three types of carrier materials, PHEA-g-C18, PHEA-g-Arg8, and PHEA-g C18-Arg8, were synthesized to examine the effects of oligoarginine and morphology of the synthesized carriers. Nile red (NR) was used as a fluorescent indicator as well as to model a hydrophobic drug. Compared with PHEA-g-C18-NR nanoparticles, the oligoarginine-conjugated nanoparticles of PHEA-g-C18-Arg8-NR and PHEA-g-Arg8 NR entered into HEI-OC1 cells at significant levels. Furthermore, the strongest fluorescence intensity was observed in nuclei when PHEA-g-C18-Arg8 nanoparticles were used. The high uptake rates of PHEA-g-C18 and PHEA-g-C18-Arg8 nanoparticles were observed in ex vivo experiments using hair cells. After the delivery of PHEA g-C18-Arg8 nanoparticles with reporter gene transfer, EGFP (enhanced green fluorescent protein) expression was monitored as an indicator of gene delivery. In the inner ear cells, PHEA-g-C18-Arg8 nanoparticles showed comparable or better transfection capabilities than the commercially available Lipofectamine reagent. PHEA-g-C18-Arg8 penetrated in vivo across the RWM of C57/BL6 mice with Nile red staining and GFP expression in various inner ear tissues. In conclusion, PHEA-g C18-Arg8 nanoparticles were successfully transported into the inner ear through the intratympanic route and are proposed as promising candidates as delivery carriers to address inner ear diseases. PMID- 26414410 TI - Association of Visceral Fat and Liver Fat With Hyperuricemia. AB - OBJECTIVE: To examine cross-sectionally whether intraabdominal fat area (IAFA), i.e., visceral fat, and liver fat assessed by computed tomography (CT) are independently associated with hyperuricemia. METHODS: Subjects were 801 Japanese men not taking antidiabetic, antihypertensive, or urate-lowering medications, without any history of renal disease, cardiovascular disease, or cancer, and with serum creatinine <1.5 mg/dl. Abdominal, thoracic, and thigh fat areas were measured by CT. Total fat area (TFA) was the sum of these fat areas. Total subcutaneous fat area (TSFA) was TFA minus IAFA. Liver fat was assessed by liver to-spleen (L/S) ratio measured by CT. Hyperuricemia was defined as serum uric acid level >7.0 mg/dl. Its association with adiposity was tested using logistic regression. RESULTS: The prevalence of hyperuricemia was 19.6% (157 men). Both greater IAFA and lower L/S ratio were independently associated with hyperuricemia in models that simultaneously included IAFA and L/S ratio: multiple-adjusted odds ratios of hyperuricemia for quintiles 3, 4, and 5 of IAFA were 2.16 (95% confidence interval [95% CI] 1.02-4.59), 2.41 (95% CI 1.13-5.16), and 4.00 (95% CI 1.81-8.85), respectively, compared to quintile 1, and the L/S ratios for quintiles 3, 2, and 1 were 2.34 (95% CI 1.16-4.75), 2.15 (95% CI 1.06-4.34), and 2.79 (95% CI 1.35-5.76), respectively, compared to quintile 5. Both IAFA and L/S ratio remained significant even after adjusting for abdominal subcutaneous fat area, TFA, TSFA, body mass index, or waist circumference. Of all fat measurements, IAFA had the strongest association with hyperuricemia by Akaike's information criteria. CONCLUSION: Greater amounts of both visceral fat and liver fat were independently associated with hyperuricemia. PMID- 26414409 TI - Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels. AB - Gelatin methacryloyl (GelMA) hydrogels have been widely used for various biomedical applications due to their suitable biological properties and tunable physical characteristics. GelMA hydrogels closely resemble some essential properties of native extracellular matrix (ECM) due to the presence of cell attaching and matrix metalloproteinase responsive peptide motifs, which allow cells to proliferate and spread in GelMA-based scaffolds. GelMA is also versatile from a processing perspective. It crosslinks when exposed to light irradiation to form hydrogels with tunable mechanical properties. It can also be microfabricated using different methodologies including micromolding, photomasking, bioprinting, self-assembly, and microfluidic techniques to generate constructs with controlled architectures. Hybrid hydrogel systems can also be formed by mixing GelMA with nanoparticles such as carbon nanotubes and graphene oxide, and other polymers to form networks with desired combined properties and characteristics for specific biological applications. Recent research has demonstrated the proficiency of GelMA-based hydrogels in a wide range of tissue engineering applications including engineering of bone, cartilage, cardiac, and vascular tissues, among others. Other applications of GelMA hydrogels, besides tissue engineering, include fundamental cell research, cell signaling, drug and gene delivery, and bio-sensing. PMID- 26414412 TI - Enhancing antimicrobial activity of TiO2/Ti by torularhodin bioinspired surface modification. AB - Implant-associated infections are a major cause of morbidity and mortality. This study was performed using titanium samples coated by anodization with a titanium dioxide (TiO2) shielded nanotube layer. TiO2/Ti surface was modified by simple immersion in torularhodin solution and by using a mussel-inspired method based on polydopamine as bio adhesive for torularhodin immobilization. SEM analysis revealed tubular microstructures of torularhodin and the PDA ability to function as a catchy anchor between torularhodin and TiO2 surface. Corrosion resistance was associated with TiO2 barrier oxide layer and nano-organized oxide layer and the torularhodin surface modification does not bring significant changes in resistance of the oxide layer. Our results demonstrated that the torularhodin modified TiO2/Ti surface could effectively prevent adhesion and proliferation of Escherichia coli, Staphylococcus aureus, Enterococcus faecalis, Bacillus subtilis, and Pseudomonas aeruginosa. The new modified titanium surface showed good biocompatibility and well-behaved haemocompatibility. This biomaterial with enhanced antimicrobial activity holds great potential for future biomedical applications. PMID- 26414411 TI - Traumatic Brain Injury Severity Affects Neurogenesis in Adult Mouse Hippocampus. AB - Traumatic brain injury (TBI) has been proven to enhance neural stem cell (NSC) proliferation in the hippocampal dentate gyrus. However, various groups have reported contradictory results on whether TBI increases neurogenesis, partially due to a wide range in the severities of injuries seen with different TBI models. To address whether the severity of TBI affects neurogenesis in the injured brain, we assessed neurogenesis in mouse brains receiving different severities of controlled cortical impact (CCI) with the same injury device. The mice were subjected to mild, moderate, or severe TBI by a CCI device. The effects of TBI severity on neurogenesis were evaluated at three stages: NSC proliferation, immature neurons, and newly-generated mature neurons. The results showed that mild TBI did not affect neurogenesis at any of the three stages. Moderate TBI promoted NSC proliferation without increasing neurogenesis. Severe TBI increased neurogenesis at all three stages. Our data suggest that the severity of injury affects adult neurogenesis in the hippocampus, and thus it may partially explain the inconsistent results of different groups regarding neurogenesis following TBI. Further understanding the mechanism of TBI-induced neurogenesis may provide a potential approach for using endogenous NSCs to protect against neuronal loss after trauma. PMID- 26414414 TI - Coral-the world's most diverse symbiotic ecosystem. AB - Zooxanthellate corals (i.e. those harbouring Symbiodinium) are the main builders of the world's shallow-water marine coral reefs. They represent intimate diverse symbioses between coral animals, single-celled photosynthetic dinoflagellates (Symbiodinium spp.), other microscopic eukaryotes, prokaryotes and viruses. Crabs and other crustaceans, worms, sponges, bivalves and hydrozoans, fishes, sea urchins, octopuses and sea stars are itinerant members of these 'rainforests of the sea'. This review focuses on the biodiversity of scleractinian coral animals and their best studied microscopic epi- and endosymbionts. In relation to coral associated species diversity, Symbiodinium internal transcribed spacer region sequence types tally 10(2) -10(3) or up to ~15 different operational taxonomic units (OTUs, or putative species at the 97% sequence identity level; this cut-off was chosen based on intragenomic sequence diversity observed in monoclonal cultures) and prokaryotes (mostly bacterial) total 10(2) -10(4) OTUs. We analysed all publically accessible 16S rRNA gene sequence data and found Gammaproteobacteria were extremely abundant, followed by Alphaproteobacteria. Notably, Archaea were poorly represented and 'unassigned OTUs' were abundant in data generated by high-throughput DNA sequencing studies of corals. We outline and compare model systems that could be used in future studies of the coral holobiont. In our future directions, we recommend a global coral sampling effort including substantial attention being paid to method of coral tissue acquisition, which compartments (mucus, tissue, skeleton) to explore, broadening the holobiont members considered and linking biodiversity with functional investigations. PMID- 26414415 TI - ALSUntangled No. 31: Protandim. PMID- 26414416 TI - Understanding affiliate stigma faced by heterosexual family and friends of LGB people: A measurement development study. AB - The present study describes the development and psychometric evaluation of the Lesbian, Gay, Bisexual Affiliate Stigma Measure (LGB-ASM). Existing qualitative research and feedback from experts in stigma research contributed to the development of 48 items that were subjected to psychometric evaluation resulting in the final 17-item measure. Exploratory factor analysis of data from 471 LGB affiliates (family members and close friends of LGB individuals) resulted in 3 factors reflecting experiences of LGB affiliate stigma including (a) public discrimination/rejection affiliate stigma, (b) vicarious affiliate stigma, and (c) public shame affiliate stigma. Confirmatory factor analysis of data from a separate 101 participants supported the stability of the 3-factor model. Further psychometric evaluation of the measure resulted in evidence supporting the reliability (i.e., Cronbach's alphas of .71 to .93), convergent validity (i.e., with stigma consciousness, r = .17 to .45; with awareness of public devaluation, r = .18 to .28), and discriminant validity (i.e., with socially desirable responding, r = -.16 to .05). The final 17-item LGB-ASM yielded 2-to 3-week test retest reliability coefficients of .74 to .76 with a sample of 61 participants. Exploratory links between the LGB-ASM and psychological distress (using the Hopkins Symptom Checklist-21) were evaluated. PMID- 26414413 TI - A Novel Closed-Head Model of Mild Traumatic Brain Injury Using Focal Primary Overpressure Blast to the Cranium in Mice. AB - Mild traumatic brain injury (TBI) from focal head impact is the most common form of TBI in humans. Animal models, however, typically use direct impact to the exposed dura or skull, or blast to the entire head. We present a detailed characterization of a novel overpressure blast system to create focal closed-head mild TBI in mice. A high-pressure air pulse limited to a 7.5 mm diameter area on the left side of the head overlying the forebrain is delivered to anesthetized mice. The mouse eyes and ears are shielded, and its head and body are cushioned to minimize movement. This approach creates mild TBI by a pressure wave that acts on the brain, with minimal accompanying head acceleration-deceleration. A single 20-psi blast yields no functional deficits or brain injury, while a single 25-40 psi blast yields only slight motor deficits and brain damage. By contrast, a single 50-60 psi blast produces significant visual, motor, and neuropsychiatric impairments and axonal damage and microglial activation in major fiber tracts, but no contusive brain injury. This model thus reproduces the widespread axonal injury and functional impairments characteristic of closed-head mild TBI, without the complications of systemic or ocular blast effects or head acceleration that typically occur in other blast or impact models of closed-skull mild TBI. Accordingly, our model provides a simple way to examine the biomechanics, pathophysiology, and functional deficits that result from TBI and can serve as a reliable platform for testing therapies that reduce brain pathology and deficits. PMID- 26414417 TI - The role of parental warmth and hostility on adolescents' prosocial behavior toward multiple targets. AB - The current study examined the influence that parental warmth/support and verbal hostility had on adolescents' prosocial behavior toward multiple targets (stranger, friend, family) using multiple reporters (self, parent, observations). Data were taken from Times 2 and 3 of a longitudinal project and included 500 adolescents and their parents (M age of child at Time 2 = 12.34). Structural equation models suggested that mother warmth was associated with prosocial behavior toward family, while father warmth was associated with prosocial behavior toward friends. Findings also suggested that adolescents' prosocial behavior was more consistently influenced by father hostility than it was by father warmth. Finally, observational reports of father hostility were associated with adolescent prosocial behavior more consistently than self- or child-reported parenting. The discussion focuses on the importance of considering target of prosocial behavior, the differences between mothers and fathers, and the role of self-reports compared to observations. PMID- 26414418 TI - Preventing adolescent depression with the family check-up: Examining family conflict as a mechanism of change. AB - Family-centered prevention programs are understudied for their effects on adolescent depression, despite considerable evidence that supports their effectiveness for preventing escalation in youth problem behavior and substance use. This study was conducted with 2 overarching goals: (a) replicate previous work that has implicated the Family Check-Up (FCU), a multilevel, gated intervention model embedded in public middle schools, as an effective strategy for preventing growth in adolescent depressive symptoms and (b) test whether changes in family conflict may be an explanatory mechanism for the long-term, protective effects of the FCU with respect to adolescent depression. This trial was conducted with 593 ethnically diverse families who were randomized to intervention (offered the FCU) or middle school as usual. Complier average causal effect (CACE) analysis revealed that engagers in the FCU evidenced less growth in depressive symptoms and family conflict from 6th through 9th grade, and post hoc analyses indicated that the FCU is related to lower rates of major depressive disorder. The second set of analyses examined family conflict as a mechanism of change for families who participated in the FCU. Families who reported short-term intervention benefits had significantly less escalation in family conflict over the middle school years; in turn, growth in family conflict explained risk for adolescent depressive symptoms. PMID- 26414420 TI - Controlling optical properties of metallic multi-shell nanoparticles through suppressed surface plasmon resonance. AB - Herein, we report the surface plasmon resonance of plasmonic multi-shell nanoparticles compared to bimetallic Ag/Au hollow nanospheres of similar final size, shape, and percent composition. The surface plasmon resonance of solid and hollow nanoparticles exhibited a quadrupole mode that was particularly prominent around the 100 nm size regime, while multi-shell nanoparticles did not show a quadrupole mode at a similar size. In the latter case, the quadrupole mode of the outermost nanoshell was suppressed by the dipole modes of the inner shells, and the suppression of the quadrupole mode was not affected by the shape of the inner nanostructures. Light interaction of the multi-shell nanoparticle was investigated through simulated electromagnetic field distribution obtained by finite-difference time domain (FDTD) calculations which were in a good agreement with the results of surface-enhanced Raman spectroscopy (SERS). PMID- 26414419 TI - Controllable in situ synthesis of silver nanoparticles on multilayered film coated silk fibers for antibacterial application. AB - Layer-by-layer (LbL) assembly is a versatile technique for the preparation of multilayered polymeric films. However, fabrication of LbL polymetic film on silk for the in situ growth of high-density silver nanoparticles (AgNPs) has not been realized. Herein poly(acrylic acid) (PAA)/poly(dimethyldiallylammonium chloride) (PDDA) multilayers are constructed on silk via the LbL approach, subsequently serving as a 3-dimensional matrix for in situ synthesis of AgNPs. After 8 rounds of LbL assembly, the silk is fully covered with a layer of polymeric film. AgNPs with good crystalline structures could be in-situ generated in the silk-coated multilayers and their amount could be tailored by adjusting the bilayer numbers. The as-prepared silk could effectively kill the existing bacteria and inhibit the bacterial growth, demonstrating the antimicrobial activity. Moreover, the release of Ag(+) from the modified silk can last for 120 h, rendering the modified silk sustainable antimicrobial activity. This work may provide a novel method to prepare AgNPs-functionalized antimicrobial silk for potential applications in textile industry. PMID- 26414421 TI - Viscosity and stability of ultra-high internal phase CO2-in-water foams stabilized with surfactants and nanoparticles with or without polyelectrolytes. AB - To date, relatively few examples of ultra-high internal phase supercritical CO2 in-water foams (also referred to as macroemulsions) have been observed, despite interest in applications including "waterless" hydraulic fracturing in energy production. The viscosities and stabilities of foams up to 0.98 CO2 volume fraction were investigated in terms of foam bubble size, interfacial tension, and bulk and surface viscosity. The foams were stabilized with laurylamidopropyl betaine (LAPB) surfactant and silica nanoparticles (NPs), with and without partially hydrolyzed polyacrylamide (HPAM). For foams stabilized with mixture of LAPB and NPs, fine ~70 MUm bubbles and high viscosities on the order of 100 cP at>0.90 internal phase fraction were stabilized for hours to days. The surfactant reduces interfacial tension, and thus facilitates bubble generation and decreases the capillary pressure to reduce the drainage rate of the lamella. The LAPB, which is in the cationic protonated form, also attracts anionic NPs (and anionic HPAM in systems containing polymer) to the interface. The adsorbed NPs at the interface are shown to slow down Ostwald ripening (with or without polymer added) and increase foam stability. In systems with added HPAM, the increase in the bulk and surface viscosity of the aqueous phase further decreases the lamella drainage rate and inhibits coalescence of foams. Thus, the added polymer increases the foam viscosity by threefold. Scaling law analysis shows the viscosity of 0.90 volume fraction foams is inversely proportional to the bubble size. PMID- 26414422 TI - Maghemite nanosorbcats for methylene blue adsorption and subsequent catalytic thermo-oxidative decomposition: Computational modeling and thermodynamics studies. AB - In this study methylene blue (MB) has been investigated for its adsorption and subsequent catalytic thermo-oxidative decomposition on surface of maghemite (gamma-Fe2O3) nanoparticles. The experimental adsorption isotherm fit well to the Freundlich model, indicating multi-sites adsorption. Computational modeling of the interaction between the MB molecule and gamma-Fe2O3 nanoparticle surface was carried out to get more insights into its adsorption behavior. Adsorption energies of MB molecules on the surface indicated that there are different adsorption sites on the surface of gamma-Fe2O3 confirming the findings regarding the adsorption isotherm. The catalytic activity of the gamma-Fe2O3 nanoparticles toward MB thermo-oxidative decomposition has been confirmed by subjecting the adsorbed MB to a thermo oxidation process up to 600 degrees C in a thermogravimetric analyzer. The experimental results showed a catalytic activity for post adsorption oxidation. The oxidation kinetics were studied using the Ozawa-Flyn-Wall (OFW) corrected method. The most probable mechanism functions were fifth and third orders for virgin MB and MB adsorbed onto gamma-Fe2O3 nanoparticles, respectively. Moreover, the results of thermodynamic transition state parameters, namely changes in Gibbs free energy of activation (DeltaG(?)), enthalpy of activation (DeltaH(?)), and entropy of activation (DeltaS(?)), emphasized the catalytic activity of gamma-Fe2O3 nanoparticles toward MB oxidation. PMID- 26414423 TI - A confocal microscopy study of micron-sized poly(N-isopropylacrylamide) microgel particles at the oil-water interface and anisotopic flattening of highly swollen microgel. AB - HYPOTHESIS: Responsive poly(N-isopropylacrylamide) microgel (PNIPAM microgel) stabilized Pickering emulsions were investigated in this study. A recent theoretical study of other researchers has suggested that large soft particles at the oil/water interface are less deformable than their small counterparts. Therefore, we expected that our micron-sized microgel particles might not significantly deform at the oil/water interface. EXPERIMENTS: We applied confocal laser scanning microscopy (CLSM) to examine the structure of soft PNIPAM-based microgel particles at the decane-water interface in a microgel-stabilized emulsion. Using micron-sized microgel particles with better labelling techniques, we could compensate the weakness in resolution of using CLSM. Seven PNIPAM-based microgel samples with various softness values and morphologies were examined at different pH values. FINDINGS: Our results demonstrate that the deformation of ordinary micron-sized microgel samples was not significant if they were not in the pH-swollen state. Nevertheless, the soft, pH-swollen microgel particles exhibited anisotropic deformation at the decane-water interface. Such flattening was not reported in previous studies. The studies of microgel particles at the oil-water interface with different imaging techniques and their comparison are valuable to help to elucidate the particles' roles in stabilizing the Pickering emulsions. PMID- 26414424 TI - Trypsin and trypsin inhibitor bind PAMAM nanoparticles: Effect of hydrophobicity on protein-polymer conjugation. AB - Protein-polymer conjugates are widely used in therapeutic drug delivery. We report the bindings of trypsin (Try) and trypsin inhibitor (Tryi) with polyamidoamine (PAMAM-G4) dendrimer at physiological conditions, using thermodynamic analysis, UV-Visible and Fourier transform infrared (FTIR) spectroscopic methods. Thermodynamic parameters DeltaS, DeltaH and DeltaG showed protein-PAMAM bindings occur via H-bonding and van der Waals contacts with trypsin inhibitor forming more stable conjugate than trypsin. PAMAM complexation induces more perturbations of trypsin inhibitor structure than trypsin with reduction of protein alpha-helix and major changes of beta-structures. The negative value of DeltaG indicates spontaneous protein-polymer conjugation at room temperature. PMID- 26414425 TI - Application of least squares support vector regression and linear multiple regression for modeling removal of methyl orange onto tin oxide nanoparticles loaded on activated carbon and activated carbon prepared from Pistacia atlantica wood. AB - Two novel and eco friendly adsorbents namely tin oxide nanoparticles loaded on activated carbon (SnO2-NP-AC) and activated carbon prepared from wood tree Pistacia atlantica (AC-PAW) were used for the rapid removal and fast adsorption of methyl orange (MO) from the aqueous phase. The dependency of MO removal with various adsorption influential parameters was well modeled and optimized using multiple linear regressions (MLR) and least squares support vector regression (LSSVR). The optimal parameters for the LSSVR model were found based on gamma value of 0.76 and sigma(2) of 0.15. For testing the data set, the mean square error (MSE) values of 0.0010 and the coefficient of determination (R(2)) values of 0.976 were obtained for LSSVR model, and the MSE value of 0.0037 and the R(2) value of 0.897 were obtained for the MLR model. The adsorption equilibrium and kinetic data was found to be well fitted and in good agreement with Langmuir isotherm model and second-order equation and intra-particle diffusion models respectively. The small amount of the proposed SnO2-NP-AC and AC-PAW (0.015 g and 0.08 g) is applicable for successful rapid removal of methyl orange (>95%). The maximum adsorption capacity for SnO2-NP-AC and AC-PAW was 250 mg g(-1) and 125 mg g(-1) respectively. PMID- 26414426 TI - Wettability alteration of oil-wet carbonate by silica nanofluid. AB - Changing oil-wet surfaces toward higher water wettability is of key importance in subsurface engineering applications. This includes petroleum recovery from fractured limestone reservoirs, which are typically mixed or oil-wet, resulting in poor productivity as conventional waterflooding techniques are inefficient. A wettability change toward more water-wet would significantly improve oil displacement efficiency, and thus productivity. Another area where such a wettability shift would be highly beneficial is carbon geo-sequestration, where compressed CO2 is pumped underground for storage. It has recently been identified that more water-wet formations can store more CO2. We thus examined how silica based nanofluids can induce such a wettability shift on oil-wet and mixed-wet calcite substrates. We found that silica nanoparticles have an ability to alter the wettability of such calcite surfaces. Nanoparticle concentration and brine salinity had a significant effect on the wettability alteration efficiency, and an optimum salinity was identified, analogous to that one found for surfactant formulations. Mechanistically, most nanoparticles irreversibly adhered to the oil wet calcite surface (as substantiated by SEM-EDS and AFM measurements). We conclude that such nanofluid formulations can be very effective as enhanced hydrocarbon recovery agents and can potentially be used for improving the efficiency of CO2 geo-storage. PMID- 26414427 TI - An Optimized Glutamate Receptor Photoswitch with Sensitized Azobenzene Isomerization. AB - A new azobenzene-based photoswitch, 2, has been designed to enable optical control of ionotropic glutamate receptors in neurons via sensitized two-photon excitation with NIR light. In order to develop an efficient and versatile synthetic route for this molecule, a modular strategy is described which relies on the use of a new linear fully protected glutamate derivative stable in basic media. The resulting compound undergoes one-photon trans-cis photoisomerization via two different mechanisms: direct excitation of its azoaromatic unit and irradiation of the pyrene sensitizer, a well-known two-photon sensitive chromophore. Moreover, 2 presents large thermal stability of its cis isomer, in contrast to other two-photon responsive switches relying on the intrinsic nonlinear optical properties of push-pull substituted azobenzenes. As a result, the molecular system developed herein is a very promising candidate for evoking large photoinduced biological responses during the multiphoton operation of neuronal glutamate receptors with NIR light, which require accumulation of the protein-bound cis state of the switch upon repeated illumination. PMID- 26414428 TI - Fast Fabrication of Flexible Functional Circuits Based on Liquid Metal Dual-Trans Printing. AB - A dual-trans method to print the first functional liquid-metal circuit layout on poly(vinyl chloride) film, and then transfer it into a poly(dimethylsiloxane) substrate through freeze phase transition processing for the fabrication of a flexible electronic device. A programmable soft electronic band and a temperature sensing module wirelessly communicate with a mobile phone, demonstrating the efficiency and capability of the method. PMID- 26414429 TI - Risk Prioritization Tool to Identify the Public Health Risks of Wildlife Trade: The Case of Rodents from Latin America. AB - Wildlife trade (both formal and informal) is a potential driver of disease introduction and emergence. Legislative proposals aim to prevent these risks by banning wildlife imports, and creating 'white lists' of species that are cleared for importation. These approaches pose economic harm to the pet industry, and place substantial burden on importers and/or federal agencies to provide proof of low risk for importation of individual species. As a feasibility study, a risk prioritization tool was developed to rank the pathogens found in rodent species imported from Latin America into the United States with the highest risk of zoonotic consequence in the United States. Four formally traded species and 16 zoonotic pathogens were identified. Risk scores were based on the likelihood of pathogen release and human exposure, and the severity of the disease (consequences). Based on the methodology applied, three pathogens (Mycobacterium microti, Giardia spp. and Francisella tularensis) in one species (Cavia porcellus) were ranked as highest concern. The goal of this study was to present a methodological approach by which preliminary management resources can be allocated to the identified high-concern pathogen-species combinations when warranted. This tool can be expanded to other taxa and geographic locations to inform policy surrounding the wildlife trade. PMID- 26414431 TI - Rhodium(III)-Catalyzed C-H Activation/Alkyne Annulation by Weak Coordination of Peresters with O-O Bond as an Internal Oxidant. AB - A redox-economic strategy has been developed, involved in an efficient Rh(III) catalyzed oxidative C-H activation and alkyne annulation with perester as the oxidizing directing group. In this process, the cleavage of an oxidizing O-O bond as an internal oxidant is described for the first time. This reaction could be carried out under mild conditions and exhibits excellent regioselectivity and wide functional groups tolerance. PMID- 26414430 TI - High Prevalence of HIV Low Abundance Drug-Resistant Variants in a Treatment-Naive Population in North Rift Kenya. AB - The advent of antiretroviral treatment (ART) has resulted in a dramatic reduction in AIDS-related morbidity and mortality. However, the emergence and spread of antiretroviral drug resistance (DR) threaten to negatively impact treatment regimens and compromise efforts to control the epidemic. It is recommended that surveillance of drug resistance occur in conjunction with scale-up efforts to ensure that appropriate first-line therapy is offered relative to the resistance that exists. However, standard resistance testing methods used in Sub-Saharan Africa rely on techniques that do not include low abundance DR variants (LADRVs) that have been documented to contribute to treatment failure. The use of next generation sequencing (NGS) has been shown to be more sensitive to LADRVS. We have carried out a preliminary investigation using NGS to determine the prevalence of LDRVS among a drug-naive population in North Rift Kenya. Antiretroviral-naive patients attending a care clinic in North Rift Kenya were requested to provide and with consent provided blood samples for DR analysis. DNA was extracted and amplified and nested PCR was conducted on the pol RT region using primers tagged with multiplex identifiers (MID). Resulting PCR amplicons were purified, quantified, and pyrosequenced using a GS FLX Titanium PicoTiterPlate (Roche). Valid pyrosequencing reads were aligned with HXB-2 and the frequency and distribution of nucleotide and amino acid changes were determined using an in-house Perl script. DR mutations were identified using the IAS-USA HIV DR mutation database. Sixty samples were successfully sequenced of which 26 were subtype A, 9 were subtype D, 2 were subtype C, and the remaining were recombinants. Forty-six (76.6%) had at least one drug resistance mutation, with 25 (41.6%) indicated as major and the remaining 21 (35%) indicated as minor. The most prevalent mutation was NRTI position K219Q/R (11/46, 24%) followed by NRTI M184V (5/46, 11%) and NNRTI K103N (4/46, 9%). Our use of NGS technology revealed a high prevalence of LADRVs among drug-naive populations in Kenya, a region with predominantly non-B subtypes. The impact of these mutations on the clinical outcome of ART can be ascertained only through long-term follow-up. PMID- 26414432 TI - Does educational intervention affect resident competence in sonographic cervical length measurement? AB - OBJECTIVE: To determine if a structured teaching module improves resident competency in transvaginal sonographic cervical length measurements. METHODS: This was a prospective cohort study involving obstetrics and gynecology residents at a single institution. Residents collected 10 transvaginal cervical images from patients with threatened preterm labor presenting to Labor and Delivery. After initial image acquisition, residents participated in a lecture-based teaching module involving a pre- and post-intervention assessment. Following the didactic session, they collected 10 additional images. All the images were scored independently by two Maternal-Fetal Medicine attending physicians based on the quality and accuracy of the measured cervical length. Pre-and post- intervention test results were compared, as well as pre- and post- intervention image scores. Parametric and nonparametric tests were used as appropriate with p < 0.05 considered significant. RESULTS: Ninety-three percent of the residents (14/15) improved their scores from pre-test to post-test or maintained an already perfect score (p < 0.01). Improvement was most significant with the junior residents. Seventy-nine percent of the residents (11/14) improved their cervical image scores after the educational session. Mean score for total residents was 73.7 + 12.6 pre-intervention and 90.2 + 9.9 post-intervention (p < 0.01) out of a total of 120. CONCLUSIONS: There is an improvement in the competence of resident measured cervical lengths via transvaginal ultrasound when a structured educational module is implemented for resident education. PMID- 26414433 TI - Post-Inpatient Brain Injury Rehabilitation Outcomes: Report from the National OutcomeInfo Database. AB - This study examined outcomes for intensive residential and outpatient/community based post-inpatient brain injury rehabilitation (PBIR) programs compared with supported living programs. The goal of supported living programs was stable functioning (no change). Data were obtained for a large cohort of adults with acquired brain injury (ABI) from the OutcomeInfo national database, a web-based database system developed through National Institutes of Health (NIH) Small Business Technology Transfer (STTR) funding for monitoring progress and outcomes in PBIR programs primarily with the Mayo-Portland Adaptability Inventory (MPAI 4). Rasch-derived MPAI-4 measures for cases from 2008 to 2014 from 9 provider organizations offering programs in 23 facilities throughout the United States were examined. Controlling for age at injury, time in program, and time since injury on admission (chronicity), both intensive residential (n = 205) and outpatient/community-based (n = 2781) programs resulted in significant (approximately 1 standard deviation [SD]) functional improvement on the MPAI-4 Total Score compared with supported living (n = 101) programs (F = 18.184, p < 0.001). Intensive outpatient/community-based programs showed greater improvements on MPAI-4 Ability (F = 14.135, p < 0.001), Adjustment (F = 12.939, p < 0.001), and Participation (F = 16.679, p < 0.001) indices than supported living programs; whereas, intensive residential programs showed improvement primarily in Adjustment and Participation. Age at injury and time in program had small effects on outcome; the effect of chronicity was small to moderate. Examination of more chronic cases (>1 year post-injury) showed significant, but smaller (approximately 0.5 SD) change on the MPAI-4 relative to supported living programs (F = 17.562, p < 0.001). Results indicate that intensive residential and outpatient/community-based PIBR programs result in substantial positive functional changes moderated by chronicity. PMID- 26414434 TI - Canagliflozin treatment of Hispanic and non-Hispanic patients with type 2 diabetes in a US managed care setting. AB - BACKGROUND: Hispanic/Latino (H/L) ethnicity is associated with higher prevalence of type 2 diabetes mellitus (T2DM) and more complications and comorbidities. Few studies of antihyperglycemic agents (AHAs) have compared H/L with non-H/L patients. Randomized controlled trials and observational studies have shown canagliflozin (CANA) is effective at lowering hemoglobin A1C (A1C). OBJECTIVE: To describe characteristics and compare glycemic control between H/L and non-H/L patients with T2DM filling their first prescription for CANA. METHODS: This retrospective cohort study examined healthcare claims for diabetic patients who filled >=1 prescription for CANA between 1 April 2013 and 31 October 2013. We captured available demographic data; ethnicity was imputed as previously published. Clinical data included the Diabetes Complications Severity Index (DCSI), A1C values, and claims for any AHA, with 6 months of follow-up. RESULTS: Our sample included 438 (11.4%) H/L individuals and 3408 (88.6%) non-H/L individuals; each cohort had 43% females. The H/L patients were younger (53 vs. 56 years, p < 0.001) with higher mean baseline A1C (8.9% vs. 8.5%, respectively; p = 0.028) compared to non-H/L patients. Mean DCSI was similar (H/L 0.92 vs. non H/L 0.84, p = 0.289) between cohorts. More H/L patients (25%) were taking >=3 AHAs at the first CANA prescription fill (vs. 21% for non-H/L; p = 0.044), most commonly metformin, followed by sulfonylureas, dipeptidyl peptidase-4 inhibitors, and basal insulin. Among patients with >=2 fills for CANA, mean adherence (proportion of days covered) was slightly lower for H/L than non-H/L patients (0.77 vs. 0.80, p = 0.003). From their respective baseline A1C values, reduction in A1C was significantly greater for H/L than non-H/L patients (1.1% vs. 0.8%; p = 0.043). CONCLUSION: Compared with non-H/L patients, our H/L patients were younger and had higher mean baseline A1C. Significant improvement in glycemic control was observed for both cohorts, with greater improvement for H/L patients. Additional research is warranted, including longer follow-up and adjusting for possible confounding factors. PMID- 26414435 TI - Prevention of conversion to abnormal transcranial Doppler with hydroxyurea in sickle cell anemia: A Phase III international randomized clinical trial. AB - Children with sickle cell anemia (SCA) and conditional transcranial Doppler (TCD) ultrasound velocities (170-199 cm/sec) may develop stroke. However, with limited available clinical data, the current standard of care for conditional TCD velocities is observation. The efficacy of hydroxyurea in preventing conversion from conditional to abnormal TCD (>=200 cm/sec), which confers a higher stroke risk, has not been studied prospectively in a randomized trial. Sparing Conversion to Abnormal TCD Elevation (SCATE #NCT01531387) was a National Heart, Lung, and Blood Institute-funded Phase III multicenter international clinical trial comparing alternative therapy (hydroxyurea) to standard care (observation) to prevent conversion from conditional to abnormal TCD velocity in children with SCA. SCATE enrolled 38 children from the United States, Jamaica, and Brazil [HbSS (36), HbSbeta(0) -thalassemia (1), and HbSD (1), median age = 5.4 years (range, 2.7-9.8)]. Because of the slow patient accrual and administrative delays, SCATE was terminated early. In an intention-to-treat analysis, the cumulative incidence of abnormal conversion was 9% (95% CI = 0-35%) in the hydroxyurea arm and 47% (95% CI = 6-81%) in observation arm at 15 months (P = 0.16). In post hoc analysis according to treatment received, significantly fewer children on hydroxyurea converted to abnormal TCD velocities when compared with observation (0% vs. 50%, P = 0.02). After a mean of 10.1 months, a significant change in mean TCD velocity was observed with hydroxyurea treatment (-15.5 vs. +10.2 cm/sec, P = 0.02). No stroke events occurred in either arm. Hydroxyurea reduces TCD velocities in children with SCA and conditional velocities. PMID- 26414436 TI - Intestine-Specific Delivery of Hydrophobic Bioactives from Oxidized Starch Microspheres with an Enhanced Stability. AB - An intestine-specific delivery system for hydrophobic bioactives with improved stability was developed. It consists of oxidized potato starch polymers, where the carboxyl groups were physically cross-linked via ferric ions. The model hydrophobic ingredients (beta-carotene) were incorporated inside the starch microspheres via a double-emulsion method. Confocal laser scanning microscopy images showed that beta-carotene were distributed homogeneously in the inner oil phase of the starch microspheres. The negative value of the zeta-potential of microspheres increased with increasing pH and decreasing ionic strength. In vitro release experiments showed that the microspheres were stable at acidic stomach conditions (pH < 2), whereas at neutral intestinal conditions (pH 7.0), they rupture to release the loaded beta-carotene. The 1,1-diphenyl-2-picrylhydrazyl radical, 2,2-diphenyl-1-(2,4,6-trinitriphenyl), scavenging activity results suggested that microsphere-encapsulated beta-carotene had an improved activity after thermal treatment at 80 degrees C. The storage stability of encapsulated beta-carotene at room temperature was also enhanced. The starch microspheres showed potential as intestine-specific carriers with an enhanced stability. PMID- 26414437 TI - Speciation genomics and a role for the Z chromosome in the early stages of divergence between Mexican ducks and mallards. AB - Speciation is a continuous and dynamic process, and studying organisms during the early stages of this process can aid in identifying speciation mechanisms. The mallard (Anas platyrhynchos) and Mexican duck (A. [p.] diazi) are two recently diverged taxa with a history of hybridization and controversial taxonomy. To understand their evolutionary history, we conducted genomic scans to characterize patterns of genetic diversity and divergence across the mitochondrial DNA (mtDNA) control region, 3523 autosomal loci and 172 Z-linked sex chromosome loci. Between the two taxa, Z-linked loci (PhiST = 0.088) were 5.2 times more differentiated than autosomal DNA (PhiST = 0.017) but comparable to mtDNA (PhiST = 0.092). This elevated Z differentiation deviated from neutral expectations inferred from simulated data that incorporated demographic history and differences in effective population sizes between marker types. Furthermore, 3% of Z-linked loci, compared to <0.1% of autosomal loci, were detected as outlier loci under divergent selection with elevated relative (PhiST ) and absolute (dXY ) estimates of divergence. In contrast, the ratio of Z-linked and autosomal differentiation among the seven Mexican duck sampling locations was close to 1:1 (PhiST = 0.018 for both markers). We conclude that between mallards and Mexican ducks, divergence at autosomal markers is largely neutral, whereas greater divergence on the Z chromosome (or some portions thereof) is likely the product of selection that has been important in speciation. Our results contribute to a growing body of literature indicating elevated divergence on the Z chromosome and its likely importance in avian speciation. PMID- 26414438 TI - Genotypic characteristics of Mycobacterium tuberculosis circulating in Xinjiang, China. AB - BACKGROUND: Tuberculosis (TB), a chronic infectious disease caused by Mycobacterium tuberculosis (MTB), poses a serious threat to human health. We investigated the genotypes of MTB in the high prevalence province Xinjiang, China. METHODS: From March 2010 to May 2013, 381 MTB isolates from patients with pulmonary TB were analyzed by molecular typing of 24 mycobacterial interspersed repetitive unit-variable number tandem repeat loci and PCR detection of the deleted regions of difference of the Beijing/W lineage and its sublineages. RESULTS: These isolates were shown to be highly polymorphic and to be composed of 345 unique genotypes, including 30 genotype clusters consisting of 2 or 3 strains and 315 individual genotypes. The genotype clustering rate was 17.32% and recent transmission index was low (9.45%). The Beijing/W lineage strains accounted for 57.48% of the isolates, and this predominant family strain was further subdivided into four sublineages: 181 (69.86%), 207 (14.61%), 105 (10.96%), and 150 (4.56%). CONCLUSIONS: The Beijing/W lineage (especially sublineage 181) strains were predominant and were associated with the transmissibility of TB in Xinjiang. Based on our data, we hypothesize that the circulating MTB strains in Xinjiang have significant genetic diversity and that the majority of the TB in Xinjiang may be explained by non-recent transmission emerging by endogenous reactivation. The possibility of outbreak is low, and current measures to control TB should first focus on standardized treatment of TB patients to prevent reactivation of latent infections. PMID- 26414440 TI - The response of broccoli (Brassica oleracea convar. italica) varieties on foliar application of selenium: uptake, translocation, and speciation. AB - A model small-scale field experiment was set up to investigate selenium (Se) uptake by four different varieties of broccoli plants, as well as the effect of Se foliar application on the uptake of essential elements for plants calcium (Ca), copper (Cu), iron (Fe), potassium (K), magnesium (Mg), manganese (Mn), phosphorus (P), sulfur (S), and zinc (Zn). Foliar application of sodium selenate (Na2SeO4) was carried out at two rates (25 and 50 g Se/ha), and an untreated control variant was included. Analyses of individual parts of broccoli were performed, whereby it was found that Se in the plant accumulates mainly in the flower heads and slightly less in the leaves, stems, and roots, regardless of the Se rate and broccoli variety. In most cases, there was a statistically significant increase of Se content in all parts of the plant, while there was no confirmed systematic influence of the addition of Se on the changing intake of other monitored elements. Selenization of broccoli leads to an effective increase in the Se content at a rate of 25 g/ha, whereas the higher rate did not result in a substantial increase of Se content compared to the lower rate in all varieties. Therefore, the rate of 25 g/ha can be recommended as effective to produce broccoli with an increased Se content suitable for consumption. Moreover, Se application resulted in an adequate increase of the main organic compounds of Se, such as selenocystine (SeCys2), selenomethionine (SeMet), and Se methylselenocysteine (Se-MeSeCys). PMID- 26414439 TI - Rebuilding Brain Circuitry with Living Micro-Tissue Engineered Neural Networks. AB - Prominent neuropathology following trauma, stroke, and various neurodegenerative diseases includes neuronal degeneration as well as loss of long-distance axonal connections. While cell replacement and axonal pathfinding strategies are often explored independently, there is no strategy capable of simultaneously replacing lost neurons and re-establishing long-distance axonal connections in the central nervous system. Accordingly, we have created micro-tissue engineered neural networks (micro-TENNs), which are preformed constructs consisting of long integrated axonal tracts spanning discrete neuronal populations. These living micro-TENNs reconstitute the architecture of long-distance axonal tracts, and thus may serve as an effective substrate for targeted neurosurgical reconstruction of damaged pathways in the brain. Cerebral cortical neurons or dorsal root ganglia neurons were precisely delivered into the tubular constructs, and properties of the hydrogel exterior and extracellular matrix internal column (180-500 MUm diameter) were optimized for robust neuronal survival and to promote axonal extensions across the 2.0 cm tube length. The very small diameter permits minimally invasive delivery into the brain. In this study, preformed micro-TENNs were stereotaxically injected into naive rats to bridge deep thalamic structures with the cerebral cortex to assess construct survival and integration. We found that micro-TENN neurons survived at least 1 month and maintained their long axonal architecture along the cortical-thalamic axis. Notably, we also found neurite penetration from micro-TENN neurons into the host cortex, with evidence of synapse formation. These micro-TENNs represent a new strategy to facilitate nervous system repair by recapitulating features of neural pathways to restore or modulate damaged brain circuitry. PMID- 26414441 TI - Fluorescent Ensemble Based on Bispyrene Fluorophore and Surfactant Assemblies: Sensing and Discriminating Proteins in Aqueous Solution. AB - A particular bispyrene fluorophore (1) with two pyrene moieties covalently linked via a hydrophilic spacer was synthesized. Fluorescence measurements reveal that the fluorescence emission of 1 could be well modulated by a cationic surfactant, dodecyltrimethylammonium bromide (DTAB). Protein sensing studies illustrate that the selected ensemble based on 1/DTAB assemblies exhibits ratiometric responses to nonmetalloproteins and turn-off responses to metalloproteins, which can be used to differentiate the two types of proteins. Moreover, negatively charged nonmetalloproteins can be discriminated from the positively charged ones according to the difference in ratiometric responses. Fluorescence sensing studies with control bispyrenes indicate that the polarity of the spacer connecting two pyrene moieties plays an important role in locating bispyrene fluorophore in DTAB assemblies, which further influences its sensing behaviors to noncovalent interacting proteins. This study sheds light on the influence of the probe structure on the sensing performance of a fluorescent ensemble based on probe and surfactant assemblies. PMID- 26414442 TI - Hovering and forward flight of the hawkmoth Manduca sexta: trim search and 6-DOF dynamic stability characterization. AB - We show that the forward flight speed affects the stability characteristics of the longitudinal and lateral dynamics of a flying hawkmoth; dynamic modal structures of both the planes of motion are altered due to variations in the stability derivatives. The forward flight speed u e is changed from 0.00 to 1.00 m s(-1) with an increment of 0.25 m s(-1). (The equivalent advance ratio is 0.00 to 0.38; the advance ratio is the ratio of the forward flight speed to the average wing tip speed.) As the flight speed increases, for the longitudinal dynamics, an unstable oscillatory mode becomes more unstable. Also, we show that the up/down (w(b)) dynamics become more significant at a faster flight speed due to the prominent increase in the stability derivative Z(u) (up/down force due to the forward/backward velocity). For the lateral dynamics, the decrease in the stability derivative L(v) (roll moment due to side slip velocity) at a faster flight speed affects a slightly damped stable oscillatory mode, causing it to become more stable; however, the t(half) (the time taken to reach half the amplitude) of this slightly damped stable oscillatory mode remains relatively long (~12T at u(e) = 1 m s(-1); T is wingbeat period) compared to the other modes of motion, meaning that this mode represents the most vulnerable dynamics among the lateral dynamics at all flight speeds. To obtain the stability derivatives, trim conditions for linearization are numerically searched to find the exact trim trajectory and wing kinematics using an algorithm that uses the gradient information of a control effectiveness matrix and fully coupled six-degrees of freedom nonlinear multibody equations of motion. With this algorithm, trim conditions that consider the coupling between the dynamics and aerodynamics can be obtained. The body and wing morphology, and the wing kinematics used in this study are based on actual measurement data from the relevant literature. The aerodynamic model of the flapping wings of a hawkmoth is based on the blade element theory, and the necessary aerodynamic coefficients, including the lift, drag and wing pitching moment, are experimentally obtained from the results of previous work by the authors. PMID- 26414445 TI - Ribozymes: How RNA catalyzes cyclization. PMID- 26414443 TI - The protein activator of protein kinase R, PACT/RAX, negatively regulates protein kinase R during mouse anterior pituitary development. AB - The murine double-stranded RNA-binding protein termed protein kinase R (PKR) associated protein X (RAX) and the human homolog, protein activator of PKR (PACT), were originally characterized as activators of PKR. Mice deficient in RAX show reproductive and developmental defects, including reduced body size, craniofacial defects and anterior pituitary hypoplasia. As these defects are not observed in PKR-deficient mice, the phenotype has been attributed to PKR independent activities of RAX. Here we further investigated the involvement of PKR in the physiological function of RAX, by generating rax(-/-) mice deficient in PKR, or carrying a kinase-inactive mutant of PKR (K271R) or an unphosphorylatable mutant of the PKR substrate eukaryotic translation initiation factor 2 alpha subunit (eIF2alpha) (S51A). Ablating PKR expression rescued the developmental and reproductive deficiencies in rax(-/-) mice. Generating rax(-/-) mice with a kinase-inactive mutant of PKR resulted in similar rescue, confirming that the rax(-/-) defects are PKR dependent; specifically that the kinase activity of PKR was required for these defects. Moreover, generating rax(-/-) mice that were heterozygous for an unphosphorylatable mutant eIF2alpha provides partial rescue of the rax(-/-) defect, consistent with mutation of one copy of the Eif2s1 gene. These observations were further investigated in vitro by reducing RAX expression in anterior pituitary cells, resulting in increased PKR activity and induction of the PKR-regulated cyclin-dependent kinase inhibitor p21(WAF1/CIP1). These results demonstrate that PKR kinase activity is required for onset of the rax(-/-) phenotype, implying an unexpected function for RAX as a negative regulator of PKR in the context of postnatal anterior pituitary tissue, and identify a critical role for the regulation of PKR activity for normal development. PMID- 26414444 TI - Notch-modifying xylosyltransferase structures support an SNi-like retaining mechanism. AB - A major question remaining in glycobiology is how a glycosyltransferase (GT) that retains the anomeric linkage of a sugar catalyzes the reaction. Xyloside alpha 1,3-xylosyltransferase (XXYLT1) is a retaining GT that regulates Notch receptor activation by adding xylose to the Notch extracellular domain. Here, using natural acceptor and donor substrates and active Mus musculus XXYLT1, we report a series of crystallographic snapshots along the reaction, including an unprecedented natural and competent Michaelis reaction complex for retaining enzymes. These structures strongly support the SNi-like reaction as the retaining mechanism for XXYLT1. Unexpectedly, the epidermal growth factor-like repeat acceptor substrate undergoes a large conformational change upon binding to the active site, providing a structural basis for substrate specificity. Our improved understanding of this retaining enzyme will accelerate the design of retaining GT inhibitors that can modulate Notch activity in pathological situations in which Notch dysregulation is known to cause cancer or developmental disorders. PMID- 26414447 TI - The roles of CD147 in the progression of gliomas. AB - Gliomas are characterized by their invasiveness, angiogenesis, glycolysis and poor prognosis. Determining how to inhibit angiogenesis and glycolysis and induce cell death in gliomas is essential to the development of an effective therapy. CD147, a highly glycosylated transmembrane glycoprotein with two Ig-like extracellular domains that belongs to the immunoglobulin superfamily, plays an important role in the regulation of tumor invasiveness, angiogenesis and glycolysis by inducing the secretion of matrix metalloproteinases and vascular endothelial growth factor and by interacting with monocarboxylate transporters. In this review, we first summarize the roles played by CD147 in gliomas and then propose that CD147 may be a complementary prognostic biomarker and a possible therapeutic target for glioma treatment. PMID- 26414448 TI - Contact Forces between TiO2 Nanoparticles Governed by an Interplay of Adsorbed Water Layers and Roughness. AB - Interparticle forces govern the mechanical behavior of granular matter and direct the hierarchical assembling of nanoparticles into supramolecular structures. Understanding how these forces change under different ambient conditions would directly benefit industrial-scale nanoparticle processing units such as filtering and fluidization. Here we rationalize and quantify the contributions of dispersion, capillary, and solvation forces between hydrophilic TiO2 nanoparticles with sub-10 nm diameter and show that the humidity dependence of the interparticle forces is governed by a delicate interplay between the structure of adsorbed water layers and the surface roughness. All-atom molecular dynamics modeling supported by force-spectroscopy experiments reveals an unexpected decrease in the contact forces at increasing humidity for nearly spherical particles, while the forces between rough particles are insensitive to strong humidity changes. Our results also frame the limits of applicability of discrete solvation and continuum capillary theories in a regime where interparticle forces are dominated by the molecular nature of surface adsorbates. PMID- 26414446 TI - Crystal structure of the Varkud satellite ribozyme. AB - The Varkud satellite (VS) ribozyme mediates rolling-circle replication of a plasmid found in the Neurospora mitochondrion. We report crystal structures of this ribozyme from Neurospora intermedia at 3.1 A resolution, which revealed an intertwined dimer formed by an exchange of substrate helices. In each protomer, an arrangement of three-way helical junctions organizes seven helices into a global fold that creates a docking site for the substrate helix of the other protomer, resulting in the formation of two active sites in trans. This mode of RNA-RNA association resembles the process of domain swapping in proteins and has implications for RNA regulation and evolution. Within each active site, adenine and guanine nucleobases abut the scissile phosphate, poised to serve direct roles in catalysis. Similarities to the active sites of the hairpin and hammerhead ribozymes highlight the functional importance of active-site features, underscore the ability of RNA to access functional architectures from distant regions of sequence space, and suggest convergent evolution. PMID- 26414449 TI - Evaluating the Effects of Metformin Use on Height in Children and Adolescents: A Meta-analysis of Randomized Clinical Trials. AB - IMPORTANCE: Metformin hydrochloride use is increasing in children and adolescents. Previous meta-analyses have identified a large variability in the effects of metformin use on body mass index changes but have not considered height changes as a confounder, to our knowledge. OBJECTIVE: To conduct a systematic review and meta-analysis of the effects of metformin use on height in children and adolescents. DATA SOURCES: Computerized databases, including MEDLINE and EMBASE, were searched up to September 9, 2014, for terms related to metformin and childhood or adolescence. STUDY SELECTION: Randomized clinical trials examining the effects of metformin use on height of participants younger than 19 years were considered eligible. Trials with cointerventions other than lifestyle changes were excluded. DATA EXTRACTION AND SYNTHESIS: Height, weight, body mass index, age, sex, metformin dosage, and study duration were independently extracted by 2 reviewers. The weighted mean differences for changes in height, weight, and body mass index were compared between the metformin and control groups using random-effects models. MAIN OUTCOME AND MEASURE: Height changes. RESULTS: Ten studies were included, with a total of 562 participants, 330 (58.7%) of whom were female. The mean age within the studies ranged from 7.9 to 16.1 years, with a high variability in most studies. The duration of metformin interventions lasted from 3 to 48 months. Overall, height changes were not significantly different between the metformin and control groups. However, stratified analyses according to the cumulative metformin dose (in milligrams per day times the number of days of treatment) showed a greater increase in height with metformin use in the 5 studies providing the largest cumulative metformin doses (weighted mean difference, 1.0; 95% CI, 0.0 to 2.0 cm) but not in the 5 studies providing the lowest doses (weighted mean difference, -0.1; 95% CI, -0.7 to 1.0 cm) compared with the control group. CONCLUSIONS AND RELEVANCE: Preliminary evidence suggests a dose-response relationship between metformin use and increases in height in children and adolescents compared with a control group. While an approximate 1-cm increase in height may appear small, it is likely underestimated given that many studies were of short duration and included older adolescents, potentially after epiphyseal growth plate closure. PMID- 26414450 TI - Cyclosporine-inhibitable Cerebral Drug Transport Does Not Influence Clinical Methadone Pharmacodynamics: Erratum. AB - [This corrects the article on p. 1281 in vol. 121, issue 6, PMID: 25072223.]. PMID- 26414451 TI - Multidimensional Analysis of Magnetic Resonance Imaging Predicts Early Impairment in Thoracic and Thoracolumbar Spinal Cord Injury. AB - Literature examining magnetic resonance imaging (MRI) in acute spinal cord injury (SCI) has focused on cervical SCI. Reproducible systems have been developed for MRI-based grading; however, it is unclear how they apply to thoracic SCI. Our hypothesis is that MRI measures will group as coherent multivariate principal component (PC) ensembles, and that distinct PCs and individual variables will show discriminant validity for predicting early impairment in thoracic SCI. We undertook a retrospective cohort study of 25 patients with acute thoracic SCI who underwent MRI on admission and had American Spinal Injury Association Impairment Scale (AIS) assessment at hospital discharge. Imaging variables of axial grade, sagittal grade, length of injury, thoracolumbar injury classification system (TLICS), maximum canal compromise (MCC), and maximum spinal cord compression (MSCC) were collected. We performed an analytical workflow to detect multivariate PC patterns followed by explicit hypothesis testing to predict AIS at discharge. All imaging variables loaded positively on PC1 (64.3% of variance), which was highly related to AIS at discharge. MCC, MSCC, and TLICS also loaded positively on PC2 (22.7% of variance), while variables concerning cord signal abnormality loaded negatively on PC2. PC2 was highly related to the patient undergoing surgical decompression. Variables of signal abnormality were all negatively correlated with AIS at discharge with the highest level of correlation for axial grade as assessed with the Brain and Spinal Injury Center (BASIC) score. A multiple variable model identified BASIC as the only statistically significant predictor of AIS at discharge, signifying that BASIC best captured the variance in AIS within our study population. Our study provides evidence of convergent validity, construct validity, and clinical predictive validity for the sampled MRI measures of SCI when applied in acute thoracic and thoracolumbar SCI. PMID- 26414452 TI - A TMEM16F point mutation causes an absence of canine platelet TMEM16F and ineffective activation and death-induced phospholipid scrambling. AB - BACKGROUND: TMEM16F is an ion channel and calcium-dependent lipid scramblase that mediates phosphatidylserine (PS) exposure on the plasma membrane. Two disparate disease phenotypes are associated with TMEM16F loss-of-function mutations: a rare bleeding disorder (Scott syndrome) and skeletal malformations due to aberrant bone mineralization in a TMEM16F knockout mouse. We therefore undertook comparative studies of TMEM16F expression in canine Scott syndrome (CSS), an autosomal recessive platelet defect. OBJECTIVES: To define anoctamin proteins and scramblase response of CSS platelets and to determine whether TMEM16F is the CSS disease gene. METHODS: CSS TMEM16F cDNA and gene were sequenced and mutation detection was performed in CSS pedigrees. Platelet fractions from CSS dogs were isolated for proteomic and immunologic characterization of TMEM16F. Annexin V was used as a flow cytometric marker of induced platelet PS externalization. RESULTS: A TMEM16F splice site mutation segregated with the CSS trait and TMEM16F protein was undetectable in CSS platelet membranes; however, a second anoctamin, TMEM16K, was found. Proteomic analyses revealed a network of 32 proteins that differentially cosegregated with platelet plasma membrane TMEM16F. CSS platelets had profoundly impaired scramblase response to pharmacologic and physiologic agents that increase intraplatelet calcium and conditions that induce apoptotic and necrotic cell death. CONCLUSIONS: CSS platelets represent a TMEM16F-null mutant model that demonstrates a central role for TMEM16F in mediating platelet PS externalization in response to activating and death signals. Platelet TMEM16F may prove a novel drug target for modulating platelet procoagulant activity and extending platelet life span. PMID- 26414453 TI - Updated evidence on adjuvant treatments for gastric cancer. AB - Gastric cancer is one of the main causes of cancer-related deaths worldwide. Even when diagnosed as a localized disease and resected with the intent to cure, recurrences frequently arise due to undetected or invisible micrometastases. Importantly, several proposed multimodal strategies to eliminate micrometastases have met some clinical success. However, while pivotal Phase III clinical trials comparing adjuvant therapies with surgery alone have confirmed the overall benefit of adjunctive treatments in patients with locally advanced gastric cancer, further improvement in postoperative outcomes is required, particularly in stage III disease. This review presents the current status of multimodal treatment strategies, with a particular focus on unresolved issues, based on updated literature searches and analysis of clinical trial databases. PMID- 26414454 TI - Occult Radiographically Evident Port-Site Hernia After Robot-Assisted Urologic Surgery: Incidence and Risk Factors. AB - PURPOSE: Laparoscopic trocar-site hernias (TSH) are rare, with a reported incidence of 1% or less. The incidence of occult radiographically evident hernias has not been described after robot-assisted urologic surgery. We evaluated the incidence and risk factors of this problem. MATERIALS AND METHODS: A single institution retrospective review of robot-assisted urologic surgery was performed from April 2009 to December 2012. Patients with preoperative and postoperative CT were included for analysis. Imaging was reviewed by two radiologists and one urologist. RESULTS: One hundred four cases were identified, including 60 partial nephrectomy, 38 prostatectomy, and 6 cystectomy. Mean age was 58 years and mean body mass index (BMI) was 29 kg/m(2). The cohort was 77% male. Ten total hernias were identified by CT in 8 patients, 2 of which were clinically evident hernias. Excluding these two hernias, occult port-site hernias were identified radiographically in seven patients. Per-patient incidence of occult TSH was 6.7% (7/104), and per-port incidence was 1.4% (8/564). All hernias were midline and 30% contained bowel. Eight of the 10 occurred at 12 mm sites (p = 0.0065) and 3 of the 10 occurred at extended incisions. Age, gender, BMI, smoking status, diabetes mellitus, immunosuppressive drug therapy, ASA score, procedure, blood loss, prior abdominal surgery, and history of hernia were not significant risk factors. Specimen size >40 g (p = 0.024) and wound infection (p = 0.0052) were significant risk factors. CONCLUSION: While the incidence of clinically evident port-site hernia remains low in robot-assisted urologic surgery, the incidence of CT-detected occult hernia was 6.7% in this series. These occurred most often in sites extended for specimen extraction and at larger port sites. This suggests more attention should be paid to fascial closure at these sites. PMID- 26414455 TI - The Application of Sheet Technology in Cartilage Tissue Engineering. AB - Cartilage tissue engineering started to act as a promising, even essential alternative method in the process of cartilage repair and regeneration, considering adult avascular structure has very limited self-renewal capacity of cartilage tissue in adults and a bottle-neck existed in conventional surgical treatment methods. Recent progressions in tissue engineering realized the development of more feasible strategies to treat cartilage disorders. Of these strategies, cell sheet technology has shown great clinical potentials in the regenerative areas such as cornea and esophagus and is increasingly considered as a potential way to reconstruct cartilage tissues for its non-use of scaffolds and no destruction of matrix secreted by cultured cells. Acellular matrix sheet technologies utilized in cartilage tissue engineering, with a sandwich model, can ingeniously overcome the drawbacks that occurred in a conventional acellular block, where cells are often blocked from migrating because of the non-nanoporous structure. Electrospun-based sheets with nanostructures that mimic the natural cartilage matrix offer a level of control as well as manipulation and make them appealing and widely used in cartilage tissue engineering. In this review, we focus on the utilization of these novel and promising sheet technologies to construct cartilage tissues with practical and beneficial functions. PMID- 26414456 TI - Is there enough evidence with evolocumab and alirocumab (antibodies to proprotein convertase substilisin-kexin type, PCSK9) on cardiovascular outcomes to use them widely? Evaluation of Sabatine MS, Giugliano RP, Wiviott SD et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-1509, and Robinson JG, Farnier M, Krempf M et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1488-99. AB - INTRODUCTION: Statins alone often do not reduce LDL cholesterol levels sufficiently to given maximum cardiovascular benefit. Thus, additional drugs are required to reduce the levels of LDL cholesterol. Monoclonal antibodies to PCSK9 have recently been shown to decrease LDL cholesterol, but it is not known whether they improve cardiovascular outcomes. AREAS COVERED: We evaluated two clinical trials reporting cardiovascular outcomes with antibodies to PCSK9, the OSLER extension with evolocumab, and the ODYSSEY LONG TERM trial with alirocumab. EXPERT OPINION: In OSLER and ODYSSEY LONG TERM, there were very few cardiovascular outcomes, but the trials do suggest that evolocumab and alirocumab may reduce these outcomes. However, there are also some safety concerns with both of these antibodies. Large clinical outcome trials are underway with both evolocumab and alirocumab, which will probably clarify both the safety concerns and any cardiovascular benefits with these antibodies. In our opinion, these antibodies may be suitable for use in subjects with familial hypercholesterolemia, who are uncontrolled with their present medications, provided intensive safety and cardiovascular monitoring is being undertaken. However, evolocumab and alirocumab should be used with caution in other subjects, until outcome studies in higher numbers of subjects have shown acceptable safety and cardiovascular profiles. PMID- 26414457 TI - The A-B-C for SORting APP. AB - This Editorial highlights a study by Hermey and colleagues in the current issue of Journal of Neurochemistry. In their study, the authors provide novel insights into single-nucleotide polymorphisms associated with Alzheimer's disease and linked to the SorCS1 gene, toward a better understanding of the interaction of sorting receptor proteins which physically interact with the amyloid-beta protein precursor (APP). SorCS1, sortilin-related VPS10 domain-containing receptor 1; SorLA, sortilin-related Receptor with A-type Repeats. Read the full article 'SorCS1 variants and amyloid precursor protein (APP) are co-transported in neurons but only SorCS1c modulates anterograde APP transport' on page 60. PMID- 26414459 TI - Reframing Depression Treatment in Heart Failure. PMID- 26414460 TI - Work Outcome in Patients With Ankylosing Spondylitis: Results From a 12-Year Followup of an International Study. AB - OBJECTIVE: To understand the impact of ankylosing spondylitis (AS) on work disability (WD) over 12 years compared with the general population, and explore factors predicting adverse work outcome, defined as new partial WD or reduction in working hours. METHODS: Source of data was the Outcome Assessments in Ankylosing Spondylitis International Study, which includes patients from The Netherlands, France, and Belgium. Standardized WD rates over time compared to the general population were calculated using indirect standardization (Dutch patients only). Cox survival analyses identified baseline predictors as well as time varying factors influencing adverse work outcome over 12 years. RESULTS: Of 215 patients, 55 (26%) were full WD at baseline and 139 (65%) were at risk for adverse work outcome during followup. When compared to the general population, WD over 12 years continued to be increased in Dutch men (incidence rate [IR] 2.9 [95% confidence interval (95% CI) 1.2, 4.6]), but less clearly for women (IR 1.2 [95% CI -0.4, 2.9]). Within the entire sample, baseline predictors of adverse work outcome over 12 years were residence in The Netherlands (versus France or Belgium) (hazard ratio [HR] 3.4 [95% CI 1.4, 8.4]) and worse Bath Ankylosing Spondylitis Functional Index (BASFI) (HR 1.2 [95% CI 1.0, 1.4]). Time-varying predictors over 12 years were residence in The Netherlands, uveitis, and either BASFI or Bath Ankylosing Spondylitis Disease Activity Index with age and inflammatory bowel disease. CONCLUSION: Although WD was already prevalent at inclusion in the cohort, a substantial proportion of patients incurred further adverse work outcome over 12 years. In addition to country of residence, uveitis, age, and self-reported physical function or disease activity predicted long-term adverse work outcome. PMID- 26414461 TI - Advanced Companion Diagnostics Facilities: Opportunity Favors the Prepared Laboratory. PMID- 26414462 TI - Safety Assurance Factors for Electronic Health Record Resilience (SAFER) Guidelines. PMID- 26414463 TI - Reed-Sternberg-Like Cells in Non-Hodgkin Lymphomas. AB - Large atypical cells with morphologic and immunophenotypic features resembling Reed-Sternberg cells can be seen in the background of reactive lymphadenopathies as well as non-Hodgkin lymphomas. The presence of these cells is an important diagnostic pitfall that must be recognized by pathologists who regularly interpret lymph node biopsies. A thorough evaluation of the morphologic and immunophenotypic features of these cells and the cellular milieu is crucial in achieving the correct diagnosis. In this review, examples of lymphomas presenting with Reed-Sternberg-like cells will be provided. Additionally, a detailed description of the common morphologic and immunophenotypic features of these cells, as well as strategies that can be used to distinguish them from the Reed Sternberg cells of classical Hodgkin lymphoma, will be emphasized. PMID- 26414464 TI - Langerhans Cell Histiocytosis: A Clinicopathologic Review and Molecular Pathogenetic Update. AB - Langerhans cell histiocytosis (LCH) comprises a wide spectrum of clinical disorders that have in common a proliferation of Langerhans-type cells with characteristic morphologic, immunophenotypic, and ultrastructural features. In part because of the diverse clinical manifestations of LCH, there has long been controversy over whether LCH is best considered a reactive process or a neoplasm. Herein, we discuss the clinical and pathologic features of LCH, including recent advances in the understanding of the molecular pathogenesis of this disease that support its categorization as a neoplasm. We also review the implications that these recently described molecular characteristics may have on risk stratification and treatment of LCH. PMID- 26414465 TI - Acute Myeloid Leukemia Genetics: Risk Stratification and Implications for Therapy. AB - Acute myeloid leukemia is a category of diseases with a common aggressive clinical presentation but with a prognosis and management that is dependent upon the underlying genetic characteristics of the neoplasm. The purpose of this brief review is to update the practicing pathologist on the current standard of care in the genetic evaluation of acute myeloid leukemia and to highlight future directions in the classification, genetic assessment, and management of these devastating diseases. PMID- 26414466 TI - MiT Family Translocation-Associated Renal Cell Carcinoma: A Contemporary Update With Emphasis on Morphologic, Immunophenotypic, and Molecular Mimics. AB - Translocation-associated renal cell carcinoma (t-RCC) is a relatively uncommon subtype of renal cell carcinoma characterized by recurrent gene rearrangements involving the TFE3 or TFEB loci. TFE3 and TFEB are members of the microphthalmia transcription factor (MiT) family, which regulates differentiation in melanocytes and osteoclasts, and MiT family gene fusions activate unique molecular programs that can be detected immunohistochemically. Although the overall clinical behavior of t-RCC is variable, emerging molecular data suggest the possibility of targeted approaches to advanced disease. Thus, distinguishing t-RCC from its morphologic, immunophenotypic, and molecular mimics may have important clinical implications. The differential diagnosis for t-RCC includes a variety of common renal neoplasms, particularly those demonstrating clear cell and papillary features; in addition, because of immunophenotypic overlap and/or shared molecular abnormalities (ie, TFE3 gene rearrangement), a distinctive set of nonepithelial renal tumors may also warrant consideration. Directed ancillary testing is an essential aspect to the workup of t-RCC cases and may include a panel of immunohistochemical stains, such as PAX8, pancytokeratins, epithelial membrane antigen, carbonic anhydrase IX, HMB-45, and Melan-A. Dual-color, break apart fluorescent in situ hybridization for TFE3 or TFEB gene rearrangement may be helpful in diagnostically challenging cases or when molecular confirmation is needed. PMID- 26414467 TI - Intraductal Carcinoma of the Prostate: Morphologic Features, Differential Diagnoses, Significance, and Reporting Practices. AB - The differential diagnosis for atypical cribriform lesions of the prostate has become increasingly complex and includes intraductal carcinoma of the prostate, high-grade prostatic intraepithelial neoplasia, and atypical intraductal proliferations. In this review, we summarize the morphologic and molecular features and significance of intraductal carcinoma of the prostate. We also summarize our institution's strategy for reporting and treatment recommendations for intraductal carcinoma of the prostate. PMID- 26414468 TI - Olmesartan-Associated Enteropathy: A Review of Clinical and Histologic Findings. AB - Olmesartan is an antihypertensive medication belonging to the angiotensin II receptor blocker class of drugs that has recently been associated with severe enteropathy. Olmesartan-associated enteropathy is uncommon and may be difficult to recognize because of its clinical and histologic similarities to other clinical entities, including celiac sprue and autoimmune enteropathy. The purpose of this article is to review the clinical and histologic findings of olmesartan associated enteropathy that have been reported in the literature and to discuss clinical entities to consider in the differential diagnosis of olmesartan associated enteropathy. PMID- 26414469 TI - Metastases to the Pancreas Encountered on Endoscopic Ultrasound-Guided, Fine Needle Aspiration. AB - Metastatic lesions in the pancreas are very uncommon and may be difficult to differentiate from the more commonly encountered primary neoplasms derived from the exocrine and endocrine pancreas because of the significant overlap in clinical presentation, imaging, and cytologic features. Metastasis to the pancreas may occur years after treatment of the primary neoplasm and is often not considered on initial evaluation because of the rarity of such events. The possibility of a metastasis to the pancreas should be entertained in patients with any prior history of malignancy because a proper diagnosis is essential in identifying surgical candidates, or avoiding potentially unnecessary surgery and facilitating triage to more appropriate nonoperative therapy. Herein, we describe intrapancreatic metastases secondary to renal cell carcinoma, melanoma, and lung carcinoma, as documented by cytologic examination of endoscopic ultrasound-guided fine-needle aspiration of the pancreatic masses. PMID- 26414470 TI - Morphologic Mimics of Invasive Lobular Carcinoma. AB - Invasive lobular carcinoma of the breast is a relatively common diagnosis. However, other carcinomatous as well as noncarcinomatous neoplasms, either primary or metastatic to the breast, may mimic invasive lobular carcinoma. As treatment may differ, establishing the correct diagnosis is paramount to providing the appropriate care for these patients. This review outlines important mimics of invasive lobular carcinoma and the key clinicopathologic and immunohistochemical features as well as additional studies helpful in establishing their diagnoses. PMID- 26414471 TI - Pulmonary Apical Cap-What's Old Is New Again. AB - The pulmonary apical cap (PAC) is a morphologically distinct type of unilateral or bilateral fibroelastotic scar involving the lung apices. Despite being relatively common and having been described more than a hundred years ago, it remains underappreciated as a unique diagnostic entity by clinicians, radiologists, and pathologists alike. Given the centrality of modern chest imaging in the workup of diseases of the lungs, it may be expected that the PAC will be biopsied with increasing frequency. As such, pathologists should be familiar with its presentation, appearance, and differential diagnosis. This article serves as a short overview of PAC and as a practical aid in its diagnosis for surgical pathologists. PMID- 26414472 TI - Atypical Spitz Tumors: A Diagnostic Challenge. AB - Spitzoid melanocytic lesions encompass a spectrum from benign Spitz nevi to malignant spitzoid melanomas. Spitzoid melanocytic neoplasms have significant morphologic and molecular differences from conventional melanocytic lesions, and prediction of biologic behavior and metastatic risk may be difficult. Most challenging is the atypical Spitz tumor, a borderline spitzoid melanocytic lesion of uncertain malignant potential that has overlapping histologic features with conventional Spitz nevus and spitzoid melanoma. Atypical Spitz tumors involve the sentinel lymph nodes at a greater frequency than conventional melanoma and frequently harbor chromosomal copy number changes, yet most cases follow an indolent course. Herein we review the clinical, microscopic, and molecular features of atypical Spitz tumors, including recent molecular advances, including the potential prognostic significance of chromosomal abnormalities, such as homozygous CDKN2A loss. PMID- 26414473 TI - Assessing the Impact of Analytical Error on Perceived Disease Severity. AB - CONTEXT: The perception of the severity of disease from laboratory results assumes that the results are free of analytical error; however, analytical error creates a spread of results into a band and thus a range of perceived disease severity. OBJECTIVE: To assess the impact of analytical errors by calculating the change in perceived disease severity, represented by the hazard ratio, using non high-density lipoprotein (nonHDL) cholesterol as an example. DESIGN: We transformed nonHDL values into ranges using the assumed total allowable errors for total cholesterol (9%) and high-density lipoprotein cholesterol (13%). Using a previously determined relationship between the hazard ratio and nonHDL, we calculated a range of hazard ratios for specified nonHDL concentrations affected by analytical error. RESULTS: Analytical error, within allowable limits, created a band of values of nonHDL, with a width spanning 30 to 70 mg/dL (0.78-1.81 mmol/L), depending on the cholesterol and high-density lipoprotein cholesterol concentrations. Hazard ratios ranged from 1.0 to 2.9, a 16% to 50% error. Increased bias widens this range and decreased bias narrows it. CONCLUSIONS: Error-transformed results produce a spread of values that straddle the various cutoffs for nonHDL. The range of the hazard ratio obscures the meaning of results, because the spread of ratios at different cutoffs overlap. The magnitude of the perceived hazard ratio error exceeds that for the allowable analytical error, and significantly impacts the perceived cardiovascular disease risk. Evaluating the error in the perceived severity (eg, hazard ratio) provides a new way to assess the impact of analytical error. PMID- 26414474 TI - Underutilization of Meta-analysis in Diagnostic Pathology. AB - CONTEXT: Underutilization of Meta-analysis No studies to our knowledge have investigated citations and utilization of meta-analysis in diagnostic pathology (DP). OBJECTIVE: To characterize meta-analyses in DP compared with meta-analyses in medicine. DESIGN: We searched PubMed for meta-analyses in 12 major DP journals without specifying years and in 4 major medicine journals in both 2006 and 2011. We compared articles' adjusted citation ratios (ACRs), defined as an article's citation count divided by the mean citations for the meta-analysis, review, and original research articles published in the same journal in the same year. RESULTS: Forty-one of 76 DP articles, 74 of 125 medicine articles in 2011, and 52 of 83 medicine articles in 2006 were qualified meta-analyses as identified by PubMed. The ACRs of DP meta-analysis articles were higher than those of original research articles (2.62 +/- 2.31 versus 0.92 +/- 0.84, P < .001) and similar to those of review articles in 2006 (2.62 +/- 2.31 versus 1.95 +/- 1.59, P = .50), but they were similar to both in 2011 (1.85 +/- 1.39 versus 0.99 +/- 1.43, P = .11; 1.85 +/- 1.39 versus 1.12 +/- 1.43, P = .21, respectively). Diagnostic pathology and medicine meta-analyses had similar ACRs (1.85 +/- 1.39 versus 1.57 +/- 1.35 in 2011, P = .60; and 2.62 +/- 2.31 versus 1.85 +/- 1.90 in 2006, P = .50, respectively). However, although DP journals published fewer meta-analyses (0.97% versus 6.66% in 2011 and 0.67% versus 4.40% in 2006, P < .001 for both), they published more meta-analyses using both original and published data than medicine (21.95% versus 1.59%, P < .001). They also published more meta-analyses per year in 2011-2014 than in 2000-2010 (6.4 +/- 1.29 versus 1.36 +/- 1.03 articles per year, P < .001). CONCLUSIONS: We found underutilization of meta analyses in DP, despite their high ACRs and recently increased utilization. More DP meta-analyses are needed. PMID- 26414475 TI - Acute Promyelocytic Leukemia: A Review and Discussion of Variant Translocations. AB - The majority of patients with acute promyelocytic leukemia (APL) manifest the t(15;17)(q24.1;q21.2) translocation; however, a minor but significant proportion of patients with APL harbor complex, cryptic, or variant translocations, which typically involve RARA. With the exception of ZBTB16/RARA, these variants have similar morphologic and immunophenotypic features as classic APL. Study of the variant forms of APL not only gives insight into the pathogenesis of APL but also allows us to understand the mechanism of retinoid therapy. It is important to identify these cryptic and variant translocations because certain variants, including ZBTB16/RARA and STAT5B/RARA, are resistant to treatment with all-trans retinoic acid, arsenic trioxide, and anthracyclines. PMID- 26414478 TI - Cavum Septi Pellucidi in Symptomatic Former Professional Football Players. AB - Post-mortem studies reveal a high rate of cavum septi pellucidi (CSP) in chronic traumatic encephalopathy (CTE). It remains, however, to be determined whether or not the presence of CSP may be a potential in vivo imaging marker in populations at high risk to develop CTE. The aim of this study was to evaluate CSP in former professional American football players presenting with cognitive and behavioral symptoms compared with noncontact sports athletes. Seventy-two symptomatic former professional football players (mean age 54.53 years, standard deviation [SD] 7.97) as well as 14 former professional noncontact sports athletes (mean age 57.14 years, SD 7.35) underwent high-resolution structural 3T magnetic resonance imaging. Two raters independently evaluated the CSP, and interrater reliability was calculated. Within National Football League players, an association of CSP measures with cognitive and behavioral functioning was evaluated using a multivariate mixed effects model. The measurements of the two raters were highly correlated (CSP length: rho = 0.98; Intraclass Correlation Coefficient [ICC] 0.99; p < 0.0001; septum length: rho = 0.93; ICC 0.96; p < 0.0001). For presence versus absence of CSP, there was high agreement (Cohen kappa = 0.83, p < 0.0001). A higher rate of CSP, a greater length of CSP, as well as a greater ratio of CSP length to septum length was found in symptomatic former professional football players compared with athlete controls. In addition, a greater length of CSP was associated with decreased performance on a list learning task (Neuropsychological Assessment Battery List A Immediate Recall, p = 0.04) and decreased test scores on a measure of estimate verbal intelligence (Wide Range Achievement Test Fourth Edition Reading Test, p = 0.02). Given the high prevalence of CSP in neuropathologically confirmed CTE in addition to the results of this study, CSP may serve as a potential early in vivo imaging marker to identify those at high risk for CTE. Future research is needed to investigate the pathomechanism underlying the development of CSP after repetitive head impacts, and its potential association with neuropathologically confirmed CTE. PMID- 26414479 TI - Values in Elderly People for Exhaled Nitric Oxide Study. AB - Ageing population is constantly increasing due to rising life expectancy; consequently, the percentage of the elderly patients with asthma is increasing, as well. Fractional exhaled nitric oxide (FeNO) is a biomarker of lung inflammation, and currently it is widely used in clinical practice for asthma diagnosis and monitoring. Yet, there are no data about normal values of FeNO in patients of more than 65 years of age with normal lung function. The aim of this study was to establish adult FeNO reference values for subjects older than 65 years, according to the international guidelines. FeNO was measured in 303 healthy, nonsmoking adults more than 65 years of age, with normal spirometry values measured using the online single-breath technique. The results were analyzed by chemiluminescent detection. The FeNO levels obtained range from 5.00 to 29.9 ppb, with a mean value of 12.48 +/- 2.80 ppb. A significant association of FeNO levels with age (p < 0.05) was observed. There was no difference in FeNO values between men and women unlike what was observed in younger patients. FeNO levels in healthy controls over 65 years of age are influenced by age as in younger adults. However, there is no difference in FeNO values in male and female seniors, in contrast with what was found in younger adults in other studies. These data can be useful for the clinician to interpret the values of FeNO assessed during clinical practice. PMID- 26414480 TI - Generation, Characterization, and Multilineage Potency of Mesenchymal-Like Progenitors Derived from Equine Induced Pluripotent Stem Cells. AB - Multipotent mesenchymal stromal cells (MSCs) are more and more frequently used to treat orthopedic injuries in horses. However, these cells are limited in their expandability and differentiation capacity. Recently, the first equine-induced pluripotent stem cell (iPSC) lines were reported by us [ 1 ]. In vitro differentiation of iPSCs into MSC-like cells is an attractive alternative to using MSCs derived from other sources, as a much larger quantity of patient specific cells with broad differentiation potential could be generated. However, the differentiation capacity of iPSCs to MSCs and the potential for use in tissue engineering have yet to be explored. In this study, equine iPSCs were induced to differentiate into an MSC-like population. Upon induction, the iPSCs changed morphology toward spindle-shaped cells similar to MSCs. The ensuing iPSC-MSCs exhibited downregulation of pluripotency-associated genes and an upregulation of MSC-associated genes. In addition, the cells expressed the same surface markers as MSCs derived from equine umbilical cord blood. We then assessed the multilineage differentiation potential of iPSC-MSCs. Although chondrogenesis was not achieved after induction with transforming growth factor-beta 3 (TGFbeta3) and/or bone morphogenic protein 4 (BMP-4) in 3D pellet culture, mineralization characteristic of osteogenesis and lipid droplet accumulation characteristic of adipogenesis were observed after chemical induction. We demonstrate a protocol for the derivation of MSC-like progenitor populations from equine iPS cells. PMID- 26414481 TI - Did the 2009 American Recovery and Reinvestment Act affect dietary intake of low income individuals? AB - This paper examines the relationship between increased Supplemental Nutritional Assistance Program (SNAP) benefits following the 2009 American Recovery and Reinvestment Act (ARRA) and the diet quality of individuals from SNAP-eligible compared to ineligible (those with somewhat higher income) households using data from the 2007-2010 National Health and Nutrition Examination Survey. The ARRA increased SNAP monthly benefits by 13.6% of the maximum allotment for a given household size, equivalent to an increase of $24 to $144 for one-to-eight person households respectively. In the full sample, we find that these increases in SNAP benefits are not associated with changes in nutrient intake and diet quality. However, among those with no more than a high school education, higher SNAP benefits are associated with a 46% increase in the mean caloric share from sugar sweetened beverages (SSBs) and a decrease in overall diet quality especially for those at the lower end of the diet quality distribution, amounting to a 9% decline at the 25th percentile. PMID- 26414482 TI - Effects of a diet containing genetically modified rice expressing the Cry1Ab/1Ac protein (Bacillus thuringiensis toxin) on broiler chickens. AB - The aim of this study was to evaluate the effect of feeding Bacillus thuringiensis (Bt) rice expressing the Cry1Ab/1Ac protein on broiler chicken. The genetically modified (GM) Bt rice was compared with the corresponding non-GM rice regarding performance of feeding groups, their health status, relative organ weights, biochemical serum parameters and occurrence of Cry1Ab/1Ac gene fragments. One hundred and eighty day-old Arbor Acres female broilers with the same health condition were randomly allocated to the two treatments (6 replicate cages with 15 broilers in each cage per treatment). They received diets containing GM rice (GM group) or its parental non-GM rice (non-GM group) at 52 57% of the air-dried diet for 42 days. The results show that the transgenic rice had a similar nutrient composition as the non-GM rice and had no adverse effects on chicken growth, biochemical serum parameters and necropsy during the 42-day feeding period. In birds fed the GM rice, no transgenic gene fragments were detected in the samples of blood, liver, kidneys, spleen, jejunum, ileum, duodenum and muscle tissue. In conclusion, the results suggest that Bt rice expressing Cry1Ab/1Ac protein has no adverse effects on broiler chicken. Therefore, it can be considered as safe and used as feed source for broiler chicken. PMID- 26414483 TI - Bandgap Tunability in Sb-Alloyed BiVO4 Quaternary Oxides as Visible Light Absorbers for Solar Fuel Applications. AB - The challenge of fine compositional tuning and microstructure control in complex oxides is overcome by developing a general two-step synthetic approach. Antimony alloyed bismuth vanadate, which is identified as a novel light absorber for solar fuel applications, is prepared in a wide compositional range. The bandgap of this quaternary oxide linearly decreases with the Sb content, in agreement with first principles calculations. PMID- 26414484 TI - Chronic Obstructive Pulmonary Disease and the Risk of Stroke. The Rotterdam Study. AB - RATIONALE: Worldwide, chronic obstructive pulmonary disease (COPD) and stroke are leading causes of death. Increasing evidence suggests an association between both diseases, either caused by an increased atherosclerosis risk in patients with COPD or as a consequence of shared risk factors between stroke and COPD. OBJECTIVES: To examine the associations between COPD and subtypes of stroke in the general population and to explore the role of cardiovascular risk factors and exacerbations on these associations. METHODS: Within the prospective population based Rotterdam Study, we followed 13,115 participants without history of stroke for occurrence of stroke. Follow up started in 1990 to 2008 and ended in 2012. COPD was related to stroke using a time-dependent Cox proportional hazard model. MEASUREMENTS AND MAIN RESULTS: COPD was diagnosed in 1,566 participants. During 126,347 person-years, 1,250 participants suffered a stroke, of which 701 were ischemic and 107 hemorrhagic. Adjusted for age, age squared, and sex, COPD was significantly associated with all stroke (hazard ratio [HR], 1.20; 95% confidence interval, 1.00-1.43), ischemic stroke (HR, 1.27; 1.02-1.59), and hemorrhagic stroke (HR, 1.70; 1.01-2.84). Adjusting for cardiovascular risk factors gave similar effect sizes. In contrast, additional adjusting for smoking attenuated the effect sizes: HR, 1.09 (0.91-1.31) for all stroke; HR, 1.13 (0.91-1.42) for ischemic stroke; and HR 1.53 (0.91-2.59) for hemorrhagic stroke. After an acute severe exacerbation, subjects with COPD had a 6.66-fold (2.42-18.20) increased risk of stroke. CONCLUSIONS: Our cohort study demonstrated a higher risk of both ischemic and hemorrhagic stroke in subjects with COPD and revealed the importance of smoking as a shared risk factor. PMID- 26414485 TI - Short Communication: Immune Activation Is Present in HIV-1-Exposed Seronegative Individuals and Is Independent of Microbial Translocation. AB - Analyses of immune activation in HIV-exposed seronegative individuals (HESN) yielded discrepant results. To clarify this issue we performed an extensive investigation of immune parameters in HESN and, in particular, we analyzed in these individuals the possible presence of microbial translocation, the most widely accepted reason driving immune activation in HIV-infected patients. Results showed that immune activation, a skewing of T lymphocyte maturation, and increased responsiveness to lipopolysaccharide (LPS) characterize the HESN phenotype; this is not driven by alterations of the gastrointestinal barrier and microbial translocation. The activation state seen in HESN may influence the induction of stronger adaptive antiviral immune responses and may represent a virus exposure-induced innate immune protective phenotype against HIV. PMID- 26414486 TI - Do consumer voices in health-care citizens' juries matter? AB - BACKGROUND: There is widespread agreement that the public should be engaged in health-care decision making. One method of engagement that is gaining prominence is the citizens' jury, which places citizens at the centre of the deliberative process. However, little is known about how the jury process works in a health care context. There is even less clarity about how consumer perspectives are heard within citizens' juries and with what consequences. OBJECTIVES: This paper focuses on what is known about the role of consumer voices within health-care citizens' juries, how these voices are heard by jurors and whether and in what ways the inclusion or exclusion of such voices may matter. RESULTS: Consumer voices are not always included in health-care citizens' juries. There is a dearth of research on the conditions under which consumer voices emerge (or not), from which sources and why. As a result, little is known about what stories are voiced or silenced, and how such stories are heard by jurors, with what consequences for jurors, deliberation, decision-makers, policy and practice. DISCUSSION AND CONCLUSION: The potential role of consumer voices in influencing deliberations and recommendations of citizens' juries requires greater attention. Much needed knowledge about the nuances of deliberative processes will contribute to an assessment of the usefulness of citizens' juries as a public engagement mechanism. PMID- 26414487 TI - Multifetal gestations with assisted reproductive technique before the single embryo transfer legislation: obstetric, neonatal outcomes and congenital anomalies. AB - OBJECTIVE: To compare perinatal, neonatal outcome and congenital anomalies of multiple gestations conceived by means of assisted reproductive techniques with spontaneously conceived multiples before the limitation of number of embryo transfer. METHODS: Cases consisted of assisted reproductive technique (ART) multifetal gestations and control group comprised of spontaneously conceived multifetal gestations delivered in the same time period. Outcomes were perinatal, neonatal outcome, long-term outcomes and congenital anomalies of multiple gestations. There were 270 multifetal pregnancies for analysis, of which 137 were achieved by ART and 133 were spontaneous in this prospective study. RESULTS: Incidences of preeclampsia, gestational diabetes, deep vein thrombosis, thrombocytopenia, intrahepatic cholestasis and preterm premature rupture of membranes were similar in ART and spontaneous groups. There was no difference in fetal malformation rates between ART and control group, but higher rates of central nervous system malformation were observed (4 (1.5%) in control, 0 in ART group, p = 0.04) in spontaneous group. No difference was seen in the perinatal mortality. CONCLUSIONS: Neonatal and maternal outcomes are comparable between ART and spontaneous multifetal gestations. Congenital fetal malformation rates between ART and spontaneous multifetal pregnancies were similar except central nervous system malformation that was more likely in spontaneously conceived ones. PMID- 26414488 TI - Spiritual peace predicts 5-year mortality in congestive heart failure patients. AB - OBJECTIVE: Spirituality is favorably related to depression, quality of life, hospitalizations, and other important outcomes in congestive heart failure (CHF) patients but has not been examined as a predictor of mortality risk in this population. Given the well-known difficulties in managing CHF, we hypothesized that spirituality would be associated with lower mortality risk, controlling for baseline demographics, functional status, health behaviors, and religiousness. METHOD: Participants were 191 CHF patients (64% male; M age = 68.6 years, SD = 10.1) who completed a baseline survey and were then followed for 5 years. RESULTS: Nearly 1/3 of the sample (32%) died during the study period. Controlling for demographics and health status, smoking more than doubled the risk of mortality, whereas alcohol consumption was associated with slightly lower risk of mortality. Importantly, adherence to healthy lifestyle recommendations was associated with halved mortality risk. Although both religion and spirituality were associated with better health behaviors at baseline in bivariate analyses, a proportional hazard model showed that only spirituality was significantly associated with reduced mortality risk (by 20%), controlling for demographics, health status, and health behaviors. CONCLUSIONS: Experiencing spiritual peace, along with adherence to a healthy lifestyle, were better predictors of mortality risk in this sample of CHF patients than were physical health indicators such as functional status and comorbidity. Future research might profitably examine the efficacy of attending to spiritual issues along with standard lifestyle interventions. PMID- 26414489 TI - Brief Report: Association of Inflammation With Development of Erosions in Patients With Hand Osteoarthritis: A Prospective Ultrasonography Study. AB - OBJECTIVE: To investigate the association between features of ultrasound-detected inflammation and development of erosive disease in patients with hand osteoarthritis (OA) over 2.3 years of followup. METHODS: The study group comprised 56 consecutive patients with hand OA (mean age 61 years, 86% female) fulfilling the American College of Rheumatology criteria. Effusion, synovial thickening, and power Doppler signal in all interphalangeal (IP) joints were assessed with ultrasonography, using standardized methods, at baseline and followup. Radiographs were scored at both time points for osteophytes/joint space narrowing using the Osteoarthritis Research Society International method and for erosive disease (E phase [erosive] and R phase [remodeling]) using the method described by Verbruggen and Veys. Erosion development was defined as progression from N phase (normal) to E phase or R phase. Joints that were in E phase or R phase at baseline were excluded. Associations were analyzed using generalized estimating equations with adjustment for age, sex, body mass index, and baseline structural abnormalities. RESULTS: At baseline, 51 IP joints (in 18 patients) and at followup 89 IP joints (in 26 patients) had erosions; thus, erosions developed in 38 IP joints. Moderate/severe synovial thickening and a power Doppler signal at baseline were associated with erosion development (adjusted odds ratio [OR] 8.8, 95% confidence interval [95% CI] 2.4-32.3 and OR 7.1, 95% CI 1.9-26.9, respectively). Persistent inflammation was particularly associated with the development of erosions. CONCLUSION: Ultrasound-detected features of inflammation are associated with the development of erosions in patients with hand OA, suggesting that inflammation plays a role in the pathogenesis of hand OA and could be a therapeutic target. PMID- 26414491 TI - The New Sexual Medicine-Integrating Pharmacotherapy, Sexual Therapy and Surgery and the 4th International Consultation on Sexual Medicine. PMID- 26414490 TI - Functional characterization of Ostreococcus tauri phototropin. AB - Phototropins (phots) regulate a range of adaptive processes in plants that serve to optimize photosynthetic efficiency and promote growth. Light sensing by Arabidopsis thaliana phots is predominantly mediated by the Light, Oxygen and Voltage sensing 2 (LOV2) flavin-binding motif located within the N-terminus of the photoreceptor. Here we characterize the photochemical and biochemical properties of phot from the marine picoalga Ostreococcus tauri phototropin (Otphot) and examine its ability to replace phot-mediated function in Arabidopsis. Photochemical properties of Otphot rely on both LOV1 and LOV2. Yet, biochemical analysis indicates that light-dependent receptor autophosphorylation is primarily dependent on LOV2. As found for Arabidopsis phots, Otphot associates with the plasma membrane and partially internalizes, albeit to a limited extent, in response to blue-light irradiation. Otphot is able to elicit a number of phot regulated processes in Arabidopsis, including petiole positioning, leaf expansion, stomatal opening and chloroplast accumulation movement. However, Otphot is unable to restore phototropism and chloroplast avoidance movement. Consistent with its lack of phototropic function in Arabidopsis, Otphot does not associate with or trigger dephosphorylation of the phototropic signalling component Non-Phototropic Hypocotyl 3 (NPH3). Taken together, these findings indicate that the mechanism of action of plant and evolutionarily distant algal phots is less well conserved than previously thought. PMID- 26414492 TI - Rituximab with high-dose methotrexate in primary central nervous system lymphoma. AB - The addition of rituximab (R) to chemotherapy improves outcomes in patients with systemic B-cell non-Hodgkin lymphomas, but the impact in patients with primary central nervous system lymphoma (PCNSL) receiving high-dose methotrexate (HDMTX) is unknown. Patients diagnosed with PCNSL at the British Columbia Cancer Agency (BCCA) between 2000 and 2013 were treated with >=1 cycle of HDMTX 8 g/m(2) every 2 weeks, to best response or 10 cycles. After 2006, rituximab 375 mg/m(2) was given every 2 weeks with HDMTX for a total of 4 doses. 49 (66%) patients received HDMTX alone and 25 (34%) HDMTX+R, with a median of 5 (range 1-10) HDMTX cycles, and no difference between groups. The median follow-up was 5 years: 8.8 years (range 3.15-13.5 years) HDMTX and 1.9 years (range 0.5-7 years) HDMTX+R. The 5 year PFS was 17%, with no difference between groups (HR: 0.75, 95% CI: 0.41-1.35; P = 0.33). The 5-year OS was 38%, with no difference between the groups OS (HR: 0.73, 95% CI: 0.35-1.52; P = 0.39). In this retrospective study comparing two subgroups of patients treated in different eras, the addition of R to HDMTX did not appear to improve outcomes in PCNSL, possibly consistent with its known poor CNS penetration. It is possible that with a larger sample size, longer follow-up, or different rituximab dosing/schedule, the addition of rituximab may lead to a statistically significant improvement in outcomes. Prospective randomized trials currently in progress will more definitively estimate the impact of the addition of rituximab to HDMTX-based chemotherapy for PCNSL. PMID- 26414493 TI - Dietary exposure to aluminium from wheat flour and puffed products of residents in Shanghai, China. AB - A dietary survey of 3431 residents was conducted by a 24-h dietary recall method in Shanghai, China, quarterly from September 2013 to September 2014. A total of 400 food samples were tested for aluminium concentration, including wheat flour and puffed products from 2011 to 2013. Probabilistic analysis was used to estimate the dietary exposure to aluminium from wheat and puffed products. The means of dietary aluminium exposure for children (2-6 years old), juveniles (7-17 years old), adults (18-65 years old) and seniors (over 65 years old) were 1.88, 0.94, 0.44 and 0.42 mg kg(-1) body weight (bw) week(-1) respectively, with a population average of 0.51 mg kg(-1) bw week(-1). The proportions of those who had aluminium exposure from wheat and puffed products lower than the provisional tolerable weekly intake (PTWI) were 77%, 90%, 97%, and 97% respectively from children to seniors. We estimated that the proportions of people at risk would decrease by 13%, 6%, 2% and 2% respectively under the new China National Standards - GB 2760-2014 National Food Safety for Standards for using food additives. The results indicated that aluminium from wheat flour and puffed products is unlikely to cause adverse health effects in the general population in Shanghai; however, children were at a higher risk of excess aluminium exposure. Significant improvements in reducing the dietary exposure to aluminium are expected in the population, especially for children after the implementation of GB 2760-2014. PMID- 26414494 TI - Current surgical strategies to treat fecal incontinence. AB - Fecal incontinence is a devastating condition, vastly under-reported, and may affect up to 18% of the population. While conservative management may be efficacious in a large portion of patients, those who are refractory will likely benefit from appropriate surgical intervention. There are a wide variety of surgical approaches to fecal incontinence management, and knowledge and experience are crucial to choosing the appropriate procedure and maximizing functional outcome while minimizing risk. In this article, we provide a comprehensive description of surgical options for fecal incontinence to help the clinician identify an appropriate intervention. PMID- 26414495 TI - Curcuminoids Modulate the PKCdelta/NADPH Oxidase/Reactive Oxygen Species Signaling Pathway and Suppress Matrix Invasion during Monocyte-Macrophage Differentiation. AB - Monocyte recruitment and invasion play critical roles in the initiation and progression of atherosclerosis. The reduction in monocyte adhesion and infiltration is thought to exert antiatherosclerotic effects. Curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) are the major active components of curcuminoids and exhibit several biological activities, including anti-inflammatory, anticarcinogenic, and hypocholesterolemic activities. The aim of this study was to investigate the antiatherogenic effects and mechanisms of curcuminoids during monocyte to macrophage differentiation. The results showed that curcumin, DMC, and BDMC (20 MUM) suppressed matrix invasion from 100.0 +/- 5.0% to 24.8 +/- 1.4%, 26.6 +/- 2.9%, and 33.7 +/- 1.7%, respectively, during PMA induced THP-1 differentiation. We found that curcuminoids significantly reduced PMA-induced CD11b and MMP-9 expression by THP-1 cells. Production of reactive oxygen species (ROS) induced by PMA (126.7 +/- 2.1%) was markedly attenuated by curcumin, DMC, and BDMC to 99.5 +/- 7.8%, 87.8 +/- 8.2%, and 89.8 +/- 7.6%, respectively, resulting in the down-regulation of CD11b and MMP-9 expression. We demonstrated that curcuminoids inhibited NADPH oxidase through the down regulation of NOX2 expression and the reduction of p47phox membrane translocation. Moreover, we found involvement of PKCdelta in the PMA-induced NOX2, CD11b, and MMP-9 mRNA expression. Curcumin, DMC, and BDMC decreased the active form of PKCdelta protein stimulated by PMA in THP-1 cells. Overall, our results reveal that curcuminoids suppress matrix invasion through the inhibition of the PKCdelta/NADPH oxidase/ROS signaling pathway during monocyte-macrophage differentiation. PMID- 26414496 TI - Long-Term Abnormalities in the Corpus Callosum of Female Concussed Athletes. AB - Concussion is an injury affecting millions of individuals annually that can be associated with long-term sequelae. Recent studies have reported long-term abnormalities in the white matter (WM) tracts of male athletes. The corpus callosum (CC) and corticospinal tract (CST) have been shown to be particularly vulnerable to concussion, which may be related to abnormal interhemispheric functional connectivity and motor impairments. These anatomical pathways, however, have not been investigated in female athletes despite the functional significance of the CC and CST to adequate sports performance. In the present study, 8 healthy, unconcussed female athletes (soccer, hockey) were compared with 10 female athletes (soccer, hockey, water polo) 6 months post-concussion. Diffusion tensor imaging (DTI) of the CC and CST was conducted in a 3T magnetic resonance imaging (MRI) scanner. DTI analysis showed no significant differences between groups within the CST but revealed differences between groups in the CC. The concussed group had lower mean diffusivity (t = 2.14; p = 0.048) and lower radial diffusivity (t = 2.91; p = 0.010) in the region of the CC projecting to the prefrontal cortex. A lower volume of WM fibers was found in the region projecting to the premotor and supplementary motor areas (t = 2.14; p = 0.048). Finally, lower axial diffusivity (AD) was observed in the CC area projecting mainly to the parietal and temporal area (t = 2.23; p = 0.041). Long-term alterations in the CC of female athletes appear to affect mostly the anterior part of the CC projecting to the prefrontal and premotor areas. Further studies are needed to determine whether these alterations are associated with a higher risk of sustaining a subsequent concussive injury. PMID- 26414497 TI - Clinical neuroscience of addiction: similarities and differences between alcohol and other drugs. AB - BACKGROUND: Existing pharmacological treatments for alcohol use disorder (AUD) and other substance use disorders (SUDs) have demonstrated only modest efficacy. Although the field has recently emphasized testing and developing new compounds to treat SUDs, there are numerous challenges inherent to the development of novel medications, and this is particularly true for SUDs. Thus, research to date has tended toward the "repurposing" approach, in which medications developed to treat other mental or physical conditions are tested as SUD treatments. Often, potential treatments are examined across numerous drugs of abuse. Several repurposed medications have shown promise in treating a specific SUD, but few have shown efficacy across multiple SUDs. Examining similarities and differences between AUD and other SUDs may shed light on these findings and offer directions for future research. METHODS: This qualitative review discusses similarities and differences in neural circuitry and molecular mechanism(s) across alcohol and other substances of abuse, and examines studies of pharmacotherapies for AUD and other SUDs. RESULTS: Substances of abuse share numerous molecular targets and involve much of the same neural circuitry, yet compounds tested because they putatively target common mechanisms have rarely indicated therapeutic promise for multiple SUDs. CONCLUSIONS: The lack of treatment efficacy across SUDs may be partially explained by limitations inherent in studying substance users, who comprise a highly heterogeneous population. Alternatively, medications may fail to show efficacy across multiple SUDs due to the fact that the differences between drug mechanisms are more important than their commonalities in terms of influencing treatment response. We suggest that exploring these differences could support novel treatment development, aid in identifying existing medications that may hold promise as treatments for specific SUDs, and ultimately advance translational research efforts. PMID- 26414499 TI - Association between Initial Fluid Choice and Subsequent In-hospital Mortality during the Resuscitation of Adults with Septic Shock. AB - BACKGROUND: Currently, guidelines recommend initial resuscitation with intravenous (IV) crystalloids during severe sepsis/septic shock. Albumin is suggested as an alternative. However, fluid mixtures are often used in practice, and it is unclear whether the specific mixture of IV fluids used impacts outcomes. The objective of this study is to test the hypothesis that the specific mixture of IV fluids used during initial resuscitation, in severe sepsis, is associated with important in-hospital outcomes. METHODS: Retrospective cohort study includes patients with severe sepsis who were resuscitated with at least 2 l of crystalloids and vasopressors by hospital day 2, patients who had not undergone any major surgical procedures, and patients who had a hospital length of stay (LOS) of at least 2 days. Inverse probability weighting, propensity score matching, and hierarchical regression methods were used for risk adjustment. Patients were grouped into four exposure categories: recipients of isotonic saline alone ("Sal" exclusively), saline in combination with balanced crystalloids ("Sal + Bal"), saline in combination with colloids ("Sal + Col"), or saline in combination with balanced crystalloids and colloids ("Sal + Bal + Col"). In-hospital mortality was the primary outcome, and hospital LOS and costs per day (among survivors) were secondary outcomes. RESULTS: In risk-adjusted Inverse Probability Weighting analyses including 60,734 adults admitted to 360 intensive care units across the United States between January 2006 and December 2010, in-hospital mortality was intermediate in the Sal group (20.2%), lower in the Sal + Bal group (17.7%, P < 0.001), higher in the Sal + Col group (24.2%, P < 0.001), and similar in the Sal + Bal + Col group (19.2%, P = 0.401). In pairwise propensity score-matched comparisons, the administration of balanced crystalloids by hospital day 2 was consistently associated with lower mortality, whether colloids were used (relative risk, 0.84; 95% CI, 0.76 to 0.92) or not (relative risk, 0.79; 95% CI, 0.70 to 0.89). The association between colloid use and in hospital mortality was inconsistent, and survival was not uniformly affected, whereas LOS and costs per day were uniformly increased. Results were robust in sensitivity analyses. CONCLUSIONS: During the initial resuscitation of adults with severe sepsis/septic shock, the types of IV fluids used may impact in hospital mortality. When compared with the administration of isotonic saline exclusively during resuscitation, the coadministration of balanced crystalloids is associated with lower in-hospital mortality and no difference in LOS or costs per day. When colloids are coadministered, LOS and costs per day are increased without improved survival. A large randomized controlled trial evaluating crystalloid choice is warranted. Meanwhile, the use of balanced crystalloids seems reasonable. (Anesthesiology 2015; 123:1385-93). PMID- 26414500 TI - Prothrombin Complex Concentrate Is Effective in Treating the Anticoagulant Effects of Dabigatran in a Porcine Polytrauma Model. AB - BACKGROUND: In the event of trauma, emergency reversal of anticoagulation therapy may be required. However, no specific reversal agents are routinely available for the direct oral anticoagulants such as dabigatran. The authors investigated four factor prothrombin complex concentrate (PCC) for treating dabigatran-induced anticoagulation in a porcine polytrauma model. METHODS: Dabigatran etexilate was given orally for 3 days and intravenously on day 4 to 32 pigs. Animals were randomized 1:1:1:1 to PCC (25, 50, or 100 U/kg) or saline. Study medication was administered 12 min after bilateral femur fractures and blunt liver injury. The primary endpoint was blood loss at 300 min. RESULTS: The mean plasma concentration of dabigatran was 487 +/- 161 ng/ml after intravenous administration. Blood loss was 3,855 +/- 258 ml in controls and 3,588 +/- 241 ml in the PCC25 group. In the PCC50 and PCC100 groups, blood loss was significantly lower: 1,749 +/- 47 ml and 1,692 +/- 97 ml, respectively. PCC50 and PCC100 effectively reduced dabigatran's effects on coagulation parameters, whereas control and (to a lesser extent) PCC25 animals developed severe coagulopathy. Sustained increases in endogenous thrombin potential occurred with PCC50 and PCC100. CONCLUSION: Four-factor PCC (50 or 100 U/kg) is effective in reducing blood loss in dabigatran-anticoagulated pigs, but higher doses may induce a procoagulant state. PMID- 26414498 TI - Neuropsychological, Metabolic, and GABAA Receptor Studies in Subjects with Repetitive Traumatic Brain Injury. AB - Repetitive traumatic brain injury (rTBI) occurs as a result of mild and accumulative brain damage. A prototype of rTBI is chronic traumatic encephalopathy (CTE), which is a degenerative disease that occurs in patients with histories of multiple concussions or head injuries. Boxers have been the most commonly studied patient group because they may experience thousands of subconcussive hits over the course of a career. This study examined the consequences of rTBI with structural brain imaging and biomolecular imaging and investigated whether the neuropsychological features of rTBI were related to the findings of the imaging studies. Five retired professional boxers (mean age, 46.8 +/- 3.19 years) and four age-matched controls (mean age, 48.5 +/- 3.32 years) were studied. Cognitive-motor related functional impairment was assessed, and all subjects underwent neuropsychological evaluation and behavioral tasks, as well as structural brain imaging and functional-molecular imaging. In neuropsychological tests, boxers showed deficits in delayed retrieval of visuospatial memory and motor coordination, which had a meaningful relationship with biomolecular imaging results indicative of neuronal injury. Morphometric abnormalities were not found in professional boxers by structural magnetic resonance imaging (MRI). Glucose metabolism was impaired in frontal areas associated with cognitive dysfunction, similar to findings in Alzheimer's disease. Low binding potential (BP) of (18)F flumazenil (FMZ) was found in the angular gyrus and temporal cortical regions, revealing neuronal deficits. These results suggested that cognitive impairment and motor dysfunction reflect chronic damage to neurons in professional boxers with rTBI. PMID- 26414501 TI - Structure and phase behaviour of diblock copolymer monolayers investigated by means of Monte Carlo simulation. AB - We use grand canonical Monte Carlo simulation paired with multiple histogram reweighting, hyperparallel tempering and finite size scaling to investigate the structure and phase behaviour of monolayers of diblock copolymers. The chain molecules are arranged on the square lattice and we consider both fully flexible and rod-coil polymer models. In contrast to the majority of previous studies we assume that the interactions between the segments belonging to one of the two subunits are weaker than the remaining segment-segment interactions. We find that when the diblock copolymer is fully flexible, this choice of the interactions leads to a suppression of the ordered phase, and the phase behaviour is analogous to that of the fully flexible homopolymer model. However, when one of the subunits is rigid, we observe the formation of a novel hairpin chessboard ordered structure with fully stretched chains bent in the middle. The topology of the phase diagram depends on the chain length. For shorter chains the global phase diagram features a critical point and a triple point. For longer chains the gas disordered liquid phase transition is suppressed and only the order-disorder transition remains stable. The resulting phase diagram is of the swan neck type. PMID- 26414503 TI - Application of the "Fat-but-Fit" paradigm in predicting 10-yr risk for an atherosclerotic cardiovascular disease (ASCVD) event using the pooled cohort risk equations among US adults. PMID- 26414502 TI - Improving natural killer cell cancer immunotherapy. AB - PURPOSE OF REVIEW: Natural killer (NK) cells are innate lymphoid cells specialized to eliminate malignant cells via direct cytotoxicity and immunoregulatory cytokine production. As such, NK cells are ideal as cellular therapy for cancer patients, and several studies have provided proof of principle that adoptively transferred NK cells can induce remissions in patients with leukemia. A clear understanding of the mechanisms underlying NK cell antitumor responses, including target cell recognition, activation status, and negative regulatory signals will improve NK cellular therapy for cancer patients. RECENT FINDINGS: Clinical studies have demonstrated the safety and preliminary efficacy of NK cell adoptive transfer, especially in hematologic malignancies. Various NK cell sources, isolation techniques, activation approaches, and ex-vivo expansion strategies are under investigation. New approaches have been developed and are being tested to optimize NK cell therapy, including ways to better target NK cells to malignant cells, increase their functional competence, facilitate expansion in patients, and limit inhibitory signals or cells. SUMMARY: NK cells represent a promising cellular immunotherapy for the treatment of cancer. In addition to adoptive cellular therapy, adjunct treatments that optimize NK cell targeting and function will enhance their potency and broaden their potential use to many cancer types. PMID- 26414504 TI - Relationships of electrocardiographic parameters with ambulatory hypertension in young and healthy adults. AB - BACKGROUND: Elevated blood pressure (BP) is a leading cardiovascular risk factor and a major determinant of left ventricular mass. Te aim of this study was to assess electrocardiographic (ECG) changes associated with hypertension in a large cohort of young and healthy adults. METHODS: Healthy individuals aged 25-41 years without known cardiovascular disease were enrolled in a population based cohort study. Resting 12-lead ECG and ambulatory 24-hour BP measurement were obtained using validated devices. Multivariable logistic regression models were constructed to assess the relationships between ECG parameters and daytime hypertension, defined as systolic daytime BP>=140, diastolic BP>=90 mmHg or use of antihypertensive treatment. RESULTS: Daytime hypertension was present among 430 of 2070 (21%) participants. Significant linear relationships were observed between daytime hypertension with RR interval (odds ratio (OR) 95% confidence interval (CI) 0.84 (0.78; 0.92)), R-wave amplitude in leads I and II (OR (95% CI) 2.04 (1.30; 3.19) and 1.61 (1.15; 2.24), and S-wave amplitudes in leads aVR, V1 and V2 with ORs (95% CI) of 3.28 (1.93; 5.59), 2.15 (1.51; 3.08) and 1.47 (1.18; 1.83), respectively. We also observed linear associations between daytime hypertension and T-wave amplitudes in leads V1 (OR (95% CI) 4.83 (2.35; 9.91)), V2 (2.18 (1.43; 3.32)), V4 (0.48 (0.29; 0.80)) and V5 (0.37 (0.19; 0.72)). CONCLUSION: Several ECG parameters are independently associated with daytime hypertension among young and healthy adults. This is one of the first studies to show significant relationships between T wave amplitude and hypertension. PMID- 26414505 TI - Organ Dose-Rate Calculations for Small Mammals at Maralinga, the Nevada Test Site, Hanford and Fukushima: A Comparison of Ellipsoidal and Voxelized Dosimetric Methodologies. AB - Radiological dosimetry for nonhuman biota typically relies on calculations that utilize the Monte Carlo simulations of simple, ellipsoidal geometries with internal radioactivity distributed homogeneously throughout. In this manner it is quick and easy to estimate whole-body dose rates to biota. Voxel models are detailed anatomical phantoms that were first used for calculating radiation dose to humans, which are now being extended to nonhuman biota dose calculations. However, if simple ellipsoidal models provide conservative dose-rate estimates, then the additional labor involved in creating voxel models may be unnecessary for most scenarios. Here we show that the ellipsoidal method provides conservative estimates of organ dose rates to small mammals. Organ dose rates were calculated for environmental source terms from Maralinga, the Nevada Test Site, Hanford and Fukushima using both the ellipsoidal and voxel techniques, and in all cases the ellipsoidal method yielded more conservative dose rates by factors of 1.2-1.4 for photons and 5.3 for beta particles. Dose rates for alpha emitting radionuclides are identical for each method as full energy absorption in source tissue is assumed. The voxel procedure includes contributions to dose from organ-to-organ irradiation (shown here to comprise 2-50% of total dose from photons and 0-93% of total dose from beta particles) that is not specifically quantified in the ellipsoidal approach. Overall, the voxel models provide robust dosimetry for the nonhuman mammals considered in this study, and though the level of detail is likely extraneous to demonstrating regulatory compliance today, voxel models may nevertheless be advantageous in resolving ongoing questions regarding the effects of ionizing radiation on wildlife. PMID- 26414507 TI - Accelerator-Based Biological Irradiation Facility Simulating Neutron Exposure from an Improvised Nuclear Device. AB - We describe here an accelerator-based neutron irradiation facility, intended to expose blood or small animals to neutron fields mimicking those from an improvised nuclear device at relevant distances from the epicenter. Neutrons are generated by a mixed proton/deuteron beam on a thick beryllium target, generating a broad spectrum of neutron energies that match those estimated for the Hiroshima bomb at 1.5 km from ground zero. This spectrum, dominated by neutron energies between 0.2 and 9 MeV, is significantly different from the standard reactor fission spectrum, as the initial bomb spectrum changes when the neutrons are transported through air. The neutron and gamma dose rates were measured using a custom tissue-equivalent gas ionization chamber and a compensated Geiger-Mueller dosimeter, respectively. Neutron spectra were evaluated by unfolding measurements using a proton-recoil proportional counter and a liquid scintillator detector. As an illustration of the potential use of this facility we present micronucleus yields in single divided, cytokinesis-blocked human peripheral lymphocytes up to 1.5 Gy demonstrating 3- to 5-fold enhancement over equivalent X-ray doses. This facility is currently in routine use, irradiating both mice and human blood samples for evaluation of neutron-specific biodosimetry assays. Future studies will focus on dose reconstruction in realistic mixed neutron/photon fields. PMID- 26414506 TI - Evolved Cellular Mechanisms to Respond to Genotoxic Insults: Implications for Radiation-Induced Hematologic Malignancies. AB - Human exposure to ionizing radiation is highly associated with adverse health effects, including reduced hematopoietic cell function and increased risk of carcinogenesis. The hematopoietic deficits manifest across blood cell types and persist for years after radiation exposure, suggesting a long-lived and multi potent cellular reservoir for radiation-induced effects. As such, research has focused on identifying both the immediate and latent hematopoietic stem cell responses to radiation exposure. Radiation-associated effects on hematopoietic function and malignancy development have generally been attributed to the direct induction of mutations resulting from radiation-induced DNA damage. Other studies have illuminated the role of cellular programs that both limit and enhance radiation-induced tissue phenotypes and carcinogenesis. In this review, distinct but collaborative cellular responses to genotoxic insults are highlighted, with an emphasis on how these programmed responses impact hematopoietic cellular fitness and competition. These radiation-induced cellular programs include apoptosis, senescence and impaired self-renewal within the hematopoietic stem cell (HSC) pool. In the context of sporadic DNA damage to a cell, these cellular responses act in concert to restore tissue function and prevent selection for adaptive oncogenic mutations. But in the contexts of whole-tissue exposure or whole-body exposure to genotoxins, such as radiotherapy or chemotherapy, we propose that these programs can contribute to long-lasting tissue impairment and increased carcinogenesis. PMID- 26414508 TI - Dose Optimization Study of AEOL 10150 as a Mitigator of Radiation-Induced Lung Injury in CBA/J Mice. AB - AEOL 10150 is a catalytic metalloporphyrin superoxide dismutase mimic being developed as a medical countermeasure for radiation-induced lung injury (RILI). The efficacy of AEOL 10150 against RILI through a reduction of oxidative stress, hypoxia and pro-apoptotic signals has been previously reported. The goal of this study was to determine the most effective dose of AEOL 10150 (daily subcutaneous injections, day 1-28) in improving 180-day survival in CBA/J mice after whole thorax lung irradiation (WTLI) to a dose of 14.6 Gy. Functional and histopathological assessments were performed as secondary end points. Estimated 180-day survival improved from 10% in WTLI alone to 40% with WTLI-AEOL 10150 at 25 mg/kg (P = 0.065) and to 30% at 40 mg/kg (P = 0.023). No significant improvement was seen at doses of 5 and 10 mg/kg or at doses between 25 and 40 mg/kg. AEOL 10150 treatment at 25 mg/kg lowered the respiratory function parameter of enhanced pause (Penh) significantly, especially at week 16 and 18 (P = 0.044 and P = 0.025, respectively) compared to vehicle and other doses. Pulmonary edema/congestion were also significantly reduced at the time of necropsy among mice treated with 25 and 40 mg/kg AEOL 10150 compared to WTLI alone (P < 0.02). In conclusion, treatment with AEOL 10150 at a dose of 25 mg/kg/day for a total of 28 days starting 24 h after WTLI in CBA/J mice was found to be the optimal dose with improvement in survival and lung function. Future studies will be required to determine the optimal duration and therapeutic window for drug delivery at this dose. PMID- 26414511 TI - Slipping on pedestrian surfaces: methods for measuring and evaluating the slip resistance. AB - Tripping, slipping and falling accidents are among the types of accident with a high incidence. This article describes the requirements concerning slip resistance, as well as the state of the art of slip resistance measurement standards in the European Community and the USA. The article also describes how risk assessment can be performed in the field. PMID- 26414512 TI - The Role of Decision Aids in Depression Care. PMID- 26414509 TI - Bouvardin is a Radiation Modulator with a Novel Mechanism of Action. AB - Protein synthesis is essential for growth, proliferation and survival of cells. Translation factors are overexpressed in many cancers and in preclinical models, their experimental inhibition has been shown to inhibit cancer growth. Differential regulation of translation also occurs upon exposure to cancer relevant stressors such as hypoxia and ionizing radiation. The failure to regulate translation has been shown to interfere with recovery after genotoxic stress. These findings suggest that modulation of translation, alone or in conjunction with genotoxins, may be therapeutic in oncology. Yet, only two drugs that directly inhibit translation are FDA-approved for oncology therapies used today. We have previously identified the protein synthesis inhibitor, bouvardin in a screen for small molecule enhancers of ionizing radiation in Drosophila melanogaster . Bouvardin was independently identified in a screen for selective inhibitors of engineered human breast cancer stem cells. Here we report the effect of bouvardin treatment in preclinical models of head and neck cancer (HNC) and glioma, two cancer types for which radiation therapy is the most common treatment. Our data show that bouvardin treatment blocked translation elongation on human ribosomes and suggest that it did so by blocking the dissociation of elongation factor 2 from the ribosome. Bouvardin and radiation enhanced the induction of clonogenic death in HNC and glioma cells, although by different mechanisms. Bouvardin treatment enhanced the radiation-induced antitumor effects in HNC tumor xenografts in mice. These data suggest that inhibition of translation elongation, particularly in combination with radiation treatment, may be a promising treatment option for cancer. PMID- 26414513 TI - Is the Availability of Delayed-Release Prednisone an Important Clinical Advance? PMID- 26414514 TI - Square-Centimeter Solution-Processed Planar CH3NH3PbI3 Perovskite Solar Cells with Efficiency Exceeding 15. AB - The preparation of uniform, high-crystallinity planar perovskite films with high aspect-ratio grains over a square-inch area is demonstrated. The best power conversion efficiency (PCE) of 16.3% (stabilized output of ~15.6%) is obtained for a planar perovskite solar cell (PSC) with 1.2 cm2 active area, and the PCE jumps to 18.3% (stabilized output of ~17.5%) for a PSC with a 0.12 cm2 active area. PMID- 26414515 TI - Nanoscopic dynamic mechanical analysis of resin-infiltrated dentine, under in vitro chewing and bruxism events. AB - The aim of this study was to evaluate the induced changes in mechanical behavior and bonding capability of resin-infiltrated dentine interfaces, after application of mechanical stimuli. Dentine surfaces were subjected to partial demineralization through 37% phosphoric acid etching followed by the application of an etch-and-rinse dentine adhesive, Single Bond (3M/ESPE). Bonded interfaces were stored in simulated body fluid during 24h, and then tested or submitted to the mechanical loading challenge. Different loading waveforms were applied: No cycling (I), 24h cycled in sine (II) or square (III) waves, sustained loading held for 24h (IV) or sustained loading held for 72h (V). Microtensile bond strength (MTBS) was assessed for the different groups. Debonded dentine surfaces were studied by field emission scanning electron microscopy (FESEM). At the resin dentine interface, both the hybrid layer (HL) and the bottom of the hybrid layer (BHL), and both peritubular and intertubular were evaluated using a nanoindenter in scanning mode. The load and displacement responses were used to perform the nano-Dynamic Mechanical analysis and to estimate the complex and storage modulus. Dye assisted Confocal Microscopy Evaluation was used to assess sealing ability. Load cycling increased the percentage of adhesive failures in all groups. Specimens load cycled in held 24h attained the highest complex and storage moduli at HL and BHL. The storage modulus was maximum in specimens load cycled in held 24h at peritubular dentine, and the lowest values were attained at intertubular dentine. The storage modulus increased in all mechanical tests, at peritubular dentine. An absence of micropermeability and nanoleakage after loading in sine and square waveforms were encountered. Porosity of the resin-dentine interface was observed when specimens were load cycled in held 72h. Areas of combined sealing and permeability were discovered at the interface of specimens load cycled in held 24h. Crack-bridging images appeared in samples load cycled with sine waveform, after FESEM examination. PMID- 26414516 TI - Modelling the degradation and elastic properties of poly(lactic-co-glycolic acid) films and regular open-cell tissue engineering scaffolds. AB - Scaffolding plays a critical rule in tissue engineering and an appropriate degradation rate and sufficient mechanical integrity are required during degradation and healing of tissue. This paper presents a computational investigation of the molecular weight degradation and the mechanical performance of poly(lactic-co-glycolic acid) (PLGA) films and tissue engineering scaffolds. A reaction-diffusion model which predicts the degradation behaviour is coupled with an entropy-based mechanical model which relates Young's modulus and the molecular weight. The model parameters are determined based on experimental data for in vitro degradation of a PLGA film. Microstructural models of three different scaffold architectures are used to investigate the degradation and mechanical behaviour of each scaffold. Although the architecture of the scaffold does not have a significant influence on the degradation rate, it determines the initial stiffness of the scaffold. It is revealed that the size of the scaffold strut controls the degradation rate and the mechanical collapse. A critical length scale due to competition between diffusion of degradation products and autocatalytic degradation is determined to be in the range 2-100MUm. Below this range, slower homogenous degradation occurs; however, for larger samples monomers are trapped inside the sample and faster autocatalytic degradation occurs. PMID- 26414519 TI - Guest editorial: Eastern Analytical Symposium 2015. PMID- 26414521 TI - Educational editorial: interpret vibrational spectra? Why bother? PMID- 26414517 TI - Adenoma development in familial adenomatous polyposis and MUTYH-associated polyposis: somatic landscape and driver genes. AB - Familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) are inherited disorders associated with multiple colorectal adenomas that lead to a very high risk of colorectal cancer. The somatic mutations that drive adenoma development in these conditions have not been investigated comprehensively. In this study we performed analysis of paired colorectal adenoma and normal tissue DNA from individuals with FAP or MAP, sequencing 14 adenoma whole exomes (eight MAP, six FAP), 55 adenoma targeted exomes (33 MAP, 22 FAP) and germline DNA from each patient, and a further 63 adenomas by capillary sequencing (41 FAP, 22 MAP). With these data we examined the profile of mutated genes, the mutational signatures and the somatic mutation rates, observing significant diversity in the constellations of mutated driver genes in different adenomas, and loss-of function mutations in WTX (9%; p < 9.99e-06), a gene implicated in regulation of the WNT pathway and p53 acetylation. These data extend our understanding of the early events in colorectal tumourigenesis in the polyposis syndromes. PMID- 26414522 TI - Detection of highly energetic materials on non-reflective substrates using quantum cascade laser spectroscopy. AB - A quantum cascade laser spectrometer was used to obtain the reflection spectra of highly energetic materials (HEMs) deposited on nonideal, low-reflectivity substrates, such as travel-bag fabric (polyester), cardboard, and wood. Various deposition methods were used to prepare the standards and samples in the study. The HEMs used were the nitroaromatic explosive 2,4,6-trinitrotoluene (TNT), the aliphatic nitrate ester pentaerythritol tetranitrate (PETN), and the aliphatic nitramine 1,3,5-trinitroperhydro-1,3,5-triazine (RDX). Chemometrics algorithms were applied to analyze the recorded spectra. Partial least squares (PLS) regression analysis was used to find the best correlation between the infrared signals and the surface concentrations of the samples, and PLS combined with discriminant analysis (PLS-DA) was used to discriminate, classify, and identity similarities in the spectral datasets. Several preprocessing steps were applied to prepare the mid-infrared spectra of HEMs deposited on the target substrates. The results demonstrate that the infrared vibrational method described in this study is well suited for the rapid screening analysis of HEMs on low-reflectivity substrates when a supervised model has been previously constructed or when a reference spectrum of the clean substrate can be acquired to be subtracted from the HEM-substrate spectrum. PMID- 26414523 TI - Oxygen rotational temperature determination using empirical analyses of C(3)Pi(v' = 2) <- X(3)Sigma(v'' = 0) transitions. AB - The spectra of molecular oxygen through C(3)Pi(v' = 2) <- X(3)Sigma(v'' = 0) transitions have been obtained by coherent microwave Rayleigh scattering (radar) from resonance-enhanced multiphoton ionization (REMPI). Measurements of rotational temperatures of molecular oxygen have been demonstrated based on the empirical analyses of the O2 spectra without the requirement of highly resolved rotational features. Three methods, including (1) linewidth fitting, (2) linear fitting, and (3) area fitting have been investigated for temperature measurements within pure oxygen, ambient air, and H2-air and CH4-air flame environments. The first two methods were applied in a moderately low temperature environment with measurement uncertainties less than 11% and 26%, respectively. The area fitting method covered a wider temperature range, from room temperature (~300 K) to flame temperature (~1700 K), with minimal dependence on the fine structures of the O2 spectra. Less elaborate than Boltzmann plot analyses of ultrafine rotational lines from congested upper rotational energy levels in O2(C(3)Pi(v' = 2)), these empirical analyses are predictably sensitive to the thermal distribution of molecular oxygen and have been successfully demonstrated as simple and quick methods for remote gas-phase temperature measurement. PMID- 26414524 TI - Laser-induced fluorescence from N2(+) ions generated by a corona discharge in ambient air. AB - In this work, we present the measurement of laser-induced fluorescence from N2(+) ions via the B(2)Sigmau(+)-X(2)Sigmag(+) band system in the near-ultraviolet. The ions were generated continuously by a plasma glow discharge in low pressure N2 and by a corona discharge in ambient air. The fluorescence decay time was found to rapidly decrease with increasing pressure leading to an extrapolated decay rate of ?10(10) s(-1) at atmospheric pressure. In spite of this quenching, we were able to observe laser induced fluorescence in ambient air by means of a time gated spectral measurement. In the process of comparing the emission signal with that of N2 spontaneous Raman scattering, ion concentrations in ambient air of order 10(8-)10(10) cm(-3) were determined. With moderate increases in laser power and collection efficiency, ion concentrations of less than 10(6) cm(-3) may be measurable, potentially enabling applications in atmospheric standoff detection of ionizing radiation from hazardous radioactive sources. PMID- 26414525 TI - Fourier transform infrared spectral detection of life in polar subsurface environments and its application to Mars exploration. AB - Cryptoendolithic lichen communities of the Dry Valleys, Antarctica, survive in an extremely inhospitable environment, finding refuge in microscopic niches where conditions suitable for life exist. Such "within-rock" communities may have evolved on Mars when conditions for life on the surface deteriorated to such an extent that they could no longer survive. Fourier transform infrared spectroscopy of unprepared whole-rock Antarctic Beacon sandstones was used to vertically profile molecular vibrations of fatty acids, proteins, and carboxylic acids created by endolithic communities. Spectral biosignatures were found localized to lichen-rich areas and were absent in crustal regions and the bulk rock substrate. These cryptoendolithic profiles will aid similar spectroscopic investigations of organic biosignatures during future Martian subsurface studies and will help in the identification of similar communities in other localities across the Earth. PMID- 26414526 TI - A prototype stationary Fourier transform spectrometer for near-infrared absorption spectroscopy. AB - A prototype stationary Fourier transform spectrometer (FTS) was constructed with a fiber-coupled lithium niobate (LiNbO3) waveguide Mach-Zehnder interferometer (MZI) for the purpose of rapid on-site spectroscopy of biological and chemical measurands. The MZI contains push-pull electrodes for electro-optic modulation, and its interferogram as a plot of intensity against voltage was obtained by scanning the modulating voltage from -60 to +60 V in 50 ms. The power spectrum of input signal was retrieved by Fourier transform processing of the interferogram combined with the wavelength dispersion of half-wave voltage determined for the MZI used. The prototype FTS operates in the single-mode wavelength range from 1200 to 1700 nm and allows for reproducible spectroscopy. A linear concentration dependence of the absorbance at lambdamax = 1451 nm for water in ethanolic solution was obtained using the prototype FTS. The near-infrared spectroscopy of solid samples was also implemented, and the different spectra obtained with different materials evidenced the chemical recognition capability of the prototype FTS. To make this prototype FTS practically applicable, work on improving its spectral resolution by increasing the maximum optical path length difference is in progress. PMID- 26414527 TI - Demixing of water and ethanol causes conformational redistribution and gelation of the cationic GAG tripeptide. AB - The cationic tripeptide GAG undergoes three conformational changes in binary mixtures of water and ethanol. At 17 mol% of ethanol conformational sampling is shifted from pPII towards beta-strands. A more pronounced shift in the same direction occurs at 40 mol%. At ca. 55 mol% of ethanol and above a peptide concentration of ca. 0.2 M the ternary peptide-water-ethanol mixture forms a hydrogel which is comprised of unusually large crystalline like non-beta sheet fibrils forming a sample spanning matrix. PMID- 26414528 TI - All-passive nonreciprocal metastructure. AB - One-way propagation of light, analogous to the directional flow of electrons in the presence of electric potential difference, has been an important goal in the wave-matter interaction. Breaking time-reversal symmetry in photonic flows is faced with challenges different from those for electron flows. In recent years several approaches and methods have been offered towards achieving this goal. Here we investigate another systematic approach to design all-passive relatively high-throughput metastructures that exhibit nonreciprocal properties and achieve wave-flow isolation. Moreover, we build on those findings and propose a paradigm for a quasi-two-dimensional metastructure that mimics the nonreciprocal property of Faraday rotation without using any magnetic or electric biasing. We envision that the proposed approaches may serve as a building block for all-passive time reversal symmetry breaking with potential applications for future nonreciprocal systems and devices. PMID- 26414530 TI - Spiral blood flow in aorta-renal bifurcation models. AB - The presence of a spiral arterial blood flow pattern in humans has been widely accepted. It is believed that this spiral component of the blood flow alters arterial haemodynamics in both positive and negative ways. The purpose of this study was to determine the effect of spiral flow on haemodynamic changes in aorta renal bifurcations. In this regard, a computational fluid dynamics analysis of pulsatile blood flow was performed in two idealised models of aorta-renal bifurcations with and without flow diverter. The results show that the spirality effect causes a substantial variation in blood velocity distribution, while causing only slight changes in fluid shear stress patterns. The dominant observed effect of spiral flow is on turbulent kinetic energy and flow recirculation zones. As spiral flow intensity increases, the rate of turbulent kinetic energy production decreases, reducing the region of potential damage to red blood cells and endothelial cells. Furthermore, the recirculation zones which form on the cranial sides of the aorta and renal artery shrink in size in the presence of spirality effect; this may lower the rate of atherosclerosis development and progression in the aorta-renal bifurcation. These results indicate that the spiral nature of blood flow has atheroprotective effects in renal arteries and should be taken into consideration in analyses of the aorta and renal arteries. PMID- 26414529 TI - The Importance of the Canonical Wnt Signaling Pathway in the Porcine Endometrial Stromal Stem/Progenitor Cells: Implications for Regeneration. AB - The regenerative ability of the endometrium is strongly associated with the presence of adult stem/progenitor cells. Purposes of the present study were (1) to establish the presence of stem/progenitor cells in porcine endometrial stroma using a clonogenic assay and (2) to investigate whether the canonical Wnt pathway affects the potential of stem/progenitor cells to undergo self-renewal or differentiation. The utility of endometrial stromal clones as a model for stem/progenitor studies was evaluated based on these cells' increased expression of mesenchymal stem cell (MSC) marker genes, including CD29, CD73, CD90, and CD105, compared with primary cultured cells. Small molecules were introduced to activate (BIO) or inhibit (XAV939) the canonical Wnt pathway during stromal clone formation. Cloning efficiency assays revealed that activation of the Wnt/beta catenin pathway promoted formation of more differentiated small clones. Moreover, activation of the Wnt/beta-catenin pathway decreased, whereas inhibition of the pathway increased MSC marker expression. Additionally, we confirmed the importance of canonical Wnt pathway stimulation in endometrial stromal cells through observing the appropriate changes in beta-catenin cellular localization. These data indicate that modulation of the canonical Wnt pathway effects the process of regeneration in the porcine endometrium during the course of the estrous cycle. PMID- 26414531 TI - Nutrient availability and nutrient use efficiency in plants growing in the transition zone between land and water. AB - The transition zone between terrestrial and freshwater habitats is highly dynamic, with large variability in environmental characteristics. Here, we investigate how these characteristics influence the nutritional status and performance of plant life forms inhabiting this zone. Specifically, we hypothesised that: (i) tissue nutrient content differs among submerged, amphibious and terrestrial species, with higher content in submerged species; and (ii) PNUE gradually increases from submerged over amphibious to terrestrial species, reflecting differences in the availability of N and P relative to inorganic C across the land-water ecotone. We found that tissue nutrient content was generally higher in submerged species and C:N and C:P ratios indicated that content was limiting for growth for ca. 20% of plant individuals, particularly those belonging to amphibious and terrestrial species groups. As predicted, the PNUE increased from submerged over amphibious to terrestrial species. We suggest that this pattern reflects that amphibious and terrestrial species allocate proportionally more nutrients into processes of importance for photosynthesis at saturating CO2 availability, i.e. enzymes involved in substrate regeneration, compared to submerged species that are acclimated to lower availability of CO2 in the aquatic environment. Our results indicate that enhanced nutrient loading may affect relative abundance of the three species groups in the land-water ecotone of stream ecosystems. Thus, species of amphibious and terrestrial species groups are likely to benefit more from enhanced nutrient availability in terms of faster growth compared to aquatic species, and that this can be detrimental to aquatic species growing in the land-water ecotone, e.g. Ranunculus and Callitriche. PMID- 26414532 TI - Chemotherapy and treatment algorithms for follicular lymphoma: a look at all options. AB - The outcome of patients with follicular lymphoma has substantially improved in recent years, mainly due to the widespread use of the monoclonal antibody rituximab and partially due to autologous and allogeneic transplantation, and the introduction of new drugs and to the improvement in diagnostic accuracy. The choice of therapy is still based on patient characteristics, extension of disease and clinical prognostic factors. The majority of patients in need of treatment are still treated with cytotoxic agents in combination with rituximab; nevertheless a number of new agents, which are active in this disease, have recently been developed. It has yet to be determined, whether they will partly or completely replace chemotherapy in the near future. This review focuses on the role and the choice of chemotherapy in different clinical situations of follicular lymphoma, in a time when chemotherapy-free treatment becomes more and more of a topic of discussion. PMID- 26414533 TI - Pregnancy outcome in patients with ankylosing spondylitis. AB - OBJECTIVE: The aim of this study was to evaluate pregnancy outcomes in women with Ankylosing Spondylitis (AS), and the course of disease during pregnancy was also assessed. METHODS: This case-control study included 60 pregnant women who delivered in our clinic between March 2007 and 2015. Twenty of them diagnosed with AS formed the study group and 40 women were chosen as the control group. These patients were chosen and reviewed by their hospital records and were evaluated retrospectively in terms of their clinical characteristics, pregnancy complications and perinatal outcomes. The Ankylosing Spondylitis Disease Activity Score (ASDAS), a new composite index to assess disease activity in AS, was used in the assessment of the patients. RESULT: No adverse pregnancy outcome was noted in pregnant patients with AS. Mean age of AS patients was significantly higher than the controls (p = 0.037). The proportion of female fetuses was higher in pregnancies with AS compared to pregnant patients with healthy controls (p = 0.041). Fourteen (70%) of 20 patients displayed decrement in ASDAS during pregnancy. Course of AS was unaltered in 6 (30%) of 20 patients during pregnancy. Otherwise, the stage of the disease during pregnancy remained unchanged in 15 (75%) of cases as postpartum exacerbation was observed in 6 (30%). The reported symptoms of patients with AS during pregnancy were arthritis and uveitis. CONCLUSIONS: Women with AS have a favorable pregnancy outcome, and pregnancy does not substantially aggravate disease activity or severity in these patients. PMID- 26414534 TI - Skin telocytes versus fibroblasts: two distinct dermal cell populations. AB - It is already accepted that telocytes (TCs) represent a new type of interstitial cells in human dermis. In normal skin, TCs have particular spatial relations with different dermal structures such as blood vessels, hair follicles, arrector pili muscles or segments of sebaceous and/or eccrine sweat glands. The distribution and the density of TCs is affected in various skin pathological conditions. Previous studies mentioned the particular (ultra)structure of TCs and also their immunophenotype, miR imprint or proteome, genome or secretome features. As fibroblast is the most common intersitital cell (also in human dermis), a dedicated comparison between human skin TCs and fibroblasts (Fbs) was required to be performed. In this study, using different techniques, we document several points of difference between human dermis TCs and Fbs. By transmission electron microscopy (TEM) and scanning electron microscopy (SEM), we demonstrated TCs with their hallmark cellular prolongations - telopodes. Thus, we showed their ultrastructural distinctiveness from Fbs. By RayBio Human Cytokine Antibody Array V analyses performed on the supernatant from separately cultured TCs and Fbs, we detected the cytokine profile of both cell types, individually. Two of 79 detected cytokines - epithelial-derived neutrophil-activating peptide 78 and granulocyte chemotactic protein-2 - were 1.5 times higher in the supernatant of TCs (comparing with Fbs). On the other hand, 37 cytokines were at least 1.5 higher in Fbs supernatant (comparing with TCs), and among them six cytokines - interleukin 5, monocyte chemotactic protein-3 (MCP-3), MCP-4, macrophage inflammatory protein-3, angiogenin, thrombopoietin - being 9.5 times higher (results also confirmed by ELISA testing). In summary, using different techniques, we showed that human dermal TCs and Fbs are different in terms of ultrastructure and cytokine profile. PMID- 26414535 TI - A brief history of the TDIF-PXY signalling module: balancing meristem identity and differentiation during vascular development. AB - 474 I. 474 II. 475 III. 475 IV. 477 V. 477 VI. 477 VII. 479 VIII. 481 482 References 482 SUMMARY: A significant proportion of terrestrial biomass is constituted of xylem cells that make up woody plant tissue. Xylem is required for water transport, and is present in the vascular tissue with a second conductive tissue, phloem, required primarily for nutrient transport. Both xylem and phloem are derived from cell divisions in vascular meristems known as the cambium and procambium. One major component that influences several aspects of plant vascular development, including cell division in the vascular meristem, vascular organization and differentiation of vascular cell types, is a signalling module characterized by a peptide ligand called TRACHEARY ELEMENT DIFFERENTIATION INHIBITORY FACTOR (TDIF) and its cognate receptor, PHLOEM INTERCALATED WITH XYLEM (PXY). In this review, we explore the literature that describes signalling components, phytohormones and transcription factors that interact with these two central factors, to control the varying outputs required in vascular tissues for normal organization and elaboration of plant vascular tissue. PMID- 26414536 TI - Associations of Circulating Soluble Tumor Necrosis Factor-alpha Receptors 1 and 2 with Interleukin-6 Levels in an Aging Cohort of Injection Drug Users with or at High Risk for HIV Infection. AB - Chronic inflammation marked by elevated interleukin (IL)-6, soluble tumor necrosis factor (TNF)-alpha receptor (sTNFR)-1, and sTNFR-2 levels may play a detrimental role in aging and HIV infection. This study aimed to evaluate the relationships of circulating IL-6 with sTNFR-1 and sTNFR-2 levels in an aging cohort of injection drug users (IDUs) with or at high risk for HIV infection. The AIDS Linked to the Intravenous Experience (ALIVE) study is a community-recruited, prospective observational study of former and current IDUs in Baltimore, Maryland. Serum IL-6, sTNFR-1, and sTNFR-2 levels were measured using standard ELISA. Multivariate linear regression analysis was employed, adjusting for age, sex, HIV status, injection drug use, comorbidities, as well as HIV viral load, CD4 T cell counts, and antiretroviral therapy where appropriate. The analysis included 1,178 participants (316 HIV positive and 862 HIV negative). In the adjusted model, sTNFR-1 and sTNFR-2 were individually associated with IL-6 (regression coefficient: 0.877 and 0.556, respectively, for all participants; 0.607 and 0.407 for HIV positives; and 0.999 and 0.628 for HIV negatives, all p < 0.0001). In the model combining sTNFR-1 and sTNFR-2, the associations for sTNFR-1 remained significant (0.693 for all participants, p < 0.0001; 0.417 for HIV positives, p < 0.05; and 0.840 for HIV negatives), while those for sTNFR-2 were no longer significant. sTNFR-1 and sTNFR-2 were positively associated with IL-6 in ALIVE participants. These findings provide initial insight into the in vivo relationship between TNF-alpha activation and IL-6 and a basis for further investigations into potential mechanisms underlying chronic inflammation in aging and HIV infection. PMID- 26414537 TI - Editorial: Unraveling Osteoarthritis Pathogenesis: New Insights Into Preradiographic Disease and Patient Phenotypes. PMID- 26414538 TI - "Productive and counterproductive job crafting: A daily diary study": Correction. PMID- 26414539 TI - The role of PET scan in monitoring the progression of fibrosing mediastinitis. AB - We present the case of a 31-year-old man who presented with acute chest pain. Computed tomography scan showed a mediastinal mass engulfing right main-stem bronchus and another mass surrounding descending aorta. Positron emission tomography (PET) scan showed high mass metabolic activity. Histopathological evaluation revealed fibroinflammatory scarring. He was diagnosed with idiopathic fibrosing mediastinitis, started on prednisone and tamoxifen treatment, and monitored with serial PET scans. Nine months after treatment initiation, paraaortic abnormality had resolved and mediastinal mass had regressed. PMID- 26414540 TI - In Response: A regulatory perspective on prioritization of emerging pollutants in the context of the Water Framework Directive. PMID- 26414541 TI - The Challenge: Prioritization of emerging pollutants. PMID- 26414542 TI - In Response: The NORMAN perspectives on prioritization of emerging pollutants. PMID- 26414543 TI - In Response: Prioritization and standard setting for pollutant mixtures in the aquatic environment: A business consultant's perspective. PMID- 26414544 TI - Adaptation, not acclimation, is the likely mechanism for reduced sensitivity of some wild Hyalella populations to pyrethroid insecticides. PMID- 26414545 TI - The authors' reply. PMID- 26414546 TI - Corrigendum. PMID- 26414548 TI - MicroRNA Expression and Association with Clinicopathologic Features in Papillary Thyroid Cancer: A Systematic Review. AB - BACKGROUND: Studies have suggested that microRNAs (miR) may be useful prognostic markers and are associated with aggressive clinicopathologic features in papillary thyroid cancer (PTC). This systematic review examined associations between miRs and aggressive clinicopathologic features in PTC. METHODS: A literature search was performed within the PubMed, Embase, Cochrane, Web of Science, and Scopus databases for papers published prior to November 24, 2014. The search was performed by combining the concepts "thyroid tumor" with "microRNA" and by using "and" as the Boolean operator. Upon retrieval of candidate studies, full-text publications were reviewed in their entirety and selected if they examined the prognostic significance between miR expression and established aggressive clinicopathologic features of PTC. RESULTS: Fifteen studies from 13 unique groups that included 807 patients were reviewed. Most of the studies were retrospective, and none included patients who had undergone routine central lymph node dissection. Expression levels of miRs-21, -34b, -130b, -135b, -146b, -151, -181b, -199b-5p, -221, -222, -451, -623, -1271, -2861, and let-7e showed significant association with at least one aggressive feature, such as large tumor size, extrathyroidal extension, multifocality, lymphovascular invasion, lymph node metastases, distant metastasis, advanced American Joint Cancer Committee stage, and presence of the BRAF(V600E) mutation. Herein we summarize the literature with regard to these associations. CONCLUSION: Further studies are needed to investigate whether miRs are independent predictors of aggressive clinicopathologic features before it can be recommended that miR expression levels should be incorporated into the management algorithm for patients with PTC. A well-designed prospective study is needed to assess these potential associations. PMID- 26414549 TI - Effects of Multiple Ventilation Courses and Duration of Mechanical Ventilation on Respiratory Outcomes in Extremely Low-Birth-Weight Infants. AB - IMPORTANCE: Extubation failure is common in extremely preterm infants. The current paucity of data on the adverse long-term respiratory outcomes associated with reinitiation of mechanical ventilation prevents assessment of the risks and benefits of a trial of extubation in this population. OBJECTIVE: To evaluate whether exposure to multiple courses of mechanical ventilation increases the risk of adverse respiratory outcomes before and after adjustment for the cumulative duration of mechanical ventilation. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective cohort study of extremely low-birth-weight (ELBW; birth weight <1000 g) infants born from January 1, 2006, through December 31, 2012, who were receiving mechanical ventilation. Analysis was conducted between November 2014 and February 2015. Data were obtained from the Alere Neonatal Database. EXPOSURES: The primary study exposures were the cumulative duration of mechanical ventilation and the number of ventilation courses. MAIN OUTCOMES AND MEASURES: The primary outcome was bronchopulmonary dysplasia (BPD) among survivors. Secondary outcomes were death, use of supplemental oxygen at discharge, and tracheostomy. RESULTS: We identified 3343 ELBW infants, of whom 2867 (85.8%) survived to discharge. Among the survivors, 1695 (59.1%) were diagnosed as having BPD, 856 (29.9%) received supplemental oxygen at discharge, and 31 (1.1%) underwent tracheostomy. Exposure to a greater number of mechanical ventilation courses was associated with a progressive increase in the risk of BPD and use of supplemental oxygen at discharge. Compared with a single ventilation course, the adjusted odds ratios for BPD ranged from 1.88 (95% CI, 1.54-2.31) among infants with 2 ventilation courses to 3.81 (95% CI, 2.88-5.04) among those with 4 or more courses. After adjustment for the cumulative duration of mechanical ventilation, the odds of BPD were only increased among infants exposed to 4 or more ventilation courses (adjusted odds ratio, 1.44; 95% CI, 1.04-2.01). The number of ventilation courses was not associated with increased risk of supplemental oxygen use at discharge after adjustment for the length of ventilation. A greater number of ventilation courses did not increase the risk of tracheostomy. CONCLUSIONS AND RELEVANCE: Among ELBW infants, a longer cumulative duration of mechanical ventilation largely accounts for the increased risk of chronic respiratory morbidity associated with reinitiation of mechanical ventilation. These results support attempts of extubation in ELBW infants receiving mechanical ventilation on low ventilator settings, even when success is not guaranteed. PMID- 26414550 TI - Saffron: Its Phytochemistry, Developmental Processes, and Biotechnological Prospects. AB - The present state of knowledge concerning developmental processes and the secondary metabolism of saffron, Crocus sativus L. (Iridaceae), along with the genes involved in these processes so far known, is reviewed. Flowers and corms constitute the most valuable parts of saffron. Corm and flower development are two key aspects to be studied in saffron to increase the yield and quality of the spice, to raise its reproductive rate, and to implement new production systems. Important knowledge about the physiology of flowering and vegetative growth has been acquired in recent years, but there is still only limited information on molecular mechanisms controlling these processes. Although some genes involved in flower formation and meristem transition in other species have been isolated in saffron, the role of these genes in this species awaits further progress. Also, genes related with the synthesis pathway of abscisic acid and strigolactones, growth regulators related with bud endodormancy and apical dominance (paradormancy), have been isolated. However, the in-depth understanding of these processes as well as of corm development is far from being achieved. By contrast, saffron phytochemicals have been widely studied. The different flower tissues and the corm have been proved to be an important source of phytochemicals with pharmacological properties. The biotechnological prospects for saffron are here reviewed on the basis of the discovery of the enzymes involved in key aspects of saffron secondary metabolism, and we also analyze the possibility of transferring current knowledge about flowering and vegetative propagation in model species to the Crocus genus. PMID- 26414551 TI - What is the impact of ethics on clinical trials? AB - Ethics has often been ignored or evaded in clinical trials, and the conditions under which global clinical trials are conducted make this problem likely to persist. Ethics can, however, have an impact at any of several stages of a trial when the individuals involved are committed. This editorial provides historical examples of ignoring, evading or, alternatively, using ethical help to improve clinical trials, and suggests that the actual role of ethics depends on the individuals involved. PMID- 26414552 TI - Probing chromium(III) from chromium(VI) in cells by a fluorescent sensor. AB - Cellular uptake of Cr(VI), followed by its reduction to Cr(III) with the formation of kinetically inert Cr(III) complexes, is a complex process. To better understand its physiological and pathological functions, efficient methods for the monitoring of Cr(VI) are desired. In this paper a selective fluorescent probe L, rhodamine hydrazide bearing a benzo[b]furan-2-carboxaldehyde group, was demonstrated as a red chemosensor for Cr(III) at about 586 nm. This probe has been used to probe Cr(III) which is reduced from Cr(VI) by reductants such as glutathione (GSH), vitamin C, cysteine (Cys), H2O2 and Dithiothreitol (DTT) by fluorescence spectra. Cr(VI) metabolism in vivo is primarily driven by Vc and GSH. Vc could reduce CrO4(2-) to Cr(III) in a faster rate than GSH. The indirectly detection limit for Cr(VI) by L+GSH system was determined to be 0.06 MUM at pH=6.2. Moreover, the confocal microscopy image experiments indicated that Cr(VI) can be reduced to Cr(III) inside cells rapidly and the resulted Cr(III) can be captured and imaged timely by L. PMID- 26414553 TI - Synthesis and multi-spectroscopic DNA binding study of 1,3,4-oxadiazole and 1,3,4 thiadiazole derivatives of fatty acid. AB - A facile and convenient synthesis of a series of fatty acid derivatives of 1,3,4 oxadiazole and 1,3,4-thiadiazole has been described. The key step of this protocol is the cyclization of acyl thiosemicarbazides via iodobenzene diacetate and methanesulfonic acid under mild conditions. The newly synthesized compounds were characterized by FT-IR, (1)HNMR, (13)CNMR and mass spectral study. The binding affinity of 5-(pentadecyl)-N-propenyl-1,3,4-oxadiazol-2-amine (3a) and 5 (heptadecyl)-2-amino-1,3,4-thiadiazole (6a) with CT-DNA has been evaluated by UV, fluorescence, Circular Dichroism (CD) and thermal denaturation studies. It has been found that these small and planer heteroaromatic compounds are capable of binding to the minor groove region of DNA. PMID- 26414554 TI - 4-(8-quinolyl)amino-7-nitro-2,1,3-benzoxadiazole as a new selective and sensitive fluorescent and colorimetric pH probe with dual-responsive ranges in aqueous solutions. AB - Fluorescent and colorimetric pH probe possess many advantages including rapid response time, nondestructive testing, and excellent pH sensitivity. However, they usually cannot be utilized simultaneously in both acidic and basic pH ranges. In this study, a new selective and sensitive fluorescent and colorimetric pH probe, 4-(8-quinolyl)amino-7-nitro-2,1,3-benzoxadiazole (1), was designated and synthesized. The optical probe exhibited dual-responsive pH ranges to both acidic and basic aqueous solutions. When the solution pH was gradually increased from 8.5 to 13.3, the absorption spectra of 1 showed an obvious hyperchromicity, accompanied with a red shift of the absorption band at 340 nm, a blue shift of the absorption band at 482 nm, and a distinct color change from orange to violet pink to yellow. Within the pH range from 2.2 to 0.2, the fluorescent spectra of 1 showed a "turn-on" response signal to solution pH. In order to understand the response mechanism of the probe to solution pH, the probe molecule was split into two parts, 8-aminoquinoline (2) and 4-amino-7- nitro-benzofurazan (3). UV-vis absorption and fluorescent experiments of 2 and 3 indicated that both are sensitive optical pH probes. Furthermore, the NMR experiment of 1 was explored in basic and acidic conditions. The results indicated that the colorimetric responses of 1 to pH under basic condition should be attributed to the deprotonation of the imino group on the quinolyl ring, and the fluorescent recognition of 1 to pH under acidic condition was probably due to the protonation of the nitrogen atoms from the benzofurazan and quinolyl rings. PMID- 26414555 TI - An insight into the metal coordination and spectroscopic properties of artistic Fe and Fe/Cu logwood inks. AB - Fe- and Fe/Cu-based logwood inks were synthesized following recipes in nineteenth and early twentieth century manuals and were characterized by EPR, ESI-MS, FTIR, and Raman spectroscopies. This multi-technique approach allowed us to shed light on the structures of the complexes responsible for the inks' colors and to obtain vibrational signatures that can be used to identify the different inks in works of art and in historic documents. Information on the nature and chemical properties of the complexes formed between a dye and a mordant is important as these determine, at least in part, their lightfastness. EPR permitted to determine the coordination environment of the metallic ions. The results of the ESI-MS analysis demonstrated, for the first time, the breakdown of the hematein molecule during the ink preparation, and that the colorants are formed by the complexation of the metallic ions by hematein breakdown products, mainly catechol and/or bicyclic compounds. The FTIR spectra obtained were found to be dominated by bands due to the binding medium and sulfates used as reagents. The Raman analysis showed that the characteristic features for the different inks studied depend on the historic recipe used, attesting to the challenges that their identification and characterization in works of art present. In the Raman spectra of the inks applied on paper, broadening of bands in the 750-400 cm(-1) range are observed when compared to the spectra of the inks' powders, possibly due to the interaction of the compounds with the cellulose in the substrate. PMID- 26414556 TI - Novel Rat Model of Weight Drop-Induced Closed Diffuse Traumatic Brain Injury Compatible with Electrophysiological Recordings of Vigilance States. AB - Traumatic brain injury (TBI) is a major cause of persistent disabilities such as sleep-wake disorders (SWD). Rodent studies of SWD after TBI are scarce, however, because of lack of appropriate TBI models reproducing acceleration-deceleration forces and compatible with electroencephalography/myography (EEG/EMG)-based recordings of vigilance states. We therefore adapted the Marmarou impact acceleration model to allow for compatibility with EEG-headset implantation. After implantation of EEG/EMG electrodes, we induced closed TBI by a frontal, angular hit with a weight-drop device (56 rats, weight 2500 g, fall height 25 cm). Subsequently, we tested our model's usefulness for long-term studies on a behavioral, electrophysiological, and histological level. Neurological, motor, and memory deficits were assessed with the neurological severity score, open field, and novel object recognition tests, respectively. EEG/EMG recordings were performed in both Sham (n = 7) and TBI (n = 7) rats before and 1, 7, and 28 days after trauma to evaluate sleep-wake proportions and post-traumatic implant stability. Histological assessments included hematoxylin and eosin staining for parenchymal damage and hemorrhage and amyloid precursor protein staining for diffuse axonal damage. All rats survived TBI without major neurological or motor deficits. Memory function was impaired after TBI at weeks 1, 2, and 3 and recovered at week 4. EEG implants were stable for at least 1 month and enabled qualitative and quantitative sleep analyses. Histological assessments revealed no major bleedings or necrosis but intense diffuse axonal damage after TBI. This approach fulfills major pre-conditions for experimental TBI models and offers a possibility to electrophysiologically study behavioral states before and after trauma. PMID- 26414557 TI - Myopic Shift during Hyperbaric Oxygenation Attributed to Lens Index Changes. AB - PURPOSE: To examine ocular lens parameters and structural changes to elucidate mechanisms underlying the myopic shift and cataract-related changes that occur in some patients during hyperbaric oxygen (HBO) therapy. METHODS: Scheimpflug images (Nidek EAS-1000) of the crystalline lens, measurements of scattered light, objective refraction, keratometry, tonometry, and axial length of the eye were obtained after the first day of HBO therapy and repeated when patients had completed 19 days of the treatment. RESULTS: Significant reduction in mean (+/- SD) optical density was found in the lens nucleus, -2.8 (+/- 4.3) units (p = 0.009) and -2.2 (+/- 4.1) units (p = 0.027) within circular and oval areas, respectively. Significant decrease in mean (+/- SD) backward scattered light was measured, -0.4 (+/- 0.8) units (p = 0.022). Mean (+/- SD) myopic shift was -0.58 (+/- 0.39) diopters (p < 0.001), whereas cortical optical density, forward scattered light, lenticular parameters, keratometry, tonometry, anterior chamber depth, and axial length of the eye appeared unchanged. CONCLUSIONS: Transient myopic shift reported in patients during HBO therapy is attributed to changes in the refractive index of the lens. No changes in lens curvatures or thickness were found after treatment. PMID- 26414558 TI - Inguinal Hernia Repair During Extraperitoneal Robot-Assisted Laparoscopic Radical Prostatectomy. AB - INTRODUCTION: One third of men undergoing radical prostatectomy have a comorbid inguinal hernia (IH). Previous studies have shown that adding total extraperitoneal (TEP) IH repair to extraperitoneal laparoscopic radical prostatectomy (LRP) lacks adverse effects. However, outcomes of extraperitoneal robot-assisted laparoscopic radical prostatectomy (RALP) and TEP are unknown. We compared RALP+TEP with LRP+TEP and also with RALP alone. METHODS: Eleven RALP+TEP cases were retrospectively compared with 26 LRP+TEP cases and 22 control RALP without TEP. Outcomes compared between groups included operative time, estimated blood loss (EBL), discharge hematocrit (hct), time to diet advancement, length of hospital stay (LOS), postoperative complications, and hernia recurrence. RESULTS: Unilateral TEP added 32 minutes to RALP and 31 minutes to LRP, whereas bilateral TEP added 80 minutes to RALP and 36 minutes to LRP. There were no differences between RALP+TEP and LRP+TEP or RALP without TEP controls in regard to EBL, discharge hct, time to diet advancement, LOS, or postoperative complications. One patient developed an anterior mesh seroma, which resolved without intervention. No IH recurrences were noted on the mean follow-up of 33 months in the RALP group and 50 months in the LRP cohort. CONCLUSIONS: Unilateral and bilateral TEP added operative time to RALP but had equivalent outcomes to both LRP+TEP and RALP alone. This is likely due to the similar surgical space used for RALP and TEP, which obviates the need for substantial further dissection. For men with prostate cancer and comorbid IH, combined RALP+TEP appears to be an appropriate surgical combination. PMID- 26414559 TI - Characteristics of traumatic intracerebral haemorrhage: An assessment of screening logs from the STITCH(Trauma) Trial. AB - INTRODUCTION: In undertaking international neurosurgical trials it is useful to understand international patient demographics and potential patient populations that study results will apply to. The STITCH(Trauma) trial included 59 centres from 20 countries, which were requested to screen all patients with traumatic intracerebral haemorrhage. This paper reviews these data. MATERIALS AND METHODS: Demographic, clinical and exclusion reason data were analysed. Comparisons were made between patients who were included in the trial and patients who were potentially eligible (but not included in the trial) and patients who were not potentially eligible. RESULTS: Screening evidence was returned for 1735 patients, 11% of these may potentially have been eligible, of whom 52% were not included because consent could not be gained. By country, median age per centre ranged from 26 years (Egypt) to 67 years (Germany), median time from injury to screening ranged from 5 h (Germany and Nepal) to 16 h (India), median intracerebral haemorrhage (ICH) volume ranged from 5 ml (Germany) to 30 ml (China), the proportion of male patients ranged from 56% (Egypt) to 91% (Canada) and the proportion of patients with both pupils reactive ranged from 68% (China) to 98% (Nepal). The most common exclusion reasons were ICH volume < 10 ml (49%) and presence of subdural haemorrhage/extradural haemorrhage or SDH/EDH requiring surgery (20%). CONCLUSION: Data presented here including international patient demographics and reasons for patient ineligibility will be useful for future traumatic ICH studies. PMID- 26414560 TI - What the obesity prevention field can learn from the gay marriage movement. PMID- 26414561 TI - Liver Fibrosis Predicts Cognitive Function Following Bariatric Surgery: A Preliminary Investigation. AB - OBJECTIVE: Obesity is a well-established risk factor for poor neurological outcomes, and bariatric surgery has been shown to improve many aspects of cognitive function. Factors underlying improved cognition following surgery are not yet fully established. A recent study of bariatric surgery patients demonstrated lower preoperative alkaline phosphatase concentrations were linked to greater postoperative cognitive improvement, but this link has not been examined via liver biopsy. The current study examined postoperative cognitive function in individuals with and without fibrosis at the time of bariatric surgery. It expected that those with fibrosis would demonstrate poorer postoperative cognition. METHODS: Thirty-six bariatric surgery patients underwent routine liver biopsy at the time of surgery and completed cognitive testing 1 month postoperatively. RESULTS: Bariatric surgery patients with fibrosis demonstrated poorer performance on a task of executive function (maze errors, P = 0.01) and verbal memory (recognition memory, P = 0.01). CONCLUSIONS: Bariatric surgery patients with fibrosis demonstrated poorer cognition following surgery, providing further evidence for the connection between liver disease and cognitive function. Future work examining mechanisms underlying bariatric postoperative cognitive changes should include examination of broader metabolic functions, particularly liver function. PMID- 26414562 TI - Effect of Duodenal-Jejunal Bypass Surgery on Glycemic Control in Type 2 Diabetes: A Randomized Controlled Trial. AB - OBJECTIVE: To determine whether upper gastrointestinal tract (UGI) bypass itself has beneficial effects on the factors involved in regulating glucose homeostasis in patients with type 2 diabetes (T2D). METHODS: A 12-month randomized controlled trial was conducted in 17 overweight/obese subjects with T2D, who received standard medical care (SC, n = 7, BMI = 31.7 +/- 3.5 kg/m(2) ) or duodenal jejunal bypass surgery with minimal gastric resection (DJBm) (n = 10; BMI = 29.7 +/- 1.9 kg/m(2)). A 5-h modified oral glucose tolerance test was performed at baseline and at 1, 6, and 12 months after surgery or starting SC. RESULTS: Body weight decreased progressively after DJBm (7.9 +/- 4.1%, 9.6 +/- 4.2%, and 10.2 +/- 4.3% at 1, 6, and 12 months, respectively) but remained stable in the SC group (P < 0.001). DJBm, but not SC, improved: (1) oral glucose tolerance (decreased 2-h glucose concentration, P = 0.039), (2) insulin sensitivity (decreased homeostasis model assessment of insulin resistance, P = 0.013), (3) early insulin response to a glucose load (increased insulinogenic index, P = 0.022), and (4) overall glycemic control (reduction in HbA1c with fewer diabetes medications). CONCLUSIONS: DJBm causes moderate weight loss and improves metabolic function in T2D. However, our study cannot separate the benefits of moderate weight loss from the potential therapeutic effect of UGI tract bypass itself on the observed metabolic improvements. PMID- 26414563 TI - Frequent Self-Weighing with Electronic Graphic Feedback to Prevent Age-Related Weight Gain in Young Adults. AB - OBJECTIVE: An intervention using Wi-Fi scales and graphic e-mail feedback, the caloric titration method (CTM), to reduce age-related weight gain over 1 year among college students was evaluated. METHODS: First-year college students (n = 167) were randomized to CTM or control (C) groups and provided Wi-Fi scales. The CTM group was instructed to weigh daily, view a weight graph e-mailed to them after weighing, and try to maintain their weight. The C group could weigh at any time but did not receive feedback. At 6 months and 1 year, the C group provided weights. For intention to treat analysis, an adjusted mixed model was used to analyze the effect of the intervention. RESULTS: Baseline body mass index was 22.9 +/- 3.0 kg/m(2) . Ninety-five percent of the CTM participants weighed >= 3 times/week, compared to 15% in the C group (P < 0.001). After 1 year, the C group had gained 1.1 +/- .4 kg whereas the CTM group lost 0.5 +/- 3.7 kg (F = 3.39, P = 0.035). The difference in weight change between the two groups at 1 year was significant (P = 0.004). Retention was 81%. CONCLUSIONS: CTM intervention was effective in preventing age-related weight gain in young adults over 1 year and thus offers promise to reduce overweight and obesity. PMID- 26414565 TI - Erratum: Cannabis use in relation to obesity and insulin resistance in the inuit population. PMID- 26414564 TI - The Human Circadian System Has a Dominating Role in Causing the Morning/Evening Difference in Diet-Induced Thermogenesis. AB - OBJECTIVE: Diet-induced thermogenesis (DIT) is lower in the evening and at night than in the morning. This may help explain why meal timing affects body weight regulation and why shift work is a risk factor for obesity. The separate effects of the endogenous circadian system--independent of behavioral cycles--and of circadian misalignment on DIT are unknown. METHODS: Thirteen healthy adults undertook a randomized crossover study with two 8-day laboratory visits: three baseline days followed either by repeated simulated night shifts including 12-h inverted behavioral cycles (circadian misalignment) or by recurring simulated day shifts (circadian alignment). DIT was determined for up to 114 min (hereafter referred to as "early DIT") following identical meals given at 8AM and 8PM in both protocols. RESULTS: During baseline days, early DIT was 44% lower in the evening than morning. This was primarily explained by a circadian influence rather than any behavioral cycle effect; early DIT was 50% lower in the biological evening than biological morning, independent of behavioral cycle influences. Circadian misalignment had no overall effect on early DIT. CONCLUSIONS: The circadian system plays a dominating role in the morning/evening difference in early DIT and may contribute to the effects of meal timing on body weight regulation. PMID- 26414566 TI - Occupational stress in oncology nurse caregiving: caring for ourselves. AB - The emotional work of oncology nurses is complex. Inherent in our job is the requirement to be exquisitely empathic. We must look after, respond to, and support numerous patients and their families. Fully present, we repeatedly listen to stories of sadness and despair. Intermittently, we must either display or suppress our emotions. All of this takes place in an occupational environment where support for the nurses' emotional well-being is nonexistent. Lacking are opportunities to vent emotions, sufficient time to grieve patients' deaths, and resources to help nurses cope with work-related stress. PMID- 26414567 TI - Oncology nurses need to get serious about cancer rehabilitation?. AB - Patients with cancer suffer greatly. Rehabilitation helps them suffer less, and yet very few patients with cancer get rehabilitation services of any kind. Oncology nurses are well positioned to see the toll that cancer and its treatment take on patients and to facilitate appropriate supportive care, including rehabilitation.?. PMID- 26414568 TI - Interventions to treat malignant pleural effusions. AB - Malignant pleural effusions (MPEs) are common complications that occur with advanced stages of cancer. In general, they indicate a poor prognosis and greatly affect quality of life (QOL). The treatment goal of MPEs is to provide relief of symptoms. The standard treatment for MPEs is talc pleurodesis; however, indwelling pleural catheters have become more frequently used. This article focuses on current management strategies for MPEs and assesses their influence on QOL.At a GlanceSymptoms of malignant pleural effusions (MPEs), which involve the accumulation of fluid in the pleural space, include dyspnea, shortness of breath, chest pain, and other issues that decrease functional status.Treatment for MPEs should be palliative, achieving immediate symptom relief and improved quality of life.The optimal treatment strategy for MPEs should have minimal side effects, require minimal or no hospitalization, and have low rates of recurrence. PMID- 26414569 TI - Impact of a nurse navigator on genomic testing and timely treatment decision making in patients with breast cancer. AB - The purpose of this quality improvement project was to define best practices for identifying appropriate patients for genomic testing and improve timeliness for ordering tests and reporting results. An interdisciplinary team of surgeons, radiologists, medical oncologists, and nurses agreed that the RN navigator would be the key person to facilitate timely access to genomic profiling. AT A GLANCE: Genomic profiling has become the standard of care for patients with early-stage breast cancer to assist in developing individualized treatment plans. Nurse navigators can play a key role in improving timeliness of care. The APN-RN model led to improvements in turnaround time and complicance with the National Comprehensive Cancer Network's recommendations for genomic testing. PMID- 26414570 TI - Evaluating the frequency of vital sign monitoring during blood transfusion: an evidence-based practice initiative. AB - Patients with cancer are often dependent on blood transfusions during treatment. Frequent vital sign monitoring during transfusions may interrupt sleep and the patient's ability to ambulate or participate in unit activities. Relying heavily on vital sign findings may also overshadow unmeasurable symptoms of transfusion reaction. The aim of this evidence-based practice initiative was to examine the evidence regarding the optimum frequency of vital sign monitoring for patients undergoing stem cell transplantation receiving blood products and to amend policy and practice to be consistent with the literature. ?AT A GLANCE?: Patients with cancer frequently require transfusion support during treatment.Inconsistencies exist in recommendations for the frequency of vital sign monitoring during transfusion.Examining best practice guidelines suggests that less frequent vital sign monitoring may be appropriate if coupled with thoughtful physiologic assessment. PMID- 26414571 TI - Proton beam therapy for pediatric malignancies. AB - Although major advances have been made in radiation techniques, concerns still exist about the treatment-related acute and long-term side effects. This issue is most notable in the pediatric population because of developing organs and tissues combined with longer life expectancies. Proton beam therapy has the advantage of a reduced dose of radiation with less scatter to normal tissue, which may lead to fewer adverse side effects.?AT A GLANCE: Many pediatric patients with cancer receive radiation therapy.Radiation treatments can cause significant acute and long-term side effects.Proton beam therapy reduces radiation scatter to normal tissues and may decrease acute and late toxicities. PMID- 26414572 TI - Preventing chemotherapy errors with comprehensive medication assessment. AB - Preventing medication and chemotherapy errors is a priority in oncology nursing. In this article, a case is presented detailing a medication error that occurred because of inadequate assessment. Such errors still can occur despite electronic systems designed to increase medication administration safety. The authors will discuss implications for oncology nurses.?AT A GLANCE: Chemotherapy errors can occur if the American Society of Clinical Oncology and Oncology Nursing Society chemotherapy administration guidelines are not practiced consistently.?Failure to observe the 10 principles of medication administration contributes to chemotherapy errors.?Electronic safeguards may not prevent chemotherapy errors.?. PMID- 26414573 TI - A systematic review of nonpharmacologic interventions for treatment-related symptoms in women with ovarian cancer. AB - BACKGROUND: Women with ovarian cancer have a continued high symptom burden in comparison to other cancer survivors secondary to ongoing chemotherapy treatment. Prolonged or ineffective management of treatment-related symptoms can contribute to treatment noncompliance, worsening of symptoms, and reduced health-related quality of life. OBJECTIVES: This review of the literature was conducted to describe experimental and quasi-experimental research addressing nonpharmacologic interventions for the treatment-related symptoms of sleep disturbance, pain, anxiety, depression, and low energy or fatigue in women with ovarian cancer and to critique the quality of interventions. METHODS: A systematic search of the literature was conducted in PubMed and yielded 136 articles. Eight articles met the inclusion criteria and were evaluated. FINDINGS: Nonpharmacologic interventions for treatment-related symptoms were complex, with an average of 4.4 components. Intervention delivery, setting, and exposure varied widely across studies. Only three studies contained details sufficient to replicate the intervention. Lack of clarity in intervention reporting may explain perceptions of clinically inefficacious symptom management in this context. Greater attention to reporting would facilitate better translation of interventions into practice and when addressing complex cancer symptom clusters. PMID- 26414574 TI - The evolving role of the nurse during the cancer treatment decision-making process: a literature review. AB - BACKGROUND: Many models of patient-physician relationships have been described since a paternalistic model was postulated in the early 1950s. Among them are the informative model, doctor-as-agent model, shared model of care, family-centered model, and Degner and Beaton's Patterns of Decision Making. OBJECTIVES: This article aims to examine the contemporary role of the nurse during the cancer treatment decision-making process. METHODS: This article reviews the current and evidence-based role of the nurse during cancer treatment decision making, and implications for practice and research are discussed. FINDINGS: Because of external forces, such as rising cost of health care, increasing healthcare consumerism, and increased emphasis on patient-centered care, the shared model of care is taking hold, particularly in the cancer setting. The evolution of these models has caused a shift in the dialogue related to cancer treatment decision making between patients and physicians, as well as oncology nurses. These events contribute to the evolving role of the nurse during the cancer treatment decision making process. PMID- 26414575 TI - An oncology nurses' guide to new targeted agents for metastatic colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC) that has metastasized before being discovered, or reoccurs following surgery, remains a major treatment challenge. Trials have established the usefulness of antiangiogenic agents and new regimens in prolonging survival in patients with advanced disease. In the United States, the antiangiogenic agents approved for treating metastatic CRC often are combined with traditional chemotherapeutic agents and include bevacizumab (Avastin(r)), ziv-aflibercept (Zaltrap(r)), and regorafenib (Stivarga(r)). OBJECTIVES: This article reviews factors that guide the development of a nursing plan for monitoring and managing patients who are receiving antiangiogenic therapies. METHODS: Regorafenib and ziv-aflibercept, two newer agents that nurses and other healthcare professionals may have had less experience with, were reviewed. FINDINGS: The key to maximizing the potential benefit of these agents is understanding where these new therapies fit in the overall scheme of treatment options and how to help patients tolerate treatment. PMID- 26414576 TI - Delirium in patients with cancer: what nurses need to know to improve care. AB - BACKGROUND: Delirium is a serious problem when caring for a patient with cancer in the hospital. Delirium causes major risks and concerns for patients, family members, and healthcare workers, and it often goes unrecognized and has many clinical manifestations. OBJECTIVES: This article aims to evaluate whether a nursing educational program on the topic of delirium would increase the nursing staff's knowledge and confidence in managing patients with delirium. METHODS: A repeated-measures research design using general linear modeling was used for this study. An evidence-based delirium protocol and an educational session were developed for the nursing staff on an inpatient medical-surgical oncology unit. The nurses attended a delirium educational session to learn about risk factors, prevention, assessment, and management of delirium, as well as the use of the delirium protocol. FINDINGS: The nursing educational program on the topic of delirium increased the nursing staff's knowledge from 69% to 86%, and overall confidence in managing patients with delirium increased from 47% to 66%. This study confirms the benefits of delirium education in the inpatient medical surgical oncology setting. PMID- 26414577 TI - Self-reported assessment of symptoms and self-care within a cohort of U.S. veterans during outpatient care for cancer. AB - BACKGROUND: This study was undertaken as part of a feasibility study of the use of a symptom checklist and self-care assessment of veterans receiving oncology outpatient treatment within the U.S. Department of Veterans Affairs system. OBJECTIVES: The study aimed to examine (a) symptom occurrence and severity as self-reported on the Therapy-Related Symptom Checklist (TRSC) by veterans at a cancer clinic, (b) symptom alleviation strategies and use of self-care, and (c) the relationship between symptom occurrence and severity and functional status and quality of life. METHODS: Veterans (N = 100) undergoing chemotherapy and/or radiation therapy participated in a cross-sectional study. Tools used, including TRSC, Symptom Alleviation. FINDINGS: Thirteen symptoms were reported by more than 35% of patients. Top-ranked symptoms by percentage occurrence and severity were feeling sluggish, taste changes, nausea, pain, constipation, loss of appetite, numbness of fingers and toes, difficulty sleeping, weight loss, hair loss, difficulty concentrating, shortness of breath, and decreased interest in sexual activity. Occurrence and severity of symptoms had significant negative correlations with functional status and with overall quality of life. Self-care (symptom alleviation) strategies that helped were medicines, diet and nutrition, and lifestyle change. Checklist use (TRSC) facilitated patient-report of symptoms during cancer treatments; self-care strategies helped relieve symptoms. PMID- 26414578 TI - Breast cancer genetic testing: more than a medical management tool. AB - BACKGROUND: Knowing whether a harmful hereditary mutation exists in BRCA1 and BRCA2 can enable women to make informed decisions regarding surveillance and surgery options to manage risk. Given the attention in the media about BRCA genetic testing, nurses need to revisit how this knowledge may affect a woman's sense of self and the forces that may influence this decision. OBJECTIVES: This article aims to understand how complex the decision to undergo genetic testing may be for some women by exploring the impact of genetic knowledge on the self, changes to customary definitions for health and illness, and ethical issues and social forces that may influence genetic testing decisions. METHODS: A review of the literature was undertaken to understand how genetic knowledge may alter meanings attached to the breast and how health is defined, and to identify ethical concerns and social forces that may affect a woman's decision to undergo or decline an offer for genetic testing. FINDINGS: An understanding and awareness of the potential benefits and harms of BRCA1 and BRCA2 genetic testing, as well as the social forces that may influence a woman's decision to undergo or decline an offer for genetic testing and the commitment to remain open to the uniqueness of each woman's situation, may enhance the nurse-patient relationship and result in a decision that is ethically in the best interest of the patient. PMID- 26414579 TI - Australian experience of neuro-oncology care coordination: a conversation. AB - BACKGROUND: The role of care coordinator was introduced to support patients, caregivers, and healthcare professionals who work within a specialty, as well as to optimize and standardize care. Specifically, the role of neuro-oncology care coordinator is a developing one-and one that has encountered various barriers and difficulties. Patients diagnosed with neurologic cancer must endure a disease trajectory and multimodal treatment approach that present unique challenges to themselves and to the healthcare system. Consequently, the care coordinator role is needed. OBJECTIVES: This article focuses on the role of the neuro-oncology care coordinator, including its challenges, the needs of patients with neurologic cancer, and the benefits this role can bring. METHODS: Three neuro-oncology care coordinators from New South Wales, Australia, discussed their role in the healthcare system via structured meetings, conversations, and email correspondence. FINDINGS: Making others aware of the issues faced by neuro oncology care coordinators, as well as their patients, may help to solidify necessary supportive roles within the healthcare system. PMID- 26414580 TI - Integrating oral health throughout cancer care. AB - Oral health is often not a priority during cancer treatment; however, patients with cancer are at increased risk for oral complications during and after treatment. This article focuses on the importance of oral health care before, during, and after cancer treatment using the head, eyes, ears, nose, oral cavity, and throat, or HEENOT, approach. AT A GLANCE: Oral health is linked to overall health, and healthcare providers must be cognizant of the oral-systemic connection with patients undergoing cancer treatment, which may cause acute and chronic oral health problems. ?Oral assessment, prevention, early recognition, and treatment of oral problems must be incorporated into cancer care, particularly with the aid of an interprofessional team to meet patients' oral care needs. ?The head, eyes, ears, nose, oral cavity, and throat, or HEENOT, approach integrates oral care into patients' history taking, physical examination, and plan of cancer care.?. PMID- 26414581 TI - Yttrium-90 radioembolization as a palliative treatment for liver tumors: a case study. AB - The best chance of cure for patients with liver cancer is surgical removal, but many tumors are too large or invasive. In addition, chemotherapy is frequently unsuccessful in this patient population. A case study is featured involving a patient determined to be a candidate for Yttrium-90 radioembolization, a minimally invasive liver-directed treatment used to target primary and metastatic liver tumors by delivering radioactive microspheres directly to the tumor. This article provides an introduction to the procedure, as well as practical information for nurses caring for patients with liver cancer following Yttrium-90 radioembolization.AT A GLANCE: Yttrium-90 radioembolization allows larger radiation doses to be used without affecting healthy tissues.An outpatient procedure, Yttrium-90 radioembolization results in fewer side effects than standard treatment.?Although Yttrium-90 radioembolization can extend and improve quality of life, its intent is palliative, not curative. PMID- 26414582 TI - Evaluation of a web course to increase evidence-based practice knowledge among nurses. AB - Evidence-based practice (EBP) is essential for quality health care, and EBP knowledge needs to be increased among nurses. Web-based courses may effectively deliver such education. In this study, data were collected about the Oncology Nursing Society web course "Developing Skills for Evidence-Based Practice" and evaluated for demographic characteristics and EBP knowledge test scores.?AT A GLANCE: No significant correlation was seen between knowledge test scores and participants' education or experience levels.Course participants had significant improvement on knowledge test scores after web course completion.?Additional studies are needed to explore the impact of EBP knowledge on clinical practice. PMID- 26414583 TI - Prophylactic antibiotics to prevent surgical site infection after breast cancer surgery. AB - This systematic review includes 11 randomized, controlled trials of mixed patient groups, including patients with or without breast cancer. Studies were included in the review only if data from patients with breast cancer could be separated from patients without breast cancer. The intervention included pre- or perioperative antibiotics used as prophylaxis for the surgery. A range of antibiotic regimens were assessed in the 11 studies, and 5 of the studies defined a similar antibiotic strategy. Five of the studies had similar choice of antibiotic, type of surgery, and length of follow-up. The reviewers excluded 27 studies because of design and data collection not matching the review requirements. PMID- 26414584 TI - Caring, sharing, and a friendship made for life. AB - A patient named "Bill" was assigned to my team in the summer of 2012 for an autologous stem cell transplantation for lymphoma. Bill had previous chemotherapy and had attained clinical status eligibility for a transplantation. Although Bill was rather quiet, he had a lot of questions about me, my family, and my travels. In turn, he shared about his work as a veterinarian, his clinic, and his two dogs that went everywhere with him. He also shared his love of the outdoors and traveling, highlighted by a trip on the Amazon River with his father and daughter. I told him that one of my hobbies is making dill pickles. He countered with stories about his bees and honey, and we agreed to share our homemade goods. PMID- 26414585 TI - A concept analysis of nurses' grief. AB - BACKGROUND: The psychological and personal well-being of nurses can change the way they care for patients. If nurses' grief is not properly managed, the nursing shortage will continue to grow. Consequently, a need exists for the identification of nurses' grief and effective interventions to manage grief to ensure the successful development and growth of the nursing profession. OBJECTIVES: This concept analysis sought to properly define nurses' grief and the role it plays in the day-to-day requirements of nurses. METHODS: A review of the literature was conducted using CINAHL(r), BioMed, EBSCOhost, and MEDLINE(r) and the following key words. FINDINGS: Nurses' grief must be incorporated into the nursing curriculum and addressed by employers. In particular, facility leaders should help promote a healthy work environment and address the need for proper grief management. Educators, managers, and nurses can benefit from acknowledging the current gap in managing nurses' grief. PMID- 26414586 TI - Analysis of denosumab on skeletal-related events in patients with advanced breast cancer. AB - BACKGROUND: Bisphosphonates, which are also known as osteoclast modifiers, are the standard of care in the treatment of skeletal-related events (SREs) in patients with breast cancer with metastatic bone disease. SREs are frequently a complication of advanced breast cancer, and they greatly increase morbidity and mortality in these patients. Unfortunately, even while undergoing bisphosphonate therapy, many patients experience SREs. In 2010, a fully human monoclonal antibody, denosumab (Xgeva(r)), was approved by the U.S. Food and Drug Administration as another option to treat SREs. OBJECTIVES: This article analyzes four primary human research studies looking at the effectiveness and safety of denosumab as compared to bisphosphonates in the prevention of SREs in this vulnerable population. METHODS: Articles published from 2006-2012 were located and reviewed through online database searches (CINAHL(r), MEDLINE(r), PubMed Plus) using the key words denosumab, skeletal-related event, breast cancer, metastases, and bisphosphonates. FINDINGS: Studies reviewed showed comparative adverse events and safety profile between denosumab and bisphosphonates. However, denosumab was shown to have increased effectiveness in the prevention of SREs. This knowledge can influence the preventive measures taken by physicians and advanced practice nurses to improve the prevention of SREs in patients with metastatic breast cancer. It can also increase staff nurse knowledge and implementation of evidence-based practice. PMID- 26414587 TI - Oral intake of ginger for chemotherapy-induced nausea and vomiting among women with breast cancer. AB - BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is among the most common and distressing symptoms experienced by patients receiving cancer treatment. Nurses play a substantial role in the prevention and management of CINV. Ginger (Zingiber officinale Roscoe) is often advocated as beneficial for nausea and vomiting. Whether the herb is truly efficacious for this condition is, however, still a matter of debate. OBJECTIVES: This experimental randomized, controlled trial was done to assess the effect of ginger on chemotherapy-related nausea and vomiting. METHODS: All patients in the study (N = 60) received standard antiemetic drugs. The patients in the study group (n = 30) also received oral ginger for the first three days of the chemotherapy cycle. No intervention was performed in the control group (n = 30) except for the routine antiemetic treatment. Nausea severity and the number of vomiting and retching episodes were measured four times each day for the first five days of the chemotherapy cycle in the patient diary. Nausea severity was evaluated using a numeric scale ranging from 0 (no nausea) to 10 (very severe nausea). FINDINGS: The researchers analyzed the five-day mean score of nausea severity and the number of vomiting and retching episodes. Based on this comparison, nausea severity and the number of vomiting episodes were significantly lower in the intervention group than in the control group (p > 0.05). However, the change in the number of retching episodes between the intervention and control groups was not statistically significant (p > 0.05). PMID- 26414588 TI - Exercise and the breast cancer survivor: the role of the nurse practitioner. AB - BACKGROUND: Patients with cancer are living longer with their disease and have improved survival rates because of early detection and more effective cancer treatments. Lifestyle modification and exercise improve clinical outcomes in breast cancer survivors. OBJECTIVES: Exercise has important implications for the survivor and should be integrated into the aftercare trajectory of survivorship. METHODS: A literature review of articles published from 2002-2014 was conducted using the key words cancer survivor, survivorship, breast cancer, collaboration, and exercise. PubMed, Cochrane Database of Systematic Reviews, and CINAHL(r) databases were searched. FINDINGS: Nurse practitioners can build an environment to motivate patients to exercise, empowering them to be active participants in their own survivorship care. Collaboration is necessary to ensure that healthy lifestyle choices, including exercise, are being discussed and implemented in survivorship care plans to help optimize patient outcomes. PMID- 26414590 TI - Venous thromboembolism: identifying patients at risk and establishing prophylaxis. AB - Venous thromboembolism (VTE) is a major cause of morbidity and mortality and is associated with substantial healthcare costs. Identification of patients at risk of developing VTE enables appropriate thromboprophylaxis to be implemented. Although no predisposing risk factors can be identified in many patients in whom VTE develops, most have at least one underlying risk factor which can be categorized according to whether it confers low, moderate, or high risk. Clinical trials have demonstrated the effectiveness of thromboprophylaxis, both non pharmacological and pharmacological, in a host of medical settings and there is sufficient evidence to support routine prophylaxis in many groups of patients. The implementation of decision making tools based on risk factor assessment improves the prescription of appropriate VTE prophylaxis. Nonetheless, thromboprophylaxis is often inadequate, with haphazard risk assessment and application of guidelines, leading to easily preventable instances of VTE. The most commonly used agents for pharmacological thromboprophylaxis of VTE are low dose unfractionated heparin; a low molecular weight heparin such as dalteparin, enoxaparin or tinzaparin; fondaparinux; warfarin; or aspirin. However, these have a number of drawbacks, principally the need for parenteral administration (with heparins) and frequent coagulation monitoring (with warfarin). The optimal anticoagulant would be orally administered, with a wide therapeutic window, rapid onset of action, predictable pharmacodynamics and pharmacokinetics, minimal interactions with food and other drugs, an ability to inhibit free and clot-bound coagulation factors, low, non-specific binding, and no requirement for routine coagulation monitoring or dose adjustment. A number of novel, single-target oral anticoagulants have been developed that appear to fulfill many of these requirements. This narrative review discusses the use of guidelines and risk assessment tools to identify patients at risk of VTE; it provides an overview of appropriate prophylaxis strategies in these patients with a summary of clinical trial results with novel oral anticoagulants. PMID- 26414592 TI - Synthesis of 2,5-Dihydrofurans via a Gold(I)-Catalyzed Formal [4 + 1] Cycloaddition of alpha-Diazoesters and Propargyl Alcohols. AB - A gold(I)-catalyzed formal [4 + 1] cycloaddition of alpha-diazoesters and propargyl alcohols is disclosed, offering access to a variety of 2,5 dihydrofurans. The reaction shows a broad substrate scope and functional group tolerance. Preliminary mechanistic investigation indicates that this reaction most likely occurs through a 5-endo-dig cyclization of an alpha-hydroxy allene intermediate. PMID- 26414591 TI - Manganese-Enhanced Magnetic Resonance Imaging as a Diagnostic and Dispositional Tool after Mild-Moderate Blast Traumatic Brain Injury. AB - Traumatic brain injury (TBI) caused by explosive munitions, known as blast TBI, is the signature injury in recent military conflicts in Iraq and Afghanistan. Diagnostic evaluation of TBI, including blast TBI, is based on clinical history, symptoms, and neuropsychological testing, all of which can result in misdiagnosis or underdiagnosis of this condition, particularly in the case of TBI of mild-to moderate severity. Prognosis is currently determined by TBI severity, recurrence, and type of pathology, and also may be influenced by promptness of clinical intervention when more effective treatments become available. An important task is prevention of repetitive TBI, particularly when the patient is still symptomatic. For these reasons, the establishment of quantitative biological markers can serve to improve diagnosis and preventative or therapeutic management. In this study, we used a shock-tube model of blast TBI to determine whether manganese-enhanced magnetic resonance imaging (MEMRI) can serve as a tool to accurately and quantitatively diagnose mild-to-moderate blast TBI. Mice were subjected to a 30 psig blast and administered a single dose of MnCl2 intraperitoneally. Longitudinal T1-magnetic resonance imaging (MRI) performed at 6, 24, 48, and 72 h and at 14 and 28 days revealed a marked signal enhancement in the brain of mice exposed to blast, compared with sham controls, at nearly all time-points. Interestingly, when mice were protected with a polycarbonate body shield during blast exposure, the marked increase in contrast was prevented. We conclude that manganese uptake can serve as a quantitative biomarker for TBI and that MEMRI is a minimally-invasive quantitative approach that can aid in the accurate diagnosis and management of blast TBI. In addition, the prevention of the increased uptake of manganese by body protection strongly suggests that the exposure of an individual to blast risk could benefit from the design of improved body armor. PMID- 26414593 TI - Ultrasound-Guided Transgluteal Percutaneous Nephrolithotomy for a Patient with Complex Urogenital Reconstruction and Ectopic Kidney. AB - BACKGROUND AND PURPOSE: Pediatric patients with urolithiasis and complex reconstructed genitourinary anatomy pose a significant surgical challenge. We describe a technique utilized to treat an obstructing calculus in the ectopic kidney of a patient with a history of cloacal exstrophy, bladder augmentation, Monti catheterizable channel, and reconstructed abdominal wall. Case and Technique: A 5-year-old female with a history of cloacal exstrophy, pelvic kidney, and reconstructed urologic and abdominal wall anatomy presented after prior shockwave lithotripsy with an obstructing ureteropelvic junction calculus with signs of sepsis. Because of the patient's previous abdominal wall reconstruction with polytetrafluoroethylene mesh and the location of her pelvic kidney, traditional methods of percutaneous nephrostomy tube placement could not be performed. Transgluteal percutaneous nephrostomy tube was placed by interventional radiology. Subsequently, a percutaneous nephrolithotomy (PCNL) was performed through this tract. CONCLUSIONS: Transgluteal PCNL is a feasible option in children with complex congenital genitourinary anomalies with a history of reconstructed anatomy. PMID- 26414595 TI - Managing hospitalized hemodialysis patients: A guide for the non-nephrologist. AB - In-hospital care of end-stage renal disease (ESRD) patients, on hemodialysis, is different from the general population in various aspects. Non-nephrologists do not typically receive specialized training to take care of these patients. However, in most circumstances, they serve as the primary attending for these patients in the hospital setting. There is paucity of the literature guiding non nephrologists on this important issue. This article highlights the key management aspects of in-hospital care of these patients that all the non-nephrologists should know. PMID- 26414594 TI - Postoperative atrial fibrillation in patients undergoing non-cardiac non-thoracic surgery: A practical approach for the hospitalist. AB - New postoperative atrial fibrillation (POAF) is the most common perioperative arrhythmia and its reported incidence ranges from 0.4 to 26% in patients undergoing non-cardiac non-thoracic surgery. The incidence varies according to patient characteristics such as age, presence of structural heart disease and other co-morbidities, as well as the type of surgery performed. POAF occurs as a consequence of adrenergic stimulation, systemic inflammation, or autonomic activation in the intra or postoperative period (e.g. due to pain, hypotension, infection) in the setting of a susceptible myocardium and other predisposing factors (e.g. electrolyte abnormalities). POAF develops between day 1 and day 4 post-surgery and it is often considered a self-limited entity. Its acute management involves many of the same strategies used in non-surgical patients but the optimal long-term management is challenging because of the limited available evidence. Several studies have shown an association between occurrence of POAF and in-hospital morbidity, mortality, and length of stay. Although, traditionally, POAF was considered to have a generally favorable long-term prognosis, recent data have shown an association with an increased risk of stroke at 1 year after hospitalization. It is unknown, however, whether strategies to prevent POAF or for rate/rhythm control when it does occur, lead to a reduction in morbidity or mortality. This suggests the need for future studies to better understand the risks associated with POAF and to determine optimal strategies to minimize long-term thromboembolic risks. In this article, we summarize the current knowledge on epidemiology, pathophysiology, and short- and long-term management of POAF after non-cardiac non-thoracic surgery with the goal of providing a practical approach to managing these patients for the non cardiologist clinician. PMID- 26414597 TI - Interspecies quantitative structure-toxicity-toxicity (QSTTR) relationship modeling of ionic liquids. Toxicity of ionic liquids to V. fischeri, D. magna and S. vacuolatus. AB - Considering the increasing uses of ionic liquids (ILs) in various industrial processes and chemical engineering operations, a complete assessment of their hazardous profile is essential. In the absence of adequate experimental data, in silico modeling might be helpful in filling data gaps for the toxicity of ILs towards various ecological indicator organisms. Using the rationale of taxonomic relatedness, the development of predictive quantitative structure-toxicity toxicity relationship (QSTTR) models allows predicting the toxicity of ILs to a particular species using available experimental toxicity data towards a different species. Such studies may employ, along with the available experimental toxicity data to a species, molecular structure features and physicochemical properties of chemicals as independent variables for prediction of the toxicity profile against another closely related species. A few such interspecies toxicity correlation models have been reported in the literature for diverse chemicals in general, but this approach has been rarely applied to the class of ionic liquids. The present study involves the use of IL toxicity data towards the bacteria Vibrio fischeri along with molecular structure derived information or computational descriptors like extended topochemical atom (ETA) indices, quantum topological molecular similarity (QTMS) descriptors and computed lipophilicity measure (logk0) for the interspecies exploration of the toxicity data towards green algae S. vacuolatus and crustacea Daphnia magna, separately. This modeling study has been performed in accordance with the OECD guidelines. Finally, predictions for a true external set have been performed to fill the data gap of toxicity towards daphnids and algae using the Vibrio toxicity data and molecular structure attributes. PMID- 26414596 TI - Six-week follow-up after HIV-1 exposure: a position statement from the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy. AB - In 2014 the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy (RAV) conducted a review and analysis of the state of knowledge on the duration of follow-up after exposure to human immunodeficiency virus (HIV). Up until then a follow-up of 12 weeks after exposure had been recommended, but improved tests and new information on early diagnosis motivated a re evaluation of the national recommendations by experts representing infectious diseases and microbiology, county medical officers, the RAV, the Public Health Agency, and other national authorities. Based on the current state of knowledge the Public Health Agency of Sweden and the RAV recommend, starting in April 2015, a follow-up period of 6 weeks after possible HIV-1 exposure, if HIV testing is performed using laboratory-based combination tests detecting both HIV antibody and antigen. If point-of-care rapid HIV tests are used, a follow-up period of 8 weeks is recommended, because currently available rapid tests have insufficient sensitivity for detection of HIV-1 antigen. A follow-up period of 12 weeks is recommended after a possible exposure for HIV-2, since presently used assays do not include HIV-2 antigens and only limited information is available on the development of HIV antibodies during early HIV-2 infection. If pre- or post exposure prophylaxis is administered, the follow-up period is recommended to begin after completion of prophylaxis. Even if infection cannot be reliably excluded before the end of the recommended follow-up period, HIV testing should be performed at first contact for persons who seek such testing. PMID- 26414598 TI - Understanding the challenges of protein flexibility in drug design. AB - INTRODUCTION: Protein-ligand interactions play key roles in various metabolic pathways, and the proteins involved in these interactions represent major targets for drug discovery. Molecular docking is widely used to predict the structure of protein-ligand complexes, and protein flexibility stands out as one of the most important and challenging issues for binding mode prediction. Various docking methods accounting for protein flexibility have been proposed, tackling problems of ever-increasing dimensionality. AREAS COVERED: This paper presents an overview of conformational sampling methods treating target flexibility during molecular docking. Special attention is given to approaches considering full protein flexibility. Contrary to what is frequently done, this review does not rely on classical biomolecular recognition models to classify existing docking methods. Instead, it applies algorithmic considerations, focusing on the level of flexibility accounted for. This review also discusses the diversity of docking applications, from virtual screening (VS) of small drug-like compounds to geometry prediction (GP) of protein-peptide complexes. EXPERT OPINION: Considering the diversity of docking methods presented here, deciding which one is the best at treating protein flexibility depends on the system under study and the research application. In VS experiments, ensemble docking can be used to implicitly account for large-scale conformational changes, and selective docking can additionally consider local binding-site rearrangements. In other cases, on the-fly exploration of the whole protein-ligand complex might be needed for accurate GP of the binding mode. Among other things, future methods are expected to provide alternative binding modes, which will better reflect the dynamic nature of protein-ligand interactions. PMID- 26414600 TI - Vascular Complications and Bleeding After Transfemoral Transcatheter Aortic Valve Implantation Performed Through Open Surgical Access. AB - Major vascular complications (VC) remain frequent after transcatheter aortic valve implantation (TAVI) and may be associated with unfavorable clinical outcomes. The objective of this study was to evaluate the rate of VC after transfemoral TAVI performed using an exclusive open surgical access strategy. From 2010 to 2014, we included in a monocentric registry all consecutive patients who underwent transfemoral TAVI. The procedures were performed with 16Fr to 20Fr sheath systems. VC were evaluated within 30 days and classified as major or minor according to the Valve Academic Research Consortium 2 definition. The study included 396 patients, 218 were women (55%), median age was 85 years (81 to 88), and the median logistic Euroscore was 15.2% (11 to 23). The balloon-expandable SAPIEN XT and the self-expandable Medtronic Core Valve prosthesis were used in 288 (72.7%) and 108 patients (27.3%), respectively. The total length of the procedure was 68 +/- 15 minutes including 13 +/- 5 minutes for the open surgical access. Major and minor VC were observed in 9 (2.3%) and 16 patients (4%), respectively, whereas life-threatening and major bleeding concerned 18 patients (4.6%). The median duration of hospitalization was 5 days (interquartile range 2 to 7), significantly higher in patients with VC (7 days [5 to 15], p <0.001). Mortality at 1-month and 1-year follow-up (n = 26, 6.6%; and n = 67, 17.2%, respectively) was not related to major or minor VC (p = 0.6). In multivariable analysis, only diabetes (odds ratio 2.5, 95% confidence interval 1.1 to 6.1, p = 0.034) and chronic kidney failure (odds ratio 3.0, 95% confidence interval 1.0 to 9.0, p = 0.046) were predictive of VC, whereas body mass index, gender, Euroscore, and lower limb arteriopathy were not. In conclusion, minimal rate of VC and bleeding can be obtained after transfemoral TAVI performed using an exclusive surgical strategy, with a particular advantage observed in high-risk bleeding patients. PMID- 26414602 TI - The Influence of Hypovolemia and Fluid Resuscitation During Hemorrhagic Shock on Apneic Oxygen Desaturation After Preoxygenation in a Swine Model. AB - BACKGROUND: Patients experiencing major bleeding often require both aggressive fluid resuscitation and rapid sequence tracheal intubation. The influence of hemorrhage-induced hypovolemia, and/or subsequent fluid resuscitation, on the time until critical oxygen desaturation is not well described. We studied the time to oxygen desaturation in a pig model of hemorrhage shock and colloid resuscitation. METHODS: After anesthetic induction with isoflurane, 9 swine (mean +/- SD = 25.3 +/- 0.6 kg) were studied with the use of a stepwise hemorrhage and fluid resuscitation model with 4 sequential stages: 600 mL hemorrhage, 600 mL hydroxyethyl starch infusion, a further 600 mL hemorrhage, and a second 600 mL hydroxyethyl starch infusion. At each stage, after 5 minutes of mechanical ventilation with 100% oxygen, we induced apnea and measured the time to oxygen desaturation (oxygen saturation [SpO2] <70%). Hemodynamic and blood gas variables were recorded, and the cerebral and peripheral tissue oxygenation indices were recorded by near-infrared spectroscopy. RESULTS: The times +/- SD to SpO2 <70% at each stage were 136 +/- 41 (baseline), 147 +/- 41 (hemorrhage), 131 +/- 38 (resuscitation), 147 +/- 38 (repeat hemorrhage), and 134 +/- 36 seconds (repeat resuscitation). The mean differences in times before and after hemorrhage were 11.2 (6.5 to 16.0, P = 0.0052) and 16.0 (11.0 to 21.0, P < 0.0001), respectively. PaO2 before and after apneic desaturation (at SpO2 < 70%) was not different between stages. On the basis of tissue oxygenation index findings, hypovolemia decreased oxygen consumption, and fluid resuscitation recovered this parameter. CONCLUSIONS: In patients with acute hemorrhagic shock, a hypovolemic state increases the duration of apnea until critical oxygen desaturation. Clinicians should thus consider the relationship between fluid resuscitation and time to desaturation when performing tracheal intubation in such patients. PMID- 26414599 TI - In Vivo Evaluation of Adipose-Derived Stromal Cells Delivered with a Nanofiber Scaffold for Tendon-to-Bone Repair. AB - Rotator cuff tears are common and cause a great deal of lost productivity, pain, and disability. Tears are typically repaired by suturing the tendon back to its bony attachment. Unfortunately, the structural (e.g., aligned collagen) and compositional (e.g., a gradient in mineral) elements that produce a robust attachment in the healthy tissue are not regenerated during healing, and the repair is prone to failure. Two features of the failed healing response are deposition of poorly aligned scar tissue and loss of bone at the repair site. Therefore, the objective of the current study was to improve tendon-to-bone healing by promoting aligned collagen deposition and increased bone formation using a biomimetic scaffold seeded with pluripotent cells. An aligned nanofibrous poly(lactic-co-glycolic acid) scaffold with a gradient in mineral content was seeded with adipose-derived stromal cells (ASCs) and implanted at the repair site of a rat rotator cuff model. In one group, cells were transduced with the osteogenic factor bone morphogenetic protein 2 (BMP2). The healing response was examined in four groups (suture only, acellular scaffold, cellular scaffold, and cellular BMP2 scaffold) using histologic, bone morphology, and biomechanical outcomes at 14, 28, and 56 days. Histologically, the healing interface was dominated by a fibrovascular scar response in all groups. The acellular scaffold group showed a delayed healing response compared to the other groups. When examining bone morphology parameters, bone loss was evident in the cellular BMP2 group compared to other groups at 28 days. When examining repair-site mechanical properties, strength and modulus were decreased in the cellular BMP2 groups compared to other groups at 28 and 56 days. These results indicated that tendon to-bone healing in this animal model was dominated by scar formation, preventing any positive effects of the implanted biomimetic scaffold. Furthermore, cells transduced with the osteogenic factor BMP2 led to impaired healing, suggesting that this growth factor should not be used in the tendon-to-bone repair setting. PMID- 26414601 TI - A Novel Bone Marrow Stimulation Technique Augmented by Administration of Ultrapurified Alginate Gel Enhances Osteochondral Repair in a Rabbit Model. AB - Cartilage injuries are a common health problem resulting in the loss of daily activities. Bone marrow stimulation technique, one of the surgical techniques for the cartilage injuries, is characterized by technical simplicity and less invasiveness. However, it has been shown to result in fibrous or fibrocartilaginous repair with inferior long-term results. This study focused on using ultrapurified alginate gel (UPAL gel) as an adjuvant scaffold in combination with a bone marrow stimulation technique. The objective of this study was to assess the efficacy of a bone marrow stimulation technique augmented by UPAL gel in a rabbit osteochondral defect model. To achieve this goal, three experimental groups were prepared as follows: defects without intervention, defects treated with a bone marrow stimulation technique, and defects treated with a bone marrow stimulation technique augmented by UPAL gel. The macroscopic and histological findings of the defects augmented by UPAL gel improved significantly more than those of the others at 16 weeks postoperatively. The combination technique elicited hyaline-like cartilage repair, unlike bone marrow stimulation technique alone. This combination procedure has the potential of improving clinical outcomes after use of a bone marrow stimulation technique for articular cartilage injuries. PMID- 26414603 TI - The Angelina effect revisited: Exploring a media-related impact on public awareness. AB - BACKGROUND: In 2013, Angelina Jolie's double mastectomy and publication of her personal treatment choice for BRCA1 positivity generated considerable media attention. To the authors' knowledge, the current study is the first prospective survey conducted among the general public to measure a quantifiable media-related effect on public awareness. METHODS: The authors analyzed the changes in the general public's awareness of reconstructive options in breast cancer among 2 female population-matched cohorts aged 18 to 65 years (1000 participants in each cohort) before (March 2013; poll 1) and after (June 2013; poll 2) the announcement of Ms. Jolie's mastectomy in May 2013. RESULTS: There was an observed increase in public awareness: significantly more women from poll 2 were aware of reconstructive breast surgery being possible after breast cancer-related mastectomy, notably with regard to autologous tissue and single-stage reconstructions. Approximately 20% of the women in poll 2 (205 women) indicated that media coverage regarding Ms. Jolie affected their interest in breast cancer. A question that was exclusive to poll 2 revealed a preference for autologous (66.2%) versus implant-based (8.2%) reconstructions, with the remainder indicating no preference (25.6%). None of the stratification variables were found to be associated with the above findings. CONCLUSIONS: To the best of the authors' knowledge, this is the first prospective study to demonstrate a statistically significant impact of a celebrity announcement on public awareness regarding breast cancer treatment. The results underscore the importance of a media-related impact for professionals in the health care sector, which can serve as a tipping point for raising awareness and improving knowledge concerning a specific disease among the general public. PMID- 26414604 TI - Telomerase Reverse Transcriptase and Peroxisome Proliferator-Activated Receptor gamma Co-Activator-1alpha Cooperate to Protect Cells from DNA Damage and Mitochondrial Dysfunction in Vascular Senescence. AB - Reduced telomere length with increasing age in dividing cells has been implicated in contributing to the pathologies of human aging, which include cardiovascular and metabolic disorders, through induction of cellular senescence. Telomere shortening results from the absence of telomerase, an enzyme required to maintain telomere length. Telomerase reverse transcriptase (TERT), the protein subunit of telomerase, is expressed only transiently in a subset of adult somatic cells, which include stem cells and smooth muscle cells. A recent report from Xiong and colleagues demonstrates a pivotal role for the transcription co-factor peroxisome proliferator-activated receptor gamma co-activator-1alpha (PGC-1alpha) in maintaining TERT expression and preventing vascular senescence and atherosclerosis in mice. Ablation of PGC-1alpha reduced TERT expression and increased DNA damage and reactive oxygen species (ROS), resulting in shortened telomeres and vascular senescence. In the ApoE(-/-) mouse model of atherosclerosis, forced expression of PGC-1alpha increased expression of TERT, extended telomeres, and reversed genomic DNA damage, vascular senescence, and the development of atherosclerotic plaques. Alpha lipoic acid (ALA) stimulated expression of PGC-1alpha and TERT and reversed DNA damage, vascular senescence, and atherosclerosis, similarly to ectopic expression of PGC-1alpha. ALA stimulated cyclic adenosine monophosphate (cAMP) signaling, which in turn activated the cAMP response element-binding protein (CREB), a co-factor for PGC 1alpha expression. The possibility that ALA might induce TERT to extend telomeres in human cells suggests that ALA may be useful in treating atherosclerosis and other aging-related diseases. However, further investigation is needed to identify whether ALA induces TERT in human cells, which cell types are susceptible, and whether such changes have clinical significance. PMID- 26414605 TI - Pilot scale application of anaerobic baffled reactor for biologically enhanced primary treatment of raw municipal wastewater. AB - A four-cell anaerobic baffled reactor (ABR) was operated for two years treating raw municipal wastewater at ambient water and air temperatures of 12-23 degrees C and -10 to 35 degrees C, respectively. The 1000-L pilot reactor operated at a 12-h hydraulic residence time and was located in the Headworks building of the Plum Creek Water Reclamation Authority. The average influent was TSS = 510 +/- 400 mg/L, BOD5 = 320 +/- 80 mg/L and the average removal of TSS and BOD5 was 83 +/- 10% and 47 +/- 15%, respectively. The TSS and BOD removal exceeded that of conventional primary clarification, with no wasting of the settled solids over the two-years and stoichiometric production of methane. The estimated energy content of the biogas produced per unit volume of wastewater treated averaged 0.45 kWh/m(3). The TSS and total COD removal in the first cell averaged 75 +/- 15% and 43 +/- 14%, respectively, but methane production was only 20% of the total observed for the full ABR. The performance of the ABR relative to the extent of solids hydrolysis and methane production can be varied by the number of cells and hydraulic residence time. The anaerobic baffled reactor is an energy positive technology that can be used for biologically enhanced primary treatment of raw municipal wastewater in cold climates. PMID- 26414606 TI - Urinary diversion 2015: controversies and new technologies: Choosing the 'right' diversion. PMID- 26414607 TI - Can multiparametric MRI rule in or rule out significant prostate cancer? AB - PURPOSE OF REVIEW: To show how multiparametric MRI can rule in the presence of significant prostate cancer (PCa), allowing for magnetic resonance-targeted biopsies to detect aggressive tumors eligible for immediate treatment and to evaluate if mp-MRI can rule out significant tumor foci to avoid overdiagnosis and overtreatment of PCa. RECENT FINDINGS: Diffusion-weighted MRI plays a major role to detect tumor foci and to rule in significant PCa. A low apparent diffusion coefficient (ADC) value indicates that high Gleason grade tumors are present. Conversely, the absence of any suspicious focus or foci with a high apparent diffusion coefficient value indicates either benign tissue or low-grade tumor SUMMARY: mp-MRI Multiparametric MRI is a highly accurate filter to detect aggressive tumors and to avoid detection of insignificant cancer. There is growing evidence that it may be indicated in any man with an elevated Prostatic Specific Antigen level before considering whether an immediate biopsy should be performed or whether a simple follow-up should be the option. PMID- 26414608 TI - Using multiparametric MRI to 'personalize' biopsy for men. AB - PURPOSE OF REVIEW: In recent years, multiparametric magnetic resonance imaging (mpMRI) of the prostate has shown promise as a modality to identify areas of suspicion within the gland which correlate with cancer location and disease extent. However, optimal individualization of prostate biopsy using mpMRI relies on aligning the relative benefits of MRI-targeted approaches with the goals of biopsy. RECENT FINDINGS: For men with prior negative biopsies, mpMRI allows improved detection of occult high-grade cancers missed by repeat systematic biopsy but also has the potential to identify men who will not benefit from repeat biopsy due to a low likelihood of significant disease. For men with prior low-grade cancer diagnosis, the addition of MRI-targeted biopsy may identify those who are poor candidates for active surveillance by detecting high-risk disease without serial biopsies. For men without prior biopsy, mpMRI and targeted biopsy may help improve high-grade cancer diagnosis and significantly limit the detection of low-risk disease. SUMMARY: mpMRI of the prostate is a promising tool to address many of the shortcomings of traditional systematic prostate biopsy. Biopsy history plays a critical role in determining how to assess the potential advantages and disadvantages of prostate mpMRI in the context of each patient. Although these benefits have been suggested by published clinical outcomes data, there is a need for prospective validation of mpMRI and MRI-targeted biopsy in comparison with the current approach of systematic biopsy for all men, to define new paradigms for prostate cancer detection and risk stratification. PMID- 26414609 TI - Health-related quality of life with urinary diversion. AB - PURPOSE OF REVIEW: Patients who undergo radical cystectomy and urinary diversion experience a lengthy period of postoperative recovery from physical, functional, social, and emotional challenges that greatly impact health-related quality of life (HRQoL). These changes affect nearly all patients and must be reviewed in detail as part of the preoperative consultation. However, quantifying a patient's risk for altered HRQoL is imprecise, thus complicating the choice for urinary diversion. RECENT FINDINGS: A recent prospective study observed improved global health status and physical, role, and social functioning in patients treated with orthotopic neobladder diversion compared with patients treated with ileal conduit diversion. In contrast, robotic-assisted radical cystectomy does not improve patient quality of life (QoL) over open radical cystectomy within the first year of surgery. Enhanced recovery protocols improve immediate postoperative QoL but their effect on long-term QoL is uncertain. SUMMARY: There is still a significant lack of understanding about the QoL between various types of urinary diversions. Recent and ongoing prospective randomized trials in the radical cystectomy population may shed light on urinary diversion-specific function and related effects on HRQoL. Ultimately, well designed, large multicenter prospective controlled trials comparing functional, social, and emotional outcomes of continent and incontinent urinary diversion are still needed. PMID- 26414610 TI - Orthotopic urinary diversion. AB - PURPOSE OF REVIEW: Orthotopic urinary diversion has been performed for more than 30 years. Although it is considered to be the gold standard form of diversion in many centers of expertise, however it is uncommonly performed outside these institutions. The purpose of this article is to review the current indications and outcomes of orthotopic diversion with a focus on male patients and to explore potential barriers to wider dissemination of the technique. RECENT FINDINGS: Approximately 75% of patients undergoing radical cystectomy today are candidates for orthotopic diversion and in the absence of absolute contraindications, very few patients chose to undergo an ileal conduit for personal reasons. In a recent quality of life study, the orthotopic neobladder was better than ileal conduit in terms of global health status and physical functioning. In a prospective randomized trial comparing a refluxing versus nonrefluxing neobladder, there was no difference in renal function after 3 years. There is currently insufficient evidence to suggest improved perioperative outcomes with the use of minimally invasive techniques. SUMMARY: There are very few absolute contraindications for an orthotopic neobladder, which remains the gold standard form of diversion at many centers of expertise. Surgeon experience and thorough preoperative counseling with realistic expectations can ensure optimal outcomes and patient satisfaction. PMID- 26414612 TI - Is It Time to Stop Paying for Computer-Aided Mammography? PMID- 26414611 TI - Cofeeding intra- and interspecific transmission of an emerging insect-borne rickettsial pathogen. AB - Cat fleas (Ctenocephalides felis) are known as the primary vector and reservoir of Rickettsia felis, the causative agent of flea-borne spotted fever; however, field surveys regularly report molecular detection of this infectious agent from other blood-feeding arthropods. The presence of R. felis in additional arthropods may be the result of chance consumption of an infectious bloodmeal, but isolation of viable rickettsiae circulating in the blood of suspected vertebrate reservoirs has not been demonstrated. Successful transmission of pathogens between actively blood-feeding arthropods in the absence of a disseminated vertebrate infection has been verified, referred to as cofeeding transmission. Therefore, the principal route from systemically infected vertebrates to uninfected arthropods may not be applicable to the R. felis transmission cycle. Here, we show both intra- and interspecific transmission of R. felis between cofeeding arthropods on a vertebrate host. Analyses revealed that infected cat fleas transmitted R. felis to naive cat fleas and rat fleas (Xenopsylla cheopis) via fleabite on a nonrickettsemic vertebrate host. Also, cat fleas infected by cofeeding were infectious to newly emerged uninfected cat fleas in an artificial system. Furthermore, we utilized a stochastic model to demonstrate that cofeeding is sufficient to explain the enzootic spread of R. felis amongst populations of the biological vector. Our results implicate cat fleas in the spread of R. felis amongst different vectors, and the demonstration of cofeeding transmission of R. felis through a vertebrate host represents a novel transmission paradigm for insect-borne Rickettsia and furthers our understanding of this emerging rickettsiosis. PMID- 26414613 TI - Why is Rheumatoid Arthritis Mortality Still High Despite the Advent of New Therapies? Comment on the Article by Widdifield et al. PMID- 26414614 TI - CD33 modulates TREM2: convergence of Alzheimer loci. AB - We used a protein quantitative trait analysis in monocytes from 226 individuals to evaluate cross-talk between Alzheimer loci. The NME8 locus influenced PTK2B and the CD33 risk allele led to greater TREM2 expression. There was also a decreased TREM1/TREM2 ratio with a TREM1 risk allele, decreased TREM2 expression with CD33 suppression and elevated cortical TREM2 mRNA expression with amyloid pathology. PMID- 26414615 TI - A direct translaminar inhibitory circuit tunes cortical output. AB - Anatomical and physiological experiments have outlined a blueprint for the feedforward flow of activity in cortical circuits: signals are thought to propagate primarily from the middle cortical layer (layer 4, L4) up to L2/3 and down to the major cortical output layer (L5). Pharmacological manipulations, however, have contested this model and have suggested that L4 may not be critical for sensory responses of neurons in either superficial or deep layers. To address these conflicting models, we reversibly manipulated L4 activity in awake, behaving mice using cell type-specific optogenetics. In contrast with both prevailing models, we found that activity in L4 directly suppressed L5, in part by activating deep, fast-spiking inhibitory neurons. Our data suggest that the net effect of L4 activity is to sharpen the spatial representations of L5 neurons. Thus, we establish a previously unknown translaminar inhibitory circuit in the sensory cortex that acts to enhance the feature selectivity of cortical output. PMID- 26414616 TI - A positive-negative mode of population covariation links brain connectivity, demographics and behavior. AB - We investigated the relationship between individual subjects' functional connectomes and 280 behavioral and demographic measures in a single holistic multivariate analysis relating imaging to non-imaging data from 461 subjects in the Human Connectome Project. We identified one strong mode of population co variation: subjects were predominantly spread along a single 'positive-negative' axis linking lifestyle, demographic and psychometric measures to each other and to a specific pattern of brain connectivity. PMID- 26414618 TI - Modeling the predictors of safety behavior in construction workers. AB - This paper presents a model that quantifies the causal relations among safety variables (latent variables) and workers' safety behavior (indicator) using statistical data and hypotheses obtained from construction workers and existing literatures, respectively. The safety variables that affect workers' safety behaviors are identified from existing studies and operationalized to measure their causal relations with the workers' behaviors. The model identifies the directions and degrees of the effect of every latent variable on the other latent variables and the indicator. Survey questionnaires were administered to construction workers in South Korea. Exploratory and confirmatory factor analyses, Cronbach's alpha and structural equation modeling were performed to test the causal hypotheses using SPSS 18.0 and AMOS 18.0. This study provides the theoretical model that predicts construction workers' safety behavior on construction sites using path diagram and analysis. PMID- 26414619 TI - Computational Lexical Analysis of the Language Commonly Used to Describe Gout. AB - OBJECTIVE: To characterize the current language that is used in describing and defining gout, its symptoms, and its treatment by reviewing recent publications in rheumatology and determining how word choice may, or may not, be reflective of recent scientific developments in gout specifically. METHODS: This was a computational linguistics study, using collocations analyses and concordance analyses on a database of scientific literature related to gout. The final data set for analysis included 2,590 articles, all relating to gout and published between May 2003 and May 2013 and amounting to 12,101,036 tokens (sentence segments). Analysis was conducted by a team of linguists and social scientists. RESULTS: Our primary finding is that current disease language in gout is marked by ambiguity and imprecision, as evidenced by numerous terms that have similar but distinct meanings, but are nevertheless used interchangeably, therefore blending the slight but significant distinctions between these words. Whereas treatment language is characterized by a multitude of terms to describe a therapeutic mechanism of action, there is a relative void of terms and phrases used to describe success (treating to target) in gout. CONCLUSION: The data suggest that the language used to describe gout could be improved and updated. A transformation from an antiquated and insufficiently descript terminological set to one that reflects the recent scientific and clinical advancements made in the category would maximize opportunities for patient and physician understanding. PMID- 26414620 TI - Evaluation of the predictive capacity of DNA variants associated with straight hair in Europeans. AB - DNA-based prediction of hair morphology, defined as straight, curly or wavy hair, could contribute to an improved description of an unknown offender and allow more accurate forensic reconstructions of physical appearance in the field of forensic DNA phenotyping. Differences in scalp hair morphology are significant at the worldwide scale and within Europe. The only genome-wide association study made to date revealed the Trichohyalin gene (TCHH) to be significantly associated with hair morphology in Europeans and reported weaker associations for WNT10A and FRAS1 genes. We conducted a study that centered on six SNPs located in these three genes with a sample of 528 individuals from Poland. The predictive capacity of the candidate DNA variants was evaluated using logistic regression; classification and regression trees; and neural networks, by applying a 10-fold cross validation procedure. Additionally, an independent test set of 142 males from six European populations was used to verify performance of the developed prediction models. Our study confirmed association of rs11803731 (TCHH), rs7349332 (WNT10A) and rs1268789 (FRAS1) SNPs with hair morphology. The combined genotype risk score for straight hair had an odds ratio of 2.7 and these predictors explained ~ 8.2% of the total variance. The selected three SNPs were found to predict straight hair with a high sensitivity but low specificity when a 10-fold cross validation procedure was applied and the best results were obtained using the neural networks approach (AUC=0.688, sensitivity=91.2%, specificity=23.0%). Application of the neural networks model with 65% probability threshold on an additional test set gave high sensitivity (81.4%) and improved specificity (50.0%) with a total of 78.7% correct calls, but a high non classification rate (66.9%). The combined TTGGGG SNP genotype for rs11803731, rs7349332, rs1268789 (European frequency=4.5%) of all six straight hair associated alleles was identified as the best predictor, giving >80% probability of straight hair. Finally, association testing of 44 SNPs previously identified to be associated with male pattern baldness revealed a suggestive association with hair morphology for rs4679955 on 3q25.1. The study results reported provide the starting point for the development of a predictive test for hair morphology in Europeans. More studies are now needed to discover additional determinants of hair morphology to improve the predictive accuracy of this trait in forensic analysis. PMID- 26414621 TI - Flexible and Stretchable Gold Microstructures on Extra Soft Poly(dimethylsiloxane) Substrates. AB - Stretchable gold microstructures are reliably transferred onto an extra-soft elastomeric substrate. Several major challenges, including failure-free transfer and reliable bonding with the substrate, are addressed. The simple and reproducible fabrication allows extensive study and optimization of the stretchability of meanders in terms of thickness, geometry, and substrate. The results provide new insights for designing stretchable electronics and novel routes for stretchrelated, mechanobiological cell-interface applications. PMID- 26414617 TI - Regeneration versus scarring in vertebrate appendages and heart. AB - Injuries to complex human organs, such as the limbs and the heart, result in pathological conditions, for which we often lack adequate treatments. While modern regenerative approaches are based on the transplantation of stem cell derived cells, natural regeneration in lower vertebrates, such as zebrafish and newts, relies predominantly on the intrinsic plasticity of mature tissues. This property involves local activation of the remaining material at the site of injury to promote cell division, cell migration and complete reproduction of the missing structure. It remains an unresolved question why adult mammals are not equally competent to reactivate morphogenetic programmes. Although organ regeneration depends strongly on the proliferative properties of cells in the injured tissue, it is apparent that various organismic factors, such as innervation, vascularization, hormones, metabolism and the immune system, can affect this process. Here, we focus on a correlation between the regenerative capacity and cellular specialization in the context of functional demands, as illustrated by appendages and heart in diverse vertebrates. Elucidation of the differences between homologous regenerative and non-regenerative tissues from various animal models is essential for understanding the applicability of lessons learned from the study of regenerative biology to clinical strategies for the treatment of injured human organs. PMID- 26414622 TI - Lethal influenza infection: Is a macrophage to blame? AB - Alveolar macrophages (AMs) are critical for immunity against influenza A virus (IAV) infection. Depletion, hyporeactivity, and disruption of AM development and differentiation are all associated with lethal IAV infection. AMs drive the innate immune response that limits IAV infection. AMs are crucial for steady state homeostasis of pulmonary surfactant, and in turn surfactant proteins regulate AMs and participate in host defense against IAV. Known factors that are necessary for AM function and differentiation in vivo include surfactant proteins, the growth factor GM-CSF, the hormone receptor PPARgamma, and the transcription factors PU.1 and Bach2. Although PU.1 and PPARgamma are downstream effectors of GM-CSF, Bach2 works independently. GM-CSF and Bach2-deficient AMs have phenotypes with immature or alternatively activated states of differentiation, respectively, and both extremes are unsuitable for surfactant homeostasis. The activation state of AMs and the local microenvironment may determine the development of symptomatic versus asymptomatic IAV infection in different individuals. PMID- 26414623 TI - Awareness of distractors is necessary to generate a strategy to avoid responding to them: A commentary on Lin and Murray (2015). AB - Lin and Murray published in the 2015 January Issue of Psychological Science a study that claims to have made the surprising discovery of unconscious effects that are stronger than equivalent conscious effects. Specifically, the authors claim to have uncovered dissociable components of aware and unaware orienting and inhibition in exogenous cueing. They suggest an awareness-dependent location based inhibition mechanism referred to as a negative attentional aftereffect. Here we argue for a simpler explanation, based on established literature, that all they have shown is response inhibition to a consciously perceived cue presented at a fixed location. PMID- 26414624 TI - Rediscovering the wound hematoma as a site of hemostasis during major arterial hemorrhage. AB - BACKGROUND: Treatments for major internal bleeding after injury include permissive hypotension to decrease the rate of blood loss, intravenous infusion of plasma or clotting factors to improve clot formation, and rapid surgical hemostasis or arterial embolization to control bleeding vessels. Yet, little is known regarding major internal arterial hemostasis, or how these commonly used treatments might influence hemostasis. OBJECTIVES: (i) To use a swine model of femoral artery bleeding to understand the perivascular hemostatic response to contained arterial hemorrhage. (ii) To directly confirm the association between hemodynamics and bleeding velocity. (iii) To observe the feasibility of delivering an activated clotting factor directly to internal sites of bleeding using a simplified angiographic approach. METHODS: Ultrasound was used to measure bleeding velocity and in vivo clot formation by elastography in a swine model of contained femoral artery bleeding with fluid resuscitation. A swine model of internal pelvic and axillary artery hemorrhage was also used to demonstrate the feasibility of local delivery of an activated clotting factor. RESULTS: In this model, clots formed slowly within the peri-wound hematoma, but eventually contained the bleeding. Central hemodynamics correlated positively with bleeding velocity. Infusion of recombinant human activated factor VII into the injured artery near the site of major internal hemorrhage in the pelvis and axillae was feasible. CONCLUSIONS: We rediscovered that clot formation within the peri-wound hematoma is an integral component of hemostasis and a feasible target for the treatment of major internal bleeding using activated clotting factors delivered using a simplified angiographic approach. PMID- 26414625 TI - Sleep quality but not sleep quantity effects on cortisol responses to acute psychosocial stress. AB - Given the well-documented deleterious health effects, poor sleep has become a serious public health concern and increasing efforts are directed toward understanding underlying pathways. One potential mechanism may be stress and its biological correlates; however, studies investigating the effects of poor sleep on a body's capacity to deal with challenges are lacking. The current study thus aimed at testing the effects of sleep quality and quantity on cortisol responses to acute psychosocial stress. A total of 73 college-aged adults (44 females) were investigated. Self-reported sleep behavior was assessed via the Pittsburgh Sleep Quality Index and salivary cortisol responses to the Trier Social Stress Test were measured. In terms of sleep quality, we found a significant three-way interaction, such that relative to bad sleep quality, men who reported fairly good or very good sleep quality showed blunted or exaggerated cortisol responses, respectively, while women's stress responses were less dependent on their self reported sleep quality. Contrarily, average sleep duration did not appear to impact cortisol stress responses. Lastly, participants who reported daytime dysfunctions (i.e. having trouble staying awake or keeping up enthusiasm) also showed a trend to blunted cortisol stress responses compared to participants who did not experience these types of daytime dysfunctions. Overall, the current study suggests gender-specific stress reactivity dysfunctions as one mechanism linking poor sleep with detrimental physical health outcomes. Furthermore, the observed differential sleep effects may indicate that while the body may be unable to maintain normal hypothalamic-pituitary-adrenal functioning in an acute psychosocial stress situation after falling prey to low sleep quality, it may retain capacities to deal with challenges during extended times of sleep deprivation. PMID- 26414626 TI - Combination of motherwort injection and oxytocin for the prevention of postpartum hemorrhage after cesarean section. AB - OBJECTIVE: To evaluate the efficacy and safety of motherwort injection combined with oxytocin for preventing postpartum hemorrhage (PPH) after cesarean section (CS). METHODS: From March 2011 and February 2013, a randomized study was conducted on 165 primipara undergoing CS. 83 and 82 cases were placed into the combination of oxytocin and motherwort group and oxytocin group, respectively. Blood loss was calculated and measured during three periods: from placental delivery to the end of CS, from the end of CS to 2 h postpartum and from 2 h postpartum to 24 h postpartum. Vital signs were also measured. RESULTS: Blood loss in the period from placental delivery to the end of CS was similar (P = 0.58) in these two arms. The quantity of total blood loss from the end of CS to 2 h postpartum (P = 0.03) and from 2 h postpartum to 24 h postpartum (P = 0.01) were significantly reduced in the combination of oxytocin and motherwort group. No significant abnormal vital signs were observed. Mild, transient side effects occurred more often in the combination of oxytocin and motherwort group. CONCLUSIONS: It is efficacious and safe that combination use of motherwort injection and oxytocin could reduce blood loss and prevent PPH after CS. PMID- 26414627 TI - Biodistribution of Infused Human Umbilical Cord Blood Cells in Alzheimer's Disease-Like Murine Model. AB - Human umbilical cord blood cells (HUCBCs), a prolific source of non-embryonic or adult stem cells, have emerged as effective and relatively safe immunomodulators and neuroprotectors, reducing behavioral impairment in animal models of Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, and stroke. In this report, we followed the bioavailability of HUCBCs in AD-like transgenic PSAPP mice and nontransgenic Sprague-Dawley rats. HUCBCs were injected into tail veins of mice or rats at a single dose of 1 * 10(6) or 2.2 * 10(6) cells, respectively, prior to harvesting of tissues at 24 h, 7 days, and 30 days after injection. For determination of HUCBC distribution, tissues from both species were subjected to total DNA isolation and polymerase chain reaction (PCR) amplification of the gene for human glycerol-3-phosphate dehydrogenase. Our results show a relatively similar biodistribution and retention of HUCBCs in both mouse and rat organs. HUCBCs were broadly detected both in the brain and several peripheral organs, including the liver, kidney, and bone marrow, of both species, starting within 7 days and continuing up to 30 days posttransplantation. No HUCBCs were recovered in the peripheral circulation, even at 24 h posttransplantation. Therefore, HUCBCs reach several tissues including the brain following a single intravenous treatment, suggesting that this route can be a viable method of administration of these cells for the treatment of neurodegenerative diseases. PMID- 26414628 TI - The Association of Glucose Metabolism and Eigenvector Centrality in Alzheimer's Disease. AB - Both fluorine-18-labeled fluorodeoxyglucose ([(18)F]FDG) positron emission tomography, examining glucose metabolism, and resting-state functional magnetic resonance imaging (rs-fMRI), using covarying blood oxygen levels, can be used to explore neuronal dysfunction in Alzheimer's disease (AD). Both measures are reported to identify similar brain regions affected in AD patients. The spatial overlap and association of [(18)F]FDG with rs-fMRI in AD patients and controls were examined to investigate whether these two measures are associated, and if so, to what extent. For 24 AD patients and 18 controls, [(18)F]FDG and rs-fMRI data were available. [(18)F]FDG standardized uptake value ratios (SUVr), with cerebellar gray matter (GM) as reference tissue, were calculated. Eigenvector centrality (EC) mapping was used to spatially analyze the functional brain network. Group differences were calculated for [(18)F]FDG and eigenvector centrality mapping (ECM) values in four cortical regions (occipital, parietal, frontal, and temporal) and across voxels, with age, gender, and GM as covariates. Correlation of [(18)F]FDG with ECM was calculated within groups. Both lowered [(18)F]FDG SUVr and EC values were seen in the parietal and occipital cortex of AD patients. However, [(18)F]FDG yielded more robust and widespread brain areas affected in AD patients; hypometabolism was also observed in the temporal cortex and regions within frontal brain areas. Poor spatial overlap of both measures was observed. No associations were found between local [(18)F]FDG SUVr and ECM. In conclusion, agreement of [(18)F]FDG and ECM in AD patients seems moderate at best. [(18)F]FDG was most accurate in distinguishing AD patients from controls. PMID- 26414629 TI - A Propensity Score Analysis of the Impact of Invasive Intracranial Pressure Monitoring on Outcomes after Severe Traumatic Brain Injury. AB - Although a recent clinical trial (BEST TRIP) demonstrated no improvement in outcomes with invasive intracranial pressure (ICP) monitoring (ICPM) following severe traumatic brain injury (TBI), its generalizability has been called into question. In several global settings ICPM is not the standard of care and is used at the discretion of the attending neurosurgeon. Our objective was to determine the impact of ICPM on mortality and 6-month functional outcomes following severe TBI. The setting was a referral trauma center with 36 intensive care unit (ICU) beds and 300-600 TBI admissions per year. During a 2-year period data were prospectively entered into a severe TBI registry. Patients with severe TBI aged >12 years meeting Brain Trauma Foundation (BTF) criteria for ICPM were included in the study. Outcomes of interest were in-hospital mortality and poor 6-month functional outcome defined as Glasgow Outcome Scale (GOS) score of 3 or lower. A propensity score based analysis incorporating known predictors of outcome in TBI was utilized to examine the impact of ICPM on outcomes. Of 1345 patients meeting study criteria 497 (37%) underwent ICPM. In-hospital mortality was 35% (471/1345). Of 454 patients for whom 6-month outcome was available, 161 (35%) suffered a poor functional outcome. Following propensity score analysis ICPM use was associated with an 8% (p = 0.002) decrease in mortality but no significant effect (p = 0.2) on functional outcome. The use of ICPM following severe TBI was associated with decreased in-hospital mortality. Further clinical trials of ICPM in TBI may be warranted. PMID- 26414630 TI - Anomalous Left Coronary Artery From the Pulmonary Artery in Infants and Toddlers Misdiagnosed as Myocarditis. AB - OBJECTIVES: Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital heart defect. Children with this anomaly are usually asymptomatic at birth and develop symptoms later on in life, which may mimic myocarditis. We sought to delineate clinical, laboratory, and epidemiological aspects of this anomaly. METHODS: A retrospective analysis of children with ALCAPA evaluated in a tertiary medical center in southern Israel was performed. A computerized search for all patients with the diagnosis of ALCAPA between 2000 and 2011 was performed. The medical records were reviewed; demographic, clinical, and laboratory data were extracted. RESULTS: A total of 9 patients were included. In 4 patients, acute deterioration required evaluation in the pediatric emergency medicine department; in all 4, the initial clinical suspicion was myocarditis. Failure to thrive was recorded in 7 (77.7%) of the 9 patients and asthma or wheezing were recorded in 5 (55.5%) of the 9 patients. Normal heart size was recorded in 4 (44.4%) of the 9 patients. Electrocardiographic abnormalities were present in all of the patients (100%). A total of 141,675 births were recorded during the study period, giving an incidence of at least 1 case (0.00635%) per 15,741 births. CONCLUSIONS: Children evaluated in the emergency medicine department with suspected myocarditis should be evaluated specifically for ALCAPA. The clinical findings that should raise the suspicion of this anomaly are failure to thrive and either a diagnosis of asthma or recurrent wheezing. PMID- 26414631 TI - Persistent Pneumonia: Time to Take a Closer Look. AB - Primary pulmonary tumors are rare in pediatrics. When they are encountered, they are usually carcinoid tumors or mucoepidermoid carcinomas. We present a patient who presented to both his primary care physician and the pediatric emergency department with recurrent bouts of wheezing and pneumonia, none of which ever completely resolved despite appropriate treatment. The patient had multiple chest films, which demonstrated the persistence of what appeared to be a right-sided infiltrate/atelectasis. Ultimately, the patient underwent a diagnostic workup that included a computed tomography scan and bronchoscopy. These studies revealed the presence of a bronchial mucoepidermoid carcinoma. The patient was successfully treated with photoablation of the lesion through the involvement of multiple subspecialists, including pediatric pulmonology, pediatric surgery, pediatric otolaryngology, and pediatric oncology. We discuss the incidence and epidemiology of pediatric bronchial tumors in general and mucoepidermoid carcinoma in particular as well as diagnosis, treatment options, and prognosis. Emergency physicians must maintain a high index of suspicion for alternate diagnoses in patients whose disease fails to respond to traditionally accepted therapy. PMID- 26414632 TI - Idiopathic Pulmonary Hemosiderosis Presenting as Anemia, Failure to Thrive, and Jaundice in a Toddler. AB - Idiopathic pulmonary hemosiderosis (IPH) is a rare disease characterized by the triad of hemoptysis, pulmonary infiltrates on chest radiograph, and anemia. Its diagnosis should be considered in any child presenting with moderate to severe anemia and failure to thrive of unclear etiology. Consideration of the differential diagnosis in such a child should include the review of both extravascular and intravascular causes of hemolysis. Systemic treatment of IPH with glucocorticoids has been shown to decrease morbidity, mortality, and disease progression to pulmonary fibrosis. Thus, diagnostic delays can impact prognosis. Here, we present a case of a 15-month-old boy with IPH who presented with anemia, jaundice, and failure to thrive, as well as a history of hemoptysis that was not initially elicited. PMID- 26414633 TI - Preliminary Report-The Long Leg Cast With a Pelvic Band: A Novel Approach to Treatment of Pediatric Femur Fractures. AB - OBJECTIVES: The aim of the study was to describe the long leg cast with a pelvic band (LLCPB), a novel alternative to spica casting for treating femur fractures in patients aged 6 months to 6 years which requires no casting above the waist, allows for hip flexion adjustments after it is applied, and does not require an operating room for placement. METHODS: Seven children aged 7.9 months to 3.7 years with femur fractures treated with the LLCPB at a single institution were retrospectively studied. All children were casted in the emergency department under conscious sedation. Radiographic and subjective outcomes were recorded. RESULTS: All 7 children achieved acceptable reduction of their fractures without the need for re-reduction or cast wedging. Five of the 7 children were discharged from the emergency department; 1 child required 1 night of hospitalization and another child required 2 nights of hospitalization. There were no complications. The cost of placing an LLCPB at our institution was $430.46. The cost of placing a spica cast in the operating room was $5427.54 to $6465.00. CONCLUSIONS: The long leg cast with a pelvic band seems to be an acceptable treatment for children aged 8 months to 4 years with spiral femur fractures. This technique has significant advantages over traditional and modified spica casts including allowing for uninhibited toileting, weight bearing on the unaffected leg, adjustment of hip flexion at any point after placement, and easier access to the perineum, abdomen, and chest for hygienic and medical purposes. Furthermore, treatment with an LLCPB presents significant potential for cost savings. PMID- 26414634 TI - An Assessment of Newly Identified Barriers to and Enablers for Prehospital Pediatric Pain Management. AB - OBJECTIVES: The aim of this study was to quantitatively assess the prevalence of newly identified barriers and enablers to prehospital narcotic analgesic administration in a sample of paramedics and determine whether these barriers and enablers differ between new and experienced paramedics. METHODS: We surveyed a convenience sample of paramedics from urban, suburban, and rural practice settings in an emergency medical services system. Descriptive statistics were calculated to describe responses, and differences between new (<=5 years) and experienced (>5 years) providers were assessed. RESULTS: There were 127 surveys analyzed; 67% of our sample was experienced and 86% considered treating pain important. Notable barriers for analgesic administration include causing more pain from intravenous catheter insertion, parental influences, difficulty assessing pain, and worry about allergic reactions. Notable enablers include belief that analgesic administration is important, education to administer analgesics, and support from agency leadership. There were statistically significant differences between new and experienced providers in the distribution of responses for survey items regarding how the importance of treating pain in children was learned, overall comfort with pediatric patients, receiving negative responses from superiors about giving pediatric patients analgesics, and usefulness of the Broselow tape for dosing fentanyl for children. Other barriers and enablers were not significantly different between new and experienced providers. CONCLUSIONS: Top barriers to prehospital pediatric analgesic administration are related to skills and knowledge deficits, whereas enablers include support from agency leadership and personal views on analgesics. This information can be used to guide interventions to improve the management of pain in children. PMID- 26414635 TI - Mental Health Screening Among Adolescents and Young Adults in the Emergency Department. AB - OBJECTIVE: To determine if a new, non-validated mental health screener can detect the prevalence of alcohol/drug abuse, traumatic exposure, and behavioral symptoms in adolescents and young adults seeking care in a pediatric emergency department (ED) for medical complaints. METHODS: An 11-item mental health screener (Emergency Department Distress Response Screener [ED-DRS] investigator developed) was created. Patients 12 years or older seen for medical complaints were assessed by physicians using the ED-DRS. Data were analyzed using the Kuder-Richardson Formula 20, chi test, Mann-Whitney U test, and Spearman correlation. RESULTS: Among 992 ED patients, mean age was 15.11 +/- 2.10 years (46.2% boys; 53.8% girls). Approximately 77.9% were Hispanic/Latino. Symptomatic patients (S) answered "yes" to at least 1 ED-DRS item; asymptomatic patients answered "no" to all items. The S patients comprised 47.5% of the sample; asymptomatic patients comprised 52.5%. Among S patients, alcohol/drug abuse frequency was 14%. The traumatic exposure frequencies included: 33.5% physically or emotionally traumatized, 29.3% bullied, 21.2% physically abused, 8.1% touched inappropriately and 7.0% exposed to domestic violence. Behavioral symptom frequencies included: 33.8% depressed mood, 30.4% anxiety, 23.8% high energy behavior, 6.6% hallucinations, and 6.2% suicidal/homicidal ideation. CONCLUSIONS: Although patients present to the ED with medical complaints, they may be at risk for concomitant mental health problems potentially discoverable using the ED-DRS. PMID- 26414636 TI - Afebrile Infants Evaluated in the Emergency Department for Serious Bacterial Infection. AB - OBJECTIVES: Afebrile infants 0 to 60 days of age are sometimes evaluated for serious bacterial infection (SBI). Our objective was to describe the clinical and laboratory findings in this population and compare them to their febrile counterparts. METHODS: We performed a retrospective observational study comparing afebrile infants undergoing an SBI evaluation to those evaluated for fever. RESULTS: We included infants who were admitted to the hospital and had at least 2 of 3 following bacterial cultures: blood, urine, or cerebrospinal fluid. Of the 1184 infants presenting to the emergency department with chief complaints that may prompt an SBI evaluation, 579 patients met our inclusion criteria with 362 in the fever group and 217 in the afebrile group. The most common chief complaints in the afebrile group were respiratory symptoms (27%), seizure (22%), vomiting/diarrhea (21%), and apparent life-threatening event (11%). Rates of true positive blood, urine, and cerebrospinal fluid cultures were 2%, 2.4%, and 0.9% respectively. All cases of bacterial meningitis were in the fever group antibiotics (P = 0.16). Infants with fever were more likely to receive antibiotics (P < 0.001), although there were no statistical differences between the 2 groups in the rates of positive blood or urine cultures. CONCLUSIONS: Afebrile infants make up a significant percentage of SBI evaluations in the emergency department. Respiratory symptoms, vomiting, and seizure-like activity are common presentations. Although rates of bacteremia and urinary tract infection are higher in the febrile group, this did not reach statistical significance, and therefore afebrile infants should still be considered at risk for SBI. PMID- 26414637 TI - Pelvic Fracture Urethral Injuries in Children: A Case Report and Appraisal of Their Emergency Management. AB - Pelvic fracture urethral injuries are uncommon injuries that are frequently overlooked in the emergency department. We present a case of a 2-year-old girl whose urethral trauma was initially missed and potentially worsened by the placement of a urinary catheter. The clinical and diagnostic features of these rare injuries are discussed along with the controversies surrounding urinary catheter placement and retrograde urethrography. PMID- 26414638 TI - SimBaby Plus Standardized Patient Teaching Model in the Teaching of Cases of Acute and Severe Bronchopneumonia in Infancy. AB - OBJECTIVE: The aim of the study was to evaluate the effectiveness of SimBaby plus standardized patient (SP) teaching model in the simulation teaching of acute and severe bronchopneumonia in infancy. METHODS: A total of 40 students majoring in clinical medicine were assigned to either group A (SimBaby group, n = 20) or group B (SP + SimBaby group, n = 20). Medical students' expertise and their ability to apply the expertise on acute and severe bronchopneumonia in infancy were assessed using a scoring method, and the impact of the teaching model of SimBaby plus SP on medical students' comprehensive clinical capacity was assessed using a questionnaire. RESULTS: The SimBaby plus SP teaching model resulted in medical students' improvement in mastery and application of the knowledge on diagnostic accuracy, airway management, endotracheal intubation, and cardiac massage, enhancement of learning interest, learning initiative, and enthusiasm, as well as abilities in assessment of information, meta-analysis, linguistic organization and expression, communication, and clinical thinking. CONCLUSIONS: The SimBaby plus SP teaching model provided students with a real simulation-based teaching case of "interrogation-physical examination-operating practices" achieving satisfactory teaching outcome and also provided a reference case example for clinical teaching of other pediatric diseases. PMID- 26414639 TI - Leukemoid Reaction in a Pediatric Patient With Diabetic Ketoacidosis. AB - Herein, we report a case of a 12-year-old girl who presented with diabetic ketoacidosis and a leukemoid reaction. Although this association has been described in a few adult patients, pediatric cases have not been reported. A leukemoid reaction is commonly defined as an elevation in the white blood cell count greater than 50,000/MUL in response to severe illness or stress other than hematologic malignancy; it is considered to be mediated by various hormones, cytokines, and factors that are released in response to inciting triggers, such as acidosis. As highlighted in our report, distinguishing a benign leukemoid reaction from a hematologic malignancy and even tumor lysis syndrome, particularly in a setting of diabetic ketoacidosis, is crucial to ensuring safe and efficacious therapeutic interventions. PMID- 26414640 TI - Case-Control Study of Injury Intervention for Preschool Children in Henggang, Shenzhen. AB - AIM: To explore effective interventions for child accidental injury prevention and to reduce the incidence of injury. METHODS: Cluster random sampling method was adopted, and children in 19 kindergartens in Henggang, Shenzhen and their parents were selected as the objects of study. Nineteen kindergartens were randomly divided into intervention group and control group to carry out the injury intervention case-control study. RESULTS: Through a series of interventions, there were certain effects. After the end of the project, the injury incidence rates of the intervention group and the control group were 4.91%, 10.64%, and the difference was significant; the average costs of treatment for injuries of the intervention group and the control group were 168.4 Yuan and 206.8 Yuan, and the difference was statistically significant; compared with before the implementation of the project, the rate of various types of injuries after the end of the project declined, in which, the rate of mechanical injury, pet bites, accidental falls, burns, and traffic accidents decreased significantly. The differences were significant. CONCLUSIONS: Injury interventions can effectively prevent and control the occurrence of injury. PMID- 26414641 TI - A Survey of Attitudes and Practices Regarding the Use of Steroid Supplementation in Pediatric Sepsis. AB - OBJECTIVE: Although corticosteroid (CS) supplementation for pediatric septic shock (PSS) is recommended by American College of Critical Care Medicine sepsis guidelines, most data are based on adult trials. Standardized protocols for stimulation testing for adrenal insufficiency (AI) and CS treatment in children have been reported, but the current state of CS use and protocols have not been evaluated in pediatric intensive care units in the United States. We surveyed a group of pediatric intensivists to assess current approaches. DESIGN: An electronic survey with 54 questions on attitudes and current use of CSs was distributed to 49 pediatric critical care and 49 pediatric endocrinology fellowship program directors. MAIN RESULTS: Twenty-one (43%) of 49 critical care recipients completed the survey. Eleven (52%) were from medical/surgical units and 10 (48%) were from medical/surgical/cardiac units, with a median of 24 beds and 1614 annual admissions. Thirteen (62%) of 21 recipients rated the importance of steroids in the management of PSS as greater than 4 or 5, with 1 being of no importance and 5 of critical importance. Nineteen (90%) of 21 recipients thought AI occurs "sometimes" or "often" in septic shock. Adrenocorticotropin stimulation testing was frequently used (19 of 21; 90%) but not in protocol. Eighteen (85%) of 21 recipients agreed that "some should" receive "steroids as it improves outcome" and 9% agreed that "most should..." Fourteen (66%) of 21 recipients reported that more than 50% of patients with vasopressor-refractory PSS receive CSs. Hydrocortisone was used in 21 (100%) of 21 recipients, but dosing and duration were variable. Concerns to limit/avoid CSs included hyperglycemia (38%), superinfections (81%), and critical illness myopathy (57%). Only 3 (14%) of 21 recipients reported that they used a CS protocol for PSS. Sixteen (76%) of 21 recipients were not comfortable drawing conclusions from adult studies for PSS. Nineteen (90%) of 21 recipients agreed that it would be important to perform a randomized trial for CS use in PSS. CONCLUSIONS: Corticosteroids are used at most centers for treatment of PSS, but significant variation in attitudes and use exists. Most centers identify AI as frequent; most report variable use of stimulation testing and dosing of CSs. Few centers currently use a standard protocol for diagnosis and treatment. Interest in performing a randomized trial for CSs remains because in part of reluctance to accept adult trial data. PMID- 26414642 TI - Factors Associated With Orthopedic Aftercare in a Publicly Insured Pediatric Emergency Department Population. AB - OBJECTIVES: Children with public insurance are less likely than children with private insurance to obtain follow-up care after emergency department (ED) care. This study aimed to determine if specific demographic and clinical factors are associated with aftercare compliance in a population of publicly insured pediatric ED patients with orthopedic injuries. METHODS: This was a retrospective case-control study of Washington, DC, children aged 0 to 17 years with public insurance discharged with isolated forearm fractures from the Children's National Medical Center ED from 2003 to 2006. Bivariable analyses and multivariable logistic regression were performed to measure the association between sociodemographic variables and failure to follow up. RESULTS: Six hundred children met the inclusion criteria. The overall cohort was 63.7% male and 81.7% African American, with a mean age of 8.8 (SE, 0.2) years. Overall, 85.7% of patients went to a follow-up orthopedic appointment, and 68.2% of patients had timely orthopedic follow-up, defined as 14 days or less after discharge from the ED. Treatment with orthopedic reduction (adjusted odds ratio [OR], 2.0 [1.33 2.93]) was positively associated with timely orthopedic follow-up, whereas older age (adjusted OR, 0.9 [0.88-0.97]) was significantly associated with failure to follow up. In the subset of patients who required orthopedic reduction in the ED, older age was significantly associated with failure to follow up (adjusted OR, 0.80 [0.74-0.94]). CONCLUSIONS: Mild fracture severity is associated with lack of orthopedic follow-up for patients with public insurance. Older age was associated with lack of follow-up, even in the subgroup with severe fractures. Targeted interventions to improve orthopedic aftercare compliance should focus on older patients with severe forearm fractures. PMID- 26414643 TI - MicroRNA-498 Inhibition Enhances the Differentiation of Human Adipose-Derived Mesenchymal Stem Cells into Podocyte-Like Cells. AB - Podocyte depletion is a key event in the progression of end-stage kidney disease (ESKD) resulting in nephrotic proteinuria and renal failure, but the treatment options are limited to dialysis and renal transplantation. So there is an urgent need for renal regenerative therapies. Generation of podocytes from human stem cells is regarded as a promising therapeutic strategy to repair or regenerate the damaged kidneys; however, the reliable induction system remains a challenge. In this study, we established a two-stage induction protocol for podocyte generation from human adipose-derived mesenchymal stem cells (hAD-MSCs). We initially established a condition that induces hAD-MSCs toward intermediate mesoderm cells with activin A and high concentration of retinoic acid (RA). Subsequently, by using the combination of activin A and low concentration of RA and BMP7, we generated podocyte-like cells expressing multiple podocyte-specific markers and able to integrate into a developing nephron of embryonic kidney explant culture and ameliorate proteinuria and kidney injure in adriamycin-treated mice. Furthermore, we identified that miRNA-498 inhibitor has potential to improve the differentiation of hAD-MSCs into podocyte-like cells and established a robust induction protocol. Thereby, our study advocated an efficient method for the induction of kidney podocyte-like (iPod) cells from hAD-MSCs and provided an ideal candidate for regenerative therapies of the kidney. PMID- 26414644 TI - Radiofrequency ablation of hepatocellular carcinoma: Mono or multipolar? AB - BACKGROUND AND AIMS: Thermo-ablation by radiofrequency is recognized as a curative treatment for early-stage hepatocellular carcinoma. However, local recurrence may occur because of incomplete peripheral tumor destruction. Multipolar radiofrequency has been developed to increase the size of the maximal ablation zone. We aimed to compare the efficacy of monopolar and multipolar radiofrequency for the treatment of hepatocellular carcinoma and determine factors predicting failure. METHODS: A total of 171 consecutive patients with 214 hepatocellular carcinomas were retrospectively included. One hundred fifty-eight tumors were treated with an expandable monopolar electrode and 56 with a multipolar technique using several linear bipolar electrodes. Imaging studies at 6 weeks after treatment, then every 3 months, assessed local effectiveness. Radiofrequency failure was defined as persistent residual tumor after two sessions (primary radiofrequency failure) or local tumor recurrence during follow up. This study received institutional review board approval (number 2014/77). RESULTS: Imaging showed complete tumor ablation in 207 of 214 lesions after the first session of radiofrequency. After a second session, only two cases of residual viable tumor were observed. During follow-up, there were 46 local tumor recurrences. Thus, radiofrequency failure occurred in 48/214 (22.4%) cases. By multivariate analysis, technique (P < 0.001) and tumor size (P = 0.023) were independent predictors of radiofrequency failure. Failure rate was lower with the multipolar technique for tumors < 25 mm (P = 0.023) and for tumors between 25 and 45 mm (P = 0.082). There was no difference for tumors >= 45 mm (P = 0.552). CONCLUSIONS: Compared to monopolar radiofrequency, multipolar radiofrequency improves tumor ablation with a subsequent lower rate of local tumor recurrence. PMID- 26414645 TI - Post-Transurethral Resection of the Prostate Inflation of Pressure-Controlled Endorectal Balloon-Impact on Postoperative Bleeding: A Preliminary Experimental Pilot Study. AB - OBJECTIVE: To evaluate the impact of rectal balloon (RB) inflation on post transurethral resection of the prostate (TURP) bleeding in patients with symptomatic benign prostatic hyperplasia. METHODS: After institutional review board approval, patients who were eligible for TURP were randomized into two equal groups, depending on whether they received postoperative endorectal balloon (RB) (GII) or not (GI). The tip of three-way Foley catheter was fixed to a balloon by a blaster strip to prepare air-tight RB. Postoperatively, the RB was inflated for 15 minutes by a pressure-controlled sphygmomanometer. Perioperative data were compared between both groups, including hemoglobin (Hb) deficit 24-hour postoperatively and at time of discharge. Functional outcomes, anorectal complaints, and adverse events were assessed perioperatively and after 1 and 3 months. RESULTS: Fifty patients were enrolled, including 13 (26%) patients who presented with indwelling urethral catheters. Baseline data and mean resected tissue weight were comparable between both groups, including preoperative Hb (p = 0.17). Immediate postoperative Hb deficit was, comparable between GI and GII patients (0.58 +/- 0.18 vs 0.60 +/- 0.2, p = 0.56) before RB inflation, respectively. However, compared to GI patients, mean Hb deficit significantly decreased in GII patients 24-hour postoperatively (0.2 +/- 0.2 vs 0.7 +/- 0.3 g, p = 0.002) and at time of discharge (0.8 +/- 0.2 vs 1.3 +/- 0.4 g, p = 0.003). GII patients needed significantly less postoperative irrigation (2.1 +/- 1.6 vs 8.3 +/- 1.8 L, p < 0.001), shorter catheterization time (2.3 +/- 0.8 vs 3.8 +/- 1.3 days, p < 0.001), and shorter hospital stay (2.6 +/- 0.5 vs 4.3 +/- 1.0 days, p < 0.001). Both groups were comparable in all functional outcomes at the most recent follow-up. Blood transfusion was needed in only one patient (4%) in GI. No patient needed recystoscopy for hematuria or clot retention in either group, while there were no anorectal complaints reported by GII patients. CONCLUSIONS: Post-TURP endorectal balloon inflation seems to be simple, safe, and an efficient procedure to reduce postoperative bleeding and irrigation volume. It is significantly associated with shorter catheterization time and hospital stay. PMID- 26414646 TI - Cerebral venous thrombosis following spinal surgery in a patient with Factor V Leiden mutation. AB - Cerebral venous thrombosis is a devastating event leading to high mortality and morbidity rates. We present a case of cerebral venous thrombosis that occurred following spinal surgery in a patient with Factor V Leiden mutation and G1691A heterozygosity. Possible prevention and treatment strategies have been discussed. PMID- 26414647 TI - Estimation of groundwater recharge via deuterium labelling in the semi-arid Cuvelai-Etosha Basin, Namibia. AB - The stable water isotope deuterium ((2)H) was applied as an artificial tracer ((2)H2O) in order to estimate groundwater recharge through the unsaturated zone and describe soil water movement in a semi-arid region of northern central Namibia. A particular focus of this study was to assess the spatiotemporal persistence of the tracer when applied in the field on a small scale under extreme climatic conditions and to propose a method to obtain estimates of recharge in data-scarce regions. At two natural sites that differ in vegetation cover, soil and geology, 500 ml of a 70% (2)H2O solution was irrigated onto water saturated plots. The displacement of the (2)H peak was analyzed 1 and 10 days after an artificial rain event of 20 mm as well as after the rainy season. Results show that it is possible to apply the peak displacement method for the estimation of groundwater recharge rates in semi-arid environments via deuterium labelling. Potential recharge for the rainy season 2013/2014 was calculated as 45 mm a(-1) at 5.6 m depth and 40 mm a(-1) at 0.9 m depth at the two studied sites, respectively. Under saturated conditions, the artificial rain events moved 2.1 and 0.5 m downwards, respectively. The tracer at the deep sand site (site 1) was found after the rainy season at 5.6 m depth, corresponding to a displacement of 3.2 m. This equals in an average travel velocity of 2.8 cm d(-1) during the rainy season at the first site. At the second location, the tracer peak was discovered at 0.9 m depth; displacement was found to be only 0.4 m equalling an average movement of 0.2 cm d(-1) through the unsaturated zone due to an underlying calcrete formation. Tracer recovery after one rainy season was found to be as low as 3.6% at site 1 and 1.9% at site 2. With an in situ measuring technique, a three-dimensional distribution of (2)H after the rainy season could be measured and visualized. This study comprises the first application of the peak displacement method using a deuterium labelling technique for the estimation of groundwater recharge in semi-arid regions. Deuterium proved to be a suitable tracer for studies within the soil-vegetation-atmosphere interface. The results of this study are relevant for the design of labelling experiments in the unsaturated zone of dry areas using (2)H2O as a tracer and obtaining estimations of groundwater recharge on a local scale. The presented methodology is particularly beneficial in data-scarce environments, where recharge pathways and mechanisms are poorly understood. PMID- 26414648 TI - Femoral condyle curvature is correlated with knee walking kinematics in ungulates. AB - The knee has been the focus of many studies linking mammalian postcranial form with locomotor behaviors and animal ecology. A more difficult task has been linking joint morphology with joint kinematics during locomotor tasks. Joint curvature represents one opportunity to link postcranial morphology with walking kinematics because joint curvature develops in response to mechanical loading. As an initial examination of mammalian knee joint curvature, the curvature of the medial femoral condyle was measured on femora representing 11 ungulate species. The position of a region of low curvature was measured using a metric termed the "angle to low curvature". This low-curvature region is important because it provides the greatest contact area between femoral and tibial condyles. Kinematic knee angles during walking were derived from the literature and kinematic knee angles across the gait cycle were correlated with angle to low curvature values. The highest correlation between kinematic knee angle and the angle to low curvature metric occurred at 20% of the walking gait cycle. This early portion of the walking gait cycle is associated with a peak in the vertical ground reaction force for some mammals. The chondral modeling theory predicts that frequent and heavy loading of particular regions of a joint surface during ontogeny will result in these regions being flatter than the surrounding joint surface. The locations of flatter regions of the femoral condyles of ungulates, and their association with knee angles used during the early stance phase of walking provides support for the chondral modeling theory. PMID- 26414649 TI - Inhibition of Lipid Oxidation in Oil-in-Water Emulsions by Interface-Adsorbed Myofibrillar Protein. AB - This study investigated the role of interfacial myofibrillar protein (MFP) in the oxidative stabilization of meat emulsions. Emulsions with 10% oil were prepared using either 2% (w/v) Tween 20 or 0.25, 0.5, and 1% (w/v) MFP and then subjected to hydroxyl radical oxidation at 4 degrees C for 0, 2, and 24 h. MFP was more readily oxidized (intrinsic fluorescence quenching, sulfur losses, and carbonyl formation) than oil [conjugated dienes and 2-thiobarbituric acid-reactive substances (TBARS)]. However, oxidized MFP in the continuous phase stimulated lipid oxidation after 24 h, sharply contrasting with interface-adsorbed MFP that inhibited TBARS formation nearly 90% (p < 0.05). Interfacial MFP from 2 h oxidized samples exhibited greater losses of fluorescence and more extensive polymerization of myosin (detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis) than MFP present in the continuous phase. Results indicated that, due to the physical localization, interface-adsorbed MFP in general and myosin in particular provided accentuated protection of emulsions against oxidation. PMID- 26414650 TI - Elimination of Granulocytic Myeloid-Derived Suppressor Cells in Lupus-Prone Mice Linked to Reactive Oxygen Species-Dependent Extracellular Trap Formation. AB - OBJECTIVE: Emerging evidence supports a crucial role of myeloid-derived suppressor cells (MDSCs) in the regulation of autoimmune diseases. However, their role in systemic lupus erythematosus (SLE) remains unknown. This study sought to address the role of MDSCs in the pathogenesis of SLE. METHODS: MDSCs from (NZB * NZW)F1 lupus-prone mice were assessed for phenotype by flow cytometry, and the function of MDSCs was analyzed by in vitro T cell proliferation assay and real time quantitative polymerase chain reaction. Extracellular trap (ET) formation was evaluated by immunofluorescence and confocal microscopy. The production of reactive oxygen species (ROS) by Ly-6G+ cells was determined by fluorescence activated cell sorting analysis. RESULTS: Expansion of MDSCs was impaired and the function of MDSCs was defective in the lymphoid organs of (NZB * NZW)F1 lupus prone mice with established disease, in which involvement of predominantly the granulocytic MDSC (G-MDSC) cell subset was observed. More specifically, the results showed that increased elimination of G-MDSCs, driven by the inflammatory milieu of lupus, could be attributed to ET formation, and that cytokines, such as interferon-alpha (IFNalpha), IFNgamma, and interleukin-6, play a role in this process. Induction of ET release by G-MDSCs was mediated by the production of ROS, since inhibition of ROS generation significantly reduced ET release. CONCLUSION: Collectively, the results of this study reveal that elimination of a crucial regulatory immune cell subset is a feature of the SLE microenvironment. These findings provide new insights into the pathogenetic mechanisms of the disease. PMID- 26414651 TI - Electrodiffusiophoresis of a large-zeta-potential particle in weak fields. AB - The electrodiffusiophoresis of a large-zeta-potential (zeta) particle in weak fields is investigated. In this large-zeta regime, Debye-layer kinetics determines O(1) perturbations to the electric- and concentration fields in the surrounding electroneutral solution. Taking these effects into account, the expressions of the slip-flow coefficient and the effective surface boundary conditions for the electric- and concentration fields are derived. For binary and symmetric electrolyte where only one ion species carries the current in the electroneutral domain, the far-field salt gradient as related to the electric field is determined. The electrodiffusiophoretic mobility is obtained for three particle geometries: sphere, cylinder and spheroid arbitrarily oriented with respect to the externally applied field. Strong departure from Smoluchowskian behavior is found. If co-ion is the current carrier, the mobility is independent of zeta, regardless of the body shape. Also, the hydrodynamic flow-field is irrotational. If counter-ion is the current carrier, the problem formulated in terms of a properly-defined scalar field (Omega), which embodies both the electric potential (Psi) and the salt concentration, becomes formally identical to the one addressed in our previous work, concerning the small-zeta regime, with negligible salt gradients. Then, all the results obtained in that study are extended and applied even to the large-zeta regime considered here, provided the new expressions now derived for the surface boundary conditions and the slip-flow coefficient are employed and Omega is used in place of Psi. The present results are discussed also in comparison with the classical studies of Dukhin et al and O'Brien et al concerning electrophoresis of highly charged particles with no salt gradient at infinity, and with recent studies of electrodiffusiophoresis, which, however, neglected the fields perturbations caused by Debye-layer kinetics. It is found that the effects addressed and incorporated in the present study determine remarkably different mobility-versus-zeta behaviour as compared to those previous theories. PMID- 26414652 TI - Predictions of bioenhancement of nonaqueous phase liquid ganglia dissolution using first- and zero-order biokinetic models. AB - The bioenhanced dissolution of nonaqueous phase liquid (NAPL) contaminants that occurs as a result of an increased concentration gradient is influenced by several factors, including the biokinetics. This is important because available data suggest that at typical NAPL source zone concentrations, descriptions of dissolution bioenhancement may require kinetic expressions ranging from first- to zero-order. In this work, an analytical model for the bioenhancement factor, E, is developed for NAPL ganglia dissolution with zero-order kinetics, and compared to a model for E with first-order kinetics. The models are analyzed and an illustrative example is provided to demonstrate the importance of using the correct biokinetics when estimating the potential magnitude of the bioenhancement of NAPL ganglia dissolution. PMID- 26414653 TI - Perioperative blood loss and gastrointestinal tolerability of etoricoxib and diclofenac in total hip arthroplasty (ETO-DIC study): a single-center, prospective double-blinded randomized controlled trial. AB - OBJECTIVE: Non-selective NSAIDs can cause serious gastrointestinal side-effects. Selective COX-2 blockers are a reasonable alternative for pain treatment. They do not seem to affect platelet function and consequently cause a lower perioperative blood loss than non-selective NSAIDs. This study compared etoricoxib and diclofenac during a perioperative (9 days) period after THA to investigate total blood loss and gastrointestinal tolerability. The hypothesis was that etoricoxib is superior to diclofenac. METHODS: A total of 100 patients (50 in each group) were included in this trial. Etoricoxib (90 mg) was administered once and diclofenac sodium (75 mg) twice daily for 9 days. Total blood loss during and after primary cementless THA was detected. The rate of adverse events (AEs) and serious adverse events (SAEs) was analyzed to detect gastrointestinal tolerability. RESULTS: The mean total blood loss (calculated) was 1548 +/- SD 468 ml in the etoricoxib (ETO) group and 1649 (SD 547) ml in the diclofenac (DIC) group. The mean duration of THA was 81 min (SD 29) in the DIC and 75 min (SD 30) in the ETO group. Hence, the mean calculated total blood loss was 101 ml higher in the DIC group. This difference was not statistically significant (p = 0.334). Fifty-six patients (28 in each group) received a cell saver retransfusion, but only one patient (ETO group) needed an additional red blood cell transfusion. The hidden blood loss was 1067 ml (SD 603) in the DIC group and 999 ml (SD 378) in the ETO group. The gastrointestinal tolerability (number of adverse and serious adverse events) was not significantly different between groups. CONCLUSION: There was no statistically significant difference in perioperative blood loss after primary THA under etoricoxib (90 mg) compared to diclofenac (75 mg). Furthermore, no gastrointestinal superiority of etoricoxib could be detected during a short period of 9 days. PMID- 26414654 TI - Chronic Aspects of Pediatric Traumatic Brain Injury: Review of the Literature. AB - Traumatic brain injury (TBI) in children, while the brain is in a state of rapid change and development, can adversely impact their development, their extended environment, and their families. The extant literature has identified several physiological, genetic, and environmental variables that predict outcomes after pediatric TBI; nonetheless, the individual course of recovery and later development of a given child is uniquely shaped by injury-related factors (e.g., nature and extent of the injury itself, the developmental status of the child) as well as a number of personal and family variables (e.g., pre-injury cognitive, genetic, and psychological status of the child, family functioning and resources, coping style). Further, the effects of a brain injury during development may or may not become evident immediately after injury depending on a number of factors. Instead, observing trajectories of development over time may allow for a better understanding of the long-term consequences in many functional domains that interest researchers, clinicians, and families. The current article reviews the chronic aspects of medical/health, cognitive/academic, emotional/behavioral, and family/social outcomes after pediatric TBI, with the goal of providing monitoring and treatment strategies for affected children and their families, as well as serving as a resource for researchers designing studies to better understand this heterogeneous population. PMID- 26414655 TI - Highly Enantioselective Construction of Fluoroalkylated Quaternary Stereocenters via Organocatalytic Dehydrated Mannich Reaction of Unprotected Hemiaminals with Ketones. AB - A general organocatalytic asymmetric dehydrated Mannich reaction of fluoroalkyl hemiaminals with ketones is reported. In this Mannich reaction, previously less explored aryl ketones showed great reactivity. By virtue of this efficient method, a wide range of biologically active beta-amino ketones were directly obtained. More importantly, two different intermediates involved in the reaction were detected and identified by (19)F NMR and HRMS analysis. Furthermore, the synthetic utility of the products was demonstrated by the synthesis of the biologically active fluoroalkyl beta-amino alcohols. PMID- 26414656 TI - Primary Cryotherapy for High-Grade Clinically Localized Prostate Cancer: Oncologic and Functional Outcomes from the COLD Registry. AB - OBJECTIVE: To evaluate the oncological and functional outcomes of primary cryotherapy in men with clinically localized, high-grade prostate cancer. SUBJECTS AND METHODS: We included all men with biopsy Gleason score >=8, localized (cT1-2) disease with a serum prostate-specific antigen (PSA) <=50 ng/mL from the Cryo On-Line Data (COLD) registry. The primary outcome was biochemical progression free survival (BPFS) as defined by the Phoenix criteria (nadir PSA +2 ng/mL). Secondary outcomes of continence (defined as strictly no leak) and potency (able to have intercourse) were patient reported. Factors influencing BPFS were evaluated individually using Kaplan Meier and in a multivariate model using Cox regression. RESULTS: Altogether, 300 men were included for analysis. The median follow-up was 18.2 months (mean 28.4) and median BPFS was 69.8 months. Based on Kaplan-Meier analysis, the estimated 2- and 5-year BPFS rate was 77.2% and 59.1%, respectively. Neoadjuvant hormonal therapy was administered to 41% of men and this tended to occur in men with larger prostates, likely as a technical consideration for downsizing before cryosurgery. At multivariate analysis, the presence of Gleason score 9 or 10 (Hazard Ratio [HR] 1.9) and a posttreatment PSA nadir of >=0.4 ng/mL (HR 5.7) were the only significant variables associated with biochemical progression using Cox regression. Complete continence was noted in 90.5% of men and potency in 17% of men at the 12-month follow-up. The incidence of rectourethral fistulae and urinary retention requiring intervention beyond temporary catheterization was 1.3% and 3.3%, respectively. CONCLUSION: Primary cryotherapy appears to be effective and safe in the community setting for high grade, clinically localized prostate cancer in the short term. PMID- 26414657 TI - Lifestyle habits of 12,800 IVF patients: Prevalence of negative lifestyle behaviors, and impact of region and insurance coverage. AB - Lifestyle habits of women undergoing in vitro fertilization (IVF) treatment are largely unknown. Therefore, this prospective study aimed to determine the prevalence of negative lifestyle habits in women undergoing IVF and determine if habits are related to the region in the United States and/or by mandated insurance coverage. A total of 12,811 ART patients were surveyed in infertility clinics throughout the US. They took an online questionnaire added to the patient portal of electronic medical record eIVF, a fertility-specific electronic health record. Of the women surveyed, 17-23% of patients drank alcohol, 2-7% smoked, 62 68% drank caffeine, < 1% used recreational drugs, and 47-62% exercised during their IVF treatment. There were a few statistically significant regional differences in health habits (p < 0.001) but there were no differences in health habits between women who resided in a state with mandated insurance coverage versus those without insurance coverage. This is the first prospective assessment of lifestyle habits across regions in the USA and by insurance coverage. The study concluded that women undergoing IVF engage in behaviors which may negatively impact their cycle. Women in certain parts of the US had significantly worse habits than other regions, but the availability of mandated insurance coverage did not impact health habits. PMID- 26414658 TI - Antineutrophil Cytoplasmic Antibody-Positive Small-Vessel Vasculitis Associated with Antithyroid Drug Therapy: How Significant Is the Clinical Problem? AB - BACKGROUND: The aim of this review was to delineate the characteristics of antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis associated with antithyroid drugs (ATD). A PubMed search was made for English language articles using the search terms antithyroid drugs AND ANCA OR ANCA associated vasculitis. SUMMARY: The literature includes approximately 260 case reports of ANCA-associated small-vessel vasculitis related to ATD, with 75% of these associated with thiouracil derivatives (propylthiouracil [PTU]) and 25% with methyl-mercapto-imidazole derivatives (MMI/TMZ). The prevalence of ANCA positive cases caused by ATD varied between 4% and 64% with PTU (median 30%), and 0% and 16% with MMI/TMZ (median 6%). Young age and the duration of ATD therapy were the main factors contributing to the emergence of ANCA positivity. Before ATD therapy initiation, the prevalence of ANCA-positive patients was 0-13%. During ATD administration, 20% of patients were found to be positive for ANCA. Only 15% of ANCA-positive patients treated with ATD exhibited clinical evidence of vasculitis, corresponding to 3% of all patients who received ATD. Clinical manifestations of ANCA-associated vasculitis related to ATD were extremely heterogeneous. When vasculitis occurred, ATD withdrawal was usually followed by rapid clinical improvement and a favorable prognosis. CONCLUSIONS: ANCA screening is not systematically recommended for individuals on ATD therapy, particularly given the decreasing use of PTU in favor of TMZ/MMI. Particular attention should be given to the pediatric population with Graves' disease who receive ATD, as well as patients treated with thiouracil derivatives and those on long-term ATD therapy. PMID- 26414659 TI - The antimicrobial activity of mecillinam, nitrofurantoin, temocillin and fosfomycin and comparative analysis of resistance patterns in a nationwide collection of ESBL-producing Escherichia coli in Norway 2010-2011. AB - BACKGROUND: The prevalence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli in Norway has been steadily increasing during the last 10-15 years as part of a global pandemic. ESBL producers frequently express co resistance to other important antimicrobial drug classes, limiting therapeutic options. This has led to regained interest in older antimicrobial agents. The aim of this study was to evaluate the antimicrobial activity of mecillinam, nitrofurantoin, temocillin and fosfomycin, as well as to perform a comparative analysis of resistance patterns in a nationwide collection of ESBL-producing E. coli. METHODS: A nationwide collection of all 105 clinical isolates of ESBL producing E. coli from the Norwegian Organisation for Surveillance of Antimicrobial Resistance (NORM) during 2010-2011 was analyzed. Detection and identification of ESBL-encoding genes were performed by PCR and sequencing for confirmation of ESBL variants of blaTEM and blaSHV (2010) or microarray (2011). Minimum inhibitory concentrations (MICs) or MIC correlates were determined using MIC gradient tests or VITEK 2, respectively. Comparative analysis of resistance patterns was performed. RESULTS: All isolates were susceptible to fosfomycin, temocillin (urinary tract breakpoint) and meropenem. For mecillinam and nitrofurantoin, 6% and 9% of the isolates, respectively, were non-susceptible. A high level of susceptibility was also observed for amikacin (95%). In contrast, the non-susceptibility proportions to ampicillin (100%), cefotaxime (97%), ceftazidime (77%), aztreonam (87%), gentamicin (42%), tobramycin (52%), ciprofloxacin (76%) and trimethoprim-sulfamethoxazole (71%) were higher. CONCLUSIONS: Overall, the in vitro susceptibility to nitrofurantoin, fosfomycin, mecillinam and temocillin was high, indicating that these drugs are good options for treating uncomplicated urinary tract infections caused by ESBL-producing E. coli. PMID- 26414660 TI - Engineering Translational Activators with CRISPR-Cas System. AB - RNA parts often serve as critical components in genetic engineering. Here we report a design of translational activators which is composed of an RNA endoribonuclease (Csy4) and two exchangeable RNA modules. Csy4, a member of Cas endoribonuclease, cleaves at a specific recognition site; this cleavage releases a cis-repressive RNA module (crRNA) from the masked ribosome binding site (RBS), which subsequently allows the downstream translation initiation. Unlike small RNA as a translational activator, the endoribonuclease-based activator is able to efficiently unfold the perfect RBS-crRNA pairing. As an exchangeable module, the crRNA-RBS duplex was forwardly and reversely engineered to modulate the dynamic range of translational activity. We further showed that Csy4 and its recognition site, together as a module, can also be replaced by orthogonal endoribonuclease recognition site homologues. These modularly structured, high-performance translational activators would endow the programming of gene expression in the translation level with higher feasibility. PMID- 26414662 TI - Visualising the problems with balancing lithium-sulfur batteries by "mapping" internal resistance. AB - Frequent and continuous determination of battery internal resistance by a simple current-interrupt method enables the visualisation of cell behaviour through the creation of resistance "maps", showing changes in resistance as a function of both capacity and cycle number. This new approach is applied here for the investigation of cell failure in the lithium-sulfur system with Li electrode excesses optimised towards practically relevant specifications. PMID- 26414661 TI - High Fat Diet Enhances beta-Site Cleavage of Amyloid Precursor Protein (APP) via Promoting beta-Site APP Cleaving Enzyme 1/Adaptor Protein 2/Clathrin Complex Formation. AB - Obesity and type 2 diabetes are risk factors of Alzheimer's disease (AD). We reported that a high fat diet (HFD) promotes amyloid precursor protein (APP) cleavage by beta-site APP cleaving enzyme 1 (BACE1) without increasing BACE1 levels in APP transgenic mice. However, the detailed mechanism had remained unclear. Here we demonstrate that HFD promotes BACE1/Adaptor protein-2 (AP 2)/clathrin complex formation by increasing AP-2 levels in APP transgenic mice. In Swedish APP overexpressing Chinese hamster ovary (CHO) cells as well as in SH SY5Y cells, overexpression of AP-2 promoted the formation of BACE1/AP-2/clathrin complex, increasing the level of the soluble form of APP beta (sAPPbeta). On the other hand, mutant D495R BACE1, which inhibits formation of this trimeric complex, was shown to decrease the level of sAPPbeta. Overexpression of AP-2 promoted the internalization of BACE1 from the cell surface, thus reducing the cell surface BACE1 level. As such, we concluded that HFD may induce the formation of the BACE1/AP-2/clathrin complex, which is followed by its transport of BACE1 from the cell surface to the intracellular compartments. These events might be associated with the enhancement of beta-site cleavage of APP in APP transgenic mice. Here we present evidence that HFD, by regulation of subcellular trafficking of BACE1, promotes APP cleavage. PMID- 26414663 TI - HIV-1 Transmitted Drug Resistance Mutations in Newly Diagnosed Antiretroviral Naive Patients in Turkey. AB - HIV-1 replication is rapid and highly error-prone. Transmission of a drug resistant HIV-1 strain is possible and occurs within the HIV-1-infected population. In this study, we aimed to determine the prevalence of transmitted drug resistance mutations (TDRMs) in 1,306 newly diagnosed untreated HIV-1 infected patients from 21 cities across six regions of Turkey between 2010 and 2015. TDRMs were identified according to the criteria provided by the World Health Organization's 2009 list of surveillance drug resistance mutations. The HIV-1 TDRM prevalence was 10.1% (133/1,306) in Turkey. Primary drug resistance mutations (K65R, M184V) and thymidine analogue-associated mutations (TAMs) were evaluated together as nucleos(t)ide reverse transcriptase inhibitor (NRTI) mutations. NRTI TDRMs were found in 8.1% (107/1,306) of patients. However, TAMs were divided into three categories and M41L, L210W, and T215Y mutations were found for TAM1 in 97 (7.4%) patients, D67N, K70R, K219E/Q/N/R, T215F, and T215C/D/S mutations were detected for TAM2 in 52 (3.9%) patients, and M41L + K219N and M41L + T215C/D/S mutations were detected for the TAM1 + TAM2 profile in 22 (1.7%) patients, respectively. Nonnucleoside reverse transcriptase inhibitor associated TDRMs were detected in 3.3% (44/1,306) of patients (L100I, K101E/P, K103N/S, V179F, Y188H/L/M, Y181I/C, and G190A/E/S) and TDRMs to protease inhibitors were detected in 2.3% (30/1,306) of patients (M46L, I50V, I54V, Q58E, L76V, V82A/C/L/T, N83D, I84V, and L90M). In conclusion, long-term and large-scale monitoring of regional levels of HIV-1 TDRMs informs treatment guidelines and provides feedback on the success of HIV-1 prevention and treatment efforts. PMID- 26414664 TI - Studying a Drug-like, RNA-Focused Small Molecule Library Identifies Compounds That Inhibit RNA Toxicity in Myotonic Dystrophy. AB - There are many RNA targets in the transcriptome to which small molecule chemical probes and lead therapeutics are desired. However, identifying compounds that bind and modulate RNA function in cellulo is difficult. Although rational design approaches have been developed, they are still in their infancies and leave many RNAs "undruggable". In an effort to develop a small molecule library that is biased for binding RNA, we computationally identified "drug-like" compounds from screening collections that have favorable properties for binding RNA and for suitability as lead drugs. As proof-of-concept, this collection was screened for binding to and modulating the cellular dysfunction of the expanded repeating RNA (r(CUG)(exp)) that causes myotonic dystrophy type 1. Hit compounds bind the target in cellulo, as determined by the target identification approach Competitive Chemical Cross-Linking and Isolation by Pull-down (C-ChemCLIP), and selectively improve several disease-associated defects. The best compounds identified from our 320-member library are more potent in cellulo than compounds identified by high-throughput screening (HTS) campaigns against this RNA. Furthermore, the compound collection has a higher hit rate (9% compared to 0.01 3%), and the bioactive compounds identified are not charged; thus, RNA can be "drugged" with compounds that have favorable pharmacological properties. Finally, this RNA-focused small molecule library may serve as a useful starting point to identify lead "drug-like" chemical probes that affect the biological (dys)function of other RNA targets by direct target engagement. PMID- 26414665 TI - Obituary: Fredric Brandt. PMID- 26414666 TI - Surgical Deroofing Procedure for the Treatment of an Auricular Pseudocyst. PMID- 26414667 TI - Tet oncogene family member 2 gene alterations in childhood acute myeloid leukemia. AB - BACKGROUND/PURPOSE: Mutations in the tet oncogene family member 2 gene (TET2) are frequently found in adult patients with acute myeloid leukemia (AML). Reports of TET2 mutations in children are limited. We assessed the prevalence of TET2 mutations in Taiwanese children with AML and analyzed their prognosis. METHODS: Between 1997 and 2010, a total of 69 consecutive children with AML were enrolled at the National Taiwan University Hospital. The analysis for TET2 mutations was performed using direct sequencing. Clinical characteristics and overall survival (OS) were compared between patients with and without TET2 alterations. RESULTS: Intronic and missense mutations were identified. No nonsense or frameshift mutations were observed. Two putative disease-causing missense mutations (S609C and A1865G) were identified in one patient. We estimated the prevalence of TET2 mutations in the current patient population to be 1.4%. The most common polymorphism was I1762V (45%), followed by V218M (12%), P29R (6%), and F868L (6%). Patients with polymorphism I1762V had an increased 10-year survival rate compared with patients without I1762V (48.4% vs. 25.7%, p = 0.049) by Chi-square test; OS was not different when examined using the Kaplan-Meier method (p = 0.104). CONCLUSION: The prevalence of TET2 mutations in children with AML compared with adults with AML was lower and less complex. Patient prognosis associated with TET2 mutations in children requires further investigation. PMID- 26414668 TI - The genomic bases of morphological divergence and reproductive isolation driven by ecological speciation in Senecio (Asteraceae). AB - Ecological speciation, driven by adaptation to contrasting environments, provides an attractive opportunity to study the formation of distinct species, and the role of selection and genomic divergence in this process. Here, we focus on a particularly clear-cut case of ecological speciation to reveal the genomic bases of reproductive isolation and morphological differences between closely related Senecio species, whose recent divergence within the last ~200,000 years was likely driven by the uplift of Mt. Etna (Sicily). These species form a hybrid zone, yet remain morphologically and ecologically distinct, despite active gene exchange. Here, we report a high-density genetic map of the Senecio genome and map hybrid breakdown to one large and several small quantitative trait loci (QTL). Loci under diversifying selection cluster in three 5 cM regions which are characterized by a significant increase in relative (F(ST)), but not absolute (d(XY)), interspecific differentiation. They also correspond to some of the regions of greatest marker density, possibly corresponding to 'cold-spots' of recombination, such as centromeres or chromosomal inversions. Morphological QTL for leaf and floral traits overlap these clusters. We also detected three genomic regions with significant transmission ratio distortion (TRD), possibly indicating accumulation of intrinsic genetic incompatibilities between these recently diverged species. One of the TRD regions overlapped with a cluster of high species differentiation, and another overlaps the large QTL for hybrid breakdown, indicating that divergence of these species may have occurred due to a complex interplay of ecological divergence and accumulation of intrinsic genetic incompatibilities. PMID- 26414669 TI - Brain contrasting ability of blood-brain-barrier-permeable nitroxyl contrast agents for magnetic resonance redox imaging. AB - PURPOSE: The detailed in vivo T1 -weighted contrasting abilities of nitroxyl contrast agents, which have been used as redox responsive contrast agents in several magnetic resonance-based imaging modalities, in mouse brain were investigated. METHODS: Distribution and pharmacokinetics of five types of five membered-ring nitroxyl radical compound were compared using T1 -weighted MRI. RESULTS: The blood-brain barrier (BBB) -impermeable 3-carboxy-2,2,5,5 tetramethylpyrrolidine-N-oxyl (CxP) could not be distributed in the brain. The slightly lipophilic 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-N-oxyl (CmP) showed slight distribution only in the ventricle, but not in the medulla and cortex. The amphiphilic 3-methoxy-carbonyl-2,2,5,5-tetramethyl-pyrrolidine-N-oxyl (MCP) had good initial uniform distribution in the brain and showed typical 2 phase signal decay profiles. A brain-seeking nitroxyl probe, acetoxymethyl 2,2,5,5-tetramethyl-pyrrolidine-N-oxyl-3-carboxylate (CxP-AM), showed an accumulating phase, and then its accumulation was maintained in the medulla and ventricle regions, but not in the cortex. The lipophilic 4-(N-methyl piperidine) 2,2,5,5-tetramethylpyrroline-N-oxyl (23c) was well distributed in the cortex and medulla, but slightly in the ventricle, and showed relatively rapid linear signal decay. CONCLUSION: Nitroxyl contrast agents equipped with a suitable lipophilic substitution group could be BBB-permeable functional contrast agents. MR redox imaging, which can estimate not only the redox characteristics but also the detailed distribution of the contrast agents, is a good candidate for a theranostic tool. Magn Reson Med 76:935-945, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26414671 TI - Correction to "Copper(I)-Catalyzed Borylative exo-Cyclization of Alkenyl Halides Containing Unactivated Double Bond". PMID- 26414672 TI - A game of snakes and ladders: negotiating the 'ups and downs' of endorsement as a nurse practitioner in Australia. AB - BACKGROUND: Australian legislation supporting the nurse practitioner (NP) role was enacted in 1998. Since then, NPs have played an important advanced practice role within the interdisciplinary healthcare team. However, the literature suggests that transition to the NP role can be challenging. AIM: This paper highlights the complex transition experiences of ten recently endorsed Australian NPs. The convoluted legislative and regulatory requirements that were negotiated by the NPs are presented as narratives. METHODS: Informed by an ethnographic approach, participants were interviewed several times during their first year. Interview transcripts were thematically analysed and aggregated into three narratives representative of key findings. KEY FINDINGS: The findings exemplify the complexity of navigating through a labyrinth of bureaucracy and the extensive negotiations required to appease those who yielded power over their future practice. CONCLUSION: This study raises awareness of the transition experiences of Australian NPs and their challenges and barriers during this time. PMID- 26414670 TI - Shared Decision Making for Antidepressants in Primary Care: A Cluster Randomized Trial. AB - IMPORTANCE: For antidepressants, the translation of evidence of comparative effectiveness into practice is suboptimal. This deficit directly affects outcomes and quality of care for patients with depression. To overcome this problem, we developed the Depression Medication Choice (DMC) encounter decision aid, designed to help patients and clinicians consider the available antidepressants and the extent to which they improved depression and other issues important to patients. OBJECTIVE: Estimate the effect of DMC on quality of the decision-making process and depression outcomes. DESIGN, SETTING, AND PARTICIPANTS: We conducted a cluster randomized trial of adults with moderate to severe depression considering treatment with an antidepressant. Primary care practices in 10 rural, suburban, and urban primary care practices across Minnesota and Wisconsin were randomly allocated to treatment of depression with or without use of the DMC decision aid. INTERVENTION: Depression Medication Choice, a series of cards, each highlighting the effect of the available options on an issue of importance to patients for use during face-to-face consultations. MAIN OUTCOMES AND MEASURES: Decision-making quality as judged by patient knowledge and involvement in decision making, patient and clinician decisional comfort (Decisional Conflict Scale) and satisfaction, encounter duration, medication adherence, depression symptoms, and the Patient Health Questionnaire for depression (PHQ-9). RESULTS: We enrolled 117 clinicians and 301 patients (67% women; mean [SD] age, 44 [15] years; mean [SD] PHQ-9 score, 15 [4]) into the trial. Compared with usual care (UC), use of DMC significantly improved patients' decisional comfort (DMC, 80% vs UC, 75%; P = .02), knowledge (DMC, 65% vs UC, 56%; P = .03), satisfaction (risk ratio [RR], from 1.25 [P = .81] to RR, 2.4 [P = .002] depending on satisfaction domain), and involvement (DMC, 47% vs UC, 33%; P<.001). It also improved clinicians' decisional comfort (DMC, 80% vs UC, 68%; P < .001) and satisfaction (RR, 1.64; P = .02). There were no differences in encounter duration, medication adherence, or improvement of depression control between arms. CONCLUSIONS AND RELEVANCE: The DMC decision aid helped primary care clinicians and patients with moderate to severe depression select antidepressants together, improving the decision-making process without extending the visit. On the other hand, DMC had no discernible effect on medication adherence or depression outcomes. By translating comparative effectiveness into patient-centered care, use of DMC improved the quality of primary care for patients with depression. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01502891. PMID- 26414673 TI - Efficacy of an Interinstitutional Mentoring Program Within Pediatric Rheumatology. AB - OBJECTIVE: The small size of many pediatric rheumatology programs translates into limited mentoring options for early career physicians. To address this problem, the American College of Rheumatology (ACR) and the Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed a subspecialty-wide interinstitutional mentoring program, the ACR/CARRA Mentoring Interest Group (AMIGO). We sought to assess the impact of this program on mentoring within pediatric rheumatology. METHODS: In a longitudinal 3-year study, participant ratings from the AMIGO pilot program were compared with those after the program was opened to general enrollment. Access to mentoring as a function of career stage was assessed by surveys of the US and Canadian pediatric rheumatologists in 2011 and 2014, before and after implementation of AMIGO. RESULTS: Participants in the pilot phase (19 dyads) and the general implementation phase (112 dyads) reported comparable success in establishing mentor contact, suitability of mentor mentee pairing, and benefit with respect to career development, scholarship, and work-life balance. Community surveys showed that AMIGO participation as mentee was high among fellows (86%) and modest among junior faculty (31%). Implementation correlated with significant gains in breadth of mentorship and in overall satisfaction with mentoring for fellows but not junior faculty. CONCLUSION: AMIGO is a career mentoring program that serves most fellows and many junior faculty in pediatric rheumatology across the US and Canada. Program evaluation data confirm that a subspecialty-wide interinstitutional mentoring program is feasible and can translate into concrete improvement in mentoring, measurable at the level of the whole professional community. PMID- 26414675 TI - Mouse models of intestinal cancer. AB - Murine models of intestinal cancer are powerful tools to recapitulate human intestinal cancer, understand its biology and test therapies. With recent developments identifying the importance of the tumour microenvironment and the potential for immunotherapy, autochthonous genetically engineered mouse models (GEMMs) will remain an important part of preclinical studies for the foreseeable future. This review will provide an overview of the current mouse models of intestinal cancer, from the Apc(Min/+) mouse, which has been used for over 25 years, to the latest 'state-of-the-art' organoid models. We discuss here how these models have been used to define fundamental processes involved in tumour initiation and the attempts to generate metastatic models, which is the ultimate cause of cancer mortality. Together these models will provide key insights to understand this complex disease and hopefully will lead to the discovery of new therapeutic strategies. PMID- 26414676 TI - An atlas of genetic correlations across human diseases and traits. AB - Identifying genetic correlations between complex traits and diseases can provide useful etiological insights and help prioritize likely causal relationships. The major challenges preventing estimation of genetic correlation from genome-wide association study (GWAS) data with current methods are the lack of availability of individual-level genotype data and widespread sample overlap among meta analyses. We circumvent these difficulties by introducing a technique-cross-trait LD Score regression-for estimating genetic correlation that requires only GWAS summary statistics and is not biased by sample overlap. We use this method to estimate 276 genetic correlations among 24 traits. The results include genetic correlations between anorexia nervosa and schizophrenia, anorexia and obesity, and educational attainment and several diseases. These results highlight the power of genome-wide analyses, as there currently are no significantly associated SNPs for anorexia nervosa and only three for educational attainment. PMID- 26414679 TI - Transepithelial Transport of PAMAM Dendrimers Across Isolated Human Intestinal Tissue. AB - Poly(amido amine) (PAMAM) dendrimers have shown transepithelial transport across intestinal epithelial barrier in rats and across Caco-2 cell monolayers. Caco-2 models innately lack mucous barriers, and rat isolated intestinal tissue has been shown to overestimate human permeability. This study is the first report of transport of PAMAM dendrimers across isolated human intestinal epithelium. It was observed that FITC labeled G4-NH2 and G3.5-COOH PAMAM dendrimers at 1 mM concentration do not have a statistically higher permeability compared to free FITC controls in isolated human jejunum and colonic tissues. Mannitol permeability was increased at 10 mM concentrations of G3.5-COOH and G4-NH2 dendrimers. Significant histological changes in human colonic and jejunal tissues were observed at G3.5-COOH and G4-NH2 concentrations of 10 mM implying that dose limiting toxicity may occur at similar concentrations in vivo. The permeability through human isolated intestinal tissue in this study was compared to previous rat and Caco-2 permeability data. This study implicates that PAMAM dendrimer oral drug delivery may be feasible, but it may be limited to highly potent drugs. PMID- 26414678 TI - Partitioning heritability by functional annotation using genome-wide association summary statistics. AB - Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here we analyze a broad set of functional elements, including cell type-specific elements, to estimate their polygenic contributions to heritability in genome wide association studies (GWAS) of 17 complex diseases and traits with an average sample size of 73,599. To enable this analysis, we introduce a new method, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers. This new method is computationally tractable at very large sample sizes and leverages genome-wide information. Our findings include a large enrichment of heritability in conserved regions across many traits, a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers and many cell type-specific enrichments, including significant enrichment of central nervous system cell types in the heritability of body mass index, age at menarche, educational attainment and smoking behavior. PMID- 26414680 TI - Exposure to flour dust in the occupational environment. AB - Exposure to flour dust can be found in the food industry and animal feed production. It may result in various adverse health outcomes from conjunctivitis to baker's asthma. In this paper, flour dust exposure in the above-mentioned occupational environments is characterized and its health effects are discussed. A peer-reviewed literature search was carried out and all available published materials were included if they provided information on the above-mentioned elements. The hitherto conducted studies show that different components of flour dust like enzymes, proteins and baker's additives can cause both non-allergic and allergic reactions among exposed workers. Moreover, the problem of exposure to cereal allergens present in flour dust can also be a concern for bakers' family members. Appreciating the importance of all these issues, the exposure assessment methods, hygienic standards and preventive measures are also addressed in this paper. PMID- 26414681 TI - Can Creatine Supplementation Improve Body Composition and Objective Physical Function in Rheumatoid Arthritis Patients? A Randomized Controlled Trial. AB - OBJECTIVE: Rheumatoid cachexia (muscle wasting) in rheumatoid arthritis (RA) patients contributes to substantial reductions in strength and impaired physical function. The objective of this randomized controlled trial was to investigate the effectiveness of oral creatine (Cr) supplementation in increasing lean mass and improving strength and physical function in RA patients. METHODS: In a double blind design, 40 RA patients were randomized to either 12 weeks' supplementation of Cr or placebo. Body composition (dual x-ray absorptiometry and bioelectrical impedance spectroscopy [BIS]), strength, and objectively assessed physical function were measured at baseline, day 6, week 12, and week 24. Data analysis was performed by analysis of covariance. RESULTS: Cr supplementation increased appendicular lean mass (ALM; a surrogate measure of muscle mass) by mean +/- SE 0.52 +/- 0.13 kg (P = 0.004 versus placebo), and total LM by 0.60 +/- 0.37 kg (P = 0.158). The change in LM concurred with the gain in intracellular water (0.64 +/- 0.22 liters; P = 0.035) measured by BIS. Despite increasing ALM, Cr supplementation, relative to placebo, failed to improve isometric knee extensor strength (P = 0.408), handgrip strength (P = 0.833), or objectively assessed physical function (P = 0.335-0.764). CONCLUSION: In patients with RA, Cr supplementation increased muscle mass, but not strength or objective physical function. No treatment-related adverse effects were reported, suggesting that Cr supplementation may offer a safe and acceptable adjunct treatment for attenuating muscle loss; this treatment may be beneficial for patients experiencing severe rheumatoid cachexia. PMID- 26414682 TI - Tooth Tissue Engineering: The Importance of Blood Products as a Supplement in Tissue Culture Medium for Human Pulp Dental Stem Cells. AB - One of the goals in using cells for tissue engineering (TE) and cell therapy consists of optimizing the medium for cell culture. The present study compares three different blood product supplements for improved cell proliferation and protection against DNA damage in cultured human dental pulp stem cells for tooth TE applications. Human cells from dental pulp were first characterized as adult stem cells (ectomesenchymal mixed origin) by flow cytometry. Next, four different cell culture conditions were tested: I, supplement-free; II, supplemented with fetal bovine serum; III, allogeneic human serum; and IV, autologous human serum. Cultured cells were then characterized for cell proliferation, mineralized nodule formation, and colony-forming units (CFU) capability. After 28 days in culture, the comet assay was performed to assess possible damage in cellular DNA. Our results revealed that Protocol IV achieved higher cell proliferation than Protocol I (p = 0.0112). Protocols II and III resulted in higher cell proliferation than Protocol I, but no statistical differences were found relative to Protocol IV. The comet assay revealed less cell damage in cells cultured using Protocol IV as compared to Protocols II and III. The damage percentage observed on Protocol II was significantly higher than all other protocols. CFUs capability was highest using Protocol IV (p = 0.0018) and III, respectively, and the highest degree of mineralization was observed using Protocol IV as compared to Protocols II and III. Protocol IV resulted in significantly improved cell proliferation, and no cell damage was observed. These results demonstrate that human blood product supplements can be used as feasible supplements for culturing adult human dental stem cells. PMID- 26414685 TI - Origin of Noise in Layered MoTe2 Transistors and its Possible Use for Environmental Sensors. AB - Low-frequency current fluctuations are monitored and the mechanism of electric noise investigated in layered 2H-type alpha-molybdenum ditelluride transistors. The charge transport mechanism of electric noise in atomically thin transition metal dichalcogenides is studied under different environments; the development of a new sensing functionality may be stimulated. PMID- 26414683 TI - The effect of oppositional parietal transcranial direct current stimulation on lateralized brain functions. AB - Cognitive functions such as numerical processing and spatial attention show varying degrees of lateralization. Transcranial direct current stimulation (tDCS) can be used to investigate how modulating cortical excitability affects performance of these tasks. This study investigated the effect of bi-parietal tDCS on numerical processing, spatial and sustained attention. It was hypothesized that tDCS would have distinct effects on these tasks because of varying lateralization (numerical processing left, spatial attention right) and that these effects are partly mediated by modulation of sustained attention. A single-blinded, crossover, sham-controlled study was performed. Eighteen healthy right-handed participants performed cognitive tasks during three sessions of oppositional parietal tDCS stimulation: sham; right anodal with left cathodal (RA/LC); and right cathodal with left anodal (RC/LA). Participants performed a number comparison task, a modified Posner task, a choice reaction task (CRT) and the rapid visual processing task (RVP). RA/LC tDCS impaired number comparison performance compared with sham, with slower responses to numerically close numbers pairs. RA/LC and RC/LA tDCS had distinct effects on CRT performance, specifically affecting vigilance level during the final block of the task. No effect of stimulation on the Posner task or RVP was found. It was demonstrated that oppositional parietal tDCS affected both numerical performance and vigilance level in a polarity-dependent manner. The effect of tDCS on numerical processing may partly be due to attentional effects. The behavioural effects of tDCS were specifically observed under high task demands, demonstrating the consequences of an interaction between stimulation type and cognitive load. PMID- 26414684 TI - How does HTLV-1 cause adult T-cell leukaemia/lymphoma (ATL)? AB - A typical person infected with the retrovirus human T-lymphotropic virus type 1 (HTLV-1) carries tens of thousands of clones of HTLV-1-infected T lymphocytes, each clone distinguished by a unique integration site of the provirus in the host genome. However, only 5% of infected people develop the malignant disease adult T cell leukaemia/lymphoma, usually more than 50 years after becoming infected. We review the host and viral factors that cause this aggressive disease. PMID- 26414687 TI - Revisiting the tale of venous thromboembolism in hospitalized medical patients. PMID- 26414686 TI - Protracted effects of chronic stress on serotonin-dependent thermoregulation. AB - Chronic stress is known to affect serotonin (5HT) neurotransmission in the brain and to alter body temperature. The body temperature is controlled in part, by the medial preoptic area (mPOA) of the hypothalamus. To investigate the effect of chronic stress on 5HT and how it affects body temperature regulation, we examined whether exposure to a chronic unpredictable stress (CUS) paradigm produces long term alterations in thermoregulatory function of the mPOA through decreased 5HT neurotransmission. Adult male Sprague-Dawley rats underwent 21 d of CUS. Four days after the last stress exposure, basal body temperature in the home cage and body temperature in a cold room maintained at 10 degrees C were recorded. The CUS rats had significantly higher subcutaneous basal body temperature at 13:00 h compared to unstressed (NoStress) rats. Whereas the NoStress rats were able to significantly elevate body temperature from basal levels at 30 and 60 min of exposure to the cold room, the CUS rats showed a hypothermic response to the cold. Treatment during CUS with metyrapone, a corticosterone synthesis inhibitor, blocked stress-induced decrease in body temperature in response to the cold challenge. CUS also decreased 5HT transporter protein immunoreactivity in the mPOA and 5HT2A/C agonist injection into the mPOA after CUS exposure caused stressed rats to exhibit a sensitized hyperthermic response to cold. These results indicate that the CUS induced changes to the 5HTergic system alter mPOA function in thermoregulation. These findings help us to explain the mechanisms underlying chronic stress-induced disorders such as chronic fatigue syndrome wherein long lasting thermoregulatory deficits are observed. PMID- 26414688 TI - Future treatment options for human African trypanosomiasis. AB - Over the past 17 years, the number of reported cases of human African trypanosomiasis (HAT) has declined by over 90%, a significant result since the disease was highlighted as a public health problem by the WHO in 1995. However, if the goal of eliminating HAT by 2020 is to be achieved, then new treatments need to be identified and developed. A plethora of compound collections has been screened against Trypanosoma brucei spp, the etiological agents of HAT, resulting in three compounds progressing to clinical development. However, due to the high attrition rates in drug discovery, it is essential that research continues to identify novel molecules. Failure to do so, will result in the absence of molecules in the pipeline to fall back on should the current clinical trials be unsuccessful. This could seriously compromise control efforts to date, resulting in a resurgence in the number of HAT cases. PMID- 26414689 TI - Do normal head ultrasounds need repeating in infants less than 30 weeks gestation? AB - OBJECTIVE: Current head ultrasound (HUS) screening recommendations in preterm infants often include a repeat HUS, regardless of initial findings. The objective of this study is to determine the rate of subsequent severe intraventricular hemorrhage (IVH), ventriculomegaly (VM), or periventricular leukomalacia (PVL) among infants < 30 weeks gestation (EGA) with a normal HUS at day of life (DOL) 4 10. METHODS: Retrospectively collected data were analyzed for all infants < 30 weeks EGA cared for in one NICU from 1 January 2010 to 31 August 2014. Infants with severe congenital anomalies were excluded. We reviewed the first three HUSs and last documented HUS. Severe IVH was defined as > Papile grade 2 and significant interval HUS change was defined as development of severe IVH, PVL, or VM. RESULTS: Of the 383 infants who had an initial screening HUS between DOL 4 and 10, 258 (67%) were initially normal and repeat screening was performed in 228 of these. None developed severe IVH on follow-up HUS. One infant developed VM secondary to GBS meningitis, and one developed echogenicity concerning for PVL that later resolved. CONCLUSIONS: Among very preterm infants with a normal HUS between DOL 4 and 10, routine follow-up HUS is unlikely to identify a significant change. PMID- 26414677 TI - Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. AB - Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ~70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (~6% increase in risk per year; P = 3 * 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms. PMID- 26414691 TI - Reactions of Th(+) + H2, D2, and HD Studied by Guided Ion Beam Tandem Mass Spectrometry and Quantum Chemical Calculations. AB - Kinetic energy dependent reactions of Th(+) with H2, D2, and HD were studied using a guided ion beam tandem mass spectrometer. Formation of ThH(+) and ThD(+) is endothermic in all cases with similar thresholds. Branching ratio results for the reaction with HD indicate that Th(+) reacts via a statistical mechanism, similar to Hf(+). The kinetic energy dependent cross sections for formation of ThH(+) and ThD(+) were evaluated to determine a 0 K bond dissociation energy (BDE) of D0(Th(+)-H) = 2.45 +/- 0.07 eV. This value is in good agreement with a previous result obtained from analysis of the Th(+) + CH4 reaction. D0(Th(+)-H) is observed to be larger than its transition metal congeners, TiH(+), ZrH(+), and HfH(+), believed to be a result of lanthanide contraction. The reactions with H2 were also explored using quantum chemical calculations that include a semiempirical estimation and explicit calculation of spin-orbit contributions. These calculations agree nicely and indicate that ThH(+) most likely has a (3)Delta1 ground level with a low-lying (1)Sigma(+) excited state. Theory also provides the reaction potential energy surfaces and BDEs that are in reasonable agreement with experiment. PMID- 26414690 TI - Hypoalbuminemia at admission is associated with increased incidence of in hospital complications in geriatric trauma patients. AB - BACKGROUND: Elderly patients are at an increased risk of protein-energy malnutrition (PEM) which increases the risk of morbidity/mortality. We evaluated the association between hypoalbuminemia at the time of emergency department (ED) admission and in-hospital complications among geriatric trauma patients. METHODS: This was an ambidirectional cohort study of geriatric (>=55 years) trauma patients treated at a Level I trauma center between May 2013 and March 2014. The exposure of interest was albumin level at ED admission (<3.6 g/dL [PEM] or >=3.6 g/dL (No PEM)]. The outcome of interest was 30-day incidence of complications. RESULTS: A total of 130 patients met study eligibility. Of these, 85 (65%) patients were in the PEM group. After adjusting for tube feeding and injury severity score, PEM at admission was associated with a 2-fold increase in the risk of 30-day overall hospital complications (hazard ratio 2.1, 95% confidence interval 1.1 to 3.8). CONCLUSION: Serum albumin level at ED admission, but not prealbumin level, is a significant predictor of in-hospital complications in geriatric trauma patients. PMID- 26414692 TI - Discontinued dermatological drugs in 2014. AB - INTRODUCTION: Dermatology is a relatively small field concerned with conditions of the hair, skin, nails and their related diseases; yet there is considerable active research and development within the field. Pharmaceutical companies seek more effective treatments through various therapeutic classes and delivery routes. However, 28 drugs have been discontinued for the treatment of dermatologic diseases in 2014. AREAS COVERED: Herein, the authors summarize the details about each discontinued drug in 2014. The dermatological conditions covered are: psoriasis, eczema, leg ulcers, wounds, allergies, acne, scleroderma, lupus erythematosus, urticaria, mastocytosis, epidermolysis bullosa, onychomycosis and one other unspecified disease. The authors also provide suggestions for improving and accelerating the future of dermatological drug development. EXPERT OPINION: It is clear that improved metrics, especially for early assessment, emphasizing clinical relevance, are necessary to increase success rate. Transparency and clear communication within the field is necessary to reduce and salvage the waste that accumulates from these costly studies. Focused attention on how preclinical and early clinical studies failed to indicate subsequent toxicity profiles in patients would accelerate drug development. Distinguishing between disappointing study results and business/financial factors is important when analyzing discontinuations. A reformed approach toward study design would aid both. Ultimately, relevance and practicality for the patient must be kept in mind at all times. PMID- 26414694 TI - Deep venous thrombosis in the nonoperated leg after primary major lower extremity arthroplasty: a retrospective study based on diagnosis using venography. AB - Venous thromboembolism (VTE) is a common complication after major orthopedic surgery. However, the reported rates of deep venous thrombosis (DVT) vary widely. Our aim was to study the incidence of DVT in the nonoperated leg after primary major lower extremity arthroplasty using bilateral venography. The records of patients who underwent total hip arthroplasty (THA) or total knee arthroplasty (TKA) at our institution between August 2013 and August 2014 were reviewed. We examined the records for a total of 380 patients, of which 244 had undergone bilateral venography 3-5 days after THA or TKA. A total of 244 patients undergoing TKA (n = 119) or THA (n = 125) were recruited for this study. DVT was diagnosed in 42 (17.2%) of the 244 patients; nine patients developed DVT in both legs, and four developed DVT only in the nonoperated leg. All of the DVTs were located in calf veins. DVT occurred more frequently after TKA than THA, especially in muscular veins. Female sex and older age were found to be positive risk factors for DVT after THA. The incidence of DVT after major lower arthroplasty is high. DVT in nonoperated legs should be carefully considered because of its potential risks, especially in left. Distal DVT also has a high risk to develop pulmonary embolism (PE). The combination of anticoagulant and pneumatic compression is a good measure to avoid proximal DVT, and it is well tolerated to stop anticoagulant if the patients were diagnosed as having no DVT. PMID- 26414693 TI - Three-Dimensional Neural Spheroid Culture: An In Vitro Model for Cortical Studies. AB - There is a high demand for in vitro models of the central nervous system (CNS) to study neurological disorders, injuries, toxicity, and drug efficacy. Three dimensional (3D) in vitro models can bridge the gap between traditional two dimensional culture and animal models because they present an in vivo-like microenvironment in a tailorable experimental platform. Within the expanding variety of sophisticated 3D cultures, scaffold-free, self-assembled spheroid culture avoids the introduction of foreign materials and preserves the native cell populations and extracellular matrix types. In this study, we generated 3D spheroids with primary postnatal rat cortical cells using an accessible, size controlled, reproducible, and cost-effective method. Neurons and glia formed laminin-containing 3D networks within the spheroids. The neurons were electrically active and formed circuitry through both excitatory and inhibitory synapses. The mechanical properties of the spheroids were in the range of brain tissue. These in vivo-like features of 3D cortical spheroids provide the potential for relevant and translatable investigations of the CNS in vitro. PMID- 26414695 TI - Prescribing patterns of target-specific oral anticoagulants: an academic hospital perspective. AB - Target-specific oral anticoagulants have been rapidly adopted into clinical practice for stroke prophylaxis and venous thromboembolism treatment, raising concerns about off-label prescribing practices. We conducted a retrospective review of consecutive patients prescribed dabigatran, rivaroxaban or apixaban prior to inpatient hospitalization over an 18-month period to examine the off label prescribing frequency, contraindications and related complications. Chart review included baseline demographics, hospital admitting service, outpatient prescribing service, renal function, therapeutic indication, echocardiographic findings, contraindications, major bleeding events and vital status. We identified 160 patients who received a target-specific oral anticoagulant prior to hospitalization. Over half (53.1%) of the patients received rivaroxaban, 43.7% received dabigatran and 3.1% received apixaban. Atrial fibrillation (68.1%) and venous thromboembolism treatment (25.6%) were the most common indications. Ninety percent of patients had a U.S. Foods and Drugs Administration (FDA)-approved indication for therapy. Major bleeding events occurred in 4.4% of patients. Cardiology was the most common prescribing and admitting service (43.8 and 31.3%), and more frequently adhered to FDA-approved indications (97 vs. 84%, P = 0.01). There were no significant differences between prescribing services regarding major contraindications (P = 0.14) and major bleeding events (P = 0.77). Off-label prescription rates for target-specific oral anticoagulants were infrequent and not associated with increased adverse events. PMID- 26414696 TI - Exercise Therapy for Parkinson's Disease: Pedaling Rate Is Related to Changes in Motor Connectivity. AB - Forced-rate lower-extremity exercise has recently emerged as a potential safe and low-cost therapy for Parkinson's disease (PD). The efficacy is believed to be dependent on pedaling rate, with rates above the subjects' voluntary exercise rates being most beneficial. In this study, we use functional connectivity magnetic resonance imaging (MRI) to further elucidate the mechanism underlying this effect. Twenty-seven PD patients were randomized to complete 8 weeks of forced-rate exercise (FE) or voluntary-rate exercise (VE). Exercise was delivered using a specialized stationary bicycle, which can augment patients' voluntary exercise rates. The FE group received assistance from the cycle. Imaging was conducted at baseline, end of therapy, and after 4 weeks of follow-up. Functional connectivity (FC) was determined via seed-based correlation analysis, using activation-based seeds in the primary motor cortex (M1). The change in FC after exercise was compared using linear correlation with pedaling rate. Results of the correlation analysis showed a strong positive correlation between pedaling rate and change in FC from the most affected M1 to the ipsilateral thalamus. This effect persisted after 4 weeks of follow-up. These results indicate that a plausible mechanism for the therapeutic efficacy of high-rate exercise in PD is that it improves thalamo-cortical connectivity. PMID- 26414698 TI - From the Editors. PMID- 26414699 TI - Nonparametric Estimation of the Probability of Detection of Flaws in an Industrial Component, from Destructive and Nondestructive Testing Data, Using Approximate Bayesian Computation. AB - We consider the problem of estimating the probability of detection (POD) of flaws in an industrial steel component. Modeled as an increasing function of the flaw height, the POD characterizes the detection process; it is also involved in the estimation of the flaw size distribution, a key input parameter of physical models describing the behavior of the steel component when submitted to extreme thermodynamic loads. Such models are used to assess the resistance of highly reliable systems whose failures are seldom observed in practice. We develop a Bayesian method to estimate the flaw size distribution and the POD function, using flaw height measures from periodic in-service inspections conducted with an ultrasonic detection device, together with measures from destructive lab experiments. Our approach, based on approximate Bayesian computation (ABC) techniques, is applied to a real data set and compared to maximum likelihood estimation (MLE) and a more classical approach based on Markov Chain Monte Carlo (MCMC) techniques. In particular, we show that the parametric model describing the POD as the cumulative distribution function (cdf) of a log-normal distribution, though often used in this context, can be invalidated by the data at hand. We propose an alternative nonparametric model, which assumes no predefined shape, and extend the ABC framework to this setting. Experimental results demonstrate the ability of this method to provide a flexible estimation of the POD function and describe its uncertainty accurately. PMID- 26414697 TI - Polymorphisms in genes in the androgen pathway and risk of Barrett's esophagus and esophageal adenocarcinoma. AB - The strong male predominance in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remains inadequately explained, but sex hormones might be involved. We hypothesized that single nucleotide polymorphisms (SNPs) in the androgen pathway influence risk of developing BE and EAC. This genetic epidemiological analysis included 14 studies from Australia, Europe and North America. Polymorphisms in 16 genes coding for the androgen pathway were analyzed using a gene-based approach: versatile gene-based test association study. This method evaluates associations between a trait and all SNPs within a specific gene rather than each SNP marker individually as in a conventional GWAS. The data were stratified for sex, body-mass index, waist-to-hip ratio, tobacco smoking and gastroesophageal reflux status. Included were data from 1,508 EAC patients, 2,383 BE patients and 2,170 control participants. SNPs within the gene CYP17A1 were associated with risk of BE in the sexes combined (p = 0.002) and in males (p = 0.003), but not in females separately (p = 0.3). This association was found in tobacco smokers (p = 0.003) and in BE patients without reflux (p = 0.004), but not in nonsmokers (p = 0.2) or those with reflux (p = 0.036). SNPs within JMJD1C were associated with risk of EAC in females (p = 0.001). However, none of these associations replicated in a subsequent sample. Fourteen other genes studied did not reach statistically significant levels of association with BE, EAC or the combination of BE and EAC, after correcting for the number of genes included in the analysis. In conclusion, genetic variants in the androgen-related genes CYP17A1 and JMJD1C might be associated with risk of BE and EAC, respectively, but replication data with larger sample sizes are needed. PMID- 26414703 TI - The Course and Predictors of Health-Related Quality of Life in Living Kidney Donors: A Systematic Review and Meta-Analysis. AB - A better understanding of the course and risk factors for impaired long-term health-related quality of life (HRQoL; ie, physical, psychological, and social relational functioning) after kidney donation might help clinicians improve the care of live kidney donors. This systematic review and meta-analysis summarizes prospective studies about the course and predictors of HRQoL in living kidney donors. Studies indicate that shortly after donation, donors have lower HRQoL, with minor to moderate changes in psychological and social-relational functioning and major changes in physical functioning. At 3-12 months after donation, HRQoL returned to baseline or was slightly reduced, particularly for fatigue, but scores were still comparable to general population norms. Results were mainly robust across surgery techniques. A limited number of studies examined risk factors for impaired HRQoL, with low psychological functioning before donation as the most consistent predictor. Based on these results, clinicians can inform potential donors that, on average, kidney donors have high long-term HRQoL; however, donors with low psychological functioning at baseline are those most at risk of impaired long-term HRQoL. Future studies should focus on other potentially relevant predictors of postdonation HRQoL, including donor eligibility criteria and donor-recipient relationships, to optimize screening and interventions for donors at risk. PMID- 26414700 TI - Robotic Rehabilitator of the Rodent Upper Extremity: A System and Method for Assessing and Training Forelimb Force Production after Neurological Injury. AB - Rodent models of spinal cord injury are critical for the development of treatments for upper limb motor impairment in humans, but there are few methods for measuring forelimb strength of rodents, an important outcome measure. We developed a novel robotic device--the Robotic Rehabilitator of the Rodent Upper Extremity (RUE)--that requires rats to voluntarily reach for and pull a bar to retrieve a food reward; the resistance of the bar can be programmed. We used RUE to train forelimb strength of 16 rats three times per week for 23 weeks before and 38 weeks after a mild (100 kdyne) unilateral contusion at the cervical level 5 (C5). We measured maximum force produced when RUE movement was unexpectedly blocked. We compared this blocked pulling force (BPF) to weekly measures of forelimb strength obtained with a previous, well-established method: the grip strength meter (GSM). Before injury, BPF was 2.6 times higher (BPF, 444.6 +/- 19.1 g; GSM, 168.4 +/- 3.1 g) and 4.9 times more variable (p < 0.001) than pulling force measured with the GSM; the two measurement methods were uncorrelated (R(2) = 0.03; p = 0.84). After injury, there was a significant decrease in BPF of 134.35 g +/- 14.71 g (p < 0.001). Together, our findings document BPF as a repeatable measure of forelimb force production, sensitive to a mild spinal cord injury, which comes closer to measuring maximum force than the GSM and thus may provide a useful measure for quantifying the effects of treatment in rodent models of SCI. PMID- 26414704 TI - Lichen-associated fungi from Paleogene amber. PMID- 26414702 TI - Altered Hypoxic-Adenosine Axis and Metabolism in Group III Pulmonary Hypertension. AB - Group III pulmonary hypertension (PH) is a highly prevalent and deadly lung disorder with limited treatment options other than transplantation. Group III PH affects patients with ongoing chronic lung injury, such as idiopathic pulmonary fibrosis (IPF). Between 30 and 40% of patients with IPF are diagnosed with PH. The diagnosis of PH has devastating consequences to these patients, leading to increased morbidity and mortality, yet the molecular mechanisms involved in the development of PH in patients with chronic lung disease remain elusive. Our hypothesis was that the hypoxic-adenosinergic system is enhanced in patients with group III PH compared with patients with IPF with no PH. Explanted lung tissue was analyzed for markers of the hypoxic-adenosine axis, including expression levels of hypoxia-inducible factor (HIF)-1A, adenosine A2B receptor, CD73, and equilibrative nucleotide transporter-1. In addition, we assessed whether altered mitochondrial metabolism was present in these samples. Increased expression of HIF-1A was observed in tissues from patients with group III PH. These changes were consistent with increased evidence of adenosine accumulation in group III PH. A novel observation of our study was of evidence suggesting altered mitochondrial metabolism in lung tissue from group III PH leading to increased succinate levels that are able to further stabilize HIF-1A. Our data demonstrate that the hypoxic-adenosine axis is up-regulated in group III PH and that subsequent succinate accumulation may play a part in the development of group III PH. PMID- 26414705 TI - The potential for remote ischemic conditioning to improve outcomes in heart failure. AB - Heart failure is the end-stage of a variety of underlying cardiovascular diseases and carries a poor prognosis. The condition is caused by a complex interaction between many pathophysiological processes including ischemia, fibrosis, ventricular remodeling, abnormal neurohumoral balance and inflammation. While traditional pharmacological treatment of heart failure often targets only one pathophysiological mechanism, remote ischemic conditioning induces a multitude of cardioprotective effects. In particular, the anti-ischemic, anti-remodeling and anti-inflammatory properties of remote ischemic conditioning may be of relevance. We propose that remote ischemic conditioning may offer a novel strategy to improve outcomes in heart failure. PMID- 26414706 TI - Inflammatory Bowel Disease in Children and Adolescents. AB - The inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn disease, are chronic inflammatory disorders of the gastrointestinal tract most often diagnosed in adolescence and young adulthood, with a rising incidence in pediatric populations. These disorders are common enough in children that most pediatricians and other pediatric clinicians will encounter children with IBD in their general practice. Inflammatory bowel disease is caused by a dysregulated mucosal immune response to the intestinal microflora in genetically predisposed hosts. Although children can present with the classic symptoms of weight loss, abdominal pain, and bloody diarrhea, many present with nonclassic symptoms of isolated poor growth, anemia, or other extraintestinal manifestations. Once IBD is diagnosed, the goals of therapy consist of eliminating symptoms, normalizing quality of life, restoring growth, and preventing complications while minimizing the adverse effects of medications. Unique considerations when treating children and adolescents with IBD include attention to the effects of the disease on growth and development, bone health, and psychosocial functioning. The purpose of this review is to provide a contemporary overview of the epidemiologic features, pathogenesis, diagnosis, and management of IBD in children and adolescents. PMID- 26414707 TI - Autologous Bone Marrow Mononuclear Cells Exert Broad Effects on Short- and Long Term Biological and Functional Outcomes in Rodents with Intracerebral Hemorrhage. AB - Autologous bone marrow-derived mononuclear cells (MNCs) are a potential therapy for ischemic stroke. However, the effect of MNCs in intracerebral hemorrhage (ICH) has not been fully studied. In this study, we investigated the effects of autologous MNCs in experimental ICH. ICH was induced by infusion of autologous blood into the left striatum in young and aged male Long Evans rats. Twenty-four hours after ICH, rats were randomized to receive an intravenous administration of autologous MNCs (1 * 10(7) cells/kg) or saline. We examined brain water content, various markers related to the integrity of the neurovascular unit and inflammation, neurological deficit, neuroregeneration, and brain atrophy. We found that MNC-treated young rats showed a reduction in the neurotrophil infiltration, the number of inducible nitric oxide synthase-positive cells, and the expression of inflammatory-related signalings such as the high-mobility group protein box-1, S100 calcium binding protein B, matrix metalloproteinase-9, and aquaporin 4. Ultimately, MNCs reduced brain edema in the perihematomal area compared with saline-treated animals at 3 days after ICH. Moreover, MNCs increased vessel density and migration of doublecortin-positive cells, improved motor functional recovery, spatial learning, and memory impairment, and reduced brain atrophy compared with saline-treated animals at 28 days after ICH. We also found that MNCs reduced brain edema and brain atrophy and improved spatial learning and memory in aged rats after ICH. We conclude that autologous MNCs can be safely harvested and intravenously reinfused in rodent ICH and may improve long-term structural and functional recovery after ICH. The results of this study may be applicable when considering future clinical trials testing MNCs for ICH. PMID- 26414708 TI - Receptor Protein Tyrosine Phosphatase alpha-Mediated Enhancement of Rheumatoid Synovial Fibroblast Signaling and Promotion of Arthritis in Mice. AB - OBJECTIVE: During rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) critically promote disease pathogenesis by aggressively invading the extracellular matrix of the joint. The focal adhesion kinase (FAK) signaling pathway is emerging as a contributor to the anomalous behavior of RA FLS. The receptor protein tyrosine phosphatase alpha (RPTPalpha), which is encoded by the PTPRA gene, is a key promoter of FAK signaling. The aim of this study was to investigate whether RPTPalpha mediates FLS aggressiveness and RA pathogenesis. METHODS: Through RPTPalpha knockdown, we assessed FLS gene expression by quantitative polymerase chain reaction analysis and enzyme-linked immunosorbent assay, invasion and migration by Transwell assays, survival by annexin V and propidium iodide staining, adhesion and spreading by immunofluorescence microscopy, and activation of signaling pathways by Western blotting of FLS lysates. Arthritis development was examined in RPTPalpha-knockout (KO) mice using the K/BxN serum-transfer model. The contribution of radiosensitive and radioresistant cells to disease was evaluated by reciprocal bone marrow transplantation. RESULTS: RPTPalpha was enriched in the RA synovial lining. RPTPalpha knockdown impaired RA FLS survival, spreading, migration, invasiveness, and responsiveness to platelet-derived growth factor, tumor necrosis factor, and interleukin-1 stimulation. These phenotypes correlated with increased phosphorylation of Src on inhibitory Y(527) and decreased phosphorylation of FAK on stimulatory Y(397) . Treatment of RA FLS with an inhibitor of FAK phenocopied the knockdown of RPTPalpha. RPTPalpha-KO mice were protected from arthritis development, which was due to radioresistant cells. CONCLUSION: By regulating the phosphorylation of Src and FAK, RPTPalpha mediates proinflammatory and proinvasive signaling in RA FLS, correlating with the promotion of disease in an FLS-dependent model of RA. PMID- 26414709 TI - Heterotrimeric G proteins interact with defense-related receptor-like kinases in Arabidopsis. AB - Heterotrimeric G proteins (G-proteins) are versatile signaling elements conserved in Eukaryotes. In animals G-proteins relay signals from 7-transmembrane spanning G protein-coupled receptors (GPCRs) to intracellular downstream effectors; however, the existence of GPCRs in plants is controversial. Contrastingly, a surplus of receptor-like kinases (RLKs) provides signal recognition at the plant cell surface. It is established that G proteins are involved in plant defense and suggested that they relay signals from defense-related RLKs. However, it is unclear how the signaling is conducted, as physical interaction between the RLKs and G proteins has not been demonstrated. Using yeast split-ubiquitin system and Bimolecular Fluorescence Complementation assays, we demonstrate physical interaction between the Galpha, Ggamma1 and Ggamma2 subunits, and the defense related RD-type receptor like kinases CERK1, BAK1 and BIR1. At the same time, no interaction was detected with the non-RD RLK FLS2. We hypothesize that G-proteins mediate signal transduction immediately downstream of the pathogenesis-related RLKs. PMID- 26414711 TI - Interstate Medical Licensure Compact: Pernicious Myths and Inescapable Facts. PMID- 26414710 TI - Role of Osteogenesis in the Formation of Randall's Plaques. PMID- 26414712 TI - Accuracy and Adequacy of Computed Tomography-Guided Lung Biopsies: Experience From a Community Hospital. AB - CONTEXT: Small tissue biopsies obtained through minimally invasive methods have become the primary diagnostic tools for the pathologic characterization and testing of lung masses. In view of recent advances in targeted therapy for non small cell lung carcinoma, and lung adenocarcinoma in particular, pathologists are now expected to thoroughly characterize lung lesions microscopically while making certain that enough tissue remains for potential molecular analysis if indicated. OBJECTIVE: To report our experience with computed tomography (CT) guided lung needle biopsies with particular concentration on diagnostic yield, diagnostic accuracy, and adequacy of tissue for molecular testing if indicated. METHODS: A retrospective observational study analyzed 224 biopsies in 222 patients undergoing CT-guided lung needle biopsies. Accuracy of diagnosis and adequacy of tissue for molecular testing, if applicable, was evaluated. A standardized protocol for specimen evaluation, triage, and processing was used. This protocol included intraprocedural real-time microscopic specimen evaluation and triage by a pathologist and use of a histologic protocol specifically designed to conserve tissue for ancillary testing. The initial biopsy was considered successful if the specimen was malignant, had specific benign features, or had nonspecific benign features with follow-up supporting benign lesion. Initial biopsy failure cases were those with inadequate tissue or a nonspecific result with highly suspicious imaging or clinical findings. RESULTS: Of the 224 biopsies, 8 cases with benign but nonspecific findings lacked follow up and were excluded from the study. The biopsy was diagnostically successful in 189 of 216 (88%) cases. Of these 189 cases, 154 (81%) were malignant, and 35 (19%) were benign. There were 28 diagnostic failures. Subsequent tissue sampling of 13 of 28 diagnostic failures found 9 (69%) to be malignant. Molecular studies were requested on 25 cases: 24 had sufficient material for some of the requested tests, and 20 had enough tissue for all requested testing. CONCLUSION: A standardized protocol and team approach for CT-guided lung needle biopsy optimizes the ability to achieve a high accurate diagnostic yield with adequate tissue for molecular testing. PMID- 26414713 TI - Quantification of Motion Palpation. AB - CONTEXT: The palpation of motions is at the heart of the practice of foreign trained osteopaths. When practicing osteopathic manual therapy (care provided by foreign-trained osteopaths) in the cranial field or osteopathic cranial manipulative medicine, the palpation of small motions (several tens of micrometers) is a key process. However, to the authors' knowledge, the smallest detectable motion has not been identified. OBJECTIVE: To quantify motion detection capacity by passive palpation. METHODS: Participants were instructed to hold a mechanical device containing a micrometric actuator between their hands and report when they felt motion while 6 series of 27 random motions were generated by the actuator. After each series, if a participant succeeded or failed to detect motion with a confidence level of greater than 98%, the motions in the next series were set to a smaller or larger magnitude, respectively. After 6 series, the individual motion detection capacity was recorded. Statistical significance was set at P=.02. RESULTS: A total of 21 participants were selected, comprising 14 osteopaths and 7 nonosteopaths. The average performance of the sample was 148 MUm. Thirteen participants (62%) perceived motions of 200 MUm or less, and 7 participants (33%) detected motions of 50 MUm or less with bare hands. Osteopathic training did not notably affect the performance. Osteopaths were twice as likely to claim detection of nonexisting motions than to miss existing ones, whereas nonosteopaths were equally subject to both types of errors. CONCLUSION: The data show human passive palpatory sensitivity to be in the range of several tens of micrometers. This range is comparable to that reported for calvarial motion (10-50 MUm). PMID- 26414715 TI - Peroneus Longus Rupture at Its Origin Managed With Platelet Rich Plasma. AB - Tears of the peroneus longus muscle are unusual, and typically involve the distal insertion at the musculotendon junction. Although tears of the mid-portion of the peroneus longus muscle/tendon complex have been reported, no reports of a tear at the origin of the peroneus muscle have been published, to the authors' knowledge. Herein a case of proximal peroneus longus muscle tear and its subsequent management with platelet rich plasma is reported. PMID- 26414714 TI - Non-Vitamin K Antagonist Oral Anticoagulants: The Clinician's New Challenge. AB - Millions of US patients are prescribed oral anticoagulants. Traditionally, oral anticoagulation was achieved with vitamin K antagonists (VKAs). In recent years, non-VKA oral anticoagulants (NOACs) have emerged that provide an effective and convenient alternative to VKAs. These agents possess very different pharmacologic properties from what the medical community has grown accustom to with the VKAs. Thus, a new knowledge base is required for NOACs. One particular challenge with the NOACs is the lack of specific reversal agent, resulting in difficulties correcting the coagulopathy induced by these drugs when needed. A review of the current literature is presented to assist clinicians in gaining knowledge of the NOACs to care for patients. PMID- 26414722 TI - Extensive Case of Subcutaneous Emphysema. PMID- 26414723 TI - Filling an Open Spot. PMID- 26414724 TI - Effects of Stem Cell Treatment in Human Patients With Peyronie Disease. AB - CONTEXT: Peyronie disease (PD) is a connective tissue disorder involving the formation of fibrous plaques in the tunica albuginea. Abnormal plaques and scar tissue create a chronic state of inflammation, causing increased curvature of the penis as well as erectile dysfunction. OBJECTIVE: To determine the feasibility and effects of using placental matrix-derived mesenchymal stem cells (PM-MSCs) in the management of PD. METHODS: In a prospective study, patients with PD were injected with PM-MSCs, and followed up at 6-week, 3-month, and 6-month intervals to assess changes in plaque volume, penile curvature, and erectile function status (measured using peak systolic velocity, end-diastolic velocity, and the International Index of Erectile Function questionnaire). RESULTS: In the 5 patients enrolled in the study, statistically significant increases in peak systolic velocity occurred after PM-MSC injection (P<.01). Of a total of 10 plaques managed, 7 had disappeared completely at 3-month follow-up. Changes in end-diastolic velocity, stretched penile length, and penile girth were not statistically significant. CONCLUSION: To our knowledge, this study is the first on the use of stem cells to manage PD in humans. The results suggest that PM-MSCs may be beneficial and effective as a nonsurgical treatment in patients with PD. Future studies with long-term follow-up in a larger sample of patients are warranted. (ClinicalTrials.gov number NCT02395029). PMID- 26414725 TI - The tumor-suppressive function of miR-1 by targeting LASP1 and TAGLN2 in esophageal squamous cell carcinoma. AB - OBJECTIVE: This study determined the expression of microRNA-1 in esophageal squamous cell carcinoma (ESCC) tissue and cell lines to evaluate its effects on clinicopathological parameters and its target genes LASP1 and TAGLN2. METHODS: The expression of miR-1, lasp1, and tagln2 was detected in 55 ESCC tissues and adjacent normal tissues by reverse transcription-polymerase chain reaction (RT PCR). The association between miR-1, lasp1, and tagln2 expression and clinicopathological characteristics was observed. MicroRNA-1 (mimics-miR-1) and its inhibitor (Inhibitor-miR-1) were transfected into esophageal cancer cells KYSE 510 and Eca 109; cell proliferation, migration, and invasion assays were carried out. Plasmid construction and dual-luciferase reporter assay were also carried out to indicate whether LASP1 and TAGLN2 were miR-1 target genes. The expression of LASP1 and TAGLN2 was detected with Western blot methods in cell lines, by immunohistochemistry in ESCC tissue. RESULTS: The gene expression level of microRNA-1 in cancer tissues was significantly lower than that in adjacent normal tissues (P < 0.01). The expression of miR-1 in ESCC was correlated with involvement of lymph nodes (P = 0.002), histologic classification (P = 0.000), and vessel invasion (P = 0.022). The expression of lasp1 and tagln2 increased in cancer tissues compared with in adjacent normal tissues (P < 0.05). MiR-1 suppresses the cell growth, migration, and invasion in vitro. The expression of LASP1 and TAGLN2 decreased in mimics-miR-1 transfected cells, and increased in inhibitor-miR-1 transfected cells. Luciferase reporter assay confirmed that LASP1 and TAGLN2 mRNA actually had the target sites of miR-1. CONCLUSIONS: miR-1 suppresses cell proliferation, invasiveness, metastasis, and progression of ESCC by binding its targeted genes LASP1 and TAGLN2. PMID- 26414726 TI - Reply. PMID- 26414727 TI - Editorial Comment. PMID- 26414728 TI - Elucidation of Pyranonigrin Biosynthetic Pathway Reveals a Mode of Tetramic Acid, Fused gamma-Pyrone, and exo-Methylene Formation. AB - Successful activation of the pyranonigrin biosynthetic gene cluster and gene knockout in Aspergillus niger plus in vivo and in vitro assays led to isolation of six new products, including a spiro cyclobutane-containing dimeric compound, which served as the basis for the proposed comprehensive pyranonigrin biosynthetic pathway. Two redox enzymes are key to forming the characteristic fused gamma-pyrone core, and a protease homologue performs the exo-methylene formation. PMID- 26414729 TI - The role of uric acid in the development of cardiovascular disease. AB - The main purpose of the present supplement, which is based on a symposium held in Bologna, 6-8 November 2014, is twofold: first of all, to reinforce the role of uric acid in the pathogenesis of gout and gout-related non-rheumatic diseases including renal involvement; second, to provide an updated review of the evidence supporting the relevant role of elevated uric acid as a risk factor for cardiovascular diseases. PMID- 26414730 TI - Why focus on uric acid? AB - In gouty patients, urate lowering therapies (ULTs) are recommended to bring serum uric acid (SUA) levels below 6.0 mg/dL, with the aim of dissolving urate depositions, thereby reducing disease impact. However, patients with hyperuricemia often present with other conditions associated with cardiovascular (CV) risk, such as high blood pressure, obesity, insulin resistance, fatty liver, and chronic kidney disease. In the last decade, several well grounded pieces of evidence showed that the elevation of uric acid often occurs prior to the development of hypertension or metabolic syndrome, thus suggesting a direct association between elevated SUA and these conditions. This paper will discuss available evidence supporting the key role of serum uric acid in the development of CV and renal disease, with a focus on the molecular mechanisms underlying this causative association. This review is based on a PubMed/Embase database search for articles on hyperuricemia and its impact on cardiovascular and renal function. PMID- 26414731 TI - Inflammation: a possible mechanism for a causative role of hyperuricemia/gout in cardiovascular disease. AB - Hyperuricemia and gout are independent risk factors associated with the development of hypertension, metabolic syndrome, vascular damage, and renal disease. Whether these risk factors are causally related to these important chronic co-morbidities remains uncertain, but inflammation may provide a mechanistic explanation. Hyperuricemia and gout negatively affect vascular function by exerting pro-oxidant effects and by decreasing nitric oxide bioavailability, thus inducing inflammation and endothelial dysfunction, which may promote hypertension, metabolic syndrome, and cardiovascular (CV) disease. This paper presents and discusses current understanding of the diverse influences promoting hyperuricemia and gout and the basis of acute and chronic hyperuricemia/gout-related inflammation. This review is based on a PubMed/Embase database search for articles on hyperuricemia and its impact on cardiovascular and renal function. PMID- 26414732 TI - Hyperuricemia, urate deposition and the association with hypertension. AB - Hyperuricemia is associated with hypertension, kidney disease, vascular and cardiovascular (CV) events. In experimental models, the inhibition of hepatic uricase induces hyperuricemia, hypertension and mild renal disease. Notably, the micro- and macrovascular changes observed in the experimental model of hyperuricemia resemble the histological changes of human hypertension. This paper presents and discusses the epidemiological correlation between high serum uric acid levels and hypertension, and reviews current evidence supporting the protective effects of the normalization of uric acid levels. This review is based on a PubMed/Embase database search for articles on hyperuricemia and its impact on cardiovascular and renal function. PMID- 26414733 TI - Detrimental role of hyperuricemia on the cardio-reno-vascular system. AB - A bulk of evidence now exists that links gout with adverse cardiovascular (CV) outcomes. However, continuing doubt remains as to whether hyperuricemia can be truly considered an independent major CV risk factor. In fact, many gouty patients who develop major CV and renal events also possess several traditional CV risk factors, the presence of which can potentially confound any relationship between gout and adverse CV events. This paper reviews the available evidence to determine whether sufficient proof exists from biological, epidemiological and clinical trial studies to support a causal relationship between gout and major CV and renal events. This review is based on a PubMed/Embase database search for articles on hyperuricemia and its impact on cardiovascular and renal function. PMID- 26414734 TI - The management of hyperuricemia with urate deposition. AB - Recent epidemiological data suggest a progressive increase of serum levels of uric acid worldwide. This rise in the prevalence of hyperuricemia may be related to the epidemic diffusion of overweight and obesity as well as the shifts in diet with increased consumption of foods rich in purines, alcoholic consumption, and soft drinks sweetened with fructose. The rise in serum uric acid levels worldwide may be regarded as leading an increased risk for gout and other systemic diseases, especially in the cardio-renal system. Therefore, careful management of hyperuricemia with urate deposition is crucial to prevent or even treat those systemic diseases. Despite this, hyperuricemia and gout often remain untreated. This paper reviews current evidence on the management of hyperuricemia with urate deposition, with a focus on its most controversial aspects. This review is based on a PubMed/Embase database search for articles on hyperuricemia and its impact on cardiovascular and renal function. PMID- 26414736 TI - An Innovative Free-Hand Puncture Technique to Reduce Radiation in Percutaneous Nephrolithotomy Using Ultrasound with Navigation System Under Magnetic Field: A Single-Center Experience in Hong Kong. AB - OBJECTIVE: Traditionally, fluoroscopy or ultrasound (US) or both are used for guiding tract creation during percutaneous nephrolithotomy (PCNL). However, the use of fluoroscopy inevitably incurs radiation exposure, which should be cut down as much as possible in view of its potential adverse effects on health: both deterministic effects and stochastic effects. Conventional US guidance, being radiation free, can serve the purpose, but it is difficult to visualize the needle tract during screening without a needle-guiding system fixed to the transducer, and hence, there is a lack of predictability and sense of security. The objective of this study is to assess the feasibility of using US with navigation system (USNS) to solve the above problems. PATIENTS AND METHODS: In 2014, we performed PCNL on 18 patients with USNS guidance. During the puncture step, the magnetic field-based navigation US could help visualize the position of the needle tract in relation to the target calix. The procedure was done in free hand without the usage of needle-guiding system attached to the transducer. Needle deviation could be detected and adjusted immediately to achieve precise puncture. RESULTS: Of the 18 patients, 83.3% (15/18) of them had their punctures effectively done with a single attempt. Three puncture procedures were performed by two urologic trainees without any previous USNS experience. The mean fluoroscopy time during dilatation was 74.6s, with no radiation at all during the puncture step. The stone clearance rate was 72.2%, with 66.7% (12/18) being tubeless procedures. The mean length of hospital stay was 4.8 days. No immediate complications related to the puncture procedure were found. CONCLUSIONS: USNS can provide radiation-free guidance for tract creation in PCNL. It is predictable, precise, reliable, and safe. Most importantly, the technique is easy to learn, particularly for urologists who are new to PCNL. PMID- 26414735 TI - Chronic Effects of Boxing: Diffusion Tensor Imaging and Cognitive Findings. AB - We used magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to evaluate the effects of boxing on brain structure and cognition in 10 boxers (8 retired, 2 active; mean age = 45.7 years; standard deviation [SD] = 9.71) and 9 participants (mean age = 43.44; SD = 9.11) in noncombative sports. Evans Index (maximum width of the anterior horns of the lateral ventricles/maximal width of the internal diameter of the skull) was significantly larger in the boxers (F = 4.52; p = 0.050; Cohen's f = 0.531). Word list recall was impaired in the boxers (F(1,14) = 10.70; p = 0.006; f = 0.84), whereas implicit memory measured by faster reaction time (RT) to a repeating sequence of numbers than to a random sequence was preserved (t = 2.52; p < 0.04). Fractional anisotropy (FA) and the apparent diffusion coefficient (ADC) measured by tractography did not significantly differ between groups. However, DTI metrics were significantly correlated with declarative memory (e.g., left ventral striatum ADC with delayed recall, r = -0.74; p = 0.02) and with RT to the repeating number sequence (r = 0.70; p = 0.04) in the boxers. Years of boxing had the most consistent, negative correlations with FA, ranging from -0.65 for the right ventral striatum to -0.92 for the right cerebral peduncle. Years of boxing was negatively related to the number of words consistently recalled over trials (r = -0.74; p = 0.02), delayed recall (r = -0.83; p = 0.003), and serial RT (r = 0.66; p = 0.05). We conclude that microstructural integrity of white matter tracts is related to declarative memory and response speed in boxers and to the extent of boxing exposure. Implications for chronic traumatic encephalopathy are discussed. PMID- 26414737 TI - Effect of dispersants on the biodegradation of South Louisiana crude oil at 5 and 25 degrees C. AB - This article reports biodegradation rates for a commercial dispersant, JD-2000, South Louisiana crude oil (SLC) alone, and SLC dispersed with JD-2000 at 5 and 25 degrees C. Results from the biodegradation experiments revealed that Component X, a chemical marker for JD-2000, rapidly degraded at both temperatures. The application of JD-2000 decreased by half the overall biodegradation rate of aliphatic compounds at 25 degrees C. At 5 degrees C, a residual fraction consisting of iso- and n-alkanes (C29-C35) persisted after 56 d. The combination of dispersant and higher temperature resulted in faster removal rates for 2- and 3-ring polycyclic aromatic hydrocarbons. When compared with Corexit 9500, our results suggest that the chemistry of the surfactant (or surfactants) in JD-2000 might have favored oil dissolution (substrate transport to the aqueous phase) as an uptake mechanism over adhesion, which requires direct contact of the biomass with the oil. PMID- 26414738 TI - Subchronic exposure to chlorpyrifos affects energy expenditure and detoxification capacity in juvenile Japanese quails. AB - Effects of pesticides on non-target organisms have been studied in several taxa at different levels of biological organization, from enzymatic to behavioral responses. Although the physiological responses may be associated with higher energy costs, little is known about metabolic costs of pesticide detoxification in birds. To fill this gap, we exposed orally (diet) 15-d old Coturnix coturnix japonica individuals to sublethal doses of chlorpyrifos (10 and 20 mg active ingredient/kg dry food) for four weeks. Carboxylesterase (CbE), butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) activities were periodically measured in multiple tissues along with measurements of resting (RMR) and maximum metabolic rates (M(sum)). Furthermore, glucuronic acid in bird excreta was also assessed at the end of the trial. While CbE and BChE activities were inhibited by chlorpyrifos in all tissues during the third and fourth weeks following pesticide treatment, AChE activity was unaffected. At this sampling times, both M(sum) and RMR expansibility decreased. These results suggest that the exposure to chlorpyrifos caused a negative effect on aerobic performance. Additionally, excretion rate of glucuronic acid was up to 2-fold higher in the 20 mg/kg group than in the control and 10-mg/kg chlorpyrifos groups. The inhibition of CbE and BChE activities corroborated that these enzymes are fulfilling their role as bioscavengers for organophosphate pesticides, decreasing its concentration and thus protecting AChE activity against inhibition by chlorpyrifos. PMID- 26414739 TI - Vicia faba bioassay for environmental toxicity monitoring: A review. AB - Higher plants are recognized as excellent genetic models to detect cytogenetic and mutagenic agents and are frequently used in environmental monitoring studies. Vicia faba (V. faba) bioassay have been used to study DNA damages i.e., chromosomal and nuclear aberrations induced by metallic compounds, pesticides, complex mixtures, petroleum derivates, toxins, nanoparticles and industrial effluents. The main advantages of using V. faba is its availability round the year, economical to use, easy to grow and handle; its use does not require sterile conditions, rate of cell division is fast, chromosomes are easy to score, less expensive and more sensitive as compared to other short-term tests that require pre-preparations. The V. faba test offers evaluation of different endpoints and tested agents can be classified as cytotoxic/genotoxic/mutagenic. This test also provides understanding about mechanism of action, whether the tested agent is clastogenic or aneugenic in nature. In view of advantages offered by V. faba test system, it is used extensively to assess toxic agents and has been emerged as an important bioassay for ecotoxicological studies. Based on the applications of V. faba test to assess the environmental quality, this article offers an overview of this test system and its efficiency in assessing the cytogenetic and mutagenic agents in different classes of the environmental concerns. PMID- 26414740 TI - A large-scale model for simulating the fate & transport of organic contaminants in river basins. AB - We present STREAM-EU (Spatially and Temporally Resolved Exposure Assessment Model for EUropean basins), a novel dynamic mass balance model for predicting the environmental fate of organic contaminants in river basins. STREAM-EU goes beyond the current state-of-the-science in that it can simulate spatially and temporally resolved contaminant concentrations in all relevant environmental media (surface water, groundwater, snow, soil and sediments) at the river basin scale. The model can currently be applied to multiple organic contaminants in any river basin in Europe, but the model framework is adaptable to any river basin in any continent. We simulate the environmental fate of perfluoroctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in the Danube River basin and compare model predictions to recent monitoring data. The model predicts PFOS and PFOA concentrations that agree well with measured concentrations for large stretches of the river. Disagreements between the model predictions and measurements in some river sections are shown to be useful indicators of unknown contamination sources to the river basin. PMID- 26414741 TI - Engineering of a highly efficient Xe2*-excilamp (xenon excimer lamp, lambdamax=172 nm, eta=40%) and qualitative comparison to a low-pressure mercury lamp (LP-Hg, lambda=185/254 nm) for water purification. AB - Excilamps are mercury-free gas-discharge sources of non-coherent VUV or UV radiation with high radiant power and a long lifetime. The most efficient excilamp that is currently available on the market is a VUV xenon excilamp system (Xe2(*)-excimer lamp, lambda(max) = 172 nm) with a stated radiant efficiency eta of 40% at an electrical input power P(el) of 20 W, 50 W or 100 W. In this paper, the use of this highly efficient Xe2(*)-excilamp (P(el) = 20 W) for water treatment is demonstrated using a recirculating laboratory photoreactor system with negative radiation geometry. The efficiency in the 172 nm initiated bleaching of aqueous solutions of Rhodamine B is compared to that initiated by a common low-pressure mercury (LP-Hg) lamp (185 nm, TNN 15/32). The dependence of the pseudo zero order rate constant k' of decolorization of RhB on the flow rate and on the initial concentration of RhB was investigated. Both lamps exhibited dependences of k' on the initial concentration of RhB, which represents a typical saturation kinetical behavior. The saturation kinetics was very prominent in the case of the Xe2(*)-excilamp. Also, the Xe2(*)-excilamp treatment exhibited a significant influence on the flow rate of the RhB aqueous solution, which was not the case during the LP-Hg lamp initiated bleaching of RhB. The results of this paper demonstrate that Xe2(*)-excilamps can be used for VUV-initiated water purification. However, to reach the maximum efficacy of the Xe2(*)-excilamp for photo-initiated water purification further engineering optimization of the photoreactor concept is necessary. PMID- 26414742 TI - Photodegradation of dissolved organic matter in ice under solar irradiation. AB - The photodegradation behavior of dissolved organic matter (DOM) with different origins in ice under solar irradiation was investigated. Exposure to sunlight at 2.7 * 10(5) J m(-2) resulted in dissolved organic carbon (DOC) reductions of 22.1 36.5% in ice. The naturally occurring DOM had higher photodegradation potentials than the wastewater-derived DOM in ice. Ultraviolet (UV)-absorbing compounds in DOM, regardless of DOM origin, had much higher photodegradation potentials than gross DOC in ice. The susceptibility of UV-absorbing compounds with natural origin to sunlight exposure in ice was higher than those derived from wastewater. Trihalomethane (THM) precursors were more susceptible to photochemical reactions than gross DOC and haloacetic acid (HAA) precursors in ice. THM precursors in naturally occurring DOM were more photoreactive than those in wastewater-derived DOM in ice, while the photoreactivity of HAA precursors in ice was independent of DOM origin. In ice, the photoreactivity of humic-like fluorescent materials, regardless of DOM origin, was higher than that of gross DOC and protein-like fluorescent materials. DOC reductions caused by sunlight irradiation were found to be negatively correlated to DOC levels, and positively correlated to the aromaticity of DOM. The photodegradation of both wastewater-derived and naturally occurring DOM in ice was significantly facilitated at both acid and alkaline pH, as compared to neutral pH. The photodegradation of DOM in ice, regardless of the origin, was facilitated by nitrate ion [Formula: see text] , nitrite ion [Formula: see text] , ferric ion (Fe(3+)) and ferrous ion (Fe(2+)), and on the other hand, was inhibited by chloridion ion (Cl(-)) and copper ion (Cu(2+)). PMID- 26414744 TI - Assistive technology use by disability type and race: exploration of a population based health survey. AB - PURPOSE: To examine the relationships among Assistive Technology (AT) use, race, type of disability and selected other demographic characteristics. METHOD: Using 2009 National Health Interview Survey, descriptive statistics, statistical interactions and binary logistic regression were performed to identify, contrast and predict the likelihood of using AT based on the type of disability among African Americans (AAs) and European Americans (EAs). RESULTS: We found that more AAs (10% within group proportion of total AAs) used AT compared to EAs (7.5% within group proportion of total EAs). Physical (p < 0.001), auditory (p = 0.028) and emotional (p = 0.008) impairments were statistically significant predictors of AT use. However, physical impairment as a predictor of AT use was greater among AAs (OR = 222.49, CI: 64.04-773.04, p < 0.001) than EAs (OR = 50.77, CI: 31.78-81.12, p < 0.001). EAs had a greater number of disabling conditions that predict the use of AT than AAs, whereas AAs had more demographic characteristics beyond race that predict AT use than EAs. CONCLUSIONS: Disparities were observed in AT usage by disability types and demographic characteristics between AAs and EAs. Moreover, the predictive strength of AT usage based on disability types and other demographic variables differed by races. Overall, the findings about the different relationships among race, disability type, and AT use are found. Implications for Rehabilitation The finding may inform the development of initiatives by rehabilitation leaders to encourage the use of AT by AAs and EAs according to their type of impairment. Having identified physical impairment as statistically significant predictor of AT use greater among AAs, rehabilitation leaders should ensure that people living with those types of disability have access to the corresponding type of AT and can use them effectively. PMID- 26414743 TI - A Clinical Framework to Facilitate Risk Stratification When Considering an Active Surveillance Alternative to Immediate Biopsy and Surgery in Papillary Microcarcinoma. AB - BACKGROUND: The 2015 American Thyroid Association thyroid cancer management guidelines endorse an active surveillance management approach as an alternative to immediate biopsy and surgery in subcentimeter thyroid nodules with highly suspicious ultrasonographic characteristics and in cytologically confirmed very low risk papillary thyroid cancer (PTC). However, the guidelines provide no specific recommendations with regard to the optimal selection of patients for an active surveillance management approach. This article describes a risk-stratified clinical decision-making framework that was developed by the thyroid cancer disease management team at Memorial Sloan Kettering Cancer Center as the lessons learned from Kuma Hospital in Japan were applied to a cohort of patients with probable or proven papillary microcarcinoma (PMC) who were being evaluated for an active surveillance management approach in the United States. SUMMARY: A risk stratified approach to the evaluation of patients with probable or proven PMC being considered for an active surveillance management approach requires an evaluation of three interrelated but distinct domains: (i) tumor/neck ultrasound characteristics (e.g., size of the primary tumor, the location of the tumor within the thyroid gland); (ii) patient characteristics (e.g., age, comorbidities, willingness to accept observation); and (iii) medical team characteristics (e.g., availability and experience of the multidisciplinary team). Based on an analysis of the critical factors within each of these domains, patients with probable or proven PTC can then be classified as ideal, appropriate, or inappropriate candidates for active surveillance. CONCLUSION: Risk stratification utilizing the proposed decision-making framework will improve the ability of clinicians to recognize individual patients with proven or probable PMC who are most likely to benefit from an active surveillance management option while at the same time identifying patients with proven or probable PMC that would be better served with an upfront biopsy and surgical management approach. PMID- 26414745 TI - MRI and planimetric CT follow-up study of patients with severe tick-borne encephalitis. AB - BACKGROUND: The aim of the study was to evaluate the magnetic resonance imaging (MRI) and planimetric computed tomography (CT) of brain lesions in patients with a history of tick-borne encephalitis (TBE); to assess the influence of steroid treatment on the brain and whether lesions were age-dependent. METHODS: A total of 19 patients with abnormal initial imaging in the acute stage of the disease had a follow-up MRI after 1 year; 34 patients hospitalized for TBE encephalitis/encephalomyelitis had planimetric CT after 10 years. RESULTS: On MRI cortico-subcortical atrophy with widening of anterior horns of the lateral ventricles and vascular changes was more marked on follow-up examination. Virchow Robin spaces dilatation, widening of the lateral ventricles, periventricular lesions, and cortico-subcortical atrophy correlated with age. Results of planimetric CT study showed increased percentage of tracings, widened anterior horns, lateral ventricles, and III ventricle, which suggest new non-age-related atrophic lesions. CONCLUSIONS: Radiological lesions in the acute phase of TBE and after recovery are non-specific. Cortico-subcortical atrophy with widening of the anterior horns of the lateral ventricles and vascular changes are most common. Long-term follow-up confirms the formation of new non-age-related cerebral atrophic lesions due to TBE. The logit model may serve as a background for the hypothesis concerning an accelerated local atrophy of the brain tissues in patients with a history of severe TBE. PMID- 26414746 TI - Automatic Control of Gene Expression in Mammalian Cells. AB - Automatic control of gene expression in living cells is paramount importance to characterize both endogenous gene regulatory networks and synthetic circuits. In addition, such a technology can be used to maintain the expression of synthetic circuit components in an optimal range in order to ensure reliable performance. Here we present a microfluidics-based method to automatically control gene expression from the tetracycline-inducible promoter in mammalian cells in real time. Our approach is based on the negative-feedback control engineering paradigm. We validated our method in a monoclonal population of cells constitutively expressing a fluorescent reporter protein (d2EYFP) downstream of a minimal CMV promoter with seven tet-responsive operator motifs (CMV-TET). These cells also constitutively express the tetracycline transactivator protein (tTA). In cells grown in standard growth medium, tTA is able to bind the CMV-TET promoter, causing d2EYFP to be maximally expressed. Upon addition of tetracycline to the culture medium, tTA detaches from the CMV-TET promoter, thus preventing d2EYFP expression. We tested two different model-independent control algorithms (relay and proportional-integral (PI)) to force a monoclonal population of cells to express an intermediate level of d2EYFP equal to 50% of its maximum expression level for up to 3500 min. The control input is either tetracycline-rich or standard growth medium. We demonstrated that both the relay and PI controllers can regulate gene expression at the desired level, despite oscillations (dampened in the case of the PI controller) around the chosen set point. PMID- 26414747 TI - A brief intervention for posttraumatic stress disorder in persons with a serious mental illness. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) is common in people with a serious mental illness, but it is often not diagnosed or treated. Recent progress has been made in developing and validating interventions for PTSD in this population, but dropout from treatment can be problematic. The present study evaluated the feasibility and clinical outcomes of a Brief program (three sessions) for the treatment of PTSD in persons with a serious mental illness. METHOD: An open clinical trial was conducted to evaluate the Brief program, which comprises three individual weekly sessions and includes education about trauma and PTSD, as well as instruction in breathing retraining for the self-management of anxiety. Eighteen predominantly minority persons with serious mental illness and PTSD were enrolled in the Brief program and assessed at baseline, 1-month posttreatment, and 3-month follow-up. RESULTS: Acceptability and tolerability of the program were high, with 15 of 18 (83%) study participants completing all three sessions. Interview-based and self-report assessments indicated significant reductions in PTSD symptoms, depression, and other symptoms at posttreatment, with treatment gains maintained at the 3-month follow-up. CONCLUSION AND IMPLICATION FOR PRACTICE: The results suggest the Brief program may be clinically beneficial to persons with serious mental illnesses and PTSD and indicate that more rigorous research is needed to evaluate the program. PMID- 26414748 TI - Getting by, getting back, and getting on: Matching mental health services to consumers' recovery goals. AB - OBJECTIVE: The goal of this study was to better understand mental health recovery from the point of view of mental health consumers to identify opportunities for practice improvements that closely align services with consumer goals and consumer-preferred outcomes. METHOD: As part of an exploratory study of recovery, semistructured interviews were conducted with 177 integrated health plan members diagnosed with schizophrenia, schizoaffective disorder, bipolar disorder, or affective psychosis. Transcripts of in-depth interviews were coded using Atlas.ti, and definitions of recovery were further subcoded. A qualitative analysis using a modified grounded theory approach and constant comparative method identified common themes and less common but potentially important recovery-related experiences and perspectives. RESULTS: Three primary and 2 cross cutting themes emerged. "Getting by" meant coping and meeting basic needs. "Getting back" meant learning to live with mental illness. "Getting on" meant living a life where mental illness was no longer prominent. Regaining control and recouping losses were cross-cutting themes. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Mental health recovery is complex and dynamic; individuals' recovery goals can be expected to change over time. Person-centered care must accommodate changing consumer priorities, services must be flexible and responsive, and outcomes need to match consumers' objectives. Clinicians can assist in (a) identifying recovery goals, (b) monitoring progress toward and recognizing movement away from goals, (c) tailoring support to different phases/stages, and (d) supporting transitions between phases/stages. (PsycINFO Database Record PMID- 26414750 TI - A palladium-catalyzed tandem reaction of 2-(2-bromobenzylidene)cyclobutanone with 2-alkynylphenol. AB - An efficient approach for the generation of benzo[b]naphtho[2,3-d]oxocin-6-ones through a palladium-catalyzed tandem reaction of 2-alkynylphenol with 2-(2 bromobenzylidene)cyclobutanone is described. This tandem process afforded the fused polycycles easily, with the formation of three bonds with high efficiency, starting from easily available materials. Good functional group tolerance as well as excellent selectivity was displayed. PMID- 26414749 TI - Job satisfaction of Department of Veterans Affairs peer mental health providers. AB - OBJECTIVES: Department of Veterans Affairs (VA) peer specialists and vocational rehabilitation specialists are Veterans employed in mental health services to help other Veterans with similar histories and experiences. Study objectives were to (a) examine job satisfaction among these employees, (b) compare them to other VA mental health workers, and (c) identify factors associated with job satisfaction across the 3 cohorts. METHODS: The study sample included 152 VA employed peer specialists and 222 vocational rehabilitation specialists. A comparison group included 460 VA employees from the same job categories. All participants completed the Job Satisfaction Index (11 aspects and overall satisfaction ratings). Linear regression was used to compare job satisfaction and identify its predictors among the 3 cohorts. RESULTS: Job satisfaction was fairly high, averaging "somewhat satisfied" to "very satisfied" in 6 (peer specialists) and 9 (vocational rehabilitation specialists) of the 11 aspects and overall job ratings. Adjusting for length of employment, age and gender resulted in no significant group differences with 2 exceptions: White peer specialists were less satisfied with pay and promotion opportunities than vocational rehabilitation specialists and comparison-group employees. Across all cohorts, shorter length of time employed in the job was associated with higher job satisfaction. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The high job satisfaction levels among the 2 peer cohorts suggest support for the policy of hiring peer specialists in the VA. Furthermore, the results are consistent with those of the nonveteran samples, indicating that integrating peer providers into mental health care is possible in VA and non-VA settings. PMID- 26414752 TI - Human hepatic ductal plate malformation-like features are seen in a variety of human postnatal nonhepatobiliary tissues. PMID- 26414751 TI - Plasma Cytokine Levels in Chronic Asymptomatic HIV-1 Subtype C Infection as an Indicator of Disease Progression in Botswana: A Retrospective Case Control Study. AB - HIV infects cells of the immune system causing immune activation and proliferation of immune cells, leading to alteration of production and activity of a number of cytokines. These changes in cytokine levels can affect the immune function, and have the potential to directly impact the course of HIV disease. We characterized plasma cytokine concentration profiles in HIV-1 subtype C chronically infected, antiretroviral therapy (ART)-naive participants to establish their influence on disease progression and viremia. Plasma levels of interleukin (IL)-1alpha, IL-7, IL-12p40, granulocyte macrophage-colony stimulating factor (GM-CSF), and interferon (IFN)-gamma were quantified in samples from 60 treatment-naive participants in the placebo arm of the completed Micronutrient-HIV disease progressions study, "Dikotlana" (2004-2009) in Gaborone, Botswana. Participants were stratified into progressors (P) and nonprogressors (NP) based on their rates of CD4(+) T cell depletion during the study period. Nonprogressors were those who had <1% CD4(+) T cell depletion at 24 months postenrollment. Progressors were defined as those with CD4(+) T cell depletion of >15% at 24 months postenrollment. Cytokine levels were compared between P and NP using the Mann-Whitney U-test. Logistic regression analysis was used to determine if cytokines predicted disease progression. Correlations of cytokines with CD4(+) T cell counts and viral loads were determined by the Spearman rank test. Median baseline CD4(+) T cell counts were 453 (Q1, Q3; 401, 592) and 479 (Q1, Q3; 401-592) for nonprogressors and progressors, respectively. Nonprogressors had a higher viral set point than progressors. IL-12p40 levels were significantly higher in the P than in NP at enrollment and 24 months (p < 0.05). Levels of IL-1alpha, IL-7, IFN-gamma, and GM-CSF did not differ significantly between the two groups. Except for IL-12p40, which displayed an inverse correlation with CD4(+) T cell counts and a direct correlation with viral load, all other cytokines showed no correlations. IL-12p40 was found to be the most significant predictor of progression and its production was most likely driven by HIV replication products as evidenced by its direct correlation with viral load. In chronic HIV-1 subtype C infection, CD4(+) T cell counts and plasma cytokine levels may not necessarily evolve in parallel, suggesting the involvement of other factors in determining the rates of CD4(+) T cell depletion. PMID- 26414754 TI - Turning Radiotherapy into an Effective Systemic Anti-cancer Treatment in Combination with Immunotherapy. PMID- 26414755 TI - Preface to the special issue on evolution and morphological diversity. PMID- 26414757 TI - Quantitative susceptibility mapping using a superposed dipole inversion method: Application to intracranial hemorrhage. AB - PURPOSE: To investigate gradient-echo phase errors caused by intracranial hemorrhage (ICH) of low signal magnitude, and propose methods to reduce artifacts from phase errors in quantitative susceptibility mapping (QSM) of ICH. METHODS: Two QSM methods are proposed: (1) mask-inversion that masks the phase of low signal magnitude regions, and (2) ICH magnetic dipole field isolation followed by susceptibility superposition using multiple boundaries for background field removal. The reconstruction methods were tested in eight subjects with ICH using standard single-echo susceptibility-weighted imaging at 1.5 Tesla with 40 ms echo time. Different phase unwrapping algorithms were also compared. RESULTS: Significant phase errors were evident inside ICHs with low signal magnitude. The mask-inversion method recovered susceptibility of ICH in numerical simulation and minimized phase error propagation in patients with ICH. The additional superposed dipole inversion process substantially suppressed and constrained streaking artifacts in all subjects. Using the proposed superposition method, ICH susceptibilities measured from long and short echo times were similar. Laplacian based phase unwrapping substantially underestimated the ICH dipole field as compared to a path-based method. CONCLUSION: The proposed methods of mask inversion as well as ICH isolation and superposition can substantially reduce artifacts in QSM of ICH. Magn Reson Med 76:781-791, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26414758 TI - Production Task Queue Optimization Based on Multi-Attribute Evaluation for Complex Product Assembly Workshop. AB - The production task queue has a great significance for manufacturing resource allocation and scheduling decision. Man-made qualitative queue optimization method has a poor effect and makes the application difficult. A production task queue optimization method is proposed based on multi-attribute evaluation. According to the task attributes, the hierarchical multi-attribute model is established and the indicator quantization methods are given. To calculate the objective indicator weight, criteria importance through intercriteria correlation (CRITIC) is selected from three usual methods. To calculate the subjective indicator weight, BP neural network is used to determine the judge importance degree, and then the trapezoid fuzzy scale-rough AHP considering the judge importance degree is put forward. The balanced weight, which integrates the objective weight and the subjective weight, is calculated base on multi-weight contribution balance model. The technique for order preference by similarity to an ideal solution (TOPSIS) improved by replacing Euclidean distance with relative entropy distance is used to sequence the tasks and optimize the queue by the weighted indicator value. A case study is given to illustrate its correctness and feasibility. PMID- 26414760 TI - Large animal models of atherosclerosis--new tools for persistent problems in cardiovascular medicine. AB - Coronary heart disease and ischaemic stroke caused by atherosclerosis are leading causes of illness and death worldwide. Small animal models have provided insight into the fundamental mechanisms driving early atherosclerosis, but it is increasingly clear that new strategies and research tools are needed to translate these discoveries into improved prevention and treatment of symptomatic atherosclerosis in humans. Key challenges include better understanding of processes in late atherosclerosis, factors affecting atherosclerosis in the coronary bed, and the development of reliable imaging biomarker tools for risk stratification and monitoring of drug effects in humans. Efficient large animal models of atherosclerosis may help tackle these problems. Recent years have seen tremendous advances in gene-editing tools for large animals. This has made it possible to create gene-modified minipigs that develop atherosclerosis with many similarities to humans in terms of predilection for lesion sites and histopathology. Together with existing porcine models of atherosclerosis that are based on spontaneous mutations or severe diabetes, such models open new avenues for translational research in atherosclerosis. In this review, we discuss the merits of different animal models of atherosclerosis and give examples of important research problems where porcine models could prove pivotal for progress. PMID- 26414759 TI - Cognitive Behavior Therapy for Depression and Self-Care in Heart Failure Patients: A Randomized Clinical Trial. AB - IMPORTANCE: Depression and inadequate self-care are common and interrelated problems that increase the risks of hospitalization and mortality in patients with heart failure (HF). OBJECTIVE: To determine the efficacy of an integrative cognitive behavior therapy (CBT) intervention for depression and HF self-care. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial with single-blind outcome assessments. Eligible patients were enrolled at Washington University Medical Center in St Louis between January 4, 2010, and June 28, 2013. The primary data analyses were conducted in February 2015. The participants were 158 outpatients in New York Heart Association Class I, II, and III heart failure with comorbid major depression. INTERVENTIONS: Cognitive behavior therapy delivered by experienced therapists plus usual care (UC), or UC alone. Usual care was enhanced in both groups with a structured HF education program delivered by a cardiac nurse. MAIN OUTCOMES AND MEASURES: The primary outcome was severity of depression at 6 months as measured by the Beck Depression Inventory. The Self-Care of Heart Failure Index Confidence and Maintenance subscales were coprimary outcomes. Secondary outcomes included measures of anxiety, depression, physical functioning, fatigue, social roles and activities, and quality of life. Hospitalizations and deaths were exploratory outcomes. RESULTS: One hundred fifty eight patients were randomized to UC (n = 79) or CBT (n = 79). Within each arm, 26 (33%) of the patients were taking an antidepressant at baseline. One hundred thirty-two (84%) of the participants completed the 6-month posttreatment assessments; 60 (76%) of the UC and 58 (73%) of the CBT participants completed every follow-up assessment (P = .88). Six-month depression scores were lower in the CBT than the UC arm on the Beck Depression Inventory (BDI-II) (12.8 [10.6] vs 17.3 [10.7]; P = .008). Remission rates differed on the BDI-II (46% vs 19%; number needed to treat [NNT] = 3.76; 95% CI, 3.62-3.90; P < .001) and the Hamilton Depression Scale (51% vs 20%; NNT = 3.29; 95% CI, 3.15-3.43; P < .001). The groups did not differ on the Self-Care Maintenance or Confidence subscales. The mean (SD) Beck Depression Inventory scores 6 months after randomization were lower in the CBT (12.8 [10.6]) than the UC arm (17.3 [10.7]), P = .008. There were no statistically significant differences between the groups on the Self-Care Maintenance or Confidence subscale scores or on physical functioning measures. Anxiety and fatigue scores were lower and mental- and HF-related quality of life and social functioning scores were higher at 6 months in the CBT than the UC arm, and there were fewer hospitalizations in the intervention than the UC arm. CONCLUSIONS AND RELEVANCE: A CBT intervention that targets both depression and heart failure self-care is effective for depression but not for HF self-care or physical functioning relative to enhanced UC. Additional benefits include reduced anxiety and fatigue, improved social functioning, and better health-related quality of life. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01028625. PMID- 26414762 TI - Acne scarring: A review of available therapeutic lasers. AB - BACKGROUND AND OBJECTIVE: The utilization of lasers in dermatology has greatly expanded in recent decades. Acne scarring is a common indication in which lasers play an important therapeutic role. STUDY DESIGN/MATERIALS AND METHODS: Available lasers include traditional ablative lasers, such as carbon dioxide and erbium lasers, traditional non-ablative lasers, such as neodymium, diode, alexandrite, pulsed dye lasers and intense pulse light, as well as both ablative, and non ablative fractional laser systems. CONCLUSION: We sought to provide a framework for understanding the various types of lasers available to treat acne scars and review the primary literature pertaining to the efficacy, safety, and advantages of each laser discussed. PMID- 26414761 TI - Black Cohosh Ameliorates Metabolic Disorders in Female Ovariectomized Rats. AB - Estrogen deficiency is associated with metabolic derangements in menopausal women. Black cohosh has been widely used as an alternative therapy in the treatment of menopausal syndrome. However, its role in metabolism needs to be defined. The aim of the present study was to investigate the long-term effect of black cohosh on glucose and lipid metabolism in a rat model of post-menopause. Adult female Sprague-Dawley rats were sham operated (SHAM), ovariectomized (OVX), OVX with the treatment of estradiol valerate (OVX + E), or OVX with the treatment of isopropanolic black cohosh extract (OVX + iCR). Body weight, body composition, and blood glucose levels of the animals were monitored. The rats were then sacrificed after 3 months of the treatments. At the end of the experiment, OVX + iCR and OVX + E rats exhibited a significant decrease in body weight gain, body and abdominal fat mass, serum triglycerides levels, hepatic fat accumulation, and adipocyte hypertrophy compared with OVX rats. In addition, insulin resistance and glucose intolerance were improved in OVX + iCR but not in OVX + E rats. No hepatotoxicity was detected in OVX + iCR animals. Furthermore, western blot analysis suggested the increased lipolysis in adipose tissue of OVX + iCR and OVX + E rats. Data from in vitro experiments using cultured primary rat adipocytes also showed that black cohosh could affect lipolysis of adipocytes. In conclusion, the long-term treatment of black cohosh at a proper dosage ameliorated metabolic derangements in OVX rats. Thus, this drug is promising for the treatment of metabolic disorders in menopausal and post-menopausal women. PMID- 26414763 TI - Fellow As Teacher Curriculum: Improving Rheumatology Fellows' Teaching Skills During Inpatient Consultation. AB - OBJECTIVE: Enhancing rheumatology fellows' teaching skills in the setting of inpatient consultation may have a broad positive impact. Such efforts may improve fellows' clinical skills and overall patient care. Most importantly, effective resident-fellow teaching interactions may not only increase residents' knowledge of rheumatology but may influence their career choice. However, a number of barriers to the resident-fellow teaching interaction have been identified, including fellows' teaching skills. We developed the Fellow As Clinical Teacher (FACT) curriculum in order to enhance fellows' teaching skills during inpatient consultation. METHODS: The FACT curriculum was delivered in two 45-minute workshops during the 3-day Winter Symposium of the Carolinas Fellows Collaborative. We evaluated its effect with self-assessment surveys and fellow performance on the objective structured teaching exercise (OSTE) before and after participation in the curriculum. RESULTS: Nineteen fellows from 4 rheumatology training programs participated in the pre- and post-curriculum OSTEs and 18 fellows completed pre- and post-curriculum surveys. OSTE scores improved on 5 of the 8 items assessed, and the total OSTE score improved as well (34.7 versus 29.5; P < 0.01) after the FACT curriculum. Fellows' self-assessment of their teaching skills and intent to teach during consultation also increased after participation in the curriculum. CONCLUSION: The FACT curriculum, focused on teaching during consultation, improved fellows' teaching skills and attitudes toward teaching. Improving and increasing fellow teaching, particularly in the consultation setting, may impact patient care, resident and fellow learning, and teaching skills of future faculty, and could potentially influence residents' career choice. PMID- 26414764 TI - Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. AB - Human regulatory T cells (T(reg) cells) that develop from conventional T cells (T(conv) cells) following suboptimal stimulation via the T cell antigen receptor (TCR) (induced T(reg) cells (iT(reg) cells)) express the transcription factor Foxp3, are suppressive, and display an active proliferative and metabolic state. Here we found that the induction and suppressive function of iT(reg) cells tightly depended on glycolysis, which controlled Foxp3 splicing variants containing exon 2 (Foxp3-E2) through the glycolytic enzyme enolase-1. The Foxp3 E2-related suppressive activity of iT(reg) cells was altered in human autoimmune diseases, including multiple sclerosis and type 1 diabetes, and was associated with impaired glycolysis and signaling via interleukin 2. This link between glycolysis and Foxp3-E2 variants via enolase-1 shows a previously unknown mechanism for controlling the induction and function of T(reg) cells in health and in autoimmunity. PMID- 26414767 TI - Influence of Solid-State Packing of Dipolar Merocyanine Dyes on Transistor and Solar Cell Performances. AB - A series of nine dipolar merocyanine dyes has been studied as organic semiconductors in transistors and solar cells. These dyes exhibited single crystal packing motifs with different dimensional ordering, which can be correlated to the performance of the studied devices. Hereby, the long-range ordering of the dyes in staircase-like slipped stacks with J-type excitonic coupling favors charge transport and improves solar cell performance. The different morphologies of transistor thin films and solar cell active layers were investigated by UV-vis, AFM, and XRD experiments. Selenium-containing donor acceptor (D-A) dimethine dye 4 showed the highest hole mobility of 0.08 cm(2) V( 1) s(-1). BHJ solar cells based on dye 4 were optimized by taking advantage of the high crystallinity of the donor material and afforded a PCE of up to 6.2%. PMID- 26414765 TI - Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity. AB - Mitochondria need to be juxtaposed to phagosomes for the synergistic production of ample reactive oxygen species (ROS) in phagocytes to kill pathogens. However, how phagosomes transmit signals to recruit mitochondria has remained unclear. Here we found that the kinases Mst1 and Mst2 functioned to control ROS production by regulating mitochondrial trafficking and mitochondrion-phagosome juxtaposition. Mst1 and Mst2 activated the GTPase Rac to promote Toll-like receptor (TLR)-triggered assembly of the TRAF6-ECSIT complex that is required for the recruitment of mitochondria to phagosomes. Inactive forms of Rac, including the human Rac2(D57N) mutant, disrupted the TRAF6-ECSIT complex by sequestering TRAF6 and substantially diminished ROS production and enhanced susceptibility to bacterial infection. Our findings demonstrate that the TLR-Mst1-Mst2-Rac signaling axis is critical for effective phagosome-mitochondrion function and bactericidal activity. PMID- 26414768 TI - The Neoadjuvant Paradigm for Development of Systemic Therapy and Precision Medicine for Bladder Cancer. PMID- 26414766 TI - Runx3 specifies lineage commitment of innate lymphoid cells. AB - Subsets of innate lymphoid cells (ILCs) reside in the mucosa and regulate immune responses to external pathogens. While ILCs can be phenotypically classified into ILC1, ILC2 and ILC3 subsets, the transcriptional control of commitment to each ILC lineage is incompletely understood. Here we report that the transcription factor Runx3 was essential for the normal development of ILC1 and ILC3 cells but not of ILC2 cells. Runx3 controlled the survival of ILC1 cells but not of ILC3 cells. Runx3 was required for expression of the transcription factor RORgammat and its downstream target, the transcription factor AHR, in ILC3 cells. The absence of Runx3 in ILCs exacerbated infection with Citrobacter rodentium. Therefore, our data establish Runx3 as a key transcription factor in the lineage specific differentiation of ILC1 and ILC3 cells. PMID- 26414769 TI - Radiation Dosimetry for Ureteroscopy Patients: A Phantom Study Comparing the Standard and Obese Patient Models. AB - PURPOSE: To determine the effect of obesity on radiation exposure during simulated ureteroscopy. METHODS: A validated anthropomorphic adult male phantom with a body mass index (BMI) of approximately 24 kg/m(2), was positioned to simulate ureteroscopy. Padding with radiographic characteristics of human fat was placed around the phantom to create an obese model with BMI of 30 kg/m(2). Metal oxide semiconductor field effect transistor (MOSFET) dosimeters were placed at 20 organ locations in both models to measure organ dosages. A portable C-arm was used to provide fluoroscopic x-ray radiation to simulate ureteroscopy. Organ dose rates were calculated by dividing organ dose by fluoroscopy time. Effective dose rate (EDR, mSv/sec) was calculated as the sum of organ dose rates multiplied by corresponding ICRP 103 tissue weighting factors. RESULTS: The mean EDR was significantly increased during left ureteroscopy in the obese model at 0.0092 +/- 0.0004 mSv/sec compared with 0.0041 +/- 0.0003 mSv/sec in the nonobese model (P < 0.01), as well as during right ureteroscopy at 0.0061 +/- 0.0002 and 0.0036 +/- 0.0007 mSv/sec in the obese and nonobese model, respectively (P < 0.01). EDR during left ureteroscopy was significantly greater than right ureteroscopy in the obese model (P = 0.02). CONCLUSIONS: Fluoroscopy during ureteroscopy contributes to the overall radiation dose for patients being treated for nephrolithiasis. Obese patients are at even higher risk because of increased exposure rates during fluoroscopy. Every effort should be made to minimize the amount of fluoroscopy used during ureteroscopy, especially with obese patients. PMID- 26414770 TI - Corrigendum to 'Herpesvirus of turkeys: Microarray analysis of host gene responses to infection' [Virology 318 (2004) 102-111]. PMID- 26414771 TI - Corrigendum to "Increased expression of cytokines, soluble cytokine receptors, soluble apoptosis ligand and apoptosis in dengue" [Virology 452-453 (2014) 42 51]. PMID- 26414772 TI - Application of the MERIT survey in the multi-criteria quality assessment of occupational health and safety management. AB - Occupational health and safety management systems apply audit examinations as an integral element of these systems. The examinations are used to verify whether the undertaken actions are in compliance with the accepted regulations, whether they are implemented in a suitable way and whether they are effective. One of the earliest solutions of that type applied in the mining industry in Poland involved the application of audit research based on the MERIT survey (Management Evaluation Regarding Itemized Tendencies). A mathematical model applied in the survey facilitates the determination of assessment indexes WOPi for each of the assessed problem areas, which, among other things, can be used to set up problem area rankings and to determine an aggregate (synthetic) assessment. In the paper presented here, the assessment indexes WOPi were used to calculate a development measure, and the calculation process itself was supplemented with sensitivity analysis. PMID- 26414773 TI - Two new proanthocyanidin trimers isolated from Cistus incanus L. demonstrate potent anti-inflammatory activity and selectivity to cyclooxygenase isoenzymes inhibition. AB - Two new proanthocyanidin trimers have been isolated from Cistus incanus herb; gallocatechin-(4alpha->6)-gallocatechin-(4alpha->8)-gallocatechin (compound 1) and epigallocatechin-3-O-gallate-(4beta->8)-epigallocatechin-3-O-gallate-(4beta >8)-gallocatechin (compound 2). The structures were determined on the basis of 1D and 2D-NMR (HSQC, HMBC) of their peracetylated derivatives, MALDI-TOF-MS and by acid-catalysed degradation with phloroglucinol. A more abundant proanthocyanidin oligomer was also isolated, purified and its chemical constitution studied by (13)C-NMR and phloroglucinol degradation. The mean molecular weight of the polymer was estimated to be about 7 to 8 flavan-3-ol-units with a ratio of procyanidin : prodelphinidin units at 1:5, some of which are derivatised by gallic acid. Water extract and higher oligomeric proanthocyanidin fractions of C. incanus significantly inhibited TPA-induced oedema when applied topically at doses of 0.5 and 1 mg/ear in mice. Furthermore, the extracts and the pure compounds inhibited COX-1 and COX-2 activities. In addition, compound 2 exhibited an IC50 of 4.5 MUM against COX-2 indicating its high selectivity towards COX-2. PMID- 26414775 TI - Poverty, Depression, or Lost in Translation? Ethnic and Language Variation in Patient-Reported Outcomes in Rheumatoid Arthritis. AB - OBJECTIVE: Despite advances in therapies, disparities in outcomes have been documented for rheumatoid arthritis (RA) patients for both ethnicity and English language proficiency. The goals of these analyses were to compare differences in RA patient-reported outcomes, by both self-identification of ethnicity and English language proficiency, and to identify factors that might explain differences among groups. METHODS: Data were collected through structured telephone interviews of a longitudinal cohort with physician-diagnosed RA (n = 438); only women were included (n = 335). Three groups were defined based on self reported ethnicity and English proficiency: white/English (n = 219), Hispanic/English (n = 39), and Hispanic/Spanish (n = 77). Outcomes examined were patient-reported physical functioning, pain, and presence of moderate or severe fatigue. Multivariate regression analyses compared outcomes among groups, adjusting for sociodemographic characteristics, health and disease factors, and depression. RESULTS: Hispanic/Spanish women had worse function, pain, and fatigue than either English-proficient group. Depression was associated with all outcomes (P < 0.0001), and accounted for greater differentials in scores than ethnicity/language proficiency. In interaction analyses, differences between women who were and were not depressed were greater for Hispanic/English than for Hispanic/Spanish. Nondepressed Hispanic/Spanish scores were significantly worse than nondepressed Hispanic/English, i.e., the impact of depression was less for Hispanic/Spanish women because both depressed and nondepressed women in this group reported worse outcomes. After adjustment for sociodemographic factors and depression, language remained significantly associated with outcomes. CONCLUSION: Disparities in patient-reported outcomes may be driven less by ethnicity than by sociodemographic or psychological factors. Measurement instruments that are not culturally appropriate and equivalent may also hamper meaningful analyses of disparities. PMID- 26414774 TI - The selectivity of responses to red-green colour and achromatic contrast in the human visual cortex: an fMRI adaptation study. AB - There is controversy as to how responses to colour in the human brain are organized within the visual pathways. A key issue is whether there are modular pathways that respond selectively to colour or whether there are common neural substrates for both colour and achromatic (Ach) contrast. We used functional magnetic resonance imaging (fMRI) adaptation to investigate the responses of early and extrastriate visual areas to colour and Ach contrast. High-contrast red green (RG) and Ach sinewave rings (0.5 cycles/degree, 2 Hz) were used as both adapting stimuli and test stimuli in a block design. We found robust adaptation to RG or Ach contrast in all visual areas. Cross-adaptation between RG and Ach contrast occurred in all areas indicating the presence of integrated, colour and Ach responses. Notably, we revealed contrasting trends for the two test stimuli. For the RG test, unselective processing (robust adaptation to both RG and Ach contrast) was most evident in the early visual areas (V1 and V2), but selective responses, revealed as greater adaptation between the same stimuli than cross adaptation between different stimuli, emerged in the ventral cortex, in V4 and VO in particular. For the Ach test, unselective responses were again most evident in early visual areas but Ach selectivity emerged in the dorsal cortex (V3a and hMT+). Our findings support a strong presence of integrated mechanisms for colour and Ach contrast across the visual hierarchy, with a progression towards selective processing in extrastriate visual areas. PMID- 26414778 TI - Modelling of oxygen vacancy aggregates in monoclinic HfO2: can they contribute to conductive filament formation? AB - Formation of metal rich conductive filaments and their rearrangements determine the switching characteristics in HfO2 based resistive random access memory (RRAM) devices. The initiation of a filament formation process may occur either via aggregation of pre-existing vacancies randomly distributed in the oxide or via generation of new oxygen vacancies close to the pre-existing ones. We evaluate the feasibility of vacancy aggregation processes by calculating the structures and binding energies of oxygen vacancy aggregates consisting of 2, 3 and 4 vacancies in bulk monoclinic (m)-HfO2 using density functional theory (DFT). We demonstrate that formation of neutral oxygen vacancy aggregates is accompanied by small energy gain, which depends on the size and shape of the aggregate. In the most strongly bound configurations, vacancies are unscreened by Hf cations and form voids within the crystal, with the larger aggregates having larger binding energy per vacancy (-0.11 to -0.18 eV). The negatively charged di-vacancy was found to have similar binding energies to the neutral one, while the positively charged di-vacancy was found to be unstable. Thus aggregation process of either neutral or negatively charged oxygen vacancies is energetically feasible. PMID- 26414776 TI - Pulse pressure amplification and its determinants. AB - BACKGROUND: Pulse pressure (PP) amplification expressed as the peripheral-to central PP ratio has gained importance in the assessment of cardiovascular phenotypes and cardiovascular risk. The aim of the present study was to assess the relationship between PP amplification, large vessel parameters and peripheral blood pressure (BP) to gain insights into the amplification phenomenon. METHODS: Peripheral BP, central BP and carotid-femoral pulse wave velocity (cfPWV) were assessed using the OMRON M6, SphygmoCor and Complior devices, respectively, in 741 adults attending the hypertension outpatient clinic. Analysis of covariance, partial correlations and multiple linear regression models were performed to assess the relationship between PP amplification, peripheral BP and cfPWV. RESULTS: PP amplification was inversely related to BP group. Women showed lower PP amplification than men (1.24 +/- 0.18 and 1.35 +/- 0.18, respectively, p < 0.001). Age, female gender and mean arterial pressure were inversely associated with PP amplification (p < 0.001), whereas heart rate and body mass index showed positive associations (p < 0.001 and p = 0.049, respectively). cfPWV was a predictor of PP amplification in men but not in women (p = 0.006 and p = 0.424, respectively). CONCLUSIONS: PP amplification is related to BP: the higher the BP, the lower the PP amplification. Gender, age and body composition have a significant impact on PP amplification. PMID- 26414777 TI - Human and Murine Tissue-Engineered Colon Exhibit Diverse Neuronal Subtypes and Can Be Populated by Enteric Nervous System Progenitor Cells When Donor Colon Is Aganglionic. AB - PURPOSE: Tissue-engineered colon (TEC) might potentially replace absent or injured large intestine, but the enteric nervous system (ENS), a key component, has not been investigated. In various enteric neuropathic diseases in which the TEC is derived from aganglionic donor colon, the resulting construct might also be aganglionic, limiting tissue engineering applications in conditions such as Hirschsprung disease (HD). We hypothesized that TEC might contain a diverse population of enteric neuronal subtypes, and that aganglionic TEC can be populated by neurons and glia when supplemented with ENS progenitor cells in the form of neurospheres. MATERIALS AND METHODS: Human and murine organoid units (OU) and multicellular clusters containing epithelium and mesenchyme were isolated from both mouse and human donor tissues, including from normally innervated and aganglionic colon. The OU were seeded onto a biodegradable scaffold and implanted within a host mouse, resulting in the growth of TEC. Aganglionic murine and human OU were supplemented with cultured neurospheres to populate the absent ENS not provided by the OU to rescue the HD phenotype. RESULTS: TEC demonstrated abundant smooth muscle and clusters of neurons and glia beneath the epithelium and deeper within the mesenchyme. Motor and afferent neuronal subtypes were identified in TEC. Aganglionic OU formed TEC with absent neural elements, but neurons and glia were abundant when aganglionic OU were supplemented with ENS progenitor cells. CONCLUSION: Murine and human TEC contain key components of the ENS that were not previously identified, including glia, neurons, and fundamental neuronal subtypes. TEC derived from aganglionic colon can be populated with neurons and glia when supplemented with neurospheres. Combining tissue engineering and cellular replacement therapies represents a new strategy for treating enteric neuropathies, particularly HD. PMID- 26414779 TI - Tuning the Tunneling Rate and Dielectric Response of SAM-Based Junctions via a Single Polarizable Atom. AB - The dielectric response and electrical properties of junctions based on self assembled monolayers (SAMs) of the form S(CH2)11X can be controlled by changing the polarizability of X (here X = H, F, Cl, Br, or I). A 1000-fold increase in the tunneling rate and a four-fold increase of the dielectric constant (epsilon r ) with increasing polarizability of X are found. PMID- 26414780 TI - Reassessment of MTBE cancer potency considering modes of action for MTBE and its metabolites. AB - A 1999 California state agency cancer potency (CP) evaluation of methyl tert butyl ether (MTBE) assumed linear risk extrapolations from tumor data were plausible because of limited evidence that MTBE or its metabolites could damage DNA, and based such extrapolations on data from rat gavage and rat and mouse inhalation studies indicating elevated tumor rates in male rat kidney, male rat Leydig interstitial cells, and female rat leukemia/lymphomas. More recent data bearing on MTBE cancer potency include a rodent cancer bioassay of MTBE in drinking water; several new studies of MTBE genotoxicity; several similar evaluations of MTBE metabolites, formaldehyde, and tert-butyl alcohol or TBA; and updated evaluations of carcinogenic mode(s) of action (MOAs) of MTBE and MTBE metabolite's. The lymphoma/leukemia data used in the California assessment were recently declared unreliable by the U.S. Environmental Protection Agency (EPA). Updated characterizations of MTBE CP, and its uncertainty, are currently needed to address a variety of decision goals concerning historical and current MTBE contamination. To this end, an extensive review of data sets bearing on MTBE and metabolite genotoxicity, cytotoxicity, and tumorigenicity was applied to reassess MTBE CP and related uncertainty in view of MOA considerations. Adopting the traditional approach that cytotoxicity-driven cancer MOAs are inoperative at very low, non-cytotoxic dose levels, it was determined that MTBE most likely does not increase cancer risk unless chronic exposures induce target-tissue toxicity, including in sensitive individuals. However, the corresponding expected (or plausible upper bound) CP for MTBE conditional on a hypothetical linear (e.g., genotoxic) MOA was estimated to be ~2 * 10(-5) (or 0.003) per mg MTBE per kg body weight per day for adults exposed chronically over a lifetime. Based on this conservative estimate of CP, if MTBE is carcinogenic to humans, it is among the weakest 10% of chemical carcinogens evaluated by EPA. PMID- 26414781 TI - Monotherapy for hepatitis B infection: a review of treatment options. AB - Chronic hepatitis B (CHB) is a global health problem, causing liver failure, cirrhosis and hepatocellular carcinoma. CHB treatment aims to prevent liver related complication. The treatment of CHB infection includes monotherapy with either interferons (IFNs) or nucleos(t)ide (NUC) analogs. IFNs have moderate antiviral effects, and their use is limited by side effects. With the availability of NUCs, IFN-intolerant and decompensated cirrhotic patients began to be treated. Lamivudine and telbivudine, nucleoside analogs, have low genetic barrier to resistance. Adefovir, a nucleotide analog, has moderate potency and potential nephrotoxicity. Entecavir and tenofovir, with their high potency, high genetic barrier to resistance and favorable safety profile are the standard of care in CHB treatment. Long-term use of NUCs with maintained viral suppression results in a decrease in liver-related complications. PMID- 26414782 TI - Differential osteogenic potential of human adipose-derived stem cells co-cultured with human osteoblasts on polymeric microfiber scaffolds. AB - The osteogenic potential of human adipose-derived stem cells (HADSCs) co-cultured with human osteoblasts (HOBs) using selected HADSCs/HOBs ratios of 1:1, 2:1, and 1:2, respectively, is evaluated. The HADSCs/HOBs were seeded on electrospun three dimensional poly[(R)-3-hydroxybutyric acid] (PHB) blended with bovine-derived hydroxyapatite (BHA). Monocultures of HADSCs and HOBs were used as control groups. The effects of PHB-BHA scaffold on cell proliferation and cell morphology were assessed by AlamarBlue assay and field emission scanning electron microscopy. Cell differentiation, cell mineralization, and osteogenic-related gene expression of co-culture HADSCs/HOBs were examined by alkaline phosphatase (ALP) assay, alizarin Red S assay, and quantitative real time PCR, respectively. The results showed that co-culture of HADSCs/HOBs, 1:1 grown into PHB-BHA promoted better cell adhesion, displayed a significant higher cell proliferation, higher production of ALP, extracellular mineralization and osteogenic-related gene expression of run-related transcription factor, bone sialoprotein, osteopontin, and osteocalcin compared to other co-culture groups. This result also suggests that the use of electrospun PHB-BHA in a co-culture HADSCs/HOBs system may serve as promising approach to facilitate osteogenic differentiation activity of HADSCs through direct cell-to-cell contact with HOBs. PMID- 26414783 TI - The clubfoot painted by Jusepe de Ribera: a controversial diagnosis. AB - The Clubfoot painted by Jose de Ribera depicts a young beggar affected by a typical equinus clubfoot. He shows a contorted right hand and wrist. His left hand holds a begging note, suggesting some difficulty to speak. This condition may be caused by a cerebral palsy, consisting of a brain injury in the left hemisphere responsible for right hemiplegia and speech disturbance. Recently, it was suggested that the boy's condition is a consequence of arthrogryposis, perhaps amyoplasia or distal arthrogryposis type A1. Some clinical features may suggest the diagnosis of Sheldon-Hall syndrome. Considering all the signs represented on the painting, the diagnosis of hemiplegia due to cerebral palsy cannot be discarded. The present article is a novel analysis of the painting based on previously proposed diagnoses of the boy's condition, namely, hemiplegia and arthrogryposis. PMID- 26414784 TI - Therapies in early development for the treatment of opiate addiction. AB - INTRODUCTION: Opiate drugs are psychoactive substances used to manage severe pain. However, their chronic use is associated with the development of addiction. Opiate addiction represents a significant public health concern. AREAS COVERED: This review focuses on the most recent advances in the pharmacological treatment of opiate addiction, from those being tested in clinical trials (Phase I and II), to preclinical studies that point to new targets. Readers will gain knowledge of the wide variety of treatments used to treat opiate addiction, including their strengths and weaknesses, and the promising pharmacological targets identified by preclinical research. EXPERT OPINION: Among the currently available agonist therapies, new dosage forms of buprenorphine can increase patient acceptability and compliance. New extended-release forms of naltrexone are building hope of retaining opiate-dependent subjects in a drug-free state. Unfortunately, the review of the literature shows that successful preclinical studies are often followed by discouraging results in human clinical trials. Nevertheless, all targets of potential interest should be tested exhaustively. Indeed, a number of new targets and research lines (genetics and neuroinflammation approaches) may lead to breakthroughs in the future. PMID- 26414785 TI - The Effect of Swelling Ratio on the Coulter Underestimation of Hydrogel Microsphere Diameters. AB - It has been demonstrated that the diameters of porous particles are underestimated by Coulter measurements. This phenomenon has also been observed in hydrogel particles, but not characterized. Since the Coulter principle uses the displacement of electrolyte to determine particle size, electrolyte contained within the swelled hydrogel microparticles results in an underestimate of actual particle diameters. The increased use of hydrogel microspheres in biomedical applications has led to the increased application of the Coulter principle to evaluate the size distribution of microparticles. A relationship between the swelling ratio of the particles and their reported Coulter diameters will permit calculation of the actual diameters of these particles. Using polyethylene glycol diacrylate hydrogel microspheres, we determined a correction factor that relates the polymer swelling ratio and the reported Coulter diameters to their actual size. PMID- 26414786 TI - From Annoying to Appreciated: Turning clinical decision support systems into a medical professional's best friend. AB - There's a big difference between driving suggestions that come from a newly licensed, know-it-all teenager and those that come from a professional racecar driver who has spent years honing skills on the course. The first is one you just want to be quiet, and the second is one you actually want to speak up. PMID- 26414787 TI - Breathing Easier: Model-based decision support for respiratory care looks beyond tomorrow. AB - Mechanical ventilation (MV) is a primary therapy for intensive care unit (ICU) patients who have respiratory failure. Up to ~60% of all ICU patients require MV, and?because they are so ill?this patient group stays in the ICU 50?100% longer. They also cost almost 100% more due to this added care, and, troublingly, have a mortality rate of almost 30%. PMID- 26414788 TI - Throw Science to the Dogs: The best models for human disease may just be right under scientists' noses--if not in their laps. AB - Opportunities for gathering vital information on cancer, heart disease, and other complicated diseases via clinical models are missed despite the at least 70 million pet dogs and 74 million pet cats in the United States alone that experience these very illnesses. This article presents a general discussion on the current state and hindrances to comparative medicine. PMID- 26414789 TI - Mind Your Composition: Clinical validation of Samsung's pocket-based bioelectrical impedance analyzers may increase consumer interest in personal health management. AB - When asked about our weight, most of us can name a figure based on prior knowledge. And while stepping on a scale gives us the ability to know that exact number and track it routinely, it does not provide insights into our body?s composition. This, at the basic level, refers to proportions of fat and lean or fat-free mass (FFM) that comprise the human body. Conventionally, the body mass index (BMI), which is the ratio of body weight in kilograms to the square of its height in meters, and anthropometric parameters like waist circumference, waist to-hip ratio, and skinfold thickness have been used to estimate the level of fatness. In fact, BMI is the de facto marker for stratifying individuals into underweight (<18.5 kg/m2), normal (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), and obese (>30 kg/m2) categories. Nonetheless, these metrics are limited in precisely characterizing individuals by percentages of body fat and muscle mass, particularly in epidemiological studies where these proportions vary across age, sex, and ethnic groups. Of note is also how, solely on the basis of BMI, a physically fit individual may be classified as overweight due to having a higher proportion of lean body mass, which outweighs fat. This highlights the importance of body composition in weight tracking and management. PMID- 26414790 TI - Next-Gen Gene Synthesis Enables Large-Scale Engineering in Biological Systems: Recent advances in synthetic biology are making this field more promising than ever. AB - As scientists make strides toward the goal of developing a form of biological engineering that's as predictive and reliable as chemical engineering is for chemistry, one technology component has become absolutely critical: gene synthesis. Gene synthesis is the process of building stretches of deoxyribonucleic acid (DNA) to order--some stretches based on DNA that exists already in nature, some based on novel designs intended to accomplish new functions. This process is the foundation of synthetic biology, which is rapidly becoming the engineering counterpart to biology. PMID- 26414791 TI - Rethinking Education: When surgeons and engineering students join forces to solve real problems, success follows. AB - The Engineers in Scrubs (EiS) training program at the University of British Columbia, affiliated with the Faculty of Applied Science?s Biomedical Engineering Graduate (BMEG) Program, is not a typical graduate school course. Nor does it follow a traditional master?s course rubric that culminates with a tidy end-of year project. Rather, the course is designed to push students to prototype innovative medical devices, encourage health care collaborations, and create an unprecedented interface between technology and health care to further medicine. PMID- 26414792 TI - New Imaging Technology May Help Doctors Diagnose Amyloidosis: Due to stringent FDA rules, U.S. imaging of the disease has lagged behind Europe but a new synthetic molecule may change that. AB - One December day in 2013, Michael Rasmussen realized that just chewing his food made him tired. Short walks felt draining. At one point, he became so tired that he sat down and didn't get up for three days. Rasmussen had been a man in perfect health. For 30 years, he lived as an artist in the Aleutian Islands in Alaska and walked or biked everywhere. He even bicycled across the United States five times. But now he had slid into a horrible medical mystery. PMID- 26414793 TI - Reconstructing Large-Scale Brain Resting-State Networks from High-Resolution EEG: Spatial and Temporal Comparisons with fMRI. AB - Functional magnetic resonance imaging (fMRI) studies utilizing measures of hemodynamic signal, such as the blood oxygenation level-dependent (BOLD) signal, have discovered that resting-state brain activities are organized into multiple large-scale functional networks, coined as resting-state networks (RSNs). However, an important limitation of the available fMRI studies is that hemodynamic signals only provide an indirect measure of the neuronal activity. In contrast, electroencephalography (EEG) directly measures electrophysiological activity of the brain. However, little is known about the brain-wide organization of such spontaneous neuronal population signals at the resting state. It is not entirely clear if or how the network structure built upon slowly fluctuating hemodynamic signals is represented in terms of fast, dynamic, and spontaneous neuronal activity. In this study, we investigated the electrophysiological representation of RSNs from simultaneously acquired EEG and fMRI data in the resting human brain. We developed a data-driven analysis approach that reconstructed multiple large-scale electrophysiological networks from high resolution EEG data alone. The networks derived from EEG were then compared with RSNs independently derived from simultaneously acquired fMRI in their spatial structures as well as temporal dynamics. Results reveal spatially and temporally specific electrophysiological correlates for the fMRI-RSNs. Findings suggest that the spontaneous activity of various large-scale cortical networks is reflected in macroscopic EEG potentials. PMID- 26414794 TI - CXCL12/CXCR4 activation by cancer-associated fibroblasts promotes integrin beta1 clustering and invasiveness in gastric cancer. AB - Cancer-associated fibroblasts (CAFs) are reportedly involved in invasion and metastasis in several types of cancer, including gastric cancer (GC), through the stimulation of CXCL12/CXCR4 signaling. However, the mechanisms underlying these tumor-promoting effects are not well understood, which limits the potential to develop therapeutic targets against CAF-mediated CXCL12/CXCR4 signaling. CXCL12 expression was analyzed in resected GC tissues from 110 patients by immunohistochemistry (IHC). We established primary cultures of normal fibroblasts (NFs) and CAFs from the GC tissues and examined the functional differences between these primary fibroblasts using co-culture assays with GC cell lines. We evaluated the efficacy of a CXCR4 antagonist (AMD3100) and a FAK inhibitor (PF 573,228) on the invasive ability of GC cells. High CXCL12 expression levels were significantly associated with larger tumor size, increased tumor depth, lymphatic invasion and poor prognosis in GC. CXCL12/CXCR4 activation by CAFs mediated integrin beta1 clustering at the cell surface and promoted the invasive ability of GC cells. Notably, AMD3100 was more efficient than PF-573,228 at inhibiting GC cell invasion through the suppression of integrin beta1/FAK signaling. These results suggest that CXCL12 derived from CAFs promotes GC cell invasion by enhancing the clustering of integrin beta1 in GC cells, resulting in GC progression. Taken together, the inhibition of CXCL12/CXCR4 signaling in GC cells may be a promising therapeutic strategy against GC cell invasion. PMID- 26414795 TI - Bone Marrow Stromal Cell Intraspinal Transplants Fail to Improve Motor Outcomes in a Severe Model of Spinal Cord Injury. AB - Bone marrow stromal cells (BMSCs) have been reported to exert potential neuroprotective properties in models of neurotrauma, although precise mechanisms underlying their benefits are poorly understood. Despite this lack of knowledge, several clinical trials have been initiated using these cells. To determine whether local mechanisms mediate BMSC neuroprotective actions, we grafted allogeneic BMSCs to sites of severe, compressive spinal cord injury (SCI) in Sprague-Dawley rats. Cells were administered 48 h after the original injury. Additional animals received allogeneic MSCs that were genetically modified to secrete brain-derived neurotrophic factor (BDNF) to further determine whether a locally administered neurotrophic factor provides or extends neuroprotection. When assessed 2 months post-injury in a clinically relevant model of severe SCI, BMSC grafts with or without BDNF secretion failed to improve motor outcomes. Thus, allogeneic grafts of BMSCs do not appear to act through local mechanisms, and future clinical trials that acutely deliver BMSCs to actual sites of injury within days are unlikely to be beneficial. Additional studies should address whether systemic administration of BMSCs alter outcomes from neurotrauma. PMID- 26414796 TI - Suppression of atopic dermatitis in mice model by reducing inflammation utilizing phosphatidylserine-coated biodegradable microparticles. AB - Controlling inflammatory response is important to avoid chronic inflammation in many diseases including atopic dermatitis (AD). In this research, we tried using a phosphatidylserine (PS)-coated microparticles in the AD mouse model for achieving the modulation of the macrophage phenotype to an anti-inflammatory state. Here, we prepared poly (D,L-lactic acid) microparticle coated with PS on the outside shell. We confirmed the cellular uptake of the PS-coated microparticle, which leads to the significant downregulation of the inflammatory cytokine production. In the mouse model of AD, the PS-coated microparticle was injected subcutaneously for a period of 12 days. The mice showed significant reduction in the development of AD symptoms comparing with the mice treated with the PC-coated microparticle. PMID- 26414797 TI - SMAD Signaling in the Airways of Healthy Rhesus Macaques versus Rhesus Macaques with Asthma Highlights a Relationship Between Inflammation and Bone Morphogenetic Proteins. AB - Bone morphogenetic protein (BMP) signaling is important for correct lung morphogenesis, and there is evidence of BMP signaling reactivation in lung diseases. However, little is known about BMP signaling patterns in healthy airway homeostasis and inflammatory airway disease and during epithelial repair. In this study, a rhesus macaque (Macaca mulatta) model of allergic airway disease was used to investigate BMP signaling throughout the airways in health, disease, and regeneration. Stereologic quantification of immunofluorescent images was used to determine the expression of BMP receptor (BMPR) Ia and phosphorylated SMAD (pSMAD) 1/5/8 in the airway epithelium. A pSMAD 1/5/8 expression gradient was found along the airways of healthy juvenile rhesus macaques (n = 3, P < 0.005). Membrane-localized BMPRIa expression was also present in the epithelium of the healthy animals. After exposure to house dust mite allergen and ozone, significant down-regulation of nuclear pSMAD 1/5/8 occurs in the epithelium. When the animals were provided with a recovery period in filtered air, proliferating cell nuclear antigen, pSMAD 1/5/8, and membrane-localized BMPRIa expression were significantly increased in the epithelium of conducting airways (P < 0.005). Furthermore, in the asthmatic airways, altered BMPRIa localization was evident. Because of the elevated eosinophil presence in these airways, we investigated the effect of eosinophil-derived proteins on BMPRIa trafficking in epithelial cells. Eosinophil-derived proteins (eosinophil-derived neurotoxin, eosinophil peroxidase, and major basic protein) induced transient nuclear translocation of membrane-bound BMPRIa. This work mapping SMAD signaling in the airways of nonhuman primates highlights a potential mechanistic relationship between inflammatory mediators and BMP signaling and provides evidence that basal expression of the BMP signaling pathway may be important for maintaining healthy airways. PMID- 26414798 TI - A situational analysis methodology to inform comprehensive HIV prevention and treatment programming, applied in rural South Africa. AB - Successful HIV prevention programming requires engaging communities in the planning process and responding to the social environmental factors that shape health and behaviour in a specific local context. We conducted two community based situational analyses to inform a large, comprehensive HIV prevention programme in two rural districts of North West Province South Africa in 2012. The methodology includes: initial partnership building, goal setting and background research; 1 week of field work; in-field and subsequent data analysis; and community dissemination and programmatic incorporation of results. We describe the methodology and a case study of the approach in rural South Africa; assess if the methodology generated data with sufficient saturation, breadth and utility for programming purposes; and evaluate if this process successfully engaged the community. Between the two sites, 87 men and 105 women consented to in-depth interviews; 17 focus groups were conducted; and 13 health facilities and 7 NGOs were assessed. The methodology succeeded in quickly collecting high-quality data relevant to tailoring a comprehensive HIV programme and created a strong foundation for community engagement and integration with local health services. This methodology can be an accessible tool in guiding community engagement and tailoring future combination HIV prevention and care programmes. PMID- 26414799 TI - Discarded Human Thymus Is a Novel Source of Stable and Long-Lived Therapeutic Regulatory T Cells. AB - Regulatory T cell (Treg)-based therapy is a promising approach to treat many immune-mediated disorders such as autoimmune diseases, organ transplant rejection, and graft-versus-host disease (GVHD). Challenges to successful clinical implementation of adoptive Treg therapy include difficulties isolating homogeneous cell populations and developing expansion protocols that result in adequate numbers of cells that remain stable, even under inflammatory conditions. We investigated the potential of discarded human thymuses, routinely removed during pediatric cardiac surgery, to be used as a novel source of therapeutic Tregs. Here, we show that large numbers of FOXP3(+) Tregs can be isolated and expanded from a single thymus. Expanded thymic Tregs had stable FOXP3 expression and long telomeres, and suppressed proliferation and cytokine production of activated allogeneic T cells in vitro. Moreover, expanded thymic Tregs delayed development of xenogeneic GVHD in vivo more effectively than expanded Tregs isolated based on CD25 expression from peripheral blood. Importantly, in contrast to expanded blood Tregs, expanded thymic Tregs remained stable under inflammatory conditions. Our results demonstrate that discarded pediatric thymuses are an excellent source of therapeutic Tregs, having the potential to overcome limitations currently hindering the use of Tregs derived from peripheral or cord blood. PMID- 26414800 TI - Integrating plant carbon dynamics with mutualism ecology. AB - Plants reward microbial and animal mutualists with carbohydrates to obtain nutrients, defense, pollination, and dispersal. Under a fixed carbon budget, plants must allocate carbon to their mutualists at the expense of allocation to growth, reproduction, or storage. Such carbon trade-offs are indirectly expressed when a plant exhibits reduced growth or fecundity in the presence of its mutualist. Because carbon regulates the costs of all plant mutualisms, carbon dynamics are a common platform for integrating these costs in the face of ecological complexity and context dependence. The ecophysiology of whole-plant carbon allocation could thus elucidate the ecology and evolution of plant mutualisms. If mutualisms are costly to plants, then they must be important but frequently underestimated sinks in the terrestrial carbon cycle. PMID- 26414801 TI - Genetics of coronary artery disease: Short people at risk? AB - Traditional cardiovascular risk factors have been in the spotlight for coronary artery disease (CAD) management over the past decades. A non-modifiable risk marker is short adult stature. However, a causal role in the etiology of CAD was always questioned, since multiple confounders may also explain the inverse association between height and CAD risk. The assumption that genetic variants affecting height do so without interference of exogenous factors allows for the testing of the association between short stature, that is, genetic markers affecting height, and CAD even without measuring height. Interestingly, these studies suggest a rather multifaceted relationship between the two complex phenotypes. Indeed, investigating 180 height-associated genetic variants in 65,066 patients with CAD and 128,383 healthy controls suggests a causal relationship of short stature and CAD risk. Multiple signaling pathways affecting growth, as well as pleiotropic effects of genetic variants affecting height and lipids, seem to underlie the association between height and CAD risk. PMID- 26414803 TI - Multidimensional Neuropathic Pain Phenotypes after Spinal Cord Injury. AB - Identifying clinical neuropathic pain phenotypes is a first step to better understand the underlying pain mechanisms after spinal cord injury (SCI). The primary purpose of the present study was to characterize multidimensional neuropathic pain phenotypes based on quantitative sensory testing (QST), pain intensity, and utilization of catastrophizing coping strategies. Thermal perception, thermal pain, and vibratory perception thresholds were assessed above and below the level of injury (LOI) in 101 persons with SCI and neuropathic pain, 18 persons with SCI and no neuropathic pain, and 50 able-bodied, pain-free controls. Cluster analysis of QST z-scores below the LOI, pain intensity ratings, and the Coping Strategies Questionnaire (CSQ) catastrophizing subscale scores in subjects with neuropathic pain resulted in two phenotypes: severe neuropathic pain (SNP) with greater pain intensity (7.39 +/- 1.57) and thermal and vibratory sensitivity compared with the moderate neuropathic pain (MNP; 5.40 +/- 1.43). A factor analysis including all CSQ subscales, the Neuropathic Pain Symptom Inventory (NPSI) total score, and thermal pain sensitivity above and below the LOI resulted in three factors: (1) adaptive pain coping including increasing activities, diverting attention, and reinterpreting pain sensations; (2) catastrophizing, neuropathic pain, and thermal sensitivity including greater NPSI total score, thermal pain sensitivity below the LOI, and catastrophizing; and (3) general pain sensitivity including greater thermal pain sensitivity above the LOI and lower catastrophizing. Our results suggest that neuropathic pain symptom severity post-SCI is significantly associated with residual spinothalamic tract function below the LOI and catastrophizing pain coping. PMID- 26414802 TI - Experience With the Priority Review Voucher Program for Drug Development. PMID- 26414804 TI - Cysteine Mutational Studies Provide Insight into a Thiol-Based Redox Switch Mechanism of Metal and DNA Binding in FurA from Anabaena sp. PCC 7120. AB - AIMS: The ferric uptake regulator (Fur) is the main transcriptional regulator of genes involved in iron homeostasis in most prokaryotes. FurA from Anabaena sp. PCC 7120 contains five cysteine residues, four of them arranged in two redox active CXXC motifs. The protein needs not only metal but also reducing conditions to remain fully active in vitro. Through a mutational study of the cysteine residues present in FurA, we have investigated their involvement in metal and DNA binding. RESULTS: Residue C101 that belongs to a conserved CXXC motif plays an essential role in both metal and DNA binding activities in vitro. Substitution of C101 by serine impairs DNA and metal binding abilities of FurA. Isothermal titration calorimetry measurements show that the redox state of C101 is responsible for the protein ability to coordinate the metal corepressor. Moreover, the redox state of C101 varies with the presence or absence of C104 or C133, suggesting that the environments of these cysteines are mutually interdependent. INNOVATION: We propose that C101 is part of a thiol/disulfide redox switch that determines FurA ability to bind the metal corepressor. CONCLUSION: This mechanism supports a novel feature of a Fur protein that emerges as a regulator, which connects the response to changes in the intracellular redox state and iron management in cyanobacteria. Antioxid. Redox Signal. 00, 000-000. PMID- 26414805 TI - Resolution of Skin Fibrosis by Neutralization of the Antifibrinolytic Function of Plasminogen Activator Inhibitor 1. AB - OBJECTIVE: Systemic sclerosis (SSc) is a fibrotic disease characterized by an obliterative vasculopathy with thrombosis and impairment of the coagulation fibrinolysis balance. Plasminogen activator inhibitor 1 (PAI-1) is the major inhibitor of profibrinolytic plasminogen activators (PAs). This study was undertaken to evaluate the contribution of PAI-1 to SSc pathology in the skin. METHODS: PAI-1 was evaluated in skin from patients with diffuse SSc (dSSc) and those with limited SSc (lSSc) by immunohistochemistry. The contribution of PAI-1 to SSc pathology was tested in vivo in murine graft-versus-host disease (GVHD) and bleomycin models of progressive skin fibrosis and in vitro in dermal human microvascular endothelial cells (HMVECs) using a monoclonal antibody that selectively prevents the binding of PAI-1 to PA. RESULTS: Skin from patients with dSSc and those with lSSc showed increased PAI-1 levels in the epidermis and microvessel endothelium. PAI-1 neutralization in the GVHD model led to a dramatic, dose-dependent improvement in clinical skin score, concomitant with vasculopathy resolution, including a reduction in fibrinolysis regulators and vascular injury markers, as well as reduced inflammation. Resolution of vasculopathy and inflammation was associated with resolution of skin fibrosis, as assessed by reduction in collagen content and expression of key profibrotic mediators, including transforming growth factor beta1 and tissue inhibitor of metalloproteinases 1. Similar to the GVHD model, PAI-1 neutralization reduced dermal inflammation and fibrosis in the bleomycin model. PAI-1 neutralization stimulated plasmin-mediated metalloproteinase 1 activation in dermal HMVECs. CONCLUSION: Our findings indicate that neutralization of the antifibrinolytic function of PAI-1 resolves skin fibrosis by limiting the extent of initial vascular injury and connective tissue inflammation. These data suggest that PAI-1 represents an important checkpoint in disease pathology in human SSc. PMID- 26414806 TI - Growth-Arrest-Specific 7 Gene Regulates Neural Crest Formation and Craniofacial Development in Zebrafish. AB - Growth-arrest-specific 7 (Gas7) is preferentially expressed in the nervous system and plays an important role during neuritogenesis in vertebrates. We recently demonstrated that gas7 is highly expressed in zebrafish neurons, where it regulates neural development. The possibility that gas7 may also regulate the development of other tissues remains to be examined. In this study, we investigate the role of Gas7 in the development of craniofacial tissues. Knockdown of gas7 using morpholino oligomers produced abnormal phenotypes in neural crest (NC) cells and their derivatives. NC-derived cartilage maturation was altered in Gas7 morphants as revealed by aberrant sox9b and dlx2 expression, a phenotype that could be rescued by coinjection of gas7 mRNA. While rhombomere morphology remained normal in Gas7 morphants, we observed reduced expression of the prechondrogenic genes sox9b and dlx2 in cells populating the posterior pharyngeal arches, but the fundamental structure of pharyngeal arches was preserved. In addition, NC cell sublineages that migrate to form neurons, glial cells, and melanocytes were altered in Gas7 morphants as revealed by aberrant expression of neurod, foxd3, and mitfa, respectively. Development of NC progenitors was also examined in Gas7 morphants at 12 hpf, and we observed that the reduction of cell precursors in Gas7 morphants was due to increased apoptosis level. These results indicate that the formation of NC progenitors and derivatives depends on Gas7 expression. Our observations also suggest that Gas7 regulates the formation of NC derivatives constituting the internal tissues of pharyngeal arches, without affecting the fundamental structure of mesodermal derived pharyngeal arches. PMID- 26414807 TI - Synthesis, characterization, crystal structure determination and biological screening of novel N-1 and C5 alkyl substituted scaffolds of pyrimidine. AB - The novel N-1 and C5 alkyl substituted derivatives of pyrimidine were synthesized by using tetrabutyl ammonium bromide (TBAB) as phase transfer catalyst at 20-25 degrees C with excellent productivity (85-95%). The new compounds were evaluated for their antibacterial activities by screening them against Gram-positive and Gram-negative bacterial strain: Staphylococcus aureus ATCC 6538P, Salmonella abony NCTC 6017: Escherichia coli ATCC 8739, Staphylococcus epidermidis ATCC 12228. Among all compounds evaluated the molecule 2c and (2g-j) exhibit the most pronounced antibacterial activity against E. coli, S. aureus and S. abony with MICs value 25 MUg/mL. PMID- 26414808 TI - Ligand binding studies, preliminary structure-activity relationship and detailed mechanistic characterization of 1-phenyl-6,6-dimethyl-1,3,5-triazine-2,4-diamine derivatives as inhibitors of Escherichia coli dihydrofolate reductase. AB - Gram-negative bacteria are implicated in the causation of life-threatening hospital-acquired infections. They acquire rapid resistance to multiple drugs and available antibiotics. Hence, there is the need to discover new antibacterial agents with novel scaffolds. For the first time, this study explores the 1,3,5 triazine-2,4-diamine and 1,2,4-triazine-2,4-diamine group of compounds as potential inhibitors of Escherichia coli DHFR, a pivotal enzyme in the thymidine and purine synthesis pathway. Using differential scanning fluorimetry, DSF, fifteen compounds with various substitutions on either the 3rd or 4th positions on the benzene group of 6,6-dimethyl-1-(benzene)-1,3,5-triazine-2,4-diamine were shown to bind to the enzyme with varying affinities. Then, the dose dependence of inhibition by these compounds was determined. Preliminary quantitative structure activity relationship analysis and docking studies implicate the alkyl linker group and the sulfonyl fluoride group in increasing the potency of inhibition. 4 [4-[3-(4,6-diamino-2,2-dimethyl-1,3,5-triazin-1-yl)phenyl]butyl]benzenesulfonyl fluoride (NSC120927), the best hit from the study and a molecule with no reported inhibition of E. coli DHFR, potently inhibits the enzyme with a Ki value of 42.50 +/- 5.34 nM, followed by 4-[6-[4-(4,6-diamino-2,2-dimethyl-1,3,5-triazin-1 yl)phenyl]hexyl]benzenesulfonyl fluoride (NSC132279), with a Ki value of 100.9 +/ 12.7 nM. Detailed kinetic characterization of the inhibition brought about by five small-molecule hits shows that these inhibitors bind to the dihydrofolate binding site with preferential binding to the NADPH-bound binary form of the enzyme. Furthermore, in search of novel diaminotriazine scaffolds, it is shown that lamotrigine, a 1,2,4-triazine-3,5-diamine and a sodium-ion channel blocker class of antiepileptic drug, also inhibits E. coli DHFR. This is the first comprehensive study on the binding and inhibition brought about by diaminotriazines of a gram-negative prokaryotic enzyme and provides valuable insights into the SAR as an aid to the discovery of novel antibiotics. PMID- 26414809 TI - Regenerative potential of human schneiderian membrane: progenitor cells and epithelial-mesenchymal transition. AB - An innate osteogenic potential of the Schneiderian membrane (SM) is progressively assessed in studies ranging from non-human species to human subjects. It has relevance for endosteal placement and osseointegration. Nestin-expressing osteogenic progenitor cells are allegedly involved in bone formation and remodelling. Nestin phenotype was not assessed previously in human SM. We therefore aimed to fill that particular gap in the literature. Bioptic samples of human adult SM were obtained during surgery from eight adult patients, operated for non-malignant pathologies. Immunohistochemistry on paraffin-embedded tissue samples used primary antibodies against nestin, CD45, CD146, cytokeratin 7 (CK7), and alpha-smooth muscle actin (alpha-SMA). Nestin expression was consistently found in endothelial cells, and was scarcely encountered in pericytes, putative stromal stem/progenitor cells, as well as in glandular epithelial cells. Moreover, woven bone formation in the periosteal layer of the SM can also be regarded as evidence of the osteogenic potential of this membrane. Nestin and CD45 expression in cells of the primary bone supports the osteogenic potential of SM nestin-expressing cells and a possible involvement of hematopoietic stem cells in maxillary sinus floor remodeling. CD146, a known inducer of epithelial mesenchymal transition (EMT), was expressed in epithelia, as was CK7. Isolated stromal cells were found expressing CD146, CK7 and alpha-SMA, suggesting that regenerative processes happening in the SM may also involve processes of EMT which generate stem/progenitor cells. This study provides additional evidence for the regenerative potential of the Schneiderian membrane and identifies potential roles for cells of its stem niche in osteogenesis. PMID- 26414811 TI - Unusual High-Temperature Reversible Phase-Transition Behavior, Structures, and Dielectric-Ferroelectric Properties of Two New Crown Ether Clathrates. AB - Molecular ferroelectrics with high-temperature reversible phase-transition behaviors are very rare and have currently become one of the hotspots in the field of ferroelectric materials. Herein we display two new crown ether clathrates possessing unusual high-temperature ferroelectric phase-transition behaviors, cyclohexyl ammonium 18-crown-6 tetrafluoroborate (or perchlorate), [Hcha-(18-crown-6)](+) [BF4](-) (1) and [Hcha-(18-crown-6)](+)[ClO4](-) (2) (Hcha = protonated cyclohexyl ammonium). We have proven their reversible structural phase transitions by variable-temperature PXRD measurements and temperature evolutions of Raman bands. Both clathrates exhibit clear ferroelectric phase transitions at about 397 and 390 K, respectively, revealed by the thermal anomalies of differential scanning calorimetry (DSC) measurements, together with abrupt dielectric anomalies in the heating and cooling processes. The measurements on ferroelectric properties using the single crystals showed optimized spontaneous polarization (Ps) of ca. 3.27 MUC cm(-2) for 1 and 3.78 MUC cm(-2) for 2. PMID- 26414810 TI - Influence of Sulfide Nanoparticles on Dissolved Mercury and Zinc Quantification by Diffusive Gradient in Thin-Film Passive Samplers. AB - Diffusive gradient in thin-film (DGT) passive samplers are frequently used to monitor the concentrations of metals such as mercury and zinc in sediments and other aquatic environments. The application of these samplers generally presumes that they quantify only the dissolved fraction and not particle-bound metal species that are too large to migrate into the sampler. However, metals associated with very small nanoparticles (smaller than the pore size of DGT samplers) can be abundant in certain environments, yet the implications of these nanoparticles for DGT measurements are unclear. The objective of this study was to determine how the performance of the DGT sampler is affected by the presence of nanoparticulate species of Hg and Zn. DGT samplers were exposed to solutions containing known amounts of dissolved Hg(II) and nanoparticulate HgS (or dissolved Zn(II) and nanoparticulate ZnS). The amounts of Hg and Zn accumulated onto the DGT samplers were quantified over hours to days, and the rates of diffusion of the dissolved metal (i.e., the effective diffusion coefficient D) into the sampler's diffusion layer were calculated and compared for solutions containing varying concentrations of nanoparticles. The results suggested that the nanoparticles deposited on the surface of the samplers might have acted as sorbents, slowing the migration of the dissolved species into the samplers. The consequence was that the DGT sampler data underestimated the dissolved metal concentration in the solution. In addition, X-ray absorption spectroscopy was employed to determine the speciation of the Hg accumulated on the sampler binding layer, and the results indicated that HgS nanoparticles did not appear to directly contribute to the DGT measurement. Overall, our findings suggest that the deployment of DGT samplers in settings where nanoparticles are relevant (e.g., sediments) may result in DGT data that incorrectly estimated the dissolved metal concentrations. Models for metal uptake into the sampler may need to be reconsidered. PMID- 26414812 TI - Low testosterone as a better predictor of mortality than sarcopenia in men with advanced liver disease. AB - BACKGROUND AND AIM: Both sarcopenia and low serum testosterone have been associated with increased mortality in men with cirrhosis. It is not known how these variables interact. METHODS: We conducted a retrospective longitudinal cohort study of 145 men referred for liver transplant evaluation between 2005 and 2012. Baseline demographics included hormone profile and model of end-stage liver disease (MELD) score. Baseline computerized tomography was reformatted to calculate skeletal muscle area at L4 using validated, Tomovision software-based methodology. The primary outcome was time to death or liver transplantation. RESULTS: Median testosterone was low at 6.2 nmol/L (ref. 10-27.6 nmol/L) as was muscle mass at 48.0 cm(2)/m(2) (ref. > 52.4 cm(2)/m(2)). Muscle mass correlated with both serum testosterone (tau = 0.132, P = 0.019) and MELD score (tau = 0.155, P = 0.007). In separate multivariable models, both sarcopenia (hazard ratio [HR] 1.05, P = 0.04) and low testosterone (HR 1.08, P = 0.01) were significantly associated with mortality independent of MELD score. When the variables MELD score, muscle area, and testosterone were entered into a single model, low testosterone but not sarcopenia remained significantly predictive of mortality (HR 1.07, P = 0.02, and HR 1.04, P = 0.09, respectively). CONCLUSION: Low testosterone and sarcopenia are both associated with increased mortality in men with advanced liver disease and may identify patients at high risk of mortality that would be missed by the MELD score alone. Low testosterone appears to be a better predictor of mortality than sarcopenia and is a simpler test to improve the prognostic value of the MELD score. Interventional trials are required to determine whether low testosterone and sarcopenia are markers or mediators of mortality in this population. PMID- 26414813 TI - Enantioselective Functionalization of Inactive sp(3) C-H Bonds Remote to Functional Group by Metal/Organo Cooperative Catalysis. AB - A metal/organo cooperative catalysis to enable the enantioselective functionalization of inactive C-H bonds gamma to the formyl group in aliphatic aldehydes has been established. Instead of using enals as substrates in traditional organocatalytic cyclization reactions, the aliphatic aldehydes directly participated in [4 + 2] cyclization with quinone derivatives exploiting molecular oxygen as oxidants to afford optically active cyclic molecules with excellent levels of enantioselectivity. This method features a combination of pot, step, and atom economy. PMID- 26414815 TI - The Foundation of International Surgery. PMID- 26414814 TI - Meeting the Mental Health Needs of the Homebound: A Psychiatric Consult Service Within a Home-Based Primary Care Program. AB - The growing population of homebound adults increasingly receives home-based primary care (HBPC) services. These patients are predominantly frail older adults who are homebound because of multiple medical comorbidities, yet they often also have psychiatric diagnoses requiring mental health care. Unfortunately, in-home psychiatric services are rarely available to homebound patients. To address unmet psychiatric need among the homebound patients enrolled in our large academic HBPC program, we piloted a psychiatric in-home consultation service. During our 16 month pilot, 10% of all enrolled HBPC patients were referred for and received psychiatric consultation. Depression and anxiety were among the most common reasons for referral. To better meet patients' medical and psychiatric needs, HBPC programs need to consider strategies to incorporate psychiatric services into their routine care plans. PMID- 26414817 TI - Clinical Role of Modified Seton Procedure and Coring Out for Treatment of Complex Anal Fistulas Associated With Hidradenitis Suppurativa. AB - A variety of techniques have been described to treat complex anal fistulas. When complex anal fistulas are associated with hidradenitis suppurativa, the treatment has to be appropriately tailored for the severity and distribution of the disease so as to remove the external fistula tract to prevent recurrence while ensuring fecal continence. Between 2007 and 2011, a total of 10 males (ranging in age from 32 to 54 years) complained of recurrent purulent discharge in the buttocks and thigh regions. The discharge had started about 12 to 18 months prior, and had increased progressively resulting in complex anal fistulas and hidradenitis suppurativa in the buttocks. They underwent surgical operation according to a modified seton procedure for complex anal fistulas and coring out for hidradenitis suppurativa. They were discharged from the hospital in 4 to 5 days, while the seton dropped spontaneously about 6 to 8 months after surgery. They have been well without any morbidities or recurrence. The present paper demonstrates that cases of complex anal fistulas associated with hidradenitis suppurativa can be successfully treated with a modified seton procedure and coring out of hidradenitis suppurativa. PMID- 26414816 TI - Neoadjuvant Long-Course Chemoradiotherapy for Rectal Cancer: Does Time to Surgery Matter? AB - The objective of this paper was to evaluate whether delaying surgery following long-course chemoradiotherapy for rectal cancer correlates with pathologic complete response. Pre-operative chemoradiotherapy (CRT) is standard practice in the UK for the management of locally advanced rectal cancer. Optimal timing of surgery following CRT is still not clearly defined. All patients with a diagnosis of rectal cancer who had undergone long-course CRT prior to surgery between January 2008 and December 2011 were included. Statistical analysis was performed using Stata 11. Fifty-nine patients received long-course CRT prior to surgery in the selected period. Twenty-seven percent (16/59) of patients showed a complete histopathologic response and 59.3% (35/59) of patients had tumor down-staging from radiologically-assessed node positive to histologically-proven node negative disease. There was no statistically significant delay to surgery after completion of CRT in the 16 patients with complete response (CR) compared with the rest of the group [IR: incomplete response; CR group median: 74.5 days (IQR: 70-87.5) and IR group median: 72 days (IQR: 57-83), P = 0.470]. Although no statistically significant predictors of either complete response or tumor nodal status down staging were identified in logistic regression analyses, a trend toward complete response was seen with longer delay to surgery following completion of long course CRT. PMID- 26414818 TI - Pneumoretroperitoneum and Pneumomediastinum Revealing a Left Colon Perforation. AB - Left colon perforation usually occurs in complicated diverticulitis or cancer. The most frequent signs are intraperitoneal abscess or peritonitis. In cases of retroperitoneal colonic perforation, diagnosis may be difficult. A 59-year-old woman presented with left thigh pain and with abdominal discomfort associated with mild dyspnea. Computed tomography scan showed air bubbles and purulent collection in the retroperitoneum, with subcutaneous emphysema extending from the left thigh to the neck. Computed tomography scan also revealed portal vein gas and thrombosis with multiple liver abscesses. An emergency laparotomy revealed a perforation of the proximal left colon. No masses were found. A left colectomy was performed. The retroperitoneum was drained and washed extensively. A negative pressure wound therapy was applied. A second-look laparotomy was performed 48 hours later. The retroperitoneum was drained and an end colostomy was performed. Intensive Care Unit postoperative stay was 9 days, and the patient was discharged on the 32nd postoperative day. Pneumoretroperitoneum and pneumomediastinum are rare signs of colonic retroperitoneal perforation. The diagnosis may be delayed, especially in the absence of peritoneal irritation. Clinical, laboratory, and especially radiologic parameters might be useful. Surgical treatment must be prompt to improve prognosis. PMID- 26414819 TI - Effect of Intraoperative Valsalva Maneuver Application on Bleeding Point Detection and Postoperative Drainage After Thyroidectomy Surgeries. AB - The purpose of this paper was to analyze the effect of Valsalva maneuver application before finalizing thyroidectomy operations on the identification of bleeding points and postoperational drainage. One hundred patients (age range, 24 76 years) with multinodular goiter, recurrent multinodular goiter, toxic diffuse multinodular goiter, or papillary thyroid cancer were included in the study and were divided into 2 groups of 50 randomly. Both groups underwent thyroidectomy operation, only 1 group received intraoperative Valsalva maneuver application (twice, 30 seconds of 30-cm PEEP). The size of the thyroid gland, the duration of operation, hospital stay, and drain usage were reported. Postoperational occurrences of drainage, hematoma, reoperation, and additional complications were compared between the groups. Valsalva maneuver application helped to identify minor bleeding points in 32% of the cases. There was no significant difference between the study groups regarding the thyroid gland size, operation duration, hospital stay, and the duration of drain usage (P > 0.05 for all). The amount of drainage as well as the frequencies of hematoma, reoperation, and further complications was not significantly different between the study groups (P > 0.05 for all). Intraoperative application of Valsalva maneuver is only useful to detect minor bleeding points in some patients during thyroidectomy operations, but it had no effect on the duration of postoperative drain usage, the amount of drainage, and risk of hematoma. Therefore, intraoperative application of Valsalva maneuver has no beneficial effect on postoperative hemorrhagic complication after thyroidectomy operations. PMID- 26414820 TI - Prevention of Incisional Surgical Site Infection Using a Subcuticular Absorbable Suture in Elective Surgery for Gastrointestinal Cancer. AB - This study examined whether subcuticular absorbable sutures actually reduce incisional SSI in patients undergoing surgery for gastrointestinal (GI) cancer. Surgical site infection (SSI) is still a source of major complications in digestive tract surgery. Reportedly, incisional SSI can be reduced using subcuticular suturing. We performed subcuticular suturing using a 4-0 absorbable monofilament in patients undergoing elective surgery for GI cancer beginning in 2008. Using an interrupted technique, sutures were placed 1.5-2.0cm from the edge of the wound, with everted subcuticular sutures created at intervals of 1.5 2.0cm. The control group consisted of cases in which the common subcutaneous suture method using clip. One hundred cases were examined in the subcuticular group. The incidence of SSI was 0% in the subcuticular suture group, compared with 13.9% in the control group; this difference was significant. Incisional SSI can be prevented using the devised subcuticular absorbable sutures in patients undergoing elective surgery for GI cancer. PMID- 26414821 TI - Delayed Appendectomy Is Safe in Patients With Acute Nonperforated Appendicitis. AB - The present study examined whether acute, nonperforated appendicitis is a surgical emergency requiring immediate intervention or a disease that can be treated with a semielective operation. Immediate appendectomy has been the gold standard in the treatment of acute appendicitis because of the risk of pathologic progression. However, this time-honored practice has been recently challenged by studies suggesting that appendectomies can be elective in some cases and still result in positive outcomes. This was a retrospective study using the charts of patients who underwent an appendectomy for acute, nonperforated appendicitis between January 2007 and February 2012. Patients were divided into 2 groups for comparison: an immediate group (those who were moved to an operating room within 12 hours after hospital arrival) and a delayed group (those within 12 to 24 hours after hospital arrival). The end points were conversion rate, operative time, perforation rate, complication rate, readmission rate, length of hospital stay, and medical costs. Of 1805 patients, 1342 (74.3%) underwent immediate operation within 12 hours after hospital arrival, whereas 463 (25.7%) underwent delayed operation within 12 to 24 hours. There were no significant differences in open conversion, operative time, perforation, postoperative complications, and readmission between the 2 groups. Length of hospital stay was significantly greater (3.7 +/- 1.7 days) and medical costs were also greater [$2346.30 +/- $735.30 (US dollars)] in the delayed group than in the immediate group [3.1 +/- 1.9 days; P = 0.000 and $2257.80 +/- $723.80 (US dollars); P = 0.026]. Delayed appendectomy is safe for patients with acute nonperforated appendicitis. PMID- 26414822 TI - Solitary Hepatic Eosinophilic Granuloma Accompanied by Eosinophilia Without Parasitosis: Report of a Case. AB - A 43-year-old Japanese woman visited for a hepatic tumor incidentally found. We suspected eosinophilic granuloma of the liver (EGL) due to visceral larva migrans (VLM). However, neither past history nor medical interview indicated a risk of parasitosis. Blood testing revealed eosinophilia, serum examination showed normal results for immunoglobulin E, and enzyme-linked immunosorbent assay yielded negative for Toxocara and Anisakis. Gastric and colonic endoscopy revealed normal features. Several imagings showed central necrosis of the tumor. After informed consent, laparoscopic resection was performed. Histopathological examination showed EGL without parasites. No recurrence had occurred postoperatively. Most reports documented that EGL are caused by VLM. However, parasites are not always demonstrable on serum, histopathological, or immunochemical examinations. When acting as allergens to induce type I responses, microscopic agents other than parasites in the intestinal tract could induce eosinophilic inflammation in the liver. Accumulation of more cases should help clarify other pathogeneses for EGL. PMID- 26414823 TI - Giant Extra-Adrenal Retroperitoneal Myelolipoma With Incidental Gastric Mesenchymal Neoplasias. AB - Extra-adrenal myelolipomas are rare, benign tumors composed of adipose tissue and hematopoietic cells. Almost all myelolipomas occur within the adrenal gland. Only 50 cases of myelolipomas were described in literature and none of these were associated with gastric mesenchymal neoplasia. A 72-year-old male patient presented to a family medicine outpatient clinic with dyspnea and urinary urgency. His abdominal sonography revealed a 9-cm intra-abdominal mass. An incidental finding was 2 separate masses 1 cm each on the serosal surface of the stomach. The pathology specimen of the retroperitoneal mass revealed myelolipoma histopathology while gastric masses were reported as spindle cell mesenchymal neoplasias. The association of gastric spindle cell tumor and myelolipoma was not reported before in medical literature. Extra-adrenal myelolipomas are rare lesions, but should be considered in the differential diagnosis of fat containing retroperitoneal masses that are well circumscribed. PMID- 26414824 TI - Management of Appendiceal Mass and Abscess. An 11-Year Experience. AB - The aim of our study is to compare the results of emergency surgery versus conservative treatment with interval surgery in patients diagnosed with appendiceal mass and abscess. A retrospective review of 48 patients with appendiceal mass and abscess treated from January 2002 to January 2013 at General Surgery Department of Kipshidze Central University Hospital was performed. Patients with emergency surgery were compared to patients treated by nonoperative management with interval surgery. Demographics, clinical profile, and operative outcomes were studied. The emergency surgery group included 25 patients, and the interval surgery group included 23 patients. The clinical characteristics of the emergency surgery and interval surgery groups were not statistically different. In the emergency surgery group, an open appendectomy was performed on 17 patients, and colonic resections (ileocecectomy or right hemicolectomy) were performed on 8 patients. In the interval surgery group, an open appendectomy was performed on 21 patients, and colonic resections were performed on 2 patients. There were no statistical differences in types of surgery, postoperative complications, operation time without colonic resections, and postoperative hospitalization period among these 2 groups. Operation time with colonic resections was of greater duration in the emergency surgery group than in the interval surgery group (P = 0.04). Both treatment methods for appendiceal mass and abscess have the same results. The surgeon must consider clinical symptoms and results of investigations in each particular case when choosing an appropriate treatment method. Prospective randomized controlled trials are required for comparing the results of all 3 treatment methods of appendiceal mass. PMID- 26414825 TI - Surgical Mortality Audit-lessons Learned in a Developing Nation. AB - Surgical audit is a systematic, critical analysis of the quality of surgical care that is reviewed by peers against explicit criteria or recognized standards. It is used to improve surgical practice with the ultimate goal of improving patient care. As the pattern of surgical care is different in the developing world, we analyzed mortalities in a referral medical institute of India to suggest interventions for improvement. An analysis of total admissions, different surgeries, and mortalities over 1 year in an urban referral medical institute of northern India was performed, followed by "peer review" of the mortalities. Mortality rates as outcomes and classification was done to provide comparative results. Of 10,005 surgical patients, 337 (male = 221, female = 116) deaths were reported over 1 year. The overall mortality rate was 3.36%, while mortality in operative cases was 1.76%. Total deaths were classified into (1) Viable: 153 (45%), (2) Nonviable: 174 (52%), and (3) Indeterminate: 10 (3%). Exclusion of the nonviable group reduced the mortality rate from 3.36% to 1.62%. Trauma was the major cause of mortality (n = 235; 70%) as compared to other surgical patients (n = 102; 30%). Increased mortality was also associated with emergency procedures (3.66%) as compared to elective surgeries (0.34%). In conclusion, audit of mortality and morbidity helps in initiating and implementing preventive strategies to improve surgical practice and patient care, and to reduce mortality rates. The mortality and morbidity forum is an important educational activity. It should be considered a mandatory activity in all postgraduate training programs. PMID- 26414826 TI - Skeletonization and Isolation of the Glissonean and Venous Branches in Liver Surgery With an Ultrasonic Scalpel Technology. AB - This study describes a novel technique for skeletonization and isolation of Glissonean and venous branches during liver surgery using a harmonic scalpel (HS). Hepatic resections with HS were performed with the skeletonization and isolation technique in 50 patients (HS group). Variables evaluated were blood loss, operative time, biliary leak, and morbidity. The results were compared with 50 hepatic resections that were performed using a previously established technique: Cavitron ultrasonic surgical aspirator with electric cautery, ligatures, and hemoclips (NHS group). The HS group had shorter total operative times (285 versus 358 minutes; P = 0.01), less blood loss (389 versus 871 mL; P = 0.034), and less crystalloid infusion (2744 versus 3299 mL; P = 0.027) compared with the NHS group. Postoperative liver function and complication rates were similar when comparing the two groups. These data demonstrate that HS is a simple, easy, and effective instrument for the skeletonization and isolation of vessels during liver transection. PMID- 26414827 TI - A Left-Sided Approach for Resection of Hepatic Caudate Lobe Hemangioma: Two Case Reports and a Literature Review. AB - Resection of the hemangioma located in the caudate lobe is a major challenge in current liver surgery. This study aimed to present our surgical technique for this condition. Two consecutive patients with symptomatic hepatic hemangioma undergoing caudate lobectomy were investigated retrospectively. First, all the blood inflow of hemangioma from the portal vein and the hepatic artery at the base of the umbilical fissure was dissected. After the tumors became soft and tender, the short hepatic veins and the ligaments between the secondary porta hepatis were severed. At last the tumors were resected from the right lobe of the liver. The whole process was finished by a left-sided approach. Blood lost in Case 1 was 1650 mL because of ligature failing in one short hepatic vein, and in the other case, 210 mL. Operation time was 236 minutes and 130 minutes, respectively. Postoperative hospital stays were 11 and 5 days, respectively. The diameter of tumors was 9.0 cm and 6.5 cm. Case 1 required blood transfusion during surgery. No complications such as biliary fistula, postoperative bleeding, and liver failure occurred. The left-sided approach produced the best results for caudate lobe resection in our cases. The patients who recovered are living well and asymptomatic. Caudate lobectomy can be performed safely and quickly by a left sided approach, which is carried out with optimized perioperative management and innovative surgical technique. PMID- 26414829 TI - Splenic Artery Pseudoaneurysm Masquerading as a Pancreatic Cyst-A Diagnostic Challenge. AB - Splenic artery pseudoaneurysm is a rare entity. Clinical diagnosis is challenging because presentation is often varied. It can range from an incidental finding to hemodynamic collapse from sudden rupture and bleeding. The most common cause of this condition is pancreatitis. We report an unusual case of a young man not known to have pancreatitis who presented with hematemesis with normal esophagogastroduodenoscopy. Imaging modalities did not lead to a definitive diagnosis, and he underwent emergency laparotomy with surgical ligation of splenic artery pseudoaneurysm for hemodynamic instability, without a definitive preoperative diagnosis. PMID- 26414828 TI - Intraductal Papillary Mucinous Neoplasm of the Pancreas: Current Perspectives. AB - In this article, we aimed to review the literature on the clinics and management of intraductal papillary mucinous neoplasm (IPMN). Intraductal papillary mucinous neoplasm of the pancreas is a mucin-producing cystic mass originating from the pancreatic ductal system. Approximately 25% of the pancreatic neoplasms resected surgically and 50% of pancreatic cysts detected incidentally are IPMNs. They can be benign or malignant in character, while malignant transformation of benign forms can be encountered. It is important to determine IPMNs in the early stages, implementation of appropriate treatment approaches, and follow-up to provide better prognosis. We reviewed the studies published in the English medical literature through PubMed and summarized the clinical features and current approaches to the treatment and follow-up of the IPMN. Due to the recent advances and widespread implementation of radiological imaging techniques, the incidental detection rate of IPMNs has increased significantly. The effective treatment of the disease is possible via the detailed diagnosis of the disease, determination of the prognostic factors, and a multidisciplinary approach. Recent literature also emphasized the molecular profile determination approaches for assessment of prognosis of patients with IPMN. Current knowledge on IPMN, a clinically important epidemiologic problem, shows that the treatment should be personalized considering the prognostic features and life expectancy of the patient. PMID- 26414830 TI - A Promising Method for Repairing Low-Level Biliary Strictures After Cholecystectomy. AB - The purpose of this study is to introduce and evaluate a new technique of repairing bile ducts by the tubular gastric wall with a vascularized pedicle. Both the end-to-end bile duct repair and Roux-en-Y hepatoenterostomy have limitations in the treatment of benign bile duct strictures after cholecystectomy. There are no other good choices to manage these cases, especially the bile duct transection injuries or partly missing common bile duct or hepatic duct. Eleven patients with partly missing common bile ducts in the Chinese People's Liberation Army General Hospital between January 2007 and December 2012 were retrospectively analyzed. The study comprised 8 females and 3 males, whose age ranged from 29 to 56 years. All patients underwent successful bile duct repair. The time of operations ranged from 210 minutes to 240 minutes. The maximal blood loss was less than 220 ml. There was no perioperative mortality and no case of gastric fistula. Postoperative complications occurred in 3 patients, including wound infection, bile leakage, and erosive gastritis. All complications were cured by conservative treatment. The mean follow-up time was 42 months. One patient was classified as Terblanche's grade II and 10 patients were classified as Terblanche's grade I. The observations indicate that this technique is a feasible and effective choice to manage low level biliary stricture after cholecystectomy, especially suitable to repair bile duct transection injuries or partly missing common bile duct or hepatic duct. PMID- 26414831 TI - Pancreatic Follicular Lymphoma Presenting as Acute Pancreatitis: Report of a Case. AB - Pancreatic B-cell lymphoma is rare; it accounts for 0.2% to 2.0% of extranodal non-Hodgkin lymphoma, and constitutes less than 0.5% of all pancreatic malignancies. Most histologic types of the pancreatic lymphoma are diffuse large B-cell lymphoma, and follicular lymphoma is quite rare. We report here a case of pancreatic follicular lymphoma that was initially detected by acute pancreatitis. This is the first reported case of pancreatic follicular lymphoma presenting with acute pancreatitis. A 71-year-old woman had epigastric and left upper quadrant abdominal pain. Computed tomography (CT) revealed features of acute pancreatitis. After standard therapy for pancreatitis, enhanced CT showed a pancreatic tumor (50 * 35 mm) in the body of the pancreas with gradual enhancement. Endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography showed a complete interruption of the pancreatic duct in the body, with mild dilation of the duct in the tail of the pancreas. Endoscopic ultrasonography revealed hypervascularity of the pancreatic tumor. The patient underwent distal pancreatectomy to remove the cause of pancreatitis and to disclose the diagnosis. Histologic examination revealed follicular lymphoma of pancreas. Despite recent improvement in clinical strategies, differential diagnosis between pancreatic lymphoma and pancreatic cancer is still difficult without histologic information. Pancreatic lymphoma should be considered as a differential diagnosis in a patient who initially presents with acute pancreatitis. PMID- 26414832 TI - Application of a Z-Shaped Umbilical Incision and a Saline-Cooled Radiofrequency Device to Single-Incision Laparoscopic Surgery for a Huge Liver Cyst: Report of a Case. AB - When compared with other diseases, few authors have reported on single-incision laparoscopic surgery (SILS) for liver cysts. We herein describe our experience with SILS for a huge liver cyst with the application of an umbilical Z-shaped incision using a gel port and a high-density monopolar saline-cooled radiofrequency device with a successful outcome. An 80-old-year woman was diagnosed with a huge liver cyst with abdominal pain. She underwent percutaneous drainage of the liver cyst and injection of both absolute ethanol and an antimicrobial agent into the liver cyst at the previous hospital. Because of re expansion of the liver cyst and symptom recurrence, we performed SILS for the liver cyst. An umbilical Z-shaped incision was made for gel port placement. After aspiration of the cystic fluid and dissection of the thin cystic wall by laparoscopic coagulating shears, the thick cystic wall was divided using an endoscopic linear stapler to avoid bleeding and bile leakage. After wide fenestration, a high-density monopolar saline-cooled radiofrequency device was applied for the ablation of the remnant membrane of the cystic wall. All maneuvers could be performed only through the gel port. The patient was discharged 4 days after surgery and was satisfied with the cosmetic results. This case shows that the application of an umbilical Z-shaped incision using a gel port and a high-density monopolar saline-cooled radiofrequency device is useful for the accomplishment of SILS for a huge liver cyst. PMID- 26414833 TI - Palliation With Endoscopic Metal Stents May Be Preferable to Surgical Intervention for Patients With Obstructive Pancreatic Head Adenocarcinoma. AB - The aim of this study was to evaluate the efficacy of endoscopically placed metal stents in comparison with operative procedures, in patients with obstructive pancreatic head cancer. Endoscopic stenting techniques and materials for gastrointestinal malignancies are constantly improving. Despite this evolution, many still consider operative procedures to be the gold standard for palliation in patients with unresectable obstructive pancreatic head cancer. This is a retrospective study of 52 patients who were diagnosed with obstructive (biliary, duodenal, or both) adenocarcinoma of the pancreatic head. Twenty-nine patients (endoscopy group) underwent endoscopic stenting. Eleven patients (bypass group) underwent biliodigestive bypass. Twelve patients (Whipple group) underwent Whipple operation with curative intent; however, histopathology revealed R1 resection (palliative Whipple). T4 disease was identified in 13 (44.8%), 7 (63.6%), and 3 (25%) patients in the endoscopy, bypass, and Whipple groups, respectively. Metastatic disease was present only in the endoscopy group (n = 12; 41.3%). There was no intervention-related mortality. Median survival was 280 days [95% confidence interval (95% CI), 103, 456 days], 157 days (95% CI, 0, 411 days), and 647 days (95% CI, 300, 993 days) for the endoscopy, bypass, and Whipple groups, respectively (P = 0.111). In patients with obstructive pancreatic head cancer, endoscopic stenting may offer equally good palliation compared with surgical double bypass. The numerically (not statistically) better survival after palliative Whipple might be explained by the smaller tumor burden in this subgroup of patients and not by the superior efficacy of this operation. PMID- 26414834 TI - Giant Cholangiolocellular Carcinoma With Early Recurrence That Was Difficult to Distinguish From Cholangiocellular Carcinoma: Report of a Case. AB - Cholangiolocellular carcinoma (CoCC) is a rare type of malignant liver tumor derived from hepatic stem cells, which exist in the canals of Hering. However, the characteristics of CoCC have not been clarified. In general, CoCC is associated with a better prognosis than cholangiocellular carcinoma (CCC). Here, we report a case of giant CoCC, which was difficult to distinguish from CCC and showed early recurrence and necrosis inside the tumor. A 59-year-old man was diagnosed with CCC based on preoperative imaging. The diameter of the tumor was approximately 14 cm, and he subsequently underwent extended right lobectomy of the liver. Histopathologic analysis revealed that tumor cells proliferated and replaced the surrounding normal liver cell cords in front of the tumor. Furthermore, the tumor cells were positive for cytokeratin 19 and epithelial membrane antigen. Epithelial membrane antigen staining pattern was positive on the membranous area of the lumen. Therefore, the tumor was diagnosed as CoCC. Although adjuvant chemotherapy was performed, intrahepatic recurrence occurred at 4 months after surgery. We present here the novel characteristics of CoCC that show early recurrence and necrosis within the tumor. These characteristics have not previously been reported in patients with CoCC. PMID- 26414835 TI - Comparison of Anterior Versus Posterior Approach in the Treatment of Thoracolumbar Fractures: A Systematic Review. AB - Despite extensive research on thoracolumbar fractures, controversy still exists about which approach is the most appropriate. Lack of evidence-based practice may result in patients being treated inappropriately. The objective of study was to perform a systematic review of the effectiveness of the anterior and posterior approaches in the treatment of thoracolumbar fractures. We conducted searches of PubMed and the Cochrane Library, searching for relevant trials up to August 2013 that compared anterior and posterior for the treatment of thoracolumbar fractures. The key words "anterior," "posterior," "thoracolumbar fracture," "CCT," and "RCT" were used. We assessed all included literature by using the Cochrane handbook (version 5.1). The results were expressed as the mean difference for continuous outcomes and risk difference for dichotomous outcomes, with a 95% confidence interval, using RevMan version 5.2. There were 3 randomized controlled trials and 11 clinical controlled trials included. The meta-analysis showed no significant difference between groups regarding Cobb angle, the Frankel scale, ASIA/JOA motor score, complications, and number of patients returning to work. Compared with the anterior approach, the posterior approach demonstrated superior canal decompression. In the burst fracture subgroup, operative times were significantly shorter and perioperative blood loss was less in the posterior approach group. The posterior approach is more effective for canal decompression, operative times, and perioperative blood loss. However, because of the lack of randomized controlled trials, and because of large sample size studies, heterogeneity was significant between reports. The optimal treatment for thoracolumbar fractures requires further study. PMID- 26414836 TI - Three-Dimensional Laparoscopic Sleeve Gastrectomy: Improved Patient Safety and Surgeon Convenience. AB - One of the aims of laparoscopic surgery is to improve upon the results obtained by open surgery. This clearly appears to have been achieved in bariatric surgery. Two-dimensional (2-D) systems have been used to date, though new 3-dimensional (3 D) technologies have been introduced in an attempt to improve surgeon vision and thus increase the safety of the surgical techniques. Sixty obese patients underwent sleeve gastrectomy using a device equipped with 3-D optics allowing surgery to be viewed by the surgeon in 3 dimensions by using a specific monitor and wearing appropriate glasses. The mean patient age was 48.1 years. The mean weight was 114 kg (range, 92-172), with a mean body mass index (BMI) of 44 +/- 5.21 kg/m(2). All surgeries were performed using the 3-D system, with a mean surgical time of 71 +/- 49.6 minutes and a mean hospital stay of 3.0 +/- 1.2 days. Only 1 intraoperative complication was recorded: retroperitoneal bleeding on insertion of the optical trocar. Over a mean follow-up period of 12 months, the mean body weight of the patients was 88 kg (range, 71-121), with a BMI of 30.56 +/- 3.98 kg/m(2) and a percentage excess weight loss of 68.14% +/- 7.89%. There was clear improvement of both the blood pressure and glucose levels. Three dimensional sleeve gastrectomy is safe, viable, and fully reproducible compared with 2-D surgery, improving visualization of the surgical field, safety, and surgeon convenience. Randomized studies involving larger patient samples are needed for the comparison of results. PMID- 26414837 TI - Phase I Dose-Escalation Study of Docetaxel, Cisplatin, and 5-Fluorouracil Combination Chemotherapy in Patients With Advanced Esophageal Carcinoma. AB - A dose-escalation study of docetaxel (DOC), cisplatin (CDDP), and 5-fluorouracil (5-FU; DCF combination regimen) was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD) and dose-limiting toxicities (DLT) in advanced esophageal carcinoma. Eighteen patients with esophageal carcinoma were enrolled and received DCF combination therapy at different dose levels. DLTs included febrile neutropenia and oral mucositis. DLT occurred in 2 out of 6 patients at level 2 and 3. The study proceeded to level 4, according to the protocol. The level 4 dose was defined as the MTD and the level 3 dose was defined as the RD. The RD for DCF combination chemotherapy for advanced esophageal carcinoma in the present study was 70 mg/m(2) DOC plus 70 mg/m(2) CDDP on day 1 plus 700 mg/m(2) 5 FU on days 1-5 at 4-week intervals. This regimen was tolerable and highly active. A phase II study has been started. PMID- 26414839 TI - It was(n't) me: Exercising restraint when choices appear self-diagnostic. AB - This research tests the hypothesis that individuals exercise restraint for actions that reflect on their self-concept (i.e., self-diagnostic actions). Experiments 1 and 2 show an action framed as occurring at the beginning or end (vs. middle) of a constructed sequence is seen as more self-diagnostic. Accordingly, Experiment 3 finds more restraint in snack choices at the framed beginning or end (vs. middle). Furthermore, the degree of importance of a goal which reflects its centrality to the self-concept-determines responses to self diagnosticity cues such as framed positions. Specifically, participants committed to financial goals (Experiment 4) and health goals (Experiment 5) were more likely to make decisions consistent with these goals at the beginning or end, but indulged and splurged in the middle. Experiment 6 shows similar patterns for judgments of magazine subscriptions, but only when individuals are faced with a decision that poses a self-control conflict for them. These results highlight the role of the self in self-control by demonstrating that people exercise restraint when decision contexts seem more telling of the self. PMID- 26414841 TI - Sowing the seeds of stereotypes: Spontaneous inferences about groups. AB - Although dispositional inferences may be consciously drawn from the trait implications of observed behavior, abundant research has shown that people also spontaneously infer trait dispositions simply in the process of comprehending behavior. These spontaneous trait inferences (STIs) can occur without intention or awareness. All research on STIs has studied STIs based on behaviors of individual persons. Yet important aspects of social life occur in groups, and people regularly perceive groups engaging in coordinated action. We propose that perceivers make spontaneous trait inferences about groups (STIGs), parallel to the STIs formed about individuals. In 5 experiments we showed that (a) perceivers made STIGs comparable with STIs about individuals (based on the same behaviors), (b) a cognitive load manipulation did not affect the occurrence of STIGs, (c) STIGs occurred for groups varying in entitativity, (d) STIGs influenced perceivers' impression ratings of those groups, and (e) STIG-based group impressions generalized to new group members. These experiments provide the first evidence for STIGs, a process that may contribute to the formation of spontaneous group impressions. Implications for stereotype formation are discussed. PMID- 26414840 TI - The scope and consequences of metaphoric thinking: Using individual differences in metaphor usage to understand how metaphor functions. AB - People often think, feel, and behave metaphorically according to conceptual metaphor theory. There are normative sources of support for this theory, but individual differences have received scant attention. This is surprising because people are likely to differ in the frequency with which they use metaphors and, therefore, the frequency with which they experience the costs and benefits of metaphoric thinking. To investigate these ideas, a 5-study program of research (total N = 532) was conducted. Study 1 developed and validated a Metaphor Usage Measure (MUM), finding that people were fairly consistent in their tendencies toward literal thought and language on the one hand versus metaphoric thought and language on the other. These differences were, in turn, consequential. Although metaphor usage predicted susceptibility to metaphor transfer effects (Studies 2 and 3), it was also linked to higher levels of emotional understanding (Studies 4 and 5). The findings provide support for several key premises of conceptual metaphor theory in the context of a new measure that can be used to track the consequences of metaphoric thinking. (PsycINFO Database Record PMID- 26414842 TI - Cognitive adaptations to stressful environments: When childhood adversity enhances adult executive function. AB - Can growing up in a stressful childhood environment enhance certain cognitive functions? Drawing participants from higher-income and lower-income backgrounds, we tested how adults who grew up in harsh or unpredictable environments fared on 2 types of executive function tasks: inhibition and shifting. People who experienced unpredictable childhoods performed worse at inhibition (overriding dominant responses), but performed better at shifting (efficiently switching between different tasks). This finding is consistent with the notion that shifting, but not inhibition, is especially useful in unpredictable environments. Importantly, differences in executive function between people who experienced unpredictable versus predictable childhoods emerged only when they were tested in uncertain contexts. This catalyst suggests that some individual differences related to early life experience are manifested under conditions of uncertainty in adulthood. Viewed as a whole, these findings indicate that adverse childhood environments do not universally impair mental functioning, but can actually enhance specific types of cognitive performance in the face of uncertainty. PMID- 26414843 TI - Men as cultural ideals: Cultural values moderate gender stereotype content. AB - Four studies tested whether cultural values moderate the content of gender stereotypes, such that male stereotypes more closely align with core cultural values (specifically, individualism vs. collectivism) than do female stereotypes. In Studies 1 and 2, using different measures, Americans rated men as less collectivistic than women, whereas Koreans rated men as more collectivistic than women. In Study 3, bicultural Korean Americans who completed a survey in English about American targets rated men as less collectivistic than women, whereas those who completed the survey in Korean about Korean targets did not, demonstrating how cultural frames influence gender stereotype content. Study 4 established generalizability by reanalyzing Williams and Best's (1990) cross-national gender stereotype data across 26 nations. National individualism-collectivism scores predicted viewing collectivistic traits as more-and individualistic traits as less-stereotypically masculine. Taken together, these data offer support for the cultural moderation of gender stereotypes hypothesis, qualifying past conclusions about the universality of gender stereotype content. PMID- 26414844 TI - Systems of meaning and transference: Implicit significant-other activation evokes shared reality. AB - Evidence shows that representations of significant others (SOs) are used in interpersonal relations-for example, in the social-cognitive process of transference (see Andersen & Chen, 2002), a process that is assumed to serve meaning-making functions (Glassman & Andersen, 1999b). Five studies tested the more specific notion that implicit activation of an SO representation in transference should indirectly activate the worldview shared with the SO, leading to its active pursuit, validation, and protection. Shared worldviews were assessed beforehand, both idiographically, as values (Studies 1 and 4), and nomothetically, as political ideology or religious beliefs (Studies 2, 3, and 5). In each experiment, participants learned about new persons, one subtly resembling their own SO. Transference was assessed (memory bias; positive evaluation; see Andersen, Reznik, & Manzella, 1996) and, crucially, as predicted, when considering the new person resembling their SO (vs. the control persons), participants showed faster response latencies in a lexical decision task to words reflecting the worldview shared with the SO (vs. held only personally, Studies 1 3, or only by the SO, Study 3). With this person, they also anticipated a more meaningful interaction and actively socially tuned to the SO-shared worldview, selecting conversation topics reflecting the SO-shared worldview (vs. personally held or SO-held topics, Studies 1-3). Finally, threatening the SO-shared worldview with this person (vs. threatening personally held, SO-held, or irrelevant worldviews) prompted goal activation to restore the disrupted meaning (Studies 4 and 5), assessed by response latency in a lexical decision task. Transference thus evokes shared meaning systems and serves epistemic functions. PMID- 26414845 TI - The atomic-scale nucleation mechanism of NiTi metallic glasses upon isothermal annealing studied via molecular dynamics simulations. AB - Nucleation is one of the most essential transformation paths in phase transition and exerts a significant influence on the crystallization process. Molecular dynamics simulations were performed to investigate the atomic-scale nucleation mechanisms of NiTi metallic glasses upon devitrification at various temperatures (700 K, 750 K, 800 K, and 850 K). Our simulations reveal that at 700 K and 750 K, nucleation is polynuclear with high nucleation density, while at 800 K it is mononuclear. The underlying nucleation mechanisms have been clarified, manifesting that nucleation can be induced either by the initial ordered clusters (IOCs) or by the other precursors of nuclei evolved directly from the supercooled liquid. IOCs and other precursors stem from the thermal fluctuations of bond orientational order in supercooled liquids during the quenching process and during the annealing process, respectively. The simulation results not only elucidate the underlying nucleation mechanisms varied with temperature, but also unveil the origin of nucleation. These discoveries offer new insights into the devitrification mechanism of metallic glasses. PMID- 26414846 TI - The Evolving HIV-1 Epidemic in Warao Amerindians Is Dominated by an Extremely High Frequency of CXCR4-Utilizing Strains. AB - We previously reported a high prevalence of HIV-1 infection in Warao Amerindians from Venezuela due to the rapid spread of a single B subtype strain. In this study we evaluated the coreceptor use of the HIV-1 strains infecting this Amerindian community. Sequences of the HIV-1 V3 loop from 56 plasma samples were genotyped for coreceptor use. An extremely high frequency of CXCR4 strains was found among HIV-1-infecting Waraos (47/49, 96%), compared to HIV-1 strains infecting the non-Amerindian Venezuelan population (35/79, 44%, p < 0.00001). Evolutionary analysis showed that a significant number of infections occurred between 1 and 12 months before collection and that a great proportion (50-70%) of HIV-1 transmissions occurred within the very early phase of infection (<=12 months). This is consistent with an initial infection dominated by an X4 strain or a very rapid selection of X4 variants after infection. This Amerindian population also exhibits the highest prevalence of tuberculosis in Venezuela, being synergistically bad prognostic factors for the evolution of morbidity and mortality in this vulnerable population. PMID- 26414847 TI - Robot-Assisted Laparoscopic Donor Nephrectomy vs Standard Laparoscopic Donor Nephrectomy: A Prospective Randomized Comparative Study. AB - OBJECTIVE: The goal of this randomized controlled trial was to compare the outcomes of robot-assisted laparoscopic donor nephrectomy (RDN) with standard laparoscopic donor nephrectomy (LDN). MATERIALS AND METHODS: Forty-five voluntary kidney donors (27 for right subgroup and 18 for left subgroup) who met inclusion and exclusion criteria were randomized into 2 groups, RDN and LDN in 1:2 ratio. Primary endpoints were visual analogue scale (VAS) pain scores, analgesic requirement, and hospital stay of donors. Secondary endpoints were donor's intraoperative and postoperative parameters, graft outcomes, and donor surgeon's difficulty scores. RESULTS: All procedures were completed without any intraoperative complications. VAS pain scores at 6, 24, and 48 hours (p = 0.00), analgesic requirement (p = 0.00), and hospital stay (p = 0.00) were less in RDN than in LDN. Longer graft arterial length could be preserved with robotic approach on right side (p = 0.03) but not on left side (p = 0.77). The RDN group required more number of ports (p = 0.00), longer retrieval time (p = 0.00), and warm ischemia time (WIT) (p = 0.01). Total operative time (p = 0.14), hemoglobin drop (p = 0.97), postoperative donor complications (p = 0.97), and the recipient estimated glomerular filtration rate at 9 months (p = 0.64) were similar in both groups. Difficulty scores of console surgeon were less in most steps on right side but not on left side. Patient-side surgeon in RDN had higher difficulty scores for retrieval. CONCLUSION: RDN is safe and is associated with better morbidity profile than LDN. Robotic approach provides technical ease and facilitates preservation of longer length of renal artery on right side. Left RDN is associated with longer WIT; however, this does not translate into poor graft outcome. PMID- 26414848 TI - Identification of a New Type of Covalent PPARgamma Agonist using a Ligand-Linking Strategy. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand activated transcription factor that plays an important role in adipogenesis and glucose metabolism. The ligand-binding pocket (LBP) of PPARgamma has a large Y shaped cavity with multiple subpockets where multiple ligands can simultaneously bind and cooperatively activate PPARgamma. Focusing on this unique property of the PPARgamma LBP, we describe a novel two-step cell-based strategy to develop PPARgamma ligands. First, a combination of ligands that cooperatively activates PPARgamma was identified using a luciferase reporter assay. Second, hybrid ligands were designed and synthesized. For proof of concept, we focused on covalent agonists, which activate PPARgamma through a unique activation mechanism regulated by a covalent linkage with the Cys285 residue in the PPARgamma LBP. Despite their biological significance and pharmacological potential, few covalent PPARgamma agonists are known except for endogenous fatty acid metabolites. With our strategy, we determined that plant-derived cinnamic acid derivatives cooperatively activated PPARgamma by combining with GW9662, an irreversible antagonist. GW9662 covalently reacts with the Cys285 residue. A docking study predicted that a cinnamic acid derivative can bind to the open cavity in GW9662 bound PPARgamma LBP. On the basis of the putative binding mode, structures of both ligands were linked successfully to create a potent PPARgamma agonist, which enhanced the transactivation potential of PPARgamma at submicromolar levels through covalent modification of Cys285. Our approach could lead to the discovery of novel high-potency PPARgamma agonists. PMID- 26414849 TI - Spontaneous lesions in endocrine glands of experimental Wistar rats and beagle dogs. AB - A retrospective analysis was undertaken at Zydus Research Centre to understand the incidences of spontaneous lesions in endocrine glands of Wistar rats and beagle dogs. The data from a total of 841 Wistar rats (418 males and 423 females) and 144 beagle dogs (72 males and 72 females) was used from placebo/vehicle treated control group of different non-clinical toxicity studies. The lesions in various endocrine glands were classified according to the species and age of the animals at termination of study. Among the endocrine glands, the highest numbers (types) of spontaneous lesions were observed in adrenal glands followed in descending order by pituitary, thyroid, endocrine pancreas and parathyroid glands in Wistar rats. In beagle dogs, highest numbers (types) of spontaneous lesions were seen in adrenals followed by thyroid, endocrine pancreas, pituitary and parathyroid gland. In adrenal glands of Wistar rats, the incidences of cortical cell vacuolation, hemorrhages and hemangiectasis/peliosis were increased with age. Incidence of peliosis at ~110 weeks of age was higher in female rats. Among the proliferative lesions in rats, higher incidences of cortical cell hyperplasia was observed followed by medullary hyperplasia, complex pheochromocytoma, cortical cell adenoma and cortical adenocarcinoma. In beagle dogs, the incidences of hemangiectasis and cortical cell vacuolation in adrenal glands were higher in 18-21 months aged dogs in both the sexes as compared to 10-12 months of age. In pituitary gland, the incidences of cystic changes were higher in older rats and dogs and the incidences were more in beagles as compared to rats. In thyroid glands, C-cell (parafollicular cells) hyperplasia/complex was observed more frequently in both the species. Few incidences of cystic changes were observed in parathyroid of 18-21 months aged beagle dogs. In endocrine pancreas, few incidences of islet-cell vacuolation, atrophy and hyperplasia were observed in both the species. The Islet cell hyperplasia was found to be more frequent in male rats at ~110 weeks of age. PMID- 26414850 TI - Regional contribution to PM1 pollution during winter haze in Yangtze River Delta, China. AB - To quantify regional sources contributing to submicron particulate matter (PM1) pollution in haze episodes, on-line measurements combining two modeling methods, namely, positive matrix factorization (PMF) and backward Lagrangian particle dispersion modeling (LPDM), were conducted for the period of one month in urban Nanjing, a city located in the western part of Yangtze River Delta (YRD) region of China. Several multi-day haze episodes were observed in December 2013. Long range transport of biomass burning from the southwestern YRD region largely contributed to PM1 pollution with more than 25% of total organics mass in a lasting heavy haze. The LPDM analysis indicates that regional transport is a main source contributing to secondary low-volatility production. The high-potential source regions of secondary low-volatility production are mainly located in areas to the northeast of the city. High aerosol pollution was mainly contributed by regional transport associated with northeastern air masses. Such regional transport on average accounts for 46% of total NR-PM1 with sulfate and aged low volatility organics being the largest fractions (>65%). PMID- 26414851 TI - Implementing constrained multi-time approach with bootstrap analysis in ME-2: An application to PM2.5 data from Florence (Italy). AB - Advanced receptor models have been recently developed and tested in order to improve the resolution of apportionment problems reducing rotational ambiguity of results and aiming at identifying a larger number of sources. In particular, multi-time model is a factor analysis method able to compute source profiles and contributions using aerosol compositional data with different time resolutions. Unlike traditional factor analysis, each measured value can be inserted into multi-time model with its original time schedule, thus all temporal information can be effectively used in the modelling process. In this work, multi-time model was expanded in order to impose constraints on modelled factors aiming at improving the source identification. Moreover, as far as we know for the first time, a suitable bootstrap technique was implemented in the multi-time scheme to estimate the uncertainty of the final constrained solutions. These implemented approaches were tested on a PM2.5 (particulate matter with aerodynamic diameter <2.5 MUm) dataset composed of 24-h samples collected during one year and hourly data sampled in parallel for two shorter periods in Florence (Italy). The daily samples were chemically characterised for elements, ions and carbonaceous components while elemental concentrations only were available for high-time resolved samples. The application of the advanced model revealed the major contribution from traffic (accounting for 37% of PM2.5 as annual average) and allowed an accurate characterisation of involved emission processes. In particular, exhaust and non-exhaust emissions were identified. The constraints imposed in the continuation run led to a better description of the factor associated to nitrates and also of biomass burning profile and the bootstrap results gave useful information to assess the reliability of source apportionment solutions. Finally, the comparison with the results computed by ME-2 base model applied to daily and hourly compositional data separately demonstrated the advantages provided by the multi-time approach. PMID- 26414852 TI - Commentary: Mapping the Human Exposome: Without It, How Can We Find Environmental Risk Factors for ALS? PMID- 26414853 TI - Occupational Exposure to Electric Shocks and Magnetic Fields and Amyotrophic Lateral Sclerosis in Sweden. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) has been consistently related to "electric occupations," but associations with magnetic field levels were generally weaker than those with electrical occupations. Exposure to electric shock has been suggested as a possible explanation. Furthermore, studies were generally based on mortality or prevalence of ALS, and studies often had limited statistical power. METHODS: Using two electric shock and three magnetic field job exposure matrices, we evaluated the relationship of occupational magnetic fields, electric shocks, electric occupations, and incident ALS in a large population based nested case-control study in Sweden. Subanalyses, specified a priori, were performed for subjects by gender and by age (less than and more than 65 years). RESULTS: Overall, we did not observe any associations between occupational magnetic field or electric shock exposure and ALS. For individuals less than 65 years old, high electric shock exposure was associated with an odds ratio (OR) of 1.22 (95% confidence interval [CI] = 1.03, 1.43). The corresponding result for the age group 65 years or older was OR = 0.92 (95% CI = 0.81, 1.05). Results were similar regardless which job exposure matrices, exposure definitions, or cutpoints were used. For electric occupations, ORs were close to unity, regardless of age. For welders, no association was observed overall, although for welders <65 years the OR was 1.52 (95% CI = 1.05, 2.21). CONCLUSIONS: In this very large population-based study based on incident ALS case subjects, we did not confirm previous observations of higher risk of ALS in electrical occupations, and provided only weak support for associations between electric shocks and ALS. PMID- 26414854 TI - Military Service and Amyotrophic Lateral Sclerosis in a Population-based Cohort. AB - BACKGROUND: Military service has been suggested to be associated with an increased risk of amyotrophic lateral sclerosis (ALS), but only one prospective study-of a volunteer cohort-has examined this question. METHODS: We prospectively assessed the relation between service in the military and ALS mortality among participants in the National Longitudinal Mortality Study, a population representative cohort of U.S. men and women surveyed from 1973 through 2002. Participant follow-up was conducted from 1979 through 2002 for ALS mortality. There were 696,743 men and 392,571 women who were 25 years old or more with military service data. In this group, there were 375 male ALS deaths and 96 female ALS deaths. Adjusted hazard ratios (HRs) were calculated using Cox proportional hazards. RESULTS: Men who served in the military had an increased adjusted ALS death rate [HR: 1.23; 95% confidence interval (CI): 0.98, 1.53] compared with those who did not serve. An increase in ALS mortality was found among those who served during World War II (HR: 1.47; 95% CI: 1.13, 1.91) but not during other time periods. This pattern of results was similar for women, but with larger confidence intervals (HR for military service: 1.26; 95% CI: 0.29, 5.59; HR for service during World War II: 2.03; 95% CI: 0.45, 9.05). CONCLUSIONS: Military personnel have an increased risk of ALS, which may be specific to certain service periods although there was no data on actual deployment. Because of the longer follow-up time for World War II veterans, we cannot rule out that increased risk for those who served during other periods would be seen with further follow-up. PMID- 26414856 TI - Estimating the Impact of Health-related Behaviors on Geographic Variation in Cardiovascular Mortality: A New Approach Based on the Synthesis of Ecological and Individual-level Data. AB - BACKGROUND: Incidence of and mortality from cardiovascular disease (CVD) exhibit a strong geographical pattern, with inhabitants of more affluent neighborhoods showing a substantially lower risk of CVD mortality than inhabitants of deprived neighborhoods. Thus far, there is insufficient evidence as to what extent these differences can be attributed to differences in health-related behaviors. METHODS: Using a Hierarchical Related Regression approach, we combined individual and aggregate (ecological) data to investigate the extent to which small-area variation in CVD mortality in Dutch neighborhoods can be explained by several behavioral risk factors (i.e., smoking, drinking, overweight, and physical inactivity). The proposed approach combines the benefits of both an ecological analysis (in terms of data availability and statistical power) and an individual level analysis (in terms of identification of the parameters and interpretation of the results). RESULTS: After correcting for differences in age and sex, accounting for differences in the behavioral risk factors reduces income-related inequalities in CVD mortality by approximately 30%. CONCLUSIONS: Direct targeting of the excess prevalence of unhealthy behaviors in deprived neighborhoods is identified as a relevant strategy to reduce inequalities in CVD mortality. Our results also show that the proposed Hierarchical Related Regression approach provides a powerful method for the investigation of small-area variation in health outcomes. PMID- 26414855 TI - Application of Latent Variable Methods to the Study of Cognitive Decline When Tests Change over Time. AB - BACKGROUND: The way a construct is measured can differ across cohort study visits, complicating longitudinal comparisons. We demonstrated the use of factor analysis to link differing cognitive test batteries over visits to common metrics representing general cognitive performance, memory, executive functioning, and language. METHODS: We used data from three visits (over 26 years) of the Atherosclerosis Risk in Communities Neurocognitive Study (N = 14,252). We allowed individual tests to contribute information differentially by race, an important factor to consider in cognitive aging. Using generalized estimating equations, we compared associations of diabetes with cognitive change using general and domain specific factor scores versus averages of equally weighted standardized test scores. RESULTS: Factor scores provided stronger associations with diabetes at the expense of greater variability around estimates (e.g., for general cognitive performance, -0.064 standard deviation units/year, standard error = 0.015, vs. 0.041 standard deviation units/year, standard error = 0.014), which is consistent with the notion that factor scores more explicitly address error in measuring assessed traits than averages of standardized tests. CONCLUSIONS: Factor analysis facilitates use of all available data when measures change over time, and further, it allows objective evaluation and correction for differential item functioning. PMID- 26414857 TI - A model-based reconstruction technique for quantitative myocardial perfusion imaging. AB - PURPOSE: To reduce saturation effects in the arterial input function (AIF) estimation of quantitative myocardial first-pass saturation recovery perfusion imaging by employing a model-based reconstruction. THEORY AND METHODS: Imaging was performed with a saturation recovery prepared radial FLASH sequence. A model based reconstruction was applied for reconstruction. By exploiting prior knowledge about the relaxation process, an image series with different saturation recovery times was reconstructed. By evaluating images with an effective saturation time of approximately 3 ms, saturation effects in the AIF determination were reduced. In a volunteer study, this approach was compared with a standard prebolus technique. RESULTS: In comparison to the low-dose injection of a prebolus acquisition, saturation effects were further reduced in the AIFs determined using the model-based approach. These effects, which were clearly visible for all six volunteers, were reflected in a statistically significant difference of up to 20% in the absolute perfusion values. CONCLUSION: The application of model-based reconstruction algorithms in quantitative myocardial perfusion imaging promises a significant improvement of the AIF determination. In addition to greatly reducing saturation effects that occur even for the prebolus methods, only a single bolus has to be applied. Magn Reson Med 76:880-887, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26414858 TI - Quantitative assessment of human and pet exposure to Salmonella associated with dry pet foods. AB - Recent Salmonella outbreaks associated with dry pet foods and treats highlight the importance of these foods as previously overlooked exposure vehicles for both pets and humans. In the last decade efforts have been made to raise the safety of this class of products, for instance by upgrading production equipment, cleaning protocols, and finished product testing. However, no comprehensive or quantitative risk profile is available for pet foods, thus limiting the ability to establish safety standards and assess the effectiveness of current and proposed Salmonella control measures. This study sought to develop an ingredients to-consumer quantitative microbial exposure assessment model to: 1) estimate pet and human exposure to Salmonella via dry pet food, and 2) assess the impact of industry and household-level mitigation strategies on exposure. Data on prevalence and concentration of Salmonella in pet food ingredients, production process parameters, bacterial ecology, and contact transfer in the household were obtained through literature review, industry data, and targeted research. A probabilistic Monte Carlo modeling framework was developed to simulate the production process and basic household exposure routes. Under the range of assumptions adopted in this model, human exposure due to handling pet food is null to minimal if contamination occurs exclusively before extrusion. Exposure increases considerably if recontamination occurs post-extrusion during coating with fat, although mean ingested doses remain modest even at high fat contamination levels, due to the low percent of fat in the finished product. Exposure is highly variable, with the distribution of doses ingested by adult pet owners spanning 3Log CFU per exposure event. Child exposure due to ingestion of 1g of pet food leads to significantly higher doses than adult doses associated with handling the food. Recontamination after extrusion and coating, e.g., via dust or equipment surfaces, may also lead to exposure due to the absence of pathogen reduction steps after extrusion or at consumer households. Exposure is potentially highest when Salmonella is transferred to human food that is left at growth-promoting conditions. This model can be applied to evaluate the impact of alternative Salmonella control measures during production, risk communication to consumers, and regulatory standards. PMID- 26414860 TI - Lupus Means Sacrifices: Perspectives of Adolescents and Young Adults With Systemic Lupus Erythematosus. AB - OBJECTIVE: Disease activity, organ damage, and treatment burden are often substantial in children and adolescents with systemic lupus erythematous (SLE), and the complex interplay among the developing child, parents, and peers makes effective management difficult. We aimed to describe the experiences and perspectives of adolescents and young adults diagnosed with juvenile-onset SLE to inform strategies for improving treatment and health outcomes. METHODS: Focus groups and face-to-face semistructured interviews were conducted with 26 patients ages 14-26 years, from 5 Australian hospitals in 2013-2014. Focus groups and interview transcripts were thematically analyzed. RESULTS: Five themes were identified: marring identity (misrepresented self, heightened self-consciousness, sense of isolation), restricting major life decisions (narrowed career options, threat to parenthood), multifaceted confusion and uncertainty (frustration at delayed diagnosis or misdiagnosis, needing age and culturally appropriate information, ambiguity about cause of symptoms, prognostic uncertainty, confronting transition to adult care), resentment of long-term treatment (restricting ambition, animosity toward medication use), and gaining resilience and coping capacities (desire for independence, developing self-reliance, recalibrating perceived disease severity, depending on family and friends, trusting physicians). CONCLUSION: Young patients with SLE perceive they have substantially limited physical and social capacities and restricted personal and career goals. Psychosocial and educational interventions targeted at improving confidence, self-efficacy, disease-related knowledge, and social support, and at resolving insecurities regarding patients' capacity for self-management may alleviate psychosocial distress and improve adherence, and thus optimize health outcomes of adolescents and young adults with SLE. PMID- 26414859 TI - The Effects of the Endocannabinoids Anandamide and 2-Arachidonoylglycerol on Human Osteoblast Proliferation and Differentiation. AB - The endocannabinoid system is expressed in bone, although its role in the regulation of bone growth is controversial. Many studies have examined the effect of endocannabinoids directly on osteoclast function, but few have examined their role in human osteoblast function, which was the aim of the present study. Human osteoblasts were treated from seeding with increasing concentrations of anandamide or 2-arachidonoylglycerol for between 1 and 21 days. Cell proliferation (DNA content) and differentiation (alkaline phosphatase (ALP), collagen and osteocalcin secretion and calcium deposition) were measured. Anandamide and 2-arachidonoylglycerol significantly decreased osteoblast proliferation after 4 days, associated with a concentration-dependent increase in ALP. Inhibition of endocannabinoid degradation enzymes to increase endocannabinoid tone resulted in similar increases in ALP production. 2 arachidonoylglycerol also decreased osteocalcin secretion. After prolonged (21 day) treatment with 2-arachidonoylglycerol, there was a decrease in collagen content, but no change in calcium deposition. Anandamide did not affect collagen or osteocalcin, but reduced calcium deposition. Anandamide increased levels of phosphorylated CREB, ERK 1/2 and JNK, while 2-arachidonoylglycerol increased phosphorylated CREB and Akt. RT-PCR demonstrated the expression of CB2 and TRPV1, but not CB1 in HOBs. Anandamide-induced changes in HOB differentiation were CB1 and CB2-independent and partially reduced by TRPV1 antagonism, and reduced by inhibition of ERK 1/2 and JNK. Our results have demonstrated a clear involvement of anandamide and 2-arachidonoylglycerol in modulating the activity of human osteoblasts, with anandamide increasing early cell differentiation and 2-AG increasing early, but decreasing late osteoblast-specific markers of differentiation. PMID- 26414861 TI - Tick-borne encephalitis--lipid peroxidation and its consequences. AB - BACKGROUND: The purpose of this study was to assess the processes of lipid peroxidation with prostaglandin derivatives and reactive aldehydes being its major indicators in cerebrospinal fluid (CSF), plasma and urine of patients with tick-borne encephalitis (TBE). MATERIALS AND METHODS: This study included 60 patients with TBE and 56 healthy subjects. Lipid peroxidation was estimated by the measurement of 4-hydroxynonenal (4-HNE), 4-hydroxyhexenal (4-HHE), malondialdehyde (MDA), acrolein, crotonaldehyde, and 4-oxononenal (4-ONE), determined by GC-MS, F2-isoprostanes and neuroprostanes (NPs) level determined by LC-MS. The level of 4-HNE-protein adducts was determined by ELISA. Phospholipase A2 (PLA2), platelet-activating factor acetylhydrolase (PAF-AH) and glutathione peroxidase (GSH-Px) activities and vitamin E level were determined spectrophotometrically and by HPLC, respectively. In parallel, the plasma levels of phospholipid acids such as arachidonic acid (AA), linoleic acid (LA) and docosahexaenoic acid (DHA) were monitored. RESULTS: A significant decrease in AA, LA, DHA level and GSH-Px activity (by about 20, 69, 11 and 18%, respectively) was observed. The consequence of enhanced phospholipid peroxidation was almost 7 times higher plasma level of F2-isoprostanes and 3-fold increase in NPs level in CSF of TBE patients. Additionally a 3.5-fold increase in the CSF level of MDA, 5 fold increase in the plasma level of 4-HNE and urine level of 4-HHE in TBE patients was observed. Decreased plasma activity of PLA2 with an increase in the PAF-AH activity was observed. CONCLUSION: Lipid peroxidation occurring during TBE development indicates its relevance in pathophysiology of this disease. Moreover lipid peroxidation products might be useful for the diagnosis of TBE. PMID- 26414862 TI - Investigational new drugs for the treatment of acute coronary syndrome. AB - INTRODUCTION: Ischemic heart disease is the most common cause of death worldwide. Despite improvements in interventional and pharmacological therapy for acute coronary syndrome (ACS), the risk of recurrent myocardial ischemia and mortality early after ACS remains high. Our improved understanding of the increasing role of inflammation in the pathogenesis of ACS and its relationship to atherosclerotic plaque rupture and thrombosis has led to the development of more potent anti-thrombotic and novel anti-inflammatory therapies for the treatment of ACS. AREAS COVERED: In this review, the authors explore: the developing pharmacotherapy in the field of cardiology for ACS; antiplatelet agents (both further development of classical modalities together with pioneering agents); evolving use of anticoagulation in its treatment, and exploration in the use of novel anti-inflammatories and biological agents. EXPERT OPINION: Data from trials involving the use of immunological and cellular-based treatments show promising results and herald further possible reduction in infarct burden in ACS alongside the possibility of recovery in cardiac function following infarction. PMID- 26414863 TI - In Vivo Anastomosis and Perfusion of a Three-Dimensionally-Printed Construct Containing Microchannel Networks. AB - The field of tissue engineering has advanced the development of increasingly biocompatible materials to mimic the extracellular matrix of vascularized tissue. However, a majority of studies instead rely on a multiday inosculation between engineered vessels and host vasculature rather than the direct connection of engineered microvascular networks with host vasculature. We have previously demonstrated that the rapid casting of three-dimensionally-printed (3D) sacrificial carbohydrate glass is an expeditious and a reliable method of creating scaffolds with 3D microvessel networks. Here, we describe a new surgical technique to directly connect host femoral arteries to patterned microvessel networks. Vessel networks were connected in vivo in a rat femoral artery graft model. We utilized laser Doppler imaging to monitor hind limb ischemia for several hours after implantation and thus measured the vascular patency of implants that were anastomosed to the femoral artery. This study may provide a method to overcome the challenge of rapid oxygen and nutrient delivery to engineered vascularized tissues implanted in vivo. PMID- 26414864 TI - Effects of waterborne fluoxetine on stress response and osmoregulation in zebrafish. AB - The presence of fluoxetine in aquatic environments has been reported for decades. Here, we investigate the effects of exposure to fluoxetine on the stress response and osmoregulation in zebrafish. We show that stress response alters osmoregulation and that fluoxetine inhibits these stress-related changes in osmoregulation. The results suggest that the presence of fluoxetine in aquatic ecosystems can cause changes in response to stress and osmoregulation in fish. PMID- 26414865 TI - Motor Readiness Increases Brain Connectivity Between Default-Mode Network and Motor Cortex: Impact on Sampling Resting Periods from fMRI Event-Related Studies. AB - The default-mode network (DMN) has been implicated in many conditions. One particular function relates to its role in motor preparation. However, the possibly complex relationship between DMN activity and motor preparation has not been fully explored. Dynamic interactions between default mode and motor networks may compromise the ability to evaluate intrinsic connectivity using resting period data extracted from task-based experiments. In this study, we investigated alterations in connectivity between the DMN and the motor network that are associated with motor readiness during the intervals between motor task trials. fMRI data from 20 normal subjects were acquired under three conditions: pure resting state; resting state interleaved with brief, cued right-hand movements at constant intervals (lower readiness); and resting state interleaved with the same movements at unpredictable intervals (higher readiness). The functional connectivity between regions of motor and DMNs was assessed separately for movement periods and intertask intervals. We found a negative relationship between the DMN and the left sensorimotor cortex during the task periods for both motor conditions. Furthermore, during the intertask intervals of the unpredictable condition, the DMN showed a positive relationship with right sensorimotor cortex and a negative relation with the left sensorimotor cortex. These findings indicate a specific modulation on motor processing according to the state of motor readiness. Therefore, connectivity studies using task-based fMRI to probe DMN should consider the influence of motor system modulation when interpreting the results. PMID- 26414866 TI - Differential protein expression and oncogenic gene network link tyrosine kinase ephrin B4 receptor to aggressive gastric and gastroesophageal junction cancers. AB - Transmembrane tyrosine-kinase Ephrin receptors promote tumor progression and/or metastasis of several malignancies including leukemia, follicular lymphoma, glioma, malignant pleural mesothelioma, papillary thyroid carcinoma, sarcomas and ovarian, breast, bladder and non-small cell lung cancers. They also drive intestinal stem cell proliferation and positioning, control intestinal tissue boundaries and are involved in liver, pancreatic and colorectal cancers, indicating involvement in additional digestive system malignancies. We investigated the role of Ephrin-B4 receptor (EPHB4), and its ligand EFNB2, in gastric and gastroesophageal junction cancers in patient cohorts through computational, mathematical, molecular and immunohistochemical analyses. We show that EPHB4 is upregulated in preneoplastic gastroesophageal lesions and its expression further increased in gastroesophageal cancers in several independent cohorts. The closely related EPHB6 receptor, which also binds EFNB2, was downregulated in all tested cohorts, consistent with its tumor-suppressive properties in other cancers. EFNB2 expression is induced in esophageal cells by acidity, suggesting that gastroesophageal reflux disease (GERD) may constitute an early triggering event in activating EFNB2-EPHB4 signaling. Association of EPHB4 to both Barrett's esophagus and to advanced tumor stages, and its overexpression at the tumor invasion front and vascular endothelial cells intimate the notion that EPHB4 may be associated with multiple steps of gastroesophageal tumorigenesis. Analysis of oncogenomic signatures uncovered the first EPHB4 associated gene network (false discovery rate: 7 * 10(-90) ) composed of a five transcription factor interconnected gene network that drives proliferation, angiogenesis and invasiveness. The EPHB4 oncogenomic network provides a molecular basis for its role in tumor progression and points to EPHB4 as a potential tumor aggressiveness biomarker and drug target in gastroesophageal cancers. PMID- 26414867 TI - Chronic alpha-Tocopherol Increases Central Monoamines Synthesis and Improves Cognitive and Motor Abilities in Old Rats. AB - Limiting enzymes in the synthesis of brain monoamines seems to be susceptible to oxidative damage, one of the most important factors in aging. It has been suggested that the use of anti-oxidants can reduce the rate of free radical production related with aging and the associated damage. Therefore, this study aims to analyze the effects of the chronic treatments with the anti-oxidant alpha tocopherol (vitamin E) on central monoamines (high-performance liquid chromatography [HPLC] analysis) mediating cognitive functions, as well as on the evaluation of memory and motor abilities in old rats measured by radial maze, Barnes maze, novel object recognition test, and rotarod test. Results show that alpha-tocopherol significantly increased in a dose- and/or time-dependent manner the synthesis rate and the levels of monoaminergic neurotransmitters (serotonin, dopamine, and noradrenaline) in the hippocampus and striatum, brain regions involved in memory processing and motor coordination. These positive neurochemical effects, largely due to an increased activity of the limiting enzymes in monoamines synthesis, tryptophan hydroxylase and tyrosine hydroxylase, were accompanied by an improvement in cognitive and motor abilities in old rats. Altogether these findings suggest that alpha-tocopherol exhibits neuroprotective actions in old rats; thus, diets with alpha-tocopherol might represent a promising strategy to mitigate or delay the cognitive and motor decline associate with aging and related-diseases. PMID- 26414868 TI - Comparing symptomatic and functional outcomes over 5 years in two nonclinical cohorts characterized by binge eating with and without objectively large episodes. AB - OBJECTIVE: The aim was to compare symptomatic and functional outcomes over 5 years in women with regular subjective (SBEs), objective (OBEs), and no regular binge eating episodes. METHOD: Data were derived from two cohorts of 330 women with high levels of eating disorders symptoms followed over 5 years. Three groups were formed: (a) regular SBEs but no regular OBEs (N = 68), (b) regular OBEs with or without regular SBEs (N = 154), and (c) with no regular binge eating episodes (N = 108). RESULTS: At baseline, the groups did not differ significantly in restraint scores and quality of life. People in the OBE group scored higher than those in the SBE group in body mass index (BMI). Those who had no regular binge eating had lower global Eating Disorder Examination Questionnaire (EDE-Q) and weight and shape concern scores than those with regular SBEs, and lower eating concern scores than either binge eating groups. Across the follow-up, there were no significant effects of being in either binge eating or the nonbinge eating group on the rates of change in BMI, general psychological distress, quality of life, or EDE-Q scores with the exception that OBE group had a significantly different rate of change in eating concern and psychological distress compared to the group without regular binge eating. DISCUSSION: Individuals that report regular SBEs without regular OBEs represent a group with similar mental hardship and outcomes to those with regular OBEs. The findings support inclusion of regular SBEs in criteria for eating disorder diagnostic categories characterized by recurrent binge eating. PMID- 26414869 TI - Melatonin for Spinal Cord Injury in Animal Models: A Systematic Review and Network Meta-Analysis. AB - Spinal cord injury (SCI) leads to loss of function below the lesion and affects individuals worldwide. An increasing number of experimental studies support the effectiveness of melatonin (MT) for SCI. Our objectives were to investigate neurological recovery and anti-oxidant effects of MT in animal models of SCI, and to explore the appropriate dose. Published MT studies in SCI animal models described in six databases were searched. Two practiced investigators selected the studies, extracted the data, and independently evaluated the quality of the included studies. A meta-analysis evaluated the effect of MT in SCI and a network meta-analysis was performed to explore the appropriate MT dose for SCI models. Thirteen studies were analyzed, of which three were high quality. The results of the meta-analysis manifested that the behavioral evaluation (Basso, Beattie, and Bresnahan scales, n = 90, p = 0.003; motor function scores, n = 92, p = 0.004; Tarlov's criteria, n = 150, p = 0.002; inclined plane test, n = 150, p = 0.001) and biochemical outcomes (malondialdehyde, n = 121, p = 0.0010; glutathione levels, n = 64, p < 0.0001; and myeloperoxidase activity, n = 32, p < 0.00001) were improved, compared with the control group, after MT administration. A dose of 12.5 mg/kg was most effective in SCI rat models. Studies indicated that MT administration significantly improved neurological recuperation and anti-oxidant effects in rat models of SCI. The appropriate dose of MT was 12.5 mg/kg for SCI rat models. The majority of included studies were low quality; however, optimal MT treatment in SCI still requires high quality studies. PMID- 26414870 TI - Work with men to end violence against women: a critical stocktake. AB - This paper provides a critical assessment of efforts to involve men in the prevention of men's violence against women. Although there is a substantial evidence base attesting to the effectiveness of at least some strategies and interventions, this field is also limited in important ways. Violence prevention efforts often have focused on changing men's attitudes, rather than also seeking to transform structural and institutional inequalities. While feminist and queer scholarship has explored diversities and pluralities in the organisation of sexuality, much violence prevention work often assumes a homogenously heterosexual male constituency. Too often this work is conceptually simplistic with regard to gender. Against this background, this paper contests and complicates several assumptions that are part of an emerging consensus in men's violence prevention: first, that it is in men's interests to support progress towards non-violence and gender equality; second, that the best people to engage and work with men are other men; and finally, the strengths and limitations of inviting and drawing on 'real men'. A critical assessment of the field's working assumptions is vital if it is to contribute to the future prevention of men's violence against women. PMID- 26414871 TI - Ultrasound-Guided Approach for L5 Dorsal Ramus Block and Fluoroscopic Evaluation in Unpreselected Cadavers. AB - BACKGROUND AND OBJECTIVES: Medial branch blocks are frequently performed to diagnose lumbar facet-joint-mediated pain. Ultrasound guidance can increase practicability and eliminate exposure to ionizing radiation when compared with fluoroscopy. However, ultrasound-guided L5 dorsal ramus block, which, together with L4 medial branch block is necessary to anesthetize the most commonly affected facet joint L5/S1, has not been described so far. The objective of this study was to develop a technique and to evaluate its accuracy with standard fluoroscopy in unpreselected cadavers. METHODS: Twenty ultrasound-guided L5 dorsal ramus block approaches were performed with a new oblique out-of-plane technique in a rotated cross-axis view bilaterally in 10 cadavers. After checking the needle position in a second perpendicular sonographic plane, the final needle position was confirmed with conventional fluoroscopy by an independent observer. RESULTS: All cadavers had significant degenerations of the lumbar spine, and 5 of them had moderate to severe spondylolisthesis. Skin-to-target distances were 42 +/-7 mm. Sixteen L5 dorsal ramus block attempts were located at the exact radiological target, 1 was slightly too lateral, and 3 were slightly too caudal (3-10 mm away). The overall success rate in unpreselected cadavers reached 80% (95% confidence interval, 56%-94%) and in the subgroup of corpses without spondylolisthesis 100% (95% confidence interval, 69%-100%). CONCLUSIONS: This is the first study to show that ultrasound-guided L5 dorsal ramus block is accurate and feasible in the absence of significant spondylolisthesis when performed with an oblique out-of-plane technique. PMID- 26414872 TI - IL-13 Inhibits Multicilin Expression and Ciliogenesis via Janus Kinase/Signal Transducer and Activator of Transcription Independently of Notch Cleavage. AB - Loss of ciliated cells and increases in goblet cells are seen in respiratory diseases such as asthma. These changes result in part from reduced differentiation of basal progenitor cells to ciliated cells during injury and repair. The T helper 2 cytokine, IL-13, has been shown to inhibit ciliated cell differentiation, but the mechanism is not clearly understood. We recently showed that Notch signaling inhibits ciliated cell differentiation in submerged culture by repressing multicilin and forkhead box J1 (FOXJ1) expression, genes required for ciliogenesis. Using a novel method to study ciliated cell differentiation, we investigated the relationship between IL-13 and Notch signaling pathways. We found that IL-13 inhibits ciliated cell differentiation by repressing multicilin and FOXJ1 expression but does so independent of Notch signaling. In addition, we show that pharmacological inhibition of Janus kinase/signal transducer and activator of transcription, but not mitogen activated protein kinase kinase, signaling rescues multicilin and FOXJ1 expression and ciliated cell differentiation in the presence of IL-13. These findings indicate that regulation of multicilin expression by two distinct signaling pathways affects ciliated cell differentiation. In addition, the requirement for Janus kinase activation in IL 13-induced inhibition of ciliogenesis provides a potential therapeutic target for the treatment of respiratory disease. PMID- 26414874 TI - Effect of fusion status of sternum in stature estimation - A study from South India. AB - Forensic anthropologists examine and identify skeletal, dismembered and commingled remains in a legal context to establish the biological profile of the deceased. Stature estimation is one of the important parameters in establishing the biological profile. The present study is planned to derive regression models for stature estimation from sternal measurements. Various factors are likely to affect stature estimation in forensic investigations. Since, none of the previous researchers have studied the effect of fusion status on stature estimation from sternum and its segments, the present study attempts to find if the fusion status of the sternum affect its reliability and accuracy in stature estimation. The sample of the present study consisted of 117 sterna that were obtained from autopsied bodies. Five measurements i.e. Length of manubrium (M), length of mesosternum (B), combined length of manusbrium and mesosternum and the (M + B), width at first sternabrae (S1) and width of 3rd sternabrae (S3) were taken on the autopsied sterna. The sterna were classified as fused (both manubriosternal and xiphisternal joints were fused), partly fused (only one of the manubriosternal or xiphisternal joints was fused) and not fused (both manubriosternal and xiphisternal joints were not fused). Regression models were derived using statistical methods. All the sternal measurements show a positive however, a weak correlation with stature. Thus, it can be concluded that the accuracy and reliability of stature estimation from sternum and its segments is quite low in practical situations. Among the sterna classified based on the fusion status, the length measurements of completely fused sterna show significant correlation with the stature. None of the other sternal measurements on the non-fused or partly fused sterna show statistically significant correlation with stature. The present study concludes that the fusion status of the sternum is likely to affect the reliability and accuracy in estimation of stature. The findings of this study however, should be considered 'preliminary' until they are corroborated by similar studies based on larger samples from different populations. PMID- 26414873 TI - Mesenchymal Stem Cells Within Gelatin/CaSO4 Scaffolds Treated Ex Vivo with Low Doses of BMP-2 and Wnt3a Increase Bone Regeneration. AB - The delivery of osteogenic factors is a proven therapeutic strategy to promote bone regeneration. Bone morphogenetic proteins (BMPs) constitute a family of cytokines with well-known osteogenic and bone regenerative abilities. However, clinical uses of BMPs require high doses that have been associated with complications such as osteolysis, ectopic bone formation, or hematoma formation. In the present work, we sought to improve bone tissue engineering through an approach that combines the use of bone marrow-derived mesenchymal stem cells (BMMSCs), composite scaffolds, and osteoinductive agents. We employed a composite gelatin/CaSO4 scaffold that allows for an early expansion of seeded BMMSCs, which is followed by an increased level of osteogenic differentiation after 10 days in culture. Furthermore, this scaffold enhanced bone formation by BMMSCs in a mouse model of critical-sized calvarial defect. More importantly, our results demonstrate that ex vivo pretreatment of BMMSCs with low amounts of BMP-2 (2 nM) and Wnt3a (50 ng/mL) for 24 h cooperatively increases the expression of osteogenic markers in vitro and bone regeneration in the critical-sized calvarial defect mouse model. These data provide a strong rationale for the development of an ex vivo cooperative use of BMP-2 and Wnt3a. Osteogenic factor cooperation might be applied to reduce the required amount of growth factors while obtaining higher therapeutic effects. PMID- 26414875 TI - Sexual dimorphism in foot length ratios among North Indian adolescents. AB - Determination of sex along with other parameters of identification like stature, age and ancestry is one of the foremost criteria in establishing the biological profile of an individual. The present study was conducted to analyze the sex differences in the foot length ratios in a North Indian adolescent population. The study was conducted on 149 females and 154 males aged from 13 to 18 years. Foot length measurements were taken from pternion to the most anterior part of each toe and designated as T1, T2, T3, T4, and T5 respectively for first to fifth toes on both the feet in each participant using standard methods and techniques. A total of ten ratios (T1:T2, T1:T3, T1:T4, T1:T5, T2:T3, T2:T4, T2:T5, T3:T4, T3:T5, and T4:T5) were thus, obtained and the same were analyzed for sex differences using Student's t-test. Stature was measured in each participant and Pearson's correlation coefficients were calculated to find the correlation between various foot length ratios, age and stature. Receiver Operating Characteristic (ROC) curve was employed to test the sexing accuracy of the variables. P-value of less than 0.05 was considered as statistically significant. Foot length dimensions from each toe (T1 to T5) and stature were found to be significantly higher in males than females. The foot length ratios did not show any statistically significant correlation with stature. Statistically significant sex differences were exhibited by ratios between T1 and T2 (p = 0.002), T1 and T3 (p = 0.001), T1 and T4 (p < 0.001), T1 and T5 (p = 0.001), and T2 and T4 (p = 0.014). Maximum sex differences were evident for foot length ratio between T1 and T4 (63.4%), and minimum for the ratio between T2 and T4 (56.5%). Though foot length measurements are significantly larger in males, its utility in sex differentiation may be limited owing to its direct correlation with stature of an individual. It has been observed that the foot length ratios are independent of stature and thus, can be considered a better sex determinant since they are not influenced by the body built of an individual. Apart from ratio between T2 and T4, only the foot length ratios with reference to first toe (T1:T2, T1:T3, T1:T4, T1:T5) were found to exhibit significant sex-differences. The present research concludes that the foot length ratios exhibit sex differences in the study population. However, its utility in forensic investigations may be limited owing to the lower sexing accuracy of foot length ratios. PMID- 26414876 TI - Retention, erosion, and loss of the carotenoid biosynthetic pathway in the nonphotosynthetic green algal genus Polytomella. PMID- 26414878 TI - Sialic Acid-Imprinted Fluorescent Core-Shell Particles for Selective Labeling of Cell Surface Glycans. AB - The expression of cell surface glycans terminating with sialic acid (SA) residues has been found to correlate with various disease states there among cancer. We here report a novel strategy for specific fluorescence labeling of such motifs. This is based on sialic acid-imprinted core-shell nanoparticles equipped with nitrobenzoxadiazole (NBD) fluorescent reporter groups allowing environmentally sensitive fluorescence detection at convenient excitation and emission wavelengths. Imprinting was achieved exploiting a hybrid approach combining reversible boronate ester formation between p-vinylphenylboronic acid and SA, the introduction of cationic amine functionalities, and the use of an NBD-appended urea-monomer as a binary hydrogen-bond donor targeting the SA carboxylic acid and OH functionalities. The monomers were grafted from 200 nm RAFT-modified silica core particles using ethylene glycol dimethacrylate (EGDMA) as cross-linker resulting in a shell thickness of ca. 10 nm. The particles displayed strong affinity for SA in methanol/water mixtures (K = 6.6 * 10(5) M(-1) in 2% water, 5.9 * 10(3) M(-1) in 98% water, B(max) ~ 10 MUmol g(-1)), whereas binding of the competitor glucuronic acid (GA) and other monosaccharides was considerably weaker (K (GA) = 1.8 * 10(3) M(-1) in 98% water). In cell imaging experiments, the particles selectively stained different cell lines in correlation with the SA expression level. This was further verified by enzymatic cleavage of SA and by staining using a FITC labeled SA selective lectin. PMID- 26414879 TI - Delivery of antigen to nasal-associated lymphoid tissue microfold cells through secretory IgA targeting local dendritic cells confers protective immunity. AB - BACKGROUND: Transmission of mucosal pathogens relies on their ability to bind to the surfaces of epithelial cells, to cross this thin barrier, and to gain access to target cells and tissues, leading to systemic infection. This implies that pathogen-specific immunity at mucosal sites is critical for the control of infectious agents using these routes to enter the body. Although mucosal delivery would ensure the best onset of protective immunity, most of the candidate vaccines are administered through the parenteral route. OBJECTIVE: The present study evaluates the feasibility of delivering the chemically bound p24gag (referred to as p24 in the text) HIV antigen through secretory IgA (SIgA) in nasal mucosae in mice. RESULTS: We show that SIgA interacts specifically with mucosal microfold cells present in the nasal-associated lymphoid tissue. p24-SIgA complexes are quickly taken up in the nasal cavity and selectively engulfed by mucosal dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin-positive dendritic cells. Nasal immunization with p24-SIgA elicits both a strong humoral and cellular immune response against p24 at the systemic and mucosal levels. This ensures effective protection against intranasal challenge with recombinant vaccinia virus encoding p24. CONCLUSION: This study represents the first example that underscores the remarkable potential of SIgA to serve as a carrier for a protein antigen in a mucosal vaccine approach targeting the nasal environment. PMID- 26414877 TI - Engineering large animal models of human disease. AB - The recent development of gene editing tools and methodology for use in livestock enables the production of new animal disease models. These tools facilitate site specific mutation of the genome, allowing animals carrying known human disease mutations to be produced. In this review, we describe the various gene editing tools and how they can be used for a range of large animal models of diseases. This genomic technology is in its infancy but the expectation is that through the use of gene editing tools we will see a dramatic increase in animal model resources available for both the study of human disease and the translation of this knowledge into the clinic. Comparative pathology will be central to the productive use of these animal models and the successful translation of new therapeutic strategies. PMID- 26414880 TI - Acute and chronic systemic corticosteroid-related complications in patients with severe asthma. AB - BACKGROUND: Many patients with severe asthma require maintenance treatment with systemic corticosteroids (SCSs) to control daily symptoms and prevent serious acute exacerbations, but chronic SCS use is associated with complications. OBJECTIVE: We sought to evaluate the risk of SCS-related complications by SCS exposure and quantify the associated health care costs and resource use in patients with severe asthma. METHODS: We performed a longitudinal, open-cohort, observational study using health insurance claims data (1997-2013: Medicaid) from Florida, Iowa, Kansas, Missouri, Mississippi, and New Jersey. Eligible patients were 12 years old or older with 2 or more asthma diagnoses and had more than 6 months of continuous SCS use. An open-cohort approach was used to classify patients' follow-up into low, medium, and high SCS exposure (<= 6, >6-12, and >12 mg/d, respectively). Multivariate generalized estimating equation models were used to estimate the adjusted risk of SCS-related complications for patients with medium and high exposure compared with patients with low exposure and quantify the resulting health care resource use and costs. RESULTS: The study included 3628 patients (mean age, 57.6 years; 68% female). Patients with medium and high SCS exposure had significantly higher risks of SCS-related complications, including infections and cardiovascular, metabolic, psychiatric, ocular, gastrointestinal, and bone-related complications (odds ratio, 1.23-2.12 by complication; P < .05 for all but one) versus those with low (reference group) SCS exposure. Medium and high SCS exposure were also associated with significantly more emergency department visits (incidence rate ratios, 1.31 [P = .0004] and 1.78 [P < .0001]) and inpatient visits (incidence rate ratios, 1.25 [P < .0001] and 1.59 [P < .0001]) versus low SCS exposure. CONCLUSIONS: A significant dose-response relationship was demonstrated between chronic SCS use and risk of SCS-related complications in patients with severe asthma. Effective SCS-sparing strategies might reduce the burden associated with SCS-related complications in patients with severe asthma. PMID- 26414881 TI - Quality assessment of occupational health and safety management at the level of business units making up the organizational structure of a coal mine: a case study. AB - The audit of the health and safety management system is understood as a form and tool of controlling. The objective of the audit is to define whether the undertaken measures and the obtained results are in conformity with the predicted assumptions or plans, whether the agreed decisions have been implemented and whether they are suitable in view of the accepted health and safety policy. This paper presents the results of an audit examination carried out on the system of health and safety management between 2002 and 2012 on a group of respondents, the employees of two mining departments (G-1 and G-2) of Jan, a coal mine. The audit was carried out using the questionnaire developed by the author based on the MERIT-APBK survey. PMID- 26414882 TI - Diagnostic Accuracy of Digital Screening Mammography With and Without Computer Aided Detection. AB - IMPORTANCE: After the US Food and Drug Administration (FDA) approved computer aided detection (CAD) for mammography in 1998, and the Centers for Medicare and Medicaid Services (CMS) provided increased payment in 2002, CAD technology disseminated rapidly. Despite sparse evidence that CAD improves accuracy of mammographic interpretations and costs over $400 million a year, CAD is currently used for most screening mammograms in the United States. OBJECTIVE: To measure performance of digital screening mammography with and without CAD in US community practice. DESIGN, SETTING, AND PARTICIPANTS: We compared the accuracy of digital screening mammography interpreted with (n = 495 818) vs without (n = 129 807) CAD from 2003 through 2009 in 323 973 women. Mammograms were interpreted by 271 radiologists from 66 facilities in the Breast Cancer Surveillance Consortium. Linkage with tumor registries identified 3159 breast cancers in 323 973 women within 1 year of the screening. MAIN OUTCOMES AND MEASURES: Mammography performance (sensitivity, specificity, and screen-detected and interval cancers per 1000 women) was modeled using logistic regression with radiologist-specific random effects to account for correlation among examinations interpreted by the same radiologist, adjusting for patient age, race/ethnicity, time since prior mammogram, examination year, and registry. Conditional logistic regression was used to compare performance among 107 radiologists who interpreted mammograms both with and without CAD. RESULTS: Screening performance was not improved with CAD on any metric assessed. Mammography sensitivity was 85.3% (95% CI, 83.6% 86.9%) with and 87.3% (95% CI, 84.5%-89.7%) without CAD. Specificity was 91.6% (95% CI, 91.0%-92.2%) with and 91.4% (95% CI, 90.6%-92.0%) without CAD. There was no difference in cancer detection rate (4.1 in 1000 women screened with and without CAD). Computer-aided detection did not improve intraradiologist performance. Sensitivity was significantly decreased for mammograms interpreted with vs without CAD in the subset of radiologists who interpreted both with and without CAD (odds ratio, 0.53; 95% CI, 0.29-0.97). CONCLUSIONS AND RELEVANCE: Computer-aided detection does not improve diagnostic accuracy of mammography. These results suggest that insurers pay more for CAD with no established benefit to women. PMID- 26414883 TI - A Double-Chambered Protein Nanocage Loaded with Thrombin Receptor Agonist Peptide (TRAP) and gamma-Carboxyglutamic Acid of Protein C (PC-Gla) for Sepsis Treatment. AB - New protein nanocages are designed bearing two functional proteins, gamma carboxyglutamic acid of protein C (PC-Gla) and thrombin receptor agonist peptide (TRAP), and have an anti-septic response. These nanoparticles reduce sepsis induced organ injury and septic mortality in vivo. Noting that there are currently no medications for severe sepsis, these results show that novel nanoparticles can be used to treat sepsis. PMID- 26414884 TI - Determination of Pain Phenotypes in Knee Osteoarthritis: A Latent Class Analysis Using Data From the Osteoarthritis Initiative. AB - OBJECTIVE: Knee osteoarthritis (OA) is a broadly applied diagnosis that may describe multiple subtypes of pain. The purpose of this study was to identify phenotypes of knee OA, using measures from the following pain-related domains: 1) knee OA pathology, 2) psychological distress, and 3) altered pain neurophysiology. METHODS: Data were selected from a total of 3,494 participants at visit 6 of the Osteoarthritis Initiative study. Latent class analysis was applied to the following variables: radiographic OA severity, quadriceps strength, body mass index, the Charlson Comorbidity Index (CCI), the Center for Epidemiologic Studies Depression Scale, the Coping Strategies Questionnaire Catastrophizing subscale, number of bodily pain sites, and knee joint tenderness at 4 sites. The resulting classes were compared on the following demographic and clinical factors: age, sex, pain severity, disability, walking speed, and use of arthritis-related health care. RESULTS: A 4-class model was identified. Class 1 (4% of the study population) had higher CCI scores. Class 2 (24%) had higher knee joint sensitivity. Class 3 (10%) had greater psychological distress. Class 4 (62%) had lesser radiographic OA, little psychological involvement, greater strength, and less pain sensitivity. Additionally, class 1 was the oldest, on average. Class 4 was the youngest, had the lowest disability, and least pain. Class 3 had the worst disability and most pain. CONCLUSION: Four distinct pain phenotypes of knee OA were identified. Psychological factors, comorbidity status, and joint sensitivity appear to be important in defining phenotypes of knee OA related pain. PMID- 26414885 TI - Outcomes in Relapsed Graves' Disease Patients Following Radioiodine or Prolonged Low Dose of Methimazole Treatment. AB - BACKGROUND: Low doses of antithyroid drugs (ATD) for extended periods may be an alternative for Graves' disease (GD) patients who relapse after a course of ATD. METHODS: Patients with GD relapse (n = 238) after discontinuation of ATD therapy for 12-24 months were retrospectively analyzed in a nonrandomized study. Radioiodine (RAI) treatment and L-thyroxine replacement was used in 114 patients, and a low dose of methimazole (MMI; 2.5-7 mg/daily) was used in 124 patients. Thyroid dysfunction, Graves' ophthalmopathy (GO) evolution, quality of life (QoL), and body weight were evaluated during the follow-up. RESULTS: The mean follow-up was 80.8 +/- 35.3 months for the RAI group, and 71.3 +/- 40.3 months for the low-dose MMI group. No notable side effects were observed in either group. Thyroid dysfunction was predominant in the RAI group (p < 0.001), and euthyroidism was more common in the MMI group (p < 0.001). GO deterioration was mainly evaluated by clinical activity score (CAS)--it was higher in the RAI group (p < 0.0005) over all periods of follow-up. Multivariate logistic analysis showed that RAI treatment was associated with no improvement in CAS during follow-up (24 months: OR = 3.51 [CI 1.02-12.03], p < 0.05; 36 months: OR = 8.46 [CI 1.47 48.58], p < 0.05; 48 months: OR = 19.52 [CI 1.70-223.10], p < 0.05; 60 months: OR = 21.1 [CI 1.5-298], p < 0.05). Kaplan-Meier survival analysis confirmed this finding (p < 0.0003). Assessment of QoL using the Short Form Health Survey's 36 parameters in stable euthyroid patients (at least six months) was similar in both groups. The RAI group patients gained more weight (p < 0.005), particularly after 24 months of follow-up. CONCLUSIONS: The use of low doses of MMI is efficient and safe, and offers better outcomes for GO than RAI treatment. Prolonged low doses of MMI may be an alternative choice for relapsed GD patients, particularly for GO patients or for patients who refuse a definitive treatment. PMID- 26414886 TI - Extrinsic factors can mediate resistance to BRAF inhibition in central nervous system melanoma metastases. AB - Here, we retrospectively review imaging of 68 consecutive unselected patients with BRAF V600-mutant metastatic melanoma for organ-specific response and progression on vemurafenib. Complete or partial responses were less often seen in the central nervous system (CNS) (36%) and bone (16%) compared to lung (89%), subcutaneous (83%), spleen (71%), liver (85%) and lymph nodes/soft tissue (83%), P < 0.001. CNS was also the most common site of progression. Based on this, we tested in vitro the efficacy of the BRAF inhibitors PLX4720 and dabrafenib in the presence of cerebrospinal fluid (CSF). Exogenous CSF dramatically reduced cell death in response to both BRAF inhibitors. Effective cell killing was restored by co-administration of a PI-3 kinase inhibitor. We conclude that the efficacy of vemurafenib is variable in different organs with CNS being particularly prone to resistance. Extrinsic factors, such as ERK- and PI3K-activating factors in CSF, may mediate BRAF inhibitor resistance in the CNS. PMID- 26414888 TI - Recent advances in transcatheter aortic valve replacement for high-risk patients. AB - Aortic stenosis is the most common valvular heart disease of old age. Patients with severe aortic stenosis who develop symptoms have a very poor prognosis without valve intervention. Surgical aortic valve replacement has historically been the only treatment option for these patients. However a significant minority are considered inoperable or at high surgical risk and therefore are refused or decline surgery. In recent years, transcatheter aortic valve replacement has emerged as an alternative treatment option in these high-risk patients. The aim of this review is to summarize the current role of transcatheter aortic valve replacement in contemporary clinical practice including recent advances in technological and procedural aspects and then discuss future directions. PMID- 26414887 TI - Detection and proportion of very early dental caries in independent living older adults. AB - BACKGROUND AND OBJECTIVES: Dental caries is an important healthcare challenge in adults over 65 years of age. Integration of oral health screening into non-dental primary care practice may improve access to preventive dental care for vulnerable populations such as the elderly. Such integration would require easy, fast, and accurate early caries detection tools. Primary goal of this study was to evaluate the diagnostic performance of optical coherence tomography (OCT) imaging for detecting very early caries in the elderly living in community-based settings. The International Caries Detection and Assessment System (ICDAS) served as gold standard. Secondary goal of this study was to provide baseline prevalence data of very early caries lesions in independent living adults aged 65+ years. MATERIALS AND METHODS: Seventy-two subjects were recruited from three sites in Southern California: a retirement community, a senior health fair, and a convalescent hospital. Clinical examination was performed using the ICDAS visual criteria and this was followed by OCT imaging. The two-dimensional OCT images (B-scan) were analyzed with simple software. Locations with a log of back-scattered light intensity (BSLI) below 2.9 were scored as sound, and areas equaling or exceeding 2.9 BSLI were considered carious. Diagnostic performance of OCT imaging was compared with ICDAS score. RESULTS: OCT-based diagnosis demonstrated very good sensitivity (95.1%) and good specificity (85.8%). 54.7% of dentate subjects had at least one tooth with very early coronal caries. CONCLUSIONS: Early coronal decay is prevalent in the unrestored pits and fissures of coronal surfaces of teeth in independent living adults aged 65+ years. Though OCT imaging coupled with a simple diagnostic algorithm can accurately detect areas of very early caries in community-based settings, existing devices are expensive and not well suited for use by non-dental health care providers. Simple, inexpensive, fast, and accurate tools for early caries detection by field health care providers working in non-traditional settings are urgently needed to support inter professional dental health management. PMID- 26414889 TI - Nitrate reduction by denitrifying anaerobic methane oxidizing microorganisms can reach a practically useful rate. AB - Methane in biogas has been proposed to be an electron donor to facilitate complete nitrogen removal using denitrifying anaerobic methane oxidizing (DAMO) microorganisms in an anaerobic ammonium oxidation (anammox) reactor, by reducing the nitrate produced. However, the slow growth and the low activity of DAMO microorganisms cast a serious doubt about the practical usefulness of such a process. In this study, a previously established lab-scale membrane biofilm reactor (MBfR), with biofilms consisting of a coculture of DAMO and anammox microorganisms, was operated to answer if the DAMO reactor can achieve a nitrate reduction rate that can potentially be applied for wastewater treatment. Through progressively increasing nitrate and ammonium loading rates to the reactor, a nitrate removal rate of 684 +/- 10 mg-N L(-1) d(-1) was achieved after 453 days of operation. This rate is, to our knowledge, by far the highest reported for DAMO reactors, and far exceeds what is predicted to be required for nitrate removal in a sidestream (5.6-135 mg-N L(-1) d(-1)) or mainstream anammox reactor (3.2-124 mg-N L(-1) d(-1)). Mass balance analysis showed that the nitrite produced by nitrate reduction was jointly reduced by anammox bacteria at a rate of 354 +/- 3 mg-N L(-1) d(-1), accompanied by an ammonium removal rate of 268 +/- 2 mg-N L(-1) d(-1), and DAMO bacteria at a rate of 330 +/- 9 mg-N L(-1) d(-1). This study shows that the nitrate reduction rate achieved by the DAMO process can be high enough for removing nitrate produced by anammox process, which would enable complete nitrogen removal from wastewater. PMID- 26414890 TI - Tracking inorganic foulants irreversibly accumulated on low-pressure membranes for treating surface water. AB - While low-pressure membrane filtration processes (i.e., microfiltration and ultrafiltration) can offer precise filtration than sand filtration, they pose the problem of reduced efficiency due to membrane fouling. Although many studies have examined membrane fouling by organic substances, there is still not enough data available concerning membrane fouling by inorganic substances. The present research investigated changes in the amounts of inorganic components deposited on the surface of membrane filters over time using membrane specimens sampled thirteen times at arbitrary time intervals during pilot testing in order to determine the mechanism by which irreversible fouling by inorganic substances progresses. The experiments showed that the inorganic components that primarily contribute to irreversible fouling vary as filtration continues. It was discovered that, in the initial stage of operation, the main membrane-fouling substance was iron, whereas the primary membrane-fouling substances when operation finished were manganese, calcium, and silica. The amount of iron accumulated on the membrane increased up to the thirtieth day of operation, after which it reached a steady state. After the accumulation of iron became static, subsequent accumulation of manganese was observed. The fact that the removal rates of these inorganic components also increased gradually shows that the size of the exclusion pores of the membrane filter narrows as operation continues. Studying particle size distributions of inorganic components contained in source water revealed that while many iron particles are approximately the same size as membrane pores, the fraction of manganese particles slightly smaller than the pores in diameter was large. From these results, it is surmised that iron particles approximately the same size as the pores block them soon after the start of operation, and as the membrane pores narrow with the development of fouling, they become further blocked by manganese particles approximately the same size as the narrowed pores. Calcium and silica are assumed to accumulate on the membrane due to their cross-linking action and/or complex formation with organic substances such as humic compounds. The present research is the first to clearly show that the inorganic components that contribute to membrane fouling differ according to the stage of membrane fouling progression; the information obtained by this research should enable chemical cleaning or operational control in accordance with the stage of membrane fouling progression. PMID- 26414891 TI - The Association between Obstructive Sleep Apnea on Diabetic Kidney Disease: A Systematic Review and Meta-Analysis. AB - STUDY OBJECTIVE: This systematic review aims to investigate the association between obstructive sleep apnea (OSA) and diabetic kidney disease (DKD). METHODS: MeSH terms and free text searches were performed on MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews from inception to April 2015. Zetoc and OpenGrey databases were queried for grey literature, and lastly, hand searches were carried out. Study selection and quality assessment were conducted by two authors. One author carried out data extraction, which was checked by other authors. The relationships between apneahypopnea index (AHI), oxygen desaturation index (ODI), time spent under 90% oxygen saturation (%TST < 90), and minimum and mean oxygen saturation (O2) on DKD were examined. RESULTS: Two longitudinal and ten cross-sectional studies were included for our narrative synthesis, and seven studies for meta-analysis. Studies that performed multi-variable analysis demonstrated significant associations between OSA (assessed using either apnea hypopnea index or ODI) and DKD in type 2 diabetes mellitus (T2DM). This was confirmed by meta-analysis (pooled OR 1.73, 95% CI: 1.13-2.64). There was some evidence to suggest that %TST < 90 may have an association with DKD. There was insufficient evidence to conclude on the relationship between minimum and mean oxygen saturation on DKD. There was no evidence available on the associations between OSA and other respiratory parameters in type 1 diabetes mellitus populations. CONCLUSIONS: There is moderate evidence that OSA is associated with DKD in patients with T2DM. Large prospective studies with long-term follow up are needed to assess the possible bi-directional mechanisms between OSA and DKD. PMID- 26414892 TI - Cortical Thinning and Altered Cortico-Cortical Structural Covariance of the Default Mode Network in Patients with Persistent Insomnia Symptoms. AB - STUDY OBJECTIVES: Recent studies have suggested that structural abnormalities in insomnia may be linked with alterations in the default-mode network (DMN). This study compared cortical thickness and structural connectivity linked to the DMN in patients with persistent insomnia (PI) and good sleepers (GS). METHODS: The current study used a clinical subsample from the longitudinal community-based Korean Genome and Epidemiology Study (KoGES). Cortical thickness and structural connectivity linked to the DMN in patients with persistent insomnia symptoms (PIS; n = 57) were compared to good sleepers (GS; n = 40). All participants underwent MRI acquisition. Based on literature review, we selected cortical regions corresponding to the DMN. A seed-based structural covariance analysis measured cortical thickness correlation between each seed region of the DMN and other cortical areas. Association of cortical thickness and covariance with sleep quality and neuropsychological assessments were further assessed. RESULTS: Compared to GS, cortical thinning was found in PIS in the anterior cingulate cortex, precentral cortex, and lateral prefrontal cortex. Decreased structural connectivity between anterior and posterior regions of the DMN was observed in the PIS group. Decreased structural covariance within the DMN was associated with higher PSQI scores. Cortical thinning in the lateral frontal lobe was related to poor performance in executive function in PIS. CONCLUSION: Disrupted structural covariance network in PIS might reflect malfunctioning of antero-posterior disconnection of the DMN during the wake to sleep transition that is commonly found during normal sleep. The observed structural network alteration may further implicate commonly observed sustained sleep difficulties and cognitive impairment in insomnia. PMID- 26414893 TI - Guided Online or Face-to-Face Cognitive Behavioral Treatment for Insomnia: A Randomized Wait-List Controlled Trial. AB - STUDY OBJECTIVES: To compare the efficacy of guided online and individual face-to face cognitive behavioral treatment for insomnia (CBT-I) to a wait-list condition. METHODS: A randomized controlled trial comparing three conditions: guided online; face-to-face; wait-list. Posttest measurements were administered to all conditions, along with 3- and 6-mo follow-up assessments to the online and face-to-face conditions. Ninety media-recruited participants meeting the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for insomnia were randomly allocated to either guided online CBT-I (n = 30), individual face-to-face CBT-I (n = 30), or wait-list (n = 30). RESULTS: At post-assessment, the online (Cohen d = 1.2) and face-to-face (Cohen d = 2.3) intervention groups showed significantly larger treatment effects than the wait list group on insomnia severity (insomnia severity index). Large treatment effects were also found for the sleep diary estimates (except for total sleep time), and anxiety and depression measures (for depression only in the face-to face condition). Face-to-face treatment yielded a statistically larger treatment effect (Cohen d = 0.9) on insomnia severity than the online condition at all time points. In addition, a moderate differential effect size favoring face-to-face treatment emerged at the 3- and 6-mo follow-up on all sleep diary estimates. Face to-face treatment further outperformed online treatment on depression and anxiety outcomes. CONCLUSIONS: These data show superior performance of face-to-face treatment relative to online treatment. Yet, our results also suggest that online treatment may offer a potentially cost-effective alternative to and complement face-to-face treatment. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT01955850. COMMENTARY: A commentary on this article appears in this issue on page 13. PMID- 26414894 TI - Rapid Eye Movement Sleep Behavior Disorder in Paraneoplastic Cerebellar Degeneration: Improvement with Immunotherapy. AB - STUDY OBJECTIVES: To report two female patients with paraneoplastic cerebellar degeneration (PCD) related to breast cancer that presented with rapid eye movement-sleep behavior disorder (RBD) and improved sleep symptoms with immunotherapy. METHODS: The two patients were evaluated through clinical scale and polysomnography before and after therapy with intravenous immunoglobulin. RESULTS: RBD was successfully treated with immunotherapy in both patients. Score on the RBD screening questionnaire dropped from 10 to 1 or 0, allied with the normalization of polysomnographic findings. CONCLUSIONS: A marked improvement in RBD after immunotherapy in PCD raises the hypothesis that secondary RBD may be an immune-mediated sleep disorder. PMID- 26414895 TI - Long-Term Cognitive Impairment in Kleine-Levin Syndrome. AB - STUDY OBJECTIVES: In Kleine-Levin syndrome (KLS), episodes of hypersomnia, cognitive, and behavioral disturbances alternate with asymptomatic periods. Because 50% of patients report decreased academic performances, we evaluated their cognitive status during asymptomatic periods, determinants of deficits, and changes during follow-up. METHODS: The cognitive assessment during asymptomatic periods in all consecutive patients with typical KLS and healthy controls included the non-verbal intelligence quotient (Raven Progressive Matrices), the Trail Making Test, the Stroop Color-Word Test, the Wechsler Memory Test, verbal fluencies, the Free and Cued Learning Memory Test, and the Rey-Osterreith Complex Figure. Cognitive status was reevaluated after 0.5 to 2 y in 44 patients. RESULTS: At baseline, compared with the 42 controls, the 122 patients with KLS exhibited lower non-verbal intelligence quotient, speed of processing, attention, and reduced retrieval strategies in episodic memory. Higher episode frequency, shorter episode duration, shorter time since last episode, deeper sleep, and megaphagia during episodes predicted impaired memory. The visuoconstructional abilities and non-verbal memory were intact. After a mean follow-up of 1.7 +/- 1.0 y, the episode frequency decreased from 4.6 +/- 4.8 to 1.7 +/- 1.9/y. The logical reasoning and attention improved, the processing speed remained low, and the retrieval strategies in verbal memory further worsened. CONCLUSIONS: In this field study, one-third of patients with KLS have long-term cognitive deficits affecting retrieval and processing speed. Cognitive function should be systematically tested in patients with KLS, which appears important to help patients in their academic studies. PMID- 26414896 TI - Cerebral Blood Flow Response to Hypercapnia in Children with Obstructive Sleep Apnea Syndrome. AB - STUDY OBJECTIVES: Children with obstructive sleep apnea syndrome (OSAS) often experience periods of hypercapnia during sleep, a potent stimulator of cerebral blood flow (CBF). Considering this hypercapnia exposure during sleep, it is possible that children with OSAS have abnormal CBF responses to hypercapnia even during wakefulness. Therefore, we hypothesized that children with OSAS have blunted CBF response to hypercapnia during wakefulness, compared to snorers and controls. METHODS: CBF changes during hypercapnic ventilatory response (HCVR) were tested in children with OSAS, snorers, and healthy controls using diffuse correlation spectroscopy (DCS). Peak CBF changes with respect to pre-hypercapnic baseline were measured for each group. The study was conducted at an academic pediatric sleep center. RESULTS: Twelve children with OSAS (aged 10.1 +/- 2.5 [mean +/- standard deviation] y, obstructive apnea hypopnea index [AHI] = 9.4 [5.1-15.4] [median, interquartile range] events/hour), eight snorers (11 +/- 3 y, 0.5 [0-1.3] events/hour), and 10 controls (11.4 +/- 2.6 y, 0.3 [0.2-0.4] events/hour) were studied. The fractional CBF change during hypercapnia, normalized to the change in end-tidal carbon dioxide, was significantly higher in controls (9 +/- 1.8 %/mmHg) compared to OSAS (7.1 +/- 1.5, P = 0.023) and snorers (6.7 +/- 1.9, P = 0.025). CONCLUSIONS: Children with OSAS and snorers have blunted CBF response to hypercapnia during wakefulness compared to controls. Noninvasive DCS blood flow measurements of hypercapnic reactivity offer insights into physiopathology of OSAS in children, which could lead to further understanding about the central nervous system complications of OSAS. PMID- 26414897 TI - A Data-Driven Analysis of the Rules Defining Bilateral Leg Movements during Sleep. AB - STUDY OBJECTIVES: The aim of this study was to describe and analyze the association between bilateral leg movements (LMs) during sleep in subjects with restless legs syndrome (RLS), in order to eventually support or challenge the current scoring rules defining bilateral LMs. METHODS: Polysomnographic recordings of 100 untreated patients with RLS (57 women and 43 males, mean age 57 y) were included. In each recording, we selected as reference all LMs that occurred during sleep and that were separated from another ipsilateral LM by at least 10 sec of EMG inactivity. For each reference LM and an evaluation interval from 5 sec before the onset to 5 sec after the offset of the reference LM, we evaluated (1) the presence or absence of contralateral leg movement activity and (2) the distribution of the onset-to-onset and (3) the offset-to-onset differences between bilateral LMs. RESULTS: We selected a mean of 368 (+/- 222 standard deviation [SD]) reference LMs per subject. For 42% (+/- 22%) of the reference LMs no contralateral leg movement activity was observed within the evaluation interval. In 55% (+/- 22%) exactly one and in 3% (+/- 2%) more than one contralateral LM was observed. A further evaluation of events where exactly one contralateral LM was observed showed that in most (1) the two LMs were overlapping (93% +/- 9% SD) and (2) were classified as bilateral according to the World Association of Sleep Medicine and the International Restless Legs Syndrome Study Group (WASM/ IRLSSG) (96% +/- 6% SD) and (3) the American Academy of Sleep Medicine scoring rules (99% +/- 2% SD). Although there was a systematic and statistically significant difference in standard LM indices during sleep based on the two different definitions of bilateral LMs, the size of the difference was not clinically meaningful (maximum individual, absolute difference in LM indices +/- 2.5). In addition, we found that the duration of LMs within bilateral LM pairs was longer compared to monolateral LMs and that the duration of the single LMs in bilateral LM pairs tended to correlate. CONCLUSIONS: The results of this study indicate that the two current standard scoring rules for the definition of bilateral LMs during sleep provide largely corresponding classifications in subjects with RLS and, in a clinical context, can be considered to be equivalent. PMID- 26414898 TI - C-reactive Protein as a Potential Biomarker of Residual Obstructive Sleep Apnea Following Adenotonsillectomy in Children. AB - STUDY OBJECTIVES: Adenotonsillectomy (AT) is first-line treatment for pediatric obstructive sleep apnea (OSA), with most children having improvements in polysomnography (PSG). However, many children have residual OSA following AT as determined through PSG. Identification of a biomarker of residual disease would be clinically meaningful to detect children at risk. We hypothesize serum high sensitivity C-reactive protein (hsCRP), an inflammatory biomarker, is predictive of residual OSA following AT. METHODS: PSG was performed both preoperatively and postoperatively on children undergoing AT for the diagnosis of OSA. HsCRP serum concentrations were determined in all children pre-AT, and in most children post AT. Resolution of OSA after AT was defined by a post-AT apnea-hypopnea index (AHI) < 1.5/h total sleep time (TST). Residual OSA was defined as a post-AT AHI > 5/h TST, which is considered clinically significant. RESULTS: AT significantly improved the AHI from 15.9 +/- 16.4 to 4.1 +/- 5.3/h TST in 182 children (P < 0.001). Of 182 children, residual OSA (post-AT AHI > 5) was seen in 46 children (25%). Among children who had hsCRP levels measured pre- and post-AT (n = 155), mean hsCRP levels pre-AT were 0.98 +/- 1.91 mg/L and were significantly reduced post-AT (0.63 +/- 2.24 mg/dL; P = 0.011). Stratification into post-AT AHI groups corresponding to < 1.5/h TST, 1.5/h TST < AHI < 5/h TST, and AHI > 5/h TST revealed post-AT hsCRP levels of 0.09 +/- 0.12, 0.57 +/- 2.28, and 1.49 +/- 3.34 mg/L with statistical significance emerging comparing residual AHI > 5/h TST compared to post-AT AHI < 1.5/h TST (P = 0.006). Hierarchical multivariate modeling confirmed that pre-AT AHI and post-AT hsCRP levels were most significantly associated with residual OSA. CONCLUSIONS: Even though AT improves OSA in most children, residual OSA is frequent. Assessment of post-AT hsCRP levels emerges as a potentially useful biomarker predicting residual OSA. PMID- 26414899 TI - Serum Vitamin D Is Significantly Inversely Associated with Disease Severity in Caucasian Adults with Obstructive Sleep Apnea Syndrome. AB - STUDY OBJECTIVES: To evaluate vitamin D (25(OH)D) levels in obstructive sleep apnea syndrome (OSAS) and possible relationships to OSAS severity, sleepiness, lung function, nocturnal heart rate (HR), and body composition. We also aimed to compare the 25(OH)D status of a subset of OSAS patients compared to controls matched for important determinants of both OSAS and vitamin D deficiency (VDD). METHODS: This was a cross-sectional study conducted at an urban, clinical sleep medicine outpatient center. We recruited newly diagnosed, Caucasian adults who had recently undergone nocturnal polysomnography. We compared body mass index (BMI), body composition (bioelectrical impedance analysis), neck circumference, sleepiness (Epworth Sleepiness Scale), lung function, and vitamin D status (serum 25-hydrpoxyvitamin D (25(OH)D) across OSAS severity categories and non-OSAS subjects. Next, using a case-control design, we compared measures of serum 25(OH)D from OSAS cases to non-OSAS controls who were matched for age, gender, skin pigmentation, sleepiness, season, and BMI. RESULTS: 106 adults (77 male; median age = 54.5; median BMI = 34.3 kg/m(2)) resident in Dublin, Ireland (latitude 53 degrees N) were recruited and categorized as non-OSAS or mild/moderate/severe OSAS. 98% of OSAS cases had insufficient 25(OH)D (< 75 nmol/L), including 72% with VDD (< 50 nmol/L). 25(OH)D levels decreased with OSAS severity (P = 0.003). 25(OH)D was inversely correlated with BMI, percent body fat, AHI, and nocturnal HR. Subsequent multivariate regression analysis revealed that 25(OH)D was independently associated with both AHI (P = 0.016) and nocturnal HR (P = 0.0419). Our separate case-control study revealed that 25(OH)D was significantly lower in OSAS cases than matched, non-OSAS subjects (P = 0.001). CONCLUSIONS: We observed widespread vitamin D deficiency and insufficiency in a Caucasian, OSAS population. There were significant, independent, inverse relationships between 25(OH)D and AHI as well as nocturnal HR, a known cardiovascular risk factor. Further, 25(OH)D was significantly lower in OSAS cases compared to matched, non-OSAS subjects. We provide evidence that 25(OH)D and OSAS are related, but the role, if any, of replenishment has not been investigated. PMID- 26414900 TI - Variability in Cumulative Habitual Sleep Duration Predicts Waking Functional Connectivity. AB - STUDY OBJECTIVES: We examined whether interindividual differences in habitual sleep patterns, quantified as the cumulative habitual total sleep time (cTST) over a 2-w period, were reflected in waking measurements of intranetwork and internetwork functional connectivity (FC) between major nodes of three intrinsically connected networks (ICNs): default mode network (DMN), salience network (SN), and central executive network (CEN). METHODS: Resting state functional magnetic resonance imaging (fMRI) study using seed-based FC analysis combined with 14-d wrist actigraphy, sleep diaries, and subjective questionnaires (N = 33 healthy adults, mean age 34.3, standard deviation +/- 11.6 y). Data were statistically analyzed using multiple linear regression. Fourteen consecutive days of wrist actigraphy in participant's home environment and fMRI scanning on day 14 at the Birmingham University Imaging Centre. Seed-based FC analysis on ICNs from resting-state fMRI data and multiple linear regression analysis performed for each ICN seed and target. cTST was used to predict FC (controlling for age). RESULTS: cTST was specific predictor of intranetwork FC when the mesial prefrontal cortex (MPFC) region of the DMN was used as a seed for FC, with a positive correlation between FC and cTST observed. No significant relationship between FC and cTST was seen for any pair of nodes not including the MPFC. Internetwork FC between the DMN (MPFC) and SN (right anterior insula) was also predicted by cTST, with a negative correlation observed between FC and cTST. CONCLUSIONS: This study improves understanding of the relationship between intranetwork and internetwork functional connectivity of intrinsically connected networks (ICNs) in relation to habitual sleep quality and duration. The cumulative amount of sleep that participants achieved over a 14-d period was significantly predictive of intranetwork and inter-network functional connectivity of ICNs, an observation that may underlie the link between sleep status and cognitive performance. PMID- 26414901 TI - Invariant Natural Killer T Cell Deficiency and Functional Impairment in Sleep Apnea: Links to Cancer Comorbidity. AB - STUDY OBJECTIVES: Emerging evidence links obstructive sleep apnea (OSA) with increased cancer incidence and mortality. Invariant natural killer T (iNKT) cells play an important role in cancer immunity. We hypothesized that patients with OSA have low number of circulating invariant natural killer T (iNKT) cells, which may also be functionally impaired. This study aims to evaluate the frequency of circulating iNKT cells in OSA. DESIGN: We evaluated the frequency of circulating iNKT cells by flow cytometry in 33 snorers being assessed for possible OSA. Using iNKT cell lines, we also evaluated the effect of exposure to hypoxia over 24 hours on apoptosis, cytotoxicity, and cytokine production. SETTING: Teaching hospital based sleep unit and research laboratory. PATIENTS: Thirty-three snorers were evaluated: 9 with no OSA (apnea-hypopnea frequency [AHI] < 5/h), 12 with mild-moderate OSA (AHI 5-30) and 12 with severe OSA (AHI > 30). MEASUREMENTS AND RESULTS: Patients with severe OSA had considerably fewer iNKT cells (0.18%) compared to patients with mild-moderate (0.24%) or no OSA (0.35%), P = 0.0026. The frequency of iNKT cells correlated negatively with apnea-hypopnea index (r = 0.58, P = 0.001), oxygen desaturation index (r = -0.58, P = 0.0003), and SpO2% < 90% (r = -0.5407, P = 0.005). The frequency of iNKT cells increased following 12 months of nCPAP therapy (P = 0.015). Hypoxia resulted in increased apoptosis (P = 0.016) and impaired cytotoxicity (P = 0.035). CONCLUSION: Patients with obstructive sleep apnea (OSA) have significantly reduced levels of circulating invariant natural killer T (iNKT) cells and hypoxia leads to impaired iNKT cell function. These observations may partly explain the increased cancer risk reported in patients with OSA. PMID- 26414902 TI - End-Tidal Carbon Dioxide Measurement during Pediatric Polysomnography: Signal Quality, Association with Apnea Severity, and Prediction of Neurobehavioral Outcomes. AB - STUDY OBJECTIVES: To identify the role of end-tidal carbon dioxide (EtCO2) monitoring during polysomnography in evaluation of children with obstructive sleep apnea syndrome (OSAS), including the correlation of EtCO2 with other measures of OSAS and prediction of changes in cognition and behavior after adenotonsillectomy. DESIGN: Analysis of screening and endpoint data from the Childhood Adenotonsillectomy Trial, a randomized, controlled, multicenter study comparing early adenotonsillectomy (eAT) to watchful waiting/supportive care (WWSC) in children with OSAS. SETTING: Multisite clinical referral settings. PARTICIPANTS: Children, ages 5.0 to 9.9 y with suspected sleep apnea. INTERVENTIONS: eAT or WWSC. MEASUREMENTS AND RESULTS: Quality EtCO2 waveforms were present for >= 75% of total sleep time (TST) in 876 of 960 (91.3%) screening polysomnograms. Among the 322 children who were randomized, 55 (17%) met pediatric criteria for hypoventilation. The mean TST with EtCO2 > 50 mmHg was modestly correlated with apnea-hypopnea index (AHI) (r = 0.33; P < 0.0001) and with oxygen saturation <= 92% (r = 0.26; P < 0.0001). After adjusting for AHI, obesity, and other factors, EtCO2 > 50 mmHg was higher in African American children than others. The TST with EtCO2 > 50 mmHg decreased significantly more after eAT than WWSC. In adjusted analyses, baseline TST with EtCO2 > 50 mmHg did not predict postoperative changes in cognitive and behavioral measurements. CONCLUSIONS: Among children with suspected obstructive sleep apnea syndrome, overnight end-tidal carbon dioxide (EtCO2) levels are weakly to modestly correlated with other polysomnographic indices and therefore provide independent information on hypoventilation. EtCO2 levels improve with adenotonsillectomy but are not as responsive as AHI and do not provide independent prediction of cognitive or behavioral response to surgery. CLINICAL TRIAL REGISTRATION: Childhood Adenotonsillectomy Study for Children with OSAS (CHAT). ClinicalTrials.gov Identifier #NCT00560859. PMID- 26414903 TI - Impaired Sleep Predicts Cognitive Decline in Old People: Findings from the Prospective KORA Age Study. AB - STUDY OBJECTIVES: To investigate the association between sleep-related characteristics and cognitive change over 3 years of follow up in an aged population. METHODS: Sleep characteristics and covariates were assessed at baseline in a standardized interview and clinical examination of the population based KORA Age Study (n = 740, mean age = 75 years). Cognitive score (determined by telephone interview for cognitive status, TICS-m) was recorded at baseline and 3 years later. RESULTS: At baseline, 82.83% (n = 613) of participants had normal cognitive status, 13.51% (n = 100) were classified with mild cognitive impairment (MCI), and 3.64% (n = 27) with probable dementia. The effect of three distinct patterns of poor sleep (difficulties initiating [DIS] or maintaining sleep [DMS], daytime sleepiness [DS] or sleep duration) were considered on a change in cognitive score with adjustments for potential confounders in generalized linear regression models. Cognitive decline was more pronounced in individuals with DMS compared to those with no DMS (beta = 1.33, 95% CI = 0.41-2.24, P < 0.001). However, the predictive power of DMS was only significant in individuals with normal cognition and not impaired subjects at baseline. Prolonged sleep duration increased the risk for cognitive decline in cognitively impaired elderly (beta = 1.86, 95% CI = 0.15-3.57, P = 0.03). Other sleep characteristics (DIS and DS) were not significantly associated with cognitive decline. CONCLUSIONS: DMS and long sleep duration were associated with cognitive decline in normal and cognitively impaired elderly, respectively. The identification of impaired sleep quality may offer intervention strategies to deter cognitive decline in the elderly with normal cognitive function. PMID- 26414904 TI - CD10, BCL6, and MUM1 expression in diffuse large B-cell lymphoma on FNA samples. AB - BACKGROUND: Gene expression profiling has divided diffuse large B-cell lymphoma (DLBCL) into 2 main subgroups: germinal center B (GCB) and non-GCB type. This classification is reproducible by immunohistochemistry using specific antibodies such as CD10, B-cell lymphoma 6 (BCL6), and multiple myeloma oncogene 1 (MUM1). Fine-needle aspiration (FNA) plays an important role in the diagnosis of non Hodgkin lymphoma, and in some cases FNA may be the only available pathological specimen. The objectives of the current study were to evaluate CD10, BCL6, and MUM1 immunostaining on FNA samples by testing the CD10, BCL6, and MUM1 algorithm on both FNA cell blocks (CB) and conventional smears (CS), evaluating differences in CB and CS immunocytochemical (ICC) performance, and comparing results with histological data. METHODS: Thirty-eight consecutive DLBCL cases diagnosed by FNA were studied. Additional passes were used to prepare CB in 22 cases and CS in 16 cases; the corresponding sections and smears were immunostained using CD10, BCL6, and MUM1 in all cases. The data obtained were compared with histological immunostaining in 24 cases. RESULTS: ICC was successful in 33 cases (18 CB and 15 CS) and not evaluable in 5 cases (4 CB and 1 CS). The CD10-BCL6-MUM1 algorithm subclassified DLBCL as GCB (9 cases) and non-GCB (24 cases). ICC data were confirmed on histologic staining in 24 cases. CONCLUSIONS: CD10, BCL6, and MUM1 ICC staining can be performed on FNA samples. The results herein prove it is reliable both on CB and CS, and is equally effective and comparable to immunohistochemistry data. PMID- 26414905 TI - Asunaprevir (BMS-650032) for the treatment of hepatitis C virus. AB - Asunaprevir, a second-generation NS3 protease inhibitor of hepatitis C virus (HCV), exhibits strong antiviral activity against HCV genotypes 1 and 4, but relatively weak activity against genotypes 2 and 3. For chronic HCV infection, asunaprevir with daclatasvir as an interferon-free dual treatment achieves a sustained virologic response of nearly 90% in genotype 1b, and a triple regimen with beclabuvir achieves an sustained virologic response >90%. Asunaprevir and daclatasvir dual treatment can be safely and effectively administered to liver transplant recipients with recurrent HCV. The major drawback of asunaprevir is its low threshold to resistance, which can be overcome by combining it with other direct-acting antivirals. Further studies of asunaprevir in combination with other direct-acting antivirals for the treatment of patients with HCV genotypes 1 or 4 and renal impairment or end-stage renal disease under hemodialysis, HIV coinfection and liver and/or kidney transplant recipients are warranted. PMID- 26414907 TI - Economic assessment of FEC-based targeted selective drenching in horses. AB - In the face of an increased prevalence of drug-resistant cyathostomin populations, a targeted selective treatment (TST) strategy based on Faecal Egg Counts (FECs) has been proposed as an alternative management strategy. However, associated costs may be a barrier to the uptake of this strategy. Our study aims to provide an economic assessment of FEC-based TST. FECs were determined in a Welsh pony herd thrice a year from 2010 to 2014. This database was used to explore the impact of FEC price, sampling strategy (individual or pooled) and labour-associated costs. Drug price was set at the cheapest level, hence providing a conservative framework to determine the maximum viable FEC price in the context of a cost-driven horse industry. The maximum viable FEC price for a cost-efficient individual based strategy was determined by an in silico bootstrap approach consisting of randomly sampling 1000 virtual pony herds of various sizes (1 to 100 ponies) from the available database and estimating the associated costs (FEC price ranging from ? 1 to ? 10, anthelmintic costs and labour-associated costs). The costs and benefits of the pooling strategy that consists of basing the decision to treat on group FEC values were also investigated. This is thought to reduce FEC-based costs but may result in highly infected individuals being left undrenched, i.e. in false-negatives, as a result of FEC overdispersion. For various pool-sizes (1-20 ponies) and various cut-off thresholds (50-200 eggs/g), we sampled 1000 pony herds in silico to estimate the associated costs and determine the number of positive ponies within a negative pool. Following these simulations, pool-based FECs of various sizes were performed on 40 ponies to compare predictions with real data. Within 4 years, anthelmintic costs were cut by 80%, albeit with free FECs. In silico estimations suggested that an individual FEC-based TST would not be cost-efficient in this context for an FEC price above ? 5. With a pooled FEC strategy, the proportion of false-negatives never exceeded 15% of the pool size. The combination of a 14-pony pool and a cut-off value of 150 eggs/g minimized total costs while keeping the number of false negatives to a reasonable level. Real data obtained from infected ponies however, suggested that pool size should not exceed 10 individuals, since the inhomogeneous mixing of faeces of larger pools probably reduced the correlation between average pooled FECs and the mean of individual FECs. Our study provides an economic framework that could be valuable for emphasizing the use of FEC-based approaches in the field. PMID- 26414906 TI - Detection of Trypanosoma vivax using PCR and LAMP during aparasitemic periods. AB - Trypanosoma vivax affects cattle herds in Africa and Americas and has been spreading rapidly in Brazil, through introduction of animals with subclinical infections and without apparent parasitemia, which makes its diagnosis challenging. PCR and LAMP are effective in detecting the presence of T. vivax DNA in situations of low parasitemia. LAMP is simpler and faster technique than PCR, and can be performed in the field, with limited resources. In this study, the capacities of conventional PCR and LAMP for detecting T. vivax in bovine blood samples classified as aparasitemic were evaluated. The capacity of conventional PCR (56.25%) for detecting positive samples was lower than that of LAMP (93.73%). This may influence the choice of screening tests for cattle herds infected with T. vivax. PMID- 26414908 TI - A Proposed Grading System to Standardize the Description of Renal Papillary Appearance at the Time of Endoscopy in Patients with Nephrolithiasis. AB - BACKGROUND AND PURPOSE: The appearance of the renal papillae in patients with nephrolithiasis can be quite variable and can range from entirely healthy to markedly diseased. The implications of such findings remain unknown. One potential reason is the lack of a standardized system to describe such features. We propose a novel grading scale to describe papillary appearance at the time of renal endoscopy. METHODS: Comprehensive endoscopic renal assessment and mapping were performed on more than 300 patients with nephrolithiasis. Recurring abnormal papillary characteristics were identified and quantified based on degree of severity. RESULTS: Four unique papillary features were chosen for inclusion in the PPLA scoring system- ductal Plugging, Pitting, Loss of contour, and Amount of Randall's plaque. Unique scores are calculated for individual papillae based on reference examples. CONCLUSIONS: The description and study of renal papillary appearance in stone formers have considerable potential as both a clinical and research tool; however, a standardized grading system is necessary before using it for these purposes. PMID- 26414910 TI - Enantioselective Synthesis of Hemiaminals via Pd-Catalyzed C-N Coupling with Chiral Bisphosphine Mono-oxides. AB - A novel approach to hemiaminal synthesis via palladium-catalyzed C-N coupling with chiral bisphosphine mono-oxides is described. This efficient new method exhibits a broad scope, provides a highly efficient synthesis of HCV drug candidate elbasvir, and has been applied to the synthesis of chiral N,N-acetals. PMID- 26414911 TI - Extraction Time of Kidneys From Deceased Donors and Impact on Outcomes. AB - Cold ischemia time (from flush to out-of-ice) and warm ischemia time (from out-of ice to reperfusion) are known to impact delayed graft function (DGF) rates and long-term allograft survival following deceased donor kidney transplantation. We propose an additional ischemia time, extraction time, beginning with aortic cross clamp and perfusion/cooling of the kidneys, and ending with removal of the kidneys and placement on ice on the backtable. During this time the kidneys rewarm, suffering an additional ischemic insult, which may impair transplant function. We measured extraction times of 576 kidneys recovered and transplanted locally between January 2006 and December 2008, then linked to Scientific Registry of Transplant Recipients (SRTR) data for outcomes. Extraction time ranged from 14 to 123 min, with a mean of 44.7 min. In SRTR-adjusted analyses, longer extraction time and DGF were statistically associated (odds ratio [OR] = 1.19 per 5 min beyond 60 min, 95% confidence interval [CI] 1.02-1.39, p = 0.03). Up to 60 min of extraction time, DGF incidence was 27.8%; by 120 min it doubled to nearly 60%. Although not statistically significant (OR = 1.19, 95% CI 0.96 1.49, p = 0.11), primary nonfunction rate also rose dramatically to nearly 20% by 120 min extraction time. Extraction time is a novel and important factor to consider when evaluating a deceased donor kidney offer and when strategizing personnel for kidney recovery. PMID- 26414909 TI - Different Bla-g T cell antigens dominate responses in asthma versus rhinitis subjects. AB - BACKGROUND AND OBJECTIVE: The allergenicity of several German cockroach (Bla-g) antigens at the level of IgE responses is well established. However, less is known about the specificity of CD4+ TH responses, and whether differences exist in associated magnitude or cytokine profiles as a function of disease severity. METHODS: Proteomic and transcriptomic techniques were used to identify novel antigens recognized by allergen-specific T cells. To characterize different TH functionalities of allergen-specific T cells, ELISPOT assays with sets of overlapping peptides covering the sequences of known allergens and novel antigens were employed to measure release of IL-5, IFNgamma, IL-10, IL-17 and IL-21. RESULTS: Using these techniques, we characterized TH responses in a cohort of adult Bla-g-sensitized subjects, either with (n = 55) or without (n = 17) asthma, and nonsensitized controls (n = 20). T cell responses were detected for ten known Bla-g allergens and an additional ten novel Bla-g antigens, representing in total a 5-fold increase in the number of antigens demonstrated to be targeted by allergen-specific T cells. Responses of sensitized individuals regardless of asthma status were predominantly TH 2, but higher in patients with diagnosed asthma. In asthmatic subjects, Bla-g 5, 9 and 11 were immunodominant, while, in contrast, nonasthmatic-sensitized subjects responded mostly to Bla-g 5 and 4 and the novel antigen NBGA5. CONCLUSIONS: Asthmatic and nonasthmatic cockroach sensitized individuals exhibit similar TH 2-polarized responses. Compared with nonasthmatics, however, asthmatic individuals have responses of higher magnitude and different allergen specificity. PMID- 26414913 TI - Functional hepatocellular regeneration measured by hepatobiliary scintigraphy, functional regeneration or functional hepatocytes? PMID- 26414914 TI - The origin of anisotropy and high density of states in the electronic structure of Cr2GeC by means of polarized soft x-ray spectroscopy and ab initio calculations. AB - The anisotropy in the electronic structure of the inherently nanolaminated ternary phase Cr2GeC is investigated by bulk-sensitive and element selective soft x-ray absorption/emission spectroscopy. The angle-resolved absorption/emission measurements reveal differences between the in-plane and out-of-plane bonding at the (0001) interfaces of Cr2GeC. The Cr L(2, 3), C K, and Ge M1, M(2, 3) emission spectra are interpreted with first-principles density-functional theory (DFT) including core-to-valence dipole transition matrix elements. For the Ge 4s states, the x-ray emission measurements reveal two orders of magnitude higher intensity at the Fermi level than DFT within the General Gradient Approximation (GGA) predicts. We provide direct evidence of anisotropy in the electronic structure and the orbital occupation that should affect the thermal expansion coefficient and transport properties. As shown in this work, hybridization and redistribution of intensity from the shallow 3d core levels to the 4s valence band explain the large Ge density of states at the Fermi level. PMID- 26414912 TI - Dose Frequency Ranging Pharmacokinetic Study of Tenofovir-Emtricitabine After Directly Observed Dosing in Healthy Volunteers to Establish Adherence Benchmarks (HPTN 066). AB - Oral preexposure prophylaxis (PrEP) trials report disparate efficacy attributed to variable adherence. HPTN 066 was conducted to establish objective, quantitative benchmarks for discrete, regular levels of adherence using directly observed dosing of tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC). Healthy, HIV-uninfected men and women were randomized to one of four oral regimens of fixed-dose TDF 300 mg/FTC 200 mg tablet for 5 weeks with all doses observed: one tablet weekly (one/week), one tablet twice weekly (two/week), two tablets twice weekly (four/week), or one tablet daily (seven/week). Trough serum TFV and FTC, peripheral blood mononuclear cell (PBMC), and CD4(+) TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) concentrations were determined throughout dosing and 2 weeks after the last dose. Rectosigmoidal, semen, and cervicovaginal samples were collected for drug assessment at end of dosing and 2 weeks later in a subset of participants. The 49 enrolled participants tolerated the regimens well. All regimens achieved steady-state concentrations by the second dose for serum TFV/FTC and by 7 days for PBMC TFV-DP/FTC-TP. Steady-state median TFV-DP predose concentrations demonstrated dose proportionality: one/week 1.6 fmol/10(6) PBMCs, two/week 9.1, four/week 18.8, seven/week, 36.3. Further, TFV-DP was consistently quantifiable 2 weeks after the last dose for the >=4/week regimens. Adherence benchmarks were identified using receiver operating characteristic curves, which had areas under the curve >=0.93 for all analytes in serum and PBMCs. Intersubject and intrasubject coefficients of variation (%CV) ranged from 33% to 63% and 14% to 34%, respectively, for all analytes in serum and PBMCs. Steady-state PBMC TFV-DP was established earlier and at lower concentrations than predicted and was the only analyte demonstrating predose concentration dose proportionality. Steady-state daily dosing serum TFV and PBMC TFV-DP was consistent with highly effective PrEP clinical trials. HPTN 066 provides adherence benchmarks for oral TFV/FTC regimens to assist interpreting study outcomes. PMID- 26414915 TI - Biomimetic hybrid porous scaffolds immobilized with platelet derived growth factor-BB promote cellularization and vascularization in tissue engineering. AB - Development of hybrid scaffolds with synergistic combination of growth factor is a promising approach to promote early in vivo wound repair and tissue regeneration. Here, we show the rapid wound healing in Wistar albino rats using biomimetic collagen-poly(dialdehyde) guar gum based hybrid porous scaffolds covalently immobilized with platelet derived growth factor-BB. The immobilized platelet derived growth factor in the hybrid scaffolds not only enhance the total protein, collagen, hexosamine, and uronic acid contents in the granulation tissue but also provide stronger tissues. The wound closure analysis reveal that the complete epithelialization period is 15.4 +/- 0.9 days for collagen poly(dialdehyde) guar gum-platelet derived growth factor hybrid scaffolds, whereas it is significantly higher for control, collagen, collagen- poly(dialdehyde) guar gum and povidine-iodine treated groups. Further, the histological evaluation shows that the immobilized platelet derived growth factor in the hybrid scaffolds induced a more robust cellular and vascular response in the implanted site. Hence, we demonstrate that the collagen-poly(dialdehyde) guar gum hybrid scaffolds loaded with platelet derived growth factor stimulates chemotactic effects in the implanted site to promote rapid tissue regeneration and wound repair without the assistance of antibacterial agents. PMID- 26414918 TI - Summaries for Patients. Evaluation of Patients With Suspected Acute Pulmonary Embolism: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians. PMID- 26414916 TI - Prospective Study on Noninvasive Assessment of Intracranial Pressure in Traumatic Brain-Injured Patients: Comparison of Four Methods. AB - Elevation of intracranial pressure (ICP) may occur in many diseases, and therefore the ability to measure it noninvasively would be useful. Flow velocity signals from transcranial Doppler (TCD) have been used to estimate ICP; however, the relative accuracy of these methods is unclear. This study aimed to compare four previously described TCD-based methods with directly measured ICP in a prospective cohort of traumatic brain-injured patients. Noninvasive ICP (nICP) was obtained using the following methods: 1) a mathematical "black-box" model based on interaction between TCD and arterial blood pressure (nICP_BB); 2) based on diastolic flow velocity (nICP_FVd); 3) based on critical closing pressure (nICP_CrCP); and 4) based on TCD-derived pulsatility index (nICP_PI). In time domain, for recordings including spontaneous changes in ICP greater than 7 mm Hg, nICP_PI showed the best correlation with measured ICP (R = 0.61). Considering every TCD recording as an independent event, nICP_BB generally showed to be the best estimator of measured ICP (R = 0.39; p < 0.05; 95% confidence interval [CI] = 9.94 mm Hg; area under the curve [AUC] = 0.66; p < 0.05). For nICP_FVd, although it presented similar correlation coefficient to nICP_BB and marginally better AUC (0.70; p < 0.05), it demonstrated a greater 95% CI for prediction of ICP (14.62 mm Hg). nICP_CrCP presented a moderate correlation coefficient (R = 0.35; p < 0.05) and similar 95% CI to nICP_BB (9.19 mm Hg), but failed to distinguish between normal and raised ICP (AUC = 0.64; p > 0.05). nICP_PI was not related to measured ICP using any of the above statistical indicators. We also introduced a new estimator (nICP_Av) based on the average of three methods (nICP_BB, nICP_FVd, and nICP_CrCP), which overall presented improved statistical indicators (R = 0.47; p < 0.05; 95% CI = 9.17 mm Hg; AUC = 0.73; p < 0.05). nICP_PI appeared to reflect changes in ICP in time most accurately. nICP_BB was the best estimator for ICP "as a number." nICP_Av demonstrated to improve the accuracy of measured ICP estimation. PMID- 26414917 TI - An Arthritis-Suppressive and Treg Cell-Inducing CD4+ T Cell Epitope Is Functional in the Context of HLA-Restricted T Cell Responses. AB - OBJECTIVE: We previously showed that mycobacterial Hsp70-derived peptide B29 induced B29-specific Treg cells that suppressed experimental arthritis in mice via cross-recognition of their mammalian Hsp70 homologs. The aim of the current study was to characterize B29 binding and specific CD4+ T cell responses in the context of human major histocompatibility complex (MHC) molecules. METHODS: Competitive binding assays were performed to examine binding of peptide B29 and its mammalian homologs to HLA molecules. The effect of B29 immunization in HLA DQ8-transgenic mice with proteoglycan-induced arthritis was assessed, followed by ex vivo restimulation with B29 to examine the T cell response. Human peripheral blood mononuclear cells were used to investigate the presence of B29-specific T cells with immunoregulatory potential. RESULTS: The binding affinity of the B29 peptide was high to moderate for multiple HLA-DR and HLA-DQ molecules, including those highly associated with rheumatoid arthritis. This binding was considered to be functional, because B29 immunization resulted in the suppression of arthritis and T cell responses in HLA-DQ8-transgenic mice. In humans, we demonstrated the presence and expansion of B29-specific CD4+ T cells, which were cross-reactive with the mammalian homologs. Using HLA-DR4+ tetramers specific for B29 or the mammalian homolog mB29b, we showed expansion of cross-reactive T cells, especially the human FoxP3+ CD4+CD25+ T cell population, after in vitro stimulation with B29. CONCLUSION: These results demonstrated a conserved fine specificity and functionality of B29-induced Treg cell responses in the context of the human MHC. Based on these findings, a path for translation of the experimental findings for B29 into a clinical immunomodulatory therapeutic approach is within reach. PMID- 26414919 TI - A Novel and Simple Modification for Management of Distal Ureter During Laparoscopic Nephroureterectomy Without Patient Repositioning: A Bulldog Clamp Technique and Description of Modified Port Placement. AB - BACKGROUND AND PURPOSE: To describe a novel and pure laparoscopic approach using a custom-made bulldog clamp with modified port placement for management of distal ureter during laparoscopic nephroureterectomy. PATIENTS AND METHODS: Between October 2013 and December 2014, 31 patients found to have upper tract urothelial carcinoma were treated using this technique. After finishing a standard laparoscopic transperitoneal nephrectomy in a 45 degrees to 60 degrees recumbent position, an additional 12-mm trocar was inserted at the lower abdomen to allow the surgeon to continue dissecting the ureter caudally toward the bladder wall without repositioning the patient. The intramural ureter was separated from the surrounding detrusor muscle and down to the bladder mucosa, until a tent-shaped bladder cuff and intramural ureter could be formed by retraction in the superior and lateral directions. Then, a custom-made laparoscopic bulldog clamp was placed at the bottom of the tent-shaped structure to prevent urine spillage, and the bladder was closed by two-layer running closure using a barbed suture. RESULTS: All surgeries were completed uneventfully. The mean operative time and estimated blood loss were 146.6 minutes and 47.3 mL, respectively. The median duration of the postoperative hospital stay was 6 days. No complications were noted. There were no positive margins in any specimen. No patients experienced stone formation or local or bladder recurrence during the 10.5-month follow-up period. CONCLUSIONS: Our novel technique fully replicates the open excision technique and conforms to the strictest oncologic principles while avoiding patient repositioning and the use of staplers (EndoGIA or Hemolock) to prevent stone formation. PMID- 26414921 TI - When tackling student debt, information, collaboration is key. PMID- 26414922 TI - Wombs in labour: Transnational commercial surrogacy in India. PMID- 26414920 TI - The economic burden of chronic obstructive pulmonary disease from 2004 to 2013. AB - OBJECTIVES: This study examines the epidemiology and economic impact of chronic obstructive pulmonary disease (COPD) at a nationwide level in South Korea. METHODS: This retrospective analysis used the societal cost-of-illness framework, consisting of direct medical costs, direct non-medical costs, and indirect costs. In order to analyze the societal costs of patients with COPD, this study used a data mining and a macro-costing method on data from a South Korean national-level health survey and a national health insurance claims database from 2004-2013. RESULTS: The total societal cost of COPD in 2013 was estimated to be $439.9 million for 1,419,914 patients. The direct medical cost for COPD was $214.3 million, which included a hospitalization cost of $96.3 million, an outpatient cost of $76.4 million, and a pharmaceutical cost of $41.6 million. The direct non medical cost was estimated at $43.5 million. The indirect overall cost associated with the morbidity and mortality of COPD was $182.2 million in 2013. CONCLUSIONS: This study showed that COPD has a major effect on healthcare costs, particularly direct medical costs. Thus, appropriate long-term interventions are recommended to lower the economic burden of COPD in South Korea. PMID- 26414923 TI - Pharmacological approaches in celiac disease. AB - Celiac disease is an autoimmune enteropathy triggered by the ingestion of gluten, characterized by immune responses toward gluten constituents and the autoantigen transglutaminase 2. The only current treatment available for celiac disease is a gluten-free diet, however there are a plethora of therapies in development for the treatment of celiac disease (e.g. vaccine), management of symptoms while consuming gluten (e.g. Necator americanus) or adjuvant therapies in conjunction with the gluten-free diet (e.g. larazotide acetate). Current approaches in development target barrier function, immune responses, detoxifying gluten or sequestering gluten. Developing therapies include those targeting environmental factors, such as the microbiota or proteases. PMID- 26414924 TI - The rare earth elements in municipal solid waste incinerators ash and promising tools for their prospecting. AB - Bottom and fly ashes from Municipal Solid Waste Incinerators (MSWI) are hazardous products that present concern for their safe management. An attractive option to reduce their impact both on the environment and the financial commitment is turning MSWI ashes into secondary raw materials. In this study we present the REE content and distribution of bottom and fly ashes from MSWI after a highly effective digestion method and samples analysis by ICP-MS. The chondrite normalised REE patterns of MSWI bottom and fly ash are comparable with that of crustal averages, suggesting a main geogenic source. Deviations from typical crustal pattern (e.g., Eu, Tb) disclose a contribution of likely anthropogenic provenance. The correlation with major elements indicates possible sources for REE and facilitates a preliminary resource assessment. Moreover, magnetic susceptibility measurements can be a useful prospecting method in urban ores made of MSWI ashes. The relationship between REE and some influencing parameters (e.g., Pricing Influence Factor) emphasises the importance of MSWI ash as alternative source of REE and the need of further efforts for REE recovery and purification from low concentrations but high flows waste. PMID- 26414925 TI - In Vivo toxicological assessment of biologically synthesized silver nanoparticles in adult Zebrafish (Danio rerio). AB - The present study examines the deleterious effect of biologically synthesized silver nanoparticles in adult zebrafish. Silver nanoparticles (AgNPs) used in the study were synthesized by treating AgNO3 with aqueous leaves extract of Malva crispa Linn., a medicinal herb as source of reductants. LC50 concentration of AgNPs at 96 h was observed as 142.2 MUg/l. In order to explore the underlying toxicity mechanisms of AgNPs, half of the LC50 concentration (71.1 MUg/l) was exposed to adult zebrafish for 14 days. Cytological changes and intrahepatic localization of AgNPs were observed in gills and liver tissues respectively, and the results concluded a possible sign for oxidative stress. In addition to oxidative stress the genotoxic effect was observed in peripheral blood cells like presence of micronuclei, nuclear abnormalities and also loss in cell contact with irregular shape was observed in liver parenchyma cells. Hence to confirm the oxidative stress and genotoxic effects the mRNA expression of stress related (MTF 1, HSP70) and immune response related (TLR4, NFKB, IL1B, CEBP, TRF, TLR22) genes were analyzed in liver tissues and the results clearly concluded that the plant extract mediated synthesis of AgNPs leads to oxidative stress and immunotoxicity in adult zebrafish. PMID- 26414926 TI - Size-dependent atmospheric deposition and inhalation exposure of particle-bound organophosphate flame retardants. AB - Atmospheric size-fractionated particles were collected at different heights in an e-waste recycling zone (QY) and urban Guangzhou (GZ), China and analyzed for organophosphate flame retardants (OPFRs). The total air concentrations of eight OPFRs were 130+/-130 and 138+/-127 ng m(-3) in QY and GZ, respectively. Compositional profiles of chlorinated OPFRs were different between QY and GZ, but the size distribution patterns of all OPFRs were not significantly different at different heights. Estimated atmospheric deposition fluxes of OPFRs were 51+/-67 and 55+/-13 MUg m(-2) d(-1) in QY and GZ, respectively, and the coarse particles (Dp>1.8 MUm) dominated both the dry and wet deposition fluxes. Moreover, not all particle-bound OPFRs were inhalable and deposited in the human respiratory tract. The calculated inhalation doses of OPFRs were much lower than the reference doses, suggesting that potential health risk due to inhalation exposure to particle-bound OPFRs in the e-waste recycling zone and urban site was low. PMID- 26414927 TI - Enhanced catalytic activity over MIL-100(Fe) loaded ceria catalysts for the selective catalytic reduction of NOx with NH3 at low temperature. AB - The development of catalysts for selective catalytic reduction (SCR) reactions that are highly active at low temperatures and show good resistance to SO2 and H2O is still a challenge. In this study, we have designed and developed a high performance SCR catalyst based on nano-sized ceria encapsulated inside the pores of MIL-100(Fe) that combines excellent catalytic power with a metal organic framework architecture synthesized by the impregnation method (IM). Transmission electron microscopy (TEM) revealed the encapsulation of ceria in the cavities of MIL-100(Fe). The prepared IM-CeO2/MIL-100(Fe) catalyst shows improved catalytic activity both at low temperatures and throughout a wide temperature window. The temperature window for 90% NOx conversion ranges from 196 to 300 degrees C. X-ray photoelectron spectroscopy (XPS) and in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFT) analysis indicated that the nano-sized ceria encapsulated inside MIL-100(Fe) promotes the production of chemisorbed oxygen on the catalyst surface, which greatly enhances the formation of the NO2 species responsible for fast SCR reactions. PMID- 26414928 TI - High-surface area mesoporous Pt/TiO2 hollow chains for efficient formaldehyde decomposition at ambient temperature. AB - Room-temperature catalytic decomposition of formaldehyde (HCHO) is considered as one of the most main methods for the removal of indoor HCHO due to its facile reaction conditions. Herein, high-surface area mesoporous Pt/TiO2 hollow chains were synthesized in high yield by using a simple microwave-hydrothermal route, followed by a combined NaOH-assisted NaBH4-reduction deposition of Pt nanoparticles on the as-obtained TiO2 surface. The catalytic activity for HCHO decomposition was evaluated at room temperature. The prepared Pt/TiO2 hollow chains with an optimal Pt loading of 0.5 wt.% exhibited high catalytic activity and recyclability. The apparent reaction rate constant of HCHO oxidation over this catalyst was approximately 1.42*10(-3) ppm(-1) min(-1), exceeding that of the commercial Degussa P25 TiO2 with equal Pt content (k=5.36*10(-4) ppm(-1) min( 1)) by a factor of approximately 2.65. The high catalytic activity of the Pt/TiO2 hollow chains could be mainly attributed to the hollow chain-like structure, high specific surface area, numerous mesopores, and high pore volume of TiO2 support. Consequently, the catalysts exhibited high adsorption capacity for HCHO, fast diffusion and transport of gas molecules, and good contact between gases and active sites. These characteristics enhanced the catalytic activity. PMID- 26414929 TI - Looking towards objective quality evaluation in colonoscopy: Analysis of visual gaze patterns. AB - BACKGROUND AND AIM: There are currently limited training and assessment tools available to novice endoscopists. A potential tool for the objective assessment of endoscopist visual search strategy is eye-tracking technology. The aim of this study is to assess whether eye-tracking technology can be used to differentiate the visual gaze patterns (VGP) of experienced and novice endoscopists, and to characterize any differences arising between the two groups. METHOD: With the use of portable eye-tracking glasses, VGP of novice (n = 20) and experienced (n = 14) endoscopists were compared while viewing a colonoscopy withdrawal through the hepatic flexure. Analysis was performed by comparing the central versus peripheral distribution and the horizontal distribution of novice and experienced endoscopist fixations, along with comparison of basic eye-tracking metrics. RESULTS: This study found that experienced endoscopists had a significantly higher percentage of fixations within the periphery of the screen (13.4% vs 23.0%, P = 0.013). Experienced endoscopists also had a significantly greater percentage of fixations on the left side of the screen (18.6% vs 33.5%, P = 0.005) that displayed the poorly visualized "inside bend" of the hepatic flexure. CONCLUSION: This study has detailed specific VGP acquired through expertise, which can potentially explain why adenomas are regularly missed at the hepatic flexure during colonoscopy. These may be useful for the training of novice colonoscopists, and further validation may utilize VGP in the development of an objective proficiency based curriculum to improve the detection of pathology and overall quality in endoscopy. PMID- 26414930 TI - Expression of Wnt3a, Wnt10b, beta-catenin and DKK1 in periodontium during orthodontic tooth movement in rats. AB - OBJECTIVE: To investigate the expression of Wnt3a, Wnt10b, beta-catenin and DKK1 in the periodontal ligament (PDL) during orthodontic tooth movement (OTM) in rats. MATERIALS AND METHODS: Nickel-titanium closed-coil springs were used to deliver an initial 50 g mesial force to the left maxillary first molars in 30 rats. The force was kept constant for 1, 3, 5, 7, 10 and 14 days until the animals were sacrificed. The right maxillary molars without force application served as control. Paraffin-embedded sections of the upper jaws were prepared for histological and immunohistochemical analyses to detect Wnt3a, Wnt10b, beta catenin and DKK1 expression in PDL. RESULTS: Wnt3a, Wnt10b, beta-catenin and DKK1 were expressed on both the ipsilateral and contralateral sides of PDL in each group. After the application of orthodontic force, the expression of beta-catenin and DKK1 was initially increased and then decreased on both sides, with maximal levels of expression at day 7 and day 10, respectively. On the compression side, Wnt3a and Wnt10b levels started to increase at day 5, while on the tension side, these two molecules began to increase at day 1. Furthermore, the expression levels of Wnt3a, Wnt10b, and beta-catenin were much stronger on the tension side than on the compression side at any of the observation points, while DKK1 level was much higher on the compression side. CONCLUSION: Wnt3a, Wnt10b, beta-catenin and DKK1 expression may be related to the periodontal tissue remodeling following the application of an orthodontic force in rats. These observations suggest that the Wnt/beta-catenin signaling pathway may play a crucial role in periodontal tissue remodeling during OTM. PMID- 26414931 TI - Statins Trigger Mitochondrial Reactive Oxygen Species-Induced Apoptosis in Glycolytic Skeletal Muscle. AB - AIMS: Although statins are the most widely used cholesterol-lowering agents, they are associated with a variety of muscle complaints. The goal of this study was to characterize the effects of statins on the mitochondrial apoptosis pathway induced by mitochondrial oxidative stress in skeletal muscle using human muscle biopsies as well as in vivo and in vitro models. RESULTS: Statins increased mitochondrial H2O2 production, the Bax/Bcl-2 ratio, and TUNEL staining in deltoid biopsies of patients with statin-associated myopathy. Furthermore, atorvastatin treatment for 2 weeks at 10 mg/kg/day in rats increased H2O2 accumulation and mRNA levels and immunostaining of the Bax/Bcl-2 ratio, as well as TUNEL staining and caspase 3 cleavage in glycolytic (plantaris) skeletal muscle, but not in oxidative (soleus) skeletal muscle, which has a high antioxidative capacity. Atorvastatin also decreased the GSH/GSSG ratio, but only in glycolytic skeletal muscle. Cotreatment with the antioxidant, quercetin, at 25 mg/kg/day abolished these effects in plantaris. An in vitro study with L6 myoblasts directly demonstrated the link between mitochondrial oxidative stress following atorvastatin exposure and activation of the mitochondrial apoptosis signaling pathway. INNOVATION: Treatment with atorvastatin is associated with mitochondrial oxidative stress, which activates apoptosis and contributes to myopathy. Glycolytic muscles are more sensitive to atorvastatin than oxidative muscles, which may be due to the higher antioxidative capacity in oxidative muscles. CONCLUSION: There is a link between statin-induced mitochondrial oxidative stress and activation of the mitochondrial apoptosis signaling pathway in glycolytic skeletal muscle, which may be associated with statin-associated myopathy. PMID- 26414933 TI - Electron-Transferred Donor/Acceptor Ferrimagnet with T(C) = 91 K in a Layered Assembly of Paddlewheel [Ru2] Units and TCNQ. AB - The donor (D)/acceptor (A) assembly reaction of the paddlewheel-type diruthenium(II,II) complex [Ru2(2,4,6-F3PhCO2)4(THF)2] (2,4,6-F3PhCO2(-) = 2,4,6 trifluorobenzoate; abbreviated hereafter as [Ru2]) with 7,7,8,8-tetracyano-p quinodimethane (TCNQ) in a p-xylene/CH2Cl2 solvent system led to the formation of a two-dimensional layered compound, [{Ru2(2,4,6-F3PhCO2)4}2(TCNQ)].2(p xylene).2CH2Cl2 (1). As expected from this D/A combination, 1 has a one-electron transfer ionic state with the D(0.5+)2A(-) formulation. This state formally derives a heterospin state composed of S = 1 for [Ru(II,II)2], S = 3/2 for [Ru(II,III)2](+), and S = 1/2 for TCNQ(*-), possibly causing intralayer ferrimagnetic spin ordering. Most of these types of compounds have an antiferromagnetic ground state because of the coupling of ferrimagnetically ordered layers in dipole antiferromagnetic interactions. However, 1 became a three-dimensional ferrimagnet with T(C) = 91 K because of the presence of interlayer ferromagnetic interactions. PMID- 26414934 TI - Electronic structure and excited state dynamics in a dicyanovinyl-substituted oligothiophene on Au(111). AB - Dicyanovinyl (DCV)-substituted oligothiophenes are promising donor materials in vacuum-processed small-molecule organic solar cells. Here, we studied the structural and the electronic properties of DCV-dimethyl-pentathiophene (DCV5T Me2) adsorbed on Au(111) from submonolayer to multilayer coverages. Using a multi technique experimental approach (low-temperature scanning tunneling microscopy/spectroscopy (STM/STS), atomic force microscopy (AFM), and two-photon photoemission (2PPE) spectroscopy), we determined the energetic position of several affinity levels as well as ionization potentials originating from the lowest unoccupied molecular orbitals (LUMO) and the highest occupied molecular orbitals (HOMO), evidencing a transport gap of 1.4 eV. Proof of an excitonic state was found to be a spectroscopic feature located at 0.6 eV below the LUMO affinity level. With increasing coverage photoemission from excitonic states gains importance. We were able to track the dynamics of several electronically excited states of multilayers by means of femtosecond time-resolved 2PPE. We resolved an intriguing relaxation dynamics involving four processes, ranging from sub-picosecond (ps) to several hundred ps time spans. These show a tendency to increase with increasing coverage. The present study provides important parameters such as energetic positions of transport levels as well as lifetimes of electronically excited states, which are essential for designing organic molecule-based optoelectronic devices. PMID- 26414932 TI - Human Induced Pluripotent Stem Cell NEUROG2 Dual Knockin Reporter Lines Generated by the CRISPR/Cas9 System. AB - Human induced pluripotent stem cell (hiPSC) technologies are powerful tools for modeling development and disease, drug screening, and regenerative medicine. Faithful gene targeting in hiPSCs greatly facilitates these applications. We have developed a fast and precise clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) technology-based method and obtained fluorescent protein and antibiotic resistance dual knockin reporters in hiPSC lines for neurogenin2 (NEUROG2), an important proneural transcription factor. Gene targeting efficiency was greatly improved in CRISPR/Cas9-mediated homology directed recombination (~ 33% correctly targeted clones) compared to conventional targeting protocol (~ 3%) at the same locus. No off-target events were detected. In addition, taking the advantage of the versatile applications of the CRISPR/Cas9 system, we designed transactivation components to transiently induce NEUROG2 expression, which helps identify transcription factor binding sites and trans-regulation regions of human NEUROG2. The strategy of using CRISPR/Cas9 genome editing coupled with fluorescence-activated cell sorting of neural progenitor cells in a knockin lineage hiPSC reporter platform might be broadly applicable in other stem cell derivatives and subpopulations. PMID- 26414935 TI - The use of esophageal stethoscope in a difficult nasogastric tube insertion during general anesthesia. PMID- 26414936 TI - In Vivo Mapping of FACT-Histone Interactions Identifies a Role of Pob3 C-terminus in H2A-H2B Binding. AB - Histone chaperones assist nucleosomal rearrangements to facilitate the passage of DNA and RNA polymerases through chromatin. The FACT (facilitates chromatin transcription) complex is a conserved histone chaperone involved in transcription, replication, and repair. The complex consists of two major subunits, Spt16 and SSRP1/Pob3 in mammals and yeast, which engage histones and DNA by multiple contacts. However, the precise mechanism of FACT function is largely unclear. Here, we used the genetically installed UV-activatable cross linker amino acid p-benzoylphenylalanine (pBPA) to map the interaction network of FACT in living yeast. Unexpectedly, we found the acidic C-terminus of Pob3 forming cross-links to histone H2A and H2B most efficiently. This observation was independent of the performed cross-linking chemistry since similar histone cross links were obtained using p-azidophenylalanine (pAzF). Further analyses identified a C-terminal nuclear localization sequence in Pob3. Its interaction with Importin-alpha interfered with H2A-H2B binding, which suggests a possible regulatory role in FACT recruitment to chromatin. Deletion of acidic residues from the Pob3 C-terminus creates a hydroxyurea-sensitive phenotype in budding yeast, suggesting a potential role for this domain in DNA replication. PMID- 26414939 TI - Commentary: Ascertaining Late Effects of Breast Cancer and Its Treatment: Can We Build a Better Mouse Trap? PMID- 26414937 TI - Investigating hydroxyl chemical exchange using a variable saturation power chemical exchange saturation transfer (vCEST) method at 3 T. AB - PURPOSE: To develop a chemical exchange saturation transfer (CEST) scheme sensitive to hydroxyl protons at 3 T. Clinical imaging of hydroxyl moieties can have an impact on osteoarthritis, neuropsychiatric disorders, and cancer. THEORY: By varying saturation amplitude linearly with frequency offset, the direct water saturation component of the Z-spectrum is flattened and can be subtracted to produce a magnetization transfer ratio difference spectrum (MTRdiff ) that isolates solute resonances. Variable saturation power allows for near optimization of hydroxyl and amine/amide moieties in one Z-spectrum. METHODS: Phantom studies were used to test vCEST performance in two environments: (1) aqueous single-solute (glycogen, glucose); (2) aqueous multiple solute (glycogen with bovine serum albumin). In vivo vCEST imaging of glycosaminoglycan content in patellar-femoral cartilage was performed in a subject with history of cartilage transplant. RESULTS: In solutions with overlapping resonances, vCEST resolves separate hydroxyl and amine/amide peaks. CEST hydroxyl signal in cartilage is negligible, but with vCEST, hydroxyl signal ranged from 2 to 5% ppm and showed distinct contrast between lesions and normal appearing cartilage. CONCLUSION: Introduced a variable saturation amplitude CEST (vCEST) scheme to improve sensitivity to exchangeable hydroxyl moieties at 3 T resulting in detection of hydroxyl in the presence of multiple solutes with overlapping resonances. Magn Reson Med 76:826-837, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26414938 TI - Cardiovascular Disease Mortality Among Breast Cancer Survivors. AB - BACKGROUND: Cardiovascular disease (CVD) is of increasing concern among breast cancer survivors. However, the burden of this comorbidity in this group relative to the general population, and its temporal pattern, remains unknown. METHODS: We compared deaths due to CVD in a population-based sample of 1,413 women with incident breast cancer diagnosed in 1996-1997, and 1,411 age-matched women without breast cancer. Date and cause of death through December 31, 2009 were assessed through the national death index and covariate data was gathered through structured interviews and medical record abstraction. Hazard ratios (HR) and 95% confidence intervals were calculated using Cox regression for overall mortality (HR) and CVD-specific death (cause-specific HR). Subdistribution HRs for CVD death were estimated from the Fine-Gray model. RESULTS: Risk of death was greater among breast cancer survivors compared with women without breast cancer (HR: 1.8 [1.5, 2.1]). An increase in CVD-related death among breast cancer survivors was evident only 7 years after diagnosis (years 0-7, cause-specific HR: 0.80 [0.53, 1.2], subdistribution HR: 0.59 [0.40, 0.87]); years 7+, cause-specific HR: 1.8 [1.3, 2.5], subdistribution HR: 1.9 [1.4, 2.7]; P interaction: 0.001). An increase in CVD-related mortality was observed among breast cancer survivors receiving chemotherapy. CONCLUSIONS: Breast cancer survivors are at greater risk for CVD-related mortality compared with women without breast cancer and this increase in risk is manifested approximately 7 years after diagnosis. Efforts should be made to identify risk factors and interventions that can be employed during this brief window to reduce the excess burden of CVD in this vulnerable population. PMID- 26414940 TI - Commentary: The Urban Environment and Violence: Moving Toward a Dynamic Understanding of Space. PMID- 26414941 TI - Mapping Activity Patterns to Quantify Risk of Violent Assault in Urban Environments. AB - BACKGROUND: We collected detailed activity paths of urban youth to investigate the dynamic interplay between their lived experiences, time spent in different environments, and risk of violent assault. METHODS: We mapped activity paths of 10- to 24-year-olds, including 143 assault patients shot with a firearm, 206 assault patients injured with other types of weapons, and 283 community controls, creating a step-by-step mapped record of how, when, where, and with whom they spent time over a full day from waking up until going to bed or being assaulted. Case-control analyses compared cases with time-matched controls to identify risk factors for assault. Case-crossover analyses compared cases at the time of assault with themselves earlier in the day to investigate whether exposure increases acted to the trigger assault. RESULTS: Gunshot assault risks included being alone (odds ratio [OR] = 1.6, 95% confidence interval [CI] = 1.3, 1.9) and were lower in areas with high neighbor connectedness (OR = 0.7, 95% CI = 0.6, 0.8). Acquiring a gun (OR = 1.4, 95% CI = 1.1, 1.6) and entering areas with more vacancy, violence, and vandalism (OR = 1.7, 95% CI = 1.1, 2.7) appeared to trigger the risk of getting shot shortly thereafter. Nongunshot assault risks included being in areas with recreation centers (OR = 1.2, 95% CI = 1.1, 1.4). Entering an area with higher truancy (OR = 1.6, 95% CI = 1.1, 2.5) and more vacancy, violence, and vandalism appeared to trigger the risk of nongunshot assault. Risks varied by age group. CONCLUSIONS: We achieved a large-scale study of the activities of many boys, adolescents, and young men that systematically documented their experiences and empirically quantified risks for violence. Working at a temporal and spatial scale that is relevant to the dynamics of this phenomenon gave novel insights into triggers for violent assault. PMID- 26414942 TI - Distributed Lag Models: Examining Associations Between the Built Environment and Health. AB - Built environment factors constrain individual level behaviors and choices, and thus are receiving increasing attention to assess their influence on health. Traditional regression methods have been widely used to examine associations between built environment measures and health outcomes, where a fixed, prespecified spatial scale (e.g., 1 mile buffer) is used to construct environment measures. However, the spatial scale for these associations remains largely unknown and misspecifying it introduces bias. We propose the use of distributed lag models (DLMs) to describe the association between built environment features and health as a function of distance from the locations of interest and circumvent a-priori selection of a spatial scale. Based on simulation studies, we demonstrate that traditional regression models produce associations biased away from the null when there is spatial correlation among the built environment features. Inference based on DLMs is robust under a range of scenarios of the built environment. We use this innovative application of DLMs to examine the association between the availability of convenience stores near California public schools, which may affect children's dietary choices both through direct access to junk food and exposure to advertisement, and children's body mass index z scores. PMID- 26414944 TI - Functionalization of a Collagen-Hydroxyapatite Scaffold with Osteostatin to Facilitate Enhanced Bone Regeneration. AB - Defects within bones caused by trauma and other pathological complications may often require the use of a range of therapeutics to facilitate tissue regeneration. A number of approaches have been widely utilized for the delivery of such therapeutics via physical encapsulation or chemical immobilization suggesting significant promise in the healing of bone defects. The study focuses on the chemical immobilization of osteostatin, a pentapeptide of the parathyroid hormone (PTHrP107-111), within a collagen-hydroxyapatite scaffold. The chemical attachment method via crosslinking supports as little as 4% release of the peptide from the scaffolds after 21 d whereas non-crosslinking leads to 100% of the peptide being released by as early as 4 d. In vitro characterization demonstrates that this cross-linking method of immobilization supports a pro osteogenic effect on osteoblasts. Most importantly, when implanted in a critical sized calvarial defect within a rat, these scaffolds promote significantly greater new bone volume and area compared to nonfunctionalized scaffolds (**p < 0.01) and an empty defect control (***p < 0.001). Collectively, this study suggests that such an approach of chemical immobilization offers greater spatiotemporal control over growth factors and can significantly modulate tissue regeneration. Such a system may be adopted for a range of different proteins and thus offers the potential for the treatment of various complex pathologies that require localized mediation of drug delivery. PMID- 26414946 TI - Is lower base rate detrimental to transcatheter aortic valve implantation patients requiring pacemakers? AB - Sudden cardiac death related to polymorphic ventricular tachycardia/ventricular fibrillation has been well reported post atrioventricular junction ablation. The practice of faster pacing rate immediately after atrioventricular junction ablation is well recognized to decrease the risk of sudden cardiac death. We propose that this practice (faster pacing rate) be implemented in patients who need permanent pacemakers secondary to transcatheter aortic valve implantation (or even surgical aortic valve interventions). PMID- 26414945 TI - Serum osteopontin levels in relation to bone mineral density and bone turnover markers in postmenopausal women. AB - Osteopontin (OPN) is an extracellular matrix protein that is expressed in bone cells such as osteoblast and osteocytes and associated with bone turnover and bone mineral density (BMD) in postmenopausal women. Here, we aimed to investigate the relationship between circulating OPN levels and BMD in postmenopausal women in Southern China. A total of 362 postmenopausal women were consecutively recruited into this study from 2011-2013. Serum levels of OPN, receptor activator of nuclear factor kappa B (NF-kappaB) ligand (RANKL), and bone turnover markers were analyzed. BMD was measured by dual energy X-ray absorptiometry. Osteoporosis and osteopenia were diagnosed according to the World Health Organization criteria. Serum OPN levels were remarkably higher in the osteoporotic group than those in the osteopenic and normal groups (all p < 0.001). The cut-off value of OPN for diagnosing postmenopausal osteoporosis was 10.1 ng/mL, which had a sensitivity of 89.5%, a specificity of 70.8%, and an area under curve of 0.953. Serum OPN was negatively correlated with parathyroid hormone (PTH), lumbar spine BMD, and femoral neck BMD (r = -0.25, p = 0.004; r = -0.66, p < 0.001; r = -0.28, p = 0.001; respectively) and positively associated with type I procollagen amino terminal propeptide (PINP), carboxy-terminal cross-linking telopeptide of type I collagen (CTX), and RANKL (r = 0.20, p = 0.020; r = 0.17, p = 0.036; r = 0.19, p = 0.028, respectively) in the osteoporotic group. In multiple regression analyses, lumbar spine BMD, PTH and RANKL were the predictors for serum OPN levels. In conclusion, OPN serum levels are negatively related to BMD and positively correlated with bone turnover levels in this group of Chinese postmenopausal women. PMID- 26414943 TI - Prenatal DDT and DDE exposure and child IQ in the CHAMACOS cohort. AB - Although banned in most countries, dichlorodiphenyl-trichloroethane (DDT) continues to be used for vector control in some malaria endemic areas. Previous findings from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) cohort study found increased prenatal levels of DDT and its breakdown product dichlorodiphenyl-dichloroethylene (DDE) to be associated with altered neurodevelopment in children at 1 and 2years of age. In this study, we combined the measured maternal DDT/E concentrations during pregnancy obtained for the prospective birth cohort with predicted prenatal DDT and DDE levels estimated for a retrospective birth cohort. Using generalized estimating equation (GEE) and linear regression models, we evaluated the relationship of prenatal maternal DDT and DDE serum concentrations with children's cognition at ages 7 and 10.5years as assessed using the Full Scale Intelligence Quotient (IQ) and 4 subtest scores (Working Memory, Perceptual Reasoning, Verbal Comprehension, and Processing Speed) of the Wechsler Intelligence Scale for Children (WISC). In GEE analyses incorporating both age 7 and 10.5 scores (n=619), we found prenatal DDT and DDE levels were not associated with Full Scale IQ or any of the WISC subscales (p value>0.05). In linear regression analyses assessing each time point separately, prenatal DDT levels were inversely associated with Processing Speed at age 7years (n=316), but prenatal DDT and DDE levels were not associated with Full Scale IQ or any of the WISC subscales at age 10.5years (n=595). We found evidence for effect modification by sex. In girls, but not boys, prenatal DDE levels were inversely associated with Full Scale IQ and Processing Speed at age 7years. We conclude that prenatal DDT levels may be associated with delayed Processing Speed in children at age 7years and the relationship between prenatal DDE levels and children's cognitive development may be modified by sex, with girls being more adversely affected. PMID- 26414947 TI - Production of a Bilayered Self-Assembled Skin Substitute Using a Tissue Engineered Acellular Dermal Matrix. AB - Our bilayered self-assembled skin substitutes (SASS) are skin substitutes showing a structure and functionality very similar to native human skin. These constructs are used, in life-threatening burn wounds, as permanent autologous grafts for the treatment of such affected patients even though their production is exacting. We thus intended to shorten their current production time to improve their clinical applicability. A self-assembled decellularized dermal matrix (DM) was used. It allowed the production of an autologous skin substitute from patient's cells. The characterization of SASS reconstructed using a decellularized dermal matrix (SASS DM) was performed by histology, immunofluorescence, transmission electron microscopy, and uniaxial tensile analysis. Using the SASS-DM, it was possible to reduce the standard production time from about 8 to 4 and a half weeks. The structure, cell differentiation, and mechanical properties of the new skin substitutes were shown to be similar to the SASS. The decellularization process had no influence on the final microstructure and mechanical properties of the DM. This model, by enabling the production of a skin substitute in a shorter time frame without compromising its intrinsic tissue properties, represents a promising addition to the currently available burn and wound treatments. PMID- 26414948 TI - Genome-wide identification and expression analysis of WNK kinase gene family in rice. AB - Eukaryotic protein kinases represent one of the largest gene families involved in diverse regulatory functions. WNK (With No Lysine) kinases are members of ser/thr protein kinase family, which lack conserved catalytic lysine (K) residue at protein kinase subdomain II and is replaced by either asparagine, serine or glycine residues. They are involved in regulation of flowering time, circadian rhythms and abiotic stresses in Arabidopsis thaliana. In the present study, we have identified 9 members of WNK in rice, showed resemblance to Arabidopsis and human WNK and clustered into five main clades phylogenetically. The predicted genes structure, bonafide conserved signature motif and domains strongly support their identity, as members of WNK kinase family. We have analyzed their chromosomal distribution, physio-chemical properties, subcellular localizations and cis-elements in the promoter regions in silico. Further, transcript analysis of OsWNK by qRT-PCR revealed their differential regulation in tissue specific and abiotic stresses libraries. In conclusion, the identification of nine OsWNK and transcript level expression pattern under abiotic stress using qRT-PCR in rice will significantly contribute towards the understanding of WNK genes in monocots and thus provide a set up for functional genomics studies of WNK protein kinases. PMID- 26414949 TI - In silico approaches for the identification of virulence candidates amongst hypothetical proteins of Mycoplasma pneumoniae 309. AB - Mycoplasma pneumoniae type 2a strain 309 is a simplest known bacterium and is the primary cause of community acquired pneumonia in the children. It mainly causes severe atypical pneumonia as well as several other non-pulmonary manifestations such as neurological, hepatic, hemolytic anemia, cardiac diseases and polyarthritis. The size of M. pneumoniae genome (Accession number: NC_016807.1) is relatively smaller as compared to other bacteria and contains 707 functional proteins, in which 204 are classified as hypothetical proteins (HPs) because of the unavailability of experimentally validated functions. The functions of the HPs were predicted by integrating a variety of protein classification systems, motif discovery tools as well as methods that are based on characteristic features obtained from the protein sequence and metabolic pathways. The probable functions of 83HPs were predicted successfully. The accuracy of the diverse tools used in the adopted pipeline was evaluated on the basis of statistical techniques of Receiver Operating Characteristic (ROC), which indicated the reliability of the functional predictions. Furthermore, the virulent HPs present in the set of 83 functionally annotated proteins were predicted by using the Bioinformatics tools and the conformational behaviours of the proteins with highest virulence scores were studied by using the molecular dynamics (MD) simulations. This study will facilitate in the better understanding of various drug resistance and pathogenesis mechanisms present in the M. pneumoniae and can be utilized in designing of better therapeutic agents. PMID- 26414950 TI - Multiple ligand simultaneous docking (MLSD): A novel approach to study the effect of inhibitors on substrate binding to PPO. AB - Multiple ligand simultaneous docking, a computational approach is used to study the concurrent interactions between substrate and the macromolecule binding together in the presence of an inhibitor. The present investigation deals with the study of the effect of different inhibitors on binding of substrate to the protein Polyphenoloxidase (PPO). The protein was isolated from Mucuna pruriens and confirmed as tyrosinases involved in L-DOPA production. The activity was measured using different inhibitors at different concentrations taking catechol as substrate. A high-throughput binding study was conducted to compare the binding orientations of individual ligands and multiple ligands employing Autodock 4.2. The results of single substrate docking showed a better binding of urea with the binding energy of -3.48 kJ mol(-1) and inter molecular energy of 3.48 kJ mol(-1) while the results of MLSD revealed that ascorbic acid combined with the substrate showed better inhibition with a decreased binding energy of 2.37 kJ mol(-1). PMID- 26414951 TI - Production of Early Diploid Males by European Colonies of the Invasive Hornet Vespa velutina nigrithorax. AB - The invasive yellow-legged hornet Vespa velutina nigrithorax was accidentally introduced in Europe in the early 2000s. As is the case in colonies of other wasp and hornet species, V. velutina colonies are known to produce sexuals (males and new queens) at the end of the summer. We show that early-stage colonies in French populations frequently produce males well before the usual reproductive period. The vast majority of the males produced are diploid, which is consistent with the loss of genetic diversity previously reported in introduced populations in France. Since males do not participate in colony activities, the production of early diploid males at the expense of workers is expected to hamper colony growth and, ultimately, decrease the expansion of the species in its invasive range in Europe. PMID- 26414952 TI - Disentangling Brain Graphs: A Note on the Conflation of Network and Connectivity Analyses. AB - Understanding the human brain remains the holy grail in biomedical science, and arguably in all of the sciences. Our brains represent the most complex systems in the world (and some contend the universe) comprising nearly 100 billion neurons with septillions of possible connections between them. The structure of these connections engenders an efficient hierarchical system capable of consciousness, as well as complex thoughts, feelings, and behaviors. Brain connectivity and network analyses have exploded over the last decade due to their potential in helping us understand both normal and abnormal brain function. Functional connectivity (FC) analysis examines functional associations between time series pairs in specified brain voxels or regions. Brain network analysis serves as a distinct subfield of connectivity analysis, in which associations are quantified for all time series pairs to create an interconnected representation of the brain (a brain network), which allows studying its systemic properties. While connectivity analyses underlie network analyses, the subtle distinction between the two research areas has generally been overlooked in the literature, with them often being referred to synonymously. However, developing more useful analytic methods and allowing for more precise biological interpretations require distinguishing these two complementary domains. PMID- 26414953 TI - Cancer risks in twins and singletons from twin and non-twin families. AB - The unique intrauterine environment has been proposed to put twins at increased risk of certain cancers compared to singletons, still large population comparisons have generally indicated lower risks in twins. To improve the understanding of potential twin influence on cancer we compared twins to their singletons siblings, to target a unique twinning influence. Singletons from twin families were contrasted to singletons from non-twin families to further capture potential twin family influence on risk of cancer. Family relations were identified using the Swedish Multi-Generation Register. Among individuals born between 1932 and 1958, 49,156 twins and N = 35,227 singletons were identified from 18,098 unique twin families. All incident cases of specific cancer types were identified in the National Cancer Register up to the end of 2007. Standardized survival functions were estimated using weighted Cox proportional hazard regression and the corresponding cumulative risks plotted against age. Overall, primary cancers were identified in 9% and 18% of all male and female twins, compared to 11% and 19% of their male and female singleton siblings. When specific cancer sites were compared using standardized cumulative risk plots, no consistent statistically significant differences were noted either between twins and singletons of twin families or between singletons of twin and non-twin families. Despite a different intrauterine experience, twinning does not seem to have any greater negative influence on life-time risks of cancer. The findings also indicate that twin family membership has no substantial influence on cancer risks. PMID- 26414954 TI - Interaction Between the FOXO1A-209 Genotype and Tea Drinking Is Significantly Associated with Reduced Mortality at Advanced Ages. AB - On the basis of the genotypic/phenotypic data from Chinese Longitudinal Healthy Longevity Survey (CLHLS) and Cox proportional hazard model, the present study demonstrates that interactions between carrying FOXO1A-209 genotypes and tea drinking are significantly associated with lower risk of mortality at advanced ages. Such a significant association is replicated in two independent Han Chinese CLHLS cohorts (p = 0.028-0.048 in the discovery and replication cohorts, and p = 0.003-0.016 in the combined dataset). We found the associations between tea drinking and reduced mortality are much stronger among carriers of the FOXO1A-209 genotype compared to non-carriers, and drinking tea is associated with a reversal of the negative effects of carrying FOXO1A-209 minor alleles, that is, from a substantially increased mortality risk to substantially reduced mortality risk at advanced ages. The impacts are considerably stronger among those who carry two copies of the FOXO1A minor allele than those who carry one copy. On the basis of previously reported experiments on human cell models concerning FOXO1A-by-tea compounds interactions, we speculate that results in the present study indicate that tea drinking may inhibit FOXO1A-209 gene expression and its biological functions, which reduces the negative impacts of FOXO1A-209 gene on longevity (as reported in the literature) and offers protection against mortality risk at oldest-old ages. Our empirical findings imply that the health outcomes of particular nutritional interventions, including tea drinking, may, in part, depend upon individual genetic profiles, and the research on the effects of nutrigenomics interactions could potentially be useful for rejuvenation therapies in the clinic or associated healthy aging intervention programs. PMID- 26414956 TI - 'There is fear but there is no other work': a preliminary qualitative exploration of the experience of sex workers in eastern Democratic Republic of Congo. AB - Two decades of conflict and insecurity have had a devastating impact on many in the Democratic Republic of Congo (DRC), including marginalised groups such as sex workers. In the province of North Kivu, many residents face desperate conditions that render them vulnerable to exploitation and abuse. As a result, many turn to the sex trade in what can often be described as 'survival sex'. This small-scale qualitative study explores the experience of urban sex workers in the eastern region of the DRC. Sex workers were recruited at their place of business and asked to participate in a semi-structured interview. Eight participants were recruited, including seven women and one man. Our analysis identified several themes: (1) economic hardship as a catalyst for joining the sex trade, (2) significant work-related violence and (3) a paucity of available resources or assistance. Responses to specific prompts indicated that sex workers do not trust law enforcement and there are significant barriers to both medical care and local resources. Further studies of this vulnerable population and its needs are encouraged in order to develop programmes that provide the means to manage the hazards of their work and obtain an alternative source of income. PMID- 26414957 TI - Polypoidal Choroidal Vasculopathy: A Distinct Disease or Manifestation of Many? PMID- 26414955 TI - Altered Neuroinflammation and Behavior after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease. AB - Traumatic brain injury (TBI) has acute and chronic sequelae, including an increased risk for the development of Alzheimer's disease (AD). TBI-associated neuroinflammation is characterized by activation of brain-resident microglia and infiltration of monocytes; however, recent studies have implicated beta-amyloid as a major manipulator of the inflammatory response. To examine neuroinflammation after TBI and development of AD-like features, these studies examined the effects of TBI in the presence and absence of beta-amyloid. The R1.40 mouse model of cerebral amyloidosis was used, with a focus on time points well before robust AD pathologies. Unexpectedly, in R1.40 mice, the acute neuroinflammatory response to TBI was strikingly muted, with reduced numbers of CNS myeloid cells acquiring a macrophage phenotype and decreased expression of inflammatory cytokines. At chronic time points, macrophage activation substantially declined in non-Tg TBI mice; however, it was relatively unchanged in R1.40 TBI mice. The persistent inflammatory response coincided with significant tissue loss between 3 and 120 days post-injury in R1.40 TBI mice, which was not observed in non-Tg TBI mice. Surprisingly, inflammatory cytokine expression was enhanced in R1.40 mice compared with non-Tg mice, regardless of injury group. Although R1.40 TBI mice demonstrated task-specific deficits in cognition, overall functional recovery was similar to non-Tg TBI mice. These findings suggest that accumulating beta-amyloid leads to an altered post-injury macrophage response at acute and chronic time points. Together, these studies emphasize the role of post-injury neuroinflammation in regulating long-term sequelae after TBI and also support recent studies implicating beta-amyloid as an immunomodulator. PMID- 26414958 TI - Theoretical Study on the Excited Electronic States of CHCl: Application to Photodissociation at 193 nm. AB - We present herein a high-level ab initio study on the electronic excited states of CHCl using the internally contracted multireference configuration interaction method including Davidson correction (icMRCI+Q). A total of 13 electronic states with energy of up to 7 eV have been investigated. The vertical transition energies, oscillator strengths, electron configurations, and transitions of the electronic states of CHCl have been calculated at the icMRCI+Q/aug-cc-pv(5+d)Z level. The potential energy curves of the electronic states have been studied along the H-C-Cl angle, the C-H bond length, and the C-Cl bond length, respectively. Our theoretical study has provided comprehensive information for understanding the interaction and the behavior of the electronic excited states of CHCl. In particular, the excited state involved in the 193 nm photodissociation as well as the corresponding dissociation dynamics have been discussed on the basis of our calculation results. The present study should shed more light on the photochemistry of CHCl in the ultraviolet region. PMID- 26414959 TI - Three-Dimensional Culture of Functional Adult Rabbit Lacrimal Gland Epithelial Cells on Decellularized Scaffold. AB - Aqueous tear-deficient dry eye disease is a multifactorial chronic disorder, in which the lacrimal gland fails to produce enough tears to maintain a healthy ocular surface. Some severe cases may develop corneal damage and significant vision loss. Treatment primarily involves palliation using ocular surface lubricants, but can only provide temporary relief. Construction of a bioengineered lacrimal gland having functional secretory epithelial cells is a potentially promising option for providing long-term relief to severe dry eye patients. Using sphere-forming culture techniques, we cultured adult rabbit lacrimal gland progenitor cells and prepared a lacrimal gland scaffold by decellularization. When progenitor cells were seeded onto the decellularized scaffold, they formed duct- and acinar-like structures in the three-dimensional culture system. Lacrimal gland epithelial cells showed good cell viability, cell differentiation, and secretory function in decellularized lacrimal gland matrix, as indicated by morphology, immunostaining, and beta-hexosaminidase secretion assay. This study demonstrated the potential suitability of utilizing tissue specific progenitor cells and a tissue-derived bioscaffold for lacrimal gland restoration. PMID- 26414960 TI - Diversity of Interstitial Lung Fibroblasts Is Regulated by Platelet-Derived Growth Factor Receptor alpha Kinase Activity. AB - Epithelial-mesenchymal cell interactions and factors that control normal lung development are key players in lung injury, repair, and fibrosis. A number of studies have investigated the roles and sources of epithelial progenitors during lung regeneration; such information, however, is limited in lung fibroblasts. Thus, understanding the origin, phenotype, and roles of fibroblast progenitors in lung development, repair, and regeneration helps address these limitations. Using a combination of platelet-derived growth factor receptor alpha-green fluorescent protein (PDGFRalpha-GFP) reporter mice, microarray, real-time polymerase chain reaction, flow cytometry, and immunofluorescence, we characterized two distinct interstitial resident fibroblasts, myo- and matrix fibroblasts, and identified a role for PDGFRalpha kinase activity in regulating their activation during lung regeneration. Transcriptional profiling of the two populations revealed a myo- and matrix fibroblast gene signature. Differences in proliferation, smooth muscle actin induction, and lipid content in the two subpopulations of PDGFRalpha expressing fibroblasts during alveolar regeneration were observed. Although CD140alpha(+)CD29(+) cells behaved as myofibroblasts, CD140alpha(+)CD34(+) appeared as matrix and/or lipofibroblasts. Gain or loss of PDGFRalpha kinase activity using the inhibitor nilotinib and a dominant-active PDGFRalpha-D842V mutation revealed that PDGFRalpha was important for matrix fibroblast differentiation. We demonstrated that PDGFRalpha signaling promotes alveolar septation by regulating fibroblast activation and matrix fibroblast differentiation, whereas myofibroblast differentiation was largely PDGFRalpha independent. These studies provide evidence for the phenotypic and functional diversity as well as the extent of specificity of interstitial resident fibroblasts differentiation during regeneration after partial pneumonectomy. PMID- 26414961 TI - HIV-positive blood donors unaware of their sexual at-risk behaviours before donation in Italy. AB - BACKGROUND AND OBJECTIVES: Despite the procedures adopted for the selection of blood donors, in Italy the HIV prevalence per 100 000 repeat tested donors (RTD) and first-time tested donors (FTD) is high compared to most other Council of Europe member states. To evaluate the effectiveness of predonation procedures, we studied both the characteristics and the undisclosed risk behaviours of HIV positive donors. MATERIALS AND METHODS: We analysed the data from the Italian blood donor surveillance system in 2009, 2010 and 2011. Based on the postdonation interview, HIV-positive donors were classified by risk behaviour (heterosexual, MSM, 'non-sexual' and 'not determined') and by time elapsed from risk behaviour to donation. In Italy, the temporary deferral for exposure to behaviour at risk is 4 months. RESULTS: In the postdonation interview, 113 HIV-positive donors (32.4%), who denied at-risk behaviours in the predonation selection, reported sexual risk behaviours <4 months prior to donation; they were predominantly males (84.1%) and RTD (63.7%). The main reason for not having reported the risk behaviour in the predonation selection was 'not realizing having engaged in at risk behaviour' (66.4%). CONCLUSION: These findings underline the need for more comprehensible educational material, a clearer predonation questionnaire, and effective information campaigns to improve the awareness of HIV sexual risk behaviours among blood donors. PMID- 26414962 TI - Increased Cardiovascular Mortality Risk in Women Discontinuing Postmenopausal Hormone Therapy. AB - CONTEXT: Current guidelines recommend annual discontinuation of postmenopausal hormone therapy (HT) to evaluate whether a woman could manage without the treatment. The impact of HT on cardiovascular health has been widely studied, but it is not known how the withdrawal of HT affects cardiovascular risk. OBJECTIVE: We evaluated the risk of cardiac or stroke death after the discontinuation of HT. Design, Patients, Interventions, and Main Outcome Measures: Altogether 332 202 Finnish women discontinuing HT between 1994 and 2009 (data from National Reimbursement register) were followed up from the discontinuation date to death due to cardiac cause (n = 3177) or stroke (n = 1952), or to the end of 2009. The deaths, retrieved from the national Cause of Death Register, were compared with the expected number of deaths in the age-standardized background population. In a subanalysis we also compared HT stoppers with HT users. RESULTS: Within the first posttreatment year, the risk of cardiac death was significantly elevated (standardized mortality ratio; 95% confidence interval 1.26; 1.16-1.37), whereas follow-up for longer than 1 year was accompanied with a reduction (0.75; 0.72 0.78). The risk of stroke death in the first posttreatment year was increased (1.63; 1.47-1.79), but follow-up for longer than 1 year was accompanied with a reduced risk (0.89; 0.85-0.94). The cardiac (2.30; 2.12-2.50) and stroke (2.52; 2.28-2.77) death risk elevations were even higher when compared with HT users. In women who discontinued HT at age younger than 60 years, but not in women aged 60 years or older, the cardiac mortality risk was elevated (1.94; 1.51-2.48). CONCLUSIONS: Increased cardiovascular death risks question the safety of annual HT discontinuation practice to evaluate whether a woman could manage without HT. PMID- 26414964 TI - Preliminary Comparative Effectiveness of Robotic Versus Open Radical Cystectomy in Elderly Patients. AB - INTRODUCTION: Treatment for muscle-invasive bladder cancer (MIBC) remains highly morbid despite improving surgical techniques. As the median age of diagnosis is 73, many patients are elderly at the time of cystectomy. We compare perioperative surgical outcomes in elderly patients undergoing robotic vs open radical cystectomy (RC). MATERIALS AND METHODS: Patients >75 years at time of RC were identified. Demographic, clinicopathologic, and perioperative variables were examined. Estimated blood loss (EBL) and length of stay (LOS) data were collected with multivariate linear regression analysis performed to assess whether technique was independently associated with outcomes. RESULTS: Eighty-seven patients >75 years of age underwent cystectomy for MIBC (58 open, 29 robotic). Mean age was 79.6 (+/-3.2) and 79.2 (+/-3.5) for open and robotic groups, respectively (p = 0.64). There were no significant differences in baseline comorbidities, clinical or pathologic stage, or use of neoadjuvant chemotherapy. The mean number of lymph nodes removed was similar (p = 0.08). Robotic cystectomy had significantly longer mean OR times (p < 0.001). On multivariate analyses, robotic surgery was associated with -389cc less EBL (95% CI -547 to -230, p < 0.001) and a -1.5-day-shortened LOS (95%CI -2.9 to -0.2, p = 0.02) compared with open surgery. There were no significant differences in surgical complications or 90-day readmission rates between the two groups. CONCLUSIONS: Robotic cystectomy is safe and feasible in an elderly population. We observed longer OR times with robotic surgery, but with decreased EBL, shorter hospital stays, and comparable complication and readmission rates with open RC. Larger prospective studies are required to confirm these findings. PMID- 26414963 TI - Sex-Specific Differences in Hepatic Fat Oxidation and Synthesis May Explain the Higher Propensity for NAFLD in Men. AB - CONTEXT AND OBJECTIVE: In most populations a greater proportion of men have hepatic steatosis than women. Sex-specific differences in hepatic dietary fatty acid (FA) metabolism have not been well characterized. We compared fasting and postprandial hepatic FA synthesis (de novo lipogenesis [DNL]) and oxidation in men and women. PARTICIPANTS AND METHODS: Fasting and postprandial hepatic FA metabolism was studied in 22 healthy men (n = 11) and women with similar age, body mass index, and liver fat content using metabolic substrates labeled with stable-isotope tracers ((2)H2O and [U(13)C]palmitate). Dietary FA oxidation was assessed by appearance of (13)C into plasma 3-hydroxybutyrate and breath CO2 as markers of liver and whole-body FA oxidation, respectively. RESULTS: Despite similar liver fat content, fasting and postprandial plasma triacylglycerol (TG) concentrations were significantly (P < .05) higher in men compared with women. The appearance of (13)C from dietary FA into plasma 3-hydroxybutyrate and breath CO2 was greater (P < .05) in women compared with men. Although the contribution of DNL into very low-density lipoprotein (VLDL)-TG was similar (~ 10%) in the fasting state, there was a divergence in pattern over the course of the study, with men maintaining a higher contribution of DNL to VLDL-TG than women (P = .006 time x sex interaction). CONCLUSIONS: The combination of lower dietary FA oxidation and a prolonged increase in DNL observed in men may represent partitioning of FA into esterification and storage pathways within the liver, leading to greater VLDL-TG production, and predispose to the sex difference in hepatic steatosis. PMID- 26414965 TI - MicroRNA 302/367 Cluster Effectively Facilitates Direct Reprogramming from Human Fibroblasts into Functional Neurons. AB - Recent studies suggest that mature somatic cells can be reprogrammed to become induced pluripotent stem cells by overexpressing specific transcription factors or microRNAs (miRNAs). Theoretically, this technique could provide a wide array of cells for therapeutics. However, the process of redifferentiation after cell reprogramming to pluripotency is inefficient and time restricted. We proposed that the differentiation of somatic cells into specific cells of another germ layer can be induced and accelerated with appropriate miRNAs and culture conditions. In human fibroblasts, we found that overexpression of pluripotency stem cell-specific miRNA-302/367 cluster, together with two other neuron-specific miRNAs (miRNA-9/9* and miRNA-124) induced fibroblasts conversion into neurons. The cells assumed neuron morphology, were positive for several neuron markers, and exhibited neuronal membrane potential feature. Moreover, concentrated expression of synaptic markers were observed in these cells in vitro and in vivo in nude mice brain, suggesting possible connectivity. To achieve efficient reprogramming, miRNA-302/367 cluster, miRNA-9/9*, and miRNA-124 were all required. The combination of the proved pluripotency-inducing miRNA-302/367 cluster and cell-specific miRNAs provides a unique strategy for one-step cellular conversion that could have important implications for studies of neuron development and neurological disease therapy. PMID- 26414966 TI - Pharmacoeconomics of long-acting atypical antipsychotics for acutely relapsed chronic schizophrenia in Finland. AB - BACKGROUND: Atypical long-acting injectable (LAI) antipsychotics are increasingly available for treating chronic schizophrenia in patients chronically non-adherent to prescribed regimens. Few economic studies have compared these products. PURPOSE: To determine the cost-effectiveness of aripiprazole (ARI-LAI), paliperidone (PP-LAI), olanzapine (OLZ-LAI), and risperidone (RIS-LAI) in patients with chronic schizophrenia in Finland. METHODS: A 1-year decision tree model was adapted with guidance from an expert panel. Patients started hospitalized in relapse; those who responded continued treatment, others were switched to secondary drugs, then clozapine in the event of 2nd line failure. Rates of adherence, stable disease, relapse, and hospitalization were taken from pivotal trials, and utilities from published research. Included were direct costs paid by the Finnish Ministry of Health, in 2015 euros. Outcomes included quality adjusted life-years (QALYs), hospitalization rates, and rates of relapse not requiring hospitalization. Model robustness was assessed using a series of 1-way and multivariate sensitivity analyses. RESULTS: Expected costs were lowest for PP LAI at 41,148?, followed by 41,543? for ARI-LAI, 42,067? for RIS-LAI and 45,406? for OLZ-LAI. Respective QALYs were 0.683, 0.671, 0.666, and 0.672. Re hospitalization rates and non-admitted relapses were 23.6% and 3.9% for PP-LAI, 28.5% and 4.1% for ARI-LAI, 28.8% and 5.0% for RIS-LAI, 28.3% and 5.2% for OLZ LAI. PP-LAI treatment was associated with the most days with stable disease (132.0), followed by OLZ-LAI (125.5), ARI-LAI (122.6), and RIS-LAI (114.4). Sensitive inputs between PP-LAI and ARI-LAI included rates of adherence, dropouts, and relapses plus drug prices; dropout and relapse rates for RIS-LAI; OLZ-LAI results were insensitive. In probability sensitivity analyses, PP-LAI dominated ARI-LAI in 75.8% of the 10,000 iterations, RIS-LAI in 83.1% and OLZ-LAI in 95.7%. CONCLUSIONS: PP-LAI dominated the other atypicals. It appears to be the preferred option for treating chronic relapsing schizophrenia. PMID- 26414967 TI - Evaluation of Patients With Suspected Acute Pulmonary Embolism: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians. AB - DESCRIPTION: Pulmonary embolism (PE) can be a severe disease and is difficult to diagnose, given its nonspecific signs and symptoms. Because of this, testing patients with suspected acute PE has increased dramatically. However, the overuse of some tests, particularly computed tomography (CT) and plasma d-dimer measurement, may not improve care while potentially leading to patient harm and unnecessary expense. METHODS: The literature search encompassed studies indexed by MEDLINE (1966-2014; English-language only) and included all clinical trials and meta-analyses on diagnostic strategies, decision rules, laboratory tests, and imaging studies for the diagnosis of PE. This document is not based on a formal systematic review, but instead seeks to provide practical advice based on the best available evidence and recent guidelines. The target audience for this paper is all clinicians; the target patient population is all adults, both inpatient and outpatient, suspected of having acute PE. BEST PRACTICE ADVICE 1: Clinicians should use validated clinical prediction rules to estimate pretest probability in patients in whom acute PE is being considered. BEST PRACTICE ADVICE 2: Clinicians should not obtain d-dimer measurements or imaging studies in patients with a low pretest probability of PE and who meet all Pulmonary Embolism Rule-Out Criteria. BEST PRACTICE ADVICE 3: Clinicians should obtain a high-sensitivity d-dimer measurement as the initial diagnostic test in patients who have an intermediate pretest probability of PE or in patients with low pretest probability of PE who do not meet all Pulmonary Embolism Rule-Out Criteria. Clinicians should not use imaging studies as the initial test in patients who have a low or intermediate pretest probability of PE. BEST PRACTICE ADVICE 4: Clinicians should use age adjusted d-dimer thresholds (age * 10 ng/mL rather than a generic 500 ng/mL) in patients older than 50 years to determine whether imaging is warranted. BEST PRACTICE ADVICE 5: Clinicians should not obtain any imaging studies in patients with a d-dimer level below the age-adjusted cutoff. BEST PRACTICE ADVICE 6: Clinicians should obtain imaging with CT pulmonary angiography (CTPA) in patients with high pretest probability of PE. Clinicians should reserve ventilation perfusion scans for patients who have a contraindication to CTPA or if CTPA is not available. Clinicians should not obtain a d-dimer measurement in patients with a high pretest probability of PE. PMID- 26414969 TI - Spironolactone for resistant hypertension--hard to resist? PMID- 26414968 TI - Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double blind, crossover trial. AB - BACKGROUND: Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure. METHODS: In this double-blind, placebo-controlled, crossover trial, we enrolled patients aged 18-79 years with seated clinic systolic blood pressure 140 mm Hg or greater (or >=135 mm Hg for patients with diabetes) and home systolic blood pressure (18 readings over 4 days) 130 mm Hg or greater, despite treatment for at least 3 months with maximally tolerated doses of three drugs, from 12 secondary and two primary care sites in the UK. Patients rotated, in a preassigned, randomised order, through 12 weeks of once daily treatment with each of spironolactone (25-50 mg), bisoprolol (5-10 mg), doxazosin modified release (4-8 mg), and placebo, in addition to their baseline blood pressure drugs. Random assignment was done via a central computer system. Investigators and patients were masked to the identity of drugs, and to their sequence allocation. The dose was doubled after 6 weeks of each cycle. The hierarchical primary endpoints were the difference in averaged home systolic blood pressure between spironolactone and placebo, followed (if significant) by the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, followed by the difference in home systolic blood pressure between spironolactone and each of the other two drugs. Analysis was by intention to treat. The trial is registered with EudraCT number 2008-007149-30, and ClinicalTrials.gov number, NCT02369081. FINDINGS: Between May 15, 2009, and July 8, 2014, we screened 436 patients, of whom 335 were randomly assigned. After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo (-8.70 mm Hg [95% CI -9.72 to -7.69]; p<0.0001), superior to the mean of the other two active treatments (doxazosin and bisoprolol; -4.26 [-5.13 to -3.38]; p<0.0001), and superior when compared with the individual treatments; versus doxazosin (-4.03 [ 5.04 to -3.02]; p<0.0001) and versus bisoprolol (-4.48 [-5.50 to -3.46]; p<0.0001). Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. All treatments were well tolerated. In six of the 285 patients who received spironolactone, serum potassium exceeded 6.0 mmol/L on one occasion. INTERPRETATION: Spironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition. FUNDING: The British Heart Foundation and National Institute for Health Research. PMID- 26414970 TI - Left-Sided Flank Pain, Fevers, and Fatigue in a 26-Year-Old Male With Seropositive Rheumatoid Arthritis. PMID- 26414971 TI - Hospice Diagnosis: Polypharmacy: A Teachable Moment. PMID- 26414972 TI - Treatment of prosthetic joint infections due to Propionibacterium. Similar results in 60 patients treated with and without rifampicin. AB - BACKGROUND AND PURPOSE: Currently, Propionibacterium is frequently recognized as a causative microorganism of prosthetic joint infection (PJI). We assessed treatment success at 1- and 2-year follow-up after treatment of Propionibacterium associated PJI of the shoulder, hip, and knee. Furthermore, we attempted to determine whether postoperative treatment with rifampicin is favorable. PATIENTS AND METHODS: We conducted a retrospective cohort study in which we included patients with a primary or revision joint arthroplasty of the shoulder, hip, or knee who were diagnosed with a Propionibacterium-associated PJI between November 2008 and February 2013 and who had been followed up for at least 1 year. RESULTS: We identified 60 patients with a Propionibacterium-associated PJI with a median duration of 21 (0.1-49) months until the occurrence of treatment failure. 39 patients received rifampicin combination therapy, with a success rate of 93% (95% CI: 83-97) after 1 year and 86% (CI: 71-93) after 2 years. The success rate was similar in patients who were treated with rifampicin and those who were not. INTERPRETATION: Propionibacterium-associated PJI treated with surgery in combination with long-term antibiotic administration had a successful outcome at 1- and 2-year follow-up irrespective of whether the patient was treated with rifampicin. Prospective studies are needed to determine whether the use of rifampicin is beneficial in the treatment of Propionibacterium-associated PJI. PMID- 26414973 TI - Effect of Melatonin on Sleep in the Perioperative Period after Breast Cancer Surgery: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - STUDY OBJECTIVES: To investigate whether administration of an oral dose of 6 mg melatonin before bedtime perioperatively in breast cancer surgery could change sleep outcomes measured by actigraphy. METHODS: This paper reports secondary outcomes from a double-blind, placebo-controlled, randomized clinical trial where patients received 6 mg melatonin (n = 27) or placebo (n = 21) approximately 60 minutes before bedtime 3 nights preoperatively until at least one week postoperatively. Participants were monitored in the entire period with actigraphy, and were instructed to complete visual analogue scale (VAS) for sleep, and the Karolinska Sleepiness Scale (KSS) each morning. RESULTS: Administration of 6 mg oral melatonin approximately 1 hour before bedtime resulted in significantly increased sleep efficiency and reduced wake after sleep onset for the entire 2-week postoperative period. No other significant differences for actigraphy determined sleep outcomes or subjective outcome parameters in the perioperative period were found between the groups. Overall, the patients sleep outcomes were within normal ranges and no participants had pathological sleep disturbances. CONCLUSIONS: Melatonin significantly changed sleep efficiency and wake after sleep onset after surgery, but had no effects on other objective sleep outcomes or on subjective sleep quality (VAS and KSS). PMID- 26414974 TI - Improvement of Cognitive and Psychomotor Performance in Patients with Mild to Moderate Obstructive Sleep Apnea Treated with Mandibular Advancement Device: A Prospective 1-Year Study. AB - STUDY OBJECTIVES: This study aimed to provide the evidence on effect of mandibular advancement device (MAD) therapy on long-term cognitive and psychomotor performance, excessive daytime sleepiness, and quality of life in patients with mild to moderate obstructive sleep apnea (OSA). METHODS: A total of 15 patients with mild to moderate OSA were treated with MAD therapy and they were followed up after 3 mo and 1 y of therapy. The patients were tested on three different tests of cognitive and psychomotor performance using the computer-based system Complex Reactionmeter Drenovac (CRD-series) at baseline and at the time of follow-up, and the 36-Item Short Form Health Survey (SF-36) questionnaire and Epworth Sleepiness Scale were used to assess their quality of life and excessive daytime sleepiness, respectively. RESULTS: The mean apnea-hypopnea index (AHI) decreased significantly from 22.9 +/- 5.9 events/h at baseline, to 9.7 +/- 4.5 events/h after 1 y of MAD therapy (p < 0.001). There was significant improvement on all three CRD-series tests used after 1 y of MAD therapy, considering total test solving time (TTST) and minimal single task solving time (MinT), whereas total number of errors committed during the tests (TE) remained unchanged. Self reported measures, excessive daytime sleepiness, and three domains of quality of life, social functioning, general health perception, and health change following MAD therapy showed significant improvements after 1 y of MAD therapy. CONCLUSIONS: This study demonstrates significant improvements in cognitive and psychomotor performance, particularly in the domain of perceptive abilities, convergent thinking (constructing and solving simple mathematical tasks) and psychomotor reaction times, excessive daytime sleepiness, and quality of life in patients with mild to moderate OSA following MAD therapy. PMID- 26414975 TI - Effects of Blast Exposure on Subjective and Objective Sleep Measures in Combat Veterans with and without PTSD. AB - STUDY OBJECTIVES: This study examined the extent to which self-reported exposure to blast during deployment to Iraq and Afghanistan affects subjective and objective sleep measures in service members and veterans with and without posttraumatic stress disorder (PTSD). METHODS: Seventy-one medication-free service members and veterans (mean age = 29.47 +/- 5.76 years old; 85% men) completed self-report sleep measures and overnight polysomnographic studies. Four multivariate analyses of variance (MANOVAs) were conducted to examine the impact of blast exposure and PTSD on subjective sleep measures, measures of sleep continuity, non-rapid eye movement (NREM) sleep parameters, and rapid eye movement (REM) sleep parameters. RESULTS: There was no significant Blast * PTSD interaction on subjective sleep measures. Rather, PTSD had a main effect on insomnia severity, sleep quality, and disruptive nocturnal behaviors. There was no significant Blast * PTSD interaction, nor were there main effects of PTSD or Blast on measures of sleep continuity and NREM sleep. A significant PTSD * Blast interaction effect was found for REM fragmentation. CONCLUSIONS: The results suggest that, although persistent concussive symptoms following blast exposure are associated with sleep disturbances, self-reported blast exposure without concurrent symptoms does not appear to contribute to poor sleep quality, insomnia, and disruptive nocturnal disturbances beyond the effects of PTSD. Reduced REM sleep fragmentation may be a sensitive index of the synergetic effects of both psychological and physical insults. PMID- 26414976 TI - Measuring Treatment Outcomes in Comorbid Insomnia and Fibromyalgia: Concordance of Subjective and Objective Assessments. AB - STUDY OBJECTIVES: In insomnia, actigraphy tends to underestimate wake time compared to diaries and PSG. When chronic pain co-occurs with insomnia, sleep may be more fragmented, including more movement and arousals. However, individuals may not be consciously aware of these arousals. We examined the baseline concordance of diaries, actigraphy, and PSG as well as the ability of each assessment method to detect changes in sleep following cognitive behavioral therapy for insomnia (CBT-I). METHODS: Adults with insomnia and fibromyalgia (n = 113) were randomized to CBT-I, CBT for pain, or waitlist control. At baseline and posttreatment, participants completed one night of PSG and two weeks of diaries/actigraphy. RESULTS: At baseline, objective measures estimated lower SOL, higher TST, and higher SE than diaries (ps < 0.05). Compared to PSG, actigraphic estimates were higher for SOL and lower for WASO (ps < 0.05). Repeated measures ANOVAs were conducted for the CBT-I group (n = 15), and significant method by time interactions indicated that the assessment methods differed in their sensitivity to detect treatment-related changes. PSG values did not change significantly for any sleep parameters. However, diaries showed improvements in SOL, WASO, and SE, and actigraphy also detected the WASO and SE improvements (ps < 0.05). CONCLUSIONS: Actigraphy was generally more concordant with PSG than with diaries, which are the recommended assessment for diagnosing insomnia. However, actigraphy showed greater sensitivity to treatment-related changes than PSG; PSG failed to detect any improvements, but actigraphy demonstrated changes in WASO and SE, which were also found with diaries. In comorbid insomnia/fibromyalgia, actigraphy may therefore have utility in measuring treatment outcomes. PMID- 26414977 TI - Derived Arterial Stiffness is Increased in Patients with Obstructive Sleep Apnea and Periodic Limb Movements during Sleep. AB - STUDY OBJECTIVES: Both periodic limb movements during sleep (PLMS) and obstructive sleep apnea (OSA) have been associated with increased risk of cardiovascular disease (CVD). OSA has also been linked to increased large arterial stiffness, which is considered an independent risk factor for CVD. We utilized a previously validated index of large artery stiffness (SIDVP) derived from the digital volume pulse (DVP) to seek comparison in patients with PLMS and OSA. METHODS: Forty-nine adult male subjects, without known comorbidities that could affect arterial stiffness or on vasoactive medication, were retrospectively identified and categorized into controls (n = 8), PLMS (n = 13), OSA (n = 17), and OSA/PLMS (n = 11). The cutoff for PLMS was a periodic limb movement index (PLMI) > 15 events/h, and for OSA an apnea-hypopnea index (AHI) > 10 events/h. SIDVP was derived from the raw data of photoplethysmography of the nocturnal polysomnography, averaged for 2 min prior to sleep study initiation (baseline), after completion in the morning, and every half hour after sleep onset. RESULTS: The groups were age/body mass index-matched. Controls showed lower baseline, morning, and overall SIDVP compared to the other groups (p < 0.01). Patients with PLMS (PLMI: 50.69 +/- 9.7 events/h) and the OSA group (AHI: 29.7 +/- 2 events/h) demonstrated similar overall SIDVP (6.78 +/- 0.08 versus 6.94 +/- 0.04, respectively, p = 0.5), whereas the OSA/PLMS (AHI: 29.35 +/- 8, PLMI: 50.63 +/- 7.2) group demonstrated the highest (7.40 +/- 0.06, p < 0.001). CONCLUSIONS: Based on an easily reproducible and applicable marker of large arterial stiffness, patients with significant PLMS had higher SIDVP when compared to controls and comparable to those with moderate/severe OSA. The OSA/PLMS group had the highest SIDVP, implying a possible additive effect of OSA and PLMS on arterial stiffness. PMID- 26414979 TI - Expiratory Time Constant and Sleep Apnea Severity in the Overlap Syndrome. AB - STUDY OBJECTIVES: Lung mechanics in the overlap of COPD and sleep apnea impact the severity of sleep apnea. Specifically, increased lung compliance with hyperinflation protects against sleep apnea, whereas increased airway resistance worsens sleep apnea. We sought to assess whether the expiratory time constant, which reflects lung mechanics, is associated with sleep apnea severity in such patients. METHODS: Polysomnographies in 34 subjects with the overlap syndrome were reviewed. Three time constants were measured for each of up to 5 stages (wake, NREM stages, and REM). The time constants were derived by fitting time and pressure coordinates on the expiratory portion of a nasal pressure signal along an exponentially decaying equation, and solving for the time constant. Demographics, morphometrics, wake end-tidal CO2, right diaphragmatic arc on a chest radiograph, and the apnea-hypopnea index (AHI) were recorded. RESULTS: The time constant was not associated with age, gender, body mass index, right diaphragmatic arc, or wake end-tidal CO2, and was not significantly different between sleep stages. A mean time constant (TC) was therefore obtained. Subjects with a TC > 0.5 seconds had a greater AHI than those with a TC <= 0.5 seconds (median AHI 58 vs. 18, respectively, p = 0.003; Odds ratio of severe sleep apnea 10.6, 95% CI 3.9-51.1, p = 0.005). CONCLUSIONS: A larger time constant in the overlap syndrome is associated with increased odds of severe sleep apnea, suggesting a greater importance of airway resistance relative to lung compliance in sleep apnea causation in these subjects. PMID- 26414980 TI - Mandibular Advancement Device-Emergent Central Sleep Apnea Can Resolve Spontaneously: A Case Report. AB - ABSTRACT: The development of treatment emergent central sleep apnea (CSA) has been described after almost all obstructive sleep apnea (OSA) therapies. While the course of positive airway pressure (PAP) emergent CSA, is better established; little is known about the natural course of mandibular advancement device (MAD) emergent CSA. Previous reports failed to comment on its natural course or report treatment with advanced ventilator modes such as adaptive servoventilation. We describe spontaneous resolution of MAD emergent CSA in a patient with moderate OSA who refused PAP. We also highlight the need for follow up polysomnography (PSG) after maximal advancement with a MAD and the possible association between MAD emergent CSA and atrial fibrillation. The exact pathophysiology of this phenomenon remains unclear but may relate to high loop gain of the respiratory system resulting in ventilatory overshoot after treatment and atrial fibrillation associated increased susceptibility to periodic ventilation. PMID- 26414978 TI - Influence of Day Length and Physical Activity on Sleep Patterns in Older Icelandic Men and Women. AB - STUDY OBJECTIVES: To identify cross-sectional and seasonal patterns of sleep and physical activity (PA) in community-dwelling, older Icelandic adults using accelerometers. METHODS: A seven-day free-living protocol of 244 (110 female) adults aged 79.7 +/- 4.9 years was conducted as part of a larger population-based longitudinal observational-cohort study in the greater Reykjavik area of Iceland. A subpopulation (n = 72) repeated the 7-day measurement during seasonal periods with greater (13.4 +/- 1.4 h) and lesser (7.7 +/- 1.8 h) daylight. RESULTS: Cross sectional analyses using multiple linear regression models revealed that day length was a significant independent predictor of sleep duration, mid-sleep, and rise time (all p < 0.05). However, the actual within-individual differences in sleep patterns of the repeaters were rather subtle between periods of longer and shorter day-lengths. Compared to women, men had a shorter sleep duration (462 +/- 80 vs. 487 +/- 68 minutes, p = 0.008), earlier rise time, and a greater number of awakenings per night (46.5 +/- 18.3 vs. 40.2 +/- 15.7, p = 0.007), but sleep efficiency and onset latency were similar between the two sexes. Daily PA was also similar between men and women and between periods of longer and shorter day lengths. BMI, age, gender, and overall PA all contributed to the variations in sleep parameters using multiple regression analysis. CONCLUSIONS: The sleep and PA characteristics of this unique population revealed some gender differences, but there was limited variation in response to significant daylight changes which may be due to long-term adaptation. PMID- 26414981 TI - Does Increased IGF-1 Concentration Have a Clear Positive Significance in Reducing Depression and Posttraumatic Arousal Symptoms? PMID- 26414982 TI - Changes in Vitamin D Status after Nasal Continuous Positive Airway Pressure: Could Alterations in Systemic Inflammatory Markers Explain These Observations? PMID- 26414984 TI - Do Evidence-Based Treatments for Circadian Rhythm Sleep-Wake Disorders Make the GRADE? Updated Guidelines Point to Need for More Clinical Research. PMID- 26414983 TI - American Academy of Sleep Medicine (AASM) Position Paper for the Use of Telemedicine for the Diagnosis and Treatment of Sleep Disorders. AB - The American Academy of Sleep Medicine's (AASM) Taskforce on Sleep Telemedicine supports telemedicine as a means of advancing patient health by improving access to the expertise of Board-Certified Sleep Medicine Specialists. However, such access improvement needs to be anchored in attention to quality and value in diagnosing and treating sleep disorders. Telemedicine is also useful to promote professionalism through patient care coordination and communication between other specialties and sleep medicine. Many of the principles and key concepts adopted here are based on U.S. industry standards, with special consideration given to the body of work by the American Telemedicine Association (http://www.americantelemed.org/), and abide by standards endorsed by the American Medical Association (http://www.ama-assn.org/). Practitioners who wish to integrate sleep telemedicine into their practice should have a clear understanding of the salient issues, key terminology, and the following recommendations from the AASM. The Taskforce recommends the following: * Clinical care standards for telemedicine services should mirror those of live office visits, including all aspects of diagnosis and treatment decisions as would be reasonably expected in traditional office-based encounters. * Clinical judgment should be exercised when determining the scope and extent of telemedicine applications in the diagnosis and treatment of specific patients and sleep disorders. * Live Interactive Telemedicine for sleep disorders, if utilized in a manner consistent with the principles outlined in this document, should be recognized and reimbursed in a manner competitive or comparable with traditional in-person visits. * Roles, expectations, and responsibilities of providers involved in the delivery of sleep telemedicine should be defined, including those at originating sites and distant sites. * The practice of telemedicine should aim to promote a care model in which sleep specialists, patients, primary care providers, and other members of the healthcare team aim to improve the value of healthcare delivery in a coordinated fashion. * Appropriate technical standards should be upheld throughout the telemedicine care delivery process, at both the originating and distant sites, and specifically meet the standards set forth by the Health Insurance Portability and Accountability Act (HIPAA). * Methods that aim to improve the utility of telemedicine exist and should be explored, including the utilization of patient presenters, local resources and providers, adjunct testing, and add-on technologies. * Quality Assurance processes should be in place for telemedicine care delivery models that aim to capture process measures, patient outcomes, and patient/provider experiences with the model(s) employed. * Time for data management, quality processes, and other aspects of care delivery related to telemedicine encounters should be recognized in value based care delivery models. * The use of telemedicine services and its equipment should adhere to strict professional and ethical standards so as not to violate the intent of the telemedicine interaction while aiming to improve overall patient access, quality, and/or value of care. * When billing for telemedicine services, it is recommended that patients, providers, and others rendering services understand payor reimbursements, and that there be financial transparency throughout the process. * Telemedicine utilization for sleep medicine is likely to rapidly expand, as are broader telehealth applications in general; further research into the impact and outcomes of these are needed. This document serves as a resource by defining issues and terminology and explaining recommendations. However, it is not intended to supersede regulatory or credentialing recommendations and guidelines. It is intended to support and be consistent with professional and ethical standards of the profession. PMID- 26414985 TI - In Memoriam: Arthur J. Spielman, PhD 1947-2015. PMID- 26414988 TI - AASM Young Investigators Research Forum Helps Ensure a Bright Future for Sleep and Circadian Research. PMID- 26414987 TI - Effect of Acute Sleep Disturbance and Recovery on Insulin-Like Growth Factor-1 (IGF-1): Possible Connections and Clinical Implications. PMID- 26414989 TI - Confronting Drowsy Driving: The American Academy of Sleep Medicine Perspective. AB - ABSTRACT: Drowsy driving is a serious public health concern which is often difficult for individual drivers to identify. While it is important for drivers to understand the causes of drowsy driving, there is still insufficient scientific knowledge and public education to prevent drowsy driving. As a result, the AASM is calling upon institutions and policy makers to increase public awareness and improve education on the issue, so our society can better recognize and prevent drowsy driving. The AASM has adopted a position statement to educate both healthcare providers and the general public about drowsy driving risks and countermeasures. PMID- 26414986 TI - Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline. AB - A systematic literature review and meta-analyses (where appropriate) were performed and the GRADE approach was used to update the previous American Academy of Sleep Medicine Practice Parameters on the treatment of intrinsic circadian rhythm sleep-wake disorders. Available data allowed for positive endorsement (at a second-tier degree of confidence) of strategically timed melatonin (for the treatment of DSWPD, blind adults with N24SWD, and children/ adolescents with ISWRD and comorbid neurological disorders), and light therapy with or without accompanying behavioral interventions (adults with ASWPD, children/adolescents with DSWPD, and elderly with dementia). Recommendations against the use of melatonin and discrete sleep-promoting medications are provided for demented elderly patients, at a second- and first-tier degree of confidence, respectively. No recommendations were provided for remaining treatments/ populations, due to either insufficient or absent data. Areas where further research is needed are discussed. PMID- 26414991 TI - Postoperative Complications in Patients with Obstructive Sleep Apnea: Where Do We Stand? PMID- 26414992 TI - sigma-Aromaticity in polyhydride complexes of Ru, Ir, Os, and Pt. AB - Transition-metal hydrides represent a unique class of compounds, which are essential for catalysis, organic synthesis, and hydrogen storage. In this work we study IrH5(PPh3)2, (RuH5(P(i)Pr3)2)(-), (OsH5(P(i)Pr3)2)(-), and OsH4(PPhMe2)3 polyhydride complexes, inspired by the recent discovery of the sigma-aromatic PtZnH5(-) cluster anion. The distinctive feature of these molecules is that, like in the PtZnH5(-) cluster, the metal is five-fold coordinated in-plane, and holds additional ligands at the axial positions. This work shows that the unusual coordination in these compounds indeed can be explained by sigma-aromaticity in the pentagonal arrangement, stabilized by the atomic orbitals on the metal. Based on this newly elucidated bonding principle, we additionally propose a new family of polyhydrides that display a uniquely high coordination. We also report the first indications of how aromaticity may impact the reactivity of these molecules. PMID- 26414990 TI - The Effects of Milnacipran on Sleep Disturbance in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled, Two-Way Crossover Study. AB - OBJECTIVE: This study examined the effects of milnacipran on polysomnographic (PSG) measures of sleep and subjective complaints in patients with fibromyalgia and disturbed sleep. METHODS: This was a single-site, double-blind, placebo controlled, two-period crossover PSG study. Eligible subjects (aged 28-72 y) were randomized (1:1) to milnacipran (100 mg/d) or placebo for crossover period 1, and vice versa for period 2. Each crossover period comprised a dose-escalation and dose-maintenance phase, with a 2-w taper/washout between periods. In-laboratory PSGs were collected at baseline, and at the end of each treatment period. The primary endpoints were the difference in PSG-recorded wake after sleep onset (WASO), number of awakenings after sleep onset (NAASO), and sleep efficiency (SE) between 4 w of maintenance treatment with milnacipran and placebo. Other PSG measures, subject-rated sleep, fatigue, physical functioning, and pain were assessed. Post hoc analysis was performed in subjects showing at least 25% reduction in pain from baseline in the Brief Pain Inventory Score (responders). RESULTS: Of 19 subjects randomized, 15 completed both periods. Subjects treated with milnacipran showed no significant improvements in WASO and NAASO, but showed reduced SE (p = 0.049). Milnacipran did not show significant improvement in other PSG parameters or subjective endpoints. Two thirds of completers met responder criteria and additionally showed a significant improvement in daily effect of pain (p = 0.043) and subjective sleep quality (p = 0.040). CONCLUSION: The data suggest that milnacipran is not sedating in most patients with fibromyalgia and improvements in sleep are likely a result of pain improvement. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT01234675. PMID- 26414993 TI - A Sustainable Multicomponent Pyrimidine Synthesis. AB - Since alcohols are accessible from indigestible biomass (lignocellulose), the development of novel preferentially catalytic reactions in which alcohols are converted into important classes of fine chemicals is a central topic of sustainable synthesis. Multicomponent reactions are especially attractive in organic chemistry as they allow the synthesis of large libraries of diversely functionalized products in a short time when run in a combinatorial fashion. Herein, we report a novel, regioselective, iridium-catalyzed multicomponent synthesis of pyrimidines from amidines and up to three (different) alcohols. This reaction proceeds via a sequence of condensation and dehydrogenation steps which give rise to selective C-C and C-N bond formations. While the condensation steps deoxygenate the alcohol components, the dehydrogenations lead to aromatization. Two equiv of hydrogen and water are liberated in the course of the reactions. PN5P-Ir-pincer complexes, recently developed in our laboratory, catalyze this sustainable multicomponent process most efficiently. A total of 38 different pyrimidines were synthesized in isolated yields of up to 93%. Strong points of the new protocol are its regioselectivity and thus the immediate access to pyrimidines that are highly and unsymmetrically decorated with alkyl or aryl substituents. The combination of this novel protocol with established methods for converting alcohols to nitriles now allows to selectively assemble pyrimidines from four alcohol building blocks and 2 equiv of ammonia. PMID- 26414994 TI - Measures of Quality of Care for People with HIV: A Scoping Review of Performance Indicators for Primary Care. AB - The healthcare of people with HIV is transitioning from specialty care to the primary healthcare (PHC) system. However, many of the performance indicators used to measure the quality of HIV care pre-date this transition. The goal of this work was to examine how existing HIV care performance indicators measure the comprehensive and longitudinal care offered in a PHC setting. A scoping review consisting of peer-reviewed and grey literature searches was performed. Two reviewers evaluated study eligibility and indicators in documents meeting inclusion criteria were extracted into a database. Indicators were matched to a PHC performance measurement framework to determine their applicability for evaluating quality of care in the PHC setting. The literature search identified 221 publications, of which 47 met inclusion criteria. 1184 indicators were extracted and removal of duplicates left 558 unique indicators. A majority of the 558 indicators fell under the 'secondary prevention' (12%) and 'care of chronic conditions' (33%) domains when indicators were matched to the PHC performance framework. Despite the imbalance, nearly all performance domains in the PHC framework were populated by at least one indicator with significant concentrations in domains such as patient-provider relationship, patient satisfaction, population and community characteristics, and access to care. Existing performance frameworks for the care of people with HIV provide a comprehensive set of indicators that align well with a PHC performance framework. Nonetheless, some important elements of care, such as patient-reported outcomes, are poorly covered by existing indicators. Advancing our understanding of how the experience of care for people with HIV is impacted by changes in health services delivery, specifically more care within the PHC system, will require performance indicators to capture this aspect of HIV care. PMID- 26414995 TI - DAZL Expression Explains Origin and Central Formation of Primordial Germ Cells in Chickens. AB - The timing and biological events associated with germ cell specification in chickens have not been determined yet. In this study, we report the origin of primordial germ cells (PGCs) and germ plasm dynamics through investigation of the expression of the chicken homolog of deleted in azoospermia-like (cDAZL) gene during germ cell specification. Asymmetric localization of germ plasm in the center of oocytes from preovulatory follicle stages leads to PGCs being formed in the center. During cleavage stages, DAZL expression pattern changes from a subcellular localization to a diffuse form before and after zygotic genome activation. Meanwhile, PGCs exhibit transcriptional active status during their specification. In addition, knockdown studies of cDAZL, which result in reduced proliferation, aberrant gene expression profiles, and PGC apoptosis in vitro, suggest its possible roles for PGC formation in chicken. In conclusion, DAZL expression reveals formation and initial positioning of PGCs in chickens. PMID- 26414996 TI - Relationship between circadian rhythm amplitude and stability with sleep quality and sleepiness among shift nurses and health care workers. AB - INTRODUCTION: Sleep is affected by the circadian cycle and its features. Amplitude and stability of circadian rhythm are important parameters of the circadian cycle. This study aims to examine the relationship between amplitude and stability of circadian rhythm with sleep quality and sleepiness. METHOD: In this cross-sectional research, 315 shift nurses and health care workers from educational hospitals of Kerman University of Medical Sciences (KUMS), Iran, were selected using a random sampling method. The Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and Circadian Type Inventory (CTI) were used to collect the required data. RESULTS: In this study, 83.2% suffered from poor sleep and one-half had moderate and excessive sleepiness. The results showed that flexibility in circadian rhythm stability, job stress and sleepiness are among the factors affecting quality sleep in shift workers. DISCUSSION: Those whose circadian rhythm amplitude was languid suffered more from sleepiness and those whose circadian stability was flexible had a better sleep. Variables including circadian rhythm stability (flexible/rigid) and amplitude (languid/vigorous) can act as predictive indices in order to employ people in a shift work system so that sleepiness and a drop in quality of sleep are prevented. PMID- 26414997 TI - Analytical Ultracentrifugation as an Approach to Characterize Recombinant Adeno Associated Viral Vectors. AB - Recombinant adeno-associated viral (rAAV) vectors represent a novel class of biopharmaceutical drugs. The production of clinical-grade rAAV vectors for gene therapy would benefit from analytical methods that are able to monitor drug product quality with regard to homogeneity, purity, and manufacturing consistency. Here, we demonstrate the novel application of analytical ultracentrifugation (AUC) to characterize the homogeneity of preparations of rAAV vectors. We show that a single sedimentation velocity run of rAAV vectors detected and quantified a number of different viral species, such as vectors harboring an intact genome, lacking a vector genome (empty particles), and containing fragmented or incomplete vector genomes. This information is obtained by direct boundary modeling of the AUC data generated from refractometric or UV detection systems using the computer program SEDFIT. Using AUC, we show that multiple parameters contributed to vector quality, including the AAV genome form (i.e., self-complementary vs. single-stranded), vector genome size, and the production and purification methods. Hence, AUC is a critical tool for identifying optimal production and purification processes and for monitoring the physical attributes of rAAV vectors to ensure their quality. PMID- 26414998 TI - Therapeutic ultrasound stimulates MC3T3-E1 cell proliferation through the activation of NF-kappaB1, p38alpha, and mTOR. AB - BACKGROUND AND OBJECTIVES: As the population ages, osteometabolic diseases and osteoporotic fractures emerge, resulting in substantial healthcare resource utilization and impaired quality of life. Many types of mechanical stimulation have the potential of being recognized by bone cells after a mechanical sign is transformed into a biological one (a process called mechanotransduction). The therapeutic ultrasound (TU) is one of several resources capable of promoting bone cell mechanical stimulation. Therefore, the main purpose of present study was to evaluate the effect of TU on the proliferation of pre-osteoblasts using in vitro bioassays. STUDY DESIGN/MATERIALS AND METHODS: We used MC3T3-E1 pre-osteoblast lineage cells kept in Alpha medium. Cells were treated using pulsed mode therapeutic ultrasound, with frequency of 1 MHz, intensity of 0.2 W/cm(2) (SATA), duty cycle of 20%, for 30 minutes. Nifedipine and rapamycin were used to further investigate the role of L-type Ca(2+) channels and mTOR pathway. Intracellular calcium, TGF-beta1, magnesium, and the mRNA levels of osteopontin, osteonectin, NF-kappaB1, p38alpha were evaluated. RESULTS: The results show that TU stimulates the growth of MC3T3-E1 cells and decreases the supernatant calcium and magnesium content. Also, it increases intracellular calcium, activates NF-kappaB1 and mTOR complex via p38alpha. Moreover, TU promoted a decrease in the TGF-beta1 synthesis, which is a cell growth inhibitor. CONCLUSIONS: Therapeutic ultrasound, with frequency of 1 MHz, intensity of 0.2 W/cm(2) (SATA) and pulsed mode, for 30 minutes, was able to increase the proliferation of preosteoblast-like bone cells. This effect was mediated by a calcium influx, with a consequent activation of the mTOR pathway, through increased NF-kappaB1 and p38alpha. PMID- 26414999 TI - Serological evidence for the presence of influenza D virus in small ruminants. AB - Influenza D virus (FLUDV) was isolated from diseased pigs with respiratory disease symptoms in 2011, and since then the new virus has also been spread to cattle. Little is known about the susceptibility of other agricultural animals and poultry to FLUDV. This study was designed to determine if other farm animals such as goats, sheep, chickens, and turkey are possible hosts to this newly emerging influenza virus. 648 goat and sheep serum samples and 250 chicken and turkey serum samples were collected from 141 small ruminant and 25 poultry farms from different geographical locations in the United States and Canada. Serum samples were examined using the hemagglutination inhibition (HI) assay and the sheep and goat samples were further analyzed using the serum neutralization assay. Results of this study showed FLUDV antibodies were detected in 13.5% (17/126) of the sampled sheep farms, and 5.2% (29/557) of tested sheep serum samples were positive for FLUDV antibodies. For the goat results, the FLUDV antibodies were detected in 13.3% (2/15) of the sampled farms, and 8.8% (8/91) of the tested goat serum samples were positive for FLUDV antibodies. Furthermore, all tested poultry serum samples were negative for FLUDV antibodies. Our data demonstrated that sheep and goat are susceptible to FLUDV virus and multiple states in U.S. have this virus infection already in these two species. This new finding highlights a need for future surveillance of FLUDV virus in small ruminants toward better understanding both the origin and natural reservoir of this new virus. PMID- 26415000 TI - Determination of 11 quinolones in bovine milk using immunoaffinity stir bar sorptive microextraction and liquid chromatography with fluorescence detection. AB - A sensitive, selective and reproducible immunoaffinity stir bar sorptive microextraction (SBSME) coupled with liquid chromatography-fluorescence method for determination of 11 quinolones (QNs) in bovine milk was developed and validated. It is first report of a broad-specificity monoclonal antibody to QNs that has been immobilized to glass bar for preparation of a re-usable immunoaffinity stir bar. Analytes were extracted by placing stir bar in milk and shaking on a rotary shaker for 30min at 30rpm, followed by liquid chromatography and fluorescence detection. The newly developed method has limits of detection for each QN from 0.05 to 0.1ng/g with intra-day and inter-day precision ranging from 3.2 to 11.9% and from 5.2 to 12.5%, respectively. This allowed us to quantitatively analyze drugs in bovine milk with the advantage of significantly simplified sample preparation. The proposed method was successfully applied to the bovine milk samples analyses with QNs, demonstrating its rare application in animal food safety analysis. PMID- 26415001 TI - Muscular Dystrophy Mutations Impair the Nuclear Envelope Emerin Self-assembly Properties. AB - More than 100 genetic mutations causing X-linked Emery-Dreifuss muscular dystrophy have been identified in the gene encoding the integral inner nuclear membrane protein emerin. Most mutations are nonsense or frameshift mutations that lead to the absence of emerin in cells. Only very few cases are due to missense or short in-frame deletions. Molecular mechanisms explaining the corresponding emerin variants' loss of function are particularly difficult to identify because of the mostly intrinsically disordered state of the emerin nucleoplasmic region. We now demonstrate that this EmN region can be produced as a disordered monomer, as revealed by nuclear magnetic resonance, but rapidly self-assembles in vitro. Increases in concentration and temperature favor the formation of long curvilinear filaments with diameters of approximately 10 nm, as observed by electron microscopy. Assembly of these filaments can be followed by fluorescence through Thioflavin-T binding and by Fourier-transform Infrared spectrometry through formation of beta-structures. Analysis of the assembly properties of five EmN variants reveals that del95-99 and Q133H impact filament assembly capacities. In cells, these variants are located at the nuclear envelope, but the corresponding quantities of emerin-emerin and emerin-lamin proximities are decreased compared to wild-type protein. Furthermore, variant P183H favors EmN aggregation in vitro, and variant P183T provokes emerin accumulation in cytoplasmic foci in cells. Substitution of residue Pro183 might systematically favor oligomerization, leading to emerin aggregation and mislocalization in cells. Our results suggest that emerin self-assembly is necessary for its proper function and that a loss of either the protein itself or its ability to self assemble causes muscular dystrophy. PMID- 26415002 TI - 3D Printed Microtransporters: Compound Micromachines for Spatiotemporally Controlled Delivery of Therapeutic Agents. AB - Functional compound micromachines are fabricated by a design methodology using 3D direct laser writing and selective physical vapor deposition of magnetic materials. Microtransporters with a wirelessly controlled Archimedes screw pumping mechanism are engineered. Spatiotemporally controlled collection, transport, and delivery of micro particles, as well as magnetic nanohelices inside microfluidic channels are demonstrated. PMID- 26415003 TI - When Should a Positive Surgical Margin Ring a Bell? An Analysis of a Multi Institutional Robot-Assisted Laparoscopic Radical Prostatectomy Database. AB - OBJECTIVE: The impact of positive surgical margin (SM) on cancer control outcomes in prostate cancer patients is a subject of continuous debate. We test the hypothesis that the impact of SM on clinical recurrence (CR) rate may vary based on the other clinical/pathologic characteristics of the tumor. MATERIALS AND METHODS: We focused on 5290 patients treated with robot-assisted radical prostatectomy and pelvic node dissection, between 2002 and 2013, at three tertiary care centers. Regression tree analysis stratified patients into risk groups based on their tumor characteristics and the corresponding CR rate. Kaplan Meier log-rank and multivariable Cox regression models tested the relationship between SM status and CR rate in each tree-generated risk group. RESULTS: Mean (median) follow-up time was 47.7 (39.0) months. Regression tree analysis that considered all available covariates, except SM status, divided patients based on their CR risk into the following risk groups: (1) high risk (any pT3b/pT4 disease); (2) intermediate risk (<=pT3a disease and pGS 8-10); (3) low risk (<=pT3a, pGS <=7, and prostate-specific antigen [PSA] >9 ng/mL); and (4) very low risk (<=pT3a, pGS <=7, and PSA <=9 ng/mL). Positive SM had a significant detrimental impact on CR risk only in two groups: intermediate risk (p < 0.001) and high risk (p = 0.01). These observations were confirmed by multivariable analyses. CONCLUSIONS: Our findings show that positive SM had a detrimental impact on CR only in a minority of patients (15%), specifically in those with advanced pathologic stage and/or pathologically poorly differentiated tumor. For all the remaining patients (85%), positive SM by itself did not increase the risk of CR. PMID- 26415004 TI - Aryl Hydrocarbon Receptor Deficiency Attenuates Oxidative Stress-Related Mesangial Cell Activation and Macrophage Infiltration and Extracellular Matrix Accumulation in Diabetic Nephropathy. AB - AIMS: Activation of glomerular mesangial cells (MCs) and functional changes of renal tubular cells are due to metabolic abnormalities, oxidative stress, and matrix accumulation in the diabetic nephropathy (DN). Aryl hydrocarbon receptor (AhR) activation has been implicated in DN. In this study, we investigated the role of AhR in the pathophysiological processes of DN using AhR knockout (AhRKO) and pharmacological inhibitor alpha-naphthoflavone mouse models. RESULTS: The increased blood glucose, glucose intolerance, MC activation, macrophage infiltration, and extracellular matrix (ECM) accumulation were significantly attenuated in AhRKO mice with diabetic inducer streptozotocin (STZ) treatment. AhR deficiency by genetic knockout or pharmacological inhibition also decreased the induction of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2), lipid peroxidation, oxidative stress, NADPH oxidase activity, and N-E carboxymethyllysine (CML, a major advanced glycation end product) in STZ-induced diabetic mice. CML showed remarkably increased AhR/COX-2 DNA-binding activity, protein-DNA interactions, gene regulation, and ECM formation in MCs and renal proximal tubular cells, which could be reversed by siRNA-AhR transfection. CML increased AhR nuclear translocation and biological activity in MCs and renal proximal tubular cells could also be effectively attenuated by antioxidants. INNOVATION: We elucidate for the first time that AhR plays an important role in MC activation, macrophage infiltration, and ECM accumulation in DN conferred by oxidative stress. CONCLUSIONS: AhR-regulated COX-2/PGE2 expression and ECM deposition through oxidative stress cascade is involved in the CML-triggered MC activation and macrophage infiltration. These findings suggest new insights into the development of therapeutic approaches to reduce diabetic microvascular complications. Antioxid. Redox Signal. 24, 217-231. PMID- 26415005 TI - Low concentrations of metal mixture exposures have adverse effects on selected biomarkers of Xenopus laevis tadpoles. AB - Polluted ecosystems may contain mixtures of metals, such that the combinations of metals, even in low concentrations, may cause adverse effects. In the present study, we focused on toxic effects of mixtures of selected metals, the LC50 values, and also their safety limit in aquatic systems imposed by the European legislation using a model organism. Xenopus laevis tadpoles were used as test organisms. They were exposed to metals or their combinations due to 96-h LC50 values. Glutathione S-transferase (GST), glutathione reductase (GR), acetylcholinesterase (AChE), carboxylesterase (CaE), glutathione peroxidase (GPx), and catalase (CAT) levels were evaluated. Metallothionein concentrations were also determined. The LC50s for Cd, Pb, and Cu were calculated as 5.81mg AI/L, 123.05mg AI/L, and 0.85mg AI/L, respectively. Low lethality ratios were observed with unary exposure of each metal in lower concentrations. Double or triple combinations of LC50 and LC50/2 concentrations caused 100% lethality with Cd+Cu and Pb+Cd+Cu mixtures, while the Pb+Cu mixture also caused high lethal ratios. The selected enzyme activities were significantly affected by metals or mixtures, and dose-related effects were determined. The metallothionein levels generally increased as related to concentration in unary metals and mixtures. Acceptable limit values of unary metals and mixtures did not significantly change metallothionein levels. The results suggest that oxidative stress-related mechanisms are involved in the toxicity induced by selected metals with combinations of very low concentrations. PMID- 26415007 TI - MyCompoundID MS/MS Search: Metabolite Identification Using a Library of Predicted Fragment-Ion-Spectra of 383,830 Possible Human Metabolites. AB - We report an analytical tool to facilitate metabolite identification based on an MS/MS spectral match of an unknown to a library of predicted MS/MS spectra of possible human metabolites. To construct the spectral library, the known endogenous human metabolites in the Human Metabolome Database (HMDB) (8,021 metabolites) and their predicted metabolic products via one metabolic reaction in the Evidence-based Metabolome Library (EML) (375,809 predicted metabolites) were subjected to in silico fragmentation to produce the predicted MS/MS spectra. This spectral library is hosted at the public MCID Web site ( www.MyCompoundID.org ), and a spectral search program, MCID MS/MS, has been developed to allow a user to search one or a batch of experimental MS/MS spectra against the library spectra for possible match(s). Using MS/MS spectra generated from standard metabolites and a human urine sample, we demonstrate that this tool is very useful for putative metabolite identification. It allows a user to narrow down many possible structures initially found by using an accurate mass search of an unknown metabolite to only one or a few candidates, thereby saving time and effort in selecting or synthesizing metabolite standard(s) for eventual positive metabolite identification. PMID- 26415009 TI - Harmful algal blooms should be treated as contaminants. PMID- 26415006 TI - Prevalence and clinical significance of nodular regenerative hyperplasia in liver biopsies. AB - BACKGROUND: Nodular regenerative hyperplasia (NRH) is a rare histological disorder associated with a wide variety of systemic diseases. AIMS: We aimed (i) to report the prevalence of NRH in a database of liver biopsies (LBs) and the frequency of portal hypertension (PHT) at diagnosis, and (ii) to investigate whether associated diseases and/or specific histological lesions, including abnormalities of the microvasculature, were related to PHT. METHODS: Patients with a histological diagnosis of NRH, referred by seven clinical departments, were retrospectively selected. Clinical, biological, radiological, haemodynamic and endoscopic data at diagnosis were recorded. LBs were reassessed for microvascular abnormalities. RESULTS: NRH was diagnosed in 4.4% of LBs (n = 159, male: 52%, mean age: 54). Among patients referred for unexplained liver enzyme abnormalities, 15% had NRH. PHT was present at diagnosis in 45 patients (38%), including 13 with portal thrombosis; 65% of patients had an associated disorder. Obliteration of portal vein branches, observed in the LBs of 17 patients (11%), was significantly associated with PHT (P = 0.02). Periportal angiomatosis, observed in 101 patients (63%), was associated with the absence of PHT (P < 10( 4) ). CONCLUSION: We suggest that NRH is a frequent histological lesion in the setting of unexplained liver enzyme abnormalities. PHT is present at the time of diagnosis in 1/3 of patients regardless of the presence of associated disease. The frequency of periportal angiomatosis in NRH without obliteration of portal vein branches, and its association with the absence of PHT suggest that obstructive portal venopathy would not represent the most frequent mechanism involved in NRH. PMID- 26415010 TI - A multi-attribute decision analysis for decommissioning offshore oil and gas platforms. AB - The 27 oil and gas platforms off the coast of southern California are reaching the end of their economic lives. Because their decommissioning involves large costs and potential environmental impacts, this became an issue of public controversy. As part of a larger policy analysis conducted for the State of California, we implemented a decision analysis as a software tool (PLATFORM) to clarify and evaluate decision strategies against a comprehensive set of objectives. Key options selected for in-depth analysis are complete platform removal and partial removal to 85 feet below the water line, with the remaining structure converted in place to an artificial reef to preserve the rich ecosystems supported by the platform's support structure. PLATFORM was instrumental in structuring and performing key analyses of the impacts of each option (e.g., on costs, fishery production, air emissions) and dramatically improved the team's productivity. Sensitivity analysis found that disagreement about preferences, especially about the relative importance of strict compliance with lease agreements, has much greater effects on the preferred option than does uncertainty about specific outcomes, such as decommissioning costs. It found a near-consensus of stakeholders in support of partial removal and "rigs-to-reefs" program. The project's results played a role in the decision to pass legislation enabling an expanded California "rigs-to-reefs" program that includes a mechanism for sharing cost savings between operators and the state. PMID- 26415019 TI - Clinical and molecular diagnosis of pathologic complete response in rectal cancer. AB - The current standard approach to locally advanced rectal cancer involves pre operative chemoradiotherapy followed by total mesorectal excision. This practice is supported by several studies that have demonstrated superior local control with this approach. This strategy, leads to a pathologic complete response (pCR) in a substantial proportion of patients treated with neoadjuvant therapy. Furthermore, pCR has been shown to be a reliable predictor of improved oncologic outcomes. This observation has led to an increased interest in the pursuit of identifying clinical, radiographic, pathologic and biochemical predictors of pCR. This review discusses the promising approaches to and most recent advancements in predicting pCR in rectal cancer. PMID- 26415018 TI - Noninvasive electrocardiographic imaging of chronic myocardial infarct scar. AB - BACKGROUND: Myocardial infarction (MI) scar constitutes a substrate for ventricular tachycardia (VT), and an accurate delineation of infarct scar may help to identify reentrant circuits and thus facilitate catheter ablation. One of the recent advancements in characterization of a VT substrate is its volumetric delineation within the ventricular wall by noninvasive electrocardiographic imaging. This paper compares, in four specific cases, epicardial and volumetric inverse solutions, using magnetic resonance imaging (MRI) with late gadolinium enhancement as a gold standard. METHODS: For patients with chronic MI, who presented at Glasgow Western Infirmary, delayed-enhancement MRI and 120-lead body surface potential mapping (BSPM) data were acquired and 4 selected cases were later made available to a wider community as part of the 2007 PhysioNet/Computers in Cardiology Challenge. These data were used to perform patient-specific inverse solutions for epicardial electrograms and morphology-based criteria were applied to delineate infarct scar on the epicardial surface. Later, the Rochester group analyzed the same data by means of a novel inverse solution for reconstructing intramural transmembrane potentials, to delineate infarct scar in three dimensions. Comparison of the performance of three specific inverse-solution algorithms is presented here, using scores based on the 17-segment ventricular division scheme recommended by the American Heart Association. RESULTS: The noninvasive methods delineating infarct scar as three-dimensional (3D) intramural distribution of transmembrane action potentials outperform estimates providing scar delineation on the epicardial surface in all scores used for comparison. In particular, the extent of infarct scar (its percentage mass relative to the total ventricular mass) is rendered more accurately by the 3D estimate. Moreover, the volumetric rendition of scar border provides better clues to potential targets for catheter ablation. CONCLUSIONS: Electrocardiographic inverse solution providing transmural distribution of ventricular action potentials is a promising tool for noninvasively delineating the extent and location of chronic MI scar. Further validation on a larger data set with detailed gold-standard data is needed to confirm observations reported in this study. PMID- 26415022 TI - Modified Genomic Sequencing PCR Using the MiSeq Platform to Identify Retroviral Integration Sites. AB - High-throughput mapping of retroviral vector integration sites (RIS) has become an invaluable tool to evaluate novel gene therapy vectors and to track clonal contribution in preclinical and clinical studies. Beard et al. (Methods Mol Biol 2014;1185:321-344) described an improved protocol developed for efficient capture, sequencing, and analysis of RIS that preserves gene-modified clonal contribution information. Here we describe adaptations to the previously published modified genomic sequencing PCR (MGS-PCR) protocol using the Illumina MiSeq paired-end sequencing platform. Lentiviral, gammaretroviral, and foamy virus vector integrations were analyzed. MGS-PCR using the MiSeq platform allows for the use of merged paired-end reads, which allows for efficient localization of RIS to published genomes. PMID- 26415024 TI - Red-Shifting Azobenzene Photoswitches for in Vivo Use. AB - Recently, there has been a great deal of interest in using the photoisomerization of azobenzene compounds to control specific biological targets in vivo. These azo compounds can be used as research tools or, in principle, could act as optically controlled drugs. Such "photopharmaceuticals" offer the prospect of targeted drug action and an unprecedented degree of temporal control. A key feature of azo compounds designed to photoswitch in vivo is the wavelength of light required to cause the photoisomerization. To pass through tissue such as the human hand, wavelengths in the red, far-red, or ideally near infrared region are required. This Account describes our attempts to produce such azo compounds. Introducing electron-donating or push/pull substituents at the para positions delocalizes the azobenzene chromophore and leads to long wavelength absorption but usually also lowers the thermal barrier to interconversion of the isomers. Fast thermal relaxation means it is difficult to produce a large steady state fraction of the cis isomer. Thus, specifically activating or inhibiting a biological process with the cis isomer would require an impractically bright light source. We have found that introducing substituents at all four ortho positions leads to azo compounds with a number of unusual properties that are useful for in vivo photoswitching. When the para substituents are amide groups, these tetra-ortho substituted azo compounds show unusually slow thermal relaxation rates and enhanced separation of n-pi* transitions of cis and trans isomers compared to analogues without ortho substituents. When para positions are substituted with amino groups, ortho methoxy groups greatly stabilize the azonium form of the compounds, in which the azo group is protonated. Azonium ions absorb strongly in the red region of the spectrum and can reach into the near-IR. These azonium ions can exhibit robust cis-trans isomerization in aqueous solutions at neutral pH. By varying the nature of ortho substituents, together with the number and nature of meta and para substituents, long wavelength switching, stability to photobleaching, stability to hydrolysis, and stability to reduction by thiols can all be crafted into a photoswitch. Some of these newly developed photoswitches can be used in whole blood and show promise for effective use in vivo. It is hoped they can be combined with appropriate bioactive targets to realize the potential of photopharmacology. PMID- 26415023 TI - Microneedle fractional radiofrequency increases epidermal hyaluronan and reverses age-related epidermal dysfunction. AB - BACKGROUND AND OBJECTIVE: Skin aging results in physiological alterations in keratinocyte activities and epidermal function, as well as dermal changes. Yet, the cellular and molecular mechanisms that cause epidermal dysfunction during skin aging are not well understood. Recently, the role of epidermal hyaluronan (HA) as an active regulator of dynamic cellular processes is getting attention and alterations in HA metabolism are thought to be important in age-related epidermal dysfunction. Microneedle fractional radiofrequency (RF) has shown effects for improving cutaneous aging. However, little is known about the effects of fractional RF on the epidermal HA and epidermal function. We investigated the effect of microneedle fractional RF on the expression of epidermal HA in young and aged mice epidermis. MATERIALS AND METHODS: We performed fractional RF on the dorsal skin of 30 8-week-old (young) hairless mice and 15 47-week-old (aged) C57BL/6J mice. Skin samples were collected on day 1, 3, and 7. HA content was measured by ELISA. Gene expressions of CD 44, HABP4, and HAS3 were measured using real time RT-PCR. Immunohistochemistry for detection of HA, CD44, PCNA, and filaggrin were performed. RESULTS: HA content and the mRNA levels of HABP4, CD44, and HAS3 were upregulated in the epidermis of both young and aged mice after microneedle fractional RF treatment. The expression was increased from day 1 after treatment and increased expression persisted on day 7. Fractional RF treatment significantly increased PCNA and filaggrin expression only in the aged mice skin. CONCLUSION: Microneedle fractional RF increased epidermal HA and CD44 expression in both young and aged mice and reversed age-related epidermal dysfunction especially in aged mice, suggesting a new mechanism involved in the skin rejuvenation effect of microneedle fractional RF. PMID- 26415025 TI - Discovery of a novel neuroprotectant, BHDPC, that protects against MPP+/MPTP induced neuronal death in multiple experimental models. AB - Progressive degeneration and death of neurons are main causes of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Although some current medicines may temporarily improve their symptoms, no treatments can slow or halt the progression of neuronal death. In this study, a pyrimidine derivative, benzyl 7-(4-hydroxy-3-methoxyphenyl)-5-methyl-4,7 dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (BHDPC), was found to attenuate dramatically the MPTP-induced death of dopaminergic neurons and improve behavior movement deficiency in zebrafish, supporting its potential neuroprotective activity in vivo. Further study in rat organotypic cerebellar cultures indicated that BHDPC was able to suppress MPP(+)-induced cell death of brain tissue slices ex vivo. The protective effect of BHDPC against MPP(+) toxicity was also effective in human neuroblastoma SH-SY5Y cells through restoring abnormal changes in mitochondrial membrane potential and numerous apoptotic regulators. Western blotting analysis indicated that BHDPC was able to activate PKA/CREB survival signaling and further up-regulate Bcl2 expression. However, BHDPC failed to suppress MPP(+)-induced cytotoxicity and the increase of caspase 3 activity in the presence of the PKA inhibitor H89. Taken together, these results suggest that BHDPC is a potential neuroprotectant with prosurvival effects in multiple models of neurodegenerative disease in vitro, ex vivo, and in vivo. PMID- 26415026 TI - Metallothionein plays a prominent role in the prevention of diabetic nephropathy by sulforaphane via up-regulation of Nrf2. AB - Sulforaphane (SFN) prevents diabetic nephropathy (DN) in type 1 diabetes via up regulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). However, it has not been addressed whether SFN also prevents DN from type 2 diabetes or which Nrf2 downstream gene(s) play(s) the key role in SFN renal protection. Here we investigated whether Nrf2 is required for SFN protection against type 2 diabetes induced DN and whether metallothionein (MT) is an Nrf2 downstream antioxidant using Nrf2 knockout (Nrf2-null) mice. In addition, MT knockout mice were used to further verify if MT is indispensable for SFN protection against DN. Diabetes increased albuminuria, renal fibrosis, and inflammation were significantly prevented by SFN, and Nrf2 and MT expression was increased. However, SFN renal protection was completely lost in Nrf2-null diabetic mice, confirming the pivotal role of Nrf2 in SFN protection from type 2 diabetes-induced DN. Moreover, SFN failed to up-regulate MT in the absence of Nrf2, suggesting that MT is an Nrf2 downstream antioxidant. MT deletion resulted in a partial, but significant attenuation of SFN renal protection from type 2 diabetes, demonstrating a partial requirement for MT for SFN renal protection. Therefore, the present study demonstrates for the first time that as an Nrf2 downstream antioxidant, MT plays an important, though partial, role in mediating SFN renal protection from type 2 diabetes. PMID- 26415027 TI - The cytoprotective effect of nitrite is based on the formation of dinitrosyl iron complexes. AB - Nitrite protects various organs from ischemia-reperfusion injury by ameliorating mitochondrial dysfunction. Here we provide evidence that this protection is due to the inhibition of iron-mediated oxidative reactions caused by the release of iron ions upon hypoxia. We show in a model of isolated rat liver mitochondria that upon hypoxia, mitochondria reduce nitrite to nitric oxide (NO) in amounts sufficient to inactivate redox-active iron ions by formation of inactive dinitrosyl iron complexes (DNIC). The scavenging of iron ions in turn prevents the oxidative modification of the outer mitochondrial membrane and the release of cytochrome c during reoxygenation. This action of nitrite protects mitochondrial function. The formation of DNIC with nitrite-derived NO could also be confirmed in an ischemia-reperfusion model in liver tissue. Our data suggest that the formation of DNIC is a key mechanism of nitrite-mediated cytoprotection. PMID- 26415029 TI - Immediate breastfeeding and skin-to-skin contact during cesarean section decreases maternal oxidative stress, a prospective randomized case-controlled study. AB - OBJECTIVE: Immediate skin-to-skin contact (ISSC) and early breastfeeding are recommended for the wellbeing of the neonate. In this study, we aimed to evaluate the effect of ISSC and early breastfeeding on maternal oxidative stress and postoperative pain. METHODS: A total of 90 patients were randomized into two groups based on the timing of skin-to-skin contact and breastfeeding. Group 1 (n = 45) was provided ISSC and breastfeeding in the operating room during the cesarean section (C/S). Group 2 (n = 45) breastfed their babies 1 h after the C/S. As markers of oxidative stress, maternal serum levels of total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress indices (OSI) were evaluated. Maternal oxytocin levels and the relation between these parameters and postoperative pain were also evaluated. RESULTS: The postoperative TAS levels were significantly higher, whereas TOS and OSI levels were lower in Group 1 than Group 2. Negative correlations between oxytocin level and postoperative TOS and OSI were observed, as was a positive correlation between oxytocin level and postoperative TAS. CONCLUSIONS: The effect of ISSC and early breastfeeding on mothers was documented for the first time in this study. Our results demonstrated ISSC and early breastfeeding during C/S reduce maternal oxidative stress. PMID- 26415028 TI - Nutrition and the science of disease prevention: a systems approach to support metabolic health. AB - Progress in nutritional science, genetics, computer science, and behavioral economics can be leveraged to address the challenge of noncommunicable disease. This report highlights the connection between nutrition and the complex science of preventing disease and discusses the promotion of optimal metabolic health, building on input from several complementary disciplines. The discussion focuses on (1) the basic science of optimal metabolic health, including data from gene diet interactions, microbiome, and epidemiological research in nutrition, with the goal of defining better targets and interventions, and (2) how nutrition, from pharma to lifestyle, can build on systems science to address complex issues. PMID- 26415030 TI - Mechanical Properties of Nanoscopic Lipid Domains. AB - The lipid raft hypothesis presents insights into how the cell membrane organizes proteins and lipids to accomplish its many vital functions. Yet basic questions remain about the physical mechanisms that lead to the formation, stability, and size of lipid rafts. As a result, much interest has been generated in the study of systems that contain similar lateral heterogeneities, or domains. In the current work we present an experimental approach that is capable of isolating the bending moduli of lipid domains. This is accomplished using neutron scattering and its unique sensitivity to the isotopes of hydrogen. Combining contrast matching approaches with inelastic neutron scattering, we isolate the bending modulus of ~13 nm diameter domains residing in 60 nm unilamellar vesicles, whose lipid composition mimics the mammalian plasma membrane outer leaflet. Importantly, the bending modulus of the nanoscopic domains differs from the modulus of the continuous phase surrounding them. From additional structural measurements and all-atom simulations, we also determine that nanoscopic domains are in-register across the bilayer leaflets. Taken together, these results inform a number of theoretical models of domain/raft formation and highlight the fact that mismatches in bending modulus must be accounted for when explaining the emergence of lateral heterogeneities in lipid systems and biological membranes. PMID- 26415032 TI - Serum vaspin and adiponectin levels in patients with prolactinoma. AB - BACKGROUND: Studies investigating serum vaspin and adiponectin levels in patients with prolactinoma are inconclusive. The aim of this study was to evaluate serum vaspin and adiponectin levels in patients with prolactinoma and healthy controls. METHODS: A total of 42 prolactinoma patients (Group 1, 21 patients; Group 2, 21 patients) and 30 healthy controls were enrolled in the study. Group 1 consisted of newly diagnosed patients who were never treated or had not received a dopamine agonist (DA) within 6 months prior to screening. Group 2 consisted of prolactinoma patients who were on DA treatment for at least 6 months at the time of screening. The control group (group 3) consisted of healthy controls. RESULTS: Patients with prolactinoma had higher homeostasis model assessment of insulin resistance and lower quantitative insulin sensitivity check index values in comparison to healthy controls (p < 0.001 for both). Serum levels of adiponectin and vaspin were also significantly lower in prolactinoma patients when compared to the control group (p < 0.01 and p < 0.001, respectively). Following adjustment for confounding factors, the respective odds ratios for prolactinoma in patients in the lower subgroup compared with those in the higher subgroup for adiponectin and vaspin were 2.733 (0.621-12.035; p > 0.05) and 5.041 (1.191-21.339; p < 0.05). CONCLUSION: This is the first study to demonstrate the presence of low vaspin levels in patients with prolactinomas. Further studies are needed to help establish the roles of vaspin and adiponectin in prolactinoma patients. PMID- 26415031 TI - F429 Regulation of Tunnels in Cytochrome P450 2B4: A Top Down Study of Multiple Molecular Dynamics Simulations. AB - The root causes of the outcomes of the single-site mutation in enzymes remain by and large not well understood. This is the case of the F429H mutant of the cytochrome P450 (CYP) 2B4 enzyme where the substitution, on the proximal surface of the active site, of a conserved phenylalanine 429 residue with histidine seems to hamper the formation of the active species, Compound I (porphyrin cation radical-Fe(IV) = O, Cpd I) from the ferric hydroperoxo (Fe(III)OOH-, Cpd 0) precursor. Here we report a study based on extensive molecular dynamic (MD) simulations of 4 CYP-2B4 point mutations compared to the WT enzyme, having the goal of better clarifying the importance of the proximal Phe429 residue on CYP 2B4 catalytic properties. To consolidate the huge amount of data coming from five simulations and extract the most distinct structural features of the five species studied we made an extensive use of cluster analysis. The results show that all studied single polymorphisms of F429, with different side chain properties: i) drastically alter the reservoir of conformations accessible by the protein, perturbing global dynamics ii) expose the thiolate group of residue Cys436 to the solvent, altering the electronic properties of Cpd0 and iii) affect the various ingress and egress channels connecting the distal sites with the bulk environment, altering the reversibility of these channels. In particular, it was observed that the wild type enzyme exhibits unique structural features as compared to all mutant species in terms of weak interactions (hydrogen bonds) that generate a completely different dynamical behavior of the complete system. Albeit not conclusive, the current computational investigation sheds some light on the subtle and critical effects that proximal single-site mutations can exert on the functional mechanisms of human microsomal CYPs which should go rather far beyond local structure characterization. PMID- 26415033 TI - Sensory and sympathetic disorders in chronic non-specific neck pain. AB - The signs of sympathetic and sensory nerve-related disorders are not widely investigated in chronic nonspecific neck pain (NNP) patients. Thus, we performed skin temperature (Tsk), evaporation and touch threshold (TT) measurements to reveal possible dysfunctions at the fingertips of NNP patients (n=60) compared with healthy controls (n=11). Neck pain intensity was the main modifier of Tsk, and age the main modifier of TT in a multivariate model. On comparisons of the subgroups of NNP patients with unilateral (n=26) and bilateral (n=34) symptoms and controls, TT differed and Tsk tended to differ, the unilateral pain patients being found to demonstrate higher TT values on both sides. Interrelations between the measured parameters were found in the controls, but not in the patients. The NNP patients exhibited signs of functional impairment of innervation reflected in changes in tactile sensitivity and vasoactive sympathetic function. These changes may be based on both central and peripheral mechanisms, which possibly differ in patients with unilateral and bilateral symptoms. PMID- 26415035 TI - A randomized, double-blind, placebo-controlled clinical trial of the efficacy of treatment with zinc in children with intractable epilepsy. AB - This study was conducted to assess the efficacy of oral zinc supplementation in children with intractable epilepsy. Forty-five children aged between three and 12 years and diagnosed with idiopathic intractable epilepsy at Assiut University Hospital, Assiut, Egypt were recruited. The patients were randomly allocated to two groups: the intervention group received oral zinc supplementation (1 mg/kg/day) while the placebo group received placebo, each for six months. The parents of each child filled in a detailed questionnaire that covered demographic characteristics, type of seizures, frequency, duration of seizures, previous hospital admissions, postictal phenomena and the occurrence of status epilepticus. The primary outcome (frequency of seizures) was compared between the two groups. Zinc supplementation resulted in a significant reduction of seizure frequency in 31% of the treated children. Zinc is an important trace element. Our results suggest that it has mildly beneficial effects in children with intractable epilepsy. We recommend further investigation of oral zinc supplementation as an adjunctive therapy for managing intractable epilepsy in children. Zinc therapy may be an option in treatment protocols for intractable epilepsy in the near future. PMID- 26415036 TI - A novel functional glucose transporter in the white shrimp Litopenaeus vannamei LvGLUT2- is up-regulated during hypoxia in hepatopancreas. AB - In hypoxia conditions, the white shrimp Litopenaeus vannamei shifts its energetic metabolism from aerobic to anaerobic, requiring more glucose uptake into the cells by GLUT proteins. We here report a novel glucose transporter in shrimp. The Lvglut2 cDNA is 2473 bp-long containing an ORF of 1458 bp encoding 486 amino acid residues. The deduced protein has the features of a facilitative sugar transporter. The Lvglut2 gene product tagged with GFP was expressed in the cell membrane of Xenopus oocytes. In the same expression system, untagged LvGLUT2 resulted to be a bidirectional glucose transporter that functions moving glucose down its concentration gradient in and out of the cell. Lvglut2 mRNA is expressed in hepatopancreas while in muscle and gills it was not detected. Hypoxia up regulates the expression of Lvglut2 transcripts in hepatopancreas. These results provide a better understanding of facilitative glucose transporters and gene regulation during hypoxia in crustaceans. PMID- 26415037 TI - Constructing Human Skin Equivalents on Porcine Acellular Peritoneum Extracellular Matrix for In Vitro Irritation Testing. AB - The irritancy of topical products has to be investigated to ensure the safety and compliance. Although several reconstructed human epidermal models have been adopted by the Organization for Economic Cooperation and Development (OECD) to replace in vivo animal irritation testing, these models are based on a single cell type and lack dermal components, which may be insufficient to reflect all of the components of irritation. In our study, we investigated the use of acellular porcine peritoneum extracellular matrix as a substrate to construct full thickness human skin equivalents (HSEs) for use as irritation screening tool. The acellular peritoneum matrix (APM) exhibited excellent skin cell attachment (>80%) and proliferation for human dermal fibroblasts (HDF) and immortalized human keratinocytes (HaCaT). APM-HSEs based on coculture of HDF and HaCaT were prepared. Increased HDF seeding density up to 5 * 10(4)/cm(2) resulted in APM HSEs with a thicker and more organized epidermis. The epidermis of APM-HSEs expressed keratin 15, a keratinocyte proliferation marker, and involucrin, a differentiation marker, respectively. To assess the use of APM-HSEs for irritation testing, six proficiency chemicals, including three nonirritants (phosphate-buffered saline, polyethylene glycol 400, and isopropanol) and three irritants (1-bromohexane, heptanol, and sodium dodecyl sulfate) were applied. The APM-HSEs were able to discriminate nonirritants from irritants based on the viability. Levels of cytokines (interleukin [IL]-1alpha, IL-1ra, IL-6, IL-8, and granulocyte macrophage colony-stimulating factor [GM-CSF]) in these treatment groups further assisted the irritancy ranking. In conclusion, we have developed partially differentiated full-thickness APM-HSEs based on acellular porcine peritoneum matrix, and these APM-HSEs demonstrated utility as an in vitro irritation screening tool. PMID- 26415038 TI - Characteristics and Survival of Anti-U1 RNP Antibody-Positive Patients With Connective Tissue Disease-Associated Pulmonary Arterial Hypertension. AB - OBJECTIVE: Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue diseases (CTDs). This study aimed to investigate the clinical and hemodynamic characteristics and survival of anti-U1 RNP-positive patients with CTD-associated PAH, with a focus on systemic sclerosis (SSc)-associated PAH. METHODS: We implemented a prospective database that included patients with CTD associated PAH for whom there were clinical, autoantibody, and mortality data. We compared clinical and hemodynamic characteristics to anti-U1 RNP antibody status. We then assessed whether anti-U1 RNP antibodies could be a prognostic factor in CTD-associated PAH with a focus on SSc-associated PAH. RESULTS: We studied a total of 342 patients with CTD-associated PAH, of whom 36 (11%) were anti-U1 RNP antibody positive. Anti-U1 RNP-positive patients were younger and less functionally impaired than were anti-U1 RNP-negative patients in CTD- and SSc associated PAH. Hemodynamic parameters were similar in anti-U1 RNP-positive and anti-U1 RNP-negative patients. In CTD-associated PAH, anti-U1 RNP positivity was associated with decreased mortality in univariable analysis (hazard ratio 0.34 [95% confidence interval 0.18-0.65], P < 0.001). In multivariable analysis, anti U1 RNP positivity was also associated with decreased mortality (hazard ratio 0.44 [95% confidence interval 0.20-0.97], P = 0.043) independently of age, sex, functional parameters, lung involvement, and hemodynamic parameters. Results were similar in SSc-associated PAH, although the association between anti-U1 RNP positivity and survival did not reach significance in univariable (hazard ratio 0.47 [95% confidence interval 0.22-1.02], P = 0.055) and multivariable (hazard ratio 0.47 [95% confidence interval 0.20-1.11], P = 0.085) analyses. CONCLUSION: Anti-U1 RNP positivity was associated with distinct clinical characteristics and survival in CTD- and SSc-associated PAH. While hemodynamic parameters were similar in anti-U1 RNP-positive and anti-U1 RNP-negative patients, our results suggest that anti-U1 RNP positivity could be a factor protecting against mortality in CTD- and SSc-associated PAH. PMID- 26415039 TI - Novel fluorine-containing DAPY derivatives as potent HIV-1 NNRTIs: a patent evaluation of WO2014072419. AB - Diarylpyrimidine (DAPY) derivatives, one family of HIV non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) with superior activities against wild-type (WT) HIV-1 and NNRTI-resistant strains, have attracted much attention in the past decade. A series of DAPY derivatives featuring a fluorine atom on the central ring were reported as novel NNRTIs in the patent WO2014072419. Some compounds exhibited robust potency against both WT and mutant strains, which were approximately equal to or higher than those of the reference drug TMC120. Moreover, it has become evident that fluorinated molecules have a remarkable record in many other potent NNRTIs. Thus, this survey provides a sampling of renowned fluorinated NNRTIs and their mode of action, with an analysis clarifying the functional roles and impact of fluorine substitution on antiviral potency. We envision that fluorinated NNRTIs will play a continuing role in affording anti HIV drug candidates for therapeutic applications. PMID- 26415040 TI - Near surface properties of mixtures of propylammonium nitrate with n-alkanols 2. Nanotribology and fluid dynamics. AB - Colloid probe friction force microscopy (FFM) has been used to study the lubricity of propylammonium nitrate (PAN) mixed with n-alkanols confined between sliding silica and mica surfaces. Mixtures of PAN with butanol, hexanol, octanol and dodecanol were investigated for various n-alkanol volume fractions to elucidate the effect of n-alkanol hydrocarbon chain length and concentration on shear forces. For all n-alkanols friction decreases with n-alkanol vol%. The trends in friction reduction with n-alkanol vol% do not correlate with changes in the bulk phase viscosity or the near surface nanostructure, and colloid probe atomic force microscope (AFM) fluid dynamic measurements showed that none of the mixtures shear thin. Thus, the reduction in friction is attributed to the n alkanol disrupting solvophobic interactions between boundary layer propylammonium ions adsorbed to the mica and near surface liquid layers. The lowest friction is obtained for pure dodecanol, which is attributed to the dodecanol forming a robust boundary layer. Friction for the other pure n-alkanols is higher because the lateral attractions between adsorbed n-alkanols are too weak to facilitate the formation of a strong boundary layer, commensurate with the decreased hydrocarbon chain length. PMID- 26415041 TI - Intrathecal Acetyl-L-Carnitine Protects Tissue and Improves Function after a Mild Contusive Spinal Cord Injury in Rats. AB - Primary and secondary ischemia after spinal cord injury (SCI) contributes to tissue and axon degeneration, which may result from decreased energy substrate availability for cellular and axonal mitochondrial adenosine triphosphate (ATP) production. Therefore, providing spinal tissue with an alternative energy substrate during ischemia may be neuroprotective after SCI. To assess this, rats received a mild contusive SCI (120 kdyn, Infinite Horizons impactor) at thoracic level 9 (T9), which causes loss of ~ 80% of the ascending sensory dorsal column axonal projections to the gracile nucleus. Immediately afterwards, the energy substrate acetyl-L-carnitine (ALC; 1 mg/day) or phosphate-buffered saline (PBS) was infused intrathecally (sub-arachnoid) for 6 days via an L5/6 catheter attached to a subcutaneous Alzet pump. ALC treatment improved overground locomotor function (Basso-Beattie-Breshnahan [BBB] score 18 vs. 13) at 6 days, total spared epicenter (71% vs. 57%) and penumbra white matter (90% vs. 85%), ventral penumbra microvessels (108% vs. 79%), and penumbra motor neurons (42% vs. 15%) at 15 days post-SCI, compared with PBS treatment. However, the ascending sensory projections (anterogradely traced with cholera toxin B from the sciatic nerves) and dorsal column white matter and perfused blood vessels were not protected. Furthermore, grid walking, a task we have shown to be dependent on dorsal column function, was not improved. Thus, mitochondrial substrate replacement may only be efficacious in areas of lesser or temporary ischemia, such as the ventral spinal cord and injury penumbra in this study. The current data also support our previous evidence that microvessel loss is central to secondary tissue degeneration. PMID- 26415042 TI - A Woman With a Novel Mutation of THAP1 With a Prominent Response to Deep Brain Stimulation of the Globus Pallidus Internus. PMID- 26415044 TI - Histopathologic Findings of Patients With Biopsy-Negative Giant Cell Arteritis Compared to Those Without Arteritis: A Population-Based Study. AB - OBJECTIVE: To evaluate whether there are histopathologic features of negative temporal artery biopsy (TAB) that allow differentiation between patients with giant cell arteritis (GCA) and those without. METHODS: All consecutive patients with negative TAB seen between January 2009 and December 2012 were selected retrospectively. Demographic, clinical, and laboratory data at presentation and at each followup visit were collected. A pathologist with expertise in vasculitis and blinded to clinical data and final diagnosis reviewed all negative TABs. Histopathologic features evaluated were the presence of a focal mediointimal scar, medial attenuation, intimal hyperplasia, fragmentation of inner elastic lamina, calcification, adventitial fibrosis, and neoangiogenesis. RESULTS: After a median (interquartile range [IQR]) followup period of, respectively, 19 months (9.2-31.2) and 26.3 months (4.9-36.7) (P = 0.041), 38 (55%) of 69 patients had a final diagnosis of TAB-negative GCA, while in the remaining 31 (45%) of 69 patients GCA was excluded. The American College of Rheumatology classification criteria for GCA were satisfied by 31 (81.6%) of 38 patients and 2 (6.5%) of 31 patients (P < 0.0001). Compared to non-GCA patients, those with TAB-negative GCA had more frequent cranial manifestations and higher erythrocyte sedimentation rates and C-reactive protein levels. The frequency of patients receiving prednisone, the mean dose, and the duration of prednisone treatment at TAB were similar in the 2 groups. There were no significant differences between TAB negative GCA and non-GCA patients in the frequencies of all the histologic features evaluated. CONCLUSION: The histologic features of negative TABs evaluated in this study do not allow for the differentiation between GCA and non GCA patients. In the absence of an inflammatory infiltrate, other histologic changes of the temporal artery wall are not specific for GCA. PMID- 26415043 TI - Partial Correlation-Based Retinotopically Organized Resting-State Functional Connectivity Within and Between Areas of the Visual Cortex Reflects More Than Cortical Distance. AB - Numerous studies have demonstrated functional magnetic resonance imaging (fMRI) based resting-state functional connectivity (RSFC) between cortical areas. Recent evidence suggests that synchronous fluctuations in blood oxygenation level dependent fMRI reflect functional organization at a scale finer than that of visual areas. In this study, we investigated whether RSFCs within and between lower visual areas are retinotopically organized and whether retinotopically organized RSFC merely reflects cortical distance. Subjects underwent retinotopic mapping and separately resting-state fMRI. Visual areas V1, V2, and V3, were subdivided into regions of interest (ROIs) according to quadrants and visual field eccentricity. Functional connectivity (FC) was computed based on Pearson's linear correlation (correlation), and Pearson's linear partial correlation (correlation between two time courses after the time courses from all other regions in the network are regressed out). Within a quadrant, within visual areas, all correlation and nearly all partial correlation FC measures showed statistical significance. Consistently in V1, V2, and to a lesser extent in V3, correlation decreased with increasing eccentricity separation. Consistent with previously reported monkey anatomical connectivity, correlation/partial correlation values between regions from adjacent areas (V1-V2 and V2-V3) were higher than those between nonadjacent areas (V1-V3). Within a quadrant, partial correlation showed consistent significance between regions from two different areas with the same or adjacent eccentricities. Pairs of ROIs with similar eccentricity showed higher correlation/partial correlation than pairs distant in eccentricity. Between dorsal and ventral quadrants, partial correlation between common and adjacent eccentricity regions within a visual area showed statistical significance; this extended to more distant eccentricity regions in V1. Within and between quadrants, correlation decreased approximately linearly with increasing distances separating the tested ROIs. Partial correlation showed a more complex dependence on cortical distance: it decreased exponentially with increasing distance within a quadrant, but was best fit by a quadratic function between quadrants. We conclude that RSFCs within and between lower visual areas are retinotopically organized. Correlation-based FC is nonselectively high across lower visual areas, even between regions that do not share direct anatomical connections. The mechanisms likely involve network effects caused by the dense anatomical connectivity within this network and projections from higher visual areas. FC based on partial correlation, which minimizes network effects, follows expectations based on direct anatomical connections in the monkey visual cortex better than correlation. Last, partial correlation-based retinotopically organized RSFC reflects more than cortical distance effects. PMID- 26415045 TI - The Silk flow-diverter stent for endovascular treatment of intracranial aneurysms. AB - Flow diverter (FD) stents represent a new endovascular technique developed for the treatment of complex intracranial aneurysms (wide neck, fusiform, large, and giant aneurysms) that are challenging for classic endovascular techniques such as coiling, balloon-assisted coiling and stent-assisted coiling. Low porosity, high metal coverage, and high pore density are the main properties of FD stents. These properties induce hemodynamic changes redirecting the blood flow away from the aneurysm and into the parent artery leading to gradual thrombosis of the aneurysm. FD stents also provide scaffolding for subsequent neoendothelial proliferation, and vessel wall remodeling. This is considered as a paradigm shift compared to prior endovascular methods, which predominantly aimed at providing treatment inside the aneurysmal sac. This paper describes in detail the first released FD stent, the Silk flow-diverter stent (Balt Extrusion, Montmorency, France), its mechanism of action and deployment technique. It reviews the pertinent literature regarding safety, efficacy and potential risks and complications associated with the use of this stent. PMID- 26415046 TI - Content, Consistency, and Quality of Black Box Warnings: Time for a Change. PMID- 26415047 TI - Traffic-related air pollution and risk for leukaemia of an adult population. AB - Air pollution causes lung cancer, but associations with other cancers have not been established. We investigated whether long-term exposure to traffic-related air pollution is associated with the risk of the general population for leukaemia. We identified 1,967 people in whom leukaemia was diagnosed in 1992 2010 from a nation-wide cancer registry and selected 3,381 control people at random, matched on sex and year of birth, from the entire Danish population. Residential addresses since 1971 were traced in a population registry, and outdoor concentrations of NOx and NO2 , as indicators of traffic-related air pollution, were calculated at each address in a dispersion model. We used conditional logistic regression to estimate the risk for leukaemia after adjustment for income, educational level, cohabitation status and co-morbidity. In linear analyses, we found odds ratios for acute myeloid leukaemia of 1.20 (95% confidence interval: 1.04-1.38) per 20 ug/m(3) increase in NOx and 1.31 (1.02 1.68) per 10 ug/m(3) increase in NO2 , calculated as time-weighted average exposure at all addresses since 1971. We found no association with chronic myeloid or lymphocytic leukaemia. This study indicates an association between long-term exposure to traffic-related air pollution and acute myeloid leukaemia in the general population, but not for other subtypes of leukaemia. PMID- 26415048 TI - Secondary task and risky driving behavior: a test of the mediating effect of situation awareness. AB - A theoretical model is developed by using a contingency perspective to hypothesize the relationship between a secondary task and risky driving behavior. It is conjectured that the relationship between the two variables is mediated by situation awareness (SA). An experiment is designed and administered to provide empirical evidence. Thirty Indonesian students as subjects were required to carry out a driving assignment in a simulated environment. Empirical evidence suggests that SA provides a partial mediation effect towards the relationship between a secondary task and risky driving behavior. It is also found that a secondary task has a significant effect on risky driving behavior. The secondary task also becomes a significant explanation of SA. In addition, working memory capacity, experience and gender are found to have no significant impact towards SA. PMID- 26415050 TI - Increasing motorcycle conspicuity - design and assessment of intervention to enhance rider safety. PMID- 26415049 TI - Outcomes of Systematic Review of Ureteroscopy for Stone Disease in the Obese and Morbidly Obese Population. AB - PURPOSE: With a rising incidence of obesity and urolithiasis, we wanted to look at the outcomes of ureteroscopy (URS) for stone management in this group of patients. METHODS: We did a systematic review of literature in accordance with Cochrane review and preferred reporting items for systematic reviews and meta analyses (PRISMA) guidelines on all English language articles between 1990 and June 2015 for URS and stone treatment in obese patients. Data were retrieved for patient and stone demographics, outcomes of URS, complications, and follow-up. RESULTS: Fifteen studies (835 patients) were identified with a mean age of 49 years and a mean body mass index (BMI) of 40.5 kg/m(2). The overall stone size was 14.2 mm (range: 3-72 mm) with almost a third of the stones in the lower pole. The initial and final stone-free rate (SFR) was 76.9% and 82.5%, respectively, with an overall complication rate of 9.3% (n = 78). Except one patient with myocardial infarction, all other complications were Clavien grade I-III. The complication rate for morbidly obese patients (17.6%) was twice that of the obese patients (8.4%), although they were all graded as Clavien I or II. CONCLUSION: URS and stone fragmentation are safe and efficient treatment methods in obese patients with a good SFR and a relatively low complication rate, although the complications tend to be higher in the morbidly obese patients. PMID- 26415052 TI - In vitro and in vivo correlates of physiological and neoplastic human Fallopian tube stem cells. AB - High-grade serous cancer (HGSC) progresses to advanced stages without symptoms and the 5-year survival rate is a dismal 30%. Recent studies of ovaries and Fallopian tubes in patients with BRCA1 or BRCA2 mutations have documented a pre metastatic intramucosal neoplasm that is found almost exclusively in the Fallopian tube, termed 'serous tubal intraepithelial carcinoma' or STIC. Moreover, other proliferations, termed p53 signatures, secretory cell outgrowths (SCOUTs), and lower-grade serous tubal intraepithelial neoplasms (STINs) fall short of STIC but share similar alterations in expression, in keeping with an underpinning of genomic disturbances involved in, or occurring in parallel with, serous carcinogenesis. To gain insight into the cellular origins of this unique tubal pathway to high-grade serous cancer, we cloned and both immortalized and transformed Fallopian tube stem cells (FTSCs). We demonstrated that pedigrees of FTSCs were capable of multipotent differentiation and that the tumours derived from transformed FTSCs shared the histological and molecular features of HGSC. We also demonstrated that altered expression of some biomarkers seen in transformed FTSCs and HGSCs (stathmin, EZH2, CXCR4, CXCL12, and FOXM1) could be seen as well in immortalized cells and their in vivo counterparts SCOUTs and STINs. Thus, a whole-genome transcriptome analysis comparing FTSCs, immortalized FTSCs, and transformed FTSCs showed a clear molecular progression sequence that is recapitulated by the spectrum of accumulated perturbations characterizing the range of proliferations seen in vivo. Biomarkers unique to STIC relative to normal tubal epithelium provide a basis for novel detection approaches to early HGSC, but must be viewed critically given their potential expression in lesser proliferations. Perturbations shared by both immortalized and transformed FTSCs may provide unique early targets for prevention strategies. Central to these efforts has been the ability to clone and perpetuate multipotent FTSCs. PMID- 26415053 TI - A multidimensional model of mothers' perceptions of parent alcohol socialization and adolescent alcohol misuse. AB - We assessed a multidimensional model of parent alcohol socialization in which key socialization factors were considered simultaneously to identify combinations of factors that increase or decrease risk for development of adolescent alcohol misuse. Of interest was the interplay between putative risk and protective factors, such as whether the typically detrimental effects on youth drinking of parenting practices tolerant of some adolescent alcohol use are mitigated by an effective overall approach to parenting and parental modeling of modest alcohol use. The sample included 1,530 adolescents and their mothers; adolescents' mean age was 13.0 (SD = .99) at the initial assessment. Latent profile analysis was conducted of mothers' reports of their attitude toward teen drinking, alcohol specific parenting practices, parental alcohol use and problem use, and overall approach to parenting. The profiles were used to predict trajectories of adolescent alcohol misuse from early to middle adolescence. Four profiles were identified: 2 profiles reflected conservative alcohol-specific parenting practices and 2 reflected alcohol-tolerant practices, all in the context of other attributes. Alcohol misuse accelerated more rapidly from Grade 6 through 10 in the 2 alcohol-tolerant compared with conservative profiles. Results suggest that maternal tolerance of some youth alcohol use, even in the presence of dimensions of an effective parenting style and low parental alcohol use and problem use, is not an effective strategy for reducing risky adolescent alcohol use. (PsycINFO Database Record PMID- 26415054 TI - The effects of e-cigarette visual appearance on craving and withdrawal symptoms in abstinent smokers. AB - Electronic cigarette (e-cigarette) use is becoming increasing popular among smokers, and there is a plethora of devices available. Nicotine delivery is clearly important for reducing tobacco craving and withdrawal symptoms, but other sensorimotor aspects of e-cigarettes (such as visual appearance) may contribute to this effect. This study explored whether it is important for an e-cigarette to visually resemble a tobacco cigarette in order to reduce craving and withdrawal symptoms. Sixty-three cigarette smokers (40% female, aged 18-65 years) who were not current e-cigarette users were randomly allocated to take ten 3-s puffs from either a white or a red first-generation e-cigarette following overnight abstinence. Current craving (urge to smoke) and nicotine withdrawal symptoms (using the Mood and Physical Symptoms Scale [MPSS]) were measured before and 10 min after use. Linear regression revealed higher craving and withdrawal symptoms in the red condition versus the white condition, but only among those who were e cigarette naive (craving: B = .76, p = .009; withdrawal symptoms: B = 2.18, p = .009), not among those with e-cigarette experience (craving: B = -.08, p = .89; withdrawal symptoms: B = .24, p = .81), and these effects differed between groups (p = .04 and 0.01 for craving and withdrawal symptoms, respectively). In conclusion, cigarette-like appearance was associated with lower craving and withdrawal symptoms, but only for those with no prior e-cigarette experience. This effect, putatively mediated via classical conditioning or expectancies, may aid understanding of smokers' initial preferences for "cigalike" e-cigarette devices. PMID- 26415051 TI - Pharmacology and Clinical Drug Candidates in Redox Medicine. AB - SIGNIFICANCE: Oxidative stress is suggested to be a disease mechanism common to a wide range of disorders affecting human health. However, so far, the pharmacotherapeutic exploitation of this, for example, based on chemical scavenging of pro-oxidant molecules, has been unsuccessful. RECENT ADVANCES: An alternative emerging approach is to target the enzymatic sources of disease relevant oxidative stress. Several such enzymes and isoforms have been identified and linked to different pathologies. For some targets, the respective pharmacology is quite advanced, that is, up to late-stage clinical development or even on the market; for others, drugs are already in clinical use, although not for indications based on oxidative stress, and repurposing seems to be a viable option. CRITICAL ISSUES: For all other targets, reliable preclinical validation and drug ability are key factors for any translation into the clinic. In this study, specific pharmacological agents with optimal pharmacokinetic profiles are still lacking. Moreover, these enzymes also serve largely unknown physiological functions and their inhibition may lead to unwanted side effects. FUTURE DIRECTIONS: The current promising data based on new targets, drugs, and drug repurposing are mainly a result of academic efforts. With the availability of optimized compounds and coordinated efforts from academia and industry scientists, unambiguous validation and translation into proof-of-principle studies seem achievable in the very near future, possibly leading towards a new era of redox medicine. PMID- 26415055 TI - Temporal variation in facilitator and client behavior during group motivational interviewing sessions. AB - There is considerable evidence for motivational interviewing (MI) in changing problematic behaviors. Research on the causal chain for MI suggests influence of facilitator speech on client speech. This association has been examined using macro (session-level) and micro (utterance-level) measures; however, effects across sessions have largely been unexplored, particularly with groups. We evaluated a sample of 129 adolescent Group MI sessions, using a behavioral coding system and timing information to generate information on facilitator and client speech (CT; change talk) within 5 successive segments (quintiles) of each group session. We hypothesized that facilitator speech (open-ended questions and reflections of CT) would be related to subsequent CT. Repeated measures analysis indicated significant quadratic and cubic trends for facilitator and client speech across quintiles. Across quintiles, cross-lagged panel analysis using a zero-inflated negative binomial model showed minimal evidence of facilitator speech on client CT, but did indicate several effects of client CT on facilitator speech, and of client CT on subsequent client CT. Results suggest that session level effects of facilitator speech on client speech do not arise from long duration effects of facilitator speech; instead, we detected effects of facilitator speech on client speech only at the beginning and end of sessions, when open questions, respectively, suppressed and enhanced client expressions of CT. Findings suggest that clinicians must remain vigilant to client CT throughout the group session, reinforcing it when it arises spontaneously and selectively employing open-ended questions to elicit it when it does not, particularly toward the end of the session. PMID- 26415056 TI - Young adult veteran perceptions of peers' drinking behavior and attitudes. AB - Social norms-based interventions have shown promise in reducing drinking behavior and the resulting consequences in young adults. Although most research has focused on young civilians (i.e., college students), some studies have investigated social norms-based interventions with active-duty military and veteran samples. Yet, research has not yet determined how to maximize the effectiveness of social norms-based interventions in this heavy-drinking population. As an initial step toward this goal, the current study utilized a community sample of 1,023 young adult veterans to examine (a) whether veteran perceptions of the drinking behavior of their veteran peers differ from their perceptions of civilian drinking behavior, (b) whether perceptions of specific veteran groups differ from the actual drinking behavior of veterans within those groups, (c) what levels of specificity in reference groups (same-gender civilians, same-branch veterans, same-gender veterans, or same-branch-and-gender veterans) are most strongly associated with veterans' own drinking, and (d) whether perceptions about others' attitudes toward drinking also contribute independently of perceived behavioral norms to veteran drinking. Findings indicated that participants perceived that other veterans drank more than civilians and that veteran groups drank more than veterans in the sample actually drank. Veteran-specific perceived behavioral norms were similar in their associations with drinking outcomes, whereas same-gender civilian perceived behavioral norms exhibited little or no associations with drinking. Veteran specific perceived attitudinal norms exhibited little or no association with drinking behavior after controlling for perceived behavioral norms. These findings can be used to inform the development of social norms interventions for young adult veterans. PMID- 26415058 TI - Parental involvement in brief interventions for adolescent marijuana use. AB - Adolescents (aged 12-18 years) identified in a school setting as abusing marijuana and other drugs were randomly assigned to complete 1 of 2 brief interventions (BIs). Adolescents and their parent (N = 259) were randomly assigned to receive either a 2-session adolescent only (BI-A) or a 2-session adolescent and additional parent session (BI-AP). Interventions were manualized and delivered in a school setting by trained counselors. Adolescents were assessed at intake and at 6 months following the completion of the intervention. Using a latent construct representing 6-month marijuana use outcomes, current findings supported previous research that BI-AP resulted in superior outcomes when compared to BI-A. The presence of a marijuana dependence diagnosis at baseline predicted poorer outcomes when compared to youth without a diagnosis. Both baseline diagnostic status and co-occurring conduct problems interacted with intervention condition in predicting marijuana use outcomes. A marijuana dependence diagnosis resulted in poorer marijuana use outcomes within the BI-A condition when compared to BI-AP. Co-occurring conduct problems were associated with poorer marijuana use outcomes within the BI-AP intervention when compared to BI-A. Implications for implementing BIs given diagnostic status, parent involvement, and co-occurring conduct problems are discussed. PMID- 26415057 TI - Associations between neighborhood alcohol availability and young adolescent alcohol use. AB - We investigated the association between alcohol outlet density and adolescent alcohol use, including whether this association differed by sociodemographic characteristics. We geocoded and mapped active license data from the year 2011 to calculate the number of outlets within multiple circular buffers of varying sizes (density), centered at households of adolescents ages 10-16 (n = 2,724). We examined 2 indicators of alcohol use: any lifetime use, but not in past month, and any past month heavy use. Cross-sectional hierarchal multivariate regression analyses were used to examine associations between alcohol outlet density and alcohol use, including the potential moderating effect of age, gender, race/ethnicity, and socioeconomic status. Analyses controlled for neighborhood level socioeconomic status and accounted for census tract-level clustering. A higher number of on- and off-premise outlets within 0.10, 0.25, and 0.50 miles around the respondents' homes was associated with higher odds of being a heavy drinker. In addition, the number of on-premise outlets within the 0.25-mile radius was associated with greater odds of lifetime drinking. For on-premise outlets where minors were not allowed (clubs/bars), we observed a positive and significant association between clubs/bars within the 0.25-mile buffer zone and higher odds of both lifetime and heavy drinking. Findings suggest that youth who are exposed to higher densities of on-premise alcohol outlets are at risk for both lifetime use and recent heavy use. It is critical to advocate for stricter laws limiting the number of alcohol outlets in neighborhoods, including clubs/bars where minors are restricted, and putting into place more stringent enforcement of age identification requirements to limit distribution of alcohol to minors. PMID- 26415059 TI - Can marijuana make it better? Prospective effects of marijuana and temperament on risk for anxiety and depression. AB - Increases in marijuana use in recent years highlight the importance of understanding how marijuana affects mental health. Of particular relevance is the effect of marijuana use on anxiety and depression given that marijuana use is highest among late adolescents/early adults, the same age range in which risk for anxiety and depression is the highest. Here we examine how marijuana use moderates the effects of temperament on level of anxiety and depression in a prospective design in which baseline marijuana use and temperament predict anxiety and depression 1 year later. We found that harm avoidance (HA) is associated with higher anxiety and depression a year later, but only among those low in marijuana use. Those higher in marijuana use show no relation between HA and symptoms of anxiety and depression. Marijuana use also moderated the effect of novelty seeking (NS), with symptoms of anxiety and depression increasing with NS only among those with high marijuana use. NS was unrelated to symptoms of anxiety and depression among those low in marijuana use. The temperament dimension of reward dependence was unrelated to anxiety and depression symptoms. Our results suggest that marijuana use does not have an invariant relationship with anxiety and depression, and that the effects of relatively stable temperament dimensions can be moderated by other contextual factors. PMID- 26415060 TI - Associations among trauma, posttraumatic stress disorder, cannabis use, and cannabis use disorder in a nationally representative epidemiologic sample. AB - Research in community and clinical samples has documented elevated rates of cannabis use and cannabis use disorders (CUDs) among individuals with trauma exposure and posttraumatic stress disorder (PTSD). However, there is a lack of research investigating relations between, and correlates of, trauma and cannabis phenotypes in epidemiologic samples. The current study examined associations between trauma (i.e., lifetime trauma exposure and PTSD) and cannabis phenotypes (i.e., lifetime cannabis use and CUD) in a nationally representative sample. Participants were individuals who participated in Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (n = 34,396; 52.4% women; age, M = 48.0 years, SD = 16.9). Lifetime DSM-IV Criterion A trauma exposure was significantly associated with lifetime cannabis use (OR = 1.215) but was only marginally associated with CUD (OR = 0.997). Within the trauma-exposed sample, lifetime PTSD showed a significant association with CUD (OR = 1.217) but was only marginally associated with lifetime cannabis use (OR = 0.992). Partially consistent with hypotheses, lifetime trauma was associated with greater odds of lifetime cannabis use, whereas PTSD was associated with greater odds of CUD. Longitudinal research investigating patterns of onset of these events/disorders is needed. PMID- 26415061 TI - Variability in medical marijuana laws in the United States. AB - Marijuana use and its distribution raise several complex health, social, and legal issues in the United States. Marijuana is prohibited in only 23 states and promarijuana laws are likely to be introduced in these states in the future. Increased access to and legalization of medical marijuana may have an impact on recreational marijuana use and perception through increased availability and decreased restrictiveness around the drug. The authors undertook an analysis to characterize the policy features of medical marijuana legislation, including an emphasis on the types of medical conditions that are included in medical marijuana laws. A high degree of variability in terms of allowable medical conditions, limits on cultivation and possession, and restrictiveness of policies was discovered. Further research is needed to determine if this variability impacts recreational use in those states. PMID- 26415063 TI - Premeditation moderates the relation between sensation seeking and risky substance use among young adults. AB - Young adulthood is a peak period for externalizing behaviors such as substance abuse and antisocial conduct. Evidence from developmental neuroscience suggests that externalizing conduct within this time period may be associated with a "developmental asymmetry" characterized by an early peak in sensation seeking combined with a relatively immature impulse control system. Trait measures of impulsivity-sensation seeking and premeditation-are psychological manifestations of these respective systems, and multiple prior studies suggest that high sensation seeking and low premeditation independently confer risk for distinct forms of externalizing behaviors. The goal of the present study was to test this developmental asymmetry hypothesis, examining whether trait premeditation moderates the effect of sensation seeking on substance use and problems, aggression, and rule-breaking behavior. Using a cross-sectional sample of college enrolled adults (n = 491), we applied zero-inflated modeling strategies to examine the likelihood and level of risky externalizing behaviors. Results indicated that lower premeditation enhanced the effect of higher sensation seeking on higher levels of positive and negative alcohol consequences, more frequent drug use, and more problematic drug use, but was unrelated to individual differences in antisocial behaviors. Our findings indicate that the developmental asymmetry between sensation seeking and a lack of premeditation is a risk factor for individual differences in problematic substance use among young adults, and may be less applicable for antisocial behaviors among high functioning individuals. PMID- 26415062 TI - Do students use contextual protective behaviors to reduce alcohol-related sexual risk? Examination of a dual-process decision-making model. AB - Recent studies suggest drinking protective behaviors (DPBs) and contextual protective behaviors (CPBs) can uniquely reduce alcohol-related sexual risk in college students. Few studies have examined CPBs independently, and even fewer have utilized theory to examine modifiable psychosocial predictors of students' decisions to use CPBs. The current study used a prospective design to examine (a) rational and reactive pathways and psychosocial constructs predictive of CPB use and (b) how gender might moderate these influences in a sample of college students. Students (n = 508) completed Web-based baseline (mid-Spring semester) and 1- and 6-month follow-up assessments of CPB use; psychosocial constructs (expectancies, normative beliefs, attitudes, and self-concept); and rational and reactive pathways (intentions and willingness). Regression was used to examine rational and reactive influences as proximal predictors of CPB use at the 6-month follow-up. Subsequent path analyses examined the effects of psychosocial constructs, as distal predictors of CPB use, mediated through the rational and reactive pathways. Both rational (intentions to use CPB) and reactive (willingness to use CPB) influences were significantly associated with increased CPB use. The examined distal predictors were found to effect CPB use differentially through the rational and reactive pathways. Gender did not significantly moderate any relationships within in the model. Findings suggest potential entry points for increasing CPB use that include both rational and reactive pathways. Overall, this study demonstrates the mechanisms underlying how to increase the use of CPBs in programs designed to reduce alcohol-related sexual consequences and victimization. PMID- 26415064 TI - The relationship between psychological distress and adolescent polydrug use. AB - Polydrug use is relatively common among adolescents. Psychological distress is associated with the use of specific drugs, and may be uniquely associated with polydrug use. The purpose of this study was to test the association of psychological distress with polydrug use using a large adolescent sample. The sample consisted of 10,273 students aged 12-17 years from the State of Victoria, Australia. Participants completed frequency measures of tobacco, alcohol, cannabis, inhalant, and other drug use in the past 30 days, and psychological distress. Control variables included age, gender, family socioeconomic status, school suspensions, academic failure, cultural background, and peer drug use. Drug-use classes were derived using latent-class analysis, then the association of psychological distress and controls with drug-use classes was modeled using multinomial ordinal regression. There were 3 distinct classes of drug use: no drug use (47.7%), mainly alcohol use (44.1%), and polydrug use (8.2%). Independent of all controls, psychological distress was higher in polydrug users and alcohol users, relative to nondrug users, and polydrug users reported more psychological distress than alcohol users. Psychological distress was most characteristic of polydrug users, and targeted prevention outcomes may be enhanced by a collateral focus on polydrug use and depression and/or anxiety. PMID- 26415065 TI - Thresholds of probable problematic gambling involvement for the German population: Results of the Pathological Gambling and Epidemiology (PAGE) Study. AB - Consumption measures in gambling research may help to establish thresholds of low risk gambling as 1 part of evidence-based responsible gambling strategies. The aim of this study is to replicate existing Canadian thresholds of probable low risk gambling (Currie et al., 2006) in a representative dataset of German gambling behavior (Pathological Gambling and Epidemiology [PAGE]; N = 15,023). Receiver-operating characteristic curves applied in a training dataset (60%) extracted robust thresholds of low-risk gambling across 4 nonexclusive definitions of gambling problems (1 + to 4 + Diagnostic and Statistical Manual for Mental Disorders-Fifth Edition [DSM-5] Composite International Diagnostic Interview [CIDI] symptoms), different indicators of gambling involvement (across all game types; form-specific) and different timeframes (lifetime; last year). Logistic regressions applied in a test dataset (40%) to cross-validate the heuristics of probable low-risk gambling incorporated confounding covariates (age, gender, education, migration, and unemployment) and confirmed the strong concurrent validity of the thresholds. Moreover, it was possible to establish robust form-specific thresholds of low-risk gambling (only for gaming machines and poker). Possible implications for early detection of problem gamblers in offline or online environments are discussed. Results substantiate international knowledge about problem gambling prevention and contribute to a German discussion about empirically based guidelines of low-risk gambling. PMID- 26415066 TI - A 10-year estimate of the incidence of decompression illness in a discrete group of recreational cave divers in Australia. AB - INTRODUCTION: The vast majority of freshwater cave diving in Australia occurs within the limestone caves of the Gambier karst in the south-east of South Australia. The incidence of decompression illness (DCI) in cave divers is presumed to be higher than open-water recreational divers because of the greater depths involved, but has not previously been reported. Our aim was to determine the incidence of DCI in cave divers, the patterns of diving and the outcome of hyperbaric treatment. METHODS: This was a retrospective cohort study of cave divers with DCI presenting to the Royal Adelaide Hospital or The Alfred Hospital over a 10-year period between 2002 and 2012. We reviewed case notes of cave divers who were treated for DCI after diving in the Mt Gambier karst. As there are no records of the number of dives performed during the study period we generated a denominator for the incidence of DCI by extrapolating available data and making a number of assumptions about the number of dives per dive permit issued. RESULTS: Sixteen patients were treated for DCI during the study period. The precipitating dive was a single deep decompression dive in seven cases, multiday repetitive dive sequences in eight and a non-decompression dive in one. Three of the 16 cases of DCI involved dives in excess of 90 metres' fresh water (mfw) using trimix. As the total estimated number of dives in the study period was approximately 57,000 the incidence of DCI in Australian cave divers was estimated to be 2.8:10,000 (0.028%). It is possible that the overall incidence of DCI is as high as 0.05%, and even higher when dives to depths greater than 90 mfw are involved. CONCLUSIONS: The estimated incidence of DCS in this series is lower than expected but consistent with other series describing DCI in cold-water recreational diving. PMID- 26415067 TI - Provisional report on diving-related fatalities in Australian waters 2010. AB - INTRODUCTION: An individual case review was conducted of known diving-related deaths that occurred in Australia in 2010. METHOD: The case studies were compiled using statements from witnesses and reports of the police and coroners. In each case, the particular circumstances of the accident and details from the post mortem examination, where available, are provided. A root cause analysis was made for each case. RESULTS: There were 20 reported fatalities, one less than the previous year. Five of the victims were female (four scuba divers) and 15 were males. Twelve deaths occurred while snorkelling and/or breath-hold diving, seven while scuba diving (one of whom was using a rebreather), and one diver died while using surface supplied breathing apparatus. At least two breath-hold divers likely drowned as a result of apnoeic hypoxia. Cardiac-related issues were thought to have contributed to the deaths of at least three and possibly five snorkellers, and of at least one, possibly two compressed gas divers. CONCLUSIONS: Snorkelling or diving alone, poor supervision, apnoeic hypoxia, pre existing medical conditions, lack of recent experience and unfamiliar and/or poorly-functioning equipment were features in several deaths in this series. Reducing delays to CT-scanning and autopsy and coroners' reports documenting that the victim of a drowning was snorkelling or scuba diving at the time are aspects of the investigation of these fatalities that could be improved. PMID- 26415068 TI - Middle ear barotrauma in a tourist-oriented, condensed open-water diver certification course: incidence and effect of language of instruction. AB - INTRODUCTION: In Professional Association of Diving Instructors (PADI) Open Water Diver certification courses that cater to tourists, instruction is often condensed and potentially delivered in a language that is not the candidate's native language. OBJECTIVE: To assess the incidence of middle ear barotrauma (MEBt) in open-water diver candidates during a condensed four-day certification course, and to determine if language of instruction affects the incidence of MEBt in these divers. METHOD: The ears of participating diving candidates were assessed prior to commencing any in-water compression. Tympanic membranes (TM) were assessed and graded for MEBt after the confined and open-water training sessions. Tympanometry was performed if the candidate had no movement of their TM during Valsalva. Photographs were taken with a digital otoscope. RESULTS: Sixty seven candidates participated in the study. Forty-eight had MEBt at some time during their course. MEBt was not associated with instruction in non-native language (adjusted odds ratio = 0.82; 95% confidence intervals 0.21-3.91). There was also no significant association between the severity of MEBt and language of instruction. CONCLUSION: Open-water diver candidates have a high incidence of MEBt. Education in non-native language does not affect the overall incidence of MEBt. PMID- 26415069 TI - The prevalence of oro-facial barotrauma among scuba divers. AB - INTRODUCTION: Barotrauma is a physical injury that results from ambient pressure changes during flying, diving or hyperbaric oxygen therapy. The aim of this study was to assess the prevalence of oro-facial barotrauma among a sample of scuba divers in Jeddah, Saudi Arabia. MATERIALS AND METHODS: Data for the study were collected through a self-reported questionnaire that was distributed to 166 divers. The questionnaire was divided into two parts, in which the first part contained demographic data and the second part consists of multiple choice questions and a few open-ended questions discussing the different signs and symptoms of orofacial barotraumas. RESULTS: One-hundred-and-sixty-three divers responded. The most frequent symptoms during diving were dry mouth (51.9%), followed by clenching (32.5%) and temporomandibular joint (TMJ) pain (19.5%), while the most frequent symptoms after diving were dry mouth (22.7%) followed by clenching and facial pain (16.9%). CONCLUSIONS: Clenching and dry mouth were common findings but are temporary in nature and do not warrant any dental intervention. TMJ and facial pain were also reported but were temporary. The use of commercial mouthpieces during diving may be related to more symptoms when compared with customized types. PMID- 26415070 TI - Does self-certification reflect the cardiac health of UK sport divers? AB - BACKGROUND: Since 2009, the United Kingdom diving incident data show an increasing number of fatalities in the over-50s age group. Previous studies also suggest some divers take cardiac medications. Since 2001, diving medicals have not been mandatory for UK sport divers. Instead, an annual medical self certification form, submitted to their club/school or training establishment, is required. We documented in a survey of UK sport divers the prevalence of cardiac events and medications and the frequency of medical certifications. METHODS: An anonymous on-line questionnaire was publicised. Measures included diver and diving demographics, prescribed medications, diagnosed hypertension, cardiac issues, events and procedures, other health issues, year of last diving medical, diagnosed persistent foramen ovale (PFO), smoking and alcohol habits, exercise and body mass index. RESULTS: Of 672 completed surveys, hypertension was reported by 119 (18%) with 25 of these (21%) having not had a diving medical. Myocardial infarction 6 (1%), coronary artery bypass grafting 3 (< 1%), atrial fibrillation 19 (3%) and angina 12 (2%) were also reported. PFOs were reported by 28 (4%), with 20 of these opting for a closure procedure. From 83 treated incidences of decompression illness (DCI), 19 divers reported that a PFO was diagnosed. CONCLUSIONS: Divers inevitably develop health problems. Some continue to dive with cardiac issues, failing to seek specialised diving advice or fully understand the role of the diving medical. Physicians without appropriate training in diving medicine may inform a diver they are safe to continue diving with their condition without appreciating the potential risks. The current procedure for medical screening for fitness to dive may not be adequate for all divers. PMID- 26415071 TI - Underwater blast injury: a review of standards. AB - The first cases of underwater blast injury appeared in the scientific literature in 1917, and thousands of service members and civilians were injured or killed by underwater blast during WWII. The prevalence of underwater blast injuries and occupational blasting needs led to the development of many safety standards to prevent injury or death. Most of these standards were not supported by experimental data or testing. In this review, we describe existing standards, discuss their origins, and we comprehensively compare their prescriptions across standards. Surprisingly, we found that most safety standards had little or no scientific basis, and prescriptions across standards often varied by at least an order of magnitude. Many published standards traced back to a US Navy 500 psi guideline, which was intended to provide a peak pressure at which injuries were likely to occur. This standard itself seems to have been based upon a completely unfounded assertion that has propagated throughout the literature in subsequent years. Based on the limitations of the standards discussed, we outline future directions for underwater blast injury research, such as the compilation of epidemiological data to examine actual injury risk by human beings subjected to underwater blasts. PMID- 26415072 TI - Cone shell envenomation: epidemiology, pharmacology and medical care. AB - The marine environment presents much danger, specifically in regards to the numerous venomous inhabitants within tropical and subtropical waters. The toxins from one such group of venomous marine snails, commonly referred to as 'cone snails', have been well documented in causing human fatalities. Yet information regarding medical treatment for cone snail envenomation is limited and poorly accessible. To correct this, medical and scientific expertise and literary review on Conus provide a basic and comprehensive directive focused on the medical treatment and post-mortem investigative analysis of cone snail envenomation. We emphasize what we expect to be the most lethal feeding group of Conus and provide a brief background to the epidemiology of their stings. We describe the venom apparatus of Conus and its utility of rapid venom delivery. We have compiled the documented incidences of Conus envenomation to offer thorough reference of known signs and symptoms - this too drawing on personal experiences in the field. We have also made available a brief background to the biochemistry and pharmacology of Conus venoms to highlight their complex nature. PMID- 26415073 TI - On diver thermal status and susceptibility to decompression sickness. AB - In a recent Letter to the Editor, Clarke, et al, indicated that divers who deliberately chill themselves on a dive to reduce risk of decompression sickness (DCS) may be misinterpreting our 2007 Navy Experimental Diving Unit (NEDU) report. Indeed, we did not advocate that divers should risk hypothermia on bottom to reduce risk of DCS, nor do we dispute the authors' overall admonition to avoid diving cold unnecessarily. However, Clarke, et al, imply more generally that results of our study are not applicable to recreational or technical divers because the dives we tested were atypical of dives undertaken by such divers. We wish to clarify that our study does have implications for recreational and technical divers, implications that should not be ignored. The dives we tested were not intended to be typical of dives undertaken in any actual operational context. Instead, we chose to expose divers to temperatures at the extremes of their thermal tolerance in order to ensure that effects of diver thermal status on DCS susceptibility would be found if such effects existed. Our initial test dive profile provided appreciable time both on bottom and during decompression to allow any differential thermal effects during these two dive phases to manifest, while affording a baseline risk of DCS that could be altered by thermal effects without exposing subjects to inordinately high risks of DCS. Our results strongly indicate that the optimal diver thermal conditions for mitigation of DCS risk or minimization of decompression time entail remaining cool during gas uptake phases of a dive and warm during off-gassing phases. While the dose-response characteristics of our observed thermal effects are almost certainly non-linear in both exposure temperature and duration, it is only reasonable to presume that the effects vary monotonically with these factors. We have no reason to presume that such responses and effects under less extreme conditions would be in directions opposite to those found under the conditions we tested. Similarly, responses to thermal exposures even more extreme than we tested might not be larger than the responses we observed, but it would be unwise to ignore the trends in our results under some unfounded presumption that the effects reverse with changes in thermal conditions beyond those tested. Finally, thermal effects on bottom and during decompression in dives to depths other than the 120 feet of sea water (fsw) or 150 fsw depths of the dives we tested are unlikely to be qualitatively different from those observed in our tested dives. The original question has therefore been answered: chill on bottom decreases DCS susceptibility while chill during decompression increases DCS susceptibility. Under conditions encountered by recreational or technical divers, the only open issue is arguably magnitudes of effects, not directions. Neither does lack of technology to control thermal status during a dive render our study results inapplicable. It only renders the diver unable to actively optimize his or her thermal exposure to minimize DCS risk or decompression obligation. Effects of diver thermal status on bottom hold regardless of whether the dive has a decompression long enough for a thermal effect to manifest in the decompression phase of the dive. We pointed out that US Navy decompression tables have historically been developed and validated with test dives in which divers were cold and working during bottom phases and cold and resting during decompression phases. Thus, our results indicate that it is not prudent for very warm divers to challenge the US Navy no-stop limits. However, becoming deliberately chilled on bottom only to remain cold during any ensuing decompression stops is similarly ill-advised. We agree with Clarke et al. that relative conservatism of some dive computer algorithms or alternative decompression tables, or the depth and time roundups necessary to determine table-based prescriptions, work in the diver's favour, but note that diving any profile to a shorter bottom time is a ready means to reduce the risk of DCS - i.e., enhance safety - without compromising comfort. Any active diver heating is best limited while on bottom to a minimal level required to safely complete on-bottom tasks, and dialled up only during decompression. Diver warming during decompression should not be so aggressive as to risk heat stress, and care should be taken to ensure that divers remain hydrated. PMID- 26415074 TI - Re: Don't dive cold when you don't have to. AB - The letter by Clarke et al unfortunately misrepresents the work at the US Navy Experimental Diving Unit (NEDU) to which it refers, and delivers a confused picture of the physiological impact of thermal status on decompression stress. A series of earlier reports outline the importance of thermal status. Being warm during a dive results in higher post-dive Doppler bubble scores. Hot water suits are associated with a higher rate of decompression sickness (DCS) than passively insulated drysuits. Post-dive cooling can prolong the risk window for developing symptoms of skin bends.The NEDU chamber study provided an elegant design to further assess the impact of thermal stress. Dives to 37 msw (120 fsw) were divided into descent/bottom and ascent/stop phases, prolonging the latter so that bottom times could be increased if results allowed without compromising the experimental structure. The water temperature was held at either 36 degrees C (97 degrees F; 'warm') or 27 degrees C (80 degrees F; 'cold'). The 'warm/cold' exposure, with a bottom time of 30 minutes, yielded a DCS rate of 22% (7/32 subject-exposures). The 'cold/warm' bottom time was increased to 70 minutes and still yielded a DCS rate of only 1.3% (2/158). Even if the effects are exaggerated by the prolonged ascent/stop phase, the dramatic results demand serious attention. Contrary to the claim made by Clarke et al in their letter, the high temperature employed in the NEDU study could almost certainly be maintained at the skin by a number of active heating garments available to the diving public. Hot water suits are not required for the effect; and the 'cold' study temperature (better described as 'cool') is clearly well within the range experienced by divers. The statement by Clarke et al that "the Navy uses their extensive mathematical expertise to select the one dive profile that, in their estimation, is the most likely to identify a difference in decompression risk..." is frankly baffling. Use of a single dive depth in no way invalidates the relevance to other dive profiles. Similarly, it is not reasonable to characterize skin temperatures lower than those produced in the study as "venturing into the unknown" and thereby invalidating the results. Scientific method does encourage the confirmation of findings. This goal, however, does not diminish the value of singular, well-designed studies. The NEDU study is certainly one of these, most valuable in reminding divers that factors beyond the pressure-time profile will affect decompression risk. Divers must have adequate thermal protection to function effectively (physically and cognitively) throughout a dive. However, excessive warming during the descent/bottom phase increases inert gas uptake and can compromise decompression safety. Practically, while it may be optimal for divers to be cool or cold during the descent/bottom phase, it is prudent to recommend a thermoneutral range and avoidance of any excessive warming. Being cool during the ascent/stop phase inhibits inert gas elimination and can compromise safety but sudden warming must be constrained to avoid reducing the gas solubility of superficial tissues that could promote localized bubble formation and symptoms of skin bends. Active heating systems are attractive, but they have the potential to create the worst decompression stress condition; excessive heating during the descent/bottom phase and cooling during the ascent/stop phase if they fail part way through a dive. The risk is still elevated, though, if the systems work throughout a dive. Gerth et al were able to increase the bottom time to 70 minutes for both the 'coldwarm' and 'warm-warm' conditions, but the rate of DCS was significantly lower for the 'cold-warm' condition (see above). This lesson is relevant to any diving exposure. Ultimately, divers need to be aware of the potential impact of thermal status. Thermal protection should preserve clear thinking and physical performance, but excessive manipulation should be avoided. For many, passive systems will provide adequate and appropriate protection. For those who need or choose active warming systems, thoughtful use is vital. Further research is required to quantify the hazards and be able to incorporate thermal status into decompression algorithms in a meaningful way. PMID- 26415075 TI - Management of severe spinal cord injury following hyperbaric exposure. AB - There is an increasing body of evidence that drainage of lumbar cerebrospinal fluid (CSF) improves functional neurological outcome after reperfusion injury to the spinal cord that occasionally follows aortic reconstructive surgery. This beneficial effect is considered owing to lowering of the CSF pressure thereby normalising spinal cord blood flow and reducing the 'secondary' cord injury caused by vascular congestion and cord swelling in the relatively confined spinal canal. Whilst lacking definitive proof, there are convincing randomised controlled trials (RCTs), cohort data and systematic reviews supporting this intervention. The therapeutic window for lumbar CSF drainage requires further elucidation; however, it appears to be days rather than hours post insult. We contend that the same benefit is likely to be achieved following other primary spinal cord injuries that cause cord swelling and elicit the 'secondary' injury. Traditionally the concept of CSF drainage has been considered more applicable to the brain as contained in a 'closed box' by lowering intracranial pressure (ICP) to improve cerebral perfusion pressure (CPP). The control of CPP is intended to limit 'secondary' brain injury and is a key concept of brain injury management. Using microdialysis in the spinal cords of trauma patients, it has been shown that intraspinal pressure (ISP) needs to be kept below 20 mmHg and spinal cord perfusion pressure (SCPP) above 70 mmHg to avoid biochemical evidence of secondary cord damage. Vasopressor have also been used in spinal cord injury to improve perfusion, however complications are common, typically cardiac in nature, and require very careful monitoring; the evidence supporting this approach is notably less convincing. Decompression illness (DCI) of the spinal cord is treated with recompression, hyperbaric oxygen, various medications designed to reduce the inflammatory response and fluid administration to normalise blood pressure and haematocrit. These management protocols are based largely on anecdote and transferred evidence from conventional cord trauma, as the low numbers and sporadic nature of DCI in divers makes RCTs nigh on impossible. Unfortunately even with best management, some patients are left with significant neurological deficit. The 'iceberg phenomenon', occurs when patients with DCI of the cord make a good neurological recovery but actually have profound cord damage as revealed in one case some four years later at post mortem and another example in a diver who developed late functional deterioration due to loss of neuronal reserve. This clinical evidence, together with animal study data, support the notion that even a modest preservation of spinal cord axons is associated with significant improvement in neurological outcome. In the light of the positive level two evidence in the vascular literature that CSF drainage limits 'secondary' injury thereby improving neurological outcome, we propose that centres with appropriate clinical experience consider using lumbar CSF drainage to normalise SCPP, as an adjunct to the conventional treatment of severe spinal cord DCI. Divers with severe spinal cord DCI are generally in the most productive years of their lives and, given the potentially devastating impact of this condition, should be given the benefit of any possible adjuvant treatment that may serve to improve long-term outcome. PMID- 26415076 TI - Cytopathologic diagnosis of oncocytic type intraductal papillary mucinous neoplasm: Criteria and clinical implications of accurate diagnosis. AB - BACKGROUND: Cytologic findings of pancreatic oncocytic-type intraductal papillary mucinous neoplasms (IPMNs)/intraductal oncocytic papillary neoplasms (IOPNs) are largely unknown. METHODS: Five IOPNs encountered by the authors were analyzed. RESULTS: Four IOPNs were located in the pancreatic head, and 1 was located in the pancreatic body/tail in 2 men and 3 women ages 56 to 84 years (mean age, 66 years). Radiologic diagnoses included pancreatic ductal adenocarcinoma (PDAC) in 2 patients, invasive cancer associated with IPMN in 1 patient, IPMN versus mucinous cystic neoplasm in 1 patient, and cystic mass in 1 patient. Cytologic findings included: hypercellular smears (4 of 5 cases) containing well formed clusters of oncocytic cells (5 of 5 cases) with prominent, slightly eccentric nucleoli (4 of 5 cases), predominantly arranged in sheets/papillary units (5 of 5 cases), with punched-out intercytoplasmic spaces (4 of 5 cases), and with occasional 3-dimensional groups and focal necrosis (3 of 5 cases). The intracytoplasmic mucin and thick extracellular mucin typical of other IPMNs were observed only in 2 cases and were very limited. The mean size on resection was 4.5 cm. Invasion was observed in 3 cases (0.1, 0.3, and 2.0 cm) of tubular-type IPMN. Initial cytologic evaluation was performed by the authors in 4 of 5 cases, which were diagnosed as IOPN (n = 3) and IPMN versus cystic PDAC (n = 1). One case was initially misdiagnosed as PDAC and, on resection, proved to be noninvasive IOPN. CONCLUSIONS: Cytologic features of IOPNs are classical, similar to their histologic counterparts, and differ significantly from other IPMN subtypes. Because of their highly complex appearance, they are often radiologically misdiagnosed as PDAC; thus, failure to recognize their characteristic features on fine-needle aspiration may lead to inappropriate treatment. Patients with IOPN have an incomparably better prognosis than patients with ordinary PDAC, even when their neoplasms are invasive. PMID- 26415078 TI - Promoting Action on Research Implementation in Health Services framework applied to TeamSTEPPS implementation in small rural hospitals. AB - BACKGROUND: A particularly useful model for examining implementation of quality improvement interventions in health care settings is the PARIHS (Promoting Action on Research Implementation in Health Services) framework developed by Kitson and colleagues. The PARIHS framework proposes three elements (evidence, context, and facilitation) that are related to successful implementation. PURPOSES: An evidence-based program focused on quality enhancement in health care, termed TeamSTEPPS (Team Strategies and Tools to Enhance Performance and Patient Safety), has been widely promoted by the Agency for Healthcare Research and Quality, but research is needed to better understand its implementation. We apply the PARIHS framework in studying TeamSTEPPS implementation to identify elements that are most closely related to successful implementation. METHODOLOGY/APPROACH: Quarterly interviews were conducted over a 9-month period in 13 small rural hospitals that implemented TeamSTEPPS. Interview quotes that were related to each of the PARIHS elements were identified using directed content analysis. Transcripts were also scored quantitatively, and bivariate regression analysis was employed to explore relationships between PARIHS elements and successful implementation related to planning activities. FINDINGS: The current findings provide support for the PARIHS framework and identified two of the three PARIHS elements (context and facilitation) as important contributors to successful implementation. PRACTICE IMPLICATIONS: This study applies the PARIHS framework to TeamSTEPPS, a widely used quality initiative focused on improving health care quality and patient safety. By focusing on small rural hospitals that undertook this quality improvement activity of their own accord, our findings represent effectiveness research in an understudied segment of the health care delivery system. By identifying context and facilitation as the most important contributors to successful implementation, these analyses provide a focus for efficient and effective sustainment of TeamSTEPPS efforts. PMID- 26415079 TI - Organizational responses to accountability requirements: Do we get what we expect? AB - BACKGROUND: In health care, accountability is being championed as a promising approach to meeting the dual imperatives of improving care quality while managing constrained budgets. PURPOSES: Few studies focus on public sector organizations' responsiveness to government imperatives for accountability. We applied and adapted a theory of organizational responsiveness to community care agencies operating in Ontario, Canada, asking the question: What is the array of realized organizational responses to government-imposed accountability requirements among community agencies that receive public funds to provide home and community care? METHODOLOGY/APPROACH: A sequential complementary mixed methods approach was used. It gathered data through a survey of 114 home and community care organizations in Ontario and interviews with 20 key informants representing 13 home and community care agencies and four government agencies. It generated findings using a parallel mixed analysis technique. FINDINGS: In addition to responses predicted by the theory, we found that organizations engage in active, as well as passive, forms of compliance; we refer to this response as internal modification in which internal policies, practices, and/or procedures are changed to meet accountability requirements. We also found that environmental factors, such as the presence of an association representing organizational interests, can influence bargaining tactics. PRACTICE IMPLICATIONS: Our study helps us to better understand the range of likely responses to accountability requirements and is a first step toward encouraging the development of accountability frameworks that favor positive outcomes for organizations and those holding them to account. Tailoring agreements to organizational environments, aligning perceived compliance with behaviors that encourage improved performance, and allowing for flexibility in accountability arrangements are suggested strategies to support beneficial outcomes. PMID- 26415080 TI - Usefulness of plasma drug monitoring in severe baclofen poisoning. PMID- 26415081 TI - IL-21-Expressing Mesenchymal Stem Cells Prevent Lethal B-Cell Lymphoma Through Efficient Delivery of IL-21, Which Redirects the Immune System to Target the Tumor. AB - Interleukin (IL)-21, a proinflammatory cytokine, has been developed as an immunotherapeutic approach due to its effects on various lymphocytes, including natural killer (NK) cells and T cells; however, the clinical success in cancer patients has been limited. Recently, mesenchymal stem cells (MSCs) have emerged as vehicles for cancer gene therapy due to their inherent migratory abilities toward tumors. In the present study, we hypothesized that MSCs, genetically modified to express high levels of IL-21 (IL-21/MSCs), can enhance antitumor responses through localized delivery of IL-21. For tumor induction, BALB/c mice were injected intravenously with syngeneic A20 B-cell lymphoma cells to develop a disseminated B-cell lymphoma model. Then, 6 days following tumor induction, the tumor-bearing mice were treated with IL-21/MSCs weekly, four times. Systemic infusion of A20 cells led to hind-leg paralysis as well as severe liver metastasis in the control group. The IL-21/MSC-treated group showed delayed tumor incidence as well as improved survival, whereas the MSC- and recombinant adenovirus-expressing IL-21 (rAD/IL-21)-treated groups did not show significant differences from the untreated mice. These therapeutic effects were associated with high levels of IL-21 delivered to the liver, which prevented the formation of tumor nodules. Furthermore, the infusion of IL-21/MSCs led to induction of effector T and NK cells, while potently inhibiting immune suppressor cells. Our findings demonstrate that IL-21-expressing MSCs have the therapeutic potential to induce potent antitumor effects against disseminated B-cell lymphoma through localized IL-21 delivery and induction of systemic antitumor immunity. PMID- 26415083 TI - Epindolidione-Based Conjugated Polymers: Synthesis, Electronic Structures, and Charge Transport Properties. AB - Development of new electron-deficient building blocks is essential to donor acceptor conjugated polymers. Herein, epindolidione (EPD) as electron-deficient unit was integrated into conjugated polymers for the investigation of field effect transistors for the first time. We systematically studied the electronic structures and charge transport properties of the EPD-based donor-acceptor polymers. They exhibit p-type transport characteristics with the highest mobility of up to 0.40 cm(2) V(-1) s(-1), thus demonstrating its great potential as a building block for polymer field-effect transistors and photovoltaics. PMID- 26415082 TI - SCARECROW-LIKE23 and SCARECROW jointly specify endodermal cell fate but distinctly control SHORT-ROOT movement. AB - Intercellular signaling through trafficking of regulatory proteins is a widespread phenomenon in plants and can deliver positional information for the determination of cell fate. In the Arabidopsis root meristem, the cell fate determinant SHORT-ROOT (SHR), a GRAS domain transcription factor, acts as a signaling molecule from the stele to the adjacent layer to specify endodermal cell fate. Upon exiting the stele, SHR activates another GRAS domain transcription factor, SCARCROW (SCR), which, together with several BIRD/INDETERMINATE DOMAIN proteins, restricts movement of SHR to define a single cell layer of endodermis. Here we report that endodermal cell fate also requires the joint activity of both SCR and its closest homologue SCARECROW-LIKE23 (SCL23). We show that SCL23 protein moves with zonation-dependent directionality. Within the meristem, SCL23 exhibits short-ranged movement from ground tissue to vasculature. Away from the meristem, SCL23 displays long-range rootward movement into meristematic vasculature and a bidirectional radial spread, respectively. As a known target of SHR and SCR, SCL23 also interacts with SCR and SHR and can restrict intercellular outspread of SHR without relying on nuclear retention as SCR does. Collectively, our data show that SCL23 is a mobile protein that controls movement of SHR and acts redundantly with SCR to specify endodermal fate in the root meristem. PMID- 26415085 TI - Pediatric Outcome after Maternal Cancer Diagnosed during Pregnancy. AB - BACKGROUND: Data on the long-term outcome of children who are exposed to maternal cancer with or without treatment during pregnancy are lacking. METHODS: In this multicenter case-control study, we compared children whose mothers received a diagnosis of cancer during the pregnancy with matched children of women without a cancer diagnosis. We used a health questionnaire and medical files to collect data regarding neonatal and general health. All children were prospectively assessed (by means of a neurologic examination and the Bayley Scales of Infant Development) at 18 months, 36 months, or both. A cardiac assessment was performed at 36 months. RESULTS: A total of 129 children (median age, 22 months; range, 12 to 42) were included in the group whose mother had cancer (prenatal-exposure group) with a matching number in the control group. During pregnancy, 96 children (74.4%) were exposed to chemotherapy (alone or in combination with other treatments), 11 (8.5%) to radiotherapy (alone or in combination), 13 (10.1%) to surgery alone, 2 (1.6%) to other drug treatments, and 14 (10.9%) to no treatment. Birth weight was below the 10th percentile in 28 of 127 children (22.0%) in the prenatal-exposure group and in 19 of 125 children (15.2%) in the control group (P=0.16). There was no significant between-group difference in cognitive development on the basis of the Bayley score (P=0.08) or in subgroup analyses. The gestational age at birth was correlated with the cognitive outcome in the two study groups. Cardiologic evaluation among 47 children at 36 months of age showed normal cardiac findings. CONCLUSIONS: Prenatal exposure to maternal cancer with or without treatment did not impair the cognitive, cardiac, or general development of children in early childhood. Prematurity was correlated with a worse cognitive outcome, but this effect was independent of cancer treatment. (Funded by Research Foundation-Flanders and others; ClinicalTrials.gov number, NCT00330447.). PMID- 26415084 TI - Treatment of pleural malignancies by photo-induction combined to systemic chemotherapy: Proof of concept on rodent lung tumors and feasibility study on porcine chest cavities. AB - BACKGROUND: Low-dose, Visudyne(r)-mediated photodynamic therapy (photo-induction) was shown to selectively enhance tumor vessel transport causing increased uptake of systemically administered chemotherapy in various tumor types grown on rodent lungs. The present experiments explore the efficacy of photo-induced vessel modulation combined to intravenous (IV) liposomal cisplatin (Lipoplatin(r)) on rodent lung tumors and the feasibility/toxicity of this approach in porcine chest cavities. MATERIAL AND METHODS: Three groups of Fischer rats underwent orthotopic sarcoma (n = 14), mesothelioma (n = 14), or adenocarcinoma (n = 12) implantation on the left lung. Half of the animals of each group had photo-induction (0.0625 mg/kg Visudyne(r), 10 J/cm(2) ) followed by IV administration of Lipoplatin(r) (5 mg/kg) and the other half received Lipoplatin(r) without photo-induction. Then, two groups of minipigs underwent intrapleural thoracoscopic (VATS) photo induction (0.0625 mg/kg Visudyne(r); 30 J/cm(2) hilum; 10 J/cm(2) apex/diaphragm) with in situ light dosimetry in combination with IV Lipoplatin(r) administration (5 mg/kg). Protocol I (n = 6) received Lipoplatin(r) immediately after light delivery and Protocol II (n = 9) 90 minutes before light delivery. Three additional animals received Lipoplatin(r) and VATS pleural biopsies but no photo induction (controls). Lipoplatin(r) concentrations were analyzed in blood and tissues before and at regular intervals after photo-induction using inductively coupled plasma mass spectrometry. RESULTS: Photo-induction selectively increased Lipoplatin(r) uptake in all orthotopic tumors. It significantly increased the ratio of tumor to lung Lipoplatin(r) concentration in sarcoma (P = 0.0008) and adenocarcinoma (P = 0.01) but not in mesothelioma, compared to IV drug application alone. In minipigs, intrapleural photo-induction combined to systemic Lipoplatin(r) was well tolerated with no toxicity at 7 days for both treatment protocols. The pleural Lipoplatin(r) concentrations were not significantly different at 10 and 30 J/cm(2) locations but they were significantly higher in protocol I compared to II (2.37 +/- 0.7 vs. 1.37 +/- 0.7 ng/mg, P < 0.001). CONCLUSION: Visudyne(r)-mediated photo-induction selectively enhances the uptake of IV administered Lipoplatin(r) in rodent lung tumors. Intrapleural VATS photo induction with identical treatment conditions combined to IV Lipoplatin chemotherapy is feasible and well tolerated in a porcine model. Lasers Surg. Med. 47:807-816, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26415077 TI - Liver Retransplantation in Patients With HIV-1 Infection: An International Multicenter Cohort Study. AB - Liver retransplantation is performed in HIV-infected patients, although its outcome is not well known. In an international cohort study (eight countries), 37 (6%; 32 coinfected with hepatitis C virus [HCV] and five with hepatitis B virus [HBV]) of 600 HIV-infected patients who had undergone liver transplant were retransplanted. The main indications for retransplantation were vascular complications (35%), primary graft nonfunction (22%), rejection (19%), and HCV recurrence (13%). Overall, 19 patients (51%) died after retransplantation. Survival at 1, 3, and 5 years was 56%, 51%, and 51%, respectively. Among patients with HCV coinfection, HCV RNA replication status at retransplantation was the only significant prognostic factor. Patients with undetectable versus detectable HCV RNA had a survival probability of 80% versus 39% at 1 year and 80% versus 30% at 3 and 5 years (p = 0.025). Recurrence of hepatitis C was the main cause of death in the latter. Patients with HBV coinfection had survival of 80% at 1, 3, and 5 years after retransplantation. HIV infection was adequately controlled with antiretroviral therapy. In conclusion, liver retransplantation is an acceptable option for HIV-infected patients with HBV or HCV coinfection but undetectable HCV RNA. Retransplantation in patients with HCV replication should be reassessed prospectively in the era of new direct antiviral agents. PMID- 26415086 TI - Cautious Optimism for Offspring of Women with Cancer during Pregnancy. PMID- 26415088 TI - Sex- and Obesity-specific Association of Aromatase (CYP19A1) Gene Variant with Apolipoprotein B and Hypertension. AB - BACKGROUND AND AIMS: Gender differences in cardiovascular disease risk have been attributed to sex hormones. The CYP19A1 protein (aromatase) plays a critical role in estrogen biosynthesis and thus affects body fat distribution and regulation. We examined the relationship between polymorphism of the CYP19A1 gene and lipoproteins, body mass index (BMI), insulin levels and HOMA index. METHODS: Randomly selected 2250 Turkish adults (aged 49.7 +/- 11.9 years; 48.6% males) were genotyped for CYP19A1 rs10046 polymorphism using hybridization probes in Real-Time PCR LC480 device. RESULTS: Distribution of the CYP19A1 rs10046 polymorphism was 28% (n = 630), 48.3 % (n = 1085) and 23.7% (n = 535) for the CC, CT and TT genotypes, respectively, and the T allele frequency was 0.48. In relation to apolipoprotein (apo)B levels, C homozygosity was associated with higher apoB in non-obese females, contrasting to being so in obese males only, and further in postmenopausal females. CC genotype in females was associated in linear regression analysis by 7.2 +/- 3.3 mg/dL higher apoB than CT + TT genotypes, independent of age and BMI. Among premenopausal females, insulin levels (p = 0.007), BMI (p = 0.05) and HOMA index (p = 0.034) were higher in C homozygotes than in T-allele carriers. However, CYP19A1 TT genotype contributed to hypertension at an OR 1.80 (95% CI 1.12-2.91), independently of age, BMI and other confounders, in males alone. CONCLUSION: The CYP19A1 rs10046 polymorphism is associated with cardiovascular risk factors such as circulating apoB, insulin resistance and hypertension in a sex- and obesity-specific manner. PMID- 26415089 TI - Do collaborative practical tests encourage student-centered active learning of gross anatomy? AB - Benefits of collaborative testing have been identified in many disciplines. This study sought to determine whether collaborative practical tests encouraged active learning of anatomy. A gross anatomy course included a collaborative component in four practical tests. Two hundred and seven students initially completed the test as individuals and then worked as a team to complete the same test again immediately afterwards. The relationship between mean individual, team, and difference (between team and individual) test scores to overall performance on the final examination (representing overall learning in the course) was examined using regression analysis. The overall mark in the course increased by 9% with a decreased failure rate. There was a strong relationship between individual score and final examination mark (P < 0.001) but no relationship for team score (P = 0.095). A longitudinal analysis showed that the test difference scores increased after Test 1 which may be indicative of social loafing and this was confirmed by a significant negative relationship between difference score on Test 4 (indicating a weaker student) and final examination mark (P < 0.001). It appeared that for this cohort, there was little peer-to-peer learning occurring during the collaborative testing and that weaker students gained the benefit from team marks without significant active learning taking place. This negative outcome may be due to insufficient encouragement of the active learning strategies that were expected to occur during the collaborative testing process. An improved understanding of the efficacy of collaborative assessment could be achieved through the inclusion of questionnaire based data to allow a better interpretation of learning outcomes. Anat Sci Educ 9: 231-237. (c) 2015 American Association of Anatomists. PMID- 26415087 TI - Reactive oxygen species mediate oridonin-induced apoptosis through DNA damage response and activation of JNK pathway in diffuse large B cell lymphoma. AB - This study investigated the cytotoxic effect of oridonin (ORI), a diterpenoid isolated from Rabdosia rubescens, in human diffuse large B cell lymphoma (DLBCL) in vitro and in vivo and the potential molecular mechanisms for ORI-induced cell apoptosis. ORI treatment caused reactive oxygen species (ROS)-mediated oxidative DNA damage response (DDR) and the c-Jun N-terminal kinase (JNK) pathway activation, leading to an induction of intrinsic apoptosis. ROS abolition blocked ORI-induced apoptosis and attenuated the expression of phospho-histone H2AX and phospho-JNK, indicating that ROS-mediated DNA damage and JNK pathway activation were involved in ORI-induced apoptosis. The systemic administration of ORI suppressed the growth of human DLBCL xenografts without showing significant toxicity. These findings suggest that ORI may have promising therapeutic application in DLBCL. PMID- 26415090 TI - Capnographic monitoring of midazolam and propofol sedation during ERCP: a randomized controlled study (EndoBreath Study). AB - BACKGROUND AND STUDY AIMS: This was to determine whether intervention based on additional capnographic monitoring reduces the incidence of hypoxemia during midazolam and propofol sedation for endoscopic retrograde cholangiopancreatography (ERCP). METHODS: Patients (American Society of Anesthesiologists [ASA] I - IV) scheduled for ERCP under midazolam and propofol sedation were randomly assigned to a control arm with standard monitoring or an interventional arm with additional capnographic monitoring. In both arms detection of apnea prompted withholding of propofol administration, stimulation of the patient, insertion of a nasopharyngeal tube, or further measures. The primary study end point was incidence of hypoxemia (oxygen saturation [Sao 2] below 90 %); secondary end points included occurrences of severe hypoxemia (Sao 2 <= 85 %), bradycardia, and hypotension, and sedation quality (patient cooperation and satisfaction). RESULTS: 242 patients were enrolled at three German endoscopy centers. Intention-to-treat analysis revealed no significant reduction in hypoxemia incidence in the capnography arm compared with the standard arm (38.0 % vs. 44.4 %, P = 0.314). Apnea was more frequently detected in the capnography arm (64.5 % vs. 6.0 %, P < 0.001). There were no differences regarding rates of bradycardia and hypotension. Per-protocol analysis showed lower incidence of hypoxemia in the capnography arm compared with the standard arm (31.5 % vs. 44.8 %, P = 0.048). There was one death related to sedation in the standard arm. Sedation quality was similar in the two groups. CONCLUSION: Intention-to-treat analysis showed hypoxemia incidence was not significantly lower in the additional capnography arm compared with standard monitoring. Additional capnographic monitoring of ventilatory activity resulted in improved detection of apnea. PMID- 26415091 TI - Direct Capture of Functional Proteins from Mammalian Plasma Membranes into Nanodiscs. AB - Mammalian plasma membrane proteins make up the largest class of drug targets yet are difficult to study in a cell free system because of their intransigent nature. Herein, we perform direct encapsulation of plasma membrane proteins derived from mammalian cells into a functional nanodisc library. Peptide fingerprinting was used to analyze the proteome of the incorporated proteins in nanodiscs and to further demonstrate that the lipid composition of the nanodiscs directly affects the class of protein that is incorporated. Furthermore, the functionality of the incorporated membrane proteome was evaluated by measuring the activity of membrane proteins: Na(+)/K(+)-ATPase and receptor tyrosine kinases. This work is the first report of the successful establishment and characterization of a cell free functional library of mammalian membrane proteins into nanodiscs. PMID- 26415092 TI - Large-Scale Assembly of Organic Highly Crystalline Multicomponent Wires through Surface-Engineered Condensation and Crystallization. AB - Highly crystalline multicomponent wire arrays are fabricated by a scalable technique, termed surface-engineered condensation and crystallization (SECC). Alignment and position are precisely controlled with the guidance of a micropillar-structured substrate with regionally different wettability and vapor flow controllability. PMID- 26415093 TI - Novel methods to optimize the effects of transcranial direct current stimulation: a systematic review of transcranial direct current stimulation patents. AB - Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that has been extensively studied. While there have been initial positive results in some clinical trials, there is still variability in tDCS results. The aim of this article is to review and discuss patents assessing novel methods to optimize the use of tDCS. A systematic review was performed using Google patents database with tDCS as the main technique, with patents filling date between 2010 and 2015. Twenty-two patents met our inclusion criteria. These patents attempt to address current tDCS limitations. Only a few of them have been investigated in clinical trials (i.e., high-definition tDCS), and indeed most of them have not been tested before in human trials. Further clinical testing is required to assess which patents are more likely to optimize the effects of tDCS. We discuss the potential optimization of tDCS based on these patents and the current experience with standard tDCS. PMID- 26415094 TI - Transfer as a function of exploration and stabilization in original practice. AB - The identification of practice conditions that provide flexibility to perform successfully in transfer is a long-standing issue in motor learning but is still not well understood. Here we investigated the hypothesis that a search strategy that encompasses both exploration and stabilization of the perceptual-motor workspace will enhance performance in transfer. Twenty-two participants practiced a virtual projection task (120 trials on each of 3 days) and subsequently performed two transfer conditions (20 trials/condition) with different constraints in the angle to project the object. The findings revealed a quadratic relation between exploration in practice (indexed by autocorrelation and distribution of error) and subsequent performance error in transfer. The integration of exploration and stabilization of the perceptual-motor workspace enhances transfer to tasks with different constraints on the scaling of motor output. PMID- 26415095 TI - Acute effects of jaw clenching using a customized mouthguard on anaerobic ability and ventilatory flows. AB - The latest findings on the ergogenic effects of a dentistry-design, bite-aligning mouthpiece require additional research to assess its impact on anaerobic ability and ventilatory parameters. This paper was aimed at determining the ergogenic acute effects of wearing a custom-made mouthpiece on oral airflow dynamics, 30-s Wingate Anaerobic Test performance parameters. Twenty-eight healthy and physically-active male subjects (age: 24.50 +/- 3.32, height: 181.34 +/- 7.4, weight: 78.14 +/- 8.21), were voluntarily studied. The subjects were first briefed on the test protocols, and then performed the 30s Wingate test and Spirometer test. The experimental trials were performed in a random counterbalanced order. We evaluate maximum expiratory volume (VEmax L min(-1)), mean power (W kg(-1)), peak power (W kg(-1)), time to peak (s), rate to fatigue (Ws(-1)) and lactate production (mMol L(-1)), rate of perceived exertion (RPE). There were significant differences between mouthguard and no-mouthguard conditions in mean power (W kg(-1)), peak power (W kg(-1)), time to peak (s), and rate to fatigue (Ws(-1)) for the 30-s Wingate Anaerobic Test. Significantly lower lactate production (mMol L(-1)) was observed, in mouthguard condition but no significant differences were found in RPE. In airflow dynamics, the VEmax L min( 1) was significantly higher when comparing the mouthguard and the no mouthguard conditions in both forced and unforced conditions. In conclusion, wearing a customized mouthguard improves anaerobic ability and increases forced expiratory volume. This study will help practitioners improve athlete's performance in anaerobic activities where high intensity action might provoke jaw-clenching, contributing in reductions of lactate and fatigue, and improving ventilatory parameters. PMID- 26415096 TI - Single-molecule spectromicroscopy: a route towards sub-wavelength refractometry. AB - We suggest a novel approach for spatially resolved probing of local fluctuations of the refractive index n in solids by means of single-molecule (SM) spectroscopy. It is based on the dependence T1(n) of the effective radiative lifetime T1 of dye centres in solids on n due to the local-field effects. Detection of SM zero-phonon lines at low temperatures gives the values of the SM natural spectral linewidth (which is inversely proportional to T1) and makes it possible to reveal the distribution of the local n values in solids. Here we demonstrate this possibility on the example of amorphous polyethylene and polycrystalline naphthalene doped with terrylene. In particular, we show that the obtained distributions of lifetime limited spectral linewidths of terrylene molecules embedded into these matrices are due to the spatial fluctuations of the refractive index local values. PMID- 26415097 TI - Mitochondrial Cytochrome c Oxidase Biogenesis Is Regulated by the Redox State of a Heme-Binding Translational Activator. AB - AIM: Mitochondrial cytochrome c oxidase (COX), the last enzyme of the respiratory chain, catalyzes the reduction of oxygen to water and therefore is essential for cell function and viability. COX is a multimeric complex, whose biogenesis is extensively regulated. One type of control targets cytochrome c oxidase subunit 1 (Cox1), a key COX enzymatic core subunit translated on mitochondrial ribosomes. In Saccharomyces cerevisiae, Cox1 synthesis and COX assembly are coordinated through a negative feedback regulatory loop. This coordination is mediated by Mss51, a heme-sensing COX1 mRNA-specific processing factor and translational activator that is also a Cox1 chaperone. In this study, we investigated whether Mss51 hemylation and Mss51-mediated Cox1 synthesis are both modulated by the reduction-oxidation (redox) environment. RESULTS: We report that Cox1 synthesis is attenuated under oxidative stress conditions and have identified one of the underlying mechanisms. We show that in vitro and in vivo exposure to hydrogen peroxide induces the formation of a disulfide bond in Mss51 involving CPX motif heme-coordinating cysteines. Mss51 oxidation results in a heme ligand switch, thereby lowering heme-binding affinity and promoting its release. We demonstrate that in addition to affecting Mss51-dependent heme sensing, oxidative stress compromises Mss51 roles in COX1 mRNA processing and translation. INNOVATION: H2O2 induced downregulation of mitochondrial translation has so far not been reported. We show that high H2O2 concentrations induce a global attenuation effect, but milder concentrations specifically affect COX1 mRNA processing and translation in an Mss51-dependent manner. CONCLUSION: The redox environment modulates Mss51 functions, which are essential for regulation of COX biogenesis and aerobic energy production. PMID- 26415098 TI - Inhibiting ERK Activation with CI-1040 Leads to Compensatory Upregulation of Alternate MAPKs and Plasminogen Activator Inhibitor-1 following Subtotal Nephrectomy with No Impact on Kidney Fibrosis. AB - Extracellular-signal regulated kinase (ERK) activation by MEK plays a key role in many of the cellular processes that underlie progressive kidney fibrosis including cell proliferation, apoptosis and transforming growth factor beta1 mediated epithelial to mesenchymal transition. We therefore assessed the therapeutic impact of ERK1/2 inhibition using a MEK inhibitor in the rat 5/6 subtotal nephrectomy (SNx) model of kidney fibrosis. There was a twentyfold upregulation in phospho-ERK1/2 expression in the kidney after SNx in Male Wistar rats. Rats undergoing SNx became hypertensive, proteinuric and developed progressive kidney failure with reduced creatinine clearance. Treatment with the MEK inhibitor, CI-1040 abolished phospho- ERK1/2 expression in kidney tissue and prevented phospho-ERK1/2 expression in peripheral lymphocytes during the entire course of therapy. CI-1040 had no impact on creatinine clearance, proteinuria, glomerular and tubular fibrosis, and alpha-smooth muscle actin expression. However, inhibition of ERK1/2 activation led to significant compensatory upregulation of the MAP kinases, p38 and JNK in kidney tissue. CI-1040 also increased the expression of plasminogen activator inhibitor-1 (PAI-1), a key inhibitor of plasmin-dependent matrix metalloproteinases. Thus inhibition of ERK1/2 activation has no therapeutic effect on kidney fibrosis in SNx possibly due to increased compensatory activation of the p38 and JNK signalling pathways with subsequent upregulation of PAI-1. PMID- 26415099 TI - Formation of High-Spin States (S = 3/2 and 2) in Linear Oligo- and Polyarylamines. AB - This article describes the study of a linear trimer and three polyarylamines PB1 3 containing a 3,4'-biphenyl ferromagnetic coupler. The synthesis of the model compound (trimer) and the polymers has been presented. The formation of radical cations was studied using electrochemical and optical (UV-vis) methods. The chemical oxidation of these compounds leads to the creation of high-spin states, evidenced by pulsed EPR nutation spectroscopy. A quartet spin state is observed for the trimer model compound, and its J exchange coupling constant has been measured experimentally (J/k = 11.8 K) and compared quantitatively to DFT calculations. Most importantly, quartet and quintet spin states have been formed for PB3 and PB2, respectively. These last two doped polymers thus exhibit the highest spin states observed to date for linear polyarylamine compounds. PMID- 26415101 TI - Benefits of contingent screening vs primary screening by cell-free DNA testing: think again. PMID- 26415100 TI - Chronic fatigue syndrome. AB - INTRODUCTION: Chronic fatigue syndrome affects between 0.006% and 3% of the population depending on the criteria of definition used, with women being at higher risk than men. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of selected treatments for chronic fatigue syndrome? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). RESULTS: At this update, searching of electronic databases retrieved 169 studies. After deduplication and removal of conference abstracts, 86 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 71 studies and the further review of 15 full publications. Of the 15 full articles evaluated, two systematic reviews, one RCT, and one further follow-up report of an RCT were added at this update. We performed a GRADE evaluation for 23 PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the effectiveness of four interventions based on information relating to the effectiveness and safety of antidepressants, cognitive behavioural therapy, corticosteroids, and graded exercise therapy. PMID- 26415102 TI - Systematic transcriptome analysis reveals elevated expression of alcohol metabolizing genes in NAFLD livers. AB - Obese animals and non-alcoholic fatty liver disease (NAFLD) patients exhibit elevated blood alcohol, suggesting potential contributions of alcohol metabolism to the development of NAFLD. Liver gene expression in patients with biopsy-proven mild (N = 40) and severe (N = 32) NAFLD were compared to that in healthy liver donors (N = 7) and alcoholic hepatitis (AH; N = 15) using microarrays. Principal components analyses (PCA) revealed similar gene expression patterns between mild and severe NAFLD which clustered with those of AH but were distinct from those of healthy livers. Differential gene expression between NAFLD and healthy livers was consistent with established NAFLD-associated genes and NAFLD pathophysiology. Alcohol-metabolizing enzymes including ADH, ALDH, CYP2E1, and CAT were up regulated in NAFLD livers. The expression level of alcohol-metabolizing genes in severe NAFLD was similar to that in AH. The NAFLD gene expression profiles provide new directions for future investigations to identify disease markers and targets for prevention and treatment, as well as to foster our understanding of NAFLD pathogenesis and pathophysiology. Particularly, increased expression of alcohol-metabolizing genes in NAFLD livers supports a role for endogenous alcohol metabolism in NAFLD pathology and provides further support for gut microbiome therapy in NAFLD management. Copyright (c) 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley (c) Sons, Ltd. PMID- 26415103 TI - Threshold-Voltage Shifts in Organic Transistors Due to Self-Assembled Monolayers at the Dielectric: Evidence for Electronic Coupling and Dipolar Effects. AB - The mechanisms behind the threshold-voltage shift in organic transistors due to functionalizing of the gate dielectric with self-assembled monolayers (SAMs) are still under debate. We address the mechanisms by which SAMs determine the threshold voltage, by analyzing whether the threshold voltage depends on the gate dielectric capacitance. We have investigated transistors based on five oxide thicknesses and two SAMs with rather diverse chemical properties, using the benchmark organic semiconductor dinaphtho[2,3-b:2',3'-f]thieno[3,2-b]thiophene. Unlike several previous studies, we have found that the dependence of the threshold voltage on the gate-dielectric capacitance is completely different for the two SAMs. In transistors with an alkyl SAM, the threshold voltage does not depend on the gate-dielectric capacitance and is determined mainly by the dipolar character of the SAM, whereas in transistors with a fluoroalkyl SAM the threshold voltages exhibit a linear dependence on the inverse of the gate-dielectric capacitance. Kelvin probe force microscopy measurements indicate this behavior is attributed to an electronic coupling between the fluoroalkyl SAM and the organic semiconductor. PMID- 26415104 TI - Prevention of abdominal adhesions and healing skin after peritoniectomy using low level laser. AB - BACKGROUND: Adhesions commonly occur after abdominal surgery and can cause bowel obstruction, chronic abdominal pain, and infertility. Their prevention remains a challenge. OBJECTIVES: To evaluate the effects of the application of low-level lasers on the prevention of adhesions and scarring of the skin after peritoniectomia. METHOD: Twenty-four New Zealand breed male rabbits, approximately 2 months of age, were randomly divided into 3 groups (n = 8): GC control group not subjected to laser, GL1-group with laser application at a dose of 0.2 J, and GL2-group with laser application at a dose of 3.6 J. All animals received a longitudinal midline incision and a bilateral resection of the peritoneal fragment, measuring 3 * 1 cm(2) . The animals received a laser treatment of one application every 24 hours, beginning at the time of surgery and lasting for a period of 4 days. After 14 days post-surgery, the animals were killed and adhesion formation was evaluated qualitatively and quantitatively by means of a laparotomy shaped inverted "U", which allowed for the verification of the broad wall of the abdominal cavity and organs. Differences were considered significant at P < 0.05. RESULTS: The adhesion formation was observed in 100% of the rabbits from groups GC and GL1, as compared to 37.5% of the rabbits from group GL2 (P < 0.01). The evaluation of the vascularization and tenacity of adhesions among the groups showed no significant difference. In groups CG and GL1, 72% and 83% of adhesions were verified between visceras, respectively whereas in GL2 occurred among abdominal wall. The tensile strength of the skin between the groups was not significant (P = 0.3106). The resistance of abdominal wall segments without skin he resistance of skin segments between groups GL2 and GC were higher than in GL1 (P = 0.01). CONCLUSION: Low-level LASER is effective in preventing intra-abdominal adhesions in rabbits without compromising strength and healing of the abdominal wall. PMID- 26415106 TI - Primary immunodeficiencies and the control of Epstein-Barr virus infection. AB - Human primary immunodeficiency (PID) states, where mutations in single immune system genes predispose individuals to certain infectious agents and not others, are experiments of nature that hold important lessons for the immunologist. The number of genetically defined PIDs is rising rapidly, as is the opportunity to learn from them. Epstein-Barr virus (EBV), a human herpesvirus, has long been of interest because of its complex interaction with the immune system. Thus, it causes both infectious mononucleosis (IM), an immunopathologic disease associated with exaggerated host responses, and at least one malignancy, EBV-positive lymphoproliferative disease, when those responses are impaired. Here, we describe the full range of PIDs currently linked with an increased risk of EBV-associated disease. These provide examples where IM-like immunopathology is fatally exaggerated, and others where responses impaired at the stage of induction, expansion, or effector function predispose to malignancy. Current evidence from this rapidly moving field supports the view that lesions in both natural killer cell and T cell function can lead to EBV pathology. PMID- 26415105 TI - A Systematic Review of Experimental Strategies Aimed at Improving Motor Function after Acute and Chronic Spinal Cord Injury. AB - While various approaches have been proposed in clinical trials aimed at improving motor function after spinal cord injury in humans, there is still limited information regarding the scope, methodological quality, and evidence associated with single-intervention and multi-intervention approaches. A systematic review performed using the PubMed search engine and the key words "spinal cord injury motor recovery" identified 1973 records, of which 39 were selected (18 from the search records and 21 from reference list inspection). Study phase ( clinicaltrials.org criteria) and methodological quality (Cochrane criteria) were assessed. Studies included proposed a broad range of single-intervention (encompassing cell therapies, pharmacology, electrical stimulation, rehabilitation) (encompassing cell therapies, pharmacology, electrical stimulation, rehabilitation) and multi-intervention approaches (that combined more than one strategy). The highest evidence level was for Phase III studies supporting the role of multi-intervention approaches that contained a rehabilitation component. Quality appraisal revealed that the percentage of selected studies classified with high risk of bias by Cochrane criteria was as follows: random sequence generation = 64%; allocation concealment = 77%; blinding of participants and personnel = 69%; blinding of outcome assessment = 64%; attrition = 44%; selective reporting = 44%. The current literature contains a high proportion of studies with a limited ability to measure efficacy in a valid manner because of low methodological strength in all items of the Cochrane risk of bias assessment. Recommendations to decrease bias are discussed and include increased methodological rigor in the study design and recruitment of study participants, and the use of electrophysiological and imaging measures that can assess functional integrity of the spinal cord (and may be sufficiently sensitive to detect changes that occur in response to therapeutic interventions). PMID- 26415107 TI - Prednisone Use and Risk of Mortality in Patients With Rheumatoid Arthritis: Moderation by Use of Disease-Modifying Antirheumatic Drugs. AB - OBJECTIVE: Medications for rheumatoid arthritis (RA) may affect survival. However, studies often include limited followup and do not account for selection bias in treatment allocation. Using a large longitudinal database, we examined the association between prednisone use and mortality in RA, and whether this risk was modified with concomitant disease-modifying antirheumatic drug (DMARD) use, after controlling for propensity for treatment with prednisone and individual DMARDs. METHODS: In a prospective study of 5,626 patients with RA followed for up to 25 years, we determined the risk of death associated with prednisone use alone and combined treatment of prednisone with methotrexate (MTX) or sulfasalazine. We used the random forests method to generate propensity scores for prednisone use and each DMARD at study entry and during followup. Mortality risks were estimated using multivariate Cox models that included propensity scores. RESULTS: During followup (median 4.97 years), 666 patients (11.8%) died. In a multivariate, propensity-adjusted model, prednisone use was associated with an increased risk of death (hazard ratio [HR] 2.83 [95% confidence interval (95% CI) 1.03-7.76]). However, there was a significant interaction between prednisone use and MTX use (P = 0.03), so that risk was attenuated when patients were treated with both medications (HR 0.99 [95% CI 0.18-5.36]). However, combination treatment also weakened the protective association of MTX with mortality. Results were similar for sulfasalazine. CONCLUSION: Prednisone use was associated with a significantly increased risk of mortality in patients with RA. This association was mitigated by concomitant DMARD use, but combined treatment also negated the previously reported beneficial association of MTX with survival in RA. PMID- 26415109 TI - Interfacial Donor-Acceptor Engineering of Nanofiber Materials To Achieve Photoconductivity and Applications. AB - Self-assembly of pi-conjugate molecules often leads to formation of well-defined nanofibril structures dominated by the columnar pi-pi stacking between the molecular planes. These nanofibril materials have drawn increasing interest in the research frontiers of nanomaterials and nanotechnology, as the nanofibers demonstrate one-dimensionally enhanced exciton and charge diffusion along the long axis, and present great potential for varying optoelectronic applications, such as sensors, optics, photovoltaics, and photocatalysis. However, poor electrical conductivity remains a technical drawback for these nanomaterials. To address this problem, we have developed a series of nanofiber structures modified with different donor-acceptor (D-A) interfaces that are tunable for maximizing the photoinduced charge separation, thus leading to increase in the electrical conductivity. The D-A interface can be constructed with covalent linker or noncovalent interaction (e.g., hydrophobic interdigitation between alkyl chains). The noncovalent method is generally more flexible for molecular design and solution processing, making it more adaptable to be applied to other fibril nanomaterials such as carbon nanotubes. In this Account, we will discuss our recent discoveries in these research fields, aiming to provide deep insight into the enabling photoconductivity of nanofibril materials, and the dependence on interface structure. The photoconductivity generated with the nanofibril material is proportional to the charge carriers density, which in turn is determined by the kinetics balance of the three competitive charge transfer processes: (1) the photoinduced electron transfer from D to A (also referred to as exciton dissociation), generating majority charge carrier located in the nanofiber; (2) the back electron transfer; and (3) the charge delocalization along the nanofiber mediated by the pi-pi stacking interaction. The relative rates of these charge transfer processes can be tuned by the molecular structure and nanoscale interface engineering. As a result, maximal photoconductivity can be achieved for different D-A nanofibril composites. The photoconductive nanomaterials thus obtained demonstrate unique features and functions when employed in photochemiresistor sensors, photovoltaics and photocatalysis, all taking advantages of the large, open interface of nanofibril structure. Upon deposition onto a substrate, the intertwined nanofibers form networks with porosity in nanometer scale. The porous structure enables three-dimensional diffusion of molecules (analytes in sensor or reactants in catalysis), facilitating the interfacial chemical interactions. For carbon nanotubes, the completely exposed pi-conjugation facilitates the surface modification through pi-pi stacking in conjunction with D-A interaction. Depending on the electronic energy levels of D and A parts, appropriate band alignment can be achieved, thus producing an electric field across the interface. Presence of such an electric field enhances the charge separation, which may lead to design of new type of photovoltaic system using carbon nanotube composite. PMID- 26415108 TI - Population-specific prognostic models are needed to stratify outcomes for African Americans with diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) demonstrates significant racial differences in age of onset, stage, and survival. To examine whether population-specific models improve prediction of outcomes for African-American (AA) patients with DLBCL, we utilized Surveillance, Epidemiology, and End Results data and compared stratification by the international prognostic index (IPI) in general and AA populations. We also constructed and compared prognostic models for general and AA populations using multivariable logistic regression (LR) and artificial neural network approaches. While the IPI adequately stratified outcomes for the general population, it failed to separate AA DLBCL patients into distinct risk groups. Our AA LR model identified age >= 55 (odds ratio 0.45, [95% CI: 0.36, 0.56], male sex (0.75, [0.60, 0.93]), and stage III/IV disease (0.43, [0.34, 0.54]) as adverse predictors of 5-year survival for AA patients. In addition, general population prognostic models were poorly calibrated for AAs with DLBCL, indicating a need for validated AA-specific prognostic models. PMID- 26415110 TI - Towards soft robotic devices for site-specific drug delivery. AB - Considerable research efforts have recently been dedicated to the establishment of various drug delivery systems (DDS) that are mechanical/physical, chemical and biological/molecular DDS. In this paper, we report on the recent advances in site specific drug delivery (site-specific, controlled, targeted or smart drug delivery are terms used interchangeably in the literature, to mean to transport a drug or a therapeutic agent to a desired location within the body and release it as desired with negligibly small toxicity and side effect compared to classical drug administration means such as peroral, parenteral, transmucosal, topical and inhalation) based on mechanical/physical systems consisting of implantable and robotic drug delivery systems. While we specifically focus on the robotic or autonomous DDS, which can be reprogrammable and provide multiple doses of a drug at a required time and rate, we briefly cover the implanted DDS, which are well developed relative to the robotic DDS, to highlight the design and performance requirements, and investigate issues associated with the robotic DDS. Critical research issues associated with both DDSs are presented to describe the research challenges ahead of us in order to establish soft robotic devices for clinical and biomedical applications. PMID- 26415111 TI - Carbon Inverse Opal Rods for Nonenzymatic Cholesterol Detection. AB - Carbon inverse opal rods made from silica photonic crystal rods are used for nonenzymatic cholesterol sensing. The characteristic reflection peak originating from the physical periodic structure works as sensing signals for quantitatively estimating cholesterol concentrations. Carbon inverse opal rods work both in cholesterol standard solutions and human serum. They are suitable for practical use in clinical diagnose. PMID- 26415112 TI - [Imaging Diagnosis of Ameloblastoma]. PMID- 26415113 TI - PaMiNI-Derived Co-Activation Patterns Indicate Differential Hierarchical Levels for Two Ventral Visual Areas of the Fusiform Gyrus. AB - PURPOSE: To investigate the distribution of co-activation patterns of the recently identified ventral visual areas FG1 and FG2 of the posterior fusiform gyrus using the novel meta-analytic approach PaMiNI (Pattern Mining in NeuroImaging). MATERIALS AND METHODS: All neuroimaging experiments reporting activation foci within FG1 or FG2 were retrieved from the BrainMap database. The stereotaxic activation foci in standard reference space were analyzed with PaMiNI. Here, Gaussian mixture modeling was applied to the stereotaxic coordinates of all foci to identify the underlying brain regions of each dataset. Then, association analysis was performed to reveal frequent co-activations across the modeled brain regions. RESULTS: Co-activation patterns of FG1 were mainly found within the visual system, i.e. in early visual areas, and were symmetrically distributed across both hemispheres. FG2 features several extra visual co-activations, mainly to inferior frontal, premotor and parietal regions. Furthermore, the co-activations of FG2 showed clear lateralization to the left FG2. CONCLUSION: FG1 shows characteristics of an intermediate visual area between the early ventral visual cortex and the category-specific higher-order areas. Co activation patterns of FG2 indicate that FG2 is a higher-order visual area that probably corresponds to the posterior fusiform face area and partly the visual word-form area. Key points. Co-activation patterns of areas FG1 and FG2 were analyzed with PaMiNI. FG1 features mainly symmetric co-activations to areas of the visual system. FG2 shows several extra-visual co-activations, which are left lateralized. FG1 corresponds to a hierarchically intermediate, FG2 to a higher order visual area. The PaMiNI approach is extended to seed-specific mapping of co activation patterns. PMID- 26415117 TI - Clinical Characteristics of Sarcoid Arthropathy: A Population-Based Study. AB - OBJECTIVE: The epidemiology and clinical characteristics of sarcoid arthropathy are not well described, as only referral-based studies have been reported. This study aimed to use the data from a geographically well-defined population to characterize the clinical characteristics of sarcoid arthropathy. METHODS: An inception cohort of patients with incident sarcoidosis in the years 1976-2013 in a geographically well-defined population was identified based on comprehensive individual medical records review. Inclusion required physician diagnosis supported by histopathology and radiologic features of intrathoracic sarcoidosis, compatible clinical presentation, and exclusion of other granulomatous diseases. Patients with joint pain were then identified from this cohort. RESULTS: In 1976 2013, all 345 incident cases of sarcoidosis were identified. Symptoms of joint pain occurred in 42 patients (mean age 41.2 years, 57.1% female, and 95% white), and 35 patients had swollen joint(s) on physical examination. Most patients had arthralgia prior to the diagnosis of sarcoidosis, with an average time to diagnosis of 21 days. Of the 35 cases, oligoarthritis (2 to 4 joints) was the most common pattern (88% of cases), followed by monoarthritis (6%) and polyarthritis (6%). Ankles were involved in 91% of cases. In the majority of patients (88%), the arthritis resolved within 6 weeks. Classic Lofgren's syndrome was observed in 11 patients (26%). CONCLUSION: Inflammatory arthritis occurs in a minority of patients with sarcoidosis. Acute oligoarthritis with bilateral ankle involvement was the most common pattern of sarcoid arthropathy. It should be noted that the generalizability of the results may be limited, as the cohort was predominantly white. PMID- 26415120 TI - Edible oil structuring: an overview and recent updates. AB - In recent years, research dealing with edible oil structuring has received considerable interest from scientific community working in the area of food formulation. Much of this interest is linked to the possibility of using structured oil in development of newer product formats with improved nutritional profile (trans fat-free, low in saturated fats and high in mono and/or poly unsaturated fatty acids). In addition to the obvious industrial need of finding the alternative formulation approach, the interesting properties of structured systems (particularly, oleogels) also makes them a fascinating subject for fundamental studies. In this paper, we attempt to give a comprehensive and concise overview of the field of oil structuring with special emphasis on the updates from recent years. Specifically, several categories of food-grade oleogelators and their potential food applications are summarized with typical examples along with a discussion on the general principles and unresolved challenges related to this emerging area. PMID- 26415118 TI - Local oxytocin tempers anxiety by activating GABAA receptors in the hypothalamic paraventricular nucleus. AB - Oxytocin (Oxt) is released in various hypothalamic and extrahypothalamic brain areas in response to anxiogenic stimuli to regulate aspects of emotionality and stress coping. We examined the anxiolytic action of Oxt in the hypothalamic paraventricular nucleus (PVN) while appraising if Oxt recruits GABA neurons to inhibit the behavioral, hormonal, and neuronal response to stress in female prairie voles (Microtus ochrogaster). Voles received an injection of Oxt in the PVN either before or after an elevated platform stress to determine a time-course for the effects of Oxt on the hormonal stress response. Subsequently, we evaluated if ante-stress injections of Oxt affected anxiety-like behaviors as well as neuronal activity in the PVN, using real-time in-vivo retrodialysis and immunohistochemistry with c-Fos expression as a biomarker of neural activity. In addition, we exposed voles to Oxt and a GABAA receptor antagonist, concurrently, to evaluate the impact of pharmacological blockade of GABAA receptors on the anxiolytic effects of Oxt. Elevated platform stress amplified anxiety-like behaviors and hypothalamic-pituitary-adrenal (HPA) axis activity-catalyzing corticotrophin-releasing hormone (CRH) neuronal activity and augmenting corticosterone release in circulation. Ante-stress Oxt injections in the PVN blocked these stress effects while promoting PVN GABA activity and release. Post stress Oxt treatments were ineffective. The anxiolytic effects of Oxt were hindered by concurrent pharmacological blockade of GABAA receptors. Together, our data demonstrate ante-stress treatments of Oxt in the PVN inhibit stress activation of the HPA axis through recruitment of GABAergic neurons, providing insights to the local circuitry and potential therapeutically-relevant mechanisms. PMID- 26415119 TI - The neurosteroidogenic enzyme 5alpha-reductase modulates the role of D1 dopamine receptors in rat sensorimotor gating. AB - Neurosteroids exert diverse modulatory actions on dopamine neurotransmission and signaling. We previously documented that the enzyme 5alpha-reductase, which catalyzes the main rate-limiting step in neurosteroid synthesis, is required for the behavioral responses of Sprague-Dawley rats to non-selective dopaminergic agonists, such as the D1-D2 receptor agonist apomorphine. Specifically, systemic and intra-accumbal administrations of the 5alpha-reductase inhibitor finasteride countered apomorphine-induced deficits of sensorimotor gating, as measured by the prepulse inhibition (PPI) of the startle reflex; the classes of dopamine receptors involved in these effects, however, remain unknown. Prior rodent studies have revealed that the contributions of dopamine receptors to PPI regulation vary depending on the genetic background; thus, we analyzed the effect of finasteride on the PPI deficits induced by selective dopamine receptor agonists in Long-Evans (a strain exhibiting PPI deficits in response to both D1 and D2 receptor agonists) and Sprague-Dawley rats (which display PPI reductions following treatment with D2, and D3, but not D1 receptor agonists). In Long-Evans rats, finasteride opposed the PPI deficits induced by activation of D1, but not D2 receptors; conversely, in Sprague-Dawley rats, finasteride prevented the reductions in %PPI and accumbal dopamine extracellular levels caused by selective stimulation of D3, but not D2 receptors; however, the effects on %PPI were not confirmed by analyses on absolute PPI values. Our findings suggest that 5alpha reductase modulates the effects of D1, but not D2 receptor agonists on sensorimotor gating. These data may help elucidate the role of neurosteroids in neuropsychiatric disorders featuring PPI deficits, including schizophrenia and Tourette syndrome. PMID- 26415121 TI - Comparison of Retrograde Intrarenal Surgery and Percutaneous Nephrolithotomy: From the View of an Anesthesiologist. AB - PURPOSE: To determine the differences among the hemodynamics, neuroendocrine stress response (NESR), and postoperative visual analogue scale (VAS) scores of pain between the procedures of retrograde intrarenal surgery (RIRS) and percutaneous nephrolithotomy (PNL) for lower pole kidney stones. PATIENTS AND METHODS: Fifty-six patients undergoing RIRS and PNL with lower puncture approach, under general anesthesia, were prospectively enrolled in our study. Perioperative blood pressure (systolic, diastolic, and mean), heart rate, and peripheral oxygen saturation (SpO2) values were recorded at intervals. Arterial blood gas (ABG) and blood glucose, serum insulin, and cortisol levels as stress response markers were analyzed in the perioperative period. Postoperative VAS scores were recorded at 30 minutes and 2, 4, 6, and 12 hours after extubation. Duration of surgery, stone sizes, and stone-free rates (SFRs) were noted. RESULTS: SFRs were 93.3% in the PNL group (28/30 patients) and 88.5% in the RIRS group (23/26 patients) (p = 0.52). There was no statistical difference between the hemodynamics of both groups. Perioperative ABGs and NESRs were similar between groups (p > 0.05). Postoperative VAS scores and analgesic consumptions were also similar between groups (p > 0.05). Duration of surgery was significantly shorter in the RIRS group (p = 0.001). Stone size was significantly higher in the PNL group (p = 0.013). CONCLUSION: Although the PNL is assumed to be more invasive than the RIRS procedure among urologists and anesthesiologists, both techniques may have similar perioperative outcomes in terms of hemodynamics, ABG, NESR, and pain scores in the management of lower pole stones with lower pole approach. PMID- 26415123 TI - Prediction, simulation, and verification of the phase noise in 80-MHz low-phase noise crystal oscillators. AB - To predict the phase noise in an 80-MHz crystal oscillator, on the basis of the classical Leeson model, we analyzed and selected the oscillator noise figure F and transistor corner frequency fc reasonably, and then calculated the loaded Q (QL) value of the oscillator according to the parameters in the selected Butler oscillation circuit. Thus, we obtained the predicted phase noise in an 80-MHz crystal oscillator according to the Leeson phase noise formula. Next, the simulation curve of the phase noise in this 80-MHz low-phase-noise crystal oscillator was obtained by establishing a transistor nonlinear model using commercial design software. Then, we debugged the 80-MHz low-phase-noise crystal oscillator prototype under the guidance of the prediction and simulation results and tested it. The measured results show that the phase noise predicted after selecting reasonable parameters for the Leeson model and the ADS simulation curve of the phase noise obtained by using the nonlinear transistor model are both close to the actual measured result. This result may be beneficial in simplifying the design process for low-phase-noise crystal oscillators. PMID- 26415122 TI - Cross Talk in HEK293 Cells Between Nrf2, HIF, and NF-kappaB Activities upon Challenges with Redox Therapeutics Characterized with Single-Cell Resolution. AB - AIM: Many transcription factors with importance in health and disease are redox regulated. However, how their activities may be intertwined in responses to redox perturbing stimuli is poorly understood. To enable in-depth characterization of this aspect, we here developed a methodology for simultaneous determination of nuclear factor E2-related factor 2 (Nrf2), hypoxia-inducible factor (HIF), and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kappaB) activation at single-cell resolution, using a new tool named pTRAF (plasmid for transcription factor reporter activation based upon fluorescence). The pTRAF allowed determination of Nrf2, HIF, and NF-kappaB activities in a high-resolution and high-throughput manner, and we here assessed how redox therapeutics affected the activities of these transcription factors in human embryonic kidney cells (HEK293). RESULTS: Cross talk was detected between the three signaling pathways upon some types of redox therapeutics, also by using inducers typically considered specific for Nrf2, such as sulforaphane or auranofin, hypoxia for HIF activation, or tumor necrosis factor alpha (TNFalpha) for NF-kappaB stimulation. Doxorubicin, at low nontoxic doses, potentiated TNFalpha-induced activation of NF kappaB and HIF, without effects in stand-alone treatment. Stochastic activation patterns in cell cultures were also considerable upon challenges with several redox stimuli. INNOVATION: A novel strategy was here used to study simultaneous activation of Nrf2, HIF, and NF-kappaB in single cells. The method can also be adapted for studies of other transcription factors. CONCLUSION: The pTRAF provides new opportunities for in-depth studies of transcription factor activities. In this study, we found that upon challenges of cells with several redox-perturbing conditions, Nrf2, HIF, and NF-kappaB are uniquely responsive to separate stimuli, but can also display marked cross talk to each other within single cells. Antioxid. Redox Signal. 26, 229-246. PMID- 26415124 TI - Development of an ultrasound microscope combined with optical microscope for multiparametric characterization of a single cell. AB - Biomechanics of the cell has been gathering much attention because it affects the pathological status in atherosclerosis and cancer. In the present study, an ultrasound microscope system combined with optical microscope for characterization of a single cell with multiple ultrasound parameters was developed. The central frequency of the transducer was 375 MHz and the scan area was 80 * 80 MUm with up to 200 * 200 sampling points. An inverted optical microscope was incorporated in the design of the system, allowing for simultaneous optical observations of cultured cells. Two-dimensional mapping of multiple ultrasound parameters, such as sound speed, attenuation, and acoustic impedance, as well as the thickness, density, and bulk modulus of specimen/cell under investigation, etc., was realized by the system. Sound speed and thickness of a 3T3-L1 fibroblast cell were successfully obtained by the system. The ultrasound microscope system combined with optical microscope further enhances our understanding of cellular biomechanics. PMID- 26415125 TI - Dual-frequency acoustic droplet vaporization detection for medical imaging. AB - Liquid-filled perfluorocarbon droplets emit a unique acoustic signature when vaporized into gas-filled microbubbles using ultrasound. Here, we conducted a pilot study in a tissue-mimicking flow phantom to explore the spatial aspects of droplet vaporization and investigate the effects of applied pressure and droplet concentration on image contrast and axial and lateral resolution. Control microbubble contrast agents were used for comparison. A confocal dual-frequency transducer was used to transmit at 8 MHz and passively receive at 1 MHz. Droplet signals were of significantly higher energy than microbubble signals. This resulted in improved signal separation and high contrast-to-tissue ratios (CTR). Specifically, with a peak negative pressure (PNP) of 450 kPa applied at the focus, the CTR of B-mode images was 18.3 dB for droplets and -0.4 for microbubbles. The lateral resolution was dictated by the size of the droplet activation area, with lower pressures resulting in smaller activation areas and improved lateral resolution (0.67 mm at 450 kPa). The axial resolution in droplet images was dictated by the size of the initial droplet and was independent of the properties of the transmit pulse (3.86 mm at 450 kPa). In post-processing, time domain averaging (TDA) improved droplet and microbubble signal separation at high pressures (640 kPa and 700 kPa). Taken together, these results indicate that it is possible to generate high-sensitivity, high-contrast images of vaporization events. In the future, this has the potential to be applied in combination with droplet-mediated therapy to track treatment outcomes or as a standalone diagnostic system to monitor the physical properties of the surrounding environment. PMID- 26415126 TI - Coherent compounding in doppler imaging. AB - Coherent compounding can provide high frame rates and wide regions of interest for imaging of blood flow. However, motion will cause out-of-phase summation, potentially causing image degradation. In this work the impact of blood motion on SNR and the accuracy of Doppler velocity estimates are investigated. A simplified model for the compounded Doppler signal is proposed. The model is used to show that coherent compounding acts as a low-pass filter on the coherent compounding Doppler signal, resulting in negatively biased velocity estimates. Simulations and flow phantom experiments are used to quantify the bias and Doppler SNR for different velocities and beam-to-flow (BTF) angles. It is shown that the bias in the mean velocity increases with increasing beam-to-flow angle and/or blood velocity, whereas the SNR decreases; losses up to 4 dB were observed in the investigated scenarios. Further, a 2-D motion correction scheme is proposed based on multi-angle vector Doppler velocity estimates. For a velocity of 1.1 v(Nyq) and a BTF angle of 75 degrees , the bias was reduced from 30% to less than 4% in simulations. The motion correction scheme was also applied to flow phantom and in vivo recordings, in both cases resulting in a substantially reduced mean velocity bias and an SNR less dependent on blood velocity and direction. PMID- 26415127 TI - Hybrid optoacoustic tomography and pulse-echo ultrasonography using concave arrays. AB - Implementation of hybrid imaging using optoacoustic tomography (OAT) and ultrasound (US) brings together the important advantages and complementary features of both methods. However, the fundamentally different physical contrast mechanisms of the two modalities may impose significant difficulties in the optimal tomographic data acquisition and image formation strategies. We investigate the applicability of the commonly applied imaging geometries for acquisition and reconstruction of hybrid optoacoustic tomography and pulse-echo ultrasound (OPUS) images. Optimization of the ultrasound image formation strategy using concave array geometry was implemented using a synthetic aperture method combined with spatial compounding. Experimental validation was performed using a custom-made multiplexer unit executing switching between the two modalities employing the same transducer array. A variety of array probes with different angular coverages were subsequently tested, including arrays for clinical hand held imaging as well as stationary arrays for tomographic small animal imaging. The results demonstrate that acquisition of OAT data by mere addition of an illumination source to the common US linear array geometry may result in significant limited-view artifacts and overall loss of image quality. On the other hand, unsatisfactory US image quality is achieved with tomographic arrays solely optimized for OAT image acquisition without considering the optimal transmit-receive beamforming parameters. Optimal selection of the array pitch size, tomographic coverage and spatial compounding parameters has achieved here an accurate hybrid imaging performance, which was experimentally showcased in tissuemimicking phantoms, post-mortem mice, and hand-held imaging of a healthy volunteer. The efficient combination of the two modalities in a single imaging device reveals the true power of functional and molecular imaging capacities of OAT in addition to the morphological and functional imaging capabilities of US. PMID- 26415129 TI - Microbubble-mediated intravascular ultrasound imaging and drug delivery. AB - Intravascular ultrasound (IVUS) provides radiation-free, real-time imaging and assessment of atherosclerotic disease in terms of anatomical, functional, and molecular composition. The primary clinical applications of IVUS imaging include assessment of luminal plaque volume and real-time image guidance for stent placement. When paired with microbubble contrast agents, IVUS technology may be extended to provide nonlinear imaging, molecular imaging, and therapeutic delivery modes. In this review, we discuss the development of emerging imaging and therapeutic applications that are enabled by the combination of IVUS imaging technology and microbubble contrast agents. PMID- 26415128 TI - Harmonic motion imaging for abdominal tumor detection and high-intensity focused ultrasound ablation monitoring: an in vivo feasibility study in a transgenic mouse model of pancreatic cancer. AB - Harmonic motion imaging (HMI) is a radiationforce- based elasticity imaging technique that tracks oscillatory tissue displacements induced by sinusoidal ultrasonic radiation force to assess the resulting oscillatory displacement denoting the underlying tissue stiffness. The objective of this study was to evaluate the feasibility of HMI in pancreatic tumor detection and high-intensity focused ultrasound (HIFU) treatment monitoring. The HMI system consisted of a focused ultrasound transducer, which generated sinusoidal radiation force to induce oscillatory tissue motion at 50 Hz, and a diagnostic ultrasound transducer, which detected the axial tissue displacements based on acquired radio frequency signals using a 1-D cross-correlation algorithm. For pancreatic tumor detection, HMI images were generated for pancreatic tumors in transgenic mice and normal pancreases in wild-type mice. The obtained HMI images showed a high contrast between normal and malignant pancreases with an average peak-to-peak HMI displacement ratio of 3.2. Histological analysis showed that no tissue damage was associated with HMI when it was used for the sole purpose of elasticity imaging. For pancreatic tumor ablation monitoring, the focused ultrasound transducer was operated at a higher acoustic power and longer pulse length than that used in tumor detection to simultaneously induce HIFU thermal ablation and oscillatory tissue displacements, allowing HMI monitoring without interrupting tumor ablation. HMI monitoring of HIFU ablation found significant decreases in the peak to-peak HMI displacements before and after HIFU ablation with a reduction rate ranging from 15.8% to 57.0%. The formation of thermal lesions after HIFU exposure was confirmed by histological analysis. This study demonstrated the feasibility of HMI in abdominal tumor detection and HIFU ablation monitoring. PMID- 26415130 TI - A 1 kHz A-scan rate pump-probe laser-ultrasound system for robust inspection of composites. AB - We recently built a fiber-optic laser-ultrasound (LU) scanner for nondestructive evaluation (NDE) of aircraft composites and demonstrated its greatly improved sensitivity and stability compared with current noncontact systems. It is also very attractive in terms of cost, stability to environmental noise and surface roughness, simplicity in adjustment, footprint, and flexibility. A new type of a balanced fiber-optic Sagnac interferometer is a key component of this all-optical LU pump-probe system. Very high A-scan rates can be achieved because no reference arm or stabilization feedback are needed. Here, we demonstrate LU system performance at 1000 A-scans/s combined with a fast 2-D translator operating at a scanning speed of 100 mm/s with a peak acceleration of 10 m/s(2) in both lateral directions to produce parallel B-scans at high rates. The fast scanning strategy is described in detail. The sensitivity of this system, in terms of noise equivalent pressure, was further improved to be only 8.3 dB above the Nyquist thermal noise limit. To our knowledge, this is the best reported sensitivity for a noncontact ultrasonic detector of this dimension used to inspect aircraft composites. PMID- 26415131 TI - Design of broadband linear micromachined ultrasonic transducer arrays by means of boundary element method coupled with normal mode theory. AB - In view of the maturity of fabrication processes for capacitive micromachined ultrasonic transducers (cMUTs), engineers and researchers now need efficient and accurate modeling tools to design linear arrays according to a set of technological specifications, such as sensitivity, bandwidth, and directivity pattern. A simplified modeling tool was developed to meet this requirement. It consists of modeling one element as a set of cMUT columns, each being a 1-D periodic array of cMUTs. Model description and assessment of simulation results are given in the first part of the paper. The approach is based on the theory of linear systems so the output data are linked to input data through a large matrix, known as an admittance matrix. In the second part of the paper, we propose reorganization of matrix equations by applying the normal mode theory. From the modal decomposition, two categories of eigenmodes are highlighted, one for which all cMUTs vibrate in phase (the fundamental mode) and the others, which correspond to localized subwavelength resonances, known as baffle modes. The last part of the paper focuses mainly on the fundamental mode and gives several design strategies to optimize the frequency response of an element. PMID- 26415132 TI - Oil saturation effects in lead metaniobate porous piezoceramic: transient material characteristics. AB - Lead metaniobate PbNb2O6 (PN) has a unique combination of high piezoelectric anisotropy; relatively low dielectric permittivity and high Curie temperature; and a low Q-factor, near 20. The very low Q-factor is the most intriguing PN property among the piezoelectric materials, and as shown in this research, this internal high dissipation and damping effect is directly related to the presence of silicon oil in the porous PN structure; consequently, it is dependent on the oil properties. To the contrary, the quality factor of PN not saturated with oil was found to be as high as nearly 400. Full sets of PN electro-mechanical constants, transient resonance and dissipation characteristics, and their temperature dependencies were determined under both conditions: PN conventionally saturated with oil and PN not saturated with oil. As was experimentally shown, at higher temperatures particularly after a 260 degrees C soak for several days, a transition from the "with oil" state to the "no oil" state takes place in the conventional PN properties; this effect is a consequence of the phase transition in the silicon oil from liquid to solid state. PMID- 26415133 TI - Unexpected results of non-invasive prenatal testing: are they all so unexpected? PMID- 26415134 TI - Smartphone-based point-of-care testing of salivary alpha-amylase for personal psychological measurement. AB - Here we report a smartphone-based potentiometric biosensor for point-of-care testing of salivary alpha-amylase (sAA), which is one of the most sensitive indices of autonomic nervous system activity, and therefore a promising non invasive biomarker for mental health. The biosensing system includes a smartphone having a sAA-detection App, a potentiometric reader and a sensing chip with preloaded reagents. The saliva sample wicks into the reaction zone on the sensing chip so that the sAA reacts with the preloaded reagents, resulting in conversion of an electron mediator Fe(CN)6(3-) to Fe(CN)6(4-). The sensing chip is then pressed by fingers to push the reaction mixture into the detection zone for the potentiometric measurement. The potential measured by the smartphone-powered potentiometric reader is sent to the smartphone App via the USB port, and converted into sAA concentration based on a calibration curve. Using our method, sAA in real human sample is quantitatively analyzed within 5 min. The results are in good agreement with that obtained using a reference method, and correlated to psychological states of the subjects. PMID- 26415135 TI - Permeability- and Surface-Energy-Tunable Polyurethane Acrylate Molds for Capillary Force Lithography. AB - A permeability- and surface-energy-controllable polyurethane acrylate (PUA) mold, a "capillary-force material (CFM)" mold, is introduced for capillary-force lithography (CFL). In CFL, the surface energy and gas permeability of the mold are crucial. However, the modulation of these two main factors at a time is difficult. Here, we introduce new CFM molds in which the surface energy and permeability can be modified by controlling the degree of cross-linking of the CFM. As the degree of cross-linking of the CFM mold increases, the surface energy and air permeability decrease. The high average functionality of the mold material makes it possible to produce patterns relatively finely and rapidly due to the high rate of capillary rise and stiffness, and the low functionality allows for patterns to form on a curved surface with conformal contact. CFMs with different functionality and controllable-interfacial properties will extend the capabilities of capillary force lithography to overcome the geometric limitations of patterning on a scale below 100 nm and micro- and nanopatterning on the curved region. PMID- 26415136 TI - Ablation of porcine ligamentum flavum with Ho:YAG, q-switched Ho:YAG, and quadrupled Nd:YAG lasers. AB - BACKGROUND AND OBJECTIVES: Ligamentum flavum (LF) is a tough, rubbery connective tissue providing a portion of the ligamentous stability to the spinal column, and in its hypertrophied state forms a significant compressive pathology in degenerative spinal stenosis. The interaction of lasers and this biological tissue have not been thoroughly studied. Technological advances improving endoscopic surgical access to the spinal canal makes selective removal of LF using small, flexible tools such as laser-coupled fiber optics increasingly attractive for treatment of debilitating spinal stenosis. Testing was performed to assess the effect of Ho:YAG, Q-switched Ho:YAG, and frequency quadrupled Nd:YAG lasers on samples of porcine LF. The objective was to evaluate the suitability of these lasers for surgical removal of LF. STUDY DESIGN/MATERIALS AND METHODS: LF was resected from porcine spine within 2 hours of sacrifice and stored in saline until immediately prior to laser irradiation, which occurred within an additional 2 hours. The optical absorbance of a sample was measured over the spectral band from 190 to 2,360 nm both before and after dehydration. For the experiments using the Ho:YAG (lambda = 2,080 nm, tp = 140 us, FWHM) and Q-Switched Ho:YAG (lambda = 2,080 nm, tp = 260 ns, FWHM) lasers, energy was delivered to the LF through a laser-fiber optic with 600 um core and NA = 0.39. For the experiment using the frequency quadrupled Nd:YAG laser (lambda = 266 nm, tp = 5 ns FWHM), rather than applying the laser energy through a laser-fiber, the energy was focused through an aperture and lens directly onto the LF. Five experiments were conducted to evaluate the effect of the given lasers on LF. First, using the Ho:YAG laser, the single-pulse laser-hole depth versus laser fluence was measured with the laser-fiber in direct contact with the LF (1 g force) and with a standoff distance of 1 mm between the laser-fiber face and the LF. Second, with the LF remaining in situ and the spine bisected along the coronal plane, the surface temperature of the LF was measured with an IR camera during irradiation with the Ho:YAG laser, with and without constant saline flush. Third, the mass loss was measured over the course of 450 Ho:YAG pulses. Fourth, hole depth and temperature were measured over 30 pulses of fixed fluence from the Ho:YAG and Q-Switched Ho:YAG lasers. Fifth, the ablation rate and surface temperature were measured as a function of fluence from the Nd:YAG laser. Several LF staining and hole-depth measurement techniques were also explored. RESULTS: Aside from the expected absorbance peaks corresponding to the water in the LF, the most significant peaks in absorbance were located in the spectral band from 190 to 290 nm and persisted after the tissue was dehydrated. In the first experiment, using the Ho:YAG laser and with the laser-fiber in direct contact with the LF, the lowest single-pulse fluence for which LF was visibly removed was 35 J/cm(2) . Testing was conducted at 6 fluences between 35 and 354 J/cm(2) . Over this range the single-pulse hole depth was shown to be near linear (R(2) = 0.9374, M = 1.6), ranging from 40 to 639 um (N = 3). For the case where the laser fiber face was displaced 1 mm from the LF surface, the lowest single-pulse fluence for which tissue was visibly removed was 72 J/cm(2) . Testing was conducted at 4 energy densities between 72 and 180 J/cm(2) . Over this range the single-pulse hole depth was shown to be near linear (R(2) = 0.8951, M = 1.4), ranging from 31 to 220 um (N = 3). In the second experiment, with LF in situ, constant flushing with room temperature saline was shown to drastically reduce surface temperature during exposure to Ho:YAG at 5 Hz with the laser-fiber in direct contact with the LF. Without saline, over 1 minute of treatment with a per pulse fluence of 141 mJ/cm(2) , the average maximum surface temperature measured 110 degrees C. With 10 cc's of saline flushed over 1 minute and a per-pulse laser fluence of 212 mJ/cm(2) , the average maximum surface temperature was 35 degrees C. In the third experiment, mass loss was shown to be linear over 450 pulses of 600 mJ from the Ho:YAG laser (212 J/cm(2) , direct contact, N = 4; 108 J/cm(2) , 1 mm standoff, N = 4). With the laser-fiber in direct contact, an average of 53 mg was removed (R(2) = 0.996, M = 0.117) and with 1 mm laser-fiber standoff, an average of 44 mg was removed (R(2) = 0.9988, M = 0.097). In the fourth experiment, 30 pulses of the Ho:YAG and Q-Switched Ho:YAG lasers at 1 mm standoff, and 5 Hz produced similar hole depths for the tested fluences of 9 J/cm(2) (151 and 154 um, respectively) and 18 J/cm(2) (470 and 442 um, respectively), though the Ho:YAG laser produced significantly more carbonization around the rim of the laser-hole. The increased carbonization was corroborated by higher measured LF temperature. In all tests with the Ho:YAG and Q-Switched Ho:YAG, an audible photo-acoustic affect coincided with the laser pulse. In the fifth experiment, with the frequency quadrupled Nd:YAG laser at 15 Hz for 450 pulses, ablation depth per pulse was shown to be linear for the fluence range of 0.18 - 0.73 J/cm(2) (R(2) = 0.989, M = 2.4). There was no noticeable photo acoustic effect nor charring around the rim of the laser-hole. CONCLUSION: The Ho:YAG, Q-Switched Ho:YAG, and frequency quadrupled Nd:YAG lasers were shown to remove ligamentum flavum (LF). A single pulse of the Ho:YAG laser was shown to cause tearing of the tissue and a large zone of necrosis surrounding the laser hole. Multiple pulses of the Ho:YAG and Q-Switched Ho:YAG lasers caused charring around the rim of the laser-hole, though the extent of charring was more extensive with the Ho:YAG laser. Charring caused by the Ho:YAG laser was shown to be mitigated by continuously flushing the affected LF with saline during irradiation. The Nd:YAG laser was shown to ablate LF with no gross visible indication of thermal damage to surrounding LF. PMID- 26415137 TI - Association of Lupus Anticoagulant With Long-Term Damage Accrual in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. AB - OBJECTIVE: Antiphospholipid antibodies (aPL) are frequently present in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) patients; however, the prognostic impact of aPL in such patients has not been elucidated. The objective of this study was to determine whether persistent aPL positivity in AAV patients was associated with increased long-term damage accrual. METHODS: Clinical data were retrospectively collected on all AAV patients who attended the vasculitis clinic at our center over a 4-year period. Data collection included presence of lupus anticoagulant (LAC) and IgG and IgM anticardiolipin (aCL) antibody titers, along with concurrent diagnosis of antiphospholipid syndrome (APS). Accumulation of long-term damage was quantified using the Vasculitis Damage Index (VDI). RESULTS: Data from 116 AAV patients were analyzed. A total of 34% (n = 40) had persistently positive aCL or LAC or a concurrent diagnosis of APS and were classified as AAV/aPL. A total of 76 patients (66%) were classified as AAV alone. LAC was present in a statistically higher proportion of AAV/aPL patients than those in the AAV-alone group (P < 0.0001). Mean VDI score was significantly higher in the AAV/aPL group at mean +/- SD 3.54 +/- 1.36 as compared to 1.96 +/- 1.42 in the AAV-alone group (P < 0.0001). Major vascular damage scores were significantly higher in the AAV/aPL group, with mean +/- SD 0.32 +/- 0.59 as compared to 0.07 +/- 0.26 in the AAV-alone group (P < 0.007). CONCLUSION: Persistently positive occurrence of aPL, in particular LAC, is present in a significant proportion of AAV patients and is associated with a higher VDI score. Clinicians should consider screening AAV patients for aPL. PMID- 26415138 TI - Meeting Report: "Proteomics from Discovery to Function:" 6th Annual Meeting of Proteomics Society, India and International Conference-A Milestone for the Indian Proteomics Community. AB - Proteomics is at the epicenter of post-genomics biotechnologies that are currently driving the next generation system science. Moreover, proteomics is a truly global science. The 6(th) Annual Meeting of Proteomics Society, India (PSI) and International Conference on "Proteomics from Discovery to Function" held from December 7-9, 2014, was a transformative endeavor for global proteomics, bringing together the luminaries in the field of proteomics for the very first time in India. This meeting report presents the lessons learned and the highlights of this international scientific conference that was comprised of nine thematic sessions, pre- and post-conference workshops, and an opportunity to cultivate enduring collaborations for proteomics science to benefit both India and global society. The conference had an unforgettable impression on the participants: for the first time, India hosted past and present President and Council members from the Human Proteome Organization (HUPO), along with eminent scientists and young scholars from India and abroad in the field of proteomics at such a large scale, a major highlight of this international event. In all, the PSI 2014 was a milestone conference that has firmly poised the Indian life sciences community as a leading contributor to post-genomics life sciences, thus cultivating crucial trans-generational capacity and inspiration by recognizing the emerging scholars and omics systems scientists who can think and conduct science from cell to society. PMID- 26415139 TI - A Global Health Diagnostic for Personalized Medicine in Resource-Constrained World Settings: A Simple PCR-RFLP Method for Genotyping CYP2B6 g.15582C>T and Science and Policy Relevance for Optimal Use of Antiretroviral Drug Efavirenz. AB - The use of pharmacogenomics (PGx) knowledge in treatment of individual patients is becoming a common phenomenon in the developed world. However, poorly resourced countries have thus far been constrained for three main reasons. First, the cost of whole genome sequencing is still considerably high in comparison to other (non genomics) diagnostics in the developing world where both science and social dynamics create a dynamic and fragile healthcare ecosystem. Second, studies correlating genomic differences with drug pharmacokinetics and pharmacodynamics have not been consistent, and more importantly, often not indexed to impact on societal end-points, beyond clinical practice. Third, ethics regulatory frames over PGx testing require improvements based on nested accountability systems and in ways that address the user community needs. Thus, CYP2B6 is a crucial enzyme in the metabolism of antiretroviral drugs, efavirenz and nevirapine. More than 40 genetic variants have been reported, but only a few contribute to differences in plasma EFV and NVP concentrations. The most widely reported CYP2B6 variants affecting plasma drug levels include c.516G>T, c.983T>C, and to a lesser extent, g.15582C>T, which should be considered in future PGx tests. While the first two variants are easily characterized, the g.15582C>T detection has been performed primarily by sequencing, which is costly, labor intensive, and requires access to barely available expertise in the developing world. We report here on a simple, practical PCR-RFLP method with vast potentials for use in resource-constrained world regions to detect the g.15582C>T variation among South African and Cameroonian persons. The effects of CYP2B6 g.15582C>T on plasma EFV concentration were further evaluated among HIV/AIDS patients. We report no differences in the frequency of the g.15582T variant between the South African (0.08) and Cameroonian (0.06) groups, which are significantly lower than reported in Asians (0.39) and Caucasians (0.31). The g.15582C/T and T/T genotypes were associated with significantly reduced EFV levels (p=0.006). This article additionally presents the policy relevance of the PGX global health diagnostics and therefore, collectively makes an original interdisciplinary contribution to the field of integrative biology and personalized medicine in developing world. Such studies are, in fact, broadly important because resource-constrained regions exist not only in developing world but also in major geographical parts of the G20 nations and the developed countries. PMID- 26415140 TI - CHI3L1 Is a Liver-Enriched, Noninvasive Biomarker That Can Be Used to Stage and Diagnose Substantial Hepatic Fibrosis. AB - Liver fibrosis is a major disease that is primarily caused by hepatitis virus infections, toxins, and alcohol abuse. Diagnosing and staging liver fibrosis are critical in guiding the treatment of chronic liver diseases, according to several international and Chinese guidelines. Liver biopsy is the gold standard for diagnosing and staging liver fibrosis, but it is invasive and suffers from several limitations. Consequently, much research has focused on the search for a noninvasive serum biomarker of fibrosis. In this study, we determined that Chitinase 3-like 1 (CHI3L1) is an abundantly expressed liver gene whose expression is highly enriched in the liver. We then compared serum levels of CHI3L1 among patients with various stages of liver fibrosis, as determined by liver biopsies, and found that the CHI3L1 levels were able to differentiate early stages of liver fibrosis (S0-S2) from late stages of liver fibrosis (S3-S4). We further showed that CHI3L1 is a good marker of substantial fibrosis, with areas under the ROC curves (AUCs) of 0.94 for substantial (S2, S3, S4) fibrosis and 0.96 for advanced (S3, S4) fibrosis. Finally, we showed that CHI3L1 is superior to hyaluronic acid (HA), type III procollagen (PCIII), laminin (LN), and type IV collagen (CIV), which are also serum biomarkers of liver fibrosis, in identifying advanced liver fibrosis in patients with HBV-related liver fibrosis in China. PMID- 26415141 TI - Clinical utility of postmortem microcomputed tomography of the fetal heart: diagnostic imaging vs macroscopic dissection. AB - OBJECTIVES: Congenital cardiac malformations are commonly identified at perinatal autopsy, which can be challenging in fetuses of early gestation and in macerated fetuses. Our objective was to examine fetal complex congenital heart disease by microcomputed tomography (micro-CT), using standard autopsy as the gold standard. METHODS: In this ethically approved study, ex-vivo isolated fetal heart and fetal heart-lung blocks underwent iodine preparation prior to micro-CT, and were fixed in formalin after the micro-CT examination. Images were acquired using a microfocus-CT scanner with individual specimen image optimization. Twenty-one indices assessed normally at autopsy were evaluated for each dataset. Cardiac dissection was performed using a dissecting microscope within 24 h of the micro CT examination. RESULTS: We examined six fetal hearts, comprising five with complex congenital cardiac malformations at a gestational age of 17-23 weeks and an anatomically normal heart of 23 weeks' gestation for reference. All specimens demonstrated excellent internal contrast at micro-CT examination, and the correct overall diagnosis was made in all cases. There was agreement for 114/126 indices assessed on micro-CT and at autopsy dissection (overall concordance of 95.8% (95% CI, 90.5-98.2%)). Micro-CT was particularly useful in the assessment of ventricular morphology in macerated fetuses. CONCLUSIONS: Micro-CT of small ex vivo fetal specimens can provide highly accurate three-dimensional rendering of complex congenital fetal heart disease. This approach represents a significant advance in postmortem imaging and confirms the potential of this technology for non-invasive examination of small fetuses and organs. PMID- 26415142 TI - 3D Atomic Arrangement at Functional Interfaces Inside Nanoparticles by Resonant High-Energy X-ray Diffraction. AB - With current science and technology moving rapidly into smaller scales, nanometer sized materials, often referred to as NPs, are produced in increasing numbers and explored for numerous useful applications. Evidence is mounting, however, that useful properties of NPs can be improved further and even new NP functionality achieved by not only controlling the NP size and shape but also interfacing chemically or structurally distinct entities into single, so-called "composite" NPs. A typical example is core-shell NPs wherein the synergy of distinct atoms at the core?shell interface endows the NPs with otherwise unachievable functionality. However, though advantageous, the concept of functional interfaces inside NPs is still pursued largely by trial-and-error. That is because it is difficut to assess the interfaces precisely at the atomic level using traditional experimental techniques and, hence, difficult to take control of. Using the core?shell interface in less than 10 nm in size Ru core-Pt shells NPs as an example, we demonstrate that precise knowledge of the 3D atomic arrangement at functional interfaces inside NPs can be obtained by resonant high-energy X-ray diffraction (XRD) coupled to element-specific atomic pair distribution function (PDF) analysis. On the basis of the unique structure knowledge obtained, we scrutinize the still-debatable influence of core?shell interface on the catalytic functionality of Ru core-Pt shell NPs, thus evidencing the usefulness of this nontraditional technique for practical applications. PMID- 26415144 TI - Percutaneous Renal Access: Surgical Factors Involved in the Acute Reduction of Renal Function. AB - INTRODUCTION AND OBJECTIVE: Studies in patients and experimental animals have shown that percutaneous nephrolithotomy (PCNL) can acutely impair glomerular filtration and renal perfusion, but the factors contributing to this decline in renal function are unknown. The present study assessed the contribution of needle puncture of the kidney vs dilation of the needle tract to the acute decline in renal hemodynamic and tubular transport function associated with PCNL surgery. MATERIALS AND METHODS: Acute experiments were performed in three groups of anesthetized adult farm pigs: sham-percutaneous access (PERC), that is, no surgical procedure (n = 7); a single-needle stick to access the renal collecting system (n = 8); expansion of the single-needle access tract with a 30F NephroMax balloon dilator and insertion of a nephrostomy sheath (n = 10). The glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and renal extraction of para-amino hippurate (EPAH, estimates tubular organic anion transporter [OAT] activity) were assessed before and 1 to 4.5 hours after sham-PERC or PERC surgical procedures. RESULTS: Overall, GFR responses were similar in all three groups. Sham-treated PERC pigs showed no significant change in ERPF over the experimental observation period, whereas a single-needle stick to access the renal collecting system resulted in renal vasoconstriction (~30% reduction in ERPF, p < 0.05). Dilation of the single-needle access tract to create the nephrostomy did not lead to a further decline in ERPF. PERC surgical procedure mediated renal vasoconstriction was most evident at the 1-hour posttreatment time point. A reduction in EPAH was only observed in pig kidneys with a nephrostomy. CONCLUSIONS: Needle puncture of the kidney for percutaneous access to the renal collecting system is the major driving force for the renal vasoconstriction observed after PCNL surgery, whereas creation of the nephrostomy appears to be largely responsible for decreasing tubular OAT activity. PMID- 26415145 TI - Immunomagnetic Reduction Assay on Des-Gamma-Carboxy Prothrombin for Screening of Hepatocellular Carcinoma. AB - The accredited biomarker alpha-fetoprotein (AFP) offers limited sensitivity and specificity in the early detection of hepatocellular carcinoma (HCC). To improve the screening performance, des-gamma-carboxy prothrombin (DCP) has been identified as another promising biomarker of HCC, combined with AFP biomarkers. The results of the commercial optical enzyme-linked immunosorbent assay (ELISA) kit easily have the interference problem due to the optical methodology. The immunomagnetic reduction (IMR) assay based on the magnetic measurement was utilized to assay DCP biomarkers without the excellent antiinterference performances. A DCP magnetic reagent, composed of iron-oxide (Fe3O4 ) magnetic nanoparticles coated with anti-DCP antibodies solved in phosphoryl-buffer solution, was synthesized and characterized. In the test of standard DCP antigens, superior antiinterference and sensitivity than optical ELISA were proved. In the animal test, the results indicate good agreement between the IMR assay findings and the tumor sizes of HCC rats at all time points after the HCC implantation. The feasibility of the developed DCP magnetic reagent with the IMR for the detection of DCP is verified, and demonstrates the high potential for future clinical applications. PMID- 26415146 TI - Development and Validation of a High-Fidelity Finite-Element Model of Monopolar Stimulation in the Implanted Guinea Pig Cochlea. AB - GOAL: To validate a new electroanatomical model of the implanted guinea pig cochlea against independently obtained in vivo voltage tomography data, and evaluate the validity of exist-ing modeling assumptions on current paths and neural excitation. METHODS: An in silico model was generated from sTSLIM images and analyzed in COMSOL Multiphysics. Tissue resistivities and boundary conditions were varied to test model sensitivity. RESULTS: The simulation was most sensitive to the resistivities of bone, perilymph, and nerve. Bone tissue in particular should be separated by morphology because different types of bone have different electrical properties. Despite having a strong impact on intrascalar voltages and exit pathways, most boundary conditions, including a new alternative proposed to account for the unmodeled return path, only had a weak effect on neural excitation. CONCLUSION: The new model demonstrated a strong correlation with the in vivo voltage data. SIGNIFICANCE: These findings address a long-standing knowledge gap about appropriate boundary conditions, and will help to promote wider acceptance of insights from computational models of the cochlea. PMID- 26415148 TI - Computer-Vision-Assisted Palm Rehabilitation With Supervised Learning. AB - Physical rehabilitation supported by the computer-assisted-interface is gaining popularity among health-care fraternity. In this paper, we have proposed a computer-vision-assisted contactless methodology to facilitate palm and finger rehabilitation. Leap motion controller has been interfaced with a computing device to record parameters describing 3-D movements of the palm of a user undergoing rehabilitation. We have proposed an interface using Unity3D development platform. Our interface is capable of analyzing intermediate steps of rehabilitation without the help of an expert, and it can provide online feedback to the user. Isolated gestures are classified using linear discriminant analysis (DA) and support vector machines (SVM). Finally, a set of discrete hidden Markov models (HMM) have been used to classify gesture sequence performed during rehabilitation. Experimental validation using a large number of samples collected from healthy volunteers reveals that DA and SVM perform similarly while applied on isolated gesture recognition. We have compared the results of HMM-based sequence classification with CRF-based techniques. Our results confirm that both HMM and CRF perform quite similarly when tested on gesture sequences. The proposed system can be used for home-based palm or finger rehabilitation in the absence of experts. PMID- 26415147 TI - Continuous Cuffless Blood Pressure Estimation Using Pulse Transit Time and Photoplethysmogram Intensity Ratio. AB - Pulse transit time (PTT) has attracted much interest for cuffless blood pressure (BP) measurement. However, its limited accuracy is one of the main problems preventing its widespread acceptance. Arterial BP oscillates mainly at high frequency (HF) because of respiratory activity, and at low frequency (LF) because of vasomotor tone. Prior studies suggested that PTT can track BP variation in HF range, but was inadequate to follow the LF variation, which is probably the main reason for its unsatisfactory accuracy. This paper presents a new indicator, the photoplethysmogram intensity ratio (PIR), which can be affected by changes in the arterial diameter, and, thus, trace the LF variation of BP. Spectral analysis of BP, PTT, PIR, and respiratory signal confirmed that PTT was related to BP in HF at the respiratory frequency, while PIR was associated with BP in LF range. We, therefore, develop a novel BP estimation algorithm by using both PTT and PIR. The proposed algorithm was validated on 27 healthy subjects with continuous Finapres BP as reference. The results showed that the mean +/- standard deviation (SD) for the estimated systolic, diastolic, and mean BP with the proposed method against reference were -0.37 +/-5.21, -0.08 +/-4.06, -0.18 +/-4.13 mmHg, and mean absolute difference (MAD) were 4.09, 3.18, 3.18 mmHg, respectively. Furthermore, the proposed method outperformed the two most cited PTT algorithms for about 2 mmHg in SD and MAD. These results demonstrated that the proposed BP model using PIR and PTT can estimate continuous BP with improved accuracy. PMID- 26415151 TI - Fast Coding of Feature Vectors Using Neighbor-to-Neighbor Search. AB - Searching for matches to high-dimensional vectors using hard/soft vector quantization is the most computationally expensive part of various computer vision algorithms including the bag of visual word (BoW). This paper proposes a fast computation method, Neighbor-to-Neighbor (NTN) search [1] , which skips some calculations based on the similarity of input vectors. For example, in image classification using dense SIFT descriptors, the NTN search seeks similar descriptors from a point on a grid to an adjacent point. Applications of the NTN search to vector quantization, a Gaussian mixture model, sparse coding, and a kernel codebook for extracting image or video representation are presented in this paper. We evaluated the proposed method on image and video benchmarks: the PASCAL VOC 2007 Classification Challenge and the TRECVID 2010 Semantic Indexing Task. NTN-VQ reduced the coding cost by 77.4 percent, and NTN-GMM reduced it by 89.3 percent, without any significant degradation in classification performance. PMID- 26415150 TI - Connected Filtering on Tree-Based Shape-Spaces. AB - Connected filters are well-known for their good contour preservation property. A popular implementation strategy relies on tree-based image representations: for example, one can compute an attribute characterizing the connected component represented by each node of the tree and keep only the nodes for which the attribute is sufficiently high. This operation can be seen as a thresholding of the tree, seen as a graph whose nodes are weighted by the attribute. Rather than being satisfied with a mere thresholding, we propose to expand on this idea, and to apply connected filters on this latest graph. Consequently, the filtering is performed not in the space of the image, but in the space of shapes built from the image. Such a processing of shape-space filtering is a generalization of the existing tree-based connected operators. Indeed, the framework includes the classical existing connected operators by attributes. It also allows us to propose a class of novel connected operators from the leveling family, based on non-increasing attributes. Finally, we also propose a new class of connected operators that we call morphological shapings. Some illustrations and quantitative evaluations demonstrate the usefulness and robustness of the proposed shape-space filters. PMID- 26415143 TI - Clinical Relevance of Biomarkers of Oxidative Stress. AB - SIGNIFICANCE: Oxidative stress is considered to be an important component of various diseases. A vast number of methods have been developed and used in virtually all diseases to measure the extent and nature of oxidative stress, ranging from oxidation of DNA to proteins, lipids, and free amino acids. RECENT ADVANCES: An increased understanding of the biology behind diseases and redox biology has led to more specific and sensitive tools to measure oxidative stress markers, which are very diverse and sometimes very low in abundance. CRITICAL ISSUES: The literature is very heterogeneous. It is often difficult to draw general conclusions on the significance of oxidative stress biomarkers, as only in a limited proportion of diseases have a range of different biomarkers been used, and different biomarkers have been used to study different diseases. In addition, biomarkers are often measured using nonspecific methods, while specific methodologies are often too sophisticated or laborious for routine clinical use. FUTURE DIRECTIONS: Several markers of oxidative stress still represent a viable biomarker opportunity for clinical use. However, positive findings with currently used biomarkers still need to be validated in larger sample sizes and compared with current clinical standards to establish them as clinical diagnostics. It is important to realize that oxidative stress is a nuanced phenomenon that is difficult to characterize, and one biomarker is not necessarily better than others. The vast diversity in oxidative stress between diseases and conditions has to be taken into account when selecting the most appropriate biomarker. PMID- 26415152 TI - Hierarchical Spatio-Temporal Probabilistic Graphical Model with Multiple Feature Fusion for Binary Facial Attribute Classification in Real-World Face Videos. AB - Recent literature shows that facial attributes, i.e., contextual facial information, can be beneficial for improving the performance of real-world applications, such as face verification, face recognition, and image search. Examples of face attributes include gender, skin color, facial hair, etc. How to robustly obtain these facial attributes (traits) is still an open problem, especially in the presence of the challenges of real-world environments: non uniform illumination conditions, arbitrary occlusions, motion blur and background clutter. What makes this problem even more difficult is the enormous variability presented by the same subject, due to arbitrary face scales, head poses, and facial expressions. In this paper, we focus on the problem of facial trait classification in real-world face videos. We have developed a fully automatic hierarchical and probabilistic framework that models the collective set of frame class distributions and feature spatial information over a video sequence. The experiments are conducted on a large real-world face video database that we have collected, labelled and made publicly available. The proposed method is flexible enough to be applied to any facial classification problem. Experiments on a large, real-world video database McGillFaces [1] of 18,000 video frames reveal that the proposed framework outperforms alternative approaches, by up to 16.96 and 10.13%, for the facial attributes of gender and facial hair, respectively. PMID- 26415149 TI - Real-Time Neuroimaging and Cognitive Monitoring Using Wearable Dry EEG. AB - GOAL: We present and evaluate a wearable high-density dry-electrode EEG system and an open-source software framework for online neuroimaging and state classification. METHODS: The system integrates a 64-channel dry EEG form factor with wireless data streaming for online analysis. A real-time software framework is applied, including adaptive artifact rejection, cortical source localization, multivariate effective connectivity inference, data visualization, and cognitive state classification from connectivity features using a constrained logistic regression approach (ProxConn). We evaluate the system identification methods on simulated 64-channel EEG data. Then, we evaluate system performance, using ProxConn and a benchmark ERP method, in classifying response errors in nine subjects using the dry EEG system. RESULTS: Simulations yielded high accuracy (AUC = 0.97 +/- 0.021) for real-time cortical connectivity estimation. Response error classification using cortical effective connectivity [short-time direct directed transfer function (sdDTF)] was significantly above chance with similar performance (AUC) for cLORETA (0.74 +/-0.09) and LCMV (0.72 +/-0.08) source localization. Cortical ERP-based classification was equivalent to ProxConn for cLORETA (0.74 +/-0.16) but significantly better for LCMV (0.82 +/-0.12) . CONCLUSION: We demonstrated the feasibility for real-time cortical connectivity analysis and cognitive state classification from high-density wearable dry EEG. SIGNIFICANCE: This paper is the first validated application of these methods to 64-channel dry EEG. This study addresses a need for robust real-time measurement and interpretation of complex brain activity in the dynamic environment of the wearable setting. Such advances can have broad impact in research, medicine, and brain-computer interfaces. The pipelines are made freely available in the open source SIFT and BCILAB toolboxes. PMID- 26415153 TI - Correlated Percolation, Fractal Structures, and Scale-Invariant Distribution of Clusters in Natural Images. AB - Natural images are scale invariant with structures at all length scales.We formulated a geometric view of scale invariance in natural images using percolation theory, which describes the behavior of connected clusters on graphs.We map images to the percolation model by defining clusters on a binary representation for images. We show that critical percolating structures emerge in natural images and study their scaling properties by identifying fractal dimensions and exponents for the scale-invariant distributions of clusters. This formulation leads to a method for identifying clusters in images from underlying structures as a starting point for image segmentation. PMID- 26415154 TI - Labeled Graph Kernel for Behavior Analysis. AB - Automatic behavior analysis from video is a major topic in many areas of research, including computer vision, multimedia, robotics, biology, cognitive science, social psychology, psychiatry, and linguistics. Two major problems are of interest when analyzing behavior. First, we wish to automatically categorize observed behaviors into a discrete set of classes (i.e., classification). For example, to determine word production from video sequences in sign language. Second, we wish to understand the relevance of each behavioral feature in achieving this classification (i.e., decoding). For instance, to know which behavior variables are used to discriminate between the words apple and onion in American Sign Language (ASL). The present paper proposes to model behavior using a labeled graph, where the nodes define behavioral features and the edges are labels specifying their order (e.g., before, overlaps, start). In this approach, classification reduces to a simple labeled graph matching. Unfortunately, the complexity of labeled graph matching grows exponentially with the number of categories we wish to represent. Here, we derive a graph kernel to quickly and accurately compute this graph similarity. This approach is very general and can be plugged into any kernel-based classifier. Specifically, we derive a Labeled Graph Support Vector Machine (LGSVM) and a Labeled Graph Logistic Regressor (LGLR) that can be readily employed to discriminate between many actions (e.g., sign language concepts). The derived approach can be readily used for decoding too, yielding invaluable information for the understanding of a problem (e.g., to know how to teach a sign language). The derived algorithms allow us to achieve higher accuracy results than those of state-of-the-art algorithms in a fraction of the time. We show experimental results on a variety of problems and datasets, including multimodal data. PMID- 26415155 TI - Supervised Evaluation of Image Segmentation and Object Proposal Techniques. AB - This paper tackles the supervised evaluation of image segmentation and object proposal algorithms. It surveys, structures, and deduplicates the measures used to compare both segmentation results and object proposals with a ground truth database; and proposes a new measure: the precision-recall for objects and parts. To compare the quality of these measures, eight state-of-the-art object proposal techniques are analyzed and two quantitative meta-measures involving nine state of the art segmentation methods are presented. The meta-measures consist in assuming some plausible hypotheses about the results and assessing how well each measure reflects these hypotheses. As a conclusion of the performed experiments, this paper proposes the tandem of precision-recall curves for boundaries and for objects-and-parts as the tool of choice for the supervised evaluation of image segmentation. We make the datasets and code of all the measures publicly available. PMID- 26415156 TI - The Information Available to a Moving Observer on Shape with Unknown, Isotropic BRDFs. AB - Psychophysical studies show motion cues inform about shape even with unknown reflectance. Recent works in computer vision have considered shape recovery for an object of unknown BRDF using light source or object motions. This paper proposes a theory that addresses the remaining problem of determining shape from the (small or differential) motion of the camera, for unknown isotropic BRDFs. Our theory derives a differential stereo relation that relates camera motion to surface depth, which generalizes traditional Lambertian assumptions. Under orthographic projection, we show differential stereo may not determine shape for general BRDFs, but suffices to yield an invariant for several restricted (still unknown) BRDFs exhibited by common materials. For the perspective case, we show that differential stereo yields the surface depth for unknown isotropic BRDF and unknown directional lighting, while additional constraints are obtained with restrictions on the BRDF or lighting. The limits imposed by our theory are intrinsic to the shape recovery problem and independent of choice of reconstruction method. We also illustrate trends shared by theories on shape from differential motion of light source, object or camera, to relate the hardness of surface reconstruction to the complexity of imaging setup. PMID- 26415157 TI - Learning to Deblur. AB - We describe a learning-based approach to blind image deconvolution. It uses a deep layered architecture, parts of which are borrowed from recent work on neural network learning, and parts of which incorporate computations that are specific to image deconvolution. The system is trained end-to-end on a set of artificially generated training examples, enabling competitive performance in blind deconvolution, both with respect to quality and runtime. PMID- 26415158 TI - Uncertain LDA: Including Observation Uncertainties in Discriminative Transforms. AB - Linear discriminant analysis (LDA) is a powerful technique in pattern recognition to reduce the dimensionality of data vectors. It maximizes discriminability by retaining only those directions that minimize the ratio of within-class and between-class variance. In this paper, using the same principles as for conventional LDA, we propose to employ uncertainties of the noisy or distorted input data in order to estimate maximally discriminant directions. We demonstrate the efficiency of the proposed uncertain LDA on two applications using state-of the-art techniques. First, we experiment with an automatic speech recognition task, in which the uncertainty of observations is imposed by real-world additive noise. Next, we examine a full-scale speaker recognition system, considering the utterance duration as the source of uncertainty in authenticating a speaker. The experimental results show that when employing an appropriate uncertainty estimation algorithm, uncertain LDA outperforms its conventional LDA counterpart. PMID- 26415159 TI - WordlePlus: Expanding Wordle's Use through Natural Interaction and Animation. AB - Wordle has been commonly used to summarize texts, with each word size-coded by its frequency of occurrences--the more often a word occurs in texts, the bigger it is. The interactive authoring tool WordlePlus leverages natural interaction and animation to give users more control over wordle development. WordlePlus supports direct manipulation of words with pen and touch interaction. It introduces two-word multitouch manipulation, such as concatenating and grouping two words, and provides pen interaction for adding and deleting words. In addition, WordlePlus employs animation to help users create more dynamic and engaging wordles. PMID- 26415160 TI - Angle-Preserving Quadrilateral Mesh Parameterization. AB - In response to their growing use in the real world, this article presents two algorithms for direct parameterization of quadrilateral meshes. The proposed algorithms are angle-preserving mappings, with one mapping a topological disk surface onto a Euclidean plane and one mapping a topological sphere surface onto a unit sphere. Specifically, for topological disk surfaces, the authors devise a discrete conformal energy function to flatten the quadrilateral meshes with a length-preserving boundary condition. For topological sphere surfaces, a derived Tuette energy function is applied to the initialization of parameterization for a mesh, and then the final spherical parametrization result is obtained by minimizing a devised harmonic energy function. Experimental results demonstrate the efficiency of the proposed methods. PMID- 26415161 TI - Key-Node-Separated Graph Clustering and Layouts for Human Relationship Graph Visualization. AB - Many graph-drawing methods apply node-clustering techniques based on the density of edges to find tightly connected subgraphs and then hierarchically visualize the clustered graphs. However, users may want to focus on important nodes and their connections to groups of other nodes for some applications. For this purpose, it is effective to separately visualize the key nodes detected based on adjacency and attributes of the nodes. This article presents a graph visualization technique for attribute-embedded graphs that applies a graph clustering algorithm that accounts for the combination of connections and attributes. The graph clustering step divides the nodes according to the commonality of connected nodes and similarity of feature value vectors. It then calculates the distances between arbitrary pairs of clusters according to the number of connecting edges and the similarity of feature value vectors and finally places the clusters based on the distances. Consequently, the technique separates important nodes that have connections to multiple large clusters and improves the visibility of such nodes' connections. To test this technique, this article presents examples with human relationship graph datasets, including a coauthorship and Twitter communication network dataset. PMID- 26415162 TI - A Comparison of Health Visualization Evaluation Techniques with Older Adults. AB - Aging-associated changes in visual acuity, cognition, and motor control in addition to attitudinal and affective perceptions of technology impact the design of information systems for older adults. Although design guidelines and cognitive theories on information visualization exist, they are often understudied for use with older adults. In an effort to evaluate interactive health visualizations with older adults, the authors applied and compared a benchmark evaluation, an insight-based evaluation, and a subjective usability questionnaire. They were unable to identify statistically significant differences between visualizations using the benchmark evaluation, but found moderate differences with the perceived usability scale and more granular differences through the insight evaluation. PMID- 26415163 TI - ENTVis: A Visual Analytic Tool for Entropy-Based Network Traffic Anomaly Detection. AB - Entropy-based traffic metrics have received substantial attention in network traffic anomaly detection because entropy can provide fine-grained metrics of traffic distribution characteristics. However, some practical issues--such as ambiguity, lack of detailed distribution information, and a large number of false positives--affect the application of entropy-based traffic anomaly detection. In this work, we introduce a visual analytic tool called ENTVis to help users understand entropy-based traffic metrics and achieve accurate traffic anomaly detection. ENTVis provides three coordinated views and rich interactions to support a coherent visual analysis on multiple perspectives: the timeline group view for perceiving situations and finding hints of anomalies, the Radviz view for clustering similar anomalies in a period, and the matrix view for understanding traffic distributions and diagnosing anomalies in detail. Several case studies have been performed to verify the usability and effectiveness of our method. A further evaluation was conducted via expert review. PMID- 26415164 TI - Body Composition Assessment in Axial CT Images Using FEM-Based Automatic Segmentation of Skeletal Muscle. AB - The proportions of muscle and fat tissues in the human body, referred to as body composition is a vital measurement for cancer patients. Body composition has been recently linked to patient survival and the onset/recurrence of several types of cancers in numerous cancer research studies. This paper introduces a fully automatic framework for the segmentation of muscle and fat tissues from CT images to estimate body composition. We developed a novel finite element method (FEM) deformable model that incorporates a priori shape information via a statistical deformation model (SDM) within the template-based segmentation framework. The proposed method was validated on 1000 abdominal and 530 thoracic CT images and we obtained very good segmentation results with Jaccard scores in excess of 90% for both the muscle and fat regions. PMID- 26415165 TI - Unifying Concepts of Statistical and Spectral Quantitative Ultrasound Techniques. AB - Quantitative ultrasound (QUS) techniques using radiofrequency (RF) backscattered signals have been used for tissue characterization of numerous organ systems. One approach is to use the magnitude and frequency dependence of backscatter echoes to quantify tissue structures. Another approach is to use first-order statistical properties of the echo envelope as a signature of the tissue microstructure. We propose a unification of these QUS concepts. For this purpose, a mixture of homodyned K-distributions is introduced to model the echo envelope, together with an estimation method and a physical interpretation of its parameters based on the echo signal spectrum. In particular, the total, coherent and diffuse signal powers related to the proposed mixture model are expressed explicitly in terms of the structure factor previously studied to describe the backscatter coefficient (BSC). Then, this approach is illustrated in the context of red blood cell (RBC) aggregation. It is experimentally shown that the total, coherent and diffuse signal powers are determined by a structural parameter of the spectral Structure Factor Size and Attenuation Estimator. A two-way repeated measures ANOVA test showed that attenuation (p-value of 0.077) and attenuation compensation (p-value of 0.527) had no significant effect on the diffuse to total power ratio. These results constitute a further step in understanding the physical meaning of first order statistics of ultrasound images and their relations to QUS techniques. The proposed unifying concepts should be applicable to other biological tissues than blood considering that the structure factor can theoretically model any spatial distribution of scatterers. PMID- 26415166 TI - Stable Overlapping Replicator Dynamics for Brain Community Detection. AB - A fundamental means for understanding the brain's organizational structure is to group its spatially disparate regions into functional subnetworks based on their interactions. Most community detection techniques are designed for generating partitions, but certain brain regions are known to interact with multiple subnetworks. Thus, the brain's underlying subnetworks necessarily overlap. In this paper, we propose a technique for identifying overlapping subnetworks from weighted graphs with statistical control over false node inclusion. Our technique improves upon the replicator dynamics formulation by incorporating a graph augmentation strategy to enable subnetwork overlaps, and a graph incrementation scheme for merging subnetworks that might be falsely split by replicator dynamics due to its stringent mutual similarity criterion in defining subnetworks. To statistically control for inclusion of false nodes into the detected subnetworks, we further present a procedure for integrating stability selection into our subnetwork identification technique. We refer to the resulting technique as stable overlapping replicator dynamics (SORD). Our experiments on synthetic data show significantly higher accuracy in subnetwork identification with SORD than several state-of-the-art techniques. We also demonstrate higher test-retest reliability in multiple network measures on the Human Connectome Project data. Further, we illustrate that SORD enables identification of neuroanatomically meaningful subnetworks and network hubs. PMID- 26415167 TI - An Automatic Learning-Based Framework for Robust Nucleus Segmentation. AB - Computer-aided image analysis of histopathology specimens could potentially provide support for early detection and improved characterization of diseases such as brain tumor, pancreatic neuroendocrine tumor (NET), and breast cancer. Automated nucleus segmentation is a prerequisite for various quantitative analyses including automatic morphological feature computation. However, it remains to be a challenging problem due to the complex nature of histopathology images. In this paper, we propose a learning-based framework for robust and automatic nucleus segmentation with shape preservation. Given a nucleus image, it begins with a deep convolutional neural network (CNN) model to generate a probability map, on which an iterative region merging approach is performed for shape initializations. Next, a novel segmentation algorithm is exploited to separate individual nuclei combining a robust selection-based sparse shape model and a local repulsive deformable model. One of the significant benefits of the proposed framework is that it is applicable to different staining histopathology images. Due to the feature learning characteristic of the deep CNN and the high level shape prior modeling, the proposed method is general enough to perform well across multiple scenarios. We have tested the proposed algorithm on three large scale pathology image datasets using a range of different tissue and stain preparations, and the comparative experiments with recent state of the arts demonstrate the superior performance of the proposed approach. PMID- 26415168 TI - DASH-N: Joint Hierarchical Domain Adaptation and Feature Learning. AB - Complex visual data contain discriminative structures that are difficult to be fully captured by any single feature descriptor. While recent work on domain adaptation focuses on adapting a single hand-crafted feature, it is important to perform adaptation of a hierarchy of features to exploit the richness of visual data. We propose a novel framework for domain adaptation using a sparse and hierarchical network (DASH-N). Our method jointly learns a hierarchy of features together with transformations that rectify the mismatch between different domains. The building block of DASH-N is the latent sparse representation. It employs a dimensionality reduction step that can prevent the data dimension from increasing too fast as one traverses deeper into the hierarchy. The experimental results show that our method compares favorably with the competing state-of-the art methods. In addition, it is shown that a multi-layer DASH-N performs better than a single-layer DASH-N. PMID- 26415169 TI - MToS: A Tree of Shapes for Multivariate Images. AB - The topographic map of a gray-level image, also called tree of shapes, provides a high-level hierarchical representation of the image contents. This representation, invariant to contrast changes and to contrast inversion, has been proved very useful to achieve many image processing and pattern recognition tasks. Its definition relies on the total ordering of pixel values, so this representation does not exist for color images, or more generally, multivariate images. Common workarounds, such as marginal processing, or imposing a total order on data, are not satisfactory and yield many problems. This paper presents a method to build a tree-based representation of multivariate images, which features marginally the same properties of the gray-level tree of shapes. Briefly put, we do not impose an arbitrary ordering on values, but we only rely on the inclusion relationship between shapes in the image definition domain. The interest of having a contrast invariant and self-dual representation of multivariate image is illustrated through several applications (filtering, segmentation, and object recognition) on different types of data: color natural images, document images, satellite hyperspectral imaging, multimodal medical imaging, and videos. PMID- 26415170 TI - Compressed image quality metric based on perceptually weighted distortion. AB - Objective quality assessment for compressed images is critical to various image compression systems that are essential in image delivery and storage. Although the mean squared error (MSE) is computationally simple, it may not be accurate to reflect the perceptual quality of compressed images, which is also affected dramatically by the characteristics of human visual system (HVS), such as masking effect. In this paper, an image quality metric (IQM) is proposed based on perceptually weighted distortion in terms of the MSE. To capture the characteristics of HVS, a randomness map is proposed to measure the masking effect and a preprocessing scheme is proposed to simulate the processing that occurs in the initial part of HVS. Since the masking effect highly depends on the structural randomness, the prediction error from neighborhood with a statistical model is used to measure the significance of masking. Meanwhile, the imperceptible signal with high frequency could be removed by preprocessing with low-pass filters. The relation is investigated between the distortions before and after masking effect, and a masking modulation model is proposed to simulate the masking effect after preprocessing. The performance of the proposed IQM is validated on six image databases with various compression distortions. The experimental results show that the proposed algorithm outperforms other benchmark IQMs. PMID- 26415171 TI - Layered compression for high-precision depth data. AB - With the development of depth data acquisition technologies, access to high precision depth with more than 8-b depths has become much easier and determining how to efficiently represent and compress high-precision depth is essential for practical depth storage and transmission systems. In this paper, we propose a layered high-precision depth compression framework based on an 8-b image/video encoder to achieve efficient compression with low complexity. Within this framework, considering the characteristics of the high-precision depth, a depth map is partitioned into two layers: 1) the most significant bits (MSBs) layer and 2) the least significant bits (LSBs) layer. The MSBs layer provides rough depth value distribution, while the LSBs layer records the details of the depth value variation. For the MSBs layer, an error-controllable pixel domain encoding scheme is proposed to exploit the data correlation of the general depth information with sharp edges and to guarantee the data format of LSBs layer is 8 b after taking the quantization error from MSBs layer. For the LSBs layer, standard 8-b image/video codec is leveraged to perform the compression. The experimental results demonstrate that the proposed coding scheme can achieve real-time depth compression with satisfactory reconstruction quality. Moreover, the compressed depth data generated from this scheme can achieve better performance in view synthesis and gesture recognition applications compared with the conventional coding schemes because of the error control algorithm. PMID- 26415172 TI - Joint Sparse Representation and Robust Feature-Level Fusion for Multi-Cue Visual Tracking. AB - Visual tracking using multiple features has been proved as a robust approach because features could complement each other. Since different types of variations such as illumination, occlusion, and pose may occur in a video sequence, especially long sequence videos, how to properly select and fuse appropriate features has become one of the key problems in this approach. To address this issue, this paper proposes a new joint sparse representation model for robust feature-level fusion. The proposed method dynamically removes unreliable features to be fused for tracking by using the advantages of sparse representation. In order to capture the non-linear similarity of features, we extend the proposed method into a general kernelized framework, which is able to perform feature fusion on various kernel spaces. As a result, robust tracking performance is obtained. Both the qualitative and quantitative experimental results on publicly available videos show that the proposed method outperforms both sparse representation-based and fusion based-trackers. PMID- 26415173 TI - Automatic Liver Segmentation Based on Shape Constraints and Deformable Graph Cut in CT Images. AB - Liver segmentation is still a challenging task in medical image processing area due to the complexity of the liver's anatomy, low contrast with adjacent organs, and presence of pathologies. This investigation was used to develop and validate an automated method to segment livers in CT images. The proposed framework consists of three steps: 1) preprocessing; 2) initialization; and 3) segmentation. In the first step, a statistical shape model is constructed based on the principal component analysis and the input image is smoothed using curvature anisotropic diffusion filtering. In the second step, the mean shape model is moved using thresholding and Euclidean distance transformation to obtain a coarse position in a test image, and then the initial mesh is locally and iteratively deformed to the coarse boundary, which is constrained to stay close to a subspace of shapes describing the anatomical variability. Finally, in order to accurately detect the liver surface, deformable graph cut was proposed, which effectively integrates the properties and inter-relationship of the input images and initialized surface. The proposed method was evaluated on 50 CT scan images, which are publicly available in two databases Sliver07 and 3Dircadb. The experimental results showed that the proposed method was effective and accurate for detection of the liver surface. PMID- 26415174 TI - Cost-Sensitive Local Binary Feature Learning for Facial Age Estimation. AB - In this paper, we propose a cost-sensitive local binary feature learning (CS LBFL) method for facial age estimation. Unlike the conventional facial age estimation methods that employ hand-crafted descriptors or holistically learned descriptors for feature representation, our CS-LBFL method learns discriminative local features directly from raw pixels for face representation. Motivated by the fact that facial age estimation is a cost-sensitive computer vision problem and local binary features are more robust to illumination and expression variations than holistic features, we learn a series of hashing functions to project raw pixel values extracted from face patches into low-dimensional binary codes, where binary codes with similar chronological ages are projected as close as possible, and those with dissimilar chronological ages are projected as far as possible. Then, we pool and encode these local binary codes within each face image as a real-valued histogram feature for face representation. Moreover, we propose a cost-sensitive local binary multi-feature learning method to jointly learn multiple sets of hashing functions using face patches extracted from different scales to exploit complementary information. Our methods achieve competitive performance on four widely used face aging data sets. PMID- 26415175 TI - Transforms for Intra Prediction Residuals Based on Prediction Inaccuracy Modeling. AB - In intra video coding and image coding, the directional intra prediction is used to reduce spatial redundancy. Intra prediction residuals are encoded with transforms. In this paper, we develop transforms for directional intra prediction residuals. In particular, we observe that the directional intra prediction is most effective in smooth regions and edges with a particular direction. In the ideal case, edges can be predicted fairly accurately with an accurate prediction direction. In practice, an accurate prediction direction is hard to obtain. Based on the inaccuracy of prediction direction that arises in the design of many practical video coding systems, we can estimate the residual covariance and propose a class of transforms based on the estimated covariance function. The proposed method is evaluated by the energy compaction property. The experimental results show that, with the proposed method, the same amount of energy in directional intra prediction residuals can be preserved with a significantly smaller number of transform coefficients. PMID- 26415176 TI - Common Visual Pattern Discovery via Nonlinear Mean Shift Clustering. AB - Discovering common visual patterns (CVPs) from two images is a challenging task due to the geometric and photometric deformations as well as noises and clutters. The problem is generally boiled down to recovering correspondences of local invariant features, and the conventionally addressed by graph-based quadratic optimization approaches, which often suffer from high computational cost. In this paper, we propose an efficient approach by viewing the problem from a novel perspective. In particular, we consider each CVP as a common object in two images with a group of coherently deformed local regions. A geometric space with matrix Lie group structure is constructed by stacking up transformations estimated from initially appearance-matched local interest region pairs. This is followed by a mean shift clustering stage to group together those close transformations in the space. Joining regions associated with transformations of the same group together within each input image forms two large regions sharing similar geometric configuration, which naturally leads to a CVP. To account for the non-Euclidean nature of the matrix Lie group, mean shift vectors are derived in the corresponding Lie algebra vector space with a newly provided effective distance measure. Extensive experiments on single and multiple common object discovery tasks as well as near-duplicate image retrieval verify the robustness and efficiency of the proposed approach. PMID- 26415177 TI - Robust Matching Cost Function for Stereo Correspondence Using Matching by Tone Mapping and Adaptive Orthogonal Integral Image. AB - Real-world stereo images are inevitably affected by radiometric differences, including variations in exposure, vignetting, lighting, and noise. Stereo images with severe radiometric distortion can have large radiometric differences and include locally nonlinear changes. In this paper, we first introduce an adaptive orthogonal integral image, which is an improved version of an orthogonal integral image. After that, based on matching by tone mapping and the adaptive orthogonal integral image, we propose a robust and accurate matching cost function that can tolerate locally nonlinear intensity distortion. By using the adaptive orthogonal integral image, the proposed matching cost function can adaptively construct different support regions of arbitrary shapes and sizes for different pixels in the reference image, so it can operate robustly within object boundaries. Furthermore, we develop techniques to automatically estimate the values of the parameters of our proposed function. We conduct experiments using the proposed matching cost function and compare it with functions employing the census transform, supporting local binary pattern, and adaptive normalized cross correlation, as well as a mutual information-based matching cost function using different stereo data sets. By using the adaptive orthogonal integral image, the proposed matching cost function reduces the error from 21.51% to 15.73% in the Middlebury data set, and from 15.9% to 10.85% in the Kitti data set, as compared with using the orthogonal integral image. The experimental results indicate that the proposed matching cost function is superior to the state-of-the-art matching cost functions under radiometric variation. PMID- 26415178 TI - Inpainting for Fringe Projection Profilometry Based on Geometrically Guided Iterative Regularization. AB - Conventional fringe projection profilometry methods often have difficulty in reconstructing the 3D model of objects when the fringe images have the so-called highlight regions due to strong illumination from nearby light sources. Within a highlight region, the fringe pattern is often overwhelmed by the strong reflected light. Thus, the 3D information of the object, which is originally embedded in the fringe pattern, can no longer be retrieved. In this paper, a novel inpainting algorithm is proposed to restore the fringe images in the presence of highlights. The proposed method first detects the highlight regions based on a Gaussian mixture model. Then, a geometric sketch of the missing fringes is made and used as the initial guess of an iterative regularization procedure for regenerating the missing fringes. The simulation and experimental results show that the proposed algorithm can accurately reconstruct the 3D model of objects even when their fringe images have large highlight regions. It significantly outperforms the traditional approaches in both quantitative and qualitative evaluations. PMID- 26415179 TI - Distributed Signal Decorrelation and Detection in Multi View Camera Networks Using the Vector Sparse Matrix Transform. AB - This paper introduces the vector sparse matrix transform (vector SMT), a new decorrelating transform suitable for performing distributed processing of high dimensional signals in sensor networks. We assume that each sensor in the network encodes its measurements into vector outputs instead of scalar ones. The proposed transform decorrelates a sequence of pairs of vector outputs, until these vectors are decorrelated. In our experiments, we simulate distributed anomaly detection by a network of cameras, monitoring a spatial region. Each camera records an image of the monitored environment from its particular viewpoint and outputs a vector encoding the image. Our results, with both artificial and real data, show that the proposed vector SMT transform effectively decorrelates image measurements from the multiple cameras in the network while maintaining low overall communication energy consumption. Since it enables joint processing of the multiple vector outputs, our method provides significant improvements to anomaly detection accuracy when compared with the baseline case when the images are processed independently. PMID- 26415180 TI - Design and Error Analysis of a Vehicular AR System with Auto-Harmonization. AB - This paper describes the design, development and testing of an AR system that was developed for aerospace and ground vehicles to meet stringent accuracy and robustness requirements. The system uses an optical see-through HMD, and thus requires extremely low latency, high tracking accuracy and precision alignment and calibration of all subsystems in order to avoid mis-registration and "swim". The paper focuses on the optical/inertial hybrid tracking system and describes novel solutions to the challenges with the optics, algorithms, synchronization, and alignment with the vehicle and HMD systems. Tracker accuracy is presented with simulation results to predict the registration accuracy. A car test is used to create a through-the-eyepiece video demonstrating well-registered augmentations of the road and nearby structures while driving. Finally, a detailed covariance analysis of AR registration error is derived. PMID- 26415181 TI - An Intelligent Decision System for Intraoperative Somatosensory Evoked Potential Monitoring. AB - Somatosensory evoked potential (SEP) is a useful, noninvasive technique widely used for spinal cord monitoring during surgery. One of the main indicators of a spinal cord injury is the drop in amplitude of the SEP signal in comparison to the nominal baseline that is assumed to be constant during the surgery. However, in practice, the real-time baseline is not constant and may vary during the operation due to nonsurgical factors, such as blood pressure, anaesthesia, etc. Thus, a false warning is often generated if the nominal baseline is used for SEP monitoring. In current practice, human experts must be used to prevent this false warning. However, these well-trained human experts are expensive and may not be reliable and consistent due to various reasons like fatigue and emotion. In this paper, an intelligent decision system is proposed to improve SEP monitoring. First, the least squares support vector regression and multi-support vector regression models are trained to construct the dynamic baseline from historical data. Then a control chart is applied to detect abnormalities during surgery. The effectiveness of the intelligent decision system is evaluated by comparing its performance against the nominal baseline model by using the real experimental datasets derived from clinical conditions. PMID- 26415182 TI - Minimizing Stimulus Current in a Wearable Pudendal Nerve Stimulator Using Computational Models. AB - After spinal cord injury, functions of the lower urinary tract may be disrupted. A wearable device with surface electrodes which can effectively control the bladder functions would be highly beneficial to the patients. A trans-rectal pudendal nerve stimulator may provide such a solution. However, the major limiting factor in such a stimulator is the high level of current it requires to recruit the nerve fibers. Also, the variability of the trajectory of the nerve in different individuals should be considered. Using computational models and an approximate trajectory of the nerve derived from an MRI study, it is demonstrated in this paper that it may be possible to considerably reduce the required current levels for trans-rectal stimulation of the pudendal nerve compared to the values previously reported in the literature. This was corroborated by considering an ensemble of possible and probable variations of the trajectory. The outcome of this study suggests that trans-rectal stimulation of the pudendal nerve is a plausible long term solution for treating lower urinary tract dysfunctions after spinal cord injury. PMID- 26415183 TI - Prediction of Protein Coding Regions Using a Wide-Range Wavelet Window Method. AB - Prediction of protein coding regions is an important topic in the field of genomic sequence analysis. Several spectrum-based techniques for the prediction of protein coding regions have been proposed. However, the outstanding issue in most of the proposed techniques is that these techniques depend on an experimentally-selected, predefined value of the window length. In this paper, we propose a new Wide-Range Wavelet Window (WRWW) method for the prediction of protein coding regions. The analysis of the proposed wavelet window shows that its frequency response can adapt its width to accommodate the change in the window length so that it can allow or prevent frequencies other than the basic frequency in the analysis of DNA sequences. This feature makes the proposed window capable of analyzing DNA sequences with a wide range of the window lengths without degradation in the performance. The experimental analysis of applying the WRWW method and other spectrum-based methods to five benchmark datasets has shown that the proposed method outperforms other methods along a wide range of the window lengths. In addition, the experimental analysis has shown that the proposed method is dominant in the prediction of both short and long exons. PMID- 26415184 TI - Applying Monte Carlo Simulation to Biomedical Literature to Approximate Genetic Network. AB - Biologists often need to know the set of genes associated with a given set of genes or a given disease. We propose in this paper a classifier system called Monte Carlo for Genetic Network (MCforGN) that can construct genetic networks, identify functionally related genes, and predict gene-disease associations. MCforGN identifies functionally related genes based on their co-occurrences in the abstracts of biomedical literature. For a given gene g , the system first extracts the set of genes found within the abstracts of biomedical literature associated with g. It then ranks these genes to determine the ones with high co occurrences with g . It overcomes the limitations of current approaches that employ analytical deterministic algorithms by applying Monte Carlo Simulation to approximate genetic networks. It does so by conducting repeated random sampling to obtain numerical results and to optimize these results. Moreover, it analyzes results to obtain the probabilities of different genes' co-occurrences using series of statistical tests. MCforGN can detect gene-disease associations by employing a combination of centrality measures (to identify the central genes in disease-specific genetic networks) and Monte Carlo Simulation. MCforGN aims at enhancing state-of-the-art biological text mining by applying novel extraction techniques. We evaluated MCforGN by comparing it experimentally with nine approaches. Results showed marked improvement. PMID- 26415185 TI - Estimating Sensorimotor Mapping From Stimuli to Behaviors to Infer C. elegans Movements by Neural Transmission Ability Through Connectome Databases. AB - One of the ultimate goals of computational neuroscience is to quantitatively connect between complex neural circuits and behaviors. In the past decades, the touch response circuit in Caenorhabditis elegans (C. elegans) has extensively been investigated in studies using genetically modified or laser-ablated worms. Synaptic connections, including chemical and electrical synapses, have been identified for most neurons in the C. elegans. However, we still do not know whether the empirically observed touch responses can be derived from connectome reconstructed from databases. To address this issue, we defined the transmission abilities (or levels) of neurons in a rate model in order to infer the behaviors of wild-type and ablated worms in response to posterior/nose/anterior touch stimuli. Our analysis showed that transmission abilities can be used to identify sensorimotor mapping from stimuli to movements and then to infer the C. elegans behaviors under simulations based on the perspective of decision-making, and provide useful information about how chemical and electronic synapses should be combined in the neural network movement analysis. This paper reveals an efficient tool that provided insights into the functions of complex neural circuits. PMID- 26415186 TI - Decomposition Techniques for Multilayer Perceptron Training. AB - In this paper, we consider the learning problem of multilayer perceptrons (MLPs) formulated as the problem of minimizing a smooth error function. As well known, the learning problem of MLPs can be a difficult nonlinear nonconvex optimization problem. Typical difficulties can be the presence of extensive flat regions and steep sided valleys in the error surface, and the possible large number of training data and of free network parameters. We define a wide class of batch learning algorithms for MLP, based on the use of block decomposition techniques in the minimization of the error function. The learning problem is decomposed into a sequence of smaller and structured minimization problems in order to advantageously exploit the structure of the objective function. Theoretical convergence results are established, and a specific algorithm is constructed and evaluated through an extensive numerical experimentation. The comparisons with the state-of-the-art learning algorithms show the effectiveness of the proposed techniques. PMID- 26415187 TI - RBoost: Label Noise-Robust Boosting Algorithm Based on a Nonconvex Loss Function and the Numerically Stable Base Learners. AB - AdaBoost has attracted much attention in the machine learning community because of its excellent performance in combining weak classifiers into strong classifiers. However, AdaBoost tends to overfit to the noisy data in many applications. Accordingly, improving the antinoise ability of AdaBoost plays an important role in many applications. The sensitiveness to the noisy data of AdaBoost stems from the exponential loss function, which puts unrestricted penalties to the misclassified samples with very large margins. In this paper, we propose two boosting algorithms, referred to as RBoost1 and RBoost2, which are more robust to the noisy data compared with AdaBoost. RBoost1 and RBoost2 optimize a nonconvex loss function of the classification margin. Because the penalties to the misclassified samples are restricted to an amount less than one, RBoost1 and RBoost2 do not overfocus on the samples that are always misclassified by the previous base learners. Besides the loss function, at each boosting iteration, RBoost1 and RBoost2 use numerically stable ways to compute the base learners. These two improvements contribute to the robustness of the proposed algorithms to the noisy training and testing samples. Experimental results on the synthetic Gaussian data set, the UCI data sets, and a real malware behavior data set illustrate that the proposed RBoost1 and RBoost2 algorithms perform better when the training data sets contain noisy data. PMID- 26415188 TI - A New Continuous-Time Equality-Constrained Optimization to Avoid Singularity. AB - In equality-constrained optimization, a standard regularity assumption is often associated with feasible point methods, namely, that the gradients of constraints are linearly independent. In practice, the regularity assumption may be violated. In order to avoid such a singularity, a new projection matrix is proposed based on which a feasible point method to continuous-time, equality-constrained optimization is developed. First, the equality constraint is transformed into a continuous-time dynamical system with solutions that always satisfy the equality constraint. Second, a new projection matrix without singularity is proposed to realize the transformation. An update (or say a controller) is subsequently designed to decrease the objective function along the solutions of the transformed continuous-time dynamical system. The invariance principle is then applied to analyze the behavior of the solution. Furthermore, the proposed method is modified to address cases in which solutions do not satisfy the equality constraint. Finally, the proposed optimization approach is applied to three examples to demonstrate its effectiveness. PMID- 26415189 TI - Sparse Bayesian Classification of EEG for Brain-Computer Interface. AB - Regularization has been one of the most popular approaches to prevent overfitting in electroencephalogram (EEG) classification of brain-computer interfaces (BCIs). The effectiveness of regularization is often highly dependent on the selection of regularization parameters that are typically determined by cross-validation (CV). However, the CV imposes two main limitations on BCIs: 1) a large amount of training data is required from the user and 2) it takes a relatively long time to calibrate the classifier. These limitations substantially deteriorate the system's practicability and may cause a user to be reluctant to use BCIs. In this paper, we introduce a sparse Bayesian method by exploiting Laplace priors, namely, SBLaplace, for EEG classification. A sparse discriminant vector is learned with a Laplace prior in a hierarchical fashion under a Bayesian evidence framework. All required model parameters are automatically estimated from training data without the need of CV. Extensive comparisons are carried out between the SBLaplace algorithm and several other competing methods based on two EEG data sets. The experimental results demonstrate that the SBLaplace algorithm achieves better overall performance than the competing algorithms for EEG classification. PMID- 26415190 TI - Efficient $?chi ^{2}$ Kernel Linearization via Random Feature Maps. AB - Explicit feature mapping is an appealing way to linearize additive kernels, such as chi2 kernel for training large-scale support vector machines (SVMs). Although accurate in approximation, feature mapping could pose computational challenges in high-dimensional settings as it expands the original features to a higher dimensional space. To handle this issue in the context of chi2 kernel SVMs learning, we introduce a simple yet efficient method to approximately linearize chi2 kernel through random feature maps. The main idea is to use sparse random projection to reduce the dimensionality of feature maps while preserving their approximation capability to the original kernel. We provide approximation error bound for the proposed method. Furthermore, we extend our method to chi2 multiple kernel SVMs learning. Extensive experiments on large-scale image classification tasks confirm that the proposed approach is able to significantly speed up the training process of the chi2 kernel SVMs at almost no cost of testing accuracy. PMID- 26415191 TI - A Comparison of Algorithms for Learning Hidden Variables in Bayesian Factor Graphs in Reduced Normal Form. AB - Bayesian-directed acyclic discrete-variable graphs are reduced to a simplified normal form made up of only replicator units (or equal constraint units), source, and single-input/single-output blocks. In this framework, the same adaptation algorithm can be applied to all the parametric blocks. We obtain and compare adaptation rules derived from a constrained maximum likelihood formulation and a minimum Kullback-Leibler divergence criterion using Karush-Kuhn-Tucker conditions. The learning algorithms are compared with two other updating equations based on localized decisions and on a variational approximation, respectively. The performance of the various algorithms is verified on synthetic data sets for various architectures. Factor graphs in reduced normal form provide an appealing framework for rapid deployment of Bayesian-directed graphs in the applications. PMID- 26415192 TI - Supraventricular Tachycardia Classification in the 12-Lead ECG Using Atrial Waves Detection and a Clinically Based Tree Scheme. AB - Specific supraventricular tachycardia (SVT) classification using surface ECG is considered a challenging task, since the atrial electrical activity (AEA) waves, which are a crucial element for obtaining diagnosis, are frequently hidden. In this paper, we present a fully automated SVT classification method that embeds our recently developed hidden AEA detector in a clinically based tree scheme. The process begins with initial noise removal and QRS detection. Then, ventricular features are extracted. According to these features, an initial AEA-wave search window is defined and a single AEA-wave is detected. Using a synthetic Gaussian signal and a linear combination of 12-lead ECG signals, all AEA-waves are detected. In accord with the atrial and ventricular information found, classification to atrial fibrillation, atrial flutter, atrioventricular nodal reentry tachycardia, atrioventricular reentry tachycardia, or sinus rhythm is performed in the framework of a clinically oriented decision tree. A study was performed to evaluate the classification from 68 patients (26 were used for the classifier's design, 42 were used for its validation). Average sensitivity of 83.21% [95% confidence interval (CI): 79.33-86.49%], average specificity of 95.80% (95% CI: 94.73-96.67%), and average accuracy of 93.29% (95% CI: 92.13 94.28%) were achieved compared to the definite diagnosis. In conclusion, the presented method may serve as a valuable decision support tool, allowing accurate detection of SVTs using noninvasive means. PMID- 26415193 TI - MISTICA: Minimum Spanning Tree-Based Coarse Image Alignment for Microscopy Image Sequences. AB - Registration of an in vivo microscopy image sequence is necessary in many significant studies, including studies of atherosclerosis in large arteries and the heart. Significant cardiac and respiratory motion of the living subject, occasional spells of focal plane changes, drift in the field of view, and long image sequences are the principal roadblocks. The first step in such a registration process is the removal of translational and rotational motion. Next, a deformable registration can be performed. The focus of our study here is to remove the translation and/or rigid body motion that we refer to here as coarse alignment. The existing techniques for coarse alignment are unable to accommodate long sequences often consisting of periods of poor quality images (as quantified by a suitable perceptual measure). Many existing methods require the user to select an anchor image to which other images are registered. We propose a novel method for coarse image sequence alignment based on minimum weighted spanning trees (MISTICA) that overcomes these difficulties. The principal idea behind MISTICA is to reorder the images in shorter sequences, to demote nonconforming or poor quality images in the registration process, and to mitigate the error propagation. The anchor image is selected automatically making MISTICA completely automated. MISTICA is computationally efficient. It has a single tuning parameter that determines graph width, which can also be eliminated by the way of additional computation. MISTICA outperforms existing alignment methods when applied to microscopy image sequences of mouse arteries. PMID- 26415195 TI - Security Games With Unknown Adversarial Strategies. AB - The security community has witnessed a significant increase in the number of different types of security threats. This situation calls for the design of new techniques that can be incorporated into security protocols to meet these challenges successfully. An important tool for developing new security protocols as well as estimating their effectiveness is game theory. This game theory framework usually involves two players or agents: 1) a protector and 2) an adversary, and two patterns of agent behavior are considered: 1) selfish behavior, where each of the agents wants to maximize his payoff; and 2) leader and follower behavior, where one agent (the leader) expects that the other agent (the follower) will respond to the leader's strategy. Such an approach assumes that the agents agree on which strategy to apply in advance. In this paper, this strong assumption is relaxed. Namely, the following question is considered: what happens if it is unknown a priori what pattern of behavior the adversary is going to use, or in other words, it is not known, what game he intends to play? Using a simple game-theoretic model, it is shown that the protector can lose if he does not take into account the possibility that the adversary can play a game other than the one the protector has in mind. Further considered is a repeated game in which the protector can learn about the presence of an adversary, and the behavior of belief probabilities is analyzed in this setting. PMID- 26415194 TI - Estimation of Respiratory Rates Using the Built-in Microphone of a Smartphone or Headset. AB - This paper proposes accurate respiratory rate estimation using nasal breath sound recordings from a smartphone. Specifically, the proposed method detects nasal airflow using a built-in smartphone microphone or a headset microphone placed underneath the nose. In addition, we also examined if tracheal breath sounds recorded by the built-in microphone of a smartphone placed on the paralaryngeal space can also be used to estimate different respiratory rates ranging from as low as 6 breaths/min to as high as 90 breaths/min. The true breathing rates were measured using inductance plethysmography bands placed around the chest and the abdomen of the subject. Inspiration and expiration were detected by averaging the power of nasal breath sounds. We investigated the suitability of using the smartphone-acquired breath sounds for respiratory rate estimation using two different spectral analyses of the sound envelope signals: The Welch periodogram and the autoregressive spectrum. To evaluate the performance of the proposed methods, data were collected from ten healthy subjects. For the breathing range studied (6-90 breaths/min), experimental results showed that our approach achieves an excellent performance accuracy for the nasal sound as the median errors were less than 1% for all breathing ranges. The tracheal sound, however, resulted in poor estimates of the respiratory rates using either spectral method. For both nasal and tracheal sounds, significant estimation outliers resulted for high breathing rates when subjects had nasal congestion, which often resulted in the doubling of the respiratory rates. Finally, we show that respiratory rates from the nasal sound can be accurately estimated even if a smartphone's microphone is as far as 30 cm away from the nose. PMID- 26415196 TI - Saturated Nussbaum Function Based Approach for Robotic Systems With Unknown Actuator Dynamics. AB - This paper presents a saturated Nussbaum function based approach for robotic systems with unknown actuator dynamics. To eliminate the effect of the control shock from the traditional Nussbaum function, a new type of the saturated Nussbaum function is developed with the idea of time-elongation. Moreover, by exploiting properties of the proposed Nussbaum function, a promising theorem is established to deal with unknown multiple actuator nonlinearities. In what follows, the proposed theorem is integrated with the adaptive control technique such that the stability analysis of the robotic system is completed. It thus guarantees that the state of the robotic system asymptotically converges to the desired trajectory. Finally, comparative studies are carried out to validate the effectiveness and the superiority of the proposed approach. PMID- 26415197 TI - Adaptive Task-Space Cooperative Tracking Control of Networked Robotic Manipulators Without Task-Space Velocity Measurements. AB - In this paper, the task-space cooperative tracking control problem of networked robotic manipulators without task-space velocity measurements is addressed. To overcome the problem without task-space velocity measurements, a novel task-space position observer is designed to update the estimated task-space position and to simultaneously provide the estimated task-space velocity, based on which an adaptive cooperative tracking controller without task-space velocity measurements is presented by introducing new estimated task-space reference velocity and acceleration. Furthermore, adaptive laws are provided to cope with uncertain kinematics and dynamics and rigorous stability analysis is given to show asymptotical convergence of the task-space tracking and synchronization errors in the presence of communication delays under strongly connected directed graphs. Simulation results are given to demonstrate the performance of the proposed approach. PMID- 26415198 TI - Causality Analysis of fMRI Data Based on the Directed Information Theory Framework. AB - This paper aims to conduct fMRI-based causality analysis in brain connectivity by exploiting the directed information (DI) theory framework. Unlike the well-known Granger causality (GC) analysis, which relies on the linear prediction technique, the DI theory framework does not have any modeling constraints on the sequences to be evaluated and ensures estimation convergence. Moreover, it can be used to generate the GC graphs. In this paper, first, we introduce the core concepts in the DI framework. Second, we present how to conduct causality analysis using DI measures between two time series. We provide the detailed procedure on how to calculate the DI for two finite-time series. The two major steps involved here are optimal bin size selection for data digitization and probability estimation. Finally, we demonstrate the applicability of DI-based causality analysis using both the simulated data and experimental fMRI data, and compare the results with that of the GC analysis. Our analysis indicates that GC analysis is effective in detecting linear or nearly linear causal relationship, but may have difficulty in capturing nonlinear causal relationships. On the other hand, DI-based causality analysis is more effective in capturing both linear and nonlinear causal relationships. Moreover, it is observed that brain connectivity among different regions generally involves dynamic two-way information transmissions between them. Our results show that when bidirectional information flow is present, DI is more effective than GC to quantify the overall causal relationship. PMID- 26415199 TI - Noncontact Monitoring of Blood Oxygen Saturation Using Camera and Dual-Wavelength Imaging System. AB - We present a noncontact method to monitor blood oxygen saturation (SpO2). The method uses a CMOS camera with a trigger control to allow recording of photoplethysmography (PPG) signals alternatively at two particular wavelengths, and determines the SpO2 from the measured ratios of the pulsatile to the nonpulsatile components of the PPG signals at these wavelengths. The signal-to noise ratio (SNR) of the SpO2 value depends on the choice of the wavelengths. We found that the combination of orange (lambda = 611 nm) and near infrared (lambda = 880 nm) provides the best SNR for the noncontact video-based detection method. This combination is different from that used in traditional contact-based SpO 2 measurement since the PPG signal strengths and camera quantum efficiencies at these wavelengths are more amenable to SpO2 measurement using a noncontact method. We also conducted a small pilot study to validate the noncontact method over an SpO2 range of 83%-98%. This study results are consistent with those measured using a reference contact SpO2 device ( r = 0.936, ). The presented method is particularly suitable for tracking one's health and wellness at home under free-living conditions, and for those who cannot use traditional contact based PPG devices. PMID- 26415200 TI - 3-D Lung Segmentation by Incremental Constrained Nonnegative Matrix Factorization. AB - Accurate lung segmentation from large-size 3-D chest-computed tomography images is crucial for computer-assisted cancer diagnostics. To efficiently segment a 3-D lung, we extract voxel-wise features of spatial image contexts by unsupervised learning with a proposed incremental constrained nonnegative matrix factorization (ICNMF). The method applies smoothness constraints to learn the features, which are more robust to lung tissue inhomogeneities, and thus, help to better segment internal lung pathologies than the known state-of-the-art techniques. Compared to the latter, the ICNMF depends less on the domain expert knowledge and is more easily tuned due to only a few control parameters. Also, the proposed slice-wise incremental learning with due regard for interslice signal dependencies decreases the computational complexity of the NMF-based segmentation and is scalable to very large 3-D lung images. The method is quantitatively validated on simulated realistic lung phantoms that mimic different lung pathologies (seven datasets), in vivo datasets for 17 subjects, and 55 datasets from the Lobe and Lung Analysis 2011 (LOLA11) study. For the in vivo data, the accuracy of our segmentation w.r.t. the ground truth is 0.96 by the Dice similarity coefficient, 9.0 mm by the modified Hausdorff distance, and 0.87% by the absolute lung volume difference, which is significantly better than for the NMF-based segmentation. In spite of not being designed for lungs with severe pathologies and of no agreement between radiologists on the ground truth in such cases, the ICNMF with its total accuracy of 0.965 was ranked fifth among all others in the LOLA11. After excluding the nine too pathological cases from the LOLA11 dataset, the ICNMF accuracy increased to 0.986. PMID- 26415201 TI - Confidence Estimation for Medical Image Registration Based On Stereo Confidences. AB - In this paper, we propose a novel method to estimate the confidence of a registration that does not require any ground truth, is independent from the registration algorithm and the resulting confidence is correlated with the amount of registration error. We first apply a local search to match patterns between the registered image pairs. Local search induces a cost space per voxel which we explore further to estimate the confidence of the registration similar to confidence estimation algorithms for stereo matching. We test our method on both synthetically generated registration errors and on real registrations with ground truth. The experimental results show that our confidence measure can estimate registration errors and it is correlated with local errors. PMID- 26415202 TI - Encoding color information for visual tracking: Algorithms and benchmark. AB - While color information is known to provide rich discriminative clues for visual inference, most modern visual trackers limit themselves to the grayscale realm. Despite recent efforts to integrate color in tracking, there is a lack of comprehensive understanding of the role color information can play. In this paper, we attack this problem by conducting a systematic study from both the algorithm and benchmark perspectives. On the algorithm side, we comprehensively encode 10 chromatic models into 16 carefully selected state-of-the-art visual trackers. On the benchmark side, we compile a large set of 128 color sequences with ground truth and challenge factor annotations (e.g., occlusion). A thorough evaluation is conducted by running all the color-encoded trackers, together with two recently proposed color trackers. A further validation is conducted on an RGBD tracking benchmark. The results clearly show the benefit of encoding color information for tracking. We also perform detailed analysis on several issues, including the behavior of various combinations between color model and visual tracker, the degree of difficulty of each sequence for tracking, and how different challenge factors affect the tracking performance. We expect the study to provide the guidance, motivation, and benchmark for future work on encoding color in visual tracking. PMID- 26415203 TI - Position-Independent Decoding of Movement Intention for Proportional Myoelectric Interfaces. AB - In this decade, myoelectric interfaces based on pattern recognition have gained considerable attention thanks to their naturalness enabling human intentions to be conveyed to and in control of a machine. However, the high variations of electromyogram signal patterns caused by arm position changes prohibit application to the real world. In this paper, we propose a novel method of decoding movement intentions robust to arm position changes towards proportional myoelectric interfaces. Specifically, we devise the position-independent decoding that estimates the likelihood of different arm positions, which we predefine during a training step, and also decodes the movement intention in a unified framework. The proposed method has an advantage that could be used to decode the movement intentions on untrained arm positions in a realistic scenario. Our experimental results showed that the proposed method could successfully decode the continuous movement intentions (e.g., flexion/extension and radial/ulnar deviation) on both trained and untrained arm positions. Our study also proved the effectiveness of the proposed method by comparing the existing methods in terms of the decoded trajectories as movement intentions in untrained arm positions. PMID- 26415204 TI - Bovine Osteochondral Tissues: A Questionable Model to Evaluate Mechanical Loading In Vitro. AB - Articular cartilage exists within synovial joints to adsorb and distribute mechanical loads to the subchondral bone. Mechanical loading is one aspect of a wide range of microenvironmental stressors that contribute to the maintenance of articular cartilage. The aim of the current study was to characterize bovine osteochondral tissues and to assess their suitability to serve as a model for investigating the effects of mechanical loading on cartilage tissue in vitro using a custom-made reactor system. Osteochondral tissues were harvested from bovine knee joints and cultured up to 24 days in loaded and unloaded conditions. Notably, we found a considerable zone-specific heterogeneity between cartilage explants harvested from the same joint as evidenced by histology and gene expression levels. Results using the reactor system revealed that differences observed after mechanical loading varied within the range of the heterogeneity observed amongst the different cartilage explants. Thus, it may be difficult to obtain reliable and reproducible data in mechanical loading experiments from these tissues in vitro, especially in cases where small variations between the experimental groups are expected. This will likely lead to the reporting of false positives or negatives in studies investigating the effect of mechanical load on the function of cartilage tissue. PMID- 26415205 TI - Flexible Bioimpedance Sensor for Label-Free Detection of Cell Viability and Biomass. AB - We introduce a flexible microfluidic bioimpedance sensor that is capable of detecting biomass and cell viability variations in a cell suspension. The sensor is developed on indium tin oxide (ITO) coated polyethylene terephthalate (PET) substrate and is devoid of gold, silicon, PDMS, or glass. In conjugation with a custom built PCB read-out module, the impedance characteristics of a cell suspension can be measured within one minute of sample introduction using liquid volumes less than 5 MUL. The portable sensor system occupies very little bench space and has the potential to be developed as a disposable electrical bioimpedance probe for rapid detection of dielectric variations in a biological suspension. The sensor is designed to generate a differential impedance spectra exclusive to a cell suspension with a dual-electrode-pair system. The potential of the sensor to discriminate between live and heat treated Saccharomyces cerevisiae is demonstrated in this study. The disposable sensor along with the distance variation technique is touted to be an inexpensive alternative to some of the existing online disposable biomass detection probes and electrochemical sensors. PMID- 26415206 TI - A Microflow Cytometer Based on a Disposable Microfluidic Chip With Side Scatter and Fluorescence Detection Capability. AB - In this paper, we present a microflow cytometer based on a polydimethylsiloxane (PDMS) microfluidic chip. The PDMS chip has a smooth sidewall because of the proposed double molding process. Thus, the side scatter (SSC) detection can be used for the cytometer. The coincidence error using the sheathless focus mechanism is less than 0.069%. Using Flow-Check alignment beads for the counting experiment, the coefficient of variation (CV) of the SSC and the fluorescein isothiocyanate (FITC) channel can reach 8.37% and 2.46%, respectively. The gating of the lymphocytes according to CD45/SSC was also demonstrated successfully. It proves that the chip is a promising solution for point of care (POC) microflow cytometers. PMID- 26415207 TI - Towards an Endpoint Cell Motility Assay by a Microfluidic Platform. AB - In vitro cell motility assays are frequently used in the study of cell migration in response to anti-cancer drug treatment. Microfluidic systems represent a unique tool for the in vitro analysis of cell motility. However, they usually rely on using time-lapse microscopy to record the spatial temporal locations of the individual cells being tested. This has created a bottleneck for microfluidic systems to perform high-throughput experiments due to requirement of a costly time-lapse microscopy system. Here, we describe the development of a portable microfluidic device for endpoint analysis of cell motility. The reported device incorporates a cell alignment feature to position the seeded cells on the same initial location, so that the cells' motilities can be analyzed based on their locations at the end of the experiment after the cells have migrated. We show that the device was able to assess cancer cell motility after treatment with a migration inhibitory drug Indole-3-carbinol on MDA-MB-231 breast cancer cells, demonstrating the applicability of our device in screening anti-cancer drug compounds on cancer cells. PMID- 26415208 TI - Predicting Hub Genes Associated with Cervical Cancer through Gene Co-Expression Networks. AB - Cervical cancer is the third most common malignancy in women worldwide. It remains a leading cause of cancer-related death for women in developing countries. In order to contribute to the treatment of the cervical cancer, in our work, we try to find a few key genes resulting in the cervical cancer. Employing functions of several bioinformatics tools, we selected 143 differentially expressed genes (DEGs) associated with the cervical cancer. The results of bioinformatics analysis show that these DEGs play important roles in the development of cervical cancer. Through comparing two differential co-expression networks (DCNs) at two different states, we found a common sub-network and two differential sub-networks as well as some hub genes in three sub-networks. Moreover, some of the hub genes have been reported to be related to the cervical cancer. Those hub genes were analyzed from Gene Ontology function enrichment, pathway enrichment and protein binding three aspects. The results can help us understand the development of the cervical cancer and guide further experiments about the cervical cancer. PMID- 26415209 TI - IAS: Interaction Specific GO Term Associations for Predicting Protein-Protein Interaction Networks. AB - Proteins carry out their function in a cell through interactions with other proteins. A large scale protein-protein interaction (PPI) network of an organism provides static yet an essential structure of interactions, which is valuable clue for understanding the functions of proteins and pathways. PPIs are determined primarily by experimental methods; however, computational PPI prediction methods can supplement or verify PPIs identified by experiment. Here, we developed a novel scoring method for predicting PPIs from Gene Ontology (GO) annotations of proteins. Unlike existing methods that consider functional similarity as an indication of interaction between proteins, the new score, named the protein-protein Interaction Association Score (IAS), was computed from GO term associations of known interacting protein pairs in 49 organisms. IAS was evaluated on PPI data of six organisms and found to outperform existing GO term based scoring methods. Moreover, consensus scoring methods that combine different scores further improved performance of PPI prediction. PMID- 26415210 TI - Nucleosome Positioning of Intronless Genes in the Human Genome. AB - Nucleosomes, the basic units of chromatin, are involved in transcription regulation and DNA replication. Intronless genes, which constitute 3 percent of the human genome, differ from intron-containing genes in evolution and function. Our analysis reveals that nucleosome positioning shows a distinct pattern in intronless and intron-containing genes. The nucleosome occupancy upstream of transcription start sites of intronless genes is lower than that of intron containing genes. In contrast, high occupancy and well positioned nucleosomes are observed along the gene body of intronless genes, which is perfectly consistent with the barrier nucleosome model. Intronless genes have a significantly lower expression level than intron-containing genes and most of them are not expressed in CD4+ T cell lines and GM12878 cell lines, which results from their tissue specificity. However, the highly expressed genes are at the same expression level between the two types of genes. The highly expressed intronless genes require a higher density of RNA Pol II in an elongating state to compensate for the lack of introns. Additionally, 5' and 3' nucleosome depleted regions of highly expressed intronless genes are deeper than those of highly expressed intron-containing genes. PMID- 26415211 TI - [Cell phone vs paracetamol]. PMID- 26415212 TI - [Pediatrics activity in military theatre]. PMID- 26415213 TI - [Parasitic intestinal infections are still frequent]. PMID- 26415214 TI - [Some reflections on the classification of African obstetric fistulas]. AB - While the English-speaking world may have reached a consensus about Kees Waaldjik's classification of obstetric fistulas, no unanimity around this classification exists among French-speaking medical workers. The objective of this review is to propose a classification, based on long experience in the care of these women, by setting up a comparison with Waaldjik's. Our classification takes two criteria into account: (1) the environment of the fistula, that is: (a) fistula with a soft (relatively unscarred) vagina, b) fistula with vaginal sclerosis (bands or adhesions, vaginal stenosis or atresia), (c) vesicovaginal fistula associated with a (high or low) rectovaginal fistula or perineal lacerations (first, second or third degree); (2) the anatomical site of fistula, of which there are five types: (a) type I: fistula of the vesicovaginal wall, (b) type II: vesico-cervico-urethral fistula, with two major subgroups: type IIA (without destruction of the urethra) and type IIB (with destruction of the urethra), type IIA being subdivided in three subgroups: IIAa, IIAB and cIAI, (c) type III fistulae trigono-Neck utero-vaginal, (d) type IV: complex mixed fistula, (e) type V, high fistulas: the vesico-cervical-uterine fistula and classical vesicouterine. CONCLUSION: Our classification is simple, not simplistic, with some resemblance to that of Waaldjjik. PMID- 26415215 TI - Fluid mechanics aspects of magnetic drug targeting. AB - Experiments and numerical simulations using a flow phantom for magnetic drug targeting have been undertaken. The flow phantom is a half y-branched tube configuration where the main tube represents an artery from which a tumour supplying artery, which is simulated by the side branch of the flow phantom, branches off. In the experiments a quantification of the amount of magnetic particles targeted towards the branch by a magnetic field applied via a permanent magnet is achieved by impedance measurement using sensor coils. Measuring the targeting efficiency, i.e. the relative amount of particles targeted to the side branch, for different field configurations one obtains targeting maps which combine the targeting efficiency with the magnetic force densities in characteristic points in the flow phantom. It could be shown that targeting efficiency depends strongly on the magnetic field configuration. A corresponding numerical model has been set up, which allows the simulation of targeting efficiency for variable field configuration. With this simulation good agreement of targeting efficiency with experimental data has been found. Thus, the basis has been laid for future calculations of optimal field configurations in clinical applications of magnetic drug targeting. Moreover, the numerical model allows the variation of additional parameters of the drug targeting process and thus an estimation of the influence, e.g. of the fluid properties on the targeting efficiency. Corresponding calculations have shown that the non-Newtonian behaviour of the fluid will significantly influence the targeting process, an aspect which has to be taken into account, especially recalling the fact that the viscosity of magnetic suspensions depends strongly on the magnetic field strength and the mechanical load. PMID- 26415216 TI - RIOK3 keeps MDA5 inactive. PMID- 26415217 TI - Acute MUS81 depletion leads to replication fork slowing and a constitutive DNA damage response. AB - The MUS81 protein belongs to a conserved family of DNA structure-specific nucleases that play important roles in DNA replication and repair. Inactivation of the Mus81 gene in mice has no major deleterious consequences for embryonic development, although cancer susceptibility has been reported. We have investigated the role of MUS81 in human cells by acutely depleting the protein using shRNAs. We found that MUS81 depletion from human fibroblasts leads to accumulation of ssDNA and a constitutive DNA damage response that ultimately activates cellular senescence. Moreover, we show that MUS81 is required for efficient replication fork progression during an unperturbed S-phase, and for recovery of productive replication following replication stalling. These results demonstrate essential roles for the MUS81 nuclease in maintenance of replication fork integrity. PMID- 26415218 TI - S-nitrosylation and MSC-mediated body composition. PMID- 26415219 TI - Targeted cancer therapy with ribosome biogenesis inhibitors: a real possibility? AB - The effects of many chemotherapeutic drugs on ribosome biogenesis have been underestimated for a long time. Indeed, many drugs currently used for cancer treatment--and which are known to either damage DNA or hinder DNA synthesis--have been shown to exert their toxic action mainly by inhibiting rRNA synthesis or maturation. Moreover, there are new drugs that have been proposed recently for cancer chemotherapy, which only hinder ribosome biogenesis without any genotoxic activity. Even though ribosome biogenesis occurs in both normal and cancer cells, whether resting or proliferating, there is evidence that the selective inhibition of ribosome biogenesis may, in some instances, result in a selective damage to neoplastic cells. The higher sensitivity of cancer cells to inhibitors of rRNA synthesis appears to be the consequence of either the loss of the mechanisms controlling the cell cycle progression or the acquisition of activating oncogene and inactivating tumor suppressor gene mutations that up-regulate the ribosome biogenesis rate. This article reviews those cancer cell characteristics on which the selective cancer cell cytotoxicity induced by the inhibitors of ribosome biogenesis is based. PMID- 26415221 TI - Wnt activated beta-catenin and YAP proteins enhance the expression of non-coding RNA component of RNase MRP in colon cancer cells. AB - RMRP, the RNA component of mitochondrial RNA processing endoribonuclease, is a non-coding RNA (ncRNA) part of the RNase MRP complex functioning in mitochondrial and ribosomal RNA processing. Even though various mutations in the RMRP gene are linked to developmental defects and pathogenesis, its relevance to cancer etiology has not been well established. Here we examined the expression of RMRP and found a significant increase in colorectal and breast cancer patient tissues. So we tested whether the oncogenic signaling pathways, Wnt/beta-catenin and Hippo/YAP pathways, are relevant to the enhanced expression of RMRP in cancer cells because of the predicted beta-catenin/TCF and YAP/TBX5 elements in the upstream regions of the RMRP gene. As expected, Wnt signal activation significantly induced the RMRP transcription thru beta-catenin and YAP transcription factors. More importantly, YAP protein was critical for RMRP transcription by association to the proximal site near the transcription start site of the RMRP gene, a Pol III promoter, along with beta-catenin and TBX5 proteins. We propose that the interplay of Wnt and Hippo signaling pathways could regulate target genes, coding or non-coding, by the beta-catenin/YAP/TBX5 transcription complex in cancer cells. PMID- 26415223 TI - Prognostic score models for survival of nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy and chemotherapy. AB - PURPOSE: To establish accurate prognostic score models to predict survival for patients with nasopharyngeal carcinoma (NPC), treated with intensity-modulated radiotherapy (IMRT) and chemotherapy. MATERIALS AND METHODS: Six hundred and seventy-five patients with newly diagnosed, nonmetastatic and histologically proven NPC who were treated with IMRT and chemotherapy were analyzed retrospectively. Samples were split randomly into a training set (n = 338) and a test set (n = 337) to analyze. All data from the training set were used to perform an extensive survival analysis and to develop multivariate nomograms based on Cox regression. Data from the test set was used as an external validation set. Risk group stratification was proposed for the nomograms. RESULTS: The nomograms are able to predict survival with a C-index for external validation of local recurrence-free survival (LRFS; 0.66, 95% CI: 0.58-0.74), distant metastasis-free survival (DMFS; 0.73, 95% CI: 0.66-0.79), and disease specific survival (DSS; 0.73, 95% CI: 0.67-0.79). The calibration curve for probability of survival showed good agreement between prediction by nomogram and actual observation. The C-index of the nomogram for LRFS, DMFS and DSS were statistically higher than the C-index values of the AJCC seventh edition (P < 0.001). In the test set, the nomogram discrimination was also superior to the AJCC Staging systems (P < 0.001). The stratification in risk groups allows significant distinction between Kaplan-Meier curves for outcome. CONCLUSIONS: Prognostic score models were successfully established and validated to predict LRFS, DMFS, and DSS over a 5-year period after IMRT and chemotherapy, which will be useful for individual treatment. PMID- 26415222 TI - Copper activates HIF-1alpha/GPER/VEGF signalling in cancer cells. AB - Copper promotes tumor angiogenesis, nevertheless the mechanisms involved remain to be fully understood. We have recently demonstrated that the G-protein estrogen receptor (GPER) cooperates with hypoxia inducible factor-1alpha (HIF-1alpha) toward the regulation of the pro-angiogenic factor VEGF. Here, we show that copper sulfate (CuSO4) induces the expression of HIF-1alpha as well as GPER and VEGF in breast and hepatic cancer cells through the activation of the EGFR/ERK/c fos transduction pathway. Worthy, the copper chelating agent TEPA and the ROS scavenger NAC prevented the aforementioned stimulatory effects. We also ascertained that HIF-1alpha and GPER are required for the transcriptional activation of VEGF induced by CuSO4. In addition, in human endothelial cells, the conditioned medium from breast cancer cells treated with CuSO4 promoted cell migration and tube formation through HIF-1alpha and GPER. The present results provide novel insights into the molecular mechanisms involved by copper in triggering angiogenesis and tumor progression. Our data broaden the therapeutic potential of copper chelating agents against tumor angiogenesis and progression. PMID- 26415224 TI - Mitochondria-targeted antioxidant preserves contractile properties and mitochondrial function of skeletal muscle in aged rats. AB - Mitochondrial dysfunction plays a central role in the pathogenesis of sarcopenia associated with a loss of mass and activity of skeletal muscle. In addition to energy deprivation, increased mitochondrial ROS damage proteins and lipids in aged skeletal muscle. Therefore, prevention of mitochondrial ROS is important for potential therapeutic strategies to delay sarcopenia. This study elucidates the pharmacological efficiency of the new developed mitochondria-targeted ROS and electron scavenger, XJB-5-131 (XJB) to restore muscle contractility and mitochondrial function in aged skeletal muscle. Male adult (5-month old) and aged (29-month old) Fischer Brown Norway (F344/BN) rats were treated with XJB for four weeks and contractile properties of single skeletal muscle fibres and activity of mitochondrial ETC complexes were determined at the end of the treatment period. XJB-treated old rats showed higher muscle contractility associated with prevention of protein oxidation in both muscle homogenate and mitochondria compared with untreated counterparts. XJB-treated animals demonstrated a high activity of the respiratory complexes I, III, and IV with no changes in citrate synthase activity. These data demonstrate that mitochondrial ROS play a causal role in muscle weakness, and that a ROS scavenger specifically targeted to mitochondria can reverse age-related alterations of mitochondrial function and improve contractile properties in skeletal muscle. PMID- 26415220 TI - The different roles of selective autophagic protein degradation in mammalian cells. AB - Autophagy is an intracellular pathway for bulk protein degradation and the removal of damaged organelles by lysosomes. Autophagy was previously thought to be unselective; however, studies have increasingly confirmed that autophagy mediated protein degradation is highly regulated. Abnormal autophagic protein degradation has been associated with multiple human diseases such as cancer, neurological disability and cardiovascular disease; therefore, further elucidation of protein degradation by autophagy may be beneficial for protein based clinical therapies. Macroautophagy and chaperone-mediated autophagy (CMA) can both participate in selective protein degradation in mammalian cells, but the process is quite different in each case. Here, we summarize the various types of macroautophagy and CMA involved in determining protein degradation. For this summary, we divide the autophagic protein degradation pathways into four categories: the post-translational modification dependent and independent CMA pathways and the ubiquitin dependent and independent macroautophagy pathways, and describe how some non-canonical pathways and modifications such as phosphorylation, acetylation and arginylation can influence protein degradation by the autophagy lysosome system (ALS). Finally, we comment on why autophagy can serve as either diagnostics or therapeutic targets in different human diseases. PMID- 26415225 TI - The BET bromodomain inhibitor, JQ1, facilitates c-FLIP degradation and enhances TRAIL-induced apoptosis independent of BRD4 and c-Myc inhibition. AB - Inhibition of BET bromodomains (BRDs) has emerged as a promising cancer therapeutic strategy. Accordingly, inhibitors of BRDs such as JQ1 have been actively developed and some have reached clinical testing. However, the mechanisms by which this group of inhibitors exerts their anticancer activity, including induction of apoptosis, have not been fully elucidated. This report reveals a previously uncovered activity of JQ1 in inducing c-FLIP degradation and enhancing TRAIL-induced apoptosis. JQ1 potently decreased c-FLIP (both long and short forms) levels in multiple cancer cell lines without apparently increasing the expression of DR5 and DR4. Consequently, JQ1, when combined with TRAIL, synergistically induced apoptosis; this enhanced apoptosis-inducing activity could be abolished by enforced expression of ectopic FLIPL or FLIPS. Hence it appears that JQ1 decreases c-FLIP levels, resulting in enhancement of TRAIL induced apoptosis. Inhibition of proteasome with MG132 prevented JQ1-induced c FLIP reduction. Moreover, JQ1 decreased c-FLIP stability. Therefore, JQ1 apparently decreases c-FLIP levels through facilitating its proteasomal degradation. Genetic inhibition of either BRD4 or c-Myc by knocking down their expression failed to mimic JQ1 in decreasing c-FLIP and enhancing TRAIL-induced apoptosis, suggesting that JQ1 induces c-FLIP degradation and enhances TRAIL induced apoptosis independent of BRD4 or c-Myc inhibition. In summary, our findings in this study highlights a novel biological function of JQ1 in modulating apoptosis and warrant further study of the potential treatment of cancer with the JQ1 and TRAIL combination. PMID- 26415226 TI - Next generation sequencing in synovial sarcoma reveals novel gene mutations. AB - Over 95% of all synovial sarcomas (SS) share a unique translocation, t(X;18), however, they show heterogeneous clinical behavior. We analyzed multiple SS to reveal additional genetic alterations besides the translocation. Twenty-six SS from 22 patients were sequenced for 409 cancer-related genes using the Comprehensive Cancer Panel (Life Technologies, USA) on an Ion Torrent platform. The detected variants were verified by Sanger sequencing and compared to matched normal DNAs. Copy number variation was assessed in six tumors using the Oncoscan array (Affymetrix, USA). In total, eight somatic mutations were detected in eight samples. These mutations have not been reported previously in SS. Two of these, in KRAS and CCND1, represent known oncogenic mutations in other malignancies. Additional mutations were detected in RNF213, SEPT9, KDR, CSMD3, MLH1 and ERBB4. DNA alterations occurred more often in adult tumors. A distinctive loss of 6q was found in a metastatic lesion progressing under pazopanib, but not in the responding lesion. Our results emphasize t(X;18) as a single initiating event in SS and as the main oncogenic driver. Our results also show the occurrence of additional genetic events, mutations or chromosomal aberrations, occurring more frequently in SS with an onset in adults. PMID- 26415227 TI - The knockdown of H19lncRNA reveals its regulatory role in pluripotency and tumorigenesis of human embryonic carcinoma cells. AB - The function of imprinted H19 long non-coding RNA is still controversial. It is highly expressed in early embryogenesis and decreases after birth and re expressed in cancer. To study the role of H19 in oncogenesis and pluripotency, we down-regulated H19 expression in vitro and in vivo in pluripotent human embryonic carcinoma (hEC) and embryonic stem (hES) cells. H19 knockdown resulted in a decrease in the expression of the pluripotency markers Oct4, Nanog, TRA-1-60 and TRA-1-81, and in the up-regulation of SSEA1; it further attenuated cell proliferation, decreased cell-matrix attachment, and up-regulated E-Cadherin expression. SCID-Beige mice transplanted with H19 down-regulated hEC cells exhibited slower kinetics of tumor formation, resulting in an increased animal survival. Tumors derived from H19 down-regulated cells showed a decrease in the expression of pluripotency markers and up-regulation of SSEA-1 and E-cadherin. Our results suggest that H19 oncogenicity in hEC cells is mediated through the regulation of the pluripotency state. PMID- 26415229 TI - A genome wide transcriptional model of the complex response to pre-TCR signalling during thymocyte differentiation. AB - Developing thymocytes require pre-TCR signalling to differentiate from CD4-CD8- double negative to CD4+CD8+ double positive cell. Here we followed the transcriptional response to pre-TCR signalling in a synchronised population of differentiating double negative thymocytes. This time series analysis revealed a complex transcriptional response, in which thousands of genes were up and down regulated before changes in cell surface phenotype were detected. Genome-wide measurement of RNA degradation of individual genes showed great heterogeneity in the rate of degradation between different genes. We therefore used time course expression and degradation data and a genome wide transcriptional modelling (GWTM) strategy to model the transcriptional response of genes up-regulated on pre-TCR signal transduction. This analysis revealed five major temporally distinct transcriptional activities that up regulate transcription through time, whereas down-regulation of expression occurred in three waves. Our model thus placed known regulators in a temporal perspective, and in addition identified novel candidate regulators of thymocyte differentiation. PMID- 26415228 TI - Low-dose ionizing radiation induces mitochondrial fusion and increases expression of mitochondrial complexes I and III in hippocampal neurons. AB - High energy ionizing radiation can cause DNA damage and cell death. During clinical radiation therapy, the radiation dose could range from 15 to 60 Gy depending on targets. While 2 Gy radiation has been shown to cause cancer cell death, studies also suggest a protective potential by low dose radiation. In this study, we examined the effect of 0.2-2 Gy radiation on hippocampal neurons. Low dose 0.2 Gy radiation treatment increased the levels of MTT. Since hippocampal neurons are post-mitotic, this result reveals a possibility that 0.2 Gy irradiation may increase mitochondrial activity to cope with stimuli. Maintaining neural plasticity is an energy-demanding process that requires high efficient mitochondrial function. We thus hypothesized that low dose radiation may regulate mitochondrial dynamics and function to ensure survival of neurons. Our results showed that five days after 0.2 Gy irradiation, no obvious changes on neuronal survival, neuronal synapses, membrane potential of mitochondria, reactive oxygen species levels, and mitochondrial DNA copy numbers. Interestingly, 0.2 Gy irradiation promoted the mitochondria fusion, resulting in part from the increased level of a mitochondrial fusion protein, Mfn2, and inhibition of Drp1 fission protein trafficking to the mitochondria. Accompanying with the increased mitochondrial fusion, the expressions of complexes I and III of the electron transport chain were also increased. These findings suggest that, hippocampal neurons undergo increased mitochondrial fusion to modulate cellular activity as an adaptive mechanism in response to low dose radiation. PMID- 26415230 TI - SP600125 has a remarkable anticancer potential against undifferentiated thyroid cancer through selective action on ROCK and p53 pathways. AB - Thyroid cancer is the most common endocrine malignancy with increasing incidence worldwide.The majority of thyroid cancer cases are well differentiated with favorable outcome. However, undifferentiated thyroid cancers are one of the most lethal human malignancies because of their invasiveness, metastatization and refractoriness even to the most recently developed therapies.In this study we show for the first time a significant hyperactivation of ROCK/HDAC6 pathway in thyroid cancer tissues, and its negative correlation with p53 DNA binding ability.We demonstrate that a small compound, SP600125 (SP), is able to induce cell death selectively in undifferentiated thyroid cancer cell lines by specifically acting on the pathogenic pathways of cancer development. In detail, SP acts on the ROCK/HDAC6 pathway involved in dedifferentiation and invasiveness of undifferentiated human cancers, by restoring its physiological activity level. As main consequence, cancer cell migration is inhibited and, at the same time, cell death is induced through the mitotic catastrophe. Moreover, SP exerts a preferential action on the mutant p53 by increasing its DNA binding ability. In TP53-mutant cells that survive mitotic catastrophe this process results in p21 induction and eventually lead to premature senescence. In conclusion, SP has been proved to be able to simultaneously block cell replication and migration, the two main processes involved in cancer development and dissemination, making it an ideal candidate for developing new drugs against anaplastic thyroid cancer. PMID- 26415231 TI - Cancer stem cells are the cause of drug resistance in multiple myeloma: fact or fiction? AB - Multiple myeloma (MM) remains a largely incurable, genetically heterogeneous plasma-cell malignancy that contains - just like many other cancers - a small fraction of clonogenic stem cell-like cells that exhibit pronounced self-renewal and differentiation capacities, but also pronounced drug resistance. These MM stem cells (MMSCs) are a controversial but highly significant issue in myeloma research because, in our opinion, they are at the root of the failure of anti neoplastic chemotherapies to transform myeloma to a manageable chronic disease. Several markers including CD138-, ALDH1+ and SP have been used to identify MMSCs; however, no single marker is reliable for the isolation of MMSC. Nonetheless, it is now known that MMSCs depend on self-renewal and pro-survival pathways, such as AKT, Wnt/beta-catenin, Notch and Hedgehog, which can be targeted with novel drugs that have shown promise in pre-clinical and clinical trials. Here, we review the pathways of myeloma "stemness", the interactions with the bone marrow microenvironment that promote drug resistance, and the obstacles that must be overcome to eradicate MMSCs and make myeloma a curable disease. PMID- 26415232 TI - The predictive value of centre tumour CD8+ T cells in patients with hepatocellular carcinoma: comparison with Immunoscore. AB - The increasing evidences suggest that Immunoscore(IS), a combinatorial density analysis of CD8+ and CD3+ cells in the centre and invasive margin of tumour (CT and IM), has an advantage over the currently used tumour staging methods in a variety of tumours; however, IS in hepatocellular carcinoma remains unreported. In this study, IS was performed on serial sections from two HCC cohorts (total 449) and compared with current tumour staging systems. Kaplan-Meier curves illustrate a positive association between a higher IS (IS>=2) and longer survival of HCC patients. Although the IS was highly related to the outcome of patients, however, IS seems not to be the optimal prognostic factor when compared with the CD8CT. As noted, among CD8CT, CD8IM, CD3CT, CD3IM and IS, CD8CT, as an independent indicator, demonstrated the highest prognostic impact on both DFS and OS in our Cox multivariate regression analysis (P< 0.0001). In our study, the minimum cut-off value was 93 CD8CT cells per mm2, to be used to divide the patients into CD8CTHi group and CD8CTLo group in clinical settings. Our results suggest that CD8CT densities analysis notably improved the accuracy of survival prediction with convenience of clinical manipulation in HCC. PMID- 26415233 TI - Retrograde TrkAIII transport from ERGIC to ER: a re-localisation mechanism for oncogenic activity. AB - In human SH-SY5Y neuroblastoma (NB) cells, nascent immature N-glycosylated 110kDa TrkA moves rapidly from the endoplasmic reticulum (ER) to the Golgi Network (GN), where it matures into the 140kDa receptor prior to being transported to the cell surface, creating GN and cell surface pools of inactive receptor maintained below the spontaneous activation threshold by a full compliment of inhibitory domains and endogenous PTPases. In contrast, the oncogenic alternative TrkAIII splice variant is not expressed at the cell surface but re-localises to intracellular membranes, within which it exhibits spontaneous ERGIC/COPI-associated activation and oncogenic Akt signalling. In this study, we characterise the mechanism responsible for TrkAIII re-localisation. Spontaneous TrkAIII activation, facilitated by D4 IG-like domain and N-glycosylation site omission, increases spontaneous activation potential by altering intracellular trafficking, inhibiting cell surface expression and eliminating an important inhibitory domain. TrkAIII, spontaneously activated within the permissive ERGIC/COPI compartment, rather than moving in an anterograde direction to the GN exhibits retrograde transport back to the ER, where it is inactivated. This sets-up self perpetuating TrkAIII re-cycling between the ERGIC and ER, that ensures continual accumulation above the spontaneous activation threshold of the ERGIC/COPI compartment. This is reversed by TrkA tyrosine kinase inhibitors, which promote anterograde transport of inactivated TrkAIII to the GN, resulting in GN associated TrkAIII maturation to a 120kDa species that is degraded at the proteasome. PMID- 26415235 TI - Surgical Services in Critical Access Hospitals, 2011. AB - In this policy brief we describe the types and volume of major surgical services provided in the inpatient and outpatient settings of Critical Access Hospitals (CAHs) in 2011. Major surgical services are those procedures that require use of an operating room (OR), regardless of whether the procedure was inpatient or outpatient. Key Findings (1) CAH discharges of patients having a major surgical procedure that required use of an OR were analyzed from four regionally representative states: Colorado, North Carolina, Vermont, and Wisconsin. The average surgical volume among all CAHs in the sample was 624 procedures per CAH per year, and only 6.8 percent of CAHs performed none. (2) The average portion of all surgery volume performed on an outpatient basis in CAHs is 77 percent. Inpatient procedure volume ranged between 20 percent and 24 percent of total surgical volume across the four states. Most of the research literature on surgery in CAHs focus on inpatient procedures only, thus missing a significant portion of the surgery volume that CAHs perform. (3) The high correlation (0.86, p <0.0001) indicates that the 3:1 ratio of outpatient-to-inpatient surgical volume was relatively consistent across CAHs. (4) Operations on the musculoskeletal system, the eye, and the digestive system accounted for 67 percent on average of all surgical procedures in CAHs. Many surgical procedures are performed on an inpatient and outpatient basis, but some are performed exclusively in one setting. PMID- 26415236 TI - [Long non-coding RNA and disease]. PMID- 26415238 TI - I extend a heartfelt. PMID- 26415237 TI - [Current topics for sports medicine: knee joint surgery under arthroscope]. PMID- 26415234 TI - Deconvoluting the complexity of autophagy and Parkinson's disease for potential therapeutic purpose. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by the preferential death of dopaminergic neurons. In the past two decades, great progress has been made toward understanding the pathogenesis of PD; however, its precise pathogenesis still remains unclear. Recently, accumulating evidence has suggested that macroautophagy (herein referred to as autophagy) is tightly linked to PD. Dysregulation of autophagic pathways has been observed in the brains of PD patients and in animal models of PD. More importantly, a number of PD-associated proteins, such as alpha-synuclein, LRRK2, Parkin and PINK1 have been further revealed to be involved in autophagy. Thus, it is now acknowledged that constitutive autophagy is essential for neuronal survival and that dysregulation of autophagy leads to PD. In this review, we focus on summarizing the relationships amongst PD-associated proteins, autophagy and PD. Moreover, we also demonstrate some autophagy-modulating compounds and autophagic microRNAs in PD models, which may provide better promising strategies for potential PD therapy. PMID- 26415239 TI - [Individual medicine-the present and the future]. PMID- 26415240 TI - [Treatment of leukemia and lymphoma: from the past to the future]. PMID- 26415241 TI - stARTing cART now! HIV treatment Italian Guidelines Update Dec. 2014. PMID- 26415242 TI - Entering the age of 'ultra-superovulation'. PMID- 26415243 TI - Distinctive hair helps ants stay cool. PMID- 26415244 TI - Moon jellies rearrange to restore symmetry. PMID- 26415245 TI - Authors' responses. PMID- 26415246 TI - My Greatest Gift. PMID- 26415247 TI - Words and Deeds: Advocacy and Our Code of Ethics. PMID- 26415248 TI - Nurses Share Concerns about Achieving Quality Patient Outcomes. PMID- 26415249 TI - Infusion Therapy Nurse a Leader and Advocate throughout her Long Career. PMID- 26415250 TI - Continuing our Work to Support Nurse Practitioners. PMID- 26415251 TI - Sacred Heart Nurses and Hospitalists Go Public with Staffing Concerns. PMID- 26415252 TI - ONA's 2015 Legislative Agenda. . PMID- 26415253 TI - The Modern School Nurse. PMID- 26415254 TI - Blood Donors Deserve Nursing Expertise. PMID- 26415255 TI - Advocate Profile: Steve Rooney, RN. PMID- 26415256 TI - Advocate Profile: Rob Campbell, RN. PMID- 26415257 TI - Advocate Profile: Virginia Smith, BSN, RN-BC. PMID- 26415258 TI - [INDICATORS OF QUALITY OF ENDOSCOPY DEPARTMENTS (CABINET) ACTIVITIES]. AB - The article presents the possible indicators of quality of endoscopy departments (cabinet) activities, developed on the basis of the experience of foreign colleagues using information resource: PubMed, Cochrane Library, MDConsult, DynaMed, Google Schola and search engine TRIP Database www.tripdatabase.com, existing regulations as well as their own experience. PMID- 26415259 TI - [ENDOCYTOSCOPY--NOVEL ENDOSCOPIC DIAGNOSTICS APPROACH: PRINCIPLES AND PROCEDURE]. AB - Endocytoscopy is one of the most novel endoscopic diagnostic procedures, providing optical magnification up to 1150 times of gastrointestinal and respiratory tract mucosa. Such approach allows real-time tissue and cellular structure visualization. Endocytoscopy, along with confocal laser endomicroscopy, can be considered as "optical biopsy" in vivo. Of course, endocytoscopy currently is experimental diagnostic method, all available endocytoscopes are prototypes. According to published data, endocytoscopy can be used in precancerous conditions and early intramucosal cancer diagnostics in esophagus, stomach, colon and bronchial tree. Different types of endocytoscopes are used for examinations: some of them are baby-scopes, with fixed magnification 570-1150 times, introduced into accessory channel of the therapeutic parent-endoscope, others--are integrated type, providing scalable magnification from 80 to 380 times. As for traditional pathology ex vivo, for endocytoscopy mucosal cell nuclei stain is needed. For vital staining during endocytoscopy methylene blue, toluidine blue and crystal violet in different concentrations are more often used. In cases of squamous-cell dysplasia or cancer, it is recommended to use 1% methylene blue solution, whereas in intestinal type metaplasia, dysplastic changes and cancer (Barrett's esophagus, P. Correa precancerous cascade, colon adenomas), 1% toluidine blue is preferred. With endocytoscopy, after vital staining, we can visualize and estimate mucosa tissue and cell characteristics: papillae, crypt and gland shapes and sizes, their integrity (tissue markers); cell nuclei size and shape, polarity and nuclear dye intensity (cell markers). PMID- 26415260 TI - [ENDOSONOGRAPHY IN THE DIFFERENTIAL DIAGNOSIS OF THE COMMON BILE DUCT STENOSIS]. AB - The article states the results of examination and treatment of 57 patients with stenosis of the common bile duct of various genesis. The main aim of the work is criteria definition and evaluation of diagnostic significance of endosonography in the differential diagnosis of benign and malignant common bile duct stenosis. The paper presents a methodology of endoscopic ultrasound and basic criteria for the differential diagnosis of tumors and other lesions of the extrahepatic bile ducts. A comparative analysis of endosonography, ultrasound, CT, MRCP was conducted. The sensitivity of endosonography in determining the nature of the common bile duct stenosis was 97.7%, a specificity 100% and accuracy 98.2%, which is superior to other methods of radiological diagnosis. In comprehensive surgical centers endosonography should be used as a method of specifying the final diagnosis to determine the nature of the common bile duct stenosis, particularly at low constriction location. PMID- 26415261 TI - [POSSIBILITY OF EARLY GASTRODUODENOSCOPY IN ASSESSING OF SEVERITY AND LOCATION OF THE NECROSIS IN ACUTE BILE PANCREATITIS]. AB - In prospective cohort study of 100 patients with acute bile pancreatitis studied endoscopic upper gastrointestinal changes depending on the location of the zone of inflammation and necrosis in the pancreas and the severity of the pancreatitis. In the overall structure changes were the most common finding of a violation of lymphflow--lymphangiectasia--67%. From 29% to 44% of patients had evidence of acute inflammation in the stomach and duodenum. Every fourth patient noted pain in moving the endoscope in the stomach or duodenum. However, direct signs of obstructive acute bile pancreatitis occurred in only 7% - 15% of cases, although extended intramural bile duct as a sign of bile hypertension occurred in 25% of cases. Revealed significant differences in the frequency of endoscopic evidence of the localization of necrosis in the head, body or tail of the pancreas. Also revealed significant differences in the structure of endoscopic findings in depending on the severity of the pancreatitis. It is shown that direct signs of obstructive bile pancreatitis is not related to the localization of inflammation, but have a close relationship with the severity of bile pancreatitis. Thus, a qualified assessment of upper gastrointestinal changes in acute bile pancreatitis can improve the topical diagnosis of necrosis in the pancreas and the early evaluation of the severity of bile pancreatitis. PMID- 26415262 TI - [ENDOSCOPIC DIAGNOSIS AND PARIETAL IMPEDANCOMETRY IN THE ASSESSMENT OF CHANGES IN THE MUCOSA OF THE DUODENUMIN PATIENTS WITH SUSPICION ON POSTCHOLECYSTECTOMY SYNDROME]. AB - The article is based on analysis of the results of continuous cohort study of 79 patients. All patients underwent endoscopic examination of the upper parts of the gastrointestinal tract and parietal impedancometry mucosa in the descending part of the duodenum. The aim of the study was to determine the effectiveness of endoscopy and the parietal impedancometry mucosa of the duodenum in patients with suspected development of postcholecystectomy syndrome. In the result of the analysis revealed that the overall structure of endoscopic changes in patients with gallstone disease and after cholecystectomy is the most common signs of chronic pancreatitis. The highest values of the impedance of the mucosa in patients with gallstones. PMID- 26415263 TI - [ULTRASONIC DIAGNOSIS OF GIRSHPRUNG ILLNESS AT CHILDREN]. AB - Use of ultrasonic diagnostics reduces number of the low-informative, invasive and connected with beam loading procedures. Objectivity of results of ultrasonic structure of an intestinal wall depends on many subjective parameters: from the device on which examination, from the expert experience, from extent of preparation of intestines, from the applied solution for contrasting, from degree of expressiveness of a desire on a defecation is conducted when filling a thick gut. PMID- 26415264 TI - [VASCULAR ENDOTHELIAL GROWTH FACTOR AND SOME INDICATORS OF ENDOTHELIAL DYSFUNCTION OF PATIENTS HAVING CHRONIC INFLAMMATORY DISEASES OF THE GASTRO DUODENAL ZONE]. AB - The aim of the study was to determine the content of vaskuloendotelian growth factor and nitric oxide in children with chronic inflammatory diseases of the stomach and duodenum. The study involved 63 children with chronic inflammatory diseases of the gastroduodenal zone. Substrate study was serum. The data obtained were compared with a group of healthy children. The highest possible content vaskuloendotelian growth factor noted in the group of children with duodenal ulcer in the acute phase and in the group of chronic gastroduodenita associated with Helicobacter pylori. According to the results of the study established the role of nitric oxide and vaskuloendotelian growth factor in the pathogenesis of gastroduodenal diseases. PMID- 26415265 TI - [AETIOLOGY AND PATHOGENESIS GASTRO-DUODENALES ULCERATIVE LESIONS IN ELDERLY]. AB - In review today conceptions of view to aetiology and pathogenesis gastro duodenales ulcerative lesions in elderly. Atherosclerosis, ischemic disease of the heart and hypertension are reasons of acute ulcers and erosions in elderly. The breaking of microcirculation are very importance. PMID- 26415266 TI - [ENDOSCOPIC MUCOSAL RESECTION WITH SUBMUCOSAL DISSECTION ESD AND THE FIRST LONG TERM RESULTS OF APPLYING THIS METHOD]. AB - This review discusses the advantages and disadvantages of endoscopic mucosal resection with submucosal dissection ESD and the first long-term results of applying this method. PMID- 26415267 TI - [DEONTOLOGICAL QUESTIONS IN PROPHYLACTIC OF ENDOSCOPIC COMPLICATIONS: THE SIGNIFICANCE OF RATIONAL AND PSYCHOLOGICAL FACTORS (analytical overview)]. AB - THE AIM OF STUDY: To evaluate the ways of reduction complications during endoscopic procedures based on principals of professional ethics and improving the quality of working area. MATERIALS AND METHODS: Data of fundamental literature, evidence based medicine, science publications and internet portals. RESULTS: Deontology is the fundamental principle of medical practice and one of the main factors of professional effectiveness. Complications in endoscopy are often the investigations of deviation from the deontological principals. The whole number of psychological factors influences on professional activity of endoscopists, where the emotional "burn-out" syndrome (EBS) occupies one of the main places. Prophylactic and timely relief of EBS serves improvement of the practical work quality. CONCLUSION: Creation of favorable working area is the strategically important task in prophylactics of endoscopy complications. The questions of practical realization of deontological principles in endoscopy are the subject of further discussion. PMID- 26415268 TI - [ANALYSIS OF THE RESULTS OF ENDOSCOPIC AND MORPHOLOGICAL STUDIES OF THE STOMACH MUCOSA WITH REDUCED PEPSINOGEN-I IN PATIENTS WITH H. PYLORI (H.P.)--ASSOCIATED GASTRITIS IN TOMSK AND TOMSK REGION]. AB - AIM OF INVESTIGATION: To explore and describe the endoscopic picture of HP- associated atrophic gastritis and to analyze the specificity of endoscopic markers indicating the presence of atrophic gastritis, intestinal metaplasia and dysplasia using high-tech methods of endoscopy in comparison with morphological characteristics of atrophic gastritis defining the degree of activity and stage of atrophic gastritis according to the system OLGA. MATERIALS AND METHODS: 40 people: males and females aged 40 to 70 years with a reduced level of pepsinogen I and a positive titre of antibodies to H. pylori in serum--were included into the study. THE RESULTS: Risk groups with atrophic gastritis based on indicators of pepsinogen 1 were formed. Endoscopic picture of H. Pylori--associated atrophic gastritis in patients with reduced level of pepsinogen I in serum is studied and described. Analysis of the specificity of endoscopic markers indicating the presence of AG, intestinal metaplasia and dysplasia using high-tech methods of endoscopy (endoscopy with high resolution, magnifying endoscopy, chromoendoscopy and narrow band imaging endoscopy (NBI) is made. Analysis of their sensitivity in comparison with the results of morphological studies of biopsy material is made. CONCLUSION: Thus, these studies show that high-resolution endoscopy in combination with magnification and chromoendoscopy allows accurately identify areas of atrophy, intestinal.Narrow band imaging endoscopy (NBI) provides a detailed picture of the vascular pattern of tissues, pattern changes typical for pathological areas of inflammatory genesis, as well as for precancers and early cancers. All these methods have high sensitivity and specificity in the diagnosis of HP-associated atrophic gastritis in comparison with the results of morphological studies of biopsy materials of stomach mucosa. PMID- 26415269 TI - [STENTING VERSUS PALLIATIVE SURGERY IN PATIENTS WITH MALIGNANT GASTROINTESTINAL STENOSIS]. AB - AIM: Retrospective analysis of the results of stenting versus surgical palliation in patients with malignant gastrointestinal stenosis. MATERIAL AND METHODS: 85 patients underwent endoscopic stenting (41) or surgical intervention (44). Level of stenosis: gastric outlet (23/38), multi-level gastric obstruction (2/3), duodenum or jejunum (12/3), gastrojejunoanastomosis (3/0) and gastroduodenoanastomosis (1/0). 49 self-expanding metal stents were implanted in 41 patients. 41 gastroenteroanastomoses and 3 jejunostomas were performed in surgical group. RESULTS: Stents were successfully inserted in all patients. Early complications were observed in 3 (7.3%) patients after stenting and in 9 (20.5%) after surgical palliation, p = 0.0755. Postoperative lethality was 2,4% (1 patient) after stenting and 31.8% (14 patients) after surgery, p = 0.0003. Mean hospital stay was 15 days in stenting group and 23 days in surgical group, p < 0.001. There was no statistically significant difference in long-term results, neither in late complications (p = 0.3691), nor in survival (p =0.3697). CONCLUSION: Endoscopic placement of self-expanding stents is an effective method of restoration of oral intake in patients with malignant gastrointestinal obstruction. Stenting is associated with equal rates of early and late complications, lower mortality and decreased in-hospital stay as compared with surgery, and therefore may be recommended as a final palliation in inoperable patients. PMID- 26415271 TI - [PSYCHOSOMATIC RELATIONSHIPS DURING GASTROINTESTINAL DISEASE ON THE MODEL OF IRRITABLE BOWEL SYNDROME]. AB - On the model of irritable bowel syndrome basic concept of psychosomatic relationships in diseases of the gastrointestinal tract and main methods of treatment tailored to their specific effects on the gastrointestinal tract are analyzed. PMID- 26415270 TI - [Using "Collegel" complex in combined therapy of rectum cancer]. AB - The method of drug delivery to the site of lesion is an important component of drug effectiveness. To maximize the effectiveness of drugs LLC "Koletex" has developed and brought into practice the drug, "Collegel" for directed drug delivery. Hydrogel based composition "Collegel" is biopolymer consists of sodium alginate. In the gel-forming polymer one or more substance introduced on a specific technology. Studies have been conducted to examine the possibility of using hydrogel "Collegel" with 5-fluorouracil as radiomodifying agent in the treatment of rectal cancer. In the group of patients who received intrarectal introduction 5-fluorouracil, metastases were observed significantly less frequently (2.8%) than in the group of patients who received surgical treatment (15.2%) and preoperative radiotherapy in monoregimen (12.6%), as well as reduced doses capecitabine concomitantly with preoperative radiotherapy (11.4%), which gives the basis for the use of intrarectal way of introduction of therapeutic doses of 5-fluorouracil during preoperative chemoradiation therapy. The newly created method of complex treatment of patients with rectal cancer to ensure adequate local control of the disease. There is no local recurrence diagnosed over the 2-year follow-up period. We have considerable experience in the application of gel "Collegel" containing antioxidant and immunomodulator "Derinat" (deoxyribonuclease sodium) for the prevention and treatment of radiation damage to normal tissues during radiotherapy of malignant tumors. Patients can be treated without interruption and significantly reduces the incidence of adverse radiation damage. PMID- 26415272 TI - [PRINCIPLES OF POSTOPERATIVE DRUG THERAPY OF COMPLICATED DUODENAL ULCERS]. AB - The article highlights the principles of individualized drug therapy of complicated duodenal ulcers in the postoperative period, based on the removal of the pathophysiological changes that occurred after different types of medical or surgical benefits. PMID- 26415273 TI - [ESOPHAGITIS, CAUSED BY HERPES SIMPLEX VIRUS: CASE REPORT]. AB - The clinical observation of the patient at the age of 56 years, with lesions of the esophagus by the herpes simplex virus has been presented. The patient complained of odynophagia and dysphagia. Treatment with proton pump inhibitors in outpatient stage was not effective. On endoscopic examination revealed multiple ulcers in all parts of the esophagus. Herpes simplex virus has been detected in biopsy specimens of esophageal mucosa by the PCR method. Treatment with acyclovir led to rapid and complete clinical recovery. Analysis of the literature allowed making the conclusion about the importance and actuality this demonstration. PMID- 26415275 TI - [Experimental Evidence of Proliferation and Reproduction of Highly Differentiated Sertoli Cells]. AB - The main results of studies regarding the biology of Sertoli cells under various experimental conditions are considered. Possible potential mechanisms underlying the transition of highly differentiated Sertoli cells to dedifferentiation, limited by proliferation and reproduction and not accompanied by significant phenotypic changes, are discussed. PMID- 26415274 TI - [A Cellular Automata Model for a Community Comprising Two Plant Species of Different Growth Forms]. AB - A cellular automata computer model for the interactions between two plant species of different growth forms--the lime hairgrass Deschampsia caespitosa (L.) P. Beauv., a sod cereal, and the moneywort Lysimachia nummularia L., a ground creeping perennial herb--is considered. Computer experiments on the self maintenance of the populations of each species against the background of a gradual increase in the share of randomly eliminated individuals, coexistence of the populations of two species, and the effect of the phytogenous field have been conducted. As has been shown, all the studied factors determine the number of individuals and self-sustainability of the simulated populations by the degree of their impact. The limits of action have been determined for individual factors; within these limits, the specific features in plant reproduction and dispersal provide sustainable coexistence of the simulated populations. It has been demonstrated that the constructed model allows for studying the long-term developmental dynamics of the plants belonging to the selected growth forms. PMID- 26415276 TI - [Metabolites of Toxigenic Fungi in Lichens of Genera Alectoria, Bryoria, Evernia, Pseudevernia, and Usnea]. AB - Complexes of mycotoxins in fruticose lichens of 14 species belonging to five genera of the family Parmeliaceae were characterized by size, composition, and content of individual components. It was shown that species of the genus Bryoria always contain five mycotoxins (sterigmatocystin, mycophenolic acid, citrinin, emodin, and alternariol). In Evernia and Pseudevernia, this list is supplemented with zearalenone, diacetoxyscirpenol, and cyclopiazonic acid or fumonisins. It was noted that Alectoria and Usnea are distinguished by a peculiar set of toxic metabolites and occupy an intermediate position according to their number. The similarities and distinctions of the mycotoxin profile in species belonging to the same genus and in specimens from different habitats are discussed. PMID- 26415277 TI - [Effect of Genotype and Medium Culture Content on Microspore-Derived Embryo Formation in Chinese Cabbage (Brassica rapa ssp. chinensis) Cv. Lastochka]. AB - The influence of different factors on microspore embryogenesis in Chinese cabbage (B. rapa ssp. chinensis) was studied. A genotype dependence for embryo formation was observed. The majority of embryos and plants were obtained from microspores isolated from flower buds (2-2.9 mm in length) and cultured in the NLN liquid medium with 13% sucrose (w/v) supplemented with 24-epibrassinolide and 1% activated charcoal. Embryos cultured on the 1/2 Murashige-Skoog culture medium with 2% sucrose (w/v), 0.1 mg/L benzylaminopurine, and 3g/L Phytagel stimulated the formation of secondary embryos that resulted in development of large number of doubled haploid plants. PMID- 26415278 TI - [The Stimulating Effect of Exometabolites of the Marine Microalgae Phaeodactylum tricornutum Bohlin on Reproduction of Listeria monocytogenes]. AB - The biological activity of ethyl acetate extract of exometabolites from the marine microalgae Phaeodactylum tricornutum against a test culture of Listeria monocytogenes 4b has been investigated. It was shown that the stimulating effect of algal exometabolites on the growth of pathogenic bacteria increased maximally by 98.3% on day 6 of the cultivation, if the active substances comprising the culture liquid of P. tricornutum were separated by successive extractions with solvents in order of increasing polarity (hexane, benzene, ethyl acetate), and by 150% on day 3, if the substances from the ethyl acetate extract of exometabolites were separated by column chromatography. It is noted that the fraction of biologically active substances maximally stimulating the growth of L. monocytogenes can be used to prepare an accumulation medium for detecting these patho- genic bacteria in marine environments and hydrobionts. PMID- 26415279 TI - [Biomorphological Features and Microevolution of the Invasive Species Bidens L. in European Russia]. AB - Species of the genus Bidens that have invaded natural communities in Europe were observed. Fourteen species have been introduced in European botanical gardens since the 18th century, but only two of them have become invasive in Russia Bidensfrondosa and B. connata. B.frondosa demonstrates microevolutional ability in the second distribution range. Nevertheless, it has a low ability of hybridization. B. frondosa has higher competitiveness compared with that of B. connata. PMID- 26415280 TI - [Contractile Tone and Contraction as Important Physiological Properties of Terminals on the Processes of Living Neurons]. AB - An attempt to summarize some static morphological renderings of reversible structural alterations of nervous processes, as well as receptor and synaptic terminals, to compare them with the mechanisms of actual transformation of living neurons and to find a common kinetic characteristic for these phenomena has been made. The contractile tone and contraction of processes of living isolated neurons are reported. The dependence of the direction of retraction on the localization of the adhesion site of the isolated cell has been detected. The retraction bulb has been identified as an indicator of all contractions of motor and sensory terminals, both alive and fixed. The process of transformation of growth cones into retraction bulbs has been investigated. The presence of mechanical tension in preterminals and interneuronal contacts has been demonstrated in vitro. Similarity of the kinetics of tissue receptor sensory terminals and growth cones has been detected during in vivo experiments. The kinetics of asynaptic dendrite contraction has been compared to the well characterized structural variability of dendritic spines. The hypothesis of a common origin of the contractile tone of all nervous elements as one of the principal nonelectrophysiological properties of a neuron has been put forward. PMID- 26415281 TI - [Embryonic and Larval Development of the Asian Seabass Lates calcarifer (Pisces: Perciformes: Latidae) under Thermostatically Controlled Conditions]. AB - Material for this study was obtained from the hatchery with brood stock of Lates calcarifer that originated from a natural population living in inshore waters off Central Vietnam. Commercial interest in L. calcarifer as an object of mariculture and wildstock fishery has resulted in several publications on its early life history; nevertheless, comprehensive description of early development of L. calcarifer based on controlled incubation of embryos and larvae has remained absent. In the present paper embryonic and larval development to the stage of anlage of pelvic fins is described in detail and illustrated with original drawings of live material on the basis of thermostatically controlled incubation of embryos at 27 degrees C and larvae at 26.8 degrees C (26.5-28.0 degrees C). The first cleavage furrow appeared at the age of 33.5 min. The duration of synchronous cleavage cycle was 16 min. About 80% of all embryos hatched at the age of 18 h. The length of newly hatched larva during the first hour after emergence from the egg shell was 1.63 +/- 0.016 mm (1.50-1.75 mm). Chronology of development of the organs, early circulatory system, and pigmentation pattern is given. The dynamics of change in the trunk and caudal body segment number in larva from hatching to the moment of anlage of pelvic fins is shown. The total number of body segments reached the maximum value of 26-27 soon after hatching and then decreased to 20-21 segments. Newly received data are discussed in a comparative context of development of some other teleosts. PMID- 26415283 TI - [Parental Care and Testosterone Secretion in Forest Rodent Males: Sensitization and Androgenic Stimulation of Parental Behavior]. AB - The reaction of males of three forest rodent species (Myodes clethrionomys, M. rutilus, Apodemus uralensis) to young animals in comparison with their dimensional characteristics and androgenization level was studied. Demonstration of parental care was detected in males of two vole species (M. clethrionomys and M. rutilus) in case of regular contacts with them (sensitization effect). It was demonstrated that the testosterone concentration in the blood serum, as well as the testosterone content in the testicles of the M. clethrionomys males (demonstrating the parental care), was higher than in the sample of males inclined to infanticide. An increased testosterone content in the testicles and blood serum was also found in the M. rutilus males that had contact with young animas. Neither demonstration of parental care nor significant differences in the testosterone concentration in the testicles and blood serum were detected in the A. uralensis males. PMID- 26415282 TI - [Content of Thyroid and Sex Steroid Hormones in Young-of-the-Year of Black Sea Trout Salmo trutta labrax from Two Spatial Groups for Different Duration of Starvation]. AB - The content of thyroid and sex steroid hormones is determined in fish-farm juveniles of Black Sea trout 5.5 months old, from the bottom and pelagic spatial groups differing in the probability of future selection of the resident or anadromous life strategies, respectively. Differences in the concentration of the aforementioned hormones are found in young-of-the-year corresponding to those in the migratory and resident forms of yearlings of trout. In the juveniles from the pelagic group at the age 0+, the level of triiodothyronine, thyroxine, and testosterone is higher than in specimens from the bottom group. Prolonged starvation results in a higher content of triiodthyronine, thyroxine, and testosterone in the blood of juveniles from both spatial groups. The concentration of estradiol-17beta increases in pelagic specimens and decreases in bottom specimens. PMID- 26415284 TI - [Biological Productivity of the Boguchanskoe Reservoir: Modeling and Prediction]. AB - A dynamic mass-balance model has been presented for the biotic energy flux in the ecosystem of the Boguchanskoe Reservoir (Angara River, Irkutsk oblast). It has been revealed that this model is controlled by the small number of input parameters and is intended for prediction of the biomass and annual production of primary producers, reducers, and consumers from various orders, including fish. The model algorithm has been described. PMID- 26415285 TI - [Morphophysiological and Behavioral Adaptations of Elk to Wintering]. AB - This paper studies morphometric parameters (body weight, weight of internal organs, body size, etc.) in 170 elk of various sex and age obtained in the Vyatka taiga area in winter. A number of physiological parameters (specific metabolism and thermal conductivity, heat loss rate, etc.) characterizing the metabolic rate and energy balance in the body were calculated for model animals (calf, male, and female). It is noted that in the transition from the first to the second half of winter the specific metabolism in model animals decreased from 20.6, 16.9, and 15.9 to 18.7, 15.4, and 14.5 kcal/(kg day), respectively. It is shown that changes in the rhythm of motor activity of elk are synchronized with the daily air temperature and the maximum flight distance depends on the amount of energy received by the body with food. PMID- 26415286 TI - [FUNCTIONAL CONDITION OF KIDNEYS IN NEWBORNS WITH CONGENITAL MALFORMATIONS IN THE PERIOPERATIVE PERIOD]. AB - The article deals with results of the study of functional condition of kidneys in newborns with congenital surgical pathology in the perioperative period. Serum cystatin C and urine beta2-microglobulin were used as a marker of acute kidney injury (AKI). The evaluation of parameters was given in dynamics--before and after surgery, and on 1st, 5th and 10th postoperative day. We analyzed prospects of using these markers in the diagnosis of AKI. PMID- 26415287 TI - [OPTIMIZATION OF EARLY DIAGNOSIS OF ACUTE KIDNEY INJURY IN NEWBORNS IN CRITICAL CONDITION]. AB - Current diagnosis of acute kidney injury (AKI) is one of the most pressing problems in the newborn in critical condition. OBJECTIVE: To determine the diagnostic value of indicators of renal blood flow as a marker of acute kidney injury in critically ill newborns. MATERIALS AND METHODS: The study included 40 infants in critical condition. A clinical assessment of severity of the condition during admission was carried out with Neonatal Multiple Organ Dysfunction Score (NEOMOD) and Neonatal Therapeutic Intervention Scoring System (NTISS). All patients underwent evaluation of clinical and instrumental parameters, including ultrasound of the renal vessels, renal vascular resistance index and speed performance. CONCLUSIONS: 1) biochemical markers used in routine clinical practice were not sufficiently informative for the diagnosis of AKI. 2) For a more accurate assessment of the risk of AKI using serum creatinine, GFR calculation and evaluation on a scale RIFLE it is should be focused on performance standards, appropriate for gestational age and birth weight. 3) Evaluation of blood flow at a particular index in the resistance of the main renal arteries had the greatest predictive value and had a relatively high sensitivity and specificity for the diagnosis of AKI. PMID- 26415289 TI - [THE DIFFICULTY IN DIAGNOSING OF RARE FORMS OF CONGENITAL DISORDERS OF AMINO ACID METABOLISM IN INFANTS (HEREDITARY TYROSINEMIA)]. AB - Diagnosis of amino acid metabolism disorders according to the clinics without laboratory diagnosis is almost impossible in infants with a history of neonatal and/or premorbid background and multi-organ failure. Mortality due to hereditary tyrosinemia type I is greater than 90%. PMID- 26415288 TI - [LABORATORY MARKERS FOR EARLY DIAGNOSIS OF NEONATAL SEPSIS]. AB - Sepsis in neonates still remains difficult issue for clinicians. This review observes literature data about early laboratory diagnosis of neonatal sepsis. The paper considers the latest information about well-known methods of sepsis diagnosis in neonates such as complete blood count, acute phase reactants, cytokine markers, their advantages and disadvantages, as well as statistical value based on different meta-analysis and large multicenter investigations in many countries. We notified the newest methods in sepsis diagnosis such as plasma amyloid A, DAMP molecules, cell surface markers CD64, CD11b, and inter-a inhibitor proteins. The review informs about analysis of genomic and proteomic profile, nucleic acids tools. This data considering for early and late neonatal sepsis and their statistical values: sensitivity, specificity, positive and negative predictive value. PMID- 26415290 TI - [THE USE OF VOLATILE AGENTS FOR SEDATION IN CHILDREN IN THE INTENSIVE CARE UNIT]. AB - Sedation is a controllable level of medication depression of consciousness during which protective reflexes, adequate breathing, and responsiveness to physical stimuli and verbal commands are retained A number of physical and psychological factors affect the psyche of patients in the intensive care unit. Central nervous system (CNS) is a primary target of action of anesthetics and analgesics, and the bi-spectral index reflects the level of sedation of CNS, regardless of what drug caused sedation. The aim of this study was to use volatile anesthetics sevoflurane and isoflurane in children for sedation in the intensive care unit. Constant use of the inhalation route of administration helps to maintain the desired level of sedation depth for the required period of time in patients who are on long-term sedation and is practical for correction. PMID- 26415291 TI - [DETERMINATION OF THE STATE OF MICROCIRCULATION BY MEANS OF COMPUTER CAPILLAROSCOPY IN CHILDREN SEDATED WITH RETENTION OF CONSCIOUSNESS IN OUTPATIENT PEDIATRIC DENTAL TREATMENT]. AB - Dental treatment of infants and pre-school children is challenging because of high rate of dental fear General anesthesia is the only option for behavioral control in this age group. In case of minor medical procedure physical restrain is also used often enough aggravating the fear An alternate method for comfortable treatment is monitored conscious sedation (MCS). Standard techniques of monitoring do not always provide accurate determination of stress level in children since the external stress manifestations may appear non-significant and unobtrusive. Computer capillaroscopy (CC) allows real time evaluation of early functional disorders at the microlevel and of anesthesia efficiency in vivo. OBJECTIVE AND METHODS: The research involved 298 children. 256 of them were treated under MCS and 42 constituted reference group treated without MCS. The groups were also divided into subgroups according to age: 0-3 and 3-6 year olds. Therapeutic and surgical treatment features were analyzed separately. MCS was conducted by means of intramuscular injection of midazolam in dosages of 0.1, 0.15, and 0.2 mg per kg. BIS, arterial blood pressure, heart rate, respiratory rate, and SpO2 were monitored at 4 stages while the following microcirculation parameters were recorded by CC: density of capillary net, the size of arterial, venous and transitional microcirculation links (ML), linear and volume bloodflow velocity, perfusion balance. The obtained data were statistically processed and analyzed with the use of Statistica Stat Soft 8.0 software. CONCLUSIONS: Children undergoing dental treatment without MCS are affected by stress. The degree of stress in surgical patients was noted to be significantly higher The absence of physiological parameters changes in children treated without MSC is not a proof of the absence of stress. The dose of 0.15 mg per kg is optimal for the comfortable level of MSC. The increase of midazolam-dose over 0.15 mg per kg is not associated with further reduction of stress. The obtained data is true for both age categories. PMID- 26415292 TI - [THE EXPERIENCE OF ANAESTHESIA MANAGEMENT FOR SENSING OF NASOLACRIMAL DUCT IN CHILDREN]. AB - Despite low invasiveness, lacrimal passages, intubation in children requires general anaesthesia to prevent traumatic and neurological complications. General anaesthesia with sevoflurane is optimal for technical simplicity, safety and controllability. Methods of face mask inhalation anesthesia with halothan and sevoflurane were compared in 996 patients. The authors have developed their own standart of performing the face mask inhalation anesthesia with sevoflurane in children during lacrimal passages intubation. This allowed to minimize the number of intra- and postoperative complications in children, to reduce period of postanesthetic observation, to advance the peroral compensation of fluid deficit. PMID- 26415293 TI - [PERIOPERATIVE MANAGEMENT IN PATIENTS WITH DISEASES OF THE CARDIOVASGULAR Yb I am IN NON-CARDIAC SURGERY (Commentary on the new European guidelines "Non-cardiac surgery: evaluation and management of cardiovascular system")]. AB - New guidelines for the perioperative management of patients with concomitant diseases of the cardiovascular system (CVS) have been published in the beginning of 2014. The guidelines were the result of joint work of the Board of experts of the European society of cardiology (ESC) and European society of anaesthesiology (ESA). Recommendations ESC/ESA-2014 thoroughly and accurately determine the algorithm of actions of the anaesthesiologist in the process of preparation and conduct of anesthesia and intensive therapy in the early postoperative period in accordance with the modern level of development of our specialty. No doubt they will be useful to all professionals involved in the process of providing medical care to patients in non-cardiac surgery with concomitant diseases of the cardiovascular system. This article, however, does not purport to be a complete summary of the cited document; it only contains, its own commentary on those provisions which are in the author's opinion the most significant and interesting. PMID- 26415294 TI - [EFFICACY AND SAFETY OF ROCURONIUM BROMIDE PRODUCED IN THE RUSSIAN FEDERATION: A SINGLE-BLIND RANDOMIZED CLINICAL TRIAL]. AB - DESIGN: A single-blind comparative prospective randomised clinical trial. OBJECTIVE: To evaluate the efficacy and safety of Russian muscular relaxant (Kruarone) in comparison with Esmerone in multicomponent balanced anesthesia during laparoscopic cholecystectomy. 80 patients (23-68 years old) were examined. The patients were randomized into two equal groups. The results showed that Kruarone was effective relaxant with rapid onset of action, providing optimal conditions for muscle relaxation for laryngoscopy and tracheal intubation. Kruarone did not require frequent administration supports, providing high quality and stable neuromuscular blockade during surgery. There was no any one case of adverse events for the entire period of 24-hour surveillance, the drug has no cumulative effect. Kruarone did not cause allergic reactions and had no significant effect on hemodynamics. Thus Kruarone 0.6 mg/kg with an average total flow rate of the drug within 55 mg (39.6-75.43 mg) has the same effectiveness and safety with Esmerone in similar dosages. PMID- 26415295 TI - [MONITORING OF INTRACRANIAL PRESSURE IN PATIENTS WITH MASSIVE ISCHEMIC STROKE]. AB - PURPOSE OF THE STUDY: To assess the role of monitoring of intracranial pressure (ICP) in patients with massive ischemic stroke within the first 5 days of the onset of the disease. MATERIAL AND METHODS: We have analyzed the results of monitoring of intracranial pressure in 10 patients with massive ischemic stroke and compared dynamics of ICP with the dynamics of intracranial pressure and the level of consciousness and dislocation of the brain according to CT RESULTS: Dislocation syndrome decompensation occurred in 6 patients, of which only 3 patients had increased intracranial pressure greater than 20 mm Hg with oppression of the level of consciousness to moderate coma and deeper The average value of transverse dislocation in these patients at the same time amounted to 17 mm. In 2 patients with atrophy of the brain we observed ICP increase over 20 mmHg. The average value of transverse dislocation in these patients was 12 mm. Conclusion: Increased intracranial pressure greater than 20 mm Hg in patients with massive ischemic stroke can occur even when the oppression of the level of consciousness to moderate coma and deeper on the background of the dislocation of the brain. In case of an atrophy of the brain, the level of ICP may not exceed 20 mm Hg even with dislocation syndrome decompensation. PMID- 26415296 TI - [MONITORING OF CEREBRAL OXYGENATION AND COGNITIVE FUNCTION IN CAROTID ENDARTERECTOMY: THE ROLE OF TRANSIENT BYPASS OF CAROTID ARTERY]. AB - BACKGROUND AND OBJECTVE: Carotid endarterectomy (CEE) is an effective surgical technique to prevent cerebral ischemia and stroke, but can be associated with intervention-related complications. The surgical shunting of the intervention area may reduce the risk of the intraoperative ipsilateral cerebral ischemia following the carotid artery clamping but is controversial. The goal of this study was to compare the cerebral tissue oxygen saturation (SctO2) and early changes of cognitive functions in CEE in the settings of transient vascular bypass and without this method. METHODS: 45 adult patients were randomized to either the bypass group (the Bypass group, n = 24) or the Controls / No Bypass (the Control group, n = 21). All patients were monitored for invasive arterial pressure, SpO, EtCO,, and cerebral oxygenation (SctO2, Fore-Sight, CASMED, USA) over the contra- and ipsilateral frontal head areas. The cognitive functions were assessed using series of Montreal Cognitive Assessment score (MoCA) before the intervention, and on 6 and 36 hrs after the CEE. RESULTS: We did not find intergroup differences in the surgery duration, degree of stenosis and baseline cognitive function. The values of SctO2 reduced significantly only above contralateral side; these changes were attenuated in the shunt group. There were no intergroup differences in postoperative cognitive function. CONCLUSION: Empiric transient vascular bypass during carotid endarterectomy did not result in significant changes of the ipsilateral cerebral oxygenation, hyperperfusion and cognitive function, but attenuated the decrease of SctO2 over the contralateral hemisphere. PMID- 26415297 TI - [M1-OPIOID RECEPTOR AND CATECHOL-O-METILTRANSFERASE GENES POLYMORPHISM EFFECTS ON PERIOPERATIVE PSYCHOLOGICAL CONDITION OF THE PATIENTS AND THE EFFECTIVENESS OF POSTOPERATIVE ANALGESIA WITH OPIOIDS]. AB - OBJECTIVE: To evaluate the influence of ul-opioid receptor (OPRM1) 118A>G and catechol-O-methyltransferase (COMT) 1947G>A gene single nucleotide polymorphisms (SNP) combinations on postoperative opioid analgesia (POA) efficacy. MATERIAL AND METHODS: In 100 consecutive patients scheduled for major urologic surgeries the SNPs of OPRM1 118A>G and COMT 1947G>A (real-time PCR), preoperative anxiety and depression level (HADS scale), POA efficacy ("Pain Out" questionnaire) have been assessed. RESULTS: Preoperative anxiety and depression, additional analgesia requirements, severity of nausea, drowsiness and incidence of vomiting were higher in OPRM1 118G allele carriers. Maximum pain intensity and pain-related restriction of mobility on first postoperative day were lower in homozygous carriers of COMT 1947A. The best response to POA in view of preoperative anxiety, analgesia efficacy and severity of nausea has been revealed in carriers of combination COMT-OPRM1 AA-AA. CONCLUSIONS: SNPs of OPRM1 118A>G and COMT 1947G>A affect the preoperative patients psychological status and POA efficacy. PMID- 26415298 TI - [ORDER OF THE RUSSIAN FEDERAL SERVICE ON SURVEILLANCE IN HEALTHCARE]. PMID- 26415299 TI - [CRITERIA FOR THE QUALITY OF RESEARCH AND PUBLICATIONS IN MODERN ANAESTHESIOLOGY]. PMID- 26415300 TI - [EXPERIENCE OF TRAINING AT THE ANESTHESIOLOGY DEPARTMENT OF THE SECOND AFFILIATED HOSPITAL OF HARBIN MEDICAL UNIVERSITY (HARBIN, CHINA)]. AB - The article deals with an experience of short term training at the anaesthesiology department of the Second Affiliated Hospital of Harbin Medical University The author (graduate student of the Sechenov First Moscow State Medical University) describes a structure of the operating unit, techniques of anaesthesia for thoracic surgery, and organization of training and clinical practice of Anaesthesiologists in China. PMID- 26415301 TI - [OPTIMIZATION OF PRECLINICAL TRAINING OF ANAESTHESIOLOGISTS BASED ON THE FORMATION OF PATHOGENIC SIMULATION LEARNING ENVIRONMENTS]. AB - Simulation training has become an important component of the postgraduate training of anaesthesiologists for several reasons: organizational difficulties in obtaining primary professional skills in a clinical setting, the opportunity to study in a hospital existing pathology only and not planned in accordance with the curriculum. This increases the risk of medical malpractice of young specialist and study may be accompanied by complications and increasing the cost of treatment. In our work, we have studied the factors of continuity of preclinical and clinical stages of anaesthesiologists training in inhalation anaesthesia based on the use of modern simulation technologies. We compared the training programs and the results of traditional and simulation techniques, defined the concept of quasi physiology and propedeutics of robots and simulators, the role of clinical scenarios and reliability of robots of 6th level of realism in the formation of pathogenic environment for simulation training. In formulating the concept of pathogenetic simulation environment, we evaluated its impact on the motivation of the trainees of studied category. The study included 23 interns, divided approximately in half into 2 groups, the 1st of which at the preclinical stage of training was trained at the real operating theater gradually studying the technique of inhalation anaesthesia with an experienced curator The 2nd group studied the same anaesthesia in clinical scenarios of a simulator robot in a simulation operating theater Other components of the curriculum in the groups did not differ. According to the results of pre-clinical training interns started prforming an anaesthesia their self under the control of supervisor (i.e. to the clinical stage). In the 1st group, a supervisor made the verdict of readiness for clinical stage, and in the 2nd trainees were tested by the performing a robotic anaesthesia maintaining targeted qualitative and quantitative parameters. The evaluation was conducted according to the quality and stability criteria of five consecutive "independent" anaesthesia, where the highest scores were 100 points, confered by a supervisor. We found that for interns' admission to the clinical stage in the 1st group, it took significantly more educational anaesthesia than in 2nd group. It was also indirectly proved expectedly greater regularity and predictability of anesthesia simulation workshops. Based on the example of the clinical scenario of inhalation anesthesia we showed a possibility of formation of pathogenic simulation environment without excessive dramatization of studing environment, while maintaining the motivation of trainees. Thus, simulation training is more efficient than traditional schemes, in terms of providing the rational use of robotic systems of 6th level of realism. PMID- 26415302 TI - [EPIDURAL ANALGESIA FOR INTRAOPERATIVE AND POSTOPERATIVE CARE IN NEWBORNS]. AB - Anesthesia care in newborns has to be complex, balanced and safe. Nowadays epidural analgesia (EA) in neonates during intra- and postoperative period is widely used in Russia. Modern EA techniques imply the installation of a catheter into epidural space at lumbar or thoracic level as well as different approach to local anesthetics dosage. Newborns have special anatomy, physiology and pharmacodynamics which have to be taken in mind when EA is used. At the present moment Ropivacine (2 mg/ml) is approved for peripheral nerve blocks in newborns. PMID- 26415303 TI - [INTRATHECAL OPIOID ANALGESIA - STATE IN THE WORLD AND IN THE RUSSIAN FEDERATION]. AB - Intrathecal opioid analgesia has been used in clinic practice since 1979 and has gained a great popularity till now due to its high analgesic potency Unfortunately it is impossible to use opioids intrathecally in Russian Federation by law because of nowadays official limitations. Russian national anaesthesiologic society should comprehend benefits and side effects of this method and make a decision if it is worth fighting for. PMID- 26415304 TI - [Congratulations to Prof. Nedashkovsky]. PMID- 26415305 TI - [Congratulations to Prof. Yevdokimov]. PMID- 26415306 TI - [In memory of Professor Victor Mizikov]. PMID- 26415307 TI - DRAWING SKILLS IN CHILDREN WITH NEURODEVELOPMENTAL DELAY AGED 2-5 YEARS. AB - In typically developing children, drawing development occurs in stages from uncontrolled strokes to complex drawing. In this study, we examined drawing development in children with neurodevelopmental delay (NDD). In order to do so, we observed the influence of age, intraventricular hemorrhage (IVH) and gender on the development of drawing skills. The sample consisted of 52 children with NDD, aged 2 years and 6 months to 5 years. All children were hospitalized for multidisciplinary team monitoring and developmental support. The evaluation of drawing development was administered by giving each child a blank A4 paper and the instruction to draw anything they wanted. All of the drawings were scored satisfactory or unsatisfactory. Descriptive statistics was employed on all relevant data to show results in frequencies and percentages. In order to determine differences between groups, the chi2-test was administered. The results showed greatest difference in drawing in children aged from 3 years to 3 years and 11 months. Children with lower IVH had better drawing scores than children with higher IVH levels. According to gender dissimilarities, a difference was found showing girls to have better drawing skills than boys. All study results pointed to the importance of early rehabilitation and continuous structured work with children with NDD. PMID- 26415308 TI - MICROBIAL PROFILE AND ANTIBIOTIC SUSCEPTIBILITY PATTERNS OF PATHOGENS CAUSING VENTILATOR- ASSOCIATED PNEUMONIA AT INTENSIVE CARE UNIT, SESTRE MILOSRDNICE UNIVERSITY HOSPITAL CENTER, ZAGREB, CROATIA. AB - Ventilator-associated pneumonia (VAP) is very common in many intensive care Units, but there are still many uncertainties about VAP, especially about the choice of initial empiric antibiotics. The incidence of specific pathogens with different susceptibility patterns causing VAP varies from hospital to hospital. This is the reason why empiric initial antibiotic treatment for VAP should be based not only on general guidelines (that recommend therapy according to the presence of risk factors for multidrug-resistant bacteria), but also on up-to date information on local epidemiology. The aim of this study was to determine the microbial profile of pathogens causing VAP and their antibiotic susceptibility patterns. The study was conducted in the 15-bed surgical and neurosurgical Intensive Care Unit, Department of Anesthesiology and Intensive Care, Sestre milosrdnice University Hospital Center, Zagreb, Croatia. Retrospective data were collected from September 2009 to March 2013. All patients that developed VAP during the study period were eligible for the study. According to study results, the incidence of VAP was 29.4%. The most commonly isolated bacterium was Staphylococcus aureus (21.1%), followed by Pseudomonas aeruginosa (19.0%) and Acinetobacter species (13.6%). All Staphylococcus aureus isolates were susceptible to vancomycin and linezolid. Pseudomonas aeruginosa showed 100% susceptibility to cefepime and very high susceptibility to pip'eracillin tazobactam (96%), ceftazidime (93%) and ciprofloxacin (89%). Ampicillin-sulbactam was highly effective for Acinetobacter species, showing resistance in only 8% of isolates. In conclusion, according to study data, appropriate empiric antibiotic therapy for patients with VAP without risk factors for multidrug-resistant bacteria is ceftriaxone and for patients with risk factors for multidrug resistant bacteria ampicillin-sulbactam plus cefepime plus vancomycin or linezolid. PMID- 26415309 TI - ULTRASOUND GUIDED FOAM SCLEROTHERAPY - THE SIMPLEST, LEAST INVASIVE, AND CHEAPEST METHOD FOR VARICOSE VEIN TREATMENT. AB - The aim is to present our experience and observations regarding varicose vein treatment by means of ultrasound guided foam sclerotherapy (UGFS). The study included 81 patients, 54 with insufficient main stem superficial veins in one limb and 27 with both limbs affected. Great saphenous vein insufficiency was diagnosed in 68, small saphenous insufficiency in 18, anterior accessory saphenous vein insufficiency in 11, and Giacomini vein insufficiency in 3 limbs. Seven limbs had combined insufficiency of great saphenous vein and small saphenous vein, and 1 limb had combined insufficiency of Giacomini vein and small saphenous vein. UGFS was employed to treat main stem vein reflux and their tributaries. Within a month after treatment, all main stem veins were occluded and only small corrections were performed occasionally to treat residual varices. Regarding side effects, skin darkening and hard lumps at the sites of varicose veins were most commonly observed. We also recorded several episodes of thrombophlebitis. Few patients experienced dry cough, visual disturbances and headache following the treatment. After six months, repeat UGFS of main stem veins had to be performed in few patients. Very few patients expressed dissatisfaction a year after treatment, mainly because of residual skin darkening. In conclusion, UGFS proved to be the simplest, quickest and cheapest method of varicose vein treatment. According to our experience, it yielded satisfactory functional and cosmetic results. Side effects do occur, but are acceptable, in particular at long term. PMID- 26415310 TI - CORRELATION BETWEEN MAMMOGRAPHY DETECTED BREAST ARTERIAL CALCIFICATIONS AND LIFESTYLE RISK FACTORS. AB - The aim of the study was to investigate the association between some lifestyle attributable risk factors of atherosclerosis, such as body mass index (BMI), oral contraceptives, hormone replacement therapy, smoking and alcohol consumption with breast arterial calcification (BAC) and its intensity on mammograms, and to assess the impact of these lifestyle risk factors on mammography findings of BAC. This prospective study included 300 women aged 47-69, i.e. a group of 149 women with BAC on mammograms and control group of 151 women without BAC. Self-reported BMI, use of oral contraceptives, hormone replacement therapy, smoking and alcohol consumption were recorded by medical interview. The presence of BAC and its intensity on mammography was compared according to the presence of high BMI and use of hormone therapy, smoking and alcohol consumption. The results showed the highest proportion of smokers (28.9%) in the group with mild BAC as compared with the groups without calcification (14.6%) and with intense calcification (12.1%). Women taking oral contraceptives had a higher level of calcified breast arteries but no significant between-group difference was found for high BMI, hormone therapy and alcohol consumption. Thus, study results showed the mammographic finding of BAC to be inadequate to identify women with some lifestyle attributable risk factors such as BMI, hormone replacement therapy, smoking and alcohol consumption. PMID- 26415311 TI - PSEUDOBULBAR AFFECT IN MULTIPLE SCLEROSIS PATIENTS. AB - The aim of the study was to determine the prevalence of pseudobulbar affect (PBA) in patients with multiple sclerosis (MS) and to analyze the link between PBA and patient age, sex, clinical course of MS, disease duration and degree of disability. The study was conducted on 79 MS patients that underwent inpatient rehabilitation at the Lipik Special Hospital for Medical Rehabilitation in the period from August 15, 2014 to February 15, 2015. PBA is a term used for an emotional disinhibition syndrome characterized by sudden and involuntary episodes of crying or laughing which are not in proportion to the stimulus applied or occur without stimulus. The condition can be present in patients with various neurological disorders, such as amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, patients having recovered from stroke, or following traumatic brain injury. The estimated prevalence in patients with MS ranges from 10% to 46.2%. As a measuring instrument in the study, we used the Center for Neurologic Study-Lability Scale (CNS-LS), where a sum 17 denoted positive finding. The total number of respondents was 79, of which 33 (41.8%) met the CNS LS criteria for the diagnosis of PBA. There was no statistically significant correlation between PBA, age and degree of disability, although PBA was more common in women and in patients with a secondary progressive form of the disease. We found that 42.4% of respondents with positive CNS-LS criteria for PBA did not inform their neurologist on the presence of sudden mood changes. The high frequency of PBA and the fact that a significant proportion of patients did not inform the neurologist on their affective disturbances call for an active approach to diagnosis and treatment. PMID- 26415312 TI - BMP-7 PROTEIN EXPRESSION IS DOWNREGULATED IN HUMAN DIABETIC NEPHROPATHY. AB - Bone morphogenetic protein-7 (BMP-7) is expressed in all parts of the normal kidney parenchyma, being highest in the epithelium of proximal tubules. It protects kidney against acute and chronic injury, inflammation and fibrosis. Diabetic nephropathy is the leading cause of chronic kidney disease, and is characterized by decreased expression of BMP-7. The aim of our study was to analyze whether the expression of BMP-7 is significantly changed in advanced stages of human diabetic nephropathy. Immunohistochemical analysis of the expression of BMP-7 was performed on archival material of 30 patients that underwent renal biopsy and had confirmed diagnosis of diabetic nephropathy. Results showed that BMP-7 was differently expressed in the cytoplasm of epithelial cells of proximal tubules and podocytes among all stages of diabetic nephropathy. At early stages of diabetic nephropathy, BMP-7 was strongly positive in proximal tubules and podocytes, while low expression was recorded in the majority of samples at advanced stages. In conclusion, increased expression of BMP-7 at initial stages of diabetic nephropathy with subsequent decrease at advanced stage highlights the role of BMP-7 in the protection of kidney structure and function. Further investigations should be focused on disturbances of BMP-7 receptors and signaling pathways in patients with diabetic nephropathy. PMID- 26415313 TI - IMPROVEMENT OF COGNITIVE EFFICIENCY THROUGH COGNITIVE TRAINING IN HEALTHY SUBJECTS. AB - The aim of the study was to explore whether application of cognitive stimulation in young healthy subjects may improve their cognitive efficiency. The study included 12 healthy young subjects divided into two groups, experimental group and control group. Prior to cognitive stimulation treatment, both groups underwent baseline measurements with selected neuropsychological tests. The groups were matched with regard to the achievement on the baseline test. Only the experimental group underwent daily application of different computer-based cognitive tasks lasting for an hour a day for two weeks. After the treatment, both groups were tested with the same neuropsychological battery used at the baseline measurement. The experimental group showed a statistically significant difference between the measurements on the variables assessing immediate retention of visual material and recognition of verbal material. In addition, qualitative analysis showed that the experimental group also had better performance on the variables assessing delayed recall of visual material, visual and verbal range of attention, and delayed recall of verbal material. In conclusion, two-week cognitive stimulation in healthy subjects improves cognitive performance, expressed as higher average values of certain neuropsychological variables. PMID- 26415314 TI - PERIORAL DERMATITIS: STILL A THERAPEUTIC CHALLENGE. AB - Perioral dermatitis is a common and often chronic dermatosis. In its classic form, it primarily affects women aged 15 to 45 years, but there are also variants including lupus-like and granulomatous perioral dermatitis, where granulomatous form is more common in childhood and affects mostly prepubescent boys. The etiopathogenesis of the disease remains unclear, but there is a frequent finding of prolonged use of topical products, especially corticosteroids, in the treatment of rosacea and seborrheic dermatitis, preceding the clinical manifestation of perioral dermatitis. Other causes important for the occurrence of the disease include various skin irritants, as well as other physical and hormonal factors, which all share the epidermal barrier dysfunction as an underlying main pathogenic factor. Clinical presentation of papulovesicular eruption in the perioral region with a typical narrow spared zone around the edge of the lips is characteristic. Therapeutic approach should be individually addressed, depending on the severity of clinical presentation and patient's age, with special attention to patient's education and continuous psychological support. In mild forms of perioral dermatitis, 'zero therapy' is the treatment of choice. In the initial treatment period, patients with steroid-induced perioral dermatitis should be closely followed up because the rebound phenomenon usually develops after cessation of previous topical treatment. In moderate disease, treatment includes topical metronidazole, erythromycin, and pimecrolimus, whereas in more severe cases the best validated choice is oral tetracycline in a subantimicrobial dose until complete remission is achieved. Systemic isotretinoin should be considered as a therapeutic option for patients refractory to all standard therapies. PMID- 26415315 TI - THE RISK OF HYPERCOAGULABILITY IN OVARIAN HYPERSTIMULATION SYNDROME. AB - Ovarian hyperstimulation syndrome (OHSS) is a rare and potentially life threatening complication of infertility treatment occurring during either the luteal phase or early pregnancy. An increasing number of thromboembolic complications associated with the increased use of assisted reproductive techniques have been reported in the literature. Identification of the risk factors is crucial for prevention of thromboembolic events in OHSS patients. Alterations in the hemostatic system cause hypercoagulability in women affected by severe OHSS. Coexistence of inherited hypercoagulable conditions increases the risk of thromboembolism. The role of clinical parameters that can help predict development of thrombosis is controversial. Patients with a personal or family history of thrombosis undergoing infertility treatment should be considered for thrombophilia screening, while routine examination of inherited thrombophilic mutations is not indicated in infertile patients. Antithrombotic primary prevention is not indicated in healthy women undergoing assisted reproductive procedures or in women with thrombophilia. Anticoagulant therapy is indicted if there is clinical evidence of thrombosis or laboratory evidence of hypercoagulability. In this review, the risks of hypercoagulability in the OHSS are discussed. PMID- 26415316 TI - PARTIAL TOPOGRAPHY-GUIDED PHOTOREFRACTIVE KERATECTOMY FOLLOWED BY CORNEAL CROSS LINKING IN THE MANAGEMENT OF PROGRESSIVE KERATOCONUS: OUR INITIAL TEN-MONTH RESULTS. AB - The aim was to assess the results achieved in keratoconic corneas submitted to the combined partial topography-guided photorefractive keratectomy (TG-PRK) and corneal cross linking (CXL) procedure performed on the same day. Four patients underwent this treatment of one eye. Corneal epithelium removal was performed by 50-micron phototherapeutic keratectomy. Then, partial TG-PRK laser treatment was applied (Wavelight Allegretto, Eye Q, 400Hz), followed by corneal collagen cross linking (CXL, 3 mW/cm2) for 30 minutes using 0.1% topical riboflavin solution. Outcome measurements included uncorrected distance visual acuity (UCDVA), best spectacle corrected distance visual acuity (BSCDVA), manifest refraction spherical equivalent, keratometry, corneal high order aberration values, and corneal tomography. At the end of 10-month follow up, all eyes showed improvement in BSCDVA of 1-5 lines on Snellen chart. All other investigated parameters showed significant improvement as well. One eye showed some topographic improvement, but no improvement in UCDVA. No corneal haze, prolonged epithelial healing or endothelial cell loss occurred. During 10-month follow up, the same-day combined TG-PRK and CXL appeared to offer tomographic improvement and better visual acuity in keratoconus patients. PMID- 26415317 TI - MAJOR ANATOMIC VARIATIONS OF PULMONARY FISSURES AND LOBES ON POSTMORTEM EXAMINATION. AB - This study was aimed at determining major accessory fissures (MAF) and absence or incompleteness of lobar or major fissures (MF) during routine forensic autopsies. Prior to starting this prospective study, forms were prepared to collect data on pulmonary lobes and fissures. In this study, 420 lungs of 210 autopsy cases were examined for incompleteness and absence of MF and complete accessory fissures. Horizontal fissures were incomplete in 18 right lungs. Incomplete oblique fissures were noted in three right and two left lungs. Unidentified abnormal fissures were determined in one left lung and five right lungs. The most common fissural abnormality was less than half complete horizontal fissure. Four right lungs had four lobes and two left lungs had three lobes because of complete accessory fissures. The number of lobes in the left and right lungs and the morphological features of both incomplete MF and MAF were determined in detail and the variations were photographed. It is concluded that, in addition to studies on computed tomography scans, autopsy series are useful for determining the variations of MF and MAF of the lungs in different populations. PMID- 26415318 TI - ADVERSE DRUG REACTIONS IN THE ORAL CAVITY. AB - Every medication may lead to adverse effects, even when used in standard doses and mode of application. In the oral cavity, adverse effects may affect every part of oral mucosa and are the result of medications taken either locally or systemically. Oral adverse reactions to drugs are not typical and therefore sometimes not easy to recognize. On diagnosing adverse side effects in the oral cavity, experienced clinician will usually diagnose the condition on the basis of detailed medical history and clinical finding. However, the only objective evidence for the offending drug is 're-challenge', i.e. exposure to the drug after its discontinuation. It carries a huge risk of anaphylactic reaction; therefore it has to be performed in a controlled hospital setting. Therapy is based on immediate exclusion of the offending drug and, if lesions are present in the oral cavity, topical or systemic corticosteroid therapy is prescribed. This article gives a review of patients with oral adverse drug reactions referred to the Department of Oral Medicine in Zagreb. PMID- 26415319 TI - TIBIAL TUBERCLE AVULSION FRACTURE IN A MALE ADOLESCENT. AB - Tibial tuberosity fractures are rare in childhood, most frequently due to excessive quadriceps muscle contraction. On performing long jump, a 15-year-old boy sustained tibial tuberosity avulsion fracture type II according to Watson Jones. The patient was treated operatively with fragment repositioning and screw fixation. Ten months after the injury and rehabilitation, he resumed his sports activities with full range knee motion. PMID- 26415320 TI - GIANT AGGRESSIVE ANGIOMYXOMA OF THE VULVA: CASE REPORT. AB - A 57-year-old multiparous housewife was hospitalized at University Clinical Center with painless, ulcerated, huge tumor of the vulva, which had progressively increased in size during the last five years. It was a firm, ulcerated mass involving the left vulva and measuring 35 cm in diameter. The vaginal orifice was deviated to the right by the tumor. The adnexa and the uterus were normal. The patient underwent total excision of the tumor in general anesthesia, and histology confirmed aggressive angiomyxoma. She had an uneventful postoperative period with satisfactory healing of the wound. PMID- 26415321 TI - RENAL CELL CARCINOMA METASTASIS TO THE SINONASAL CAVITY: CASE REPORT. AB - Renal cell carcinoma accounts for 3% of all adult malignant tumors. Common sites of metastases are lungs, bone, liver, brain and adrenal glands. Metastatic disease to the head and neck ranges from 15% to 30%. The 5-year survival rate after nephrectomy is 60%-75%, but with multiorgan metastases the 5-year survival rate is significantly lower, 0-7%. A case is presented of a female patient diagnosed with renal cell carcinoma metastases to the paranasal sinuses, diagnosed and treated at the Department of ENT and Head and Neck Surgery, Zadar General Hospital, Zadar, Croatia. The tumor was surgically removed. Unfortunately, the patient died one year after the procedure due to multiorgan failure. Although metastases of renal cell carcinoma to the head and neck are very rare, it should be first suspected when investigating a metastatic tumor in this region. Surgical excision offers the best hope for long term survival. In case of unresectable tumor, other treatment options should be considered such as radiotherapy, immunotherapy and chemotherapy. PMID- 26415322 TI - DYSPHONIA AS AN UNCOMMON PRESENTATION OF PONTOCEREBELLAR CHOROID PLEXUS PAPILLOMA. AB - A case is presented of a patient with dysphonia, hearing loss and ataxia due to vestibulocochlear and vagal nerve compression by choroid plexus papilloma in the cerebellopontine angle. Choroid plexus papillomas are rare tumors usually arising in the lateral and fourth ventricle, and rarely found in the cerebellopontine angle, making the neuroimaging characteristics usually not sufficient for diagnosis. Patients usually present with headache and hydrocephalus but tumors in the cerebellopontine angle can cause vestibulocochlear dysfunction and cerebellar symptoms. Dysphonia along with hearing loss was a dominant symptom in the case presented. After complete surgical removal of the tumor, deterioration of dysphonia was noticed; it could be explained as peripheral vagal nerve neuropathy due to tumor compression and intraoperative manipulation. In this case report, we describe dysphonia as an uncommon presentation of a rare posterior fossa tumor. To our knowledge, a case of choroid plexus papilloma presenting with dysphonia has not been described before. Our case extends the differential diagnosis of dysphonia from the otorhinolaryngological to the neurosurgical field. PMID- 26415323 TI - COEXISTENCE OF ADDISON'S DISEASE AND PERNICIOUS ANEMIA: IS THE NEW CLASSIFICATION OF AUTOIMMUNE POLYGLANDULAR SYNDROME APPROPRIATE? AB - A case of autoimmune polyglandular syndrome (APS) is presented. A 45-year-old man was admitted due to fatigue, malaise and inappetence. He had a history of primary hypothyroidism and was on levothyroxine substitution therapy. One year before, he was diagnosed with normocytic anemia and vitamin B12 deficiency, which was treated with vitamin B12 substitution therapy. Physical examination revealed hypotension and marked hyperpigmentation. Laboratory testing showed hyponatremia, hyperkaliemia and severe normocytic anemia. Endocrinological evaluation disclosed low morning cortisol and increased adrenocorticotropic hormone levels. Hence, the diagnosis of Addison's disease was established. Additional laboratory workup showed positive parietal cell antibodies. However, his vitamin B12 levels were increased due to vitamin B12 supplementation therapy, which was initiated earlier. Gastroscopy and histopathology of gastric mucosa confirmed atrophic gastritis. Based on prior low serum vitamin B12 levels, positive parietal cell antibodies and atrophic gastritis, the patient was diagnosed with pernicious anemia. Hydrocortisone supplementation therapy was administered and titrated according to urinary-free cortisol levels. Electrolyte disbalance and red blood cell count were normalized. This case report demonstrates rather unique features of pernicious anemia in a patient with Addison's disease. It also highlights the link between type II and type III APS. Not only do they share the same etiological factors, but also overlap in pathophysiological and clinical characteristics. This case report favors older classification of APS, which consolidates all endocrine and other organ-specific autoimmune diseases into one category. This is important since it might help avoid pitfalls in the diagnosis and treatment of patients with APS. PMID- 26415324 TI - JAK INHIBITOR CLINICAL RESPONSE IN POLYARTHRITIS: CASE REPORT. AB - The heterogeneity of rheumatoid arthritis (RA) presentation and molecular signature of RA subclasses in patients with early changes of small peripheral joints still remains a challenging problem. In clinical setting, classification of the disease subtypes is not possible and treatment adjustment is based on the continuous Disease Activity Score for disease severity recognition. A new approach in the treatment appears with the novel non biologic targeted synthetic disease-modifying antirheumatic drugs from the group of Janus kinase 1 and 3 (JAKI and JAK3), blocking interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21. We report a case of a 48-year-old patient who had suffered from polyarthritis from his age 40. Initial laboratory tests showed low inflammatory parameters and magnetic resonance imaging of both hands indicated an early stage of RA. Methylprednisolone and methotrexate therapy was initiated. The patient underwent additional tests, but there was not sufficient evidence for a precise diagnosis. According to the European League Against Rheumatism/American College of Rheumatology score-based algorithm, the patient was classified as seronegative RA based on joint involvement, duration of the disease, and synovitis not better explained by another disease. A partial clinical effect of the administered therapy (steroids as monotherapy and in combination, methotrexate and leflunomide) was noticed with the use of systemic steroids, but dramatic improvement was only achieved with a JAK inhibitor targeted therapy. Although the use of anti TNF-alpha blocker is a proposed procedure and the drug has not yet been registered in Europe, we took the opportunity to apply this new medication option. The patient, a construction worker, was treated for 20 months, which led to complete remission of the disease, without the need of basic or corticosteroid therapy. Full functional capacity necessary in his demanding job was also achieved. This result raised a question of timely introduction of immunomodulators in the polyarthritis treatment steps. PMID- 26415325 TI - INITIAL SYMPTOMATIC PITUITARY METASTASIS IN A PATIENT WITH PROSTATE FOAMY GLAND CARCINOMA: TAILORING SAFE AND EFFECTIVE THERAPY. AB - Metastases to pituitary gland are unusual and mostly asymptomatic, presenting with local symptoms in one of ten patients, and only 3%-5% of them are of prostate origin. Here we report and evaluate the effectiveness and safety of multimodal treatment in a patient with pituitary metastasis of a prostate foamy gland carcinoma. A 78-year-old male patient presented with blurred vision and headache without a previous history of malignancy. Magnetic resonance imaging scans revealed a large sellar mass, with infiltration of the surrounding structures. Maximal transsphenoidal reduction of pituitary metastasis was performed, with a histologic finding of metastatic prostate foamy gland adenocarcinoma. Evaluation of the prostate specific antigen revealed a very high level (1461 ng/mL) and foamy gland carcinoma was found on prostate needle biopsy. The patient received 3D conformal external beam radiotherapy with 6 MV photons to the sellar and parasellar region with a tumor dose of 44 Gy, followed by androgen deprivation therapy. Follow up magnetic resonance imaging done after radiotherapy showed shrinkage of the tumor process, with rapid prostate specific antigen decline to 0.3 ng/mL. The visual function was fully established and headache resolved. On the last follow up 14 months after the diagnosis, the patient was alive and free from clinical signs of disease. Tailored treatment, including limited radiotherapy in a higher palliative dose, in a patient with foamy gland symptomatic pituitary metastatic disease resulted in good local and systemic control of the disease. In older male patients with clinical and/or radiologic characteristics suggestive of metastatic pituitary disease, the prostate specific antigen test should be included as part of the work-up. PMID- 26415326 TI - HISTORICAL REVIEW. PMID- 26415327 TI - The Final Journey. . PMID- 26415328 TI - Oral Care: When To Help, When To Encourage. PMID- 26415329 TI - Cloud Computing: Implications For Providers. PMID- 26415330 TI - 20 to Watch: Scaling New Heights--PART 2. PMID- 26415331 TI - The Long and Winding Road--A New Editor's Perspective. PMID- 26415332 TI - Effect of Luting Cement Space on the Strain Response of Gold Crowns Under Static Compressive Loading. AB - The aim the work was to investigate the effect of varying degrees of luting cement thickness on the strain of the cemented gold alloy crowns under compression. Five dies with their corresponding crowns were fabricated using a lost wax technique. Three gold crowns for each die were fabricated under the control of specific die spacer layers to provide a space of 40 um (10 layers of die-spacer thickness) and 80 um (20 layers of die-spacer thickness). The crowns were subsequently cemented using zinc phosphate cement. The crowns were subjected to gradual static compressive loading between 10N to 250N (Newton) and the strain measured simultaneously. The results were statistically analysed using Independent t-test for the different die-spacer thickness at the 95% confidence interval (p = 0.05). It was found that a significant relationship in the three thicknesses. It was concluded that the absence of die-spacer significantly reduced strain response, whereas a very little change in the strain recorded as the die spacer layers has increased. Clinically, decreasing the number of die spacer layers is advantageous as it provides a lower strain response under static compressive loading that would improve the longevity of the cemented full crowns inside the patient's mouth. PMID- 26415333 TI - Hardness Changes of Tissue Conditioners in Various Storage Media: An in Vitro Study. AB - The aim of the present study was to evaluate the effects of storage media on the longitudinal hardness changes of tissue conditioning materials. Four tissue conditioning materials were used for fabrication of 80 disc-shaped specimens and divided in four groups, stored in four storage media. The specimens underwent artificial ageing corresponding to 30 nights of extra-oral storage. Hardness measurements were obtained at nine intervals between 8 and 240 hours after specimen fabrication. To test the effects of storage media on hardness we employed multivariate modelling (Bonferroni correction; alpha = 0.05). The materials exhibited varying hardness changes, most pronounced when stored in ambient air. PMID- 26415334 TI - An Investigation into the Accuracy of Two Currently Available Dental Impression Materials in the Construction of Cobalt-Chromium Frameworks for Removable Partial Dentures. AB - This study investigated the suitability of irreversible hydrocolloid as an impression material for cobalt-chromium framework construction. Scans of casts derived from (1) alginate and (2) addition-cured polyvinylsiloxane impressions were superposed on to a control. The differences within and between groups were compared at fixed landmarks. The investigation revealed a high degree of scan coincidence within and between groups. However, certain features, such as undercuts, resulted in a lower degree of scan coincidence. Irreversible hydrocolloid appears to be a viable alternative to addition-cured polyvinyl siloxane as an impression material for cobalt-chromium framework construction. PMID- 26415335 TI - The Influence of Sonic and Ultrasonic Vibration on the Shear Bond Strength of a Selected Resin Luting Cement. AB - PURPOSE: This study determined the effect of sonic and ultrasonic instrumentation on the shear bond strengths of Panavia 21, a popular cement for the luting of resin-bonded restorations. METHODS: 84 Ni-Cr cylinders were cemented to randomly selected resin composite substrates using Panavia 21 following the manufacturer's instructions. The Ni-Cr-composite specimens were divided into 7 groups of 12 specimens each based upon the procedure used for removing the excess cement. For Group 1 (Co) specimens the excess cement was removed with microbrushes immediately after cementation. Groups 2 through 7 were based on the use of vibrating instrument and the time period after which the excess material was removed. These included the cement, Panavia 21, three vibrating instruments, Sonic with a universal tip (So), Piezoelectric ultrasonic with a USPIS tip (Pu), Magnetorestrive ultrasonic with a FS1-100 tip (Mu) and two different time periods, soon after cementation (9m) and one hour after cementation (1h). Once excess cement REMOVAL WAS COMPLETED, THE SPECIMENS WERE SUBJECTED TO SHEAR TESTING. RESULTS: Mean Shear Bond strengths ranged from 16.03 MPa (Co) to 19.91 MPa (So 1h). Statistical analysis demonstrated that interaction of the main effects were significant (F = 4.27, p = 0.042). Post-hoc analysis demonstrated that the effect of timing was significant in all the instrumented groups. The majority of the tested specimens failed cohesively compared to mainly adhesive failures for the control group. CONCLUSIONS: The effect of type of instrumentation immediately following polymerization setting had no effect on the shear bond strengths however a delay of 1 hour for all types of instrumentation had a beneficial effect of improving observed shear bond strengths. PMID- 26415336 TI - The Bond Strength of Resin Bonded Bridge Retainers to Abutments of Differing Proportions of Enamel and Composite. AB - Four groups of specimens were constructed using bovine enamel and composite resin. After a period of ageing, the specimens were roughened and acid etched before they were cemented to air abraded base metal alloy beams with a universal resin cement. After further ageing, tensile peel testing was carried out using a Universal Testing Machine. The force required to produce failure increased as the amount of composite resin on the bonding surface of the abutment increased. This difference reached statistical significance (p < 0.5) when the abutments contained > 50% composite. The mode of failure was mixed on the majority of retainers. Within the limitations of the study, findings suggest that RBB retainers can be cemented to abutments restored with composite resin without a reduction in bond strength. PMID- 26415337 TI - The Windowed Removable Partial Denture: A Treatment Option for Patients with Lone Standing Teeth. AB - The decision as to whether to retain or extract a single remaining natural tooth prior to the provision of dentures can be a difficult one. If the tooth is left in situ, the development of an adequate peripheral seal around the denture is not possible thereby compromising the appliance' retention. If the tooth is extracted the possibility of gaining direct retention with the use of clasps or attachments is lost. This paper aims to illustrate the use of windowed removable partial denture design and review the literature relevant to this area. The use of such a design can enhance the retention of the appliance by encircling the lone standing tooth/teeth utilising an elastomeric permanent soft lining material. PMID- 26415338 TI - Too Much To Swallow? A Case Report Of An Ingested Denture. AB - Ingested foreign bodies can prove a significant and potentially fatal threat. A case is reviewed where a patient swallowed his upper Kennedy Class I removable partial denture, highlighting the potential problems of this prosthesis design and the management of this scenario. PMID- 26415339 TI - Prevalence of Gingivitis, Plaque accumulation and Decayed, Missing and Filled Teeth among slum population in Bangladesh. AB - A cross-sectional survey, using cluster sampling technique, of slum population, was done to explore the oral health status and the prevalence of common oral diseases. A close ended questionnaire comprising Decayed, Missing and Filled Teeth (DMFT) Index, Gingival Index (Loe and Silness) and Plaque Index was applied to evaluate and record oral diseases, in both male and female population, covering a wide range of age groups. Clinical examination was carried out in different shum set ups, including slum schools by trained and calibrated examiners. Three thousand nine hundred and four (3904) slum dwellers participated in the survey. Prevalence of Caries was expressed in mean DMFT, recording of gingival status followed the method of Loe and Silness, oral hygiene status was evaluated using Plaque index. Mean decayed component, of the DMFT, was significantly higher than filling and missing component. Both decayed and missing components showed increasing trend, and filling components decreased as the age progressed. Prevalence of gingivitis and plaque accumulation was remarkably high among slum dwellers. Significantly high level of common oral diseases was found among Tongi slum dwellers. PMID- 26415340 TI - Overt and subclinical hypothyroidism among Bangladeshi pregnant women and its effect on fetomaternal outcome. AB - OBJECTIVES: Thyroid disorders are among the common endocrine problems in pregnant women. It is now well established that not only overt but subclinical thyroid dysfunction also has adverse effects on maternal and fetal outcome. There are few data from Bangladesh about the prevalence of thyroid dysfunction in pregnancy. With this background, this study aims to find out thyroid dysfunction (both overt and subclinical hypothyroidism) in pregnancy and its impact on obstetrical outcome. METHODS: We studied the evaluation of 50 admitted pregnancies corresponding to 29 women with subclinical hypothyroidism and rest 21 was overt hypothyroidism. Detailed history and examination were performed. Apart from routine obstetrical investigations, Thyroid Stimulating Hormone (TSH) estimation was done. Their obstetrical and perinatal outcomes were noted. RESULTS: Overt hypothyroidism was significantly (p < 0.05) higher in 25 to 44 years age group. However two and three abortions were significantly (p < 0.05) higher in overt hypothyroidism patients. In sub clinical hypothyroidism 86.2% conceived firstly within 2 years and 66.7% in overt hypothyroidism patients conceived firstly in between 3 to 5 years after marriage. Overt hypothyroids were prone to have pregnancy-induced hypertension 42.9%, intrauterine growth restriction (P = 0.001) and gestational diabetes (38.1%) as compared to subclinical cases. Neonatal complications were significantly more in overt hypothyroidism group. Mean TSH level was significantly (p < 0.05) higher in overt hypothyroidism patients but mean FT4 level was almost similar in both groups. Majority of the patient underwent caesarean section in both groups due to associated medical and obstetrical complications. None of the babies showed hypothyroidism by cord blood tests. In this analysis our results showed that overt hypothyroidism among Bangladeshi pregnant women are associated with more maternal complication & adverse parental outcome than subclinical hypothyroidism. The adequate treatment of hypothyroidism during gestation minimizes risks and generally, makes it possible for pregnancies to be carried to term without complications. Significant adverse effects on maternal and fetal outcome were seen emphasizing the importance of routine antenatal thyroid screening. PMID- 26415341 TI - The Household Health Spending and Impoverishment: Findings from the Households Survey in Shiraz, Iran. AB - The present study aimed to investigate the households' impoverishment due to the healthcare costs in Shiraz in 2012. In this household's survey, 800 households were studied in Shiraz. The study sample was selected using stratified and cluster sampling in the urban and rural areas, respectively. The information was collected using the household section of the World Health Survey questionnaire. In order to determine impoverishment due to health spending, at first, the households' food-based poverty line (subsistence expenditure) was measured. Then, households' health expenditure was subtracted from their total expenditure and if the obtained value was lower than the households' food-based poverty line, the households was considered to be impoverished due to health expenditures. The collected data were entered into the SPSS (version 16) statistical software and analyzed using descriptive statistic, Chi-square test, and logistic regression in backward method. The study results showed that 7.1% of the households (CI: 0.071 +/- 0.018) were impoverished because of healthcare expenditures. Besides, the households in the first quintile were more likely to be faced with poverty compared to those in the other quintiles (p < 0.05). Being covered by health insurance did not affect the protection from poverty due to health costs. Moreover, the participants living in rural areas were faced with poverty more than those living in urban areas (p < 0.05). It seems that health expenditure can be an economic shock for household in Shiraz and through spending on health a household may fall into poverty. As insurance had no effect on impoverishment, it implies that change in health insurance plans and ways of health financing is necessary. PMID- 26415342 TI - Postoperative Perfluro-N-Octane tamponade for complex retinal detachment surgery. AB - AIM: To study outcomes after using perfluoro-n-octane (PFO) as a short-term postoperative vitreous substitute in eyes undergoing primary vitrectomy with or without sclera buckling for complex rhegmatogenous retinal detachments with inferior/multiple breaks or giant retinal tears (GRTs) or retinal detachment with extensive proliferative vitreoretinopathy (PVR). METHODS: A prospective study was carried out where in 43 patients (Group 1) PFO was exchanged with silicon oil in the same surgical procedure and in 22 patients (Group 2) PFO was kept for 3 days and then exchanged with silicon oil by a separate surgical procedure. The respective surgeon took the decision whether to exchange PFO on the same day or after 3 days. The patients were followed up for 6 months to analyze the anatomical attachment rates, visual acuity gain, and postoperative complications in both the groups. RESULTS: There were 33 male and 10 female patients in group 1 and 18 male and 4 female patients in group 2. Mean age distribution in group 1 was 38.88 years (SD +/- 21.45) and in group 2 was 38.09 years (SD +/- 16.36). Mean preoperative best corrected visual acuity in group 1 was 2.02 +/- 0.58 and in group 2 was 2.01 +/- 0.53 logarithm of the minimum angle of resolution (LogMAR). The LogMAR Visual acuity in group 1 improved to 1.76 +/- 0.43 after 1 month (P = 0.01, paired t test) and to 1.62 +/- 0.62 after 6 months (P = 0.01, paired T test). This visual acuity in group 2 improved to 1.85 +/- 0.42 after 1 month (P = 0.24, paired T test) and 1.90 +/- 0.72 after 6 months (P = 0.49, paired T test). There was no difference regarding visual improvement in between two groups after 1 month and 6 months of follow-up (P = 0.125, independent sample T test). The retina was detached in 6 patients (14%) in group 1 and in 7 patients (31%) in group 2 after 6 months of follow-up. There was no statistically significant difference in between two groups regarding final attachment of retina (P = 0.109, Fisher exact test). There was also no significant complication. like increased posterior capsular opacification or glaucoma found after retaining PFO for 3 days. Conclusion: Perfluoro-n-octane is efficacious and safe as a short term vitreous substitute in primary rhegmatogenous retinal detachment repair cases with inferior/multiple breaks or GRTs or with extensive PVR. But keeping perfluoro-n-octane for 3 days does not significantly reduce the risk of re detachment with complex rhegmatogenous retinal detachment cases. PMID- 26415343 TI - Reference values of 6 minutes walk test (6 MWT) in Bangladeshi healthy subjects aged 25-55 years. AB - INTRODUCTION: The six minute walk test (6MWT) is increasingly accepted worldwide to assess functional exercise capacity of cardiac and pulmonary diseases for its simplicity. AIMS AND OBJECTIVES: The aim of the present study was to provide reference values for 6 Minute Walk Distance (6MWD) and other primary variables such as oxygen saturation (SaO2), pulse rate (PR) and breathlessness perception done in 6MWT. METHODS: We studied a sample of 190 healthy subjects (53 females) of age between 25-55 years (37.9 +/- 8.5 years). Baseline lung functions including forced expiratory volume in 1st second (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio were measured by a flow sensing spirometer. All subjects performed 6MWT according to standard protocol provided by the American Thoracic Society (ATS) guidelines. The fatigue and dyspnoea was measured before and after 6MWT by modified Borg scale. The SaO2 and PR were measured also by a light weight pulse oxymeter. RESULTS: The mean 6MWD was 466.7 +/- 69.4 meter, ranging from 213 to 659 meter and the mean Distance Work (DW) was 28732 +/- 7024 kg-m. Dyspnoea status and oxygen saturation remained unaltered throughout the walk. Mean resting and walking SaO2 values were, respectively, 97.1 +/- 1.3% and 96.8 +/- 1.5%: The mean change in SaO2 was 3 +/- 1.5%. PR was significantly affected by the walk. Mean resting and maximum PR after walking were respectively, 80 +/- 7 and 103 +/- 12 bpm (p < .01). Gender significantly affected the 6MWD (p < .01). In all subjects, the 6MWD was inversely and directly related, respectively, to age (r = .15; P < .05) and height (r = .41; P < .01). CONCLUSION: This study showed reference values for the 6MWT variables of subjects in Bangladeshi population. PMID- 26415344 TI - Association of Immunofluorescence pattern of Antinuclear Antibody with Specific Autoantibodies in the Bangladeshi Population. AB - Antinuclear antibody (ANA) is useful in the diagnosis of connective tissue disorder (CTD). Association of specific autoantibodies with the immunofluorescence pattern of ANA in CTD, noted in western literature has been considered as reference in all over the world. However, in Bangladesh no such research work or data correlating the autoantibodies and their ANA patterns is found. Objective of the study was to identify an association between immunofluorescence patterns of antinuclear antibody on HEp-2 cell and more specific antinuclear reactivities (e.g. anti-dsDNA and anti-extractable nuclear antigen) in the serum samples of CTD patients. Serum samples of 152 CTD patients (Systemic lupus erythematosus, Rhumatoid arthritis, Sjogren's syndrome, Systemic sclerosis, Polymyositis, Mixed connective tissue disease) were diagnosed clinically, attending at Bangabandhu Sheikh Mujib Medical University (BSMMU) during the study period of January, 2010 to December, 2010. Samples were subjected for ANA testing by Indirect Immunofluorescence (IIF) on HEp-2 cell (ALPHADIA) in dilution of 1:40, anti-dsDNA by ELISA and anti- extractable nuclear antigen (anti-ENA) by Dot Immunoblot. Dot blot strips were tested for anti-Sm, anti-RNP, anti-SSA/Ro, anti-SSB/La, anti-Scl-70 and anti-Jo-1. Out of 152 patients 110 (72.3%) cases were ANA positive by IIF on HEp-2 cell. ANA positive sera exhibited four fluorescence patterns such as speckled (50.8%), peripheral (21.6%) , homogenous (18.1%) and nucleolar pattern (9%). Peripheral pattern and homogenous pattern was predominantly associated with anti-dsDNA (p < 0.05). Speckled pattern was significantly associated with anti-ENA (p < 0.05).The most commonly identified antinuclear autoreactivity was directed towards anti-RNP (25.7%) then anti-Scl-70 (20%), anti-SSA (14.2%) and anti-SSB (5.7%). Multiple anti-ENA reactivities were identified in 34.28% cases. Peripheral and homogenous pattern is strongly associated with anti-dsDNA and speckled pattern may predict anti-ENA (specially ribonucleoprotiens). As a definite correlation between the ANA patterns and the group of antibodies was detected by dot immunoblot, one could predict presence of certain specific auto antibodies for a particular ANA pattern identified. This may restrict on the cost of laboratory investigations in a developing country like Bangladesh. Thus, ANA-IIF method may reduce the expense of detailed immunological work-up with minimal loss in diagnostic accuracy. PMID- 26415345 TI - Study on oxidative stress and antioxidant level in patients of acute myocardial infarction before and after regular treatment. AB - In acute myocardial infarction (AMI), lack of oxygen delivery to myocardium leads to generation of reactive oxygen species (ROS) which play an important role in the pathogenesis of AMI. Endogenous anti-oxidants protect the myocardial tissues from the deleterious effect of free radical mediate injury. The study evaluates the extent of oxidative stress and antioxidant status against ROS in AMI patients and amelioration of oxidative stress after regular treatment and also assesses the association between oxidative stress and risk factors for atherosclerosis like dyslipidemia and diabetes mellitus (DM). The study was conducted on 72 AMI patients and age and sex matched 18 healthy controls. Patients were assigned to four groups, AMI without dyslipidemia or DM, with dyslipidemia, with DM and with both dyslipidemia and DM. Plasma malondialdehyde (MDA) and GSH content and vitamin E levels were determined on admission into hospital and on the 5th day of treatment. Plasma MDA level increased significantly (p < 0.001) and erythrocyte GSH and plasma vitamin E levels were decreased (p < 0.001) in all the groups of patients as compared to control. On the 50th day of regular treatment MDA level reduced (p < 0.001) and GSH and vitamin E levels increased (p < 0.001) in patients. The plasma MDA level was significantly higher (p < 0.001) in patients with both dyslipidemia and DM or with only DM in comparison to patients without dyslipidemia and DM. The difference in the GSH level between patients with risk factors and without risk factors was not significant. It may be conclude that an imbalance exists between oxidant and antioxidant molecules in AMI patients which shift towards oxidative side and regular treatment restores this balance. There may be some association between oxidative stress in AMI and risk factors like dyslipidemia and diabetes mellitus. PMID- 26415346 TI - Fingerprints: A simple method for Screening Hemophilic Patients. AB - BACKGROUND: The present study aims to compare hemophilic patients' fingerprint types with the normal people to help diagnose the disease, particularly new occurrences of the disease. METHOD: This case-control study was conducted in 2012. Sixty two patients with hemophilia type A and 62 normal healthy people were selected. The type of fingerprint was determined by a forensic specialist who was kept unaware of the participants' group. Using advanced Henry method, the main types of fingerprints were classified as arch, loop, whorl, as well as other types. RESULTS: In the control group, loop type (65%) and in the case group the whorl type (34%) were the most frequent fingerprint type (p < 0.001) and there was a significant difference of fingerprint in each finger between two groups. In addition, the average number of whorl type in the patients with mild disease was significantly higher and the average number of arch and other types of fingerprints was significantly lower than patients with moderate or severe disease. CONCLUSION: The findings of the present study indicated that not only are the fingerprints of normal and hemophilic people different, but also a difference was observed between hemophilic patients with the mild factor level and patients with moderate or severe one. PMID- 26415347 TI - The Substance of De Spiritu. AB - The aim of this paper is to depict the anatomical and physiological doctrines of the treatise entitled Piepsilonrhoiota pinuepsilonupsilonMUalphatauomicronsigma, or De spiritu. By closely examining the contents of the treatise on its own accord, rather than through its Aristotelian or Hellenistic contexts, we attempt to overcome the aporetic and often disconnected style of the author, and to present a coherent picture of his doctrine of pneuma, its roles in the body, the anatomical structures in which it acts, and its relation to the soul. We argue that the author envisions three main systems in the body: arteriai, by which external air is taken in, turned into pneuma and distributed to different parts of the body; phlebes, by which blood is produced and distributed; bones and neura, which support the body and effect locomotion. Pneuma is shown to run through the system of arteriai, whereby it performs vital activities such as thermoregulation, digestion and pulsation. It is also engaged in activities such as perception and locomotion, in the form of the "connate pneuma," which, we propose, is a component of bodily parts. The author connects pneuma very closely with soul, and although he is familiar with Aristotle's doctrine of the soul, he does not see to embrace it. PMID- 26415348 TI - The Context of De Spiritu. AB - This paper underlines the importance of the Pseudo-Aristotelian treatise De spiritu for our knowledge of early Hellenistic anatomical and physiological theories. We claim that the treatise verifies reports on certain 4th- and 3rd century conceptions and debates otherwise attested only in later sources, and offers invaluable information on otherwise unknown ideas and discussions. Our claim is based on ten case-studies in which we explore the relation between the views found in De spiritu and known to us from other ancient sources, regarding ten specific topics. Following the results of our case-studies, we argue that De spiritu should be dated to the early decades of the 3rd century BC, after the circulation of the doctrines of Praxagoras of Cos, but before the discovery of the central nervous system by Herophilus and Erasistratus. PMID- 26415349 TI - Plato's Embryology. AB - Embryology was a subject that inspired great cross-disciplinary discussion in antiquity, and Plato's Timaeus made an important contribution to this discussion, though Plato's precise views have remained a matter of controversy, especially regarding three key questions pertaining to the generation and nature of the seed: whether there is a female seed; what the nature of seed is; and whether the seed contains a preformed human being. In this paper I argue that Plato's positions on these three issues can be adequately determined, even if some other aspects of his theory cannot. In particular, it is argued that (i) Plato subscribes to the encephalo-myelogenic theory of seed, though he places particular emphasis on the soul being the true seed; (ii) Plato is a two-seed theorist, yet the female seed appears to make no contribution to reproduction; and (iii) Plato cannot be an advocate of preformationism. PMID- 26415350 TI - The Eclipse of the Sun: Sun-dials, Clocks and Natural Time in the Late Seventeenth Century. AB - The Sun, in the early seventeenth century was, as it always had been, the ultimate arbiter of time-measurement In the last quarter of the century however this role was called into question as the new precision of post-Huygenian clocks revealed that natural time and the artificial mean time of the clock were not the same. Initially the question was little understood by the general public. The paper examines some early attempts to explain why "Sun-time" in 1700 was no longer "true-time." PMID- 26415351 TI - Roman vs. Arabic Computistics in Twelfth-Century England: A Newly Discovered Source (Collatio Compoti Romani et Arabici). AB - A frequently overlooked aspect of the knowledge transfer from Arabic into Latin in the twelfth century is the introduction of the Islamo-Arabic calendar, which confronted Western computists with a radically different scheme of lunar reckoning that was in some ways superior to the 19-year lunar cycle of the Roman Church. One of the earliest sources to properly discuss this new system and compare it to the old one is the anonymous Collatio Compoti Romani et Arabici, found in a manuscript from Tewkesbury Abbey, Gloucestershire. This article contains the first edition and translation of this previously unknown text, preceded by an analysis of its content and sources. As will be argued, the text was written in the second quarter of the twelfth century as a reaction to the astronomical tables of al-Khwaizmi, recently translated by Adelard of Bath, as well as to eclipse observations that had exposed the flaws of the 'Roman' computation. PMID- 26415352 TI - On the Time of the Intellect: The Interpretation of De Anima 3.6 (43ob 7-20) in Renaissance and Early Modern Italian Philosophy. AB - This article argues that an original debate over the relationship between time and the intellect took place in Northern Italy in the second half of the sixteenth century, which was part of a broader reflection on the temporality of human mental acts. While human intellectual activity was said to be 'above time' during the Middle Ages, Renaissance scholars such as Marcantonio Genua (1491 1563), Giulio Castellani (1528-1586), Antonio Montecatini (1537-1599) and Francesco Piccolomini (1520-1604), greatly influenced by the Simplician and Alexandrist interpretations of Aristotle's works, proposed alterna- tive conceptions based on the interpretation of De anima 3.6 (430b 7-20) according to which intellectual acts happen in a both 'undivided' and 'divisible time'. In order to explain Aristotle's puzzling claim, they were led to conceive of intellectual activity as a process similar to sensation, corresponding to a certain lapse of time (Castellani), an instant (Montecatini), or a mix of instantaneousness and concrete duration (Piccolomini), depending on their theoretical options. PMID- 26415354 TI - Euclidization in the Almagestum parvum. AB - The Almagestum parvum, a summary of Ptolemy's Almagest written around the year 1200, provided a new stylistic framework for the content of theAlmagest's first six books. The author of the Almagestum parvum used a narrower range of types of mathematical writing and supplied his work with principles, which were listed at the beginning of each book and which were followed by propositions and demonstrations. Specific values were to a large extent replaced by general quantities, which would stand for a class of particulars. These and similar changes in the Almagestum parvum reveal the author's concern with reshaping astronomy into a discipline in the mold of Euclid's Elements, which emphasized the generality of propositions and proofs and connected Ptolemaic astronomy to the "mathematical toolbox" available in the Middle Ages. The Almagestum parvum was an influential part of a larger trend of understanding Ptolemaic astronomy in a non-Ptolemaic style. PMID- 26415353 TI - Aristotle on Like-partedness and the Like-parted Bodies. AB - This paper offers an interpretation of Aristotle's treatment of the homoeomerous, or like-parted, bodies. I argue that they are liable to be far more complexly structured than is commonly supposed. While Aristotelian homoeomers have no intrinsic macrostructural properties, they are, in an important class of cases, essentially marked by the presence and absence of microstructural ones. As I show, these microstructural properties allow Aristotle to neatly demarcate the non-elemental homoeomers from the elements. That demarcation, in turn, helps to clarify Aristotle's conceptions of both homoeomery and what it is to be a bodily element. On Aristotle's account, I argue, a homoeomerous body, as such, is divisible into at least one part that is the same specific kind as the whole. Elemental bodies are the limiting case. For Aristotle, an elemental body is only divisible into parts that are of the same specific kind as the whole. PMID- 26415356 TI - [CLINICAL CHARACTERISTICS OF T1 HIGH GRADE BLADDER CANCER]. AB - OBJECTIVES: We retrospectively evaluated characteristics of T1 high-grade bladder cancer in patients in our hospitals. PATIENTS AND METHODS: Data was reviewed from 134 patients who were diagnosed with T1 high-grade bladder cancer and who underwent transurethral resection (TUR) in our hospitals between January 2006 and December 2012. The clinical course for each patient, the recurrence and progression rates, and the risk factors for recurrence and progression were evaluated. RESULTS: The median follow-up was 31.5 months. A second TUR was performed in 55 patients (41.0%), and showed 32 cases of residual tumor (58.2%) and 4 cases of upstaging (7.3%). The recurrence rate was 41.5%. The risk factors for recurrence were (1) no muscle obtained in initial TUR, (2) no BCG, and (3) no second TUR. The progression rate was 10.5%; no significant risk factors were identified for progression. Within the T1 high-grade bladder cancer cohort, a total of 31 patients underwent radical cystectomy (RC). When we graphed cancer specific survival (CSS) curves stratified by pathological T stage at the time of RC, and then compared findings from the upstage group (greater than pT2) and the non-upstage group (less than pT2), the CSS rate was significantly higher in the non-upstage group (p = 0.0027). CONCLUSION: No muscle in initial TUR, no BCG, and no second TUR are factors associated with recurrence of T1 high-grade bladder cancer. Further investigation is needed for preventing recurrence and progression and for improving survival following radical cystectomy in T1 high-grade bladder cancer. PMID- 26415357 TI - [CLINICAL SURVEILLANCE OF PROSTATE CANCER--COMPARISON WITH CLINICAL MASS STUDY IN JAPAN]. AB - OBJECTIVES: We report on the treatment trends and outcomes for prostate cancer in our clinic retrospectively, and compared our data with the domestic clinical mass study for prostate cancer. We then validated the legitimacy of our selected therapy for prostate cancer. PATIENTS AND METHODS: Eight hundred and eighteen patients at our clinic had histologically confirmed adenocarcinomas of the prostate between January, 2000 and January, 2013. RESULTS: The age distribution was from 47 to 100 years-old, with a median age of 72 years-old at diagnosis. Clinical TNM staging indicated that 301 cases (36.8%) were stage I, 303 cases (37.0%) were stage II, 101 cases (12.3%) were stage III and 113 cases (13.8%) were stage IV. Three hundred and fifty two cases (43.0%) received some form of androgen deprivation therapy (ADT). Retropubic prostatectomy (RPX) or radiation therapy (RT), including external beam radiation therapy and brachytherapy, was performed in 242 (29.6%) and 136 (16.6%) cases, respectively. The median overall survival was 56.3 months and the respective cause specific 5 year and 10 year survival rates of the 818 cases were 92.0% and 77.8%. Respectively, they were 100% and 100% for T1, 98.7% and 97.4% for T2, 90.7% and 38.5% for T3, and 60.8% and 38.9% for T4. JUA (Japanese Urological Association) Cancer Registration Statistics includes 11,385 eligible cases of prostate cancer, and had the same distribution and the same therapy trends as our data base. NUORG (Nara Uro oncological Research Group), the data base of 2,303 prostate cancer patients, and our clinical study had the same distribution of D'Amico risk groups. Finally we validated JCAP (Japan Study Group of Prostate Cancer) recommended J-CAPRA scores in our prostate cancer patients who received primary androgen deprivation therapies. Progression free survival and cause specific survival were related to J-CAPRA scores. DISCUSSION/CONCLUSION: The Japanese prostate cancer patients have higher prostate-specific antigen at diagnosis, higher Gleason score and higher clinical stage than the US patients. The higher rate of primary androgen deprivation therapy is characteristic for the Japanese patients. PMID- 26415358 TI - [LAPAROSCOPIC ADRENALECTOMY: COMPARISON OF TRANSPERITONEAL AND RETROPERITONEAL APPROACHES]. AB - OBJECTIVE: Laparoscopic adrenalectomy is generally performed by either a transperitoneal approach (TA) or a retroperitoneal approach (RA). However, the optimal selection criteria for each approach are unclear. We investigated the factors affecting the safety of laparoscopic adrenalectomy to evaluate the optimal criteria for each approach. PATIENTS AND METHODS: In total, 149 patients who underwent laparoscopic adrenalectomy from February 1994 to July 2013 were retrospectively analyzed. We performed TA for 75 tumors in 73 patients and RA for 78 tumors in 76 patients. Patient characteristics and operative outcomes were compared between the two groups. Furthermore, operative outcomes in patients with some surgical risks were specifically compared between the two approaches. RESULTS: Patient characteristics were similar between the two groups, although the patients in the RA group were significantly older than those in the TA group. Four patients with a large pheochromocytoma in the TA group had excessive blood loss and one of them was given blood transfusion. However, there was no difference in intraoperative blood loss (p = 0.091). The other serious adverse events were not observed. CONCLUSIONS: The present findings suggest that both RA and TA can be effective surgical strategies, with close attention to large pheochromocytoma to avoid excessive hemorrhage. PMID- 26415359 TI - [ADRENAL HEMORRHAGE: 6 CASES AND A REVIEW OF 57 REPORTED CASES]. AB - PURPOSE: The guidelines on adrenal hemorrhage has not established in Japan. In this article, we discuss the management of adrenal hemorrhage. OBJECTS AND METHODS: We experienced 6 patients from November 2004 to September 2013 in The University of Tokyo Hospital and The Fraternity Memorial Hospital, and we searched 57 cases already reported in Japan by using Japan Medical Abstracts Society (http://search.jamas.or.jp/). So we analyzed total 63 adrenal hemorrhage cases in Japan. RESULTS: In 63 cases, 5 cases were performed TAE, 3 cases were performed emergent surgeries, 13 cases were managed conservatively and elective surgeries were performed in the other cases. 5 cases were fulfilled criteria for Hb < 10 g/dl and the maximum diameter of the hematoma > 10 cm. Of 5 cases, 4 cases were performed emergent hemostasis. CONCLUSIONS: Adrenal hemorrhages caused by metastatic tumor tend to be serious anemia. In addition, the most patients with adrenal hemorrhages, who had Hb < 10 g/dl and the maximum diameter of the hematoma > 10 cm, required immediate medical treatment, e.g. TAE or surgical hemostasis. PMID- 26415360 TI - [UNDIFFERENTIATED CARCINOMA OF THE URETER WITH FETAL CLINICAL COURSE: A CASE REPORT]. AB - Undifferentiated carcinoma of ureter is rare neoplastic lesion, and the natural history of undifferentiated carcinoma of ureter has not been known well yet. We hereby presented an autopsy case of undifferentiated carcinoma of the ureter with rapid progression from the initial stage. A 62-year-old male visited the local urologist complaining of asymptomatic gross hematuria. Cystoscopy revealed the outflow of hematuria from the right ureteral orifice. Abdominal CT showed the right hydronephrosis with atrophic change of the renal parenchyma and the stenosis of upper ureter. He was referred to our hospital on suspicion of a right ureteral tumor. Magnetic resonance imaging and retrograde ureterography did not reveal a tumor in the right ureter. He complained of low back pain 4 months after the initial hematuria, and CT revealed the diffuse enlargement of the right kidney, swelling of the abdominal lymph nodes, and lung nodules. Renal biopsy was done, and only undifferentiated cells were revealed histopathologically without any specific findings to diagnose the primary organ. The tumor increased progressively, and he died about 6 months after the initial gross hematuria. Autopsy was performed, and urothelial carcinoma was found in the right ureter as the primary lesion. The ureteral tumor infiltrated to the right kidney, right adrenal gland, liver, duodenum, and pancreas with undifferentiation. Undifferentiated tumor cells were also found in distant metastatic lesion including the abdominal lymph nodes, left adrenal gland, liver, lung, pleura, and peritoneum. PMID- 26415361 TI - [A CASE OF G-CSF PRODUCING SARCOMATOID CARCIONOMA OF URETER]. AB - We report a case of sarcomatoid carcinoma of the ureter in a 82-year-old woman. She was admitted to our hospital with right hydronephrosis. A computed tomography (CT) and retrograde pyelography (RP) showed a solid tumor at right ureter with right hydronephrosis and 3 cm solid tumor on the right abdominal wall. She underwent laparoscopic nephroureterectomy and excision of abdominal subcutaneous tumor. Pathological diagnosis was urothelial carcinoma with sarcomatoid variant, pT3, grade 3 and abdominal wall metastasis. Other metastasis occured in left kidney and ileum about 1 month after the operation, and then she underwent laparoscopic partial nephrectomy and ileocecal resection. The histopathological diagnosis was sarcomatoid carcinoma with positive staining for granulocyte-colony stimulating factor (G-CSF). The paient died of multiple metastases 5 months after first operation. As far as we know, this is the first report of G-CSF producing infiltrating sarcomatoid carcinoma of the ureter in Japanese paper. PMID- 26415362 TI - [DISSEMINATED CARCINOMATOSIS OF THE BONE MARROW WITH UROTHELIAL CARCINOMA]. AB - Disseminated carcinomatosis of the bone marrow with urothelial carcinoma in a 75 year-old man: A case study. A 75-year-old-man had first medical examination due to gross hematuria. The imaging study and cystoscopy revealed left ureteral and bladder tumor. The patient was referred for a laparoscopic assisted left nephroureterectomy and transurethral resection of a bladder tumor (TUR-Bt). Pathological findings included urothelial carcinoma, high grade, both a pT3 ureteral tumor and a pTa bladder tumor. The patient received 2 courses of gemcitabine and cisplatin and 1 course of methotrexate, epirubicin and nedaplatin as adjuvant chemotherapy. TUR-Bt was performed twice due to recurrence in the bladder and similar pathological findings. The patient received intravesical instillation of pirarubicin (THP 30 mg in 30 mL of saline) to prevent recurrence in the bladder, but discontinued in the 3rd time because of gross hematuria. The patient was then admitted to our hospital due to gross hematuria, general fatigue, and abnormal findings in the blood analysis. On admission, pancytopenia was detected and the serum ALP level had increased to 30,266 IU/L. A biopsy and bone marrow aspiration were performed because a super bone scan image was obtained using a bone scintigram. Diffuse bone marrow metastasis of the urothelial carcinoma was observed in the pathological evaluations. Therefore, our diagnosis was urothelial carcinoma with disseminated carcinomatosis of the bone marrow. Although treatment with zoledronic acid and blood transfusion were performed, the patient died 20 days after the admission. To the best of our knowledge, this is the first case of disseminated carcinomatosis of the bone marrow with urothelial carcinoma. PMID- 26415363 TI - [ANEURYSMAL TYPE RENAL ARTERIOVENOUS FISTULA WITH GIANT VENOUS ANEURYSM, MIMICKING RENAL CELL CARCINOMA: A CASE REPORT]. AB - A 39-year-old man was referred to our clinic for a 7 cm tumor in the right kidney, found by simple CT scan. It was suspected as renal cell carcinoma accompanying tumor emboli in the inferior vena cava by enhanced CT scan. For further evaluation of the tumor emboli, color Doppler ultrasound and enhanced MRI was performed. They showed a large cystic lesion with high velocity turbulent flow and flow voids in T2-weighted imaging, it seemed as giant venous aneurysm of the right renal vein. Subsequently, angiography revealed aneurysmal type renal arteriovenous fistula (AVF), transarterial embolization (TAE) of the arterial feeder with coils was performed on the same day. After 6 months from embolization, there was no recurrences or reinterventions. Color Doppler ultrasound and MRI are beneficial in distinguishing vascular disease from neoplastic disease which may sometimes mimick in other diagnostic imaging studies. In addition TAE seems to be an effective treatment for the AVF. PMID- 26415364 TI - [A CASE OF RIGHT PYONEPHROSIS DUE TO URETERAL STONES IN A HEMODIALYSIS PATIENT]. AB - We report a case of a 64-year-old male with right pyonephrosis due to ureteral stones in association with chronic renal failure. The patient had been treated with hemodialysis for fourteen years. He was admitted to the Department of Internal Medicine of Kurobe City Hospital with chief complaints of fever and lumbago in January 2013. CT demonstrated a right pyonephrosis accompanied by right ureteral stones positioned in the middle and lower ureter. The stones could not be detected by KUB. He was consequently referred to the Department of Urology. Firstly, percutaneous nephrostomy for the right kidney was performed, and 200 ml of pyuria was discharged at that time. Urine culture demonstrated Escherichia coli. Secondly, rigid transurethral ureterolithotripsy (TUL) for the right ureteral stones was performed using Lithoclast, and a ureteral stent was indwelled on day 15 after nephrostomy construction. The nephrostomy catheter and ureteral stent were removed 10 and 21 days after the operation, respectively. The constituents of the stone were CaOx (26%) and CaP (74%). Right hydronephrosis improved and the patient showed no pyelonephritis for 1 year postoperatively. PMID- 26415365 TI - [MASSIVE HEMORRHAGE FROM THE FISTULA FORMATION BETWEEN CUTANEOUS URETEROSTOMY AND INFERIOR EPIGASTRIC ARTERY: A CASE REPORT]. AB - A 87-year-old man received radical nephroureterectomy for right renal pelvic cancer in 2009 and left cutaneous ureterostomy after radical cystectomy for bladder cancer in 2013. He visited the hospital for exchanging a 7 or 8 Fr single J catheter every 2 to 4 weeks. Eleven months after the 2nd operation, massive bleeding from the stoma occurred when ureteral catheter was exchanged. Contrast enhanced computed tomography showed that left inferior epigastric artery was located close to left ureter. Angiography of the left inferior epigastric artery didn't show an obvious fistula, but revealed the stoma was surrounded by ramified new blood vessels from left inferior epigastric artery. We suspected a rupture of the vessels and performed embolization for the branch of inferior epigastric artery to left ureter. This embolization made it possible for the bleeding to be controlled. Massive bleeding from the branch of inferior epigastric artery is very rare, and we report the case and review the literature. PMID- 26415366 TI - [SUCCESSFUL INGUINAL ORCHIECTOMY IN A PATIENT WITH A PAINFUL METASTATIC SPERMATIC CORD TUMOR: A CASE REPORT]. AB - A 71-year-old man was referred to our department due to inflammation in the right scrotum. A tumor in the right spermatic cord was suspected on palpation, and abdominal computed tomography revealed a 4-cm mass in the tail of the pancreas and a low-density lesion in the liver segment 6. In addition, the patient's serum level of CA19-9 was high, at 135.7 U/mi. We referred the patient to our institution's Department of Gastroenterology, where he was diagnosed as having a liver metastasis from pancreatic cancer. Despite three courses of gemcitabine and erlotinib combination therapy for pancreatic cancer, his serum level of CA19-9 increased to 744.0 U/m, indicating no response to chemotherapy. Because uncontrollable pain developed in the right scrotum and right inguinal area during the course of treatment, inguinal orchiectomy was performed for pain management and pathological diagnosis. Careful examination revealed a hard, whitish tumor occupying the right spermatic cord and extending from the epididymis to the internal inguinal ring. Because a palpable mass in the peritoneum near the internal inguinal ring was detected, part of the peritoneum was resected concurrently. Pathological findings were remarkable with spermatic cord metastasis and peritoneal dissemination from pancreatic cancer. Pain subsided postoperatively and no analgesics were needed. Pancreatic cancer accompanied by spermatic cord metastasis and peritoneal dissemination is extremely rare. Surgical resection in the present case provided effective treatment of the intractable pain due to spermatic cord metastasis. To the best of our knowledge, this is only the 14th case reported in Japan of spermatic cord metastasis from pancreatic cancer as a primary cancer. PMID- 26415367 TI - NY-BR-1 Antigen Expression and anti-NY-BR-1 IgG in Egyptian Breast Cancer Patients: Clinicopathological and Prognostic Significance. AB - Breast cancer is the most common gynecological malignancy in the world. In Egypt, it ranks the first among female malignancies with incidence of 37.7%. Over the last decades, the integration of prognostic and predictive markers in treatment decisions has led to more individualized and optimized therapy. NY-BR-1 antigen has been shown to be frequently expressed in breast cancers. The study aimed to assess the tissue expression of NY-BR-1 antigen and serum IgG antibody to this antigen in Egyptian breast cancer females. The study was conducted on 60 females (10 healthy, 10 having benign breast lesions, 40 with malignant breast cancer). NY-BR-1 Ag expression was evaluated by immunohistochemistry and anti-NY-BR-1 IgG was assessed by ELISA. Results revealed a significant difference in NY-BR-1 Ag expression between benign and malignant breast cancer patients. There was a significant correlation between NY-BR-1 antigen expression and estrogen receptor's status (P = 0.019), stage of the disease (P = 0.008), menopausal status (P = 0.008), lymph node involvement (P = 0.022) and anti-NY-BR-1 IgG (P = 0.032) among the studied individuals. In addition, there was a statistically significant increase in anti-NY-BR-1 IgG O.D. results among malignant breast cancer group. It is correlated with tumor type (P < 0.001) and progesterone receptor status (P = 0.038). In conclusion, our work may represent a step towards identification of a new prognostic marker specific for breast cancer. PMID- 26415368 TI - Serum 25-hydroxyvitamin D and CD4+CD25(+high) FoxP3+ Regulatory T cell as Predictors of Severity of Bronchial Asthma in Children. AB - Bronchial asthma (BA) is one of the common chronic diseases of childhood. Vitamin D deficiency has been associated with BA. Suppressor regulatory T cells (Treg) are important for the induction, maintenance of immunological tolerance to allergens. This study assessed serum 25-hydroxyvitamin D (vitamin D) and the percentages of CD4+CD25+(high) Foxp3+ Treg, in peripheral blood, as predictors of asthma severity and level of clinical control. The study enrolled 72 children divided equally between asthmatic children (AC) and age and sex matched controls. Diagnostic criteria and level of asthma severity followed the Global Initiative for Asthma guidelines. Serum vitamin D was determined by an immunoassay and the percentages of CD4+CD25+ig Foxp3+ Treg by flow cytometry. Serum vitamin D level and percentage of CD4+CD25+(high) Treg were lower in AC compared to controls (P < 0.001) whereas Fox p3 expression was higher in AC compared to controls, P < 0.001. Serum vitamin D levels were lower in severe asthma compared to mild and moderate forms (P = 0.008) and in uncontrolled attacks compared to partially or completely controlled children. No difference in percentage of Treg in relation to asthma severity and clinical control was observed. Since AC has decreased serum vitamin D with inverse relationship between its levels and asthma severity, we conclude that it can be used to predict severity of asthma. PMID- 26415369 TI - Tumor Infiltrating T Lymphocytes and Apoptosis in Colorectal Cancer. AB - Dysfunction of the immune system in colorectal cancer (CRC) can be due to a number of reasons including apoptosis of tumour infiltrating lymphocytes (TILs). The aims of this study was to investigate TILs in colorectal cancer and characterize apoptosis of TILs using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay for detecting DNA fragments. We used monoclonal antibodies (mAbs) to T lymphocytes to detect TILs and double immunohistochemistry to assess apoptosis. T lymphocytes were detected in the immune infiltrate in CRC. TUNEL staining disclosed a high level of cell death among TILs. Apoptosis of T lymphocytes showed significant correlation with Dukes' stage (P = 0.02), lymphatic metastasis (P = 0.03), vascular metastasis (P = 0.01), lymph node metastasis (P = 0.02) and age of patient (P = 0.01). In conclusion, CRC may elude immunological surveillance by inducing apoptosis of TILs. PMID- 26415370 TI - Level of IL-16 and Reticulated Platelets Percentage during the Clinical Course of Immune Thrombocytopenic Purpura in Children. AB - Immune thrombocytopenic purpura (ITP) is an immune-mediated acquired disease with transient or persistent decrease of thrombocytes number in the blood. Cytokines play important roles in the immune regulation and are known to be deregulated in autoimmune diseases. This study aimed to investigate serum IL-16 levels in relation to reticulated platelets in children with ITP and platelet count. Twenty six children with ITP (11 with newly diagnosed ITP, 9 with persistent ITP and 6 with chronic ITP) and 12 age-matched healthy children controls were studied. Serum level of IL-16 and reticulated platelets count were assessed by Enzyme Linked Immunosorbent Assay (ELISA) and flow cytometry respectively. Serum IL-16 levels were significantly higher in patients as compared to controls (P < 0.001). Within patients, the levels were higher in newly diagnosed compared to persistent and chronic ITP (P < 0.01) and (P < 0.001) respectively. IL-16 levels were also significantly higher in persistent ITP compared to chronic ITP (P < 0.001). Reticulated platelets were also elevated in patients compared to controls and the increase was significant in newly diagnosed group (P < 0.05). Negative correlation was found between IL-16 level and reticulated platelets and platelets counts (r = -0.284, P = 0.028, r = 0.274 P = 0.25) respectively. It is concluded that IL-16 may be valuable in predicting the clinical course of pediatrics ITP. Measurement of reticulated platelets may provide significant information about thrombopoietic activity during the clinical course of ITP in children. PMID- 26415371 TI - Serum Level of Growth Arrest-Specific 6 (Gas6) Protein and Genetic Variations in the Gas6 Gene in Patients with Type 2 Diabetes Mellitus. AB - Growth arrest-specific protein 6 (Gas6) belongs to a family of vitamin K dependent coagulation proteins. Plasma levels of Gas6 are associated to altered glucose tolerance. This study aimed at determining whether c.843+7G>A Gas6 polymorphism is associated with the development of type 2 diabetes mellitus. The study included 50 patients with type 2 diabetes and 40 matched controls. The Gas6 protein was measured in serum using ELISA and Gas6 gene polymorphism by polymerase chain reaction-Restriction Fragment Length Polymorphism. The GG genotype was the most prevalent in the diabetic patient. The frequency of A allele in the diabetic group was lower than the control group (P < 0.05). Serum concentrations of Gas6 were lower among type 2 diabetes patients than controls (P < 0.001). Since the AA genotype was expressed at a lower frequency in type2 diabetes patients compared to controls, a protective role for this Gas6 variant in type 2 diabetic patients may be concluded. PMID- 26415372 TI - Detection of Cytotoxic T-Lymphocyte Associated Antigen-4 Gene Polymorphism in Type 1 Diabetes Mellitus. AB - Type 1 diabetes is one of the most common chronic childhood illnesses. Interplay between genetic susceptibility and environmental factors is thought to provide the fundamental element for the disease. It has been shown that more than 40 genetic loci are associated with T1DM. Important one among these is the CTLA-4. This work aimed to detect Cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4) gene polymorphism in patients with type 1 diabetes mellitus T1DM using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to clarify its role in the susceptibility to T1DM. The study was carried out on forty unrelated Egyptian children with TIDM. Twenty unrelated healthy children were enrolled as a control group. Blood samples were collected from patients and control groups and subjected to CTLA-4 gene polymorphism analysis using polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP). CTLA-4 G allele and GG homozygous genotype were significantly increased in T1DM patients than in control group (P < 0.001, P = 0.002 respectively). There was significant association between the three CTLA-4 genotypes (AA, AG, GG) and diabetic complications (p = 0.002), AG and GG polymorphisms were associated with complications of diabetes with ratio 84.6% and 100% respectively. While no association was found with sex, weight, height, risk factors of diabetes or insulin treatment. It was concluded that there is a strong association between AG polymorphism and T1DM (P = 0.002). PMID- 26415373 TI - IL-17 Producing Cells and RORgammat mRNA Transcriptional Factor in Cirrhotic and HCC Egyptian Patients. AB - Retinoic acid-related orphan receptor gT (RORgammaT) is the orphan nuclear receptor that regulates the development of Th17 cells and the expression of IL 17. The differentiation of Th17 cells is associated with the upregulation of RORgammaT mRNA, and the mechanisms regulating that process in human cells are not well understood. RORgammat as transcription factor was selectively expressed in Th17 cells and is regulated by STAT3. The relationship between Th17 cells and tumor immunopathology has been controversial. Aim of the study is to evaluate Th17 cells and RORgammat transcriptional factor in cirrhotic, early and advanced HCC patients. Ninety patients were studied (30 cirrhotic, 30 early stage and 30 advanced stage HCC patients). They were recruited from the National Liver Institute, Menoufia University, and subjected to full clinical examination, investigations to detect liver cirrhosis, portal vein thrombosis and tumor staging. Peripheral blood mononuclear cells (PBMCs) were stimulated with cytosim, ionomycin and monensin, and surface (CD4-PE)as well as intracellular staining for Th17 (IL-17 FITC) was performed. Analysis of cells was carried out using FACS Calibur. RORgammat mRNA expression in PBMCs was measured by real time RT- PCR. Cirrhotic patients showed increased Th17% cells, without significant change in RORgammat mRNA as compared to early stage HCC. Advanced stage HCC patients showed significant increase of Th17 cells% and RORgammat mRNA compared to studied patients group. Positive correlation of Th17 and RORgammatmRNA was found with aminotransferases and bilirubin levels while, negative with serum albumin in advanced stage patients group (P < 0.001). Both markers were significantly increased with tumor size; RORgammat mRNA increased with multiple tumor foci. In conclusion, Th17 cells and RORgammat may be useful prognostic markers for advanced liver cirrhosis and HCC. PMID- 26415374 TI - Prognostic Value of Serum Free Light Chain in Multiple Myeloma. AB - The measurement of serum free light chain (sFLC) has been shown to be valuable in screening for the presence of plasma cell dyscrasia as well as for baseline prognosis in newly diagnosed patients. The aim of the present work was to study the prognostic value of sFLC in multiple myeloma in relation to other serum biomarkers, response to therapy and survival. Forty five newly diagnosed patients with MM were included in the study. Patients were divided into responders and non responders groups according to response to therapy. sFLC and serum Amyloid A (SAA) were measured by immunonephelometry. The non-responders group showed a statistically significant higher kappa/lambda or lambda/kappa ratio and higher beta2 microglobulin level, but lower albumin level at presentation, as compared to the responders group (P < 0.001). However, no statistically significant difference was detected between the two groups regarding SA A or calcium levels. Comparison between sFLC ratio obtained before and after therapy revealed significant decrease after treatment in the responders group (P = 0.05). Survival was significantly inferior in patients with an FLC ratio of >= 2.6 or <= 0.56 compared with those with an FLC ratio that was between 0.56 and 2.6 (P = 0.002). PMID- 26415375 TI - Immunomodulatory Effects of Levofloxacin on Patients with Pneumonia in Assiut University Hospitals. AB - The immunomodulatory effects of antibiotics could influence the degree of systemic and local responses to infection, so investigation of their intrinsic influence on the host's inflammatory response appears to be essential. Fluoroquinolones are known to exert modulatory activity on immune responses to microbial infection. However the mechanism of this immunmodulation has not been well elucidated. The aim of the work, is to assess the immunomodulatory effects of a levofloxacin, through examining its effect on the concentrations of tumor necrosis factor alpha (TNF-alpha) and Interleukin - 10 (IL-10) in serum of pneumonic patients. After following local research ethics committee approval and informed consent. This study included 40 patients with different types of pneumonia, admitted to department of Chest Diseases, Faculty of Medicine, Assiut University Hospitals, Egypt. Also, 10 healthy volunteers served as randomized controls. Both patients and controls received levofloxacin (750 mg once daily for 10 days). Serum levels of TNF-alpha and IL-10 were measured in patients and control before and after levofloxacin administration (750 mg once daily for 10 days) using human TNF-alpha and IL-10 ELISA kits respectively. Levofloxacin caused a statistically significant decrease in the mean level of TNF-alpha in both patients (20.82 +/- 1.31 pg/ml) (P < 0.009) and control group (17.12 +/- 0.84 pg/ml) (P < 0.004). In contrast, there was statistically significant increase (P < 0.000) in the mean level of IL-1 0 in patients (61.75 +/- 2.85 pg/ml) while statistically significant decrease (P < 0.005) in control group (28.57 +/- 1.37 pg/ml). In conclusion, our study demonstrates that treatment with levofloxacin affects production of TNF-alpha as a pro-inflammatory cytokine and IL-10 as an anti-inflammatory cytokines which may provide additional benefits in treatment of respiratory tract infections that are independent of its antibacterial properties. PMID- 26415376 TI - [L-Lysine-alpha-Oxidase in vitro Activity in Experiments on Models of Viruses Sindbis, Forest-Spring Encephalitis, Western Nile, Tyaginya and Dhori]. AB - The antitumor effect of L-lysine-alpha-oxidase from the culture fluid of Trichoderma harzianum Rifai F-180 was investigated for the first time. The in vitro studies revealed its high activity on a model of the forest-spring encephalitis virus and no activity against the Sindbis, Western Nile, Tyaginya and Dhori viruses. PMID- 26415377 TI - [Estimation of Probiotic Lactobacilli Drug Resistance]. AB - An actual problem of analysis of probiotic lactobacilli resistance to antibiotics and other drugs used in the treatment of gastro-intestinal disturbances has been for the first time solved. The levels of resistance of 19 strains of Lactobacillus (14 strains of L. fermentum, 4 strains of L.plantarum and 1 strain of L.rhamnosus) isolated from commercial probiotics and sour milk products to 14 antibiotics of various nature, i.e. beta-lactams, aminoglycosides, macrolides, clindamycin, vancomycin, rifampicin, ciprofloxacin, tetracycline and chloramphenicol were determined. All the isolates were practically susceptible to the drugs of the first line antihelicobacterial therapy, i.e. amoxicillin and clarithromycin, that makes inexpedient the parallel use of the probiotics containing the above lactobacilli in the treatment of gastritis and gastric ulcer, despite the lactobacilli antagonism with respect to Helicobacter pylory. Lactobacilli are as well resistant to mesalazin and can be used for correction of dysbiosis in inflammatory affections of the intestine. PMID- 26415378 TI - [Determination of Microbial Susceptibility to Sulfanilamides by Electrooptic Analysis]. AB - The effect of sulfanilamides (soluble streptocid as an example) on changing of the electrophysical properties (EP) of microbial cells of Escherichia coli XL-1, BL-Ril, Pseudomonasputida C-11 and BA-11 was studied. It was shown that significant changes in the orientation spectra (OS) of the cell suspensions incubated at various concentrations of the sulfanilamide resulted in changing of the electrooptic (EO) signal of the cell suspension at the first five frequencies of the orientation electric field (10-1000 Hz) with the use of soluble streptocid in a concentration of 0.3 mcg/ml. The dynamics of the drug effect on the microbial cells demonstrated a decrease of the EO signal value 5 minutes after the exposure by -59% vs. the control (the cells not exposed to the drug). During the following exposure the EO signal value practically did not change (within 5%). The changes of the OS of the cell suspensions exposed to soluble streptocid significantly differed for the susceptible and resistant strains. Determination of the activity of sulfanilamides by electrooptic analysis of microbial cell suspensions was considered possible. Changing of the microbial suspencion OS under the effect of sulfanilamides can be used as a test on the microbial cell susceptibility to drugs. PMID- 26415379 TI - [Antibiotic Resistance of Microbial Isolates from Long-Term Healing Wounds Exposed to Light of Various Wave Lengths]. AB - The data on inhibition of the growth of microorganisms of a characteristic spectrum and antibiotic resistance isolated from long-term healing wounds by light of various wave ranges are presented. The growing cultures on blood agar were exposed to polarized light, red and infrared, ultraviolet of medium- and short-wave continuous modes accustomed in physiotherapy of wounds.The effect of light in some way induced inhibition of the growth, but complete recovery was stated only after the use of ultraviolet light when confirmed quantitatively in terms of the CFU. PMID- 26415380 TI - [Kinetics of Virus Load HCV-RNA in Blood Serum and Peripheral Mononuclear Cells in a Patient with Hepatocirrhosis and Chronic Virus Hepatitis C Termination Treated According to Noninterferon Treatment Scheme (Cycloferon + Ribavirin)]. AB - A clinical case of hepatocirrhosis with chronic hepatitis C termination (1b genotype) is described. Taking into account the cirrhotic stage of the disease, the extrahepatic HCV replication in the peripheral mononuclears, unfavourable HCV genotype, infavourable IL-28B gene polymorphism, inefficiency of the previous two courses of the standard antiviral therapy (PegIFN + ribavirin) and secondary immune deficiency, noninterferon antiviral therapy for 24 weeks was used in the treatment of the patient: interferon-inductive therapy with cycloferon in combination with ribavirin. There was observed by the 12th week of the treatment biochemical remission and a significant decrease of the virus load from 1 x 10(7) IU/ml to 7 x 10(5) IU/ml in the blood serum and from 1.35 x 10(7) IU/ml to 8 x 10(5) IU/m in the peripheral mononuclears. Investigation of the molecular biological markers of the viremia (PCR HCV-RNA) in the cells of peripheral mononuclears is an obligatory diagnostic technology in cases with suspected extrahepatic HCV infection. The kinetics of the virus load and the positive dynamics of the immunological indices in the patient at the cirrhotic stage of chronic virus hepatitis C are indicative of the efficient etiopathogenic approach with the use of the noninterferon treatment scheme (cycloferon + ribavirin), when recombinant interferons are contraindicated. PMID- 26415381 TI - [Brown Seaweeds as a Source of New Pharmaceutical Substances with Antibacterial Action]. AB - At present the increase of antibiotic resistance in infection agents to antimicrobial drugs requires discovery of new antimicrobial substances with improved pharmacological properties and novel mechanisms of action, to which microorganisms do not develop resistance. Three areas are of interest for the search: recovery of new compounds from natural objects, including aquatic organisms, chemical modification of the known antibiotic molecules, discovery of compounds with antimicrobial activity among some new chemical structures which have no analogues in nature. The review is mainly concerned with discussion of antibacterial, antiviral and antifungal activity of sulfated polysaccharides (fucoidans) and extracts of brown, red and green algae, as well as of antioxidant, antiinflammatory, immunomodulatory and antiendotoxin properties that contribute to their antiinfective action. Such an activity makes fucoidans promising as a basis for developing new drugs for therapy of infectious diseases. PMID- 26415383 TI - Stop DSM! PMID- 26415382 TI - [ERCC1 as a Marker of Ovarian Cancer Resistance to Platinum Drugs]. AB - The review is concerned with the crucial marker of nucleotide excision repair ERCC1 and its contribution to platinum resistance of ovarian cancer. All the variants of the laboratory and clinical ERCC1 assessment in the ovarian cancer tissue (single nucleotide polymorphisms of the ERCC1 gene, levels of mRNA or protein) are considered. Data on the prognostic and predictive value of ERCC1 as a marker of the response to platinum-based therapy in ovarian cancer are systematized. The authors discuss the possible causes of heterogeneity of the results and emphasize the necessity of a unified and integrated approach to evaluation of ERCC1 in the tumor. The publications cited in the Search Engine Pub Med up to January 2015 were analyzed. PMID- 26415384 TI - Comparison of the Diagnostic Image Quality of the Canine Maxillary Dentoalveolar Structures Obtained by Cone Beam Computed Tomography and 64-Multidetector Row Computed Tomography. AB - The objective of this blinded study was to validate the use of cone beam computed tomography (C) for imaging of the canine maxillary dentoalveolar structures by comparing its diagnostic image quality with that of 64-multidetector row CT Sagittal slices of a tooth-bearing segment of the maxilla of a commercially purchased dog skull embedded in methylmethacrylate were obtained along a line parallel with the dental arch using a commercial histology diamond saw. The slice of tooth-bearing bone that best depicted the dentoalveolar structures was chosen and photographed. The maxillary segment was imaged with cone beam CT and 64 multidetector row CT. Four blinded evaluators compared the cone beam CT and 64 multidetector row CT images and image quality was scored as it related to the anatomy of dentoalveolar structures. Trabecular bone, enamel, dentin, pulp cavity, periodontal ligament space, and lamina dura were scored In addition, a score depicting the evaluators overall impression of the image was recorded. Images acquired with cone beam CT were found to be significantly superior in image quality to images acquired with 64-multidetector row CT overall, and in all scored categories. In our study setting cone beam CT was found to be a valid and clinically superior imaging modality for the canine maxillary dentoalveolar structures when compared to 64-multidetector row CT. PMID- 26415385 TI - Oral Manifestations of Chronic Kidney Disease and Renal Secondary Hyperparathyroidism: A Comparative Review. AB - Recent epidemiological studies have demonstrated that significant associations exist between oral disease and diseases involving non-oral tissues. Occasionally, the roles may be reversed and the oral cavity can be severely affected by systemic disease originating in another part of the body. Renal secondary hyperparathyroidism is a common endocrinopathy that occurs as a consequence of chronic azotemic kidney disease. Renal osteodystrophy, the most dramatic clinical consequence of renal secondary hyperparathyroidism is uncommon, but can result in demineralization of maxillofacial bones, loosening of teeth, and pathological jaw fractures. The purpose of this report is to update the current understanding of the pathophysiology of this endocrine disease and to compare the oral manifestations of renal secondary hyperparathyroidism in humans and companion animals. A 50-year review of the veterinary literature was undertaken to examine the clinical presentation of renal osteodystrophy in dogs, and to determine what clinical consequences of renal secondary hyperparathyroidism have been reported in domestic cats. PMID- 26415386 TI - The Negative Effects of Volatile Sulphur Compounds. AB - Oral malodor has been studied extensively in humans but not necessarily to the same degree in our veterinary patients where malodor constitutes a significant problem. Breath malodor may originate from the mouth, or from an extra oral source, originating from other organ systems such as gastrointestinal, respiratory, or even systemic disease. Oral malodor is a result of microbial metabolism of exogenous and endogenous proteinaceous substrates leading to the production of compounds such as indole, skatole, tyramine, cadaverine, puterescine, mercaptans, and sulphides. Volatile sulphur compounds have been shown to be the main cause of oral malodor. Although most clients perceive oral malodor to be primarily a cosmetic problem, there is an increasing volume of evidence in human dental literature demonstrating that volatile sulphur compounds produced by bacteria, even at low concentrations, are toxic to tissues and play a role in the pathogenesis of periodontitis. This article reviews the current available literature in human dentistry looking at these negative effects. No veterinary studies have been conducted looking at the negative effects of volatile sulphur compounds specifically, but as this article highlights, we should be aware of the potential negative effects of volatile sulphur compounds and consider this an area of future research. PMID- 26415387 TI - Peripheral Giant Cell Granuloma in a Dog. AB - Peripheral giant cell granuloma is considered rare in the dog with little known about the clinicopathologic features. There are few reports in the veterinary literature concerning this benign, reactive lesion, formerly known as giant cell epulis. In humans, the four most commonly described reactive epulides are focal fibrous hyperplasia (fibrous epulis), pyogenic granuloma, peripheral ossifying fibroma, and peripheral giant cell granuloma. This case report describes the diagnosis and surgical management of a peripheral giant cell granuloma in a dog. PMID- 26415388 TI - Elodontoma in Two Guinea Pigs. AB - Elodontoma was diagnosed in two pet guinea pigs, one involving a maxillary premolar tooth and the other affecting a mandibular incisor tooth. Diagnostic imaging, including radiographs, computed tomography, and oral endoscopy was performed in order to quantify dental disease. Diagnostic imaging was also used to guide treatment of acquired dental disease, which included intraoral restoration of normal occlusal plane and tooth extraction using an extraoral approach. These are the first histologically confirmed cases of elodontoma in guinea pigs. PMID- 26415389 TI - Maxillary Calcifying Epithelial Odontogenic Tumor in a Siberian Tiger (Panthera tigris altaica). PMID- 26415390 TI - Bilateral Rostral Mandibulectomy in the Dog. PMID- 26415391 TI - [Regulation on Female-male Flower Ratio of Monoecious Plant Schisandra chinensis Based on Reactive Oxygen Species (ROS)]. AB - OBJECTIVE: To study the effect of reactive oxygen species on female-male flower ratio of Schisandra chinensis in order to improve the yield. METHODS: Spraying different concentration solution of H2O2, paraquat and sodium dithionite on the leaves of Schisandra chinensis before fruit bud initiation. RESULTS: Exogenous sodium dithionite (O2- carrier) increased the female-male flower ratio greatly from 7.6% to 42.3%. H2O2 and paraquat (OH- carrier) had little effect. CONCLUSION: The regulation effects vary according to different ROS. Exogenous sodium dithionite has the best effect. PMID- 26415392 TI - [Effects of Pb Stress on Photosynthetic Pigment Biosynthesis and Growth of Rabdosia rubescens]. AB - OBJECTIVE: To study the impacts of lead (Pb) stress on the leaf photosynthetic pigment and the growth of Rabdosia rubescens,in order to provide a basis for planting area selection and growth regulation. METHODS: Taking chlorophyll a, chlorophyll b, carotenoids, growth rate, biomass and Pb content as the indexes, the Ramets hydroponic experiments at Pb concentration levels (135,270 and 540 mg/L) in the time(20, 35 and 50 d) were carried out. Photosynthetic pigment content was determined by spectrophotometer, and Pb mass fraction was detected with plasma emission spectrometer. RESULTS: There was uncertain effect on chlorophyll and carotenoid synthesis in different Pb concentrations in-early period (20 and 35 d). At the time of 50 d, the chlorophyll content was higher in the low-mid Pb concentrations, significantly lower in the high Pb concentration compared with the control group, and there were no significant differences on carotenoid contents in different Pb concentrations. CONCLUSION: Low-mid Pb concentrations can promote chlorophyll synthesis, and the bioaccumulation of high Pb concentration can inhibit the chlorophyll synthesis, and then restrict the growth of Rabdosia rubescens. PMID- 26415393 TI - [Relationship Between Seedling Grade of Glycyrrhiza uralensis and Plant Biomass Accumulation, Yield and Quality of Product]. AB - OBJECTIVE: To research the relationship between the seedling grade of Glycyrrhiza uralensis and the biomass accumulation, yield and quality of product, so as to provide basis for establishing seedling standard. METHODS: The weight of single seedling root was measured and the seedlings were divided into three grades by the clustering analysis. The different grade treatments of seedlings were made to conduct field trials and laboratory experiments. RESULTS: The weight of the whole plant and dry root in growth period of grades 1 and 2 (the weight of single root greater than 10.0 g) were larger than grade 3, and the yield was also the case. The root of Glycyrrhiza uralensis, growing for three years, of grades 1 and 2 contained higher contents of active compounds than grade 3 and the content of glycyrrhizin and liquiritin in the root of Glycyrrhiza uralensis of all treatments were higher than the standard of Chinese Pharmacopoeia (2010 edition). CONCLUSION: The plant from the grades 1 and 2 seedlings with larger growth increment,higher output and better quality is the best seedling in cultivation. PMID- 26415394 TI - [Study on High-yield Cultivation Measures for Arctii Fructus]. AB - OBJECTIVE: To find out the high yield cultivation measures for Arctii Fructus. METHODS: Completely randomized block experiment design method was used in the field planting, to analyze the effect of different cultivation way on agronomic characters, phenological phase,quality and quantity of Arctii Fructus. RESULTS: Arctium lappa planted on August 28 had the best results of plant height, thousand seeds weight and yield. The highest yield of Arctii Fructus was got at the density of 1,482 plants/667 m2. Arctiin content was in an increase trend with the planting time delay and planting density increasing. The plant height, thousand seeds weight, yield and arctiin content by split application of fertilizer were significantly higher than that by one-time fertilization. Compared with open field Arctium lappa, plant height, yield, arctiin content and relative water content of plastic film mulching Arctium lappa was higher by 7.74%, 10.87%, 6.38% and 24.20%, respectively. In the topping Arctium lappa, the yield was increased by 11.09%, with 39. 89% less branching number. Early planting time and topping shortened the growth cycle of Arctium lappa plant. CONCLUSION: The high-yield cultivation measures of Arctii Fructus are: around August 28 to sowing, planting density of 1 482 plants/667 m2, split application of fertilizer for four times, covering film on surface of the soil and topping in bolting. PMID- 26415395 TI - [Changes of Serum Gonadal Hormones Levels During Musk-secreting Period and Estrus of Moschus berezovskii]. AB - OBJECTIVE: To detect concentrations of serum gonadal hormones (testosterone, estradiol and progesterone) in musk-secreting period and estrus of Moschus berezovskii, and to study the association of serum gonadal hormones concentrations and musk-secreting. METHODS: The concentrations of serum gonadal hormones were detected with magnetic particle separation ELISA. RESULTS: During musk-secreting period, concentration changes of three serum gonadal hormones showed clear regularity, three crests occurred synchronously. Before musk secreting period, testosterone, estradiol and progesterone concentrations were at its lower level, in prime musk-secreting period, they increased rapidly to respective highest peak; at later musk-secreting period, they quickly dropped to close to its previous levels before musk-secreting period. During estrus, serum testosterone concentration increased to lower peaks than that at later musk secreting period. Estradiol remained at a low level and progesterone level was closed to zero. Serum testosterone concentrations in prime musk-secreting period were 114.4 ~ 190.5 times of estrus. During musk-secreting period, there were significant positive correlation among three serum gonadal hormone levels, a positive correlation between musk yield and serum testosterone levels, and negative correlation of musk yield with serum estradiol and progesterone levels as well as musk deer ages. CONCLUSION: Serum testosterone concentrations in prime musk-secreting period increase to the highest levels,which can provide reference in musk secretion induced by artificial means. PMID- 26415396 TI - [Determination of Five Active Components in Morinda officinalis from Different Habitats by HPLC]. AB - OBJECTIVE: To establish a sensitive and specific high performance liquid chromatography (HPLC) method for simultaneous determination of alizarin anthraquinones (1-methoxy-2-hydroxy anthraquinone,1,2-dimethoxy-3-hydroxy anthraquinone, rubiadin-1- methylether, 1,3-dihydroxy-2-methoxy anthraquinone, rubiadin) in Morinda officinalis from different habitats. METHODS: The analysis was carried out on an Ecosil C18 column (250 mm x 4.6 mm, 5 um) and detected with an UV detector at the wavelength of 277 nm. Gradient elution was carried out with acetonitrile-0.2% phosphoric acid at the flow rate of 0. 8 mL/min. The column temperature was set at 30 degrees C. RESULTS: The calibration curves were linear in the range of 0.2856-34.27 g/mL for 1-methoxy-2-hydroxy anthraquinone (r = 0.9999), 0.3268-39.22 g/mL for 1,2-dimethoxy-3-hydroxy anthraquinone (r = 0.9999), 0.3450-41.40 ug/mL for rubiadin-1- methylether (r = 0.9999), 0.1248-14. 98 ug/mL for 1,3-dihydroxy-2-methoxy anthraquinone (r = 0.9999) and 0.0508-6.096 ug/ mL for rubiadin (r = 0.9994), respectively. The average recoveries of the five components were 99.4%, 100.2%, 101.4%, 97.2%, 103.2%, respectively. The content of active components of samples from 10 different hatitats were in the range of 0.0025-0.0722 mg/ g, 0.0016-0.0658 mg/g, 0.0022-0.0684 mg/g, 0.0182 0.3965 mg/g and 0. 0014-0.0179 mg/g. CONCLUSION: The established method is accurate, reliable, and can be used for the simultaneous determination of the five components in Morinda officinalis, which provides a scientific basis for the quality evaluation of Morinda officinalis. PMID- 26415397 TI - [Investigation Report of Tripterygium wilfordii and Tripterygium hypoglaucum]. AB - OBJECTIVE: To get the information of resources, cultivation, commodity circulation and other aspects of Tripterygium wilfordii and Tripterygium hypoglaucum. METHODS: Collect samples in 13 locations of Tripterygium wilfordii and Tripterygium hypoglaucum, compare their plant morphological characteristics and growth habit, and investigate their wild resources conditions, planting information, easy-confused varieties and different commodity features. RESULTS: (1) Tripterygium wilfordii and Tripterygium hypoglaucum were mainly collected under woods or on the edge of woods,and light and moisture attributed to their distribution to some extent. (2) Wild resources of Tripterygium wilfordii and Tripterygium hypoglaucum were shrinking, and both of their cultivation history were relatively short and their cultivation technique were still in a low level. (3) Due to lack of harvesting and processing standards, decoction pieces, varying from roots, rhizomes to stems of plants, were all sold as commercial medicines. CONCLUSION: Wild resources of Tripterygium wilfordii and Tripterygium hypoglaucum are shrinking,and the standardized research on cultivation-harvest processing and commercial medicines remains to be further carried out. PMID- 26415398 TI - [Preliminary Investigation of Medicinal Plant Resources in Kangle County, Gansu Province]. AB - OBJECTIVE: To study the medicinal plant resources and their diversity in Kangle County, Gansu Province, and to provide scientific basis on utilization and protection of the medicinal plant resources of the county. METHODS: By field survey, sample collection, taxonomic identification and data verification methods. RESULTS: There were 258 species, 65 families in existing medicinal plants, of which 43 species, 39 genera and 24 families were national protection medicinal plants. Dominant families were mainly Asteraceae and Rosaceae. In this area,the plants used whole herbs and roots ( or rhizomes) as medicinal materials represented 40.31% and 25.19% respectively, and antipyretic and rheumatism medicine accounted for 28.68% and 12.79% respectively. 12 medicinal plants were cultivated and the cultivated area was 3,000 hectares. CONCLUSION: However, the reserves of most medicinal plants are less enough and the resources are diminishing increasingly in recent years. So we should accelerate the research progress as well as developing and utilizing rationally on the premise of protection. PMID- 26415399 TI - [Influence on Strychni Semen's Analgesic Effect and Toxicity of Milk-Impregnated- Processing-Technology of Traditional Uighur Medicine]. AB - OBJECTIVE: To investigate the effects of different processing methods on analgesic effect and toxicity of Strychni Semen, and to provide the scientific basis of milk-impregnated-processing-technology of traditional Uighur medicine for toxic medicines. METHODS: Three different methods, frying with sand of traditional Chinese medicine (1), cooled milk-impregnated-processing-technology of traditional Uighur medicine (2), and heated milk-impregnated-processing technology of traditional Uighur medicine (3) were used to process raw Strychni Semen and the processed products were compared with those in the raw drug (4). Karber method was used to caculate the LD50. RESULTS: The LD50 of (4), (1), (2) and (3)were 273.0, 289.3, 289.3 and 339.2 mg/kg,successively. Low dose group of heated milk-impregnated-processing-technology, low and high dose groups of cooled milk-impregnated-processing-technology had significant inhibition on the acetic acid-induced writhing reaction in mice (P < 0.05). CONCLUSION: Strychni Semen processed by cooled and heated milk can enhance the analgesic effect in mice while improving the LD50 of mouse, which illustrates milk-impregnated-processing- technology's pharmacological mechanism on efficacy enhancing and toxicity reducing of Strychni Semen. PMID- 26415400 TI - [HPLC Fingerprint Study and Quantitative Determination of Index Components of Pilea aquarum]. AB - OBJECTIVE: To establish an HPLC fingerprint and a quantitative determination method for determination of index components of Pilea aquarum. METHODS: The HPLC fingerprint of Pilea aquarum were determined on an Agilent Zorbax SB-C18 column (250 mm x 4.6 mm, 5 um), eluted with mobile phase containing of acetonitrile-0.2% acetic acid in a gradient mode. The temperature of column was 30 degrees C. The flow rate was 0.8 mL/min and the detection wavelength was set at 330 nm. The chromatograms of 24 batches of Pilea aquarum were compared by the software of Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine (version 2004 A). The contents of luteoloside and cosmosiin were also determined simultaneously. RESULTS: The HPLC fingerprint of Pilea aquarum had been established. There were ten common peaks,two chromatographic peaks of which were identified by reference substances. The samples of Pilea aquarum from different habitats can be distinguished from their fingerprints, the contents of luteoloside and cosmosiin varied greatly. CONCLUSION: This method has desirable precision, stability, repeatability, and can be applied for identification and quality control of Pilea aquarum. PMID- 26415401 TI - [Material Composition Research on Tibetan Medicine "Brag-zhun"]. AB - OBJECTIVE: To study the material composition of Tibetan medicine "Brag-zhun", and to provide the basis for interpretation of its source and reference for the establishment of quality standards. METHODS: Pharmacognosy routine method was used in macroscopic and microscopic identifications, inductively coupled plasma spectrometry was carried out to determine 26 kinds of mineral elements,and X-ray diffraction analysis was used for the crystalline phase detection of Brag-zhun. The content of calcium,organic matter, humic acid and fulvic acid was determined according to GB/T 14610-2008, "technical specification for soil analysis" , GB/T 11957-2001 and capacity titration, respectively. Moisture, ash content, acid insoluble ash content and water soluble extract were determined with reference to the Chinese Pharmacopoeia (2010 edition). RESULTS: Animal feces were commonly found in Brag-zhun, the main crystal phase was SiO2, 26 kinds of mineral elements content in total was about 3%, 13 batches of medicinal materials in organic matter content was 29.03%-71.79%. Humic acid content was 28.37%-58.51%; fulvic acid content was 19.69%-41.43%; moisture was 5.2% -11.7%; total ash content was 17.82%-64.39%; acid insoluble ash content was 2.10%-39.09%; and water soluble extract was 28.39%-57.40%. CONCLUSION: The traditional record of Brag-zhun from molten juice is lack of scientific basis. The mineral elements in Brag-zhun exist in amorphous. Brag-zhun contains a lot of organic matter including humic acid and fulvic acid, and inorganic matter mainly comes from sediment. The organic matter in rock has gone through a long geological evolution. PMID- 26415402 TI - [Study on Chemical Composition of Phyllanthus emblica]. AB - OBJECTIVE: To study the chemical constituents of Phyllanthus emblica. METHODS: The chemical constituents were isolated and purified by silica gel, polyamide and Sephadex LH-20 chromatography. Their structures were elucidated by physicochemical proper- ties and spectral analysis. RESULTS: 13 compounds were isolated and identified as Triacontanol (1), Triacontanoic acid (2), beta-Amyrin ke- tone (3), Betulonic acid (4), Daucosterol (5), Lupeol acetate (6), beta Amyrin-3-palmitate (7), Gallic acid (8), Betulinic acid (9), Ursolic acid (10), Oleanolic acid (11), Quercetin (12) and Rutin (13). CONCLUSION: Compounds 1,2,4,6,7,9,10 and 11 are obtained from Phyllanthus emblica for the first time. PMID- 26415403 TI - [Study on Chemical Constituents of Fermented Antrodia camphorata Powder]. AB - OBJECTIVE: To study the chemical constituents of fermented Antrodia camphorata powder. METHODS: 15 compounds were isolated from Antrodia camphorata by Silica gel column chromatography, ODS column chromatography, gel column chromatography, preparative liquid phase chromatography separation technique, as well as recrystallization. RESULTS: On the basis of their physical and chemical properties and spectral data,their structures were identified as Ferulic acid (1), Inositol (2), beta-Sitosterol (3),Vanillin (4),Vanillic acid (5), Butyric acid (6), Daucosterol (7), p-Hydroxycinnamic acid (8), Lauric acid (9), Inosine (10), Uridine (11), Adenine (12), D(+)-Sucrose (13), Arachidic acid (14) and Guanosine (15). CONCLUSION: Compounds 1, 5, 6 and 8-15 are isolated from fermented powder for the first time. PMID- 26415404 TI - [Chemical Constituents from Cremastra appendiculata]. AB - OBJECTIVE: To study the chemical constituents of Cremastra appendiculata. METHODS: The compounds were isolated by repeated column chromatography with silica gel, Sephadex LH-20 and ODS-HPLC. The structures were elucidated by analysis of spectroscopic data(1H-NMR and 13C-NMR). RESULTS: Ten compounds were isolated from the EtOAc extract in the tuber of Cremastra appendiculata. Their structures were identified as shancigusin I (I), 4-O-beta-D-glucopyranosyl cinnamate (II), bulbocodin D (III), blestriarene A (IV), 7-hydroxy-2,4-dimethoxy phenanthrene (V), coelonin (VI), militarine (VII), gastrodine (VIII), 3 hydroxyphenylpropionic acid (IX) and cinnamic acid (X). CONCLUSION: Compounds I III, IX and X are isolated from Cremastra appendiculata for the first time. PMID- 26415405 TI - [Study on Chemical Constituents of Peanut Hull]. AB - OBJECTIVE: To investigate the chemical constituents of peanut hull. METHODS: Several chromatography methods such as silica gel and Sephadex LH-20 combined with recrystallization were applied to isolate the compounds. Based on spectrum technologies (MS,1H-NMR and 13C-NMR) and physico-chemical methods, structures of isolated compounds were identified. RESULTS: Twelve compounds were isolated and elucidated as luteolin (1), diosmetin (2), 5,7,3',4'-tetrahydroxy-8-prenyflavone (3),5,7,3'-trihydroxy-4'- methoxy-8-prenylflavone(4), eriodicrtyol (5), racemoflavone (6), hydnocarpin (7), 5,7-dihydroxy chromone (8), 5-hydroxy chromone- 7-O-beta-D-glucoside (9), ferulic acid (10), beta-sitosterol (11) and daucosterol(12). CONCLUSION: Except compounds 1, 5 and 8, all compounds are obtained from peanut hull for the first time. PMID- 26415406 TI - [Chemical Constituents from Leaves of "Chuju" Chrysanthemum morifolium and Their Antioxidant Activities in vitro]. AB - OBJECTIVE: To study the chemical constituents from the leaves of "Chuju" Chrysanthemum morifolium. METHODS: All compounds were separated and purified by column chromatography over silica gel, Sephadex LH-20 and preparative HPLC. Their structures were identified by spectral methods including 1H-NMR and 13C-NMR. RESULTS: 21 compounds were isolated and identified as octa-cosyl alcohol (1), beta-sitosterol (2), lupeol (3), alpha-amyrin (4), daucosterol (5), ineupatorolide B (6), syringin (7), chlorogenic acid (8), petasiphenol (9), physcion (10), acacetin (11), eupatilin (12), quercetin (13), diosmetin (14), luteolin (15), apigenin (16), apigenin- 7-O-beta-D-glucopyranoside (17), quercetin-3-O-beta-D-glucopyranoside (18), luteolin-7-O-beta-D-gluco pyranoside (19), apigenin-7-O-beta-D- neospheroside (20), and acacetin-7-O-beta-D-glucoside (21). CONCLUSION: Compounds 1-12, 18 and 20 are isolated from this plant for the first time. Compounds 10, 13, 14, 15 and 16 have shown strong antioxidant activities by DPPH . scavenging activity better than Vit C. PMID- 26415407 TI - [Determination of Dencichine and Its Isomer in Panax notoginseng by Pre-column Derivatization HPLC]. AB - OBJECTIVE: To establish a method to determine dencichine (beta-ODAP) and its isomer (alpha-ODAP) in Panax notoginseng by pre-column derivatization HPLC with 1 fluoro-2,4-dinitrobenzene (FDNB). METHODS: A Luna-C18 column (250 mm x 4.6 mm, 5 um) was used, acetonitrile- (HAc-NaAc) as the mobile phase with the ratio of 17:83, the detection wavelength was 360 nm, the column temperature was 40 degrees C, and 20 uL of sample was injected for HPLC analysis. RESULTS: In 0.30 50.50 ug/mL,beta-ODAP had a good linear relationship with peak area, A2 = 140.50C1 + 72.30, r1 = 0.9995; In 0.10-16.15 ug/mL, alpha-ODAP has a good linear relationship with peak area, A2 = 106.60C2 + 56.00, r2 = 0.9992. CONCLUSION: There are appreciable beta-ODAP and alpha-ODAP in different samples of Panax notoginseng. The method is simple, rapid, accurate and can be used for the detection of dencichine and its isomer in other samples. PMID- 26415408 TI - [Study on Chemical Constituents of Lonicera japonica Bud]. AB - OBJECTIVE: To study the chemical constituents of Lonicera japonica bud. METHODS: The compounds were isolated and repeatedly purified by silica gel column chromatography, gel column chromatography and ODS chromatography. The structures were elucidated by physicochemical properties, MS and NMR. RESULTS: Eight compounds were isolated and their structures were identified as protocatechuic acid (1), 5-hydroxy-7,3',4'-trimethoxyflavone (2), hyperoside (3), 4 hydroxycinnamic acid (4), ethyl caffeate(5), apigenin (6), 5-hydroxy-6,7,8,4' tetramethoxyflavone (7), and ethyl laurate (8). CONCLUSION: Compounds 5, 7 and 8 are obtained from this genus for the first time. PMID- 26415409 TI - [Study on Chemical Constituents of Fat-soluble Extraction from Lepidium meyenii]. AB - OBJECTIVE: To study the chemical constituents of the fat-soluble extraction from Lepidium meyenii root. METHODS: Different extraction methods were studied, including supercritical carbon dioxide extraction, circumfluence extraction and steam distillation. Chemical constituents of the fat-soluble extraction from Lepidium meyenii were analyzed by GC/MS. RESULT: The number of compounds isolated by the above four methods were 38, 31, 14, 21 (specific gravity less than 1 in steam distillation) , and 25 (specific gravity greater than 1 in steam distillation), accounting for 85.79%, 81.18%, 62.08%, 98.36% (specific gravity less than 1 in steam distillation) and 81.54% (specific gravity greater than 1 in steam distillation) of each total peak area, respectively. CONCLUSION: This study lays a certain foundation for further study and development of functional factors in Lepidium meyenii root. PMID- 26415410 TI - [Volatile Oil Analysis of Piper hongkongense form Different Hatbitats by GC-MS]. AB - OBJECTIVE: To analyze the volatile oil in Piper hongkongense from five different habitats. METHODS: The volatile oil was analyzed by GC-MS. RESULT: The volatile components oil of each sample varied significantly. Caryophyllene, alpha caryophyllene and nerolidol 2 were common constituents of five samples. The volatile oil and chemical constituent contents of fresh sample were higher than that of the old sample. CONCLUSION: The volatile oil and chemical constituent contents of Piper hongkongense from different habitats have sig- nificant differences, which are affected by habitats, harvest season, storage time and so on. PMID- 26415411 TI - [Simultaneous Determination of Three Components in Ficus microcarpa Leaves by HPLC]. AB - OBJECTIVE: To develop an HPLC method for the content determination of benzoic acid, 4-hydroxyphenylacetic acid and acetosyringonecas in Ficus microcarpa Leaves. METHODS: The determination was performed on Purospher(r) STAR C18 (250 mm x 4.6 mm,5 um). The mobile phase was consisted of acetonitrile-0.2% phosphoric acid aqueous solution with linear gradient elution and the flow rate of 1.0 mL/min. The column temperature was set at 35 degrees C and the detection wavelength was 270 nm. RESULTS: The linear range of benzoic acid, 4 hydroxyphenylacetic acid and acetosyringonecas was 0.0121-1.21 ug (r = 0.9995), 0.423-42.32 [Lg ( r = 0.9999) and 0.047-4.70 pg( r = 0. 9996) , respectively. The average recovery was 100.7, 101.2 and 96.5 respectively. CONCLUSION: This method is simple,reproducible,and can be used for determination of three components of benzoic acid, 4-hydroxyphenylacetic acid and acetosyringonecas in Ficus microcarpa Leaves. PMID- 26415412 TI - [Effect of Madecassoside on Intestinal Mucosal Immunity in Collagen-Induced Arthritis Rats]. AB - OBJECTIVE: To explore the changes of intestinal mucosal immunity in collagen induced arthritis rats and the impact of madecassoside on these changes. METHODS: Collagen-induced arthritis was established in female Wistar rats. Treatment group was orally administrated madecassoside once daily for consecutive 21 days, while blank control and model groups were orally administered saline at the same volume. The concentrations of sIgA in small intestine content and IFN-gamma in small intestinal tissue homogenate were determined by ELISA. The proportions of CD4+ T and CD8+ T in the epithelium and laminar propria of small intestine were detected by flow cytometry, and the ratios of CD4+/CD8+ were calculated. The relative expressions of CD80, CD86, IL-6, IL-12 and Foxp3 mRNA in the small intestine were determined by real-time PCR. RESULTS: Compared with blank control rats, the concentrations of sIgA in small intestine content and IFN-gamma in small intestinal tissue homogenate from model rats were increased, the ratios of CD4+/CD8+ in the epithelium and laminar propria of small intestine were higher and the relative expressions of CD80, CD86, IL-6 and IL-12 mRNA in the small intestine were increased. Madecassoside treatment decreased the concentrations of sIgA in small intestine content and IFN-gamma in small intestinal tissue, downregulated the ratios of CD4+/CD8+ in the epithelium and laminar propria and decreased the relative expressions of CD80, CD86, IL-6 and IL-12 mRNA, while upregulated the relative expression of Foxp3 mRNA in the small intestine. CONCLUSION: The intestinal mucosal immune response is enhanced in collagen induced arthritis rats, the antigen presenting cells are activated abnormally and the immune tolerance is disturbed. Madecassoside treatment can downregulate the intestinal mucosal immune response and benefit for the induction and maintenance of intestinal immune tolerance. PMID- 26415413 TI - [Effect of Ju-Pi-Tang on Cisplatin-induced Emetic Model in Minks]. AB - OBJECTIVE: To study the antiemetic effect of Ju-Pi-Tang from Jin Kui Yao Lue on cisplatin-induced emetic model in minks, and to observe the immunoexpression of peripheral and central c-fos and substance P. METHODS: The minks were randomly divided into blank control group, Ju-Pi-Tang blank control group, model group, ondansetron group, aprepitant group, Ju-Pi-Tang (in high-, mid-, and low-dose) groups. Every group was administered with the antiemetic agent or distilled water on 24 h before cisplatin injection. The antiemetic effect of drugs was investigated in the emetic model of minks induced by cisplatin in 72 h observation. Immunohistochemistry was used to compare the differences of c-fos and substance P expression in the area postrema of brain and distal ileum tissues. RESULTS: During observation period,compared with model group,the frequency cisplatin induced retching and vomiting was significantly reduced by Ju Pi-Tang in high- and mid-dose groups, during the 0-24 h acute period, the number of retching of Ju-Pi-Tang in high-dose group was decreased more than aprepitant group, during the 24-72 h delayed period, the number of both retching and vomiting was decreased more than ondansetron group, after 72 h of cisplatin administration, compared with model group, the grey levels of c-fos and substance P expression in distal ileum and brain tissues of Ju-Pi-Tang groups were higher significantly. CONCLUSION: Ju-Pi-Tang has a good effect against cisplatin-induced emesis in minks. PMID- 26415414 TI - [Effect of Curcumin on Cerebral Ischemia-reperfusion Injury in Rats]. AB - OBJECTIVE: To investigate the effect of curcumin on cerebral ischemia-reperfusion injury in rats and its mechanism. METHODS: 250 male SD rats were randomly divided into five groups:sham group (Sham group), ischemia-reperfusion group (I/R group), curcumin groups with dosage of 30 mg/kg (Cur30 group), 100 mg/kg (Cur100 group) and 300 mg/kg (Cur300 group). The brain tissue damage degree, leukocyte cells infiltration, levels of TNF-alpha and MMP-9 expressions, and blood-brain barrier permeability were detected. RESULTS: At the same time point,the score of brain tissue injury,number of leukocyte, expression of MMP-9 and TNF-alpha, and Evans blue dye of I/R group and Curs group were higher than those of Sham group (P < 0.05). The score of brain tissue damage degree, number of leukocyte, expression of MMP-9 and TNF-alpha, and Evans blue dye of Cur groups were lower than those of I/R group (P < 0.05). The Cur100 group had the best effect. CONCLUSION: Curcumin can decrease cerebral ischemia reperfusion pathological damage significantly and suppressed the expression of MMP-9 and TNF-alpha, and Evans blue dye, brain tissue damage, leukocyte infiltration, which may be involved in protective mechanisms of curcumin. PMID- 26415415 TI - [Protective Effect of Component Compatibility Sini Decoction on Hypothyroidism Induced Renal Damage in Rats]. AB - OBJECTIVE: To investigate the protective effect of component compatibility Sini Decoction on hypothyroidism induced renal damage in rats. METHODS: The hypothyroidism model were established by 0.1% propylthiouracil (PTU) solution 10 m/kg for consecutive 15 days. Rats were randomly divided into model group, component compatibility Sini Decoction groups[ CSD 9. 6,4. 8 and 2. 4 g/ (kg . d)] and positive control group [Euthyrox 9 ug/(kg . d)]. Radioimmunoassay was used to determine the serum T3 and T4 levels; serum BUN content was detected by UV spectrophotometer and ELISA method were used to measure the CYS-C content. The kidney was weighed, and the pathological changes of the renal were detected by HE stain. RESULTS: Compared with blank control group, kidney weight coefficient, serum T3 and T4 levels in model group were decreased, while serum BUN and CYS-C contents were increased (P < 0.05 or P < 0.01). Compared with model group, serum T3 and T4 contents were increased and serum BUN and CYS-C contents were decreased (P < 0.05) in Sini Decoction groups [CSD 9.6 and 4.8 g/(kg . d)] and positive control group. The HE stain results showed that component compatibility Sini Decoction and Euthyrox could relieve glomerular atrophy and renal tubular epithelial cell injury in rats. CONCLUSION: Component compatibility Sini Decoction has a curative effect on hypothyroidism induced renal damage in rats. PMID- 26415416 TI - [Study on Optimum Extraction Process of Water Soluble Protein from Coicis Semen]. AB - OBJECTIVE: To optimize the extraction process of water soluble protein from Coicis Semen. METHODS: Coicis Semen was used to extract protein with cysteine hydrochloride aqueous solution in alkaline environment. The single factor test was conducted with the factors of extraction temperature, extraction pH, solid liquid ratio and extraction time. In combination with single factor test results, a 4 factors 3 levels orthogonal experiment was designed with the factors of extraction temperature, extraction pH, solid-liquid ratio and extraction time. The effect of various factors on the results and the interactions were analyzed by range analysis, variance analysis and partial least squares regression analysis. RESULTS: The optimum extraction process of water soluble protein from Coicis Semen was as follows: the extraction temperature was 40 degrees C , the extraction pH was 10, the solid-liquid ratio was 1:20 and the extraction time was 4 h. The interaction of temperature and solid-liquid ratio, as well as temperature and extraction time would lower protein extraction rate. CONCLUSION: The optimized extraction process is economical, simple, reasonable and practicable. PMID- 26415417 TI - [Optimization of Extraction Process of Total Flavonoids from Schizonepeta tenuifolia Based on Analytical Hierarchy Process with Dose-Effect Comparison Method]. AB - OBJECTIVE: To optimize conditions for extracting total flavonoids from Schizonepeta tenuifolia by the method of analytical hierarchy process with the correlation method of dose-effect. METHODS: Take the amount and concentration of ethanol,the extraction time and times as examine factors, with the inhibition rate of Caco-2 human cloning colonic cancer cell as index to optimize the optimum conditions of total flavonoids from Schizonepeta tenuifolia by orthogonal experiment design, and analyze the Pearson correlation coefficient between the total flavonoids content, hesperidin content, extraction rate and pharmacodynamics indexes through SPSS 19.0 software to determine the dose-effect comparative indicators, and then analytic hierarchy process is adopted to define the weight coefficients range of the content of total flavonoids and hesperidin. RESULTS: The best extraction process conditions were as follows:15 times the amount of 75% ethanol, water circumfluence extracting for 3 times,each time for 2 hours; The weight coefficient ranges of the content of total flavonoids and hesperidin were 0.7500-0.9000 and 0.1000-0.2500 respectively. CONCLUSION: Using the comprehensive scores of the content of total flavonoids and hesperidin, which is calculated by weight coefficient ranges that based on the analytical hierarchy process,to replace the inhibition rate as the indicator to optimize the optimum extraction process is scientific and reasonable. This optimization process is simple and practical,which provides a new method for selecting the best extraction indicators to get effective ingredients from traditional Chinese medicine. PMID- 26415418 TI - [Study on Error Analysis of Nonlinear Function Coefficient of FAIMS]. AB - The solution of ion mobility's nonlinear function coefficients alpha2 and alpha4 is the basis for achieving substance identification of High Field Asymmetric waveform Ion Mobility Spectrometry (FAIMS). Currently, nonlinear function coefficients alpha2 and alpha4 lack priors, meanwhile, existed solving results about alpha2 and alpha4 are deficient in error evaluation standard. In this article, acetone, isopropanol and 1, 2-dichlorobenzene were detected under different dispersion voltage by homemade FAIMS. In general, the spectrum peak of same sample at different dispersion voltage value is unique. Different dispersion voltage and corresponding compensation voltage value determines the value of alpha2 and alpha4. According to sample spectra at different dispersion voltage value, groups of spectral characteristics were obtained. Affirmatory number of data which were selected from multiple sets of compensation voltage value and dispersion voltage value, so that they were utilized to solved out lots of alpha2 and alpha4. Lots of factor have an effect on the accuracy of the solving results of alpha2 and alpha4, for instance, value of compensation voltage and dispersion voltage, style of fetching points of dispersion voltage, and so on. Comparing to other factors, style and amount of dispersion voltage is likely to control. By data analyzing huge amounts of alpha2 and alpha4 data, this paper explored their characteristic of distribution and correlation about them, research influence of number and method to fetch dispersion voltage detected points for error of solving results. After fitting frequency of alpha2 and alpha4, it was found that they conform to normal distribution, goodness of fitting exceed 0. 96, thus standard deviation of their distribution are able to evaluate error of solving results. In addition, a strong correlation exists between them, relevance of sample is -0. 977, -0. 968, -0. 992 respectively. With increasing of computing selected points, the corresponding error of solving results decrease. By comparing the standard deviation of method to fetch dispersion voltage detected points, found that detecting frequency in case of detecting maximum and the 70% of maximum of dispersion voltage value is lower at approximately same standard deviation, solving effect was optimized in unique fetching points style. Based on the premise of ensuring the accuracy of solving results of alpha2 and alpha4, it is obvious that reducing the frequency of detections for FAIMS effectively. It created favorable conditions for rapid field detection and precise spectral analysis. PMID- 26415419 TI - [Research Progress on Laser-Induced Breakdown Spectroscopy Based on Resonance Excitation]. AB - Laser-induced breakdown spectroscopy (LIBS), a new kind of atomic spectrum analysis technology, has attracted much atterition of the researchers due to its characteristics of real-time, simultaneous multi-element analysis, and no sample preparation. However, the poor analytical sensitivity has been an important factor that restricts the development of this technology. LIBS based on resonance excitation combines atomic fluorescence spectroscopy and laser-induced breakdown spectroscopy and selectively excites the target elements. In this way, the analytical sensitivity of LIBS can be improved substantially and its application for trace elements detection is greatly expanded. In this paper, the research development of LIBS based on resonance excitation is summarized. The generation of atomic, fluorescence spectrum in laser-induced plasma, the typical classification and the basic principle of LIBS based on resonance. excitation are introduced. The influence of ablation laser energy, resonant laser energy and wavelength, delay between the ablation laser and the resonant laser, and the gate width on spectral enhancement are analyzed in detail. The application status and deficiencies of LIBS based on resonance excitation in the fields of metallurgy, environmental monitoring and isotope detection are elaborated. Future prospects of LIBS based on resonance excitation are also described. PMID- 26415420 TI - [Radiative Properties of Cirrus Clouds Based on Hexagonal and Spherical Ice Crystals Models]. AB - Single scattering properties for spherical and hexagonal ice crystal models with different size parameters and wavelengths were employed to calculate satellite observed radiation and downward flux in ground surface using RSTAR radiative transfer model. Results indicated that simulated satellite observed radiation and ground surface downward radiant flux from different shapes of ice crystal models were different. The difference in the spectral radiation fluxes between 0. 4 and 1. 0 um was largest, and particle shapes affected the downward radiant flux significantly. It was verified that the proper selection of the effective ice crystal model is not only important for retrieval of the microphysical and optical parameters of the cirrus cloud, but also important for obtaining the radiant flux on the earth's surface correctly. These results are important for retrieving cloud microphysical parameters and simulation of the ground surface downward radiant flux. PMID- 26415421 TI - [Study of PL Spectra of PbSe Quantum Dots for IC Chip Temperature Dependence]. AB - Colloidal PbSe QDs were prepared with the particle size of 3. 6, 5. 1 and 6. 0 nm, and the temperature-dependent optical properties of colloidal PbSe QDs were investigated. At the room temperature, the experiment showed that there is red shift with increasing temperature; photoluminescence spectra of large size colloidal PbSe QDs is blue shifted with increasing temperature. Proposed a temperature detection method of integrated circuit was proposed based on photoluminescence spectra of colloidal PbSe QDs. The method for temperature detection includes colloidal PbSe quantum dots deposited on the surface of the printed circuit board, colloidal PbSe quantum dots of the surface are excited by the laser and infrared spectrometer receives photoluminescence spectra. Image acquisition system used for micron scale areas of temperature detection collects a tiny and specific areas imaging in the surface of chip. Experiments showed that the measurement accuracy is +/-3 degrees C and the relative error is less than 5%. PMID- 26415422 TI - [Real-Time Stability Monitoring of Photonic Crystal Sensing System Based on Guided-Mode Resonance Effect]. AB - The detection limit of antibody content has reached level of nanograms per milliliter due to high sensitivity and extremely narrow band of photonic crystal (PC) filter. The PC filter based on guided-mode resonance (GIR) effect can also be applied to detecting the molecular interactions. As the transducing element, one-dimensional PC filters transform biological information to photoelectric signal on optical spectrum analyzer (OSA). The main sensing performance is the change of peak-wavelength of PC filter. The sensing system using PC filter is restricted to the system stability which determines the effectiveness of detecting data. So in this paper, a detecting system we designed is briefly addressed. The morphology and the spectrum of PC filter we fabricated are tested. Considering the coupling light loss and integration of the system, noise signal in spectrum is going to affect the detecting results. To monitor the influence, realization of real-time monitoring the changes of the peak wavelength of PC filter is mainly illustrated. The monitoring is realized by transferring detecting data to computer in time and the results can represent the stability of the system. The program is compiled by Lab VIEW. In our experiment, the shift of 0. 25 nm of the peak wavelength caused by vibration of platform or unsteadiness of light source is within the sensitivity of the PC filter obtained by simulation, so we proposed this system we mentioned can be used in sensing most kind of bulk reagents. PMID- 26415423 TI - The Application of Quality Identification in Honey by Photoacoustic Spectroscopy. AB - The photoacoustic spectrum of glucose, sucrose and honey solutions in the visible range are measured by using the single-light photoacoustic spectrometer, and are compared with the spectra from spedtrophotometry method. The spectral characteristics of the above solutions show that the spectral background intensity and spectral profile have some differences for different kinds of solutions. The spectra of the three kinds of solutions all have strong peak value at 485 and 655 nm, but the intensity ratios between the two peaks are different. Besides, there are characteristic peak at 475, 576 and 630 nm for glucose, and the sucrose has apparent characteristic peak at 632 nm, these characteristic peaks can be used for detecting whether the natural honey has been added glucose or sucrose. By comparing two kinds of spectrum of the same solution, the intensity of photoacoustic spectrum is more responsive to the wavelength, indicating photoacoustic spectrometry has a higher sensitivity in the test of material composition. PMID- 26415424 TI - [Terahertz Spectrum Modulation with Liquid Crystal Spatial Light Modulator]. AB - Terahertz wave with modulation spectrum is valuable in many fields. Terahertz spectrum has been modulated with a pure-phase liquid crystal spatial light modulator by shaping the femtosecond laser beam profile. In the experiment, terahertz wave is generated by femtosecond laser pulses in mode of Optical Rectification and then its signals are detected by a terahertz time-domain spectroscopy system. Phase maps obtained with the GS algorithm are loaded to get the shaped beam profile. Therefore, Terahertz spectrum has been successfully modulated by changing the detection range and beam profile parameters. Simultaneously, the simulations have been performed with the Fresnel diffraction, and they agree with the experimental results well. The results show that the modulation of the THz spectrum with this method is feasible. PMID- 26415425 TI - [Classification of THz Transmission Spectrum Based on Kevnel Function of Convex Combination]. AB - In the present paper, support vector machine (SVM) based on convex combination kernel function will be used for classification of THz pulse transmission spectra. Wavelet transform is used in data pre-processing. Peaks and valleys are regarded as location features of THz pulse transmission spectra, which are injected into maximum interval features of term frequency-inverse document frequency (TF-IDF). We can conclude weight of each sampling point from the information theory. The weight represents the possibility that sampling point becomes feature. According to the situation that different terahertz-transmission spectra are lack of obvious features, we composed a SVM classification model based on convex combination kernel function. Evaluation function should be used as an evaluation method for obtaining the parameters of optimal convex combination to achieve a better accuracy. When the optimal parameter of kenal founction was determined, we should compose the model for process of classification and prediction. Compared with the single kernel function, the method can be combined with transmission spectroscopic features with classification model iteratively. Thanks to the dimensional mapping process, outstanding margin of features can be gained for the samples of different terahertz transmission spectrum. We carried out experiments using different samples The results demonstrated that the new approach is on par or superior in terms of accuracy and much better in feature fusion than SVM with single kernel function. PMID- 26415426 TI - [Influence of Concentration Sequence on the Signal-to-Noise Ratio of Cross Peaks of 2D Asynchronous Spectra Generated by Using the DAOSD Approach]. AB - In the present work, computer simulation was performed on a model chemical system where two solutes (denoted as P and Q, respectively) are dissolved in the same solution. Under intermolecular interaction between P and Q, part of P undergoes subtle structural variation and converts into U while part of Q converts into V. The strength of intermolecular interaction can be characterized by the corresponding equilibrium constant K. Our preliminary studies indicate that the S/N ratio of cross peak increases considerably as n increases. Moreover, the S/N ratio of the cross peak from the asynchronous spectra can be improved significantly when the suitable concentrations of P and Q are adopted. This work is helpful for a selection of suitable concentration sequence to maximize S/N ratio of cross peaks in the 2D asynchronous spectra generated by using the DAOSD approach proposed in our previous study so that weak intermolecular interaction can be probed. PMID- 26415427 TI - [FTIR Noise Calibration in Quantitative Estimate of VOCs Concentration]. AB - The Classical Least Square regression (CLS) is one of the most popular regression methods in FTIR quantitative estimation. However, CLS is the best unbiased estimator only under the assumption that error (noise) in the spectrum has equal variance, which usually is not the case in FTIR. This paper proposed a noise calibration method for FTIR spectrum analysis. Based on measured variance of noise in the FTIR spectrum by computer, the Weighted Least Square regression (WLS) method is used in quantitative estimation. The experiment results showed that the WLS performs much better than CLS in quantitative estimation of VOCs pollution. PMID- 26415428 TI - [FTIR and 13C NMR Analysis of Dissolved Organic Matter (DOM) in the Treatment Process of Tannery Wastewater]. AB - Nowadays, the wastewater quantity discharged yearly from tannery industry is around 0. 2 billion t in China. The contaminants of tannery wastewater include macromolecular organic matters, such as grease, fur scraps and collagen, and the alkaline wastewater appears to be of high content of salt and COD. The quality of tannery wastewater is monitored strictly among all kinds of industry wastewater. In the treatment process of tannery wastewater, the quality of inlet and outlet water is generally analyzed. In fact, the transformation behavior of contaminants should be additionally checked to optimize the treatment conditions. Dissolved organic matter (DOM) is commonly existed in water-bodies and helpful to understand the physicochemical characteristics, while the related work should be further studied on tannery wastewater. The approaches of elemental analysis, thermal gravimetric analysis (TG), Fourier infrared spectroscopy (FTIR) and 13C nuclear magnetic resonance (13C NMR) were used to reveal the characteristics of DOM in the treatment process of tannery wastewater. The results showed the carbon content of DOM samples increased gradually, atomic ratios of H/C increased firstly and then decreased, indicating the organic matters were decomposed into chain structures firstly, finally forming the component hard to degraded. The pyrolysis process of DOM mainly proceeded in the regions of 110~530 degrees C (aliphatic compound, protein, etc. ) and 530~800 degrees C (aromatic ring, single bond of C-C, etc. ). The functional groups of DOM included -OH, -NH2, C=O and so on, and the aromatic substances were detected, shown from FTIR figures, in the later period of the reaction, caused by the metabolism effect of micro organism. The content of alkoxy-C increased to the maximum in the second biochemical pond, and the minimum content of aromatic-C appeared in the second biochemical pond, suggesting the transformation behavior of carbon functional groups. The investigation on DOM in tannery wastewater is significant to understand the purification mechanism of contaminants in tannery wastewater. PMID- 26415429 TI - [Retrieval of the Optical Thickness and Cloud Top Height of Cirrus Clouds Based on AIRS IR High Spectral Resolution Data]. AB - A study was carried out to retrieve optical thickness and cloud top height of cirrus clouds from the Atmospheric Infrared Sounder (AIRS) high spectral resolution data in 1070~1135 cm-1 IR band using a Combined Atmospheric Radiative Transfer model (CART) by brightness temperature difference between model simulation and AIRS observation. The research is based on AIRS LIB high spectral infrared observation data combined with Moderate Resolution Imaging Spectroradiometer (MODIS) cloud product data. Brightness temperature spectra based, on the retrieved cirrus optical thickness and cloud top height were simulated and compared with brightness temperature spectra of AIRS observation in the 650~1150 cm-1 band. The cirrus optical thickness and cloud top height retrieved were compared with brightness temperature of AIRS for channel 760 (900.56 cm-1, 11. 1 um) and cirrus reflectance of MODIS cloud product. And cloud top height retrieved was compared with cloud top height from MODIS. Results show that the brightness temperature spectra simulated were basically consistent with AIRS observation under the condition of retrieval in the 650~1150 cm-1 band. It means that CART can be used to simulate AIRS brightness temperature spectra. The retrieved cirrus parameters are consistent with brightness temperature of AIRS for channel 11. 1 um with low brightness temperature corresponding to large cirrus optical thickness and high cloud top height. And the retrieved cirrus parameters are consistent with cirrus reflectance of MODIS cloud product with high cirrus reflectance corresponding to large cirrus optical thickness and high cloud top height. Correlation coefficient of brightness temperature between retrieved cloud top height and MODIS cloud top height was relatively high. They are mostly located in the range of 8. 5~11.5 km, and their probability distribution trend is approximately identical. CART model is feasible to retrieve cirrus properties, and the retrieval is reliable. PMID- 26415430 TI - [Study on the Influence of Mineralizer on the Preparation of Calcium Aluminates Based on Infrared Spectroscopy]. AB - In this study, effect of mineralizer on the structure and spectraproperties of calcium aluminates formation was extensively studied. Medium or low-grade bauxite and calcium carbonate were used as raw material and mineralizer CaF2 as additive. Calcium aluminates can be obtained after mixing fully, calcination and grinding. The prepared calcium aluminates can be directly used for the production of polyaluminiumchloride (PAC), polymeric aluminum sulfate, sodium aluminate and some other water treatment agents. The calcium aluminates preparation technology was optimized by investigating the mass ratio of raw materials (bauxiteand calcium carbonate) and mineralizer CaF2 dosage. The structure and spectra properties of bauxite and calcium aluminates were characterized by Fourier transform infrared(FTIR) spectroscopy analysis and the mineralization mechanism of the mineralizer was studied. FTIR spectra indicated that the addition of mineralizer promoted the decomposition and transformation of the diaspore, gibbsite and kaolinite, the decomposition of calcium carbonate, and more adequately reaction between bauxite and calcium carbonate. In addition, not only Ca in calcium carbonate and Si in bauxite were more readily reacted, but also Si O, Si-O-Al and Al-Si bonds in the bauxite were more fractured which contributed to the release of Al in bauxite, and therefore, the dissolution rate of Al2O3 could be improved. The dissolution rate of Al2O3 can be promoted effectively when the mineralizer CaF2 was added in a mass ratio amount of 3%. And the mineralizer CaF2 cannot be fully functioned, when its dosage was in a mass percent of 1. 5%. Low-grade bauxite was easier to sinter for the preparation of calcium aluminates comparing with the highgrade one. The optimum material ratio for the preparation of calcium aluminates calcium at 1 250 degrees C was the mass ratio between bauxite and calcium carbonate of 1 : 0. 6 and mineralizer CaF2 mass ratio percent of 3%. PMID- 26415431 TI - [Effects of Different Pretreatment Methods on the Phenylketonuria Screening Model by FTIR/ATR Spectroscopy]. AB - To establish a phenylketonuria screening model by FTIR/ATR spectroscopy, and to compare the effects of different pretreatment methods, such as baseline correction, smoothing, derivation, Fourier deconvolution, on the model quality. A consensus partial least squares regression method (cPLS) was used to build the quantitative model of phenylalanine in dried blood spots. The effects of different pretreatment methods on the model performance were investigated, using the correlation coefficient (r), root mean square error of prediction (RMSEP), mean relative error (MRE) and predictive accuracy (Acc). The nine-point smoothing coupled with the first differential was found to perform the best. Compared with the model by the original spectra, its r, RMSEP, MRE and Acc were improved from 0. 822 7, 115. 8, 0. 395 and 94. 6 to 0. 889 9, 102. 2, 0. 286 and 100, respectively. With the advantages of fast speed, easy process, no reagents consumption and environmental protection, the present method is expected to become a simple and green technology for rapidly screening the neonatal phenylketonuria in a large population. PMID- 26415432 TI - Rapid Isolation of Phenol Degrading Bacteria by Fourier Transform Infrared (FTIR) Spectroscopy. AB - Phenol is an important chemical engineering material and ubiquitous in industry wastewater, its existence has become a thorny issue in many developed and developing country. More and more stringent standards for effluent all over the world with human realizing the toxicity of phenol have been announced. Many advanced biological methods are applied to industrial wastewater treatment with low cost, high efficiency and no secondary pollution, but the screening of function microorganisms is certain cumbersome process. In our study a rapid procedure devised for screening bacteria on solid medium can degrade phenol coupled with attenuated total reflection fourier transform infrared (ATR-FTIR) which is a detection method has the characteristics of efficient, fast, high fingerprint were used. Principal component analysis (PCA) is a method in common use to extract fingerprint peaks effectively, it couples with partial least squares (PLS) statistical method could establish a credible model. The model we created using PCA-PLS can reach 99. 5% of coefficient determination and validation data get 99. 4%, which shows the promising fitness and forecasting of the model. The high fitting model is used for predicting the concentration of phenol at solid medium where the bacteria were grown. The highly consistent result of two screening methods, solid cultural with ATR-FTIR detected and traditional liquid cultural detected by GC methods, suggests the former can rapid isolate the bacteria which can degrade substrates as well as traditional cumbersome liquid cultural method. Many hazardous substrates widely existed in industry wastewater, most of them has specialize fingerprint peaks detected by ATR-FTIR, thereby this detected method could be used as a rapid detection for isolation of functional microorganisms those can degrade many other toxic substrates. PMID- 26415433 TI - [Study on Hollow Brick Wall's Surface Temperature with Infrared Thermal Imaging Method]. AB - To address the characteristic of uneven surface temperature of hollow brick wall, the present research adopts soft wares of both ThermaCAM P20 and ThermaCAM Reporter to test the application of infrared thermal image technique in measuring surface temperature of hollow brick wall, and further analyzes the thermal characteristics of hollow brick wall, and building material's impact on surface temperature distribution including hollow brick, masonry mortar, and so on. The research selects the construction site of a three-story-high residential, carries out the heat transfer experiment, and further examines the exterior wall constructed by 3 different hollow bricks including sintering shale hollow brick, masonry mortar and brick masonry. Infrared thermal image maps are collected, including 3 kinds of sintering shale hollow brick walls under indoor heating in winter; and temperature data of wall surface, and uniformity and frequency distribution are also collected for comparative analysis between 2 hollow bricks and 2 kinds of mortar masonry. The results show that improving heat preservation of hollow brick aid masonry mortar can effectively improve inner wall surface temperature and indoor thermal environment; non-uniformity of surface temperature decreases from 0. 6 to 0. 4 degrees C , and surface temperature frequency distribution changes from the asymmetric distribution into a normal distribution under the condition that energy-saving sintering shale hollow brick wall is constructed by thermal mortar replacing cement mortar masonry; frequency of average temperature increases as uniformity of surface temperature increases. This research provides a certain basis for promotion and optimization of hollow brick wall's thermal function. PMID- 26415434 TI - [Research of Straw Biomass Based on NIR by Wavelength Selection of IPLS-SPA]. AB - The whole spectrum usually contains a lot of redundant information in the near infrared spectroscopy model, the presence of redundant information will increase the model resolution time and increase the difficulty of parsing model, Therefore, how to select the characteristic wavelength quickly and effectly is very crucial. In this paper, we combined the algorithm based on SPA (successive projections algorithm ) with IPLS (interval partial least squares ) to selec the characteristic wavelength in the fermentation of wheat straw microbial biomass, A total of 85 samples prepared by measuring microbial biomass using glucosamine method, 68 samples are chosen as calibration set and 17 simples are chosen as verification set. First, the whole spectral region 520 points are segmented modeling according to the interval wavelength point size 10, 20, 30, 40 and 4 450~4 925 cm-1, 9 194~9 993 cm-1 two-band range are selected as the characteristic wavelength band, then pick out the new feature wavelength points by Successive Projections Algorithm band and Genetic Algorithm (GA), comprehensive analysis and comparison the result of model. The experimental results show that the using of IPLS-SPA algorithm to select the combination band 4 450~4 925 cm-1 & 9 194~9 993 cm-1 has the best modeling effect, compared with the modeling of whole spectrum, the wavelength points decrease from 520 to 10, the correction coefficient of determination R2 rised from 0. 884 9 to 0. 945 28, root mean square error (RMSE) dropped from 11. 104 9 to 8. 203 3, although the genetic algorithm model achieved the better accuracy, but the results are instable and have a strong randomness , while IPLS combined SPA method can select characteristic wavelength information stability and accurately, which can improve the model calculation speed and reduce the fitting difficulty of the model, it can be used as a new reference method for band selection. The results show that using near infrared spectroscopy method for straw biomass rapid detection is feasible. PMID- 26415435 TI - [Applied Research in Grade Estimation of Surimi by Near Infrared Spectroscopy]. AB - The feasibility of utilizing near infrared spectroscopy for estimating frozen and thawed white croaker surimi with different grades was presented in the research. First-derivative and standard normal variable transformation were used as pretreatment method, then principal component analysis was carried out on the processed datas. Establish grade estimation model on white croaker surimi with different grades by principal component analysis-mahalanobis distance pattern recognition method. Seven kinds of physicochemical indexes (moisture, protein, crude fat, salt-soluble protein, gel strength, water-holding ability and whiteness) of white croaker surimi with different grades were determinated. We came to the following conclusions. Firstly, white croaker surimi with three grade could be distinguished effectively by principal component analysis. Secondly, the model of grade estimation established by principal component analysis-mahalanobis distance pattern recognition method had better performance on frozen white croaker surimi than thawed ones, the former's comprehensive accuracy was 96. 3 % with the latter's is 83. 3%. Thirdly, the physicochemical indexes of white croaker surimi with different grades had some distinctions. The research indicated that near infrared spectroscopy could estimate the grade of white croaker surimi rapidly and nondestructively. PMID- 26415436 TI - [Quantitative Detection of Chinese Cabbage Clubroot Based on FTIR Spectroscopy]. AB - Clubroot, caused by Plasmodiophora brassicae, is considered the most devastating soilborne disease in Brassica crops. It has emerged as a serious disease threatening the cruciferous crop production industry in China. Nowadays, the detection techniques for P. brassicae are laborious, time-consuming and low sensitivity. Rapid and effective detection methods are needed. The objective of this study is to develop a Fourier transform infrared spectrometer (FTIR) technique for detection of P. brassicae effectively and accurately. FTIR and Real time PCR techniques were applied in quantitative detection of P. brassicae. Chinese cabbages were inoculated with P. brassicae. By analyzing the FTIR spectra of P. brassicae, infected clubroots and healthy roots, three specific bands 1 105, 1 145 and 1 228 cm-1 were selected. According to the correlation between the peak areas at these sensitive bands and Real-time PCR Ct value, quantitative evaluation model of P. brassicae was established based on FTIR y=34. 17 +12. 24x 9. 81x2 - 6. 05x3, r=0. 98 (p<0. 05). To validate accuracy of the model, 10 clubroot samples were selected randomly from field, and detected by FTIR spectrum model, the results showed that the average error is 1. 60%. This demonstrated that the FTIR technology is an available one for the quantitative detection of P. brassicae in clubroot, and it provides a new method for quantitative and quickly detection of Chinese cabbage clubroot. PMID- 26415437 TI - [Measurement of Soil Total Nitrogen Using Near Infrared Spectroscopy Combined with RCA and SPA]. AB - Visible near spectra tecnnology was adopted to detect soil total nitrogen content. 394 soil samples were collected from Wencheng, Zhejiang province to be used for calibration model (n=263) and independent prediction set (n=131). Raw spectra and wavelength-reduced spectra with five different pretreatment methods (SG smoothing, SNV, MSC, 1st-D and 2nd-D) were compared to determine the optimal wavelength range and pretreatment method for analysis. The results with 5 different pretreatment methods were not improved compared to that both of full spectra PLS model and wavelength reduction spectra model. Spectral variable selection is an important strategy in spectrum modeling analysis, because it tends to parsimonious data representation and can lead to multivariate models with better performance. In order to simply calibration models, the wavelength variables selected by two different variable selection methods (i. e. regression coefficient analysis (RCA) and successive projections algorithm (SPA) were proposed to be the inputs of calibration methods of PLS, MLR and LS-SVM models separately. These calibration models were also compared to select the best model to predict soil TN. In total, 9 different models were built ahd the best results indicated that PLS, MLR and LS-SVM obtained the highest precision with determination coefficient of prediction R2(pre) =0. 81, RMSEP=0. 0031 and RPD=2. 26 based on wavelength variables selected by RCA (0. 0002) and SPA as inputs of models. SPA-MLR model and other three models based on 7 sensitive variables selected by RC using 0. 0002 regression coefficient threshold value obtained the best result with R2(pre), RMSEP and RPD as 0. 81, 0. 0031 and 2. 26. This prediction accuracy is classied to be very good. For all the models, it could be concluded that RCA and SPA could be very useful ways to selected sensitive wavelengths, and the selected wavelengths were effective to estimate soil TN. It is recommended to adopt SPA variable selection or RCA variable selection method with both linear and nonlinear calibration models for measurement of the soil TN using Vis-NIR spectroscopy technology, and wavelengths selection could be very useful to reduce collinearity and redundancies of spectra. PMID- 26415438 TI - [Characterization of Wood Surface Treated with Electroless Copper Plating by Near Infrared Spectroscopy Technology]. AB - Wood electromagnetic shielding material, which was made by treating wood with electroless plating, not only keep the superior characteristics of wood, but also improve the conductivity, thermal conductivity and electromagnetic shielding properties of wood. The emergence of this material opens the way to the value added exploitation of wood and widens the processing and application field for the electromagnetic shielding material. In order to explore the feasibility of using NIR technology to investigate the properties of wood electromagnetic shielding material, this study analysis the samples before and after copper plated process by the NIR spectroscopy coupled with principal component analysis (PCA). The results showed that (1) there exist significant differences between samples before and after copper plated process both on the spectral shape and absorption, and the great differences can also be seen in the samples with different treat time, especially for the samples with 5 min treat time; (2) after PCA analysis, six clusters from the samples before and after copper plated process were separately distributed in the score plot, and the properties of untreated wood and sensitized wood were similar, and the properties of samples for 25 and 40 min treat time were also similar in order that these samples were close to each other, all of which might suggest that the NIR spectroscopy reflected major feature information about material treatment; (3) After comparing the PCA performance between NIR and visible spectral region, it could be found that the classification performance of samples before and after copper plated process based on the NIR region were better than that based on the visible region, and the information of color on the surface of samples were preferably reflected in the visible region, which could indicate that there are more information about samples' surface characters using the visible spectroscopy coupled with NIR spectroscopy and it is feasible to use visible-NIR technology to investigate the surface characteristics of natural polymers treated with electroless copper plating. PMID- 26415439 TI - [Investigation of the Interaction between 1,3-Dimethylurea and Solvent by Raman Methods]. AB - Urea family plays significant role in the bio-science area. Because of the unique frame, they can form Hydrogen bond with water as well as other substance. Hydrogen bonds are normal weak interactions in the system of bio-molecules. A Raman spectrum is the most powerful method to obscure the Hydrogen bond interaction between molecules. Initially, we measure the Raman spectra of DMU crystal, and then use density function theory with a B3LYP/6-311G* * basis set to optimize the geometry structure and calculate the vibrational frequency of gas phase DMU, which assigns the Raman pecks. Then, measure the solvent. When dissolving DMU in water, the interaction between DMU-DMU will replaced by the interaction between water-DMU. The orbital hybridization of nitrogen atoms changes from the solid-state the sp' orbital hybridization to sp3. So, the frame of this molecule goes from in-planet to out of plant during this process. PMID- 26415440 TI - [Surface Enhanced Raman Spectroscopic Studies on the Coupling Effect of Multilayer Au@SiO2 Film]. AB - The SiO2 shell with the thickness of 4 nm was attached onto high surface enhanced Raman spectroscopy (SERS) active Au core nanoparticles to obtain Au@SiO2 core shell nanoparticles by the hydrolysis of sodium silicate solution with the boiling water bath. The inert shell of SiO2 isolated the direct interaction of Au nanoparticles and probe molecules. The stable, compact and uniform monolayer nanoparticles film was self assembled at water/oil interface, and one to six monolayers film was transferred to Si wafer as SERS substrates through layer by layer technique. The relationship between the SERS activities and layers of the monolayer nanoparticles film on Si surface was investigated. The SERS mapping was developed to determine the layers of the Au@SiO2 film. The coupling effect among the Au@SiO2 films was explored by changing the adsorption location of the probe on the multilayer films. The result revealed that the monolayer film was a favourable candidate with high-quality performances for the SERS application. The SERS signal was distributed on the surface with high uniformity at the same monolayer film, and it was enhanced in the intensity with the increase in film layers. It reached the maximun intensity as the film was over five layers. It indicated that the SERS signal was contributed mainly by the first five monolayers. The probe molecules were immobilized onto the first monolayer nanoparticles film, and the SERS signal from the probe approached to the maximum as the second monolayer covered the probe modified first nanoparticles film. It was dominated by the coupling effect ("hot spots") of the adjacent layers. The SERS signal decreased in intensity when the third layer was transferred onto the second layer, and it disappeared after the fouth layer was covered, mainly duo to the shield of the nanoparticles film to the incident laser and Raman signal. The preliminary results provided guidance for fabricating optimal SERS substrates. PMID- 26415441 TI - [Raman and EDXRF Study on Overglaze Decorations of Jingdezhen Ceramics]. AB - Overglaze decoration porcelain is an important category of ancient Chinese ceramics, which has significant artistic value and scientific value. Nondestructive analysis methods such as Raman spectroscopy and EDXRF were used to analyze the overglaze decorations on the Jingdezhen ceramic samples of Yuan, Ming and Qing Dynasty. The recipe and color mechanism of the overglaze pigments were discussed according to the chemical composition and phase composition analysis. The study found that dark red overglaze decorations of ancient Honglvcai, Wucai and famille rose in Jingdezhen are colored by hematite, yellow color is lead tin yellow, carmine decoration is colored by gold less than 0. 1 % in concentration, and green decorations are colored by bivalent copper ion. The result also indicates that the effective combination of Raman spectroscopy and EDXRF can play an important role in the deep research on ceramic artifacts, especially for the overglaze decoration pigments which are interveined each other. PMID- 26415442 TI - [Fast Discrimination of Drugs by Improved Projection Algorithm Based on Raman Spectroscopy]. AB - The projection algorithm used in mixture analysis to determine whether there is unknown disturbance existing in grey system can not accurately identify different samples and similar samples at the same time when it is used in the identification of drugs, because of the insufficient criteria. In the present study, one of its criteria for whether the size of measurement error of testing sample is at a limited level is improved for whether the size and distribution of measurement error is equal and similar between testing sample and standard sample. By testing 6 kinds of normal drugs (including BAYER Aspirin Enteric coated Tablets, TYLENOL Acetaminophen Sustained Release Tablets, BAYER Compound Paracetamol Tablets(II), HUAZHONG Compound Vitamin C, HUAZHONG Vitamin B and MADINGLIN Demperidone Tablets) and 3 kinds of similar drugs of aspirin (including BAYER Aspirin Enteric-coated Tablets, Shanghai SINE Aspirin Enteric-coated Tablets and Bamyl Aspirin Effervescent Tablets), it was found that the un improved projection algorithm directly used in discrimination of drugs shows poor performance with many problems existing, however, the improved projection algorithm can discriminate different drugs and similar drugs with accuracy up to 100%. The improved projection algorithm can be a universal, accurate and reliable automated pharmaceutical identification algorithm and can provide a reference for the study on identification of substance. PMID- 26415443 TI - [Detection of Ethoprophos Using SERS Coupled with Magnetic Fe3O4/Ag Composite Materials]. AB - The magnetic Fe3O4/Ag composite materials were synthesized by reducing AgNO3 with sodium citrate in the presence of Fe3O4 which were prepared by co-precipitation firstly. The enrichment and extraction of ethoprophos assembled on Fe3O4/Ag were achieved with the applied magnetic field. The different concentrations of ethoprophos adsorbed on Fe3O4/Ag were analyzed by SERS and it was showed that the trace analysis of ethoprophos had been established, while the enhancement factor of probe molecules on Fe3O4/Ag was 1. 48 X 10(5). The structure and morphology of Fe3O4/Ag were characterized by UV-Vis, EDX and TEM. Compared with Ag, the UV-Vis absorption peak of Fe3O4/Ag shifted from 417 to 369 nm, and the UV-Vis of Fe3O4 almost had no characteristic absorption peak in this region. At the same time, it was showed that the surface properties of Fe3O4/Ag changed with Raman enhancement effect during the aggregation process of Ag around the surface of Fe3O4. Further EDX images of micro area element analysis suggested that the chemical composition of products were Ag, Fe and O while the Cu peak was from the copper mesh. In addition, TEM images indicated that the average particle size of Fe3O4 was between 30 and 60 nm with shape tended to be spherical. And the silver nanoparticles were attached to the Fe3O4 particles and agglomeration occured. Density functional theory calculations which can be applied to qualitative judgment of molecule was carried out to obtain the molecular optimization structure and theoretical Raman spectra. It was found that the stabilized SERS signals were detected under the saturated adsorption equilibrium after 15 min. Finally, Raman response of ethoprophos was achieved with lower than 2 X 10(-8) mol . L-1 , indicatint that the established method had reached the requirements of ethoprophos residues detection and could be used for analysis of sulfur containing organophosphorus pesticide. PMID- 26415444 TI - [Locally Dynamically Moving Average Algorithm for the Fully Automated Baseline Correction of Raman Spectrum]. AB - The baseline correction is an, extremely important spectral preprocessing step and can significantly improve the accuracy of the subsequent spectral analysis algorithm. At present most of the baseline correction algorithms are manual and semi-automated. The manual baseline correction depends on the user experience and its accuracy is greatly affected by the subjective factor. The semi-automated baseline correction needs to set different optimizing parameters for different Raman spectra, which will be inconvenient to users. In this paper, a locally.dynamically moving average algorithm (LDMA) for the fully automated baseline correction is presented and its basic ideas.and steps are demonstrated in detail. In the LDMA algorithm the modified moving averaging algorithm (MMA) is used to strip the Raman peaks. By automatically finding the baseline subintervals of the raw Raman spectrum to divide the total spectrum range into multi Raman peak subintervals, the LDMA algorithm succeed in dynamically changing the window half width of the MA algorithm and controlling the numbers of the smoothing iterations in each Raman peak subinterval. Hence, the phenomena of overcorrection and under-correction are avoided to the most degree. The LDMA algorithm has achieved great effect not only to the synthetic Raman spectra with the convex, exponential, or sigmoidal baseline but also to the real Raman spectra. PMID- 26415445 TI - [A De-Noising Algorithm for Fluorescence Detection Signal of Mineral Oil in Water by SWT]. AB - Fluorescence analysis is an important means of detecting mineral oil in water pollutants because of high sensitivity, selectivity, ease of design, etc. Noise generated from Photo detector will affect the sensitivity of fluorescence detection system, so the elimination of fluorescence signal noise has been a hot issue. For the fluorescence signal, due to the length increase of the branch set, it produces some boundary issues. The dbN wavelet family can flexibly balance the border issues, retain the useful signals and get. rid of noise, the de-noising effects of dbN families are compared, the db7 wavelet is chosen as the optimal wavelet. The noisy fluorescence signal is statically decomposed into 5 levels via db7 wavelet, and the thresholds are chosen adaptively based on the wavelet entropy theory. The pure fluorescence signal is obtained after the approximation coefficients and detail coefficients quantified by thresholds reconstructed. Compared with the DWT, the signal de-noised via SWT has the advantage of information integrity and time translation invariance. PMID- 26415446 TI - [Light Absorption Characteristics of FeS2-Fe1-xS Heterostructures Synthesized under Hydrothermal Conditions]. AB - Fe-S series, especially FeS2 and Fe1-x S is the main component of crustal rocks as important metal sulphides. Pyrite (FeS2) shows a promising vision in solar cell materials for its high absorption coefficient and suitable band gap. Predecessors have done some researches on the photovoltaic properties of Fe-S series under different conditions. However, little researches have been done on the coexisted sulphide of FeS2 and Fe1-xS. FeS2 and Fe1-xS often appear as symbiotically due to their similar formation conditions. So the study on the optical absorption characteristics of FeS2 and Fe1-xS are of important significance. In order to study the optical absorption characteristics of FeS2 Fe1-xS heterostructures, using the SEM and XRD to characterize the morphology, composition and structure, respectively. The results show that the samples were cubic pyrite with a certain amount of pyrhotite (Fe1-xS). The crystal partical size was between 5 and 10 nm. Measurement of the absorption spectrum was performed using Cary 500 UV-Vis-NIR spectrophotoineter, acquiring the results of 1 860-1 889 nm, and the absorption peak in 1879nm. According to the band gap (eV) formula, the band gap value is calculated to be 0. 657 8 eV. The extreme electrical-to-optical conversion efficiency achieved was about 15%. By the first principles, we analysed the reason of the changing of the band gap value, and then compared the result with previous one. The internal structure of mineral is the important factor affecting the photoelectric conversion. The light absorption characteristics of FeS2-Fel-xS heterostructures synthesized under hydrothermal conditions is better than the characteristics from natural pyrite with defects of Co and Ni. The heterostructures can improve the electrical-to-optical conversion efficiency and provide scientific basis for the absorption characteristics research of Fe-S series materials. PMID- 26415447 TI - Effect of Exogenous Phytase Addition on Soil Phosphatase Activities: a Fluorescence Spectroscopy Study. AB - The utilization of organic phosphorus (P) has directly or indirectly improved after exogenous phytase was added to soil. However, the mechanism by which exogenous phytase affected the soil phosphatases (phosphomonoesterase and phosphodiesterase) activities was not clear. The present work was aimed to study red soil, brown soil and cinnamon soil phosphomonoesterase (acid and alkaline) (AcP and AlP) and phosphodiesterase (PD) activities responding to the addition of exogenous phytase (1 g phytase/50 g air dry soil sample) based on the measurements performed via a fluorescence detection method combined with 96 microplates using a TECAN Infinite 200 Multi-Mode Microplate Reader. The results indicated that the acid phosphomonoesterase activity was significantly enhanced in red soil (p<=0. 01), while it was significantly reduced in cinnamon soil; alkaline phosphomonoesterase activity was significantly enhanced in cinnamon soil (p<= 0. 01), while it was significantly reduced in red soil; phosphodiesterase activity was increased in three soils but it was significantly increased in brown soil (p<=0. 01) after the addition of exogenous phytase. The activities still remained strong after eight days in different soils, which indicated that exogenous phytase addition could be enhance soil phosphatases activities effectively. This effect was not only related to soil properties, such as pH and phosphorus forms, but might also be related to the excreted enzyme amount of the stimulating microorganism. Using fluorescence spectroscopy to study exogenous phytase addition influence on soil phosphatase activities was the first time at home and abroad. Compared with the conventional spectrophotometric method, the fluorescence microplate method is an accurate, fast and simple to use method to determine the relationships among the soil phosphatases activities. PMID- 26415448 TI - The Fluorescence Enhancement of Mercury Detected in Food Based on Rhodamine Derivatives. AB - Recently, the problem of food security is more and more serious, and people pay attention to mercury because of the toxic of it. A new approach for the determination of mercury content in foodstuff is devised. In this paper, first, we design and synthesis a new kind of fluorescent probe whose matrix based on rhodamine B, hydrazine hydrate and hydroxy benzaldehyde. Through the analysis of H-NMR spectra of the synthesized product L1, we confirm that the synthetic substance is the adjacent carboxyl benzaldehyde hydrazone structure generation of rhodamine B. Then, we measure the fluorescence signal intensity of the probe with different concentrations of mercury ions fully upon complexation by fluorescence spectrometer and we can study the relationship between the mercury ion concentration and the fluorescence intensity and draw the standard working curve. Following, It's time to discuss the microwave digestion processing of tea, after digestion we use the synthetic probe Li for determination of mercury content in tea. The experimental results show that the maximum excitation wavelength of the probe and coordination compound are 568. 05 and 560. 00 nm, the maximum emission wavelength are 587. 94 and 580. 00 nm. Then we can find the best testing conditions to improve the degree of accuracy, that is: room temperature, 50% the methanol solution, 3. 0 mL pH 4. 0 buffer solution, in the extent of 30 min. The experimental results show that Na+, K+, Ca2+, Cu2+, Zn2+, Al3+ have little impact on the fluorescence intensity of the:probe. Fe3+, Mg2+, Ba2+ has a weak enhancement to the fluorescence intensity of the probe. While a low concentrations of Hg2+ have an obviously enhanced effect on the fluorescence intensity of the probe. In contrast to other metal ions, the probe for Hg2+ has a good selectivity. Linear relationship between the magnitude of increase in fluorescence intensity and concentration of mercury ion was in the range of 5~20 ng . L-1 with detection limit (3S/N) of 1. 9 ng . L-1. The proposed method was applied to determination of mercury ion in samples of tea and sausage and the obtained result and sample recovery were all satisfactory. The methods of analysis instrument has the advantages of simple structure, sensitivity, high accuracy, good selectivity and less volume of simple, without the need for enrichment, being very practical. PMID- 26415449 TI - [Fluorescence Determination of Trace Se with the Hydride-K13-Rhodamine 6G System]. AB - Se is a necessary trace element for human and animals, but the excess intake of Se caused poison. Thus, it is very important to determination of Se in foods and water. The target of this study is development of a new, sensitive and selective hydride generation-molecular fluorescence method for the determination of Se. In 0. 36 mol . L-1 sulfuric acid, NaBH4 as reducing agent, Se (IV) is reduced to H2 Se. Usin3-g I solution as absorption liquid3, I- is reduced to I- by H2Se. When adding rhodamine 6G, Rhodamine 6G and I3- form association particles, which lead to the fluorescence intensity decreased. When Se(IV) existing, Rhodamine 6G and I3- bind less, And the remaining amount of Rhodamine 6G increase. So the fluorescence intensity is enhanced. The analytical conditions were optimized, a 0. 36 ml . L-1 H2SO4, 21. 6.g . L-1 NaBH4, 23.3 um . L-1 rhodamine 6G, and 50 umol . L-1 KI3 were chosen for use. When the excitation wavelength is at 480nm, the Rayleigh scattering peak does not affect the fluorescence recording, and was selected for determination of Se. Under the selected conditions, Se(IV) concentration in the 0. 02~0. 60 ug . mL-1 range and the increase value of the fluorescence intensity (DeltaF) at 562 nm linear relationship. The linear regression equation is DeltaF562 nm =12. 6c + 20. 9. The detecton limit was 0.01 u.g . L-1. The influence of coexistence substances on the hydride generatin molecular fluorescence determination of 5. 07 X10(-6) mol . L-1 Se(IV) was considered in details. Results showed that this new fluorescence method is of high selectivity, that is, 0. 5 mmol. L-1 Ba2+, Ca2+, Zn2+ and Fe3+, 0. 25 mmol . L-1 . Mg2+, 0. 05 mmol . L-1 K+, 0. 2 mmol . L-1 Al3+, 0. 025 mmol . L-1 Te(VI) do not interfere with the determination. The influence of Hg2+, CD2+ and Cu2+ that precipitate with Se(IV), can be eliminated by addition of complex reagent. This hydride generation-molecular fluorescence method has been applied to determination of trace Se in water samples, PMID- 26415450 TI - [Determination of Trace Boron Based on Gold Nanorod Plasmonic Resonance Rayleigh Scattering Energy Transfer to the Coordinate]. AB - B is a necessary trace element for human and animals, but the excess intake of B caused poison. Thus, it is very important to determination of B in foods and water. The target of this study is development of a new, sensitive and selective resonance Rayleigh scattering energy transfer (RRS-ET) for the determination of B. The combination of energy transfer with resonance Rayleigh scattering (RRS) has developed a new technology called RRS-ET, which can realize selective and sensitive detection of boric acid. The gold nanorods in diameter of 12 nm and length of 37 nm were prepared by the seed growth procedure. In pH 5. 6 NH4 Ac-HAc buffer solution and in the presence of azomethine-H (AMH), the gold nanorod particles exhibited a strong resonance Rayleigh scattering (RRS) peak at 404 nm. In the presence of boric acid, it reacts with AMH to form AMH-boric acid (AMH-B) complexes. When the complexe as a receptor close to the gold nanorod as a donor, the resonance Rayleigh scattering energy transfer (RRS-ET) take placed that resulted in the Rayleigh scattering signal quenching. With the increase of the concentration of boric acid, the formed complexes increased, the scattering light energy of gold nanorod transfer to the complexes increased, resulting in the Rayleigh scattering intensity linearly reduced at 404 nrn. The decreased RRS intensity responds linearly to the concentration of boron over 10~750 ng . mL-1 B, with a regress equation of DeltaI404 nm =3. 53c+24 and a detection of 5 ng mL 1 B. The influence of coexistence substances on the RRS-ET determination of 2. 3 X 10(-7) mol . L-1 B was considered in details. Results showed that this new RRS ET method is of high selectivity, that is, 4 X 10(-4) mol . L-1 Mn2+, Cd2+, Zn2+, Bi+, Na+, Al3+, glucose, Hg2+, IO3-, F-, SO(2-)3, SiO3-, NO3-, CIO4-, H2O2, mannitol, glycerol, and ethylene glycol, 4X 10(-5) mol . L-1 L-tyrosine, and 2 X 10(-4) mol . L-1 L-glutamic acid do not interfere with the determination. Based on this, a new sensitive, selective, simple and rapid RRS-ET method has been developed for the determination of trace boron in six mineral water samples that contain 24. 9, 29. 3, 57. 9, 59. 0, 84. 9, and 105. 1 ng . mL-1 B, with relative standard deviation of 1. 6%~ 4. 1% and recovery of 95. 61~9. 6%. PMID- 26415452 TI - [Optimizing Color Rendering for Mixed-Color White Light LED]. AB - To optimize color rendering of mixed-color LEDs, the Gaussian model was used to analyze the color-mixed LED's spectrum power distribution. The peak wavelength "lambdam", spectral half width "Deltalambda" and amplitude "A" were basic parameters for optimizing color rendering R9, which is very important for objects to be colorful and vivid under the white light LED's'illuminating. The typical methods for color mixing were used to get white light LEDs. Result was that to get the satisfied color rendering index, one of the color primaries should be certain and then other color primaries would be analyzed through changing three basic parameters step by step. It was concluded that the analysis in this paper would be referential to optimize the color-mixed white LED's color rendering. PMID- 26415451 TI - [Study of Determination of Oil Mixture Components Content Based on Quasi-Monte Carlo Method]. AB - Gasoline, kerosene, diesel is processed by crude oil with different distillation range. The boiling range of gasoline is 35 ~205 degrees C. The boiling range of kerosene is 140~250 degrees C. And the boiling range of diesel is 180~370 degrees C. At the same time, the carbon chain length of differentmineral oil is different. The carbon chain-length of gasoline is within the scope of C7 to C11. The carbon chain length of kerosene is within the scope of C12 to C15. And the carbon chain length of diesel is within the scope of C15 to C18. The recognition and quantitative measurement of three kinds of mineral oil is based on different fluorescence spectrum formed in their different carbon number distribution characteristics. Mineral oil pollution occurs frequently, so monitoring mineral oil content in the ocean is very important. A new method of components content determination of spectra overlapping mineral oil mixture is proposed, with calculation of characteristic peak power integrationof three-dimensional fluorescence spectrum by using Quasi-Monte Carlo Method, combined with optimal algorithm solving optimum number of characteristic peak and range of integral region, solving nonlinear equations by using BFGS(a rank to two update method named after its inventor surname first letter, Boyden, Fletcher, Goldfarb and Shanno) method. Peak power accumulation of determined points in selected area is sensitive to small changes of fluorescence spectral line, so the measurement of small changes of component content is sensitive. At the same time, compared with the single point measurement, measurement sensitivity is improved by the decrease influence of random error due to the selection of points. Three-dimensional fluorescence spectra and fluorescence contour spectra of single mineral oil and the mixture are measured by taking kerosene, diesel and gasoline as research objects, with a single mineral oil regarded whole, not considered each mineral oil components. Six characteristic peaks are selected for characteristic peak power integration to determine components content of mineral oil mixture of gasoline, kerosene and diesel by optimal algorithm. Compared with single point measurement of peak method and mean method, measurement sensitivity is improved about 50 times. The implementation of high precision measurement of mixture components content of gasoline, kerosene and diesel provides a practical algorithm for components content direct determination of spectra overlapping mixture without chemical separation. PMID- 26415453 TI - [Differential Reflectance Spectroscopy for In-Situ Monitoring of Organic Thin Films Growth in Vacuum Environment]. AB - For realizing the real-time monitoring of organic thin film preparation process in vacuum environment, the present paper proposes a high precision measurement approach based on differential reflectance spectroscopy (DRS). An optical system was constructed with off the shelf optical components, such as off-axis parabolic mirror, optical flat and optical fiber. A differential algorithm was employed to analyze the spectral signals. Based on the homebuilt setup, instability induced by variation of temperature was investigated. It was concluded that with the good control of temperature and air flow, the measurement repeatability of this system is better than 2 per thousand for a long-term period. Furthermore, an initial stage of organic thin film growth of pentacene molecules on the surface of Au was studied. As compared with the data of film thickness gauge and atomic force microscope, DR spectra accurately recorded the fine optical evolution with sub monolayer resolution, which is related to the growth of the thin film. As a result, the DR optical system exhibits characteristics of broad spectrum (range from 300 to 820 nm), high stability (repeatability better than 2X 10(-3)), and high precision (sub-monolayer resolution) after efforts were done to decrease the influences on the spectral quality produced by misalignments of the optical components, the defects of the optics, and the disturbances of the environmental conditions. It is indicated that the proposed DR method is suitable for real-time online monitoring of thin film growth with high precision. PMID- 26415454 TI - [Building Change Detection Based on Multi-Level Rules Classification with Airborne LiDAR Data and Aerial Images]. AB - The present paper proposes a new building change detection method combining Lidar point cloud with aerial image, using multi-level rules classification algorithm, to solve building change detection problem between these two kinds of heterogeneous data. Then, a morphological post-processing method combined with area threshold is proposed. Thus, a complete building change detection processing flow that can be applied to actual production is proposed. Finally, the effectiveness of the building change detection method is evaluated, processing the 2010 airborne LiDAR point cloud data and 2009 high resolution aerial image of Changchun City, Jilin province, China; in addition, compared with the object oriented building change detection method based on support vector machine (SVM) classification, more analysis and evaluation of the suggested method is given. Experiment results show that the performance of the proposed building change detection method is ideal. Its Kappa index is 0. 90, and correctness is 0. 87, which is higher than the object-oriented building change detection method based on SVM classification. PMID- 26415455 TI - [Preliminary Investigation of the Amount, the Molecular Weight and the Activity of Polysaccharides from Chaenomeles Speciosa Fruits in Ethanol Fractional Precipitation]. AB - Chaenomeles speciosa fruits were extracted using water. The extracts were precipitated with 20%~95% (phi) ethanol, respectively. The amount of total polysaccharide was measured with phenol-sulfuric acid method. A method using high performance size-exclusion chromatography (HPSEC) equipped with multiangle laser light-scattering photometry (MALLS) and differential refractometry (RI) was presented for determining the molecular weight and molecular weigh distribution. RAW264.7 macrophage were cultured and stimulated with the polysaccharides in vitro and the production of nitric oxide in the cells was determined by the Griess assay. The aim of the study is to determine the amount and the molecular weight of the polysaccharides from Chaenomeles speciosa fruits, and preliminary investigate the immunomodulatory activity, The study provided the basis datas for the further research of Chaenomeles speciosa fruits. , and provided a simple and system method for the research of natural polysaccharide. The ethanol fractional precipitation showed that the order of total polysaccharide content was 95%>80%>40% >=60%>20%. The results indicated that most polysaccharide from Chaenomeles speciosa fruits might be precipitated when ethanol concentration was up to 95% (T) and the crude polysaccharide purity had risen from 35. 1% to 45. 0% when the concentration of ethanol increased from 20% to 95%. HPSEC-MALLS-RI system showed that all the polysaccharide samples had the similar compositions. They appeared three chromatographic peaks and the retention time were not apparently different. The Mw were 6. 570 X 10(4) g . mol-1 and 1. 393 X 10(4) g . mol-1 respectively, and one less than 10 000 which was failure to obtain accurate values. The molecular weight of the first two polysaccharide distribution index(Mw/Mn)were 1. 336 and 1. 639 respectively. The polysaccharide samples had not exhibited immunomodulatory activity assessed on the basis of nitric oxide production by RAW264. 7 macrophage cells in the experiment. PMID- 26415456 TI - [Relationship between the Trypsin Activity and Conformational Change Caused by Ultra High Static Pressure]. AB - Trypsin was treated by high pressure technology, and its spatial structure was changed, the relationship between structural changes and trypsin activity was investigated. The secondary structure change of trypsin after pressure treatment was observed by Fourier transform infrared spectroscopy(FTIR). Moreover its tertiary structure change was observed by fluorescence spectroscopy; and its activity was tested using Folin phenol method. The results showed that, compared with the untreated(0.1 MPa), trypsin activity change was significant(p<0. 05) under different pressure(100~600 MPa) treatment at 37 degrees C for 20 min. After treated with 300 MPa, its activity was 0. 386 times higher than the untreated. Secondary structure of trypsin was analysed using FTIR, and the peak area ratio of alpha-helix and beta-tum in secondary structure was the maximum(2. 749); Endogenous fluorescence spectra intensity was the maximum (1 353) at excitation wavelength 295 nm, and was 4 262 at excitation wavelength 280 nm; exogenous fluorescent spectra intensity was 2 022 at excitation wavelength 228 nm, all these change was remarkable(p<0. 05) comparing with the untreated. Therefore, ultrahigh pressure processing influence on the spatial structure of trypsin and induce enzyme activity.change. Trypsin activity is relate to the peak area ratio of alpha-helix and beta-turn and the exposure degree of Trp and other hydrophobic a mino acid residues and Tyr. PMID- 26415457 TI - Synthesis, Structure and Spectroscopy Study of a 1D Copper Coordination Polymer Based on a Carboxybenzyl Viologen Ligand and SCN-Anion. AB - A zwitterionic viologen derivative ligand, 1,1'-bis(4-carboxybenzyl)-4 4' bipyridinium dichloride (H2BpybcCl2) as a multifunctional ligand, has been synthesized incorporating a 4,4'-bipyridine core with two carboxylate groups as a. building block, specifically designed for the rational construction of metal organic frameworks. H2BpybcCl2 ligand is a multifunctional ligand that contains viologen's specific functions and carboxylate coordination groups. The coordination polymers of viologen carboxylate with copper thiocyanate are not reported to date. A novel copper coordination polymer, [Cu(SCN)2 (Bpybc)] (I) was by solution diffusion method and characterized by single-crystal X-ray diffraction, XRD, elemental analyses, IR spectroscopy, UV-Vis DRS, TG analysis and liquid-state luminescent properties. Compound I crystallized in the monoclinic system with C2/c space group. Crystal data for complex I is as follow: a=19. 508(4) A, b=9. 474(2) A, c =16. 963(3) A, alpha=90 degrees , beta=124. 92(3) degrees , gamma=90 degrees . Two SCN-anions were coordinated to the Cu2+ cation forming a [Cu(SCN)2] unit. Complex I was built up by [Cu(SCN)2] units bridged sequentially by ladder-shaped Bpybc ligands to form one-dimensional zigzag chains running along the [203] direction. The chains were held together by pi-pi interaction between the pyridine rings and phenyl rings, thus yielding a 3 D extended supramolecular network. The UV-Visible absorption spectra show the absorption bands of pi-pi* transitions of Bpybc ligands and d-->d transition of Cu2+. The liquid-state luminescent property of compound I was investigated at room temperature. Attractively, the complex exhibits strong blue emission peak at 533 nm (lambdaEx=360 nn) that can be assigned to intraligand transition of Bpybc ligand when it was excited at 360 nm. PMID- 26415458 TI - Crop Classification Based on Time Series MODIS EVI and Ground Observation for Three Adjoining Years in Xinjiang. AB - There is a regular use of Moderate Resolution Imaging Spectroradiometer (MODIS) 250 meter EVI to classify the crops on a regional level throughout the world. A rapid agricultural land use change attributed to new Chinese agriculture policy is attracting many researchers to focus. The objective of this study is to present a more straightforward multiyear classification methodology using time series MODIS EVI with 250 meters spatial resolution and subsequent field data in Xinjiang, China. An extensive polygon based ground reference annual crop data were collected for the years 2011, 2012 and 2013 throughout the study area. The most pure pixel within each polygon was selected which eases crop differentiation. Artificial Immune Network (ABNet) was used to classify cotton, maize, wheat/others, rice and grapes, dominating most of the study area. The data of two different years were used together to classify the crop of next year, as 2011 and 2012 were used to classify crops of 2013. Classification results were validated using the same year ground data. Results showed the classification accuracy above 80% for each year with kappa coefficient of 0. 7 and above. However more research and additional ground reference data are needed to classify a range of crops in the study area which will give a more detailed view of the land use land cover change strengthening agriculture decisions practices in the future. PMID- 26415459 TI - [Estimating Leaf Area Index of Crops Based on Hyperspectral Compact Airborne Spectrographic Imager (CASI) Data]. AB - The fast estimation of leaf area index (LAI) is significant for learning the crops growth, monitoring the disease and insect, and assessing the yield of crops. This study used the hyperspectral compact airborne spectrographic imager (CASI) data of Zhangye city, in Heihe River basin, on July 7, 2012, and extracted the spectral reflectance accurately. The potential of broadband and red-edge vegetation index for estimating the LAI of crops was comparatively investigated by combined with the field measured data. On this basis, the sensitive wavebands for estimating the LAI of crops were selected and two new spectral indexes (NDSI and RSI) were constructed, subsequently, the spatial distribution of LAI in study area was analyzed. The result showed that broadband vegetation index NDVI had good effect for estimating the LAI when the vegetation coverage is relatively lower, the R2 and RMSE of estimation model were 0. 52, 0. 45 (p<0. 01) , respectively. For red-edge vegetation index, CIred edge took the different crop types into account fully, thus it gained the same estimation accuracy with NDVI. NDSI(569.00, 654.80) and RSI(597.60, 654.80) were constructed by using waveband combination algorithm, which has superior estimation results than NDVI and CIred edge. The R2 of estimation model used NDSI(569.00, 654.80) was 0. 77(p<0. 000 1), it mainly used the wavebands near the green peak and red valley of vegetation spectrum. The spatial distribution map of LAI was made according to the functional relationship between the NDSI(569.00, 654.80) and LAI. After analyzing this map, the LAI values were lower in the northwest of study area, this indicated that more fertilizer should be increased in this area. This study can provide technical support for the agricultural administrative department to learn the growth of crops quickly and make a suitable fertilization strategy. PMID- 26415460 TI - [Hyperspectral Band Selection Based on Spectral Clustering and Inter-Class Separability Factor]. AB - With the development of remote sensing technology and imaging spectrometer, the resolution of hyperspectral remote sensing image has been continually improved, its vast amount of data not only improves the ability of the remote sensing detection but also brings great difficulties for analyzing and processing at the same time. Band selection of hyperspectral imagery can effectively reduce data redundancy and improve classification accuracy and efficiency. So how to select the optimum band combination from hundreds of bands of hyperspectral images is a key issue. In order to solve these problems, we use spectral clustering algorithm based on graph theory. Firstly, taking of the original hyperspectral image bands as data points to be clustered , mutual information between every two bands is calculated to generate the similarity matrix. Then according to the graph partition theory, spectral decomposition of the non-normalized Laplacian matrix generated by the similarity matrix is used to get the clusters, which the similarity between is small and the similarity within is large. In order to achieve the purpose of dimensionality reduction, the inter-class separability factor of feature types on each band is calculated, which is as the reference index to choose the representative bands in the clusters furthermore. Finally, the support vector machine and minimum distance classification methods are employed to classify the hyperspectral image after band selection. The method in this paper is different from the traditional unsupervised clustering method, we employ spectral clustering algorithm based on graph theory and compute the interclass separability factor based on a priori knowledge to select bands. Comparing with traditional adaptive band selection algorithm and band index based on automatically subspace divided algorithm, the two sets of experiments results show that the overall accuracy of SVM is about 94. 08% and 94. 24% and the overall accuracy of MDC is about 87. 98% and 89. 09%, when the band selection achieves a relatively optimal number of clusters using the method propoesd in this paper. It effectively remains spectral information and improves the classification accuracy. PMID- 26415461 TI - [Effect of Foliar Dustfall Content (FDC) on High Spectral Characteristics of Pear Leaves and Remote Sensing Quantitative Inversion of FDC]. AB - The precipitation of floating and sinking dust on leaves of plants is called as foliar dustfall. To monitor foliar dustfall, it will provide fundamental basis for environmental assessment and agricultural disaster evaluation of dust area. Therefore, the aim of this work to (1) study the effect of foliar dustfall content (FDC) on high spectral characteristics of pear leaves, (2) analyze the relationship between reflectances and FDC, and (3) establish high spectral remote sensing quantitative inversion model of FDC. The results showed that FDC increased reflectances of visible band (400~700 nrn) with maximum band of 666 nm. Absolute and relative rates of change were -10. 50% and -62. 89%, respectively. The FDC decreased reflectances of near infrared band (701 ~ 1 050 nm) with maximum band of 758 nm. Absolute and relative rates of change were 12. 04% and 41. 75%, respectively. After dustfall was removed, reflection peak of green light and absorption valley of red and blue light became prominent, and slope of 500~750 nm wake band increased when FDC was more than 20 g . m-2. While FDC just slightly affected shape and area of reflection peak of green light when FDC was less than 20 g . m-2. FDC were positive and negative correlated with reflectances of visible band and near infrared band, respectively. Maximum correlation coefficient (0. 61) showed at 663 nm. All of 7 inversion models, the model based on the first-order differential of logarithm of the reciprocal had better stability and predictive ability. The coefficient of determination(R2), root mean square error (RMSE) and relative percent deviation (RPD) of this model were 0. 78, 3. 37 and 2. 09, respectively. The results of this study can provide a certain reference basis for hyperspectral remote sensing of FDC. PMID- 26415462 TI - Research and Evaluation on Wear in Power-Shift Steering Transmission Through Oil Spectral Analysis with RKPCA Method. AB - The most common methodology used in element concentration measurement and analyzing of wear particles is Atomic emission (AE) spectroscopy. The present paper presents an evaluation method on wear in power-shift steering transmission (PSST). By removing the problematic components which were highly correlated with oil additives, the robust kernel principal component analysis (RKPCA) method and the principal component analysis (PCA) method were accessed to extract the principal components of spectral data for oil samples collected from the life cycle test of PSST in different stage and to calculate the amount of each principal component and its contribution rate respectively. A comparison between the above mentioned two methods was made to show that RKPCA method has fewer amounts of principal components and higher cumulative contribution rate indicating that RKPCA method acts more effectively in variable dimension reduction due to the outliers and nonlinearity of spectral data. Therefore, the effectiveness of RKPCA method in classification and identification of the wear in friction pairs was demonstrated subsequently. through the correlation analysis between the variable coefficients of RKPCA and metal elements of friction pairs. The demonstration showed that RKPCA functioned precisely in the classification and identification of the wear in friction pairs, and in the evaluation on the wear in PSST. Thereafter, to detect the threshold point where the wear took place, the fuzzy C-means clustering algorithm was introduced to classify the RKPCA eigenvalues, and the results were compared with that of the spectral clustering algorithm. The fuzzy C-means clustering algorithm showed higher sensitivity in detecting the threshold point indicting a more precise evaluation on the wear in PSST. It is clear that the introduction of RKPCA method in wear evaluation, which takes the eigenvalues of spectral data as a critical variable to classify and identify the wear in different friction pairs as well as in the integral PSST configuration, shows better accuracy in wear prediction and will contribute to the reliable determination of life between overhauls and the accurate positioning of worn-out parts. As might be expected, the proposed method can be extended to other cases of wear detection and evaluation in complex mechanical system. PMID- 26415463 TI - [Application of LIBS in Element Analysis of Nanometer Thin Film Prepared on Silicon Basement]. AB - In order to develop a method to analyze the metal elements in the thin film samples rapidly, directly and without sample preparation, a laboratory LIBS system was established recently for nanometer film analysis. This system could determine the position of sample plane, observe the profiles of sample after pulse-material interaction and detect the plasma morphologyand spectral emission at the same time. Samplesused were ZrO2 films about 40 nm thickness prepared on Si by a sol-gel process, and they were located on a manual X-Y-Z translational stage with theaccuracy of 0. 01 mm. Final results showed that the positional accuracy is about 20uLm with the help of two CW lasers, and the RSD of repeatability of single-shot spectra could be to 1. 6%. We investigated special morphology of plasma, variation tendency of signal intensity as a function of pulse energy, LTSD (laser focus to sample distance) and time, which provide cornerstone for optimizing experimental parameters under the conditions of room temperature and atmospheric pressure. We calculated plasma temperature by way of Boltzmann curve and electron density through the acquired data. We also appraised necessary LTE conditions for quantitativeanalysis. PMID- 26415464 TI - [Comparative Experiment and Spectrometric Analysis on Characteristics of Enclosed Inductively Coupled Plasma]. AB - In the present paper, the spectrum analytic method was used to comparatively study the ICP electron density distribution through two typical ICP sources (spiral-type and planar-type) in closed quartz chamber. The E-H mode transition of inductively coupled plasma and power coupling efficiency were researched through the change in the relative intensity of argon ion spectral line (476. 45 nm). Electron density distribution on the antennas-vertical plane of different ICP source was calculated through non-hydrogen-like Stark broadening of spectral line method. The test results show that the ICP electronic density distribution in H-mode discharge is significantly impacted by skin current of alternating magnetic field. The skin depth decreases with the increase in discharge power. Meanwhile, the bulk of the main plasma narrows and electron density increases. On the vertical plane of the antenna, electron density distribution presents center symmetry by spiral-ICP source and bimodal by planar-ICP source. The power coupling efficiency is directly affected bysource antenna shape and capacitive coupling effect. The relative intensity of the argon spectrum shows that the power coupling efficiency of spiral-type source is lower than that of planar-type source. The proposed experimental method provides a way to obtain a plasma source in closed quartz cube chamber with the highest electron density ranging from 1. 4X 10(17) to 2. 5 X 10(17) m-3 (spiral-ICP source) and 1. 8 X 10(17) to 3. 0 X 10(17) m-3 (planar-ICP source). PMID- 26415465 TI - [Determination of SiO2 in Groundwater and Mineral Water by Inductively Coupled Plasma-Atomic Emission Spectrometry]. AB - The concentration of silica in groundwater and mineral water was determined by inductively coupled plasma-atomic emission spectrometry (ICP-AES). After a more sensitive analytical line of silicon was chosen, the effects of operating conditions of the ICP spectrometer on the analysis results were investigated, at the same time, the impact of coexisting ions on determination results of SiO2 was also considered and eliminated. The transmit power of 1 350 W, observation height of 12 mm, the nebulizer pressure of 0. 20 MPa and the pump speed of analysis of 75 r . min-1 were selected by experimental conditions. Under the optimum analytical conditions of spectrometer, the method was used for the determination of SiO2 in groundwater and mineral water with the detection limit of 0. 017. mg . L-1, recoveries between 94. 10% and 103. 8%, and relative standard deviation (RSD)s<=3. 06%. Compared with the results of silicon molybdenum yellow spectrophotometry, the results were basically consistent with the relative deviation <=3. 00%. In conclusion, the method is simple and efficient with high precision and accuracy, and can be used for research and routine production. PMID- 26415466 TI - [Influence of Spectral Pre-Processing on PLS Quantitative Model of Detecting Cu in Navel Orange by LIBS]. AB - Cu in navel orange was detected rapidly by laser-induced breakdown spectroscopy (LIBS) combined with partial least squares (PLS) for quantitative analysis, then the effect on the detection accuracy of the model with different spectral data ptetreatment methods was explored. Spectral data for the 52 Gannan navel orange samples were pretreated by different data smoothing, mean centralized and standard normal variable transform. Then 319~338 nm wavelength section containing characteristic spectral lines of Cu was selected to build PLS models, the main evaluation indexes of models such as regression coefficient (r), root mean square error of cross validation (RMSECV) and the root mean square error of prediction (RMSEP) were compared and analyzed. Three indicators of PLS model after 13 points smoothing and processing of the mean center were found reaching 0. 992 8, 3. 43 and 3. 4 respectively, the average relative error of prediction model is only 5. 55%, and in one word, the quality of calibration and prediction of this model are the best results. The results show that selecting the appropriate data pre processing method, the prediction accuracy of PLS quantitative model of fruits and vegetables detected by LIBS can be improved effectively, providing a new method for fast and accurate detection of fruits and vegetables by LIBS. PMID- 26415467 TI - ICP-AES Determination of Mineral Content in Boletus tomentipes Collected from Different Sites of China. AB - P, Na, Ca, Cu, Fe, Mg, Zn, As, Cd, Co, Cr and Ni, contents have been examined in caps and stipes of Boletus tomentipes collected from different sites of Yunnan province, southwest China. The elements were determined using inductively coupled plasma atomic emission spectroscopy (ICP-AES) with microwave digestion. P, Ca, Mg, Fe, Zn and Cu were the most abundant amongst elements determined in Boletus tomentipes. The caps were richer in P, Mg, Zn and Cd, and the stipes in Ca, Co and Ni. Cluster analysis showed a difference between Puer (BT7 and BT8) and other places. The PCA explained about 77% of the total variance, and the minerals differentiating these places were P (PC1) together with Ca, Cu, Fe, Mg, As and Ni, Na (PC2) together with Cd, and Zn (PC3). The results of this study imply that element concentrations of a mushroom are mutative when collected from the different bedrock soil geochemistry. PMID- 26415468 TI - [Determination of Total Selenium and Arsenic in Coal by Wet Digestion Hydride Generation Atomic Fluorescence Spectrometry (HG-AFS)]. AB - In the present work we presented a new method for determination of total Se and As in coal by electric hot plate-mixed acids-hydride generation atomic fluorescence spectrometry (HG-AFS), the wet digestion method. The detailed operation procedures of the new method are as follows: About 0. 05~0. 10 g of powdered (200 mesh) coal sample was placed in a glass beaker, 10 mL of nitric acid (HNO3) and 2 mL of perchloric acid (HClO4) were added to the beaker in sequence, then the beaker was covered with a watching glass and placed in a fume cupboard standing overnight. The beaker was placed on an electric hot plate (180 degrees C) for sample decomposition the next day. The beaker was moved away from the electric hot plate when white smoke arose in the beaker, the sample color turned white or grey and the solution turned clear. Three milliliter of hydrochloric acid (HCl) solution (6 mol . L-1) was added to the beaker after the temperature of the beaker returned to room temperature. The beaker was heated on the electric hot plate again, and then moved away when white smoke started arising again. One milliliter of HCI was added in the beaker after the temperature of the beaker returned to room temperature. After that, the digested sample was transferred to a 25 mL test tube which was filled with ultrapure water to the tube's full volume. This solution was used for Se determination directly. Three milliliter of the Se test solution prepared above was transferred to a 15 mL glass test tube, 1 mL of thiourea/ascorbic acid solution (2. 5 g . mL-1) and 1 mL of the concentrated HCl was added to the 15 mL test tube. The test tube was then filled with ultrapure water to its full volume. The solution was used for As determination after shaking well and 40 min standing. Finally, Se and As concentrations in these prepared solutions were measured by using the AFS-9780 instrument (Beijing Haiguang Instrument Co. , LTD, Beijing, China). Two Chinese Coal Certified Reference Materials (GBW11115 and GBW11117) were tested using this method, and the recoveries of As were 99. 7%~100. 3% and the relative standard deviation (RSD) for As and Se were 5. 6%~6. 0% and 11. 1%~13. 5%, respectively. The limits of detection (LOD) of the method for Se and As determination were 0. 01 and 0. 05 ug . L-1, respectively. These results indicated that this new method was suitable for Se and As determination in coal, and it had the advantages of simple operation, high accuracy and reproducibility compared with the Chinese National Standard method. PMID- 26415469 TI - [Development of Micro-Spectrometer with a Function of Timely Temperature Compensation]. AB - Temperature drift will be brought to Micro-Spectrometer used for demodulating the Varied Line-Space(VLS) grating position sensor on aircraft due to high-low temperature shock. We successfully made a Micro-Spectrometer, for the VLS grating position sensor on aircraft, which still have stable output under temperature shock enviro nment. In order to present a real time temperature compensation scheme, the effects temperature change has on Micro-Spectrometer are analyzed and the traditional cross Czerny-Turner (C-T)optical structure is optimized. Both optical structures are analyzed by optics design software ZEMAX and proved that comparedwithtraditional cross C-T optical structure, the newone can accomplish not only smaller spectrum drift but also spectrum drift with better linearity. Based on the new optical structure. The scheme of using reference wavelength to accomplish real time temperature compensation was proposed and a Micro-fiber Spectrometer was successfully manufactured, whith is with Volume of 80 mm X 70 mmX 70 mm, integration time of 8 ~1 000 ms and FullWidthHalfMaximum(FWHM) of 2 nm. Experiments show that the new spectrometer meets the design requirement. Under high temperature in the range of nearly 60 degrees C, the standard error of wavelength of this new spectrometer is smaller than 0. 1 nm, and the maximum error of wavelength is 0. 14 nm, which is much smaller than required 0. 3 nm. Innovations of this paper are the schemeof real time temperature compensation, the new cross C-T optical structure and a Micro-fiber Spectrometer based on it. PMID- 26415470 TI - [Design of a Component and Transmission Imaging Spectrometer]. AB - In the reflection-based imaging spectrometer, multiple reflection(diffraction) produces stray light and it is difficult to assemble. To address that, a high performance transmission spectral imaging system based on general optical components was developed. On the basis of simple structure, the system is easy to assemble. And it has wide application and low cost compared to traditional imaging spectrometers. All components in the design can be replaced according to different application situations, having high degree of freedom. In order to reduce the influence of stray light, a method based on transmission was introduced. Two sets of optical systems with different objective lenses were simulated; the parameters such as distortion, MTF and aberration.were analyzed and optimized in the ZEMAX software. By comparing the performance of system with different objective len 25 and 50 mm, it can be concluded that the replacement of telescope lens has little effect on imaging quality of whole system. An imaging spectrometer is developed successfully according design parameters. The telescope lens uses double Gauss structures, which is beneficial to reduce field curvature and distortion. As the craftsmanship of transmission-type plane diffraction grating is mature, it can be used without modification and it is easy to assemble, so it is used as beam-split. component of the imaging spectrometer. In addition, the real imaging spectrometer was tested for spectral resolution and distortion. The result demonstrates that the system has good ability in distortion control, and spectral resolution is 2 nm. These data satisfy the design requirement, and obtained spectrum of deuterium lamp through calibrated system are ideal results. PMID- 26415471 TI - [Design and Optimization of Surface Plasmon Resonance Sensor Based on Side Polished Single-Mode Fiber]. AB - Fiber-coupling surface Plasmon resonance sensor has attractive advantages of information transmission such as small volume, anti-electric magnetic field interference, and online real-time remote detection. In order to improve the performance of the sensor, the effect of the residual fiber thickness and the silver film thickness to the sensitivity of the sensor and the depth of the resonance peaks and full width ar half maximum (FWHM) are analyzed respectively. The results show that the increasing fiber residual thickness weakens the SPR phenomenon, and that the increasing silver film thickness widens the resonance peak, while the sensitivity of the sensor does not change monotonously. Through the integration of refractive index sensing sensitivity and full width at half maximum, figure of merit is presented and regarded as the optimized objective. The optimal design is achieved in the case of the fiber residual thickness for 66. 5 um, and the silver film thickness for 50 nm. The optimized design with the figure of merit of 98. 67 is expected to be applied in the bio-chemical sensing and analysis. PMID- 26415472 TI - [New Implementation Technique of USED Phase Matching for CARS]. AB - Phase matching is one of the key techniques in temperature measuring by coherent anti-Stokes Raman scattering (CARS). In order to overcome the disadvantages of large background radiation, inconvenient adjusting and low-usage of Stokes laser energy in traditional unstable-resonator spatially enhanced detection (USED) phase matching, new implementation technique of USED CARS phase matching is researched. A piece of oblique reflector, which is as big as the Stokes spot and with an angle of 45 degrees, was used to replace the annular reflector in traditional USED to reflect the Stokes fully. Then, pump laser shines from the back of the oblique reflector to satisfy USED phase matching with reflected Stokes. In the new USED CARS phase matching, background radiation caused by reflecting was weakened for the area of oblique reflector is smaller than that of annular reflector; Furthermore, oblique reflector can be used as an adjusting component in experiments which can make beam path adjusting more easier; Finally, Stokes laser was in high-usage for it was fully reflected by the oblique reflector. Temperature measuring results on laminar flame suggest that new USED CARS phase matching has lower standard deviation and it is a more effective phase matching method. PMID- 26415474 TI - [A Concept Design of Flat-Field Spectrograph for Wide Wavelength Range]. AB - The radiation spectrum from the plasmas contains a large amount of information of plasmas. Thus, one of the most effective methods to detecting the plasma parameters is measure the plasma radiation spectrum. Until now, since the restriction of the Toshiba mechanically ruled aberration-corrected concave gratings, the measurable wavelength range of the incidence flat-field grazing spectrometer in the soft X-ray range are only from 5 to 40 nm. In order to extend the wavelength rang of grazing incidence flat-field spectrometer, first, a grazing incidence concave reflection grating ray-trace code is written using optical path equation. Second, under the same conditions with reference 6, we compare our numerical results with Harada's results. The results show that our results agree very well with the results of Harada. The results of comparison show that our ray-trace code is believable. Finally, the variety of the flat field curves are detailedly investigated using the ray-trace code with the different grazing incidence conditions. The results show that the measurable wavelength range of the incidence flat-field grazing spectrometer are extended to 5~80 nm from the soft X-ray wavelength range of 5~40 nm. This result theoretically demonstrates the possibility of expanded the traditional band flat field grazing incidence spectrometer from soft X-ray band to the extreme ultraviolet (XUV), and also bring a new design ideas for improving the use of grazing incidence flat field concave grating. PMID- 26415473 TI - [Searching for WDMS Candidates In SDSS-DR10 With Automatic Method]. AB - The Sloan Digital Sky Survey (SDSS) has released the latest data (DR10) which covers the first APOGEE spectra. The massive spectra can be used for large sample research inscluding the structure and evolution of the Galaxy and multi-wave-band identi cation. In addition, the spectra are also ideal for searching for rare and special objects like white dwarf main-sequence star (WDMS). WDMS consist of a white dwarf primary and a low-mass main-sequence (MS) companion which has positive significance to the study of evolution and parameter of close binaries. WDMS is generally discovered by repeated imaging of the same area of sky, measuring light curves for objects or through photometric selection with follow up observations. These methods require significant manual processing time with low accuracy and the real-time processing requirements can not be satisfied. In this paper, an automatic and efficient method for searching for WDMS candidates is presented. The method Genetic Algorithm (GA) is applied in the newly released SDSS-DR10 spectra. A total number of 4 140 WDMS candidates are selected by the method and 24 of them are new discoveries which prove that our approach of finding special celestial bodies in massive spectra data is feasible. In addition, this method is also applicable to mining other special celestial objects in sky survey telescope data. We report the identfication of 24 new WDMS with spectra. A compendium of positions, mjd, plate and fiberid of these new discoveries is presented which enrich the spectral library and will be useful to the research of binary evolution models. PMID- 26415475 TI - [The Stability and Measuring Technology of the Maximum Optical Path Difference of Photo-Elastic Modulator Interferograms]. AB - In order to improve the accuracy and stability of the rebuilt spectrums, it is necessary that stability analysis and nicety measuring of the maximum optical path difference of interferograms in the photo-elastic modulator Fourier transform spectrometers(PEM-FTS). The maximum optical difference of interferograms is uncertain parameter, and it is relate to the resonant state, characteristic of frequency-thermal drift and driving voltage of PEM. Therefore, based on the principle of photo-elastic modulator Fourier transform interferometer, the model of the freguency-thermal drift is built, and the variety of the maximum optical path difference is analyzed; A measuring method of the maximum optical path difference is put forward, which is zero-crossing counting of laser's interference signal when the driving signal of PEM is as the standard. In the method the dual channel high-speed comparator and FPGA are used to transform sine wave to square wave, to realize zero-crossing trigger counting and errors compensation. On the condition that the 670. 8 nm laser is as the power source to produce the reference interferograms by the PEM interferometer, the 77. 471 um maximum optical path difference could be measured by the zero crossing counting the measuring errors is less than 0. 167 nm, the rebuilt spectral peak wavelength errors of the infrared blackbody is less than 2 nm. the result is content with PEM-FTS. PMID- 26415476 TI - [Research on Anti-Camouflaged Target System Based on Spectral Detection and Image Recognition]. AB - To be able to quickly and efficiently identify Enemy camouflaged maneuvering targets in the wild environment, target recognition system was designed based on spectral detection technology and video target recognition method. System was composed of the visible light image acquisition module and static interferometer module. The system used image recognition technology to obtain two dimensional video images of measurement region, and through spectrum detection technology to identify targets. Ultimately, measured target was rebuilt on the corresponding position in the image, so the visual target recognition was realized. After the theoretical derivation, identifiable target function formula of the system was obtained, and based on the functional relationship to complete the quantitative experiments for target recognition. In the experiments, maneuvering target in the battlefield environment was simulated by a car. At different distances, the background was respectively selected to detect a flat wasteland, bushes and abandoned buildings. Obvious target, coated camouflage target and covered disguises target was respectively spectrum detection. Experimental results show that spectrum detection technology can overcome the shortcomings of unrecognized the camouflaged target by traditional image target recognition method. Testing background had some influence on spectrum detection results, and the continuity of the background was conducive to target recognition. Covered disguises target was the hardest to identify in various camouflage mode. As the distance between the target and the system increases, signal to noise ratio of the system was reduced. In summary, the system can achieve effective recognition of camouflaged targets to meet the design requirements. PMID- 26415477 TI - [Spectral Smoothing with Adaptive Multiscale Window Average]. AB - In order to smooth the spectra automatically and reliably, a spectral smoothing algorithm with adaptive multiscale window average (AWMA) is demonstrated. In this method, different positions of the spectra are smoothed by windows of different width, and the width of the windows will directly affect smoothing. The window with inappropriate width may cause excessive denoising (peak distortion or loss) or inadequate denoising (the flat region of the spectra still contains a lot of noise). So, how to get the right width of the window is the key of spectral smoothing. The algorithm optimized the width of windows by an iterative method, and verified whether the width is the best according to statistical Z-test. In order to increase the reliability of the algorithm, a comprehensive comparison of the thresholds of hypothesis according to simulation data of different SNR was performed. When the threshold is set to 1. 1, the denoising effect can be the best. In this work, the AMWA algorithm was tested by simulated spectra and real syectra, and it can automatically adapt to different spectral shape and different noise intensity. A comprehensive comparison of AMWA smoothing, Savitzky-Golay smoothing and moving average smoothing was performed in this paper, and the AMWA algorithm is better than the other two algorithms. Results show that the AMWA algorithm not only has better denoising effect, but also has higher accuracy and fidelity. This method has achieved great effect not only to simulated spectra but also to real spectra. PMID- 26415478 TI - A Model-Based Temperature-Prediction Method by Temperature-Induced Spectral Variation and Correction of the Temperature Effect. AB - In the present paper, a new model-based method was proposed for temperature prediction and correction. First, a temperature prediction model was obtained from training samples; then, the temperature of test samples were predicted; and finally, the correction model was used to reduce the nonlinear effects of spectra from temperature variations. Two experiments were used to verify the proposed method, including a water-ethanol mixture experiment and a ternary mixture experiment. The results show that, compared with classic method such as continuous piecewise direct standardization (CPDS), our method is efficient for temperature correction. Furthermore, the temperatures of test samples are not necessary in the proposed method, making it easier to use in real applications. PMID- 26415479 TI - Craig Richmond. the value of transparency in improving patient education. PMID- 26415480 TI - Developing the metrics for payment reform. PMID- 26415481 TI - Soft-leadership competencies for today's healthcare finance executives. AB - With the healthcare industry changing rapidly, organizations seek finance leaders who have skills that go beyond traditional expertise in revenue and expenses. These additional competencies fall under the heading of soft-leadership skills and include the ability to be strategy-oriented, agile, passionate, inspirational, influential, communicative, dependable, driven, integrative, and engaged. Networking, participation in a mentoring program, and continuing education provide avenues for finance leaders to develop these sorts of skills. PMID- 26415483 TI - Infusing the capital review process with rigor and discipline. AB - Intermountain Healthcare gleaned four key insights from inside and outside the industry when reviewing best practices in capital decision making: Evidence-based decision making and disciplined analysis are as critical in healthcare finance as in any other industry. Comparing various scenarios under value-based payment allows for better modeling than does performing traditional, volume-based pro formas. Reviewing large capital projects at a granular level helps identify opportunities to add or subtract services. A comprehensive look-back process identifies lessons learned from approved projects-and helps ensure that proposals are defensible. PMID- 26415482 TI - Lost opportunity. Fairly assigning value to physician administrative services. AB - The Resource-Based Relative Value System sets values for physician services that can be used to estimate the value of time spent on administrative tasks. This methodology assigns an appropriate place-of-service qualifier and the appropriate percentage of Medicare rates to the time being spent on administrative tasks. A variation of this methodology allows for a rate to be determined for an entire physician group or specialty. PMID- 26415484 TI - 'Capital ideas' for health care in 2015. AB - Key factors in planning for healthcare financing in 2015 include: New rules related to municipal advisors. Long-term interest rates and the cost of traditional versus synthetic fixed-rate debt. Ways to use interest-rate swaps to take advantage of synthetic fixed-rate debt. Lesser-known structures that may make variable-rate financing advantageous. PMID- 26415485 TI - Getting the right asset mix. AB - To accurately measure service costs associated with medical equipment, hospitals should undertake a four-step process: Form a core project team and define the project's scope. Collect data. Employ forensic accounting to ascertain the actual service costs for clinical equipment. Analyze key metrics to identify savings opportunities PMID- 26415486 TI - Demystifying patient price estimates. The advantages of transparency. AB - With the increase of high-deductible health plans, more consumers want to know the cost of their health care before they purchase services. A healthcare organization should formulate transparent price policies that: Fit with its intentions, processes, and goals. Ensure consumers are thoroughly educated about their financial responsibilities. Include the use of consumer pricing tools that help patients feel like empowered consumers. Reflect an enterprisewide culture of transparency. PMID- 26415487 TI - Elevating revenue cycle performance across the enterprise. AB - Healthcare organizations can effectively bridge the revenue cycle gap between hospitals and physician practices by positioning themselves strategically for integration in six ways: Making sure they are culturally ready. Installing leaders who are comfortable with both hospital and physician operations. Developing a clear plan for the initiative. Investing in integrated technology. Using consistent data definitions. Pursuing improvements that yield the best possible results. PMID- 26415489 TI - The value proposition in action. PMID- 26415488 TI - Patient throughput collaborative yields positive results for New Jersey hospitals. AB - Collecting and analyzing data was a key step in a process improvement initiative undertaken by several hospitals in New Jersey. The hospitals found that patient flow problems commonly stemmed from uneven use of operating rooms and unenforced admission/discharge policies on inpatient units. Shared solutions included improving staff communication and enforcing admission/discharge policies. PMID- 26415490 TI - ACOs: from unicorns to pacesetters in four years. PMID- 26415491 TI - Comparative performance of hospitals based on credit ratings. PMID- 26415492 TI - Actinomyces gerencseriae hip prosthesis infection: a case report. AB - INTRODUCTION: Actinomyces bacteria are part of the human oropharyngeal microbiota. They have been associated with abdominal, cervicofacial and thoracic infections and a few cases of joint infections have also been described. In particular, Actinomyces gerencseriae, formerly described as Actinomyces israelii serovar II, has rarely been associated with human infections, mostly involving cervicofacial lesions and periodontal diseases. Here, we report one case of hip prosthesis infection due to A. gerencseriae. CASE PRESENTATION: A 72-year-old Caucasian male developed an inflammatory collection on the outside of the right thigh where a hip prosthesis had been implanted for 11 years. Culturing a fluid sample from the collection puncture found Staphylococcus hominis and a Gram positive bacillus unidentified by matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MALDI-TOF). Sequencing the 16S rRNA gene amplified from both the specimen and the isolate identified A. gerencseriae. Treatment adjusted with amoxicillin and trimethropim-sulfamethoxazole cured the infection. CONCLUSION: The recently described A. gerencseriae has rarely been involved in human infections. We report the first case of A. gerencseriae joint infection in a hip prosthesis. PMID- 26415493 TI - Changing trends in hospitalization rates associated with psychosis: Spain, 1980 2009. AB - PURPOSE: To analyze the prevalence of hospitalization attributable to psychosis in Spain over the last three decades. METHODS: Longitudinal analysis (1980-2009) of age-adjusted hospital discharges rates associated with psychosis (ICD9 290-8) in all Spanish hospitals. DATA SOURCE: Spanish Hospital Morbidity Survey. RESULTS: The hospitalization rate associated with psychotic episodes had been gradually increasing since 1980 until 2004; an abrupt turnaround observed in 2004 marks the beginning of a steady decline in the rate. The turning point described is not observed for each of the psychotic diagnoses separately analyzed. However, it is clearly seen when data are grouped in diagnosis-related groups (organic psychosis, functional psychosis and substance-induced psychosis) since the time course of the diseases within the major diagnostic groups are interrelated as evidenced by shared turning points which collectively display a common time course pattern. Main hospital indicators and antipsychotic drug prescriptions were analyzed for any possible turning point in mid-2000s. Psychiatric hospital beds and length of stays remained stable by 2004; the hospitalizations associated with non-psychotic psychiatric pathologies show no turning point in 2004. However, an abrupt change on antipsychotic drug prescriptions is precisely observed in 2004. CONCLUSIONS: After decades of linear growth, hospitalizations for psychotic patients begin to decline in 2004, coinciding with the start of last generation atypical antipsychotic drug consumption in Spain. Some of the psychotic diagnostic rates evolve in an interrelated manner which calls into question the diagnosis and nosological boundaries between some of these pathologies. PMID- 26415494 TI - Clustering reveals limits of parameter identifiability in multi-parameter models of biochemical dynamics. AB - BACKGROUND: Compared to engineering or physics problems, dynamical models in quantitative biology typically depend on a relatively large number of parameters. Progress in developing mathematics to manipulate such multi-parameter models and so enable their efficient interplay with experiments has been slow. Existing solutions are significantly limited by model size. RESULTS: In order to simplify analysis of multi-parameter models a method for clustering of model parameters is proposed. It is based on a derived statistically meaningful measure of similarity between groups of parameters. The measure quantifies to what extend changes in values of some parameters can be compensated by changes in values of other parameters. The proposed methodology provides a natural mathematical language to precisely communicate and visualise effects resulting from compensatory changes in values of parameters. As a results, a relevant insight into identifiability analysis and experimental planning can be obtained. Analysis of NF-kappaB and MAPK pathway models shows that highly compensative parameters constitute clusters consistent with the network topology. The method applied to examine an exceptionally rich set of published experiments on the NF-kappaB dynamics reveals that the experiments jointly ensure identifiability of only 60% of model parameters. The method indicates which further experiments should be performed in order to increase the number of identifiable parameters. CONCLUSIONS: We currently lack methods that simplify broadly understood analysis of multi parameter models. The introduced tools depict mutually compensative effects between parameters to provide insight regarding role of individual parameters, identifiability and experimental design. The method can also find applications in related methodological areas of model simplification and parameters estimation. PMID- 26415495 TI - Diagnostic performance of measuring antibodies to the glycopeptidolipid core antigen specific to Mycobacterium avium complex in patients with rheumatoid arthritis: results from a cross-sectional observational study. AB - INTRODUCTION: The aim of this study was to investigate the diagnostic performance of measuring antibodies to the glycopeptidolipid (GPL) core antigen specific to Mycobacterium avium complex (MAC) in patients with rheumatoid arthritis (RA). METHODS: We cross-sectionally investigated anti-GPL antibodies and radiographs of 396 patients with RA. A diagnosis of MAC pulmonary disease (MAC-PD) was made according to the criteria by the American Thoracic Society and the Infectious Diseases Society of America. Serum immunoglobulin A antibodies to MAC-specific GPL core antigen were measured by an enzyme immunoassay. All patients with RA with abnormal shadows on chest x-rays underwent chest computed tomography (CT). Bronchoscopy was performed on patients with negative cultures for MAC by expectorated sputum and positive CT findings compatible with MAC-PD. RESULTS: Ten patients were newly diagnosed with MAC-PD. Eight individuals who already had diagnoses of MAC-PD at the time of enrollment and nineteen who had negative expectorated sputum cultures for MAC and positive CT images compatible with MAC PD and who refused bronchoscopy were excluded from the following analysis. Anti GPL antibodies were detected in 12 of 369 patients. Eight of the ten patients with MAC-PD and 4 of 359 patients without MAC-PD tested positive for the anti-GPL antibodies. The specificity and sensitivity were 99 % and 80 %, respectively. Positive and negative predictive values were 67 %, and 97 %, respectively. When we analyzed diagnostic performance of the antibodies in 57 patients with RA who had abnormal shadows on chest x-rays, the positive and negative predictive values were 100 %, and 96 %, respectively. Twelve patients underwent bronchoscopy. Bronchoalveolar lavage fluid (BALF) samples from six patients were positive for MAC, and BALF samples from the remainder were negative. Anti-GPL antibodies were detected in the sera of all six patients with positive results for MAC by BALF sampling, whereas the antibodies were not detected in the sera from the remainder with negative results for MAC by BALF sampling. CONCLUSIONS: The measurement of anti-GPL antibodies is useful as a supplementary diagnostic tool for MAC-PD in patients with RA and may provide a new strategy, in combination with chest x-ray and CT, for differentiating MAC-PD from other pulmonary comorbidities in patients with RA. PMID- 26415496 TI - Lifetime co-occurrence of violence victimisation and symptoms of psychological ill health: a cross-sectional study of Swedish male and female clinical and population samples. AB - BACKGROUND: Lifetime co-occurrence of violence victimisation is common. A large proportion of victims report being exposed to multiple forms of violence (physical, sexual, emotional violence) and/or violence by multiple kinds of perpetrators (family members, intimate partners, acquaintances/strangers). Yet much research focuses on only one kind of victimisation. The aim of this study was to investigate the association between symptoms of psychological ill health, and A) exposure to multiple forms of violence, and B) violence by multiple perpetrators. METHOD: Secondary analysis of cross-sectional data previously collected for prevalence studies on interpersonal violence in Sweden was used. Respondents were recruited at hospital clinics (women n = 2439, men n = 1767) and at random from the general population (women n = 1168, men n = 2924). Multinomial regression analysis was used to estimate associations between exposure to violence and symptoms of psychological ill health. RESULTS: Among both men and women and in both clinical and population samples, exposure to multiple forms of violence as well as violence by multiple perpetrators were more strongly associated with symptoms of psychological ill health than reporting one form of violence or violence by one perpetrator. For example, in the female population sample, victims reporting all three forms of violence were four times more likely to report many symptoms of psychological ill health compared to those reporting only one form of violence (adj OR: 3.8, 95 % CI 1.6-8.8). In the male clinical sample, victims reporting two or three kind of perpetrators were three times more likely to report many symptoms of psychological ill health than those reporting violence by one perpetrator (adj OR 3.3 95 % CI 1.9-5.9). DISCUSSION: The strong association found between lifetime co-occurrence of violence victimisation and symptoms of psychological ill-health is important to consider in both research and clinic work. If only the effect of one form of violence or violence by one kind of perpetrator is considered this may lead to a misinterpretation of the association between violence and psychological ill health. When the effect of unmeasured traumata is ignored, the full burden of violence experienced by victims may be underestimated. CONCLUSION: Different kinds of victimisation can work interactively, making exposure to multiple forms of violence as well as violence by multiple perpetrators more strongly associated with symptoms of psychological ill health than any one kind of victimisation alone. PMID- 26415497 TI - Animal models for photodynamic therapy (PDT). AB - Photodynamic therapy (PDT) employs non-toxic dyes called photosensitizers (PSs), which absorb visible light to give the excited singlet state, followed by the long-lived triplet state that can undergo photochemistry. In the presence of ambient oxygen, reactive oxygen species (ROS), such as singlet oxygen and hydroxyl radicals are formed that are able to kill cancer cells, inactivate microbial pathogens and destroy unwanted tissue. Although there are already several clinically approved PSs for various disease indications, many studies around the world are using animal models to investigate the further utility of PDT. The present review will cover the main groups of animal models that have been described in the literature. Cancer comprises the single biggest group of models including syngeneic mouse/rat tumours that can either be subcutaneous or orthotopic and allow the study of anti-tumour immune response; human tumours that need to be implanted in immunosuppressed hosts; carcinogen-induced tumours; and mice that have been genetically engineered to develop cancer (often by pathways similar to those in patients). Infections are the second biggest class of animal models and the anatomical sites include wounds, burns, oral cavity, ears, eyes, nose etc. Responsible pathogens can include Gram-positive and Gram-negative bacteria, fungi, viruses and parasites. A smaller and diverse group of miscellaneous animal models have been reported that allow PDT to be tested in ophthalmology, atherosclerosis, atrial fibrillation, dermatology and wound healing. Successful studies using animal models of PDT are blazing the trail for tomorrow's clinical approvals. PMID- 26415498 TI - Replication study of the vitamin D receptor (VDR) genotype association with skeletal muscle traits and sarcopenia. AB - Polymorphisms in the vitamin D receptor (VDR) gene are some of the most studied in relation to skeletal muscle traits and significant associations have been observed by multiple groups. One such paper by our group provided the first evidence of a genetic association with sarcopenia in men, but that finding has yet to be replicated in an independent cohort. In the present study, we examined multiple VDR polymorphisms in relation to skeletal muscle traits and sarcopenia in 864 men and women across the adult age span. In addition to VDR genotypes and haplotypes, measurements of skeletal muscle strength and fat-free mass (FFM) were determined in all subjects and a measure of sarcopenia was calculated. We observed significant associations between Fok1 and Bsm1 genotypes and skeletal muscle strength in men and women, though these associations were modest and no significant associations were observed for these polymorphisms and muscle mass traits nor for Bsm1-Taq1 haplotype with muscle strength. Fok1 FF genotype was associated with an increased the risk of sarcopenia in older women compared to f allele carriers (1.3-fold higher risk). These results support previous findings that VDR genetic variation appears to impact skeletal muscle strength and risk for sarcopenia but the influence is modest. PMID- 26415499 TI - Expression of calpain-like proteins and effects of calpain inhibitors on the growth rate of Angomonas deanei wild type and aposymbiotic strains. AB - BACKGROUND: Angomonas deanei is a trypanosomatid parasite of insects that has a bacterial endosymbiont, which supplies amino acids and other nutrients to its host. Bacterium loss induced by antibiotic treatment of the protozoan leads to an aposymbiotic strain with increased need for amino acids and results in increased production of extracellular peptidases. In this work, a more detailed examination of A. deanei was conducted to determine the effects of endosymbiont loss on the host calpain-like proteins (CALPs), followed by testing of different calpain inhibitors on parasite proliferation. RESULTS: Western blotting showed the presence of different protein bands reactive to antibodies against calpain from Drosophila melanogaster (anti-Dm-calpain), lobster calpain (anti-CDPIIb) and cytoskeleton-associated calpain from Trypanosoma brucei (anti-CAP5.5), suggesting a possible modulation of CALPs influenced by the endosymbiont. In the cell-free culture supernatant of A. deanei wild type and aposymbiotic strains, a protein of 80 kDa cross-reacted with the anti-Dm-calpain antibody; however, no cross reactivity was found with anti-CAP5.5 and anti-CDPIIb antibodies. A search in A. deanei genome for homologues of D. melanogaster calpain, T. brucei CAP5.5 and lobster CDPIIb calpain revealed the presence of hits with at least one calpain conserved domain and also with theoretical molecular mass consistent with the recognition by each antibody. No significant hit was observed in the endosymbiont genome, indicating that calpain molecules might be absent from the symbiont. Flow cytometry analysis of cells treated with the anti-calpain antibodies showed that a larger amount of reactive epitopes was located intracellularly. The reversible calpain inhibitor MDL28170 displayed a much higher efficacy in diminishing the growth of both strains compared to the non-competitive calpain inhibitor PD150606, while the irreversible calpain inhibitor V only marginally diminished the proliferation. CONCLUSIONS: Altogether, these results indicate that distinct calpain-like molecules are expressed by A. deanei, with a possible modulation in the expression influenced by the endosymbiont. In addition, treatment with MDL28170 affects the growth rate of both strains, as previously determined in the human pathogenic species Leishmania amazonensis and Trypanosoma cruzi, with whom A. deanei shares immunological and biochemical relationships. PMID- 26415500 TI - A comparison of confidence interval methods for the intraclass correlation coefficient in community-based cluster randomization trials with a binary outcome. AB - BACKGROUND: Many investigators rely on previously published point estimates of the intraclass correlation coefficient rather than on their associated confidence intervals to determine the required size of a newly planned cluster randomized trial. Although confidence interval methods for the intraclass correlation coefficient that can be applied to community-based trials have been developed for a continuous outcome variable, fewer methods exist for a binary outcome variable. The aim of this study is to evaluate confidence interval methods for the intraclass correlation coefficient applied to binary outcomes in community intervention trials enrolling a small number of large clusters. Existing methods for confidence interval construction are examined and compared to a new ad hoc approach based on dividing clusters into a large number of smaller sub-clusters and subsequently applying existing methods to the resulting data. METHODS: Monte Carlo simulation is used to assess the width and coverage of confidence intervals for the intraclass correlation coefficient based on Smith's large sample approximation of the standard error of the one-way analysis of variance estimator, an inverted modified Wald test for the Fleiss-Cuzick estimator, and intervals constructed using a bootstrap-t applied to a variance-stabilizing transformation of the intraclass correlation coefficient estimate. In addition, a new approach is applied in which clusters are randomly divided into a large number of smaller sub-clusters with the same methods applied to these data (with the exception of the bootstrap-t interval, which assumes large cluster sizes). These methods are also applied to a cluster randomized trial on adolescent tobacco use for illustration. RESULTS: When applied to a binary outcome variable in a small number of large clusters, existing confidence interval methods for the intraclass correlation coefficient provide poor coverage. However, confidence intervals constructed using the new approach combined with Smith's method provide nominal or close to nominal coverage when the intraclass correlation coefficient is small (<0.05), as is the case in most community intervention trials. CONCLUSION: This study concludes that when a binary outcome variable is measured in a small number of large clusters, confidence intervals for the intraclass correlation coefficient may be constructed by dividing existing clusters into sub clusters (e.g. groups of 5) and using Smith's method. The resulting confidence intervals provide nominal or close to nominal coverage across a wide range of parameters when the intraclass correlation coefficient is small (<0.05). Application of this method should provide investigators with a better understanding of the uncertainty associated with a point estimator of the intraclass correlation coefficient used for determining the sample size needed for a newly designed community-based trial. PMID- 26415501 TI - A cell-based model system links chromothripsis with hyperploidy. AB - A remarkable observation emerging from recent cancer genome analyses is the identification of chromothripsis as a one-off genomic catastrophe, resulting in massive somatic DNA structural rearrangements (SRs). Largely due to lack of suitable model systems, the mechanistic basis of chromothripsis has remained elusive. We developed an integrative method termed "complex alterations after selection and transformation (CAST)," enabling efficient in vitro generation of complex DNA rearrangements including chromothripsis, using cell perturbations coupled with a strong selection barrier followed by massively parallel sequencing. We employed this methodology to characterize catastrophic SR formation processes, their temporal sequence, and their impact on gene expression and cell division. Our in vitro system uncovered a propensity of chromothripsis to occur in cells with damaged telomeres, and in particular in hyperploid cells. Analysis of primary medulloblastoma cancer genomes verified the link between hyperploidy and chromothripsis in vivo. CAST provides the foundation for mechanistic dissection of complex DNA rearrangement processes. PMID- 26415502 TI - Differentially expressed microRNAs in bone marrow mesenchymal stem cell-derived microvesicles in young and older rats and their effect on tumor growth factor beta1-mediated epithelial-mesenchymal transition in HK2 cells. AB - INTRODUCTION: The prevalence of renal fibrosis is higher in older than in younger individuals. Through paracrine activity, bone marrow mesenchymal stem cell derived microvesicles (BM-MSC-MVs) influence the process of renal fibrosis. Differences in microRNA (miRNA) expression of BM-MSC-MVs that correlate with the age of the subjects and the correlation between miRNA expression and the process of renal fibrosis have not been established. The present study aimed to analyze differences in miRNA expression of BM-MSC-MVs between young or older rats and its influence on tumor growth factor-beta 1 (TGF-beta1)-mediated epithelial mesenchymal transition (EMT) of HK2 cells to explore the causes of renal fibrosis in aged tissues. METHODS: miRCURY LNA Array (version 18.0) was used to identify differentially expressed miRNAs in BM-MSC-MVs of 3- and 24-month-old Fisher344 rats. Reverse transcription-polymerase chain reaction was used to verify miRNA levels in BM-MSC-MVs and in the serum of rats. A TGF-beta1-mediated EMT model was used to study the effects of BM-MSC-MVs and differentially expressed miRNAs on EMT. RESULTS: BM-MSCs from older rats showed more severe aging phenotypes compared with those of young rats. In addition, the growth rate and cell migration of BM-MSCs derived from older rats were significantly reduced. In secreted BM-MSC-MVs, the expression of miR-344a, miR-133b-3p, miR-294, miR-423 3p, and miR-872-3p was significantly downregulated in older rats than in younger rats (P < 0.05), and the serum level of these miRNAs exhibited the same patterns. Intervention using BM-MSC-MVs resulted in the weakening of TGF-beta1-mediated EMT in the aged rats. MiR-344a, miR-133b-3p, and miR-294 affected TGF-beta1-mediated EMT in HK2 cells. Among these, miR-133b-3p and miR-294 significantly inhibited TGF-beta1-mediated EMT in HK2 cells (P < 0.05). CONCLUSIONS: In older rats, the inhibitory effect of BM-MSC-MVs on TGF-beta1-mediated HK2 cell EMT was weaker than that observed in younger rats. In addition, miR-133b-3p and miR-294, which were downregulated in BM-MSC-MVs of older rats, remarkably inhibited TGF-beta1 mediated EMT in HK2 cells, suggesting that these may play a role in the fibrosis of aging renal tissues. PMID- 26415503 TI - Inhaled carbon monoxide protects time-dependently from loss of hypoxic pulmonary vasoconstriction in endotoxemic mice. AB - BACKGROUND: Inhaled carbon monoxide (CO) appears to have beneficial effects on endotoxemia-induced impairment of hypoxic pulmonary vasoconstriction (HPV). This study aims to specify correct timing of CO application, it's biochemical mechanisms and effects on inflammatory reactions. METHODS: Mice (C57BL/6; n = 86) received lipopolysaccharide (LPS, 30 mg/kg) intraperitoneally and subsequently breathed 50 ppm CO continuously during defined intervals of 3, 6, 12 or 18 h. Two control groups received saline intraperitoneally and additionally either air or CO, and one control group received LPS but breathed air only. In an isolated lung perfusion model vasoconstrictor response to hypoxia (FiO2 = 0.01) was quantified by measurements of pulmonary artery pressure. Pulmonary capillary pressure was estimated by double occlusion technique. Further, inflammatory plasma cytokines and lung tissue mRNA of nitric-oxide-synthase-2 (NOS-2) and heme oxygenase-1 (HO 1) were measured. RESULTS: HPV was impaired after LPS-challenge (p < 0.01). CO exposure restored HPV-responsiveness if administered continuously for full 18 h, for the first 6 h and if given in the interval between the 3(rd) and 6(th) hour after LPS-challenge (p < 0.05). Preserved HPV was attributable to recovered arterial resistance and associated with significant reduction in NOS-2 mRNA when compared to controls (p < 0.05). We found no effects on inflammatory plasma cytokines. CONCLUSION: Low-dose CO prevented LPS-induced impairment of HPV in a time-dependent manner, associated with a decreased NOS-2 expression. PMID- 26415505 TI - "Poppy" yeast. PMID- 26415504 TI - AIF inhibits tumor metastasis by protecting PTEN from oxidation. AB - Apoptosis-inducing factor (AIF) exerts dual roles on cell death and survival, but its substrates as a putative oxidoreductase and roles in tumorigenesis remain elusive. Here, we report that AIF physically interacts with and inhibits the oxidation of phosphatase and tensin homolog on chromosome ten (PTEN), a tumor suppressor susceptible for oxidation-mediated inactivation. More intriguingly, we also identify PTEN as a mitochondrial protein and the ectopic expression of mitochondrial targeting sequence-carrying PTEN almost completely inhibits Akt phosphorylation in PTEN-deficient cells. AIF knockdown causes oxidation-mediated inactivation of the lipid phosphatase activity of PTEN, with ensuing activation of Akt kinase, phosphorylation of the Akt substrate GSK-3beta, and activation of beta-catenin signaling in cancer cells. Through its effect on beta-catenin signaling, AIF inhibits epithelial-mesenchymal transition (EMT) and metastasis of cancer cells in vitro and in orthotopically implanted xenografts. Accordingly, the expression of AIF is correlated with the survival of human patients with cancers of multiple origins. These results identify PTEN as the substrate of AIF oxidoreductase and reveal a novel function for AIF in controlling tumor metastasis. PMID- 26415506 TI - ABCG2 impairs the activity of the aurora kinase inhibitor tozasertib but not of alisertib. AB - BACKGROUND: Recently, we have shown that the ATP-binding cassette (ABC) transporter ABCB1 interferes with the anti-cancer activity of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) but not of the aurora kinase A and B inhibitor alisertib (MLN8237). Preliminary data had suggested tozasertib also to be a substrate of the ABC transporter ABCG2, another ABC transporter potentially involved in cancer cell drug resistance. Here, we studied the effect of ABCG2 on the activity of tozasertib and alisertib. RESULTS: The tozasertib concentration that reduces cell viability by 50% (IC50) was dramatically increased in ABCG2 transduced UKF-NB-3(ABCG2) cells (48.8-fold) compared to UKF-NB-3 cells and vector-transduced control cells. The ABCG2 inhibitor WK-X-34 reduced tozasertib IC50 to the level of non-ABCG2-expressing UKF-NB-3 cells. Furthermore, ABCG2 depletion from UKF-NB-3(ABCG2) cells using another lentiviral vector expressing an shRNA against the bicistronic mRNA of ABCG2 and eGFP largely re-sensitised these cells to tozasertib. In contrast, alisertib activity was not affected by ABCG2 expression. CONCLUSIONS: Tozasertib but not alisertib activity is affected by ABCG2 expression. This should be considered within the design and analysis of experiments and clinical trials investigating these compounds. PMID- 26415507 TI - Individual and community level determinants of childhood full immunization in Ethiopia: a multilevel analysis. AB - BACKGROUND: Expanded program on immunization is one of the most successful and cost effective public health interventions that protect children against vaccine preventable diseases. The full childhood immunization coverage in many parts of Ethiopia is far from optimal. Hence, the main objective of this study was to assess factors associated with childhood full immunization in Ethiopia. METHODS: The data source for this study was the 2011 Ethiopian Demographic and Health Survey. Multilevel regression analysis techniques were used to conduct the analysis. Accordingly a two level multilevel regression analysis model was built with individuals (level 1) nested with in communities (level 2). RESULTS: A total of 4983 children aged 12-59 months nested within 520 clusters were included in the analysis. According to the analysis results, in the year 2011, 26 % of children less than 5 years old were fully immunized in Ethiopia. Being born at health institutions, higher level of maternal education, media exposure, region of residence and residing in communities possessing higher maternal antenatal care services utilization were positively associated with childhood full immunization. In contrary to this, the number children aged less than 5 years in the household was negatively associated with childhood full immunization. The random effect results indicated that 21 % of the variation among the communities was due to community level factors. CONCLUSIONS: It was found that various individual and contextual factors were associated with childhood full immunization. In addition, significant community level variation remains after having controlled individual and community level factors which is an indicative of a need for further research on community level factors. Hence, utilizing multilevel modeling in determining the effect of both individual and contextual level factors simultaneously had brought an important output which may help planners, policy and decision makers to emphasize on both individuals and communities in which they live. PMID- 26415508 TI - Differential replicative ability of clinical dengue virus isolates in an immunocompetent C57BL/6 mouse model. AB - BACKGROUND: Several experimental animal models have been used to study the pathogenesis of dengue disease; however, most of the studies used laboratory adapted viruses, which lack the virulence of viruses circulating in humans. The aim of this study was to analyze the ability of clinical Dengue virus (DENV) isolates (D2/BR/RP/RMB/09 and D3/BR/SL3/02) to infect immunocompetent C57BL/6 mice. METHODS: Two strategies of intraperitoneal infection, which were based on the concept of the antibody dependent enhancement phenomenon, were used. In one strategy, the animals were inoculated with macrophages infected in vitro with dengue viruses, which were incubated with enhancing antibodies, and in the other strategy, the animals were inoculated with a complex of enhancing antibodies and dengue viruses. RESULTS: The D3/BR/SL3/08 isolate showed a higher ability of infection (virus RNA was more frequently detected in the serum and in several organs) in the experimental model compared to both the D2/BR/RP/RMB/2009 isolate and a laboratory adapted DENV-1 strain (Mochizuki strain), regardless of the infection strategy used. The main features of the D3/BR/SL3/08 isolate were its neuroinvasiveness and the induction of an extended period of viremia. Enhancing antibodies did not influence on the infection of animals when macrophages were used, but the level of viremia was increased when they were used as a complex with a D3/BR/SL3/02 isolate. DISCUSSION: We showed that DENV isolates could infect immunocompetent C57BL/6 mice, which have has been previously used to study some aspect of dengue disease when infected with laboratory adapted strains. DENV genome was detected in the same organs found in humans when autopsy and biopsy samples were analyzed, showing that C57BL/6 mice reproduce some aspects of the DENV tropism observed in humans. The main difference observed between the D3/BR/SL3/02 and D2/BR/RP/RMB/2009 clinical isolates was the neuroinvasive ability of the first one. Neuroinvasiveness has been described in some DENV infected cases and is common for other members of the Flavivirus genus. CONCLUSIONS: These results suggest that C57BL/6 mice can be used as an experimental model to evaluate virulence differences among DENV clinical isolates. PMID- 26415509 TI - Gloriosa superba poisoning mimicking an acute infection- a case report. AB - BACKGROUND: Gloriosa superba (GSb) is a highly poisonous plant and its toxicity is due to anti-mitotic effects of constituents such as colchicine and gloriosine on rapidly proliferating cells. Poisoning is known to cause very rapid and severe clinical manifestations due gastro intestinal, neurological, cardiac and bone marrow toxicity. CASE PRESENTATION: A young male presented with an acute onset febrile illness associated with diarrhoea, confusion, haematuria and aggressive behavior of 4 days duration. He developed subconjunctival haemorrhages, bleeding gums, neck stiffness, bilateral papilloedema, tender hepatomegaly and features suggestive of subacute intestinal obstruction. He had progressive reduction in white cell counts, platelets and derrangements in liver functions. The illness mimicked acute severe leptospirosis or dengue. On day 9 of illness he started to loose his hair and was totally alopecic by day 14. At this stage of illness, possibility of GSb poisoning was suspected. He admitted the act of self harm after repeated questioning. CONCLUSION: His presentation mimicked an acute severe tropical febrile illness such as leptospirosis or dengue until he started to loose his hair. Therefore we feel that Clinicians practicing in tropical setting where Gloriosa superba is endemic should be aware of its clinical presentations and should always consider the possibility of ingestion of Gloriosa superba when the patient has pancytopenia and develops shedding of hairs which results in total alopecia in a case of unexplained gastroenterocolitis, rather investigating. PMID- 26415510 TI - BARD1 mediates TGF-beta signaling in pulmonary fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a rapid progressive fibro proliferative disorder with poor prognosis similar to lung cancer. The pathogenesis of IPF is uncertain, but loss of epithelial cells and fibroblast proliferation are thought to be central processes. Previous reports have shown that BARD1 expression is upregulated in response to hypoxia and associated with TGF-beta signaling, both recognized factors driving lung fibrosis. Differentially spliced BARD1 isoforms, in particular BARD1beta, are oncogenic drivers of proliferation in cancers of various origins. We therefore hypothesized that BARD1 and/or its isoforms might play a role in lung fibrosis. METHODS: We investigated BARD1 expression as a function of TGF-beta in cultured cells, in mice with experimentally induced lung fibrosis, and in lung biopsies from pulmonary fibrosis patients. RESULTS: FL BARD1 and BARD1beta were upregulated in response to TGF-beta in epithelial cells and fibroblasts in vitro and in vivo. Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length (FL) BARD1 and BARD1beta in fibrotic tissues. CONCLUSION: Our data suggest that FL BARD1 and BARD1beta might be mediators of pleiotropic effects of TGF-beta. In particular BARD1beta might be a driver of proliferation and of pulmonary fibrosis pathogenesis and progression and represent a target for treatment. PMID- 26415511 TI - Underweight body mass index is a risk factor of mortality in outpatients with nocturia in Japan. AB - BACKGROUND: Although nocturia has been reported to increase mortality in elderly individuals, the particular risk factors that are associated with this event are unclear. Therefore, we evaluated risk factors for death in outpatients with nocturia. METHODS: Between October 2002 and December 2009, 250 consecutive patients with nocturia were enrolled in two general hospitals in Japan. Among them, 193 patients were able to be followed for at least 1 year and up to 9 years (median 4.8 years) if the patients did not die. Mortality rates and risk factors were evaluated in the nocturic outpatients. RESULTS: Two- and 5-year survival of the nocturic outpatients was 94.6% [95% confidence interval (CI) = 92.2-97.1] and 82.6% (95% CI = 75.4-87.8), respectively. Higher Charlson Comorbidity Score, lower body mass index (BMI) and lower Physical Component Summary of Short Form-36 item scores were significantly correlated with mortality (p < 0.0001, p < 0.005 and p < 0.05, respectively) in multivariate analysis. The International Prostate Symptom Score, Pittsburgh Sleep Quality Index, Mental or Role/Social Component Summary of Short Form-36 item scores and Nocturnal Polyuria index were not significantly correlated with mortality. The mortality rate was significantly higher in subjects with an underweight BMI (<18.50) compared with a normal range (18.50-24.99) or overweight (>=25.00) BMI [p < 0.00005, hazard ratio (HR) = 5.84, 95% CI = 2.03-16.8; p < 0.0005, HR = 5.92, 95% CI = 1.94-18.0]. CONCLUSIONS: Additional attention is required for nocturic outpatients with not only a high Charlson Comorbidity Score but also an underweight BMI because of their high mortality. Large prospective studies are warranted to validate this finding and extend more. PMID- 26415512 TI - Concurrent and predictive validity of physical activity measurement items commonly used in clinical settings--data from SCAPIS pilot study. AB - BACKGROUND: As the understanding of how different aspects of the physical activity (PA) pattern relate to health and disease, proper assessment is increasingly important. In clinical care, self-reports are the most commonly used assessment technique. However, systematic comparisons between questions regarding concurrent or criterion validity are rare, as are measures of predictive validity. The aim of the study was to examine the concurrent (using accelerometry as reference) and predictive validity (for metabolic syndrome) of five PA questions. METHODS: A sample of 948 middle-aged Swedish men and women reported their PA patterns via five different questions and wore an accelerometer (Actigraph GT3X) for a minimum of 4 days. Concurrent validity was assessed as correlations and ROC-analyses. Predictive validity was assessed using logistic regression, controlling for potential confounders. RESULTS: Concurrent validity was low-to-moderate (r <0.35 and ROC AUC <0.7) with large misclassifications regarding time spent sitting/sedentary and in moderate-to vigorous PA. The predictive validity of the questions was good, and one question (PHAS) showed an 80 % decreased odds-ratio of having metabolic syndrome, after taking potential confounders into consideration. DISCUSSION: In this mixed sample of adults, both concurrent and predictive validity vaired between items and between measures of the physical activity pattern. The PHAS and WALK items are proposed for assessment of adherence to PA recommendations. CONCLUSION: Assessing PA patterns using self-report measures results in methodological problems when trying to predict individual risk for the metabolic syndrome, as the concurrent validity generally was low. However, several of the investigated questions may be useful for assessing risk at a group level, showing better predictive validity. PMID- 26415514 TI - Probing the interaction of Rh, Co and bimetallic Rh-Co nanoparticles with the CeO2 support: catalytic materials for alternative energy generation. AB - The interaction of CeO2-supported Rh, Co and bimetallic Rh-Co nanoparticles, which are active catalysts in hydrogen production via steam reforming of ethanol, a process related to renewable energy generation, was studied by X-ray diffraction (XRD), high resolution electron microscopy (HRTEM), X-ray photoelectron spectroscopy (XPS) and low energy ion scattering (LEIS). Furthermore, diffuse reflectance infrared spectroscopy (DRIFTS) of adsorbed CO as a probe molecule was used to characterize the morphology of metal particles. At small loadings (0.1%), Rh is in a much dispersed state on ceria, while at higher contents (1-5%), Rh forms 2-8 nm particles. Between 473-673 K pronounced oxygen transfer from ceria to Rh is observed and at 773 K significant agglomeration of Rh occurs. On reduced ceria, XPS indicates a possible electron transfer from Rh to ceria. The formation of smaller ceria crystallites upon loading with Co was concluded from XRD and HRTEM; for 10% Co, the CeO2 particle size decreased from 27.6 to 10.7 nm. A strong dissolution of Co into ceria and a certain extent of encapsulation by ceria were deduced by XRD, XPS and LEIS. In the bimetallic system, the presence of Rh enhances the reduction of cobalt and ceria. During thermal treatments, reoxidation of Co occurs, and Rh agglomeration as well as oxygen migration from ceria to Rh are hindered in the presence of cobalt. PMID- 26415513 TI - Mini-Tn7 vectors for stable expression of diguanylate cyclase PleD* in Gram negative bacteria. AB - BACKGROUND: The cyclic diguanylate (c-di-GMP) is currently considered an ubiquitous second messenger in bacteria that influences a wide range of cellular processes. One of the methodological approaches to unravel c-di-GMP regulatory networks involves raising the c-di-GMP intracellular levels, e.g. by expressing a diguanylate cyclase (DGC), to provoke phenotypic changes. RESULTS: We have constructed mini-Tn7 delivery vectors for the integration and stable expression of the pleD* gene encoding a highly active DGC, which can be used to artificially increase the intracellular levels of c-di-GMP in Gram negative bacteria. The functionality of these new vectors has been validated in several plant interacting alpha- and gamma-proteobacteria. Similarly to vector plasmid-borne pleD*, the genome-borne mini-Tn7pleD* constructs provide significant increases in intracellular c-di-GMP, provoking expected phenotypic changes such as enhanced polysaccharide production, biofilm formation and reduced motility. However, the mini-Tn7pleD* constructs resulted far more stable in the absence of antibiotics than the plasmid-based pleD* constructs. Furthermore, we have also implemented an inducible system to modulate pleD* expression and intracellular c-di-GMP rises "on demand". CONCLUSIONS: mini-Tn7pleD* constructs are very stable and are maintained during bacterial free-living growth as well as during interaction with eukaryotic hosts, in the absence of selective pressure. This high stability ensures experimental homogeneity in time and space with regard to enhancing c-di GMP intracellular levels in bacteria of interest. PMID- 26415515 TI - Photobiological properties of 3-psoralenacetic acids. AB - Some 4,8-dimethyl-3-psoralenacetic acids were synthesized and studied. All the designed psoralenacetic acids bear alkyl or cycloalkyl substituents at the furan ring. These psoralenacetic acids were shown to be a novel class of psoralen derivatives characterized by an interesting photobiological profile. The carboxylic group at the 3 position, useful to confer hydrophilic properties, appears to be detrimental to the classical intercalation into DNA, likely because of repulsive interactions with the negative surface of the macromolecule. Nevertheless, the new derivatives possess a notable photoantiproliferative activity, due to a peculiar mechanism of action consisting of a decarboxylation step before exerting their photobiological activity. The most active compound 2 is able to induce a noteworthy photocytotoxic effect, with GI50 values being submicromolar on human tumor cell lines and no effect in the dark. The involvement of DNA photoaddition after UVA light-mediated decarboxylation and ROS formation is responsible for its biological activity, as demonstrated comparing the activity profile of the decarboxylated analogue. However, other biological targets seem to be involved in the photooxidative damage, such as proteins. Compound 2 could thus be considered as a prodrug, inactive without UVA light but activated upon specific irradiation, thus preventing unselective side effects and opening new perspectives on agents useful in photochemotherapy. PMID- 26415516 TI - Full-color structured illumination optical sectioning microscopy. AB - In merits of super-resolved resolution and fast speed of three-dimensional (3D) optical sectioning capability, structured illumination microscopy (SIM) has found variety of applications in biomedical imaging. So far, most SIM systems use monochrome CCD or CMOS cameras to acquire images and discard the natural color information of the specimens. Although multicolor integration scheme are employed, multiple excitation sources and detectors are required and the spectral information is limited to a few of wavelengths. Here, we report a new method for full-color SIM with a color digital camera. A data processing algorithm based on HSV (Hue, Saturation, and Value) color space is proposed, in which the recorded color raw images are processed in the Hue, Saturation, Value color channels, and then reconstructed to a 3D image with full color. We demonstrated some 3D optical sectioning results on samples such as mixed pollen grains, insects, micro-chips and the surface of coins. The presented technique is applicable to some circumstance where color information plays crucial roles, such as in materials science and surface morphology. PMID- 26415517 TI - Underperception of Naps in Older Adults Referred for a Sleep Assessment: An Insomnia Trait and a Cognitive Problem? AB - OBJECTIVES: To examine the frequency and determinants of underperception of naps in older adults referred for a sleep assessment. DESIGN: Prospective study. SETTING: Outpatient geriatric sleep clinic. PARTICIPANTS: Individuals aged 60 and older referred for insomnia complaints or suspected sleep apnea (N = 135). MEASUREMENTS: Tests included clinical interview, sleepiness scale, anxiety and depression scale, Insomnia Severity Index (ISI), Mini-Mental State Examination (MMSE), and overnight polysomnography, followed by multiple sleep latency tests. At the end of each of four nap opportunities, participants answered whether they had slept during the test. Nap underperception was defined as two or more unperceived naps. RESULTS: Of the 105 participants who napped at least twice, 42 (40%) did not perceive at least two naps. These participants had lower MMSE scores (P = .01) and were more likely to be taking benzodiazepines (P = .008) than the 63 participants who did not underperceive their naps but had similar demographic characteristics, sleep diagnoses, depression and anxiety scores, and polysomnography measures. Both groups had similarly short mean daytime sleep latencies (9.7 +/- 4.5 minutes and 9.8 +/- 3.7 minutes), but participants who underperceived their naps scored lower on the Epworth Sleepiness Scale (5.6 +/- 4.0, vs 9.6 +/- 4.8, P < .001). An ISI of 11 or greater, a MMSE score of 26 or less, and a sleepiness score of 8 or less were each independently associated with underperception of naps. The combination of these three factors yielded a positive predictive value of 93% and a negative predictive value of 71% for nap underperception. CONCLUSION: Older adults referred for sleep consultation with cognitive impairment and greater insomnia symptoms frequently underperceive naps, leading them to underestimate their level of sleepiness. In such cases, objective measures of daytime sleepiness would be better than the Epworth Sleepiness Scale. PMID- 26415519 TI - Vitamin D Supplementation in the Treatment of Chronic Heart Failure: A Meta analysis of Randomized Controlled Trials. AB - BACKGROUND: In recent years, there has been growing evidence that vitamin D deficiency is associated with the development and progression of chronic heart failure (CHF). HYPOTHESIS: Additional supplementation of vitamin D may have protective effects in patients with CHF. METHODS: We searched PubMed, Embase, and Cochrane databases through June 2015 and included 7 randomized controlled trials that investigated the effects of vitamin D on cardiovascular outcomes in patients with CHF. Then, we performed a meta-analysis of clinical trials to confirm whether vitamin D supplementation is beneficial in CHF patients. The weighted mean difference (WMD) and 95% confidence interval (CI) were calculated using fixed- or random-effects models. RESULTS: Our pooled results indicated that additional supplementation of vitamin D was not superior to conventional treatment in terms of left ventricular ejection fraction, N-terminal pro-B-type natriuretic peptide, and 6-minute walk distance. Moreover, vitamin D supplementation was associated with significant decreases in the levels of tumor necrosis factor-alpha (WMD: -2.42 pg/mL, 95% CI: -4.26 to -0.57, P < 0.05), C reactive protein (WMD: -0.72 mg/L, 95% CI: -1.42 to -0.02, P < 0.05), and parathyroid hormone (WMD: -13.44 pg/mL, 95% CI: -21.22 to -5.67, P < 0.05). CONCLUSIONS: Vitamin D supplementation may decrease serum levels of parathyroid hormone and inflammatory mediators in CHF patients, whereas it has no beneficial effects on improvement of left ventricular function and exercise tolerance. PMID- 26415520 TI - Randomized controlled trial of a self-efficacy enhancement program for the cardiac rehabilitation of Thai patients with myocardial infarction. AB - This study examined the effects of a self-efficacy enhancement program for the cardiac rehabilitation of Thai patients who had a myocardial infarction. Sixty six hospitalized patients of various ages and both genders were randomly assigned to either an experimental or a control group. Participants in the experimental group took part in three individualized in-hospital education sessions and three weekly sessions of telephone counseling. The control group primarily engaged in a supervised exercise and activities of a daily living performance regimen, and received education in this regard. Self-efficacy and functional status were measured via questionnaire. Four weeks after discharge, the experimental group was found to have significantly higher total self-efficacy and functional status scores than the control group. In addition, the experimental group exhibited significantly higher subscale scores on social activity, household tasks, occupation, and exercise self-efficacy than the control group. These results indicate that the program is effective in improving the self-efficacy and functional status of Thai patients who have had a myocardial infarction. PMID- 26415521 TI - Adult pre B-cell acute lymphoblastic leukemia with unusually large proportion of bone marrow CD45 bright/high SSc blasts. AB - BACKGROUND: We present a pre B-ALL patient with the rare clinical manifestation of extramedullary disease, and a normal hemogram. This patient's blasts expressed bright CD45 and high side scatter (SSc) placing the cells in the monocyte gate. METHODS: Samples from peripheral blood and bone marrow (BM) aspirate from a 50 year-old female patient were immunophenotyped by multiparametric flow cytometry. RESULTS: Flow cytometry studies of the BM aspirate showed a large monocyte gate with 90-95% of the cells expressing an abnormal B cell phenotype. Peripheral white blood cells count was normal and cytogenetic analysis of the BM revealed a normal karyotype. CONCLUSION: It was not possible, based on CD45/SSc to identify a lymphoblast population in this pre B-ALL patient. Although bright expression of CD45 B-ALL blasts has been associated with poor prognosis to the best of our knowledge, the combination of bright CD45 blasts with high SSc has not been reported. As CD45 expression vs. SSc is routinely measured in the diagnostics of acute leukemias, a possible association between CD45 bright positivity and extramedullary disease or prognosis warrants further exploration. (c) 2015 International Clinical Cytometry Society. PMID- 26415522 TI - Multicomponent One-pot Reactions Towards the Synthesis of Stereoisomers of Dipicolylamine Complexes. AB - Reported are multi-component one-pot syntheses of chiral complexes [M(L(R) OR')Cl2 ] or [M(L(R) SR')Cl2 ] from the mixture of an N-substituted ethylenediamine, pyridine-2-carboxaldehyde, a primary alcohol or thiol and MCl2 utilizing in-situ formed cyclized Schiff bases where a C-O bond, two stereocenters, and three C-N bonds are formed (M=Zn, Cu, Ni, Cd; R=Et, Ph; R'=Me, Et, nPr, nBu). Tridentate ligands L(R) OR' and L(R) SR' comprise two chiral centers and a hemiaminal ether or hemiaminal thioether moiety on the dipicolylamine skeleton. Syn-[Zn(L(Ph) OMe)Cl2 ] precipitates out readily from the reaction mixture as a major product whereas anti-[Zn(L(Ph) OMe)Cl2 ] stays in solution as minor product. Both syn-[Zn(L(Ph) OMe)Cl2 ] and anti-[Zn(L(Ph) OMe)Cl2 ] were characterized using NMR spectroscopy and mass spectrometry. Solid state structures revealed that syn-[Zn(L(Ph) OMe)Cl2 ] adopted a square pyramidal geometry while anti-[Zn(L(Ph) OMe)Cl2 ] possesses a trigonal bipyramidal geometry around the Zn centers. The scope of this method was shown to be wide by varying the components of the dynamic coordination assembly, and the structures of the complexes isolated were confirmed by NMR spectroscopy, mass spectrometry, and X ray crystallography. Syn complexes were isolated as major products with Zn(II) and Cu(II) , and anti complexes were found to be major products with Ni(II) and Cd(II) . Hemiaminals and hemiaminal ethers are known to be unstable and are seldom observed as part of cyclic organic compounds or as coordinated ligands assembled around metals. It is now shown, with the support of experimental results, that linear hemiaminal ethers or thioethers can be assembled without the assistance of Lewis acidic metals in the multi-component assembly, and a possible pathway of the formation of hemiaminal ethers has been proposed. PMID- 26415518 TI - Matrix metalloproteinase-10: a novel biomarker for idiopathic pulmonary fibrosis. AB - BACKGROUND: Matrix metalloproteinases (MMPs) are believed to be involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF), and MMP-7 has been described as a useful biomarker for IPF. However, little is known regarding the significance of MMP-10 as a biomarker for IPF. METHODS: This observational cohort study included 57 patients with IPF. Serum MMPs were comprehensively measured in all patients, and the relationships between these markers and both disease severity and prognosis were evaluated. Bronchoalveolar lavage fluid (BALF) MMP-7 and -10 levels were measured in 19 patients to investigate the correlation between these markers and their corresponding serum values. Immunohistochemical staining for MMP-10 was also performed in IPF lung tissue. RESULTS: Serum MMP-7 and -10 levels correlated significantly with both the percentage of predicted forced vital capacity (rho = -0.31, p = 0.02 and rho = -0.34, p < 0.01, respectively) and the percentage of predicted diffusing capacity of the lung for carbon monoxide (rho = -0.32, p = 0.02 and rho = -0.43, p < 0.01, respectively). BALF MMP-7 and -10 levels correlated with their corresponding serum concentrations. Only serum MMP-10 predicted clinical deterioration within 6 months and overall survival. In IPF lungs, the expression of MMP-10 was enhanced and localized to the alveolar epithelial cells, macrophages, and peripheral bronchiolar epithelial cells. CONCLUSIONS: MMP-10 may be a novel biomarker reflecting both disease severity and prognosis in patients with IPF. PMID- 26415523 TI - Functional and Clinical Consequences of Novel alpha-Galactosidase A Mutations in Fabry Disease. AB - Fabry disease (FD) is a rare metabolic disorder of glycosphingolipid storage caused by mutations in the GLA gene encoding lysosomal hydrolase alpha galactosidase A (alpha-gal A). Recently, the diagnostic procedure for FD has advanced in several ways, through the development of a specific biomarker (lyso Gb3) and the implementation of newborn screenings, which acted as a catalyst to augment general awareness of the disease. Heterologous over-expression of alpha gal A variants and subsequent in vitro measurement of enzyme activity provided molecular data to elucidate the relationship between mutation, enzyme damage, lyso-Gb3 biomarker levels, and clinical phenotype. This knowledge is the foundation for improved counseling with regard to prognosis and therapeutic decisions. Herein, we resume the approach of in vitro characterization, with a further 73 mainly novel GLA gene mutations. Patient lyso-Gb3 data were available for most of the mutations. All mutations were tested for responsiveness to pharmacological chaperone treatment and phenotypic data for 61 hemizygous male and 116 heterozygous female patients carrying a mutation associated with >= 20% residual activity, formerly classified as "mild" variant, were collected in order to evaluate the pathogenicity. We conclude that a mild GLA variant is typically characterized by high residual enzyme activity and normal biomarker levels. We found evidence that these variants can still be classified as a distinctive, but milder, sub-type of FD. PMID- 26415524 TI - Colloidal dual-band gap cell for photocatalytic hydrogen generation. AB - We report that the internal quantum efficiency for hydrogen generation in spherical, Pt-decorated CdS nanocrystals can be tuned by quantum confinement, resulting in higher efficiencies for smaller than for larger nanocrystals (17.3% for 2.8 nm and 11.4% for 4.6 nm diameter nanocrystals). We attribute this to a larger driving force for electron and hole transfer in the smaller nanocrystals. The larger internal quantum efficiency in smaller nanocrystals enables a novel colloidal dual-band gap cell utilising differently sized nanocrystals and showing larger external quantum efficiencies than cells with only one size of nanocrystals (9.4% for 2.8 nm particles only and 14.7% for 2.8 nm and 4.6 nm nanocrystals). This represents a proof-of-principle for future colloidal tandem cell. PMID- 26415525 TI - Clinical and neurobiological advances in promoting regeneration of the ventral root avulsion lesion. AB - Root avulsions due to traction to the brachial plexus causes complete and permanent loss of function. Until fairly recent, such lesions were considered impossible to repair. Here we review clinical repair strategies and current progress in experimental ventral root avulsion lesions. The current gold standard in patients with a root avulsion is nerve transfer, whereas reimplantation of the avulsed root into the spinal cord has been performed in a limited number of cases. These neurosurgical repair strategies have significant benefit for the patient but functional recovery remains incomplete. Developing new ways to improve the functional outcome of neurosurgical repair is therefore essential. In the laboratory, the molecular and cellular changes following ventral root avulsion and the efficacy of intervention strategies have been studied at the level of spinal motoneurons, the ventral spinal root and peripheral nerve, and the skeletal muscle. We present an overview of cell-based pharmacological and neurotrophic factor treatment approaches that have been applied in combination with surgical reimplantation. These interventions all demonstrate neuroprotective effects on avulsed motoneurons, often accompanied with various degrees of axonal regeneration. However, effects on survival are usually transient and robust axon regeneration over long distances has as yet not been achieved. Key future areas of research include finding ways to further extend the post-lesion survival period of motoneurons, the identification of neuron-intrinsic factors which can promote persistent and long-distance axon regeneration, and finally prolonging the pro-regenerative state of Schwann cells in the distal nerve. PMID- 26415527 TI - Maternal and paternal support for physical activity and healthy eating in preschool children: a cross-sectional study. AB - BACKGROUND: Parental support is a key influence on children's health behaviours; however, no previous investigation has simultaneously explored the influence of mothers' and fathers' social support on eating and physical activity in preschool aged children. This study evaluated the singular and combined effects of maternal and paternal support for physical activity (PA) and fruit and vegetable consumption (FV) on preschoolers' PA and FV. METHODS: A random sample comprising 173 parent-child dyads completed validated scales assessing maternal and paternal instrumental support and child PA and FV behaviour. Pearson correlations, controlling for child age, parental age, and parental education, were used to evaluate relationships between maternal and paternal support and child PA and FV. K-means cluster analysis was used to identify families with distinct patterns of maternal and paternal support for PA and FV, and one-way ANOVA examined the impact of cluster membership on child PA and FV. RESULTS: Maternal and paternal support for PA were positively associated with child PA (r = 0.37 and r = 0.36, respectively; P < 0.001). Maternal but not paternal support for FV was positively associated with child FV (r = 0.35; P < 0.001). Five clusters characterised groups of families with distinct configurations of maternal and paternal support for PA and FV: 1) above average maternal and paternal support for PA and FV, 2) below average maternal and paternal support for PA and FV, 3) above average maternal and paternal support for PA but below average maternal and paternal support for FV, 4) above average maternal and paternal support for FV but below average maternal and paternal support for PA, and 5) above average maternal support but below average paternal support for PA and FV. Children from families with above average maternal and paternal support for both health behaviours had higher PA and FV levels than children from families with above average support for just one health behaviour, or below average support for both behaviours. CONCLUSIONS: The level and consistency of instrumental support from mothers and fathers for PA and FV may be an important target for obesity prevention in preschool-aged children. PMID- 26415526 TI - Epidemiology of invasive candidiasis in a surgical intensive care unit: an observational study. AB - BACKGROUND: Invasive candidiasis (IC) is a frequent and life-threatening infection in critically ill patients. The aim of this study was to evaluate the epidemiology of IC and the antifungal susceptibility of etiological agents in patients admitted to our surgical intensive care unit (SICU) in Spain. METHODS: We designed a prospective, observational, single center, population-based study in a SICU. We included all consecutive adult patients (>=18 years old) who had documented IC, either on admission or during their stay, between January 2012 and December 2013. RESULTS: There were a total of 22 episodes of IC in the 1149 patients admitted during the 24-month study. The overall IC incidence was 19.1 cases per 1000 admissions. Thirteen cases of IC (59.1%) were intra-abdominal candidiasis (IAC) and 9 (40.9%) were candidemias. All cases of IAC were patients with secondary peritonitis and severe sepsis or septic shock. The overall crude mortality rate was 13.6%; while, it was 33% in patients with candidemia. All patients with IAC survived, including one patient with concomitant candidemia. The most common species causing IC was Candida albicans (13; 59.1%) followed by Candida parapsilosis (5; 22.7%), and Candida glabrata (2; 9.1%). There was also one case each (4.5%) of Candida krusei and Candida tropicalis. Thus, the ratio of non-C. albicans (9) to C. albicans (13) was 1:1.4. There was resistance to fluconazole and itraconazole in 13.6% of cases. Resistance to other antifungals was uncommon. CONCLUSIONS: Candida parapsilosis was the second most common species after C. albicans, indicating the high prevalence of non-C. albicans species in the SICU. Resistance to azoles, particularly fluconazole, should be considered when starting an empirical treatment. Although IAC is a very frequent form of IC in critically ill surgical patients, prompt antifungal therapy and adequate source control appears to lead to a good outcome. However, our results are closely related to our ICU and any generalization must be taken with caution. Therefore, further investigations are needed. PMID- 26415528 TI - A meta-analysis of in vitro antibiotic synergy against Acinetobacter baumannii. AB - The aim of the work was to describe the different in vitro models for testing synergism of antibiotics and gather the results of antibiotic synergy against multidrug-resistant Acinetobacter baumannii (MDR-Ab). The different original articles were obtained from different web sites. In order to compare the results obtained by the different methods for synergy testing, the Pearson chi-square and the Fischer tests were used. Moreover, non-parametric chi-square test was used in order to compare the frequency distribution in each analysed manuscript. In the current meta-analysis 24 manuscripts, which encompassed 2016 tests of in vitro synergism of different antimicrobials against MDR-Ab, were revised. Checkerboard synergy testing was used in 11 studies, which encompasses 1086 tests (53.9%); time-kill assays were applied in 12 studies, which encompass 359 tests (17.8%); gradient diffusion methods were used in seven studies, encompassing 293 tests (14.5%). And, finally, time-kill plus checkerboard were applied in two studies, encompassing 278 tests (13.8%). By comparing these data, checkerboard and time kill methods were significantly more used than gradient diffusion methods (p<0.005). Regarding synergy rates obtained on the basis of the applied method, checkerboard provided 227 tests (20.9%) with a synergistic effect; time-kill assays yielded 222 tests (61.8%) with a synergistic effect; gradient diffusion methods only provided 29 tests (9.9%) with a synergistic effect; and, finally, time-kill plus checkerboard yielded just 15 tests (5.4%) with a synergistic effect. When comparing these percentages, synergy rates reported by time-kill methods were significantly higher than that obtained by checkerboard and gradient diffusion methods (p<0.005). On the basis of the revised data, the combinations of a bactericidal antibiotic plus Tigecycline, Vancomycin or Teicoplanin are not recommended. The best combinations of antibiotics are those which include bactericidal antibiotics such as Carbapenems, Fosfomycin, Amikacin, Polymyxins, Rifampicin and Ampicillin/Sulbactam. PMID- 26415529 TI - Detection of Escherichia coli sequence type 131 clonal group among extended spectrum beta-lactamase-producing E. coli using VITEK MS Plus matrix-assisted laser desorption ionization-time of flight mass spectrometry. AB - We investigated the performance of the VITEK MS Plus system for the detection of Escherichia coli sequence type 131 (ST131) among extended-spectrum beta-lactamase producing E. coli isolates. The SARAMIS software could discriminate the 67 ST131 isolates from 82 non-ST131 isolates with a sensitivity of 86.6% and a specificity of 95.1%. PMID- 26415530 TI - Immunoproteomic technology offers an extraordinary diagnostic approach for Toxoplasma gondii infection. AB - Immunoproteomic technology offers an exceptional tool to fill the blanks that still exist in diagnosis of Toxoplasma gondii infection despite its annotated sequence. The pitfalls of serological assays and current immunoproteomic approaches are accentuated, and new approaches are presented to improve the signal and to eliminate the noise produced by blocking-specific background. This review also highlights examples where immunoproteomic studies have contributed to broaden our understanding of toxoplasmosis diagnosis. Further promising solutions, which immunoproteomic technology can grant for toxoplasmosis diagnosis are part of an intense discussion. PMID- 26415531 TI - The effects of arginase inhibitor on lung oxidative stress and inflammation caused by pneumoperitoneum in rats. AB - BACKGROUND: Pneumoperitoneum-induced oxidative stress and organ injury are known to be associated with nitric oxide (NO) inactivation. Because arginase competes with NO synthase (NOS) for a common substrate, L-arginine, arginase inhibition may increase NO bioavailability. Therefore, we evaluated the ability of the arginase inhibitor, 2 (S)-amino-6-boronohexanoic acid (ABH), to attenuate pneumoperitoneum-induced decrease of NO bioavailability and lung injury. METHODS: Thirty rats were randomly divided into the following groups: 1) the PP-ABH group received a subcutaneous injection of ABH (5 mg/kg) 1 h before induction of pneumoperitoneum (insufflation to intraperitoneal pressure of 15 mmHg for 60 min); 2) the PP group received saline by subcutaneous injection 1 h before induction of pneumoperitoneum; and 3) the control group received saline by subcutaneous injection before a sham procedure with no gas insufflation. After desufflation, blood was collected to determine levels of plasma nitrite, NOS, inflammatory cytokines, and malondialdehyde, a marker of oxidative stress. Lung tissue was obtained for histological evaluation. RESULTS: We found that plasma nitrite levels were lower in the PP group and higher in the PP-ABH group, compared with controls (P <0.01 and P <0.05, respectively). In the PP group, endothelial NOS activity was decreased and inducible NOS activity was increased compared with the PP-ABH and control groups. Malondialdehyde levels increased 3 fold in the PP group and 2-fold in the PP-ABH group compared with controls. Tumor necrosis factor-alpha, interleukin-6, and interleukin-1beta levels were elevated in the PP group compared to the control group, but the increase in cytokine production was attenuated or blocked in the PP-ABH group. Lung injury scores were 4.8-fold higher in the PP group and 2-fold higher in the PP-ABH group compared with controls (P <0.001 and P <0.01, respectively). DISCUSSION: Pneumoperitoneum decreases NO bioavailability and increases the inflammation cytokines, resulting in organ injuries. Inhibition of arginase activity could maintain NO bioavailability by attenuating pneumoperitoneum-induced changes in NOS activity. In addition, arginase inhibition attenuated the oxidative stress and inflammation and decreased the severity of lung injury caused by pneumoperitoneum. CONCLUSIONS: By increasing NO bioavailability and suppressing oxidative stress and inflammation, pretreatment with an arginase inhibitor may protect against lung injury caused by pneumoperitoneum. PMID- 26415533 TI - Avoiding pediatric readmissions: Quite a challenge! PMID- 26415532 TI - Antioxidant and cytotoxic activities of three species of tropical seaweeds. AB - BACKGROUND: Three species of seaweeds (Padina tetrastromatica, Caulerpa racemosa and Turbinaria ornata) are widely consumed by Asians as nutraceutical food due to their antioxidant properties. Studies have shown that these seaweeds exhibit bioactivities which include antimicrobial, antiviral, anti-hypertensive and anticoagulant activities. However, investigations into the mechanisms of action pertaining to the cytotoxic activity of the seaweeds are limited. The aim of this study was to determine the antioxidant and cytotoxic activities of whole extracts of P. tetrastromatica, C. racemosa and T. ornata, including the cellular events leading to the apoptotic cell death of the extract treated-MCF-7 cells. Bioassay guided fractionation was carried out and the compounds identified. METHODS: Powdered samples were sequentially extracted for 24 h. Their antioxidant activities were assessed by the DPPH radical, superoxide, nitric oxide and hydroxyl radical scavenging assays. The cytotoxic activity of the extract-treated MCF-7cells was assessed using the MTT assay. The most potent fraction was subjected to bioassay guided fractionation with column chromatography. All the fractions were tested for cytotoxic activity, caspase activity and effect on DNA fragmentation. RESULTS: All three seaweeds showed potent radical scavenging activities in the various assays. The activity of the cellular antioxidant enzymes, superoxide dismutase, catalase and glutathione reductase, in MCF-7 cells, decreased in a time-dependent manner. The partially purified fractions exhibited higher cytotoxic activity, as assessed by the MTT assay, than the whole extracts in the breast adenocarcinoma cell line, MCF-7. LC-MS analysis revealed the presence of bioactive alkaloids such as camptothecin, lycodine and pesudopelletierine. CONCLUSION: Based on the results obtained, all three seaweeds are rich sources of enzymatic and non-enzymatic antioxidants which could contribute to their reported medicinal benefits. PMID- 26415534 TI - Takotsubo cardiomyopathy: Near drowning and hanging sound familiar. PMID- 26415535 TI - Relationship between a perioperative intravenous fluid administration strategy and acute kidney injury following off-pump coronary artery bypass surgery: an observational study. AB - INTRODUCTION: Saline-based and hydroxyethyl starch solutions are associated with increased risk of renal dysfunction. In the present study, we tested the hypothesis that balanced solutions and a limited volume of hydroxyethyl starch solution (renal protective fluid management [RPF] strategy) would decrease the incidence of postoperative acute kidney injury (AKI) and improve clinical outcomes in patients undergoing off-pump coronary artery bypass graft surgery (OPCAB). METHODS: We investigated 783 patients who underwent elective OPCAB. All patients who underwent OPCAB between 1 January 2010 and 4 July 2012 formed the control group and were given intravenous fluids with saline-based solutions and unlimited volumes of colloid solutions. All patients who underwent OPCAB between 5 July 2012 and 31 December 2013 formed the RPF group and were given intravenous fluids with RPF. The primary outcome was the incidence of postoperative AKI. Secondary outcomes included the incidence of severe AKI, requirement for renal replacement therapy, renal outcome at the time of discharge, and other clinical outcomes. RESULTS: Postoperative AKI occurred in 33 patients (14.4 %) in the RPF group compared with 210 patients (37.9 %) in the control group (P < 0.001). The incidences of severe AKI and persistent AKI after OPCAB were significantly lower, and the postoperative extubation time and duration of hospital stay were significantly shorter, in patients in the RPF group than in those in the control group. After adjustment by multivariate regression analyses and inverse probability of treatment weighting adjustment, the RPF group was independently associated with a lower incidence of postoperative AKI, severe AKI, and persistent AKI and a shorter postoperative extubation time and duration of hospital stay. CONCLUSIONS: The RPF strategy is associated with a significantly decreased incidence of postoperative, severe, and persistent AKI in patients undergoing OPCAB, although residual confounding may be present. PMID- 26415536 TI - Homograft reconstruction of the right ventricular outflow tract in adults with congenital heart disease: a systematic review. AB - Reconstruction of the right ventricular outflow tract with a homograft is an established surgical method in congenital heart disease. Studies from children and adolescents suggest that homograft durability is shorter than the life expectancy of the patient; therefore, durability in adults is addressed in this systematic review. The PubMed database was searched in May 2012 and repeated in May 2015 with the terms 'homograft AND pulmonary valve', generating 665 hits. We included only studies involving more than 50 patients with a mean or median age >18 years. Six studies with a cumulative total of 560 patients were included. The long-term mortality rate was 2-8.8% at 8.1-10 years. Reintervention was common during patients' life spans, with a 10-year event-free survival rate of 78-80%. Early postoperative echocardiographic or magnetic resonance imaging defects appear to predict rapid homograft degeneration. Further studies on various malformations and risk markers for degeneration are needed to make qualified and accurate decisions regarding lifetime management. PMID- 26415537 TI - Behavioral experiences as drivers of oligodendrocyte lineage dynamics and myelin plasticity. AB - Many behavioral experiences are known to promote hippocampal neurogenesis. In contrast, the ability of behavioral experiences to influence the production of oligodendrocytes and myelin sheath formation remains relatively unknown. However, several recent studies indicate that voluntary exercise and environmental enrichment can positively influence both oligodendrogenesis and myelination, and that, in contrast, social isolation can negatively influence myelination. In this review we summarize studies addressing the influence of behavioral experiences on oligodendrocyte lineage cells and myelin, and highlight potential mechanisms including experience-dependent neuronal activity, metabolites, and stress effectors, as well as both local and systemic secreted factors. Although more study is required to better understand the underlying mechanisms by which behavioral experiences regulate oligodendrocyte lineage cells, this exciting and newly emerging field has already revealed that oligodendrocytes and their progenitors are highly responsive to behavioral experiences and suggest the existence of a complex network of reciprocal interactions among oligodendrocyte lineage development, behavioral experiences, and brain function. Achieving a better understanding of these relationships may have profound implications for human health, and in particular, for our understanding of changes in brain function that occur in response to experiences. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'. PMID- 26415539 TI - Enhanced photoelectrocatalytic performance of alpha-Fe2O3 thin films by surface plasmon resonance of Au nanoparticles coupled with surface passivation by atom layer deposition of Al2O3. AB - The short lifetime of photogenerated charge carriers of hematite (alpha-Fe2O3) thin films strongly hindered the PEC performances. Herein, alpha-Fe2O3 thin films with surface nanowire were synthesized by electrodeposition and post annealing method for photoelectrocatalytic (PEC) water splitting. The thickness of the alpha-Fe2O3 films can be precisely controlled by adjusting the duration of the electrodeposition. The Au nanoparticles (NPs) and Al2O3 shell by atom layer deposition were further introduced to modify the photoelectrodes. Different constructions were made with different deposition orders of Au and Al2O3 on Fe2O3 films. The Fe2O3-Au-Al2O3 construction shows the best PEC performance with 1.78 times enhancement by localized surface plasmon resonance (LSPR) of NPs in conjunction with surface passivation of Al2O3 shells. Numerical simulation was carried out to investigate the promotion mechanisms. The high PEC performance for Fe2O3-Au-Al2O3 construction electrode could be attributed to the Al2O3 intensified LSPR, effective surface passivation by Al2O3 coating, and the efficient charge transfer due to the Fe2O3-Au Schottky junctions. PMID- 26415538 TI - Gabapentin potentiates sensitivity to the interoceptive effects of alcohol and increases alcohol self-administration in rats. AB - Gabapentin, a drug used in the treatment of epileptic seizures and neuropathic pain, has shown efficacy in the treatment of alcohol dependence. Moreover, given that gabapentin is used in the general population (e.g., non-dependent individuals, social drinkers), we sought to utilize preclinical assessments to examine the effects of gabapentin on sensitivity to moderate alcohol doses and alcohol self-administration in rats with a history of moderate drinking. To this end, we assessed whether gabapentin (0, 10, 30, 120 mg/kg, IG) pretreatment alters sensitivity to experimenter- and self-administered alcohol, and whether gabapentin alone has alcohol-like discriminative stimulus effects in rats trained to discriminate alcohol dose (1 g/kg, IG) vs. water. Second, we assessed whether gabapentin (0, 10, 30, 60 mg/kg, IG) would alter alcohol self-administration. Gabapentin pretreatment potentiated the interoceptive effects of both experimenter-administered and self-administered alcohol in discrimination-trained rats. Additionally, the highest gabapentin doses tested (30 and 120 mg/kg) were found to have partial alcohol-like discriminative stimulus effects when administered alone (e.g., without alcohol). In the self-administration trained rats, gabapentin pretreatment (60 mg/kg) resulted in an escalation in alcohol self-administration. Given the importance of interoceptive drug cues in priming and maintaining self-administration, these data define a specific behavioral mechanism (i.e., potentiation of alcohol effects) by which gabapentin may increase alcohol self-administration in non-dependent populations. PMID- 26415540 TI - Polarization Properties in Apertureless-Type Scanning Near-Field Optical Microscopy. AB - Polarization properties of apertureless-type scanning near-field optical microscopy (a-SNOM) were measured experimentally and were also analyzed using a finite-difference time-domain (FDTD) simulation. Our study reveals that the polarization properties in the a-SNOM are maintained and the a-SNOM works as a wave plate expressed by a Jones matrix. The measured signals obtained by the lock in detection technique could be decomposed into signals scattered from near-field region and background signals reflected by tip and sample. Polarization images measured by a-SNOM with an angle resolution of 1 degrees are shown. FDTD analysis also reveals the polarization properties of light in the area between a tip and a sample are p-polarization in most of cases. PMID- 26415541 TI - Paraboloid Structured Silicon Surface for Enhanced Light Absorption: Experimental and Simulative Investigations. AB - In this paper, we present an optical model that simulates the light trapping and scattering effects of a paraboloid texture surface first time. This model was experimentally verified by measuring the reflectance values of the periodically textured silicon (Si) surface with the shape of a paraboloid under different conditions. A paraboloid texture surface was obtained by electrochemical etching Si in the solution of hydrofluoric acid, dimethylsulfoxide (DMSO), and deionized (DI) water. The paraboloid texture surface has the advantage of giving a lower reflectance value than the hemispherical, random pyramidal, and regular pyramidal texture surfaces. In the case of parabola, the light can be concentrated in the direction of the Si surface compared to the hemispherical, random pyramidal, and regular pyramidal textured surfaces. Furthermore, in a paraboloid textured surface, there can be a maximum value of 4 or even more by anisotropic etching duration compared to the hemispherical or pyramidal textured surfaces which have a maximum h/D (depth and diameter of the texture) value of 0.5. The reflectance values were found to be strongly dependent on the h/D ratio of the texture surface. The measured reflectance values were well matched with the simulated ones. The minimum reflectance value of ~4 % was obtained at a wavelength of 600 nm for an h/D ratio of 3.75. The simulation results showed that the reflectance value for the h/D ratio can be reduced to ~0.5 % by reducing the separations among the textures. This periodic paraboloidal structure can be applied to the surface texturing technique by substituting with a conventional pyramid textured surface or moth-eye antireflection coating. PMID- 26415542 TI - Controlled Fabrication of Nanoporous Oxide Layers on Zircaloy by Anodization. AB - We have presented a mechanism to explain why the resulting oxide morphology becomes a porous or a tubular nanostructure when a zircaloy is electrochemically anodized. A porous zirconium oxide nanostructure is always formed at an initial anodization stage, but the degree of interpore dissolution determines whether the final morphology is nanoporous or nanotubular. The interpore dissolution rate can be tuned by changing the anodization parameters such as anodization time and water content in an electrolyte. Consequently, porous or tubular oxide nanostructures can be selectively fabricated on a zircaloy surface by controlling the parameters. Based on this mechanism, zirconium oxide layers with completely nanoporous, completely nanotubular, and intermediate morphologies between a nanoporous and a nanotubular structure were controllably fabricated. PMID- 26415543 TI - Identification of novel nitroreductases from Bacillus cereus and their interaction with the CB1954 prodrug. AB - Directed enzyme prodrug therapy is a form of cancer chemotherapy in which bacterial prodrug-activating enzymes, or their encoding genes, are directed to the tumour before administration of a prodrug. The prodrug can then be activated into a toxic drug at the tumour site, reducing off-target effects. The bacterial nitroreductases are a class of enzymes used in this therapeutic approach and although very promising, the low turnover rate of prodrug by the most studied nitroreductase enzyme, NfnB from Escherichia coli (NfnB_Ec), is a major limit to this technology. There is a continual search for enzymes with greater efficiency, and as part of the search for more efficient bacterial nitroreductase enzymes, two novel enzymes from Bacillus cereus (strain ATCC 14579) have been identified and shown to reduce the CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) prodrug to its respective 2'-and 4'-hydroxylamine products. Both enzymes shared features characteristic of the nitro-FMN-reductase superfamily including non-covalently associated FMN, requirement for the NAD(P)H cofactor, homodimeric, could be inhibited by Dicoumarol (3,3'-methylenebis(4-hydroxy-2H-chromen-2-one)), and displayed ping pong bi bi kinetics. Based on the biochemical characteristics and nucleotide alignment with other nitroreductase enzymes, one enzyme was named YdgI_Bc and the other YfkO_Bc. Both B. cereus enzymes had greater turnover for the CB1954 prodrug compared with NfnB_Ec, and in the presence of added NADPH cofactor, YfkO_Bc had superior cell killing ability, and produced mainly the 4' hydroxylamine product at low prodrug concentration. The YfkO_Bc was identified as a promising candidate for future enzyme prodrug therapy. PMID- 26415545 TI - Ultrasound-guided bilateral stellate ganglion blockade to treat digital ischemia in a patient with sepsis: a case report. AB - PURPOSE: This case report describes the use of ultrasound-guided stellate ganglion blockade to treat sepsis-related digital ischemia in the intensive care unit (ICU). CLINICAL FEATURES: A 71-yr-old female was admitted to the ICU with septic shock and acute respiratory distress syndrome (ARDS) following an initial right hemicolectomy complicated by an anastomotic leak and peritonitis. The patient's condition was further complicated by an abdominal abscess 22 days later. She had type-2 diabetes mellitus and hypertension but no history of vascular disease. With continuing sepsis from the abscess and requiring mechanical ventilation due to ARDS, she developed upper limb digital ischemia refractory to treatment with a low dose of dobutamine and isosorbide dinitrate. We subsequently performed ultrasound-guided bilateral stellate ganglion blockade with the intent of restoring perfusion to her fingers before digital necrosis developed. One hour after each stellate ganglion block, the symptoms of digital ischemia completely resolved. The benefit persisted for two days, and then a repeat block was performed with similar results. CONCLUSIONS: This case illustrates the potential advantages of ultrasound-guided stellate ganglion blockade for the treatment of sepsis-related digital ischemia refractory to standard therapy. PMID- 26415544 TI - Functional expression of the 11 human Organic Anion Transporting Polypeptides in insect cells reveals that sodium fluorescein is a general OATP substrate. AB - Organic Anion Transporting Polypeptides (OATPs), encoded by genes of the Solute Carrier Organic Anion (SLCO) family, are transmembrane proteins involved in the uptake of various compounds of endogenous or exogenous origin. In addition to their physiological roles, OATPs influence the pharmacokinetics and drug-drug interactions of several clinically relevant compounds. To examine the function and molecular interactions of human OATPs, including several poorly characterized family members, we expressed all 11 human OATPs at high levels in the baculovirus Sf9 cell system. We measured the temperature- and inhibitor-sensitive cellular accumulation of sodium fluorescein and fluorescein-methotrexate, two fluorescent substrates of the OATPs, OATP1B1 and 1B3. OATP1B1 and 1B3 were functional in Sf9 cells, showing rapid uptake (t1/2(fluorescein-methotrexate) 2.64 and 4.16 min, and t1/2(fluorescein) 6.71 and 5.58 min for OATP1B1 and 1B3, respectively) and high-affinity transport (Km(fluorescein-methotrexate) 0.23 and 0.53 MUM, and Km(fluorescein) 25.73 and 38.55 MUM for OATP1B1 and 1B3, respectively) of both substrates. We found that sodium fluorescein is a general substrate of all human OATPs: 1A2, 1B1, 1B3, 1C1, 2A1, 2B1, 3A1, 4A1, 4C1, 5A1 and 6A1, while fluorescein-methotrexate is only transported by 1B1, 1B3, 1A2 and 2B1. Acidic extracellular pH greatly facilitated fluorescein uptake by all OATPs, and new molecular interactions were detected (between OATP2B1 and Imatinib, OATP3A1, 5A1 and 6A1 and estradiol 17-beta-d-glucuronide, and OATP1C1 and 4C1 and prostaglandin E2). These studies demonstrate, for the first time, that the insect cell system is suitable for the functional analysis of the entire human OATP family, and for drug-OATP interaction screening. PMID- 26415546 TI - Concepts of safety reporting. PMID- 26415548 TI - Three cases of right frontal megalencephaly: Clinical characteristics and long term outcome. AB - AIM: To delineate the clinical and neuroimaging characteristics of localized megalencephaly involving the right frontal lobe. METHOD: Data from three patients aged 14-16 years at the last follow-up were retrospectively reviewed. RESULTS: All the patients were normal on neurological examination with no signs of hemiparesis. Enlargement of the right frontal lobe with increased volume of subcortical and deep white matter, as well as thickening of the ipsilateral genu of the corpus callosum was common. The onset of epilepsy was 4-7 years of age, with seizure types of massive myoclonus in two and generalized tonic-clonic in two, which could be eventually controlled by antiepileptics. Interictal electroencephalography showed frontal alpha-like activity in one, and abundant spike-wave complexes resulting in diffuse continuous spike-wave activity during sleep in two patients even after suppression of clinical seizures. Psychomotor development appeared unaffected or slightly delayed before the onset of epilepsy, but became mildly disturbed during follow-up period of 7-11 years. CONCLUSION: Certain patients with right frontal megalencephaly can present with a milder epileptic and intellectual phenotype among those with localized megalencephaly and holohemispheric hemimegalencephaly, whose characteristic as epileptic encephalopathy was assumed from this study. PMID- 26415547 TI - Targeted temperature management for acute encephalopathy in a Japanese secondary emergency medical care hospital. AB - BACKGROUND: The goals of this study, conducted in our secondary emergency care hospital, were to assess the effectiveness of targeted temperature management (TTM) for acute encephalopathy secondary to status epilepticus and to consider appropriate adaptations for use of TTM in this setting. METHODS: Medical records of patients admitted with acute encephalopathy to Hirakata City Hospital between January 2010 and December 2014 were retrospectively reviewed. Cases treated with TTM (36 degrees C) and methylprednisolone pulse (MP) therapy (TTM/MP) were compared with those treated with conventional MP regarding clinical courses and outcomes. RESULTS: In total, 20 children were retrospectively enrolled. In the TTM/MP group (10 cases) all survived intact. In the MP group (10 cases), 4 cases were left with neurological sequelae. Furthermore, in the TTM/MP group, the body temperature dropped more quickly. For pediatricians in this secondary emergency hospital, implementing the body temperature management system was not difficult. There were no complications caused by hypothermia. DISCUSSION: Use of TTM as the initial treatment for acute encephalopathy in the early-onset stage is possible in a secondary emergency care hospital. However, some acute encephalopathy cases are the so-called fulminant type; DIC or shock develops soon after onset and so it is sometimes difficult to introduce TTM. Fulminant-type patients should be transported to tertiary emergency care hospitals. Secondary emergency care hospitals must carefully select cases for TTM, keeping the possibility of transport to a tertiary emergency hospital in mind at all times. PMID- 26415550 TI - Gender differences in the relationship between resting heart rate variability and 24-hour blood pressure variability. AB - The study explored the relationship between time- and frequency-domain indices of cardiac autonomic control and 24 h blood pressure variability (BPV) in a sample of healthy men and women. Vagally mediated cardiac control was inversely related to 24 h BPV, and measures of cardiac autonomic control were better predictors of systolic BPV in men and better predictors of diastolic BPV in women. These findings may help researchers to understand the disparity in cardiovascular disease morbidity and mortality between men and women. PMID- 26415551 TI - [Family access to Neonatal Intensive Care Units in Latin America: A reality to improve]. AB - INTRODUCTION: Family access to NICUs has benefits for the newborn (NB) and family, as the main way of humanised care. OBJECTIVE: To determine the current state of parents and families access to NICUs in Latin America. METHODS: A cross sectional study was conducted in 15 countries using two questionnaires: 1) directed at head nurses with management and supervision activities, and 2) nurses with care tasks. The features and modes of functioning were examined; the use access guides, personal opinion on the rights to enter, risks, interference, or collaboration as regards the patient, and nursing role in decisions. Nursing leaders of each country identified contacts and obtained authorisation under the regulations of each country. The responses were analysed centrally with the participants remaining anonymous. RESULTS: Out of 640 questionnaires issued, responses were received by 226 (35%). Among 52 NICU, 63% have a place for mothers to stay (only 27% overnight), and in 31 (60%) there are notices with fixed schedules for visiting the NB. Unrestricted access exists in only 19 NICU (36%), but for siblings and grandparents it is more restricted (it is not possible in 29%). Among the 174 nurses that responded, 76% feel that mothers should always have access, but these percentages decrease for fathers, siblings and grandparents. A large majority (77%) believe that nursing staff would favour access, and 35% would make it difficult. In addition, 48% believed that access interferes with nursing care. care. CONCLUSION: A cultural change is needed in the NICUs in Latin America in order to respect the rights of newborns and their families during hospitalisation. PMID- 26415549 TI - Randomised controlled trial of temoporfin photodynamic therapy plus chemotherapy in nonresectable biliary carcinoma--PCS Nordic study. AB - BACKGROUND: Photodynamic therapy (PDT) in combination with stent have shown promising results in the treatment of biliary tract cancer (BTC) in patients not suitable for surgery. Chemotherapy has been shown to improve survival in patients with local advanced and metastatic BTC. MATERIAL AND METHODS: In the current randomized trial the combination of chemotherapy and stent with and without temoporfin (Foscan) photodynamic therapy (PDT), with a primary endpoint on feasibility and safety, has been performed. Ten patients in each group. RESULTS: No serious, acute procedure-related complication related to PDT or the treatment combination was seen. The number of patients with cholangitis was equal in both groups. In the PDT group--arm A--two patients had cutaneous erythema after sun exposition, one of them with a localized blister. No neutropenic infection was seen. Quality of Life (QoL) was similar in both treatment groups. Progression free survival was numerically longer in the PDT group. CONCLUSION: The treatment combination was feasible. There was no serious complication related to PDT or the treatment combination. Number of cholangitis was equal in both groups, two abscesses were observed in the PDT group. Progression free survival was numerically longer in the PDT group. PMID- 26415552 TI - Physapubescin B Exhibits Potent Activity against Human Prostate Cancer In Vitro and In Vivo. AB - The present data showed that a natural compound isolated from the plant Physalis pubescens L. (Solanaceae), physapubescin B, exhibited antitumor activity against prostate cancer in vitro and in vivo. Treating prostate cancer cells with physapubescin B resulted in the accumulation of cells in the G2/M phase, which was associated with reduced Cdc25C levels and increased levels of CyclinB1, P21 as well as p-Cdk1 (Tyr15). Additionally, reactive oxygen species (ROS) generation was increased in physapubescin B-treated PC-3 cells. Furthermore, the physapubescin B-induced decrease of Cdc25C protein expression together with the G2/M phase cell cycle arrest were significantly abrogated by antioxidant NAC and GSH. Our data also demonstrated that physapubescin B exhibited strong in vivo antitumor efficacy in human prostate cancer PC3 xenograft. In conclusion, our results provide clear evidence that physapubescin B exhibits antitumor activity both in vitro and in vivo and deserves further development as an anticancer agent. PMID- 26415553 TI - Biomechanical influences on head posture and the respiratory movements of the chest. AB - PURPOSE: The head represents 6% of total body weight, therefore it can significantly affect the biomechanics of human posture control, movements and activities. When set out of vertical body axis, head position interferes with the work of the other links in the kinematic chain. The aim of our study was to evaluate the effect of head posture on the breathing activities of the chest. MATERIAL AND METHODS: The research was conducted on a group of 65 patients (51 years +/- 9.8 years), including 48 women and 17 men. Head posture and chest movements were assessed using a photogrammetric method. RESULTS: The results confirmed the existence of a negative correlation between head position in the sagittal plane and movements of lower ribs. Forward head posture resulted in lower amplitude of costal arch motion: for the transverse plane Spearman's R = 0.296, for the frontal plane; -0.273, -0.289. Tilting the head in the frontal plane also influenced the change in the biomechanics of breathing and contributed to a reduction of respiratory movements of the lower ribs Spearman's R = -0.260. CONCLUSIONS: Changing the position of the head causes disturbances in the three dimensional shape of the chest and its respiratory movements. PMID- 26415555 TI - Innocent Cardiac Murmur in Puppies: Prevalence, Correlation with Hematocrit, and Auscultation Characteristics. AB - BACKGROUND: The aims of this study were to establish the prevalence of innocent cardiac murmurs in clinically healthy puppies, to investigate a possible correlation between the presence of an innocent murmur and hematocrit, and to describe the auscultation characteristics of innocent murmurs. HYPOTHESIS: Lower hematocrit contributes to the genesis of innocent murmurs. ANIMALS: Five hundred and eighty-four client-owned clinically healthy puppies, between 20 and 108 days old. METHODS: Two cross-sectional surveys with a 1-year (n = 389 pups) pilot and a half-year (n = 195 pups) principal study periods. Cardiac auscultation was performed by a single, board-certified cardiologist. Hematocrit was measured with an automatized hematology analyzer. Echocardiography was performed only on puppies with a cardiac murmur in the principal study. RESULTS: In the pilot study, 15% of the dogs had a murmur. Innocent murmur was diagnosed in 28% of the 195 dogs in the principal study. Innocent murmurs were systolic, mostly with a musical character and with a maximal intensity of 2 of 6, and mostly with the point of maximal intensity in the left cardiac base. The hematocrit was significantly lower in the group with a murmur compared to the group without (P = .023). CONCLUSIONS AND CLINICAL IMPORTANCE: Innocent murmur was a common finding in puppies at the age when the first veterinary controls usually take place. Physiologic anemia contributes to the genesis of innocent murmurs in puppies. Rising hematocrit in growing puppies can explain the spontaneous disappearance of innocent murmurs with aging. Hematocrit did not differentiate innocent murmurs from abnormal murmurs. PMID- 26415556 TI - Lower urinary tract symptoms among Caucasian-European men who have sex with men: findings from a real-life survey. AB - BACKGROUND: Prevalence of and severity of lower urinary tract symptoms (LUTS) according to male sexual orientation have been scantly analysed. We aimed to assess the prevalence and severity of LUTS in a cohort of Caucasian-European men who have sex with men seeking medical help for uroandrologic reasons other than LUTS. METHODS: Data from 949 consecutive individuals in an outpatient setting were analysed. Severity of LUTS was measured with the International Prostate Symptom Score (IPSS). Men with storage symptoms scored 1-3 and ? 4 (of 15), and voiding symptoms scored 1-4 and ? 5 (of 20) were considered as having mild and moderate-to-severe symptoms, respectively. For individual symptoms, patients with scores ? 1 were deemed symptomatic (according to Apostolidis et al.(15)). Descriptive statistics and logistic regression models tested the association between LUTS and sexual orientation. RESULTS: Complete data were available for 213 (22.4%) men who have sex with men (MSM) and 736 (77.6%) heterosexuals (mean age (s.d.): 41.0 (12.2) vs 39.9 (12.1) years). Compared with heterosexuals, MSM reported higher rates of total IPSS scores suggestive of moderate (21.6% vs 20%) and severe LUTS (3.8% vs 2.4%) (P=0.004). Similarly, MSM showed higher rates of mild (48.8% vs 45.2%) and moderate-to-severe (39.4% vs 30.4%) storage symptoms (all P<0.001), and of mild (45.1% vs 34.8%) and moderate-to-severe (20.2% vs 19.2%) voiding symptoms (all P<0.01). MSM status was an independent predictor of mild voiding symptoms (odds ratio (OR): 1.40; P=0.004), moderate-to-severe storage symptoms (OR: 1.40; P=0.04) and severe total IPSS (OR: 1.49; P=0.03), after adjusting for other variables. CONCLUSIONS: These findings suggest a higher prevalence and severity of LUTS in MSM compared with heterosexual men seeking medical help for uroandrologic reasons other than LUTS. PMID- 26415557 TI - Negative Impact of Unidirectional Host-versus-Graft Killer Cell Immunoglobulin like Receptor Ligand Mismatch on Transplantation Outcomes after Unmanipulated Haploidentical Peripheral Blood Stem Cell Transplantation for Acute Myeloid Leukemia. AB - This study explored the influence of mismatched inhibitory killer cell immunoglobulin-like receptor (KIR) ligands on the outcome of haploidentical transplantation using T cell-replete, granulocyte colony-stimulating factor mobilized peripheral blood stem cells in adult patients with acute myeloid leukemia (AML). Three groups were examined: unidirectional graft-versus-host KIR ligand mismatched (GVH-KIR-MM; n = 33), bidirectional KIR ligand matched (KIR-M; n = 41), and unidirectional host-versus-graft KIR ligand mismatched (HVG-KIR-MM; n = 26). All recipients were treated with the same conditioning regimen (800 cGy total body irradiation, fludarabine, busulfan, and antithymocyte globulin). After a median follow-up of 26 months, the 2-year cumulative incidence of relapse was significantly higher in HVG-KIR-MM (40.3% +/- 10.3%) versus others (18.9% +/- 4.8%, P = .044). In the standard-risk group, the 2-year disease-free survival (DFS) was significantly lower in HVG-KIR-MM (51.8% +/- 11.2%) compared with GVH KIR-MM (88% +/- 8.1%, P = .025). Multivariate analysis showed that HVG-KIR-MM was significantly associated with higher relapse (hazard ratio [HR], 10.7; P = .002) and lower DFS (HR, 3.4; P = .012). Subgroup analysis revealed increased DFS with higher doses of CD3(+)CD8(+) and CD3(-)CD56(+) grafts in GVH-KIR-MM (90.9% +/- 8.7%, P = .006); there was no such effect in the other groups. Although our conclusions are limited by the absence of donor KIR genotype data, our study suggests unidirectional KIR ligand incompatibility in the host-versus-graft vector has a detrimental effect on T cell-replete haploidentical transplantation outcomes in adult patients with AML. PMID- 26415558 TI - A Two-Step Haploidentical Versus a Two-Step Matched Related Allogeneic Myeloablative Peripheral Blood Stem Cell Transplantation. AB - Haploidentical stem cell transplantation (SCT) offers a transplantation option to patients who lack an HLA-matched donor. We developed a 2-step approach to myeloablative allogeneic hematopoietic stem cell transplantation for patients with haploidentical or matched related (MR) donors. In this approach, the lymphoid and myeloid portions of the graft are administered in 2 separate steps to allow fixed T cell dosing. Cyclophosphamide is used for T cell tolerization. Given a uniform conditioning regimen, graft T cell dose, and graft-versus-host disease (GVHD) prophylaxis strategy, we compared immune reconstitution and clinical outcomes in patients undergoing 2-step haploidentical versus 2-step MR SCT. We retrospectively compared data on patients undergoing a 2-step haploidentical (n = 50) or MR (n = 27) peripheral blood SCT for high-risk hematological malignancies and aplastic anemia. Both groups received myeloablative total body irradiation conditioning. Immune reconstitution data included flow cytometric assessment of T cell subsets at day 28 and 90 after SCT. Both groups showed comparable early immune recovery in all assessed T cell subsets except for the median CD3/CD8 cell count, which was higher in the MR group at day 28 compared with that in the haploidentical group. The 3-year probability of overall survival was 70% in the haploidentical group and 71% in the MR group (P = .81), while the 3-year progression-free survival was 68% in the haploidentical group and 70% in the MR group (P = .97). The 3-year cumulative incidence of nonrelapse mortality was 10% in the haploidentical group and 4% in the MR group (P = .34). The 3-year cumulative incidence of relapse was 21% in the haploidentical group and 27% in the MR group (P = .93). The 100-day cumulative incidence of overall grades II to IV acute GVHD was higher in the haploidentical group compared with that in the MR group (40% versus 8%, P < .001), whereas the grades III and IV acute GVHD was not statistically different between both groups (haploidentical, 6%; MR, 4%; P = .49). The cumulative incidence of cytomegalovirus reactivation was also higher in the haploidentical group compared to the MR group (haploidentical, 68%; MR, 19%; P < .001). There were no deaths from GVHD in either group. Using an identical conditioning regimen, graft T cell dose, and GVHD prophylaxis strategy, comparable early immune recovery and clinical outcomes were observed in the 2-step haploidentical and MR SCT recipients. PMID- 26415554 TI - Expanding the biotechnology potential of lactobacilli through comparative genomics of 213 strains and associated genera. AB - Lactobacilli are a diverse group of species that occupy diverse nutrient-rich niches associated with humans, animals, plants and food. They are used widely in biotechnology and food preservation, and are being explored as therapeutics. Exploiting lactobacilli has been complicated by metabolic diversity, unclear species identity and uncertain relationships between them and other commercially important lactic acid bacteria. The capacity for biotransformations catalysed by lactobacilli is an untapped biotechnology resource. Here we report the genome sequences of 213 Lactobacillus strains and associated genera, and their encoded genetic catalogue for modifying carbohydrates and proteins. In addition, we describe broad and diverse presence of novel CRISPR-Cas immune systems in lactobacilli that may be exploited for genome editing. We rationalize the phylogenomic distribution of host interaction factors and bacteriocins that affect their natural and industrial environments, and mechanisms to withstand stress during technological processes. We present a robust phylogenomic framework of existing species and for classifying new species. PMID- 26415559 TI - Umbilical Cord Blood Transplantation Outcomes in Acute Myelogenous Leukemia/Myelodysplastic Syndrome Patients Aged >=70 Years. AB - The maximum age of patients receiving allogeneic hematopoietic stem cell transplantation (alloHCT) has been moving up over time. However, the availability of a suitable HLA-matched sibling donor may limit access of this patient population to alloHCT. We retrospectively investigated the outcomes of umbilical cord blood transplantation (UCBT) after reduced-intensity conditioning regimens in patients aged >=70 years with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) between 2010 and 2014. During this period 70 patients with AML/MDS were referred to our center for alloHCT consideration. Twenty-two patients (33%) received alloHCT: 10 UCBT, 9 HLA full-matched sibling donor transplantation, 2 haploidentical alloHCT, and 1 unrelated donor alloHCT. In UCBT, cumulative incidences of nonrelapse mortality and relapse were 20% and 30% at 2 years, respectively. The cumulative incidence of acute graft-versus-host disease (GVHD) at day +100 and chronic GVHD at 2 years was 10%. Seven patients had viral reactivation/infections. Rates of overall survival and disease-free survival were 60% and 50% at 2 years, respectively. Moreover, these outcomes seemed to be similar to that of patients aged 60 to 69 years receiving UCBT (n = 60) and patients aged >=70 years receiving HLA full-matched sibling donor transplantation (n = 9). These results suggest that UCBT is feasible in selected AML/MDS patients aged >=70 years. In fact, UCBT shortens the required time for an unrelated donor search and thus increases the chance of proceeding with alloHCT, which might contribute to higher rates of alloHCT in the referral group. Outcomes of UCBT are promising; however, larger studies with a longer follow-up are needed. PMID- 26415560 TI - High Incidence of Afebrile Bloodstream Infection Detected by Surveillance Blood Culture in Patients on Corticosteroid Therapy after Allogeneic Hematopoietic Stem Cell Transplantation. AB - Bloodstream infections (BSI) are still important complications after allogeneic hematopoietic stem cell transplantation (allo-SCT). Patients who are receiving corticosteroid therapy can develop BSI without fever. The utility of surveillance blood cultures in these situations is controversial. We retrospectively analyzed 74 patients who received a corticosteroid consisting of >=.5 mg/kg prednisolone or equivalent after allo-SCT. In principle, we performed surveillance blood culture weekly for these patients. Sixteen patients (21.6%) developed definite BSI. In a multivariate analysis, a myeloablative conditioning regimen, high-risk disease status at allo-SCT, and the presence of a central venous catheter at the initiation of corticosteroid therapy were identified as independent significant risk factors for the development of definite BSI. At the first definite BSI episode, 7 patients (46.7%) were afebrile and diagnosed by surveillance blood culture. However, 6 of these 7 afebrile patients showed various signs that could be attributed to infection at the time of positive blood culture. In conclusion, patients receiving corticosteroid therapy after allo-SCT frequently develop afebrile BSI. Although surveillance blood culture might be beneficial in these situations, it also seems important to not miss the signs of BSI, even when patients are afebrile. PMID- 26415561 TI - On/off-switchable anti-neoplastic nanoarchitecture. AB - Throughout the world, there are increasing demands for alternate approaches to advanced cancer therapeutics. Numerous potentially chemotherapeutic compounds are developed every year for clinical trial and some of them are considered as potential drug candidates. Nanotechnology-based approaches have accelerated the discovery process, but the key challenge still remains to develop therapeutically viable and physiologically safe materials suitable for cancer therapy. Here, we report a high turnover, on/off-switchable functionally popping reactive oxygen species (ROS) generator using a smart mesoporous titanium dioxide popcorn (TiO2 Pops) nanoarchitecture. The resulting TiO2 Pops, unlike TiO2 nanoparticles (TiO2 NPs), are exceptionally biocompatible with normal cells. Under identical conditions, TiO2 Pops show very high photocatalytic activity compared to TiO2 NPs. Upon on/off-switchable photo activation, the TiO2 Pops can trigger the generation of high-turnover flash ROS and can deliver their potential anticancer effect by enhancing the intracellular ROS level until it crosses the threshold to open the 'death gate', thus reducing the survival of cancer cells by at least six times in comparison with TiO2 NPs without affecting the normal cells. PMID- 26415562 TI - Optical Limiting and Theoretical Modelling of Layered Transition Metal Dichalcogenide Nanosheets. AB - Nonlinear optical property of transition metal dichalcogenide (TMDC) nanosheet dispersions, including MoS2, MoSe2, WS2, and WSe2, was performed by using Z-scan technique with ns pulsed laser at 1064 nm and 532 nm. The results demonstrate that the TMDC dispersions exhibit significant optical limiting response at 1064 nm due to nonlinear scattering, in contrast to the combined effect of both saturable absorption and nonlinear scattering at 532 nm. Selenium compounds show better optical limiting performance than that of the sulfides in the near infrared. A liquid dispersion system based theoretical modelling is proposed to estimate the number density of the nanosheet dispersions, the relationship between incident laser fluence and the size of the laser generated micro-bubbles, and hence the Mie scattering-induced broadband optical limiting behavior in the TMDC dispersions. PMID- 26415564 TI - Diffuse cavernous hemangioma of the rectum: case report and literature review. PMID- 26415563 TI - Adult autologous mesenchymal stem cells for the treatment of suspected non infectious inflammatory diseases of the canine central nervous system: safety, feasibility and preliminary clinical findings. AB - BACKGROUND: Non-infectious inflammatory diseases of the canine central nervous system (CNS) are common idiopathic disorders grouped under the term meningoencephalomyelitis of unknown origin (MUO). Ante mortem diagnosis is achieved via assessment of clinical signs, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis, but the definitive diagnosis needs histopathological examination. MUO are mostly considered as autoimmune CNS disorders, so that suppressing the immune reaction is the best management method for patients. Mesenchymal stem cells (MSCs) are under investigation to treat autoimmune and degenerative disorders due to their immunomodulatory and regenerative properties. This study aims to verify the safety, feasibility, and efficacy of MSCs treatment in canine idiopathic autoimmune inflammatory disorders of the CNS. METHODS: Eight dogs presented with acute onset and rapid progression of multifocal neurological signs were selected to the study. In all patients' physical and neurological examinations, MRI and CSF analyses were performed. Clinical diagnosis in all cases was MUO. All selected dogs responded initially to immunosuppressive drugs (prednisone and a combination of prednisolone and cytosine arabinoside) but developed undesirable side effects. For all eight dogs, the owners considered euthanasia but accepted cell therapy as a last possibility. Autologous bone marrow MSCs (BMMSCs), isolated, cultured, and expanded, were administered by intrathecal (IT) injection in the cisterna magna intravenously (IV) and by intra-arterial (IA) injection in the right carotid artery. Adverse effects and clinical response were monitored for 6 months up to 2-year follow-up. RESULTS: The use of autologous BMMSCs in dogs with MUO was safe for IT, IV, and IA injections. No major short- or long-term adverse effects were registered. All the dogs presented early improvement in their general and neurological conditions, with particular effect on cervical pain. The group of dogs treated by IT+IA administration showed a shorter time of reaction to therapy compared to the group treated by IT+IV administration. CONCLUSIONS: MSCs treatment in dogs affected by MOU is safe and feasible. A larger group of dogs is needed to confirm these results as well as CNS histology in order to better understand the underlying mechanisms. PMID- 26415565 TI - Factors associated with reclassification of hyperplastic polyps after pathological reassessment from screening and surveillance colonoscopies. AB - INTRODUCTION: A substantial interobserver variation in the differential diagnosis of hyperplastic polyps (HPs) and sessile or traditional serrated adenomas (SSAs/TSAs) has been described. METHODS: The aim of this study is to determine the magnitude of reclassification of HPs and associated factors after pathological reassessment of specimens from screening and surveillance colonoscopies, and to estimate its consequences for follow-up recommendations. RESULTS: Among 1694 screening and surveillance colonoscopies, a total of 536 polyps were initially diagnosed as HPs and remained unchanged in 88.5% (n = 474), whereas 7.6 (n = 41) and 1.1% (n = 6) were reclassified as SSA and TSA, respectively. Compared to definite HPs, SSAs were found more frequently in men than in women (82.9 vs. 61.2%, p < 0.05), and in individuals >=65.0 years (51.2 vs. 31.6%, p = 0.05). Also, more SSAs were >5 mm in size (36.6 vs. 6.3%, p < 0.05) and were localized in the proximal colon (31.7 vs. 11.8%, p < 0.05). In a mixed model analysis, age >=65.0 years (OR 4.13, 95% CI 1.22-14.2), snare polypectomy (OR 23.6, 95% CI 4.86-115), and coincident advanced adenomas (OR 7.56, 95% CI 1.31-43.5) were significantly (p < 0.05) associated with reclassification to SSAs. Only 0.53% of patients had received false recommendations for follow-up visits based on the incorrect HP diagnosis. A c.1799T>A, p.V600E BRAF mutation was detected in 21.9 % (n = 9) of reclassified SSAs. CONCLUSION: Considering these factors may be helpful in serrated lesions that are difficult to allocate. Incorrect recommendations regarding control colonoscopy intervals due to misdiagnosed HPs can explain only a small fraction of interval colorectal cancers. PMID- 26415567 TI - Of ATPase activity, cellular energy distribution, and linking depolarization and division. PMID- 26415566 TI - Further studies of the down-regulation by Factor I of the C3b feedback cycle using endotoxin as a soluble activator and red cells as a source of CR1 on sera of different complotype. AB - In this paper we have extended our earlier studies of the action of increasing Factor I concentration on complement activation by using a soluble activator, lipopolysaccharide (LPS) endotoxin, and using human erythrocytes as a source of CR1 - the co-factor needed for the final clip of iC3b to C3dg by Factor I. Using this more physiological system, the results show that we can predict that a quite modest increase in Factor I concentration - 22 ug/ml of extra Factor I - will convert the activity of the highest risk sera to those of the lowest risk. Preliminary experiments have been performed with erythrocytes allotyped for CR1 number. While we have not been able to perform an adequate study of their co factor activities in our assays, preliminary experiments suggest that when Factor I levels are increased the difference produced by different allotypes of red cells is largely overcome. This suggests that in patients with paroxysmal nocturnal haemoglobinuria (PNH) treated with eculizumab, additional treatment with Factor I may be very useful in reducing the need for blood transfusion. We have also explored the age-related allele frequency for the two polymorphisms of Factor H and the polymorphism of C3. In our population, unlike the 1975 study, we found no age variation in the allele frequency in these polymorphisms. This may, however, reflect that the Cambridge BioResource volunteers do not include many very young or very elderly patients, and in general comprise a population not greatly at risk of death from infectious disease. PMID- 26415568 TI - Diffusion of myosin light chain kinase on actin: A mechanism to enhance myosin phosphorylation rates in smooth muscle. AB - Smooth muscle myosin (SMM) light chain kinase (MLCK) phosphorylates SMM, thereby activating the ATPase activity required for muscle contraction. The abundance of active MLCK, which is tightly associated with the contractile apparatus, is low relative to that of SMM. SMM phosphorylation is rapid despite the low ratio of MLCK to SMM, raising the question of how one MLCK rapidly phosphorylates many SMM molecules. We used total internal reflection fluorescence microscopy to monitor single molecules of streptavidin-coated quantum dot-labeled MLCK interacting with purified actin, actin bundles, and stress fibers of smooth muscle cells. Surprisingly, MLCK and the N-terminal 75 residues of MLCK (N75) moved on actin bundles and stress fibers of smooth muscle cell cytoskeletons by a random one dimensional (1-D) diffusion mechanism. Although diffusion of proteins along microtubules and oligonucleotides has been observed previously, this is the first characterization to our knowledge of a protein diffusing in a sustained manner along actin. By measuring the frequency of motion, we found that MLCK motion is permitted only if acto-myosin and MLCK-myosin interactions are weak. From these data, diffusion coefficients, and other kinetic and geometric considerations relating to the contractile apparatus, we suggest that 1-D diffusion of MLCK along actin (a) ensures that diffusion is not rate limiting for phosphorylation, (b) allows MLCK to locate to areas in which myosin is not yet phosphorylated, and (c) allows MLCK to avoid getting "stuck" on myosins that have already been phosphorylated. Diffusion of MLCK along actin filaments may be an important mechanism for enhancing the rate of SMM phosphorylation in smooth muscle. PMID- 26415569 TI - A novel Ca2+-feedback mechanism extends the operating range of mammalian rods to brighter light. AB - Sensory cells adjust their sensitivity to incoming signals, such as odor or light, in response to changes in background stimulation, thereby extending the range over which they operate. For instance, rod photoreceptors are extremely sensitive in darkness, so that they are able to detect individual photons, but remain responsive to visual stimuli under conditions of bright ambient light, which would be expected to saturate their response given the high gain of the rod transduction cascade in darkness. These photoreceptors regulate their sensitivity to light rapidly and reversibly in response to changes in ambient illumination, thereby avoiding saturation. Calcium ions (Ca2+) play a major role in mediating the rapid, subsecond adaptation to light, and the Ca2+-binding proteins GCAP1 and GCAP2 (or guanylyl cyclase-activating proteins [GCAPs]) have been identified as important mediators of the photoreceptor response to changes in intracellular Ca2+. However, mouse rods lacking both GCAP1 and GCAP2 (GCAP-/-) still show substantial light adaptation. Here, we determined the Ca2+ dependency of this residual light adaptation and, by combining pharmacological, genetic, and electrophysiological tools, showed that an unknown Ca2+-dependent mechanism contributes to light adaptation in GCAP-/- mouse rods. We found that mimicking the light-induced decrease in intracellular [Ca2+] accelerated recovery of the response to visual stimuli and caused a fourfold decrease of sensitivity in GCAP /- rods. About half of this Ca2+-dependent regulation of sensitivity could be attributed to the recoverin-mediated pathway, whereas half of it was caused by the unknown mechanism. Furthermore, our data demonstrate that the feedback mechanisms regulating the sensitivity of mammalian rods on the second and subsecond time scales are all Ca2+ dependent and that, unlike salamander rods, Ca2+-independent background-induced acceleration of flash response kinetics is rather weak in mouse rods. PMID- 26415571 TI - A sequence of basic residues in the porcine circovirus type 2 capsid protein is crucial for its co-expression and co-localization with the replication protein. AB - Porcine circovirus type 2 (PCV2) encodes two major proteins: the replication protein (Rep) and the capsid protein (Cap). Cap displays a conserved stretch of basic residues situated on the inside of the capsid, whose role is so far unknown. We used a reverse-genetics approach to investigate its function and found that mutations in these amino acids hindered Cap mRNA translation and hampered Cap/Rep co-localization, yielding unfit viruses. Intriguingly, co transfection with a WT PCV2 of a different genotype partially rescued mutant Cap expression, showing the importance of this basic pattern for efficient translation of Cap mRNA into protein. Our results show that Cap and Rep are expressed independently of each other, and that this amino acid sequence of Cap is vital for virus propagation. This study provides a method for studying unfit PCV2 virions and offers new insights into the intracellular modus vivendi of PCV2. PMID- 26415570 TI - A chimeric prokaryotic pentameric ligand-gated channel reveals distinct pathways of activation. AB - Recent high resolution structures of several pentameric ligand-gated ion channels have provided unprecedented details of their molecular architecture. However, the conformational dynamics and structural rearrangements that underlie gating and allosteric modulation remain poorly understood. We used a combination of electrophysiology, double electron-electron resonance (DEER) spectroscopy, and x ray crystallography to investigate activation mechanisms in a novel functional chimera with the extracellular domain (ECD) of amine-gated Erwinia chrysanthemi ligand-gated ion channel, which is activated by primary amines, and the transmembrane domain of Gloeobacter violaceus ligand-gated ion channel, which is activated by protons. We found that the chimera was independently gated by primary amines and by protons. The crystal structure of the chimera in its resting state, at pH 7.0 and in the absence of primary amines, revealed a closed pore conformation and an ECD that is twisted with respect to the transmembrane region. Amine- and pH-induced conformational changes measured by DEER spectroscopy showed that the chimera exhibits a dual mode of gating that preserves the distinct conformational changes of the parent channels. Collectively, our findings shed light on both conserved and divergent features of gating mechanisms in this class of channels, and will facilitate the design of better allosteric modulators. PMID- 26415572 TI - Phytogenic pigments in animal nutrition: potentials and risks. AB - Phytogenic pigments are secondary plant compounds responsible for coloring effects in plant tissues. In particular, phenolic flavonoids and terpenoid carotenoids, but also rare compounds like curcumin and betalain, form this group of biochemical agents used in animal nutrition. From the perspective of ecological mutuality between plants and animals, these compounds are of crucial importance because they serve as visual attraction for herbivores but also signal nutritional and/or health-promoting values. This review focuses on the properties of phytogenic pigments which are likely to impact feed intake and preferences of livestock. Also natural prophylactic and/or therapeutic properties and, in particular, the potential of pigments to enhance quality and health value of animal products for human consumption are important issues. Nevertheless, reasonable limits of use due to possible adverse indications have been suggested recently. Pathways of digestion, metabolism and excretion in animals play a crucial role not only in the evaluation of effectiveness but also in the prediction of potential risks for human consumption. The popularity of natural feed additives is growing; therefore, more research work is needed to better understand metabolic pathways in the animal's body and to better estimate the potentials and risks of pigmenting plant compounds used in animal nutrition. PMID- 26415574 TI - Influenza Plasmid DNA Vaccines: Progress and Prospects. AB - Current influenza vaccines have long been used to fight flu infectious; however, recent advances highlight the importance of produce new alternatives. Even though traditional influenza vaccines are safe and usually effective, they need to be uploaded every year to anticipate circulating flu viruses. This limitation together with the use of embryonated chicken eggs as the substrate for vaccine production, is time-consuming and could involve potential biohazards in growth of new virus strains. Plasmid DNA produced by prokaryote microorganisms and encoding foreign proteins had emerged as a promising therapeutic tool. This technology allows the expression of a gene of interest by eukaryotic cells in order to induce protective immune responses against the pathogen of interest. In this review, we discuss the strategies to choose the best DNA vaccine to be applied in the treatment and prevention of influenza. Specifically, we give an update of influenza DNA vaccines developments, all involved techniques, their main characteristics, applicability and technical features to obtain the best option against influenza infections. PMID- 26415573 TI - Stem Cell-Mediated Exon Skipping of the Dystrophin Gene by the Bystander Effect. AB - Duchenne muscular dystrophy (DMD) is characterized by the loss of a functional dystrophin protein; the muscles of DMD patients progressively degenerate as a result of mechanical stress during contractions, and the condition eventually leads to premature death. By means antisense oligonucleotides (AONs), it is possible to modulate pre-mRNA splicing eliminating mutated exons and restoring dystrophin open reading frame. To overcome the hurdles in using AONs for therapeutic interventions, we exerted engineered human DMD stem cells with a lentivirus, which permanently and efficiently delivered the cloned AONs. Here we describe for the first time the exosome-mediated release of AONs from engineered human DMD CD133+ stem cells allowing the rescue of murine dystrophin expression. Finally, upon release, AONs could be internalized by host cells suggesting a potential role of exosomes acting as vesicular carriers for DMD gene therapy. PMID- 26415575 TI - Lentiviral-Mediated Gene Therapy in Fanconi Anemia-A Mice Reveals Long-Term Engraftment and Continuous Turnover of Corrected HSCs. AB - Fanconi anemia is a DNA repair-deficiency syndrome mainly characterized by cancer predisposition and bone marrow failure. Trying to restore the hematopoietic function in these patients, lentiviral vector-mediated gene therapy trials have recently been proposed. However, because no insertional oncogenesis studies have been conducted so far in DNA repair-deficiency syndromes such as Fanconi anemia, we have carried out a genome-wide screening of lentiviral insertion sites after the gene correction of Fanca(-/-) hematopoietic stem cells (HSCs), using LAM-PCR and 454-pyrosequencing. Our studies first demonstrated that transduction of Fanca(-/-) HSCs with a lentiviral vector designed for clinical application efficiently corrects the phenotype of Fanconi anemia repopulating cells without any sign of toxicity. The identification of more than 6,500 insertion sites in primary and secondary recipients showed a polyclonal pattern of reconstitution, as well as a continuous turnover of corrected Fanca(-/-) HSC clones, without evidences of selection towards specific common integration sites. Taken together our data show, for the first time in a DNA repair-deficiency syndrome, that lentiviral vector-mediated gene therapy efficiently corrects the phenotype of affected HSCs and promotes a healthy pattern of clonal turnover in vivo. These studies will have a particular impact in the development of new gene therapy trials in patients affected by DNA repair syndromes, particularly in Fanconi anemia. PMID- 26415576 TI - Contemporary Animal Models For Human Gene Therapy Applications. AB - Over the past three decades, gene therapy has been making considerable progress as an alternative strategy in the treatment of many diseases. Since 2009, several studies have been reported in humans on the successful treatment of various diseases. Animal models mimicking human disease conditions are very essential at the preclinical stage before embarking on a clinical trial. In gene therapy, for instance, they are useful in the assessment of variables related to the use of viral vectors such as safety, efficacy, dosage and localization of transgene expression. However, choosing a suitable disease-specific model is of paramount importance for successful clinical translation. This review focuses on the animal models that are most commonly used in gene therapy studies, such as murine, canine, non-human primates, rabbits, porcine, and a more recently developed humanized mice. Though small and large animals both have their own pros and cons as disease-specific models, the choice is made largely based on the type and length of study performed. While small animals with a shorter life span could be well-suited for degenerative/aging studies, large animals with longer life span could suit longitudinal studies and also help with dosage adjustments to maximize therapeutic benefit. Recently, humanized mice or mouse-human chimaeras have gained interest in the study of human tissues or cells, thereby providing a more reliable understanding of therapeutic interventions. Thus, animal models are of great importance with regard to testing new vector technologies in vivo for assessing safety and efficacy prior to a gene therapy clinical trial. PMID- 26415578 TI - TREAT: tamper-resistant envelope allocation technique for a multisite study. PMID- 26415577 TI - Field-wide meta-analyses of observational associations can map selective availability of risk factors and the impact of model specifications. AB - OBJECTIVES: Instead of evaluating one risk factor at a time, we illustrate the utility of "field-wide meta-analyses" in considering all available data on all putative risk factors of a disease simultaneously. STUDY DESIGN AND SETTING: We identified studies on putative risk factors of pterygium (surfer's eye) in PubMed, EMBASE, and Web of Science. We mapped which factors were considered, reported, and adjusted for in each study. For each putative risk factor, four meta-analyses were done using univariate only, multivariate only, preferentially univariate, or preferentially multivariate estimates. RESULTS: A total of 2052 records were screened to identify 60 eligible studies reporting on 65 putative risk factors. Only 4 of 60 studies reported both multivariate and univariate regression analyses. None of the 32 studies using multivariate analysis adjusted for the same set of risk factors. Effect sizes from different types of regression analyses led to significantly different summary effect sizes (P-value < 0.001). Observed heterogeneity was very high for both multivariate (median I(2), 76.1%) and univariate (median I(2), 85.8%) estimates. No single study investigated all 11 risk factors that were statistically significant in at least one of our meta analyses. CONCLUSION: Field-wide meta-analyses can map availability of risk factors and trends in modeling, adjustments and reporting, as well as the impact of differences in model specification. PMID- 26415579 TI - Fermi level engineering of topological insulator films by tuning the substrates. AB - The Fermi level of the topological insulators (TIs) Bi2Se3 and Bi2Te3 is usually well above the Dirac points, which is ascribed to the intrinsic donor defects, such as antisites and anion vacancies. We show here by first-principles calculations that the substrates can modulate the Fermi level of TIs considerably. It is found that in Bi2Se3/graphene and Bi2Te3/Si(1 1 1), the substrates play the role of electron donor due to their lower workfunctions and push up the Fermi level of the TIs. Thicker TI films are found to have larger density of states and hence the charge transferred to TI leads to a smaller Fermi level shift, in good agreement with experiments. We propose to use high workfunction substrates to counterbalance the upward shift of the Fermi level due to the donor defects. Our calculations found that the fluorinated substrates F graphene and F-Si(1 1 1) have very high workfunction and become electron acceptors, leading to a downward shift of the Fermi level of TIs. PMID- 26415580 TI - Iron(II) spin crossover complexes with diaminonaphthalene-based Schiff base-like ligands: mononuclear complexes. AB - The synthesis of new Schiff base-like ligands with extended pi-system and their iron complexes is described. Some of the iron(ii) complexes with N-heterocycles as axial ligands show spin crossover behaviour. The influence of the extended aromatic system on cooperative interactions is investigated by single crystal X ray structure analysis, X-ray powder diffraction, and magnetic measurements. A combination of C-Hpi and C-HO interactions is made responsible for up to 10 K wide thermal hysteresis loops. PMID- 26415581 TI - Response inhibition and interference control in patients with bipolar I disorder and first-degree relatives. AB - OBJECTIVES: The current study aimed to assess both response inhibition (RI) and interference control (IC) in euthymic patients with bipolar disorder (BD-Ps) as well as asymptomatic first-degree relatives (BD-Rs) and healthy controls (HCs) in order to evaluate trait-as opposed to illness-associated features of these components. METHODS: BD-Ps (n = 35) who had been in the euthymic state for at least six months, BD-Rs (n = 30), and HCs (n = 33) completed a Stop-Signal Task (SST) and Stroop Task to assess RI and IC, respectively. Groups were compared on the stop-signal reaction time (SSRT), stop-signal delay (SSD), mean reaction time on go trials (go-RT), Stroop interference score (S-interference), and number of errors on the color-word-naming trial (S-error). Associations between the patient's clinical features and RI and IC, between the patient's treatment and RI and IC, and between RI and IC in each group were investigated. RESULTS: BD-Ps and BD-Rs had significantly shorter go-RT and SSD, and longer SSRT compared to HCs, with these scores being similar between the BD-Ps and BD-Rs. Also, both BD-Ps and BD-Rs made significantly more S-errors than HCs, whereas, the S-interference score was not significantly different between groups. There were no significant correlations between Stroop Task and SST scores within each group, nor between clinical features or treatment variables and RI and IC in BD-Ps. CONCLUSIONS: Overall, impairment in RI and IC (only on S-error score) was present in both patients and relatives. The persistence of these deficits in the absence of mood symptoms suggests that these features may represent candidate endophenotypes for bipolar disorder. PMID- 26415582 TI - Editorial: Television sets and traumatic brain injury. PMID- 26415583 TI - Performance comparison of various feature detector-descriptors and temporal models for video-based assessment of laparoscopic skills. AB - BACKGROUND: Despite the significant progress in hand gesture analysis for surgical skills assessment, video-based analysis has not received much attention. In this study we investigate the application of various feature detector descriptors and temporal modeling techniques for laparoscopic skills assessment. METHODS: Two different setups were designed: static and dynamic video-histogram analysis. Four well-known feature detection-extraction methods were investigated: SIFT, SURF, STAR-BRIEF and STIP-HOG. For the dynamic setup two temporal models were employed (LDS and GMMAR model). Each method was evaluated for its ability to classify experts and novices on peg transfer and knot tying. RESULTS: STIP-HOG yielded the best performance (static: 74-79%; dynamic: 80-89%). Temporal models had equivalent performance. Important differences were found between the two groups with respect to the underlying dynamics of the video-histogram sequences. CONCLUSIONS: Temporal modeling of feature histograms extracted from laparoscopic training videos provides information about the skill level and motion pattern of the operator. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26415584 TI - Pruritus in psoriasis: An update. AB - BACKGROUND AND OBJECTIVE: Psoriasis is one of the most common chronic inflammatory skin diseases, found in about 1-3% of the general population. Pruritus affects about 60-90% of patients with psoriasis. The aim of this review was to summarize current knowledge about the pathogenesis and treatment of this symptom in psoriasis patients. RESULTS: Majority of psoriatic patients consider pruritus as the most bothersome symptom. The pathogenesis of pruritus is still unknown but the major concept of its origin is focused on neurogenic inflammation. Possible itch mediators include neuropeptides released from dermal nerve endings upon various stimuli, which were found to be abnormally expressed in itchy psoriatic plaques. Another important phenomenon supporting the idea of neurogenic inflammation as a key player in pruritus accompanying psoriasis is abnormal innervations of psoriatic skin. Possibly increased innervation density in psoriasis may decrease the threshold for pruritic stimuli. It is also suggested that pruritus in psoriasis might be related to abnormal functioning of the peripheral opioid system. Despite the high frequency of pruritus in psoriasis, to date there is no single antipruritic therapy dedicated specifically to treat itch in this disease. CONCLUSIONS: Neurogenic inflammation seems to be important for itchiness in psoriasis. Treatment of pruritus in patients with psoriasis should be directed towards the resolution of skin lesions, as disease remission usually is linked with pruritus relief. PMID- 26415586 TI - A water soluble glucopyranosyl conjugate as a selective and reactive probe for cysteine in a buffer and its application to living cells. AB - A water soluble and biocompatible glucopyranosyl conjugate (L) has been synthesized and characterized by various techniques. The L has been employed to recognize Cys selectively among the naturally occurring amino acids in HEPES buffer at physiological pH. A minimum detection limit of 2.5 * 10(-7) M was shown by L for Cys in the buffer at pH = 7.4. The reactivity of L towards biological thiols as demonstrated by emission and absorption is supported by the observed increase in the fluorescence intensity; however, Cys shows a maximum increase owing to its better nucleophilicity. The reactivity of Cys on L is demonstrated by (1)H NMR, ESI MS, emission and absorption spectroscopy, and the formation of the binary complex was supported by ESI MS. The control molecular study revealed the necessity of the glyco-moiety to bring water solubility and biological adaptability. The cellular studies support that the conjugate L is biologically adaptable and shows effective intracellular fluorescence emission upon reacting with intracellular thiols. PMID- 26415585 TI - Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK STAT pathway in Sezary syndrome. AB - Sezary syndrome (SS) is an aggressive leukaemia of mature T cells with poor prognosis and limited options for targeted therapies. The comprehensive genetic alterations underlying the pathogenesis of SS are unknown. Here we integrate whole-genome sequencing (n=6), whole-exome sequencing (n=66) and array comparative genomic hybridization-based copy-number analysis (n=80) of primary SS samples. We identify previously unknown recurrent loss-of-function aberrations targeting members of the chromatin remodelling/histone modification and trithorax families, including ARID1A in which functional loss from nonsense and frameshift mutations and/or targeted deletions is observed in 40.3% of SS genomes. We also identify recurrent gain-of-function mutations targeting PLCG1 (9%) and JAK1, JAK3, STAT3 and STAT5B (JAK/STAT total ~11%). Functional studies reveal sensitivity of JAK1-mutated primary SS cells to JAK inhibitor treatment. These results highlight the complex genomic landscape of SS and a role for inhibition of JAK/STAT pathways for the treatment of SS. PMID- 26415587 TI - Seminal fluid factors regulate activin A and follistatin synthesis in female cervical epithelial cells. AB - Seminal fluid induces pro-inflammatory cytokines and elicits an inflammation-like response in the cervix. Here, Affymetrix microarray and qPCR was utilised to identify activin A (INHBA) and its inhibitor follistatin (FST) amongst the cytokines induced by seminal plasma in Ect1 ectocervical epithelial cells, and a similar response was confirmed in primary ectocervical epithelial cells. TGFB is abundant in seminal plasma and all three TGFB isoforms induced INHBA in Ect1 and primary cells, and neutralisation of TGFB in seminal plasma suppressed the INHBA response. Bacterial lipopolysaccharide in seminal plasma also elicited INHBA, but potently suppressed FST production. There was moderate reciprocal inhibition between FST and INHBA, and cross-attenuating effects were seen. These data identify TGFB and potentially LPS as factors mediating seminal plasma-induced INHBA synthesis in cervical cells. INHBA and FST induced by seminal fluid in cervical tissues may thus contribute to regulation of the post-coital response in women. PMID- 26415588 TI - Detection of metabolites discriminating subtypes of thyroid cancer: Molecular profiling of FFPE samples using the GC/MS approach. AB - One of the critical issues in thyroid cancer diagnostic is differentiation between follicular adenoma, follicular carcinoma and the follicular variant of papillary carcinoma, which in some cases is not possible based on histopathological features only. In this paper we performed molecular profiling of thyroid tissue aiming to identify metabolites characteristic for different types of thyroid cancer. FFPE tissue specimens were analysed from 5 different types of thyroid malignancies (follicular, papillary/classical variant, papillary/follicular variant, medullary and anaplastic cancers), benign follicular adenoma and normal thyroid. Extracted metabolites were identified and semi-quantified using the GC/MS approach. There were 28 metabolites identified, whose abundances were significantly different among different types of thyroid tumours, including lipids, carboxylic acids, and saccharides. We concluded, that multi-component metabolome signature could be used for classification of different subtypes of follicular thyroid lesions. Moreover, potential applicability of the GC/MS-based analysis of FFPE tissue samples in diagnostics of thyroid cancer has been proved. PMID- 26415589 TI - Brain lipid sensing and the neural control of energy balance. AB - Fatty acid (FA) -sensitive neurons are present in the brain, especially the hypothalamus, and play a key role in the neural control of energy and glucose homeostasis including feeding behavior, secretion insulin and action. Subpopulations of neurons in the arcuate and ventromedial hypothalamic nuclei are selectively either activated or inhibited by FA. Molecular effectors of these FA effects include ion channels such as chloride, potassium or calcium. In addition, at least half of the responses in the hypothalamic ventromedial FA neurons are mediated through interaction with the FA translocator/receptor, FAT/CD36, that does not require metabolism to activate intracellular signaling downstream. Recently, an important role of lipoprotein lipase in FA detection has also been demonstrated not only in the hypothalamus, but also in the hippocampus and striatum. Finally, FA could overload energy homeostasis via increased hypothalamic ceramide synthesis which could, in turn, contribute to the pathogenesis of diabetes of obesity and/or type 2 in predisposed individuals by disrupting the endocrine signaling pathways of insulin and/or leptin. PMID- 26415590 TI - Fibroblast growth factor-21, energy balance and obesity. AB - Fibroblast growth factor (FGF)-21 is an endocrine member of the FGF family with healthy effects on glucose and lipid metabolism. FGF21 reduces glycemia and lipidemia in rodent models of obesity and type 2 diabetes. In addition to its effects improving insulin sensitivity, FGF21 causes weight loss by increasing energy expenditure. Activation of the thermogenic activity of brown adipose tissue and promotion of the appearance of the so-called beige/brite type of brown adipocytes in white fat are considered the main mechanisms underlying the leaning effects of FGF21. Paradoxically, however, obesity in rodents and humans is characterized by high levels of FGF21 in the blood. Some degree of resistance to the actions of FGF21 has been proposed as part of the endocrine alterations in obesity. The resistance in adipose tissue from obese rodents and patients is likely attributable to abnormally low levels of the FGF co-receptor beta-Klotho, required for FGF21 cellular action. However, native FGF21 and FGF21 derivatives retain their healthy metabolic and weight-loss effects when used as pharmacological agents to treat obese rodents and humans. FGF21 derivatives or molecules mimicking FGF21 action appear to be interesting candidates for the development of novel anti-obesity drugs designed to increase energy expenditure. PMID- 26415591 TI - Steroid hormone influence on melanomagenesis. AB - Disparities in the prognosis and incidence of melanoma between male and female patients have led clinicians to explore the influence of steroid hormones on the development and progression of this malignancy. A better understanding of the disparities of melanoma behavior between sexes and ages could lead to improved prevention and treatment options. There are multiple themes in the literature that unify the physiologic functions of estrogen and androgen receptors; herein we discuss and map their pathways. Overall, it is important to understand that the differences in melanoma behavior between the sexes are multifactorial and likely involve interactions between the immune system, endocrine system, and environment, namely UV-radiation. Melanoma deserves a spot among hormone sensitive tumors, and if tamoxifen is re-introduced for future therapy, tissue ratios of estrogen receptors should be obtained beforehand to assess their therapeutic predictive value. Because androgens, estrogens, and their receptors are involved in signaling of commonly mutated melanoma pathways, potential synergistic properties of the recently developed molecular kinase inhibitors that target those pathways may exist. PMID- 26415592 TI - Modeling of electrochemical double layers in thermodynamic non-equilibrium. AB - We consider the contact between an electrolyte and a solid electrode. At first we formulate a thermodynamic consistent model that resolves boundary layers at interfaces. The model includes charge transport, diffusion, chemical reactions, viscosity, elasticity and polarization under isothermal conditions. There is a coupling between these phenomena that particularly involves the local pressure in the electrolyte. Therefore the momentum balance is of major importance for the correct description of the boundary layers. The width of the boundary layers is typically very small compared to the macroscopic dimensions of the system. In the second step we thus apply the method of asymptotic analysis to derive a simpler reduced bulk model that already incorporates the electrochemical properties of the double layers into a set of new boundary conditions. With the reduced model, we analyze the double layer capacitance for a metal-electrolyte interface. PMID- 26415593 TI - Taurine Protected Against the Impairments of Neural Stem Cell Differentiated Neurons Induced by Oxygen-Glucose Deprivation. AB - Cell transplantation of neural stem cells (NSCs) is a promising approach for neurological recovery both structurally and functionally. However, one big obstacle is to promote differentiation of NSCs into neurons and the followed maturation. In the present study, we aimed to investigate the protective effect of taurine on the differentiation of NSCs and subsequent maturation of their neuronal lineage, when exposed to oxygen-glucose deprivation (OGD). The results suggested that taurine (5-20 mM) promoted the viability and proliferation of NSCs, and it protected against 8 h of OGD induced impairments. Furthermore, 20 mM taurine promoted NSCs to differentiate into neurons after 7 days of culture, and it also protected against the suppressive impairments of 8 h of OGD. Consistently, taurine (20 mM) promoted the neurite sprouting and outgrowth of the NSC differentiated neurons after 14 days of differentiation, which were significantly inhibited by OGD (8 h). At D21, the mushroom spines and spine density were promoted or restored by 20 mM taurine. Taken together, the enhanced viability and proliferation of NSCs, more differentiated neurons and the promoted maturation of neurons by 20 mM taurine support its therapeutic application during stem cell therapy to enhance neurological recovery. Moreover, it protected against the impairments induced by OGD, which may highlight its role for a more direct therapeutic application especially in an ischemic stroke environment. PMID- 26415595 TI - pi-Extension of a 4-ethoxy-1,3-thiazole via aryl alkyne cross coupling: synthesis and exploration of the electronic structure. AB - A series of four donor aryl alkynyl substituted thiazole derivatives 3a-d and three similar aryl donor-acceptor systems 6a-c have been synthesized. All compounds bear different electron-donating groups in the 5-position of the thiazole core. The influence of both electron donor strength and the additional phenylethynyl unit on photophysical properties, i.e. UV/Vis absorption, fluorescence emission and fluorescence lifetime, has been evaluated. Additionally, theoretical calculations have been performed at the CAM-B3LYP/6 31+G(d,p) level and good agreement with the experimental data has been achieved. The new derivatives synthesized via palladium catalyzed cross coupling are characterised by moderately strong emission between 474 and 538 nm (PhiF = 0.35 0.39) and Stokes' shifts ranging from 0.54 to 0.79 eV (4392-6351 cm(-1)). The smaller chromophores of type 6 exhibit modest to high fluorescence emission (PhiF = 0.45-0.76) between 470 and 529 nm and their Stokes' shifts range from 0.59 to 0.65 eV (4765-5251 cm(-1)). PMID- 26415594 TI - Effects on Spatial Cognition and Nociceptive Behavior Following Peripheral Nerve Injury in Rats with Lesion of the Striatal Marginal Division Induced by Kainic Acid. AB - Neuropathic pain and cognitive deficit are frequently comorbidity in clinical, but their underlying correlation and mechanisms remain unclear. Here, we utilized a combined rat model including kainic acid (KA) injection into bilateral striatal marginal division and chronic constriction nerve injury (CCI). PET/CT scans revealed that the SUVmax of KA rats was significantly decreased when compared to naive and saline rats. In contrast to the naive and saline rats, KA rats had longer latencies in locating the hidden platform on day 4, 5 in Morris water maze task. Thermal hyperalgesia and mechanical allodynia of KA rats were alleviated following CCI. Immunostaining results showed that substance P was markedly increased within ipsilateral spinal cord dorsal horn of KA rats after CCI, especially on the post-operative day 14. By means of real-time PCR, the up regulation of GluR within ipsilateral spinal cord dorsal horn was observed in all KA and CCI rats. PKCgamma, IL-6 and NF-kappaB were up-regulated in both CCI rats when compared to naive and their respective sham rats. These results suggest that cognitive impairment of rats altered the pain behaviors, and these intracellular regulators play crucial roles in the process of neuropathic pain. PMID- 26415598 TI - Aggression Norms in the Classroom Social Network: Contexts of Aggressive Behavior and Social Preference in Middle Childhood. AB - In a cross-sectional sample of African-American 2nd-4th grade students (N = 681), we examine the moderating effects of classroom overt and relational aggression norms on peers' social acceptance of classmates who exhibit overt and relational aggression in urban schools. Extending theory and research on classroom norms, we integrate social network data to adjust aggression norms based on children's direct and indirect connections in the classroom. Results of multilevel models indicate that network-based classroom aggression norms moderated relations between children's aggressive behavior and their social preference. Specifically, children benefited socially when their form of aggressive behavior fit with what was normative in the classroom social context. The moderating effect of classroom aggression norms was stronger for the association between overt aggression and social preference than relational aggression and social preference. Relationally aggressive youth were socially preferred by peers regardless of the classroom norm, although this positive association was magnified in classrooms with higher levels of relational aggression. Future research focused on aggression norms within classroom social networks are discussed and implications for school prevention efforts are considered. PMID- 26415596 TI - The association of cholesterol absorption gene Numb polymorphism with Coronary Artery Disease among Han Chinese and Uighur Chinese in Xinjiang, China. AB - BACKGROUND: Hypercholesterolemia is a major risk factor for coronary artery disease (CAD). As Numb is an important regulating factor for intestinal cholesterol absorption and plasma cholesterol level, the aim of the present study is to assess the association between human Numb gene polymorphism and CAD among Han and Uighur Chinese. METHODS: We have conducted two independent case-control studies in Han Chinese (384 CAD patients and 433 controls) and Uighur Chinese (506 CAD patients and 351 controls) subjects. All subjects were genotyped for four kinds of SNPs (rs12435797, rs2108552, rs1019075 and rs17781919) and SNP is used as a genetic marker for human Numb gene. Genotyping was undertaken using TaqMan SNP genotyping assay, and the subjects' ethnicity and gender were considered in the analysis. RESULTS: We found that rs2108552 was associated with CAD in the dominant model (CC vs CG + GG) for the total Han Chinese population (n = 200) and Han Chinese males (n = 115) (P = 0.004 and P = 0.001, respectively). The difference remained statistically significant after multivariate adjustment (total: OR = 1.687, P = 0.004; male: OR = 1.498, P = 0.006). Further, for the total (n = 817) and male (n = 490) Han Chinese, the frequency of the haplotype (T C-T-C) was significantly higher in the CAD patients than in the controls (P = 0.004 and P = 0.002), and the frequency of the haplotype (G-G-T-C) was significantly lower in the CAD patients than in the control subjects (P = 0.013, P = 0.007). In addition, for the total (n = 857) and male (n = 582) Uighur Chinese, we observed that rs12435797 was associated with CAD in an additive and recessive model (P = 0.021 and P = 0.009; P = 0.048 and P = 0.034). However, the difference did not remain statistically significant after multivariate adjustment. The overall distribution of rs2108552, rs1019075 and rs17781919 genotypes, alleles and the frequency of the haplotype established by four SNPs showed no significant difference between CAD patients and control subjects in the total, male and female Uighur Chinese. CONCLUSIONS: The results of this study indicate that CC genotype of rs2108552 and T-C-T-C haplotypes in Numb gene is a possible risk genetic marker and G allele and G-G-T-C haplotypes is a possible protective genetic marker for CAD in male Han Chinese. PMID- 26415597 TI - Maternal psychological distress in primary care and association with child behavioural outcomes at age three. AB - Observational studies indicate children whose mothers have poor mental health are at increased risk of socio-emotional behavioural difficulties, but it is unknown whether these outcomes vary by the mothers' mental health recognition and treatment status. To examine this question, we analysed linked longitudinal primary care and research data from 1078 women enrolled in the Born in Bradford cohort. A latent class analysis of treatment status and self-reported distress broadly categorised women as (a) not having a common mental disorder (CMD) that persisted through pregnancy and the first 2 years after delivery (N = 756, 70.1 %), (b) treated for CMD (N = 67, 6.2 %), or (c) untreated (N = 255, 23.7 %). Compared to children of mothers without CMD, 3-year-old children with mothers classified as having untreated CMD had higher standardised factor scores on the Strengths and Difficulties Questionnaire (d = 0.32), as did children with mothers classified as having treated CMD (d = 0.27). Results were only slightly attenuated in adjusted analyses. Children of mothers with CMD may be at risk for socio-emotional and behavioural difficulties. The development of effective treatments for CMD needs to be balanced by greater attempts to identify and treat women. PMID- 26415599 TI - PROKARYO: an illustrative and interactive computational model of the lactose operon in the bacterium Escherichia coli. AB - BACKGROUND: We are creating software for agent-based simulation and visualization of bio-molecular processes in bacterial and eukaryotic cells. As a first example, we have built a 3-dimensional, interactive computer model of an Escherichia coli bacterium and its associated biomolecular processes. Our illustrative model focuses on the gene regulatory processes that control the expression of genes involved in the lactose operon. Prokaryo, our agent-based cell simulator, incorporates cellular structures, such as plasma membranes and cytoplasm, as well as elements of the molecular machinery, including RNA polymerase, messenger RNA, lactose permease, and ribosomes. RESULTS: The dynamics of cellular 'agents' are defined by their rules of interaction, implemented as finite state machines. The agents are embedded within a 3-dimensional virtual environment with simulated physical and electrochemical properties. The hybrid model is driven by a combination of (1) mathematical equations (DEQs) to capture higher-scale phenomena and (2) agent-based rules to implement localized interactions among a small number of molecular elements. Consequently, our model is able to capture phenomena across multiple spatial scales, from changing concentration gradients to one-on-one molecular interactions. We use the classic gene regulatory mechanism of the lactose operon to demonstrate our model's resolution, visual presentation, and real-time interactivity. Our agent-based model expands on a sophisticated mathematical E. coli metabolism model, through which we highlight our model's scientific validity. CONCLUSION: We believe that through illustration and interactive exploratory learning a model system like Prokaryo can enhance the general understanding and perception of biomolecular processes. Our agent-DEQ hybrid modeling approach can also be of value to conceptualize, illustrate, and- eventually--validate cell experiments in the wet lab. PMID- 26415600 TI - Fixed and Modifiable Correlates of Drug-Eluting Stent Thrombosis From a Large All Comers Registry: Insights From ADAPT-DES. AB - BACKGROUND: Previous studies evaluating correlates of stent thrombosis (ST) have included mostly patients with bare metal stents and early-generation drug-eluting stents (DES) and have not systematically evaluated the role of intravascular ultrasound-guided stenting and high platelet reactivity on clopidogrel. The purpose of this study was to evaluate the frequency and correlates of ST in patients receiving DES, specifically examining the impact of risk factors modifiable by physician and patient behavior. METHODS AND RESULTS: Assessment of Dual Anti-platelet Therapy With Drug-Eluting Stents (ADAPT-DES) was a multicenter, prospective study in patients undergoing successful coronary intervention with DES in whom routine platelet reactivity testing was performed. Definite or probable ST occurred in 92 (1.1%) of 8582 patients within 2 years. Independent baseline correlates of ST included presentation with an acute coronary syndrome (hazard ratio [HR]=1.81, P=0.01), insulin-treated diabetes mellitus (HR=1.91, P=0.02), previous myocardial infarction (HR=1.75, P=0.02), and peripheral arterial disease (HR=2.01, P=0.01). Independent treatment-related correlates included use of early generation DES (HR=1.75, P=0.02), no procedural intravascular ultrasound guidance (HR=1.75, P=0.04), and premature discontinuation of dual antiplatelet therapy (HR=2.67, P=0.003); high platelet reactivity on clopidogrel trended as a correlate of ST (HR=1.49, P=0.08). The 2 year risk of ST ranged from 0.3% to 10.0% when 0 to 3 modifiable risk factors were present. CONCLUSIONS: After successful DES implantation, ST occurred within 2 years in 1.1% of patients and was strongly associated with fixed and modifiable risk factors. The frequency of ST may be reduced with intravascular ultrasound guided stenting, assiduous adherence to dual antiplatelet therapy, and adequate P2Y12 platelet receptor inhibition. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00638794. PMID- 26415601 TI - Letter by Nunez-Gil et al Regarding Article, "Is Aspiration Thrombectomy Beneficial in Patients Undergoing Primary Percutaneous Coronary Intervention? Meta-Analysis of Randomized Trials". PMID- 26415602 TI - Response to Letter Regarding Article, "Is Aspiration Thrombectomy Beneficial in Patients Undergoing Primary Percutaneous Coronary Intervention? Meta-Analysis of Randomized Trials". PMID- 26415603 TI - Global change feed-back inhibits cyanobacterial photosynthesis. AB - Cyanobacteria are an important component of aquatic ecosystems, with a proliferation of massive cyanobacterial blooms predicted worldwide under increasing warming conditions. In addition to temperature, other global change related variables, such as water column stratification, increases in dissolved organic matter (DOM) discharge into freshwater systems and greater wind stress (i.e., more opaque and mixed upper water column/epilimnion) might also affect the responses of cyanobacteria. However, the combined effects of these variables on cyanobacterial photosynthesis remain virtually unknown. Here we present evidence that this combination of global-change conditions results in a feed-back mechanism by which, fluctuations in solar ultraviolet radiation (UVR, 280-400 nm) due to vertical mixing within the epilimnion act synergistically with increased DOM to impair cyanobacterial photosynthesis as the water column progressively darkens. The main consequence of such a feed-back response is that these organisms will not develop large blooms in areas of latitudes higher than 30 degrees , in both the Northern and Southern Hemispheres, where DOM inputs and surface wind stress are increasing. PMID- 26415604 TI - Hyperparathyroidism Associated with Long-Term Proton Pump Inhibitors Independent of Concurrent Bisphosphonate Therapy in Elderly Adults. AB - OBJECTIVES: To measure the effect of proton pump inhibitors (PPIs), with and without concurrent bisphosphonates, on parathyroid hormone (PTH), vitamin D, and calcium. DESIGN: Retrospective chart review of individuals 60 years and older. Subjects with reduced renal function (creatinine >1.3 mg/dL) and low vitamin D (<30 ng/mL) were excluded. SETTING: Academic geriatric outpatient center in southern midwest. PARTICIPANTS: Individuals aged 60 and older with concurrent calcium, PTH, vitamin D, and creatinine laboratory measurements (N = 80) meeting labeled criteria. MEASUREMENTS: Serum calcium, PTH, vitamin D, and creatinine. RESULTS: Chronic PPI exposure was associated with statistically significantly higher PTH (65.5 vs 30.3 pg/mL, P < .001; normal range 10-55 pg/mL) and lower calcium (9.1 vs 9.4 mg/dL, P = .02; normal range 8.5-10.5 mg/dL) than no PPI exposure. Chronic PPI exposure with concurrent BP therapy was associated with statistically significantly higher PTH (65.2 vs 43.4 pg/mL, P = .05) and lower calcium (9.2 vs 9.6 mg/dL, P = .04) than BP therapy only. CONCLUSION: Based on the present study, chronic PPI exposure in elderly adults is associated with mild hyperparathyroidism regardless of concurrent oral BP administration. PMID- 26415605 TI - Analytical performance of a point-of-care device in monitoring patients on oral anticoagulation with vitamin K antagonists. AB - BACKGROUND: [Please check the following sentence for clarity: "Point-of-care devices measuring international normalized ratio have clinical appeal, reports of 'off-label' in-hospital/primary care use report improved time to intervention/dose adjustment."]Point-of-care devices measuring international normalized ratio have clinical appeal, reports of 'off-label' in-hospital/primary care use report improved time to intervention/dose adjustment. We evaluated the accuracy and precision of a device for such multiple patient use compared to a reference laboratory. METHODS: The point-of-care international normalized ratio result of patients on oral anticoagulation at the Vascular Surgery clinic was compared to the reference to check for statistical and clinical correlation. This was a prospective case-control study design with sample size calculated for sensitivity of 87.5%, precision 5% and desired confidence level 95%. RESULTS: There were 168 patients tested; 55% were male, the mean age was 45.4. Sixty per cent were in the target international normalized ratio range. Tests were done for statistical and clinical correlation. The international normalized ratio range using the point-of-care device was 0.8-7.5 (reference lab 0.8-10), mean international normalized ratio was 2.22 +/- 1.6 (point-of-care device) compared to 2.46 +/- 1.3 (reference lab). The mean absolute difference was 0.79 +/- 0.92 and the mean relative difference was 8.1% +/- 1.03. Data was analysed using a Bland-Altman plot yielding a mean of 0.738 (standard deviation 0.92). Concordance between the tests was 75% with r2 = 0.52 on linear regression. Using an error grid plot, excellent clinical correlation was seen in 63.8%. In 5.4% major corrective action was needed but potentially missed if relying on the point-of care device. CONCLUSION: The accuracy and precision of this point-of-care device is moderate. It may have potential utility only where access to a reference lab is difficult. PMID- 26415606 TI - [Radiation-free diagnosis of scoliosis : An overview of the surface and spine topography]. AB - BACKGROUND: Scoliosis is a complex three-dimensional deformity of the spine, which usually occurs during childhood and adolescence. Up to now, whole spine X rays have been the therapeutic gold standard in the diagnosis and follow-up of scoliosis. AIM: This review gives a brief overview of the history, technical background and possible fields of use for video-rasterstereography METHODS: Alternative measurement systems have been developed over the past few years for the treatment of scoliosis, because of the risk of radiation exposure of X-rays. The rasterstereographic system Formetric (Diers International GmbH, Schlagenbad) allows a radiation-free, three-dimensional analysis of the back surface and the spine. OUTLOOK: Even dynamic measurements can now be conducted with this rasterstereographic system, which will help to further understand and analyze the human spine. PMID- 26415607 TI - [Physical therapy for idiopathic scoliosis]. AB - OBJECTIVE: The objective is the description and summary of the current state of idiopathic scoliosis treatment with physical therapy based on new scientific knowledge and concluded from more than 15 years of experience as a leading physician in two well-known clinics specializing in the conservative treatment of scoliosis. MATERIALS AND METHODS: Based on current scientific publications on physical therapy in scoliosis treatment and resulting from the considerable personal experience gained working with conservative treatment and consulting scoliosis patients (as inpatients and outpatients), the current methods of physical therapy have been compared and evaluated. RESULTS: Physical therapy according to Schroth and Vojta therapy are at present the most common and effective methods in the physical treatment of idiopathic scoliosis. These methods can be applied during inpatient or outpatient treatment or intensified in the practice of specialized therapists. DISCUSSION: As there are only a few scientific studies on this subject, the author's findings are based mainly on his own experiences of the conservative treatment of idiopathic scoliosis. Athough these experiences are the results of over 15 years of working in the field of therapy, and the Schroth method in combination with corrective bracing presents highly promising results, it would nevertheless be desirable to conduct detailed scientific studies to verify the effectiveness of conservative treatment. PMID- 26415609 TI - Isolation of Circulating Melanoma Cells. AB - Circulating melanoma cells (CMCs) represent critical mediators of metastatic melanoma progression. However, isolation and characterization of CMCs has been challenging due to the low frequency of these cells and the paucity of melanoma specific cell surface markers. Herein, we describe a method for the isolation of CMCs that employs two independent markers, displays high sensitivity for CMC enrichment, and can be readily adapted to include additional molecular melanoma markers of interest. CMCs isolated by this method are enriched for ABCB5-positive melanoma stem cells, are tumorigenic in xenotransplantation assays, and can be used for phenotypical, genetic, and functional investigations of CMC biology. PMID- 26415608 TI - [Simultaneous thoracoscopically assisted anterior release in prone position and posterior scoliosis correction : What are the limits?]. AB - BACKGROUND: In spite of modern pedicle-based systems, the correction of a rigid rib hump or hypokyphosis remains a problem in posterior-only scoliosis surgery. As there has so far been no reliable method of predicting the intraoperative extent of kyphosis restoration or rib hump correction by posterior-only surgery, it has been difficult to determine the indication for an additional anterior release. METHODS: The method described here circumvents this dilemma. Like an optional module, horacoscopically assisted release in prone position (TARP) can be added when it is obvious during posterior surgery that the correction is insufficient. RESULTS: Between 1996 and 2005, a total of 161 patients (115 male, 46 female) under the age of 30, including 113 cases of idiopathic scoliosis, were released by simultaneous TARP and posterior surgery. Using the two-portal technique, 131 were mobilized from the right and 30 from the left hand side. Average surgical time spanned 69 min, in which on average 3.2 apical segments were addressed. In 3 individuals, an additional retroperitoneoscopic release was used to liberate a rigid lumbar curve. After 10 years, in a prospectively evaluated subgroup of 32 patients with adolescent idiopathic scoliosis, the index curve had maintained a coronal correction of 70 % (immediately post-surgery 75 %), kyphosis was permanently normalized at 30 degrees (Th5-Th12), and indirect rib hump was reduced to 2.2 cm. In 23 out of 32 patients the lumbar curve corrected spontaneously, obviating the need for fusion. In 13 patients, the lower instrumented vertebra lay at Th12 or higher, thus leaving the thoraco-lumbar junction fairly free. Minor complications (Huang 1or 2) occurred in 4 patients; 1 patient with hematothorax required revision. A distance <25 mm from the spine to the chest wall precludes TARP. Other limitations (e.g., pleural adhesions) were not encountered. CONCLUSION: Long-term evaluation after 10-18 years shows that an additional thoracoscopically assisted anterior release at the same time as a posterior standard scoliosis procedure is a justified and effective tool, yielding better results and maintaining them. PMID- 26415610 TI - Pre-operative serum alkaline phosphatase as a predictive indicator of post operative hypocalcaemia in patients undergoing total thyroidectomy. AB - OBJECTIVE: This study aimed to evaluate whether a pre-operative elevated serum alkaline phosphatase level is a potential predictor of post-operative hypocalcaemia after total thyroidectomy. METHODS: Data was retrospectively collected from the case notes of patients who had undergone total thyroidectomy. Patients were divided into Graves' disease and non-Graves' groups. Pre-operative and post-operative biochemical markers, including serum calcium, alkaline phosphatase and parathyroid hormone levels, were reviewed. RESULTS: A total of 225 patients met the inclusion criteria. Graves' disease was the most common indication (n = 134; 59.5 per cent) for thyroidectomy. Post-operative hypocalcaemia developed in 48 patients (21.3 per cent) and raised pre-operative serum alkaline phosphatase was noted in 94 patients (41.8 per cent). Raised pre operative serum alkaline phosphatase was significantly associated with post operative hypocalcaemia, particularly in Graves' disease patients (p < 0.05). CONCLUSION: Pre-operative serum alkaline phosphatase measurements help to predict post-thyroidectomy hypocalcaemia, especially in patients who do not develop hypoparathyroidism. Ascertaining the pre-operative serum alkaline phosphatase level in patients undergoing total thyroidectomy may help surgeons to identify at risk patients. PMID- 26415611 TI - Erratum to: Plasma levels of matrix metalloproteinase-2, -3, -10, and tissue inhibitor of metalloproteinase-1 are associated with vascular complications in patients with type 1 diabetes: the EURODIAB Prospective Complications Study. PMID- 26415612 TI - The Effectiveness of Visual Short-Time Neurofeedback on Brain Activity and Clinical Characteristics in Alcohol Use Disorders: Practical Issues and Results. AB - The present study was carried out to examine the efficacy of alpha/theta neurofeedback (NF) with a new visual paradigm in a cohort of alcohol use disordered (AUD) patients (n = 25) treated in an Austrian therapeutic community center. The experimental study design focused on changes in absolute and relative resting EEG band power as well as in clinical variables, including depression (Beck Depresion Inventory [BDI-V]), psychiatric symptoms (Brief Symptom Inventory [BSI], coping (Freiburg Questionnaire on Coping with Illness [FKV-lis]), psychotherapy motivation (Therapy Motivation Questionnaire [FPTM-23]), sense of coherence (Sense of Coherence Scale [SOC-13]), posttraumatic growth (Posttraumatic Growth Inventory [PPR]), and alcohol cravings (Alcohol Craving Questionnaire [ACQ]). For measuring training effects, participants were randomly allocated to 2 groups: an experimental group (EG, n = 13) and a control group (CG, n = 12). Patients in EG received 12 sessions of visual NF training over a period of 6 weeks to enhance alpha (8-12 Hz) and theta (4-7 Hz) frequency band power in addition to the standard treatment program of the rehabilitation center. Participants in CG received no additional NF intervention. The multivariate analysis of covariance (MANCOVA) showed a change by trend in absolute alpha and theta power in the EG. Even though no MANCOVA effects were found in the clinical scales, AUD patients reported increasing control of their brain activity during the course of NF. However, changes in several clinical scales (BDI-V, BSI, FKV lis, PPR) from pre- to posttest were observed only in the EG contrary to the CG. The findings of this pilot study provide first evidence for the practicality and effectiveness of visual short-term NF as an additive intervention in the therapeutic community. PMID- 26415613 TI - Robot-sewn Ivor-Lewis anastomosis: preliminary experience and technical details. AB - INTRODUCTION: Robot-assisted minimally invasive esophagectomy with intra-thoracic anastomosis showed encouraging results but there is a lack of data to demonstrate the safety and feasibility. OBJECTIVE: The aim of this study is to report our experience in RA-ILE (robotic-assisted Ivor-Lewis esophagectomy) with robotic hand-sewn anastomosis. METHODS: This is a retrospective study of patients who underwent robotic-assisted esophagectomy in prone position with intrathoracic anastomosis for malignant neoplasm of the esophagus or esophago-gastric junction. RESULTS: From January 2012 to December 2014 we performed eight completely robot assisted esophagectomy without intra-operative complication. The mortality rate at 30-day was zero. In two patients we observed a partial leakage of the gastric tube that required revision. The mean operative time was 499 +/- 46 min including robotic set up and patient positioning. The median hospital-stay was 10 days. Complete (R0) resection was accomplished in all patients and the mean number of lymph nodes removed was 37.6 +/- 14 .7. CONCLUSIONS: This preliminary experience suggests that robotic-assisted RA-ILE for malignant lesions is a real surgical option compared with conventional surgery with satisfactory results. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26415614 TI - Evolving understanding on the aetiology of thermally provoked itch. AB - BACKGROUND AND OBJECTIVES: Itch is one of the major symptoms in dermatology clinics, and severely impairs the quality of life. Itch is frequently produced by environmental stimuli, especially heat or warmth. Changes of temperature on the skin surface and noxious heat stimuli augment and develop itch, respectively. Thermally provoked itch is sometimes intractable with existing treatments. DATA BASES AND DATA TREATMENT: Recent researches, linking heat sensation and itch, were searched in MEDLINE literature database through PubMed. RESULTS: Recent studies of the transient receptor potential cation channel subfamily vanilloid type 1 (TRPV1), the calcitonin gene-related peptide (CGRP) and the vesicular glutamate transporter 2 (VGLUT2), which link noxious heat and itch, contribute to a much better understanding of the thermally evoked itch process. From a clinical perspective, a warm sensation is a major provocative factor for subjects with atopic dermatitis. The accumulation of artemin (also known as enovin or neublastin) in the dermis of lesional skin can possibly provide a pathological mechanism for warmth-provoked itch. CONCLUSIONS: This mini-review describes recent results of both basic and clinical research related to thermally provoked itch. PMID- 26415615 TI - Recommendations for managing a suboptimal response to biologics for moderate-to severe psoriasis: A Belgian perspective. AB - Over the past decade, biologics have become the gold standard in the treatment of moderate-to-severe psoriasis for patients who have failed or who have contraindications to traditional systemic treatments. However, although practical recommendations on how to treat a suboptimal response to biologics exist in other chronic inflammatory diseases, they are only just beginning to emerge for psoriasis. This article aims to formulate recommendations in the case of a suboptimal response of psoriasis to biologics in the Belgian setting. A Belgian taskforce of psoriasis experts was convened to review the results of a literature search and formulate recommendations based on the available evidence and provide expert opinion to address gaps in the evidence. The taskforce has proposed a treatment algorithm for patients with a primary non-response or a secondary loss of response to help address an unmet need. Expert recommendations have been developed to address treatment strategies in case of a primary or secondary suboptimal response to biologics in the treatment of moderate-to-severe psoriasis in Belgium. PMID- 26415617 TI - Effects of the ornidazole enantiomers on the central nervous system: Involvement of the GABAA receptor. AB - This is the preliminary study of the sedative and muscle relaxation activity of ornidazole enantiomers, which are widely used in the treatment of susceptible protozoal infections and anaerobic bacterial infections. Adverse effects on the central nervous system (CNS) are the main side effects of ornidazole during its clinical application. The aim of this study was to compare the different central inhibitory effects between S-(-) ornidazole and R-(+) ornidazole in mice and clarify the possible mechanisms. In the present study, central effects of ornidazole were evaluated by open-field test and rota-rod test, and such effects were reversed by pre-treatment with flumazenil (i.p., 10 mg/kg) suggesting that ornidazole exhibits such action by interacting with the GABAergic system. Then, the functional difference between S-(-) ornidazole and R-(+) ornidazole was further explored by evaluating the contents of glutamate (Glu) and gamma aminobutyric acid (GABA) in the brain, and Western blot was used to measure glutamic acid decarboxylase (GAD65/67) expression in the mice cerebral cortex. We found that R-(+) ornidazole mediated an increase in GABA level while decreased the level of glutamate through upregulation of GAD65/67 in the cerebral cortex. Taken together, our study suggests that R-(+) ornidazole mediate stronger central inhibitory effects than S-(-) ornidazole through interaction with the GABAergic system. PMID- 26415618 TI - In vitro anticancer activity of methyl caffeate isolated from Solanum torvum Swartz. fruit. AB - The present study was undertaken to investigate the anticancer activity of methyl caffeate isolated from Solanum torvum Swartz. fruit and to explore the molecular mechanisms of action in MCF-7 cells. Cytotoxic properties of hexane, ethyl acetate and methanol extracts were carried out against MCF-7 cells using the 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Ethyl acetate extract showed good cytototoxic activities compared to hexane and methanol extracts. Methyl caffeate was isolated from the ethyl acetate extract using column chromatography. Cytotoxic properties of methyl caffeate was investigated against MCF-7, A549, COLO320, HepG-2 and Vero cells. The compound showed potent cytotoxic properties against MCF-7 cells compared to A549, COLO320 and HepG-2 cells. Methyl caffeate significantly reduced cell proliferation and increased formation of fragmented DNA and apoptotic body in MCF-7 cells. Bcl-2, Bax, Bid, p53, caspase-3, PARP and cytochrome c release were detected by western blot analysis. The activities of caspases-3 and PARP gradually increased after the addition of isolated compound. Bcl-2 protein was down regulated; Bid and Bax were up regulated after the treatment with methyl caffeate. Molecular docking studies showed that the compound bound stably to the active sites of poly (ADP-ribose) polymerase-1 (PARP1), B cell CLL/lymphoma-2 (BCL-2), E3 ubiquitin-protein ligase (MDM2) and tubulin. The results strongly suggested that methyl caffeate induced apoptosis in MCF-7 cells via caspase activation through cytochrome c release from mitochondria. PMID- 26415616 TI - A global meta-analysis of the relative extent of intraspecific trait variation in plant communities. AB - Recent studies have shown that accounting for intraspecific trait variation (ITV) may better address major questions in community ecology. However, a general picture of the relative extent of ITV compared to interspecific trait variation in plant communities is still missing. Here, we conducted a meta-analysis of the relative extent of ITV within and among plant communities worldwide, using a data set encompassing 629 communities (plots) and 36 functional traits. Overall, ITV accounted for 25% of the total trait variation within communities and 32% of the total trait variation among communities on average. The relative extent of ITV tended to be greater for whole-plant (e.g. plant height) vs. organ-level traits and for leaf chemical (e.g. leaf N and P concentration) vs. leaf morphological (e.g. leaf area and thickness) traits. The relative amount of ITV decreased with increasing species richness and spatial extent, but did not vary with plant growth form or climate. These results highlight global patterns in the relative importance of ITV in plant communities, providing practical guidelines for when researchers should include ITV in trait-based community and ecosystem studies. PMID- 26415619 TI - O-Alkylated derivatives of quercetin induce apoptosis of MCF-7 cells via a caspase-independent mitochondrial pathway. AB - The aim of this study was to investigate the antitumor effects of two novel alkylated derivatives of quercetin, 7-O-butylquercetin (BQ) and 7-O geranylquercetin (GQ), in MCF-7 human breast cancer cells and explore the possible cellular mechanism of the related apoptotic effects. Our data showed that BQ and GQ were more toxic to MCF-7 cells and had better accumulation ability in MCF-7 cells than quercetin. Morphological observations and DNA fragmentation pattern suggested that the derivatives could induce apoptosis in MCF-7 cells. Derivatives-induced apoptosis could not be reversed by Z-VAD-FMK and N-acetyl cysteine demonstrated that the apoptosis was independent on caspase and reactive oxygen species. Western blot assay showed that endonuclease G and apoptosis inducing factor might be relative to the apoptosis. Alkylation of quercetin at 7 O position can enhance the apoptosis inducing effect and cell accumulation ability relative to quercetin. This structural alteration brings changes on apoptosis pathway as well. PMID- 26415620 TI - Pharmacokinetics and immunogenicity of a recombinant human butyrylcholinesterase bioscavenger in macaques following intravenous and pulmonary delivery. AB - Recombinant (r) and native butyrylcholinesterse (BChE) are potent bioscavengers of organophosphates (OPs) such as nerve agents and pesticides and are undergoing development as antidotal treatments for OP-induced toxicity. Because of the lethal properties of such agents, regulatory approval will require extensive testing under the Animal Rule. However, human (Hu) glycoprotein biologicals, such as BChE, present a challenge for assessing immunogenicity and efficacy in heterologous animal models since any immune responses to the small species differences in amino acids or glycans between the host and biologic may alter pharmacodynamics and preclude accurate efficacy testing; possibly underestimating their potential protective value in humans. To establish accurate pharmacokinetic and efficacy data, an homologous animal model has been developed in which native and PEGylated forms of CHO-derived rMaBChE were multiply injected into homologous macaques with no induction of antibody. These now serve as controls for assessing the pharmacokinetics and immunogenicity in macaques of multiple administrations of PEGylated and unmodified human rBChE (rHuBChE) by both intravenous (IV) and pulmonary routes. The results indicate that, except for maximal concentration (Cmax), the pharmacokinetic parameters following IV injection with heterologous PEG-rHuBChE were greatly reduced even after the first injection compared with homologous PEG-rMaBChE. Anti-HuBChE antibody responses were induced in all monkeys after the second and third administrations regardless of the route of delivery; impacting rates of clearance and usually resulting in reduced endogenous MaBChE activity. These data highlight the difficulties inherent in assessing pharmacokinetics and immunogenicity in animal models, but bode well for the efficacy and safety of rHuBChE pretreatments in homologous humans. PMID- 26415623 TI - Entropy-stabilized oxides. AB - Configurational disorder can be compositionally engineered into mixed oxide by populating a single sublattice with many distinct cations. The formulations promote novel and entropy-stabilized forms of crystalline matter where metal cations are incorporated in new ways. Here, through rigorous experiments, a simple thermodynamic model, and a five-component oxide formulation, we demonstrate beyond reasonable doubt that entropy predominates the thermodynamic landscape, and drives a reversible solid-state transformation between a multiphase and single-phase state. In the latter, cation distributions are proven to be random and homogeneous. The findings validate the hypothesis that deliberate configurational disorder provides an orthogonal strategy to imagine and discover new phases of crystalline matter and untapped opportunities for property engineering. PMID- 26415622 TI - Prevalence of Alcohol and Other Substance Use in Patients with Eating Disorders. AB - OBJECTIVE: The major aim of this study was to investigate any association between binge eating and purging and alcohol and substance use. METHOD: The Eating Disorder Questionnaire was completed by 2966 patients. Each patient was assigned to an approximate diagnostic group based on a DSM-5-based algorithm. RESULTS: Patients with bulimia nervosa (BN) used alcohol/other substances with higher frequencies compared to patients with anorexia nervosa-restricting type (AN-R), binge eating disorder (BED), and eating disorder not otherwise specified (EDNOS; p < 0.001). Patients with anorexia nervosa-binge eating/purging type (AN-BP) were more likely to use alcohol/substances than those with AN-R [odds ratio for alcohol use: 3.58 (p < 0.01); odds ratio for substance use: 30.14 (p < 0.01)]. Higher frequencies of binge eating and purging were associated with higher frequencies of substance use. DISCUSSION: Patients who manifest both binge eating and purging behaviour are at higher risk of substance use which may have important treatment implications. PMID- 26415624 TI - Mediating effects of nocturnal blood pressure and morning surge on the contributions of arterial stiffness and sodium intake to morning blood pressure: A path analysis. AB - BACKGROUND: The aim of this study was to evaluate the mediating effects of nocturnal blood pressure (BP) and morning surge on the contribution of arterial stiffness and sodium intake to morning BP in a middle-aged general population. METHODS: The study included 124 subjects aged 30-59 years, from rural Yeoju County, Gyeonggi Province, South Korea. Ambulatory BP monitoring, 24 h urinary sodium excretion (24 h UNa) and brachial-ankle pulse wave velocity (baPWV) measurements were performed in all subjects. RESULTS: The mean +/- SD age was 48.1 +/- 8.2 years and the proportion of male subjects was 41.1%. After adjusting for covariates, morning systolic blood pressure (SBP) was significantly correlated with morning surge [coefficient = 0.761, 95% confidence interval (CI) 0.651-0.872, p < 0.001], nocturnal SBP (coefficient = 0.576, 95% CI 0.454-0.698, p < 0.001) and baPWV (coefficient = 3.550, 95% CI 1.447-5.653, p = 0.001). Path analysis modeling revealed that baPWV had significant direct (0.035, p = 0.013) and indirect effects (0.042, p = 0.012) on morning SBP. The indirect effect mediated by nocturnal SBP was statistically significant (0.054, p = 0.005), but the indirect effect mediated by the morning surge was not significant. The 24 h UNa had no significant direct or indirect effects on morning SBP. CONCLUSION: baPWV had significant direct and indirect effects on morning SBP. The indirect effect was mediated by nocturnal SBP, but not by morning surge. The 24 h UNa had neither significant direct nor indirect effects on morning SBP. PMID- 26415621 TI - Autoantigen Microarray for High-throughput Autoantibody Profiling in Systemic Lupus Erythematosus. AB - Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the production of autoantibodies to a broad range of self-antigens. Profiling the autoantibody repertoire using array-based technology has emerged as a powerful tool for the identification of biomarkers in SLE and other autoimmune diseases. Proteomic microarray has the capacity to hold large number of self antigens on a solid surface and serve as a high-throughput screening method for the determination of autoantibody specificities. The autoantigen arrays carrying a wide variety of self-antigens, such as cell nuclear components (nucleic acids and associated proteins), cytoplasmic proteins, phospholipid proteins, cell matrix proteins, mucosal/secreted proteins, glomeruli, and other tissue-specific proteins, have been used for screening of autoantibody specificities associated with different manifestations of SLE. Arrays containing synthetic peptides and molecular modified proteins are also being utilized for identification of autoantibodies targeting to special antigenic epitopes. Different isotypes of autoantibodies, including IgG, IgM, IgA, and IgE, as well as other Ig subtypes, can be detected simultaneously with multi-color labeled secondary antibodies. Serum and plasma are the most common biologic materials for autoantibody detection, but other body fluids such as cerebrospinal fluid, synovial fluid, and saliva can also be a source of autoantibody detection. Proteomic microarray as a multiplexed high-throughput screening platform is playing an increasingly important role in autoantibody diagnostics. In this article, we highlight the use of autoantigen microarrays for autoantibody exploration in SLE. PMID- 26415625 TI - Colorimetric detection of biological hydrogen sulfide using fluorosurfactant functionalized gold nanorods. AB - As a well-known environmental pollutant but also an important gaseous transmitter, the specific detection of hydrogen sulfide (H2S) is significant in biological systems. In this study, fluorosurfactant functionalized gold nanorods (FSN-AuNRs) have been proposed to act as selective colorimetric nanoprobes for H2S. With the combination of strong gold-S interactions and small FSN bilayer interstices, FSN-AuNRs demonstrate favorable selectivity and sensitivity toward H2S over other anions and small biological molecules. The practical application of the present method in biological H2S detection was validated with human and mouse serum samples. Moreover, the proposed nanoprobe can also be used for evaluating the activity of H2S synthetase. PMID- 26415626 TI - Sputum smear-positive pulmonary tuberculosis: Is sputum smear examination required to discontinue airborne precautions? AB - OBJECTIVE: Our aim was to evaluate the criteria required to discontinue airborne precautions for patients presenting with sputum smear-positive pulmonary tuberculosis as the need for sputum smear examinations is still a matter of debate. METHOD: We conducted a retrospective study in the University Hospitals of Strasbourg (France) from July 2011 to July 2013. Our aim was to describe the results of sputum smear examinations and cultures obtained from treated patients presenting with drug-sensitive pulmonary tuberculosis. We included 97 patients in the study. CONCLUSION: Nearly half of patients for whom a sputum smear examination was performed had a negative sputum direct examination but a positive culture. According to the literature, those patients are still likely to be contagious. This questions the safety of discontinuing airborne precautions in this situation. We also observed a great disparity in physicians' behaviors. Only half of them waited to get a negative sputum direct examination before discontinuing airborne precautions. PMID- 26415627 TI - A Simple Method for the Preparation of TiO2 /Ag-AgCl@Polypyrrole Composite and Its Enhanced Visible-Light Photocatalytic Activity. AB - A novel and facile method was developed to prepare a visible-light driven TiO2 /Ag-AgCl@polypyrrole (PPy) photocatalyst with Ag-AgCl nanoparticles supported on TiO2 nanofibers and covered by a thin PPy shell. During the synthesis, the PPy shell and Ag-AgCl nanoparticles were prepared simultaneously onto TiO2 nanofibers, which simplified the preparation procedure. In addition, because Ag AgCl aggregates were fabricated via partly etching the Ag nanoparticles, their size was well controlled at the nanoscale, which was beneficial for improvement of the contact surface area. Compared with reference photocatalysts, the TiO2 /Ag AgCl@PPy composite exhibited an enhanced photodegradation activity towards rhodamine B under visible-light irradiation. The superior photocatalytic property originated from synergistic effects between TiO2 nanofibers, Ag-AgCl nanoparticles and the PPy shell. Furthermore, the TiO2 /Ag-AgCl@PPy composite could be easily separated and recycled without obvious reduction in activity. PMID- 26415628 TI - New avenues for improving pancreatic ductal adenocarcinoma (PDAC) treatment: Selective stroma depletion combined with nano drug delivery. AB - The effectiveness of chemotherapy in PDAC is hampered by the dynamic interaction between stroma and cancer cell. The two opposing schools of thought - non depletion of the stroma vs its depletion - to better drug efficacy are here discussed. Disrupting stroma-cancer cell interaction to reduce tumor progression and promote apoptosis is identified as the new direction of treatment for PDAC. Clinical data have shown that elimination of fibrosis and blockade of the Hedgehog pathway in stroma effectively promote drug delivery to tumor site and apoptosis. Reduced stiffness of ECM, lower fibrosis, higher permeability and higher blood flow after stroma depletion increase drug delivery. Combination strategies involving selective stroma depletion coupled with chemotherapy is currently proving to be the most efficient at clinical level. Striking the right balance between fibrosis depletion and angiogenesis promotion resulting in enhanced drug delivery and apoptosis is a major challenge. The use of nano drug delivery devices coupled with stroma depletion is emerging as the next phase treatment for PDAC. The breakthrough to combat PDAC will likely be a combination of early diagnosis and the emerging chemotherapy strategies. PMID- 26415629 TI - Immunolocalization indicates that both original and regenerated lizard tail tissues contain populations of long retaining cells, putative stem/progenitor cells. AB - The regeneration of the tail in lizards is likely sustained by stem/progenitor cells located in the stump after amputation of the tail. This microscopic and ultrastructural study shows the localization of 5-bromo-deoxy-uridine (5BrdU) long retaining labeled cells in different tissues of the tail stump. These putative stem/progenitor cells are sparsely detected in the epidermis of scales, adipose tissue, intermuscle connective septa, myosatellite cells, and perichondrion of the vertebrae. Most of 5BrdU-labeled cells are present in the bone marrow of vertebrae as hemocytoblasts and reticulate cells, whereas more numerous myelocytes and polychromatophilic erythroblasts show a variable level of nuclear labeling. 5BrdU and tritiated-thymidine labeled and unlabeled hemopoietic cells are seen in circulating vessels and in the blastema where their maturation is completed. This observation indicates that the entire differentiation span of both white and red blood cells, at least during tail regeneration, lasts longer than 4 weeks. Labeled polychromatophilic erythroblasts and heterophilic and basophilic myelocytes are present in the synusoidal vessels of the regenerating tail. This study indicates that extravasating blood cells involved in immunity make large part of the forming blastema cell population, but are replaced by mesenchymal cells of different origin. The presence of long retaining labeled cells in tissues of the tail stump is likely connected to the production of blastema mesenchymal cells. Although no direct cell-lineage study has been done, histological, immunocytochemical, and autoradiographic studies have indicated that it is from these tissues that proliferating cells appear mainly localized after tail amputation and blastema formation. PMID- 26415630 TI - Tunable release of ophthalmic therapeutics from injectable, resorbable, thermoresponsive copolymer scaffolds. AB - The sustained release of ophthalmic therapeutics to the posterior segment of the eye is a challenge. Injectable polymer materials have the potential to reduce injection frequency by providing long term therapeutic delivery. Copolymers with varying N-isopropylacrylamide, acrylamide (AAm), acrylic acid N hydroxysuccinimide, and (r)-alpha-acryloyloxy-beta,beta-dimethyl-gamma butyrolactone (DBA) were synthesized by RAFT polymerization to develop injectable, resorbable, and thermoresponsive copolymer scaffolds. Upon injection into physiological conditions, these copolymers undergo a temperature induced gelation to form a drug releasing scaffold. Modification of the copolymer's AAm/DBA ratio and molecular weight afforded significant and precise control over the scaffold's physical properties and subsequent drug release profile. Hydrolytic DBA ring-opening enables redissolution of the copolymers for clearance from the body. Precise control over the drug release profile from these copolymer scaffolds by simple alteration of composition and molecular weight provides an efficient method to customize the minimally invasive delivery of therapeutics to the posterior segment of the eye. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 53-62, 2017. PMID- 26415631 TI - Exploring the nature of the liquid-liquid transition in silicon: a non-activated transformation. AB - In contrast to other glass formers, silicon exhibits a thermodynamic discontinuity between its liquid and amorphous solid states. Some researchers have conjectured that a first-order phase transition occurs between two forms of liquid silicon: the high-density liquid (HDL) and the low-density liquid (LDL). Despite the fact that several computer simulations have supported a liquid-liquid phase transition (LLPT) in silicon, recent work based on surface free energy calculations contradicts its existence and the authors of this work have argued that the proposed LLPT has been mistakenly interpreted [J. Chem. Phys., 2013, 138, 214504]. A similar controversy has also arisen in the case of water because of discrepancies in the calculation of its free energy surface [Nature, 2014, 510, 385; J. Chem. Phys., 2013, 138, 214504]. Current evidence supporting or not supporting the LLPT is mostly derived from the thermodynamic stability of the LDL phase. Provided that the HDL-LDL transition is a first-order transition, the formation of LDL silicon should be an activated process. Following this idea, the nature of the LLPT should be clarified by tracing the kinetic path toward LDL silicon. In this work, we focus on the transformation process from HDL to LDL phases and use the mean first passage time (MFPT) method to examine thermodynamic and dynamic trajectories. The MFPT results show that the presumed HDL-LDL transition is not characterized by a thermodynamic activated process but by a continuous dynamic transformation. LDL silicon is actually a mixture of the high density liquid and a low-density tetrahedral network. We show that the five membered Si-Si rings in the LDL network play a critical role in stabilizing the low-density network and suppressing the crystallization. PMID- 26415632 TI - A finite element model of the L4-L5-S1 human spine segment including the heterogeneity and anisotropy of the discs. AB - With the aim to study disc degeneration and the risk of injury during occupational activities, a new finite element (FE) model of the L4-L5-S1 segment of the human spine was developed based on the anthropometry of a typical Colombian worker. Beginning with medical images, the programs CATIA and SOLIDWORKS were used to generate and assemble the vertebrae and create the soft structures of the segment. The software ABAQUS was used to run the analyses, which included a detailed model calibration using the experimental step-wise reduction data for the L4-L5 component, while the L5-S1 segment was calibrated in the intact condition. The range of motion curves, the intradiscal pressure and the lateral bulging under pure moments were considered for the calibration. As opposed to other FE models that include the L5-S1 disc, the model developed in this study considered the regional variations and anisotropy of the annulus as well as a realistic description of the nucleus geometry, which allowed an improved representation of experimental data during the validation process. Hence, the model can be used to analyze the stress and strain distributions in the L4-L5 and L5-S1 discs of workers performing activities such as lifting and carrying tasks. PMID- 26415633 TI - Pursuing shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS) for concomitant detection of breast lesions and microcalcifications. AB - Although tissue staining followed by morphologic identification remains the gold standard for diagnosis of most cancers, such determinations relying solely on morphology are often hampered by inter- and intra-observer variability. Vibrational spectroscopic techniques, in contrast, offer objective markers for diagnoses and can afford disease detection prior to alterations in cellular and extracellular architecture by furnishing a rapid "omics"-like view of the biochemical status of the probed specimen. Here, we report a classification approach to concomitantly detect microcalcification status and local pathological state in breast tissue, featuring a combination of vibrational spectroscopy that focuses on the tumor and its microenvironment, and multivariate data analysis of spectral markers reflecting molecular expression. We employ the unprecedented sensitivity and exquisite molecular specificity offered by Au@SiO2 shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS) to probe the presence of calcified deposits and distinguish between normal breast tissues, fibroadenoma, atypical ductal hyperplasia, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC). By correlating the spectra with the corresponding histologic assessment, we developed partial least squares-discriminant analysis derived decision algorithm that provides excellent diagnostic power in the fresh frozen sections (overall accuracy of 99.4% and 93.6% using SHINs for breast lesions with and without microcalcifications, respectively). The performance of this decision algorithm is competitive with or supersedes that of analogous algorithms employing spontaneous Raman spectroscopy while enabling facile detection due to the considerably higher intensity of SHINERS. Our results pave the way for rapid tissue spectral pathology measurements using SHINERS that can offer a novel stain free route to accurate and economical diagnoses without human interpretation. PMID- 26415634 TI - Influence of the linkage type between the polymer backbone and side groups on the surface segregation of methyl groups during film formation. AB - Although poly(vinyl acetate) (PVAc) differs from poly(methyl acrylate) (PMA) only in the reversed position of the ester group, a large difference in the concentration dependence of the casting solution on the corresponding surface structure of the cast films of PVAc, PMA and poly(methyl methacrylate) (PMMA) was observed. The hydrophobicity of both PMA and PMMA films increased with increasing concentration of the corresponding polymer solution, whereas cast PVAc films showed the reverse trend. The surface structure of the cast films prepared with different concentrations of the casting solution, characterized by sum frequency generation (SFG) vibrational spectra, showed that the order of the methylene groups increased while that of the acetyl methyl group decreased on the surface of cast PVAc film with increasing concentration of casting solution. However, the order of the ester methyl group increased and that of methylene groups did not change for cast PMA films with increasing concentration of casting solution. The cast PMMA film showed a reverse trend compared with the corresponding PMA film. It is apparent that well-ordered ester or acetyl methyl groups on the surface, which are oriented away from the polymer film, rather than methylene groups, play an important role in determining surface hydrophobicity, as the latter shield the OC[double bond, length as m-dash]O groups of PVAc, PMA and PMMA film surfaces from being exposed, resulting in low surface free energy. The reason for this difference is attributed to the relatively low energy for ester methyl group reorientation, an ester group structure nearer to the trans state and more regular local configuration of segments in concentrated solutions of PMA and PMMA compared to that of PVAc. PMID- 26415635 TI - Does LLETZ excision margin status predict residual disease in women who have undergone post-treatment cervical cytology and high-risk human papillomavirus testing? AB - OBJECTIVE: This study looks at the importance of large loop excision of the transformation zone (LLETZ) excision margins and residual cervical intraepithelial neoplasia (CIN) in women undertaking high-risk human papillomavirus (hrHPV) test of cure (TOC). METHODS: A retrospective cohort study with interval analysis performed June 2007 and June 2012 on all women undertaking treatment for CIN and subsequent hrHPV TOC 6 months post LLETZ. RESULTS: Final analysis group comprised 2093 women treated by LLETZ (1396 completely excised; 697 incompletely excised). 298 out of 1794 women (13%) were hrHPV positive at TOC. Thirty-six women who failed TOC and attended colposcopy had residual CIN. No statistically significant difference existed between the completely and incompletely excised groups with regards to the detection of residual CIN at 6 months post-treatment. There was no correlation of margins of excision with hrHPV status at TOC. The overall cure rate at TOC was 98%. CONCLUSIONS: TOC pathways recommend subsequent follow-up in primary care. This study identified no safety issues with TOC pathways. We can no longer assess histological failure rates at 12 months; we, therefore, recommend that this measure of treatment failure be redefined for post TOC women. It seems time to question the benefits of routine excision margins reporting, in the absence of invasion, for treated CIN. Future reporting needs to be reconsidered by the Royal College of Pathologists. PMID- 26415636 TI - Flexible coherent control of plasmonic spin-Hall effect. AB - The surface plasmon polariton is an emerging candidate for miniaturizing optoelectronic circuits. Recent demonstrations of polarization-dependent splitting using metasurfaces, including focal-spot shifting and unidirectional propagation, allow us to exploit the spin degree of freedom in plasmonics. However, further progress has been hampered by the inability to generate more complicated and independent surface plasmon profiles for two incident spins, which work coherently together for more flexible and tunable functionalities. Here by matching the geometric phases of the nano-slots on silver to specific superimpositions of the inward and outward surface plasmon profiles for the two spins, arbitrary spin-dependent orbitals can be generated in a slot-free region. Furthermore, motion pictures with a series of picture frames can be assembled and played by varying the linear polarization angle of incident light. This spin enabled control of orbitals is potentially useful for tip-free near-field scanning microscopy, holographic data storage, tunable plasmonic tweezers, and integrated optical components. PMID- 26415637 TI - Gender Influence on Weight Loss After Laparoscopic Sleeve Gastrectomy. PMID- 26415638 TI - Safety and efficacy of regional citrate anticoagulation in continuous venovenous hemodialysis in the presence of liver failure: the Liver Citrate Anticoagulation Threshold (L-CAT) observational study. AB - INTRODUCTION: Regional citrate anticoagulation (RCA) for continuous renal replacement therapy is widely used in intensive care units (ICUs). However, concern exists about the safety of citrate in patients with liver failure (LF). The aim of this study was to evaluate safety and efficacy of RCA in ICU patients with varying degrees of impaired liver function. METHODS: In a multicenter, prospective, observational study, 133 patients who were treated with RCA and continuous venovenous hemodialysis (RCA-CVVHD) were included. Endpoints for safety were severe acidosis or alkalosis (pH <=7.2 or >=7.55, respectively) and severe hypo- or hypercalcemia (ionized calcium <=0.9 or >=1.5 mmol/L, respectively) of any cause. The endpoint for efficacy was filter lifetime. For analysis, patients were stratified into three predefined liver function or LF groups according to their baseline serum bilirubin level (normal liver function <=2 mg/dl, mild LF >2 to <=7 mg/dl, severe LF >7 mg/dl). RESULTS: We included 48 patients with normal liver function, 43 with mild LF, and 42 with severe LF. LF was predominantly due to ischemia (39 %) or multiple organ dysfunction syndrome (27 %). The frequency of safety endpoints in the three patient strata did not differ: severe alkalosis (normal liver function 2 %, mild LF 0 %, severe LF 5 %; p = 0.41), severe acidosis (normal liver function 13 %, mild LF 16 %, severe LF 14 %; p = 0.95), severe hypocalcemia (normal liver function 8 %, mild LF 14 %, severe LF 12 %; p = 0.70), and severe hypercalcemia (0 % in all strata). Only three patients showed signs of impaired citrate metabolism. Overall filter patency was 49 % at 72 h. After censoring for stop of the treatment due to non clotting causes, estimated 72-h filter survival was 96 %. CONCLUSIONS: RCA-CVVHD can be safely used in patients with LF. The technique yields excellent filter patency and thus can be recommended as first-line anticoagulation for the majority of ICU patients. TRIAL REGISTRATION: ISRCTN Registry identifier: ISRCTN92716512 . Date assigned: 4 December 2008. PMID- 26415639 TI - MicroRNA let-7e Is a Potential Circulating Biomarker of Acute Stage Ischemic Stroke. AB - The aim of this study is to determine the expression levels and clinical significance of circulating microRNAs (miRNAs), let-7e and miR-338 at different stages following ischemic stroke (IS). Seventy-two patients with IS at the acute stage were enrolled and monitored at different stages, and 51 healthy volunteers were served as the normal controls. Expression of let-7e and miR-338 in serum and cerebral spinal fluid (CSF) samples was analyzed by real-time quantitative PCR. The relationship between expression levels of let-7e and miR-338, National Institutes of Health Stroke Scale (NIHSS) scores, and the levels of serum CRP was analyzed, respectively. Compared to healthy controls, serum let-7e expression levels were significantly increased, while serum miR-338 expression levels were slightly increased in IS patients. Expression levels of Let-7e in serum varied at different stages in IS patients with the lowest expression in the recover stage and highest expression in the acute stage. However, serum miR-338 expression in IS patients was not significantly different in any stage. Compared to healthy controls and nonacute stages of IS groups, let-7e expression in CSF was markedly upregulated in IS patients at the acute stage. Different from that of let-7e, miR 338 expression in CSF was upregulated in IS patients only at the subacute stage but not in the acute stage. Meanwhile, let-7e, which was not significantly correlated with NIHSS scores (r = 0.29, P > 0.05), was positively correlated with the serum CRP levels (r = 0.67, P = 0.033). There is no significant correlation between the miR-338 expression levels and NIHSS scores or serum CRP levels. Moreover, let-7e, but not miR-338, had a high consistency in expression when tested both in CSF and serum samples. Finally, serum let-7e showed a specificity up to 73.4 % and a sensitivity of 82.8 % in IS patients at the acute stage, whereas serum miR-338 in IS patients showed a specificity up to 53.2 % and a sensitivity of 71.9 % in the acute stage. Expression levels of let-7e in serum may serve as a useful noninvasive circulating biomarker for the acute stage of ischemic stroke. PMID- 26415640 TI - Pulmonary Vein-to-Pulmonary Artery Ratio is an Echocardiographic Index of Congestive Heart Failure in Dogs with Degenerative Mitral Valve Disease. AB - BACKGROUND: Early recognition of left-sided congestive heart failure (CHF) in dogs with degenerative mitral valve disease (DMVD) is important because it influences medical therapy, timing of follow-up, and outcome. HYPOTHESIS: Pulmonary vein diameter-to-pulmonary artery diameter ratio (PV/PA) measured by echocardiography can predict CHF. ANIMALS: Ninety-eight client-owned dogs, 37 controls, and 61 dogs with DMVD. METHODS: Prospective clinical cohort study. History, physical examination and Doppler-echocardiography were performed. Dogs were classified as International Small Animal Cardiac Health Council class I, II or III. Congestive heart failure was identified in a subset of 56 dogs based on radiographic findings. The PV/PA was measured in bidimensional (2D) and M-mode by 2 investigators blinded to the radiologists' conclusions. RESULTS: Interobserver coefficients of variation for PV/PA acquisition and measurement were <10%. The PV/PA in control dogs was approximately 1 and increased with class of heart failure. The presence of CHF could be best predicted by measuring PV/PA in 2D echocardiography (cut-off, 1.7; area under the curve, 0.98; CI, 0.97-0.98; P < .001) with a sensitivity of 96% and a specificity of 91%. CONCLUSION AND CLINICAL IMPORTANCE: The PV/PA is a simple and reproducible echocardiographic variable that increases with class of heart failure and may help discriminate dogs in CHF from asymptomatic dogs with DMVD. Additional studies are required to determine whether PV/PA might provide additional information in the integrated interpretation of Doppler-echocardiographic indices of left ventricular filling pressures and could be used for rapid assessment of CHF in dogs in a critical care setting. PMID- 26415643 TI - Capture myopathy in hooved mammals and human Takotsubo syndrome. PMID- 26415642 TI - A clinical research pathway towards developing new insights into cardiomyopathy. PMID- 26415641 TI - Adenoviral vector carrying glial cell-derived neurotrophic factor for direct gene therapy in comparison with human umbilical cord blood cell-mediated therapy of spinal cord injury in rat. AB - STUDY DESIGN: Experimental study. OBJECTIVE: To evaluate the treatment of spinal cord injury with glial cell-derived neurotrophic factor (GDNF) delivered using an adenoviral vector (AdV-GDNF group) in comparison with treatment performed using human umbilical cord blood mononuclear cells (UCB-MCs)-transduced with an adenoviral vector carrying the GDNF gene (UCB-MCs+AdV-GDNF group) in rat. SETTING: Kazan, Russian Federation. METHODS: We examined the efficacy of AdV-GDNF and UCB-MCs+AdV-GDNF therapy by conducting behavioral tests on the animals and morphometric studies on the spinal cord, performing immunofluorescence analyses on glial cells, investigating the survival and migration potential of UCB-MCs, and evaluating the expression of the recombinant GDNF gene. RESULTS: At the 30th postoperative day, equal positive locomotor recovery was observed after both direct and cell-based GDNF therapy. However, after UCB-MCs-mediated GDNF therapy, the area of preserved tissue and the number of spared myelinated fibers were higher than those measured after direct GDNF gene therapy. Moreover, we observed distinct changes in the populations of glial cells; expression patterns of the specific markers for astrocytes (GFAP, S100B and AQP4), oligodendrocytes (PDGFalphaR and Cx47) and Schwann cells (P0) differed in various areas of the spinal cord of rats treated with AdV-GDNF and UCB-MCs+AdV-GDNF. CONCLUSION: The differences detected in the AdV-GDNF and UCB-MCs+AdV-GDNF groups could be partially explained by the action of UCB-MCs. We discuss the insufficiency and the advantages of these two methods of GDNF gene delivery into the spinal cord after traumatic injury. PMID- 26415644 TI - Regulation of secondary metabolite production in the fungal tomato pathogen Cladosporium fulvum. AB - Cladosporium fulvum is a non-obligate biotrophic fungal tomato pathogen for which fifteen secondary metabolite (SM) gene clusters were previously identified in its genome. However, most of these SM biosynthetic pathways remain cryptic during growth in planta and in different in vitro conditions. The sole SM produced in vitro is the pigment cladofulvin. In this study, we attempted to activate cryptic pathways in order to identify new compounds produced by C. fulvum. For this purpose, we manipulated orthologues of the global regulators VeA, LaeA and HdaA known to regulate SM biosynthesis in other fungal species. In C. fulvum, deleting or over-expressing these regulators yielded no new detectable SMs. Yet, quantification of cladofulvin revealed that CfHdaA is an activator whilst CfVeA and CfLaeA seemed to act as repressors of cladofulvin production. In the wild type strain, cladofulvin biosynthesis was affected by the carbon source, with highest production under carbon limitation and traces only in presence of saccharose. Repression of cladofulvin production by saccharose was dependent on both CfVeA and CfLaeA. Deletion of CfVeA or CfLaeA caused production of sterile mycelia, whilst Deltacfhdaa deletion mutants sporulated, suggesting that cladofulvin production is not linked to asexual reproduction. Profiling the transcription of these regulators showed that CfHdaA-mediated regulation of cladofulvin production is independent of both CfVeA and CfLaeA. Our data suggest CfLaeA directly affects cladofulvin production whilst the effect of CfVeA is indirect, suggesting a role for CfLaeA outside of the Velvet complex. In conclusion, our results showed that regulation of SM production in C. fulvum is different from other fungi and indicate that manipulation of global regulators is not a universal tool to discover new fungal natural products. PMID- 26415645 TI - Temperature/pH Responsive Hydrogels Based on Poly(ethylene glycol) and Functionalized Poly(e-caprolactone) Block Copolymers for Controlled Delivery of Macromolecules. AB - PURPOSE: To assess the potential of triblock copolymers based on poly(ethylene glycol) (PEG) and functionalized poly(epsilon-caprolactone) as temperature/pH responsive gels for controlled delivery of macromolecules. METHODS: Poly(alpha carboxylate-co-alpha-benzylcarboxylate-epsilon-caprolactone)-PEG-poly(alpha carboxylate-co-alpha-benzylcarboxylate-epsilon-caprolactone) (PCBCL-PEG-PCBCL) was synthesized through ring opening polymerization of alpha-benzyl carboxylate epsilon-caprolactone by PEG, followed by 30% debenzylation of the lateral blocks. The effect of Tris buffer and pH on the sol-gel transition temperature of PCBCL PEG-PCBCL was assessed. The temperature/pH responsive release of tetramethylrhodamine-dextran (TMR-D) (10 and 40 kDa) from PCBCL-PEG-PCBCL was investigated. RESULTS: Replacement of water with Tris buffer reduced PCBCL-PEG PCBCL sol-gel transition temperature. Thermo-reversible hydrogels were only formed at pHs >= 5.0, but PCBCL-PEG-PCBCL transition temperature was not affected by pH above pH 5.0. In contrast to Pluronic F127 that released 100% of TMR-D within 2 h, PCBCL-PEG-PCBCL hydrogel controlled TMR-D release efficiently at pH = 7.4 and 37 degrees C (~27 and 11% TMRD 10 and 40 kDa release within 150 h, respectively). At 50 degrees C or pH = 9.0, TMR-D release was increased slightly, while at room temperature or pH = 5.0, no control over TMR-D release was observed by PCBCL-PEG-PCBCL hydrogel. CONCLUSION: PCBCL-PEG-PCBCL hydrogel provides depot release of macromolecules at physiological conditions. This release can be triggered through changes in the temperature or pH. PMID- 26415646 TI - Modulation of Cell-Mediated Immunity to Suppress High Fat Diet-Induced Obesity and Insulin Resistance. AB - PURPOSE: To assess the effect of immune modulators, cyclosporin A and fingolimod, on high fat diet-induced obesity and insulin resistance. METHODS: C57BL/6 mice were fed a high fat diet and injected intraperitoneally with cyclosporine A, fingolimod, or vehicle twice weekly for 15 weeks. Body weight and food intake were manually measured every other day. Glucose tolerance test, insulin sensitivity, and body composition were examined and compared between the control and the immune modulator treated animals. Tissue samples were collected at the end of the experiment and examined for serum biochemistry, histology, and mRNA levels of marker genes for inflammation, and glucose and lipid metabolism in white and brown adipose tissues and in the liver. RESULTS: Cyclosporine A and fingolimod suppressed high fat diet-induced weight gain, reduced hepatic fat accumulation, and improved insulin sensitivity. The beneficial effects are associated with altered expression of F4/80, Cd68, Il-6, Tnf-alpha, and Mcp-1 genes, which are involved in macrophage-related chronic inflammation in adipose and hepatic tissues. CONCLUSION: Immune modulation represents an important intervention for obesity and obesity-associated insulin resistance. PMID- 26415648 TI - Plic-1, a new target in repressing epileptic seizure by regulation of GABAAR function in patients and a rat model of epilepsy. AB - Dysfunction of gamma-aminobutyric acid A (GABAA) receptors (GABAARs) is a prominent factor affecting intractable epilepsy. Plic-1, an ubiquitin-like protein enriched in the inhibitory synapses connecting GABAARs and the ubiquitin protease system (UPS), plays a key role in the modification of GABAAR functions. However, the relationship between Plic-1 and epileptogenesis is not known. In the present study, we aimed to investigate Plic-1 levels in patients with temporal lobe epilepsy, as well as the role of Plic-1 in regulating onset and progression of epilepsy in animal models. We found that Plic-1 expression was significantly decreased in patients with epilepsy as well as pilocarpine- and pentylenetetrazol (PTZ)-induced rat epileptic models. Intrahippocampal injection of the PePalpha peptide, which disrupts Plic-1 binding to GABAARs, significantly shortened the latency of seizure onset, and increased the seizure severity and duration in these two epileptic models. Overexpressed Plic-1 through lentivirus transfection into a PTZ model resulted in a reduction in both seizure severity and generalized tonic-clonic seizure duration. Whole-cell clamp recordings revealed that the PePalpha peptide decreased miniature inhibitory postsynaptic currents (mIPSCs) whereas overexpressed Plic-1 increased mIPSCs in the pyramidal neurons of the hippocampus. These effects can be blocked by picrotoxin, a GABAAR inhibitor. Our results indicate that Plic-1 plays an important role in managing epileptic seizures by enhancing seizure inhibition through regulation of GABAARs at synaptic sites. PMID- 26415647 TI - Predicting Mouse Liver Microsomal Stability with "Pruned" Machine Learning Models and Public Data. AB - PURPOSE: Mouse efficacy studies are a critical hurdle to advance translational research of potential therapeutic compounds for many diseases. Although mouse liver microsomal (MLM) stability studies are not a perfect surrogate for in vivo studies of metabolic clearance, they are the initial model system used to assess metabolic stability. Consequently, we explored the development of machine learning models that can enhance the probability of identifying compounds possessing MLM stability. METHODS: Published assays on MLM half-life values were identified in PubChem, reformatted, and curated to create a training set with 894 unique small molecules. These data were used to construct machine learning models assessed with internal cross-validation, external tests with a published set of antitubercular compounds, and independent validation with an additional diverse set of 571 compounds (PubChem data on percent metabolism). RESULTS: "Pruning" out the moderately unstable / moderately stable compounds from the training set produced models with superior predictive power. Bayesian models displayed the best predictive power for identifying compounds with a half-life >=1 h. CONCLUSIONS: Our results suggest the pruning strategy may be of general benefit to improve test set enrichment and provide machine learning models with enhanced predictive value for the MLM stability of small organic molecules. This study represents the most exhaustive study to date of using machine learning approaches with MLM data from public sources. PMID- 26415649 TI - miR-21 promotes renal fibrosis in diabetic nephropathy by targeting PTEN and SMAD7. AB - The cytokine transforming growth factor (TGF)-beta1 plays a central role in diabetic nephropathy (DN) with data implicating the miRNA (miR) miR-21 as a key modulator of its prosclerotic actions. In the present study, we demonstrate data indicating that miR-21 up-regulation positively correlates with the severity of fibrosis and rate of decline in renal function in human DN. Furthermore, concomitant analyses of various models of fibrotic renal disease and experimental DN, confirm tubular miR-21 up-regulation. The fibrotic changes associated with increased miR-21 levels are proposed to include the regulation of TGF-beta1 mediated mothers against decapentaplegic homolog 3 (SMAD3)- and phosphoinositide 3-kinase (PI3K)-dependent signalling pathways via co-ordinated repression of mothers against decapentaplegic homolog 7 (SMAD7) and phosphatase and tensin homologue (PTEN) respectively. This represents a previously uncharacterized interaction axis between miR-21 and PTEN-SMAD7. Targeting of these proteins by miR-21 resulted in de-repression of the respective pathways as reflected by increases in SMAD3 and V-Akt murine thymoma viral oncogene homolog 1 (AKT) phosphorylation. Many of the changes typically induced by TGF-beta1, including phosphorylation of signalling mediators, were further enhanced by miR-21. Collectively, these data present a unified model for a key role for miR-21 in the regulation of renal tubular extracellular matrix (ECM) synthesis and accumulation and provide important insights into the molecular pathways implicated in the progression of DN. PMID- 26415650 TI - Assembly and Function of the Precursor B-Cell Receptor. AB - During early stages of development, precursor B lymphocytes express a characteristic type of antigen receptor known as the pre-B-cell receptor (pre BCR). This receptor differs from conventional BCRs in that it possesses a germ line-encoded surrogate light chain (SLC), which is associated with the signal transduction machinery via heavy chain (HC) proteins that have been generated by productive rearrangement of the immunoglobulin HC genes. The pre-BCR marks a key step of B-cell commitment, as it activates the B-cell-specific signaling cascade and mediates the selection, expansion, and differentiation of cells expressing a productively rearranged HC protein. Another difference between the pre-BCR and conventional BCR might be the initial event that triggers receptor activation, as the pre-BCR is activated in the absence of external ligands, while conventional BCRs require antigen for activation. Nonetheless, the pre-BCR downstream signaling cascade is largely similar to that of the BCR suggesting that the characteristic LC of the pre-BCR mediates important receptor interactions thereby providing distinctive, germ line-encoded features to the pre-BCR. In fact, the SLC enables the pre-BCR to act as a surrogate autoreactive receptor. Here, we outline the structure and function of the pre-BCR and how the autonomous signaling capacity might be a direct consequence of pre-BCR assembly. In addition to its role in early B-cell development, we discuss how the ordered activation of downstream signaling cascades enables the pre-BCR to activate seemingly opposing cellular programs such as proliferation and differentiation. PMID- 26415651 TI - Erratum to: The association between CYP1A1 genetic polymorphisms and coronary artery disease in the Uygur and Han of China. PMID- 26415652 TI - Structural comparison of O-antigen gene clusters of Legionella pneumophila and its application of a serogroup-specific multiplex PCR assay. AB - The Legionella pneumophila serogroups O1, O4, O6, O7, O10 and O13 are pathogenic strains associated with pneumonia. The surface O-antigen gene clusters of L. pneumophila serogroups O4, O6, O7, O10 and O13 were sequenced and analyzed, with the function annotated on the basis of homology to that of the genes of L. pneumophila serogroup O1 (L. pneumophila subsp. pneumophila str. Philadelphia 1). The gene locus of the six L. pneumophila serogroups contains genes of yvfE, neuABCD, pseA-like for nucleotide sugar biosynthesis, wecA for sugar transfer, and wzm as well as wzt for O-antigen processing. The detection of O-antigen genes allows the fine differentiation at species and serogroup level without the neccessity of nucleotide sequencing. The O-antigen-processing genes wzm and wzt, which were found to be distinctive for different for different serogroups, have been used as the target genes for the detection and identification of L. pneumophila strains of different O serogroups. In this report, a multiplex PCR assay based on wzm or wzt that diferentiates all the six serogroups by amplicon size was developed with the newly designed specific primer pairs for O1 and O7, and the specific primer pairs for O4, O6, O10, and O13 reported previously. The array was validated by analysis of 34 strains including 15 L. pneumophila O standard reference strains, eight reference strains of other Legionella non pneumophila species, six other bacterial species, and five L. pneumophila environmental isolates. The detection sensitivity was one ng genomic DNA. The accurate and sensitive assay is suitable for the identification and detection of strains of these serogroups in environmental and clinical samples. PMID- 26415653 TI - Detection of chlorine and bromine in free liquid from the sphenoid sinus as an indicator of seawater drowning. AB - We have investigated the usefulness of elemental analysis by energy-dispersive X ray spectroscopy (EDX) in the examination of free liquid from the sphenoid sinus of drowning victims. We detected both chlorine and bromine in liquid taken from the sphenoid sinus of seawater drowning victims. Because these elements were below the quantification limit in freshwater cases, we could easily distinguish seawater from freshwater drowning cases. Detection of these elements from the liquid in the sphenoid sinuses of drowning victims may be useful as a supportive measure for seawater drowning. PMID- 26415654 TI - With reference to the letter to the editor by Henssge (Leg Med (Tokyo). 2015 Jul 29. http://dx.doi.org/10.1016/j.legalmed.2015.05.005.): "'With reference to the article by Hubig et al.: Temperature based forensic death time estimation: The standard model in experimental test' (Legal Med 2015 XX)". PMID- 26415655 TI - Allele frequencies for 21 autosomal short tandem repeat loci obtained using GlobalFiler in a sample of 1501 individuals from the Japanese population. AB - Allele frequencies for 21 autosomal short tandem repeat loci (D3S1358, vWA, D16S539, CSF1PO, TPOX, D8S1179, D21S11, D18S51, D2S441, D19S433, TH01, FGA, D22S1045, D5S818, D13S317, D7S820, SE33, D10S1248, D1S1656, D12S391, and D2S1338) were obtained using the GlobalFiler kit from 1501 unrelated individuals sampled from the Japanese population. PMID- 26415656 TI - Vertical transport in graphene-hexagonal boron nitride heterostructure devices. AB - Research in graphene-based electronics is recently focusing on devices based on vertical heterostructures of two-dimensional materials. Here we use density functional theory and multiscale simulations to investigate the tunneling properties of single- and double-barrier structures with graphene and few-layer hexagonal boron nitride (h-BN) or hexagonal boron carbon nitride (h-BC2N). We find that tunneling through a single barrier exhibit a weak dependence on energy. We also show that in double barriers separated by a graphene layer we do not observe resonant tunneling, but a significant increase of the tunneling probability with respect to a single barrier of thickness equal to the sum of the two barriers. This is due to the fact that the graphene layer acts as an effective phase randomizer, suppressing resonant tunneling and effectively letting a double-barrier structure behave as two single-barriers in series. Finally, we use multiscale simulations to reproduce a current-voltage characteristics resembling that of a resonant tunneling diode, that has been experimentally observed in single barrier structure. The peak current is obtained when there is perfect matching between the densities of states of the cathode and anode graphene regions. PMID- 26415657 TI - Steroid Sulfatase Inhibitors Based on Phosphate and Thiophosphate Flavone Analogs. AB - A series of phosphate and thiophosphate flavone derivatives were synthesized and biologically evaluated in vitro for inhibition of steroid sulfatase (STS) activity. The described synthesis includes the straightforward preparation of 7 hydroxy-2-phenyl-4H-chromen-4-one 3a, 2-(4-fluorophenyl)-7-hydroxy-4H-chromen-4 one 3b, 7-hydroxy-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one 3c, 7-hydroxy-2 (p-tolyl)-4H-chromen-4-one 3d modified with different phosphate or thiophosphate moieties. The inhibitory properties of the synthesized compounds were tested against human placenta STS. Some of the novel STS inhibitors had good activities against STS. In particular, the bis-(4-oxo-2-(p-tolyl)-4H-chromen-7-yl) hydrogenthiophosphate, 6i had the most potent inhibitory effect with an IC50 value of 3.25 uM as compared to an IC50 value of 8.50 uM for the 2-(4 trifluoromethylphenyl)-chromen-4-one-7-O-sulfamate used as a reference. PMID- 26415658 TI - Complete genome sequence of Lactobacillus paracasei L9, a new probiotic strain with high lactic acid-producing capacity. AB - Lactobaillus paracasei L9 (CGMCC No. 9800) is a new strain with probiotic properties originating from healthy human intestine. Previous studies evidenced that the strain regulates immune modulation and contributes to the production of high amounts of lactic acid. The genome of L. paracasei L9 contains a circular 3076,437-bp chromosome, encoding 3044 CDSs, 15 rRNA genes and 59 tRNA genes. PMID- 26415659 TI - Complete genome sequence of Arthrobacter sp. ERGS1:01, a putative novel bacterium with prospective cold active industrial enzymes, isolated from East Rathong glacier in India. AB - We report the complete genome sequence of Arthrobacter sp. ERGS1:01, a novel bacterium which produces industrial enzymes at low temperature. East Rathong glacier in Sikkim Himalayas is untouched and unexplored for microbial diversity though it has a rich source of glaciers, alpine and meadows. Genome sequence has provided the basis for understanding its adaptation under harsh condition of Himalayan glacier, its ability to produce cold active industrial enzymes and has unlocked opportunities for microbial bioprospection from East Rathong glacier. PMID- 26415660 TI - Complete genome sequence of Photorhabdus temperata subsp. thracensis 39-8 T, an entomopathogenic bacterium for the improved commercial bioinsecticide. AB - Photorhabdus temperata subsp. thracensis 39-8(T), a symbiotic bacterium from an entomopathogenic nematode Heterorhabditis bacteriophora, is a novel bacterium harboring insect pathogenicity. Herein, we present the complete genome sequence of strain 39-8(T), which consists of one circular chromosome of 5,147,098 bp with a GC content of 44.10%. This genetic information will provide insights into biotechnological applications of the genus Photorhabdus producing insecticidal toxins, leading to the enhanced commercial bioinsecticide in agricultural pest control. PMID- 26415661 TI - CATCHing putative causative variants in consanguineous families. AB - BACKGROUND: Consanguinity is an important risk factor for autosomal recessive (AR) disorders. Extended genomic regions identical by descent (IBD) in the offspring of consanguineous parents give rise to recessive disorders with identical (homozygous) pathogenic variants in both alleles. However, many clinical phenotypes presenting in the offspring of consanguineous couples are still of unknown etiology. Nowadays advances in High Throughput Sequencing provide an excellent opportunity to achieve a molecular diagnosis or to identify novel candidate genes. RESULTS: To exploit all available information from the family structure we developed CATCH, an algorithm that combines genotyped SNPs of all family members for the optimal detection of Runs Of Homozygosity (ROH) and exome sequencing data from one affected individual to identify putative causative variants in consanguineous families. CONCLUSIONS: CATCH proved to be effective in discovering known or putative new causative variants in 43 out of 50 consanguineous families. Among them, novel variants causative of familial thrombocytopenia, sclerosis bone dysplasia and the first homozygous loss-of function mutation in FGFR3 in human causing severe skeletal deformities, tall stature and hearing impairment were identified. PMID- 26415662 TI - Phenothiazines as a solution for multidrug resistant tuberculosis: From the origin to present. AB - Historically, multiplicity of actions in synthetic compounds is a rule rather than exception. The science of non-antibiotics evolved in this background. From the antimalarial and antitrypanosomial dye methylene blue, chemically similar compounds, the phenothiazines, were developed. The phenothiazines were first recognised for their antipsychotic properties, but soon after their antimicrobial functions came to be known and then such compounds were designated as non antibiotics. The emergence of highly drug-resistant bacteria had initiated an urgent need to search for novel affordable compounds. Several phenothiazines awakened the interest among scientists to determine their antimycobacterial activity. Chlorpromazine, trifluoperazine, methdilazine and thioridazine were found to have distinct antitubercular action. Thioridazine took the lead as researchers repeatedly claimed its potentiality. Although thioridazine is known for its central nervous system and cardiotoxic side-effects, extensive and repeated in vitro and in vivo studies by several research groups revealed that a very small dose of thioridazine is required to kill tubercle bacilli inside macrophages in the lungs, where the bacteria try to remain and multiply silently. Such a small dose is devoid of its adverse side-effects. Recent studies have shown that the (-) thioridazine is a more active antimicrobial agent and devoid of the toxic side effects normally encountered. This review describes the possibilities of bringing down thioridazine and its (-) form to be combined with other antitubercular drugs to treat infections by drug-resistant strains of Mycobacterium tuberculosis and try to eradicate this deadly disease. PMID- 26415663 TI - Combined use of a new SNP-based assay and multilocus SSR markers to assess genetic diversity of Xylella fastidiosa subsp. pauca infecting citrus and coffee plants. AB - Two haplotypes of Xylella fastidiosa subsp. pauca (Xfp) that correlated with their host of origin were identified in a collection of 90 isolates infecting citrus and coffee plants in Brazil, based on a single-nucleotide polymorphism in the gyrB sequence. A new single-nucleotide primer extension (SNuPE) protocol was designed for rapid identification of Xfp according to the host source. The protocol proved to be robust for the prediction of the Xfp host source in blind tests using DNA from cultures of the bacterium, infected plants, and insect vectors allowed to feed on Xfp-infected citrus plants. AMOVA and STRUCTURE analyses of microsatellite data separated most Xfp populations on the basis of their host source, indicating that they were genetically distinct. The combined use of the SNaPshot protocol and three previously developed multilocus SSR markers showed that two haplotypes and distinct isolates of Xfp infect citrus and coffee in Brazil and that multiple, genetically different isolates can be present in a single orchard or infect a single tree. This combined approach will be very useful in studies of the epidemiology of Xfp-induced diseases, host specificity of bacterial genotypes, the occurrence of Xfp host jumping, vector feeding habits, etc., in economically important cultivated plants or weed host reservoirs of Xfp in Brazil and elsewhere. PMID- 26415665 TI - Use of E-beam radiation to eliminate Listeria monocytogenes from surface mould cheese. AB - Camembert and Brie soft cheese varieties were subjected to E-beam irradiation as a sanitation treatment. The effects of treatments on microbiota and selected physicochemical properties were also studied. The absorbed doses required to meet the food safety objective (FSO) according to EU and USDA criteria for Listeria monocytogenes were 1.27 and 2.59 kGy, respectively. The bacterial load, mainly lactic acid bacteria, was reduced by the treatment but injured cells were recovered during storage at 14 degrees C. The radiation treatment gave rise to negligible changes in the pH and water activity at doses required to achieve microbial safety. PMID- 26415664 TI - Strong correlation between the antifungal effect of amphotericin B and its inhibitory action on germ-tube formation in a Candida albicans URA+ strain. AB - The hypothetical capacity of amphotericin B to suppress the formation of germ tubes, which is the first step of yeast-to-hypha conversion in Candida albicans, has been investigated in the wild-type strain CEY.1 (CAI.4-URA+). Exponential cells exposed to concentrations of amphotericin B below or around the MIC90, exhibited a weak reduction in the percentage of human serum-induced germ-tube formation at 37oC compared with a non-exposed control. However, the dimorphic transition was drastically suppressed after addition of potentially lethal doses of amphotericin B, which also caused severe cell killing. In contrast, an identical experimental approach carried out with the fungistatic compound 5 fluorocytosine had no significant effect on the level of the germ-tube formation. Together, these results strongly point to a close correlation between the fungicidal action of amphotericin B and its ability to impair morphogenetic conversion in C. albicans. PMID- 26415666 TI - Solar water disinfection (SODIS): Impact on hepatitis A virus and on a human Norovirus surrogate under natural solar conditions. AB - This study evaluates the effectiveness of solar water disinfection (SODIS) in the reduction and inactivation of hepatitis A virus (HAV) and of the human Norovirus surrogate, murine Norovirus (MNV-1), under natural solar conditions. Experiments were performed in 330 ml polyethylene terephthalate (PET) bottles containing HAV or MNV-1 contaminated waters (10(3) PFU/ml) that were exposed to natural sunlight for 2 to 8 h. Parallel experiments under controlled temperature and/or in darkness conditions were also included. Samples were concentrated by electropositive charged filters and analysed by RT-real time PCR (RT-qPCR) and infectivity assays. Temperature reached in bottles throughout the exposure period ranged from 22 to 40oC. After 8 h of solar exposure (cumulative UV dose of ~828 kJ/m2 and UV irradiance of ~20 kJ/l), the results showed significant (P<0.05) reductions from 4.0 (+/-0.56)x10(4) to 3.15 (+/-0.69)x10(3) RNA copies/100ml (92.1%, 1.1 log) for HAV and from 5.91 (+/-0.59)x10(4) to 9.24 (+/-3.91)x10(3) RNA copies/100 ml (84.4%, 0.81 log) for MNV-1. SODIS conditions induced a loss of infectivity between 33.4% and 83.4% after 4 to 8 h in HAV trials, and between 33.4% and 66.7% after 6 h to 8 h in MNV-1 trials. The results obtained indicated a greater importance of sunlight radiation over the temperature as the main factor for viral reduction. PMID- 26415667 TI - Increasing antibiotic resistance in preservative-tolerant bacterial strains isolated from cosmetic products. AB - To ensure the microbiological quality, consumer safety and organoleptic properties of cosmetic products, manufacturers need to comply with defined standards using several preservatives and disinfectants. A drawback regarding the use of these preservatives is the possibility of generating cross insusceptibility to other disinfectants or preservatives, as well as cross resistance to antibiotics. Therefore, the objective of this study was to understand the adaptive mechanisms of Enterobacter gergoviae, Pseudomonas putida and Burkholderia cepacia that are involved in recurrent contamination in cosmetic products containing preservatives. Diminished susceptibility to formaldehyde donors was detected in isolates but not to other preservatives commonly used in the cosmetics industry, although increasing resistance to different antibiotics (beta-lactams, quinolones, rifampicin, and tetracycline) was demonstrated in these strains when compared with the wild-type strain. The outer membrane protein modifications and efflux mechanism activities responsible for the resistance trait were evaluated. The development of antibiotic-resistant microorganisms due to the selective pressure from preservatives included in cosmetic products could be a risk for the emergence and spread of bacterial resistance in the environment. Nevertheless, the large contribution of disinfection and preservation cannot be denied in cosmetic products. PMID- 26415668 TI - Properties of Lactobacillus reuteri chitosan-calcium-alginate encapsulation under simulated gastrointestinal conditions. AB - The protective effects of encapsulation on the survival of Lactobacillus reuteri and the retention of the bacterium's probiotic properties under simulated gastrointestinal conditions were investigated. Viable counts and the remaining probiotic properties of calcium (Ca)-alginate encapsulated (A group), chitosan-Ca alginate encapsulated (CA group), and unencapsulated, free L. reuteri (F group) were determined. Encapsulation improved the survival of L. reuteri subjected to simulated gastrointestinal conditions, with the greatest protective effect achieved in the CA group. The degree of cell membrane injury increased with increasing bile salt concentrations at constant pH, but the extent of injury was less in the encapsulated than in the free cells. Adherence rates were, in descending order: CA (0.524%)>A (0.360%)>F (0.275%). Lactobacillus reuteri cells retained their antagonistic activity toward Listeria monocytogenes even after incubation of the lactobacilli under simulated gastrointestinal conditions. Displacement of the pathogen by cells released from either of the encapsulation matrices was higher than that by free cells. The safety of L. reuteri was demonstrated in an in vitro invasion assay. PMID- 26415669 TI - Pulmonary sarcoidosis is associated with high-level inducible co-stimulator (ICOS) expression on lung regulatory T cells--possible implications for the ICOS/ICOS-ligand axis in disease course and resolution. AB - Sarcoidosis is a granulomatous inflammatory disorder of unknown aetiology. The increased frequency of activated lung CD4(+) T cells with a T helper type 1 (Th1) cytokine profile in sarcoidosis patients is accompanied by a reduced proportion and/or impaired function of regulatory T cells (Tregs ). Here we evaluated the expression of the inducible co-stimulator (ICOS) on lung and blood CD4(+) T cell subsets in sarcoidosis patients with different prognosis, by flow cytometry. Samples from the deep airways were obtained by bronchoalveolar lavage (BAL). We show that Tregs from the inflamed lung of sarcoidosis patients were characterized by a unique ICOS(high) phenotype. High-level ICOS expression was restricted to Tregs from the inflamed lung and was absent in blood Tregs of sarcoidosis patients as well as in lung and blood Tregs of healthy volunteers. In addition, lung Tregs exhibited increased ICOS expression compared to sarcoid-specific lung effector T cells. Strikingly, ICOS expression on Tregs was in particularly high in the lungs of Lofgren's syndrome (LS) patients who present with acute disease which often resolves spontaneously. Moreover, blood monocytes from LS patients revealed increased ICOS-L levels compared to healthy donors. Sarcoidosis was associated with a shift towards a non-classical monocyte phenotype and the ICOS L(high) phenotype was restricted to this particular monocyte subset. We propose a potential implication of the ICOS/ICOS-L immune-regulatory axis in disease activity and resolution and suggest to evaluate further the suitability of ICOS as biomarker for the prognosis of sarcoidosis. PMID- 26415670 TI - Investigating the influence of KIBRA and CLSTN2 genetic polymorphisms on cross sectional and longitudinal measures of memory performance and hippocampal volume in older individuals. AB - The variability of episodic memory decline and hippocampal atrophy observed with increasing age may partly be explained by genetic factors. KIBRA (kidney and brain expressed protein) and CLSTN2 (calsyntenin 2) are two candidate genes previously linked to episodic memory performance and volume of the hippocampus, a key memory structure. However, whether polymorphisms in these two genes also influence age-related longitudinal memory decline and hippocampal atrophy is still unknown. Using data from two independent cohorts, the Sydney Memory and Ageing Study and the Older Australian Twins Study, we investigated whether the KIBRA and CLSTN2 genetic polymorphisms (rs17070145 and rs6439886) are associated with episodic memory performance and hippocampal volume in older adults (65-90 years at baseline). We were able to examine these polymorphisms in relation to memory and hippocampal volume using cross-sectional data and, more importantly, also using longitudinal data (2 years between testing occasions). Overall we did not find support for an association of KIBRA either alone or in combination with CLSTN2 with memory performance or hippocampal volume, nor did variation in these genes influence longitudinal memory decline or hippocampal atrophy in two cohorts of older adults. PMID- 26415672 TI - Nanoparticle shape anisotropy and photoluminescence properties: Europium containing ZnO as a Model Case. AB - The precise control over electronic and optical properties of semiconductor (SC) materials is pivotal for a number of important applications like in optoelectronics, photocatalysis or in medicine. It is well known that the incorporation of heteroelements (doping as a classical case) is a powerful method for adjusting and enhancing the functionality of semiconductors. Independent from that, there already has been a tremendous progress regarding the synthesis of differently sized and shaped SC nanoparticles, and quantum-size effects are well documented experimentally and theoretically. Whereas size and shape control of nanoparticles work fairly well for the pure compounds, the presence of a heteroelement is problematic because the impurities interfere strongly with bottom up approaches applied for the synthesis of such particles, and effects are even stronger, when the heteroelement is aimed to be incorporated into the target lattice for chemical doping. Therefore, realizing coincident shape control of nanoparticle colloids and their doping still pose major difficulties. Due to a special mechanism of the emulsion based synthesis method presented here, involving a gelation of emulsion droplets prior to crystallization of shape anisotropic ZnO nanoparticles, heteroelements can be effectively entrapped inside the lattice. Different nanocrystal shapes such as nanorods, -prisms, -plates, and -spheres can be obtained, determined by the use of certain emulsification agents. The degree of morphologic alterations depends on the type of incorporated heteroelement M(n+), concentration, and it seems that some shapes are more tolerant against doping than others. Focus was then set on the incorporation of Eu(3+) inside the ZnO particles, and it was shown that nanocrystal shape and aspect ratios could be adjusted while maintaining a fixed dopant level. Special PL properties could be observed implying energy transfer from ZnO excited near its band-gap (3.3 eV) to the Eu(3+) states mediated by defect luminescence of the nanoparticles. Indications for an influence of shape on photoluminescence (PL) properties were found. Finally, rod-like Eu@ZnO colloids were used as tracers to investigate their uptake into biological samples like HeLa cells. The PL was sufficient for identifying green and red emission under visible light excitation. PMID- 26415671 TI - Error-related brain activity dissociates hoarding disorder from obsessive compulsive disorder. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is associated with an abnormally large error-related negativity (ERN), an electrophysiological measure of error monitoring in response to performance errors, but it is unclear if hoarding disorder (HD) also shows this abnormality. This study aimed to determine whether the neurophysiological mechanisms underlying error monitoring are similarly compromised in HD and OCD. METHOD: We used a visual flanker task to assess ERN in response to performance errors in 14 individuals with HD, 27 with OCD, 10 with HD+OCD, and 45 healthy controls (HC). Age-corrected performance and ERN amplitudes were examined using analyses of variance and planned pairwise group comparisons. RESULTS: A main effect of hoarding on ERN (p = 0.031) was observed, indicating ERN amplitudes were attenuated in HD relative to non-HD subjects. A group * age interaction effect on ERN was also evident. In HD-positive subjects, ERN amplitude deficits were significantly greater in younger individuals (r = 0.479, p = 0.018), whereas there were no significant ERN changes with increasing age in OCD and HC participants. CONCLUSIONS: The reduced ERN in HD relative to OCD and HC provides evidence that HD is neurobiologically distinct from OCD, and suggests that deficient error monitoring may be a core pathophysiological feature of HD. This effect was particularly prominent in younger HD participants, further suggesting that deficient error monitoring manifests most strongly early in the illness course and/or in individuals with a relatively early illness onset. PMID- 26415673 TI - The relationships between illness and treatment perceptions with adherence to diabetes self-care: A comparison between Arabic-speaking migrants and Caucasian English-speaking patients. AB - AIMS: To compare illness and treatment perceptions between Arabic-speaking immigrants and Caucasian English-speaking people with type 2 diabetes, and explore the relationships between these beliefs and adherence to self-care activities. METHODS: A cross-sectional study was conducted in healthcare settings with large Arabic populations in metropolitan and rural Victoria, Australia. Adherence to self-care activities, illness and treatment perceptions, and clinical data were recorded. Bivariate associations for continuous normally distributed variables were tested with Pearson's correlation. Non-parametric data were tested using Spearman's rank correlation coefficient. RESULTS: 701 participants were recruited; 392 Arabic-speaking participants (ASPs) and 309 English-speaking participants (ESPs). There were significant relationships between participants' illness and treatment perceptions and adherence to diabetes self-care activities. ASPs' negative beliefs about diabetes were strongly and significantly correlated with poorer adherence to diet recommendations, exercise, blood glucose testing and foot care. ASPs were significantly less adherent to all aspects of diabetes self-care compared with ESPs: dietary behaviours (P=<0.01; 95% confidence interval (CI)=-1.17, -0.84), exercise and physical activity (P=<0.001, 95% CI -1.14, -0.61), blood glucose testing (P=<0.001) and foot-care (P=<0.001). 52.8% of ASPs were sceptical about prescribed diabetes treatment compared with only 11.2% of the ESPs. 88.3% of ASPs were non-adherent to prescribed medication, compared with 45.1% of ESPs. CONCLUSIONS: Arabic-speaking migrants' illness and treatment perceptions were significantly different from the English-speaking group. There is a pressing need to develop new innovative interventions that deliver much-needed improvements in adherence to self-care activities and key health outcomes. PMID- 26415674 TI - Many parallels between itch and pain research. PMID- 26415675 TI - Emu oil decreases atherogenic plaque formation in cafeteria diet-induced obese rats. AB - BACKGROUND: Atherosclerosis-induced coronary heart disease - caused by elevated levels of low-density lipoproteins (LDL) and inflammation - is one of the most prevalent diseases. Monounsaturated fatty acids are reported to prevent atherosclerosis; emu oil is a rich source of monounsaturated fatty acid, and we hypothesize that emu oil supplementation could lower inflammation and prevent atherosclerosis in diet-induced obese (DIO) animals. Male Wistar rats were randomly divided into five groups (n = 6), and fed with normal diet (chow pellet; ND), or with cafeteria diet (CD), or with CD along with emu oil supplementation at three different doses: ED1 (2 mL), ED2 (4 mL) and ED3 (8 mL) kg(-1) body weight (BW), respectively. RESULTS: After 12 weeks, the animals were sacrificed and serum was analysed for measuring lipid profile, C-reactive proteins, testosterone and luteinizing hormone. Histopathological studies were performed to observe atherogenic changes in thoracic aorta. Restoration of altered lipid and hormonal profiles, and inhibition of atherogenic changes in thoracic aorta, were observed with supplementation of emu oil, confirming its anti-atherosclerotic activity. CONCLUSION: The high content of oleic acid in emu oil could have orchestrated - either solely or in combination with linoleic and linolenic acids causing the upregulation of testosterone biosynthesis and inhibition of atheromatous plaque formation in diet-induced obese animals. (c) 2015 Society of Chemical Industry. PMID- 26415676 TI - Next-generation-sequencing-based identification of familial hypercholesterolemia related mutations in subjects with increased LDL-C levels in a latvian population. AB - BACKGROUND: Familial hypercholesterolemia (FH) is one of the commonest monogenic disorders, predominantly inherited as an autosomal dominant trait. When untreated, it results in early coronary heart disease. The vast majority of FH remains undiagnosed in Latvia. The identification and early treatment of affected individuals remain a challenge worldwide. Most cases of FH are caused by mutations in one of four genes, APOB, LDLR, PCSK9, or LDLRAP1. The spectrum of disease-causing variants is very diverse and the variation detection panels usually used in its diagnosis cover only a minority of the disease-causing gene variants. However, DNA-based tests may provide an FH diagnosis for FH patients with no physical symptoms and with no known family history of the disease. Here, we evaluate the use of targeted next-generation sequencing (NGS) to identify cases of FH in a cohort of patients with coronary artery disease (CAD) and individuals with abnormal low-density lipoprotein-cholesterol (LDL-C) levels. METHODS: We used targeted amplification of the coding regions of LDLR, APOB, PCSK9, and LDLRAP1, followed by NGS, in 42 CAD patients (LDL-C, 4.1-7.2 mmol/L) and 50 individuals from a population-based cohort (LDL-C, 5.1-9.7 mmol/L). RESULTS: In total, 22 synonymous and 31 nonsynonymous variants, eight variants in close proximity (10 bp) to intron-exon boundaries, and 50 other variants were found. We identified four pathogenic mutations (p.(Arg3527Gln) in APOB, and p.(Gly20Arg), p.(Arg350*), and c.1706-10G > A in LDLR) in seven patients (7.6 %). Three possible pathogenic variants were also found in four patients. CONCLUSION: NGS-based methods can be used to detect FH in high-risk individuals when they do not meet the defined clinical criteria. PMID- 26415677 TI - Online technology use in physiotherapy teaching and learning: a systematic review of effectiveness and users' perceptions. AB - BACKGROUND: The use of online technologies in health professionals' education, including physiotherapy, has been advocated as effective and well-accepted tools for enhancing student learning. The aim of this study was to critically review the effectiveness, and user perceptions of online technology for physiotherapy teaching and learning. METHODS: Following databases were systematically searched on the 31(st) of August 2013 for articles describing implementation of online technologies into physiotherapy teaching and learning: ERIC, CINAHL, Web of Science, Academic search complete, ProQuest Nursing and Allied Health Source, Medline, Embase, and Scopus. No language, design or publishing date restrictions were imposed. Risk of bias was assessed using the 2011 Mixed Methods Appraisal Tool checklist (MMAT). RESULTS: A total of 4133 articles were retrieved; 22 articles met the inclusion criteria and were accepted for final analysis: 15 on the effectiveness of technology, and 14 on users' perceptions. Included studies used three designs: case study (14 articles), controlled trial (3), and randomized controlled trial (5). Studies investigated both pre-registration physiotherapy students (1523) and physiotherapy professionals (171). The quality of studies ranged from 67 to 100 % on the MMAT checklist which can be considered moderate to excellent. More than half of the studies (68 %) received scores greater than 80 %. Studies typically investigated websites and discussion boards. The websites are effective in enhancing practical skills performance, and discussion boards in knowledge acquisition, as well as in development of critical and reflective thinking. Students' perceptions of the use of websites were mostly positive, providing students with entertaining, easy accessible resources. Perceived barriers to the use of websites included difficulties with internet connection, insufficiently interactive material, or personal preference for paper based materials. Discussion boards were perceived as deepening students' thinking and facilitating reflection, allowing for learning from multiple perspectives, and providing easy communication and support. CONCLUSIONS: The results of this review suggest that online technologies (i.e., websites and discussion boards) have many benefits to offer for physiotherapy teaching and learning; There was minimal evidence of barriers for the use of online technologies, however, addressing the identified ones could enhance adherence to use of online technologies in health professionals' education. PMID- 26415678 TI - Angiotensin-converting enzyme inhibitor induced angioedema: predictors of mechanical ventilation and treatment approaches. PMID- 26415679 TI - Ventilatory support of patients with sepsis or septic shock in resource-limited settings. PMID- 26415680 TI - Predicting fluid responsiveness in 100 critically ill children: the effect of baseline contractility. AB - PURPOSE: Fluid overload is a risk factor for poor outcome in intensive care; thus volume loading should be tailored towards patients who are likely to increase stroke volume. We aimed to evaluate the paediatric predictive ability (stroke volume increase of at least 15 % after fluid bolus) of novel and established volumetric and dynamic haemodynamic variables, and assess the influence of baseline contractility on response. METHODS: We assessed 142 volume loading episodes (10 ml/kg crystalloid) in 100 critically ill ventilated children, median (interquartile) weight 10 (5.6-15) kg. Eight advanced haemodynamic variables were assessed using two commercially available devices. Systemic ventricular contractility was measured as the maximum rate of systolic arterial pressure rise. RESULTS: Overall, predictive ability was poor, with volumetric variables performing better than dynamic (area under receiver operating characteristic curves ranged from 0.53 to 0.67). The best predictor was total end-diastolic volume index; however, this did not increase in a consistent way with volume loading, with change post volume being weakly related to baseline values (r = 0.19, p = 0.02). A multivariable model quantified the importance of contractility in stroke volume response. Children with high baseline contractility (>=75th centile) typically achieved a positive stroke volume response when end-diastolic volume values changed by 10-15 ml/m(2.6), whereas patients with low contractility (<=25th centile) typically required end-diastolic volume increases of 35-40 ml/m(2.6). CONCLUSIONS: Current paediatric predictors of volume response perform poorly; prediction may be improved if baseline contractility is taken into account. PMID- 26415681 TI - Understanding coma in bacterial meningitis. PMID- 26415683 TI - Novel non-local effects in three-terminal hybrid devices with quantum dot. AB - We predict non-local effect in the three-terminal hybrid device consisting of the quantum dot (QD) tunnel coupled to two normal and one superconducting reservoirs. It manifests itself as the negative non-local resistance and results from the competition between the ballistic electron transfer (ET) and the crossed Andreev scattering (CAR). The effect is robust both in the linear and non-linear regimes. In the latter case the screening of charges and the long-range interactions play significant role. We show that sign change of the non-local conductance depends on the subgap Shiba/Andreev states, and it takes place even in absence of the Coulomb interactions. The effect is large and can be experimentally verified using the four probe setup. Since the induced non-local voltage changes sign and magnitude upon varying the gate potential and/or coupling of the quantum dot to the superconducting lead, such measurement could hence provide a controlled and precise method to determine the positions of the Shiba/Andreev states. Our predictions ought to be contrasted with non-local effects observed hitherto in the three-terminal planar junctions where the residual negative non-local conductance has been observed at large voltages, related to the Thouless energy of quasiparticles tunneling through the superconducting slab. PMID- 26415682 TI - Cytomegalovirus reactivation and mortality in patients with acute respiratory distress syndrome. AB - PURPOSE: Cytomegalovirus (CMV) reactivation occurs frequently in patients with the acute respiratory distress syndrome (ARDS) and has been associated with increased mortality. However, it remains unknown whether this association represents an independent risk for poor outcome. We aimed to estimate the attributable effect of CMV reactivation on mortality in immunocompetent ARDS patients. METHODS: We prospectively studied immunocompetent ARDS patients who tested seropositive for CMV and remained mechanically ventilated beyond day 4 in two tertiary intensive care units in the Netherlands from 2011 to 2013. CMV loads were determined in plasma weekly. Competing risks Cox regression was used with CMV reactivation status as a time-dependent exposure variable. Subsequently, in sensitivity analyses we adjusted for the evolution of disease severity until onset of reactivation using marginal structural modeling. RESULTS: Of 399 ARDS patients, 271 (68%) were CMV seropositive and reactivation occurred in 74 (27%) of them. After adjustment for confounding and competing risks, CMV reactivation was associated with overall increased ICU mortality (adjusted subdistribution hazard ratio (SHR) 2.74, 95% CI 1.51-4.97), which resulted from the joint action of trends toward an increased mortality rate (direct effect; cause specific hazard ratio (HR) 1.58, 95% CI 0.86-2.90) and a reduced successful weaning rate (indirect effect; cause specific HR 0.83, 95% CI 0.58-1.18). These associations remained in sensitivity analyses. The population-attributable fraction of ICU mortality was 23% (95% CI 6-41) by day 30 (risk difference 4.4, 95% CI 1.1-7.9). CONCLUSION: CMV reactivation is independently associated with increased case fatality in immunocompetent ARDS patients who are CMV seropositive. PMID- 26415684 TI - Unmet needs: relevance to medical technology innovation? AB - This paper describes and discusses the role of unmet needs in the innovation of new medical technologies using the National Institute for Health Research Devices for Dignity (D4D) Healthcare Technology Co-operative as a case study. It defines an unmet need, providing a spectrum of classification and discusses the benefits and the challenges of identifying unmet need and its influence on the innovation process. The process by which D4D has captured and utilized unmet needs to drive technology innovation is discussed and examples given. It concludes by arguing that, despite the challenges, defining and reviewing unmet need is a fundamental factor in the success of medical technology innovation. PMID- 26415685 TI - Unsaturated but not saturated fatty acids induce transcriptional regulation of CCL2 in pancreatic acini. A potential role in acute pancreatitis. PMID- 26415687 TI - Is there any substrate that is better than Ir(1 0 0) for diamond nucleation? AB - The initial nucleation of adsorbed carbon (-C) and hydrocarbon groups (-CH,-C2H2, CH2 and -CH3) on Ir, Pt, Au, Rh, and Co(1 0 0) surfaces are investigated for diamond heteroepitaxial. It is revealed that the carbon-hydrogen ratios of the adsorbed species play a key role: The relative stabilities of these species vary while the coverage increases; at full coverage, only -C2H2 is favorable on the surface. The Ir(1 0 0) surface is unique: it binds with the -C2H2 the most strongly. The study not only answers why Ir(1 0 0) is by far the best substrate for diamond heteroepitaxy, but also points out the searching direction for even better substrate materials. PMID- 26415688 TI - Antibiotic dose optimization in critically ill patients. AB - The judicious use of existing antibiotics is essential for preserving their activity against infections. In the era of multi-drug resistance, this is of particular importance in clinical areas characterized by high antibiotic use, such as the ICU. Antibiotic dose optimization in critically ill patients requires sound knowledge not only of the altered physiology in serious infections - including severe sepsis, septic shock and ventilator-associated pneumonia - but also of the pathogen-drug exposure relationship (i.e. pharmacokinetic/pharmacodynamic index). An important consideration is the fact that extreme shifts in organ function, such as those seen in hyperdynamic patients or those with multiple organ dysfunction syndrome, can have an impact upon drug exposure, and constant vigilance is required when reviewing antibiotic dosing regimens in the critically ill. The use of continuous renal replacement therapy and extracorporeal membrane oxygenation remain important interventions in these patients; however, both of these treatments can have a profound effect on antibiotic exposure. We suggest placing emphasis on the use of therapeutic drug monitoring and dose individualization when optimizing therapy in these settings. PMID- 26415686 TI - Imaging disulfide dinitroxides at 250 MHz to monitor thiol redox status. AB - Measurement of thiol-disulfide redox status is crucial for characterization of tumor physiology. The electron paramagnetic resonance (EPR) spectra of disulfide linked dinitroxides are readily distinguished from those of the corresponding monoradicals that are formed by cleavage of the disulfide linkage by free thiols. EPR spectra can thus be used to monitor the rate of cleavage and the thiol redox status. EPR spectra of (1)H,(14)N- and (2)H,(15)N-disulfide dinitroxides and the corresponding monoradicals resulting from cleavage by glutathione have been characterized at 250 MHz, 1.04 GHz, and 9 GHz and imaged by rapid-scan EPR at 250 MHz. PMID- 26415689 TI - Commonness, rarity, and intraspecific variation in traits and performance in tropical tree seedlings. AB - One of the few rules in ecology is that communities are composed of many rare and few common species. Trait-based investigations of abundance distributions have generally focused on species-mean trait values with mixed success. Here, using large tropical tree seedling datasets in China and Puerto Rico, we take an alternative approach that considers the magnitude of intraspecific variation in traits and growth as it relates to species abundance. We find that common species are less variable in their traits and growth. Common species also occupy core positions within community trait space indicating that they are finely tuned for the available conditions. Rare species are functionally peripheral and are likely transients struggling for success in the given environment. The work highlights the importance of considering intraspecific variation in trait-based ecology and demonstrates asymmetry in the magnitude of intraspecific variation among species is critical for understanding of how traits are related to abundance. PMID- 26415690 TI - Cardiolipin metabolism and its causal role in the etiology of the inherited cardiomyopathy Barth syndrome. AB - Cardiolipin (CL) is a phospholipid with many unique characteristics. CL is synthesized in the mitochondria and resides almost exclusively within the mitochondrial inner membrane. Unlike most phospholipids that have two fatty acyl chains, CL possesses four fatty acyl chains resulting in unique biophysical characteristics that impact several biological processes including membrane fission and fusion. In addition, several proteins directly bind CL including proteins within the electron transport chain, the ADP/ATP carrier, and proteins that mediate mitophagy. Tafazzin is an enzyme that remodels saturated fatty acyl chains within CL to unsaturated fatty acyl chains, loss of function mutations in the TAZ gene encoding tafazzin are causal for the inherited cardiomyopathy Barth syndrome. Cells from Barth syndrome patients as well as several models of Barth have reduced mitochondrial functions including impaired electron transport chain function and increased reactive oxygen species (ROS) production. Mitochondria in cells from Barth syndrome patients, as well as several model organism mimics of Barth syndrome, are large and lack cristae consistent with the recently described role of CL participating in the generation of mitochondrial membrane contact sites. Cells with an inactive TAZ gene have also been shown to have a decreased capacity to undergo mitophagy when faced with stresses such as increased ROS or decreased mitochondrial quality control. This review describes CL metabolism and how defects in CL metabolism cause Barth syndrome, the etiology of Barth syndrome, and known modifiers of Barth syndrome phenotypes some of which could be explored for their amelioration of Barth syndrome in higher organisms. PMID- 26415692 TI - Suicide attempts in major depressive episode: evidence from the BRIDGE-II-Mix study. AB - OBJECTIVES: The Bipolar Disorders: Improving Diagnosis, Guidance, and Education (BRIDGE-II-Mix) study aimed to estimate the frequency of mixed states in patients with a major depressive episode (MDE) according to different definitions and to compare their clinical validity, looking into specific features such as suicidality. METHODS: A total of 2,811 subjects were enrolled in this multicenter cross-sectional study. Psychiatric symptoms, and sociodemographic and clinical variables were collected. The analysis compared the characteristics of patients with MDE with (MDE-SA group) and without (MDE-NSA) a history of suicide attempts. RESULTS: The history of suicide attempts was registered in 628 patients (22.34%). In the MDE-SA group, women (72.5%, p = 0.028), (hypo)mania in first-degree relatives (20.5%, p < 0.0001), psychotic features (15.1%, p < 0.0001), and atypical features (9.2%, p = 0.009) were more prevalent. MDE-SA patients' previous responses to treatment with antidepressants included more (hypo)manic switches [odds ratio (OR) = 1.97, 95% confidence interval (CI): 1.58-2.44, p < 0.0001], treatment resistance (OR = 2.07, 95% CI: 1.72-2.49, p < 0.0001), mood lability (OR = 1.98, 95% CI: 1.65-2.39, p < 0.0001), and irritability (OR = 1.80, 95% CI: 1.48-2.17, p < 0.0001). Multivariate analysis evidenced that risky behavior, psychomotor agitation and impulsivity, and borderline personality and substance use disorders were the variables most frequently associated with previous suicide attempts. In the MDE-SA group, 75 patients (11.9%) fulfilled Diagnostic and Statistical Manual (DSM)-5 criteria for MDE with mixed features, and 250 patients (39.8%) fulfilled research-based diagnostic criteria for a mixed depressive episode. CONCLUSIONS: Important differences between MDE-SA and MDE-NSA patients have emerged. Early identification of symptoms such as risky behavior, psychomotor agitation, and impulsivity in patients with MDE, and treatment of mixed depressive states could represent a major step in suicide prevention. PMID- 26415693 TI - Evaluation of mass drug administration in the program to control imported lymphatic filariasis in Thailand. AB - BACKGROUND: Migration plays a major role in the emergence and resurgence of lymphatic filariasis (LF) in many countries. Because of the high prevalence of Imported Bancroftian Filariasis (IBF) caused by nocturnally periodic Wuchereria bancrofti and the intensive movement of immigrant workers from endemic areas, Thailand has implemented two doses of 6 mg/kg diethylcarbamazine (DEC) with interval of 6 months to prevent IBF. In areas where immigrants are very mobile, the administration of DEC may be compromised. This study aimed to evaluate DEC administration and its barriers in such areas. METHODS: A cross-sectional study with two-stage stratified cluster sampling was conducted. We selected Myanmar immigrants aged >18 years from factory and fishery areas of Samut Sakhon Province for interview with a structured questionnaire. We also interviewed health personnel regarding the functions of the LF program and practice of DEC delivery among immigrants. Associations were measured by multiple logistic regression, at P <0.05. RESULTS: DEC coverage among the immigrants was 75 %, below the national target. All had received DEC only once during health examinations at general hospitals for work permit renewals. None of the health centers in each community provided DEC. Significant barriers to DEC access included being undocumented (adjusted OR = 74.23; 95 % CI = 26.32-209.34), unemployed (adjusted OR = 5.09; 95 % CI = 3.39-7.64), daily employed (adjusted OR = 4.33; 95 % CI = 2.91-6.46), short-term immigrant (adjusted OR = 1.62; 95 % CI = 1.04-2.52) and living in a fishery area (adjusted OR = 1.57; 95 % CI = 1.04-2.52). Incorrect perceptions about the side-effects of DEC also obstructed DEC access for Myanmar immigrants. All positive LF antigenic immigrants reported visiting and emigrating from LF endemic areas. CONCLUSION: Hospital-based DEC administration was an inappropriate approach to DEC delivery in areas with highly mobile Myanmar immigrants. Incorporating health-center personnel in DEC delivery twice yearly and improving the perceptions of DEC side effects would likely increase DEC coverage among Myanmar immigrants. PMID- 26415691 TI - Antidiabetic treatment with gliptins: focus on cardiovascular effects and outcomes. AB - The traditional oral pharmacological therapy for type 2 diabetes mellitus (T2DM) has been based on the prescription of metformin, a biguanide, as first line antihyperglycemic agent world over. It has been demonstrated that after 3 years of treatment, approximately 50% of diabetic patients could achieve acceptable glucose levels with monotherapy; but by 9 years this had declined to only 25%. Therefore, the implementation of a combined pharmacological therapy acting via different pathways becomes necessary, and its combination with a compound of the sulfonylurea group was along decades the most frequently employed prescription in routine clinical practice. Meglitinides, glitazones and alpha-glucosidase inhibitors were subsequently developed, but the five mentioned groups of oral antihyperglycemic agents are associated with variable degrees of undesirable or even severe cardiovascular events. The gliptins-also called dipeptidyl peptidase 4 (DPP4) inhibitors--are an additional group of antidiabetic compounds with increasing clinical use. We review the status of the gliptins with emphasis on their capabilities to positively or negatively affect the cardiovascular system, and their potential involvement in major adverse cardiovascular events (MACE). Alogliptin, anagliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin and vildagliptin are the compounds currently in clinical use. Regardless differences in chemical structure and metabolic pathways, gliptins as a group exert favorable changes in experimental models. These changes, as an almost general rule, include improved endothelial function, reduction of inflammatory markers, oxidative stress ischemia/reperfusion injury and atherogenesis. In addition, increased adiponectin levels and modest decreases in lipidemia and blood pressure were reported. In clinical settings, several trials--notably the longer one, employing sitagliptin, with a mean follow-up period of 3 years--did not show an increased risk for ischemic events. Anyway, it should be emphasized that the encouraging results from basic science were not yet translated into clinical evidence, probably due the multiple and pleiotropic enzymatic effects of DPP4 inhibition. Moreover, when employing saxagliptin, while the drug was not associated with an augmented risk for ischemic events, it should be pinpointed that the rate of hospitalization for heart failure was significantly increased. Gliptins as a group constitute a widely accepted therapy for the management of T2DM, usually as a second-line medication. Nonetheless, for the time being, a definite relationship between gliptins treatment and improved cardiovascular outcomes remains uncertain and needs yet to be proven. PMID- 26415694 TI - The polymorphism rs763780 in the IL-17F gene is associated with response to biological drugs in patients with psoriasis. AB - Psoriasis improves when IL-17 is blocked. Anti-TNF drugs reduce the IL-17 signaling pathway, and anti-IL-17 drugs are being developed to treat moderate-to severe psoriasis. We analyzed three SNPs in IL-17A (rs2275913 and rs10484879) and IL-17F (rs763780) to look for an association with psoriasis and/or with response to anti-TNF drugs or ustekinumab. We included 197 healthy controls and 194 patients with moderate-to-severe psoriasis. The results of the univariate analysis showed an association between rs10484879 and psoriasis, although this relationship disappeared after adjustment for HLA-C (rs12191877). We also found an association between rs763780 (IL-17F) and response to ustekinumab (n = 70) and infliximab (n = 37) at 3 and 6 months and an association between rs763780 and the response to adalimumab at 6 months (n = 67). PMID- 26415695 TI - Facilitated Fe Nutrition by Phenolic Compounds Excreted by the Arabidopsis ABCG37/PDR9 Transporter Requires the IRT1/FRO2 High-Affinity Root Fe(2+) Transport System. PMID- 26415696 TI - A Pivotal Role of DELLAs in Regulating Multiple Hormone Signals. AB - Plant phenotypic plasticity is controlled by diverse hormone pathways, which integrate and convey information from multiple developmental and environmental signals. Moreover, in plants many processes such as growth, development, and defense are regulated in similar ways by multiple hormones. Among them, gibberellins (GAs) are phytohormones with pleiotropic actions, regulating various growth processes throughout the plant life cycle. Previous work has revealed extensive interplay between GAs and other hormones, but the molecular mechanism became apparent only recently. Molecular and physiological studies have demonstrated that DELLA proteins, considered as master negative regulators of GA signaling, integrate multiple hormone signaling pathways through physical interactions with transcription factors or regulatory proteins from different families. In this review, we summarize the latest progress in GA signaling and its direct crosstalk with the main phytohormone signaling, emphasizing the multifaceted role of DELLA proteins with key components of major hormone signaling pathways. PMID- 26415697 TI - Convenient preparation of deuterium-labeled analogs of peptides containing N substituted glycines for a stable isotope dilution LC-MS quantitative analysis. AB - N-substituted glycines constitute mimics of natural amino acids that are of great interest in the peptide-based drug development. Peptoids-oligo(N-substituted glycines) have been recently demonstrated to be highly active peptidomimetics in biological systems, resistant to proteolytic degradation. We developed a method of the deuterium labeling of peptidomimetics containing N-substituted glycine residues via H/D exchange of their alpha-carbon hydrogen atoms. The labeling was shown to be easy, inexpensive, and without the use of derivatization reagents or the need for a further purification. The deuterons introduced at the alpha-carbon atoms do not undergo a back exchange under acidic conditions during liquid chromatography mass spectrometry (LC-MS) analysis. The LC-MS analysis of a mixture of isotopologues revealed a co-elution of deuterated and nondeuterated forms of the peptidomimetics, which may be useful in the quantitative isotope dilution analysis of peptoids and other derivatives of N-substituted glycines. PMID- 26415698 TI - Assessment of a panel of interleukin-8 reporter lung epithelial cell lines to monitor the pro-inflammatory response following zinc oxide nanoparticle exposure under different cell culture conditions. AB - BACKGROUND: Stably transfected lung epithelial reporter cell lines pose an advantageous alternative to replace complex experimental techniques to monitor the pro-inflammatory response following nanoparticle (NP) exposure. Previously, reporter cell lines have been used under submerged culture conditions, however, their potential usefulness in combination with air-liquid interface (ALI) exposures is currently unknown. Therefore, the aim of the present study was to compare a panel of interleukin-8 promoter (pIL8)-reporter cell lines (i.e. green or red fluorescent protein (GFP, RFP), and luciferase (Luc)), originating from A549 lung epithelial type II-like cells cells, following NPs exposure under both submerged and ALI conditions. METHODS: All cell lines were exposed to zinc oxide (ZnO) NPs at 0.6 and 6.2 MUg/cm(2) for 3 and 16 hours under both submerged and ALI conditions. Following physicochemical characterization, the cytotoxic profile of the ZnO-NPs was determined for each exposure scenario. Expression of IL-8 from all cell types was analyzed at the promoter level and compared to the mRNA (qRT PCR) and protein level (ELISA). RESULTS: In summary, each reporter cell line detected acute pro-inflammatory effects following ZnO exposure under each condition tested. The pIL8-Luc cell line was the most sensitive in terms of reporter signal strength and onset velocity following TNF-alpha treatment. Both pIL8-GFP and pIL8-RFP also showed a marked signal induction in response to TNF alpha, although only after 16 hrs. In terms of ZnO-NP-induced cytotoxicity pIL8 RFP cells were the most affected, whilst the pIL8-Luc were found the least responsive. CONCLUSIONS: In conclusion, the use of fluorescence-based reporter cell lines can provide a useful tool in screening the pro-inflammatory response following NP exposure in both submerged and ALI cell cultures. PMID- 26415700 TI - Raltegravir Plus Nevirapine as Maintenance Antiretroviral Therapy in HIV-Positive Patients: Safety, Efficacy and Pharmacokinetics. AB - BACKGROUND: Tolerability, long-term toxicities and selection of resistant variants limit the use and efficacy of antiretroviral drugs in HIV-positive patients. Novel combinations are needed for mantaining long-term control of HIV replication; nevertheless scarse data are available on protease inhibitor-free dual antiretroviral therapies. METHODS: A multi-centric retrospective study was conducted including HIV-1-positive patients on raltegravir/nevirapine dual regimens. Plasma concentrations were measured as therapeutic drug monitoring while a subset of patients underwent intensive 12-hour pharmacokinetic evaluation. RESULTS: A total of 77 patients switching from successful regimens (76.6% male, median age 52 years) was included; 10 patients on raltegravir plus nevirapine once-daily while 67 subjects on twice-daily schedule. After a median follow-up of 32 months 69 patients (89.6%) were still successfully on treatment. Three patients discontinued for side effects (skin rash or hepatoxicity). Virological failure was observed in five patients (6.5%, 3 on once-daily schedule): in 4 patients (80%) resistance-associated mutations were observed (4 reverse transcriptase, 2 integrase). Triglycerides decreased in patients switching with lipid abnormalities (n=52) and estimated creatinine clearance increased in those with less than 60 ml/min (n=13). Median trough raltegravir and nevirapine concentrations were 83 ng/ml (32-227) and 5460 ng/ml (4037-7221); intensive 12-hours pharmacokinetic parameters (n=7) were similar to published data. CONCLUSION: Dual therapy with raltegravir/nevirapine in selected patients was highly effective over a 32-month follow up: virological failure was infrequent (6.5%), most common with once-daily schedule (60%) and often associated with the selection of resistance-associated mutations (80%). Twice daily raltegravir plus nevirapine deserves further clinical evaluation as an NRTI and PI-sparing strategy in selected patients. PMID- 26415699 TI - A resilient formin-derived cortical actin meshwork in the rear drives actomyosin based motility in 2D confinement. AB - Cell migration is driven by the establishment of disparity between the cortical properties of the softer front and the more rigid rear allowing front extension and actomyosin-based rear contraction. However, how the cortical actin meshwork in the rear is generated remains elusive. Here we identify the mDia1-like formin A (ForA) from Dictyostelium discoideum that generates a subset of filaments as the basis of a resilient cortical actin sheath in the rear. Mechanical resistance of this actin compartment is accomplished by actin crosslinkers and IQGAP-related proteins, and is mandatory to withstand the increased contractile forces in response to mechanical stress by impeding unproductive blebbing in the rear, allowing efficient cell migration in two-dimensional-confined environments. Consistently, ForA supresses the formation of lateral protrusions, rapidly relocalizes to new prospective ends in repolarizing cells and is required for cortical integrity. Finally, we show that ForA utilizes the phosphoinositide gradients in polarized cells for subcellular targeting. PMID- 26415701 TI - HIV-1 is spreading out of former high-risk population through heterosexual transmission in Hebei, China. AB - INTRODUCTION: Multiple specific populations, including MSMs, IDUs, and FPDs, are involved in HIV epidemic in China. In the recent years, HIV transmission due to heterosexual transmission also contributed greatly to HIV epidemic in China. Very few studies have been fulfilled to characterize relationships of HIV-1 strains prevalent in different populations. In this study, the phylogenetic relationships of HIV-1 spreading in different populations were investigated. MATERIALS AND METHODS: HIV-1 sero-positive patients infected through different routes were enrolled into the study. Nested RT-PCR was used to amplify HIV gag and pol genes followed by sequencing. RESULTS: Multiple subtypes, including subtype B (52.1%), CRF01_AE (34.4%), CRF07_BC (6.3%), subtype C (4.2%), CRF02_AG (1.0%), CRF08_BC (1.0%) and unique recombination forms (1.0%) were identified. Phylogenetic analysis showed that strains from MSM, IDU, and FPDs grouped into clusters separately. However, strains identified in heterosexual transmitted population intermixed with all of other high risk populations. DISCUSSION AND CONCLUSION: The genetic data supposed that HIV-1 was spreading out of MSMs, IDUs, and FPDs through heterosexual transmission in Hebei, China. Urgent prevention and behavior intervention in the population will be necessary. Furthermore, the detailed sequence data will help the design of HIV-1 vaccines in China. Sequence Data: All of sequences have been deposited into the GenBank with the accession number: KJ820007-KJ820144. PMID- 26415703 TI - Layer-by-layer assemblies for antibacterial applications. AB - The adhesion and proliferation of bacteria on various artificial surfaces affects the functionality of these specific interfaces. To overcome the problems caused by bacterial growth on these surfaces, various antibacterial coatings were developed. In this review, we summarized most of the antibacterial surfaces prepared by the Layer-by-Layer (LbL) assembly approach and classified these LbL films based on their antibacterial mechanisms. In the first group, the bactericidal LbL assemblies which incorporate various biocides including heavy metals, antibiotics, cationic molecules, antimicrobial peptides and enzymes are able to kill surrounding or contacted bacteria. In the second group, we focused on the physical aspects of film surfaces. Bacterial adhesion resistant LbL films have been fabricated to adjust the substrate surface properties such as surface free energy (or wettability), roughness, and surface charge which may affect the adhesion of bacteria. Furthermore, as an enhancement in the antibacterial efficiency, multifunctional LbL assemblies combining both bactericidal and adhesion resistant functionalities were discussed. The advantages and limitations of these antibacterial LbL assemblies were summarized and subsequently directions for future development were proposed. PMID- 26415702 TI - The modulation of carbonyl reductase 1 by polyphenols. AB - Carbonyl reductase 1 (CBR1), an enzyme belonging to the short-chain dehydrogenases/reductases family, has been detected in all human tissues. CBR1 catalyzes the reduction of many xenobiotics, including important drugs (e.g. anthracyclines, nabumetone, bupropion, dolasetron) and harmful carbonyls and quinones. Moreover, it participates in the metabolism of a number of endogenous compounds and it may play a role in certain pathologies. Plant polyphenols are not only present in many human food sources, but are also a component of many popular dietary supplements and herbal medicines. Many studies reviewed herein have demonstrated the potency of certain flavonoids, stilbenes and curcuminoids in the inhibition of the activity of CBR1. Interactions of these polyphenols with transcriptional factors, which regulate CBR1 expression, have also been reported in several studies. As CBR1 plays an important role in drug metabolism as well as in the protection of the organism against potentially harmful carbonyls, the modulation of its expression/activity may have significant pharmacological and/or toxicological consequences. Some polyphenols (e.g. luteolin, apigenin and curcumin) have been shown to be very potent CBR1 inhibitors. The inhibition of CBR1 seems useful regarding the increased efficacy of anthracycline therapy, but it may cause the worse detoxification of reactive carbonyls. Nevertheless, all known information about the interactions of polyphenols with CBR1 have only been based on the results of in vitro studies. With respect to the high importance of CBR1 and the frequent consumption of polyphenols, in vivo studies would be very helpful for the evaluation of risks/benefits of polyphenol interactions with CBR1. PMID- 26415705 TI - Deworming and the immune status of HIV positive pre-antiretroviral therapy individuals in Arba Minch, Chencha and Gidole hospitals, Southern Ethiopia. AB - BACKGROUND: Helminths/HIV co-infections are very common in developing countries, especially in Africa. The effect of overlapping distribution of HIV and helminths becomes important because concomitant infection may exacerbate disease outcome of HIV infection. The study aimed at determining the effect of deworming on the immune status of helminth/HIV coinfected Pre-ART HIV patients attending three health institutions in Southern Ethiopia. METHODS: 97 HIV-positive Pre-ART individuals were observed into 2 groups on the basis of helminth co-infection and no infection. Out of these, 66 study participants were helminths/HIV co-infected and the remaining 31 study participants were helminths (-)/HIV (+) control. Helminth/HIV co-infected participants CD4+ T-cell count was done at baseline, after 15 weeks and 6 months after antihelminthics treatment. Data were analyzed using SPSS version 16. RESULTS: Ascaris lumbricoides was the highest prevalent soil transmitted helminths in Pre-ART individuals in this study. CD4+ T-cell count in the Ascaris lumricoides/HIV co-infected was significantly higher (P = 0.05) and (P < 0.05) after 15 weeks and 6 months post-antihelminthics treatment respectively. Also, after antihelminthic therapy, the CD4+ T-cell count significantly increased (P < 0.005) in all treated helminth infections. CONCLUSIONS: The study showed that treatment of ascariasis had a significant effect on CD4+ T-cell count increase in the treated Pre-ART Ascaris lumbricoides/HIV co-infected individuals; whereas the same positive effect was not evident for other intestinal helminth parasites detected in the study. In conclusion, this finding on Ascaris lumbricoides-specific nature of immune interaction in helminth/HIV co-infection may partly explain the inconsistent reports on the role of intestinal helminths on progression of HIV infection to AIDS. Therefore, a well-designed longitudinal study on helminth species-specific HIV/helminth co-infection will be needed to fully establish the possible benefits of deworming in intestinal helminth/HIV co-infection. PMID- 26415706 TI - Bronchial compression following pulmonary artery stenting in single ventricle lesions: how to prevent, and how to decompress. AB - OBJECTIVES: To assess airway compression during pulmonary artery (PA) intervention in single ventricle (SV) palliation. BACKGROUND: SV lesions with a prominent neo-aortic root are considered a high risk for branch PA and/or bronchial stenosis. PA stenting is well established, but may result in ipsilateral bronchial compression. METHODS: Single-centre retrospective analysis of 19 palliated SV patients with branch PA stenosis and close proximity to the ipsilateral main bronchus who underwent cardiac catheterisation at a median age and weight of 8.5 years (0.5-25) and 16.5 kg (6-82) between 12/2011 and 05/2015. RESULTS: Two of the 19 patients suffered an almost-closed left-main bronchus (LMB) following PA stenting. Fortunately, LMB decompression succeeded in both those patients by re-shaping the PA stents by compressing the chest while splinting the LMB with an inflated balloon. To prevent the other 17 patients from suffering this serious complication, we adopted a thorough preparation strategy: 13 patients underwent safe simultaneous bronchoscopy and cardiac catheterisation; in the remaining 4 patients CT-angiography enabled accurate risk evaluation prior to re-catheterisation. CONCLUSIONS: In SV lesions accompanied by branch PA stenosis, thorough preparation via cross-sectional imaging is mandatory, including simultaneous bronchoscopy and cardiac catheterisation in selected cases, to rule out any airway compression before considering endovascular stent implantation. If a PA stent's compression has already caused severe bronchial obstruction, our balloon-splinted decompression technique should be considered. PMID- 26415708 TI - Amphibian antimicrobial peptide fallaxin analogue FL9 affects virulence gene expression and DNA replication in Staphylococcus aureus. AB - The rapid rise in antibiotic-resistant pathogens is causing increased health concerns, and consequently there is an urgent need for novel antimicrobial agents. Antimicrobial peptides (AMPs), which have been isolated from a wide range of organisms, represent a very promising class of novel antimicrobials. In the present study, the analogue FL9, based on the amphibian AMP fallaxin, was studied to elucidate its mode of action and antibacterial activity against the human pathogen Staphylococcus aureus. Our data showed that FL9 may have a dual mode of action against S. aureus. At concentrations around the MIC, FL9 bound DNA, inhibited DNA synthesis and induced the SOS DNA damage response, whereas at concentrations above the MIC the interaction between S. aureus and FL9 led to membrane disruption. The antibacterial activity of the peptide was maintained over a wide range of NaCl and MgCl(2) concentrations and at alkaline pH, while it was compromised by acidic pH and exposure to serum. Furthermore, at subinhibitory concentrations of FL9, S. aureus responded by increasing the expression of two major virulence factor genes, namely the regulatory rnaIII and hla, encoding alpha-haemolysin. In addition, the S. aureus-encoded natural tolerance mechanisms included peptide cleavage and the addition of positive charge to the cell surface, both of which minimized the antimicrobial activity of FL9. Our results add new information about FL9 and its effect on S. aureus, which may aid in the future development of analogues with improved therapeutic potential. PMID- 26415707 TI - Matrix metalloproteinase-9-dependent mechanisms of reduced contractility and increased stiffness in the aging heart. AB - PURPOSE: Matrix metalloproteinases (MMPs) collectively degrade all extracellular matrix (ECM) proteins. Of the MMPs, MMP-9 has the strongest link to the development of cardiac dysfunction. Aging associates with increased MMP-9 expression in the left ventricle (LV) and reduced cardiac function. We investigated the effect of MMP-9 deletion on the cardiac ECM in aged animals. EXPERIMENTAL DESIGN: We used male and female middle-aged (10- to16-month old) and old (20- to 24-month old) wild-type (WT) and MMP-9 null mice (n = 6/genotype/age). LVs were decellularized to remove highly abundant mitochondrial proteins that could mask identification of relative lower abundant components, analyzed by shotgun proteomics, and proteins of interest validated by immunoblot. RESULTS: Elastin microfibril interface-located protein 1 (EMILIN-1) decreased with age in WT (p < 0.05), but not in MMP-9 null. EMILIN-1 promotes integrin dependent cell adhesion and EMILIN-1 deficiency has been associated with vascular stiffening. Talin-2, a cytoskeletal protein, was elevated with age in WT (p < 0.05), and MMP-9 deficiency blunted this increase. Talin-2 is highly expressed in adult cardiac myocytes, transduces mechanical force to the ECM, and is activated by increases in substrate stiffness. Our results suggest that MMP-9 deletion may reduce age-related myocardial stiffness, which may explain improved cardiac function in MMP-9 null animals. CONCLUSIONS: We identified age-related changes in the cardiac proteome that are MMP-9 dependent, suggesting MMP-9 as a possible therapeutic target for the aging patient. PMID- 26415709 TI - Changes in supraspinal and spinal excitability of the biceps brachii following brief, non-fatiguing submaximal contractions of the elbow flexors in resistance trained males. AB - The purpose of the current study was to assess the effects of 5 brief (2s), intermittent, submaximal elbow flexors voluntary contractions at 50% of maximal voluntary contraction (MVC) on measures of central (i.e. supraspinal and spinal) excitability. Supraspinal and spinal excitability of the biceps brachii were assessed via transcranial magnetic stimulation (TMS) of the motor cortex and transmastoid electrical stimulation (TMES) of the corticospinal tract, respectively. TMS-induced motor-evoked potentials (MEPs), TMES-induced cervicomedullary-evoked potentials (CMEPs), Erb's point peripheral nerve stimulation and MVC were assessed prior to and following submaximal voluntary contractions at 50% of MVC. The MEP to CMEP ratio increased (584+/-77.2%; p=0.011) and CMEP amplitudes decreased (62+/-3.0%; p=0.02) immediately post exercise. MVC force output did not change immediately post-exercise. The results suggest that brief, non-fatiguing intermittent submaximal voluntary contractions transiently enhance supraspinal excitability while decreasing spinal excitability. The impact of these changes on one's ability to generate or maintain force production remains unknown. PMID- 26415710 TI - Porous poly (D,L-lactide-co-glycolide) acid/biosilicate(r) composite scaffolds for bone tissue engineering. AB - This study evaluated the effects of the Biosilicate(r) and poly (D,L-lactic-co glycolic) acid composites on bone repair in a tibial bone defect model in rats by means of using histological evaluation (histopathological and morphometric analysis) and gene expression analysis. Eighty male Wistar rats (12 weeks old, weighing +/-300 g) were randomly divided into two groups: Biosilicate(r) group (BG) and Biosilicate(r) /PLGA group (BG/PLGA). Each group was euthanized at 3, 7, 14, and 21 days after surgery (n = 10 animals per time point). The main findings showed that the incorporation of PLGA into BG had a significant effect on the morphological structure of the material, accelerating mass loss, decreasing the pH and increasing the calcium release. Furthermore, histologic analysis revealed that the BG/PLGA showed increased material degradation, accompanied by higher bone formation compared to BG, after 21 days of implantation. In addition, qRT PCR analysis showed that BG/PLGA induced an upregulation of the osteogenic genes related to BMP4, Runx2, ALP, and OC. These results show that the present BG/PLGA composite may be used as a bone graft for inducing bone repair. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 63-71, 2017. PMID- 26415712 TI - Influence of selective digestion of elastin and collagen on mechanical properties of human aortas. AB - PURPOSE: There are two families of fibres taking part in the process of mechanical loads transfer, i.e. elastin and collagen fibres. Their number, spatial arrangement and specific properties determine the capacity of a blood vessels to resist mechanical loads resulting from the impact of blood on vessel walls. The purpose of the present paper is to define the load-bearing capacities of elastin and collagen scaffolds equivalent to natural fibre arrangements of human aorta and produced by selective digestion. METHODS: Samples of thoracic human aortas were digested by using phosphate buffer of trypsin at pH 8.0 for 22 hours in order to degrade elastin and by autoclaving followed by incubation in 90% formic acid for 22 hours. The efficacy of digestion was assessed immunohistochemically. Mechanical properties of pre-stretched native and digested samples were determined by uniaxial tensile test. RESULTS: Samples subjected to autoclaving have been successfully deprived of both types of collagen and elastin has been intact. Treatment with trypsin caused a removal of elastin and the presence of type I and IV collagen was demonstrated. Digestion of aortic samples either by formic acid or trypsin has resulted significantly decreasing mechanical properties in comparison with native samples. CONCLUSIONS: Collagen and elastin scaffold-like stuctures have been effectively produced by selective digestion of thoracic human aorta and their contribution to the load-bearing process was evaluated. Isolated collagen network are more durable and stiffer and less deformable than elastin network, hence are responsible for load-bearing process at higher strain since the range of working of elastin is at lower strain values. PMID- 26415711 TI - Physical Function and Disability After Acute Care and Critical Illness Hospitalizations in a Prospective Cohort of Older Adults. AB - OBJECTIVES: To investigate associations between acute care and critical illness hospitalizations and performance on physical functional measures and activities of daily living (ADLs). DESIGN: Prospective cohort study. SETTING: Large health maintenance organization. PARTICIPANTS: Two thousand nine hundred twenty-six participants in Adult Changes in Thought, a study of aging enrolling dementia free individuals aged 65 and older not living in a nursing home from 1994 to September 30, 2008 (N = 2,926). MEASUREMENTS: The exposure of interest was hospitalization during study participation, subdivided by presence of critical illness. Outcomes included gait speed, grip strength, chair stand speed, and difficulty and dependence in performing ADLs measured at biennial visits. RESULTS: Median time between hospital discharge and the next study visit was 311 days (interquartile range (IQR) 151-501 days) after acute care hospitalization and 359 days (IQR 181-420 days) after critical illness hospitalization. Gait speed was slower after acute care (-0.05 m/s, 95% confidence interval (CI) = 0.01 0.04 m/s slower, P < .001) and critical illness (-0.16 m/s, 95% CI = -0.22 to 0.10, P < .001). Grip was weaker after acute care hospitalization (-0.8 kg, 95% CI = -1.0 to -0.6, P < .001) but not significantly different after critical illness hospitalization. Chair-stand speed was slower after acute care hospitalization (-0.04 stands/s, 95% CVI = -0.05 to -0.04, P < .001) and critical illness hospitalization (-0.09, 95% CI = -0.15 to -0.03, P = .003). The odds of difficulty with (odds ratio (OR) = 1.4, 95% CI = 1.2-1.6, P < .001) or dependence in (OR = 2.0, 95% CI = 1.2-3.2, P = .006) one or more ADLs was higher after acute care hospitalization, as were the odds of difficulty with (OR = 1.9, 95% CI = 1.1 3.6, P = .03) or dependence in (OR = 7.9, 95% CI = 2.5-25.7, P = .001) one or more ADLs after critical illness. CONCLUSION: In older adults, hospitalization, especially for critical illness, was associated with clinically relevant decline in gait and chair stand speed and strongly associated with difficulty with and dependence in ADLs. PMID- 26415714 TI - Local Health Integration Networks: Build on their purpose. AB - This article provides a high-level overview on the creation of Local Health Integration Networks (LHINs) and illustrates the complexities involved in their implementation. To understand regional structures such as LHINs, one must understand the context in which design and execution takes place. The article ends with a commentary on how Ontario is performing post-LHINs and discusses next steps. PMID- 26415713 TI - Implementation of an antenatal magnesium sulfate protocol for fetal neuroprotection in preterm infants. AB - The aim of our study was to assess the feasibility of implementing a protocol for the use of magnesium sulfate to prevent cerebral palsy. This retrospective single center study included all women with fetuses of gestational age <33 weeks of gestation whose birth was planned or expected within 24 hours from September 2011 to December 2012. They were to receive magnesium sulfate, administered intravenously as a 4-g bolus followed by a constant infusion of 1 g per hour. If delivery had not occurred after 12 hours and was no longer considered imminent, the infusion was to be discontinued. The study included 119 women, 81 (68.1%) of whom received magnesium sulfate. Among the latter, 71 (87.5%) gave birth within 24 hours. The reasons treatment was not given were: omission by medical team (19/38, 50%), urgent delivery (18/38, 47.4%), and contraindication to treatment (1/38, 2.6%). The mean gestational age at protocol implementation was 29.6 +/- 2.1 weeks. Maternal monitoring, especially at the onset of infusion, appeared suboptimal. No major maternal side effects were observed. Our study shows that implementing a protocol for prevention of cerebral palsy by magnesium sulfate is feasible in a tertiary obstetric center. PMID- 26415715 TI - The First Nations Health Authority: A transformation in healthcare for BC First Nations. AB - More than 10 years of negotiation and a series of political agreements led to the formation of a new First Nations health governance structure in British Columbia and the beginning of new relationships in health between First Nations, federal, and provincial governments. The First Nations Health Authority is the service delivery arm of this structure and the first-of-its-kind for Canada. Equitable and innovative health service and governance partnerships can bring decision making closer to home and into the hands of First Nations communities and allows using the best of western medicine combined with holistic and traditional practices. Decolonizing old relationships and building new partnerships are leading to greater alignment of culturally safe and effective health services through coordination, integration, and shared decision-making in British Columbia. PMID- 26415716 TI - High speed, high temperature electrical characterization of phase change materials: metastable phases, crystallization dynamics, and resistance drift. AB - During the fast switching in Ge2Sb2Te5 phase change memory devices, both the amorphous and fcc crystalline phases remain metastable beyond the fcc and hexagonal transition temperatures respectively. In this work, the metastable electrical properties together with crystallization times and resistance drift behaviour of GST are studied using a high-speed, device-level characterization technique in the temperature range of 300 K to 675 K. PMID- 26415717 TI - Comment on "Curvature capillary migration of microspheres" by N. Sharifi-Mood, I. B. Liu, K. J. Stebe, Soft Matter, 2015, 11, 6768. AB - In a recent paper, Sharifi-Mood et al. studied colloidal particles trapped at a liquid interface with opposite principal curvatures c1 = -c2. In the theory part, they claim that the trapping energy vanishes at second order in Deltac = c1 - c2, which would invalidate our previous result [Phys. Rev. E: Stat., Nonlinear, Soft Matter Phys., 2006, 74, 041402]. Here we show that this claim arises from an improper treatment of the outer boundary condition on the deformation field. For both pinned and moving contact lines, we find that the outer boundary is irrelevant, which confirms our previous work. More generally, we show that the trapping energy is determined by the deformation close to the particle and does not depend on the far-field. PMID- 26415718 TI - Mechanical control of magnetism in oxygen deficient perovskite SrTiO3. AB - Mechanical control of magnetism in perovskite oxides is an important and promising approach in spintronics. Based on the first-principles calculations, we demonstrate that a negative pressure leads to a great enhancement of magnetic moment in deficient SrTiO3 with oxygen vacancies, whereas a positive pressure results in the gradual disappearance of magnetism. Spin charge density, Bader charge analysis and electronic density of states successfully elucidate the origin and underlying physics of the enhancement and disappearance of magnetism. It is found that the split electronic states of dz(2), dyz and dzx in the 3d orbitals of Ti atoms remarkably contribute to the occupancy of majority spin states under negative pressure, which induces a large magnetic moment. Under positive pressure, however, the equal occupancy of both majority and minority t2g and eg states leads to the disappearance of magnetization. In addition, both negative and positive pressures can largely lower the vacancy formation enthalpy, suggesting that the oxygen vacancy is preferable with pressure. Our findings may provide a mechanism to achieve the pressure control of magnetization in nonmagnetic perovskite oxides. PMID- 26415719 TI - Fetal cardiovascular remodeling persists at 6 months in infants with intrauterine growth restriction. AB - OBJECTIVES: Intrauterine growth restriction is associated with increased cardiovascular risk later in life but the link between fetal disease and postnatal risk is not well-documented. We evaluated longitudinally the association between cardiovascular remodeling in small-for-gestational-age (SGA) fetuses and at 6 months of age. METHODS: A cohort of 80 SGA fetuses (defined by estimated fetal and birth weights < 10(th) centile) delivered > 34 weeks' gestation was compared with 80 normally grown age-matched control fetuses, with follow-up at 6 months of corrected age (i.e. 6 months from estimated date of delivery according to first-trimester crown-rump length). Cardiovascular evaluation included a comprehensive echocardiographic assessment in both fetuses and infants and blood pressure and aortic intima-media thickness (aIMT) measurement in infants. Parameters were adjusted by linear regression analysis for gender, gestational age at delivery, pre-eclampsia, prenatal glucocorticoid exposure, Cesarean delivery, admission to neonatal intensive care unit and body surface area. RESULTS: Both pre- and postnatally, when compared with controls, the SGA group showed a more globular cardiac shape (left sphericity index: controls 2.06 vs SGA 1.87 (P = 0.022) prenatally and 1.92 vs 1.67 (P = 0.007) postnatally), as well as signs of systolic longitudinal dysfunction (systolic annular peak velocity (S'): 7.2 vs 6.3 cm/s (P = 0.003) prenatally and 7.9 vs 6.4 cm/s (P < 0.001) postnatally; tricuspid annular plane systolic excursion: 7.2 vs 6.8 mm (P = 0.015) prenatally and 16.0 vs 14.2 mm (P < 0.001) postnatally) and diastolic dysfunction (left isovolumetric relaxation time: 46 vs 52 ms (P < 0.001) prenatally and 50 vs 57 ms (P = 0.034) postnatally). In addition, infants in the SGA group had increased mean blood pressure (mean: 61 vs 70 mmHg, P < 0.001) and maximum aIMT (0.57 vs 0.66 mm; P < 0.001). CONCLUSIONS: Primary cardiovascular changes are already present in the SGA fetus and persist at 6 months of age. These data support prenatal cardiovascular remodeling as a mechanistic pathway of increased risk later in life in cases of SGA, regardless of Doppler abnormalities. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26415720 TI - Ablation of hippocampal neurogenesis in mice impairs the response to stress during the dark cycle. AB - The functional role of adult neurogenesis in the hippocampus remains the subject of intense speculation. One recent hypothesis is that adult-born neurons contribute to the endocrine and behavioural outputs of the stress response. Here we show a genetic model system to ablate neurogenesis by inducibly deleting Tbr2 gene function specifically in the hippocampus and corroborate our findings in a radiation-based model of neurogenesis deprivation. We found that mice with ablation of new neurons in the dentate gyrus exhibit reduced anxiety during the dark cycle. After restraint stress, corticosterone levels in neurogenesis deficient mice decreased more quickly than controls and were more sensitive to suppression by dexamethasone. Furthermore, glucocorticoid receptor target genes and neuronal activity markers showed reduced expression after stress in neurogenesis-deficient mice. These findings suggest that newborn neurons in the hippocampus are involved in sensing and eliciting an appropriate response to stress. PMID- 26415721 TI - Traffic deaths before and after birth. PMID- 26415722 TI - Cytoscape.js: a graph theory library for visualisation and analysis. AB - Cytoscape.js is an open-source JavaScript-based graph library. Its most common use case is as a visualization software component, so it can be used to render interactive graphs in a web browser. It also can be used in a headless manner, useful for graph operations on a server, such as Node.js. AVAILABILITY AND IMPLEMENTATION: Cytoscape.js is implemented in JavaScript. Documentation, downloads and source code are available at http://js.cytoscape.org. CONTACT: gary.bader@utoronto.ca. PMID- 26415725 TI - XPIWIT--an XML pipeline wrapper for the Insight Toolkit. AB - The Insight Toolkit offers plenty of features for multidimensional image analysis. Current implementations, however, often suffer either from a lack of flexibility due to hard-coded C++ pipelines for a certain task or by slow execution times, e.g. caused by inefficient implementations or multiple read/write operations for separate filter execution. We present an XML-based wrapper application for the Insight Toolkit that combines the performance of a pure C++ implementation with an easy-to-use graphical setup of dynamic image analysis pipelines. Created XML pipelines can be interpreted and executed by XPIWIT in console mode either locally or on large clusters. We successfully applied the software tool for the automated analysis of terabyte-scale, time resolved 3D image data of zebrafish embryos. AVAILABILITY AND IMPLEMENTATION: XPIWIT is implemented in C++ using the Insight Toolkit and the Qt SDK. It has been successfully compiled and tested under Windows and Unix-based systems. Software and documentation are distributed under Apache 2.0 license and are publicly available for download at https://bitbucket.org/jstegmaier/xpiwit/downloads/. CONTACT: johannes.stegmaier@kit.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26415723 TI - ScreenBEAM: a novel meta-analysis algorithm for functional genomics screens via Bayesian hierarchical modeling. AB - MOTIVATION: Functional genomics (FG) screens, using RNAi or CRISPR technology, have become a standard tool for systematic, genome-wide loss-of-function studies for therapeutic target discovery. As in many large-scale assays, however, off target effects, variable reagents' potency and experimental noise must be accounted for appropriately control for false positives. Indeed, rigorous statistical analysis of high-throughput FG screening data remains challenging, particularly when integrative analyses are used to combine multiple sh/sgRNAs targeting the same gene in the library. METHOD: We use large RNAi and CRISPR repositories that are publicly available to evaluate a novel meta-analysis approach for FG screens via Bayesian hierarchical modeling, Screening Bayesian Evaluation and Analysis Method (ScreenBEAM). RESULTS: Results from our analysis show that the proposed strategy, which seamlessly combines all available data, robustly outperforms classical algorithms developed for microarray data sets as well as recent approaches designed for next generation sequencing technologies. Remarkably, the ScreenBEAM algorithm works well even when the quality of FG screens is relatively low, which accounts for about 80-95% of the public datasets. AVAILABILITY AND IMPLEMENTATION: R package and source code are available at: https://github.com/jyyu/ScreenBEAM. CONTACT: ac2248@columbia.edu, jose.silva@mssm.edu, yujiyang@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26415724 TI - Drug-set enrichment analysis: a novel tool to investigate drug mode of action. AB - MOTIVATION: Automated screening approaches are able to rapidly identify a set of small molecules inducing a desired phenotype from large small-molecule libraries. However, the resulting set of candidate molecules is usually very diverse pharmacologically, thus little insight on the shared mechanism of action (MoA) underlying their efficacy can be gained. RESULTS: We introduce a computational method (Drug-Set Enrichment Analysis-DSEA) based on drug-induced gene expression profiles, which is able to identify the molecular pathways that are targeted by most of the drugs in the set. By diluting drug-specific effects unrelated to the phenotype of interest, DSEA is able to highlight phenotype-specific pathways, thus helping to formulate hypotheses on the MoA shared by the drugs in the set. We validated the method by analysing five different drug-sets related to well known pharmacological classes. We then applied DSEA to identify the MoA shared by drugs known to be partially effective in rescuing mutant cystic fibrosis transmembrane conductance regulator (CFTR) gene function in Cystic Fibrosis. AVAILABILITY AND IMPLEMENTATION: The method is implemented as an online web tool publicly available at http://dsea.tigem.it. CONTACT: dibernardo@tigem.it SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26415726 TI - Computational probing protein-protein interactions targeting small molecules. AB - MOTIVATION: With the booming of interactome studies, a lot of interactions can be measured in a high throughput way and large scale datasets are available. It is becoming apparent that many different types of interactions can be potential drug targets. Compared with inhibition of a single protein, inhibition of protein protein interaction (PPI) is promising to improve the specificity with fewer adverse side-effects. Also it greatly broadens the drug target search space, which makes the drug target discovery difficult. Computational methods are highly desired to efficiently provide candidates for further experiments and hold the promise to greatly accelerate the discovery of novel drug targets. RESULTS: Here, we propose a machine learning method to predict PPI targets in a genomic-wide scale. Specifically, we develop a computational method, named as PrePPItar, to Predict PPIs as drug targets by uncovering the potential associations between drugs and PPIs. First, we survey the databases and manually construct a gold standard positive dataset for drug and PPI interactions. This effort leads to a dataset with 227 associations among 63 PPIs and 113 FDA-approved drugs and allows us to build models to learn the association rules from the data. Second, we characterize drugs by profiling in chemical structure, drug ATC-code annotation, and side-effect space and represent PPI similarity by a symmetrical S-kernel based on protein amino acid sequence. Then the drugs and PPIs are correlated by Kronecker product kernel. Finally, a support vector machine (SVM), is trained to predict novel associations between drugs and PPIs. We validate our PrePPItar method on the well-established gold-standard dataset by cross-validation. We find that all chemical structure, drug ATC-code, and side-effect information are predictive for PPI target. Moreover, we can increase the PPI target prediction coverage by integrating multiple data sources. Follow-up database search and pathway analysis indicate that our new predictions are worthy of future experimental validation. CONCLUSION: In conclusion, PrePPItar can serve as a useful tool for PPI target discovery and provides a general heterogeneous data integrative framework. AVAILABILITY AND IMPLEMENTATION: PrePPItar is available at http://doc.aporc.org/wiki/PrePPItar. CONTACT: ycwang@nwipb.cas.cn or ywang@amss.ac.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26415727 TI - Association between self-reported snoring and arterial stiffness: data from the Brisighella Heart Study. AB - The correlation of both obstructive sleep apnoea syndrome (OSAS) and snoring with cardiovascular risk is well known, but its investigation is complex and not suitable for studying large cohorts of subjects. Thus, we prospectively evaluated 1476 non-pharmacologically treated subjects selected from the last survey of the Brisighella Heart Study. Snoring and sleep apnoea were investigated asking the subjects if they were aware of snoring during the night, and if this was associated with episodes of apnoea. A full set of clinical and laboratory parameters were evaluated, while augmentation index (AIx), and pulse wave velocity (PWV) were recorded with the Vicorder((r)) apparatus. A logistic regression analysis identifies as main independent predictors of AIx age (OR 1.058, 95% CI 1.043-1.065, p < 0.001), Body Mass Index (OR 1.046, 95% CI 1.014 1.079, p = 0.005), and apolipoprotein B (OR 1.014, 95% CI 1.004-1.023, p = 0.001). The main independent predictors of PWV are snoring (OR 1.215, 95% CI 1.083-1.390, p < 0.001), and snoring with apnoea (OR 1.351, 95% CI 1.135-1.598, p = 0.014), age (OR 1.078, 95% CI 1.052-1.089, p < 0.001), serum uric acid [SUA] (OR 1.093, 95% CI 1.026-1.151, p < 0.001) and mean arterial pressure (OR 1.042, 95% CI 1.024-1.056, p < 0.001). In conclusion, in our cohort of overall healthy subjects, self-reported snoring and sleep apnoea are independently associated with a higher PVW, and AIx is statistically significantly higher in snorers with or without sleep apnoea than in non-snorers. Body Mass Index and apolipoprotein B are associated with AIx, while SUA and mean arterial pressure are related to PWV. PMID- 26415729 TI - Role of TBATB in nano indium oxide catalyzed C-S bond formation. AB - Nano sized indium oxide is found to be an efficient catalyst for the conversion of thiols to sulfides using Na2CO3 as base and TBATB as reagent in DMSO at 110 degrees C. Here in situ generation of bromo intermediate by TBATB takes place through indium surface. A variety of aryl sulfides can be synthesized in excellent yields from less reactive chlorides, boronic acids and thiols. PMID- 26415728 TI - Neutrophil Gelatinase-Associated Lipocalin in Dogs With Sepsis Undergoing Emergency Laparotomy: A Prospective Case-Control Study. AB - BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is an early indicator of acute kidney injury (AKI) in dogs and its use has not been evaluated in dogs with sepsis. ANIMALS: Fifteen dogs with sepsis requiring laparotomy (study dogs) and 10 dogs undergoing surgery for intervertebral disc disease (control dogs). OBJECTIVE: To determine whether NGAL increases in dogs with sepsis undergoing emergency laparotomy and whether it is correlated with development of AKI and survival. METHODS: Longitudinal study conducted at a referral teaching hospital. Serum neutrophil gelatinase-associated lipocalin (sNGAL), urinary NGAL normalized to urinary creatinine concentration (UNCR), and serum creatinine concentration were measured at 4 time points (admission, after anesthesia, and 24 and 48 hours postsurgery). Development of AKI (increase in serum creatinine concentration of 0.3 mg/dL) and in-hospital mortality were recorded. Linear mixed-model analysis was employed to assess differences between groups over time. Mann-Whitney U-test was performed for comparison of continuous variables between groups and Chi square or Fisher's exact tests were used to assess correlation between discrete data. RESULTS: Serum NGAL and UNCR were significantly higher in study dogs across all time points (P = .007 and P < .001, respectively) compared with controls. Urinary NGAL normalized to creatinine in the study group was not significantly different between survivors (n = 12) and nonsurvivors (n = 3). Dogs that received hydroxyethyl starch had significantly higher UNCR across all time points (P = .04) than those that did not. DISCUSSION CONCLUSION: Serum neutrophil gelatinase-associated lipocalin and UNCR are increased in dogs with sepsis requiring emergency laparotomy. Additional studies are needed to evaluate its role as a marker of AKI in this population. PMID- 26415730 TI - Abundance of specific mRNA transcripts impacts hatching success in European eel, Anguilla anguilla L. AB - Maternal mRNA governs early embryonic development in fish and variation in abundance of maternal transcripts may contribute to variation in embryonic survival and hatch success in European eel, Anguilla anguilla. Previous studies have shown that quantities of the maternal gene products beta-tubulin, insulin like growth factor 2 (igf2), nucleoplasmin (npm2), prohibitin 2 (phb2), phosphatidylinositol glycan biosynthesis class F protein 5 (pigf5), and carnitine O-palmitoyltransferase liver isoform-like 1 (cpt1) are associated with embryonic developmental competence in other teleosts. Here, the relations between relative mRNA abundance of these genes in eggs and/or embryos and egg quality, was studied and analyzed. We compared egg quality of the two groups: i) batches with hatching and ii) batches with no hatching. Results showed no significant differences in relative mRNA abundance between the hatch and no hatching groups for any of the selected genes at 0, 2.5, and 5HPF. However, at 30HPF the hatch group showed significantly higher abundance of cpt1a, cpt1b, beta-tubulin, phb2, and pigf5 transcripts than the no hatch group. Therefore, these results indicate that up regulation of the transcription of these genes in European eel after the mid blastula transition, may be needed to sustain embryonic development and hatching success. PMID- 26415731 TI - Associations of arterial carbon dioxide and arterial oxygen concentrations with hospital mortality after resuscitation from cardiac arrest. AB - INTRODUCTION: Arterial concentrations of carbon dioxide (PaCO2) and oxygen (PaO2) during admission to the intensive care unit (ICU) may substantially affect organ perfusion and outcome after cardiac arrest. Our aim was to investigate the independent and synergistic effects of both parameters on hospital mortality. METHODS: This was a cohort study using data from mechanically ventilated cardiac arrest patients in the Dutch National Intensive Care Evaluation (NICE) registry between 2007 and 2012. PaCO2 and PaO2 levels from arterial blood gas analyses corresponding to the worst oxygenation in the first 24 h of ICU stay were retrieved for analyses. Logistic regression analyses were performed to assess the relationship between hospital mortality and both categorized groups and a spline based transformation of the continuous values of PaCO2 and PaO2. RESULTS: In total, 5,258 cardiac arrest patients admitted to 82 ICUs in the Netherlands were included. In the first 24 h of ICU admission, hypocapnia was encountered in 22 %, and hypercapnia in 35 % of included cases. Hypoxia and hyperoxia were observed in 8 % and 3 % of the patients, respectively. Both PaCO2 and PaO2 had an independent U-shaped relationship with hospital mortality and after adjustment for confounders, hypocapnia and hypoxia were significant predictors of hospital mortality: OR 1.37 (95 % CI 1.17-1.61) and OR 1.34 (95 % CI 1.08-1.66). A synergistic effect of concurrent derangements of PaCO2 and PaO2 was not observed (P = 0.75). CONCLUSIONS: The effects of aberrant arterial carbon dioxide and arterial oxygen concentrations were independently but not synergistically associated with hospital mortality after cardiac arrest. PMID- 26415732 TI - MiR-140-3p suppressed cell growth and invasion by downregulating the expression of ATP8A1 in non-small cell lung cancer. AB - MicroRNAs (miRNAs) as a class of small noncoding RNA molecules regulate the expression of targeted gene. The dysregulation of microRNAs is reported to be involved in carcinogenesis and tumor progression. Here, we identified miR-140-3p as a downregulated microRNA in most cancer tissues including lung cancer tissues, compared with their normal counterparts. MiR-140-3p was observed to perform its tumor suppressor function via its inhibition on cell growth, migration and invasion but its induction of cell apoptosis. Furthermore, the growth of non small-cell lung cancer (NSCLC) cells in nude mouse models were suppressed by overexpression of miR-140-3p. ATP8A1 was demonstrated as a novel direct target of miR-140-3p using a luciferase assay. The increased level of intracellular ATP8A1 protein attenuated the inhibitor role of miR-140-3p in the growth and mobility of NSCLC cell. A regulation mechanism of miR-140-3p for the development and progression of NSCLC through downregulating the ATP8A1 expression was first discovered in the present study. PMID- 26415733 TI - PI-88 inhibits postoperative recurrence of hepatocellular carcinoma via disrupting the surge of heparanase after liver resection. AB - Phosphomannopentaose sulfate (PI-88), an effective inhibitor of heparanase (HPSE), exhibited anti-recurrence and anti-metastasis activity in preliminary clinical trials of hepatocellular carcinoma (HCC); however, the underlying mechanisms remain uncertain. Our aim was to reveal the mechanism by which PI-88 inhibits recurrence and intrahepatic metastasis. A tissue microarray containing samples from 352 HCC patients was used to determine HPSE expression. We performed enzyme-linked immunosorbent assay (ELISA) to detect plasma levels of HPSE in 40 HCC patients. We also used quantitative polymerase chain reaction, western blot analysis, and immunohistochemical staining to assess HPSE expression of HCC cell lines and tissues. The in vitro effects of PI-88 were examined by cell proliferation and migration assays. In vivo PI-88 activity was assessed using murine orthotopic HCC models. Intratumoral HPSE was an independent prognostic marker for postsurgical overall survival (P = 0.001) and time to recurrence (P < 0.001) of HCC patients with hepatectomy. Elevated levels of HPSE were detected both in postsurgical plasma of HCC patients and an orthotopic mouse model after hepatectomy. PI-88 inhibited tumor recurrence and metastasis after liver resection in the mouse model. In vitro expression of HPSE was up-regulated by overexpression of early growth response 1 (EGR1), which is induced after hepatectomy. Up-regulation of HPSE enhanced the sensitivity of HCC cells to PI-88 and the inhibitive effect of PI-88 on cell proliferation and migration. Our data show that PI-88 effectively inhibits postoperative recurrence and intrahepatic metastasis of HCC, providing an experimental basis for the clinical application of PI-88 in HCC patients who have undergone hepatectomy. PMID- 26415735 TI - Assisting the bereaved: A systematic review of the evidence for grief counselling. AB - BACKGROUND: Supporting people after bereavement is a priority area for many health services. Investment in bereavement care must be supported by a rigorous evidence-base. AIM: To examine the (1) relative proportion of descriptive, measurement and intervention research in grief counselling and (2) quality and effectiveness of intervention studies. DESIGN: Systematic review of studies published in the area of grief counselling. DATA SOURCES: MEDLINE, Embase, Cochrane Library and PsycINFO databases were searched for studies published between 2000 and 2013. Eligible papers were categorised into descriptive, measurement, review, commentaries and intervention studies. Intervention studies were assessed against the Cochrane Effective Practice and Organisation of Care methodological criteria, and papers meeting criteria were assessed for quality. The impact of interventions on grief, psychological morbidity and quality of life was examined. RESULTS: A total of 126 data-based papers, including 47 descriptive, 3 measurement and 76 grief counselling intervention studies were included. Only 59% (n = 45) of intervention studies met Effective Practice and Organisation of Care design criteria. Overall, study quality was poor, with the majority of interventions showing a risk of bias in several key areas. The three studies that met all criteria showed mixed effectiveness. CONCLUSION: Grief counselling interventions require a strong rationale for design, and a systematic approach to development and evaluation. Descriptive research efforts should inform this process, focusing on homogeneity in sample, identification of risk factors for complicated grief and the impact of extraneous factors on intervention effects. Interventions should include comparisons to usual care, as well as replication to confirm positive findings. PMID- 26415736 TI - Discovering the hidden benefits of cognitive interviewing in two languages: The first phase of a validation study of the Integrated Palliative care Outcome Scale. AB - BACKGROUND: The Integrated Palliative care Outcome Scale is a newly developed advancement of the Palliative care Outcome Scale. It assesses patient-reported symptoms and other concerns. Cognitive interviewing is recommended for questionnaire refinement but not adopted widely in palliative care research. AIM: To explore German- and English-speaking patients' views on the Integrated Palliative care Outcome Scale with a focus on comprehensibility and acceptability, and subsequently refine the questionnaire. METHODS: Bi-national (United Kingdom/Germany) cognitive interview study using 'think aloud' and verbal probing techniques. Interviews were audio-recorded, transcribed verbatim and analysed using thematic analysis and pre-defined categories. Results from both countries were collated and discussed. The Integrated Palliative care Outcome Scale was then refined by consensus. SETTING/PARTICIPANTS: Purposely sampled patients from four palliative care teams in palliative care units, general hospital wards and in the community. RESULTS: A total of 15 German and 10 UK interviews were conducted. Overall, comprehension and acceptability of the Integrated Palliative care Outcome Scale were good. Identified difficulties comprised the following: (1) comprehension problems with specific terms (e.g. 'mouth problems') and length of answer options; (2) judgement difficulties, for example, due to the 3-day recall for questions; and (3) layout problems. Combining the results from both countries (e.g. regarding 'felt good about yourself') and discussing them from both languages' perspectives resulted in wider consideration of the items' meaning, enabling more detailed refinement. CONCLUSION: Cognitive interviewing proved valuable to increase face and content validity of the questionnaire. The concurrent approach in two languages - to our knowledge the first such approach in palliative care - benefited the refinement. Psychometric validation of the refined Integrated Palliative care Outcome Scale is now underway. PMID- 26415734 TI - Comparison of meta-analyses among elastosonography (ES) and positron emission tomography/computed tomography (PET/CT) imaging techniques in the application of prostate cancer diagnosis. AB - The early diagnosis of prostate cancer (PCa) appears to be of vital significance for the provision of appropriate treatment programs. Even though several sophisticated imaging techniques such as positron emission tomography/computed tomography (PET/CT) and elastosonography (ES) have already been developed for PCa diagnosis, the diagnostic accuracy of these imaging techniques is still controversial to some extent. Therefore, a comprehensive meta-analysis in this study was performed to compare the accuracy of various diagnostic imaging methods for PCa, including 11C-choline PET/CT, 11C-acetate PET/CT, 18F-fluorocholine PET/CT, 18F-fluoroglucose PET/CT, transrectal real-time elastosonography (TRTE), and shear-wave elastosonography (SWE). The eligible studies were identified through systematical searching for the literature in electronic databases including PubMed, Cochrane, and Web of Science. On the basis of the fixed-effects model, the pooled sensitivity (SEN), specificity (SPE), and area under the receiver operating characteristics curve (AUC) were calculated to estimate the diagnostic accuracy of 11C-choline PET/CT, 11C-acetate PET/CT, 18F-fluorocholine (FCH) PET/CT, 18F-fluoroglucose (FDG) PET/CT, TRTE, and SWE. All the statistical analyses were conducted with R language Software. The present meta-analysis incorporating a total of 82 studies demonstrated that the pooled sensitivity of the six imaging techniques were sorted as follows: SWE > 18F-FCH PET/CT > 11C choline PET/CT > TRTE > 11C-acetate PET/CT > 18F-FDG PET/CT; the pooled specificity were also compared: SWE > 18F-FCH PET/CT > 11C-choline PET/CT > TRTE > 18F-FDG PET/CT > 11C-acetate PET/CT; finally, the pooled diagnostic accuracy of the six imaging techniques based on AUC were ranked as below: SWE > 18F-FCH PET/CT > 11C-choline PET/CT > TRTE > 11C-acetate PET/CT > 18F-FDG PET/CT. SWE and 18F-FCH PET/CT imaging could offer more assistance in the early diagnosis of PCa than any other studied imaging techniques. However, the diagnostic ranking of the six imaging techniques might not be applicable to the clinical phase due to the shortage of stratified analysis. PMID- 26415737 TI - The relevance of educating doctors, pharmacists and older patients about potentially inappropriate medications. AB - Providing appropriate pharmacotherapy to older people can be difficult since older people are more at risk of developing adverse drug reactions due to age related physiological changes. The use of potentially inappropriate medications (PIMs) among older people is common throughout the globe, and is a cause for concern due to their clinical, humanistic and economic implications. Nevertheless, it appears that doctors and pharmacists have limited knowledge regarding PIMs. Moreover, uninformed older patients may use PIMs without considering their potential negative consequences. There is a need, therefore, to educate doctors, pharmacists and older patients about PIMs. Geriatric pharmacotherapy education with an emphasis on appropriate prescribing, and PIMs, should be included in the medical and pharmacy teachings at the undergraduate, postgraduate and continuing education levels. Moreover, older patients should be informed about PIMs and the possible risks that they may pose. PMID- 26415738 TI - Training on the use of a bespoke continuing professional development framework improves the quality of CPD records. AB - BACKGROUND: Using continuing professional development (CPD) as part of the revalidation of pharmacy professionals has been proposed in the UK but not implemented. We developed a CPD outcomes framework ('the framework') for scoring CPD records, where the score range was -100 to +150 based on demonstrable relevance and impact of the CPD on practice. OBJECTIVE: This exploratory study aimed to test the outcome of training people to use the framework, through distance-learning material (active intervention), by comparing CPD scores before and after training. SETTING: Pharmacy professionals were recruited in the UK in Reading, Banbury, Southampton, Kingston-upon-Thames and Guildford in 2009. METHOD: We conducted a randomised, double-blinded, parallel-group, before and after study. The control group simply received information on new CPD requirements through the post; the active intervention group also received the framework and associated training. Altogether 48 participants (25 control, 23 active) completed the study. All participants submitted CPD records to the research team before and after receiving the posted resources. The records (n = 226) were scored blindly by the researchers using the framework. A subgroup of CPD records (n = 96) submitted first (before-stage) and rewritten (after-stage) were analysed separately. MAIN OUTCOME MEASURE: Scores for CPD records received before and after distributing group-dependent material through the post. RESULTS: Using a linear-regression model both analyses found an increase in CPD scores in favour of the active intervention group. For the complete set of records, the effect was a mean difference of 9.9 (95 % CI 0.4-19.3), p value = 0.04. For the subgroup of rewritten records, the effect was a mean difference of 17.3 (95 % CI 5.6-28.9), p value = 0.0048. CONCLUSION: The intervention improved participants' CPD behaviour. Training pharmacy professionals to use the framework resulted in better CPD activities and CPD records, potentially helpful for revalidation of pharmacy professionals. PMID- 26415739 TI - Persistent expression and function of P-glycoprotein on peripheral blood lymphocytes identifies corticosteroid resistance in patients with systemic lupus erythematosus. AB - Corticosteroids (CS) are the mainstay of treatment in systemic lupus erythematosus (SLE) patients. However, some patients have poor response to CS treatment. Among the multiple mechanisms of CS resistance, overexpression of P glycoprotein (P-gp) on peripheral blood lymphocytes (PBL) may be one of them as this result in efflux of CS from lymphocytes. Thus, we evaluated the role of P-gp protein on PBLs in patients with SLE in its response to CS therapy. SLE patients (n = 42) (fulfilling ACR revised criteria) who were naive to CS and immunosuppressive drugs were enrolled. Disease activity was assessed using SLE disease activity index (SLEDAI) and expression, and function of P-gp was evaluated by flow cytometry at baseline and after 3 months of therapy with CS. At 3 months, patients with SLEDAI >4 and SLEDAI <=4 were grouped as nonresponders and responders, respectively. P-gp expression was significantly increased on PBLs of SLE patients as compared to healthy controls (p < 0.001). P-gp expression and function correlated with SLEDAI (r = 0.49, p = 0.005; and r = 0.49, p = 0.001, respectively). P-gp expression and function were not different in responders and nonresponders at baseline. However, at 3 months of CS therapy, P-gp expression and function decreased in responders (p < 0.001 and p < 0.005, respectively), whereas in nonresponders, it remained unchanged. Persistent overexpression and activity of P-gp are associated with poor response to CS in CS naive patients of SLE. PMID- 26415740 TI - Prevalence of soluble peptidylarginine deiminase 4 (PAD4) and anti-PAD4 antibodies in autoimmune diseases. AB - The objectives of this study are to investigate the prevalence of PAD4 and anti PAD4 antibodies (Abs) in autoimmune diseases and to clarify their association with anticitrullinated protein antibodies (ACPAs) and shared epitope (SE) in patients with rheumatoid arthritis (RA). Levels of human PAD4 and anti-PAD4 Abs in serum or plasma were measured using sandwich ELISA. Samples were obtained from patients with RA (n = 148), SLE (n = 36), or SS (n = 37) and from healthy controls (HCs; n = 40). Antibodies against cyclic citrullinated glucose-6 phosphate isomerase (GPI) (CCG)-2, CCG-7, anti-CEP-1, and anti-CCP Abs were also measured using ELISA. Patients with RA were genotyped for HLA-DRB1. The human PAD4 and anti-PAD4 Ab levels were compared with the ACPA and SE in patients with RA. The PAD4 levels were 111.9 U/ml in the RA, 30.4 U/ml in the SLE, 81.9 U/ml in the SS patients, and 46.6 U/ml in the HCs. The PAD4 levels were significantly higher in the RA than in the SLE patients or the HCs. Anti-PAD4 Abs were detected in 29.7 % of the patients with RA, but not in the patients with SLE or SS, nor in the HCs. In the RA patients, the PAD4 levels in the anti-PAD4 Ab-negative group were significantly higher than those in the anti-PAD4 Ab-positive group. Moreover, anti-CCG-2, CCG-7, CEP-1, and anti-CCP Ab levels were significantly higher in the anti-PAD4 Ab-positive group than in the anti-PAD4 Ab-negative group. In the RA patients, the PAD4 levels were not correlated with ACPAs. Neither PAD4 nor anti-PAD4 Abs were significantly correlated with the presence of SE alleles. The PAD4 levels were higher in RA than in SLE or HC. Anti-PAD4 Abs appeared specifically in patients with RA. Moreover, anti-PAD4 Abs were associated with ACPAs. PMID- 26415742 TI - Variational methods for fitting complex Bayesian mixed effects models to health data. AB - We consider approximate inference methods for Bayesian inference to longitudinal and multilevel data within the context of health science studies. The complexity of these grouped data often necessitates the use of sophisticated statistical models. However, the large size of these data can pose significant challenges for model fitting in terms of computational speed and memory storage. Our methodology is motivated by a study that examines trends in cesarean section rates in the largest state of Australia, New South Wales, between 1994 and 2010. We propose a group-specific curve model that encapsulates the complex nonlinear features of the overall and hospital-specific trends in cesarean section rates while taking into account hospital variability over time. We use penalized spline-based smooth functions that represent trends and implement a fully mean field variational Bayes approach to model fitting. Our mean field variational Bayes algorithms allow a fast (up to the order of thousands) and streamlined analytical approximate inference for complex mixed effects models, with minor degradation in accuracy compared with the standard Markov chain Monte Carlo methods. PMID- 26415741 TI - Feeding butter with elevated content of trans-10, cis-12 conjugated linoleic acid to obese-prone rats impairs glucose and insulin tolerance. AB - BACKGROUND: We recently demonstrated that feeding a natural CLAt10,c12-enriched butter to lean female rats resulted in small, but significant increases in fasting glucose and insulin concentrations, and impaired insulin tolerance. Our goal was to extend these findings by utilizing the diabetes-prone female fatty Zucker rat. Rats were fed custom diets containing 45 % kcal of fat derived from control and CLAt10,c12-enriched butter for 8 weeks. METHODS: CLA t10,c12-enriched butter was prepared from milk collected from cows fed a high fermentable carbohydrate diet to create subacute rumen acidosis (SARA); control (non-SARA) butter was collected from cows fed a low grain diet. Female fatty Zucker rats (10 weeks old) were randomly assigned to one of four diet treatments: i) low fat (10 % kcal), ii) 45 % kcal lard, iii) 45 % kcal SARA butter, or iv) 45 % kcal non SARA butter. A low fat fed lean Zucker group was used as a control group. After 8 weeks, i) glucose and insulin tolerance tests, ii) insulin signaling in muscle, adipose and liver, and iii) metabolic caging measurements were performed. RESULTS: Glucose and insulin tolerance were significantly impaired in all fatty Zucker groups, but to the greatest extent in the LARD and SARA conditions. Insulin signaling (AKT phosphorylation) was impaired in muscle, visceral (perigonadal) adipose tissue and liver in fatty Zucker rats, but was generally similar across dietary groups. Physical activity, oxygen consumption, food intake and weight gain were also similar amongst the various fatty Zucker groups. CONCLUSIONS: Increasing the consumption of a food naturally enriched with CLAt10,c12 significantly worsens glucose and insulin tolerance in a diabetes prone rodent model. This outcome is not explained by changes in tissue insulin signaling, physical activity, energy expenditure, food intake or body mass. PMID- 26415743 TI - [Impact of pharmaceutical intervention in preventing relapses in depression in Primary Care]. AB - OBJECTIVE: To evaluate the long-term impact of a brief pharmacist intervention (PI) compared with usual care (UC) on prevention of depression relapse. DESIGN: randomised controlled clinical trial SETTING: Primary Care PARTICIPANTS: Of the 179 depressed patients initiating antidepressants, the 113 whose clinical symptoms had remitted (main definition) at 6 months assessment were selected for this secondary study (PI=58; UC=55). INTERVENTION: PI was an interview to promote medication adherence when patients get antidepressants from pharmacy. MAIN MEASUREMENTS: Baseline, 3 months, and six-months follow-up assessments were made. The severity of depressive symptoms was evaluated with PHQ9. Patients presenting a remission of symptoms were selected. The patient medical records were reviewed to identify a relapse in the following 12 months by using 4 indicators. RESULTS: There was a lower proportion of patients that relapsed in the PI group than in the UC group 18 months after initiation of treatment, but the difference was not statistically significant either in the intent-to-treat analysis (OR=0.734 [95%CI; 0.273-1.975]) or the per-protocol analysis (OR=0.615 [95%CI; 0.183 2.060]). All the sensitivity analyses showed consistent results. The sample size and adherence to the protocol in the intervention group were low. CONCLUSION: PI group showed a non-statistically significant tendency towards presenting fewer relapses. This could be related to the improvement in adherence among patients that received the intervention. PMID- 26415744 TI - Mapping viscoelastic properties of healthy and pathological red blood cells at the nanoscale level. AB - In order to pass through the microcirculation, red blood cells (RBCs) need to undergo extensive deformations and to recover the original shape. This extreme deformability is altered by various pathological conditions. On the other hand, an altered RBC deformability can have major effects on blood flow and can lead to pathological implications. The study of the viscoelastic response of red blood cells to mechanical stimuli is crucial to fully understand deformability changes under pathological conditions. However, the typical erythrocyte biconcave shape hints to a complex and intrinsically heterogeneous mechanical response that must be investigated by using probes at the nanoscale level. In this work, the local viscoelastic behaviour of healthy and pathological red blood cells was probed by Atomic Force Microscopy (AFM). Our results clearly show that the RBC stiffness is not spatially homogeneous, suggesting a strong correlation with the erythrocyte biconcave shape. Moreover, our nanoscale mapping highlights the key role played by viscous forces, demonstrating that RBCs do not behave as pure elastic bodies. The fundamental role played by viscous forces is further strengthened by the comparison between healthy and pathological (diabetes mellitus) RBCs. It is well known that pathological RBCs are usually stiffer than the healthy ones. Our measures unveil a more complex scenario according to which the difference between normal and pathological red blood cells does not merely lie in their stiffness but also in a different dynamical response to external stimuli that is governed by viscous forces. PMID- 26415745 TI - Cumulative Attributable Difference: An Infection Metric That Reflects a Value System. PMID- 26415746 TI - Understanding barriers to home-based and self-care in-center hemodialysis. AB - Despite superior outcomes and lower associated costs, relatively few patients with end-stage renal disease undergo self-care or home hemodialysis. Few studies have examined patient- and physician-specific barriers to self-care and home hemodialysis in the modern era. The degree to which innovative technology might facilitate the adoption of these modalities is unknown. We surveyed 250 patients receiving in-center hemodialysis and 51 board-certified nephrologists to identify key barriers to adoption of self-care and home hemodialysis. Overall, 172 (69%) patients reported that they were "likely" or "very likely" to consider self-care hemodialysis if they were properly trained on a new hemodialysis system designed for self-care or home use. Nephrologists believed that patients were capable of performing many dialysis-relevant tasks, including: weighing themselves (98%), wiping down the chair and machine (84%), clearing alarms during treatment (53%), taking vital signs (46%), and cannulating vascular access (41%), but thought that patients would be willing to do the same in only 69%, 34%, 31%, 29%, and 16%, respectively. Reasons that nephrologists believe patients are hesitant to pursue self-care or home hemodialysis do not correspond in parallel or by priority to reasons reported by patients. Self-care and home hemodialysis offer several advantages to patients and dialysis providers. Overcoming real and perceived barriers with new technology, education and coordinated care will be required for these modalities to gain traction in the coming years. PMID- 26415747 TI - Phosphorylation of alphaB-crystallin: Role in stress, aging and patho physiological conditions. AB - BACKGROUND: alphaB-crystallin, once thought to be a lenticular protein, is ubiquitous and has critical roles in several cellular processes that are modulated by phosphorylation. Serine residues 19, 45 and 59 of alphaB-crystallin undergo phosphorylation. Phosphorylation of S45 is mediated by p44/42 MAP kinase, whereas S59 phosphorylation is mediated by MAPKAP kinase-2. Pathway involved in S19 phosphorylation is not known. SCOPE OF REVIEW: The review highlights the role of phosphorylation in (i) oligomeric structure, stability and chaperone activity, (ii) cellular processes such as apoptosis, myogenic differentiation, cell cycle regulation and angiogenesis, and (iii) aging, stress, cardiomyopathy-causing alphaB-crystallin mutants, and in other diseases. MAJOR CONCLUSIONS: Depending on the context and extent of phosphorylation, alphaB-crystallin seems to confer beneficial or deleterious effects. Phosphorylation alters structure, stability, size distribution and dynamics of the oligomeric assembly, thus modulating chaperone activity and various cellular processes. Phosphorylated alphaB crystallin has a tendency to partition to the cytoskeleton and hence to the insoluble fraction. Low levels of phosphorylation appear to be protective, while hyperphosphorylation has negative implications. Mutations in alphaB-crystallin, such as R120G, Q151X and 464delCT, associated with inherited myofibrillar myopathy lead to hyperphosphorylation and intracellular inclusions. An ongoing study in our laboratory with phosphorylation-mimicking mutants indicates that phosphorylation of R120GalphaB-crystallin increases its propensity to aggregate. GENERAL SIGNIFICANCE: Phosphorylation of alphaB-crystallin has dual role that manifests either beneficial or deleterious consequences depending on the extent of phosphorylation and interaction with cytoskeleton. Considering that disease causing mutants of alphaB-crystallin are hyperphosphorylated, moderation of phosphorylation may be a useful strategy in disease management. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease. PMID- 26415748 TI - The body fades away: investigating the effects of transparency of an embodied virtual body on pain threshold and body ownership. AB - The feeling of "ownership" over an external dummy/virtual body (or body part) has been proven to have both physiological and behavioural consequences. For instance, the vision of an "embodied" dummy or virtual body can modulate pain perception. However, the impact of partial or total invisibility of the body on physiology and behaviour has been hardly explored since it presents obvious difficulties in the real world. In this study we explored how body transparency affects both body ownership and pain threshold. By means of virtual reality, we presented healthy participants with a virtual co-located body with four different levels of transparency, while participants were tested for pain threshold by increasing ramps of heat stimulation. We found that the strength of the body ownership illusion decreases when the body gets more transparent. Nevertheless, in the conditions where the body was semi-transparent, higher levels of ownership over a see-through body resulted in an increased pain sensitivity. Virtual body ownership can be used for the development of pain management interventions. However, we demonstrate that providing invisibility of the body does not increase pain threshold. Therefore, body transparency is not a good strategy to decrease pain in clinical contexts, yet this remains to be tested. PMID- 26415749 TI - Attachment Style and Less Severe Forms of Sexual Coercion: A Systematic Review. AB - Few studies have examined how attachment insecurity (i.e., attachment anxiety, attachment avoidance) is associated with the more subtle and less severe forms of sexual coercion, such as verbal threats and partner manipulation. This is despite the fact that past research has indicated some of the relationship behaviors exhibited by insecurely attached individuals represent behaviors indicative of either the perpetration or victimization of less severe forms of sexual coercion. The aim of this study was to conduct a systematic review on the association between attachment style and less severe forms of sexual coercion. Our search, which included published journal papers, book chapters, and theses published between January 1970 and October 2014, yielded 1091 records. Examination of these records against exclusion criteria yielded 11 studies that focused on the associations between attachment orientation and perpetration of sexual coercion (n = 3), sexual coercion victimization (n = 3), or both perpetration and victimization (n = 5). Findings revealed that attachment anxiety appeared to be more consistently associated with being the victim of sexual coercion than attachment avoidance. In terms of perpetration, attachment avoidance was more consistently associated with sexual coercion. These findings were observed when examining the association between attachment dimensions and motives for sexual coercion. The findings also revealed gender to be a moderator for victimization. This review provides insights into how attachment style may influence the perpetration and victimization of sexual coercion. PMID- 26415750 TI - Evaluation of a dilution method for non-evaluable results in the detection of Chlamydia trachomatis and Neisseria gonorrhoeae with the Cobas 4800 platform. AB - INTRODUCTION: A variable percentage of samples analysed using the Cobas 4800 assay can give an invalid result by PCR inhibition or erroneous due to incorrect DNA extraction with the Cobas 4800 CT/NG test. METHOD: An analysis was performed using the vortex agitation and dilution protocol on the original sample (swab or urine) for a total of 116 samples. In order to analyse the sensitivity of this method, 100 samples (swabs and urine) with known results were retested. RESULTS: A total of 98.3% (114/116) of the samples analysed were resolved with this protocol with 100% agreement after reviewing clinical data, Gram stain, and other samples analysed in parallel from the same patient. DISCUSSION: The data indicate no loss of sensitivity with this protocol; thus Cobas 4800 users could use this method without the need for alternative methods. PMID- 26415751 TI - A systematic review of reliable and valid tools for the measurement of patient participation in healthcare. AB - INTRODUCTION: Patient participation in healthcare is recognised internationally as essential for consumer-centric, high-quality healthcare delivery. Its measurement as part of continuous quality improvement requires development of agreed standards and measurable indicators. AIM: This systematic review sought to identify strategies to measure patient participation in healthcare and to report their reliability and validity. In the context of this review, patient participation was constructed as shared decision-making, acknowledging the patient as having critical knowledge regarding their own health and care needs and promoting self-care/autonomy. METHODS: Following a comprehensive search, studies reporting reliability or validity of an instrument used in a healthcare setting to measure patient participation, published in English between January 2004 and March 2014 were eligible for inclusion. RESULTS: From an initial search, which identified 1582 studies, 156 studies were retrieved and screened against inclusion criteria. Thirty-three studies reporting 24 patient participation measurement tools met inclusion criteria, and were critically appraised. The majority of studies were descriptive psychometric studies using prospective, cross-sectional designs. Almost all the tools completed by patients, family caregivers, observers or more than one stakeholder focused on aspects of patient professional communication. Few tools designed for completion by patients or family caregivers provided valid and reliable measures of patient participation. There was low correlation between many of the tools and other measures of patient satisfaction. CONCLUSION: Few reliable and valid tools for measurement of patient participation in healthcare have been recently developed. Of those reported in this review, the dyadic Observing Patient Involvement in Decision Making (dyadic OPTION) tool presents the most promise for measuring core components of patient participation. There remains a need for further study into valid, reliable and feasible strategies for measuring patient participation as part of continuous quality improvement. PMID- 26415752 TI - Response of human bone marrow-derived MSCs on triphasic Ca-P substrate with various HA/TCP ratio. AB - Calcium phosphates (Ca-P) are used commonly as artificial bone substitutes to control the biodegradation rate of an implant in the body fluid. This study examined the in vitro proliferation of human bone marrow-derived mesenchymal stem cells (hBMSCs) on triphasic Ca-P samples. For this aspect, hydroxyapatite (HA), dicalcium phosphate dehydrate (DCPD), and calcium hydroxide (Ca(OH)2 ) were mixed at various ratios, cold compacted, and sintered at 1250 degrees C in air. X-ray diffraction showed that the beta-tricalcium phosphate (TCP) to alpha-TCP phase transformation increased with increasing DCPD/HA ratio. The micro-hardness deceased with increasing TCP content, whereas the mean grain size and porosity increased with increasing TCP concentration. To evaluate the in vitro degree of adhesion and proliferation on the HA/TCP samples, human BMSCs were incubated on the HA/TCP samples and analyzed by a cells proliferation assay, expression of the extracellular matrix (ECM) genes, such as alpha-smooth muscle actin (alpha-SMA) and fibronectin (FN), and FITC-phalloidin fluorescent staining. In terms of the interactions of human BMSCs with the triphasic Ca-P samples, H50T50 (Ca/P = 1.59) markedly enhanced cell spreading, proliferation, FN, and alpha-SMA compared with H100T0 (Ca/P = 1.67). Interestingly, these results show that among the five HA/TCP samples, H50T50 is the optimal Ca-P composition for in vitro cell proliferation. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 72-80, 2017. PMID- 26415753 TI - Complete genome sequencing of a genotype 3 hepatitis E virus strain identified in a swine farm in Italy. AB - In this study, we investigated hepatitis E virus (HEV) infection in piglets sampled in two farms in southern Italy. The virus was detected in 11 out of 15 animals tested. Based on sequence analysis, the 6 Italian strains examined belonged to two clusters containing both swine and human strains of either genotype 3 subtype e or f from Europe and Japan. The two Italian strain clusters shared nucleotide identity of 81.8% and 87.5% in the ORF2 (capsid protein) and ORF1 (RdRp) diagnostic fragments, respectively, confirming the heterogeneity of genotype 3 viruses circulating in pigs in Italy. The complete genome of one genotype 3 subtype e strain and the full ORF2 and ORF3 coding regions of one of the genotype 3f strains, obtained in this study, were compared to other HEV sequences available on line (NCBI database). The results of analysis showed that porcine strains clustered together with human and swine strains detected in Europe. Most changes in the coding region corresponded to synonymous mutations, and only the ORF3 showed a positive selection. Further, analyses are needed to understand the clinical significance of HEV genotypes and subtypes. PMID- 26415754 TI - Ribosomal protein L4 interacts with viral protein VP3 and regulates the replication of infectious bursal disease virus. AB - VP3 protein is a structural protein which plays important roles in the virus assembly and the inhibition of antiviral innate immunity of infectious bursal disease virus (IBDV). To explore the potential roles of VP3 in the interplay of IBDV with the host cell, an immunoprecipitation (IP)-coupled mass spectra (MS) screening was performed and the host cellular ribosomal protein L4 (RPL4) was identified as a putative interacting partner of VP3 protein. The interaction of RPL4 with VP3 was further confirmed by co-immunoprecipitation (co-IP) and their colocalization in DF1 cells were observed by confocal microscopy. In addition, knockdown of RPL4 in DF1 cells resulted in reductions of the viral protein pVP2 expression and the virus titers, which reveals a significant role of RPL4 in IBDV replication. Taken together, we indicated for the first time that ribosomal protein L4 (RPL4) was an interacting partner of VP3 and involved in the modulation of IBDV replication. The present study contributes to further understanding the pathogenic mechanism of IBDV. PMID- 26415755 TI - Generation of a recombinant West Nile virus stably expressing the Gaussia luciferase for neutralization assay. AB - West Nile virus (WNV) is a neurotropic human pathogen that has caused increasing infected cases over recent years. There is currently no licensed vaccine or effective drug for prevention and treatment of WNV infection in humans. To facilitate antiviral drug discovery and neutralizing antibody detection, a WNV cDNA clone containing a luciferase reporter gene was constructed through incorporating Gaussia luciferase (Gluc) gene within the capsid-coding region of WNV genome. Transfection of BHK-21 cells with the cDNA clone-derived RNA generated luciferase reporter WNV (WNV-Gluc) and the stable WNV-Gluc with high titers (>10(7)PFU/ml) was obtained through plaque purification. Luciferase activity was used to effectively quantify the viral production of WNV-Gluc. Using the reporter virus WNV-Gluc, we developed a luciferase based assay in a 12-well format for evaluating neutralizing antibodies. The reporter virus could be a powerful tool for epidemiological investigation of WNV, vaccine evaluation, antiviral drug screening, and the study of WNV replication and pathogenesis. PMID- 26415756 TI - A novel delivery platform based on Bacteriophage MS2 virus-like particles. AB - Our objective here is to review the novel delivery platform based on Bacteriophage MS2 virus-like particles (VLPs), including introduction to their structure, their potential as a delivery platform, and their expected use in medicine and other fields. Bacteriophage MS2 VLPs are nanoparticles devoid of viral genetic material and can self-assemble from the coat protein into an icosahedral capsid. As a novel delivery platform, they possess numerous features that make them suitable and attractive for targeted delivery of RNAs or DNAs, epitope peptides, and drugs within the protein capsid. In short, as a novel delivery platform, MS2 VLPs are suitable for delivery of targeted agents and hold promise for use in diagnostics, vaccines, and therapeutic modalities. PMID- 26415757 TI - Understanding hikers who approached a hazardous river in Yosemite National Park. AB - OBJECTIVES: To understand the perceptions and motivations of hikers who approached a swift river at locations that have been associated with drowning in the past. METHODS: A survey was completed by 399 adults who had been observed getting 'too close' to the Merced River. The questionnaire covered trail familiarity, information sources, timing and motivation of their decision, perceived safety, knowledge and opinion of park rules. RESULTS: Sixty-eight per cent of invited hikers agreed to participate. Almost all had received advance information about their hike, but most often that did not include a river warning. Most respondents were observed in the risk zone by the footbridge, and their most frequent motivation was to 'cool off'. Ninety-two per cent of hikers reported feeling very or somewhat safe by the river. Their risk perceptions did not correlate with expert ratings of danger. Males, younger subjects and those who had hiked the trail before were more likely to enter the most hazardous parts of the risk zone. Eleven per cent of people at the footbridge and 43% at the top of the waterfall thought that the park should not allow visitors to go where they had been. The most common reason they gave for this view was that the location was unsafe. CONCLUSIONS: While this needs assessment identified channels for informing hikers of drowning risk, there are indications that they might not personalise such warnings. Another option would be to explore cooling alternatives that could compete with the swift water that runs along many hiking trails. PMID- 26415758 TI - Hybrid upconversion nanomaterials for optogenetic neuronal control. AB - Nanotechnology-based approaches offer the chemical control required to develop precision tools suitable for applications in neuroscience. We report a novel approach employing hybrid upconversion nanomaterials, combined with the photoresponsive ion channel channelrhodopsin-2 (ChR2), to achieve near-infrared light (NIR)-mediated optogenetic control of neuronal activity. Current optogenetic methodologies rely on using visible light (e.g. 470 nm blue light), which tends to exhibit high scattering and low tissue penetration, to activate ChR2. In contrast, our approach enables the use of 980 nm NIR light, which addresses the short-comings of visible light as an excitation source. This was facilitated by embedding upconversion nanomaterials, which can convert NIR light to blue luminescence, into polymeric scaffolds. These hybrid nanomaterial scaffolds allowed for NIR-mediated neuronal stimulation, with comparable efficiency as that of 470 nm blue light. Our platform was optimized for NIR mediated optogenetic control by balancing multiple physicochemical properties of the nanomaterial (e.g. size, morphology, structure, emission spectra, concentration), thus providing an early demonstration of rationally-designing nanomaterial-based strategies for advanced neural applications. PMID- 26415759 TI - Polysaccharide utilization locus and CAZYme genome repertoires reveal diverse ecological adaptation of Prevotella species. AB - The results of metagenomic studies have clearly established that bacteria of the genus Prevotella represent one of the important groups found in the oral cavity and large intestine of man, and they also dominate the rumen. They belong to the Bacteroidetes, a phylum well-known for its polysaccharide degrading potential that stems from the outer membrane-localized enzyme/binding protein complexes encoded in polysaccharide utilization loci (PULs). Dozens of Prevotella species have been described, primarily from the oral cavity, and many of them occur simultaneously at the same sites, but research on their ecological adaptation has been neglected. Therefore, in this study, the repertoires of PULs and carbohydrate acting enzymes (CAZYmes) found in Prevotella genomes were analyzed and it was concluded that the Prevotella species were widely heterogeneous in this respect and displayed several distinct adaptations with regard to the number, source and nature of the substrates apparently preferred for growth. PMID- 26415760 TI - Trends in the growth of literature of telemedicine: A bibliometric analysis. AB - Over the past two decades, the use of telemedicine as a way to provide medical services has grown as communication technologies advance and patients seek more convenient ways to receive care. Because developments within this field are still rapidly evolving, identifying trends within telemedicine literature is an important task to help delineate future directions of telemedicine research. In this study, we analyzed 7960 telemedicine-related publication records found in the Science Citations Index - Expanded database between 1993 and 2012. Bibliometric analyses revealed that while the total growth in telemedicine literature has been significant in the last twenty years, the publication activity per country and over time has been variable. While the United States led the world in the cumulative number of telemedicine publications, Norway ranked highest when we ordered countries by publications per capita. We also saw that the growth in the number of publications per year has been inconsistent over the past two decades. Our results identified that neuroscience neurology and nursing as two fields of research in telemedicine that have seen considerable growth in interest in this field, and are poised to be the focus of research activity in the near future. PMID- 26415761 TI - Our experience in using the brachial venae comitantes as a native vascular access for hemodialysis. AB - A native arteriovenous fistula is the preferred vascular access for patients on long-term hemodialysis. In the absence of suitable superficial veins, the deep venous system can be used. We intend to present our experience in using the brachial venae comitantes (VC) to create a native arteriovenous fistula. From January 2012 to December 2014, we utilized the brachial vena comitantes to create 12 arteriovenous fistulae. Data from these 12 subjects were analyzed retrospectively to produce this case series. The average age of our subjects was 55.6 years. Forty-two percent of the subjects were women. Fifty percent of the subjects had diabetes mellitus and 58% had hypertension. We achieved a functional patency rate of 58% at 1 month's follow up after maturation. The brachio-brachial vena comitans fistula is a safe and plausible option in patients with no other suitable veins for a native fistula, more so in the hands of experienced surgeons. The longer time to cannulation has to be taken into consideration when creating a VC fistula. In suitable patients with end-stage renal disease, it can delay the use of an arteriovenous graft or a tunneled central venous catheter. PMID- 26415762 TI - Vitamin C supplementation in pregnancy. AB - BACKGROUND: Vitamin C supplementation may help reduce the risk of pregnancy complications such as pre-eclampsia, intrauterine growth restriction and maternal anaemia. There is a need to evaluate the efficacy and safety of vitamin C supplementation in pregnancy. OBJECTIVES: To evaluate the effects of vitamin C supplementation, alone or in combination with other separate supplements on pregnancy outcomes, adverse events, side effects and use of health resources. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2015) and reference lists of retrieved studies. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials evaluating vitamin C supplementation in pregnant women. Interventions using a multivitamin supplement containing vitamin C or where the primary supplement was iron were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: Twenty-nine trials involving 24,300 women are included in this review. Overall, 11 trials were judged to be of low risk of bias, eight were high risk of bias and for 10 trials it was unclear. No clear differences were seen between women supplemented with vitamin C alone or in combination with other supplements compared with placebo or no control for the risk of stillbirth (risk ratio (RR) 1.15, 95% confidence intervals (CI) 0.89 to 1.49; 20,038 participants; 11 studies; I2 = 0%; moderate quality evidence), neonatal death (RR 0.79, 95% CI 0.58 to 1.08; 19,575 participants; 11 studies; I2 = 0%), perinatal death (average RR 1.07, 95% CI 0.77 to 1.49; 17,105 participants; seven studies; I2 = 35%), birthweight (mean difference (MD) 26.88 g, 95% CI -18.81 to 72.58; 17,326 participants; 13 studies; I2 = 69%), intrauterine growth restriction (RR 0.98, 95% CI 0.91 to 1.06; 20,361 participants; 12 studies; I2 = 15%; high quality evidence), preterm birth (average RR 0.99, 95% CI 0.90 to 1.10; 22,250 participants; 16 studies; I2 = 49%; high quality evidence), preterm PROM (prelabour rupture of membranes) (average RR 0.98, 95% CI 0.70 to 1.36; 16,825 participants; 10 studies; I2 = 70%; low quality evidence), term PROM (average RR 1.26, 95% CI 0.62 to 2.56; 2674 participants; three studies; I2 = 87%), and clinical pre-eclampsia (average RR 0.92, 95% CI 0.80 to 1.05; 21,956 participants; 16 studies; I2 = 41%; high quality evidence).Women supplemented with vitamin C alone or in combination with other supplements compared with placebo or no control were at decreased risk of having a placental abruption (RR 0.64, 95% CI 0.44 to 0.92; 15,755 participants; eight studies; I2 = 0%; high quality evidence) and had a small increase in gestational age at birth (MD 0.31, 95% CI 0.01 to 0.61; 14,062 participants; nine studies; I2 = 65%), however they were also more likely to self-report abdominal pain (RR 1.66, 95% CI 1.16 to 2.37; 1877 participants; one study). In the subgroup analyses based on the type of supplement, vitamin C supplementation alone was associated with a reduced risk of preterm PROM (average RR 0.66, 95% CI 0.48 to 0.91; 1282 participants; five studies; I2 = 0%) and term PROM (average RR 0.55, 95% CI 0.32 to 0.94; 170 participants; one study). Conversely, the risk of term PROM was increased when supplementation included vitamin C and vitamin E (average RR 1.73, 95% CI 1.34 to 2.23; 3060 participants; two studies; I2 = 0%). There were no differences in the effects of vitamin C on other outcomes in the subgroup analyses examining the type of supplement. There were no differing patterns in other subgroups of women based on underlying risk of pregnancy complications, timing of commencement of supplementation or dietary intake of vitamin C prior to trial entry. The GRADE quality of the evidence was high for intrauterine growth restriction, preterm birth, and placental abruption, moderate for stillbirth and clinical pre eclampsia, low for preterm PROM. AUTHORS' CONCLUSIONS: The data do not support routine vitamin C supplementation alone or in combination with other supplements for the prevention of fetal or neonatal death, poor fetal growth, preterm birth or pre-eclampsia. Further research is required to elucidate the possible role of vitamin C in the prevention of placental abruption and prelabour rupture of membranes. There was no convincing evidence that vitamin C supplementation alone or in combination with other supplements results in other important benefits or harms. PMID- 26415763 TI - A conceptual framework for economic optimization of an animal health surveillance portfolio. AB - Decision making on hazard surveillance in livestock product chains is a multi hazard, multi-stakeholder, and multi-criteria process that includes a variety of decision alternatives. The multi-hazard aspect means that the allocation of the scarce resource for surveillance should be optimized from the point of view of a surveillance portfolio (SP) rather than a single hazard. In this paper, we present a novel conceptual approach for economic optimization of a SP to address the resource allocation problem for a surveillance organization from a theoretical perspective. This approach uses multi-criteria techniques to evaluate the performances of different settings of a SP, taking cost-benefit aspects of surveillance and stakeholders' preferences into account. The credibility of the approach has also been checked for conceptual validity, data needs and operational validity; the application potentials of the approach are also discussed. PMID- 26415764 TI - Associations of infant milk feed type on early postnatal growth of offspring exposed and unexposed to gestational diabetes in utero. AB - PURPOSE: Infants on prolonged breastfeeding are known to grow slower during the first year of life. It is still unclear if such effects are similar in offspring exposed to gestational diabetes (GDM) in utero. We examined the associations of infant milk feeding on postnatal growth from birth till 36 months of age in offspring exposed and unexposed to GDM. METHODS: Pregnant mothers undertook 75 g 2-h oral glucose tolerance tests at 26-28 weeks of gestation for GDM diagnosis. Up to 9 measurements of offspring weight and length were collected from birth till 36 months, and interviewer-administered questionnaires were used to ascertain the duration of breastfeeding. RESULTS: There was a statistically significant interaction between GDM status and breastmilk intake by any (p interaction = 0.038) or exclusive/predominant breastfeeding (p interaction = 0.035) for the outcome of conditional weight gain. In offspring of non-GDM mothers (n = 835), greater breastmilk intake (BF >= 4 milk months) was associated with lower conditional gains in weight [B (95 % CI) -0.48 (-0.58, -0.28); p < 0.001] within the first year of life, as well as decreasing weight SDS velocity [ 0.01 (-0.02, -0.005); p < 0.001] and BMI SDS velocity [-0.008 (0.01, -0.002); p = 0.008] across age in the first 36 months. In offspring of GDM mothers (n = 181), however, greater breastmilk intake was associated with increased conditional gains in weight [0.72 (0.23, 1.20); p = 0.029] and BMI SDS [0.49 (0.04, 0.95); p = 0.04] in the first 6 months and did not demonstrate the decreasing weight and BMI SDS velocity observed in offspring of non-GDM mothers. CONCLUSIONS: The reduced weight gain in the first year of life conferred by greater breastmilk intake in non-GDM children was not observed in GDM children. CLINICAL TRIAL REGISTRATION: This study is registered under the Clinical Trials identifier NCT01174875; http://www.clinicaltrials.gov/ct2/show/NCT01174875?term=GUSTO&rank=2 . PMID- 26415765 TI - Inflammatory mediator-induced modulation of GABAA currents in human sensory neurons. AB - The purpose of the present study was to characterize the properties of A-type GABA receptor (GABAA receptor) currents in human sensory neurons. Neurons were obtained from adult organ donors. GABAA currents were recorded in isolated neurons. Both large inactivating low-affinity currents and smaller persistent high-affinity currents were present in all of the 129 neurons studied from 15 donors. The kinetics of human GABAA currents were slower than those in rat sensory neurons. GABA currents were completely blocked by bicuculline (10 MUM), and persistent currents were activated by the delta-subunit-preferring agonist, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol (THIP). The GABA current equilibrium potential was ~ 20 mV more hyperpolarized than in rat neurons. Both low- and high-affinity currents were increased by inflammatory mediators but via different second messenger pathways. These results highlight potentially important species differences in the properties of ion channels present in their native environment and suggest the use of human sensory neurons may be a valuable tool to test compounds prior to use in humans. PMID- 26415766 TI - Effects of chronic peripheral olfactory loss on functional brain networks. AB - The effects of sensory loss on central processing in various sensory systems have already been described. The olfactory system holds the special ability to be activated by a sensorimotor act, without the presentation of an odor. In this study, we investigated brain changes related to chronic peripheral smell loss. We included 11 anosmic patients (eight female, three male; mean age, 43.5 years) with smell loss after an infection of the upper respiratory tract (mean disease duration, 4.64 years) and 14 healthy controls (seven female, seven male; mean age, 30.1 years) in a functional magnetic resonance imaging experiment with a sniffing paradigm. Data were analyzed using group-independent component analysis and functional connectivity analysis. Our results revealed a spatially intact olfactory network in patients, whereas major aberrations due to peripheral loss were observed in functional connectivity through a variety of distributed brain areas. This is the first study to show the re-organization caused by the lack of peripheral input. The results of this study indicate that anosmic patients hold the ability to activate an olfaction-related functional network through the sensorimotor component of odor-perception (sniffing). The areas involved were not different from those that emerged in healthy controls. However, functional connectivity appears to be different between the two groups, with a decrease in functional connectivity in the brain in patients with chronic peripheral sensory loss. We can further conclude that the loss of the sense of smell may induce far reaching effects in the whole brain, which lead to compensatory mechanisms from other sensory systems due to the close interconnectivity of the olfactory system with other functional networks. PMID- 26415767 TI - Phoenixin: A candidate pruritogen in the mouse. AB - Phoenixin (PNX) is a 14-amino acid amidated peptide (PNX-14) or an N-terminal extended 20-residue amidated peptide (PNX-20) recently identified in neural and non-neural tissue. Mass spectrometry analysis identified a major peak corresponding to PNX-14, with negligible PNX-20, in mouse spinal cord extracts. Using a previously characterized antiserum that recognized both PNX-14 and PNX 20, PNX-immunoreactivity (irPNX) was detected in a population of dorsal root ganglion (DRG) cells and in cell processes densely distributed to the superficial layers of the dorsal horn; irPNX cell processes were also detected in the skin. The retrograde tracer, Fluorogold, injected subcutaneously (s.c.) to the back of the cervical and thoracic spinal cord of mice, labeled a population of DRG, some of which were also irPNX. PNX-14 (2, 4 and 8 mg/kg) injected s.c.to the nape of the neck provoked dose-dependent repetitive scratching bouts directed to the back of the neck with the hindpaws. The number of scratching bouts varied from 16 to 95 in 30 min, commencing within 5 min post-injection and lasted 10-15 min. Pretreatment of mice at -20 min with nalfurafine (20 MUg/kg, s.c.), the kappa opioid receptor agonist, significantly reduced the number of bouts induced by PNX 14 (4 mg/kg) compared with that of saline-pretreated mice. Our results suggest that the peptide, PNX-14, serves as one of the endogenous signal molecules transducing itch sensation in the mouse. PMID- 26415768 TI - Protection against cognitive impairment and modification of epileptogenesis with curcumin in a post-status epilepticus model of temporal lobe epilepsy. AB - Epileptogenesis is a dynamic process initiated by insults to the brain that is characterized by progressive functional and structural alterations in certain cerebral regions, leading to the appearance of spontaneous recurrent seizures. Within the duration of the trauma to the brain and the appearance of spontaneous recurrent seizures, there is typically a latent period, which may offer a therapeutic window for preventing the emergence of epilepsy. Previous animal studies have shown that curcumin can attenuate acute seizure severity and brain oxidative stress, but the effect of curcumin on epileptogenesis has not been studied. We examined the effect of continued administration of curcumin during the latent period on epileptogenesis and the deleterious consequences of status epilepticus in adult rats in a post-status epilepticus model of temporal lobe epilepsy induced by kainic acid. We demonstrate that, while administration of curcumin treatment during the latent period does not prevent occurrence of spontaneous recurrent seizures after status epilepticus, it can attenuate the severity of spontaneous recurrent seizures and protect against cognitive impairment. Thus, treatment with curcumin during the latent period following status epilepticus is beneficial in modifying epileptogenesis. PMID- 26415769 TI - New uses of LFPs: Pathway-specific threads obtained through spatial discrimination. AB - Local field potentials (LFPs) reflect the coordinated firing of functional neural assemblies during information coding and transfer across neural networks. As such, it was proposed that the extraordinary variety of cytoarchitectonic elements in the brain is responsible for the wide range of amplitudes and for the coverage of field potentials, which in most cases receive contributions from multiple pathways and populations. The influence of spatial factors overrides the bold interpretations of customary measurements, such as the amplitude and polarity, to the point that their cellular interpretation is one of the hardest tasks in Neurophysiology. Temporal patterns and frequency bands are not exclusive to pathways but rather, the spatial configuration of the voltage gradients created by each pathway is highly specific and may be used advantageously. Recent technical and analytical advances now make it possible to separate and then reconstruct activity for specific pathways. In this review, we discuss how spatial features specific to cells and populations define the amplitude and extension of LFPs, why they become virtually indecipherable when several pathways are co-activated, and then we present the recent advances regarding their disentanglement using spatial discrimination techniques. The pathway-specific threads of LFPs have a simple cellular interpretation, and the temporal fluctuations obtained can be applied to a variety of new experimental objectives and improve existing approaches. Among others, they facilitate the parallel readout of activity in several populations over multiple time scales correlating them with behavior. Also, they access information contained in irregular fluctuations, facilitating the testing of ongoing plasticity. In addition, they open the way to unravel the synaptic nature of rhythmic oscillations, as well as the dynamic relationships between multiple oscillatory activities. The challenge of understanding which waves belong to which populations, and the pathways that provoke them, may soon be overcome. PMID- 26415770 TI - An optimized method for measuring hypocretin-1 peptide in the mouse brain reveals differential circadian regulation of hypocretin-1 levels rostral and caudal to the hypothalamus. AB - The hypocretin/orexin system regulates, among other things, sleep and energy homeostasis. The system is likely regulated by both homeostatic and circadian mechanisms. Little is known about local differences in the regulation of hypocretin activity. The aim of this study was to establish an optimized peptide quantification method for hypocretin-1 extracted from different mouse brain areas and use this method for investigating circadian fluctuations of hypocretin-1 levels in these areas. The results show that hypocretin-1 peptide can be extracted from small pieces of intact tissue, with sufficient yield for measurements in a standard radioimmunoassay. Utilizing the optimized method, it was found that prepro-hypocretin mRNA and peptide show circadian fluctuations in the mouse brain. This study further demonstrates that the hypocretin-1 peptide level in the frontal brain peaks during dark as does prepro-hypocretin mRNA in the hypothalamus. However, in midbrain and brainstem tissue caudal to the hypothalamus, there was less circadian fluctuation and a tendency for higher levels during the light phase. These data suggest that regulation of the hypocretin system differs between brain areas. PMID- 26415771 TI - Anchoring the "floating arm": Use of proprioceptive and mirror visual feedback from one arm to control involuntary displacement of the other arm. AB - Arm movement control takes advantage of multiple inputs, including those originating from the contralateral arm. In the mirror paradigm, it has been suggested that control of the unseen arm, hidden by the mirror, is facilitated by the reflection of the other, moving arm. Although proprioceptive feedback originating from the moving arm, (the image of which is reflected in the mirror), is always coupled with visual feedback in the mirror paradigm, the former has received little attention. We recently showed that the involuntary arm movement following a sustained, isometric contraction, known as the "floating arm" or "Kohnstamm phenomenon", was adjusted to the passive-motorized displacement of the other arm. However, provision of mirror feedback, that is, the reflection in the mirror of the passively moved arm, did not add to this coupling effect. Therefore, the interlimb coupling in the mirror paradigm may to a large extent have a proprioceptive origin rather than a visual origin. The objective of the present study was to decouple mirror feedback and proprioceptive feedback from the reflected, moving arm and evaluate their respective contributions to interlimb coupling in the mirror paradigm. First (in Experiment 1, under eyes closed conditions), we found that masking the proprioceptive afferents of the passively moved arm (by co-vibrating the antagonistic biceps and triceps muscles) suppressed the interlimb coupling between involuntary displacement of one arm and passive displacement of the other. Next (in Experiment 2), we masked proprioceptive afferents of the passively moved arm and specifically evaluated mirror feedback. We found that interlimb coupling through mirror feedback (though significant) was weaker than interlimb coupling through proprioceptive feedback. Overall, the present results show that in the mirror paradigm, proprioceptive feedback is stronger and more consistent than visual-mirror feedback in terms of the impact on interlimb coupling. PMID- 26415773 TI - PROGRAM. PMID- 26415772 TI - Overexpression of alphaCaMKII impairs behavioral flexibility and NMDAR-dependent long-term depression in the medial prefrontal cortex. AB - The medial prefrontal cortex (mPFC) participates in the behavioral flexibility. As a major downstream molecule in the NMDA receptor signaling, alpha Ca(2+)/calmodulin-dependent protein kinase II (alphaCaMKII) is crucial for hippocampal long-term potentiation (LTP) and hippocampus-related memory. However, the role of alphaCaMKII in mPFC-related behavioral flexibility and mPFC synaptic plasticity remains elusive. In the present study, using chemical-genetic approaches to temporally up-regulate alphaCaMKII activity, we found that alphaCaMKII-F89G transgenic mice exhibited impaired behavioral flexibility in Y water maze arm reversal task. Notably, in vitro electrophysiological analysis showed normal basal synaptic transmission, LTP and depotentiation, but selectively impaired NMDAR-dependent long-term depression (LTD) in the mPFC of alphaCaMKII-F89G transgenic mice. In accordance with the deficit in NMDAR dependent LTD, alphaCaMKII-F89G transgenic mice exhibited impaired AMPAR internalization during NMDAR-dependent chemical LTD expression in the mPFC. Furthermore, the above deficits in behavioral flexibility, NMDAR-dependent LTD and AMPAR internalization could all be reversed by 1-naphthylmethyl (NM)-PP1, a specific inhibitor of exogenous alphaCaMKII-F89G activity. Taken together, our results for the first time indicate that alphaCaMKII overexpression in the forebrain impairs behavioral flexibility and NMDAR-dependent LTD in the mPFC, and supports the notion that there is a close relationship between NMDAR-dependent LTD and behavioral flexibility. PMID- 26415774 TI - Increased epigenetic alterations at the promoters of transcriptional regulators following inadequate maternal gestational weight gain. AB - Epigenetic modifications are thought to serve as a memory of exposure to in utero environments. However, few human studies have investigated the associations between maternal nutritional conditions during pregnancy and epigenetic alterations in offspring. In this study, we report genome-wide methylation profiles for 33 postpartum placentas from pregnancies of normal and foetal growth restriction with various extents of maternal gestational weight gain. Epigenetic alterations accumulate in the placenta under adverse in utero environments, as shown by application of Smirnov-Grubbs' outlier test. Moreover, hypermethylation occurs frequently at the promoter regions of transcriptional regulator genes, including polycomb targets and zinc-finger genes, as shown by annotations of the genomic and functional features of loci with altered DNA methylation. Aberrant epigenetic modifications at such developmental regulator loci, if occurring in foetuses as well, will elevate the risk of developing various diseases, including metabolic and mental disorders, later in life. PMID- 26415776 TI - Enhanced efficacy of chemotherapy for breast cancer stem cells by simultaneous suppression of multidrug resistance and antiapoptotic cellular defense. AB - While chemotherapy is universally recognized as a frontline treatment strategy for breast cancer, it is not always successful; among the leading causes of treatment failure is existing and/or acquired multidrug resistance. Cancer stem cells (CSCs), which constitute a minority of the cells of a tumor, are acknowledged to be responsible for increased resistance to chemo-drugs through a combination of increased expression of ATP-binding cassette transporters (ABC transporters), an increased anti-apoptotic defense, and/or the ability for extensive DNA repair like normal stem cells. Consequently, more effective therapy, especially targeted to CSCs, is urgently required. We studied the characteristics of 231-CSCs (CD44+/CD24-) sorted from human MDA-MB-231 breast cancer cells and demonstrated that 231-CSCs exhibited enhanced capacities for proliferation, migration, tumorigenesis and chemotherapy resistance. To address these multifunctional facets of CSCs, we devised a non-ionic surfactant-based vesicle (niosome) co-delivery system to simultaneously deliver siRNAs, targeted to both the ABC transporter (ABCG2) and the anti-apoptosis defense gene (BCL2), and doxorubicin (DOX) to CSCs. The rationale is to sensitize CSCs to DOX by down regulating the drug-resistance gene ABCG2 and simultaneously induce apoptosis by lowering BCL2 expression. The co-delivery system (CDS) successfully delivered siRNAs and DOX to the cytoplasm and nuclei, respectively, and resulted in a down regulation of ABCG2- and BCL2 mRNAs in CSCs by 60% and 65%, respectively, compared to the control. A corresponding decrease in protein expression was observed using Western blotting. The IC50 of DOX in CSCs concurrently decreased significantly. Our result established CDS as a promising multi-drug delivery platform for cancer treatment. STATEMENT OF SIGNIFICANCE: Cancer stem cells (CSCs) are acknowledged to be responsible for increased resistance to chemo-drugs through a combination of increased expression of ABC transporters, an increased anti-apoptotic defense, and/or the ability for extensive DNA repair like normal stem cells. Consequently, effective therapy, especially to CSCs, is urgently required. In current study, we studied the characteristics of 231-CSCs sorted from human MDA-MB-231 breast cancer cells and found that 231-CSCs possessed enhanced proliferation, migration, tumorigenesis, and DOX resistance. We employed a non-ionic surfactant-based vesicle (niosome) delivery system to simultaneously deliver siRNAs targeted to multi-drug resistance genes, and DOX to kill 231-CSCs. The CDS showed an enhanced therapeutic effect by resensitizing 231-CSCs to DOX and may constitute a promising candidate for cancer chemotherapy. PMID- 26415777 TI - Contribution of fibronectin and vitronectin to the adhesion and morphology of MC3T3-E1 osteoblastic cells to poly(NaSS) grafted Ti6Al4V. AB - This study is focused on understanding the underlying mechanisms involved in the improved in vitro and in vivo responses of osteoblasts on poly(sodium styrene sulfonate) (poly(NaSS)) functionalized Ti6Al4V surfaces. We probed the contribution of cell-adhesive glycoproteins fibronectin (Fn) and vitronectin (Vn) in the initial adhesion of MC3T3-E1 osteoblastic cells to poly(NaSS) functionalized and control Ti6Al4V surfaces. Firstly, culture media containing serum depleted of Fn and Vn (DD) were used to establish the contribution of Fn and Vn in the adhesion and spreading of cells on poly(NaSS) grafted and control surfaces. Compared to ungrafted surfaces, poly(NaSS) grafted surfaces enhanced the levels of cell adhesion, cell spreading and the formation of intracellular actin cytoskeleton and focal contacts in serum treatments where Fn or Vn were present (FBS, DD+Fn, DD+Vn). Cell responses to Fn were more significant than to Vn. Secondly, blocking Fn and Vn integrin receptors using antibodies to alpha5beta1 (Fn) and alphavbeta1 (Vn) showed that adhesion of cells to poly(NaSS) grafted surfaces principally involved the Fn integrin receptor alpha5beta1. Thirdly, blocking of the heparin and cell-binding regions of Fn molecule (RGD, C HB, N-HB) showed that grafting with poly(NaSS) altered the conformation of Fn. Together these outcomes explained why the presence of sulfonate (SO3(-)) groups grafted on the Ti6Al4V surface enhanced the early cell adhesion and spreading processes which determine clinical success for applications that require osseointegration. STATEMENT OF SIGNIFICANCE: This study is devoted to the basic analysis of the mechanism at the origin of the improved in vitro and in vivo osteoblast cell responses exhibited by poly(sodium styrene sulfonate) (poly(NaSS)) functionalized Ti6Al4V surfaces. The aim was to probe the contribution of cell adhesive glycoproteins fibronectin and vitronectin in the initial adhesion of MC3T3-E1 osteoblastic cells to poly(NaSS) functionalized Ti6Al4V surfaces. The outcomes of this research explained why the presence of SO3(-) (sulfonate) groups grafted on the Ti6Al4V surface enhanced the early cell adhesion and spreading processes which determine clinical success for applications that require osseointegration. This work is a step further in the research of poly(NaSS), a very promising bioactive polymer with potential to the orthopedic and dental fields. PMID- 26415775 TI - Heterochromatin Protein 1beta (HP1beta) has distinct functions and distinct nuclear distribution in pluripotent versus differentiated cells. AB - BACKGROUND: Pluripotent embryonic stem cells (ESCs) have the unique ability to differentiate into every cell type and to self-renew. These characteristics correlate with a distinct nuclear architecture, epigenetic signatures enriched for active chromatin marks and hyperdynamic binding of structural chromatin proteins. Recently, several chromatin-related proteins have been shown to regulate ESC pluripotency and/or differentiation, yet the role of the major heterochromatin proteins in pluripotency is unknown. RESULTS: Here we identify Heterochromatin Protein 1beta (HP1beta) as an essential protein for proper differentiation, and, unexpectedly, for the maintenance of pluripotency in ESCs. In pluripotent and differentiated cells HP1beta is differentially localized and differentially associated with chromatin. Deletion of HP1beta, but not HP1alpha, in ESCs provokes a loss of the morphological and proliferative characteristics of embryonic pluripotent cells, reduces expression of pluripotency factors and causes aberrant differentiation. However, in differentiated cells, loss of HP1beta has the opposite effect, perturbing maintenance of the differentiation state and facilitating reprogramming to an induced pluripotent state. Microscopy, biochemical fractionation and chromatin immunoprecipitation reveal a diffuse nucleoplasmic distribution, weak association with chromatin and high expression levels for HP1beta in ESCs. The minor fraction of HP1beta that is chromatin-bound in ESCs is enriched within exons, unlike the situation in differentiated cells, where it binds heterochromatic satellite repeats and chromocenters. CONCLUSIONS: We demonstrate an unexpected duality in the role of HP1beta: it is essential in ESCs for maintaining pluripotency, while it is required for proper differentiation in differentiated cells. Thus, HP1beta function both depends on, and regulates, the pluripotent state. PMID- 26415778 TI - Plant diversity shapes microbe-rhizosphere effects on P mobilisation from organic matter in soil. AB - Plant species richness (PSR) increases nutrient uptake which depletes bioavailable nutrient pools in soil. No such relationship between plant uptake and availability in soil was found for phosphorus (P). We explored PSR effects on P mobilisation [phosphatase activity (PA)] in soil. PA increased with PSR. The positive PSR effect was not solely due to an increase in Corg concentrations because PSR remained significant if related to PA:Corg . An increase in PA per unit Corg increases the probability of the temporal and spatial match between substrate, enzyme and microorganism potentially serving as an adaption to competition. Carbon use efficiency of microorganisms (Cmic :Corg ) increased with increasing PSR while enzyme exudation efficiency (PA:Cmic ) remained constant. These findings suggest the need for efficient C rather than P cycling underlying the relationship between PSR and PA. Our results indicate that the coupling between C and P cycling in soil becomes tighter with increasing PSR. PMID- 26415779 TI - Reply from Authors re: Tracy L. Rose, Matthew I. Milowsky. A Small Step Toward Improving Salvage Treatment for Metastatic Bladder Cancer--At What Cost? Eur Urol 2016;69:642-44: Combination Chemotherapy as a Viable Salvage Therapy Strategy for Advanced Urothelial Carcinoma. PMID- 26415780 TI - What are the perspectives for technology platforms in the field of neuroscience? PMID- 26415781 TI - Thresholds for self-motion perception in roll without and with visual fixation target--the visualvestibular interaction effect. AB - The purpose of this study was to establish the selfmotion perception threshold, in roll, in the visualvestibular interaction (VVI) state, creating an oculogyral illusion, and to compare this threshold to the self-motion perception threshold in darkness. A further aim was to investigate the dynamics of the threshold at a low frequency range (0.1-1 Hz) of sinusoidal rotation. Seven healthy subjects were tested. A motion platform was used to generate motion. Single cycles of sinusoidal acceleration at four frequencies (0.1, 0.2, 0.5 and 1 Hz) were used as motion stimuli. To avoid otolith stimulation, subjects were rotated about a vertical axis in supine position. To evoke an oculogyral illusion subjects were instructed to fixate their gaze on a cross-shaped object aligned with their head, which rotated with them. The results show a lowering of the self-motion perception threshold in the VVI state, significant for the frequencies 0.1 and 0.2 Hz (p<0.05). In all the subjects, visual fixation on the cross evoked an oculogyral illusion. The threshold in both tested conditions was frequency dependent: it decreased with increasing frequency values. However, this effect was consistently stronger in darkness across all frequencies (p<0.05). In conclusion, the application of sinusoidal rotation during roll at low frequencies in the VVI condition evokes oculogyral illusion. This interaction lowers the self motion perception threshold compared to that measured during rotation in darkness. This testing method could be of practical benefit in clinical application for revealing brain dysfunction involving integrative mechanisms of perception. PMID- 26415782 TI - Effects of dispositional optimism on quality of life, emotional distress and disability in Parkinson's disease outpatients under rehabilitation. AB - This study was performed with the aim of assessing dispositional optimism (DO) in a sample of Parkinson's disease (PD) patients, in order to evaluate its association with clinical outcomes and its impact on rehabilitation. Before entering an outpatient rehabilitation program, 58 participants suffering from idiopathic PD completed the Life Orientation Test-Revised (LOT-R) to evaluate their level of DO, the WHO-5 scale to evaluate their health-related quality of life (HR-QoL), the Hospital Anxiety and Depression Scale (HADS) to identify emotional distress, and the Barthel Index to evaluate their level of disability. All the measures were repeated four months later, at their discharge from the program. Disease stage and severity measures (Unified Parkinson's Disease Rating Scale) were also taken into consideration. Correlations and multivariate regression analyses compared DO with the health-related variables. On admission a high level of DO was found to be associated with less severe disease, a better quality of life (QoL) and lower emotional distress, but not with level of disability (Barthel Index). Consistent results were found at discharge. The level of DO di not change after rehabilitation, while anxiety was significantly reduced, especially in subjects with low LOT-R and high HADS scores. The Barthel Index values significantly improved. At discharge, participants with high DO showed the best improvements in disability and in QoL. Effects of dispositional optimism on quality of life, emotional distress and disability in Parkinson's disease outpatients under rehabilitation In conclusion, a high level of DO was associated with QoL, HADS and UPDRS both on admission and at discharge. The level of DO remained stable after rehabilitation, while disability and anxiety were reduced. Participants with high DO generally had better QoL, and better clinical and psychological performances. PMID- 26415783 TI - Semantic profiles in mild cognitive impairment associated with Alzheimer's and Parkinson's diseases. AB - The temporal and the prefrontal cortices have different roles in semantic information processing: the temporal lobe is where knowledge is stored (Graham and Hodges, 1997), whereas the prefrontal cortex is more specifically involved in executive aspects of semantic processing. Relatively little is known about the semantic profiles of mild cognitive impairment (MCI) in Alzheimer's disease (AD) and Parkinson's disease (PD). This observational study investigated naming and semantic questionnaire performances in three groups of subjects: 10 patients with the amnestic-type MCI prodrome of AD (aMCI), 10 patients with early-stage executive-type MCI in PD (MCI-PD), and 10 normal subjects. The MCI-PD subjects demonstrated inferior performances on a semantic questionnaire, whereas the aMCI group displayed modest difficulties in a naming task. These differences may be explained by topographical differences in pathological involvement. Since the frontal areas are more functionally impaired in PD, we hypothesize that the semantic deficit may be a consequence of a deficiency in control of semantic processing. On the other hand, the semantic deficit in aMCI may be related to a lexical-semantic storage dysfunction resulting from pathological involvement of the temporal lobe. PMID- 26415784 TI - Preferential occurrence of attacks during night sleep and/or upon awakening negatively affects migraine clinical presentation. AB - It is well known that migraine attacks can preferentially occur during night sleep and/or upon awakening, however the possible implications of this timing on migraine clinical presentation remain unclear. The aim of this study was to assess the possible consequences of sleep-related migraine (defined as >= 75% of migraine attacks occurring during night sleep and/or upon awakening) on the migraine clinical picture (i.e. migraine-related disability, attack severity, use of symptomatic drugs), subjective sleep quality, excessive daytime sleepiness and fatigue. Two hundred consecutive migraine without aura patients were enrolled; patients with comorbid disorders or chronic medication use were excluded. 39% of the migraineurs included in the study received a diagnosis of sleep-related migraine. The mean frequency of migraine attacks (days per month) did not significantly differ between the patients with and those without sleep-related migraine, whereas migraine-related disability (p<0.0001), mean attack severity (p<0.0001), and monthly intake of symptomatic drugs (p<0.0001) were significantly higher in patients with migraine preferentially occurring at night-time and/or upon awakening. Subjective sleep quality and excessive daytime sleepiness did not differ significantly between the two groups, whereas fatigue was significantly more present in the patients with sleep-related migraine (p=0.0001). These data seem to support the hypothesis that patients with sleep-related migraine represent a subset of individuals with a more severe and disabling clinical presentation of migraine and greater impairment of daily functioning, as suggested by the higher degree of fatigue. Migraineurs with night-time attacks Preferential occurrence of attacks during night sleep and/or upon awakening negatively affects migraine clinical presentation also showed a greater use of symptomatic drugs, possibly related to delayed use of symptomatic treatment. The identification of subtypes of patients with a higher disability risk profile could have crucial implications for individually tailored management of migraine patients. PMID- 26415786 TI - Sex differences in MDMA-induced toxicity in Sprague-Dawley rats. AB - Recent evidence demonstrates that female subjects show exaggerated responses to 3,4-methylenedioxymethamphetamine (MDMA) compared with males. The aim of our study was to evaluate sex differences and the role of endogenous gonadal hormones on the effects of MDMA. Fifty-six intact and gonadectomized male and female Sprague-Dawley rats were randomly assigned to either MDMA (5 mg/kg) or saline treatment. Learning and memory were assessed using the Morris water maze (MWM). The expression of Bax and Bcl-2 in the hippocampus was detected by Western blotting. Behavioral analysis showed that MDMA led to memory impairment in both male and female rats. The female rats showed more sensitivity to impairment than the males, as assessed using all the memory parameters in the MWM. Ovariectomy attenuated the MDMA-induced memory impairment. By contrast, orchiectomized rats showed more impairment than MDMA-treated intact male rats. Bcl-2 and Bax were down-regulated and up-regulated in MDMA-treated male and female rats, respectively. MDMA treatment in the orchiectomized rats led to upregulation of Bax and down-regulation of Bcl-2. Ovariectomy attenuated the MDMA-induced up regulation of Bax and caused more expression of Bcl-2 compared with what was observed in the MDMA-treated intact female rats. In summary, female rats showed exaggerated responses to the effects of MDMA and this may be explained by endogenous gonadal hormones. PMID- 26415785 TI - TMS-evoked N100 responses as a prognostic factor in acute stroke. AB - Rehabilitation programs, to be efficiently tailored, need clear prognostic markers. In acute stroke, neurophysiological measures, such as motor evoked potentials (MEPs), have been proposed, although with discordant results. The aim of this study was to identify a reliable neurophysiological measure of recovery in acute post-stroke individuals by combining MEPs and the N100 component of transcranial magnetic stimulation-evoked potentials (TEPs). Nine acute post stroke subjects were included. Clinical evaluation performed in the first week after the event included administration of the European Stroke Scale and Barthel Index and recording of MEPs and TEPs; administration of the clinical scales was repeated after one and three months. The presence/absence of MEPs and TEPs showed correlations with motor outcome. Individuals with a poorer outcome showed absence of both MEPs and TEPs; absence of MEPs alone was related to a partial recovery. Given the results of this exploratory study, further investigation is needed to define the accuracy of combined use of MEPs and TEPs as an approach for predicting motor recovery after acute stroke. PMID- 26415787 TI - Encephalopathy with status epilepticus during sleep (ESES) induced by oxcarbazepine in idiopathic focal epilepsy in childhood. AB - Encephalopathy with status epilepticus during sleep (ESES) is an age-related disorder characterized by neuropsychological regression, epilepsy and a typical EEG pattern of continuous epileptiform activity (> 85%) during NREM sleep. Cases of worsening or induction of ESES with phenytoin, carbamazepine and phenobarbital have been reported. We describe a child with benign epilepsy with centrotemporal spikes (BECTS) in whom treatment with oxcarbazepine (OXC) induced ESES. The patient was studied through repeated clinical-neuropsychological evaluations and 24-hour EEG recordings. He was treated with OXC two months after epilepsy onset. One month after starting OXC, he developed an abrupt and severe cognitive deterioration. A 24-hour EEG and neuropsychological tests showed an electroclinical picture compatible with ESES. Withdrawal of OXC and introduction of other drugs were followed by a prompt improvement. Five months after ESES onset, a 24-hour EEG was normal. Our report indicates that OXC can induce ESES in BECTS. PMID- 26415788 TI - "Boosting" in Paralympic athletes with spinal cord injury: doping without drugs. AB - The intentional activation of autonomic dysreflexia (AD, also called "boosting"), a practice sometimes used by athletes affected by spinal cord injury (SCI), is banned by the International Paralympic Committee (IPC). Although various studies have addressed doping and AD as separate issues, studies evaluating AD as a doping method are lacking. The aim of this brief review is to contribute to better understanding of the relationship between doping and AD. We conducted a literature search of the PubMed database (from 1994 onwards). The key search terms "autonomic dysreflexia" and "boosting" were crossreferenced with "sport performance". The official Paralympic website was also viewed. AD is a potent sympathetic reflex, due to a massive release of noradrenaline, that results in marked vasoconstriction distal to the level of the lesion. Athletes with SCI often self-inflict physical suffering in order to induce this phenomenon, which carries high health risks (i.e., hypertension, cerebral hemorrhage, stroke and sudden death). Boosting is a practice that can be compared to doping methods and the IPC expressly prohibits it. Any deliberate attempt to induce AD, if detected, will lead to disqualification from the sporting event and subsequent investigation by the IPC Legal and Ethics Committee. PMID- 26415789 TI - In situ loading of well-dispersed silver nanoparticles on nanocrystalline magnesium oxide for real-time monitoring of catalytic reactions by surface enhanced Raman spectroscopy. AB - The surface-enhanced Raman spectroscopy (SERS) technique is of great importance for insight into the transient reaction intermediates and mechanistic pathways involved in heterogeneously catalyzed chemical reactions under actual reaction conditions, especially in water. Herein, we demonstrate a facile method for in situ synthesis of nanocrystalline magnesium oxide-Ag(0) (nano MgO-Ag(0)) hybrid nanomaterials with dispersed Ag nanoparticles (Ag NPs) on the surface of nanocrystalline magnesium oxide (nano MgO) via Sn(2+) linkage and reduction. As a benefit from the synergy effect of nano MgO and Ag NPs, the nano MgO-Ag(0) exhibited both excellent SERS and catalytic activities for the reduction of 4 nitrothiophenol in the presence of NaBH4. The nano MgO-Ag(0) was used for real time monitoring of the catalytic reaction process of 4-nitrothiophenol to 4 aminothiophenol in an aqueous medium by observing the SERS signals of the reactant, intermediate and final products. The intrinsic reaction kinetics and reaction mechanism of this reaction were also investigated. This SERS-based synergy technique provides a novel approach for quantitative in situ monitoring of catalytic chemical reaction processes. PMID- 26415790 TI - The Efficacy and Safety of Wenxin Keli in Patients with Frequent Premature Ventricular Contractions: A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Trial. AB - BACKGROUND: Premature ventricular contractions (PVCs) are common in the general population, and frequent PVCs may result in the poor quality of life or even the damage of cardiac function. We examined the efficacy and safety of a traditional Chinese medicine Wenxin Keli for the treatment of frequent PVCs among a relatively large Chinese cohort. METHODS: We performed a randomized, double blind, placebo-controlled, parallel-group, multicenter trial. A total of 1200 eligible participants were randomly assigned in a ratio of 1:1 to receive Wenxin Keli or the placebo for 4 weeks. The primary and secondary endpoint was the change of PVC numbers and PVC-related symptoms after a 4-week treatment compared with baseline, respectively. In addition, vital signs, laboratory values, and electrocardiographic parameters were assessed in a safety analysis. RESULTS: At the initial evaluation, no significant differences in the baseline characteristics were observed between the Wenxin Keli group and the placebo group. A smaller number of PVCs was observed after the 4-week treatment than at baseline, in both the Wenxin Keli group (5686 +/- 5940 vs. 15,138 +/- 7597 beats/d, P < 0.001) and the placebo group (10,592 +/- 8009 vs. 14,529 +/- 5929 beats/d, P < 0.001); moreover, the Wenxin Keli group demonstrated a significantli greater reduction in the frequency of PVCs than the placebo group (P < 0.001). In a full analysis set, patients in the Wenxin Keli group exhibited significantly higher total effective responses in the reduction of PVCs compared to those in the placebo group (83.8% vs. 43.5%,P < 0.001). The per-protocol analysis yielded similar results (83.0% vs. 39.3%,P < 0.001). Treatment with Wenxin Keli also demonstrated superior performance compared to the placebo with respect to PVC related symptoms. No severe adverse effects attributable to Wenxin Keli were reported. CONCLUSIONS: Wenxin Keli treatment effectively reduced the overall number of PVCs and alleviated PVC-related symptoms in patients without structural heart diseases and had no severe side effects. PMID- 26415791 TI - Quantitative Measurement of Cerebral Perfusion with Intravoxel Incoherent Motion in Acute Ischemia Stroke: Initial Clinical Experience. AB - BACKGROUND: Intravoxel incoherent motion (IVIM) has the potential to provide both diffusion and perfusion information without an exogenous contrast agent, its application for the brain is promising, however, feasibility studies on this are relatively scarce. The aim of this study is to assess the feasibility of IVIM perfusion in patients with acute ischemic stroke (AIS). METHODS: Patients with suspected AIS were examined by magnetic resonance imaging within 24 h of symptom onset. Fifteen patients (mean age was 68.7 +/- 8.0 years) who underwent arterial spin labeling (ASL) and diffusion-weighted imaging (DWI) were identified as having AIS with ischemic penumbra were enrolled, where ischemic penumbra referred to the mismatch areas of ASL and DWI. Eleven different b-values were applied in the biexponential model. Regions of interest were selected in ischemic penumbras and contralateral normal brain regions. Fast apparent diffusion coefficients (ADCs) and ASL cerebral blood flow (CBF) were measured. The paired t- test was applied to compare ASL CBF, fast ADC, and slow ADC measurements between ischemic penumbras and contralateral normal brain regions. Linear regression and Pearson's correlation were used to evaluate the correlations among quantitative results. RESULTS: The fast ADCs and ASL CBFs of ischemic penumbras were significantly lower than those of the contralateral normal brain regions (1.93 +/- 0.78 alphaMUm2/ms vs. 3.97 +/- 2.49 alphaMUm2/ms, P = 0.007; 13.5 +/- 4.5 ml.100 g 1.min-1 vs. 29.1 +/- 12.7 ml.100 g-1.min-1, P < 0.001, respectively). No significant difference was observed in slow ADCs between ischemic penumbras and contralateral normal brain regions (0.203 +/- 0.090 alphaMUm2/ms vs. 0.198 +/- 0.100 alphaMUm2/ms, P = 0.451). Compared with contralateral normal brain regions, both CBFs and fast ADCs decreased in ischemic penumbras while slow ADCs remained the same. A significant correlation was detected between fast ADCs and ASL CBFs (r = 0.416, P < 0.05). No statistically significant correlation was observed between ASL CBFs and slow ADCs, or between fast ADCs and slow ADCs (r = 0.111, P = 0.558; r = 0.200, P = 0.289, respectively). CONCLUSIONS: The decrease in cerebral blood perfusion primarily results in the decrease in fast ADC in ischemic penumbras; therefore, fast ADC can reflect the perfusion situation in cerebral tissues. PMID- 26415792 TI - Application of Minimum Effective Cuff Inflating Volume for Laryngeal Mask Airway and its Impact on Postoperative Pharyngeal Complications. AB - BACKGROUND: High intracuff pressure can cause severe pharyngeal complications including sore throat or hoarseness after laryngeal mask airway (LMA) removal postoperatively. Though the application of minimum effective cuff inflating volume is suggested to maintain airway sealing and adequacy of ventilation for patients receiving general anesthesia with LMA at lower level of the intracuff pressure, it is currently not a standard care in most of the anesthetic departments. In this study, the minimum effective cuff inflating volume was determined for classic LMA Well LeadTM (Well Lead Medical Co., Ltd., China) and its impact on postoperative pharyngeal complications was also explored. METHODS: Patients with American Society of Anesthesiologists physical status (I-III) undergoing the short-duration urological surgery were recruited in this trial. First, the minimum effective cuff inflating volume was determined for size 4 or 5 LMA Well Lead in the study 1. Immediately following placement and confirmation of ideal LMA position, the cuff was inflated with 5, 7, 10 ml of air and up to 30 ml at 5 ml increment. The intracuff pressure, oropharyngeal leak pressure (OLP), and inspiratory peak airway pressure under positive pressure ventilation at the corresponding cuff volume as indicated above were recorded. Second, the enrolled patients were randomly allocated into minimum effective cuff inflating volume group (MC) and routine care (RC) group in the study 2. The minimum effective cuff inflating volume was applied and maintained in MC group, whereas the cuff volume was inflated with half of the maximum cuff inflating volume recommended by manufacturer in RC group throughout the surgical procedure and stay in postanesthesia care unit prior to LMA removal. The incidence of pharyngeal complications at 0, 2, 24, and 48 h after removal of LMA and other intra operative adverse events were also documented. RESULTS: The intracuff pressure varied with the cuff inflating volume in a positive linear correlation manner (Y = 11.68X - 42.1, r(2) = 0.9191) under the range of 5-30 ml for size 4 LMA. In similar with size 4 LMA, the data were also showed the linear relationship between the intracuff pressure and the cuff inflating volume (Y = 7.39X - 10.9, r(2) = 0.8855) for size 5 LMA. The minimal effective cuff inflating volume for size 4 or 5 LMA was 7-9 ml in combination of considering OLP needed to maintain airway sealing during intermittently positive pressure ventilation. The intracuff pressure in MC group was lower compared with RC group (63.0 +/- 3.7 vs. 126.4 +/- 24.0 cmH2O for size 4 LMA; 55.6 +/- 2.4 vs. 138.5+/- 26.8 cmH2O for size 5 LMA; P < 0.0001). The incidence of pharyngeal adverse events was lower in MC group versus the RC group at 2, 24 h after LMA removal. CONCLUSIONS: The relationship between the cuff inflating volume and the intracuff pressure for size 4 or 5 LMA Well Lead(TM) is in a linear correlation manner at the range of 5-30 ml. The minimal cuff inflating volume is adequate for satisfactory airway sealing and consequently associated with lower incidence of postoperative pharyngeal complications for LMA Well Lead.TM. PMID- 26415793 TI - The Dose-response of Intrathecal Ropivacaine Co-administered with Sufentanil for Cesarean Delivery under Combined Spinal-epidural Anesthesia in Patients with Scarred Uterus. AB - BACKGROUND: Spinal anesthesia is considered as a reasonable anesthetic option in lower abdominal and lower limb surgery. This study was to determine the dose response of intrathecal ropivacaine in patients with scarred uterus undergoing cesarean delivery under combined spinal-epidural anesthesia. METHODS: Seventy five patients with scarred uterus undergoing elective cesarean delivery under combined spinal-epidural anesthesia were enrolled in this randomized, double blinded, dose-ranging study. Patients received 6, 8, 10, 12, or 14 mg intrathecal hyperbaric ropivacaine with 5 MUg sufentanil. Successful spinal anesthesia was defined as a T4sensory level achieved with no need for epidural supplementation. The 50% effective dose (ED50) and 95% effective dose (ED95) were calculated with a logistic regression model. RESULTS: ED50and ED95of intrathecal hyperbaric ropivacaine for patients with scarred uterus undergoing cesarean delivery under combined spinal-epidural anesthesia (CSEA) were 8.28 mg (95% confidence interval [CI]: 2.28-9.83 mg) and 12.24 mg (95% CI: 10.53-21.88 mg), respectively. CONCLUSION: When a CSEA technique is to use in patients with scarred uterus for an elective cesarean delivery, the ED50and ED95of intrathecal hyperbaric ropivacaine along with 5 MUg sufentanil were 8.28 mg and 12.24 mg, respectively. In addition, this local anesthetic is unsuitable for emergent cesarean delivery, but it has advantages for ambulatory patients. PMID- 26415794 TI - The Application of an Anatomical Database for Fetal Congenital Heart Disease. AB - BACKGROUND: Fetal congenital heart anomalies are the most common congenital anomalies in live births. Fetal echocardiography (FECG) is the only prenatal diagnostic approach used to detect fetal congenital heart disease (CHD). FECG is not widely used, and the antenatal diagnosis rate of CHD varies considerably. Thus, mastering the anatomical characteristics of different kinds of CHD is critical for ultrasound physicians to improve FECG technology. The aim of this study is to investigate the applications of a fetal CHD anatomic database in FECG teaching and training program. METHODS: We evaluated 60 transverse section databases including 27 types of fetal CHD built in the Prenatal Diagnosis Center in Peking University People's Hospital. Each original database contained 400-700 cross-sectional digital images with a resolution of 3744 pixels * 5616 pixels. We imported the database into Amira 5.3.1 (Australia Visage Imaging Company, Australia) three-dimensional (3D) software. The database functions use a series of 3D software visual operations. The features of the fetal CHD anatomical database were analyzed to determine its applications in FECG continuing education and training. RESULTS: The database was rebuilt using the 3D software. The original and rebuilt databases can be displayed dynamically, continuously, and synchronically and can be rotated at arbitrary angles. The sections from the dynamic displays and rotating angles are consistent with the sections in FECG. The database successfully reproduced the anatomic structures and spatial relationship features of different fetal CHDs. We established a fetal CHD anatomy training database and a standardized training database for FECG. Ultrasound physicians and students can learn the anatomical features of fetal CHD and FECG through either centralized training or distance education. CONCLUSIONS: The database of fetal CHD successfully reproduced the anatomic structures and spatial relationship of different kinds of fetal CHD. This database can be widely used in anatomy and FECG teaching and training. PMID- 26415795 TI - Lupus Myocarditis: A Case-Control Study from China. AB - BACKGROUND: Myocarditis is an uncommon but serious manifestation of systemic lupus erythematosus (SLE). This study aimed to investigate clinical characteristics and outcomes of lupus myocarditis (LM) and to determine risk factors of LM in hospitalized Chinese patients with SLE. METHODS: We conducted a retrospective case-control study. A total of 25 patients with LM from 2001 to 2012 were enrolled as the study group, and 100 patients with SLE but without LM were randomly pooled as the control group. Univariable analysis was performed using Chi-square tests for categorical variables, and the Student's t-test or Mann-Whitney U-test was performed for continuous variables according to the normality. RESULTS: LM presented as the initial manifestation of SLE in 7 patients (28%) and occurred mostly at earlier stages compared to the controls (20.88 +/- 35.73 vs. 44.08 +/- 61.56 months, P = 0.008). Twenty-one patients (84%) experienced episodes of symptomatic heart failure. Echocardiography showed that 23 patients (92%) had decreased left ventricular ejection fraction (<50%) and all patients had wall motion abnormalities. A high SLE Disease Activity Index was the independent risk factor in the development of LM (odds ratio = 1.322, P < 0.001). With aggressive immunosuppressive therapies, most patients achieved satisfactory outcome. The in-hospital mortality was not significantly higher in the LM group than in the controls (4% vs. 2%,P = 0.491). CONCLUSIONS: LM could result in cardiac dysfunction and even sudden death. High SLE disease activity might potentially predict the occurrence of LM at the early stage of SLE. Characteristic echocardiographic findings could confirm the diagnosis of LM. Early aggressive immunosuppressive therapy could improve the cardiac outcome of LM. PMID- 26415797 TI - Vagus Nerve Stimulation for Pediatric and Adult Patients with Pharmaco-resistant Epilepsy. AB - BACKGROUND: Over past two decades, vagus nerve stimulation (VNS) has been widely used and reported to alleviate seizure frequency worldwide, however, so far, only hundreds of patients with pharmaco-resistant epilepsy (PRE) have been treated with VNS in mainland China. The study aimed to evaluate the effectiveness of VNS for Chinese patients with PRE and compare its relationship with age cohort and gender. METHODS: We retrospectively assessed the clinical outcome of 94 patients with PRE, who were treated with VNS at Beijing Fengtai Hospital and Beijing Tiantan Hospital between November 2008 and April 2014 from our database of 106 consecutive patients. The clinical data analysis was retrospectively examined. RESULTS: Seizure frequency significantly decreased with VNS therapy after intermittent stimulation of the vagus nerve. At last follow-up, we found McHugh classifications of Class I in 33 patients (35.1%), Class II in 27 patients (28.7%), Class III in 20 patients (21.3%), Class IV in 3 patients (3.2%), and Class V in 11 patients (11.7%). Notably, 8 (8.5%) patients were seizure-free while >=50% seizure frequency reduction occurred in as many as 60 patients (63.8%). Furthermore, with regard to the modified Engel classification, 12 patients (12.8%) were classified as Class I, 11 patients (11.7%) were classified as Class II, 37 patients (39.4%) were classified as Class III, 34 patients (36.2%) were classified as Class IV. We also found that the factors of gender or age are not associated with clinical outcome. CONCLUSIONS: This comparative study confirmed that VNS is a safe, well-tolerated, and effective treatment for Chinese PRE patients. VNS reduced the seizure frequency regardless of age or gender of studied patients. PMID- 26415796 TI - Spinal Cord Kinking in Thoracic Myelopathy Caused by Ossification of the Ligamentum Flavum. AB - BACKGROUND: Ossification of the ligamentum flavum (OLF) is being increasingly recognized as a cause of thoracic myelopathy. This study was to describe a rare clinical entity of spinal cord kinking (SK) in thoracic myelopathy secondary to OLF. METHODS: The data of 95 patients with thoracic myelopathy secondary to OLF were analyzed retrospectively. The incidence and location of SK were determined using preoperative magnetic resonance imaging (MRI). The clinical presentation and radiological characteristics in patients with SK were analyzed. Posterior en bloc laminectomy with OLF was performed, and the surgical results were evaluated. RESULTS: SK was found in seven patients (7.4%) based on preoperative MRI. The patients included one male and six females with an average age of 55.6 years (range, 48-64 years). Five patients presented with radiculomyelopathy and two presented with typical thoracic myelopathy of spastic paraparesis. In all cases, the kinking was located just above the end of the spinal cord where the conus medullaris (CM) was compressed by the OLF. The degree of SK varied from mild to severe. The tip of the CM was located between the upper third of T11 to the lower third of L1, above the lower edge of L1. With an average follow-up of 30.4 months, the modified Japanese Orthopedic Association score significantly improved from 5.7 +/- 1.8 preoperatively to 8.9 +/- 1.4 postoperatively (t = 12.05; P < 0.0001) with an improvement rate of 63.1 +/- 12.3%. CONCLUSIONS: SK is a rare radiological phenomenon. It is typically located at the thoracolumbar junction, where the CM is compressed by the OLF. Our findings indicate that these patients may benefit from a posterior decompressive procedure. PMID- 26415798 TI - The Surgical Treatment and Outcome of Nonmetastatic Extremity Osteosarcoma with Pathological Fractures. AB - BACKGROUND: Recent studies have suggested that the presence of a pathological fracture does not impact on oncologic outcomes and the feasibility of limb salvage surgery (LSS) in appropriately selected patients when combined with neoadjuvant chemotherapy. These have largely been single institutional studies with limited numbers. The Eastern Asian Musculoskeletal Oncology Group reviewed the data from three large volume Asian orthopedic oncology centers to determine whether the presence of a pathologic fracture affected outcomes in osteosarcoma patients. METHODS: A retrospective review of the data was conducted. Ninety-five cases of nonmetastatic extremity osteosarcoma with a pathological fracture and 887 cases without fracture treated during the same period were compared. RESULTS: In the fracture group, the LSS rate was 62.1%, and the rate of amputation was 37.9%. In the nonfracture group, the LSS rate was 74.7%, and the amputation was 25.3%. In patients with a pathologic fracture, the rate of local recurrence for LSS and amputation groups was 8.5% and 2.8%, respectively. In this group, the 5 year survival in the LSS group was 66% as against. 46.8% in the amputation group. CONCLUSIONS: Our study suggests that surgically treated patients with pathologic fractures in osteosarcoma have adequate local control and do not have a poorer outcome compared to patients without a fracture. Though osteosarcoma with a pathologic fracture is not a contraindication for limb salvage, appropriate case selection is important when deciding local control options to ensure adequate oncologic clearance. PMID- 26415799 TI - Can Tracheostomy Improve Outcome and Lower Resource Utilization for Patients with Prolonged Mechanical Ventilation? AB - BACKGROUND: It is not clear whether the benefits of tracheostomy remain the same in the population. This study aimed to better examine the effect of tracheostomy on clinical outcome among prolonged ventilator patients. METHODS: Data were from the medical claims data in Taiwan. A total of 3880 patients with ventilator use for more than 14 days between 2005 and 2009 were identified. Among them, 645 patients with tracheostomy conducted within 30 days of ventilator use were compared to 2715 patients without tracheostomy on death during hospitalization and study period, and successful weaning and medical utilization during hospitalization. Cox proportional hazards and linear regression models were used to examine the associations between tracheostomy and the main outcomes. RESULTS: The tracheostomy rate was 30%, and 55% of tracheostomies were performed within 30 days of mechanical ventilation. After adjustments, patients with tracheostomy were at a lower risk of death during hospitalization (hazard ratio [HR] =0.51; 95% confidence interval [CI] =0.43-0.61) and 5-year observation (HR = 0.73; 95% CI = 0.66-0.81), and a lower probability of successful weaning (HR = 0.88; 95% CI = 0.79-0.99). Higher medical use was also observed in patients with tracheostomy. CONCLUSIONS: The beneficial effect for tracheostomy observed in our data was the reduction of death. However, patients with tracheostomy were less likely to wean and more likely to consume medical resources. PMID- 26415800 TI - Phosphoproteomics Analysis of Endometrium in Women with or without Endometriosis. AB - BACKGROUND: The molecular mechanisms underlying the endometriosis are still not completely understood. In order to test the hypothesis that the approaches in phosphoproteomics might contribute to the identification of key biomarkers to assess disease pathogenesis and drug targets, we carried out a phosphoproteomics analysis of human endometrium. METHODS: A large-scale differential phosphoproteome analysis, using peptide enrichment of titanium dioxide purify and sequential elution from immobilized metal affinity chromatography with linear trap quadrupole-tandem mass spectrometry, was performed in endometrium tissues from 8 women with or without endometriosis. RESULTS: The phosphorylation profiling of endometrium from endometriosis patients had been obtained, and found that identified 516 proteins were modified at phosphorylation level during endometriosis. Gene ontology annotation analysis showed that these proteins were enriched in cellular processes of binding and catalytic activity. Further pathway analysis showed that ribosome pathway and focal adhesion pathway were the top two pathways, which might be deregulated during the development of endometriosis. CONCLUSIONS: That large-scale phosphoproteome quantification has been successfully identified in endometrium tissues of women with or without endometriosis will provide new insights to understand the molecular mechanisms of the development of endometriosis. PMID- 26415801 TI - Direct-acting Antiviral Agents Resistance-associated Polymorphisms in Chinese Treatment-naive Patients Infected with Genotype 1b Hepatitis C Virus. AB - BACKGROUND: It has been reported that several baseline polymorphisms of direct acting antivirals (DAAs) agents resistance-associated variants (RAVs) would affect the treatment outcomes of patients chronically infected with hepatitis C virus (CHC). The aim of this study is to investigate the prevalence of DAAs RAVs in treatment-naIve GT1b CHC patients. METHODS: Direct sequencing and ultra-deep sequencing of the HCV NS3, NS5A, and NS5B gene were performed in baseline serum samples of treatment-naIve patients infected with genotype 1b hepatitis C virus (HCVs). RESULTS: One hundred and sixty CHC patients were studied. Complete sequence information was obtained for 145 patients (NS3), 148 patients (NS5A), and 137 patients (NS5B). Treatment-failure associated variants of DAAs were detected: 56.6% (82/145) of the patients presented S122G for simeprevir (NS3 protease inhibitor); 10.1% (14/148) of the patients presented Y93H for daclatasvir and ledipasvir (NS5A protein inhibitors); 94.2% (129/137) of the patients presented C316N for sofosbuvir (NS5B polymerase inhibitor). Nearly, all of the DAAs RAVs detected by ultra-deep sequencing could be detected by direct sequencing. CONCLUSIONS: The majority of genotype 1b CHC patients in China present a virus population carrying HCV DAAs RAVs. Pretreatment sequencing of HCV genome might need to be performed when patients infected with GT1b HCV receiving DAAs-containing regimens in China. Population sequencing would be quite quantified for the work. PMID- 26415802 TI - Prognostic Significance of MiR-34a Expression in Patients with Gastric Cancer after Radical Gastrectomy. AB - BACKGROUND: MiR-34a dysregulation has been implicated in tumorigenesis and progression of gastric cancer, but its role in prognosis of patients with gastric cancer remains unknown. The aim of this study was to investigate the expression and prognostic significance of miR-34a in gastric cancer patients after radical gastrectomy. METHODS: Quantitative real-time polymerase chain reaction was performed to detect the expression of miR-34a in human gastric cancer cell lines and tissues in 76 patients with gastric adenocarcinoma from China. Results are assessed for association with clinical features and overall survival (OS) using Kaplan-Meier analysis. Prognostic values of miR-34a expression and clinical outcomes were evaluated by Cox regression analysis. A molecular prognostic stratification scheme incorporating miR-34a expression was determined using receiver operating characteristic analysis. RESULTS: The results show that the expression level of miR-34a was decreased in human gastric cancer cell lines and tissues, and down-regulated expression of miR-34a was associated with Lauren classification (P = 0.034). Decreased miR-34a expression in gastric cancer tissues was positively correlated with poor OS of gastric cancer patients (P = 0.013). Further multivariate Cox regression analysis suggested that miR-34a expression was an independent prognostic indicator for gastric cancer (P = 0.027). Applying the prognostic value of miR-34a expression to tumor node metastasis (TNM) stage system showed a better prognostic value in patients with gastric cancer than miR-34a expression (P = 0.0435) or TNM stage (P = 0.0249) alone. CONCLUSION: The results reinforce the critical role for the down-regulated miR-34a expression in gastric cancer and suggest that miR-34a could be a prognostic indicator for this disease. PMID- 26415803 TI - Inhibition of Alveolar Macrophage Pyroptosis Reduces Lipopolysaccharide-induced Acute Lung Injury in Mice. AB - BACKGROUND: Pyroptosis is the term for caspase-1-dependent cell death associated with pro-inflammatory cytokines. The role of alveolar macrophage (AM) pyroptosis in the pathogenesis of the acute lung injury and acute respiratory distress syndrome (ALI/ARDS) remains unclear. METHODS: C57BL/6 wild-type mice were assigned to sham, lipopolysaccharide (LPS) + vehicle, LPS + acetyl-tyrosyl-valyl- alanyl-aspartyl-chloromethylketone (Ac-YVAD-CMK) and LPS + Z-Asp-Glu-Val-Asp fluoromethylketone groups. Mice were given intraperitoneal (IP) injections of LPS. Drugs were IP injected 1 h before LPS administration. Mice were sacrificed 16 h after LPS administration, and AMs were isolated. Western blot analysis for active caspase-1 and cleaved caspase-3, evaluation of lung injury and a cytokine release analysis were performed. AMs were treated with LPS and adenosine triphosphate (ATP); caspase-1-dependent cell death was evaluated using flow cytometry; the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) pyroptosomes were examined by immunofluorescence. RESULTS: The expression of activated caspase-1 in AMs was enhanced following LPS challenge compared with the sham group. In the ex vivo study, the caspase 1/propidium iodide-positive cells, caspase-1 specks and ASC pyroptosomes were up regulated in AMs following LPS/ATP stimulation. The specific caspase-1 inhibitor Ac-YVAD-CMK inhibited the activation of caspase-1 and pyroptotic cell death. Ac YVAD-CMK also reduced the lung injury, pulmonary edema and total protein in bronchoalveolar lavage fluid (BALF). In addition, Ac-YVAD-CMK significantly inhibited interleukin-alpha2 (IL-1alpha2) release both in serum and BALF and reduced the levels of IL-18, tumor necrosis factor-alpha+/- (TNF-alpha+/-), High Mobility Group Box 1 (HMGB1) in BALF during LPS-induced ALI/ARDS. CONCLUSIONS: This study reported AM pyroptosis during LPS-induced ALI/ARDS in mice and has demonstrated that Ac-YVAD-CMK can prevent AM-induced pyroptosis and lung injury. These preliminary findings may form the basis for further studies to evaluate this pathway as a target for prevention or reduction of ALI/ARDS. PMID- 26415804 TI - Improved Survival and Neurological Outcomes after Cardiopulmonary Resuscitation in Toll-like Receptor 4-mutant Mice. AB - BACKGROUND: Toll-like receptor 4 (TLR4) is a crucial receptor in the innate immune system and noninfectious immune responses. It has been reported that TLR4 participates in the pathological course of ischemia/reperfusion (I/R) injury. However, the role of TLR4 in the process of I/R injury after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) is still unknown. In this study, we investigated the effects of TLR4 mutation on survival and neurological outcome in a mouse model of CA/CPR. METHODS: A model of potassium-induced CA was performed on TLR4-mutant mice (C3H/HeJ) and wild-type mice (C3H/HeN). After 3 min of untreated CA, resuscitation was attempted with chest compression, ventilation, and intravenous epinephrine. Behavioral tests were performed on mice on day 3 after CPR. The morphological changes in hippocampal neurons were assessed by light and electron microscopy. Expressions of TLR4 and intercellular adhesion molecule-1 (ICAM-1) were detected by Western blot. Levels of tumor necrosis factor-alpha (TNF-alpha) and myeloperoxidase (MPO) were measured with enzyme linked immunosorbent assay (ELISA). RESULTS: On day 3 after resuscitation the overall mortality was 33.33% in C3H/HeJ group compared with 53.33% in C3H/HeN group (P < 0.05). And there was much higher central tendency in C3H/HeJ group than C3H/HeN group during open field test (P < 0.05). Meanwhile, the percentage of nonviable neurons was 21.16% in C3H/HeJ group compared with 53.11% in C3H/HeN group (P < 0.05). And there were significantly lower levels of hippocampal TNF alpha and MPO in C3H/HeJ mice (TNF-alpha: 6.85+/-1.19 ng/mL, MPO: 0.33+/-0.11 U/g) than C3H/HeN mice (TNF-alpha: 11.36+/-2.12 ng/mL, MPO: 0.54+/-0.17 U/g) (all P < 0.01). CPR also significantly increased the expressions of TLR4 and ICAM-1 in C3H/HeN group. However, the expression of ICAM-1 was much lower in C3H/HeJ group than in C3H/HeN group after CPR (P < 0.01). CONCLUSION: TLR4 signaling is involved in brain damage and in inflammation triggered by CA/CPR. PMID- 26415805 TI - Neuroprotective Effect of Compound Anisodine in a Mouse Model with Chronic Ocular Hypertension. AB - BACKGROUND: Compound anisodine (CA) is a compound preparation made from hydrobromide anisodine and procaine hydrochloride. The former is an M-choline receptor blocker with the function of regulating the vegetative nervous system, improving microcirculation, and so on. The latter is an antioxidant with the activities of neuroprotection. This study aimed to investigate the potential neuroprotection of CA, which affects the degeneration of the retinal ganglion cells (RGCs) in an animal model with chronic ocular hypertension. METHODS: Female C57BL/6J mice (n = 24) were divided randomly into four groups: normal control group without any treatment (Group A, n = 6); CA control group with feeding the CA solution (Group B, n = 6); microbeads (MBs) control group with injecting MB into the anterior chamber (Group C, n = 6); CA study group with MB injection and with feeding the CA solution (Group D, n = 6). Intraocular pressure (IOP) was measured every 3 days after MB injection. At the 21st day, neurons were retrograde-labeled by Fluoro-Gold (FG). Animals were sacrificed on the 27th day. Retinal flat mounts were stained immunohistologically by alpha2-III-tubulin. FG retrograde-labeled RGCs, alpha2-III-tubulin-positive RGCs, and alpha2-III-tubulin positive nerve fibers were quantified. RESULTS: Mice of Groups C and D expressed the incidence of consistent IOP elevation, which is above the IOP level of Group A with the normal one. There is no significant difference in IOP between Groups A and B (P > 0.05). On the 27th day, there were distinct loss in stained RGCs and nerve fibers from Groups C and D compared with Group A (allP < 0.001). The quantity was significantly higher in Group D as compared to Group C (allP < 0.001) but lower than Group A (allP > 0.001). There was no significant difference in the quantity of RGCs and nerve fibers between Groups A and B (allP > 0.05). CONCLUSIONS: These findings suggest that CA plays an importantly neuroprotective role on RGCs in a mouse model with chronic ocular hypertension. PMID- 26415806 TI - Salvianolic Acid B Down-regulates Matrix Metalloproteinase-9 Activity and Expression in Tumor Necrosis Factor-alpha-induced Human Coronary Artery Endothelial Cells. AB - BACKGROUND: Salvianolic acid B (Sal B) is a bioactive water-soluble compound of Salviae miltiorrhizae, a traditional herbal medicine that has been used clinically for the treatment of cardiovascular diseases. This study sought to evaluate the effect of Sal B on matrix metalloproteinase-9 (MMP-9) and on the underlying mechanisms in tumor necrosis factor-alpha+/- (TNF-alpha+/-)-activated human coronary artery endothelial cells (HCAECs), a cell model of Kawasaki disease. METHODS: HCAECs were pretreated with 1-10 alphaMUmol/L of Sal B, and then stimulated by TNF-alpha+/- at different time points. The protein expression and activity of MMP-9 were determined by Western blot assay and gelatin zymogram assay, respectively. Nuclear factor-kappaB (NF-kappaB) activation was detected with immunofluorescence, electrophoretic mobility shift assay, and Western blot assay. Protein expression levels of mitogen-activated protein kinase (c-Jun N terminal kinase [JNK], extra-cellular signal-regulated kinase [ERK], and p38) were determined by Western blot assay. RESULTS: After HCAECs were exposed to TNF alpha+/-, 1-10 alphaMUmol/L Sal B significantly inhibited TNF-alpha+/--induced MMP-9 expression and activity. Furthermore, Sal B significantly decreased IkappaBalpha+/- phosphorylation and p65 nuclear translocation in HCAECs stimulated with TNF-alpha+/- for 30 min. In addition, Sal B decreased the phosphorylation of JNK and ERK1/2 proteins in cells treated with TNF-alpha+/- for 10 min. CONCLUSIONS: The data suggested that Sal B suppressed TNF-alpha+/- induced MMP-9 expression and activity by blocking the activation of NF-kappaB, JNK, and ERK1/2 signaling pathways. PMID- 26415807 TI - Mass Casualty Incident Primary Triage Methods in China. AB - OBJECTIVE: To evaluate the technical characteristics and application of mass casualty incident (MCI) primary triage (PT) methods applied in China. DATA SOURCES: Chinese literature was searched by Chinese Academic Journal Network Publishing Database (founded in June 2014). The English literature was searched by PubMed (MEDLINE) (1950 to June 2014). We also searched Official Websites of Chinese Central Government's (http://www.gov.cn/), National Health and Family Planning Commission of China (http://www.nhfpc.gov.cn/), and China Earthquake Information (http://www.csi.ac.cn/). STUDY SELECTION: We included studies associated with mass casualty events related to China, the PT applied in China, guidelines and standards, and application and development of the carding PT method in China. RESULTS: From 3976 potentially relevant articles, 22 met the inclusion criteria, 20 Chinese, and 2 English. These articles included 13 case reports, 3 retrospective analyses of MCI, two methods introductions, three national or sectoral criteria, and one simulated field testing and validation. There were a total of 19 kinds of MCI PT methods that have been reported in China from 1950 to 2014. In addition, there were 15 kinds of PT methods reported in the literature from the instance of the application. CONCLUSIONS: The national and sectoral current triage criteria are developed mainly for earthquake relief. Classification is not clear. Vague criteria (especially between moderate and severe injuries) operability are not practical. There are no triage methods and research for children and special populations. There is no data and evidence supported triage method. We should revise our existing classification and criteria so it is clearer and easier to be grasped in order to build a real, practical, and efficient PT method. PMID- 26415808 TI - Application of Lung Ultrasonography in the Diagnosis of Childhood Lung Diseases. AB - In this paper, we focus on the characteristics of LUS in diagnosing childhood pulmonary disease. LUS is convenient, noninvasive, and free of radiation. It helps in the differentiation of lung diseases. Therefore, LUS has the potential to become a reference instrument for bedside dynamic respiratory monitoring. We hope that this review will help clinicians become acquainted with LUS and will accelerate the extensive application of LUS in children. PMID- 26415809 TI - Diced Costal Cartilage for Augmentation Rhinoplasty. PMID- 26415810 TI - Clinical Features and Prognosis of Ocular Myasthenia Gravis Patients with Different Phenotypes. PMID- 26415811 TI - A Rare Case of Ovarian Cancer Presenting with Paraneoplastic Cerebellar Degeneration and Limbic Encephalitis. PMID- 26415812 TI - Myocyte Enhancer Factor-2A Gene Mutation and Coronary Artery Disease. AB - BACKGROUND: Premature ventricular contractions (PVCs) are common in the general population, and frequent PVCs may result in the poor quality of life or even the damage of cardiac function. We examined the efficacy and safety of a traditional Chinese medicine Wenxin Keli for the treatment of frequent PVCs among a relatively large Chinese cohort. METHODS: We performed a randomized, double blind, placebo-controlled, parallel-group, multicenter trial. A total of 1200 eligible participants were randomly assigned in a ratio of 1:1 to receive Wenxin Keli or the placebo for 4 weeks. The primary and secondary endpoint was the change of PVC numbers and PVC-related symptoms after a 4-week treatment compared with baseline, respectively. In addition, vital signs, laboratory values, and electrocardiographic parameters were assessed in a safety analysis. RESULTS: At the initial evaluation, no significant differences in the baseline characteristics were observed between the Wenxin Keli group and the placebo group. A smaller number of PVCs was observed after the 4-week treatment than at baseline, in both the Wenxin Keli group (5686 +/- 5940 vs. 15,138 +/- 7597 beats/d, P < 0.001) and the placebo group (10,592 +/- 8009 vs. 14,529 +/- 5929 beats/d, P < 0.001); moreover, the Wenxin Keli group demonstrated a significantly greater reduction in the frequency of PVCs than the placebo group (P < 0.001). In a full analysis set, patients in the Wenxin Keli group exhibited significantly higher total effective responses in the reduction of PVCs compared to those in the placebo group (83.8% vs. 43.5%,P < 0.001). The per-protocol analysis yielded similar results (83.0% vs. 39.3%,P < 0.001). Treatment with Wenxin Keli also demonstrated superior performance compared to the placebo with respect to PVC related symptoms. No severe adverse effects attributable to Wenxin Keli were reported. CONCLUSIONS: Wenxin Keli treatment effectively reduced the overall number of PVCs and alleviated PVC-related symptoms in patients without structural heart diseases and had no severe side effects. PMID- 26415813 TI - Acute Myocardial Infarction Due to Stent Thrombosis After Administration of Intravenous Epinephrine for Anaphylaxis. PMID- 26415814 TI - Paget-Schroetter Syndrome. PMID- 26415815 TI - Endobronchial Solitary Fibrous Tumor: Imaging and Bronchoscopic Findings. PMID- 26415816 TI - Adenoma of the Ciliary Pigment Epithelium with Diffuse Iris Pigment Dispersion. PMID- 26415817 TI - Development of a validated questionnaire to measure the self-perceived competence of primary health professionals in providing nutrition care to patients with chronic disease. AB - BACKGROUND: Nutrition is an important aspect of chronic disease prevention and management by primary health professionals, including GPs, dietitians, practice nurses, diabetes educators and exercise professionals. In order to better understand how to improve the delivery of nutrition care, it is important to have valid and reliable tools to measure self-perceived competence. OBJECTIVE: This study aimed to develop a valid, structured, questionnaire that measures the self perceived competence of primary health professionals to provide nutrition care to patients with chronic disease. METHODS: The development of the questionnaire was carried out in four stages (1): preparation of scope and structure, through a literature review and consultation with an expert reference group (2); development of questionnaire items, which were refined through feedback from the reference group and 18 primary health professionals (3); investigation of internal consistency and concurrent validity through a pilot study on 118 primary health professionals (4) and investigation of test-retest reliability through a pilot study on 33 primary health professionals who completed the questionnaire twice, 2-3 weeks apart. RESULTS: Stages 1 and 2 resulted in four constructs and 35 questions in the questionnaire. Stage 3 confirmed internal consistency, with Cronbach's alpha ranging from 0.88 to 0.98 for each construct and 0.98 for all items combined. Dietitians scored significantly higher than speech pathologists (P < 0.05) in each construct, confirming concurrent validity. Stage 4 confirmed test-retest reliability, with correlation coefficients ranging from 0.89 to 0.94 for each construct and 0.95 for all items combined. CONCLUSION: The NUTrition COMPetence (NUTCOMP) questionnaire is a valid, reliable and suitable tool that can be used to directly inform professional development and identify opportunities to support safe and effective practice. PMID- 26415819 TI - Xanthine oxidase injurious response in acute joint injury. AB - BACKGROUND: While acute trauma is a major cause of osteoarthritis, its etiology is poorly understood. We sought to determine whether xanthine oxidase (XO), a major producer of reactive oxygen species, plays a role in the early events of acute joint injury. METHODS: We analyzed synovial fluid from 23 subjects with recent severe acute knee injury. As a control we evaluated SF from 23 individuals with no or minimal knee osteoarthritis. We measured XO activity, reactive oxygen+reactive nitrogen species (ROS+RNS), protein oxidative damage (carbonyl), the type II collagen synthesis marker procollagen II c-propeptide (CPII) and the type II collagen degradation marker collagen type II telopeptide (CTx-II). We also measured the proinflammatory cytokine IL-6. RESULTS: XO and ROS+RNS were higher (p=0.02 and p=0.001 respectively) in acute injury than control and were strongly positively associated (r=0.62, p=0.004). Carbonyl was higher in acute injury than control (p=0.0002) and was positively correlated with XO (r=0.68, p=0.0007) as well as with ROS+RNS (r=0.71, p=0.004). CPII was higher in acute injury than control (p<0.0001) and was negatively correlated with XO (r=-0.49, p=0.017). While CTxII was not significantly higher in acute injury than control, it was positively correlated with CPII (r=0.71, p=0.0002). IL-6 was higher in acute injury than control (p<0.0001). CONCLUSIONS: These results are consistent with a potentially injurious effect of XO activity in acute joint injury characterized by excess free radical production and oxidative damage. These effects are associated with an inhibition of type II collagen production that may impede the ability of the injured joint to repair. PMID- 26415820 TI - MicroRNA in prostate cancer. AB - In the United States of America male prostate cancer (PCa) is the most dominant malignancy and the second highest cause of cancer-related mortality risk compared to lung and colon cancers. MicroRNAs (miRNAs) are a class of endogenously expressed small, non-coding, single-stranded RNA which function as regulators of gene expression. They influence various physiological and pathophysiological processes. In this review, we focus on the regulation of miRNAs in prostate cancer and their mechanisms which contribute to prostate carcinogenesis. The relation of miRNAs with androgen signaling is highlighted and the prospects of miRNAs for clinical therapies are discussed. PMID- 26415821 TI - A novel quantitative evaluation method for quality control results. AB - BACKGROUND: Quality control (QC) procedures using stable control materials are important for preventing systematic errors (SEs). While the current QC methods assess QC results semi-quantitatively, we designed a novel quantitative QC procedure (QQCP). METHODS: QC results were expressed as Z-scores to analyze results quantitatively. The decision values were accumulated up to 30, with three decision values per run, and were compared to rejection criteria at each run. The probability for false rejection (Pfr) and error detection (Ped) for the QQCP and Westgard multirule methods were estimated using simulated QC data with SEs ranging from 0 to 3 standard deviations (SDs). RESULTS: The Pfr of the QQCP was 3.4% at the 10th run. When 2 QC materials with the same SEs (0.5 SD and 1.0 SD) were used, the Peds were 36.1% and 95.7% at run 10, respectively. When the SE of each material was greater than 1.5 SDs, the Ped reached 100% at run 10. The QQCP could detect more than 99% of errors in the 6th, 4th, 3rd, and 2nd runs for 2 QC results with 1.5, 2.0, 2.5, and 3.0 SD SEs, respectively. CONCLUSION: The QQCP exhibited a Ped value up to 3.3-fold higher than the Westgard method. Implementation of the QQCP would satisfy the high quality goals derived from biological variations. PMID- 26415822 TI - Interventions to increase engagement with rehabilitation in adults with acquired brain injury: A systematic review. AB - Rehabilitation in adults with acquired brain injury is often hampered by a lack of client engagement with the rehabilitation process, leading to frustration, withdrawal of services and poorer recovery. Motivation, apathy and awareness are potential mechanisms underlying engagement, but few studies have suggested potential intervention techniques. A systematic review of the literature was carried out to identify and evaluate interventions designed to increase rehabilitation engagement in adults with acquired brain injury. Database searches used the following terms: rehabilitation, brain injury, and compliance/engagement/adherence in PsychInfo, Medline, Cinahl, Embase, AMED, Web of Knowledge, PsycBite, Cochrane clinical trials, and clinicaltrials.org. Hand searches were conducted of reference lists and relevant journals. Fifteen studies were included in the review. Intervention techniques fell into two broad categories: behavioural modification techniques and cognitive/meta-cognitive skills. Contingent reward techniques were most effective at increasing adherence and compliance, while interventions enabling clients' active participation in rehabilitation appeared to increase engagement and motivation. The review highlighted methodological and measurement inconsistencies in the field and suggested that interventions should be tailored to clients' abilities and circumstances. PMID- 26415818 TI - Differential involvement of cortical and cerebellar areas using dominant and nondominant hands: An FMRI study. AB - Motor fMRI studies, comparing dominant (DH) and nondominant (NDH) hand activations have reported mixed findings, especially for the extent of ipsilateral (IL) activations and their relationship with task complexity. To date, no study has directly compared DH and NDH activations using an event related visually guided dynamic power-grip paradigm with parametric (three) forces (GF) in healthy right-handed subjects. We implemented a hierarchical statistical approach aimed to: (i) identify the main effect networks engaged when using either hand; (ii) characterise DH/NDH responses at different GFs; (iii) assess contralateral (CL)/IL-specific and hemisphere-specific activations. Beyond confirming previously reported results, this study demonstrated that increasing GF has an effect on motor response that is contextualised also by the use of DH or NDH. Linear analysis revealed increased activations in sensorimotor areas, with additional increased recruitments of subcortical and cerebellar areas when using the NDH. When looking at CL/IL-specific activations, CL sensorimotor areas and IL cerebellum were activated with both hands. When performing the task with the NDH, several areas were also recruited including the CL cerebellum. Finally, there were hand-side-independent activations of nonmotor-specific areas in the right and left hemispheres, with the right hemisphere being involved more extensively in sensori-motor integration through associative areas while the left hemisphere showing greater activation at higher GF. This study shows that the functional networks subtending DH/NDH power-grip visuomotor functions are qualitatively and quantitatively distinct and this should be taken into consideration when performing fMRI studies, particularly when planning interventions in patients with specific impairments. PMID- 26415824 TI - Interobserver agreement in assessment of polycystic ovarian morphology using pattern recognition. PMID- 26415823 TI - beta-Lapachone and Paclitaxel Combination Micelles with Improved Drug Encapsulation and Therapeutic Synergy as Novel Nanotherapeutics for NQO1-Targeted Cancer Therapy. AB - beta-Lapachone (LPC) is a novel cytotoxic agent that is bioactivated by NADP(H): quinone oxidoreductase 1 (NQO1), an enzyme elevated in a variety of tumors, such as non-small cell lung cancer (NSCLC), pancreatic cancer, liver cancer, and breast cancer. Despite its unique mechanism of action, its clinical evaluation has been largely hindered by low water solubility, short blood half-life, and narrow therapeutic window. Although encapsulation into poly(ethylene glycol)-b poly(D,L-lactic acid) (PEG-PLA) micelles could modestly improve its solubility and prolong its half-life, the extremely fast intrinsic crystallization tendency of LPC prevents drug loading higher than ~2 wt %. The physical stability of the LPC-loaded micelles is also far from satisfactory for further development. In this study, we demonstrate that paclitaxel (PTX), a front-line drug for many cancers, can provide two functions when coencapsulated together with LPC in the PEG-PLA micelles; first, as a strong crystallization inhibitor for LPC, thus to significantly increase the LPC encapsulation efficiency in the micelle from 11.7 +/- 2.4% to 100.7 +/- 2.2%. The total drug loading efficiency of both PTX and LPC in the combination polymeric micelle reached 100.3 +/- 3.0%, and the drug loading density reached 33.2 +/- 1.0%. Second, the combination of LPC/PTX demonstrates strong synergistic cytotoxicity effect against the NQO1 overexpressing cancer cells, including A549 NSCLC cells, and several pancreatic cancer cells (combination index <1). In vitro drug release study showed that LPC was released faster than PTX either in phosphate-buffered saline (PH = 7.4) or in 1 M sodium salicylate, which agrees with the desired dosing sequence of the two drugs to exert synergistic pharmacologic effect at different cell checkpoints. The PEG-PLA micelles coloaded with LPC and PTX offer a novel nanotherapeutic, with high drug loading, sufficient physical stability, and biological synergy to increase drug delivery efficiency and optimize the therapeutic window for NOQ1-targeted therapy of cancer. PMID- 26415826 TI - Femtosecond laser controlled wettability of solid surfaces. AB - Femtosecond laser microfabrication is emerging as a hot tool for controlling the wettability of solid surfaces. This paper introduces four typical aspects of femtosecond laser induced special wettability: superhydrophobicity, underwater superoleophobicity, anisotropic wettability, and smart wettability. The static properties are characterized by the contact angle measurement, while the dynamic features are investigated by the sliding behavior of a liquid droplet. Using different materials and machining methods results in different rough microstructures, patterns, and even chemistry on the solid substrates. So, various beautiful wettabilities can be realized because wettability is mainly dependent on the surface topography and chemical composition. The distinctions of the underlying formation mechanism of these wettabilities are also described in detail. PMID- 26415825 TI - The role of sensory modality in prepulse inhibition: An ontogenetic study. AB - Deficits in prepulse inhibition (PPI), a measure of sensorimotor gating, are observed in neurodevelopmental and neuropsychiatric disorders. Despite the large PPI literature, the majority of studies characteristically employ tests with one interstimulus interval (ISI), of one modality, at one age. In the context of the auditory startle response (ASR), the present study examined (1) the profile for the ontogeny of PPI through adulthood in Long-Evans hooded rats with a reasonably comprehensive ISI function, (2) whether the ontogenetic profile for PPI is sensitive to modality of the prepulse stimulus, as a within-session variable, and (3) whether the maturation of PPI differs for males and females. Despite the basic effect of more pronounced PPI in adult relative to preweanling animals, each sensory modality displayed a unique ontogenetic profile for PPI, without any compelling evidence for major differences between males and females, in accordance with the known temporal course of peripheral and central maturational profiles of sensory systems in the rat. The context for assessing auditory PPI (auditory and tactile vs. auditory and visual prepulses) influenced the overall startle response, i.e., a shift in the height of the entire profile, but did not significantly impact the auditory PPI profile per se. The translational relevance of preclinical sensorimotor assessments to patients with neurodevelopmental and/or neuropsychiatric disorders depends partly on an understanding of the ontogeny of sensorimotor gating in different sensory systems, and can be strengthened with the use of a reasonably comprehensive number of ISIs to provide relatively precise and defined response functions. PMID- 26415827 TI - Hydrometallurgical Recovery of Metals from Large Printed Circuit Board Pieces. AB - The recovery of precious metals from waste printed circuit boards (PCBs) is an effective recycling process. This paper presents a promising hydrometallurgical process to recover precious metals from waste PCBs. To simplify the metal leaching process, large pieces of PCBs were used instead of a pulverized sample. The chemical coating present on the PCBs was removed by sodium hydroxide (NaOH) treatment prior to the hydrometallurgical treatment. Among the leaching reagents examined, hydrochloric acid (HCl) showed great potential for the recovery of metals. The HCl-mediated leaching of waste PCBs was investigated over a range of conditions. Increasing the acid concentration decreased the time required for complete metal recovery. The shaking speed showed a pronounced positive effect on metal recovery, but the temperature showed an insignificant effect. The results showed that 1 M HCl recovered all of the metals from 4 cm * 4 cm PCBs at room temperature and 150 rpm shaking speed in 22 h. PMID- 26415828 TI - Standalone medical device software: The evolving regulatory framework. AB - The paper provides an introduction to the regulatory landscape affecting a particular category of medical technology, namely standalone software-sometimes referred to as 'software as a medical device'. To aid the reader's comprehension of an often complex area, six case studies are outlined and discussed before the paper continues to provide detail of how software with a medical purpose in its own right can potentially be classified as a medical device. The reader is provided an appreciation of how to go about classifying such software and references to support the developer new to the field in locating detailed regulatory support documents and contact points for advice. PMID- 26415829 TI - Mannan-decorated thiolated Eudragit microspheres for targeting antigen presenting cells via nasal vaccination. AB - Mucosal vaccination of protein as an antigen requires appropriate delivery or adjuvant systems to deliver antigen to mucosal immune cells efficiently and generate valid immune responses. For successful nasal immunization, the obstacles imposed by the normal process of mucociliary clearance which limits residence time of applied antigens and low antigen delivery to antigen presenting cells (APCs) in nasal associated lymphoid tissue (NALT) need to be overcome for the efficient vaccination. Here, we prepared mucoadhesive and mannan-decorated thiolated Eudragit microspheres (Man-TEM) as a nasal vaccine carrier to overcome the limitations. Mucoadhesive thiolated Eudragit (TE) were decorated with mannan for targeting mannose receptors (MR) in antigen presenting cells (APCs) to obtain efficient immune responses. The potential adjuvant ability of Man-TEM for intranasal immunization was confirmed by in vitro and in vivo experiments. In mechanistic study using APCs in vitro, we obtained that Man-TEM enhanced the receptor-mediated endocytosis by stimulating the MR receptors of APCs. The nasal vaccination of OVA-loaded Man-TEM in mice showed higher levels of serum IgG and mucosal sIgA than the soluble OVA group due to the specific recognition of MR of APCs by the mannan in the Man-TEM. These results suggest that mucoadhesive and Man-TEM may be a promising candidate for nasal vaccine delivery system to elicit systemic and mucosal immunity. PMID- 26415830 TI - Encapsulation in a rapid-release liposomal formulation enhances the anti-tumor efficacy of pemetrexed in a murine solid mesothelioma-xenograft model. AB - We recently developed a PEG-coated liposome encapsulating the anti-folate drug pemetrexed (PMX). Such liposomal formulations have shown potent cytotoxic effects against malignant pleural mesothelioma (MPM) cells in vitro. In the present study, we investigated the pharmacokinetics, bio-distribution and in vivo anti tumor efficacy of two liposomal PMX formulations with different drug release rates in a murine mesothelioma-xenograft model. Liposomes with different PMX release rates were prepared via manipulating liposomal membrane fluidity through incorporating either a solid-phase (HSPC) or a fluid-phase (POPC) phospholipid. Both liposomal PMX formulations showed prolonged plasma pharmacokinetics and were accumulated to a similar extent in tumors and other tissues, presumably, due to surface modification with polyethylene glycol (PEG). In a murine mesothelioma xenograft model, interestingly, PMX encapsulated in a fast-release POPC liposome produced superior tumor growth suppression compared with either free PMX or PMX encapsulated in a slow-release HSPC liposome. Such in vivo anti-tumor efficacy was accomplished mainly by a potent induction of apoptosis within tumor tissue by the released PMX from POPC liposomes. Our results clearly emphasize the therapeutic efficacy of liposomal PMX over free PMX in conquering aggressive solid tumors such as malignant mesothelioma. A guarantee of the targeted delivery of PMX to tumor cells helps overcome some of the major shortcomings encountered with the use of free PMX. PMID- 26415831 TI - Family members' needs and experiences of driving disruption due to health conditions or ageing. AB - PURPOSE: Family members often assume the caregiving role and provide practical assistance and emotional support when an individual is experiencing driving disruption due to health conditions or ageing. The purpose of this study was to understand the experiences, viewpoints and needs of family members with regards to an individual undergoing driving disruption across various population groups. METHOD: A scoping review was conducted through searching across six databases and hand searching articles published from 1985 to 2013. Findings from the articles specific to the aims of the review were extracted and summarised into common topics. RESULTS: Twenty-seven articles were included; dementia or cognitive impairment (16 articles), older adults (8 articles) and brain injury (3 articles). The most common topic raised was related to decisions and consequences for the individual. Other concerns were related to family members' occupational role changes, emotional and communication issues and support needs of family members and their recommendations for services. CONCLUSIONS: This review revealed the impact of driving disruption on family members but research is limited, especially in the area of brain injury. The majority of articles did not set out to explore family members' experiences and needs and this highlights an area that requires critical attention. IMPLICATIONS FOR REHABILITATION: Health professionals should be aware of the potential impact of driving disruption on family members. Family members frequently raise concerns regarding the decisions and consequences for their relative, but also bring up personal concerns such as changes to their own occupational roles and the communication and emotional issues they face during driving disruption. Unique challenges arise between family members of individuals of different health conditions, thus highlighting the importance of family caregiving research in various population groups. PMID- 26415832 TI - Posttranscriptional silencing of the lncRNA MALAT1 by miR-217 inhibits the epithelial-mesenchymal transition via enhancer of zeste homolog 2 in the malignant transformation of HBE cells induced by cigarette smoke extract. AB - Lung cancer is regarded as the leading cause of cancer-related deaths, and cigarette smoking is one of the strongest risk factors for the development of lung cancer. However, the mechanisms for cigarette smoke-induced lung carcinogenesis remain unclear. The present study investigated the effects of an miRNA (miR-217) on levels of an lncRNA (MALAT1) and examined the role of these factors in the epithelial-mesenchymal transition (EMT) induced by cigarette smoke extract (CSE) in human bronchial epithelial (HBE) cells. In these cells, CSE caused decreases of miR-217 levels and increases in lncRNA MALAT1 levels. Over expression of miR-217 with a mimic attenuated the CSE-induced increase of MALAT1 levels, and reduction of miR-217 levels by an inhibitor enhanced expression of MALAT1. Moreover, the CSE-induced increase of MALAT1 expression was blocked by an miR-217 mimic, indicating that miR-217 negatively regulates MALAT1 expression. Knockdown of MALAT1 reversed CSE-induced increases of EZH2 (enhancer of zeste homolog 2) and H3K27me3 levels. In addition to the alteration from epithelial to spindle-like mesenchymal morphology, chronic exposure of HBE cells to CSE increased the levels of EZH2, H3K27me3, vimentin, and N-cadherin and decreased E cadherin levels, effects that were reversed by MALAT1 siRNA or EZH2 siRNA. The results indicate that miR-217 regulation of EZH2/H3K27me3 via MALAT1 is involved in CSE-induced EMT and malignant transformation of HBE cells. The posttranscriptional silencing of MALAT1 by miR-217 provides a link, through EZH2, between ncRNAs and the EMT and establishes a mechanism for CSE-induced lung carcinogenesis. PMID- 26415833 TI - Compound- and sex-specific effects on programming of energy and immune homeostasis in adult C57BL/6JxFVB mice after perinatal TCDD and PCB 153. AB - Early life exposure to endocrine disrupting compounds has been linked to chronic diseases later in life, like obesity and related metabolic disorders. We exposed C57BL/6JxFVB hybrid mice to the aryl hydrocarbon receptor agonist 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) and the constitutive androstane receptor/pregnane X receptor agonist polychlorinated biphenyl 153 (PCB 153) in an experimental design relevant for human exposure. Exposure occurred during gestation and lactation via maternal feed to a wide dose range (TCDD: 10-10,000 pg/kg body weight/day; PCB 153: 0.09-1406 MUg/kg body weight/d). Then exposure was ceased and offspring were followed up to 1 year of age. Metabolic parameters like body weight, fat pad weights, glucose tolerance, endocrine serum profile, and neurobehavioral and immunological parameters were determined. Body weight was transiently affected by both compounds throughout the follow-up. TCDD-exposed males showed decreased fat pad and spleen weights and an increase in IL-4 production of splenic immune cells. In contrast, females showed increased fat pad weights and production of IFNgamma. PCB 153-exposed males showed an increase in glucose, whereas females showed an increase in glucagon, a decrease in pancreas weight, and an increase in thymus weight. In conclusion, early life exposure to TCDD appears to affect programming of energy and immune homeostasis in offspring, whereas the effects of perinatal PCB 153 were mainly on programming of glucose homeostasis. Both compounds act sex-specifically. Lowest derived BMDLs (lower bounds of the (two sided) 90%-confidence interval for the benchmark dose) for both compounds are not lower than current tolerable daily intakes. PMID- 26415834 TI - Redox cycling of endogenous copper by ferulic acid leads to cellular DNA breakage and consequent cell death: A putative cancer chemotherapy mechanism. AB - Ferulic acid (FA) is a plant polyphenol showing diverse therapeutic effects against cancer, diabetes, cardiovascular and neurodegenerative diseases. FA is a known antioxidant at lower concentrations, however at higher concentrations or in the presence of metal ions such as copper, it may act as a pro-oxidant. It has been reported that copper levels are significantly raised in different malignancies. Cancer cells are under increased oxidative stress as compared to normal cells. Certain therapeutic substances like polyphenols can further increase this oxidative stress and kill cancer cells without affecting the proliferation of normal cells. Through various in vitro experiments we have shown that the pro-oxidant properties of FA are enhanced in the presence of copper. Comet assay demonstrated the ability of FA to cause oxidative DNA breakage in human peripheral lymphocytes which was ameliorated by specific copper-chelating agent such as neocuproine and scavengers of ROS. This suggested the mobilization of endogenous copper in ROS generation and consequent DNA damage. These results were further validated through cytotoxicity experiments involving different cell lines. Thus, we conclude that such a pro-oxidant mechanism involving endogenous copper better explains the anticancer activities of FA. This would be an alternate non-enzymatic, and copper-mediated pathway for the cytotoxic activities of FA where it can selectively target cancer cells with elevated levels of copper and ROS. PMID- 26415835 TI - Synergy of multi-scale toughening and protective mechanisms at hierarchical branch-stem interfaces. AB - Biological materials possess a variety of artful interfaces whose size and properties are adapted to their hierarchical levels and functional requirements. Bone, nacre, and wood exhibit an impressive fracture resistance based mainly on small crystallite size, interface organic adhesives and hierarchical microstructure. Currently, little is known about mechanical concepts in macroscopic biological interfaces like the branch-stem junction with estimated 10(14) instances on earth and sizes up to few meters. Here we demonstrate that the crack growth in the upper region of the branch-stem interface of conifer trees proceeds along a narrow predefined region of transversally loaded tracheids, denoted as sacrificial tissue, which fail upon critical bending moments on the branch. The specific arrangement of the tracheids allows disconnecting the overloaded branch from the stem in a controlled way by maintaining the stem integrity. The interface microstructure based on the sharply adjusted cell orientation and cell helical angle secures a zig-zag crack propagation path, mechanical interlock closing after the bending moment is removed, crack gap bridging and self-repairing by resin deposition. The multi scale synergetic concepts allows for a controllable crack growth between stiff stem and flexible branch, as well as mechanical tree integrity, intact physiological functions and recovery after the cracking. PMID- 26415836 TI - Benzodiazepine Prescribing in Older Adults in U.S. Ambulatory Clinics and Emergency Departments (2001-10). AB - OBJECTIVES: To assess trends in benzodiazepine use from 2001 to 2010 in older adults in U.S. ambulatory clinics and emergency departments (EDs). DESIGN: Retrospective analysis. SETTING: 2001 to 2010 National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS). PARTICIPANTS: Individuals aged 65 and older for whom the reason for visit might prompt a physician to use a benzodiazepine (e.g., anxiety, detoxification, back sprain). MEASUREMENTS: The NAMCS and NHAMCS were used to evaluate U.S. ambulatory clinic and ED visits. Encounters involving individuals aged 65 and older for whom a benzodiazepine might be prescribed were analyzed. Trends in benzodiazepine use in these visits were explored, and predictors of use were assessed using survey weighted chi-square tests and logistic regression. RESULTS: From 2001 to 2010, benzodiazepines were used in 16.6 million of 133.3 million ambulatory clinic visits and 1.9 million of 18.1 million ED visits with the selected reasons for the visits. There was no change in benzodiazepine use in either setting over the study period, although benzodiazepine use for those aged 85 and older increased from 8.9% to 19.3% in ambulatory clinics and 10.1% to 17.2% in EDs. Individuals visiting clinics with anxiety were five times as likely to receive benzodiazepines (odds ratio (OR) = 4.8), and those in EDs were twice as likely (OR = 2.3). CONCLUSION: Despite safety concerns, benzodiazepine use in older adults in U.S. ambulatory clinics and EDs did not change from 2001 to 2010. In the oldest individuals, who are at higher risk of adverse events, a greater increase was seen than in those aged 65 to 84. Additional measures may be needed to promote alternatives to benzodiazepines. PMID- 26415837 TI - Alzheimer's disease drug development based on Computer-Aided Drug Design. AB - Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by the excessive deposition of amyloids in the brain. The pathological features mainly include the extracellular amyloid plaques and intracellular neurofibrillary tangles, which are the production of amyloid precursor protein (APP) processed by the alpha-, beta- and gamma-secretases. Based on the amyloid cascade hypotheses of AD, a large number of amyloid-beta agents and secretase inhibitors against AD have been recently developed by using computational methods. This review article describes pathophysiology of AD and the structure of the Abeta plaques, beta- and gamma-secretases, and discusses the recent advances in the development of the amyloid agents for AD therapy and diagnosis by using Computer-Aided Drug Design approach. PMID- 26415838 TI - Ultrahigh volumetric capacitance and cyclic stability of fluorine and nitrogen co doped carbon microspheres. AB - Highly porous nanostructures with large surface areas are typically employed for electrical double-layer capacitors to improve gravimetric energy storage capacity; however, high surface area carbon-based electrodes result in poor volumetric capacitance because of the low packing density of porous materials. Here, we demonstrate ultrahigh volumetric capacitance of 521 F cm(-3) in aqueous electrolytes for non-porous carbon microsphere electrodes co-doped with fluorine and nitrogen synthesized by low-temperature solvothermal route, rivaling expensive RuO2 or MnO2 pseudo-capacitors. The new electrodes also exhibit excellent cyclic stability without capacitance loss after 10,000 cycles in both acidic and basic electrolytes at a high charge current of 5 A g(-1). This work provides a new approach for designing high-performance electrodes with exceptional volumetric capacitance with high mass loadings and charge rates for long-lived electrochemical energy storage systems. PMID- 26415839 TI - PUPIL: A Software Integration System for Multi-Scale QM/MM-MD Simulations and Its Application to Biomolecular Systems. AB - PUPIL (Program for User Package Interfacing and Linking) implements a distinctive multi-scale approach to hybrid quantum mechanical/molecular mechanical molecular dynamics (QM/MM-MD) simulations. Originally developed to interface different external programs for multi-scale simulation with applications in the materials sciences, PUPIL is finding increasing use in the study of complex biological systems. Advanced MD techniques from the external packages can be applied readily to a hybrid QM/MM treatment in which the forces and energy for the QM region can be computed by any of the QM methods available in any of the other external packages. Here, we give a survey of PUPIL design philosophy, main features, and key implementation decisions, with an orientation to biomolecular simulation. We discuss recently implemented features which enable highly realistic simulations of complex biological systems which have more than one active site that must be treated concurrently. Examples are given. PMID- 26415841 TI - A Practical Quantum Mechanics Molecular Mechanics Method for the Dynamical Study of Reactions in Biomolecules. AB - Quantum mechanics/molecular mechanics (QM/MM) methods are excellent tools for the modeling of biomolecular reactions. Recently, we have implemented a new QM/MM method (Fireball/Amber), which combines an efficient density functional theory method (Fireball) and a well-recognized molecular dynamics package (Amber), offering an excellent balance between accuracy and sampling capabilities. Here, we present a detailed explanation of the Fireball method and Fireball/Amber implementation. We also discuss how this tool can be used to analyze reactions in biomolecules using steered molecular dynamics simulations. The potential of this approach is shown by the analysis of a reaction catalyzed by the enzyme triose phosphate isomerase (TIM). The conformational space and energetic landscape for this reaction are analyzed without a priori assumptions about the protonation states of the different residues during the reaction. The results offer a detailed description of the reaction and reveal some new features of the catalytic mechanism. In particular, we find a new reaction mechanism that is characterized by the intramolecular proton transfer from O1 to O2 and the simultaneous proton transfer from Glu 165 to C2. PMID- 26415840 TI - Efficient Calculation of Enzyme Reaction Free Energy Profiles Using a Hybrid Differential Relaxation Algorithm: Application to Mycobacterial Zinc Hydrolases. AB - Determination of the free energy profile for an enzyme reaction mechanism is of primordial relevance, paving the way for our understanding of the enzyme's catalytic power at the molecular level. Although hybrid, mostly DFT-based, QM/MM methods have been extensively applied to this type of studies, achieving accurate and statistically converged results at a moderate computational cost is still an open challenge. Recently, we have shown that accurate results can be achieved in less computational time, combining Jarzynski's relationship with a hybrid differential relaxation algorithm (HyDRA), which allows partial relaxation of the solvent during the nonequilibrium steering of the reaction. In this work, we have applied this strategy to study two mycobacterial zinc hydrolases. Mycobacterium tuberculosis infections are still a worldwide problem and thus characterization and validation of new drug targets is an intense field of research. Among possible drug targets, recently two essential zinc hydrolases, MshB (Rv1170) and MA-amidase (Rv3717), have been proposed and structurally characterized. Although possible mechanisms have been proposed by analogy to the widely studied human Zn hydrolases, several key issues, particularly those related to Zn coordination sphere and its role in catalysis, remained unanswered. Our results show that mycobacterial Zn hydrolases share a basic two-step mechanism. First, the attacking water becomes deprotonated by the conserved base and establishes the new C-O bond leading to a tetrahedral intermediate. The intermediate requires moderate reorganization to allow for proton transfer to the amide N and C-N bond breaking to occur in the second step. Zn ion plays a key role in stabilizing the tetrahedral intermediate and balancing the negative charge of the substrate during hydroxide ion attack. Finally, comparative analysis of other Zn hydrolases points to a convergent mechanistic evolution. PMID- 26415842 TI - Explicit Drug Re-positioning: Predicting Novel Drug-Target Interactions of the Shelved Molecules with QM/MM Based Approaches. AB - With the demand to enhance the speed of the drug discovery process there has been an increased usage of computational approaches in drug discovery studies. However because of their probabilistic outcomes, the challenge is to exactly mimic the natural environment which can provide the exact charge polarization effect while estimating the binding energy between protein and ligand. There has been a large number of scoring functions from simple one to the complex one available for estimating binding energy. The quantum mechanics/molecular mechanics (QM/MM) hybrid approach has been the preferred choice of interest since last decade for modeling reactions in biomolecular systems. The application of QM/MM approach has been expanded right from rescoring the already known complexes and depicting the correct position of some novel molecule to ranking a large number of molecules. It is expected that the application of QM/MM-based scoring will grow in all areas of drug discovery. However, the most promising area will be its application in repositioning, that is, assigning novel functions or targets to the already existing drugs, as this would stop the rising attrition rates as well as reduce the overall time and cost of drug discovery procedure. PMID- 26415843 TI - Enzymatic Halogenases and Haloperoxidases: Computational Studies on Mechanism and Function. AB - Despite the fact that halogenated compounds are rare in biology, a number of organisms have developed processes to utilize halogens and in recent years, a string of enzymes have been identified that selectively insert halogen atoms into, for instance, a CH aliphatic bond. Thus, a number of natural products, including antibiotics, contain halogenated functional groups. This unusual process has great relevance to the chemical industry for stereoselective and regiospecific synthesis of haloalkanes. Currently, however, industry utilizes few applications of biological haloperoxidases and halogenases, but efforts are being worked on to understand their catalytic mechanism, so that their catalytic function can be upscaled. In this review, we summarize experimental and computational studies on the catalytic mechanism of a range of haloperoxidases and halogenases with structurally very different catalytic features and cofactors. This chapter gives an overview of heme-dependent haloperoxidases, nonheme vanadium-dependent haloperoxidases, and flavin adenine dinucleotide dependent haloperoxidases. In addition, we discuss the S-adenosyl-l-methionine fluoridase and nonheme iron/alpha-ketoglutarate-dependent halogenases. In particular, computational efforts have been applied extensively for several of these haloperoxidases and halogenases and have given insight into the essential structural features that enable these enzymes to perform the unusual halogen atom transfer to substrates. PMID- 26415844 TI - The Importance of the MM Environment and the Selection of the QM Method in QM/MM Calculations: Applications to Enzymatic Reactions. AB - In this chapter, we discuss the influence of an anisotropic protein environment on the reaction mechanisms of saccharopine reductase and uroporphyrinogen decarboxylase, respectively, via the use of a quantum mechanical and molecular mechanical (QM/MM) approach. In addition, we discuss the importance of selecting a suitable DFT functional to be used in a QM/MM study of a key intermediate in the mechanism of 8R-lipoxygenase, a nonheme iron enzyme. In the case of saccharopine reductase, while the enzyme utilizes a substrate-assisted catalytic pathway, it was found that only through treating the polarizing effect of the active site, via the use of an electronic embedding formalism, was agreement with experimental kinetic data obtained. Similarly, in the case of uroporphyrinogen decarboxylase, the effect of the protein environment on the catalytic mechanism was found to be such that the calculated rate-limiting barrier is in good agreement with related experimentally determined values for the first decarboxylation of the substrate. For 8R-lipoxygenase, it was found that the geometries and energies of the multicentered open-shell intermediate complexes formed during the mechanism are quite sensitive to the choice of the density functional theory method. Thus, while density functional theory has become the method of choice in QM/MM studies, care must be taken in the selection of a particular high-level method. PMID- 26415845 TI - QM and QM/MM Methods Compared: Case Studies on Reaction Mechanisms of Metalloenzymes. AB - The review focus is a comparison of QM and QM/MM modeling techniques applied to study of metalloenzymes. The chapter aim is to highlight many of the advantages and potential pitfalls of the exciting and revolutionary QM/MM techniques using both large QM/MM systems and QM-only modeling as references. The review is illustrated by case studies for isopenicillin N synthase, ethylbenzene dehydrogenase, cytochrome P450 enzyme, AlkB DNA repair enzyme as well as 4 hydroxyphenylpyruvate dioxygenase. We find many advantages in various QM/MM techniques, over the more traditional QM cluster approaches, while at the same time offering some advice about how to avoid potential complications arising from some of these approaches' most notable drawbacks. We conclude that while there will always be an important role for QM cluster models, in computational studies, the revolutionary developments in QM/MM techniques open a bright and exciting future of new research. PMID- 26415846 TI - QM/MM Studies Reveal How Substrate-Substrate and Enzyme-Substrate Interactions Modulate Retaining Glycosyltransferases Catalysis and Mechanism. AB - Glycosyltransferases (GTs) catalyze the biosynthesis of glycosidic linkages by transferring a monosaccharide from a nucleotide sugar donor to an acceptor substrate, and they do that with exquisite regio- and stereospecificity. Retaining GTs act with retention of the configuration at the anomeric carbon of the transferred sugar. Their chemical mechanism has been under debate for long as conclusive experimental data to confirm the mechanism have been elusive. In the past years, quantum mechanical/molecular mechanical (QM/MM) calculations have shed light on the mechanistic discussion. Here, we review the work carried out in our group investigating three of these retaining enzymes (LgtC, alpha3GalT, and GalNAc-T2). Our results support the controversial front-side attack mechanism as the general mechanism for most retaining GTs. The latest structural data are in agreement with these findings. QM/MM calculations have revealed how enzyme substrate and substrate-substrate interactions modulate the transfer reaction catalyzed by these enzymes. Moreover, they provide an explanation on why in some cases a strong nucleophilic residue is found on the beta-face of the sugar, opening the door to a shift toward a double-displacement mechanism. PMID- 26415847 TI - Excited States and Photochemistry of Chromophores in the Photoactive Proteins Explored by the Combined Quantum Mechanical and Molecular Mechanical Calculations. AB - A photoactive protein usually contains a unique chromophore that is responsible for the initial photoresponse and functions of the photoactive protein are determined by the interaction between the chromophore and its protein surroundings. The combined quantum mechanical and molecular mechanical (QM/MM) approach is demonstrated to be a very useful tool for exploring structures and functions of a photoactive protein with the chromophore and its protein surroundings treated by the QM and MM methods, respectively. In this review, we summarize the basic formulas of the QM/MM approach and emphasize its applications to excited states and photoreactions of chromophores in rhodopsin protein, photoactive yellow protein, and green fluorescent protein. PMID- 26415848 TI - Preface. PMID- 26415849 TI - NetBenchmark: a bioconductor package for reproducible benchmarks of gene regulatory network inference. AB - BACKGROUND: In the last decade, a great number of methods for reconstructing gene regulatory networks from expression data have been proposed. However, very few tools and datasets allow to evaluate accurately and reproducibly those methods. Hence, we propose here a new tool, able to perform a systematic, yet fully reproducible, evaluation of transcriptional network inference methods. RESULTS: Our open-source and freely available Bioconductor package aggregates a large set of tools to assess the robustness of network inference algorithms against different simulators, topologies, sample sizes and noise intensities. CONCLUSIONS: The benchmarking framework that uses various datasets highlights the specialization of some methods toward network types and data. As a result, it is possible to identify the techniques that have broad overall performances. PMID- 26415850 TI - No hospital left behind? Education policy lessons for value-based payment in healthcare. AB - Value-based payment systems have been widely implemented in healthcare in an effort to improve the quality of care. However, these programs have not broadly improved quality, and some evidence suggests that they may increase inequities in care. No Child Left Behind is a parallel effort in education to address uneven achievement and inequalities. Yet, by penalizing the lowest performers, No Child Left Behind's approach to accountability has led to a number of unintended consequences. This article draws lessons from education policy, arguing that financial incentives should be designed to support the lowest performers to improve quality. PMID- 26415851 TI - A forgotten chiral spiro compound revisited: 3,3'-dimethyl-3H,3'H-2,2' spirobi[[1,3]benzothiazole]. AB - The title compound was obtained as a side product during dimerization-oxidation steps of the carbene generated from N-methylbenzothiazolium iodide. Chromatography on (S,S)-Whelk O1 column showed on cooling a typical plateau shape chromatogram indicating an exchange between two enantiomers on the column. The thermal barrier to racemization was determined (85 kJ.mol(-1) at 10 degrees C) by dynamic high-performance liquid chromatography (DHPLC).The absolute configuration of the first (M) and second eluted (P) enantiomers on the (S, S) Whelk O1 column was established by comparing the reconstructed circular dichroism (CD) spectra from the CD detector signal and the calculated CD spectrum of the (P) enantiomer. Mass spectrometry revealed that 3,3'-dimethyl-3H,3'H-2,2' spirobi[[1,3]benzothiazole] can be viewed as a masked thiophenate attached to a benzothiazolium framework. PMID- 26415852 TI - Synthesis, molecular structure, and chiroptical properties of dibenzylidene derivatives of bicyclo[3.3.1]nonane and brexane. AB - Synthesis of several enantiomerically pure unsaturated bicyclo[3.3.1]nonane and related brexane (tricyclo[4.3.0.0(3,7) ]nonane) derivatives bearing exocyclic benzylidene substituents from readily available (+)-(1S,5S)-bicyclo[3.3.1]nonane 2,6-dione was accomplished. Molecular geometry and chiroptical properties of compounds with enone and styrene chromophores were studied by X-ray diffraction analysis, molecular modeling, and circular dichroism (CD) spectroscopy. Difunctional 3,7-dibenzylidenebicyclo[3.3.1]nonanes, such as and , exhibited intense CD couplets, arising from the exciton coupling between the two unsaturated chromophores. The observed negative sign of the exciton couplets is congruent with the negative twist (negative chirality) defined by the two interacting transition dipoles. The sign of the Cotton effect corresponding to the pi->pi* transitions in the CD spectra of monoenone and tricyclic brexane acetate was correlated with the intrinsic dissymmetry (helicity) of the styrene chromophore. PMID- 26415853 TI - Zwitterionic phosphorylated quinines as chiral solvating agents for NMR spectroscopy. AB - Because of their unique 3D arrangement, naturally occurring Cinchona alkaloids and their synthetic derivatives have found wide-ranging applications in chiral recognition. Recently, we determined the enantioselective properties of C-9 phosphate mixed triesters of quinine as versatile chiral solvating agents in nuclear magnetic resonance (NMR) spectroscopy. In the current study, we introduce new zwitterionic members of this class of molecules containing a negatively charged phosphate moiety (i.e., ethyl, n-butyl and phenyl hydrogen quininyl phosphate). An efficient approach for synthesizing these compounds is elaborated, and full characterization, including conformational and autoaggregation phenomena studies, was performed. Therefore, their ability to induce NMR anisochrony of selected enantiomeric substrates (i.e., primarily N-DNB-protected amino acids and their methyl esters) was analyzed compared to uncharged diphenyl quininyl phosphate and its positively charged quaternary ammonium hydrochloride salt. In addition, (1) H and (13) C NMR experiments revealed their enantiodiscrimination potential toward novel analytes, such as secondary amines and nonprotected amino acids. PMID- 26415856 TI - Functional Micro-Dispensers based on Micro-Electro-Mechanical-Systems (MEMS) integrated with fabrics as functional materials to protect humans from mosquito feeding. AB - Functional Micro-Dispensers (FMDs) based on Micro-Electro-Mechanical-Systems (MEMS) were designed to deliver spatial repellents that reduce the ability of mosquitoes to feed on humans. FMDs were integrated with fabrics as functional materials for protection against mosquito bites. The use of MEMS devices provides an unprecedented control over the release kinetics by means of integration with electronics for selective and timely activation of each device to perform controlled release of pesticides in air. In addition, because MEMS manufacturing techniques evolved from the microelectronic industry, FMDs can be mass produced at very low cost. Trials using FMDs that contained transfluthrin improved protection against mosquito feeding in human subjects above that of permethrin treated uniform fabric worn on the arm of the volunteer. The overall reduction in feeding was approximately 90% compared to the untreated fabric control, and about 50% reduction compared to the permethrin-treated fabric control. The devices were efficacious over course of 32 days. FMDs have the potential for a simple and cost effective implementation for mass adoption as wearable devices integrated in fabrics as active functional materials. PMID- 26415855 TI - Chemically modified RNA activated matrices enhance bone regeneration. AB - There exists a dire need for improved therapeutics to achieve predictable bone regeneration. Gene therapy using non-viral vectors that are safe and efficient at transfecting target cells is a promising approach to overcoming the drawbacks of protein delivery of growth factors. Here, we investigated the transfection efficiency, cytotoxicity, osteogenic potential and in vivo bone regenerative capacity of chemically modified ribonucleic acid (cmRNA) (encoding BMP-2) complexed with polyethylenimine (PEI) and made comparisons with PEI complexed with conventional plasmid DNA (encoding BMP-2). The polyplexes were fabricated at an amine (N) to phosphate (P) ratio of 10 and characterized for transfection efficiency using human bone marrow stromal cells (BMSCs). The osteogenic potential of BMSCs treated with these polyplexes was validated by determining the expression of bone-specific genes, osteocalcin and alkaline phosphatase as well as through the detection of bone matrix deposition. Using a calvarial bone defect model in rats, it was shown that PEI-cmRNA (encoding BMP-2)-activated matrices promoted significantly enhanced bone regeneration compared to PEI-plasmid DNA (BMP-2)-activated matrices. Our proof of concept study suggests that scaffolds loaded with non-viral vectors harboring cmRNA encoding osteogenic proteins may be a powerful tool for stimulating bone regeneration with significant potential for clinical translation. PMID- 26415857 TI - Down-regulated microRNA-124 expression as predictive biomarker and its prognostic significance with clinicopathological features in breast cancer patients. AB - BACKGROUND: MicroRNAs (miRNAs) have been documented as playing important roles in cancer development. In this study, we investigated to clarify the clinicopathological significance and prognostic value of miR-124 in breast cancer. METHODS: Quantitative Real-time PCR method was used to assess the expression levels of miR-124 in breast cancer patients and the association of miR 124 expression levels with the clinicopathological characteristics in breast cancer patients. Survival and Multivariate Cox proportional hazards model analysis was used to evaluate whether the miR-124 expression level and various clinicopathological characteristics were independent prognostic marker for breast cancer patients. RESULTS: We found that the lower expression of miR-124 in breast cancer specimens compared with corresponding adjacent normal breast tissues P < 0.05. Results showed that decreased expression of miR-124 was significantly related to advanced clinical stage (stage III and IV) (P = 0.021) and positive lymph node-metastasis (P = 0.011). Patients with low expression of miR-124 had significantly shorter overall survival (70.2 %) than patients who had cancers with high miR-124 expression (29.8), (logrank test P = 0.021). Moreover, Multivariate Cox proportional hazards model analysis indicated that lowr miR-124 expression was found to be independently linked to poor survival of patients with breast cancer and other factors were not significantly associated with survival of patients. CONCLUSION: Our data suggested that decreased expression of miR-124 has prognostic value in breast cancer and may serve as a prognostic marker for breast cancer, and also downregulation of miR-124 was inversely associated with the lymph node metastasis in breast cancer. PMID- 26415854 TI - Surface plasmon resonance as a high throughput method to evaluate specific and non-specific binding of nanotherapeutics. AB - Surface plasmon resonance (SPR) is a powerful analytical technique used to quantitatively examine the interactions between various biomolecules, such as proteins and nucleic acids. The technique has been particularly useful in screening and evaluating binding affinity of novel small molecule and biomolecule derived therapeutics for various diseases and applications including lupus medications, thrombin inhibitors, HIV protease inhibitors, DNA gyrase inhibitors and many others. Recently, there has been increasing interest in nanotherapeutics (nanoRx), due to their unique properties and potential for controlled release of encapsulated drugs and structure-specific targeting to diseased tissues. NanoRx offer the potential to solve many drug delivery challenges by enabling, specific interactions between molecules on the surface of the nanoparticle and molecules in the diseased tissue, while minimizing off-target interactions toward non diseased tissues. These properties are largely dependent upon careful control and balance of nanoRx interactions and binding properties with tissues in vivo. Given the great promise of nanoRx with regard to engineering specific molecular interactions, SPR can rapidly quantify small aliquots of nanoRx formulations for desired and undesired molecular interactions. Moving forward, we believe that utilization of SPR in the screening and design of nanoRx has the potential to greatly improve the development of targeted nanoRx formulations and eventually lead to improved therapeutic efficacy. In this review, we discuss (1) the fundamental principles of SPR and basic quantitative analysis of SPR data, (2) previous applications of SPR in the study of non-particulate therapeutics and nanoRx, and (3) future opportunities for the use of SPR in the evaluation of nanoRx. PMID- 26415858 TI - Bladder symptoms and urodynamic observations of patients with endometriosis confirmed by laparoscopy. AB - INTRODUCTION AND HYPOTHESIS: Patients with deep infiltrating pelvic endometriosis (DIE) often describe having lower urinary tract symptoms (LUTS). Bladder pain syndrome in women is also often associated with endometriosis. In this study, we aimed to describe the characteristics of LUTS and urodynamic observations in patients with posterior endometriosis versus those with posterior and anterior endometriosis. METHODS: This was a prospective observational study of 30 patients from two gynecologic surgical settings with experience in DIE surgery. All patients underwent preoperative standardized investigation including detailed evaluation of LUTS and urodynamic studies. During surgery, endometriosis locations were recorded and correlated to symptoms and urodynamic observations. RESULTS: Twenty-three patients (76.7 %) had one or more LUTS symptoms and 29 (96.7 %) had one or more abnormalities at urodynamic examination. At surgery, all patients had posterior endometriosis and ten of them also had anterior endometriosis. Patients with anterior endometriosis had increased bladder sensation (90.0 % versus 45.0 %, p = 0.024) and painful bladder filling (70.0 % versus 30.0, p = 0.04) compared with patients with posterior endometriosis only. Voiding symptoms (60.0 %), impairment of flowmetry (30.0 %), and increased maximum urethral closure pressure (90.0 %) were frequent and not correlated with any specific location. CONCLUSIONS: Endometriosis infiltrating the bladder wall is associated with painful bladder symptoms. Dysfunctional voiding suggests an impairment of the inferior hypogastric plexus by posterior DIE. Clinical preoperative evaluation of bladder function should be systematic; urodynamic tests could be of interest in selected patients with DIE. Endometriosis may be a major cause of bladder pain syndrome. PMID- 26415859 TI - Reduced apurinic/apyrimidinic endonuclease 1 activity and increased DNA damage in mitochondria are related to enhanced apoptosis and inflammation in the brain of senescence- accelerated P8 mice (SAMP8). AB - The senescence- accelerated mouse prone 8 (SAMP8) is a well- characterized animal model of senescence that shows early age- related neurodegeneration with impairment in learning and memory skills when compared with control senescence- resistant mice (SAMR1). In the current study, we investigated whether such impairment could be partly due to changes in mitochondrial DNA (mtDNA) repair capacity and mitochondrial DNA damage in the brain of SAMP8 mice. Besides we studied whether these potential changes were related to modifications in two major processes likely involved in aging and neurodegeneration: apoptosis and inflammation. We observed that the specific activity of one of the main mtDNA repair enzymes, the mitochondrial APE1, showed an age- related reduction in SAMP8 animals, while in SAMR1 mice mitochondrial APE1 increased with age. The reduction in mtAPE1 activity in SAMP8 animals was associated with increased levels of the DNA oxidative damage marker 8oxodG in mtDNA. Our results also indicate that these changes were related to a premature increase in apoptotic events and inflammation in the brain of SAMP8 mice when compared to SAMR1 counterparts. We suggest that the premature neurodegenerative phenotype observed in SAMP8 animals might be due, at least in part, to changes in the processing of mtDNA oxidative damage, which would lead to enhancement of apoptotic and inflammatory processes. PMID- 26415860 TI - Hemoglobin thresholds for transfusion in pediatric patients at a large academic health center. AB - BACKGROUND: Although prior studies support the use of a hemoglobin (Hb) transfusion trigger of 7 to 8 g/dL for most hospitalized adults, there are few studies in pediatric populations. We therefore investigated transfusion practices and Hb triggers in hospitalized children. STUDY DESIGN AND METHODS: We performed a historical cohort study comparing transfusion practices in hospitalized children by service within a single academic institution. Blood utilization data from transfused patients (n = 3370) were obtained from electronic records over 4 years. Hb triggers and posttransfusion Hb levels were defined as the lowest and last Hb measured during hospital stay, respectively, in transfused patients. The mean and percentile distribution for Hb triggers were compared to the evidence based restrictive transfusion threshold of 7 g/dL. RESULTS: Mean Hb triggers were above the restrictive trigger (7 g/dL) for eight of 12 pediatric services. Among all of the services, there were significant differences between the mean Hb triggers (>2.5 g/dL, p<0.0001) and between the posttransfusion Hb levels (>3 g/dL, p < 0.0001). The variation between the 10th and 90th percentiles for triggers (up to 4 g/dL, p < 0.0001) and posttransfusion Hb levels (up to 6 g/dL, p < 0.0001) were significant. Depending on the service, between 25 and 90% of transfused patients had Hb triggers higher than the restrictive range. CONCLUSIONS: Red blood cell (RBC) transfusion therapy varies significantly in hospitalized children with mean Hb triggers above a restrictive threshold for most services. Our findings suggest that transfusions may be overused and that implementing a restrictive transfusion strategy could decrease the use of RBC transfusions, thereby reducing the associated risks and costs. PMID- 26415861 TI - Spontaneous social distancing in response to a simulated epidemic: a virtual experiment. AB - BACKGROUND: Studies of social distancing during epidemics have found that the strength of the response can have a decisive impact on the outcome. In previous work we developed a model of social distancing driven by individuals' risk attitude, a parameter which determines the extent to which social contacts are reduced in response to a given infection level. We showed by simulation that a strong response, driven by a highly cautious risk attitude, can quickly suppress an epidemic. However, a moderately cautious risk attitude gives weak control and, by prolonging the epidemic without reducing its impact, may yield a worse outcome than doing nothing. In real societies, social distancing may arise spontaneously from individual choices rather than being imposed centrally. There is little data available about this as opportunistic data collection during epidemics is difficult. Our study uses a simulated epidemic in a computer game setting to measure the social distancing response. METHODS: Two hundred thirty participants played a computer game simulating an epidemic on a spatial network. The player controls one individual in a population of 2500 (with others controlled by computer) and decides how many others to contact each day. To mimic real-world trade-offs, the player is motivated to make contact by being rewarded with points, while simultaneously being deterred by the threat of infection. Participants completed a questionnaire regarding psychological measures of health protection motivation. Finally, simulations were used to compare the experimentally-observed response to epidemics with no response. RESULTS: Participants reduced contacts in response to infection in a manner consistent with our model of social distancing. The experimentally observed response was too weak to halt epidemics quickly, resulting in a somewhat reduced attack rate and a substantially reduced peak attack rate, but longer duration and fewer social contacts, compared to no response. Little correlation was observed between participants' risk attitudes and the psychological measures. CONCLUSIONS: Our cognitive model of social distancing matches responses to a simulated epidemic. If these responses indicate real world behaviour, spontaneous social distancing can be expected to reduce peak attack rates. However, additional measures are needed if it is important to stop an epidemic quickly. PMID- 26415862 TI - Genetic Diversity of Brazilian Bovine Pestiviruses Detected Between 1995 and 2014. AB - Pestivirus infections in ruminants result in significant economic losses worldwide. The aetiological agents are three species from the genus Pestivirus, family Flaviviridae, including bovine viral diarrhoea virus type 1 (BVDV-1), BVDV 2, border disease virus (BDV), and an atypical pestivirus named HoBi-like pestivirus. In this study, eighty-nine pestivirus isolates that were collected in Brazil between 1995 and 2014 and that originated from either cattle, fetal bovine serum (FBS) or as cell culture contaminants were genotyped based on a comparison of gene sequences from their 5' untranslated regions (5'UTR), N-terminal autoprotease (Npro ) and envelope glycoprotein 2 (E2). Of these isolates, 53.9% of the sequences were genotyped as BVDV-1, 33.7% as BVDV-2 and 12.4% as HoBi-like pestivirus. The prevalence of subgenotypes within the species was as follows: BVDV-1a (35.9%), BVDV-2b (31.4%), BVDV-1b (10.1%), BVDV-1d (6.7%), BVDV-2c (2.2%) and BVDV-1e (1.1%). BVDV-2c and BVDV-1e were detected for the first time in Brazil. This study revealed extensive genetic diversity among Brazilian pestivirus isolates, and the combination of pestiviruses that was detected is unique to Brazil. This information may serve as a foundation for designing and evaluating diagnostic tools and in the development of more effective vaccines; therefore, it may potentially contribute to pestivirus control and eradication. PMID- 26415863 TI - Squamous cell carcinoma arising from a Zenker's diverticulum: contribution of FDG PET/CT to the diagnosis. PMID- 26415864 TI - Cloning and molecular ontogeny of digestive enzymes in fed and food-deprived developing gilthead seabream (Sparus aurata) larvae. AB - We have determined the expression pattern of key pancreatic enzymes precursors (trypsinogen, try; chymotrypsinogen, ctrb; phospholipase A2, pla2; bile salt activated lipase, cel; and alpha-amylase, amy2a) during the larval stage of gilthead seabream (Sparus aurata) up to 60days after hatching (dph). Previously, complete sequences of try, cel, and amy2a were cloned and phylogenetically analyzed. One new isoform was found for cel transcript (cel1b). Expression of all enzyme precursors was detected before the mouth opening. Expression of try and ctrb increased during the first days of development and then maintained high values with some fluctuations during the whole larval stage. The prolipases pla2 and cel1b increased from first-feeding with irregular fluctuation until the end of the experiment. Contrarily, cel1a maintained low expression values during most of the larval stage increasing at the end of the period. Nevertheless, cel1a expression was negligible as compared with cel1b. The expression of amy2a sharply increased during the first week followed by a gradual decrease. In addition, a food-deprivation experiment was performed to find the differences in relation to presence/absence of gut content after the opening of the mouth. The food-deprived larvae died at 10dph. The expression levels of all digestive enzymes increased up to 7dph, declining sharply afterwards. This expression pattern up to 7dph was the same observed in fed larvae, confirming the genetic programming during the early development. Main digestive enzymes in gilthead seabream larvae exhibited the same expression profiles than other marine fish with carnivorous preferences in their juvenile stages. PMID- 26415865 TI - Structural and functional characterization of neuromedin S in the teleost fish, zebrafish (Danio rerio). AB - Neuromedin S (NMS) has been demonstrated to have important roles in many vertebrate physiological processes. However, the function of NMS in teleost fishes remains unclear. We explored the physiological roles of the NMS gene in the zebrafish model. An NMS cDNA was cloned from zebrafish brain tissue, and the full-length cDNA sequence was 521 bp in length and encoded a precursor of 110 amino acid residues. Interestingly, fish prepro-NMS is predicted to generate a short 34-residue peptide, designated as NMS-related peptide (NMSRP). Zebrafish prepro-NMS does not contain the NMS peptide which is found in the NMS precursors of mammals, and just retains the MNSRP peptide. A multiple-species sequence alignment showed that NMSRPs are conserved among the other sampled vertebrates. Zebrafish NMS mRNA was detected by RT-PCR revealing a tissue-specific distribution with high levels of expression in the brain, spleen, ovary, pituitary, and muscle. Furthermore, the locations of NMS-expressing cells in the zebrafish brain were detected by in situ hybridization in the parvocellular preoptic nucleus (PPa), the ventral zone of the periventricular hypothalamus (Hv), and lateral hypothalamic nucleus (LH). The levels of NMS mRNA in the hypothalamus were significantly increased after three days of food deprivation. Administration of zebrafish NMSRP by intraperitoneal injection significantly promoted the expression of neuropeptide Y (NPY) and orexin, suggesting an orexigenic role for NMSRP in zebrafish. The present study offers a new understanding of the NMS gene in vertebrates and increases our knowledge of the neuroendocrine regulation of feeding. PMID- 26415866 TI - Microfluidics-based single-step preparation of injection-ready polymeric nanosystems for medical imaging and drug delivery. AB - Translation of therapeutic polymeric nanosystems to patients and industry requires simplified, reproducible and scalable methods for assembly and loading. A single-step in-line process based on nanocoprecipitation of oxazoline-siloxane block copolymers in flow-focusing poly(dimethylsiloxane) microfluidics was designed to manufacture injection-ready nanosystems. Nanosystem characteristics could be controlled by copolymer concentration, block length and chemistry, microchannel geometry, flow rate, aqueous/organic flow rate ratio and payload concentration. The well-tolerated nanosystems exhibited differential cell binding and payload delivery and could confer sensitivity to photodynamic therapy to HeLa cancer cells. Such injection-ready nanosystems carrying drugs, diagnostic or functional materials may facilitate translation to clinical application. PMID- 26415867 TI - Erratum to: Optimal timing of clopidogrel discontinuation in Japanese patients: platelet aggregation test using the VerifyNow(r) system. PMID- 26415868 TI - Necrotizing Fasciitis and The Diabetic Foot. AB - Necrotizing fasciitis (NF) represents a rapidly progressive, life-threatening infection involving skin, soft tissue, and deep fascia. An early diagnosis is crucial to treat NF effectively. The disease is generally due to an external trauma that occurs in predisposed patients: the most important risk factor is represented by diabetes mellitus. NF is classified into 3 different subtypes according to bacterial strains responsible: type 1 associated to polymicrobial infection, type 2 NF, generally associated to Streptococcus species, often associated to Staphylococcus aureus and, eventually, Type 3, due to Gram-negative strains, such as Clostridium difficile or Vibrio. NF is usually characterized by the presence of the classic triad of symptoms: local pain, swelling, and erythema. In daily clinical practice immune-compromised or neuropathic diabetic patients present with atypical symptomatology. This explains the high percentage of misdiagnosed cases in the emergency department and, consequently, the worse outcome presented by these patients. Prompt aggressive surgical debridement and antibiotic systemic therapy are the cornerstone of its treatment. These must be associated with an accurate systemic management, consisting in nutritional support, glycemic compensation, and hemodynamic stabilization. Innovative methods, such as negative pressure therapy, once the acute conditions have resolved, can help fasten the surgical wound closure. Prompt management can improve prognosis of patients affected from NF reducing limb loss and saving lives. PMID- 26415869 TI - Mastering variation: variance components and personalised medicine. AB - Various sources of variation in observed response in clinical trials and clinical practice are considered, and ways in which the corresponding components of variation might be estimated are discussed. Although the issues have been generally well-covered in the statistical literature, they seem to be poorly understood in the medical literature and even the statistical literature occasionally shows some confusion. To increase understanding and communication, some simple graphical approaches to illustrating issues are proposed. It is also suggested that reducing variation in medical practice might make as big a contribution to improving health outcome as personalising its delivery according to the patient. It is concluded that the common belief that there is a strong personal element in response to treatment is not based on sound statistical evidence. PMID- 26415870 TI - Hygromycin B-induced cell death is partly mediated by reactive oxygen species in rice (Oryza sativa L.). AB - The aminoglycoside antibiotic hygromycin B (Hyg) inhibits prokaryotic, chloroplast and mitochondrial protein synthesis. Because of the toxic effect of Hyg on plant cells, the HPT gene, encoding hygromycin phosphotransferase, has become one of the most widely used selectable markers in plant transformation. Yet the mechanism behind Hyg-induced cell lethality in plants is not clearly understood. In this study, we aimed to decipher this mechanism. With Hyg treatment, rice calli exhibited cell death, and rice seedlings showed severe growth defects, leaf chlorosis and leaf shrinkage. Rice seedlings also exhibited severe lipid peroxidation and protein carbonylation, for oxidative stress damage at the cellular level. The production of reactive oxygen species such as O2(.-), H2O2 and OH(.) was greatly induced in rice seedlings under Hyg stress, and pre treatment with ascorbate increased resistance to Hyg-induced toxicity indicating the existence of oxidative stress. Overexpression of mitochondrial Alternative oxidase1a gene without HPT selection marker in rice enhanced tolerance to Hyg and attenuated the degradation of protein content, whereas the rice plastidial glutathione reductase 3 mutant showed increased sensitivity to Hyg. These results demonstrate that Hyg-induced cell lethality in rice is not only due to the inhibition of protein synthesis but also mediated by oxidative stress. PMID- 26415871 TI - Analysis of full-text publication and publishing predictors of abstracts presented at an Italian public health meeting (2005-2007). AB - BACKGROUND: In Public Health, a thorough review of abstract quality evaluations and the publication history of studies presented at scientific meetings has never been conducted. To analyse the long-term outcome of quality abstracts submitted to conferences of Italian Society of Hygiene and Public Health (SItI) from 2005 to 2007, we conducted a second analysis of previously published material aiming to estimate full-text publication rate of high quality abstract presented at Italian public health meetings, and to identify predictors of full-text publication. METHODS: The search was undertaken through scientific databases and search engines and through the web sites of the major Italian journals of Public Health. For each publication confirmed as a full text paper, the journal name, impact factor, year of publication, gender of the first author, type of study design, characteristics of the results and sample size were collected. RESULTS: The overall publication rate of the abstracts presented is 23.5%; most of the papers were published in Public Health journals (average impact factor: 3.007). Non universitary affiliation had resulted in a lower probability of publication, while some of the Conference topics had predisposed the studies to an increased likelihood of publication as well as poster form presentation. CONCLUSIONS: The method presented in this study provides a good framework for the evaluation of the scientific evidence. The findings achieved should be taken into consideration by the Scientific Societies during the contributions selection phase, with the aim of achieving a continuous improvement of work quality. In the future, it would be interesting to survey the abstract authors to identify reasons for unpublished data. PMID- 26415873 TI - Health knowledge and health practices in Makeni, Sierra Leone: a community-based household survey. AB - BACKGROUND: We characterize health knowledge and practices in urban and rural Makeni, Sierra Leone, drawing comparisons between areas served by community health workers (CHWs) with those that are not. We also inquire about causes of infant and maternal mortality and how they are understood in the local context. Our objective was to provide a baseline understanding of health knowledge and practices in Makeni during the implementation of a CHW program. METHODS: We conducted 100 household interviews in Makeni City and rural villages in the surrounding area. We compared data between urban and rural areas to identify differences in health knowledge and practices. RESULTS: Our sample size covered 855 individuals. Insecticide treated bednet ownership was lower in urban settings compared to rural populations (58% vs 94%; p<.001). With regards to maternal mortality, most respondents indicated 'no clinic' (lack of clinical care or skipped antenatal care visits) as the primary cause (n=35), followed by bleeding (n=17), 'lack of blood' (anemia) (n=11) and 'will of God' (n=11). CONCLUSIONS: This initial survey of health knowledge and practices in rural and urban Makeni, Sierra Leone, highlights some simple opportunities for community health promotion, health education programming and behavioral interventions. Findings will inform future iterations of a CHW training module for community health education. PMID- 26415872 TI - Molecular epidemiology and distribution of serotypes, genotypes, and antibiotic resistance genes of Streptococcus agalactiae clinical isolates from Guelma, Algeria and Marseille, France. AB - This study describes, for the first time, the genetic and phenotypic diversity among 93 Streptococcus agalactiae (group B Streptococcus, GBS) isolates collected from Guelma, Algeria and Marseille, France. All strains were identified by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The molecular support of antibiotic resistance and serotyping were investigated by polymerase chain reaction (PCR). The phylogenetic lineage of each GBS isolate was determined by multilocus sequence typing (MLST) and grouped into clonal complexes (CCs) using eBURST. The isolates represented 37 sequence types (STs), 16 of which were novel, grouped into five CCs, and belonging to seven serotypes. Serotype V was the most prevalent serotype in our collection (44.1%). GBS isolates of each serotype were distributed among multiple CCs, including cps III/CC19, cps V/CC1, cps Ia/CC23, cps II/CC10, and cps III/CC17. All isolates presented susceptibility to penicillin, whereas resistance to erythromycin was detected in 40% and tetracycline in 82.2% of isolates. Of the 37 erythromycin resistant isolates, 75.7% showed the macrolide-lincosamide-streptogramin B (MLSB) resistant phenotype and 24.3% exhibited the macrolide (M)-resistant phenotype. Constitutive MLSB resistance (46%) mediated by the ermB gene was significantly associated with the Guelma isolates, whereas the M resistance phenotype (24.3%) mediated by the mefA/E gene dominated among the Marseille isolates and belonged to ST-23. Tetracycline resistance was predominantly due to tetM, which was detected alone (95.1%) or associated with tetO (3.7%). These results provide epidemiological data in these regions that establish a basis for monitoring increased resistance to erythromycin and also provide insight into correlations among clones, serotypes, and resistance genes. PMID- 26415874 TI - Preparing pharmacists to deliver a targeted service in hypertension management: evaluation of an interprofessional training program. AB - BACKGROUND: Non-adherence to medicines by patients and suboptimal prescribing by clinicians underpin poor blood pressure (BP) control in hypertension. In this study, a training program was designed to enable community pharmacists to deliver a service in hypertension management targeting therapeutic adjustments and medication adherence. A comprehensive evaluation of the training program was undertaken. METHODS: Tailored training comprising a self-directed pre-work manual, practical workshop (using real patients), and practice scenarios, was developed and delivered by an inter-professional team (pharmacists, GPs). Supported by practical and written assessment, the training focused on the principles of BP management, BP measurement skills, and adherence strategies. Pharmacists' experience of the training (expectations, content, format, relevance) was evaluated quantitatively and qualitatively. Immediate feedback was obtained via a questionnaire comprising Likert scales (1 = "very well" to 7 = "poor") and open-ended questions. Further in-depth qualitative evaluation was undertaken via semi-structured interviews several months post-training (and post service implementation). RESULTS: Seventeen pharmacists were recruited, trained and assessed as competent. All were highly satisfied with the training; other than the 'amount of information provided' (median score = 5, "just right"), all aspects of training attained the most positive score of '1'. Pharmacists most valued the integrated team-based approach, GP involvement, and inclusion of real patients, as well as the pre-reading manual, BP measurement workshop, and case studies (simulation). Post-implementation the interviews highlighted that comprehensive training increased pharmacists' confidence in providing the service, however, training of other pharmacy staff and patient recruitment strategies were highlighted as a need in future. CONCLUSIONS: Structured, multi modal training involving simulated and inter-professional learning is effective in preparing selected community pharmacists for the implementation of new services in the context of hypertension management. This training could be further enhanced to prepare pharmacists for the challenges encountered in implementing and evaluating services in practice. PMID- 26415876 TI - MLCT sensitizers in photochemical upconversion: past, present, and potential future directions. AB - This treatment highlights the historical development of MLCT sensitizers in photochemical upconversion while indentifying current state-of-the-art and exciting opportunities in this arena moving towards the future. PMID- 26415875 TI - Lymphomatosis cerebri: a rare form of primary central nervous system lymphoma. Analysis of 7 cases and systematic review of the literature. AB - BACKGROUND: Primary central nervous system lymphomas may present as diffuse, nonenhancing infiltrative lesions. This rare variant is termed lymphomatosis cerebri (LC). We did a systematic review and analysis of the literature, adding our own cases, to better characterize LC in order to improve early diagnosis and treatment. METHODS: PubMed, ISI Web of Knowledge, and hospital databases were reviewed. Information was extracted regarding demographic, clinical, histological, cerebrospinal fluid (CSF), neuroimaging, and treatment variables. The impact of single parameters on overall survival (OS) was determined by applying univariate and multivariate analyses. RESULTS: Forty-two patients were included (median age: 58 y; range: 28-80 y). At consultation, 52% of patients had a poor KPS. The most common presenting symptom was cognitive decline (59.5%). Imaging studies showed supratentorial and infratentorial infiltration in 55% of patients and bilateral hemispheric involvement in 95%. CSF pleocytosis was present in 51.5% of the patients. Median time to diagnosis was 4.5 (range: 1-30) months, and the diagnosis was not established until autopsy for 33% of patients. The median OS was 2.95 (range: 0.33-56) months; however, those patients who received methotrexate had a median OS of 13.8 (range: 0.7-56) months. Analysis identified KPS >= 70 (HR: 0.32; 95% CI: 0.114-0.894; P = .03) and treatment with methotrexate (HR: 0.19; 95% CI: 0.041-0.886; P = .034) as independent favorable prognostic factors, whereas T-cell lymphoma was independently related with a worse outcome (HR: 6.62; 95% CI: 1.317-33.316; P = .022). CONCLUSIONS: LC is a misdiagnosed entity associated with considerable diagnostic delay. MRI evidence of bilateral hemispheric involvement and CSF pleocytosis should be alerts for this diagnosis. Treatment with methotrexate-based chemotherapy must be considered, especially for patients with good KPS. PMID- 26415878 TI - Large scale analysis of the mutational landscape in beta-glucuronidase: A major player of mucopolysaccharidosis type VII. AB - The lysosomal storage disorders are a group of 50 unique inherited diseases characterized by unseemly lipid storage in lysosomes. These malfunctions arise due to genetic mutations that result in deficiency or reduced activities of the lysosomal enzymes, which are responsible for catabolism of biological macromolecules. Sly syndrome or mucopolysaccharidosis type VII is a lysosomal storage disorder associated with the deficiency of beta-glucuronidase (EC 3.2.1.31) that catalyzes the hydrolysis of beta-D-glucuronic acid residues from the non-reducing terminal of glycosaminoglycan. The effects of the disease causing mutations on the framework of the sequences and structure of beta glucuronidase (GUSBp) were analyzed utilizing a variety of bioinformatic tools. These analyses showed that 211 mutations may result in alteration of the biological activity of GUSBp, including previously experimentally validated mutations. Finally, we refined 90 disease causing mutations, which presumably cause a significant impact on the structure, function, and stability of GUSBp. Stability analyses showed that mutations p.Phe208Pro, p.Phe539Gly, p.Leu622Gly, p.Ile499Gly and p.Ile586Gly caused the highest impact on GUSBp stability and function because of destabilization of the protein structure. Furthermore, structures of wild type and mutant GUSBp were subjected to molecular dynamics simulation to examine the relative structural behaviors in the explicit conditions of water. In a broader view, the use of in silico approaches provided a useful understanding of the effect of single point mutations on the structure function relationship of GUSBp. PMID- 26415877 TI - Downregulating p22phox ameliorates inflammatory response in Angiotensin II induced oxidative stress by regulating MAPK and NF-kappaB pathways in ARPE-19 cells. AB - Oxidative stress and inflammation are two interrelated biological events implicated in the pathogenesis of many diseases. Reactive oxygen species (ROS) produced under oxidative stress play a key role in pathological conditions. Inhibition of p22phox, an indispensable component of the NADPH oxidase (NOX) complex comprising the main source of ROS, plays a protective role in many ocular conditions by inhibiting the activation of NOXs and the generation of ROS. However, little is understood regarding the role of p22phox in oxidative stress related inflammation in the eye. We used a p22phox small interfering RNA (siRNA) to transfect the retinal pigment epithelium (RPE)-derived cell line ARPE-19, and human primary RPE (hRPE) cells, then stimulated with Ang II. We observed a potent anti-inflammatory effect and studied the underlying mechanism. Downregulating p22phox resulted in decreased ROS generation, a reduction of NOXs (NOX1, 2, 4) and a decrease in inflammatory cytokine. In addition, p22phox downregulation reduced the activation of the MAPK and NF-kappaB signaling pathways. We conclude that inhibition of p22phox has an anti-inflammatory effect in Ang II-induced oxidative stress. Suppressing the MAPK and NF-kappaB pathways is involved in this protective effect. These results suggest that p22phox may provide a promising therapeutic target for oxidative stress-induced ocular inflammation. PMID- 26415879 TI - MicroRNA-23a regulates 3T3-L1 adipocyte differentiation. AB - MicroRNAs (miRNAs) are small, non-coding RNAs, which are involved in regulation of a variety of biological processes. Since previous studies regarding the role of miRNAs in the regulation of adipogenic differentiation have shown that miRNA 27a, one member of miRNA-23a~27a~24 cluster, could suppress adipogenesis. We now investigated whether miRNA-23a regulates adipogenic differentiation. In the present study, we showed that the expression of miRNA-23a is decreased during the process of adipogenic differentiation. Over-expression of miRNA-23a decreased lipid accumulation and triglyceride content in 3T3-L1 adipocytes. Our results also demonstrated that miRNA-23a decreases mRNA levels of adipocyte-specific genes involved in lipogenic transcription, fatty acid synthesis and fatty acid transport. These findings suggested miRNA-23a to be a new type of adipogenic depressor and to play an important role in regulating adipocyte differentiation. PMID- 26415880 TI - D-dimer levels in maintenance hemodialysis patients: High prevalence of positive values also in the group without predisposing diseases. AB - We aimed to estimate the prevalence of elevated D-dimer levels in all chronic hemodialysis patients and those without additional disease, and to identify factors associated with increased D-dimer. In 167 chronic hemodialysis patients from our center, D-dimer was measured before dialysis. The effects of age, C reactive protein (CRP), recent acute illness, vascular access, anticoagulation type, dialysis vintage, and chronic diseases, considered to predispose for increased D-dimer levels, were analyzed. The median D-dimer in the whole group was 966 (inter-quartile range [IQR] 524-1947) MUg/L and was positive (>500 MUg/L) in 75% of cases. D-dimer was positive in 91% of patients with acute illness, 76% of those with predisposing chronic diseases, but was still positive in 52% of patients without additional disease (i.e., acute illness or predisposing chronic diseases) - median D-dimer was 538.5 (IQR 359-966) MUg/L. D-dimer was correlated to patients' age, but not dialysis vintage. In univariate analysis, the D-dimer levels were significantly higher in patients with atrial fibrillation, ischemic heart disease, recent acute illness, increased CRP, dialyzed over a catheter, and on citrate anticoagulation. Multivariate logistic regression showed that only age >65 years (odds ratio [OR] 2.93), catheter (OR 4.86), and positive CRP (OR 4.07) were independently associated with positive D-dimer at 500 MUg/L cut-off, while the significance of age disappeared at 2000 MUg/L cut-off. To conclude, the high prevalence of positive D-dimer values even in hemodialysis patients without additional disease limits the use of D-dimer for exclusion of thromboembolic diseases in hemodialysis patients. PMID- 26415881 TI - TRPV4 channels: physiological and pathological role in cardiovascular system. AB - TRPV4 channels are non-selective cation channels permeable to Ca(2+), Na(+), and Mg(2+) ions. Recently, TRPV4 channels have received considerable attention as these channels are widely expressed in the cardiovascular system including endothelial cells, cardiac fibroblasts, vascular smooth muscles, and peri vascular nerves. Therefore, these channels possibly play a pivotal role in the maintenance of cardiovascular homeostasis. TRPV4 channels critically regulate flow-induced arteriogenesis, TGF-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts, and heart failure-induced pulmonary edema. These channels also mediate hypoxia-induced increase in proliferation and migration of pulmonary artery smooth muscle cells and progression of pulmonary hypertension. These channels also maintain flow-induced vasodilation and preserve vascular function by directly activating Ca(2+)-dependent KCa channels. Furthermore, these may also induce vasodilation and maintain blood pressure indirectly by evoking the release of NO, CGRP, and substance P. The present review discusses the evidences and the potential mechanisms implicated in diverse responses including arteriogenesis, cardiac remodeling, congestive heart failure-induced pulmonary edema, pulmonary hypertension, flow-induced dilation, regulation of blood pressure, and hypoxic preconditioning. PMID- 26415883 TI - SDHC methylation in gastrointestinal stromal tumors (GIST): a case report. AB - BACKGROUND: Gastrointestinal stromal tumors (GIST) recently have been recognized as a genetically and biologically heterogeneous disease. In addition to KIT or PDGFRA mutated GIST, mutational inactivation of succinate dehydrogenase (SDH) subunits has been detected in the KIT/PDGFRA wild-type subgroup, referred to as SDH deficient (dSDH). Even though most dSDH GIST harbor mutations in SDHx subunit genes, some are SDHx wild type. Epigenetic regulation by DNA methylation of CpG islands recently has been found to be an alternative mechanism underlying the lack of SDH complex in GIST. CASE PRESENTATION: We report a particular case of dSDH GIST, previously analyzed with microarrays and next-generation sequencing, for which no molecular pathogenetic events have been identified. Gene expression analysis showed remarkable down-modulation of SDHC mRNA with respect to all other GIST samples, both SDHA-mutant and KIT/PDGFRA-mutant GIST. By a bisulfite methylation assay targeted to 2 SDHC CpG islands, we detected hypermethylation of the SDHC promoter. CONCLUSION: Herein we report an additional case of dSDH GIST without SDHx mutation but harboring hypermethylation in the SDHC promoter, thus confirming the complexity of the molecular background of this subtype of GIST. PMID- 26415884 TI - A call to arms against "The Phantom of Epilepsy". PMID- 26415882 TI - Chromatin interaction analysis reveals changes in small chromosome and telomere clustering between epithelial and breast cancer cells. AB - BACKGROUND: Higher-order chromatin structure is often perturbed in cancer and other pathological states. Although several genetic and epigenetic differences have been charted between normal and breast cancer tissues, changes in higher order chromatin organization during tumorigenesis have not been fully explored. To probe the differences in higher-order chromatin structure between mammary epithelial and breast cancer cells, we performed Hi-C analysis on MCF-10A mammary epithelial and MCF-7 breast cancer cell lines. RESULTS: Our studies reveal that the small, gene-rich chromosomes chr16 through chr22 in the MCF-7 breast cancer genome display decreased interaction frequency with each other compared to the inter-chromosomal interaction frequency in the MCF-10A epithelial cells. Interestingly, this finding is associated with a higher occurrence of open compartments on chr16-22 in MCF-7 cells. Pathway analysis of the MCF-7 up regulated genes located in altered compartment regions on chr16-22 reveals pathways related to repression of WNT signaling. There are also differences in intra-chromosomal interactions between the cell lines; telomeric and sub telomeric regions in the MCF-10A cells display more frequent interactions than are observed in the MCF-7 cells. CONCLUSIONS: We show evidence of an intricate relationship between chromosomal organization and gene expression between epithelial and breast cancer cells. Importantly, this work provides a genome-wide view of higher-order chromatin dynamics and a resource for studying higher-order chromatin interactions in two cell lines commonly used to study the progression of breast cancer. PMID- 26415885 TI - Compassion or stigma? How adults bereaved by alcohol or drugs experience services. AB - How to promote compassionate care within public services is a concern in several countries; specifically, some British healthcare scandals highlight poor care for service users who may readily be stigmatised as 'other'. The article therefore aims to understand better the relationship between stigma and compassion. As people bereaved by a drug- or alcohol-related death often experience stigma, the article draws on findings from a major British study, conducted during 2012-2015 by the authors, of people bereaved in this way, in order to see how service provision can be improved. One hundred and six bereaved family members were interviewed in depth about their experiences of loss and support. Thematic analysis developed theoretical understandings of participants' lived experiences. This article analyses our data on how bereaved people experienced stigma and kindness from practitioners of all kinds. We found that stigma can be mitigated by small acts of kindness from those encountered after the death. Stigma entails stereotyping, othering and disgust, each of which has emotional and cognitive aspects; kindness entails identification and fellow feeling; professionalism has classically entailed emotional detachment, but interviewees found cold professionalism as disturbing as explicit disgust. Drawing on theories concerning the end of life, bereavement and emotional labour, the article analyses the relationship between stigma, kindness and professionalism, and identifies some strategies to counter stigmatisation and foster compassion. PMID- 26415886 TI - Validity and reliability of an online extended version of the Nordic Musculoskeletal Questionnaire (NMQ-E2) to measure nurses' fitness. AB - AIMS AND OBJECTIVES: To describe modifications to a second extended version of the Nordic Musculoskeletal Questionnaire for online use in nursing populations, and check validity and reliability. BACKGROUND: The Nordic Musculoskeletal Questionnaire has been used to assess the severity and impact of musculoskeletal symptoms in occupational groups. The reliability of a previous extended version was established for paper-based, self-administration among nursing students. This current study extended the questionnaire to collect more information regarding musculoskeletal symptoms in all nine body regions and their work-relatedness, as an instrument is needed to gather evidence about the impact of fitness levels on occupational musculoskeletal disorders among nurses. DESIGN: Psychometric evaluation. METHOD: Sixty-five undergraduate nurses completed the online extended Nordic Musculoskeletal Questionnaire twice. Content validity was examined by expert review and construct validity by exploratory factor analysis of 90 responses from the first completion. Reliability was checked by examining internal consistency, kappa statistics, proportions of observed, and positive and negative agreements, intra-class correlation coefficient and standard error of measurement. RESULTS: The instrument had high internal consistency and exploratory factor analysis revealed it was a relatively homogenous (unidimensional) measure of musculoskeletal symptom severity. Age of onset of symptoms questions were reliable, with high mean intra-class correlation coefficients and low mean standard errors of measurement. Overall, questions showed high mean strengths of agreement and proportions of observed agreement: three-quarters of the prevalence questions and 99% of the severity/impact questions had 10% or fewer disagreements. CONCLUSIONS: Modifications to the Nordic Musculoskeletal Questionnaire and online administration did not diminish its validity or reliability for obtaining information about the severity of nurses' musculoskeletal symptoms. RELEVANCE TO CLINICAL PRACTICE: Occupational musculoskeletal disorders are an issue for nurses. This questionnaire can be used to monitor nurses' musculoskeletal health, and in musculoskeletal disorder prevention studies. PMID- 26415888 TI - Controlled release of drugs in electrosprayed nanoparticles for bone tissue engineering. AB - Generating porous topographic substrates, by mimicking the native extracellular matrix (ECM) to promote the regeneration of damaged bone tissues, is a challenging process. Generally, scaffolds developed for bone tissue regeneration support bone cell growth and induce bone-forming cells by natural proteins and growth factors. Limitations are often associated with these approaches such as improper scaffold stability, and insufficient cell adhesion, proliferation, differentiation, and mineralization with less growth factor expression. Therefore, the use of engineered nanoparticles has been rapidly increasing in bone tissue engineering (BTE) applications. The electrospray technique is advantageous over other conventional methods as it generates nanomaterials of particle sizes in the micro/nanoscale range. The size and charge of the particles are controlled by regulating the polymer solution flow rate and electric voltage. The unique properties of nanoparticles such as large surface area-to-volume ratio, small size, and higher reactivity make them promising candidates in the field of biomedical engineering. These nanomaterials are extensively used as therapeutic agents and for drug delivery, mimicking ECM, and restoring and improving the functions of damaged organs. The controlled and sustained release of encapsulated drugs, proteins, vaccines, growth factors, cells, and nucleotides from nanoparticles has been well developed in nanomedicine. This review provides an insight into the preparation of nanoparticles by electrospraying technique and illustrates the use of nanoparticles in drug delivery for promoting bone tissue regeneration. PMID- 26415890 TI - Ion transport and selectivity in biomimetic nanopores with pH-tunable zwitterionic polyelectrolyte brushes. AB - Inspired by nature, functionalized nanopores with biomimetic structures have attracted growing interests in using them as novel platforms for applications of regulating ion and nanoparticle transport. To improve these emerging applications, we study theoretically for the first time the ion transport and selectivity in short nanopores functionalized with pH tunable, zwitterionic polyelectrolyte (PE) brushes. In addition to background salt ions, the study takes into account the presence of H(+) and OH(-) ions along with the chemistry reactions between functional groups on PE chains and protons. Due to ion concentration polarization, the charge density of PE layers is not homogeneously distributed and depends significantly on the background salt concentration, pH, grafting density of PE chains, and applied voltage bias, thereby resulting in many interesting and unexpected ion transport phenomena in the nanopore. For example, the ion selectivity of the biomimetic nanopore can be regulated from anion-selective (cation-selective) to cation-selective (anion-selective) by diminishing (raising) the solution pH when a sufficiently small grafting density of PE chains, large voltage bias, and low background salt concentration are applied. PMID- 26415889 TI - Phasic stabilization of motor output after auditory and visual distractors. AB - To maintain steady motor output, distracting sensory stimuli need to be blocked. To study the effects of brief auditory and visual distractors on the human primary motor (M1) cortex, we monitored magnetoencephalographic (MEG) cortical rhythms, electromyogram (EMG) of finger flexors, and corticomuscular coherence (CMC) during right-hand pinch (force 5-7% of maximum) while 1-kHz tones and checkerboard patterns were presented for 100 ms once every 3.5-5 s. Twenty-one subjects (out of twenty-two) showed statistically significant ~20-Hz CMC. Both distractors elicited a covert startle-like response evident in changes of force and EMG (~50% of the background variation) but without any visible movement, followed by ~1-s enhancement of CMC (auditory on average by 75%, P < 0.001; visual by 33%, P < 0.05) and rolandic ~20-Hz rhythm (auditory by 14%, P < 0.05; visual by 11%, P < 0.01). Directional coupling of coherence from muscle to the M1 cortex (EMG->MEG) increased for ~0.5 s at the onset of the CMC enhancement, but only after auditory distractor (by 105%; P < 0.05), likely reflecting startle related proprioceptive afference. The 20-Hz enhancements occurred in the left M1 cortex and were for the auditory stimuli preceded by an early suppression (by 7%, P < 0.05). Task-unrelated distractors modulated corticospinal coupling at ~20 Hz. We propose that the distractors triggered covert startle-like responses, resulting in proprioceptive afference to the cortex, and that they also transiently disengaged the subject's attention from the fine-motor task. As a result, the corticospinal output was readjusted to keep the contraction force stable. PMID- 26415887 TI - The role of fatty acids in insulin resistance. AB - Insulin resistance is a multi-faceted disruption of the communication between insulin and the interior of a target cell. The underlying cause of insulin appears to be inflammation that can either be increased or decreased by the fatty acid composition of the diet. However, the molecular basis for insulin resistance can be quite different in various organs. This review deals with various types of inflammatory inputs mediated by fatty acids, which affect the extent of insulin resistance in various organs. PMID- 26415891 TI - Validation and utilization of a TFE3 break-apart FISH assay for Xp11.2 translocation renal cell carcinoma and alveolar soft part sarcoma. AB - BACKGROUND: Xp11.2 or TFE3 translocation renal cell carcinomas (RCC) and alveolar soft part sarcoma (ASPS) are characterized by chromosome translocations involving the Xp11.2 breakpoint resulting in transcription factor TFE3 gene fusions. The most common translocations documented in TFE3 RCCs are t(X;1) (p11.2;q21) and t(X;17) (p11.2;q25) which leads to fusion of TFE3 gene on Xp11.2 with PRCC or ASPL respectively. TFE3 immunohistochemistry (IHC) has been inconsistent over time due to background staining problems in part related to fixation issues. Karyotyping to detect TFE3 gene rearrangement requires typically unavailable fresh tissue. Reverse transcriptase-polymerase chain reaction (RT-PCR) is generally very challenging due to degradation of RNA in archival material. The study objective was to develop and validate a TFE3 break-apart fluorescence in situ hybridization (FISH) assay to confirm Xp11 translocation RCCs and ASPS. METHODS: Representative sections of formalin-fixed paraffin-embedded tissue blocks were selected in 40 possible cases. Approximately 60 tumor cells were analyzed in the targeted region. The validation of TFE3 FISH was done with 11 negative and two positive cases. Cut off for a positive result was validated as >7.15 % positive nuclei with any pattern of break-apart signals. FISH evaluation was done blinded of the immunohistochemical or karyotype data. RESULTS: Three out of forty cases were positive for the TFE3 break-apart signals by FISH. The negative cases were reported as clear cell RCC with papillary features (10), clear cell RCC with sarcomatoid areas (2), Papillary RCC with clear cell areas (9), Chromophobe RCC (2), RCC, unclassified type (3) and renal medullary carcinoma (1). 3 of the negative cases were consultation cases for renal tumor with unknown histology. Seven negative cases were soft tissue tumor suspicious for ASPS. CONCLUSION: Our study validates the utility of TFE3 break-apart FISH on formalin-fixed paraffin-embedded tissue sections for diagnosis and confirmation of Xp11.2 translocation RCCs and ASPS. PMID- 26415894 TI - Proteomics of the Roseobacter clade, a window to the marine microbiology landscape. AB - Oceans are powered by metabolically-active microorganisms which are main drivers of global biogeochemical cycles on Earth. A decade ago, marine microbiology was boosted with next-generation sequencing capacities and the launch of large metagenomics surveys. High-performing proteomics is now comprehensive enough for reaching genome-wide and systems-wide scales. It is highly complementary to transcriptomics in order to analyze functional dynamics of marine microbes and microbial complex systems. Next-generation proteomics allows new perspectives for better understanding microbial lifestyles and uncovering the complexity of microbial communities. Here, we review the proteomics approaches and outcomes of recent work carried out on one of the most thoroughly studied marine generalist microorganisms, i.e. the Roseobacter clade, as pivotal examples. We also discuss how the study of the proteome of these organisms has helped in the understanding of the ecological strategy and lifestyle of this relevant marine clade, not only in laboratory cultures but also in its natural environment. PMID- 26415893 TI - Challenges in detection and treatment of multidrug resistant tuberculosis patients in Vietnam. AB - BACKGROUND: Vietnam is ranked 14(th) among 27 countries with high burden of multidrug-resistant tuberculosis (MDR-TB). In 2009, the Vietnamese government issued a policy on MDR-TB called Programmatic Management of Drug-resistant Tuberculosis (PMDT) to enhance and scale up diagnosis and treatment services for MDR-TB. Here we assess the PMDT performance in 2013 to determine the challenges to the successful identification and enrollment for treatment of MDR-TB in Vietnam. METHODS: In 35 provinces implementing PMDT, we quantified the number of MDR-TB presumptive patients tested for MDR-TB by Xpert MTB/RIF and the number of MDR-TB patients started on second-line treatment. In addition, existing reports and documents related to MDR-TB policies and guidelines in Vietnam were reviewed, supplemented with focus group discussions and in-depth interviews with MDR-TB key staff members. RESULTS: 5,668 (31.2 %) of estimated 18,165 MDR-TB presumptive cases were tested by Xpert MTB/RIF and second-line treatment was provided to 948 out of 5100 (18.7 %) of MDR-TB patients. Those tested for MDR-TB were 340/3224 (10.5 %) of TB-HIV co-infected patients and 290/2214 (13.1 %) of patients who remained sputum smear-positive after 2 and 3 months of category I TB regimen. Qualitative findings revealed the following challenges to detection and enrollment of MDR-TB in Vietnam: insufficient TB screening capacity at district hospitals where TB units were not available and poor communication and implementation of policy changes. Instructions for policy changes were not always received, and training was inconsistent between training courses. The private sector did not adequately report MDR-TB cases to the NTP. CONCLUSIONS: The proportion of MDR-TB patients diagnosed and enrolled for second-line treatment is less than 20 % of the estimated total. The low enrollment is largely due to the fact that many patients at risk are missed for MDR-TB screening. In order to detect more MDR-TB cases, Vietnam should intensify case finding of MDR-TB by a comprehensive strategy to screen for MDR-TB among new cases rather than targeting previously treated cases, in particular those with HIV co-infection and contacts of MDR-TB patients, and should engage the private sector in PMDT. PMID- 26415895 TI - Evaluating the use of plerixafor in stem cell mobilisation - an economic analysis of the PHANTASTIC trial. AB - Plerixafor is an effective haematopoietic stem cell mobilising agent in candidates for autologous transplantation, including patients with myeloma and lymphoma. Here we compare 98 plerixafor recipients in the PHANTASTIC trial with 151 historic controls mobilised by conventional chemotherapy (each with granulocyte colony-stimulating factor, G-CSF). Seventy (71.4%) plerixafor mobilised patients achieved the composite primary endpoint of >=4 * 10(6) CD34+ cells kg(-1) in <=2 aphereses and no clinically significant neutropenia, compared to 48 (31.8%) historic controls (P < 0.001), and this significant advantage was maintained in scenario analyses testing components of this composite endpoint. A patient-level cost analysis was undertaken for 249 patients, which included the cost of remobilising patients where initial mobilisation had failed. Combined mean treatment cost for plerixafor mobilised patients was L12,679 compared with L11,694 for historical controls. However, plerixafor produces an average saving of L3,828 per lymphoma patient but average cost increase by L5,245 per myeloma patient. The present data demonstrate cost-effectiveness for plerixafor as a first line mobilisation agent, certainly for lymphoma patients, where substantial resource savings and achievement of the primary endpoint are likely. J. Clin. Apheresis 31:434-442, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26415892 TI - Prior human polyomavirus and papillomavirus infection and incident lung cancer: a nested case-control study. AB - PURPOSE: To test whether infection with select human polyomaviruses (HPyV) and human papillomaviruses (HPV) is associated with incident lung cancer. METHODS: We performed a nested case-control study, testing serum from the carotene and retinol efficacy trial, conducted 1985-2005, for antibodies to Merkel cell (MCV), KI (KIV), and WU (WUV) HPyVs as well as to six high-risk and two low-risk HPV types. Incident lung cancer cases (n = 200) were frequency-matched with controls (n = 200) on age, enrollment and blood draw dates, intervention arm assignment, and the number of serum freeze/thaw cycles. Sera were tested using multiplex liquid bead microarray antibody assays. We used logistic regression to assess the association between HPyV and HPV antibodies and lung cancer. RESULTS: There was no evidence of a positive association between levels of MCV, KIV, or WUV antibodies and incident lung cancer (p corrected >0.10 for all trend tests; odds ratio (OR) range 0.72-1.09, p corrected >0.10 for all). There was also no evidence for a positive association between HPV 16 or 18 infection and incident lung cancer (p corrected >=0.10 for all trend tests; OR range 0.25-2.54, p > 0.05 for all OR > 1), but the number of persons with serologic evidence of these infections was small. CONCLUSIONS: Prior infection with any of several types of HPyV or HPV was not associated with subsequent diagnosis of lung cancer. Infection with these viruses likely does not influence a person's risk of lung cancer in Western smoking populations. PMID- 26415896 TI - Quantitative evaluation of positive phi angle propensity in flexible regions of proteins from three-bond J couplings. AB - (3)JHNHalpha and (3)JC'C' couplings can be readily measured in isotopically enriched proteins and were shown to contain precise information on the backbone torsion angles, phi, sampled in disordered regions of proteins. However, quantitative interpretation of these couplings required the population of conformers with positive phi angles to be very small. Here, we demonstrate that this restriction can be removed by measurement of (3)JC'Halpha values. Even though the functional forms of the (3)JC'Halpha and (3)JHNHalpha Karplus equations are the same, large differences in their coefficients enable accurate determination of the fraction of time that positive phi angles are sampled. A four-dimensional triple resonance HACANH[C'] E.COSY experiment is introduced to simultaneously measure (3)JC'Halpha and (3)JHNC' in the typically very congested spectra of disordered proteins. High resolution in these spectra is obtained by non-uniform sampling (in the 0.1-0.5% range). Application to the intrinsically disordered protein alpha-synuclein shows that while most residues have close-to zero positive phi angle populations, up to 16% positive phi population is observed for Asn residues. Positive phi angle populations determined with the new approach agree closely with consensus values from protein coil libraries and prior analysis of a large set of other NMR parameters. The combination of (3)JHNC' and (3)JC'C' provides information about the amplitude of phi angle dynamics. PMID- 26415898 TI - Dysferlin deficiency blunts beta-adrenergic-dependent lusitropic function of mouse heart. AB - Dysferlin is a cell membrane bound protein with a role in the repair of skeletal and cardiac muscle cells. Deficiency of dysferlin leads to limb-girdle muscular dystrophy 2B (LGMD2B) and Miyoshi myopathy. In cardiac muscle, dysferlin is located at the intercalated disc and transverse tubule membranes. Loss of dysferlin causes death of cardiomyocytes, notably in ageing hearts, leading to dilated cardiomyopathy and heart failure in LGM2B patients. To understand the primary pathogenesis and pathophysiology of dysferlin cardiomyopathy, we studied cardiac phenotypes of young adult dysferlin knockout mice and found early myocardial hypertrophy with largely compensated baseline cardiac function. Cardiomyocytes isolated from dysferlin-deficient mice showed normal shortening and re-lengthening velocities in the absence of external load with normal peak systolic Ca(2+) but slower Ca(2+) re-sequestration than wild-type controls. The effects of isoproterenol on relaxation velocity, left ventricular systolic pressure and stroke volume were blunted in dysferlin-deficient mouse hearts compared with that in wild-type hearts. Young dysferlin-deficient mouse hearts expressed normal isoforms of myofilament proteins whereas the phosphorylation of ventricular myosin light chain 2 was significantly increased, implying a molecular response to the impaired lusitropic function. These early phenotypes of diastolic cardiac dysfunction and blunted lusitropic response of cardiac muscle to beta-adrenergic stimulation indicate a novel pathogenic mechanism of dysferlin cardiomyopathy. PMID- 26415897 TI - The effects of stimulus complexity on the preattentive processing of self generated and nonself voices: An ERP study. AB - The ability to differentiate one's own voice from the voice of somebody else plays a critical role in successful verbal self-monitoring processes and in communication. However, most of the existing studies have only focused on the sensory correlates of self-generated voice processing, whereas the effects of attentional demands and stimulus complexity on self-generated voice processing remain largely unknown. In this study, we investigated the effects of stimulus complexity on the preattentive processing of self and nonself voice stimuli. Event-related potentials (ERPs) were recorded from 17 healthy males who watched a silent movie while ignoring prerecorded self-generated (SGV) and nonself (NSV) voice stimuli, consisting of a vocalization (vocalization category condition: VCC) or of a disyllabic word (word category condition: WCC). All voice stimuli were presented as standard and deviant events in four distinct oddball sequences. The mismatch negativity (MMN) ERP component peaked earlier for NSV than for SGV stimuli. Moreover, when compared with SGV stimuli, the P3a amplitude was increased for NSV stimuli in the VCC only, whereas in the WCC no significant differences were found between the two voice types. These findings suggest differences in the time course of automatic detection of a change in voice identity. In addition, they suggest that stimulus complexity modulates the magnitude of the orienting response to SGV and NSV stimuli, extending previous findings on self-voice processing. PMID- 26415899 TI - Evaluation of conjunctival swab sampling in the diagnosis of canine leishmaniasis: A two-year follow-up study in Cukurova Plain, Turkey. AB - The diagnosis of canine leishmaniasis (CanL) in symptomatic and asymptomatic dogs is a very important and problematic public health issue in Turkey. A longitudinal study was carried out on dogs in selected villages in the Cukurova Plain in Turkey, from July 2011 to June 2013, where cutaneous (CL) and visceral (VL) leishmaniasis is endemic. The study aimed to determine the prevalence of CanL and to evaluate the early diagnostic performance of the non-invasive conjunctival swab nested PCR (CS n-PCR) test in comparison with the Indirect Fluorescent Antibody Test (IFAT). The consecutive blood and CS samples from a representative number of dogs (80-100 dogs/each survey) were collected in a cohort of 6 villages located in the area. Clinical symptoms, demographic and physical features about each dog were noted and lymph node aspiration samples were obtained from selected dogs with lymphadenopathy. In four surveys during the period, a total of 338 sets (blood and CS) of samples from 206 dogs were obtained, such that 83 dogs were sampled more than once. In the cross-sectional analysis, the CanL prevalence was found to be 27.18% (between 7.14% and 39.13%) by IFAT and 41.74% (between 29.03% and 46.66%) by CS n-PCR. The isolated strains were identified as Leishmania infantum MON-1 (n=9) and MON-98 (n=2) by MLEE analysis. Genetic studies targeting the Hsp70 and ITS1 regions performed on 11 dog isolates also showed two clear separate groups. According to IFAT results, 24 of the 83 dogs sampled more than once showed seroconversion (n=19) or a four-fold increase in Ab titers (n=5), while 17 were positive in the initial screening. Forty-two dogs stayed negative during the whole period. The natural Leishmania exposure rate was detected as 31.14% in the study area. CS n-PCR only detected Leishmania infection earlier than IFAT in 8 dogs. No statistical difference was found after the analysis of demographical and physical data. The results indicated that (i) circulation of the dog population is very common in settlements in the Cukurova Plain, but the disease prevalence is high and stable, (ii) the performance of CS n-PCR for detecting Leishmania-dog contact is higher than IFAT, (iii) and some of the parasites isolated from dogs have different zymodemes and/or genotypes from previous human and sand fly isolates; suggesting the probability of two different cycles of leishmaniasis in this particular area. This hypothesis should be supported by future studies targeting vectors and reservoirs. PMID- 26415900 TI - Heterotrophic bacteria from an extremely phosphate-poor lake have conditionally reduced phosphorus demand and utilize diverse sources of phosphorus. AB - Heterotrophic Proteobacteria and Actinobacteria were isolated from Lake Matano, Indonesia, a stratified, ferruginous (iron-rich), ultra-oligotrophic lake with phosphate concentrations below 50 nM. Here, we describe the growth of eight strains of heterotrophic bacteria on a variety of soluble and insoluble sources of phosphorus. When transferred to medium without added phosphorus (P), the isolates grow slowly, their RNA content falls to as low as 1% of cellular dry weight, and 86-100% of the membrane lipids are replaced with amino- or glycolipids. Similar changes in lipid composition have been observed in marine photoautotrophs and soil heterotrophs, and similar flexibility in phosphorus sources has been demonstrated in marine and soil-dwelling heterotrophs. Our results demonstrate that heterotrophs isolated from this unusual environment alter their macromolecular composition, which allows the organisms to grow efficiently even in their extremely phosphorus-limited environment. PMID- 26415901 TI - Depression--An emerging indication for botulinum toxin treatment. AB - The treatment of glabellar frown lines with botulinum toxin injection is one of the most prevalent procedures in esthetic medicine. It is possible that the popularity of this intervention is not only owing to its cosmetic effect but also to modulatory effects on mood and affectivity. Recently, a series of studies including three randomized controlled trials have consistently shown that such effects can be used in the treatment of depression. Predominantly female patients suffering from partly chronic and treatment resistant unipolar depression experienced a quick, strong and sustained improvement in depressive symptoms after a single glabellar treatment with botulinum toxin A as a sole or adjunctive therapy. If these findings are further corroborated in additional studies, the ever-growing spectrum of applications for botulinum toxin may spread into the field of psychiatry, showing that the superficial paralysis of facial muscles may, probably via proprioceptive feedback mechanisms, have profound effects on the emotional brain. PMID- 26415902 TI - Characterizing Tityus discrepans scorpion venom from a fractal perspective: Venom complexity, effects of captivity, sexual dimorphism, differences among species. AB - A characteristic of venom elution patterns, shared with many other complex systems, is that many their features cannot be properly described with statistical or euclidean concepts. The understanding of such systems became possible with Mandelbrot's fractal analysis. Venom elution patterns were produced using the reversed phase high performance liquid chromatography (HPLC) with 1 mg of venom. One reason for the lack of quantitative analyses of the sources of venom variability is parametrizing the venom chromatograms' complexity. We quantize this complexity by means of an algorithm which estimates the contortedness (Q) of a waveform. Fractal analysis was used to compare venoms and to measure inter- and intra-specific venom variability. We studied variations in venom complexity derived from gender, seasonal and environmental factors, duration of captivity in the laboratory, technique used to milk venom. PMID- 26415903 TI - Induction of IL-12 from human monocytes after stimulation with Androctonus crassicauda scorpion venom. AB - The objective of this study was to evaluate the capacity of venom from Androctonus crassicauda to induce expression/production of interleukin (IL)-12 by isolated human monocytes. For this purpose, isolated human monocytes were exposed to different concentrations of the venom (0.16-20 MUg/ml) for varying periods (6, 12, and 24 h). Apart from measures of venom cytotoxicity (i.e., lactase dehydrogenase activity [LDH] release), measures of IL-12 p40 mRNA (by Real-time PCR) of IL-12 release (by ELISA) were performed. The results showed that the venom produced significant concentration- and duration of incubation-dependent cytotoxicity. Expression of IL-12 p40 mRNA was significantly increased at all exposure timepoints relative to that in unexposed cells, but was maximal after 6 h of exposure. At that timepoint, the effect from a dose of 2.5 MUg venom/ml provided the maximal increase among all doses tested. At the level of the protein itself, IL-12 production remained almost consistently elevated (vs. unexposed control values) across all exposure timepoints, with the greatest formation again occurring after 6 h of incubation at a dose of 2.5 MUg venom/ml. The findings from this study demonstrated that venom from the A. crassicauda scorpion contained active constituents that could induce a sustained activation of human monocytes that was manifested, in part, as promotion of the expression/production of IL-12. PMID- 26415904 TI - Evaluation of the preclinical efficacy of four antivenoms, distributed in sub Saharan Africa, to neutralize the venom of the carpet viper, Echis ocellatus, from Mali, Cameroon, and Nigeria. AB - Snakebite envenoming causes a heavy toll in sub-Saharan Africa in terms of mortality and sequelae. In the West African savannah, the viperid Echis ocellatus is responsible for the vast majority of bites. In the last decades, several new antivenoms have been introduced for the treatment of these envenomings, although the assessment of their preclinical efficacy against the venom of E. ocellatus has been studied only for some of them. This work analyzed comparatively the ability of four antivenoms (FAV Afrique, EchiTAb G, EchiTAB-Plus-ICP((r)), and InoserpTM Panafricain) to neutralize lethal, hemorrhagic, and in vitro coagulant activities of the venoms of E. ocellatus from Mali, Cameroon, and Nigeria. In addition, an immunoaffinity chromatography antivenomic protocol was used to assess the ability of the four antivenoms to bind to the proteins of these venoms. Results showed that all the antivenoms were effective in the neutralization of the three effects investigated, and were able to immunocapture, completely or partially, the most abundant components in the E. ocellatus venoms from the geographical origins sampled. Our observations also highlighted quantitative differences between antivenoms in their neutralizing and antivenomics profiles, especially regarding neutralization of in vitro coagulant activity, suggesting that different doses of these antivenoms are probably needed for an effective treatment of human envenomings by this species. PMID- 26415905 TI - The non-competitive blockade of GABAA receptors by an aqueous extract of water hemlock (Cicuta douglasii) tubers. AB - Water hemlocks (Cicuta spp.) are acutely toxic members of the Umbellierae family; the toxicity is due to the presence of C17-polyacetylenes such as cicutoxin. There is only limited evidence of noncompetitive antagonism by C17-polyacetylenes at GABAA receptors. In this work with WSS-1 cells, we documented the noncompetitive blockade of GABAA receptors by an aqueous extract of water hemlock (Cicuta douglasii) and modulated the actions of the extract with a pretreatment of 10 MUM midazolam. PMID- 26415906 TI - Differences in potency and categorical agreement between colistin and polymyxin B when testing 15,377 clinical strains collected worldwide. AB - Gram-negative bacilli (n=15,377) were tested against colistin (polymyxin E) and polymyxin B by a commercial broth microdilution method (Sensititre(r)). Among Pseudomonas aeruginosa and Acinetobacter spp., colistin and polymyxin B MIC values were within +/-1 doubling dilution for >99.0% of strains. Among Klebsiella spp. and Escherichia coli, 55.0 and 53.2% of strains displayed a colistin MIC 2 fold lower than polymyxin B, but polymyxin B was slightly more potent than colistin against strains with decreased susceptibility to either polymyxin. PMID- 26415907 TI - Tuning all-Optical Analog to Electromagnetically Induced Transparency in nanobeam cavities using nanoelectromechanical system. AB - We report the observations of all-optical electromagnetically induced transparency in nanostructures using waveguide side-coupled with photonic crystal nanobeam cavities, which has measured linewidths much narrower than individual resonances. The quality factor of transparency resonance can be 30 times larger than those of measured individual resonances. When the gap between cavity and waveguide is reduced to 10 nm, the bandwidth of destructive interference region can reach 10 nm while the width of transparency resonance is 0.3 nm. Subsequently, a comb-drive actuator is introduced to tune the line shape of the transparency resonance. The width of the peak is reduced to 15 pm and the resulting quality factor exceeds 10(5). PMID- 26415908 TI - Genetics affect lung disease and smoking behaviour, study finds. PMID- 26415909 TI - Na(+) diffusion kinetics in nanoporous metal-hexacyanoferrates. AB - Metal-hexacyanoferrates (metal-HCFs) are promising candidates for cathode materials of sodium-ion secondary batteries (SIBs). Here, we systematically investigated Na(+) diffusion constants (D) and the activation energies (Ea) of metal-HCFs against the framework size (= a/2). We found that the magnitude of D (Ea) systematically increases (decreases) with increases in a, indicating that steric hindrance plays a dominant role in Na(+) diffusion. PMID- 26415910 TI - In vitro Differentiation of Germ Cells from Stem Cells. AB - Stem cells are unique cell types with the ability of self-renewal and differentiation, which mainly include embryonic stem cells, induced pluripotent stem cells, and adult stem cells. Recently, several research groups have reported that stem cells can differentiate into germ cells under appropriate conditions in vitro. Advances in this field have revealed new perspectives for reproductive and regenerative medicine. Here, we review the progress of in vitro gamete production from stem cells. PMID- 26415911 TI - microRNAs and Molecular Pathogenesis of Microcephaly. AB - Microcephaly is a clinical condition defined as a reduction in head circumference and brain volume. The abnormal brain size may result from pathological neural stem cell (NSC) proliferation, survival, differentiation and migration during the development of the cerebral cortex. This process is controlled by many factors, including microRNAs that normally silence target genes at the posttranscriptional level. In this review, we will discuss the roles of microRNAs involved in different stages of the cortical development to shed light on the pathogenesis of microcephaly. Understanding the molecular mechanisms of microRNA-mediated cortical development may help develop a means of microRNA-based diagnosis and treatment for microcephaly in humans. PMID- 26415912 TI - Mesenchymal Stem Cells and Cell Therapy for Bone Repair. AB - Mesenchymal stem cells (MSCs) represent a new therapeutic paradigm for a number of diseases because they possess unique biological characteristics such as multipotency, immunomodulation and production of cytokines. Currently, 425 MSC based clinical trials have been conducted for at least 12 kinds of pathological conditions, with many completed trials demonstrating the safety and efficacy of MSCs. Here, we provide an overview of the clinical status of MSCs by searching the public clinical trials database http://clinicaltrials.gov. Particularly, the role of MSCs in clinical trials to treat bone defects and injuries is highlighted. PMID- 26415913 TI - Stem Cell Therapy and Immunological Rejection in Animal Models. AB - With their capability to undergo unlimited self-renew and to differentiate into various functional cells, human pluripotent stem cells, including embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), hold great promise in regenerative medicine to treat currently incurable diseases. Significant progress has been achieved in differentiating pluripotent stem cells into various functional cells, such as pancreatic beta cells, neural cells, hepatocytes, and cardiomyocytes. In addition, three hESC-based therapies to treat spinal cord injury, macular degeneration and type 1 diabetes have entered clinical trial. However, there remain several major bottlenecks that hinder the clinical trial of stem cell based therapy. One such key challenge is the immune rejection of cells derived from allogeneic hESCs. The challenge of immune rejection is mitigated by recent discovery of iPSCs, raising the hope that patient-specific hiPSCs can be differentiated into autologous cells for transplantation into the same patient without the concern of immune rejection. However, due to the oncogenic potential of the reprogramming factors and the reprogramming- induced DNA damage, there remain safety concerns about the cancer risk and immunogenicity of hiPSC-derived cells. This review discusses recent progress in our understanding of the immunogenicity of pluripotent stem cells and the development of new strategies to resolve this challenge. PMID- 26415914 TI - Inhalable, large porous PLGA microparticles loaded with paclitaxel: preparation, in vitro and in vivo characterization. AB - Large porous particles (LPPs) could be used as a useful carrier for non-invasive delivery to the deep lung. Pulmonary delivery of paclitaxel-loaded LPPs (PTX LPPs) can help to eliminate the highly complicated and harmful solvent used in PTX parenteral formulations. PTX-LPPs with mass median aerodynamic diameter (MMAD) of 5.74 +/- 0.09 MUm, high encapsulation efficiency and good aerosolisation properties were produced using ammonium bicarbonate as porogen. Cytotoxicity of PTX-LPPs on A549 and Calu-6 cell lines was comparable with Free PTX. Endotracheal administration of PTX-LPPs in rats exhibited PTX plasma concentration in the therapeutic range which lasted 4-fold longer than i.v. injection. The bioavailability was measured as 51 +/- 7.1%. The lung targeting efficiency (Te) of PTX-LPPs was 11.9-fold higher than i.v. administration. PTX LPPs could deliver a higher PTX to lung with a non-toxic plasma level in a longer duration which shows their pulmonary delivery suitability. PMID- 26415915 TI - Liking, salt taste perception and use of table salt when consuming reduced-salt chicken stews in light of South Africa's new salt regulations. AB - This study investigated the impact of salt reduction on liking, salt taste perception, and use of table salt when consuming chicken stew in light of South Africa's new salt recommendations. In total, 432 South-African consumers (aged 35.2 +/- 12.3 years) consumed a full portion of a chicken stew meal once at a central location. Four stock cube powders varying in salt content were used to prepare chicken stews: 1) no reduction - 2013 Na level; regular salt level as currently available on the South African market (24473 mg Na/100 g), 2) salt reduction smaller than 2016 level, i.e. 10%-reduced (22025 mg Na/100 g), 3) 2016 salt level, as per regulatory prescriptions (18000 mg Na/100 g), 4) 2019 salt level, as per regulatory prescriptions (13000 mg Na/100 g). Consumers were randomly allocated to consume one of the four meals. Liking, salt taste perception, and use of table salt and pepper were measured. Chicken stews prepared with reduced-salt stock powders were equally well-liked as chicken stews with the current salt level. Moreover, a gradual reduction of the salt in the chicken stews resulted in a reduced salt intake, up to an average of 19% for the total group compared to the benchmark 2013 Na level stew. However, 19% of consumers compensated by adding salt back to full compensation in some cases. More salt was added with increased reductions of salt in the meals, even to the point of full compensation. Further investigation into the impacts of nutrition communication and education about salt reduction on salt taste perception and use is needed. This research provides new consumer insights on salt use and emphasises the need for consumer-focused behaviour change approaches, in addition to reformulation of products. PMID- 26415916 TI - Thinking about quantity: the intertwined development of spatial and numerical cognition. AB - There are many continuous quantitative dimensions in the physical world. Philosophical, psychological, and neural work has focused mostly on space and number. However, there are other important continuous dimensions (e.g., time and mass). Moreover, space can be broken down into more specific dimensions (e.g., length, area, and density) and number can be conceptualized discretely or continuously (i.e., natural vs real numbers). Variation on these quantitative dimensions is typically correlated, e.g., larger objects often weigh more than smaller ones. Number is a distinctive continuous dimension because the natural numbers (i.e., positive integers) are used to quantify collections of discrete objects. This aspect of number is emphasized by teaching of the count word sequence and arithmetic during the early school years. We review research on spatial and numerical estimation, and argue that a generalized magnitude system is the starting point for development in both domains. Development occurs along several lines: (1) changes in capacity, durability, and precision, (2) differentiation of the generalized magnitude system into separable dimensions, (3) formation of a discrete number system, i.e., the positive integers, (4) mapping the positive integers onto the continuous number line, and (5) acquiring abstract knowledge of the relations between pairs of systems. We discuss implications of this approach for teaching various topics in mathematics, including scaling, measurement, proportional reasoning, and fractions. PMID- 26415917 TI - Bio-Derived, Binderless, Hierarchically Porous Carbon Anodes for Li-ion Batteries. AB - Here we explore the electrochemical performance of pyrolyzed skins from the species A. bisporus, also known as the Portobello mushroom, as free-standing, binder-free, and current collector-free Li-ion battery anodes. At temperatures above 900 degrees C, the biomass-derived carbon nanoribbon-like architectures undergo unique processes to become hierarchically porous. During heat-treatment, the oxygen and heteroatom-rich organics and potassium compounds naturally present in the mushroom skins play a mutual role in creating inner void spaces throughout the resulting carbon nanoribbons, which is a process analogous to KOH-activation of carbon materials seen in literature. The pores formed in the pyrolytic carbon nanoribbons range in size from sub-nanometer to tens of nanometers, making the nanoribbons micro, meso, and macroporous. Detailed studies were conducted on the carbon nanoribbons using SEM and TEM to study morphology, as well as XRD and EDS to study composition. The self-supporting nanoribbon anodes demonstrate significant capacity increase as they undergo additional charge/discharge cycles. After a pyrolysis temperature of 1100 degrees C, the pristine anodes achieve over 260 mAh/g after 700 cycles and a Coulombic efficiency of 101.1%, without the use of harmful solvents or chemical activation agents. PMID- 26415918 TI - Emergency department syndromic surveillance providing early warning of seasonal respiratory activity in England. AB - Seasonal respiratory infections place an increased burden on health services annually. We used a sentinel emergency department syndromic surveillance system to understand the factors driving respiratory attendances at emergency departments (EDs) in England. Trends in different respiratory indicators were observed to peak at different points during winter, with further variation observed in the distribution of attendances by age. Multiple linear regression analysis revealed acute respiratory infection and bronchitis/bronchiolitis ED attendances in patients aged 1-4 years were particularly sensitive indicators for increasing respiratory syncytial virus activity. Using near real-time surveillance of respiratory ED attendances may provide early warning of increased winter pressures in EDs, particularly driven by seasonal pathogens. This surveillance may provide additional intelligence about different categories of attendance, highlighting pressures in particular age groups, thereby aiding planning and preparation to respond to acute changes in EDs, and thus the health service in general. PMID- 26415921 TI - [Castleman's disease: Rapid desensitization for hypersensitivity reaction to rituximab]. AB - INTRODUCTION: Rapid desensitization allows secure administration of a drug and is indicated when there is no therapeutic alternative. CASE REPORT: We report a 49 year-old patient who presented with a hypersensitivity reaction following an infusion of rituximab (375mg/m(2)) in the context of a Castleman's syndrome. After a clinical flare (splenomegaly, adenopathies) despite treatment with tocilizumab, anakinra and valganciclovir, the reintroduction of rituximab was decided, according to the rapid desensitization protocol. Four full dose desensitizations were successfully performed allowing immediate clinical improvement (apyrexia, loss of sweating and lymphadenopathy, splenomegaly partial regression) and biological (negativation of HHV8 viral load, and disappearance of neutropenia, anemia and thrombocytopenia). CONCLUSION: Rapid desensitization is a promising method for the pursuit of rituximab therapy after a hypersensitivity reaction and should be considered in patients with no acceptable therapeutic alternative. PMID- 26415919 TI - Epilepsy priorities in Europe: A report of the ILAE-IBE Epilepsy Advocacy Europe Task Force. AB - The European Forum on Epilepsy Research (ERF2013), which took place in Dublin, Ireland, on May 26-29, 2013, was designed to appraise epilepsy research priorities in Europe through consultation with clinical and basic scientists as well as representatives of lay organizations and health care providers. The ultimate goal was to provide a platform to improve the lives of persons with epilepsy by influencing the political agenda of the EU. The Forum highlighted the epidemiologic, medical, and social importance of epilepsy in Europe, and addressed three separate but closely related concepts. First, possibilities were explored as to how the stigma and social burden associated with epilepsy could be reduced through targeted initiatives at EU national and regional levels. Second, ways to ensure optimal standards of care throughout Europe were specifically discussed. Finally, a need for further funding in epilepsy research within the European Horizon 2020 funding programme was communicated to politicians and policymakers participating to the forum. Research topics discussed specifically included (1) epilepsy in the developing brain; (2) novel targets for innovative diagnostics and treatment of epilepsy; (3) what is required for prevention and cure of epilepsy; and (4) epilepsy and comorbidities, with a special focus on aging and mental health. This report provides a summary of recommendations that emerged at ERF2013 about how to (1) strengthen epilepsy research, (2) reduce the treatment gap, and (3) reduce the burden and stigma associated with epilepsy. Half of the 6 million European citizens with epilepsy feel stigmatized and experience social exclusion, stressing the need for funding trans-European awareness campaigns and monitoring their impact on stigma, in line with the global commitment of the European Commission and with the recommendations made in the 2011 Written Declaration on Epilepsy. Epilepsy care has high rates of misdiagnosis and considerable variability in organization and quality across European countries, translating into huge societal cost (0.2% GDP) and stressing the need for cost-effective programs of harmonization and optimization of epilepsy care throughout Europe. There is currently no cure or prevention for epilepsy, and 30% of affected persons are not controlled by current treatments, stressing the need for pursuing research efforts in the field within Horizon 2020. Priorities should include (1) development of innovative biomarkers and therapeutic targets and strategies, from gene and cell-based therapies to technologically advanced surgical treatment; (2) addressing issues raised by pediatric and aging populations, as well as by specific etiologies and comorbidities such as traumatic brain injury (TBI) and cognitive dysfunction, toward more personalized medicine and prevention; and (3) translational studies and clinical trials built upon well-established European consortia. PMID- 26415923 TI - Perspectives of clinical handover processes: a multi-site survey across different health professionals. AB - AIMS AND OBJECTIVES: To examine the perspectives of health professionals of different disciplines about clinical handover. BACKGROUND: Ineffective handovers can cause major problems relating to the lack of delivery of appropriate care. DESIGN: A prospective, cross-sectional design was conducted using a survey about clinical handover practices. METHODS: Health professionals employed in public metropolitan hospitals, public rural hospitals and community health centres were involved. The sample comprised doctors, nurses and allied health professionals, including physiotherapists, social workers, pharmacists, dieticians and midwives employed in Western Australia, New South Wales, South Australia and the Australian Capital Territory. The survey sought information about health professionals' experiences about clinical handover; their perceived effectiveness of clinical handover; involvement of patients and family members; health professionals' ability to confirm understanding and to clarify clinical information; role modelling behaviour of health professionals; training needs; adverse events encountered and possibilities for improvements. RESULTS: In all, 707 health professionals participated (response rate = 14%). Represented professions were nursing (60%), medicine (22%) and allied health (18%). Many health professionals reported being aware of adverse events where they noticed poor handover was a significant cause. Differences existed between health professions in terms of how effectively they gave handover, perceived effectiveness of bedside handover vs. nonbedside handover, patient and family involvement in handover, respondents' confirmation of understanding handover from their perspective, their observation of senior health professionals giving feedback to junior health professionals, awareness of adverse events and severity of adverse events relating to poor handovers. CONCLUSIONS: Complex barriers impeded the conduct of effective handovers, including insufficient opportunities for training, lack of role modelling, and lack of confidence and understanding about handover processes. RELEVANCE TO CLINICAL PRACTICE: Greater focus should be placed on creating opportunities for senior health professionals to act as role models. Sophisticated approaches should be implemented in training and education. PMID- 26415922 TI - [Retroperitoneal fibrosis in adults: Main characteristics and relevance of the diagnostic procedures based on a retrospective multicenter study on 77 cases]. AB - INTRODUCTION: Retroperitoneal fibrosis (RPF) is a rare disorder characterized by the sheathing of retroperitoneal structures by fibro-inflammatory process. It can be either isolated or associated with an underlying disease or condition. In the absence of consistent and consensual approach, the objective of this study was to assess the relevance of diagnostic tests performed during the diagnostic work-up of RPF. METHODS: Seventy-seven patients were included in this retrospective multicenter study. The diagnosis of RPF was defined by the presence of a thickened circumferential homogeneous tissue unsheathing the infrarenal aorta, excluding peri-aneurysmal fibrosis and a clear evidence of a cancer. RESULTS: In 62 cases (80.5%), the RPF was considered as being primary or "idiopathic". Surgical (n=31) or CT-guided (n=9) biopsies of the RPF were performed in half of the patients showing some fibrotic or non-specific inflammatory lesions in 98% of cases. A bone marrow biopsy was performed in 23 patients leading to diagnosis of low grade B cell non-Hodgkin lymphoma in a single patient who also had a monoclonal gammopathy IgM. The systematic search for autoantibodies or serum tumor markers was of no diagnostic value. CONCLUSIONS: Although the diagnostic procedure was heterogeneous, no cause or associated disease was found in the majority of cases of FRP in this series. In the absence of any clinical or paraclinical evidence suggesting an underlying disease or any atypical features at presentation, a number of non-invasive tests (autoantibodies, tumor markers, bone scintigraphy) and also more invasive diagnostic tests (bone marrow and RPF biopsies) seem of little relevance. PMID- 26415924 TI - Bayesian modeling and inference for diagnostic accuracy and probability of disease based on multiple diagnostic biomarkers with and without a perfect reference standard. AB - The area under the receiver operating characteristic (ROC) curve (AUC) is used as a performance metric for quantitative tests. Although multiple biomarkers may be available for diagnostic or screening purposes, diagnostic accuracy is often assessed individually rather than in combination. In this paper, we consider the interesting problem of combining multiple biomarkers for use in a single diagnostic criterion with the goal of improving the diagnostic accuracy above that of an individual biomarker. The diagnostic criterion created from multiple biomarkers is based on the predictive probability of disease, conditional on given multiple biomarker outcomes. If the computed predictive probability exceeds a specified cutoff, the corresponding subject is allocated as 'diseased'. This defines a standard diagnostic criterion that has its own ROC curve, namely, the combined ROC (cROC). The AUC metric for cROC, namely, the combined AUC (cAUC), is used to compare the predictive criterion based on multiple biomarkers to one based on fewer biomarkers. A multivariate random-effects model is proposed for modeling multiple normally distributed dependent scores. Bayesian methods for estimating ROC curves and corresponding (marginal) AUCs are developed when a perfect reference standard is not available. In addition, cAUCs are computed to compare the accuracy of different combinations of biomarkers for diagnosis. The methods are evaluated using simulations and are applied to data for Johne's disease (paratuberculosis) in cattle. PMID- 26415925 TI - Cytotoxic effects of 4-octylphenol on fish hepatocytes. AB - The present study was conducted to determine cytotoxic effects of 4-octylphenol (4-OP) on primary cultured hepatocytes of pearl mullet (Alburnus tarichi). Lactate dehydrogenase (LDH) release, malondialdehyde (MDA) level, antioxidant enzymes [superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione-S transferase (GST)] and glutathione (GSH) content were measured after 24-h exposure to 4-OP. 4-OP caused dose- and time-dependent increases in LDH release. Significant induction of MDA level and decrease in GSH content were found. SOD and GPx activities were decreased while GST activity was increased. These findings suggest that 4-OP leads to cytotoxicity by depressing antioxidant defenses in fish hepatocytes. PMID- 26415926 TI - Evaluation of rational use of veterinary drugs especially antimicrobials and anthelmintics in Bishoftu, Central Ethiopia. AB - BACKGROUND: Rational use of drugs in veterinary medicine has numerous benefits, such as increasing efficacy, decreasing the potential adverse effects, reducing risk of drug residue and combating development of microorganism's drug resistance. METHODS: A retrospective study with the aim of evaluating the current rational use of veterinary drugs was conducted at college of veterinary medicine and agriculture veterinary teaching hospital and Ada district veterinary clinic, central Ethiopia. One thousand eight hundred and nineteen animal patients' encounters were randomly selected for the study from prescription papers and prescription registration books retrospectively. RESULTS: The average number of drugs prescribed per encounter was 1.23 with maximum of five. The percentage of encounters in which antimicrobials and anthelmintics was prescribed were 54.4% (1216/2235) and 38.9% (869/2235), respectively. The percentages of drugs prescribed by generic name and from essential veterinary drug list were 90.1% (2014/2235) and 99.7% (2229/2235), respectively. The most commonly prescribed antimicrobials and anthelmintics were oxytetracycline 1016 (45.5%), penicillin and streptomycin combination 168 (7.5%), sulfa drugs 23 (1.0%), and albendazole 732 (32.8%) and ivermectin 137 (6.1%). Among the 1819 animal-patient encounters, only 57% (n = 1037) of the prescriptions were written adequately, 43% (n = 782) incorrectly prescribed and 1179 cases of the adequately specified prescription were tentatively diagnosed. For 656 (53.9%) and 233 (26.8%) inadequately specified cases antimicrobials and anthelmintics were prescribed, respectively. Antibiotics were prescribed irrationally for cases which were tentatively diagnosed as parasitic 21.6 % (n = 262) and viral to prevent secondary bacterial complications 6.0% (n = 73). Among all patients that were admitted to veterinary clinics, 96.6% (1757) were treated empirically without getting correct laboratory supported diagnosis. Chi Square test for trend analysis showed a statistically significant association between irrational drug usage and year (p = 0.000). CONCLUSIONS: The findings had shown problems in generic prescribing, incorrect diagnosis, and non-availability of standard veterinary treatment guideline and drug formulary in the study area. Therefore, veterinary drugs, specially, antimicrobial agents should be judiciously used; and a wide scale study to safeguard the public from drug residual effects and antimicrobial resistance development is recommended. PMID- 26415927 TI - RDTs as a source of DNA to study Plasmodium falciparum drug resistance in isolates from Senegal and the Comoros Islands. AB - BACKGROUND: The World Health Organization has recommended rapid diagnostic tests (RDTs) for use in the diagnosis of suspected malaria cases. In addition to providing quick and accurate detection of Plasmodium parasite proteins in the blood, these tests can be used as sources of DNA for further genetic studies. As sulfadoxine-pyrimethamine is used currently for intermittent presumptive treatment of pregnant women in both Senegal and in the Comoros Islands, resistance mutations in the dhfr and dhps genes were investigated using DNA extracted from RDTs. METHODS: The proximal portion of the nitrocellulose membrane of discarded RDTs was used for DNA extraction. This genomic DNA was amplified using HRM to genotype the molecular markers involved in resistance to sulfadoxine pyrimethamine: dhfr (51, 59, 108, and 164) and dhps (436, 437, 540, 581, and 613). Additionally, the msp1 and msp2 genes were amplified to determine the average clonality between Grande-Comore (Comoros) and Thies (Senegal). RESULTS: A total of 201 samples were successfully genotyped at all codons by HRM; whereas, in 200 msp1 and msp2 genes were successfully amplified and genotyped by nested PCR. A high prevalence of resistance mutations were observed in the dhfr gene at codons 51, 59, and 108 as well as in the dhps gene at codons 437 and 436. A novel mutant in dhps at codon positions 436Y/437A was observed. The dhfr I164L codon and dhps K540 and dhps A581G codons had 100 % wild type alleles in all samples. CONCLUSION: The utility of field-collected RDTs was validated as a source of DNA for genetic studies interrogating frequencies of drug resistance mutations, using two different molecular methods (PCR and High Resolution Melting). RDTs should not be discarded after use as they can be a valuable source of DNA for genetic and epidemiological studies in sites where filter paper or venous blood collected samples are nonexistent. PMID- 26415928 TI - A comparative study of red and blue light-emitting diodes and low-level laser in regeneration of the transected sciatic nerve after an end to end neurorrhaphy in rabbits. AB - This study aimed at evaluating the effects of red and blue light-emitting diodes (LED) and low-level laser (LLL) on the regeneration of the transected sciatic nerve after an end-to-end neurorrhaphy in rabbits. Forty healthy mature male New Zealand rabbits were randomly assigned into four experimental groups: control, LLL (680 nm), red LED (650 nm), and blue LED (450 nm). All animals underwent the right sciatic nerve neurotmesis injury under general anesthesia and end-to-end anastomosis. The phototherapy was initiated on the first postoperative day and lasted for 14 consecutive days at the same time of the day. On the 30th day post surgery, the animals whose sciatic nerves were harvested for histopathological analysis were euthanized. The nerves were analyzed and quantified the following findings: Schwann cells, large myelinic axons, and neurons. In the LLL group, as compared to other groups, an increase in the number of all analyzed aspects was observed with significance level (P < 0.05). This finding suggests that postoperative LLL irradiation was able to accelerate and potentialize the peripheral nerve regeneration process in rabbits within 14 days of irradiation. PMID- 26415929 TI - Effects of low-level laser therapy on the expression of osteogenic genes during the initial stages of bone healing in rats: a microarray analysis. AB - This study evaluated the morphological changes produced by LLLT on the initial stages of bone healing and also studied the pathways that stimulate the expression of genes related to bone cell proliferation and differentiation. One hundred Wistar rats were divided into control and treated groups. Noncritical size bone defects were surgically created at the upper third of the tibia. Laser irradiation (Ga-Al-As laser 830 nm, 30 mW, 94 s, 2.8 J) was performed for 1, 2, 3, 5, and 7 sessions. Histopathology revealed that treated animals produced increased amount of newly formed bone at the site of the injury. Moreover, microarray analysis evidenced that LLLT produced a significant increase in the expression TGF-beta, BMP, FGF, and RUNX-2 that could stimulate osteoblast proliferation and differentiation, which may be related to improving the deposition of newly formed bone at the site of the injury. Thus, it is possible to conclude that LLLT improves bone healing by producing a significant increase in the expression of osteogenic genes. PMID- 26415930 TI - The case for using country-specific scoring coefficients for scoring the SF-12, with scoring implications for the SF-36. AB - PURPOSE: To examine the validity of using the same scoring coefficients across countries for the SF-12. METHODS: We test the equality of scoring coefficients derived for a contraction of the SF-36, the Short Form 12 (SF-12), using a large international database drawn from nine countries, to test equality between Australia and twelve other country/language groups. First, we checked that the theoretical structure of the SF-12 as set out by Ware and colleagues, but including a correlation between physical and mental health, provided an adequate fit to the data for each country/language group in a confirmatory factor analysis. We then compared Australia to all of these country/language groups in multiple-group models to assess whether a model producing common factor score coefficients provided an adequate fit to the data. We also derived Chi-squared tests for the differences between the restricted and unrestricted models, to test the equality of the factor score coefficients across countries. RESULTS: We found that the theoretical structure of the SF-12, with a correlation between physical and mental health, provides an adequate fit to the data for all country/language groups except Hungary. Further, all the unrestricted multiple-group models provide an adequate fit to the data. In contrast, none of the multiple-group models restricted to common parameters provide an adequate fit to the data. The significance tests confirm that the constraints on parameter values produce significantly different models to the unrestricted models. CONCLUSIONS: We conclude that researchers should derive their own country-specific scoring coefficients for physical and mental health summary scores. PMID- 26415931 TI - Differences between work and leisure in temporal patterns of objectively measured physical activity among blue-collar workers. AB - BACKGROUND: Leisure time physical activity (LTPA) is generally associated with favorable cardiovascular health outcomes, while occupational physical activity (OPA) shows less clear, or even opposite, cardiovascular effects. This apparent paradox is not sufficiently understood, but differences in temporal patterns of OPA and LTPA have been suggested as one explanation. Our aim was to investigate the extent to which work and leisure (non-occupational time) differ in temporal activity patterns among blue-collar workers, and to assess the modification of these patterns by age and gender. METHODS: This study was conducted on a cross sectional sample of male (n = 108) and female (n = 83) blue-collar workers, aged between 21 and 65 years. Physical activity and sedentary behavior were assessed using accelerometers (Actigraph GT3X+) worn on the thigh and trunk for four consecutive days. Temporal patterns of OPA and LTPA were retrieved using Exposure Variation Analysis (EVA), and expressed in terms of percentage of work and leisure time spent in uninterrupted periods of different durations (<1 min, 1-5 min, 5-10 min, 10-30 min, 30-60 min and > 60 min) of sitting, standing, and walking. Repeated measures ANOVA and linear regression analyses were used to test a) possible differences between OPA and LTPA in selected EVA derivatives, and b) the modification of these differences by age and gender. RESULTS: OPA showed a larger percentage time walking in brief (<5 min) periods [mean (SD): 33.4 % (12.2)], and less time in prolonged (>30 min) sitting [7.0 % (9.3)] than LTPA [walking 15.4 % (5.0); sitting 31.9 % (15.3)], even after adjustment for the difference between work and leisure in total time spent in each activity type. These marked differences in the temporal pattern of OPA and LTPA were modified by gender, but not age. CONCLUSION: We found that the temporal patterns of OPA and LTPA among blue-collar workers were markedly different even after adjustment for total physical activity time, and that this difference was modified by gender. We recommend using EVA derivatives in future studies striving to disentangle the apparent paradoxical cardiovascular effect of physical activity at work and during leisure. PMID- 26415933 TI - Injuries of neural tracts in a patient with CADASIL: a diffusion tensor imaging study. AB - BACKGROUND: We report a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), who showed injuries of the neural tracts, which was demonstrated by diffusion tensor tractography (DTT). CASE PRESENTATION: A 64-year-old male patient and seven age-matched control volunteers were recruited. Since approximately 1.5 years ago, he had felt mild weakness of the right arm and was diagnosed as CADASIL by the finding of the exon 11 mutation of the NOTCH3 gene approximately 10 months ago. T2-weighted and FLAIR brain MRI images obtained at admission showed high signal intensity lesions in the subcortical gray matter and periventricular white matter. He showed mild quadriparesis, mild dysarthria, mild cognitive impairment, and emotional problems. Diffusion tensor imaging was performed and nine neural tracts (corticospinal tract, corticobulbar tract, corticofugal tract from the supplementary motor area, corticofugal tract from the premotor cortex, thalmoprefrontal tract [TPT] to the dorsolateral prefrontal cortex, TPT to the ventrolateral prefrontal cortex, TPT to the orbitoprefrontal cortex, fornix, and cingulum) were reconstructed. Fractional anisotropy (FA), mean diffusivity (MD), and tract volume of each neural tract were measured. All neural tracts except for the left fornix showed at least one more abnormality in terms of DTT parameters (decrement of FA, increment of MD, or decrement of tract volume). CONCLUSION: We demonstrated injuries of the neural tracts in a patient with CADASIL. It appears that clinical manifestations in this patient were related to injuries of the neural tracts. PMID- 26415932 TI - A survey of perceived training differences between ophthalmology residents in Hong Kong and China. AB - BACKGROUND: To study the differences in ophthalmology resident training between China and the Hong Kong Special Administrative Region (HKSAR). METHODS: Training programs were selected from among the largest and best-known teaching hospitals. Ophthalmology residents were sent an anonymous 48-item questionnaire by mail. Work satisfaction, time allocation between training activities and volume of surgery performed were determined. RESULTS: 50/75 residents (66.7 %) from China and 20/26 (76.9 %) from HKSAR completed the survey. Age (28.9 +/- 2.5 vs. 30.2 +/ 2.9 years, p = 0.15) and number of years in training (3.4 +/- 1.6 vs. 2.8 +/- 1.5, p = 0.19) were comparable between groups. The number of cataract procedures performed by HKSAR trainees (extra-capsular, median 80.0, quartile range: 30.0, 100.0; phacoemulsification, median: 20.0, quartile range: 0.0, 100.0) exceeded that for Chinese residents (extra-capsular: median = 0, p < 0.0001; phacoemulsification: median = 0, p < 0.0001). Chinese trainees spent more time completing medical charts (>50 % of time on charts: 62.5 % versus 5.3 %, p < 0.0001) and received less supervision (>=90 % of training supervised: 4.4 % versus 65 %, p < 0.0001). Chinese residents were more likely to feel underpaid (96.0 % vs. 31.6 %, p < 0.0001) and hoped their children would not practice medicine (69.4 % vs. 5.0 %, p = 0.0001) compared HKSAR residents. CONCLUSIONS: In this study, ophthalmology residents in China report strikingly less surgical experience and supervision, and lower satisfaction than HKSAR residents. The HKSAR model of hands-on resident training might be useful in improving the low cataract surgical rate in China. PMID- 26415934 TI - QCT of the proximal femur--which parameters should be measured to discriminate hip fracture? AB - SUMMARY: For quantitative computed tomography (QCT), most relevant variables to discriminate hip fractures were determined. A multivariate analysis showed that trabecular bone mineral density (BMD) of the trochanter with "cortical" thickness of the neck provided better fracture discrimination than total hip integral BMD. A slice-by-slice analysis of the neck or the inclusion of strength-based parameters did not improve fracture discrimination. INTRODUCTION: For QCT of the proximal femur, a large variety of analysis parameters describing bone mineral density, geometry, or strength has been considered. However, in each given study, generally just a small subset was used. The aim of this study was to start with a comprehensive set and then select a best subset of QCT parameters for discrimination of subjects with and without acute osteoporotic hip fractures. METHODS: The analysis was performed using the population of the European Femur Fracture (EFFECT) study (Bousson et al. J Bone Min Res: Off J Am Soc Bone Min Res 26:881-893, 2011). Fifty-six female control subjects (age 73.2 +/- 9.3 years) were compared with 46 female patients (age 80.9 +/- 11.1 years) with acute hip fractures. The QCT analysis software MIAF-Femur was used to virtually dissect the proximal femur and analyze more than 1000 parameters, predominantly in the femoral neck. A multivariate best-subset analysis was used to extract the parameters best discriminating hip fractures. All results were adjusted for age, height, and weight differences between the two groups. RESULTS: For the discrimination of all proximal hip fractures as well as for cervical fractures alone, the measurement of neck parameters suffices (area under the curve (AUC) = 0.84). Parameters characterizing bone strength are discriminators of hip fractures; however, in multivariate models, only "cortical" cross-sectional area in the neck center remained as a significant contributor. The combination of one BMD parameter, trabecular BMD of the trochanter, and one geometry parameter, "cortical" thickness of the neck discriminated hip fracture with an AUC value of 0.83 which was significantly better than 0.77 for total femur BMD alone. A comprehensive slice-based analysis of the neck along its axis did not significantly improve hip fracture discrimination. CONCLUSIONS: If QCT of the hip is performed, the analysis should include neck and trochanter. In particular, for fractures of any type, a comprehensive slice-based analysis of the neck along its axis did not significantly improve hip fracture discrimination nor did the inclusion of strength-related parameters other than "cortical" area or thickness. One BMD and one geometry parameter, in this study, the combination of trabecular BMD of the trochanter and of "cortical" thickness of the neck resulted in significant hip fracture discrimination. PMID- 26415935 TI - A flow cytometric approach to study the mechanism of gene delivery to cells by gemini-lipid nanoparticles: an implication for cell membrane nanoporation. AB - BACKGROUND: Gemini-lipid nanoparticles have been received major attention recently as non-viral delivery systems due to their successful non-invasive gene delivery through tough barriers such as eye and skin. The aim of this study was to evaluate non-viral gene delivery by a series of dicationic gemini surfactant phospholipid nanoparticles (GL-NPs) and to explore their mechanism of interaction with cellular membranes of murine PAM212 epidermal keratinocytes. METHODS: NPs containing pCMV-tdTomato plasmid encoding red fluorescent protein (RFP) were prepared using 12 different gemini surfactants (m-s-m, with m = 12, 16 and 18C alkyl tail and s = 3 and 7C polymethylene spacer group and 7C substituted spacers with 7NH and 7NCH3) and dioleoylphosphatidylethanolamine helper lipid. RFP gene expression and cell viability status were evaluated using flow cytometry. MitoTracker Deep Red mitochondrial stain and the cell impermeable Sytox red nuclear stain were used as indicators of cell viability and cell membrane integrity, respectively. RESULTS: No significant viability loss was detected in cells transfected with 18-3-18, 18-7-18, 18-7NH-18, and 18-7NCH3-18 NPs, whereas a significant reduction of viability was detected in cells treated with 12-3-12, 12-7-12, 12-7NH-12, 16-7NH-16, or 16-7NCH3-16 GL-NPs. Compared to Lipofectamine Plus, 18-3-18 GL-NPs showed higher transfection efficiency and comparable viability profile by evaluation using MitoTracker Deep Red in PAM212 cells. Flow cytometric analysis of PAM212 cells stained with Sytox red revealed two cell populations with low and high fluorescent intensity, representing cells with partially-porated and highly-porated membranes, respectively. Additional combined staining with MitoTracker and ethidium homodimer showed that that 18-3-18 GL-NPs disturbed cell membrane integrity, while cells were still alive and had mitochondrial activity. CONCLUSION: Taken together, this study demonstrated that 18-3-18 GL-NPs have higher transfection efficiency and comparable viability profile to the commercial Lipofectamine Plus, and the interaction of 18-3-18 GL NPs with PAM212 cell membranes involves a permeability increase, possibly through the formation of nanoscale pores, which could explain efficient gene delivery. This novel nanoconstruct appears to be a promising delivery system for further skin gene therapy studies in vivo. PMID- 26415937 TI - MRI scanning increases eightfold in Canadian women with breast cancer. PMID- 26415938 TI - Editorial: Cell therapy and regenerative medicine. PMID- 26415936 TI - Adenosine A2A receptor plays an important role in radiation-induced dermal injury. AB - Ionizing radiation is a common therapeutic modality and following irradiation dermal changes, including fibrosis and atrophy, may lead to permanent changes. We have previously demonstrated that occupancy of A2A receptor (A2AR) stimulates collagen production, so we determined whether blockade or deletion of A2AR could prevent radiation-induced fibrosis. After targeted irradiation (40 Gy) of the skin of wild-type (WT) or A2AR knockout (A2ARKO) mice, the A2AR antagonist ZM241385 was applied daily for 28 d. In irradiated WT mice treated with the A2AR antagonist, there was a marked reduction in collagen content and skin thickness, and ZM241385 treatment reduced the number of myofibroblasts and angiogenesis. After irradiation, there is an increase in loosely packed collagen fibrils, which is significantly diminished by ZM241385. Irradiation also induced an increase in epidermal thickness, prevented by ZM241385, by increasing the number of proliferating keratinocytes. Similarly, in A2ARKO mice, the changes in collagen alignment, skin thickness, myofibroblast content, angiogenesis, and epidermal hyperplasia were markedly reduced following irradiation. Radiation-induced changes in the dermis and epidermis were accompanied by an infiltrate of T cells, which was prevented in both ZM241385-treated and A2ARKO mice. Radiation therapy is administered to a significant number of patients with cancer, and radiation reactions may limit this therapeutic modality. Our findings suggest that topical application of an A2AR antagonist prevents radiation dermatitis and may be useful in the prevention or amelioration of radiation changes in the skin. PMID- 26415939 TI - Prevalence and clinical correlates of Schistosoma mansoni co-infection among malaria infected patients, Northwest Ethiopia. AB - BACKGROUND: In Ethiopia, where malaria and schistosomiasis are co-endemic, co infections are expected to be high. However, data about the prevalence of malaria schistosomiasis co-infection and their clinical correlation is lacking. Therefore, the aim of this study was to assess prevalence of Schistosoma mansoni co-infection and associated clinical correlates in malaria patients. METHODS: A cross-sectional study was conducted in 2013 at Chwahit Health Center, in northwest Ethiopia. Blood film positive malaria patients (N = 205) were recruited for the study. Clinical, parasitological, hematological, and biochemical parameters were assessed from every study participant. Stool samples were also collected and processed with Kato-Katz technique to diagnose and classify intensity of Schistosoma mansoni. RESULTS: The prevalence of Schistosoma mansoni and malaria co-infection was 19.5%. The age group of 16-20 years old was significantly associated with co-infection. Co-infected patients with a moderate heavy egg burden of Schistosoma mansoni had significantly high mean Plasmodium parasitemia. On the other hand, age group of 6-10 years old and moderate-heavy Schistosoma mansoni co-infection were significantly associated with severe malaria. CONCLUSIONS: Prevalence of malaria and Schistosoma mansoni co-infection in the study area was considerably high. Severity of malaria and parasitemia of Plasmodium were associated with certain age groups and intensity of concurrent Schistosoma mansoni. Further study is needed to explore the underlying mechanisms of interaction between malaria and Schistosoma mansoni. PMID- 26415940 TI - Survival of the grouped, or three's a crowd? Repetition blindness in groups of letters and words. AB - When stimuli are presented rapidly, repetitions are often undetected--a phenomenon called "repetition blindness" (RB; Kanwisher Cognition, 27, 117-143, 1987). Grouping of nonlinguistic items has been found to prevent RB (Goldfarb & Treisman Psychonomic Bulletin & Review, 18, 1042-1049, 2011). In order to determine whether this effect could be found with letters and words, participants viewed rapid serial visual presentation and brief simultaneous visual presentation streams containing groups of linguistic stimuli and provided judgments of frequency. The collection of reaction times and an explicit question about strategy use allowed for analyses of the participants' processing strategies. Two groups of participants emerged: one that demonstrated RB for groups of stimuli, and another that demonstrated enhanced perception with stimulus grouping. These participant groups did not appear to differ on the basis of explicit processing strategies or reaction times. PMID- 26415941 TI - Teaching history taking to medical students: a systematic review. AB - BACKGROUND: This paper is an up-to-date systematic review on educational interventions addressing history taking. The authors noted that despite the plethora of specialized training programs designed to enhance students' interviewing skills there had not been a review of the literature to assess the quality of each published method of teaching history taking in undergraduate medical education based on the evidence of the program's efficacy. METHODS: The databases PubMed, PsycINFO, Google Scholar, opengrey, opendoar and SSRN were searched using key words related to medical education and history taking. Articles that described an educational intervention to improve medical students' history-taking skills were selected and reviewed. Included studies had to evaluate learning progress. Study quality was assessed using the Medical Education Research Study Quality Instrument (MERSQI). RESULTS: Seventy-eight full text articles were identified and reviewed; of these, 23 studies met the final inclusion criteria. Three studies applied an instructional approach using scripts, lectures, demonstrations and an online course. Seventeen studies applied a more experiential approach by implementing small group workshops including role play, interviews with patients and feedback. Three studies applied a creative approach. Two of these studies made use of improvisational theatre and one introduced a simulation using Lego(r) building blocks. Twenty-two studies reported an improvement in students' history taking skills. Mean MERSQI score was 10.4 (range 6.5 to 14; SD = 2.65). CONCLUSIONS: These findings suggest that several different educational interventions are effective in teaching history taking skills to medical students. Small group workshops including role-play and interviews with real patients, followed by feedback and discussion, are widespread and best investigated. Feedback using videotape review was also reported as particularly instructive. Students in the early preclinical state might profit from approaches helping them to focus on interview skills and not being distracted by thinking about differential diagnoses or clinical management. The heterogeneity of outcome data and the varied ways of assessment strongly suggest the need for further research as many studies did not meet basic methodological criteria. Randomized controlled trials using external assessment methods, standardized measurement tools and reporting long-term data are recommended to evaluate the efficacy of courses on history taking. PMID- 26415942 TI - Evidence for temporal population replacement and the signature of ecological adaptation in a major Neotropical malaria vector in Amazonian Peru. AB - BACKGROUND: The major Neotropical malaria vector, Anopheles darlingi, was reintroduced into the Iquitos, Loreto, Peru area during the early 1990s, where it displaced other anophelines and caused a major malaria epidemic. Since then, case numbers in Loreto have fluctuated, but annual increases have been reported since 2012. METHODS: The population genetic structure of An. darlingi sampled before and after the introduction of long-lasting insecticidal nets (LLINs) was investigated to test the hypothesis of temporal population change (2006 vs. 2012). Current samples of An. darlingi were used to test the hypothesis of ecological adaptation to human modified (highway) compared with wild (riverine) habitat, linked to forest cover. In total, 693 An. darlingi from nine localities in Loreto, Peru area were genotyped using 13 microsatellite loci. To test the hypothesis of habitat differentiation in An. darlingi biting time patterns, HBR and EIR, four collections of An. darlingi from five localities (two riverine and three highway) were analysed. RESULTS: Analyses of microsatellite loci from seven (2006) and nine settlements (2012-2014) in the Iquitos area detected two distinctive populations with little overlap, although it is unclear whether this population replacement event is associated with LLIN distribution or climate. Within the 2012-2014 population two admixed subpopulations, A and B, were differentiated by habitat, with B significantly overrepresented in highway, and both in near-equal proportions in riverine. Both subpopulations had a signature of expansion and there was moderate genetic differentiation between them. Habitat and forest cover level had significant effects on HBR, such that Plasmodium transmission risk, as measured by EIR, in peridomestic riverine settlements was threefold higher than in peridomestic highway settlements. HBR was directly associated with available host biomass rather than forest cover. CONCLUSIONS: A population replacement event occurred between 2006 and 2012-2014, concurrently with LLIN distribution and a moderate El Nino event, and prior to an increase in malaria incidence. The likely drivers of this replacement cannot be determined with current data. The present-day An. darlingi population is composed of two highly admixed subpopulations, which appear to be in an early stage of differentiation, triggered by anthropogenic alterations to local habitat. PMID- 26415943 TI - The minimally invasive approach is associated with reduced surgical site infections in obese patients undergoing proctectomy. AB - BACKGROUND: While laparoscopic colorectal resection may be underused in technically challenging circumstances, the minimally invasive approach may in fact maximally benefit patients at the greatest risk of complications. Obesity and proctectomy pose particular technical challenges during laparoscopic resection and are also associated with the greatest risks of complications, especially surgical site infections (SSIs). We evaluated the role of laparoscopy in minimizing SSI in such patients. METHODS: From the American College of Surgeons-National Surgical Quality Improvement Program database, outcomes for obese [body mass index (BMI) >= 30 kg/m(2)] and non-obese (BMI < 30 kg/m(2)) patients undergoing colectomy or proctectomy between 2006 and 2011 by the laparoscopic (laparoscopic colectomy, laparoscopic proctectomy) or open (open colectomy, open proctectomy) approaches were compared. A univariate analysis was used to determine the influence of laparoscopic surgery within each group on SSI, and a multivariate analysis evaluated the influence of laparoscopy on SSI for obese patients undergoing proctectomy. RESULTS: OC patients were more likely than OP, LC, and LP, respectively, to undergo emergency operation and have an American Society of Anesthesiologists (ASA) score of 3-5. Overall SSI rates after OC, OP, LC, and LP were 15.2, 17.6, 8.6, and 10.1 %, respectively (p < 0.001), and for obese patients, the rates were 18.7, 22.3, 10.7, and 13.3 % (p < 0.001). On univariate analysis, open surgery, obesity, proctectomy, younger age, race, steroid use, diabetes, chronic obstructive pulmonary disease, prior wound infection, transfusion history, previous operation within 30 days, coronary artery or vascular disease, ASA class 3-5, tobacco use, resident involvement, male gender, albumin <3.5 g/dL, and emergent operation were associated with a higher risk of SSI. Laparoscopy reduced the risk of SSI by at least 35 % across all BMI classes and procedures, an effect that persisted on multivariate analysis even in obese patients undergoing proctectomy. CONCLUSIONS: In colorectal surgery, an already high-risk outlier for SSI, obesity and proctectomy are associated with the highest risk of SSI. Despite the particular technical challenges of laparoscopy in these circumstances, the minimally invasive approach attenuates the risk of SSI in these high-risk patients and thus should be strongly considered during treatment planning. PMID- 26415944 TI - Strategy for the difficult-to-reach ileal pouch-anal anastomosis: technical steps of an in vivo application of a mesenteric-lengthening technique. PMID- 26415945 TI - The negative impact of spasticity on the health-related quality of life of stroke survivors: a longitudinal cohort study. AB - BACKGROUND: Spasticity often leads to symptomatic and functional problems that can cause disability for stroke survivors. We studied whether spasticity has a negative impact on health-related quality of life (HRQoL). METHODS: As part of the Greater Cincinnati/Northern Kentucky Stroke Study (NCT00642213), 460 ischemic stroke patients were interviewed during hospitalization and then followed over time. HRQoL was measured by the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores of the Short Form-12 (SF-12), EuroQol-5 dimension (EQ-5D), and Stroke-Specific Quality of Life (SSQOL) instruments, with lower scores indicating worse health. HRQoL differences between stroke survivors with and without spasticity were compared, adjusting for age, race, stroke severity, pre-stroke function, and comorbidities. RESULTS: Of the 460 ischemic stroke patients, 328 had spasticity data available 3 months after their stroke (mean age of 66 years, 49% were female, and 26% were black). Of these patients, 54 (16%) reported having spasticity. Three months following their stroke, patients who reported spasticity had lower mean scores on the PCS (29.6 +/- 1.4 vs 37.3 +/- 0.6; P < .001), EQ-5D (0.59 +/- 0.03 vs 0.71 +/- 0.01; P < .001), and SSQOL (3.57 +/- 0.08 versus 3.78 +/- 0.03; P = .03) compared with patients who did not report spasticity. Lower HRQoL scores were also observed at the 1-year (PCS, EQ-5D, and SSQOL) and 2-year (EQ-5D and SSQOL) interviews in those with spasticity compared with those without spasticity. CONCLUSIONS: Statistically and clinically meaningful differences in HRQoL exist between stroke survivors with and without spasticity. PMID- 26415946 TI - Implementation of safety checklists in surgery: a realist synthesis of evidence. AB - AIM: The aim of this review is to present a realist synthesis of the evidence of implementation interventions to improve adherence to the use of safety checklists in surgery. BACKGROUND: Surgical safety checklists have been shown to improve teamwork and patient safety in the operating room. Yet, despite the benefits associated with their use, universal implementation of and compliance with these checklists has been inconsistent. DATA SOURCES: An overview of the literature from 2008 is examined in relation to checklist implementation, compliance, and sustainability. REVIEW METHODS: Pawson's and Rycroft-Malone's realist synthesis methodology was used to explain the interaction between context, mechanism, and outcome. This approach incorporated the following: defining the scope of the review, searching and appraising the evidence, extracting and synthesising the findings, and disseminating, implementing, and evaluating the evidence. We identified two theories a priori that explained contextual nuances associated with implementation and evaluation of checklists in surgery: the Normalisation Process Theory and Responsive Regulation Theory. RESULTS: We identified four a priori propositions: (1) Checklist protocols that are prospectively tailored to the context are more likely to be used and sustained in practice, (2) Fidelity and sustainability is increased when checklist protocols can be seamlessly integrated into daily professional practice, (3) Routine embedding of checklist protocols in practice is influenced by factors that promote or inhibit clinicians' participation, and (4) Regulation reinforcement mechanisms that are more contextually responsive should lead to greater compliance in using checklist protocols. The final explanatory model suggests that the sustained use of surgical checklists is discipline-specific and is more likely to occur when medical staff are actively engaged and leading the process of implementation. Involving clinicians in tailoring the checklist to better fit their context of practice and giving them the opportunity to reflect and evaluate the implementation intervention enables greater participation and ownership of the process. CONCLUSIONS: A major limitation in the surgical checklist literature is the lack of robust descriptions of intervention methods and implementation strategies. Despite this, two consequential findings have emerged through this realist synthesis: First, the sustained use of surgical checklists is discipline specific and is more successful when physicians are actively engaged and leading implementation. Second, involving clinicians in tailoring the checklist to their context and encouraging them to reflect on and evaluate the implementation process enables greater participation and ownership. PMID- 26415948 TI - Erratum to: Early postoperative mortality after simultaneous or staged bilateral primary total hip arthroplasty: an observational register study from the Swedish Hip Arthroplasty Register. PMID- 26415947 TI - The PfAlba1 RNA-binding protein is an important regulator of translational timing in Plasmodium falciparum blood stages. AB - BACKGROUND: Transcriptome-wide ribosome occupancy studies have suggested that during the intra-erythrocytic lifecycle of Plasmodium falciparum, select mRNAs are post-transcriptionally regulated. A subset of these encodes parasite virulence factors required for invading host erythrocytes, and are currently being developed as vaccine candidates. However, the molecular mechanisms that govern post-transcriptional regulation are currently unknown. RESULTS: We explore the previously identified DNA/RNA-binding protein PfAlba1, which localizes to multiple foci in the cytoplasm of P. falciparum trophozoites. We establish that PfAlba1 is essential for asexual proliferation, and subsequently investigate parasites overexpressing epitope-tagged PfAlba1 to identify its RNA targets and effects on mRNA homeostasis and translational regulation. Using deep sequencing of affinity-purified PfAlba1-associated RNAs, we identify 1193 transcripts that directly bind to PfAlba1 in trophozoites. For 105 such transcripts, 43 % of which are uncharacterized and 13 % of which encode erythrocyte invasion components, the steady state levels significantly change at this stage, evidencing a role for PfAlba1 in maintaining mRNA homeostasis. Additionally, we discover that binding of PfAlba1 to four erythrocyte invasion mRNAs, Rap1, RhopH3, CDPK1, and AMA1, is linked to translation repression in trophozoites whereas release of these mRNAs from a PfAlba1 complex in mature stages correlates with protein synthesis. CONCLUSIONS: We show that PfAlba1 binds to a sub-population of asexual stage mRNAs and fine-tunes the timing of translation. This mode of post-transcriptional regulation may be especially important for P. falciparum erythrocyte invasion components that have to be assembled into apical secretory organelles in a highly time-dependent manner towards the end of the parasite's asexual lifecycle. PMID- 26415949 TI - Effects of Vascular Endothelial Growth Factor in Recovery Phase of Acute Lung Injury in Mice. AB - AIM: To test the hypothesis that exogenous administration of vascular endothelial growth factor (VEGF) promotes lung repair in acute lung injury (ALI). METHODS: ALI was induced by intranasal lipopolysaccharide (LPS) administration in mice, followed by different treatment protocols for 7 days in 3 groups (n = 6, each) including the LPS, the VEGF and the anti-VEGF group. At day 7, peripheral blood and lungs were collected. Lung wet-to-dry (W/D) ratio and lung injury score were measured. Immunohistochemistry assay was employed to detect the number of pulmonary vessels. Circulating endothelial progenitor cells (EPCs) was detected using flow cytometric analysis, and the apoptosis of lung cells was determined by TUNEL staining. RESULTS: VEGF treatment reduced W/D ratio and pulmonary neutrophil infiltration in the VEGF group compared with the LPS group. The treatment of VEGF increased the number of pulmonary vessels, and significantly increased the number of circulating EPC cells. Moreover, administration of VEGF decreased the percentage of apoptotic cells in the VEGF group. CONCLUSIONS: Our results suggest that VEGF may contribute to vascular endothelial repair and function as a protective factor against ALI. PMID- 26415950 TI - Sublethal imidacloprid effects on honey bee flower choices when foraging. AB - Neonicotinoids, systemic neuro-active pesticides similar to nicotine, are widely used in agriculture and are being investigated for a role in honey bee colony losses. We examined one neonicotinoid pesticide, imidacloprid, for its effects on the foraging behavior of free-flying honey bees (Apis mellifera anatoliaca) visiting artificial blue and white flowers. Imidacloprid doses, ranging from 1/5 to 1/50 of the reported LD50, were fed to bees orally. The study consisted of three experimental parts performed sequentially without interruption. In Part 1, both flower colors contained a 4 MUL 1 M sucrose solution reward. Part 2 offered bees 4 MUL of 1.5 M sucrose solution in blue flowers and a 4 MUL 0.5 M sucrose solution reward in white flowers. In Part 3 we reversed the sugar solution rewards, while keeping the flower color consistent. Each experiment began 30 min after administration of the pesticide. We recorded the percentage of experimental bees that returned to forage after treatment. We also recorded the visitation rate, number of flowers visited, and floral reward choices of the bees that foraged after treatment. The forager return rate declined linearly with increasing imidacloprid dose. The number of foraging trips by returning bees was also affected adversely. However, flower fidelity was not affected by imidacloprid dose. Foragers visited both blue and white flowers extensively in Part 1, and showed greater fidelity for the flower color offering the higher sugar solution reward in Parts 2 and 3. Although larger samples sizes are needed, our study suggests that imidacloprid may not affect the ability to select the higher nectar reward when rewards were reversed. We observed acute, mild effects on foraging by honey bees, so mild that storage of imidacloprid tainted-honey is very plausible and likely to be found in honey bee colonies. PMID- 26415951 TI - Label noise in subtype discrimination of class C G protein-coupled receptors: A systematic approach to the analysis of classification errors. AB - BACKGROUND: The characterization of proteins in families and subfamilies, at different levels, entails the definition and use of class labels. When the adscription of a protein to a family is uncertain, or even wrong, this becomes an instance of what has come to be known as a label noise problem. Label noise has a potentially negative effect on any quantitative analysis of proteins that depends on label information. This study investigates class C of G protein-coupled receptors, which are cell membrane proteins of relevance both to biology in general and pharmacology in particular. Their supervised classification into different known subtypes, based on primary sequence data, is hampered by label noise. The latter may stem from a combination of expert knowledge limitations and the lack of a clear correspondence between labels that mostly reflect GPCR functionality and the different representations of the protein primary sequences. RESULTS: In this study, we describe a systematic approach, using Support Vector Machine classifiers, to the analysis of G protein-coupled receptor misclassifications. As a proof of concept, this approach is used to assist the discovery of labeling quality problems in a curated, publicly accessible database of this type of proteins. We also investigate the extent to which physico chemical transformations of the protein sequences reflect G protein-coupled receptor subtype labeling. The candidate mislabeled cases detected with this approach are externally validated with phylogenetic trees and against further trusted sources such as the National Center for Biotechnology Information, Universal Protein Resource, European Bioinformatics Institute and Ensembl Genome Browser information repositories. CONCLUSIONS: In quantitative classification problems, class labels are often by default assumed to be correct. Label noise, though, is bound to be a pervasive problem in bioinformatics, where labels may be obtained indirectly through complex, many-step similarity modelling processes. In the case of G protein-coupled receptors, methods capable of singling out and characterizing those sequences with consistent misclassification behaviour are required to minimize this problem. A systematic, Support Vector Machine-based method has been proposed in this study for such purpose. The proposed method enables a filtering approach to the label noise problem and might become a support tool for database curators in proteomics. PMID- 26415952 TI - Is accurate and reliable blood loss estimation the 'crucial step' in early detection of postpartum haemorrhage: an integrative review of the literature. AB - BACKGROUND: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality in low-income countries and severe maternal morbidity in many high income countries. Poor outcomes following PPH are often attributed to delays in the recognition and treatment of PPH. Experts have suggested that improving the accuracy and reliability of blood loss estimation is the crucial step in preventing death and morbidity from PPH. However, there is little guidance on how this can be achieved. The aim of this integrative review was to evaluate the various methods of assessing maternal blood loss during childbirth. METHODS: A systematic, integrative review of published research studies was conducted. All types of studies were included if they developed, tested, or aimed to improve methods and skills in quantifying blood loss during childbirth, or explored experiences of those involved in the process. RESULTS: Thirty-six studies were included that evaluated the accuracy of visual estimation; tested methods to improve skills in measurement; examined their effect on PPH diagnosis and treatment, and / or explored additional factors associated with blood loss evaluation. The review found that health professionals were highly inaccurate at estimating blood loss as a volume. Training resulted in short term improvements in skills but these were not retained and did not improve clinical outcomes. Multi-faceted interventions changed some clinical practices but did not reduce the incidence of severe PPH or the timing of responses to excessive bleeding. Blood collection bags improved the accuracy of estimation but did not prevent delays or progression to severe PPH. Practitioners commonly used the nature and speed of blood flow, and the condition of the woman to indicate that the blood loss was abnormal. CONCLUSIONS: Early diagnosis of PPH should improve maternal outcomes, but there is little evidence that this can be achieved through improving the accuracy of blood loss volume measurements. The diagnosis may rely on factors other than volume, such as speed of blood flow and nature of loss. A change in direction of future research is required to explore these in more detail. PMID- 26415953 TI - Antidepressants normalize elevated Toll-like receptor profile in major depressive disorder. AB - RATIONALE: Abnormalities in Toll-like receptor (TLR) expression in depression have been inferred in part from observed increases in TLR4 levels in peripheral blood mononuclear cells (PBMCs) and postmortem brains of depressed and suicidal patients. Our previous study found differences in the TLR expression in PBMCs between healthy controls and patients with major depressive disorder. Normalization of increased TLR4 in PBMCs by cognitive behavior psychotherapy has been reported. However, the effects of antidepressants remain unknown. OBJECTIVES: Changes in TLR1-9 expression levels of PBMCs were examined in 56 patients with MDD. The 17-item Hamilton Depression Rating Scale (HAMD-17) and mRNA expression levels of TLRs were assessed in parallel with a housekeeping gene using qRT-PCR before and after treatment with antidepressants. RESULTS: TLR3, TLR4, TLR5, TLR7, TLR8, and TLR9 were expressed at elevated levels in patients with MDD and were significantly decreased by treatment with antidepressants for 4 weeks. Antidepressant treatment completely normalized TLR3, TLR5, TLR7, TLR8, and TLR9 levels, whereas TLR1, TLR2, TLR4, and TLR6 were decreased to below normal levels. A subgroup analysis found that only TLR3 was significantly higher at baseline in the nonremission group. In addition, a multiple linear regression analysis revealed that only low TLR3 before treatment predicted improvement in HAMD-17 scores. CONCLUSIONS: These findings suggest that antidepressant treatment exerts anti-inflammatory effects in patients with MDD and identify TLR profiles as a predictor of response to antidepressant therapy. Further studies investigating the effects of manipulating individual TLRs on depression are needed to fully elucidate the underlying mechanism. PMID- 26415956 TI - Participant-Direction in a Culturally Diverse, Rural Population: The Hawaii Community Living Program. AB - The Hawaii Community Living Program was a participant-direction pilot project aimed at rural, multicultural, and community-dwelling older adults at risk of institutionalization. This evaluation examined participant outcomes, and explored the role of culture, health literacy, and rural settings in participant-direction programs. The program enrolled 91 participants and, of these enrollees, helped 84 (92.3%) participants avoid institutionalization and spend down to Medicaid. Findings indicated that Program Coaches needed to be culturally appropriate and creative in arranging for services and the delivery of goods and supplies. Results suggested that participants need to be health literate to direct their care, but further research is needed. PMID- 26415954 TI - The continuous performance test (rCPT) for mice: a novel operant touchscreen test of attentional function. AB - RATIONALE: Continuous performance tests (CPTs) are widely used to assess attentional processes in a variety of disorders including Alzheimer's disease and schizophrenia. Common human CPTs require discrimination of sequentially presented, visually patterned 'target' and 'non-target' stimuli at a single location. OBJECTIVES: The aims of this study were to evaluate the performance of three popular mouse strains on a novel rodent touchscreen test (rCPT) designed to be analogous to common human CPT variants and to investigate the effects of donepezil, a cholinesterase inhibitor and putative cognitive enhancer. METHODS: C57BL/6J, DBA/2J and CD1 mice (n = 15-16/strain) were trained to baseline performance using four rCPT training stages. Then, probe tests assessed the effects of parameter changes on task performance: stimulus size, duration, contrast, probability, inter-trial interval or inclusion of flanker distractors. rCPT performance was also evaluated following acute administration of donepezil (0-3 mg/kg, i.p.). RESULTS: C57BL/6J and DBA/2J mice showed similar acquisition rates and final baseline performance following rCPT training. On probe tests, rCPT performance of both strains was sensitive to alteration of visual and/or attentional demands (stimulus size, duration, contrast, rate, flanker distraction). Relative to C57BL/6J, DBA/2J mice exhibited (1) decreasing sensitivity (d') across the 45-min session, (2) reduced performance on probes where the appearance of stimuli or adjacent areas were changed (size, contrast, flanking distractors) and (3) larger dose- and stimulus duration-dependent changes in performance following donepezil administration. In contrast, CD1 mice failed to acquire rCPT (stage 3) and pairwise visual discrimination tasks. CONCLUSIONS: rCPT is a potentially useful translational tool for assessing attention in mice and for detecting the effects of nootropic drugs. PMID- 26415955 TI - Spontaneous poisoning by Hovenia dulcis in dairy cattle in Southwest Parana, Brazil. AB - Livestock poisoning by plants is a frequent occurrence which determines severe losses, such as the fall in the milk and meat production, the cost of expensive treatments, the state of immunosuppression, or even the animal's death. Cattle ingest toxic plants only when there is food shortage, when they cannot select what they eat, or when they ingest food for preference, which is the case of Hovenia dulcis fruits, very rich in sucrose. This plant is widely distributed in the southern and southeastern Brazilian regions. In literature, there are some cases of severe human liver injury associated with a long-term of H. dulcis leaf and fruit tea intake, and only one report regarding spontaneous poisoning of goats caused by this plant ingestion. However, its toxic effects associated with spontaneous ingestion by cattle have never been reported. This paper reports the first case of spontaneous poisoning in cattle by H. dulcis, which occurred in a dairy farm in southwest Parana, Brazil. Three cattle individuals showed anorexia, ruminal atony, severe diarrhea and neurological tournament, head pressing, blindness, ataxia, and circling. The necropsy of the animals was done, and the remaining alterations were restricted to the digestive system and brain. The clinical signs presented by the animals are characteristic of polioencephalomalacia (PEM), caused by changes in the thiamine metabolism. Furthermore, clinical signs, gross, and microscopic lesions as well as the large amount of the plant throughout the digestive segment led to a diagnosis. PMID- 26415957 TI - Cross-cultural perspectives on the patient-provider relationship: a qualitative study exploring reflections from Ghanaian medical students following a clinical rotation in the United States. AB - BACKGROUND: In international health experiences, learners are exposed to different culturally-based patient care models. Little is known about student perceptions of patient-provider interactions when they travel from low-to high resource settings. The purpose of this study was to explore these reflections among a subset of Ghanaian medical students who participated in clinical rotations at the University of Michigan Medical School (UMMS). METHODS: In-depth, semi-structured interviews lasting 60-90 min were conducted with 15 individuals who had participated in 3-to 4-week clinical rotations at UMMS between January 2008 and December 2011. Interviews were conducted from March to August 2012 and transcribed verbatim, then independently coded by three investigators. Investigators compared open codes and reached a consensus regarding major themes. RESULTS: Participating Ghanaian medical students reported that their perspectives of the patient-provider relationship were significantly affected by participation in a UMMS rotation. Major thematic areas included: (1) observations of patient care during the UMMS rotation, including patient comfort and privacy, physician behavior toward patients, and patient behavior; (2) reflections on the role of humanism and respect within patient care; (3) barriers to respectful care; and (4) transformation of student behaviors and attitudes. Students also reported integrating more patient-centered care into their own medical practice upon return to Ghana DISCUSSION: Participation in a US-based clinical rotation has the potential to introduce medical students from resource-limited settings to a different paradigm of patient-provider interactions, which may impact their future behavior and perspectives regarding patient care in their home countries. CONCLUSIONS: Students from under-resourced settings can derive tremendous value from participation in clinical electives in more affluent settings, namely through exposure to a different type of medical care. PMID- 26415958 TI - An organizational analysis of road traffic crash prevention to explain the difficulties of a national program in a low income country. AB - BACKGROUND: Road traffic crashes (RTC), that daily kill 3400 people and leave 15,000 with a permanent disability could be prevented through the implementation of safety programs developed in partnership with governments and institutions. The relationship between key stakeholders can be a crucial determinant to the effectiveness of road safety programs. This issue has rarely been addressed. We conducted a detailed organizational analysis of the stakeholders involved in road safety programs in Lao People's Democratic Republic (Lao PDR). METHODS: A case study was performed. The framework used was a snowball effect in which the characterization of all key stakeholders and the links between them, as well as the factors that led to these links, were determined. The effect of the relations between key stakeholders on the prevention of RTC was assessed through an analysis of the transactional, intangible and controlling factors that influence these relationships. RESULTS: The design and implementation of road safety programs in Lao PDR suffer from weak relationships between stakeholders and a poorly functional bicephal leadership between the Ministry of Public Works and Transport and the non-governmental organisation called Handicap International. This poor coordination between key stakeholders is evident, particularly in the area of collective action and is reinforced by a lack of interest from several different stakeholders. Most agencies do not prioritize road safety. Uneven distribution of funding is another contributing factor. Strengthening the leadership is crucial to the success of the program. Some organisations have skills, power the decision making and the allocation of resources in regards to road safety programs. Encouraging participation of these organizations through a more prominent position would thus result in a better collaboration. Non-monetary rewards would further help to strengthen collaborative work. CONCLUSION: The bicephal nature of the leadership of road safety programs proves detrimental, is associated with a weak coalition between stakeholders, and contributes to the declaimed poor effectiveness of the existing programs. The study has identified non-monetary and realistic means of strengthening the collaboration between key stakeholders. Stakeholders need to revise their interpretive schemes, in order to actively support the reinforcement of government leadership of road safety policies. PMID- 26415959 TI - Associations between urbanicity and malaria at local scales in Uganda. AB - BACKGROUND: Sub-Saharan Africa is expected to show the greatest rates of urbanization over the next 50 years. Urbanization has shown a substantial impact in reducing malaria transmission due to multiple factors, including unfavourable habitats for Anopheles mosquitoes, generally healthier human populations, better access to healthcare, and higher housing standards. Statistical relationships have been explored at global and local scales, but generally only examining the effects of urbanization on single malaria metrics. In this study, associations between multiple measures of urbanization and a variety of malaria metrics were estimated at local scales. METHODS: Cohorts of children and adults from 100 households across each of three contrasting sub-counties of Uganda (Walukuba, Nagongera and Kihihi) were followed for 24 months. Measures of urbanicity included density of surrounding households, vegetation index, satellite-derived night-time lights, land cover, and a composite urbanicity score. Malaria metrics included the household density of mosquitoes (number of female Anopheles mosquitoes captured), parasite prevalence and malaria incidence. Associations between measures of urbanicity and malaria metrics were made using negative binomial and logistic regression models. RESULTS: One site (Walukuba) had significantly higher urbanicity measures compared to the two rural sites. In Walukuba, all individual measures of higher urbanicity were significantly associated with a lower household density of mosquitoes. The higher composite urbanicity score in Walukuba was also associated with a lower household density of mosquitoes (incidence rate ratio = 0.28, 95 % CI 0.17-0.48, p < 0.001) and a lower parasite prevalence (odds ratio, OR = 0.44, CI 0.20-0.97, p = 0.04). In one rural site (Kihihi), only a higher density of surrounding households was associated with a lower parasite prevalence (OR = 0.15, CI 0.07-0.34, p < 0.001). And, in only one rural site (Nagongera) was living where NDVI <=0.45 associated with higher incidence of malaria (IRR = 1.35, CI 1.35-1.70, p = 0.01). CONCLUSIONS: Urbanicity has been shown previously to lead to a reduction in malaria transmission at large spatial scales. At finer scales, individual household measures of higher urbanicity were associated with lower mosquito densities and parasite prevalence only in the site that was generally characterized as being urban. The approaches outlined here can help better characterize urbanicity at the household level and improve targeting of control interventions. PMID- 26415960 TI - Tonsillectomy reduces recurrence of IgA nephropathy in mesangial hypercellularity type categorized by the Oxford classification. AB - BACKGROUND: In patients with IgA nephropathy (IgAN), recurrence after steroid pulse therapy is associated with reduced renal survival. However, the predictors of recurrence have not yet been clarified. METHODS: All patients who received 6 month steroid pulse therapy from 2004 to 2010 in our four affiliated hospitals and achieved a reduction of proteinuria to <0.4 g/day 1 year after treatment were retrospectively evaluated. The primary outcome was proteinuria >=1.0 g/day during follow-up or additional antiproteinuric therapy. Two histological classifications were evaluated, the Oxford Classification with a split system and Japanese histological grades (HGs) with a lumped system. RESULTS: During a median follow up of 3.4 years, 27 (26.7 %) of the 101 patients showed recurrence. Multivariate analysis showed that HG was the only significant predictor of recurrence, with HG 2+3+4 vs HG 1 having a hazard ratio of 7.38 (95 % confidence interval 1.52-133). Furthermore, in patients with mesangial hypercellularity according to the Oxford Classification, cumulative rate of recurrence-free survival was greater in patients with steroid therapy plus tonsillectomy compared with those who received steroid therapy alone (Log-rank test, P = 0.022). However, this association was not observed in patients without mesangial hypercellularity. CONCLUSIONS: HG is a novel predictor of recurrence after steroid pulse therapy in patients with IgAN. Moreover, the combination of steroid pulse therapy plus tonsillectomy may indicate a lower risk of recurrence in patients with mesangial hypercellularity, as defined by the Oxford Classification. PMID- 26415961 TI - Using realist review to inform intervention development: methodological illustration and conceptual platform for collaborative care in offender mental health. AB - BACKGROUND: This paper reports how we used a realist review, as part of a wider project to improve collaborative mental health care for prisoners with common mental health problems, to develop a conceptual platform. The importance of offenders gaining support for their mental health, and the need for practitioners across the health service, the criminal justice system, and the third sector to work together to achieve this is recognised internationally. However, the literature does not provide coherent analyses of how these ambitions can be achieved. This paper demonstrates how a realist review can be applied to inform complex intervention development that spans different locations, organisations, professions, and care sectors. METHODS: We applied and developed a realist review for the purposes of intervention development, using a three-stage process. (1) An iterative database search strategy (extending beyond criminal justice and offender health) and groups of academics, practitioners, and people with lived experience were used to identify explanatory accounts (n = 347). (2) From these accounts, we developed consolidated explanatory accounts (n = 75). (3) The identified interactions between practitioners and offenders (within their organisational, social, and cultural contexts) were specified in a conceptual platform. We also specify, step by step, how these explanatory accounts were documented, consolidated, and built into a conceptual platform. This addresses an important methodological gap for social scientists and intervention developers about how to develop and articulate programme and implementation theory underpinning complex interventions. RESULTS: An integrated person-centred system is proposed to improve collaborative mental health care for offenders with common mental health problems (near to and after release) by achieving consistency between the goals of different sectors and practitioners, enabling practitioners to apply scientific and experiential knowledge in working judiciously and reflectively, and building systems and aligning resources that are centred on offenders' health and social care needs. CONCLUSIONS: As part of a broader programme of work, a realist review can make an important contribution to the specification of theoretically informed interventions that have the potential to improve health outcomes. Our conceptual platform has potential application in related systems of health and social care where integrated, and person-centred care is a goal. PMID- 26415962 TI - Let it be? Pain control attempts critically amplify attention to somatosensory input. AB - Recent studies have suggested that the threat of pain may redirect attention towards specific features of the pain stimulus via attentional control settings. For instance, it has been shown that anticipating pain results in attentional prioritization of the location where pain is expected. In contemporary theories on attention and pain, it has been argued that pain control motivation-e.g., attempting to avoid pain-is capable of enhancing these effects. The present study investigated if the threat of pain prioritizes attention towards somatosensory input over other sensory information, and if pursuing a pain control goal augments this effect. In a Temporal Order Judgment experiment, 41 participants were presented with visuo-tactile stimulus pairs and asked to judge which stimulus they had perceived first. Half of all trials were associated with the threat of acute pain, while the other half was not. Furthermore, half of our sample was encouraged to avoid the administration of pain by means of a specified behavioral response, whereas the other half was not. In line with our hypotheses, we found the threat of pain to prioritize attention towards the somatosensory modality, i.e., participants tended to perceive the tactile stimulus as occurring earlier in time than the visual stimulus. Interestingly, in-depth analyses suggested that this effect was predominantly carried by participants who were engaged in pain control efforts. These findings support the idea that pain goals exert top-down attentional control prioritizing pain-relevant sensory information. Clinical relevance and future directions are discussed. PMID- 26415963 TI - Cell culture on hydrophilicity-controlled silicon nitride surfaces. AB - Cell culture on silicon nitride membranes is required for atmospheric scanning electron microscopy, electron beam excitation assisted optical microscopy, and various biological sensors. Cell adhesion to silicon nitride membranes is typically weak, and cell proliferation is limited. We increased the adhesion force and proliferation of cultured HeLa cells by controlling the surface hydrophilicity of silicon nitride membranes. We covalently coupled carboxyl groups on silicon nitride membranes, and measured the contact angles of water droplets on the surfaces to evaluate the hydrophilicity. We cultured HeLa cells on the coated membranes and evaluated stretch of the cell. Cell migration and confluence were observed on the coated silicon nitride films. We also demonstrated preliminary observation result with direct electron beam excitation assisted optical microscope. PMID- 26415964 TI - Assessment of heavy metal pollution in Cordoba (Spain) by biomonitoring foraging honeybee. AB - Due to features that make them outstanding environmental bioindicator, colonies of Apis mellifera are being used to study environmental pollution. The primary objective of this research was to use honeybee colonies to identify heavy metals and determine their utility for environmental management. Five stations each with two A. mellifera hives were strategically located in urban, industrial, agricultural and forested areas within the municipality of Cordoba (Spain), and foraging bees were collected from April to December in 2007, 2009 and 2010 to analyse spatial and temporal variation in Pb, Cr, Ni and Cd pollution. Metal concentrations, in milligram per kilogram of honeybee, were determined by inductively coupled plasma-atomic emission spectrometry and graphite furnace atomic absorption spectrophotometry. Significant differences in concentrations were found among the various locations and periods. The highest number of values exceeding the upper reference thresholds proposed for this study (Pb, 0.7 mg/kg; Cr, 0.12 mg/kg; Ni, 0.3 mg/kg; and Cd, 0.1 mg/kg) was observed for Pb and Cr (6.25% respectively), station S4 (13.22%), year 2007 (20.83%) and in months of May and July (11.90% each). Regarding the Cd, which was analysed only in 2010, the highest number of values exceeding the upper reference thresholds was 40%. Biomonitoring with colonies of A. mellifera could contribute to improved surveillance and control systems for atmospheric pollution by integrating qualitative and quantitative assessments, thus facilitating prevention and readiness in the event of environmental crises. PMID- 26415965 TI - methylPipe and compEpiTools: a suite of R packages for the integrative analysis of epigenomics data. AB - BACKGROUND: Numerous methods are available to profile several epigenetic marks, providing data with different genome coverage and resolution. Large epigenomic datasets are then generated, and often combined with other high-throughput data, including RNA-seq, ChIP-seq for transcription factors (TFs) binding and DNase-seq experiments. Despite the numerous computational tools covering specific steps in the analysis of large-scale epigenomics data, comprehensive software solutions for their integrative analysis are still missing. Multiple tools must be identified and combined to jointly analyze histone marks, TFs binding and other omics data together with DNA methylation data, complicating the analysis of these data and their integration with publicly available datasets. RESULTS: To overcome the burden of integrating various data types with multiple tools, we developed two companion R/Bioconductor packages. The former, methylPipe, is tailored to the analysis of high- or low-resolution DNA methylomes in several species, accommodating (hydroxy-)methyl-cytosines in both CpG and non-CpG sequence context. The analysis of multiple whole-genome bisulfite sequencing experiments is supported, while maintaining the ability of integrating targeted genomic data. The latter, compEpiTools, seamlessly incorporates the results obtained with methylPipe and supports their integration with other epigenomics data. It provides a number of methods to score these data in regions of interest, leading to the identification of enhancers, lncRNAs, and RNAPII stalling/elongation dynamics. Moreover, it allows a fast and comprehensive annotation of the resulting genomic regions, and the association of the corresponding genes with non-redundant GeneOntology terms. Finally, the package includes a flexible method based on heatmaps for the integration of various data types, combining annotation tracks with continuous or categorical data tracks. CONCLUSIONS: methylPipe and compEpiTools provide a comprehensive Bioconductor-compliant solution for the integrative analysis of heterogeneous epigenomics data. These packages are instrumental in providing biologists with minimal R skills a complete toolkit facilitating the analysis of their own data, or in accelerating the analyses performed by more experienced bioinformaticians. PMID- 26415966 TI - Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults. AB - BACKGROUND: There is emerging evidence that glutamatergic system dysfunction might play an important role in the pathophysiology of bipolar depression. This review focuses on the use of glutamate receptor modulators for depression in bipolar disorder. OBJECTIVES: 1. To assess the effects of ketamine and other glutamate receptor modulators in alleviating the acute symptoms of depression in people with bipolar disorder.2. To review the acceptability of ketamine and other glutamate receptor modulators in people with bipolar disorder who are experiencing acute depression symptoms. SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR, to 9 January 2015). This register includes relevant randomised controlled trials (RCTs) from: the Cochrane Library (all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). We cross-checked reference lists of relevant papers and systematic reviews. We did not apply any restrictions to date, language or publication status. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing ketamine, memantine, or other glutamate receptor modulators with other active psychotropic drugs or saline placebo in adults with bipolar depression. DATA COLLECTION AND ANALYSIS: At least two review authors independently selected studies for inclusion, assessed trial quality and extracted data. Primary outcomes for this review were response rate and adverse events. Secondary outcomes included remission rate, depression severity change scores, suicidality, cognition, quality of life, and dropout rate. We contacted study authors for additional information. MAIN RESULTS: Five studies (329 participants) were included in this review. All included studies were placebo controlled and two-armed, and the glutamate receptor modulators - ketamine (two trials), memantine (two trials), and cytidine (one trial) - were used as add-on drugs to mood stabilisers. The treatment period ranged from a single intravenous administration (all ketamine studies), to repeated administration for memantine and cytidine (8 to 12 weeks, and 12 weeks, respectively). Three of the studies took place in the USA, one in Taiwan, and in one, the location was unclear. The majority (70.5%) of participants were from Taiwan. All participants had a primary diagnosis of bipolar disorder, according to the DSM-IV or DSM-IV-TR, and were in a current depressive phase. The severity of depression was at least moderate in all but one study.Among all glutamate receptor modulators included in this review, only ketamine appeared to be more efficacious than placebo 24 hours after the infusion for the primary outcome, response rate (odds ratio (OR) 11.61, 95% confidence interval (CI) 1.25 to 107.74; P = 0.03; I2 = 0%, 2 studies, 33 participants). This evidence was rated as low quality. The statistically significant difference disappeared at three days, but the mean estimate still favoured ketamine (OR 8.24, 95% CI 0.84 to 80.61; 2 studies, 33 participants; very low quality evidence). We found no difference in response between ketamine and placebo at one week (OR 4.00, 95% CI 0.33 to 48.66; P = 0.28, 1 study; 18 participants; very low quality evidence).There was no significant difference between memantine and placebo in response rate one week after treatment (OR 1.08, 95% CI 0.06 to 19.05; P = 0.96, 1 study, 29 participants), two weeks (OR 4.88, 95% CI 0.78 to 30.29; P = 0.09, 1 study, 29 participants), four weeks (OR 5.33, 95% CI 1.02 to 27.76; P = 0.05, 1 study, 29 participants), or at three months (OR, 1.66, 95% CI 0.69 to 4.03; P = 0.26, I2 = 36%, 2 studies, 261 participants). These findings were based on very low quality evidence.There was no significant difference between cytidine and placebo in response rate at three months (OR, 1.13, 95% CI 0.30 to 4.24; P = 0.86, 1 study, 35 participants; very low quality evidence).For the secondary outcome of remission, no significant differences were found between ketamine and placebo, nor between memantine and placebo. For the secondary outcome of change scores from baseline on depression scales, ketamine was more effective than placebo at 24 hours (MD -11.81, 95% CI -20.01 to -3.61; P = 0.005, 2 studies, 32 participants) but not at one or two weeks after treatment. There was no difference between memantine and placebo for this outcome.We found no significant differences in terms of adverse events between placebo and ketamine, memantine, or cytidine. There were no differences between ketamine and placebo, memantine and placebo, or cytidine and placebo in total dropouts. No data were available on dropouts due to adverse effects for ketamine or cytidine; but no difference was found between memantine and placebo. AUTHORS' CONCLUSIONS: Reliable conclusions from this review are severely limited by the small amount of data usable for analysis. The body of evidence about glutamate receptor modulators in bipolar disorder is even smaller than that which is available for unipolar depression. Overall, we found limited evidence in favour of a single intravenous dose of ketamine (as add-on therapy to mood stabilisers) over placebo in terms of response rate up to 24 hours; ketamine did not show any better efficacy in terms of remission in bipolar depression. Even though ketamine has the potential to have a rapid and transient antidepressant effect, the efficacy of a single intravenous dose may be limited. Ketamine's psychotomimetic effects could compromise study blinding; this is a particular issue for this review as no included study used an active comparator, and so we cannot rule out the potential bias introduced by inadequate blinding procedures.We did not find conclusive evidence on adverse events with ketamine. To draw more robust conclusions, further RCTs (with adequate blinding) are needed to explore different modes of administration of ketamine and to study different methods of sustaining antidepressant response, such as repeated administrations. There was not enough evidence to draw meaningful conclusions for the remaining two glutamate receptor modulators (memantine and cytidine). This review is limited not only by completeness of evidence, but also by the low to very low quality of the available evidence. PMID- 26415967 TI - Beyond the Audiology Clinic: Innovations and Possibilities of Connected Health. PMID- 26415969 TI - Innovations and Possibilities in Connected Health. AB - BACKGROUND: Health care is being fundamentally changed by telemedicine. Telemedicine uses communication technologies in prevention, disease management, home health care, long-term (chronic) care, emergency medicine, and many other applications including audiology. Telemedicine is being adopted and integrated into the health care enterprise at an exponential rate and it is often difficult to keep up with all of these changes. Other key drivers such as the Affordable Care Act and other federal health care initiatives are pushing the adoption of telemedicine and catalyzing a flood of interest in telemedicine, telehealth, and m-Health. PURPOSE: This paper provides an overview of telehealth models and will describe methodologies as they pertain to clinical practice. The goal is to provide the principles behind the practice of telemedicine and how they can be applied to teleaudiology programs. There is a very large body of evidence supporting the benefits and utility of telehealth in terms of technology, economic value, and impact on patients. However, there are still barriers to acceptance, so we must address these challenges and involve all relevant stakeholders if telehealth is to become an integral part of the health care system. Clinical guidelines for telemedicine developed by experts who are practicing it on a daily basis is one way to help overcome these barriers, so attention will be devoted to a discussion of current guidelines. CONCLUSIONS: Telemedicine is not a unique clinical specialty, but rather uses telecommunication technologies to reach out to patients to reduce barriers to care in underserved areas, improve patient care and accessibility to specialists, decrease professional isolation in rural areas, help medical practitioners expand their practice reach, and save patients from having to travel or be transported to receive high quality care. PMID- 26415968 TI - A Store-and-Forward Tele-Audiology Solution to Promote Efficient Screenings for Ototoxicity during Cisplatin Cancer Treatment. AB - BACKGROUND: Tele-audiology improves access, controls cost, and improves efficiency of many aspects within health care. We have developed and validated a device, the ototoxicity identification device (OtoID), which enables remote hearing monitoring by a patient during chemotherapy treatment. Aspects of the design such as patient self-testing and texting of results to the audiology clinic are important features of this device. PURPOSE: The purpose of this article is to present the efficacy and effectiveness of the OtoID hearing screener. RESEARCH DESIGN: A repeated measures design was used in this study. STUDY SAMPLE: Twenty-one veterans undergoing cisplatin chemotherapy were recruited in this study. DATA COLLECTION AND ANALYSIS: Participants were tested using the OtoID at each cisplatin treatment by an audiologist using the manual mode of test and the participant using the automated mode of test. Test sensitivity and specificity were developed from the detection (yes/no) of an American Speech-Language-Hearing Association (ASHA) change in hearing. RESULTS: The OtoID had a test sensitivity of 80.6% and specificity of 85.3%. A logistic regression model analysis of the probability of an ASHA shift identified by the automated OtoID was conducted. Separate models were fit to establish effects of age, average baseline thresholds in the sensitive range for ototoxicity (SRO), and dose of cisplatin on the probability of a positive hearing change result. Interactions were also included to evaluate these effects on the sensitivity and false-positive rates of the automated test. Results indicated no statistically significant effects of age, of baseline hearing in the SRO frequencies, or of cisplatin dose. CONCLUSIONS: The OtoID automated test can be recommended for use. The automated test provides significant personnel efficiencies. The modem with simple text messaging function recently added to the device improves on these efficiencies. PMID- 26415971 TI - Ubiquitous Real-World Sensing and Audiology-Based Health Informatics. AB - BACKGROUND: Hearing impairment and hearing rehabilitation strategies have historically been studied within the confines of a sound booth under controlled experimental conditions. The real world is quite different from the clinical setting and it is important to study how a person with hearing impairment interacts with the world both with and without a hearing assist intervention. A person's ability to hear enables them to communicate and to effectively interact with the world. If a person suffers from hearing impairment, we might anticipate that they could become more disengaged from the world, more socially isolated, potentially depressed, and have additional comorbidities such as cognitive and physical impairment. Indeed, prior research has shown that hearing impairment is associated with social isolation, decreased functional ability and mobility, fall risk, diabetes, and cognitive impairment. However, nearly all of the work that has been done in this area of assessing the impact of hearing impairment on a person's social, cognitive, and physical health has been done through clinical tests or self-report studies using questionnaires and surveys that attempt to objectively quantify various aspects of health. Unfortunately, clinical tests, questionnaires, and surveys oftentimes inaccurately assess a person's true social, cognitive, and physical health. Only when a person is observed in their natural living environment can a more accurate assessment of health be obtained. The ability to assess hearing health, social engagement, cognitive, and physical health in natural living environments is becoming possible with the advent of ubiquitous sensing capabilities. PURPOSE: Here we discuss some of the work that has been done by our group and others that may be of use to the field of audiology e-health. The purpose of this article is not to present new experimental data, but rather to describe a new method of using advanced in-home sensing techniques to better understand how hearing diagnostics, interventions, and rehabilitation influence the lives and behaviors of patients. PMID- 26415970 TI - Connected Audiological Rehabilitation: 21st Century Innovations. AB - BACKGROUND: Tele-audiology provides a means to offer audiologic rehabilitation (AR) in a cost-, resource-, and time-effective manner. If designed appropriately, it also has the capability of personalizing rehabilitation to the user in terms of content, depth of detail, etc., thus permitting selection of the best content for a particular individual. Synchronous/real-time data collection, store and forward telehealth, remote monitoring and mobile health using smartphone applications have each been applied to components of audiologic rehabilitation intervention (sensory management, instruction in the use of technology and control of the listening environment, perceptual and communication strategies training, and counseling). In this article, the current state of tele audiological rehabilitation interventions are described and discussed. RESULTS: The provision of AR via tele-audiology potentially provides a cost-effective mechanism for addressing barriers to the routine provision of AR beyond provisions of hearing technology. Furthermore, if designed appropriately, it has the capability of personalizing rehabilitation to the user in terms of content, depth of detail, etc., thus permitting selection of the best content for a particular individual. However, effective widespread implementation of tele audiology will be dependent on good education of patients and clinician alike, and researchers must continue to examine the effectiveness of these new approaches to AR in order to ensure clinicians provide effective evidence-based rehabilitation to their patients. CONCLUSIONS: While several barriers to the widespread use of tele-audiology for audiologic rehabilitation currently exist, it is concluded that through education of patients and clinicians alike, it will gain greater support from practitioners and patients over time and will become successfully and widely implemented. PMID- 26415972 TI - The Acoustic Test Environment for Hearing Testing. AB - BACKGROUND: Audiology clinics traditionally employ expensive, prefabricated sound rooms to create an environment that is sufficiently quiet for accurate hearing tests. There is seldom any analysis of the need for or benefit from such enclosures. There may be less expensive methods that would decrease the cost of and increase access to hearing testing. PURPOSE: This report provides information concerning the need for and effectiveness of sound rooms and an analysis of the audiometric test ranges for various earphone/room combinations. RESEARCH DESIGN: Acoustic measurements made in four rooms were analyzed with the attenuation provided by various earphone designs to determine the maximum permissible ambient noise levels and the corresponding audiometric test ranges. STUDY SAMPLE: The measurements and calculations were performed with four test rooms and five earphone designs. DATA COLLECTION AND ANALYSIS: Ambient noise levels and earphone attenuation characteristics were used to calculate the noise levels that reach the ear. Those were compared to the maximum permissible ambient noise levels that are provided in ANSI S3.1-1999 or calculated from measured attenuation levels. These measurements were used to calculate testable ranges for each room/earphone combination. RESULTS: The various room/earphone combinations resulted in minimum test levels that ranged from -10 to 20 dB HL at various test frequencies. CONCLUSIONS: When the actual benefits of expensive prefabricated sound rooms are assessed based on the range of hearing levels that can be tested, the effectiveness of that approach becomes highly questionable. Less expensive methods based on planning the clinic space, use of inexpensive sound treatments, and selecting an appropriate earphone can be effective in almost any space that would be used for hearing testing. PMID- 26415973 TI - Tele-audiology: Expanding Access to Hearing Care and Enhancing Patient Connectivity. AB - BACKGROUND: Tele-audiology within the Department of Veterans Affairs has expanded significantly in response to growing Veteran hearing needs and issues, namely maldistribution of provider resources and continued lags in timely access to care. Although tele-audiology originated from successive telemedicine programs dating back to the early 1960s, the innovation that is currently being developed broadens tele-audiology and hearing care practice to virtual care modalities such as clinical video telehealth, store-and-forward telehealth, home telehealth, mobile health applications, secure messaging, and electronic consults. PURPOSE: The purpose of this article is to address current and emerging tele-audiology initiatives in context of a connected health care practice model. It includes information on initiatives within the Department of Veterans Affairs, provides an overview of current and potential modalities for improving patient hearing care, and identifies the challenges that exist in implementing and sustaining these services. Information is intended to stimulate creative thinking about future innovative service delivery models. CONCLUSION: Significant challenges exist in the evolution of innovative tele-audiology services. Despite barriers, these initiatives have the potential to match existing capacity with emerging patient demands in a mutually beneficial partnership and can be successfully integrated into diverse health care and private sector organizations. PMID- 26415976 TI - Interplay between histone H1 structure and function. AB - H1 linker histones are involved both in the maintenance of higher-order chromatin structure and in gene regulation. Histone H1 exists in multiple isoforms, is evolutionarily variable and undergoes a large variety of post-translational modifications. We review recent progress in the understanding of the folding and structure of histone H1 domains with an emphasis on the interactions with DNA. The importance of intrinsic disorder and hydrophobic interactions in the folding and function of the carboxy-terminal domain (CTD) is discussed. The induction of a molten globule-state in the CTD by macromolecular crowding is also considered. The effects of phosphorylation by cyclin-dependent kinases on the structure of the CTD, as well as on chromatin condensation and oligomerization, are described. We also address the extranuclear functions of histone H1, including the interaction with the beta-amyloid peptide. PMID- 26415975 TI - Alzheimer's Disease Risk and Progression: The Role of Nutritional Supplements and their Effect on Drug Therapy Outcome. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly population. Despite significant advancements in understanding the genetic and molecular basis of AD, the pathology still lacks treatments that can slow down or reverse the progression of cognitive deterioration. Recently, the relationship between nutrient deficiency and dementia onset has been highlighted. AD is in fact a multifactorial pathology, so that a multi-target approach using combinations of micronutrients and drugs could have beneficial effects on cognitive function in neurodegenerative brain disorders leading to synaptic degeneration. Primarily, this review examines the most recent literature regarding the effects of nutrition on the risk/progression of the disease, focusing attention mostly on antioxidants agents, polyunsaturated fatty acids and metals. Secondly, it aims to figure out if nutritional supplements might have beneficial effects on drug therapy outcome. Even if nutritional supplements showed contrasting evidence of a likely effect of decreasing the risk of AD onset that could be studied more deeply in other clinical trials, no convincing data are present about their usefulness in combination with drug therapies and their effectiveness in slowing down the disease progression. PMID- 26415977 TI - My gut feeling says rest: Increased intestinal permeability contributes to chronic diseases in high-intensity exercisers. AB - Chronic diseases are the leading cause of death and disability worldwide, and many of these conditions are linked to chronic inflammation. One potential cause of chronic inflammation is an increased intestinal epithelial permeability. Recent studies have demonstrated that parasympathetic stimulation via the efferent abdominal vagus nerve increases the expression and proper localization of tight junction proteins and decreases intestinal epithelial permeability. This finding may provide a novel approach for treating and preventing many chronic conditions. Importantly, physical activity is associated with increased resting parasympathetic (vagal) activity and lower risk of chronic diseases. However, high intensity long duration exercise can be harmful to overall health. Specifically, individuals who frequently exercise strenuously and for longer time intervals have the same mortality rates as sedentary individuals. This may be explained, in part, by longer periods of reduced vagal activity as vagal activity is markedly reduced both during and after intense exercise. We hypothesize that one mechanism by which exercise provides its health benefits is by increasing resting vagal activity and decreasing intestinal epithelial permeability, thus decreasing chronic inflammation. Additionally, we hypothesize that long periods of reduced vagal activity in individuals who exercise at high intensities and for longer durations, decrease the integrity of the intestinal barrier, putting them at greater risk of chronic inflammation and a host of chronic diseases. Thus, this hypothesis provides a conceptual link between the well-established benefits of frequent exercise and the paradoxical deleterious effects of prolonged, high intensity exercise without adequate rest. PMID- 26415978 TI - Nitrates are safe in patients with glaucoma. PMID- 26415979 TI - beta-elemene inhibits monocyte-endothelial cells interactions via reactive oxygen species/MAPK/NF-kappaB signaling pathway in vitro. AB - The recruitment of monocytes to the active endothelial cells is an early step in the formation of atherosclerotic lesions; therefore, the inhibition of monocyte endothelial cells interactions may serve as a potential therapeutic strategy for atherosclerosis. Recent studies suggest that beta-elemene can protect against atherosclerosis in vivo and vitro; however, the mechanism underlying the anti atherosclerotic effect by beta-elemene is not clear yet. In this study, we aimed to investigate the effects of beta-elemene on the monocyte-endothelial cells interactions in the initiation of atherosclerosis in vitro. Our results showed that beta-elemene protects human umbilical vein endothelial cells (HUVECs) from hydrogen peroxide-induced endothelial cells injury in vitro. Besides, this molecule inhibits monocyte adhesion and transendothelial migration across inflamed endothelium through the suppression of the nuclear factor-kappa B dependent expression of cell adhesion molecules. Further, beta-elemene decreases generation of reactive oxygen species (ROS) and prevents the activation of mitogen-activated protein kinase (MAPK) signaling pathway in HUVECs. In conclusion, this study would provide a new pharmacological evidence of the significance of beta-elemene as a future drug for prevention and treatment of atherosclerosis. PMID- 26415980 TI - Inhibitory effect of fluvoxamine on beta-casein expression via a serotonin independent mechanism in human mammary epithelial cells. AB - Selective serotonin reuptake inhibitors (SSRIs) are widely used as a first-line therapy in postpartum depression. The objective of this study was to determine the mechanism underlying the inhibitory effects of the SSRI, fluvoxamine, on beta casein expression, an indicator of lactation, in MCF-12A human mammary epithelial cells. Expression levels of serotonin (5-hydroxytryptamine; 5-HT) transporter, an SSRI target protein, and tryptophan hydroxylase 1, a rate-limiting enzyme in 5-HT biosynthesis, were increased in MCF-12A cells by prolactin treatment. Treatment with 1 MUM fluvoxamine for 72 h significantly decreased protein levels of beta casein and phosphorylated signal transducer and activator transcription 5 (pSTAT5). Extracellular 5-HT levels were significantly increased after exposure to 1 MUM fluvoxamine, in comparison with those of untreated and vehicle-treated cells; however, extracellular 5-HT had little effect on the decrease in beta casein expression. Expression of glucose-related protein 78/binding immunoglobulin protein, a regulator of endoplasmic reticulum (ER) stress, was significantly increased after treatment with 1 MUM fluvoxamine for 48 h. Exposure to tunicamycin, an inducer of ER stress, also decreased expression of beta-casein and pSTAT5 in a manner similar to fluvoxamine. Our results indicate that fluvoxamine suppresses beta-casein expression in MCF-12A cells via inhibition of STAT5 phosphorylation caused by induction of ER stress. Further studies are required to confirm the effect of fluvoxamine on the function of mammary epithelial cells. PMID- 26415981 TI - Endogenous oestrogens do not regulate endothelial nitric oxide production in early postnatal rats. AB - Previously we showed that endothelium of 1-2-weeks old rats exerts an anticontractile effect due to spontaneous NO production which correlates with a higher eNOS expression level compared to adult rats. Oestrogens are powerful regulators of eNOS expression and activity in arterial endothelium. This study tested the hypothesis that anticontractile influence of endothelium in young rats is regulated by endogenous oestrogens. Wistar rats were daily treated with ICI 182,780 or letrozole (oestrogen receptor antagonist and aromatase inhibitor, respectively; s.c., 1mg/kg/day) from the second postnatal day, control pups received vehicle injections. At the age of 10-12-days we studied contraction of saphenous arteries using wire myography. ELISA and qPCR were used to evaluate blood sex steroids levels and mRNA expression in arterial tissue, respectively. Ten-12 days old male rats compared to adult male rats demonstrated 78% higher serum 17beta-oestradiol concentration and several-fold increase in mRNA contents of oestrogen receptors (ERalpha and GPER1). However, treatments with ICI 182,780 or letrozole did not affect arterial sensitivity to methoxamine (alpha1 adrenoceptor agonist) in 10-12-days old males. The blockade of NO-synthase with L NNA caused tonic contraction and potentiated the response to methoxamine, these effects were similar in control and both treated groups. The sensitivity of endothelium-denuded saphenous arteries to NO-donor DEA/NO did not differ between control and treated groups as well. In addition, treatments with ICI 182,780 or letrozole did not change eNOS expression level in arterial tissue. Our results suggest that endogenous oestrogens do not regulate anticontractile effect of NO during early postnatal development in rats. PMID- 26415982 TI - The adenosine A2A receptor antagonist, istradefylline enhances anti-parkinsonian activity induced by combined treatment with low doses of L-DOPA and dopamine agonists in MPTP-treated common marmosets. AB - The adenosine A2A receptor antagonist, istradefylline improves motor function in patients with advanced Parkinson's disease (PD) optimally treated with a combination of L-DOPA and a dopamine agonist without increasing the risk of troublesome dyskinesia. However, the effects of istradefylline on motor function when administered in combination with low dose of L-DOPA and dopamine agonists as occurs in early PD are unknown. We investigated whether istradefylline enhances the combined anti-parkinsonian effects of a suboptimal dose of L-DOPA and a threshold dose of either the non-ergot dopamine agonist, ropinirole or the ergot dopamine agonist, pergolide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset. Threshold doses of ropinirole (0.025-0.075 mg/kg p.o.) and pergolide (0.01 mg/kg p.o.) produced a weak anti-parkinsonian effect. Co-administration of a suboptimal dose of L-DOPA (2.5mg/kg p.o.) with threshold doses of the dopamine agonists enhanced their anti-parkinsonian effect that led to increased 'ON' time without dyskinesia appearing. Administering istradefylline (10mg/kg p.o.) with the threshold doses of dopamine agonists and the suboptimal dose of L-DOPA in a triple combination caused a further enhancement of the anti parkinsonian response but dyskinesia was still absent. In early PD, dopamine agonists are often used as first-line monotherapy, but efficacy is usually lost within a few years, at which time L-DOPA is added but with the risk of dyskinesia appearance. These results show that istradefylline is effective in improving motor function in combination with low dose dopaminergic drug treatment without provoking dyskinesia. PMID- 26415983 TI - Regulation of PGE2 signaling pathways and TNF-alpha signaling pathways on the function of bone marrow-derived dendritic cells and the effects of CP-25. AB - This study was to investigate PGE2 and TNF-alpha signaling pathway involving in the maturation and activation of bone marrow dendritic cells (DCs) and the effect of CP-25. Bone marrow DCs were isolated and stimulated by PGE2 and TNF-alpha respectively. The markers of maturation and activation expressed on DCs, such as CD40, CD80, CD83, CD86, MHC-II, and the ability of antigen uptake of DCs were analyzed by flow cytometry. The proliferation of T cells co-cultured with DCs, the signaling pathways of PGE2-EP4-cAMP and TNF-alpha-TRADD-TRAF2-NF-kappaB in DCs were analyzed. The results showed that both PGE2 and TNF-alpha up-regulated the expressions of CD40, CD80, CD83, CD86, and MHC-II, decreased the antigen uptake of DCs, and DCs stimulated by PGE2 or TNF-alpha could increase T cell proliferation. CP-25 (10(-5), 10(-6), and 10(-7)mol/l) decreased significantly the expressions of CD40, CD80, CD83, CD86 and MHC-II, increased the antigen uptake of DCs, and suppressed T cell proliferation induced by DCs. PGE2 increased the expressions of EP4, NF-kappaB and down-regulated cAMP level of DCs. TNF-alpha could also up-regulate TNFR1, TRADD, TRAF2, and NF-kappaB expression of DCs. CP 25 (10(-5), 10(-6), and 10(-7)mol/l) decreased the expressions of EP4 and NF kappaB, increased cAMP level in DCs stimulated by PGE2. CP-25 (10(-5), 10(-6), and 10(-7)mol/l) also could down-regulate significantly TNFR1, TRADD, TRAF2, and NF-kappaB expression in DCs stimulated by TNF-alpha. These results demonstrate that PGE2 and TNF-alpha could enhance DCs functions by mediating PGE2-EP4-cAMP pathway, TNF-alpha-TNFR1-TRADD-TRAF2-NF-kappaB pathway respectively. CP-25 might inhibit the function of DCs through regulating PGE2-EP4-cAMP and TNF-alpha-TNFR1 TRADD-TRAF2-NF-kappaB pathways. PMID- 26415984 TI - Pd2Au36(SR)24 cluster: structure studies. AB - The location of the Pd atoms in Pd2Au36(SC2H4Ph)24, is studied both experimentally and theoretically. X-ray photoelectron spectroscopy (XPS) indicates oxidized Pd atoms. Palladium K-edge extended X-ray absorption fine structure (EXAFS) data clearly show Pd-S bonds, which is supported by far infrared spectroscopy and by comparing theoretical EXAFS spectra in R space and circular dichroism spectra of the staple, surface and core doped structures with experimental spectra. PMID- 26415986 TI - Effect of co-administration of probiotics with polysaccharide based colon targeted delivery systems to optimize site specific drug release. AB - Significant clinical success of colon targeted dosage forms has been limited by their inappropriate release profile at the target site. Their failure to release the drug completely in the colon may be attributed to changes in the colonic milieu because of pathological state, drug effect and psychological stress accompanying the diseased state or, a combination of these. Alteration in normal colonic pH and bacterial picture leads to incomplete release of drug from the designed delivery system. We report the effectiveness of a targeted delivery system wherein the constant replenishment of the colonic microbiota is achieved by concomitant administration of probiotics along with the polysaccharide based drug delivery system. Guar gum coated spheroids of sulfasalazine were prepared. In the dissolution studies, these spheroids showed markedly higher release in the simulated colonic fluid. In vivo experiments conducted in rats clearly demonstrated the therapeutic advantage of co-administration of probiotics with guar gum coated spheroids. Our results suggest that concomitant use of probiotics along with the polysaccharide based delivery systems can be a simple strategy to achieve satisfactory colon targeting of drugs. PMID- 26415985 TI - Coordinating activation strategy for C(sp(3))-H/C(sp(3))-H cross-coupling to access beta-aromatic alpha-amino acids. AB - The past decade has witnessed significant advances in C-H bond functionalizations with the discovery of new mechanisms. Non-precious transition-metal-catalysed radical oxidative coupling for C(sp(3))-H bond transformations is an appealing strategy for C-C bond formations. The radical oxidative C(sp(3))-H/C(sp(3))-H cross-coupling reactions of alpha-C(sp(3))-H bonds of amines with free radicals represent a conceptual and practical challenge. We herein develop the coordinating activation strategy to illustrate the nickel-catalysed radical oxidative cross-coupling between C(sp(3))-H bonds and (hetero)arylmethyl free radicals. The protocol can tolerate a rich variety of alpha-amino acids and (hetero)arylmethanes as well as arylmethylenes and arylmethines, affording a large library of alpha-tertiary and alpha-quaternary beta-aromatic alpha-amino acids. This process also features low-cost metal catalyst, readily handled and easily removable coordinating group, synthetic simplicity and gram-scale production, which would enable the potential for economical production at commercial scale in the future. PMID- 26415987 TI - Mucus permeating nano-carrier systems. PMID- 26415988 TI - Heart rate response to a caudal block in children anesthetized with sevoflurane after ultrasound confirmation of placement. AB - INTRODUCTION: Previous studies identified decreasing heart rate (HR) as a predictor of successful caudal placement in children using halothane and isoflurane. No changes were found in HR in the one study using sevoflurane. We documented HR changes in children following a caudal block during sevoflurane anesthesia utilizing ultrasound to confirm successful caudal placement. METHODS: Seventy-one children (1-82 months) were anesthetized with sevoflurane. A caudal block was placed with confirmation by ultrasound. Four aliquots of bupivacaine 0.2% with epinephrine 5 MUg . cc(-1) were administered for a total volume of 1 cc . kg(-1) with HR recorded for 4 min. The outcomes measured were HR changes from the initial baseline and during each 1-min interval. The age-related differences in HR were also analyzed. RESULTS: Heart rate change from the initial baseline after placing the caudal needle and allowing for equilibration ranged from -10.2% to +8.9% and the HR change from the baseline at the start of each aliquot injection ranged from -9.5% to +8.9%. Most participants (n = 60, 84.5%) experienced at least one HR reduction over the observation period. For patients < 36 months, the HR change ranged from -11 to +12 b . min(-1) (mean -0.3); for patients aged >= 36 months, the HR change ranged from -10 to +6 b . min(-1) (mean -1.1). CONCLUSIONS: Heart rate changes following a caudal block in children <= 82 months of age anesthetized with sevoflurane is not a reliable indicator of a successful block. Despite 100% caudal success, many children had no decrease in HR, and in those that did, the decline was of a magnitude indeterminate from beat to-beat variability. PMID- 26415990 TI - Salvage computed tomography-guided transhepatic radiofrequency ablation for unresected aldosteronoma of adrenohepatic fusion after adrenalectomy. AB - Adrenalectomy is a treatment of choice for functioning adrenocortical adenoma. We experienced a case of unresected aldosteronoma after right adrenalectomy. Computed tomography-guided transhepatic radiofrequency ablation was carried out to treat the unresected functioning adenoma. The purpose of our case report was to show the clinical findings, computed tomography imaging features and computed tomography-guided transhepatic ablation techniques for adrenocortical adenoma arising from adrenohepatic fusion. PMID- 26415989 TI - Radiofrequency ablation under 3D intraoperative Iso-C C-arm navigation for the treatment of osteoid osteomas. AB - OBJECTIVE: To evaluate the efficacy of intraoperative three-dimensional (3D) Iso C C-arm-navigated percutaneous radiofrequency ablation (RFA) of osteoid osteomas. METHODS: 35 patients (20 males and 15 females) with osteoid osteomas underwent treatment with intraoperative 3D Iso-C C-arm navigation-guided RFA. The tumour was first biopsied for pathological examination, the core needle was removed and the RFA needle was inserted into the nidus. Post-operative X-rays and CT scans were performed to evaluate the degree of ablation and to assess for recurrence at 3-month follow-up. Patients also completed a visual analogue scale (VAS) both pre operatively and 3 days post-operatively to subjectively assess pain. RESULTS: Pathological diagnosis confirmed osteoid osteoma in 19 cases. The other 16 cases were not pathologically diagnosed owing to inadequate biopsy specimens. In all cases, localized pain was immediately relieved following RFA. Patients reported significantly decreased pain, with mean pre-operative VAS scores of 3.4 reducing to 0.80 at 3 days post-operatively and further to 0.06 at 3-month follow-up (p < 0.05). The mean follow-up time was 15.5 months (range: 3-38 months). CONCLUSION: 3D Iso-C C-arm navigation-guided RFA is a safe and effective option for the treatment of osteoid osteomas and may be considered in place of intraoperative CT guided and open resection. ADVANCES IN KNOWLEDGE: C-arm image-guided percutaneous RFA mitigates the need for pre-operative CT as well as intraoperative scintigraphy, provides real-time imaging of the anatomy, facilitates accurate resection of the tumour and enables immediate confirmation of excision. PMID- 26415991 TI - The dynamic pattern of recurrence in curatively resected non-small cell lung cancer patients: Experiences at a single institution. AB - PURPOSE: To investigate the hazard function of tumor recurrence in patients with completely (R0) resected non-small cell lung cancer. METHODS: A total of 1374 patients treated between 2003 and 2009 with complete resection and systematic lymph node dissection were studied. The risk of recurrence at a given time after operation was studied utilizing the cause-specific hazard function. Recurrence was categorized as local recurrence or distant recurrence. The risk distribution was assessed using clinical and pathological factors. RESULTS: The hazard function for recurrence presented an early peak at approximately 10 months after surgery and maintained a tapered plateau-like tail extending up to 8 years. A similar risk pattern was detected for both local recurrence and distant recurrence, while the risk of distant recurrence was higher than that of local recurrence. The double-peaked pattern of hazard rate was present in several subgroups, such as p-stage IA patients. A comparison of histology and status of nodal involvement showed that pN1-2 adenocarcinoma patients demonstrated a high hazard rate of distant recurrence and that pN0 adenocarcinoma patients exhibited a small recurrent risk for a longer time. Squamous cell carcinoma patients showed only little difference in risk. CONCLUSIONS: The data may be useful to select patients at high risk of recurrence and may provide information for each patient to decide how to manage the postoperative follow-up individually. PMID- 26415992 TI - Anti-angiogenic-specific adverse events in patients with non-small cell lung cancer treated with nintedanib and docetaxel. AB - OBJECTIVES: LUME-Lung 1 was a randomized, placebo-controlled, Phase III trial investigating nintedanib+docetaxel versus placebo+docetaxel in patients with advanced NSCLC progressing after first-line chemotherapy. Progression-free survival was significantly improved with nintedanib+docetaxel in the overall population and overall survival was significantly improved in the pre-specified analysis of patients with adenocarcinoma. We evaluated the frequency of characteristic adverse events (AEs) commonly seen with existing anti-angiogenic agents. MATERIALS AND METHODS: The incidence and intensity of AEs were evaluated in all patients who received at least one dose of study medication (N=1307) and for the two main histologies: adenocarcinoma (n=653) and squamous cell carcinoma (SCC; n=553). AEs of special interest were analyzed by category, preferred term, and worst CTCAE grade and included perforation, hypertension, bleeding, thromboembolic events, and skin disorders. RESULTS AND CONCLUSION: The incidence of patients with all-grade gastrointestinal (GI) perforations was low and balanced between arms (0.5% in both) and across histologies; the incidence of non GI perforations was 1.2% with nintedanib+docetaxel versus 0.2% with placebo+docetaxel. The incidence of some events was higher with nintedanib+docetaxel versus placebo+docetaxel; hypertension (3.5% vs 0.9%), rash (11.0% vs 8.1%), and cutaneous adverse reactions (13.0% vs 10.7%). Rash and cutaneous adverse reactions were predominantly Grade 1-2 with both treatments. The incidence of all-grade bleeding was also slightly higher in nintedanib+docetaxel-treated patients (14.1% vs 11.6%) driven by between treatment differences in the SCC subpopulation; most events were Grade 1-2. The proportion of patients with a thromboembolic event was low and comparable between arms for all grades (5.1% vs 4.6%) and Grade >=3 (2.1% vs 3.1%). Safety evaluation of the LUME-Lung 1 study showed that the frequency of AEs commonly associated with other anti-angiogenic agents was lower with nintedanib+docetaxel. Survival benefits from addition of nintedanib to docetaxel in patients with adenocarcinoma after first-line therapy can be achieved alongside a manageable safety profile. PMID- 26415994 TI - Role of circulating-tumor DNA analysis in non-small cell lung cancer. AB - The discovery of actionable driver mutations such as epidermal growth factor receptor (EGFR) and microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) and their highly responses to EGFR and ALK tyrosine kinase inhibitors (TKIs) in patients with advanced non-small-cell lung cancer (NSCLC) allowed precise medicine into reality. However, a substantial part of patients still have no sufficient tissue to perform genomic analysis. As a promising noninvasive biomarker and potential surrogate for the entire tumor genome, circulating tumor DNA (ctDNA) has been applied to the detection of driver gene mutations and epigenetic alteration and monitoring of tumor burden, acquired resistance, tumor heterogeneity and early diagnosis. Since precise therapy is a strategy that optimal therapy is decided based on simultaneous tumor genome information, ctDNA, as a liquid biopsy, may help to perform dynamic genetic surveillance. In this paper we will perspectively discuss the biology and identification of ctDNA in the blood of NSCLC patients and its clinical applications in patient management. PMID- 26415993 TI - Comparison of clinical outcome after first-line platinum-based chemotherapy in different types of KRAS mutated advanced non-small-cell lung cancer. AB - OBJECTIVES: As suggested by in-vitro data, we hypothesize that subtypes of KRAS mutated non-small cell lung cancer (NSCLC) respond differently to chemotherapy regimens. METHODS: Patients with advanced NSCLC and known KRAS mutation, treated with first-line platinum-based chemotherapy, were retrieved from hospital databases. PRIMARY OBJECTIVE: to investigate overall response rate (ORR), progression free survival (PFS) and overall survival (OS) between different types of platinum-based chemotherapy per type of KRAS mutation. RESULTS: 464 patients from 17 hospitals, treated between 2000 and 2013, were included. The majority of patients had stage IV disease (93%), had a history of smoking (98%) and known with an adenocarcinoma (91%). Most common types of KRAS mutation were G12C (46%), G12V (20%) and G12D (10%). Platinum was combined with pemetrexed (n=334), taxanes (n=68) or gemcitabine (n=62). Patients treated with taxanes had a significant improved ORR (50%) compared to pemetrexed (21%) or gemcitabine (25%; p<0.01). Patients treated with bevacizumab in addition to taxanes (n=38) had the highest ORR (62%). The PFS was significantly improved in patients treated with taxanes compared to pemetrexed (HR=0.72, p=0.02), but not OS (HR=0.87, p=0.41). In patients with G12V, significantly improved ORR (p<0.01) was observed for taxanes, but not PFS or OS. Patients with G12C or G12D mutation had comparable ORR, PFS and OS in all treatment groups. CONCLUSION: KRAS mutated NSCLC patients treated with taxane-based chemotherapy had best ORR. Response to chemotherapy regimens was different in types of KRAS mutation. Especially patients with G12V had better response to taxane treatment. PMID- 26415995 TI - Analysis of serum protein levels of angiogenic factors and their soluble receptors as markers of response to cediranib in the NCIC CTG BR.24 clinical trial. AB - OBJECTIVES: Prognostic and predictive ability of circulating vascular endothelial growth factor (VEGF), stromal derived factor (SDF)-1alpha and soluble VEGF receptors (sVEGFR) 2 and 3, were evaluated in non-small cell lung cancer (NSCLC) patients enrolled in NCIC Clinical Trials Group BR. 24 comparing chemotherapy with or without cediranib. MATERIALS AND METHODS: Biomarker levels were assessed by ELISA in serum from 149/296 enrolled patients at baseline and 146/149 patients after one treatment cycle. Experimental cut-offs for baseline measures determined using a graphic method were: VEGF-A: < or >=1 ng/ml, SDF-1alpha: <= or >3.5 ng/ml, sVEGFR2: < or >=11 ng/ml and sVEGFR3: < or >=35.5 ng/ml. Changes in markers from baseline to on-treatment were predefined as increased >=10%, stable within 10% or decreased >=10%. Cox regression models were used to correlate biomarkers with patient characteristics and outcomes including progression-free survival (PFS) and overall survival (OS). RESULTS: No baseline biomarker was prognostic for OS, however, high baseline sVEGFR2 was prognostic for better PFS (p=0.0008) in the chemotherapy alone arm. Low baseline sVEGFR2 or sVEGFR3 were predictive of PFS benefit from cediranib (interaction p=0.06 and p=0.05, respectively). While on treatment, VEGF-A increases were associated with better PFS (p=0.02) and OS (p=0.01) for cediranib treated patients. Decreases in sVEGFR2 (p=0.01) or sVEGFR3 (p=0.02) were also predictive of better OS in cediranib treated patients. CONCLUSIONS: Low baseline sVEGFR2 and sVEGFR3 were predictive for PFS benefit from cediranib, whereas increases in VEGF-A and decreases in sVEGFR2 or sVEGFR3 levels from baseline to on-treatment were predictive of an OS benefit from cediranib in chemotherapy treated NSCLC patients. Validation of these results is warranted. PMID- 26415996 TI - The impact of respiratory gated positron emission tomography on clinical staging and management of patients with lung cancer. AB - OBJECTIVES: Respiratory motion artefacts during positron emission tomography (PET) deteriorate image quality, potentially introducing diagnostic uncertainties. The objective of this study was to determine the impact of optimal respiratory gating on clinical staging and management of patients with primary lung cancer. MATERIALS AND METHODS: From our fast-track outpatient diagnostic program, 55 patients with primary lung cancer, who underwent whole body [(18)F] fluorodeoxyglucose (FDG) PET, were included. Respiratory gating was performed on bed positions covering the thorax and abdomen. Independent reading was conducted by two nuclear medicine physicians. The observers scored the number and anatomical location of the lesions, lymph node basins and the presence of distant metastasis in non-gated and gated images. A tumor (T), lymph node (N), and metastasis (M) stage was assigned to each patient according to the 7th revision of the TNM classification. Staging accuracy was determined using histopathological data and follow-up CT imaging. In addition, a management plan was created for each patient based on non-gated and gated images by an experienced pulmonologist. RESULTS: For nuclear medicine physician 1 and 2, respiratory gating resulted in detection of more lesions in five and eight patients (9% and 15%) respectively. However, this did not result in any migration in T or M-stage. Migration in N-stage was observed in four and seven patients (7% and 13%) for nuclear medicine physician 1 and 2 respectively. Staging accuracy was slightly improved when respiratory gating was performed. Furthermore, there was substantial agreement in patient management between non-gated and gated images. CONCLUSIONS: Respiratory gating improved staging accuracy, mainly in assessment of lymph node involvement. However, the effect on patient management was limited due to the presence of already advanced disease stage in many patients. These findings suggest that the expected impact of respiratory gating will be solely on management of patients with early disease. PMID- 26415997 TI - Neural networks of tinnitus in humans: Elucidating severity and habituation. AB - The article reviews current data about the neural correlates of an individual's reaction to tinnitus, primarily from studies that employ magnetic resonance imaging (MRI). Human studies employing brain imaging remain the most commonly used method to understand neural biomarkers of the reaction to tinnitus, a subjective hearing disorder. Evidence from anatomical and functional MRI studies is reviewed to better understand the large-scale neural networks implicated in tinnitus habituation and severity. These networks are concerned with attention, audition, and emotion, both during tasks and at 'rest' when no goal-directed activity is expected. I place the data in the context of published literature and current theories about tinnitus severity, while explaining the challenges and limitations of human MRI studies. A possible model of habituation to tinnitus is described, that of the attention system (via the frontal cortex) suppressing the response from the amygdala and the use of alternate nodes of the limbic system such as the insula and the parahippocampal gyrus when mediating emotion. PMID- 26415999 TI - Dynamics of task-set carry-over: evidence from eye-movement analyses. AB - Trial-to-trial carry-over of task sets (i.e., task-set inertia) is often considered as a primary reason for task-switch costs. Yet, we know little about the dynamics of such carry-over effects, in particular how much they are driven by the most recent trial rather than characterized by a more continuous memory gradient. Using eye-tracking, we examined in a 3-task, switching paradigm whether there is a greater probability of non-target fixations to stimuli associated with the previously relevant attentional set than to those associated with the less recent set. Indeed, we found strong evidence for more interference (expressed in terms of non-target fixations) from recent than from less-recent tasks and that in particular the interference from pre-switch trials contributed substantially to the overall pattern of response-time switch costs. Moreover, task-set carry over was dominated by the most-recent trial when subjects could expect task repetitions (with a 33 % switch rate). In comparison, when tasks were selected randomly (with a 66 % switch rate), interference from the most recent trial decreased, whereas interference from less-recent trials increased. In sum, carry over interference dynamics were characterized both by a gradual recency gradient and expectations about task-transition probabilities. Beyond that, there was little evidence for a unique role of the most-recent trial. PMID- 26415998 TI - Psychometric properties of the Tinnitus Functional Index (TFI): Assessment in a UK research volunteer population. AB - OBJECTIVES: Questionnaires are essential for measuring tinnitus severity and intervention-related change but there is no standard instrument used routinely in research settings. Most tinnitus questionnaires are optimised for measuring severity but not change. However, the Tinnitus Functional Index (TFI) claims to be optimised for both. It has not however been fully validated for research purposes. Here we evaluate the relevant psychometric properties of the TFI, specifically the questionnaire factor structure, reproducibility, validity and responsiveness guided by quality criteria for the measurement properties of health-related questionnaires. METHODS: The study involved a retrospective analysis of data collected for 294 members of the general public who participated in a randomised controlled trial of a novel tinnitus device (ClinicalTrials.gov Identifier: NCT01541969). Participants completed up to eight commonly used assessment questionnaires including the TFI, Tinnitus Handicap Inventory (THI), Tinnitus Handicap Questionnaire (THQ), a Visual Analogue Scale of loudness (VAS Loudness), Percentage Annoyance question, the Beck's Depression Inventory (BDI), Beck's Anxiety Inventory (BAI), and the World Health Organisation Quality of Life Bref (WHOQOL-BREF). A series of analyses assessed the study objectives. Forty four participants completed the TFI at a second visit (within 7-21 days and before receiving any intervention) providing data for reproducibility assessments. RESULTS: The 8-factor structure was not fully confirmed for this general (non-clinical) population. Whilst it was acceptable standalone subscale, the 'auditory' factor showed poor loading with the higher order factor 'functional impact of tinnitus'. Reproducibility assessments for the overall TFI indicate high internal consistency (alpha = 0.80) and extremely high reliability (ICC: 0.91), whilst agreement was borderline acceptable (93%). Construct validity was demonstrated by high correlations between scores on the TFI and THI (r = 0.82) and THQ (r = 0.82), moderate correlations with VAS-L (r = 0.46), PR-A (r = 0.58), BDI (r = 0.57), BAI (r = 0.39) and WHOQOL (r = -0.48). Floor effects were observed for more than 50% of the items. A smallest detectable change score of 22.4 is proposed for the TFI global score. CONCLUSION: Even though the proposed 8 factor structure was not fully confirmed for this population, the TFI appears to cover multiple symptom domains, and to measure the construct of tinnitus with an excellent reliability in distinguishing between patients. While the TFI may discriminate those whose tinnitus is not a problem, floor effects in many items means it is less appropriate as a measure of change in this subgroup. Further investigation is needed to determine whether these effects are relevant in other populations. PMID- 26416000 TI - Mind wandering during film comprehension: The role of prior knowledge and situational interest. AB - This study assessed the occurrence and factors that influence mind wandering (MW) in the domain of film comprehension. The cascading model of inattention assumes that a stronger mental representation (i.e., a situation model) during comprehension results in less MW. Accordingly, a suppression hypothesis suggests that MW would decrease as a function of having the knowledge of the plot of a film prior to viewing, because the prior-knowledge would help to strengthen the situation model during comprehension. Furthermore, an interest-moderation hypothesis would predict that the suppression effect of prior-knowledge would only emerge when there was interest in viewing the film. In the current experiment, 108 participants either read a short story that depicted the plot (i.e., prior-knowledge condition) or read an unrelated story of equal length (control condition) prior to viewing the short film (32.5 minutes) entitled The Red Balloon. Participants self-reported their interest in viewing the film immediately before the film was presented. MW was tracked using a self-report method targeting instances of MW with metacognitive awareness. Participants in the prior-knowledge condition reported less MW compared with the control condition, thereby supporting the suppression hypothesis. MW also decreased over the duration of the film, but only for those with prior-knowledge of the film. Finally, prior-knowledge effects on MW were only observed when interest was average or high, but not when interest was low. PMID- 26416001 TI - Role of personality and expectations for itch and scratching induced by audiovisual itch stimuli. AB - Itch is an unpleasant, bodily sensation, which--similar to pain--evokes behavioral reactions. As a response to itch, people start scratching. There are different ways to provoke itch and subsequent scratching in experimental settings. A non-invasive method to induce itch and scratching is the presentation of itch-related (audio-) visual stimulus material, like slide-supported lectures on skin diseases or crawling insects. Also, watching videos showing other people scratching provokes itch and the desire to scratch. In this review, we focus on psychological factors, which were shown to be associated with itch and scratching provoked by (audio-) visual itch stimuli. First, we summarize the findings on the relationship between personality characteristics and (audio-) visually induced itch. Agreeableness and self-consciousness were shown to be associated with induced itch and scratching in patients with chronic skin diseases, while neuroticism was linked to induced itch in healthy subjects. Second, we present results of a recent study, in which we altered the expectations towards audio visually induced itch and scratching by changing the information given on upcoming itch stimuli. It was shown that subjects being informed about itch stimuli in a neutral way displayed a shorter scratch duration in itch inducing situations than subjects having catastrophizing expectations. Also, the increase in scratch duration and in the number of scratch movements induced by audiovisual itch stimuli was higher when the patients were not informed about itch induction. Thus, in itch patients neither catastrophizing nor trivializing symptoms seems to be helpful. PMID- 26416002 TI - Effects of oral administration of trimethoprim-sulfamethoxazole on tear production in clinically normal guinea pigs. AB - OBJECTIVE: To determine the effects of short-term oral administration of trimethoprim-sulfamethoxazole on tear production in clinically normal guinea pigs. ANIMAL STUDIED: Thirty-two healthy adult Abyssinian guinea pigs were used in this study. PROCEDURE: One day before the start of the trial, the pretreatment baseline phenol red thread test (PRTT) values were recorded. Sixteen guinea pigs in the treated group received 25 mg/kg trimethoprim-sulfamethoxazole orally twice a day for 14 days. The other sixteen guinea pigs were used as untreated controls and received a placebo during the study. All the ophthalmic tests were performed without chemical restraint. PRTT values were evaluated in both eyes of all the guinea pigs using a commercial PRTT strip of a single lot number on days 0 (baseline), 15, and 21 after starting the trial. RESULTS: The pretreatment baseline mean +/- SD PRTT values for the treatment and control groups were 11.12 +/- 3.82 mm/15 s and 11.93 +/- 2.73 mm/15 s, respectively. After 14 days of drug administration, the mean +/- SD PRTT values for the treatment and control groups were 10.87 +/- 3.11 mm/15 s and 13.00 +/- 2.47 mm/15 s, respectively. On Day 21, the mean +/- SD PRTT values for the treatment and control groups were 12.62 +/- 4.05 mm/15 s and 12.87 +/- 2.99 mm/15 s, respectively. Significant decreases in the PRTT values, compared with the pretreatment baseline values, were not observed in the treatment group on Day 15 (P = 0.14) and Day 21 (P = 0.31). CONCLUSIONS: Trimethoprim-sulfamethoxazole did not decrease tear production in the guinea pigs in this study. PMID- 26416003 TI - Dyslipidaemia: Promising new therapy for lysosomal acid lipase deficiency. PMID- 26416004 TI - Trastuzumab is not a tyrosine kinase inhibitor. PMID- 26416005 TI - Mechanisms underlying trastuzumab activity are complex. PMID- 26416007 TI - Statin Use and Serum Lipid Levels Are Associated With Survival Outcomes After Surgery for Renal Cell Carcinoma. AB - OBJECTIVE: To evaluate the association of statin use and preoperative serum lipid parameters with oncologic outcomes following surgery for renal cell carcinoma. METHODS: A total of 850 patients who underwent surgery for localized renal cell carcinoma at our institution from 2000 to 2012 were included. Use of statins, preoperative serum lipid profile, and comprehensive clinicopathologic features were retrospectively recorded. Kaplan-Meier analysis and multivariate Cox proportional hazards model were employed to compare survival outcomes. RESULTS: There were 342 statin users and 508 non-users. Median follow-up was 25.0 months. Statin users were older, had greater body mass index, and had worse performance status than non-users. Tumor pathologic characteristics were balanced between groups. Five-year recurrence free survival (RFS) was 77.9% for non-users compared with 87.6% for statin users (P = .004). After adjustment for clinicopathologic variables, statin use was independently associated with improved RFS (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.33-0.86, P = .011) and overall survival (HR 0.45, 95%CI 0.28-0.71, P = .001). In patients with available serum lipid parameters (n = 193), 5-year RFS was 83.8% for patients with triglycerides <250 mg/dL compared with 33.3% for those with triglycerides >250 mg/dL (P <.0001). Elevated serum triglycerides (>250 mg/dL) was independently associated with worse RFS (HR 2.69, 95%CI 1.22-5.93, P = .015) on multivariate analysis. CONCLUSION: Statin use was independently associated with improved survival, whereas elevated serum triglyceride levels correlated with worse oncologic outcomes in this cohort. These findings warrant validation in prospective studies. PMID- 26416008 TI - Coffee, Tea, Cola, and Bladder Cancer Risk: Dose and Time Relationships. AB - OBJECTIVE: To further analyze the relation between coffee, tea, and energy drinks and bladder cancer risk, considering dose, duration, and other time-related factors. METHODS AND RESULTS: A multicentric case-control study on 690 bladder cancer cases and 665 hospital controls was conducted in Italy between 2003 and 2014. Odds ratios (ORs) for bladder cancer were estimated using multiple logistic regression models. Sex-, age-, and tobacco-adjusted ORs were 1.27 (95% confidence interval [CI] 0.84-1.94) for current drinkers and 1.69 (95% CI 1.05-2.72) for lifetime drinkers of >=4 cups/day, compared with non- or occasional coffee drinkers. The corresponding ORs for an increment of 1 cup/day were 1.03 (95% CI 0.96-1.11) and 1.07 (95% CI 0.99-1.15). No association was found between bladder cancer risk and duration or age at starting, and no significant heterogeneity was found according to age and sex, although a slight increased risk emerged in never smokers. Decaffeinated coffee, tea, cola, and energy drinks were not related with bladder cancer risk. CONCLUSION: Our study found no significant relation between coffee and bladder cancer risk after accounting for smoking, although the OR was above unity for high lifetime habit. The lack of dose and duration relationships, however, suggests the absence of a causal relation. PMID- 26416009 TI - Unsuccessful Medical Expulsive Therapy: A Cost to Waiting? AB - OBJECTIVE: To compare clinical outcomes between patients with ureteral stones who underwent an unsuccessful trial of medical expulsive therapy (MET) and patients who did not attempt MET. METHODS: We reviewed the clinical records of all potential candidates for MET who were referred from the emergency department to a subspecialty stone clinic. RESULTS: Of 348 potential candidates, 133 patients (38%) went directly to surgery (NMET) and 215 patients (62%) initiated MET. In the latter group, MET was unsuccessful in 45 patients (21%) (UMET). Stone symptoms were the primary rationale for surgery in 20 (44%) UMET patients and 69 (52%) NMET patients. The UMET patients were more likely to be younger and have smaller, more distal stones than NMET patients. All stones were cleared by ureteroscopy. The average interval from stone clinic assessment to surgery was longer in the UMET patients (17 days) than in the NMET patients (1 day; P <.001). The UMET patients underwent more preoperative computed-tomography scans (2.1) than did the NMET patients (1; P <0.001). There were no differences between the 2 groups in the residual stone burden, pre- or postoperative repeat visits to the emergency department, or repeat surgery. CONCLUSION: In this population, we did not observe any detrimental impact of an unsuccessful trial of MET (beyond the additional time and imaging costs). If more confident and effective symptom control could be achieved, expansion of utilization and duration of MET may be a path to improved patient outcomes and cost control. PMID- 26416010 TI - Linking transcriptomics and proteomics in spermatogenesis. AB - Spermatogenesis is a complex and tightly regulated process leading to the continuous production of male gametes, the spermatozoa. This developmental process requires the sequential and coordinated expression of thousands of genes, including many that are testis-specific. The molecular networks underlying normal and pathological spermatogenesis have been widely investigated in recent decades, and many high-throughput expression studies have studied genes and proteins involved in male fertility. In this review, we focus on studies that have attempted to correlate transcription and translation during spermatogenesis by comparing the testicular transcriptome and proteome. We also discuss the recent development and use of new transcriptomic approaches that provide a better proxy for the proteome, from both qualitative and quantitative perspectives. Finally, we provide illustrations of how testis-derived transcriptomic and proteomic data can be integrated to address new questions and how the 'proteomics informed by transcriptomics' technique, by combining RNA-seq and MS-based proteomics, can contribute significantly to the discovery of new protein-coding genes or new protein isoforms expressed during spermatogenesis. PMID- 26416006 TI - New medical therapies for heart failure. AB - Heart failure (HF) can rightfully be called the epidemic of the 21(st) century. Historically, the only available medical treatment options for HF have been diuretics and digoxin, but the capacity of these agents to alter outcomes has been brought into question by the scrutiny of modern clinical trials. In the past 4 decades, neurohormonal blockers have been introduced into clinical practice, leading to marked reductions in morbidity and mortality in chronic HF with reduced left ventricular ejection fraction (LVEF). Despite these major advances in pharmacotherapy, our understanding of the underlying disease mechanisms of HF from epidemiological, clinical, pathophysiological, molecular, and genetic standpoints remains incomplete. This knowledge gap is particularly evident with respect to acute decompensated HF and HF with normal (preserved) LVEF. For these clinical phenotypes, no drug has been shown to reduce long-term clinical event rates substantially. Ongoing developments in the pharmacotherapy of HF are likely to challenge our current best-practice algorithms. Novel agents for HF therapy include dual-acting neurohormonal modulators, contractility-enhancing agents, vasoactive and anti-inflammatory peptides, and myocardial protectants. These novel compounds have the potential to enhance our armamentarium of HF therapeutics. PMID- 26416012 TI - Junior doctors to be balloted on industrial action. PMID- 26416011 TI - Integrative analyses reveal transcriptome-proteome correlation in biological pathways and secondary metabolism clusters in A. flavus in response to temperature. AB - To investigate the changes in transcript and relative protein levels in response to temperature, complementary transcriptomic and proteomic analyses were used to identify changes in Aspergillus flavus grown at 28 degrees C and 37 degrees C. A total of 3,886 proteins were identified, and 2,832 proteins were reliably quantified. A subset of 664 proteins was differentially expressed upon temperature changes and enriched in several Kyoto Encyclopedia of Genes and Genomes pathways: translation-related pathways, metabolic pathways, and biosynthesis of secondary metabolites. The changes in protein profiles showed low congruency with alterations in corresponding transcript levels, indicating that post-transcriptional processes play a critical role in regulating the protein level in A. flavus. The expression pattern of proteins and transcripts related to aflatoxin biosynthesis showed that most genes were up-regulated at both the protein and transcript level at 28 degrees C. Our data provide comprehensive quantitative proteome data of A. flavus at conducive and nonconducive temperatures. PMID- 26416013 TI - SOAP-V: Introducing a method to empower medical students to be change agents in bending the cost curve. AB - Medical students must learn how to practice high-value, cost-conscious care. By modifying the traditional SOAP (Subjective-Objective-Assessment-Plan) presentation to include a discussion of value (SOAP-V), we developed a cognitive forcing function designed to promote discussion of high-value, cost-conscious care during patient delivery. The SOAP-V model prompts the student to consider (1) the evidence that supports a test or treatment, (2) the patient's preferences and values, and (3) the financial cost of a test or treatment compared to alternatives. Students report their findings to their teams during patient care rounds. This tool has been successfully used at 3 medical schools. Preliminary results find that students who have been trained in SOAP-V feel more empowered to address the economic healthcare crisis, are more comfortable in initiating discussions about value, and are more likely to consider potential costs to the healthcare system. PMID- 26416014 TI - A new nanocomposite forward osmosis membrane custom-designed for treating shale gas wastewater. AB - Managing the wastewater discharged from oil and shale gas fields is a big challenge, because this kind of wastewater is normally polluted by high contents of both oils and salts. Conventional pressure-driven membranes experience little success for treating this wastewater because of either severe membrane fouling or incapability of desalination. In this study, we designed a new nanocomposite forward osmosis (FO) membrane for accomplishing simultaneous oil/water separation and desalination. This nanocomposite FO membrane is composed of an oil-repelling and salt-rejecting hydrogel selective layer on top of a graphene oxide (GO) nanosheets infused polymeric support layer. The hydrogel selective layer demonstrates strong underwater oleophobicity that leads to superior anti-fouling capability under various oil/water emulsions, and the infused GO in support layer can significantly mitigate internal concentration polarization (ICP) through reducing FO membrane structural parameter by as much as 20%. Compared with commercial FO membrane, this new FO membrane demonstrates more than three times higher water flux, higher removals for oil and salts (>99.9% for oil and >99.7% for multivalent ions) and significantly lower fouling tendency when investigated with simulated shale gas wastewater. These combined merits will endorse this new FO membrane with wide applications in treating highly saline and oily wastewaters. PMID- 26416015 TI - Adherence to surgical hand rubbing directives in a hospital district of Southwest Finland. AB - BACKGROUND: The primary objective was to measure the compliance with alcohol based surgical hand rubbing (SHR) among operation room personnel. The secondary objective was to evaluate the effect of feedback sessions on compliance. METHODS: This was a prospective observational before-after intervention study. Between October 2010 and June 2012 the hygiene nurses observed SHR among operation room personnel in the hospital district of Southwest Finland. After feedback sessions a second observation round was conducted in the main operation room of Turku University Hospital. The first observation round comprised 477 observations: 259 (54%) were doctors, 190 (40%) nurses and 28 (5%) other personnel. In the second observation round a total of 210 observations were made. RESULTS: During the first round in 42% of observations the 3 min SHR time recommended by WHO was used. Median times for SHR were 1 min 50 s (range 0 min to 5 min 44 s) for doctors and 3 min 25 s (range 1 min 1 s to 8 min 15 s) for nurses, respectively (p < 0.0001). In 40% of observations hands were not properly dried after a wash before applying SHR and in 45% hands were not allowed to dry properly after SHR before donning surgical gloves. After feedback, time for SHR did not significantly improve but technique did. CONCLUSIONS: SHR was performed incorrectly in most observations even after feedback. The results stress the importance of more effective education, helping techniques and positive role models for operation room personnel to promote SHR. PMID- 26416016 TI - Predictors of condom use behaviour among male street labourers in urban Vietnam using a modified Information-Motivation-Behavioral Skills (IMB) model. AB - HIV risk in vulnerable groups such as itinerant male street labourers is often examined via a focus on individual determinants. This study provides a test of a modified Information-Motivation-Behavioral Skills (IMB) model to predict condom use behaviour among male street workers in urban Vietnam. In a cross-sectional survey using a social mapping technique, 450 male street labourers from 13 districts of Hanoi, Vietnam were recruited and interviewed. Collected data were first examined for completeness; structural equation modelling was then employed to test the model fit. Condoms were used inconsistently by many of these men, and usage varied in relation to a number of factors. A modified IMB model had a better fit than the original IMB model in predicting condom use behaviour. This modified model accounted for 49% of the variance, versus 10% by the original version. In the modified model, the influence of psychosocial factors was moderately high, whilst the influence of HIV prevention information, motivation and perceived behavioural skills was moderately low, explaining in part the limited level of condom use behaviour. This study provides insights into social factors that should be taken into account in public health planning to promote safer sexual behaviour among Asian male street labourers. PMID- 26416017 TI - Reward breaks through center-surround inhibition via anterior insula. AB - Focusing attention on a target creates a center-surround inhibition such that distractors located close to the target do not capture attention. Recent research showed that a distractor can break through this surround inhibition when associated with reward. However, the brain basis for this reward-based attention is unclear. In this fMRI study, we presented a distractor associated with high or low reward at different distances from the target. Behaviorally the low-reward distractor did not capture attention and thus did not cause interference, whereas the high-reward distractor captured attention only when located near the target. Neural activity in extrastriate cortex mirrored the behavioral pattern. A comparison between the high-reward and the low-reward distractors presented near the target (i.e., reward-based attention) and a comparison between the high reward distractors located near and far from the target (i.e., spatial attention) revealed a common frontoparietal network, including inferior frontal gyrus and inferior parietal sulcus as well as the visual cortex. Reward-based attention specifically activated the anterior insula (AI). Dynamic causal modelling showed that reward modulated the connectivity from AI to the frontoparietal network but not the connectivity from the frontoparietal network to the visual cortex. Across participants, the reward-based attentional effect could be predicted both by the activity in AI and by the changes of spontaneous functional connectivity between AI and ventral striatum before and after reward association. These results suggest that AI encodes reward-based salience and projects it to the stimulus driven attentional network, which enables the reward-associated distractor to break through the surround inhibition in the visual cortex. PMID- 26416018 TI - Simultaneous enantioselective determination of triadimefon and its metabolite triadimenol in edible vegetable oil by gel permeation chromatography and ultraperformance convergence chromatography/tandem mass spectrometry. AB - A novel, sensitive, and efficient enantioselective method for the determination of triadimefon and its metabolite triadimenol in edible vegetable oil, was developed by gel permeation chromatography and ultraperformance convergence chromatography/tandem triple quadrupole mass spectrometry. After the vegetable oil samples were prepared using gel permeation chromatography, the eluent was collected, evaporated, and dried with nitrogen gas. The residue was redissolved by adding methanol up to a final volume of 1 mL. The analytes of six enantiomers were analyzed on Chiralpak IA-3 column (150 * 4.6 mm) using compressed liquid CO2 mixed 14 % co-solvents, comprising methanol/acetonitrile/isopropanol = 20/20/60 (v/v/v) in the mobile phase at 30 degrees C, and the total separation time was less than 4 min at a flow rate of 2 mL/min. Quantification was achieved using matrix-matched standard calibration curves. The overall mean recoveries for six enantiomers from vegetable oil were 90.1-97.3 %, with relative standard deviations of 0.8-5.4 % intra-day and 2.3-5.0 % inter-day at 0.5, 5, and 50 MUg/kg levels. The limits of quantification were 0.5 MUg/kg for all enantiomers based on five replicate extractions at the lowest fortified level in vegetable oil. Moreover, the absolute configuration of six enantiomers had been determined based on comparisons of the vibrational circular dichroism experimental spectra with the theoretical curve obtained by density functional theory calculations. Application of the proposed method to the 40 authentic vegetable oil samples from local markets suggests its potential use in enantioselective determination of triadimefon and triadimenol enantiomers. Graphical Abstract Chemical structures and UPC(2)-MS/MS separation chromatograms of triadimefon and triadimenol. PMID- 26416020 TI - Characterisation of a fibre optic Raman probe within a hypodermic needle. AB - We demonstrate the first use of a multifibre Raman probe that fits inside the bore of a hypodermic needle. A Raman probe containing multiple collection fibres provides improved signal collection efficiency in biological samples compared with a previous two-fibre design. Furthermore, probe performance (signal-to-noise ratios) compared favourably with the performance achieved in previous Raman microscope experiments able to distinguish between benign lymph nodes, primary malignancies in lymph nodes and secondary malignancies in lymph nodes. The experimental measurements presented here give an indication of the sampling volume of the Raman needle probe in lymphoid tissues. Liquid tissue phantoms were used that contained scattering medium encompassing a range of scattering properties similar to those of a variety of tissue types, including lymph node tissues. To validate the appropriateness of the phantoms, the sampling depth of the probe was also measured in excised lymph node tissue. More than 50 % of Raman photons collected were found to originate from between the tip of the needle and a depth of 500 MUm into the tissue. The needle probe presented here achieves spectral quality comparable to that in numerous studies previously demonstrating Raman disease discrimination. It is expected that this approach could achieve targeted subcutaneous tissue measurements and be viable for use for the in vivo Raman diagnostics of solid organs located within a few centimetres below the skin's surface. Graphical Abstract Schematic of multi-fibre Raman needle probe with disposible tips and proximal optical filtration. PMID- 26416019 TI - Design of a sensitive fluorescent polarization immunoassay for rapid screening of milk for cephalexin. AB - In this paper we describe the development of a sensitive, fast, and easily performed fluorescence polarization immunoassay for determination of cephalexin in milk. The experimental work was performed to increase sensitivity and specificity. Therefore, the structures of the tracers were varied by synthesis of both cephalexin (CEX) and cephalotin (CET) conjugates with a variety of fluorescent labels. Two rabbit antisera containing antibodies against cephalexin and cephalotin were tested in homologous and heterologous combinations with the tracers. For every working antibody-tracer combination, the analytical conditions and cross-reactivity for structural analogues-cephalosporins and other antibiotics that could also be present in milk-were determined. It was found that the highest sensitivity was achieved by use of the homologous pair CET-EDF-anti CET antibody (limit of detection (LOD) 0.4 MUg kg(-1) for standard solutions prepared in buffer), but this combination was not appropriate because of high cross-reactivity with CET. For subsequent experiments, therefore, CEX- EDF-anti CEX antibody were chosen (LOD 0.8 MUg kg(-1) for standard solutions prepared in buffer). Part of this manuscript is devoted to the variation of precipitation agents for pretreatment of milk before analysis; milk is an extremely complicated matrix. The optimum protein precipitation agent was methanol. This technique for cephalexin determination was characterized by a limit of detection of 1 MUg kg( 1). The method was validated by using naturally contaminated and spiked milk samples. The results obtained corresponded very well with those obtained by HPLC, which was used as confirmation method. PMID- 26416021 TI - Pharmacokinetic study of Gastrodia elata in rats. AB - The pharmacokinetics of parishin, gastrodin, Gastrodia elata extract and Rhizoma Gastrodiae capsule was investigated by intragastric and/or intravenous administration to rats. Parishin was metabolized into nine metabolites after intravenous administration, and the area under the curve (AUC0-infinity) of parishin and its metabolites (except parishin G and parishin E) increased nonlinearly from 72.5 to 220 mg/kg. When combining regression equation with the AUC0-infinity and dose of gastrodin injection, the percent conversion of parishin to gastrodin was obtained as 50 %. Based on multi-active metabolites of parishin in vivo, integrated pharmacokinetic mode was established. It is notable that each metabolite from parishin shares the similar metabolic process at three dosages of parishin and the bioavailability of parishin was approximately 14 %. The integrated pharmacokinetic mode was successfully applied to evaluate the holistic pharmacokinetics of gastrodin injection, G. elata extract and Rhizoma Gastrodiae capsule. The results showed that the holistic pharmacokinetics of gastrodin injection and G. elata extract was closed to that of gastrodin, but for parishin and Rhizoma Gastrodiae capsule, integrated pharmacokinetic parameters were more suitable to evaluate its holistic pharmacokinetics. Graphical abstract Pharmacokinetic study of Gastrodia elata in rats. PMID- 26416022 TI - Screening of pharmaceuticals and illicit drugs in wastewater and surface waters of Spain and Italy by high resolution mass spectrometry using UHPLC-QTOF MS and LC-LTQ-Orbitrap MS. AB - The existence of pharmaceuticals and illicit drugs (PIDs) in environmental waters has led many analytical chemists to develop screening methods for monitoring purposes. Water samples can contain a huge number of possible contaminants, commonly at low concentrations, which makes their detection and identification problematic. Liquid chromatography coupled with high resolution mass spectrometry (LC-HRMS) has proven itself effective in the screening of environmental contaminants. The present work investigates the use of the most popular HRMS instruments, quadrupole time-of-flight and linear trap quadrupole-Orbitrap, from two different laboratories. A suspect screening for PIDs was carried out on wastewater (influent and effluent) and surface water samples from Castellon, Eastern Spain, and Cremona, Northern Italy, incorporating a database of 107 PIDs (including 220 fragment ions). A comparison between the findings of both instruments and of the samples was made which highlights the advantages and drawbacks of the strategies applied in each case. In total, 28 compounds were detected and/or identified by either/both instruments with irbesartan, valsartan, benzoylecgonine and caffeine being the most commonly found compounds across all samples. PMID- 26416023 TI - Differential Plasma-cell evolution is linked with Dermatophagoides pteronyssinus immunotherapy response. AB - Allergic rhinitis is highly prevalent worldwide. Immunotherapy has been shown to control its symptoms, however, up to 30% of patients may not respond. Previous studies of the immunological mechanisms involved in allergen-immunotherapy (AIT) have focused on the humoral and T-cell response and several studies have evaluated some B-cell subpopulations during AIT and their role in immunological tolerance. However, although B and plasma-cell subpopulations are two of the most important cellular subtypes involved in allergic reactions, their relation with AIT efficacy remains unelucidated. The objective was to analyze the effects of immunotherapy on different B and plasma-cell subpopulations and whether these changes correlate with the clinical response to the treatment. Although no changes are found in B-cell subpopulations, responder patients show increased levels of memory B-cells even before the beginning of treatment. Changes in plasma-cell subpopulations are found, mainly in circulating inflammatory plasma cells that could affect the response to the allergen. Moreover, an early increase of specific-IgG4 and IgG4 secreting-cells was found. All these suggest that the determination of the memory B-cells before the initiation of the treatment, and the quantification of IgG4 and IgG4-secreting-cells in the first months of immunotherapy, could serve as markers for the clinical response to treatment. PMID- 26416024 TI - Increased duplex stabilization in porphyrin-LNA zipper arrays with structure dependent exciton coupling. AB - Porphyrins were attached to LNA uridine building blocks via rigid 5-acetylene or more flexible propargyl-amide linkers and incorporated into DNA strands. The systems show a greatly increased thermodynamic stability when using as little as three porphyrins in a zipper arrangement. Thermodynamic analysis reveals clustering of the strands into more ordered duplexes with both greater negative DeltaDeltaS and DeltaDeltaH values, and less ordered duplexes with small positive DeltaDeltaS differences, depending on the combination of linkers used. The exciton coupling between the porphyrins is dependent on the flanking DNA sequence in the single stranded form, and on the nature of the linker between the nucleobase and the porphyrin in the double stranded form; it is, however, also strongly influenced by intermolecular interactions. This system is suitable for the formation of stable helical chromophore arrays with sequence and structure dependent exciton coupling. PMID- 26416025 TI - Physical therapy vs. internet-based exercise training (PATH-IN) for patients with knee osteoarthritis: study protocol of a randomized controlled trial. AB - BACKGROUND: Physical activity improves pain and function among individuals with knee osteoarthritis (OA), but most people with this condition are inactive. Physical therapists play a key role in helping people with knee OA to increase appropriate physical activity. However, health care access issues, financial constraints, and other factors impede some patients from receiving physical therapy (PT) for knee OA. A need exists to develop and evaluate other methods to provide physical activity instruction and support to people with knee OA. This study is examining the effectiveness of an internet-based exercise training (IBET) program designed for knee OA, designed by physical therapists and other clinicians. METHODS/DESIGN: This is a randomized controlled trial of 350 participants with symptomatic knee OA, allocated to three groups: IBET, standard PT, and a wait list (WL) control group (in a 2:2:1 ratio, respectively). The study was funded by the Patient Centered Outcomes Research Institute, which conducted a peer review of the proposal. The IBET program provides patients with a tailored exercise program (based on functional level, symptoms, and current activity), video demonstrations of exercises, and guidance for appropriate exercise progression. The PT group receives up to 8 individual visits with a physical therapist, mirroring standard practice for knee OA and with an emphasis on a home exercise program. Outcomes are assessed at baseline, 4 months (primary time point) and 12 months (to assess maintenance of treatment effects). The primary outcome is the Western Ontario and McMaster Universities Osteoarthritis Index, and secondary outcomes include objective physical function, satisfaction with physical function, physical activity, depressive symptoms and global assessment of change. Linear mixed models will be used to compare both the IBET and standard PT groups to the WL control group, examine whether IBET is non inferior to PT (a treatment that has an established evidence base for knee OA), and explore whether participant characteristics are associated with differential effects of IBET and/or standard PT. This research is in compliance with the Helsinki Declaration and was approved by the Institutional Review Board of the University of North Carolina at Chapel Hill. DISCUSSION: The IBET program could be disseminated widely at relatively low cost and could be an important resource for helping patients with knee OA to adopt and maintain appropriate physical activity. This trial will provide an important evaluation of the effectiveness of this IBET program for knee OA. TRIAL REGISTRATION: NCT02312713. PMID- 26416026 TI - Mutation in WDR4 impairs tRNA m(7)G46 methylation and causes a distinct form of microcephalic primordial dwarfism. AB - BACKGROUND: Primordial dwarfism is a state of extreme prenatal and postnatal growth deficiency, and is characterized by marked clinical and genetic heterogeneity. RESULTS: Two presumably unrelated consanguineous families presented with an apparently novel form of primordial dwarfism in which severe growth deficiency is accompanied by distinct facial dysmorphism, brain malformation (microcephaly, agenesis of corpus callosum, and simplified gyration), and severe encephalopathy with seizures. Combined autozygome/exome analysis revealed a novel missense mutation in WDR4 as the likely causal variant. WDR4 is the human ortholog of the yeast Trm82, an essential component of the Trm8/Trm82 holoenzyme that effects a highly conserved and specific (m(7)G46) methylation of tRNA. The human mutation and the corresponding yeast mutation result in a significant reduction of m(7)G46 methylation of specific tRNA species, which provides a potential mechanism for primordial dwarfism associated with this lesion, since reduced m(7)G46 modification causes a growth deficiency phenotype in yeast. CONCLUSION: Our study expands the number of biological pathways underlying primordial dwarfism and adds to a growing list of human diseases linked to abnormal tRNA modification. PMID- 26416028 TI - Staphylococcus aureus food poisoning among Bulawayo City Council employees, Zimbabwe, 2014. AB - BACKGROUND: Bulawayo City Council held an Integrated Result Based Management workshop among 86 employees from August 18-22, 2014 at Ikhwezi Training Centre in Bulawayo City. On August 21, 2014, a report of diarrhoea among Council employees attending the workshop was received. We investigated the outbreak to determine the risk factors associated with diarrhoea at Ikhwezi Training Centre, Bulawayo City. METHOD: A retrospective cohort study was conducted where 74 Council employees were interviewed on food consumed and presenting signs and symptoms. Stool specimens and hand swabs were collected for culture. Water samples were collected for bacteriological analysis. Food samples were not available. Data were analysed using Epi InfoTM to generate frequencies, means, proportions, risk ratios, and attributable risk. RESULTS: Of the 74 employees interviewed 34 (45.9%) were males and 40 (54%) were females. The response rate was 94%. The common signs and symptoms included abdominal cramps (88.7%), and watery diarrhoea (86.8%). The overall attack rate was 71.6%. Eating stewed chicken (RR = 2.52, 95% CI 1.30-4.89) served at hour 13:00 during lunch on August 20, 2014 at Ikhwezi Training Centre was the only significant risk factor associated with food poisoning. Drinking purified bottled water [RR = 0.67, 95% CI (0.57-0.79)] was found to be protective. Staphylococcus aureus was isolated from the hands and nails of food handlers. CONCLUSION: The outbreak was due to food poisoning and was most likely caused by the Staphylococcus aureus formed toxins. Stewed chicken served during lunch on August 20, 2014 was the possible source of infection. Contamination might have occurred during food handling and preparation. Training of food handlers in basic food hygiene and safety is recommended. PMID- 26416027 TI - Social and economic costs and health-related quality of life in non institutionalised patients with cystic fibrosis in the United Kingdom. AB - BACKGROUND: This study aimed to determine the societal economic burden and health related quality of life (HRQOL) of cystic fibrosis (CF) patients in the UK. METHODS: A bottom-up cost-of-illness, cross-sectional, retrospective analysis of 74 patients was conducted aiming to estimate the economic impact of CF. Data on demographic characteristics, health resource utilisation, informal care, productivity losses and HRQOL were collected from questionnaires completed by patients or their caregivers. HRQOL was measured with the EuroQol 5-domain (EQ 5D) instrument. RESULTS: Using unit costs for 2012 we found that the average annual cost for a CF patient was ?48,603, with direct health care costs amounting to ?20,854 (42.9 % of total costs), direct non-health care costs being ?21,528 (44.3 %) and indirect costs attributable to productivity losses being ?6,222 (12.8 %). On average, the largest expenditures by far were accounted for by informal care (44.1 %), followed by medications (14.5 %), acute hospitalisations (13.9 %), early retirement (9.1 %) and outpatient and primary health care visits (7.9 %). Sharp differences existed depending on whether CF patients were in need of caregiver help (?76,271 versus ?26,335). In adult CF patients, mean EQ-5D index scores were 0.64 (0.93 in the general population) and mean EQ-5D visual analogue scale scores were 62.23 (86.84 in the general population); among caregivers, these scores were 0.836 and 80.85, respectively. DISCUSSION: Our analysis highlights the importance of the economic and quality of life consequences of CF from a societal perspective. The results highlight that beyond conventional costs such as acute hospitalisations, medication and outpatient and primary care visits, indirect costs related to informal care and early retirement, have significant societal implications. Similarly, our analysis showed that the average EQ-5D index score of adult CF patients was significantly lower than in the general population, an indication that a methodological bias may exist in using the latter in economic analyses. CONCLUSION: CF poses a significant cost burden on UK society, with non-health care and indirect costs representing 57 % of total average costs, and HRQOL being considerably lower than in the general population. PMID- 26416031 TI - When patients and surgeons disagree about surgical outcome: investigating patient factors and chart note communication. AB - OBJECTIVE: Effective physician-patient communication is a critical component of a clinical practice and in order to achieve optimal patient outcomes. We aimed to investigate indirect effects of physician-patient communication by examining the relationship between a physician-patient mismatch in perceived outcomes and content in the medical record's clinical note. We compared patient records whose perceived subjective assessment of surgery outcomes agreed or disagreed with the surgeon's perception of that outcome (Subjective Disagreement). METHODS: This study included 172 spine surgery patients at a teaching hospital. Patient reported outcomes included the Oswestry Disability Index; the Short-Form 36; and a Visual Analogue Scale items for leg and back pain. We content-analyzed the clinical note in the medical record, and used logistic regression to evaluate predictors of Subjective Disagreement (n = 41 disagreed vs. 131 agreed). RESULTS: Patient and surgeon agreed in 76% of cases and disagreed in 24% of cases. Patients who assessed their outcome worse than their surgeons tended to be less educated and involved in litigation. They also tended to report worsened mental health and leg pain. Content analysis revealed group differences in surgeon communication patterns in the chart notes related to how symptom change was emphasized, how follow-up was described, and a specific word reference. Specifically, disagreement was predicted by using "much" to emphasize the findings and noting long-term prognosis. Agreement was predicted by use of positive emphasis terms, having an "as-needed" follow-up plan, and using "happy" in the chart note. CONCLUSION: The nature of measuring outcomes of surgery is based on patient perception. In surgeon-patient perspective mismatches, patient factors may serve as barriers to improvement. Worsened change on patient-reported mental health may be an independent factor which colors the patient's general perceptions. This aspect of treatment may be missed by the spine surgeon. Chart note communication styles reflect the subjective disagreement. Investigating and/ or treating mental health deterioration may be valuable in resolving this mismatch and for overall outcome. PMID- 26416029 TI - Protocol for a statewide randomized controlled trial to compare three training models for implementing an evidence-based treatment. AB - BACKGROUND: Evidence-based treatments (EBTs) are available for treating childhood behavioral health challenges. Despite EBTs' potential to help children and families, they have primarily remained in university settings. Little empirical evidence exists regarding how specific, commonly used training and quality control models are effective in changing practice, achieving full implementation, and supporting positive client outcomes. METHODS/DESIGN: This study (NIMH RO1 MH095750; ClinicalTrials.gov Identifier: NCT02543359), which is currently in progress, will evaluate the effectiveness of three training models (Learning Collaborative (LC), Cascading Model (CM), and Distance Education (DE)) to implement a well-established EBT , Parent-Child Interaction Therapy, in real world, community settings. The three models differ in their costs, skill training, quality control methods, and capacity to address broader implementation challenges. The project is guided by three specific aims: (1) to build knowledge about training outcomes, (2) to build knowledge about implementation outcomes, and (3) to test the differential impact of training clinicians using LC, CM, and DE models on key client outcomes. Fifty (50) licensed psychiatric clinics across Pennsylvania were randomized to one of the three training conditions: (1) LC, (2) CM, or (3) DE. The impact of training on practice skills (clinician level) and implementation/sustainment outcomes (clinic level) are being evaluated at four timepoints coinciding with the training schedule: baseline, 6 (mid), 12 (post), and 24 months (1 year follow-up). Immediately after training begins, parent-child dyads (client level) are recruited from the caseloads of participating clinicians. Client outcomes are being assessed at four timepoints (pre-treatment, 1, 6, and 12 months after the pre-treatment). DISCUSSION: This proposal builds on an ongoing initiative to implement an EBT statewide. A team of diverse stakeholders including state policy makers, payers, consumers, service providers, and academics from different, but complementary areas (e.g., public health, social work, psychiatry), has been assembled to guide the research plan by incorporating input from multidimensional perspective. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02543359. PMID- 26416030 TI - Are work return and leaves of absence predictable after an unstable pelvic ring injury? AB - BACKGROUND: Resuming work after surgical treatment of an unstable pelvic ring injury is often impeded because of residual disability. The aim of this study was to test which factors influence return to work, ability to return to the same job function as before the injury, leaves of absence, and incapacitation after sustaining a pelvic fracture. MATERIALS AND METHODS: We performed a retrospective study on patients with surgically treated pelvic fractures. Medical records were reviewed to document patients' demographic data, the extent of follow-up care, diagnosis of the injury (according to the Tile system of classification), type of surgical treatment, injury severity, and the time from trauma to definitive surgery. We also recorded the classification of patients' physical status according to the American Society of Anesthesiologists (ASA) and details about admission to the intensive care unit (ICU). Patients were interviewed to note the number of days before returning to work and their ability to maintain their previously held jobs. RESULTS: Fifty patients were included in the study, and their mean age was 46.3 +/- 12.6 years. The median time to return to work was 195 days. Twelve patients (24 %) lost their jobs and 17 (34 %) resumed their previous job with a change of tasks. ICU admission and time from trauma to definitive surgery were negatively correlated with return to the previously held job. Returning to the same job tasks was not associated with any of the factors investigated. Polytrauma, ICU admission, and time from trauma to definitive surgery were associated with longer leaves of absence. CONCLUSIONS: Work reintegration after pelvic ring injuries is a major issue for patients and health care systems: 58 % of patients were not able to return to or lost their job. Factors correlated with leaves of absence were injury severity, delayed definitive fixation, and ICU admission. LEVEL OF EVIDENCE: IV (case series). PMID- 26416032 TI - Indolent lymphomas in the pediatric population: follicular lymphoma, IRF4/MUM1+ lymphoma, nodal marginal zone lymphoma and chronic lymphocytic leukemia. AB - Indolent lymphomas in the pediatric population were discussed during the 2014 European Association for Haematopathology/Society of Hematopathology workshop in Istanbul, Turkey. This session was focused on pediatric-type follicular lymphoma (FL), and its differential diagnosis with the newly recognized entity of IRF4/MUM1+ lymphomas mainly involving Waldeyer's ring. The differential diagnosis between t(14;18) negative FL grade 1/2 and pediatric-type FL in adults was highlighted. The overlapping pathological and clinical features between FL and nodal marginal zone lymphoma (NMZL) in children and young adults were recognized and morphologic and immunophenotypical criteria helpful for the differential diagnosis were presented. Both pediatric-type FL and NMZL are indolent processes that should be distinguished from atypical lymphoid hyperplasia of the tonsils and lymph nodes. The demonstration of a B cell monoclonal population by molecular studies is strongly recommended for the diagnosis. Recognition of these indolent variants to avoid overtreatment was emphasized. Whereas most indolent lymphomas in the pediatric population show characteristic clinical, pathologic, and genetic features that differ from the adult counterpart, other rare indolent lymphoid tumors such as chronic lymphocytic leukemia (CLL) have similar characteristics. In this report, novel findings, areas of special interest, and diagnostic challenges emerging from the cases submitted to the workshop will be discussed. PMID- 26416033 TI - GREMLIN 2 Mutations and Dental Anomalies. AB - Isolated or nonsyndromic tooth agenesis or hypodontia is the most common human malformation. It has been associated with mutations in MSX1, PAX9, EDA, AXIN2, EDAR, EDARADD, and WNT10A. GREMLIN 2 (GREM2) is a strong bone morphogenetic protein (BMP) antagonist that is known to regulate BMPs in embryogenesis and tissue development. Bmp4 has been shown to have a role in tooth development. Grem2(-/-) mice have small, malformed maxillary and mandibular incisors, indicating that Grem2 has important roles in normal tooth development. Here, we demonstrate for the first time that GREM2 mutations are associated with human malformations, which include isolated tooth agenesis, microdontia, short tooth roots, taurodontism, sparse and slow-growing hair, and dry and itchy skin. We sequenced WNT10A, WNT10B, MSX1, EDA, EDAR, EDARADD, AXIN2, and PAX9 in all 7 patients to rule out the effects of other ectodermal dysplasias and other tooth related genes and did not find mutations in any of them. GREM2 mutations exhibit variable expressivity even within the same families. The inheritance is autosomal dominant with incomplete penetrance. The expression of Grem2 during the early development of mouse teeth and hair follicles and the evaluation of the likely effects of the mutations on the protein structure substantiate these new findings. PMID- 26416035 TI - Role of of Nuclear Medicine in the multidisciplinary management of prostate cancer. PMID- 26416034 TI - CD44 single nucleotide polymorphism and isoform switching may predict gastric cancer recurrence. AB - BACKGROUND AND OBJECTIVES: The clinical implications of single nucleotide polymorphisms (SNPs) in CD44 remain unclear. This study examined the relationships of CD44 SNPs with clinicopathological parameters and prognosis in Japanese gastric cancer patients. METHODS: The CD44 SNPs were analyzed in 11 gastric cancer cell lines and 517 clinical specimens. The expression of CD44 standard (CD44s) and CD44 variant 9 isoform (CD44v9) transcripts were measured by quantitative real-time polymerase chain reaction. RESULTS: The CD44 rs187116 A/A, A/G, and G/G genotypes were present in 10.3%, 45.1%, and 44.7% of patients, respectively. The presence of CD44 rs187116 A/G or G/G genotypes was significantly associated with positive peritoneal washing cytology (P = 0.012). Disease-free survival of patients with these genotypes was significantly worse than in those with the A/A genotype (P = 0.039). Multivariate analysis showed that the CD44 rs187116 was independently prognostic of disease-free survival (P = 0.047). The CD44s/CD44v9 ratio was significantly lower in patients with the CD44 rs187116 A/A genotype than in those with the A/G (P = 0.046) and G/G (P = 0.047) genotypes. CONCLUSIONS: The CD44 rs187116 genotype could predict disease recurrence in Japanese gastric cancer patients, and the SNP was associated with CD44 isoform switching. PMID- 26416036 TI - Fluorodeoxyglucose positron emission tomography in pulmonary carcinoid tumors. AB - AIM: The role of fluorodeoxyglucose positron emission tomography (FDG-PET) as an additional investigation to computer tomography for pulmonary carcinoid tumors remains controversial. The aim of this study was to assess the role of FDG-PET for the diagnosis and staging of pulmonary carcinoid tumors. METHODS: We performed a retrospective mono-institutional analysis of data from 97 patients with pathologically confirmed pulmonary carcinoid tumor who had been operated on between July 1998 and April 2009 and had had a preoperative FDG-PET scan performed. RESULTS: Sixty-five (67%) of the 97 tumors were typical (TC) and 32 (33%) atypical (AC) carcinoid tumors. Overall FDG-PET sensitivity was 67% being lower for TC (60%) than for AC (81%) (P=0.04). FDG-PET negative tumors were smaller than FDG-PET positive tumors, with a respective median size of 15 and 17 mm (P=0.02). Median SUVmax for FDG-PET-positive tumors was 4.0 (2.8-5.1) with no difference between TC and AC tumors. Median Ki-67 expression was respectively 4.7% and 3.1% for FDG-PET positive and FDG-PET negative tumors (P=0.05). During a median follow-up of 49 months (interquartile range 30-63 months), 9 patients (4TC, 5AC) developed recurrent disease. Neither SUVmax nor Ki-67 expression resulted associated with disease-free survival. CONCLUSION: With an overall sensitivity of 67%, FDG-PET has shown to be useful in the preoperative work-up of patients with suspect lung carcinoid tumors. In particular it could have a role in larger tumors. These results warrant a prospective evaluation of FDG-PET in the staging of lung carcinoid tumor. PMID- 26416037 TI - A quantitative study about thyroid stunning after diagnostic whole-body scanning with 74 MBq 131I in patients with differentiated thyroid carcinoma. AB - AIM: The aim of this paper was to explore by a quantitative method whether a 74 MBq 131I scanning activity produces a stunning effect in patients with differentiated thyroid carcinoma (DTC). METHODS: We included 70 patients with DTC who had their first radioiodine treatment for ablation of thyroid remnants and/or metastases. All the patients received 1850~7400 MBq 131I. Before ablation, 34 patients (group A) performed a diagnostic scan (Dscan) 24 hours after the administration of 74 MBq 131I; 36 patients (group B) received 131I therapy without a previous Dscan. A therapeutic scan (Tscan) was performed after the ablation. The fractional concentrations of 131I in remnants or functional metastases were quantified on Dscan and Tscan, and were expressed as Dx and Tx respectively. The level of significance was set at 0.05. RESULTS: For group A, 67 foci were found both on Dscan and Tscan, the mean Dx and Tx was 26.13+/-37.98 and 7.46+/-10.63 (P=0.000), respectively. For group B, 70 foci were found on Tscan, the mean Tx was 15.23+/-17.23, which was higher than group A significantly (P=0.002). CONCLUSION: 74 MBq 131I for diagnostic scan can decrease the uptake of 131I by thyroid remnants or metastases, the thyroid stunning exists. PMID- 26416038 TI - VEGAWES: variational segmentation on whole exome sequencing for copy number detection. AB - BACKGROUND: Copy number variations are important in the detection and progression of significant tumors and diseases. Recently, Whole Exome Sequencing is gaining popularity with copy number variations detection due to low cost and better efficiency. In this work, we developed VEGAWES for accurate and robust detection of copy number variations on WES data. VEGAWES is an extension to a variational based segmentation algorithm, VEGA: Variational estimator for genomic aberrations, which has previously outperformed several algorithms on segmenting array comparative genomic hybridization data. RESULTS: We tested this algorithm on synthetic data and 100 Glioblastoma Multiforme primary tumor samples. The results on the real data were analyzed with segmentation obtained from Single nucleotide polymorphism data as ground truth. We compared our results with two other segmentation algorithms and assessed the performance based on accuracy and time. CONCLUSIONS: In terms of both accuracy and time, VEGAWES provided better results on the synthetic data and tumor samples demonstrating its potential in robust detection of aberrant regions in the genome. PMID- 26416039 TI - Reply to "Serum high-sensitivity C-reactive protein in patients with obstructive sleep apnea with special reference to metabolic syndrome" by Kawada (Letter to the Editor). PMID- 26416040 TI - Alternated intra-arterial and intravitreal chemotherapy for advanced intraocular retinoblastoma: preliminary successful results without systemic chemotherapy. AB - To describe the efficacy of intravitreal chemotherapy (IViC) preceded by intra arterial chemotherapy (IAC) for the treatment of advanced stage retinoblastoma. This non-comparative interventional case series retrospectively reviewed the medical records of six patients who presented within months of each other with unilateral retinoblastoma, Reese-Ellsworth stage Vb/D of ABC classification in the affected eye. After clinical and ophthalmoscopic evaluation, they underwent MRI to exclude local and CNS dissemination. The IAC was given to treat retinal masses and intravitreal injections to treat vitreous seeding. Patients had received two cycles (six infusions) of IAC, and from six up to ten melphalan injections into the vitreous, with an interval of 7-10 days between them. From one to four intravitreal injections were performed for partial remission or consolidation. No permanent complications of procedures have been reported. All patients underwent to bimonthly MRI examination, during treatment and every 3 months for 1 year after last injection, to exclude orbital dissemination. Successful control (100 %) of tumor masses and vitreous seeds was achieved in all cases at 12 months follow-up. Complications were posterior lens opacity, acute ischemic papillitis, partial CVR thrombosis, hypotonia (case 1), partial vitreous hemorrhage (case 4). No complications appeared in cases 2, 3, 5, and 6. No intraocular or orbital tumor recurrence or retinoblastoma metastases (follow-up range, 12-33 months) were observed. Sequential IAC and intravitreal melphalan for advanced retinoblastoma allowed to provide retinal and vitreous seed control. PMID- 26416041 TI - Prognostic impact of tumor lymphocytic infiltrates in patients with breast cancer undergoing neoadjuvant chemotherapy. AB - PURPOSE: The presence of a pronounced tumor lymphocytic infiltrate (TLI) is deemed to reflect the presence of an immunoinflammatory response against the tumor and may thus have prognostic significance. We investigated the prognostic value of TLI detected in pathological specimens collected following neoadjuvant chemotherapy (NACT) in patients with breast cancer. METHODS: 100 consecutive patients with breast cancer (mean age 47.8+/-11.4 years) who were scheduled to undergo anthracycline-and/or taxane-containing NACT were enrolled. Specimens collected after NACT were scored with the 4-point Klintrup scoring criteria for the presence of TLI. RESULTS: 60 patients had low-grade TLI and 40 high-grade TLI. Comparison of the patient population according to low-grade vs high-grade TLI revealed statistically significant difference both in terms of disease-free survival (DFS) (log rank-4.28, p<0.05) and overall survival (OS) (log rank=3.96, p<0.05), with high-grade TLI patients showing a better prognosis. Multivariate Cox regression analysis identified postoperative tumor size and low-grade TLI as the two main independent adverse prognostic factors. CONCLUSION: High-grade TLI may interfer with tumor growth and can represent a favorable prognostic factor in women with breast cancer undergoing NACT. PMID- 26416042 TI - Evolution of treatment and high-risk features in resectable locally advanced Head and Neck squamous cell carcinoma with special reference to extracapsular extension of nodal disease. AB - The employment of surgery as a single treatment modality for patients with resectable locally advanced head and neck squamous cell carcinoma (HNSCC) has been associated with high rates of locoregional recurrences even after adequate resection. The addition of postoperative radiotherapy (RT) as adjuvant to surgical resection for advanced HNSCC was investigated in an effort to decrease locoregional failure rates and improve treatment outcome. The unsatisfactory results in terms of locoregional control (LRC) and survival rates achieved with postoperative RT in patients with high-risk features have led to the necessity of exploring the role of concurrent chemotherapy in the adjuvant treatment in resectable advanced HNSCC with confirmed presence of high-risk pathological features. Two prospective randomized independent trials designed and conducted by Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) demonstrated that the addition of cisplatin-based chemotherapy improved LRC and disease-free survival (DFS). Significant improvement in overall survival (OS) with the use of postoperative concurrent chemoradiotherapy (CCRT) was observed in the EORTC trial. High-risk pathological features in patients with resected head and neck cancer representing adverse prognostic factors that are predictive for local and/or regional recurrence are related to the primary tumor and/or metastatic lymph nodes in the neck. Extracapsular extension (ECE) of nodal disease in the neck has been confirmed as a high-risk pathological feature negatively influencing LRC and survival in patients treated with either postoperative RT or postoperative CCRT. This article reviews the historical progress in the management of resectable locally advanced HNSCC and the impact of ECE on clinical outcome in patients treated with adjuvant therapy following surgery. It can be concluded that strong evidence exists for an improved outcome for high-risk resected patients treated with adjuvant CCRT. Precise definition of the presence of ECE is highly recommended in order to provide proper selection of patients who would benefit from the postoperative CCRT. PMID- 26416043 TI - The effect of obesity on recurrence pattern in early breast cancer patients. AB - PURPOSE: Obesity is a well known risk factor for breast cancer recurrence and poor prognosis. We studied the effect of body mass index (BMI) on recurrence pattern in early breast cancer patients. METHODS: This retrospective cross sectional study analyzed the data of 2731 early stage breast cancer patients. Patients who had metastatic disease at the time of diagnosis and with unknown BMI values were excluded from study (N=276). Patients were classified into three BMI categories: normal body weight, overweight, and obese. The recurrent/metastatic sites of patients were grouped in 8 categories: local, contralateral, lymph node, bone, lung, liver, brain and others. The association between first relapse site of early breast cancer patients and BMI categories were evaluated. RESULTS: The median patient age was 48 years (range 18-92). The median follow up time was 40 months (range 1-284). During follow-up, 469 (17.1%) patients developed recurrence and/or metastasis. Of 2455 total patients, 853 (34.6%) were classified as having normal weight, 898 (36.2%) were overweighted and 704 (29.2%) were obese. In the whole patient group no relation between metastatic sites and BMI groups was noticed. The first primary metastatic sites were also not associated with BMI groups in pre and postmenopausal subpopulations. In obese patients, disease free survival (DFS) was shorter compared to normal weighted patients, but the difference was not significant. There was no significant difference between site specific DFS in relation to BMI categorization. Obese and overweighted patients had significantly shorter overall survival (OS) compared to the normal-weight group (p=0.003). CONCLUSION: Although obesity had no effect on recurrence pattern of early breast cancer patients, obese early breast cancer patients had shorter OS compared to their normal-weight counterparts. PMID- 26416044 TI - Hepatic steatosis is associated with higher incidence of liver metastasis in patients with metastatic breast cancer; an observational clinical study. AB - PURPOSE: To investigate the relationship between hepatic steatosis (HS) (at the time of diagnosis) and hepatic metastasis (at the time of diagnosis and follow up) in metastatic breast cancer (BC) patients by using computed tomography (CT). METHODS: A total of 107 metastatic BC patients who had an abdominal CT were retrospectively enrolled in this study. Patients without HS (N=79) were regarded as the control group and those with HS constituted the HS study group (N-28). RESULTS: Hepatic metastases at diagnosis and during follow-up were more common in patients with HS (p=0.018 and p=0.041, respectively) and in the premenopausal group (p<0.001 and p=0.004, respectively), whereas they were similar in patients with and without HS in the postmenopausal group (p=0.655 and p=0.656, respectively). Overall survival rates were similar in patients with and without HS (p=0.606). CONCLUSION: Hepatic metastases at diagnosis and during follow-up were more frequent in patients with HS, especially in premenopausal patients. Survival was similar in both groups. PMID- 26416045 TI - Lack of association between +405 G/C polymorphism in VEGF and breast cancer risk: A meta-analysis. AB - PURPOSE: To explore whether the vascular endothelial growth factor (VEGF) +405 G/C polymorphism confers susceptibility to breast cancer (BC) by conducting a meta-analysis. METHODS: Publications addressing the association between the VEGF +405 G/C polymorphism and BC risk were selected from the PubMed, Embase and Google Scholar databases. Data were extracted from studies by three independent reviewers. The meta-analysis was performed by STATA 12.0 software, and odds ratio (OR) with 95% confidence interval (CI) were calculated. RESULTS: Finally, 10 case control studies were retrieved with a total of 8,855 BC patients and 9,393 controls. No significant association was identified between VEGF +405 G/C polymorphism and BC risk in overall populations under 5 models (C vs G: OR=1.001, 95% CI=0.896-1.119, p=0.987; CC vs GG: OR=1.006, 95% CI=0.853-1.186, p=0.997; CG vs GG: OR= 0.985, 95% CI=0.823-1.178, p=0.779; CC vs CGs/GG: OR=1.019, 95% CI=0.921-1.127, p=0.722; CC/CG vs GG: OR=0.985, 95% CI=0.835-1.162, p=0.862), and also in the subgroup analysis by ethnicity. CONCLUSION: Our study confirms that there is a lack of association between the VEGF +405 G/C polymorphism and BC risk. PMID- 26416046 TI - Epidemiological and clinicopathological characteristics of BRCA-positive and BRCA negative breast cancer patients in Greece. AB - PURPOSE: BRCA mutation carriers can benefit from targeted clinical interventions. On the other hand, families with evident aggregation of breast cancer (BC) cases and a BRCA-negative genetic test can still be considered as of elevated risk, since the underlying genetic factor remains unidentified. In the present study, we compared clinical and demographic characteristics between BRCA1 mutation carriers (BRCA1mut) and non-carriers (non-BRCA1) in a Greek group of BC patients (n=321). METHODS: Data were collected and analyzed from 321 women with BC, with 131 patients screened for pathogenic mutations in the high-penetrant genes BRCA1 and BRCA2. Collected data included demographics, pedigrees, tumor histopathology and immunohistochemistry findings. RESULTS: In BRCA1mut patients, their mothers and grand- mothers were diagnosed at a younger age compared to non-BRCA1 carriers. Additionally, BRCA1mut patients were diagnosed with mainly estrogen receptor (ER) negative (p<0.001), Her-2 negative (p<0.05) and triple negative (p<0.01) tumors. The youngest generation was diagnosed with familial breast cancer (FBC) 9.7 years earlier than their mothers (p<0.001). Age at BC diagnosis negatively correlated with the nuclear grade of breast tumors (r=-0.3, p<0.05). Among parous individuals, the number of full-term pregnancies significantly correlated with the age at BC onset (r=0.19, p<0.05). CONCLUSION: Despite their similarities, FBC cases with identified BRCA1 mutations exhibit a clearly distinct profile. We have identified an anticipation effect in FBC patients, with significantly reduced age at diagnosis in younger generations. Increased parity seems to prevent early BC onset. This is the first study comparing clinical and demographic characteristics of FBC BRCA1mut and non-carriers in a Greek cohort. PMID- 26416047 TI - Genetic polymorphisms in cell cycle regulatory genes CCND1 and CDK4 are associated with susceptibility to breast cancer. AB - PURPOSE: This study was performed to screen cyclin D1 (CCND1) and cyclin dependent kinases (CDK4) genes in order to evaluate their association with breast carcinogenesis. METHODS: The germline screening of these genes was carried out by combining polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP), followed by DNA sequence analysis. A total of 400 individuals (200 breast cancer patients and 200 healthy controls) were recruited prospectively for this study. RESULTS: Sequence analyses of the coding region of CCND1 revealed 12 mutations. When analyzed, a significant association was found between CCND1 mutations and breast cancer. It was observed that a 6-fold increased breast cancer risk (odds ratio/OR=5.75, 95% confidence interval/CI=1.26 26.33) was associated with Cys7Tyr in breast cancer patients when compared with healthy controls. In addition, a 5-fold increased breast cancer risk was associated with Trp63Stop mutation (OR=5.44, 95% CI=1.82-16.23), 10861C>A (OR=4.84; 95% CI=1.60-14.58) and 7720insTT (OR=5.32, 95% CI=1.98-14.23) in breast cancer patients compared to healthy controls. Concerning CDK4 gene, 5 mutations were identified and a significant association was observed between CDK4 gene mutations and breast cancer. It was observed that a 6-fold increased risk of breast cancer (OR=5.71, 95% CI=0.29-4.65) was associated with 5693 T>A. In addition, a 5-fold increased risk of breast cancer (OR=5.05, 95% CI=2.17-11.78) was associated with 5732 G>A in breast cancer patients compared to controls. CONCLUSION: In this study, our results showed that CCND1 and CDK4 mutations are associated with an increased risk of breast cancer, and may serve as biomarkers for early diagnosis and detection of breast cancer. PMID- 26416048 TI - Ipsilateral in-breast tumor recurrence after breast conserving therapy: true recurrence versus new primary tumor. AB - PURPOSE: To classify ipsilateral in-breast cancer recurrences (IBCR) in patients treated with conservative surgery and radiation therapy, either as new primary tumor (NP) or true recurrence (TR) and to assess the prognostic and therapeutic importance of this classification. METHODS: The records of 107 patients treated for local tu- mor recurrence after breast-conserving therapy (BCT) at the National Cancer Center, Sofia, between March 1999 and May 2011 were retrospectively analysed. The patients'primary tumors were up to 2 cm in size. For their primary tumors all patients underwent quadrantectomy, axillary lymph node dissection and postoperative radiotherapy (RT) up to 50 Gy. In cases with nodal metastasis additional RT has been used. Adjuvant chemotherapy and hormonotherapy have been used according to the clinical indications and depending of the patient's condition. Every attempt was made to define a tumor as a TR or NP, based on the changes in location and histology. (99m)Tc-MIBI SPECT-CT was used to localize the site of recurrence. RESULTS: Forty-four (41.1%) of the relapses were TR and 63 (58.9%) NPs. Out of 63 relapses defined as NPs, 54 (85.7%) changed the location and 49 (68.3%) had a different histology. The age of patients with TR and with NP did not differ significantly at the time of diagnosis of the primary tumor (TR 48.8+/-10.45 years vs NP 50.8+/-10.56; p<0.330), but those who developed TR were significantly younger than those with NP at the time of recurrence (TR 53 years, 66+/-11.1 vs NP 58.15+10.6; p<0.05). Recurrences defined as NPs, developed after a significantly longer period of time in comparison to the TRs (7.4+/-2.6 years vs 4.8+/-2.2 years; p<0.0001). Five year overall survival of patients with TR was significantly lower compared to patients with NP (31.8% vs 96.7% p=0.0001). CONCLUSIONS: Recurrences developing after BCT represent different clinical events, having different origin, prognosis and, therefore, requiring different type of treatment. It seems that a significant part of the recurrences that develop in the residual parenchyma, following BCT, are new carcinomas. PMID- 26416050 TI - Quality of life in colorectal cancer patients: an Izmir Oncology Group (IZOG) study. AB - PURPOSE: To investigate the variables of quality of life (QoL) among Turkish patients with colorectal cancer (CRC). METHODS: In this prospective study we investigated the QoL of Turkish CRC patients. Two hundred and twenty two patients with CRC were included. The sociodemographic form and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) were used. RESULTS: The study group consisted of 142 males (64%) and 80 females (36%). The mean patient age was 55.68+/-11.387 years. The majority of the patients (36.9%) had local disease while advanced-stage disease and locally advanced stage disease had 32.2% and 28.8% of the patients; respectively. The mean QoL score was moderate (62.81+/- 27.0). The most common complaints were fatigue, economic difficulties and constipation. Gender, education level and disease stage were associated with QoL. Physical, role and social functioning were more adversely affected in female patients. Compared to women, men had significantly more favorable global QoL (p=0.044). Some functional scales were worse in advanced disease compared to other stages.These outcomes were statistically significant in the functional scales of global health (p=0.007), physical (p=0.03), cognitive (p=0.01) and emotional function (p=0.007). Patients with advanced disease had worse outcomes in some symptoms (nausea, vomiting, dyspnea, loss of appetite and financial distress). CONCLUSIONS: Female gender and advanced disease were strongly associated with poorer QoL among Turkish CRC patients. PMID- 26416049 TI - Clinical presentation and management of gastro-intestinal and pancreatic secondary metastatic tumors. AB - PURPOSE: As progress regarding the treatment has occurred over recent years in oncology, more patients with metastatic disease are presented for diagnosis and further management. The purpose of this study was to reveal the incidence, location and to describe the clinical characteristics and outcome in a series of patients diagnosed with pancreatic, small and large bowel metastatic tumors that underwent metastasectomy. METHODS: A total of 12 patients (7 male and 5 female) diagnosed with extrahepatic gastrointestinal (GI) and pancreatic metastases from 2001 to 2013 were operated for resection of secondary metastatic tumors to the small and large bowel and the pancreas. Four out of 12 patients were asymptomatic and a secondary tumor was detected during follow up. RESULTS: The median interval revealing the metastatic tumor since the management of the primary tumor was 6.5 years (range 1-27). Primary tumors were malignant melanoma (4 patients), renal cell carcinoma (RCC; 2 patients), leiomyosarcoma of the uterus (2 patients), lobular breast cancer, mesenchymal chondrosarcoma of the skull, endometrial adenocarcinoma and a non-Hodgkin lymphoma (one case each). The median follow-up was 15 months (range 4-120). CONCLUSIONS: Metastatic secondary tumors have to be considered especially when the patient's medical history includes a previous malignancy. They may also occasionally present as the initial manifestation of an occult primary lesion leading to diagnostic difficulty. Although radical surgery is the most effective approach, treatment and survival grossly depend on histological type and the stage of the primary disease. Hence, management of these patients should be individualized by a multidisciplinary team. PMID- 26416051 TI - Factors influencing cost, length of hospital stay and mortality in colorectal cancer. AB - PURPOSE: Colorectal cancers (CRCs) are the most common cancers in the world after lung and prostate cancer in men and breast and lung cancer in women, and usually occur in the recto-sigmoid region. There are many factors that affect their morbidity and mortality. Some markers have been evaluated to predict disease prognosis. However, a gold standard prognostic biomarker has not yet been found for CRC. In the present study, we aimed to evaluate the factors associated with the duration and cost of hospital stay and mortality. METHODS: Patients who were admitted to the emergency service and general surgery clinic with abdominal pain, rectal bleeding, weight loss, diminished stool discharge, and ileus were included in this study. Recorded were patient age, gender, comorbid factors, family history, surgical treatment procedure, elective or urgent surgical intervention, bowel cleansing before surgery, pathological stage, neutrophil/lymphocyte ratio (NLR), red cell distribution width (RDW), mean platelet volume (MPV) and CEA, CA 19.9 and hemoglobin levels. RESULTS: The mean patient age was 61.2+/-12.4 years. The male/female ratio was 0.596(81/136). Emergency surgery was an independent factor increasing the cost and length of hospital stay (p=0.007 and p=0.018). Additionally, patients >65 years of age had increased length of hospital stay and mortality (p=0.008 and p=0.024, respectively). Anemic patients had 50% higher mortality risk compared with patients with normal hemoglobin levels (p=0.030). CONCLUSION: Based on our results, anemic patients in the geriatric population who underwent emergency CRC surgery may have higher costs, longer hospital stay and greater mortality rates than other CRC patients. PMID- 26416052 TI - Significance of serum and bile tumor markers in the diagnostic approach of patients with malignant pancreatobiliary disease. AB - PURPOSE: Serum and bile tumor markers are under intense scrutiny for the diagnosis of malignant disease. The purpose of our study was to report the usefulness of serum and bile tumor markers for the discrimination between benign and malignant pancreatobiliary diseases. METHODS: Between March 2010 and May 2013, 95 patients with obstructive jaundice or history of biliary obstruction, were included in the study. During ERCP, bile samples were obtained for measurement of tumor markers CEA, CA19- 9, CA125, CA72-4 and CA242. Serum samples were taken before ERCP for the same measurements. The patients were divided into two groups: patients with malignant disease and patients with benign disease. RESULTS: Serum tumor marker levels were significantly higher in patients with malignant disease. Serum CA242 and CA19-9 exhibited the highest diagnostic accuracy (76.8% and 73.7%, respectively). CA125 and CA72-4 levels in bile samples were significantly higher in patients with malignant disease. Bile CA125, CEA and CA72-4 achieved the best diagnostic accuracy (69, 65 and 65), respectively). The combined detection of CA19-9, CA242 in serum and CA125, CA72-4 in bile along with total bilirubin levels, showed the best diagnostic accuracy (81%). CONCLUSIONS: Serum and bile tumor markers, when studied alone, lack the diagnostic yield to discriminate benign from malignant pancreatobiliary diseases. In cases of diagnostic dilemmas the combination of serum and bile markers might be helpful. PMID- 26416053 TI - Transcatheter arterial chemoembolization combined with microwave coagulation therapy and the perioperative care for patients with hepatocellural carcinoma. AB - PURPOSE: To explore the value of artificial hydrothorax microwave coagulation combined with transcatheter arterial chemoembolization (TACE) therapy in the treatment of ultrasound-invisible malignant tumors in the hepatic dome (mainly hepatocellular carcinoma/HCC) and the perioperative care for the patients. METHODS: Sixty-eight patients with malignant liver tumors in the hepatic dome were treated with a combination therapy of TACE and microwave coagulation via an artificially induced hydrothorax. Their perioperative condition was under close observation and the nursing care was intensified. Paracentesis of the chest was successfully carried out via the positioning of ultrasound and guidance of microwave to the tumor site, so that the tumor could be treated with cold cycle microwave coagulation therapy. RESULTS: After treatment, 3/68 patients (4.4%) achieved complete tumor ablation, while 59/68 (86.8%) achieved tumor ablation >50% or tumor shrinkage >30%. Another 6/68 patients (8.8%) achieved tumor ablation <50% or tumor shrinkage <30%. Of 45 patients, 42 (93.3%) obtained a reduction of AFP level >50% post-therapy, 28/37 patients (75.7%) achieved a reduction of CEA level >50%, 23/29 patients (79.3%) achieved a reduction of CA19 9 level> 50%; 3/68 patients (4.4%) survived for 4 to 6 months, 31/68 (45.6%) survived >6 months and 34/68 (50%) survived >12 months. No bleeding, liver failure, infection or needle tract seeding occurred after the operation, and no treatment-related deaths occurred. CONCLUSION: Microwave coagulation combined with TACE for HCC in the hepatic dome is safe and effective. Perioperative observation and nursing care can not only reduce the complications but also improve the therapeutic effect and the patient quality of life. PMID- 26416055 TI - Laparoscopic left lateral hepatectomy for colorectal metastasis is the standard of care. AB - PURPOSE: Over the last decade, laparoscopic liver surgery has significantly evolved. The aim of this study was to analyse the outcomes of Laparoscopic Left Lateral Hepatectomy (LLLH) for colorectal cancer (CRC) metastases in a tertiary referral hepato-pancreato-biliary centre. METHODS: A consecutive series of patients undergoing LLLH between January 2009 and April 2013 were analysed using prospectively collected data in a tertiary referral HPB centre. In particular, the study focused on patients who had LLLH for colorectal liver metastasis (CRLM). The following features were analysed: operative time, intraoperative blood loss, number and size of tumours, resection margins, complication rates, follow up period and recurrence rates. RESULTS: A total of 17 patients were finally included. There were no bile leaks or collections and no postoperative bleeding. The median hospital stay was 4 days (range 2-10). The median size of the metastatic lesions was 28.1 mm (range 8-56). The resection was R0 in all except 2 patients (11%) where the margin was less than 1 mm. The mean resection margin was 14.6 mm (range 1-50). Eight patients (47%) did not develop any recurrence till latest follow up. Seven patients (41%) developed recurrence in the liver or lungs. The median time to recurrence was 11 months (range 2-12). There was only one death in the follow up period (22-77 months). Sixteen patients (94%) were alive at the latest follow up. CONCLUSION: LLLH for CRLM is safe and can be performed with low complication rates, adequate resection margins, short hospital stay, and oncologic outcomes similar to those of open surgery. PMID- 26416054 TI - In vivo study of the effect of combining endostatin gene therapy with 32P-colloid on hepatocarcinoma and its functioning mechanism. AB - PURPOSE: To investigate the therapeutic effect of combining 32P colloid radiotherapy with endostatin anti-angiogenesis therapy on hepatocellular carcinoma (HCC) cells. METHODS: HCC mouse models were prepared using H22 cells and randomly divided into four groups. The mice were administered phosphate buffered saline (PBS), (32)Pcolloid, secretory endostatin encoding plasmid and combination of 32P and endostatin, respectively. Seven, 14 and 21 days after treatment the mice were sacrificed. Expression of endostatin was confirmed using western blot. Tumor growth rate, microvessel density (MVD) in the solid tumor and apoptotic index (AI) of tumor cells was analyzed using immunohistochemistry and TUNEL methods. RESULTS: (1): From the western blot results, 1400 bp endostatin specific protein bands were observed in the samples from groups 3 and 4, but not in the other two groups; (2): The tumor growth rate of groups 2, 3 and 4 was significantly decreased compared to group 1 and that of group 4 was significantly lower than group 2 and 3 (3): The MVD of group 1 was greatly higher than in the other groups (4): The AI of group 4 was dramatically higher than in the other groups. CONCLUSIONS: (32)Pcolloid radiotherapy or endostatin anti-angiogenesis therapy were able to inhibit the growth of HCC cells in vivo, while the combination of (32)P and endostatin showed much better therapeutic effect in HCC treatment. PMID- 26416056 TI - Evaluation of c-kit (CD 117) expression as a prognostic factor in testicular germ cell tumors: an Izmir Oncology Group (IZOG) study. AB - PURPOSE: Despite the successful use of targeted and molecular therapies in other cancers, little progress has been made in the management of testicular germ cell tumors (TGCTs). c-kit (CD 117) is a good target for cancer treatment and possesses an impressive role in the current oncological practice. We aimed to evaluate c-kit expression in early stage TGCTs as a prognostic factor. METHODS: Patients with TGCTs who were referred to the Medical Oncology Clinic and underwent curative surgical operation were included in our study before starting chemo- therapy. Immunohistochemistry was performed on formalin-fixed and paraffin embedded three-micrometer thick sections with CD 117 Rabbit Anti c-kit in vitro gene kit. Biochemically, we utilized AFP and beta-HCG Immunlite 2000 device with solid phase chemiluminescent immunometric method, and LDH Roche models with the DP-standardized UV method. AFP 0-15 ng/ml, beta-HCG < 0.1 mlu/ml and LDH 240-480 mg/dl were considered as normal values. RESULTS: Sixty-five patients were included in our study. Forty-one (63%) patients had non-seminoma tumors (NSGCTs) and 24 (37%) had seminoma. Statistically significant c-kit expression was found in patients with seminoma (p<0.0001). There was no difference between negative or positive c-kit expression in terms of clinicopathological characteristics, including preoperative serum levels of AFP, beta-HCG, LDH, lymph node involvement, distant metastasis, and IGCCCG risk classification. No correlation was found between these parameters and 5-year progression free survival (PFS) rate except for tumor stage, presence of lymph node metastasis and IGCCCG score (p=0.001, p=0.04, and p=0.0001, respectively). Five-year PFS rate of patients with positive CD 117 was 72.2% (95% CI, 54.6-89.8), and 56.6% (95% CI, 31.2-82.1) for those without CD 117 expression involvement (p=0.12). CONCLUSION: So far, there has been no significant breakthrough in the treatment of cisplatin refractory TGCTs in the era of targeted therapies. No prognostic importance of c kit expression has been found in our study. However, we believe that c-kit expression, in numerical terms, can be considered as a good prognostic factor for patients with TGCTs. The fact that all seminoma cases displayed positive c-kit expression is what we think has driven this result. PMID- 26416057 TI - Combination of adjuvant radiotherapy and androgen deprivation therapy after radical prostatectomy in high risk prostate cancer patients - results from retrospective analysis. AB - PURPOSE: We retrospectively evaluated the outcome in prostate cancer (PCa) patients receiving combination of adjuvant radiotherapy (ART) and androgen deprivation therapy (ADT) after radical prostatectomy (RP). METHODS: Between 2004 and 2012, 132 patients were referred for ART to the Department of Oncology, University Hospital, Split. Fifty-six consecutive patients with at least one proven or possible adverse prognostic factor such as pelvic lymph nodes invasion (LNI), lymphovascular invasion (LVI), high tumor grade and high preoperative prostatic specific antigen (PSA) level received combination of ART and ADT, while 76 patients received ART alone. The ADT consisted of a luteinizing hormone releasing hormone (LHRH) agonist or bicalutamide at a dose of 150 mg per day. The duration of ADT was left at the discretion of the treating physician and it lasted 6 to 36 months (median 24).The effect of combination of ART and ADT on biochemical relapse-free survival (bRFS), metastases-free survival (mFS), disease specific survival (DSS) and overall survival (OS) was estimated using the Kaplan Meier method. RESULTS: After a median follow-up time of 61 months (range 13.6 113), the 5- and 7-year bRFS were 90.5 and 77.2%, respectively. Distant relapse occurred in 5 patients, resulting in 5- and 7-year mFS of 95.9 and 81.7%, respectively. During follow-up, 7 patients died (2 PCa deaths), resulting in 5- and 7-year DSS and OS of 100% and 94.7% and 90.6 and 81.5%, respectively. CONCLUSIONS: This retrospective study shows high bRFS, mFS, DSS and OS rates with the combination of ART and ADT in high-risk PCa patients. PMID- 26416058 TI - Robotic-assisted radical prostatectomy - the 5-year Romanian experience. AB - PURPOSE: Radical prostatectomy is the standard therapeutic approach for localized prostate cancer. After the implementation of robotic surgery in Romania, the indication extended progressively to locally advanced prostate cancer. Our objective was to evaluate the oncological and functional outcomes in patients undergoing robotic-assisted radical prostatectomy (RARP), 5 years after the first intervention in Romania. METHODS: Between November 2009 and July 2014, 207 RARPs were performed using the da Vinci SI Surgical System. Perioperative data were prospectively collected. The oncological and functional follow-up was up to 55 months (range 3-55). RESULTS: Patient stratification according to D'Amico risk categories was 16% low risk, 56.7% intermediate risk and 27.3% high risk. Median console time was 210 min (range 160-360). Median blood loss was 300 ml (range 50 1300), transfusion being required in 2.9% of the cases. Histopathological examinations showed pT3 in 40.8% of the cases, with a positive surgical margin rate of 21.1%, 13.6% for pT2, and 32.1% for pT3. Continence rate (0-1 daily safety pad) at 6, 12, 24 and 55 months was 88.3, 88.8, 90.1, and 93.7% respectively. Overall sexual function restoration rate at 6, 12, 24 and 55 months was 41.1, 44.4, 47.4 and 53%, respectively. Biochemical recurrence rate during follow-up was 6.9%. CONCLUSIONS: RARP is a minimally invasive therapeutic approach for prostate cancer, with acceptable outcomes, even in countries such as Romania, where the detection rate for localized prostate cancer is lower compared to other European countries due to lack of national screening programs. PMID- 26416059 TI - Association of p16 gene methylation with prostate cancer risk: a meta-analysis. AB - PURPOSE: The tumor suppressor gene p16 is frequently silenced and inactivated by hypermethylation in human cancers, including prostate cancer. However, the association between the methylation status of p16 and prostate cancer risk remains ambiguous. This study aimed to assess the association of p16 methylation with prostate cancer risk by a comprehensive metaanalysis. METHODS: Relevant studies were identified by searching PubMed, Embase and Web of Science databases before October 2014 with no restrictions. The strength of the association between p16 methylation and prostate cancer risk was assessed by combined odds ratio (OR) and 95 % confidence interval (CI). The between-study heterogeneity and the contributions of single studies to the final results were tested by chi-square based Q test and sensitivity analyses, respectively. Publication bias was evaluated by funnel plots. RESULTS: A total of 1,296 samples from 12 independent studies were enrolled in the present metaanalysis. Overall, a significant association was observed between p16 methylation and prostate cancer risk (OR=3.06; 95% CI:1.34- 6.98;p=0.008). Stratified analyses by ethnic groups further revealed that prostate cancer risk was increased for individuals carrying the methylated p16 compared with those with unmethylated p16 in Caucasian populations (OR=2.51;95% CI:1.01-6.26;p=0.047) and Asian populations (OR=9.50;95% CI:1.78-50.61;p=0.008). CONCLUSIONS: This study identified a strong association of p16 methylation with prostate cancer risk and suggested that p16 methylation might be a potential biomarker for prostate cancer. PMID- 26416060 TI - Interfraction variation in prostate cancer - analysis of 11726 cone-beam CT. AB - PURPOSE: To investigate the setup margins in prostate cancer treatment without using daily online repositioning methods. METHODS: We analysed the data from patients treated with curative-intend radiotherapy. Each patient underwent a series of pretreatment online localizations during daily setup using conebeam CT. The skin-prostate shifts and bone-prostate shifts were recorded in anteroposterior (AP), craniocaudal (CC), and laterolateral (LL)direction. The safety margins based on van Herk equation (2.5Sigma+0.7sigma) were calculated and the correlations between margins and various patient characteristics and prostate locations were investigated. RESULTS: A total of 307 patients were included, representing 11,726 localisations resulting in 70,356 shifts. The man skin prostate setup inaccuracy was 0.8 +/- 5.4mm in AP, 1.3 +/- 4.8mm for CC, and 0.1 +/- 5.6mm in LL direction. The man bone-prostate setup inaccuracy was 0.4 +/- 3.3mm in AP, 0.1 +/- 2.5mm for CC, and 0.1 +/- 1.4mm in LL direction. According to van Herk equation, clinical target volume (CTV)-planning target volume (PTV) margins of 11.4, 10.6, and 11.8 mm (AP, CC, and LL, respectively) would be required for setup using skin markers and margins of 7.0, 4.7, and 2.1mm would be necessary for setup using bone structures. The average rectal area < 11cm(2) and volume of bladder > 300 cm(3) were associated with smaller CTV-PTV margins for setup using bone structures. The largest margins (15.8 mm in LL direction) were needed in patients with body mass index (BMI) > 35 using skin markers. CONCLUSIONS: Our results confirm that the commonly used CTV-PTV margins are inadequate. PMID- 26416061 TI - Clinical significance of nucleostemin and proliferating cell nuclear antigen protein expression in non-small cell lung cancer. AB - PURPOSE: To investigate the expression and significance of the expression of nucleostemin (NS) and proliferating cell nuclear antigen (PCNA) protein in non small cell lung cancer (NSCLC). METHODS: Immunohistochemistry (streptavidin peroxidase method) was used to detect NS and PCNA expression in 53 NSCLC samples and 15 normal lung samples. RESULTS: NS protein expression was detected in 54.7% (29/53) of the NSCLC samples and 0% (0/15) of the normal lung samples (p<0.01). Furthermore, the positive expression rate of PCNA was 6.67% (1/15) in normal lung samples and 71.7% (38/53) in NSCLC samples (p<0.05). Also, the NS protein expression rate was 65.2% (15/23) in adenocarcinoma tissue samples, significantly higher than that in squamous tissues, where the NS expression rate was 46.7% (14/30) (p<0.05). In addition, the NS expression rate of 42.9% (15/35) in well or moderately differentiated tumor tissues was lower than the rate of 77.8% (14/18) in poorly differentiated tumor tissues (p<0.05). The grade of differentiation had no correlation with tumor-node-metastasis (TNM) stage and lymph node metastasis (p>0.05). Also, the positive expression rate of PCNA was significantly higher in NSCLC samples than in normal lung samples (p<0.05). In addition, a positive correlation was found between NS and PCNA expression in NSCLC (p<0.05). CONCLUSION: The highly valuable tumor molecular markers, NS and PCNA, had higher expression levels in NSCLC samples. Combined detection of NS and PCNA may be important for the early diagnosis of lung cancer and individualized therapy, having also an important role in predicting tumor prognosis. PMID- 26416062 TI - Wnt/beta-catenin signaling pathway in lung cancer stem cells is a potential target for the development of novel anticancer drugs. AB - PURPOSE: In the present study, we have analyzed the regulation of Wnt/beta catenin signaling in lung adenocarcinoma stem cells (CSCs), that are responsible for tumor recurrence. METHODS: Lung cancer samples were studied for the presence of cancer stem like cells and analyzed by flow cytometry. Then, the sorted cells were analyzed for the stem cell surface markers and Wnt/beta-catenin signaling pathways. Moreover, the sorted side population (SP) and non-SP cells were also subjected to drug resistance assay. RESULTS: Western blot analysis showed that the protein level of beta-catenin was highly upregulated in fluorescence activated cells (FACs) sorted SP cells which led to elevated expression of stem cell protein Oct-4 that is responsible for SP cells' self-renewal. RT-PCR revealed that the relative mRNA expression level of Wnt target gene cyclin D was significantly higher (p<0.01) in SP cells, enhancing thus the cell proliferation rate and clone formation efficiency. In addition, the matrigel invasion assay revealed that SP cells were highly invasive than non-SP cells. CONCLUSION: In the present study we demonstrated that lung adenocarcinoma samples contain a small population of tumor-initiating SP cells which possess the characteristic features of CSCs. Wnt/beta-catenin mediated increased expression of beta-catenin, Oct-4 and cyclin D in SP cells but not in non-SP cells was also observed. FACs-purified SP cells are resistant to a number of chemotherapeutic drugs. Our data suggest that the use of novel anticancer drugs, targeting Wnt/beta-catenin signaling pathways, may help eradicate the lung cancers stem cells. PMID- 26416063 TI - Expression and clinical contribution of MRGD mRNA in non-small cell lung cancers. AB - PURPOSE: MAS-related G protein-coupled receptor, member D (MRGD) has been reported to be involved in tumorigenesis in vivo. However, the clinical role of MRGD in non-small cell lung cancer (NSCLC) remains unclarified. The purpose of the current study was to detect the expression of MRGD mRNA in NSCLC formalin fixed (FF), paraffin-embedded (PE) tissues and to investigate the clinicopathological significance of the MRGD level in NSCLC patients. METHODS: The expression of MRGD mRNA was examined in 125 NSCLC tissue samples together with paired para-noncancerous FF/PE tissues by using real time quantitative PCR (qRT-PCR). Furthermore, the relationship between MRGD level and clinicopathological parameters of NSCLC was analyzed. RESULTS: The average level of MRGD in NSCLC tumor tissues (1.0682+/-0.6096) was remarkably higher than that in the adjacent non-cancerous lung tissue (0.3994+/-0.2838, p<0.001). The area under curve (AUC) of receiver operating characteristic curve (ROC) of MRGD mRNA was 0.853 (95% CI: 0.808-0.898, p(0.001). Moreover, the level of MRGD mRNA was found to be correlated to lymph node metastasis (r=0.219, p=0.014), tumor size (r=0.221, p=0.013) and clinical TNM stage (r=0.187, p=0.037). Finally, the survival of patients in high MGRD expression group was 7.94+/-9.85 months, remarkably shorter than that of the low expression group (20.84+/-1.19 months, p=0.049). CONCLUSIONS: MRGD may be a vital diagnostic and prognostic factor in NSCLC. MRGD possesses the potential to become a new target for the molecular therapy of NSCLC. PMID- 26416064 TI - Inhibition of tumor necrosis factor alpha using RNA interference in oral squamous cell carcinoma. AB - PURPOSE: Oral squamous cell carcinoma (OSCC) is a disease with increased prevalence and unfavorable prognosis calling for development of novel therapeutic strategies. Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine implicated in the development and progression of cancer. The present study was designed to assess the impact of TNF-alpha specific inhibition using small interference RNA (siRNA) in SSC-4 cells, a representative model for OSCC. METHODS: The present study evaluated the effect of TNF-alpha inhibition using siRNA as inhibitory mechanism on SCC-4 cells. The study focused on the effect of TNF-alpha inhibition on apoptosis, autophagy and invasion in parallel with a panel of 20 genes involved in apoptosis and angiogenesis. RESULTS: TNF-alpha inhibition was related with reduction of cell viability, activation of apoptosis and autophagy in parallel with the inhibition of migration in SCC-4 cells. Evaluating the impact on gene expression levels, inhibition of FASL-FADD, NFkappaB, SEMA 3C, TNF-alpha, TGFB1, VEGFA, along with activation of PDGFB and SEMA 3D was observed. Our study confirms the important role of TNF-alpha and sustains that it might be a therapeutic target in OSCC. CONCLUSIONS: TNF-alpha is a key mediator of the immune system, with important role in OSCC tumorigenesis, and might be considered as a therapeutic target using siRNA technology, particularly for those risk cases having FASL/FADD overexpressed. PMID- 26416065 TI - Cardiac tumors: a retrospective multicenter institutional study. AB - PURPOSE: Primary cardiac tumors are uncommon but not extremely rare. Cardiac tumors, mostly intracavitary, include benign and malignant tumors that arise from the endocardium, heart valves or myocardium. This retrospective study summarizes the experience of the Cardiac Surgery Departments of three tertiary Hospitals in this field, and particularly in cardiac myxomas, over the last 29 years. Herein, we present the results of cardiac tumors excision in relation to postoperative morbidity and mortality. METHODS: Between 1985 and 2014, 117 patients, aged from 16 to 82 years, underwent resection of a cardiac tumor. RESULTS: Ninety one of the tumors (77.78%) were myxomas, 15 of them (12.82%) were other primary cardiac tumors, 7 of them (5.98%) were infra-diaphragmatic tumors and the remaining 4 tumors (3.42%) were benign intracavitary masses (thrombi). Patients operated on for a cardiac tumor had a 30-day mortality rate of 3.29%. Atrial fibrillation appeared in 21 out of 91 patients (23.07%) operated on for cardiac myxoma, while neurological complications were observed in 3 patients (3.29%). Re-exploration for bleeding was performed in 5 out of 91 cases (5.49%) and recurrence occurred in 4.39% of myxomas. CONCLUSIONS: Despite being rare, primary cardiac tumors require open heart intervention soon after their diagnosis in order to prevent complications and achieve low mortality rates. PMID- 26416066 TI - Evaluation of mycosis fungoides management by total skin electron beam therapy with "translational technique". AB - PURPOSE: The aim of this study was to evaluate the outcomes of total skin electron beam therapy (TSEBT) with "translational technique" in the management of mycosis fungoides (MF). METHODS: Between January 1995 and October 2014, 51 patients with MF were treated using TSEBT with translational technique. The total dose was 2800-3600 cGy, de-livered in 7 to 20 fractions. Out of the total 51 patients, 22 (43.1%) had T2 (generalized patch/plaque) disease, 20 (39.3%) had T3 disease (tumor stage), and 9 (17.6%) had T4 (erythrodermic) disease. Radiation related late skin injury parameters including atrophy, pigmentation changes, hair loss, telangiectasia and ulceration were assessed according to RTOG/EORTC Late Radiation Morbidity Scoring Schema after at least 3 months from TSEBT. RESULTS: Treatment response was categorized as complete remission (CR), partial remission (PR), or non-responding (NR) lesions. After TSEBT with translational technique, CR rate was 68.6% and PR rate 23.5%, while the NR rate was 7.9%. Overall, the rates of grade 1, grade 2, grade 3, and grade 4 toxicity were 17.6% )9 patients), 39.3% (20 patient), 35.3% (18 patients), and 7.8% (4 patients), respectively. At a median follow-up of 79 months (range 14-142), overall survival (OS) and disease free survival (DFS) rates were 83% and 46%, respectively. CONCLUSION: For patients with MF refractory to topical chemotherapy and phototherapy, TSEBT with translational technique offers excellent local control (LC: CR+PR) and favorable OS rates along with substantial relief of symptoms. PMID- 26416067 TI - Splenic irradiation as palliative treatment for symptomatic splenomegaly due to secondary myelofibrosis: a multi-institutional experience. AB - PURPOSE: To evaluate the impact of splenic irradiation as a palliative treatment for symptomatic splenomegaly due to secondary myelofibrosis. METHODS: Seventeen patients with chronic myelogenous leukemia and 3 with idiopathic polycythaemia presented with splenomegaly, splenic pain and anemia. Due to symptomatic splenomegaly, despite first-line treatment, the patients underwent splenic irradiation. Two patients received two different schedules of external radiotherapy (580 cGy in 5 fractions and 600 cGy in 6 fractions). Eight patients received 980 cGy in 14 fractions. Ten patients received two courses of 360 cGy in 6 fractions, 3 months apart. Median follow-up was 12 months post irradiation. RESULTS: The patients showed excellent response to treatment one month post radiotherapy, while treatment was well tolerated without severe toxicity. The dimensions of the spleen decreased significantly. Pain-related Visual Analogue Score (VAS) regressed after completion of irradiation. During 12-month follow-up all patients maintained the benefit of radiotherapy. CONCLUSION: This study indicates that splenic irradiation could be a safe and effective palliative treatment for symptomatic splenomegaly due to secondary myelofibrosis. PMID- 26416068 TI - Cutaneous melanoma in Turkey: analysis of 1157 patients in the Melanoma Turkish Study. AB - PURPOSE: To develop a large Turkish National Melanoma registry in order to define demographic and clinicopathologic characteristics of patients with melanoma. METHODS: The data was collected from 1635 patients with melanoma through a web based registry system in 22 centers. Herein we present the results of 1157 patients with cutaneous melanoma. RESULTS: The patient median age was 56.4 years and 646 (55.8%) were males. The commonest subtype was superficial spreading type (357, 30.9%). The commonest primary site was the lower extremities (N=353, 30.5%). The most common Breslow thickness was 1-2 mm (361 patients, 43.5%). Only 104 (12.5%) patients had a thickness <1mm. Among 694 patients with available data, 136 (19.6%) presented with stage 4 disease while the most frequent stage was stage 3, encountered in 393 (56.6% patients). CONCLUSION: Our melanoma registry is the largest in our country providing a snapshot view of cutaneous melanoma and its care. Our patients presented with more advanced stages and they had worse prognosis compared to SEER database. PMID- 26416069 TI - Association of heme oxygenase-1 polymorphisms with cancer risk: A systematic review and meta-analysis. AB - PURPOSE: Observational studies have recently focused on the association between heme oxygenase-1 (HMOX1) gene promoter polymorphisms and cancer risk. However, conflicting results have been obtained. To derive a precise estimate of the association, a systematic review and meta-analysis were conducted. METHODS: This study followed the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses. PubMed, Medline, Embase and Web of Knowledge were systematically searched for relevant studies. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for the allelic and genotypic comparisons according to the homozygous, heterozygous, dominant, and recessive genetic models. Between-study heterogeneity was quantified through I2 statistics, and publication bias was appraised by using funnel plots. Sensitivity analyses were conducted to evaluate the robustness of the meta-analysis findings. RESULTS: Meta-analysis of 9 studies involving 2491 cases and 3380 controls did not reveal any significant association of the HMOX-1 (GT)n and 413A>T polymorphisms with cancer risk. Stratified analysis by ethnicity showed a statistically significant association between (GT)n repeat length variant and susceptibility to cancer for the heterozygous genetic model among Asian populations (OR=1.42, 95% CI: 1.04 1.95, Pheterogeneity=0.218), which is a robust finding according to sensitivity analysis. Funnel plot inspection did not reveal any publication bias. CONCLUSION: In conclusion, this study comprehensively examined the available literature on the association of HMOX-1 (GT)n and 413A>T polymorphisms with cancer risk. Meta analysis results suggest (GT)n repeat length polymorphism as a potential susceptibility variant for cancer in Asians. Additional large-scale and well designed studies are needed to confirm these results. PMID- 26416070 TI - Stereotactic body radiation therapy patient specific quality assurance using a two-dimensional array at extended source to surface distance. AB - METHODS: Five patients with 38 fields have been analyzed in this study. The plans were optimized for the following clinical sites: one liver, one lung, one brain, one prostate and one spine. The detector array used for the measurements was the PTW Seven29 array. All the plans were optimized and calculated using Eclipse v8.9. The center of the array was setup at 215 cm from the source and all the fields were measured and analyzed one by one. All the 30 measurements were performed on a NovalisTX linear accelerator equipped with a high definition multileaf collimator. The evaluation was based mainly on gamma index passing rates using 2 mm distance to agreement (DTA) and 2% dose difference. RESULTS: The accuracy of the Eclipse Treatment Planning System (TPS) at extended Source to Surface Distances (SSDs) using an ionization chamber was measured to be within 1.0%. All the field measurements were performed and analyzed 35 individually. The percent of the points that had a gamma index of less than 1 using 3%/3 mm was >99% for all the measurements. In order to better evaluate our process and distinguish smaller differences a new set of results was obtained by applying gamma index tolerances of 2%/2mm. In this case, the gamma index passing rates ranged from 90.8 to 100% (95.5%+/-3%). The profile comparison showed that the detector array measurements followed closely the calculated 40 profiles, even for fields optimized with multiple peaks and valleys. CONCLUSION: The choice of the IMRT QA device has an important role in the results of the patient specific QA of the delivered dose to the patient in the case of small targets as in the treatment of spinal targets. In this study, we demonstrated that an extended SSD measurement can improve the sampling resolution of a two-dimensional (2D) detector array, in our case the PTW 45 Seven29 array. This method was shown to be accurate and efficient for measuring highly modulated small fields for pre treatment patient specific QA. PMID- 26416071 TI - Primary thyroid lymphoma: The two ends of the spectrum. AB - We describe two different cases of prinary thyroid lymphoma (PTL). PTL is a rare malignancy. Nevertheless, it frequently presents diagnostic and therapeutic challenges. The first patient, a 79-year-old female, presented with a large, painless thyroid mass accompanied by severe obstructive symptoms of the upper respiratory and gastrointestinal track. The second patient (67-year-old female) presented with nodular goiter. Thyroidectomy - performed on the first patient for alleviation of obstructive symptoms - revealed the presence of a diffuse large B cell lymphoma. Although she was administered standard chemotherapy she deceased four months later. In the second patient, primary thyroid lymphoma was an incidental finding following thyroidectomy performed for nodular goiter. These two cases illustrate the variable course of PTL, the possibility of which should be kept into consideration in clinical practice. PMID- 26416072 TI - Early start of adjuvant chemotherapy in breast cancer. PMID- 26416073 TI - Extremely high level of CA 19-9 in a patient with metastatic pancreatic cancer and chronic renal failure- Second highest level of CA 19-9 in the literature. PMID- 26416074 TI - Avenzoar's (1091-1162) clinical description of cancer. AB - In the 11(th) and 12(th) century the Western caliphate flourished, making Cordoba the capital of physicians and philosophers. During that period lived and practised the famous physician Ibn Zuhr or Avenzoar. In his monumental treatise Al Taysir, Avenzoar provided the first clinical description of a polypoid colorectal tumour as well as the case of a uterine cancer and a basal cell carcinoma. His medical work remained popular through middle ages, influencing the development of western medicine. PMID- 26416075 TI - Cost effectiveness and resource allocation of Plasmodium falciparum malaria control in Myanmar: a modelling analysis of bed nets and community health workers. AB - BACKGROUND: Funding for malaria control and elimination in Myanmar has increased markedly in recent years. While there are various malaria control tools currently available, two interventions receive the majority of malaria control funding in Myanmar: (1) insecticide-treated bed nets and (2) early diagnosis and treatment through malaria community health workers. This study aims to provide practical recommendations on how to maximize impact from investment in these interventions. METHODS: A simple decision tree is used to model intervention costs and effects in terms of years of life lost. The evaluation is from the perspective of the service provider and costs and effects are calculated in line with standard methodology. Sensitivity and scenario analysis are undertaken to identify key drivers of cost effectiveness. Standard cost effectiveness analysis is then extended via a spatially explicit resource allocation model. FINDINGS: Community health workers have the potential for high impact on malaria, particularly where there are few alternatives to access malaria treatment, but are relatively costly. Insecticide-treated bed nets are comparatively inexpensive and modestly effective in Myanmar, representing a low risk but modest return intervention. Unlike some healthcare interventions, bed nets and community health workers are not mutually exclusive nor are they necessarily at their most efficient when universally applied. Modelled resource allocation scenarios highlight that in this case there is no "one size fits all" cost effectiveness result. Health gains will be maximized by effective targeting of both interventions. PMID- 26416076 TI - Repairing the basic defect in cystic fibrosis - one approach is not enough. AB - Cystic fibrosis has attracted much attention in recent years due to significant advances in the pharmacological targeting of the basic defect underlying this recessive disorder: the deficient functional expression of mutant cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels at the apical membrane of epithelial cells. However, increasing evidence points to the reduced efficacy of single treatments, thus reinforcing the need to combine several therapeutic strategies to effectively target the multiple basic defect(s). Protein-repair therapies that use potentiators (activating membrane-located CFTR) or correctors (promoting the relocation of intracellular-retained trafficking mutants of CFTR) in frequent mutations such as F508del and G551D have been put forward and made their way to the clinic with moderate to good efficiency. However, alternative (or additional) approaches targeting the membrane stability of mutant proteins, or correcting the cellular phenotype through a direct effect upon other ion channels (affecting the overall electrolyte transport or simply promoting alternative chloride transport) or targeting less frequent mutations (splicing variants, for example), have been proposed and tested in the field of cystic fibrosis (CF). Here, we cover the different strategies that rely on novel findings concerning the CFTR interactome and signalosome through which it might be possible to further influence the cellular trafficking and post-translational modification machinery (to increase rescued CFTR abundance and membrane stability). We also highlight the new data on strategies aiming at the regulation of sodium absorption or to increase chloride transport through alternative channels. The development and implementation of these complementary approaches will pave the way to combinatorial therapeutic strategies with increased benefit to CF patients. PMID- 26416077 TI - Bordetella filamentous hemagglutinin and fimbriae: critical adhesins with unrealized vaccine potential. AB - Pertussis, or whooping cough, is a highly contagious respiratory disease that is caused by the Gram-negative bacterium Bordetella pertussis, which is transmitted exclusively from human to human. While vaccination against B. pertussis has been successful, replacement of the whole cell vaccine with an acellular component vaccine has correlated with reemergence of the disease, especially in adolescents and infants. Based on their presumed importance in mediating adherence to host tissues, filamentous hemagglutinin (FHA) and fimbria (FIM) were selected as components of most acellular pertussis vaccines. In this review, we describe the biogenesis of FHA and FIM, recent data that show that these factors do, in fact, play critical roles in adherence to respiratory epithelium, and evidence that they also contribute to persistence in the lower respiratory tract by modulating the host immune response. We also discuss shortcomings of whole cell and acellular pertussis vaccines and the possibility that FHA and FIM could serve as effective protective antigens in next-generation vaccines. PMID- 26416079 TI - Heterotopic ossification in the submental triangle remote from the vascular pedicle after reconstruction with a fibular free flap: a previously unreported complication. AB - Fibular free flaps are routinely used to reconstruct segmental mandibular defects after resection. While ossification of the vascular pedicle is uncommon but well reported, to our knowledge, heterotopic ossification remote from the pedicle has not previously been described. We report a case in which this occurred. It serves as a reminder that bony, hard lumps in the neck can present years after reconstruction with a fibular flap. PMID- 26416078 TI - Bacterial nucleators: actin' on actin. AB - The actin cytoskeleton is a key target of numerous microbial pathogens, including protozoa, fungi, bacteria and viruses. In particular, bacterial pathogens produce and deliver virulence effector proteins that hijack actin dynamics to enable bacterial invasion of host cells, allow movement within the host cytosol, facilitate intercellular spread or block phagocytosis. Many of these effector proteins directly or indirectly target the major eukaryotic actin nucleator, the Arp2/3 complex, by either mimicking nucleation promoting factors or activating upstream small GTPases. In contrast, this review is focused on a recently identified class of effector proteins from Gram-negative bacteria that function as direct actin nucleators. These effector proteins mimic functional activities of formins, WH2-nucleators and Ena/VASP assembly promoting factors demonstrating that bacteria have coopted the complete set of eukaryotic actin assembly pathways. Structural and functional analyses of these nucleators have revealed several motifs and/or mechanistic activities that are shared with eukaryotic actin nucleators. However, functional effects of these proteins during infection extend beyond plain actin polymerization leading to interference with other host cell functions such as vesicle trafficking, cell cycle progression and cell death. Therefore, their use as model systems could not only help in the understanding of the mechanistic details of actin polymerization but also provide novel insights into the connection between actin dynamics and other cellular pathways. PMID- 26416080 TI - Metastases from the lung presenting as a parotid lump. AB - We report a case of a 59-year-old man who presented with a preauricular facial lump that was suspected to be a parotid malignancy based on fine needle aspiration. A chest radiograph and a computed tomogram showed a mass in the lungs and several metastases, and caused a diagnostic dilemma as to the origin of the parotid mass, which was later confirmed to be metastatic disease that had arisen from a carcinoma of unknown origin. Infraclavicular metastasis to the parotid is rare but should not be overlooked particularly in patients who present with coexisting conditions, or when cytological findings are atypical. PMID- 26416082 TI - Reviewing the Role of Resveratrol as a Natural Modulator of Microglial Activities. AB - Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a natural phytoalexin found in grape-skin, exerts multiple biological activities, including anti-inflammatory, antiproliferative and antioxidant effects. In the past few years, mounting evidence has suggested that resveratrol is neuroprotective against a number of neurological diseases. An important contributor to the pathogenesis of neurological disorders is neuroinflammation, of which microglial activation is an important hallmark. It is possible that M1/M2 polarization of microglia may play an important role in controlling the balance between promoting and resolving neuroinflammation in the CNS. Immunomodulatory strategies capable of redirecting the microglial response toward the neuroprotective M2 phenotype could offer attractive options for neurodegenerative diseases with inflammatory components. The neuroprotective actions of resveratrol seem to be attributable to its anti inflammatory properties, due not only to its direct scavenger effects versus toxic molecules but also to a capacity to upregulate natural anti-inflammatory defences, thus counteracting excessive responses of classically activated M1 microglia. The goal of this review is to summarize recent insights into the therapeutic potential of resveratrol as a natural modulator of microgliamediated neurotoxicity. PMID- 26416081 TI - Examining inequalities in uptake of maternal health care and choice of provider in underserved urban areas of Mumbai, India: a mixed methods study. AB - BACKGROUND: Discussions of maternity care in developing countries tend to emphasise service uptake and overlook choice of provider. Understanding how families choose among health providers is essential to addressing inequitable access to care. Our objectives were to quantify the determinants and choice of maternity care provider in Mumbai's informal urban settlements, and to explore the reasons underlying their choices. METHODS: The study was conducted in informal urban communities in eastern Mumbai. We developed regression models using data from a census of married women aged 15-49 to test for associations between maternal characteristics and uptake of care and choice of provider. We then conducted seven focus group discussions and 16 in-depth interviews with purposively selected participants, and used grounded theory methods to examine the reasons for their choices. RESULTS: Three thousand eight hundred forty-eight women who had given birth in the preceding 2 years were interviewed in the census. The odds of institutional prenatal and delivery care increased with education, economic status, and duration of residence in Mumbai, and decreased with parity. Tertiary public hospitals were the commonest site of care, but there was a preference for private hospitals with increasing socio-economic status. Women were more likely to use tertiary public hospitals for delivery if they had fewer children and were Hindu. The odds of delivery in the private sector increased with maternal education, wealth, age, recent arrival in Mumbai, and Muslim faith. Four processes were identified in choosing a health care provider: exploring the options, defining a sphere of access, negotiating autonomy, and protective reasoning. Women seeking a positive health experience and outcome adopted strategies to select the best or most suitable, accessible provider. CONCLUSIONS: In Mumbai's informal settlements, institutional maternity care is the norm, except among recent migrants. Poor perceptions of primary public health facilities often cause residents to bypass them in favour of tertiary hospitals or private sector facilities. Families follow a complex selection process, mediated by their ability to mobilise economic and social resources, and a concern for positive experiences of health care and outcomes. Health managers must ensure quality services, a functioning regulatory mechanism, and monitoring of provider behaviour. PMID- 26416083 TI - Elucidating the spatio-temporal dynamics of an emerging wildlife pathogen using approximate Bayesian computation. AB - Emerging pathogens constitute a severe threat for human health and biodiversity. Determining the status (native or non-native) of emerging pathogens, and tracing back their spatio-temporal dynamics, is crucial to understand the eco evolutionary factors promoting their emergence, to control their spread and mitigate their impacts. However, tracing back the spatio-temporal dynamics of emerging wildlife pathogens is challenging because (i) they are often neglected until they become sufficiently abundant and pose socio-economical concerns and (ii) their geographical range is often little known. Here, we combined classical population genetics tools and approximate Bayesian computation (i.e. ABC) to retrace the dynamics of Tracheliastes polycolpus, a poorly documented pathogenic ectoparasite emerging in Western Europe that threatens several freshwater fish species. Our results strongly suggest that populations of T. polycolpus in France emerged from individuals originating from a unique genetic pool that were most likely introduced in the 1920s in central France. From this initial population, three waves of colonization occurred into peripheral watersheds within the next two decades. We further demonstrated that populations remained at low densities, and hence undetectable, during 10 years before a major demographic expansion occurred, and before its official detection in France. These findings corroborate and expand the few historical records available for this emerging pathogen. More generally, our study demonstrates how ABC can be used to determine the status, reconstruct the colonization history and infer key evolutionary parameters of emerging wildlife pathogens with low data availability, and for which samples from the putative native area are inaccessible. PMID- 26416084 TI - The effects of intervention based on supportive leadership behaviour on Iranian nursing leadership performance: a randomized controlled trial. AB - AIMS: To assess the effects of a workshop on supportive leadership behaviour (SLB) on the performance of head nurses, using a randomized controlled trial design. BACKGROUND: The effect of transformational leadership on SLB in nursing management is emphasised. METHODS: A total of 110 head nurses working at university hospitals were included randomly in two control and intervention groups. The head nurses in the intervention group participated in supportive leadership training, but the control group did not. Performance in supportive leadership was assessed with a validated instrument, which six subordinates used to assess their head nurse (n = 731). RESULTS: There was a significant difference in SLB scores from baseline to the 3 month follow-up (P < 0.0001). Moreover, the post-intervention scores were significantly higher in the intervention group, compared with the control group (P < 0.0001). The results showed that in the intervention group, the effect sizes were greater for males (50%) than for females (36%) and greater for married participants (42%) than for single participants (37%). CONCLUSION: The workshop on supportive leadership behaviour, particularly the interactive multifaceted training, improved the leadership performance of the head nurses who participated in this study. IMPLICATIONS FOR NURSING MANAGERS: Health policy decision makers should apply SLB, which is a significant leadership style, to improve the outcomes in other groups of health care management, such as physicians. Future studies are needed to investigate the effects of such workshops in longer periods of follow up. PMID- 26416085 TI - Will a second biopsy sample affect treatment decisions in patients with chronic hepatitis B? AB - BACKGROUND AND AIM: Liver biopsy is the gold standard for assessment of fibrosis in patients with hepatitis B. However, it has some disadvantages, including inter observer and intra-observer variability in biopsy interpretation and specimen variation. A standard biopsy specimen represents only about 0.0002 % of the whole liver. It has been shown that two biopsy samples collected during a procedure have significant influence on the diagnostic performance of interpretation in patients with hepatitis C or non-alcoholic steatohepatitis. Therefore, we aimed to assess the influence of collecting two liver biopsy samples during a single procedure for staging and grading chronic hepatitis B. PATIENTS AND METHODS: 27 patients were included in the study. The median age of the patients was 43.51 +/- 11.69. Fifteen patients were female, 12 patients were male. In the biopsy procedure, two samples of liver lobes were obtained. Grade and stage scores were compared between the two samples. Fibrosis staging and grading were assessed according to the Ishak scoring system. RESULTS: Numbers of portal tract and biopsy size were equal in the two samples. There was a significant difference between the samples in terms of histological activity index (p value = 0.04). However, the difference was not enough to distinguish the mild and moderate stages. On the other hand, no significant difference in fibrosis staging between the two samples was found. CONCLUSIONS: With this relatively small size of patients, in this study, we showed that a proper liver biopsy size is sufficient to predict treatment decisions in chronic hepatitis B patients. However, further studies are needed to show the association of sampling variability in patients with hepatitis B. PMID- 26416086 TI - Macroscopic ordering of helical pores for arraying guest molecules noncentrosymmetrically. AB - Helical nanostructures have attracted continuous attention, not only as media for chiral recognition and synthesis, but also as motifs for studying intriguing physical phenomena that never occur in centrosymmetric systems. To improve the quality of signals from these phenomena, which is a key issue for their further exploration, the most straightforward is the macroscopic orientation of helices. Here as a versatile scaffold to rationally construct this hardly accessible structure, we report a polymer framework with helical pores that unidirectionally orient over a large area (~10 cm(2)). The framework, prepared by crosslinking a supramolecular liquid crystal preorganized in a magnetic field, is chemically robust, functionalized with carboxyl groups and capable of incorporating various basic or cationic guest molecules. When a nonlinear optical chromophore is incorporated in the framework, the resultant complex displays a markedly efficient nonlinear optical output, owing to the coherence of signals ensured by the macroscopically oriented helical structure. PMID- 26416088 TI - Allelic diversity of KIR3DL1/3DS1 in a southern Chinese population. AB - The inhibitory KIR3DL1 and the activating KIR3DS1 segregate as alleles of the same locus. KIR3DL1 is highly diversified at the allele level and KIR3DL1 alleles exhibit varied levels of expression and ligand binding affinity resulting in varied degrees of NK cell inhibition. Previous studies have shown that the KIR3DL1/3DS1 polymorphism associated with viral infection, cancer and transplantation. However, little is known about the population distribution of KIR3DL1/3DS1 alleles in Chinese. The present study examined allelic diversity of KIR3DL1/3DS1 in a southern Chinese population (N=306) using PCR-SSP and sequencing based typing. The presence of KIR3DL1 and KIR3DS1 were detected in 97.1% and 34.0% of the tested individuals respectively. A total of 10 KIR3DL1 alleles (including 2 novel ones) and 6 KIR3DS1 alleles (including 5 novel ones) were identified. Common KIR3DL1 alleles (>10%) were KIR3DL1*01502 (74.8%), KIR3DL1*00501 (23.9%) and KIR3DL1*00701 (15.7%). KIR3DS1*01301 was the predominant KIR3DS1 allele with other KIR3DS1 alleles only sporadically observed. The knowledge of the allelic polymorphism of KIR3DL1/3DS1 may help to better understand the role played by KIR3DL1/3DS1 in associated diseases and clinical transplantation in southern Chinese. PMID- 26416087 TI - A gene feature enumeration approach for describing HLA allele polymorphism. AB - HLA genotyping via next generation sequencing (NGS) poses challenges for the use of HLA allele names to analyze and discuss sequence polymorphism. NGS will identify many new synonymous and non-coding HLA sequence variants. Allele names identify the types of nucleotide polymorphism that define an allele (non synonymous, synonymous and non-coding changes), but do not describe how polymorphism is distributed among the individual features (the flanking untranslated regions, exons and introns) of a gene. Further, HLA alleles cannot be named in the absence of antigen-recognition domain (ARD) encoding exons. Here, a system for describing HLA polymorphism in terms of HLA gene features (GFs) is proposed. This system enumerates the unique nucleotide sequences for each GF in an HLA gene, and records these in a GF enumeration notation that allows both more granular dissection of allele-level HLA polymorphism and the discussion and analysis of GFs in the absence of ARD-encoding exon sequences. PMID- 26416089 TI - Evolution of the hemagglutinin expressed by human influenza A(H1N1)pdm09 and A(H3N2) viruses circulating between 2008-2009 and 2013-2014 in Germany. AB - This report describes the evolution of the influenza A(H1N1)pdm09 and A(H3N2) viruses circulating in Germany between 2008-2009 and 2013-2014. The phylogenetic analysis of the hemagglutinin (HA) genes of both subtypes revealed similar evolution of the HA variants that were also seen worldwide with minor exceptions. The analysis showed seven distinct HA clades for A(H1N1)pdm09 and six HA clades for A(H3N2) viruses. Herald strains of both subtypes appeared sporadically since 2008-2009. Regarding A(H1N1)pdm09, herald strains of HA clade 3 and 4 were detected late in the 2009-2010 season. With respect to A(H3N2), we found herald strains of HA clade 3, 4 and 7 between 2009 and 2012. Those herald strains were predominantly seen for minor and not for major HA clades. Generally, amino acid substitutions were most frequently found in the globular domain, including substitutions near the antigenic sites or the receptor binding site. Differences between both influenza A subtypes were seen with respect to the position of the indicated substitutions in the HA. For A(H1N1)pdm09 viruses, we found more substitutions in the stem region than in the antigenic sites. In contrast, in A(H3N2) viruses most changes were identified in the major antigenic sites and five changes of potential glycosylation sites were identified in the head of the HA monomer. Interestingly, we found in seasons with less influenza activity a relatively high increase of substitutions in the head of the HA in both subtypes. This might be explained by the fact that mutations under negative selection are subsequently compensated by secondary mutations to restore important functions e.g. receptor binding properties. A better knowledge of basic evolution strategies of influenza viruses will contribute to the refinement of predictive mathematical models for identifying novel antigenic drift variants. PMID- 26416090 TI - Direct Microsurgical Embolectomy for an Acute Distal Basilar Artery Occlusion. AB - BACKGROUND: Acute basilar artery occlusion is associated with high mortality rates, up to 35%-40%. Early revascularization by intravenous thrombolysis, intra arterial thrombolysis, and endovascular mechanical embolectomy is considered the best option to date. The objective of this technical report is to present the direct microsurgical embolectomy technique for an acute distal basilar artery occlusion as an urgent life-saving revascularization procedure. METHODS: A 71 year-old male patient suffered from an acute embolic basilar artery occlusion and became unconscious (Glasgow Coma Scale 4). Computed tomography angiography and MRA revealed the distal basilar artery occlusion along with an increased diffusion-weighted imaging signal in the corresponding territory. After an individual case discussion, the patient underwent a microsurgical embolectomy via a frontotemporal craniotomy and an anterior temporal approach. RESULTS: Intraoperative indocyanine green and postoperative computed tomography angiography revealed complete revascularization of the previously occluded basilar quadfurcation. The patient steadily recovered and was able to walk with assistance after 4 weeks. CONCLUSIONS: Microsurgical embolectomy can be an effective treatment option for acute distal basilar artery occlusion in selected cases with experienced surgeons, but a critical preoperative decision-making process is needed. PMID- 26416091 TI - Caudal Zona Incerta/VOP Radiofrequency Lesioning Guided by Combined Stereotactic MRI and Microelectrode Recording for Posttraumatic Midbrain Resting-Kinetic Tremor. AB - OBJECTIVE: Reporting the outcome of two patients who underwent unilateral ablative stereotactic surgery to treat pharmacologic resistant posttraumatic tremor (PTT). METHODS: We present two patients (31 and 47 years old) with refractory PTT severely affecting their quality of life. Under stereotactic guidance, refined by T2-weighted magnetic resonance imaging and double-channel multiunit microelectrode recording (MER), three sequential radiofrequency lesions were performed in the caudal zona incerta (cZi) up to the base of thalamus (VOP). Effects of cZi/VOP lesion were prospectively rated with a tremor rating scale. RESULTS: Both patients demonstrated intraoperative tremor suppression with sustained results up to 18 months follow-up, with improvement of 92% and 84%, respectively, on the tremor rating scale. Tremor improvement was associated with enhancement functionality and quality of life for the patients. The patients returned to their work after the procedure. No adverse effects were observed up to the last follow-up. CONCLUSION: Radiofrequency lesion of the cZi/VOP target was effective for posttraumatic tremor in both cases. The use of T2-weighted images and MER was found helpful in increasing the precision and safety of the procedure, because it leads the RF probe by relying on neighbor structures based on thalamus and subthalamic nucleus. PMID- 26416092 TI - Repeatability of Cone Spacing Measures in Eyes With Inherited Retinal Degenerations. AB - PURPOSE: To determine short-term variability of adaptive optics scanning laser ophthalmoscopy (AOSLO)-derived cone spacing measures in eyes with inherited retinal degenerations (IRD) and in normal eyes. METHODS: Twenty IRD patients and 10 visually normal subjects underwent AOSLO imaging at two visits separated by no more than 1 month (NCT00254605). Cone spacing was measured in multiple macular regions in each image by three independent graders. Variability of cone spacing measures between visits, between graders, and between eyes was determined and correlated with standard clinical measures. RESULTS: Cone spacing was measured in 2905 regions. Interobserver agreement was high both in normal eyes and eyes with IRD (mean intraclass correlation coefficient [ICC] = 0.838 for normal and 0.892 for eyes with IRD). Cone spacing measures were closely correlated between visits (ICC > 0.869 for both study groups). Mean relative intervisit spacing difference (absolute difference in measures divided by the mean at each region) was 4.0% for normal eyes and 4.9% for eyes with IRD. Cone spacing measures from fellow eyes of the same subject showed strong agreement for all subjects (ICC > 0.85 for both study groups). CONCLUSIONS: Adaptive optics scanning laser ophthalmoscopy-derived macular cone spacing measures were correlated between observers, visits, and fellow eyes of the same subject in normal eyes and in eyes with IRD. This information may help establish the role of cone spacing measures derived from images of the cone mosaic obtained with AOSLO as a sensitive biomarker for longitudinal tracking of photoreceptor loss during disease progression and in response to treatment. (ClinicalTrials.gov number, NCT00254605.). PMID- 26416093 TI - Relationship Between Location of Retinal Nerve Fiber Layer Defect and Curvature of Retinal Artery Trajectory in Eyes With Normal Tension Glaucoma. AB - PURPOSE: To quantify the degree of curvature of the retinal artery trajectory (RAT) and to investigate the relationship between the curvature and the location of a retinal nerve fiber layer defect (NFLD) in eyes with normal tension glaucoma (NTG). METHODS: This was a retrospective observational study of 88 eyes of 88 NTG patients who had a wedge-shaped NFLD. The retinal artery trajectory and the position of the NFLD were assessed in the fundus photographs. The course of the supra and infratemporal retinal arteries were marked on a color fundus photograph and fitted to a second degree polynomial curve (ax[x]/100 + bx + c) using ImageJ. The coefficient "a" was used for the curvature of the trajectory. The proximity of the NFLD to the fovea (supra-NFLD angle, infra-NFLD angle) was determined by two methods. The relationship between the RAT and the supra-NFLD angle and the infra-NFLD angle was determined by linear regression analyses. RESULTS: Fifty-six eyes had a supratemporal NFLD and 69 eyes had an infratemporal NFLD. The steepness of the RAT was significantly correlated with the supra-NFLD angle 1 (R = -0.27, P = 0.041) and angle 2 (R = -0.28, P = 0.040), but not with the infra NFLD angle 1 (R = -0.06, P = 0.61) and angle 2 (R = -0.21, P = 0.078). CONCLUSIONS: The supratemporal NFLDs were located closer to the fovea in eyes with the retinal artery closer to the fovea in NTG patients. The steepness of the trajectory of the temporal retinal artery can be one predictor of the proximity of the NFLD to the fovea. PMID- 26416094 TI - Alzheimer Disease Cerebrospinal Fluid Biomarkers Moderate Baseline Differences and Predict Longitudinal Change in Attentional Control and Episodic Memory Composites in the Adult Children Study. AB - Cognitive measures that are sensitive to biological markers of Alzheimer disease (AD) pathology are needed to (a) facilitate preclinical staging, (b) identify individuals who are at the highest risk for developing clinical symptoms, and (c) serve as endpoints for evaluating the efficacy of interventions. The present study assesses the utility of two cognitive composite scores of attentional control and episodic memory as markers for preclinical AD pathology in a group of cognitively normal older adults (N = 238), as part of the Adult Children Study. All participants were given a baseline cognitive assessment and follow-up assessments every 3 years over an 8-year period, as well as a lumbar puncture within 2 years of the initial assessment to collect cerebrospinal fluid (CSF) and amyloid tracer Pittsburgh compound-B scan for amyloid imaging. Results indicated that attentional control was correlated with levels of Abeta42 at the initial assessment whereas episodic memory was not. Longitudinally, individuals with high CSF tau exhibited a decline in both attention and episodic memory over the course of the study. These results indicate that measures of attentional control and episodic memory can be used to evaluate cognitive decline in preclinical AD and provide support that CSF tau may be a key mechanism driving longitudinal cognitive change. PMID- 26416098 TI - Parental choice on normalising cosmetic genital surgery. PMID- 26416095 TI - Hot and Cool Executive Functions in Children with Attention-Deficit/Hyperactivity Disorder and Comorbid Oppositional Defiant Disorder. AB - While neuropsychological deficits in both "hot" and "cool" executive functions (EFs) have been documented among individuals with attention-deficit/hyperactivity disorder (ADHD), these EF deficits are not universal across all individuals with this diagnosis. One potential moderator of executive dysfunction may be the presence of comorbid oppositional defiant disorder (ODD). This study examined the association between "hot" and "cool" EFs and comorbid ODD in children with ADHD. Thirty-three children with ADHD and comorbid ODD (ADHD+ODD), 67 with ADHD without ODD (ADHD-ODD), and 30 typically developing controls participated. Children were 7-12 years of age. "Cool" EFs were assessed with a spatial span task and a card sorting test. "Hot" EFs were assessed using a delay discounting task and a gambling task. ADHD-ODD and ADHD+ODD groups performed more poorly on "cool" EF tasks than controls, but did not differ from each other. Furthermore, the number of ADHD symptoms, but not ODD symptoms, was associated with "cool" EF scores. The three groups did not differ on "hot" EF tasks and the number of ADHD or ODD symptoms was unrelated to "hot" EF scores. In sum, children with ADHD presented with "cool" EF deficits which appear to be unrelated to ODD comorbidity. However, "hot" EF deficits were not present among children with ADHD, irrespective of comorbid ODD status. PMID- 26416100 TI - Pharmacokinetics of clomipramine during pregnancy. AB - PURPOSE: Clomipramine is one of the drugs for depression during pregnancy; however, pharmacokinetic data of clomipramine and its active metabolite desmethylclomipramine in this vulnerable period are lacking. In this study, we describe clomipramine and desmethylclomipramine concentrations including their ratios during pregnancy. Second, we describe Center for Epidemiologic Studies Depression scale (CES-D) scores during pregnancy. METHODS: During 13 pregnancies, every trimester and 3 months after pregnancy, the clomipramine and desmethylclomipramine concentrations were measured with LC-MSMS and the severity of depression was assessed by taking the CES-D score. All concentrations used in our calculations were in fact the ratio between actual plasma concentration (MUg/l) and the actual dose (mg). We compared differences in ratios between trimesters by using the Friedman test. RESULTS: Studying 12 women and 13 pregnancies, we found no changes in mean clomipramine concentrations, a statistically significant decrease in mean desmethylclomipramine concentrations (p = 0.014) and a significant decrease in the ratio of desmethylclomipramine/clomipramine mean concentrations during pregnancy (p = 0.014) compared to the post-partum period. Sub-therapeutic concentrations of clomipramine and desmethylclomipramine were found in three patients during whole pregnancy. CONCLUSIONS: The mean concentrations of the pharmacologically active metabolite of clomipramine and desmethylclomipramine changes during pregnancy, where a decrease in mean concentrations was found during pregnancy. In case of recurrent disease, we recommend to control clomipramine and its metabolite concentrations, while both are active. PMID- 26416101 TI - Risk factors for potentially inappropriate prescribing to older patients in primary care. AB - PURPOSE: The aim of this study is to determine modifiable risk factors contributing to potentially inappropriate prescribing in older primary care outpatients (>=65 years). METHODS: Two separate, age- and sex-matched case control studies were carried out simultaneously at the Primary Health Care Center Kragujevac, Serbia, during the period September 2013-September 2014. The cases were defined as patients with at least one prescription for potentially inappropriate medication (PIM) according to Screening Tool of Older Persons potentially inappropriate Prescriptions (STOPP) criteria (n = 122), and patients who had at least one potential prescribing omission (PPO) listed in Screening Tool to Alert doctors to the Right Treatment (START) criteria (n = 108), while the control groups consisted of patients without such outcomes (n = 244 and n = 216, respectively). RESULTS: A total of 138 PIM and 161 PPO events were identified using 26 (41.3 %) of STOPP criteria and 17 (77.3 %) of START indicators, respectively. The unhealthy behaviors including at least two of the following: sedentary lifestyle, improper nutrition, active smoking or heavy alcohol consumption (adjusted OR 2.57, 95 % CI 1.28-5.20), use of multiple drugs (five to eight drugs, adjusted OR 3.05, 95 % CI 1.59-5.85; >=9 of drugs adjusted OR 7.17, 95 % CI 3.07-16.74) and frequent contacts between patients chosen general practitioners (GPs) and pharmaceutical sales representatives (adjusted OR 2.28, 95 % CI 1.10-4.75), were identified as major risk factors for PIM use. Patients who were handled by GPs from smaller practices (adjusted OR 0.51, 95 % CI 0.29-0.93), those with more organ systems affected by the extremely severe disorders and those who often visited the outpatient specialist services (adjusted OR 0.88, 95 % CI 0.81-0.95), had a significantly reduced risk of PPO. CONCLUSIONS: This study suggests that avoidance of major polypharmacy, use of nonpharmacological measures to improve lifestyle habits and decreasing the exposure of physicians to drug promotional material may reduce the risk of PIM use in older primary care outpatients. The only modifiable protective factors for PPOs were working environment of the patients chosen GPs and more frequent ambulatory visits to specialists. PMID- 26416102 TI - Optimizing Intradermal Administration of Cryopreserved Plasmodium falciparum Sporozoites in Controlled Human Malaria Infection. AB - Controlled human malaria infection (CHMI) is a powerful tool to evaluate malaria vaccine and prophylactic drug efficacy. Until recently CHMI was only carried out by the bite of infected mosquitoes. A parenteral method of CHMI would standardize Plasmodium falciparum sporozoite (PfSPZ) administration, eliminate the need for expensive challenge facility infrastructure, and allow for use of many P. falciparum strains. Recently, intradermal (ID) injection of aseptic, purified, cryopreserved PfSPZ was shown to induce P. falciparum malaria; however, 100% infection rates were not achieved by ID injection. To optimize ID PfSPZ dosing so as to achieve 100% infection, 30 adults aged 18-45 years were randomized to one of six groups composed of five volunteers each. The parameters of dose (1 * 10(4) versus 5 * 10(4) PfSPZ total dose per volunteer), number of injections (two versus eight), and aliquot volume per ID injection (10 MUL versus 50 MUL) were studied. Three groups attained 100% infection: 1 * 10(4) PfSPZ in 50 MUL/2 doses, 1 * 10(4) PfSPZ in 10 MUL/2 doses, and 5 * 10(4) PfSPZ in 10 MUL/8 doses. The group that received 5 * 10(4) PfSPZ total dose in eight 10 MUL injections had a 100% infection rate and the shortest prepatent period (mean of 12.7 days), approaching the prepatent period for the current CHMI standard of five infected mosquitoes. PMID- 26416103 TI - Analysis of Risk and Burden of Dysentery Associated with Floods from 2004 to 2010 in Nanning, China. AB - This study aimed to examine the association between floods and the morbidity of dysentery and to quantify the burden of dysentery due to floods in Nanning, China. A generalized additive mixed model was conducted to assess the relationship between monthly morbidity of dysentery and floods from 2004 to 2010. The years lived with disability (YLDs) of dysentery attributable to floods were then estimated based on the WHO framework of the burden of disease study for calculating the potential impact fraction. The relative risk (RR) of floods on the morbidity of dysentery was 1.44 (95% confidence interval [CI] = 1.18-1.75). The models suggest that a potential 1-day rise in flood duration may lead to 8% (RR = 1.08, 95% CI = 1.04-1.12) increase in the morbidity of dysentery. The average attributable YLD per 1,000 of dysentery caused by floods were 0.013 in males, 0.005 in females, and 0.009 in persons. Our study confirms that floods have significantly increased the risk and the burden of dysentery in the study area. Public health action should be taken to prevent and control the potential risk of dysentery after floods. Vulnerable groups such as males and children should be paid more attention. PMID- 26416104 TI - Pharmacokinetic Interactions Between Quinine and Lopinavir/Ritonavir in Healthy Thai Adults. AB - This study aimed to investigate the pharmacokinetic interactions between quinine and lopinavir boosted with ritonavir (LPV/r) in healthy Thai adults (8 males and 12 females). Period 1 (day 1): subjects received a single oral dose of 600 mg quinine sulfate. Period 2: subjects received LPV/r (400/100 mg) twice daily. Period 3: subjects received a single quinine sulfate dose plus LPV/r twice a day. Intensive blood sampling was performed during each phase. Quinine AUC0-48h (area under the plasma concentration-time curve from time 0 to 48 hours), AUC0-infinity (area under the plasma concentration-time curve from time 0 to infinity), and Cmax (maximum concentration over the time-span specified), were 56%, 57%, and 47% lower, respectively, in the presence of LPV/r. 3-Hydroxyquinine AUC0-48h, AUC0 infinity, and Cmax were significantly lower and the metabolite-to-parent ratio was significantly reduced. Lopinavir and ritonavir exposures were not significantly reduced with quinine coadministration, but Cmax of both drugs were significantly lower. The geometric mean ratio (GMR) and 90% CI of AUC0-48h, AUC0 infinity, and Cmax for quinine, 3-hydroxyquinine, lopinavir, and ritonavir lay outside the bioequivalent range of 0.8-1.25. Drug treatments during all periods were generally well tolerated. The reduction in systemic exposure of quinine and 3-hydroxyquinine with concomitant LPV/r use raises concerns of suboptimal exposure. Studies in HIV/malaria coinfection patients are needed to determine the clinical impact to decide if any change to the quinine dose is warranted. PMID- 26416105 TI - Rapid Tests and the Diagnosis of Visceral Leishmaniasis and Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome Coinfection. AB - After the emergence of the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), the number of visceral leishmaniasis (VL) HIV/AIDS coinfections has increased worldwide. Herein, we assessed the usefulness of an rK39-based immunochromatographic test (rK39 ICT) (DiaMed-IT LEISH((r)); DiaMed AG, Cressier-sur-Morat, Switzerland) and a latex agglutination test (KAtex; Kalon Biological, Guildford, United Kingdom) for urinary antigen detection to diagnose VL in 15 HIV/AIDS patients from northeastern Brazil. VL diagnosis was based on clinical findings, cytology, serology, parasite DNA, and/or urinary antigen detection. VL was confirmed in seven out of 15 HIV/AIDS patients. Only three patients were positive in bone marrow cytology, three patients were conventional polymerase chain reaction (PCR) positive, while six were real-time PCR positive. All patients were direct agglutination test (DAT) (Royal Tropical Institute, Amsterdam, The Netherlands) positive; of these, four were positive by rK39 ICT and five by KAtex. Large-scale studies are needed to validate the use of the KAtex in the national public health laboratory network in Brazil, aiming at improving the diagnosis of VL in HIV/AIDS patients in this country. PMID- 26416106 TI - Predictive Malaria Risk and Uncertainty Mapping in Nchelenge District, Zambia: Evidence of Widespread, Persistent Risk and Implications for Targeted Interventions. AB - Malaria risk maps may be used to guide policy decisions on whether vector control interventions should be targeted and, if so, where. Active surveillance for malaria was conducted through household surveys in Nchelenge District, Zambia from April 2012 through December 2014. Households were enumerated based on satellite imagery and randomly selected for study enrollment. At each visit, participants were administered a questionnaire and a malaria rapid diagnostic test (RDT). Logistic regression models were used to construct spatial prediction risk maps and maps of risk uncertainty. A total of 461 households were visited, comprising 1,725 participants, of whom 48% were RDT positive. Several environmental features were associated with increased household malaria risk in a multivariable logistic regression model adjusting for seasonal variation. The model was validated using both internal and external evaluation measures to generate and assess root mean square error, as well as sensitivity and specificity for predicted risk. The final, validated model was used to predict and map malaria risk including a measure of risk uncertainty. Malaria risk in a high, perennial transmission setting is widespread but heterogeneous at a local scale, with seasonal variation. Targeting malaria control interventions may not be appropriate in this epidemiological setting. PMID- 26416107 TI - Investigating a Non-Mesh Mosquito Net Among Outdoor Sleeping Nomadic Communities in Kenya. AB - Rising reports of exophagic malaria vectors make even more pressing the need for alternatives to traditional, mesh, long-lasting insecticidal nets (LLINs) designed for indoor sleeping and often inadequate in the protection of outdoor sleeping populations. This study tests and evaluates the retention, utilization, and durability of novel, non-mesh nets designed for outdoor use. Longitudinal, cross-sectional surveys were conducted, the physical condition of nets was assessed, and bio-efficacy and insecticide content were tested. At 22 months, retention was 98.0%; 97.1% of nets fell within the World Health Organization (WHO) category of being in "good" condition; none were in the "torn" category. At 18 months post-distribution, 100% of nets had at least WHO Pesticide Evaluation Scheme (WHOPES)-acceptable levels of insecticide, this proportion was 66.7% at 22 months. This novel mosquito net has the potential to provide a durable and context-specific tool to prevent malaria among traditionally hard-to-protect and highly vulnerable populations. PMID- 26416108 TI - Predictive Value of School-Aged Children's Schistosomiasis Prevalence and Egg Intensity for Other Age Groups in Western Kenya. AB - World Health Organization recommendations for the timing and target population for mass drug administration (MDA) for schistosomiasis are based on the prevalence of infection in school children within a given community. In a large study comparing MDA approaches for Schistosoma mansoni control, we evaluated whether prevalence of infection and egg burdens in 9- to 12-year-old students reflected infection levels in young children and adults in the same community. Cross-sectional surveys of preadolescents (9-12 years old) were compared with those of first year students (5-8 years old) in 225 villages and adults (20-55 years old) in 150 villages along the Kenyan shores of Lake Victoria. Village schistosomiasis prevalence and intensity levels in preadolescents strongly correlated (P < 0.0001) with prevalence and infection intensity for other age groups in the community. Our findings suggest that S. mansoni prevalence and intensity among 9- to 12-year-olds are valid for community sampling purposes in mapping for MDAs. PMID- 26416109 TI - Chikungunya Virus Infections Among Patients with Dengue-Like Illness at a Tertiary Care Hospital in the Philippines, 2012-2013. AB - Chikungunya virus (CHIKV) often co-circulates with dengue virus (DENV). A cross sectional surveillance study was conducted at a tertiary hospital in Manila, Philippines, to describe the prevalence and characteristics of DENV and CHIKV infections among patients seeking care for dengue-like illness. Acute blood samples from patients >= 6 months of age clinically diagnosed with dengue from November 2012 to December 2013 underwent reverse transcription polymerase chain reaction (RT-PCR) to detect DENV and CHIKV RNA. A total of 118 patients with clinically diagnosed dengue (age range = 1-89 years, mean = 22 years; male-to female ratio = 1.51) were tested by DENV RT-PCR; 40 (34%) were DENV PCR-positive (age range = 1-45 years, mean = 17 years). All DENV serotypes were detected: 11 (28%) DENV-1, 6 (15%) DENV-2, 6 (15%) DENV-3, and 17 (42%) DENV-4. Of 112 patients clinically diagnosed with dengue and tested by CHIKV RT-PCR, 11 (10%) were CHIKV PCR-positive (age range = 2-47 years, mean = 20.3 years). No coinfections were detected. Presenting signs/symptoms did not differ between DENV and CHIKV-positive cases. Sequencing of envelope 1 gene from two CHIKV PCR positive samples showed Asian genotype. This study highlights the potential for misdiagnosis of medically attended CHIKV infections as DENV infection and the difficulty in clinically differentiating dengue and chikungunya based on presenting signs/symptoms alone. This underscores the necessity for diagnostic laboratory tests to distinguish CHIKV infections in the background of actively co circulating DENV. PMID- 26416110 TI - Deforestation and Malaria on the Amazon Frontier: Larval Clustering of Anopheles darlingi (Diptera: Culicidae) Determines Focal Distribution of Malaria. AB - We performed bimonthly mosquito larval collections during 1 year, in an agricultural settlement in the Brazilian Amazon, as well as an analysis of malaria incidence in neighboring houses. Water collections located at forest fringes were more commonly positive for Anopheles darlingi larvae and Kulldorff spatial analysis pinpointed significant larval clusters at sites directly beneath forest fringes, which were called larval "hotspots." Remote sensing identified 43 "potential" hotspots. Sampling of these areas revealed an 85.7% positivity rate for A. darlingi larvae. Malaria was correlated with shorter distances to potential hotpots and settlers living within 400 m of potential hotspots had a 2.60 higher risk of malaria. Recently arrived settlers, usually located closer to the tip of the triangularly shaped deforestation imprints of side roads, may be more exposed to malaria due to their proximity to the forest fringe. As deforestation progresses, transmission decreases. However, forest remnants inside deforested areas conferred an increased risk of malaria. We propose a model for explaining frontier malaria in the Amazon: because of adaptation of A. darlingi to the forest fringe ecotone, humans are exposed to an increased transmission risk when in proximity to these areas, especially when small dams are created on naturally running water collections. PMID- 26416112 TI - Feasibility of Using the Mosquito Blood Meal for Rapid and Efficient Human and Animal Virus Surveillance and Discovery. AB - Mosquito blood meals taken from humans and animals potentially represent a useful source of blood for the detection of blood-borne pathogens. In this feasibility study, Anopheles stephensi mosquitoes were fed with blood meals spiked with dengue virus type 2 (DENV-2) and harvested at serial time points. These mosquitoes are not competent vectors, and the virus is not expected to replicate. Ingested blood was spotted on Whatman FTA cards and stored at room temperature. Mosquito abdomens were removed and stored at -80 degrees C. Control blood meal aliquots were stored in vials or applied onto FTA cards. After 4 weeks of storage, the samples were extracted using beadbeating and QIAamp Viral RNA kit (Qiagen Sciences, Germantown, MD). Recovered viral RNA was analyzed by DENV-2 TaqMan RT-PCR assay and next-generation sequencing (NGS). Overall viral RNA recovery efficiency was 15% from the directly applied dried blood spots and approximately 20% or higher for dried blood spots made by blotting mosquito midgut on FTA cards. Viral RNA in mosquito-ingested blood decreases over time, but remains detectable 24 hours after blood feeding. The viral sequences in FTA stored specimens can be maintained at room temperature. The strategy has the potential utility in expedited zoonotic virus discovery and blood-borne pathogen surveillance. PMID- 26416111 TI - Point-of-Care Ultrasound Assessment of Tropical Infectious Diseases--A Review of Applications and Perspectives. AB - The development of good quality and affordable ultrasound machines has led to the establishment and implementation of numerous point-of-care ultrasound (POCUS) protocols in various medical disciplines. POCUS for major infectious diseases endemic in tropical regions has received less attention, despite its likely even more pronounced benefit for populations with limited access to imaging infrastructure. Focused assessment with sonography for HIV-associated TB (FASH) and echinococcosis (FASE) are the only two POCUS protocols for tropical infectious diseases, which have been formally investigated and which have been implemented in routine patient care today. This review collates the available evidence for FASH and FASE, and discusses sonographic experiences reported for urinary and intestinal schistosomiasis, lymphatic filariasis, viral hemorrhagic fevers, amebic liver abscess, and visceral leishmaniasis. Potential POCUS protocols are suggested and technical as well as training aspects in the context of resource-limited settings are reviewed. Using the focused approach for tropical infectious diseases will make ultrasound diagnosis available to patients who would otherwise have very limited or no access to medical imaging. PMID- 26416113 TI - First Report of Aedes aegypti Transmission of Chikungunya Virus in the Americas. AB - During a chikungunya fever outbreak in late 2014 in Chiapas, Mexico, entomovirological surveillance was performed to incriminate the vector(s). In neighborhoods, 75 households with suspected cases were sampled for mosquitoes, of which 80% (60) harbored Aedes aegypti and 2.7% (2) Aedes albopictus. A total of 1,170 Ae. aegypti and three Ae. albopictus was collected and 81 pools were generated. Although none of the Ae. albopictus pools were chikungunya virus (CHIKV)-positive, 18 Ae. aegypti pools (22.8%) contained CHIKV, yielding an infection rate of 32.3/1,000 mosquitoes. A lack of herd immunity in conjunction with high mosquito populations, poor vector control services in this region, and targeted collections in locations of human cases may explain the high infection rate in this vector. Consistent with predictions from experimental studies, Ae. aegypti appears to be the principal vector of CHIKV in southern Mexico, while the role of Ae. albopictus remains unknown. PMID- 26416114 TI - Challenges in Obtaining Estimates of the Risk of Tuberculosis Infection During Overseas Deployment. AB - Estimates of the risk of tuberculosis (TB) infection resulting from overseas deployment among U.S. military service members have varied widely, and have been plagued by methodological problems. The purpose of this study was to estimate the incidence of TB infection in the U.S. military resulting from deployment. Three populations were examined: 1) a unit of 2,228 soldiers redeploying from Iraq in 2008, 2) a cohort of 1,978 soldiers followed up over 5 years after basic training at Fort Jackson in 2009, and 3) 6,062 participants in the 2011-2012 National Health and Nutrition Examination Survey (NHANES). The risk of TB infection in the deployed population was low-0.6% (95% confidence interval [CI]: 0.1-2.3%)-and was similar to the non-deployed population. The prevalence of latent TB infection (LTBI) in the U.S. population was not significantly different among deployed and non-deployed veterans and those with no military service. The limitations of these retrospective studies highlight the challenge in obtaining valid estimates of risk using retrospective data and the need for a more definitive study. Similar to civilian long-term travelers, risks for TB infection during deployment are focal in nature, and testing should be targeted to only those at increased risk. PMID- 26416115 TI - An Unusual Cutaneous Manifestation in a Patient with Murine Typhus. AB - Murine typhus is a flea-borne febrile illness caused by Rickettsia typhi. Although often accompanied by rash, an inoculation lesion has not been observed as it is with many tick- and mite-transmitted rickettsioses. We describe a patient with murine typhus and an unusual cutaneous manifestation at the site of rickettsial inoculation. PMID- 26416116 TI - Cost of Dengue Vector Control Activities in Malaysia. AB - Dengue fever, an arbovirus disease transmitted by Aedes mosquitoes, has recently spread rapidly, especially in the tropical countries of the Americas and Asia Pacific regions. It is endemic in Malaysia, with an annual average of 37,937 reported dengue cases from 2007 to 2012. This study measured the overall economic impact of dengue in Malaysia, and estimated the costs of dengue prevention. In 2010, Malaysia spent US$73.5 million or 0.03% of the country's GDP on its National Dengue Vector Control Program. This spending represented US$1,591 per reported dengue case and US$2.68 per capita population. Most (92.2%) of this spending occurred in districts, primarily for fogging. A previous paper estimated the annual cost of dengue illness in the country at US$102.2 million. Thus, the inclusion of preventive activities increases the substantial estimated cost of dengue to US$175.7 million, or 72% above illness costs alone. If innovative technologies for dengue vector control prove efficacious, and a dengue vaccine was introduced, substantial existing spending could be rechanneled to fund them. PMID- 26416117 TI - Blood-Borne Candidatus Borrelia algerica in a Patient with Prolonged Fever in Oran, Algeria. AB - To improve the knowledge base of Borrelia in north Africa, we tested 257 blood samples collected from febrile patients in Oran, Algeria, between January and December 2012 for Borrelia species using flagellin gene polymerase chain reaction sequencing. A sequence indicative of a new Borrelia sp. named Candidatus Borrelia algerica was detected in one blood sample. Further multispacer sequence typing indicated this Borrelia sp. had 97% similarity with Borrelia crocidurae, Borrelia duttonii, and Borrelia recurrentis. In silico comparison of Candidatus B. algerica spacer sequences with those of Borrelia hispanica and Borrelia garinii revealed 94% and 89% similarity, respectively. Candidatus B. algerica is a new relapsing fever Borrelia sp. detected in Oran. Further studies may help predict its epidemiological importance. PMID- 26416118 TI - Effectiveness of Large-Scale Chagas Disease Vector Control Program in Nicaragua by Residual Insecticide Spraying Against Triatoma dimidiata. AB - Chagas disease is one of the most serious health problems in Latin America. Because the disease is transmitted mainly by triatomine vectors, a three-phase vector control strategy was used to reduce its vector-borne transmission. In Nicaragua, we implemented an indoor insecticide spraying program in five northern departments to reduce house infestation by Triatoma dimidiata. The spraying program was performed in two rounds. After each round, we conducted entomological evaluation to compare the vector infestation level before and after spraying. A total of 66,200 and 44,683 houses were sprayed in the first and second spraying rounds, respectively. The entomological evaluation showed that the proportion of houses infested by T. dimidiata was reduced from 17.0% to 3.0% after the first spraying, which was statistically significant (P < 0.0001). However, the second spraying round did not demonstrate clear effectiveness. Space-time analysis revealed that reinfestation of T. dimidiata is more likely to occur in clusters where the pre-spray infestation level is high. Here we discuss how large-scale insecticide spraying is neither effective nor affordable when T. dimidiata is widely distributed at low infestation levels. Further challenges involve research on T. dimidiata reinfestation, diversification of vector control strategies, and implementation of sustainable vector surveillance. PMID- 26416119 TI - Three-dimensional kinematic analysis of ankle, knee, hip, and pelvic rotation during gait in patients after anterior cruciate ligament reconstruction - early results. AB - BACKGROUND: The goal of this study was to biomechanically assess tibial rotation in the knee joint simultaneous changes in rotation of large joints of the lower limbs and pelvis during gait in patients during early postoperative stages following anterior cruciate ligament (ACLR) reconstruction. We hypothesized that tibial rotation is associated with changes in rotation of the large joints of the lower limbs and the pelvis during gait in patients after ACLR reconstruction. METHODS: The patients were divided into two groups. The ACLR group (n = 32 males) underwent primary ACLR in one leg and postoperative physiotherapy. The control group (n = 30 males) had no knee injuries. After clinical assessment in both groups, the values of kinematic parameters of foot, tibial, femoral, and pelvic rotation were measured during gait on a flat surface using the three-dimensional BTS Smart System. In the ACLR group, measurements were taken during the 4th, 9th, and 14th weeks of postoperative physiotherapy. The results of the ACLR group were compared with those of the control group. RESULTS: During gait, between the 9th and 14th weeks following ACLR, there are normal values of foot, tibia, and pelvic rotation in the operated legs compared with results obtained from un-operated legs and the control group. DISCUSSION: Analysis of rotations occurring only in knee joints does not reflect all of the multiarticular disorders of gait kinematics. The study also suggests that analyzing tibial rotation in the knee joint with simultaneous changes in rotation in large joints of the lower limbs provides better opportunities than singular analysis of rotation in the knee joint for the assessment of disorders in gait kinematics. CONCLUSIONS: In gait, at the maximal extension of the knee during preparation for the stance phase, external hip rotation patterns have not been fully restored 14 weeks after ACLR. PMID- 26416120 TI - Preanesthetic nurse communication with children and parents--an observational study. AB - BACKGROUND: The impact of communication within the perioperative period is an area of increasing research interest. Suggestions are phrases or actions that can lead to subconscious nonvolitional changes in patient perception, mood, and/or behavior. Statements functioning as suggestions may induce positive or negative perceptual responses and experiences. Children and anxious patients are particularly responsive to the effects of suggestion. We aimed to identify positively and negatively worded statements used during the provision of preoperative information by nursing staff in a tertiary referral center for pediatric care. METHODS: Audio recordings of preoperative consultations between nurses, children, and their parents were made between February and May 2014. Two researchers independently reviewed the transcripts and identified positively and negatively worded suggestions. Examples of negative suggestions were, 'he is going to be sore for a week or two' or 'normal to feel a bit sick....', and a positive suggestion was 'so she will be feeling quite comfortable...'. RESULTS: There were 51 consultations transcribed and analyzed. Of the 130 suggestions independently agreed by both researchers to be either positive or negative, 40 were identified as positive (31%) and 90 negative (69%). Commonly occurring negative suggestions described: pain in 21 consultations (41%); nausea and sickness in 19 (37%); and irritability or agitation in nine (18%). Positive suggestions included a description of a return of normal activities such as eating and drinking in 14 (28%), comfort in nine (18%), and well-being in nine (18%). Twelve consultations (24%) contained only negative suggestions, while four (8%) had only positive suggestions. CONCLUSIONS: This is the first prospective observational study investigating the language used by nurses during the preoperative child-parent encounter. Suggestions for negative perceptual experiences were frequently used during the preoperative nurse consultations. Education of nurses regarding awareness and understanding of negative suggestions and their potential adverse effects is recommended. PMID- 26416121 TI - Salt stress-induced modulations in the shoot proteome of Brassica juncea genotypes. AB - Indian mustard [Brassica juncea (L.) Czern and Coss] is cultivated mainly in the northwestern agroclimatic region of India and suffers huge losses in productivity due to salinization. In an effort to figure out adaptation strategies of Indian mustard to salt stress, we conducted a comparative proteome analysis of shoots of its two genotypes, with contrasting sensitivity to salt stress. Differential expression of 21 proteins was observed during the two-dimensional electrophoresis (2DE). The identified salt-stress-responsive proteins were associated with different functional processes including osmoregulation, photosynthesis, carbohydrate metabolism, ion homeostasis, protein synthesis and stabilization, energy metabolism, and antioxidant defense system. Salt-tolerant genotype (CS-52) showed a relatively higher expression of proteins involved in turgor regulation, stabilization of photosystems and proteins, and salt compartmentalization, as compared to salt-sensitive genotype (Pusa Varuna). Our results suggest that modulating the expression of salt-responsive proteins can pave the way for developing salt tolerance in the Indian mustard plants. PMID- 26416122 TI - Effect of chemo-mechanical disintegration on sludge anaerobic digestion for enhanced biogas production. AB - The effect of combined surfactant-dispersion pretreatment on dairy waste activated sludge (WAS) reduction in anaerobic digesters was investigated. The experiments were performed with surfactant, Sodium dodecyl sulfate (SDS) in the range of 0.01 to 0.1 g/g suspended solids (SS) and disperser with rpm of 5000 25,000. The COD (chemical oxygen demand) solubilization, suspended solids reduction, and biogas generation increased for an energy input of 7377 kJ/kg total solids (TS) (12,000 rpm, 0.04 g/g SS, and 30 min) and were found to be 38, 32, and 75 %, higher than that of control. The pretreated sludge improved the performance of semicontinuous anaerobic digesters of 4 L working volume operated at four different SRTs (sludge retention time). SRT of 15 days was found to be appropriate showing 49 and 51 % reduction in SS and volatile solids (VS), respectively. The methane yield of the pretreated sample was observed to be 50 mL/g VS removed which was observed to be comparatively higher than the control (12 mL/g VS removed) at optimal SRT of 15 days. To the best of the authors' knowledge, this study is the first to be reported and not yet been documented in literature. PMID- 26416123 TI - Iron and copper catalysis of PCDD/F formation. AB - The formation of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F) was explored during de novo tests designed to compare the catalytic activity of copper (II) chloride (CuCl2) with that of iron (III) oxide (Fe2O3) and to test some synergistic effect between these two catalytic compounds. Both copper chloride (CuCl2) and iron oxide (Fe2O3) were earlier proposed as catalysts to explain the PCDD/F emissions from, e.g. municipal solid waste incineration (MSWI). In addition, haematite (Fe2O3) is the main iron ore and could be responsible for the typical iron ore sintering plant fingerprint. A total of nine model fly ash (MFA) samples were prepared by mixing and grinding of sodium chloride (NaCl), activated carbon and a powder matrix of silica (SiO2) with the selected metal compound(s). The conditions of these de novo tests were 1 h in duration, 350 degrees C in a flow of synthetic combustion gas (10 vol.% oxygen in nitrogen). The effect of Fe-Cu catalyst concentration on yield and distribution pattern of PCDD/F was systematically explored; three strongly differing ratios of [Fe]:[Cu] were considered (1:1, 10:1 and 100:1) to study the potential interactions of Fe2O3 and CuCl2 suggested earlier. The results show some slight rise of PCDD/F formed with raising iron concentration from 0 to 10.1 wt% (no Cu added; 0.1 wt% Cu), as well as strong surging of both amount and average chlorination level of PCDD/F when rising amounts of copper (0 to 1.1 wt%) are introduced. The resulting fingerprints are compared with those from sintering and from MSWI. PMID- 26416124 TI - Simulation of aromatic polycyclic hydrocarbons remobilization from a river sediment using laboratory experiments supported by passive sampling techniques. AB - Resuspension of bedded sediments was simulated under laboratory-controlled conditions in order to assess the amount of polycyclic aromatic hydrocarbons (PAH) remobilized in the dissolved fraction during one short and vigorous mixing. The desorbed amount of PAH was compared to the exchangeable fraction, the total amount of PAH sorbed on the sediment particles, and the dissolved PAH amount contained in the interstitial pore waters in order to evaluate the contribution of each fraction to the total amount of PAH released. To monitor the desorption of PAH and measure low trace level concentrations, passive samplers were used in an experimental open flow through exposure simulator. Results show that for the selected sediment, a substantial fraction of sorbed PAH (69 % of the total amount) is not available for remobilization in a depleted medium. Obtained data pinpoint that over 9 days, only 0.007 % of PAH are desorbed by passive diffusion through a water-sediment interface area of 415 cm(2) and that an intense resuspension event of 15 min induces desorption of 0.015 % of PAH during the following 9 days. Results also highlight that during resuspension simulation, modifications of the sediment and the water body occurred since partitioning constants of some pollutants between sediment and water have significantly decreased. PMID- 26416126 TI - Erratum to: Disentangling Multiple Sclerosis and depression: an adjusted depression screening score for patient-centered care. PMID- 26416125 TI - beta-aminobutyric acid mediated drought stress alleviation in maize (Zea mays L.). AB - The present study highlights the role of beta-aminobutyric acid (BABA) in alleviating drought stress effects in maize (Zea mays L.). Chemical priming was imposed by pretreating 1-week-old plants with 600 MUM BABA prior to applying drought stress. Specific activities of key antioxidant enzymes and metabolites (ascorbate and glutathione) levels of ascorbate-glutathione cycle were studied to unravel the priming-induced modulation of plant defense system. Furthermore, changes in endogenous ABA and JA concentrations as well as mRNA expressions of key genes involved in their respective biosynthesis pathways were monitored in BABA-primed (BABA+) and non-primed (BABA-) leaves of drought-challenged plants to better understand the mechanistic insights into the BABA-induced hormonal regulation of plant response to water-deficit stress. Accelerated stomatal closure, high relative water content, and less membrane damage were observed in BABA-primed leaves under water-deficit condition. Elevated APX and SOD activity in non-primed leaves found to be insufficient to scavenge all H2O2 and O2 (.-) resulting in oxidative burst as evident after histochemical staining with NBT and DAB. A higher proline accumulation in non-primed leaves also does not give much protection against drought stress. Increased GR activity supported with the enhanced mRNA and protein expressions might help the BABA-primed plants to maintain a high GSH pool essential for sustaining balanced redox status to counter drought-induced oxidative stress damages. Hormonal analysis suggests that in maize, BABA-potentiated drought tolerance is primarily mediated through JA dependent pathway by the activation of antioxidant defense systems while ABA biosynthesis pathway also plays an important role in fine-tuning of drought stress response. PMID- 26416128 TI - Protein Aggregates May Differ in Water Entrapment but Are Comparable in Water Confinement. AB - Aggregate size and density are related to gel morphology. In the context of the water distribution in complex food systems, in this study, it was aimed to investigate whether protein aggregates varying in size and density differ in entrapped and confined water. Heat-set soy protein aggregates (1%, v/v) prepared in the presence of 3.5 mM divalent salts increased in size and decreased in apparent density following the salt type order MgSO4, MgCl2, CaSO4, and CaCl2. In the absence of applied (centrifugal) forces, larger and less dense aggregates entrap more water. When force is applied from larger and more deformable aggregates, more water can be displaced. Entrapped water of ~8-13 g of water/g of protein is associated with (pelleted) aggregates, of which approximately 4.5-8.5 g of water/g of protein is not constrained in exchangeability with the solvent. The amount of confined water within aggregates was found to be independent of the aggregate density and accounted for ~3.5 g of water/g of protein. Confined water in aggregates is hindered in its diffusion because of physical structure constraints and, therefore, not directly exchangeable with the solvent. These insights in the protein aggregate size and deformability in relation to water entrapment and confinement could be used to tune water holding on larger length scales when force is applied. PMID- 26416127 TI - Mammography Adherence in African-American Women: Results of a Randomized Controlled Trial. AB - BACKGROUND: Breast cancer is the second leading cause of cancer mortality among women in the developed world. Mammography screening is especially important for African-Americans because they experience a greater mortality (OR = 1.38) than Caucasians despite having a lower incidence of breast cancer. PURPOSE: The purpose of this study was to compare the effects of two interventions with usual care on mammography adherence among African-American women. METHODS: A subsample of African-American women (n = 244) aged 41-65 years who had not had a mammogram in the last 15 months and no history of breast cancer was randomly assigned to receive (1) mailed interactive DVD, (2) computer-tailored telephone counseling, or (3) usual care. RESULTS: The DVD intervention was five times more effective than usual care for promoting mammography screening at 6 months follow-up among women who earned less than $30,000 (OR = 5.3). Compared to usual care, neither the DVD nor phone produced significant effects for women with household incomes >$30,000. CONCLUSION: Use of a mailed DVD for low-income African-American women may be an effective way to increase mammography adherence. PMID- 26416129 TI - Intubation of the Neurologically Injured Patient. AB - BACKGROUND: Intubation of the neurologically injured patient is a critical procedure that must be done in a manner to prevent further neurologic injury. Although many different medications and techniques have been used to meet specific needs, there is little to no evidence to support many claims. OBJECTIVE: To review the literature regarding important topics relating to intubating patients with neurologic injury. DISCUSSION: Airway management requires ideal preoxygenation and airway maneuvers to minimize manipulation of the larynx and to maximize first-pass success. There is no evidence that lidocaine pretreatment decreases intracerebral pressure (ICP). Fentanyl can be used to help blunt the hemodynamic response to intubation. Esmolol is another medication that can blunt the hemodynamic response. Ketamine can be used and is possibly the ideal agent, having a neutral hemodynamic profile. A prefasciculation dose for neuromuscular blockade has not been shown to have any effect on ICP. CONCLUSIONS: Ideal intubation conditions should be obtained through the use of airway manipulation techniques and appropriate medication choice for rapid sequence intubation in patients who are neurologically injured. PMID- 26416130 TI - Septal Hematoma Following Nasal Trauma. PMID- 26416131 TI - Hypothermia-induced Rhabdomyolysis: A Case Report. AB - BACKGROUND: A 29-year-old man was lost in the bush with minimal clothing for almost 2 days. CASE REPORT: The patient in this case developed rhabdomyolysis with subsequent acute kidney injury. He was treated with passive warming and intravenous fluids, with resolution of the kidney injury. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patients who present with hypothermia may develop rhabdomyolysis with subsequent acute kidney injury. If not identified, renal failure may develop. This is easily preventable if the practitioner is aware of the possible consequences of cold exposure, orders the appropriate test, and administers corrective treatment. PMID- 26416132 TI - Use of Proteolytic Enzymes in the Treatment of Proteinaceous Esophageal Food Impaction. AB - BACKGROUND: Proteinaceous esophageal food impaction typically requires endoscopic intervention. An alternative approach is the use of proteolytic enzymes. Concerns regarding the use of proteolytic enzymes include the risk of perforation and aspiration pneumonitis. OBJECTIVE: We retrospectively reviewed our series of 69 patients treated with papain to determine the safety and efficacy of proteolytic enzymes. METHODS: Patients were retrospectively reviewed if treated for an esophageal food impaction from 1999 through 2008. RESULTS: Median age was 56 years (range 19-91 years), with 46 male and 23 female patients. In 27 patients (39%) this was their first presentation, in 14 (20%) it was the second, and 28 (41%) had multiple previous episodes. Meat was the cause in 49 (71%), chicken in 6 (9%), fish in 3 (4%), and unspecified in 11 (16%). All patients presented with dysphagia for solids, 56 (81%) could not tolerate liquids. Papain solution, 1 tsp in 8 oz of water, was given to patients in an unlimited quantity. Papain was successful in relieving the obstruction in 60 patients (87%). The remaining 9 patients (13%) underwent endoscopy with successful retrieval. No patient suffered a perforation, either with papain ingestion or endoscopy. There were no episodes of pneumonitis or pneumonia. CONCLUSIONS: We have used proteolytic enzymes with a high success rate and with minimal complication. Further, if proteolytic enzymes fail, endoscopy can be performed safely and effectively. We recommend the use of proteolytic enzymes as the initial management in all patients with proteinaceous food impaction of the esophagus. PMID- 26416133 TI - Impact of Age on Pain Perception for Typical Painful Diagnoses in the Emergency Department. AB - BACKGROUND: Age-related differences in pain perception have been demonstrated in experimental settings but have been investigated scarcely and without valid scale in the clinical framework. OBJECTIVES: To examine the effect of age on pain perception for recognized painful diagnoses encountered in the emergency department (ED). METHODS: A post-hoc analysis of real-time archived data was performed in a tertiary urban and a secondary regional ED. We included all consecutive adult patients (>=18 years) with the following diagnosis at discharge: renal colic, pancreatitis, appendicitis, headache/migraine, dislocation and extremities fractures, and a pain evaluation of >=1 (0-10, verbal numerical scale) at triage. The primary outcome was to compare for each of these diagnoses the level of pain intensity between four age groups (18-44; 45-64; 65 74; 75+ years). RESULTS: A total of 15,670 patients (48% women) were triaged with a mean pain intensity of 7.7 (SD=2.0). Women exhibited greater pain scores than men for pancreatitis, headache/migraine, and extremity fracture. Renal colic, pancreatitis, appendicitis, and headache/migraine showed a linear decrease in pain scores with age whereas dislocation and extremity fractures did not present age differences. Mean differences in pain intensity scores between young adults (18-44 years) and patients aged >=75 years were 0.79 (95% confidence interval [95% CI] 0.5-1.1) for renal colic, 1.1 (95% CI 0.7-1.4) for pancreatitis, 0.70 (95% CI 0.2-1.2) for appendicitis, and 0.86 (95% CI 0.6-1.1) for headache/migraine. CONCLUSION: Older patients perceive similar pain for dislocation and extremity fractures and less for visceral and headache/migraine pain; however, these age differences may not be clinically important. PMID- 26416134 TI - Moxifloxacin Use and Its Association on the Diagnosis of Pulmonary Tuberculosis in An Inner City Emergency Department. AB - BACKGROUND: Moxifloxacin can be used in the treatment of tuberculosis, its effect on the diagnosis and treatment of pulmonary tuberculosis is not well characterized. OBJECTIVE: To identify patients from the St. Paul's Hospital emergency department (ED) treated with moxifloxacin who also had sputum sent for investigation of possible tuberculosis and the impact on sensitivity of acid-fast bacilli (AFB) smears and time to initiation of tuberculosis treatment. METHODS: We conducted a retrospective single-center cohort study on patients that were prescribed moxifloxacin in the ED during a 5-year period and had samples collected for pulmonary tuberculosis. All AFB samples obtained throughout the hospital in patients not exposed to moxifloxacin during the same time period were also examined. RESULTS: Two-thousand six hundred and seventy-three patients who were admitted to St. Paul's Hospital through the ED received moxifloxacin during the study period. 273 (10.2%) of these patients were subsequently investigated for tuberculosis, with 9 positive cases of Mycobacterium tuberculosis (3.3%). One thousand three hundred and sixty-nine patients not exposed to moxifloxacin were screened for tuberculosis with 33 active cases (2.4%). The false-negative rate for AFB smears in the exposed group was 85.2% vs. 53.8% in the unexposed group (relative risk of false-negative AFB = 1.55; 95% CI 1.24-2.03). Time to initiation of anti-tuberculosis therapy was significantly delayed in the exposed group, with median time to initiation of 14 days vs. 2 days (p = 0.013). CONCLUSIONS: Exposure to moxifloxacin is associated with significantly increased rates of false-negative AFB smears and was associated with a significant delay in the initiation of anti-tuberculosis therapy. PMID- 26416135 TI - Race-related Healthcare Disparities Among California Workers: Public Health Considerations for Immigration Reform. AB - BACKGROUND: Healthcare disparities are prevalent in medicine and identifying them will provide healthcare professionals, administrators, and policy makers needed information to address this public health concern. OBJECTIVE: To evaluate racial and ethnic disparities in the rates of hospital admission and death among California workers. METHODS: We performed an analysis of hospital and emergency department (ED) data from the Office of Statewide Health Planning and Development (OSHPD). Data was collected from California licensed acute care hospitals from 2008-2010. INCLUSION CRITERIA: patients >15 years of age whose expected source of payment was worker's compensation. EXCLUSION CRITERIA: patients <15 years; had missing data for age, sex, race, or injury; or were injured by a suicide attempt, poisoning, or complication of medical procedure. Multivariate logistic regression was used to evaluate the relationship of race/ethnicity and admission/death rates. RESULTS: There were 393,298 patients discharged from the ED and 23,343 patients admitted from ED had workers compensation as their expected sources of payment and 150,277 met our inclusion criteria. The annual rate of ED treated injuries was 209/100,000 for Caucasians 343/100,000 for Hispanics, 258/100,000 for blacks and 97/100,000 for Asians. Compared to Caucasians, admission odds ratios (OR) were 1.15 (95% CI 1.07-1.25) for Hispanics, 1.08 (95% CI 0.87-1.33) for blacks, and 0.78 (95% CI 0.63-0.97) for Asians. CONCLUSION: We observed race and ethnicity related healthcare disparities among the occupationally injured in California, with Hispanics having the highest odds of admission and annual incidence of ED treated injuries. No difference in mortality rates was observed. PMID- 26416136 TI - Spectrum of Extramammary Malignant Neoplasms in the Breast With Radiologic Pathologic Correlation. AB - Although primary breast cancer is the most common malignancy identified by breast imaging, extramammary malignancies may also rarely be encountered. These uncommon lesions may reflect primary neoplasms of nonmammary origin as well as secondary metastatic lesions, and include lymphoma, melanoma, neuroendocrine tumors, gastrointestinal tract malignancies, and angiosarcoma among other entities. Malignant extramammary breast lesions may be encountered during routine mammographic screening, identified during the diagnostic evaluation of a palpable breast abnormality, or may be detected incidentally during imaging of other organs of interest. As such, the radiologist should have familiarity with the appearance of these lesions. This article focuses on a review of several of the most common extramammary metastases to the breast, as well as a few lesions that may develop as either primary or secondary lesions. PMID- 26416137 TI - Introducing a short version of the Geneva Emotion Recognition Test (GERT-S): Psychometric properties and construct validation. AB - The ability to accurately interpret others' emotional expressions in the face, voice, and body is a crucial component of successful social functioning and has been shown to predict better outcomes in private and professional life. To date, emotion recognition ability (ERA) has mostly been measured with tests that heavily rely on static pictures of the face and on few emotions, restricting their content validity. Recently, Schlegel, Grandjean, and Scherer (Psychological Assessment, 26, 666-672, 2014) published a new test that measures ERA in a more comprehensive fashion, by (1) including a wide range of 14 positive and negative emotions and (2) using video clips with sound that simultaneously present facial, vocal, and bodily emotional cues. This article introduces the short version of the Geneva Emotion Recognition Test (the GERT-S), and presents two studies (total N = 425) that examine the internal consistency, factor structure, and convergent and discriminant validity of the test. The results show that the GERT-S is a unidimensional test with good internal consistency. Furthermore, the GERT-S was substantially positively correlated with other ERA tests, with tests of emotional understanding and emotion management, and with cognitive ability. Taken together, the present studies demonstrate the usefulness of the GERT-S as an instrument for the brief and reliable assessment of ERA. It is available, free of charge and in seven different languages, for academic research use. Given the brief test-taking time (approx. 10 min) and its possible administration via different online platforms, the GERT-S can easily be integrated by researchers into their own studies. PMID- 26416138 TI - The tool for the automatic analysis of text cohesion (TAACO): Automatic assessment of local, global, and text cohesion. AB - This study introduces the Tool for the Automatic Analysis of Cohesion (TAACO), a freely available text analysis tool that is easy to use, works on most operating systems (Windows, Mac, and Linux), is housed on a user's hard drive (rather than having an Internet interface), allows for the batch processing of text files, and incorporates over 150 classic and recently developed indices related to text cohesion. The study validates TAACO by investigating how its indices related to local, global, and overall text cohesion can predict expert judgments of text coherence and essay quality. The findings of this study provide predictive validation of TAACO and support the notion that expert judgments of text coherence and quality are either negatively correlated or not predicted by local and overall text cohesion indices, but are positively predicted by global indices of cohesion. Combined, these findings provide supporting evidence that coherence for expert raters is a property of global cohesion and not of local cohesion, and that expert ratings of text quality are positively related to global cohesion. PMID- 26416139 TI - Cortical network architecture for context processing in primate brain. AB - Context is information linked to a situation that can guide behavior. In the brain, context is encoded by sensory processing and can later be retrieved from memory. How context is communicated within the cortical network in sensory and mnemonic forms is unknown due to the lack of methods for high-resolution, brain wide neuronal recording and analysis. Here, we report the comprehensive architecture of a cortical network for context processing. Using hemisphere-wide, high-density electrocorticography, we measured large-scale neuronal activity from monkeys observing videos of agents interacting in situations with different contexts. We extracted five context-related network structures including a bottom up network during encoding and, seconds later, cue-dependent retrieval of the same network with the opposite top-down connectivity. These findings show that context is represented in the cortical network as distributed communication structures with dynamic information flows. This study provides a general methodology for recording and analyzing cortical network neuronal communication during cognition. PMID- 26416140 TI - AMPA receptor mediated synaptic excitation drives state-dependent bursting in Purkinje neurons of zebrafish larvae. AB - Purkinje neurons are central to cerebellar function and show membrane bistability when recorded in vitro or in vivo under anesthesia. The existence of bistability in vivo in awake animals is disputed. Here, by recording intracellularly from Purkinje neurons in unanesthetized larval zebrafish (Danio rerio), we unequivocally demonstrate bistability in these neurons. Tonic firing was seen in depolarized regimes and bursting at hyperpolarized membrane potentials. In addition, Purkinje neurons could switch from one state to another spontaneously or with current injection. While GABAAR or NMDAR were not required for bursting, activation of AMPARs by climbing fibers (CFs) was sufficient to trigger bursts. Further, by recording Purkinje neuron membrane potential intracellularly, and motor neuron spikes extracellularly, we show that initiation of motor neuron spiking is correlated with increased incidence of CF EPSPs and membrane depolarization. Developmentally, bistability was observed soon after Purkinje neuron specification and persists at least until late larval stages. PMID- 26416141 TI - Comment on Azmahani et al. "Steroidogenic enzymes, their related transcription factors and nuclear receptors in human sebaceous glands under normal and pathological conditions". PMID- 26416142 TI - Assay reproducibility of serum androgen measurements using liquid chromatography tandem mass spectrometry. AB - BACKGROUND: Valid and precise measures of androgen concentrations are needed for etiologic studies of hormonally-related cancers. We developed a high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with two sample preparations to measure 11 androgens, including adrenal and gonadal androgenic precursors and their 5alpha-reduced metabolites. METHODS: Androgen levels were measured in serum from 20 healthy volunteers (5 men, 10 premenopausal women, 5 postmenopausal women). Two blinded, randomized aliquots per individual were assayed in each of three batches. A fourth batch of samples was measured at an external laboratory using comparable methodology to measure 9 of the 11 androgens. Coefficients of variation (CV) and intraclass correlation coefficients (ICC) were calculated from the individual components of variance. Comparability of 9 androgens across laboratories was assessed using Spearman ranked correlations, Deming regression and bias plots. RESULTS: The laboratory CVs were <5% and ICCs were uniformly high (>95%) for all androgens measured across sex/menopausal status groups. Spearman ranked correlations for 9 hormones measured in the comparison laboratory were high (>0.85), suggesting good agreement. CONCLUSION: Our high-performance LC-MS/MS assays of 11 androgens, including adrenal and gonadal androgenic precursors and their 5alpha-reduced metabolites demonstrated excellent laboratory reproducibility, and good comparability with an established method that measured 9 of the 11 hormones tested. The serum androgen metabolite assays are suitable for use in epidemiologic research. PMID- 26416144 TI - Oral health and post-discharge complications in stroke survivors. PMID- 26416143 TI - A systematic review of training programmes for recruiters to randomised controlled trials. AB - BACKGROUND: Recruitment to randomised controlled trials (RCTs) is often difficult. Clinician related factors have been implicated as important reasons for low rates of recruitment. Clinicians (doctors and other health professionals) can experience discomfort with some underlying principles of RCTs and experience difficulties in conveying them positively to potential trial participants. Recruiter training has been suggested to address identified problems but a synthesis of this research is lacking. The aim of our study was to systematically review the available evidence on training interventions for recruiters to randomised trials. METHODS: Studies that evaluated training programmes for trial recruiters were included. Those that provided only general communication training not linked to RCT recruitment were excluded. Data extraction and quality assessment were completed by two reviewers independently, with a third author where necessary. RESULTS: Seventeen studies of 9615 potentially eligible titles and abstracts were included in the review: three randomised controlled studies, two non-randomised controlled studies, nine uncontrolled pre-test/post-test studies, two qualitative studies, and a post-training questionnaire survey. Most studies were of moderate or weak quality. Training programmes were mostly set within cancer trials, and usually consisted of workshops with a mix of health professionals over one or two consecutive days covering generic and trial specific issues. Recruiter training programmes were well received and some increased recruiters' self-confidence in communicating key RCT concepts to patients. There was, however, little evidence that this training increased actual recruitment rates or patient understanding, satisfaction, or levels of informed consent. CONCLUSIONS: There is a need to develop recruiter training programmes that can lead to improved recruitment and informed consent in randomised trials. PMID- 26416145 TI - Novel Therapies for Chronic Lymphocytic Leukemia: A Canadian Perspective. AB - Chronic lymphocytic leukemia (CLL) is the most common adult lymphoproliferative disorder in Western countries. The current standard of care for CLL is chemoimmunotherapy, typically with fludarabine, cyclophosphamide, and rituximab (FCR). However, most patients with CLL are elderly with comorbidities and are unable to tolerate FCR. In order to choose the best treatment for each individual patient, physicians must balance efficacy with toxicity. In addition, most currently available treatments are ineffective in CLL patients with loss of TP53. Two groups of novel therapeutic agents-anti-CD20 monoclonal antibodies and small molecule inhibitors-are attempting to address these issues, and 5 of these agents have progressed to phase 3 trials: obinutuzumab, idelalisib, ibrutinib, venetoclax (ABT-199), and duvelisib (IPI-145). We present the current evidence for these novel agents in the treatment of CLL, along with the perspectives of 4 Canadian oncology experts. PMID- 26416146 TI - Towards an understanding of the structural basis for insect olfaction by odorant receptors. AB - Insects have co-opted a unique family of seven transmembrane proteins for odour sensing. Odorant receptors are believed to have evolved from gustatory receptors somewhere at the base of the Hexapoda and have expanded substantially to become the dominant class of odour recognition elements within the Insecta. These odorant receptors comprise an obligate co-receptor, Orco, and one of a family of highly divergent odorant "tuning" receptors. The two subunits are thought to come together at some as-yet unknown stoichiometry to form a functional complex that is capable of both ionotropic and metabotropic signalling. While there are still no 3D structures for these proteins, site-directed mutagenesis, resonance energy transfer, and structural modelling efforts, all mainly on Drosophila odorant receptors, are beginning to inform hypotheses of their structures and how such complexes function in odour detection. Some of the loops, especially the second extracellular loop that has been suggested to form a lid over the binding pocket, and the extracellular regions of some transmembrane helices, especially the third and to a less extent the sixth and seventh, have been implicated in ligand recognition in tuning receptors. The possible interaction between Orco and tuning receptor subunits through the final intracellular loop and the adjacent transmembrane helices is thought to be important for transducing ligand binding into receptor activation. Potential phosphorylation sites and a calmodulin binding site in the second intracellular loop of Orco are also thought to be involved in regulating channel gating. A number of new methods have recently been developed to express and purify insect odorant receptor subunits in recombinant expression systems. These approaches are enabling high throughput screening of receptors for agonists and antagonists in cell-based formats, as well as producing protein for the application of biophysical methods to resolve the 3D structure of the subunits and their complexes. PMID- 26416147 TI - Early BCG vaccine to low-birth-weight infants and the effects on growth in the first year of life: a randomised controlled trial. AB - BACKGROUND: Randomised trials have shown that early Bacille Calmette-Guerin (BCG) vaccine reduces overall neonatal and infant mortality. However, no study has examined how BCG affects growth. We investigated the effect on infant growth of early BCG vaccine given to low-birth-weight (LBW) infants. METHODS: Two-thousand three hundred forty-three LBW infants were randomly allocated 1:1 to "early BCG" (intervention group) or "late BCG" (current practice). Furthermore, a subgroup (N = 1717) were included in a two-by-two randomised trial in which they were additionally randomised 1:1 to vitamin A supplementation (VAS) or placebo. Anthropometric measurements were obtained 2, 6, and 12 months after enrolment. RESULTS: Overall there was no effect of early BCG on growth in the first year of life. The effect of early BCG on weight and mid-upper-arm circumference at 2 months tended to be beneficial among girls but not among boys (interaction between "early BCG" and sex: weight p = 0.03 and MUAC p = 0.04). This beneficial effect among girls was particularly seen among the largest infants weighing 2.0 kg or more at inclusion. CONCLUSION: Though BCG vaccination is not recommended to be given to LBW infants at birth in Guinea-Bissau, early BCG had no negative effect on infant growth and may have had a beneficial effect for girls. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT00146302). PMID- 26416148 TI - Retinoic acid metabolism proteins are altered in trichoblastomas induced by mouse papillomavirus 1. AB - Skin cancer burden is significant as treatment costs have skyrocketed to $8.1 million annually and some forms metastasize, such as cutaneous squamous cell carcinoma (cSCC) and melanoma. cSCC is caused by altered growth factor signaling induced by chemical carcinogens, ultraviolet light (UV) exposure, and infections with papillomaviruses (PVs). One of the few options for preventing cSCC in high risk patients is oral retinoids. While much is understood about retinoid treatments and metabolism in mouse models of chemically and UV exposure induced cSCC, little is known about the role of retinoids in PV-induced cSCC. To better understand how retinoid metabolism is altered in cSCC, we examined the expression of this pathway in the newly discovered mouse papillomavirus (MmuPV1), which produces trichoblastomas in dorsal skin but not cSCC. We found significant increases in a rate-limiting enzyme involved in retinoic acid synthesis and retinoic acid binding proteins, suggestive of increased RA synthesis, in MmuPV1 induced tumors in B6.Cg-Foxn1(nu)/J mice. Similar increases in these proteins were seen after acute UVB exposure in Crl:SKH1-Hr(hr) mice and in regressing pre cancerous lesions in a chemically-induced mouse model, suggesting a common mechanism in limiting the progression of papillomas to full blown cSCC. PMID- 26416149 TI - Bone growth resumption following in vivo static and dynamic compression removals on rats. AB - Mechanical loadings influence bone growth and are used in pediatric treatments of musculoskeletal deformities. This in vivo study aimed at evaluating the effects of static and dynamic compression application and subsequent removal on bone growth, mineralization and neuropathic pain markers in growing rats. Forty-eight immature rats (28 days old) were assigned in two groups (2- and 4 weeks experiment duration) and four subgroups: control, sham, static, and dynamic. Controls had no surgery. A micro-loading device was implanted on the 6th and 8th caudal vertebrae of shams without loading, static loading at 0.2 MPa or dynamic loading at 0.2 MPa +/- 30% and 0.1 Hz. In 2-week subgroups, compression was maintained for 15 days prior to euthanasia, while in 4- week subgroups, compression was removed for 10 additional days. Growth rates, histomorphometric parameters and mineralization intensity were quantified and compared. At 2 weeks, growth rates and growth plate heights of loaded groups (static/dynamic)were significantly lower than shams (p b 0.01).However, at 4 weeks, both growth rates and growth plate heights of loaded groups were similar to shams. At 4 weeks, alizarin red intensity was significantly higher in dynamics compared to shams (p b 0.05) and controls (p b 0.01). Both static and dynamic compressions enable growth resumption after loading removal, while preserving growth plate histomorphometric integrity. However, mineralization was enhanced after dynamic loading removal only. Dynamic loading showed promising results for fusionless treatment approaches for musculoskeletal deformities. PMID- 26416151 TI - Immunotherapy: Anti-PD-1 therapies-a new first-line option in advanced melanoma. PMID- 26416150 TI - Knee loading protects against osteonecrosis of the femoral head by enhancing vessel remodeling and bone healing. AB - Osteonecrosis of the femoral head is a serious orthopedic problem. Moderate loads with knee loading promote bone formation, but their effects on osteonecrosis have not been investigated. Using a rat model, we examined a hypothesis that knee loading enhances vessel remodeling and bone healing through the modulation of the fate of bone marrow-derived cells. In this study, osteonecrosis was induced by transecting the ligamentum teres followed by a tight ligature around the femoral neck. For knee loading, 5 N loads were laterally applied to the knee at 15 Hz for 5 min/day for 5 weeks. Changes in bone mineral density (BMD) and bone mineral content (BMC) of the femur were measured by pDEXA, and ink infusion was performed to evaluate vessel remodeling. Femoral heads were harvested for histomorphometry, and bone marrow-derived cells were isolated to examine osteoclast development and osteoblast differentiation. The results showed that osteonecrosis significantly induced bone loss, and knee loading stimulated both vessel remodeling and bone healing. The osteonecrosis group exhibited the lowest trabecular BV/TV (p b 0.001) in the femoral head, and lowest femoral BMD and BMC (both p b 0.01). However, knee loading increased trabecular BV/TV (p b 0.05) as well as BMD (pb 0.05) and BMC (p b 0.01). Osteonecrosis decreased the vessel volume (pb 0.001), vessel number (pb 0.001) and VEGF expression (p b 0.01), and knee loading increased them (pb 0.001, pb 0.001 and p b 0.01). Osteonecrosis activated osteoclast development, and knee loading reduced its formation, migration, adhesion and the level of "pit" formation (pb 0.001, pb 0.01, pb 0.001 and pb 0.001). Furthermore, knee loading significantly increased osteoblast differentiation and CFU-F (both p b 0.001). A significantly positive correlation was observed between vessel remodeling and bone healing (both p b 0.01). These results indicate that knee loading could be effective in repair osteonecrosis of the femoral head in a rat model. This effect might be attributed to promoting vessel remodeling, suppressing osteoclast development, and increasing osteoblast and fibroblast differentiation. In summary, the current study suggests that knee loading might potentially be employed as a non-invasive therapy for osteonecrosis of the femoral head. PMID- 26416152 TI - Surgical treatment of nonpalpable primary invasive and in situ breast cancer. AB - Breast cancer is the most-common cancer among women worldwide, and over one-third of all cases diagnosed annually are nonpalpable at diagnosis. The increasingly widespread implementation of breast-screening programmes, combined with the use of advanced imaging modalities, such as magnetic resonance imaging (MRI), will further increase the numbers of patients diagnosed with this disease. The current standard management for nonpalpable breast cancer is localized surgical excision combined with axillary staging, using sentinel-lymph-node biopsy in the clinically and radiologically normal axilla. Wire-guided localization (WGL) during mammography is a method that was developed over 40 years ago to enable lesion localization preoperatively; this technique became the standard of care in the absence of a better alternative. Over the past 20 years, however, other technologies have been developed as alternatives to WGL in order to overcome the technical and outcome-related limitations of this technique. This Review discusses the techniques available for the surgical management of nonpalpable breast cancer; we describe their advantages and disadvantages, and highlight future directions for the development of new technologies. PMID- 26416153 TI - Haematological cancer: PROLONGing PFS with ofatumumab in patients with CLL. PMID- 26416154 TI - Brimonidine gel 0.33% rapidly improves patient-reported outcomes by controlling facial erythema of rosacea: a randomized, double-blind, vehicle-controlled study. AB - BACKGROUND: Facial redness contributes to impaired psychosocial functioning in rosacea patients and the only approved treatment for erythema is topical brimonidine gel 0.33%. OBJECTIVES: To evaluate patient-reported outcomes, as well as efficacy and safety, in subjects with self-perceived severe erythema treated with brimonidine gel 0.33% compared to vehicle. METHODS: An 8-day multicenter, randomized study comparing once-daily brimonidine gel 0.33% with vehicle gel using a facial redness questionnaire, subject satisfaction questionnaire and a patient diary of facial redness control to assess patient-reported outcomes. RESULTS: Of the 92 included subjects with self-perceived severe erythema, very few were satisfied with their appearance at baseline (4.2% brimonidine group, 0 vehicle group). On Day 8, significantly more brimonidine group subjects were satisfied with their facial appearance compared to vehicle group (36.9% vs. 21.5%; P < 0.05), with the overall treatment effect (69.6% vs. 40.4%; P < 0.01), and with the improvement in their facial redness (67.4% vs. 33.3%; P < 0.001). More brimonidine group subjects were able to control their facial redness daily (e.g. 83.0% vs. 38.9% on Day 1). On Day 8, significantly more brimonidine group subjects than vehicle group had at least a one-grade improvement from baseline in the Clinician Erythema Assessment score (71.7% vs. 35.7%; P = 0.0011) and Patient Self-Assessment score (76.1% vs. 47.6%; P = 0.004). More subjects in the brimonidine group (29.2%) reported treatment-related adverse events than in the vehicle group (15.9%) but most were mild and transient. CONCLUSIONS: Once-daily brimonidine gel 0.33% allowed patients to rapidly control their facial redness and significantly improved patient-reported outcomes in the treatment of persistent facial erythema of rosacea. PMID- 26416155 TI - Hybrid Monoterpenoid Indole Alkaloids Obtained as Artifacts from Rauvolfia tetraphylla. AB - Five new hybrid monoterpenoid indole alkaloids bearing an unusual 2,2-dimethyl-4 oxopiperidin-6-yl moiety, namely rauvotetraphyllines F-H (1, 3, 4), 17-epi rauvotetraphylline F (2) and 21-epi-rauvotetraphylline H (5), were isolated from the aerial parts of Rauvolfia tetraphylla. Their structures were established by extensive spectroscopic analysis. The new alkaloids were evaluated for their cytotoxicity in vitro against five human cancer cell lines. PMID- 26416156 TI - Adult social position and sick leave: the mediating effect of physical workload. AB - OBJECTIVE: This study aimed to quantify how much of the adult social gradient in sick leave can be attributed to the mediating role of physical workload while accounting for the role of childhood and adolescent social position and neuroticism. METHODS: Our sample consisted of 2099 women and 1229 men from a Norwegian birth cohort study (born 1967-1976) who participated in the Nord Trondelag Health Study (2006-2008) (HUNT3). Data on sick leave (defined as >16 calendar days; 2006-2009) and social position during childhood, adolescence, and adulthood were obtained from national registers. Study outcome was time-to-first sick leave spell. Physical workload and neuroticism were self-reported in HUNT3. Mediating effects through physical workload were estimated using a method based on the additive hazards survival model. RESULTS: A hypothetical change from highest to lowest group in adult social position was, for women, associated with 51.6 [95% confidence interval (95% CI) 24.7-78.5] additional spells per 100,000 person-days at risk, in a model adjusted for childhood and adolescent social position and neuroticism. The corresponding rate increase for men was 41.1 (95% CI 21.4-60.8). Of these additional spells, the proportion mediated through physical workload was 24% (95% CI 10-49) and 30% (95% CI 10-63) for women and men, respectively. CONCLUSIONS: The effect of adult social position on sick leave was partly mediated through physical workload, even while accounting for earlier life course factors. Our findings provide support that interventions aimed at reducing physical workload among those with lower adult social position could reduce sick leave risk. PMID- 26416157 TI - Drug hypersensitivity in children: report from the pediatric task force of the EAACI Drug Allergy Interest Group. AB - When questioned, about 10% of the parents report suspected hypersensitivity to at least one drug in their children. However, only a few of these reactions can be confirmed as allergic after a diagnostic workup. There is still a lack of knowledge on drug hypersensitivity (DH) epidemiology, clinical spectrum, and appropriate diagnostic methods particularly in children. Meanwhile, the tools used for DH management in adults are applied also for children. Whereas this appears generally acceptable, some aspects of DH and management differ with age. Most reactions in children are still attributed to betalactams. Some manifestations, such as nonsteroidal anti-inflammatory drug-associated angioedema and serum sickness-like reactions, are more frequent among young patients as compared to adults. Risk factors such as viral infections are particularly frequent in children, making the diagnosis challenging. The practicability and validity of skin test and other diagnostic procedures need further assessment in children. This study presents an up-to-date review on epidemiology, clinical spectrum, diagnostic tools, and current management of DH in children. A new general algorithm for the study of these reactions in children is proposed. Data are presented focusing on reported differences between pediatric and adult patients, also identifying unmet needs to be addressed in further research. PMID- 26416159 TI - Smoking history is associated to cognitive impairment in Parkinson's disease. AB - INTRODUCTION: Patients with Parkinson's disease (PD) are more likely to suffer from cognitive impairment and dementia than healthy older adults. The aim of this study was to investigate smoking history as a risk factor for cognitive decline in PD. METHOD: One hundred thirty-nine PD patients aged 50 years and older (Hoehn and Yahr = 1-3) were recruited from a clinical database. Global cognitive function was assessed with the Mini-Mental State Examination (MMSE) and smoking history was investigated as part of a standard clinical interview. A multiple linear regression analysis was used to develop a model for predicting participants' MMSE scores from age, education, Hoehn and Yahr stage, disease duration, the number of vascular risk factors and the number of smoking pack years. RESULTS: The regression model significantly accounted for 22.9% of the variance in MMSE scores. Significant predictors were education (beta = .312, p < .001), age (beta = -.215, p = .013) and total smoking pack-years (beta = -.180, p = .029). In former smokers, the number of years since quitting had no effect on global cognition and there were no significant difference between patients who had quit smoking more than 10 years ago and those who had quit less than 10 years ago, F(1, 63) = 1.72, p = .195. CONCLUSION: Smoking history was associated to global cognitive impairment in PD even in patients who had quit smoking. These results are in line with findings in healthy older adults that have linked smoking to cognitive impairment, global brain atrophy and functional changes. Future studies should consider a broader assessment of cognitive functions. PMID- 26416158 TI - Mitochondrial ADP/ATP exchange inhibition: a novel off-target mechanism underlying ibipinabant-induced myotoxicity. AB - Cannabinoid receptor 1 (CB1R) antagonists appear to be promising drugs for the treatment of obesity, however, serious side effects have hampered their clinical application. Rimonabant, the first in class CB1R antagonist, was withdrawn from the market because of psychiatric side effects. This has led to the search for more peripherally restricted CB1R antagonists, one of which is ibipinabant. However, this 3,4-diarylpyrazoline derivative showed muscle toxicity in a pre clinical dog study with mitochondrial dysfunction. Here, we studied the molecular mechanism by which ibipinabant induces mitochondrial toxicity. We observed a strong cytotoxic potency of ibipinabant in C2C12 myoblasts. Functional characterization of mitochondria revealed increased cellular reactive oxygen species generation and a decreased ATP production capacity, without effects on the catalytic activities of mitochondrial enzyme complexes I-V or the complex specific-driven oxygen consumption. Using in silico off-target prediction modelling, combined with in vitro validation in isolated mitochondria and mitoplasts, we identified adenine nucleotide translocase (ANT)-dependent mitochondrial ADP/ATP exchange as a novel molecular mechanism underlying ibipinabant-induced toxicity. Minor structural modification of ibipinabant could abolish ANT inhibition leading to a decreased cytotoxic potency, as observed with the ibipinabant derivative CB23. Our results will be instrumental in the development of new types of safer CB1R antagonists. PMID- 26416162 TI - Layer-dependent surface potential of phosphorene and anisotropic/layer-dependent charge transfer in phosphorene-gold hybrid systems. AB - The surface potential and the efficiency of interfacial charge transfer are extremely important for designing future semiconductor devices based on the emerging two-dimensional (2D) phosphorene. Here, we directly measured the strong layer-dependent surface potential of mono- and few-layered phosphorene on gold, which is consistent with the reported theoretical prediction. At the same time, we used an optical way photoluminescence (PL) spectroscopy to probe charge transfer in the phosphorene-gold hybrid system. We firstly observed highly anisotropic and layer-dependent PL quenching in the phosphorene-gold hybrid system, which is attributed to the highly anisotropic/layer-dependent interfacial charge transfer. PMID- 26416161 TI - Neural responses to kindness and malevolence differ in illness and recovery in women with anorexia nervosa. AB - In anorexia nervosa, problems with social relationships contribute to illness, and improvements in social support are associated with recovery. Using the multiround trust game and 3T MRI, we compare neural responses in a social relationship in three groups of women: women with anorexia nervosa, women in long term weight recovery from anorexia nervosa, and healthy comparison women. Surrogate markers related to social signals in the game were computed each round to assess whether the relationship was improving (benevolence) or deteriorating (malevolence) for each subject. Compared with healthy women, neural responses to benevolence were diminished in the precuneus and right angular gyrus in both currently-ill and weight-recovered subjects with anorexia, but neural responses to malevolence differed in the left fusiform only in currently-ill subjects. Next, using a whole-brain regression, we identified an office assessment, the positive personalizing bias, that was inversely correlated with neural activity in the occipital lobe, the precuneus and posterior cingulate, the bilateral temporoparietal junctions, and dorsal anterior cingulate, during benevolence for all groups of subjects. The positive personalizing bias is a self-report measure that assesses the degree with which a person attributes positive experiences to other people. These data suggest that problems in perceiving kindness may be a consistent trait related to the development of anorexia nervosa, whereas recognizing malevolence may be related to recovery. Future work on social brain function, in both healthy and psychiatric populations, should consider positive personalizing biases as a possible marker of neural differences related to kindness perception. PMID- 26416160 TI - Histopathological features of endometrial carcinomas associated with POLE mutations: implications for decisions about adjuvant therapy. AB - AIMS: To characterize the histomorphological features of endometrial carcinomas (ECs) harbouring polymerase epsilon (POLE) mutations. METHODS AND RESULTS: Forty three ECs with POLE mutations were compared with a cohort of 202 ECs. Most POLE mutated ECs were endometrioid [34/43 (79%)]; the remaining tumours were mixed [6/43 (14%)], serous [2/43 (5%)], and clear cell [1/43 (2%)]. The endometrioid carcinomas were predominantly International Federation of Gynecology and Obstetrics grade 3 (27/43, 63%). The histotype distribution did not differ from that of control ECs (P = 0.69), but the grade of the EC was higher (P < 0.0005). Both nuclear grade and mitotic index were significantly higher in POLE-mutated ECs than in the comparison cohort. POLE-mutated ECs were associated with peritumoral lymphocytes and numerous tumour-infiltrating lymphocytes. Lymphovascular invasion was present in 20 of 43 tumours. Adjuvant radiotherapy and adjuvant chemotherapy would be offered in up to 80% and 40% of patients, respectively, on the basis of stage, grade, lymphovascular invasion, and histotype. CONCLUSIONS: POLE-mutated ECs are typically of high grade, with prominent lymphocytic infiltration, but they are not sufficiently distinctive to allow accurate diagnosis based on routine haematoxylin and eosin staining. Even though POLE-mutated tumours are associated with an excellent prognosis, current guidelines for giving adjuvant treatment for EC result in most patients receiving adjuvant therapy. PMID- 26416163 TI - Pain and Health-Related Quality of Life After Pediatric Inpatient Surgery. AB - Around 4 million children undergo inpatient surgery in the United States each year, however little is known about the impact of surgery and postoperative pain on children's health-related quality of life (HRQOL) during the weeks and months after surgery. We measured pain and HRQOL in a large, heterogeneous pediatric postsurgical population from baseline to 1-month follow-up. Over a 20-month period, parents of 915 children age 2 to 18 years (mean = 9.6 years), 50% male, 56% white, admitted to surgical services at a children's hospital enrolled in the study. Parent participants reported on sociodemographics, child HRQOL, and pain characteristics at baseline and 1 month after discharge. Although most of the children recovered to baseline by 1 month after hospital discharge, 23% of children had a significant decline in HRQOL. Logistic regression analyses found that increasing child age (odds ratio = 2.1 for age 13-18 years) and the presence of moderate-severe postsurgical pain at 1 month (odds ratio = 5.7) were significantly associated with deterioration in HRQOL from baseline to 1-month follow-up (P < .05 for each variable). Although HRQOL returns to the baseline level for most children, a sizeable proportion have significant deterioration in HRQOL associated with continued postsurgical pain at 1 month after hospital discharge from surgery. PERSPECTIVE: This study addresses an important gap in the literature, examining pain and health-related quality of life in a broad population of children undergoing a wide range of inpatient surgeries. Evaluation of inpatient health services from a patient and family perspective is essential in evaluating outcomes of surgical care. PMID- 26416164 TI - Strategies to engage stakeholders in research to improve acute care delivery. AB - Many families involved in research are well versed in the care system due to chronic conditions. Engagement of families of children with serious acute illnesses is infrequent, and no studies have documented the feasibility or acceptability of different methods of family engagement. We describe a model used in the Hospital-to-Home Outcomes study, which utilized a novel approach of short term focused engagement of families and other stakeholders to incorporate the unique viewpoints of families whose care experience is primarily focused around the period surrounding their child's hospitalization for acute illness. PMID- 26416165 TI - Response to imatinib in patient with corticosteroid-unresponsive idiopathic hypereosinophilic syndrome. PMID- 26416166 TI - Identity management and sense of belonging to gay community among young rural Thai same-sex attracted men: implications for HIV prevention and treatment. AB - Young Thai men who have sex with men continue to have high HIV prevalence and incidence in spite of much investment in community-based prevention approaches. To make HIV services more appropriate for same-sex attracted young men in Thailand, it needs to be considered how target groups view themselves and manage their identities. This paper derives from a qualitative study of 25 same-sex attracted rural young Thai men. It identifies five tactics men employed to manage the discrepancy between their preferences and parental/societal expectations regarding gender and sexuality, and discusses how the young men viewed themselves in the wider context of Thai society, including whether they felt part of a separate gay community. Participants usually did not adopt a gay social identity and were reluctant to join in gay community activities beyond dating. Hence, they would likely experience barriers in accessing gay community-based HIV services. HIV services targeting young same-sex attracted Thai men need to be diversified if they are to be more inclusive, appropriate and effective. PMID- 26416168 TI - A tiered asthma hazard characterization and exposure assessment approach for evaluation of consumer product ingredients. AB - Asthma is a complex syndrome with significant consequences for those affected. The number of individuals affected is growing, although the reasons for the increase are uncertain. Ensuring the effective management of potential exposures follows from substantial evidence that exposure to some chemicals can increase the likelihood of asthma responses. We have developed a safety assessment approach tailored to the screening of asthma risks from residential consumer product ingredients as a proactive risk management tool. Several key features of the proposed approach advance the assessment resources often used for asthma issues. First, a quantitative health benchmark for asthma or related endpoints (irritation and sensitization) is provided that extends qualitative hazard classification methods. Second, a parallel structure is employed to include dose response methods for asthma endpoints and methods for scenario specific exposure estimation. The two parallel tracks are integrated in a risk characterization step. Third, a tiered assessment structure is provided to accommodate different amounts of data for both the dose-response assessment (i.e., use of existing benchmarks, hazard banding, or the threshold of toxicological concern) and exposure estimation (i.e., use of empirical data, model estimates, or exposure categories). Tools building from traditional methods and resources have been adapted to address specific issues pertinent to asthma toxicology (e.g., mode-of action and dose-response features) and the nature of residential consumer product use scenarios (e.g., product use patterns and exposure durations). A case study for acetic acid as used in various sentinel products and residential cleaning scenarios was developed to test the safety assessment methodology. In particular, the results were used to refine and verify relationships among tiered approaches such that each lower data tier in the approach provides a similar or greater margin of safety for a given scenario. PMID- 26416167 TI - Antibiotics in neonatal life increase murine susceptibility to experimental psoriasis. AB - Psoriasis is an inflammatory skin disease affecting ~2% of the world's population, but the aetiology remains incompletely understood. Recently, microbiota have been shown to differentially regulate the development of autoimmune diseases, but their influence on psoriasis is incompletely understood. We show here that adult mice treated with antibiotics that target Gram-negative and Gram-positive bacteria develop ameliorated psoriasiform dermatitis induced by imiquimod, with decreased pro-inflammatory IL-17- and IL-22-producing T cells. Surprisingly, mice treated neonatally with these antibiotics develop exacerbated psoriasis induced by imiquimod or recombinant IL-23 injection when challenged as adults, with increased IL-22-producing gammadelta(+) T cells. 16S rRNA gene compositional analysis reveals that neonatal antibiotic-treatment dysregulates gut and skin microbiota in adults, which is associated with increased susceptibility to experimental psoriasis. This link between neonatal antibiotic mediated imbalance in microbiota and development of experimental psoriasis provides precedence for further investigation of its specific aetiology as it relates to human psoriasis. PMID- 26416170 TI - Multivalency effects on Pseudomonas aeruginosa biofilm inhibition and dispersal by glycopeptide dendrimers targeting lectin LecA. AB - The galactose specific lectin LecA partly mediates the formation of antibiotic resistant biofilms by Pseudomonas aeruginosa, an opportunistic pathogen causing lethal airways infections in immunocompromised and cystic fibrosis patients, suggesting that preventing LecA binding to natural saccharides might provide new opportunities for treatment. Here 8-fold (G3) and 16-fold (G4) galactosylated analogs of GalAG2, a tetravalent G2 glycopeptide dendrimer LecA ligand and P. aeruginosa biofilm inhibitor, were obtained by convergent chloroacetyl thioether (ClAc) ligation between 4-fold or 8-fold chloroacetylated dendrimer cores and digalactosylated dendritic arms. Hemagglutination inhibition, isothermal titration calorimetry and biofilm inhibition assays showed that G3 dendrimers bind LecA slightly better than their parent G2 dendrimers and induce complete biofilm inhibition and dispersal of P. aeruginosa biofilms, while G4 dendrimers show reduced binding and no biofilm inhibition. A binding model accounting for the observed saturation of glycopeptide dendrimer galactosyl groups and LecA binding sites is proposed based on the crystal structure of a G3 dendrimer LecA complex. PMID- 26416169 TI - Response of plant nutrient stoichiometry to fertilization varied with plant tissues in a tropical forest. AB - Plant N:P ratios are widely used as indices of nutrient limitation in terrestrial ecosystems, but the response of these metrics in different plant tissues to altered N and P availability and their interactions remains largely unclear. We evaluated changes in N and P concentrations, N:P ratios of new leaves (<1 yr), older leaves (>1 yr), stems and mixed fine roots of seven species after 3-years of an N and P addition experiment in a tropical forest. Nitrogen addition only increased fine root N concentrations. P addition increased P concentrations among all tissues. The N * P interaction reduced leaf and stem P concentrations, suggesting a negative effect of N addition on P concentrations under P addition. The reliability of using nutrient ratios as indices of soil nutrient availability varied with tissues: the stoichiometric metrics of stems and older leaves were more responsive indicators of changed soil nutrient availability than those of new leaves and fine roots. However, leaf N:P ratios can be a useful indicator of inter-specific variation in plant response to nutrients availability. This study suggests that older leaf is a better choice than other tissues in the assessment of soil nutrient status and predicting plant response to altered nutrients using nutrients ratios. PMID- 26416171 TI - Do age and sex impact on the absolute cell numbers of human brain regions? AB - What is the influence of sex and age on the quantitative cell composition of the human brain? By using the isotropic fractionator to estimate absolute cell numbers in selected brain regions, we looked for sex- and age-related differences in 32 medial temporal lobes (comprised basically by the hippocampal formation, amygdala and parahippocampal gyrus), sixteen male (29-92 years) and sixteen female (25-82); and 31 cerebella, seventeen male (29-92 years) and fourteen female (25-82). These regions were dissected from the brain, fixed and homogenized, and then labeled with a DNA-marker (to count all nuclei) and with a neuron-specific nuclear marker (to estimate neuron number). Total number of cells in the medial temporal lobe was found to be 1.91 billion in men, and 1.47 billion in women, a difference of 23 %. This region showed 34 % more neurons in men than in women: 525.1 million against 347.4 million. In contrast, no sex differences were found in the cerebellum. Regarding the influence of age, a quadratic correlation was found between neuronal numbers and age in the female medial temporal lobe, suggesting an early increase followed by slight decline after age 50. The cerebellum showed numerical stability along aging for both neurons and non-neuronal cells. In sum, results indicate a sex-related regional difference in total and neuronal cell numbers in the medial temporal lobe, but not in the cerebellum. On the other hand, aging was found to impact on cell numbers in the medial temporal lobe, while the cerebellum proved resilient to neuronal losses in the course of life. PMID- 26416173 TI - The sentinel node procedure in early stage cervical cancer, taking the next step; a diagnostic review. AB - OBJECTIVE: Recent reviews on the sentinel lymph node (SLN) procedure in cervical cancer have shown that bilateral SLN detection and ultra staging are safe and superior options compared to a unilateral detection, frozen section and H&E analysis. So far, nobody identified a subgroup of patients in whom a SLN procedure may replace pelvic lymph node dissection (PLND). METHODS: We searched PubMed, Embase, CINAHL and Cochrane from inception up to November 26, 2014. Studies reporting SLN detection, and/or histological outcome of the SLN were included. Methodological quality was assessed with the Quality Assessment of Diagnostic Accuracy Studies tool by two independent reviewers. Data to complete 2*2 contingency tables were obtained, and patient-, study- and technique characteristics were extracted. Results were pooled and plotted in forest plots. RESULTS: Forty-seven studies (4130 patients) were analyzed. Pooled data of diagnostic accuracy on ultra staging (18 studies; 1275 patients) showed a sensitivity of 94% (95% CI 80-99%) and negative predictive values ranging between 91 and 100%. After ultra staging, 19 false negative results remained. Prerequisites such as early FIGO stage (IA2, IB1, IIA primary tumor size <40mm), no suspicious pre-, and per-operative lymph nodes, and bilateral negative SLNs after ultra staging resulted in 1 remaining false negative result among 1257 patients (0.08%). Pooled data on a combined tracer in early stage cervical cancer patients with primary tumor size <20mm (6 studies; 276 patients) resulted in 87% bilateral SLN detection. CONCLUSIONS: Early stage cervical cancer patients (FIGO IA2, IB1, IIA primary tumor size <40mm) who have no suspicious pre-, and per operative lymph nodes, and have bilateral negative SLNs after ultra staging, have a residual risk of 0.08% (1/1257) on occult metastases. On the basis of these results we recommend not to perform a full PLND in these patients. PMID- 26416174 TI - Outcome of elderly patients who receive intensive care at a regional hospital in Hong Kong. AB - OBJECTIVE: To evaluate the clinical outcome (180-day mortality) of very elderly critically ill patients (age >=80 years) and compare with those aged 60 to 79 years. DESIGN: Historical cohort study. SETTING: Regional hospital, Hong Kong. PATIENTS: Patients aged >=60 years admitted between 1 January 2009 and 31 December 2013 to the Intensive Care Unit of the hospital. RESULTS: Over 5 years, 4226 patients aged >=60 years were admitted (55.5% total intensive care unit admissions), of whom 32.8% were aged >=80 years. The proportion of patients aged >=80 years increased over 5 years. As expected, those aged >=80 years carried more significant co-morbidities and a higher disease severity compared with those aged 60 to 79 years. They required more mechanical ventilatory support, were less likely to receive renal replacement therapy, and had a higher intensive care unit/hospital/180-day mortality compared with those aged 60 to 79 years. Nonetheless, 71.8% were discharged home and 62.2% survived >180 days following intensive care unit admission. Cox regression analysis revealed that Acute Physiology and Chronic Health Evaluation IV-minus-Age score, emergency admission, intensive care unit admission due to cardiovascular problem, neurosurgical cases, presence of significant co-morbidities (diabetes mellitus, metastatic carcinoma, leukaemia, or myeloma), and requirement for mechanical ventilation independently predicted 180-day mortality. CONCLUSIONS: The proportion of critically ill patients aged >=80 years increased over a 5-year period. Despite having more significant co-morbidities, greater disease severity, and higher intensive care unit/hospital/180-day mortality rate compared with those aged 60 to 79 years, 71.8% of those >=80 years could be discharged home and 62.2% survived >180 days following intensive care unit admission. Disease severity, presence of co morbidities, requirement for mechanical ventilation, emergency cases, and admission diagnosis independently predicted 180-day mortality. PMID- 26416172 TI - A roadmap for precision medicine in the epilepsies. AB - Technological advances have paved the way for accelerated genomic discovery and are bringing precision medicine clearly into view. Epilepsy research in particular is well suited to serve as a model for the development and deployment of targeted therapeutics in precision medicine because of the rapidly expanding genetic knowledge base in epilepsy, the availability of good in-vitro and in-vivo model systems to efficiently study the biological consequences of genetic mutations, the ability to turn these models into effective drug-screening platforms, and the establishment of collaborative research groups. Moving forward, it is crucial that these collaborations are strengthened, particularly through integrated research platforms, to provide robust analyses both for accurate personal genome analysis and gene and drug discovery. Similarly, the implementation of clinical trial networks will allow the expansion of patient sample populations with genetically defined epilepsy so that drug discovery can be translated into clinical practice. PMID- 26416175 TI - Why do Hong Kong patients need total hip arthroplasty? An analysis of 512 hips from 1998 to 2010. AB - INTRODUCTION: The number of patients undergoing total hip replacement surgeries has increased as a result of a rise in the ageing population. This study reviewed the demographics and disease spectrum leading to primary total hip replacement in the Chinese population from 1998 to 2010. METHODS: This case series was conducted in a university teaching hospital in Hong Kong. Data from the prospective joint registry of all patients who underwent primary total hip replacement from January 1998 to December 2010 were reviewed. Patients' age and sex, diagnosis, as well as the Harris Hip Scores before operation and at the last follow-up were described. RESULTS: There were 512 primary total hip replacements performed on 419 patients (43.4% males) during the study period. All had clinical follow-up for at least 2 years. The mean age of the patients was 57.6 (standard deviation, 16.6) years. In males, the main aetiology was osteonecrosis (50.9%), ankylosing spondylitis (19.5%), and post-traumatic arthritis (8.5%). For females, it was osteonecrosis (33.0%), primary osteoarthritis (18.8%), and post-traumatic arthritis (15.8%). Alcohol-induced (52.5%) and idiopathic (40.7%) was the most common cause of osteonecrosis in males and females, respectively. The mean preoperative Harris Hip Score and that at last follow-up was 43.9 (standard deviation, 18.3) and 89.7 (standard deviation, 13.0), respectively. CONCLUSIONS: Osteonecrosis was the most common aetiology leading to total hip replacement although there were different causes in both sexes leading to it. The clinical result in terms of Harris Hip Score was good for all patients who required total hip replacement. PMID- 26416176 TI - Dual use of VA and non-VA hospitals by Veterans with multiple hospitalizations. AB - BACKGROUND: Veterans who are hospitalized in both VA and non-VA hospitals within a short timespan may be at risk for fragmented or conflicting care. To determine the characteristics of these "dual users," we analyzed administrative hospital discharge data for VA-enrolled veterans of any age in seven states, including any VA or non-VA hospitalizations they had in 2004-2007. METHOD: For VA enrollees in Arizona, Iowa, Louisiana, Florida, South Carolina, Pennsylvania, or New York in 2007, we merged 2004-2007 discharge data for all VA hospitalizations and all non VA hospitalizations listed in state health department or hospital association databases. For patients hospitalized in 2007, we compared those younger or older than 65 years who had one or multiple hospitalizations during the year, split into users of VA hospitals, non-VA hospitals, or both ("dual users"), on demographics, priority for VA care, travel times, principal diagnoses, co morbidities, lengths of stay, and prior (2004-2006) hospitalizations, using chi square analysis or ANOVA. Multiply hospitalized patients were compared with multinomial logistic regressions to predict non-VA and dual use. Payers for non VA hospitalizations also were compared across groups. RESULTS: Of unique inpatients in 2007, 38 % of those 65 or older were hospitalized more than once during the year, as were 32 % of younger patients; 3 and 8 %, respectively, were dual users. Dual users averaged the most index-year (3.7) and prior (1.5) hospitalizations, split evenly between VA and non-VA. They also had higher rates of admission for circulatory diseases, symptoms/signs/ill-defined conditions, and injury and poisoning, and more admissions for multiple diagnostic categories; among younger patients they had the highest rate of mental disorders admissions. Higher income, non-rural residence, greater time to VA care, lower VA priority, prior non-VA hospitalization, no prior VA hospitalization, and several medical categories predicted greater non-VA use. Among younger patients, however, mental disorders predicted more dual use but less exclusively non-VA use. Dual users' non-VA admissions were more likely than others' to be covered by payers other than Medicare or commercial insurance. CONCLUSIONS: Younger dual users require more medical and psychiatric treatment, and rely more on government funding sources. Effective care coordination for these inpatients might improve outcomes while reducing taxpayer burden. PMID- 26416177 TI - Feasibility and effectiveness of the baby friendly community initiative in rural Kenya: study protocol for a randomized controlled trial. AB - BACKGROUND: Interventions promoting optimal infant and young child nutrition could prevent a fifth of under-5 deaths in countries with high mortality. Poor infant and young child feeding practices are widely documented in Kenya, with potential detrimental effects on child growth, health and survival. Effective strategies to improve these practices are needed. This study aims to pilot implementation of the Baby Friendly Community Initiative (BFCI), a global initiative aimed at promoting optimal infant and young child feeding practices, to determine its feasibility and effectiveness with regards to infant feeding practices, nutrition and health outcomes in a rural setting in Kenya. METHODS: The study, employing a cluster-randomized trial design, will be conducted in rural Kenya. A total of 12 clusters, constituting community units within the government's Community Health Strategy, will be randomized, with half allocated to the intervention and the other half to the control arm. A total of 812 pregnant women and their respective children will be recruited into the study. The mother-child pairs will be followed up until the child is 6 months old. Recruitment will last approximately 1 year from January 2015, and the study will run for 3 years, from 2014 to 2016. The intervention will involve regular counseling and support of mothers by trained community health workers and health professionals on maternal, infant and young child nutrition. Regular assessment of knowledge, attitudes and practices on maternal, infant and young child nutrition will be done, coupled with assessment of nutritional status of the mother-child pairs and morbidity for the children. Statistical methods will include analysis of covariance, multinomial logistic regression and multilevel modeling. The study is funded by the NIH and USAID through the Program for Enhanced Research (PEER) Health. DISCUSSION: Findings from the study outlined in this protocol will inform potential feasibility and effectiveness of a community based intervention aimed at promoting optimal breastfeeding and other infant feeding practices. The intervention, if proved feasible and effective, will inform policy and practice in Kenya and similar settings, particularly regarding implementation of the baby friendly community initiative. TRIAL REGISTRATION: ISRCTN03467700 ; Date of Registration: 24 September 2014. PMID- 26416178 TI - A rare accessory muscle in the hand--the flexor digitorum superficialis indicis. AB - Accessory muscles are easily overlooked during imaging evaluation. Although usually discovered incidentally, they are occasionally symptomatic. With increasing utilization of cross-sectional imaging, the radiologist should be prepared to readily identify these anomalous muscles. It is particularly important to distinguish these anatomical variants from soft-tissue tumors prior to invasive intervention, reserving biopsy and surgery for children who are symptomatic. This report discusses a case of a flexor digitorum superficialis indicis muscle, an extremely rare but well-described accessory muscle, presenting as a painful mass in a 15-year-old girl. The report includes the clinical presentation, radiologic findings, and the significance to management. PMID- 26416179 TI - Hypodermin A, a potential agent for prevention of allogeneic acute rejection. AB - Immunosuppressive agents play an important role in the success of organ transplantation, however the chronic toxicity of these agents is a major issue over the long-term. Hypodermin A (HA) is an enzyme secreted by the larvae of Hypoderma lineatum (Diptera: Oestridae), and has been implicated in immunosuppression in cattle. Malassagne et al. have demonstrated that HA can degrade the C3 protein, and could be used to prevent hyperacute xenogeneic rejection. We found that overexpression of HA in RAW264.7 cells induced significant secretion of prostaglandin E2 (PGE2), which mediates a variety of innate and adaptive immune responses through four E-type prostanoid (EP) receptor subtypes (EP1-4). PGE2 is useful in the management of allogeneic acute rejection. In addition, we found that induction of PGE2 expression downregulates the expression of interferon (IFN)-gamma and interleukin (IL)-2, and promotes the secretion of IL-10 in vitro through the EP4 receptor. It was previously shown that activation of IL-2 and IFN-gamma is involved in allograft acute rejection. IL-10 is known to prevent inflammation, and can improve allograft survival rates. We concluded that besides preventing hyperacute xenogeneic rejection, HA might also be a potential therapeutic candidate for ameliorating acute rejection during allotransplantation. PMID- 26416180 TI - Microvascular integrity plays an important role for graft survival after experimental skin transplantation. AB - BACKGROUND: Every transplanted organ relies on a reliable and sound vascular system. Therefore, our study focused on the investigation if platelet inhibition alone or combined with mTOR-inhibition has a beneficial effect on the microvascular integrity in allogeneic murine skin grafts. METHODS: Skin transplantation was performed from fully MHC-mismatched C57BL/6 (H-2b) donors to CBA/J (H-2k) recipient mice. Skin allograft recipients were assigned to several experimental groups and either treated with clopidogrel alone, everolimus alone or a combination of both. Graft survival was evaluated and transplants were harvested after 8 days and analyzed for CD31 and C4d by immunohistochemistry. RESULTS: Untreated allografts showed a reduced amount of CD31 on postoperative day 8 as well as an increase in C4d compared to isografts. All treated animals showed a significant improvement regarding CD31 [1577.7 +/- 200.4 (clopidogrel)/1702.8 +/- 151.1 (clopidogrel + everolimus) vs. 479.7 +/- 184.2 (control), n = 8, p b 0.05] and C4d [420.9 +/- 70.9 (clopidogrel)/324.5 +/- 77.3 (clopidogrel + everolimus) vs. 772.4 +/- 159.7 (control), n = 8, p b 0.05]. In addition, skin grafts of animals treated with clopidogrel and everolimus survived significantly longer compared to untreated controls [19.2 +/- 4.2 d vs. 12.8 +/- 2.4 d, n= 10, p b 0.05]. CONCLUSION: In this study we could show that clopidogrel alone and in combination with everolimus substantially improved microvascular integrity and resulted in increased survival time of skin grafts. PMID- 26416181 TI - Relationship between developmental canal stenosis and surgical results of anterior decompression and fusion in patients with cervical spondylotic myelopathy. AB - BACKGROUND: Anterior cervical decompression and fusion (ACDF) has long been the preferred treatment for cervical spondylotic myelopathy (CSM). However, few studies have focused on surgical results of CSM in patients with developmental canal stenosis (DCS). The purpose of this study was to investigate DCS as a comorbidity in patients with CSM and the correlation between surgical results and DCS. METHODS: From January 1995 to December 2005, 122 patients treated with ACDF for CSM were enrolled in this retrospective study. Pavlov's ratio was used to evaluate cervical spinal canal size, with a value of < 0.82 at least one level indicating DCS. Patients were divided into two groups: those with DCS preoperatively (DCS group, n = 50 [41.0 %]) and those without DCS (non-DCS group, n = 72). Clinical data and radiological parameters were compared between groups. RESULTS: There were no significant differences in preoperative and 2-year follow up Japanese Orthopedic Association scores between groups. Both groups achieved satisfactory fusion rates (DCS, 92.0 %; non-DCS, 93.0 %). Adjacent-segment degeneration (ASD) was detected in 66.0 % of patients in the DCS group and in 43.0 % of patients in the non-DCS group (p = 0.01). However, there was no significant difference in the incidence of ASD requiring surgery between groups (p = 0.20). DISCUSSION: DCS is a common comorbidity in patients with CSM. The findings of this study have added knowledge on the correlation between DCS and ASD after anterior fusion surgery. CONCLUSIONS: DCS did not affect neurologic improvement postoperatively at short-term follow-up. Although DCS increased the incidence of ASD after anterior fusion, it did not predict ASD requiring surgery. Therefore, patients with DCS must receive close follow-up. PMID- 26416182 TI - Nonsense mutations in the rhodopsin gene that give rise to mild phenotypes trigger mRNA degradation in human cells by nonsense-mediated decay. AB - Eight different nonsense mutations in the human rhodopsin gene cause retinitis pigmentosa (RP), an inherited degenerative disease of the retina that can lead to complete blindness. Although all these nonsense mutations lead to premature termination codons (PTCs) in rhodopsin mRNA, some display dominant inheritance, while others are recessive. Because nonsense-mediated decay (NMD) can degrade mRNAs containing PTCs and modulate the inheritance patterns of genetic diseases, we asked whether any of the nonsense mutations in the rhodopsin gene generated mRNAs that were susceptible to degradation by NMD. We hypothesized that nonsense mutations that caused mild RP phenotypes would trigger NMD, whereas those that did not engage NMD would cause more severe RP phenotypes-presumably due to the toxicity of the truncated protein. To test our hypothesis, we transfected human rhodopsin nonsense mutants into HEK293 and HT1080 human cells and measured transcript levels by qRT-PCR. In both cell lines, rhodopsin mutations Q64X and Q344X, which cause severe phenotypes that are dominantly inherited, yielded the same levels of rhodopsin mRNA as wild type. By contrast, rhodopsin mutations W161X and E249X, which cause recessive RP, showed decreased rhodopsin mRNA levels, consistent with NMD. Rhodopsin mutant Y136X, a dominant mutation that causes late-onset RP with a very mild pathology, also gave lower mRNA levels. Treatment of cells with Wortmannin, an inhibitor of NMD, eliminated the degradation of Y136X, W161X, and E249X rhodopsin mRNAs. These results suggest that NMD modulates the severity of RP in patients with nonsense mutations in the rhodopsin gene. PMID- 26416183 TI - Association of Autophagy in the Cell Death Mediated by Dihydrotestosterone in Autoreactive T Cells Independent of Antigenic Stimulation. AB - Gender disparity is well documented in the mouse model of experimental autoimmune encephalomyelitis (EAE) induced with proteolipid protein (PLP) 139-151, in which female, but not male, SJL mice show a chronic relapsing-remitting paralysis. Furthermore, dihydrotestosterone (DHT) has been shown to ameliorate the severity of EAE, but the underlying mechanisms of its protective effects are unclear. Using major histocompatibility complex (MHC) class II dextramers for PLP 139-151, we tested the hypothesis that DHT selectively modulates the expansion and functionalities of antigen-specific T cells. Unexpectedly, we noted that DHT induced cell death in antigen-specific, autoreactive T cells, but the effects were not selective, because both proliferating and non-proliferating cells were equally affected independent of antigenic stimulation. Furthermore, DHT-exposed PLP 139-151-specific T cells did not show any shift in cytokine production; rather, frequencies of cytokine-producing PLP-specific T cells were significantly reduced, irrespective of T helper (Th) 1, Th2, and Th17 subsets of cytokines. By evaluating cell death and autophagy pathways, we provide evidence for the induction of autophagy to be associated with cell death caused by DHT. Taken together, the data provide new insights into the role of DHT and indicate that cell death and autophagy contribute to the therapeutic effects of androgens in autoreactive T cells. PMID- 26416184 TI - The Quality of Genetic Counseling and Connected Factors as Evaluated by Male BRCA1/2 Mutation Carriers in Finland. AB - There is little written about the quality of genetic counseling for men with the BRCA1/2 mutation. The purpose of this study was to describe the quality of genetic counseling and connected factors according to Finnish male BRCA1/2 mutation carriers' (n = 35) perspectives and reasons for seeking genetic counseling. Data were collected from the Departments of Clinical Genetics at five Finnish university hospitals. The exploratory study design was conducted using a 51-item questionnaire based on a previously devised quality of counseling model and analyzed using non-parametric tests and principle content analysis. The satisfaction level with genetic counseling was high, especially with regard to the content of genetic counseling. The benefit of genetic counseling on the quality of life differed significantly (p < 0.001-0.009) from other factors. In particular, genetic counseling was in some cases associated to reduce the quality of life. Only 49 % of the male carriers felt they received sufficient counseling on social support. Attention to individual psychosocial support was proposed as an improvement to genetic counseling. Primary and secondary reasons for seeking genetic counseling and background information, such as education, affected the perceived quality of genetic counseling. The results of the study could be used to tailor genetic counseling for male BRCA1/2 mutation carriers. PMID- 26416185 TI - Assessment of the Readability of Genetic Counseling Patient Letters. AB - Patient letters are a powerful tool that genetic counselors use to communicate with their patients. Patient letters are often sent to provide information on a new diagnosis, reiterate test results, and to serve as a permanent record of the visit. Patient letters, however, are only helpful if the patients can understand them. More than 50 % of the US population reads below a 9th grade reading level and over one-third of the population has low health literacy skills. In this study we evaluate the readability of genetic counseling patient letters by assessing reading level, image use, and terminology use. One hundred forty-nine genetic counselors participated in the survey and of these, 79 submitted a sample patient letter. Analyses of the letters revealed a mean reading level of 10.93. On average, 6 genetic terms were included in each letter, and only 25 % of these terms were defined. Analyses of survey responses revealed over 75 % of the genetic counselors did not include images in their patient letters. These results indicate there is room for improvement in order to make genetic counseling patient letters more accessible to the general population. PMID- 26416186 TI - Direct Observation of Long Electron-Hole Diffusion Distance in CH3NH3PbI3 Perovskite Thin Film. AB - In high performance perovskite based solar cells, CH3NH3PbI3 is the key material. We carried out a study on charge diffusion in spin-coated CH3NH3PbI3 perovskite thin film by transient fluorescent spectroscopy. A thickness-dependent fluorescent lifetime was found. By coating the film with an electron or hole transfer layer, [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) or 2,2',7,7' tetrakis(N,N-di-p-methoxyphenylamine)-9,9'-spirobifluorene (Spiro-OMeTAD) respectively, we observed the charge transfer directly through the fluorescence quenching. One-dimensional diffusion model was applied to obtain long charge diffusion distances in thick films, which is ~1.7 MUm for electrons and up to ~6.3 MUm for holes. Short diffusion distance of few hundreds of nanometer [corrected] was also observed in thin films. This thickness dependent charge diffusion explained the formerly reported short charge diffusion distance (~100 nm) in films and resolved its confliction to thick working layer (300-500 nm) in real devices. This study presents direct support to the high performance perovskite solar cells and will benefit the devices' design. PMID- 26416187 TI - Temporal Trends in the Incidence and Natural History of Diverticulitis: A Population-Based Study. AB - OBJECTIVES: Data on the incidence and natural history of diverticulitis are largely hospital-based and exclude the majority of diverticulitis patients, who are treated in an outpatient setting for uncomplicated diverticulitis. We assessed temporal trends in the epidemiology of diverticulitis in the general population. METHODS: Through the Rochester Epidemiology Project we reviewed the records of all individuals with a diagnosis of diverticulitis from 1980 to 2007 in Olmsted County, Minnesota, USA. RESULTS: In 1980-1989, the incidence of diverticulitis was 115/100,000 person-years, which increased to 188/100,000 in 2000-2007 (P<0.001). Incidence increased with age (P<0.001); however, the temporal increase was greater in younger people (P<0.001). Ten years after the index and second diverticulitis episodes, 22% and 55% had a recurrence, respectively. This recurrence rate was greater in younger people (hazard ratio (HR) per decade 0.63; 95% confidence interval (CI), 0.59-0.66) and women (HR 0.68; 95% CI, 0.58-0.80). Complications were seen in 12%; this rate did not change over time. Recurrent diverticulitis was associated with a decreased risk of complications (P<0.001). Age was associated with increased risk of local (odds ratio (OR) 1.27 per decade; 95% CI, 1.04-1.57) and systemic (OR 1.83; 95% CI, 1.20-2.80) complications. Survival after diverticulitis was lower in older people (P<0.001) and men (P<0.001) and worsened over time (P<0.001). The incidence of surgery for diverticulitis did not change from 1980 to 2007. CONCLUSIONS: The incidence of diverticulitis has increased by 50% in 2000-2007 compared with 1990 1999, and more so in younger people. Complications are relatively uncommon. Recurrent diverticulitis is frequent but typically uncomplicated. Younger people with diverticulitis have less severe disease, more recurrence, and better survival. PMID- 26416188 TI - Autofluorescence-Directed Confocal Endomicroscopy in Combination With a Three Biomarker Panel Can Inform Management Decisions in Barrett's Esophagus. AB - OBJECTIVES: Barrett's esophagus (BE) surveillance with white-light endoscopy and quadrantic biopsies (Seattle protocol) is resource intensive and limited by sampling error. Previous work suggests that autofluorescence imaging (AFI) in combination with a molecular panel might reduce the number of biopsies, but this was not sufficiently sensitive for low-grade dysplasia, now a point for endoscopic intervention. Here we used AFI to direct narrow-field imaging tools for real-time optical assessment of dysplasia and biopsies for a biomarker panel. We compared the new diagnostic algorithm with the current standard. METHODS: A total of 55 patients with BE were recruited at a single tertiary referral center. Patients underwent high-resolution endoscopy followed by AFI. AFI-targeted areas (n=194) were examined in turn by narrow-band imaging with magnification (NBIz) and probe-based confocal laser endomicroscopy (pCLE). Biopsies were taken from AFI-targeted areas and tested using an established molecular panel comprising aneuploidy plus cyclin A and p53 immunohistochemistry. RESULTS: In the per patient analysis the overall sensitivity and specificity of AFI-targeted pCLE were 100% and 53.6% for high-grade dysplasia/intramucosal cancer and 96.4% and 74.1% for any grade of dysplasia, respectively. NBIz had equal specificity for dysplasia detection (74.1%), but significantly lower sensitivity (57.1%) than pCLE. The time required to perform AFI-targeted pCLE was shorter that that taken by the Seattle protocol (P=0.0004). We found enrichment of molecular abnormalities in areas with optical dysplasia by pCLE (P<0.001), regardless of histologic dysplasia. The addition of the 3-biomarker panel reduced the false positive rate of pCLE by 50%, leading to sensitivity and specificity for any grade of dysplasia of 89.2% and 88.9%, respectively. CONCLUSIONS: The combination of pCLE on AFI-targeted areas and a 3-biomarker panel identifies patients with dysplasia. PMID- 26416189 TI - The Link between the Appendix and Ulcerative Colitis: Clinical Relevance and Potential Immunological Mechanisms. AB - The human appendix has long been considered as a vestigial organ, an organ that has lost its function during evolution. In recent years, however, reports have emerged that link the appendix to numerous immunological functions in humans. Evidence has been presented for an important role of the appendix in maintaining intestinal health. This theory suggests that the appendix may be a reservoir or 'safe house' from which the commensal gut flora can rapidly be reestablished if it is eradicated from the colon. However, the appendix may also have a role in the development of inflammatory bowel disease (IBD). Several large epidemiological cohort studies have demonstrated the preventive effect of appendectomy on the development of ulcerative colitis, a finding that has been confirmed in murine colitis models. In addition, current studies are examining the possible therapeutic effect of an appendectomy to modulate disease course in patients with ulcerative colitis. This literature review assesses the current knowledge about the clinical and immunological aspects of the vermiform appendix in IBD and suggests that the idea of the appendix as a vestigial remnant should be discarded. PMID- 26416190 TI - Low-grade dysplasia in ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer. AB - OBJECTIVES: The aim of this study was to identify risk factors associated with development of high-grade dysplasia (HGD) or colorectal cancer (CRC) in ulcerative colitis (UC) patients diagnosed with low-grade dysplasia (LGD). METHODS: Patients with histologically confirmed extensive UC, who were diagnosed with LGD between 1993 and 2012 at St Mark's Hospital, were identified and followed up to 1 July 2013. Demographic, endoscopic, and histological data were collected and correlated with the development of HGD or CRC. RESULTS: A total of 172 patients were followed for a median of 48 months from the date of initial LGD diagnosis (interquartile range (IQR), 15-87 months). Overall, 33 patients developed HGD or CRC (19.1% of study population; 20 CRCs) during study period. Multivariate Cox proportional hazard analysis revealed that macroscopically non polypoid (hazard ratio (HR), 8.6; 95% confidence interval (CI), 3.0-24.8; P<0.001) or invisible (HR, 4.1; 95% CI, 1.3-13.4; P=0.02) dysplasia, dysplastic lesions >=1 cm in size (HR, 3.8; 95% CI, 1.5-13.4; P=0.01), and a previous history of "indefinite for dysplasia" (HR, 2.8; 95% CI, 1.2-6.5; P=0.01) were significant contributory factors for HGD or CRC development. Multifocal dysplasia (HR, 3.9; 95% CI, 1.9-7.8; P<0.001), metachronous dysplasia (HR, 3.5; 95% CI, 1.6 7.5; P=0.001), or a colonic stricture (HR, 7.4; 95% CI, 2.5-22.1; P<0.001) showed only univariate correlation to development of HGD or CRC. CONCLUSIONS: Lesions that are non-polypoid or endoscopically invisible, large (>=1 cm), or preceded by indefinite dysplasia are independent risk factors for developing HGD or CRC in UC patients diagnosed with LGD. PMID- 26416191 TI - Clinical and pathophysiological consequences of alterations in the microbiome in cirrhosis. AB - Cirrhosis is a major cause of mortality worldwide. Exponential rises in prevalence have been observed secondary to increases in obesity and alcohol consumption. Multiple lines of evidence implicate gut-derived bacteria and bacterial ligands as a central driver of pathogenesis. Recent developments in culture-independent techniques have facilitated a more accurate description of microbiome composition in cirrhosis and led to the description of measures of dysbiosis shown to be associated with disease. More importantly, metagenomic studies are adding to an understanding of the functional contribution of the microbiota and may prove to be a more clinically relevant biomarker than phylogenetic studies. Much like other dysbiotic states such as inflammatory bowel disease, the microbiota in cirrhosis is characterized by a low microbial and genetic diversity. Therapeutic strategies to diminish this process are currently limited to selective intestinal decontamination with antibiotics. This review summarizes the available data and develops a framework for the use of current and future treatment strategies to diminish the consequences of dysbiosis in cirrhosis. Interventional strategies to bind bacterial products in the gut lumen and blood, and modulate the magnitude of host sensing mechanisms remain an unmet clinical need. A greater understanding of the host-microbiota interaction in cirrhosis is of key importance to inform future interventional strategies to diminish the currently escalating burden of the disease. PMID- 26416192 TI - Risk of Celiac Disease in the First- and Second-Degree Relatives of Patients With Celiac Disease: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: First-degree relatives (FDRs) of patients with celiac disease (CD) are at high risk for CD and prevalence among them varies from 1.6 to 38%. The risk of having CD among FDRs if the FDR is sister, brother, mother, father, son, or daughter of index patient with CD is not known. We conducted a meta-analysis and calculated pooled prevalence of CD among FDRs, second-degree relatives (SDRs), and specific relations with index patient. METHODS: On search of literature, 2,259 articles appeared of which 54 articles were included in this meta-analysis. Diagnosis of CD was based on standard criteria. RESULTS: Pooled prevalence of CD was 7.5% (95% confidence interval (CI) 6.3%, 8.8%) in 10,252 FDRs and 2.3% (95% CI 1.3%, 3.8%) in 642 SDRs. Pooled prevalence of CD was highest in siblings (8.9%), followed by offsprings (7.9%) and parents (3.0%). Female FDRs had higher prevalence than male FDRs (8.4% vs. 5.2%, P=0.047). While sisters and daughters of index patient had the highest risk of having CD (1 in 7 and 1 in 8, respectively), the risk was 1 in 13 in sons, 1 in 16 in brothers, 1 in 32 in mothers, and 1 in 33 in fathers. There were also differences in the pooled prevalence of CD in FDRs according to their geographic location. CONCLUSIONS: Pooled prevalence of CD among FDRs is 7.5% and varies considerably with their relationship with the index patient. The risk of CD in FDRs also varies according to gender and geographical location. PMID- 26416193 TI - Long-Term Loss of Response in Proton Pump Inhibitor-Responsive Esophageal Eosinophilia Is Uncommon and Influenced by CYP2C19 Genotype and Rhinoconjunctivitis. AB - OBJECTIVES: Proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE) is diagnosed in at least one-third of patients with suspected eosinophilic esophagitis (EoE). We aimed to evaluate the durability and factors influencing long-term efficacy of PPI therapy. METHODS: Retrospective multicenter cohort study of patients with PPI-REE who had at least 12 months of follow-up. PPI therapy was tapered to the lowest dose, which maintained clinical remission. Primary outcomes were the proportion of patients with loss of histological response (<15 eos/HPF) and predictors of loss of response. CYP2C19 polymorphisms were determined from blood samples in a subset of patients. RESULTS: Seventy-five PPI-REE patients were included (mean follow-up 26 months (12-85)), of whom fifty five (73%) had sustained histological remission on low-dose PPI therapy. Loss of response was significantly higher in those patients with a CYP2C19 rapid metabolizer genotype (36% vs. 6%, P = 0.01) and with rhinoconjunctivitis (40% vs. 13%, P = 0.007). On the multivariate analysis, a CYP2C19 rapid metabolizer genotype (odds ratio (OR) 12.5; 95% confidence interval (CI): 1.3-115.9) and rhinoconjunctivitis (OR 8.6; 95% CI: 1.5-48.7) were independent predictors of loss of response. Among relapsing patients, eosinophilia was limited to the distal esophagus in 14/20 (70%). Nine of ten relapsers, with distal eosinophilia, all showing a CYP2C19 rapid metabolizer genotype, regained histological remission after PPI dose intensification. CONCLUSIONS: Most PPI-REE patients remain in long term remission on low-dose PPI therapy. CYP2C19 rapid metabolizer genotypes and rhinoconjunctivitis were independent predictors of loss of response to PPI, but patients frequently responded to PPI dose escalation. PMID- 26416194 TI - Changing Nomenclature for PBC: From 'Cirrhosis' to 'Cholangitis'. PMID- 26416195 TI - Right Or Left in COLonoscopy (ROLCOL)? A Randomized Controlled Trial of Right- versus Left-Sided Starting Position in Colonoscopy. AB - OBJECTIVES: Colonoscopy is technically challenging and can cause discomfort for patients. We aimed to test whether right-sided starting position for colonoscopy would result in shorter procedure time and greater patient comfort when compared with conventional left-sided starting position. METHODS: We conducted a randomized controlled trial in which patients were randomized to begin in either the right- (RL) or conventional left-lateral (LL) position. One hundred and sixty three adult patients undergoing scheduled colonoscopy were stratified by age, gender, body mass index, and experience of the endoscopist. Patients were then randomized 1:1 in permuted blocks. The primary outcome measure was time to cecal intubation and secondary outcome measures included patient comfort that was evaluated by visual analog comfort scale. RESULTS: Median time to reach the cecum was quicker when colonoscopy began with patients positioned RL rather than LL (P=0.0078). Moreover, patients found RL more comfortable than LL (P=0.02). Multiple linear regression confirmed starting position in colonoscopy as an independent determinant of time to reach the cecum (P=0.007). Women and those who had previously undergone abdominal surgery gained the greatest benefit from right sided positioning (RL vs. LL: 498 vs. 824 s; P=0.03 and 498 vs. 797 s; P=0.006, respectively). CONCLUSIONS: Our study reveals that right-sided positioning at the start of colonoscopy results in more comfortable and quicker procedures. Of the factors identified by multiple linear regression to independently have an impact on time to reach the cecum, only starting position is modifiable. Right-sided starting position may therefore be of benefit in colonoscopy, in particular for women and patients who have previously undergone abdominal surgery. PMID- 26416197 TI - A review of sarcocystosis in camels and redescription of Sarcocystis cameli and Sarcocystis ippeni sarcocysts from the one-humped camel (Camelus dromedarius). AB - There is considerable confusion concerning Sarcocystis species in camels. Five species: Sarcocystis cameli, Sarcocystis ippeni, Sarcocystis camelicanis, Sarcocystis camelocanis and Sarcocystis miescheri were named with inadequate descriptions and no type specimens. Here, we review literature on sarcocystosis in camels worldwide and redescribe structure of S. cameli and S. ippeni sarcocysts by light- and transmission electron microscopy (LM and TEM). Eight sarcocysts from the oesophagi of two camels (Camelus dromedarius) from Egypt were studied. By LM, all sarcocysts were thin-walled with barely visible projections on the cyst walls. By TEM, two structurally distinct sarcocysts were recognized by unique villar protrusions (vp) not found in sarcocysts from any other host. Sarcocysts of S. cameli had vp of type 9 j. The sarcocyst wall had upright slender vp, up to 3.0 uM long and 0.5 uM wide; the total thickness of the sarcocyst wall with ground substance (gs) layer was 3.5 uM. On each vp, there were rows of knob-like protrusions that appeared to be interconnected. The vp had microtubules that originated at midpoint of the gs and continued up to the tip; microtubules were smooth, without any granules or dense areas. Bradyzoites were approximately 14-15 * 3-4 uM in size with typical organelles. Sarcocystis ippeni sarcocysts had type 32 sarcocyst wall characterized by conical vp with an electron dense knob. The total thickness of the sarcocyst wall (from the base of gs to vp tip) was 2.3-3.0 uM. The vp were up to 1.2 uM wide at the base and 0.25 uM at the tip. Microtubules in vp originated at midpoint of gs and continued up to tip; microtubules were criss-crossed, smooth and without granules or dense areas. Bradyzoites were 12.0-13.5 * 2.0-3.0 uM in size. Sarcocystis camelicanis, S. camelocanis and S. miescheri are considered invalid. PMID- 26416198 TI - B-1 cells contribute to susceptibility in experimental infection with Leishmania (Leishmania) chagasi. AB - The immune response to leishmaniasis is complex, and the result of infection depends on both the genetic composition of the Leishmania species and the immunity of the host. Clinical and experimental evidence suggest that the activation of B cells leads to exacerbation of visceral leishmaniasis. However, the role of B-1 cells (a subtype of B lymphocytes) in the pathogenesis of experimental visceral leishmaniasis has not yet been elucidated. In this study, we investigated the importance of B-1 cells in experimental infection with Leishmania. (L.) chagasi. Our results showed that BALB/XID mice (X-linked immunodeficient mice which are genetically deficient in B-1 cells) infected with L. (L.) chagasi for 45 days had a significant reduction in parasite load in the spleen when compared with control mice. Cytokine analysis showed that the BALB/XID mice had lower amounts of IL-10 in their sera compared with control group. In addition, the transfer of B-1 cells from wild type mice into IL-10KO animals led to an increase in susceptibility to L. (L.) chagasi infection in the IL-10KO mice, suggesting that the IL-10 produced by these cells is important in experimental infection. Our results suggest that B-1 cells may play an important role in susceptibility to L. (L.) chagasi. PMID- 26416199 TI - Regadenoson Stress Real-Time Myocardial Perfusion Echocardiography for Detection of Coronary Artery Disease: Feasibility and Accuracy of Two Different Ultrasound Contrast Agents. AB - BACKGROUND: The aim of this study was to compare the efficacy of myocardial perfusion (MP) and wall motion (WM) analysis obtained with real-time myocardial contrast echocardiography (RTMCE) and two widely used contrast agents in detecting coronary artery disease after injection of the vasodilator regadenoson. METHODS: One hundred fifty patients were studied at two academic centers using regadenoson (400-MUg intravenous bolus) vasodilator stress RTMCE (7.5% Optison infusion [n = 50] or 1.5% Definity infusion [n = 100]). Both MP and WM with RTMCE were analyzed at rest and after regadenoson bolus. Comparisons of WM and MP sensitivity, specificity, and accuracy were made. Quantitative angiography was performed in all patients within 1 month of the regadenoson stress study (>50% and >70% diameter stenosis was considered significant). Reviewers were blinded to all clinical and quantitative angiographic data. RESULTS: Rate-pressure product after regadenoson was higher in Optison than Definity patients (P = .004). Using a 50% diameter stenosis on quantitative angiography as a reference standard, overall sensitivity, specificity, and accuracy for combined WM and MP analysis were not different for both agents (Optison, 77%, 64%, and 73%; Definity, 80%, 74%, and 78%; P = NS). The sensitivity, specificity, and accuracy of WM analysis alone for Optison were 68%, 71%, and 69% compared with 60%, 72%, and 66% for Definity (P = NS). Adding MP analysis improved the sensitivity and accuracy of Definity for detecting both >50% and >70% stenoses (P < .001 vs WM), while MP analysis did not improve the sensitivity of Optison for detecting either >50 or >70% stenoses. CONCLUSIONS: RTMCE during regadenoson stress using either Optison or Definity is a rapid and effective method for the detection of coronary artery disease. The ability of MP imaging to improve WM accuracy may depend on the rate pressure product achieved. PMID- 26416201 TI - An Ethnographic Meta-Synthesis of Three Southwestern Rural Studies. AB - OBJECTIVE: The objectives were to synthesize cumulative findings across three critical ethnographic, community-partnered studies in the southwestern United States and to describe the process of meta-ethnography for that analysis. DESIGN AND SAMPLE: The meta-ethnography followed the design of Noblit and Hare for constructing an analysis of composite data, informed by community-based participatory research and Stringer's ethnographic strategies of Look-Think-Act. The three studies occurred in rural settings of Colorado and New Mexico, engaging 129 total participants, along with community organizations and agencies as partners. METHODS: Methods consisted of detailed review of each original study, mapping of major concepts and themes, and general analysis, interpretation, and synthesis across the studies. RESULTS: Overall themes were: health is the capacity to care for oneself and do work, meaningful relationships are key in health care interactions, patterns of discrimination persist in rural settings, poor literacy and health literacy are barriers, and food insecurity is a growing concern for older rural adults. CONCLUSIONS: Resolutions involve practice, policy, and research and must incorporate all stakeholder groups in rural settings; a participatory approach is critical to prioritize and impact existing inequities; and work is needed to extend education and understanding of multiple cultures, groups, customs, and rural contexts. PMID- 26416200 TI - Prospectively identified deficits in sagittal plane hip-ankle coordination in female athletes who sustain a second anterior cruciate ligament injury after anterior cruciate ligament reconstruction and return to sport. AB - BACKGROUND: Athletes who return to sport after anterior cruciate ligament reconstruction are at increased risk of future ACL injury. Altered coordination of lower extremity motion may increase this risk. The purpose of this study was to prospectively determine if altered lower extremity coordination patterns exist in athletes who go on to sustain a 2nd anterior cruciate ligament injury. METHODS: Sixty-one female athletes who were cleared to return to sport after anterior cruciate ligament reconstruction were included. Hip-ankle coordination was assessed prior to return to sport with a dynamic postural coordination task. Within 12 months, 14 patients sustained a 2nd ACL injury. Fourteen matched subjects were selected for comparative analysis. Cross-recurrence quantification analysis characterized hip-ankle coordination patterns. A group * target speed (slow vs. fast) * leg (involved vs. uninvolved) analysis of variance was used to identify differences. FINDINGS: A main effect of group (P = 0.02) indicated that the single injury group exhibited more stable hip-ankle coordination [166.2 (18.9)] compared to the 2nd injury group [108.4 (10.1)]. A leg * group interaction was also observed (P = .04). The affected leg of the single injury group exhibited more stable coordination [M = 187.1 (23.3)] compared to the affected leg of the 2nd injury group [M = 110.13 (9.8)], P = 0.03. INTERPRETATION: Hip-ankle coordination was altered in female athletes who sustained a 2nd anterior cruciate ligament injury after return to sport. Failure to coordinate lower extremity movement in the absence of normal knee proprioception may place the knee at risk. PMID- 26416202 TI - Hepatitis C-like viruses are produced in cells from rabbit and hare DNA. AB - Hepatitis C virus (HCV), a major causative agent of acute and chronic liver disease, belongs to the Flaviviridae family and contains a single-strand positive sense RNA genome, which upon virus entry and uncoating, functions as mRNAs and thus can be directly translated into proteins by host cell machinery. To date the HCV origin remains unclear and HCV life cycle and pathogenesis are not enlightened processes due to the absence of HCV efficient cell cultures systems or animals models. Here we show that rabbit and hare HCV-like viruses, RHCV and HHCV respectively, are formed after the inoculation of genomic DNA in Madin-Darby bovine kidney cell line cultures. RHCV is closely related to the HCV-1a/HCV-1b genotypes and HHCV is more closely related to the HCV-1b genotype. These findings could contribute to the understanding of HCV origin as well as clarify the virus life cycle, pathogenesis, evolution and diversity. PMID- 26416203 TI - Dissecting susceptibility from exogenous triggers: the model of alopecia areata and associated inflammatory skin diseases. AB - BACKGROUND: Alopecia areata (AA) is a T-cell-driven autoimmune disease of the hair follicle and frequently reported to be associated with inflammatory skin diseases (ISD) such as atopic eczema (AE) or psoriasis. Interestingly, AA on the one hand and both AE and psoriasis on the other hand are believed to be driven by mutually antagonistic T-cell subsets. OBJECTIVE: To characterize AA-specific T cell profiles and inflammatory pattern by intra-individual comparison of AA and coexistent ISD. METHODS: 112 patients with AA were recruited and investigated for coexisting ISD. In-depth analyses were performed in patients with AA and AE (n = 2), AA and psoriasis (n = 1), AA and psoriasis and AE (n = 1) and AA and lichen planus (n = 1), using histology, immunohistochemistry and cytokine staining of T cells isolated from lesional skin. RESULTS: Of 112 AA patients investigated, 23 suffered from an ISD. The prevalence of AE, vitiligo, psoriasis and lichen planus was higher in the investigated AA cohort than in the normal population. The clinical as well as histological phenotype of AA the coexistent ISD were unequivocal. In line with this, T-cell infiltrates were found to be disease characteristics with AA and lichen planus dominated by CD8+ and IFN-gamma+ TNF alpha+ producing T cells while psoriasis lesions in the same patients were dominated by IL-17+ and AE by IL-4+ T cells. CONCLUSION: AA patients have a higher incidence of various T-cell-driven inflammatory skin diseases than the normal population, a phenomenon which might relate to over-activation of skin homing T cells and to specific immune triggers as the primary cause of inflammation. More importantly, we showed that by using AA as a model disease, our approach of intra-individual comparison of distinct inflammatory responses in the same patient is feasible and offers the unique possibility to gain insights into disease pathogenesis independent from genetic susceptibilities. PMID- 26416204 TI - Antagonistic within-host interactions between plant viruses: molecular basis and impact on viral and host fitness. AB - Double infections of related or unrelated viruses frequently occur in single plants, the viral agents being inoculated into the host plant simultaneously (co infection) or sequentially (super-infection). Plants attacked by viruses activate sophisticated defence pathways which operate at different levels, often at significant fitness costs, resulting in yield reduction in crop plants. The occurrence and severity of the negative effects depend on the type of within-host interaction between the infecting viruses. Unrelated viruses generally interact with each other in a synergistic manner, whereas interactions between related viruses are mostly antagonistic. These can incur substantial fitness costs to one or both of the competitors. A relatively well-known antagonistic interaction is cross-protection, also referred to as super-infection exclusion. This type of interaction occurs when a previous infection with one virus prevents or interferes with subsequent infection by a homologous second virus. The current knowledge on why and how one virus variant excludes or restricts another is scant. Super-infection exclusion between viruses has predominantly been attributed to the induction of RNA silencing, which is a major antiviral defence mechanism in plants. There are, however, presumptions that various mechanisms are involved in this phenomenon. This review outlines the current state of knowledge concerning the molecular mechanisms behind antagonistic interactions between plant viruses. Harmful or beneficial effects of these interactions on viral and host plant fitness are also characterized. Moreover, the review briefly outlines the past and present attempts to utilize antagonistic interactions among viruses to protect crop plants against destructive diseases. PMID- 26416205 TI - Pistachio (Pistacia vera L.) Detection and Quantification Using a Murine Monoclonal Antibody-Based Direct Sandwich Enzyme-Linked Immunosorbent Assay. AB - A commercially available direct sandwich enzyme-linked immunosorbent assay (ELISA) (BioFront Technologies, Tallahassee, FL, USA) using murine anti-pistachio monoclonal antibodies (mAbs) as capture and detection antibodies was evaluated. The assay was sensitive (limit of detection = 0.09 +/- 0.02 ppm full fat pistachio, linear detection range = 0.5-36 ppm, 50% maximum signal concentration = 7.9 +/- 0.7 ppm), reproducible (intra- and inter-assay variability < 24% CV), and rapid (post-extraction testing time ~ 1.5 h). The target antigen was stable and detectable in whole pistachio seeds subjected to autoclaving (121 degrees C, 15 psi, 15, 30 min), blanching (100 degrees C, 5, 10 min), frying (191 degrees C, 1 min), microwaving (500, 1000 W, 3 min), and dry roasting (140 degrees C, 30 min; 168 degrees C, 12 min). No cross-reactivity was observed in 156 food matrices, each tested at 100,000 ppm, suggesting the ELISA to be pistachio specific. The pistachio recovery ranges for spiked (10 ppm) and incurred (10 50000 ppm) food matrices were 93.1-125.6% and 35.7-112.2%, respectively. The assay did not register any false-positive or -negative results among the tested commercial and laboratory prepared samples. PMID- 26416206 TI - Identifying the domains of context important to implementation science: a study protocol. AB - BACKGROUND: There is growing recognition that "context" can and does modify the effects of implementation interventions aimed at increasing healthcare professionals' use of research evidence in clinical practice. However, conceptual clarity about what exactly comprises "context" is lacking. The purpose of this research program is to develop, refine, and validate a framework that identifies the key domains of context (and their features) that can facilitate or hinder (1) healthcare professionals' use of evidence in clinical practice and (2) the effectiveness of implementation interventions. METHODS/DESIGN: A multi-phased investigation of context using mixed methods will be conducted. The first phase is a concept analysis of context using the Walker and Avant method to distinguish between the defining and irrelevant attributes of context. This phase will result in a preliminary framework for context that identifies its important domains and their features according to the published literature. The second phase is a secondary analysis of qualitative data from 13 studies of interviews with 312 healthcare professionals on the perceived barriers and enablers to their application of research evidence in clinical practice. These data will be analyzed inductively using constant comparative analysis. For the third phase, we will conduct semi-structured interviews with key health system stakeholders and change agents to elicit their knowledge and beliefs about the contextual features that influence the effectiveness of implementation interventions and healthcare professionals' use of evidence in clinical practice. Results from all three phases will be synthesized using a triangulation protocol to refine the context framework drawn from the concept analysis. The framework will then be assessed for content validity using an iterative Delphi approach with international experts (researchers and health system stakeholders/change agents). DISCUSSION: This research program will result in a framework that identifies the domains of context and their features that can facilitate or hinder: (1) healthcare professionals' use of evidence in clinical practice and (2) the effectiveness of implementation interventions. The framework will increase the conceptual clarity of the term "context" for advancing implementation science, improving healthcare professionals' use of evidence in clinical practice, and providing greater understanding of what interventions are likely to be effective in which contexts. PMID- 26416207 TI - TriGlycerides and high-density lipoprotein cholesterol ratio compared with homeostasis model assessment insulin resistance indexes in screening for metabolic syndrome in the chinese obese children: a cross section study. AB - BACKGROUND: Metabolic Syndrome (MS) is prevalant in China, especially according to the pediatric obesity group. Based on the MS-CHN2012 definition for Chinese children and adolescents the need to explore and establish a convienent MS screening become imminent. This study aims to investigate the optimal cut-off values, compare the accuracy for the (TriGlycerides (TG) to High-Density Lipoprotein Cholesterol (HDL-C)) (TG/HDL-C) ratio and Homeostasis Model Assessment Insulin Resistance (HOMA-IR) indexs to identify Metabolic Syndrome in obese pediatric population in China. METHOD: A total sample of 976 children (female 286 male 690, BMI > = 95 percentile) aged from 6-16 years underwent a medical assessment including a physical examination and investigations of total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, insulin, glucose, and oral glucose tolerance test to identify the components of Metabolic Syndrome. The validity and accuracy between TG/HDL-C ratio and HOMA-IR were compared by Receiver Operating Characteristics analysis (ROC). RESULT: TG/HDL-C ratio achieved a larger ROC Area under Curve (AUC = 0.843) than HOMA-IR indexes (0.640, 0.625 for HOMA1-IR, HOMA2-IR respectively) to screen for Metabolic Syndrome. The cut-off values for MS were: TG/HDL-C ratio > 1.25 (sensitivity: 80%; specificity: 75%), HOMA1-IR > 4.59 (sensitivity: 58.7%; specificity: 65.5%) and HOMA2-IR > 2.76 (sensitivity: 53.2%; specificity: 69.5%). The results kept robust after stratified by gender, age group and pubertal stage. DISCUSSION: TG/HDL-C ratio was a better indicator than the HOMA-IR to screen for a positive diagnosis for MS. Furthermore, the TG/HDL-C ratio was superior to the HOMA-IR indexes even after the control of possible confusions from the gender, age group and puberty stage. CONCLUSION: TG/HDL-C ratio proved a better index than HOMA-IR in screening for MS in obese children and adolescents. TG/HDL-C ratio has a discriminatory power in detecting potential MS in the Chinese obese pediatric population. PMID- 26416209 TI - Effect of orthodontic brackets and different wires on radiofrequency heating and magnetic field interactions during 3.0-T MRI. PMID- 26416208 TI - MicroRNAs; easy and potent targets in optimizing therapeutic methods in reparative angiogenesis. AB - The age-related senescence of adult tissues is associated with the decreased level of angiogenic capability and with the development of a degenerative disease such as atherosclerosis which thereafter result in the deteriorating function of multiple systems. Findings indicate that tissue senescence not only diminishes repair processes but also promotes atherogenesis, serving as a double-edged sword in the development and prognosis of ischaemia-associated diseases. Evidence evokes microRNAs (miRNAs) as molecular switchers that underlie cellular events in different tissues. Here, miRNAs would promote new potential targets for optimizing therapeutic methods in blood flow recovery to the ischaemic area. Effectively beginning an ischaemia therapy, a more characteristic of miRNA changes in adult tissues is prerequisite and in the forefront. It may also be a preliminary phase in treatment strategies by stem cell-based therapy. PMID- 26416210 TI - Participation of dectin-1 receptor on NETs release against Paracoccidioides brasiliensis: Role on extracellular killing. AB - Paracoccidioides brasiliensis is a dimorphic fungus from the Paracoccidioides genus, which is the causative agent of paracoccidioidomycosis, a chronic, subacute or acute mycosis, with visceral and cutaneous involvement. This disease that is acquired through inhalation primarily attacks the lungs but, can spread to other organs. Phagocytic cells as neutrophils play an important role during innate immune response against this fungus, but studies on antifungal activities of these cells are scarce. In addition to their ability to eliminate pathogens by phagocytosis and antimicrobial secretions, neutrophils can trap and kill microorganisms by release of extracellular structures composed by DNA and antimicrobial proteins, called neutrophil extracellular traps (NETs). Here, we provide evidence that P. brasiliensis virulent strain (P. brasiliensis 18) induces NETs release. These structures were well evidenced by scanning electron microscopy, and specific NETs compounds such as histone, elastase and DNA were shown by confocal microscopy. In addition, we have shown that dectin-1 receptor is the main PRR to which fungus binds to induce NETS release. Fungi were ensnared by NETs, denoting the role of these structures in confining the fungus, avoiding dissemination. NETs were also shown to be involved in fungus killing, since fungicidal activity detected before and mainly after neutrophils activation with TNF-alpha, IFN-gamma and GM-CSF was significantly inhibited by cocultures treatment with DNAse. PMID- 26416211 TI - Suppression of IL-10 production by activated B cells via a cell contact-dependent cyclooxygenase-2 pathway upregulated in IFN-gamma-treated mesenchymal stem cells. AB - The immunoregulatory properties of mesenchymal stem cells (MSCs) have been well documented in various models in vitro and in vivo. Furthermore, a population of regulatory B cells (Bregs) that produce relatively high concentrations of IL-10 has been recently described. To study the relationship between MSCs and Bregs, we analyzed the effects of MSCs on IL-10 production by lipopolysaccharide (LPS) activated mouse B cells. The production of IL-10 by B cells remained preserved in the presence of MSCs and was even significantly enhanced by IFN-gamma. However, the production of IL-10 was strongly suppressed in cultures containing MSCs and IFN-gamma. Preincubation of MSCs, but not of B cells, with IFN-gamma induced the suppression of IL-10 secretion in cultures containing MSCs and B cells. The supernatants from IFN-gamma-treated MSCs had no inhibitory effect, and the suppression of IL-10 production was abrogated if the MSCs and B cells were separated in a transwell system. Analysis of the gene expression of IFN-gamma- or IFN-gamma and LPS-treated MSCs revealed a strong upregulation of genes for indoleamine-2,3-dioxygenase (IDO), cyclooxygenase-2 (Cox-2) and programmed cell death-ligand 1 (PD-L1). While the inhibition of IDO activity or the inclusion of the neutralization monoclonal antibody anti-PD-L1 did not abrogate the suppression, indomethacin, an inhibitor of Cox-2, completely inhibited the MSC mediated suppression of IL-10 production. Accordingly, the production of IL-10 by B cells was inhibited by exogenous prostaglandin E2. The results thus suggest that IFN-gamma-treated MSCs strongly inhibit IL-10 production by activated B cells by a mechanism requiring cell contact and involving the Cox-2 pathway. PMID- 26416212 TI - Malignancy-associated pruritus. AB - Malignancy-associated pruritus can be the result of a neoplasm's local effect on tissue or due to the systemic reaction to malignancy. A systemic reaction to malignancy has been termed 'paraneoplastic itch' and can be the first sign of an underlying malignancy. Paraneoplastic itch is most commonly caused by lymphoproliferative malignancies, and severity of itch correlates with stage of disease in Hodgkin's lymphoma and polycythemia vera. Non-melanoma skin cancer is the most common type of malignancy-associated pruritus, and recent data indicate that pruritus is associated with more than one-third of non-melanoma skin cancers. Cutaneous T-cell lymphomas (CTCL), particularly more advanced stages, cause intractable pruritus and recent investigations into the pathophysiology of CTCL-associated itch have implicated cyotokine interleukin-31 as a putative mediator. Treatments that reduce itch in CTCL patients, such as histone deacetylase inhibitors (HDACi), Mogamulizumab, a novel monoclonal antibody against chemokine receptor type-4, and oral corticosteroids, have demonstrated a correlation between their anti-pruritic effect and reduced serum levels of interleukin-31. PMID- 26416213 TI - Prenatal exposure to integerrimine N-oxide enriched butanolic residue from Senecio brasiliensis affects behavior and striatal neurotransmitter levels of rats in adulthood. AB - Pyrrolizidine alkaloids (PAs) are toxins that are exclusively biosynthesized by plants and are commonly present in foods and herbs. PAs are usually associated with poisoning events in livestock and human beings. The aim of the present study was to evaluate the behavioral and neurochemical effects of prenatal exposure to PA integerrimine N-oxide of rats in adulthood. Pregnant Wistar rats received integerrimine N-oxide from the butanolic residue of Senecio brasiliensis by gavage on gestational days 6-20 at doses of 3, 6 and 9 mg/kg. During adulthood of the offspring, the following behavioral tests were performed: open-field, plus maze, forced swimming, catalepsy and stereotypy. Histological analyses and monoamine levels were measured. Male offspring from dams that were exposed to 9 mg/kg showed an increase in locomotion in the open-field test, an increased frequency of entries and time spent in open arms in elevated plus-maze test, as well as decreased swimming time. In the female offspring from dams that were exposed to 9 mg/kg, there was an increased time of climbing in forced swimming and intensity of stereotyped behavior. The histological study indicates an increase in the number of multinucleated cells in the liver (6 and 9 mg/kg). In neurotransmitter analysis, specifically in the striatum, we observed change in dopamine and serotonin levels in the middle dose. Thus, our results indicate that prenatal exposure to integerrimine N-oxide changed behavior in adulthood and neurotransmitter levels in the striatum. Our results agree with previous studies, which showed that integerrimine N-oxide impaired physical and neurobehavioral development in childhood that can persist until adulthood. PMID- 26416214 TI - Rapid and Effective Virucidal Activity of Povidone-Iodine Products Against Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and Modified Vaccinia Virus Ankara (MVA). AB - INTRODUCTION: Since the first case of Middle East Respiratory Syndrome coronavirus (MERS-CoV) infection was reported in 2012, the virus has infected more than 1300 individuals in 26 countries, and caused more than 480 deaths. Human-to-human transmission requires close contact, and has typically occurred in the healthcare setting. Improved global awareness, together with improved hygiene practices in healthcare facilities, has been highlighted as key strategies in controlling the spread of MERS-CoV. This study tested the in vitro efficacy of three formulations of povidone iodine (PVP-I: 4% PVP-I skin cleanser, 7.5% PVP-I surgical scrub, and 1% PVP-I gargle/mouthwash) against a reference virus (Modified vaccinia virus Ankara, MVA) and MERS-CoV. METHODS: According to EN14476, a standard suspension test was used to assess virucidal activity against MVA and large volume plating was used for MERS-CoV. All products were tested under clean (0.3 g/L bovine serum albumin, BSA) and dirty conditions (3.0 g/L BSA + 3.0 mL/L erythrocytes), with application times of 15, 30, and 60 s for MVA, and 15 s for MERS-CoV. The products were tested undiluted, 1:10 and 1:100 diluted against MVA, and undiluted against MERS-CoV. RESULTS: A reduction in virus titer of >=4 log10 (corresponding to an inactivation of >=99.99%) was regarded as evidence of virucidal activity. This was achieved versus MVA and MERS-CoV, under both clean and dirty conditions, within 15 s of application of each undiluted PVP I product. CONCLUSION: These data indicate that PVP-I-based hand wash products for potentially contaminated skin, and PVP-I gargle/mouthwash for reduction of viral load in the oral cavity and the oropharynx, may help to support hygiene measures to prevent transmission of MERS-CoV. FUNDING: Mundipharma Research GmbH & Co. PMID- 26416215 TI - Sebastien Sasseville: dreaming with type 1 diabetes. PMID- 26416216 TI - Access to primary care in Italy: time for a shake-up? PMID- 26416217 TI - QSAR and molecular docking studies on oxindole derivatives as VEGFR-2 tyrosine kinase inhibitors. AB - The three-dimensional quantitative structure-activity relationships (3D-QSAR) were established for 30 oxindole derivatives as vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitors by using comparative molecular field analysis (CoMFA) and comparative similarity indices analysis comparative molecular similarity indices analysis (CoMSIA) techniques. With the CoMFA model, the cross-validated value (q(2)) was 0.777, the non-cross-validated value (R(2)) was 0.987, and the external cross-validated value ([Formula: see text]) was 0.72. And with the CoMSIA model, the corresponding q(2), R(2) and [Formula: see text] values were 0.710, 0.988 and 0.78, respectively. Docking studies were employed to bind the inhibitors into the active site to determine the probable binding conformation. The binding mode obtained by molecular docking was in good agreement with the 3D-QSAR results. Based on the QSAR models and the docking binding mode, a set of new VEGFR-2 tyrosine kinase inhibitors were designed, which showed excellent predicting inhibiting potencies. The result revealed that both QSAR models have good predictive capability to guide the design and structural modification of homologic compounds. It is also helpful for further research and development of new VEGFR-2 tyrosine kinase inhibitors. PMID- 26416218 TI - Development: Maternal hyperglycaemia affects cardiac development. PMID- 26416221 TI - Cardiovascular endocrinology: High-intensity interval training benefits patients with T2DM. PMID- 26416220 TI - Diabetes: Metformin and renal insufficiency-is 45, or even 30, the new 60? PMID- 26416219 TI - Scope and limitations of iodothyronine deiodinases in hypothyroidism. AB - The coordinated expression and activity of the iodothyronine deiodinases regulate thyroid hormone levels in hypothyroidism. Once heralded as the pathway underpinning adequate thyroid-hormone replacement therapy with levothyroxine, the role of these enzymes has come into question as they have been implicated in both an inability to normalize serum levels of tri-iodothyronine (T3) and the incomplete resolution of hypothyroid symptoms. These observations, some of which were validated in animal models of levothyroxine monotherapy, challenge the paradigm that tissue levels of T3 and thyroid-hormone signalling can be fully restored by administration of levothyroxine alone. The low serum levels of T3 observed among patients receiving levothyroxine monotherapy occur as a consequence of type 2 iodothyronine deiodinase (DIO2) in the hypothalamus being fairly insensitive to ubiquitination. In addition, residual symptoms of hypothyroidism have been linked to a prevalent polymorphism in the DIO2 gene that might be a risk factor for neurodegenerative disease. Here, we discuss how these novel findings underscore the clinical importance of iodothyronine deiodinases in hypothyroidism and how an improved understanding of these enzymes might translate to therapeutic advances in the care of millions of patients with this condition. PMID- 26416222 TI - Evidence that smooth pursuit velocity, not eye position, modulates alpha and beta oscillations in human middle temporal cortex. AB - Suppression of 5-25 Hz oscillations have been observed in MT+ during pursuit eye movements, suggesting oscillations that play a role in oculomotor control and/or the integration of extraretinal signals during pursuit. The amplitude of these rhythms appears to covary with head-centered eye position, but an alternative is that they depend on a velocity signal that lags the movement of the eyes. To investigate, we explored how alpha and beta amplitude changes related to ongoing eye movement depended on pursuit at different eccentricities. The results revealed largely identical patterns of modulation in the alpha and beta amplitude, irrespective of the eccentricity at which the pursuit eye movement was performed. The signals we measured therefore do not depend on head-centered position. A second experiment was designed to investigate whether the alpha and beta oscillations depended on the direction of pursuit, as opposed to just speed. We found no evidence that alpha or beta oscillations depended on direction, but there was a significant effect of eye speed on the magnitude of the beta suppression. This suggests distinct functional roles for alpha and beta suppression in pursuit behavior. PMID- 26416223 TI - Case report: clear cell hidradenocarcinoma of the nail bed. PMID- 26416224 TI - UN adopts new global health targets to supersede the millennium goals. PMID- 26416225 TI - Tobacco smoke exposure and multiplexed immunoglobulin E sensitization in children: a population-based study. AB - BACKGROUND: Although there is evidence that exposure to tobacco smoke is harmful to children's respiratory health, the effects of tobacco smoke exposure on the regulation of immunoglobulin E (IgE)-mediated immune responses to specific allergens remain unclear. This study aimed to investigate the relationship between objectively assessed tobacco smoke exposure and specific IgE profiles for a broad spectrum of allergens in a population setting. METHODS: Children aged 5 18 years (N = 1315) were assessed using serum cotinine measurement and microarray based multiplexed detection of specific IgE against 40 allergens. RESULTS: Serum cotinine levels were positively associated with sensitization to foods (adjusted odds ratio [AOR] = 4.95; 95% CI: 1.59-15.34), cockroaches (AOR = 3.77; 95% CI: 1.49-9.51), and pollen (AOR = 2.84; 95% CI: 1.20-6.73) while the association was borderline significant for animals (AOR = 2.53; 95% CI: 0.92-6.93). No associations were found for sensitization against mites, mold, and latex. When considering the degree of allergic sensitization, serum cotinine levels were positively correlated to the number of sensitization to cockroaches (P = 0.004), pollen (P = 0.006), and foods (P < 0.001), with statistically significant positive dose-response relationships (all P < 0.01). Similar results were observed when summing up specific IgE concentrations for the aforementioned allergen categories. CONCLUSIONS: The association between tobacco smoke exposure and IgE sensitization to environmental allergens varies for different allergens among children. This study demonstrates that elevated serum cotinine levels are significantly associated with IgE sensitization to cockroaches, grass pollen, and certain foods, with potential dose-dependent relationships. PMID- 26416226 TI - Beta Cells Secrete Significant and Regulated Levels of Insulin for Long Periods when Seeded onto Acellular Micro-Scaffolds. AB - The aim of this work is to obtain significant and regulated insulin secretion from human beta cells ex vivo. Long-term culture of human pancreatic islets and attempts at expanding human islet cells normally result in loss of beta-cell phenotype. We propose that to obtain proper ex vivo beta cell function, there is a need to develop three-dimensional structures that mimic the natural islet tissue microenvironment. We here describe the preparation of endocrine micro pancreata (EMPs) that are made up of acellular organ-derived micro-scaffolds seeded with human intact or enzymatically dissociated islets. We show that EMPs constructed by seeding whole islets, freshly enzymatically-dissociated islets or even dissociated islets grown first in standard monolayer cultures express high levels of key beta-cell specific genes and secrete quantities of insulin per cell similar to freshly isolated human islets in a glucose-regulated manner for more than 3 months in vitro. PMID- 26416227 TI - Spontaneous shape transition of thin films into ZnO nanowires with high structural and optical quality. AB - ZnO nanowires are usually formed by physical and chemical deposition techniques following the bottom-up approach consisting in supplying the reactants on a nucleation surface heated at a given temperature. We demonstrate an original alternative approach for the formation of ZnO nanowire arrays with high structural and optical quality, which is based on the spontaneous transformation of a ZnO thin film deposited by sol-gel process following a simple annealing. The development of these ZnO nanowires occurs through successive shape transitions, including the intermediate formation of pyramid-shaped islands. Their nucleation under near-equilibrium conditions is expected to be governed by thermodynamic considerations via the total free energy minimization related to the nanowire shape. It is further strongly assisted by the drastic reordering of the matter and by recrystallization phenomena through the massive transport of zinc and oxygen atoms towards the localized growth areas. The spontaneous shape transition process thus combines the easiness and low-cost of sol-gel process and simple annealing with the assets of the vapor phase deposition techniques. These findings cast a light on the fundamental mechanisms driving the spontaneous formation of ZnO nanowires and, importantly, reveal the great technological potential of the spontaneous shape transition process as a promising alternative approach to the more usual bottom-up approach. PMID- 26416228 TI - Lower glycolysis carries a higher flux than any biochemically possible alternative. AB - The universality of many pathways of core metabolism suggests a strong role for evolutionary selection, but it remains unclear whether existing pathways have been selected from a large or small set of biochemical possibilities. To address this question, we construct in silico all possible biochemically feasible alternatives to the trunk pathway of glycolysis and gluconeogenesis, one of the most highly conserved pathways in metabolism. We show that, even though a large number of alternative pathways exist, the alternatives carry lower flux than the real pathway under typical physiological conditions. We also find that if physiological conditions were different, different pathways could outperform those found in nature. Together, our results demonstrate how thermodynamic and biophysical constraints restrict the biochemical alternatives that are open to evolution, and suggest that the existing trunk pathway of glycolysis and gluconeogenesis may represent a maximal flux solution. PMID- 26416229 TI - The challenges of introducing routine G6PD testing into radical cure: a workshop report. AB - The only currently available drug that effectively removes malaria hypnozoites from the human host is primaquine. The use of 8-aminoquinolines is hampered by haemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. Recently a number of qualitative and a quantitative rapid diagnostic test (RDT) format have been developed that provide an alternative to the current standard G6PD activity assays. The WHO has recently recommended routine testing of G6PD status prior to primaquine radical cure whenever possible. A workshop was held in the Philippines in early 2015 to discuss key challenges and knowledge gaps that hinder the introduction of routine G6PD testing. Two point-of-care (PoC) test formats for the measurement of G6PD activity are currently available: qualitative tests comparable to malaria RDT as well as biosensors that provide a quantitative reading. Qualitative G6PD PoC tests provide a binomial test result, are easy to use and some products are comparable in price to the widely used fluorescent spot test. Qualitative test results can accurately classify hemizygous males, heterozygous females, but may misclassify females with intermediate G6PD activity. Biosensors provide a more complex quantitative readout and are better suited to identify heterozygous females. While associated with higher costs per sample tested biosensors have the potential for broader use in other scenarios where knowledge of G6PD activity is relevant as well. The introduction of routine G6PD testing is associated with additional costs on top of routine treatment that will vary by setting and will need to be assessed prior to test introduction. Reliable G6PD PoC tests have the potential to play an essential role in future malaria elimination programmes, however require an improved understanding on how to best integrate routine G6PD testing into different health settings. PMID- 26416230 TI - Melatonin treatment during the incubation of sensitization attenuates methamphetamine-induced locomotor sensitization and MeCP2 expression. AB - Behavior sensitization is a long-lasting enhancement of locomotor activity after exposure to psychostimulants. Incubation of sensitization is a phenomenon of remarkable augmentation of locomotor response after withdrawal and reflects certain aspects of compulsive drug craving. However, the mechanisms underlying these phenomena remain elusive. Here we pay special attention to the incubation of sensitization and suppose that the intervention of this procedure will finally decrease the expression of sensitization. Melatonin is an endogenous hormone secreted mainly by the pineal gland. It is effective in treating sleep disorder, which turns out to be one of the major withdrawal symptoms of methamphetamine (MA) addiction. Furthermore, melatonin can also protect neuronal cells against MA induced neurotoxicity. In the present experiment, we treated mice with low dose (10mg/kg) of melatonin for 14 consecutive days during the incubation of sensitization. We found that melatonin significantly attenuated the expression of sensitization. In contrast, the vehicle treated mice showed prominent enhancement of locomotor activity after incubation. MeCP2 expression was also elevated in the vehicle treated mice and melatonin attenuated its expression. Surprisingly, correlation analysis suggested significant correlation between MeCP2 expression in the nucleus accumbens (NAc) and locomotion in both saline control and vehicle treated mice, but not in melatonin treated ones. MA also induced MeCP2 over expression in PC12 cells. However, melatonin failed to reduce MeCP2 expression in vitro. Our results suggest that melatonin treatment during the incubation of sensitization attenuates MA-induced expression of sensitization and decreases MeCP2 expression in vivo. PMID- 26416231 TI - Editorial: Harmful and Beneficial Effect of Aspirin on Gastrointestinal Tract. PMID- 26416232 TI - Editorial: New Trends in Pharmaceutical Nanotechnology. PMID- 26416233 TI - Dairy products consumption and metabolic syndrome in adults: systematic review and meta-analysis of observational studies. AB - The association of dairy products consumption with risk of metabolic syndrome (MetS) has been inconsistently reported in observational studies. A systematic review and meta-analysis of published observational studies was conducted to quantitatively evaluate this association. Relevant studies were identified by searching PubMed and EMBASE databases and by carefully checking the bibliographies of retrieved full reports and related reviews. Eligible studies were observational studies that investigated the association between dairy products consumption and risk of MetS in adults, with risk estimates available. Random-effects model was assigned to calculate the summary risk estimates. The final analysis included 15 cross-sectional studies, one case-control study and seven prospective cohort studies. Higher dairy consumption significantly reduced MetS by 17% in the cross-sectional/case-control studies (odds ratio = 0.83, 95% confidence interval [CI], 0.73-0.94), and by 14% (relative risk [RR] = 0.86, 95% CI, 0.79-0.92) in cohort studies. The inverse dairy-MetS association was consistent in subgroup and sensitivity analyses. The dose-response analysis of the cohort studies conferred a significant 6% (RR = 0.94, 95% CI, 0.90-0.98) reduction in the risk of MetS for each increment in dairy consumption of one serving/d. No significant publication bias was observed. Our findings suggest an inverse dose-response relationship between dairy consumption and risk of MetS. PMID- 26416235 TI - Visible-light-promoted chloramination of olefins with N-chlorosulfonamide as both nitrogen and chlorine sources. AB - A visible-light-promoted chloramination of olefins is reported. N Chlorosulfonamides serve as both nitrogen and chlorine sources. These reactions provide a simple, efficient, regioselective, and atom-economical method for the preparation of vicinal haloamine derivatives under mild reaction conditions. A variety of olefins were tolerated, and chloramination products were obtained in good yields. PMID- 26416234 TI - Meaning in life and perceived quality of life in Switzerland: results of a representative survey in the German, French and Italian regions. AB - BACKGROUND: The concept of meaning in life (MIL) has become a central one in recent years, particularly in psycho-oncology and palliative care. The Schedule for Meaning in Life Evaluation (SMILE) has been developed to allow individuals to choose the life areas that they consider to be important for their own MIL. This approach relates to the "World Health Organisation" definition of quality of life (QOL) as an individual's perception of his own position. The aims of this study were (i) to assess MIL in a representative sample of the Swiss population according to the three linguistic regions and (ii) to evaluate whether MIL constitutes a significant determinant of the perceived QOL. METHODS: A telephone survey of the Swiss population, performed by a professional survey company, was conducted between November and December 2013. The interview included the SMILE, perceived QOL (0-10) and health status (1-5), and various sociodemographic variables. In the SMILE, an index of weighting (IOW, 20-100), an index of satisfaction (IOS, 0-100), and a total SMILE index (IOWS, 0-100) are calculated from the areas mentioned by the participants as providing MIL. RESULTS: Among the 6671 telephonic contacts realized, 1015 (15%) participants completed the survey: 405 French, 400 German and 210 Italian participants. "Family" (80.2%), "occupation/work" (51%), and "social relations" (43.3%) were the most cited MIL relevant categories. Italian participants listed "health" more frequently than German and French participants (50.4% vs 31.5% and 24.8% respectively, chi(2) = 12.229, p = .002). Age, gender, education, employment, and marital status significantly influenced either the MIL scores or the MIL-relevant categories. Linear regression analyses indicate that 24.3% of the QOL variance (p = .000) is explained by health status (B = .609, IC = .490-.728, p = .000), MIL (B = .034, IC = .028-.041, p = .000) and socioeconomic status (F = 11.01, p = .000). CONCLUSION: The major finding of our analysis highlights the positive and significant influence of MIL on the perceived QOL in a representative sample of a general, multilingual and multicultural population. This result indicates that the existential dimension is not only determinant for QOL in some critical life events, as shown e.g. in psycho-oncology and palliative care, but also in everyday life. PMID- 26416236 TI - Rheological and microstructural properties of the chia seed polysaccharide. AB - Chia seed polysaccharide (CSP) was extracted from chia (Salvia hispanica) seeds, and its rheological and microstructural properties in aqueous solutions were studied. CSP solution exhibited Newtonian and shear thinning flow patterns depending on shear rate when the concentration was <=0.06% (w/v). CSP solutions at concentrations >0.06% (w/v) exhibited strong shear thinning behaviour within the shear rate tested (0.001-300s(-1)). The transition from dilute to semi-dilute regime occurred at a critical concentration (C*) of 0.03gdL(-1). The intrinsic viscosity was high (~16dLg(-1)) and concentration dependence of zero shear viscosity in the semi-dilute regime followed eta0?C(2.7) relationship. The storage modulus (G') was higher than the loss modulus (G") at all experimental frequencies and their frequency dependence was negligible at all tested concentrations. Apparent shear viscosity was smaller than dynamic complex viscosity at equivalent values of deformation and G' varied with the square of concentration indicating a gel-like behaviour in CSP solutions within 0.02-3.0% (w/v) concentrations. Controlled acid hydrolysis of purified CSP yielded various low molecular fractions with fairly uniform polydispersity giving a Mark-Houwink Sakurada relationship of intrinsic viscosity equaling to 1.52*10(-4) (molecular weight)(0.803) (dLg(-1)). PMID- 26416237 TI - Structural studies of Helix aspersa agglutinin complexed with GalNAc: A lectin that serves as a diagnostic tool. AB - Lectins belong to a differentiated group of proteins known to possess sugar binding properties. Due to this fact, they are interesting research targets in medical diagnostics. Helix aspersa agglutinin (HAA) is a lectin that recognizes the epitopes containing alpha-d-N-acetylgalactosamine (GalNAc), which is present at the surface of metastatic cancer cells. Although several reports have already described the use of HAA as a diagnostic tool, this protein was not characterized on the molecular level. Here, we present for the first time the structural information about lectin isolated from mucus of Helix aspersa (garden snail). The amino acid sequence of this agglutinin was determined by Edman degradation and tertiary as well as quaternary structure by X-ray crystallography. The high resolution crystal structure (1.38A) and MALDI-TOF mass spectrometry analysis provide the detailed information about a large part of the HAA natural glycan chain. The topology of the GalNAc binding cleft and interaction with lectin are very well defined in the structure and fully confirmed by STD HSQC NMR spectroscopy. Together, this provides structural clues regarding HAA specificity and opens possibilities to rational modifications of this important diagnostic tool. PMID- 26416238 TI - Binding interaction between rice glutelin and amylose: Hydrophobic interaction and conformational changes. AB - The interaction of rice glutelin (RG) with amylose was characterized by spectroscopic and molecular docking studies. The intrinsic fluorescence of RG increased upon the addition of amylose. The binding sites, binding constant and thermodynamic features indicated that binding process was spontaneous and the main driving force of the interaction was hydrophobic interaction. The surface hydrophobicity of RG decreased with increasing amount of amylose. Furthermore, synchronous fluorescence and circular dichroism (CD) spectra provided data concerning conformational and micro-environmental changes of RG. With the concentration of amylose increasing, the polarity around the tyrosine residues increased while the hydrophobicity decreased. Alteration of protein conformation was observed with increasing of alpha-helix and reducing of beta-sheet. Finally, a visual representation of two binding sites located in the amorphous area of RG was presented by molecular modeling studies. PMID- 26416239 TI - Kinetics of Spanish broom peroxidase obeys a Ping-Pong Bi-Bi mechanism with competitive inhibition by substrates. AB - In plants, adverse conditions often induce an increase in reactive oxygen species (ROS) such as hydrogen peroxide (H2O2). H2O2 is reduced to water, and thus becomes detoxified by enzymes such as Cytisus multiflorus peroxidase (CMP). Here, the steady-state kinetics of the H2O2-supported oxidation of different organic substrates by CMP was investigated. Analysis of the initial rates vs. H2O2 and reducing substrate concentrations proved to be consistent with a substrate inhibited Ping-Pong Bi-Bi reaction mechanism. The phenomenological approach expresses the peroxidase Ping-Pong mechanism in the form of the Michaelis-Menten equation and affords an interpretation of the effects in terms of the kinetic parameters [Formula: see text] , [Formula: see text] , kcat, [Formula: see text] , [Formula: see text] and of the microscopic rate constants, k1 and k3, of the shared three-step catalytic cycle of peroxidases. PMID- 26416240 TI - Emerging patterns of genetic variation in the New Zealand endemic scallop Pecten novaezelandiae. AB - Both historical and contemporary processes influence the genetic structure of species, but the relative roles of such processes are still difficult to access. Population genetic studies of species with recent evolutionary histories such as the New Zealand endemic scallop Pecten novaezelandiae (<1 Ma) permit testing of the effects of recent processes affecting gene flow and shaping genetic structure. In addition, studies encompassing the entire distributional range of species can provide insight into colonization processes. Analyses of genetic variation in P. novaezelandiae (952 individuals from 14 locations, genotyped at 10 microsatellite loci) revealed a weak but significant regional structure across the distributional range of the species, as well as latitudinal gradients of genetic diversity and differentiation: estimates of migration rates supported these patterns. Our results suggest that the observed genetic structure and latitudinal gradients reflect a stepping-stone model of colonization (north to south) and emerging divergence of populations as a result of ongoing limitations to gene flow and insufficient time to reach migration-drift equilibrium. The low levels of interpopulation and interregional genetic differentiation detected over hundreds of kilometres reflect the recent evolutionary history of P. novaezelandiae and stand in contrast to patterns reported for other evolutionary older species at the same spatial scale. The outcomes of this study contribute to a better understanding of evolutionary processes influencing the genetic variation of species and provide vital information on the genetic structure of P. novaezelandiae. PMID- 26416241 TI - Multiple violence victimisation associated with sexual ill health and sexual risk behaviours in Swedish youth. AB - OBJECTIVES: To address the associations between emotional, physical and sexual violence, specifically multiple violence victimisation, and sexual ill health and sexual risk behaviours in youth, as well as possible gender differences. METHODS: A cross-sectional population-based survey among sexually experienced youth using a questionnaire with validated questions on emotional, physical, and sexual violence victimisation, sociodemographics, health risk behaviours, and sexual ill health and sexual risk behaviours. Proportions, unadjusted/adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: The participants comprised 1192 female and 1021 male students aged 15 to 22 years. The females had experienced multiple violence (victimisation with two or three types of violence) more often than the males (21% vs. 16%). The associations between multiple violence victimisation and sexual ill health and sexual risk behaviours were consistent for both genders. Experience of/involvement in pregnancy yielded adjusted ORs of 2.4 (95% CI 1.5-3.7) for females and 2.1 (95% CI 1.3-3.4) for males, and early age at first intercourse 2.2 (95% CI 1.6-3.1) for females and 1.9 (95% CI 1.2-3.0) for males. No significantly raised adjusted ORs were found for non-use of contraceptives in young men or young women, or for chlamydia infection in young men. CONCLUSIONS: Several types of sexual ill health and sexual risk behaviours are strongly associated with multiple violence victimisation in both genders. This should be taken into consideration when counselling young people and addressing their sexual and reproductive health. PMID- 26416242 TI - Avian Podocytes, Which Lack Nephrin, Use Adherens Junction Proteins at Intercellular Junctions. AB - Nephrin, a major intercellular junction (ICJ) molecule of mammalian podocytes in the renal glomerulus, is absent in the avian genome. We hypothesized that birds use ICJ molecules other than nephrin in their podocytes. Therefore, in the present study, we examined the possible involvement of adherens junction (AJ) proteins in the ICJs of avian podocytes. We found the AJ proteins N-cadherin and alpha- and beta-catenins in podocytes of quail and chickens but not in those of rats, pigs or humans. The AJ proteins were prominent in avian glomerulus-rich fractions in immunoblot analyses, and in immunofluorescence microscopy analyses, they were localized along glomerular capillary walls appearing in at least two staining patterns: weakly diffuse and distinctly granular. Immunoelectron microscopy demonstrated that the significant accumulation of immunogold particles for the AJ proteins were especially evident in avian slit diaphragms and AJs. Furthermore, N-cadherin was found to be expressed in all nephron cells in the early developmental stage but became confined to podocytes during maturation. These results indicate that avian slit diaphragms clearly express AJ proteins as compared with that in the mammal-where AJ proteins are suppressed to an extremely low level-and that avian podocytes are interconnected by AJs per se in addition to slit diaphragms. PMID- 26416243 TI - Long-Term Administration of High-Fat Diet Corrects Abnormal Bone Remodeling in the Tibiae of Interleukin-6-Deficient Mice. AB - In this study, we aimed to evaluate the influence of diet-induced obesity on IL-6 deficiency-induced bone remodeling abnormality. Seven-week-old IL-6(-/-) mice and their wild type (WT) littermates were fed a standard diet (SD) or high-fat diet (HFD) for 25 weeks. Lipid formation and bone metabolism in mice tibiae were investigated by histochemical analysis. Both IL-6(-/-) and WT mice fed the HFD showed notable body weight gain, thickened cortical bones, and adipose accumulation in the bone marrow. Notably, the HFD normalized the bone phenotype of IL-6(-/-) mice to that of their WT counterpart, as characterized by a decrease in bone mass and the presence of an obliquely arranged, plate-like morphology in the trabecular bone. Alkaline phosphatase and osteocalcin expressions were attenuated in both genotypes after HFD feeding, especially for the IL-6(-/-) mice. Meanwhile, tartrate-resistant acid phosphatase staining was inhibited, osteoclast apoptosis rate down-regulated (revealed by TUNEL assay), and the proportion of cathepsin K (CK)-positive osteoclasts significantly increased in IL 6(-/-) mice on a HFD as compared with IL-6(-/-) mice on standard chow. Our results demonstrate that HFD-induced obesity reverses IL-6 deficiency-associated bone metabolic disorders by suppressing osteoblast activity, upregulating osteoclastic activity, and inhibiting osteoclast apoptosis. PMID- 26416245 TI - The value of forceps biopsy and core needle biopsy in prediction of pathologic complete remission in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. AB - Patients with pathological complete remission (pCR) after treated with neoadjuvant chemoradiotherapy (nCRT) have better long-term outcome and may receive conservative treatments in locally advanced rectal cancer (LARC). The study aimed to evaluate the value of forceps biopsy and core needle biopsy in prediction of pCR in LARC treated with nCRT. In total, 120 patients entered this study. Sixty-one consecutive patients received preoperative forceps biopsy during endoscopic examination. Ex vivo core needle biopsy was performed in resected specimens of another 43 consecutive patients. The accuracy for ex vivo core needle biopsy was significantly higher than forceps biopsy (76.7% vs. 36.1%; p < 0.001). The sensitivity for ex vivo core needle biopsy was significantly lower in good responder (TRG 3) than poor responder (TRG <= 2) (52.9% vs. 94.1%; p = 0.017). In vivo core needle biopsy was further performed in 16 patients with good response. Eleven patients had residual cancer cells in final resected specimens, among whom 4 (36.4%) patients were biopsy positive. In conclusion, routine forceps biopsy was of limited value in identifying pCR after nCRT. Although core needle biopsy might further identify a subset of patients with residual cancer cells, the accuracy was not substantially increased in good responders. PMID- 26416246 TI - Visualizing the antivascular effect of bortezomib on the hypoxic tumor microenvironment. AB - Bortezomib, a novel proteasome inhibitor, has been approved for treating multiple myeloma and mantle cell lymphoma and studied pre-clinically and clinically for solid tumors. Preferential cytotoxicity of bortezomib was found toward hypoxic tumor cells and endothelial cells in vitro. The purpose of this study is to investigate the role of a pretreatment hypoxic tumor microenvironment on the effects of bortezomib in vitro and ex vivo, and explore the feasibility of dynamic contrast enhanced magnetic resonance imaging (DCE MRI) to noninvasively evaluate the biological effects of bortezomib. It was shown in vitro by Western blot, flow cytometry, and ELISA that bortezomib accumulated HIF-1alpha in non functional forms and blocks its hypoxia response in human colorectal cancer cell lines. Ex vivo experiments were performed with fluorescent immunohistochemical staining techniques using multiple endogenous and exogenous markers to identify hypoxia (pimonidazole, HRE-TKeGFP), blood flow/permeability (Hoechst 33342), micro-vessels (CD31 and SMA), apoptosis (cleaved caspase 3) and hypoxia response (CA9). After bortezomib administration, overall apoptosis index was significantly increased and blood perfusion was dramatically decreased in tumor xenografts. More importantly, apoptosis signals were found preferentially located in moderate and severe pretreatment hypoxic regions in both tumor and endothelial cells. Meanwhile, DCE MRI examinations showed that the tumor blood flow and permeability decreased significantly after bortezomib administration. The present study revealed that bortezomib reduces tumor hypoxia response and blood perfusion, thus, presenting antivascular properties. It will be important to determine the hypoxic/perfusion status pre- and during treatment at further translational studies. PMID- 26416244 TI - Targeting of cytosolic phospholipase A2alpha impedes cell cycle re-entry of quiescent prostate cancer cells. AB - Cell cycle re-entry of quiescent cancer cells has been proposed to be involved in cancer progression and recurrence. Cytosolic phospholipase A2alpha (cPLA2alpha) is an enzyme that hydrolyzes membrane glycerophospholipids to release arachidonic acid and lysophospholipids that are implicated in cancer cell proliferation. The aim of this study was to determine the role of cPLA2alpha in cell cycle re-entry of quiescent prostate cancer cells. When PC-3 and LNCaP cells were rendered to a quiescent state, the active form of cPLA2alpha with a phosphorylation at Ser505 was lower compared to their proliferating state. Conversely, the phospho cPLA2alpha levels were resurgent during the induction of cell cycle re-entry. Pharmacological inhibition of cPLA2alpha with Efipladib upon induction of cell cycle re-entry inhibited the re-entry process, as manifested by refrained DNA synthesis, persistent high proportion of cells in G0/G1 and low percentage of cells in S and G2/M phases, together with a stagnant recovery of Ki-67 expression. Simultaneously, Efipladib prohibited the emergence of Skp2 while maintained p27 at a high level in the nuclear compartment during cell cycle re entry. Inhibition of cPLA2alpha also prevented an accumulation of cyclin D1/CDK4, cyclin E/CDK2, phospho-pRb, pre-replicative complex proteins CDC6, MCM7, ORC6 and DNA synthesis-related protein PCNA during induction of cell cycle re-entry. Moreover, a pre-treatment of the prostate cancer cells with Efipladib during induction of cell cycle re-entry subsequently compromised their tumorigenic capacity in vivo. Hence, cPLA2alpha plays an important role in cell cycle re entry by quiescent prostate cancer cells. PMID- 26416247 TI - LGR5 is associated with tumor aggressiveness in papillary thyroid cancer. AB - PURPOSE: Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a cancer stem cell marker and a down-stream target in Wnt/beta-catenin signaling. In human papillary thyroid cancer (PTC), over activation of Wnt/beta-catenin has been associated with tumor aggressiveness. PATIENTS AND METHODS: Using established human cell lines (TPC-1, KTC-1, Nthy-ori-3-1), we report LGR5 and R spondin (RSPO1-3) overexpression in PTC and manipulate LGR5 and Wnt/beta-catenin signaling via both pharmacologic and genetic interventions. We test the association of LGR5 tumor expression with markers of PTC aggressiveness using a Discovery Cohort (n = 26 patients) and a Validation Cohort (n = 157 patients). Lastly, we explore the association between LGR5 and the BRAFV600E mutation (n = 33 patients). RESULTS: Our results reveal that LGR5 and its ligand, RSPO, are overexpressed in human PTC, whereby Wnt/beta-catenin signaling regulates LGR5 expression and promotes cellular migration. In two separate cohorts of patients, LGR5 and RSPO2 were associated with markers of tumor aggressiveness including: lymph node metastases, vascular invasion, increased tumor size, aggressive histology, advanced AJCC TNM stage, microscopic extra thyroidal extension, capsular invasion, and macroscopic invasion. As a biomarker, LGR5 positivity predicts lymph node metastasis with 95.5% sensitivity (95% CI 88.8%-98.7%) and 61% specificity (95% CI: 48.4%-72.4%) and has a negative predictive value (NPV) of 91.3% (95% CI 79.2%-97.5%) for lymph node metastatic disease. In human PTC, LGR5 is also strongly associated with the BRAFV600E mutation (p = 0.005). CONCLUSION: We conclude that overexpression of LGR5 is associated with markers of tumor aggressiveness in human PTC. LGR5 may serve as a future potential biomarker for patient risk stratification and loco regional metastases in PTC. PMID- 26416248 TI - RhoGDI deficiency induces constitutive activation of Rho GTPases and COX-2 pathways in association with breast cancer progression. AB - Rho GDP Dissociation Inhibitor (RhoGDI) is a key regulator of Rho GTPases. Here we report that loss of RhoGDI significantly accelerated xenograft tumor growth of MDA-MB-231 cells in animal models. At the molecular level, RhoGDI depletion resulted in constitutive activation of Rho GTPases, including RhoA, Cdc42, and Rac1. This was accompanied by Rho GTPase translocation from the cytosol to membrane compartments. Notably, COX-2 protein levels, mRNA expression, and biological activity were markedly increased in RhoGDI-deficient cells. The upregulated expression of COX-2 was directly associated with increased Rho GTPase activity. Further, we assessed the expression level of RhoGDI protein in breast tumor specimens (n = 165) by immunohistochemistry. We found that RhoGDI expression is higher in the early stages of breast cancer followed by a significant decrease in malignant tumors and metastatic lesions (p < 0.01). These data suggest that downregulation of RhoGDI could be a critical mechanism of breast tumor development, which may involve the hyperactivation of Rho GTPases and upregulation of COX-2 activity. Additional studies are warranted to evaluate the therapeutic potential of inhibiting Rho GTPases and COX-2 for treating breast cancers. PMID- 26416249 TI - Direct production of functional matrix metalloproteinase--14 without refolding or activation and its application for in vitro inhibition assays. AB - Human matrix metalloproteinase (MMP)-14, a membrane-bound zinc endopeptidase, is one of the most important cancer targets because it plays central roles in tumor growth and invasion. Large amounts of active MMP-14 are required for cancer research and the development of chemical or biological MMP-14 inhibitors. Current methods of MMP-14 production through refolding and activation are labor intensive, time-consuming, and often associated with low recovery rates, lot-to lot variation and heterogeneous products. Here, we report direct production of the catalytic domain of MMP-14 in the periplasmic space of Escherichia coli. 0.5 mg/L of functional MMP-14 was produced without tedious refolding or problematic activation process. MMP-14 prepared by simple periplasmic treatment can be readily utilized to evaluate the potencies of chemical and antibody-based inhibitors. Furthermore, co-expression of both MMP-14 and antibody Fab fragments in the periplasm facilitated inhibitory antibody screening by avoiding purification of MMP-14 or Fabs. We expect this MMP-14 expression strategy can expedite the development of therapeutic drugs targeting MMPs with biological significance. PMID- 26416250 TI - Secondary compounds enhance flammability in a Mediterranean plant. AB - Some plant secondary compounds, such as terpenes, are very flammable; however, their role in enhancing plant flammability is poorly understood and often neglected in reviews on plant chemical ecology. This is relevant as there is growing evidence that flammability-enhancing traits are adaptive in fire-prone ecosystems. We analyzed the content of monoterpenes and sesquiterpenes, performed flammability tests and genotyped microsatellite markers, all in the same individuals of Rosmarinus officinalis, to evaluate the link between the content of terpenes, flammability and the genetic similarity among individuals. The results suggest that terpenes enhance flammability in R. officinalis, and that variability in flammability among individuals is likely to have a genetic basis. Overall our results suggest that the capacity to produce and store terpenes can be considered a flammability-enhancing trait and could have an adaptive value in fire-prone ecosystems. PMID- 26416251 TI - Life habits, hox genes, and affinities of a 311 million-year-old holometabolan larva. AB - BACKGROUND: Holometabolous insects are the most diverse, speciose and ubiquitous group of multicellular organisms in terrestrial and freshwater ecosystems. The enormous evolutionary and ecological success of Holometabola has been attributed to their unique postembryonic life phases in which nonreproductive and wingless larvae differ significantly in morphology and life habits from their reproductive and mostly winged adults, separated by a resting stage, the pupa. Little is known of the evolutionary developmental mechanisms that produced the holometabolous larval condition and their Paleozoic origin based on fossils and phylogeny. RESULTS: We provide a detailed anatomic description of a 311 million-year-old specimen, the oldest known holometabolous larva, from the Mazon Creek deposits of Illinois, U.S.A. The head is ovoidal, downwardly oriented, broadly attached to the anterior thorax, and bears possible simple eyes and antennae with insertions encircled by molting sutures; other sutures are present but often indistinct. Mouthparts are generalized, consisting of five recognizable segments: a clypeo labral complex, mandibles, possible hypopharynx, a maxilla bearing indistinct palp-like appendages, and labium. Distinctive mandibles are robust, triangular, and dicondylic. The thorax is delineated into three, nonoverlapping regions of distinctive surface texture, each with legs of seven elements, the terminal-most bearing paired claws. The abdomen has ten segments deployed in register with overlapping tergites; the penultimate segment bears a paired, cercus-like structure. The anterior eight segments bear clawless leglets more diminutive than the thoracic legs in length and cross-sectional diameter, and inserted more ventrolaterally than ventrally on the abdominal sidewall. CONCLUSIONS: Srokalarva berthei occurred in an evolutionary developmental context likely responsible for the early macroevolutionary success of holometabolous insects. Srokalarva berthei bore head and prothoracic structures, leglet series on successive abdominal segments - in addition to comparable features on a second taxon eight million years-younger - that indicates Hox-gene regulation of segmental and appendage patterning among earliest Holometabola. Srokalarva berthei body features suggest a caterpillar-like body plan and head structures indicating herbivory consistent with known, contemporaneous insect feeding damage on seed plants. Taxonomic resolution places Srokalarva berthei as an extinct lineage, apparently possessing features closer to neuropteroid than other holometabolous lineages. PMID- 26416252 TI - Haiti and the health marketplace: the role of the private, informal market in filling the gaps left by the state. AB - BACKGROUND: In most societies the health marketplace is pluralistic in character, with a mix of formal and informal providers. In high-income countries, state regulation of the market helps ensure quality and access and mitigate market failures. In the present study, using Haiti as a case study, we explore what happens to the functioning of the pluralistic health marketplace in severely disrupted environments where the informal sector is able to flourish. METHODS: The overall research design was qualitative. Research methods included an extensive documentary and policy analysis, based on peer-reviewed articles, books and "grey" literature--government policy and program reports, unpublished research and evaluations, reviews and reviews from key multilateral and bilateral donors, and non-government organisations, combined with field site visits and in depth key informant interviews (N = 45). RESULTS: The findings show that state fragility has resulted in a privatised, commoditised and largely unregulated and informal health market. While different market segments can be identified, in reality the boundaries between international/domestic, public/private, for profit/not-for-profit, legal/illegal are hazy and shifting. DISCUSSION: The lack of state capacity to provide an enabling environment, establish, and enforce its regulatory framework has resulted in a highly segmented, heterogeneous and informal health market. The result is deplorable health indices which are far below regional averages and many other low-income countries. CONCLUSIONS: Working in fragile states with limited capacity to undertake the core function of securing the health of its population requires new and innovative ways of working. This needs longer time-frames, combining incremental top-down and bottom up strategies which recognize and work with state and civil society, public and private actors, formal and informal institutions, and progressively facilitate changes in the different market functions of supply, demand, regulation and supporting functions. PMID- 26416254 TI - Virulence evolution at the front line of spreading epidemics. AB - Understanding and predicting the spatial spread of emerging pathogens is a major challenge for the public health management of infectious diseases. Theoretical epidemiology shows that the speed of an epidemic is governed by the life-history characteristics of the pathogen and its ability to disperse. Rapid evolution of these traits during the invasion may thus affect the speed of epidemics. Here we study the influence of virulence evolution on the spatial spread of an epidemic. At the edge of the invasion front, we show that more virulent and transmissible genotypes are expected to win the competition with other pathogens. Behind the front line, however, more prudent exploitation strategies outcompete virulent pathogens. Crucially, even when the presence of the virulent mutant is limited to the edge of the front, the invasion speed can be dramatically altered by pathogen evolution. We support our analysis with individual-based simulations and we discuss the additional effects of demographic stochasticity taking place at the front line on virulence evolution. We confirm that an increase of virulence can occur at the front, but only if the carrying capacity of the invading pathogen is large enough. These results are discussed in the light of recent empirical studies examining virulence evolution at the edge of spreading epidemics. PMID- 26416253 TI - A cluster randomised feasibility trial evaluating nutritional interventions in the treatment of malnutrition in care home adult residents. AB - BACKGROUND: Protein energy malnutrition (PEM) predisposes individuals to disease, delays recovery from illness and reduces quality of life. Care home residents in the United Kingdom are especially vulnerable, with an estimated 30 to 42 % at risk. Evidence for nutritional interventions to address PEM in the care home setting is lacking. Widely used techniques include food-based intervention and/or the use of prescribed oral nutritional supplements. To define outcomes and optimise the design for an adequately powered definitive trial to compare the efficacy of established nutritional interventions in this setting, a cluster randomised feasibility trial with a 6-month intervention was undertaken. METHODS: Care home residents with or at risk of malnutrition were identified across six UK care home sites from September to December 2013. Homes were cluster randomised to standard care (SC), food-based intervention (FB) or oral nutritional supplement intervention (ONS), for 6 months. Key outcomes were trial feasibility and the acceptability of design, allocated interventions and outcome assessments. Anthropometry, dietary intake, healthcare resource usage and participant-reported outcome measures were assessed at baseline and at 3 and 6 months. RESULTS: All six care homes approached were recruited and retained. Of the 110 residents at risk of malnutrition, 85 % entered the trial, and 68 % completed the 6-month intervention. Pre-specified success criteria for feasibility were met for recruitment and retention, intervention acceptability (resident compliance >=60 %) and measurement of weight, body mass index (BMI), mid-upper arm circumference and dietary intake (data completeness >80 %). Measurement of handgrip strength and triceps skinfold thickness was not found to be feasible in this population. The 95 % confidence interval (CI) data suggested sensitivity to change in dietary intake for weight, BMI and energy intake between baseline and 3 months when each intervention (FB and ONS) was compared with SC. CONCLUSIONS: A definitive trial comparing the efficacy of nutritional support interventions in increasing weight and BMI in malnourished care home residents can be conducted. However, whilst the design was feasible, this trial has highlighted the lack of clinically and patient-relevant outcome measures that are appropriate for use in this setting for both research and clinical practice. In particular, this trial identified a need for a more simple measure of functional status, which considers the limitations of functional tests in the care home population. TRIAL REGISTRATION: Current Controlled Trials ISRCTN38047922 , Date assigned: 22 April 2014. PMID- 26416255 TI - Harnessing Enzymatic Promiscuity in Myxochelin Biosynthesis for the Production of 5-Lipoxygenase Inhibitors. AB - The siderophore myxochelin A is a potent inhibitor of human 5-lipoxygenase (5 LO). To clarify whether the iron-chelating properties of myxochelin A are responsible for this activity, several analogues of this compound were generated in the native producer Pyxidicoccus fallax by precursor-directed biosynthesis. Testing in a cell-free assay unveiled three derivatives with bioactivity comparable with that of myxochelin A. Furthermore, it became evident that inhibition of 5-LO by myxochelins does not correlate with their iron affinities. PMID- 26416256 TI - Developing a carob-based milk beverage using different varieties of carob pods and two roasting treatments and assessing their effect on quality characteristics. AB - BACKGROUND: This work aimed at formulating a carob-based milk beverage and assessing its chemical and sensory properties. Six varieties of carob pods, each processed into roasted and unroasted powders, were used to develop 12 prototypes of the beverage. Chemical and physico-chemical analyses (moisture, ash, fibre, protein, sugars, total-phenolics, total-antioxidants, water activity and colour) and sensory tests were conducted. RESULTS: The variety of carob pod had a significant effect on all chemical variables in carob powders (P < 0.01), except for sugars, and when incorporated in the beverage, on moisture, total phenolics, total antioxidant activity and colour parameters (L, a, b; P-values < 0.001). Roasting treatment significantly increased fibre, total phenolics, total antioxidant activity (P-values < 0.001), fructose, glucose (P-values < 0.05), and a-value levels (P < 0.01), significantly lowered moisture (P < 0.05), water activity, L- and b-values (P-values < 0.001) in carob powders; and significantly increased the beverage's total phenolics, a-value (P-values < 0.001) and total antioxidant activity (P < 0.01). Roasting treatment significantly increased the beverage's acceptability ratings. Beverages formulated with roasted carob powder had higher ratings for level of residue, colour, caramel odour, mocha odour and flavour, roasted coffee odour and flavour, viscosity mouthfeel and bitter aftertaste. Principal component analysis was conducted; PC1 and PC2 separated attributes according to roasting treatment and variety of carob pods, respectively. CONCLUSION: The use of Akkari roasted and Baladi Ikleem el Kharoob roasted to formulate a carob-based milk beverage is recommended. (c) 2015 Society of Chemical Industry. PMID- 26416257 TI - Accurate pan-specific prediction of peptide-MHC class II binding affinity with improved binding core identification. AB - A key event in the generation of a cellular response against malicious organisms through the endocytic pathway is binding of peptidic antigens by major histocompatibility complex class II (MHC class II) molecules. The bound peptide is then presented on the cell surface where it can be recognized by T helper lymphocytes. NetMHCIIpan is a state-of-the-art method for the quantitative prediction of peptide binding to any human or mouse MHC class II molecule of known sequence. In this paper, we describe an updated version of the method with improved peptide binding register identification. Binding register prediction is concerned with determining the minimal core region of nine residues directly in contact with the MHC binding cleft, a crucial piece of information both for the identification and design of CD4(+) T cell antigens. When applied to a set of 51 crystal structures of peptide-MHC complexes with known binding registers, the new method NetMHCIIpan-3.1 significantly outperformed the earlier 3.0 version. We illustrate the impact of accurate binding core identification for the interpretation of T cell cross-reactivity using tetramer double staining with a CMV epitope and its variants mapped to the epitope binding core. NetMHCIIpan is publicly available at http://www.cbs.dtu.dk/services/NetMHCIIpan-3.1 . PMID- 26416258 TI - Fournier's gangrene at a tertiary health facility in northwestern Tanzania: a single centre experiences with 84 patients. AB - BACKGROUND: Fournier's gangrene (FG) is a rare, rapidly progressive, necrotizing fasciitis of the external genitalia and perineum, leading to soft-tissue necrosis. Despite antibiotics and aggressive debridement, the mortality rate of FG remains high. This study describes our experiences in the management of FG and identifies prognostic factors. METHODS: This was a descriptive retrospective study of patients with FG treated at Bugando Medical Centre between November 2006 and April 2014. RESULTS: A total of 84 patients (M:F = 41:1) were studied. The median age was 34 years (range 15-76 years). The most common predisposing factor was diabetes mellitus (16.7%). Nine (11.3%) patients were HIV positive. Bacterial culture results were obtained in only 46 (54.8%) patients. Of these, 38(82.6%) had polymicrobial bacterial growth while 8 (17.4%) had monomicrobial bacterial growth. Escherichia coli (28.3%) were the most frequent bacterial organism isolated. All the microorganisms isolated showed high resistance to commonly used antibiotics except for Meropenem and imipenem, which were 100% sensitive each respectively. All patients were treated with a common approach of resuscitation, broad-spectrum antibiotics, and wide surgical excision. The median length of hospital stay (LOS) was 28 days and mortality rate was 28.6%. Systemic inflammatory response syndrome and diabetes mellitus were significantly associated with prolonged LOS (p < 0.001), whereas advancing age (>60 years), late presentation (>48 h), systemic inflammatory response syndrome on admission, diabetes mellitus, extension of infection to the abdominal wall, FG severity score >9 and HIV infection with CD4 count <200 MUl/cells) were independent predictors of mortality (p < 0.001). CONCLUSION: Fournier's gangrene remains a very severe disease with high mortality rates. Early recognition of infection associated with invasive and aggressive treatment is essential for attempting to reduce mortality rates associated with this disease in our setting. PMID- 26416259 TI - [Preliminary results for ambulatory surgery for vaginal prolapse]. AB - OBJECTIVE, PATIENTS AND METHODS: From a study of 65 patients with vaginal prolapse, we studied 56 patients treated by the Elevate technic during an ambulatory hospitalisation. RESULTS: Seven patients failed to the ambulatory protocol and needed to stay. Three of them for urinary retention. Eighty-eight percent of the patients were satisfied by this protocol. CONCLUSION: This study shows the feasibility of prolapse surgery in an ambulatory settings. PMID- 26416260 TI - Microfluidic Integration of a Cloth-Based Hybridization Array System (CHAS) for Rapid, Colorimetric Detection of Enterohemorrhagic Escherichia coli (EHEC) Using an Articulated, Centrifugal Platform. AB - We describe the translation of a cloth-based hybridization array system (CHAS), a colorimetric DNA detection method that is used by food inspection laboratories for colony screening of pathogenic agents, onto a microfluidic chip format. We also introduce an articulated centrifugal platform with a novel fluid manipulation concept based on changes in the orientation of the chip with respect to the centrifugal force field to time the passage of multiple components required for the process. The platform features two movable and motorized carriers that can be reoriented on demand between 0 and 360 degrees during stage rotation. Articulation of the chip can be used to trigger on-the-fly fluid dispensing through independently addressable siphon structures or to relocate solutions against the centrifugal force field, making them newly accessible for downstream transfer. With the microfluidic CHAS, we achieved significant reduction in the size of the cloth substrate as well as the volume of reagents and wash solutions. Both the chip design and the operational protocol were optimized to perform the entire process in a reliable, fully automated fashion. A demonstration with PCR-amplified genomic DNA confirms on-chip detection and identification of Escherichia coli O157:H7 from colony isolates in a colorimetric multiplex assay using rfbO157, fliCH7, vt1, and vt2 genes. PMID- 26416261 TI - Altered terminal Schwann cell morphology precedes denervation in SOD1 mice. AB - In mice that express SOD1 mutations found in human motor neuron disease, degeneration begins in the periphery for reasons that remain unknown. At the neuromuscular junction (NMJ), terminal Schwann cells (TSCs) have an intimate relationship with motor terminals and are believed to help maintain the integrity of the motor terminal. Recent evidence indicates that TSCs in some SOD1 mice exhibit abnormal functional properties, but other aspects of possible TSC involvement remain unknown. In this study, an analysis of TSC morphology and number was performed in relation to NMJ innervation status in mice which express the G93A SOD1 mutation. At P30, all NMJs of the fast medial gastrocnemius (MG) muscle were fully innervated by a single motor axon but 50% of NMJs lacked TSC cell bodies and were instead covered by the processes of Schwann cells with cell bodies located on the preterminal axons. NMJs in P30 slow soleus muscles were also fully innervated by single motor axons and only 5% of NMJs lacked a TSC cell body. At P60, about 25% of MG NMJs were denervated and lacked labeling for TSCs while about 60% of innervated NMJs lacked TSC cell bodies. In contrast, 96% of P60 soleus NMJs were innervated while 9% of innervated NMJs lacked TSC cell bodies. The pattern of TSC abnormalities found at P30 thus correlates with the pattern of denervation found at P60. Evidence from mice that express the G85R SOD1 mutation indicate that TSC abnormalities are not unique for mice that express G93A SOD1 mutations. These results add to an emerging understanding that TSCs may play a role in motor terminal degeneration and denervation in animal models of motor neuron disease. PMID- 26416262 TI - Exercise pathophysiology and the role of oxygen therapy in idiopathic interstitial pneumonia. AB - Exercise limitation is a common feature in idiopathic interstitial pneumonia (IIP). There are multiple contributing pathophysiological mechanisms, including ventilatory mechanical limitation, impaired gas exchange, pulmonary vascular insufficiency and peripheral muscle dysfunction. Progressive exertional dyspnoea and functional incapacity impact significantly on quality of life. Exercise induced desaturation is frequently observed and is predictive of poorer outcomes. Tests to assess the cardiorespiratory system under stress (e.g. cardiopulmonary exercise testing and the 6-min walk test) can provide important physiologic and prognostic information as adjuncts to resting measurements of lung function. Despite many advances in understanding disease mechanisms, therapies to improve exercise capacity, symptom burden and quality of life are lacking. Exercise training and supplemental oxygen are two potential interventions that require closer evaluation in patients with IIP. PMID- 26416263 TI - Supplementation of metabolizable protein during late gestation and fetal number impact ewe organ mass, maternal serum hormone and metabolite concentrations, and conceptus measurements. AB - To examine the effects of maternal metabolizable protein (MP) supplementation during late gestation on serum hormone and metabolites and organ masses, multiparous ewes (n = 45) carrying singletons or twins were allotted randomly (within pregnancy group) to 1 of 3 treatments: 60% (MP60), 80% (MP80), or 100% (MP100) of MP requirements. Blood samples were drawn before the initiation of diets (day 100) and before slaughter (day 130) for chemistry panel analysis and weekly for hormone analysis including progesterone (P4) and estradiol-17beta (E2). At day 130, ewe organ masses were recorded. Despite being fed isocaloric diets, MP60 ewes gained less weight throughout pregnancy compared with MP80 and MP100 ewes which were similar. Although diet did not impact E2 or P4 concentrations, ewes carrying twins had greater (P < 0.05) concentrations of both as gestation advanced. Albumin, aspartate aminotransferase, and total protein were reduced (P < 0.05) in MP60 compared with MP100 ewes near term. There was a diet by fetal number interaction (P = 0.03) for lactate dehydrogenase. Twin carrying MP80 ewes had greater lactate dehydrogenase compared with all other groups on day 130 of gestation. Ewes that were fed MP80 had greater body weight on day 130 of gestation compared with MP60 ewes. Kidney and heart weights were lighter in MP60 ewes compared with MP80 ewes. There was a maternal diet by fetal number interaction (P = 0.05) on fetal weight per unit empty ewe body weight. In ewes carrying singletons, MP60 ewes supported less fetal weight compared with MP100. In contrast, MP60 ewes supported more fetal mass compared with MP100 ewes when carrying twins. The level of protein, and not just total energy, in the diet appears to impact some aspects of the maternal system. Moreover, it appears some measurements of mobilizing maternal body resources are enhanced in ewes carrying twins. PMID- 26416264 TI - PDZD7 and hearing loss: More than just a modifier. AB - Deafness is the most frequent sensory disorder. With over 90 genes and 110 loci causally implicated in non-syndromic hearing loss, it is phenotypically and genetically heterogeneous. Here, we investigate the genetic etiology of deafness in four families of Iranian origin segregating autosomal recessive non-syndromic hearing loss (ARNSHL). We used a combination of linkage analysis, homozygosity mapping, and a targeted genomic enrichment platform to simultaneously screen 90 known deafness-causing genes for pathogenic variants. Variant segregation was confirmed by Sanger sequencing. Linkage analysis and homozygosity mapping showed segregation with the DFNB57 locus on chromosome 10 in two families. Targeted genomic enrichment with massively parallel sequencing identified causal variants in PDZD7: a homozygous missense variant (p.Gly103Arg) in one family and compound heterozygosity for missense (p.Met285Arg) and nonsense (p.Tyr500Ter) variants in the second family. Screening of two additional families identified two more variants: (p.Gly228Arg) and (p.Gln526Ter). Variant segregation with the hearing loss phenotype was confirmed in all families by Sanger sequencing. The missense variants are predicted to be deleterious, and the two nonsense mutations produce null alleles. This report is the first to show that mutations in PDZD7 cause ARNSHL, a finding that offers addition insight into the USH2 interactome. We also describe a novel likely disease-causing mutation in CIB2 and illustrate the complexity associated with gene identification in diseases that exhibit large genetic and phenotypic heterogeneity. PMID- 26416265 TI - Pain pressure threshold of a muscle tender spot increases following local and non local rolling massage. AB - BACKGROUND: The aim of the present study was to determine the acute effect of rolling massage on pressure pain threshold (PPT) in individuals with tender spots in their plantar flexor muscles. METHODS: In a randomized control trial and single blinded study, tender spots were identified in 150 participants' plantar flexor muscles (gastrocnemius or soleus). Then participants were randomly assigned to one of five intervention groups (n = 30): 1) heavy rolling massage on the calf that exhibited the higher tenderness (Ipsi-R), 2) heavy rolling massage on the contralateral calf (Contra-R), 3) light stroking of the skin with roller massager on the calf that exhibited the higher tenderness (Sham), 4) manual massage on the calf that exhibited the higher tenderness (Ipsi-M) and 5) no intervention (Control). PPT was measured at 30 s and up to 15 min post intervention via a pressure algometer. RESULTS: At 30 s post-intervention, the Ipsi-R (24 %) and Contra-R (21 %) demonstrated higher (p < 0.03) PPT values compared with Control and Sham. During 15 min post-intervention, PPT was higher (p < 0.05) following Ipsi-R (19.2 %), Contra-R (15.9 %) and Ipsi-M (10.9 %) compared with Control. There was no difference between the effects of three deep tissue massages (Ipsi-R, Ipsi-M and Contra-R) on PPT. DISCUSSION: Whereas the increased PPT following ipsilateral massage (Ipsi-R and Ipsi-M) might be attributed to the release of fibrous adhesions; the non-localized effect of rolling massage on the contralateral limb suggests that other mechanisms such as a central pain-modulatory system play a role in mediation of perceived pain following brief tissue massage. CONCLUSION: Overall, rolling massage over a tender spot reduces pain perception. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT02528812 ), August 19(th), 2015. PMID- 26416266 TI - Extrinsic thoracic spinal cord compression related to supine position: from diagnosis to the creation of a spinal protection shield. AB - BACKGROUND: Rapidly progressing extrinsic spinal cord compression syndromes are rare, especially when the compression is associated with the supine position. PURPOSE: This work presents a case of extrinsic thoracic spinal cord compression related to the supine position and describes our approach from diagnosis to the technical therapeutic creation of a spinal protection shield. STUDY DESIGN: One case of a patient suffering from extrinsic spinal cord compression syndrome is reported. PATIENT SAMPLE: We report the case of a Coptic priest patient who, as a result of Pott disease sequelae, underwent several decompressive and stabilizing surgeries for major kyphoscoliosis. Consequently, he developed extrinsic thoracic spinal cord compression caused by the supine position. OUTCOME MEASURES: After each instrumentation device removal, we noticed progressive severe paraparesis when the patient was supine. Imaging assessment confirmed spinal dynamic and intermittent compressions triggered by the supine position, which was facilitated by the exposure and vulnerability of the thoracic spine cord. METHODS: We implanted a tailored titanium mesh spinal protection shield and a trapezius flap for spine coverage. This work presents the diagnostic aspects as well as several surgical technique options. RESULTS: At the 6-year follow-up, the patient's neurologic conditions were significantly improved. We report neurologic improvements, no sphincter disorder, persistent spasticity, and lower limbs weakness not affecting full ambulation. CONCLUSIONS: To our knowledge, no other case of spinal protection shield in compressions caused by the supine position have been studied. The surgical and technical management therefore remains innovative. PMID- 26416267 TI - Qualitative Effects of Monovalent Vaccination Against Rotavirus: A Comparison of North America and South America. AB - Rotavirus is the most common cause of severe gastroenteritis in young children worldwide. The introduction of vaccination programs has led to a significant reduction in number of hospitalizations due to rotavirus in North and South American countries. Little work has been done, however, to examine the differential impact of vaccination as a function of strain distribution and strain-specific vaccine efficacy. We developed a two-strain epidemiological model of rotavirus transmission, and used it to examine the effects of a monovalent vaccine (Rotarix) on the qualitative behaviors of infection levels in a population. For contrast, we parameterized our model with strain distribution data from North America and from South America. In all cases, the introduction of the vaccine led to significant decreases in the prevalence of primary infection due to both strains for a decade or more, after which the overall prevalence recovers to near pre-vaccination levels. The prevalence of G1P[8] is significantly higher in North America (73 % of all rotavirus infections) compared to that in South America (34 %). Our model predicts that the introduction of Rotarix might result in major strain replacement in regions such as North America where the prevalence of G1P[8] is relatively high, due to higher efficacy of Rotarix against infection caused by G1P[8], while regions with lower prevalence of G1P[8], such as South America, are not susceptible to major strain replacement. PMID- 26416269 TI - FTY720 Abrogates Collagen-Induced Arthritis by Hindering Dendritic Cell Migration to Local Lymph Nodes. AB - Because dendritic cells (DCs) play critical roles in the pathogenesis of rheumatoid arthritis, modulation of their functions could serve as a novel therapy. In this study, we demonstrated that FTY720 treatment significantly suppressed the incidence and severity of collagen-induced arthritis (CIA) in DBA/1J mice via the modulation of DC functions. In FTY720-treated CIA mice, a decrease in the number of DCs in local draining lymph nodes (LNs) was observed. In vitro, FTY720 inhibited the trafficking of LPS-stimulated bone marrow-derived DCs (BMDCs). Decreased secretion of CCL19 and downregulation of CCR7 on DCs may explain the mechanisms underlying the impairment of DC migration induced by FTY720. In a DC-induced mouse arthritis model, FTY720 treatment also suppressed the incidence and severity of arthritis, which was correlated with a decrease in the migration of injected BMDCs to draining LNs. Although lower levels of costimulatory molecules (CD40, CD80, and CD86) and I-A(q) expressed on LN DCs were observed in FTY720-treated mice, in vitro analysis showed no effect of FTY720 on LPS-stimulated BMDC maturation. Furthermore, LN cells from FTY720 treated CIA mice displayed diminished production of proinflammatory cytokines in response to collagen II and Con A stimulation. In addition, the ratio of Th1/Th2 in the draining LNs of mice with DC-induced arthritis was decreased upon FTY720 treatment. This finding was consistent with the fact that FTY720 suppressed IL 12p70 production in cultured BMDCs. Taken together, these results indicate that inhibition of DC migration by FTY720 may provide a novel approach in treating autoimmune diseases such as rheumatoid arthritis. PMID- 26416268 TI - A Gene Expression Signature That Correlates with CD8+ T Cell Expansion in Acute EBV Infection. AB - Virus-specific CD8(+) T cells expand dramatically during acute EBV infection, and their persistence is important for lifelong control of EBV-related disease. To better define the generation and maintenance of these effective CD8(+) T cell responses, we used microarrays to characterize gene expression in total and EBV specific CD8(+) T cells isolated from the peripheral blood of 10 individuals followed from acute infectious mononucleosis (AIM) into convalescence (CONV). In total CD8(+) T cells, differential expression of genes in AIM and CONV was most pronounced among those encoding proteins important in T cell activation/differentiation, cell division/metabolism, chemokines/cytokines and receptors, signaling and transcription factors (TF), immune effector functions, and negative regulators. Within these categories, we identified 28 genes that correlated with CD8(+) T cell expansion in response to an acute EBV infection. In EBV-specific CD8(+) T cells, we identified 33 genes that were differentially expressed in AIM and CONV. Two important TF, T-bet and eomesodermin, were upregulated and maintained at similar levels in both AIM and CONV; in contrast, protein expression declined from AIM to CONV. Expression of these TF varied among cells with different epitope specificities. Collectively, gene and protein expression patterns suggest that a large proportion, if not a majority of CD8(+) T cells in AIM are virus specific, activated, dividing, and primed to exert effector activities. High expression of T-bet and eomesodermin may help to maintain effector mechanisms in activated cells and to enable proliferation and transition to earlier differentiation states in CONV. PMID- 26416270 TI - Cutting Edge: CTLA-4Ig Inhibits Memory B Cell Responses and Promotes Allograft Survival in Sensitized Recipients. AB - Sensitized recipients with pretransplant donor-specific Abs are at higher risk for Ab-mediated rejection than nonsensitized recipients, yet little is known about the properties of memory B cells that are central to the recall alloantibody responses. Using cell enrichment and MHC class I tetramers, C57BL/6 mice sensitized with BALB/c splenocytes were shown to harbor H-2K(d)-specific IgG(+) memory B cells with a post-germinal center phenotype (CD73(+)CD273(+)CD38(hi)CD138(-)GL7(-)). These memory B cells adoptively transferred into naive mice without memory T cells recapitulated class-switched recall alloantibody responses. During recall, memory H-2K(d)-specific B cells preferentially differentiated into Ab-secreting cells, whereas in the primary response, H-2K(d)-specific B cells differentiated into germinal center cells. Finally, our studies revealed that, despite fundamental differences in alloreactive B cell fates in sensitized versus naive recipients, CTLA-4Ig was unexpectedly effective at constraining B cell responses and heart allograft rejection in sensitized recipients. PMID- 26416272 TI - Mechanistic Basis for Epitope Proofreading in the Peptide-Loading Complex. AB - The peptide-loading complex plays a pivotal role in Ag processing and is thus central to the efficient immune recognition of virally and malignantly transformed cells. The underlying mechanism by which MHC class I (MHC I) molecules sample immunodominant peptide epitopes, however, remains poorly understood. In this article, we delineate the interaction between tapasin (Tsn) and MHC I molecules. We followed the process of peptide editing in real time after ultra-fast photoconversion to pseudoempty MHC I molecules. Tsn discriminates between MHC I loaded with optimal and MHC I bound to suboptimal cargo. This differential interaction is key to understanding the kinetics of epitope proofreading. To elucidate the underlying mechanism at the atomic level, we modeled the Tsn/MHC I complex using all-atom molecular dynamics simulations. We present a catalytic working cycle, in which Tsn binds to MHC I with suboptimal cargo and thereby adjusts the energy landscape in favor of MHC I complexes with immunodominant epitopes. PMID- 26416271 TI - Continuous Antigenic Stimulation of DO11.10 TCR Transgenic Mice in the Presence or Absence of IL-1beta: Possible Implications for Mechanisms of T Cell Depletion in HIV Disease. AB - Untreated HIV disease is associated with chronic immune activation and CD4(+) T cell depletion. A variety of mechanisms have been invoked to account for CD4(+) T cell depletion in this setting, but the quantitative contributions of these proposed mechanisms over time remain unclear. We turned to the DO11.10 TCR transgenic mouse model, where OVA is recognized in the context of H-2(d), to explore the impact of chronic antigenic stimulation on CD4(+) T cell dynamics. To model dichotomous states of persistent Ag exposure in the presence or absence of proinflammatory stimulation, we administered OVA peptide to these mice on a continuous basis with or without the prototypic proinflammatory cytokine, IL 1beta. In both cases, circulating Ag-specific CD4(+) T cells were depleted. However, in the absence of IL-1beta, there was limited proliferation and effector/memory conversion of Ag-specific T cells, depletion of peripheral CD4(+) T cells in hematolymphoid organs, and systemic induction of regulatory Foxp3(+)CD4(+) T cells, as often observed in late-stage HIV disease. By contrast, when OVA peptide was administered in the presence of IL-1beta, effector/memory phenotype T cells expanded and the typical symptoms of heightened immune activation were observed. Acknowledging the imperfect and incomplete relationship between Ag-stimulated DO11.10 TCR transgenic mice and HIV-infected humans, our data suggest that CD4(+) T cell depletion in the setting of HIV disease may reflect, at least in part, chronic Ag exposure in the absence of proinflammatory signals and/or appropriate APC functions. PMID- 26416273 TI - Species-Specific Minimal Sequence Motif for Oligodeoxyribonucleotides Activating Mouse TLR9. AB - Synthetic oligodeoxyribonucleotides (ODNs) containing unmethylated CpG recapitulate the activation of TLR9 by microbial DNA. ODNs are potent stimulators of the immune response in cells expressing TLR9. Despite extensive use of mice as experimental animals in basic and applied immunological research, the key sequence determinants that govern the activation of mouse TLR9 by ODNs have not been well defined. We performed a systematic investigation of the sequence motif of B class phosphodiester ODNs to identify the sequence properties that govern mouse TLR9 activation. In contrast to ODNs activating human TLR9, where the minimal sequence motif for the receptor activation comprises a pair of closely positioned CpGs we found that the mouse TLR9 requires a single CpG positioned 4-6 nt from the 5'-end. Activation is augmented by a 5'TCC sequence one to three nucleotides from the CG. The distance of the CG dinucleotide of four to six nucleotides from the 5'-end and the ODN's length fine-tunes activation of mouse macrophages. Length of the ODN <23 and >29 nt decreases activation of dendritic cells. The ODNs with minimal sequence induce Th1-type cytokine synthesis in dendritic cells and confirm the expression of cell surface markers in B cells. Identification of the minimal sequence provides an insight into the sequence selectivity of mouse TLR9 and points to the differences in the receptor selectivity between species probably as a result of differences in the receptor binding sites. PMID- 26416274 TI - Polarization of Monocytic Myeloid-Derived Suppressor Cells by Hepatitis B Surface Antigen Is Mediated via ERK/IL-6/STAT3 Signaling Feedback and Restrains the Activation of T Cells in Chronic Hepatitis B Virus Infection. AB - Chronic hepatitis B virus (HBV) infection is characterized by T cell tolerance to virus. Although inhibition of T cell responses by myeloid-derived suppressor cells (MDSCs) has been observed in patients with chronic hepatitis B (CHB), the mechanism for expansion of MDSCs remains ambiguous. In this study, a significant increased frequency of monocytic MDSCs (mMDSCs) was shown positively correlated to level of HBsAg in the patients with CHB. We further found hepatitis B surface Ag (HBsAg) efficiently promoted differentiation of mMDSCs in vitro, and monocytes in PBMCs performed as the progenitors. This required the activation of ERK/IL 6/STAT3 signaling feedback. Importantly, the mMDSCs polarized by HBsAg in vitro acquired the ability to suppress T cell activation. Additionally, treatment of all-trans retinoic acid, an MDSC-targeted drug, restored the proliferation and IFN-gamma production by HBV-specific CD4(+) and CD8(+) T cells in PBMCs from patients with CHB and prevented increase of viral load in mouse model. In summary, HBsAg maintains HBV persistence and suppresses T cell responses by promoting differentiation of monocytes into mMDSCs. A therapy aimed at the abrogation of MDSCs may help to disrupt immune suppression in patients with CHB. PMID- 26416277 TI - MHC/Peptide-Specific Interaction of the Humoral Immune System: A New Category of Antibodies. AB - Abs bind to unprocessed Ags, whereas cytotoxic CD8(+) T cells recognize peptides derived from endogenously processed Ags presented in the context of class I MHC complexes. We screened, by ELISA, human sera for Abs reacting specifically with the influenza matrix protein (IMP)-derived peptide(58-66) displayed by HLA-A*0201 complexes. Among 653 healthy volunteers, blood donors, and women on delivery, high-titered HLA-A*0201/IMP(58-66) complex-specific IgG Abs were detected in 11 females with a history of pregnancies and in 1 male, all HLA-A*0201(-). These Abs had the same specificity as HLA-A*0201/IMP(58-66)-specific cytotoxic T cells and bound neither to HLA-A*0201 nor the peptide alone. No such Abs were detected in HLA-A*0201(+) volunteers. These Abs were not cross-reactive to other self-MHC class I alleles displaying IMP(58-66), but bound to MHC class I complexes of an HLA nonidentical offspring. HLA-A*0201/IMP(58-66) Abs were also detected in the cord blood of newborns, indicating that HLA-A*0201/IMP(58-66) Abs are produced in HLA-A*0201(-) mothers and enter the fetal blood system. That Abs can bind to peptides derived from endogenous Ags presented by MHC complexes opens new perspectives on interactions between the cellular and humoral immune system. PMID- 26416275 TI - Regulation of Adaptive NK Cells and CD8 T Cells by HLA-C Correlates with Allogeneic Hematopoietic Cell Transplantation and with Cytomegalovirus Reactivation. AB - Mass cytometry was used to investigate the effect of CMV reactivation on lymphocyte reconstitution in hematopoietic cell transplant patients. For eight transplant recipients (four CMV negative and four CMV positive), we studied PBMCs obtained 6 mo after unrelated donor hematopoietic cell transplantation (HCT). Forty cell-surface markers, distinguishing all major leukocyte populations in PBMC, were analyzed with mass cytometry. This group included 34 NK cell markers. Compared with healthy controls, transplant recipients had higher HLA-C expression on CD56(-)CD16(+) NK cells, B cells, CD33(bright) myeloid cells, and CD4CD8 T cells. The increase in HLA-C expression was greater for CMV-positive HCT recipients than for CMV negative recipients. Present in CMV-positive HCT recipients, but not in CMV-negative HCT recipients or controls, is a population of killer cell Ig-like receptor (KIR)-expressing CD8 T cells not previously described. These CD8 T cells coexpress CD56, CD57, and NKG2C. The HCT recipients also have a population of CD57(+)NKG2A(+) NK cells that preferentially express KIR2DL1. An inverse correlation was observed between the frequencies of CD57(+)NKG2C(+) NK cells and CD57(+)NKG2A(+) NK cells. Although CD57(+)NKG2A(+) NK cells are less abundant in CMV-positive recipients, their phenotype is of a more activated cell than the CD57(+)NKG2A(+) NK cells of controls and CMV negative HCT recipients. These data demonstrate that HCT and CMV reactivation are associated with an increased expression of HLA-C. This could influence NK cell education during lymphocyte reconstitution. The increased inhibitory KIR expression by proliferating CMV-specific CD8 T cells suggests regulatory interactions between HLA-C and KIR might promote Graft-versus-Leukemia effects following transplantation. PMID- 26416276 TI - SHIP-1 Couples to the Dectin-1 hemITAM and Selectively Modulates Reactive Oxygen Species Production in Dendritic Cells in Response to Candida albicans. AB - Dectin-1 (Clec7a) is a paradigmatic C-type lectin receptor that binds Syk through a hemITAM motif and couples sensing of pathogens such as fungi to induction of innate responses. Dectin-1 engagement triggers a plethora of activating events, but little is known about the modulation of such pathways. Trying to define a more precise picture of early Dectin-1 signaling, we explored the interactome of the intracellular tail of the receptor in mouse dendritic cells. We found unexpected binding of SHIP-1 phosphatase to the phosphorylated hemITAM. SHIP-1 colocalized with Dectin-1 during phagocytosis of zymosan in a hemITAM-dependent fashion. Moreover, endogenous SHIP-1 relocated to live or heat-killed Candida albicans-containing phagosomes in a Dectin-1-dependent manner in GM-CSF-derived bone marrow cells (GM-BM). However, SHIP-1 absence in GM-BM did not affect activation of MAPK or production of cytokines and readouts dependent on NF-kappaB and NFAT. Notably, ROS production was enhanced in SHIP-1-deficient GM-BM treated with heat-killed C. albicans, live C. albicans, or the specific Dectin-1 agonists curdlan or whole glucan particles. This increased oxidative burst was dependent on Dectin-1, Syk, PI3K, phosphoinositide-dependent protein kinase 1, and NADPH oxidase. GM-BM from CD11c?SHIP-1 mice also showed increased killing activity against live C. albicans that was dependent on Dectin-1, Syk, and NADPH oxidase. These results illustrate the complexity of myeloid C-type lectin receptor signaling, and how an activating hemITAM can also couple to intracellular inositol phosphatases to modulate selected functional responses and tightly regulate processes such as ROS production that could be deleterious to the host. PMID- 26416278 TI - Human beta Defensin-3 Increases CD86 Expression on Monocytes by Activating the ATP-Gated Channel P2X7. AB - Human beta defensin-3 (hBD-3), an epithelial cell-derived antimicrobial peptide, mediates chemotaxis and activation of myeloid cells. In this study, we provide evidence that hBD-3 induces the costimulatory molecule CD86 on primary human monocytes by a mechanism involving autocrine activation of ionotropic P2X7 receptors (P2X7R) by ATP. Incubation of monocytes with hBD-3 resulted in increased expression of both the CD80 and CD86 costimulatory molecules. Treatment of monocytes with a selective P2X7R antagonist inhibited the ability of hBD-3 to induce expression of CD86 but not CD80. The hBD-3-dependent upregulation of CD86 was also attenuated in monocytes incubated with apyrase, a potent scavenger of extracellular ATP. Finally, direct activation of monocyte P2X7R by exogenous ATP mimicked the ability of hBD-3 to induce CD86 expression. These data suggest that hBD-3 induces monocyte activation by both P2X7-dependent (CD86 upregulation) and P2X7-independent (CD80 upregulation) signaling mechanisms and raise the possibility that activation of P2X7R could play an important role in shaping the inflammatory microenvironment in conditions where hBD-3 is highly expressed, such as psoriasis or oral carcinoma. PMID- 26416279 TI - Fibrocytes Differ from Macrophages but Can Be Infected with HIV-1. AB - Fibrocytes (fibroblastic leukocytes) are recently identified as unique hematopoietic cells with features of both macrophages and fibroblasts. Fibrocytes are known to contribute to the remodeling or fibrosis of various injured tissues. However, their role in viral infection is not fully understood. In this study, we show that differentiated fibrocytes are phenotypically distinguishable from macrophages but can be infected with HIV-1. Importantly, fibrocytes exhibited persistently infected cell-like phenotypes, the degree of which was more apparent than macrophages. The infected fibrocytes produced replication-competent HIV-1, but expressed HIV-1 mRNA at low levels and strongly resisted HIV-1-induced cell death, which enabled them to support an extremely long-term HIV-1 production at low but steady levels. More importantly, our results suggested that fibrocytes were susceptible to HIV-1 regardless of their differentiation state, in contrast to the fact that monocytes become susceptible to HIV-1 after the differentiation into macrophages. Our findings indicate that fibrocytes are the previously unreported HIV-1 host cells, and they suggest the importance of considering fibrocytes as one of the long-lived persistently infected cells for curing HIV-1. PMID- 26416280 TI - ATF3 Is a Key Regulator of Macrophage IFN Responses. AB - Cytokines and IFNs downstream of innate immune pathways are critical for mounting an appropriate immune response to microbial infection. However, the expression of these inflammatory mediators is tightly regulated, as uncontrolled production can result in tissue damage and lead to chronic inflammatory conditions and autoimmune diseases. Activating transcription factor 3 (ATF3) is an important transcriptional modulator that limits the inflammatory response by controlling the expression of a number of cytokines and chemokines. However, its role in modulating IFN responses remains poorly defined. In this study, we demonstrate that ATF3 expression in macrophages is necessary for governing basal IFN-beta expression, as well as the magnitude of IFN-beta cytokine production following activation of innate immune receptors. We found that ATF3 acted as a transcriptional repressor and regulated IFN-beta via direct binding to a previously unidentified specific regulatory site distal to the Ifnb1 promoter. Additionally, we observed that ATF3 itself is a type I IFN-inducible gene, and that ATF3 further modulates the expression of a subset of inflammatory genes downstream of IFN signaling, suggesting it constitutes a key component of an IFN negative feedback loop. Consistent with this, macrophages deficient in Atf3 showed enhanced viral clearance in lymphocytic choriomeningitis virus and vesicular stomatitis virus infection models. Our study therefore demonstrates an important role for ATF3 in modulating IFN responses in macrophages by controlling basal and inducible levels of IFNbeta, as well as the expression of genes downstream of IFN signaling. PMID- 26416282 TI - Engagement of the Aryl Hydrocarbon Receptor in Mycobacterium tuberculosis Infected Macrophages Has Pleiotropic Effects on Innate Immune Signaling. AB - Understanding the mechanisms of host macrophage responses to Mycobacterium tuberculosis is essential for uncovering potential avenues of intervention to boost host resistance to infection. Macrophage transcriptome profiling revealed that M. tuberculosis infection strongly induced the expression of several enzymes controlling tryptophan catabolism. These included IDO1 and tryptophan 2,3 dioxygenase, which catalyze the rate-limiting step in the kynurenine pathway, producing ligands for the aryl hydrocarbon receptor (AHR). The AHR and heterodimeric partners AHR nuclear translocator and RELB are robustly expressed, and AHR and RELB levels increased further during infection. Infection enhanced AHR/AHR nuclear translocator and AHR/RELB DNA binding and stimulated the expression of AHR target genes, including that encoding the inflammatory cytokine IL-1beta. AHR target gene expression was further enhanced by exogenous kynurenine, and exogenous tryptophan, kynurenine, or synthetic agonist indirubin reduced mycobacterial viability. Comparative expression profiling revealed that AHR ablation diminished the expression of numerous genes implicated in innate immune responses, including several cytokines. Notably, AHR depletion reduced the expression of IL23A and IL12B transcripts, which encode subunits of IL-23, a macrophage cytokine that stimulates production of IL-22 by innate lymphoid cells. AHR directly induced IL23A transcription in human and mouse macrophages through near-upstream enhancer regions. Taken together, these findings show that AHR signaling is strongly engaged in M. tuberculosis-infected macrophages and has widespread effects on innate immune responses. Moreover, they reveal a cascade of AHR-driven innate immune signaling, because IL-1beta and IL-23 stimulate T cell subsets producing IL-22, another direct target of AHR transactivation. PMID- 26416281 TI - Effect of IL-7 Therapy on Naive and Memory T Cell Homeostasis in Aged Rhesus Macaques. AB - Aging is associated with gradual deterioration of adaptive immune function, a hallmark of which is the profound loss of naive T cells (TN) associated with decline in thymic output and export of new cells into the peripheral T cell pool. Because the lymphotropic cytokine IL-7 plays crucial roles in both development of TN in the thymus and TN homeostasis in the periphery, we sought to determine the extent to which therapeutic administration of IL-7 could reverse TN deficiency in aging rhesus macaques (RM), either by enhancement of the demonstrably reduced thymopoiesis or by peripheral TN expansion. Our results indicate that treatment of both adult (8-15 y) and old (>20 y) RM with recombinant simian IL-7 (rsIL-7) results in only transient increases in peripheral CD4(+) and CD8(+) TN numbers with no long-term benefit, even with repeated therapy. This transient effect was due to peripheral TN expansion and not enhanced thymic function, and appeared to be limited by induction of IL-7 nonresponsiveness. However, rsIL-7 therapy had a more promising effect on the central memory T cell (TCM) population (both CD4(+) and CD8(+)) in adult and old RM, doubling the numbers of these cells in circulation and maintaining this larger population long term. IL-7 therapy did not reduce TCR diversity of the memory T cell compartment, suggesting that rsIL-7 induced expansion was symmetrical. Thus, although rsIL-7 failed to counter age associated TN loss, the ability of this therapy to expand clonotypically diverse CD4(+) and CD8(+) TCM populations might potentially improve adaptive immune responsiveness in the elderly. PMID- 26416283 TI - Protein Tyrosine Phosphatase SHP-1 Modulates T Cell Responses by Controlling Cbl b Degradation. AB - Previously, we demonstrated that CD28 and CTLA-4 signaling control Casitas-B lineage lymphoma (Cbl)-b protein expression, which is critical for T cell activation and tolerance induction. However, the molecular mechanism(s) of this regulation remains to be elucidated. In this study, we found that Cbl-b fails to undergo tyrosine phosphorylation upon CD3 stimulation because SHP-1 is recruited to and dephosphorylates Cbl-b, whereas CD28 costimulation abrogates this interaction. In support of this finding, T cells lacking SHP-1 display heightened tyrosine phosphorylation and ubiquitination of Cbl-b upon TCR stimulation, which correlates with decreased levels of Cbl-b protein. The aberrant Th2 phenotype observed in T cell-specific Shp1(-/-) mice is reminiscent of heightened Th2 response in Cblb(-/-) mice. Indeed, overexpressing Cbl-b in T cell-specific Shp1( /-) T cells not only inhibits heightened Th2 differentiation in vitro, but also Th2 responses and allergic airway inflammation in vivo. Therefore, SHP-1 regulates Cbl-b-mediated T cell responses by controlling its tyrosine phosphorylation and ubiquitination. PMID- 26416284 TI - Synthesis and Characterization of PLGA Shell Microcapsules Containing Aqueous Cores Prepared by Internal Phase Separation. AB - The preparation of microcapsules consisting of poly(D,L-lactide-co-glycolide) (PLGA) polymer shell and aqueous core is a clear challenge and hence has been rarely addressed in literature. Herein, aqueous core-PLGA shell microcapsules have been prepared by internal phase separation from acetone-water in oil emulsion. The resulting microcapsules exhibited mean particle size of 1.1 +/- 0.39 MUm (PDI = 0.35) with spherical surface morphology and internal poly-nuclear core morphology as indicated by scanning electron microscopy (SEM). The incorporation of water molecules into PLGA microcapsules was confirmed by differential scanning calorimetry (DSC). Aqueous core-PLGA shell microcapsules and the corresponding conventional PLGA microspheres were prepared and loaded with risedronate sodium as a model drug. Interestingly, aqueous core-PLGA shell microcapsules illustrated 2.5-fold increase in drug encapsulation in comparison to the classical PLGA microspheres (i.e., 31.6 vs. 12.7%), while exhibiting sustained release behavior following diffusion-controlled Higuchi model. The reported method could be extrapolated to encapsulate other water soluble drugs and hydrophilic macromolecules into PLGA microcapsules, which should overcome various drawbacks correlated with conventional PLGA microspheres in terms of drug loading and release. PMID- 26416285 TI - High Rates of Diabetes Mellitus, Pre-diabetes and Obesity Among Somali Immigrants and Refugees in Minnesota: A Retrospective Chart Review. AB - We examined the prevalence of cardiovascular risk factors among Somali refugees at a midwestern hospital in the U.S. This was a retrospective cohort study of 1007 adult Somali patients and an age and frequency-matched cohort of non-Somali patients actively empanelled to a large, academic primary care practice network in the Midwest United States between January 1, 2011 and December 31, 2012. Cardiovascular risk factors were obtained by chart review and compared between the two cohorts using a Chi squared test. Median age was 35 years (Q1, Q3; 27, 50). The prevalence of diabetes was significantly higher among Somali versus non Somali patients (12.1 vs 5.3 %; p = 0.0001), as was prediabetes (21.3 vs 17.2 %; p < 0.02) and obesity (34.6 vs 32.1 %; p = 0.047). After adjusting for age, sex, body mass index, education and employment, among the Somali patients, the odds ratio (95 % confidence interval) for diabetes was 2.78 (1.76-4.40) and 1.57 (1.16 2.13) for pre-diabetes. There was a significantly higher prevalence of diabetes, pre-diabetes and obesity among Somali patients compared with non-Somali patients. Further research into the specific causes of these disparities and development of targeted effective and sustainable interventions to address them is needed. PMID- 26416287 TI - Increasing fruit and vegetable intake: where are we at and how do we reach recommendations? PMID- 26416286 TI - A streamlined search technology for identification of synergistic drug combinations. AB - A major key to improvement of cancer therapy is the combination of drugs. Mixing drugs that already exist on the market may offer an attractive alternative. Here we report on a new model-based streamlined feedback system control (s-FSC) method, based on a design of experiment approach, for rapidly finding optimal drug mixtures with minimal experimental effort. We tested combinations in an in vitro assay for the viability of a renal cell adenocarcinoma (RCC) cell line, 786 O. An iterative cycle of in vitro testing and s-FSC analysis was repeated a few times until an optimal low dose combination was reached. Starting with ten drugs that target parallel pathways known to play a role in the development and progression of RCC, we identified the best overall drug combination, being a mixture of four drugs (axitinib, erlotinib, dasatinib and AZD4547) at low doses, inhibiting 90% of cell viability. The removal of AZD4547 from the optimized drug combination resulted in 80% of cell viability inhibition, while still maintaining the synergistic interaction. These optimized drug combinations were significantly more potent than monotherapies of all individual drugs (p < 0.001, CI < 0.3). PMID- 26416288 TI - Factors within the family environment such as parents' dietary habits and fruit and vegetable availability have the greatest influence on fruit and vegetable consumption by Polish children. AB - OBJECTIVE: To identify determinants of fruit and vegetable (F&V) consumption among school-aged children. DESIGN: A survey study was conducted in October 2010. The questionnaire contained questions concerning social and demographic data, lifestyle and dietary habits, particularly the frequency of F&V consumption, availability of F&V and knowledge about recommended amounts of F&V intake. SETTING: Polish primary schools. SUBJECTS: Children (n 1255) aged 9 years from randomly selected primary schools and their parents. RESULTS: The children's consumption of fruit and of vegetables was influenced by the fruit consumption and vegetable consumption of their parents (r=0.333 and r=0.273, respectively; P=0.001), parents encouraging their children to eat F&V (r=0.259 and r=0.271, respectively; P=0.001), giving children F&V to take to school (r=0.338 and r=0.321, respectively; P=0.001) and the availability of F&V at home (r=0.200 and r=0.296, respectively; P=0.001). Parental education influenced only the frequency of fruit consumption (r=0.074; P=0.01). A correlation between parents' knowledge of the recommended intakes and the frequency of vegetable and fruit consumption by children was noticed (r=0.258 and r=0.192, respectively, P=0.001). CONCLUSIONS: Factors within the family environment such as parents' dietary habits and F&V availability had the greatest influence on the F&V consumption by children. Educational activities aimed at parents are crucial to increase the consumption of F&V among children. PMID- 26416289 TI - Assessing the cross-sectional and inter-temporal validity of the Household Food Insecurity Access Scale (HFIAS) in Burundi. AB - OBJECTIVE: To examine the cross-sectional and inter-temporal validity of the Household Food Insecurity Access Scale (HFIAS) for rural households in Burundi. DESIGN: Longitudinal survey about food security and agricultural production, individually administered by trained interviewers in June 2007 and 2012. SETTING: Ngozi, north of Burundi. SUBJECTS: Three hundred and fourteen household heads were interviewed. RESULTS: Tobit models showed that the HFIAS was significantly correlated with objective measures of food security, in this case total annual food production (P<0.01), livestock keeping (P<0.01) and coffee production (P<0.01) in both 2007 and 2012. This confirms that the HFIAS is cross-sectionally valid and corroborates the findings of previous studies. However, while total food production decreased by more than 25 % in terms of energy between 2007 and 2012, households reported an improvement in their perceived food security over the same period, with the HFIAS decreasing from 13.9 to 10.8 (P<0.001). This finding questions the inter-temporal validity of the HFIAS. It may be partly explained through response shifts, in which households assess their own food security status in comparison to that of their peers. CONCLUSIONS: The evidence from our study suggests that the HFIAS is cross-sectionally valid, but may not be inter-temporally valid, and should not be used as a single indicator to study temporal trends in food security. PMID- 26416290 TI - Using nutrient profiling to prevent misleading food marketing. PMID- 26416293 TI - Generalized eczema craquele (asteatotic dermatitis) associated with pemetrexed treatment. PMID- 26416291 TI - Late radiation side effects, cosmetic outcomes and pain in breast cancer patients after breast-conserving surgery and three-dimensional conformal radiotherapy : Risk-modifying factors. AB - BACKGROUND AND PURPOSE: The purpose of this work was to identify parameters influencing the risk of late radiation side effects, fair or poor cosmetic outcomes (COs) and pain in breast cancer patients after breast-conserving therapy (BCT) and three-dimensional conformal radiotherapy (3D-CRT). PATIENTS AND METHODS: Between 2006 and 2013, 159 patients were treated at the Hannover Medical School. Physician-rated toxicity according to the LENT-SOMA criteria, CO and pain were assessed by multivariate analysis. RESULTS: LENT-SOMA grade 1-4 toxicity was observed as follows: fibrosis 10.7 %, telangiectasia 1.2 %, arm oedema 8.8 % and breast oedema 5.0 %. In addition, 15.1 % of patients reported moderate or severe breast pain, and 21.4 % complained about moderate or severe pain in the arm or shoulder. In multivariate analysis, axillary clearing (AC) was significantly associated with lymphoedema of the arm [odds ratio (OR) 4.37, p = 0.011, 95 % confidence interval (CI) 1.4-13.58]. Breast oedema was also highly associated with AC (OR 10.59, p = 0.004, 95 % CI 2.1-53.36), a ptosis grade 2/3 or pseudoptosis and a bra size >= cup C (OR 5.34, p = 0.029, 95 % CI 1.2-24.12). A ptosis grade 2/3 or pseudoptosis and a bra size >= cup C were the parameters significantly associated with an unfavourable CO (OR 3.19, p = 0.019, 95 % CI 1.2 8.4). Concerning chronic breast pain, we found a trend related to the prescribed radiation dose including boost (OR 1.077, p = 0.060, 95 % CI 0.997-1.164). Chronic shoulder or arm pain was statistically significantly associated with lymphoedema of the arm (OR 3.9, p = 0.027, 95 % CI 1.17-13.5). CONCLUSION: Chronic arm and breast oedema were significantly influenced by the extent of surgery (AC). Ptotic and large breasts were significantly associated with unfavourable COs and chronic breast oedema. Late toxicities exclusive breast pain were not associated with radiotherapy parameters. PMID- 26416294 TI - Resistance to Streptomyces turgidiscabies in potato involves an early and sustained transcriptional reprogramming at initial stages of tuber formation. AB - Common scab, caused by species from the bacterial genus Streptomyces, is an important disease of potato (Solanum tuberosum) crops worldwide. Early tuberization is a critical period for pathogen infection; hence, studies of host gene expression responses during this developmental stage can be important to expand our understanding of the infection process and to identify putative resistance genes. In an infection experiment with the highly susceptible potato cultivar Saturna and the relatively resistant cultivar Beate, transcription profiles were obtained by RNA sequencing at two developmental stages: the early hook stage and the early tuber formation stage. Our results indicate that 'Beate' mounts an early and sustained response to infection by S. turgidiscabies, whereas the defence response by 'Saturna' ceases before the early tuber formation stage. Most pronounced were the putative candidate defence-associated genes uniquely expressed in 'Beate'. We observed an increase in alternative splicing on pathogen infection at the early hook stage for both cultivars. A significant down regulation of genes involved in the highly energy-demanding process of ribosome biogenesis was observed for the infected 'Beate' plants at the early hook stage, which may indicate an allocation of resources that favours the expression of defence-related genes. PMID- 26416297 TI - Longitudinal domain wall formation in elongated assemblies of ferromagnetic nanoparticles. AB - Through evaporation of dense colloids of ferromagnetic ~13 nm epsilon-Co particles onto carbon substrates, anisotropic magnetic dipolar interactions can support formation of elongated particle structures with aggregate thicknesses of 100-400 nm and lengths of up to some hundred microns. Lorenz microscopy and electron holography reveal collective magnetic ordering in these structures. However, in contrast to continuous ferromagnetic thin films of comparable dimensions, domain walls appear preferentially as longitudinal, i.e., oriented parallel to the long axis of the nanoparticle assemblies. We explain this unusual domain structure as the result of dipolar interactions and shape anisotropy, in the absence of inter-particle exchange coupling. PMID- 26416295 TI - Meta-analysis of risk factors for nonsuicidal self-injury. AB - Nonsuicidal self-injury (NSSI) is a prevalent and dangerous phenomenon associated with many negative outcomes, including future suicidal behaviors. Research on these behaviors has primarily focused on correlates; however, an emerging body of research has focused on NSSI risk factors. To provide a summary of current knowledge about NSSI risk factors, we conducted a meta-analysis of published, prospective studies longitudinally predicting NSSI. This included 20 published reports across 5078 unique participants. Results from a random-effects model demonstrated significant, albeit weak, overall prediction of NSSI (OR=1.59; 95% CI: 1.50 to 1.69). Among specific NSSI risk factors, prior history of NSSI, cluster b, and hopelessness yielded the strongest effects (ORs>3.0); all remaining risk factor categories produced ORs near or below 2.0. NSSI measurement, sample type, sample age, and prediction case measurement type (i.e., binary versus continuous) moderated these effects. Additionally, results highlighted several limitations of the existing literature, including idiosyncratic NSSI measurement and few studies among samples with NSSI histories. These findings indicate that few strong NSSI risk factors have been identified, and suggest a need for examination of novel risk factors, standardized NSSI measurement, and study samples with a history of NSSI. PMID- 26416298 TI - Dynamic blood flow to the retrograde limb of the internal mammary vein in breast reconstruction with free flap. AB - BACKGROUND: In free flap breast reconstruction, the retrograde limb of the internal mammary vein (IMV) is occasionally used as a second recipient vein. In this study, we evaluated the dynamic blood flow to the retrograde limb of the IMV (retrograde IMV) at the anastomosed site via indocyanine green (ICG) angiography METHODS: In 40 patients undergoing free flap breast reconstruction, we evaluated the dynamic blood flow as "stain(+)" if a stain by ICG was observed and, "flow(+)" if a smooth blood flow was recognized. RESULTS: Based on the ICG angiography, "stain(+)" was observed in all cases, but "flow(+)" was detected in only 72.5% of the cases. There was no severe complication. CONCLUSION: This study shows that thrombosis is prone to occur in the second recipient vein in the 27.5% of the cases with no smooth flow, and therefore, the retrograde IMV may not function as a back-up in these cases. PMID- 26416299 TI - Structure and Activity Changes of Phytohemagglutinin from Red Kidney Bean (Phaseolus vulgaris) Affected by Ultrahigh-Pressure Treatments. AB - Phytohemagglutin (PHA), purified from red kidney beans (Phaseolus vulgaris) by Affi-Gel blue affinity chromatography, was subjected to ultrahigh-pressure (UHP) treatment (150, 250, 350, and 450 MPa). The purified PHA lost its hemagglutination activity after 450 MPa treatment and showed less pressure tolerance than crude PHA. However, the saccharide specificity and alpha glucosidase inhibition activity of the purified PHA did not change much after UHP treatment. Electrophoresis staining by periodic acid-Schiff (PAS) manifested that the glycone structure of purified PHA remained stable even after 450 MPa pressure treatment. However, electrophoresis staining by Coomassie Blue as well as circular dichroism (CD) and differential scanning calorimetry (DSC) assay proved that the protein unit structure of purified PHA unfolded when treated at 0-250 MPa but reaggregates at 250-450 MPa. Therefore, the hemagglutination activity tends to be affected by the protein unit structure, while the stability of the glycone structure contributed to the remaining alpha-glucosidase inhibition activity. PMID- 26416300 TI - Recent progress for the synthesis of selected carbocyclic nucleosides. AB - Nucleoside analogs are extremely useful for the development of therapeutic agents to control viral diseases and cancer. Among the numerous modifications on the nucleoside skeleton, replacement of the oxygen of the furanose ring by a CH2 group resulted in increased flexibility and higher resistance to phosphorylases and led to carbocyclic nucleoside analogs (or carbanucleosides). The broad spectrum of biological activities of carbocyclic nucleosides led to tremendous research interest in their syntheses. The article documents recent strategies for the synthesis of active carbocyclic nucleosides by presenting individual case studies, such as the neplanocins, entecavir and selected fluorinated carbocyclic nucleosides. Furthermore, it provides new insights into new directions for more potent and active carbocyclic nucleoside analogs. PMID- 26416301 TI - Bronchioalveolar morphogenesis of human bronchial epithelial cells depending upon hepatocyte growth factor. AB - Lung alveolar regeneration occurs in adult human lungs as a result of proliferation, differentiation and alveolar morphogenesis of stem cells. It is increasingly being believed that bronchial epithelial cells (BECs) have a potential as stem cells, because they are potent to differentiate into multiple central and peripheral lung cell types in three-dimensional (3D) cultures, and they develop multiple foci with well-differentiated histogenesis after transformed into neoplastic cells. In this study, we investigated morphogenic abilities of HBE135 human BECs immortalized by E6/E7 oncogene in 3D cultures. When HBE135 cells were cultured alone or co-cultured with endothelial cells, the cells formed spherical colonies without branching. However, in co-culture with lung fibroblast MRC-9 cells, HBE135 cells formed colonies with bronchioalveolar like complex branching, suggesting that MRC-9-derived soluble factor(s) are responsible for the branching formation. MRC-9 cells, not endothelial cells, were found to highly express hepatocyte growth factor (HGF), a soluble molecule involved in liver and kidney regeneration. An anti-HGF neutralizing antibody severely suppressed the complex branching formation, but addition of HGF could not sufficiently compensate the morphogenic effects of MRC-9 cells, suggesting that MCR-9-derived HGF was necessary but insufficient for the bronchioalveolar structure formation. Immunohistochemistry revealed that Met, a cognate receptor for HGF, was highly expressed and phosphorylated in neoplastic BECs from lung adenocarcinomas with well-differentiated, not poorly differentiated, histogenesis. These results are consistent with the notion that BECs have an aspect of stem cells. This aspect appears to become manifest through HGF-Met signalling pathway activation. PMID- 26416302 TI - Education and training for implementation science: our interest in manuscripts describing education and training materials. AB - Alongside the growth in interest in implementation science, there has been a marked increase in training programs, educational courses, degrees, and other offerings in implementation research and practice to meet the demand for this expertise. We believe that the science of capacity building has matured but that we can advance it further by shining light on excellent work in this area and by highlighting gaps for future research. At Implementation Science, we regularly receive manuscripts that describe or evaluate training materials, competencies, and competency development in implementation curricula. We are announcing a renewed interest in manuscripts in this area, with specifications described below. PMID- 26416303 TI - Can pretreatment serum calcium level predict the efficacy of methotrexate in the treatment of severe plaque psoriasis? AB - BACKGROUND: The efficacy of methotrexate (MTX) varies in the treatment of psoriasis. OBJECTIVE: We sought to identify an indicator from routine pretreatment tests to predict MTX efficacy in the treatment of psoriasis. METHODS: In a retrospective analysis of 77 psoriatic patients, the correlation between MTX efficacy and pretreatment routine test results was analyzed with Spearman correlation. The potential risks were further evaluated with a linear regression model. Receiver operating characteristic analysis was performed to examine the effectiveness of serum total calcium (tCa) to predict the effect of MTX on psoriasis. The highest Youden index was used to determine the cutoff point, with which the positive and negative predictive values were calculated. Synergistic effects of MTX and calcium on keratinocyte growth and psoriasis-like mouse model were also investigated. RESULTS: The pretreatment tCa level exhibited the closest association with MTX efficacy. The relative psoriasis improvement with tCa was 61.07% (95% confidence interval, 42.85-79.29; P < .001) and better improvements were observed in patients with higher tCa (r = 0.588; P < .002). MTX inhibited keratinocyte growth, which was enhanced synergistically by calcium. In a psoriasis-like mouse model, MTX strongly inhibited epidermis proliferation in the high-calcium group. LIMITATIONS: One limitation of our study is the relatively small sample size. CONCLUSION: Pretreatment tCa level has the highest correlation with MTX efficacy, which might be useful in predicting beneficial treatment results in psoriasis. Larger studies are required to confirm our findings. PMID- 26416305 TI - Epidemiology of uraemic itch: New data. AB - Chronic itch (CI) is a frequent and impairing symptom in haemodialysis (HD) patients. Within the last decades, worldwide variations were reported in the prevalence of itch in HD patients, ranging from 10 to 77%. Regional differences and especially the irregular pattern of itch in HD may explain why CI is still not well perceived and underestimated in HD patients. The pathogenesis is still unclear and therapy is ineffective in the majority of cases. There is a great diversity of prevalence estimates of itch used in different studies as well, as the study population greatly differs, especially when investigating CI in HD. Due to the demographic situation with a rising number of aged patients and increasing survival rates in HD, the number of HD patients will continuously grow, especially in the Western countries. Up to now, representative epidemiological data on CI in HD were missing. GEHIS (German Epidemiological Hemodialysis Itch Study) was established in 2012 as a representative prospective cross-sectional study. Eight hundred and sixty HD patients from a randomly selected cluster sample were included. The primary outcome measures were different prevalence measures of CI. The point prevalence was 25.2%, the 12-month prevalence was 27.2% and the lifetime prevalence of CI was 35.2%. General health status and health related quality of life (HRQOl) were significantly impaired in those with CI. Due to the comparability of standards in HD quality, these results can be transferred to Western countries. This study demonstrates that CI is a frequent, long-lasting burden in HD patients affecting every fourth HD patient (point prevalence) and more than every third HD patient at some point in their lifetime. PMID- 26416304 TI - Associations between the prevalence of influenza vaccination and patient's knowledge about antibiotics: a cross-sectional study in the framework of the APRES-project in Austria. AB - BACKGROUND: This study aimed to identify associations between GP patient's knowledge about the spectrum of effectiveness of antibiotics and the probability of vaccination against influenza. The underlying hypothesis was that individuals with an understanding that antibiotics are ineffective against viruses, common colds, and flu were more likely to be vaccinated than persons lacking this knowledge. METHODS: This cross-sectional study was conducted within the context of the European APRES project in Austria. Between November 2010 and July 2011, patients were recruited from GP practices to complete questionnaires about their knowledge about antibiotics and their influenza vaccination status. Statistical analyses included subgroup analyses and logistic regression models. RESULTS: Data of 3224 patients was analyzed, demonstrating that patients with better knowledge concerning antibiotics had a significantly higher likelihood of being vaccinated (OR 1.35, CI 95 % 1.18-1.54). While the overall vaccination rate was low (18.6 % in 2009/2010 and 14.0 % in 2010/2011), elderly compared to younger adults (OR 0.06 CI 95 % 0.03-0.13) and healthcare workers (OR 2.24, CI 95 % 1.42-3.54) demonstrated higher likelihood of vaccination. Additionally, female GPs had significantly more vaccinated patients than male GPs (OR 2.90, CI 95 % 1.32 6.40). DISCUSSION: There has been little prior study on the association between a patient's knowledge of the effectiveness spectrum of antibiotics and influenza vaccination status. Given the public health imperative to increase annual prevalence of influenza vaccination, understanding this educational gap can improve specificity in counseling as well as vaccination rates. Ultimately, we found that those with a better knowledge on about antibiotics had a significantly higher likelihood of being vaccinated. CONCLUSIONS: The results of this study demonstrate that vaccination prevalence is associated with patient's knowledge about antibiotics. It can be concluded that one strategy to improve the overall low vaccination rates for seasonal influenza in Austria would be, particularly for male GPs, to have a specific discussion with patients about these circumstances by focusing on younger patients. Further, public health efforts could supplement in-office strategies to improve this area of health literacy. PMID- 26416306 TI - Periodontal-disease-associated biofilm: A reservoir for pathogens of medical importance. AB - The ecological diversity of the periodontal microenvironment may provide suitable conditions for the colonization of species not usually considered members of the oral microbiota. In this investigation, we aimed to determine the prevalence and levels of pathogenic species of medical relevance in the microbiota of individuals with distinct periodontal clinical status. Subgingival biofilm was obtained from patients with periodontal health (H, n = 81), gingivitis (G, n = 55), generalized aggressive (AgP, n = 36) or chronic periodontitis (CP, n = 98), and analyzed for 39 microbial taxa using a checkerboard DNA-DNA hybridization technique. Microbial differences among groups, as well as associations between clinical and microbiological parameters were sought by non-parametric and univariate correlation tests. Neisseria spp., Peptostreptococus anaerobius, Candida albicans, enterobacteria, Pseudomonas aeruginosa, Eubacterium saphenum, Clostridium difficile and Olsenella uli were detected in high mean prevalence and counts in the subgingival microbiota of the study population. Species that were more related to periodontal inflammation and tissue destruction at the patient and site levels included enterobacteria, C. albicans, Neisseria spp., P. aeruginosa, O. uli, Hafnia alvei, Serratia marcescens and Filifactor alocis (p < 0.05). In contrast, Fusobacterium necrophorum, Lactobacillus acidophilus, Staphylococcus aureus and Streptococcus pneumoniae were associated with periodontal health (p < 0.05). Pathogenic species of medical importance may be detected in high prevalence and levels in the periodontal microbiota. Regardless of their role in periodontal health or disease, the periodontal biofilm may be a source for dissemination and development of systemic infections by these pathogenic microorganisms. PMID- 26416307 TI - Host antioxidant enzymes and TLR-2 neutralization modulate intracellular survival of Staphylococcus aureus: Evidence of the effect of redox balance on host pathogen relationship during acute staphylococcal infection. AB - Staphylococcus aureus is an important pathogen in bone disease and innate immune recognition receptor, TLR-2 is reported to be crucial for inflammatory bone loss. Role of TLR-2 in bacterial clearance and cytokine response to S. aureus infection in murine bone marrow macrophages has been reported but the role of host derived ROS in host-pathogen relationship still remains an obvious question. In the present study, blocking of SOD and catalase in TLR-2 neutralized fresh bone marrow cells (FBMC) with Diethyldithiocarbamic acid (DDC) and 3-Amino-1,2,4 triazole (ATZ), separately, during acute S. aureus infection, produces moderate level of ROS and limits inflammation as compared with only TLR-2 non-neutralized condition and leads to decreased bacterial count compared with only TLR-2 neutralized condition. In summary, host SOD and catalase modulates ROS generation, cytokine levels and TLR-2 expression in FBMCs during acute S. aureus infection which might be useful in the alleviation of S. aureus infection and bone loss. PMID- 26416308 TI - Qualitative and quantitative pharmacophore-similarity assessment of anthranilamide-based factor Xa inhibitors: applications on similar molecules with identical biological endpoints. AB - It is a conventional practice to exclude molecules with identical biological endpoints to avoid bias in the resulting hypothesis model. Despite the diverse chemical functionalities, the receptor interactions of such molecules are often unexplored. The present study motivates the selection of these molecules diversified by single atom or functional group compared to internal molecules as external set and helps in the understanding of corresponding effects toward receptor interactions and biological endpoints. Applied on anthranilamide-series of factor Xa analogs, the inhibitory activities were correlated (r(2) = 0.99) and validated (q(2) = 0.68) with distance-based pharmacophore descriptors using support vector machine. The selected external set molecules exhibited better prediction accuracy by securing activities less than one residual threshold. The effect on inhibitory activity was assessed by the examination of pharmacophore similarity and its interactions with key residues of Human factor Xa enzyme using molecular docking approach. Furthermore, qualitative pharmacophore models were developed on the subset of molecular dataset divided as most actives, moderately actives and least actives, to recognize crucial activity governing pharmacophore features. The outcome of this study will bring new insights about the requirements of pharmacophore features and prioritizes its selection in the design and optimization of potent Xa inhibitors. PMID- 26416309 TI - Gene expression: Environmental noise control. PMID- 26416310 TI - Epigenetics: Bad Karma reduces palm oil yields. PMID- 26416313 TI - Effects of composition modulation on the luminescence properties of Eu(3+) doped Li1-xAgxLu(MoO4)2 solid-solution phosphors. AB - Double molybdate scheelite-type solid-solution phosphors Li1-xAgxLu1 y(MoO4)2:yEu(3+) were synthesized by the solid state reaction method, and their crystal structures and luminescence properties were investigated in detail. The composition modulation and structural evolution of this series of samples were studied and the selected AgEu(MoO4)2, AgLu(MoO4)2, LiLu(MoO4)2 and LiEu(MoO4)2 phases were analyzed based on the Rietveld refinement. Depending on the variation of the Li/Ag ratio in Li1-xAgxLu1-y(MoO4)2:yEu(3+) phosphors, the difference in the luminescence properties of Li1-xAgxLu1-y(MoO4)2:yEu(3+) phosphors was ascribed to two factors, one reason could be assigned to the coupling effect and the nonradiative transition between the energy levels of LixAg1-xLu(MoO4)2 matrices and the activator Eu(3+), another could be due to the near ultraviolet energy absorption and transmission efficiency between the charge-transfer (CT) band of O(2-)-Mo(6+) and the 4f -> 4f emissive transitions of Eu(3+). The ultraviolet-visible diffuse reflection spectra (UV-vis DRS) and Raman spectra analysis were also used to verify the above mechanism. PMID- 26416311 TI - Molecular insights into transgenerational non-genetic inheritance of acquired behaviours. AB - Behavioural traits in mammals are influenced by environmental factors, which can interact with the genome and modulate its activity by complex molecular interplay. Environmental experiences can modify social, emotional and cognitive behaviours during an individual's lifetime, and result in acquired behavioural traits that can be transmitted to subsequent generations. This Review discusses the concept of, and experimental support for, non-genetic transgenerational inheritance of acquired traits involving the germ line in mammals. Possible mechanisms of induction and maintenance during development and adulthood are considered along with an interpretation of recent findings showing the involvement of epigenetic modifications and non-coding RNAs in male germ cells. PMID- 26416312 TI - Multi-modality image-based computational analysis of haemodynamics in aortic dissection. AB - Aortic dissection is a disease whereby an injury in the wall of the aorta leads to the creation of a true lumen and a false lumen separated by an intimal flap which may contain multiple communicating tears between the lumina. It has a high associated morbidity and mortality, but at present, the timing of surgical intervention for stable type B dissections remains an area of debate. Detailed knowledge of haemodynamics may yield greater insight into the long-term outcomes for dissection patients by providing a greater understanding of pressures, wall shear stress and velocities in and around the dissection. In this paper, we aim to gather further insight into the complex haemodynamics in aortic dissection using medical imaging and computational fluid dynamics modelling. Towards this end, several computer models of the aorta of a patient presenting with an acute Stanford type B dissection were created whereby morphometric parameters related to the dissection septum were altered, such as removal of the septum, and the variation of the number of connecting tears between the lumina. Patient-specific flow data acquired using 2D PC-MRI in the ascending aorta were used to set the inflow boundary condition. Coupled zero-dimensional (Windkessel) models representing the distal vasculature were used to define the outlet boundary conditions and tuned to match 2D PC-MRI flow data acquired in the descending aorta. Haemodynamics in the dissected aorta were compared to those in an equivalent 'healthy aorta', created by virtually removing the intimal flap (septum). Local regions of increased velocity, pressure, wall shear stress and alterations in flow distribution were noted, particularly in the narrow true lumen and around the primary entry tear. The computed flow patterns compared favourably with those obtained using 4D PC-MRI. A lumped-parameter heart model was subsequently used to show that in this case there was an estimated 14 % increase in left ventricular stroke work with the onset of dissection. Finally, the effect of secondary connecting tears (i.e. those excluding the primary entry and exit tears) was also studied, revealing significant haemodynamic changes when no secondary tears are included in the model, particularly in the true lumen where increases in flow over [Formula: see text] and drops in peak pressure of 18 % were observed. PMID- 26416314 TI - History note: tragedy of Thorotrast. PMID- 26416315 TI - Evaluation of a school screening programme for young people from refugee backgrounds. AB - AIM: To describe the development of the Optimising Health and Learning Program, guided by the only available published framework for the delivery of health services to newly arrived refugee children and report on the evaluation of the programme. METHODS: We conducted process and impact evaluation using a mixed methods approach. The sample was 294 refugee young people enrolled in two Intensive English Centres in New South Wales. We collected quantitative data (demographic and clinical information) as well as qualitative data via focus groups, key informant interviews, surveys and programme documentation. Qualitative data were subjected to thematic analysis; programme documents underwent document review. RESULTS: There were high levels of programme participation (90%), and the yield from routine health screening was high (80% of participants screened positive for two or more health conditions). All identified programme development strategies were implemented; programme partners and participants reported satisfaction with the programme. Sixteen programme partners were identified with a high level of intersectoral collaboration reported. Significant in-kind contributions and seed funding enabled the uptake of the programme to increase from one to five Intensive English Centres over a 4-year period. CONCLUSION: Process and impact evaluation identified that the programme was well implemented and met its stated objectives of increasing the detection of health conditions likely to impact on student health and learning; linkage of newly arrived students and their families with primary health care; and coordination of care across primary health and specialist services. PMID- 26416316 TI - Direct infection of primary endothelial cells with human cytomegalovirus prevents angiogenesis and migration. AB - Human cytomegalovirus (hCMV) is a beta herpesvirus that establishes lifelong infection. Although the virus does not usually cause overt clinical symptoms in immunocompetent individuals it can have deleterious effects in immunocompromised patients, such as those on post-transplant medication or with HIV infection. hCMV is the most common congenital infection and can lead to serious fetal sequelae. Endothelial cells (ECs) are natural hosts for hCMV in vivo, therefore, investigations of how this cell type is modulated by infection are key to understanding hCMV pathogenesis. Previous studies have examined the effect of secretomes from hCMV-infected cells on EC angiogenesis, whereas the effect of direct infection on this process has not been so well investigated. Here, we show that placental ECs are viral targets during congenital infection and that vessels in infected tissue appear morphologically abnormal. We demonstrate that the clinical hCMV strain VR1814 impaired EC tube assembly in in vitro angiogenesis assays and inhibited wound healing ability in scratch assays. Secretomes from infected cultures did not impair angiogenesis of uninfected ECs, suggesting that cell-intrinsic changes, as opposed to secreted factors, were responsible. We observed viral gene transcription dependent downregulation of the expression of angiogenesis-associated genes, including angiopoietin-2, TEK receptor and vascular endothelial growth factor receptors. An alternative clinical hCMV stain, TB40E showed similar effects on EC angiogenesis. Together, our data indicate that direct infection with hCMV can induce an anti-migratory and anti-angiogenic EC phenotype, which could have a detrimental effect on the vasculature development in infected tissues. PMID- 26416317 TI - Distribution and immunotoxicity by intravenous injection of iron nanoparticles in a murine model. AB - With the increased application of iron oxide nanoparticles (FeNPs) for biomedical imaging purposes, concerns regarding the onset of the unexpected adverse health effects following exposure have been rapidly raised. In this study, we investigated the tissue distribution and immunotoxicity of FeNPs (2 and 4 mg kg( 1)) over time (2, 4 and 13 weeks) after single intravenous injection. At 13 weeks after a single injection, the iron levels increased in all measured tissues compared to the control, and iron accumulation was notable in the liver, spleen and thymus. These changes were accompanied by changes in levels of redox reaction related elements, including copper, manganese, zinc and cobalt. In addition, as compared to the control, the number of white blood cells and percentage of neutrophils significantly increased in the treated groups, and the interleukin-8 secretion and lactate dehydrogenase release were clearly elevated in the treated groups along with enhanced expressions of chemotaxis-related proteins. However, expression of antigen presenting related proteins attenuated following accumulation of FeNPs. Taken together, we suggest that FeNPs may primarily induce toxicity in the liver and immune system, and immunotoxicological evaluation should be considered to predict adverse health effects following exposure to NPs. PMID- 26416318 TI - Microdemographic Determinants of Population Recovery among the Northern Ache. AB - A pattern of population crash and rapid recovery is a common feature of the pacification and settlement experience of the indigenous peoples of tropical South America. Despite the obvious importance of these events to the demographic and anthropological sciences as a whole, as well as their significant practical implications, little is known about the microdemographic determinants of these paired phenomena. Using methods of asymptotic and stochastic demographic analysis, we reconstructed the microdemographic drivers of this history among one indigenous population: the Northern Ache of eastern Paraguay. This article explores the implications of these relationships for understanding the overall demographic turnaround observed within similar groups, as well as for the future trajectory of the Northern Ache in particular. PMID- 26416319 TI - Mitochondrial DNA Suggests a Western Eurasian Origin for Ancient (Proto-) Bulgarians. AB - Ancient (proto-) Bulgarians have long been thought of as a Turkic population. However, evidence found in the past three decades shows that this is not the case. Until now, this evidence has not included ancient mitochondrial DNA (mtDNA) analysis. To fill this void, we collected human remains from the 8th to the 10th century AD located in three necropolises in Bulgaria: Nojarevo (Silistra region) and Monastery of Mostich (Shumen region), both in northeastern Bulgaria, and Tuhovishte (Satovcha region) in southwestern Bulgaria. The phylogenetic analysis of 13 ancient DNA samples (extracted from teeth) identified 12 independent haplotypes, which we further classified into mtDNA haplogroups found in present day European and western Eurasian populations. Our results suggest a western Eurasian matrilineal origin for proto-Bulgarians, as well as a genetic similarity between proto- and modern Bulgarians. Our future work will provide additional data that will further clarify proto-Bulgarian origins, thereby adding new clues to the current understanding of European genetic evolution. PMID- 26416320 TI - Identification of Whole Mitochondrial Genomes from Venezuela and Implications on Regional Phylogenies in South America. AB - Recent studies have expanded and refined the founding haplogroups of the Americas using whole mitochondrial (mtDNA) genome analysis. In addition to pan-American lineages, specific variants have been identified in a number of studies that show higher frequencies in restricted geographical areas. To further characterize Native American maternal lineages and specifically examine local patterns within South America, we analyzed 12 maternally unrelated Yekuana whole mtDNA genomes from one village (Sharamana) that include the four major Native American haplogroups A2, B2, C1, and D1. Based on our results, we propose a reconfiguration of one subhaplogroup A2 (A2aa) that is specific to South America and identify other singleton branches across the four haplogroups. Furthermore, we show nucleotide diversity values that increase from north to south for haplogroups C1 and D1. The results from our work add to the growing mitogenomic data that highlight local phylogenies and support the rapid genetic differentiation of South American populations, which has been correlated with the linguistic diversity in the region by previous studies. PMID- 26416321 TI - Hemochromatosis: Niche Construction and the Genetic Domino Effect in the European Neolithic. AB - Hereditary hemochromatosis is caused by a potentially lethal recessive gene (HFE, C282Y allele) that increases iron absorption and reaches polymorphic levels in northern European populations. Because persons carrying the allele absorb iron more readily than do noncarriers, it has often been suggested that HFE is an adaptation to anemia. We hypothesize positive selection for HFE began during or after the European Neolithic with the adoption of an iron-deficient high-grain and dairying diet and consequent anemia, a finding confirmed in Neolithic and later European skeletons. HFE frequency compared with rate of lactase persistence in Eurasia yields a positive linear correlation coefficient of 0.86. We suggest this is just one of many mutations that became common after the adoption of agriculture. PMID- 26416322 TI - Genetic Admixture and Flavor Preferences: Androstenone Sensitivity in Malagasy Populations. AB - The genetic basis of androstenone anosmia has been well studied due to androstenone's putative role as a human sex pheromone and its presence in pork meat. Polymorphisms have been identified on the olfactory receptor gene OR7D4, which significantly affect perception of androstenone pleasantness and intensity in several Western populations. This study aims to investigate androstenone sensitivity and the influence of OR7D4 polymorphisms in non-Western populations. Androstenone perception was tested in 132 individuals from Madagascar using a double three-alternative choice test with two concentrations of androstenone (0.17 and 1.7 ug/ml). We found that Malagasy populations described this molecule in a similar way to European populations, and 21% of the sample was not able to smell androstenone. In contrast to previous studies, there was no significant evidence of the influence of rs61729907: C>T (R88W) and rs5020278: C>T polymorphisms (T133M) on androstenone sensitivity in Malagasy populations. We found, however, a significant effect of the polymorphism rs61732668 (P79L) and a significant difference in androstenone perception between populations in different locations across Madagascar. This study indicates the existence of population-specific factors in androstenone sensitivity, suggesting that population history has a role in shaping an individual's smell and flavor preferences and food preferences in general. PMID- 26416323 TI - Low Mitochondrial DNA Diversity in an Ancient Population from China: Insight into Social Organization at the Fujia Site. AB - To gain insight into the social organization of a population associated with the Dawenkou period, we performed ancient DNA analysis of 18 individuals from human remains from the Fujia site in Shandong Province, China. Directly radiocarbon dated to 4800-4500 cal BP, the Fujia site is assumed to be associated with a transitional phase from matrilineal clans to patrilineal monogamous families. Our results reveal a low mitochondrial DNA diversity from the site and population. Combined with Y chromosome data, the pattern observed at the Fujia site is most consistent with a matrilineal community. The patterns also suggest that the bond of marriage was de-emphasized compared with the bonds of descent at Fujia. PMID- 26416325 TI - Supraesophageal reflux disease: solving a riddle wrapped in a mystery inside an enigma. PMID- 26416326 TI - Family history of colorectal cancer: it is time to rethink screening recommendations. PMID- 26416328 TI - Interaction between amiodarone and sofosbuvir-based treatment for hepatitis C virus infection: potential mechanisms and lessons to be learned. PMID- 26416327 TI - Interferon-gamma and Tumor Necrosis Factor-alpha Produced by T Cells Reduce the HBV Persistence Form, cccDNA, Without Cytolysis. AB - BACKGROUND & AIMS: Viral clearance involves immune cell cytolysis of infected cells. However, studies of hepatitis B virus (HBV) infection in chimpanzees have indicated that cytokines released by T cells also can promote viral clearance via noncytolytic processes. We investigated the noncytolytic mechanisms by which T cells eliminate HBV from infected hepatocytes. METHODS: We performed a cytokine enzyme-linked immunosorbent assay of serum samples from patients with acute and chronic hepatitis B. Liver biopsy specimens were analyzed by in situ hybridization. HepG2-H1.3 cells, HBV-infected HepaRG cells, and primary human hepatocytes were incubated with interferon-gamma (IFNgamma) or tumor necrosis factor-alpha (TNF-alpha), or co-cultured with T cells. We measured markers of HBV replication, including the covalently closed circular DNA (cccDNA). RESULTS: Levels of IFNgamma and TNF-alpha were increased in serum samples from patients with acute vs chronic hepatitis B and controls. In human hepatocytes with stably replicating HBV, as well as in HBV-infected primary human hepatocytes or HepaRG cells, IFNgamma and TNF-alpha each induced deamination of cccDNA and interfered with its stability; their effects were additive. HBV-specific T cells, through secretion of IFNgamma and TNF-alpha, inhibited HBV replication and reduced cccDNA in infected cells without the direct contact required for cytolysis. Blocking IFNgamma and TNF-alpha after T-cell stimulation prevented the loss of cccDNA. Deprivation of cccDNA required activation of nuclear APOBEC3 deaminases by the cytokines. In liver biopsy specimens from patients with acute hepatitis B, but not chronic hepatitis B or controls, hepatocytes expressed APOBEC3A and APOBEC3B. CONCLUSIONS: IFNgamma and TNF-alpha, produced by T cells, reduce levels of HBV cccDNA in hepatocytes by inducing deamination and subsequent cccDNA decay. PMID- 26416329 TI - Therapy with direct-acting antivirals for genotype 3 patients: interferon's last gasp? PMID- 26416330 TI - Diagnosing minimal hepatic encephalopathy: from the ivory tower to the real world. PMID- 26416331 TI - Deciphering the genetic code of gastrointestinal diseases among African Americans. PMID- 26416332 TI - Generation and flow cytometric quality control of clinical-scale TCRalphabeta/CD19-depleted grafts. AB - BACKGROUND: The depletion of TCRalphabeta+ T cells and CD19+ B cells is a graft purification method for haploidentical stem cell transplantation (HSCT) retaining stem cells, NK cells and TCRgammadelta+ T cells. To avoid treatment-related occurrence of severe GvHD a precise quantification of residual TCRalphabeta+ T cells in the graft is of essential importance. METHODS: Nine stem cell grafts were purified immunomagnetically on a CliniMACS device and flow cytometric quality control (QC) was performed before and after TCRalphabeta/CD19-depletion. RESULTS: As a challenge a new 10-color QC-panel was established, which enables accurate quantification of the graft composition. The binding sites of residual TCRalphabeta+ T and CD19+ B cells were at least partly occupied by depletion antibodies impeding flow cytometric analysis. Based on respective controls and an assumed variation coefficient of 18%, the detection limit of residual TCRalphabeta T cells was 1 cell/ul. and 0.002% of CD45+ cells. Log-depletion of TCRalphabeta and CD19 cells was -3.9 and -3.3, respectively. The recovery was 82.1%, 67.1% and 72.7% for stem cells, NK cells and for TCRgammadelta+ T cells. CONCLUSIONS: In clinical use this method may help to improve transplantation outcome, due to the correct application of the desired stem cell and the limited T cell dose. The panel is designed for the QC following TCRalphabeta/CD19 depletion but is adaptable to other depletion strategies as well. (c) 2015 International Clinical Cytometry Society. PMID- 26416333 TI - Identification of an iridium(III) complex with anti-bacterial and anti-cancer activity. AB - Group 9 transition metal complexes have been widely explored as therapeutic agents due to their unique geometry, their propensity to undergo ligand exchanges with biomolecules and their diverse steric and electronic properties. These metal complexes can offer distinct modes of action in living organisms compared to carbon-based molecules. In this study, we investigated the antimicrobial and anti proliferative abilities of a series of cyclometallated iridium(III) complexes. The iridium(III) complex 1 inhibited the growth of S. aureus with MIC and MBC values of 3.60 and 7.19 MUM, respectively, indicating its potent bactericidal activity. Moreover, complex 1 also exhibited cytotoxicity against a number of cancer cell lines, with particular potency against ovarian, cervical and melanoma cells. This cyclometallated iridium(III) complex is the first example of a substitutionally-inert, Group 9 organometallic compound utilized as a direct and selective inhibitor of S. aureus. PMID- 26416334 TI - The Incremental Effects of Manual Therapy or Booster Sessions in Addition to Exercise Therapy for Knee Osteoarthritis: A Randomized Clinical Trial. AB - STUDY DESIGN: A factorial randomized controlled trial. OBJECTIVES: To investigate the addition of manual therapy to exercise therapy for the reduction of pain and increase of physical function in people with knee osteoarthritis (OA), and whether "booster sessions" compared to consecutive sessions may improve outcomes. BACKGROUND: The benefits of providing manual therapy in addition to exercise therapy, or of distributing treatment sessions over time using periodic booster sessions, in people with knee OA are not well established. METHODS: All participants had knee OA and were provided 12 sessions of multimodal exercise therapy supervised by a physical therapist. Participants were randomly allocated to 1 of 4 groups: exercise therapy in consecutive sessions, exercise therapy distributed over a year using booster sessions, exercise therapy plus manual therapy without booster sessions, and exercise therapy plus manual therapy with booster sessions. The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC score; 0-240 scale) at 1-year follow-up. Secondary outcome measures were the numeric pain-rating scale and physical performance tests. RESULTS: Of 75 participants recruited, 66 (88%) were retained at 1-year follow-up. Factorial analysis of covariance of the main effects showed significant benefit from booster sessions (P = .009) and manual therapy (P = .023) over exercise therapy alone. Group analysis showed that exercise therapy with booster sessions (WOMAC score, -46.0 points; 95% confidence interval [CI]: -80.0, -12.0) and exercise therapy plus manual therapy (WOMAC score, -37.5 points; 95% CI: -69.7, -5.5) had superior effects compared with exercise therapy alone. The combined strategy of exercise therapy plus manual therapy with booster sessions was not superior to exercise therapy alone. CONCLUSION: Distributing 12 sessions of exercise therapy over a year in the form of booster sessions was more effective than providing 12 consecutive exercise therapy sessions. Providing manual therapy in addition to exercise therapy improved treatment effectiveness compared to providing 12 consecutive exercise therapy sessions alone. Trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000460808). PMID- 26416335 TI - Mirror Symmetry Breaking by Chirality Synchronisation in Liquids and Liquid Crystals of Achiral Molecules. AB - Spontaneous mirror symmetry breaking is an efficient way to obtain homogeneously chiral agents, pharmaceutical ingredients and materials. It is also in the focus of the discussion around the emergence of uniform chirality in biological systems. Tremendous progress has been made by symmetry breaking during crystallisation from supercooled melts or supersaturates solutions and by self assembly on solid surfaces and in other highly ordered structures. However, recent observations of spontaneous mirror symmetry breaking in liquids and liquid crystals indicate that it is not limited to the well-ordered solid state. Herein, progress in the understanding of a new dynamic mode of symmetry breaking, based on chirality synchronisation of transiently chiral molecules in isotropic liquids and in bicontinuous cubic, columnar, smectic and nematic liquid crystalline phases is discussed. This process leads to spontaneous deracemisation in the liquid state under thermodynamic control, giving rise to long-term stable symmetry-broken fluids, even at high temperatures. These fluids form conglomerates that are capable of extraordinary strong chirality amplification, eventually leading to homochirality and providing a new view on the discussion of emergence of uniform chirality in prebiotic systems. PMID- 26416336 TI - Site and mechanism of the colokinetic action of the ghrelin receptor agonist, HM01. AB - BACKGROUND: It has been recently demonstrated that the ghrelin receptor agonist, HM01, caused defecation in rats that were treated to provide a model for the constipation of Parkinson's disease. HM01 significantly increased fecal output and increased Fos activity in neurons of the hypothalamus and hindbrain, but not in the spinal defecation center. Other ghrelin agonists act on the defecation center. METHODS: Receptor pharmacology was examined in ghrelin receptor (GHSR1a) transfected cells. Anesthetized rats were used to investigate sites and mechanisms of action. KEY RESULTS: HM01 activated rat GHSR1a at nanomolar concentrations and was antagonized by the GHSR1a antagonist, YIL781. HM01, intravenous, was potent to activate propulsive colorectal contractions. This was prevented by pelvic nerve section and by intravenous YIL781, but not by spinal cord section rostral to the defecation centers. Direct intrathecal application of HM01 to the defecation center at spinal level L6-S1 initiated propulsive contractions of the colorectum. CONCLUSIONS & INFERENCES: HM01 stimulates GHSR1a receptors on neurons in the lumbosacral defecation centers to cause propulsive contractions and emptying of the colorectum. It has greater potency when given systemically, compared with other GHSR1a agonists. PMID- 26416337 TI - Simultaneous Determination of Naturally Occurring Estrogens and Mycoestrogens in Milk by Ultrahigh-Performance Liquid Chromatography-Tandem Mass Spectrometry Analysis. AB - A simple, fast, and reproducible method for the simultaneous determination of natural estrogens and mycoestrogens (resorcylic acid lactones) in milk by ultrahigh-performance liquid chromatography combined with electrospray ionization triple quadrupole tandem mass spectrometry (UHPLC/ESI-MS/MS) is described. The extraction was carried out by solid-phase extraction (SPE) using graphitized carbon black as solid sorbent. The use of carbon black allowed us to avoid any type of sample pretreatment, and the extraction was performed simply by diluting milk samples in water. Correlation coefficient values were obtained in the range between 0.9991 and 1, with good recoveries (67-107% at the lowest spiked level), repeatability (4.8-16.8%), and reproducibility (3.2-16.3%). Moreover, a very low matrix effect was observed for both estrogens and mycoestrogens. With respect to a previous method based on SPE with Oasis MAX cartridges, the one here described allowed us to detect all the analytes under investigation, at the lowest tested concentration level, including free estrogens (in particular estriol). Finally, the developed UHPLC/ESI-MS/MS method was applied to the analysis of some whole milk samples from different lactating animals (cow, goat, and donkey) as well as ultrahigh-temperature-treated cow milk and powder milk samples. PMID- 26416338 TI - Gut microbiota: The gut virome and bacterial microbiome-the early years. PMID- 26416339 TI - Epidemiology and Characteristics of Episodic Breathlessness in Advanced Cancer Patients: An Observational Study. AB - CONTEXT: Episodic breathlessness is a relevant aspect in patients with advanced cancer. OBJECTIVES: The aim of this study was to assess the different aspects of this clinical phenomenon. METHODS: A consecutive sample of patients with advanced cancer admitted to different settings for a period of six months was surveyed. The presence of background breathlessness and episodic breathlessness, their intensity (numerical scale 0-10), and drugs used for treatment were collected. Factors inducing episodic breathlessness and its influence on daily activities were investigated. RESULTS: Of 921 patients, 29.3% (n = 269) had breathlessness and 134 patients (49.8%) were receiving drugs for background breathlessness. In the multivariate analysis, the risk of breathlessness increased with chronic obstructive pulmonary disease, although it decreased in patients receiving disease-oriented therapy and patients with gastrointestinal tumors. The prevalence of episodic breathlessness was 70.9% (n = 188), and its mean intensity was 7.1 (SD 1.6). The mean duration of untreated episodic breathlessness was 19.9 minutes (SD 35.3); 41% of these patients were receiving drugs for episodic breathlessness. The majority of episodic breathlessness events (88.2%) were triggered by activity. In the multivariate analysis, higher Karnofsky Performance Status levels were significantly related to episodic breathlessness, although patients receiving disease-oriented therapy were less likely to have episodic breathlessness. CONCLUSION: This study showed that episodic breathlessness frequently occurs in patients with breathlessness in the advanced stage of disease, has a severe intensity, and is characterized by rapid onset and short duration, which require rapid measures. PMID- 26416340 TI - Sitting Time, Fidgeting, and All-Cause Mortality in the UK Women's Cohort Study. AB - INTRODUCTION: Sedentary behaviors (including sitting) may increase mortality risk independently of physical activity level. Little is known about how fidgeting behaviors might modify the association. METHODS: Data were from the United Kingdom (UK) Women's Cohort Study. In 1999-2002, a total of 12,778 women (aged 37 78 years) provided data on average daily sitting time, overall fidgeting (irrespective of posture), and a range of relevant covariates including physical activity, diet, smoking status, and alcohol consumption. Participants were followed for mortality over a mean of 12 years. Proportional hazards Cox regression models estimated the relative risk of mortality in high (versus low) and medium (versus low) sitting time groups. RESULTS: Fidgeting modified the risk associated with sitting time (p=0.04 for interaction), leading us to separate groups for analysis. Adjusting for covariates, sitting for >=7 hours/day (versus <5 hours/day) was associated with 30% increased all-cause mortality risk (hazard ratio [HR]=1.30, 95% CI=1.02, 1.66) only among women in the low fidgeting group. Among women in the high fidgeting group, sitting for 5-6 hours/day (versus <5 hours/day) was associated with decreased mortality risk (HR=0.63, 95% CI=0.43, 0.91), adjusting for a range of covariates. There was no increased mortality risk from longer sitting time in the middle and high fidgeting groups. CONCLUSIONS: Fidgeting may reduce the risk of all-cause mortality associated with excessive sitting time. More detailed and better-validated measures of fidgeting should be identified in other studies to replicate these findings and identity mechanisms, particularly measures that distinguish fidgeting in a seated from standing posture. PMID- 26416341 TI - Epidemiology and costs of patients with toxic epidermal necrolysis: a 27-year retrospective study. AB - BACKGROUND: Recently, the importance of reporting the results and principles of management in Toxic epidermal necrolysis (TEN) patients was underscored. Treatment of TEN focuses on supportive care, often provided in a burn centre setting. Mortality in TEN patients can be high; the SCORTEN score is a scoring system that predicts mortality in patients with TEN. The predictive value of the SCORTEN score in our setting is unclear, as are the treatment costs of TEN patients. OBJECTIVE: To describe patient characteristics, treatment, outcome and direct medical costs of patients with TEN treated in one Dutch burn centre in a 27-year period. In addition, determinants of mortality and the predictive value of the SCORTEN score were assessed. METHODS: A retrospective study was conducted in all patients with TEN (including Stevens-Johnson syndrome (SJS) and overlap SJS-TEN) admitted to the burn centre Rotterdam between January 1987 and December 2013. The discriminative value of the SCORTEN score was assessed by receiver operator characteristics curve analysis. RESULTS: A total of 63 patients were admitted in 27-year period. Overall mortality was 39.7%, mortality in TEN patients (>30%TBSA) was 37.1%. A higher age (OR = 1.04, 95%CI: 1.02-1.07) and comorbidity (OR = 4.25, 95%CI: 1.2-14.7) were associated with mortality. The discriminative value of the SCORTEN prediction model in our population was limited (AUC=0.72, 95%CI: 0.57-0.86). The mean direct medical hospital-based costs was ?41.361. CONCLUSION: Toxic epidermal necrolysis is a severe adverse drug reaction, with a high mortality. Elderly patients and patients with comorbidity, especially circulatory comorbidity, have a relatively high risk of decease. The SCORTEN score, a frequently used prediction model in patients with TEN, underestimated the mortality in our study, mainly due to limited availability in patients with a good prognosis. The treatment of patient with TEN is associated with high direct medical hospital-based costs, also compared to burn patients in general. PMID- 26416342 TI - NbRABG3f, a member of Rab GTPase, is involved in Bamboo mosaic virus infection in Nicotiana benthamiana. AB - The screening of differentially expressed genes in plants after pathogen infection can uncover the potential host factors required for the pathogens. In this study, an up-regulated gene was identified and cloned from Nicotiana benthamiana plants after Bamboo mosaic virus (BaMV) inoculation. The up-regulated gene was identified as a member of the Rab small guanosine triphosphatase (GTPase) family, and was designated as NbRABG3f according to its in silico translated product with high identity to that of RABG3f of tomato. Knocking down the expression of NbRABG3f using a virus-induced gene silencing technique in a protoplast inoculation assay significantly reduced the accumulation of BaMV. A transiently expressed NbRABG3f protein in N. benthamiana plants followed by BaMV inoculation enhanced the accumulation of BaMV to approximately 150%. Mutants that had the catalytic site mutation (NbRABG3f/T22N) or had lost their membrane targeting capability (NbRABG3f/DeltaC3) failed to facilitate the accumulation of BaMV in plants. Because the Rab GTPase is responsible for vesicle trafficking between organelles, a mutant with a fixed guanosine diphosphate form was used to identify the donor compartment. The use of green fluorescent protein (GFP) fusion revealed that GFP-NbRABG3f/T22N clearly co-localized with the Golgi marker. In conclusion, BaMV may use NbRABG3f to form vesicles derived from the Golgi membrane for intracellular trafficking to deliver unidentified factors to its replication site; thus, both GTPase activity and membrane-targeting ability are crucial for BaMV accumulation at the cell level. PMID- 26416343 TI - The Effects of Job Insecurity on Health Care Utilization: Findings from a Panel of U.S. Workers. AB - OBJECTIVE: To examine the impacts of job insecurity during the recession of 2007 2009 on health care utilization among a panel of U.S. employees. DATA SOURCES/STUDY SETTING: Linked administrative and claims datasets on a panel of continuously employed, continuously insured individuals at a large multisite manufacturing firm that experienced widespread layoffs (N = 9,486). STUDY DESIGN: We employed segmented regressions to examine temporal discontinuities in utilization during 2006-2012. To assess the effects of job insecurity, we compared individuals at high- and low-layoff plants. Because the dataset includes multiple observations for each individual, we included individual-level fixed effects. PRINCIPAL FINDINGS: We found discontinuous increases in outpatient (3.5 visits/month/10,000 individuals, p = .002) and emergency (0.4 visits/month/10,000 individuals, p = .05) utilization in the panel of all employees. Compared with individuals at low-layoff plants, individuals at high-layoff plants decreased outpatient utilization (-4.0 visits/month/10,000 individuals, p = .008), suggesting foregone preventive care, with a marginally significant increase in emergency utilization (0.4 visits/month/10,000 individuals, p = .08). CONCLUSIONS: These results suggest changes in health care utilization and potentially adverse impacts on employee health in response to job insecurity during the latest recession. This study contributes to our understanding of the impacts of economic crises on the health of the U.S. working population. PMID- 26416344 TI - An evidence-based review of systemic treatments for itch. AB - BACKGROUND AND OBJECTIVE: Many treatment modalities are used for itch treatment in daily medical practices without adequate evidence of their efficacy. The purpose of this study was to provide an evidence-based review of the literature as to the clinical benefits of systemic anti-itch treatments. DATABASES AND DATA TREATMENT: We performed a systematic review and, when appropriate, meta-analysis from available placebo-controlled randomized controlled trails (RCTs). A systematic search of the literature was performed using Pub Med, Cochrane Library and EMBASE. The primary outcome was the change in the itch score comparing the intervention group and placebo group. The meta-analysis method was used to calculate the pooled outcome of each treatment modality. RESULTS: Twenty-six eligible RCTs were included. We found evidence for the effectiveness of: naltrexone (in cholestatic itch and atopic eczema), nalfurafine (in uraemic itch), gabapentin (in uraemic itch) and ursodeoxycholic acid (in intrahepatic cholestasis of pregnancy). The results of two RCTs with naltrexone in uremic itch are conflicting. On the other hand, we did not find any benefit from ondansetron (in cholestatic and uraemic itch), ergocalciferol (in uraemic itch), colesevelam (in cholestatic itch) or gabapentin (in cholestatic itch). The possible effectiveness of sertraline, paroxetine, cromolyn sodium, zinc sulphate, omega-3 fatty acid, montelukast, doxepin and rifampin need to be confirmed from future large studies, because the available evidence is insufficient. CONCLUSIONS: The findings from this study suggest the effective therapeutic approaches for itch. The major limitations are that there are small numbers of available RCTs and methodological differences across studies. PMID- 26416345 TI - Smoking affects the oral glucose tolerance test profile and the relationship between glucose and HbA1c in gestational diabetes mellitus. AB - AIMS: Current smokers in the general population have a lower 2 h plasma glucose after an oral glucose tolerance test (OGTT) and a higher HbA1c than non-smokers, but the relationships between OGTT/HbA1c and smoking status have not been addressed in pregnancy. We analysed glycaemic measurements in women with gestational diabetes mellitus in relation to smoking status. METHODS: We performed a review of the prospectively collected database of the diabetes and pregnancy clinic. We included women with gestational diabetes mellitus and a singleton pregnancy who delivered between 1986 and 2006. Bivariate and multivariate analyses were used to evaluate patient characteristics in relation to smoking status. RESULTS: A total of 2361 women met the inclusion criteria: 556 (23.5%) were active smokers, 266 (11.3%) quit during pregnancy and 1539 (65.2%) were non-smokers. Most baseline characteristics were similar across groups. Diagnostic OGTT was performed at a gestational age of [median (25th, 75(th) centiles)] 29 weeks (26, 33). Women who smoked at the beginning of pregnancy had a higher 1-h plasma glucose than non-smokers [11.8 (11, 12.7), 11.6 (11, 12.6) and 11.5 (10.8, 12.5) mmol/l, for active smokers, those who quit during pregnancy and non-smokers, respectively, P < 0.001] and a lower 3-h plasma glucose [7.3 (5.9, 8.4), 7.6 (6.4, 8.7) and 8.0 (6.8, 9.0) mmol/l, respectively, P < 0.001]. HbA1c was higher in women who smoked at the beginning of pregnancy. Multiple regression analysis confirmed the independent association of smoking status with HbA1c and OGTT plasma glucose. CONCLUSIONS: In women with gestational diabetes mellitus who smoke at the beginning of pregnancy, the shape of the OGTT is consistent with accelerated glucose absorption, and HbA1c is higher than expected for glycaemic values. PMID- 26416346 TI - In vitro expression of cytokeratin 18, 19 and tube formation of adipose-derived stem cells induced by the breast epithelial cell line HBL-100. AB - Fat transplantation is increasingly used in breast augmentation; and recently, the issue of safety concerns from a cellular and molecular point of view has been raised. In this study, attentions were paid to the interaction between adipose derived stem cells (ADSC) and mammary epithelial cells: human breast cancer cell line - 100 (HBL - 100) cells were used to simulate the normal microenvironment in breast tissue, ADSCs were harvest from human and co-cultured with HBL-100 cells. It was found that ADSCs formed tube-like structures in the co-culture with HBL 100 cells in contrast to the normal morphology of ADSCs in the control group. In addition, the immunofluorescence imaging showed that cytokeratin 18 and 19 (CK18 and 19) were significantly expressed in ADSCs after the co-culture with HBL-100 cells. The ultrastructure of those ADSCs also showed epithelial changes. In conclusion, ADSCs are not biological stable when co-cultured with HBL-100 cells. They differentiate into epithelial-like cells with the expression of epithelial surface marks (CK 18, 19) and form tube-like structures. This may offer an important evidence for the further study of clinical application of transplanting ADSCs rich adipose tissue into the breast in the future. PMID- 26416348 TI - Pharmacokinetics of ketorolac tromethamine in horses after intravenous, intramuscular, and oral single-dose administration. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are an integral component of equine analgesia, yet currently available NSAIDs are both limited in their analgesic efficacy and have adverse effects. The NSAID ketorolac tromethamine (KT) is widely used in humans as a potent morphine-sparing analgesic drug but has not been fully evaluated in horses. The purpose of this study was to determine the pharmacokinetic profile of KT in horses after intravenous (i.v.), intramuscular (i.m.), and oral (p.o.) administration. Nine healthy adult horses received a single 0.5-mg/kg dose of KT via each route of administration. Plasma was collected up to 48 h postadministration and analyzed for KT concentration using HPLC/MS/MS. Noncompartmental analysis of i.v. dosage indicated a mean plasma clearance of 8.4 (mL/min)/kg and an estimated mean volume of distribution at steady-state of 0.77 L/kg. Noncompartmental analysis of i.v., i.m., and p.o. dosages indicated mean residence times of 2.0, 2.6, and 7.1 h, respectively. The drug was rapidly absorbed after i.m. and p.o. administration, and mean bioavailability was 71% and 57% for i.m. and p.o. administration, respectively. Adverse effects were not observed after i.v., i.m., and p.o. administration. More studies are needed to evaluate the analgesic and anti-inflammatory properties of KT in horses. PMID- 26416349 TI - Raman spectroscopy as probe of nanometre-scale strain variations in graphene. AB - Confocal Raman spectroscopy has emerged as a major, versatile workhorse for the non-invasive characterization of graphene. Although it is successfully used to determine the number of layers, the quality of edges, and the effects of strain, doping and disorder, the nature of the experimentally observed broadening of the most prominent Raman 2D line has remained unclear. Here we show that the observed 2D line width contains valuable information on strain variations in graphene on length scales far below the laser spot size, that is, on the nanometre-scale. This finding is highly relevant as it has been shown recently that such nanometre scaled strain variations limit the carrier mobility in high-quality graphene devices. Consequently, the 2D line width is a good and easily accessible quantity for classifying the crystalline quality, nanometre-scale flatness as well as local electronic properties of graphene, all important for future scientific and industrial applications. PMID- 26416350 TI - The Effects of Platelet-Rich Plasma on Cell Proliferation and Adipogenic Potential of Adipose-Derived Stem Cells. AB - BACKGROUND: Platelet-rich plasma (PRP) contains multiple growth factors and has been shown to enhance fat graft survival after lipotransfer. However, the molecular mechanisms mediating this effect remain unknown. Adipose-derived stem cells (ASCs) play an important role in fat graft survival and are a likely target for PRP-mediated effects. This study seeks to investigate the impact of PRP on ASC proliferation and adipogenic differentiation. METHODS: Human ASCs were isolated using our laboratory protocol. The experiments were divided into four arms: (1) ASCs cultured in general culture medium alone; (2) ASCs in general culture medium + 5%, 10%, 15%, or 20% PRP; (3) ASCs cultured in adipogenic differentiation medium alone; (4) ASCs cultured in adipogenic medium + 5%, 10%, 15%, or 20% PRP. Cell proliferation was analyzed and comparative m-RNA expression of adipogenic genes was assessed by quantitative PCR. Protein expression was determined by western blot. RESULTS: PRP significantly enhanced proliferation of ASCs, even in the presence of antiproliferative, proadipogenic media. In contrast, PRP inhibited adipogenic differentiation in adipogenic media, evidenced by decreased intracellular lipid accumulation and reduced adipogenic gene expression (PPAR-gamma and FABP4). Inhibition appears to occur through downregulation of bone morphogenetic protein receptor IA (BMPRIA) and fibroblast growth factor receptor 1 (FGFR1). Interestingly, PRP elicited these effects across the entire range of doses studied. CONCLUSIONS: PRP appears to modulate ASC function primarily by enhancing cell proliferation. The consequences of its impact on adipogenesis are less clear. Enhanced proliferation initially might set the stage for more robust regeneration and adipogenesis at later time points, providing an important target for ongoing research. PMID- 26416351 TI - Pharmacological inhibition of Bcl-xL sensitizes osteosarcoma to doxorubicin. AB - High-grade conventional osteosarcoma is the most common primary bone tumor. Prognosis for osteosarcoma patients is poor and resistance to chemotherapy is common. We performed an siRNA screen targeting members of the Bcl-2 family in human osteosarcoma cell lines to identify critical regulators of osteosarcoma cell survival. Silencing the anti-apoptotic family member Bcl-xL but also the pro apoptotic member Bak using a SMARTpool of siRNAs as well as 4/4 individual siRNAs caused loss of viability. Loss of Bak impaired cell cycle progression and triggered autophagy. Instead, silencing Bcl-xL induced apoptotic cell death. Bcl xL was expressed in clinical osteosarcoma samples but mRNA or protein levels did not significantly correlate with therapy response or survival. Nevertheless, pharmacological inhibition of a range of Bcl-2 family members showed that inhibitors targeting Bcl-xL synergistically enhanced the response to the chemotherapeutic agent, doxorubicin. Indeed, in osteosarcoma cells strongly expressing Bcl-xL, the Bcl-xL-selective BH3 mimetic, WEHI-539 potently enhanced apoptosis in the presence of low doses of doxorubicin. Our results identify Bcl xL as a candidate drug target for sensitization to chemotherapy in patients with osteosarcoma. PMID- 26416352 TI - The chimeric antibody chLpMab-7 targeting human podoplanin suppresses pulmonary metastasis via ADCC and CDC rather than via its neutralizing activity. AB - Podoplanin (PDPN/Aggrus/T1alpha) binds to C-type lectin-like receptor-2 (CLEC-2) and induces platelet aggregation. PDPN is associated with malignant progression, tumor metastasis, and poor prognosis in several types of cancer. Although many anti-human PDPN (hPDPN) monoclonal antibodies (mAbs), such as D2-40 and NZ-1, have been established, these epitopes are limited to the platelet aggregation stimulating (PLAG) domain (amino acids 29-54) of hPDPN. Recently, we developed a novel mouse anti-hPDPN mAb, LpMab-7, which is more sensitive than D2-40 and NZ-1, using the Cancer-specific mAb (CasMab) method. The epitope of LpMab-7 was shown to be entirely different from that of NZ-1, a neutralizing mAb against the PLAG domain according to an inhibition assay and lectin microarray analysis. In the present study, we produced a mouse-human chimeric anti-hPDPN mAb, chLpMab-7. ChLpMab-7 showed high antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Furthermore, chLpMab-7 inhibited the growth of hPDPN-expressing tumors in vivo. Although chLpMab-7 recognizes a non PLAG domain of hPDPN, it suppressed the hematogenous metastasis of hPDPN expressing tumors. These results indicated that chLpMab-7 suppressed tumor development and hematogenous metastasis in a neutralization-independent manner. In conclusion, hPDPN shows promise as a target in the development of a novel antibody-based therapy. PMID- 26416353 TI - Methionine adenosyltransferase alpha2 sumoylation positively regulate Bcl-2 expression in human colon and liver cancer cells. AB - Ubiquitin-conjugating enzyme 9 (Ubc9) is required for sumoylation and inhibits apoptosis via Bcl-2 by unknown mechanism. Methionine adenosyltransferase 2A (MAT2A) encodes for MATalpha2, the catalytic subunit of the MATII isoenzyme that synthesizes S-adenosylmethionine (SAMe). Ubc9, Bcl-2 and MAT2A expression are up regulated in several malignancies. Exogenous SAMe decreases Ubc9 and MAT2A expression and is pro-apoptotic in liver and colon cancer cells. Here we investigated whether there is interplay between Ubc9, MAT2A and Bcl-2. We used human colon and liver cancer cell lines RKO and HepG2, respectively, and confirmed key finding in colon cancer specimens. We found MATalpha2 can regulate Bcl-2 expression at multiple levels. MATalpha2 binds to Bcl-2 promoter to activate its transcription. This effect is independent of SAMe as MATalpha2 catalytic mutant was also effective. MATalpha2 also directly interacts with Bcl-2 to enhance its protein stability. MATalpha2's effect on Bcl-2 requires Ubc9 as MATalpha2's stability is influenced by sumoylation at K340, K372 and K394. Overexpressing wild type (but not less stable MATalpha2 sumoylation mutants) protected from 5-fluorouracil-induced apoptosis in both colon and liver cancer cells. Colon cancer have higher levels of sumoylated MATalpha2, total MATalpha2, Ubc9 and Bcl-2 and higher MATalpha2 binding to the Bcl-2 P2 promoter. Taken together, Ubc9's protective effect on apoptosis may be mediated at least in part by sumoylating and stabilizing MATalpha2 protein, which in turn positively maintains Bcl-2 expression. These interactions feed forward to further enhance growth and survival of the cancer cell. PMID- 26416356 TI - Erythropoietin in the treatment of carbon monoxide neurotoxicity in rat. AB - Erythropoietin (EPO) plays a critical role in the development of the nervous system. In this study, the effects of EPO in carbon monoxide (CO) neurotoxicity were examined. Rats were exposed to 3000 ppm CO for 1 h and then different doses of EPO were administrated intraperitoneally. After 24 h, glial fibrillary acidic protein (GFAP) levels in the serum were determined and water content of brain and the extravasation of a tracer (Evans blue) were measured. Brain lipid peroxidation, myeloperoxidase activity Myelin basic protein (MBP) and BAX/BcL2 protein relative expressions were determined. Cation exchange chromatography was used to evaluate MBP alterations. Seven days after exposure, pathological assessment was performed after Kluver-Barrera staining. EPO reduced malondialdehyde levels at all doses (2500, 5000 and 10,000 u/kg). Lower doses of EPO (625, 1250, 2500 u/kg) significantly decreased the elevated serum levels of GFAP. EPO could not reduce the water content of the edematous poisoned brains. However, at 5000 and 10,000 u/kg it protected the blood brain barrier against integrity loss as a result of CO. EPO could significantly decrease the MPO activity. CO-mediated oxidative stress caused chemical alterations in MBP and EPO could partially prevent these biochemical changes. Fewer vacuoles and demyelinated fibers were found in the EPO-treated animals. EPO (5000 u/kg) could restore the MBP density. CO increased brain BAX/Bcl-2 ratio 38.78%. EPO reduced it 38.86%. These results reveal that EPO could relatively prevent different pathways of neurotoxicity by CO poisoning and thus has the potential to be used as a novel approach to manage this poisoning. PMID- 26416355 TI - Opposite regulation of MDM2 and MDMX expression in acquisition of mesenchymal phenotype in benign and cancer cells. AB - Plasticity of cancer cells, manifested by transitions between epithelial and mesenchymal phenotypes, represents a challenging issue in the treatment of neoplasias. Both epithelial-mesenchymal transition (EMT) and mesenchymal epithelial transition (MET) are implicated in the processes of metastasis formation and acquisition of stem cell-like properties. Mouse double minute (MDM) 2 and MDMX are important players in cancer progression, as they act as regulators of p53, but their function in EMT and metastasis may be contradictory. Here, we show that the EMT phenotype in multiple cellular models and in clinical prostate and breast cancer samples is associated with a decrease in MDM2 and increase in MDMX expression. Modulation of EMT-accompanying changes in MDM2 expression in benign and transformed prostate epithelial cells influences their migration capacity and sensitivity to docetaxel. Analysis of putative mechanisms of MDM2 expression control demonstrates that in the context of defective p53 function, MDM2 expression is regulated by EMT-inducing transcription factors Slug and Twist. These results provide an alternative context-specific role of MDM2 in EMT, cell migration, metastasis, and therapy resistance. PMID- 26416354 TI - Sensitization of multidrug-resistant human cancer cells to Hsp90 inhibitors by down-regulation of SIRT1. AB - The effectiveness of Hsp90 inhibitors as anticancer agents was limited in multidrug-resistant (MDR) human cancer cells due to induction of heat shock proteins (Hsps) such as Hsp70/Hsp27 and P-glycoprotein (P-gp)-mediated efflux. In the present study, we showed that resistance to Hsp90 inhibitors of MDR human cancer cells could be overcome with SIRT1 inhibition. SIRT1 knock-down or SIRT1 inhibitors (amurensin G and EX527) effectively suppressed the resistance to Hsp90 inhibitors (17-AAG and AUY922) in several MDR variants of human lymphoblastic leukemia and human breast cancer cell lines. SIRT1 inhibition down-regulated the expression of heat shock factor 1 (HSF1) and subsequently Hsps and facilitated Hsp90 multichaperone complex disruption via hyperacetylation of Hsp90/Hsp70. These findings were followed by acceleration of ubiquitin ligase CHIP-mediated mutant p53 (mut p53) degradation and subsequent down-regulation of P-gp in 17-AAG treated MDR cancer cells expressing P-gp and mut p53 after inhibition of SIRT1. Therefore, combined treatment with Hsp90 inhibitor and SIRT1 inhibitor could be a more effective therapeutic approach for Hsp90 inhibitor-resistant MDR cells via down-regulation of HSF1/Hsps, mut p53 and P-gp. PMID- 26416357 TI - Identification, sequencing and comparative analysis of pBp15.S plasmid from the newly described entomopathogen Bacillus pumilus 15.1. AB - The Bacillus pumilus 15.1 strain, a recently described entomopathogenic strain active against Ceratitis capitata, contains at least two extrachromosomal elements, pBp15.1S and pBp15.1B. Given that B. pumilus is not a typical entomopathogenic bacterium, the acquisition of this extrachromosomal DNA may explain why B. pumilus 15.1 is toxic to an insect. One of the plasmids present in the strain, the pBp15.1S plasmid, was sub-cloned, sequenced and analyzed using bioinformatics to identify any potential virulence factor. The pBp15.1S plasmid was found to be 7785 bp in size with a GC content of 35.7% and 11 putative ORFs. A replication module typical of a small rolling circle plasmid and a sensing and regulatory system specific for plasmids was found in pBp15.1S. Additionally, we demonstrated the existence of ssDNA in plasmid preparations suggesting that pBp15.1S replicates by the small rolling circle mechanism. A gene cluster present in plasmid pPZZ84 from a distantly isolated B. pumilus strain was also present in pBp15.1S. The plasmid copy number of pBp15.1S in exponentially growing B. pumilus cells was determined to be 33 copies per chromosome. After an extensive plasmid characterization, no known virulence factor was found so a search in the other extrachromosomal elements of the bacteria is needed. PMID- 26416358 TI - Co(OH)2/RGO/NiO sandwich-structured nanotube arrays with special surface and synergistic effects as high-performance positive electrodes for asymmetric supercapacitors. AB - High power density, high energy density and excellent cycling stability are the main requirements for high-performance supercapacitors (SCs) that will be widely used for portable consumer electronics and hybrid electric vehicles. Here we investigate novel types of hybrid Co(OH)2/reduced graphene oxide (RGO)/NiO sandwich-structured nanotube arrays (SNTAs) as positive electrodes for asymmetric supercapacitors (ASCs). The synthesized Co(OH)2/RGO/NiO SNTAs exhibit a significantly improved specific capacity (~1470 F g(-1) at 5 mV s(-1)) and excellent cycling stability with ~98% Csp retention after 10 000 cycles because of the fast transport and short diffusion paths for electroactive species, the high utilization rate of electrode materials, and special synergistic effects among Co(OH)2, RGO, and NiO. The high-performance ASCs are assembled using Co(OH)2/RGO/NiO SNTAs as positive electrodes and active carbon (AC) as negative electrodes, and they exhibit a high energy density (115 Wh kg(-1)), a high power density (27.5 kW kg(-1)) and an excellent cycling stability (less 5% Csp loss after 10 000 cycles). This study shows an important breakthrough in the design and fabrication of multi-walled hybrid nanotube arrays as positive electrodes for ASCs. PMID- 26416359 TI - Shape Displays: Spatial Interaction with Dynamic Physical Form. AB - Shape displays are an emerging class of devices that emphasize actuation to enable rich physical interaction, complementing concepts in virtual and augmented reality. The ability to render form introduces new opportunities to touch, grasp, and manipulate dynamic physical content and tangible objects, in both nearby and remote environments. This article presents novel hardware, interaction techniques, and applications, which point to the potential for extending the ways that we traditionally interact with the physical world, empowered by digital computation. PMID- 26416360 TI - Reducing Visual Discomfort with HMDs Using Dynamic Depth of Field. AB - Although head-mounted displays (HMDs) are ideal devices for personal viewing of immersive stereoscopic content, exposure to VR applications on them results in significant discomfort for the majority of people, with symptoms including eye fatigue, headaches, nausea, and sweating. A conflict between accommodation and vergence depth cues on stereoscopic displays is a significant cause of visual discomfort. This article describes the results of an evaluation used to judge the effectiveness of dynamic depth-of-field (DoF) blur in an effort to reduce discomfort caused by exposure to stereoscopic content on HMDs. Using a commercial game engine implementation, study participants report a reduction of visual discomfort on a simulator sickness questionnaire when DoF blurring is enabled. The study participants reported a decrease in symptom severity caused by HMD exposure, indicating that dynamic DoF can effectively reduce visual discomfort. PMID- 26416361 TI - Sensing Thumb-to-Finger Taps for Symbolic Input in VR/AR Environments. AB - Thumb-to-finger tap interaction can be employed to perform eyes-free, discrete, symbolic input in virtual and augmented reality environments. The DigiTap device is worn on the wrist to keep the hand free from any instrumentation so as not to impair tactile sense and dexterity. DigiTap senses the jerk that is caused by a tap and takes an image sequence to detect the tap location. The device can recognize taps at 12 different locations on the fingers, and at some positions, it can even distinguish between different tap strengths. The authors conducted an extended user study to evaluate users' abilities to interact with the device and perform symbolic input. PMID- 26416362 TI - Visual Perspective and Feedback Guidance for VR Free-Throw Training. AB - Accurate distance perception and natural interactions are mandatory conditions when training precision aiming tasks in VR. However, many factors specific to virtual environments (VEs) lead to differences in the way users execute a motor task in VR versus the real world. To investigate these differences, the authors performed a study on basketball beginners' free-throw performance in VEs under different visual conditions. Although the success rate is not statistically different, some adaptations occurred in the way the users performed the task, depending on the visual conditions. In the third-person perspective visual condition, the release parameters indicate that the users more accurately estimated distance to target. Adding visual guidance information (gradual depth information showing the ideal ball trajectory) also led to more natural motor behavior. The final aim of this study was to develop a reliable basketball free throw training system in VEs, so the authors compared beginners' performances in VR with experts' models of performance. Their results show that most of the performance variables tended to evolve closer to the experts' performance during the training in the VE. PMID- 26416363 TI - Toward Standard Usability Questionnaires for Handheld Augmented Reality. AB - Usability evaluations are important to improving handheld augmented reality (HAR) systems. However, no standard questionnaire considers perceptual and ergonomic issues found in HAR. The authors performed a systematic literature review to enumerate these issues. Based on these issues, they created a HAR usability scale that consists of comprehensibility and manipulability scales. These scales measure general system usability, ease of understanding the information presented, and ease of handling the device. The questionnaires' validity and reliability were evaluated in four experiments, and the results show that the questionnaires consistently correlate with other subjective and objective measures of usability. The questionnaires also have good reliability based on the Cronbach's alpha. Researchers and professionals can directly use these questionnaires to evaluate their own HAR applications or modify them with the insights presented in this article. PMID- 26416364 TI - Contiguous Animated Edge-Based Cartograms for Traffic Visualization. AB - An experimental model animates contiguous computer cartograms by distorting the topological lengths of their edges. Using traffic information for the city of Lisbon, the authors distort a road map to depict traffic velocities. Areas of the city distend when velocities are low and compress when velocities are high. This model is applied to two visualizations: a trajectory visualization of vehicles, creating a temperature map for traffic velocities, and a figurative visualization that portrays Lisbon as a system of pulsing blood vessels. The proposed model can efficiently generate and animate edge-based cartograms with low representation errors. PMID- 26416365 TI - More Than Telling a Story: Transforming Data into Visually Shared Stories. AB - The authors take a closer look at how the visualization community has discussed visual storytelling and present a visual data storytelling process, incorporating steps involved in finding insights (explore data), turning these insights into a narrative (make a story), and communicating this narrative to an audience (tell a story). They also discuss opportunities for future research in visualization as a storytelling medium in the light of this broader process. PMID- 26416366 TI - Breathing Life into Shapes. AB - Shape articulation transforms a lifeless geometric object into a vibrant character. Computers enrich artists' toolsets dramatically. They not only endow artists with the power to manipulate virtual 2D and 3D scenes, but they also eliminate tedium and expedite prototyping, freeing artists to focus on creative aspects. With such power comes a temptation to lean entirely on the computer. Computationally intensive animation systems sacrifice real-time feedback for physical accuracy. How can we leverage modern computational power to create the best possible shape deformations while maintaining real-time performance as a mandatory invariant? This article summarizes efforts to answer this, culminating in a deformation system with the quality of slow, nonlinear optimization, but at lightning speed. PMID- 26416367 TI - Evaluating and Grading Students in Large-Scale Image Processing Courses. AB - In undergraduate practical courses, it is common to work with groups of 100 or more students. These large-scale courses bring their own challenges. For example, course problems are too small and lack "the big picture"; grading becomes burdensome and repetitive for the teaching staff; and it is difficult to detect cheating. Based on their experience with a traditional large-scale practical course in image processing, the authors developed a novel course approach to teaching "Introduction to Digital Image Processing" (or EDBV, from the German course title Einfuhrung in die Digitale Bild-Verarbeitung) for all undergraduate students of media informatics and visual computing and medical informatics at the TU Wien. PMID- 26416368 TI - Evidence based policy making and the 'art' of commissioning - how English healthcare commissioners access and use information and academic research in 'real life' decision-making: an empirical qualitative study. AB - BACKGROUND: Policymakers such as English healthcare commissioners are encouraged to adopt 'evidence-based policy-making', with 'evidence' defined by researchers as academic research. To learn how academic research can influence policy, researchers need to know more about commissioning, commissioners' information seeking behaviour and the role of research in their decisions. METHODS: In case studies of four commissioning organisations, we interviewed 52 people including clinical and managerial commissioners, observed 14 commissioning meetings and collected documentation e.g. meeting minutes and reports. Using constant comparison, data were coded, summarised and analysed to facilitate cross case comparison. RESULTS: The 'art of commissioning' entails juggling competing agendas, priorities, power relationships, demands and personal inclinations to build a persuasive, compelling case. Policymakers sought information to identify options, navigate ways through, justify decisions and convince others to approve and/or follow the suggested course. 'Evidence-based policy-making' usually meant pragmatic selection of 'evidence' such as best practice guidance, clinicians' and users' views of services and innovations from elsewhere. Inconclusive or negative research was unhelpful in developing policymaking plans and did not inform disinvestment decisions. Information was exchanged through conversations and stories, which were fast, flexible and suited the rapidly changing world of policymaking. Local data often trumped national or research-based evidence. Local evaluations were more useful than academic research. DISCUSSION: Commissioners are highly pragmatic and will only use information that helps them create a compelling case for action.Therefore, researchers need to start producing more useful information. CONCLUSIONS: To influence policymakers' decisions, researchers need to 1) learn more about local policymakers' priorities 2) develop relationships of mutual benefit 3) use verbal instead of writtencommunication 4) work with intermediaries such as public health consultants and 5) co-produce local evaluations. PMID- 26416369 TI - Validity, reliability and support for implementation of independence-scaled procedural assessment in laparoscopic surgery. AB - BACKGROUND: There is no widely used method to evaluate procedure-specific laparoscopic skills. The first aim of this study was to develop a procedure-based assessment method. The second aim was to compare its validity, reliability and feasibility with currently available global rating scales (GRSs). METHODS: An independence-scaled procedural assessment was created by linking the procedural key steps of the laparoscopic cholecystectomy to an independence scale. Subtitled and blinded videos of a novice, an intermediate and an almost competent trainee, were evaluated with GRSs (OSATS and GOALS) and the independence-scaled procedural assessment by seven surgeons, three senior trainees and six scrub nurses. Participants received a short introduction to the GRSs and independence-scaled procedural assessment before assessment. The validity was estimated with the Friedman and Wilcoxon test and the reliability with the intra-class correlation coefficient (ICC). A questionnaire was used to evaluate user opinion. RESULTS: Independence-scaled procedural assessment and GRS scores improved significantly with surgical experience (OSATS p = 0.001, GOALS p < 0.001, independence-scaled procedural assessment p < 0.001). The ICCs of the OSATS, GOALS and independence scaled procedural assessment were 0.78, 0.74 and 0.84, respectively, among surgeons. The ICCs increased when the ratings of scrub nurses were added to those of the surgeons. The independence-scaled procedural assessment was not considered more of an administrative burden than the GRSs (p = 0.692). DISCUSSION/CONCLUSION: A procedural assessment created by combining procedural key steps to an independence scale is a valid, reliable and acceptable assessment instrument in surgery. In contrast to the GRSs, the reliability of the independence-scaled procedural assessment exceeded the threshold of 0.8, indicating that it can also be used for summative assessment. It furthermore seems that scrub nurses can assess the operative competence of surgical trainees. PMID- 26416370 TI - Laparoscopic transhiatal esophagectomy improves hospital outcomes and reduces cost: a single-institution analysis of laparoscopic-assisted and open techniques. AB - BACKGROUND: Several case series have demonstrated that laparoscopic transhiatal esophagectomy (LTHE) is associated with favorable perioperative outcomes compared to historical data for open transhiatal esophagectomy (OTHE). Contemporaneous evaluation of open and laparoscopic THE is rare, limiting meaningful comparison of techniques. METHODS: All patients who underwent OTHE (n = 32) and LTHE (n = 41) during the introduction of the latter procedure at our institution (1/2012 4/2014) were identified, and patient charts were retrospectively reviewed. RESULTS: Indications for operation included 69 patients with esophageal malignancy (adenocarcinoma: 64; squamous cell carcinoma: 4; melanoma: 1) and 4 patients with benign disease. There were no significant differences in clinicopathologic variables between OTHE and LTHE cohorts, except for an increased rate of cardiovascular disease in the LTHE cohort (p = 0.04). There was no significant difference in median operative time or operative complications, yet LTHE was associated with a lower incidence of intraoperative blood transfusion (p < 0.01). There were no 30-day mortalities. LTHE was associated with a reduced time to reach 24-h tube feeding goals (p = 0.02), shorter length of hospital stay (p = 0.01), and 6 % reduced median direct cost (p = 0.04). There were no significant differences in rates of major perioperative morbidities. Patients were followed for a median of 11.0 months during which there were no significant differences between cohorts in disease-free survival or overall survival. CONCLUSION: When compared to OTHE, LTHE improves surgical outcomes and decreases hospital costs; short-term oncologic outcomes are similar. LTHE is preferable to OTHE in patients requiring transhiatal esophagectomy. PMID- 26416371 TI - A novel method of delta-shaped intracorporeal double-tract reconstruction in totally laparoscopic proximal gastrectomy. AB - BACKGROUND: The purpose of this study is to depict a novel delta-shaped intracorporeal double-tract reconstruction (DT) for totally laparoscopic (TL) proximal gastrectomy (PG), and to evaluate its safety and feasibility by analyzing its surgical and postoperative outcomes. PATIENTS AND METHODS: We retrospectively reviewed the cases of 21 patients who underwent TLPG and TLDT (TLPG-DT) from January to December 2014 in our hospital. The data of clinicopathologic characteristics, surgical and postoperative outcomes, and follow-up findings were collected and analyzed. RESULTS: The mean duration of the operation was 173.8 +/- 21.8 min, including 27.8 +/- 5.3 min of reconstruction. The blood loss was 109.2 +/- 96.3 mL. The mean number of LNs dissected was 25.7 +/- 4.7. The mean time of the first flatus was at postoperative day 2.3 +/- 1.0, and the mean postoperative hospital stay was 6.8 +/- 2.5 days. The early complications rate was 9.5 %, including one intraperitoneal hemorrhage and one pulmonary infection (both were managed through conservative methods and no re operation occurred). The rate of complications in late stage was also 9.5 %, including one diarrhea and one reflux symptom claim. Among the total 21 cases, 17 patients were followed up more than 6 months, showing no signs of reflux esophagitis or anastomotic stenosis. The mean weight loss in 3 and 6 months after the operation was 4.3 and 5.7 %, respectively. CONCLUSION: Totally laparoscopic delta-shaped intracorporeal double-tract reconstruction is a safe, feasible and minimally invasive reconstruction method with excellent postoperative outcomes in terms of preventing reflux esophagitis and anastomotic stenosis. TLPG-DT might serve as a promising treatment for proximal gastric cancer of early stage. PMID- 26416372 TI - Laparoscopic radical cholecystectomy for suspected early gall bladder carcinoma: thinking beyond convention. AB - BACKGROUND: Gall bladder cancer (GBC) is the most common and aggressive malignancy of the biliary tract with extremely poor prognosis. Radical resection remains the only potential curative treatment for operable lesions. Although laparoscopic approach is now considered as standard of care for many gastrointestinal malignancies, surgical community is still reluctant to use this approach for GBC probably because of fear of tumor dissemination, inadequate lymphadenectomy and overall nihilistic approach. Aim of this study was to share our initial experience of laparoscopic radical cholecystectomy (LRC) for suspected early GBC. METHODS: From 2008 to 2013, 91 patients were evaluated for suspected GBC, of which, 14 patients had early disease and underwent LRC. RESULTS: Mean age of the cohort was 61.14 +/- 4.20 years with male/female ratio of 1:1.33. Mean operating time was 212.9 +/- 26.73 min with mean blood loss of 196.4 +/- 63.44 ml. Mean hospital stay was 5.14 +/- 0.86 days without any 30-day mortality. Bile leak occurred in two patients. Out of 14 patients, 12 had adenocarcinoma, one had xanthogranulomatous cholecystitis and another had adenomyomatosis of gall bladder as final pathology. Resected margins were free in all (>1 cm). Median number of lymph nodes resected was 8 (4-14). Pathological stage of disease was pT2N0 in eight, pT2N1 in three and pT3N0 in one patient. Median follow-up was 51 (14-70) months with 5-year survival 68.75 %. CONCLUSIONS: Laparoscopic radical cholecystectomy with lymphadenectomy can be a viable alternative for management of early GBC in terms of technical feasibility and oncological clearance along with offering the conventional advantages of minimal access approach. PMID- 26416375 TI - SAGES presidential address: a SAGES Magical Mystery Tour. PMID- 26416373 TI - Safety analysis of primary bariatric surgery in patients on chronic dialysis. AB - BACKGROUND: Due to the steady increase in patients on chronic dialysis, more of these patients are undergoing elective operations. The literature on safety and postoperative outcomes in dialysis-dependent patients following elective bariatric surgery is scant. We compared the 30-day major morbidity and mortality rates in dialysis-dependent (DD) and non-dependent (ND) patients after primary bariatric surgery. METHODS: From American College of Surgeons National Surgical Quality Improvement Program, we identified patients, who underwent primary bariatric surgery between 2005 and 2013. Thirty-day postoperative outcomes were compared between DD and ND patients. Logistic regression was used to determine the prognostic impact of dependence on chronic dialysis on the 30-day postoperative outcomes. RESULTS: Two hundred and thirty-four DD and 113,677 ND patients were analyzed. DD patients had a higher baseline risk profile compared to ND patients. Thirty-day mortality rates for DD and ND patients were 0.43 and 0.11 %, respectively (P = 0.134). DD patients had a higher 30-day major morbidity compared to ND patients (5.98 vs. 2.31 %; P < 0.001, respectively). Despite a crude OR of 2.70 (95 % CI 1.57-4.63) after adjusting for confounding, dependence on dialysis was not found to be an independent predictor of major morbidity. CONCLUSIONS: Primary bariatric surgery is safe in patients dependent on dialysis with an acceptable 30-day postoperative morbidity and mortality. Even though dependence on dialysis does not independently increase the risk of 30-day adverse outcomes following primary bariatric surgery, the comorbid conditions in this patient population render them at risk. The higher prevalence of major morbidities in this group is mainly due to the impact from older age, male sex, higher BMI, cardiac comorbidities, and hypertension. PMID- 26416374 TI - Pros and cons of the gasless laparoscopic transhiatal esophagectomy for upper esophageal carcinoma. AB - BACKGROUND: Controversies on how to treat upper esophageal carcinoma have existed for several decades. With the application of minimally invasive techniques, surgical treatment to upper esophageal carcinoma tends to show more advantages and attract more patients. Up to now, most hospitals adopted the combined thoracoscopic and laparoscopic esophagectomy (CTLE) as the way of minimally invasive surgery for upper esophageal carcinoma. But CTLE to treat upper esophageal carcinoma has its drawbacks, such as demanding certain pulmonary function and severe postoperative regurgitation. In 2011, we developed the gasless laparoscopic transhiatal esophagectomy (LTE) to treat upper esophageal carcinoma, which showed some advantages. The aim of this article was to compare LTE with CTLE in treating upper thoracic or cervical esophageal carcinoma and assess the value of LTE. METHODS: From 2009 to 2014, esophagectomy has been performed by the introduction of minimally invasive surgery in a total of 83 patients with upper thoracic or cervical esophageal carcinoma. Among these patients, LTE was performed in 27 cases (Group 1), while CTLE was performed in the other 56 (Group 2). Neoadjuvant chemotherapy was done in patients of Group 1. RESULTS: There were no operation-related deaths and conversion to open procedure. There was no significant difference in postoperative complications, ventilation time, ICU stay, hospital stay, and anastomotic leak rates between the two groups. But LTE was associated with shorter operative time and less intraoperative blood loss. In Group 2, 21 (37.5 %) patients had postoperative pulmonary complications, while in Group 1, there were 6 (22.2 %) patients having pulmonary complications at least one time. Results of 24-h pH monitoring and manometry showed that postoperative laryngo-pharyngeal reflux (PLPR) was more severe in Group 2 patients than in Group 1; for Group 1, PLPR mainly occurred on sleep stage, while for Group 2, PLPR might exist all the day with short intervals and last longer at night. The median overall survival was 27.2 months after CTLE and 30.8 months after LTE (P = 0.962). There was no significant difference in survival at 2, 3 and 4 years between the two groups. CONCLUSIONS: Compared with CTLE, LTE is a more minimally invasive approach to effectively treat patients with upper esophageal carcinoma. Laryngo-pharyngeal reflux after LTE was less severe than that after CTLE, which might lower incidence of pulmonary complications. For the elderly patients, LTE seems more suitable. PMID- 26416376 TI - The utility of radiological upper gastrointestinal series and clinical indicators in detecting leaks after laparoscopic sleeve gastrectomy: a case-controlled study. AB - BACKGROUND: Leak after laparoscopic sleeve gastrectomy (LSG) often presents after hospital discharge, making timely diagnosis difficult. This study evaluates the utility of radiological upper gastrointestinal (UGI) series and clinical indicators in detecting leak after LSG. METHODS: A retrospective case-controlled study of 1762 patients who underwent LSG from 2006 to 2014 was performed. All patients with radiographically confirmed leaks were included. Controls consisted of patients who underwent LSG without leak, selected using a 10:1 case-match. Data included baseline patient characteristics, surgical characteristics, and UGI series results. Clinical indicators including vital signs, SIRS criteria, and pain score were compared between patients who developed leak and controls. RESULTS: Of 1762 LSG operations, 20 (1.1 %) patients developed leaks and were compared with 200 case-matched controls. Three patients developed leak during their index admission [mean = 1.3 days, range (1, 2)], while the majority (n = 17) were discharged and developed symptoms at a mean of 17.1 days [range (4, 63)] postoperatively. Patients diagnosed with leak were similar to controls in baseline and surgical characteristics. Contrast extravasation on routine postoperative UGI identified two patients with early leaks, but was negative in the remainder (89 %). Patients with both early and delayed leaks demonstrated significant clinical abnormalities at the time of leak presentation, prior to confirmatory radiographic study. In multiple regression analysis, independent clinical factors associated with leak included fever [OR 16.6, 95 % CI (4.04, 68.10), p < 0.0001], SIRS criteria [OR 7.0, 95 % CI (1.47, 33.26), p = 0.014], and pain score >=9 [OR 19.1, 95 % CI (1.38, 263.87), p = 0.028]. CONCLUSIONS: Contrast extravasation on routine postoperative radiological UGI series may detect early leaks after LSG, but the vast majority of leaks demonstrate normal results and present 2-3 weeks after discharge. Therefore, clinical indicators (specifically fever, SIRS criteria, and pain score) are the most useful factors to raise concern for leaks prior to confirmatory radiographic study and may be used as criteria to selectively obtain UGI studies after LSG. PMID- 26416377 TI - Evaluating quality across minimally invasive platforms in colorectal surgery. AB - INTRODUCTION: There is an increasing emphasis on optimizing and measuring surgical quality. The safety and efficacy of minimally invasive techniques have been proven; however, direct comparison of outcomes across platforms has not been performed. Our goal was to compare operative times and quality across three minimally invasive platforms in colorectal surgery. METHODS: A prospective database was reviewed for elective minimally invasive surgery (MIS) cases from 2008 to 2014. Patients were stratified into multiport laparoscopic, single incision laparoscopic (SILS) or robotic-assisted laparoscopic approaches (RALS). Demographics, perioperative, and postoperative outcomes were analyzed. Multivariate regression analysis was used to predict the demographic and procedural factors and outcomes associated with each platform. The main outcome measures were operative time and surgical quality by approach. RESULTS: A total of 1055 cases were evaluated-28.4 % LAP, 18.5 % RALS, and 53.1 % SILS. RALS had the most complex patients, pathology, and procedures. The main diagnosis for RALS was rectal cancer (49.5 %), patients predominantly underwent pelvic surgery (72.8 %), had higher rates of neoadjuvant chemoradiation (p < 0.001) and stoma creation (p < 0.001). RALS had the longest operative time and highest complication and readmissions rates (all p < 0.001). Multiport patients were older than SILS and RALS (p = 0.021), had the most intraoperative complications (p < 0.001), conversions (p < 0.001), and had the longest length of stay (p = 0.001). SILS had the shortest operative times (p < 0.001), length of stay (p = 0.001), and lowest rates of complications (p < 0.001), readmissions (p < 0.001), and unplanned reoperation (p = 0.014). All platforms offered high quality (HARM score 0) from overall short LOS, low readmission, and mortality rates. CONCLUSIONS: Multiport, RALS, and SILS each serve a distinct demographic and disease profile and have predictable outcomes. All have risks and benefits, but offer overall high-quality care with a composite of LOS, readmission, and mortality rates. Operative times were directly associated with readmission rates. As all three platforms offer good quality, the choice of which MIS approach to use should be guided by demographics and disease process. PMID- 26416378 TI - Laparoscopic deroofing for polycystic liver disease using laparoscopic fusion indocyanine green fluorescence imaging. AB - BACKGROUND: Laparoscopic deroofing is widely used for the treatment of symptomatic polycystic liver disease (PCLD). However, bile leakage is a common complication of surgical management for PCLD. Until now, indocyanine green fluorescence imaging (IGFI) has played an active role in hepatobiliary surgery. Herein, we report the effective application of a laparoscopic fusion IGFI system, known as PINPOINT, for laparoscopic deroofing. METHODS: In this study, we performed laparoscopic deroofing for PCLD using the laparoscopic fusion IGFI system. We conducted the procedure mainly under the normal view mode, occasionally switching to the fusion IGFI mode. First, we confirmed that the liver cysts did not contain bile using the fusion IGFI mode and then used a percutaneous puncture needle to remove the fluid from some of the giant cysts. Second, using the fusion IGFI mode, we were able to detect thin biliary branches and to adjust the division line of the cyst wall accordingly or, occasionally, to ligate the branches. Finally, we searched for and identified unexpected small bile leakage and then closed it using sutures. RESULTS: The laparoscopic fusion IGFI system can simultaneously show fluorescent images, such as cholangiography and the liver parenchyma, on the normal color view. In the fusion IGFI mode, the intrahepatic bile duct and liver parenchyma can be easily discriminated in real time throughout the procedure. Accordingly, the laparoscopic fusion IGFI system is useful for the surgical treatment of PCLD, in which the boundary between the liver cysts and the liver parenchyma can otherwise be difficult to identify. This technique also enables the branches of Glisson's capsule to be identified without any other intervention. CONCLUSION: The novel application of the laparoscopic fusion IGFI system allows reliable navigation for PCLD surgery. PMID- 26416379 TI - Stent-in-stent technique for removal of embedded partially covered self-expanding metal stents. AB - BACKGROUND: Removal of embedded partially covered self-expanding metal stents (PCSEMS) is associated with an increased risk of adverse events compared with removal of fully covered self-expanding stents (FCSES) due to tissue ingrowth. Successful removal of embedded PCSEMS has been described by the stent-in-stent (SIS) technique. AIMS: To report the first US experience from three high-volume quaternary care centers on the safety and efficacy of the SIS technique for removal of embedded PCSEMS. METHODS: Retrospective study of outcomes for consecutive patients who underwent the SIS for removal of embedded PCSEMS over a 5-year period. RESULTS: Twenty-seven embedded PCSEMS were successfully removed using the SIS technique (100 %) from 25 patients (11 males), median age 65 (range 37-80). All stents were successfully removed in one endoscopic session (no repeat SIS procedures were required for persistently embedded stents). The embedded PCSEMS had been in situ for a median of 76 days (range 26-501). Median SIS dwell time (FCSES in situ of PCSEMS) was 13 days (interquartile range 8-16 days; range 4-212 days). One adverse event (self-limited bleeding) occurred during a median follow-up period of 3 months (range 1-32). No patients died, required surgery, or had long-term disability due to adverse events attributed to the SIS technique. Twelve patients required additional interventions following SIS procedure for persistence or recurrence of the underlying pathology. CONCLUSION: When performed by experienced endoscopists, safe and effective removal of embedded PCSEMS can be achieved via the SIS technique. PMID- 26416380 TI - Management of non-acute gastrointestinal defects using the over-the-scope clips (OTSCs): a retrospective single-institution experience. AB - INTRODUCTION: Advanced endoscopic techniques provide novel therapies for complications historically treated with surgical interventions. Over-the-scope clips (OTSCs) have recently been shown to be effective at endoscopic closure of gastrointestinal (GI) defects. We hypothesize that by following classic surgical principles of fistula management, a high rate of long-term success can be achieved with endoscopic closure of non-acute GI tract defects. METHODS: A retrospective review of a single-institution prospectively maintained database (2012-2015) of all patients referred for the management of GI leaks or fistulae who underwent attempted closure with the OTSC system (Ovesco, Germany) was performed. Acute perforations were excluded. The primary endpoint was long-term success defined by the absence of radiographic or clinical evidence of leak or fistula during follow-up. Patients were stratified by success or failure of OTSC closure and compared with Fisher's exact and Mann-Whitney U tests. RESULTS: We identified 22 patients with 28 defects (22 fistulae and 6 leaks). Most patients were female (59 %) with a mean age of 54 years (+/-14), median BMI of 29, and prior bariatric procedure (55 %). Comorbidities included smoking history (68 %) and diabetes (23 %). The majority of defects were solitary (64 %), involved the upper GI tract (82 %), and had been present for >30 days (50 %). Multiple therapeutic interventions were necessary in 46 % of defects. There were no adverse outcomes related to OTSC placement or misfiring. Endoscopic adjuncts were used in 61 % of cases. Overall success rate was 82 % (100 % for leaks and 76 % for fistulae) at a median follow-up of 4.7 months (IQR 2.1-8.4 months). Predictors of success and failure could not be distinguished due to limited sample size. CONCLUSIONS: Over-the-scope clips can be safely and effectively used in patients presenting with GI leaks and fistulae. Further research is required to characterize the determinants of long-term success and risk factors for failure. PMID- 26416381 TI - A prospective analysis of GERD after POEM on anterior myotomy. AB - BACKGROUND: Peroral endoscopic myotomy (POEM) is an emerging, minimally invasive procedure capable of overcoming limitations of achalasia treatments, but gastroesophageal reflux disease (GERD) after POEM is of concern and its risk factors have not been evaluated. This prospective study examined GERD and the association of POEM with reflux esophagitis. METHODS: Achalasia patients were recruited from a single center. The pre- and postoperative assessments included Eckardt scores, manometry, endoscopy, and pH monitoring. RESULTS: Between September 2011 and November 2014, 105 patients underwent POEM; 70 patients were followed up 3 months after POEM. Postoperatively, significant reductions were observed in lower esophageal sphincter (LES) pressure [from 40.0 +/- 22.8 to 20.7 +/- 14.0 mmHg (P < 0.05)], LES residual pressure [from 22.1 +/- 13.3 to 11.4 +/- 6.6 mmHg (P < 0.05)], and Eckardt scores [from 5.7 +/- 2.5 to 0.7 +/- 0.8 (P < 0.05)]. Symptomatic GERD and moderate reflux esophagitis developed in 5 and 11 patients (grade B, n = 8; grade C, n = 3), respectively, and were well controlled with proton pump inhibitors. Univariate logistic regression analysis revealed integrated relaxation pressure was a predictor of >=grade B reflux esophagitis. No POEM factors were found to be associated with reflux esophagitis. CONCLUSION: POEM is effective and safe in treating achalasia, with no occurrence of clinically significant refractory GERD. Myotomy during POEM, especially of the gastric side, was not associated with >=grade B (requiring medical intervention) reflux esophagitis. Extended gastric myotomy (2-3 cm) during POEM is recommended to improve outcomes. PMID- 26416382 TI - Flower-like supramolecular self-assembly of phosphonic acid appended naphthalene diimide and melamine. AB - Diverse supramolecular assemblies ranging from nanometres to micrometers of small aromatic pi-conjugated functional molecules have attracted enormous research interest in light of their applications in optoelectronics, chemosensors, nanotechnology, biotechnology and biomedicines. Here we study the mechanism of the formation of a flower-shaped supramolecular structure of phosphonic acid appended naphthalene diimide with melamine. The flower-shaped assembly formation was visualised by scanning electron microscope (SEM) and transmission electron microscopy (TEM) imaging, furthermore, XRD and DLS used to determined mode of aggregation. Characteristically, phosphonic acid-substituted at imide position of NDIs possess two important properties resulting in the formation of controlled flower-like nanostructures: (i) the aromatic core of the NDI which is designed to optimize the dispersive interactions (pi-pi stacking and van der Waals interactions) between the cores within a construct and (ii) phosphonic acid of NDI interact with malamine through molecular recognition i.e. strong hydrogen bonding (H-bonding). We believe such arrangements prevent crystallization and favour the directional growth of flower-like nanostructure in 3D fashion. These works demonstrate that complex self-assembly can indeed be attained through hierarchical non-covalent interactions of two components. Furthermore, flower like structures built from molecular recognition by these molecules indicate their potential in other fields if combined with other chemical entities. PMID- 26416383 TI - Multilocus species trees and species delimitation in a temporal context: application to the water shrews of the genus Neomys. AB - BACKGROUND: Multilocus data are becoming increasingly important in determining the phylogeny of closely related species and delimiting species. In species complexes where unequivocal fossil calibrations are not available, rigorous dating of the coalescence-based species trees requires accurate mutation rates of the loci under study but, generally, these rates are unknown. Here, we obtained lineage-specific mutation rates of these loci from a higher-level phylogeny with a reliable fossil record and investigated how different choices of mutation rates and species tree models affected the split time estimates. We implemented this strategy with a genus of water shrews, Neomys, whose taxonomy has been contentious over the last century. RESULTS: We sequenced 13 introns and cytochrome b from specimens of the three species currently recognized in this genus including two subspecies of N. anomalus that were originally described as species. A Bayesian multilocus species delimitation method and estimation of gene flow supported that these subspecies are distinct evolutionary lineages that should be treated as distinct species: N. anomalus (sensu stricto), limited to part of the Iberian Peninsula, and N. milleri, with a larger Eurasian range. We then estimated mutation rates from a Bayesian relaxed clock analysis of the mammalian orthologues with several fossil calibrations. Next, using the estimated Neomys-specific rates for each locus in an isolation-with-migration model, the split time for these sister taxa was dated at 0.40 Myr ago (with a 95 % confidence interval of 0.26 - 0.86 Myr), likely coinciding with one of the major glaciations of the Middle Pleistocene. We also showed that the extrapolation of non-specific rates or the use of simpler models would lead to very different split time estimates. CONCLUSIONS: We showed that the estimation of rigorous lineage-specific mutation rates for each locus allows the inference of robust split times in a species tree framework. These times, in turn, afford a better understanding of the timeframe required to achieve isolation and, eventually, speciation in sister lineages. The application of species delimitation methods and an accurate dating strategy to the genus Neomys helped to clarify its controversial taxonomy. PMID- 26416384 TI - Association of DNA methyltransferases expression with global and gene-specific DNA methylation in colorectal cancer cells. AB - There are conflicting reports regarding the association between DNA methyltransferases (DNMTs) expression and global or gene-specific DNA methylation in colorectal cancer (CRC) cells. To correlate DNMTs expression with DNA methylation, we quantified DNMT1, DNMT3A and DNMT3B mRNA levels in five CRC cell lines (HCT116, LS180, HT29/219, Caco2 and SW742) by real-time reverse transcriptase polymerase chain reaction (PCR) assay. In addition, we examined the global 5-methyl cytosine levels and the methylation patterns of 12 CpG islands in these CRC cells by enzyme-linked immunosorbent assay and methylation-specific PCR methods, respectively. The average expression levels of three DNMTs in HCT116, Caco2, HT29/219 and SW742, relative to the expression level in LS180 (taken to be 1), were 90.1, 31.6, 2.66 and 1.86. Our data indicated that overall about 1.45%, 1.03%, 0.98%, 0.86% and 0.85% of the cytosines were methylated in the genome of HCT116, Caco2, HT29/219, SW742 and LS180 cells, respectively. The 5-mC percentages were positively correlated with the relative cellular DNMTs expression in five CRC cell lines as verified by Pearson correlation test. However, we found no positive correlation between mRNA expression of DNMTs and gene promoter hypermethylation in these cells. Our results suggest that cellular DNMT expression is positively correlated with global DNA methylation level but not with regional DNA hypermethylation at each locus. PMID- 26416385 TI - Phenylephrine Pharmacokinetics and First-Pass Metabolism: What Is an Ideal Pharmacokinetic Surrogate? PMID- 26416386 TI - Rates of motorcycle helmet use and reasons for non-use among adults and children in Luang Prabang, Lao People's Democratic Republic. AB - BACKGROUND: Motorcycles make up 81 % of the total vehicle population and 74 % of road traffic deaths in Lao PDR. Helmets reduce the risk and severity of injuries resulting from motorcycle accidents by 72 %. Although Lao law mandates motorcycle helmet use among drivers and passengers, the prevalence of helmet use in Luang Prabang, Lao PDR is unknown. This project aimed to measure the prevalence of motorcycle helmet use among riders (i.e., drivers and passengers) in Luang Prabang. METHODS: An observational survey in Luang Prabang was conducted in February 2015 to measure the prevalence of motorcycle helmet use among drivers and passengers. Additionally, non-helmet wearing riders were surveyed to identify the reasons for helmet non-use. RESULTS: Of 1632 motorcycle riders observed, only 16.2 % wore helmets. Approximately 29 % of adults wore helmets while less than 1 % of all children wore helmets. When surveyed about attitudes towards helmet use, the majority of adult drivers indicated that they did not like how adult helmets feel or made them look. Additionally, almost half of motorcyclists who did not own child helmets reported that their child was too young to wear a helmet. CONCLUSIONS: Our finding that children wear helmets at significantly lower rates compared to adults is consistent with findings from neighboring countries in Southeast Asia. Results of this study have implications for public health campaigns targeting helmet use, especially among children. PMID- 26416387 TI - Missing steps in a staircase: a qualitative study of the perspectives of key stakeholders on the use of adaptive designs in confirmatory trials. AB - BACKGROUND: Despite the promising benefits of adaptive designs (ADs), their routine use, especially in confirmatory trials, is lagging behind the prominence given to them in the statistical literature. Much of the previous research to understand barriers and potential facilitators to the use of ADs has been driven from a pharmaceutical drug development perspective, with little focus on trials in the public sector. In this paper, we explore key stakeholders' experiences, perceptions and views on barriers and facilitators to the use of ADs in publicly funded confirmatory trials. METHODS: Semi-structured, in-depth interviews of key stakeholders in clinical trials research (CTU directors, funding board and panel members, statisticians, regulators, chief investigators, data monitoring committee members and health economists) were conducted through telephone or face to-face sessions, predominantly in the UK. We purposively selected participants sequentially to optimise maximum variation in views and experiences. We employed the framework approach to analyse the qualitative data. RESULTS: We interviewed 27 participants. We found some of the perceived barriers to be: lack of knowledge and experience coupled with paucity of case studies, lack of applied training, degree of reluctance to use ADs, lack of bridge funding and time to support design work, lack of statistical expertise, some anxiety about the impact of early trial stopping on researchers' employment contracts, lack of understanding of acceptable scope of ADs and when ADs are appropriate, and statistical and practical complexities. Reluctance to use ADs seemed to be influenced by: therapeutic area, unfamiliarity, concerns about their robustness in decision making and acceptability of findings to change practice, perceived complexities and proposed type of AD, among others. CONCLUSIONS: There are still considerable multifaceted, individual and organisational obstacles to be addressed to improve uptake, and successful implementation of ADs when appropriate. Nevertheless, inferred positive change in attitudes and receptiveness towards the appropriate use of ADs by public funders are supportive and are a stepping stone for the future utilisation of ADs by researchers. PMID- 26416388 TI - Effectiveness of agalsidase alfa enzyme replacement in Fabry disease: cardiac outcomes after 10 years' treatment. AB - BACKGROUND: To explore long-term effects of agalsidase alfa on Fabry disease cardiomyopathy in adults. METHODS: Retrospective analysis of prospectively collected data at a single center in Mainz, Germany, revealed that 45 adult patients (21 men, 24 women) had received agalsidase alfa for approximately 10 years. Data were extracted for cardiac and heart failure status, echocardiographic evaluations of cardiac structure and function, and renal function at treatment start and during agalsidase alfa treatment. RESULTS: After 10 years of agalsidase alfa treatment, heart failure classification had improved by at least 1 class in 22/42 patients, and angina scores were stable or improved in 41/42 patients. During treatment, no patients without left ventricular hypertrophy (LVH) at treatment initiation developed LVH, and no patients with LVH at treatment initiation showed a decline in left ventricular mass. CONCLUSIONS: Approximately 10 years of agalsidase alfa treatment appeared to have beneficial effects for controlling progression and improving some symptoms of Fabry associated cardiomyopathy. PMID- 26416389 TI - Discriminating nutritional quality of foods using the 5-Color nutrition label in the French food market: consistency with nutritional recommendations. AB - PURPOSE: Our objectives were to assess the performance of the 5-Colour nutrition label (5-CNL) front-of-pack nutrition label based on the Food Standards Agency nutrient profiling system to discriminate nutritional quality of foods currently on the market in France and its consistency with French nutritional recommendations. METHODS: Nutritional composition of 7777 foods available on the French market collected from the web-based collaborative project Open Food Facts were retrieved. Distribution of products across the 5-CNL categories according to food groups, as arranged in supermarket shelves was assessed. Distribution of similar products from different brands in the 5-CNL categories was also assessed. Discriminating performance was considered as the number of color categories present in each food group. In the case of discrepancies between the category allocation and French nutritional recommendations, adaptations of the original score were proposed. RESULTS: Overall, the distribution of foodstuffs in the 5 CNL categories was consistent with French recommendations: 95.4% of 'Fruits and vegetables', 72.5% of 'Cereals and potatoes' were classified as 'Green' or 'Yellow' whereas 86.0% of 'Sugary snacks' were classified as 'Pink' or 'Red'. Adaptations to the original FSA score computation model were necessary for beverages, added fats and cheese in order to be consistent with French official nutritional recommendations. CONCLUSION: The 5-CNL label displays a high performance in discriminating nutritional quality of foods across food groups, within a food group and for similar products from different brands. Adaptations from the original model were necessary to maintain consistency with French recommendations and high performance of the system. PMID- 26416390 TI - Service users' and carers' views on research towards stratified medicine in psychiatry: a qualitative study. AB - BACKGROUND: Approximately 30% of people with a diagnosis of schizophrenia receive little to no benefit from current medications. There is therefore an urgent need to develop more precisely targeted and effective treatments. Identifying biomarkers to predict response to treatment and stratify patients into groups may be a way forward. However, we know little about service users' and carers' attitudes regarding such a 'stratified medicine' approach for psychiatry-nor how this might impact on their willingness to participate in stratified medicine research. This paper presents psychiatric service user and carer views on research to develop stratified medicine for treatment resistant schizophrenia, and explores the conditions under which people would be prepared to participate in a trial and their willingness to undergo various research procedures. METHODS: Participatory methods were used throughout. A consultation was undertaken with an existing Service User Advisory Group (SUAG) in order to establish a topic guide. Service user focus groups were then conducted by service user researchers in Manchester, London and Edinburgh (totalling 18 people) and one carer focus group in London, attended by eight participants. Focus groups were digitally recorded, the transcripts analysed in NVivo 10 using a simple thematic analysis, and quotations de-identified to protect participants. RESULTS: The data reflected enthusiasm for the potential of stratified medicine and both service users and carers demonstrated a strong desire to help others. However, some service users and carers feared poor performance on neuropsychological assessments, and reported that certain medication side effects might discourage them from undergoing procedures demanding immobility and concentration. Concerns were voiced that stratified medicine could encourage an overemphasis on biological symptoms, at the expense of psychosocial factors and subjective experience. CONCLUSIONS: People with experience of treatment resistant schizophrenia would welcome stratified medicine research; however researchers should take into account how such experience might inflect service users' willingness to undergo various procedures in the context of this research. These results reinforce the value of service user perspectives in the development and evaluation of novel treatment approaches. PMID- 26416392 TI - Factors affecting (223)Ra therapy: clinical experience after 532 cycles from a single institution. AB - PURPOSE: The aim of this study was to identify baseline features that predict outcome in (223)Ra therapy. METHODS: We retrospectively reviewed 110 patients with metastatic castration-resistant prostate cancer treated with (223)Ra. End points were overall survival (OS), progression-free survival (PFS), bone event free survival (BeFS), and bone marrow failure (BMF). The following parameters were evaluated prior to the first (223)Ra cycle: serum levels of hemoglobin (Hb), prostate-specific antigen (PSA), alkaline phosphatase (ALP), Eastern Cooperative Oncology Group (ECOG) status, pain score, use of chemotherapy, and external beam radiation therapy (EBRT). During/after (223)Ra we evaluated: the total number of radium cycles (RaTot), the PSA doubling time (PSADT), and the use of chemotherapy, EBRT, abiraterone, and enzalutamide. RESULTS: A significant reduction of ALP (p < 0.001) and pain score (p = 0.041) occurred throughout the (223) Ra cycles. The risk of progression was associated with declining ECOG status [hazard ratio (HR) = 3.79; p < 0.001] and decrease in PSADT (HR = 8.22; p < 0.001). RaTot, ALP, initial ECOG status, initial pain score, and use of abiraterone were associated with OS (p <= 0.008), PFS (p <= 0.003), and BeFS (p <= 0.020). RaTot, ALP, initial ECOG status, and initial pain score were significantly associated with BMF (p <= 0.001) as well as Hb (p < 0.001) and EBRT (p = 0.009). On multivariable analysis, only RaTot and abiraterone remained significantly associated with OS (p < 0.001; p = 0.033, respectively), PFS (p < 0.001; p = 0.041, respectively), and BeFS (p < 0.001; p = 0.019, respectively). Additionally, RaTot (p = 0.027) and EBRT (p = 0.013) remained significantly associated with BMF. CONCLUSION: Concomitant use of abiraterone and (223)Ra seems to have a beneficial effect, while the EBRT may increase the risk of BMF. PMID- 26416393 TI - IL-1A rs1800587, IL-1B rs1143634 and IL-1R1 rs2234650 polymorphisms in Iranian patients with systemic sclerosis. AB - Systemic Sclerosis (SSc) is a systemic autoimmune disorder, with ambiguous pathogenesis. Genetic and environmental factors were proved to be correlated with SSc aetiology. Single nucleotide polymorphisms (SNPs) in cytokine genes can alter the structure and function of the cytokines and consequently may increase the susceptibility to a specific disease. In this study, we investigated SNPs of the IL-1 gene cluster in Iranian SSc patients. We obtained blood samples from 170 SSc patients and 213 healthy individuals. Cytokine genotyping results were obtained by polymerase chain reaction with sequence-specific primers (PCR-SSP). IL-1A rs1800587, IL-1B rs1143634 and IL-1R1 rs2234650 were evaluated for SNP study. The frequency of the IL-1B rs1143634 CT genotype was significantly lower in SSc patients compared to the controls (OR = 0.584; 95% CI = 0.385-0.886; P-value = 0.023), so we propose that CT genotype of this allele might be protective. According to our haplotype analysis, CCC haplotype frequency is higher in the control group compared to SSc patients (OR = 1.575; 95% CI = 1.176-2.111; P-value = 0.008) and in contrast, CTC haplotype frequency is lower in the control group compared to SSc patients (OR = 0.152; 95% CI = 0.047-0.484; P-value = 0.002), so they might decrease and increase the susceptibility of having SSc, respectively. In addition, we reported two significant diplotypes frequency differences among SSc patients and healthy individuals. It is highly important that there is not much resemblance between the IL-1 gene cluster polymorphism in different populations, so we can indicate that SNPs may play critical roles when they are combined with other genetic and environmental factors. PMID- 26416391 TI - Reliability of radioisotope-guided sentinel lymph node biopsy in penile cancer: verification in consideration of the European guidelines. AB - BACKGROUND: Lymph node (LN) staging in penile cancer has strong prognostic implications. This contrasts with the high morbidity of extended inguinal LN dissection (LND) or over-treatment of many patients. Therefore, inguinal dynamic sentinel node biopsy (DSNB) or modified LND is recommended by the European Association of Urology (EAU) guidelines to evaluate the nodal status of patients with clinically node-negative penile cancer. This study analyzed the reliability and morbidity of radioguided DSNB in penile cancer under consideration of the current EAU recommendations in an experienced center with long-term follow-up. METHODS: Thirty-four patients who received primary surgery and had radioguided inguinal DSNB for penile cancer (>= T1G2) were included (July 2004 to July 2013). Preoperative sentinel LN (SLN) mapping was performed using lymphoscintigraphy after peritumoral injection of (99m)Technetium nanocolloid on the day of surgery. During surgery, SLNs were detected using a gamma probe. According to the EAU guidelines, a secondary ipsilateral radical inguinal LND was performed in patients who had positive SLNs. The false-negative and complication rates of DSNB were assessed. RESULTS: A total of 32 patients were analyzed. Two patients were lost to follow-up. A total of 166 SLNs (median, 5; range, 1-15) were removed and 216 LNs (SLNs + non-SLNs; median, 6; range, 2-19) were dissected. LN metastases were found in five of the 32 (15.6 %) patients and nine of the 166 (5.4 %) SLNs were found to contain metastases. None of the remaining 50 non-SLNs contained metastases. In only one of the five SLN-positive patients, a singular further metastasis was detected by secondary radical inguinal LND. During follow-up (median, 30.5; range, 5-95 months) no inguinal nodal recurrence was detected. DSNB-related complications occurred in 11.1 % of explored groins. DISCUSSION AND CONCLUSIONS: Radioguided DSNB is a suitable procedure for LN staging in penile cancer considering the EAU recommendations and with the required experience. Under these circumstances, patients can be spared from higher morbidity without compromising the detection of LN metastases or therapeutic implications. Improvement of the methodology used to perform DSNB should be developed further to decrease the risk of missing LN metastases and to simplify the procedure. PMID- 26416394 TI - Levetiracetam for the treatment of status epilepticus. AB - Status epilepticus (SE) is a common, severe neurological disorder, and prolonged seizures in SE may result in irreversible brain damage in association with high disability and mortality rates. Thus, termination of seizures as soon as possible is vital for the successful treatment of this disease. Levetiracetam, a new broad spectrum anti-epileptic drug, can be used to rapidly and effectively control SE episodes with few side effects. Thus, an understanding of the use of this drug to treat SE will help clinicians to more effectively control SE and improve patient prognosis. PMID- 26416395 TI - Management of epilepsy during pregnancy. AB - Over a million women with epilepsy are of childbearing age in the USA and require careful consideration of not only type of antiepileptic drug (AED) but also dosage, in the event of a planned or unplanned pregnancy. Careful selection of AEDs can lower the potential adverse effects of AEDs while maintaining seizure control for the health of not only on the patient, the mother, but also the unborn fetus. The number of treatment options has increased significantly in the last 20 years and remarkable progress has been made in characterizing the risks AEDs pose to pregnant women and fetuses. There are now robust data on teratogenesis, a growing body of data on neonatal/obstetrical outcomes and on neurodevelopmental problems associated with each AED, and some data about seizure control during pregnancy. Based on clinical evidence so far, levetiracetam and lamotrigine have emerged as the safest during pregnancy, although others may also be suitable. Despite being a common belief, not all polytherapy combinations may be detrimental, especially when avoiding valproate and topiramate. Here, we review the available clinical research, highlighting recent findings and provide thoughts for future directions in the field. PMID- 26416396 TI - Recognition and treatment of autonomic disturbances in Parkinson's disease. AB - Symptoms of dysautonomia are common in Parkinson's disease (PD), and almost all the functional autonomic subsystems can be involved in PD. However, they are still under-recognized in everyday clinical practice. Autonomic dysfunction can be observed in the early stages of PD, affect a substantial proportion of patients, impact quality of life and can also help in differential diagnosis. This review aims to provide an overview of the pathophysiology, clinical manifestations, relevant examination and treatment of cardiovascular, gastrointestinal, urogenital, thermoregulatory and pupil autonomic dysfunctions in Parkinson's disease. PMID- 26416397 TI - The relevance of pre-motor symptoms in Parkinson's disease. AB - Parkinson's disease (PD) has a wide range of non-motor symptoms including; constipation, sleep disturbance, deficits in vision and olfaction, mood disorders and cardiac autonomic dysfunction. Several of these non-motor symptoms can manifest prior to the onset of motor symptoms. Recognizing these pre-motor symptoms may enable early diagnosis of PD. Currently, no single pre-motor symptom is able to predict the development of PD with 100% sensitivity or specificity. Ongoing studies in several independent at-risk cohorts should reveal the potential of combinations of pre-motor symptoms and multi-stage screening strategies to identify individuals at increased risk of PD. PD progression may be governed by a prion-like spread of a-syn throughout the nervous system. Identifying individuals at the earliest stage will likely be critical to preventing the pathological progression of PD, highlighting the relevance of pre motor symptoms in the future treatment of the disease. PMID- 26416398 TI - A parsimonious statistical method to detect groupwise differentially expressed functional connectivity networks. AB - Group-level functional connectivity analyses often aim to detect the altered connectivity patterns between subgroups with different clinical or psychological experimental conditions, for example, comparing cases and healthy controls. We present a new statistical method to detect differentially expressed connectivity networks with significantly improved power and lower false-positive rates. The goal of our method was to capture most differentially expressed connections within networks of constrained numbers of brain regions (by the rule of parsimony). By virtue of parsimony, the false-positive individual connectivity edges within a network are effectively reduced, whereas the informative (differentially expressed) edges are allowed to borrow strength from each other to increase the overall power of the network. We develop a test statistic for each network in light of combinatorics graph theory, and provide p-values for the networks (in the weak sense) by using permutation test with multiple-testing adjustment. We validate and compare this new approach with existing methods, including false discovery rate and network-based statistic, via simulation studies and a resting-state functional magnetic resonance imaging case-control study. The results indicate that our method can identify differentially expressed connectivity networks, whereas existing methods are limited. PMID- 26416399 TI - Simulation and prediction of protein production in fed-batch E. coli cultures: An engineering approach. AB - An overall model describing the dynamic behavior of fed-batch E. coli processes for protein production has been built, calibrated and validated. Using a macroscopic approach, the model consists of three interconnected blocks allowing simulation of biomass, inducer and protein concentration profiles with time. The model incorporates calculation of the extra and intracellular inducer concentration, as well as repressor-inducer dynamics leading to a successful prediction of the product concentration. The parameters of the model were estimated using experimental data of a rhamnulose-1-phosphate aldolase-producer strain, grown under a wide range of experimental conditions. After validation, the model has successfully predicted the behavior of different strains producing two different proteins: fructose-6-phosphate aldolase and omega-transaminase. In summary, the presented approach represents a powerful tool for E. coli production process simulation and control. PMID- 26416400 TI - Reverse sural flap with an adipofascial extension for reconstruction of soft tissue defects with dead spaces in the heel and ankle. AB - INTRODUCTION: The reconstruction of soft tissue defects with dead spaces in the heel and ankle is challenging. This article describes our experience in the reconstruction of such defects using the reverse sural flap with an adipofascial extension. METHOD: Reverse sural flaps with an adipofascial extension were used in 26 patients with soft tissue defects in the heel (n = 24) or ankle (n = 2). Extended adipofascial tissue was utilized to fill the dead space. The sizes of the adipofascial extensions varied from 2.0 to 5.0 cm in length and 4.0 to 12.5 cm in width. RESULT: Twenty-three flaps survived completely, and lateral marginal necrosis occurred in three flaps. All the recipient-site wounds healed without any signs of infection. The reconstruction outcomes were excellent in 20 patients and good in 6 patients according to the criteria of Boyden et al. CONCLUSION: The extended adipofascial tissue of the reverse sural flap improves closure of the dead spaces in soft tissue defects of the heel and ankle and thus provides beneficial conditions for the treatment of infection and reconstruction of both the function and contour of the soft tissue defects with dead spaces in the heel and ankle. PMID- 26416401 TI - Non operative management of blunt splenic trauma: a prospective evaluation of a standardized treatment protocol. AB - PURPOSE: The advantages of the conservative approach for major spleen injuries are still debated. This study was designed to evaluate the safety and effectiveness of NOM in the treatment of minor (grade I-II according with the American Association for the Surgery of Trauma; AAST) and severe (AAST grade III V) blunt splenic trauma, following a standardized treatment protocol. METHODS: All the hemodynamically stable patients with computer tomography (CT) diagnosis of blunt splenic trauma underwent NOM, which included strict clinical and laboratory observation, 48-72 h contrast-enhanced ultrasonography (CEUS) follow up and splenic angioembolization, performed both in patients with admission CT evidence of vascular injuries and in patients with falling hematocrit during observation. RESULTS: 87 patients [32 (36.7 %) women and 55 (63.2 %) men, median age 34 (range 14-68)] were included. Of these, 28 patients (32.1 %) had grade I, 22 patients (25.2 %) grade II, 20 patients (22.9 %) grade III, 11 patients (12.6 %) grade IV and 6 patients (6.8 %) grade V injuries. The overall success rate of NOM was 95.4 % (82/87). There was no significant difference in the success rate between the patients with different splenic injuries grade. Of 24 patients that had undergone angioembolization, 22 (91.6 %) showed high splenic injury grade. The success rate of embolization was 91.6 % (22/24). No major complications were observed. The minor complications (2 pleural effusions, 1 pancreatic fistula and 2 splenic abscesses) were successfully treated by EAUS or CT guided drainage. CONCLUSIONS: The non operative management of blunt splenic trauma, according to our protocol, represents a safe and effective treatment for both minor and severe injuries, achieving an overall success rate of 95 %. The angiographic study could be indicated both in patients with CT evidence of vascular injuries and in patients with high-grade splenic injuries, regardless of CT findings. PMID- 26416402 TI - A small case series of aortic balloon occlusion in trauma: lessons learned from its use in ruptured abdominal aortic aneurysms and a brief review. AB - BACKGROUND: EndoVascular and Hybrid Trauma Management (EVTM) is an emerging concept for the early treatment of trauma patients using aortic balloon occlusion (ABO), embolization agents and stent grafts to stop ongoing traumatic bleeding. These techniques have previously been implemented successfully in the treatment of ruptured aortic aneurysm. AIMS: We describe our very recent experience of EVTM using ABO in bleeding patients and lessons learned over the last 20 years from the endovascular treatment of ruptured abdominal aortic aneurysms (rAAA). We also briefly describe current knowledge of ABO usage in trauma. METHODS: A small series of educational cases in our hospital is described, where endovascular techniques were used to gain temporary hemorrhage control. The methods used for rAAA and their applicability to EVTM with a multidisciplinary approach are presented. RESULTS: Establishing femoral arterial access immediately on arrival at the emergency room and use of an angiography table in the surgical suite may facilitate EVTM at an early stage. ABO may be an effective method for the temporary stabilization of severely hemodynamically unstable patients with hemorrhagic shock, and may be useful as a bridge to definitive treatment of the bleeding patients. CONCLUSION: EVTM, including the usage of ABO, can be initiated on patient arrival and is feasible. Further data need to be collected to investigate proper indications for ABO, best clinical usage, results and potential complications. Accordingly, the ABOTrauma Registry has recently been set up. Existing experiences of EVTM and lessons from the endovascular treatment of rAAA may be useful in trauma management. PMID- 26416403 TI - HFE p.C282Y gene variant is associated with varicose veins in Russian population. AB - Recently, the association of polymorphism rs1800562 (p.C282Y) in the hemochromatosis (HFE) gene with the increased risk of venous ulceration was shown. We hypothesized that HFE gene polymorphism might be involved not only in ulceration process, but also in susceptibility to primary varicose veins. We genotyped HFE p.C282Y (rs1800562) and p.H63D (rs1799945) variants in patients with primary varicose veins (n = 463) and in the control group (n = 754). In our study, p.282Y variant (rs1800562 A allele) was significantly associated with the risk of varicose veins (OR 1.79, 95 % CI = 1.11-2.89, P = 0.02). A borderline significant reverse association of p.63D variant (rs1799945 G allele) with venous leg ulcer development was revealed in Russians (OR 0.25, 95 % CI = 0.06-1.00, P = 0.05), but not in the meta-analysis (P = 0.56). We conclude that the HFE gene polymorphism can affect the risk of developing primary varicose veins. PMID- 26416405 TI - Longevity and aging. Mechanisms and perspectives. AB - Longevity can mostly be determined with relative accuracy from birth and death registers when available. Aging is a multifactorial process, much more difficult to quantitate. Every measurable physiological function declines with specific speeds over a wide range. The mechanisms involved are also different, genetic factors are of importance for longevity determinations. The best-known genes involved are the Sirtuins, active at the genetic and epigenetic level. Aging is multifactorial, not "coded" in the genome. There are, however, a number of well studied physical and biological parameters involved in aging, which can be determined and quantitated. We shall try to identify parameters affecting longevity as well as aging and suggest some reasonable predictions for the future. PMID- 26416404 TI - Increased inflammatory markers with altered antioxidant status persist after clinical recovery from severe sepsis: a correlation with low HDL cholesterol and albumin. AB - Markers of oxidative stress and antioxidant status in relation to inflammatory mediators in septic patients (SPs) during the course of sepsis and after recovery were analysed. Patients were 30 critically ill adults in severe sepsis/septic shock, 19 of which completed 3 samplings (S1: within 24 h after onset of sepsis, S7: 7 days after S1, R7: 7 days after clinical recovery). Comparing SPs with healthy controls (HCs), enhanced C-reactive protein, procalcitonin, bilirubin and CuZn-superoxide dismutase activity were found at S1 only. Oxidized low-density lipoprotein, conjugated dienes and nitrotyrosine were increased at S1, culminated at S7 and reverted nearly to HC levels at R7. Reduced catalase activity and serum amyloid were observed at S1 and endured until R7. Increase in IL-6, IL-10 and tumour necrosis factor alpha (TNF-alpha) with accompanying decrease in apolipoprotein A1, high-density lipoprotein (HDL) cholesterol, selenium, zinc, albumin, paraoxonase 1 and glutathione peroxidase 1 activity appeared at S1 and persisted until R7. TNF-alpha, IL-10 and markers of oxidative stress were in negative correlation with HDL cholesterol and albumin at R7. After clinical recovery, increased cytokines and decreased antioxidants were accompanied by lower albumin and HDL cholesterol levels. During this important and beneficial period of tissue repair, patients with prolonged persistence of this status are probably more vulnerable to secondary infections and should be dealt with as constituting a high-risk population. PMID- 26416406 TI - Hypertrophic cardiomyopathy - Obstructive form as hematological disease, from hemodynamic to hematologic abnormalities. PMID- 26416408 TI - Isolation, Identification, and Autotoxicity Effect of Allelochemicals from Rhizosphere Soils of Flue-Cured Tobacco. AB - Autotoxicity, defined as a deleterious allelopathic effect among individuals of the same plant species, is considered as one of the factors that contributes to replant failure. Tobacco, as an important cultured and economic crop over the world, has been often hampered by replant failure. In view of the seriousness of this problem, the allelochemicals of flue-cured tobacco and their allelopathic effects were investigated. The extracts of rhizosphere soil exhibited phytotoxic activities against Lactuca sativa and autotoxic activities against tobacco itself. Bioassay-guided fractionation of the extract led to the isolation of six compounds, the structures of which were elucidated by spectroscopic analysis. Among them, beta-cembrenediol (1), di-n-hexyl phthalate (2), and bis(2 propylheptyl) phthalate (3) showed observably phytotoxic activities against L. sativa seedlings and autotoxic activities on tobacco. The allelochemicals were then verified in the root zone soils of flue-cured tobacco by high-performance liquid chromatography (HPLC). These results provide new insights into the allelopathic mechanisms involved in the replant failure of flue-cured tobacco. PMID- 26416407 TI - Trends in the incidences of acute myocardial infarction in coastal and inland areas in Japan: The Yamagata AMI Registry. AB - BACKGROUND: It has been reported that there are regional differences in the incidence of acute myocardial infarction (AMI) in Japan. The purpose of this study was to investigate trends in regional differences in AMI incidence and dyslipidemia between coastal and inland areas. METHODS: We investigated trends in AMI incidence and risk factors in 5325 first-ever AMI patients residing in a coastal area (n=1817), a rural inland area (n=1959), or an urban inland area (n=1549) for the periods 1994-2002, and 2003-2010, using data from the Yamagata AMI Registry. RESULTS: Patients in the coastal area were significantly older than those in rural and urban inland areas and had a lower prevalence of dyslipidemia. The age-adjusted incidence rate of AMI was significantly lower in coastal and rural inland areas patients than those from urban inland area (males: 43.3, 42.2, and 51.3/10(5) person-years; females: 17.4, 20.0, and 23.7/10(5) person-years, respectively) during 2 observation periods. Due to a large increase in AMI incidence in younger males of the coastal area and a decrease in AMI incidence in late elderly females of the urban inland area, no significant regional differences in the age-adjusted incidence rates of AMI were observed during the 2003-2010 period in both genders. The increase in AMI incidence in males in the coastal area was associated with an increasing prevalence of dyslipidemia. CONCLUSION: There were no longer any regional differences observed in AMI incidence, which was considered to be associated with increased dyslipidemia especially in the coastal area. PMID- 26416409 TI - Design of an internal amplification control for a duplex PCR used in the detection of Shiga toxin producing Escherichia coli in pediatric feces. AB - A conventional PCR targeted directly to the detection of Shiga toxin-producing Escherichia coli (STEC) in diarrheal stools of symptomatic patients may require the introduction of internal controls to detect false negative results. In the present study, we designed a competitive internal amplification control (IAC) to be included in a well-known PCR protocol used to amplify the stx1and stx2 genes from STEC isolates. The IAC was introduced in the PCR reaction and amplified when E. coli O157:H7 cultures and contaminated pediatric feces were assayed. When STEC concentration was 10(3) CFU ml(-1) in pure culture and 10(4) CFU g(-1) in contaminated stools, the IAC at concentration of 0.143 pg MUl(-1) in the PCR reaction mixture was co-amplified with the stx2 sequence, producing bands of 279 and 349 bp, respectively. These STEC values were considered the detection limits of the duplex PCR. The specific detection of STEC by duplex PCR including IAC might be achieved directly on pediatric feces when the pathogen load reaches concentrations of at least 10(4) CFU g(-1). PMID- 26416410 TI - Going against the grain. PMID- 26416411 TI - Defining the Impact of Surgical Approach on Perioperative Outcomes for Patients with Gastric Cardia Malignancy. AB - BACKGROUND: Gastric cardia cancer is currently treated with several operations. The purpose of the current study was to compare outcomes associated with three common operative approaches. METHODS: The ACS-NSQIP Participant Use File was searched to identify all patients with gastric cardia malignancy who underwent total gastrectomy (TG), transhiatal esophagectomy (THE), or thoraco-abdominal esophagectomy (TAE) between 2005 and 2012. Demographic, perioperative risk factors, and outcomes were analyzed. RESULTS: Overall, there were 982 patients identified in the database who met inclusion criteria. The median age was 65 years (range 20-88) and 807 (82.2%) were male. The number of patients allocated to each approach was 204 TGs (20.8%), 271 THE (27.6%), and 507 TAE (51.6%). All approaches had similar major morbidity, cardiopulmonary morbidity, and 30-day mortality, however, TAE was associated with the highest overall morbidity (TAE 49.9% vs. TG 40.7% and THE 43.5%, p = 0.048). The independent risk factors predicting mortality were age greater than 65 years, history of myocardial infarction, and postoperative cardiopulmonary morbidity. CONCLUSIONS: For patients with proximal gastric cancer, the three most common operative approaches were associated with clinically-significant rates of overall and major morbidity. Approach-associated morbidity should be considered along with tumor location and extent when choosing a technique for resection of gastric cardia malignancy. PMID- 26416412 TI - High prevalence of colonization of oral cavity by respiratory pathogens in frail older patients with oropharyngeal dysphagia. AB - BACKGROUND: Aspiration pneumonia (AP) is caused by dysfunctional swallowing resulting in aspiration of material colonized by respiratory pathogens. The aim of this study was to assess and compare the swallowing physiology, health status, oral health status, and oral/nasal microbiota in frail older patients (FOP) with oropharyngeal dysphagia (OD) and a control group. METHODS: We studied 47 FOP (>70 year) with OD by videofluoroscopy (17 with acute pneumonia -APN-, 15 with prior pneumonia-PNP- and 15 without) and 14 older controls without OD (H). Oral/nasal colonization by five respiratory pathogens was evaluated by qPCR, whereas commensal microbiota composition was assessed by pyrosequencing. KEY RESULTS: (i) Frail older patients with OD presented similar comorbidities, poor functionality, polymedication, and prevalent videofluoroscopic signs of impaired safety of swallow (33.3-61.5%). However, patients with OD-APN also presented malnutrition, delayed laryngeal vestibule closure (409.23 +/- 115.6 ms; p < 0.05), and silent aspirations (15.6%). (ii) Oral health was poor in all groups, 90% presented periodontitis and 72%, caries. (iii) Total bacterial load was similar in all groups, but higher in the oropharynx (>10(8) CFU/mL) than in the nose (<10(6) CFU/mL) (p < 0.0001). Colonization by respiratory pathogens was very high: 93% in OD patients (p < 0.05 vs H); 93% in OD-PNP (p < 0.05 vs H); 88% in OD-APN (p = 0.07 vs H), and lower in controls (67%). CONCLUSIONS & INFERENCES: Frail older patients with OD had impaired health status, poor oral health, high oral bacterial load, and prevalence of oral colonization by respiratory pathogens and VFS signs of impaired safety of swallow, and were therefore at risk for contracting AP. PMID- 26416413 TI - Multistep, effective drug distribution within solid tumors. AB - The distribution of drugs within solid tumors presents a long-standing barrier for efficient cancer therapies. Tumors are highly resistant to diffusion, and the lack of blood and lymphatic flows suppresses convection. Prolonged, continuous intratumoral drug delivery from a miniature drug source offers an alternative to both systemic delivery and intratumoral injection. Presented here is a model of drug distribution from such a source, in a multistep process. At delivery onset the drug mainly affects the closest surroundings. Such 'priming' enables drug penetration to successive cell layers. Tumor 'void volume' (volume not occupied by cells) increases, facilitating lymphatic perfusion. The drug is then transported by hydraulic convection downstream along interstitial fluid pressure (IFP) gradients, away from the tumor core. After a week tumor cell death occurs throughout the entire tumor and IFP gradients are flattened. Then, the drug is transported mainly by 'mixing', powered by physiological bulk body movements. Steady state is achieved and the drug covers the entire tumor over several months. Supporting measurements are provided from the LODER system, releasing siRNA against mutated KRAS over months in pancreatic cancer in-vivo models. LODER was also successfully employed in a recent Phase 1/2 clinical trial with pancreatic cancer patients. PMID- 26416414 TI - Imatinib dose escalation versus sunitinib as a second line treatment in KIT exon 11 mutated GIST: a retrospective analysis. AB - We retrospectively reviewed data from 123 patients (KIT exon 11 mutated) who received sunitinib or dose-escalated imatinib as second line.All patients progressed on imatinib (400 mg/die) and received a second line treatment with imatinib (800 mg/die) or sunitinib (50 mg/die 4 weeks on/2 off or 37.5 mg/day). Deletion versus other KIT 11 mutation was recorded, correlated with clinical benefits.64% received imatinib, 36% sunitinib. KIT exon 11 mutation was available in 94 patients. With a median follow-up of 61 months, median time to progression (TTP) in patients receiving sunitinib and imatinib was 10 (95% CI 9.7-10.9) and 5 months (95% CI 3.6-6.7) respectively (P = 0.012). No difference was found in overall survival (OS) (P = 0.883). In imatinib arm, KIT exon 11 deletions was associated with a shorter TTP (7 vs 17 months; P = 0.02), with a trend in OS (54 vs 71 months P = 0.063). No difference was found in patients treated with sunitinib (P = 0.370).A second line with sunitinib was associated with an improved TTP in KIT exon 11 mutated patients progressing on imatinib 400 mg/die. Deletions in exon 11 seemed to be correlated with worse outcome in patients receiving imatinib-based second line. PMID- 26416415 TI - miR-134 in extracellular vesicles reduces triple-negative breast cancer aggression and increases drug sensitivity. AB - Exosomes (EVs) have relevance in cell-to-cell communication carrying pro tumorigenic factors that participate in oncogenesis and drug resistance and are proposed to have potential as self-delivery systems. Advancing on our studies of EVs in triple-negative breast cancer, here we more comprehensively analysed isogenic cell line variants and their EV populations, tissues cell line variants and their EV populations, as well as breast tumour and normal tissues. Profiling 384 miRNAs showed EV miRNA content to be highly representative of their cells of origin. miRNAs most substantially down-regulated in aggressive cells and their EVs originated from 14q32. Analysis of miR-134, the most substantially down regulated miRNA, supported its clinical relevance in breast tumours compared to matched normal breast tissue. Functional studies indicated that miR-134 controls STAT5B which, in turn, controls Hsp90. miR-134 delivered by direct transfection into Hs578Ts(i)8 cells (in which it was greatly down-regulated) reduced STAT5B, Hsp90, and Bcl-2 levels, reduced cellular proliferation, and enhanced cisplatin induced apoptosis. Delivery via miR-134-enriched EVs also reduced STAT5B and Hsp90, reduced cellular migration and invasion, and enhanced sensitivity to anti Hsp90 drugs. While the differing effects achieved by transfection or EV delivery are likely to be, at least partly, due to specific amounts of miR-134 delivered by these routes, these EV-based studies identified miRNA-134 as a potential biomarker and therapeutic for breast cancer. PMID- 26416416 TI - TP53 and MDM2 single nucleotide polymorphisms influence survival in non-del(5q) myelodysplastic syndromes. AB - P53 is a key regulator of many cellular processes and is negatively regulated by the human homolog of murine double minute-2 (MDM2) E3 ubiquitin ligase. Single nucleotide polymorphisms (SNPs) of either gene alone, and in combination, are linked to cancer susceptibility, disease progression, and therapy response. We analyzed the interaction of TP53 R72P and MDM2 SNP309 SNPs in relationship to outcome in patients with myelodysplastic syndromes (MDS). Sanger sequencing was performed on DNA isolated from 208 MDS cases. Utilizing a novel functional SNP scoring system ranging from +2 to -2 based on predicted p53 activity, we found statistically significant differences in overall survival (OS) (p = 0.02) and progression-free survival (PFS) (p = 0.02) in non-del(5q) MDS patients with low functional scores. In univariate analysis, only IPSS and the functional SNP score predicted OS and PFS in non-del(5q) patients. In multivariate analysis, the functional SNP score was independent of IPSS for OS and PFS. These data underscore the importance of TP53 R72P and MDM2 SNP309 SNPs in MDS, and provide a novel scoring system independent of IPSS that is predictive for disease outcome. PMID- 26416417 TI - Phospho-ERK1/2 levels in cancer cell nuclei predict responsiveness to radiochemotherapy of rectal adenocarcinoma. AB - Locally advanced rectal adenocarcinoma is treated with radiochemotherapy (RCT) before surgery. The response to RCT is heterogeneous and consensus regarding reliable predictors is lacking. Since the ERK pathway is implicated in radioprotection, we examined pretreatment biopsies from 52 patients by immunohistochemistry for phosphorylated ERK (pERK). Immunostaining for pERK was considerably enhanced by use of alkaline demasking. Nuclear staining occurred in both cancer cells and stromal cells. Blind-coded sections were scored by 2 independent investigators. In patients showing no residual tumor after RCT (TRG1), staining for pERK in cancer, but not stromal, cell nuclei was significantly weaker than in patients showing a poor RCT response (TRG1 vs TRG4: p = 0.0001). Nuclear staining for pERK predicted poor responders, as illustrated by receiver operating characteristic curves with an area under curve of 0.86 (p = 0.0007) and also predicted downstaging (area under curve: 0.76; p = 0.01). A number of controls documented the specificity of the optimized staining method and results were confirmed with another pERK antibody. Thus, staining for pERK in cancer cell nuclei can predict the response to RCT and may help spare poor responders this treatment. These results also raise the question whether inhibitors of ERK activation may serve as response modifiers of RCT. PMID- 26416418 TI - The eye lens: age-related trends and individual variations in refractive index and shape parameters. AB - The eye lens grows throughout life by cell accrual on its surface and can change shape to adjust the focussing power of the eye. Varying concentrations of proteins in successive cell layers create a refractive index gradient. The continued growth of the lens and age-related changes in proteins render it less able to alter shape with loss of capacity by the end of the sixth decade of life. Growth and protein ageing alter the refractive index but as accurate measurement of this parameter is difficult, the nature of such alterations remains uncertain. The most accurate method to date for measuring refractive index in intact lenses has been developed at the SPring-8 synchrotron. The technique, based on Talbot interferometry, has an X-ray source and was used to measure refractive index in sixty-six human lenses, aged from 16 to 91 years. Height and width were measured for forty-five lenses. Refractive index contours show decentration in some older lenses but individual variations mask age-related trends. Refractive index profiles along the optic axis have relatively flat central sections with distinct micro-fluctuations and a steep gradient in the cortex but do not exhibit an age related trend. The refractive index profiles in the equatorial aspect show statistical significance with age, particularly for lenses below the age of sixty that had capacity to alter shape in vivo. The maximum refractive index in the lens centre decreases slightly with age with considerable scatter in the data and there are age-related variations in sagittal thickness and equatorial height. PMID- 26416419 TI - Antigen-specific human NKT cells from tuberculosis patients produce IL-21 to help B cells for the production of immunoglobulins. AB - Natural killer T (NKT) cells from mouse and human play an important role in the immune responses against Mycobacterium tuberculosis. However, the function of CD3(+)TCRvbeta11(+) NKT cells at the local site of M. tuberculosis infection remains poorly defined. In the present study, we found that after stimulation with M. tuberculosis antigens, NKT cells isolated from tuberculosis (TB) pleural fluid mononuclear cells (PFMCs) produced IL-21 and other cytokines including IFN gamma, TNF-alpha, IL-2 and IL-17. IL-21-expressing NKT cells in PFMCs displayed effector memory phenotype, expressing CD45RO(high)CD62L(low)CCR7(low). Moreover, NKT cells expressed high levels of CXCR5 and all of IL-21-expressing NKT cells co expressed CXCR5. The frequency of BCL-6-expression was higher in IL-21-expressing but not in non-IL-21-expressing CD3(+)TCRvbeta11(+) NKT cells. Sorted CD3(+)TCRvbeta11(+) NKT cells from PFMCs produced IFN-gamma and IL-21 after stimulation, which expressed CD40L. Importantly, CD3(+)TCRvbeta11(+) NKT cells provided help to B cells for the production of IgG and IgA. Taken together, our data demonstrate that CD3(+)TCRvbeta11(+) NKT cells from a local site of M. tuberculosis infection produce IL-21, express CXCR5 and CD40L, help B cells to secrete IgG and IgA, and may participate in local immune responses against M. tuberculosis infection. PMID- 26416420 TI - PDGF upregulates CLEC-2 to induce T regulatory cells. AB - The effect of platelet derived growth factor (PDGF) on immune cells is not elucidated. Here, we demonstrate PDGF inhibited the maturation of human DCs and induced IL-10 secretion. Culture of PDGF-DCs with T cells induced the polarization of T cells towards FoxP3 expressing T regulatory cells that secreted IL-10. Gene expression studies revealed that PDGF induced the expression of C type lectin like receptor member 2, (CLEC-2) receptor on DCs. Furthermore, DCs transfected with CLEC-2 induced T regulatory cells in DC-T cell co-culture. CLEC 2 is naturally expressed on platelets. Therefore, to confirm whether CLEC-2 is responsible for inducing the T regulatory cells, T cells were cultured with either CLEC-2 expressing platelets or soluble CLEC-2. Both conditions resulted in the induction of regulatory T cells. The generation of T regulatory cells was probably due to the binding of CLEC-2 with its ligand podoplanin on T cells, since crosslinking of podoplanin on the T cells also resulted in the induction of T regulatory cells. These data demonstrate that PDGF upregulates the expression of CLEC-2 on cells to induce T regulatory cells. PMID- 26416421 TI - Plasma miR-200b in ovarian carcinoma patients: distinct pattern of pre/post treatment variation compared to CA-125 and potential for prediction of progression-free survival. AB - Ovarian carcinomas (OvCa) are highly heterogeneous malignancies. We investigated four circulating plasma microRNAs (miR-21, miR-34a, miR-200b and miR-205) as candidate biomarkers. Using qPCR, we assessed the plasma concentration of these markers in 101 women, including 51 previously untreated OvCa patients, 25 healthy women and 25 patients bearing benign pelvic lesions. For a subset of 33 OvCa patients, the assay was repeated at the end of the primary treatment. The pattern of variations (post- minus pre-treatment) of concentration was compared to that of CA-125. A Cox regression model was used to study the association between variations and the progression-free survival (PFS). Plasma miR-200b proved to have a greater average concentration in OvCa samples (median 2-DeltaDeltaCt = 15.18) than in samples linked to non-malignant lesions (median 2-DeltaDeltaCt = 1.26, p-value = 0.0004). Its concentration was highly heterogeneous among OvCa patients, without any correlations with the FIGO stage and the pre-treatment CA 125 level. The decrease in CA-125 concentration was constant and often dramatic, while the variations of miR-200b concentration were much more diverse. The variation of miR-200b was marginally associated with the PFS (hazard ratio=2.95 95%CI=[0.94; 9.28], p=0.06) while miR-200b as a continuous time-dependent variable was significantly associated (HR=1.06 [1.02; 1.10], p=0.003). This study is the first direct empirical evidence that miR-200b can provide additional information, independent of CA-125 in OvCa patients. PMID- 26416422 TI - Kruppel-like factor 2 suppresses mammary carcinoma growth by regulating retinoic acid signaling. AB - The transcription factor Kruppel-like factor 2 (KLF2) displays anticarcinogenic activities but the mechanism that underlies this activity is unknown. We show here that KLF2 is markedly downregulated in human breast cancers and that its expression positively correlates with breast cancer patient survival. We show further that KLF2 suppresses tumor development by controlling the transcriptional activity of the vitamin A metabolite retinoic acid (RA). RA regulates gene transcription by activating two types of nuclear receptors: RA receptors (RARs), which inhibit tumor development, and peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta), which promotes tumorigenesis. The partitioning of RA between these receptors is regulated by two carrier proteins: cellular retinoic acid-binding protein 2 (CRABP2), which delivers RA to RARs, and fatty acid binding protein 5 (FABP5), which shuttles ligands to PPARbeta/delta. We show that KLF2 induces the expression of CRABP2 and RARgamma and inhibits the expression FABP5 and PPARbeta/delta thereby shifting RA signaling from the pro-carcinogenic FABP5/PPARbeta/delta to the growth-suppressing CRABP2/RAR path. The data thus reveal that KLF2 suppresses tumor growth by controlling the transcriptional activities of RA. PMID- 26416423 TI - Positron emission tomography imaging of cardiomyocyte apoptosis with a novel molecule probe [18F]FP-DPAZn2. AB - Cardiomyocyte apoptosis plays a causal role in the development and progression of heart failure. Currently, there is no effective imaging agent that can be used to detect cardiomyocyte apoptosis in vivo. To target phosphatidylserine (PS) on the surface of the dying cell, we synthesized a novel 18F-labeled Zn2+-dipicolylamine (DPA) analog, [18F]FP-DPAZn2, and evaluated it for noninvasive imaging of cardiomyocyte apoptosis. In vitro, the fluorescence imaging of dansyl-DPAZn2 was suitable for detecting cardiomyocyte apoptosis, which was confirmed by confocal immunofluorescence imaging, terminal dUTP nick-end labeling (TUNEL) assay, and western blot assay. The in vivo biodistribution showed that the uptake ratios of [18F]FP-DPAZn2 in the heart were 4.41+/-0.29% ID/g at 5 min, 2.40 +/- 0.43% ID/g at 30 min, 1.63 +/- 0.26% ID/g at 60 min, and 1.43% +/- 0.07 ID/g at 120 min post injection. In vivo, the [18F]FP-DPAZn2 PET images showed more cardiac accumulation of radioactivity 60 min post-injection in acute myocardial infarction (AMI) rats than in normal rats, which was consistent with the findings of a histological analysis of the rat cardiac tissues in vitro. [18F]FP-DPAZn2 PET imaging has the capability for myocardial apoptosis detection, but the method will require improved myocardial uptake for the noninvasive evaluation of cardiomyocyte apoptosis in clinical settings. PMID- 26416424 TI - Loss of p27Kip1 promotes metaplasia in the pancreas via the regulation of Sox9 expression. AB - p27Kip1 (p27) is a negative regulator of proliferation and a tumor suppressor via the inhibition of cyclin-CDK activity in the nucleus. p27 is also involved in the regulation of other cellular processes, including transcription by acting as a transcriptional co-repressor. Loss of p27 expression is frequently observed in pancreatic adenocarcinomas in human and is associated with decreased patient survival. Similarly, in a mouse model of K-Ras-driven pancreatic cancer, loss of p27 accelerates tumor development and shortens survival, suggesting an important role for p27 in pancreatic tumorigenesis. Here, we sought to determine how p27 might contribute to early events leading to tumor development in the pancreas. We found that K-Ras activation in the pancreas causes p27 mislocalization at pre neoplastic stages. Moreover, loss of p27 or expression of a mutant p27 that does not bind cyclin-CDKs causes the mislocalization of several acinar polarity markers associated with metaplasia and induces the nuclear expression of Sox9 and Pdx1 two transcription factors involved in acinar-to-ductal metaplasia. Finally, we found that p27 directly represses transcription of Sox9, but not that of Pdx1. Thus, our results suggest that K-Ras activation, the earliest known event in pancreatic carcinogenesis, may cause loss of nuclear p27 expression which results in derepression of Sox9, triggering reprogramming of acinar cells and metaplasia. PMID- 26416426 TI - Hippo transducer TAZ promotes epithelial mesenchymal transition and supports pancreatic cancer progression. AB - Transcriptional co-activator with PDZ binding motif (TAZ) is a transducer of the Hippo pathway and promotes cancer development and progression. In the present study, we sought to determine the roles and underlying mechanisms of elevated expression and activation of TAZ in pancreatic cancer development and progression. The mechanistic role of TAZ and Hippo signaling in promotion of pancreatic cancer development and progression was examined using cell culture, molecular biology, and mouse models. The relevance of our experimental and mechanistic findings was validated using human pancreatic tumor specimens. We found that TAZ expression was markedly higher in pancreatic tumors than in normal pancreatic tissue. Further analysis of the correlation of TAZ expression with tissue microarray clinicopathologic parameters revealed that this expression was positively associated with tumor differentiation. Also, TAZ expression was higher in pancreatic cancer cell lines than in pancreatic ductal epithelial cells. TAZ activation in pancreatic cancer cells promoted their proliferation, migration, invasion, and epithelial-mesenchymal transition. Further mechanistic studies demonstrated that aberrant expression and activation of TAZ in pancreatic cancer cells resulted from suppression of the expression of Merlin, a positive regulator upstream of the Hippo pathway, and that the oncogenic function of TAZ in pancreatic cancer cells was mediated by TEA/ATTS domain transcription factors. Therefore, TAZ functioned as an oncogene and promoted pancreatic cancer epithelial-mesenchymal transition and progression. TAZ thus may be a target for effective therapeutic strategies for pancreatic cancer. PMID- 26416425 TI - Frequent DPH3 promoter mutations in skin cancers. AB - Recent reports suggested frequent occurrence of cancer associated somatic mutations within regulatory elements of the genome. Based on initial exome sequencing of 21 melanomas, we report frequent somatic mutations in skin cancers in a bidirectional promoter of diphthamide biosynthesis 3 (DPH3) and oxidoreductase NAD-binding domain containing 1 (OXNAD1) genes. The UV-signature mutations occurred at sites adjacent and within a binding motif for E-twenty six/ternary complex factors (Ets/TCF), at -8 and -9 bp from DPH3 transcription start site. Follow up screening of 586 different skin lesions showed that the DPH3 promoter mutations were present in melanocytic nevi (2/114; 2%), melanoma (30/304; 10%), basal cell carcinoma of skin (BCC; 57/137; 42%) and squamous cell carcinoma of skin (SCC; 12/31; 39%). Reporter assays carried out in one melanoma cell line for DPH3 and OXNAD1 orientations showed statistically significant increased promoter activity due to -8/-9CC > TT tandem mutations; although, no effect of the mutations on DPH3 and OXNAD1 transcription in tumors was observed. The results from this study show occurrence of frequent somatic non-coding mutations adjacent to a pre-existing binding site for Ets transcription factors within the directional promoter of DPH3 and OXNAD1 genes in three major skin cancers. The detected mutations displayed typical UV signature; however, the functionality of the mutations remains to be determined. PMID- 26416429 TI - Cross cultural adaptation of the English version of the IOF-QLQ to Polish, to assess the health-related quality-of-life of patients after a distal radius fracture. AB - BACKGROUND: A distal radius fracture (DRF) is a common injury that can cause significant pain and lead to a prolonged decrease in physical, emotional, and social functioning. In modern randomized clinical trials, assessing outcomes after a DRF, health-related quality-of-life (HRQoL) is a "must-be" endpoint. Additionally, HRQoL assessments are essential in the clinical decision-making process. The aim of this study to cross-culturally adapt the International Osteoporosis Foundation Quality of Life Questionnaire (IOF QLQ) for patients with a DRF to Polish. METHODS: A standard forward-backward translation procedure and pilot-testing were used to prepare the Polish version of the IOF QLQ for use in this case-control study. Patients were eligible if they were between 18-80 years and were within 1-3 days after a non-comminuted DRF. The study group was gender and aged matched with healthy controls. All DRF patients filled out the Polish version of the IOF QLQ, the SF-36 and a demographic questionnaire. Assessment points were set as soon as possible after the fracture, 7 days, 6 weeks, 3, 6, 12, and 18 months after the fracture. Standard validity and reliability analyses were performed. RESULTS: Ninety-seven patients (73 women - 75.3%) with a mean age of 62.4 +/- 7.1 years agreed to take part in the study. The control group consisted of 81 patients (60 women - 74.1%) with a mean age 63.9 +/- 8.2 years. No significant differences were found between the mean age of patients and controls (p = 0.19). Cronbach's alpha coefficients showed positive internal consistency (0.79-0.89). The interclass correlations for the IOF QLQ domains and the overall score ranged from 0.85 to 0.92. Satisfactory convergent and discriminant validity of the IOF QLQ was seen. CONCLUSIONS: The Polish version of the IOF QLQ for patients with a DRF is a reliable and valid tool for measuring HRQoL. It can be fully recommended for use in clinical settings in the Polish population. When combined with the SF-36 the IOF QLQ allows to obtain a comprehensive HRQoL assessment in patients with a DRF. PMID- 26416428 TI - Effects of normobaric oxygen and melatonin on reperfusion injury: role of cerebral microcirculation. AB - In order to protect the brain before an irreversible injury occurs, penumbral oxygenation is the primary goal of current acute ischemic stroke treatment. However, hyperoxia treatment remains controversial due to the risk of free radical generation and vasoconstriction. Melatonin is a highly potent free radical scavenger that protects against ischemic stroke. Considering its anti oxidant activity, we hypothesized that melatonin may augment the survival promoting action of normobaric oxygen (NBO) and prevent brain infarction. Herein, we exposed mice to 30 or 90 min of intraluminal middle cerebral artery occlusion (MCAo) and evaluated the effects of NBO (70% or 100% over 90 min), administered either alone or in combination with melatonin (4 mg/kg, i.p.), on disseminate neuronal injury, neurological deficits, infarct volume, blood-brain barrier (BBB) permeability, cerebral blood flow (CBF) and cell signaling. Both NBO and particularly melatonin alone reduced neuronal injury, neurological deficits, infarct volume and BBB permeability, and increased post-ischemic CBF, evaluated by laser speckle imaging (LSI). They also improved CBF significantly in the ischemic- core and penumbra, which was associated with reduced IgG extravasation, DNA fragmentation, infarct volume, brain swelling and neurological scores. Levels of phosphorylated Akt, anti-apoptotic Bcl-xL, pro-apoptotic Bax and endothelial nitric oxide synthase (NOS) were re-regulated after combined oxygen and melatonin delivery, whereas neuronal and inducible NOS, which were increased by oxygen treatment, were not influenced by melatonin. Our present data suggest that melatonin and NBO are promising approaches for the treatment of acute-ischemic stroke, which encourage proof-of-concept studies in human stroke patients. PMID- 26416430 TI - 'We usually just start dancing our Indian dances': urban American Indian (AI) female youths' negotiation of identity, health and the body. AB - In this article, we utilise qualitative research techniques to explore how 14 urban American Indian (AI) females (aged 11-17) living in the state of Maryland discursively construct and experience health and the body, as well as how/if traditional culture shapes their understandings. In doing so, we address a significant gap in the knowledge base concerning the health beliefs of urban AI youth, and build upon research utilising a decolonising approach. Using a two step process of thematic analysis and poststructuralist discourse analysis, we arrived at three key findings: (1) while youths are taught (and learn) mainstream lessons about health and bodily norms (mostly at school), they negotiate these lessons in complex and at times contradictory ways; (2) they do not view their AI status as conferring more or less risk upon them or their community; and (3) AI identity appears to be fluid in nature, becoming more salient, even a resource, in certain situations. We conclude with a discussion of the importance of spaces within the urban context in shaping youths' embodied subjectivities, and in particular, contrast the space of the school with that of the urban AI community centre. PMID- 26416427 TI - MYC-driven aggressive B-cell lymphomas: biology, entity, differential diagnosis and clinical management. AB - MYC, a potent oncogene located at chromosome locus 8q24.21, was identified initially by its involvement in Burkitt lymphoma with t(8;14)(q24;q32). MYC encodes a helix-loop-helix transcription factor that accentuates many cellular functions including proliferation, growth and apoptosis. MYC alterations also have been identified in other mature B-cell neoplasms and are associated with aggressive clinical behavior. There are several regulatory factors and dysregulated signaling that lead to MYC up-regulation in B-cell lymphomas. One typical example is the failure of physiological repressors such as Bcl6 or BLIMP1 to suppress MYC over-expression. In addition, MYC alterations are often developed concurrently with other genetic alterations that counteract the proapoptotic function of MYC. In this review, we discuss the physiologic function of MYC and the role that MYC likely plays in the pathogenesis of B-cell lymphomas. We also summarize the role MYC plays in the diagnosis, prognostication and various strategies to detect MYC rearrangement and expression. PMID- 26416432 TI - EDUCATION AND IMAGING. Hepatobiliary and Pancreatic: Rapid growing cystic ovarian metastasis from pancreatic cancer. AB - Pancreatic cancer rarely develops cystic ovarian metastasis. We present a 63-year old female patient with unresectable pancreas head cancer. Seven months after the introduction of the chemoradiotherapy, a giant intrapelvic cystic tumor with rapid growth was found. The tumor was resected because the patient complained of severe bloating and no other new metastatic sites could be identified. Postoperative pathological examination diagnosed it as an ovarian metastasis from the pancreas cancer. PMID- 26416431 TI - Anticancer Platelet-Mimicking Nanovehicles. AB - A core-shell nanovehicle coated with a platelet membrane (PM) is developed for targeted and site-specific delivery of an extracellularly active drug and an intracellular functional small-molecular drug, leading to enhanced antitumor efficacy. This PM-coated nanovehicle can also effectively eliminate the circulating tumor cells in vivo and inhibit development of tumor metastasis. PMID- 26416433 TI - The pathogenesis of Prurigo nodularis--'Super-Itch' in exploration. AB - Prurigo nodularis (PN) is characterized by multiple hyperkeratotic nodules, papules and the presence of intensive pruritus. This leads to an impaired quality of life and high burden due not only to the severe itch but also the chronic, skin lesions and lack of treatment options. The pathogenesis of PN is not completely clarified. Previous studies have demonstrated just how important the interaction between cutaneous nerve fibres and immune cells is. Besides a reduced intraepidermal nerve fibre density, there are increased dermal levels of neuropeptides such as substance P, calcitonin gene-related peptide and nerve growth factor, as well as a predominant presence of eosinophils and mast cells. An interaction of these factors results in a complex relationship which will be discussed in this article. PMID- 26416434 TI - Vacuum-and-solvent-free fabrication of organic semiconductor layers for field effect transistors. AB - We demonstrate that cold and hot isostatic pressing (CIP and HIP) is a novel, alternative method for organic semiconductor layer fabrication, where organic powder is compressed into a layer shape directly on a substrate with 200 MPa pressure. Spatial gaps between powder particles and the other particles, substrates, or electrodes are crushed after CIP and HIP, making it possible to operate organic field-effect transistors (OFETs) containing the compressed powder as the semiconductor. The CIP-compressed powder of 2,7-dioctyl[1]benzothieno[3,2 b][1]benzothiophene (C8-BTBT) had a hole mobility of (1.6 +/- 0.4) * 10(-2) cm(2)/Vs. HIP of C8-BTBT powder increased the hole mobility to an amorphous silicon-like value (0.22 +/- 0.07 cm(2)/Vs) because of the growth of the C8-BTBT crystallites and the improved continuity between the powder particles. The vacuum and solution processes are not involved in our CIP and HIP techniques, offering a possibility of manufacturing OFETs at low cost. PMID- 26416435 TI - Ultrafast Heme Dynamics of Ferric Cytochrome c in Different Environments: Electronic, Vibrational, and Conformational Relaxation. AB - The excited-state dynamics of ferric cytochrome c (Cyt c), an important electron transfer heme protein, in acidic to alkaline medium and in its unfolded form are investigated by using femtosecond pump-probe spectroscopy, exciting the heme and Tryptophan (Trp) to understand the electronic, vibrational, and conformational relaxation of the heme. At 390 nm excitation, the electronic relaxation of heme is found to be ~150 fs at different pH values, increasing to 480 fs in the unfolded form. Multistep vibrational relaxation dynamics of the heme, including fast and slow processes, are observed at pH 7. However, in the unfolded form and at pH 2 and 11, fast phases of vibrational relaxation dominate, revealing the energy dissipation occurring through the covalent bond interaction between the heme and the nearest amino acids. A significant shortening of the excited-state lifetime of Trp is observed at various pH values at 280 nm excitation due to resonance energy transfer to the heme. The longer time constant (25 ps) observed in the unfolded form is attributed to a complete global conformational relaxation of Cyt c. PMID- 26416436 TI - Intersubject and Interday Variability in Human Tear and Meibum Lipidomes: A Pilot Study. AB - PURPOSE: Our aim was to quantitate day-to-day changes in the tear and meibum lipid profile of individual subjects in a pilot study of healthy humans. METHODS: Matched tear and meibum samples were obtained from four subjects on three consecutive days. Quantitative lipid profiles of human basal tears and meibum were compared using multivariate analysis by principal components. RESULTS: Substantial differences in the lipid profile between subjects were observed, while lipid profiles were steady across the three consecutive days of sampling. Multivariate principal component analysis demonstrated that lysophosphatidylcholine was the largest variant lipid class between subjects in tears, while wax esters comprised the most variation between subjects in meibum secretions. CONCLUSION: Interday variability is shown to be much smaller than interpatient variability, suggesting that tears and meibum subjects both have unique profiles in humans. PMID- 26416437 TI - Medical Racism. PMID- 26416439 TI - Enforcing the International Code of Marketing of Breast-milk Substitutes for Better Promotion of Exclusive Breastfeeding: Can Lessons Be Learned? AB - Exclusive breastfeeding, one of the best natural resources, needs protection and promotion. The International Code of Marketing of Breast-milk Substitutes (the Code), which aims to prevent the undermining of breastfeeding by formula advertising, faces implementation challenges. We reviewed frequently overlooked challenges and obstacles that the Code is facing worldwide, but particularly in Southeast Asia. Drawing lessons from various countries where we work, and following the example of successful public health interventions, we discussed legislation, enforcement, and experiences that are needed to successfully implement the Code. Successful holistic approaches that have strengthened the Code need to be scaled up. Community-based actions and peer-to-peer promotions have proved successful. Legislation without stringent enforcement and sufficient penalties is ineffective. The public needs education about the benefits and ways and means to support breastfeeding. It is crucial to combine strong political commitment and leadership with strict national regulations, definitions, and enforcement. National breastfeeding committees, with the authority to improve regulations, investigate violations, and enforce the laws, must be established. Systematic monitoring and reporting are needed to identify companies, individuals, intermediaries, and practices that infringe on the Code. Penalizing violators is crucial. Managers of multinational companies must be held accountable for international violations, and international legislative enforcement needs to be established. Further measures should include improved regulations to protect the breastfeeding mother: large-scale education campaigns; strong penalties for Code violators; exclusion of the formula industry from nutrition, education, and policy roles; supportive legal networks; and independent research of interventions supporting breastfeeding. PMID- 26416438 TI - Human scaphoid non-unions exhibit increased osteoclast activity compared to adjacent cancellous bone. AB - Scaphoid bones have a high prevalence for non-union. Even with adequate treatment, bone regeneration may not occur in certain instances. Although this condition is well described, the molecular pathology of scaphoid non-unions is still poorly defined. In this study, gene expression of osteogenic and angiogenic growth and transcription factors as well as inflammatory mediators were analysed in human scaphoid non-unions and intraindividually compared to adjacent autologous cancellous bone from the distal radius. In addition, histology and immunohistochemical stainings were performed to verify qRT-PCR data. Gene expression analysis revealed a significant up-regulation of RANKL, ALP, CYCLIN D1, MMP-13, OPG, NFATc1, TGF-beta and WNT5A in scaphoid non-unions. Interestingly, RANKL and NFATc1, both markers for osteoclastogenesis, were significantly induced in non-unions. Moreover, WNT5A was highly up-regulated in all non-union samples. TRAP staining confirmed the observation of induced osteoclastogenesis in non-unions. With respect to genes related to osteogenesis, alkaline phosphatase was significantly up-regulated in scaphoid non-unions. No differences were detectable for other osteogenic genes such as RUNX-2 or BMP-2. Importantly, we did not detect differences in angiogenesis between scaphoid non unions and controls in both gene expression and immunohistochemistry. Summarized, our data indicate increased osteoclast activity in scaphoid non-unions possibly as a result of the alterations in RANKL, TGF-beta and WNT5A expression levels. These data increase our understanding for the reduced bone regeneration capacity present in scaphoid non-unions and may translate into the identification of new therapeutic targets to avoid secondary damages and prevent occurrence of non unions to scaphoid bones. PMID- 26416440 TI - Feeding Mode of Australian Infants in the First 12 Months of Life. AB - BACKGROUND: In 2011, Australia published a set of 6 population-level indicators assessing breastfeeding, formula use, and the introduction of soft/semisolid/solid foods. OBJECTIVES: This study aimed to report the feeding practices of Australian infants against these indicators and determine the predictors of early breastfeeding cessation and introduction of solids. METHODS: Mother-infant dyads (N = 1470) were recruited postnatally in 2 Australian capital cities and regional areas of 1 state between February 2008 and March 2009. Demographic and feeding intention data were collected by self-completed questionnaire at infant birth, with feeding practices (current feeding mode, age of breastfeeding cessation, age of formula and/or solids introduction) reported when the infant was between 4 and 7 months of age, and around 13 months of age. Multiple logistic regression was used to determine the predictors of breastfeeding cessation and solids introduction. RESULTS: Although initiation of breastfeeding was almost universal (93.3%), less than half of the infants were breastfed to 6 months (41.7%) and 33.3% were receiving solids by 4 months. Women who were socially disadvantaged, younger, less educated, unpartnered, primiparous, and/or overweight were most likely to have ceased breastfeeding before 6 months of age, and younger and/or less educated women were most likely to have introduced solid food by 4 months of age. Not producing adequate milk was the most common reason provided for cessation of breastfeeding. CONCLUSION: The feeding behaviors of Australian infants in the first 12 months fall well short of recommendations. Women need anticipatory guidance as to the indicators of breastfeeding success and the tendency of women to doubt the adequacy of their breast milk supply warrants further investigation. PMID- 26416441 TI - The MCCB impairment profile in a Spanish sample of patients with schizophrenia: Effects of diagnosis, age, and gender on cognitive functioning. AB - The MATRICS Consensus Cognitive Battery (MCCB) was administered to 293 schizophrenia outpatients and 210 community residents in Spain. Our first objective was to identify the age- and gender-corrected MCCB cognitive profile of patients with schizophrenia. The profile of schizophrenia patients showed deficits when compared to controls across the seven MCCB domains. Reasoning and Problem Solving and Social Cognition were the least impaired, while Visual Learning and Verbal Learning showed the greatest deficits. Our second objective was to study the effects on cognitive functioning of age and gender, in addition to diagnosis. Diagnosis was found to have the greatest effect on cognition (Cohen's d>0.8 for all MCCB domains); age and gender also had effects on cognitive functioning, although to a lesser degree (with age usually having slightly larger effects than gender). The effects of age were apparent in all domains (with better performance in younger subjects), except for Social Cognition. Gender had effects on Attention/Vigilance, Working Memory, Reasoning and Problem Solving (better performance in males), and Social Cognition (better performance in females). No interaction effects were found between diagnosis and age, or between diagnosis and gender. This lack of interactions suggests that age and gender effects are not different in patients and controls. PMID- 26416442 TI - Cognitive course in first-episode psychosis and clinical correlates: A 4 year longitudinal study using the MATRICS Consensus Cognitive Battery. AB - While cognitive impairments are prevalent in first-episode psychosis, the course of these deficits is not fully understood. Most deficits appear to remain stable, however there is uncertainty regarding the trajectory of specific cognitive domains after illness onset. This study investigates the longitudinal course of cognitive deficits four years after a first-episode of psychosis and the relationship of performance with clinical course and response to treatment. Twenty three individuals with psychotic illness, matched with 21 healthy volunteers, were assessed using the MATRICS Consensus Cognitive Battery at illness onset and 4 years later. We also investigated the relationship between cognitive deficits and quality of life and clinical indices. Verbal learning and two measures of processing speed had marked poorer trajectory over four years compared to the remaining cognitive domains. Processing speed performance was found to contribute to the cognitive deficits in psychosis. Poorer clinical outcome was associated with greater deficits at illness onset in reasoning and problem solving and social cognition. Cognitive deficits did not predict quality of life at follow-up, nor did diagnosis subtype differentiate cognitive performance. In conclusion, an initial psychotic episode may be associated with an additional cost on verbal learning and two measures of processing speed over a time spanning at least four years. Moreover, processing speed, which has been manipulated through intervention in previous studies, may represent a viable therapeutic target. Finally, cognition at illness onset may have a predictive capability of illness course. PMID- 26416443 TI - Prevalence and correlates of psychotic like experiences in a nationally representative community sample of adolescents in Ireland. AB - Adolescent psychotic like experiences (PLEs) are an important area of research, yet only a small number of community surveys have investigated their psychosocial correlates. This study presents the prevalence and correlates of three types of PLEs in a nationally representative community sample of 12-19 year olds in Ireland (N=5910). Correlates are considered across five domains: demographic, stressful life experiences, emotional/behavioral problems, substance use, and personal resources. Auditory hallucinations were reported by 13.7% of participants, 10.4% reported visual hallucinations and 13.1% reported paranoid thoughts. Participants who had experienced two of the three PLEs were assigned "risk" status (10.4%; n=616). Using binary logistic regression, PLEs were associated with a range of correlates across the five domains. Key correlates of risk status include depression (OR 4.07; 95% CI 3.39-4.88), low self-esteem (OR 4.03 95% CI 3.34-4.86), low optimism (OR 3.56; 95% CI 2.96-4.28), school misconduct (OR 3.10 95%; CI 2.56-3.75), and high avoidance coping (OR 2.86 95% CI 2.34-3.49). These associations remained significant in a multivariate analysis. While correlates for each of the three PLEs were similar, there were some nuances in these patterns. Notably, demographic and substance use variables were the weakest groups of correlates. Personal resources (e.g. self-esteem, optimism and coping) have been poorly studied in the adolescent PLE literature and these findings provide important insights for future research and intervention design. PMID- 26416445 TI - FXR induces SOCS3 and suppresses hepatocellular carcinoma. AB - Suppressor of cytokine signaling 3 (SOCS3) is regarded as a vital repressor in the liver carcinogenesis mainly by inhibiting signal transducer and activator of transcription 3 (STAT3) activity. Farnesoid X Receptor (FXR), highly expressed in liver, has an important role in protecting against hepatocellular carcinoma (HCC). However, it is unclear whether the tumor suppressive activity of FXR involves the regulation of SOCS3. In the present study, we found that activation of FXR by its specific agonist GW4064 in HCC cells inhibited cell growth, induced cell cycle arrest at G1 phase, elevated p21 expression and repressed STAT3 activity. The above anti-tumor effects of FXR were dramatically alleviated by knockdown of SOCS3 with siRNA. Reporter assay revealed that FXR activation enhanced the transcriptional activity of SOCS3 promoter. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay displayed that FXR directly bound to IR9 DNA motif within SOCS3 promoter region. The in vivo study in nude mice showed that treatment with FXR ligand GW4064 could decelerate the growth of HCC xenografts, up-regulate SOCS3 and p21 expression and inhibit STAT3 phosphorylation in the xenografts. These results suggest that induction of SOCS3 may be a novel mechanism by which FXR exerts its anti-HCC effects, and the FXR-SOCS3 signaling may serve as a new potential target for the prevention/treatment of HCC. PMID- 26416444 TI - Homozygous mdm2 SNP309 cancer cells with compromised transcriptional elongation at p53 target genes are sensitive to induction of p53-independent cell death. AB - A single nucleotide polymorphism (T to G) in the mdm2 P2 promoter, mdm2 SNP309, leads to MDM2 overexpression promoting chemotherapy resistant cancers. Two mdm2 G/G SNP309 cancer cell lines, MANCA and A875, have compromised wild-type p53 that co-localizes with MDM2 on chromatin. We hypothesized that MDM2 in these cells inhibited transcription initiation at the p53 target genes p21 and puma. Surprisingly, following etoposide treatment transcription initiation occurred at the compromised target genes in MANCA and A875 cells similar to the T/T ML-1 cell line. In all cell lines tested there was equally robust recruitment of total and initiated RNA polymerase II (Pol II). We found that knockdown of MDM2 in G/G cells moderately increased expression of subsets of p53 target genes without increasing p53 stability. Importantly, etoposide and actinomycin D treatments increased histone H3K36 trimethylation in T/T, but not G/G cells, suggesting a G/G correlated inhibition of transcription elongation. We therefore tested a chemotherapeutic agent (8-amino-adenosine) that induces p53-independent cell death for higher clinically relevant cytotoxicity. We demonstrated that T/T and G/G mdm2 SNP309 cells were equally sensitive to 8-amino-adenosine induced cell death. In conclusion for cancer cells overexpressing MDM2, targeting MDM2 may be less effective than inducing p53-independent cell death. PMID- 26416447 TI - Hydrogen peroxide inducible clone-5 mediates reactive oxygen species signaling for hepatocellular carcinoma progression. AB - One of the signaling components involved in hepatocellular carcinoma (HCC) progression is the focal adhesion adaptor paxillin. Hydrogen peroxide inducible clone-5 (Hic-5), one of the paralogs of paxillin, exhibits many biological functions distinct from paxillin, but may cooperate with paxillin to trigger tumor progression. Screening of Hic-5 in 145 surgical HCCs demonstrated overexpression of Hic-5 correlated well with intra- and extra-hepatic metastasis. Hic-5 highly expressed in the patient derived HCCs with high motility such as HCC329 and HCC353 but not in the HCCs with low motility such as HCC340. Blockade of Hic-5 expression prevented constitutive migration of HCC329 and HCC353 and HGF induced cell migration of HCC340. HCC329Hic-5(-), HCC353Hic-5(-), HCC372Hic-5(-), the HCCs stably depleted of Hic-5, exhibited reduced motility compared with each HCC expressing Scramble shRNA. Moreover, intra/extrahepatic metastasis of HCC329Hic-5(-) in SCID mice greatly decreased compared with HCC329Scramble. On the other hand, ectopic Hic-5 expression in HCC340 promoted its progression. Constitutive and HGF-induced Hic-5 expression in HCCs were suppressed by the reactive oxygen species (ROS) scavengers catalase and dithiotheritol and c-Jun N terminal kinase (JNK) inhibitor SP600125. On the contrary, depletion of Hic-5 blocked constitutive and HGF-induced ROS generation and JNK phosphorylation in HCCs. Also, ectopic expression of Hic-5 enhanced ROS generation and JNK phosphorylation. These highlighted that Hic-5 plays a central role in the positive feedback ROS-JNK signal cascade. Finally, the Chinese herbal derived anti-HCC peptide LZ-8 suppressed constitutive Hic-5 expression and JNK phosphorylation. In conclusion, Hic-5 mediates ROS-JNK signaling and may serve as a therapeutic target for prevention of HCC progression. PMID- 26416446 TI - Evaluation of a novel human IgG1 anti-claudin3 antibody that specifically recognizes its aberrantly localized antigen in ovarian cancer cells and that is suitable for selective drug delivery. AB - Membrane protein claudin3 has been recently suggested as a marker for biologically aggressive tumors and a possible target for the therapeutic delivery of active anti-cancer compounds. Claudin3-binding molecules such as the Clostridium perfringens enterotoxin (CPE), CPE-related molecules, and murine and chimeric antibodies have shown promising antitumor efficacy in preclinical oncological settings. We first engineered a fully human anti-claudin3 IgG1 antibody (IgGH6) by fusing the human IgG1 Fc-domain to the anti-claudin3 scFvH6 previously isolated from a pre-immune phage display library. The construct was expressed in mammalian cells and specifically targeted claudin3 endogenously expressed on the surface of different human ovarian cancer cell lines. No detectable cross-reactivity with other homologous claudins was observed. The epitope recognized by IgGH6 is located within the minor extracellular domain of claudin3 and becomes accessible only in tumor cells characterized by incomplete junction formation. Confocal microscopy experiments demonstrated that IgGH6 was actively internalized in tumor cells after binding to native claudin3 and co localized, likely within intracellular vesicles, with the C-CPE peptide. Preliminary results indicate that IgGH6 accumulated in vivo in free claudin3 ovarian carcinoma xenografts. For its selective uptake in tumor cells and its human nature, IgGH6 represents a valuable candidate for antibody-drug conjugate therapeutic applications in ovarian cancer patients. PMID- 26416448 TI - MicroRNAs as prognostic molecular signatures in renal cell carcinoma: a systematic review and meta-analysis. AB - This is a systematic review of studies investigating the prognostic value of different microRNAs (miRs) in renal cell carcinoma (RCC). Twenty-seven relevant studies were identified, with a total of 2578 subjects. We found that elevated expression of miR-21, miR-1260b, miR-210, miR-100, miR-125b, miR-221, miR-630, and miR-497 was associated with a poor prognosis in RCC patients. Conversely, decreased expression of miR-106b, miR-99a, miR-1826, miR-215, miR-217, miR-187, miR-129-3p, miR-23b, miR-27b, and miR-126 was associated with a worse prognosis. We performed meta-analyses on studies to address the prognostic value of miR-21, miR-126, miR-210, and miR-221. This revealed that elevated miR-21 expression was associated with shorter overall survival (OS; hazard ratio [HR], 2.29; 95% confidence interval [CI], 1.28-4.08), cancer specific survival (CSS; HR, 4.16; 95% CI, 2.49-6.95), and disease free survival (DFS; HR, 2.15; 95% CI, 1.16-3.98). The decreased expression of miR-126 was associated with shorter CSS (HR, 0.35; 95% CI, 0.15-0.85), OS (HR, 0.45; 95% CI, 0.30-0.69), and DFS (HR 0.30; 95% CI, 0.18-0.50). Our comprehensive systematic review reveals that miRs, especially miR 21 and miR-126, could be promising prognostic markers and useful therapeutic targets in RCC. PMID- 26416449 TI - CCL18 from tumor-associated macrophages promotes angiogenesis in breast cancer. AB - The infiltration of tumor-associated macrophages (TAMs) is associated with extensive angiogenesis, which contributes to a poor prognosis in breast cancer. However, anti-angiogenic therapy with VEGF-specific monotherapy has been unsuccessful in treating breast cancer, and the molecular mechanisms associated with chemoresistance remain unclear. Here, we investigated whether CCL18, a chemokine produced by TAMs, can stimulate angiogenesis in breast cancer, as well as the underlying mechanisms. Double immunohistochemical staining for CCL18 and CD34/CD31/vWF was performed in 80 breast cancer samples to study the correlation between CCL18+ TAMs and microvascular density (MVD). Cocultures of TAMs with human umbilical vein endothelial cells (HUVECs) were used to model the inflammatory microenvironment, and CCL18-induced angiogenesis was evaluated both in vitro and in vivo. We demonstrated that CCL18+ TAM infiltration positively associated with MVD in breast cancer samples, which was correlated with tumor metastasis and poor prognosis. We confirmed, both in vitro and in vivo, that CCL18 and VEGF synergistically promoted endothelial cell migration and angiogenesis. Conversely, blocking CCL18 or VEGF with neutralizing antibodies synergistically inhibited the promigratory effects of TAMs. Silencing PITPNM3, a putative CCL18 receptor, on the surface of HUVECs abrogated CCL18-mediated promigration and the enhancement of HUVEC tube formation, independently of VEGFR signaling. Moreover, CCL18 exposure induced the endothelial-mesenchymal transformation and activated ERK and Akt/GSK-3beta/Snail signaling in HUVECs, thereby contributing to its pro-angiogenic effects. In conclusion, our findings suggest that CCL18 released from TAMs promotes angiogenesis and tumor progression in breast cancer; thus, CCL18 may serve as a novel target for anti-angiogenic therapies. PMID- 26416450 TI - Acquired resistance to 5-fluorouracil via HSP90/Src-mediated increase in thymidylate synthase expression in colon cancer. AB - 5-fluorouracil (5-FU), one of the first-line chemotherapeutic agents for the treatment of gastrointestinal malignancies, has shown limited efficacy. The expression of thymidylate synthase (TYMS) has been reported to be associated with the resistance to 5-FU. Here, we demonstrate that the enhanced HSP90 function and subsequent activation of Src induce expression of TYMS and acquired resistance to 5-FU in colon cancer. We show that the persistent 5-FU treatment granted 5-FU sensitive HCT116 colon cancer cells morphologic, molecular, and behavioral characteristic of the epithelial-mesenchymal transition (EMT), contributing to emergence of acquired resistance to 5-FU. HCT116/R, a HCT116 colon cancer cell subline carrying acquired resistance to 5-FU, showed increased expression and activation of HSP90's client proteins and transcriptional up-regulation of TYMS. Forced overexpression of HSP90 or constitutive active Src in HCT116 cells increased TYMS expression. Conversely, pharmacological blockade of HSP90 or Src in HCT116/R cells effectively suppressed the changes involved in 5-FU resistance in vitro and xenograft tumor growth, hematogenous spread, and metastatic tumor development in vivo. This study suggests a novel function of HSP90-Src pathway in regulation of TYMS expression and acquisition of 5-FU resistance. Thus, therapeutics targeting this pathway may be an effective clinical strategy to overcome 5-FU resistance in colon cancer. PMID- 26416451 TI - p62/IMP2 stimulates cell migration and reduces cell adhesion in breast cancer. AB - p62/IMP2 is an oncofetal protein that is overexpressed in several types of cancer, and is a member of the family of insulin-like growth factor 2 mRNA binding proteins. We previously reported that high levels of p62/IMP2 autoantibody are present in sera from cancer patients, compared to healthy individuals. Here, we report the overexpression of p62/IMP2 in tumor tissues of 72 out of 104 cases of human breast cancer, and high levels of p62/IMP2 autoantibody in patients' sera (in 63 out of 216 cases). To explore the role of p62/IMP2 in breast cancer progression, we generated p62/IMP2 transfected variants of two human breast cancer cell lines: MDA-MB-231 and LM2-4. Using in vitro assays we found that overexpression of p62/IMP2 can increase cell migration, and reduce cell adhesion to extracellular matrix (ECM) proteins. A Human Extracellular Matrix and Adhesion Molecules qPCR array was performed with our generated variants, and it identified a group of mRNAs whose expression was altered with p62/IMP2 overexpression, including connective tissue growth factor (CTGF) mRNA - which we show to be a p62/IMP2 binding partner. Overall, our results provide new insights into the molecular mechanism by which p62/IMP2 can contribute to breast cancer progression. PMID- 26416452 TI - EMMPRIN regulates tumor growth and metastasis by recruiting bone marrow-derived cells through paracrine signaling of SDF-1 and VEGF. AB - EMMPRIN, a cell adhesion molecule highly expressed in a variety of tumors, is associated with poor prognosis in cancer patients. Mechanistically, EMMPRIN has been characterized to contribute to tumor development and progression by controlling the expression of MMPs and VEGF. In the present study, by using fluorescently labeled bone marrow-derived cells (BMDCs), we found that the down regulation of EMMPRIN expression in cancer cells reduces tumor growth and metastasis, and is associated with the reduced recruitment of BMDCs. Further protein profiling studies suggest that EMMPRIN controls BMDC recruitment through regulating the secretion of soluble factors, notably, VEGF and SDF-1. We demonstrate that the expression and secretion of SDF-1 in tumor cells are regulated by EMMPRIN. This study reveals a novel mechanism by which EMMPRIN promotes tumor growth and metastasis by recruitment of BMDCs through controlling secretion and paracrine signaling of SDF-1 and VEGF. PMID- 26416453 TI - Association of glutathione S-transferase T1 and M1 polymorphisms with prostate cancer susceptibility in populations of Asian descent: a meta-analysis. AB - BACKGROUND: Genetic polymorphism was hypothesized to be reason of variation in prostate cancer incidence among different racial group. Based on that published data on the association of prostate cancer susceptibility with polymorphisms in genes encoding Glutathione S-transferases (GSTs) were inconclusive, the aim of this study was to more precisely address the role of GSTs polymorphisms (especially, GSTT1 and GSTM1 deletions) on prostate cancer risk in Asian descent. METHODS: A meta-analysis including 8 articles with 711 cases and 1122 controls for GSTT1 and 1098 cases and 1588 controls for GSTM1 was performed. RESULTS: Significantly increased prostate cancer risk was found among subjects carrying GSTM1 null genotype (odds ratio (OR) = 1.403; 95% confidence interval (CI) = 1.088 - 1.808) but not among subjects carrying GSTT1 deletion genotype (OR = 0.959; 95%CI = 0.709 - 1.297). When stratified by country, the null genotype of GSTT1 neither increased nor decreased prostate cancer risk significantly in China (OR = 1.355; 95%CI = 0.895 - 2.049), Japan (OR = 0.812; 95%CI = 0.545 - 1.211), and Korea (OR = 1.056; 95%CI = 0.727 - 1.534). While significant association of elevated prostate cancer risk with GSTM1 deletion were found in China (OR = 1.665; 95%CI = 1.324 - .094) and Korea (OR = 1.914; 95%CI = 1.311 - 2.793) but not in Japan (OR = 0.980; 95%CI = 0.726 - 1.321). CONCLUSIONS: In summary, this meta-analysis suggested that the null genotype of GSTM1 rather than GSTT1 may be involved in the etiology of prostate cancer in Asian population. PMID- 26416454 TI - MiR-200b regulates autophagy associated with chemoresistance in human lung adenocarcinoma. AB - Chemoresistance remains a major clinical problem in combating human lung adenocarcinoma (LAD), and abnormal autophagy is closely associated with this phenomenon. In the present study, an inverse correlation between miR-200b and autophagy-associated gene 12 (ATG12) expressions was observed in docetaxel resistant (SPC-A1/DTX and H1299/DTX) and sensitive (SPC-A1 and H1299) LAD cells as well as in tissue samples. Further study showed that miR-200b directly targeted ATG12 in LAD. Moreover, miR-200b-dependent ATG12 downregulation inhibited autophagy and enhanced the chemosensitivity of SPC-A1/DTX and H1299/DTX cells both in vivo and in vitro. LAD chemoresistance is therefore closely related to downregulation of miR-200b and the corresponding upregulation of ATG12. These results provide new evidence for the mechanisms governing the microRNA (miRNA) ATG12 network and their possible contribution to autophagy modulation and LAD chemoresistance. PMID- 26416455 TI - TQ inhibits hepatocellular carcinoma growth in vitro and in vivo via repression of Notch signaling. AB - Thymoquinone (TQ) has been reported to possess anti-tumor activity in various types of cancer. However, its effects and molecular mechanism of action in hepatocellular carcinoma (HCC) are still not completely understood. We observed that TQ inhibited tumor cell growth in vitro, where treatment with TQ arrested the cell cycle in G1 by upregulating p21 and downregulating cyclinD1 and CDK2 expression; moreover, TQ induced apoptosis by decreasing expression of Bcl-2 and increasing expression of Bax. Simultaneously, TQ demonstrated a suppressive impact on the Notch pathway, where overexpression of NICD1 reversed the inhibitory effect of TQ on cell proliferation, thereby attenuating the repressive effects of TQ on the Notch pathway, cyclinD1, CDK2 and Bcl-2, and also diminishing upregulation of p21 and Bax. In a xenograft model, TQ inhibited HCC growth in nude mice; this inhibitory effect in vivo, as well as of HCC cell growth in vitro, was associated with a discernible decline in NICD1 and Bcl-2 levels and a dramatic rise in p21 expression. In conclusion, TQ inhibits HCC cell growth by inducing cell cycle arrest and apoptosis, achieving these effects by repression of the Notch signaling pathway, suggesting that TQ represents a potential preventive or therapeutic agent in HCC patients. PMID- 26416456 TI - Isolated locoregional recurrence patterns of breast cancer after mastectomy and adjuvant systemic therapies in the contemporary era. AB - PURPOSE: To evaluate the recurrence patterns in a series of patients who presented with isolated locoregional recurrences (ILRRs) after mastectomy and adjuvant systemic therapies in the contemporary era. METHODS: A total of 235 patients who developed ILRRs between 2005 and 2013 were classified into subgroups based on nodal status, hormone receptor status, and biologic subtype. The annual frequency of recurrences, association between biologic subtype and interval to recurrence (ITR), and anatomical distribution were evaluated. RESULTS: For the entire group, recurrence peaked within the first 3 years after mastectomy, and then decreased significantly with time. Node-positive patients were observed to recur early, and a greater proportion recurred within 5 years (86.7% vs. 72.8%, chi2 = 6.83, P = 0.008) than did node-negative subgroup. Overall, the median ITR was 33.2 (range, 4.5 - 236) months. Biologic subtype specific median ITR were 43.3 (7.9 - 236.0) months for luminal A, 42.2 (6.1 - 143.3) months for luminal B, 23.8 (6.9 - 47.3) months for luminal HER2, 18.2 (6.6 - 117.5) months for HER2, and 21.8 (4.5 - 138.2) months for TNBC, and their difference was statistically significant (chi2 = 7.4, P = 0.001). Among all ILRRs, 51.5% (n = 121) were isolated to regional nodes. CONCLUSIONS: We demonstrates that the time course is consistent with previous description, biologic subtype is associated with ITR, and regional nodes is the most common place for recurrences in this series of patients who developed ILRRs following mastectomy and contemporary adjuvant systemic therapies but without PMRT. PMID- 26416457 TI - Detection of recurrent cytogenetic aberrations in multiple myeloma: a comparison between MLPA and iFISH. AB - Multiple myeloma (MM) is a genetically heterogeneous disease with diverse clinical characteristics and outcomes. Recently, multiplex ligation-dependent probe amplification (MLPA) has emerged as an effective and robust method for the detection of cytogenetic aberrations in MM patients. In the present study, MLPA analysis was applied to analyze cytogenetics of CD138 tumor cells of 59 MM samples, and its result was compared, retrospectively, with the interphase fluorescence in situ hybridization (iFISH) data. We firstly established the normal range of each of the 42 diagnostic probes using healthy donor samples. A total of 151 aberrations were detected in 59 patient samples, and 49/59 cases (83.1%) harbored at least one copy number variation. Overall, 0-7 aberrations were detected per case using MLPA, indicating the heterogeneity and complexity of MM cytogenetics. We showed the high efficiency of MLPA and the high congruency of the two methods to assess cytogenetic aberrations. Considering that MLPA analysis is not reliable when the aberration only exits in a small population of tumor cells, it is essential to use both MLPA and iFISH as complementary techniques for the diagnosis of MM. PMID- 26416458 TI - KRAS mutations affect prognosis of non-small-cell lung cancer patients treated with first-line platinum containing chemotherapy. AB - KRAS mutations seem to indicate a poor outcome in Non-Small-Cell Lung Cancer (NSCLC) but such evidence is still debated. The aim of this planned ancillary study within the TAILOR trial was to assess the prognostic value of KRAS mutations in advanced NSCLC patients treated with platinum-based first-line chemotherapy. Patients (N = 540), enrolled in the study in 52 Italian hospitals, were centrally genotyped twice in two independent laboratories for EGFR and KRAS mutational status.Of these, 247 patients were eligible and included in the present study. The primary endpoint was overall survival (OS) according to KRAS mutational status in patients harboring EGFR wild-type.Sixty (24.3%) out of 247 patients harbored KRAS mutations. Median OS was 14.3 months and 10.6 months in wild-type and mutated KRAS patients, respectively (unadjusted Hazard Ratio [HR]=1.41, 95%Confidence Interval [CI]: 1.03-1.94 P = 0.032; adjusted HR=1.39, 95%CI: 1.00-1.94 P = 0.050). This study, with all consecutive patients genotyped, indicates that the presence of KRAS mutations has a mild negative impact on OS in advanced NSCLC patient treated with a first-line platinum-containing regimen. TRIAL REGISTRATION: clinicaltrials.gov identifierNCT00637910. PMID- 26416459 TI - Sorafenib-induced defective autophagy promotes cell death by necroptosis. AB - Autophagy is one of the main cytoprotective mechanisms that cancer cells deploy to withstand the cytotoxic stress and survive the lethal damage induced by anti cancer drugs. However, under specific conditions, autophagy may, directly or indirectly, induce cell death. In our study, treatment of the Atg5-deficient DU145 prostate cancer cells, with the multi-tyrosine kinase inhibitor, sorafenib, induces mitochondrial damage, autophagy and cell death. Molecular inhibition of autophagy by silencing ULK1 and Beclin1 rescues DU145 cells from cell death indicating that, in this setting, autophagy promotes cell death. Re-expression of Atg5 restores the lipidation of LC3 and rescues DU145 and MEF atg5-/- cells from sorafenib-induced cell death. Despite the lack of Atg5 expression and LC3 lipidation, DU145 cells form autophagosomes as demonstrated by transmission and immuno-electron microscopy, and the formation of LC3 positive foci. However, the lack of cellular content in the autophagosomes, the accumulation of long-lived proteins, the presence of GFP-RFP-LC3 positive foci and the accumulated p62 protein levels indicate that these autophagosomes may not be fully functional. DU145 cells treated with sorafenib undergo a caspase-independent cell death that is inhibited by the RIPK1 inhibitor, necrostatin-1. Furthermore, treatment with sorafenib induces the interaction of RIPK1 with p62, as demonstrated by immunoprecipitation and a proximity ligation assay. Silencing of p62 decreases the RIPK1 protein levels and renders necrostatin-1 ineffective in blocking sorafenib-induced cell death. In summary, the formation of Atg5-deficient autophagosomes in response to sorafenib promotes the interaction of p62 with RIPK leading to cell death by necroptosis. PMID- 26416460 TI - Vanadium toxicity in the thymic development. AB - The purpose of this study was to define the toxic effects of vanadium on thymic development in broilers fed on diets supplemented with 0, 5, 15, 30, 45 and 60 mg/kg of vanadium for 42 days. We examined the changes of relative weigh, cell cycle phase, apoptotic cells, and protein expression of Bcl-2, Bax, and caspase-3 in the thymus by the methods of flow cytometry, TUNEL (terminal-deoxynucleotidyl transferase mediated nick end labeling) and immunohistochemistry. The results showed that dietary high vanadium (30 mg/kg, 45 mg/kg and 60 mg/kg) caused the toxic effects on thymic development, which was characterized by decreasing relative weigh, increasing G0/G1 phase (a prolonged nondividing state), reducing S phase (DNA replication) and proliferating index (PI), and increasing percentages of apoptotic thymocytes. Concurrently, the protein expression levels of Bax and caspase-3 were increased, and protein expression levels of Bcl-2 were decreased. The thymic development suppression caused by dietary high vanadium further leads to inhibitive effects on T lymphocyte maturity and activity, and cellular immune function. The above-mentioned results provide new evidences for further understanding the vanadium immunotoxicity. In contrast, dietary 5 mg/kg vanadium promoted the thymic development by increasing relative weigh, decreasing G0/G1 phase, increasing S phase and PI, and reducing percentages of apoptotic thymocytes when compared to the control group and high vanadium groups. PMID- 26416462 TI - Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia. AB - In patients with chronic myeloid leukemia (CML), first-line imatinib treatment leads to 8-year overall survival (OS) probabilities above 80%. Many patients die of reasons unrelated to CML. This work tackled the reassessment of prognosis under particular consideration of the probabilities of dying of CML. Analyses were based on 2290 patients with chronic phase CML treated with imatinib in six clinical trials. 'Death due to CML' was defined by death after disease progression. At 8 years, OS was 89%. Of 208 deceased patients, 44% died of CML. Higher age, more peripheral blasts, bigger spleen and low platelet counts were significantly associated with increased probabilities of dying of CML and determined a new long-term survival score with three prognostic groups. Compared with the low-risk group, the patients of the intermediate- and the high-risk group had significantly higher probabilities of dying of CML. The score was successfully validated in an independent sample of 1120 patients. In both samples, the new score differentiated probabilities of dying of CML better than the Sokal, Euro and the European Treatment and Outcome Study (EUTOS) score. The new score identified 61% low-risk patients with excellent long-term outcome and 12% high-risk patients. The new score supports the prospective assessment of long term antileukemic efficacy and risk-adapted treatment. PMID- 26416461 TI - CD56dimCD57+NKG2C+ NK cell expansion is associated with reduced leukemia relapse after reduced intensity HCT. AB - We have recently described a specialized subset of human natural killer (NK) cells with a CD56(dim)CD57(+)NKG2C(+) phenotype that expand specifically in response to cytomegalovirus (CMV) reactivation in hematopoietic cell transplant (HCT) recipients and exhibit properties characteristic of adaptive immunity. We hypothesize that these cells mediate relapse protection and improve post-HCT outcomes. In 674 allogeneic HCT recipients, we found that those who reactivated CMV had lower leukemia relapse (26% (17-35%), P=0.05) and superior disease-free survival (DFS) (55% (45-65%) P=0.04) 1 year after reduced intensity conditioning (RIC) compared with CMV seronegative recipients who experienced higher relapse rates (35% (27-43%)) and lower DFS (46% (38-54%)). This protective effect was independent of age and graft-vs-host disease and was not observed in recipients who received myeloablative regimens. Analysis of the reconstituting NK cells demonstrated that CMV reactivation is associated with both higher frequencies and greater absolute numbers of CD56(dim)CD57(+)NKG2C(+) NK cells, particularly after RIC HCT. Furthermore, expansion of these cells at 6 months posttransplant independently trended toward a lower 2-year relapse risk. Together, our data suggest that the protective effect of CMV reactivation on posttransplant relapse is in part driven by adaptive NK cell responses. PMID- 26416463 TI - Validation of the Questionnaire to Identify Knee Symptoms (QuIKS) using Rasch analysis. AB - BACKGROUND: The Questionnaire to Identify Knee Symptoms (QuIKS) was recently developed to promote activity by screening for experiences related to early symptoms in people with emergent chronic knee pain problems, such as osteoarthritis (OA) - like knee pain. The main purpose of the current study was to evaluate measurement properties of the QuIKS using Rasch analysis in a sample of people with knee symptoms consistent with symptomatic knee OA. METHOD: This study used cross-sectional data. The sample was 200 subjects along the following knee health continuum: pain-free healthy knees (n = 55) from a university community, knee pain with no knee OA diagnosis (n = 111) from a university affiliated medical clinic, and patients with surgeon-diagnosed symptomatic knee OA awaiting high tibial osteotomy (n = 34) from a sports medicine surgical clinic. The 13-item QuIKS was evaluated for its factor structure, item- and person-fit, item's category response structure, differential item functioning by sex and obesity status, local item dependency, unidimensionality, and test precision. Subsequently, the QuIKS underwent known-groups analysis and convergent validity with the Knee injury and Osteoarthritis Outcome Score (KOOS). RESULTS: In the QuIKS, each item's category response structure was modified. No differential item functioning was observed. Local item dependency informed the formation of four testlets. This refined QuIKS obtained summary fit to the Rasch measurement model, unidimensionality, reliability (person separation index = 0.82), and interval-level scoring. Subsequently, the Rasch-validated QuIKS (QuIKS R) demonstrated excellent known-groups validity and good convergent validity with the KOOS (Spearman's rho = 0.45 to 0.77). CONCLUSIONS: The QuIKS-R provides interval-level quantification of knee symptoms-related experiences in people with knee symptoms consistent with symptomatic knee OA. Its scores might be useful for clinicians for promoting activity in individuals with early symptoms consistent with symptomatic knee OA. PMID- 26416464 TI - Awareness, experiences and perceptions of telehealth in a rural Queensland community. AB - BACKGROUND: Telehealth can offer alternative options for receiving healthcare services in rural locations, improving access and reducing costs associated with traveling for services. However, the full potential of telehealth has not been realised with slow and fragmented uptake. This study describes the awareness, experiences and perceptions of telehealth in an Australian rural community. METHODS: Semi-structured interviews were undertaken with 47 participants from three rural towns in the Darling Downs region of Queensland. Content analysis was used to abstract themes and core concepts from the interviews. RESULTS: Three participants were healthcare providers who had all previously used telehealth in their clinical practice. Twenty-seven (57 %) participants regularly travelled to access specialist healthcare. While 28 (60 %) participants were aware of telehealth, only six (13 %) had actually used telehealth services; three as patients and three as healthcare providers. Major themes evident included: acceptance of the need to travel; paternalism and empowerment; and trust and misconceptions. CONCLUSIONS: For telehealth initiatives to be successful, there needs to be greater public awareness and understanding of the potential benefits of telehealth. Empowering patients as partners in the delivery of healthcare may be an important factor in the growth of telehealth services. PMID- 26416465 TI - F-box protein interactions with the hallmark pathways in cancer. AB - F-box proteins (FBP) are the substrate specifying subunit of Skp1-Cul1-FBP (SCF) type E3 ubiquitin ligases and are responsible for directing the ubiquitination of numerous proteins essential for cellular function. Due to their ability to regulate the expression and activity of oncogenes and tumour suppressor genes, FBPs themselves play important roles in cancer development and progression. In this review, we provide a comprehensive overview of FBPs and their targets in relation to their interaction with the hallmarks of cancer cell biology, including the regulation of proliferation, epigenetics, migration and invasion, metabolism, angiogenesis, cell death and DNA damage responses. Each cancer hallmark is revealed to have multiple FBPs which converge on common signalling hubs or response pathways. We also highlight the complex regulatory interplay between SCF-type ligases and other ubiquitin ligases. We suggest six highly interconnected FBPs affecting multiple cancer hallmarks, which may prove sensible candidates for therapeutic intervention. PMID- 26416466 TI - Tumor-extracellular matrix interactions: Identification of tools associated with breast cancer progression. AB - Several evidences support the concept that cancer development and progression are not entirely cancer cell-autonomous processes, but may be influenced, and possibly driven, by cross-talk between cancer cells and the surrounding microenvironment in which, besides immune cells, stromal cells and extracellular matrix (ECM) play a major role in regulating distinct biologic processes. Stroma and ECM-related signatures proved to influence breast cancer progression, and to contribute to the identification of tumor phenotypes resistant to cytotoxic and hormonal treatments. The possible clinical implications of the interplay between tumor cells and the microenvironment, with special reference to ECM remodelling, will be discussed in this review. PMID- 26416467 TI - Moving Knowledge Acquisition From the Lecture Hall to the Student Home: A Prospective Intervention Study. AB - BACKGROUND: Podcasts are popular with medical students, but the impact of podcast use on learning outcomes in undergraduate medical education has not been studied in detail. OBJECTIVE: Our aim was to assess the impact of podcasts accompanied by quiz questions and lecture attendance on short- and medium-term knowledge retention. METHODS: Students enrolled for a cardio-respiratory teaching module were asked to prepare for 10 specific lectures by watching podcasts and submitting answers to related quiz questions before attending live lectures. Performance on the same questions was assessed in a surprise test and a retention test. RESULTS: Watching podcasts and submitting answers to quiz questions (versus no podcast/quiz use) was associated with significantly better test performance in all items in the surprise test and 7 items in the retention test. Lecture attendance (versus no attendance) was associated with higher test performance in 3 items and 1 item, respectively. In a linear regression analysis adjusted for age, gender, and overall performance levels, both podcast/quiz use and lecture attendance were significant predictors of student performance. However, the variance explained by podcast/quiz use was greater than the variance explained by lecture attendance in the surprise test (38.7% vs. 2.2%) and retention test (19.1% vs. 4.0%). CONCLUSIONS: When used in conjunction with quiz questions, podcasts have the potential to foster knowledge acquisition and retention over and above the effect of live lectures. PMID- 26416468 TI - Optimum initial loading dose of vancomycin for pneumonia caused by methicillin resistant Staphylococcus aureus. PMID- 26416469 TI - Human papillomavirus and polyomavirus coinfections among Chinese men who have sex with men. PMID- 26416470 TI - Clinical evaluation of the newly developed infectious disease/fever screening radar system using the neural network and fuzzy grouping method for travellers with suspected infectious diseases at Narita International Airport Clinic. PMID- 26416471 TI - Telaprevir-based therapy for treatment of HIV-1 and hepatitis C virus co-infected patients: An early access programme. AB - OBJECTIVES: HPC3005 is a multicentre, open-label, telaprevir trial in HCV/HIV coinfected patients with severe fibrosis or compensated cirrhosis. METHODS: Patients were treated with telaprevir 750 mg every 8 h (1125 mg if on efavirenz) plus pegylated interferon-alpha (PEG-IFN, 180 MUg once-weekly) and ribavirin (RBV, 800 mg/day) for 12 weeks, followed by 36 weeks of PEG-IFN/RBV. RESULTS: Mean age was 44 years, 97/118 patients were male and all were Caucasian, 68 had severe fibrosis and 50 had cirrhosis. Seventy-eight had HCV RNA levels >=800 000 IU/mL, 72 had HCV genotype 1a, baseline HIV RNA was <50 copies/mL in 112 patients. Overall, 114/118 patients continued antiretroviral treatment, 4 were untreated. Seventy-five patients received tenofovir and 74 emtricitabine; in addition 53 received atazanavir/ritonavir, 43 raltegravir, and 24 efavirenz. By intention-to-treat, 78 (66%) patients achieved SVR24. Nineteen discontinued telaprevir, 8 for virological endpoint, 5 for adverse events (2 anaemia, 2 rash, 1 asthenia), 5 for non-compliance and 1 withdrew consent. The most common adverse events were anaemia (36 patients), thrombocytopaenia (33), rash (26), bilirubin increase (17), and neutropenia (16). CONCLUSIONS: In this early access programme in coinfected patients with severe fibrosis or cirrhosis, 66% of patients achieved SVR. The most common adverse events were haematological. CLINICAL TRIAL NUMBER: NCT01500616. PMID- 26416472 TI - Prognostic potential of 1,3-beta-d-glucan levels in bronchoalveolar lavage fluid samples. AB - OBJECTIVES: The objective of this study was to investigate the prognostic potential of 1,3-beta-d-glucan (BDG) testing in bronchoalveolar lavage fluid (BALF) samples. METHODS: A total of 300 BALF samples from 252 patients were investigated for BDG (Fungitell((r)) assay). Prognostic potential of BALF BDG was evaluated by using: i.) Kaplan-Meier analysis, and ii.) multivariable Cox hazard regression analyses. RESULTS: BALF BDG levels were found to be significantly higher in samples with Candida spp. colonization (p < 0.001). A total of 61/252 patients (24.2%) died within 90-days of BALF sampling (18.1% of patients with BALF BDG <200 pg/mL, 32.4% with BALF BDG >=200 pg/mL). Kaplan-Meier analysis revealed that overall cumulative 90-day mortality was significantly higher in those with BALF BDG levels >=200 pg/mL when compared to those with levels <200 pg/mL (log-rank p = 0.006, Breslow p = 0.005 and Tarone-Ware p = 0.005). The multivariable Cox regression analysis showed that BALF BDG levels were a strong predictor of 90-day overall mortality, with a hazard ratio of 1.048 (per 100 pg/mL increase of BALF BDG). CONCLUSION: False positive BALF BDG results in the presence of Candida spp. colonization of the lower respiratory tract may explain the limited diagnostic potential of BALF BDG testing. In contrast, prognostic potential of BALF BDG may be promising. PMID- 26416473 TI - Clindamycin and rifampicin: No bull's eye without a target. PMID- 26416474 TI - Salmonella in the tropical household environment--Everyday, everywhere. AB - OBJECTIVES: To determine the prevalence of Salmonella in the environment of case and control houses, and compare serovars isolated from cases and their houses. METHODS: From 2005 to 2008, we tested samples from houses of 0-4 year old cases and community controls in Darwin and Palmerston for Salmonella. Case isolates were compared with environmental isolates. S. Ball and S. Urbana isolates were compared using Multiple Amplification of Phage Locus Typing (MAPLT) and Multiple Locus Variable number of tandem repeat Analysis (MLVA). RESULTS: Salmonella were found in 47/65 (72%) case houses and 18/29 (62%) control houses; these proportions were not significantly different. In 21/47 (45%) houses, case and environmental isolates (from animal faeces, soil and vacuums) were indistinguishable. Multiple serovars were isolated from 20 (31%) case and 6 (21%) control houses. All but one environmental isolate are known human pathogens in the Northern Territory (NT). Each of the four pairs of S. Ball and S. Urbana were indistinguishable. CONCLUSIONS: Animal faeces were the most likely source of salmonellosis in cases. The similar prevalence of house isolates suggests that Salmonella is ubiquitous in this environment. The distinction of S. Ball and S. Urbana subtypes enabled linkage of human illness to environmental exposure. Environmental contamination with Salmonella is an important source of sporadic infection in children in the tropics. PMID- 26416475 TI - Individual and household-level risk factors for sporadic salmonellosis in children. AB - OBJECTIVES: To explore risk factors for sporadic salmonellosis at the individual and household level in children in tropical Darwin, where animal faeces contaminated with Salmonella is thought to be common. METHODS: A 2-year community based case-control study of children aged 0-4 years residing in Darwin and Palmerston from June 2006. Variables included behaviour, health, food, family and housing characteristics. Environmental samples were taken from houses of case and control children. RESULTS: Of children whose parents were contacted, 59/131 cases and 95/222 controls were included. Salmonella was isolated from 41/56 (73%) case houses and 18/29 (62%) control houses (p = 0.29). Multivariate analyses showed breastfeeding 0.16 (p = 0.02), increasing age (months) 0.89 (p = 0.00) and daily vacuuming 0.18 (p = 0.06) were protective; consuming powdered formula milk 4.88 (p = 0.02), pet ownership 4.86 (p = 0.02), oral contact with animals 7.85 (p = 0.05), recent antibiotic use 10.01 (p = 0.03) and sweeping in the presence of children 3.73 (p = 0.04) were associated with sporadic salmonellosis. CONCLUSIONS: Salmonellosis in children under 5 years of age is associated with potentially modifiable risk factors other than food. Breastfeeding beyond 6 months, careful hygiene when preparing formula milk and around pets, frequent cleaning of infant play areas especially quick removal of animal faeces are behaviours likely to reduce childhood sporadic salmonellosis. PMID- 26416476 TI - Characterization of structural elements in native autoinducing peptides and non native analogues that permit the differential modulation of AgrC-type quorum sensing receptors in Staphylococcus aureus. AB - Staphylococcus aureus uses short macrocyclic peptides (i.e., autoinducing peptides, or AIPs) to assess its local population density in a cell-cell signaling mechanism called quorum sensing (QS). At high cell numbers, this pathogen can initiate many virulent behaviors that allow for the establishment of infection. Binding of the AIP signal to its cognate transmembrane AgrC-type receptor is a critical event in the QS signaling cascade; consequently, interference of AIP:receptor interactions may have the potential to prevent and eradicate certain S. aureus infections. To date, four pairs of AIP:AgrC receptors have been identified in S. aureus, each pair being utilized by a specific S. aureus group (I-IV). Other staphylococcal species also use closely related, but distinct, AIP:AgrC pairs to control QS. We seek to develop non-native ligands capable of intercepting AIP:AgrC binding in each S. aureus group and in related species. As these bacteria may use their respective AIP signal to attenuate the QS systems of other groups/species, such ligands would provide valuable chemical tools to probe possible interference mechanisms in a range of contexts. In the current study, we used solution-phase NMR techniques to characterize the 3-D structures of a set of known native and non-native peptides that have differential modulatory activity in certain AgrC receptors. Analysis of these structures revealed several distinct structural motifs that belay differential activity in selected S. aureus AgrC receptors (i.e., AgrC-I, AgrC-II, and AgrC III). The results of this study can be leveraged for the design of new synthetic ligands with enhanced selectivities and potencies for these AgrC receptors. PMID- 26416477 TI - Orexin Receptor Antagonists: Historical Perspectives and Future Opportunities. AB - The orexin receptors OX1 and OX2 play important roles in the regulation of sleep wake cycles, feeding, reward and energy homeostasis. Since these G protein coupled receptors were deorphanised in 1998, more than 200 patents containing orexin receptor antagonists have been filed and, in 2014, suvorexant (Belsomra(r)) became the first of these compounds to receive approval from the FDA. Suvorexant is a dual orexin receptor antagonist (DORA) which is available for the treatment of insomnia. This review provides a historical perspective on the discovery and development of DORAs as well as selective OX1 receptor antagonists (1-SORAs) and selective OX2 receptor antagonists (2-SORAs). 2-SORAs are under clinical evaluation for their ability to modulate sleep, and 1-SORAs have shown promise for the treatment of addiction in pre-clinical animal models. Detailed medicinal chemistry case studies are presented and future opportunities for orexin receptor antagonists are considered. PMID- 26416478 TI - Effects of cyano, ethynyl and ethylenedioxy groups on the photophysical properties of carbazole-based porphyrins. AB - The synthesis and photophysical properties of cyano and ethynyl substituted carbazole-based porphyrins were investigated. The introduction of ethynyl groups induced red shifts, while that of cyano groups induced blue shifts of their absorption bands, which was supported by MO calculations. Ethylenedioxy-appended porphyrins were also prepared via a coupling reaction. The conjugated and electronic substituent effects on the photophysical properties of the carbazole based porphyrins have been elucidated by using both experimental results and calculations. Among these porphyrins, the ethylenedioxy-appended selenaporphyrin displayed intensified and red-shifted absorption in the NIR region up to 1178 nm. PMID- 26416479 TI - Mobile Phone App Aimed at Improving Iron Intake and Bioavailability in Premenopausal Women: A Qualitative Evaluation. AB - BACKGROUND: Low iron intake can lead to iron deficiency, which can result in impaired health and iron-deficiency anemia. A mobile phone app, combining successful dietary strategies to increase bioavailable iron with strategies for behavior change, such as goal setting, monitoring, feedback, and resources for knowledge acquisition, was developed with the aim to increase bioavailable iron intake in premenopausal women. OBJECTIVE: To evaluate the content, usability, and acceptability of a mobile phone app designed to improve intake of bioavailable dietary iron. METHODS: Women aged 18-50 years with an Android mobile phone were invited to participate. Over a 2-week period women were asked to interact with the app. Following this period, semistructured focus groups with participants were conducted. Focus groups were audio recorded and analyzed via an inductive open-coding method using the qualitative analysis software NVivo 10. Themes were identified and frequency of code occurrence was calculated. RESULTS: Four focus groups (n=26) were conducted (age range 19-36 years, mean 24.7, SD 5.2). Two themes about the app's functionality were identified (frequency of occurrence in brackets): interface and design (134) and usability (86). Four themes about the app's components were identified: goal tracker (121), facts (78), photo diary (40), and games (46). A number of suggestions to improve the interface and design of the app were provided and will inform the ongoing development of the app. CONCLUSIONS: This research indicates that participants are interested in iron and their health and are willing to use an app utilizing behavior change strategies to increase intake of bioavailable iron. The inclusion of information about the link between diet and health, monitoring and tracking of the achievement of dietary goals, and weekly reviews of goals were also seen as valuable components of the app and should be considered in mobile health apps aimed at adult women. PMID- 26416481 TI - Behavioural abnormalities in children with new-onset nephrotic syndrome receiving corticosteroid therapy: results of a prospective longitudinal study. AB - BACKGROUND: Corticosteroid therapy can cause behavioural abnormalities in children with nephrotic syndrome. The objective of this study was to explore the timing of the appearance of abnormalities in their first episode. METHODS: Forty five children with a first episode of idiopathic nephrotic syndrome (30 aged 2-5 and 15 aged 6-14 years) were assessed for behavioural problems using the Child Behaviour Checklist (CBCL) before, and after 6 and 12 weeks of oral steroid treatment. Sixty healthy children were included as controls. RESULTS: In both age groups, marked abnormalities of externalising behaviour were noticed, specifically in the domains of aggressive behaviour and attention problems. Clinical range or borderline externalising abnormalities were present in 73% of the younger children and 60% of the schoolchildren after 6 weeks of treatment. In the schoolchildren, abnormal internalising behaviour was also noted at 6 weeks, in 40% at borderline level and in 20% within the clinical range. Elevated scores were observed for the anxious/depressed and withdrawn/depressed domains. Most changes persisted at the 12-week observation. CONCLUSIONS: Children of both age groups showed significant attention problems and aggressive and abnormal externalising behaviour within 6 weeks of starting treatment. Parents should be informed and counselled about this potential adverse effect of steroid therapy. PMID- 26416480 TI - Can office blood pressure readings predict masked hypertension? AB - BACKGROUND: Studies in children with chronic kidney disease indicate a high prevalence of masked hypertension detected by ambulatory blood pressure monitoring (ABPM). However, it is not well known if the frequency of masked hypertension is related to the level of normal casual blood pressure (BP). METHODS/RESULTS: We hypothesized that lower levels of normal casual BP are associated with a lower prevalence of masked hypertension. Data from the chronic kidney disease (CKiD) cohort were analyzed cross-sectionally across multiple visits. The majority of children with normal casual BP also had normal wake and sleep ABP (60 %), even at the highest percentiles of casual BP. The frequency of masked hypertension was lower in children with casual BP <=25th percentile versus those with casual BP in 26-50th percentile and casual BP in 51-90th percentile during both wake and sleep periods. In children with the lowest normal casual BP levels (<=25th percentile), the frequency of abnormal mean wake or sleep ABP was 2-7 %, and of abnormal BP load was 6-16 %. CONCLUSIONS: These data suggest that masked hypertension is unlikely if the casual BP is found to be in the low normal range. PMID- 26416482 TI - The Abundant Histone Chaperones Spt6 and FACT Collaborate to Assemble, Inspect, and Maintain Chromatin Structure in Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae Spt6 protein is a conserved chromatin factor with several distinct functional domains, including a natively unstructured 30-residue N-terminal region that binds competitively with Spn1 or nucleosomes. To uncover physiological roles of these interactions, we isolated histone mutations that suppress defects caused by weakening Spt6:Spn1 binding with the spt6-F249K mutation. The strongest suppressor was H2A-N39K, which perturbs the point of contact between the two H2A-H2B dimers in an assembled nucleosome. Substantial suppression also was observed when the H2A-H2B interface with H3-H4 was altered, and many members of this class of mutations also suppressed a defect in another essential histone chaperone, FACT. Spt6 is best known as an H3-H4 chaperone, but we found that it binds with similar affinity to H2A-H2B or H3-H4. Like FACT, Spt6 is therefore capable of binding each of the individual components of a nucleosome, but unlike FACT, Spt6 did not produce endonuclease-sensitive reorganized nucleosomes and did not displace H2A-H2B dimers from nucleosomes. Spt6 and FACT therefore have distinct activities, but defects can be suppressed by overlapping histone mutations. We also found that Spt6 and FACT together are nearly as abundant as nucleosomes, with ~24,000 Spt6 molecules, ~42,000 FACT molecules, and ~75,000 nucleosomes per cell. Histone mutations that destabilize interfaces within nucleosomes therefore reveal multiple spatial regions that have both common and distinct roles in the functions of these two essential and abundant histone chaperones. We discuss these observations in terms of different potential roles for chaperones in both promoting the assembly of nucleosomes and monitoring their quality. PMID- 26416484 TI - Oxidative Etching of Hexagonal Boron Nitride Toward Nanosheets with Defined Edges and Holes. AB - Lateral surface etching of two-dimensional (2D) nanosheets results in holey 2D nanosheets that have abundant edge atoms. Recent reports on holey graphene showed that holey 2D nanosheets can outperform their intact counterparts in many potential applications such as energy storage, catalysis, sensing, transistors, and molecular transport/separation. From both fundamental and application perspectives, it is desirable to obtain holey 2D nanosheets with defined hole morphology and hole edge structures. This remains a great challenge for graphene and is little explored for other 2D nanomaterials. Here, a facile, controllable, and scalable method is reported to carve geometrically defined pit/hole shapes and edges on hexagonal boron nitride (h-BN) basal plane surfaces via oxidative etching in air using silver nanoparticles as catalysts. The etched h-BN was further purified and exfoliated into nanosheets that inherited the hole/edge structural motifs and, under certain conditions, possess altered optical bandgap properties likely induced by the enriched zigzag edge atoms. This method opens up an exciting approach to further explore the physical and chemical properties of hole- and edge-enriched boron nitride and other 2D nanosheets, paving the way toward applications that can take advantage of their unique structures and performance characteristics. PMID- 26416483 TI - MicroRNAs and Their Targets Are Differentially Regulated in Adult and Neonatal Mouse CD8+ T Cells. AB - Immunological memory, which protects organisms from re-infection, is a hallmark of the mammalian adaptive immune system and the underlying principle of vaccination. In early life, however, mice and other mammals are deficient at generating memory CD8+ T cells, which protect organisms from intracellular pathogens. The molecular basis that differentiates adult and neonatal CD8+ T cells is unknown. MicroRNAs (miRNAs) are both developmentally regulated and required for normal adult CD8+ T cell functions. We used next-generation sequencing to identify mouse miRNAs that are differentially regulated in adult and neonatal CD8+ T cells, which may contribute to the impaired development of neonatal memory cells. The miRNA profiles of adult and neonatal cells were surprisingly similar during infection; however, we observed large differences prior to infection. In particular, miR-29 and miR-130 have significant differential expression between adult and neonatal cells before infection. Importantly, using RNA-Seq, we detected reciprocal changes in expression of messenger RNA targets for both miR-29 and miR-130. Moreover, targets that we validated include Eomes and Tbx21, key genes that regulate the formation of memory CD8+ T cells. Notably, age-dependent changes in miR-29 and miR-130 are conserved in human CD8+ T cells, further suggesting that these developmental differences are biologically relevant. Together, these results demonstrate that miR-29 and miR-130 are likely important regulators of memory CD8+ T cell formation and suggest that neonatal cells are committed to a short-lived effector cell fate prior to infection. PMID- 26416486 TI - The mechanism of a phosphazene-phosphazane rearrangement. AB - The phosphazene-phosphazane rearrangement of N3P3Cl5O(CH2)2OC(=O)CMe=CH2 (8) has been examined in detail using one and two dimensional NMR ((31)P, (1)H) spectroscopy and mass spectrometry. The mixed phosphazene-phosphazane [NPCl2]2[N((CH2)2OC(=O)CMe=CH2)P(O)Cl] (14), [NPCl2]2[NHP(O)Cl] (13) and a two ring assembly [NPCl2]2[NP(O{(NPCl2)2(N((CH2)2OC(=O)CMe=CH2)P(O)}] (15) have all been detected in the product mixture. The rate of the rearrangement has been measured at five temperatures by (31)P and (1)H NMR. The reaction is first order in 8 (T1/2 at 111 degrees is 4.65 hours). The activation enthalpy is positive and the activation entropy is negative. A mechanism involving competing intra and inter molecular processes which fits the product distribution and kinetic data has been proposed. Several other methyacrylphosphazenes were examined under the same thermolysis conditions. The rearrangement was observed and the rates obtained in cases where the (CH2)2 spacer unit of the methacrylate was replaced by linear and branched propyl units. The rearrangement was not observed when the methacrylate was appended to a spirocyclic unit, the spacer unit was extended to the n-butyl group and when the methacrylate unit was replaced by a methoxy group. These results are all consistent with the proposed mechanism. This investigation resolves conflicting results previous reported for the rearrangement. PMID- 26416485 TI - Effect of selective CCK1 receptor antagonism on accommodation and tolerance of intestinal gas in functional gut disorders. AB - BACKGROUND: Participants with functional gut disorders develop gas retention and symptoms in response to intestinal gas loads that are well tolerated by healthy subjects. To determine the role of cholecystokinin (CCK1 ) receptors on gas transit and tolerance in women with functional gut disorders. METHODS: In 12 healthy women, and 24 women with functional gut disorders (12 dyspepsia and 12 constipation-predominant irritable bowel syndrome) gas was infused into the jejunum at 12 mL/min for 3 h with simultaneous duodenal lipid infusion (intralipid 1 kcal/min), while measuring anal gas evacuation and abdominal symptoms on a 0-6 score scale. Triple-blind paired studies during iv infusion of dexloxiglumide (2.5 mg/kg bolus plus 5 mg/kg h continuous infusion), a selective CCK1 inhibitor, or saline (control) were performed in random order. RESULTS: During saline infusion participants with functional gut disorders developed significantly greater gas retention and abdominal symptoms than healthy subjects (394 +/- 40 mL vs 265 +/- 35 mL and 2.8 +/- 0.3 vs 1.9 +/- 0.4 highest abdominal symptom score, respectively; P < 0.05 for both). Dexloxiglumide increased gas retention in both groups (514 +/- 35 mL and 439 +/- 60 mL, respectively; P = 0.033 vs saline for both); however, despite the larger retention, dexloxiglumide reduced abdominal symptoms (2.3 +/- 0.2 score and 0.8 +/- 0.3 score, respectively; P = 0.05 vs saline for both). Post-hoc analysis showed that, the decrease in abdominal symptoms was more pronounced in those participants with functional gut disorders with higher basal abdominal symptoms than in the rest (P = 0.037). CONCLUSION: Inhibition of CCK1 receptors by dexloxiglumide increases intestinal gas retention and reduces abdominal symptoms in response to by intestinal gas loads. European Clinical Trials Database (EudraCT 2005-003338-16). PMID- 26416487 TI - Round and round we go. PMID- 26416488 TI - Studies towards the stabilisation of a mushroom phytase produced by submerged cultivation. AB - A novel phytase from Ganoderma australe G24 was produced by submerged cultivation and recovery. Liquid and solid forms of phytase were developed; both types of product were formulated using different additives. Ganoderma australe G24 phytase was very stable in liquid form with NaCl and sodium acetate buffer. Solid form products were obtained by spray-drying using different polymers to encapsulate the phytase and the capsules obtained were analyzed by electron microscopy. Micrographs confirmed micro and nanoparticles formed with maltodextrin (300 nm to 7-8 um) without the presence of agglomerates. The use of maltodextrin for solid formulation of G. australe G24 phytase is recommended, and resulted in good stability after the drying process and during storage (shelf life). Kinetic models of phytase inactivation in the microencapsulated powders over time were proposed for the different stabilizing additives. Inactivation rate constants, half-lives and D values (decimal reduction time) were obtained. Phytase encapsulated with maltodextrin remained stable after 90 days, with k 0.0019 day( 1) and a half-life (t1/2) of 367.91 days(-1). PMID- 26416490 TI - Modifiable factors and cognitive dysfunction in breast cancer survivors: a mixed method systematic review. AB - PURPOSE: It is unknown why some breast cancer survivors experience cancer-related cognitive impairments (CRCI) after cancer treatment, and modifiable risk factors for CRCI remain to be explicated. This mixed-method systematic review synthesizes quantitative and qualitative evidence for relationships between modifiable factors and CRCI in breast cancer survivors who receive chemotherapy as part of their treatment. METHODS: Keyword Searches of PubMed/Medline, PsychINFO, and CINAHL were performed for January 2005 through June 2015. Studies that provided data on associations between modifiable biological, behavioral, environmental, and psychosocial factors and cognition were included. RESULTS: Twenty-two quantitative studies and five qualitative studies were identified after applying inclusion and exclusion criteria yielding evidence for significant relationships among modifiable biological (inflammatory cytokines), behavioral (sleep quality, physical activity), and psychosocial (stress, distress, affect) factors and CRCI. CONCLUSION: Many women unfortunately experience CRCI after breast cancer chemotherapy, with limited treatment options available to improve cognitive function. This review synthesizes current evidence to support the associations between modifiable factors and CRCI and can inform research to evaluate these factors prospectively. The clinical implications of these findings suggest that lifestyle factors such as physical activity, stress management, and sleep quality may be appropriate targets for behavioral interventions to improve cognitive function following breast cancer chemotherapy; however, further research is necessary. PMID- 26416492 TI - Decreased connexin 43 in astrocytes inhibits the neuroinflammatory reaction in an acute mouse model of neonatal sepsis. AB - Neonatal sepsis is common in neonatal intensive care units, often complicated by injury to the immature brain. Previous studies have shown that the expression of the gap junction protein connexin 43 (Cx43) in the brain decreases when stimulated by neuro-inflammatory drugs such as lipopolysaccharide (LPS). Here we showed that partial deletion of Cx43 in astrocytes resulted in weakened inflammatory responses. The up-regulation of pro-inflammatory cytokines was significantly reduced in mice with partial deletion of Cx43 in astrocytes compared with wild-type littermates after systemic LPS injection. Moreover, microglial activation was inhibited in mice with partial deletion of Cx43. These results showed that Cx43 in astrocytes plays a critical role in neuro inflammatory responses. This work provides a potential therapeutic target for inhibiting neuro-inflammatory responses in neonatal sepsis. PMID- 26416493 TI - Medication use and potentially inappropriate medications in those with limited prognosis living in residential aged care. AB - AIM: To compare the prevalence in residential aged care (RAC) of preventative and potentially inappropriate medications (PIMs) in those who died within 12 months versus those alive after 12 months. METHODS: Firstly, a cross-sectional survey of 6196 people living in RAC in Auckland. Secondly, a research physician searched electronic hospital records in one District Health Board for a sub-sample (n = 222) of these residents. Classes of medications and dates of death were obtained from the Ministry of Health databases. Those who died versus those alive at 12 months were compared. RESULTS: Over half of the 6196 participants received antihypertensives and/or antiplatelet agents. Cardiovascular preventative medications were significantly more common in those who died within 12 months. Seventy percent in high-level care received psychotropics. PIMs were commonly used. CONCLUSIONS: Use of preventative medications is common in RAC, especially during the last year of life. Psychotropics are very commonly used, despite being potentially inappropriate. PMID- 26416491 TI - Dysgeusia and weight loss under treatment with vismodegib: benefit of nutritional management. AB - PURPOSE: Whereas vismodegib is effective in the treatment of locally advanced/metastatic basal cell carcinoma, dysgeusia and weight loss are common side effects of such treatment. The main objective of this study was to monitor the nutritional status of vismodegib-treated patients. Secondary objective was to assess the incidence of dysgeusia and the benefit of early nutritional management. METHODS: This prospective study included all patients who started vismodegib between October 2011 and May 2013 at Nantes University Hospital. Prior to July 2012, patients treated with vismodegib had not received any specific nutritional management (Historical cohort). Body weight and presence of dysgeusia were recorded monthly. Patients treated after July 2012 (Nutrition cohort) were evaluated by a physician of the Nutrition Support Unit and received dietary counseling at vismodegib initiation. A standardized nutritional management protocol was initiated in case of significant weight loss. RESULTS: Forty-five patients (21 and 24 in the Nutrition and Historical cohort, respectively) were enrolled. In the Nutrition cohort, five patients (24 %) were undernourished at vismodegib initiation, and the 6-month cumulative incidence of dysgeusia was 71 %. Eight patients (38 %) and 13 patients (54 %) had a weight loss greater than 5 % in the Nutrition and Historical cohort, respectively (p = 0.3727). CONCLUSION: The results of this pilot study suggest the benefit of early nutritional screening. The potential benefit of nutritional support in this setting warrants further investigation. PMID- 26416494 TI - Irrigation of Cutaneous Abscesses Does Not Improve Treatment Success. AB - STUDY OBJECTIVE: Irrigation of the cutaneous abscess cavity is often described as a standard part of incision and drainage despite no randomized, controlled studies showing benefit. Our goal is to determine whether irrigation of a cutaneous abscess during incision and drainage in the emergency department (ED) decreases the need for further intervention within 30 days compared with no irrigation. METHODS: We performed a single-center, prospective, randomized, nonblinded study of ED patients receiving an incision and drainage for cutaneous abscess, randomized to irrigation or no irrigation. Patient characteristics and postprocedure pain visual analog scale score were obtained. Thirty-day telephone follow-up was conducted with a standardized data form examining need for further intervention, which was defined as repeated incision and drainage, antibiotic change, or abscess-related hospital admission. RESULTS: Of 209 enrolled patients, 187 completed follow-up. The irrigation and no-irrigation groups were similar with respect to diabetes, immunocompromise, fever, abscess size, cellulitis, and abscess location, but the irrigation group was younger (mean age 36 versus 40 years) and more often treated with packing (89% versus 75%) and outpatient antibiotics (91% versus 73%). The need for further intervention was not different in the irrigation (15%) and no-irrigation (13%) groups (difference 2%; 95% confidence interval -8% to 12%). There was no difference in pain visual analog scale scores (5.6 versus 5.7; difference 0.1; 95% confidence interval -0.7 to 0.9). CONCLUSION: Although there were baseline differences between groups, irrigation of the abscess cavity during incision and drainage did not decrease the need for further intervention. PMID- 26416495 TI - Biasing the odds: Approaches to capturing, understanding and exploiting functional selectivity in GPCRs. AB - There is significant expectation in the pharmacological community that an understanding of biased signalling will lead to the development of new drugs and a better understanding of molecular targets in the in vivo context. I think it is safe to say that Pharma is withholding judgment on the promise and potential of what they view as an interesting pharmacological curiosity. That said, beyond successes of biased ligands in clinical trials and their appearance on the market, what it is need is a clear plan and the right tools and analytical methods to characterize functional selectivity from in cellulo to in vivo. In this issue of Methods, we have put together a series of articles that help lay out a methodological and analytical framework to help get us there. PMID- 26416496 TI - Mislocalization-related disease gene discovery using gene expression based computational protein localization prediction. AB - Protein sorting is an important mechanism for transporting proteins to their target subcellular locations after their synthesis. Mutations on genes may disrupt the well regulated protein sorting process, leading to a variety of mislocation related diseases. This paper proposes a methodology to discover such disease genes based on gene expression data and computational protein localization prediction. A kernel logistic regression based algorithm is used to successfully identify several candidate cancer genes which may cause cancers due to their mislocation within the cell. Our results also showed that compared to the gene co-expression network defined on Pearson correlation coefficients, the nonlinear Maximum Correlation Coefficients (MIC) based co-expression network give better results for subcellular localization prediction. PMID- 26416498 TI - Acute kidney injury: New antagonist prevents I/R injury. PMID- 26416497 TI - Phosphate and FGF-23 homeostasis after kidney transplantation. AB - Dysregulated phosphate metabolism is a common consequence of chronic kidney disease, and is characterized by a high circulating level of fibroblast growth factor (FGF)-23, hyperparathyroidism, and hyperphosphataemia. Kidney transplantation can elicit specific alterations to phosphate metabolism that evolve over time, ranging from severe hypophosphataemia (<0.5 mmol/l) to hyperphosphataemia (>1.50 mmol/l) and high FGF-23 levels. The majority of renal transplant recipients develop hypophosphataemia during the first 3 months after transplantation as a consequence of relatively slow adaptation of FGF-23 and parathyroid hormone levels to restored renal function, and the influence of immunosuppressive drugs. By 3-12 months after transplantation, phosphate homeostasis is at least partially restored in the majority of recipients, which is paralleled by a substantially reduced risk of cardiovascular-associated morbidity and mortality compared with the pre-transplantation setting. Many renal transplant recipients, however, exhibit persistent abnormalities in phosphate homeostasis, which is often due to multifactorial causes, and may contribute to adverse outcomes on the cardiovascular system, kidney, and bone. Dietary and pharmacologic interventions might improve phosphate homeostasis in renal transplant recipients, but additional insight into the pathophysiology of transplantation-associated abnormalities in phosphate homeostasis is needed to further optimize disease management and improve prognosis for renal transplant recipients. PMID- 26416500 TI - Risk factors: Contribution of low GFR to the global burden of disease. PMID- 26416499 TI - Nephrology research--the past, present and future. AB - Important advances have been made in basic and clinical nephrology research over the past decade, with improved pathological insights into various disease processes and the introduction of new treatments for diseases such as atypical haemolytic uraemic syndrome. However, many challenges remain. In this Viewpoint, we asked five Nature Reviews Nephrology Advisory Board members, who have been associated with the journal since its launch in November 2005, to reflect on the progress and roadblocks of the past 10 years. They also comment on areas where effort and money should be invested and how they expect the field to progress in the next 10 years. PMID- 26416501 TI - Energy regulation in context: Free-living female arctic ground squirrels modulate the relationship between thyroid hormones and activity among life history stages. AB - Thyroid hormones (THs), key regulators of lipid and carbohydrate metabolism, are likely modulators of energy allocation within and among animal life history stages. Despite their role in modulating metabolism, few studies have investigated whether THs vary among life history stages in free-living animals or if they exhibit stage-specific relationships to total energy expenditure and activity levels. We measured plasma total triiodothyronine (tT3) and thyroxine (tT4) at four, discrete life history stages of female arctic ground squirrels from two different populations in northern Alaska to test whether plasma THs correlate with life history stage-specific changes in metabolic rate and energy demand. We also tested whether THs explained individual variation in aboveground activity levels within life history stages. T3 peaked during lactation and was lowest during pre-hibernation fattening, consistent with known changes in basal metabolism and core body temperature. In contrast, T4 was elevated shortly after terminating hibernation but remained low and stable across other life-history stages in the active season. THs were consistently higher in the population that spent more time above-ground but the relationship between THs and activity varied among life history stages. T3 was positively correlated with activity only during lactation (r(2)=0.50) whereas T4 was positively correlated with activity immediately following lactation (r(2)=0.48) and during fattening (r(2)=0.53). Our results support the hypothesis that THs are an important modulator of basal metabolism but also suggest that the relationship between THs and activity varies among life history stages. PMID- 26416502 TI - The association between job strain and coronary heart disease: a meta-analysis of prospective cohort studies. AB - BACKGROUND: Studies about work stress and the risk of coronary heart disease (CHD) have yielded inconsistent results. This meta-analysis aimed to investigate the association between job strain and the risk of CHD. METHODS: We searched PubMed and Embase databases for studies reporting data on job strain and the risk of CHD. Studies were included if they reported multiple-adjusted relative risk (RR) with 95% confidence interval (CI) with respect to CHD from job strain. RESULTS: Fourteen prospective cohort studies comprising 232,767 participants were included. The risk of CHD was increased in high-strain (RR 1.26; 95% CI 1.12 1.41) and passive jobs (RR 1.14; 95% CI 1.02-1.29) but not in active jobs (RR 1.09; 95% CI 0.97-1.22), when compared with low-strain group. The increased risk of CHD in high-strain and passive jobs was mainly driven by studies with a follow up duration of >= 10 years. Neither the low-control (RR 1.06; 95% CI 0.93-1.19) nor high-demand (RR 1.13; 95% CI 0.97-1.32) dimension was independently associated with the risk of CHD. CONCLUSIONS: Individuals with high-strain and passive jobs were more likely to experience a CHD event. Intervention programs incorporating individual and organizational levels are crucial for reducing job strain and the risk of CHD. PMID- 26416503 TI - Advances in Peptides as Therapeutic Drugs. PMID- 26416504 TI - Executive function and weight status in children: A one-year longitudinal perspective. AB - There is considerable evidence for an association between obesity and impaired executive function (EF) in adolescents and adults. However, little research has examined EF in overweight or obese children. Furthermore, data on EF in underweight individuals is lacking. In addition, there is no consensus on the directionality of the relationship between Body Mass Index (BMI) and EF, and longitudinal studies are rare. Thus, the present study examined whether children differ in their performance on a battery of EF tasks depending on their weight status (underweight, normal-weight, overweight), and investigated the longitudinal cross-lagged associations between EF and BMI. Hot EF (delay of gratification, affective decision-making), cool EF (attention shifting, inhibition, working memory [WM] updating), and BMI were assessed in 1,657 German elementary-school children at two time points, approximately one year apart. Overweight children exhibited slightly poorer attention shifting, WM updating, and affective decision-making abilities as compared to normal-weight children. Unexpectedly, they did not show any deficits in inhibition or delay of gratification. EF levels of underweight children did not differ significantly from those of normal-weight children. Furthermore, poor attention shifting and enhanced affective decision-making predicted a slightly higher BMI one year later, and a higher BMI also predicted poorer attention shifting and WM updating one year later. The latter association between BMI and subsequent EF scores, however, diminished when controlling for socioeconomic status. Results indicate that hot and cool EF plays a role in the weight development of children, and might be a promising factor to address in preventive interventions. PMID- 26416505 TI - Application of Mannich bases to the synthesis of hydroxymethylated isoflavonoids as potential antineoplastic agents. AB - The regiospecific Mannich aminomethylation of 7-hydroxyisoflavonoids using bis(N,N-dimethylamino)methane afforded C-8 substituted N,N-dimethylaminomethyl adducts, and the regioselective aminomethylation of 5-hydroxy-7 methoxyisoflavonoids afforded predominantly the C-6 substituted N,N dimethylaminomethyl adducts. Acetylation of these C-6 or C-8 Mannich bases with potassium acetate in acetic anhydride provided access to the corresponding acetoxymethyl derivatives that were subsequently converted to hydroxymethyl- and methoxymethyl-substituted 5-hydroxy- or 7-hydroxyisoflavonoids related to naturally occurring flavonoids. The C-8 acetoxymethyl, hydroxymethyl or methoxymethyl-substituted isoflavonoids possessed promising inhibitory potency in the low micromolar range in a prostate cancer PC-3 cell proliferation assay. PMID- 26416506 TI - The importance of defining focal assemblages when evaluating amphibian and reptile responses to land use. AB - Habitat loss and degradation are primary threats to amphibians and reptiles, but the relative effects of common land uses on assemblages and the mechanisms that underlie faunal responses are poorly studied. We reviewed the effects of four prevalent types of habitat alteration (urbanization, agriculture, livestock grazing, and silviculture) on amphibian and reptile species richness and abundance by summarizing reported responses in the literature and by estimating effect sizes across studies for species richness in each land-use type. We then used a multinomial model to classify species as natural habitat specialists, generalists, and disturbed habitat specialists and examined variation in effect sizes for each land-use type according to habitat specialization categories. There were mixed conclusions from individual studies, some reporting negative, neutral, or positive effects of land use on species richness and total abundance. A large proportion of studies reported species-specific effects of individual species abundance. However, in our analysis of effect sizes, we found a general trend of negative effects of land use on species richness. We also demonstrate that habitat associations of common species and species turnover can explain variation in the effect of land use on herpetofauna. Our review highlights the pervasive negative effects of common land uses on amphibians and reptiles, the importance of identifying groups vulnerable to land-use change (e.g., forest associated species) in conservation studies, and the potential influence of disturbance-associated species on whole assemblage analyses. PMID- 26416507 TI - Mitochondrial regulation of macrophage cholesterol homeostasis. AB - This review explores the relationship between mitochondrial structure and function in the regulation of macrophage cholesterol metabolism and proposes that mitochondrial dysfunction contributes to loss of the elegant homeostatic mechanisms which normally maintain cellular sterol levels within defined limits. Mitochondrial sterol 27-hydroxylase (CYP27A1) can generate oxysterol activators of liver X receptors which heterodimerise with retinoid X receptors, enhancing the transcription of ATP binding cassette transporters (ABCA1, ABCG1, and ABCG4), that can remove excess cholesterol via efflux to apolipoproteins A-1, E, and high density lipoprotein, and inhibit inflammation. The activity of CYP27A1 is regulated by the rate of supply of cholesterol substrate to the inner mitochondrial membrane, mediated by a complex of proteins. The precise identity of this dynamic complex remains controversial, even in steroidogenic tissues, but may include steroidogenic acute regulatory protein and the 18 kDa translocator protein, together with voltage-dependent anion channels, ATPase AAA domain containing protein 3A, and optic atrophy type 1 proteins. Certainly, overexpression of StAR and TSPO proteins can enhance macrophage cholesterol efflux to apoA-I and/or HDL, while perturbations in mitochondrial function, or changes in the expression of mitochondrial fusion proteins, alter the efficiency of cholesterol efflux. Molecules which can sustain or improve mitochondrial function or increase the activity of the protein complex involved in cholesterol transfer may have utility in resolving the problem of dysregulated macrophage cholesterol homeostasis, a condition which may contribute to inflammation, atherosclerosis, nonalcoholic steatohepatitis, osteoblastic bone resorption, and some disorders of the central nervous system. PMID- 26416508 TI - Sexually dimorphic morphology and swimming performance relationships in wild-type zebrafish Danio rerio. AB - This study compared prolonged swimming performance (Ucrit ) between male and female Danio rerio, and characterized how body shape was associated with this performance measure in each sex. When swimming in small (n = 6) mixed-sex groups at 28 degrees C, males swam, on average, over 10 cm s(-1) faster than females despite being significantly smaller. Body shape was sexually dimorphic, with males and females exhibiting small, but statistically significant differences in most aspects of body shape. Body shape explained 18 and 43% of the variation in Ucrit among males and females. In general, effects of body shape on swimming performance appeared to be sex limited, whereby different aspects of body shape affected performance in each sex, although the contribution of the distance between pelvic and anal fins to swimming performance was weakly sexually antagonistic. PMID- 26416510 TI - Correction. NILVAD protocol: a European multicenter double-blind placebo controlled trial of nilvadipine in mild-to-moderate Alzheimer's disease. PMID- 26416509 TI - Divergence and adaptive evolution of the gibberellin oxidase genes in plants. AB - BACKGROUND: The important phytohormone gibberellins (GAs) play key roles in various developmental processes. GA oxidases (GAoxs) are critical enzymes in GA synthesis pathway, but their classification, evolutionary history and the forces driving the evolution of plant GAox genes remain poorly understood. RESULTS: This study provides the first large-scale evolutionary analysis of GAox genes in plants by using an extensive whole-genome dataset of 41 species, representing green algae, bryophytes, pteridophyte, and seed plants. We defined eight subfamilies under the GAox family, namely C19-GA2ox, C20-GA2ox, GA20ox,GA3ox, GAox-A, GAox-B, GAox-C and GAox-D. Of these, subfamilies GAox-A, GAox-B, GAox-C and GAox-D are described for the first time. On the basis of phylogenetic analyses and characteristic motifs of GAox genes, we demonstrated a rapid expansion and functional divergence of the GAox genes during the diversification of land plants. We also detected the subfamily-specific motifs and potential sites of some GAox genes, which might have evolved under positive selection. CONCLUSIONS: GAox genes originated very early-before the divergence of bryophytes and the vascular plants and the diversification of GAox genes is associated with the functional divergence and could be driven by positive selection. Our study not only provides information on the classification of GAox genes, but also facilitates the further functional characterization and analysis of GA oxidases. PMID- 26416512 TI - Correction. Heavier smoking may lead to a relative increase in waist circumference: evidence for a causal relationship from a Mendelian randomisation meta-analysis. PMID- 26416511 TI - Associations of pregnancy-associated plasma protein-A level with essential hypertension and hypertensive disorders in pregnancy in Chinese population: a meta-analysis of 20 research studies involving 3332 individuals. AB - OBJECTIVE: To explore the associations between serum pregnancy-associated plasma protein-A (PAPP-A) level, and essential hypertension (EH) and hypertensive disorders in pregnancy (HDP) in Chinese population. METHODS: Pertinent studies were independently searched in PubMed, Embase, Cochrane Library, Chinese Biomedical Database (CBM), Wanfang databases and China National Knowledge Infrastructure (CNKI). The standardised mean difference (SMD) with 95% CIs was used to estimate the size of the effect. The subgroup analyses and meta regression analysis were performed to identify the sources of heterogeneity among studies. Sensitivity analysis was conducted to assess the stability of the results. The publication bias between studies was examined by using Begg's funnel plots and Egger's test. RESULTS: A total of 20 studies involving 1493 patients and 1839 controls were included in the current meta-analysis. The PAPP-A level was significantly higher in EH patients than in controls (SMD=1.960, 95% CI 1.305 to 2.615, p<0.001), and significant associations were observed in all subgroups. The PAPP-A level was also significantly higher in HDP patients than in healthy pregnant women (SMD=2.249; 95% CI 1.324 to 3.173, p<0.001). The positive association between PAPP-A level and the risk of HDP was consistently observed in all subgroups except the subgroup with low NOS score. CONCLUSIONS: The present meta-analysis suggests that an elevated PAPP-A level may be associated with susceptibilities to EH and HDP. PMID- 26416513 TI - Distinct subgroups of paroxysmal nocturnal hemoglobinuria (PNH) with cytopenia: results from South Korean National PNH Registry. AB - We retrospectively assessed the clinical characteristics of patients with paroxysmal nocturnal hemoglobinuria (PNH) according to severity of cytopenia. A total of 282 patients with hematological parameters assessed at the time of diagnosis of PNH were included. There were 24 patients with PNH/severe aplastic anemia (SAA) (at least two of the three criteria; hemoglobin <=8 g/dL; absolute neutrophil count (ANC) <0.5 * 10(9)/L; platelet count <20 * 10(9)/L), 96 patients with PNH/aplastic anemia (AA) (at least two of the three criteria; hemoglobin <=10 g/dL; ANC 0.5-1.5 * 10(9)/L; platelet count 20-100 * 10(9)/L), and 162 classic PNH patients. Compared with the classic PNH subgroup, the PNH/SAA subgroup had a significantly lower median granulocyte PNH clone size (26.7 vs. 51.0 %, P = 0.021) and lower incidence of lactate dehydrogenase >=1.5 times the upper limit of normal (52.9 vs. 80.0 %, P = 0.049). The incidence of thromboembolism was similar in both subgroups. Overall survival was significantly lower in the PNH/SAA subgroup than in the classic PNH subgroup (P = 0.033). Our findings suggest that identification of patients with PNH/SAA at the time of diagnosis is important because of different clinical manifestations and poorer outcome compared with patients with classic PNH (clinicaltrials.gov identifier: #NCT01224483). PMID- 26416514 TI - Cyclo(phenylalanine-proline) induces DNA damage in mammalian cells via reactive oxygen species. AB - Cyclo(phenylalanine-proline) is produced by various organisms such as animals, plants, bacteria and fungi. It has diverse biological functions including anti fungal activity, anti-bacterial activity and molecular signalling. However, a few studies have demonstrated the effect of cyclo(phenylalanine-proline) on the mammalian cellular processes, such as cell growth and apoptosis. In this study, we investigated whether cyclo(phenylalanine-proline) affects cellular responses associated with DNA damage in mammalian cells. We found that treatment of 1 mM cyclo(phenylalanine-proline) induces phosphorylation of H2AX (S139) through ATM CHK2 activation as well as DNA double strand breaks. Gene expression analysis revealed that a subset of genes related to regulation of reactive oxygen species (ROS) scavenging and production is suppressed by the cyclo(phenylalanine-proline) treatment. We also found that cyclo(phenylalanine-proline) treatment induces perturbation of the mitochondrial membrane, resulting in increased ROS, especially superoxide, production. Collectively, our study suggests that cyclo(phenylalanine-proline) treatment induces DNA damage via elevation of ROS in mammalian cells. Our findings may help explain the mechanism underlying the bacterial infection-induced activation of DNA damage response in host mammalian cells. PMID- 26416515 TI - Expression of pluripotency markers in the bovine uterus with adenomyosis. AB - BACKGROUND: Adenomyosis is a proliferative uterine dysfunction with unknown aetiology. One possible mechanism of its development involves disturbances in stem cell differentiation in uterine tissue. Previously, we identified pluripotent/multipotent cells in the bovine uterus, therefore our present study focused on determining expression of pluripotency markers, NANOG, OCT4 and SOX2, in bovine adenomyotic tissues and cells. FINDINGS: Immunolocalisation revealed protein expression of NANOG, OCT4 and SOX2 in both normal and adenomyotic uteri. mRNA expression for NANOG and OCT4 was increased in tissues obtained from uteri with adenomyosis compared to controls, but at the protein level there were no significant differences. mRNA expression for all three pluripotency markers was higher in myometrial cells isolated from uteri with adenomyotic lesions than in those isolated from normal uteri. The protein level of NANOG and SOX2 was decreased in stromal cells from adenomyotic tissues, whereas the level of OCT4 and SOX2 was increased in myometrial cells obtained from dysfunctional uteri. CONCLUSIONS: The results indicate significant changes in expression of pluripotency markers in adenomyotic compared to normal uteri, which suggest the involvement of uterine stem cells in adenomyosis. PMID- 26416516 TI - Terrein reduces age-related inflammation induced by oxidative stress through Nrf2/ERK1/2/HO-1 signalling in aged HDF cells. AB - This study investigated whether multiple bioactivity of terrein such as anti inflammatory and anti-oxidant inhibits age-related inflammation by promoting an antioxidant response in aged human diploid fibroblast (HDF) cells. HDF cells were cultured serially for in vitro replicative senescence. To create the ageing cell phenotype, intermediate stage (PD31) HDF cells were brought to stress-induced premature senescence (SIPS) using hydrogen peroxide (H2 O2). Terrein increased cell viability even with H2O2 stress and reduced inflammatory molecules such as intracellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2), interleukin 1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha). Terrein reduced also phospho-extracellular kinase receptor1/2 (p-EKR1/2) signalling in aged HDF cells. SIPS cells were attenuated for age-related biological markers including reactive oxygen species (ROS), senescence associated beta-galactosidase (SA beta gal.) and the aforementioned inflammatory molecules. Terrein induced the induction of anti-oxidant molecules, copper/zinc-superoxide defence (Cu/ZnSOD), manganese superoxide dismutase (MnSOD) and heme oxygenase-1 (HO-1) in SIPS cells. Terrein also alleviated reactive oxygen species formation through the Nrf2/HO-1/p ERK1/2 pathway in aged cells. The results indicate that terrein has an alleviative function of age-related inflammation characterized as an anti oxidant. Terrein might be a useful nutraceutical compound for anti-ageing. PMID- 26416517 TI - Application of a patient-derived xenograft model in cytolytic viral activation therapy for nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is an Epstein Barr virus (EBV)-related malignancy in which the tumor microenvironment plays a pivotal role in tumor progression. Here, we developed two patient-derived xenograft (PDX) mouse lines from engrafted NPC metastatic tumors. Positive staining for EBV-encoded small RNAs confirmed that these tumors harbored EBV, and gene expression profile analyses further showed that the PDX was highly similar to the primary parent tumor. In vivo drug screening using the PDX system demonstrated that gemcitabine had the best antitumor effect among the tested drugs. The donor of this PDX also showed excellent responsiveness to gemcitabine treatment. The combination of gemcitabine and valproic acid exerted synergistic antitumor effects. Further addition of ganciclovir to this two-drug combination regimen enhanced cytolytic viral activation, yielding the best antitumor response among tested regimens. Treatment with this three-drug combination regimen decreased plasma EBV-DNA load, tumor viral concentration, and the number of viable tumor cells to a greater extent than the two-drug gemcitabine and valproic acid combination. These results highlight the value of PDX models in the development of EBV-targeted strategies to treat NPC. PMID- 26416519 TI - Can Parsimonious Practice Please Patients and Practitioners? The Case of Spine Imaging. PMID- 26416518 TI - Reference values for amino acids and acylcarnitines in peripheral blood in Quarter horses and American Miniature horses. AB - BACKGROUND: Free amino acids and acylcarnitines circulating in the blood can be used for diagnosis for metabolic illness and imbalances. To date, the normal reference ranges of amino acids and acylcarnitines in horse peripheral blood have not been established. In this study, the concentrations of 12 amino acids and 26 acylcarnitines were determined by tandem mass spectrometry in complete blood from 100 healthy horses (50 Quarter horses (QH) [23 males and 27 females] and 50 American Miniature horses (AMH) [15 males and 35 females]) with no signs of metabolic disease. The means and standard deviations were determined and data statistically analyzed. FINDINGS: Concentrations of short, medium, and long chain acylcarnitines were significantly higher in male AMH than in male QH. The concentrations of the amino acids alanine, arginine, glycine, proline (glycogenic), and leucine (ketogenic) were higher in the QH than in the AMH. Female AMH had higher concentrations of propionylcarnitine, leucine, proline, arginine, and ornithine than female QH. CONCLUSIONS: Normal reference ranges of amino acids and acylcarnitines were established for AMH and QH. Significant differences were found in concentration of these compounds between breeds and gender. PMID- 26416520 TI - Cone-beam CT to assess bony fusion following anterior cervical interbody fusion. AB - PURPOSE: Assessment of bony fusion following anterior cervical interbody fusion (ACIF) is usually done by plain film or CT. We present the first clinical application of Cone-Beam CT (CBCT) to evaluate bony fusion after ACIF. METHODS: A 56-year-old man with disc herniation at C6-C7 underwent ACIF surgery using a compressed nanocrystalline hydroxyapatite interbody device (nanOss-C, Pioneer Surgical Marquette, MI, USA) and a nanocrystalline hydroxyapatite bone graft filler (nanOss Bioactive, Pioneer Surgical Marquette, MI, USA). Imaging follow-up was performed by CBCT (NewTom 5G, QR Srl, Verona, Italy) at 1 day, 6 weeks, 3 and 9 months post-operatively. Two independent assessors quantitatively measured the greyscale changes of the bone graft filler and qualitatively evaluated the bony fusion process. RESULTS: Quantitative analysis of the images showed a steadily increasing matrix density of the bone graft filler over the 9 months follow-up, suggesting increasing calcification. Qualitative evaluation demonstrated different stages of the bone fusion process within the disc space around the cage, at the interface between cage and endplates, and at the interface between bone graft filler and the endplates. CONCLUSIONS: CBCT provides high-resolution cross-sectional imaging of the cervical spine after ACIF. For the first time, in vivo evaluation of the bone graft filler within the centre of the circumferentially radiodense cage and detailed cross-sectional evaluation of bone fusion was achieved. Confirmation of these promising outlooks of CBCT in a large cohort of ACIF patients is needed with regard to routine clinical application and evaluation of different interbody devices. PMID- 26416521 TI - Which is the best IVF/ICSI protocol to be used in poor responders receiving growth hormone as an adjuvant treatment? A prospective randomized trial. AB - This open label randomized study aims to define the best protocol to be used with growth hormone in poor responders, with comparison performed to delineate which protocol offers the best cycle outcomes. Two-hundred eighty-seven poor responders were included. The patients were randomly allocated into four groups receiving growth hormone (GH) as an adjuvant therapy added to either long or short agonist protocol, miniflare or antagonist protocols. The short/GH gave significantly lower mean number of oocytes when compared with the long/GH, antagonist/GH and miniflare/GH (4 +/- 1.69 versus 5.06 +/- 1.83, 4.95 + / = 1.90 and4.98 +/- 2.51, respectively p = 0.005). Considering the number of fertilized oocytes, the long/GH showed significantly higher levels than short/GH and antagonist/GH (3.73 +/- 1.47 versus 3.02 +/- 1.52 and 2.89 +/- 1.14, respectively). The main drawback is that it required significantly higher HMG dose and longer duration of stimulation. The long/GH was superior when compared with the three protocols regarding the number of oocytes retrieved and fertilized. But, when considering the clinical pregnancy rates, there was a difference in favor of the long/GH but not reaching a statistically significant value (ClinicalTrials.gov Identifier: NCT01897324). PMID- 26416522 TI - Using Video Games to Enhance Motivation States in Online Education: Protocol for a Team-Based Digital Game. AB - BACKGROUND: Video and computer games for education have been of interest to researchers for several decades. Over the last half decade, researchers in the health sector have also begun exploring the value of this medium. However, there are still many gaps in the literature regarding the effective use of video and computer games in medical education, particularly in relation to how learners interact with the platform, and how the games can be used to enhance collaboration. OBJECTIVE: The objective of the study is to evaluate a team-based digital game as an educational tool for engaging learners and supporting knowledge consolidation in postgraduate medical education. METHODS: A mixed methodology will be used in order to establish efficacy and level of motivation provided by a team-based digital game. Second-year medical students will be recruited as participants to complete 3 matches of the game at spaced intervals, in 2 evenly distributed teams. Prior to playing the game, participants will complete an Internet survey to establish baseline data. After playing the game, participants will voluntarily complete a semistructured interview to establish motivation and player engagement. Additionally, metrics collected from the game platform will be analyzed to determine efficacy. RESULTS: The research is in the preliminary stages, but thus far a total of 54 participants have been recruited into the study. Additionally, a content development group has been convened to develop appropriate content for the platform. CONCLUSIONS: Video and computer games have been demonstrated to have value for educational purposes. Significantly less research has addressed how the medium can be effectively utilized in the health sector. Preliminary data from this study would suggest there is an interest in games for learning in the medical student body. As such, it is beneficial to undertake further research into how these games teach and engage learners in order to evaluate their role in tertiary and postgraduate medical education in the future. PMID- 26416524 TI - [BK 5103 "UV light-induced skin cancer" as a new occupational disease: Third ordinance for amendment of the Occupational Diseases Act]. PMID- 26416523 TI - Improved orthologous databases to ease protozoan targets inference. AB - BACKGROUND: Homology inference helps on identifying similarities, as well as differences among organisms, which provides a better insight on how closely related one might be to another. In addition, comparative genomics pipelines are widely adopted tools designed using different bioinformatics applications and algorithms. In this article, we propose a methodology to build improved orthologous databases with the potential to aid on protozoan target identification, one of the many tasks which benefit from comparative genomics tools. METHODS: Our analyses are based on OrthoSearch, a comparative genomics pipeline originally designed to infer orthologs through protein-profile comparison, supported by an HMM, reciprocal best hits based approach. Our methodology allows OrthoSearch to confront two orthologous databases and to generate an improved new one. Such can be later used to infer potential protozoan targets through a similarity analysis against the human genome. RESULTS: The protein sequences of Cryptosporidium hominis, Entamoeba histolytica and Leishmania infantum genomes were comparatively analyzed against three orthologous databases: (i) EggNOG KOG, (ii) ProtozoaDB and (iii) Kegg Orthology (KO). That allowed us to create two new orthologous databases, "KO + EggNOG KOG" and "KO + EggNOG KOG + ProtozoaDB", with 16,938 and 27,701 orthologous groups, respectively. Such new orthologous databases were used for a regular OrthoSearch run. By confronting "KO + EggNOG KOG" and "KO + EggNOG KOG + ProtozoaDB" databases and protozoan species we were able to detect the following total of orthologous groups and coverage (relation between the inferred orthologous groups and the species total number of proteins): Cryptosporidium hominis: 1,821 (11 %) and 3,254 (12 %); Entamoeba histolytica: 2,245 (13 %) and 5,305 (19 %); Leishmania infantum: 2,702 (16 %) and 4,760 (17 %). Using our HMM-based methodology and the largest created orthologous database, it was possible to infer 13 orthologous groups which represent potential protozoan targets; these were found because of our distant homology approach. We also provide the number of species-specific, pair-to-pair and core groups from such analyses, depicted in Venn diagrams. CONCLUSIONS: The orthologous databases generated by our HMM-based methodology provide a broader dataset, with larger amounts of orthologous groups when compared to the original databases used as input. Those may be used for several homology inference analyses, annotation tasks and protozoan targets identification. PMID- 26416525 TI - Bacterial contamination of propofol vials used in operating rooms of a third level hospital. AB - We found a 6.1% bacterial contamination rate among 198 propofol vials collected after clinical use in 12 operating rooms of a high-complexity hospital in Cali, Colombia. Some propofol vials were used for extended periods (up to 72 hours), and only 26.1% of vials were punctured once. Median time of use, although not statistically significant, was higher in positive samples (7.2 vs 3.5 hours, P = .08). Education on the topic should stress that vials are single-patient use and must be immediately discarded after use. PMID- 26416526 TI - Integrated measures for prevention of invasive Candida infections in preterm infants in a Chinese neonatal intensive care unit. AB - BACKGROUND: The increasing incidence of invasive Candida infections (ICIs) in preterm infants in the neonatal intensive care unit (NICU) of Xinhua Hospital aroused our concern. We undertook a retrospective study to evaluate the efficacy of different preventive measures for ICI in preterm infants. METHODS: Preterm infants with gestational age (GA) <33 weeks admitted between 2010 and 2013 were divided into 3 groups according to the preventive measures applied in different periods: the control group (CG), fluconazole group (FG), and integrated measures group (IMG). We analyzed the incidence of ICI and distribution of fungal pathogens in these 3 groups, and also evaluated the efficiency of various measures in preventing ICIs in preterm infants. RESULTS: The study sample comprised 261 preterm infants born at <33 weeks GA, including 94 in the CG, 99 in the FG, and 68 in the IMG. The differences among the groups were not significant at baseline. ICI developed in 41 of the 261 infants (15.7%). The incidence of ICI varied significantly among the groups: 22.3% in the CG (21/94), 18.2% in the FG (18/99), and only 2.9% in the IMG (2/68) (P = .003). ICI was less frequent in the IMG compared with the CG (P <.001) and the FG (P = .003). CONCLUSIONS: The integrated measures approach is meaningful for the prevention of ICIs in preterm infants in NICUs with many patients but inadequate medical resources in some developing countries. PMID- 26416527 TI - Effect of geographic region and seasonality on Clostridium difficile incidence and hospital mortality. PMID- 26416528 TI - Disinfection of reusable elastomeric respirators by health care workers: A feasibility study and development of standard operating procedure. PMID- 26416529 TI - Transformation priming helps to disambiguate sudden changes of sensory inputs. AB - Retinal input is riddled with abrupt transients due to self-motion, changes in illumination, object-motion, etc. Our visual system must correctly interpret each of these changes to keep visual perception consistent and sensitive. This poses an enormous challenge, as many transients are highly ambiguous in that they are consistent with many alternative physical transformations. Here we investigated inter-trial effects in three situations with sudden and ambiguous transients, each presenting two alternative appearances (rotation-reversing structure-from motion, polarity-reversing shape-from-shading, and streaming-bouncing object collisions). In every situation, we observed priming of transformations as the outcome perceived in earlier trials tended to repeat in subsequent trials and this repetition was contingent on perceptual experience. The observed priming was specific to transformations and did not originate in priming of perceptual states preceding a transient. Moreover, transformation priming was independent of attention and specific to low level stimulus attributes. In summary, we show how "transformation priors" and experience-driven updating of such priors helps to disambiguate sudden changes of sensory inputs. We discuss how dynamic transformation priors can be instantiated as "transition energies" in an "energy landscape" model of the visual perception. PMID- 26416530 TI - Development and validation of UPLC and LC-MS/MS methods for the simultaneous determination of anti-obesity drugs in foods and dietary supplements. AB - Recently, the number of the cases in which weight loss products have been sold with illegal adulterants has increased, as awareness of the problems of obesity grows. In this study, we developed simultaneous analysis methods to rapidly and accurately identify ingredients illegally mixed with foods and dietary supplements. Twenty-three anti-obesity drugs in foods and dietary supplements were determined by developed and validated UPLC and LC-MS/MS methods. The UPLC method were validated for the LOD and LOQ in the ranges 0.05-3.0 and 0.2-10.0 MUg/mL, respectively. The determination coefficient was over 0.999, precision was <6.2 %, and the accuracy was 80.8-103.9 %. The mean recoveries ranged from 80.3 to 109.3 % and RSD of stability was less than 2.1 %. The determination of the 23 anti-obesity drugs was accomplished by electrospray ionization LC-MS/MS using multiple reaction monitoring (MRM). The LODs and LOQs were in the ranges 0.03-7.5 and 0.09-30.0 ng/mL, respectively. The LC-MS/MS method was validated for linearity (r(2) > 0.99), precision (RSD < 10.7 %), accuracy (94.1-109.1 %), recovery (80.5-113.5 %), and the RSD of stability was <7.8 %. Using the newly developed and validated method, 193 samples were tested, and 55 were found to be adulterated. PMID- 26416531 TI - Structure of Liver Receptor Homolog-1 (NR5A2) with PIP3 hormone bound in the ligand binding pocket. AB - The nuclear receptor LRH-1 (Liver Receptor Homolog-1, NR5A2) is a transcription factor that regulates gene expression programs critical for many aspects of metabolism and reproduction. Although LRH-1 is able to bind phospholipids, it is still considered an orphan nuclear receptor (NR) with an unknown regulatory hormone. Our prior cellular and structural studies demonstrated that the signaling phosphatidylinositols PI(4,5)P2 (PIP2) and PI(3,4,5)P3 (PIP3) bind and regulate SF-1 (Steroidogenic Factor-1, NR5A1), a close homolog of LRH-1. Here, we describe the crystal structure of human LRH-1 ligand binding domain (LBD) bound by PIP3 - the first phospholipid with a head group endogenous to mammals. We show that the phospholipid hormone binds LRH-1 with high affinity, stabilizing the receptor LBD. While the hydrophobic PIP3 tails (C16/C16) are buried inside the LRH-1 ligand binding pocket, the negatively charged PIP3 head group is presented on the receptor surface, similar to the phosphatidylinositol binding mode observed in the PIP3-SF-1 structure. Thus, data presented in this work reinforce our earlier findings demonstrating that signaling phosphatidylinositols regulate the NR5A receptors LRH-1 and SF-1. PMID- 26416532 TI - Numerical geometry of map and model assessment. AB - We are describing best practices and assessment strategies for the atomic interpretation of cryo-electron microscopy (cryo-EM) maps. Multiscale numerical geometry strategies in the Situs package and in secondary structure detection software are currently evolving due to the recent increases in cryo-EM resolution. Criteria that aim to predict the accuracy of fitted atomic models at low (worse than 8A) and medium (4-8 A) resolutions remain challenging. However, a high level of confidence in atomic models can be achieved by combining such criteria. The observed errors are due to map-model discrepancies and due to the effect of imperfect global docking strategies. Extending the earlier motion capture approach developed for flexible fitting, we use simulated fiducials (pseudoatoms) at varying levels of coarse-graining to track the local drift of structural features. We compare three tracking approaches: naive vector quantization, a smoothly deformable model, and a tessellation of the structure into rigid Voronoi cells, which are fitted using a multi-fragment refinement approach. The lowest error is an upper bound for the (small) discrepancy between the crystal structure and the EM map due to different conditions in their structure determination. When internal features such as secondary structures are visible in medium-resolution EM maps, it is possible to extend the idea of point based fiducials to more complex geometric representations such as helical axes, strands, and skeletons. We propose quantitative strategies to assess map-model pairs when such secondary structure patterns are prominent. PMID- 26416533 TI - Crystal structure of halogenase PltA from the pyoluteorin biosynthetic pathway. AB - Pyoluteorin is an antifungal agent composed of a 4,5-dichlorinated pyrrole group linked to a resorcinol moiety. The pyoluteorin biosynthetic gene cluster in Pseudomonas fluorescens Pf-5 encodes the halogenase PltA, which has been previously demonstrated to perform both chlorinations in vitro. PltA selectively accepts as a substrate a pyrrole moiety covalently tethered to a nonribosomal peptide thiolation domain PltL (pyrrolyl-S-PltL) for FAD-dependent di chlorination, yielding 4,5-dichloropyrrolyl-S-PltL. We report a 2.75 A-resolution crystal structure of PltA in complex with FAD and chloride. PltA is a dimeric enzyme, containing a flavin-binding fold conserved in flavin-dependent halogenases and monooxygenases, and an additional unique helical region at the C terminus. This C-terminal region blocks a putative substrate-binding cleft, suggesting that a conformational change involving repositioning of this region is necessary to allow binding of the pyrrolyl-S-PltL substrate for its dichlorination by PltA. PMID- 26416534 TI - Population Pharmacokinetic Analysis of Lanreotide Autogel/Depot in the Treatment of Neuroendocrine Tumors: Pooled Analysis of Four Clinical Trials. AB - BACKGROUND AND OBJECTIVES: Lanreotide Autogel (lanreotide Depot in the USA) has demonstrated anti-tumor activity and control of the symptoms associated with hormone hypersecretion in patients with neuroendocrine tumors. The objectives of this study were to describe the pharmacokinetics of lanreotide Autogel administered 4-weekly by deep subcutaneous injections of 60, 90, or 120 mg in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), to quantify the magnitude of inter-patient variability (IPV), and to identify those patient characteristics that impact on pharmacokinetics. METHODS: Analyses were based on pooled data from clinical trials. A total of 1541 serum concentrations from 290 patients were analyzed simultaneously by the population approach using NONMEM version 7.2. Covariates evaluated included demographics, renal and hepatic function markers, and disease-related parameters. RESULTS: Serum profiles were described by a one-compartment disposition model in which the absorption process was characterized by two parallel pathways following first- and zero-order kinetics. The estimated apparent volume of distribution was 18.3 L. The estimated apparent total serum clearance for a typical 74 kg patient was 513 L/day, representing a substantial difference in clearance in this population of patients with respect to healthy volunteers that could not be explained by any of the covariates tested. Body weight was the only covariate to show a statistically significant effect on the pharmacokinetic profile, but due to the overlap between the pharmacokinetic profiles of patients with lower or higher body weights the effect of body weight on clearance was not considered clinically relevant. The IPV was low for clearance (27%) and moderate to high for volume of distribution (150%) and the absorption constant (61%). CONCLUSIONS: Using two mechanisms of absorption, the pharmacokinetics of lanreotide Autogel were well-described in patients with GEP-NET. None of the patient characteristics tested were of clinical relevance to potential dose adjustment in clinical practice. PMID- 26416535 TI - Interactions of Non-Phosphorous Glycerolipids with DNA: Energetics, Molecular Docking and Topoisomerase I Attenuation. AB - The phosphorus-containing glycerolipid based antitumor drugs (edelfosine as a prototype) are currently in clinical trials. To avoid the use of potentially harmful phosphoric reagents in the preparation of biologically active glycerolipids, and to obtain the compounds without the phosphoester bond cleavable inside the cells, we developed the synthesis of non-phosphorous glycerolipids (NPGLs) with neutral or cationic polar 'heads'. In this study, we analyzed the ability of novel NPGLs L1-L5 to interact with duplex DNA and interfere with the DNA modifying enzyme topoisomerase I (topo I). In cell-free systems, NPGLs formed highly affine complexes with DNA. Molecular docking revealed that NPGLs fitted very well into the DNA minor groove. Compounds L2 (with two long hydrophobic 'tails') and L4 (with ethylimidazolium cationic group), the most affine DNA binders, showed the best calculated energies of complex formation with DNA and topo I. The models demonstrated the binding of NPGLs to the topo I site known for interaction with conventional inhibitors. Each NPGL attenuated the topo I mediated unwinding of supercoiled DNA. Again, L2 and, to a lesser extent, L4 were the most potent topo I inhibitors. Thus, NPGLs with polar 'heads' emerge as a new class of DNA ligands and interfacial topo I antagonists. PMID- 26416536 TI - Multiple sclerosis: smoking in patients with multiple sclerosis--is it ever too late to quit? PMID- 26416537 TI - Alzheimer disease: APOE*epsilon4-associated increase in AD risk linked to phospholipid dysregulation. PMID- 26416538 TI - Alzheimer disease: possible prion-like transmission of AD-like pathology in humans. PMID- 26416540 TI - Alzheimer disease: neurogranin in the CSF signals early Alzheimer disease and predicts disease progression. PMID- 26416539 TI - CAP--advancing the evaluation of preclinical Alzheimer disease treatments. AB - If we are to find treatments to postpone, reduce the risk of, or completely prevent the clinical onset of Alzheimer disease (AD), we need faster methods to evaluate promising preclinical AD treatments, new ways to work together in support of common goals, and a determination to expedite the initiation and performance of preclinical AD trials. In this article, we note some of the current challenges, opportunities and emerging strategies in preclinical AD treatment. We describe the Collaboration for Alzheimer's Prevention (CAP)-a convening, harmonizing and consensus-building initiative to help stakeholders advance AD prevention research with rigour, care and maximal impact-and we demonstrate the impact of CAP on the goals and design of new preclinical AD trials. PMID- 26416541 TI - Prevalence of Cardiovascular Disease and Cardiac Symptoms: Left and Right Ventricular Function in Adults With Osteogenesis Imperfecta. AB - BACKGROUND: Osteogenesis imperfecta (OI), also known as brittle bone disease or Lobstein syndrome, is a congenital bone disorder characterized by brittle bones that are prone to fracture. People with OI are born with defective connective tissue in most cases secondary to a deficiency of type-I collagen, which represents approximately 75% of total collagen in the adult myocardium. The purpose of our study was to assess the prevalence of cardiomyopathy, electrocardiogram (ECG) abnormalities, and cardiovascular symptoms among patients with OI. METHODS: We studied 99 adults with OI from the national OI registry in Norway. Patients were divided into type I, III, and IV, and 52 control subjects. History and physical examination, ECG, and echocardiographic parameters of left ventricular (LV) and right ventricular (RV) systolic and diastolic function were obtained. RESULTS: ECG abnormalities and cardiac symptoms were more common among patients with OI. RV and LV systolic peak velocity were significantly lower and diastolic mitral tricuspid valve wave and early diastolic tissue Doppler velocity ratio increased in the OI group compared with the control subjects; 5.7 +/- 1.2 vs 6.3 +/- 1.2 cm/s (P < 0.05) and 8 +/- 1.8 vs 9.5 +/- 1.4 cm/s (P < 0.05) and 9.8 +/- 2.6 vs 7.4 +/- 2.0 (P < 0.05) and 8.6 +/- 3.3 vs 6.1 +/- 1.4, respectively. In multivariate analysis OI was found to be an independent risk factor for RV systolic and diastolic dysfunction. CONCLUSIONS: Cardiac symptoms and ECG changes are common among patients with OI. Our study findings suggest RV and LV systolic and diastolic function to be impaired in patients with OI compared with normal individuals. In multivariate analysis, however, OI was an independent predictor only of reduced RV systolic and diastolic function. PMID- 26416542 TI - A Novel Inherited Mutation in PRKAR1A Abrogates PreRNA Splicing in a Carney Complex Family. AB - BACKGROUND: Carney complex (CNC) is an autosomal dominant inherited disease, characterized by spotty skin pigmentation, cardiac and cutaneous myxomas, and endocrine overactivity. We report on a Chinese CNC family with a novel mutation in the protein kinase A regulatory subunit 1 (PRKAR1A) gene. METHODS: Target exome sequencing was performed to identify the mutation of PRKAR1A in 2 members of the CNC family. RESULTS: The proband was a young man with typical CNC, including pigmentation, cutaneous myxomas, cardiac myxoma, Sertoli cell tumour of his left testis, and multiple hypoechoic thyroid nodules. His mother also had CNC with skin pigmentation, cutaneous myxomas, and a cardiac myxoma. Target-exome capture analysis revealed that the proband and the mother carried a novel heterozygous mutation in the exon 6 splicing donor site of PRKAR1A. Sequencing analysis of myxoma messenger RNA revealed that the mutation abrogated exon 6 preRNA splicing, leading to a frameshift starting at Valine 185 and premature translation termination in intron 6. The truncated enzyme lacks the functional cyclic adenosine monophosphate (cAMP) binding domain at the C-terminus, causing PRKAR1A haploinsufficiency. CONCLUSIONS: In this study we report on a novel splicing mutation in the PRKAR1A gene that adds to the genetic heterogeneity of CNC. PMID- 26416543 TI - Mortality changes after grants from the Global Fund to Fight AIDS, tuberculosis and malaria: an econometric analysis from 1995 to 2010. AB - BACKGROUND: Since its founding in 2002, the Global Fund to Fight AIDS, Tuberculosis, and Malaria (Global Fund) has become the dominant multilateral health financier in low- and middle-income countries. The health impact of the Global Fund remains unknown because existing evaluations measure intermediate outcomes or do not account for preexisting and counterfactual trends. METHODS: We conducted an econometric analysis of data from all countries eligible to receive Global Fund grants from 1995 to 2010, prior to and during the Global Fund's activities. We analyzed three outcomes: all-cause adult (15-59 years), all-cause under-five, and malaria-specific under-five mortality. Our main exposure was a continuous longitudinal measure of Global Fund disbursements per capita. We used panel fixed effect regressions, and analyzed mortality trends controlling for health spending, health worker density (a measure of health system capacity), gross domestic product, urbanization, and country fixed-effects. RESULTS AND DISCUSSION: We find that following Global Fund disbursements, adult mortality rate declined by 1.4 % per year faster with every $10 per capita increase in disbursements (p = 0.005). Similarly, malaria-specific under-five mortality declined by 6.9 % per year faster (p = 0.033) with every $10 high per capita Global Fund disbursements. However, we find no association between Global Fund support and all-cause under-five mortality. These findings were consistent after subanalyses by baseline HIV prevalence, adjusting for effects of concurrent health aid from other donors, and varying time lags between funding and mortality changes. CONCLUSIONS: Grants from the Global Fund are closely related to accelerated reductions in all-cause adult mortality and malaria-specific under five mortality. However, up to 2010 the Global Fund has not measurably contributed to reducing all-cause under-five mortality. PMID- 26416544 TI - A homozygous loss-of-function mutation in inositol monophosphatase 1 (IMPA1) causes severe intellectual disability. AB - The genetic basis of intellectual disability (ID) is extremely heterogeneous and relatively little is known about the role of autosomal recessive traits. In a field study performed in a highly inbred area of Northeastern Brazil, we identified and investigated a large consanguineous family with nine adult members affected by severe ID associated with disruptive behavior. The Genome-Wide Human SNP Array 6.0 microarray was used to determine regions of homozygosity by descent from three affected and one normal family member. Whole-exome sequencing (WES) was performed in one affected patient using the Nextera Rapid-Capture Exome kit and Illumina HiSeq2500 system to identify the causative mutation. Potentially deleterious variants detected in regions of homozygosity by descent and not present in either 59 723 unrelated individuals from the Exome Aggregation Consortium (Browser) or 1484 Brazilians were subject to further scrutiny and segregation analysis by Sanger sequencing. Homozygosity-by-descent analysis disclosed a 20.7-Mb candidate region at 8q12.3-q21.2 (lod score: 3.11). WES identified a homozygous deleterious variant in inositol monophosphatase 1 (IMPA1) (NM_005536), consisting of a 5-bp duplication (c.489_493dupGGGCT; chr8: 82,583,247; GRCh37/hg19) leading to a frameshift and a premature stop codon (p.Ser165Trpfs*10) that cosegregated with the disease in 26 genotyped family members. The IMPA1 gene product is responsible for the final step of biotransformation of inositol triphosphate and diacylglycerol, two second messengers. Despite its many physiological functions, no clinical phenotype has been assigned to this gene dysfunction to date. Additionally, IMPA1 is the main target of lithium, a drug that is at the forefront of treatment for bipolar disorder. PMID- 26416545 TI - Dimensional depression severity in women with major depression and post-traumatic stress disorder correlates with fronto-amygdalar hypoconnectivty. AB - Depressive symptoms are common in multiple psychiatric disorders and are frequent sequelae of trauma. A dimensional conceptualization of depression suggests that symptoms should be associated with a continuum of deficits in specific neural circuits. However, most prior investigations of abnormalities in functional connectivity have typically focused on a single diagnostic category using hypothesis-driven seed-based analyses. Here, using a sample of 105 adult female participants from three diagnostic groups (healthy controls, n=17; major depression, n=38; and post-traumatic stress disorder, n=50), we examine the dimensional relationship between resting-state functional dysconnectivity and severity of depressive symptoms across diagnostic categories using a data-driven analysis (multivariate distance-based matrix regression). This connectome-wide analysis identified foci of dysconnectivity associated with depression severity in the bilateral amygdala. Follow-up seed analyses using subject-specific amygdala segmentations revealed that depression severity was associated with amygdalo-frontal hypo-connectivity in a network of regions including bilateral dorsolateral prefrontal cortex, anterior cingulate and anterior insula. In contrast, anxiety was associated with elevated connectivity between the amygdala and the ventromedial prefrontal cortex. Taken together, these results emphasize the centrality of the amygdala in the pathophysiology of depressive symptoms, and suggest that dissociable patterns of amygdalo-frontal dysconnectivity are a critical neurobiological feature across clinical diagnostic categories. PMID- 26416547 TI - Fixation times in evolutionary games with the Moran and Fermi processes. AB - We combined the standard Moran and Fermi process into a mixed process with two strategies C (co-operation) and D (defection). In a well-mixed population of size N+M, N individuals have the same update mechanism as that of Moran process, while the other M individuals have the same update mechanism as that of Fermi process. We obtain the balance equations of the conditional fixation time and unconditional fixation time. What these equations are doing is to make numerical sense for all the figures. We find that the expectation values of conditional fixation times of a single co-operator are smaller than the average values of the standard Moran and Fermi process. In addition, the conditional fixation time of a single co-operator with update rule of Moran is larger than that of Fermi when the intensity of selection is sufficiently small. The simulation results show that the unconditional fixation time of a co-operator who obtains more information is smaller. In addition, the larger the difference of individuals' payoff, the smaller the unconditional fixation time. PMID- 26416546 TI - Cell-specific abnormalities of glutamate transporters in schizophrenia: sick astrocytes and compensating relay neurons? AB - Excitatory amino-acid transporters (EAATs) bind and transport glutamate, limiting spillover from synapses due to their dense perisynaptic expression primarily on astroglia. Converging evidence suggests that abnormalities in the astroglial glutamate transporter localization and function may underlie a disease mechanism with pathological glutamate spillover as well as alterations in the kinetics of perisynaptic glutamate buffering and uptake contributing to dysfunction of thalamo-cortical circuits in schizophrenia. We explored this hypothesis by performing cell- and region-level studies of EAAT1 and EAAT2 expression in the mediodorsal nucleus of the thalamus in an elderly cohort of subjects with schizophrenia. We found decreased protein expression for the typically astroglial localized glutamate transporters in the mediodorsal and ventral tier nuclei. We next used laser-capture microdissection and quantitative polymerase chain reaction to assess cell-level expression of the transporters and their splice variants. In the mediodorsal nucleus, we found lower expression of transporter transcripts in a population of cells enriched for astrocytes, and higher expression of transporter transcripts in a population of cells enriched for relay neurons. We confirmed expression of transporter protein in neurons in schizophrenia using dual-label immunofluorescence. Finally, the pattern of transporter mRNA and protein expression in rodents treated for 9 months with antipsychotic medication suggests that our findings are not due to the effects of antipsychotic treatment. We found a compensatory increase in transporter expression in neurons that might be secondary to a loss of transporter expression in astrocytes. These changes suggest a profound abnormality in astrocyte functions that support, nourish and maintain neuronal fidelity and synaptic activity. PMID- 26416548 TI - Preimplantation death of xenomitochondrial mouse embryo harbouring bovine mitochondria. AB - Mitochondria, cellular organelles playing essential roles in eukaryotic cell metabolism, are thought to have evolved from bacteria. The organization of mtDNA is remarkably uniform across species, reflecting its vital and conserved role in oxidative phosphorylation (OXPHOS). Our objectives were to evaluate the compatibility of xenogeneic mitochondria in the development of preimplantation embryos in mammals. Mouse embryos harbouring bovine mitochondria (mtB-M embryos) were prepared by the cell-fusion technique employing the haemagglutinating virus of Japan (HVJ). The mtB-M embryos showed developmental delay at embryonic days (E) 3.5 after insemination. Furthermore, none of the mtB-M embryos could implant into the maternal uterus after embryo transfer, whereas control mouse embryos into which mitochondria from another mouse had been transferred developed as well as did non-manipulated embryos. When we performed quantitative PCR (qPCR) of mouse and bovine ND5, we found that the mtB-M embryos contained 8.3% of bovine mitochondria at the blastocyst stage. Thus, contamination with mitochondria from another species induces embryonic lethality prior to implantation into the maternal uterus. The heteroplasmic state of these xenogeneic mitochondria could have detrimental effects on preimplantation development, leading to preservation of species-specific mitochondrial integrity in mammals. PMID- 26416549 TI - Enhancement of Mechanical Properties and Testing of Nitinol Stents in Cerebral Aneurysm Simulation Models. AB - Stents are promising medical devices widely used in the prevention of cerebral aneurysm rupture. As the performance of stents depends on their mechanical properties and cell configuration, the aim of this study was to optimize the stent design and test the hemodynamic properties by using computational solid mechanics and computational fluid dynamics. In order to test their performance, computer-based cerebral aneurysm models that mimic the conditions present after implantation into the human brain were tested. The strut configuration selected was the closed-cell type, and nitinol was chosen as the material for stent manufacture because the innate characteristics of this material increase stent flexibility. Three ideal sample stent types with different cell configurations were manufactured. Computational solid mechanics analysis of the sample stents showed over 30% difference in flexibility between stents. Furthermore, using a cerebral aneurysm model simulation, we found that the stents eased the hemodynamic factors of the cerebral aneurysm and lessened the flow velocity influx into the sac. A decrease in flow velocity led to a 50-60% reduction in wall shear stress, which is expected to prevent aneurysm rupture under clinical conditions. Stent design optimization was carried out by simulation and electropolishing. Corrosion resistance and surface roughness were evaluated after electropolishing performed under variable conditions, but 40 V and 10 s were the most optimal. PMID- 26416550 TI - A new synthesis of carbon encapsulated Fe5C2 nanoparticles for high-temperature Fischer-Tropsch synthesis. AB - Using a simple thermal treatment under a CO flow, uniform micrometer-sized iron oxalate dihydrate cubes prepared by hydrothermal reaction were transformed into Fe5C2@C nanoparticles to form a mesoporous framework; the final structure was successfully applied to the high-temperature Fischer-Tropsch reaction and it showed high activity (CO conversion = 96%, FTY = 1.5 * 10(-4) molCO gFe(-1) s( 1)) and stability. PMID- 26416551 TI - Radical 1,2-aryl migration in alpha,alpha-diaryl allylic alcohols toward beta silyl ketones. AB - A copper-catalyzed radical 1,2-aryl migration in alpha,alpha-diaryl allylic alcohols is developed, leading to beta-silyl carbonyl compounds in moderate to good yields. The migration of aryls with lower aromaticity is favored. This procedure features the employment of silanes as commercially available materials. PMID- 26416552 TI - Improving Caregivers' Perceptions Regarding Patient Goals of Care/End-of-Life Issues for the Multidisciplinary Critical Care Team. AB - OBJECTIVE: With population aging and growth, use of critical care medicine at the end of life continues to rise, while many critical care providers are not adequately trained regarding goals of care/end-of-life (GOC/EOL) issues. A multidisciplinary intensive care unit (ICU) team intervention regarding GOC/EOL communication will enhance the clinical abilities of all critical care providers when discussing GOC/EOL issues and increase ICU staff comfort level while improving transitions for patients to a comfort care approach. DESIGN: This study was a preintervention/postintervention survey evaluation. SETTING: This study was conducted at an academic tertiary surgical burn trauma ICU. POPULATION: The intervention was provided to nursing, ancillary staff, house staff, and attending physicians. INTERVENTION: An initial survey was circulated among the critical care staff for baseline expectations, satisfaction, and understanding of GOC/EOL care. A robust intervention was begun including the creation of a multidisciplinary GOC/EOL team, communication tools for providers, patient-family pamphlets, standardized EOL order sets, and formalized didactic sessions. Subsequently, the same survey was circulated and compared to baseline data. MEASUREMENTS: Preintervention/postintervention survey data were reviewed and statistically analyzed. MAIN RESULTS: Our survey response rate for preintervention/postintervention was 50.4% and 36.1%, respectively. The intervention generated heightened interest in improving family communication and provided focal direction to foster this growth. Based on the serial surveys regarding our intervention, statistically significant staff improvements were seen in "work stress" (P = .04), "EOL information" (P = .006), and "space allotment" (P = .001). Improved congruence of families and health care providers regarding decision over intensity of care was also noted. CONCLUSION: We created a novel unit-based multidisciplinary program for improved EOL/GOC approaches in the critical care setting. A similarly formatted program could be adapted by other ICUs. Benefits of such a program include improving caregivers' perceptions regarding EOL/GOC issues and fostering critical care team growth. PMID- 26416553 TI - The impact of Indonesian peatland degradation on downstream marine ecosystems and the global carbon cycle. AB - Tropical peatlands are among the most space-efficient stores of carbon on Earth containing approximately 89 Gt C. Of this, 57 Gt (65%) are stored in Indonesian peatlands. Large-scale exploitation of land, including deforestation and drainage for the establishment of oil palm plantations, is changing the carbon balance of Indonesian peatlands, turning them from a natural sink to a source via outgassing of CO2 to the atmosphere and leakage of dissolved organic carbon (DOC) into the coastal ocean. The impacts of this perturbation to the coastal environment and at the global scale are largely unknown. Here, we evaluate the downstream effects of released Indonesian peat carbon on coastal ecosystems and on the global carbon cycle. We use a biogeochemical box model in combination with novel and literature observations to investigate the impact of different carbon emission scenarios on the combined ocean-atmosphere system. The release of all carbon stored in the Indonesian peat pool, considered as a worst-case scenario, will increase atmospheric pCO2 by 8 ppm to 15 ppm within the next 200 years. The expected impact on the Java Sea ecosystems is most significant on the short term (over a few hundred years) and is characterized by an increase of 3.3% in phytoplankton, 32% in seagrass biomass, and 5% decrease in coral biomass. On the long term, however, the coastal ecosystems will recover to reach near pre-excursion conditions. Our results suggest that the ultimate fate of the peat carbon is in the deep ocean with 69% of it landing in the deep DIC pool after 1000 years, but the effects on the global ocean carbonate chemistry will be marginal. PMID- 26416554 TI - PTBP1 and PTBP2 impaired autoregulation of SRSF3 in cancer cells. AB - Splicing factors are key players in the regulation of alternative splicing of pre mRNAs. Overexpression of splicing factors, including SRSF3, has been strongly linked with oncogenesis. However, the mechanisms behind their overexpression remain largely unclear. Autoregulation is a common mechanism to maintain relative stable expression levels of splicing factors in cells. SRSF3 regulates its own expression by enhancing the inclusion of an alternative exon 4 with an in-frame stop codon. We found that the inclusion of SRSF3 exon 4 is impaired in oral squamous cell carcinoma (OSCC) cells. PTBP1 and PTBP2 bind to an exonic splicing suppressor in exon 4 and inhibit its inclusion, which results in overexpression of full length functional SRSF3. Overexpression of SRSF3, in turn, promotes PTBP2 expression. Our results suggest a novel mechanism for the overexpression of oncogenic splicing factor via impairing autoregulation in cancer cells. PMID- 26416555 TI - Dynamic development of public attitudes towards science policymaking. AB - Understanding the heterogeneity of mechanisms that form public attitudes towards science and technology policymaking is essential to the establishment of an effective public engagement platform. Using the 2011 public opinion survey data from Japan (n = 6,136), I divided the general public into three categories: the Attentive public, who are willing to actively engage with science and technology policymaking dialogue; the Interested public, who have moderate interest in science and technology but rely on experts for policy decisions; and the Residual public, who have minimal interest in science and technology. On the basis of the results of multivariate regression analysis, I have identified several key predispositions towards science and technology and other socio-demographic characteristics that influence the shift of individuals from one category of the general public to another. The findings provide a foundation for understanding how to induce more accountable, evidence-based science and technology policymaking. PMID- 26416556 TI - The role of shear in crystallization kinetics: From suppression to enhancement. AB - In many technical applications crystallization proceeds in the presence of stresses and flows, hence the importance to understand the crystallization mechanism in simple situations. We employ molecular dynamics simulations to study the crystallization kinetics of a nearly hard sphere liquid that is weakly sheared. We demonstrate that shear flow both enhances and suppresses the crystallization kinetics of hard spheres. The effect of shear depends on the quiescent mechanism: suppression in the activated regime and enhancement in the diffusion-limited regime for small strain rates. At higher strain rates crystallization again becomes an activated process even at densities close to the glass transition. PMID- 26416557 TI - An efficient thermostable organophosphate hydrolase and its application in pesticide decontamination. AB - In vitro evolution of enzymes represents a powerful device to evolve new or to improve weak enzymatic functions. In the present work a semi-rational engineering approach has been used to design an efficient and thermostable organophosphate hydrolase, starting from a lactonase scaffold (SsoPox from Sulfolobus solfataricus). In particular, by in vitro evolution of the SsoPox ancillary promiscuous activity, the triple mutant C258L/I261F/W263A has been obtained which, retaining its inherent stability, showed an enhancement of its hydrolytic activity on paraoxon up to 300-fold, achieving absolute values of catalytic efficiency up to 10(5) M(-1) s(-1). The kinetics and structural determinants of this enhanced activity were thoroughly investigated and, in order to evaluate its potential biotechnological applications, the mutant was tested in formulations of different solvents (methanol or ethanol) or detergents (SDS or a commercial soap) for the cleaning of pesticide-contaminated surfaces. PMID- 26416558 TI - Plasma levels of OLFM4 in normals and patients with gastrointestinal cancer. AB - Olfactomedin 4 (OLFM4) is a secreted glycoprotein predominantly expressed in bone marrow and gastrointestinal tissues. Aberrant expression of OLFM4 has been shown in several cancers. However, the clinical significance hereof is currently controversial. OLFM4 has been proposed as a candidate biomarker of gastrointestinal cancers. To address this, we developed monoclonal antibodies against synthetic peptides representing various segments of OLFM4. We examined expression of OLFM4 in epithelial cells by immunohistochemistry and found that OLFM4 is highly expressed in proliferating benign epithelial cells and in some carcinoma cells. We developed an Enzyme Linked Immunosorbent Assay for OLFM4 and investigated whether plasma levels of OLFM4 reflect colorectal malignancies, but were unable to see any such association. Instead, we observed two populations of individuals with respect to OLFM4 levels in plasma, the majority with OLFM4 in plasma between 0 and 0.1 MUg/ml, mean 0.028 MUg/ml while 10% of both normals and patients with cancers had OLFM4 between 4 and 60 MUg/ml, mean 15 MUg/ml. The levels were constant over time. The background for this high plasma level is not known, but must be taken into account if OLFM4 is used as biomarker for GI cancers. PMID- 26416559 TI - Pseudomonas aeruginosa isolates and their antimicrobial susceptibility pattern among catheterized patients at Jimma University Teaching Hospital, Jimma, Ethiopia. AB - BACKGROUND: Pseudomonas aeruginosa is among the most common bacterial pathogens with wide spread distribution in health care settings. Despite advances in medical and surgical care and introduction of wide variety of antimicrobial agents, Pseudomonas aeruginosa continues to cause life threatening infection. Thus, this study aims to isolate and determine antimicrobial susceptibility patterns of Pseudomonas aeruginosa from catheterized patients with urinary tract infection. RESULT: A cross-sectional study was conducted from January to May, 2013. Urine specimens of 73 catheterized patients who developed urinary tract infection after catheterization were collected from sampling port of the catheter. The urine samples were inoculated on MaConckey and blood agar plates, and incubated at 37 degrees C for 24 h. The isolates were identified by conventional microbiological tests. Antimicrobial susceptibility pattern was determined by modified Kirby-Bauer disk diffusion method. From a total of 73 urine samples collected P. aeruginosa was isolated from 36 (49.32%) catheterized patients; 17 (23.29%) males and 19 (26.03%) females. While all P. aeruginosa isolates were found to be susceptible to Norfloxacin and Ciprofloxacin most isolates were also susceptible to Gentamicin (86.12%). CONCLUSION: The result shows higher prevalence of P. aeruginosa isolates among catheterized patients and the isolates were susceptible to the antimicrobials studied. All P. aeruginosa isolates were susceptible to Ciprofloxacin and Norfloxacin with some of the isolates shown resistance to Gentamicin. While the susceptibility of the isolates to the two fluoroquinolones is a good news for the prescribers their future rational prescription and use should be the main focus. PMID- 26416560 TI - In silico exploration of c-KIT inhibitors by pharmaco-informatics methodology: pharmacophore modeling, 3D QSAR, docking studies, and virtual screening. AB - c-KIT is a component of the platelet-derived growth factor receptor family, classified as type-III receptor tyrosine kinase. c-KIT has been reported to be involved in, small cell lung cancer, other malignant human cancers, and inflammatory and autoimmune diseases associated with mast cells. Available c-KIT inhibitors suffer from tribulations of growing resistance or cardiac toxicity. A combined in silico pharmacophore and structure-based virtual screening was performed to identify novel potential c-KIT inhibitors. In the present study, five molecules from the ZINC database were retrieved as new potential c-KIT inhibitors, using Schrodinger's Maestro 9.0 molecular modeling suite. An atom featured 3D QSAR model was built using previously reported c-KIT inhibitors containing the indolin-2-one scaffold. The developed 3D QSAR model ADHRR.24 was found to be significant (R2 = 0.9378, Q2 = 0.7832) and instituted to be sufficiently robust with good predictive accuracy, as confirmed through external validation approaches, Y-randomization and GH approach [GH score 0.84 and Enrichment factor (E) 4.964]. The present QSAR model was further validated for the OECD principle 3, in that the applicability domain was calculated using a "standardization approach." Molecular docking of the QSAR dataset molecules and final ZINC hits were performed on the c-KIT receptor (PDB ID: 3G0E). Docking interactions were in agreement with the developed 3D QSAR model. Model ADHRR.24 was explored for ligand-based virtual screening followed by in silico ADME prediction studies. Five molecules from the ZINC database were obtained as potential c-KIT inhibitors with high in -silico predicted activity and strong key binding interactions with the c-KIT receptor. PMID- 26416563 TI - Formulation of Nanoparticles Against TB--A Review. AB - Tuberculosis is a major public health concern. The present article reviews the current updates on the usage of nanoparticles against tuberculosis and recent patents that could develop into novel therapeutics available to the clinical armamentarium for the TB management. The drug delivery systems involving nanoparticles are suitable against chronic diseases such as tuberculosis. Polymers in many forms like liposomes, dendrimers, Nanoemulsions can be used as synthetic and natural carriers for first line and second line drugs employed for chemotherapy. Not only are the drugs sustainably released in organs and plasma, but also their dosages as well as adverse effects have been reduced, the drug interaction has increased and the drug resistant bacteria have been targeted. The hurdles in the development of anti-tuberculosis have made Nano medicines to act as a silver lining. PMID- 26416561 TI - Alternative translation initiation codons for the plastid maturase MatK: unraveling the pseudogene misconception in the Orchidaceae. AB - BACKGROUND: The plastid maturase MatK has been implicated as a possible model for the evolutionary "missing link" between prokaryotic and eukaryotic splicing machinery. This evolutionary implication has sparked investigations concerning the function of this unusual maturase. Intron targets of MatK activity suggest that this is an essential enzyme for plastid function. The matK gene, however, is described as a pseudogene in many photosynthetic orchid species due to presence of premature stop codons in translations, and its high rate of nucleotide and amino acid substitution. RESULTS: Sequence analysis of the matK gene from orchids identified an out-of-frame alternative AUG initiation codon upstream from the consensus initiation codon used for translation in other angiosperms. We demonstrate translation from the alternative initiation codon generates a conserved MatK reading frame. We confirm that MatK protein is expressed and functions in sample orchids currently described as having a matK pseudogene using immunodetection and reverse-transcription methods. We demonstrate using phylogenetic analysis that this alternative initiation codon emerged de novo within the Orchidaceae, with several reversal events at the basal lineage and deep in orchid history. CONCLUSION: These findings suggest a novel evolutionary shift for expression of matK in the Orchidaceae and support the function of MatK as a group II intron maturase in the plastid genome of land plants including the orchids. PMID- 26416562 TI - Regulation of deoxynucleotide metabolism in cancer: novel mechanisms and therapeutic implications. AB - Regulation of intracellular deoxynucleoside triphosphate (dNTP) pool is critical to genomic stability and cancer development. Imbalanced dNTP pools can lead to enhanced mutagenesis and cell proliferation resulting in cancer development. Therapeutic agents that target dNTP synthesis and metabolism are commonly used in treatment of several types of cancer. Despite several studies, the molecular mechanisms that regulate the intracellular dNTP levels and maintain their homeostasis are not completely understood. The discovery of SAMHD1 as the first mammalian dNTP triphosphohydrolase provided new insight into the mechanisms of dNTP regulation. SAMHD1 maintains the homeostatic dNTP levels that regulate DNA replication and damage repair. Recent progress indicates that gene mutations and epigenetic mechanisms lead to downregulation of SAMHD1 activity or expression in multiple cancers. Impaired SAMHD1 function can cause increased dNTP pool resulting in genomic instability and cell-cycle progression, thereby facilitating cancer cell proliferation. This review summarizes the latest advances in understanding the importance of dNTP metabolism in cancer development and the novel function of SAMHD1 in regulating this process. PMID- 26416564 TI - Biomodulation of capecitabine by paclitaxel and carboplatin in advanced solid tumors and adenocarcinoma of unknown primary. AB - Paclitaxel and carboplatin upregulate thymidine phosphorylase and thus may provide synergistic antitumor activity in combination with capecitabine (CTX). We, therefore, performed a phase I/II study of CTX. In the phase I study, patients with advanced solid tumors received carboplatin on day 1, paclitaxel on days 1, 8, 15 and capecitabine orally twice a day on days 8-21, every 4 weeks. Phase II patients with advanced adenocarcinoma of unknown primary (ACUP) were treated at the maximal tolerable dose. The phase I study enrolled 29 patients evaluable for dose limiting toxicity. The recommended phase II dose was capecitabine 750 mg/m(2) bid, paclitaxel 60 mg/m(2)/week and carboplatin AUC of 6. There were 9 confirmed responses, 5 partial responses and disease stabilization >3 months in 14 patients. The phase II study was prematurely terminated at 25 patients due to cessation of funding. The objective response rate was 32 % (95 % CI 0.15-0.54), the median progression-free survival 5.5 months (95 % CI 2.8-10.8 months) and the median overall survival 10.8 months (95 % CI 6.0-32.0 months). CTX demonstrated acceptable tolerability and antitumor activity. At the recommended dose level in patients with ACUP, this regimen showed encouraging preliminary activity. PMID- 26416565 TI - Mechanism of action of ixabepilone and its interactions with the betaIII-tubulin isotype. AB - Ixabepilone (Ixempra, BMS-247550), a semisynthetic analog of epothilone B, is a microtubule-targeted drug in clinical use for treatment of metastatic or locally advanced breast cancer. Ixabepilone's binding and mechanism of action on microtubules and their dynamics, as well as its interactions with isotypically altered microtubules, both in vitro and in tumor cells, have not been described. Microtubules are dynamic polymers of the protein tubulin that function in mitosis, intracellular transport, cell proliferation, and migration. They continually undergo dynamic instability, periods of slow growth and rapid shortening that are crucial to these cell functions. We determined ixabepilone's microtubule binding and polymerization effects in vitro and also determined its effects on inhibition of dynamic instability in vitro and in cells, both with and without removal of the betaIII isotype of tubulin. The betaIII isotype of tubulin is associated with drug resistance and tumor aggressivity. We found that removal (in vitro) and knockdown (in cells) of betaIII-tubulin led to increased inhibition of microtubule dynamic instability by ixabepilone. Depletion of betaIII-tubulin from MCF7 human breast cancer cells also induced increased mitotic arrest by ixabepilone. Thus, betaIII-tubulin expression suppresses the antitumor effects of ixabepilone, indicating that increased betaIII-tubulin may be an important contributor to the development of resistance to ixabepilone. PMID- 26416566 TI - Developing a mental health care plan in a low resource setting: the theory of change approach. AB - BACKGROUND: Scaling up mental healthcare through integration into primary care remains the main strategy to address the extensive unmet mental health need in low-income countries. For integrated care to achieve its goal, a clear understanding of the organisational processes that can promote and hinder the integration and delivery of mental health care is essential. Theory of Change (ToC), a method employed in the planning, implementation and evaluation of complex community initiatives, is an innovative approach that has the potential to assist in the development of a comprehensive mental health care plan (MHCP), which can inform the delivery of integrated care. We used the ToC approach to develop a MHCP in a rural district in Ethiopia. The work was part of a cross country study, the Programme for Improving Mental Health Care (PRIME) which focuses on developing evidence on the integration of mental health in to primary care. METHODS: An iterative ToC development process was undertaken involving multiple workshops with stakeholders from diverse backgrounds that included representatives from the community, faith and traditional healers, community associations, non-governmental organisations, Zonal, Regional and Federal level government offices, higher education institutions, social work and mental health specialists (psychiatrists and psychiatric nurses). The objective of this study is to report the process of implementing the ToC approach in developing mental health care plan. RESULTS: A total of 46 persons participated in four ToC workshops. Four critical path dimensions were identified: community, health facility, administrative and higher level care organisation. The ToC participants were actively engaged in the process and the ToC encouraged strong commitment among participants. Key opportunities and barriers to implementation and how to overcome these were suggested. During the workshops, a map incorporating the key agreed outcomes and outcome indicators was developed and finalized later. CONCLUSIONS: The ToC approach was found to be an important component in the development of the MHCP and to encourage broad political support for the integration of mental health services into primary care. The method may have broader applicability in planning complex health interventions in low resource settings. PMID- 26416567 TI - Eighty percent of French sport winners in Olympic, World and Europeans competitions have mutations in the hemochromatosis HFE gene. AB - The HFE gene encodes a protein involved in iron homeostasis; individuals with mutations in both alleles develop hemochromatosis. 27% of the French population is heterozygous for mutations in this gene. We found that 80% of the French athletes who won international competitions in rowing, Nordic skiing and judo display mutations in one allele of HFE, thus demonstrating the existence of a favourable phenotype linked to this heterozygosity. PMID- 26416568 TI - The sensitive and selective adsorption of aromatic compounds with highly crosslinked polymer nanoparticles. AB - This study presents the preparation and characterization of a nanoscale Davankov type hyper-crosslinked-polymer (HCP) as an adsorbent of benzene-ring-containing dyes and organic pollutants. HCP nanoparticles post-crosslinked from a poly(DVB co-VBC) precursor were synthesized in this study, possessing ultrahigh surface area, hydrophobicity and stability. The as-synthesized Davankov-type HCP exhibited a rapid and selective adsorption ability towards the benzene-ring containing dyes due to its highly conjugated structure. Besides, for the first time, the prepared HCP nanoparticles were adopted for the adsorption of nonpolar organic pollutants by means of solid-phase microextraction (SPME). Owing to its high hydrophobicity, diverse pore size distribution and highly conjugated structure, a 10 MUm HCP coating exhibited excellent adsorption abilities towards benzene-ring-containing polycyclic aromatic hydrocarbons (PAHs) and benzene series compounds (benzene, toluene, ethylbenzene and o-xylene; abbreviated to BTEX) and to highly hydrophobic long-chain n-alkanes. Finally, the HCP nanoparticles-coated SPME fiber was applied to the simultaneous analysis of five PAHs in environmental water samples and satisfactory recoveries were achieved. The findings could provide a new benchmark for the exploitation of superb HCPs as effective adsorbents for SPME or other adsorption applications. PMID- 26416570 TI - The benefits/risks of treatment of non-severe hypertension in pregnancy and choice of drug remain unanswered. PMID- 26416572 TI - Precision Medicine for Pediatric Cancer. AB - In a recent study, whole-exome and transcriptome sequencing identified potentially actionable findings that led to effective treatments for some children with advanced and rare cancers. The findings demonstrate that genomic sequencing data can be effectively integrated into the clinical management of pediatric patients. PMID- 26416571 TI - Dose-response curve slope helps predict therapeutic potency and breadth of HIV broadly neutralizing antibodies. AB - A new generation of HIV broadly neutralizing antibodies (bnAbs) with remarkable potency, breadth and epitope diversity has rejuvenated interest in immunotherapeutic strategies. Potencies defined by in vitro IC50 and IC80 values (50 and 80% inhibitory concentrations) figure prominently into the selection of clinical candidates; however, much higher therapeutic levels will be required to reduce multiple logs of virus and impede escape. Here we predict bnAb potency at therapeutic levels by analysing dose-response curve slopes, and show that slope is independent of IC50/IC80 and specifically relates to bnAb epitope class. With few exceptions, CD4-binding site and V3-glycan bnAbs exhibit slopes >1, indicative of higher expected therapeutic effectiveness, whereas V2-glycan, gp41 membrane-proximal external region (MPER) and gp120-gp41 bnAbs exhibit less favourable slopes <1. Our results indicate that slope is one major predictor of both potency and breadth for bnAbs at clinically relevant concentrations, and may better coordinate the relationship between bnAb epitope structure and therapeutic expectations. PMID- 26416573 TI - Pappa2 deletion in mice affects male but not female fertility. AB - BACKGROUND: Recent studies have found associations between the gene encoding pregnancy associated plasma protein-A2 (PAPP-A2), a protease of insulin-like growth factor binding protein -5 (IGFBP-5), and measures of female reproductive performance in cattle. The purpose of the present study was to test the effects of Pappa2 deletion on reproduction in mice. FINDINGS: We measured the fertility and offspring growth of Pappa2 deletion females, and also performed reciprocal matings (i.e., deletion males mated to control females) to control for the effects of offspring genotype. Ovarian and testicular IGFBP-5 levels were measured by Western blotting. As expected, deletion of Pappa2 increased ovarian IGFBP-5 levels. However, Pappa2 deletion in females had no effect on the interval between pairing and the birth of the first litter, the interval between the births of the first and second litters, or litter size. Offspring weight was lower in the offspring of Pappa2 deletion females, but effects of similar magnitude were observed in the offspring of Pappa2 deletion males, suggesting that the effects were due to heterozygosity for the deletion in the offspring. Pappa2 deletion in males had no effect on litter size or the interval between pairing and the birth of the first litter. However, the interval between the births of the first and second litters was significantly longer in deletion males. CONCLUSIONS: Pappa2 deletion had no effect on female reproductive performance. In contrast, Pappa2 deletion had subtle effects on male fertility, although the underlying mechanism remains to be elucidated. PMID- 26416575 TI - Phytotoxicity and Cytotoxicity of Essential Oil from Leaves of Plectranthus amboinicus, Carvacrol, and Thymol in Plant Bioassays. AB - The essential oil of Plectranthus amboinicus and its chemotypes, carvacrol and thymol, were evaluated on the germination and root and aerial growth of Lactuca sativa and Sorghum bicolor and in acting on the cell cycle of meristematic root cells of L. sativa. The main component found in the oil by analysis in gas chromatography-mass spectrometry and gas chromatography flame ionization detection was carvacrol (88.61% in area). At a concentration of 0.120% (w v(-1)), the oil and its chemotypes retarded or inhibited the germination and decreased root and aerial growth in monocot and dicot species used in the bioassays. In addition, all substances caused changes in the cell cycle of the meristematic cells of L. sativa, with chromosomal alterations occurring from the 0.015% (w v( 1)) concentration. The essential oil of P. amboinicus, carvacrol, and thymol have potential for use as bioherbicides. PMID- 26416576 TI - Function of polar glycerolipids in flower development in Arabidopsis thaliana. AB - The flower lipidome is an unexplored frontier of plant lipid research as compared with the major advances in photosynthetic or storage organs. However, ample evidence from recent molecular biological studies suggests that lipids play crucial roles in coordinating flower development rather than being an inert end product of metabolism. This review summarizes the current understanding of the function of glycerolipids in flower development in Arabidopsis thaliana. PMID- 26416574 TI - Implementation of a Care Pathway for Primary Palliative Care in 5 research clusters in Belgium: quasi-experimental study protocol and innovations in data collection (pro-SPINOZA). AB - BACKGROUND: Starting with early identification of palliative care patients by general practitioners (GPs), the Care Pathway for Primary Palliative Care (CPPPC) is believed to help primary health care workers to deliver patient- and family centered care in the last year of life. The care pathway has been pilot-tested, and will now be implemented in 5 Belgian regions: 2 Dutch-speaking regions, 2 French-speaking regions and the bilingual capital region of Brussels. The overall aim of the CPPPC is to provide better quality of primary palliative care, and in the end to reduce the hospital death rate. The aim of this article is to describe the quantitative design and innovative data collection strategy used in the evaluation of this complex intervention. METHODS/DESIGN: A quasi-experimental stepped wedge cluster design is set up with the 5 regions being 5 non-randomized clusters. The primary outcome is reduced hospital death rate per GPs' patient population. Secondary outcomes are increased death at home and health care consumption patterns suggesting high quality palliative care. Per research cluster, GPs will be recruited via convenience sampling. These GPs -volunteering to be involved will recruit people with reduced life expectancy and their informal care givers. Health care consumption data in the last year of life, available for all deceased people having lived in the research clusters in the study period, will be used for comparison between patient populations of participating GPs and patient populations of non-participating GPs. Description of baseline characteristics of participating GPs and patients and monitoring of the level of involvement by GPs, patients and informal care givers will happen through regular, privacy-secured web-surveys. Web-survey data and health consumption data are linked in a secure way, respecting Belgian privacy laws. DISCUSSION: To evaluate this complex intervention, a quasi-experimental stepped wedge cluster design has been set up. Context characteristics and involvement level of participants are important parameters in evaluating complex interventions. It is possible to securely link survey data with health consumption data. By appealing to IT solutions we hope to be able to partly reduce respondent burden, a known problem in palliative care research. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02266069. PMID- 26416577 TI - Fatty acid transport proteins in disease: New insights from invertebrate models. AB - The dysregulation of lipid metabolism has been implicated in various diseases, including diabetes, cardiopathies, dermopathies, retinal and neurodegenerative diseases. Mouse models have provided insights into lipid metabolism. However, progress in the understanding of these pathologies is hampered by the multiplicity of essential cellular processes and genes that modulate lipid metabolism. Drosophila and Caenorhabditis elegans have emerged as simple genetic models to improve our understanding of these metabolic diseases. Recent studies have characterized fatty acid transport protein (fatp) mutants in Drosophila and C. elegans, establishing new models of cardiomyopathy, retinal degeneration, fat storage disease and dermopathies. These models have generated novel insights into the physiological role of the Fatp protein family in vivo in multicellular organisms, and are likely to contribute substantially to progress in understanding the etiology of various metabolic disorders. Here, we describe and discuss the mechanisms underlying invertebrate fatp mutant models in the light of the current knowledge relating to FATPs and lipid disorders in vertebrates. PMID- 26416578 TI - Lipid emulsions for parenteral nutrition in critical illness. AB - Critical illness is a life-threatening multisystem process that can result in significant morbidity and mortality. In most patients, critical illness is preceded by a physiological deterioration, characterized by a catabolic state and intense metabolic changes, resulting in malnutrition and impaired immune functions. In this context, parenteral lipid emulsions may modulate inflammatory and immune reactions, depending on their fatty acid composition. These effects appear to be based on complex modifications in the composition and structure of cell membranes, through eicosanoid and cytokine synthesis and by modulation of gene expression. The pathophysiological mechanisms underlying these fatty acid induced immune function alterations in critical ill patients are however complex and partially understood. Indeed, despite a very abundant literature, experimental and clinical data remain contradictory. The optimization of lipid emulsion composition thus represents a major challenge for clinical medicine, to adequately modulate the inflammatory pathways. In the present review, we first address the metabolic response to aggression, the effects of parenteral lipid emulsions on inflammation and immunity, and finally the controversial place of these lipid emulsions during critical illness. The analysis furthermore highlights the pathophysiological mechanisms underlying the differential effects of lipid emulsions and their potential for improving the handling of critically ill patients. PMID- 26416579 TI - Effect of statin therapy on paraoxonase-1 status: A systematic review and meta analysis of 25 clinical trials. AB - BACKGROUND: Decreased activity of the enzyme paraoxonase-1 (PON1) has been demonstrated in cardiovascular diseases. Statins, the forefront of pharmacotherapy for dyslipidemia, have been shown to enhance PON1 activity but clinical findings have not been conclusive. OBJECTIVE: To systematically review the clinical findings on the impact of statin therapy on PON1 status (protein concentrations and activities of paraoxonase and arylesterase) and calculate an effect size for the mentioned effects through meta-analysis of available data. METHODS: Scopus and Medline databases were searched to identify clinical trials. A random-effects model and the generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the one study remove approach. Random-effects meta-regression was performed to assess the impact of potential confounders on the estimated effect sizes. RESULTS: Meta analysis suggested that statin therapy is associated with a significant elevation of PON1 paraoxonase and arylesterase activities, but not PON1 protein concentration. The PON1-enhancing effects of statins were robust in the sensitivity analyses and were independent of statin dose, treatment duration and changes in plasma low-density lipoprotein cholesterol concentration. CONCLUSION: The increase of paraoxonase and arylesterase activities with statins is a pleiotropic lipid-independent clinical benefit that may partly explain the putative effects of statins in preventing cardiovascular outcomes. PMID- 26416580 TI - Inhibition of the Rho/Rho kinase pathway prevents lipopolysaccharide-induced hyperalgesia and the release of TNF-alpha and IL-1beta in the mouse spinal cord. AB - Administration of lipopolysaccharide (LPS) by various routes produces profound inflammatory pain hypersensitivity. However, the molecular events that induce this response remain largely uncharacterized. In the present study, we sought to elucidate the role of the Rho/Rho kinase (ROCK) pathway in the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta) following injection of LPS into the mouse paw, which is associated with nociceptive behavior. The spinal cord of LPS-treated mice showed increased active GTP-bound RhoA and upregulation of ROCK2 and c-fos compared to the normal saline group. Furthermore, the inflammation-related cytokines TNF-alpha and IL-1beta were markedly increased in the spinal dorsal horn after intraplantar injection of LPS. However, the latter effects were prevented by prophylactic intrathecal administration of the Rho inhibitor (C3 exoenzyme) or the ROCK inhibitor (Y27632). Collectively, our results suggest that the Rho/ROCK signaling pathway plays a critical role in LPS-induced inflammatory pain and that this pathway is coincident with the release of the pro-nociceptive cytokines TNF-alpha and IL 1beta, which produces hyperalgesia. PMID- 26416581 TI - Transcriptomes of parents identify parenting strategies and sexual conflict in a subsocial beetle. AB - Parenting in the burying beetle Nicrophorus vespilloides is complex and, unusually, the sex and number of parents that can be present is flexible. Such flexibility is expected to involve specialized behaviour by the two sexes under biparental conditions. Here, we show that offspring fare equally well regardless of the sex or number of parents present. Comparing transcriptomes, we find a largely overlapping set of differentially expressed genes in both uniparental and biparental females and in uniparental males including vitellogenin, associated with reproduction, and takeout, influencing sex-specific mating and feeding behaviour. Gene expression in biparental males is similar to that in non-caring states. Thus, being 'biparental' in N. vespilloides describes the family social organization rather than the number of directly parenting individuals. There was no specialization; instead, in biparental families, direct male parental care appears to be limited with female behaviour unchanged. This should lead to strong sexual conflict. PMID- 26416582 TI - Fast probe of local electronic states in nanostructures utilizing a single-lead quantum dot. AB - Transport measurements are powerful tools to probe electronic properties of solid state materials. To access properties of local electronic states in nanostructures, such as local density of states, electronic distribution and so on, micro-probes utilizing artificial nanostructures have been invented to perform measurements in addition to those with conventional macroscopic electronic reservoirs. Here we demonstrate a new kind of micro-probe: a fast single-lead quantum dot probe, which utilizes a quantum dot coupled only to the target structure through a tunneling barrier and fast charge readout by RF reflectometry. The probe can directly access the local electronic states with wide bandwidth. The probe can also access more electronic states, not just those around the Fermi level, and the operations are robust against bias voltages and temperatures. PMID- 26416584 TI - An Internet-Based Means of Monitoring Quality of Life in Post-Prostate Radiation Treatment: A Prospective Cohort Study. AB - BACKGROUND: Widespread integration of the Internet has resulted in an increase in the feasibility of using Web-based technologies as a means of communicating with patients. It may be possible to develop secure and standardized systems that facilitate Internet-based patient-reported outcomes which could be used to improve patient care. OBJECTIVE: This study investigates patient interest in participating in an online post-treatment disease outcomes and quality of life monitoring program developed specifically for patients who have received radiation treatment for prostate cancer at a regional oncology center. METHODS: Patients treated for prostate cancer between 2007 and 2011 (N=1113) at the British Columbia Cancer Agency, Centre for the Southern Interior were invited by mail to participate in a standardized questionnaire related to their post treatment health. Overall participation rates were calculated. In addition, demographics, access to broadband Internet services, and treatment modalities were compared between participants and nonparticipants. RESULTS: Of the 1030 eligible invitees, 358 (358/1030, 34.7%) completed the online questionnaire. Participation rates were higher in individuals younger than age 60 when compared to those age 60 or older (42% vs 31%) and also for those living in urban areas compared with rural (37% vs 29%) and in those who received brachytherapy versus external beam radiotherapy (EBRT) (41% vs 31%). Better participation rates were seen in individuals who had access to Internet connectivity based on the different types of broadband services (DSL 35% for those with DSL connectivity vs 29% for those without DSL connectivity; cable 35% vs 32%; wireless 38% vs 26%). After adjusting for age, the model indicates that lack of access to wireless broadband connectivity, living in a rural area, and receiving EBRT were significant predictors of lower participation. CONCLUSIONS: This study demonstrates that participation rates vary in patient populations within the interior region of British Columbia, especially with older patients, those in rural areas, and those with limited access to quality Internet services. PMID- 26416585 TI - Engineering of high yield production of L-serine in Escherichia coli. AB - L-serine is a widely used amino acid that has been proposed as a potential building block biochemical. The high theoretical yield from glucose makes a fermentation based production attractive. In order to achieve this goal, serine degradation to pyruvate and glycine in E. coli MG1655 was prevented by deletion of three L-serine deaminases sdaA, sdaB, and tdcG, as well as serine hydroxyl methyl transferase (SHMT) encoded by glyA. Upon overexpression of the serine production pathway, consisting of a feedback resistant version of serA along with serB and serC, this quadruple deletion strain showed a very high serine production yield (0.45 g/g glucose) during small-scale batch fermentation in minimal medium. Serine, however, was found to be highly toxic even at low concentrations to this strain, which lead to slow growth and production during fed batch fermentation, resulting in a serine production of 8.3 g/L. The production strain was therefore evolved by random mutagenesis to achieve increased tolerance towards serine. Additionally, overexpression of eamA, a cysteine/homoserine transporter was demonstrated to increase serine tolerance from 1.6 g/L to 25 g/L. During fed batch fermentation, the resulting strain lead to the serine production titer of 11.7 g/L with yield of 0.43 g/g glucose, which is the highest yield reported so far for any organism. PMID- 26416583 TI - Management of Hematologic Malignancies: Special Considerations in Pregnant Women. AB - The diagnosis and management of hematologic malignancy during pregnancy is a significant challenge. This is due to both medical and ethical considerations regarding when and how to treat this special sub-group of patients. Recurring uncertainties remain around appropriate imaging techniques, timing and dosage of chemotherapy, and timing of delivery. In this article we examine and summarize current literature in this field to assist physicians in their understanding and management of this patient group. Special attention has been given to diagnostic and staging procedures, risks associated with chemotherapy at different stages of gestation, and chemotherapy-dose adaption during pregnancy. In addition, recommended guidelines for management of lymphoma, leukemia, and planning delivery are discussed. A multidisciplinary team approach is critical for patient care, as is shared decision making with the patient and family. PMID- 26416586 TI - Changes in determinants of compulsory community treatment over 11 years. A population-based analysis of linked mental health databases. AB - Differences in patient characteristics, legislation and service setting may explain variations in the reported efficacy of compulsory treatment orders (CTOs). Our objective was to investigate factors associated with CTO placement in Western Australia and see if there were any changes over the 11 years following their introduction. We used three linked Western Australian databases to compare 2958 patients on community treatment orders with an equal number of controls matched on age, sex and diagnosis, as well as 2832 consecutive controls selected on date of discharge from inpatient care or CTO placement. Multivariate analyses were used to further examine potential predictors of a CTO. The incidence of CTOs, and the characteristics of patients placed on these orders, showed little change over 11 years. They tended to be younger and male with schizophrenia or other non-affective psychotic disorders. Previous health service use as an inpatient or outpatient also predicted compulsory community treatment. Psychiatrists in Western Australia appear to be applying community treatment orders to similar types of patient as elsewhere, but unlike other jurisdictions, use has not increased. We need further research to establish the relative contribution of patient characteristics, legislation and service setting toward the use and outcome of CTOs. PMID- 26416587 TI - Psychosocial functioning of individuals with schizophrenia in community housing facilities and the psychiatric hospital in Zurich. AB - Individuals with severe mental illness frequently have difficulties in obtaining and maintaining adequate accommodation. If they are not willing or able to adapt to requirements of traditional supported housing institutions they may live in sheltered and emergency accommodation. Adequate mental health services are rarely available in these facilities. The aim of the present study was to evaluate mental health, functional and social status of individuals living in community sheltered housing facilities. A cross-sectional survey of n=338 individuals in sheltered housing compared to a sample of patients at intake in acute inpatient psychiatry (n=619) concerning clinical and social variables was carried out in the catchment area of Zurich. Matched subsamples of individuals with schizophrenia (n=168) were compared concerning functioning and impairments on the Health of the Nation Outcome Scales (HoNOS). Individuals with schizophrenia in sheltered housing (25% of the residents) have significantly more problems concerning substance use, physical illness, psychopathological symptoms other than psychosis and depression, and relationships, daily activities and occupation than patients with schizophrenia at intake on an acute psychiatric ward. Community sheltered accommodation although conceptualized to prevent homelessness in the general population de facto serve as housing facilities for individuals with schizophrenia and other severe mental illness. PMID- 26416588 TI - Associations between five-factor model of the Positive and Negative Syndrome Scale and plasma levels of monoamine metabolite in patients with schizophrenia. AB - The five-factor model of the Positive and Negative Syndrome Scale (PANSS) for schizophrenia symptoms is the most common multiple-factor model used in analyses; its use may improve evaluation of symptoms in schizophrenia patients. Plasma monoamine metabolite levels are possible indicators of clinical symptoms or response to antipsychotics in schizophrenia. We investigated the association between five-factor model components and plasma monoamine metabolites levels to explore the model's biological basis. Plasma levels of homovanillic acid (HVA), 3 methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were measured using high-performance liquid chromatography in 65 Japanese patients with schizophrenia. Significant negative correlation between plasma 5 HIAA levels and the depression/anxiety component was found. Furthermore, significant positive correlation was found between plasma MHPG levels and the excitement component. Plasma HVA levels were not correlated with any five-factor model component. These results suggest that the five-factor model of the PANSS may have a biological basis, and may be useful for elucidating the psychopathology of schizophrenia. Assessment using the five-factor model may enable understanding of monoaminergic dysfunction, possibly allowing more appropriate medication selection. Further studies of a larger number of first episode schizophrenia patients are needed to confirm and extend these results. PMID- 26416589 TI - Perceptual abnormalities related to sensory gating deficit are core symptoms in adults with ADHD. AB - This study investigated and compared perceptual abnormalities related to sensory gating deficit in adult patients with Attention Deficit Disorder with Hyperactivity (A-ADHD) and adult patients with schizophrenia. Subjects were evaluated with the Sensory Gating Inventory (SGI). We compared SGI scores between patients with A-ADHD, patients with schizophrenia and healthy subjects. We also assessed the relationship between SGI scores and clinical symptoms, and evaluated the ability of the SGI to detect perceptual abnormalities in A-ADHD. Seventy adult patients with ADHD reported higher SGI scores than the 70 healthy subjects and the 70 patients with schizophrenia. The inattention factor of the ASRS correlated significantly with the overall SGI score. The ROC AUC for the overall SGI score in the A-ADHD group (versus the healthy group) illustrated good performance. The findings suggest that i) perceptual abnormalities are core symptoms of adult patients with ADHD and ii) the attention of patients with A ADHD may be involuntarily drowned by many irrelevant environmental stimuli leading to their impaired attention on relevant stimuli. They also confirm that the SGI could be a useful self-report instrument to diagnose the clinical features of A-ADHD. PMID- 26416590 TI - Psychiatric comorbidity in women and men with eating disorders results from a large clinical database. AB - Psychiatric comorbidity is common in patients with eating disorders (ED), but prevalence estimates are heterogeneous, probably due to methodological differences between studies (population, diagnostic method, sampling procedure etc.) and a few studies include men. The aim of this study is to investigate psychiatric DSM-IV Axis I comorbidity in a large sample of adult patients, both males and females, with the whole spectrum of DSM-IV ED diagnoses. Initial presentation assessment data on 11,588 adult men and women presenting to specialist ED clinics in Sweden between 2008 and 2012 were extracted from a large clinical database. Diagnostics were based on semi-structured interviews (SCID-I) and the Structured Eating Disorder Interview (SEDI). Seventy-one percent of the patients with ED had at least one other Axis I disorder. The most common type of diagnosis was anxiety disorders (53%), where generalized anxiety disorder was the most common diagnosis. The highest levels of comorbidity were found for women with Binge Eating Disorder (BED) and men with Bulimia Nervosa (BN). Findings are consistent with previous research showing a high prevalence of psychiatric comorbidity in both men and women with ED. The small gender differences observed seem negligible compared to the general similarity in comorbidity. PMID- 26416592 TI - Rotifer dynamics in three shallow lakes from the Salado river watershed (Argentina): the potential modulating role of incident solar radiation. AB - In turbid Pampean lakes, incident solar radiation is a major driver of plankton seasonal dynamics. Higher light availability in summer translates into higher primary production, and therefore more food for zooplankton grazers. However, experimental evidence suggests that food produced under the high irradiance conditions prevailing in summer are less suitable to sustain rotifer population growth than that produced under the lower irradiance conditions typical of winter. Here, we analysed time series datasets corresponding to three shallow lakes from the Salado river watershed. This analysis provided evidence for similar seasonal patterns of rotifer relative abundance over a large geographic area. In addition, we performed life table experiments to test the hypothesis that natural seston produced in winter could sustain higher population growth rates than seston produced in summer. We suggest that the natural seasonal changes in temperature and food generate successive time windows, which may be capitalized by the different grazer species, resulting in predictable phenology of grazer populations. PMID- 26416591 TI - Family history of alcoholism is related to increased D2 /D3 receptor binding potential: a marker of resilience or risk? AB - The aim of this study was to examine the relationship between family history of alcohol use disorder and striatal dopamine using positron emission tomography imaging. Participants were 84 healthy, 18- to 30-year-old, social drinkers recruited via fliers and newspaper advertisements. At assessment, participants completed measures of lifetime personal and family substance use and psychiatric symptoms. Participants underwent two consecutive positron emission tomography scans using the D2 /D3 dopamine receptor radioligand [11 C]raclopride. Scans were preceded by intravenous saline and amphetamine 0.3 mg/kg, providing measures of baseline [11 C]raclopride binding potential (BPND ) and change in [11 C]raclopride (DeltaBPND ). Subjective ratings of stimulant drug effects were collected during scans. Subjects were classified as family history positive (FHP) if they reported any first-degree relative with alcohol use disorder (AUD) and family history negative (FHN) if no first-degree relatives had history of AUD. Participants were predominantly White (69.0 percent) and male (62.1 percent). Baseline [11 C]raclopride BPND was generally higher in FHP compared with FHN subjects across striatal subdivisions. There were no differences in DeltaBPND across regions. Negative subjective drug effects were more pronounced in FHP than in FHN subjects. While FHN subjects evidenced the expected positive relationship between DeltaBPND and positive subjective drug effects, this relationship was disrupted in FHP subjects. There are key differences in dopamine status and subjective stimulant drug experiences as a function of family AUD history. These findings have important implications for understanding risk for AUD development in FHP offspring. PMID- 26416593 TI - Homeostatic dysregulation proceeds in parallel in multiple physiological systems. AB - An increasing number of aging researchers believes that multi-system physiological dysregulation may be a key biological mechanism of aging, but evidence of this has been sparse. Here, we used biomarker data on nearly 33, 000 individuals from four large datasets to test for the presence of multi-system dysregulation. We grouped 37 biomarkers into six a priori groupings representing physiological systems (lipids, immune, oxygen transport, liver function, vitamins, and electrolytes), then calculated dysregulation scores for each system in each individual using statistical distance. Correlations among dysregulation levels across systems were generally weak but significant. Comparison of these results to dysregulation in arbitrary 'systems' generated by random grouping of biomarkers showed that a priori knowledge effectively distinguished the true systems in which dysregulation proceeds most independently. In other words, correlations among dysregulation levels were higher using arbitrary systems, indicating that only a priori systems identified distinct dysregulation processes. Additionally, dysregulation of most systems increased with age and significantly predicted multiple health outcomes including mortality, frailty, diabetes, heart disease, and number of chronic diseases. The six systems differed in how well their dysregulation scores predicted health outcomes and age. These findings present the first unequivocal demonstration of integrated multi-system physiological dysregulation during aging, demonstrating that physiological dysregulation proceeds neither as a single global process nor as a completely independent process in different systems, but rather as a set of system-specific processes likely linked through weak feedback effects. These processes--probably many more than the six measured here--are implicated in aging. PMID- 26416594 TI - Allopurinol hypersensitivity: investigating the cause and minimizing the risk. AB - Allopurinol is the most commonly prescribed urate-lowering therapy for the management of gout. Serious adverse reactions associated with allopurinol, while rare, are feared owing to the high mortality. Such reactions can manifest as a rash combined with eosinophilia, leukocytosis, fever, hepatitis and progressive kidney failure. Risk factors for allopurinol-related severe adverse reactions include the recent introduction of allopurinol, the presence of the HLA-B(*)58:01 allele, and factors that influence the drug concentration. The interactions between allopurinol, its metabolite, oxypurinol, and T cells have been studied, and evidence exists that the presence of the HLA-B(*)58:01 allele and a high concentration of oxypurinol function synergistically to increase the number of potentially immunogenic-peptide-oxypurinol-HLA-B(*)58:01 complexes on the cell surface, thereby increasing the risk of T-cell sensitization and a subsequent adverse reaction. This Review will discuss the above issues and place this in the clinical context of reducing the risk of serious adverse reactions. PMID- 26416595 TI - Rheumatoid arthritis: Autoantibodies, citrullinated histones and initiation of synovitis. PMID- 26416596 TI - The inflammasome in fibromyalgia and CRPS: a microglial hypothesis? PMID- 26416597 TI - Osteoarthritis: Genetically modified ADSCs as cell therapy for OA? PMID- 26416598 TI - Osteochondrosis, but not lameness, is more frequent among free-range pigs than confined herd-mates. AB - BACKGROUND: Organic pig production is expanding and amongst the objectives of organic farming are enhancing animal health and welfare. However, some studies have reported a higher prevalence of lameness and joint condemnation at slaughter in free-range/organic pigs than in conventionally raised pigs. Organic slaughter pigs have free-range housing in which indoor and outdoor access is compulsory, while in conventional farming the pigs are commonly confined to indoor pens. The present study evaluated the effects of free-range and confined housing on lameness prevalence in a herd of 106 finisher pigs, and whether osteochondrosis and Erysipelothrix rhusiopathiae associated arthritis influences these effects. We also evaluated the association between clinical lameness during the rearing period and joint condemnations at slaughter. RESULTS: Seventy free-range and 36 confined housed fattener pigs were scored for their gait twice during the rearing period and 848 joints were evaluated post mortem. Osteochondrosis was more frequent among free-range than confined pigs (P < 0.05), and when present it was also more severe (P < 0.001). Pigs with more numerous and more severe osteochondral lesions had their gait affected more than did pigs with fewer such lesions (P < 0.05). Hence it was a paradox that we did not detect more lameness among the free-range pigs than the confined pigs. E. rhusiopathiae associated arthritis was not diagnosed. The association between gait remarks/clinical lameness and joint condemnations at slaughter was not significant. CONCLUSIONS: The results indicate that free-range housing may have both positive and negative effects on locomotory traits. Free-range pigs may be less clinically affected by osteochondrosis than are confined pigs. One explanation for this effect may be strengthening of joint supportive tissue and pain relief promoted by exercise. Visual gait scoring missed serious joint lesions that probably were harmful to the pigs, and should therefore not be used as a sole indicator of joint/leg health in welfare inspection of pigs. The association between gait scores and joint condemnation appeared to be poor. This study was limited to one herd, and so more and larger studies on the effects of free-range housing on lameness severity and osteochondrosis development in pigs are recommended. PMID- 26416599 TI - A CCL21 chemokine of tongue sole (Cynoglossus semilaevis) promotes host resistance against bacterial infection. AB - Chemokines are a large family of chemotactic cytokines. Based on the arrangement of the first two cysteine residues, chemokines are divided into four groups, one of which is the CC chemokine group. In this study, we characterized a CC chemokine, CsCCL21, from half-smooth tongue sole (Cynoglossus semilaevis), and analyzed its activity. CsCCL21 contains two conserved N-terminal cysteine residues in a NCCL motif and is phylogenetically related to the CCL19/21/25 subgroup of CC chemokines. CsCCL21 was constitutively expressed in nine tissues and significantly upregulated by bacterial and viral infection. The recombinant CsCCL21 (rCsCCL21) induced migration of peripheral blood leukocytes. When the two conserved cysteine residues in the NCCL motif were mutated, the chemotactic activity of rCsCCL21 was abolished. rCsCCL21 enhanced the resistance of tongue sole against bacterial infection, but the mutant protein with NCCL mutation lacked this antibacterial effect. Taken together, these results suggest that CsCCL21 is a functional CC chemokine with the ability to recruit leukocytes and is involved in antibacterial immunity in a manner that requires the conserved NCCL motif. PMID- 26416601 TI - Diffuse fatty metamorphosis of a large, well-differentiated hepatocellular carcinoma originating in the normal liver: a case report and literature review. AB - Fatty changes are frequently observed in small, well-differentiated hepatocellular carcinomas (HCCs), but are rarely observed in large (over 30 mm in diameter) lesions. Here, we report a 76-year-old man who developed a large (58 mm in diameter), well-differentiated HCC with diffuse extensive fatty changes in the right lobe of the liver. He had no history of alcohol abuse, obesity, or hepatitis B or C infection, and no autoantibodies, but he did have type 2 diabetes. The serum alpha-fetoprotein level was within the normal range, and ultrasonography showed a round hyperechoic lesion. Dynamic contrast-enhanced computed tomography revealed a tumor with inhomogeneous low attenuation in the arterial, portal, and venous phases, mimicking an angiomyolipoma. The patient underwent central bisegmentectomy of the liver, and the histological diagnosis was well-differentiated HCC with diffuse extensive fatty changes. The surrounding non-cancerous area was normal. A review of the published literature found six published cases of large, well-differentiated HCC with extensive fatty changes. Unlike the patients in most previous reports, our patient did not have any underlying liver disease and had no history of alcohol abuse. PMID- 26416600 TI - Analysis of the miRNA-mRNA-lncRNA networks in ER+ and ER- breast cancer cell lines. AB - Recently, rapid advances in bioinformatics analysis have expanded our understanding of the transcriptome to a genome-wide level. miRNA-mRNA-lncRNA interactions have been shown to play critical regulatory role in cancer biology. In this study, we discussed the use of an integrated systematic approach to explore new facets of the oestrogen receptor (ER)-regulated transcriptome. The identification of RNAs that are related to the expression status of the ER may be useful in clinical therapy and prognosis. We used a network modelling strategy. First, microarray expression profiling of mRNA, lncRNA and miRNA was performed in MCF-7 (ER-positive) and MDA-MB-231 cells (ER- negative). A co-expression network was then built using co-expression relationships of the differentially expressed mRNAs and lncRNAs. Finally, the selected miRNA-mRNA network was added to the network. The key miRNA-mRNA-lncRNA interaction can be inferred from the network. The mRNA and non-coding RNA expression profiles of the cells with different ER phenotypes were distinct. Among the aberrantly expressed miRNAs, the expression levels of miR-19a-3p, miR-19b-3p and miR-130a-3p were much lower in the MCF-7 cells, whereas that of miR-148b-3p was much higher. In a cluster of miR-17-92, the expression levels of six of seven miRNAs were lower in the MCF-7 cells, in addition to miR-20b in the miR-106a-363 cluster. However, the levels of all the miRNAs in the miR-106a-25 cluster were higher in the MCF-7 cells. In the co expression networking, CD74 and FMNL2 gene which is involved in the immune response and metastasis, respectively, had a stronger correlation with ER. Among the aberrantly expressed lncRNAs, lncRNA-DLEU1 was highly expressed in the MCF-7 cells. A statistical analysis revealed that there was a co-expression relationship between ESR1 and lncRNA-DLEU1. In addition, miR-19a and lncRNA-DLEU1 are both located on the human chromosome 13q. We speculate that miR-19a might be co-expressed with lncRNA-DLEU1 to co-regulate the expression of ESR1, which influences the occurrence and development of breast cancer cells with different levels of ER expression. Our findings reveal that the status of ER is mainly due to the differences in the mRNA and ncRNA profile between the breast cancer cell lines, and highlight the importance of studying the miRNA-mRNA-lncRNA interactions to completely illustrate the intricate transcriptome. PMID- 26416602 TI - Development and Validation of a Multiclass Method for Analysis of Veterinary Drug Residues in Milk Using Ultrahigh Performance Liquid Chromatography Electrospray Ionization Quadrupole Orbitrap Mass Spectrometry. AB - This paper presents the development and validation of a multiclass method for the analysis of veterinary drug residues in milk using ultrahigh performance liquid chromatography electrospray ionization quadrupole Orbitrap mass spectrometry (UHPLC/ESI Q-Orbitrap). The 12 classes of veterinary drugs (a total of 125) included in this study were endectocides, fluoroquinolones, ionophores, macrolides, nitroimidazole, NSAIDs, beta-lactams, penicillins, phenicols, sulfonamides, tetracyclines, and aminoglycosides. Veterinary drug residues in milk were extracted using a modified salting-out supported liquid extraction (SOSLE) method, which entailed the precipitation of milk proteins using an extraction buffer (oxalic acid and EDTA, pH 3) and acetonitrile, a salting-out acetonitrile/water phase separation using ammonium sulfate, and solid-phase extraction (SPE) using polymeric reversed-phase sorbent cartridges. The final extracts were concentrated and reconstituted into a buffer solution and analyzed using UHPLC/ESI Q-Orbitrap mass spectrometry. The developed method was validated using a nested experimental design to evaluate the method performance characteristics, such as overall recovery, intermediate precision, and measurement uncertainty. The method was able to quantify or screen up to 105 veterinary drugs from 11 different classes, except aminoglycosides. The limits of quantification were as low as 1.0 MUg/kg, with an analytical range from 1.0 to 100.0 MUg/kg in milk. PMID- 26416603 TI - Revealing Annexin A2 and ARF-6 enrollment during Trypanosoma cruzi extracellular amastigote-host cell interaction. AB - BACKGROUND: Invasion of host cells by Trypanosoma cruzi extracellular amastigotes is host actin polymerization-dependent. However, the role of proteins related to actin dynamics during invasion by amastigotes remains to be investigated. Here we describe the role of Annexin A2 and ARF-6 during extracellular amastigote mammalian cell interactions. FINDINGS: Our results showed ARF-6 accumulation in the amastigote-containing parasitophorous vacuole containing amastigote forms; demonstrated ARF-6 and Annexin A2 critical impact over parasite cell invasion and revealed the effect of Annexin A2 expression on intracellular parasite multiplication. CONCLUSION: ARF-6 and Annexin A2 are involved in invasion of mammalian cells by T. cruzi amastigotes. PMID- 26416604 TI - Vitamin D metabolism-related genetic variants, dietary protein intake and improvement of insulin resistance in a 2 year weight-loss trial: POUNDS Lost. AB - AIMS/HYPOTHESIS: Vitamin D and related genetic variants are associated with obesity and insulin resistance. We aimed to examine whether vitamin D metabolism related variants affect changes in body weight and insulin resistance in response to weight-loss diets varying in macronutrient content. METHODS: Three vitamin D metabolism-related variants, DHCR7 rs12785878, CYP2R1 rs10741657 and GC rs2282679, were genotyped in 732 overweight/obese participants from a 2 year weight-loss trial (POUNDS Lost). We assessed genotype effects on changes in body weight, fasting levels of glucose and insulin, and HOMA-IR at 6 months (up to 656 participants) and 2 years (up to 596 participants) in response to low-protein vs high-protein diets, and low-fat vs high-fat diets. RESULTS: We found significant interactions between DHCR7 rs12785878 and diets varying in protein, but not in fat, on changes in insulin and HOMA-IR at both 6 months (p for interaction <0.001) and 2 years (p for interaction <= 0.03). The T allele (vitamin-D increasing allele) of DHCR7 rs12785878 was associated with greater decreases in insulin and HOMA-IR (p < 0.002) in response to high-protein diets, while there was no significant genotype effect on changes in these traits in the low-protein diet group. Generalised estimating equation analyses indicated significant genotype effects on trajectory of changes in insulin resistance over the 2 year intervention in response to high-protein diets (p < 0.001). We did not observe significant interaction between the other two variants and dietary protein or fat on changes in these traits. CONCLUSIONS/INTERPRETATION: Our data suggest that individuals carrying the T allele of DHCR7 rs12785878 might benefit more in improvement of insulin resistance than noncarriers by consuming high-protein weight-loss diets. TRIAL REGISTRATION: ClinicalTrials.gov NCT00072995. PMID- 26416605 TI - Pharmacokinetics of Budesonide Administered with Surfactant in Premature Lambs: Implications for Neonatal Clinical Trials. AB - Bronchopulmonary dysplasia (BPD) is a chronic lung disease of premature human infants, which may persist through adulthood. Airway inflammation has been firmly established in the pathogenesis of BPD. Previous studies to reduce airway inflammation with high-dose dexamethasone demonstrated adverse neurological outcomes, despite lower incidences of BPD. Instillation of budesonide and surfactant can facilitate early extubation and reduce the incidence of BPD and death among very low birth weight infants. However, the pharmacokinetics of budesonide and its distribution into the lung and brain are unknown. Therefore, 5 premature lambs were administered 0.25 mg/kg budesonide, with surfactant as the vehicle. Plasma and tissue samples were taken from the lambs for measurement of budesonide, 16alpha- hydroxy prednisolone, and budesonide palmitate using LC/MS/MS. Peak plasma budesonide concentrations were inversely correlated with the oxygenation index (correlation coefficient of -0.75). plasma budesonide concentrations were extremely low (~10% of expected) for two lambs that had high oxygenation indices and were excluded from further analyses. For the remaining 5 premature lambs, a non-compartmental analysis demonstrated an AUCinf of 148.77 +/ 28.16 h*MUg/L, half-life of 4.76 +/- 1.79 h, and Cmax of 46.17 +/- 17.71 ug/L. Using population pharmacokinetic methods, a onecompartment model with exponential residual error and first-order absorption adequately described the data. The apparent clearance and apparent volume of distribution of budesonide were estimated at 6.29 L/h (1.99 L/h/kg) and 29.1 L (9.2 L/kg), respectively. Budesonide and budesonide palmitate, but not 16alpha-hydroxy prednisolone, were detected in lung tissue. In this study, budesonide and its metabolites were not detected in the brain, which suggests that intratracheal instillation suggests that after local pulmonary deposition, there is no evidence of budesonide accumulation in the central nervous system. Overall, these results show that peak plasma budesonide concentrations are inversely correlated with the oxygenation index and that lung-specific delivery of budesonide avoids accumulation of budesonide in the brain. PMID- 26416607 TI - Cytomegalovirus as a potential trigger for systemic lupus erythematosus: a case report. AB - BACKGROUND: The role of cytomegalovirus infection in triggering systemic lupus erythematosus remains a subject of debate. Here, we present a case of childhood systemic lupus erythematosus with concomitant cytomegalovirus infection, which sheds light on the relationship between these conditions and their treatment in pediatric patients. CASE PRESENTATION: A 12-year-old Japanese girl with no history of systemic illness was diagnosed with systemic lupus erythematosus and concomitant primary cytomegalovirus infection. Her anti-cytomegalovirus immunoglobulin G antibodies were elevated during diagnosis and treatment. Further, the patient's cytomegalovirus pp65 antigenemia level was slightly elevated (1 cell per 5 * 10(4) cells). Treatment included the administration of ganciclovir, prednisolone, methylprednisolone, and cyclophosphamide, none of which prompted adverse effects. The patient was in good condition at the most recent follow-up. CONCLUSION: Ganciclovir treatment is not completely safe, and there are no clinical guidelines regarding its use in patients with systemic lupus erythematosus triggered by cytomegalovirus infection. Our experience with this case suggests that the decision to administer ganciclovir treatment in pediatric cases should be guided by a variety of factors in addition to the cytomegalovirus antigenemia level. These factors include lymphopenia, renal biopsy results, and cytomegalovirus DNA levels detected by polymerase chain reaction. The details of our patient's presentation and treatment should prove illustrative to other clinicians who face similar cases. PMID- 26416606 TI - Effectiveness of a walking programme to support adults with intellectual disabilities to increase physical activity: walk well cluster-randomised controlled trial. AB - BACKGROUND: Programs to change health behaviours have been identified as one way to reduce health inequalities experienced by disadvantaged groups. The objective of this study was to examine the effectiveness of a behaviour change programme to increase walking and reduce sedentary behaviour of adults with intellectual disabilities. METHODS: We used a cluster randomised controlled design and recruited participants over 18 years old and not regularly involved in physical activity from intellectual disabilities community-based organisations. Assessments were carried out blind to allocation. Clusters of participants were randomly allocated to the Walk Well program or a 12-week waiting list control. Walk Well consisted of three face-to-face physical activity consultations incorporating behaviour change techniques, written resources for participants and carers, and an individualised, structured walking programme. The primary outcome measured with accelerometers was change in mean step count per day between baseline and 12 weeks. Secondary outcomes included percentage time per day sedentary and in moderate-vigorous physical activity (MVPA), body mass index (BMI), and subjective well being. RESULTS: One hundred two participants in 50 clusters were randomised. 82 (80.4%) participants completed the primary outcome. 66.7% of participants lived in the most deprived quintile on the Scottish Index of Multiple Deprivation. At baseline, participants walked 4780 (standard deviation 2432) steps per day, spent 65.5% (standard deviation 10.9) of time sedentary and 59% percent had a body mass in the obesity range. After the walking programme, the difference between mean counts of the Walk Well and control group was 69.5 steps per day [95% confidence interval (CI) -1054 to 1193.3]. There were no significant between group differences in percentage time sedentary 1.6% (95% CI -2.984 to 6.102), percentage time in MVPA 0.3% (95% CI -0.7 to 1.3), BMI -0.2 kg/m(2) (95% CI -0.8 to 0.4) or subjective well-being 0.3 (95% CI -0.9 to 1.5). CONCLUSIONS: This is the first published trial of a walking program for adults with intellectual disabilities. Positively changing physical activity and sedentary behaviours may require more intensive programmes or upstream approaches to address the multiple social disadvantages experienced by adults with intellectual disabilities. Since participants spent the majority of their time sedentary, home-based programmes to reduce sitting time may be a viable health improvement approach. TRIAL REGISTRATION: Current Controlled Trials ISRCTN50494254. PMID- 26416608 TI - [Formula: see text]Current knowledge on motor disorders in children with autism spectrum disorder (ASD). AB - Motor symptomatology in autism is currently poorly understood, and still not included in the autism spectrum disorder (ASD) diagnostic criteria, although some studies suggest the presence of motor disturbances in this syndrome. We provide here a literature review on early motor symptoms in autism, focusing on studies on psychomotor issues (tone, postural control, manual dexterity, handedness, praxis). The approach adopted in research to study altered motor behaviors is generally global and there is no detailed semiology of the motor or neuromotor disorders observed in people with ASD. This global approach does not enable understanding of the neuro-developmental mechanisms involved in ASD. Identification of clinical neuro-psychomotor profiles in reference to a standard would help to better understand the origin and the nature of the disorders encountered in ASD, and would thus give new directions for treatment. PMID- 26416609 TI - In silico evolution of diauxic growth. AB - BACKGROUND: The glucose effect is a well known phenomenon whereby cells, when presented with two different nutrients, show a diauxic growth pattern, i.e. an episode of exponential growth followed by a lag phase of reduced growth followed by a second phase of exponential growth. Diauxic growth is usually thought of as a an adaptation to maximise biomass production in an environment offering two or more carbon sources. While diauxic growth has been studied widely both experimentally and theoretically, the hypothesis that diauxic growth is a strategy to increase overall growth has remained an unconfirmed conjecture. METHODS: Here, we present a minimal mathematical model of a bacterial nutrient uptake system and metabolism. We subject this model to artificial evolution to test under which conditions diauxic growth evolves. RESULTS: As a result, we find that, indeed, sequential uptake of nutrients emerges if there is competition for nutrients and the metabolism/uptake system is capacity limited. DISCUSSION: However, we also find that diauxic growth is a secondary effect of this system and that the speed-up of nutrient uptake is a much larger effect. Notably, this speed-up of nutrient uptake coincides with an overall reduction of efficiency. CONCLUSIONS: Our two main conclusions are: (i) Cells competing for the same nutrients evolve rapid but inefficient growth dynamics. (ii) In the deterministic models we use here no substantial lag-phase evolves. This suggests that the lag phase is a consequence of stochastic gene expression. PMID- 26416610 TI - Vertebral artery injury during foraminal decompression in "low-risk" cervical spine surgery: incidence and management. AB - OBJECTIVES: Vertebral artery injury (VAI) during foraminal decompression in cervical spine surgery in the absence of repositioning or screw stabilization is rare. Without immediate recognition and treatment, it may have disastrous consequences. We aimed to describe the incidence and management of iatrogenic VAI in low-risk cervical spine surgery. MATERIALS AND METHODS: The records of all patients who underwent surgical procedures of the cervical spine between January 2007 and May 2012 were retrospectively consecutively evaluated. Anterior cervical discectomy and fusion or arthroplasty as well as dorsal foraminal decompression through the Frykholm approach in degenerative diseases were defined as low-risk surgeries (n = 992). RESULTS: VAI occurred in 0.3 % (n = 3) of 992 procedures: in one case during a dorsal foraminal decompression, and in two cases during the anterior cervical discectomy and fusion (ACDF) of two or four levels, respectively. In the first case, the VAI was intraoperatively misdiagnosed. Despite an initially uneventful course, the patient suffered hemorrhage from a pseudoaneurysm of the injured VA 1 month after surgery. The aneurysm was successfully occluded by endovascular coiling. In both ACDF cases, angiography and endovascular stenting of the lacerated segment proceeded immediately after the surgery. All three patients suffered no permanent deterioration. CONCLUSIONS: In a high-volume surgical center, the incidence of VAI during low-risk cervical spine surgery is extremely low, comprising 0.3 % of all cases. The major risks are delayed sequels of the vessel wall laceration. In cases of VAI, immediate angiographic diagnostics and generous indications for endovascular treatment are obligatory. PMID- 26416611 TI - Temporal lobe epilepsy and cavernous malformations: surgical strategies and long term outcomes. AB - OBJECTIVE: Cerebral cavernous malformations (CCM) of the temporal lobe often present with seizures. Surgical resection of these lesions can offer durable seizure control. There is, however, no universally accepted methodology for assessing and surgically treating these patients. We propose an algorithm to maximize positive surgical outcomes (seizure control) while minimizing post surgical neurological deficit. METHODS: A retrospective review of 34 patients who underwent epilepsy surgery for radiographically proven temporal lobe CCM was conducted. Patients underwent a relatively standard work-up for seizure localization. In patients with mesial temporal lobe epilepsy (MTLE), a complete resection of the epileptogenic zone was performed including amygdalo hippocampectomy in addition to a lesionectomy if not contraindicated by pre operative work-up. Patients with neocortical epilepsy underwent intraoperative electrocorticography (ECoG)-guided lesionectomy. RESULTS: Seizure-free rate for mesial and neocortical (anterior, lateral, and basal) location was 90 vs. 83 %, respectively. Complete resection of the lesion, irrespective of location, was statistically significant for seizure control (p = 0.018). There was no difference in seizure control based on disease duration or location (p > 0.05). Patients with mesial temporal CCM who presented with MTLE were presumed to also have mesial temporal sclerosis (MTS), or dual pathology. These patients underwent routine resection of the mesial structures. Interestingly, patients who had MTLE and basal (neocortical) lesions who underwent a mesial resection for suspected MTS were found not to have dual pathology. CONCLUSIONS: Patients with temporal lobe CCM should be offered resection for durable seizure control, prevention of secondary epileptogenic foci, and elimination of hemorrhage risk. The preoperative work-up should follow a team approach. Surgical intervention should include complete lesionectomy in all cases. Intra or extra-operative ECoG for neocortical lesions may be beneficial. Management of mesial temporal CCMs (archicortex) should consider resection of a well-defined epileptogenic zone (including mesial structures) due to high probability of pathologically proven MTS. The use of this treatment algorithm is useful for the education and treatment of these patients. PMID- 26416612 TI - Determinants of patient-reported experience of cancer services responsiveness. AB - BACKGROUND: In coming years, patient-reported data are expected to play a more prominent role in ensuring early and efficient detection of healthcare system dysfunctions, developing interventions and evaluating their effects on health outcomes, and monitoring quality of care from the patient's perspective. The concept of responsiveness relates to patient-reported experience measures that focus on the system's response to service users' legitimate expectations. We explored this concept in an effort to address unresolved issues related to measuring and interpreting patient experience. Our objectives in this study were to report on patients' perceptions of cancer services responsiveness and to identify patient characteristics and organizational attributes that are potential determinants of a positive patient-reported experience. METHODS: A cross sectional survey was conducted of 1379 cancer patients in nine participating ambulatory cancer clinics in hospitals across the province of Quebec, Canada. They were invited to complete the Cancer Services Responsiveness tool, a 19-item questionnaire evaluating patients' perceptions of the responsiveness of cancer services. Sociodemographic data and self-reported clinical and organizational data were collected. Descriptive statistical analysis, univariate and multivariate logistic regressions were performed. RESULTS: The patients surveyed generally perceived cancer services as highly responsive. The individual determinants of overall responsiveness found to be significant were self-assessed health status, age, and education level; organizational determinants were academic affiliation and geographic location of the clinic. DISCUSSION: Responsiveness refers to distinctive indicators of healthcare quality focused on patient-provider interactions and presents a complementary picture to other patient-reported experience measures. The identified determinants of patients' positive experience with cancer services provide valuable information to guide care providers in targeting quality improvements. CONCLUSIONS: Finally, our results suggest these determinants should be further studied to eliminate confounders and produce usable results. PMID- 26416613 TI - Current noise as a probe for Wigner molecules. AB - The effects of a Wigner molecule on the current noise and conductance of a one dimensional quantum dot with two electrons are investigated. Focusing on a lateral transport setup, the sequential regime is considered. Tunnelling rates through the dot are evaluated within an exact diagonalisation scheme. They strongly depend on electron interactions, showing a markedly different behaviour in the presence of a Wigner molecule with respect to the weak interactions case, and thus modify the transport and current noise and the dot. For weak interactions negative differential conductance and super-Poissonian noise are found. As interactions increase, a Wigner molecule develops: it suppresses the negative differential conductance and turns the shot noise to sub-Poissonian values. In particular, the noise is found to be a sensitive probe of the Wigner molecule. PMID- 26416615 TI - Design and synthesis of aromatic molecules for probing electric fields at the nanoscale. AB - We propose using halogenated organic dyes as nanoprobes for electric fields and show their greatly enhanced Stark coefficients using density functional theory (DFT) calculations. We analyse halogenated variants of three molecules that have been of interest for cryogenic single molecule spectroscopy: perylene, terrylene, and dibenzoterrylene, with the zero-phonon optical transitions at blue, red, and near-infrared. Out of all the combinations of halides and binding sites that are calculated, we have found that fluorination of the optimum binding site induces a dipole difference between the ground and excited states larger than 0.5 D for all three molecules with the highest value of 0.69 D for fluoroperylene. We also report on the synthesis of 3-fluoroterrylene and the bulk spectroscopy of this compound in liquid and solid organic environments. PMID- 26416614 TI - Development and initial evaluation of a semi-automatic approach to assess perivascular spaces on conventional magnetic resonance images. AB - PURPOSE: Perivascular spaces (PVS) are associated with ageing, cerebral small vessel disease, inflammation and increased blood brain barrier permeability. Most studies to date use visual rating scales to assess PVS, but these are prone to observer variation. METHODS: We developed a semi-automatic computational method that extracts PVS on bilateral ovoid basal ganglia (BG) regions on intensity normalised T2-weighted magnetic resonance images. It uses AnalyzeTM10.0 and was applied to 100 mild stroke patients' datasets. We used linear regression to test association between BGPVS count, volume and visual rating scores; and between BGPVS count & volume, white matter hyperintensity (WMH) rating scores (periventricular: PVH; deep: DWMH) & volume, atrophy rating scores and brain volume. RESULTS: In the 100 patients WMH ranged from 0.4 to 119ml, and total brain tissue volume from 0.65 to 1.45l. BGPVS volume increased with BGPVS count (67.27, 95%CI [57.93 to 76.60], p<0.001). BGPVS count was positively associated with WMH visual rating (PVH: 2.20, 95%CI [1.22 to 3.18], p<0.001; DWMH: 1.92, 95%CI [0.99 to 2.85], p<0.001), WMH volume (0.065, 95%CI [0.034 to 0.096], p<0.001), and whole brain atrophy visual rating (1.01, 95%CI [0.49 to 1.53], p<0.001). BGPVS count increased as brain volume (as % of ICV) decreased (-0.33, 95%CI [-0.53 to -0.13], p=0.002). COMPARISON WITH EXISTING METHOD: BGPVS count and volume increased with the overall increase of BGPVS visual scores (2.11, 95%CI [1.36 to 2.86] for count and 0.022, 95%CI [0.012 to 0.031] for volume, p<0.001). Distributions for PVS count and visual scores were also similar. CONCLUSIONS: This semi-automatic method is applicable to clinical protocols and offers quantitative surrogates for PVS load. It shows good agreement with a visual rating scale and confirmed that BGPVS are associated with WMH and atrophy measurements. PMID- 26416616 TI - Lyme Disease Presenting as a Spontaneous Knee Effusion. AB - Musculoskeletal complaints, which are frequently associated with Lyme disease, often prompt patients to see a physician. In particular, transient episodes of spontaneous knee effusion are common early in the progression of Lyme disease, and, if left untreated, 60% of patients diagnosed with the disease develop Lyme arthritis. This disease is easily treated with antibiotics; therefore, inclusion of Lyme disease in the differential diagnosis as a potential cause of a spontaneous knee effusion can prevent the development of more severe symptoms associated with the disease. However, the time required to receive test results and the inconsistencies between serum and synovial tests can complicate diagnosis of the disease. PMID- 26416617 TI - Editorial: Calcium in Heart Disease: The Ubiquitous Ion. PMID- 26416618 TI - Association of left atrial function with incident atypical atrial flutter after atrial fibrillation ablation. AB - BACKGROUND: Symptomatic left atrial (LA) flutter (LAFL) is common after atrial fibrillation (AF) ablation. OBJECTIVE: The purpose of this study was to examine the association of baseline LA function with incident LAFL after AF ablation. METHODS: The source cohort included 216 patients with cardiac magnetic resonance (CMR) before initial AF ablation between 2010 and 2013. Patients who underwent cryoballoon or laser ablation, patients with AF during CMR, and those with suboptimal CMR, or missing follow-up data were excluded. Baseline LA volume and function were assessed by feature-tracking CMR analysis. RESULTS: The final cohort included 119 patients (mean age 58.9 +/- 11 years; 76.5% men; 70.6% patients with paroxysmal AF). During a median follow-up of 421 days (interquartile range 235-751 days), 22 patients (18.5%) had incident LAFL. Baseline LA volume was similar between the 2 groups. In contrast, baseline reservoir, conduit, and contractile function of the LA were significantly impaired in patients with incident LAFL. Baseline global peak longitudinal atrial strain (PLAS) <22.65% predicted incident LAFL with 86% sensitivity and 68% specificity (C statistic 0.76). In a multivariable model adjusting for age, heart failure, and LA volume, PLAS (hazard ratio 0.9 per % increase in PLAS; P = .003) and LA linear lesions (hazard ratio 2.94; P = .020) were independently associated with incident LAFL. The coexistence of PLAS <22.65% and linear lesions was associated with 9-fold increased hazard of incident LAFL. CONCLUSION: Baseline LA function and linear lesions were independently associated with incident LAFL after AF ablation. Linear lesions should be limited to selected cases, especially in patients with impaired LA function. PMID- 26416620 TI - Flecainide monotherapy is an option for selected patients with catecholaminergic polymorphic ventricular tachycardia intolerant of beta-blockade. PMID- 26416619 TI - Mitral valve prolapse and sudden cardiac arrest in the community. AB - BACKGROUND: Mitral valve prolapse (MVP) is relatively common in the general population with recently reported prevalence of 1% and familial clustering (Framingham Heart Study). However, its association with ventricular arrhythmias and sudden cardiac arrest (SCA) remains controversial. OBJECTIVES: The purpose of this study was to characterize the frequency and clinical profile of patients with MVP who suffer SCA in the community. METHODS: Patients with SCA cases were prospectively identified in the population-based Oregon Sudden Unexpected Death Study (population ~1 million). The presence of MVP was identified from echocardiograms recorded prior but unrelated to the SCA event. The detailed clinical profile of patients with SCA and MVP was compared with that of SCA patients without MVP to identify potential differences. RESULTS: A total of 729 SCA patients were evaluated over a 12-year period (mean age 69.5 +/- 14.8 years; 64.6% men). MVP was observed in 17 (2.3%) prior to the SCA event (95% confidence interval 1.2%-3.4%). Mitral regurgitation was present in 14 SCA patients with MVP (82.3%) and was moderate or severe in 10 (58.8%). Compared with SCA patients without MVP, SCA patients with MVP were younger (mean age 60.9 +/- 16.4 years vs 69.7 +/- 14.7 years; P = .02), with fewer risk factors (diabetes 5.9% vs 46.4%; P = .001; hypertension 41.2% vs 78.9%; P = .001) or known coronary disease (29.4% vs 65.6%; P < .001). CONCLUSION: MVP was observed in a small proportion (2.3%) of SCA patients in the general population, suggesting a low risk overall. Since SCA patients with MVP were characterized by younger age and relatively low cardiovascular comorbidity, a focus on imaging for valve structure/insufficiency as well as genetics could aid future risk stratification approaches. PMID- 26416621 TI - Diffuse fibrosis leads to a decrease in unipolar voltage: Validation in a swine model of premature ventricular contraction-induced cardiomyopathy. AB - BACKGROUND: Frequent premature ventricular contractions (PVCs) may lead to dilated cardiomyopathy. A leftward shift in the unipolar voltage distribution in patients with cardiomyopathy has also been described and attributed to increased fibrosis. OBJECTIVES: We established a swine model of PVC-induced cardiomyopathy and assessed (1) whether an increase in left ventricular fibrosis occurs and (2) whether increased fibrosis leads to a leftward shift in the unipolar voltage distribution. METHODS: Ten swine underwent implantation of ventricular pacemakers; 6 programmed to deliver a 50% PVC burden and 4 controls without pacing. Voltage maps were acquired at baseline and after 14 weeks of ventricular bigeminy. RESULTS: In the PVC group, left ventricular ejection fraction decreased from 67% +/- 7% to 44% +/- 15% (P < .05) with no change in controls (71% +/- 6% to 73% +/- 4%; P = .56). The fifth percentile of the bipolar and unipolar voltage distribution at baseline was 1.63 and 5.36 mV, respectively. In the control group, after 14 weeks of pacing there was no significant change in % bipolar voltage <1.5 mV (pre 1.2% vs post 2.2%; P = .34) or % unipolar voltage <5.5 mV (pre 4.0% vs post 3.5%; P = .20). In the PVC group, there was a significant increase in % unipolar voltage <5.5 mV (5.4% vs 12.6%; P < .01), with a leftward shift in the unipolar voltage distribution. Histologically, % fibrosis was increased in the PVC group (control 1.8% +/- 1.3% vs PVC 3.4% +/- 2.6%; P < .01). CONCLUSION: PVC-induced cardiomyopathy in swine leads to an increase in interstitial fibrosis and a leftward shift in the unipolar voltage distribution. These findings are consistent with findings in humans with PVC-induced cardiomyopathy. PMID- 26416625 TI - Towards defect-free 1-D GaAs/AlGaAs heterostructures based on GaAs nanomembranes. AB - We demonstrate the growth of defect-free zinc-blende GaAs nanomembranes by molecular beam epitaxy. Our growth studies indicate a strong impact of As4 re emission and shadowing in the growth rate of the structures. The highest aspect ratio structures are obtained for pitches around 0.7-1 MUm and a gallium rate of 1 A s(-1). The functionality of the membranes is further illustrated by the growth of quantum heterostructures (such as quantum wells) and the characterization of their optical properties at the nanoscale. This proves the potential of nanoscale membranes for optoelectronic applications. PMID- 26416622 TI - Structure and Antioxidant Activities of Proanthocyanidins from Elephant Apple (Dillenia indica Linn.). AB - Proanthocyanidins were isolated and purified from fruits of elephant apple (Dillenia indica Linn.) and their structural and bioactive properties were examined. Bate-Smith alcoholysis, FTIR, and (13) C NMR spectra revealed that elephant apple proanthocyanidins (EAPs) contained a dominant amount of B-type procyanidins (PC) with a minor amount of B-type prodelphinidins (PD) but no A type interflavan linkage. (13) C NMR spectrum indicated that the cis isomer was dominant in EAPs. The electron spray ionization and matrix-assisted laser desorption ionization time of flight mass spectra of EAPs showed the clear ion peaks corresponding to B-type PC dimer to B-type PD with degree of polymerization of 11. EAPs had strong antioxidant activity, which was evidenced by the high oxygen radical scavenging capacity at 1.06 * 10(4) MUmol TE/g and ferric reducing antioxidant power of 2320 MUmol Fe(II)/g. The results suggest that EAPs could be extracted to be used as promising functional food materials. PRACTICAL APPLICATION: In this study, the elephant apple proanthocyanidins (EAPs) with a yield of 0.23% were identified for the first time as dominant B-type poly(catechin/epicatechin) but no A-type interflavan linkage. EAPs had higher ORAC and FRAP values compared to commercial grape seed proanthocyanidins, suggesting that EAPs may be used as promising functional food materials. PMID- 26416623 TI - Local bacteria affect the efficacy of chemotherapeutic drugs. AB - In this study, the potential effects of bacteria on the efficacy of frequently used chemotherapies was examined. Bacteria and cancer cell lines were examined in vitro and in vivo for changes in the efficacy of cancer cell killing mediated by chemotherapeutic agents. Of 30 drugs examined in vitro, the efficacy of 10 was found to be significantly inhibited by certain bacteria, while the same bacteria improved the efficacy of six others. HPLC and mass spectrometry analyses of sample drugs (gemcitabine, fludarabine, cladribine, CB1954) demonstrated modification of drug chemical structure. The chemoresistance or increased cytotoxicity observed in vitro with sample drugs (gemcitabine and CB1954) was replicated in in vivo murine subcutaneous tumour models. These findings suggest that bacterial presence in the body due to systemic or local infection may influence tumour responses or off-target toxicity during chemotherapy. PMID- 26416626 TI - Stall no more at polyproline stretches with the translation elongation factors EF P and IF-5A. AB - Synthesis of polyproline proteins leads to translation arrest. To overcome this ribosome stalling effect, bacteria depend on a specialized translation elongation factor P (EF-P), being orthologous and functionally identical to eukaryotic/archaeal elongation factor e/aIF-5A (recently renamed 'EF5'). EF-P binds to the stalled ribosome between the peptidyl-tRNA binding and tRNA-exiting sites, and stimulates peptidyl-transferase activity, thus allowing translation to resume. In their active form, both EF-P and e/aIF-5A are post-translationally modified at a positively charged residue, which protrudes toward the peptidyl transferase center when bound to the ribosome. While archaeal and eukaryotic IF 5A strictly depend on (deoxy-) hypusination (hypusinylation) of a conserved lysine, bacteria have evolved diverse analogous modification strategies to activate EF-P. In Escherichia coli and Salmonella enterica a lysine is extended by beta-lysinylation and subsequently hydroxylated, whereas in Pseudomonas aeruginosa and Shewanella oneidensis an arginine in the equivalent position is rhamnosylated. Inactivation of EF-P, or the corresponding modification systems, reduces not only bacterial fitness, but also impairs virulence. Here, we review the function of EF-P and IF-5A and their unusual posttranslational protein modifications. PMID- 26416627 TI - Systemic Inflammatory Response Syndrome in End-Stage Heart Failure Patients Following Continuous-Flow Left Ventricular Assist Device Implantation: Differences in Plasma Redox Status and Leukocyte Activation. AB - The role of oxidative stress and leukocyte activation has not been elucidated in developing systemic inflammatory response syndrome (SIRS) in heart failure (HF) patients after continuous-flow left ventricular assist device (CF-LVAD) implantation. The objective of this study was to investigate the change of plasma redox status and leukocyte activation in CF-LVAD implanted HF patients with or without SIRS. We recruited 31 CF-LVAD implanted HF patients (16 SIRS and 15 non SIRS) and 11 healthy volunteers as the control. Pre- and postimplant blood samples were collected from the HF patients. Plasma levels of oxidized low density lipoprotein (oxLDL), malondialdehyde (MDA), total antioxidant capacity (TAC), superoxide dismutase (SOD) in erythrocyte, myeloperoxidase (MPO), and polymorphonuclear elastase (PMN-elastase) were measured. The HF patients had a preexisting condition of oxidative stress than healthy controls as evident from the higher oxLDL and MDA levels as well as depleted SOD and TAC. Leukocyte activation in terms of higher plasma MPO and PMN-elastase was also prominent in HF patients than controls. Persistent oxidative stress and reduced antioxidant status were found to be more belligerent in HF patients with SIRS after the implantation of CF-LVAD when compared with non-SIRS patients. Similar to oxidative stress, the activation of blood leukocyte was significantly highlighted in SIRS patients after implantation compared with non-SIRS. We identified that the plasma redox status and leukocyte activation became more prominent in CF-LVAD implanted HF patients who developed SIRS. Our findings suggest that plasma biomarkers of oxidative stress and leukocyte activation may be associated with the development of SIRS after CF-LVAD implant surgery. PMID- 26416631 TI - Huge pseudoaneurysm and cystic adventitial disease from popliteal artery entrapment. PMID- 26416628 TI - G protein-coupled estrogen receptor 1 (GPER 1) mediates estrogen-induced, proliferation of leiomyoma cells. AB - G protein-coupled estrogen receptor 1 (GPER-1, formerly known as GPR30) has been proposed as the receptor for estrogen-induced, growth of leiomyomas though its precise mechanisms of action are not clear. We obtained leiomyoma cells (LC) and normal smooth muscle cells from 28 women (n = 28, median age 38 years, median parity 1.0). We incubated them with 17-beta estradiol (E(2)), after blocking, or upregulating, expression of GPER-1 with ICI182,780 (a GPER-1 agonist) and siGPR30, respectively. We evaluated the role of GPER-1 in the mitogen-activated protein kinase (MAPK) signaling pathway using Western blot analysis. We studied cell proliferation with 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide, and, mitotic activity with phosphohistone H3 (PPH3) expression in leiomyoma, and, matched, normal, smooth muscle tissues using standard immunohistochemistry. Downregulation of GPER-1 expression with siGPR30 partially attenuated the E(2)-activated MAPK signaling pathway (p < 0.01). Upregulation of GPER-1 with ICI182,780 enhanced the E(2)-activated MAPK signaling pathway (p < 0.01). ICI182,780 enhanced E(2)-induced proliferation of LC (p < 0.01), while knock down of the GPER-1 gene with GPER-1 small interfering RNA partially inhibited E(2)-induced cell proliferation (p < 0.01). There were no significant differences in PPH3 expression between LCs and normal smooth muscle tissues (p > 0.05). Neither ICI182,780 nor siGPR30 increased mitosis in LCs (p > 0.05). Our results indicate that GPER-1 mediates proliferation of estrogen-induced, LC by activating the MAPK pathway, and, not by promoting mitosis. PMID- 26416632 TI - Aortopulmonary window and interrupted aortic arch with Eisenmenger syndrome in an adult. PMID- 26416633 TI - Letter by Guazzi regarding article, "right ventricular function in heart failure with preserved ejection fraction: a community-based study". PMID- 26416634 TI - Response to letter regarding article, "right ventricular function in heart failure with preserved ejection fraction: a community-based study". PMID- 26416635 TI - Letter by Seropian and Abbate regarding article, "effect of tumor necrosis factor inhibitor treatment on proximal right coronary chronic total occlusion in a patient with rheumatoid arthritis". PMID- 26416636 TI - Response to letter regarding article, "effect of tumor necrosis factor inhibitor treatment on proximal right coronary chronic total occlusion in a patient with rheumatoid arthritis". PMID- 26416637 TI - Letter by Shah and Buch regarding article, "prasugrel plus aspirin beyond 12 months is associated with improved outcomes after TAXUS Liberte paclitaxel eluting coronary stent placement". PMID- 26416638 TI - Letter by Jeger and Pfisterer regarding article, "prasugrel plus aspirin beyond 12 months is associated with improved outcomes after TAXUS Liberte paclitaxel eluting coronary stent placement". PMID- 26416639 TI - Response to letters regarding article, "prasugrel plus aspirin beyond 12 months is associated with improved outcomes after TAXUS Liberte paclitaxel-eluting coronary stent placement". PMID- 26416640 TI - Correction. PMID- 26416641 TI - Sphingolipids contribute to acetic acid resistance in Zygosaccharomyces bailii. AB - Lignocellulosic raw material plays a crucial role in the development of sustainable processes for the production of fuels and chemicals. Weak acids such as acetic acid and formic acid are troublesome inhibitors restricting efficient microbial conversion of the biomass to desired products. To improve our understanding of weak acid inhibition and to identify engineering strategies to reduce acetic acid toxicity, the highly acetic-acid-tolerant yeast Zygosaccharomyces bailii was studied. The impact of acetic acid membrane permeability on acetic acid tolerance in Z. bailii was investigated with particular focus on how the previously demonstrated high sphingolipid content in the plasma membrane influences acetic acid tolerance and membrane permeability. Through molecular dynamics simulations, we concluded that membranes with a high content of sphingolipids are thicker and more dense, increasing the free energy barrier for the permeation of acetic acid through the membrane. Z. bailii cultured with the drug myriocin, known to decrease cellular sphingo-lipid levels, exhibited significant growth inhibition in the presence of acetic acid, while growth in medium without acetic acid was unaffected by the myriocin addition. Furthermore, following an acetic acid pulse, the intracellular pH decreased more in myriocin-treated cells than in control cells. This indicates a higher inflow rate of acetic acid and confirms that the reduction in growth of cells cultured with myriocin in the medium with acetic acid was due to an increase in membrane permeability, thereby demonstrating the importance of a high fraction of sphingolipids in the membrane of Z. bailii to facilitate acetic acid resistance; a property potentially transferable to desired production organisms suffering from weak acid stress. PMID- 26416642 TI - Letter in response to manuscript IJC-D-15-04003 entitled "Comment on antidepressant use in cardiovascular diseases" by Dr. Onur Durmaz. PMID- 26416643 TI - Carbon-bridged oligo(p-phenylenevinylene)s for photostable and broadly tunable, solution-processable thin film organic lasers. AB - Thin film organic lasers represent a new generation of inexpensive, mechanically flexible devices for spectroscopy, optical communications and sensing. For this purpose, it is desired to develop highly efficient, stable, wavelength-tunable and solution-processable organic laser materials. Here we report that carbon bridged oligo(p-phenylenevinylene)s serve as optimal materials combining all these properties simultaneously at the level required for applications by demonstrating amplified spontaneous emission and distributed feedback laser devices. A series of six compounds, with the repeating unit from 1 to 6, doped into polystyrene films undergo amplified spontaneous emission from 385 to 585 nm with remarkably low threshold and high net gain coefficients, as well as high photostability. The fabricated lasers show narrow linewidth (<0.13 nm) single mode emission at very low thresholds (0.7 kW cm(-2)), long operational lifetimes (>10(5) pump pulses for oligomers with three to six repeating units) and wavelength tunability across the visible spectrum (408-591 nm). PMID- 26416644 TI - How can collaboration be strengthened between public health and primary care? A Dutch multiple case study in seven neighbourhoods. AB - BACKGROUND: Although public health and primary care share the goal of promoting the health and wellbeing of the public, the two health sectors find it difficult to develop mutually integrated plans and to collaborate with each other. The aim of this multiple case study was to compare seven neighbourhoods in which a stepwise approach based on two central tools (district health profile and policy dialogue) was used to develop integrated district plans and promote collaboration. METHODS: The stepwise approach involved the following steps: 1 Getting to know the neighbourhood, 2 Assembling the workgroup, 3 Analysing the neighbourhood, 4 Developing a district health profile, 5 Preparing policy dialogue, 6 Holding local dialogues, 7 Embedding integrated district plans and collaboration. To supervise this process, a core team was assembled for each neighbourhood, consisting of people drawn from both public health and primary care. Both the use of the two tools and the collaboration were studied by means of documentary analysis, interviews, questionnaires and observations. RESULTS: The seven neighbourhoods differed in the way the two tools of the stepwise approach were used: general versus focused profiles, the actors involved, the aims of the dialogue or the intensity of the steps. There were also similarities: profile indicators (e.g., population prognosis, vulnerability) and dialogue themes (e.g., obesity, social cohesion). The local actors experienced that the combination of both tools facilitates the process of bringing public health and primary care closer together, and that it is essential to invest sufficiently in the integration of profile data and in involving appropriate actors in the dialogue (e.g., GPs, residents). Collaboration was perceived as positive (e.g., feels involved, focus on consensus), but a starting process. Local actors also believe that the stepwise approach supported the process. CONCLUSION: A stepwise approach involving the combined use of district health profiles and policy dialogues promotes the integrated planning of health activities and facilitates collaboration between public health and primary care at the local level. Local differences may arise in the intensity and form of the various steps, but because they are practical and clearly defined, they remain transferrable to other neighbourhoods. PMID- 26416645 TI - Progression of cervical dilatation. PMID- 26416647 TI - Pioglitazone--when is a prescription drug safe? PMID- 26416646 TI - CALHM1 and its polymorphism P86L differentially control Ca2+homeostasis, mitogen activated protein kinase signaling, and cell vulnerability upon exposure to amyloid beta. AB - The mutated form of the Ca2+channel CALHM1 (Ca2+homeostasis modulator 1), P86L CALHM1, has been correlated with early onset of Alzheimer's disease (AD). P86L CALHM1 increases production of amyloid beta (Abeta) upon extracellular Ca2+removal and its subsequent addback. The aim of this study was to investigate the effect of the overexpression of CALHM1 and P86L-CALHM, upon Abeta treatment, on the following: (i) the intracellular Ca2+signal pathway; (ii) cell survival proteins ERK1/2 and Ca2+/cAMP response element binding (CREB); and (iii) cell vulnerability after treatment with Abeta. Using aequorins to measure the effect of nuclear Ca2+concentrations ([Ca2+]n ) and cytosolic Ca2+concentrations ([Ca2+]c ) on Ca2+entry conditions, we observed that baseline [Ca2+]n was higher in CALHM1 and P86L-CALHM1 cells than in control cells. Moreover, exposure to Abeta affected [Ca2+]c levels in HeLa cells overexpressing CALHM1 and P86L-CALHM1 compared with control cells. Treatment with Abeta elicited a significant decrease in the cell survival proteins p-ERK and p-CREB, an increase in the activity of caspases 3 and 7, and more frequent cell death by inducing early apoptosis in P86L-CALHM1-overexpressing cells than in CALHM1 or control cells. These results suggest that in the presence of Abeta, P86L-CALHM1 shifts the balance between neurodegeneration and neuronal survival toward the stimulation of pro-cytotoxic pathways, thus potentially contributing to its deleterious effects in AD. PMID- 26416650 TI - Asymmetry in prefrontal resting-state EEG spectral power underlies individual differences in phasic and sustained cognitive control. AB - In our daily life, we constantly exert sustained and phasic cognitive control processes to manage multiple competing task sets and rapidly switch between them. Increasing research efforts are attempting to unveil how the brain mediates these processes, highlighting the importance of the prefrontal cortex. An intriguing question concerns the influence of hemispheric asymmetries and whether it may be generalized to different cognitive domains depending on lateralized processing. Another currently open question concerns the underlying causes of the observed huge inter-individual variability in cognitive control abilities. Here we tackle these issues by investigating whether participants' hemispheric asymmetry in intrinsic (i.e., resting-state-related) brain dynamics can reflect differences in their phasic and/or sustained cognitive control abilities regardless of the cognitive domain. To this aim, we recorded human participants' resting-state electroencephalographic activity and performed a source-based spectral analysis to assess their lateralized brain dynamics at rest. Moreover, we used three task switching paradigms involving different cognitive domains to assess participants' domain-general phasic and sustained cognitive control abilities. By performing a series of correlations and an intersection analysis, we showed that participants with stronger left- and right-lateralized intrinsic brain activity in the middle frontal gyrus were more able, respectively, to exert phasic and sustained cognitive control. We propose that the variability in participants' prefrontal hemispheric asymmetry in the intrinsic electrophysiological spectral profile reflects individual differences in preferentially engaging either the left lateralized, phasic or the right-lateralized, sustained cognitive control processes to regulate their behavior in response to changing task demands, regardless of the specific cognitive domain involved. PMID- 26416648 TI - Vascular autorescaling of fMRI (VasA fMRI) improves sensitivity of population studies: A pilot study. AB - The blood oxygenation level-dependent (BOLD) signal is widely used for functional magnetic resonance imaging (fMRI) of brain function in health and disease. The statistical power of fMRI group studies is significantly hampered by high inter subject variance due to differences in baseline vascular physiology. Several methods have been proposed to account for physiological vascularization differences between subjects and hence improve the sensitivity in group studies. However, these methods require the acquisition of additional reference scans (such as a full resting-state fMRI session or ASL-based calibrated BOLD). We present a vascular autorescaling (VasA) method, which does not require any additional reference scans. VasA is based on the observation that slow oscillations (<0.1Hz) in arterial blood CO2 levels occur naturally due to changes in respiration patterns. These oscillations yield fMRI signal changes whose amplitudes reflect the blood oxygenation levels and underlying local vascularization and vascular responsivity. VasA estimates proxies of the amplitude of these CO2-driven oscillations directly from the residuals of task related fMRI data without the need for reference scans. The estimates are used to scale the amplitude of task-related fMRI responses, to account for vascular differences. The VasA maps compared well to cerebrovascular reactivity (CVR) maps and cerebral blood volume maps based on vascular space occupancy (VASO) measurements in four volunteers, speaking to the physiological vascular basis of VasA. VasA was validated in a wide variety of tasks in 138 volunteers. VasA increased t-scores by up to 30% in specific brain areas such as the visual cortex. The number of activated voxels was increased by up to 200% in brain areas such as the orbital frontal cortex while still controlling the nominal false positive rate. VasA fMRI outperformed previously proposed rescaling approaches based on resting-state fMRI data and can be readily applied to any task-related fMRI data set, even retrospectively. PMID- 26416649 TI - Transcranial functional ultrasound imaging of the brain using microbubble enhanced ultrasensitive Doppler. AB - Functional ultrasound (fUS) is a novel neuroimaging technique, based on high sensitivity ultrafast Doppler imaging of cerebral blood volume, capable of measuring brain activation and connectivity in rodents with high spatiotemporal resolution (100MUm, 1ms). However, the skull attenuates acoustic waves, so fUS in rats currently requires craniotomy or a thinned-skull window. Here we propose a non-invasive approach by enhancing the fUS signal with a contrast agent, inert gas microbubbles. Plane-wave illumination of the brain at high frame rate (500Hz compounded sequence with three tilted plane waves, PRF=1500Hz with a 128 element 15MHz linear transducer), yields highly-resolved neurovascular maps. We compared fUS imaging performance through the intact skull bone (transcranial fUS) versus a thinned-skull window in the same animal. First, we show that the vascular network of the adult rat brain can be imaged transcranially only after a bolus intravenous injection of microbubbles, which leads to a 9dB gain in the contrast to-tissue ratio. Next, we demonstrate that functional increase in the blood volume of the primary sensory cortex after targeted electrical-evoked stimulations of the sciatic nerve is observable transcranially in presence of contrast agents, with high reproducibility (Pearson's coefficient rho=0.7+/-0.1, p=0.85). Our work demonstrates that the combination of ultrafast Doppler imaging and injection of contrast agent allows non-invasive functional brain imaging through the intact skull bone in rats. These results should ease non-invasive longitudinal studies in rodents and open a promising perspective for the adoption of highly resolved fUS approaches for the adult human brain. PMID- 26416651 TI - V1 surface size predicts GABA concentration in medial occipital cortex. AB - A number of recent studies have established a link between behavior and the anatomy of the primary visual cortex (V1). However, one often-raised criticism has been that these studies provide little insight into the mechanisms of the observed relationships. As inhibitory neural interactions have been postulated as an important mechanism for those behaviors related to V1 anatomy, we measured the concentration of inhibitory gamma-amino butyric acid (GABA) in the medial occipital cortex where V1 is located using magnetic resonance spectroscopy (MRS) and estimated the surface area of V1 using fMRI retinotopic mapping. We found a significant positive relationship between GABA concentration and V1 surface area. This relationship was present irrespective of whether the MRS voxel had a fixed size across participants or was proportionally sized to each individual's V1 surface area. Hence, individuals with a larger V1 had a higher GABA concentration in the medial occipital cortex. By tying together V1 size and GABA concentration, our findings point towards individual differences in the level of neural inhibition that might partially mediate the relationships between behavior and V1 neuroanatomy. In addition, they illustrate how stable microscopic properties of neural activity and function are reflected in macro-measures of V1 structure. PMID- 26416652 TI - FIACH: A biophysical model for automatic retrospective noise control in fMRI. AB - Different noise sources in fMRI acquisition can lead to spurious false positives and reduced sensitivity. We have developed a biophysically-based model (named FIACH: Functional Image Artefact Correction Heuristic) which extends current retrospective noise control methods in fMRI. FIACH can be applied to both General Linear Model (GLM) and resting state functional connectivity MRI (rs-fcMRI) studies. FIACH is a two-step procedure involving the identification and correction of non-physiological large amplitude temporal signal changes and spatial regions of high temporal instability. We have demonstrated its efficacy in a sample of 42 healthy children while performing language tasks that include overt speech with known activations. We demonstrate large improvements in sensitivity when FIACH is compared with current methods of retrospective correction. FIACH reduces the confounding effects of noise and increases the study's power by explaining significant variance that is not contained within the commonly used motion parameters. The method is particularly useful in detecting activations in inferior temporal regions which have proven problematic for fMRI. We have shown greater reproducibility and robustness of fMRI responses using FIACH in the context of task induced motion. In a clinical setting this will translate to increasing the reliability and sensitivity of fMRI used for the identification of language lateralisation and eloquent cortex. FIACH can benefit studies of cognitive development in young children, patient populations and older adults. PMID- 26416654 TI - Stability of Crushed Tedizolid Phosphate Tablets for Nasogastric Tube Administration. AB - Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infections. To determine whether the expected dose of tedizolid phosphate can be delivered via nasogastric tube in patients who have difficulty swallowing and in whom venous access is not suitable, this in vitro study evaluated the recovery of tedizolid phosphate 200-mg tablets after crushing, dispersion in water, and passage through a nasogastric tube. To analyze the chemical stability of the crushed tablet dispersed in water, the aqueous preparation was assayed initially after dispersion and again after 4 h at room temperature. Recovery of tedizolid phosphate after the crushed tablets were dispersed in water and passed through nasogastric tubes ranged from 92.5 to 97.1 %, which is within the specified acceptance criteria of 90 to 110 %. There was no significant change in recovery values after 4 h of storage at room temperature (93.9 % initially and 94.7 % after 4 h). The stability and recovery findings support the feasibility of administering an aqueous dispersion of crushed tedizolid phosphate tablets through a nasogastric tube in patients who have difficulty swallowing and in whom intravenous administration is not possible. PMID- 26416653 TI - Determinant Factors of the Direct Medical Costs Associated with Genotype 1 Hepatitis C Infection in Treatment-Experienced Patients. AB - OBJECTIVE: Limited evidence is available on predictors of medical resource utilization (MRU) and related direct costs, especially in treatment-experienced patients infected with genotype 1 hepatitis C virus (HCV). This study aimed at investigating patient and treatment characteristics that predict MRU and related non-drug costs in treatment-experienced patients with chronic hepatitis C (CHC) treated with simeprevir (SMV) or telapravir (TVR) in combination with pegylated interferon and ribavirin (PegIFN/R). PATIENTS AND METHODS: A total of 709 patients who completed the 72-week ATTAIN trial were included in the study. Cost data were analysed from the UK NHS perspective. Descriptive statistics and regression analyses were used to determine patterns and predictors of total MRU related costs associated with SMV/PegIFN/R and TVR/PegIFN/R. RESULTS: Independent predictors for total MRU-related costs were age, region and the following interaction terms: (1) gender * F3-F4 METAVIR score * baseline viral load (BLVL), (2) body mass index (BMI) * F3-F4 METAVIR score * prior response to PegIFN/R and (3) gender * achievement of SVR at 12 weeks (SVR12) * BLVL. A F3-F4 METAVIR score was a stronger predictor of total MRU-related costs than SVR12. Predictors of adverse events included older age, female gender, low BMI, TVR/PegIFN/R and SVR12. Wilcoxon rank sum test revealed comparable total MRU-related costs between SMV/PegIFN/R and TVR/PegIFN/R. CONCLUSION: To the best of our knowledge, this study is the first to describe the relationship between commonly admitted predictors of MRU-related costs and their joint effect on total MRU-related costs in treatment-experienced patients with CHC. The identified predictors of MRU related costs suggest that significant treatment costs can be avoided by starting treatment early before the disease progresses. Furthermore, adverse events seem to be the most important factor to take into consideration for the choice of treatment, especially when therapeutic options are associated with similar levels of medical resource utilization and associated costs. PMID- 26416655 TI - Rivaroxaban: An Evaluation of its Cardiovascular Benefit-Risk Profile Across Indications Based on Numbers Needed to Treat or Harm, and on Clinically Meaningful Endpoint Comparisons. AB - The decision to prescribe anticoagulant therapy must consider the balance between reducing the risk of thromboembolic events and increasing the risk of bleeding. Although assessments of net clinical outcomes with oral anticoagulants are not new, this article presents an evaluation of benefit-risk by considering only events of substantial and comparable clinical relevance (i.e., events with serious long-term sequelae likely to have irreversible consequences, including death). This is based on the concept of the number of patients who need to be treated to elicit one beneficial [number needed to treat (NNT)] or harmful [number needed to harm (NNH)] event. The approach is illustrated using data from phase III trials of rivaroxaban, selected because it has the broadest range of approved indications of the novel oral anticoagulants. For example, in the ATLAS ACS 2 TIMI 51 trial of rivaroxaban plus standard antiplatelet therapy following an acute coronary syndrome event, the current analysis demonstrates that 63 patients need to be treated (over 24 months) to prevent one all-cause mortality event compared with placebo (NNT = 63). Conversely, 500 patients need to be treated to cause one additional intracranial hemorrhage (NNH = 500). The most relevant and clinically meaningful assessment of benefit-risk may therefore be achieved by focusing only on events of greatest concern to patients and physicians, namely those with (potentially) long-lasting, severe consequences. Although there are clear limitations to this type of analysis, rivaroxaban appears to demonstrate a broadly favorable benefit-risk profile across multiple clinical indications. PMID- 26416656 TI - Infectious Diseases Society of America and Gain-of-Function Experiments With Pathogens Having Pandemic Potential. PMID- 26416657 TI - Gain-of-Function Research and the Relevance to Clinical Practice. AB - The ongoing moratorium on gain-of-function (GOF) research with highly pathogenic avian influenza virus, severe acute respiratory syndrome coronavirus, and Middle East respiratory syndrome coronavirus has drawn attention to the current debate on these research practices and the potential benefits and risks they present. While much of the discussion has been steered by members of the microbiology and policy communities, additional input from medical practitioners will be highly valuable toward developing a broadly inclusive policy that considers the relative value and harm of GOF research. This review attempts to serve as a primer on the topic for the clinical community by providing a historical context for GOF research, summarizing concerns about its risks, and surveying the medical products that it has yielded. PMID- 26416659 TI - Preparation and Characterization of Polymeric Surfactants Based on Epoxidized Soybean Oil Grafted Hydroxyethyl Cellulose. AB - Epoxidized soybean oil (ESO) grafted hydroxyethyl cellulose (HEC) was prepared via ring-opening polymerization, in which the hydroxyl groups of HEC acted as initiators and the polymeric ESO were covalently bonded to the HEC. Hydrolysis of ESO-grafted HEC (ESO-HEC) was performed with sodium hydroxide, and the hydrolyzed ESO-HEC (H-ESO-HEC) products were characterized via Fourier transform infrared (FT-IR) and (1)H and (13)C nuclear magnetic resonance (NMR) spectroscopies, high temperature gel permeation chromatography (HT-GPC), and differential scanning calorimetry (DSC). The results indicated that ring-opening polymerization of ESO occurred with the hydroxyl groups of HEC as initiators. The molecular weights of the H-ESO-HEC products were varied by adjusting the mass ratio of HEC and ESO. Through neutralizing the carboxylic acid of H-ESO-HEC with sodium hydroxide, novel polymeric surfactants (H-ESO-HEC-Na) were obtained, and the effects of polymeric surfactants on the surface tension of water were investigated as a function of concentration of H-ESO-HEC-Na. The H-ESO-HEC-Na was effective at lowering the surface tension of water to 26.33 mN/m, and the critical micelle concentration (CMC) value decreased from 1.053 to 0.157 g/L with increases in molecular weights of the polymeric surfactants. Rheological measurements indicated that the H-ESO-HEC-Na solutions changed from pseudoplastic property to Newtonian with increasing shear rate. PMID- 26416658 TI - Cathepsin K Contributes to Cavitation and Collagen Turnover in Pulmonary Tuberculosis. AB - Cavitation in tuberculosis enables highly efficient person-to-person aerosol transmission. We performed transcriptomics in the rabbit cavitary tuberculosis model. Among 17 318 transcripts, we identified 22 upregulated proteases. Five type I collagenases were overrepresented: cathepsin K (CTSK), mast cell chymase-1 (CMA1), matrix metalloproteinase 1 (MMP-1), MMP-13, and MMP-14. Studies of collagen turnover markers, specifically, collagen type I C-terminal propeptide (CICP), urinary deoxypyridinoline (DPD), and urinary helical peptide, revealed that cavitation in tuberculosis leads to both type I collagen destruction and synthesis and that proteases other than MMP-1, MMP-13, and MMP-14 are involved, suggesting a key role for CTSK. We confirmed the importance of CTSK upregulation in human lung specimens, using immunohistochemical analysis, which revealed perigranulomatous staining for CTSK, and we showed that CTSK levels were increased in the serum of patients with tuberculosis, compared with those in controls (3.3 vs 0.3 ng/mL; P = .005). PMID- 26416660 TI - Femicide and murdered women's children: which future for these children orphans of a living parent? AB - BACKGROUND: To assess the prevalence of femicides in Italy over the last three years and the potential long lasting effects of these traumatic events for the children of a woman who dies a violent death. METHODS: The data used in this study come from an internet search for the number of femicides occurring in Italy between 1(st) January, 2012 and 31(st) October, 2014. RESULTS: The total number of femicides was 319; the average age of murdered women was 47.50 +/- 19.26. Cold arms in the form of sharp object -mostly knives- have caused the death of 102/319 women; firearms were used in 87/319 cases; asphyxiation was the chosen method in 52/319 cases. About the place where the femicides occurred, 209/319 were committed inside the victim's house. Children of women who died a violent death were 417 with a total of 180 minors in less than three years. A total of 52/417 children were witness to the killing and, among these 30/52 were minors; in 18/417 cases, children were murdered together with their mother and among these 9/18 were minors. CONCLUSIONS: Long-term studies are needed to ascertain what happens to these children, to understand what are the most appropriate psychological treatments, the best decisions about the contact with their father and the best placement for these children. PMID- 26416661 TI - Elevated microRNA-25 inhibits cell apoptosis in lung cancer by targeting RGS3. AB - The non-small-cell lung cancer (NSCLC) is the most common type of lung cancer that affects the human health. But, the underlying mechanisms and effective therapy are still absent. MicroRNAs (miRNAs) are small RNAs that specifically bind to the 3' untranslated region (3'UTR) of its target and regulate the protein level of the target at post-transcriptional level. A lot of miRNAs had been found abnormally regulated in the NSCLC patients, and understanding their specific roles in the pathogenesis of NSCLC will help us to develop novel therapeutic approaches. Here, we reported that miR-25 is dramatically upregulated in NSCLC tissues and negatively correlated with RGS3 protein. A conserved binding sequence in the 3'UTR of RGS3 gene to miR-25 was identified, and overexpression of miR-25 induces the RGS3 inhibition. Importantly, suppression of miR-25 facilitates the cell apoptosis and retards the cell proliferation in A549 and H520 cell lines. Our data provide a novel miR-25/RGS3 signal in the development of lung cancer. PMID- 26416662 TI - Affect, Affective Variability, and Physical Health: Results from a Population Based Investigation in China. AB - BACKGROUND: There is good evidence linking positive affect with adaptive psychological and physical health outcomes and negative affect with maladaptive outcomes, in multiple contexts and samples. However, recent research has suggested that the fluctuation of emotions, known as affective variability, may also be an important correlate of individuals' health. PURPOSE: The present study examined the relationship between affect, affective variability, and self reported health status in a large representative sample of adults in China. METHOD: We analyzed cross-sectional data retrieved from the World Health Organization's study on global ageing and adults' health. A total of 15,050 Chinese adults (aged between 18 and 99) from China reported their affective experiences during the previous day, perceived health, and their history of multiple chronic illnesses from their medical records (stroke, angina, diabetes, chronic lung disease, depression, and hypertension). Hierarchical multiple regression and logistic regression analyses were employed to analyze the data. RESULTS: Independent of individuals' mean levels of affect, affective variability was negatively related to subjective health conditions and positively related to diagnosed illness status, after controlling for demographic variables. Results suggest that affective variability increases the likelihood of reported impaired health and diagnosis of affect-related illnesses such as angina and depression. CONCLUSION: The present study highlighted the importance of studying the impact of affective variability, in addition to that of mean affect levels, on health. PMID- 26416665 TI - Green Propolis: Thirteen Constituents of Polar Extract and Total Flavonoids Evaluated During Six Years through RP-HPLC. AB - In order to verify the chemical qualities of polar extract of Green Propolis produced in the State of Minas Gerais, Brazil, was analyzed by means of RP-HPLC, the concentration of eleven flavonoids, Artepillin C and p-coumaric acid were analyzed by means of RP-HPLC. Samples were collected in the months of February, March, May, July, September, and October, during a period of six years (2008 to 2013) and the results compared with purchased standards. Artepillin C was the main constituent (80-90%) found in all samples. Lower concentrations of p coumaric acid, chrysin and kaempferide were observed in March, and of ricin and galangin in September. Respectively, these months correspond to the end of Summer and Spring period in Brazil. The variation in concentration of the analyzed constituents always occurred in the same month, during the entire six years of evaluation period. All thirteen constituents of Green Propolis were detected throughout the study period, and the average concentration of each one was similar in relation to the respective monthly collection period of each year. Due to similarities among chemical constituents of Green Propolis with those present in B. dracuncufolia, this plant was identified as being the principal source of Green Propolis. PMID- 26416663 TI - Rapid metagenomic identification of viral pathogens in clinical samples by real time nanopore sequencing analysis. AB - We report unbiased metagenomic detection of chikungunya virus (CHIKV), Ebola virus (EBOV), and hepatitis C virus (HCV) from four human blood samples by MinION nanopore sequencing coupled to a newly developed, web-based pipeline for real time bioinformatics analysis on a computational server or laptop (MetaPORE). At titers ranging from 10(7)-10(8) copies per milliliter, reads to EBOV from two patients with acute hemorrhagic fever and CHIKV from an asymptomatic blood donor were detected within 4 to 10 min of data acquisition, while lower titer HCV virus (1 * 10(5) copies per milliliter) was detected within 40 min. Analysis of mapped nanopore reads alone, despite an average individual error rate of 24 % (range 8 49 %), permitted identification of the correct viral strain in all four isolates, and 90 % of the genome of CHIKV was recovered with 97-99 % accuracy. Using nanopore sequencing, metagenomic detection of viral pathogens directly from clinical samples was performed within an unprecedented <6 hr sample-to-answer turnaround time, and in a timeframe amenable to actionable clinical and public health diagnostics. PMID- 26416666 TI - Branchial cysts: an unusual cause of a mediastinal mass: a case report. AB - INTRODUCTION: Complex embryological processes form the head and neck of humans. It is not flawless; remnants lead to sinuses or cysts, commonly in the head and neck region. CASE PRESENTATION: We present the a case of an 8-year-old boy, a primary school pupil, from rural Kenya with chronic cough, wheezing, difficulty in breathing and dyspnea on exertion. He was treated with antibiotics and antitubercular drugs without improvement prior to referral to our hospital. A computed tomography scan of his chest revealed a superior mediastinal mass extending into his neck. A diagnosis of a brachial cleft cyst was made and our patient underwent a successful excision of the mass through a median strenotomy and neck dissection. CONCLUSIONS: Branchial cysts of the neck are common, accounting for 20% of pediatric neck masses. Usually they present as a neck mass but in our case it presented as a mediastinal mass, which is a very rare clinical presentation. Surgical excision is the mainstay of treatment. To the surgeon, the embryology and anatomy should be absolutely clear as dissection may be challenging due to the close proximity and variable course of the cystic stalk to major neck vessels and nerves. PMID- 26416664 TI - Global comparison of chromosome X genes of pulmonary telocytes with mesenchymal stem cells, fibroblasts, alveolar type II cells, airway epithelial cells, and lymphocytes. AB - BACKGROUND: Telocytes (TCs) are suggested as a new type of interstitial cells with specific telopodes. Our previous study evidenced that TCs differed from fibroblasts and stem cells at the aspect of gene expression profiles. The present study aims to search the characters and patterns of chromosome X genes of TC specific or TC-dominated gene profiles and fingerprints, investigate the network of principle genes, and explore potential functional association. METHODS: We compared gene expression profiles in chromosome X of pulmonary TCs with mesenchymal stem cells (MSC), fibroblasts (Fb), alveolar type II cells (ATII), airway basal cells (ABC), proximal airway cells (PAC), CD8(+) T cells come from bronchial lymph nodes (T-BL), or CD8(+) T cells from lungs (T-L) by global analyses, and selected the genes which were consistently up or down regulated (>1 fold) in TCs compared to other cells as TC-specific genes. The functional and characteristic networks were identified and compared by bioinformatics tools. RESULTS: We selected 31 chromosome X genes as the TC-specific or dominated genes, among which 8 up-regulated (Flna, Msn, Cfp, Col4a5, Mum1l1, Rnf128, Syn1, and Srpx2) and 23 down-regulated (Abcb7, Atf1, Ddx26b, Drp2, Fam122b, Gyk, Irak1, Lamp2, Mecp2, Ndufb11, Ogt, Pdha1, Pola1, Rab9, Rbmx2, Rhox9, Thoc2, Vbp1, Dkc1, Nkrf, Piga, Tmlhe and Tsr2), as compared with other cells. CONCLUSIONS: Our data suggested that gene expressions of chromosome X in TCs are different with those in other cells in the lung tissue. According to the selected TC-specific genes, we infer that pulmonary TCs function as modulators which may enhance cellular growth and migration, resist senescence, protect cells from external stress, regulate immune responses, participate in tissue remodeling and repair, regulate neural function, and promote vessel formation. PMID- 26416667 TI - Fine-Mapping the Wheat Snn1 Locus Conferring Sensitivity to the Parastagonospora nodorum Necrotrophic Effector SnTox1 Using an Eight Founder Multiparent Advanced Generation Inter-Cross Population. AB - The necrotrophic fungus Parastagonospora nodorum is an important pathogen of one of the world's most economically important cereal crops, wheat (Triticum aestivum L.). P. nodorum produces necrotrophic protein effectors that mediate host cell death, providing nutrients for continuation of the infection process. The recent discovery of pathogen effectors has revolutionized disease resistance breeding for necrotrophic diseases in crop species, allowing often complex genetic resistance mechanisms to be broken down into constituent parts. To date, three effectors have been identified in P. nodorum. Here we use the effector, SnTox1, to screen 642 progeny from an eight-parent multiparent advanced generation inter cross (i.e., MAGIC) population, genotyped with a 90,000-feature single-nucleotide polymorphism array. The MAGIC founders showed a range of sensitivity to SnTox1, with transgressive segregation evident in the progeny. SnTox1 sensitivity showed high heritability, with quantitative trait locus analyses fine-mapping the Snn1 locus to the short arm of chromosome 1B. In addition, a previously undescribed SnTox1 sensitivity locus was identified on the long arm of chromosome 5A, termed here QSnn.niab-5A.1. The peak single-nucleotide polymorphism for the Snn1 locus was converted to the KASP genotyping platform, providing breeders and researchers a simple and cheap diagnostic marker for allelic state at Snn1. PMID- 26416670 TI - Finite-size effects and interactions in artificial graphene formed by repulsive scatterers. AB - We carry out a numerical real-space study on electrons confined in a two dimensional triangular lattice of repulsive scattering centres. The system represents a qualitative model of molecular graphene, where the electron gas is confined between the scattering molecules in a hexagonal configuration. Our main interest is, on one hand, in the comparability of a finite system (flake) and a fully periodic one, and, on the other hand, in the role of the Coulombic electron electron interactions and the relative strength of the scattering centres. Our real-space study shows in detail how the density of states of the fully periodic system-containing the Dirac point-is gradually formed as the size of the flake is increased. Good qualitative agreement with the experimental density of states is obtained. Our study confirms the minor role of the electron-electron interactions with selected system parameters, and shows in detail that large scattering amplitudes are required to obtain a distinctive Dirac point in the density of states. PMID- 26416669 TI - Toppled television sets and head injuries in the pediatric population: a framework for prevention. AB - Injuries to children caused by falling televisions have become more frequent during the last decade. These injuries can be severe and even fatal and are likely to become even more common in the future as TVs increase in size and become more affordable. To formulate guidelines for the prevention of these injuries, the authors systematically reviewed the literature on injuries related to toppling televisions. The authors searched MEDLINE, PubMed, Embase, Scopus, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Cochrane Library, and Google Scholar according to the Cochrane guidelines for all studies involving children 0-18 years of age who were injured by toppled TVs. Factors contributing to injury were categorized using Haddon's Matrix, and the public health approach was used as a framework for developing strategies to prevent these injuries. The vast majority (84%) of the injuries occurred in homes and more than three-fourths were unwitnessed by adult caregivers. The TVs were most commonly large and elevated off the ground. Dressers and other furniture not designed to support TVs were commonly involved in the TV-toppling incident. The case fatality rate varies widely, but almost all deaths reported (96%) were due to brain injuries. Toddlers between the ages of 1 and 3 years most frequently suffer injuries to the head and neck, and they are most likely to suffer severe injuries. Many of these injuries require brain imaging and neurosurgical intervention. Prevention of these injuries will require changes in TV design and legislation as well as increases in public education and awareness. Television toppling injuries can be easily prevented; however, the rates of injury do not reflect a sufficient level of awareness, nor do they reflect an acceptable effort from an injury prevention perspective. PMID- 26416668 TI - Genome Sequences of Three Phytopathogenic Species of the Magnaporthaceae Family of Fungi. AB - Magnaporthaceae is a family of ascomycetes that includes three fungi of great economic importance: Magnaporthe oryzae, Gaeumannomyces graminis var. tritici, and Magnaporthe poae. These three fungi cause widespread disease and loss in cereal and grass crops, including rice blast disease (M. oryzae), take-all disease in wheat and other grasses (G. graminis), and summer patch disease in turf grasses (M. poae). Here, we present the finished genome sequence for M. oryzae and draft sequences for M. poae and G. graminis var. tritici. We used multiple technologies to sequence and annotate the genomes of M. oryzae, M. poae, and G. graminis var. tritici. The M. oryzae genome is now finished to seven chromosomes whereas M. poae and G. graminis var. tritici are sequenced to 40.0* and 25.0* coverage respectively. Gene models were developed by the use of multiple computational techniques and further supported by RNAseq data. In addition, we performed preliminary analysis of genome architecture and repetitive element DNA. PMID- 26416671 TI - Cortical inhibitory deficits in premanifest and early Huntington's disease. AB - Although progress has been made towards understanding the gross cortical and subcortical pathology of Huntington's disease (HD), there remains little understanding of the progressive pathophysiological changes that occur in the brain circuits underlying the disease. Transcranial magnetic stimulation (TMS) enables investigation of the functional integrity of cortico-subcortical pathways, yet it has not been widely applied in HD research to date. This study sought to characterise profiles of cortical excitability, including inhibition and facilitation, in groups of premanifest and symptomatic HD participants via the use of TMS. We also investigated the clinical, neurocognitive and psychiatric correlates of cortical excitability to better understand the development of phenotypic heterogeneity. The sample comprised 16 premanifest HD, 12 early symptomatic HD and 17 healthy control participants. Single- and paired-pulse TMS protocols were administered to the left primary motor cortex, with surface electromyography recorded from the abductor pollicis brevis muscle. Short interval cortical inhibition was significantly reduced in symptomatic HD, compared with premanifest HD and controls, and was significantly correlated with pathological burden and neurocognitive performance. There was also reduced long interval cortical inhibition in both premanifest and symptomatic HD, compared with controls, which was associated with pathological burden and psychiatric disturbances. Motor thresholds, cortical silent periods and intracortical facilitation did not differ across groups. Our results provide important new insights into pathophysiological changes in cortico-subcortical circuits across disease stages in HD. We propose that neurophysiological measures obtained via TMS have potential utility as endophenotypic biomarkers in HD, given their association with both pathological burden and clinical phenotype. PMID- 26416672 TI - Impact of neonatal anoxia on adult rat hippocampal volume, neurogenesis and behavior. AB - Neonates that suffer oxygen deprivation during birth can have long lasting cognitive deficits, such as memory and learning impairments. Hippocampus, one of the main structures that participate in memory and learning processes, is a plastic and dynamic structure that conserves during life span the property of generating new cells which can become neurons, the so-called neurogenesis. The present study investigated whether a model of rat neonatal anoxia, that causes only respiratory distress, is able to alter the hippocampal volume, the neurogenesis rate and has functional implications in adult life. MRI analysis revealed significant hippocampal volume decrease in adult rats who had experienced neonatal anoxia compared to control animals for rostral, caudal and total hippocampus. In addition, these animals also had 55.7% decrease of double labelled cells to BrdU and NeuN, reflecting a decrease in neurogenesis rate. Finally, behavioral analysis indicated that neonatal anoxia resulted in disruption of spatial working memory, similar to human condition, accompanied by an anxiogenic effect. The observed behavioral alterations caused by oxygen deprivation at birth might represent an outcome of the decreased hippocampal neurogenesis and volume, evidenced by immunohistochemistry and MRI analysis. Therefore, based on current findings we propose this model as suitable to explore new therapeutic approaches. PMID- 26416673 TI - Apigenin ameliorates chronic mild stress-induced depressive behavior by inhibiting interleukin-1beta production and NLRP3 inflammasome activation in the rat brain. AB - Increasing evidence suggests that inflammation and oxidative stress may contribute to the development of major depressive disorder (MDD). Apigenin, a type of bioflavonoid widely found in citrus fruits, has a number of biological actions including anti-inflammatory and antioxidant effects. Although apigenin has potential antidepressant activity, the mechanisms of this effect remain unclear. The present study aims to investigate the effects of apigenin on behavioral changes and inflammatory responses induced by chronic unpredictable mild stress (CUMS) in rats. GW9662, a selective peroxisome proliferator-activated receptor gamma (PPARgamma) inhibitor, was administered 30 min before apigenin. We found that treatment with apigenin (20mg/kg, intragastrically) for three weeks remarkably ameliorated CUMS-induced behavioral abnormalities, such as decreased locomotor activity and reduced sucrose consumption. In response to oxidative stress, the NLRP3 inflammasome was activated and IL-1beta secretion increased in the prefrontal cortex (PFC) of CUMS rats. However, apigenin treatment upregulated PPARgamma expression and downregulated the expression of NLRP3, which subsequently downregulated the production of IL-1beta. In addition, GW9662 diminished the inhibitory effects of apigenin on the NLRP3 inflammasome. In conclusion, our results demonstrate that apigenin exhibits antidepressant-like effects in CUMS rats, possibly by inhibiting IL-1beta production and NLRP3 inflammasome expression via the up-regulation of PPARgamma expression. PMID- 26416674 TI - Optical micro-spectroscopy of single metallic nanoparticles: quantitative extinction and transient resonant four-wave mixing. AB - We report a wide-field imaging method to rapidly and quantitatively measure the optical extinction cross-section sigma(ext) (also polarisation resolved) of a large number of individual gold nanoparticles, for statistically-relevant single particle analysis. We demonstrate a sensitivity of 5 nm(2) in sigma(ext), enabling detection of single 5 nm gold nanoparticles with total acquisition times in the 1 min range. Moreover, we have developed an analytical model of the polarisation resolved sigma(ext), which enabled us to extract geometrical particle aspect ratios from the measured sigma(ext). Using this method, we have characterized a large number of nominally-spherical gold nanoparticles in the 10 100 nm size range. Furthermore, the method provided measurements of in-house fabricated nanoparticle conjugates, allowing distinction of individual dimers from single particles and larger aggregates. The same particle conjugates were investigated correlatively by phase-resolved transient resonant four-wave mixing micro-spectroscopy. A direct comparison of the phase-resolved response between single gold nanoparticles and dimers highlighted the promise of the four-wave mixing technique for sensing applications with dimers as plasmon rulers. PMID- 26416676 TI - Towards consistent generation of pancreatic lineage progenitors from human pluripotent stem cells. AB - Human pluripotent stem cells can in principle be used as a source of any differentiated cell type for disease modelling, drug screening, toxicology testing or cell replacement therapy. Type I diabetes is considered a major target for stem cell applications due to the shortage of primary human beta cells. Several protocols have been reported for generating pancreatic progenitors by in vitro differentiation of human pluripotent stem cells. Here we first assessed one of these protocols on a panel of pluripotent stem cell lines for capacity to engender glucose sensitive insulin-producing cells after engraftment in immunocompromised mice. We observed variable outcomes with only one cell line showing a low level of glucose response. We, therefore, undertook a systematic comparison of different methods for inducing definitive endoderm and subsequently pancreatic differentiation. Of several protocols tested, we identified a combined approach that robustly generated pancreatic progenitors in vitro from both embryo derived and induced pluripotent stem cells. These findings suggest that, although there are intrinsic differences in lineage specification propensity between pluripotent stem cell lines, optimal differentiation procedures may consistently direct a substantial fraction of cells into pancreatic specification. PMID- 26416675 TI - Evolution of normal and neoplastic tissue stem cells: progress after Robert Hooke. AB - The appearance of stem cells coincides with the transition from single-celled organisms to metazoans. Stem cells are capable of self-renewal as well as differentiation. Each tissue is maintained by self-renewing tissue-specific stem cells. The accumulation of mutations that lead to preleukaemia are in the blood forming stem cell, while the transition to leukaemia stem cells occurs in the clone at a progenitor stage. All leukaemia and cancer cells escape being removed by scavenger macrophages by expressing the 'don't eat me' signal CD47. Blocking antibodies to CD47 are therapeutics for all cancers, and are currently being tested in clinical trials in the US and UK. PMID- 26416677 TI - Somatic cell nuclear transfer: origins, the present position and future opportunities. AB - Nuclear transfer that involves the transfer of the nucleus from a donor cell into an oocyte or early embryo from which the chromosomes have been removed was considered first as a means of assessing changes during development in the ability of the nucleus to control development. In mammals, development of embryos produced by nuclear transfer depends upon coordination of the cell cycles of donor and recipient cells. Our analysis of nuclear potential was completed in 1996 when a nucleus from an adult ewe mammary gland cell controlled development to term of Dolly the sheep. The new procedure has been used to target the first precise genetic modification into livestock; however, the greatest inheritance of the Dolly experiment was to make biologists think differently. If unknown factors in the recipient oocyte could reprogramme the nucleus to a stage very early in development then there must be other ways of making that change. Within 10 years, two laboratories working independently established protocols by which the introduction of selected transcription factors changes a small proportion of the treated cells to pluripotent stem cells. This ability to produce 'induced pluripotent stem cells' is providing revolutionary new opportunities in research and cell therapy. PMID- 26416678 TI - Present and future challenges of induced pluripotent stem cells. AB - Growing old is our destiny. However, the mature differentiated cells making up our body can be rejuvenated to an embryo-like fate called pluripotency which is an ability to differentiate into all cell types by enforced expression of defined transcription factors. The discovery of this induced pluripotent stem cell (iPSC) technology has opened up unprecedented opportunities in regenerative medicine, disease modelling and drug discovery. In this review, we introduce the applications and future perspectives of human iPSCs and we also show how iPSC technology has evolved along the way. PMID- 26416679 TI - Direct somatic lineage conversion. AB - The predominant view of embryonic development and cell differentiation has been that rigid and even irreversible epigenetic marks are laid down along the path of cell specialization ensuring the proper silencing of unrelated lineage programmes. This model made the prediction that specialized cell types are stable and cannot be redirected into other lineages. Accordingly, early attempts to change the identity of somatic cells had little success and was limited to conversions between closely related cell types. Nuclear transplantation experiments demonstrated, however, that specialized cells even from adult mammals can be reprogrammed into a totipotent state. The discovery that a small combination of transcription factors can reprogramme cells to pluripotency without the need of oocytes further supported the view that these epigenetic barriers can be overcome much easier than assumed, but the extent of this flexibility was still unclear. When we showed that a differentiated mesodermal cell can be directly converted to a differentiated ectodermal cell without a pluripotent intermediate, it was suggested that in principle any cell type could be converted into any other cell type. Indeed, the work of several groups in recent years has provided many more examples of direct somatic lineage conversions. Today, the question is not anymore whether a specific cell type can be generated by direct reprogramming but how it can be induced. PMID- 26416680 TI - From gristle to chondrocyte transplantation: treatment of cartilage injuries. AB - This review addresses the progress in cartilage repair technology over the decades with an emphasis on cartilage regeneration with cell therapy. The most abundant cartilage is the hyaline cartilage that covers the surface of our joints and, due to avascularity, this tissue is unable to repair itself. The cartilage degeneration seen in osteoarthritis causes patient suffering and is a huge burden to society. The surgical approach to cartilage repair was non-existing until the 1950s when new surgical techniques emerged. The use of cultured cells for cell therapy started as experimental studies in the 1970s that developed over the years to a clinical application in 1994 with the introduction of the autologous chondrocyte transplantation technique (ACT). The technology is now spread worldwide and has been further refined by combining arthroscopic techniques with cells cultured on matrix (MACI technology). The non-regenerating hypothesis of cartilage has been revisited and we are now able to demonstrate cell divisions and presence of stem-cell niches in the joint. Furthermore, cartilage derived from human embryonic stem cells and induced pluripotent stem cells could be the base for new broader cell treatments for cartilage injuries and the future technology base for prevention and cure of osteoarthritis. PMID- 26416681 TI - Treatment of Parkinson's disease using cell transplantation. AB - The clinical trials with intrastriatal transplantation of human fetal mesencephalic tissue, rich in dopaminergic neurons, in Parkinson's disease (PD) patients show that cell replacement can work and in some cases induce major, long lasting improvement. However, owing to poor tissue availability, this approach can only be applied in very few patients, and standardization is difficult, leading to wide variation in functional outcome. Stem cells and reprogrammed cells could potentially be used to produce dopaminergic neurons for transplantation. Importantly, dopaminergic neurons of the correct substantia nigra phenotype can now be generated from human embryonic stem cells in large numbers and standardized preparations, and will soon be ready for application in patients. Also, human induced pluripotent stem cell-derived dopaminergic neurons are being considered for clinical translation. Available data justify moving forward in a responsible way with these dopaminergic neurons, which should be tested, using optimal patient selection, cell preparation and transplantation procedures, in controlled clinical studies. PMID- 26416682 TI - Stem cells for the treatment of heart failure. AB - Stem cell-based therapy is currently tested in several trials of chronic heart failure. The main question is to determine how its implementation could be extended to common clinical practice. To fill this gap, it is critical to first validate the hypothesis that the grafted stem cells primarily act by harnessing endogenous repair pathways. The confirmation of this mechanism would have three major clinically relevant consequences: (i) the use of cardiac-committed cells, since even though cells primarily act in a paracrine manner, such a phenotype seems the most functionally effective; (ii) the optimization of early cell retention, rather than of sustained cell survival, so that the cells reside in the target tissue long enough to deliver the factors underpinning their action; and (iii) the reliance on allogeneic cells, the expected rejection of which should only have to be delayed since a permanent engraftment would no longer be the objective. One step further, the long-term objective of cell therapy could be to use the cells exclusively for producing factors and then to only administer them to the patient. The production process would then be closer to that of a biological pharmaceutic, thereby facilitating an extended clinical use. PMID- 26416683 TI - T cell engineering as therapy for cancer and HIV: our synthetic future. AB - It is now well established that the immune system can control and eliminate cancer cells. Adoptive T cell transfer has the potential to overcome the significant limitations associated with vaccine-based strategies in patients who are often immune compromised. Application of the emerging discipline of synthetic biology to cancer, which combines elements of genetic engineering and molecular biology to create new biological structures with enhanced functionalities, is the subject of this overview. Various chimeric antigen receptor designs, manufacturing processes and study populations, among other variables, have been tested and reported in recent clinical trials. Many questions remain in the field of engineered T cells, but the encouraging response rates pave a wide road for future investigation into fields as diverse as cancer and chronic infections. PMID- 26416684 TI - Progressing a human embryonic stem-cell-based regenerative medicine therapy towards the clinic. AB - Since the first publication of the derivation of human embryonic stem cells in 1998, there has been hope and expectation that this technology will lead to a wave of regenerative medicine therapies with the potential to revolutionize our approach to managing certain diseases. Despite significant resources in this direction, the path to the clinic for an embryonic stem-cell-based regenerative medicine therapy has not proven straightforward, though in the past few years progress has been made. Here, with a focus upon retinal disease, we discuss the current status of the development of such therapies. We also highlight some of our own experiences of progressing a retinal pigment epithelium cell replacement therapy towards the clinic. PMID- 26416685 TI - Stem cells and the evolving notion of cellular identity. AB - Stem cells are but one class of the myriad types of cells within an organism. With potential to self-renew and capacity to differentiate, stem cells play essential roles at multiple stages of development. In the early embryo, pluripotent stem cells represent progenitors for all tissues while later in development, tissue-restricted stem cells give rise to cells with highly specialized functions. As best understood in the blood, skin and gut, stem cells are the seeds that sustain tissue homeostasis and regeneration, while in other tissues like the muscle, liver, kidney and lung, various stem or progenitor cells play facultative roles in tissue repair and response to injury. Here, I will provide a brief perspective on the evolving notion of cellular identity and how reprogramming and transcription factor-mediated conversions of one cell type into another have fundamentally altered our assumptions about the stability of cell identity, with profound long-term implications for biomedical research and regenerative medicine. PMID- 26416687 TI - Cells: from Robert Hooke to cell therapy--a 350 year journey. PMID- 26416686 TI - Cell-based therapy technology classifications and translational challenges. AB - Cell therapies offer the promise of treating and altering the course of diseases which cannot be addressed adequately by existing pharmaceuticals. Cell therapies are a diverse group across cell types and therapeutic indications and have been an active area of research for many years but are now strongly emerging through translation and towards successful commercial development and patient access. In this article, we present a description of a classification of cell therapies on the basis of their underlying technologies rather than the more commonly used classification by cell type because the regulatory path and manufacturing solutions are often similar within a technology area due to the nature of the methods used. We analyse the progress of new cell therapies towards clinical translation, examine how they are addressing the clinical, regulatory, manufacturing and reimbursement requirements, describe some of the remaining challenges and provide perspectives on how the field may progress for the future. PMID- 26416688 TI - Robotic surgery in children: adopt now, await, or dismiss? AB - The role of robot-assisted surgery in children remains controversial. This article aims to distil this debate into an evidence informed decision-making taxonomy; to adopt this technology (1) now, (2) later, or (3) not at all. Robot assistance is safe, feasible and effective in selected cases as an adjunctive tool to enhance capabilities of minimally invasive surgery, as it is known today. At present, expectations of rigid multi-arm robotic systems to deliver higher quality care are over-estimated and poorly substantiated by evidence. Such systems are associated with high costs. Further comparative effectiveness evidence is needed to define the case-mix for which robot-assistance might be indicated. It seems unlikely that we should expect compelling patient benefits when it is only the mode of minimally invasive surgery that differs. Only large higher-volume institutions that share the robot amongst multiple specialty groups are likely to be able to sustain higher associated costs with today's technology. Nevertheless, there is great potential for next-generation surgical robotics to enable better ways to treat childhood surgical diseases through less invasive techniques that are not possible today. This will demand customized technology for selected patient populations or procedures. Several prototype robots exclusively designed for pediatric use are already under development. Financial affordability must be a high priority to ensure clinical accessibility. PMID- 26416689 TI - Forebrain microglia from wild-type but not adult 5xFAD mice prevent amyloid-beta plaque formation in organotypic hippocampal slice cultures. AB - The role of microglia in amyloid-beta (Abeta) deposition is controversial. In the present study, an organotypic hippocampal slice culture (OHSC) system with an in vivo-like microglial-neuronal environment was used to investigate the potential contribution of microglia to Abeta plaque formation. We found that microglia ingested Abeta, thereby preventing plaque formation in OHSCs. Conversely, Abeta deposits formed rapidly in microglia-free wild-type slices. The capacity to prevent Abeta plaque formation was absent in forebrain microglia from young adult but not juvenile 5xFamilial Alzheimer's disease (FAD) mice. Since no loss of Abeta clearance capacity was observed in both wild-type and cerebellar microglia from 5xFAD animals, the high Abeta1-42 burden in the forebrain of 5xFAD animals likely underlies the exhaustion of microglial Abeta clearance capacity. These data may therefore explain why Abeta plaque formation has never been described in wild-type mice, and point to a beneficial role of microglia in AD pathology. We also describe a new method to study Abeta plaque formation in a cell culture setting. PMID- 26416690 TI - Strengthening health systems capacity to monitor and evaluate programmes targeted at reducing abortion-related maternal mortality in Jessore district, Bangladesh. AB - BACKGROUND: Abortion related deaths as a proportion of maternal mortality appears to have fallen dramatically in Bangladesh from 5 % in 2001 to 1 % in 2010. Yet complications from menstrual regulation (MR) and unsafe abortion continue to cause deleterious health, economic and social consequences for women in the country. METHODS: This quasi experimental design study with a baseline (January to December 2008) and an endline survey (August to October 2009) was conducted in 69 public, private, and NGO sector health facilities in Jessore district of Bangladesh with the objective of adapting and implementing a set of process indicators, specifically to supplement the indicators for monitoring emergency obstetric care interventions. At the baseline, we collected retrospective data from all 69 health facilities that provided MR, legal abortion or post-abortion care (PAC), by reviewing their last one year's records. Three months after introducing the safe menstrual regulation and abortion care (SMRAC) model, endline data was collected. Signal function (critical services that facilities must perform in order to prevent and treat abortion complications) analysis was used to characterize facilities as providing basic care, comprehensive care, or neither. Facility mapping, and records on services provided and complications treated were used to further characterize service availability and to describe service use and quality. RESULTS: No facilities fulfilled criteria for 'comprehensive' care at either the baseline or end line while only one met the 'basic' criteria during the endline of the project. Recommended uterine evacuation technology, manual vacuum aspiration (MVA) was used for 100.0 % of MR clients but only for 8.0 % or fewer PAC patients. MR clients were 37.5 times more likely than PAC patients to leave facilities with a contraceptive method (75.0 % vs. 2.0 %). CONCLUSION: Persistent use of older uterine evacuation technologies was observed when recommended techniques were widely available in the facilities. Notable gaps were identified in providing post-abortion contraceptive services for women treated for PAC. By systematic implementation of the SMRAC model, health systems can track and measure progress and gaps in their implementation and identify strategies for further reduction of abortion-related morbidity and mortality in Bangladesh. PMID- 26416691 TI - Magnetic colorimetric immunoassay for human interleukin-6 based on the oxidase activity of ceria spheres. AB - A novel magnetic colorimetric immunoassay strategy was designed for sensitive detection of human interleukin-6 (IL-6) using ceria spheres as labels. Ceria spheres showed excellent oxidase activity, which can directly catalyze the oxidation of substrate o-phenylenediamine (OPD) to a stable yellow product, 2,3 diaminophenazine (oxOPD). The absorbance of oxOPD was recorded to reflect the level of IL-6. The relatively mild conditions made the immunoassay strategy more robust, reliable, and easy. A linear relationship between absorbance intensity and the logarithm of IL-6 concentrations was obtained in the range of 0.0001-10 ng mL(-1) with a detection limit of 0.04 pg mL(-1) (S/N = 3). The colorimetric immunoassay exhibited high sensitivity and specificity for the detection of IL-6. This immunoassay has been successfully applied in the detection of IL-6 in serum samples and can be readily extended toward the on-site monitoring of cancer biomarkers in serum samples. PMID- 26416692 TI - Identification of RNase-resistant RNAs in Saccharomyces cerevisiae extracts: Separation from chromosomal DNA by selective precipitation. AB - High-quality chromosomal DNA is a requirement for many biochemical and molecular biological techniques. To isolate cellular DNA, standard protocols typically lyse cells and separate nucleic acids from other biological molecules using a combination of chemical and physical methods. After a standard chemical-based protocol to isolate chromosomal DNA from Saccharomyces cerevisiae and then treatment with RNase A to degrade RNA, two RNase-resistant bands persisted when analyzed using gel electrophoresis. Interestingly, such resistant bands did not appear in preparations of Escherichia coli bacterial DNA after RNase treatment. Several enzymatic, chemical, and physical methods were employed in an effort to remove the resistant RNAs, including use of multiple RNases and alcohol precipitation, base hydrolysis, and chromatographic methods. These experiments resulted in the development of a new method for isolation of S. cerevisiae chromosomal DNA. This method utilizes selective precipitation of DNA in the presence of a potassium acetate/isopropanol mixture and produces high yields of chromosomal DNA without detectable contaminating RNAs. PMID- 26416694 TI - Prevalence and distribution patterns of amphetamine and methamphetamine consumption in a federal state in southwestern Germany using wastewater analysis. AB - BACKGROUND: Wastewater analysis is a new approach developed to estimate drug (of abuse) consumption in large communities, such as cities or even whole countries. AIMS: This paper presents data on the loads of amphetamine and methamphetamine measured in ten wastewater treatment plants in different parts of a German federal state. It provides an estimation of the intensity of the consumption and a comparison to other regions in Germany and Europe. METHODS: Consumption of amphetamine and methamphetamine was estimated by analysis of drug residues in composite 24h samples of wastewater after mechanical treatment over one week by liquid chromatography-high resolution tandem mass spectrometry. Samples were collected from the inlet of ten wastewater treatment plants (WWTP) in the federal state of Saarland, representing bigger cities (>200,000 inhabitants), medium sized cities (>50,000 inhabitants), small cities (>25,000 inhabitants), and villages (<25,000 inhabitants). In each WWTP, samples were taken daily for seven consecutive days in July 2014. RESULTS: We observed differences of amphetamine versus methamphetamine loads (expressed as mg/day/1000 inhabitants): Amphetamine loads were much higher in all tested WWTPs indicating a low prevalence of methamphetamine abuse in the federal state of Saarland at the tested period. These findings are in line with previous reports about the distribution of amphetamine and methamphetamine in Germany and Europe. CONCLUSIONS: The approach confirms that wastewater analysis can provide valuable data about the abuse pattern of drugs of abuse in cities and larger areas. It can be useful for planning interventions aimed at specific areas and substances. PMID- 26416695 TI - Alterations of neuronal precursor cells in stages of human adult neurogenesis in heroin addicts. AB - BACKGROUND: Adult neurogenesis has been shown to occur throughout life and different brain pathologies were demonstrated to be associated with altered neurogenesis. Here, an impact of heroin addiction on neurogenesis in humans is hypothesised. METHODS: Post mortem hippocampal specimens of drug addicts with known heroin abuse and a group of non-addictive control subjects were analysed, using antibodies indicating different stages of neurogenesis. The subgranular zone of the dentate gyrus was examined qualitatively and quantitatively. RESULTS: The data indicate (i) a decreased number of neural precursor cells, (ii) accompanied by low rates of proliferation and (iii) a marked loss of dendritic trees in targeting cells in heroin fatalities. (iv) The age-dependent increase of differentiating cells in the healthy controls was not observed in the addicts. Additionally, double immunofluorescence labelling indicated the precursor nature of Musashi-1 positive cells in the human subgranular zone of the dentate gyrus. CONCLUSIONS: Present data firstly demonstrate the influence of drug addiction with known heroin abuse on different developmental stages of progenitors in the dentate gyrus. The patterns of antibody staining suggest a distinct inhibition of neurogenesis at the stage of neural precursor cells and revealed morphological changes in targeting cells in cases of heroin addicts as compared to healthy controls. These alterations could be considerable for memory and cognitive deficits as well as addictive behaviour in chronic drug abusers and may give rise to specific pro-neurogenic therapies. PMID- 26416693 TI - Next generation sequencing profiling identifies miR-574-3p and miR-660-5p as potential novel prognostic markers for breast cancer. AB - BACKGROUND: Prognostication of Breast Cancer (BC) relies largely on traditional clinical factors and biomarkers such as hormone or growth factor receptors. Due to their suboptimal specificities, it is challenging to accurately identify the subset of patients who are likely to undergo recurrence and there remains a major need for markers of higher utility to guide therapeutic decisions. MicroRNAs (miRNAs) are small non-coding RNAs that function as post-transcriptional regulators of gene expression and have shown promise as potential prognostic markers in several cancer types including BC. RESULTS: In our study, we sequenced miRNAs from 104 BC samples and 11 apparently healthy normal (reduction mammoplasty) breast tissues. We used Case-control (CC) and Case-only (CO) statistical paradigm to identify prognostic markers. Cox-proportional hazards regression model was employed and risk score analysis was performed to identify miRNA signature independent of potential confounders. Representative miRNAs were validated using qRT-PCR. Gene targets for prognostic miRNAs were identified using in silico predictions and in-house BC transcriptome dataset. Gene ontology terms were identified using DAVID bioinformatics v6.7. A total of 1,423 miRNAs were captured. In the CC approach, 126 miRNAs were retained with predetermined criteria for good read counts, from which 80 miRNAs were differentially expressed. Of these, four and two miRNAs were significant for Overall Survival (OS) and Recurrence Free Survival (RFS), respectively. In the CO approach, from 147 miRNAs retained after filtering, 11 and 4 miRNAs were significant for OS and RFS, respectively. In both the approaches, the risk scores were significant after adjusting for potential confounders. The miRNAs associated with OS identified in our cohort were validated using an external dataset from The Cancer Genome Atlas (TCGA) project. Targets for the identified miRNAs were enriched for cell proliferation, invasion and migration. CONCLUSIONS: The study identified twelve non-redundant miRNAs associated with OS and/or RFS. These signatures include those that were reported by others in BC or other cancers. Importantly we report for the first time two new candidate miRNAs (miR-574-3p and miR-660-5p) as promising prognostic markers. Independent validation of signatures (for OS) using an external dataset from TCGA further strengthened the study findings. PMID- 26416696 TI - Sample size calculation for before-after experiments with partially overlapping cohorts. AB - We investigate sample size calculation for before-after experiments where the outcome of interest is binary and the enrolled subjects contribute a mixed type of data: some subjects contribute complete pairs of before- and after intervention outcomes, while some subjects contribute incomplete data (before intervention only or after-intervention only). We use the GEE approach to derive a closed-form sample size formula by treating the incomplete observations as missing data in a generalized linear model. The impacts of various designing factors are appropriately accounted for in the sample size formula, including intervention effect, baseline response rate, within-subject correlation, and distribution of missing values in the before- and after-intervention periods. We illustrate sample size estimation using a real application example. We conduct simulation studies to demonstrate that the proposed sample size maintains the nominal power and type I error under a wide spectrum of trial configurations. PMID- 26416697 TI - Predictors and Outcomes of Burnout in Primary Care Physicians. AB - OBJECTIVE: To assess relationships between primary care work conditions, physician burnout, quality of care, and medical errors. METHODS: Cross-sectional and longitudinal analyses of data from the MEMO (Minimizing Error, Maximizing Outcome) Study. Two surveys of 422 family physicians and general internists, administered 1 year apart, queried physician job satisfaction, stress and burnout, organizational culture, and intent to leave within 2 years. A chart audit of 1795 of their adult patients with diabetes and/or hypertension assessed care quality and medical errors. KEY RESULTS: Women physicians were almost twice as likely as men to report burnout (36% vs 19%, P < .001). Burned out clinicians reported less satisfaction (P < .001), more job stress (P < .001), more time pressure during visits (P < .01), more chaotic work conditions (P < .001), and less work control (P < .001). Their workplaces were less likely to emphasize work life balance (P < .001) and they noted more intent to leave the practice (56% vs 21%, P < .001). There were no consistent relationships between burnout, care quality, and medical errors. CONCLUSIONS: Burnout is highly associated with adverse work conditions and a greater intention to leave the practice, but not with adverse patient outcomes. Care quality thus appears to be preserved at great personal cost to primary care physicians. Efforts focused on workplace redesign and physician self-care are warranted to sustain the primary care workforce. PMID- 26416698 TI - Application of Sensory Evaluation, HS-SPME GC-MS, E-Nose, and E-Tongue for Quality Detection in Citrus Fruits. AB - In this study, electronic tongue (E-tongue), headspace solid-phase microextraction gas chromatography-mass spectrometer (GC-MS), electronic nose (E nose), and quantitative describe analysis (QDA) were applied to describe the 2 types of citrus fruits (Satsuma mandarins [Citrus unshiu Marc.] and sweet oranges [Citrus sinensis {L.} Osbeck]) and their mixing juices systematically and comprehensively. As some aroma components or some flavor molecules interacted with the whole juice matrix, the changes of most components in the fruit juice were not in proportion to the mixing ratio of the 2 citrus fruits. The potential correlations among the signals of E-tongue and E-nose, volatile components, and sensory attributes were analyzed by using analysis of variance partial least squares regression. The result showed that the variables from the sensor signals (E-tongue system and E-nose system) had significant and positive (or negative) correlations to the most variables of volatile components (GC-MS) and sensory attributes (QDA). The simultaneous utilization of E-tongue and E-nose obtained a perfect classification result with 100% accuracy rate based on linear discriminant analysis and also attained a satisfying prediction with high coefficient association for the sensory attributes (R(2) > 0.994 for training sets and R(2) > 0.983 for testing sets) and for the volatile components (R(2) > 0.992 for training sets and R(2) > 0.990 for testing sets) based on random forest. Being easy-to-use, cost-effective, robust, and capable of providing a fast analysis procedure, E-nose and E-tongue could be used as an alternative detection system to traditional analysis methods, such as GC-MS and sensory evaluation by human panel in the fruit industry. PRACTICAL APPLICATION: Being easy-to-use, cost-effective, robust, and capable of providing a fast analysis procedure, E-nose and E-tongue could be used as an alternative detection system to traditional analysis methods for characterizing food flavors. Based on those results, one can draw a conclusion that the fusion system composed of E-tongue and E-nose could guarantee a satisfying result in the prediction of sensory attributes and volatile components for fruit quality profile. PMID- 26416699 TI - Investigating the effect of structural transition on aggregation of beta lactoglobulin. AB - beta-lactoglobulin (BLG), the major bovine whey protein, is a well-characterized globular protein. It is a model protein for studying the structural transition and aggregation. BLG unfolds and aggregates through chemical and physical processes. It is a predominantly beta-sheet protein but, the non-native alpha helical intermediate accumulates in its folding pathway. The present study aims to understand more about which stage of the protein folding is prone to aggregation. The intermediate states were trapped by TFE and their aggregation and structural changes evaluated, for this purpose. The experiments were carried out at various pH values, ionic strengths, protein concentrations and heating times by turbidity measurements, circular dichroism and fluorescence spectroscopy. Furthermore, the aggregated species at various molecular weights were detected by SDS-PAGE. Only a small change was observed in the secondary and tertiary structures of the protein at 10% TFE, but a further increase of TFE concentration results in induction of new alpha-helical structure and disruption of the rigid tertiary structure. The turbidity measurement indicated that the aggregation of BLG reaches a maximum level at 10% TFE on all experimental conditions and from this point forward, it decreases with increasing the amount of TFE. In conclusion, the results showed that the alpha-helical state is resistant to aggregation, in spite that its tertiary structure is partially unfolded. BLG becomes prone to aggregation, when its non-native alpha-helical structure converts to the beta-sheet structure. PMID- 26416701 TI - Facile synthesis of hydrangea flower-like hierarchical gold nanostructures with tunable surface topographies for single-particle surface-enhanced Raman scattering. AB - The physicochemical properties of noble metal nanocrystals depend strongly on their size and shape, and it is becoming clear that the design and facile synthesis of particular nanostructures with tailored shape and size is especially important. Herein a novel class of hydrangea flower-like hierarchical gold nanostructures with tunable surface topographies and optical properties are prepared for the first time by a facile, one-pot, seedless synthesis using ascorbic acid (AA) to reduce hydrogen tetrachloroaurate (HAuCl4) in the presence of (1-hexadecyl)trimethylammonium chloride (CTAC). The morphologies of the synthesized gold nanoflowers are controlled and fine-tuned by varying the synthetic conditions such as the concentration of reagents and the growth temperature. Due to their unique hierarchical three-dimensional (3D) structures with rich hot spots, these gold nanoflowers exhibit an efficient performance in single-particle surface-enhanced Raman scattering (SERS). The work stands out as an interesting approach for anisotropic particle synthesis and morphological control, and the proposed novel, hierarchical gold nanoflowers have a number of exciting potential applications in SERS-based sensors. PMID- 26416702 TI - Affect-regulated exercise: an alternative approach for lifestyle modification in overweight/obese women with polycystic ovary syndrome. AB - OBJECTIVE: Affect-regulated exercise ("ARE") is an alternative approach to guide exercise intensity based on feeling of pleasure. The aim of this study was to analyze if overweight/obese women with polycystic ovary syndrome (PCOS) meet the American College of Sports Medicine (ACSM) recommendation regarding to exercise intensity to improve health status during a single bout of "ARE". METHODS: A sample of 14 overweight/obese women with PCOS (18-34 years) performed a single bout of "ARE" (40 min of aerobic exercise on outdoor track). The Feeling Scale (FS) was used to guide "ARE" intensity/pace maintaining an affective valence between "good" and "very good" during all time. Heart rate (HR), speed, % of HR at first and second ventilatory threshold (VT1 and VT2) and time spent at moderate (64-76% of HR(max)) and vigorous (77-95% of HR(max)) intensity during "ARE" were measured with a global positioning system (GPS) device. RESULTS: Volunteers exercised at 73% (68-78%) of HR(max), 5.8 (5.2-6.2) km/h, 93.4% of HR at VT1 (89.3-98.2) and 80.5% of HR at VT2 (75.3-84.6) and spent >80% of time at moderate intensity. CONCLUSIONS: Overweight/obese women with PCOS met the ACSM recommendation regarding exercise intensity to improve health status when exercised between "good" and "very good" of FS. Thus, "ARE" may be an interesting approach to be used in clinical practice regarding to exercise prescription and/or physical activity advice. PMID- 26416704 TI - Liver transplantation for secondary liver tumours. PMID- 26416703 TI - CBX7 and miR-9 are part of an autoregulatory loop controlling p16(INK) (4a). AB - Polycomb repressive complexes (PRC1 and PRC2) are epigenetic regulators that act in coordination to influence multiple cellular processes including pluripotency, differentiation, cancer and senescence. The role of PRCs in senescence can be mostly explained by their ability to repress the INK4/ARF locus. CBX7 is one of five mammalian orthologues of Drosophila Polycomb that forms part of PRC1. Despite the relevance of CBX7 for regulating senescence and pluripotency, we have a limited understanding of how the expression of CBX7 is regulated. Here we report that the miR-9 family of microRNAs (miRNAS) downregulates the expression of CBX7. In turn, CBX7 represses miR-9-1 and miR-9-2 as part of a regulatory negative feedback loop. The miR-9/CBX7 feedback loop is a regulatory module contributing to induction of the cyclin-dependent kinase inhibitor (CDKI) p16(INK4a) during senescence. The ability of the miR-9 family to regulate senescence could have implications for understanding the role of miR-9 in cancer and aging. PMID- 26416705 TI - Exciton dynamics of C60-based single-photon emitters explored by Hanbury Brown Twiss scanning tunnelling microscopy. AB - Exciton creation and annihilation by charges are crucial processes for technologies relying on charge-exciton-photon conversion. Improvement of organic light sources or dye-sensitized solar cells requires methods to address exciton dynamics at the molecular scale. Near-field techniques have been instrumental for this purpose; however, characterizing exciton recombination with molecular resolution remained a challenge. Here, we study exciton dynamics by using scanning tunnelling microscopy to inject current with sub-molecular precision and Hanbury Brown-Twiss interferometry to measure photon correlations in the far field electroluminescence. Controlled injection allows us to generate excitons in solid C60 and let them interact with charges during their lifetime. We demonstrate electrically driven single-photon emission from localized structural defects and determine exciton lifetimes in the picosecond range. Monitoring lifetime shortening and luminescence saturation for increasing carrier injection rates provides access to charge-exciton annihilation dynamics. Our approach introduces a unique way to study single quasi-particle dynamics on the ultimate molecular scale. PMID- 26416706 TI - An augmented supermatrix phylogeny of the avian family Picidae reveals uncertainty deep in the family tree. AB - The accumulation of DNA sequence data in public repositories allows for phylogenetic inference on unprecedented taxonomic scales using supermatrix approaches. Careful analysis of available data allows strategic augmentation with new sequences in order to maximize taxonomic sampling and coverage of informative loci. I inferred relationships among 179 species (76%) in the avian family Picidae (woodpeckers, piculets, and wrynecks), using publicly available sequence data supplemented with targeted sequencing to increase species-level and locus level sampling and maximize resolution. Results of these analyses generally corroborate previous molecular studies, with consensus on the membership of most genera and tribes. However, several newly placed taxa show surprising affinities, and several genera as currently delineated appear to be paraphyletic. Relationships among major clades of Picidae remain poorly resolved, particularly among the three lineages of piculets, the unusual woodpecker genus Hemicircus, and the remaining woodpeckers, and among the major groups of true woodpeckers (Picinae). If these deep relationships are to be resolved, phylogenomic approaches may be necessary. PMID- 26416707 TI - The systematics of carnivorous sponges. AB - Carnivorous sponges are characterized by their unique method of capturing mesoplanktonic prey coupled with the complete or partial reduction of the aquiferous system characteristic of the phylum Porifera. Current systematics place the vast majority of carnivorous sponges within Cladorhizidae, with certain species assigned to Guitarridae and Esperiopsidae. Morphological characters have not been able to show whether this classification is evolutionary accurate, and whether carnivory has evolved once or in several lineages. In the present paper we present the first comprehensive molecular phylogeny of the carnivorous sponges, interpret these results in conjunction with morphological characters, and propose a revised classification of the group. Molecular phylogenies were inferred using 18S rDNA and a combined dataset of partial 28S rDNA, COI and ALG11 sequences. The results recovered carnivorous sponges as a clade closely related to the families Mycalidae and Guitarridae, showing family Cladorhizidae to be monophyletic and also including carnivorous species currently placed in other families. The genus Lycopodina is resurrected for species currently placed in the paraphyletic subgenus Asbestopluma (Asbestopluma) featuring forceps spicules and lacking sigmas or sigmancistras. The genera Chondrocladia and Cladorhiza are found to be monophyletic. However, results indicate that the subgenus Chondrocladia is polyphyletic with respect to the subgenera Meliiderma and Symmetrocladia. Euchelipluma, formerly Guitarridae, is retained, but transferred to Cladorhizidae. The four known carnivorous species currently in Esperiopsis are transferred to Abyssocladia. Neocladia is a junior homonym and is here renamed Koltunicladia. Our results provide strong evidence in support of the hypothesis that carnivory in sponges has evolved only once. While spicule characters mostly reflect monophyletic groups at the generic level, differences between genera represent evolution within family Cladorhizidae rather than evolution of carnivory in separate lineages. Conflicting spicule characters can be reinterpreted to support the inclusion of all carnivorous sponges within Cladorhizidae, and a carnivorous habit should thus be considered the main diagnostic character in systematic classification. PMID- 26416708 TI - Differences in Self-Reported Physical Activity and Body Mass Index Among Older Hispanic and Non-Hispanic White Men and Women: Findings from the 2009 California Health Interview Survey. AB - Older Hispanic Americans are a rapidly growing minority group who are disproportionately affected by diabetes mellitus and obesity. Given the importance of physical activity, particularly leisure-time activity, in the management of diabetes mellitus and obesity, the current study examined ethnic and sex differences in walking for transportation, leisure-time walking, moderate activity (not including walking), and vigorous activity between Hispanic and non Hispanic white (NHW) older adults (age 55 and older) using the 2009 California Health Interview Survey, a population-based survey representative of California's noninstitutionalized population. The total sample consisted of 21,702 participants (20,148 NHW (7,968 men, 12,180 women) and 1,554 Hispanic (609 men, 945 women)). Multivariable logistic and linear regression analyses were adjusted for sociodemographic characteristics. The findings revealed that Hispanic men and women were significantly less likely to engage in self-reported leisure-time walking and vigorous activity than NHW men (adjusted odds ratio (aOR) = 0.71, 95% confidence interval (CI) = 0.51-0.99) and women (aOR = 0.60, 95% CI = 0.42-0.87). Regardless of ethnic group, men were more likely than women to engage in self reported walking for transportation (aOR = 0.71, 95% CI = 0.58-0.87), moderate activity (aOR = 0.68, 95% CI = 0.57-0.81), and vigorous activity (aOR = 0.58, 95% CI = 0.50-0.68). All types of self-reported physical activity were associated with lower body mass index (BMI; P < .001), although significant interactions between sex and leisure time walking (P < .001), moderate activity (P < .001), and vigorous activity (P < .001) indicated that women who engaged in these activities reported the lowest BMIs. The findings highlight the importance of emphasizing walking in efforts to increase moderate and vigorous activity, particularly for older women. PMID- 26416709 TI - Removal of simulated biofilm: a preclinical ergonomic comparison of instruments and operators. AB - BACKGROUND: Periodontal scaling might cause musculoskeletal disorders, and scaling instruments might not only have different effectiveness and efficiency but also differ in their ergonomic properties. The present study assessed ergonomic working patterns of experienced (EO) and less experienced operators (LO) when using hand and powered devices for periodontal scaling and root planning. METHODS: In an experimental study using periodontally affected manikins, sonic (AIR), ultrasonic (TIG) and hand instruments (GRA) were used by 11 operators (7 EO/4 LO) during simulated supportive periodontal therapy. Using an electronic motion monitoring system, we objectively assessed the working frequency and positioning of hand, neck and head. Operators' subjective evaluation of the instruments was recorded using a questionnaire. RESULTS: Hand instruments were used with the lowest frequency (2.57 +/- 1.08 s(-1)) but greatest wrist deviation (59.57 +/- 53.94 degrees ). EO used instruments more specifically than LO, and generally worked more ergonomically, with less inclination of head and neck in both the frontal and sagittal planes, especially when using hand instruments. All groups found hand instruments more tiring and difficult to use than powered instruments. CONCLUSION: Regardless of operators' experience, powered instruments were used more ergonomically and were subjectively preferred compared to hand instruments. CLINICAL RELEVANCE: The use of hand instruments has potential ergonomic disadvantages. However, with increasing experience, operators are able to recognise and mitigate possible risks. PMID- 26416710 TI - Patients Treated at Low-Volume Centers have Higher Rates of Incomplete Resection and Compromised Outcomes: Analysis of 31,129 Patients with Papillary Thyroid Cancer. AB - BACKGROUND: Data on the importance of margin status after total thyroidectomy for papillary thyroid cancer (PTC) remain limited. This study sought to identify factors associated with positive margins and to determine the impact of positive margins on survival for patients with PTC. METHODS: The National Cancer Data Base (1998-2006) was queried for patients with PTC who had undergone total thyroidectomy. The patients were divided into three groups based on margin status (negative, microscopically positive, and macroscopically positive). Patient demographic, clinical, and pathologic features were evaluated. A binary logistic regression model was developed to identify factors associated with positive margins. A Cox proportional hazards model was developed to identify factors associated with survival. RESULTS: Of the 31,129 patients enrolled in the study, 91.3 % had negative margins, 8.1 % had microscopically positive margins, and 0.6 % had macroscopically positive margins. The patients with negative margins were younger and more likely to be female, white, covered by private insurance, and treated at an academic or high-volume center (p < 0.05). They had smaller tumors and were less likely to have advanced-stage disease. After multivariable adjustment, increasing patient age [odds ratio (OR) = 1.02; p < 0.01], government insurance (OR = 1.20; p < 0.01), and no insurance (OR = 1.34; p = 0.01) were associated with positive margins. Reception of surgery at a high-volume facility (OR = 0.72; p < 0.01) was protective. After multivariable adjustment, both microscopically [hazard ratio (HR), 1.49; p < 0.01] and macroscopically positive margins (HR = 2.38; p < 0.01) were associated with compromised survival. CONCLUSIONS: Several vulnerable patient populations have a higher risk of incomplete resection after thyroidectomy for PTC. High-risk thyroid cancer patients should be referred to high-volume centers to optimize outcomes. PMID- 26416711 TI - The Prognostic Significance of Histone Lysine Demethylase JMJD3/KDM6B in Colorectal Cancer. AB - BACKGROUND: Jumonji-domain containing 3 (JMJD3) affects transcriptional regulation by demethylating lysine 27 residue of histone 3. We investigated its function and prognostic significance in colorectal cancer (CRC). METHODS: The influence of JMJD3 on cell proliferation was assessed using quantitative RT-PCR and western blot on the downstream target gene of JMJD3, in knock-down (KD) experiments and clinical samples from 151 CRC patients. RESULTS: Cells with KD JMJD3 significantly increased proliferation through cell cycle progression and apoptosis suppression. Expression of P15INK4B was remarkably decreased in KD JMJD3 cells; and JMJD3 expression strongly correlated with p15INK4B expression in clinical CRC samples (P < 0.001, r = 0.566). Low JMJD3 also was an independent predictor of poor prognosis (P = 0.042) in surgically resected CRC patients. CONCLUSIONS: JMJD3 has prognostic significance in CRC and mediates p15INK4B expression. These results imply that elucidation of the JMJD3 role may lead to a new therapeutic approach for CRC patients. PMID- 26416713 TI - Compromised Outcome of Papillary Thyroid Cancer at Low-Volume Treatment Centers: Practice Makes Perfect? PMID- 26416712 TI - Microcalcifications in 1657 Patients with Pure Ductal Carcinoma in Situ of the Breast: Correlation with Clinical, Histopathologic, Biologic Features, and Local Recurrence. AB - PURPOSE: This study was designed to determine the relationship of microcalcification morphology and distribution with clinical, histopathologic, biologic features, and local recurrence (LR) in patients with pure ductal carcinoma in situ (DCIS) of the breast. METHODS: All patients with pure DCIS who underwent preoperative mammography at our institution from 1996 through 2009 were identified. Mammographic findings were classified according to the ACR BI-RADS lexicon. Associations between mammographic findings and clinical, histopathologic, biologic characteristics, and LR were analyzed. Statistical inference used multiple logistic regression and Cox proportional hazards regression adjusted for age and confounding due to bias from nonrandomized selection of radiation therapy. RESULTS: We identified 1657 patients with microcalcifications visualized on mammography. The mean age at diagnosis was 55 years (SD, 11). The mean follow-up was 7 years (range 1-16). Ipsilateral LR was 4 % in segmentectomy (987) and 1.5 % in mastectomy (670) patients. Increased LR risk was seen in patients with dense breast tissue (p < 0.05) and larger DCIS size (p < 0.01). Radiation therapy was associated with a 2.8-fold decrease in the LR risk. Fine linear (branching) microcalcifications were associated with 5.2 fold increase in LR. Extremely dense breast tissue was associated with positive/close margins (p = 0.04) and multicentricity (p < 0.01). Younger women were more likely to have extremely dense breast tissue (p < 0.0001), multicentric disease (p < 0.0004), and undergo mastectomy (p < 0.0001). CONCLUSIONS: Dense breast tissue, large DCIS size, and fine linear (branching) microcalcifications were associated with increased LR, yet overall LR rates remained low. Extremely dense breast tissue was a risk factor for multicentricity and positive margins in DCIS. PMID- 26416714 TI - Verification of WFA-Sialylated MUC1 as a Sensitive Biliary Biomarker for Human Biliary Tract Cancer. AB - BACKGROUND: The diagnostic accuracy of biliary cytology is limited. A novel sandwich enzyme-linked immunosorbent assay that combined Wisteria floribunda agglutinin (WFA) and anti-sialylated mucin 1 (MUC1) monoclonal antibody to target bile samples was recently developed. This study was designed to verify the diagnostic accuracy of WFA-sialylated MUC1 as a sensitive biliary biomarker for human biliary tract cancer. METHODS: Bile samples from 27 patients with benign disease and 174 patients with biliary tract cancer were analyzed. A receiver operated characteristic curve analysis for biliary WFA-sialylated MUC1 and serum CA19-9 levels was performed to determine the cutoff value for the prediction of the presence of biliary tract cancer. RESULTS: Biliary WFA-sialylated MUC1 levels were significantly higher in the biliary tract cancer group compared with the benign group (P < 0.001). The cutoff value of WFA-sialylated MUC1 for discriminating biliary tract cancer was 10.5. The sensitivity of WFA-sialylated MUC1 in discriminating biliary tract cancer was much higher (82.2 %) than that of cytology (23.6 %) when this cutoff value was used. The cutoff value of serum CA19 9 for discriminating biliary tract cancer was 38 IU/L in the same cohort. All patients with biliary WFA-sialylated MUC1 and serum CA19-9 above the cutoff values had biliary tract cancer, and no patient with benign disease was categorized in this group. CONCLUSIONS: Biliary WFA-sialylated MUC1 is a useful biomarker for the differentiation of biliary tract cancer. The sensitivity of WFA sialylated MUC1 was clearly higher than that of biliary cytology. Further data collection is necessary to validate the clinical usefulness of this biomarker. PMID- 26416715 TI - Prognostic Significance of Neutrophil-to-Lymphocyte Ratio and Platelet-to Lymphocyte Ratio in Oncologic Outcomes of Esophageal Cancer: A Systematic Review and Meta-analysis. AB - BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been reported to predict oncologic outcomes in patients with various types of cancer. However, their prognostic value in patients with esophageal cancer is unclear. In this meta-analysis, we evaluated the prognostic significance of NLR and PLR in esophageal cancer patients. METHODS: We performed comprehensive searches of electronic databases to identify studies that evaluated the prognostic impact of pretreatment NLR and PLR in esophageal cancer patients. The end points were overall survival (OS), disease-free survival, and clinicopathologic parameters. A meta-analysis using random-effects models was performed to calculate hazard ratios (HRs) or odds ratios with 95 % confidence intervals (CIs). RESULTS: Seven retrospective, observational, cohort studies involving 1540 patients were included. All seven studies evaluated NLR, and four evaluated PLR. Both high NLR (HR 1.40, 95 % CI 1.08-1.81, P = 0.01) and high PLR (HR 1.59, 95 % CI 1.14-2.21, P = 0.006) were significantly predictive of poorer OS. NLR was not a significant predictor of disease-free survival. High PLR (HR 1.85, 95 % CI 1.50-2.28, P < 0.00001) but not NLR was significantly predictive of poorer OS in a subgroup of patients who underwent curative surgery without neoadjuvant chemoradiation. Both high NLR and high PLR were significantly associated with deeper tumor invasion and lymph node metastasis. CONCLUSIONS: NLR and PLR are associated with tumor progression and are predictive of poorer survival in patients with esophageal cancer. These ratios may thus help to inform treatment decisions and predict treatment outcomes. PMID- 26416716 TI - Potential causes of sudden cardiac death in nemaline myopathy. PMID- 26416718 TI - In the eye of the neutrophil swarm-navigation signals that bring neutrophils together in inflamed and infected tissues. AB - Neutrophils are sentinel cells that express in higher vertebrates >30 chemokine and chemoattractant receptors to sense and quickly react to tissue damage signals. Intravital microscopy studies in mouse models of wounding, inflammation, and infection have revealed that neutrophils form cell swarms at local sites of tissue injury and cell death. This swarming response is choreographed by chemokines, lipids, and other chemoattractants, controlling sequential phases of highly coordinated chemotaxis, intercellular signal relay, and cluster formation among neutrophils. This review will give a brief overview about the basic principles and key molecules that have led to the refined multistep model of how neutrophils come together to isolate sites of tissue injury and microbial invasion from healthy tissue. Whereas auto- and paracrine signaling among neutrophils during later phases of swarming can provide a level of self organization for robust navigation in diverse inflammatory settings, guidance factors from primary tissue lesions, resident bystander cells, and dying cells regulate the initial phases of the swarming response. This review will discuss how the specific environmental context and mixture of attractants at the locally inflamed site can lead to variants of the multistep attraction model and influence the extent of neutrophil swarming, ranging from accumulations of only few individual cells to the aggregation of several hundreds of neutrophils, as found in abscesses. Given the critical roles of neutrophils in both host protection and tissue destruction, novel insights on neutrophil swarming might provide useful for the therapeutic modulation of neutrophil-dependent inflammatory processes. PMID- 26416717 TI - Sepsis-induced selective parvalbumin interneuron phenotype loss and cognitive impairments may be mediated by NADPH oxidase 2 activation in mice. AB - BACKGROUND: Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction caused by many pathological events, including neuroinflammation and oxidative stress damage. Increasing evidence suggests that parvalbumin (PV) interneurons play a key role in the cognitive process, whereas the dysfunction of these interneurons has been implicated in a number of major psychiatric disorders. Here, we aimed to investigate whether enhanced inflammation and oxidative stress mediated PV interneuron phenotype loss plays a role in sepsis-induced cognitive impairments. METHODS: Male C57BL/6 mice were subjected to cecal ligation and puncture or sham operation. For the interventional study, the animals were chronically treated with a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin, at 5 mg/kg. The mice were euthanized at the indicated time points, and the brain tissues were harvested for determination of the PV, membrane subunit of NADPH oxidase gp91(phox), and markers of oxidative stress (4-hydroxynonenal and malondialdehyde) and inflammation (tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, and IL-10). A separate cohort of animals was used to evaluate the behavioral alterations by the open field and fear conditioning tests. Primary hippocampal neuronal cultures were used to investigate the mechanisms underlying the dysfunction of PV interneurons. RESULTS: Sepsis resulted in cognitive impairments, which was accompanied by selective phenotype loss of PV interneurons and increased gp91(phox), 4 hydroxynonenal, malondialdehyde, IL-1beta, and IL-6 expressions. Notably, these abnormalities could be rescued by apocynin treatment. CONCLUSION: Selective phenotype loss of PV interneurons, as a result of NADPH oxidase 2 (Nox2) activation, might partly contribute to cognitive impairments in a mouse model of SAE. PMID- 26416719 TI - Systematic review and meta-analysis of the sero-epidemiological association between Epstein-Barr virus and rheumatoid arthritis. AB - INTRODUCTION: Infection with Epstein-Barr virus (EBV) has been suggested to contribute to the pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). We sought to determine whether prior infection with the virus occurs more frequently in patients with RA compared to controls. METHODS: We performed a systematic review and meta-analyses of studies that reported the prevalence of anti-EBV antibodies in the sera of cases with RA and controls by searching Medline and Embase databases from 1946 to 2014, with no language restriction. Mantel-Haenszel odds ratios for the detection of anti-EBV antibodies were calculated, and meta-analyses conducted. Quality assessments were performed using a modified version of the Newcastle-Ottawa scale. RESULTS: Twenty-three studies were included. Quality assessment found most studies reported acceptable selection criteria but poor descriptions of how cases and controls were recruited. When all studies were included, there was a statistically significant higher seroprevalence of anti-VCA IgG in patients with RA compared to controls with an odds ratio (OR) of 1.61 (95 % confidence interval (CI) 1.05-2.46, p = 0.03), which is a similar-sized summary OR to that reported for systemic lupus erythematosus (SLE). However, when studies were restricted to those reporting more plausible levels of exposure to EBV in the control groups, no significant association was apparent, OR 1.47 (95 % CI 0.88-2.46, p = 0.14). Using anti-EBNA 1 or anti-EA IgG as markers of previous infection also did not yield significant associations (OR 1.05, 95 % CI 0.68-1.61, p = 0.82; OR 2.2, 95 % CI 0.86-5.65, p = 0.10 respectively). CONCLUSIONS: Overall, these findings do not demonstrate an association between EBV seroprevalence and RA and therefore do not support the hypothesis that prior infection with EBV predisposes to the development of RA. This contrasts with meta-analyses that indicate EBV infection is associated with multiple sclerosis and SLE. PMID- 26416720 TI - The Impact of Fluid Inertia on In Vivo Estimation of Mitral Valve Leaflet Constitutive Properties and Mechanics. AB - We examine the influence of the added mass effect (fluid inertia) on mitral valve leaflet stress during isovolumetric phases. To study this effect, oscillating flow is applied to a flexible membrane at various frequencies to control inertia. Resulting membrane strain is calculated through a three-dimensional reconstruction of markers from stereo images. To investigate the effect in vivo, the analysis is repeated on a published dataset for an ovine mitral valve (Journal of Biomechanics 42(16): 2697-2701). The membrane experiment demonstrates that the relationship between pressure and strain must be corrected with a fluid inertia term if the ratio of inertia to pressure differential approaches 1. In the mitral valve, this ratio reaches 0.7 during isovolumetric contraction for an acceleration of 6 m/s(2). Acceleration is reduced by 72% during isovolumetric relaxation. Fluid acceleration also varies along the leaflet during isovolumetric phases, resulting in spatial variations in stress. These results demonstrate that fluid inertia may be the source of the temporally and spatially varying stiffness measurements previously seen through inverse finite element analysis of in vivo data during isovolumetric phases. This study demonstrates that there is a need to account for added mass effects when analyzing in vivo constitutive relationships of heart valves. PMID- 26416722 TI - MicroRNAs in obesity-associated disorders. AB - The emergence of a worldwide obesity epidemic has dramatically increased the prevalence of insulin resistance and metabolic syndrome, predisposing individuals to a greater risk for the development of non-alcoholic fatty liver disease, type II diabetes and atherosclerotic cardiovascular diseases. Current available pharmacological interventions combined with diet and exercise-based managements are still poorly effective for weight management, likely in part due to an incomplete understanding of regulatory mechanisms and pathways contributing to the systemic metabolic abnormalities under disturbed energy homeostasis. MicroRNAs, small non-coding RNAs that regulate posttranscriptional gene expression, have been increasingly described to influence shifts in metabolic pathways under various obesity-related disease settings. Here we review recent discoveries of the mechanistic role that microRNAs play in regulating metabolic functions in liver and adipose tissues involved in obesity associated disorders, and briefly discusses the potential candidates that are being pursued as viable therapeutic targets. PMID- 26416721 TI - The Incompatibility of Living Systems: Characterizing Growth-Induced Incompatibilities in Expanded Skin. AB - Skin expansion is a common surgical technique to correct large cutaneous defects. Selecting a successful expansion protocol is solely based on the experience and personal preference of the operating surgeon. Skin expansion could be improved by predictive computational simulations. Towards this goal, we model skin expansion using the continuum framework of finite growth. This approach crucially relies on the concept of incompatible configurations. However, aside from the classical opening angle experiment, our current understanding of growth-induced incompatibilities remains rather vague. Here we visualize and characterize incompatibilities in living systems using skin expansion in a porcine model: We implanted and inflated two expanders, crescent, and spherical, and filled them to 225 cc throughout a period of 21 days. To quantify the residual strains developed during this period, we excised the expanded skin patches and subdivided them into smaller pieces. Skin growth averaged 1.17 times the original area for the spherical and 1.10 for the crescent expander, and displayed significant regional variations. When subdivided into smaller pieces, the grown skin patches retracted heterogeneously and confirmed the existence of incompatibilities. Understanding skin growth through mechanical stretch will allow surgeons to improve-and ultimately personalize-preoperative treatment planning in plastic and reconstructive surgery. PMID- 26416723 TI - Development of a Magnetic Attachment Method for Bionic Eye Applications. AB - Successful visual prostheses require stable, long-term attachment. Epiretinal prostheses, in particular, require attachment methods to fix the prosthesis onto the retina. The most common method is fixation with a retinal tack; however, tacks cause retinal trauma, and surgical proficiency is important to ensure optimal placement of the prosthesis near the macula. Accordingly, alternate attachment methods are required. In this study, we detail a novel method of magnetic attachment for an epiretinal prosthesis using two prostheses components positioned on opposing sides of the retina. The magnetic attachment technique was piloted in a feline animal model (chronic, nonrecovery implantation). We also detail a new method to reliably control the magnet coupling force using heat. It was found that the force exerted upon the tissue that separates the two components could be minimized as the measured force is proportionately smaller at the working distance. We thus detail, for the first time, a surgical method using customized magnets to position and affix an epiretinal prosthesis on the retina. The position of the epiretinal prosthesis is reliable, and its location on the retina is accurately controlled by the placement of a secondary magnet in the suprachoroidal location. The electrode position above the retina is less than 50 microns at the center of the device, although there were pressure points seen at the two edges due to curvature misalignment. The degree of retinal compression found in this study was unacceptably high; nevertheless, the normal structure of the retina remained intact under the electrodes. PMID- 26416724 TI - Exploring cardio-pulmonary interactions by examining the ventilatory, pulmonary gas exchange, and heart rate kinetics response to high-intensity cycle exercise in COPD patients. PMID- 26416725 TI - Implementation and development of early intervention in psychosis services in Italy: a national survey promoted by the Associazione Italiana Interventi Precoci nelle Psicosi. AB - AIM: This is the first comprehensive, nationwide survey aimed at collecting evidence about the process of implementation and development of early intervention in psychosis (EIP) services (EIPs) in Italy, following the establishment of the pilot program 'Programma 2000' in 1999 and the publishing of the Italian National Guidelines in 2007. This survey covers all the Departments of Mental Health (DMHs) operating in Italy in 2013. METHODS: Using a purpose designed form to assess EIP implementation, all directors of public mental health services for adults throughout Italy (n = 216) were asked to provide information about the activities of EIP-relevant local services. The initial delivery was followed by a request for a prompt response. RESULTS: Out of 216 enquired DMHs, 103 provided computable answers to the survey (response rate = 48%). Among responders, 45 (44%) reported the implementation of EIP (one out of five DMHs operating in Italy). About a half of the active EIPs also targeted patients at ultra-high risk of psychosis (n = 27). Strict application of guidelines related to drug prescription was reported in 35% of EIPs. Conversely, 90% provided some kind of structured psychotherapy and psychoeducation. Among EIPs, a minority reported willingness to provide initial assessment/contact at the patient's home. CONCLUSION: Albeit slowly, the implementation of EIP is spreading throughout the Italian public network of mental health. There is still a wide variability in the distribution of EIP services across the Italian territory. Further efforts are necessary to stimulate policy endorsement and resource allocation, as well as to support the poorest zones. PMID- 26416726 TI - Development of 'Redox Arrays' for identifying novel glutathionylated proteins in the secretome. AB - Proteomics techniques for analysing the redox status of individual proteins in complex mixtures tend to identify the same proteins due to their high abundance. We describe here an array-based technique to identify proteins undergoing glutathionylation and apply it to the secretome and the proteome of human monocytic cells. The method is based on incorporation of biotinylated glutathione (GSH) into proteins, which can then be identified following binding to a 1000 protein antibody array. We thus identify 38 secreted and 55 intracellular glutathionylated proteins, most of which are novel candidates for glutathionylation. Two of the proteins identified in these experiments, IL-1 sRII and Lyn, were then confirmed to be susceptible to glutathionylation. Comparison of the redox array with conventional proteomic methods confirmed that the redox array is much more sensitive, and can be performed using more than 100-fold less protein than is required for methods based on mass spectrometry. The identification of novel targets of glutathionylation, particularly in the secretome where the protein concentration is much lower, shows that redox arrays can overcome some of the limitations of established redox proteomics techniques. PMID- 26416727 TI - Identification of carbohydrate anomers using ion mobility-mass spectrometry. AB - Carbohydrates are ubiquitous biological polymers that are important in a broad range of biological processes. However, owing to their branched structures and the presence of stereogenic centres at each glycosidic linkage between monomers, carbohydrates are harder to characterize than are peptides and oligonucleotides. Methods such as nuclear magnetic resonance spectroscopy can be used to characterize glycosidic linkages, but this technique requires milligram amounts of material and cannot detect small amounts of coexisting isomers. Mass spectrometry, on the other hand, can provide information on carbohydrate composition and connectivity for even small amounts of sample, but it cannot be used to distinguish between stereoisomers. Here, we demonstrate that ion mobility mass spectrometry--a method that separates molecules according to their mass, charge, size, and shape--can unambiguously identify carbohydrate linkage-isomers and stereoisomers. We analysed six synthetic carbohydrate isomers that differ in composition, connectivity, or configuration. Our data show that coexisting carbohydrate isomers can be identified, and relative concentrations of the minor isomer as low as 0.1 per cent can be detected. In addition, the analysis is rapid, and requires no derivatization and only small amounts of sample. These results indicate that ion mobility-mass spectrometry is an effective tool for the analysis of complex carbohydrates. This method could have an impact on the field of carbohydrate synthesis similar to that of the advent of high-performance liquid chromatography on the field of peptide assembly in the late 1970s. PMID- 26416729 TI - Crystal structure of human glycine receptor-alpha3 bound to antagonist strychnine. AB - Neurotransmitter-gated ion channels of the Cys-loop receptor family are essential mediators of fast neurotransmission throughout the nervous system and are implicated in many neurological disorders. Available X-ray structures of prokaryotic and eukaryotic Cys-loop receptors provide tremendous insights into the binding of agonists, the subsequent opening of the ion channel, and the mechanism of channel activation. Yet the mechanism of inactivation by antagonists remains unknown. Here we present a 3.0 A X-ray structure of the human glycine receptor-alpha3 homopentamer in complex with a high affinity, high-specificity antagonist, strychnine. Our structure allows us to explore in detail the molecular recognition of antagonists. Comparisons with previous structures reveal a mechanism for antagonist-induced inactivation of Cys-loop receptors, involving an expansion of the orthosteric binding site in the extracellular domain that is coupled to closure of the ion pore in the transmembrane domain. PMID- 26416730 TI - Two independent and primitive envelopes of the bilobate nucleus of comet 67P. AB - The factors shaping cometary nuclei are still largely unknown, but could be the result of concurrent effects of evolutionary and primordial processes. The peculiar bilobed shape of comet 67P/Churyumov-Gerasimenko may be the result of the fusion of two objects that were once separate or the result of a localized excavation by outgassing at the interface between the two lobes. Here we report that the comet's major lobe is enveloped by a nearly continuous set of strata, up to 650 metres thick, which are independent of an analogous stratified envelope on the minor lobe. Gravity vectors computed for the two lobes separately are closer to perpendicular to the strata than those calculated for the entire nucleus and adjacent to the neck separating the two lobes. Therefore comet 67P/Churyumov Gerasimenko is an accreted body of two distinct objects with 'onion-like' stratification, which formed before they merged. We conclude that gentle, low velocity collisions occurred between two fully formed kilometre-sized cometesimals in the early stages of the Solar System. The notable structural similarities between the two lobes of comet 67P/Churyumov-Gerasimenko indicate that the early-forming cometesimals experienced similar primordial stratified accretion, even though they formed independently. PMID- 26416731 TI - Plasticity-driven individualization of olfactory coding in mushroom body output neurons. AB - Although all sensory circuits ascend to higher brain areas where stimuli are represented in sparse, stimulus-specific activity patterns, relatively little is known about sensory coding on the descending side of neural circuits, as a network converges. In insects, mushroom bodies have been an important model system for studying sparse coding in the olfactory system, where this format is important for accurate memory formation. In Drosophila, it has recently been shown that the 2,000 Kenyon cells of the mushroom body converge onto a population of only 34 mushroom body output neurons (MBONs), which fall into 21 anatomically distinct cell types. Here we provide the first, to our knowledge, comprehensive view of olfactory representations at the fourth layer of the circuit, where we find a clear transition in the principles of sensory coding. We show that MBON tuning curves are highly correlated with one another. This is in sharp contrast to the process of progressive decorrelation of tuning in the earlier layers of the circuit. Instead, at the population level, odour representations are reformatted so that positive and negative correlations arise between representations of different odours. At the single-cell level, we show that uniquely identifiable MBONs display profoundly different tuning across different animals, but that tuning of the same neuron across the two hemispheres of an individual fly was nearly identical. Thus, individualized coordination of tuning arises at this level of the olfactory circuit. Furthermore, we find that this individualization is an active process that requires a learning-related gene, rutabaga. Ultimately, neural circuits have to flexibly map highly stimulus specific information in sparse layers onto a limited number of different motor outputs. The reformatting of sensory representations we observe here may mark the beginning of this sensory-motor transition in the olfactory system. PMID- 26416728 TI - The soft palate is an important site of adaptation for transmissible influenza viruses. AB - Influenza A viruses pose a major public health threat by causing seasonal epidemics and sporadic pandemics. Their epidemiological success relies on airborne transmission from person to person; however, the viral properties governing airborne transmission of influenza A viruses are complex. Influenza A virus infection is mediated via binding of the viral haemagglutinin (HA) to terminally attached alpha2,3 or alpha2,6 sialic acids on cell surface glycoproteins. Human influenza A viruses preferentially bind alpha2,6-linked sialic acids whereas avian influenza A viruses bind alpha2,3-linked sialic acids on complex glycans on airway epithelial cells. Historically, influenza A viruses with preferential association with alpha2,3-linked sialic acids have not been transmitted efficiently by the airborne route in ferrets. Here we observe efficient airborne transmission of a 2009 pandemic H1N1 (H1N1pdm) virus (A/California/07/2009) engineered to preferentially bind alpha2,3-linked sialic acids. Airborne transmission was associated with rapid selection of virus with a change at a single HA site that conferred binding to long-chain alpha2,6-linked sialic acids, without loss of alpha2,3-linked sialic acid binding. The transmissible virus emerged in experimentally infected ferrets within 24 hours after infection and was remarkably enriched in the soft palate, where long-chain alpha2,6-linked sialic acids predominate on the nasopharyngeal surface. Notably, presence of long-chain alpha2,6-linked sialic acids is conserved in ferret, pig and human soft palate. Using a loss-of-function approach with this one virus, we demonstrate that the ferret soft palate, a tissue not normally sampled in animal models of influenza, rapidly selects for transmissible influenza A viruses with human receptor (alpha2,6-linked sialic acids) preference. PMID- 26416732 TI - The genomic landscape of response to EGFR blockade in colorectal cancer. AB - Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy, here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours, all of which were KRAS wild-type. We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and delineate new avenues for intervention in managing colorectal cancer. PMID- 26416733 TI - SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef. AB - HIV-1 Nef and the unrelated mouse leukaemia virus glycosylated Gag (glycoGag) strongly enhance the infectivity of HIV-1 virions produced in certain cell types in a clathrin-dependent manner. Here we show that Nef and glycoGag prevent the incorporation of the multipass transmembrane proteins serine incorporator 3 (SERINC3) and SERINC5 into HIV-1 virions to an extent that correlates with infectivity enhancement. Silencing of both SERINC3 and SERINC5 precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. The infectivity of nef-deficient virions increased more than 100-fold when produced in double knockout human CD4(+) T cells that lack both SERINC3 and SERINC5, and re expression experiments confirmed that the absence of SERINC3 and SERINC5 accounted for the infectivity enhancement. Furthermore, SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. SERINC3 and SERINC5 are highly expressed in primary human HIV-1 target cells, and inhibiting their downregulation by Nef is a potential strategy to combat HIV/AIDS. PMID- 26416734 TI - HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation. AB - HIV-1 Nef, a protein important for the development of AIDS, has well characterized effects on host membrane trafficking and receptor downregulation. By an unidentified mechanism, Nef increases the intrinsic infectivity of HIV-1 virions in a host-cell-dependent manner. Here we identify the host transmembrane protein SERINC5, and to a lesser extent SERINC3, as a potent inhibitor of HIV-1 particle infectivity that is counteracted by Nef. SERINC5 localizes to the plasma membrane, where it is efficiently incorporated into budding HIV-1 virions and impairs subsequent virion penetration of susceptible target cells. Nef redirects SERINC5 to a Rab7-positive endosomal compartment and thereby excludes it from HIV 1 particles. The ability to counteract SERINC5 was conserved in Nef encoded by diverse primate immunodeficiency viruses, as well as in the structurally unrelated glycosylated Gag from murine leukaemia virus. These examples of functional conservation and convergent evolution emphasize the fundamental importance of SERINC5 as a potent anti-retroviral factor. PMID- 26416736 TI - Erratum: Structural imprints in vivo decode RNA regulatory mechanisms. PMID- 26416737 TI - Corrigendum: Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment. PMID- 26416735 TI - Structure and mechanism of the mammalian fructose transporter GLUT5. AB - The altered activity of the fructose transporter GLUT5, an isoform of the facilitated-diffusion glucose transporter family, has been linked to disorders such as type 2 diabetes and obesity. GLUT5 is also overexpressed in certain tumour cells, and inhibitors are potential drugs for these conditions. Here we describe the crystal structures of GLUT5 from Rattus norvegicus and Bos taurus in open outward- and open inward-facing conformations, respectively. GLUT5 has a major facilitator superfamily fold like other homologous monosaccharide transporters. On the basis of a comparison of the inward-facing structures of GLUT5 and human GLUT1, a ubiquitous glucose transporter, we show that a single point mutation is enough to switch the substrate-binding preference of GLUT5 from fructose to glucose. A comparison of the substrate-free structures of GLUT5 with occluded substrate-bound structures of Escherichia coli XylE suggests that, in addition to global rocker-switch-like re-orientation of the bundles, local asymmetric rearrangements of carboxy-terminal transmembrane bundle helices TM7 and TM10 underlie a 'gated-pore' transport mechanism in such monosaccharide transporters. PMID- 26416738 TI - Non-coding RNA: Antibiotic tricks a switch. PMID- 26416739 TI - Phenology: Spring greening in a warming world. PMID- 26416741 TI - Corrigendum: Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. PMID- 26416740 TI - Multiple mechanisms for CRISPR-Cas inhibition by anti-CRISPR proteins. AB - The battle for survival between bacteria and the viruses that infect them (phages) has led to the evolution of many bacterial defence systems and phage encoded antagonists of these systems. Clustered regularly interspaced short palindromic repeats (CRISPR) and the CRISPR-associated (cas) genes comprise an adaptive immune system that is one of the most widespread means by which bacteria defend themselves against phages. We identified the first examples of proteins produced by phages that inhibit a CRISPR-Cas system. Here we performed biochemical and in vivo investigations of three of these anti-CRISPR proteins, and show that each inhibits CRISPR-Cas activity through a distinct mechanism. Two block the DNA-binding activity of the CRISPR-Cas complex, yet do this by interacting with different protein subunits, and using steric or non-steric modes of inhibition. The third anti-CRISPR protein operates by binding to the Cas3 helicase-nuclease and preventing its recruitment to the DNA-bound CRISPR-Cas complex. In vivo, this anti-CRISPR can convert the CRISPR-Cas system into a transcriptional repressor, providing the first example-to our knowledge-of modulation of CRISPR-Cas activity by a protein interactor. The diverse sequences and mechanisms of action of these anti-CRISPR proteins imply an independent evolution, and foreshadow the existence of other means by which proteins may alter CRISPR-Cas function. PMID- 26416742 TI - Erratum: Mechanism of phospho-ubiquitin-induced PARKIN activation. PMID- 26416743 TI - Neurobiology: Individuality sniffed out in flies. PMID- 26416745 TI - Corrigendum: Biocontainment of genetically modified organisms by synthetic protein design. PMID- 26416744 TI - Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. AB - Haematopoietic stem cells (HSCs) reside in a perivascular niche but the specific location of this niche remains controversial. HSCs are rare and few can be found in thin tissue sections or upon live imaging, making it difficult to comprehensively localize dividing and non-dividing HSCs. Here, using a green fluorescent protein (GFP) knock-in for the gene Ctnnal1 in mice (hereafter denoted as alpha-catulin(GFP)), we discover that alpha-catulin(GFP) is expressed by only 0.02% of bone marrow haematopoietic cells, including almost all HSCs. We find that approximately 30% of alpha-catulin-GFP(+)c-kit(+) cells give long-term multilineage reconstitution of irradiated mice, indicating that alpha-catulin GFP(+)c-kit(+) cells are comparable in HSC purity to cells obtained using the best markers currently available. We optically cleared the bone marrow to perform deep confocal imaging, allowing us to image thousands of alpha-catulin-GFP(+)c kit(+) cells and to digitally reconstruct large segments of bone marrow. The distribution of alpha-catulin-GFP(+)c-kit(+) cells indicated that HSCs were more common in central marrow than near bone surfaces, and in the diaphysis relative to the metaphysis. Nearly all HSCs contacted leptin receptor positive (Lepr(+)) and Cxcl12(high) niche cells, and approximately 85% of HSCs were within 10 MUm of a sinusoidal blood vessel. Most HSCs, both dividing (Ki-67(+)) and non-dividing (Ki-67(-)), were distant from arterioles, transition zone vessels, and bone surfaces. Dividing and non-dividing HSCs thus reside mainly in perisinusoidal niches with Lepr(+)Cxcl12(high) cells throughout the bone marrow. PMID- 26416746 TI - Declining global warming effects on the phenology of spring leaf unfolding. AB - Earlier spring leaf unfolding is a frequently observed response of plants to climate warming. Many deciduous tree species require chilling for dormancy release, and warming-related reductions in chilling may counteract the advance of leaf unfolding in response to warming. Empirical evidence for this, however, is limited to saplings or twigs in climate-controlled chambers. Using long-term in situ observations of leaf unfolding for seven dominant European tree species at 1,245 sites, here we show that the apparent response of leaf unfolding to climate warming (ST, expressed in days advance of leaf unfolding per degrees C warming) has significantly decreased from 1980 to 2013 in all monitored tree species. Averaged across all species and sites, ST decreased by 40% from 4.0 +/- 1.8 days degrees C(-1) during 1980-1994 to 2.3 +/- 1.6 days degrees C(-1) during 1999 2013. The declining ST was also simulated by chilling-based phenology models, albeit with a weaker decline (24-30%) than observed in situ. The reduction in ST is likely to be partly attributable to reduced chilling. Nonetheless, other mechanisms may also have a role, such as 'photoperiod limitation' mechanisms that may become ultimately limiting when leaf unfolding dates occur too early in the season. Our results provide empirical evidence for a declining ST, but also suggest that the predicted strong winter warming in the future may further reduce ST and therefore result in a slowdown in the advance of tree spring phenology. PMID- 26416747 TI - In situ structural analysis of the human nuclear pore complex. AB - Nuclear pore complexes are fundamental components of all eukaryotic cells that mediate nucleocytoplasmic exchange. Determining their 110-megadalton structure imposes a formidable challenge and requires in situ structural biology approaches. Of approximately 30 nucleoporins (Nups), 15 are structured and form the Y and inner-ring complexes. These two major scaffolding modules assemble in multiple copies into an eight-fold rotationally symmetric structure that fuses the inner and outer nuclear membranes to form a central channel of ~60 nm in diameter. The scaffold is decorated with transport-channel Nups that often contain phenylalanine-repeat sequences and mediate the interaction with cargo complexes. Although the architectural arrangement of parts of the Y complex has been elucidated, it is unclear how exactly it oligomerizes in situ. Here we combine cryo-electron tomography with mass spectrometry, biochemical analysis, perturbation experiments and structural modelling to generate, to our knowledge, the most comprehensive architectural model of the human nuclear pore complex to date. Our data suggest previously unknown protein interfaces across Y complexes and to inner-ring complex members. We show that the transport-channel Nup358 (also known as Ranbp2) has a previously unanticipated role in Y-complex oligomerization. Our findings blur the established boundaries between scaffold and transport-channel Nups. We conclude that, similar to coated vesicles, several copies of the same structural building block--although compositionally identical- engage in different local sets of interactions and conformations. PMID- 26416748 TI - Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. AB - Despite major advances in understanding the molecular and genetic basis of cancer, metastasis remains the cause of >90% of cancer-related mortality. Understanding metastasis initiation and progression is critical to developing new therapeutic strategies to treat and prevent metastatic disease. Prevailing theories hypothesize that metastases are seeded by rare tumour cells with unique properties, which may function like stem cells in their ability to initiate and propagate metastatic tumours. However, the identity of metastasis-initiating cells in human breast cancer remains elusive, and whether metastases are hierarchically organized is unknown. Here we show at the single-cell level that early stage metastatic cells possess a distinct stem-like gene expression signature. To identify and isolate metastatic cells from patient-derived xenograft models of human breast cancer, we developed a highly sensitive fluorescence-activated cell sorting (FACS)-based assay, which allowed us to enumerate metastatic cells in mouse peripheral tissues. We compared gene signatures in metastatic cells from tissues with low versus high metastatic burden. Metastatic cells from low-burden tissues were distinct owing to their increased expression of stem cell, epithelial-to-mesenchymal transition, pro survival, and dormancy-associated genes. By contrast, metastatic cells from high burden tissues were similar to primary tumour cells, which were more heterogeneous and expressed higher levels of luminal differentiation genes. Transplantation of stem-like metastatic cells from low-burden tissues showed that they have considerable tumour-initiating capacity, and can differentiate to produce luminal-like cancer cells. Progression to high metastatic burden was associated with increased proliferation and MYC expression, which could be attenuated by treatment with cyclin-dependent kinase (CDK) inhibitors. These findings support a hierarchical model for metastasis, in which metastases are initiated by stem-like cells that proliferate and differentiate to produce advanced metastatic disease. PMID- 26416750 TI - HIV: Antiviral action countered by Nef. PMID- 26416751 TI - Erratum: IgG1 protects against renal disease in a mouse model of cryoglobulinaemia. PMID- 26416749 TI - Mediator kinase inhibition further activates super-enhancer-associated genes in AML. AB - Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling transcription factors and oncogenes. BRD4 and CDK7 are positive regulators of SE-mediated transcription. By contrast, negative regulators of SE-associated genes have not been well described. Here we show that the Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We report that the natural product cortistatin A (CA) selectively inhibits Mediator kinases, has anti-leukaemic activity in vitro and in vivo, and disproportionately induces upregulation of SE-associated genes in CA sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the transcription factors CEBPA, IRF8, IRF1 and ETV6 (refs 6 8). The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has anti-leukaemic activity. Individually increasing or decreasing the expression of these transcription factors suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to the dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types, and can be pharmacologically targeted as a therapeutic approach to AML. PMID- 26416752 TI - New genomic and fossil data illuminate the origin of enamel. AB - Enamel, the hardest vertebrate tissue, covers the teeth of almost all sarcopterygians (lobe-finned bony fishes and tetrapods) as well as the scales and dermal bones of many fossil lobe-fins. Enamel deposition requires an organic matrix containing the unique enamel matrix proteins (EMPs) amelogenin (AMEL), enamelin (ENAM) and ameloblastin (AMBN). Chondrichthyans (cartilaginous fishes) lack both enamel and EMP genes. Many fossil and a few living non-teleost actinopterygians (ray-finned bony fishes) such as the gar, Lepisosteus, have scales and dermal bones covered with a proposed enamel homologue called ganoine. However, no gene or transcript data for EMPs have been described from actinopterygians. Here we show that Psarolepis romeri, a bony fish from the the Early Devonian period, combines enamel-covered dermal odontodes on scales and skull bones with teeth of naked dentine, and that Lepisosteus oculatus (the spotted gar) has enam and ambn genes that are expressed in the skin, probably associated with ganoine formation. The genetic evidence strengthens the hypothesis that ganoine is homologous with enamel. The fossil evidence, further supported by the Silurian bony fish Andreolepis, which has enamel-covered scales but teeth and odontodes on its dermal bones made of naked dentine, indicates that this tissue originated on the dermal skeleton, probably on the scales. It subsequently underwent heterotopic expansion across two highly conserved patterning boundaries (scales/head-shoulder and dermal/oral) within the odontode skeleton. PMID- 26416753 TI - Selective small-molecule inhibition of an RNA structural element. AB - Riboswitches are non-coding RNA structures located in messenger RNAs that bind endogenous ligands, such as a specific metabolite or ion, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Demonstrating this potential, however, has proven difficult and is restricted to structurally similar antimetabolites and semi synthetic analogues of their cognate ligand, thus greatly restricting the chemical space and selectivity sought for such inhibitors. Here we report the discovery and characterization of ribocil, a highly selective chemical modulator of bacterial riboflavin riboswitches, which was identified in a phenotypic screen and acts as a structurally distinct synthetic mimic of the natural ligand, flavin mononucleotide, to repress riboswitch-mediated ribB gene expression and inhibit bacterial cell growth. Our findings indicate that non-coding RNA structural elements may be more broadly targeted by synthetic small molecules than previously expected. PMID- 26416754 TI - Structural basis for gene regulation by a B12-dependent photoreceptor. AB - Photoreceptor proteins enable organisms to sense and respond to light. The newly discovered CarH-type photoreceptors use a vitamin B12 derivative, adenosylcobalamin, as the light-sensing chromophore to mediate light-dependent gene regulation. Here we present crystal structures of Thermus thermophilus CarH in all three relevant states: in the dark, both free and bound to operator DNA, and after light exposure. These structures provide visualizations of how adenosylcobalamin mediates CarH tetramer formation in the dark, how this tetramer binds to the promoter -35 element to repress transcription, and how light exposure leads to a large-scale conformational change that activates transcription. In addition to the remarkable functional repurposing of adenosylcobalamin from an enzyme cofactor to a light sensor, we find that nature also repurposed two independent protein modules in assembling CarH. These results expand the biological role of vitamin B12 and provide fundamental insight into a new mode of light-dependent gene regulation. PMID- 26416755 TI - Binding of dinitrogen to an iron-sulfur-carbon site. AB - Nitrogenases are the enzymes by which certain microorganisms convert atmospheric dinitrogen (N2) to ammonia, thereby providing essential nitrogen atoms for higher organisms. The most common nitrogenases reduce atmospheric N2 at the FeMo cofactor, a sulfur-rich iron-molybdenum cluster (FeMoco). The central iron sites that are coordinated to sulfur and carbon atoms in FeMoco have been proposed to be the substrate binding sites, on the basis of kinetic and spectroscopic studies. In the resting state, the central iron sites each have bonds to three sulfur atoms and one carbon atom. Addition of electrons to the resting state causes the FeMoco to react with N2, but the geometry and bonding environment of N2-bound species remain unknown. Here we describe a synthetic complex with a sulfur-rich coordination sphere that, upon reduction, breaks an Fe-S bond and binds N2. The product is the first synthetic Fe-N2 complex in which iron has bonds to sulfur and carbon atoms, providing a model for N2 coordination in the FeMoco. Our results demonstrate that breaking an Fe-S bond is a chemically reasonable route to N2 binding in the FeMoco, and show structural and spectroscopic details for weakened N2 on a sulfur-rich iron site. PMID- 26416756 TI - Corrigendum: Recoded organisms engineered to depend on synthetic amino acids. PMID- 26416760 TI - Quantitative single molecule FRET efficiencies using TIRF microscopy. AB - Forster resonance energy transfer (FRET) microscopy at the single molecule level has the potential to yield information on intra and intermolecular distances within the 2-10 nm range of molecules or molecular complexes that undergo frequent conformation changes. A pre-requirement for obtaining accurate distance information is to determine quantitative instrument independent FRET efficiency values. Here, we applied and evaluated a procedure to determine quantitative FRET efficiencies directly from individual fluorescence time traces of surface immobilized DNA molecules without the need for external calibrants. To probe the robustness of the approach over a wide range of FRET efficiencies we used a set of doubly labelled double stranded DNA samples, where the acceptor position was varied systematically. Interestingly, we found that fluorescence contributions arising from direct acceptor excitation following donor excitation are intrinsically taken into account in these conditions as other correction factors can compensate for inaccurate values of these parameters. We give here guidelines, that can be used through tools within the iSMS software (), for determining quantitative FRET and assess uncertainties linked with the procedure. Our results provide insights into the experimental parameters governing quantitative FRET determination, which is essential for obtaining accurate structural information from a wide range of biomolecules. PMID- 26416758 TI - Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination. AB - Enhancing repair of myelin is an important but still elusive therapeutic goal in many neurological disorders. In multiple sclerosis, an inflammatory demyelinating disease, endogenous remyelination does occur but is frequently insufficient to restore function. Both parenchymal oligodendrocyte progenitor cells and endogenous adult neural stem cells resident within the subventricular zone are known sources of remyelinating cells. Here we characterize the contribution to remyelination of a subset of adult neural stem cells, identified by their expression of Gli1, a transcriptional effector of the sonic hedgehog pathway. We show that these cells are recruited from the subventricular zone to populate demyelinated lesions in the forebrain but never enter healthy, white matter tracts. Unexpectedly, recruitment of this pool of neural stem cells, and their differentiation into oligodendrocytes, is significantly enhanced by genetic or pharmacological inhibition of Gli1. Importantly, complete inhibition of canonical hedgehog signalling was ineffective, indicating that the role of Gli1 both in augmenting hedgehog signalling and in retarding myelination is specialized. Indeed, inhibition of Gli1 improves the functional outcome in a relapsing/remitting model of experimental autoimmune encephalomyelitis and is neuroprotective. Thus, endogenous neural stem cells can be mobilized for the repair of demyelinated lesions by inhibiting Gli1, identifying a new therapeutic avenue for the treatment of demyelinating disorders. PMID- 26416761 TI - Interplay between density and superconducting quantum critical fluctuations. AB - We consider the case of a density-driven metal-superconductor transition in the proximity of an electronic phase separation. In particular, we investigate the interplay between superconducting fluctuations and density fluctuations, which become quantum critical when the electronic phase separation vanishes at zero temperature into a quantum critical point. In this situation, the critical dynamical density fluctuations strongly affect the dynamics of the Cooper-pair fluctuations, which acquire a more singular character with a z = 3 dynamical critical index. This gives rise to a scenario that possibly rules the disappearance of superconductivity when the electron density is reduced by electrostatic gating at the LaAlO3/SrTiO3 interface. PMID- 26416757 TI - A novel locus of resistance to severe malaria in a region of ancient balancing selection. AB - The high prevalence of sickle haemoglobin in Africa shows that malaria has been a major force for human evolutionary selection, but surprisingly few other polymorphisms have been proven to confer resistance to malaria in large epidemiological studies. To address this problem, we conducted a multi-centre genome-wide association study (GWAS) of life-threatening Plasmodium falciparum infection (severe malaria) in over 11,000 African children, with replication data in a further 14,000 individuals. Here we report a novel malaria resistance locus close to a cluster of genes encoding glycophorins that are receptors for erythrocyte invasion by P. falciparum. We identify a haplotype at this locus that provides 33% protection against severe malaria (odds ratio = 0.67, 95% confidence interval = 0.60-0.76, P value = 9.5 * 10(-11)) and is linked to polymorphisms that have previously been shown to have features of ancient balancing selection, on the basis of haplotype sharing between humans and chimpanzees. Taken together with previous observations on the malaria-protective role of blood group O, these data reveal that two of the strongest GWAS signals for severe malaria lie in or close to genes encoding the glycosylated surface coat of the erythrocyte cell membrane, both within regions of the genome where it appears that evolution has maintained diversity for millions of years. These findings provide new insights into the host-parasite interactions that are critical in determining the outcome of malaria infection. PMID- 26416762 TI - MC3T3-E1 Cells Behavior on Surfaces Bombarded by Argon Ions in Planar Cathode Discharge. AB - To evaluate the effect of topography in nanoscale, titanium surfaces were bombarded by argon ions (a chemically inert gas), in an atmosphere of plasma. The effects of surface parameters on morphology, adhesion, proliferation, and MC3T3 E1 preosteoblasts differentiation were analyzed. Nontreated (smooth) surfaces were used as a control. The levels of average roughness (Ra) observed in bombarded and smooth titanium surfaces were of 95 and 14 nm, respectively. The wettability increased on treated surfaces. The number of attached cells (30 and 60 min) was significantly higher on the bombarded surface. The cell proliferation after 3 and 7 days was also significantly higher on the ion-bombarded surface. In addition, the ALP activity and expression of osteocalcin were higher in cells grown on the treated surface. The results showed that bombardment with argon ions increased the roughness and the wettability of the Ti surface, promoting a significant increase in the adhesion, proliferation, and differentiation of preosteoblasts. PMID- 26416763 TI - The decrease in histone methyltransferase EZH2 in response to fluid shear stress alters endothelial gene expression and promotes quiescence. AB - High uniform fluid shear stress (FSS) is atheroprotective and preserves the endothelial phenotype and function through activation of downstream mediators such as MAPK7 (Erk5). Endothelial cells respond to FSS thanks to mechanotransduction. However, how the resulting signaling is integrated and resolved at the epigenetic level remains elusive. We hypothesized that Polycomb methyltransferase EZH2 is involved in the effects of FSS in human endothelial cells. We showed that FSS decreases the expression of the Polycomb methyltransferase EZH2. Despite simultaneous activation of MAPK7, MAPK7 pathway does not directly influence the transcription of EZH2. Interestingly though, the knockdown of EZH2 activates the protective MAPK7 signaling in endothelial cells, even in the absence of FSS. To understand the influence of the FSS-decreased expression of EZH2 on endothelial transcriptome, we performed RNA-seq and differential gene expression analysis. We identified candidate groups of genes dependent on both EZH2 and FSS. Among those, Gene Ontology overrepresentation analysis revealed highly significant enrichment of the cell cycle-related genes, suggesting changes in proliferation. Indeed, the depletion of EZH2 strongly inhibited endothelial proliferation, indicating cell cycle arrest. The concomitant decrease in CCNA expression suggests the transition of endothelial cells into a quiescent phenotype. Further bioinformatical analysis suggested TXNIP as a possible mediator between EZH2 and cell cycle-related gene network. Our data show that EZH2 is a FSS-responsive gene. Decreased EZH2 levels enhance the activation of the atheroprotective MAPK7 signaling. Decrease in EZH2 under FSS mediates the decrease in the expression of the network of cell cycle-related genes, which allows the cells to enter quiescence. EZH2 is therefore important for the protective effects of FSS in endothelium. PMID- 26416766 TI - What Data Do States Collect Related to School Nurses, School Health, and the Health Care Provided? AB - School nurses collect data to report to their school district and state agencies. However, there is no national requirement or standard to collect specific data, and each state determines its own set of questions. This study resulted from a joint resolution between the National Association of State School Nurse Consultants and the National Association of School Nurses. The study sought to determine whether similar data points were collected so that comparisons could be made among states and to develop a framework to incorporate the data. Thirty-two states provided their questionnaires or reports. There were 855 data points that could be divided into data related to staff and to students. No categories were measured by all states. The most common data points were the number of students, health screenings, and the number of students with particular conditions for whom the district provided services. A framework for data collection is proposed. PMID- 26416764 TI - Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is the most common reproductive disorder in women, yet there is little consensus regarding its aetiology. Here we perform a genome-wide association study of PCOS in up to 5,184 self-reported cases of White European ancestry and 82,759 controls, with follow-up in a further ~2,000 clinically validated cases and ~100,000 controls. We identify six signals for PCOS at genome-wide statistical significance (P<5 * 10(-8)), in/near genes ERBB4/HER4, YAP1, THADA, FSHB, RAD50 and KRR1. Variants in/near three of the four epidermal growth factor receptor genes (ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are associated with PCOS at or near genome-wide significance. Mendelian randomization analyses indicate causal roles in PCOS aetiology for higher BMI (P=2.5 * 10(-9)), higher insulin resistance (P=6 * 10(-4)) and lower serum sex hormone binding globulin concentrations (P=5 * 10(-4)). Furthermore, genetic susceptibility to later menopause is associated with higher PCOS risk (P=1.6 * 10(-8)) and PCOS-susceptibility alleles are associated with higher serum anti Mullerian hormone concentrations in girls (P=8.9 * 10(-5)). This large-scale study implicates an aetiological role of the epidermal growth factor receptors, infers causal mechanisms relevant to clinical management and prevention, and suggests balancing selection mechanisms involved in PCOS risk. PMID- 26416765 TI - Comprehensive analysis of the flowering genes in Chinese cabbage and examination of evolutionary pattern of CO-like genes in plant kingdom. AB - In plants, flowering is the most important transition from vegetative to reproductive growth. The flowering patterns of monocots and eudicots are distinctly different, but few studies have described the evolutionary patterns of the flowering genes in them. In this study, we analysed the evolutionary pattern, duplication and expression level of these genes. The main results were as follows: (i) characterization of flowering genes in monocots and eudicots, including the identification of family-specific, orthologous and collinear genes; (ii) full characterization of CONSTANS-like genes in Brassica rapa (BraCOL genes), the key flowering genes; (iii) exploration of the evolution of COL genes in plant kingdom and construction of the evolutionary pattern of COL genes; (iv) comparative analysis of CO and FT genes between Brassicaceae and Grass, which identified several family-specific amino acids, and revealed that CO and FT protein structures were similar in B. rapa and Arabidopsis but different in rice; and (v) expression analysis of photoperiod pathway-related genes in B. rapa under different photoperiod treatments by RT-qPCR. This analysis will provide resources for understanding the flowering mechanisms and evolutionary pattern of COL genes. In addition, this genome-wide comparative study of COL genes may also provide clues for evolution of other flowering genes. PMID- 26416767 TI - Current Backpack Weight Status for Primary Schoolchildren in Colima, Mexico. AB - The purpose of the study was to identify the current status of backpack weight in primary schoolchildren in Colima, Mexico, in relation to gender, school grade level, and body mass index. A cross-sectional study was conducted on 240 randomly selected children from 20 primary schools. The participating children's parents signed statements of informed consent. Descriptive statistics, the chi(2) test, Student's t-test, and Kruskal-Wallis test were used. The mean age was 8.55 +/- 2 years (range: 5-12 years). Seventy-eight percent of the schoolchildren presented with a backpack overload that was greater than 10% of their body weight. No significant differences were found in relation to gender. Four out of every five schoolchildren presented with backpack overload, exposing them to a potential health problem. Education and public policy prevention strategies for this situation should be implemented in Mexico and other regions of the world with the same problem. PMID- 26416768 TI - Quality improvement training for core medical and general practice trainees: a pilot study of project participation, completion and journal publication. AB - BACKGROUND AND OBJECTIVES: Small-scale quality improvement projects are expected to make a significant contribution towards improving the quality of healthcare. Enabling doctors-in-training to design and lead quality improvement projects is important preparation for independent practice. Participation is mandatory in speciality training curricula. However, provision of training and ongoing support in quality improvement methods and practice is variable. We aimed to design and deliver a quality improvement training package to core medical and general practice specialty trainees and evaluate impact in terms of project participation, completion and publication in a healthcare journal. METHOD: A quality improvement training package was developed and delivered to core medical trainees and general practice specialty trainees in the west of Scotland encompassing a 1-day workshop and mentoring during completion of a quality improvement project over 3 months. A mixed methods evaluation was undertaken and data collected via questionnaire surveys, knowledge assessment, and formative assessment of project proposals, completed quality improvement projects and publication success. RESULTS: Twenty-three participants attended the training day with 20 submitting a project proposal (87%). Ten completed quality improvement projects (43%), eight were judged as satisfactory (35%), and four were submitted and accepted for journal publication (17%). Knowledge and confidence in aspects of quality improvement improved during the pilot, while early feedback on project proposals was valued (85.7%). CONCLUSION: This small study reports modest success in training core medical trainees and general practice specialty trainees in quality improvement. Many gained knowledge of, confidence in and experience of quality improvement, while journal publication was shown to be possible. The development of educational resources to aid quality improvement project completion and mentoring support is necessary if expectations for quality improvement are to be realised. PMID- 26416769 TI - Trends in Biotechnological Drugs for Cancer Treatment. AB - BACKGROUND: Biotechnology, which promoted revolutions in many fields, generates great expectations for the future, mainly in the pharmaceutical sector for the treatment of several diseases. Cancer is a leading cause of death worldwide and due to its complexity and singularity, there are a number of challenges that limit the development of new drugs for antitumor therapies, making the research for cancer treatment one of the most exploited in the medical field. OBJECTIVE: The main objective of this article is to identify trends of biotechnological advances that may have application in improving cancer therapies. METHOD: Information from patent applications of biotechnological drugs in the last five years was retrieved using Thomson Reuters Integrity database. RESULTS: Cancer is the leading therapeutic condition found in patent documents. The subject matter most cited in patent applications includes monoclonal antibodies, adoptive cell therapy, RNA interference and new vaccine peptides. CONCLUSION: The analysis of the documents has provided an overview of new biological alternatives for use in cancer treatment, showing potential avenues for years to come. PMID- 26416772 TI - Correction: Assessing dimerisation degree and cooperativity in a biomimetic small molecule model by pulsed EPR. AB - Correction for 'Assessing dimerisation degree and cooperativity in a biomimetic small-molecule model by pulsed EPR' by K. Ackermann et al., Chem. Commun., 2015, 51, 5257-5260. PMID- 26416770 TI - Changes in Frailty After Kidney Transplantation. AB - OBJECTIVES: To understand the natural history of frailty after an aggressive surgical intervention, kidney transplantation (KT). DESIGN: Prospective cohort study (December 2008-March 2014). SETTING: Baltimore, Maryland. PARTICIPANTS: Kidney transplantation recipients (N = 349). MEASUREMENTS: The Fried frailty score was measured at the time of KT and during routine clinical follow-up. Using a Cox proportional hazards model, factors associated with improvements in frailty score after KT were identified. Using a longitudinal analysis, predictors of frailty score changes after KT were identified using a multilevel mixed-effects Poisson model. RESULTS: At KT, 19.8% of recipients were frail; 1 month after KT, 33.3% were frail; at 2 months, 27.7% were frail; and at 3 months, 17.2% were frail. On average, frailty scores had worsened by 1 month (mean change 0.4, P < .001), returned to baseline by 2 months (mean change 0.2, P = .07), and improved by 3 months (mean change -0.3, P = .04) after KT. The only recipient or transplant factor associated with improvement in frailty score after KT was pre KT frailty (hazard ratio = 2.55, 95% confidence interval (CI) = 1.71-3.82, P < .001). Pre-KT frailty status (relative risk (RR) = 1.49, 95% CI = 1.29-1.72, P < .001), recipient diabetes mellitus (RR = 1.26, 95% CI = 1.08-1.46, P = .003), and delayed graft function (RR = 1.22, 95% CI = 1.04-1.43, P = .02) were independently associated with long-term changes in frailty score. CONCLUSION: After KT, in adult recipients of all ages, frailty initially worsens but then improves by 3 months. Although KT recipients who were frail at KT had higher frailty scores over the long term, they were most likely to show improvements in their physiological reserve after KT, supporting the transplantation in these individuals and suggesting that pretransplant frailty is not an irreversible state of low physiological reserve. PMID- 26416773 TI - Indirect quantum sensors: improving the sensitivity in characterizing very weakly coupled spins. AB - We propose a scheme to increase the sensitivity and thus the detection volume of nanoscale single molecule magnetic resonance imaging. The proposal aims to surpass the T1 limited detection of the sensor by taking advantage of a long lived ancillary nuclear spin to which the sensor is coupled. We show how this nuclear spin takes over the role of the sensor spin, keeping the characteristic time-scales of detection on the same order but with a longer life-time allowing it to detect a larger volume of the sample, which is not possible by the sensor alone. PMID- 26416771 TI - Maternal bile acid transporter deficiency promotes neonatal demise. AB - Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse neonatal survival and is estimated to impact between 0.4 and 5% of pregnancies worldwide. Here we show that maternal cholestasis (due to Abcb11 deficiency) produces neonatal death among all offspring within 24 h of birth due to atelectasis producing pulmonary hypoxia, which recapitulates the neonatal respiratory distress of human ICP. Neonates of Abcb11-deficient mothers have elevated pulmonary bile acids and altered pulmonary surfactant structure. Maternal absence of Nr1i2 superimposed on Abcb11 deficiency strongly reduces maternal serum bile acid concentrations and increases neonatal survival. We identify pulmonary bile acids as a key factor in the disruption of the structure of pulmonary surfactant in neonates of ICP. These findings have important implications for neonatal respiratory failure, especially when maternal bile acids are elevated during pregnancy, and highlight potential pathways and targets amenable to therapeutic intervention to ameliorate this condition. PMID- 26416774 TI - Neurosyphilis presenting as parkinsonism. AB - In the postantibiotic era, neurosyphilis continues to have a significant incidence, especially in certain subpopulations. We report, for the first time, neurosyphilis presenting as parkinsonism without more typical neurosyphilitic clinical features. A 53-year-old man developed clinical features of gradual onset consistent with idiopathic Parkinson's disease but was found to have positive treponemal serology and cerebrospinal fluid Venereal Disease Research Laboratory (VRDL) reaction. Antibiotic treatment dramatically improved all the parkinsonian symptoms. However, over the subsequent 15 years, the patient slowly deteriorated again in a manner typical of idiopathic Parkinson's disease. A dopaminergic deficit was demonstrated on ((123)I)FP-CIT SPECT. This is the first report in the postantibiotic era of neurosyphilis presenting as relatively pure parkinsonism. Blood test screening for syphilis is therefore appropriate if there is any clinical doubt about an idiopathic parkinsonian presentation. The patient's late second deterioration may suggest that the neurosyphilitic basal ganglial insult primed or accelerated development of idiopathic-like disease. PMID- 26416776 TI - Irreversible order-disorder transformation of Ge(0 0 1) probed by scanning tunnelling microscopy. AB - We investigate the surface structure of Ge(0 0 1) during the (2 * 1)-(1 * 1) phase transition occurring at T > 1130 K by high-resolution scanning tunnelling microscopy. We find a drastic size reduction of dimerized domains in line with substantial dimer breakup accompanied by surface roughening. Completing the picture provided by previous spectroscopic observations, probing with high spatial resolution reveals the nucleation of several nanodomains with distinct vicinal orientations and reconstructions. The structural transformation is irreversible and is not observed for other singular faces of Ge. PMID- 26416775 TI - Giant cell arteritis: a closer look at its ophthalmological manifestations. AB - Giant cell arteritis with ocular involvement is an ocular emergency. Arteritic anterior ischaemic optic neuropathy (AAION) is the most common ophthalmological manifestation associated with this disease. Visual loss is usually permanent with rare cases showing visual recovery. Visual improvement, if it occurs, is generally limited, and the visual field defects are persistent and severe. The main goal of AAION treatment is the preservation of vision in the fellow eye. In patients with neurophthalmological manifestations, high-dose corticosteroids should be initiated immediately and aggressively, and maintained thereafter. We present a case of AAION and severe vision loss where significant visual recovery was seen after treatment. PMID- 26416777 TI - What are the best predictors for successful GnRH antagonist protocol in in vitro fertilization (IVF) treatment? AB - OBJECTIVE: To determine factors that affect the success rate of GnRH antagonist protocol in in vitro fertilization (IVF) treatment. DESIGN: Retrospective cohort study. PATIENTS: Patients who underwent IVF cycle with their first GnRH antagonist protocol. INTERVENTION: Antagonist protocol during IVF treatment. The main outcome measurements were; Number of retrieved oocytes, embryo quality and pregnancy rate. RESULTS: Gravidity was negatively correlated with number of eggs (p = 0.017), while total follicle number >=15 (p = 0.044) and E(2) on day of human chorionic gonadotropin (HCG) (p = 0.000) had a positive correlation with number of eggs. Maximum follicle size at HCG administration showed a trend toward an inverse correlation (p = 0.053). Addition of LH to drug stimulation was negatively correlated with number of eggs in comparison to rFSH only (p = 0.013 and 0.0000, respectively). Age and number of frozen eggs were negatively correlated with successful pregnancy (p = 0.025 and 0.004, respectively), while embryo quality, gravidity and number of embryos were positive (p = 0.011 and 0.014, respectively). CONCLUSION: Controlled parameters like timing of antagonist start, duration of antagonist and the optimal leading follicle diameter for HCG triggering had no effect on treatment outcomes. PMID- 26416778 TI - Anti-Pseudomonas aeruginosa activity of 1,10-phenanthroline-based drugs against both planktonic- and biofilm-growing cells. AB - OBJECTIVES: The beneficial antimicrobial properties of 1,10-phenanthroline (phen) based drugs, together with the imperative need to develop new chemotherapeutic options for prevention/treatment of infections caused by MDR Gram-negative bacteria, led us to evaluate the effects of phen, 1,10-phenanthroline-5,6-dione (phendione), [Ag(phendione)2]ClO4 and [Cu(phendione)3](ClO4)2.4H2O on planktonic- and biofilm-growing Pseudomonas aeruginosa. METHODS: Thirty-two non-duplicated Brazilian clinical isolates of P. aeruginosa with distinct genetic backgrounds were used in all experiments. The effect of test compounds on planktonic bacterial proliferation was determined as recommended by CLSI protocol. The effect on biofilm formation was evaluated by crystal violet incorporation (biomass determination) and XTT (viability assay). Mature biofilm disorganization was evidenced by staining with crystal violet. RESULTS: Phen-based compounds presented anti-P. aeruginosa activity, but with different potencies concerning the geometric mean MIC: [Cu(phendione)3](2+) (7.76 MUM) > [Ag(phendione)2](+) (14.05 MUM) > phendione (31.15 MUM) > phen (579.28 MUM). MICs of each compound were similar irrespective of whether the P. aeruginosa isolates were susceptible or resistant to classical antimicrobials (ceftazidime, meropenem and imipenem). The pretreatment of bacteria with phen, phendione and phendione's metal derivatives at 0.5 * MIC value inhibited biofilm formation, particularly the use of [Cu(phendione)3](2+) and [Ag(phendione)2](+), which significantly reduced both biomass (48% and 44%, respectively) and viability (78% and 77%, respectively). The compounds studied also disrupted mature biofilm in a dose-dependent manner, especially [Ag(phendione)2](+) and [Cu(phendione)3](2+) (IC50, 9.39 and 10.16 MUM, respectively). CONCLUSIONS: Coordination of phendione to Ag(+) and Cu(2+) represents a new promising group of anti-infective agents, which revealed a potent anti-P. aeruginosa action against both planktonic- and biofilm-growing cells. PMID- 26416779 TI - A small Acinetobacter plasmid carrying the tet39 tetracycline resistance determinant. PMID- 26416780 TI - Population pharmacokinetics of meropenem administered as a prolonged infusion in children with cystic fibrosis. AB - OBJECTIVES: Meropenem is frequently used to treat pulmonary exacerbations in children with cystic fibrosis (CF) in the USA. Prolonged-infusion meropenem improves the time that free drug concentrations remain above the MIC (fT> MIC) in adults, but data in CF children are sparse. We describe the population pharmacokinetics, tolerability and treatment burden of prolonged-infusion meropenem in CF children. METHODS: Thirty children aged 6-17 years with a pulmonary exacerbation received 40 mg/kg meropenem every 8 h; each dose was administered as a 3 h infusion. Pharmacokinetics were determined using population methods in Pmetrics. Monte Carlo simulation was employed to compare 0.5 with 3 h infusions to estimate the probability of pharmacodynamic target attainment (PTA) at 40% fT> MIC. NCT#01429259. RESULTS: A two-compartment model fitted the data best with clearance and volume predicted by body weight. Clearance and volume of the central compartment were 0.41 +/- 0.23 L/h/kg and 0.30 +/- 0.17 L/kg, respectively. Half-life was 1.11 +/- 0.38 h. At MICs of 1, 2 and 4 mg/L, PTAs for the 0.5 h infusion were 87.6%, 70.1% and 35.4%, respectively. The prolonged infusion increased PTAs to >99% for these MICs and achieved 82.8% at 8 mg/L. Of the 30 children, 18 (60%) completed treatment with prolonged infusion; 5 did so at home without any reported burden. Nine patients were changed to a 0.5 h infusion when discharged home. CONCLUSIONS: In these CF children, meropenem clearance was greater compared with published values from non-CF children. Prolonged infusion provided an exposure benefit against pathogens with MICs >=1 mg/L, was well tolerated and was feasible to administer in the hospital and home settings, the latter depending on perception and family schedule. PMID- 26416781 TI - In vitro evaluation of dual carbapenem combinations against carbapenemase producing Enterobacteriaceae. AB - OBJECTIVES: This study aimed to analyse the in vitro activity of dual combinations of carbapenems against Klebsiella pneumoniae producing the main carbapenemase types. METHODS: MIC values of the carbapenems, imipenem, meropenem, ertapenem and doripenem were determined alone and in dual combinations for 20 clinical K. pneumoniae isolates producing representative carbapenemases, i.e. OXA 48 (n = 6), NDM-1 (n = 4), NDM-1 + OXA-48 (n = 2) and KPC-2 (n = 8). MICs were also determined for Escherichia coli recombinant strains with or without permeability defects producing NDM-1, OXA-48 or KPC-2. In vitro synergy combination testing was performed using the microdilution and chequerboard techniques. Fractional inhibitory concentration indexes were calculated to determine whether the combinations were synergistic, indifferent or antagonistic. RESULTS: All carbapenemase producers were resistant to the tested carbapenems, with most isolates showing MICs of carbapenems >32 mg/L. None of the combinations was antagonistic. For KPC producers, synergistic combinations were observed with imipenem/ertapenem (5/8 isolates), imipenem/doripenem (4/8), imipenem/doripenem (4/8), meropenem/doripenem (3/8) and ertapenem/doripenem (3/8), while no synergy was observed with meropenem/ertapenem. For OXA-48 producers, synergies were observed with imipenem/ertapenem and with imipenem/meropenem for both isolates tested. Notably, combining imipenem with a non-carbapenem beta-lactam (cefalotin) did not give any synergistic result. No synergy was observed for all NDM-1 and NDM-1+OXA-48 producers. Time-kill assays confirmed most of the data obtained by chequerboard testing. CONCLUSIONS: The data strongly support the hypothesis that dual carbapenem combinations might be effective against serine-beta-lactamase producers (KPC, OXA-48). The imipenem-containing combinations appeared to be the most efficient. PMID- 26416782 TI - A Spanish Study on Psychological Predictors of Quality of Life in People with HIV. AB - In Spain little research has focused on assessment of health indicators, both physical and psychological, in people living with HIV. The aim of this study is to evaluate a set of different indicators that allow us to identify psychological factors that may be influencing the quality of life of these people. The sample consist of 744 people infected with HIV aged between from 18 to 82 years (M = 43.04; SD = 9.43). Results show that factors such as self-esteem and leading a healthy lifestyle act as protectors in both, physical and mental health. On the other hand, financial problems, body disfigurement, and depressive mood could have harmful effects on both, physical and mental health. The structural model reveals depressed mood as the factor with greatest influence upon mental health, which in turn can be largely explained by factors such as the stress generated by HIV and personal autonomy. This work has allowed us to identify the vulnerability and protective factors that play a significant role in the physical and mental HRQOL of persons with HIV, providing guidelines for design and implementation of psychological intervention programs aimed to improve HRQOL in this population. PMID- 26416783 TI - The role of seaweed bioactives in the control of digestion: implications for obesity treatments. AB - Seaweeds are an underutilised nutritional resource that could not only compliment the current western diet but potentially bring additional health benefits over and above their nutritional value. There are four groups of seaweed algae; green algae (Chlorophyceae), red algae (Rhodophycae), blue-green algae (Cyanophyceae) and brown algae (Phaeophyceae). Seaweeds are rich in bioactive components including polysaccharides and polyphenols. Polysaccharides content, such as fucoidan, laminarin, as well as alginate is generally high in brown seaweeds which are also a source of polyphenols such as phenolic acids, flavonoids, phlorotannin, stilbenes and lignans. These components have been shown to reduce the activity of digestive enzymes, modulating enzymes such as alpha-amylase, alpha-glucosidase, pepsin and lipase. This review discusses the effect of several of these components on the digestive processes within the gastrointestinal tract; focusing on the effect of alginate on pancreatic lipase activity and its potential health benefits. Concluding that there is evidence to suggest alginate has the potential to be used as an obesity treatment, however, further in vivo research is required and an effective delivery method for alginate must be designed. PMID- 26416784 TI - One-year-old fear memories rapidly activate human fusiform gyrus. AB - Fast threat detection is crucial for survival. In line with such evolutionary pressure, threat-signaling fear-conditioned faces have been found to rapidly (<80 ms) activate visual brain regions including the fusiform gyrus on the conditioning day. Whether remotely fear conditioned stimuli (CS) evoke similar early processing enhancements is unknown. Here, 16 participants who underwent a differential face fear-conditioning and extinction procedure on day 1 were presented the initial CS 24 h after conditioning (Recent Recall Test) as well as 9-17 months later (Remote Recall Test) while EEG was recorded. Using a data driven segmentation procedure of CS evoked event-related potentials, five distinct microstates were identified for both the recent and the remote memory test. To probe intracranial activity, EEG activity within each microstate was localized using low resolution electromagnetic tomography analysis (LORETA). In both the recent (41-55 and 150-191 ms) and remote (45-90 ms) recall tests, fear conditioned faces potentiated rapid activation in proximity of fusiform gyrus, even in participants unaware of the contingencies. These findings suggest that rapid processing enhancements of conditioned faces persist over time. PMID- 26416786 TI - Tools and pipelines for BioNano data: molecule assembly pipeline and FASTA super scaffolding tool. AB - BACKGROUND: Genome assembly remains an unsolved problem. Assembly projects face a range of hurdles that confound assembly. Thus a variety of tools and approaches are needed to improve draft genomes. RESULTS: We used a custom assembly workflow to optimize consensus genome map assembly, resulting in an assembly equal to the estimated length of the Tribolium castaneum genome and with an N50 of more than 1 Mb. We used this map for super scaffolding the T. castaneum sequence assembly, more than tripling its N50 with the program Stitch. CONCLUSIONS: In this article we present software that leverages consensus genome maps assembled from extremely long single molecule maps to increase the contiguity of sequence assemblies. We report the results of applying these tools to validate and improve a 7x Sanger draft of the T. castaneum genome. PMID- 26416785 TI - Escalating risk and the moderating effect of resistance to peer influence on the P200 and feedback-related negativity. AB - Young people frequently socialize together in contexts that encourage risky decision making, pointing to a need for research into how susceptibility to peer influence is related to individual differences in the neural processing of decisions during sequentially escalating risk. We applied a novel analytic approach to analyze EEG activity from college-going students while they completed the Balloon Analogue Risk Task (BART), a well-established risk-taking propensity assessment. By modeling outcome-processing-related changes in the P200 and feedback-related negativity (FRN) sequentially within each BART trial as a function of pump order as an index of increasing risk, our results suggest that analyzing the BART in a progressive fashion may provide valuable new insights into the temporal neurophysiological dynamics of risk taking. Our results showed that a P200, localized to the left caudate nucleus, and an FRN, localized to the left dACC, were positively correlated with the level of risk taking and reward. Furthermore, consistent with our hypotheses, the rate of change in the FRN was higher among college students with greater self-reported resistance to peer influence. PMID- 26416787 TI - Nocturnal enuresis: prevalence and risk factors among school-aged children with sickle-cell anaemia in a South-east Nigerian city. AB - BACKGROUND: Sickle-cell anaemia (SCA) is the most common inherited haemoglobinopathy affecting the Negroid race. Renal complications such as enuresis can occur during childhood. Reports show that children and adolescents with SCA may be at a higher risk of nocturnal enuresis than their counterparts with normal haemoglobin genotype. AIMS: The study aims to determine the prevalence of nocturnal enuresis and possible risk factors among school-aged children with SCA in a South-east Nigerian city. METHODS: A hospital-based and cross-sectional descriptive study of 70 school-aged children with SCA who met the study criteria, and 70 age- and sex-matched controls with normal haemoglobin genotype was conducted in the Paediatric Sickle-cell Anaemia Clinic of the University of Nigeria Teaching Hospital (UNTH) Enugu. Data was subjected to multivariate analysis using logistic regression model with nocturnal enuresis as the dependent variable and the possible risk factors as the independent variables. RESULTS: The prevalence of nocturnal enuresis among the Subjects and the Controls was 31.4 and 21.4 % respectively (p = 0.180). It was significantly higher among male Subjects (48.7 %) than among male Controls (23.1 %) [OR (95 % CI) =8.14 (2.12-31.24), p < 0.001]; and among Subjects whose parents had a childhood history of enuresis [OR (95 %) =10.39 (2.45-44.05), p = 0.002]. The difference in the prevalence of enuresis in the female cohort was however not significant. CONCLUSIONS: Children with SCA have a tendency to develop nocturnal enuresis when compared to their non-affected counterparts. Male gender and parental childhood history of nocturnal enuresis are potential socio-demographic risk factors. PMID- 26416788 TI - Better prioritization to increase research value and decrease waste. AB - In a recent study published in BMC Medicine, Singh Ospina and colleagues outlined the important gaps between ongoing research and research needs in the field of endocrinology. Many recommendations from clinical practice guidelines are based on a low level of evidence, thereby resulting in research gaps. Despite the publication of around 25,000 randomized controlled trials each year, ongoing research does not cover most of these gaps. In contrast, trials are planned when sufficient data are already available for decision making, which results in redundant research and exposes patients to unnecessary risks. This lack of prioritization contributes to the enormous problem of waste in research. A systematic approach to accumulate the available body of evidence is necessary to determine when we have sufficient evidence and when we have knowledge gaps, defined as research questions with no or a low level of evidence available. Systematic registration of research gaps and their prioritization may help to organize future research. Some initiatives exist, but they need to be generalized.Please see related research: http://www.biomedcentral.com/1741 7015/13/187. PMID- 26416789 TI - The effect of a reversible shear transformation on plastic deformation of an amorphous solid. AB - Langevin dynamics simulations are performed to investigate the plastic response of a model glass to a local shear transformation in a quiescent system. The deformation of the material is induced by a spherical inclusion that is gradually strained into an ellipsoid of the same volume and then reverted back into the sphere. We show that the number of cage-breaking events increases with increasing strain amplitude of the shear transformation. The results of numerical simulations indicate that the density of cage jumps is larger in the cases of weak damping or slow shear transformation. Remarkably, we also found that, for a given strain amplitude, the peak value of the density profiles is a function of the ratio of the damping coefficient and the time scale of the shear transformation. PMID- 26416790 TI - Advanced thyroid carcinoma in pregnancy: case report of two pregnancies. AB - Differentiated thyroid carcinoma is one of the most frequently diagnosed cancers during pregnancy, second only to breast cancer. Therefore, it would be of value to determine if there are pregnancy-related physiological effects that impact long-term prognosis for patients with this disease. Hormone effects attributable to beta-human chorionic gonadotropin and estrogens seem particularly likely. We present a case of a 40-year-old woman with thyroid follicular carcinoma with accompanying bone metastases. The cancer was discovered immediately after childbirth and the woman became pregnant again when the disease was in an advanced stage. We describe the cancer evolution and present the maternal and fetal results. Pregnancy in women with advanced thyroid carcinoma could affect long-term prognosis. However, more studies are needed to evaluate this hypothesis. In this unique case, there were two pregnancies and the second occurred in an advanced state of the disease. We evaluated how these pregnancies could affect short-term prognosis of the disease. PMID- 26416791 TI - Predicting direct and indirect breeding values for survival time in laying hens using repeated measures. AB - BACKGROUND: Minimizing bird losses is important in the commercial layer industry. Selection against mortality is challenging because heritability is low, censoring is high, and individual survival depends on social interactions among cage members. With cannibalism, mortality depends not only on an individual's own genes (direct genetic effects; DGE) but also on genes of its cage mates (indirect genetic effects; IGE). To date, studies using DGE-IGE models have focussed on survival time but their shortcomings are that censored records were considered as exact lengths of life and models assumed that IGE were continuously expressed by all cage members even after death. However, since dead animals no longer express IGE, IGE should ideally be time-dependent in the model. Neglecting censoring and timing of IGE expression may reduce accuracy of estimated breeding values (EBV). Thus, our aim was to improve prediction of breeding values for survival time in layers that present cannibalism. METHODS: We considered four DGE-IGE models to predict survival time in layers. One model was an analysis of survival time and the three others treated survival in consecutive months as a repeated binomial trait (repeated measures models). We also tested whether EBV were improved by including timing of IGE expression in the analyses. Approximate EBV accuracies were calculated by cross-validation. The models were fitted to survival data on two purebred White Leghorn layer lines W1 and WB, each having monthly survival records over 13 months. RESULTS: Including the timing of IGE expression in the DGE-IGE model reduced EBV accuracy compared to analysing survival time. EBV accuracy was higher when repeated measures models were used. However, there was no universal best model. Using repeated measures instead of analysing survival time increased EBV accuracy by 10 to 21 and 2 to 12 % for W1 and WB, respectively. We showed how EBV and variance components estimated with repeated measures models can be translated into survival time. CONCLUSIONS: Our results suggest that prediction of breeding values for survival time in laying hens can be improved using repeated measures models. This is an important result since more accurate EBV contribute to higher rates of genetic gain. PMID- 26416792 TI - A Large State Medicaid Outpatient Advanced Imaging Utilization Management Program: Substantial Savings Without the Need for Denials. AB - A decade of rapidly rising outpatient advanced imaging utilization ended toward the end of the past decade, with slow growth since. This has been attributed to repetitive reimbursement cuts, medical radiation exposure concerns, increasing deductibles and patient copayments, and the influence of radiology benefit management companies. State Medicaid programs have been reluctant to institute radiology benefit management preauthorization programs since the time burden for obtaining test approval could cause providers to drop out. Also, these patients may lack the knowledge to appeal denials, and medically necessary tests could be denied with adverse outcomes. Little data exist demonstrating the efficacy of such programs in decreasing utilization and cost. We report a 2-year experience with an outpatient advanced imaging prior notification program for a large state Medicaid fee-for-service population. The program did not allow any denials, but nevertheless the data reveal a large, durable decrease in advanced imaging utilization and cost. PMID- 26416793 TI - Editorial: From Multiple Hits to Multiple Therapeutic Targets of Non-Alcoholic Fatty Liver Disease. PMID- 26416794 TI - Evaluation of antioxidative and antitumor activities of extracted flavonoids from Pink Lady apples in human colon and breast cancer cell lines. AB - The antioxidative and anticancer effects of extracted flavonoids from Pink Lady apples on human colon cancer LoVo cells and breast cancer MCF-7 cells were evaluated. It was found that the antioxidative property of the peel-flavonoids (Peel-F) was more effective than that of the flesh-flavonoids (Flesh-F). Meanwhile, both the Peel-F and Flesh-F can inhibit cancer cell growth in a dose dependent manner, with the IC50 values of 110.33 +/- 2.52 mg mL(-1) and 378.14 +/ 1.64 mg mL(-1) for LoVo cells and 58.42 +/- 1.39 mg mL(-1) and 296.06 +/- 3.71 mg mL(-1) for MCF-7 cells. This led to the conclusion that the Peel-F were more effective against cancer cells than the Flesh-F, and that the scavenging ROS effects were significantly higher in the Peel-F in vitro. Moreover, we also found that the generation of ROS is a critical mediator in apple flavonoid-induced cell apoptosis and the induction effect of the Peel-F was significantly higher than that of the Flesh-F. PMID- 26416796 TI - In Memoriam: Charles M. Mansbach II (1937 - 2015). PMID- 26416795 TI - Quantitative analysis of the murine lipid droplet-associated proteome during diet induced hepatic steatosis. AB - Hepatic steatosis is characterized by the accumulation of lipid droplets (LDs), which are composed of a neutral lipid core surrounded by a phospholipid monolayer embedded with many proteins. Although the LD-associated proteome has been investigated in multiple tissues and organisms, the dynamic changes in the murine LD-associated proteome in response to obesity and hepatic steatosis have not been studied. We characterized the hepatic LD-associated proteome of C57BL/6J male mouse livers following high-fat feeding using isobaric tagging for relative and absolute quantification. Of the 1,520 proteins identified with a 5% local false discovery rate, we report a total of 48 proteins that were increased and 52 proteins that were decreased on LDs in response to high-fat feeding. Most notably, ribosomal and endoplasmic reticulum proteins were increased and extracellular and cytosolic proteins were decreased in response to high-fat feeding. Additionally, many proteins involved in fatty acid catabolism or xenobiotic metabolism were enriched in the LD fraction following high-fat feeding. In contrast, proteins involved in glucose metabolism and liver X receptor or retinoid X receptor activation were decreased on LDs of high-fat-fed mice. This study provides insights into unique biological functions of hepatic LDs under normal and steatotic conditions. PMID- 26416797 TI - Preparation of intravenous cholesterol tracer using current good manufacturing practices. AB - Studies of human reverse cholesterol transport require intravenous infusion of cholesterol tracers. Because insoluble lipids may pose risk and because it is desirable to have consistent doses of defined composition available over many months, we investigated the manufacture of cholesterol tracer under current good manufacturing practice (CGMP) conditions appropriate for phase 1 investigation. Cholesterol tracer was prepared by sterile admixture of unlabeled cholesterol or cholesterol-d7 in ethanol with 20% Intralipid((r)). The resulting material was filtered through a 1.2 micron particulate filter, stored at 4 degrees C, and tested at time 0, 1.5, 3, 6, and 9 months for sterility, pyrogenicity, autoxidation, and particle size and aggregation. The limiting factor for stability was a rise in thiobarbituric acid-reacting substances of 9.6-fold over 9 months (P < 0.01). The emulsion was stable with the Z-average intensity weighted mean droplet diameter remaining at 60 nm over 23 months. The zeta potential (a measure of negative surface charge protecting from aggregation) was unchanged at -36.2. Rapid cholesterol pool size was 25.3 +/- 1.3 g. Intravenous cholesterol tracer was stable at 4 degrees C for 9 months postproduction. CGMP manufacturing methods can be achieved in the academic setting and need to be considered for critical components of future metabolic studies. PMID- 26416798 TI - Takotsubo cardiomyopathy in myasthaenia gravis crisis confirmed by cardiac MRI. AB - Myasthaenia gravis crisis and Takotsubo cardiomyopathy are rare conditions that can be precipitated by emotional or physical stress. Myasthaenia gravis has a variety of cardiac manifestations but Takotsubo cardiomyopathy, particularly in male patients, has rarely been reported. We describe a unique case of a 70-year old man who developed Takotsubo cardiomyopathy during his first presentation with a myasthaenia gravis crisis. He had not received plasmapharesis or immunoglobulin therapy. Striking ECG traces and cardiac MRI helped to confirm the diagnosis. Cardiac manifestations of myasthaenia gravis and myasthaenia gravis itself have overlapping symptoms; the importance of cardiac monitoring and clinical vigilance in such cases is discussed. The utility of cardiac MRI in assessing cardiac manifestations of myasthaenia gravis is also highlighted. PMID- 26416799 TI - Association between intrauterine mild hyperglycemia and post-natal high-fat diet with adiponectin and AMPK pathway genes. AB - To investigate the mechanisms of maternal-fetal interactions in the setting of gestational diabetes mellitus. We investigated the long-term effects of intrauterine mild hyperglycemia and a postnatal high-fat diet on the glucose metabolism of adult offspring, and explored the role of adiponectin on hepatic gluconeogenesis. Twenty-one pregnant Wistar rats were randomly divided into an intrauterine hyperglycemia group (group D, n = 14) and a control group (group C, n = 7). Offspring were divided into four groups according to intrauterine blood glucose level and post-weaning dietary patterns (high-fat diet groups: DF and CF or normal diet groups: DN and CN, n = 8 per group). The average birth weights of group D offspring were higher than for group C. In the DF rats, low adiponectin mRNA expression in perirenal and epididymal fat was significantly positively correlated with low hepatic AdipoR1 mRNA expression and significantly correlated with high hepatic PEPCK, G-6-Pase, and PGC-1alpha mRNA levels. In DF rats, hepatic P-AMPK was cytoplasmically located and its level was decreased; in these rats, hepatic CRTC2 was expressed in the nucleus and its level was significantly increased. Our study shows that the dietary structure of offspring has a large influence on the incidence of abnormal glucose tolerance. PMID- 26416800 TI - Memory and Mechanism. PMID- 26416801 TI - Cystic lesion of the fourth ventricle: Role of CISS. PMID- 26416802 TI - Metastatic breast cancer in a man with nonprogressive ataxia and epilepsy. PMID- 26416803 TI - Association of prone position with sudden unexpected death in epilepsy. PMID- 26416804 TI - Mindfulness therapy and seizures. PMID- 26416805 TI - Mystery Case: Intracranial hemorrhage in adult vein of Galen malformation. PMID- 26416806 TI - Clinical Reasoning: A 73-year-old man with diplopia and ataxia. PMID- 26416807 TI - Escherichia coli O157:H7 strains harbor at least three distinct sequence types of Shiga toxin 2a-converting phages. AB - BACKGROUND: Shiga toxin-producing Escherichia coli O157:H7 is a foodborne pathogen that causes severe human diseases including hemolytic uremic syndrome (HUS). The virulence factor that mediates HUS, Shiga toxin (Stx), is encoded within the genome of a lambdoid prophage. Although draft sequences are publicly available for a large number of E. coli O157:H7 strains, the high sequence similarity of stx-converting bacteriophages with other lambdoid prophages poses challenges to accurately assess the organization and plasticity among stx converting phages due to assembly difficulties. METHODS: To further explore genome plasticity of stx-converting prophages, we enriched phage DNA from 45 ciprofloxacin-induced cultures for subsequent 454 pyrosequencing to facilitate assembly of the complete phage genomes. In total, 22 stx2a-converting phage genomes were closed. RESULTS: Comparison of the genomes distinguished nine distinct phage sequence types (PSTs) delineated by variation in obtained sequences, such as single nucleotide polymorphisms (SNPs) and insertion sequence element prevalence and location. These nine PSTs formed three distinct clusters, designated as PST1, PST2 and PST3. The PST2 cluster, identified in two clade 8 strains, was related to stx2a-converting phages previously identified in non-O157 Shiga-toxin producing E. coli (STEC) strains associated with a high incidence of HUS. The PST1 cluster contained phages related to those from E. coli O157:H7 strain Sakai (lineage I, clade 1), and PST3 contained a single phage that was distinct from the rest but most related to the phage from E. coli O157:H7 strain EC4115 (lineage I/II, clade 8). Five strains carried identical stx2a-converting phages (PST1-1) integrated at the same chromosomal locus, but these strains produced different levels of Stx2. CONCLUSION: The stx2a-converting phages of E. coli O157:H7 can be categorized into at least three phage types. Diversification within a phage type is mainly driven by IS629 and by a small number of SNPs. Polymorphisms between phage genomes may help explain differences in Stx2a production between strains, however our data indicates that genes encoded external to the phage affect toxin production as well. PMID- 26416808 TI - Objectively Measured Sedentary Time and Cardiometabolic Biomarkers in US Hispanic/Latino Adults: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL). AB - BACKGROUND: Sedentary behavior is recognized as a distinct construct from lack of moderate-vigorous physical activity and is associated with deleterious health outcomes. Previous studies have primarily relied on self-reported data, whereas data on the relationship between objectively measured sedentary time and cardiometabolic biomarkers are sparse, especially among US Hispanics/Latinos. METHODS AND RESULTS: We examined associations of objectively measured sedentary time (via Actical accelerometers for 7 days) and multiple cardiometabolic biomarkers among 12 083 participants, aged 18 to 74 years, from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Hispanics/Latinos of diverse backgrounds (Central American, Cuban, Dominican, Mexican, Puerto Rican, and South American) were recruited from 4 US cities between 2008 and 2011. Sedentary time (<100 counts/min) was standardized to 16 hours/d of wear time. The mean sedentary time was 11.9 hours/d (74% of accelerometer wear time). After adjustment for moderate-vigorous physical activity and confounding variables, prolonged sedentary time was associated with decreased high-density lipoprotein cholesterol (P=0.04), and increased triglycerides, 2-hour glucose, fasting insulin, and homeostatic model assessment of insulin resistance (all P<0.0001). These associations were generally consistent across age, sex, Hispanic/Latino backgrounds, and physical activity levels. Even among individuals meeting physical activity guidelines, sedentary time was detrimentally associated with several cardiometabolic biomarkers (diastolic blood pressure, high-density lipoprotein cholesterol, fasting and 2-hour glucose, fasting insulin and homeostatic model assessment of insulin resistance; all P<0.05). CONCLUSIONS: Our large population-based, objectively derived data showed deleterious associations between sedentary time and cardiometabolic biomarkers, independent of physical activity, in US Hispanics/Latinos. Our findings emphasize the importance of reducing sedentary behavior for the prevention of cardiometabolic diseases, even in those who meet physical activity recommendations. PMID- 26416809 TI - Vascular Smooth Muscle Cell Senescence Promotes Atherosclerosis and Features of Plaque Vulnerability. AB - BACKGROUND: Although vascular smooth muscle cell (VSMC) proliferation is implicated in atherogenesis, VSMCs in advanced plaques and cultured from plaques show evidence of VSMC senescence and DNA damage. In particular, plaque VSMCs show shortening of telomeres, which can directly induce senescence. Senescence can have multiple effects on plaque development and morphology; however, the consequences of VSMC senescence or the mechanisms underlying VSMC senescence in atherosclerosis are mostly unknown. METHODS AND RESULTS: We examined the expression of proteins that protect telomeres in VSMCs derived from human plaques and normal vessels. Plaque VSMCs showed reduced expression and telomere binding of telomeric repeat-binding factor-2 (TRF2), associated with increased DNA damage. TRF2 expression was regulated by p53-dependent degradation of the TRF2 protein. To examine the functional consequences of loss of TRF2, we expressed TRF2 or a TRF2 functional mutant (T188A) as either gain- or loss-of-function studies in vitro and in apolipoprotein E(-/-) mice. TRF2 overexpression bypassed senescence, reduced DNA damage, and accelerated DNA repair, whereas TRF2(188A) showed opposite effects. Transgenic mice expressing VSMC-specific TRF2(T188A) showed increased atherosclerosis and necrotic core formation in vivo, whereas VSMC-specific TRF2 increased the relative fibrous cap and decreased necrotic core areas. TRF2 protected against atherosclerosis independent of secretion of senescence-associated cytokines. CONCLUSIONS: We conclude that plaque VSMC senescence in atherosclerosis is associated with loss of TRF2. VSMC senes cence promotes both atherosclerosis and features of plaque vulnerability, identifying prevention of senescence as a potential target for intervention. PMID- 26416811 TI - Postpartum Hypertension: "It Ain't Over 'til It's Over". PMID- 26416810 TI - Epidemiology and Mechanisms of De Novo and Persistent Hypertension in the Postpartum Period. AB - BACKGROUND: The pathophysiology of hypertension in the immediate postpartum period is unclear. METHODS AND RESULTS: We studied 988 consecutive women admitted to a tertiary medical center for cesarean section of a singleton pregnancy. The angiogenic factors soluble fms-like tyrosine kinase 1 and placental growth factor, both biomarkers associated with preeclampsia, were measured on antepartum blood samples. We then performed multivariable analyses to determine factors associated with the risk of developing postpartum hypertension. Of the 988 women, 184 women (18.6%) developed postpartum hypertension. Of the 184 women, 77 developed de novo hypertension in the postpartum period, and the remainder had a hypertensive disorder of pregnancy in the antepartum period. A higher body mass index and history of diabetes mellitus were associated with the development of postpartum hypertension. The antepartum ratio of soluble fms-like tyrosine kinase 1 to placental growth factor positively correlated with blood pressures in the postpartum period (highest postpartum systolic blood pressure [r=0.29, P<0.001] and diastolic blood pressure [r=0.28, P<0.001]). Moreover, the highest tertile of the antepartum ratio of soluble fms-like tyrosine kinase 1 to placental growth factor was independently associated with postpartum hypertension (de novo hypertensive group: odds ratio, 2.25; 95% confidence interval, 1.19-4.25; P=0.01; in the persistent hypertensive group: odds ratio, 2.61; 95% confidence interval, 1.12-6.05; P=0.02) in multivariable analysis. Women developing postpartum hypertension had longer hospitalizations than those who remained normotensive (6.5+/-3.5 versus 5.7+/-3.4 days; P<0.001). CONCLUSIONS: Hypertension in the postpartum period is relatively common and is associated with prolonged hospitalization. Women with postpartum hypertension have clinical risk factors and an antepartum plasma angiogenic profile similar to those found in women with preeclampsia. These data suggest that women with postpartum hypertension may represent a group of women with subclinical or unresolved preeclampsia. PMID- 26416812 TI - Magnetic nanoparticle-mediated hyperthermia therapy induces tumour growth inhibition by apoptosis and Hsp90/AKT modulation. AB - PURPOSE: We have evaluated the hyperthermia efficacy of oleic acid-functionalised Fe(3)O(4) magnetic nanoparticles (MN-OA) under in vivo conditions and elucidated the underlying mechanism of tumour growth inhibition. MATERIALS AND METHODS: The efficacy and mechanism of tumour growth inhibition by MN-OA-mediated magnetic hyperthermia therapy (MHT) was evaluated in a murine fibrosarcoma tumour model (WEHI-164) using techniques such as TUNEL assay, Western blotting (WB), immunofluorescence (IF) staining and histopathological examination. In addition, bio-distribution of MN-OA in tumour/other target organs and its effect on normal organ function were studied by Prussian blue staining and serum biochemical analysis, respectively. RESULTS: MN-OA-induced MHT resulted in significant inhibition of tumour growth as determined by measurement of tumour volume, as well as by in vivo imaging of tumour derived from luciferase-transfected WEHI-164 cells. Histopathology analysis showed presence of severe apoptosis and reduced tumour cells proliferation, which was further confirmed by TUNEL assay, reduced expression of Ki-67 and enhanced level of cleaved caspase-3, in tumours treated with MHT. Moreover, expression of heat stress marker, Hsp90 and its client protein, AKT/PKB was reduced by ~50 and 80%, respectively, in tumours treated with MHT as studied by WB and IF staining. Serum analysis suggested insignificant toxicity of MN-OA (in terms of liver and kidney function), which was further correlated with minimal accumulation of MN-OA in target organs. CONCLUSIONS: These results suggest the involvement of apoptosis and Hsp90/AKT modulation in MN OA-mediated MHT-induced tumour growth inhibition. PMID- 26416813 TI - High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. AB - OBJECTIVES: Habitual diet plays a major role in shaping the composition of the gut microbiota, and also determines the repertoire of microbial metabolites that can influence the host. The typical Western diet corresponds to that of an omnivore; however, the Mediterranean diet (MD), common in the Western Mediterranean culture, is to date a nutritionally recommended dietary pattern that includes high-level consumption of cereals, fruit, vegetables and legumes. To investigate the potential benefits of the MD in this cross-sectional survey, we assessed the gut microbiota and metabolome in a cohort of Italian individuals in relation to their habitual diets. DESIGN AND RESULTS: We retrieved daily dietary information and assessed gut microbiota and metabolome in 153 individuals habitually following omnivore, vegetarian or vegan diets. The majority of vegan and vegetarian subjects and 30% of omnivore subjects had a high adherence to the MD. We were able to stratify individuals according to both diet type and adherence to the MD on the basis of their dietary patterns and associated microbiota. We detected significant associations between consumption of vegetable based diets and increased levels of faecal short-chain fatty acids, Prevotella and some fibre-degrading Firmicutes, whose role in human gut warrants further research. Conversely, we detected higher urinary trimethylamine oxide levels in individuals with lower adherence to the MD. CONCLUSIONS: High-level consumption of plant foodstuffs consistent with an MD is associated with beneficial microbiome-related metabolomic profiles in subjects ostensibly consuming a Western diet. TRIAL REGISTRATION NUMBER: This study was registered at clinical trials.gov as NCT02118857. PMID- 26416814 TI - Inspecting the Mechanism: A Longitudinal Analysis of Socioeconomic Status Differences in Perceived Influenza Risks, Vaccination Intentions, and Vaccination Behaviors during the 2009-2010 Influenza Pandemic. AB - BACKGROUND: Influenza vaccination is strongly associated with socioeconomic status, but there is only limited evidence on the respective roles of socioeconomic differences in vaccination intentions versus corresponding differences in follow-through on initial vaccination plans for subsequent socioeconomic differences in vaccine uptake. METHODS: Nonparametric mean smoothing, linear regression, and probit models were used to analyze longitudinal survey data on perceived influenza risks, behavioral vaccination intentions, and vaccination behavior of adults during the 2009-2010 influenza A/H1N1 ("swine flu") pandemic in the United States. Perceived influenza risks and behavioral vaccination intentions were elicited prior to the availability of H1N1 vaccine using a probability scale question format. H1N1 vaccine uptake was assessed at the end of the pandemic. RESULTS: Education, income, and health insurance coverage displayed positive associations with behavioral intentions to get vaccinated for pandemic influenza while employment was negatively associated with stated H1N1 vaccination intentions. Education and health insurance coverage also displayed significant positive associations with pandemic vaccine uptake. Moreover, behavioral vaccination intentions showed a strong and statistically significant positive partial association with later H1N1 vaccination. Incorporating vaccination intentions in a statistical model for H1N1 vaccine uptake further highlighted higher levels of follow-through on initial vaccination plans among persons with higher education levels and health insurance. LIMITATIONS: Sampling bias, misreporting in self-reported data, and limited generalizability to nonpandemic influenza are potential limitations of the analysis. CONCLUSIONS: Closing the socioeconomic gap in influenza vaccination requires multipronged strategies that not only increase vaccination intentions by improving knowledge, attitudes, and beliefs but also facilitate follow-through on initial vaccination plans by improving behavioral control and access to vaccination for individuals with low education, employed persons, and the uninsured. PMID- 26416815 TI - Proteomic changes of the porcine small intestine in response to chronic heat stress. AB - Acute heat stress (HS) negatively affects intestinal integrity and barrier function. In contrast, chronic mild HS poses a distinct challenge to animals. Therefore, this study integrates biochemical, histological and proteomic approaches to investigate the effects of chronic HS on the intestine in finishing pigs. Castrated male crossbreeds (79.00 +/- 1.50 kg BW) were subjected to either thermal neutral (TN, 21 degrees C; 55% +/- 5% humidity; n=8) or HS conditions (30 degrees C; 55% +/- 5% humidity; n=8) for 3 weeks. The pigs were sacrificed after 3 weeks of high environmental exposure and the plasma hormones, the intestinal morphology, integrity, and protein profiles of the jejunum mucosa were determined. Chronic HS reduced the free triiodothyronine (FT3) and GH levels. HS damaged intestinal morphology, increased plasma d-lactate concentrations and decreased alkaline phosphatase activity of intestinal mucosa. Proteome analysis of the jejunum mucosa was conducted by 2D gel electrophoresis and mass spectrometry. Fifty-three intestinal proteins were found to be differentially abundant, 18 of which were related to cell structure and motility, and their changes in abundance could comprise intestinal integrity and function. The down regulation of proteins involved in tricarboxylic acid cycle (TCA cycle), electron transport chain (ETC), and oxidative phosphorylation suggested that chronic HS impaired energy metabolism and thus induced oxidative stress. Moreover, the changes of ten proteins in abundance related to stress response and defense indicated pigs mediated long-term heat exposure and counteracted its negative effects of heat exposure. These findings have important implications for understanding the effect of chronic HS on intestines. PMID- 26416816 TI - Abnormal Patella Height Based on Insall-Salvati Ratio and its Correlation with Patellar Cartilage Lesions: An Extremity-Dedicated Low-Field Magnetic Resonance Imaging Analysis of 1703 Chinese Cases. AB - BACKGROUND AND AIMS: Diagnostic performance of patellar position for patellar cartilage lesions remains unclear. The aim of this study was to assess the abnormal patella height and its correlation with chondral lesions of the patellofemoral joint in China. MATERIAL AND METHODS: A total of 1703 consecutive patients who performed knee joint examination using an extremity-dedicated low field magnetic resonance imaging were enrolled in this study. Patellar cartilage lesions were diagnosed based on the result of magnetic resonance imaging and clinical data. Patella height was defined as the ratio of patellar tendon length to patellar length according to Insall-Salvati index. Patella alta and infera were defined as tendon length/patellar length >1.2 and <0.8, respectively. RESULTS: The total prevalence of patellar cartilage lesions was 38.0%. The prevalence in females was significantly higher than that in males (46.4% vs 28.8%, p < 0.001). Age notably increased the incidence of patellar cartilage lesions (p < 0.001). Logistic regression analysis showed that tendon length/patellar length ratio was significantly correlated with patellar cartilage lesions (odds ratio = 6.380, p < 0.001). Furthermore, patients with cartilage lesions showed significantly higher rates of patella alta and infera (p < 0.001). In addition, receiver operating characteristic curve analysis demonstrated that abnormal patella height had statistical significance in diagnosing cartilage lesions (p < 0.001). However, the area under the curve (0.596; 95% confidence interval: 0.568-0.624) and sensitivity (47.0%) were relatively low, while the specificity was 72.2%. CONCLUSIONS: Patients with patellar cartilage lesions have an increased tendon length/patellar length ratio. The abnormal patella height is significantly correlated with chondral lesions and can be used as a potential diagnostic marker. PMID- 26416817 TI - A rare case of racemose neurocysticercosis and its complications. Case report. AB - Neurocysticercosis is a central nervous system infection caused by the pork tapeworm Taenia solium. The disease is endemic in Central and South America, Asia and Africa. Racemose neurocysticercosis refers to cysts in the subarachnoid space and is characterized by proliferative lobulated cysts without a scolex. We report a case of a 43-year-old woman with an eight-month history of headaches, ataxia and loss of vision. CT and MRI showed an intraventricular cyst, causing entrapment of Monro foramina and hydrocephalus, smaller cysts at subarachnoid space in temporal lobes, Sylvian fissures, supra-selar and perimesencephalic cisterns, and an intra-orbital cyst. Additionally, there were acute ischemic vascular lesions on the left thalamus and corpus callosum splenium and subacute ischemic lesions of both occipital lobes. The diagnosis of racemose cysticercosis was made after biopsy and drainage of the intraventricular cyst. It is important to recognize neurocysticercosis as a differential diagnosis in intra-cranial cysts, not only intraparenchymal cysts. PMID- 26416818 TI - Labelling and imaging of single endogenous messenger RNA particles in vivo. AB - RNA molecules carry out widely diverse functions in numerous different physiological processes in living cells. The RNA life cycle from transcription, through the processing of nascent RNA, to the regulatory function of non-coding RNA and cytoplasmic translation of messenger RNA has been studied extensively using biochemical and molecular biology techniques. In this Commentary, we highlight how single molecule imaging and particle tracking can yield further insight into the dynamics of RNA particles in living cells. In the past few years, a variety of bright and photo-stable labelling techniques have been developed to generate sufficient contrast for imaging of single endogenous RNAs in vivo. New imaging modalities allow determination of not only lateral but also axial positions with high precision within the cellular context, and across a wide range of specimen from yeast and bacteria to cultured cells, and even multicellular organisms or live animals. A whole range of methods to locate and track single particles, and to analyze trajectory data are available to yield detailed information about the kinetics of all parts of the RNA life cycle. Although the concepts presented are applicable to all types of RNA, we showcase here the wealth of information gained from in vivo imaging of single particles by discussing studies investigating dynamics of intranuclear trafficking, nuclear pore transport and cytoplasmic transport of endogenous messenger RNA. PMID- 26416819 TI - Diabetes and Aortic Aneurysm. PMID- 26416820 TI - Liver Function is Associated With Response to Clopidogrel Therapy in Patients Undergoing Angioplasty and Stenting. AB - The relationship between liver function and clopidogrel response has not been studied so far. We therefore sought to investigate the associations between 3 parameters of liver synthesis and on-treatment platelet reactivity to adenosine diphosphate in patients on dual antiplatelet therapy. On-treatment platelet reactivity was determined by the VerifyNow P2Y12 assay in 316 patients undergoing angioplasty with stent implantation for cardiovascular disease. Cholinesterase, serum albumin, and total cholesterol levels were measured by internationally standardized assays in the hospital's central laboratory. On-treatment platelet reactivity by the VerifyNow P2Y12 assay correlated inversely with cholinesterase, serum albumin, and total cholesterol levels (all P <= .02). The inverse associations of cholinesterase and serum albumin levels with platelet reactivity remained significant after adjustment for cytochrome P450 loss-of-function polymorphisms and other factors that were previously associated with high on treatment residual platelet reactivity (HRPR; both P < .05). Patients without HRPR by the VerifyNow P2Y12 assay had significantly higher levels of serum albumin and total cholesterol than patients with HRPR (both P = .008). In conclusion, liver function is associated with response to clopidogrel therapy in patients undergoing angioplasty and stenting for cardiovascular disease. PMID- 26416824 TI - Engaging Parents Who Quit Smoking in Antismoking Socialization of Children: A Novel Approach to Relapse Prevention. AB - INTRODUCTION: Data from a randomized controlled trial designed primarily to test the effect of an antismoking socialization parenting program on child initiation of smoking were used to test the subsidiary hypothesis that providing antismoking socialization to children would lower the odds of relapse within a sub-sample of parents who had recently quit smoking. METHODS: Over 13 months, 11 state Quitlines provided contact information for callers who were parents of 8- to 10 year-old children. Of 1604 parents enrolled in the trial, 689 (344 treatment; 345 control) had quit smoking cigarettes for at least 24 hours after calling a Quitline. Their data were used to test for group differences in 30-day abstinence measured using telephone interviews conducted 7 and 12 months post-baseline. Analyses of parents with complete follow-up data and intent-to-treat analyses incorporating parents lost to follow-up are presented. RESULTS: Among 465 parents with complete follow-up data, treatment group parents had twice the odds of being abstinent 12 months post-baseline (adjusted OR = 2.01; P = .001) relative to controls. Intent-to-treat analysis with all 689 parents, in which those lost to follow-up were coded as having relapsed, showed a smaller though significant treatment effect on 30-day abstinence at 12 months (adjusted OR = 1.58; P = .017). CONCLUSIONS: This study is the first to observe that engaging parents who have quit smoking in antismoking socialization of children can lower their odds of relapse. Additional research is needed to replicate this finding and to identify the psychological mechanisms underlying the observed effect. IMPLICATIONS: There is a clear the need for research to develop new relapse prevention strategies. This study is the first to observe that engaging parents who have quit smoking in antismoking socialization of children can lower their odds of relapse. PMID- 26416823 TI - E-Cigarettes and the Drug Use Patterns of Adolescents. AB - INTRODUCTION: This study examines the role of e-cigarettes in the drug use patterns of adolescents. Of specific interest is whether adolescent e-cigarette users fall into a group of (1) youth who do not use traditional drugs of abuse or (2) polysubstance users. METHODS: Using latent class analysis, we identify major "classes" of substance users on the basis of recent use of e-cigarettes, alcohol, marijuana, cigarettes, and prescription drugs. Analyses are conducted separately for adolescents in 8th, 10th, and 12th grades. Data come from 16 615 participants in the 2014 Monitoring the Future survey. RESULTS: Youth who do not use traditional drugs of abuse account for about 50% of e-cigarette users in 8th grade, 35% in 10th grade, and 17% in 12th grade. These youth come from a large "low-level users" group found in each grade, characterized by low probability of use for all substances (e-cigarette probability in this group for 8th graders = .046; 10th graders = .071; 12th graders = .027). Other e-cigarette users come from a smaller, "poly-users" group found in each grade, characterized by high-to moderate probabilities (.83-.21) of using e-cigarettes and other substances. Specific to 12th grade is a third, additional polysubstance group characterized by high likelihood of e-cigarette use (.93). CONCLUSIONS: The proportion of e cigarette users who do not use traditional drugs of abuse is larger at younger ages. Longitudinal panel studies starting at 8th and 10th grades may best inform the current debate on whether e-cigarette use is a risk or protective factor for future transition to the use of other substances. IMPLICATIONS: The proportion of e-cigarette users who do not use traditional drugs of abuse is larger at younger ages. Longitudinal panel studies starting at 8th and 10th grades may best inform the current debate on whether e-cigarette use is a risk or protective factor for future transition to the use of other substances. PMID- 26416825 TI - Genetic Risk Determinants for Cigarette Smoking Dependence in Mexican Mestizo Families. AB - INTRODUCTION: Tobacco smoking is a leading cause of mortality in developed and developing countries. Despite antitobacco and smoke-free policies, the prevalence of active smokers in Mexican urban populations has remained stable. Mexican smokers differ from Caucasian and other ethnic groups, probably due to sociocultural and genetic background characteristics. This study explored the effect of known genetic variants on smoking behavior in Mexico City residents. METHODS: Three hundred sixty-four Mexican Mestizo Mexico City residents from 87 families with at least one smoker were assessed for association of 12 gene variants of six candidate genes (CHRNA4, CHRNB2, DRD2, ANKK1, SLC6A3, and CYP2A6) with cigarette consumption, age of initiation and smoking duration. The Family Based Association Test, an extension of the Transmission Disequilibrium Test, was used to perform family-based association analysis. RESULTS: The Family Based Association Test showed statistically significant association between the rs2072658 polymorphism of the CHRNB2 gene and smoking-related phenotypes such as: smoking status (SS), age of onset (AO), years of smoking, and psychological dependence (PD) evaluated by the Glover-Nilsson Smoking Behavior Questionnaire. After Bonferroni correction, only the association with AO remained significant (P = .003). Statistically significant association was also observed for the CYP2A6 rs28399433 T allele with SS (P = .003) and PD (P = .003). CONCLUSIONS: Our results indicate effects of the rs2072658 CHRNB2 and rs28399433 CYP2A6 gene variants on AO, SS and PD in Mexican Mestizo smokers. A mild effect of other analyzed gene variants, which may contribute to a putative polygenic predisposition for smoking, is suggested. IMPLICATIONS: The understanding of genetic and environmental determinants in the Mexican population is important for other Latin American populations as well, living in their own countries or moving to other ones, particular due to the current migration characteristics and particular genetic background like the Mexican Mestizo and other Central American populations with similar characteristics and migrating to neighbor developed countries, introducing their own smoking behavior and contributing importantly to the genetic pool of the receptor country. PMID- 26416827 TI - Lumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects. AB - Cystic fibrosis (CF) is a genetic disorder that causes multiorgan morbidity and premature death, most commonly from pulmonary dysfunction. Mutations in the CF transmembrane conductance regulator (CFTR) gene, of which almost 2000 have been described, result in a dysfunctional CFTR protein. This protein is an adenosine triphosphate binding anion channel, present primarily at the surface of epithelial cells. Loss of function mutations in this anion channel result in decreased or absent chloride/bicarbonate transport. The subsequent abnormal salt and water transport at epithelial cell surfaces leads to thickened secretions, and infection or inflammation in affected organs. In the last 20 years, therapeutics have been developed to treat the signs and symptoms of CF. However, in 2012, the small molecule drug, ivacaftor, became the first approved therapy that addresses the basic defect in CF. Ivacaftor is a potentiator of CFTR channels defective in their chloride/bicarbonate gating/conductance, but present at the epithelial cell surface. It is only approved for 10 mutations carried by approximately 7% of the population of patients with CF. F508del is the most common CFTR mutation, present in homozygosity in approximately 50% of patients with CF. The F508del mutation results in multiple CFTR channel defects that require both correction (stabilization of misfolded CFTR and trafficking to the epithelial cell membrane) and potentiation. This article reviews the in vitro and clinical trial data for the potential use of the potentiator, ivacaftor, and the corrector, lumacaftor, in patients with CF. PMID- 26416828 TI - Commentary: Key Issues, Concluding Thoughts, and Future Directions for the Study of Trauma and Child Health. PMID- 26416826 TI - Recent advances in central congenital hypothyroidism. AB - Central congenital hypothyroidism (CCH) may occur in isolation, or more frequently in combination with additional pituitary hormone deficits with or without associated extrapituitary abnormalities. Although uncommon, it may be more prevalent than previously thought, affecting up to 1:16 000 neonates in the Netherlands. Since TSH is not elevated, CCH will evade diagnosis in primary, TSH based, CH screening programs and delayed detection may result in neurodevelopmental delay due to untreated neonatal hypothyroidism. Alternatively, coexisting growth hormones or ACTH deficiency may pose additional risks, such as life threatening hypoglycaemia. Genetic ascertainment is possible in a minority of cases and reveals mutations in genes controlling the TSH biosynthetic pathway (TSHB, TRHR, IGSF1) in isolated TSH deficiency, or early (HESX1, LHX3, LHX4, SOX3, OTX2) or late (PROP1, POU1F1) pituitary transcription factors in combined hormone deficits. Since TSH cannot be used as an indicator of euthyroidism, adequacy of treatment can be difficult to monitor due to a paucity of alternative biomarkers. This review will summarize the normal physiology of pituitary development and the hypothalamic-pituitary-thyroid axis, then describe known genetic causes of isolated central hypothyroidism and combined pituitary hormone deficits associated with TSH deficiency. Difficulties in diagnosis and management of these conditions will then be discussed. PMID- 26416829 TI - Response of Vibrio cholerae to the Catecholamine Hormones Epinephrine and Norepinephrine. AB - In Escherichia coli or Salmonella enterica, the stress-associated mammalian hormones epinephrine (E) and norepinephrine (NE) trigger a signaling cascade by interacting with the QseC sensor protein. Here we show that Vibrio cholerae, the causative agent of cholera, exhibits a specific response to E and NE. These catecholates (0.1 mM) enhanced the growth and swimming motility of V. cholerae strain O395 on soft agar in a medium containing calf serum, which simulated the environment within the host. During growth, the hormones were converted to degradation products, including adrenochrome formed by autooxidation with O2 or superoxide. In E. coli, the QseC sensor kinase, which detects the autoinducer AI 3, also senses E or NE. The genome of V. cholerae O395 comprises an open reading frame coding for a putative protein with 29% identity to E. coli QseC. Quantitative reverse transcriptase PCR (qRT-PCR) experiments revealed increased transcript levels of the qseC-like gene and of pomB, a gene encoding a structural component of the flagellar motor complex, under the influence of E or NE. Phentolamine blocks the response of E. coli QseC to E or NE. A V. cholerae mutant devoid of the qseC-like gene retained the phentolamine-sensitive motility in the presence of E, whereas NE-stimulated motility was no longer inhibited by phentolamine. Our study demonstrates that V. cholerae senses the stress hormones E and NE. A sensor related to the histidine kinase QseC from E. coli is identified and is proposed to participate in the sensing of NE. IMPORTANCE: Vibrio cholerae is a Gram-negative bacterium that may cause cholera, a severe illness with high mortality due to acute dehydration caused by diarrhea and vomiting. Pathogenic V. cholerae strains possess virulence factors like the cholera toxin (CTX) and the toxin-coregulated pilus (TCP) produced in response to signals provided by the host. In pathogenic enterobacteria, the stress-associated hormones epinephrine (E) and norepinephrine (NE) of the human host act as signal molecules for the production of virulence factors and promote bacterial growth by the sequestration of iron from the host. Here we show that V. cholerae, like some enterobacteria, benefits from these stress hormones and possesses a sensor to recognize them. PMID- 26416830 TI - In Silico Discovery and In Vitro Validation of Catechol-Containing Sulfonohydrazide Compounds as Potent Inhibitors of the Diguanylate Cyclase PleD. AB - Biofilm formation is responsible for increased antibiotic tolerance in pathogenic bacteria. Cyclic di-GMP (c-di-GMP) is a widely used second-messenger signal that plays a key role in bacterial biofilm formation. c-di-GMP is synthesized by diguanylate cyclases (DGCs), a conserved class of enzymes absent in mammals and hence considered attractive molecular targets for the development of antibiofilm agents. Here, the results of a virtual screening approach aimed at identifying small-molecule inhibitors of the DGC PleD from Caulobacter crescentus are described. A three-dimensional (3D) pharmacophore model, derived from the mode of binding of GTP to the active site of PleD, was exploited to screen the ZINC database of compounds. Seven virtual hits were tested in vitro for their ability to inhibit the activity of purified PleD by using circular dichroism spectroscopy. Two drug-like molecules with a catechol moiety and a sulfonohydrazide scaffold were shown to competitively inhibit PleD at the low micromolar range (50% inhibitory concentration [IC50] of ~11 MUM). Their predicted binding mode highlighted key structural features presumably responsible for the efficient inhibition of PleD by both hits. These molecules represent the most potent in vitro inhibitors of PleD identified so far and could therefore result in useful leads for the development of novel classes of antimicrobials able to hamper biofilm formation. IMPORTANCE: Biofilm-mediated infections are difficult to eradicate, posing a threatening health issue worldwide. The capability of bacteria to form biofilms is almost universally stimulated by the second messenger c-di-GMP. This evidence has boosted research in the last decade for the development of new antibiofilm strategies interfering with c-di-GMP metabolism. Here, two potent inhibitors of c-di-GMP synthesis have been identified in silico and characterized in vitro by using the well-characterized DGC enzyme PleD from C. crescentus as a structural template and molecular target. Given that the protein residues implied as crucial for enzyme inhibition are found to be highly conserved among DGCs, the outcome of this study could pave the way for the future development of broad-spectrum antibiofilm compounds. PMID- 26416831 TI - An Electrostatic Net Model for the Role of Extracellular DNA in Biofilm Formation by Staphylococcus aureus. AB - Staphylococcus aureus is an important human pathogen that can form biofilms on various surfaces. These cell communities are protected from the environment by a self-produced extracellular matrix composed of proteins, DNA, and polysaccharide. The exact compositions and roles of the different components are not fully understood. In this study, we investigated the role of extracellular DNA (eDNA) and its interaction with the recently identified cytoplasmic proteins that have a moonlighting role in the biofilm matrix. These matrix proteins associate with the cell surface upon the drop in pH that naturally occurs during biofilm formation, and we found here that this association is independent of eDNA. Conversely, the association of eDNA with the matrix was dependent on matrix proteins. Both proteinase and DNase treatments severely reduced clumping of resuspended biofilms; highlighting the importance of both proteins and eDNA in connecting cells together. By adding an excess of exogenous DNA to DNase-treated biofilm, clumping was partially restored, confirming the crucial role of eDNA in the interconnection of cells. On the basis of our results, we propose that eDNA acts as an electrostatic net, interconnecting cells surrounded by positively charged matrix proteins at a low pH. IMPORTANCE: Extracellular DNA (eDNA) is an important component of the biofilm matrix of diverse bacteria, but its role in biofilm formation is not well understood. Here we report that in Staphylococcus aureus, eDNA associates with cells in a manner that depends on matrix proteins and that eDNA is required to link cells together in the biofilm. These results confirm previous studies that showed that eDNA is an important component of the S. aureus biofilm matrix and also suggest that eDNA acts as an electrostatic net that tethers cells together via the proteinaceous layer of the biofilm matrix. PMID- 26416832 TI - AraR, an l-Arabinose-Responsive Transcriptional Regulator in Corynebacterium glutamicum ATCC 31831, Exerts Different Degrees of Repression Depending on the Location of Its Binding Sites within the Three Target Promoter Regions. AB - In Corynebacterium glutamicum ATCC 31831, a LacI-type transcriptional regulator AraR, represses the expression of l-arabinose catabolism (araBDA), uptake (araE), and the regulator (araR) genes clustered on the chromosome. AraR binds to three sites: one (BSB) between the divergent operons (araBDA and galM-araR) and two (BSE1 and BSE2) upstream of araE. L-Arabinose acts as an inducer of the AraR mediated regulation. Here, we examined the roles of these AraR-binding sites in the expression of the AraR regulon. BSB mutation resulted in derepression of both araBDA and galM-araR operons. The effects of BSE1 and/or BSE2 mutation on araE expression revealed that the two sites independently function as the cis elements, but BSE1 plays the primary role. However, AraR was shown to bind to these sites with almost the same affinity in vitro. Taken together, the expression of araBDA and araE is strongly repressed by binding of AraR to a single site immediately downstream of the respective transcriptional start sites, whereas the binding site overlapping the -10 or -35 region of the galM-araR and araE promoters is less effective in repression. Furthermore, downregulation of araBDA and araE dependent on l-arabinose catabolism observed in the BSB mutant and the AraR-independent araR promoter identified within galM-araR add complexity to regulation of the AraR regulon derepressed by L-arabinose. IMPORTANCE: Corynebacterium glutamicum has a long history as an industrial workhorse for large-scale production of amino acids. An important aspect of industrial microorganisms is the utilization of the broad range of sugars for cell growth and production process. Most C. glutamicum strains are unable to use a pentose sugar L-arabinose as a carbon source. However, genes for L-arabinose utilization and its regulation have been recently identified in C. glutamicum ATCC 31831. This study elucidates the roles of the multiple binding sites of the transcriptional repressor AraR in the derepression by L-arabinose and thereby highlights the complex regulatory feedback loops in combination with l-arabinose catabolism-dependent repression of the AraR regulon in an AraR-independent manner. PMID- 26416833 TI - Evolution of Mycolic Acid Biosynthesis Genes and Their Regulation during Starvation in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis, the etiological agent of tuberculosis, is a Gram positive bacterium with a unique cell envelope composed of an essential outer membrane. Mycolic acids, which are very-long-chain (up to C100) fatty acids, are the major components of this mycomembrane. The enzymatic pathways involved in the biosynthesis and transport of mycolates are fairly well documented and are the targets of the major antituberculous drugs. In contrast, only fragmented information is available on the expression and regulation of the biosynthesis genes. In this study, we report that the hadA, hadB, and hadC genes, which code for the mycolate biosynthesis dehydratase enzymes, are coexpressed with three genes that encode proteins of the translational apparatus. Consistent with the well-established control of the translation potential by nutrient availability, starvation leads to downregulation of the hadABC genes along with most of the genes required for the synthesis, modification, and transport of mycolates. The downregulation of a subset of the biosynthesis genes is partially dependent on RelMtb, the key enzyme of the stringent response. We also report the phylogenetic evolution scenario that has shaped the current genetic organization, characterized by the coregulation of the hadABC operon with genes of the translational apparatus and with genes required for the modification of the mycolates. IMPORTANCE: Mycobacterium tuberculosis infects one-third of the human population worldwide, and despite the available therapeutic arsenal, it continues to kill millions of people each year. There is therefore an urgent need to identify new targets and develop a better understanding of how the bacterium is adapting itself to host defenses during infection. A prerequisite of this understanding is knowledge of how this adaptive skill has been implanted by evolution. Nutrient scarcity is an environmental condition the bacterium has to cope with during infection. In many bacteria, adaptation to starvation relies partly on the stringent response. M. tuberculosis's unique outer membrane layer, the mycomembrane, is crucial for its viability and virulence. Despite its being the target of the major antituberculosis drugs, only scattered information exists on how the genes required for biosynthesis of the mycomembrane are expressed and regulated during starvation. This work has addressed this issue as a step toward the identification of new targets in the fight against M. tuberculosis. PMID- 26416835 TI - Disparate worlds drawing closer together: cardiovascular biomarkers predict cancer outcomes in treatment-naive patients. PMID- 26416834 TI - The Sugar Kinase That Is Necessary for the Catabolism of Rhamnose in Rhizobium leguminosarum Directly Interacts with the ABC Transporter Necessary for Rhamnose Transport. AB - Rhamnose catabolism in Rhizobium leguminosarum was found to be necessary for the ability of the organism to compete for nodule occupancy. Characterization of the locus necessary for the catabolism of rhamnose showed that the transport of rhamnose was dependent upon a carbohydrate uptake transporter 2 (CUT2) ABC transporter encoded by rhaSTPQ and on the presence of RhaK, a protein known to have sugar kinase activity. A linker-scanning mutagenesis analysis of rhaK showed that the kinase and transport activities of RhaK could be separated genetically. More specifically, two pentapeptide insertions defined by the alleles rhaK72 and rhaK73 were able to uncouple the transport and kinase activities of RhaK, such that the kinase activity was retained, but cells carrying these alleles did not have measurable rhamnose transport rates. These linker-scanning alleles were localized to the C terminus and N terminus of RhaK, respectively. Taken together, the data led to the hypothesis that RhaK might interact either directly or indirectly with the ABC transporter defined by rhaSTPQ. In this work, we show that both N- and C-terminal fragments of RhaK are capable of interacting with the N-terminal fragment of the ABC protein RhaT using a 2-hybrid system. Moreover, if RhaK fragments carrying either the rhaK72 or rhaK73 allele were used, this interaction was abolished. Phylogenetic and bioinformatic analysis of the RhaK fragments suggested that a conserved region in the N terminus of RhaK may represent a putative binding domain. Alanine-scanning mutagenesis of this region followed by 2-hybrid analysis revealed that a substitution of any of the conserved residues greatly affected the interaction between RhaT and RhaK fragments, suggesting that the sugar kinase RhaK and the ABC protein RhaT interact directly. IMPORTANCE: ABC transporters involved in the transport of carbohydrates help define the overall physiological fitness of bacteria. The two largest groups of transporters are the carbohydrate uptake transporter classes 1 and 2 (CUT1 and CUT2, respectively). This work provides the first evidence that a kinase that is necessary for the catabolism of a sugar can directly interact with a domain from the ABC protein that is necessary for its transport. PMID- 26416836 TI - Cardiovascular biomarkers in patients with cancer and their association with all cause mortality. AB - OBJECTIVE: Patients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer. METHODS: We prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy. N-terminal pro BNP (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET 1), copeptin, hsTnT, proinflammatory markers interleukin 6 (IL-6) and C reactive protein (CRP), and cytokines serum amyloid A (SAA), haptoglobin and fibronectin were measured. All-cause mortality was defined as primary endpoint. RESULTS: During a median follow-up of 25 (IQR 16-31) months, 186 (34%) patients died. All cardiovascular hormones and hsTnT levels rose with tumour stage progression. All markers were significant predictors of mortality with HRs per IQR of 1.54 (95% CI 1.24 to 1.90, p<0.001) for NT-proBNP, 1.40 (95% CI 1.10 to 1.79, p<0.01) for MR proANP, 1.31 (95% CI 1.19 to 1.44, p<0.001) for MR-proADM, 1.21 (95% CI 1.14 to 1.30, p<0.001) for CT-proET-1, 1.22 (95% CI 1.04 to 1.42, p=0.014) for copeptin and 1.21 (95% CI 1.13 to 1.32, p<0.001) for hsTnT, independent of age, gender, tumour entity and stage, and presence of cardiac comorbidities. NT-proBNP, MR proANP, MR-proADM and hsTnT displayed a significant correlation with IL-6 and CRP. CONCLUSIONS: Circulating levels of cardiovascular peptides like NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were elevated in an unselected population of patients with cancer prior to induction of any cardiotoxic anticancer therapy. The aforementioned markers and copeptin were strongly related to all-cause mortality, suggesting the presence of subclinical functional and morphological myocardial damage directly linked to disease progression. PMID- 26416837 TI - Very abnormal T waves in a 37-year-old man. PMID- 26416838 TI - The reciprocal interaction between LV remodelling and allograft outcomes in kidney transplant recipients. AB - OBJECTIVE: This study aimed to investigate the incidence and related clinical factors of LV hypertrophy (LVH) regression after kidney transplantation and its effect on graft outcome. METHODS: Among the 3373 kidney transplant recipients who were enrolled in a multicentre cohort from 1997 to 2012, a total of 767 patients who underwent echocardiography before and after transplantation were included in this study followed for a median of 7.5 years. RESULTS: LVH regression steadily increased from 7.4% at 1 year to 35.4% at 5 year over the 5-year post transplantation period. The probability of LVH regression decreased in the patients who received a kidney transplant due to end-stage renal disease of unknown aetiology (p=0.041) or who underwent pretransplant haemodialysis (p=0.020). The probability of LVH regression also decreased as the pretransplant LV mass index (p<0.001) and post-transplant systolic blood pressure increased (p=0.005). Conversely, LVH regression was significantly associated with the highest tertile of the pretransplant haemoglobin level (p=0.029). Furthermore, in the 5th year after transplantation, persistent LVH was independently associated with allograft failure (HR 1.95; 95% CI 1.14 to 3.33; p=0.015) and the LV mass index reliably predicted graft outcome. CONCLUSIONS: LVH consistently regressed after kidney transplantation in most patients. Persistent LVH, low haemoglobin levels and elevated blood pressure were associated with an increased risk of allograft failure in kidney transplant recipients. PMID- 26416840 TI - Two different nucleotide substitutions of APC gene in a family with familial adenomatous polyposis. AB - Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome leading to colorectal cancer. This disease appears as a result of germline mutation in adenomatous polyposis coli (APC) gene. The aim of the present study is to report the association between two different nucleotide substitutions detected in a family with FAP. In the proband, p.His1172Gln (c.3516delT) was detected in exon 15 of the APC gene. Furthermore, p.His1172Gln (c.3516delT) and, in addition to this mutation, p.Met1413Val (c.4237 A > G) were detected in exon 15 in both daughters of the proband. However, we believe that single nucleotide change in codon 1413 may be a polymorphic variant and deletion T in codon 1172 of APC gene is associated with FAP, attenuated FAP and extracolonic FAP involvement. Along with common use of genetic tests in the clinical practice, genotype-phenotype correlation may be recognized better and useful for early diagnosis and prevention of familial cancer syndromes. PMID- 26416839 TI - Backscatter-difference Measurements of Cancellous Bone Using an Ultrasonic Imaging System. AB - Backscatter-difference measurements may be used to detect changes in bone caused by osteoporosis. The backscatter-difference technique measures the power difference between two portions of an ultrasonic backscatter signal. The goal of this study is to evaluate the feasibility of using an ultrasonic imaging system to perform backscatter-difference measurements of bone. Ultrasonic images and backscatter signals were acquired from 24 specimens of human cancellous bone. The signals were analyzed in the frequency domain to determine the normalized mean backscatter-difference (nMBD) and in the time domain to determine the normalized backscatter amplitude ratio (nBAR). The images were analyzed to determine the normalized pixel value difference (nPVD), which measures the difference in average pixel brightness between regions of interest placed at two different depths in the image. All three parameters were found to increase with bone mineral density. The signal-based parameters, nMBD and nBAR, correlated well with bone mineral density, yielding linear correlation coefficients that ranged from 0.74 to 0.87. The image based parameter, nPVD, performed somewhat less well, yielding correlation coefficients that ranged from 0.42 to 0.81. These results suggest that ultrasonic imaging systems may be used to perform backscatter difference measurements for the purpose of ultrasonic bone assessment. PMID- 26416841 TI - "I Didn't Know Whether I Was Right or Wrong or Just Bewildered": Ambiguity, Responsibility, and Silencing Women's Talk of Men's Domestic Violence. AB - Little has been written about the impact on women of the man's obscuring and deflecting of responsibility when domestic violence is used by him against her. Women's advocates report that women who seek shelter from domestic violence assume blame for the violence and struggle to shift from this position of responsibility. Women are likely to be silenced if they assume responsibility and are less likely to come forward. In this study, we use discourse analysis to describe the ambiguities around responsibility that worked to silence 20 women and the sociocultural influences that supported this ambiguity. We discuss the implications for prevention. PMID- 26416842 TI - Clergy Perceptions of Sexual Assault Victimization. AB - Although congregants often turn to clergy for help in dealing with personal difficulties, including marital problems, substance abuse issues, and mental illness, survivors of sexual assault do not commonly turn to clergy for support or guidance. This study utilized a mixed-methods approach, online survey, and semi-structured interviews to determine how clergy perceive sexual assault victimization. The results of this study showed that more blame was assigned to the victim as the relationship with the perpetrator became closer, with the exception of marital rape. This study also found that hostile sexism was a predictor of negative attitudes toward rape victims. PMID- 26416843 TI - Depressive symptoms and psychosocial aspects of work in bank employees. AB - BACKGROUND: The financial sector has seen an increase in the number of cases of violence and stress, which can result in adverse health outcomes, including depressive symptoms, but studies related to stress at work and depression for these workers are scarce. AIMS: To investigate the association between exposure to psychosocial work stressors and depressive symptoms in bank employees. METHODS: A self-administered questionnaire was completed by a sample of bank employees in Para and Amapa, Brazil. The survey assessed sociodemographic characteristics, mental health (Patient Health Questionnaire-9), Demand-Control Support and Effort-Reward Imbalance (ERI). Outcomes included two levels of depressive symptoms: major depressive symptoms (MDS) and other forms of depressive symptoms (ODS). Logistic regression models were used to estimate associations between depressive symptoms, the two job stress models and relevant covariates. RESULTS: Of 2806 eligible subjects, there were 1445 respondents (52% response rate) and the final analyses included 1046 participants. The overall prevalence of depressive symptoms was 32% (MDS = 18%; ODS = 14%), with no statistically significant difference between men and women. High demands, low levels of control and low social support were associated with MDS and/or ODS, adjusted for gender, age and other work-related conditions. High effort/low reward, over-commitment and ERI were also associated with MDS and ODS. CONCLUSIONS: Psychosocial conditions in banking activity involving high strain, low social support at work, high effort with low reward and over-commitment may represent possible risk factors for depressive symptoms in bank employees. PMID- 26416844 TI - Neck and upper back pain among eye care professionals. AB - BACKGROUND: Ophthalmologists and optometrists have reported a higher prevalence of neck, hand/wrist and lower back pain than family medicine physicians. Work related musculoskeletal disorders have not previously been studied in Saudi eye care professionals. AIMS: To determine the magnitude and determinants of neck and upper back pain among eye care professionals at a tertiary hospital in Saudi Arabia in 2013. METHODS: A cross-sectional study using a close-ended questionnaire to determine the frequency of neck and back pain and its association with age, sex, weight, comorbidities, duration of professional work, history of injury and physician sub-speciality. RESULTS: The response rate was 82% and 165 eye care professionals participated, 70% (113) of whom reported neck and back pain. The rate was similar in ophthalmologists and allied eye care professionals and among surgical and medical ophthalmologists. The prevalence rate of neck and upper back pain was not associated with number of years in the profession, comorbidities, self-reported weight or injury. Pain appeared to be associated with reported physical discomfort during professional activities (P < 0.01) but not with mental stress. Pain was thought to be work related by 50% of participants. A lower rate of neck and upper back pain was associated with regular exercise [odds ratio = 0.5 (95% confidence interval 0.2-0.9)]. CONCLUSIONS: Neck and back pain was reported by 70% of eye care professionals. The pain was graded as mild to moderate and improved when on holidays. Regular physical exercise appeared to prevent or reduce neck and upper back pain. PMID- 26416845 TI - Lymphocytic choriomeningitis virus infection induced by percutaneous exposure. AB - We report a case of acquired lymphocytic choriomeningitis virus (LCMV) infection due to an accidental percutaneous inoculation of LCMV at work. The injured worker developed a flu-like syndrome, followed by pericarditis and meningoencephalitis. Seroconversion was confirmed by ELISA. The patient made a complete recovery. We review measures undertaken to prevent a similar event and propose a follow-up protocol in the event of accidental LCMV exposure. PMID- 26416846 TI - Cerebrospinal Fluid Hypernatremia Elevates Sympathetic Nerve Activity and Blood Pressure via the Rostral Ventrolateral Medulla. AB - Elevated NaCl concentrations of the cerebrospinal fluid increase sympathetic nerve activity (SNA) in salt-sensitive hypertension. Neurons of the rostral ventrolateral medulla (RVLM) play a pivotal role in the regulation of SNA and receive mono- or polysynaptic inputs from several hypothalamic structures responsive to hypernatremia. Therefore, the present study investigated the contribution of RVLM neurons to the SNA and pressor response to cerebrospinal fluid hypernatremia. Lateral ventricle infusion of 0.15 mol/L, 0.6 mol/L, and 1.0 mol/L NaCl (5 uL/10 minutes) produced concentration-dependent increases in lumbar SNA, adrenal SNA, and arterial blood pressure, despite no change in splanchnic SNA and a decrease in renal SNA. Ganglionic blockade with chlorisondamine or acute lesion of the lamina terminalis blocked or significantly attenuated these responses, respectively. RVLM microinjection of the gamma-aminobutyric acid (GABAA) agonist muscimol abolished the sympathoexcitatory response to intracerebroventricular infusion of 1 mol/L NaCl. Furthermore, blockade of ionotropic glutamate, but not angiotensin II type 1, receptors significantly attenuated the increase in lumbar SNA, adrenal SNA, and arterial blood pressure. Finally, single-unit recordings of spinally projecting RVLM neurons revealed 3 distinct populations based on discharge responses to intracerebroventricular infusion of 1 mol/L NaCl: type I excited (46%; 11/24), type II inhibited (37%; 9/24), and type III no change (17%; 4/24). All neurons with slow conduction velocities were type I cells. Collectively, these findings suggest that acute increases in cerebrospinal fluid NaCl concentrations selectively activate a discrete population of RVLM neurons through glutamate receptor activation to increase SNA and arterial blood pressure. PMID- 26416847 TI - Generation of Hypertension-Associated STK39 Polymorphism Knockin Cell Lines With the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 System. AB - Previous genome-wide association studies identified serine threonine kinase 39 (STK39), encoding STE20/SPS1-related proline/alanine-rich kinase, as one of a limited number of hypertension susceptibility genes. A recent meta-analysis confirmed the association of STK39 intronic polymorphism rs3754777 with essential hypertension, among previously reported hypertension-associated STK39 polymorphisms. However, the biochemical function of this polymorphism in the mechanism responsible for hypertension is yet to be clarified. We generated rs3754777G>A knockin human cell lines with clustered regularly interspaced short palindromic repeats-mediated genome engineering. Homozygous (A/A) and heterozygous (G/A) knockin human embryonic kidney cell lines were generated using a double nickase, single-guide RNAs targeting STK39 intron 5 around single nucleotide polymorphism, and a 100-bp donor single-stranded DNA oligonucleotide. Reverse transcription polymerase chain reaction with sequencing analyses revealed the identical STK39 transcripts among the wild-type and both knockin cell lines. Quantitative reverse transcription polymerase chain reaction showed increased STK39 mRNA expression, and immunoblot analysis revealed increases in total and phosphorylated STE20/SPS1-related proline/alanine-rich kinase with increased phosphorylated Na-K-Cl cotransporter isoform 1 in both knockin cell lines. The largest increases in these molecules were observed in the homozygous cell line. These findings indicated that this intronic polymorphism increases STK39 transcription, leading to activation of the STE20/SPS1-related proline/alanine rich kinase-solute carrier family 12A signaling cascade. Increased interactions between STE20/SPS1-related proline/alanine-rich kinase and the target cation chloride cotransporters may be responsible for hypertension susceptibility in individuals with this polymorphism. PMID- 26416850 TI - A tale of five cities: Using recycling frameworks to analyse inclusive recycling performance. AB - 'Recycling' is a source of much confusion, particularly when comparing solid waste systems in high-income countries with those in low- and middle-income countries. Few analysts can explain why the performance and structure of recycling appears to be so different in rich countries from poor ones, nor why well-meaning efforts to implement recycling so often fail. The analysis of policy drivers, and the Integrated Sustainable Waste Management (ISWM) framework, come close to an explanation.This article builds on these earlier works, focusing in on five cities profiled in the 2010 UN-Habitat publication (Scheinberg A, Wilson DC and Rodic L (2010) Solid Waste Management in the World's Cities. UN-Habitat's Third Global Report on the State of Water and Sanitation in the World's Cities. Newcastle-on-Tyne, UK: Earthscan Publications). Data from these cities and others provides the basis for developing a new tool to analyse inclusive recycling performance. The points of departure are the institutional and economic relationships between the service chain, the public obligation to remove waste, pollution, and other forms of disvalue, and the value chain, a system of private enterprises trading valuable materials and providing markets for recyclables. The methodological innovation is to use flows of materials and money as indicators of institutional relationships, and is an extension of process flow diagramming.The authors are using the term 'recycling framework analysis' to describe this new form of institutional analysis. The diagrams increase our understanding of the factors that contribute to high-performance inclusive recycling. By focusing on institutional relationships, the article seeks to improve analysis, planning, and ultimately, outcomes, of recycling interventions. PMID- 26416848 TI - Adenosine Attenuates Human Coronary Artery Smooth Muscle Cell Proliferation by Inhibiting Multiple Signaling Pathways That Converge on Cyclin D. AB - The goal of this study was to determine whether and how adenosine affects the proliferation of human coronary artery smooth muscle cells (HCASMCs). In HCASMCs, 2-chloroadenosine (stable adenosine analogue), but not N(6)-cyclopentyladenosine, CGS21680, or N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide, inhibited HCASMC proliferation (A2B receptor profile). 2-Chloroadenosine increased cAMP, reduced phosphorylation (activation) of ERK and Akt (protein kinases known to increase cyclin D expression and activity, respectively), and reduced levels of cyclin D1 (cyclin that promotes cell-cycle progression in G1). Moreover, 2-chloroadenosine inhibited expression of S-phase kinase-associated protein-2 (Skp2; promotes proteolysis of p27(Kip1)) and upregulated levels of p27(Kip1) (cell-cycle regulator that impairs cyclin D function). 2-Chloroadenosine also inhibited signaling downstream of cyclin D, including hyperphosphorylation of retinoblastoma protein and expression of cyclin A (S phase cyclin). Knockdown of A2B receptors prevented the effects of 2-chloroadenosine on ERK1/2, Akt, Skp2, p27(Kip1), cyclin D1, cyclin A, and proliferation. Likewise, inhibition of adenylyl cyclase and protein kinase A abrogated 2-chloroadenosine's inhibitory effects on Skp2 and stimulatory effects on p27(Kip1) and rescued HCASMCs from 2 chloroadenosine-mediated inhibition. Knockdown of p27(Kip1) also reversed the inhibitory effects of 2-chloroadenosine on HCASMC proliferation. In vivo, peri arterial (rat carotid artery) 2-chloroadenosine (20 MUmol/L for 7 days) downregulated vascular expression of Skp2, upregulated vascular expression of p27(Kip1), and reduced neointima hyperplasia by 71% (P<0.05; neointimal thickness: control, 37 424+/-18 371 pixels; treated, 10 352+/-2824 pixels). In conclusion, the adenosine/A2B receptor/cAMP/protein kinase A axis inhibits HCASMC proliferation by blocking multiple signaling pathways (ERK1/2, Akt, and Skp2) that converge at cyclin D, a key G1 cyclin that controls cell-cycle progression. PMID- 26416849 TI - Placental-Specific sFLT-1 e15a Protein Is Increased in Preeclampsia, Antagonizes Vascular Endothelial Growth Factor Signaling, and Has Antiangiogenic Activity. AB - In preeclampsia, the antiangiogenic factor soluble fms-like tyrosine kinase-1 (sFLT-1) is released from placenta into the maternal circulation, causing endothelial dysfunction and organ injury. A recently described splice variant, sFLT-1 e15a, is primate specific and the most abundant placentally derived sFLT 1. Therefore, it may be the major sFLT-1 isoform contributing to the pathophysiology of preeclampsia. sFLT-1 e15a protein remains poorly characterized: its bioactivity has not been comprehensively examined, and serum levels in normal and preeclamptic pregnancy have not been reported. We generated and validated an sFLT-1 e15a-specific ELISA to further characterize serum levels during pregnancy, and in the presence of preeclampsia. Furthermore, we performed assays to examine the bioactivity and antiangiogenic properties of sFLT-1 e15a protein. sFLT-1 e15a was expressed in the syncytiotrophoblast, and serum levels rose across pregnancy. Strikingly, serum levels were increased 10-fold in preterm preeclampsia compared with normotensive controls. We confirmed sFLT-1 e15a is bioactive and is able to inhibit vascular endothelial growth factor signaling of vascular endothelial growth factor receptor 2 and block downstream Akt phosphorylation. Furthermore, sFLT-1 e15a has antiangiogenic properties. sFLT-1 e15a decreased endothelial cell migration, invasion, and inhibited endothelial cell tube formation. Administering sFLT-1 e15a blocked vascular endothelial growth factor induced sprouts from mouse aortic rings ex vivo. We have demonstrated that sFLT-1 e15a is increased in preeclampsia, antagonizes vascular endothelial growth factor signaling, and has antiangiogenic activity. Future development of diagnostics and therapeutics for preeclampsia should consider targeting placentally derived sFLT-1 e15a. PMID- 26416851 TI - Comparison of alternative remediation technologies for recycled gravel contaminated with heavy metals. AB - To evaluate the effects of different remediation methods on heavy metals contaminated recycled gravel, three immobilization agents (monopotassium phosphate, lime, nano-iron) and two mobilization agents (glyphosate, humic acid (HA)) were studied and compared. Results indicated that nano-iron powder was found to be more effective to immobilize Zn, Cu, Pb and Cd. Meanwhile, glyphosate presents a higher mobilization effect than HA with removal rates of about 66.7% for Cd, more than 80% for Cr, Cu and Zn, and the highest removal percentage of 85.9% for Cr. After the mobilization by glyphosate, the leaching rates of Zn, Cu and Cr were about 0.8%, and below 0.2% for Pb and Cd. The leaching rates after nano-iron powder treatment were 1.18% for Zn, 0.96% for Cr, 0.61% for Cu, 0.45% for Pb and Cd not detected. The formation and disappearance of metal (Zn/Cu/Cr/Pb/Cd) compounds were firmly confirmed through X-ray diffraction and scanning electron microscopy analyses on crystalline phases and morphological surface structures. PMID- 26416852 TI - Arabidopsis Intracellular NHX-Type Sodium-Proton Antiporters are Required for Seed Storage Protein Processing. AB - The Arabidopsis intracellular sodium-proton exchanger (NHX) proteins AtNHX5 and AtNHX6 have a well-documented role in plant development, and have been used to improve salt tolerance in a variety of species. Despite evidence that intracellular NHX proteins are important in vacuolar trafficking, the mechanism of this role is poorly understood. Here we show that NHX5 and NHX6 are necessary for processing of the predominant seed storage proteins, and also influence the processing and activity of a vacuolar processing enzyme. Furthermore, we show by yeast two-hybrid and bimolecular fluorescence complementation (BiFC) technology that the C-terminal tail of NHX6 interacts with a component of Retromer, another component of the cell sorting machinery, and that this tail is critical for NHX6 activity. These findings demonstrate that NHX5 and NHX6 are important in processing and activity of vacuolar cargo, and suggest a mechanism by which NHX intracellular (IC)-II antiporters may be involved in subcellular trafficking. PMID- 26416853 TI - Cefepime Therapy for Monomicrobial Enterobacter cloacae Bacteremia: Unfavorable Outcomes in Patients Infected by Cefepime-Susceptible Dose-Dependent Isolates. AB - A new category of cefepime susceptibility, susceptible dose dependent (SDD), for Enterobacteriaceae, has been suggested to maximize its clinical use. However, clinical evidence supporting such a therapeutic strategy is limited. A retrospective study of 305 adults with monomicrobial Enterobacter cloacae bacteremia at a medical center from 2008 to 2012 was conducted. The patients definitively treated with in vitro active cefepime (cases) were compared with those treated with a carbapenem (controls) to assess therapeutic effectiveness. The 30-day crude mortality rate is the primary endpoint, and clinical prognostic factors are assessed. Of 144 patients receiving definitive cefepime or carbapenem therapy, there were no significant differences in terms of age, sex, comorbidity, source of bacteremia, disease severity, or 30-day mortality (26.4% versus 22.2%; P = 0.7) among those treated with cefepime (n = 72) or a carbapenem (n = 72). In the multivariate analysis, the presence of critical illness, rapidly fatal underlying disease, extended-spectrum beta-lactamase (ESBL) producers, and cefepime-SDD (cefepime MIC, 4 to 8 MUg/ml) isolates was independently associated with 30-day mortality. Moreover, those infected by cefepime-SDD isolates with definitive cefepime therapy had a higher mortality rate than those treated with a carbapenem (5/7 [71.4%], versus 2/11 [18.2%]; P = 0.045). Cefepime is one of the therapeutic alternatives for cefepime-susceptible E. cloacae bacteremia but is inefficient for cases of cefepime-SDD E. cloacae bacteremia compared with carbapenem therapy. PMID- 26416854 TI - Fitness Studies of Azole-Resistant Strains of Aspergillus fumigatus. AB - Isogenic bar-coded strains of Aspergillus fumigatus carrying the G54W or M220K mutation in Cyp51A were constructed. In vitro, the growth and conidiation capacities of the mutants were similar to those of the parental strain. Competition studies in the absence of azoles showed that there was no adverse fitness cost for the azole-resistant A. fumigatus strains in vitro or in vivo compared to the parental strain. PMID- 26416855 TI - Efficacy of humanized high-dose meropenem, cefepime, and levofloxacin against Enterobacteriaceae isolates producing Verona integron-encoded metallo-beta lactamase (VIM) in a murine thigh infection model. AB - We aimed to describe the in vivo activity of humanized pharmacokinetic exposures of meropenem and comparators against Verona integron-encoded metallo-beta lactamase (MBL) (VIM)-producing Enterobacteriaceae in a murine model. Levofloxacin activity was predicted by its MIC, and cefepime activity displayed variability, whereas meropenem produced a >1 log CFU reduction against all isolates despite high MICs indicative of resistance. Our results suggest that despite in vitro resistance, high-dose meropenem may be a possible option against infections caused by Enterobacteriaceae producing MBL-type carbapenemases. PMID- 26416857 TI - Different Therapeutic Outcomes of Benznidazole and VNI Treatments in Different Genders in Mouse Experimental Models of Trypanosoma cruzi Infection. AB - The lack of translation between preclinical assays and clinical trials for novel therapies for Chagas disease (CD) indicates a need for more feasible and standardized protocols and experimental models. Here, we investigated the effects of treatment with benznidazole (Bz) and with the potent experimental T. cruzi CYP51 inhibitor VNI in mouse models of Chagas disease by using different animal genders and parasite strains and employing distinct types of therapeutic schemes. Our findings confirm that female mice are less vulnerable to the infection than males, show that male models are less susceptible to treatment with both Bz and VNI, and thus suggest that male models are much more suitable for selection of the most promising antichagasic agents. Additionally, we have found that preventive protocols (compound given at 1 dpi) result in higher treatment success rates, which also should be avoided during advanced steps of in vivo trials of novel anti-T. cruzi drug candidates. Another consideration is the relevance of immunosuppression methods in order to verify the therapeutic profile of novel compounds, besides the usefulness of molecular diagnostic tools (quantitative PCR) to ascertain compound efficacy in experimental animals. Our study aims to contribute to the development of more reliable methods and decision gates for in vivo assays of novel antiparasitic compounds in order to move them from preclinical to clinical trials for CD. PMID- 26416858 TI - Comparison of Borate Bioactive Glass and Calcium Sulfate as Implants for the Local Delivery of Teicoplanin in the Treatment of Methicillin-Resistant Staphylococcus aureus-Induced Osteomyelitis in a Rabbit Model. AB - There is growing interest in biomaterials that can cure bone infection and also regenerate bone. In this study, two groups of implants composed of 10% (wt/wt) teicoplanin (TEC)-loaded borate bioactive glass (designated TBG) or calcium sulfate (TCS) were created and evaluated for their ability to release TEC in vitro and to cure methicillin-resistant Staphylococcus aureus (MRSA)-induced osteomyelitis in a rabbit model. When immersed in phosphate-buffered saline (PBS), both groups of implants provided a sustained release of TEC at a therapeutic level for up to 3 to 4 weeks while they were gradually degraded and converted to hydroxyapatite. The TBG implants showed a longer duration of TEC release and better retention of strength as a function of immersion time in PBS. Infected rabbit tibiae were treated by debridement, followed by implantation of TBG or TCS pellets or intravenous injection with TEC, or were left untreated. Evaluation at 6 weeks postimplantation showed that the animals implanted with TBG or TCS pellets had significantly lower radiological and histological scores, lower rates of MRSA-positive cultures, and lower bacterial loads than those preoperatively and those of animals treated intravenously. The level of bone regeneration was also higher in the defects treated with the TBG pellets. The results showed that local TEC delivery was more effective than intravenous administration for the treatment of MRSA-induced osteomyelitis. Borate glass has the advantages of better mechanical strength, more desirable kinetics of release of TEC, and a higher osteogenic capacity and thus could be an effective alternative to calcium sulfate for local delivery of TEC. PMID- 26416856 TI - Genome Expression Profiling-Based Identification and Administration Efficacy of Host-Directed Antimicrobial Drugs against Respiratory Infection by Nontypeable Haemophilus influenzae. AB - Therapies that are safe, effective, and not vulnerable to developing resistance are highly desirable to counteract bacterial infections. Host-directed therapeutics is an antimicrobial approach alternative to conventional antibiotics based on perturbing host pathways subverted by pathogens during their life cycle by using host-directed drugs. In this study, we identified and evaluated the efficacy of a panel of host-directed drugs against respiratory infection by nontypeable Haemophilus influenzae (NTHi). NTHi is an opportunistic pathogen that is an important cause of exacerbation of chronic obstructive pulmonary disease (COPD). We screened for host genes differentially expressed upon infection by the clinical isolate NTHi375 by analyzing cell whole-genome expression profiling and identified a repertoire of host target candidates that were pharmacologically modulated. Based on the proposed relationship between NTHi intracellular location and persistence, we hypothesized that drugs perturbing host pathways used by NTHi to enter epithelial cells could have antimicrobial potential against NTHi infection. Interfering drugs were tested for their effects on bacterial and cellular viability, on NTHi-epithelial cell interplay, and on mouse pulmonary infection. Glucocorticoids and statins lacked in vitro and/or in vivo efficacy. Conversely, the sirtuin-1 activator resveratrol showed a bactericidal effect against NTHi, and the PDE4 inhibitor rolipram showed therapeutic efficacy by lowering NTHi375 counts intracellularly and in the lungs of infected mice. PDE4 inhibition is currently prescribed in COPD, and resveratrol is an attractive geroprotector for COPD treatment. Together, these results expand our knowledge of NTHi-triggered host subversion and frame the antimicrobial potential of rolipram and resveratrol against NTHi respiratory infection. PMID- 26416859 TI - Two Simple Rules for Improving the Accuracy of Empiric Treatment of Multidrug Resistant Urinary Tract Infections. AB - The emergence of multidrug-resistant (MDR) uropathogens is making the treatment of urinary tract infections (UTIs) more challenging. We sought to evaluate the accuracy of empiric therapy for MDR UTIs and the utility of prior culture data in improving the accuracy of the therapy chosen. The electronic health records from three U.S. Department of Veterans Affairs facilities were retrospectively reviewed for the treatments used for MDR UTIs over 4 years. An MDR UTI was defined as an infection caused by a uropathogen resistant to three or more classes of drugs and identified by a clinician to require therapy. Previous data on culture results, antimicrobial use, and outcomes were captured from records from inpatient and outpatient settings. Among 126 patient episodes of MDR UTIs, the choices of empiric therapy against the index pathogen were accurate in 66 (52%) episodes. For the 95 patient episodes for which prior microbiologic data were available, when empiric therapy was concordant with the prior microbiologic data, the rate of accuracy of the treatment against the uropathogen improved from 32% to 76% (odds ratio, 6.9; 95% confidence interval, 2.7 to 17.1; P < 0.001). Genitourinary tract (GU)-directed agents (nitrofurantoin or sulfa agents) were equally as likely as broad-spectrum agents to be accurate (P = 0.3). Choosing an agent concordant with previous microbiologic data significantly increased the chance of accuracy of therapy for MDR UTIs, even if the previous uropathogen was a different species. Also, GU-directed or broad-spectrum therapy choices were equally likely to be accurate. The accuracy of empiric therapy could be improved by the use of these simple rules. PMID- 26416860 TI - In Vitro Activity of Ceftaroline against Staphylococcus aureus Isolates Collected in 2012 from Latin American Countries as Part of the AWARE Surveillance Program. AB - The in vitro activities of ceftaroline and comparators, using broth microdilution, were determined against 1,066 Staphylococcus aureus isolates from hospitalized patients. Seventeen medical centers from Latin American countries contributed isolates. Methicillin-resistant S. aureus (MRSA) percentages ranged from 46% (Brazil) to 62% (Argentina). All methicillin-susceptible S. aureus (MSSA) isolates were susceptible to ceftaroline. Ceftaroline activity against MRSA varied with MIC90s of 0.5 (Venezuela) to 2 (Brazil, Chile, and Colombia) MUg/ml, which was the highest MIC value. ST-5 was the most common sequence type. PMID- 26416861 TI - In Vitro Activity of Miltefosine against Candida albicans under Planktonic and Biofilm Growth Conditions and In Vivo Efficacy in a Murine Model of Oral Candidiasis. AB - The generation of a new antifungal against Candida albicans biofilms has become a major priority, since biofilm formation by this opportunistic pathogenic fungus is usually associated with an increased resistance to azole antifungal drugs and treatment failures. Miltefosine is an alkyl phospholipid with promising antifungal activity. Here, we report that, when tested under planktonic conditions, miltefosine displays potent in vitro activity against multiple fluconazole-susceptible and -resistant C. albicans clinical isolates, including isolates overexpressing efflux pumps and/or with well-characterized Erg11 mutations. Moreover, miltefosine inhibits C. albicans biofilm formation and displays activity against preformed biofilms. Serial passage experiments confirmed that miltefosine has a reduced potential to elicit resistance, and screening of a library of C. albicans transcription factor mutants provided additional insight into the activity of miltefosine against C. albicans growing under planktonic and biofilm conditions. Finally, we demonstrate the in vivo efficacy of topical treatment with miltefosine in the murine model of oropharyngeal candidiasis. Overall, our results confirm the potential of miltefosine as a promising antifungal drug candidate, in particular for the treatment of azole-resistant and biofilm-associated superficial candidiasis. PMID- 26416862 TI - Cell Wall Recycling-Linked Coregulation of AmpC and PenB beta-Lactamases through ampD Mutations in Burkholderia cenocepacia. AB - In many Gram-negative pathogens, mutations in the key cell wall-recycling enzyme AmpD (N-acetyl-anhydromuramyl-L-alanine amidase) affect the activity of the regulator AmpR, which leads to the expression of AmpC beta-lactamase, conferring resistance to expanded-spectrum cephalosporin antibiotics. Burkholderia cepacia complex (Bcc) species also have these Amp homologs; however, the regulatory circuitry and the nature of causal ampD mutations remain to be explored. A total of 92 ampD mutants were obtained, representing four types of mutations: single nucleotide substitution (causing an amino acid substitution or antitermination of the enzyme), duplication, deletion, and IS element insertion. Duplication, which can go through reversion, was the most frequent type. Intriguingly, mutations in ampD led to the induction of two beta-lactamases, AmpC and PenB. Coregulation of AmpC and PenB in B. cenocepacia, and likely also in many Bcc species with the same gene organization, poses a serious threat to human health. This resistance mechanism is of evolutionary optimization in that ampD is highly prone to mutations allowing rapid response to antibiotic challenge, and many of the mutations are reversible in order to resume cell wall recycling when the antibiotic challenge is relieved. PMID- 26416863 TI - High Efficacy of Finafloxacin on Helicobacter pylori Isolates at pH 5.0 Compared with That of Other Fluoroquinolones. AB - Finafloxacin is a novel fluoroquinolone with improved antimicrobial efficacy, especially in an acidic environment. The efficacy of finafloxacin for the inhibition of Helicobacter pylori infection was compared with the efficacies of levofloxacin and moxifloxacin at neutral and acidic pH. The impacts of gyrA point mutation on the efficacy of those three fluoroquinolones were also investigated. A total of 128 clinical H. pylori strains were utilized. MICs of levofloxacin, moxifloxacin, and finafloxacin were determined at pH 5.0 and pH 7.0 by the agar dilution method. The impact of gyrA point mutations that are responsible for fluoroquinolone resistance was analyzed; the results showed 50 strains with an Asn-87 point mutation, 48 strains with an Asp-91 point mutation, and the remaining 30 strains with no gyrA mutations. The use of finafloxacin led to MIC values at pH 5.0 that were lower than the values seen at pH 7.0 for 112 strains (112/128, 87.5%), and this proportion was higher than that seen with moxifloxacin (21/128, 16.4%, P < 0.001). Finafloxacin also demonstrated a rate of susceptibility (MIC, <1 MUg/ml) (37.5%, 48/128) at pH 5.0 that was higher than that seen with moxifloxacin (2.3%, 3/128) (P < 0.001). The trends were similar regardless of which of the Asn-87, Asp-91, and A2143 point mutations were present. In conclusion, the superior antimicrobial efficacy of finafloxacin against H. pylori in an acidic environment suggests the possible use of finafloxacin for treatment of H. pylori infection, as has been proposed by its developer, Merlion Pharma. PMID- 26416864 TI - The Pathogen-Derived Aminoglycoside Resistance 16S rRNA Methyltransferase NpmA Possesses Dual m1A1408/m1G1408 Specificity. AB - Chemical modification of 16S rRNA can confer exceptionally high-level resistance to a diverse set of aminoglycoside antibiotics. Here, we show that the pathogen derived enzyme NpmA possesses dual m(1)A1408/m(1)G1408 activity, an unexpected property apparently unique among the known aminoglycoside resistance 16S rRNA (m(1)A1408) methyltransferases. Although the biological significance of this activity remains to be determined, such mechanistic variation in enzymes acquired by pathogens has significant implications for development of inhibitors of these emerging resistance determinants. PMID- 26416865 TI - K13-Propeller Polymorphisms in Plasmodium falciparum Isolates from Patients in Mayotte in 2013 and 2014. AB - Plasmodium falciparum isolates were collected from 29 malaria patients treated with artemether-lumefantrine in Mayotte in 2013 and 2014. Twenty-four cases (83%) consisted of imported malaria. Seventeen percent of the isolates presented mutations in one of the six K13-propeller blades (N490H, F495L, N554H/K, and E596G). A total of 23.8% of the isolates from the Union of Comoros showed K13 propeller polymorphisms. Three of the 18 isolates (16.7%) from Grande Comore showed polymorphisms (N490H, N554K, and E596G). PMID- 26416866 TI - Fluoroquinolone Impact on Nasal Methicillin-Resistant and Methicillin-Sensitive Staphylococcus aureus Colonization Durations in Neurologic Long-Term-Care Facilities. AB - Staphylococcus aureus nasal carriage is a risk factor for subsequent infection. Estimates of colonization duration vary widely among studies, and factors influencing the time to loss of colonization, especially the impact of antibiotics, remain unclear. We conducted a prospective study on patients naive for S. aureus colonization in 4 French long-term-care facilities. Data on nasal colonization status and potential factors for loss of colonization were collected weekly. We estimated methicillin-resistant S. aureus (MRSA) and methicillin sensitive S. aureus (MSSA) colonization durations using the Kaplan-Meier method and investigated factors for loss of colonization using shared-frailty Cox proportional hazards models. A total of 285 S. aureus colonization episodes were identified in 149 patients. The median time to loss of MRSA or MSSA colonization was 3 weeks (95% confidence interval, 2 to 8 weeks) or 2 weeks (95% confidence interval, 2 to 3 weeks), respectively. In multivariable analyses, the methicillin resistance phenotype was not associated with S. aureus colonization duration (P = 0.21); the use of fluoroquinolones (hazard ratio, 3.37; 95% confidence interval, 1.31 to 8.71) and having a wound positive for a nonnasal strain (hazard ratio, 2.17; 95% confidence interval, 1.15 to 4.07) were associated with earlier loss of MSSA colonization, while no factor was associated with loss of MRSA colonization. These results suggest that the methicillin resistance phenotype does not influence the S. aureus colonization duration and that fluoroquinolones are associated with loss of MSSA colonization but not with loss of MRSA colonization. PMID- 26416868 TI - Evaluation of the Rapidec Carba NP Test Kit for Detection of Carbapenemase Producing Gram-Negative Bacteria. AB - Recently, bioMerieux, France, introduced the Rapidec Carba NP test kit for rapid detection of carbapenemase-producing Gram-negative bacteria. This kit was evaluated in this study, and we report sensitivity, specificity, and positive and negative predictive values of 92.6%, 96.2%, 95.83%, and 92.6%, respectively. The test was easy to perform and interpret and relatively inexpensive ($5/Rs 300 per test) and provides a practical solution for early detection of carbapenemase producing, multidrug-resistant Gram-negative bacteria. PMID- 26416867 TI - Fitness Cost of Rifampin Resistance in Neisseria meningitidis: In Vitro Study of Mechanisms Associated with rpoB H553Y Mutation. AB - Rifampin chemoprophylaxis against Neisseria meningitidis infections led to the onset of rifampin resistance in clinical isolates harboring point mutations in the rpoB gene, coding for the RNA polymerase beta chain. These resistant strains are rare in medical practice, suggesting their decreased fitness in the human host. In this study, we isolated rifampin-resistant rpoB mutants from hypervirulent serogroup C strain 93/4286 and analyzed their different properties, including the ability to grow/survive in different culture media and in differentiated THP-1 human monocytes and to compete with the wild-type strain in vitro. Our results demonstrate that different rpoB mutations (H553Y, H553R, and S549F) may have different effects, ranging from low- to high-cost effects, on bacterial fitness in vitro. Moreover, we found that the S549F mutation confers temperature sensitivity, possibly explaining why it is observed very rarely in clinical isolates. Comparative high-throughput RNA sequencing analysis of bacteria grown in chemically defined medium demonstrated that the low-cost H553Y substitution resulted in global transcriptional changes that functionally mimic the stringent response. Interestingly, many virulence-associated genes, including those coding for meningococcal type IV pili, porin A, adhesins/invasins, IgA protease, two-partner secretion system HrpA/HrpB, enzymes involved in resistance to oxidative injury, lipooligosaccharide sialylation, and capsular polysaccharide biosynthesis, were downregulated in the H553Y mutant compared to their level of expression in the wild-type strain. These data might account for the reduced capacity of this mutant to grow/survive in differentiated THP-1 cells and explain the rarity of H553Y mutants among clinical isolates. PMID- 26416869 TI - In Vitro Activities of Primaquine-Schizonticide Combinations on Asexual Blood Stages and Gametocytes of Plasmodium falciparum. AB - Currently, the World Health Organization recommends addition of a 0.25-mg base/kg single dose of primaquine (PQ) to artemisinin combination therapies (ACTs) for Plasmodium falciparum malaria as a gametocytocidal agent for reducing transmission. Here, we investigated the potential interactions of PQ with the long-lasting components of the ACT drugs for eliminating the asexual blood stages and gametocytes of in vitro-cultured P. falciparum strains. Using the SYBR green I assay for asexual parasites and a flow cytometry-based assay for gametocytes, we determined the interactions of PQ with the schizonticides chloroquine, mefloquine, piperaquine, lumefantrine, and naphthoquine. With the sums of fractional inhibitory concentrations and isobolograms, we were able to determine mostly synergistic interactions for the various PQ and schizonticide combinations on the blood stages of P. falciparum laboratory strains. The synergism in inhibiting asexual stages and gametocytes was highly evident with PQ naphthoquine, whereas synergism was moderate for the PQ-piperaquine, PQ chloroquine, and PQ-mefloquine combinations. We have detected potentially antagonistic interactions between PQ and lumefantrine under certain drug combination ratios, suggesting that precautions might be needed when PQ is added as the gametocytocide to the artemether-lumefantrine ACT (Coartem). PMID- 26416870 TI - Effects of Antiviral Drugs on Organic Anion Transport in Human Placental BeWo Cells. AB - Placental drug transfer is important for achieving better pharmacotherapy in pregnant women and in fetuses. In the present study, we examined the effects of anti-hepatitis C virus (HCV) and anti-HIV drugs on organic anion transport in human placental BeWo cells. The cellular uptake of two fluorescence organic anions, 8-(2-[fluoresceinyl]aminoethylthio)adenosine-3',5'-cyclic monophosphate (8-FcAMP) and fluorescein, was temperature and concentration dependent. The Michaelis constant (Km) and the maximum uptake rate (Vmax) for 8-FcAMP transport in BeWo cells were estimated to be 6.45 +/- 0.75 MUM and 25.55 +/- 5.93 pmol/mg protein/10 min, respectively. The Km and Vmax values for fluorescein uptake were estimated to be 31.2 +/- 11.8 MUM and 510.9 +/- 90.6 pmol/mg protein/10 min, respectively. Several known substrates of organic anion transporters in human placenta, including atorvastatin, glibenclamide, estrone-3-sulfate, and rifampin, inhibited cellular uptake of 8-FcAMP and fluorescein in BeWo cells. Transport of 8-FcAMP and fluorescein was inhibited by the antiviral drugs boceprevir, telaprevir, elvitegravir, and maraviroc. These findings suggest that some antiviral drugs are sufficiently potent to influence placental drug transfer and cause drug-drug interactions. PMID- 26416871 TI - Impact of Hydroxychloroquine-Loaded Polyurethane Intravaginal Rings on Lactobacilli. AB - The use of polymeric devices for controlled sustained delivery of drugs is a promising approach for the prevention of HIV-1 infection. Unfortunately, certain microbicides, when topically applied vaginally, may be cytotoxic to vaginal epithelial cells and the protective microflora present within the female genital tract. In this study, we evaluated the impact of hydroxychloroquine (HCQ)-loaded, reservoir-type, polyurethane intravaginal rings (IVRs) on the growth of Lactobacillus crispatus and Lactobacillus jensenii and on the viability of vaginal and ectocervical epithelial cells. The IVRs were fabricated using hot melt injection molding and were capable of providing controlled release of HCQ for 24 days, with mean daily release rates of 17.01 +/- 3.6 MUg/ml in sodium acetate buffer (pH 4) and 29.45 +/- 4.84 MUg/ml in MRS broth (pH 6.2). Drug-free IVRs and the released HCQ had no significant effects on bacterial growth or the viability of vaginal or ectocervical epithelial cells. Furthermore, there was no significant impact on the integrity of vaginal epithelial cell monolayers, in comparison with controls, as measured by transepithelial electrical resistance. Overall, this is the first study to evaluate the effects of HCQ-loaded IVRs on the growth of vaginal flora and the integrity of vaginal epithelial cell monolayers. PMID- 26416872 TI - Novel Type XII Staphylococcal Cassette Chromosome mec Harboring a New Cassette Chromosome Recombinase, CcrC2. AB - Excision and integration of staphylococcal cassette chromosome mec (SCCmec) are mediated by cassette chromosome recombinases (Ccr), which play a crucial role in the worldwide spread of methicillin resistance in staphylococci. We report a novel ccr gene, ccrC2, in the SCCmec of a Staphylococcus aureus isolate, BA01611, which showed 62.6% to 69.4% sequence identities to all published ccrC1 sequences. A further survey found that the ccrC2 gene was mainly located among coagulase negative staphylococci (CoNS) and could be found in staphylococcal isolates from China, the United States, France, and Germany. The ccr gene complex harboring the ccrC2 gene was designated a type 9 complex, and the SCCmec of BA01611 was considered a novel type and was designated type XII (9C2). This novel SCCmec element in BA01611 was flanked by a pseudo-SCC element (PsiSCCBA01611) carrying a truncated ccrA1 gene. Both individual SCC elements and a composite SCC were excised from the chromosome based on detection of extrachromosomal circular intermediates. We advocate inclusion of the ccrC2 gene and type 9 ccr gene complex during revision of the SCCmec typing method. PMID- 26416873 TI - Antimicrobial Activity of Gallium Protoporphyrin IX against Acinetobacter baumannii Strains Displaying Different Antibiotic Resistance Phenotypes. AB - A paucity of effective, currently available antibiotics and a lull in antibiotic development pose significant challenges for treatment of patients with multidrug resistant (MDR) Acinetobacter baumannii infections. Thus, novel therapeutic strategies must be evaluated to meet the demands of treatment of these often life threatening infections. Accordingly, we examined the antibiotic activity of gallium protoporphyrin IX (Ga-PPIX) against a collection of A. baumannii strains, including nonmilitary and military strains and strains representing different clonal lineages and isolates classified as susceptible or MDR. Susceptibility testing demonstrated that Ga-PPIX inhibits the growth of all tested strains when cultured in cation-adjusted Mueller-Hinton broth, with a MIC of 20 MUg/ml. This concentration significantly reduced bacterial viability, while 40 MUg/ml killed all cells of the A. baumannii ATCC 19606(T) and ACICU MDR isolate after 24-h incubation. Recovery of ATCC 19606(T) and ACICU strains from infected A549 human alveolar epithelial monolayers was also decreased when the medium was supplemented with Ga-PPIX, particularly at a 40-MUg/ml concentration. Similarly, the coinjection of bacteria with Ga-PPIX increased the survival of Galleria mellonella larvae infected with ATCC 19606(T) or ACICU. Ga-PPIX was cytotoxic only when monolayers or larvae were exposed to concentrations 16-fold and 1,250 fold higher than those showing antibacterial activity, respectively. These results indicate that Ga-PPIX could be a viable therapeutic option for treatment of recalcitrant A. baumannii infections regardless of the resistance phenotype, clone lineage, time and site of isolation of strains causing these infections and their iron uptake phenotypes or the iron content of the media. PMID- 26416874 TI - Validation and Application of a Liquid Chromatography-Tandem Mass Spectrometry Method To Determine the Concentrations of Sofosbuvir Anabolites in Cells. AB - Sofosbuvir (SOF) is a highly efficacious and well-tolerated uridine nucleotide analog that inhibits the hepatitis C virus (HCV) NS5B polymerase enzyme. SOF is administered as a prodrug, which undergoes intracellular phosphorylation by host enzymes to a monophosphate, diphosphate, and finally a pharmacologically active triphosphate. In order to fully understand the clinical pharmacology of SOF, there is a great need to determine the intracellular phosphate concentrations of the drug. We describe the validation and utilization of a method to characterize SOF's disposition into various in vivo cell types, including hepatocytes, peripheral blood mononuclear cells (PBMC), and red blood cells (RBC). Standard bioanalytical validation criteria were applied to lysed cellular matrices, with a validated linear range of 50 to 50,000 fmol/sample for each phosphate moiety. The assay was utilized to collect the first data demonstrating concentrations of phosphorylated anabolites formed in PBMC, hepatocytes, and RBC in vivo during SOF therapy. Median concentrations in PBMC were 220 (range, 51.5 to 846), 70.2 (range, 25.8 to 275), and 859 (range, 54.5 to 6,756) fmol/10(6) cells in the monophosphate, diphosphate, and triphosphate fractions, respectively. In contrast, RBC triphosphate concentrations were much lower than those of PBMC, as the median concentration was 2.91 (range, 1.14 to 10.4) fmol/10(6) cells. The PBMC triphosphate half-life was estimated at 26 h using noncompartmental approaches, while nonlinear mixed-effect modeling was used to estimate a 69 h half-life for this moiety in RBC. The validated method and the data it generates provide novel insight into the cellular disposition of SOF and its phosphorylated anabolites in vivo. PMID- 26416875 TI - Impact of 2-Weeks Continuous Increase in Retrograde Shear Stress on Brachial Artery Vasomotor Function in Young and Older Men. AB - BACKGROUND: Although acute elevation in retrograde shear rate (SR) impairs endothelial function, no previous study has explored the effect of prolonged elevation of retrograde SR on conduit artery vascular function. We examined the effect of 2-weeks elevation of retrograde SR on brachial artery endothelial function in young and in older men. METHODS AND RESULTS: Thirteen healthy young (23+/-2 years) and 13 older men (61+/-5 years) were instructed to continuously wear a compression sleeve around the right forearm to chronically (2 weeks) elevate brachial artery retrograde SR in 1 arm. We assessed SR, diameter, and flow-mediated dilation in both the sleeve and contralateral control arms at baseline and after 30 minutes and 2 weeks of continuous sleeve application. The sleeve intervention increased retrograde SR after 30 minutes and 2 weeks in both young and older men (P=0.03 and 0.001, respectively). In young men, brachial artery flow-mediated dilation % was lower after 30 minutes and 2 weeks (P=0.004), while resting artery diameter was reduced after 2 weeks (P=0.005). The contralateral arm showed no change in retrograde SR or flow-mediated dilation % (P=0.32 and 0.26, respectively), but a decrease in diameter (P=0.035). In older men, flow-mediated dilation % and diameter did not change in either arm (all P>0.05). CONCLUSIONS: Thirty-minute elevation in retrograde SR in young men caused impaired endothelial function, while 2-week exposure to elevated levels of retrograde SR was associated with a comparable decrease in endothelial function. Interestingly, these vascular changes were not present in older men, suggesting age-related vascular changes to elevation in retrograde SR. PMID- 26416876 TI - Hemodynamic Correlates of Abnormal Aortic Root Dimension in an Adult Population: The Strong Heart Study. AB - BACKGROUND: We evaluated the relationship of aortic root dimension (ARD) with flow output and both peripheral and central blood pressure, using multivariable equations predicting ideal sex-specific ARD at a given age and body height. METHODS AND RESULTS: We measured echocardiographic diastolic ARD at the sinuses of Valsalva in 3160 adults (aged 42+/-16 years, 61% women) from the fourth examination of the Strong Heart Study who were free of prevalent coronary heart disease, and we compared measured data with the theoretical predicted value to calculate a z score. Central blood pressure was estimated by applanation tonometry of the radial artery in 2319 participants. ARD z scores were divided into tertiles representing small, normal, and large ARD. Participants with large ARD exhibited greater prevalence of central obesity and higher levels of inflammatory markers and lipids (0.05=75% likelihood of indicating CWD. Examples include 318.2 Profound intellectual disabilities and 780.72 Functional quadriplegia. CWDA sensitivity was 0.75 (95% confidence interval 0.63-0.84) compared with parent report and 0.98 (0.95-0.99) compared with physician assessment; its specificity was 0.86 (0.72-0.95) and 0.50 (0.41-0.59), respectively. CONCLUSIONS: ICD-9-CM codes can be classified by their likelihood of indicating CWD. CWDA triangulates well with parent report and physician assessment of child disability status. CWDA is a new tool that can be used to assess care quality for CWD. PMID- 26416936 TI - Maternal Versus Infant Vitamin D Supplementation During Lactation: A Randomized Controlled Trial. AB - OBJECTIVE: Compare effectiveness of maternal vitamin D3 supplementation with 6400 IU per day alone to maternal and infant supplementation with 400 IU per day. METHODS: Exclusively lactating women living in Charleston, SC, or Rochester, NY, at 4 to 6 weeks postpartum were randomized to either 400, 2400, or 6400 IU vitamin D3/day for 6 months. Breastfeeding infants in 400 IU group received oral 400 IU vitamin D3/day; infants in 2400 and 6400 IU groups received 0 IU/day (placebo). Vitamin D deficiency was defined as 25-hydroxy-vitamin D (25(OH)D) <50 nmol/L. 2400 IU group ended in 2009 as greater infant deficiency occurred. Maternal serum vitamin D, 25(OH)D, calcium, and phosphorus concentrations and urinary calcium/creatinine ratios were measured at baseline then monthly, and infant blood parameters were measured at baseline and months 4 and 7. RESULTS: Of the 334 mother-infant pairs in 400 IU and 6400 IU groups at enrollment, 216 (64.7%) were still breastfeeding at visit 1; 148 (44.3%) continued full breastfeeding to 4 months and 95 (28.4%) to 7 months. Vitamin D deficiency in breastfeeding infants was greatly affected by race. Compared with 400 IU vitamin D3 per day, 6400 IU/day safely and significantly increased maternal vitamin D and 25(OH)D from baseline (P < .0001). Compared with breastfeeding infant 25(OH)D in the 400 IU group receiving supplement, infants in the 6400 IU group whose mothers only received supplement did not differ. CONCLUSIONS: Maternal vitamin D supplementation with 6400 IU/day safely supplies breast milk with adequate vitamin D to satisfy her nursing infant's requirement and offers an alternate strategy to direct infant supplementation. PMID- 26416939 TI - Preterm Infant Attendance at Health Supervision Visits. AB - OBJECTIVES: To assess the adherence of premature infants with the American Academy of Pediatrics health supervision visit schedule, factors affecting adherence, and the association of adherence with preventive care. METHODS: Retrospective cohort of all infants <=35 weeks' gestation, born 2005 to 2009, receiving care at a 30-site primary care network for at least 24 months (n = 1854). Adherence was defined as having a health supervision visit within each expected time period during the first 18 months of life. Logistic regression identified sociodemographic and medical factors associated with nonadherence and risk-adjusted association between nonadherence and outcomes. RESULTS: Only 43% received all expected health supervision visits. Those with Medicaid insurance (adjusted odds ratio [AOR] 0.46, 95% confidence interval [CI] 0.35-0.60), a visit without insurance (AOR 0.46, 95% CI 0.32-0.67), chronic illness (AOR 0.7, 95% CI 0.51-0.97), and black race (AOR 0.7, 95% CI 0.50-0.98) were less adherent, whereas provider continuity of care (AOR 2.89, 95% CI 1.92-4.37) and lower birth weight (AOR 1.67, 95% CI 1.02-2.73) increased adherence. Infants <100% adherent were less likely to be up to date with immunizations and receive recommended preventive care. In nearly half of missed visit windows, no health supervision visit was scheduled. CONCLUSIONS: Fewer than half of premature infants were fully adherent with the preventive health schedule with associated gaps in health monitoring and immunization delays. These data suggest the importance of health supervision visits and the need to explore scheduling facilitators for those at risk for nonadherence. PMID- 26416940 TI - Chronic Pain Assessment Tools for Cerebral Palsy: A Systematic Review. AB - BACKGROUND AND OBJECTIVE: Chronic pain in children with cerebral palsy (CP) is underrecognized, leading to detriments in their physical, social, and mental well being. Our objective was to identify, describe, and critique pediatric chronic pain assessment tools and make recommendations for clinical use for children with CP. Secondly, develop an evidence-informed toolbox to support clinicians in the assessment of chronic pain in children with disabilities. METHODS: Ovid Medline, Cumulative Index to Nursing and Allied Health Literature, and Embase databases were systematically searched by using key terms "chronic pain" and "clinical assessment tool" between January 2012 and July 2014. Tools from multiple pediatric health conditions were explored contingent on inclusion criteria: (1) children 1 to 18 years; (2) assessment focus on chronic pain; (3) psychometric properties reported; (4) written in English between 1980 and 2014. Pediatric chronic pain assessment tools were extracted and corresponding validation articles were sought for review. Detailed tool descriptions were composed and each tool underwent a formal critique of psychometric properties and clinical utility. RESULTS: Of the retrieved 2652 articles, 250 articles met eligibility, from which 52 chronic pain assessment tools were retrieved. A consensus among interprofessional working group members determined 7 chronic pain interference tools to be of importance. Not all tools have been validated with children with CP nor is there 1 tool to meet the needs of all children experiencing chronic pain. CONCLUSIONS: This study has systematically reviewed and recommended, through expert consensus, valid and reliable chronic pain interference assessment tools for children with disabilities. PMID- 26416941 TI - Health Care Issues for Children and Adolescents in Foster Care and Kinship Care. AB - Children and adolescents who enter foster care often do so with complicated and serious medical, mental health, developmental, oral health, and psychosocial problems rooted in their history of childhood trauma. Ideally, health care for this population is provided in a pediatric medical home by physicians who are familiar with the sequelae of childhood trauma and adversity. As youth with special health care needs, children and adolescents in foster care require more frequent monitoring of their health status, and pediatricians have a critical role in ensuring the well-being of children in out-of-home care through the provision of high-quality pediatric health services, health care coordination, and advocacy on their behalves. PMID- 26416942 TI - Intraurethral Lidocaine for Urethral Catheterization in Children: A Randomized Controlled Trial. AB - OBJECTIVES: To determine whether lidocaine is superior to nonanesthetic lubricant (NAL) for relieving pain in children undergoing urethral catheterization (UC). METHODS: Children 0 to 24 months requiring UC were randomized to NAL or topical and intraurethral 2% lidocaine gel. Primary outcome was facial grimacing in the pre to during drug administration and catheterization phases. Secondary outcome was caregiver satisfaction by using a Visual Analog Scale. RESULTS: There were 133 participants (n = 68 lidocaine, n = 65 NAL). There were no significant differences in mean (SD) scores during UC between lidocaine and NAL (86.4% [121.5%] vs 85.2% [126.6%]), respectively (Delta [confidence interval (CI)] = 1.2 [-21.0 to 49.0], P = .4). There was a significantly greater difference in mean (SD) scores during instillation of lidocaine versus NAL (61.8% [105.6%] vs 3.2% [84.9%]), respectively (Delta [CI] -58.6 [-95.0 to -32.0], P < .001). There were no significant differences in mean (SD) parental satisfaction scores between lidocaine and NAL (4.8 [3.2] vs 5.9 [2.9]), respectively (CI-0.1 to 2.2; P = .06). In the subgroup analysis, age, gender, and positive urine culture did not significantly influence between-group differences in facial grimacing. CONCLUSIONS: Compared with NAL, topical and intraurethral lidocaine is not associated with significant pain reduction during UC, but significantly greater pain during instillation. Therefore, clinicians may consider using noninvasive pain-reducing strategies for young children who require UC. PMID- 26416944 TI - Is Intravenous Iron Supplementation Safe to Administer to Patients on Hemodialysis with Active Infection--What Do We Know, and What More Do We Need to Know? PMID- 26416943 TI - Receipt of Intravenous Iron and Clinical Outcomes among Hemodialysis Patients Hospitalized for Infection. AB - BACKGROUND AND OBJECTIVES: Anemia guidelines for CKD recommend withholding intravenous iron in the setting of active infection, although no data specifically support this recommendation. This study aimed to examine the association between intravenous iron and clinical outcomes among hemodialysis patients hospitalized for infection. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a retrospective observational cohort study using data from the US Renal Data System of 22,820 adult Medicare beneficiaries on in-center hemodialysis who had received intravenous iron in the 14 days preceding their first hospitalization for bacterial infection in 2010. In multivariable analyses, the association between receipt of intravenous iron at any point from the day of hospital admission to discharge and all-cause 30-day mortality, mortality in 2010, length of hospital stay, and readmission for infection or death within 30 days of discharge was evaluated. RESULTS: There were 2463 patients (10.8%) who received intravenous iron at any point from the day of admission to discharge. Receipt of intravenous iron was not associated with age, dialysis vintage, or comorbidities. There were 2618 deaths within 30 days of admission and 6921 deaths in 2010 (median follow-up 173 days; 25th and 75th percentiles, 78-271 days). The median length of stay was 7 days (25th and 75th percentiles, 5-12 days). Receipt of intravenous iron was not associated with higher 30-day mortality (odds ratio, 0.86; 95% confidence interval [95% CI], 0.74 to 1.00), higher mortality in 2010 (hazard ratio, 0.92; 95% CI, 0.85 to 1.00), longer mean length of stay (10.1 days [95% CI, 9.7 to 10.5] versus 10.5 days [95% CI, 10.3 to 10.7]; P=0.05), or readmission for infection or death within 30 days of discharge (odds ratio, 1.08; 95% CI, 0.96 to 1.22) compared with no receipt of intravenous iron. CONCLUSIONS: This analysis does not support withholding intravenous iron upon admission for bacterial infection in hemodialysis patients, although clinical trials are required to make definitive recommendations. PMID- 26416945 TI - The Role of Ethnic Variation and CKD. PMID- 26416947 TI - Evaluation of the Hemodynamic Effects of Intravenous Amiodarone Formulations During the Maintenance Phase Infusion. AB - BACKGROUND: Two of the excipients in intravenous formulations of amiodarone, polysorbate 80 and benzyl alcohol, have been shown to cause hypotension. A newer formulation of amiodarone, which contains cyclodextrin, is devoid of these excipients. OBJECTIVE: To evaluate the change in mean arterial pressure when utilizing 2 intravenous amiodarone formulations. METHODS: This was a retrospective cohort analysis conducted at an academic medical center. Patients received intravenous amiodarone containing either polysorbate 80/benzyl alcohol (control) or cyclodextrin (cyclodextrin). Patients received these formulations based on a standard institutional protocol of 1 mg/min for 6 hours, followed by 0.5 mg/min for at least 18 hours or until discontinued by the provider. All data were collected from the medical record and included changes in blood pressures, time to lowest systolic blood pressure, concurrent antihypertensive use, and number of patients requiring treatment for hypotension. RESULTS: A total of 160 patients (120 control, 40 cyclodextrin) were included. There was a statistically significant difference in mean arterial pressure between the groups receiving the control formulation of amiodarone compared with the cyclodextrin formulation across the 24-hour maintenance phase infusion (P < 0.001). There was a significant difference between formulations with regard to the change in mean arterial pressure during the 0- to 6-hour and 12- to 18-hour time blocks. There was a statistically significant difference in the number of patients receiving fluid boluses for treatment of hypotension (P = 0.001). CONCLUSIONS: The excipients in the formulation of intravenous amiodarone may have a significant role in the hypotensive effects seen throughout the duration the maintenance phase infusion. PMID- 26416946 TI - Prevalence and Correlates of CKD in Hispanics/Latinos in the United States. AB - BACKGROUND AND OBJECTIVES: The prevalence of ESRD among Hispanics/Latinos is 2 fold higher than in non-Hispanic whites. However, little is known about the prevalence of earlier stages of CKD among Hispanics/Latinos. This study estimated the prevalence of CKD in US Hispanics/Latinos. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a cross-sectional study of 15,161 US Hispanic/Latino adults of Cuban, Dominican, Mexican, Puerto Rican, Central American, and South American backgrounds enrolled in the multicenter, prospective, population-based Hispanic Community Health Study/Study of Latinos (HCHS/SOL). In addition, the prevalence of CKD in Hispanics/Latinos was compared with other racial/ethnic groups in the 2007-2010 National Health and Nutrition Examination Survey (NHANES). Prevalent CKD was defined as an eGFR <60 ml/min per 1.73 m(2) (estimated with the 2012 Chronic Kidney Disease Epidemiology Collaboration eGFR creatinine-cystatin C equation) or albuminuria based on sex-specific cut points determined at a single point in time. RESULTS: The overall prevalence of CKD among Hispanics/Latinos was 13.7%. Among women, the prevalence of CKD was 13.0%, and it was lowest in persons with South American background (7.4%) and highest (16.6%) in persons with Puerto Rican background. In men, the prevalence of CKD was 15.3%, and it was lowest (11.2%) in persons with South American background and highest in those who identified their Hispanic background as "other" (16.0%). The overall prevalence of CKD was similar in HCHS/SOL compared with non-Hispanic whites in NHANES. However, prevalence was higher in HCHS/SOL men and lower in HCHS/SOL women versus NHANES non-Hispanic whites. Low income, diabetes mellitus, hypertension, and cardiovascular disease were each significantly associated with higher risk of CKD. CONCLUSIONS: Among US Hispanic/Latino adults, there was significant variation in CKD prevalence among Hispanic/Latino background groups, and CKD was associated with established cardiovascular risk factors. PMID- 26416948 TI - Predictors of Pregnancy in Female Veterans Receiving a Hormonal Contraceptive Pill, Patch, or Ring. AB - BACKGROUND: Pregnancy rates in veterans are an understudied phenomenon. OBJECTIVE: The objective of this study was to identify predictors of pregnancy within 1 year of starting hormonal contraception among female veterans. METHODS: This was a retrospective, cohort study of female veterans from Veterans Affairs facilities within Southern California and Nevada, who newly started hormonal contraception (pill, patch, or ring only) between October 2008 and September 2012. Pregnancy was defined as any event corresponding to a pregnant state using ICD-9 codes. Patients were followed for 1 year post-initiation. Multivariate logistic regression analysis was performed. RESULTS: The final analysis included a total of 2166 patients. Approximately 5.9% (n = 127) of patients became pregnant during follow-up. Increased odds of pregnancy were associated with the following: mental health disease (odds ratio [OR] 1.69, 95% confidence interval [CI] 1.15-2.58), lowest socioeconomic quintile (OR 1.50, 95% CI 1.05-2.09), and Christian faith (OR 1.69, 95% CI 1.31-2.41). Age groups 25 to 34 years (OR 0.55, 95% CI 0.38-0.92] and 35 to 44 years (OR 0.32, 95% CI 0.06-0.64) were both associated with decreased odds of pregnancy versus age group 18 to 24 years. CONCLUSION: This study successfully identified several predictors of pregnancy in female veterans starting a pill, patch, or ring form of hormonal contraception. Female veterans in the lowest socioeconomic quintile, aged 18 to 24 years, diagnosed with a mental health disorder, and of Christian faith were found to be at significantly higher odds of a pregnancy. Identification of these at-risk populations may help clinicians and policy makers choose strategies to identify which patients could benefit the most from more effective long-acting reversible contraception therapy. PMID- 26416950 TI - Evaluation of Statin Prescribing for Secondary Prevention in Primary Care Following New Guideline Recommendations. AB - BACKGROUND: The American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Treatment of Blood Cholesterol recommends high intensity statin therapy for most patients with established atherosclerotic cardiovascular disease (ASCVD) versus previously recommended low-density lipoprotein cholesterol targets. The impact of the ACC/AHA guidelines on prescribing patterns in primary care is uncertain. OBJECTIVE: To describe the prescribing habits of statin therapy in primary care patients with ASCVD before and after the ACC/AHA guidelines were published. METHODS: This retrospective observational study evaluated patients with ASCVD who were seen in at least 1 of 8 primary care clinics in the University of Colorado Health system. It received expedited approval by the Colorado Multiple Institutional Review Board. The primary outcome measure was the proportion of patients with established ASCVD prescribed high-intensity statin therapy within 1 year before or after guideline release. RESULTS: In total, 220 patients were included in the analysis with 110 in the before and 110 in the after cohort. For the primary outcome analysis, the rate of high-intensity statin utilization in the before versus after groups was significantly greater (25.5% vs 41.8%, P = 0.01). For ages 76 to 89 years, 36 of 37 and 29 of 30 patients in the before and after groups were receiving moderate- to high-intensity statin therapy (97.3% vs 96.7%, P = 0.99). Subgroup analysis in the after cohort for all ages showed no change in statin therapy for 77% of patients. CONCLUSIONS: High-intensity statin prescribing increased in patients with ASCVD after release of the ACC/AHA cholesterol guidelines. Our data indicate that national evidence-based guidelines may influence clinical practice in very high risk patients. PMID- 26416949 TI - Off-Label Use of Agents for Management of Serious or Life-threatening Angiotensin Converting Enzyme Inhibitor-Induced Angioedema. AB - OBJECTIVE: To evaluate the place in therapy of fresh frozen plasma (FFP), C1 esterase concentrate (C1-INH), ecallantide, and icatibant in the management of angiotensin-converting enzyme inhibitor-induced angioedema (ACEI-IA). DATA SOURCES: A literature search was performed using PubMed (1946 through August 2015) and Embase (<1966 through August 2015). References from identified articles were reviewed. STUDY SELECTION AND DATA EXTRACTION: Consensus papers, practice guidelines, case reports/series, clinical trials, and meeting abstracts published in English and involving humans were included. DATA SYNTHESIS: No medications are currently Food and Drug Administration-approved for managing ACEI-IA. Emerging evidence suggests that FFP and medications approved for management of acute attacks of hereditary angioedema, another bradykinin-mediated event, may be effective for use in ACEI-IA. Positive efficacy results were reported with FFP and C1-INH while mixed results have been seen with ecallantide. Off-label icatibant has the most evidence supporting its use in ACEI-IA with rapid symptom resolution (10 minutes to 6 hours) and avoidance of intubation and tracheotomy in several cases. These agents were well-tolerated in ACEI-IA. CONCLUSION: ACEI-IA is typically a self-limiting event. First-line therapies include ACEI discontinuation, observation, and supportive medications (eg, corticosteroids, antihistamines, and epinephrine). Symptom progression can be life-threatening and may require interventions such as tracheotomy and intubation. Off-label use of FFP and medications approved for hereditary angioedema have resulted in rapid resolution of symptoms and avoidance of intubation. Among these agents, icatibant has the most supporting evidence and has been incorporated into practice guidelines and algorithms as a second-line agent for serious life-threatening ACE IA. PMID- 26416951 TI - Incidence of Hypoglycemia in Patients With Low eGFR Treated With Insulin and Dextrose for Hyperkalemia. AB - BACKGROUND: Hyperkalemia is a potentially life-threatening condition that is common in kidney disease patients. Insulin is used to treat hyperkalemia, but may cause hypoglycemia, especially in kidney disease when insulin may be metabolized more slowly. OBJECTIVE: We compared the rates of hypoglycemia in patients with low estimated glomerular filtration rate (eGFR) using high versus low doses of insulin for hyperkalemia to determine if lower doses of insulin would decrease the incidence of hypoglycemia. METHODS: This was a retrospective study of hospitalized patients receiving intravenous insulin for hyperkalemia during a 6 month period. Patients with low eGFR were analyzed based on how much insulin they received: high dose (10 units, n = 78) versus low dose (5 units, n = 71). Postdose nadir blood glucose values were examined for up to 8 hours after the dose. The percentage of hypoglycemia (blood glucose <=70 mg/dl) and a subset of severe hypoglycemia (blood glucose <50 mg/dl) were then reported for each dose group. RESULTS: A total of 149 doses were identified in patients with low eGFR. The rates of hypoglycemia were 16.7% and 19.7% (P = 0.79), respectively, among high-dose (n = 78) and low-dose (n = 71) groups. Rates of severe hypoglycemia were 8.9% and 7.0%, respectively (P = 0.90). More than 28% of hypoglycemic episodes with high doses occurred after 4 hours (median = 2.5 hours) compared with 14.3% with low doses (median = 2.38 hours). CONCLUSION: There was no difference in the rate of hypoglycemia or severe hypoglycemia between high or low doses of insulin in patients with low eGFR. We recommend monitoring up to 6 hours after insulin use in hyperkalemia. PMID- 26416953 TI - Correction. PMID- 26416952 TI - Navigating the plant cell: intracellular transport logistics in the green kingdom. AB - Intracellular transport in plant cells occurs on microtubular and actin arrays. Cytoplasmic streaming, the rapid motion of plant cell organelles, is mostly driven by an actin-myosin mechanism, whereas specialized functions, such as the transport of large cargo or the assembly of a new cell wall during cell division, are performed by the microtubules. Different modes of transport are used, fast and slow, to either haul cargo over long distances or ascertain high-precision targeting, respectively. Various forms of the actin-specific motor protein myosin XI exist in plant cells and might be involved in different cellular functions. PMID- 26416954 TI - What triggers migraine aura? PMID- 26416955 TI - Shemamruthaa, a Herbal Formulation Induces Apoptosis in Breast Cancer Cells and Inhibits Tumor Progression in Rats. AB - Phytochemicals present in plants are more effective than their individual constituents in preventing cancer through synergetic effects. From this perspective, Shemamruthaa, a herbal formulation was evaluated with a view to potentiate more intense anticancer property. This study investigates the anticancer activity of Shemamruthaa in breast cancer (MDA-MB 231) cell lines and its cancer therapeutic potential in 7,12-dimethylbenz[a]anthracene induced breast cancer rats. Results of MTT, trypan blue, and apoptotic marker assays suggested that Shemamruthaa can induce cytotoxicity in cancer cells, in a concentration- and time-dependent manner. Oral administration of Shemamruthaa effectively suppressed the tumor progression as evidenced by decrease in tumor volume and modulation of oxidant-antioxidant status and resulted in extended life span. Gas chromatography-mass spectrometry and high-performance liquid chromatography analysis of Shemamruthaa revealed the presence of pyrogallol, 5 hydrxoymethylfurfural, trilinolein, and flavonoids. Finally, we show that Shemamruthaa contains potential anticancer agents acting either singly or in combination against breast cancer cell proliferation. PMID- 26416956 TI - Nihal Altan-Bonnet: Tracking viruses that hijack membranes. PMID- 26416957 TI - When cell biology meets theory. AB - Cell biologists now have tools and knowledge to generate useful quantitative data. But how can we make sense of these data, and are we measuring the correct parameters? Moreover, how can we test hypotheses quantitatively? To answer these questions, the theory of physics is required and is essential to the future of quantitative cell biology. PMID- 26416958 TI - Sam37 is crucial for formation of the mitochondrial TOM-SAM supercomplex, thereby promoting beta-barrel biogenesis. AB - Biogenesis of mitochondrial beta-barrel proteins requires two preprotein translocases, the general translocase of the outer membrane (TOM) and the sorting and assembly machinery (SAM). TOM and SAM form a supercomplex that promotes transfer of beta-barrel precursors. The SAM core complex contains the channel protein Sam50, which cooperates with Sam35 in precursor recognition, and the peripheral membrane protein Sam37. The molecular function of Sam37 has been unknown. We report that Sam37 is crucial for formation of the TOM-SAM supercomplex. Sam37 interacts with the receptor domain of Tom22 on the cytosolic side of the mitochondrial outer membrane and links TOM and SAM complexes. Sam37 thus promotes efficient transfer of beta-barrel precursors to the SAM complex. We conclude that Sam37 functions as a coupling factor of the translocase supercomplex of the mitochondrial outer membrane. PMID- 26416960 TI - Reevaluating alphaE-catenin monomer and homodimer functions by characterizing E cadherin/alphaE-catenin chimeras. AB - As part of the E-cadherin-beta-catenin-alphaE-catenin complex (CCC), mammalian alphaE-catenin binds F-actin weakly in the absence of force, whereas cytosolic alphaE-catenin forms a homodimer that interacts more strongly with F-actin. It has been concluded that cytosolic alphaE-catenin homodimer is not important for intercellular adhesion because E-cadherin/alphaE-catenin chimeras thought to mimic the CCC are sufficient to induce cell-cell adhesion. We show that, unlike alphaE-catenin in the CCC, these chimeras homodimerize, bind F-actin strongly, and inhibit the Arp2/3 complex, all of which are properties of the alphaE-catenin homodimer. To more accurately mimic the junctional CCC, we designed a constitutively monomeric chimera, and show that E-cadherin-dependent cell adhesion is weaker in cells expressing this chimera compared with cells in which alphaE-catenin homodimers are present. Our results demonstrate that E cadherin/alphaE-catenin chimeras used previously do not mimic alphaE-catenin in the native CCC, and imply that both CCC-bound monomer and cytosolic homodimer alphaE-catenin are required for strong cell-cell adhesion. PMID- 26416959 TI - ATP8B1-mediated spatial organization of Cdc42 signaling maintains singularity during enterocyte polarization. AB - During yeast cell polarization localization of the small GTPase, cell division control protein 42 homologue (Cdc42) is clustered to ensure the formation of a single bud. Here we show that the disease-associated flippase ATPase class I type 8b member 1 (ATP8B1) enables Cdc42 clustering during enterocyte polarization. Loss of this regulation results in increased apical membrane size with scattered apical recycling endosomes and permits the formation of more than one apical domain, resembling the singularity defect observed in yeast. Mechanistically, we show that to become apically clustered, Cdc42 requires the interaction between its polybasic region and negatively charged membrane lipids provided by ATP8B1. Disturbing this interaction, either by ATP8B1 depletion or by introduction of a Cdc42 mutant defective in lipid binding, increases Cdc42 mobility and results in apical membrane enlargement. Re-establishing Cdc42 clustering, by tethering it to the apical membrane or lowering its diffusion, restores normal apical membrane size in ATP8B1-depleted cells. We therefore conclude that singularity regulation by Cdc42 is conserved between yeast and human and that this regulation is required to maintain healthy tissue architecture. PMID- 26416961 TI - Muller glia provide essential tensile strength to the developing retina. AB - To investigate the cellular basis of tissue integrity in a vertebrate central nervous system (CNS) tissue, we eliminated Muller glial cells (MG) from the zebrafish retina. For well over a century, glial cells have been ascribed a mechanical role in the support of neural tissues, yet this idea has not been specifically tested in vivo. We report here that retinas devoid of MG rip apart, a defect known as retinoschisis. Using atomic force microscopy, we show that retinas without MG have decreased resistance to tensile stress and are softer than controls. Laser ablation of MG processes showed that these cells are under tension in the tissue. Thus, we propose that MG act like springs that hold the neural retina together, finally confirming an active mechanical role of glial cells in the CNS. PMID- 26416962 TI - PAR-4 and anillin regulate myosin to coordinate spindle and furrow position during asymmetric division. AB - During asymmetric cell division, the mitotic spindle and polarized myosin can both determine the position of the cytokinetic furrow. However, how cells coordinate signals from the spindle and myosin to ensure that cleavage occurs through the spindle midzone is unknown. Here, we identify a novel pathway that is essential to inhibit myosin and coordinate furrow and spindle positions during asymmetric division. In Caenorhabditis elegans one-cell embryos, myosin localizes at the anterior cortex whereas the mitotic spindle localizes toward the posterior. We find that PAR-4/LKB1 impinges on myosin via two pathways, an anillin-dependent pathway that also responds to the cullin CUL-5 and an anillin independent pathway involving the kinase PIG-1/MELK. In the absence of both PIG 1/MELK and the anillin ANI-1, myosin accumulates at the anterior cortex and induces a strong displacement of the furrow toward the anterior, which can lead to DNA segregation defects. Regulation of asymmetrically localized myosin is thus critical to ensure that furrow and spindle midzone positions coincide throughout cytokinesis. PMID- 26416963 TI - PDK2-mediated alternative splicing switches Bnip3 from cell death to cell survival. AB - Herein we describe a novel survival pathway that operationally links alternative pre-mRNA splicing of the hypoxia-inducible death protein Bcl-2 19-kD interacting protein 3 (Bnip3) to the unique glycolytic phenotype in cancer cells. While a full-length Bnip3 protein (Bnip3FL) encoded by exons 1-6 was expressed as an isoform in normal cells and promoted cell death, a truncated spliced variant of Bnip3 mRNA deleted for exon 3 (Bnip3Deltaex3) was preferentially expressed in several human adenocarcinomas and promoted survival. Reciprocal inhibition of the Bnip3Deltaex3/Bnip3FL isoform ratio by inhibiting pyruvate dehydrogenase kinase isoform 2 (PDK2) in Panc-1 cells rapidly induced mitochondrial perturbations and cell death. The findings of the present study reveal a novel survival pathway that functionally couples the unique glycolytic phenotype in cancer cells to hypoxia resistance via a PDK2-dependent mechanism that switches Bnip3 from cell death to survival. Discovery of the survival Bnip3Deltaex3 isoform may fundamentally explain how certain cells resist Bnip3 and avert death during hypoxia. PMID- 26416964 TI - RUN and FYVE domain-containing protein 4 enhances autophagy and lysosome tethering in response to Interleukin-4. AB - Autophagy is a key degradative pathway coordinated by external cues, including starvation, oxidative stress, or pathogen detection. Rare are the molecules known to contribute mechanistically to the regulation of autophagy and expressed specifically in particular environmental contexts or in distinct cell types. Here, we unravel the role of RUN and FYVE domain-containing protein 4 (RUFY4) as a positive molecular regulator of macroautophagy in primary dendritic cells (DCs). We show that exposure to interleukin-4 (IL-4) during DC differentiation enhances autophagy flux through mTORC1 regulation and RUFY4 induction, which in turn actively promote LC3 degradation, Syntaxin 17-positive autophagosome formation, and lysosome tethering. Enhanced autophagy boosts endogenous antigen presentation by MHC II and allows host control of Brucella abortus replication in IL-4-treated DCs and in RUFY4-expressing cells. RUFY4 is therefore the first molecule characterized to date that promotes autophagy and influences endosome dynamics in a subset of immune cells. PMID- 26416965 TI - mTOR and differential activation of mitochondria orchestrate neutrophil chemotaxis. AB - Neutrophils use chemotaxis to locate invading bacteria. Adenosine triphosphate (ATP) release and autocrine purinergic signaling via P2Y2 receptors at the front and A2a receptors at the back of cells regulate chemotaxis. Here, we examined the intracellular mechanisms that control these opposing signaling mechanisms. We found that mitochondria deliver ATP that stimulates P2Y2 receptors in response to chemotactic cues, and that P2Y2 receptors promote mTOR signaling, which augments mitochondrial activity near the front of cells. Blocking mTOR signaling with rapamycin or PP242 or mitochondrial ATP production (e.g., with CCCP) reduced mitochondrial Ca(2+) uptake and membrane potential, and impaired cellular ATP release and neutrophil chemotaxis. Autocrine stimulation of A2a receptors causes cyclic adenosine monophosphate accumulation at the back of cells, which inhibits mTOR signaling and mitochondrial activity, resulting in uropod retraction. We conclude that mitochondrial, purinergic, and mTOR signaling regulates neutrophil chemotaxis and may be a pharmacological target in inflammatory diseases. PMID- 26416966 TI - PC7 and the related proteases Furin and Pace4 regulate E-cadherin function during blastocyst formation. AB - The first cell differentiation in mammalian embryos segregates polarized trophectoderm cells from an apolar inner cell mass (ICM). This lineage decision is specified in compacted morulae by cell polarization and adhesion acting on the Yes-associated protein in the Hippo signaling pathway, but the regulatory mechanisms are unclear. We show that morula compaction and ICM formation depend on PC7 and the related proprotein convertases (PCs) Furin and Pace4 and that these proteases jointly regulate cell-cell adhesion mediated by E-cadherin processing. We also mapped the spatiotemporal activity profiles of these proteases by live imaging of a transgenic reporter substrate in wild-type and PC mutant embryos. Differential inhibition by a common inhibitor revealed that all three PCs are active in inner and outer cells, but in partially nonoverlapping compartments. E-cadherin processing by multiple PCs emerges as a novel mechanism to modulate cell-cell adhesion and fate allocation. PMID- 26416967 TI - CRISP1 as a novel CatSper regulator that modulates sperm motility and orientation during fertilization. AB - Ca(2+)-dependent mechanisms are critical for successful completion of fertilization. Here, we demonstrate that CRISP1, a sperm protein involved in mammalian fertilization, is also present in the female gamete and capable of modulating key sperm Ca(2+) channels. Specifically, we show that CRISP1 is expressed by the cumulus cells that surround the egg and that fertilization of cumulus-oocyte complexes from CRISP1 knockout females is impaired because of a failure of sperm to penetrate the cumulus. We provide evidence that CRISP1 stimulates sperm orientation by modulating sperm hyperactivation, a vigorous motility required for penetration of the egg vestments. Moreover, patch clamping of sperm revealed that CRISP1 has the ability to regulate CatSper, the principal sperm Ca(2+) channel involved in hyperactivation and essential for fertility. Given the critical role of Ca(2+) for sperm motility, we propose a novel CRISP1 mediated fine-tuning mechanism to regulate sperm hyperactivation and orientation for successful penetration of the cumulus during fertilization. PMID- 26416968 TI - A Src inhibitor regulates the cell cycle of human pluripotent stem cells and improves directed differentiation. AB - Driving human pluripotent stem cells (hPSCs) into specific lineages is an inefficient and challenging process. We show that a potent Src inhibitor, PP1, regulates expression of genes involved in the G1 to S phase transition of the cell cycle, activates proteins in the retinoblastoma family, and subsequently increases the differentiation propensities of hPSCs into all three germ layers. We further demonstrate that genetic suppression of Src regulates the activity of the retinoblastoma protein and enhances the differentiation potential of hPSCs across all germ layers. These positive effects extend beyond the initial germ layer specification and enable efficient differentiation at subsequent stages of differentiation. PMID- 26416969 TI - Human substantia nigra neurons encode decision outcome and are modulated by categorization uncertainty in an auditory categorization task. AB - The ability to categorize stimuli - predator or prey, friend or foe - is an essential feature of the decision-making process. Underlying that ability is the development of an internally generated category boundary to generate decision outcomes. While classic temporal difference reinforcement models assume midbrain dopaminergic neurons underlie the prediction error required to learn boundary location, these neurons also demonstrate a robust response to nonreward incentive stimuli. More recent models suggest that this may reflect a motivational aspect to performing a task which should be accounted for when modeling dopaminergic neuronal behavior. To clarify the role of substantia nigra dopamine neurons in uncertain perceptual decision making, we investigated their behavior using single neuron extracellular recordings in patients with Parkinson's disease undergoing deep brain stimulation. Subjects underwent a simple auditory categorical decision making task in which they had to classify a tone as either low- or high-pitched relative to an explicit threshold tone and received feedback but no reward. We demonstrate that the activity of human SN dopaminergic neurons is predictive of perceptual categorical decision outcome and is modulated by uncertainty. Neuronal activity was highest during difficult (uncertain) decisions that resulted in correct responses and lowest during easy decisions that resulted in incorrect responses. This pattern of results is more consistent with a "motivational" role with regards to perceptual categorization and suggests that dopamine neurons are most active when critical information - as represented by uncertainty - is available for learning decision boundaries. PMID- 26416970 TI - Kir6.2 activation by sulfonylurea receptors: a different mechanism of action for SUR1 and SUR2A subunits via the same residues. AB - ATP-sensitive potassium channels (K-ATP channels) play a key role in adjusting the membrane potential to the metabolic state of cells. They result from the unique combination of two proteins: the sulfonylurea receptor (SUR), an ATP binding cassette (ABC) protein, and the inward rectifier K(+) channel Kir6.2. Both subunits associate to form a heterooctamer (4 SUR/4 Kir6.2). SUR modulates channel gating in response to the binding of nucleotides or drugs and Kir6.2 conducts potassium ions. The activity of K-ATP channels varies with their localization. In pancreatic beta-cells, SUR1/Kir6.2 channels are partly active at rest while in cardiomyocytes SUR2A/Kir6.2 channels are mostly closed. This divergence of function could be related to differences in the interaction of SUR1 and SUR2A with Kir6.2. Three residues (E1305, I1310, L1313) located in the linker region between transmembrane domain 2 and nucleotide-binding domain 2 of SUR2A were previously found to be involved in the activation pathway linking binding of openers onto SUR2A and channel opening. To determine the role of the equivalent residues in the SUR1 isoform, we designed chimeras between SUR1 and the ABC transporter multidrug resistance-associated protein 1 (MRP1), and used patch clamp recordings on Xenopus oocytes to assess the functionality of SUR1/MRP1 chimeric K-ATP channels. Our results reveal that the same residues in SUR1 and SUR2A are involved in the functional association with Kir6.2, but they display unexpected side-chain specificities which could account for the contrasted properties of pancreatic and cardiac K-ATP channels. PMID- 26416971 TI - Deletion of glycerol channel aquaporin-9 (Aqp9) impairs long-term blood glucose control in C57BL/6 leptin receptor-deficient (db/db) obese mice. AB - Deletion of the glycerol channel aquaporin-9 (Aqp9) reduces postprandial blood glucose levels in leptin receptor-deficient (db/db) obese mice on a C57BL/6 * C57BLKS mixed genetic background. Furthermore, shRNA-mediated reduction of Aqp9 expression reduces liver triacylglycerol (TAG) accumulation in a diet-induced rat model of obesity. The aim of this study was to investigate metabolic effects of Aqp9 deletion in coisogenic db/db mice of the C57BL/6 background. Aqp9(wt) db/db and Aqp9(-/-) db/db mice did not differ in body weight and liver TAG contents. On the C57BL/6 genetic background, we observed elevated plasma glucose in Aqp9(-/-) db/db mice (+1.1 mmol/L, life-time average), while plasma insulin concentration was reduced at the time of death. Glucose levels changed similarly in pentobarbital anesthetized, glucagon challenged Aqp9(wt) db/db and Aqp9(-/-) db/db mice. Liver transcriptional profiling did not detect differential gene expression between genotypes. Metabolite profiling revealed a sex independent increase in plasma glycerol (+55%) and glucose (+24%), and reduction in threonate (all at q < 0.1) in Aqp9(-/-) db/db mice compared to controls. Metabolite profiling thus confirms a role of AQP9 in glycerol metabolism of obese C57BL/6 db/db mice. In this animal model of obesity Aqp9 gene deletion elevates plasma glucose and does not alleviate hepatosteatosis. PMID- 26416972 TI - Hierarchical organization of long-range circuits in the olfactory cortices. AB - How sensory information is processed within olfactory cortices is unclear. Here, we examined long-range circuit wiring between different olfactory cortical regions of acute mouse brain slices using a channelrhodopsin-2 (ChR2)-based neuronal targeting approach. Our results provide detailed information regarding the synaptic properties of the reciprocal long-range monosynaptic glutamatergic projections (LRMGP) between and within anterior piriform cortex (aPC), posterior piriform cortex (pPC), and lateral entorhinal cortex (LEC), thereby creating a long-range inter- and intracortical circuit diagrams at the level of synapses and single cortical neurons. Our results reveal the following information regarding hierarchical intra- and intercortical organizations: (i) there is massive bottom up (i.e., rostral-caudal) excitation within the LRMGP accompanied with strong feedforward (FF) inhibition; (ii) there are convergent FF connections onto LEC from both aPC and pPC; (iii) feedback (FB) intercortical connections are weak with a significant fraction of presumptive silent synapses; and (iv) intra and intercortical long-range connections lack layer specificity and their innervation of interneurons are stronger than neighboring pyramidal neurons. The elucidation of the distinct hierarchical organization of long-range olfactory cortical circuits paves the way for further understanding of higher order cortical processing within the olfactory system. PMID- 26416973 TI - Effects of decreased lactate accumulation after dichloroacetate administration on exercise training-induced mitochondrial adaptations in mouse skeletal muscle. AB - Recent studies suggested that lactate accumulation can be a signal for mitochondrial biogenesis in skeletal muscle. We investigated whether reductions in lactate concentrations in response to dichloroacetate (DCA), an activator of pyruvate dehydrogenase, attenuate mitochondrial adaptations after exercise training in mice. We first confirmed that DCA administration (200 mg/kg BW by i.p. injection) 10 min before exercise decreased muscle and blood lactate concentrations after high-intensity interval exercise (10 bouts of 1 min treadmill running at 40 m/min with a 1 min rest). At the same time, exercise induced signal cascades did not change by pre-exercise DCA administration. These results suggested that DCA administration affected only lactate concentrations after exercise. We next examined the effects of acute DCA administration on mRNA expressions involved with mitochondrial biogenesis after same high-intensity interval exercise and the effects of chronic DCA administration on mitochondrial adaptations after high-intensity interval training (increasing intensity from 38 to 43 m/min by the end of training period). Acute DCA administration did not change most of the exercise-induced mRNA upregulation. These data suggest that lactate reductions by DCA administration did not affect transcriptional activation after high-intensity interval exercise. However, chronic DCA administration attenuated, in part, mitochondrial adaptations such as training induced increasing rates of citrate synthase (P = 0.06), beta-hydroxyacyl CoA dehydrogenase activity (P < 0.05), cytochrome c oxidase IV (P < 0.05) and a fatty acid transporter, fatty acid translocase/CD36 (P < 0.05), proteins after exercise training. These results suggest that lactate accumulation during high-intensity interval exercise may be associated with mitochondrial adaptations after chronic exercise training. PMID- 26416974 TI - Uteroplacental insufficiency leads to hypertension, but not glucose intolerance or impaired skeletal muscle mitochondrial biogenesis, in 12-month-old rats. AB - Growth restriction impacts on offspring development and increases their risk of disease in adulthood which is exacerbated with "second hits." The aim of this study was to investigate if blood pressure, glucose tolerance, and skeletal muscle mitochondrial biogenesis were altered in 12-month-old male and female offspring with prenatal or postnatal growth restriction. Bilateral uterine vessel ligation induced uteroplacental insufficiency and growth restriction in offspring (Restricted). A sham surgery was also performed during pregnancy (Control) and some litters from sham mothers had their litter size reduced (Reduced litter), which restricted postnatal growth. Growth-restricted females only developed hypertension at 12 months, which was not observed in males. In Restricted females only homeostasis model assessment for insulin resistance was decreased, indicating enhanced hepatic insulin sensitivity, which was not observed in males. Plasma leptin was increased only in the Reduced males at 12 months compared to Control and Restricted males, which was not observed in females. Compared to Controls, leptin, ghrelin, and adiponectin were unaltered in the Restricted males and females, suggesting that at 12 months of age the reduction in body weight in the Restricted offspring is not a consequence of circulating adipokines. Skeletal muscle PGC-1alpha levels were unaltered in 12-month-old male and female rats, which indicate improvements in lean muscle mass by 12 months of age. In summary, sex strongly impacts the cardiometabolic effects of growth restriction in 12 month-old rats and it is females who are at particular risk of developing long term hypertension following growth restriction. PMID- 26416975 TI - TLR4 mutant mice are protected from renal fibrosis and chronic kidney disease progression. AB - Chronic kidney disease (CKD) is associated with persistent low-grade inflammation and immunosuppression. In this study we tested the role of Toll-like receptor 4, the main receptor for endotoxin (LPS), in a mouse model of renal fibrosis and in a model of progressive CKD that better resembles the human disease. C3HeJ (TLR4 mutant) mice have a missense point mutation in the TLR4 gene, rendering the receptor nonfunctional. In a model of renal fibrosis after folic acid injection, TLR4 mutant mice developed less interstititial fibrosis in comparison to wild type (WT) mice. Furthermore, 4 weeks after 5/6 nephrectomy with continuous low dose angiotensin II infusion, C3HeOuJ (TLR4 WT) mice developed progressive CKD with albuminuria, increased serum levels of BUN and creatinine, glomerulosclerosis, and interstitial fibrosis, whereas TLR4 mutant mice were significantly protected from CKD progression. TLR4 WT mice also developed low grade systemic inflammation, splenocyte apoptosis and increased expression of the immune inhibitory receptor PD-1 in the spleen, which were not observed in TLR4 mutant mice. In vitro, endotoxin (LPS) directly upregulated NLRP3 inflammasome expression in renal epithelial cells via TLR4. In summary, TLR4 contributes to renal fibrosis and CKD progression, at least in part, via inflammasome activation in renal epithelial cells, and may also participate in the dysregulated immune response that is associated with CKD. PMID- 26416976 TI - Case report: proximal tubule impairment following volatile anesthetic exposure. AB - The safety of contemporary volatile anesthetic agents with respect to kidney function is well established, and growing evidence suggests that volatile anesthetics even protect against ischemic nephropathy. However, studies examining effects of volatile anesthetics on kidney function frequently demonstrate transient proteinuria and glycosuria following exposure to these agents, although the cause of these findings has not been thoroughly examined. We describe the case of a patient who underwent a neurosurgical procedure, then experienced glycosuria without hyperglycemia that resolved within days. Following a second neurosurgical procedure, the patient again developed glycosuria, now associated with ketonuria. Further examination demonstrated nonalbuminuric proteinuria in conjunction with urinary wasting of phosphate and potassium, indicative of proximal tubule impairment. We suggest that transient proximal tubule impairment may play a role in the proteinuria and glycosuria described following volatile anesthetic exposure and discuss the relationship between these observations and the ability of these agents to protect against ischemic nephropathy. PMID- 26416978 TI - Transcriptomic Evidence for the Evolution of Shoot Meristem Function in Sporophyte-Dominant Land Plants through Concerted Selection of Ancestral Gametophytic and Sporophytic Genetic Programs. PMID- 26416977 TI - Weak endogenous Ca2+ buffering supports sustained synaptic transmission by distinct mechanisms in rod and cone photoreceptors in salamander retina. AB - Differences in synaptic transmission between rod and cone photoreceptors contribute to different response kinetics in rod- versus cone-dominated visual pathways. We examined Ca(2+) dynamics in synaptic terminals of tiger salamander photoreceptors under conditions that mimicked endogenous buffering to determine the influence on kinetically and mechanistically distinct components of synaptic transmission. Measurements of IC l(Ca) confirmed that endogenous Ca(2+) buffering is equivalent to ~0.05 mmol/L EGTA in rod and cone terminals. Confocal imaging showed that with such buffering, depolarization stimulated large, spatially unconstrained [Ca(2+)] increases that spread throughout photoreceptor terminals. We calculated immediately releasable pool (IRP) size and release efficiency in rods by deconvolving excitatory postsynaptic currents and presynaptic Ca(2+) currents. Peak efficiency of ~0.2 vesicles/channel was similar to that of cones (~0.3 vesicles/channel). Efficiency in both cell types was not significantly affected by using weak endogenous Ca(2+) buffering. However, weak Ca(2+) buffering speeded Ca(2+)/calmodulin (CaM)-dependent replenishment of vesicles to ribbons in both rods and cones, thereby enhancing sustained release. In rods, weak Ca(2+) buffering also amplified sustained release by enhancing CICR and CICR stimulated release of vesicles at nonribbon sites. By contrast, elevating [Ca(2+)] at nonribbon sites in cones with weak Ca(2+) buffering and by inhibiting Ca(2+) extrusion did not trigger additional release, consistent with the notion that exocytosis from cones occurs exclusively at ribbons. The presence of weak endogenous Ca(2+) buffering in rods and cones facilitates slow, sustained exocytosis by enhancing Ca(2+)/CaM-dependent replenishment of ribbons in both rods and cones and by stimulating nonribbon release triggered by CICR in rods. PMID- 26416979 TI - Anarchy Is a Molecular Signature of Worker Sterility in the Honey Bee. AB - Worker sterility is a defining characteristic of eusociality. The existence of the sterile worker caste remains a fundamental question for evolutionary biology as it requires the existence of genes that reduce personal reproduction. Currently, little is known about the proximate mechanisms underpinning worker sterility. Studies into a mutant "anarchistic" strain (in which workers can activate their ovaries) of honey bee, Apis mellifera, identified a list of candidate genes that regulate ovary activation. We quantified the expression of the four most promising candidate genes (Anarchy, Pdk1, S6k, and Ulk3) in nonactivated and activated ovaries of wild-type workers. Ovarian expression of Anarchy, a peroxisomal membrane protein, predicts the ovary state of workers with 88.2% accuracy. Increased expression of Anarchy in the ovary is strongly associated with suppression of oogenesis and its expression is sensitive to the presence of the queen. Therefore, Anarchy satisfies key criteria for a "gene underlying altruism". When we knocked down expression of Anarchy in the ovary using RNA interference (RNAi) we altered the expression of Buffy, a gene that regulates programmed cell death. Whole-mount multiplex fluorescent in situ hybridization (mFISH) shows Anarchy transcripts localize to degenerating oocytes within the ovary. Our results suggest that Anarchy is involved in the regulation of oogenesis through programmed cell death. The evolution of facultative worker sterility most likely occurred when the conserved mechanism of programmed cell death was co-opted to regulate ovary activation. Anarchy may therefore be the first example of a gene that has evolved through kin selection to regulate worker sterility. PMID- 26416981 TI - Substitution Model Adequacy and Assessing the Reliability of Estimates of Virus Evolutionary Rates and Time Scales. AB - Determining the time scale of virus evolution is central to understanding their origins and emergence. The phylogenetic methods commonly used for this purpose can be misleading if the substitution model makes incorrect assumptions about the data. Empirical studies consider a pool of models and select that with the highest statistical fit. However, this does not allow the rejection of all models, even if they poorly describe the data. An alternative is to use model adequacy methods that evaluate the ability of a model to predict hypothetical future observations. This can be done by comparing the empirical data with data generated under the model in question. We conducted simulations to evaluate the sensitivity of such methods with nucleotide, amino acid, and codon data. These effectively detected underparameterized models, but failed to detect mutational saturation and some instances of nonstationary base composition, which can lead to biases in estimates of tree topology and length. To test the applicability of these methods with real data, we analyzed nucleotide and amino acid data sets from the genus Flavivirus of RNA viruses. In most cases these models were inadequate, with the exception of a data set of relatively closely related sequences of Dengue virus, for which the GTR+Gamma nucleotide and LG+Gamma amino acid substitution models were adequate. Our results partly explain the lack of consensus over estimates of the long-term evolutionary time scale of these viruses, and indicate that assessing the adequacy of substitution models should be routinely used to determine whether estimates are reliable. PMID- 26416980 TI - The Roles of Compensatory Evolution and Constraint in Aminoacyl tRNA Synthetase Evolution. AB - Mitochondrial protein translation requires interactions between transfer RNAs encoded by the mitochondrial genome (mt-tRNAs) and mitochondrial aminoacyl tRNA synthetase proteins (mt-aaRS) encoded by the nuclear genome. It has been argued that animal mt-tRNAs have higher deleterious substitution rates relative to their nuclear-encoded counterparts, the cytoplasmic tRNAs (cyt-tRNAs). This dynamic predicts elevated rates of compensatory evolution of mt-aaRS that interact with mt-tRNAs, relative to aaRS that interact with cyt-tRNAs (cyt-aaRS). We find that mt-aaRS do evolve at significantly higher rates (exemplified by higher dN and dN/dS) relative to cyt-aaRS, across mammals, birds, and Drosophila. While this pattern supports a model of compensatory evolution, the level at which a gene is expressed is a more general predictor of protein evolutionary rate. We find that gene expression level explains 10-56% of the variance in aaRS dN/dS, and that cyt aaRS are more highly expressed in addition to having lower dN/dS values relative to mt-aaRS, consistent with more highly expressed genes being more evolutionarily constrained. Furthermore, we find no evidence of positive selection acting on either class of aaRS protein, as would be expected under a model of compensatory evolution. Nevertheless, the signature of faster mt-aaRS evolution persists in mammalian, but not bird or Drosophila, lineages after controlling for gene expression, suggesting some additional effect of compensatory evolution for mammalian mt-aaRS. We conclude that gene expression is the strongest factor governing differential amino acid substitution rates in proteins interacting with mitochondrial versus cytoplasmic factors, with important differences in mt-aaRS molecular evolution among taxonomic groups. PMID- 26416982 TI - Corrigendum. PMID- 26416983 TI - Cyclin E1 plays a key role in balancing between totipotency and differentiation in human embryonic cells. AB - STUDY HYPOTHESIS: We aimed to investigate if Cyclin E1 (CCNE1) plays a role in human embryogenesis, in particular during the early developmental stages characterized by a short cell cycle. STUDY FINDING: CCNE1 is expressed in plenipotent human embryonic cells and plays a critical role during hESC derivation via the naive state and, potentially, normal embryo development. WHAT IS KNOWN ALREADY: A short cell cycle due to a truncated G1 phase has been associated with the high developmental capacity of embryonic cells. CCNE1 is a critical G1/S transition regulator. CCNE1 overexpression can cause shortening of the cell cycle and it is constitutively expressed in mouse embryonic stem cells and cancer cells. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: We investigated expression of CCNE1 in human preimplantation embryo development and embryonic stem cells (hESC). Functional studies included CCNE1 overexpression in hESC and CCNE1 downregulation in the outgrowths formed by plated human blastocysts. Analysis was performed by immunocytochemistry and quantitative real-time PCR. Mann-Whitney statistical test was applied. MAIN RESULTS AND THE ROLE OF CHANCE: The CCNE1 protein was ubiquitously and constitutively expressed in the plenipotent cells of the embryo from the 4-cell stage up to and including the full blastocyst. During blastocyst expansion, CCNE1 was downregulated in the trophectoderm (TE) cells. CCNE1 shortly co-localized with NANOG in the inner cell mass (ICM) of expanding blastocysts, mimicking the situation in naive hESC. In the ICM of expanded blastocysts, which corresponds with primed hESC, CCNE1 defined a subpopulation of cells different from NANOG/POU5F1-expressing pluripotent epiblast (EPI) cells and GATA4/SOX17-expressing primitive endoderm (PrE) cells. This CCNE1-positive cell population was associated with visceral endoderm based on transthyretin expression and marked the third cell lineage within the ICM, besides EPI and PrE, which had never been described before. We also investigated the role of CCNE1 by plating expanded blastocysts for hESC derivation. As a result, all the cells including TE cells re-gained CCNE1 and, consequently, NANOG expression, resembling the phenotype of naive hESC. The inhibition of CCNE1 expression with siRNA blocked proliferation and caused degeneration of those plated cells. LIMITATIONS, REASONS FOR CAUTION: The study is based on a limited number of good-quality human embryos donated to research. WIDER IMPLICATIONS OF THE FINDINGS: Our study sheds light on the processes underlying the high developmental potential of early human embryonic cells. The CCNE1-positive plenipotent cell type corresponds with a phenotype that enables early human embryos to recover after fragmentation, cryodamage or (single cell) biopsy on day 3 for preimplantation genetic diagnosis. Knowledge on the expression and function of genes responsible for this flexibility will help us to better understand the undifferentiated state in stem cell biology and might enable us to improve technologies in assisted reproduction. LARGE SCALE DATA: NA STUDY FUNDING AND COMPETING INTERESTS: This research is supported by grants from the Fund for Scientific Research - Flanders (FWO-Vlaanderen), the Methusalem (METH) of the VUB and Scientific Research Fond Willy Gepts of UZ Brussel. There are no competing interests. PMID- 26416984 TI - A 19-Year-Old Girl With Rectal Bleeding: Broadening Pediatricians' Differential Diagnoses. PMID- 26416986 TI - Tuberculosis elimination in Canada: Truce or victory? PMID- 26416987 TI - Terra firma-forme dermatosis. PMID- 26416988 TI - Child sexual abuse in Nunavut linked to suicide. PMID- 26416990 TI - Hygiene and sanitation: medical, social and psychological concerns. PMID- 26416989 TI - Diagnosis and management of iliofemoral deep vein thrombosis: clinical practice guideline. PMID- 26416991 TI - Is the US ready for ICD-10? PMID- 26416992 TI - A 38-year-old man who uses crack cocaine. PMID- 26416994 TI - Mental health needs targeted federal funds. PMID- 26416993 TI - Domestic impact of tuberculosis screening among new immigrants to Ontario, Canada. AB - BACKGROUND: All Canadian immigrants undergo screening for tuberculosis (TB) before immigration, and selected immigrants must undergo postimmigration surveillance for the disease. We sought to quantify the domestic health impact of screening for TB in all new immigrants and to identify mechanisms to enhance effectiveness and efficiency of this screening. METHODS: We linked preimmigration medical examination records from 944,375 immigrants who settled in Ontario between 2002 and 2011 to active TB reporting data in Ontario between 2002 and 2011. Using a retrospective cohort study design, we measured birth country specific rates of active TB detected through preimmigration screening and postimmigration surveillance. We then quantified the proportion of active TB cases among residents of Ontario born abroad that were detected through postimmigration surveillance. Using Cox regression, we identified independent predictors of active TB postimmigration. RESULTS: Immigrants from 6 countries accounted for 87.3% of active TB cases detected through preimmigration screening, and 10 countries accounted for 80.4% of cases detected through postimmigration surveillance. Immigrants from countries with a TB (all-sites) incidence rate of less than 30 cases per 100 000 persons resulted in pre- and postimmigration detection of 2.4 and 0.9 cases per 100 000 immigrants, respectively. Postimmigration surveillance detected 2.6% of active TB cases in Ontario residents born abroad, and TB was detected a median of 18 days earlier in those undergoing surveillance than in those who were not referred to surveillance or who did not comply. Predictors of active TB postimmigration included radiographic markers of old TB, birth country, immigration category, location of application for residency, immune status and age. INTERPRETATION: Universal screening for TB in new immigrants has a modest impact on the domestic burden of active TB and is highly inefficient. Focusing preimmigration screening in countries with high incidence rates and revising criteria for postimmigration surveillance could increase the effectiveness and efficiency of screening. PMID- 26416995 TI - Social participation and coronary heart disease risk in a large prospective study of UK women. AB - BACKGROUND: Participation in social activities is thought to prevent heart disease, but evidence is inconclusive. DESIGN: We assessed whether participating in social activities reduces the risk of coronary heart disease (CHD) in a large prospective study of 735,159 middle-aged UK women. METHODS: Women reported their participation in eight social activities (religious group, voluntary work, adult education, art/craft/music, dancing, sports club, yoga, bingo) and were followed for first CHD event (hospital admission or death) over the next 8.6 years. Cox regression models were used to estimate relative risks for CHD incidence by participation in each and in any of the social activities. RESULTS: After adjustment for age and region only, every activity except bingo was associated with a reduced risk of CHD (n = 30,756 cases in total). However, after additional adjustment for 11 factors (deprivation, education, smoking, physical activity, body mass index, alcohol, marital status, self-rated health, happiness, hypertension, diabetes), every relative risk estimate moved close to 1.0. For example, for participation in any of the activities compared with none, the relative risk adjusted for age and region only was 0.83 (99% confidence interval 0.81-0.86), but changed to 1.06 (99% confidence interval 1.02-1.09) after additional adjustment. Adjustment for education, self-rated health, smoking and physical activity attenuated the associations most strongly. Residual confounding and other unmeasured factors may well account for any small remaining associations. CONCLUSIONS: Associations between participation in various social activities and CHD risk appear to be largely or wholly due to confounding by personal characteristics of the participants. PMID- 26416996 TI - Impacts of intensive follow-up on the long-term prognosis of percutaneous coronary intervention in acute coronary syndrome patients - a single center prospective randomized controlled study in a Chinese population. AB - OBJECTIVES: To investigate the impact of cardiologist-coordinated intensive follow-up on the long-term prognosis of percutaneous coronary intervention in Chinese patients. METHODS: We recruited 964 patients who had acute coronary syndrome and underwent successful percutaneous coronary intervention in the First Hospital Affiliated to Henan University of Science and Technology, China. Participants were randomly assigned into the intensive follow-up (n = 479) and usual follow-up group (control group, n = 485). They received secondary prevention education during hospitalization and telephone follow-ups after discharge. The control group received telephone calls from nurses, while the intensive follow-up group received telephone calls and medical consultations from cardiologists. Both groups were followed up for 36 months. RESULTS: (1) At 36 months, the proportions of all-cause death, cardiac death and cumulative major adverse cardiovascular events (MACEs) were 5.3%, 4.4% and 18.6% in the intensive follow-up group. These events were significantly lower than in the control group (10.1%, 9.3 % and 28.8% (p = 0.004, p = 0.003 and p < 0.001). (2) Multivariable Cox regression analysis identified intensive follow-up as an independent predictor of survival, cardiac death-free survival and MACE-free survival. (hazard ratio (HR) = 0.487, 95% confidence interval (CI) 0.298-0.797, p = 0.004; HR = 0.466, 95% CI 0.274-0.793, p = 0.005; HR = 0.614, 95% CI 0.464-0.811, p = 0.001). Kaplan-Meier analysis revealed that patients in the intensive follow-up groups had longer survival (log rank = 8.565, p = 0.003), cardiac death-free survival (log rank = 8.769, p = 0.003) and MACE-free survival (log rank = 15.928, p < 0.001). (3) The average medical cost was significantly less in the intensive follow-up group, especially the cost for re-hospitalization (US$582.74 +/- 1753.20 vs. US$999.32 +/- 2434.57, p = 0.003). The bleeding events were similar. (4) Patients in the intensive follow-up group had significantly better controls of cardiovascular risk factors and medication adherence. CONCLUSIONS: A cardiologist-coordinated intensive follow-up program markedly decreased cardiovascular risk factors, reduced medical costs, promoted medication adherence and improved the long-term prognosis of patients after percutaneous coronary intervention in the Chinese population. PMID- 26416998 TI - Oncologists' Experiences and Attitudes About Their Role in Philanthropy and Soliciting Donations From Grateful Patients. AB - PURPOSE: Physician participation in philanthropy is important to marshal resources that allow hospitals to pursue their missions, but little is known about how physicians participate and their attitudes toward participation. METHODS: To characterize philanthropic roles physicians play and their attitudes about participation and its ethical acceptability, medical oncologists affiliated with the 40 National Cancer Institute-designated comprehensive cancer centers were randomly sampled and surveyed to evaluate experiences and attitudes regarding participation in philanthropy at their institutions. Responses were tabulated; significant associations by physicians' characteristics were explored. RESULTS: A total of 405 (52%) physicians responded; 62% were men, and 72% were white. Most (71%) had been exposed to their institution's fundraising/development staff; 48% of those were taught how to identify patients who would be good donors; 26% received information about ethical guidelines for soliciting donations from their patients; 21% were taught how their institution ensures Health Insurance Portability and Accountability Act compliance. A third (32%) of respondents had been asked to directly solicit a donation from their patients for their institution, of whom half declined to do so. Those who had solicited from their patients had been in practice significantly longer (mean, 19 v 13 years; P < .001). A substantial minority (37%) felt comfortable talking to their patients about donation (men more than women, 43% v 26%; P = .008); however, 74% agreed it could interfere with the physician-patient relationship, and 52% believe conflict of interest exists. CONCLUSION: Institutions are asking physicians to directly solicit their patients for donations with variability in physicians' perceptions of the impact on relationships with patients and responses toward those requests. PMID- 26416997 TI - Intratumoral Heterogeneity of ALK-Rearranged and ALK/EGFR Coaltered Lung Adenocarcinoma. AB - PURPOSE: Genetic intratumoral heterogeneity has a profound influence on the selection of clinical treatment strategies and on addressing resistance to targeted therapy. The purpose of this study was to explore the potential effect of intratumoral heterogeneity on both genetic and pathologic characteristics of ALK-rearranged lung adenocarcinoma (LADC). METHODS: We tested ALK fusions and EGFR mutations in 629 patients with LADC by using laser-capture microdissection to capture spatially separated tumor cell subpopulations in various adenocarcinoma subtypes and to test for ALK fusions and EGFR mutations in ALK rearranged, EGFR-mutated, and ALK/EGFR coaltered LADCs to compare the oncogenic driver status between different tumor cell subpopulations in the same primary tumor. RESULTS: Among the 629 patients, 30 (4.8%) had ALK fusions, 364 (57.9%) had EGFR mutations, and two had ALK fusions that coexisted with EGFR mutations. Intratumoral heterogeneity of ALK fusions were identified in nine patients by reverse-transcriptase polymerase chain reaction. In the two patients with an ALK/EGFR coaltered status, genetic intratumoral heterogeneity was observed both between different growth patterns and within the same growth pattern. The relative abundance of ALK and EGFR alterations was different in the same captured area. ALK fusions were positively associated with a micropapillary pattern (P = .002) and were negatively associated with a lepidic pattern (P = .008) in an expanded statistical analysis of 900 individual adenocarcinoma components, although they appeared to be more common in acinar-predominant LADCs in the analysis of 629 patients. CONCLUSION: Intratumoral genetic heterogeneity was demonstrated to coexist with histologic heterogeneity in both single-driver and ALK/EGFR coaltered LADCs. Altered oncogenic drivers in spatially separated subclones of the same tumor may be different. PMID- 26416999 TI - Epirubicin Plus Cyclophosphamide Followed by Docetaxel Versus Epirubicin Plus Docetaxel Followed by Capecitabine As Adjuvant Therapy for Node-Positive Early Breast Cancer: Results From the GEICAM/2003-10 Study. AB - PURPOSE: Capecitabine is an active drug in metastatic breast cancer (BC). GEICAM/2003-10 is an adjuvant trial to investigate the integration of capecitabine into a regimen of epirubicin and docetaxel for node-positive early BC. PATIENTS AND METHODS: Patients with operable node-positive BC (T1-3/N1-3) were eligible. After surgery, 1,384 patients were randomly assigned to receive epirubicin plus cyclophosphamide (EC; 90 and 600 mg/m(2), respectively, * four cycles), followed by docetaxel (100 mg/m(2) * four cycles; EC-T) or epirubicin plus docetaxel (ET; 90 and 75 mg/m(2), respectively, * four cycles), followed by capecitabine (1,250 mg/m(2) twice a day on days 1 to 14, * four cycles; ET-X); all regimens were given every 3 weeks. The primary end point was invasive disease free survival. Secondary end points included safety (with an alopecia-specific study) and overall survival (OS). RESULTS: After a median follow-up of 6.6 years and 297 events, 86% of patients who received EC-T and 82% of those who received ET-X were invasive disease free at 5 years (hazard ratio, 1.30; 95% CI, 1.03 to 1.64; log-rank P = .03). The OS difference between arms was not statistically significant (hazard ratio, 1.13; 95% CI, 0.82 to 1.55; log-rank P = .46). The most frequent grade 3 to 4 adverse events in the EC-T versus ET-X arms were neutropenia (19% v 10%), with 7% febrile neutropenia across arms; fatigue (13% v 11%); diarrhea (3% v 11%); hand-foot syndrome (2% v 20%); mucositis (6% v 5%); vomiting (both, 5%); and myalgia (4.5% v 1%). Incomplete scalp hair recovery was more frequent in the EC-T than ET-X arm (30% v 14%), and patients who received EC T wore wigs significantly longer than those who received ET-X (8.35 v 6.03 months). CONCLUSION: Invasive disease-free survival, but not OS, was significantly superior for patients with node-positive early BC who received the adjuvant standard schedule EC-T than for those who received the experimental ET-X regimen. Toxicity profiles differed substantially across arms. PMID- 26417000 TI - Evolutionary Precision Medicine: A Role for Repeat Epidermal Growth Factor Receptor Analysis in ALK-Rearranged Lung Adenocarcinoma? PMID- 26417001 TI - Adjuvant Hormone Therapy May Improve Survival in Epithelial Ovarian Cancer: Results of the AHT Randomized Trial. AB - PURPOSE: To assess the effects of adjuvant hormone therapy (AHT) on survival and disease outcome in women with epithelial ovarian cancer. PATIENTS AND METHODS: Participants were premenopausal and postmenopausal women who had been diagnosed with epithelial ovarian cancer (any International Federation of Gynecology and Obstetrics stage) 9 or fewer months previously. Ineligible patients included those with deliberately preserved ovarian function, with a history of a hormone dependent malignancy, or with any contraindications to hormone-replacement therapy. Patients were centrally randomly assigned in a 1:1 ratio to either AHT for 5 years after random assignment or no AHT (control). Main outcome measures were overall survival (OS), defined as time from random assignment to death (any cause), and relapse-free survival, defined as time from random assignment to relapse or death (any cause). Patients who continued, alive and relapse free, were censored at their last known follow-up. RESULTS: A total of 150 patients (n = 75, AHT; n = 75, control) were randomly assigned from 1990 to 1995 from 19 centers in the United Kingdom, Spain, and Hungary; all patients were included in intention-to-treat analyses. The median follow-up in alive patients is currently 19.1 years. Of the 75 patients with AHT, 53 (71%) have died compared with 68 (91%) of 75 patients in the control group. OS was significantly improved in patients who were receiving AHT (hazard ratio, 0.63; 95% CI, 0.44 to 0.90; P = .011). A similar effect was seen for relapse-free survival (hazard ratio, 0.67; 95% CI, 0.47 to 0.97; P = .032). Effects remained after adjustment for known prognostic factors. CONCLUSION: These results show that women who have severe menopausal symptoms after ovarian cancer treatment can safely take hormone replacement therapy, and this may, in fact, infer benefits in terms of OS in addition to known advantages in terms of quality of life. PMID- 26417002 TI - Psychosocial Outcomes in Adult Survivors of Retinoblastoma. AB - PURPOSE: Survival rates for individuals diagnosed with retinoblastoma (RB) exceed 95% in the United States; however, little is known about the long-term psychosocial outcomes of these survivors. PATIENTS AND METHODS: Adult RB survivors, diagnosed from 1932 to 1994 and treated in New York, completed a comprehensive questionnaire adapted from the Childhood Cancer Survivor Study (CCSS), by mail or telephone. Psychosocial outcomes included psychological distress, anxiety, depression, somatization, fear of cancer recurrence, satisfaction with facial appearance, post-traumatic growth, and post-traumatic stress symptoms; noncancer CCSS siblings served as a comparison group. RESULTS: A total of 470 RB survivors (53.6% with bilateral RB; 52.1% female) and 2,820 CCSS siblings were 43.3 (standard deviation [SD], 11) years and 33.2 (SD, 8.4) years old at the time of study, respectively. After adjusting for sociodemographic factors, RB survivors did not have significantly higher rates of depression, somatization, distress, or anxiety compared with CCSS siblings. Although RB survivors were more likely to report post-traumatic stress symptoms of avoidance and/or hyperarousal (both P < .01), only five (1.1%) of 470 met criteria for post traumatic stress disorder. Among survivors, having a chronic medical condition did not increase the likelihood of psychological problems. Bilateral RB survivors were more likely than unilateral RB survivors to experience fears of cancer recurrence (P < .01) and worry about their children being diagnosed with RB (P < .01). However, bilateral RB survivors were no more likely to report depression, anxiety, or somatic complaints than unilateral survivors. CONCLUSION: Most RB survivors do not have poorer psychosocial functioning compared with a noncancer sample. In addition, bilateral and unilateral RB survivors seem similar with respect to their psychological symptoms. PMID- 26417003 TI - Perceived discrimination is associated with health behaviours among African Americans in the Jackson Heart Study. AB - BACKGROUND: Using Jackson Heart Study data, we examined associations of multiple measures of perceived discrimination with health behaviours among African Americans (AA). METHODS: The cross-sectional associations of everyday, lifetime and burden of discrimination with odds of smoking and mean differences in physical activity, dietary fat and sleep were examined among 4925 participants aged 35-84 years after adjustment for age and socioeconomic status (SES). RESULTS: Men reported slightly higher levels of everyday and lifetime discrimination than women and similar levels of burden of discrimination as women. After adjustment for age and SES, everyday discrimination was associated with more smoking and a greater percentage of dietary fat in men and women (OR for smoking: 1.13, 95% CI 1.00 to 1.28 and 1.19, 95% CI 1.05 to 1.34; mean difference in dietary fat: 0.37, p<0.05 and 0.43, p<0.01, in men and women, respectively). Everyday and lifetime discrimination were associated with fewer hours of sleep in men and women (mean difference for everyday discrimination: 0.08, p<0.05 and -0.18, p<0.001, respectively; and mean difference for lifetime discrimination: -0.08, p<0.05 and -0.24, p<0.001, respectively). Burden of discrimination was associated with more smoking and fewer hours of sleep in women only. CONCLUSIONS: Higher levels of perceived discrimination were associated with select health behaviours among men and women. Health behaviours offer a potential mechanism through which perceived discrimination affects health in AA. PMID- 26417004 TI - Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis. AB - Ectopic lymphoid-like structures (ELSs) reminiscent of secondary lymphoid organs often develop at sites of chronic inflammation where they contribute to immune mediated pathology. Through evaluation of synovial tissues from rheumatoid arthritis (RA) patients, we now show that low interleukin-27 (IL-27) expression corresponds with an increased incidence of ELS and gene signatures associated with their development and activity. The presence of synovial ELS was also noted in mice deficient in the IL-27 receptor (IL-27R) after the onset of inflammatory arthritis. Here, pathology was associated with increased synovial expression of pro-inflammatory cytokines, homeostatic chemokines, and transcriptional regulators linked with lymphoid neogenesis. In both clinical and experimental RA, synovial ELS coincided with the heightened local expression of cytokines and transcription factors of the Th17 and T follicular helper (Tfh) cell lineages, and included podoplanin-expressing T cells within lymphoid aggregates. IL-27 inhibited the differentiation of podoplanin-expressing Th17 cells, and an increased number of these cells were observed in IL-27R-deficient mice with inflammatory arthritis. Thus, IL-27 appears to negatively regulate ELS development in RA through control of effector T cells. These studies open new opportunities for patient stratification and treatment. PMID- 26417005 TI - CCR4 promotes medullary entry and thymocyte-dendritic cell interactions required for central tolerance. AB - Autoimmunity results from a breakdown in central or peripheral tolerance. To establish central tolerance, developing T cells must enter the thymic medulla, where they scan antigen-presenting cells (APCs) displaying a diverse array of autoantigens. If a thymocyte is activated by a self-antigen, the cell undergoes either deletion or diversion into the regulatory T cell (T reg) lineage, thus maintaining self-tolerance. Mechanisms promoting thymocyte medullary entry and interactions with APCs are incompletely understood. CCR4 is poised to contribute to central tolerance due to its expression by post-positive selection thymocytes, and expression of its ligands by medullary thymic dendritic cells (DCs). Here, we use two-photon time-lapse microscopy to demonstrate that CCR4 promotes medullary entry of the earliest post-positive selection thymocytes, as well as efficient interactions between medullary thymocytes and DCs. In keeping with the contribution of thymic DCs to central tolerance, CCR4 is involved in regulating negative selection of polyclonal and T cell receptor (TCR) transgenic thymocytes. In the absence of CCR4, autoreactive T cells accumulate in secondary lymphoid organs and autoimmunity ensues. These studies reveal a previously unappreciated role for CCR4 in the establishment of central tolerance. PMID- 26417007 TI - Floral Induction in Arabidopsis by FLOWERING LOCUS T Requires Direct Repression of BLADE-ON-PETIOLE Genes by the Homeodomain Protein PENNYWISE. AB - Flowers form on the flanks of the shoot apical meristem (SAM) in response to environmental and endogenous cues. In Arabidopsis (Arabidopsis thaliana), the photoperiodic pathway acts through FLOWERING LOCUS T (FT) to promote floral induction in response to day length. A complex between FT and the basic leucine zipper transcription factor FD is proposed to form in the SAM, leading to activation of APETALA1 and LEAFY and thereby promoting floral meristem identity. We identified mutations that suppress FT function and recovered a new allele of the homeodomain transcription factor PENNYWISE (PNY). Genetic and molecular analyses showed that ectopic expression of BLADE-ON-PETIOLE1 (BOP1) and BOP2, which encode transcriptional coactivators, in the SAM during vegetative development, confers the late flowering of pny mutants. In wild-type plants, BOP1 and BOP2 are expressed in lateral organs close to boundaries of the SAM, whereas in pny mutants, their expression occurs in the SAM. This ectopic expression lowers FD mRNA levels, reducing responsiveness to FT and impairing activation of APETALA1 and LEAFY. We show that PNY binds to the promoters of BOP1 and BOP2, repressing their transcription. These results demonstrate a direct role for PNY in defining the spatial expression patterns of boundary genes and the significance of this process for floral induction by FT. PMID- 26417006 TI - Repression of Lateral Organ Boundary Genes by PENNYWISE and POUND-FOOLISH Is Essential for Meristem Maintenance and Flowering in Arabidopsis. AB - In the model plant Arabidopsis (Arabidopsis thaliana), endogenous and environmental signals acting on the shoot apical meristem cause acquisition of inflorescence meristem fate. This results in changed patterns of aerial development seen as the transition from making leaves to the production of flowers separated by elongated internodes. Two related BEL1-like homeobox genes, PENNYWISE (PNY) and POUND-FOOLISH (PNF), fulfill this transition. Loss of function of these genes impairs stem cell maintenance and blocks internode elongation and flowering. We show here that pny pnf apices misexpress lateral organ boundary genes BLADE-ON-PETIOLE1/2 (BOP1/2) and KNOTTED-LIKE FROM ARABIDOPSIS THALIANA6 (KNAT6) together with ARABIDOPSIS THALIANA HOMEOBOX GENE1 (ATH1). Inactivation of genes in this module fully rescues pny pnf defects. We further show that BOP1 directly activates ATH1, whereas activation of KNAT6 is indirect. The pny pnf restoration correlates with renewed accumulation of transcripts conferring floral meristem identity, including FD, SQUAMOSA PROMOTER BINDING PROTEIN LIKE genes, LEAFY, and APETALA1. To gain insight into how this module blocks flowering, we analyzed the transcriptome of BOP1-overexpressing plants. Our data suggest a central role for the microRNA156-SQUAMOSA PROMOTER BINDING PROTEIN-LIKE-microRNA172 module in integrating stress signals conferred in part by promotion of jasmonic acid biosynthesis. These data reveal a potential mechanism by which repression of lateral organ boundary genes by PNY-PNF is essential for flowering. PMID- 26417008 TI - 9-Lipoxygenase-Derived Oxylipins Activate Brassinosteroid Signaling to Promote Cell Wall-Based Defense and Limit Pathogen Infection. AB - The oxylipins, a large family of oxygenated lipid derivatives, regulate plant development and immunity. Two members of the 9-lipoxygenase (9-LOX) oxylipin pathway, 9-hydroxyoctadecatrienoic acid and 9-ketooctadecatrienoic acid, control root development and plant defense. Studies in Arabidopsis (Arabidopsis thaliana) using a series of 9-hydroxyoctadecatrienoic acid- and 9-ketooctadecatrienoic acid insensitive nonresponding to oxylipins (noxy) mutants showed the importance of the cell wall as a 9-LOX-induced defense component and the participation of NOXY proteins in signaling cell wall damage. Here, we examined 9-LOX signaling using the mutants lox1lox5, which lacks 9-LOX activity, and noxy2-2, which shows oxylipin insensitivity and mitochondrial dysfunction. Mutants in brassinosteroids (BRs), a class of plant hormones necessary for normal plant growth and the control of cell wall integrity, were also analyzed. Several lines of evidence indicated that 9-LOX-derived oxylipins induce BR synthesis and signaling to activate cell wall-based responses such as callose deposition and that constitutive activation of BR signaling in bri1-EMS-suppressor 1-D (bes1-D) plants enhances this response. We found that constitutive BR signaling in bes1-D and brassinolide-resistant 1-1D (bzr1-1D) mutants conferred resistance to Pseudomonas syringae. bes1-D and bzr1-1D showed increased resistance to Golovinomyces cichoracearum, an obligate biotrophic fungus that penetrates the cell wall for successful infection, whereas susceptibility was enhanced in lox1lox5 and noxy2-2. Our results indicate a sequential action of 9-LOX and BR signaling in activating cell wall-based defense, and this response prevents pathogen infection. These results show interaction between the 9-LOX and BR pathways and help to clarify their role in modulating plant defense. PMID- 26417010 TI - Remora fish suction pad attachment is enhanced by spinule friction. AB - The remora fishes are capable of adhering to a wide variety of natural and artificial marine substrates using a dorsal suction pad. The pad is made of serial parallel pectinated lamellae, which are homologous to the dorsal fin elements of other fishes. Small tooth-like projections of mineralized tissue from the dorsal pad lamella, known as spinules, are thought to increase the remora's resistance to slippage and thereby enhance friction to maintain attachment to a moving host. In this work, the geometry of the spinules and host topology as determined by micro-computed tomography and confocal microscope data, respectively, are combined in a friction model to estimate the spinule contribution to shear resistance. Model results are validated with natural and artificially created spinules and compared with previous remora pull-off experiments. It was found that spinule geometry plays an essential role in friction enhancement, especially at short spatial wavelengths in the host surface, and that spinule tip geometry is not correlated with lamellar position. Furthermore, comparisons with pull-off experiments suggest that spinules are primarily responsible for friction enhancement on rough host topologies such as shark skin. PMID- 26417009 TI - Functional Analysis of the Arabidopsis TETRASPANIN Gene Family in Plant Growth and Development. AB - TETRASPANIN (TET) genes encode conserved integral membrane proteins that are known in animals to function in cellular communication during gamete fusion, immunity reaction, and pathogen recognition. In plants, functional information is limited to one of the 17 members of the Arabidopsis (Arabidopsis thaliana) TET gene family and to expression data in reproductive stages. Here, the promoter activity of all 17 Arabidopsis TET genes was investigated by pAtTET::NUCLEAR LOCALIZATION SIGNAL-GREEN FLUORESCENT PROTEIN/beta-GLUCURONIDASE reporter lines throughout the life cycle, which predicted functional divergence in the paralogous genes per clade. However, partial overlap was observed for many TET genes across the clades, correlating with few phenotypes in single mutants and, therefore, requiring double mutant combinations for functional investigation. Mutational analysis showed a role for TET13 in primary root growth and lateral root development and redundant roles for TET5 and TET6 in leaf and root growth through negative regulation of cell proliferation. Strikingly, a number of TET genes were expressed in embryonic and seedling progenitor cells and remained expressed until the differentiation state in the mature plant, suggesting a dynamic function over developmental stages. The cis-regulatory elements together with transcription factor-binding data provided molecular insight into the sites, conditions, and perturbations that affect TET gene expression and positioned the TET genes in different molecular pathways; the data represent a hypothesis generating resource for further functional analyses. PMID- 26417011 TI - Larger lacertid lizard species produce higher than expected iliotibialis muscle power output: the evolution of muscle contractile mechanics with body size. AB - Increases in body size can lead to alterations in morphology, physiology, locomotor performance and behaviour of animals. Most studies considering the effects of scaling on muscle performance have studied within-species effects, with few studies considering differences between species. A previous review of published data indicates that maximum muscle-shortening velocity decreases, but that maximum isometric stress does not change, with increased body mass across species of terrestrial animals. However, such previous analyses do not account for the phylogenetic relatedness of the species studied. Our aim was to use phylogenetically informed analysis to determine the effects of body size on isolated iliotibialis muscle performance across 17 species of lacertid lizards. Between one and five individuals were used to obtain mean performance values for each species. We analysed the relationship between each variable and body size, as estimated by snout-vent length (SVL), whilst taking into account the phylogenetic relationships between species. We found that isometric tetanus relaxation time, maximal tetanus stress (force per muscle cross-sectional area) and maximal work loop power output (normalised to muscle mass) all significantly increased with greater SVL. In contrast, fatigue resistance during repeated work loops significantly decreased with SVL and there was no effect of size on tetanus activation time. When we compare our findings with those that would be predicted by dynamic similarity, then as these lacertid species become bigger, there is a greater than expected increase in the normalised muscle power output, probably to counter the larger than expected increase in body mass. PMID- 26417012 TI - Transcriptome profiling reveals mechanisms for the evolution of insect seasonality. AB - Rapid evolutionary change in seasonal timing can facilitate ecological speciation and resilience to climate warming. However, the molecular mechanisms behind shifts in animal seasonality are still unclear. Evolved differences in seasonality occur in the European corn borer moth (Ostrinia nubilalis), in which early summer emergence in E-strain adults and later summer emergence in Z-strain adults is explained by a shift in the length of the termination phase of larval diapause. Here, we sample from the developmental time course of diapause in both strains and use transcriptome sequencing to profile regulatory and amino acid changes associated with timing divergence. Within a previously defined quantitative trait locus (QTL), we nominate 48 candidate genes, including several in the insulin signaling and circadian rhythm pathways. Genome-wide transcriptional activity is negligible during the extended Z-strain termination, whereas shorter E-strain termination is characterized by a rapid burst of regulatory changes involved in resumption of the cell cycle, hormone production and stress response. Although gene expression during diapause termination in Ostrinia is similar to that found previously in flies, nominated genes for shifts in timing are species specific. Hence, across distant relatives the evolution of insect seasonality appears to involve unique genetic switches that direct organisms into distinct phases of the diapause pathway through wholesale restructuring of conserved gene regulatory networks. PMID- 26417013 TI - Acquisition and expression of memories of distance and direction in navigating wood ants. AB - Wood ants, like other central place foragers, rely on route memories to guide them to and from a reliable food source. They use visual memories of the surrounding scene and probably compass information to control their direction. Do they also remember the length of their route and do they link memories of direction and distance? To answer these questions, we trained wood ant (Formica rufa) foragers in a channel to perform either a single short foraging route or two foraging routes in opposite directions. By shifting the starting position of the route within the channel, but keeping the direction and distance fixed, we tried to ensure that the ants would rely upon vector memories rather than visual memories to decide when to stop. The homeward memories that the ants formed were revealed by placing fed or unfed ants directly into a channel and assessing the direction and distance that they walked without prior performance of the food ward leg of the journey. This procedure prevented the distance and direction walked being affected by a home vector derived from path integration. Ants that were unfed walked in the feeder direction. Fed ants walked in the opposite direction for a distance related to the separation between start and feeder. Vector memories of a return route can thus be primed by the ants' feeding state and expressed even when the ants have not performed the food-ward route. Tests on ants that have acquired two routes indicate that memories of the direction and distance of the return routes are linked, suggesting that they may be encoded by a common neural population within the ant brain. PMID- 26417014 TI - Patterns of oxygen consumption during simultaneously occurring elevated metabolic states in the viviparous snake Thamnophis marcianus. AB - Snakes exhibit large factorial increments in oxygen consumption during digestion and physical activity, and long-lasting sub-maximal increments during reproduction. Under natural conditions, all three physiological states may occur simultaneously, but the integrated response is not well understood. Adult male and female checkered gartersnakes (Thamnophis marcianus) were used to examine increments in oxygen consumption (i.e. V(O2)) and carbon dioxide production (i.e. V(CO2)) associated with activity (Act), digestion (Dig) and post-prandial activity (Act+Dig). For females, we carried out these trials in the non reproductive state, and also during the vitellogenic (V) and embryogenic (E) phases of a reproductive cycle. Endurance time (i.e. time to exhaustion, TTE) was recorded for all groups during Act and Act+Dig trials. Our results indicate that male and non-reproductive female T. marcianus exhibit significant increments in V(O2) during digestion (~5-fold) and activity (~9-fold), and that Act+Dig results in a similar increment in V(O2) (~9- to 10-fold). During reproduction, resting V(O2) increased by 1.6- to 1.7-fold, and peak increments during digestion were elevated by 30-50% above non-reproductive values, but values associated with Act and Act+Dig were not significantly different from non-reproductive values. During Act+Dig, endurance time remained similar for all of the groups in the present study. Overall, our results indicate that prioritization is the primary pattern of interaction in oxygen delivery exhibited by this species. We propose that the metabolic processes associated with digestion, and perhaps reproduction, are temporarily compromised during activity. PMID- 26417015 TI - Interactive effects of seawater acidification and elevated temperature on biomineralization and amino acid metabolism in the mussel Mytilus edulis. AB - Seawater acidification and warming resulting from anthropogenic production of carbon dioxide are increasing threats to marine ecosystems. Previous studies have documented the effects of either seawater acidification or warming on marine calcifiers; however, the combined effects of these stressors are poorly understood. In our study, we examined the interactive effects of elevated carbon dioxide partial pressure (P(CO2)) and temperature on biomineralization and amino acid content in an ecologically and economically important mussel, Mytilus edulis. Adult M. edulis were reared at different combinations of P(CO2) (pH 8.1 and 7.8) and temperature (19, 22 and 25 degrees C) for 2 months. The results indicated that elevated P(CO2) significantly decreased the net calcification rate, the calcium content and the Ca/Mg ratio of the shells, induced the differential expression of biomineralization-related genes, modified shell ultrastructure and altered amino acid content, implying significant effects of seawater acidification on biomineralization and amino acid metabolism. Notably, elevated temperature enhanced the effects of seawater acidification on these parameters. The shell breaking force significantly decreased under elevated P(CO2), but the effect was not exacerbated by elevated temperature. The results suggest that the interactive effects of seawater acidification and elevated temperature on mussels are likely to have ecological and functional implications. This study is therefore helpful for better understanding the underlying effects of changing marine environments on mussels and other marine calcifiers. PMID- 26417016 TI - Chela asymmetry in a durophagous crab: predominance of right-handedness and handedness reversal is linked to chela size and closing force. AB - The swimming crab Portunus trituberculatus is a durophagous brachyuran. Right handed crabs are predominant, but left-handed crabs are also found in nature. Left-handedness may arise from loss of the right crusher. We examined whether heterochely (morphology) was correlated with differences in closing force (physical property) and handedness (behaviour). The closing force was stronger in larger chela with greater apodeme height and handedness resided in the chela with stronger closing force. With loss of the right chela (autotomy), handedness transitioned from the right to left chela, and all crabs were left-handed thereafter. Reversed handedness was accompanied with a reduction of size and closing force in the regenerated right chela, and growth of the original left chela. After handedness reversal, dentition on the left dactylus of the newly converted crusher was close to that of the original right crusher, but did not attain the same shape, even after 10 moults. Left-handed crabs were significantly worse than right-handed crabs at crushing hard-shelled prey. Chela formation was symmetrical in the zoea, and heterochely and right-handedness started in the megalopa, regardless of maternal handedness. Since the left chela is capable of being the crusher, heterochely may be caused by differences in morphogenetic velocity between the right and left chelae, under a signal discriminating right from left. Right-handedness is an attribute of P. trituberculatus, that would be inheritable across generations. It is probable that right-handedness was used in the earliest durophagous crabs, and this trend has been succeeded to extant species. PMID- 26417017 TI - Whole genome duplications in plants: an overview from Arabidopsis. AB - Polyploidy is a common event in plants that involves the acquisition of more than two complete sets of chromosomes. Allopolyploidy originates from interspecies hybrids while autopolyploidy originates from intraspecies whole genome duplication (WGD) events. In spite of inconveniences derived from chromosomic rearrangement during polyploidization, natural plant polyploids species often exhibit improved growth vigour and adaptation to adverse environments, conferring evolutionary advantages. These advantages have also been incorporated into crop breeding programmes. Many tetraploid crops show increased stress tolerance, although the molecular mechanisms underlying these different adaptation abilities are poorly known. Understanding the physiological, cellular, and molecular mechanisms coupled to WGD, in both allo- and autopolyploidy, is a major challenge. Over the last few years, several studies, many of them in Arabidopsis, are shedding light on the basis of genetic, genomic, and epigenomic changes linked to WGD. In this review we summarize and discuss the latest advances made in Arabidopsis polyploidy, but also in other agronomic plant species. PMID- 26417018 TI - HvEXPB7, a novel beta-expansin gene revealed by the root hair transcriptome of Tibetan wild barley, improves root hair growth under drought stress. AB - Tibetan wild barley is a treasure trove of useful genes for crop improvement including abiotic stress tolerance, like drought. Root hair of single-celled structures plays an important role in water and nutrition uptake. Polyethylene glycol-induced drought stress hydroponic/petri-dish experiments were performed, where root hair morphology and transcriptional characteristics of two contrasting Tibetan wild barley genotypes (drought-tolerant XZ5 and drought-sensitive XZ54) and drought-tolerant cv. Tadmor were compared. Drought-induced root hair growth was only observed in XZ5. Thirty-six drought tolerance-associated genes were identified in XZ5, including 16 genes specifically highly expressed in XZ5 but not Tadmor under drought. The full length cDNA of a novel beta-expansin gene (HvEXPB7), being the unique root hair development related gene in the identified genes, was cloned. The sequence comparison indicated that HvEXPB7 carried both DPBB_1 and Pollon_allerg_1 domains. HvEXPB7 is predominantly expressed in roots. Subcellular localization verified that HvEXPB7 is located in the plasma membrane. Barley stripe mosaic virus induced gene silencing (BSMV-VIGS) of HvEXPB7 led to severely suppressed root hairs both under control and drought conditions, and significantly reduced K uptake. These findings highlight and confer the significance of HvEXPB7 in root hair growth under drought stress in XZ5, and provide a novel insight into the genetic basis for drought tolerance in Tibetan wild barley. PMID- 26417020 TI - Good and bad protons: genetic aspects of acidity stress responses in plants. AB - Physiological aspects of acidity stress in plants (synonymous with H(+) rhizotoxicity or low-pH stress) have long been a focus of research, in particular with respect to acidic soils where aluminium and H(+) rhizotoxicities often co occur. However, toxic H(+) and Al(3+) elicit different response mechanisms in plants, and it is important to consider their effects separately. The primary aim of this review was to provide the current state of knowledge regarding the genetics of the specific reactions to low-pH stress in growing plants. A comparison of the results gleaned from quantitative trait loci analysis and global transcriptome profiling of plants in response to high proton concentrations revealed a two-stage genetic response: (i) in the short-term, proton pump H(+)-ATPases present the first barrier in root cells, allocating an excess of H(+) into either the apoplast or vacuole; the ensuing defence signaling system involves auxin, salicylic acid, and methyl jasmonate, which subsequently initiate expression of STOP and DREB transcription factors as well as chaperone ROF; (2) the long-term response includes other genes, such as alternative oxidase and type II NAD(P)H dehydrogenase, which act to detoxify dangerous reactive oxygen species in mitochondria, and help plants better manage the stress. A range of transporter genes including those for nitrate (NTR1), malate (ALMT1), and heavy metals are often up-regulated by H(+) rhizotoxicity. Expansins, cell-wall related genes, the gamma-aminobutyric acid shunt and biochemical pH-stat genes also reflect changes in cell metabolism and biochemistry in acidic conditions. However, the genetics underlying the acidity stress response of plants is complicated and only fragmentally understood. PMID- 26417019 TI - Transcription factor StWRKY1 regulates phenylpropanoid metabolites conferring late blight resistance in potato. AB - Quantitative resistance is polygenically controlled and durable, but the underlying molecular and biochemical mechanisms are poorly understood. Secondary cell wall thickening is a critical process in quantitative resistance, regulated by transcriptional networks. This paper provides compelling evidence on the functionality of StWRKY1 transcription factor, in a compatible interaction of potato-Phytophthora infestans, to extend our knowledge on the regulation of the metabolic pathway genes leading to strengthening the secondary cell wall. A metabolomics approach was used to identify resistance-related metabolites belonging to the phenylpropanoid pathway and their biosynthetic genes regulated by StWRKY1. The StWRKY1 gene in resistant potato was silenced to decipher its role in the regulation of phenylpropanoid pathway genes to strengthen the secondary cell wall. Sequencing of the promoter region of StWRKY1 in susceptible genotypes revealed the absence of heat shock elements (HSEs). Simultaneous induction of both the heat shock protein (sHSP17.8) and StWRKY1 following pathogen invasion enables functioning of the latter to interact with the HSE present in the resistant StWRKY1 promoter region. EMSA and luciferase transient expression assays further revealed direct binding of StWRKY1 to promoters of hydroxycinnamic acid amide (HCAA) biosynthetic genes encoding 4-coumarate:CoA ligase and tyramine hydroxycinnamoyl transferase. Silencing of the StWRKY1 gene was associated with signs of reduced late blight resistance by significantly increasing the pathogen biomass and decreasing the abundance of HCAAs. This study provides convincing evidence on the role of StWRKY1 in the regulation of downstream genes to biosynthesize HCAAs, which are deposited to reinforce secondary cell walls. PMID- 26417021 TI - Transcriptome analysis of an apple (Malus * domestica) yellow fruit somatic mutation identifies a gene network module highly associated with anthocyanin and epigenetic regulation. AB - Using RNA-seq, this study analysed an apple (Malus*domestica) anthocyanin deficient yellow-skin somatic mutant 'Blondee' (BLO) and its red-skin parent 'Kidd's D-8' (KID), the original name of 'Gala', to understand the molecular mechanisms underlying the mutation. A total of 3299 differentially expressed genes (DEGs) were identified between BLO and KID at four developmental stages and/or between two adjacent stages within BLO and/or KID. A weighted gene co expression network analysis (WGCNA) of the DEGs uncovered a network module of 34 genes highly correlated (r=0.95, P=9.0*10(-13)) with anthocyanin contents. Although 12 of the 34 genes in the WGCNA module were characterized and known of roles in anthocyanin, the remainder 22 appear to be novel. Examining the expression of ten representative genes in the module in 14 diverse apples revealed that at least eight were significantly correlated with anthocyanin variation. MdMYB10 (MDP0000259614) and MdGST (MDP0000252292) were among the most suppressed module member genes in BLO despite being undistinguishable in their corresponding sequences between BLO and KID. Methylation assay of MdMYB10 and MdGST in fruit skin revealed that two regions (MR3 and MR7) in the MdMYB10 promoter exhibited remarkable differences between BLO and KID. In particular, methylation was high and progressively increased alongside fruit development in BLO while was correspondingly low and constant in KID. The methylation levels in both MR3 and MR7 were negatively correlated with anthocyanin content as well as the expression of MdMYB10 and MdGST. Clearly, the collective repression of the 34 genes explains the loss-of-colour in BLO while the methylation in MdMYB10 promoter is likely causal for the mutation. PMID- 26417022 TI - High atmospheric carbon dioxide-dependent alleviation of salt stress is linked to RESPIRATORY BURST OXIDASE 1 (RBOH1)-dependent H2O2 production in tomato (Solanum lycopersicum). AB - Plants acclimate rapidly to stressful environmental conditions. Increasing atmospheric CO2 levels are predicted to influence tolerance to stresses such as soil salinity but the mechanisms are poorly understood. To resolve this issue, tomato (Solanum lycopersicum) plants were grown under ambient (380 MUmol mol(-1)) or high (760 MUmol mol(-1)) CO2 in the absence or presence of sodium chloride (100mM). The higher atmospheric CO2 level induced the expression of RESPIRATORY BURST OXIDASE 1 (SlRBOH1) and enhanced H2O2 accumulation in the vascular cells of roots, stems, leaf petioles, and the leaf apoplast. Plants grown with higher CO2 levels showed improved salt tolerance, together with decreased leaf transpiration rates and lower sodium concentrations in the xylem sap, vascular tissues, and leaves. Silencing SlRBOH1 abolished high CO2 -induced salt tolerance and increased leaf transpiration rates, as well as enhancing Na(+) accumulation in the plants. The higher atmospheric CO2 level increased the abundance of a subset of transcripts involved in Na(+) homeostasis in the controls but not in the SlRBOH1-silenced plants. It is concluded that high atmospheric CO2 concentrations increase salt stress tolerance in an apoplastic H2O2 dependent manner, by suppressing transpiration and hence Na(+) delivery from the roots to the shoots, leading to decreased leaf Na(+) accumulation. PMID- 26417023 TI - Kranz and single-cell forms of C4 plants in the subfamily Suaedoideae show kinetic C4 convergence for PEPC and Rubisco with divergent amino acid substitutions. AB - The two carboxylation reactions performed by phosphoenolpyruvate carboxylase (PEPC) and ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) are vital in the fixation of inorganic carbon for C4 plants. The abundance of PEPC is substantially elevated in C4 leaves, while the location of Rubisco is restricted to one of two chloroplast types. These differences compared with C3 leaves have been shown to result in convergent enzyme optimization in some C4 species. Investigation into the kinetic properties of PEPC and Rubisco from Kranz C4, single cell C4, and C3 species in Chenopodiaceae s. s. subfamily Suaedoideae showed that these major carboxylases in C4 Suaedoideae species lack the same mutations found in other C4 systems which have been examined; but still have similar convergent kinetic properties. Positive selection analysis on the N terminus of PEPC identified residues 364 and 368 to be under positive selection with a posterior probability >0.99 using Bayes empirical Bayes. Compared with previous analyses on other C4 species, PEPC from C4 Suaedoideae species have different convergent amino acids that result in a higher K m for PEP and malate tolerance compared with C3 species. Kinetic analysis of Rubisco showed that C4 species have a higher catalytic efficiency of Rubisco (k catc in mol CO2 mol(-1) Rubisco active sites s(-1)), despite lacking convergent substitutions in the rbcL gene. The importance of kinetic changes to the two-carboxylation reactions in C4 leaves related to amino acid selection is discussed. PMID- 26417024 TI - Interleukin 21 and Its Receptor Play a Role in Proliferation, Migration and Invasion of Breast Cancer Cells. AB - Interleukin 21 (IL21) is a cytokine produced predominantly by cluster of differentiation 4 (CD4+) T-cells and natural killer T-cells. There exists evidence that IL21 is implicated in various immunological processes through its specific receptor (IL21R). However, the participation of IL21 in the pathogenesis of solid tumors is not fully conclusive. In the present study, we demonstrated that there was differential expression of IL21R in breast cancer cells using reverse transcription-polymerase chain reaction (RT-PCR), western blotting and sequence analysis. The expression of IL21R was stronger in MDA-231 cells, weaker in MCF7 but negative in ZR-75.1 cells. The invasion and migratory capacity of IL21R+ MDA-231 cells was enhanced by IL21 in a dose-dependent manner. After IL21R was knocked-down by siRNA gene silencing, the response of MDA-231 to treatment with IL21 was attenuated. We found that siRNA silencing of IL21R also spontaneously suppressed cell proliferation. However, IL21 had no additional effect on the proliferation of MDA-231 cells. We also found that IL21R was involved in signaling pathways of matrix metalloproteinases (MMPs), that are crucial for spreading and migration of metastatic MDA231 cells. In conclusion, we unveiled the roles of IL21R in breast cancer cells, which enhances our knowledge on immunological regulation of cancer cells through the axis of IL21 and its receptor. PMID- 26417025 TI - Circulating Messenger RNA Profiling with Microarray and Next-generation Sequencing: Cross-platform Comparison. AB - BACKGROUND: Circulating mRNA is a less invasive and more easily accessed source of samples for biomedical research and clinical applications. However, it is of poor quality. We explored and compared the ability of two high-throughput platforms for the profiling of circulating mRNA regarding their ability to retrieve useful information out of this type of samples. MATERIALS AND METHODS: Circulating mRNAs from three non-small cell lung cancer patients and three healthy controls were analyzed by the cDNA-mediated annealing, selection, extension, and ligation (DASL) assay and high-throughput RNA sequencing (RSEQ). Twelve genes were selected for further confirmation by reverse transcription quantitative polymerase chain reaction (RT-qPCR). RESULTS: The overall expression profiles derived from the two platforms showed modest-to-moderate correlation. Genes with higher expression levels had higher cross-platform concordance than those of medium- and low-expression levels. In addition, the pathway signatures identified by gene set enrichment analysis from both platforms were in agreement. The RT-q PCR results for the selected genes correlated well with that of RSEQ. CONCLUSION: Genes with higher expression levels have cross-platform concordance and can be potential biomarkers. Furthermore, RSEQ is a better tool for profiling circulating mRNAs. PMID- 26417027 TI - Interleukin-24 (IL-24) Expression and Biological Impact on HECV Endothelial Cells. AB - BACKGROUND: IL-24, also termed MDA-7, is a member of the IL-10 family of cytokines. IL-24 is reported to be expressed in a series of cell lines, including keratinocytes as well as breast, lung and prostate cancer cells, but was primarily found in a human melanoma cell line. IL-24 is suggested to have many biological properties displaying anti-tumour effects via induction of apoptosis, suppressing proliferation, invasion and metastasis of cancer cells. IL-24 has also been reported to inhibit the migration of cancer cells and keratinocytes, and have anti-angiogeneic properties. The biological functions of IL-24 are regulated through both autocrine and paracrine methods. However, currently there exists little knowledge regarding the effect of IL-24 on endothelial cell biology. MATERIALS AND METHODS: The impact of rhIL-24 on human endothelial HECV cell growth, migration, trans-endothelial resistance and angiogenic potential was examined using cellular functional assays. Additionally, the relationship between IL-24 and a number of cell junction proteins were examined using immunofluorescence staining. RESULTS: IL-24 and receptor molecules was found to be expressed in HECV endothelial cells. Treatment of this cell line with rhIL-24 was found to promote cell migration rates and suppress tubule formation. CONCLUSION: Treatment of HECV cells with rhIL-24 can promote migration and inhibit tubule formation but does not impact cell growth or permeability at the tested concentrations. Potential links between IL-24 and AKT or PLCgamma-related pathways with regard to these effects are also presented in the present study. PMID- 26417026 TI - Gene-expression Profiling in Non-small Cell Lung Cancer with Invasion of Mediastinal Lymph Nodes for Prognosis Evaluation. AB - BACKGROUND/AIM: The aim of the study was to determine the pathways and expression profile of the genes that might predict response to neoadjuvant chemotherapy in patients with stage IIIA non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We evaluated, by microarray, the gene-expression profile of tumoral mediastinal lymph node samples surgically removed from 27 patients with stage IIIA NSCLC before neoadjuvant chemotherapy treatment. Depending on the response to the induction treatment, the patients were divided in two groups: group A: patients whose disease evolved, stabilized or who had minor response to chemotherapy, and group B: patients whose disease stabilized or had major response to chemotherapy. RESULTS: The microarray experiments identified 1,127 genes with a modified expression in the tumoral tissue compared to normal tissue with p<=0.05 and 44 genes with p<=0.01. The identified up-regulated genes between tumoral versus normal tissue included collagen, type I, alpha 1 (COL1A1), inhibin beta A (INHBA) and thioredoxin interacting protein (TXNIP). Pathways identified with a false-discovery rate of <0.005 included: cytokine pathways, focal adhesion or extracellular matrix receptor interaction. CONCLUSION: Our approach identified important characteristics of NSCLC and pointed-out molecular differences between sub-groups of patients based on their response to therapy. PMID- 26417028 TI - Comparative Proteomics of Tumor and Paired Normal Breast Tissue Highlights Potential Biomarkers in Breast Cancer. AB - BACKGROUND/AIM: Breast cancer is the most common type of cancer among women worldwide, and about 57,000 new cases are expected for the Brazilian population in 2015. Elucidation of protein expression and modification is essential for the biological understanding, early diagnosis and therapeutics of breast cancer. The main objectives of the study are comparison between the proteome of tumor and paired non-tumor breast cancer tissues, describing all identified proteins, highlighting the ones most differentially expressed and comparing the data with existing literature. MATERIALS AND METHODS: The five paired samples from patients with invasive ductal carcinoma were analyzed by 2-DE and MS. RESULTS: We collected 161 identified spots corresponding to 110 distinct proteins. Forty three differentially-expressed spots were common to at least two samples, and the ten proteins with the highest-fold changes were CASPE, ENOG, TPM1, CAPG, VIME, TPM3, TRFE, PDIA6, WDR61 and PDIA3. Metabolic enzymes and proteins with binding functions were the most representative functional classes of proteins with increased and decreased expression in tumor tissue respectively. CONCLUSION: Taking the fold change as a parameter, we point to future targets to be studied by functional methods in a search for biomarkers for initiation and progress of breast cancer. PMID- 26417029 TI - Impact of PTEN IVS4 Polymorphism (rs3830675) on Cancer Susceptibility: An Updated Meta-analysis. AB - BACKGROUND/AIM: Phosphatase and tensin homolog (PTEN) acts as a tumor suppressor gene through the action of its phosphatase protein product. We performed a meta analysis to evaluate their relationship. MATERIALS AND METHODS: A comprehensive database search was performed. Odds ratios (OR) with 95% confidence intervals (CI) were calculated to assess the association between PTEN IVS4 polymorphism and cancer. RESULTS: The meta-analysis indicated that PTEN IVS4 (-/-) genotype was significantly associated with the risk of cancer (OR=1.47, 95% CI=1.11-1.84), especially for digestive cancer (OR=1.67, 95% CI=1.28-2.18) compared to the (+/+) genotype. Moreover, the (-) allele of PTEN IVS4 polymorphism was also significantly associated with the risk of cancer (OR=1.27, 95% CI=1.14-1.41), especially for digestive cancer (OR=1.42, 95% CI=1.16-1.74) compared to the (+) allele. No significant association was observed between PTEN IVS4 (+/-) genotype and risk of cancer. CONCLUSION: PTEN IVS4 (-/-) genotype was significantly associated with increased risk of cancer especially for digestive tract cancer compared to the (+/+) genotype. A similar phenomenon was observed in the (-) allele of PTEN IVS4 polymorphism compared to the (+) allele and the recessive effect model. PMID- 26417031 TI - Correction. PMID- 26417032 TI - Genomic Surveillance Elucidates Persistent Wild Poliovirus Transmission During 2013-2015 in Major Reservoir Areas of Pakistan. AB - BACKGROUND: Despite tremendous efforts in the fight against polio, Pakistan bears the highest proportion of poliomyelitis cases among the 3 endemic countries including Afghanistan and Nigeria. Apart from insecurity and inaccessibility challenges, the substantial shift of unimmunized children from North Waziristan due to recent military operations was presumed to favor the widespread poliovirus infection in Pakistan. METHODS: To better understand the current epidemiological situation, we analyzed the virologic data of wild poliovirus type 1 (WPV1) strains detected in Pakistan during 2013-2015. RESULTS: Five genetic clusters (A E) were identified with at least 5% nucleotide divergence in the viral protein 1 (VP1) coding region. Peshawar, Quetta, and Karachi were found to be the major endemic foci where multiple discrete genetic lineages of WPV1 were detected. Phylogenetic analysis suggests that wild poliovirus strains from endemic regions were genetically distant (with 5%-15% VP1 nucleotide divergence) from those detected in North Waziristan cases, excluding the possibility of a recent progenitor of WPV1 instigating single-source transmission across the country. Orphan lineages detected in Rawalpindi, Lahore, Hyderabad, Sukkur, and Jacobabad revealed silent transmission and the need for vigilant surveillance. Sustenance of analogous genetic lineages over a period of 3 years highlights multiple unimmunized foci present to maintain viral genetic diversity. CONCLUSIONS: Our findings are inconsistent with the hypothesis that impoverished populations from North Waziristan serve as a possible determinant of widespread poliomyelitis infection in Pakistan and further emphasize the need to scale-up clinical and environmental surveillance as well as immunization activities. PMID- 26417033 TI - Poliomyelitis in Pakistan. PMID- 26417034 TI - All-Cause Mortality and Progression Risks to Hepatic Decompensation and Hepatocellular Carcinoma in Patients Infected With Hepatitis C Virus. AB - BACKGROUND: A key question in care of patients with chronic hepatitis C virus (HCV) infection is beginning treatment immediately vs delaying treatment. Risks of mortality and disease progression in "real world" settings are important to assess the implications of delaying HCV treatment. METHODS: This was a cohort study of HCV patients identified from 4 integrated health systems in the United States who had liver biopsies during 2001-2012. The probabilities of death and progression to hepatocellular carcinoma, hepatic decompensation (hepatic encephalopathy, esophageal varices, ascites, or portal hypertension) or liver transplant were estimated over 1, 2, or 5 years by fibrosis stage (Metavir F0-F4) determined by biopsy at beginning of observation. RESULTS: Among 2799 HCV monoinfected patients who had a qualifying liver biopsy, the mean age at the time of biopsy was 50.7 years. The majority were male (58.9%) and non-Hispanic white (66.9%). Over a mean observation of 5.0 years, 261 (9.3%) patients died and 34 (1.2%) received liver transplants. At 5 years after biopsy, the estimated risk of progression to hepatic decompensation or hepatocellular carcinoma was 37.2% in stage F4, 19.6% in F3, 4.7% in F2, and 2.3% in F0-F1 patients. Baseline biopsy stage F3 or F4 and platelet count below normal were the strongest predictors of progression to hepatic decompensation or hepatocellular carcinoma. CONCLUSIONS: The risks of death and progression to liver failure varied greatly by fibrosis stage. Clinicians and policy makers could use these progression risk data in prioritization and in determining the timing of treatment for patients in early stages of liver disease. PMID- 26417035 TI - Susceptibility Loci for Clinical Coronary Artery Disease and Subclinical Coronary Atherosclerosis Throughout the Life-Course. AB - BACKGROUND: Recent genome-wide association studies have identified 49 single nucleotide polymorphisms associated with clinical coronary artery disease. The mechanism by which these loci influence risk remains largely unclear. METHODS AND RESULTS: We examined the association between a genetic risk score composed of high-risk alleles at the 49 single nucleotide polymorphisms and the degree of subclinical coronary atherosclerosis in 7798 participants from 6 studies stratified into 4 age groups at the time of assessment (15-34, 35-54, 55-74, and >75 years). Atherosclerosis was quantified by staining and direct visual inspection of the right coronary artery in the youngest group and by scanning for coronary artery calcification in the remaining groups. We defined cases as subjects within the top quartile of degree of atherosclerosis in 3 groups and as subjects with a coronary artery calcium score >0 in the fourth (35-54 years) where less than one quarter had any coronary artery calcium. In our meta-analysis of all strata, we found 1-SD increase in the genetic risk score increased the risk of advanced subclinical coronary atherosclerosis by 36% (P=8.3*10(-25)). This increase in risk was significant in all 4 age groups including the youngest group where atherosclerosis consisted primarily of raised lesions without macroscopic evidence of plaque rupture or thrombosis. Results were similar when we restricted the genetic risk score to 32 single nucleotide polymorphisms not associated with traditional risk factors or when we adjusted for traditional risk factors. CONCLUSIONS: A genetic risk score for clinical coronary artery disease is associated with advanced subclinical coronary atherosclerosis throughout the life-course. This association is apparent even at the earliest, uncomplicated stages of atherosclerosis. PMID- 26417036 TI - The Frequency, Characteristics, and Outcomes Among Cancer Patients With Delirium Admitted to an Acute Palliative Care Unit. AB - BACKGROUND: Delirium is a common neuropsychiatric condition seen in patients with severe illness, such as advanced cancer. Few published studies are available of the frequency, course, and outcomes of standardized management of delirium in advanced cancer patients admitted to acute palliative care unit (APCU). In this study, we examined the frequency, characteristics, and outcomes of delirium in patients with advanced cancer admitted to an APCU. METHODS: Medical records of 609 consecutive patients admitted to the APCU from January 2011 through December 2011 were reviewed. Data on patients' demographics; Memorial Delirium Assessment Scale (MDAS) score; palliative care specialist (PCS) diagnosis of delirium; delirium etiology, subtype, and reversibility; late development of delirium; and discharge outcome were collected. Delirium was diagnosed with MDAS score >=7 and by a PCS using Diagnostic and Statistical Manual, 4th edition, Text Revision criteria. All patients admitted to the APCU received standardized assessments and management of delirium per best practice guidelines in delirium management. RESULTS: Of 556 patients in the APCU, 323 (58%) had a diagnosis of delirium. Of these, 229 (71%) had a delirium diagnosis on admission and 94 (29%) developed delirium after admission to the APCU. Delirium reversed in 85 of 323 episodes (26%). Half of patients with delirium (n = 162) died. Patients with the diagnosis of delirium had a lower median overall survival than those without delirium. Patients who developed delirium after admission to the APCU had poorer survival (p <= .0001) and a lower rate of delirium reversal (p = .03) compared with those admitted with delirium. CONCLUSION: More than half of the patients admitted to the APCU had delirium. Reversibility occurred in almost one-third of cases. Diagnosis of delirium was associated with poorer survival. PMID- 26417038 TI - Exploring Knowledge, Attitudes, and Practices Related to Breast and Cervical Cancers in Mongolia: A National Population-Based Survey. AB - BACKGROUND: Mongolia bears the second-highest cancer burden in the world (5,214 disability-adjusted life years per 100,000 people, age standardized). To determine drivers of the growing burden of noncommunicable diseases, including breast and cervical cancers, a national knowledge, attitudes, and practices (KAP) survey was implemented in 2010. METHODS: This paper analyzed the results of the 2010 KAP survey, which sampled 3,450 households nationally. Reflecting Mongolian screening policies, women aged 30 and older were included in analyses of questions regarding breast and cervical cancer (n = 1,193). Univariate and multivariate odds ratios (MORs) were derived through logistic regression to determine associations between demographic covariables (residence, age, education, employment) and survey responses. RESULTS: This study found that 25.7% (95% confidence interval [CI]: 23.3-28.3) and 22.1% (95% CI: 19.8-24.5) of female participants aged 30 years or older self-rated their knowledge of breast and cervical cancers, respectively, as "none." Employment and education were associated with greater awareness of both cancers and participation in screening examinations (p < .05). Clinical breast examinations were more common among rural than urban participants (MOR: 1.492; 95% CI: 1.125-1.979). Of all female participants, 17% (95% CI: 15.3-18.5) knew that cervical cancer is vaccine preventable. CONCLUSION: Our results suggest that cancer control in Mongolia should emphasize health education, particularly among lower-educated, rural, and unemployed women. The health infrastructure should be strengthened to reflect rural to urban migration. Finally, although there is awareness that early detection improves outcomes, a significant proportion of women do not engage in screening. These trends warrant further research on barriers and solutions. IMPLICATIONS FOR PRACTICE: The rising burden of breast and cervical cancers, particularly in low- and middle-income countries, necessitates the development of effective strategies for cancer control. This paper examines barriers to health service use in Mongolia, a country with a high cancer burden. The 2010 national knowledge, attitude and practices survey data indicate that cancer control efforts should focus on improving health education among lower-educated, rural, and unemployed populations, who display the least knowledge of breast and cervical cancers. Moreover, the findings support the need to emphasize individual risk for disease in cancer education and ensure that the health-care infrastructure reflects Mongolia's urbanization. PMID- 26417037 TI - Attitudes and Beliefs Toward Supportive and Palliative Care Referral Among Hematologic and Solid Tumor Oncology Specialists. AB - BACKGROUND: Palliative care (PC) referrals are often delayed for patients with hematologic malignancies. We examined the differences in attitudes and beliefs toward PC referral between hematologic and solid tumor specialists and how their perception changed with use of the service name "supportive care" (SC). MATERIALS AND METHODS: We randomly surveyed 120 hematologic and 120 solid tumor oncology specialists at our tertiary care cancer center to examine their attitudes and beliefs toward PC and SC referral. RESULTS: Of the 240 specialists, 182 (76%) responded. Compared with solid tumor specialists, hematologic specialists were less likely to report that they would refer symptomatic patients with newly diagnosed cancer to PC (solid tumor, 43% vs. hematology, 21%; p = .002). A significantly greater proportion of specialists expressed that they would refer a patient with newly diagnosed cancer to SC than PC (solid tumor specialists: SC, 81% vs. PC, 43%; p < .001; hematology specialists: SC, 66% vs. PC, 21%; p < .001). The specialists perceived that PC was more likely than SC to be a barrier for referral (PC, 36% vs. SC, 3%; p < .001), to be synonymous with hospice (PC, 53% vs. SC, 6%; p < .001), to decrease hope (PC, 58% vs. SC, 8%; p < .001), and to be less appropriate for treatment of chemotherapy side effects (PC, 64% vs. SC, 19%; p < .001). On multivariate analysis, female clinicians (odds ratio [OR], 4.5; 95% confidence interval [CI], 1.3-15.2; p = .02) and the perception that PC is a barrier for referral (OR, 3.0; 95% CI, 1.2-7.6; p = .02) were associated with PC referral if the service name "SC" was used. CONCLUSION: Hematologic specialists were less likely to refer patients early in the disease trajectory and were conducive to referral with the service name SC instead of PC. IMPLICATIONS FOR PRACTICE: The present survey of oncology specialists found that hematologic specialists were less likely than solid tumor specialists to report that they would refer symptomatic patients with newly diagnosed cancer to palliative care. However, both groups were significantly more willing to refer patients early in the disease trajectory if the service name "supportive care" were used instead of "palliative care." These findings suggest that rebranding might help to overcome the stigma associated with palliative care and improve patient access to palliative care services. PMID- 26417039 TI - Outpatient Intraperitoneal Catumaxomab Therapy for Malignant Ascites Related to Advanced Gynecologic Neoplasms. AB - BACKGROUND: Catumaxomab (CATU) is a trifunctional antibody approved for intraperitoneal (i.p.) treatment of malignant ascites (MA) related to carcinomas expressing the epithelial cell-adhesion molecule (EpCAM). CATU is mostly given to hospitalized patients, although outpatient treatment seems appropriate in selected individuals. This observational trial sought to obtain more detailed information regarding the feasibility of CATU in outpatients with MA related to various gynecologic tumors, including epithelial ovarian (EOC) and metastatic breast cancer (MBC). MATERIALS AND METHODS: A total of 30 patients were included, 17 with EOC, 7 with MBC, and 6 with other malignancies. The patients had failed a median of 5 (range 1-12) previous systemic treatments. CATU was administered via an indwelling i.p. catheter at four increasing doses (i.e., 10, 20, 50, and 150 ug) given at 4-day intervals over 2 weeks. Toxicities were scored according to the Common Terminology Criteria for Adverse Events, version 4.03. Puncture-free survival (PuFS) was calculated from the start of CATU until the next puncture for MA, death, or loss to follow-up. Overall survival (OS) was calculated from the start of CATU to death from any reason or loss to follow-up. We also investigated various clinical parameters to predict PuFS and OS. These included age, tumor type, performance status, intensity of pretreatment, presence of extraperitoneal metastases, relative lymphocyte count at baseline, patient adherence to therapy, and the patients' ability to undergo systemic treatment after CATU. RESULTS: CATU was exclusively given on an outpatient basis, and 19 patients (63.3%) received all four planned i.p. instillations. Toxicity was the reason for discontinuation in only 2 patients. Toxicity was generally manageable, with abdominal pain, nausea/vomiting, fatigue, and fever the predominant adverse effects. Secondary hospitalization was necessary for 7 patients (23.3%), with a general deteriorated condition in 5 and fever/infection or abdominal pain in 1 patient each. Subsequent systemic treatment was possible in 11 patients (36.7%). Only 5 patients (16.7%) required a second puncture after i.p. CATU. The median PuFS was 56 days, and the median OS was 79.5 days. Positive predictors of both PuFS and OS were performance status, absence of extraperitoneal tumor, the capability to receive all four CATU infusions, and the ability to undergo subsequent systemic treatment. CONCLUSION: Outpatient i.p. CATU therapy for MA related to various gynecologic carcinomas is safe and effective in producing good ascites control in most individuals, allowing for subsequent systemic therapy in a substantial proportion of patients. IMPLICATIONS FOR PRACTICE: Intraperitoneal treatment with the trifunctional antibody catumaxomab (CATU) was possible in a selected population of 30 outpatients with malignant ascites due to epithelial female genital tract or breast carcinoma. Toxicity was largely manageable. Patients in good condition at baseline, without extraperitoneal tumor and/or liver metastases, and with the ability to complete all four planned CATU instillations and the capability of undergoing subsequent systemic therapy benefited the most in terms of both puncture-free and overall survival. Outpatient i.p. CATU is safe and effective in a selected group of patients with malignant ascites due to various gynecologic malignancies and could be cost-saving compared with an inpatient approach. PMID- 26417040 TI - Facial whisker pattern is not sufficient to instruct a whisker-related topographic map in the mouse somatosensory brainstem. AB - Facial somatosensory input is relayed by trigeminal ganglion (TG) neurons and serially wired to brainstem, thalamus and cortex. Spatially ordered sets of target neurons generate central topographic maps reproducing the spatial arrangement of peripheral facial receptors. Facial pattern provides a necessary template for map formation, but may be insufficient to impose a brain somatotopic pattern. In mice, lower jaw sensory information is relayed by the trigeminal nerve mandibular branch, whose axons target the brainstem dorsal principal sensory trigeminal nucleus (dPrV). Input from mystacial whiskers is relayed by the maxillary branch and forms a topographic representation of rows and whiskers in the ventral PrV (vPrV). To investigate peripheral organisation in imposing a brain topographic pattern, we analysed Edn1(-/-) mice, which present ectopic whisker rows on the lower jaw. We found that these whiskers were innervated by mandibular TG neurons which initially targeted dPrV. Unlike maxillary TG neurons, the ectopic whisker-innervating mandibular neuron cell bodies and pre-target central axons did not segregate into a row-specific pattern nor target the dPrV with a topographic pattern. Following periphery-driven molecular repatterning to a maxillary-like identity, mandibular neurons partially redirected their central projections from dPrV to vPrV. Thus, while able to induce maxillary-like molecular features resulting in vPrV final targeting, a spatially ordered lower jaw ectopic whisker pattern is insufficient to impose row-specific pre-target organisation of the central mandibular tract or a whisker-related matching pattern of afferents in dPrV. These results provide novel insights into periphery dependent versus periphery-independent mechanisms of trigeminal ganglion and brainstem patterning in matching whisker topography. PMID- 26417043 TI - De novo DNA methylation through the 5'-segment of the H19 ICR maintains its imprint during early embryogenesis. AB - Genomic imprinting is a major monoallelic gene expression regulatory mechanism in mammals, and depends on gamete-specific DNA methylation of specialized cis regulatory elements called imprinting control regions (ICRs). Allele-specific DNA methylation of the ICRs is faithfully maintained at the imprinted loci throughout development, even in early embryos where genomes undergo extensive epigenetic reprogramming, including DNA demethylation, to acquire totipotency. We previously found that an ectopically introduced H19 ICR fragment in transgenic mice acquired paternal allele-specific methylation in the somatic cells of offspring, whereas it was not methylated in sperm, suggesting that its gametic and postfertilization modifications were separable events. We hypothesized that this latter activity might contribute to maintenance of the methylation imprint in early embryos. Here, we demonstrate that methylation of the paternally inherited transgenic H19 ICR commences soon after fertilization in a maternal DNMT3A- and DNMT3L-dependent manner. When its germline methylation was partially obstructed by insertion of insulator sequences, the endogenous paternal H19 ICR also exhibited postfertilization methylation. Finally, we refined the responsible sequences for this activity in transgenic mice and found that deletion of the 5' segment of the endogenous paternal H19 ICR decreased its methylation after fertilization and attenuated Igf2 gene expression. These results demonstrate that this segment of the H19 ICR is essential for its de novo postfertilization DNA methylation, and that this activity contributes to the maintenance of imprinted methylation at the endogenous H19 ICR during early embryogenesis. PMID- 26417041 TI - Excitability governs neural development in a hippocampal region-specific manner. AB - Neuronal activity, including intrinsic neuronal excitability and synaptic transmission, is an essential regulator of brain development. However, how the intrinsic neuronal excitability of distinct neurons affects their integration into developing circuits remains poorly understood. To investigate this problem, we created several transgenic mouse lines in which intrinsic excitability is suppressed, and the neurons are effectively silenced, in different excitatory neuronal populations of the hippocampus. Here we show that CA1, CA3 and dentate gyrus neurons each have unique responses to suppressed intrinsic excitability during circuit development. Silenced CA1 pyramidal neurons show altered spine development and synaptic transmission after postnatal day 15. By contrast, silenced CA3 pyramidal neurons seem to develop normally. Silenced dentate granule cells develop with input-specific decreases in spine density starting at postnatal day 11; however, a compensatory enhancement of neurotransmitter release onto these neurons maintains normal levels of synaptic activity. The synaptic changes in CA1 and dentate granule neurons are not observed when synaptic transmission, rather than intrinsic excitability, is blocked in these neurons. Thus, our results demonstrate a crucial role for intrinsic neuronal excitability in establishing hippocampal connectivity and reveal that neuronal development in each hippocampal region is distinctly regulated by excitability. PMID- 26417042 TI - ProNodal acts via FGFR3 to govern duration of Shh expression in the prechordal mesoderm. AB - The secreted glycoprotein sonic hedgehog (Shh) is expressed in the prechordal mesoderm, where it plays a crucial role in induction and patterning of the ventral forebrain. Currently little is known about how Shh is regulated in prechordal tissue. Here we show that in the embryonic chick, Shh is expressed transiently in prechordal mesoderm, and is governed by unprocessed Nodal. Exposure of prechordal mesoderm microcultures to Nodal-conditioned medium, the Nodal inhibitor CerS, or to an ALK4/5/7 inhibitor reveals that Nodal is required to maintain both Shh and Gsc expression, but whereas Gsc is largely maintained through canonical signalling, Nodal signals through a non-canonical route to maintain Shh. Further, Shh expression can be maintained by a recombinant Nodal cleavage mutant, proNodal, but not by purified mature Nodal. A number of lines of evidence suggest that proNodal acts via FGFR3. ProNodal and FGFR3 co immunoprecipitate and proNodal increases FGFR3 tyrosine phosphorylation. In microcultures, soluble FGFR3 abolishes Shh without affecting Gsc expression. Further, prechordal mesoderm cells in which Fgfr3 expression is reduced by Fgfr3 siRNA fail to bind to proNodal. Finally, targeted electroporation of Fgfr3 siRNA to prechordal mesoderm in vivo results in premature Shh downregulation without affecting Gsc. We report an inverse correlation between proNodal-FGFR3 signalling and pSmad1/5/8, and show that proNodal-FGFR3 signalling antagonises BMP-mediated pSmad1/5/8 signalling, which is poised to downregulate Shh. Our studies suggest that proNodal/FGFR3 signalling governs Shh duration by repressing canonical BMP signalling, and that local BMPs rapidly silence Shh once endogenous Nodal-FGFR3 signalling is downregulated. PMID- 26417044 TI - Genome-wide assessment of differential effector gene use in embryogenesis. AB - Six different populations of cells were isolated by fluorescence-activated cell sorting from disaggregated late blastula- and gastrula-stage sea urchin embryos according to the regulatory states expressed in these cells, as reported by recombineered bacterial artificial chromosomes producing fluorochromes. Transcriptomes recovered from these embryonic cell populations revealed striking, early differential expression of large cohorts of effector genes. The six cell populations were presumptive pigment cells, presumptive neurogenic cells, presumptive skeletogenic cells, cells from the stomodeal region of the oral ectoderm, ciliated band cells and cells from the endoderm/ectoderm boundary that will give rise both to hindgut and to border ectoderm. Transcriptome analysis revealed that each of these domains specifically expressed several hundred effector genes at significant levels. Annotation indicated the qualitative individuality of the functional nature of each cell population, even though they were isolated from embryos only 1-2 days old. In no case was more than a tiny fraction of the transcripts enriched in one population also enriched in any other of the six populations studied. As was particularly clear in the cases of the presumptive pigment, neurogenic and skeletogenic cells, all three of which represent precociously differentiating cell types of this embryo, most specifically expressed genes of given cell types are not significantly expressed at all in the other cell types. Thus, at the effector gene level, a dramatic, cell type-specific pattern of differential gene regulation is established well before any significant embryonic morphogenesis has occurred. PMID- 26417045 TI - Leflunomide Induces Pulmonary and Hepatic CYP1A Enzymes via Aryl Hydrocarbon Receptor. AB - Emerging evidence indicates that the aryl hydrocarbon receptor (AhR) plays a crucial role in normal physiologic homeostasis. Additionally, aberrant AhR signaling leads to several pathologic states in the lung and liver. Activation of AhR transcriptionally induces phase I (CYP1A) detoxifying enzymes. Although the effects of the classic AhR ligands such as 3-methylcholanthrene and dioxins on phase 1 enzymes are well studied in rodent lung, liver, and other organs, the toxicity profiles limit their use as therapeutic agents in humans. Hence, there is a need to identify and investigate nontoxic AhR ligands not only to understand the AhR biology but also to develop the AhR as a clinically relevant therapeutic target. Leflunomide is a Food and Drug Administration-approved drug in humans that is known to have AhR agonist activity in vitro. Whether it activates AhR and induces phase 1 enzymes in vivo is unknown. Therefore, we tested the hypothesis that leflunomide will induce pulmonary and hepatic CYP1A enzymes in C57BL/6J wild type mice, but not in AhR-null mice. We performed real-time reverse-transcription polymerase chain reaction analyses for CYP1A1/2 mRNA expression, western blot assays for CYP1A1/2 protein expression, and ethoxyresorufinO-deethylase assay for CYP1A1 catalytic activity. Leflunomide increased CYP1A1/A2 mRNA, protein, and enzymatic activities in wild-type mice. In contrast, leflunomide failed to increase pulmonary and hepatic CYP1A enzymes in AhR-null mice. In conclusion, we provide evidence that leflunomide induces pulmonary and hepatic CYP1A enzymes via the AhR. PMID- 26417046 TI - A Multicentre Evaluation of Risk Factors for Anastomotic Leakage After Restorative Proctocolectomy with Ileal Pouch-Anal Anastomosis for Inflammatory Bowel Disease. AB - BACKGROUND: Anastomotic leakage is a major complication after restorative proctocolectomy with ileal pouch-anal anastomosis [IPAA]. Identification of patients at high risk of leakage may influence surgical decision making. The aim of this study was to identify risk factors associated with anastomotic leakage after restorative proctocolectomy with IPAA. METHODS: Between September 1990 and January 2015, patients who underwent IPAA for inflammatory bowel disease [IBD] were identified from prospectively maintained databases of three tertiary referral centres. Retrospective chart review identified additional data on demographic and surgical variables. Multivariable regression models were developed to identify risk factors for anastomotic leakage. Separate analyses were performed for type of procedure. RESULTS: A total of 640 patients [56.9% male] were included, with a median age of 38 years [interquartile range 29-48]; 96 [15.0%] patients developed anastomotic leakage. Multivariable regression analysis demonstrated that being overweight (body mass index [BMI] > 25], (odds ratio [OR] 1.92; 95% confidence interval [CI] 1.15 - 3.18), and American Society of Anesthesiologists classification [ASA score > 2] [OR 1.91; 95% CI 1.03 - 3.54] were independent risk factors for anastomotic leakage in patients who underwent a completion proctectomy. A disease course of > 5 years [OR 2.34; 95% CI 1.42 - 3.87] and concurrent combination of anti-tumour necrosis factor [TNF] and steroids [OR 6.40; 95% CI 1.76 - 23.20] were independent risk factors for anastomotic leakage in patients who underwent a proctocolectomy and IPAA. CONCLUSIONS: Independent risk factors for anastomotic leakage in IBD patients undergoing IPAA are BMI >25, ASA score >2, disease course > 5 years, and concurrent steroid and anti-TNF treatment, with a different risk profile for one stage proctocolectomy and completion proctectomy procedures. PMID- 26417047 TI - Reintroduction of Anti-TNFalpha Therapy After (or even During) Anti-TNFalpha associated Tuberculosis in Immune-mediated Diseases. PMID- 26417048 TI - Image-guided Percutaneous Drainage for Treatment of Post-Surgical Anastomotic Leak in Patients with Crohn's Disease. AB - BACKGROUND AND AIMS: Anastomotic leaks with abscess formation are a common complication after bowel surgery in Crohn's disease patients. Image-guided percutaneous drainage is an attractive alternative to reoperation because of decreased morbidity and length of hospital stay. Because data for this specific population are scarce, the purpose of this study is to determine the safety and efficacy of image-guided percutaneous drainage in the management of post-surgical anastomotic leak in patients with Crohn's disease. METHODS: A total of 41 patients who underwent percutaneous drain placement for the treatment of fluid collections due to anastomotic leak from September 2004 to November 2013 were retrospectively identified from the electronic medical record and picture archiving and communication system. Data recorded included number, size, and location of anastomotic leaks, number of drains placed, number of follow-up visits, post-drainage complications, abscess resolution, and subsequent surgeries. RESULTS: In all, 41 patients with 76 fluid collections were identified as having received percutaneous drains. The mean number of targeted fluid collections per patient was 1.5, and the mean duration between surgery and percutaneous drain placement was 18.5 days. The mean number of drains placed was 1.6, and the median drain size was 10 French [range 8-16 French]. One of 41 [2.4%] patients experienced a minor complication from drain placement [injury to a superficial abdominal artery] and no major complications occurred. Two of 41 [4.9%] patients required repeat surgeries. CONCLUSIONS: Image-guided percutaneous drainage for the treatment of post-surgical anastomotic leaks in Crohn's patients is effective and safe, with low rates of complications and reoperations. PMID- 26417050 TI - Vigilante Science. PMID- 26417049 TI - Autophagy Contributes to the Induction of Anti-TNF Induced Macrophages. AB - BACKGROUND AND AIMS: Anti-tumour necrosis factor [TNF] antibodies induce regulatory macrophages which display a phenotype resembling M2 type macrophages. Anti-TNF induced macrophages [Mphiind] have immunosuppressive and wound healing properties. The factors that contribute to the induction of Mphiind remain to be explored. Autophagy has been described as a factor that is important for the induction and function of M2 type macrophages. We studied the contribution of autophagy to the induction of Mphiind. METHODS: We studied the effect of autophagy on Mphiind in vitro using peripheral blood mononuclear cells. Interferon gamma [IFN-gamma] induced macrophages [Mphi1] were generated by culturing monocytes in the presence of IFN-gamma. Mphiind were generated by performing mixed lymphocyte reactions [MLR] in the presence of anti-TNF antibodies; 28 healthy donors were genotyped for rs_2241880 [ATG16L1]. Cells were analysed by autophagy gene array, immunofluorescence, western blot, flowcytometry, 3H-thymidine incorporation and MTS assay. RESULTS: Mphiind had a different expression profile of autophagy related transcripts with increased expression of 33/40 altered genes compared with Mphi1. In addition, autophagic activity was increased in Mphiind compared with Mphi1. Induction of Mphiind was positively correlated to the number of wild-type alleles for the ATG16L1 T300A risk allele present in the culture. Finally, the autophagy-related protein cathepsin S was highly expressed in Mphiind and inhibition resulted in decreased viability as well as decreased expression of CD206. CONCLUSIONS: Mphiind have increased levels of autophagy compared with inflammatory Mphi1, and the induction of these macrophages is impaired in donors carrying the T300A risk allele for the ATG16L1. Given the association between Mphiind and clinical response, this suggests that an intact autophagy pathway may be important for an optimal response to anti-TNF therapy in inflammatory bowel disease. PMID- 26417051 TI - Visualizing the Photosynthetic Membrane Proteins in Situ: Atomic Force Microscopy. PMID- 26417052 TI - Nutrient Signaling by Nitrate and Calcium. PMID- 26417053 TI - From Leaf to Kernel: Trehalose-6-Phosphate Signaling Moves Carbon in the Field. PMID- 26417054 TI - CORRECTIONS. PMID- 26417055 TI - CORRECTIONS. PMID- 26417056 TI - Corrigendum. AB - Treatment steps, surgery and hospitalization rates during the first year of follow-up in patients with inflammatory bowel diseases from the 2011 ECCO-EpiCom inception cohort. This paper, which was previously published in Vol. 9 Iss. 9, listed an incorrect author name. Limas Kupcinskas was incorrectly referred to as 'Limas Kupcinskap'. PMID- 26417058 TI - Beyond ejection fraction: an integrative approach for assessment of cardiac structure and function in heart failure. AB - Left ventricular ejection fraction (LVEF) has been the central parameter used for diagnosis and management in patients with heart failure. A good predictor of adverse outcomes in heart failure when below ~45%, LVEF is less useful as a marker of risk as it approaches normal. As a measure of cardiac function, ejection fraction has several important limitations. Calculated as the stroke volume divided by end-diastolic volume, the estimation of ejection fraction is generally based on geometric assumptions that allow for assessment of volumes based on linear or two-dimensional measurements. Left ventricular ejection fraction is both preload- and afterload-dependent, can change substantially based on loading conditions, is only moderately reproducible, and represents only a single measure of risk in patients with heart failure. Moreover, the relationship between ejection fraction and risk in patients with heart failure is modified by factors such as hypertension, diabetes, and renal function. A more complete evaluation and understanding of left ventricular function in patients with heart failure requires a more comprehensive assessment: we conceptualize an integrative approach that incorporates measures of left and right ventricular function, left ventricular geometry, left atrial size, and valvular function, as well as non imaging factors (such as clinical parameters and biomarkers), providing a comprehensive and accurate prediction of risk in heart failure. PMID- 26417057 TI - Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes: results from the PLATO study. AB - AIMS: Growth differentiation factor-15 (GDF-15) predicts death and composite cardiovascular (CV) events in patients with acute coronary syndrome (ACS). We investigated the independent associations between GDF-15 levels and major bleeding, the extent of coronary lesions and individual CV events in patients with ACS. METHODS AND RESULTS: Growth differentiation factor-15 was analysed at baseline ( ITALIC! n = 16 876) in patients with ACS randomized to ticagrelor or clopidogrel in the PLATO (PLATelet inhibition and patient Outcomes) trial. Growth differentiation factor-15 levels were related to extent of coronary artery disease (CAD) and to all types of non-coronary artery bypass grafting (CABG) related major bleeding, spontaneous myocardial infarction (MI), stroke, and death during 12-month follow-up. In Cox proportional hazards models adjusting for established risk factors for CV disease and prognostic biomarkers (N-terminal pro B-type natriuretic peptide, cystatin C, high-sensitive C-reactive protein, and high-sensitive troponin T), 1 SD increase in ln GDF-15 was associated with increased risk of major bleeding with a hazard ratio (HR) 1.37 (95% confidence interval: 1.25-1.51) and with a similar increase in risk across different bleeding locations. For the same increase in ln GDF-15, the HR for the composite of CV death, spontaneous MI, and stroke was 1.29 (1.21-1.37), CV death 1.41 (1.30 1.53), all-cause death 1.41 (1.31-1.53), spontaneous MI 1.15 (1.05-1.26), and stroke 1.19 (1.01-1.42). The ITALIC! C-statistic improved for the prediction of CV death and non-CABG-related major bleeding when adding GDF-15 to established risk factors. CONCLUSIONS: In patients with ACS, higher levels of GDF-15 are associated with raised risks of all types of major non-CABG-related bleeding, spontaneous MI, and stroke as well as CV and total mortality and seem to improve risk stratification for CV-mortality and major bleeding beyond established risk factors. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov; NCT00391872. PMID- 26417059 TI - Sonolysis in Prevention of Brain Infarction During Carotid Endarterectomy and Stenting (SONOBUSTER): a randomized, controlled trial. AB - AIMS: Previous case series have detected silent brain infarctions in as many as one-third of patients after carotid endarterectomy (CEA) and in up to two-thirds of patients after carotid angioplasty and stenting (CAS). Sonolysis employs ultrasound to facilitate disruption of thrombi and has been shown to be safe and effective for improving long-term outcomes following acute stroke. Here, we examined whether intraoperative sonolysis alters the risk of new brain ischaemic lesions during CEA or CAS. METHODS AND RESULTS: All consecutive patients with internal carotid stenosis >=70% indicated for CEA/CAS were screened in this prospective study. Patients were allocated randomly to sonolysis and control groups. Neurological examination, cognitive function tests, and brain magnetic resonance imaging (MRI) were conducted before intervention and at 24 and 30 days post-surgery. Of the 487 screened patients, 121 (87 males; mean age, 66.65 +/- 7.17 years) were allocated to the sonolysis group and 121 (75; 66.02 +/- 8.11 years) to the control group. New brain ischaemic lesions on post-procedure MRI were significantly less frequent in the sonolysis group than in the control group (31.4% of patients vs. 47.1%; P = 0.018). Sonolysis and CEA were identified as independent predictors of reduced brain ischaemic risk [sonolysis: odds ratio (OR) = 0.450 (0.215-0.942), P = 0.034 and CEA: OR = 0.208 (0.087-0.495), P < 0.001]. Stroke or transient ischaemic attack occurred in one sonolysis patient and three control patients (P = 0.372). No significant group differences were found in post-intervention cognitive test scores (P > 0.3). CONCLUSION: This study provides Class II evidence that sonolysis during CEA or CAS reduces the risk of new brain ischaemic lesions. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov (NCT01591005). PMID- 26417062 TI - Single-incision thoracoscopic surgery and conventional video-assisted thoracoscopic surgery: a retrospective comparative study of perioperative clinical outcomes?. AB - OBJECTIVES: To assess the feasibility, safety and postoperative wound pain of single-incision thoracoscopic surgery (SITS) for Stage I lung cancer in patients who had previously undergone surgery compared with conventional video-assisted thoracoscopic surgery (c-VATS). METHODS: Lobectomy by SITS (60) and c-VATS (20) was performed for Stage I lung cancer between 2011 and 2014. In SITS, an ~ 5-cm small incision was placed at the fourth or fifth intercostal space from the anterior to posterior axillary line. C-VATS was performed via three or four ports using trocars only. The evaluation items were general operative outcomes, pain stress using the Numeric Rating scale (NRS) on postoperative days 3, 7 and 30, and some pathological symptoms related to the neuropathic wound pain through the operative course. The number of days of use of analgesic agents was also evaluated for 1 month after surgery. RESULTS: SITS showed similar perioperative outcomes (postoperative hospital stay, blood loss, surgical time, drainage duration, creatine phosphokinase (CPKmax), creactive protein (CRPmax) and frequency of postoperative complications) to those of c-VATS. Additionally, the average NRS in SITS decreased on postoperative days 7 and 30 (Day 7: 2.4 +/- 0.4 vs 4.2 +/- 0.3, P = 0.041, Day 30: 1.7 +/- 0.4 vs 3.3 +/- 0.3, P = 0.038) and the number of days analgesic agents were administered was also reduced (SITS: 8.1 +/- 0.9 vs c-VATS 13.1 +/- 1.2 days, P = 0.045). The frequency of allodynia, hyperalgesia, hypaesthesia and numbness was significantly reduced in the SITS group. CONCLUSIONS: Although conclusive evidence has not yet been obtained, SITS is more minimally invasive in regard to postoperative wound pain compared with c VATS. This procedure should be considered as a treatment option for early-stage lung cancer. PMID- 26417063 TI - Reply to Kadan et al. PMID- 26417061 TI - Efficacy of Antiarrhythmic Drugs Short-Term Use After Catheter Ablation for Atrial Fibrillation (EAST-AF) trial. AB - AIMS: Substantial portion of early arrhythmia recurrence after catheter ablation for atrial fibrillation (AF) is considered to be due to irritability in left atrium (LA) from the ablation procedure. We sought to evaluate whether 90-day use of antiarrhythmic drug (AAD) following AF ablation could reduce the incidence of early arrhythmia recurrence and thereby promote reverse remodelling of LA, leading to improved long-term clinical outcomes. METHODS AND RESULTS: A total of 2038 patients who had undergone radiofrequency catheter ablation for paroxysmal, persistent, or long-lasting AF were randomly assigned to either 90-day use of Vaughan Williams class I or III AAD (1016 patients) or control (1022 patients) group. The primary endpoint was recurrent atrial tachyarrhythmias lasting for >30 s or those requiring repeat ablation, hospital admission, or usage of class I or III AAD at 1 year, following the treatment period of 90 days post ablation. Patients assigned to AAD were associated with significantly higher event-free rate from recurrent atrial tachyarrhythmias when compared with the control group during the treatment period of 90 days [59.0 and 52.1%, respectively; adjusted hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.73-0.96; P = 0.01]. However, there was no significant difference in the 1-year event-free rates from the primary endpoint between the groups (69.5 and 67.8%, respectively; adjusted HR 0.93; 95% CI 0.79-1.09; P = 0.38). CONCLUSION: Short-term use of AAD for 90 days following AF ablation reduced the incidence of recurrent atrial tachyarrhythmias during the treatment period, but it did not lead to improved clinical outcomes at the later phase. PMID- 26417060 TI - Stent thrombosis and restenosis: what have we learned and where are we going? The Andreas Gruntzig Lecture ESC 2014. AB - Modern-day stenting procedures leverage advances in pharmacotherapy and device innovation. Patients treated with contemporary antiplatelet agents, peri procedural antithrombin therapy and new-generation drug-eluting stents (DES) have excellent outcomes over the short to medium term. Indeed, coupled with the reducing costs of these devices in most countries there remain very few indications where patients should be denied treatment with standard-of-care DES therapy. The two major causes of stent failure are stent thrombosis (ST) and in stent restenosis (ISR). The incidence of both has reduced considerably in recent years. Current clinical registries and randomized trials with broad inclusion criteria show rates of ST at or <1% after 1 year and ~0.2-0.4% per year thereafter; rates of clinical ISR are 5% respectively. Angiographic surveillance studies in large cohorts show rates of angiographic ISR of ~10% with new generation DES. The advent of high-resolution intracoronary imaging has shown that in many cases of late stent failure neoatherosclerotic change within the stented segment represents a final common pathway for both thrombotic and restenotic events. In future, a better understanding of the pathogenesis of this process may translate into improved late outcomes. Moreover, the predominance of non-stent-related disease as a cause of subsequent myocardial infarction during follow-up highlights the importance of lifestyle and pharmacological interventions targeted at modification of the underlying disease process. Finally, although recent developments focus on strategies which circumvent the need for chronically indwelling stents--such as drug-coated balloons or fully bioresorbable stents-more data are needed before the wider use of these therapies can be advocated. PMID- 26417064 TI - Red cell distribution width may not have a good prospective predictive value in patients with transcatheter aortic valve implantation. PMID- 26417065 TI - DIAGNOSIS OF ENDOCRINE DISEASE: On the need for national-, racial-, or ethnic specific standards for the assessment of bone maturation. AB - In an attempt to overcome ethnic and racial differences in skeletal maturation, the use of ethnic-specific standards has been suggested. Do we need such standards? Based on a fundamental understanding of phenotypic plasticity and an individual's ability to respond to environmental cues, the author argues that we do not need ethnic-specific standards for bone maturity. I suggest that we use a unified international standard of bone maturity for comparing the health, nutrition, and quality of life of all children, regardless of their race, nationality, and ethnicity. PMID- 26417066 TI - The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression. AB - The Hippo signaling pathway controls organ size and tumorigenesis through a kinase cascade that inactivates Yes-associated protein (YAP). Here, we show that YAP plays a central role in controlling the progression of cervical cancer. Our results suggest that YAP expression is associated with a poor prognosis for cervical cancer. TGF-alpha and amphiregulin (AREG), via EGFR, inhibit the Hippo signaling pathway and activate YAP to induce cervical cancer cell proliferation and migration. Activated YAP allows for up-regulation of TGF-alpha, AREG, and EGFR, forming a positive signaling loop to drive cervical cancer cell proliferation. HPV E6 protein, a major etiological molecule of cervical cancer, maintains high YAP protein levels in cervical cancer cells by preventing proteasome-dependent YAP degradation to drive cervical cancer cell proliferation. Results from human cervical cancer genomic databases and an accepted transgenic mouse model strongly support the clinical relevance of the discovered feed forward signaling loop. Our study indicates that combined targeting of the Hippo and the ERBB signaling pathways represents a novel therapeutic strategy for prevention and treatment of cervical cancer. PMID- 26417068 TI - Endothelial miR-17~92 cluster negatively regulates arteriogenesis via miRNA-19 repression of WNT signaling. AB - The contribution of endothelial-derived miR-17~92 to ischemia-induced arteriogenesis has not been investigated in an in vivo model. In the present study, we demonstrate a critical role for the endothelial-derived miR-17~92 cluster in shaping physiological and ischemia-triggered arteriogenesis. Endothelial-specific deletion of miR-17~92 results in an increase in collateral density limbs and hearts and in ischemic limbs compared with control mice, and consequently improves blood flow recovery. Individual cluster components positively or negatively regulate endothelial cell (EC) functions in vitro, and, remarkably, ECs lacking the cluster spontaneously form cords in a manner rescued by miR-17a, -18a, and -19a. Using both in vitro and in vivo analyses, we identified FZD4 and LRP6 as targets of miR-19a/b. Both of these targets were up regulated in 17~92 KO ECs compared with control ECs, and both were shown to be targeted by miR-19 using luciferase assays. We demonstrate that miR-19a negatively regulates FZD4, its coreceptor LRP6, and WNT signaling, and that antagonism of miR-19a/b in aged mice improves blood flow recovery after ischemia and reduces repression of these targets. Collectively, these data provide insights into miRNA regulation of arterialization and highlight the importance of vascular WNT signaling in maintaining arterial blood flow. PMID- 26417067 TI - Defective autophagy is a key feature of cerebral cavernous malformations. AB - Cerebral cavernous malformation (CCM) is a major cerebrovascular disease affecting approximately 0.3-0.5% of the population and is characterized by enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral hemorrhages. Cerebral cavernous malformation is a genetic disease that may arise sporadically or be inherited as an autosomal dominant condition with incomplete penetrance and variable expressivity. Causative loss-of-function mutations have been identified in three genes, KRIT1 (CCM1), CCM2 (MGC4607), and PDCD10 (CCM3), which occur in both sporadic and familial forms. Autophagy is a bulk degradation process that maintains intracellular homeostasis and that plays essential quality control functions within the cell. Indeed, several studies have identified the association between dysregulated autophagy and different human diseases. Here, we show that the ablation of the KRIT1 gene strongly suppresses autophagy, leading to the aberrant accumulation of the autophagy adaptor p62/SQSTM1, defective quality control systems, and increased intracellular stress. KRIT1 loss-of-function activates the mTOR-ULK1 pathway, which is a master regulator of autophagy, and treatment with mTOR inhibitors rescues some of the mole-cular and cellular phenotypes associated with CCM. Insufficient autophagy is also evident in CCM2-silenced human endothelial cells and in both cells and tissues from an endothelial-specific CCM3 knockout mouse model, as well as in human CCM lesions. Furthermore, defective autophagy is highly correlated to endothelial-to-mesenchymal transition, a crucial event that contributes to CCM progression. Taken together, our data point to a key role for defective autophagy in CCM disease pathogenesis, thus providing a novel framework for the development of new pharmacological strategies to prevent or reverse adverse clinical outcomes of CCM lesions. PMID- 26417070 TI - Glacial reduction and millennial-scale variations in Drake Passage throughflow. AB - The Drake Passage (DP) is the major geographic constriction for the Antarctic Circumpolar Current (ACC) and exerts a strong control on the exchange of physical, chemical, and biological properties between the Atlantic, Pacific, and Indian Ocean basins. Resolving changes in the flow of circumpolar water masses through this gateway is, therefore, crucial for advancing our understanding of the Southern Ocean's role in global ocean and climate variability. Here, we reconstruct changes in DP throughflow dynamics over the past 65,000 y based on grain size and geochemical properties of sediment records from the southernmost continental margin of South America. Combined with published sediment records from the Scotia Sea, we argue for a considerable total reduction of DP transport and reveal an up to ~ 40% decrease in flow speed along the northernmost ACC pathway entering the DP during glacial times. Superimposed on this long-term decrease are high-amplitude, millennial-scale variations, which parallel Southern Ocean and Antarctic temperature patterns. The glacial intervals of strong weakening of the ACC entering the DP imply an enhanced export of northern ACC surface and intermediate waters into the South Pacific Gyre and reduced Pacific Atlantic exchange through the DP ("cold water route"). We conclude that changes in DP throughflow play a critical role for the global meridional overturning circulation and interbasin exchange in the Southern Ocean, most likely regulated by variations in the westerly wind field and changes in Antarctic sea ice extent. PMID- 26417069 TI - A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease with no effective treatment. DMD muscle pathogenesis is characterized by chronic inflammation, oxidative stress, and fibrosis. Statins, cholesterol-lowering drugs, inhibit these deleterious processes in ischemic diseases affecting skeletal muscle, and therefore have potential to improve DMD. However, statins have not been considered for DMD, or other muscular dystrophies, principally because skeletal-muscle-related symptoms are rare, but widely publicized, side effects of these drugs. Here we show positive effects of statins in dystrophic skeletal muscle. Simvastatin dramatically reduced damage and enhanced muscle function in dystrophic (mdx) mice. Long-term simvastatin treatment vastly improved overall muscle health in mdx mice, reducing plasma creatine kinase activity, an established measure of muscle damage, to near-normal levels. This reduction was accompanied by reduced inflammation, more oxidative muscle fibers, and improved strength of the weak diaphragm muscle. Shorter-term treatment protected against muscle fatigue and increased mdx hindlimb muscle force by 40%, a value comparable to current dystrophin gene-based therapies. Increased force correlated with reduced NADPH Oxidase 2 protein expression, the major source of oxidative stress in dystrophic muscle. Finally, in old mdx mice with severe muscle degeneration, simvastatin enhanced diaphragm force and halved fibrosis, a major cause of functional decline in DMD. These improvements were accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress. Together, our findings highlight that simvastatin substantially improves the overall health and function of dystrophic skeletal muscles and may provide an unexpected, novel therapy for DMD and related neuromuscular diseases. PMID- 26417071 TI - Mechanisms of cyclic AMP/protein kinase A- and glucocorticoid-mediated apoptosis using S49 lymphoma cells as a model system. AB - Cyclic AMP/protein kinase A (cAMP/PKA) and glucocorticoids promote the death of many cell types, including cells of hematopoietic origin. In wild-type (WT) S49 T lymphoma cells, signaling by cAMP and glucocorticoids converges on the induction of the proapoptotic B-cell lymphoma-family protein Bim to produce mitochondria dependent apoptosis. Kin(-), a clonal variant of WT S49 cells, lacks PKA catalytic (PKA-Calpha) activity and is resistant to cAMP-mediated apoptosis. Using sorbitol density gradient fractionation, we show here that in kin(-) S49 cells PKA-Calpha is not only depleted but the residual PKA-Calpha mislocalizes to heavier cell fractions and is not phosphorylated at two conserved residues (Ser(338) or Thr(197)). In WT S49 cells, PKA-regulatory subunit I (RI) and Bim coimmunoprecipitate upon treatment with cAMP analogs and forskolin (which increases endogenous cAMP concentrations). By contrast, in kin(-) cells, expression of PKA-RIalpha and Bim is prominently decreased, and increases in cAMP do not increase Bim expression. Even so, kin(-) cells undergo apoptosis in response to treatment with the glucocorticoid dexamethasone (Dex). In WT cells, glucorticoid-mediated apoptosis involves an increase in Bim, but in kin(-) cells, Dex-promoted cell death appears to occur by a caspase 3-independent apoptosis inducing factor pathway. Thus, although cAMP/PKA-Calpha and PKA-R1alpha/Bim mediate apoptotic cell death in WT S49 cells, kin(-) cells resist this response because of lower levels of PKA-Calpha and PKA-RIalpha subunits as well as Bim. The findings for Dex-promoted apoptosis imply that these lymphoma cells have adapted to selective pressure that promotes cell death by altering canonical signaling pathways. PMID- 26417072 TI - Mechanisms of leiomodin 2-mediated regulation of actin filament in muscle cells. AB - Leiomodin (Lmod) is a class of potent tandem-G-actin-binding nucleators in muscle cells. Lmod mutations, deletion, or instability are linked to lethal nemaline myopathy. However, the lack of high-resolution structures of Lmod nucleators in action severely hampered our understanding of their essential cellular functions. Here we report the crystal structure of the actin-Lmod2162-495 nucleus. The structure contains two actin subunits connected by one Lmod2162-495 molecule in a non-filament-like conformation. Complementary functional studies suggest that the binding of Lmod2 stimulates ATP hydrolysis and accelerates actin nucleation and polymerization. The high level of conservation among Lmod proteins in sequence and functions suggests that the mechanistic insights of human Lmod2 uncovered here may aid in a molecular understanding of other Lmod proteins. Furthermore, our structural and mechanistic studies unraveled a previously unrecognized level of regulation in mammalian signal transduction mediated by certain tandem-G-actin binding nucleators. PMID- 26417073 TI - Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness. AB - Single cardiomyocytes contain myofibrils that harbor the sarcomere-based contractile machinery of the myocardium. Cardiomyocytes differentiated from human pluripotent stem cells (hPSC-CMs) have potential as an in vitro model of heart activity. However, their fetal-like misalignment of myofibrils limits their usefulness for modeling contractile activity. We analyzed the effects of cell shape and substrate stiffness on the shortening and movement of labeled sarcomeres and the translation of sarcomere activity to mechanical output (contractility) in live engineered hPSC-CMs. Single hPSC-CMs were cultured on polyacrylamide substrates of physiological stiffness (10 kPa), and Matrigel micropatterns were used to generate physiological shapes (2,000-um(2) rectangles with length:width aspect ratios of 5:1-7:1) and a mature alignment of myofibrils. Translation of sarcomere shortening to mechanical output was highest in 7:1 hPSC CMs. Increased substrate stiffness and applied overstretch induced myofibril defects in 7:1 hPSC-CMs and decreased mechanical output. Inhibitors of nonmuscle myosin activity repressed the assembly of myofibrils, showing that subcellular tension drives the improved contractile activity in these engineered hPSC-CMs. Other factors associated with improved contractility were axially directed calcium flow, systematic mitochondrial distribution, more mature electrophysiology, and evidence of transverse-tubule formation. These findings support the potential of these engineered hPSC-CMs as powerful models for studying myocardial contractility at the cellular level. PMID- 26417074 TI - Ecosystem carbon stocks and sequestration potential of federal lands across the conterminous United States. AB - Federal lands across the conterminous United States (CONUS) account for 23.5% of the CONUS terrestrial area but have received no systematic studies on their ecosystem carbon (C) dynamics and contribution to the national C budgets. The methodology for US Congress-mandated national biological C sequestration potential assessment was used to evaluate ecosystem C dynamics in CONUS federal lands at present and in the future under three Intergovernmental Panel on Climate Change Special Report on Emission Scenarios (IPCC SRES) A1B, A2, and B1. The total ecosystem C stock was estimated as 11,613 Tg C in 2005 and projected to be 13,965 Tg C in 2050, an average increase of 19.4% from the baseline. The projected annual C sequestration rate (in kilograms of carbon per hectare per year) from 2006 to 2050 would be sinks of 620 and 228 for forests and grasslands, respectively, and C sources of 13 for shrublands. The federal lands' contribution to the national ecosystem C budget could decrease from 23.3% in 2005 to 20.8% in 2050. The C sequestration potential in the future depends not only on the footprint of individual ecosystems but also on each federal agency's land use and management. The results presented here update our current knowledge about the baseline ecosystem C stock and sequestration potential of federal lands, which would be useful for federal agencies to decide management practices to achieve the national greenhouse gas (GHG) mitigation goal. PMID- 26417075 TI - Topology-defined units in numerosity perception. AB - What is a number? The number sense hypothesis suggests that numerosity is "a primary visual property" like color, contrast, or orientation. However, exactly what attribute of a stimulus is the primary visual property and determines numbers in the number sense? To verify the invariant nature of numerosity perception, we manipulated the numbers of items connected/enclosed in arbitrary and irregular forms while controlling for low-level features (e.g., orientation, color, and size). Subjects performed discrimination, estimation, and equality judgment tasks in a wide range of presentation durations and across small and large numbers. Results consistently show that connecting/enclosing items led to robust numerosity underestimation, with the extent of underestimation increasing monotonically with the number of connected/enclosed items. In contrast, grouping based on color similarity had no effect on numerosity judgment. We propose that numbers or the primitive units counted in numerosity perception are influenced by topological invariants, such as connectivity and the inside/outside relationship. Beyond the behavioral measures, neural tuning curves to numerosity in the intraparietal sulcus were obtained using functional MRI adaptation, and the tuning curves showed that numbers represented in the intraparietal sulcus were strongly influenced by topology. PMID- 26417076 TI - Asymmetric nanotopography biases cytoskeletal dynamics and promotes unidirectional cell guidance. AB - Many biological and physiological processes depend upon directed migration of cells, which is typically mediated by chemical or physical gradients or by signal relay. Here we show that cells can be guided in a single preferred direction based solely on local asymmetries in nano/microtopography on subcellular scales. These asymmetries can be repeated, and thereby provide directional guidance, over arbitrarily large areas. The direction and strength of the guidance is sensitive to the details of the nano/microtopography, suggesting that this phenomenon plays a context-dependent role in vivo. We demonstrate that appropriate asymmetric nano/microtopography can unidirectionally bias internal actin polymerization waves and that cells move with the same preferred direction as these waves. This phenomenon is observed both for the pseudopod-dominated migration of the amoeboid Dictyostelium discoideum and for the lamellipod-driven migration of human neutrophils. The conservation of this mechanism across cell types and the asymmetric shape of many natural scaffolds suggest that actin-wave-based guidance is important in biology and physiology. PMID- 26417077 TI - Mathematical framework for activity-based cancer biomarkers. AB - Advances in nanomedicine are providing sophisticated functions to precisely control the behavior of nanoscale drugs and diagnostics. Strategies that coopt protease activity as molecular triggers are increasingly important in nanoparticle design, yet the pharmacokinetics of these systems are challenging to understand without a quantitative framework to reveal nonintuitive associations. We describe a multicompartment mathematical model to predict strategies for ultrasensitive detection of cancer using synthetic biomarkers, a class of activity-based probes that amplify cancer-derived signals into urine as a noninvasive diagnostic. Using a model formulation made of a PEG core conjugated with protease-cleavable peptides, we explore a vast design space and identify guidelines for increasing sensitivity that depend on critical parameters such as enzyme kinetics, dosage, and probe stability. According to this model, synthetic biomarkers that circulate in stealth but then activate at sites of disease have the theoretical capacity to discriminate tumors as small as 5 mm in diameter-a threshold sensitivity that is otherwise challenging for medical imaging and blood biomarkers to achieve. This model may be adapted to describe the behavior of additional activity-based approaches to allow cross-platform comparisons, and to predict allometric scaling across species. PMID- 26417078 TI - Modeling the effect of locus coeruleus firing on cortical state dynamics and single-trial sensory processing. AB - Neuronal responses to sensory stimuli are not only driven by feedforward sensory pathways but also depend upon intrinsic factors (collectively known as the network state) that include ongoing spontaneous activity and neuromodulation. To understand how these factors together regulate cortical dynamics, we recorded simultaneously spontaneous and somatosensory-evoked multiunit activity from primary somatosensory cortex and from the locus coeruleus (LC) (the neuromodulatory nucleus releasing norepinephrine) in urethane-anesthetized rats. We found that bursts of ipsilateral-LC firing preceded by few tens of milliseconds increases of cortical excitability, and that the 1- to 10-Hz rhythmicity of LC discharge appeared to increase the power of delta-band (1-4 Hz) cortical synchronization. To investigate quantitatively how LC firing might causally influence spontaneous and stimulus-driven cortical dynamics, we then constructed and fitted to these data a model describing the dynamical interaction of stimulus drive, ongoing synchronized cortical activity, and noradrenergic neuromodulation. The model proposes a coupling between LC and cortex that can amplify delta-range cortical fluctuations, and shows how suitably timed phasic LC bursts can lead to enhanced cortical responses to weaker stimuli and increased temporal precision of cortical stimulus-evoked responses. Thus, the temporal structure of noradrenergic modulation may selectively and dynamically enhance or attenuate cortical responses to stimuli. Finally, using the model prediction of single-trial cortical stimulus-evoked responses to discount single-trial state dependent variability increased by ~70% the sensory information extracted from cortical responses. This suggests that downstream circuits may extract information more effectively after estimating the state of the circuit transmitting the sensory message. PMID- 26417079 TI - Mesoscopic quantum emitters from deterministic aggregates of conjugated polymers. AB - An appealing definition of the term "molecule" arises from consideration of the nature of fluorescence, with discrete molecular entities emitting a stream of single photons. We address the question of how large a molecular object may become by growing deterministic aggregates from single conjugated polymer chains. Even particles containing dozens of individual chains still behave as single quantum emitters due to efficient excitation energy transfer, whereas the brightness is raised due to the increased absorption cross-section of the suprastructure. Excitation energy can delocalize between individual polymer chromophores in these aggregates by both coherent and incoherent coupling, which are differentiated by their distinct spectroscopic fingerprints. Coherent coupling is identified by a 10-fold increase in excited-state lifetime and a corresponding spectral red shift. Exciton quenching due to incoherent FRET becomes more significant as aggregate size increases, resulting in single aggregate emission characterized by strong blinking. This mesoscale approach allows us to identify intermolecular interactions which do not exist in isolated chains and are inaccessible in bulk films where they are present but masked by disorder. PMID- 26417080 TI - Orbital pacing of carbon fluxes by a ~9-My eccentricity cycle during the Mesozoic. AB - Eccentricity, obliquity, and precession are cyclic parameters of the Earth's orbit whose climatic implications have been widely demonstrated on recent and short time intervals. Amplitude modulations of these parameters on million-year time scales induce "grand orbital cycles," but the behavior and the paleoenvironmental consequences of these cycles remain debated for the Mesozoic owing to the chaotic diffusion of the solar system in the past. Here, we test for these cycles from the Jurassic to the Early Cretaceous by analyzing new stable isotope datasets reflecting fluctuations in the carbon cycle and seawater temperatures. Our results document a prominent cyclicity of ~9 My in the carbon cycle paced by changes in the seasonal dynamics of hydrological processes and long-term sea level fluctuations. These paleoenvironmental changes are linked to a great eccentricity cycle consistent with astronomical solutions. The orbital forcing signal was mainly amplified by cumulative sequestration of organic matter in the boreal wetlands under greenhouse conditions. Finally, we show that the ~9 My cycle faded during the Pliensbachian, which could either reflect major paleoenvironmental disturbances or a chaotic transition affecting this cycle. PMID- 26417081 TI - Glycan modulation and sulfoengineering of anti-HIV-1 monoclonal antibody PG9 in plants. AB - Broadly neutralizing anti-HIV-1 monoclonal antibodies, such as PG9, and its derivative RSH hold great promise in AIDS therapy and prevention. An important feature related to the exceptional efficacy of PG9 and RSH is the presence of sulfated tyrosine residues in their antigen-binding regions. To maximize antibody functionalities, we have now produced glycan-optimized, fucose-free versions of PG9 and RSH in Nicotiana benthamiana. Both antibodies were efficiently sulfated in planta on coexpression of an engineered human tyrosylprotein sulfotransferase, resulting in antigen-binding and virus neutralization activities equivalent to PG9 synthesized by mammalian cells ((CHO)PG9). Based on the controlled production of both sulfated and nonsulfated variants in plants, we could unequivocally prove that tyrosine sulfation is critical for the potency of PG9 and RSH. Moreover, the fucose-free antibodies generated in N. benthamiana are capable of inducing antibody-dependent cellular cytotoxicity, an activity not observed for (CHO)PG9. Thus, tailoring of the antigen-binding site combined with glycan modulation and sulfoengineering yielded plant-produced anti-HIV-1 antibodies with effector functions superior to PG9 made in CHO cells. PMID- 26417082 TI - Intermittent collective dynamics emerge from conflicting imperatives in sheep herds. AB - Among the many fascinating examples of collective behavior exhibited by animal groups, some species are known to alternate slow group dispersion in space with rapid aggregation phenomena induced by a sudden behavioral shift at the individual level. We study this phenomenon quantitatively in large groups of grazing Merino sheep under controlled experimental conditions. Our analysis reveals strongly intermittent collective dynamics consisting of fast, avalanche like regrouping events distributed on all experimentally accessible scales. As a proof of principle, we introduce an agent-based model with individual behavioral shifts, which we show to account faithfully for all collective properties observed. This offers, in turn, an insight on the individual stimulus/response functions that can generate such intermittent behavior. In particular, the intensity of sheep allelomimetic behavior plays a key role in the group's ability to increase the per capita grazing surface while minimizing the time needed to regroup into a tightly packed configuration. We conclude that the emergent behavior reported probably arises from the necessity to balance two conflicting imperatives: (i) the exploration of foraging space by individuals and (ii) the protection from predators offered by being part of large, cohesive groups. We discuss our results in the context of the current debate about criticality in biology. PMID- 26417084 TI - TMEM16F is required for phosphatidylserine exposure and microparticle release in activated mouse platelets. AB - Phosphatidylserine (PtdSer) exposure on the surface of activated platelets requires the action of a phospholipid scramblase(s), and serves as a scaffold for the assembly of the tenase and prothrombinase complexes involved in blood coagulation. Here, we found that the activation of mouse platelets with thrombin/collagen or Ca(2+) ionophore at 20 degrees C induces PtdSer exposure without compromising plasma membrane integrity. Among five transmembrane protein 16 (TMEM16) members that support Ca(2+)-dependent phospholipid scrambling, TMEM16F was the only one that showed high expression in mouse platelets. Platelets from platelet-specific TMEM16F-deficient mice exhibited defects in activation-induced PtdSer exposure and microparticle shedding, although alpha granule and dense granule release remained intact. The rate of tissue factor induced thrombin generation by TMEM16F-deficient platelets was severely reduced, whereas thrombin-induced clot retraction was unaffected. The imaging of laser induced thrombus formation in whole animals showed that PtdSer exposure on aggregated platelets was TMEM16F-dependent in vivo. The phenotypes of the platelet-specific TMEM16F-null mice resemble those of patients with Scott syndrome, a mild bleeding disorder, indicating that these mice may provide a useful model for human Scott syndrome. PMID- 26417083 TI - Administration of thimerosal-containing vaccines to infant rhesus macaques does not result in autism-like behavior or neuropathology. AB - Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Some anecdotal reports suggest that ASD is related to exposure to ethyl mercury, in the form of the vaccine preservative, thimerosal, and/or receiving the measles, mumps, rubella (MMR) vaccine. Using infant rhesus macaques receiving thimerosal containing vaccines (TCVs) following the recommended pediatric vaccine schedules from the 1990s and 2008, we examined behavior, and neuropathology in three brain regions found to exhibit neuropathology in postmortem ASD brains. No neuronal cellular or protein changes in the cerebellum, hippocampus, or amygdala were observed in animals following the 1990s or 2008 vaccine schedules. Analysis of social behavior in juvenile animals indicated that there were no significant differences in negative behaviors between animals in the control and experimental groups. These data indicate that administration of TCVs and/or the MMR vaccine to rhesus macaques does not result in neuropathological abnormalities, or aberrant behaviors, like those observed in ASD. PMID- 26417086 TI - Genetic specificity of face recognition. AB - Specific cognitive abilities in diverse domains are typically found to be highly heritable and substantially correlated with general cognitive ability (g), both phenotypically and genetically. Recent twin studies have found the ability to memorize and recognize faces to be an exception, being similarly heritable but phenotypically substantially uncorrelated both with g and with general object recognition. However, the genetic relationships between face recognition and other abilities (the extent to which they share a common genetic etiology) cannot be determined from phenotypic associations. In this, to our knowledge, first study of the genetic associations between face recognition and other domains, 2,000 18- and 19-year-old United Kingdom twins completed tests assessing their face recognition, object recognition, and general cognitive abilities. Results confirmed the substantial heritability of face recognition (61%), and multivariate genetic analyses found that most of this genetic influence is unique and not shared with other cognitive abilities. PMID- 26417085 TI - Noninvasive brain cancer imaging with a bispecific antibody fragment, generated via click chemistry. AB - Early diagnosis remains a task of upmost importance for reducing cancer morbidity and mortality. Successful development of highly specific companion diagnostics targeting aberrant molecular pathways of cancer is needed for sensitive detection, accurate diagnosis, and opportune therapeutic intervention. Herein, we generated a bispecific immunoconjugate [denoted as Bs-F(ab)2] by linking two antibody Fab fragments, an anti-epidermal growth factor receptor (EGFR) Fab and an anti-CD105 Fab, via bioorthogonal "click" ligation of trans-cyclooctene and tetrazine. PET imaging of mice bearing U87MG (EGFR/CD105(+/+)) tumors with (64)Cu labeled Bs-F(ab)2 revealed a significantly enhanced tumor uptake [42.9 +/- 9.5 percentage injected dose per gram (%ID/g); n = 4] and tumor-to-background ratio (tumor/muscle ratio of 120.2 +/- 44.4 at 36 h postinjection; n = 4) compared with each monospecific Fab tracer. Thus, we demonstrated that dual targeting of EGFR and CD105 provides a synergistic improvement on both affinity and specificity of (64)Cu-NOTA-Bs-F(ab)2. (64)Cu-NOTA-Bs-F(ab)2 was able to visualize small U87MG tumor nodules (<5 mm in diameter), owing to high tumor uptake (31.4 +/- 10.8%ID/g at 36 h postinjection) and a tumor/muscle ratio of 76.4 +/- 52.3, which provided excellent sensitivity for early detection. Finally, we successfully confirmed the feasibility of a ZW800-1-labeled Bs-F(ab)2 for near-infrared fluorescence imaging and image-guided surgical resection of U87MG tumors. More importantly, our rationale can be used in the construction of other disease-targeting bispecific antibody fragments for early detection and diagnosis of small malignant lesions. PMID- 26417087 TI - NhaA antiporter functions using 10 helices, and an additional 2 contribute to assembly/stability. AB - The Escherichia coli Na(+)/H(+) antiporter (Ec-NhaA) is the best-characterized of all pH-regulated Na(+)/H(+) exchangers that control cellular Na(+) and H(+) homeostasis. Ec-NhaA has 12 helices, 2 of which (VI and VII) are absent from other antiporters that share the Ec-NhaA structural fold. This alpha-hairpin is located in the dimer interface of the Ec-NhaA homodimer together with a beta sheet. Here we examine computationally and experimentally the role of the alpha hairpin in the stability, dimerization, transport, and pH regulation of Ec-NhaA. Evolutionary analysis (ConSurf) indicates that the VI-VII helical hairpin is much less conserved than the remaining transmembrane region. Moreover, normal mode analysis also shows that intact NhaA and a variant, deleted of the alpha-hairpin, share similar dynamics, suggesting that the structure may be dispensable. Thus, two truncated Ec-NhaA mutants were constructed, one deleted of the alpha-hairpin and another also lacking the beta-sheet. The mutants were studied at physiological pH in the membrane and in detergent micelles. The findings demonstrate that the truncated mutants retain significant activity and regulatory properties but are defective in the assembly/stability of the Ec-NhaA dimer. PMID- 26417089 TI - Extent of hippocampal atrophy predicts degree of deficit in recall. AB - Which specific memory functions are dependent on the hippocampus is still debated. The availability of a large cohort of patients who had sustained relatively selective hippocampal damage early in life enabled us to determine which type of mnemonic deficit showed a correlation with extent of hippocampal injury. We assessed our patient cohort on a test that provides measures of recognition and recall that are equated for difficulty and found that the patients' performance on the recall tests correlated significantly with their hippocampal volumes, whereas their performance on the equally difficult recognition tests did not and, indeed, was largely unaffected regardless of extent of hippocampal atrophy. The results provide new evidence in favor of the view that the hippocampus is essential for recall but not for recognition. PMID- 26417088 TI - Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth. AB - Mothers with obesity or gestational diabetes mellitus have low circulating levels of adiponectin (ADN) and frequently deliver large babies with increased fat mass, who are susceptible to perinatal complications and to development of metabolic syndrome later in life. It is currently unknown if the inverse correlation between maternal ADN and fetal growth reflects a cause-and-effect relationship. We tested the hypothesis that ADN supplementation in obese pregnant dams improves maternal insulin sensitivity, restores normal placental insulin/mechanistic target of rapamycin complex 1 (mTORC1) signaling and nutrient transport, and prevents fetal overgrowth. Compared with dams on a control diet, female C57BL/6J mice fed an obesogenic diet before mating and throughout gestation had increased fasting serum leptin, insulin, and C-peptide, and reduced high-molecular-weight ADN at embryonic day (E) 18.5. Placental insulin and mTORC1 signaling was activated, peroxisome proliferator-activated receptor-alpha (PPARalpha) phosphorylation was reduced, placental transport of glucose and amino acids in vivo was increased, and fetal weights were 29% higher in obese dams. Maternal ADN infusion in obese dams from E14.5 to E18.5 normalized maternal insulin sensitivity, placental insulin/mTORC1 and PPARalpha signaling, nutrient transport, and fetal growth without affecting maternal fat mass. Using a mouse model with striking similarities to obese pregnant women, we demonstrate that ADN functions as an endocrine link between maternal adipose tissue and fetal growth by regulating placental function. Importantly, maternal ADN supplementation reversed the adverse effects of maternal obesity on placental function and fetal growth. Improving maternal ADN levels may serve as an effective intervention strategy to prevent fetal overgrowth caused by maternal obesity. PMID- 26417091 TI - Dark matter universe. AB - Most of the mass in the universe is in the form of dark matter--a new type of nonbaryonic particle not yet detected in the laboratory or in other detection experiments. The evidence for the existence of dark matter through its gravitational impact is clear in astronomical observations--from the early observations of the large motions of galaxies in clusters and the motions of stars and gas in galaxies, to observations of the large-scale structure in the universe, gravitational lensing, and the cosmic microwave background. The extensive data consistently show the dominance of dark matter and quantify its amount and distribution, assuming general relativity is valid. The data inform us that the dark matter is nonbaryonic, is "cold" (i.e., moves nonrelativistically in the early universe), and interacts only weakly with matter other than by gravity. The current Lambda cold dark matter cosmology--a simple (but strange) flat cold dark matter model dominated by a cosmological constant Lambda, with only six basic parameters (including the density of matter and of baryons, the initial mass fluctuations amplitude and its scale dependence, and the age of the universe and of the first stars)--fits remarkably well all the accumulated data. However, what is the dark matter? This is one of the most fundamental open questions in cosmology and particle physics. Its existence requires an extension of our current understanding of particle physics or otherwise point to a modification of gravity on cosmological scales. The exploration and ultimate detection of dark matter are led by experiments for direct and indirect detection of this yet mysterious particle. PMID- 26417090 TI - No barrier to emergence of bathyal king crabs on the Antarctic shelf. AB - Cold-water conditions have excluded durophagous (skeleton-breaking) predators from the Antarctic seafloor for millions of years. Rapidly warming seas off the western Antarctic Peninsula could now facilitate their return to the continental shelf, with profound consequences for the endemic fauna. Among the likely first arrivals are king crabs (Lithodidae), which were discovered recently on the adjacent continental slope. During the austral summer of 2010 - 2011, we used underwater imagery to survey a slope-dwelling population of the lithodid Paralomis birsteini off Marguerite Bay, western Antarctic Peninsula for environmental or trophic impediments to shoreward expansion. The population density averaged ~ 4.5 individuals * 1,000 m(-2) within a depth range of 1,100 - 1,500 m (overall observed depth range 841-2,266 m). Images of juveniles, discarded molts, and precopulatory behavior, as well as gravid females in a trapping study, suggested a reproductively viable population on the slope. At the time of the survey, there was no thermal barrier to prevent the lithodids from expanding upward and emerging on the outer shelf (400- to 550-m depth); however, near-surface temperatures remained too cold for them to survive in inner-shelf and coastal environments (<200 m). Ambient salinity, composition of the substrate, and the depth distribution of potential predators likewise indicated no barriers to expansion of lithodids onto the outer shelf. Primary food resources for lithodids--echinoderms and mollusks--were abundant on the upper slope (550-800 m) and outer shelf. As sea temperatures continue to rise, lithodids will likely play an increasingly important role in the trophic structure of subtidal communities closer to shore. PMID- 26417092 TI - Placebo analgesia and its opioidergic regulation suggest that empathy for pain is grounded in self pain. AB - Empathy for pain activates brain areas partially overlapping with those underpinning the first-hand experience of pain. It remains unclear, however, whether such shared activations imply that pain empathy engages similar neural functions as first-hand pain experiences. To overcome the limitations of previous neuroimaging research, we pursued a conceptually novel approach: we used the phenomenon of placebo analgesia to experimentally reduce the first-hand experience of pain, and assessed whether this results in a concomitant reduction of empathy for pain. We first carried out a functional MRI experiment (n = 102) that yielded results in the expected direction: participants experiencing placebo analgesia also reported decreased empathy for pain, and this was associated with reduced engagement of anterior insular and midcingulate cortex: that is, areas previously associated with shared activations in pain and empathy for pain. In a second step, we used a psychopharmacological manipulation (n = 50) to determine whether these effects can be blocked via an opioid antagonist. The administration of the opioid antagonist naltrexone blocked placebo analgesia and also resulted in a corresponding "normalization" of empathy for pain. Taken together, these findings suggest that pain empathy may be associated with neural responses and neurotransmitter activity engaged during first-hand pain, and thus might indeed be grounded in our own pain experiences. PMID- 26417093 TI - Motifs of VDAC2 required for mitochondrial Bak import and tBid-induced apoptosis. AB - Voltage-dependent anion channel (VDAC) proteins are major components of the outer mitochondrial membrane. VDAC has three isoforms with >70% sequence similarity and redundant roles in metabolite and ion transport. However, only Vdac2(-/-) (V2(-/ )) mice are embryonic lethal, indicating a unique and fundamental function of VDAC2 (V2). Recently, a specific V2 requirement was demonstrated for mitochondrial Bak import and truncated Bid (tBid)-induced apoptosis. To determine the relevant domain(s) of V2 involved, VDAC1 (V1) and V2 chimeric constructs were created and used to rescue V2(-/-) fibroblasts. Surprisingly, the commonly cited V2-specific N-terminal extension and cysteines were found to be dispensable for Bak import and high tBid sensitivity. In gain-of-function studies, V2 (123-179) was the minimal sequence sufficient to render V1 competent to support Bak insertion. Furthermore, in loss-of-function experiments, T168 and D170 were identified as critical residues. These motifs are conserved in zebrafish V2 (zfV2) that also rescued V2-deficient fibroblasts. Because high-resolution structures of zfV2 and mammalian V1 have become available, we could superimpose these structures and recognized that the critical V2-specific residues help to create a distinctive open "pocket" on the cytoplasmic surface that could facilitate Bak recruitment. PMID- 26417094 TI - Chemical, experimental, and morphological evidence for diagenetically altered melanin in exceptionally preserved fossils. AB - In living organisms, color patterns, behavior, and ecology are closely linked. Thus, detection of fossil pigments may permit inferences about important aspects of ancient animal ecology and evolution. Melanin-bearing melanosomes were suggested to preserve as organic residues in exceptionally preserved fossils, retaining distinct morphology that is associated with aspects of original color patterns. Nevertheless, these oblong and spherical structures have also been identified as fossilized bacteria. To date, chemical studies have not directly considered the effects of diagenesis on melanin preservation, and how this may influence its identification. Here we use time-of-flight secondary ion mass spectrometry to identify and chemically characterize melanin in a diverse sample of previously unstudied extant and fossil taxa, including fossils with notably different diagenetic histories and geologic ages. We document signatures consistent with melanin preservation in fossils ranging from feathers, to mammals, to amphibians. Using principal component analyses, we characterize putative mixtures of eumelanin and phaeomelanin in both fossil and extant samples. Surprisingly, both extant and fossil amphibians generally exhibit melanosomes with a mixed eumelanin/phaeomelanin composition rather than pure eumelanin, as assumed previously. We argue that experimental maturation of modern melanin samples replicates diagenetic chemical alteration of melanin observed in fossils. This refutes the hypothesis that such fossil microbodies could be bacteria, and demonstrates that melanin is widely responsible for the organic soft tissue outlines in vertebrates found at exceptional fossil localities, thus allowing for the reconstruction of certain aspects of original pigment patterns. PMID- 26417095 TI - Enhanced precipitation variability decreases grass- and increases shrub productivity. AB - Although projections of precipitation change indicate increases in variability, most studies of impacts of climate change on ecosystems focused on effects of changes in amount of precipitation, overlooking precipitation variability effects, especially at the interannual scale. Here, we present results from a 6-y field experiment, where we applied sequences of wet and dry years, increasing interannual precipitation coefficient of variation while maintaining a precipitation amount constant. Increased precipitation variability significantly reduced ecosystem primary production. Dominant plant-functional types showed opposite responses: perennial-grass productivity decreased by 81%, whereas shrub productivity increased by 67%. This pattern was explained by different nonlinear responses to precipitation. Grass productivity presented a saturating response to precipitation where dry years had a larger negative effect than the positive effects of wet years. In contrast, shrubs showed an increasing response to precipitation that resulted in an increase in average productivity with increasing precipitation variability. In addition, the effects of precipitation variation increased through time. We argue that the differential responses of grasses and shrubs to precipitation variability and the amplification of this phenomenon through time result from contrasting root distributions of grasses and shrubs and competitive interactions among plant types, confirmed by structural equation analysis. Under drought conditions, grasses reduce their abundance and their ability to absorb water that then is transferred to deep soil layers that are exclusively explored by shrubs. Our work addresses an understudied dimension of climate change that might lead to widespread shrub encroachment reducing the provisioning of ecosystem services to society. PMID- 26417097 TI - Vaccines and autism in primate model. PMID- 26417096 TI - Metabotropic glutamate receptor signaling is required for NMDA receptor-dependent ocular dominance plasticity and LTD in visual cortex. AB - A feature of early postnatal neocortical development is a transient peak in signaling via metabotropic glutamate receptor 5 (mGluR5). In visual cortex, this change coincides with increased sensitivity of excitatory synapses to monocular deprivation (MD). However, loss of visual responsiveness after MD occurs via mechanisms revealed by the study of long-term depression (LTD) of synaptic transmission, which in layer 4 is induced by acute activation of NMDA receptors (NMDARs) rather than mGluR5. Here we report that chronic postnatal down regulation of mGluR5 signaling produces coordinated impairments in both NMDAR dependent LTD in vitro and ocular dominance plasticity in vivo. The data suggest that ongoing mGluR5 signaling during a critical period of postnatal development establishes the biochemical conditions that are permissive for activity-dependent sculpting of excitatory synapses via the mechanism of NMDAR-dependent LTD. PMID- 26417099 TI - Naturalization fosters the long-term political integration of immigrants. AB - Does naturalization cause better political integration of immigrants into the host society? Despite heated debates about citizenship policy, there exists almost no evidence that isolates the independent effect of naturalization from the nonrandom selection into naturalization. We provide new evidence from a natural experiment in Switzerland, where some municipalities used referendums as the mechanism to decide naturalization requests. Balance checks suggest that for close naturalization referendums, which are decided by just a few votes, the naturalization decision is as good as random, so that narrowly rejected and narrowly approved immigrant applicants are similar on all confounding characteristics. This allows us to remove selection effects and obtain unbiased estimates of the long-term impacts of citizenship. Our study shows that for the immigrants who faced close referendums, naturalization considerably improved their political integration, including increases in formal political participation, political knowledge, and political efficacy. PMID- 26417098 TI - Global biogeography of human infectious diseases. AB - The distributions of most infectious agents causing disease in humans are poorly resolved or unknown. However, poorly known and unknown agents contribute to the global burden of disease and will underlie many future disease risks. Existing patterns of infectious disease co-occurrence could thus play a critical role in resolving or anticipating current and future disease threats. We analyzed the global occurrence patterns of 187 human infectious diseases across 225 countries and seven epidemiological classes (human-specific, zoonotic, vector-borne, non vector-borne, bacterial, viral, and parasitic) to show that human infectious diseases exhibit distinct spatial grouping patterns at a global scale. We demonstrate, using outbreaks of Ebola virus as a test case, that this spatial structuring provides an untapped source of prior information that could be used to tighten the focus of a range of health-related research and management activities at early stages or in data-poor settings, including disease surveillance, outbreak responses, or optimizing pathogen discovery. In examining the correlates of these spatial patterns, among a range of geographic, epidemiological, environmental, and social factors, mammalian biodiversity was the strongest predictor of infectious disease co-occurrence overall and for six of the seven disease classes examined, giving rise to a striking congruence between global pathogeographic and "Wallacean" zoogeographic patterns. This clear biogeographic signal suggests that infectious disease assemblages remain fundamentally constrained in their distributions by ecological barriers to dispersal or establishment, despite the homogenizing forces of globalization. Pathogeography thus provides an overarching context in which other factors promoting infectious disease emergence and spread are set. PMID- 26417100 TI - Stress impairs cognitive flexibility in infants. AB - In human adults, learning and memory under acute stress are characterized by an increased use of rigid habitual response strategies at the cost of flexible cognitive strategies. The immediate effects of stress on cognitive functioning early in life are not well understood. Here we show experimentally that acute stress leads human infants to perform habitual behavior rigidly. We found that 15 mo-old infants exposed to stress thereafter kept performing a previously effective action, even after the action suddenly became ineffective. Infants in a no-stress control group flexibly adjusted their behavior by disengaging from the newly ineffective action in favor of exploring an alternative action. This finding demonstrates that stress impairs infants' ability to adjust their behavior to changing circumstances. PMID- 26417102 TI - Opinion: The time has come for offshore wind power in the United States. PMID- 26417101 TI - Generation of Th17 cells in response to intranasal infection requires TGF-beta1 from dendritic cells and IL-6 from CD301b+ dendritic cells. AB - Intranasal (i.n.) infections preferentially generate Th17 cells. We explored the basis for this anatomic preference by tracking polyclonal CD4(+) T cells specific for an MHC class II-bound peptide from the mucosal pathogen Streptococcus pyogenes. S. pyogenes MHC class II-bound peptide-specific CD4(+) T cells were first activated in the cervical lymph nodes following i.n. inoculation and then differentiated into Th17 cells. S. pyogenes-induced Th17 formation depended on TGF-beta1 from dendritic cells and IL-6 from a CD301b(+) dendritic cell subset located in the cervical lymph nodes but not the spleen. Thus, the tendency of i.n. infection to induce Th17 cells is related to cytokine production by specialized dendritic cells that drain this site. PMID- 26417103 TI - Evolution of moth sex pheromone composition by a single amino acid substitution in a fatty acid desaturase. AB - For sexual communication, moths primarily use blends of fatty acid derivatives containing one or more double bonds in various positions and configurations, called sex pheromones (SPs). To study the molecular basis of novel SP component (SPC) acquisition, we used the tobacco hornworm (Manduca sexta), which uses a blend of mono-, di-, and uncommon triunsaturated fatty acid (3UFA) derivatives as SP. We identified pheromone-biosynthetic fatty acid desaturases (FADs) MsexD3, MsexD5, and MsexD6 abundantly expressed in the M. sexta female pheromone gland. Their functional characterization and in vivo application of FAD substrates indicated that MsexD3 and MsexD5 biosynthesize 3UFAs via E/Z14 desaturation from diunsaturated fatty acids produced by previously characterized Z11 desaturase/conjugase MsexD2. Site-directed mutagenesis of sequentially highly similar MsexD3 and MsexD2 demonstrated that swapping of a single amino acid in the fatty acyl substrate binding tunnel introduces E/Z14-desaturase specificity to mutated MsexD2. Reconstruction of FAD gene phylogeny indicates that MsexD3 was recruited for biosynthesis of 3UFA SPCs in M. sexta lineage via gene duplication and neofunctionalization, whereas MsexD5 representing an alternative 3UFA producing FAD has been acquired via activation of a presumably inactive ancestral MsexD5. Our results demonstrate that a change as small as a single amino acid substitution in a FAD enzyme might result in the acquisition of new SP compounds. PMID- 26417104 TI - New roles for DNA cytosine modification, eRNA, anchors, and superanchors in developing B cell progenitors. AB - B-cell fate is orchestrated by a series of well-characterized developmental regulators. Here, we found that the onset of B-cell development was accompanied by large-scale changes in DNA cytosine modifications associated with promoters, enhancers, and anchors. These changes were tightly linked to alterations in transcription factor occupancy and nascent RNA (eRNA) transcription. We found that the prepro-B to the pro-B-cell transition was associated with a global exchange of DNA cytosine modifications for polycomb-mediated repression at CpG islands. Hypomethylated regions were found exclusively in the active/permissive compartment of the nucleus and were predominantly associated with regulatory elements or anchors that orchestrate the folding patterns of the genome. We identified superanchors, characterized by clusters of hypomethylated CCCTC binding factor (CTCF)-bound elements, which were predominantly located at boundaries that define topological associated domains. A particularly prominent hypomethylated superanchor was positioned down-stream of the Ig heavy chain (Igh) locus. Analysis of global formaldehyde-cross-linking studies indicated that the Igh locus superanchor interacts with the VH region repertoire across vast genomic distances. We propose that the Igh locus superanchor sequesters the VH and DHJH regions into a spatial confined geometric environment to promote rapid first passage times. Collectively, these studies demonstrate how, in developing B cells, DNA cytosine modifications associated with regulatory and architectural elements affect patterns of gene expression, folding patterns of the genome, and antigen receptor assembly. PMID- 26417107 TI - Experimental test of the viscous anisotropy hypothesis for partially molten rocks. AB - Chemical differentiation of rocky planets occurs by melt segregation away from the region of melting. The mechanics of this process, however, are complex and incompletely understood. In partially molten rocks undergoing shear deformation, melt pockets between grains align coherently in the stress field; it has been hypothesized that this anisotropy in microstructure creates an anisotropy in the viscosity of the aggregate. With the inclusion of anisotropic viscosity, continuum, two-phase-flow models reproduce the emergence and angle of melt enriched bands that form in laboratory experiments. In the same theoretical context, these models also predict sample-scale melt migration due to a gradient in shear stress. Under torsional deformation, melt is expected to segregate radially inward. Here we present torsional deformation experiments on partially molten rocks that test this prediction. Microstructural analyses of the distribution of melt and solid reveal a radial gradient in melt fraction, with more melt toward the center of the cylinder. The extent of this radial melt segregation grows with progressive strain, consistent with theory. The agreement between theoretical prediction and experimental observation provides a validation of this theory. PMID- 26417106 TI - The TWD40-2 protein and the AP2 complex cooperate in the clathrin-mediated endocytosis of cellulose synthase to regulate cellulose biosynthesis. AB - Cellulose biosynthesis is performed exclusively by plasma membrane-localized cellulose synthases (CESAs). Therefore, the trafficking of CESAs to and from the plasma membrane is an important mechanism for regulating cellulose biosynthesis. CESAs were recently identified as cargo proteins of the classic adaptor protein 2 (AP2) complex of the clathrin-mediated endocytosis (CME) pathway. The AP2 complex of the CME pathway is conserved in yeast, animals, and plants, and has been well characterized in many systems. In contrast, the recently discovered TPLATE complex (TPC), which is proposed to function as a CME adaptor complex, is only conserved in plants and a few other eukaryotes. In this study, we discovered that the TWD40-2 protein, a putative member of the TPC, is also important for the endocytosis of CESAs. Genetic analysis between TWD40-2 and AP2M of the AP2 complex revealed that the roles of TWD40-2 in CME are both distinct from and cooperative with the AP2 complex. Loss of efficient CME in twd40-2-3 resulted in the unregulated overaccumulation of CESAs at the plasma membrane. In seedlings of twd40-2-3 and other CME-deficient mutants, a direct correlation was revealed between endocytic deficiency and cellulose content deficiency, highlighting the importance of controlled CESA endocytosis in regulating cellulose biosynthesis. PMID- 26417105 TI - Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins. AB - Many microbes create and maintain pathogen-containing vacuoles (PVs) as an intracellular niche permissive for microbial growth and survival. The destruction of PVs by IFNgamma-inducible guanylate binding protein (GBP) and immunity-related GTPase (IRG) host proteins is central to a successful immune response directed against numerous PV-resident pathogens. However, the mechanism by which IRGs and GBPs cooperatively detect and destroy PVs is unclear. We find that host cell priming with IFNgamma prompts IRG-dependent association of Toxoplasma- and Chlamydia-containing vacuoles with ubiquitin through regulated translocation of the E3 ubiquitin ligase tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6). This initial ubiquitin labeling elicits p62-mediated escort and deposition of GBPs to PVs, thereby conferring cell-autonomous immunity. Hypervirulent strains of Toxoplasma gondii evade this process via specific rhoptry protein kinases that inhibit IRG function, resulting in blockage of downstream PV ubiquitination and GBP delivery. Our results define a ubiquitin centered mechanism by which host cells deliver GBPs to PVs and explain how hypervirulent parasites evade GBP-mediated immunity. PMID- 26417108 TI - A parasitic nematode releases cytokinin that controls cell division and orchestrates feeding site formation in host plants. AB - Sedentary plant-parasitic cyst nematodes are biotrophs that cause significant losses in agriculture. Parasitism is based on modifications of host root cells that lead to the formation of a hypermetabolic feeding site (a syncytium) from which nematodes withdraw nutrients. The host cell cycle is activated in an initial cell selected by the nematode for feeding, followed by activation of neighboring cells and subsequent expansion of feeding site through fusion of hundreds of cells. It is generally assumed that nematodes manipulate production and signaling of the plant hormone cytokinin to activate cell division. In fact, nematodes have been shown to produce cytokinin in vitro; however, whether the hormone is secreted into host plants and plays a role in parasitism remained unknown. Here, we analyzed the spatiotemporal activation of cytokinin signaling during interaction between the cyst nematode, Heterodera schachtii, and Arabidopsis using cytokinin-responsive promoter:reporter lines. Our results showed that cytokinin signaling is activated not only in the syncytium but also in neighboring cells to be incorporated into syncytium. An analysis of nematode infection on mutants that are deficient in cytokinin or cytokinin signaling revealed a significant decrease in susceptibility of these plants to nematodes. Further, we identified a cytokinin-synthesizing isopentenyltransferase gene in H. schachtii and show that silencing of this gene in nematodes leads to a significant decrease in virulence due to a reduced expansion of feeding sites. Our findings demonstrate the ability of a plant-parasitic nematode to synthesize a functional plant hormone to manipulate the host system and establish a long term parasitic interaction. PMID- 26417110 TI - Global transcriptional repression: An initial and essential step for Plasmodium sexual development. AB - Gametocytes are nonreplicative sexual forms that mediate malaria transmission to a mosquito vector. They are generated from asexual blood-stage parasites that proliferate in the circulation. However, little is known about how this transition is genetically regulated. Here, we report that an Apetala2 (AP2) family transcription factor, AP2-G2, regulates this transition as a transcriptional repressor. Disruption of AP2-G2 in the rodent malaria parasite Plasmodium berghei did not prevent commitment to the sexual stage but did halt development before the appearance of sex-specific morphologies. ChIP-seq analysis revealed that AP2-G2 targeted ~1,500 genes and recognized a five-base motif in their promoters. Most of these target genes are required for asexual proliferation of the parasites in the blood, suggesting that AP2-G2 blocks the program that precedes asexual replication to promote conversion to the sexual stage. Microarray analysis showed that the identified targets constituted ~70% of the up-regulated genes in AP2-G2-depleted parasites, suggesting that AP2-G2 actually functions as a repressor in gametocytes. A promoter assay using a centromere plasmid demonstrated that the binding motif functions as a cis-acting negative regulatory element. These results suggest that global transcriptional repression, which occurs during the initial phase of gametocytogenesis, is an essential step in Plasmodium sexual development. PMID- 26417109 TI - Minimal model for collective kinetochore-microtubule dynamics. AB - Chromosome segregation during cell division depends on interactions of kinetochores with dynamic microtubules (MTs). In many eukaryotes, each kinetochore binds multiple MTs, but the collective behavior of these coupled MTs is not well understood. We present a minimal model for collective kinetochore-MT dynamics, based on in vitro measurements of individual MTs and their dependence on force and kinetochore phosphorylation by Aurora B kinase. For a system of multiple MTs connected to the same kinetochore, the force-velocity relation has a bistable regime with two possible steady-state velocities: rapid shortening or slow growth. Bistability, combined with the difference between the growing and shrinking speeds, leads to center-of-mass and breathing oscillations in bioriented sister kinetochore pairs. Kinetochore phosphorylation shifts the bistable region to higher tensions, so that only the rapidly shortening state is stable at low tension. Thus, phosphorylation leads to error correction for kinetochores that are not under tension. We challenged the model with new experiments, using chemically induced dimerization to enhance Aurora B activity at metaphase kinetochores. The model suggests that the experimentally observed disordering of the metaphase plate occurs because phosphorylation increases kinetochore speeds by biasing MTs to shrink. Our minimal model qualitatively captures certain characteristic features of kinetochore dynamics, illustrates how biochemical signals such as phosphorylation may regulate the dynamics, and provides a theoretical framework for understanding other factors that control the dynamics in vivo. PMID- 26417111 TI - Increased threat of tropical cyclones and coastal flooding to New York City during the anthropogenic era. AB - In a changing climate, future inundation of the United States' Atlantic coast will depend on both storm surges during tropical cyclones and the rising relative sea levels on which those surges occur. However, the observational record of tropical cyclones in the North Atlantic basin is too short (A.D. 1851 to present) to accurately assess long-term trends in storm activity. To overcome this limitation, we use proxy sea level records, and downscale three CMIP5 models to generate large synthetic tropical cyclone data sets for the North Atlantic basin; driving climate conditions span from A.D. 850 to A.D. 2005. We compare pre anthropogenic era (A.D. 850-1800) and anthropogenic era (A.D.1970-2005) storm surge model results for New York City, exposing links between increased rates of sea level rise and storm flood heights. We find that mean flood heights increased by ~1.24 m (due mainly to sea level rise) from ~A.D. 850 to the anthropogenic era, a result that is significant at the 99% confidence level. Additionally, changes in tropical cyclone characteristics have led to increases in the extremes of the types of storms that create the largest storm surges for New York City. As a result, flood risk has greatly increased for the region; for example, the 500-y return period for a ~2.25-m flood height during the pre-anthropogenic era has decreased to ~24.4 y in the anthropogenic era. Our results indicate the impacts of climate change on coastal inundation, and call for advanced risk management strategies. PMID- 26417112 TI - Reply to Lee: Downward bias in heritability estimation is not due to simplified linkage equilibrium SNP simulation. PMID- 26417113 TI - Implications of simplified linkage equilibrium SNP simulation. PMID- 26417114 TI - A new level of regulation in gluconeogenesis: metabolic state modulates the intracellular localization of aldolase B and its interaction with liver fructose 1,6-bisphosphatase. AB - Understanding how glucose metabolism is finely regulated at molecular and cellular levels in the liver is critical for knowing its relationship to related pathologies, such as diabetes. In order to gain insight into the regulation of glucose metabolism, we studied the liver-expressed isoforms aldolase B and fructose-1,6-bisphosphatase-1 (FBPase-1), key enzymes in gluconeogenesis, analysing their cellular localization in hepatocytes under different metabolic conditions and their protein-protein interaction in vitro and in vivo. We observed that glucose, insulin, glucagon and adrenaline differentially modulate the intracellular distribution of aldolase B and FBPase-1. Interestingly, the in vitro protein-protein interaction analysis between aldolase B and FBPase-1 showed a specific and regulable interaction between them, whereas aldolase A (muscle isozyme) and FBPase-1 showed no interaction. The affinity of the aldolase B and FBPase-1 complex was modulated by intermediate metabolites, but only in the presence of K(+). We observed a decreased association constant in the presence of adenosine monophosphate, fructose-2,6-bisphosphate, fructose-6-phosphate and inhibitory concentrations of fructose-1,6-bisphosphate. Conversely, the association constant of the complex increased in the presence of dihydroxyacetone phosphate (DHAP) and non-inhibitory concentrations of fructose-1,6-bisphosphate. Notably, in vivo FRET studies confirmed the interaction between aldolase B and FBPase-1. Also, the co-expression of aldolase B and FBPase-1 in cultured cells suggested that FBPase-1 guides the cellular localization of aldolase B. Our results provide further evidence that metabolic conditions modulate aldolase B and FBPase-1 activity at the cellular level through the regulation of their interaction, suggesting that their association confers a catalytic advantage for both enzymes. PMID- 26417115 TI - Robust Optimization of Biological Protocols. AB - When conducting high-throughput biological experiments, it is often necessary to develop a protocol that is both inexpensive and robust. Standard approaches are either not cost-effective or arrive at an optimized protocol that is sensitive to experimental variations. We show here a novel approach that directly minimizes the cost of the protocol while ensuring the protocol is robust to experimental variation. Our approach uses a risk-averse conditional value-at-risk criterion in a robust parameter design framework. We demonstrate this approach on a polymerase chain reaction protocol and show that our improved protocol is less expensive than the standard protocol and more robust than a protocol optimized without consideration of experimental variation. PMID- 26417116 TI - Family and Teacher Characteristics as Predictors of Parent Involvement in Education During Early Childhood Among Afro-Caribbean and Latino Immigrant Families. AB - Parent involvement is a robust predictor of academic achievement, but little is known about school- and home-based involvement in immigrant families. Drawing on ecological theories, the present study examined contextual characteristics as predictors of parent involvement among Afro-Caribbean and Latino parents of young students in urban public schools. Socioeconomic disadvantage was associated with lower home-based involvement. Several factors were associated with higher involvement, including parents' connection to their culture of origin and to U.S. culture, engagement practices by teachers and parent-teacher ethnic consonance (for Latinos only). Findings have implications for promoting involvement among immigrant families of students in urban schools. PMID- 26417117 TI - Microstructures and superconducting properties of high performance MgB2 thin films deposited from a high-purity, dense Mg-B target. AB - High quality, c-axis oriented, MgB2 thin films were successfully grown on 6H-SiC substrates using pulsed laser deposition (PLD) with subsequent in situ annealing. To obtain high purity films free from oxygen contamination, a dense Mg-B target was specially made from a high temperature, high pressure reaction of Mg and B to form large-grained (10~50 um) MgB2. Microstructural analysis via electron microscopy found that the resulting grains of the film were composed of ultrafine columnar grains of 19-30 nm. XRD analysis showed the MgB2 films to be c-axis oriented; the a-axis and c-axis lattice parameters were determined to be 3.073 +/ 0.005 A and 3.528 +/- 0.010 A, respectively. The superconducting critical temperature, Tc,onset , increased monotonically as the annealing temperature was increased, varying from 25.2 K to 33.7 K. The superconducting critical current density as determined from magnetic measurements, Jcm , at 5 K, was 105 A/cm2 at 7.8 T; at 20 K, 105 A/cm2 was reached at 3.1 T. The transport and pinning properties of these films were compared to "powder-in-tube" (PIT) and "internal infiltration" (AIMI) processed wires. Additionally, examination of the pinning mechanism showed that when scaled to the peak in the pinning curve, the films follow the grain boundary, or surface, pinning mechanism quite well, and are similar to the response seen for C doped PIT and AIMI strands, in contrast to the behavior seen in undoped PIT wires, in which deviations are seen at high b (b = B/Bc2 ). On the other hand, the magnitude of the pinning force was similar for the thin films and AIMI conductors, unlike the values from connectivity suppressed PIT strands. PMID- 26417118 TI - A comparative study between intrathecal dexmedetomidine and fentanyl as adjuvant to intrathecal bupivacaine in lower abdominal surgeries: A randomized trial. AB - CONTEXT: Spinal anesthesia is preferred choice of anesthesia in lower abdominal surgeries since long time. However problem with this is limited duration of action, so for long duration surgeries alternative are required. Dexmedetomidine is a highly selective alpha-2-adrenergic agonist has property to potentiate the action of local anesthetic used in spinal anesthesia. Fentanyl is an opioid and it has also the same property. AIMS: To compare the efficacy, analgesic effects, and side-effects of dexmedetomidine and fentanyl as adjuvant to bupivacaine for lower abdominal surgery. SETTINGS AND DESIGN: The type of this study was double blind randomized trial. SUBJECTS AND METHODS: A total of 80 patients were randomly allocated in two Group D and Group F. Group D were injected injection bupivacaine 0.5% heavy * 3.0 ml + 0.5 ml of preservative free normal saline containing 5 MUg dexmedetomidine. Group F were received injection bupivacaine 0.5% heavy * 3.0 ml + 0.5 ml fentanyl equivalent to 25 MUg. STATISTICAL ANALYSIS USED: The statistical analysis was performed using SPSS (Statistical Package for Social Sciences) version 15.0 statistical analysis software. RESULTS: The results show that highest sensitivity level of T6 and T8 was achieved by higher proportion of subjects from Group D when compared to Group F and sensitivity level T7 was achieved by higher proportion of subjects of Group F when compared to Group D. Duration of analgesic properties was significantly higher in Group D when compared to Group F. CONCLUSION: The findings in the present study suggested that intrathecal adjuvant use of dexmedetomidine as compared to fentanyl provides a longer sensory and motor blockade and also prolongs the postoperative analgesic effect. PMID- 26417119 TI - A prospective randomized controlled study comparing intrathecal bupivacaine combined with fentanyl and sufentanil in abdominal and lower limb surgeries. AB - BACKGROUND: Hyperbaric bupivacaine along with either fentanyl or sufentanil as additive, has been widely used in spinal anesthesia. In the present study, we compared the analgesic effects of intrathecal fentanyl versus sufentanil combined with bupivacaine for surgical procedures over the abdomen and lower limbs. SETTINGS AND DESIGN: This was randomized controlled study conducted in a tertiary care hospital attached to a medical school. METHODS: Sixty American Society of Anesthesiologists I and II patients were randomized into three groups by sealed envelope technique. Group 1 was to receive bupivacaine with fentanyl; group 2 to receive bupivacaine with sufentanil and group 3 to receive bupivacaine with saline (control), intrathecally. The parameters checked were hemodynamic changes, onset and duration of sensory block, duration of analgesia and maximal sensory level achieved. STATISTICAL ANALYSIS: The data collected were analyzed using chi2 test and paired Student's t-test. RESULTS: The time taken for the onset of analgesia was longest in the control group followed by fentanyl group. The earliest onset of action of 9.35 +/- 1.92 min was recorded in sufentanil group. Duration of sensory blockade and analgesia was longest for fentanyl group than the other groups. Adverse effects noted were more for sufentanil group but were self-limiting. CONCLUSION: Fentanyl with bupivacaine produced prolonged analgesia and delayed two-segment regression and demonstrated reduced incidence of complications as compared with intrathecal sufentanil. As the quality of analgesia was complete and comparable, fentanyl emerges as a better option for analgesia and it is much economical too when compared to sufentanil. PMID- 26417120 TI - Comparative evaluation of cost effectiveness and recovery profile between propofol and sevoflurane in laparoscopic cholecystectomy. AB - BACKGROUND: Anesthetic agents should be chosen not only on the basis of safety efficacy profile, but also on the economic aspect. Propofol and sevoflurane are commonly utilized anesthetic agent for general anesthesia. AIM: The present study was designated to compare cost-effectiveness and recovery profile between propofol and sevoflurane for induction, maintenance or both. SETTINGS AND DESIGN: Randomized controlled, participant and data operator blinded trial. MATERIALS AND METHODS: Ninety patients undergoing laparoscopic cholecystectomy were randomized into three equal groups to receive: Group P to receive injection propofol for both induction and maintenance; Group PS to receive injection propofol for induction and sevoflurane for maintenance; and Group S to receive sevoflurane for both induction and maintenance of general anesthesia, respectively. Cost analysis, hemodynamic parameter, and recovery profile were compared between these groups. STATISTICAL ANALYSIS: One-way analysis of variance test or Fisher's exact test/Chi-square test whichever appropriate. RESULTS: Total cost of anesthesia was highest in Group P and lowest in Group S. Mean time to extubation and time to follow verbal commands was lowest in Group S than Group P or Group P/S. Hemodynamic parameter was more stable in Group S. CONCLUSION: We conclude that sevoflurane appears to be better anesthetic agents in terms of cost-effectiveness and recovery profile. PMID- 26417121 TI - Effect of preoperative pregabalin on postoperative pain relief in thyroidectomy patients: A prospective observational study. AB - BACKGROUND: Effective management of postoperative pain leads to increased patient satisfaction, earlier mobilization, reduced hospital stay and costs. One of the methods used for management of postoperative pain is preemptive analgesia blockade of afferent nerve fibers before a painful stimulus. It modifies peripheral and central nervous system processing of noxious stimuli and reduces postoperative opioid consumption. In this study, we sought to determine whether the preoperative use of pregabalin reduced postoperative pain and morphine consumption in thyroidectomy. MATERIALS AND METHODS: The observation was conducted on patients undergoing thyroidectomy surgery in two groups of 30 each. Of the two groups, one received a single oral dose of pregabalin 1 h preoperatively. Both the group of patients undergoes anesthesia in a similar manner. Following surgery the efficacy of the preoperative dose of pregabalin is observed by measuring the total opioid consumption 6 h postoperatively and assessing verbal numeric pain scales. RESULTS: The mean time to request of rescue analgesia in pregabalin group was 322.07 +/- 69.106 min when compared to morphine group 256.33 +/- 111.978 min (P < 0.05). The mean pain scores in the postoperative period were also significantly lower in patients receiving pregabalin. CONCLUSION: Single oral dose of pregabalin was effective in reducing acute postoperative pain in thyroidectomy patients. It prolongs the time to the request of rescue analgesia and also results in lower postoperative pain scores in the immediate postoperative period. However a statistically significant low opioid consumption could not be proved. PMID- 26417122 TI - A study to compare the overall effectiveness between midazolam and dexmedetomidine during monitored anesthesia care: A randomized prospective study. AB - BACKGROUND: Monitored anesthesia care (MAC) combines intravenous sedation along with local anesthetic infiltration or nerve block. Several drugs have been used for MAC, but all are associated with complications. Dexmedetomidine is a selective alpha2-adrenoceptor agonist with both sedative and analgesic properties and is devoid of respiratory depressant effects. Its short elimination half-life makes it an attractive agent for sedation during MAC. AIM: Comparative evaluation of dexmedetomidine and midazolam for MAC. METHODS: In this prospective, randomized, double-blind study, 50 American Society of Anesthesiologist I and II patients undergoing a surgical or diagnostic procedure of <1 h requiring MAC were enrolled. Dexmedetomidine-ketamine (Group "KD") patients (n = 25) received intravenous (I.V.) dexmedetomidine 1 mcg/kg over 10 min followed by 0.5 mg/kg of I.V. ketamine. Midazolam-ketamine patients (n = 25) received I.V. midazolam 0.05 mg/kg over 10 min followed by 0.5 mg/kg of I.V. ketamine to get a targeted level of sedation (<=4 using Observer's Assessment of Alertness/Sedation Scale score). Inadequate sedation (e.g., 15% increase in mean arterial blood pressure or heart rate, decrease in degree of calmness, increase in respiratory rate, physical movement) was treated by a ketamine bolus of 0.5 mg/kg as a rescue analgesia. STATISTICAL ANALYSIS: The statistical tests used in the study are unpaired Student's t-test for continuous variables and Chi-square test for categorical variables. Mann-Whitney test was used to assess the patient and surgeon satisfaction. Data were expressed as mean +/- standard deviation. Value of P < 0.05 is considered significant and P < 0.0001 as highly significant. RESULTS: Clinically desired sedation and analgesia was achieved earlier and better with dexmedetomidine. Patients and surgeons satisfaction were significantly higher with dexmedetomidine. The requirement of additional sedation and analgesia was less in dexmedetomidine (KD) group. CONCLUSION: During MAC dexmedetomidine provides better sedation and analgesia than midazolam. PMID- 26417123 TI - Effects of isobaric ropivacaine with or without fentanyl in subarachnoid blockade: A prospective double-blind, randomized study. AB - BACKGROUND: The addition of fentanyl to ropivacaine has shown to improve the quality of analgesia without compromising its benefits such as early mobilization and early voiding. AIM: The aim of the study was to evaluate the effects of the isobaric ropivacaine in combination with fentanyl and compare it with the isobaric ropivacaine alone in spinal anesthesia for lower abdominal and lower limb surgeries. SETTINGS AND DESIGN: Double-blinded randomized controlled trial. SUBJECTS AND METHODS: Hundred patients belonging to American Society of Anesthesiologists physical status I and II scheduled for either lower abdominal or lower limb surgery under spinal anesthesia were included. The study was a prospective double-blinded randomized controlled trial where patients were randomly allocated into two groups to receive either 2.5 ml of 0.75% (18.75 mg) isobaric ropivacaine with 25 MUg fentanyl (Group RF) or 2.5 ml of 0.75% (18.75 mg) isobaric ropivacaine with 0.5 ml of 0.9% saline (Group R) intrathecally. STATISTICAL ANALYSIS: Data analysis was done by Student's unpaired t-test. SPSS version 16 was used. P < 0.05 was considered as statistically significant. RESULTS: We found no significant difference in hemodynamics, onset of sensory and motor block, peak level of block, recovery from motor block, return of micturition and incidence of side effects with the addition of fentanyl to ropivacaine. First request for analgesia was required earlier in the control group. There was also a significant prolongation of the duration of sensory block (mean - 341.6 min) and postoperative analgesia in Group RF (mean - 442.2 min) (P < 0.001). CONCLUSION: The addition of fentanyl to ropivacaine significantly prolongs the duration of postoperative analgesia with clinically insignificant influence on hemodynamics and motor blockade with minimal side effects. PMID- 26417124 TI - Comparison of levobupivacaine and levobupivacaine with fentanyl in infraumbilical surgeries under spinal anaesthesia. AB - BACKGROUND: Intrathecal opioids added to low dose local anesthetics in spinal anaesthesia intensifies sensory block without affecting sympathetic blockade. Aim was to evaluate the safety and efficacy of intrathecal levobupivacaine plain versus levobupivacaine plus fentanyl in infraumbilical surgeries. MATERIALS AND METHODS: In a prospective randomized double blind study, 100 patients of American Society of Anesthesiologists grades I and II of either sex, 20-65 years of age were included after approval from the Ethics Committee. Informed consent was taken and patients were randomly divided into two groups of 50 each, to receive either 2 ml of 0.5% isobaric levobupivacaine (group L) or 2 ml of 0.5% isobaric levobupivacaine + 25 MUg fentanyl (group LF) intrathecally. Patients were monitored for sensory and motor block characteristics, postoperative analgesia, haemodynamics and side effects and complications for 24 h. RESULTS: Onset of sensory block and time to maximum sensory block was rapid in group LF (4.8 +/- 1.50 and 8.46 +/- 1.87 min) as compared to group L (7.6 +/- 1.46 and 15.80 +/- 2.43 min) (P < 0.000). Maximum sensory block was T6 in group LF and T8 in group L. Maximum Bromage score was 2 in both groups but was achieved earlier in group LF (P < 0.000). Duration of sensory and motor block was significantly prolonged in group LF (270.98 +/- 28.60 and 188.52 +/- 9.81 min) as compared to group L (197.58 +/- 11.20 and 152.76 +/- 9.79 min). Total duration of analgesia was also prolonged in group LF (265.16 +/- 26.18 min) as compared to group L (168.16 +/- 11.08 min). Patients remained haemodynamically stable and side effects and complications were comparable in both groups. Data was analyzed using "Chi-square test" and "unpaired t-test." CONCLUSION: Addition of fentanyl to levobupivacaine leads to early onset and prolonged duration of sensory and motor block as well as postoperative analgesia with stable haemodynamics and minimal side effects. PMID- 26417125 TI - A comparative study-efficacy and safety of combined spinal epidural anesthesia versus spinal anesthesia in high-risk geriatric patients for surgeries around the hip joint. AB - CONTEXT: Combined spinal epidural anesthesia (CSEA) has a significant advantage by enabling the use of low dose intrathecal local anesthetic, with knowledge that the epidural catheter may be used to extend the block as necessary. CSEA is useful in high-risk geriatric patients by providing greater hemodynamic stability. AIM: This study is designed to compare the clinical effects of CSEA versus spinal anesthesia in high-risk geriatric patients undergoing surgeries around the hip joint. MATERIALS AND METHODS: Sixty patients aged >65 years, American Society of Anaesthesiology III and IV were randomly allocated into two equal groups. Group A (n = 30) received CSEA with 1 ml (5 mg) of 0.5% hyperbaric bupivacaine with 25 MUg fentanyl through spinal route, and the expected incompleteness of spinal block was managed with small incremental dose of 0.5% isobaric bupivacaine through epidural catheter, 1-1.5 ml for every unblocked segment to achieve T10 sensory level. Group B (n = 30) received spinal anesthesia with 2.5 ml (12.5 mg) of 0.5% hyperbaric bupivacaine and 25 MUg fentanyl. RESULT: Both the groups showed rapid onset, excellent analgesia and good quality motor block. Group A showed a significantly less incidence of hypotension (P < 0.01) along with the provision of prolonging analgesia as compared to Group B. CONCLUSION: CSEA is a safe, effective, reliable technique with better hemodynamic stability along with the provision of prolonging analgesia compared to spinal anesthesia for high-risk geriatric patients undergoing surgeries around the hip joint. PMID- 26417126 TI - Comparative evaluation of 0.75% ropivacaine with clonidine and 0.5% bupivacaine with clonidine in infraclavicular brachial plexus block. AB - BACKGROUND: Infraclavicular brachial block with coracoids approach has gained popularity because of consistent bony landmarks and less chances of vascular puncture and pneumothorax. AIM: The aim of this study was to evaluate the effect of adding clonidine to bupivacaine or ropivacaine on the onset and duration of sensory and motor block and duration of analgesia in infraclavicular block. MATERIALS AND METHODS: In a prospective randomized double-blind study, 60 patients of 18-65 years were randomly divided in to two groups of 30 each. Infraclavicular block was performed with 30 ml of 0.75% ropivacaine + 150 MUg clonidine in group R and 30 ml of 0.5% bupivacaine + 150 MUg clonidine in group B and were compared for onset and duration of sensory and motor block, postoperative analgesia, side-effects and complications. RESULTS: Significant differences were observed in the time for onset of sensory block (5.80 +/- 5.12 min in group R and 4.87 +/- 1.46 min in group B, P < 0.05); onset of motor block (11.37 +/- 2.66 min in group R and 9.60 +/- 1.78 min in group B, P < 0.05); duration of sensory and motor block (10.07 +/- 0.91 and 9.03 +/- 0.89 h in group R and 12.50 +/- 1.14 and 10.67 +/- 1.18 h in group B respectively, P < 0.01) and duration of analgesia (15.30 +/- 1.39 h in group R and 18.07 +/- 1.66 h in group B). No significant difference was observed in hemodynamics, sedation, side effects and complications. STATISTICAL ANALYSIS: Variables were compared using Chi-square test for nonparametric data and Student's t-test for parametric data. CONCLUSION: Addition of clonidine to bupivacaine lead to early onset and prolonged duration of sensory and motor block with prolonged analgesia as compared to the addition of clonidine to ropivacaine. PMID- 26417127 TI - A comparative study of intrathecal clonidine and dexmedetomidine on characteristics of bupivacaine spinal block for lower limb surgeries. AB - INTRODUCTION: Intrathecal clonidine or dexmedetomidine has improved the quality of spinal anesthesia, this clinical study was undertaken to assess the behavior of intrathecal clonidine as an adjuvant to bupivacaine in augmenting sensory block in patients undergoing lower limb surgeries. MATERIALS AND METHODS: We studied 150 patients, between 18 and 60 years of age, patients were randomly divided into three groups of 50 each Group B: 0.5% bupivacaine 15 mg + 0.5 ml normal saline Group C: 0.5% bupivacaine 15 mg + 50 MUg clonidine Group D: 0.5% bupivacaine 15 mg + 5 MUg dexmedetomidine. Onset and duration of sensory block and motor block, the highest level of sensory blockade, duration of analgesia, and side-effects were assessed. RESULTS: The onset of motor block was faster in Group C and Group D as compared to Group B, The time to reach Bromage scale 3 was fastest in Group C followed by Group D P < 0.001. The duration of sensory, motor blockade and duration of analgesia was longer in Groups C and D as compared to Group B, longest in Group D followed by C and B. The time to regression time to S1 dermatome was. It was longest in Group D followed by Group C and then Group B. Intergroup comparison B to C, B to D and C to D was significant. Duration of analgesia was significantly prolonged in Group C and Group D (P < 0.001) with a mean duration of 309.6 +/- 50.99 min in Group C and 336.8 +/- 55.38 min in Group D as compared to 204.8 +/- 16.81 min in Group B. Intergroup comparison B to C, B to D and Group C to D was significant. Duration was longest in Group D followed by Group C and then Group B. CONCLUSION: Supplementation of bupivacaine spinal block with a low dose of intrathecal dexmedetomidine (5 MUg) or clonidine (50 MUg) produces a significantly shorter onset of motor and sensory block and a significantly longer sensory and motor block than bupivacaine alone. PMID- 26417128 TI - Caudal-epidural bupivacaine versus ropivacaine with fentanyl for paediatric postoperative analgesia. AB - BACKGROUND AND AIMS: Caudal-epidural, the most commonly used regional analgesia technique, is virtually free of measurable hemodynamic effects, thus adding a new dimension to the evolving necessity of pediatric postoperative pain management. Though, bupivacaine is the most commonly used drug for this purpose, ropivacaine has emerged as a safer alternative, with the addition of opioids, like fentanyl, increasing the effective duration of analgesia. With this overview, our present study was designed to compare the postoperative analgesic efficacy of bupivacaine fentanyl and ropivacaine-fentanyl combinations by caudal-epidural technique in pediatric infraumbilical surgeries. MATERIALS AND METHODS: Totally, 60 pediatric patients, of either sex, aged between 2 and 8 years, American Society of Anesthesiologists physical status I and II, undergoing elective infraumbilical surgeries were assigned into two groups, Group BF receiving bupivacaine 0.25%, 0.7 ml/kg and Group RF receiving ropivacaine 0.25%, 0.7 ml/kg with fentanyl 1 MUg/kg added to each group. Assessment of pain was done using "Hannallah pain scale." Consumption of the total amount of rescue analgesic and time to requirement of the first dose, as also duration of motor blockade were noted. Perioperative hemodynamics and any adverse effects were monitored at regular intervals. RESULTS: The RF Group experienced significantly longer duration of effective postoperative analgesia, with significantly shorter duration of motor blockade and lesser total analgesic requirement in comparison to the BF Group. Hemodynamically, patients in both the groups, were equally stable. CONCLUSION: Ropivacaine, with an equipotent analgesic efficacy and a lesser duration of motor block, can be used as an alternative to bupivacaine for pediatric postoperative pain care through the caudal route. PMID- 26417129 TI - A comparison of intranasal ketamine and intranasal midazolam for pediatric premedication. AB - AIMS AND OBJECTIVES: The aim of our study is to compare the efficacy and side effects of Ketamine and Midazolam administered nasally for the pediatric premedication. MATERIALS AND METHODS: We studied 100 American Society of Anesthesiology I and II children aged from 1 to 10 years undergoing various surgical procedures. Totally, 50 children were evaluated for nasal ketamine (using 50 mg/ml vials) at the dose of 5 mg/kg and the other 50 received nasal midazolam 0.2 mg/kg, before induction in operation theater each patient was observed for onset of sedation, degree of sedation, emotional status being recorded with a five point sedation scale, response to venipuncture and acceptance of mask, whether readily, with persuasion or refuse. RESULTS: The two groups were homogenous. Midazolam showed a statistically significant early onset of sedation (10.76 +/- 2.0352 vs. 16.42 +/- 2.0696 min). There were no significant differences in venipuncture score, sedation scale at 20 min, acceptance of mask and oxygen saturation throughout the study. Significant tachycardia and 'secretions were observed in the ketamine group intra operatively. Postoperatively emergence (8% vs. 0%) and secretions (28% vs. 4%) were significant in the ketamine group. Nausea and vomiting occurred in l6% versus 10% for midazolam and ketamine group. CONCLUSIONS: Both midazolam and ketamine nasally are an effective pediatric premedication. Midazolam has an early onset of sedation and is associated with fewer side-effects. PMID- 26417130 TI - Efficacy of alpha2 agonists in obtunding rise in intraocular pressure after succinylcholine and that following laryngoscopy and intubation. AB - CONTEXT: Elevation of intraocular pressure (IOP) is an inherent and inadvertent association with the use of succinylcholine and alpha2 agonists can be used to obtund this effect. AIMS: The study was aimed to assess the efficacy of intravenous dexmedetomidine and clonidine premedication in attenuating rise in IOP during laryngoscopy and intubation following administration of succinylcholine. SETTINGS AND DESIGN: This prospective, observational study was conducted in 40 patients aged 20-60 years undergoing non ophthalmic surgical procedures. SUBJECTS AND METHODS: For patients in Group D, dexmedetomidine 0.4 mcg/kg and in Group C clonidine 1 MUg/kg over 10 min was administered before induction. All patients were induced with propofol. Laryngoscopy and intubation were performed 1 min after administration of succinylcholine 2 mg/kg. STATISTICAL ANALYSIS USED: Mann-Whitney, Chi-square and Wilcoxon tests. RESULTS: Mean baseline IOP of both groups were comparable (15.4 +/- 2.6 vs. 14.7 +/- 2.3). Following premedication and induction, IOP decreased in both groups and the reduction was significantly more in Group D. Following administration of succinylcholine and 1 min after intubation IOP raised and exceeded the baseline value in Group C (16.0 +/- 1.6 and 18.6 +/- 2.2). Though there was an increase in IOP in Group D (12.0 +/- 1.9 and 14.0 +/- 2.1), it did not reach up to baseline values. Then there was a gradual reduction in IOP in both groups at 3, 5, and 10 min and Group D continued to have a significantly low IOP than Group C up to 10 min. CONCLUSIONS: Dexmedetomidine 0.4 MUg/kg resulted in a reduction of IOP and blunted the increase in IOP, which followed administration of succinylcholine, laryngoscopy, and intubation. Though clonidine 1 MUg/kg reduced IOP, it did not prevent rise in IOP following succinylcholine, laryngoscopy, and intubation. PMID- 26417131 TI - Motor response evaluation during brachial plexus block anesthesia: An ultrasonography aided study. AB - BACKGROUND: The sparing of ulnar nerve often leads to the failure of the upper limb blockade. It has been claimed that local anesthetic injection at the site of stimulator evoked finger flexion response is associated with highest success rate of a successful block. The lower trunk stimulation of plexus should yield similar results as this trunk contributes significantly for median and ulnar nerves of hand and forearm. MATERIALS AND METHODS: The patients with intact anatomical upper limb structures underwent (a) combined ultrasound (USG) assisted nerve stimulator evoked motor response evaluation or in (b) open brachial plexus trunk stimulation evaluations. The individual patient's lower trunk stimulation motor responses were documented. RESULTS: When combined the results of both USG and open plexus groups, wrist flexion was seen in 52%, finger flexion in 61% and forearm pronation or twitches of anterior compartment in 48% of total subjects studied. These responses were noted either separately or in combinations. CONCLUSION: We conclude other than finger flexion, the wrist flexion the forearm twitches, pronation and wrist adduction may be used for lower trunk blockade and thus for higher accuracy. PMID- 26417132 TI - Effects of different types of pharyngeal packing in patients undergoing nasal surgery: A comparative study. AB - CONTEXT: Postoperative throat complaints such as postoperative sore throat (POST), dysphagia, and hoarseness frequently arises after tracheal intubation and throat packing for patient undergoing general anesthesia. This condition is very disturbing to patient. Avoiding POST is a major priority for these patients because preventing postoperative complications contributes to patient satisfaction. AIMS: To describe and analyze the postoperative throat effects of nasopharyngeal packing and oropharyngeal packing in patients undergoing nasal surgery. SETTINGS AND DESIGN: A randomized comparative study. SUBJECTS AND METHODS: After obtaining approval of Ethical Committee 40 patients were included in study. After this patient were randomly allocated into two groups of 20 each. Group A - in which the oropharynx was packed and Group B - inwhich the nasopharynx was packed. General anesthesia were given and throat packing was done and patients were interviewed postoperatively for any throat complications such as sore throat, difficulty in swallowing (dysphagia), hoarseness of voice, throat irritation, and any other symptom pertaining to the study were noted and data were analyzed. STATISTICAL ANALYSIS USED: T-test to compare the age, while Chi square test and Fisher's exact test were used to compare sex distribution, sore throat, dysphagia, hoarseness, and throat irritation. RESULTS: Results showed statistically significant difference in incidence and severity of POST in Group A patients when compared to Group B patients to be more. Patients in Group A had a higher incidence of dysphagia when compared to their Group B counterparts. With respect to the incidence of hoarseness and throat irritation, there was no statistical significance between the groups. CONCLUSION: We concluded that the site of pharyngeal packing influences the incidence and severity of POST and as well as the incidence of dysphagia after general anesthesia. The use of nasopharyngeal packing in the patients undergoing nasal surgeries might lead to a reduction of the same. PMID- 26417133 TI - Anesthetic management of a newborn with occipital meningocele for magnetic resonance imaging. AB - Cranial Meningocoele is a term which represents herniation of meninges and cerebrospinal fluid through the congenital defect in the cranium. Anaesthetic challenges in the management of neonates with occipital meningocoele include airway management and proper positioning of the neonate without pressure on the meningocoele sac so as to preventthe rupture of the membranes. Associated congenital anomalies also can cause anaesthesia and procedure related complications. Other difficulties include performing a difficult airway case in an unfamiliar environment outside operation theatre. We report a case of 6 day old neonate with occipital meningocoele posted for MRI brain and the successful anaesthetic management. PMID- 26417134 TI - Unusual but completely avoidable complication during central venous catheterization. AB - Central venous catheterization is generally a safe procedure, but several complications such as pneumothorax, arrhythmias, arterial puncture, infection, and thrombosis are known to occur even in the experienced hands. Complications related to guide wire are very rare and mostly relate to the expertise of operating person. We hereby report a rare but completely avoidable complication, that is, complete loss of the guide wire into the subclavian vein which was successfully retrieved by surgery. PMID- 26417135 TI - I-gel saves the day: Bradycardia and apnea in a patient undergoing burr hole and evacuation for a subdural hematoma under scalp block. AB - Awake craniotomy is generally performed in scalped block, although it is safe, but this procedure can sometimes produce severe hemodynamic disturbances. Here, we reported a case of 32-year-old male, who came for burr hole and during the craniotomy performed under scalped block developed bradycardia and became apneic as manifested by the absence of ETCO2 and no chest excursions. An I-gel was inserted rather than intubating the patient and the case was managed very well and which showed the importance of supraglottic airway devices in our day to day practice. PMID- 26417136 TI - Difficult airway challenges-intubation and extubation matters in a case of large goiter with retrosternal extension. AB - Thyroid diseases have an anesthetic implication that includes difficult airway management, uncontrolled hyperthyroidism, hypothyroidism and postthyroidectomy complications. Securing airway: Intubation and extubation both require skillful management and timely decision to reduce morbidity and mortality in the case of large goiter with retrosternal extension that leads to tracheal compression and deviation. We present the anesthetic management in a patient with a large goiter with retrosternal extension leading to tracheal compression and deviation. We managed the case with an awake fiberoptic intubation and guided extubation. PMID- 26417137 TI - Management of bilateral recurrent laryngeal nerve paresis after thyroidectomy. AB - Bilateral recurrent laryngeal nerve (RLN) injury is rare for benign thyroid lesions (0.2%). After extubation-stridor, respiratory distress, aphonia occurs due to the closure of the glottic aperture necessitating immediate intervention and emergency intubation or tracheostomy. Intra-operative identification and preservation of the RLN minimizes the risk of injury. It is customary to expect RLN problems after thyroid surgery especially if malignancy, big thyroid, distorted anatomical problems and difficult airway that can lead to intubation trauma. Soon after extubating, it is essential to the anesthetist to check the vocal cord movements on phonation and oropharyngeal reflexes competency. But this case is specially mentioned to convey the message that in spite of absence of above mentioned predisposing factors for complications and good recovery profile specific to thyroid, there can be unanticipated airway compromise that if not attended to immediately may cost patient's life. This is a case of postextubation stridor following subtotal thyroidectomy due to bilateral RLN damage and its management. PMID- 26417138 TI - Malpositioning of central venous cannula inserted through internal jugular vein after failed cannulation through ipsilateral subclavian vein. AB - The anesthesiologist is frequently involved in the task of achieving central venous access either for intraoperative uses or postoperative purposes or Intensive Care Unit care. We are usually aware of the common complications of subclavian approach, such as arterial puncture, bleeding, pneumothorax, misplacement in the ipsilateral internal jugular vein (IJV) or contralateral brachiocephalic or subclavian vein. In this case report, we highlight the possibility of malpositioning of central venous cannula inserted through IJV into the anterior extra pleural plane after failed subclavian cannulation attempts. PMID- 26417139 TI - Management of atypical eclampsia with intraventricular hemorrhage: A rare experience and learning! AB - Cerebrovascular accident during hypertensive disorder of pregnancy is a rare entity, but carries high risk of mortality and morbidity due to its unpredictable onset and late diagnosis. Here, we report an unusual case of 20-year-old primigravida with 34 weeks gestation having no risk factor, which developed sudden atypical eclampsia and intracranial hemorrhage within few hours. She was successfully managed by multidisciplinary approach including emergency cesarean section and conservative neurological treatment for intraventricular hemorrhage. PMID- 26417141 TI - Electrocardiographic changes after lung resection: Case report and brief review. AB - The incidence of acute coronary syndrome after a lung resection is less, especially in an asymptomatic patient. However, arrhythmias are very commonly encountered which can be benign or may require anti-arrhythmic agents thereby increasing stay postoperatively in the Intensive Care Unit. We encountered unexpected ST-T changes after a left upper lobectomy under general anesthesia in a 60-year-old lady in the immediate postoperative period that made us to review the literature for electrocardiographic abnormalities after lung resection surgeries. PMID- 26417140 TI - Obstruction of a non-resterilized reinforced endotracheal tube during craniotomy under general anesthesia. AB - Many cases of reinforced endotracheal tube (ETT) obstruction were reported in the literature. In most of these cases, the obstruction was related to the use of a resterilized tube with or without the use of nitrous oxide (N2O). Resterilization and autoclaving of the tube may result in dissection or formation of a bleb between the two layers of the tube that may expand after the use of N2O. We describe a case of acute non-resterilized reinforced ETT obstruction, by bleb formation, during occipital craniotomy under general anesthesia. PMID- 26417142 TI - Anaesthetic management of beta thalassemia major with hypersplenism for splenectomy in pediatric age group: Report of four cases. AB - Beta thalassemia is the most common cause of hemolytic anemia in India. Hereby we are reporting four cases of beta thalassemia major aged between 5 and 10 years posted for splenectomy over a period of 2 months. These patients were on repeated blood transfusions since the day of diagnosis, and two patients had a history of cardiac failure. In addition to emphasizing the anesthetic challenges, the purpose of reporting such cases is to raise the awareness of the disease and prevention of the same by aggressive screening and prenatal diagnosis. PMID- 26417143 TI - Anesthetic management of a large cystic hygroma in a newborn. AB - Cystic hygroma is a congenital benign tumor occurring due to the accumulation of lymph and during its anesthetic management difficulties are known to be encountered. A newborn baby presented with a massive swelling in the front of the neck. It was an antenatally diagnosed case of cystic hygroma with intraoral extension proving to be an anticipated difficult airway. Following inhalational induction, mask ventilation was possible, and the child was successfully intubated. Intra-operative period was uneventful, and the tumor was completely excised. Postoperatively, the child was ventilated for 24 h in view of anticipated airway edema. PMID- 26417144 TI - Cardiac arrest following butane inhalation. AB - Butane is a commonly misused volatile agent, and a cause of intoxication. We present a case, who had a syncope and persistent ventricular fibrillation during the course of resuscitation. We discussed the management of this case in the intensive care unit and the accompanying difficulties in the light of the current literature. PMID- 26417146 TI - Fixation of bilateral condylar fractures with maxillary and mandibular nerve blocks. AB - Mandibulo facial injuries present special problems to the anesthesiologist in terms of the difficult airway. Hence, if regional anesthesia could be possible, it necessarily removes the major concern with airway access. We present a case of bilateral mandibular condylar fracture dislocation with the maxillary and mandibular nerve blocks on both sides. The surgery went on smoothly without any perioperative problems. PMID- 26417145 TI - The anesthetic considerations while performing supraclavicular brachial plexus block in emergency surgical patients using a nerve stimulator. AB - Regional anesthesia is favored in patients who undergo emergency extremity (limb) surgery, and specifically so in the absence of fasting status. In the absence of ultrasonic guidance, the nerve stimulator still remains a valuable tool in performing a brachial block, but its use is difficult in an emergency surgical patient and greater cautious approach is essential. We identified the supraclavicular plexus by the nerve stimulation-motor response technique as follows. Anterior chest muscles contractions, diaphragmatic contraction, deltoid contractions, and posterior shoulder girdle muscle contractions when identified were taken as "negative response" with decreasing stimulating current. A forearm muscle contraction, especially "wrist flexion" and "finger flexion" at 0.5 mA of current was taken as "positive response." If no positive response was identified, the "elbow flexion" was considered as the final positive response for successful drug placement. The series of patients had difficulty for administering both general and regional anesthesia and we considered them as complex scenarios. The risk of the block failure was weighed heavily against the benefits of its success. The described series includes patients who had successful outcomes in the end and the techniques, merits, and risks are highlighted. PMID- 26417147 TI - Anesthetic management of a patient with hypertrophic cardiomyopathy with atrial flutter posted for percutaneous nephrolithotomy. AB - Hypertrophic cardiomyopathy (HCM) is a most common genetic cardiovascular disorder, characterized by asymmetric hypertrophy of the interventricular septum that leads to intermittent obstruction of the left ventricular outflow tract (LVOT). Clinical presentation ranges from absence of symptoms to sudden death in the young and disability at any age. Although patients are asymptomatic in basal conditions, but anesthesia and surgical stress can lead to exacerbation of the LVOT obstruction and may complicate the perioperative course. Therefore, complete understanding of the pathophysiology and anesthetic implications is needed for the successful perioperative outcome. We describe the successful management of a case of HCM with atrial flutter posted for percutaneous nephrolithotomy. PMID- 26417148 TI - Hypopituitarism: A rare sequel of cerebral malaria - Presenting as delayed awakening from general anesthesia. AB - We report a case of delayed emergence from anesthesia in a 37-year-old male who came for emergency laparoscopic appendicectomy. This patient is hailing from one of the endemic zones of Malaria, Orissa State in India. Two months ago he had cerebral malaria and was treated in our intensive care unit. After recovering from cerebral malaria, he presented to us for acute abdomen, and he was taken for emergency laparoscopic appendicectomy. He had delayed emergence of around 2 h to extubate from the time of completion of surgery in spite of termination of anesthetic agents. Further investigations showed to have decreased serum levels of thyroid hormones and cortisol levels in the postoperative period. The Physician promptly diagnosed the condition as hypopituitarism a known sequel of cerebral malaria. The secondary thyroid insufficiency contributing to the delayed emergence from anesthesia. We also review the pertinent literature related to this rare sequelae of cerebral malaria and its perioperative implication to the anesthesiologist. PMID- 26417149 TI - Timely decision-making: How it saved us!!! PMID- 26417151 TI - Front of Pack Labels Enhance Attention to Nutrition Information in Novel & Commercial Brands. AB - OBJECTIVES: 1) To assess whether Front-of-Pack (FOP) nutrition labels garner attention more readily than more complete, mandated nutrition information (the Nutrition Facts Panel (NFP), required in the US), and 2) To determine whether label design characteristics, specifically, color coding and/or coding with facial icons, increase attention to the FOP label. METHODS: In two experiments, we tracked the allocation of attention while participants (n=125) viewed novel and commercial packages with varied FOP designs using a change detection methodology. RESULTS: We found empirical evidence that FOP labels are attended more often, and earlier, than the currently mandated NFP, and that this benefit is due both to its placement on the front of the package and to the design characteristics of the FOP. Specifically, the use of color in FOPs increased attention to the label, but there was no evidence that coding information via facial icons impacted attention. CONCLUSIONS: Our work supports a growing body of evidence supporting the use of FOP labels to attract attention to nutritional information. Findings may be relevant to inform policy decisions on labeling standards. PMID- 26417150 TI - Polymorphism on Chromosome 9p21.3 Is Associated with Severity and Early-Onset CAD in Type 2 Diabetic Tunisian Population. AB - Multiple association studies found that the human 9p21.3 chromosome locus is a risk factor for atherosclerosis. The purpose of this study was to investigate the association of the severity and early-onset of coronary artery disease with variant rs1333049 on chromosome 9p21.3 polymorphism and the impact of this variant on cardiovascular risk factors in type 2 diabetic patients. The study population consisted of a control CAD group (101 patients) and 273 consecutive type 2 diabetic patients. Severity and extent of coronary atherosclerosis were scored numerically using the Gensini scoring system. The diabetic population was divided into three groups according to Gensini score: Group 1: no stenosis; Group 2: moderate CAD; Group 3, severe CAD. The homozygous CC genotype of rs1333049 was significantly associated with CAD in Group 2 (OR: 1.36; p = 0.02) and Group 3 (OR: 5.77, p < 0.001) compared to Group 1 (OR: 0.18; p = 0.2) and control group (OR: 0.22; p = 0.21). Among diabetic patients with early-onset CAD, CC genotype carriers had significantly higher Gensini scores than non-CC genotype carriers (49 +/- 21.3 versus 14.87 +/- 25.22; p < 0.001). The homozygous CC genotype of rs1333049 confers a magnified risk of early-onset and severe CAD in type 2 diabetic Tunisian population. PMID- 26417152 TI - Substance abuse and parenting among African American mothers of adolescents. PMID- 26417154 TI - Can Establishment of Human Microbiome be Customized After Birth with Local Traditions of First Feed and Intimate Kissing? PMID- 26417153 TI - IL-4 Inhibits IL-1beta-Induced Depressive-Like Behavior and Central Neurotransmitter Alterations. AB - It has been known that activation of the central innate immune system or exposure to stress can disrupt balance of anti-/proinflammatory cytokines. The aim of the present study was to investigate the role of pro- and anti-inflammatory cytokines in the modulation of depressive-like behaviors, the hormonal and neurotransmitter systems in rats. We investigated whether centrally administered IL-1beta is associated with activation of CNS inflammatory pathways and behavioral changes and whether treatment with IL-4 could modulate IL-1beta-induced depressive-like behaviors and central neurotransmitter systems. Infusion of IL-4 significantly decreased IL-1beta-induced anhedonic responses and increased social exploration and total activity. Treatment with IL-4 markedly blocked IL-1beta-induced increase in PGE2 and CORT levels. Also, IL-4 reduced IL-1beta-induced 5-HT levels by inhibiting tryptophan hydroxylase (TPH) mRNA and activating serotonin transporter (SERT) in the hippocampus, and levels of NE were increased by activating tyrosine hydroxylase (TH) mRNA expression. These results demonstrate that IL-4 may locally contribute to the regulation of noradrenergic and serotonergic neurotransmission and may inhibit IL-1beta-induced behavioral and immunological changes. The present results suggest that IL-4 modulates IL-1beta induced depressive behavior by inhibiting IL-1beta-induced central glial activation and neurotransmitter alterations. IL-4 reduced central and systemic mediatory inflammatory activation, as well as reversing the IL-1beta-induced alterations in neurotransmitter levels. The present findings contribute a biochemical pathway regulated by IL-4 that may have therapeutic utility for treatment of IL-1beta-induced depressive behavior and neuroinflammation which warrants further study. PMID- 26417155 TI - Association of Serum Magnesium Deficiency with Insulin Resistance in Type 2 Diabetes Mellitus. AB - BACKGROUND: Insulin resistance (IR) is the key pathophysiological defect that leads to the development of type 2 diabetes mellitus. The purpose of this study was to estimate serum magnesium level and insulin sensitivity indices among type 2 diabetes mellitus patients and to see an association between them. METHODS: This study was carried out among 38 type 2 diabetic patients and forty age and sex matched controls. Serum fasting glucose, magnesium, insulin, urea, and creatinine levels were estimated. Insulin sensitivity indices, homeostasis model assessment for insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) levels were calculated as per formulae. RESULTS: A highly significant low serum magnesium level was found in diabetic subjects as compared to the controls. Statistically significant high HOMA levels (>2.6) and low QUICKI levels (<0.33) were found among the case group. An inverse, statistically significant correlation was found between serum magnesium and fasting insulin level. A highly statistically significant inverse correlation was found between serum magnesium and HOMA level, and a positive correlation was found between serum magnesium and QUICKI level, that is, serum magnesium level decreases with increase in IR. A strong association was also found between fasting serum insulin level and insulin sensitivity indices. CONCLUSION: This study showed a lower serum magnesium level in diabetic patients compared to control. A strong association was also found between serum magnesium level and insulin sensitivity indices. For proper management of type 2 diabetes, it may, therefore, be necessary to treat hypomagnesemia in these patients. PMID- 26417156 TI - Epidermal Growth Factor Receptor Expression in Triple Negative and Nontriple Negative Breast Carcinomas. AB - INTRODUCTION: The panel of markers used for molecular classification include estrogen receptors (ER), progesterone receptors (PR), human epidermal growth factor receptor (HER)-2/neu, p53, Bcl-2 and basal markers like cytokeratin 5/6 or epidermal growth factor receptor (EGFR). Among these, EGFR plays an important role and is associated with bad prognosis. AIMS AND OBJECTIVES: To study EGFR expression in triple negative breast carcinoma (TNBC) and non-TNBCs (NTNBCs). MATERIALS AND METHODS: Fifty cases of breast carcinomas were classified and graded according to World Health Organization and Nottingham modification of Scarff-Bloom-Richardson (SBR) system, respectively. The age of the patients ranged from 28 to 69 years. Histological features such as necrosis, pushing borders, lymphocytic infiltrate and periductal elastosis were noted. The panel of markers used in our study included ER, PR, HER-2/neu and EGFR. EGFR expression was assessed based on membrane staining. Chi-square test was applied for statistical analysis to compare EGFR expression with hormonal status and prognostic factors. P < 0.05 was considered significant. RESULTS: The mean age was 49.8 +/- 7.2 years. There were 44 (88%) infiltrating ductal carcinoma, 3 (6%) medullary carcinoma and 3 (6%) mucinous carcinoma. EGFR expression was common in young patients and was predominant in TNBC (89.47%), was also expressed in few cases of NTNBC. There was a positive correlation of EGFR expression (P = 0.03491) with a high grade. Medullary carcinomas were triple negative and strongly expressed EGFR. EGFR expression was inversely associated with ER status and showed strong association with necrosis and lymphocytic infiltrate, but not with pushing border and periductal elastosis. CONCLUSION: EGFR is an important marker to stratify patients with breast cancer according to molecular classification. Its expression correlated positively with young age, higher SBR grade, necrosis, lymphocytic infiltrate and inversely with hormonal receptor expression. PMID- 26417157 TI - Clinicomycological Study of Dermatophytosis in South India. AB - INTRODUCTION: Dermatophytic infections are commonly encountered a problem and constitute more than 50% of cases in dermatology outpatient departments. Diagnosis of these infections requires the proper use of laboratory methods. OBJECTIVES: This study was conducted to know the etiology of dermatophytosis in patients attending Tertiary Care Level Hospital in South India and to compare the efficacy of Sabouraud's dextrose agar (SDA) with actidione and dermatophyte test medium (DTM) in isolating and identifying dermatophytes. MATERIALS AND METHODS: A total of 110 samples which included 101 skin samples and 9 hair samples from clinically suspected dermatophytosis were collected. Direct microscopy by KOH and culture on SDA with actidione and DTM were done. RESULTS: Of 110 samples collected, 58.18% were KOH positive for fungal filaments and 56.36% were culture positive for dermatophytes. More number of cases were observed between age groups of 21-40 years. Males were more affected compared to females. Tinea corporis was the common clinical presentation observed (40%). Trichophyton rubrum (58.06%) was the predominant isolate recovered in all clinical presentations but Trichophyton violaceum was the most common isolate in tinea capitis. All culture positives were grown on both SDA with actidione and DTM. Appearance of growth was earlier on DTM that is, within 10 days compared to SDA with actidione where growth started appearing only after 10 days. This is statistically significant P < 0.0001 (chi(2) = 71.6). Species level identification on primary isolation was possible when grown on SDA with actidione and it was not possible with the growth on DTM on primary isolation. CONCLUSION: DTM is a good screening medium in laboratory diagnosis of dermatophytosis when compared to SDA with actidione. But DTM is inferior to SDA with actidione in identification of dermatophyte species. PMID- 26417158 TI - Etiology of Pancytopenia: An Observation from a Referral Medical Institution of Eastern Region of India. AB - BACKGROUND: Pancytopenia is a relatively common hematological condition, the etiological factors of which vary widely in different geographic location. Determining the specific etiology is of immense importance for appropriate management. AIMS AND OBJECTIVES: The present study was undertaken to delineate etiological factors leading to pancytopenia in a Tertiary Care Hospital of West Bengal from Eastern Region of India. MATERIALS AND METHODS: A prospective study was conducted for a period of 2 years in which 248 patients were included. After obtaining a relevant clinical history, physical examination was done followed by complete blood count including peripheral blood smears examination, relevant biochemical, and radiological investigations. Afterward, bone marrow aspiration and biopsy were performed and microscopically examined. RESULTS: Among 248 patients studied, 156 (62.9%) were males and 92 (37.09%) were females. The mean age of the patients was 33 years. Aplastic anemia was the most common cause of pancytopenia that was observed in 83 cases (33.47%) followed by megaloblastic anemia in 52 cases (20.97%), leishmaniasis in 34 patients (13.71%), hypersplenism also in 34 patients (13.71%), and tuberculosis and other connective tissue disorders in 18 cases (7.26%). The occurrence of aplastic anemia was statistically significant in pediatric (<=15 years) age group. CONCLUSION: Aplastic anemia was found to be the most common cause of pancytopenia in this study, which is in contrast to studies conducted from other regions of India. Delineation of etiologies of pancytopenia in various regions can help in defining diagnostic and therapeutic strategies, which is expected to contribute toward the better management of such patients. PMID- 26417159 TI - Comparison Between Conventional and Automated Techniques for Blood Grouping and Crossmatching: Experience from a Tertiary Care Centre. AB - CONTEXT: The routine immunohematological tests can be performed by automated as well as manual techniques. These techniques have advantages and disadvantages inherent to them. AIMS: The present study aims to compare the results of manual and automated techniques for blood grouping and crossmatching so as to validate the automated system effectively. MATERIALS AND METHODS: A total of 1000 samples were subjected to blood grouping by the conventional tube technique (CTT) and the automated microplate LYRA system on Techno TwinStation. A total of 269 samples (multitransfused patients and multigravida females) were compared for 927 crossmatches by the CTT in indirect antiglobulin phase against the column agglutination technique (CAT) performed on Techno TwinStation. RESULTS: For blood grouping, the study showed a concordance in results for 942/1000 samples (94.2%), discordance for 4/1000 (0.4%) samples and uninterpretable result for 54/1000 samples (5.4%). On resolution, the uninterpretable results reduced to 49/1000 samples (4.9%) with 951/1000 samples (95.1%) showing concordant results. For crossmatching, the automated CAT showed concordant results in 887/927 (95.6%) and discordant results in 3/927 (0.32%) crossmatches as compared to the CTT. Total 37/927 (3.9%) crossmatches were not interpretable by the automated technique. CONCLUSIONS: The automated system shows a high concordance of results with CTT and hence can be brought into routine use. However, the high proportion of uninterpretable results emphasizes on the fact that proper training and standardization are needed prior to its use. PMID- 26417160 TI - Prevalence of Mupirocin Resistance Among Staphylococci, its Clinical Significance and Relationship to Clinical Use. AB - INTRODUCTION: Mupirocin competitively inhibits bacterial isoleucyl transfer-RNA synthetase and inhibit bacterial protein synthesis. Widespread usage and over the counter availability of the drug has resulted in resistance among Staphylococcus species. OBJECTIVES: This study aimed to determine the overall prevalence of mupirocin resistance among staphylococci. Correlate clinical significance of mupirocin resistance and its relationship to clinical use. METHODS: Consecutive, nonrepetitive, clinical isolates of Staphylococcus aureus (n = 98), and coagulase negative staphylococci (CoNS) (n = 45) from skin and soft-tissue infections between January 2014 and June 2014 were studied. Antibiotic susceptibility testing was done according to Clinical and Laboratory Standards Institute guidelines. Low- and high-level mupirocin resistance was screened by using 5 ug and 200 ug discs respectively and confirmed by agar dilution. Annual consumption of mupirocin was studied and correlated with resistance. RESULTS: High-level mupirocin resistance was found in 8.2% S. aureus and 15.6% of CoNS, while low level mupirocin resistance was found in 17% S. aureus and 8.9% CoNS. High-level mupirocin resistance was more common in methicillin-sensitive S. aureus isolates when compared with methicillin-resistant S. aureus isolates (P < 0.05). Mupirocin resistant S. epidermidis were associated with methicillin resistance and constitutive clindamycin resistance. CONCLUSION: High prevalence of mupirocin resistance was found in the present study. Increased prevalence of mupirocin resistance among community-acquired staphylococci demands the judicious use of the drug in the community. PMID- 26417161 TI - Vancomycin-resistance Enterococcal Colonization in Hospitalized Patients in Relation to Antibiotic Usage in a Tertiary Care Hospital of North India. AB - BACKGROUND: Alarming rise of vancomycin-resistant enterococci (VRE) is a global cause of concern. Several factors have been held responsible for such rise, of which antibiotic usage is a prominent one. OBJECTIVE: This study was undertaken to determine the intestinal VRE colonization rate amongst hospitalized patients in relation to use of various antibiotics in the Intensive Care Unit (ICU) of a tertiary care university hospital, India. MATERIALS AND METHODS: Stool samples were collected weekly from all the patients in the adult ICU for a period of 6 months and processed for isolation and phenotypic and genotypic characterization of VRE isolates. Patient and treatment details were noted and cases (those with VRE in stool) and controls (those without VRE in stool) were compared statistically. Further, a multivariate analysis was done to identify those antibiotics as independent risk factors for VRE colonization. RESULTS: VRE colonization was found in 34.56% (28/81) of the patients studied, with the majority 75% (21/28) carrying the vanA gene. The cases had significantly more (P < 0.05) duration of hospital stay and antibiotic exposure. Intake of metronidazole, vancomycin, and piperacillin-tazobactam were identified as significant risk factors both in univariate and multivariate analysis. CONCLUSION: A potential reservoir of VRE was thus revealed even in low VRE prevalence setting. Based on this high colonization status, restriction of empirical antibiotic use, reviewing of the ongoing antibiotic policy, and active VRE surveillance as an integral part of infection control strategy were suggested. PMID- 26417162 TI - Relationship Between Insulin Resistance and Mean Platelet Volume in Gestational Diabetes Mellitus. AB - OBJECTIVES: A few studies have investigated the relationship between mean platelet volume (MPV) and gestational diabetes mellitus (GDM), and in these studies the relationship between MPV and insulin resistance has not been analyzed. Our aim in this study was to compare MPV values of the pregnant women with or without GDM and evaluate the relationship between MPV and homeostasis model assessment insulin resistance index (HOMA-IR) in pregnant women. MATERIALS AND METHODS: One hundred and fourteen with GDM measurements being obtained before any dietary advice or therapy with insulin or hypoglycemic agents were given, and 76 with healthy pregnant women were included the study. RESULTS: In the group with GDM, MPV value was found to be significantly higher than that of the control group (10.2 fl [8.0-12.2] vs. 9.9 fl [5.81-10.9], P = 0.004). HOMA-IR value was detected to be significantly higher in the group with GDM (2.46 [1.5-5.88] vs. 1.30 [0.17-2.92], P < 0.001). A positive correlation between MPV and HOMA-IR was found (r = 0.30, P = 0.002). CONCLUSION: We have shown that MPV was significantly elevated in GDM patients when compared to healthy pregnant women. Furthermore, we found that there was a positive correlation between MPV and HOMA-IR. PMID- 26417163 TI - Febrile Neutropenia in Hematological Malignancies: Clinical and Microbiological Profile and Outcome in High Risk Patients. AB - BACKGROUND AND OBJECTIVES: Febrile neutropenia (FN) is considered a medical emergency. Patients with hematological malignancies (HM) commonly experience FN. Broad spectrum antibiotics have to be started empirically to prevent complications. This study depicts the clinical profile, microbiological profile, antibiotic sensitivity pattern, and outcome in high risk HM. MATERIALS AND METHODS: In this prospective study, 72 patients with hematologic malignancies, diagnosed and treated for 108 high risk febrile neutropenic episodes from August 2011 to January 2013 at a Regional Cancer Center, in South India were analyzed. Cefoperazone-sulbactum was used as a first-line empiric antibiotic. RESULTS: Majority of the patients with FN episodes had acute myeloid leukemia. Overall culture positivity was 29.62%. The most common organisms isolated were Gram negative bacilli (63.64%), with Escherichia coli being the most frequent pathogen. All Gram-negative organisms were sensitive to imipenem, whereas sensitivity pattern to other antibiotics were as follows: 85.71%, 78.26%, 69.52%, 63.64%, 41.66% and 47.05% for pipercillin-tazoactum, meropenem, cefoperazone sulbactum, amikacin, ceftazidime, ciprofloxacin respectively. Overall mortality was 13.5%. Most of the patients responded to empiric antibiotic cefoperazone sulbactum. CONCLUSIONS: In the hematologic malignancies particularly in acute leukemia, there is high risk of developing FN. Empiric therapy with cefoperazone sulbactum as a first line leads to satisfactory outcome in high risk FN and therapy should be tailored to the most appropriate antibiotics according to the bacterial culture results. PMID- 26417165 TI - Achromobacter Xylosoxidans Bloodstream Infection in Elderly Patient with Hepatocellular Carcinoma: Case Report and Review of Literature. AB - Achromobacter xylosoxidansis a nonfermentative Gram-negative organism, known to cause opportunistic infection in humans. We report a case of septicemia in a 76 year-old male patient with underlying hepatocellular carcinoma due to A. xylosoxidans, which showed a different antimicrobial susceptibility pattern from what is usually reported. From aerobic blood culture of the patient, A. xylosoxidans was isolated which was found to be sensitive to amoxicillin clavulanic acid, piperacillin-tazobactam, ceftazidime, cefoperazone-sulbactam, meropenem, minocycline, tigecycline, and trimethoprim/sulfamethoxazole. The patient recovered with amoxicillin-clavulanic acid treatment, which was given empirically to the patient. The present case highlights the possible role of amoxicillin-clavulanic acid for treatment of bloodstream infection with A. xylosoxidans. PMID- 26417164 TI - Renal Abscess Caused by Salmonella Typhi. AB - Salmonella typhi is a true pathogen, which is capable of causing both intestinal and extraintestinal infections. Unusual presentations of Salmonella should always be kept in mind as this organism can cause disease in almost any organ of the body. S. typhi has been reported to cause the life-threatening infections such as meningitis, endocarditis, myocarditis, empyema, and hepatic abscess. Renal involvement by S. typhi is a relatively rare presentation. We report a case of renal abscess caused by S. typhi in an afebrile, 10-year-old child who did not have any clinical history of enteric fever. To our knowledge, this is the first reported case of isolation of S. typhi from the renal abscess, and interestingly this isolate was found to be resistant to quinolones. PMID- 26417166 TI - Transfusion-acquired Hemoglobinopathies: A Report of Two Cases. AB - Transfusion-acquired hemoglobinopathy occurs when a carrier of hemoglobinopathy with no significant abnormalities donates blood, and the blood is transfused to a recipient. This process can lead to spurious results in the recipient without any clinical abnormality or infrequently can result in disastrous situations. The incidental finding of such posttransfusion related abnormal peaks in hemoglobin high-performance liquid chromatography (Hb HPLC) may cause diagnostic dilemmas and result in unnecessary laboratory testing. Here, we report two such cases of transfusion-acquired hemoglobinopathies, which were subsequently resolved by the abnormally low percentage of the Hb variants, transient nature of the peaks, and parental Hb HPLC. PMID- 26417167 TI - Perinatal Autopsy Findings in a Case of De Novo Hypohidrotic Ectodermal Dysplasia. AB - Ectodermal dysplasia are group of inherited disorders involving the developmental defects of ectodermal structures like hair, teeth, nails, sweat glands, and others. X-linked recessive inheritance is most common. Here we describe perinatal autopsy findings in a case of de novo ectodermal dysplasia in a female fetus. To the best of our knowledge, this is the first fetal autopsy description in a case of ectodermal dysplasia. PMID- 26417168 TI - Concomitant Infections of Influenza A H1N1 and Disseminated Cryptococcosis in an HIV Seropositive Patient. AB - Respiratory viral infections, especially influenza have a potential to form a fatal association with cryptococcosis in the setting of compromised immunity. Considering the lethality of these two infections, we report an unusual case of dual infection of pandemic influenza A H1N1 and disseminated cryptococcosis in an HIV seropositive individual. PMID- 26417170 TI - ISMP Survey Reveals User Issues With Carpuject Prefilled Syringes. AB - An ISMP survey finds problems involving proper use of Carpuject prefilled syringes. PMID- 26417169 TI - Cyclosporine Drug Levels: Comparison of the Architect 1000i with the Siemens Dimension RXL System. PMID- 26417171 TI - ACO Final Rule Slights Pharmacy: No "Give" on Drug Pricing, Cost Shifting, and Other Concerns. AB - The Centers for Medicare and Medicaid Service's final ACO rule offers little for pharmacists. PMID- 26417173 TI - Pharmaceutical Approval Update. AB - Sacubitril/valsartan (Entresto) for chronic heart failure; brexpiprazole (Rexulti) for major depressive disorder and schizophrenia; and lumacaftor/ivacaftor (Orkambi) for cystic fibrosis involving specific CFTR mutations. PMID- 26417174 TI - Two Draft FDA Guidance Documents Stir Controversy: Hospital and 503B Pharmacy Repackaging and Compounding Are at Issue. AB - The Food and Drug Administration hopes to close gaps in laws related to repackaging of pharmaceuticals or biologics by hospital pharmacies and bulk compounding facilities. PMID- 26417175 TI - Caring for Glucose-6-Phosphate Dehydrogenase (G6PD)-Deficient Patients: Implications for Pharmacy. AB - This article explores the basis of glucose-6-phosphate dehydrogenase deficiency and defines the role that health care informatics can play in optimal treatment. PMID- 26417176 TI - The Affordable Care Act, Five Years Later: Policies, Progress, and Politics. AB - The Affordable Care Act, which recently survived a second Supreme Court challenge, has increased health care access without causing most of the disruption critics feared. PMID- 26417177 TI - Professional Roles Evolve With Changing Landscape of Legal Risk. AB - Opioid-use monitoring, medication-error prevention, and counseling/duty-to-warn issues illustrate new or emerging legal risks for pharmacists as their roles expand. PMID- 26417178 TI - Researchers Expand Focus on Progressive Forms Of Multiple Sclerosis: Efforts to Pinpoint the Beginning of Disease May Yield Clues to Treatment. AB - With disease-modifying treatments available for relapsing-remitting multiple sclerosis (MS), the quest for therapies for progressive MS has become a key focus of research. PMID- 26417180 TI - European Society of Medical Oncology: 17th World Congress on Gastrointestinal Cancer. AB - We review sessions on metastatic colorectal cancer and hepatocellular carcinoma. PMID- 26417181 TI - Multiple Sclerosis: Progress, but No Cure. AB - Agents are approved to treat exacerbations and symptoms and as disease-modifying therapy. Most therapies in the works would address relapsing forms of the disease. PMID- 26417179 TI - Part 2: Introduction to the Pharmacotherapy of Parkinson's Disease, With a Focus on the Use of Dopaminergic Agents. AB - This second of five articles reviews Parkinson's disease pharmacotherapy, focusing on dopaminergic agents such as levodopa/carbidopa and dopamine receptor agonists. PMID- 26417182 TI - Atherosclerotic Plaque Composition Is Still an Almost Unrecognized Factor of Risk Stratification in Patients with Carotid Artery Disease. PMID- 26417184 TI - Assessment of Carotid Artery Stenosis and the Use of Statins. AB - General thinking has previously centered on managing carotid artery stenosis (CAS) by carotid endarterectomy and subsequently, stenting for higher risk patients. However for CAS and other forms of vascular disease, especially when asymptomatic, there is new emphasis on defining underlying mechanisms. Knowledge of these mechanisms can lead to medical treatments that result in possible atherosclerotic plaque stabilization, and even plaque regression, including in the patient with CAS. For now, the key medication class for a medical approach are the statins. Their use is supported by good cardiovascular clinical trial evidence including some directed carotid artery studies, especially with a demonstrated decrease in carotid intima-media thickness. Procedural controversy still exists but the current era in medicine offers significant support for medical management of asymptomatic CAS while techniques to recognize the vulnerable plaque evolve. If CAS converts to a symptomatic status, early referral for endarterectomy or stenting is indicated. PMID- 26417185 TI - Multimodality Imaging of Carotid Stenosis. AB - Four diagnostic modalities are used to image the following internal carotid artery: digital subtraction angiography (DSA), duplex ultrasound (DUS), computed tomography angiography (CTA), and magnetic resonance angiography (MRA). The aim of this article is to describe the potentials of these techniques and to discuss their advantages and disadvantages. Invasive DSA is still considered the gold standard and is an indivisible part of the carotid stenting procedure. DUS is an inexpensive but operator-dependent tool with limited visibility of the carotid artery course. Conversely, CTA and MRA allow assessment of the carotid artery from the aortic arch to intracranial parts. The disadvantages of CTA are radiation and iodine contrast medium administration. MRA is without radiation but contrast-enhanced MRA is more accurate than noncontrast MRA. The choice of methods depends on the clinical indications and the availability of methods in individual centers. However, the general approach to patient with suspected carotid artery stenosis is to first perform DUS and then other noninvasive methods such as CTA, MRA, or transcranial Doppler US. PMID- 26417186 TI - Utilization of Intravascular Ultrasound during Carotid Artery Stenting. AB - For patients at high risk for surgery, carotid artery stenting (CAS) is a viable alternative to help reduce risk of stroke for patients with high-grade carotid artery stenosis; however, a higher incidence of perioperative stroke has been observed in patients undergoing stenting compared to those undergoing open surgery. Intravascular ultrasound (IVUS) is commonly used during coronary artery procedures to help evaluate lesions and to guide stent placement. Multiple groups have sought to determine whether IVUS could also be used during CAS. While IVUS has been shown to be both feasible and safe during CAS, there is limited evidence that demonstrates direct improvement in procedural outcomes. Further studies focusing on clinical outcomes should be conducted in order to justify routine use of this technology during CAS. PMID- 26417183 TI - Pathophysiology and Medical Treatment of Carotid Artery Stenosis. AB - Stroke is the third leading cause of mortality. Approximately 80 to 85% strokes are ischemic due to carotid artery stenosis (CAS). The prevalence of significant CAS is 7% in women and 9% in men. Severe asymptomatic CAS varies from 0 to 3.1%. Prevalence of symptomatic CAS is high in patients with peripheral arterial disease. CAS is due to atherosclerosis, the major risk factors for which include dyslipidemia, hypertension, diabetes, obesity, cigarette smoking, advanced glycation end products (AGEs) and its receptors (RAGE, soluble RAGE [sRAGE]), lack of exercise and C-reactive protein (CRP). This article discusses the basic mechanism of atherosclerosis and the mechanisms by which these risk factors induce atherosclerosis. The role of AGEs and its receptors in the development and progression of CAS has been discussed in detail. Lifestyle changes and medical treatment of CAS such as lifestyle changes, lipid-lowering agents, antihypertensive agents, antidiabetic drugs, anti-AGE therapy, measures to elevate soluble receptors of AGE (sRAGE, esRAGE). CRP-lowering agents have been discussed in detail. The drugs especially lipid-lowering agents, and antihypertensive and antidiabetic drugs suppress, regress, and slow the progression of CAS. The possible role of lowering the levels of AGEs and raising the levels of sRAGE in the treatment of CAS has been proposed. Lifestyle changes besides medical treatment have been stressed. Lifestyle changes and medical treatment not only would slow the progression of CAS but would also regress the CAS. PMID- 26417187 TI - Ascending Aortic Proaneurysmal Genetic Mutations with Antiatherogenic Effects. AB - Thoracic aortic aneurysms are common and are associated with a high morbidity and mortality. Despite this lethal diagnosis, there is an increasing body of evidence to suggest that the diagnosis of an aneurysm, specifically in the ascending thoracic aorta, may significantly reduce the risk of developing systemic atherosclerosis. Clinical observations in the operating room have shown pristine blood vessels in patients undergoing surgery for thoracic aortic aneurysms. There is now evidence that both the carotid intima-media thickness and arterial calcification, which are early and late signs of atherosclerosis respectively, are decreased in those with thoracic aortic aneurysms. These clinical studies are supported by molecular, genetic, and pharmacological evidence. Two principle mechanisms have been identified to explain the relationship of a proaneurysmal state conferring protection from atherosclerosis. These include an excess proteolytic balance of matrix metalloproteinase activity, leading to fragmentation of elastic lamellae and disordered collagen deposition. In addition, transforming growth factor beta modulates vascular smooth muscle cells, extracellular matrix, and leukocytes. This confers protection from the initial plaque formation and, later provides stability to the plaque possibly through alteration of the types I and II transforming growth factor beta receptor ratio. Furthermore, studies are now beginning to establish an important role for statins and estradiol in modulating these complex pathways. In the future, as our understanding of these complex mechanisms underlying aneurysmal protection against atherosclerosis increases, corresponding therapies may be developed to offer protection from atherosclerosis. PMID- 26417188 TI - Intravascular Near-Infrared Spectroscopy: A Possible Tool for Optimizing the Management of Carotid Artery Disease. AB - Stroke is the second most common cause of morbidity and mortality in the Western nations. It is estimated that approximately one-fifth of all strokes or transient ischemic attacks are caused by carotid artery disease. Thus, treatment of carotid artery disease as a mean of stroke prevention is extremely important. Since the introduction of carotid endarterectomy, debate has persisted over the treatment strategy for carotid artery disease. Current recommendations have many potential flaws because they are often based on older trials performed before the introduction of modern pharmacotherapy and are mostly based on the angiographic degree of stenosis, without an emphasis on the pathophysiology of the disease. Most carotid events are caused by rupture or distal embolization of the content of an unstable atherosclerotic plaque with a large lipid pool. Thus, it is plausible that the information regarding the composition of the atherosclerotic plaque could play an important role in deciding on a treatment strategy. In this review article, we provide information about near-infrared spectroscopy, a new invasive imaging modality, which seems to be capable of providing such information. PMID- 26417189 TI - Carotid Artery Stenting-Historical Context, Trends, and Innovations. AB - Surgical carotid endarterectomy (CEA) has been proven effective in both primary and secondary stroke prevention and, until recently, has been considered the standard treatment approach for patients with severe carotid artery disease. Because of its technical limitations and less favorable outcomes, carotid artery stenting (CAS) has been offered preferably to patients considered to be too comorbid to undergo surgical treatment. However, CAS has evolved over time into a reliable method and is currently considered an alternative to CEA. The aim of this review was to discuss the historical aspects, trends, and innovations in CAS. PMID- 26417190 TI - Predicting Hemodynamic Changes of Cerebral Blood Flow during Temporal Carotid Occlusion: A Review of Current Knowledge with Implication for Carotid Artery Stenting. AB - Carotid artery disease (CAD) plays an important role in the stroke development and its prevalence increases with aging of the population. Its wide variability of clinical manifestation ranges from incidental asymptomatic finding to devastating or fatal stroke, although cerebral collateral circulation is considered one of the major modifying factors. Over time, carotid artery stenting (CAS) has evolved into a reputable method for the treatment of patients with severe CAD. With expanding use of proximal protection systems resembling surgical clamp, there is an increasing demand to understand collateral cerebral circulation to protect patients from periprocedural hypoperfusion, which increases the risk of cerebral events. Transcranial Doppler ultrasound (TCD) is a useful tool allowing monitoring in real time during procedure patients cerebral hemodynamic status providing the operator with valuable information. Its role in predicting periprocedural hypoperfusion is, however, less well established. In this article, we discuss the role of cerebral collateral circulation, summarize the current knowledge regarding its evaluation with TCD and suggest future implications for CAS. PMID- 26417191 TI - Comparative Review of the Treatment Methodologies of Carotid Stenosis. AB - The treatment of carotid stenosis entails three methodologies, namely, medical management, carotid angioplasty and stenting (CAS), as well as carotid endarterectomy (CEA). The North American Symptomatic Carotid Endarterectomy Trial (NASCET) and European Carotid Surgery Trial (ECST) have shown that symptomatic carotid stenosis greater than 70% is best treated with CEA. In asymptomatic patients with carotid stenosis greater than 60%, CEA was more beneficial than treatment with aspirin alone according to the Asymptomatic Carotid Atherosclerosis (ACAS) and Asymptomatic Carotid Stenosis Trial (ACST) trials. When CAS is compared with CEA, the CREST resulted in similar rates of ipsilateral stroke and death rates regardless of symptoms. However, CAS not only increased adverse effects in women, it also amplified stroke rates and death in elderly patients compared with CEA. CAS can maximize its utility in treating focal restenosis after CEA and patients with overwhelming cardiac risk or prior neck irradiation. When performing CEA, using a patch was equated to a more durable result than primary closure, whereas eversion technique is a new methodology deserving a spotlight. Comparing the three major treatment strategies of carotid stenosis has intrinsic drawbacks, as most trials are outdated and they vary in their premises, definitions, and study designs. With the newly codified best medical management including antiplatelet therapies with aspirin and clopidogrel, statin, antihypertensive agents, strict diabetes control, smoking cessation, and life style change, the current trials may demonstrate that asymptomatic carotid stenosis is best treated with best medical therapy. The ongoing trials will illuminate and reshape the treatment paradigm for symptomatic and asymptomatic carotid stenosis. PMID- 26417193 TI - The Paramount Role of the Anterior Communicating Artery in the Collateral Cerebral Circulation. AB - Clinical manifestation of carotid occlusive disease is largely dependent on the severity of stenosis and the capability of collateral circulation. However, due to the complexity and difficulty in evaluation, cerebral collateral circulation has, so far, remained underappreciated. We report a patient with advanced extracranial arterial disease (including the right subclavian steal, occlusion of the right external carotid artery, and severe stenosis of the left vertebral artery), who underwent transient right internal carotid artery occlusion during carotid intervention. Throughout the occlusion, the flow into the right hemisphere (monitored by transcranial Doppler ultrasound in the right middle cerebral artery) was sufficient despite almost totally dependent on the anterior communicating artery, which highlights its role as the most potent collateral pathway. PMID- 26417192 TI - Carotid Endarterectomy: Current Concepts and Practice Patterns. AB - Background Stroke is the number one cause of disability and third leading cause of death among adults in the United States. A major cause of stroke is carotid artery stenosis (CAS) caused by atherosclerotic plaques. Randomized trials have varying results regarding the equivalence and perioperative complication rates of stents versus carotid endarterectomy (CEA) in the management of CAS. Objectives We review the evidence for the current management of CAS and describe the current concepts and practice patterns of CEA. Methods A literature search was conducted using PubMed to identify relevant studies regarding CEA and stenting for the management of CAS. Results The introduction of CAS has led to a decrease in the percentage of CEA and an increase in the number of CAS procedures performed in the context of all revascularization procedures. However, the efficacy of stents in patients with symptomatic CAS remains unclear because of varying results among randomized trials, but the perioperative complication rates exceed those found after CEA. Conclusions Vascular surgeons are uniquely positioned to treat carotid artery disease through medical therapy, CEA, and stenting. Although data from randomized trials differ, it is important for surgeons to make clinical decisions based on the patient. We believe that CAS can be adopted with low complication rate in a selected subgroup of patients, but CEA should remain the standard of care. This current evidence should be incorporated into practice of the modern vascular surgeon. PMID- 26417194 TI - Fibromuscular Dysplasia of Renal and Carotid Arteries. AB - We report here two cases of fibromuscular dysplasia (FMD). The first case describes an asymptomatic 75-year-old man with FMD of the right internal carotid artery. The second case reports a 17-year-old man who presented with arterial hypertension caused by FMD of the left renal artery and was subsequently successfully treated by angioplasty. FMD is a rare nonatherosclerotic, noninflammatory angiopathy, which can involve almost every arterial vascular bed. It is a less common cause of stenosis of renal and carotid arteries. FMD can present with arterial hypertension when it involves renal arteries or with ischemic stroke or transient ischemic attack when the disease affects the carotid or vertebral arteries. Many cases are asymptomatic and may be discovered incidentally. Percutaneous transluminal angioplasty should be used in patients with a stenosis of the renal artery causing arterial hypertension. On the contrary, conservative therapy should be chosen in patients with asymptomatic and extensive lesions of the carotid arteries. PMID- 26417195 TI - Rare Case of Takayasu Arteritis with Concurrent Aneurysmal Dilation and Stenosis. AB - Takayasu arteritis is a rare, chronic large vessel vasculitis that primarily affects women aged 10 to 40 years of Asian descent. The inflammatory processes of the disease can result in stenosis and/or occlusion of the aorta and its branches, causing a wide range of symptoms. Rarely, damage of the elastic lamina or muscular media can cause aneurysmal dilation of the affected vessel. Diagnosis is based on the clinical presentation, laboratory proof of inflammation, and imaging finding of wall thickening in the acute phase and later arterial stenosis or occlusion. Management includes disease control with immunosuppression and some patients might require revascularization. Here, we present a rare case of Takayasu arteritis with both right common carotid artery aneurysmal dilation and stenosis at a conforming site. Although aneurysmal dilation has been sparsely reported in the Takayasu arteritis literature, our case may represent the distinct finding of concomitant dilation and stenosis in this disease. PMID- 26417197 TI - Expression Divergence of Duplicate Genes in the Protein Kinase Superfamily in Pacific Oyster. AB - Gene duplication has been proposed to serve as the engine of evolutionary innovation. It is well recognized that eukaryotic genomes contain a large number of duplicated genes that evolve new functions or expression patterns. However, in mollusks, the evolutionary mechanisms underlying the divergence and the functional maintenance of duplicate genes remain little understood. In the present study, we performed a comprehensive analysis of duplicate genes in the protein kinase superfamily using whole genome and transcriptome data for the Pacific oyster. A total of 64 duplicated gene pairs were identified based on a phylogenetic approach and the reciprocal best BLAST method. By analyzing gene expression from RNA-seq data from 69 different developmental and stimuli-induced conditions (nine tissues, 38 developmental stages, eight dry treatments, seven heat treatments, and seven salty treatments), we found that expression patterns were significantly correlated for a number of duplicate gene pairs, suggesting the conservation of regulatory mechanisms following divergence. Our analysis also identified a subset of duplicate gene pairs with very high expression divergence, indicating that these gene pairs may have been subjected to transcriptional subfunctionalization or neofunctionalization after the initial duplication events. Further analysis revealed a significant correlation between expression and sequence divergence (as revealed by synonymous or nonsynonymous substitution rates) under certain conditions. Taken together, these results provide evidence for duplicate gene sequence and expression divergence in the Pacific oyster, accompanying its adaptation to harsh environments. Our results provide new insights into the evolution of duplicate genes and their expression levels in the Pacific oyster. PMID- 26417196 TI - Assessing Adolescent Substance Abuse Programs with Updated Quality Indicators: The Development of a Consumer Guide for Adolescent Treatment. AB - When adolescent substance abuse requires treatment, few parents know which treatment features are important and which treatment programs are effective. There are few resources to help them select appropriate care. We describe early work on an evaluation method and comparative treatment guide for parents based upon the premise that the quality of a program and its potential effectiveness is a function of the number and frequency of evidence-based treatment practices (EBPs) delivered. Thus, we describe the development of and measurement approach for a set of EBPs toward the goal of developing a Consumer Guide to Adolescent Substance Abuse Treatment. PMID- 26417198 TI - Alview: Portable Software for Viewing Sequence Reads in BAM Formatted Files. AB - The name Alview is a contraction of the term Alignment Viewer. Alview is a compiled to native architecture software tool for visualizing the alignment of sequencing data. Inputs are files of short-read sequences aligned to a reference genome in the SAM/BAM format and files containing reference genome data. Outputs are visualizations of these aligned short reads. Alview is written in portable C with optional graphical user interface (GUI) code written in C, C++, and Objective-C. The application can run in three different ways: as a web server, as a command line tool, or as a native, GUI program. Alview is compatible with Microsoft Windows, Linux, and Apple OS X. It is available as a web demo at https://cgwb.nci.nih.gov/cgi-bin/alview. The source code and Windows/Mac/Linux executables are available via https://github.com/NCIP/alview. PMID- 26417199 TI - Directed Differentiation of Pluripotent Stem Cells into Kidney. AB - Pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), represent an ideal substrate for regenerating kidney cells and tissue lost through injury and disease. Recent studies have demonstrated the ability to differentiate PSCs into populations of nephron progenitor cells that can organize into kidney epithelial structures in three dimensional contexts. While these findings are highly encouraging, further studies need to be performed to improve the efficiency and specificity of kidney differentiation. The identification of specific markers of the differentiation process is critical to the development of protocols that effectively recapitulate nephrogenesis in vitro. In this review, we summarize the current studies describing the differentiation of ESCs and iPSCs into cells of the kidney lineage. We also present an analysis of the markers relevant to the stages of kidney development and differentiation and propose a new roadmap for the directed differentiation of PSCs into nephron progenitor cells of the metanephric mesenchyme. PMID- 26417201 TI - Molecular Dynamics Approach in the Comparison of Wild-Type and Mutant Paraoxonase 1 Apoenzyme Form. AB - There is some evidence linking the mammalian paraoxonase-1 (PON1) loops (L1 and L2) to an increased flexibility and reactivity of its active site with potential substrates. The aim of this work is to study the structural, dynamical, and functional effects of the most flexible regions close to the active site and to determine the impact of mutations on the protein. For both models, wild-type (PON1wild) and PON1 mutant (PON1mut) models, the L1 loop and Q/R and L/M mutations were constructed using MODELLER software. Molecular dynamics simulations of 20 ns at 300 K on fully modeled PON1wild and PON1mut apoenzyme have been done. Detailed analyses of the root-mean-square deviation and fluctuations, H-bonding pattern, and torsion angles have been performed. The PON1wild results were then compared with those obtained for the PON1mut. Our results show that the active site in the wild-type structure is characterized by two distinct movements of opened and closed conformations of the L1 and L2 loops. The alternating and repetitive movement of loops at specific times is consistent with the presence of 11 defined hydrogen bonds. In the PON1mut, these open-closed movements are therefore totally influenced and repressed by the Q/R and L/M mutations. In fact, these mutations seem to impact the PON1mut active site by directly reducing the catalytic core flexibility, while maintaining a significant mobility of the switch regions delineated by the loops surrounding the active site. The impact of the studied mutations on structure and dynamics proprieties of the protein may subsequently contribute to the loss of both flexibility and activity of the PON1 enzyme. PMID- 26417200 TI - Biomarkers for Sepsis: What Is and What Might Be? AB - Every year numerous individuals develop the morbid condition of sepsis. Therefore, novel biomarkers that might better inform clinicians treating such patients are sorely needed. Difficulty in identifying such markers is in part due to the complex heterogeneity of sepsis, resulting from the broad and vague definition of this state/condition based on numerous possible clinical signs and symptoms as well as an incomplete understanding of the underlying pathobiology of this complex condition. This review considers some of the attempts that have been made so far, looking at both the pro- and anti-inflammatory response to sepsis, as well as genomic analysis, as sources of potential biomarkers. Irrespective, for functional biomarker(s) of sepsis to successfully translate from the laboratory to a clinical setting, the biomarker must be target specific and sensitive as well as easy to implement/interpret, and be cost effective, such that they can be utilized routinely in patient diagnosis and treatment. PMID- 26417203 TI - Everolimus in the Treatment of Metastatic Breast Cancer. AB - The discovery of the mammalian target of rapamycin (mTOR) molecular pathway has brought insight into its vital role in breast cancer pathogenesis. Several clinical trials have shown that the mTOR inhibitor everolimus could improve patient outcomes in several subtypes of breast cancer, including hormone receptor positive, human epidermal growth factor receptor-negative metastatic disease that has progressed after prior endocrine therapy. This review summarizes findings from clinical trials that have demonstrated the benefit of everolimus in metastatic breast cancer and highlights some new research directions utilizing everolimus. PMID- 26417202 TI - Impact of Chronic Pain on Treatment Prognosis for Patients with Opioid Use Disorder: A Systematic Review and Meta-analysis. AB - BACKGROUND: While a number of pharmacological interventions exist for the treatment of opioid use disorder, evidence evaluating the effect of pain on substance use behavior, attrition rate, and physical or mental health among these therapies has not been well established. We aim to evaluate these effects using evidence gathered from a systematic review of studies evaluating chronic non cancer pain (CNCP) in patients with opioid use disorder. METHODS: We searched the Medline, EMBASE, PubMed, PsycINFO, Web of Science, Cochrane Database of Systematic Reviews, ProQuest Dissertations and theses Database, Cochrane Central Register of Controlled Trials, World Health Organization International Clinical Trials Registry Platform Search Portal, and National Institutes for Health Clinical Trials Registry databases to identify articles evaluating the impact of pain on addiction treatment outcomes for patients maintained on opioid agonist therapy. RESULTS: Upon screening 3,540 articles, 14 studies with a combined sample of 3,128 patients fulfilled the review inclusion criteria. Results from the meta-analysis suggest that pain has no effect on illicit opioid consumption [pooled odds ratio (pOR): 0.70, 95%CI 0.41-1.17; I (2) = 0.0] but a protective effect for reducing illicit non-opioid substance use (pOR: 0.57, 95%CI 0.41-0.79; I (2) = 0.0). Studies evaluating illicit opioid consumption using other measures demonstrate pain to increase the risk for opioid abuse. Pain is significantly associated with the presence of psychiatric disorders (pOR: 2.18; 95%CI 1.6, 2.9; I (2) = 0.0%). CONCLUSION: CNCP may increase risk for continued opioid abuse and poor psychiatric functioning. Qualitative synthesis of the findings suggests that major methodological differences in the design and measurement of pain and treatment response outcomes are likely impacting the effect estimates. PMID- 26417204 TI - Subverting Subversion: A Review on the Breast Cancer Microenvironment and Therapeutic Opportunities. AB - This review combines the recent research on the subject of tumor immunology and methods of correcting the immune system's reaction to the tumor microenvironment while impeding the survival and growth of tumor cells, with a focus on breast cancer. Induction of hypoxia-inducible genes in the microenvironment leads to lowering of its pH. This impedes the adaptive immune response and acts to recruit cells of the immune system, which suppress the immune response. Regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and their derivatives coordinate an anti-autoimmunity response and a healing response in concert with tumor-secreted cytokines, enzymes, and antigens. Together, they suppress a proper immune reaction to tumor cells and promote cellular reproduction (Fig. 1). In addition, the hypoxia-inducible response and components of the tumor microenvironment such as cancer-associated fibroblasts (CAFs) also create an ideal environment for tumor growth and metastasis via neoangiogenesis and increased motility. Broad-spectrum chemotherapy drugs are problematic as breast cancer cells develop resistance through selective loss of a novel target and downregulation of apoptotic factors. A better understanding of the tumor microenvironment offers new therapeutic opportunities to rescue the immune response, inhibit cancer cell growth pathways, and subvert the tumor microenvironment with little toxicity and side effects. PMID- 26417206 TI - "Now I Can Do Better": A Study of Obese Women's Experiences Following a Nonprescriptive Nutritional Intervention. AB - The present study analyzed obese women's experiences following a nonprescriptive nutritional intervention, implemented through a 1-year program based on the Health at Every Size((r)) philosophy. We employed an action research method and conducted three focus groups during the intervention. We identified five interpretative axes across the focus groups, as follows: conflicts and perceptions; gaining motivation, perspective, and positioning; becoming autonomous eaters; acquiring tools; and the meetings between the nutritional therapist and participant. Our findings revealed varying levels of readiness among participants in adapting to the intervention and varying valuations of achievements related to eating and health, independent of body-weight changes. Participants reported benefiting from and expressed approval of the intervention. Participants reported positive behavioral and attitudinal changes to their diet and improvements to diet quality, diet structure, and consumption. Finally, participants seemed to show increased autonomy concerning diet and indicated increased confidence, comfort, flexibility, and positivity of attitude regarding eating. PMID- 26417207 TI - Robotic Approaches to Palatoplasty and the Treatment of Velopharyngeal Dysfunction. AB - The operative techniques used to address palatoplasty and velopharyngeal dysfunction rely on traditional methods of surgical exposure and tissue handling. As the role of robotic surgical systems has expanded, emphasis has shifted from extirpative to reconstructive applications. We discuss the possible role of surgical telemanipulation systems in the treatment of these diagnoses. Furthermore, we present a feasibility study that addresses a commonly performed treatment of velopharyngeal dysfunction-posterior pharyngeal flap (PPF). In brief, PPFs were successfully performed on a small series of cadaveric human specimens. The technical aspects of the procedure, including telemanipulator set up, positioning, surgical instrumentation, and timing are described in detail. All cadavers underwent successful performance of PPFs. Operative times were within an acceptable range and use of the robotic system demonstrated a steep learning curve. Many of the potential advantages and costs associated with robotic surgical systems are discussed. PMID- 26417205 TI - Selective Regulation of Oocyte Meiotic Events Enhances Progress in Fertility Preservation Methods. AB - Following early embryonic germ cell migration, oocytes are surrounded by somatic cells and remain arrested at diplotene stage until luteinizing hormone (LH) surge. Strict regulation of both meiotic arrest and meiotic resumption during dormant stage are critical for future fertility. Inter-cellular signaling system between the somatic compartment and oocyte regulates these meiotic events and determines the follicle quality. As well as the collected number of eggs, their qualities are also important for in vitro fertilization (IVF) outcome. In spontaneous and IVF cycles, germinal vesicle (GV)-stage oocytes, premature GV breakdown, and persistence of first meiotic arrest limit the reproductive performance. Likewise, both women with premature ovarian aging and young cancer women are undergoing chemoradiotherapy under the risk of follicle loss because of unregulated meiotic events. Understanding of oocyte meiotic events is therefore critical for the prevention of functional ovarian reserve. High levels of cyclic guanosine monophophate (cGMP), cyclic adenosine monophophate (cAMP) and low phosphodiesterase (PDE) 3A enzyme activity inside the oocyte are responsible for maintaining of meiotic arrest before the LH surge. cGMP is produced in the somatic compartment, and natriuretic peptide precursor C (Nppc) and natriuretic peptide receptor 2 (Npr2) regulate its production. cGMP diffuses into the oocyte and reduces the PDE3A activity, which inhibits the conversion of cAMP to the 5'AMP, and cAMP levels are enhanced. In addition, oocyte itself has the ability to produce cAMP. Taken together, accumulation of cAMP inside the oocyte induces protein kinase activity, which leads to the inhibition of maturation-promoting factor and meiotic arrest also continues. By stimulating the expression of epidermal growth factor, LH inhibits the Nppc/Npr2 system, blocks cGMP synthesis, and initiates meiotic resumption. Oocytes lacking the functional of this pathway may lead to persistence of the GV oocyte, which reduces the number of good quality eggs. Selective regulation of somatic cell signals and oocyte meiotic events enhance progress in fertility preservation methods, which may give us the opportunity to prevent follicle loss in prematurely aging women and young women with cancer are undergoing chemoradiotherapy. PMID- 26417209 TI - Te Whiringa Ora: person-centred and integrated care in the Eastern Bay of Plenty, New Zealand. AB - Te Whiringa Ora is a community-based programme in New Zealand that facilitates interdisciplinary care for patients and their family. It targets those with a chronic disease whom have high inpatient admissions or emergency department presentations. It is based in a rural part of New Zealand that has a large indigenous population, and a relatively high level of social deprivation. The programme makes use of culturally appropriate care coordinators, and uses telephone support and tele-monitoring to aid self-management. The programme has been running for three years and has shown a reduction on hospital presentations, as compared to an equivalent population (not enrolled in the programme). This case study outlines the programme, and focuses specifically on the implementation processes, and lessons learnt. PMID- 26417208 TI - Advances in the Treatment of Syndromic Midface Hypoplasia Using Monobloc and Facial Bipartition Distraction Osteogenesis. AB - Midface hypoplasia or retrusion remains a persistent feature of syndromic craniosynostosis years after successful treatment of the cranium. Although expansion of the cranial vault in infancy by traditional fronto-orbital advancement, posterior expansion, or both, can treat the immediate intracranial constriction, midface hypoplasia and its stigmata of exorbitism, sleep apnea, central face concavity, and malocclusion remain suboptimally treated. Initial enthusiasm for the procedures was tempered due to a high rate of infectious complications; timing and indications for surgery continue to stir controversy. During the last decade renewed interest with the monobloc and facial bipartition procedure using distraction osteogenesis with either an internal or external distraction system has decreased morbidity significantly. These procedures have re-emerged as powerful and comprehensive tools in the treatment of syndromic midface hypoplasia. PMID- 26417210 TI - Bridging the chronic care gap: HealthOne Mt Druitt, Australia. AB - HealthOne was part of a state-wide initiative to invest in new community-based facilities for collocating services. The HealthOne Mount Druitt is a virtual hub and spoke organisation established in 2006 in a socially disadvantaged part of Western Sydney based out of a new community health hub. The model is based on 'virtual' care planning and aims to improve coordination of care for older people with complex health needs, reduce unnecessary hospitalisations and ensure appropriate referral to community and specialist health services. General practitioner liaison nurses (GPLNs) work closely with clients as well as general practitioners (GPs) and other health care providers. Primary health care providers reported improved communication and coordination of services, and there have been lower levels of utilisation of the emergency department (ED) for patients following enrolment in the programme. HealthOne provides an example of how a virtual organisation together with highly skilled care coordinators can overcome some of the barriers to providing integrated care created by fragmented funding streams and care delivery systems. PMID- 26417211 TI - Managing high-risk patients: the Mass General care management programme. AB - The Massachusetts General Care Management Program (Mass General CMP or CMP) was designed as a federally supported demonstration to test the impact of intensive, practice-based care management on high-cost Medicare fee-for-service (FFS) beneficiaries-primarily older persons-with multiple hospitalisations and multiple chronic conditions. The Massachusetts General Care Management Program operated over a 6-year period in two phases (3 years each). It started during the first phase at Massachusetts General Hospital, a major academic medical centre in Boston, Massachusetts in collaboration with Massachusetts General Physicians Organisation. During the second phase, the programme expanded to two more affiliated sites in and around the Boston area, including a community hospital, as well as incorporated several modifications primarily focused on the management of transitions to post-acute care in skilled nursing facilities. At the close of the demonstration in July 2012, Mass General Massachusetts General Care Management Program became a component of a new Pioneer accountable care organisation (ACO). The Massachusetts General Care Management Program is focused on individuals meeting defined eligibility criteria who are offered care that is integrated by a case manager embedded in a primary care practice. The demonstration project showed substantial cost savings compared to fee-for-service patients served in the traditional Medicare system but no impact on hospital readmissions. The Massachusetts General Care Management Program does not rest upon a "whole systems" approach to integrated care. It is an excellent example of how an innovative care co-ordination programme can be implemented in an existing health-care organisation without making fundamental changes in its underlying structure or the way in which direct patient care services are paid for. The accountable care organisation version of the Massachusetts General Care Management Program includes the staffing structure, standards of practice, collaborative approach to care transitions and information technology tools that were used in the original demonstration project. PMID- 26417212 TI - PRISMA: Program of Research to Integrate the Services for the Maintenance of Autonomy. A system-level integration model in Quebec. AB - The Program of Research to Integrate the Services for the Maintenance of Autonomy (PRISMA) began in Quebec in 1999. Evaluation results indicated that the PRISMA Project improved the system of care for the frail elderly at no additional cost. In 2001, the Quebec Ministry of Health and Social Services made implementing the six features of the PRISMA approach a province-wide goal in the programme now known as RSIPA (French acronym). Extensive Province-wide progress has been made since then, but ongoing challenges include reducing unmet need for case management and home care services, creating incentives for increased physician participation in care planning and improving the computerized client chart, among others. PRISMA is the only evaluated international model of a coordination approach to integration and one of the few, if not the only, integration model to have been adopted at the system level by policy-makers. PMID- 26417213 TI - Determinants of 25-Hydroxyvitamin D Concentrations in Infants and Toddlers. AB - BACKGROUND: Resurgence of rickets and recognition of excessive prevalence of hypovitaminosis D among all age groups in the western hemisphere have refocused attention on vitamin D nutrition. OBJECTIVE: To examine the prevalence of hypovitaminosis D [25-hydroxyvitamin D [25(OH)D] <30ng/mL] and characterize the determinants of 25(OH)D concentrations in 8- to 24-month-old healthy infants and toddlers living in Pittsburgh, Pennsylvania. METHODS: Serum 25(OH)D concentrations were measured and dietary intake of vitamin D, mode of feeding, summertime sun exposure characteristics, and skin color (sun-reactive skin type and melanin index) were assessed. RESULTS: A total of 111 healthy 8- to 24-month old children (mean age [+/-SD] 14.4 [+/-3.5] months; male, 51%; black, 67%) were studied. Serum 25(OH)D concentration was <30 ng/mL in 16% (n=18) of the children. Median (interquartile) 25(OH)D concentration was lower in children who were >= 13 months vs. <13 months of age [35 (31, 40.5) vs. 40 (35.8, 44.3) ng/mL, p=0.013]; with sun-reactive skin type IV and V vs. I, II, and III [36 (31, 41) vs. 44 (36.5, 48.5) ng/mL, p=0.001]; and examined during fall/winter vs. spring/summer [35.5 (32.5, 38.5) vs. 39 (32.5, 44) ng/mL, p=0.05]. Age and skin type were significant independent predictors of 25(OH)D. CONCLUSIONS: Concentrations of 25(OH)D tend to be lower in infants and toddlers during fall/winter, and in children who are older (>=13 months vs. <13 months of age) and have darker skin tone. Benefits of enhancement of 25(OH)D concentrations during fall/winter and in children with higher sun-reactive skin type need further exploration. PMID- 26417214 TI - Association of the virulence factors of Helicobacter pylori and gastric mucosal interleukin-17/23 mRNA expression in dyspeptic patients. AB - The molecular pathways that control Helicobacter pylori (Hp)-associated inflammatory reaction are complex, but locally induced cytokines and virulence factors seem to have a major role in maintaining the ongoing inflammation. Therefore this study was aimed to evaluate the association of the virulence factors of Hp and gastric mucosal interleukin-17/23 mRNA expression in dyspeptic patients. Mucosal IL-17 and IL-23 mRNA expression in H. pylori infected and non infected gastric biopsies were determined by real-time RT-PCR. Virulence factors, vac-A and cag-A were evaluated using PCR. There was no significant difference in mucosal IL-17 and IL-23 mRNA expression between H. pylori infected and non infected patients. Their expression in mucosa did not correlate with chronic gastritis and chronic active gastritis. IL-17 and IL-23 mRNA expression in mucosa of patients with vacA m1 were significantly higher than those observed in patients with vacA m2. The severity of polymorphonuclear infiltration and chronic active gastritis was higher in cag-A positive than cag-A negative patients. H. pylori infections carrying the vacA m1 allele have higher IL-17 and IL-23 mRNA and the current study suggests that the virulence factor vacA allele's m1 are important for the severe gastric inflammation. PMID- 26417215 TI - Optimization of dilute acid pretreatment of water hyacinth biomass for enzymatic hydrolysis and ethanol production. AB - The present study was conducted for the optimization of pretreatment process that was used for enzymatic hydrolysis of lignocellulosic biomass (Water Hyacinth, WH), which is a renewable resource for the production of bioethanol with decentralized availability. Response surface methodology has been employed for the optimization of temperature ((o)C), time (hr) and different concentrations of maleic acid (MA), sulfuric acid (SA) and phosphoric acid (PA) that seemed to be significant variables with P < 0.05. High F and R (2) values and low P-value for hydrolysis yield indicated the model predictability. The pretreated biomass producing 39.96 g/l, 39.86 g/l and 37.9 g/l of reducing sugars during enzymatic hydrolysis with yield 79.93, 78.71 and 75.9 % from PA, MA and SA treated respectively. The order of catalytic effectiveness for hydrolysis yield was found to be phosphoric acid > maleic acid > sulfuric acid. Mixture of sugars was obtained during dilute acid pretreatment with glucose being the most prominent sugar while pure glucose was obtained during enzymatic hydrolysis. The resulting sugars, obtained during enzymatic hydrolysis were finally fermented to ethanol, with yield 0.484 g/g of reducing sugars which is 95 % of theoretical yield (0.51 g/g glucose) by using commercial baker's yeast (Sacchromyces cerveasiae). PMID- 26417216 TI - Scatter-search with support vector machine for prediction of relative solvent accessibility. AB - Proteins have vital roles in the living cells. The protein function is almost completely dependent on protein structure. The prediction of relative solvent accessibility gives helpful information for the prediction of tertiary structure of a protein. In recent years several relative solvent accessibility (RSA) prediction methods including those that generate real values and those that predict discrete states have been developed. The proposed method consists of two main steps: the first one, provided subset selection of quantitative features based on selected qualitative features and the second, dedicated to train a model with selected quantitative features for RSA prediction. The results show that the proposed method has an improvement in average prediction accuracy and training time. The proposed method can dig out all the valuable knowledge about which physicochemical features of amino acids are deemed more important in prediction of RSA without human supervision, which is of great importance for biologists and their future researches. PMID- 26417217 TI - Comparing the effect of clofibrate and phenobarbital on the newborns with hyperbilirubinemia. AB - The aim of treating hyperbilirubinemia is preventing the serum bilirubin to reach neurotoxic levels, which is done by phototherapy or blood transfusion. However, pharmacological treatments still remain vague. Therefore the effects of adding either clofibrate or phenobarbital on treatment outcomes was evaluated in icteric non-hemolitic newborns. Ninety neonates were divided in three groups. Two groups were prescribed 100 mg/kg clofibrate or 5 mg/kg phenobarbital orally as single dose on arrival, in addition to phototherapy. The control group only received phototherapy. Serum bilirubin was evaluated at the reception and 12, 24, 48 and 72 hours after beginning of drug therapy. Total bilirubin levels decreased in treated groups compared with the control group in all samples taken (12, 24, 48 and 72 hours). Clofibrate effect in decreasing bilirubin level was more prominent (14 % and 32 % after 12 and 72 h respectively). In addition duration of hospitalization and length of phototherapy decreased in clofibrate and phenobarbital groups compared with control group (1.5, 2 days respectively, vs. 2.6 days). Therefore using clofibrate and phenobarbital in icteric neonates are supportive not only by decreasing the serum bilirubin level, but also by lessening the duration of hospitalization and phototherapy. Thus in addition to cost benefits for the patient these drugs can reduce the risks of transfusion, and clofibrate seems more promising in this regard. PMID- 26417218 TI - Prevalence of ESBL, AmpC beta-lactamases and MRSA among uropathogens and its antibiogram. AB - Urinary tract infections (UTIs) are one of the most common bacterial infections in humans. Current knowledge on antimicrobial susceptibility pattern is essential for appropriate therapy. Therefore the aim of the present study was to determine the distribution and antibiotic susceptibility pattern of bacterial strains, with special reference to ESBL, AmpC beta-lactamase and MRSA production. A total of 325 clinical isolates were collected from UTI patients from various tertiary care hospitals over a period of 6 months (June 2011 to December 2011). The antimicrobial susceptibility to various drugs was studied by the disc diffusion method as guided by CLSI guidelines. Confirmation of the extended spectrum beta lactamase (ESBL), AmpC beta-lactamase and methicillin resistant Staphylococcus aureus (MRSA) production was done by an E-test respectively. Of the 325 isolates, 225 were characterized as gram negative and 77 isolates as S. aureus isolates. The majority (69.3 %) of the isolates were from females compared to males (30.7 %). Prevalence of ESBL and AmpC beta-lactamase and the coexistence of the phenotype (ESBL+ AmpC beta-lactamase) and MRSA in the urinary isolates were found to be 48.9 %, 20.4 %, 6.2 % and 27.5 % respectively. Ampicillin/sulbactam, norfloxacin should be no longer considered as first line of drugs for UTI, because of high resistance. Parentral drugs such as aminoglycosides, carbapenems and piperacillin/tazobactum can be the alternative choice for complicated UTI. Also, control measures such as judicious use of antibiotics, formulation of infection committee may control the spread of resistance. PMID- 26417219 TI - Effects of drought stress on the seed germination and early seedling growth of the endemic desert plant Eremosparton songoricum (Fabaceae). AB - Eremosparton songoricum (Litv.) Vass. is an endemic and extremely drought resistant desert plant with populations that are gradually declining due to the failure of sexual recruitment. The effects of drought stress on the seed germination and physiological characteristics of seeds and seedlings were investigated. The results showed that the germination percentage decreased with an increase of polyethylene glycol 6000 (PEG) concentration: -0.3 MPa (5 % PEG) had a promoting effect on seed germination, -0.9 MPa (15 % PEG) dramatically reduced germination, and -1.8 MPa (30 % PEG) was the threshold for E. songoricum germination. However, the contents of proline and soluble sugars and the activity of CAT increased with increasing PEG concentrations. At the young seedling stage, the proline content and CAT, SOD and POD activities all increased at 2 h and then decreased; except for a decrease at 2 h, the MDA content also increased compared to the control (0 h). These results indicated that 2 h may be a key response time point for E. songoricum to resist drought stress. The above results demonstrate that drought stress can suppress and delay the germination of E. songoricum and that the seeds accumulate osmolytes and augment the activity of antioxidative enzymes to cope with drought injury. E. songoricum seedlings are sensitive to water stress and can quickly respond to drought but cannot tolerate drought for an extended period. Although such physiological and biochemical changes are important strategies for E. songoricum to adapt to a drought-prone environment, they may be, at least partially, responsible for the failure of sexual reproduction under natural conditions. PMID- 26417220 TI - The effects of ursolic acid on cytokine production via the MAPK pathways in leukemic T-cells. AB - Ursolic acid (UA) is a pentacyclic triterpenoid carboxylic acid that is found in plants and herbal products. It is one of the chemopreventive agents, which can suppress cancer cell proliferation and induce apoptosis. UA possesses various biological activities including anticancer, anti-inflammatory, anti-oxidative and hepatoprotective activity. We investigated the effect of UA on cytokine production via the MAPK pathways in Jurkat leukemic T-cells, showing that UA inhibited cell growth and proliferation of Jurkat cells, as well as suppressing PMA/PHA induced IL-2 and TNF-alpha production in a concentration and time dependent manner. The inhibition of IL-2 and TNF-alpha production by UA involved the c-Jun N-terminal kinase (JNK) pathway, but not the extracellular-signal regulated protein kinase (ERK) pathway. Future utilization of UA as a chemopreventive or therapeutic agent may provide an alternative option for leukemia treatments. PMID- 26417221 TI - Modulatory effect of semelil (ANGIPARSTM) on isoproterenol induced cardiac injury. AB - Administration of semelil (ANGIPARSTM) has been successful in the treatment of diabetic foot ulcer. Considering the improvement of blood flow and anti inflammatory effect that are attributed to this drug, we investigated its effect on cardiovascular performance in rabbits with isoproterenol (ISO) induced myocardial injury. Animal groups included: control group; ISO group, received ISO 50 mg/kg s.c. for two consecutive days; S1+ISO, S5+ISO and S10+ISO groups, received semelil 1, 5, and 10 mg/kg/day i.p. respectively, 30 min before ISO. On the 3(rd) day, electrocardiogram (ECG) and hemodynamic parameters were recorded; blood samples were taken and hearts were removed for lab investigations. ISO induced heart injury, ECG disturbance, raise of cardiac troponin I and significant decrease in LVSP (p<0.05), +dp/dt max (p<0.01), -dp/dt max (p<0.05) along with increase of LVEDP (p<0.01). Semelil had no significant effects on ECG and plasma cardiac troponin I. Impairment of +dp/dt max and -dp/dt max was significantly improved in S5+ISO and S10+ISO groups (P<0.05 versus ISO). In addition, LVSP and LVEDP was somewhat recovered in these groups, although semelil (1 mg/kg/day) to some extent exacerbated the myocardial lesions induced by ISO (P<0.05). Therefore, in stressful conditions, semelil may improve myocardial contractility; however, it may aggravate the severity of injury. PMID- 26417222 TI - Combined 3D-QSAR modeling and molecular docking study on multi-acting quinazoline derivatives as HER2 kinase inhibitors. AB - A series of new quinazoline derivatives has been recently reported as potent multi-acting histone deacetylase (HDAC), epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER2) inhibitors. HER2 is one of the major targets for the treatment of breast cancer and other carcinomas. Three dimensional structure-activity relationship (3D-QSAR) is a well-known technique, which is used to drug design and development. This technique is used for quantitatively predicting the interaction between a molecule and the active site of a specific target. For each 3D-QSAR study, a three-dimensional model is created from a large curve fit to find a fitting between computational descriptors and biological activity. This model could be used as a predictive tool in drug design. The best model has the highest correlation between theoretical and experimental data. Self-Organizing Molecular Field Analysis (SOMFA), a grid-based and alignment-dependent 3D-QSAR method, is employed to study the correlation between the molecular properties and HER2 inhibitory potency of the quinazoline derivatives. Before presentation of inhibitor structures to SOMFA study, conformation of inhibitors was determined by AutoDock4, HyperChem and AutoDock Vina, separately. Overall, six independent models were produced and evaluated by the statistical partial least square (PLS) analysis. Among the several generated 3D-QSARs, the best model was selected on the basis of its statistical significance and predictive potential. The model derived from the superposition of docked conformation with AutoDock Vina with reasonable cross-validated q(2) (0.767), non cross-validated r(2) (0.815) and F test (97.22) values showed a desirable predictive capability. Analysis of SOMFA model could provide some useful information in the design of novel HER2 kinase inhibitors with better spectrum of activity. PMID- 26417223 TI - Post transplant lymphoproliferative disorder: a case series and review of literature. AB - Post-transplant lymphoproliferative disorder (PTLD) is a recognized complication exclusive to solid organ transplant recipients and carries a high mortality. We retrospectively reviewed records of all renal transplant recipients under follow up at our institution over the last seven years (2005-2011). We reviewed the patient characteristics, immunosuppression regimen and risk factors for the development of PTLD and its outcomes in our transplant cohort. Four out of 63 patients were diagnosed with PTLD. PTLD was incidentally diagnosed on a transplant biopsy that was performed for an unexplained rise in serum creatinine in three patients. The fourth patient presented with left submandibular lymphadenopathy. Majority presented within 18 months of renal transplantation. After the diagnosis of PTLD on graft biopsy, all patients were fully investigated and two patients had systemic involvement. In the patients with systemic involvement, reduction of immunosuppression and anti B cell therapy with Rituximab was used with good success. The patient with submandibular lymphadenopathy received chemotherapy in addition to reduction of immunosuppression. Three PTLD cases were polyclonal and diagnosed early whereas the fourth case was monoclonal. PTLD can sometimes be incidentally diagnosed on an allograft biopsy performed for rejection. The incidence of PTLD in our centre is higher than reports from other centres but our outcome is good if recognised and treated early. PMID- 26417224 TI - Antioxidative, antimicrobial and cytotoxic properties of Isatis floribunda Boiss. ex Bornm. extracts. AB - The Isatis species has antibacterial, anticancer and antiviral properties and these important endemic plants grow widely in various parts of Anatolian-Turkey. In the present study, the antioxidant activities of Isatis floribunda Boiss. ex Bornm. flower and root extracts were determined with total antioxidant activity, free radical scavenging activity, ferric ion reducing power, and cupric ion reducing antioxidant capacity assay. The total phenolic compounds and flavonoids were also examined for the extracts. The antimicrobial activities of the extracts were investigated by using the disc diffusion and microdilution-broth methods against human and fish pathogen microorganisms. The phenolic composition of I. floribunda root methanolic extract was analyzed by high performance liquid chromatography (HPLC). The major component in the extract was cholorogenic acid (1980.20 ug/g). The cytotoxic effect of the methanolic root extract was also tested on human breast cell (MCF12A). The results showed that I. floribunda could be used as a natural source in the food and feed industry and clinical and food chemistry, and that the antimicrobial agents could be used against human and fish pathogens. PMID- 26417225 TI - Novel inhibitor discovery against aromatase through virtual screening and molecular dynamic simulation: a computational approach in drug design. AB - Inhibition of aromatase (CYTP450) as a key enzyme in the estrogen biosynthesis could result in regression of estrogen-dependent tumors and even preventing the promotion of breast cancer. Although today potent steroid and non-steroid inhibitors of aromatase are available, isoflavanone derivatives as natural compounds with least side effects have been described as the candidate for a new generation of aromatase inhibitors. 2a as an isoflavanone derivative is the most potent inhibitor of aromatase, synthesized by Bonfield et al. (2012[7]). In our computational study, the mentioned compound was used as the template for virtual screening. Between 286 selected compounds with 70 % of structural similarity to 2a, 150 of them showed lower docking energy in comparison with 2a. Compound 2a_1 with 11.2 kcal/mol had the lowest docking energy. Interaction of 2a_1 with aromatase was further investigated and compared with 2a and androstenedione (ASD) as a natural substrate of aromatase, through 20 ns of molecular dynamic simulation. Analysis of trajectories showed, while ASD interacts with aromatase through hydrogen bonds and 2a just interacts via hydrophobic forces, 2a_1 not only accommodates in the hydrophobic active site of aromatase in a suitable manner but it also makes a stable coordination with iron atom of aromatase heme group via OB. PMID- 26417226 TI - Preventive effect of N-acetylcysteine in a mouse model of steroid resistant acute exacerbation of asthma. AB - Oxidative stress appears to have an important role in glucocorticoid insensitivity, as a crucial problem in asthma therapy. We studied the preventive effect of antioxidant N-acetylcysteine (NAC) on the airway hyper-responsiveness (AHR) and the accumulation of inflammatory cells in the airways in an animal model of steroid resistant acute exacerbation of asthma. Systemically sensitized Balb/C mice were exposed to Ovalbumin aerosol on days 13, 14, 15 and 16, followed by intratracheal lipopolysaccharide (LPS) to induce acute exacerbation. NAC (intraperitoneal, 320 mg/kg 30 min before and 12 hours after each challenge) reduced hyper-responsiveness with/out dexamethasone. LPS application caused neutrophilia in bronchoalveolar lavage fluid (BALF) and eosinophil count was higher than respective control in BALF as well as neutrophils after dexamethasone treatment. NAC significantly decreased neutrophil and eosinophil count in BALF as well as inflammatory cytokines (IL-13 and IL-5).We concluded that addition of NAC to asthma therapy has beneficial preventive effects in an animal model of steroid resistant acute exacerbation of asthma. PMID- 26417228 TI - Computational modeling and validation studies of 3-D structure of neuraminidase protein of H1N1 influenza A virus and subsequent in silico elucidation of piceid analogues as its potent inhibitors. AB - Emergence of the drug resistant variants of the Influenza A virus in the recent years has aroused a great need for the development of novel neuraminidase inhibitors for controlling the pandemic. The neuraminidase (NA) protein of the influenza virus has been the most potential target for the anti-influenza. However, in the absence of any experimental structure of the drug targeting NA protein of H1N1 influenza A virus as zanamivir and oseltamivir, the comprehensive study of the interaction of the drug molecules with the target protein has been missing. Hence in this study a computational 3-D structure of neuraminidase of H1N1 influenza A virus has been developed using homology modeling technique, and the same was validated for its reliability by ProSA web server in term of energy profile & Z scores and PROCHECK program followed by Ramachandran plot. Further, the developed 3-D model had been employed for docking studies with the class of compounds as Piceid and its analogs. In this context, two novel compounds (ChemBank ID 2110359 and 3075417) were found to be more potent inhibitors of neuraminidase than control drugs as zanamivir and oseltamivir in terms of their robust binding energies, strong inhibition constant (Ki) and better hydrogen bond interactions between the protein-ligand complex. The interaction of these compounds with NA protein has been significantly studied at the molecular level. PMID- 26417227 TI - Cannabis-induced impairment of learning and memory: effect of different nootropic drugs. AB - Cannabis sativa preparations are the most commonly used illicit drugs worldwide. The present study aimed to investigate the effect of Cannabis sativa extract in the working memory version of the Morris water maze (MWM; Morris, 1984[43]) test and determine the effect of standard memory enhancing drugs. Cannabis sativa was given at doses of 5, 10 or 20 mg/kg (expressed as Delta(9)-tetrahydrocannabinol) alone or co-administered with donepezil (1 mg/kg), piracetam (150 mg/ kg), vinpocetine (1.5 mg/kg) or ginkgo biloba (25 mg/kg) once daily subcutaneously (s.c.) for one month. Mice were examined three times weekly for their ability to locate a submerged platform. Mice were euthanized 30 days after starting cannabis injection when biochemical assays were carried out. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, glucose and brain monoamines were determined. Cannabis resulted in a significant increase in the time taken to locate the platform and enhanced the memory impairment produced by scopolamine. This effect of cannabis decreased by memory enhancing drugs with piracetam resulting in the most-shorter latency compared with the cannabis. Biochemically, cannabis altered the oxidative status of the brain with decreased MDA, increased GSH, but decreased nitric oxide and glucose. In cannabis-treated rats, the level of GSH in brain was increased after vinpocetine and donepezil and was markedly elevated after Ginkgo biloba. Piracetam restored the decrease in glucose and nitric oxide by cannabis. Cannabis caused dose-dependent increases of brain serotonin, noradrenaline and dopamine. After cannabis treatment, noradrenaline is restored to its normal value by donepezil, vinpocetine or Ginkgo biloba, but increased by piracetam. The level of dopamine was significantly reduced by piracetam, vinpocetine or Ginkgo biloba. These data indicate that cannabis administration is associated with impaired memory performance which is likely to involve decreased brain glucose availability as well as alterations in brain monoamine neurotransmitter levels. Piracetam is more effective in ameliorating the cognitive impairments than other nootropics by alleviating the alterations in glucose, nitric oxide and dopamine in brain. PMID- 26417229 TI - Effect of subclinical, clinical and supraclinical doses of calcium channel blockers on models of drug-induced hepatotoxicity in rats. AB - Drug-related hepatotoxicity is the leading cause of acute liver failure, and hepatic problems are responsible for a significant number of liver transplantations and deaths worldwide. Calcium has been associated with various metabolic processes that lead to cell death and apoptosis, and increased cytosolic Ca(2+) has been implicated in hepatotoxicity. This study was designed to investigate the effects of calcium channel blockers (CCBs) on isoniazid rifampicin, zidovudine and erythromycin-induced hepatotoxicity in rats. Treatment groups comprised control, hepatotoxicant, hepatotoxicant along with each of silymarin, nifedipine, verapamil and diltiazem at subclinical, clinical and supraclinical doses. A day to the end of treatment for each model, rats were subjected to the hexobarbitone-induced hypnosis test. On the last days of treatment, blood samples were collected and serum was analyzed for relevant biochemical parameters. Animals were sacrificed after blood collection and livers were harvested, and samples obtained for in vivo antioxidant indices assay and histopathology. The hepatotoxicants significantly increased serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), as well as duration of sleep in the hypnosis test. These drugs significantly reduced the hepatic levels of reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and increased the level of malondialdehyde (MDA). The CCBs at the various doses significantly reversed the effects of isoniazid-rifampicin, zidovudine and erythromycin. The results obtained in this study suggest that the CCBs possess hepatoprotective activity in drug-induced hepatotoxicity and may be beneficial at the subclinical and clinical doses. PMID- 26417230 TI - Blocking of rat hippocampal Cx36 by quinine accelerates kindling epileptogenesis. AB - There are abundant studies indicating that blocking gap junctions (GJs) containing connexin 36 (Cx36) inhibit seizures. However, recent evidences demonstrate proconvulsant effect of such intervention. Electrical coupling between GABAergic interneurons in CA1 region of hippocampus is mediated through Cx36 GJs. We investigated effect of quinine, a specific blocker of Cx36, on the seizure severity and epileptogenesis in amygala kindling model of epilepsy in rats. Quinine (1, 50, 100, 500 and 2000 uM/rat) was injected directly into the CA1 and kindled seizure parameters including behavioral seizure stage, duration of evoked afterdischarges, and duration of generalized seizures behavior were recorded 10 min afterward. Moreover, quinine (1, 30, and 100 uM/rat) was injected intra CA1 once daily during kindling development. At the doses used, quinine had no significant effect on amygdala-kindled seizures. However, quinine 100 uM significantly accelerated kindling rate. Blockade of Cx36 GJs coupling and consequent disruption of inhibitory transmission in GABAergic interneurons in CA1 area seems to be responsible for the antiepileptogenic effect of quinine. PMID- 26417231 TI - Fenugreek seed extract treats peripheral neuropathy in pyridoxine induced neuropathic mice. AB - Trigonella foenum graecum commonly known as Fenugreek exerts normoglycemic and insulinotropic effects in humans by compounds from its seed and leaf extracts. Some studies reported that treating pregnant mice with fenugreek seed could cause toxic effects on the nervous system of its pubs during developmental growth, while in some other studies neuroprotective properties were considered for it. Safety of anti-diabetic drugs for nervous system is very important because peripheral neuropathy is a common complication of diabetes and hazardous drugs could worsen it. In this study, the effect of treatment with fenugreek seed extract on the function of sciatic nerves of neuropathic mice was evaluated. Neuropathy was induced in male mice by pyridoxine intoxication. After that, animals were treated with 0.2, 2 and 20 mg/kg of hydro-alcoholic extract of fenugreek seeds for 10 days, tail flick, electrophysiological and histological assays were performed to evaluate the effect of fenugreek seed extract on function of the peripheral nerves. Our data showed that fenugreek has anti neuropathic effect and restores the function of nerve fibers. Results of electrophysiological recordings stated that the highest rate of healing was occurred in 20 mg/kg fenugreek extract treated animals. In conclusion, findings of the present study demonstrate that treatment with fenugreek seed extract can potentially facilitate healing from pyridoxine induced peripheral neuropathy in mice. PMID- 26417233 TI - Protective effect of Tribulus terrestris L. fruit aqueous extracton lipid profile and oxidative stress in isoproterenol induced myocardial necrosis in male albino Wistar rats. AB - The objective of the present study was to evaluate the possible protective effects of Tribulus terrestris fruit aqueous extract (TTFAEt) on lipid profile and oxidative stress in isoproterenol (ISO) induced myocardial necrosis in albino Wistar rats. Albino Wistar rats were divided into normal control, TTFAEt alone treated, ISO control and pretreated (TTFAEt+ISO) groups. The extract was administered at a dose of 50 mg/kg body weight for 40 days orally by gavage and ISO was administered at a dose of 85 mg/kg body weight for two consecutive days intraperitoneally at an interval of 24 h. ISO induced myocardial infarction (MI) was confirmed by disturbances in serum lipid profile, heart tissue lipid peroxidation and antioxidant enzyme levels. There was a significant increase in the levels of serum total cholesterol (32.60 %), triglycerides (41.30 %), very low density lipoproteins (81.81 %), low density lipoproteins (84%) and phospholipids (38.88 %) and a significant decrease in the levels of high density lipoproteins (33.33 %) in the ISO control group when compared to normal controls. Additionally, there is a significant decrease in the levels of heart tissue antioxidant enzymes such as superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase and depletion of reduced glutathione, which indicates enhanced lipid peroxidation(172 %). Pretreatment with extract significantly showed a protective effect against ISO altered lipid profile, lipid peroxidation and antioxidant enzyme levels. The present study showed therapeutic effect of TTFAEt on lipid profile and oxidative stress in isoproterenol (ISO) induced myocardial necrosis in experimental rats. PMID- 26417232 TI - Coriandrum sativum L. seed extract mitigates lipotoxicity in RAW 264.7 cells and prevents atherogenic changes in rats. AB - This study was designed to assess the efficacy of Coriandrum sativum L. (CS) in preventing in vitro low density lipoprotein (LDL) oxidation mediated macrophage modification. Further, an in vivo study was also conducted to confirm upon the efficacy of CS seed extract in alleviating pathophysiological alterations of high cholesterol diet induced atherosclerosis in rats. Copper mediated cell free oxidation of LDL accounted for elevated indices of malondialdehyde (MDA), lipid hydroperoxide (LHP)and protein carbonyl (PC) and a progressive increment in conjugate diene (CD) levels whereas, reverse set of changes were recorded in presence of CS extract. Cell mediated LDL oxidation (using RAW 264.7 cells) accounted for lowered MDA production and oxidized LDL (Ox-LDL) mediated cell death in presence of CS extract and the same was attributed to its potent antioxidant and free radical scavenging potentials. High cholesterol fed atherogenic rats showed elevated lipid indices, evidences of LDL oxidation, plaque formation in thoracic aorta. The same was further validated with immunostaining of cell adhesion molecules and hematoxylin and eosin (HXE) staining. However, co-supplementation of CS to atherogenic rats recorded significant lowering of the above mentioned parameters further strengthening the claim that CS extract is instrumental in preventing onset and progression of atherosclerosis. PMID- 26417234 TI - Synthesis of novel dopamine derived multidirectional ligands from cyanuric chloride: structural and antimicrobial studies. AB - Two monopodal (2,4-dichloro-6-(3-hydroxytyramine)-1,3,5-triazine) and tripodal (2,4,6-(3-hydroxytyramine)-1,3,5-triazine) s-triazine derivatives were prepared through the reaction of cyanuric chloride (2,4,6-trichloro-1,3,5-triazine) and 3 hydroxytyramine hydrochloride (dopamine hydrochloride). The structures of the compounds were identified by FT-IR, 1H NMR, 13C NMR, thermal analysis and elemental analysis. Their antimicrobial activities were carried out using the broth microdilution method in dimethyl sulfoxide (DMSO): Phosphate Buffered Saline (PBS) against eight bacteria and one yeast. The results of the test were compared with ampicillin. It was determined that CCDOP1, CCDOP3 and DOP have significant antibacterial and antifungal activity. These three chemicals revealed strong antibacterial activity against the E. coli and S. aureus strains used in the study. S. aureus was the most sensitive strain against dopamine hydrochloride and E. coli was the most sensitive bacteria against CCDOP1. PMID- 26417235 TI - Factors affecting the adoption of healthcare information technology. AB - In order to improve the quality and performance of healthcare services, healthcare information technology is among the most important technology in healthcare supply chain management. This study sets out to apply and test the Unified Theory of Acceptance and Use of Technology (UTAUT), to examine the factors influencing healthcare Information Technology (IT) services. A structured questionnaire was developed and distributed to healthcare representatives in each province surveyed in Thailand. Data collected from 400 employees including physicians, nurses, and hospital staff members were tested the model using structural equation modeling technique. The results found that the factors with a significant effect are performance expectancy, effort expectancy and facilitating conditions. They were also found to have a significant impact on behavioral intention to use the acceptance healthcare technology. In addition, in Thai provincial areas, positive significance was found with two factors: social influence on behavioral intention and facilitating conditions to direct using behavior. Based on research findings, in order for healthcare information technology to be widely adopted and used by healthcare staffs in healthcare supply chain management, the healthcare organizational management should improve healthcare staffs' behavioral intention and facilitating conditions. PMID- 26417236 TI - 5,10-methylene tetrahydrofolate reductase C677T gene polymorphism, homocysteine concentration and the extent of premature coronary artery disease in southern Iran. AB - Elevated level of plasma homocysteine (Hcy) has been identified as an independent risk factor for coronary artery disease (CAD). Furthermore, numerous studies have documented the influences of a common polymorphism (C677T) of methylenetetrahydrofolate reductase (MTHFR) on homocysteine levels. However the relationship between this mutation and cardiovascular diseases (CVD) has remained as a controversial issue. The present study was undertaken to investigate the relationship between C677T polymorphism of MTHFR gene, plasma total Hcy levels and the number of affected vessels as a criterion for the extent of CAD. MTHFR genotypes and plasma homocysteine (HCY) concentrations were examined in 231 patients and 300 healthy subjects who underwent diagnostic coronary angiography. A multiple linear regression analysis was performed to identify the predictors of Hcy levels whereas logistic regression model was built to determine the association of Hcy quartiles with the risk of CAD adjusted for risk factors. The prevalence of MTHFR genotypes was similar between CAD patients and non-CAD individuals while the geometric mean of Hcy values was significantly higher in patient group (14.13 +/- 4.11 MUmol/l) than in control group (10.19 +/- 3.52 MUmol/l) (P < 0.001). Moreover, unlike the MTHFR polymorphism, Hcy concentration increased with increasing number of stenosed vessels and the CAD risk increased about 2 folds in the top two Hcy quartiles (>= 17.03 and 13.20-17.02 MUmol/l) compared with the lowest quartile (<= 9.92 MUmol/l) after controlling for conventional risk factors (P<0.001 for both). Our data suggest that hyperhomocysteinaemia (HHcy) is significantly associated to CAD risk increase as well as to the extent of coronary atherosclerosis. PMID- 26417237 TI - Activation of sphingosine 1-phosphate receptor-1 by SEW2871 improves cognitive function in Alzheimer's disease model rats. AB - Sphingosine-1 phosphate (S1P) is involved in a variety of cellular processes via activation of S1P receptors (S1PRs; S1PR1 to S1PR5) that are highly expressed in the brain. It has been shown that the level of S1P is reduced in the brain of Alzheimer's disease (AD) patients. However, there is no study designed to evaluate the expression of S1PRs in AD brains. The objectives of the present work are (1) to examine the expression of S1PR1-3 in the hippocampus of beta amyloid (Abeta) 1-42 injected rats and (2) to clarify the effects of chronic S1PR1 activation on S1PR1-3 levels, spatial memory deficit and hippocampal damage in AD rats. SEW2871, the S1PR1 selective agonist, repeatedly was injected intraperitoneally during a period of two weeks. Upon Western Blot data bilateral intrahippocampal injection of Abeta1-42 decreased the expression of S1PR1 while increased S1PR2 level and did not affect that of S1PR3. We found that chronic administration of SEW2871 inhibited the reduction of S1PR1 expression and ameliorated spatial memory impairment in the Morris water maze task in rats. In addition, SEW2871 attenuated the Abeta1-42-induced hippocampal neuronal loss according to Nissl staining findings. Data in the current study highlights the importance of S1PR1 signaling pathway deregulation in AD development and suggests that activation of S1PR1 may represent a potential approach for developing new therapeutics to manage memory deficit and apoptosis associated with neurodegenerative disorders such as AD. PMID- 26417238 TI - Acceleration of pro-caspase-3 maturation and cell migration inhibition in human breast cancer cells by phytoconstituents of Rheum emodi rhizome extracts. AB - The aggressive nature of estrogen receptor (ER)-negative breast cancer subtype obligates for innovative targeted therapies. The present study aimed to investigate the phytoconstituents and specific anticancer activities of Rheum emodi rhizome, a known food source used locally to treat various ailments. Petroleum ether extracts (hot [PHR] and cold [PCR]) of R. emodi, exhibited significant free radical scavenging potentials through DPPH and reducing power assays, rendering them as good sources of antioxidants. The extracts, PHR and PCR had shown significant (P < 0.05) cancer-cell-specific cytotoxicity in the assayed cells (MDA-MB-231 [breast carcinoma] and WRL-68 [non-tumoral]) at 100 MUg/ml, and 50 and 100 MUg/ml concentrations respectively. Extracts also induced fervent apoptosis in ER-negative cells (MDA-MB-231) compared to ER-positive subtype (MCF 7), and found to involve CPP32/caspase-3 in its apoptosis induction mechanism. Moreover, extracts had an inevitable potential to inhibit the migration of metastatic breast cancer cells (MDA-MB-231) in vitro. Further, the active principles of extracts were identified through HPLC and GC-MS analysis to reveal major polyphenolics, 4,7-Dimethyl-(octahydro)indolo[4,3-fg]quinolin-10-one, 5-Oxo isolongifolene, Valencene-2, and other quinone, quinoline and anthraquinone derivatives. The extracts are thus good candidates to target malignant ER negative breast cancer, and the identified phytoconstituents could be eluted in further exploratory studies for use in dietary-based anti-breast cancer therapies. PMID- 26417239 TI - Effect of drought on safflower natural dyes and their biological activities. AB - Drought is the main abiotic constraint that affects crop species behaviour regarding bio-chemical responses. The current study was conducted to examine the effect of water deficit on growth, phenolic and carotenoid contents as well as the antioxidant and antimicrobial activities of two Carthamus tinctorius varieties (Jawhara and 104) flowers. Hence, plants were treated with different levels of water deficit: control (100 %), moderate water deficit (50 %) and severe water deficit (25 %). Obtained results showed that plant growth was significantly (p < 0.05) reduced under 50 %. Drought increased flower phenolic acids contents especially gallic acid where they increased significantly (p < 0.05) by 2.73 fold (104) and by 2.87 fold (Jawhara) with respect to controls under 50 %. However, the amounts of this major compound were reduced at 25 % by 9.66 % (104) and 3.83 % (Jawhara). Similar to phenolic compounds, total carotenoid content was at its highest level especially for Jawhara with an increase by 35.19 % at 50 %. On the other hands, C. tinctorius flowers extracts exhibited high antiradical activity as compared to BHT. A gradual increase by 35.29 % (Jawhara) and 33.33 % (104) especially under 25 % was observed. Moreover, under 50 %, the antimicrobial activity increased significantly (p < 0.05) by 30 % and 10.05 % against Aspergillus carbonarus and Pseudomonas aerogenosa, respectively. Taken together, our findings suggest that C. tinctorius could be a raw material for production of natural dyes under moderate salinity conditions. PMID- 26417240 TI - Automatic quantitative analysis of morphology of apoptotic HL-60 cells. AB - Morphological identification is a widespread procedure to assess the presence of apoptosis by visual inspection of the morphological characteristics or the fluorescence images. The procedure is lengthy and results are observer dependent. A quantitative automatic analysis is objective and would greatly help the routine work. We developed an image processing and segmentation method which combined the Otsu thresholding and morphological operators for apoptosis study. An automatic determination method of apoptotic stages of HL-60 cells with fluorescence images was developed. Comparison was made between normal cells, early apoptotic cells and late apoptotic cells about their geometric parameters which were defined to describe the features of cell morphology. The results demonstrated that the parameters we chose are very representative of the morphological characteristics of apoptotic cells. Significant differences exist between the cells in different stages, and automatic quantification of the differences can be achieved. PMID- 26417242 TI - Evaluation of adenosine deaminase (ADA) isoenzymes activity and tumor necrosis factor-alpha (TNFalpha) concentration in chronic heart failure. AB - INTRODUCTION: Chronic heart failure (CHF) has recently been considered as an inflammatory disease. Enhanced production of tumor necrosis factor-alpha (TNFalpha) in CHF patients has been proved. To compensate deleterious effects of TNalpha, the concentration of adenosine is increased in CHF. However, concurrent determination of serum TNFalpha and enzymatic activities of ADA and its ADA1 and ADA2 isoenzymes, as the main regulators of adenosine concentration, has not yet been carried out. MATERIALS AND METHODS: Blood samples were collected from 52 CHF patients and 55 healthy controls. Laboratory routine tests were performed, and after determining the concentration of TNFalpha, total ADA (tADA) as well as ADA1 and ADA2 isoenzyme activities were measured. RESULTS: Mean concentration of TNFalpha increased over 2 fold in CHF patients (12.54 +/- 11.69 pg/ml compared with 6.0 +/- 6.58 pg/ml in controls). The highest level of TNFalpha was observed in patients with the final stage of the disease (NHYA IV subgroup), according to the New York Heart Association classification. tADA activity was significantly lower in CHF patients compared with controls (19.29 +/- 9.73 and 24.3 +/- 6.01 U/L, respectively). ADA2 activity markedly decreased in CHF patients and showed a direct correlation with tADA (r = 0.641, P = 0001). In addition, the lowest levels of tADA and ADA2 activities were observed in patients from the 4(th) quartile of NYHA classification. CONCLUSION: Adenosine deaminase activity is reduced in CHF patients to give rise to the concentration of adenosine, thereby attenuating pathologic consequences of CHF. Therefore, it is concluded that ADA activity is of paramount importance in pathophysiology of heart failure and might be used for diagnostic purposes or treatment targets. PMID- 26417244 TI - On-site cellulase production by Trichoderma reesei 3EMS35 mutant and same vessel saccharification and fermentation of acid treated wheat straw for ethanol production. AB - Bioethanol production from lignocellulosic raw materials involves process steps like pre-treatment, enzymatic hydrolysis, fermentation and distillation. In this study, wheat straw was explored as feedstock for on-site cellulase production by T. reesei 3EMS35 mutant, and as a substrate for second generation bioethanol production from baker yeast. Scanning electron microscopy (SEM) and X-ray diffractography (XRD) of untreated wheat straw (UWS) and acid treated wheat straw (TWS) were done to understand the structural organization and changes in the cellulase accessibility and reactivity. The effect of delignification and structural modification for on-site cellulase enzyme production was comparably studied. The efficiency of crude cellulase enzyme for digestion of UWS and TWS and then production of ethanol from TWS was studied using same-vessel saccharification and fermentation (SVSF) technique, both in shaking flasks as well as in fermenters. Two different methods of operation were tested, i.e. the UWSEnz method, where UWS was used for on-site enzyme production, and TWSEnz method where TWS was applied as substrate for cellullase production. Results obtained showed structural modifications in cellulose of TWS due to delignification, removal of wax and change of crystallinity. UWS was better substrate than TWS for cellulase production due to the fact that lignin did not hinder the enzyme production by fungus but acted as a booster. On-site cellulase enzyme produced by T. reesei 3EMS35 mutant hydrolyzed most of cellulose (91 %) in TWS within first 24 hrs. Shake flasks experiments showed that ethanol titers and yields with UWSEnz were 2.9 times higher compared to those obtained with TWSEnz method respectively. Comparatively, titer of ethanol in shake flask experiments was 10 % higher than this obtained in 3 L fermenter with UWSEnz. Outcomes from this investigation clearly demonstrated the potential of on-site cellulase enzyme production and SVSF for ethanol production from wheat straw. PMID- 26417243 TI - Balance of inflammatory pathways and interplay of immune cells in the liver during homeostasis and injury. AB - Multiple potentially harmful stimuli challenge the liver, the chief metabolic and detoxifying organ of the human body. Due to its central anatomical location, continuous blood flow from the gastrointestinal tract through the hepatic sinusoids allows the metabolically active hepatocytes, the non-parenchymal cells and the various immune cell populations residing and patrolling in the liver to interact with antigens and microbiological components coming from the intestine. Cytokines are key mediators within the complex interplay of intrahepatic immune cells and hepatocytes, because they can activate effector functions of immune cells as well as hepatocytic intracellular signaling pathways controlling cellular homeostasis. Kupffer cells and liver-infiltrating monocyte-derived macrophages are primary sources of cytokines such as tumor necrosis factor (TNF). The liver is also enriched in natural killer (NK) and natural killer T (NKT) cells, which fulfill functions in pathogen defense, T cell recruitment and modulation of fibrogenic responses. TNF can activate specific intracellular pathways in hepatocytes that influence cell fate in different manners, e.g. pro apoptotic signals via the caspase cascade, but also survival pathways, namely the nuclear factor (NF)-kappaB pathway. NF-kappaB regulates important functions in liver physiology and pathology. The exact dissection of the contribution of recruited and resident immune cells, their soluble cytokine and chemokine mediators and the intracellular hepatocytic response in liver homeostasis and injury could potentially identify novel targets for the treatment of acute and chronic liver disease, liver fibrosis or cirrhosis. PMID- 26417241 TI - Particles from preformed polymers as carriers for drug delivery. AB - Biodegradable and biocompatible polymers are widely used for the encapsulation of drug molecules. Various particulate carriers with different sizes and characteristics have been prepared by miscellaneous techniques. In this review, we reported the commonly used preformed polymer based techniques for the preparation of micro and nano-structured materials intended for drug encapsulation. A description of polymer-solvent interaction was provided. The most widely used polymers were reported and described and their related research studies were mentioned. Moreover, principles of each technique and its crucial operating conditions were described and discussed. Recent applications of all the reported techniques in drug delivery were also reviewed. PMID- 26417245 TI - Thymoquinone and curcumin attenuate gentamicin-induced renal oxidative stress, inflammation and apoptosis in rats. AB - The present study was aimed to investigate the possible protective effects of thymoquinone (TQ) and curcumin (Cur) on gentamicin (GM)-induced nephrotoxicity in rats. Rats were divided into four groups as follows: group 1 received normal saline and served as normal controls, group 2 received GM only, group 3 concurrently received GM and TQ and group 4 concurrently received GM and Cur. At day 21, rats were sacrificed and samples were collected for assaying serum tumor necrosis factor alpha (TNF-alpha), urea and creatinine levels, and renal lipid peroxidaion, glutathione (GSH) content as well as glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities. In addition, kidneys were collected for histopathological examination and immunohistochemical determination of the antiapoptotic protein, B-cell lymphoma 2 (Bcl-2). The biochemical results showed that GM-induced nephrotoxicity was associated with a significant increase in serum TNF-alpha, urea and creatinine as well as renal lipid peroxidation. On the other hand, renal GSH content and GPx and SOD activities were significantly declined. Concomitant administration of either TQ or Cur efficiently alleviated the altered biochemical and histopathological features. In conclusion, both TQ and Cur showed more or less similar marked renoprotective effect against GM induced nephrotoxicity through their antioxidant, anti-inflammatory and anti apoptotic efficacies. PMID- 26417247 TI - Hypochoeris radicata attenuates LPS-induced inflammation by suppressing p38, ERK, and JNK phosphorylation in RAW 264.7 macrophages. AB - Hypochoeris radicata, an invasive plant species, is a large and growing threat to ecosystem integrity on Jeju Island, a UNESCO World Heritage site. Therefore, research into the utilization of H. radicata is important and urgently required in order to solve this invasive plant problem in Jeju Island. The broader aim of our research is to elucidate the biological activities of H. radicata, which would facilitate the conversion of this invasive species into high value-added products. The present study was undertaken to identify the pharmacological effects of H. radicata flower on the production of inflammatory mediators in macrophages. The results indicate that the ethyl acetate fraction of H. radicata extract (HRF-EA) inhibited the production of pro-inflammatory molecules such as NO, iNOS, PGE2, and COX-2, and cytokines such as TNF-alpha, IL-1beta, and IL-6 in LPS-stimulated RAW 264.7 cells. Furthermore, the phosphorylation of MAPKs such as p38, ERK, and JNK was suppressed by HRF-EA in a concentration-dependent manner. In addition, through HPLC and UPLC fingerprinting, luteolins were also identified and quantified as extract constituents. On the basis of these results, we suggest that H. radicata may be considered possible anti-inflammatory candidates for pharmaceutical and/or cosmetic applications. PMID- 26417248 TI - Immunomodulatory potential of a bioactive fraction from the leaves of Phyllostachys bambusoides (bamboo) in BALB/c mice. AB - In order to evaluate the role of ethyl acetate fraction (PB-EtAC) obtained from the Phyllostachys bambusoides leaves in the modulation of immune responses, detailed studies were carried out using a panel of in vivo assays. Oral administration of PB-EtAC (50-200 mg/Kg) stimulated the IgM and IgG titre expressed in the form of haemagglutination antibody (HA) titre. Further, it elicited a dose related increase in the delayed type hypersensitivity reaction (DTH) after 24 and 48 h in BALB/c mice. Besides augmenting the humoral and cell mediated immune response, the concentration of cytokines (IFN-gamma, IL-2, and IL 4) in serum with respect to T cell interactions also increased significantly. It also induced macrophage phagocytosis, and nitric oxide (NO) production which resulted in a high degree of protection against Candida albicans and carbon clearance. Moreover, the enhancement in CD4 and CD8 cell populations as revealed by flow cytometry. Taken together this in vivo and ex vivo preclinical data, our results suggested that PB-EtAC acts as an effective immunostimulator eliciting both Th1 and Th2 immune responses. We are reporting first time the immunostimulatory potential of P. bambusoides and it might be regarded as a biological response modifier. PMID- 26417246 TI - Select a suitable treatment strategy for Crohn's disease: step-up or top-down. AB - Crohn's Disease (CD) is a chronic immune-mediated disorder with progressive and destructive course. Current guidelines on the treatment strategy still recommend a step-up approach with sequential prescription of corticosteroids and immunosuppressives. However, mounting evidences manifested that top-down therapy with early administration of anti-TNF or combination of immunosuppressives can achieve more rapid and higher rate of mucosal healing and has the potential of modifying the natural course of disease. Therefore, who is suitable to accept and when to start anti-TNF therapy have attracted the attention of gastroenterologists. And what benefit/risk can be expected from the two strategies should be carefully taken into account by clinicians. Age stratification, special patients, disease location and extension, genetic and serologic testing are predictors of disease progression and complication and thus guide a personalized treatment approach in CD. A definition of early CD has been proposed to select an algorithm for treatment of moderate-to-severe CD with a suitable strategy. To date mucosal healing has been widely used, the Lemann score, which assesses the extent and severity of bowel damage at a specific time point and over time, and is a new disability index for patients with CD, will be considered as a new endpoint for future studies of treatment strategies. Besides medicines of the two strategies, surgery, vaccine, Leukocytapheresis and stem cell therapy are all effective therapeutic approaches which lead to another thinking about what should they be putted in the conditional pyramid. However, we are trying to answer these questions. PMID- 26417249 TI - Detrimental effects of bisphenol A on development and functions of the male reproductive system in experimental rats. AB - Bisphenol A (BPA) is widely used in manufacturing industries. It is commonly detected in the environment and was reported to exert oestrogenic effects which may be harmful to the reproductive system. The present study was carried out to observe the effects of oral administration of BPA on the development of the reproductive organs and plasma sex hormone levels in prepubertal male Sprague Dawley (SD) rats. Prepubertal male SD rats (n=8 in each group) were administered BPA in the doses of 1, 5, 10 and 100 mg/kg BW (body weight) via oral gavage for a period of 6 weeks. The control animals received the vehicle for BPA (Tween 80 in distilled water). Following 6 weeks of BPA exposure, the rats exhibited less evidence of spermatogenesis. There was seminiferous epithelial damage which included disruption of intercellular junctions and sloughing of germ cells into the seminiferous tubular lumen. Furthermore, the lumina of the seminiferous tubules and the epididymis of these animals were filled with immature germ cells and cellular debris. This damage may lead to the significant reduction in the seminiferous tubular diameter in BPA-treated animals. These findings were associated with the significant lower plasma testosterone and 17beta-oestradiol levels. There was no significant difference between the body weight gain, the absolute as well as relative testis weight or epididymal weight of BPA-treated animals when compared to the control animals. The findings provided further evidence of the detrimental effects of BPA on the male reproductive system. PMID- 26417250 TI - Response of liver antioxidant defense system to acute and chronic physical and psychological stresses in male rats. AB - The aim of this study was to evaluate the effect of acute and chronic physical and psychological stressors on the induction of oxidative stress in male rat liver. Male Wistar rats were randomly divided into 3 groups as following: control, physical and psychological stress groups. Stress was induced by communication box for one (acute), fifteen and thirty (chronic) days. Once stressor periods ended, rats were anesthetized and their liver dissected out for later assessments. Exposure to physical stress enhanced liver superoxide dismutase (SOD) (19.44 %) and glutathione S-transferase (GST) (21.84 %) activities and decreased glutathione (GSH) (30.03 %) level on the 1(st) day (p<0.05). SOD (24.13 and 18.43 %) and GST (27.77 and 21.27 %) activities were significantly increased, while catalase activity (29.74 and 24.41 %) and GSH level (35.05 and 31.05 %) were decreased in psychological stress group after 1 and 15 days (p<0.01 and p<0.05) compared to the 1(st) day value in control group, respectively. Psychological stress induced an increase in liver malondialdehyde (MDA) (46 %) and plasma corticosterone (36 %) levels on the 1(st) day (p<0.05). However, all parameters returned to their basal value after 30 days of stress. The results suggest that exposure to acute physical and psychological stressors induce the production of reactive oxygen species and oxidative stress in rat liver due to GSH depletion and the decreased catalase activity. The elevation of lipid peroxidation and corticosterone level in acute psychological stress may lead to more profound oxidative damage than acute physical stress. Moreover, cell protection in hepatic tissue of chronically stressed rats is indicative of possible late adaptation of the animals to stress. PMID- 26417251 TI - Influence of environmental variability on phylogenetic diversity and trait diversity within Calligonum communities. AB - Since phylogenetic data provide the evolutionary history of the species and traits are the result of adaptation to the environmental conditions, joint analysis of these two aspects and ecological data may illuminate that how ecological processes affect the evolution of species and assembly of communities. In this study, we compared the community structure of sibling communities in order to illuminate the influence of environmental variability. We chose different Calligonum communities as research subjects which grow in active sand dunes and stabilized sand fields. Our results show that species which co-occurred in C. rubicundum community have greater phylogenetic evenness compared to species in other communities where co-occurring plants had similar traits. Soil variability might legitimately explain this result. Based on the similarity between the pattern of trait diversity and the pattern of phylogenetic diversity, we inferred that the evolution of traits is conservative and species of all but C. rubicundum communities are under more intense selection pressure. PMID- 26417253 TI - Vascular loop in the cerebellopontine angle causing pulsatile tinnitus and headache: a case report. AB - Tinnitus is a common disorder, it can be classified as pulsatile and non pulsatile or objective and subjective. Pulsatile tinnitus is less common than non pulsatile and can be due to vascular tumour such as glomus or vascular abnormality. We presented an interesting case of a 30 year-old Malay lady with a two-year history of pulsatile tinnitus which was worsening in three months duration. It was associated with intermittent headache. Clinical examination and tuning fork test were unremarkable. Apart from mild hearing loss at high frequency on the left ear, the pure tone audiogram (PTA) was otherwise normal. In view of the patient's young age with no risk factor for high frequency loss, a magnetic resonance imaging (MRI) was performed to look for any abnormality in the cerebellopontine angle. It revealed a single vessel looping around the left vestibulocochlear and facial nerves at the cisternal portion, likely a branch of the anteroinferior cerebellar artery (AICA). Literature review on the pathophysiology and treatment option in this condition is discussed. PMID- 26417252 TI - Autophagy and radiosensitization in cancer. AB - Autophagy is a natural self-degradative process by which cells eliminate misfolded proteins and damaged organelles. Autophagy has been shown to have multiple functions in tumor cells that may be dependent on the tumor type and the treatment conditions. Autophagy can have a cytoprotective role and be thought of as a survival mechanism or be cytotoxic in nature and mediate cell death. Radiation, one of the primary treatments for many different types of cancer, almost uniformly promotes autophagy in tumor cells. While autophagy produced in response to radiation is often considered to be cytoprotective, radiation-induced autophagy has also been shown to mediate susceptibility to radiation. This review addresses the complexity of autophagy in response to radiation treatment in three different cancer models, specifically lung cancer, breast cancer and glioblastoma. A deeper understanding of the different roles played by autophagy in response to radiation should facilitate the development of approaches for enhancing the therapeutic utility of radiation by providing strategies for combination treatment with unique radiosensitizers as well as preventing the initiation of strategies which are likely to attenuate the effectiveness of radiation therapy. PMID- 26417254 TI - Analysis of concentration-dependent effects of copper and PCB on different Chattonella spp. microalgae (raphidophyceae) cultivated in artificial seawater medium. AB - In the present study, the effect on the chlorophyll a and the total protein content as well as the Chattonella spp. cell viability were examined after concentration-dependent exposure to CuCl2 and Aroclor 1242. The comparison between various raphidophyte strains provides an insight into the different susceptibilities to contaminants of Chattonella subsalsa (CSNAV-1), C. marina var. marina (CMCV-1) and C. marina var. ovata (COPV-2). The microalgae were cultivated in artificial seawater medium. Exponentially growing microalgae (8-10 days in culture) were used for exposure experiments. We observed in all three raphidophyte species cytotoxicity-mediated modifications beginning at concentrations of 150 and 200 uM of the heavy metal copper after 24 hours exposure. But interestingly, the three strains exhibited only slight differences in their susceptibility to CuCl2. C. subsalsa and C. marina var. marina cells were first affected at the chlorophyll a level and in cell viability. The total protein amount was reduced significantly only after exposure to 300 uM of CuCl2. However, C. marina var. ovata microalgae showed similar reduction curves for all three analysed cytotoxicity endpoints after heavy metal exposure. On the other hand, after Aroclor 1242 incubation the cytotoxic modification pattern indicated clearly the different susceptibilities of the three raphidophyte strains. C. subsalsa cells noticeably exhibited a decrease in the analysed pigment amount (30 20 % compared to that of the control) already after 0.007 mg/L PCB exposure. In contrast, cell viability and total protein content were slightly reduced and fell below the 50 % threshold after 0.7 and 3.3 mg/L of Aroclor 1242, respectively. Interestingly, C. marina var. ovata showed almost no cytotoxic modification caused by the PCB mixture. Only the concentration of 0.7 mg/L Aroclor 1242 clearly affected the cell viability. As opposed to that we observed a concentration-dependent decrease of cell viability and chlorophyll a amount in CMCV-1 microalgae. These observations confirmed that the susceptibility of the raphidophytes strains CSNAV-1, CMCV-1 and COPV-2 is contaminant-dependent. We showed differences even between two variants of Chattonella (Chattonella marina var. marina and C. marina var. ovata). Furthermore, we were able to show the different mode of action of two common pollutants by simple cytotoxic parameters like total protein and chlorophyll a content as well as by cell counting analysis. PMID- 26417255 TI - Conformational instability of human prion protein upon residue modification: a molecular dynamics simulation study. AB - Technical strategies like amino acid substitution and residue modification have been widely used to characterize the importance of key amino acids and the role that each residue plays in the structural and functional properties of protein molecules. However, there is no systematic approach to assess the impact of the substituted/modified amino acids on the conformational dynamics of proteins. In this investigation to clarify the effects of residue modifications on the structural dynamics of human prion protein (PrP), a comparative molecular dynamics simulation study on the native and the amino acid-substituted analog at position 208 of PrP has been performed. It is believed that Arginine to Histidine mutation at position 208 is responsible for the structural transition of the native form of human prion protein to the pathogenic isoform causing Creutzfeldt Jakob disease (CJD). So, three 10 ns molecular dynamics simulations on three model constructs have been performed. Simulation results indicated considerable differences of conformational fluctuations for Alanine substituted construct (PrPALA) and the analog form (PrPSB) comprising the neutralized state of the Arginine residue at position 208 of the human prion protein. According to our data, substitution of the Arginine residue by the uncharged state of this residue induces some reversible structural alterations in the intrinsically flexible loop area including residues 167-171 of PrP. Thus, deprotonation of Arg(208) is a weak perturbation to the structural fluctuations of the protein backbone and the resulting construct behaves almost identical as its native form. Otherwise, Alanine substitution at position 208 imposed an irreversible impact on the secondary and tertiary structure of the protein, which leads to conformational instabilities in the remote hot region comprising residues 190-195 of the C terminal part of helix 2. Based on the results, it could be deduced that the observed conformational transitions upon Arg(208) to His point mutation, which is the main reason for CJD, may be mainly related to the structural instabilities due to the induced-conformational changes that caused alterations in local/spatial arrangements of the force distributions in the backbone of the human prion protein. PMID- 26417256 TI - Pomegranate peel attenuates hyperglycemic effects of alloxan-induced diabetic rats. PMID- 26417257 TI - Design, synthesis and anticonvulsant activity of some new 6,8-halo-substituted-2h [1,2,4]triazino[5,6-b]indole-3(5h)-one/-thione and 6,8-halo-substituted 5-methyl 2h-[1,2,4]triazino[5,6-b]indol-3(5h)-one/-thione. AB - A new series of 6,8-halo-substituted-2H-[1,2,4]triazino[5,6-b]indole-3(5H)-one/ thione and 6,8-halo-substituted 5-methyl-2H-[1,2,4]triazino[5,6-b]indol-3(5H) one/-thione (5a-5l) were designed and synthesized keeping in view of the structural requirement of pharmacophore. The above compounds were characterized by thin layer chromatography and spectral analysis. Anticonvulsant activity of the synthesized compounds was evaluated by the maximal electroshock (MES) test. Neurotoxicity and CNS depressant effects were evaluated by the rotarod motor impairment and Porsolt's force swim tests, respectively. A computational study was carried out, for calculation of pharmacophore pattern, prediction of pharmacokinetic properties and toxicity properties. The above study revealed that the compounds 8-chloro-2H-[1,2,4]triazino[5,6-b]indol-3(5H)-one (5e), 6,8-dibromo 2H-[1,2,4]triazino[5,6-b]indol-3(5H)-one (5i) and 6,8-dibromo-5-methyl-2H [1,2,4]triazino[5,6-b]indol-3(5H)-one (5k) possess excellent anticonvulsant activity in the series with little CNS depressant effect and no neurotoxicity as compared to standard drugs phenytoin and carbamazepine. PMID- 26417258 TI - Level set method for segmentation of infrared breast thermograms. AB - Breast thermography is a physiological test that provides information based on the temperature changes in breast. It records the temperature distribution of a body using the infrared radiation emitted by the surface of that body. Precancerous tissue and the area around a cancerous tumor have higher temperature due to angiogenesis, and higher chemical and blood vessel activity than a normal breast; hence breast thermography has potential to detect early abnormal changes in breast tissues. It can detect the first sign of forming up cancer before mammography can detect. The thermal information can be shown in a pseudo colored image where each color represents a specific range of temperature. Various methods can be applied to extract hot regions for detecting suspected regions of interests in the breast infrared images and potentially suspicious tissues. Image segmentation techniques can play an important role to segment and extract these regions in the breast infrared images. Shape, size and borders of the hottest regions of the images can help to determine features which are used to detect abnormalities. In this paper, three image segmentation methods: k-means, fuzzy c means and level set are discussed and compared. These three methods are tested for different cases such as fibrocystic, inflammatory cancer cases. The hottest regions of thermal breast images in all cases are extracted and compared to the original images. According to the results, level set method is a more accurate approach and has potential to extract almost exact shape of tumors. PMID- 26417259 TI - Imprinting genes associated with endometriosis. AB - PURPOSE: Much work has been carried out to investigate the genetic and epigenetic basis of endometriosis and proposed that endometriosis has been described as an epigenetic disease. The purpose of this study was to extract the imprinting genes that are associated with endometriosis development. METHODS: The information on the imprinting genes can be accessed publicly from a web-based interface at http://www.geneimprint.com/site/genes-by-species. RESULTS: In the current version, the database contains 150 human imprinted genes derived from the literature. We searched gene functions and their roles in particular biological processes or events, such as development and pathogenesis of endometriosis. From the genomic imprinting database, we picked 10 genes that were highly associated with female reproduction; prominent among them were paternally expressed genes (DIRAS3, BMP8B, CYP1B1, ZFAT, IGF2, MIMT1, or MIR296) and maternally expressed genes (DVL1, FGFRL1, or CDKN1C). These imprinted genes may be associated with reproductive biology such as endometriosis, pregnancy loss, decidualization process and preeclampsia. DISCUSSION: This study supports the possibility that aberrant epigenetic dysregulation of specific imprinting genes may contribute to endometriosis predisposition. PMID- 26417260 TI - Nanoencapsulation for drug delivery. AB - Nanoencapsulation of drug/small molecules in nanocarriers (NCs) is a very promising approach for development of nanomedicine. Modern drug encapsulation methods allow efficient loading of drug molecules inside the NCs thereby reducing systemic toxicity associated with drugs. Targeting of NCs can enhance the accumulation of nanonencapsulated drug at the diseased site. This article focussed on the synthesis methods, drug loading, drug release mechanism and cellular response of nanoencapsulated drugs on liposomes, micelles, carbon nanotubes, dendrimers, and magnetic NCs. Also the uses of these various NCs have been highlighted in the field of nanotechnology. PMID- 26417261 TI - In vitro study of parasite elimination and endothelial protection by curcumin: adjunctive therapy for cerebral malaria. AB - Plasmodium falciparum infection can abruptly progress to severe malaria and cerebral malaria. Despite the current efficiency of antimalarial drugs in killing parasites, no specific effective treatment has been found for cerebral malaria. Thus, a new strategy targeting both parasite elimination and endothelial cell protection is urgently needed in this field. In this study, we determined whether curcumin, which has blood-brain permeability, antioxidative activity and/or immunomodulation property, provided a potential effect on both parasite elimination and endothelial protection. Murine brain microvascular endothelial cells (bEnd.3; ATCC) were cocultured with Plasmodium falciparum-infected red blood cells (Pf-IRBC), peripheral blood mononuclear cell (PBMC) and platelets. Apoptosis of endothelial cells was demonstrated by annexin V staining. Interestingly, curcumin exhibited high efficiency of antimalarial activity (IC50 ~10 uM) and decreased bEnd.3 apoptosis down to 60.0 % and 79.6 % upon pre treatment and co-treatment, respectively, with Pf-IRBC, platelets and PBMC. Our findings open up a high feasibility of applying curcumin as a potential adjunctive compound for cerebral malaria treatment in the future. PMID- 26417263 TI - Antioxidant and antiulcer potential of aqueous leaf extract of Kigelia africana against ethanol-induced ulcer in rats. AB - Ethnobotanical claims regarding Kigelia africana reported antiulcer properties as part of its medicinal application. In this work, aqueous leaf extract from K. africana was investigated for its phytochemical constituents and antiulcer potential against ethanol-induced ulcer in rats. The participation of oxidative stress on ethanol-induced ulcer and the potential protective antioxidant activity of K. africana extracts were investigated by determining vitamin C and thiobarbituric acid reactive species (TBARS) contents in the gastric mucosa of rats. The HPLC analysis showed the presence of gallic acid, chlorogenic acid, caffeic acid and also the flavonoids rutin, quercetin and kaempferol in the aqueous plant extract. Oral treatment with K. africana extract (1.75; 3.5; 7 and 14 mg/kg) one hour after ulcer induction with ethanol decreased in a dose dependent manner the ulcer index. Ethanol increased significantly stomachal TBARS levels and decreased vitamin C content when compared to the control animals. K. africana blunted the ethanol-induced oxidative stress and restored vitamin C content to the control levels. The present results indicate that the aqueous leaf extract from K. africana possesses antiulcer potential. The presence of flavonoids in plant extract suggests that its antiulcerogenic potential is associated with antioxidant activity. Of particular therapeutic potential, K. africana was effective against ethanol even after the induction of ulcer, indicating that it can have protective and curative effects against gastric lesion. PMID- 26417262 TI - Mycoplasmas and cancer: focus on nucleoside metabolism. AB - The standard of care for patients suffering cancer often includes treatment with nucleoside analogues (NAs). NAs are internalized by cell-specific nucleobase/nucleoside transporters and, after enzymatic activation (often one or more phosphorylation steps), interfere with cellular nucleo(s)(t)ide metabolism and DNA/RNA synthesis. Therefore, their efficacy is highly dependent on the expression and activity of nucleo(s)(t)ide-metabolizing enzymes, and alterations thereof (e.g. by down/upregulated expression or mutations) may change the susceptibility to NA-based therapy and/or confer drug resistance. Apart from host cell factors, several other variables including microbial presence may determine the metabolome (i.e. metabolite concentrations) of human tissues. Studying the diversity of microorganisms that are associated with the human body has already provided new insights in several diseases (e.g. diabetes and inflammatory bowel disease) and the metabolic exchange between tissues and their specific microbiota was found to affect the bioavailability and toxicity of certain anticancer drugs, including NAs. Several studies report a preferential colonization of tumor tissues with some mycoplasma species (mostly Mycoplasma hyorhinis). These prokaryotes are also a common source of cell culture contamination and alter the cytostatic activity of some NAs in vitro due to the expression of nucleoside catabolizing enzymes. Mycoplasma infection may therefore bias experimental work with NAs, and their presence in the tumor microenvironment could be of significance when optimizing nucleoside-based cancer treatment. PMID- 26417264 TI - Encapsulation of catechin and epicatechin on BSA NPS improved their stability and antioxidant potential. AB - Nanoencapsulation of antioxidant molecules on protein nanoparticles (NPs) could be an advanced approach for providing stable, better food nutraceuticals and anticancer drugs. The bioavailability and stability of catechin (CAT) and epicatechin (ECAT) were very poor. In the present study, the CAT and ECAT were loaded on bovine serum albumin (BSA) NPs following desolvation method. The transmission electron microscope (TEM) and atomic force microscope (AFM) recorded size of CAT-BSA NPs and ECAT-BSA NPs were 45 +/- 5 nm and 48 +/- 5 nm respectively. The encapsulation efficiency of CAT and ECAT on BSA NPs was found to be 60.5 and 54.5 % respectively. CAT-BSA NPs and ECAT-BSA NPs show slow and sustained in vitro release. The CAT-BSA NPs and ECAT-BSA NPs were stable in solution at various temperatures 37 degrees C, 47 degrees C and 57 degrees C. DPPH assay revealed that CAT and ECAT maintained their functional activity even after encapsulation on BSA NPs. Furthermore, the efficacy of CAT-BSA NPs and ECAT BSA NPs determined against A549 cell lines was found to be improved. CAT and ECAT aptly encapsulated in BSA NPs, showed satisfactory sustained release, maintained antioxidant potential and found improved efficacy. This has thus suggested their more effective use in food and nutraceuticals as well as in medical field. PMID- 26417266 TI - EST sequencing and gene expression profiling in Scutellaria baicalensis. AB - Scutellaria baicalensis is an important medicinal plant, but few genomic resources are available for this species, as well as for other non-model plants. One of the major new directions in genome research is to discover the full spectrum of genes transcribed from the whole genome. Here, we report extensive transcriptome data of the early growth stage of S. baicalensis. This transcriptome consensus sequence was constructed by de novo assembly of shotgun sequencing data, obtained using multiple next-generation DNA sequencing (NGS) platforms (Roche/454 GS_FLX+ and Illumina/Solexa HiSeq2000). We show that this new approach to obtain extensive mRNA is an efficient strategy for genome-wide transcriptome analysis. We obtained 1,226,938 and 161,417,646 reads using the GS_FLX and the Illumina/Solexa HiSeq2000, respectively. De novo assembly of the high-quality GS_FLX and Illumina reads (95 % and 75 %) resulted in more than 82 Mb of mRNA consensus sequence, which we assembled into 51,188 contigs, with at least 500 bp per contig. Of these contigs, 39,581 contained known genes, as determined by BLASTX searches against non-redundant NCBI database. Of these, 20,498 different genes were expressed during the early growth stage of S. baicalensis. We have made the expressed sequences available on a public database. Our results demonstrate the utility of combining NGS technologies as a basis for the development of genomic tools in non-model, medicinal plant species. Knowledge of all described genes and quantitation of the expressed genes, including the transcription factors involved, will be useful in studies of the biology of S. baicalensis gene regulation. PMID- 26417267 TI - Polyacrylamide hydrogel encapsulated E. coli expressing metal-sensing green fluorescent protein as a potential tool for copper ion determination. AB - A simple, inexpensive and field applicable metal determination system would be a powerful tool for the efficient control of metal ion contamination in various sources e.g. drinking-water, water reservoir and waste discharges. In this study, we developed a cell-based metal sensor for specific and real-time detection of copper ions. E. coli expressing metal-sensing green fluorescent protein (designated as TG1/(CG)6GFP and TG1/H6CdBP4GFP) were constructed and served as a metal analytical system. Copper ions were found to exert a fluorescence quenching effect, while zinc and cadmium ions caused minor fluorescence enhancement in the engineered bacterial suspension. To construct a user-friendly and reagentless metal detection system, TG1/H6CdBP4GFP and TG1/(CG)6GFP were encapsulated in polyacrylamide hydrogels that were subsequently immobilized on an optical fiber equipped with a fluorescence detection module. The sensor could be applied to measure metal ions by simply dipping the encapsulated bacteria into a metal solution and monitoring fluorescence changes in real time as a function of the metal concentration in solution. The sensor system demonstrated high specificity toward copper ions. The fluorescence intensities of the encapsulated TG1/(CG)6GFP and TG1/H6CdBP4GFP were quenched by approximately 70 % and 80 % by a high-dose of copper ions (50 mM), respectively. The level of fluorescence quenching exhibited a direct correlation with the copper concentration, with a linear correlation coefficient (r) of 0.99. The cell-based metal sensor was able to efficiently monitor copper concentrations ranging between 5 M and 50 mM, encompassing the maximum allowed copper contamination in drinking water (31.15 M) established by the WHO. Furthermore, the cell-based metal sensor could undergo prolonged storage for at least 2 weeks without significantly influencing the copper sensitivity. PMID- 26417265 TI - Cytochrome P450 enzyme mediated herbal drug interactions (Part 1). AB - It is well recognized that herbal supplements or herbal medicines are now commonly used. As many patients taking prescription medications are concomitantly using herbal supplements, there is considerable risk for adverse herbal drug interactions. Such interactions can enhance the risk for an individual patient, especially with regard to drugs with a narrow therapeutic index such as warfarin, cyclosporine A and digoxin. Herbal drug interactions can alter pharmacokinetic or/and pharmacodynamic properties of administered drugs. The most common pharmacokinetic interactions usually involve either the inhibition or induction of the metabolism of drugs catalyzed by the important enzymes, cytochrome P450 (CYP). The aim of the present article is to provide an updated review of clinically relevant metabolic CYP-mediated drug interactions between selected herbal supplements and prescription drugs. The commonly used herbal supplements selected include Echinacea, Ginkgo biloba, garlic, St. John's wort, goldenseal, and milk thistle. To date, several significant herbal drug interactions have their origins in the alteration of CYP enzyme activity by various phytochemicals. Numerous herbal drug interactions have been reported. Although the significance of many interactions is uncertain but several interactions, especially those with St. John's wort, may have critical clinical consequences. St. John's wort is a source of hyperforin, an active ingredient that has a strong affinity for the pregnane xenobiotic receptor (PXR). As a PXR ligand, hyperforin promotes expression of CYP3A4 enzymes in the small intestine and liver. This in turn causes induction of CYP3A4 and can reduce the oral bioavailability of many drugs making them less effective. The available evidence indicates that, at commonly recommended doses, other selected herbs including Echinacea, Ginkgo biloba, garlic, goldenseal and milk thistle do not act as potent or moderate inhibitors or inducers of CYP enzymes. A good knowledge of the mechanisms of herbal drug interactions is necessary for assessing and minimizing clinical risks. These processes help prediction of interactions between herbal supplements and prescription drugs. Healthcare professionals should remain vigilant for potential interactions between herbal supplements/medicines and prescription drugs, especially for drugs with a narrow therapeutic index are used. PMID- 26417269 TI - Antifungal potential of essential oil and ethanol extracts of Lonicera japonica Thunb. against dermatophytes. AB - The antifungal potential of essential oil and ethanolic leaf extracts of Lonicera japonica Thunb. was evaluated for controlling the growth of dermatophytes. The oil (1,000 ppm) and extracts (1,500 ppm) of L. japonica revealed 55.1-70.3 % and 40.1-65.5 % antidermatophytic effect against Microsporum canis KCTC 6348, 6349, 6591, Trichophyton rubrum KCTC 6345, 6352, 6375, Trichophyton mentagrophytes KCTC 6077 and 6085, respectively, along with their respective minimum inhibitory concentrations ranging from 62.5-500 and 125-1,000 ug/ml. Also, the oil had strong detrimental effect on spore germination of all the tested dermatophytes as well as concentration and time-dependent kinetic inhibition of M. canis KCTC 6348. The results demonstrated that L. japonica oil and extracts could be potential sources of natural fungicides to protect human and animals from fungal infections. PMID- 26417268 TI - Arylesterase activity is associated with antioxidant intake and paraoxonase-1 (PON1) gene methylation in metabolic syndrome patients following an energy restricted diet. AB - The arylesterase (ARE) activity linked to the paraoxonase-1 (PON1) gene is known to protect lipoproteins from oxidation and provide defense against metabolic syndrome (MetS) and cardiovascular diseases. The epigenetic regulation of enzymatic activities is gaining importance nowadays. This research aimed to assess the potential relationships between the ARE activity with the methylation levels of the PON1 gene transcriptional regulatory region, anthropometrics, biochemical markers and antioxidant dietary components. Forty-seven subjects (47 +/- 10 y.o; BMI 36.2 +/- 3.8 kg/m(2); 46.8 % female) with MetS features, who followed a six-month energy-restricted dietary weight-loss intervention, were included in this study (www.clinicaltrials.gov; NCT01087086). Anthropometric, biochemical, enzymatic and dietary data were assessed using validated procedures. PON1 transcriptional regulatory region methylation was analyzed by a microarray technical approach. Volunteers reduced ARE activity in parallel with body weight (p = 0.005), BMI (p = 0.006), total fat mass (p = 0.020), diastolic blood pressure (p = 0.018), mean blood pressure (p = 0.022) and triglycerides (p = 0.014). Methylation levels of some CpG sites of the PON1 gene correlated negatively with ARE activity (p < 0.05). Interestingly, dietary vitamin C (p = 0.001), tocopherols (p = 0.009) and lycopene (p = 0.038) were positively associated with ARE activity and showed an inverse correlation (p = 0.004, p = 0.029 and p = 0.021, respectively) with the methylation of some selected CpG sites of the PON1 gene. In conclusion, ARE activity decreased in parallel with MetS-related markers associated to the energy restriction, while dietary antioxidants might enhance the ARE activity by lowering the PON1 gene methylation in patients with MetS features. PMID- 26417270 TI - Synthesis, preclinical evaluation and antidepressant activity of 5-substituted phenyl-3-(thiophen-2-yl)-4, 5-dihydro-1H-pyrazole-1-carbothioamides. AB - A series of phenyl-3-(thiophen-2-yl)-4, 5-dihydro-1H-pyrazole-1-carbothioamides (TTa-TTg) were synthesized by the ring closure reaction of phenyl-1-(thiophen-2 yl) prop-2-en-1-ones with thiosemicarbazide in alcoholic basic medium. All the final derivatives were evaluated for their antidepressant and neurotoxicity screening. The structures of the compounds were characterized by IR, 1H NMR, 13C NMR, Mass and elemental analyses. Preclinical evaluation of the compounds were ascertained by in silico toxicity, blood-brain barrier and human oral absorption prediction. In this series, 5-(4-hydroxyphenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H pyrazole-1 carbothioamide (TTg) reduced immobility time 61.17 and 62.05 % in both force swimming and tail suspension test respectively at 10 mg/kg dose level when compared to the standard Imipramine without influencing the baseline locomotion. Moreover it was observed that the titled scaffold possessing electron withdrawing chlorine atom in the 4(th) position of aromatic ring of the scaffold also showed good the antidepressant activity. In conclusion, the behavioural investigation revealed that thiophene based pyrazolines having a carbothioamide tail unit in the N1 position may be therapeutically useful as potential antidepressant medications. PMID- 26417271 TI - DNA damaging and biochemical effects of potassium tetraborate. AB - Potassium tetraborate (PTB) is a product resulting from the controlled reaction of potassium hydroxide, water and boric acid (BA). It is used in many areas of industry such as disinfectant, detergent and treatment of contact lenses. PTB is one of the boron compounds which is most commonly used in many areas of industry although very limited information is available concerning its toxicity. Therefore, in this study, it is aimed to determine genetic and biochemical effects of PTB in human blood cell cultures (n=4). PTB was added into culture tubes at various concentrations (0-1280 ug/ml). Micronucleus (MN) and chromosomal aberration (CA) tests were performed for genotoxic damage influences estimation. In addition, biochemical parameters (total antioxidant capacity (TAC) and total oxidative status (TOS) were examined to determine oxidative effects. The results indicated that all tested concentrations of PTB were found to be non-genotoxic. In addition, low concentrations (1.25, 2.5 and 5 ug/ml) of PTB caused increases of TAC levels. Furthermore, all concentrations of PTB were not changed the TOS levels in cultured human blood cells. Based on these results, in this study it has been reported for the first time that PTB is not genotoxic and it increases the antioxidant capacity in human peripheral blood lymphocytes. PMID- 26417272 TI - Phytochemicals for treatment of diabetes. AB - Diabetes Mellitus (DM) is one of the most prevalent metabolic disorders characterized by increased blood glucose levels and improper primary metabolism resulting from the defects in insulin secretion, insulin action, or both. It is one of the most common health problems worldwide, and the prevalence of this disease is rapidly increasing, leading to microvascular (retinopathy, neuropathy and nephropathy) and macrovascular (heart attack, stroke and peripheral vascular disease) complications (Umar et al., 2010[18]). The number of individuals with diabetes is increasing due to population growth, aging, urbanization and increasing prevalence of obesity and physical inactivity. According to recent estimates, the greatest absolute increase in the number of patients with diabetes will be in India and the total number is projected to 79.4 million in 2030. It is expected that about 366 million are likely to be diabetic by the year 2030 (Rahman and Zaman, 1989[14]). Medicinal plants are the main source of organic compounds such as polyphenols, tannins, alkaloids, carbohydrates, terpenoids, steroids and flavonoids. These organic compounds represent a source for the discovery and development of new types of antidiabetic molecules. Many compounds isolated from plant sources have been reported to show antidiabetic activity. The key messages summarize some recent information in the field of antidiabetic phytochemicals. PMID- 26417273 TI - A case of suicide attempt with Zolpidem - will Zolpidem show up on standard urine toxicology screening? PMID- 26417274 TI - Highlight report: Validation of prognostic genes in lung cancer. PMID- 26417276 TI - Risks to health professionals from hazardous drugs in Iran: a pilot study of understanding of healthcare team to occupational exposure to cytotoxics. AB - Ongoing concerns exist regarding the dangers inherent when handling cytotoxics, particularly drugs which are in parenteral formulations. On occasions, nurses and medical doctors have been preparing and administrating these drugs in the open spaces of wards in the absence of suitable personal protective equipment (PPE) and safety cabinets. To explore further into the severity of occupational hazards, we conducted our research in order to evaluate the healthcare's understanding of occupational exposure to cytotoxics and occurrence of any side effects. A cross-sectional study using a self-administered questionnaire was distributed amongst oncology nurses in nine specialized cancer centers in Tehran. The questionnaire was based on most reputable international guidelines, aiming to evaluate the attitude, knowledge and safe practices of nurses' handling cytotoxic drugs. The gathered data and reported side effects were compared between "oncology/hematology" and "non-oncology" participants. The majority of nurses from oncology wards were aware of the potential hazards associated with handling of chemotherapy and reported high levels of compliance with the use of PPE during reconstitution of antineoplastic agents. Almost all nurses reported the use of a safety cabinet during preparation, however only 55 % reported that they have annual medical checkups and 45 % reported having received specialized training. This work was also to evaluate the experimental procedures as well as cleaning solutions used to reduce the level exposure. While the level of knowledge about antineoplastic agents is high among nurses, along with the level of PPE use, medical surveillance and employee training seems to be lagging behind. PMID- 26417277 TI - Effects of Khaya senegalensis leaves on performance, carcass traits, hemtological and biochemical parameters in rabbits. AB - One of the challenges facing farmers today is to ensure adequate integration of natural resources into animal feeds. The aim of the present study is to evaluate the effects of Khaya senegalensis (KS) leaves on the performance of growing male rabbits, carcass traits and biochemical as well as hematological parameters. Thirty New Zealand White male growing rabbits were randomly divided into 3 groups (10 rabbits per group). Group I (control) received standard rabbit diet. Rabbits in group II and group III were fed standard rabbit diet supplemented with 35 % and 65 % KS leaves, respectively. All rabbits were fed daily for 25 days. The performance parameters and carcass criteria, including daily body weight gain, final body weight, and the percentage of dressing, were increased in rabbits fed 35 % KS when compared to the control group. Kidney and liver weight ratios increased significantly in group II but dropped in group III. Furthermore, liver enzymes - alanine aminotransferase and aspartate transaminase and kidney function parameters - urea, and creatinine - increased in both group II (significant P<0.05) and in group III (significant P<0.01) when compared to the control group. Moreover, KS leaves induced a significant increase (P<0.05) in the total white blood cell count, the percentage of granulocytes and the platelet count; whereas, the percentage of lymphocytes, red blood cell count, hemoglobin content, mean corpuscular hemoglobin, mean corpuscular volume and mean corpuscular hemoglobin concentration were not statistically significantly changed. This study demonstrates that the performance parameters and carcass traits are improved by the replacement of rabbit's diet with KS leaves. However, KS leaves may adversely affect liver and kidney function in a dose-dependent manner. Therefore, further studies are required to elucidate the maximum tolerable and toxic, as well as lethal doses, and to isolate the pharmacologically active components from KS leaves. PMID- 26417278 TI - In silico protein modeling: possibilities and limitations. PMID- 26417279 TI - The obesity paradox is not observed in chronic heart failure patients with metabolic syndrome. AB - INTRODUCTION: Although being overweight or obese is a risk factor for cardiovascular disease, obese subjects often live longer than their lean peers, and this is known as the obesity paradox. We investigated the impact of obesity on cardiac prognosis in chronic heart failure (CHF) patients, with or without metabolic syndrome. DESIGN AND METHODS: We divided 374 consecutive CHF patients into two groups according to their mean body mass index (BMI) and prospectively followed them for 2 years. RESULTS: There were 126 cardiac events, including 32 cardiac deaths and 94 re-hospitalizations. Kaplan-Meier analysis revealed a significantly lower cardiac event rate in the higher BMI group (log-rank test P < 0.001) in all patients and those patients without metabolic syndrome. There was no association between BMI and cardiac prognosis in patients with metabolic syndrome. Cox hazard analysis revealed that a higher BMI was associated with favorable cardiac outcomes in all patients and patients without metabolic syndrome, after adjusting for confounding factors. However, this finding did not extend to patients with metabolic syndrome. CONCLUSIONS: The advantages of obesity are not found in CHF patients with metabolic syndrome. PMID- 26417275 TI - Non-alcoholic fatty liver disease, diet and gut microbiota. AB - Non-alcoholic fatty liver disease (NAFLD) is a severe liver disease that is increasing in prevalence with the worldwide epidemic of obesity and its related insulin-resistance state. Evidence for the role of the gut microbiota in energy storage and the subsequent development of obesity and some of its related diseases is now well established. More recently, a new role of gut microbiota has emerged in NAFLD. The gut microbiota is involved in gut permeability, low-grade inflammation and immune balance, it modulates dietary choline metabolism, regulates bile acid metabolism and produces endogenous ethanol. All of these factors are molecular mechanisms by which the microbiota can induce NAFLD or its progression toward overt non-alcoholic steatohepatitis. Modification of the gut microbiota composition and/or its biochemical capacity by specific dietary or pharmacological interventions may advantageously affect host metabolism. Large scale intervention trials, investigating the potential benefit of prebiotics and probiotics in improving cardiometabolic health in high-risk populations, are fervently awaited. PMID- 26417280 TI - Chemical composition and antibacterial activity of essential oils from the Tunisian Allium nigrum L. AB - The chemical composition of the essential oils of different Allium nigrum L. organs and the antibacterial activity were evaluated. The study is particularly interesting because hitherto there are no reports on the antibacterial screening of this species with specific chemical composition. Therefore, essential oils from different organs (flowers, stems, leaves and bulbs) obtained separately by hydrodistillation were analyzed using gas chromatography-mass spectrometry (GC MS). The antibacterial activity was evaluated using the disc and microdilution assays. In total, 39 compounds, representing 90.8-96.9 % of the total oil composition, were identified. The major component was hexadecanoic acid (synonym: palmitic acid) in all the A. nigrum organs oils (39.1-77.2 %). We also noted the presence of some sesquiterpenes, mainly germacrene D (12.8 %) in leaves oil) and some aliphatic compounds such as n-octadecane (30.5 %) in bulbs oil. Isopentyl isovalerate, 14-oxy-alpha-muurolene and germacrene D were identified for the first time in the genus Allium L. All the essential oils exhibited antimicrobial activity, especially against Enterococcus faecalis and Staphylococcus aureus. The oil obtained from the leaves exhibited an interesting antibacterial activity, with a Minimum Inhibitory Concentration (MIC) of 62.50 ug/mL against these two latter strains. The findings showed that the studied oils have antibacterial activity, and thus great potential for their application in food preservation and natural health products. PMID- 26417281 TI - Enriched environment attenuates changes in water-maze performance and BDNF level caused by prenatal alcohol exposure. AB - Prenatal exposure to alcohol can result in fetal alcohol syndrome (FAS), characterized by significant changes in the physiology, structural plasticity of hippocampal function, including long-term deficits in learning and memory. Environmental enrichment has long been known to improve motor and cognitive function levels, causes several neurochemical and morphological alterations in the brain. Therefore, the effects of environmental enrichment on the neurobehavioral and neurotrophic changes in mice exposed prenatally to alcohol were investigated in this study. The pregnant dams were given 25 % ethanol (w/v) or isocaloric sucrose by liquid diet from gestation day 7 to 20. After weaning on postnatal day 28, offspring were exposed to standard cage (CC, CFAS) or enriched living conditions (CE, EFAS) for 8 weeks. Neurobehavioral studies both on hippocampus-dependent spatial learning and place and cue learning strategy, a striatum-dependent test, were measured by the Morris water maze task. Moreover, the reverse-transcriptase polymerase chain reaction (RT-PCR) technique was also used in order to study the expression of brain-derived neurotrophic factor (BDNF) level in both the hippocampus and striatum of mice. Neurobehavioral studies show that animals exposed prenatally to alcohol were impaired as shown in both hippocampal-dependent spatial/place and striatal-dependent response/cue learning tests. Moreover, the levels of BDNF expression both in the hippocampus and striatum of mice were also decreased. Interestingly, environmental enrichment can ameliorate the effects of prenatal alcohol exposure both on the neurobehavioral and neurotrophic levels. These observations indicated that enriched environment attenuated memory impairment of prenatal alcohol exposure both in hippocampal and striatal circuitry. PMID- 26417282 TI - Quantification of three-dimensional structures in liver tissue: bile canalicular and sinusoidal networks. PMID- 26417283 TI - Exercise protects against obesity induced semen abnormalities via downregulating stem cell factor, upregulating Ghrelin and normalizing oxidative stress. AB - Increased oxidative stress and hormonal imbalance have been hypothesized to underlie infertility in obese animals. However, recent evidence suggests that Ghrelin and Stem Cell Factor (SCF) play an important role in fertility, in lean individuals. Therefore, this study aimed at investigating whether changes in the levels of Ghrelin and SCF in rat testes underlie semen abnormal parameters observed in obese rats, and secondly, whether endurance exercise or Orlistat can protect against changes in Ghrelin, SCF, and/or semen parameters in diet induced obese rats. Obesity was modelled in male Wistar rats using High Fat Diet (HFD) 12 week protocol. Eight week-old rats (n=40) were divided into four groups, namely, Group I: fed with a standard diet (12 % of calories as fat); Group II: fed HFD (40 % of calories as fat); Group III: fed the HFD with a concomitant dose of Orlistat (200 mg/kg); and Group IV: fed the HFD and underwent 30 min daily swimming exercise. The model was validated by measuring the levels of testosterone, FSH, LH, estradiol, leptin, triglycerides, total, HDL, and LDL cholesterol, and final change in body weight. Levels were consistent with published obesity models (see Results). As predicted, the HFD group had a 76.8 % decrease in sperm count, 44.72 % decrease in sperm motility, as well as 47.09 % increase in abnormal sperm morphology. Unlike the control group, in the HFD group (i.e. obese rats) Ghrelin mRNA and protein were elevated, while SCF mRNA and protein were diminished in the testes. Furthermore, in the HFD group, SOD and GPx activities were significantly reduced, 48.5+/-5.8 % (P=0.0012) and 45.6+/-4.6 % (P=0.0019), respectively, while TBARS levels were significantly increased (112.7+/-8.9 %, P=0.0001). Finally, endurance exercise training and Orlistat administration individually and differentially protected semen parameters in obese rats. The mechanism includes, but is not limited to, normalizing the levels of Ghrelin, SCF, SOD, GPx and TBARS. In rat testes, diet induced obesity down regulates SCF expression, upregulates Ghrelin expression, and deteriorate oxidative stress levels, which are collectively detrimental to semen parameters. Exercise, and to a lesser extent Orlistat administration, protected effectively against this detrimental effect. PMID- 26417284 TI - EGFR tyrosine kinase targeted compounds: in vitro antitumor activity and molecular modeling studies of new benzothiazole and pyrimido[2,1-b]benzothiazole derivatives. AB - In this study, we illustrate computer aided drug design of new benzothiazole and pyrimido[2,1-b]benzothiazole derivatives as epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors. Compounds 1-5 were screened at NCI, USA, for antitumor activity against non-small cell lung cancer (NCI-H522), colon cancer (HCT-116, HCT-15 and HT29) and breast cancer (MDA-MB-468 and MDA-MB 231/ATCC) cell lines in which EGFR is overexpressed in varying levels. Results indicated that these compounds are more potent antitumor agents compared to erlotinib against HT29 and MDA-MB-231/ATCC cell lines. Compound 3 showed GI50 value of 22.3 nM against NCI-H522 cell line, while erlotinib exhibited GI50 value of 1 uM against the same cell line. In addition, these compounds were studied for their EGFR tyrosine kinase inhibitory activity. Virtual screening utilizing molecular modeling and QSAR techniques enabled the understanding of the pharmacophoric requirements for antitumor activity. Docking the designed compounds into the ATP binding site of EGFR-TK domain was done to predict the analogous binding mode of these compounds to the EGFR-TK inhibitors. PMID- 26417285 TI - Nesfatin-1: role as possible new anti-obesity treatment. AB - In this article, we review on the current concepts about Nesfatin-1 as a new anti obesity treatment and evaluate the existing issues in the context of this knowledge and the available literature. The intent is to enable clinicians to know Nesfatin-1 as a new anti-obesity treatment and make rational decisions based on this perspective as possible clinical application. Future research should seek to clarify whether Nesfatin-1 would be beneficial in the management of obesity. PMID- 26417287 TI - Conformational changes of a chemically modified HRP: formation of a molten globule like structure at pH 5. AB - Horseradish peroxidase is an all alpha-helical enzyme, which widely used in biochemistry applications mainly because of its ability to enhance the weak signals of target molecules. This monomeric heme-containing plant peroxidase is also used as a reagent for the organic synthesis, biotransformation, chemiluminescent assays, immunoassays, bioremediation, and treatment of wastewaters as well. Accordingly, enhancing stability and catalytic activity of this protein for biotechnological uses has been one of the important issues in the field of biological investigations in recent years. In this study, pH-induced structural alterations of native (HRP), and modified (MHRP) forms of Horseradish peroxidase have been investigated. Based on the results, dramatic loss of the tertiary structure and also the enzymatic activity for both forms of enzymes recorded at pH values lower than 6 and higher than 8. Ellipticiy measurements, however, indicated very slight variations in the secondary structure for MHRP at pH 5. Spectroscopic analysis also indicated that melting of the tertiary structure of MHRP at pH 5 starts at around 45 degrees C, which is associated to the pKa of His 42 that has a serious role in keeping of the heme prostethic group in its native position through natural hydrogen bond network in the enzyme structure. According to our data, a molten globule like structure of a chemically modified form of Horseradish peroxidase at pH 5 with initial steps of conformational transition in tertiary structure with almost no changes in the secondary structure has been detected. Despite of some conformational changes in the tertiary structure of MHRP at pH 5, this modified form still keeps its catalytic activity to some extent besides enhanced thermal stability. These findings also indicated that a molten globular state does not necessarily preclude efficient catalytic activity. PMID- 26417286 TI - Hydroxymethylation of DNA: an epigenetic marker. PMID- 26417288 TI - Testing chemical carcinogenicity by using a transcriptomics HepaRG-based model? AB - The EU FP6 project carcinoGENOMICS explored the combination of toxicogenomics and in vitro cell culture models for identifying organotypical genotoxic- and non genotoxic carcinogen-specific gene signatures. Here the performance of its gene classifier, derived from exposure of metabolically competent human HepaRG cells to prototypical non-carcinogens (10 compounds) and hepatocarcinogens (20 compounds), is reported. Analysis of the data at the gene and the pathway level by using independent biostatistical approaches showed a distinct separation of genotoxic from non-genotoxic hepatocarcinogens and non-carcinogens (up to 88 % correct prediction). The most characteristic pathway responding to genotoxic exposure was DNA damage. Interlaboratory reproducibility was assessed by blindly testing of three compounds, from the set of 30 compounds, by three independent laboratories. Subsequent classification of these compounds resulted in correct prediction of the genotoxicants. As expected, results on the non-genotoxic carcinogens and the non-carcinogens were less predictive. In conclusion, the combination of transcriptomics with the HepaRG in vitro cell model provides a potential weight of evidence approach for the evaluation of the genotoxic potential of chemical substances. PMID- 26417289 TI - Treatment with platelet lysate induces endothelial differentation of bone marrow mesenchymal stem cells under fluid shear stress. AB - By considering stem cell-based therapies as a new hope for the treatment of some tragic diseases, marrow stromal cells or marrow mesenchymal stem cells (MSCs) were considered as a suitable and safe multipotential cell source for this new therapeutic approach. For this purpose, many investigations have been performed on differentiation of MSCs toward specific cell lines to overcome the demand for providing the organ specific cells for cell therapy or preparation of engineered tissues. In the present study, differentiation of MSCs to endothelial cells (ECs) by mechanical and chemical stimulation was evaluated. Fluid shear stress (FSS) was used as mechanical inducer, while platelet lysate (PL) and estradiol (E) were used as chemical induction factors. MSCs were placed under FSS with different forces (2, 5 and 10dyn/cm(2)) for different periods (6, 12 and 24 hours). In some groups, PL and E were added to the culture media to evaluate their effect on expression of EC specific markers. This investigation revealed that FSS with low tension (2.5-5 dyn/cm(2)) for a long time (24 hours) or high tension (10 dyn/cm(2)) in short time (6 hours) in the presence of PL could differentiate MSCs toward ECs. The presence of PL was necessary for initiation of endothelial differentiation, and in the absence of PL, there was not any expression of CD34 and Cadherin5 (Cdh5) among cells. Adding E to the culture medium did not change the rate of endothelial differentiation under FSS. Generated endothelial progenitors could produce von Willebrand factor (vWF) after two weeks culture and also they formed tubular structures after culture on matrigel. PMID- 26417290 TI - Watermelon lycopene and allied health claims. AB - Presently, functional foods and nutraceuticals are gaining immense importance in the prevention of various maladies through dietary regimen module. Consumption of fruits and vegetables based diet has pursuit a range of bioactive components, especially phytochemicals targeting life threatening ailments. In this context, lycopene is an extensively studied antioxidant potentially present in watermelon, tomato, pink guava etc. Watermelon is one of the unique sources having readily available cis-isomeric lycopene. The distinctive aroma of watermelon is imparted by medium- and short-chain fatty acids along with geranial, beta-ionone and neral. Its consumption has been escalated owing to rich nutritional profile and allied health benefits. It is effective in reducing the extent of cancer insurgence, cardiovascular disorders, diabetes and macular diseases. The structural characteristics, physiochemical properties and therapeutic effects of lycopene are the limelight of the manuscript. However, further research investigations are still needed to address the health enhancing potential of watermelon lycopene. PMID- 26417291 TI - Sodium valproate enhances urethane tumorigenicity in lungs of male but not female mice. AB - In the study, the possible effect of sodium valproate (NaVP) on urethane-induced lung tumors in mice has been evaluated. BALB/c mice (n = 120; 4-6 weeks old, both sexes) were used in the following groups: 1) urethane-treated, 2) urethane-NaVP treated, 3) only NaVP-treated, 4) control. In the same groups, castrated male mice (n = 48) were investigated. Urethane was given by intraperitoneal injections 10 mg/mouse, twice a week, the total dose 50 mg/mouse. In NaVP-treated mice, the 0.4 % NaVP aqueous solution was offered to mice ad libitum. The duration of the experiment was 6 months. The number of tumors per mouse in urethane-NaVP-treated males was significantly higher than in those treated with urethane only (13.82 +/ 1.12 vs 6.77 +/- 0.43, p < 0.0001). No significant difference in the number of tumors per mouse was revealed while comparing the female urethane- and urethane NaVP-treated groups (6.50 +/- 0.79 vs 8.15 +/- 0.55, p = 0.105). No difference in the number of tumors per mouse was found in urethane-NaVP-treated castrated males as compared with urethane-treated castrated males. However, in the urethane-NaVP treated castrated males the number of tumors per mouse was significantly lower than in analogous non-castrated males (7.8 +/- 1.67 vs 13.82 +/- 1.12, p < 0.01). NaVP combined with urethane potentiates urethane tumorigenicity in BALB/c non castrated but not in female and castrated male mice. These data indicate an important role of testosterone in the urethane-NaVP induced lung tumorigenesis. PMID- 26417292 TI - Biochemical composition and bioactivity screening of various extracts from Dunaliella salina, a green microalga. AB - The current study examines the antimicrobial and antioxidant properties of different extracts of the microalga Dunaliella salina Teodoresco (Dunaliellaceae), their fatty acid composition and the antimicrobial activity of the oil. Antimicrobial and antioxidant activities were evaluated by obtaining extracts of D. salina in n-hexane, dichloromethane, ethanol, and methanol. To evaluate the antimicrobial activity, the extracts, and fatty acids from D. salina were assessed by the disc diffusion and microdilution techniques against pathogenic microorganisms including fish and clinical/food-borne. The MBC or MFC values of the extracts and fatty acids ranged from 0.63 to 10.00 mg/ml. The antioxidant activity was studied by phosphomolybdenum and DPPH assays and beta carotene/linoleic acid tests. In addition, the total phenolic and flavonoid contents were evaluated and the fatty acid composition was determined using gas chromatography. Palmitic, alpha-linolenic, and oleic acids were discovered to be the major components of the fatty acids. These findings have demonstrated that the extracts and oil from D. salina could be used as natural antimicrobials and antioxidants in the food/feed and pharmaceutical industry and as a biodiesel because of its high unsaturated fatty acid content. PMID- 26417294 TI - Cancer incidence in North West Algeria (Mascara) 2000-2010: results from a population-based cancer registry. AB - Cancer is a leading cause of death worldwide accounting for 7.4 million deaths. Cancer has become a major public health concern in Algeria. The aim of the present study was to estimate cancer incidence in Mascara Province based on the population-based cancer registry. We analyzed data from the cancer registry of Mascara covering all cancer cases diagnosed by all methods and included in the registry from 1(st) January 2000 to 31(st) December 2010. The results are presented as incidence rates of cases by site, sex, age, and crude rate. Age standardized rates per 100,000 person-years (ASRs) were calculated, using the direct method of standardization to the world population. A total of 1875 cases of invasive cancer were recorded. The mean age of diagnosis for all cancers was 52.66 +/- 0.5 in men and 59.18 +/- 0.6 in women. The ASR for all cancers in females was 27.8 per 100,000, and that for males was 23.6 per 100,000. The most important finding of the present study was the high incidence of liver cancer among males and females in Mascara. Among females, breast cancer was the most frequently reported followed by Cervix uteri, liver and colon. The most frequent cancer types in males were lung, colon, esophagus and stomach and liver. Cancer incidence in Mascara province was lower than that reported in other national and regional registries. Findings of the present study revealed high incidence of liver cancer in the province, the highest in Algeria, suggesting high prevalence of risk factors. PMID- 26417295 TI - Distributions of susceptibility loci of Parkinson's disease and multiple sclerosis on human chromosomes. PMID- 26417293 TI - Mutant p53 protein expression and antioxidant status deficiency in breast cancer. AB - It is well recognized that cancers develop and grow as a result of disordered function of tumor suppressor genes and oncogenes, which may be exploited for screening purposes. Extensive evidence indicated tumor suppressor protein p53 as candidate marker for mutation identification. We have investigated mutant p53 protein expression in human breast tumors in relation to antioxidant status deficiency. The study included 100 breast cancer patients. p53 protein expression was evaluated by Western blot assay and immunostaining using a CM-1, DO-7 and Pab240 antibodies. Antioxidant parameters and lipid peroxidation were estimated by biochemical analyses. Western blotting with epitopespecific monoclonal antibody Pab240 strongly suggests that nuclear extracts from breast cancer cells express mutant forms of p53. It is of interest that the mutant forms of p53 overexpression in conjunction with the appearance of nuclear bodies are observed in highly aggressive carcinomas. Expression of isoform Deltap53 (45 kDa) and isoform of ~ 29 kDa were more common in cases with LN metastasis. These studies point out the molecular consequences of oxidative stress (lipid peroxides, LP, p<0.001) and antioxidant status deficiency (copper, zinc superoxid dismutase, SOD, p<0.001; catalase, CAT, p<0.01; glutathione reductase, GR, p<0.001; glutathione, GSH, p<0.05) and indicate the importance of p53 mutation as the commonest genetic alteration detected in breast cancer cells. The expression of mutant p53 is correlated to increased lipid peroxides (0.346, p<0.05 ) and lowered antioxidant activity of CAT (- 0.437, p<0.01) in the breast cancer patients. PMID- 26417297 TI - Identification of circulating miRNAs profiles that distinguish malignant pleural mesothelioma from lung adenocarcinoma. AB - Accurate diagnosis of malignant pleura mesothelioma (MPM) is challenging. Differential diagnosis of MPM versus lung adenocarcinoma (AD) is particularly difficult, yet clinically important since the two neoplasias call for different treatment approaches. Circulating miRNA-profiling to identify miRNAs that can be used to distinguish MPM from AD has not been reported. We conducted a wide screening study of miRNA profiles in serum pools of MPM patients (N = 11), AD patients (N = 36), and healthy subjects (N = 45) to identify non-invasive biomarkers for differential diagnosis of MPM and AD, using deep sequencing. Sequencing detected up to 300 known miRNAs and up to 25 novel miRNAs species in the serum samples. Among known miRNAs, 7 were upregulated in MPM and 12 were upregulated in AD compared to healthy controls. Of these, eight were distinctive for AD and three were unique for MPM. Direct comparison of the miRNA profiles for MPM and AD revealed differences in miRNA levels that could be useful for differential diagnosis. No differentially expressed novel miRNAs were found. Further bioinformatics analysis indicated that three upregulated miRNAs in MPM are associated with the p38 pathway. There are unique alterations in serum miRNAs in MPM and AD compared to healthy controls, as well as differences between MPM and AD profiles. Differing miRNA levels between MPM and AD may be useful for differential diagnosis. A potential association to p38 pathway of three upregulated miRNAs in MPM was revealed. PMID- 26417298 TI - Induction of spinal long-term synaptic potentiation is sensitive to inhibition of neuronal NOS in L5 spinal nerve-transected rats. AB - The role of neuronal nitric oxide synthase (nNOS) in the central mechanism of neuropathic pain and long-term potentiation (LTP) of peripheral afferents remains obscure. The current study investigated the effect of intrathecal application of 7-nitroindazole (7-NI), a selective nNOS inhibitor (8.15 ug/5ul), on mechanical allodynia on day 14 after L5 spinal nerve transection. Furthermore, using in vivo single unit extracellular recording, we examined the effect of 7-NI on the induction of LTP of Adelta- and C-fiber-evoked responses. We have demonstrated that 7-NI attenuates nerve-injury-evoked mechanical allodynia. Additionally, our electrophysiological study has shown that the spinal administration of 7-NI significantly inhibits the induction of the LTP of Adelta- and C-fiber-evoked responses on day 14 after neuropathy. These data suggest that activation of nNOS may be crucial for the induction of the spinal LTP of Adelta- and C-fiber-evoked responses following peripheral nerve damage. PMID- 26417296 TI - Biology of PXR: role in drug-hormone interactions. AB - Hormonal homeostasis is essential for a variety of physiological and pathological processes. Elimination and detoxification of xenobiotics, such as drugs introduced into the human body, could disrupt the balance of hormones due to the induction of drug metabolizing enzymes (DMEs) and transporters. Pregnane X receptor (PXR, NR1I2) functions as a master xenobiotic receptor involved in drug metabolism and drug-drug interactions by its coordinated transcriptional regulation of phase I and phase II DMEs and transporters. Recently, increasing evidences indicate that PXR can also mediate the endocrine disruptor function and thus impact the integrity of the endocrine system. This review focuses primarily on the recent advances in our understanding of the function of PXR in glucocorticoid, mineralocorticoid, androgen and estrogen homeostasis. The elucidation of PXR-mediated drug-hormone interactions might have important therapeutic implications in dealing with hormone-dependent diseases and safety assessment of drugs. PMID- 26417300 TI - Chemical composition and antimicrobial activity of the essential oil from leaves of Algerian Melissa officinalis L. AB - The essential oil obtained from leaves of Melissa officinalis L. (Family of Lamiaceae) growing in Algeria, was investigated for its chemical composition and in vitro antimicrobial activity. The chemical composition was determined by hydrodistillation and analyzed by GC/MS and GC-FID. Sixty-three compounds were identified in the essential oil, representing 94.10 % of the total oil and the yields were 0.34 %. The major component was geranial (44.20 %). Other predominant components were neral (30.20 %) and citronellal (6.30 %). The in vitro antimicrobial activity was determined by paper disk agar diffusion testing and minimum inhibitory concentration (MIC) using 7 bacteria (3 Gram-positive and 4 Gram-negative), 2 yeasts and 3 fungi. The results showed that the essential oil presented high antimicrobial activity against all microorganisms targeted mainly against five human pathogenic bacteria, one yeast Candida albicans and two phytopathogenic fungi tested. The minimum inhibitory concentrations (MIC) ranged from 1.00 to 5.00 uL/mL. PMID- 26417299 TI - Serum protein electrophoresis under effective control of HIV-1 disease progression. AB - In this report, we compared the serum protein electrophoresis (SPE) patterns in a subset of HIV-1-infected subjects who did not progress to AIDS without antiretroviral treatment with those in whose control of disease progression was achieved by highly active antiretroviral therapy (HAART). SPE and immunofixation electrophoresis were performed on Helena Electrophoresis System according to manufacturer's instructions. The percentage of SPE abnormalities, resembling chronic inflammation, was significantly higher in HIV-1-infected subject without HAART compared with those under HAART (p = 0.001). The majority of individuals under HAART showed evidence of oligoclonal bands on the gamma-band against a polyclonal background compared with those without HAART but beta-gamma-band bridging was more evident. Immunofixation pattern was consistent with oligoclonal hypergammaglobulinaemia of IgG kappa type, which was found to be more intense in group without HAART. HIV clinical status did not show appreciable effect on the SPE pattern in subjects without HAART. However, under effective HAART, subjects with better CD4 T-cell count were associated with higher gamma-globulin band. In group without HAART, acute infection was found to be associated the higher gamma globulin fraction compared with chronic infection. The opposite was the case under effective HAART. HIV infected subjects that did not progress to AIDS were associated with markedly abnormal SPE pattern. Overall results reflect the host ability compensate defective cellular immunity in HIV-1 infection with humoral immune responses. These findings underscore the usefulness of SPE monitoring HIV disease management and identifying individuals that may not progress to full blown AIDS in the absence of treatment. PMID- 26417301 TI - Anti-inflammatory activity and chemical composition of the essential oils from Senecio flammeus. AB - Many species from Senecio genus have been used in traditional medicine, and their pharmacological activities have been demonstrated. This study investigated the chemical composition and anti-inflammatory activities of essential oils from Senecio flammeus. A total of 48 components representing 98.41 % of the total oils were identified. The main compounds in the oils were alpha-farnesene (11.26 %), caryophyllene (8.69 %), n-hexadecanoic acid (7.23 %), and alpha-pinene (6.36 %). The anti-inflammatory activity of the essential oils was evaluated in rodents (10 90 mg/kg bw) in classical models of inflammation [carrageenan-induced paw edema, 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced ear edema, and cotton pellet induced granuloma]. The essential oils at doses of 10, 30, and 90 mg/kg bw significantly reduced carrageenan-induced paw edema by 17.42 % (P < 0.05), 52.90 % (P < 0.05), and 66.45 % (P < 0.05) 4 h after carrageenan injection, respectively, and significantly reduced myeloperoxidase activity (P < 0.05). The essential oils (10, 30, and 90 mg/kg) also produced a significant dose-dependent response to reduce TPA-induced ear edema by 20.27 % (P < 0.05), 33.06 % (P < 0.05), and 53.90 % (P < 0.05), respectively. The essential oils produced significant dose-response anti-inflammatory activity against cotton pellet induced granuloma that peaked at the highest dose of 90 mg/kg (49.08 % wet weight and 47.29 % dry weight). Results demonstrate that the essential oils of S. flammeus were effective in the treatment of both acute and chronic inflammatory conditions, thereby supporting the traditional use of this herb. PMID- 26417302 TI - 6-7-Dimethoxy-4-methylcoumarin suppresses pro-inflammatory mediator expression through inactivation of the NF-kappaB and MAPK pathways in LPS-induced RAW 264.7 cells. AB - In this study, we investigated the ability of 6,7-dimethoxy-4-methylcoumarin (DMC) to inhibit lipopolysaccharide (LPS)-induced expression of pro-inflammatory mediators in mouse macrophage (RAW 264.7) cells, and the molecular mechanism through which this inhibition occurred. Our results indicated that DMC downregulated LPS-induced nitric oxide (NO) synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, thereby reducing the production of NO and prostaglandin E2 (PGE2) in LPS-activated RAW 264.7 cells. Furthermore, DMC suppressed LPS-induced production of pro-inflammatory cytokines such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha. To elucidate the mechanism underlying the anti-inflammatory activity of DMC, we assessed its effects on the mitogen activated protein kinase (MAPK) pathway and the activity and expression of nuclear transcription factor kappa-B (NF-kappaB). The experiments demonstrated that DMC inhibited LPS-induced phosphorylation of extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinase (JNK), and p38. In addition, it attenuated LPS-induced NF-kappaB activation via the inhibition of IkappaB-alpha phosphorylation. Taken together, these data suggest that DMC exerts its anti inflammatory effects in RAW 264.7 cells through the inhibition of LPS-stimulated NF-kappaB and MAPK signaling, thereby downregulating the expression of pro inflammatory mediators. PMID- 26417303 TI - An overview of platelet indices for evaluating platelet function in children with scorpion envenomation. AB - The aim of this study was to assess the correlation between platelet indices and scorpion envenomations (SE). Medical records of 76 children who were hospitalised for scorpion stings in the paediatric intensive care unit (PICU) between February 2013 and November 2013, and 55 healthy children who were similar to the patient group in terms of age and sex, were analysed retrospectively. The leucocyte (WBC), thrombocyte (PLT), plateletcrit (PCT), platelet distribution width (PDW) and mean platelet volume (MPV) values of the 76 children with SE were recorded. These values were compared with the healthy control group. Significantly higher WBC and PDW values were noted in patients with SE in comparison to the controls. Patients with SE had significantly lower mean MPV values compared to the healthy controls (9.03 +/- 1.26 compared to 10.43 +/- 1.44 fL, respectively; p < 0.001). Although the mean platelet count was slightly elevated in the SE group, no statistically significant difference existed between the two groups (p = 0.097). Furthermore, the mean PCT values in the SE group compared to the control group were slightly decreased, but this decrease was not statistically significant (p = 0.141). A significant inverse correlation existed between the MPV values and the WBC (r = -0.450, p < 0.01) and PLT counts (r = -0.420, p < 0.01). The PLT values were significantly correlated with the PCT values (r = 0.687, p < 0.01). This study demonstrated that SE may lead to several alterations in platelet indices. Significantly lower values of MPV and higher values of PDW were detected in SE patients. However, the increase in the platelet counts and the decrease in the PCT values were not significant. PMID- 26417304 TI - Alleviation of hyperglycemia and hyperlipidemia by Phyllanthus virgatus forst extract and its partially purified fraction in streptozotocin induced diabetic rats. AB - Since, we previously demonstrated that sequentially extracted methanolic fraction showed marked antioxidant and antidiabetic property in vitro, the present study was design to evaluate the beneficial effects of Phyllanthus virgatus methanolic extract and its partially purified fraction on hyperglycemia and hyperlipidemia in streptozotocin (STZ) induced diabetic rats. The plant extract was subjected to repeated thin layer chromatographic fractionation followed by GC-MS analysis of active fraction. TLC data illustrated the presence of six prominent bands and the prelimnary screening of these bands against alpha-amylase inhibitory activity showed that the band with Rf value 0.514 has marked inhibitory property (IC50, 48 ug/ml). The diabetic rats were treated for four weeks with methanolic extract of P. virgatus (50 and 10 mg/rat/day), partially isolated active fraction (0.5 and 0.1 mg/rat/day) and glibenclamide (0.1 mg/rat/day). The level of fasting blood glucose (FBG), hemoglobin, glycated hemoglobin (HbA1c) and insulin were significantly alleviated in plant extract and partially purified fraction treated group after 28 days of administration. Moreover, total cholesterol (TC), triglycerides (TG), low density lipoprotein-cholesterol (LDL-C), very low density lipoprotein-cholesterol (VLDL-C) and high density lipoprotein cholesterol (HDL-C) were also markedly ameliorated in the entire treatment group, with a maximum restoration observed in group treated with partially purified fraction (0.5 mg/rat/day). The results demonstrate a strong antidiabetic and hypolipidemic impact of plant extract and its partially purified fraction coupled with their potent antioxidative property, which can provide additional benefits in the inhibition of oxidative stress and hence in the prevention and treatment of diabetes as well as diabetes linked hyperlipidemia. PMID- 26417305 TI - Managing post stroke hyperglycaemia: moderate glycaemic control is better? An update. AB - Post stroke hyperglycaemia (PSH) is prevalent in acute ischaemic stroke (AIS) patients and it has been associated with a dismal outcome of death and disability. Insulin has been proven to attenuate glucose effectively in stroke patients, thus many trials over the years had studied the efficacy of intensive treatment aiming at normalization of blood sugar level in order to improve the bleak outcomes of PSH. However, tight glycaemic control failed to be translated into clinical benefits and the outcomes are no different from the conventional approach, despite the costly healthcare expenditure invested. On the contrary, it brings more significant harm than the intended benefit, as 1 in every 9 treated patients had symptomatic hypoglycaemia. Thus, the benefits of tight glucose control, if any, are overshadowed by this potential risk of hypoglycaemia causing permanent neurological injury. Therefore, international practice guidelines recommend for less aggressive treatment to maintain blood glucose level within an appropriate range in AIS patients. However, there are limited details for stroke specific glycaemic management and this made management of PSH particularly difficult. This review is to discuss and provide suggestions concerning glycaemic control in acute ischaemic stroke; the direction of its future prospective clinical trials and the treatment strategy required based on recent literature. PMID- 26417306 TI - Atrial natriuretic peptide gene - a potential biomarker for long QT syndrome. AB - This study highlights the possible implication of NPPA (natriuretic peptide precursor A) gene in the etiology of Long QT syndrome (LQTS) by population-based as well as familial study. Three SNPs of NPPA - C-664G, C1363A and T1766C were examined by molecular analyses in LQTS, controls and first degree relatives (FDRs). This study revealed a possible association of 1364 C>A SNP 'C' allele with LQTS (p = 0.0013). All three SNPs were in tight linkage disequilibrium. The familial study highlights the association of NPPA SNP with cLQTS and implicating it as a potential biomarker in South Indian population. PMID- 26417308 TI - Highlights in tumor metabolome research: Choline metabolism influences integrin expression and supports cell attachment. PMID- 26417307 TI - Targeting protein kinase A in cancer therapy: an update. AB - Protein Kinase A (PKA) is a well known member of the serine-threonin protein kinase superfamily. PKA, also known as cAMP-dependent protein kinase, is a multi unit protein kinase that mediates signal transduction of G-protein coupled receptors through its activation upon cAMP binding. The widespread expression of PKA subunit genes, and the myriad of mechanisms by which cAMP is regulated within a cell suggest that PKA signaling is one of extreme importance to cellular function. It is involved in the control of a wide variety of cellular processes from metabolism to ion channel activation, cell growth and differentiation, gene expression and apoptosis. Importantly, since it has been implicated in the initiation and progression of many tumors, PKA has been proposed as a novel biomarker for cancer detection, and as a potential molecular target for cancer therapy. Here, we highlight some features of cAMP/PKA signaling that are relevant to cancer biology and present an update on targeting PKA in cancer therapy. PMID- 26417309 TI - Isolation and structure elucidaton of polyphenols from Loranthus micranthus Linn. parasitic on Hevea brasiliensis with antiinflammatory property. AB - The present study was carried out to evaluate the anti-inflammatory activities of polyphenols isolated from the leaves of mistletoe (Loranthus micranthus Linn.) parasitic on Hevea brasiliensis. The anti-inflammatory properties of the isolated compounds were evaluated on the basis of their ability to inhibit the production of nitric oxide (NO) and tumuor necrosis factor-alpha (TNF-alpha) in lipopolysaccharide (LPS) activated RAW 264.7 mouse macrophages. Semi-preparative HPLC separation of the ethyl acetate (EtOAc) and butanol (n-BuOH) fractions of the leaves of mistletoe (Loranthus micranthus Linn) parasitic on Hevea brasiliensis led to the isolation of four polyphenols: 3-O-(3,4,5 trimethoxybenzoyl)-(-)-epicatechin (TMECG) (1); (-)-epicatechin-3-O-(3"-O-methyl) gallate (ECG3"Me) (2); rutin (3) and peltatoside (4). Compounds 1-4 were isolated for the first time from this plant while 1 was isolated for the first time in nature. These compounds (1-4) were readily identified by comparison of their spectroscopic data with those reported in the literature. The polyphenols proved to have anti-inflammatory activity as evidenced by the suppression of inducible nitric oxide (iNO) and cytokine (TNF-alpha) levels in the culture supernatant of lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages. However, the study showed that the quercetin diglycosides showed stronger inhibition of proinflammatory mediators than the epicatechin derivates. These data provide evidence that polyphenolic compounds isolated from the mistletoe parasitic on Hevea brasiliensis may contribute to its anti-inflammatory properties by inhibiting the expression of inducible nitric oxide and proinflammatory cytokines such as tumour necrosis factor-alpha. PMID- 26417311 TI - Inhibitors of pancreatic lipase: state of the art and clinical perspectives. AB - Obesity is a disorder of lipid metabolism and continues to be a global problem, ranking fifth for deaths worldwide. It also leads to diabetes, cardiovascular disorders, musculoskeletal disorders and some types of cancer. Obesity is regarded as the output of a long-term imbalance between energy intake and energy expenditure. Digestion and absorption of dietary lipids by pancreatic lipase, a major source of excess calorie intake, can be targeted for development of anti obesity agents. Being the major factor of concern, food materials and edible plants are most widely studied for the anti-obesity activity, so that they can be incorporated in the routine diet. In this review, an attempt was made to present a current scenario of the bioactive compounds from plant and microbial origin that have been investigated for their pancreatic lipase inhibition. Compounds belonging to various classes of natural products such as alkaloids, carotenoids, glycosides, polyphenols, polysaccharides, saponins and terpenoids are well studied while lipophilic compounds from microbial sources are the most active against the pancreatic lipase. Few studies on the synthetic analogues, structurally similar to the triglycerides have been described in the review. Despite of tremendous research on the finding of potential pancreatic lipase inhibitor, very few compounds have entered the clinical studies and no new molecule after orlistat has been marketed. Along with HTS based screening, detailed structure-activity relationship studies on semi-synthetic and synthetic derivatives might also provide a direction for the development of potential lead(s) or pharmacophore for pancreatic lipase inhibition in order to treat and/or prevent obesity and related disorders. PMID- 26417310 TI - Cytochrome P450 enzyme mediated herbal drug interactions (Part 2). AB - To date, a number of significant herbal drug interactions have their origins in the alteration of cytochrome P450 (CYP) activity by various phytochemicals. Among the most noteworthy are those involving St. John's wort and drugs metabolized by human CYP3A4 enzyme. This review article is the continued work from our previous article (Part 1) published in this journal (Wanwimolruk and Prachayasittikul, 2014[ref:133]). This article extends the scope of the review to six more herbs and updates information on herbal drug interactions. These include black cohosh, ginseng, grape seed extract, green tea, kava, saw palmetto and some important Chinese medicines are also presented. Even though there have been many studies to determine the effects of herbs and herbal medicines on the activity of CYP, most of them were in vitro and in animal studies. Therefore, the studies are limited in predicting the clinical relevance of herbal drug interactions. It appeared that the majority of the herbal medicines have no clear effects on most of the CYPs examined. For example, the existing clinical trial data imply that black cohosh, ginseng and saw palmetto are unlikely to affect the pharmacokinetics of conventional drugs metabolized by human CYPs. For grape seed extract and green tea, adverse herbal drug interactions are unlikely when they are concomitantly taken with prescription drugs that are CYP substrates. Although there were few clinical studies on potential CYP-mediated interactions produced by kava, present data suggest that kava supplements have the ability to inhibit CYP1A2 and CYP2E1 significantly. Therefore, caution should be taken when patients take kava with CYP1A2 or CYP2E1 substrate drugs as it may enhance their therapeutic and adverse effects. Despite the long use of traditional Chinese herbal medicines, little is known about the potential drug interactions with these herbs. Many popularly used Chinese medicines have been shown in vitro to significantly change the activity of human CYP. However, with little confirming evidence from clinical studies, precaution should be exercised when patients are taking Chinese herbal medicines concomitantly with drugs that are CYP substrates. Currently there is sufficient evidence to indicate that herbal drug interactions can occur and may lead to serious clinical consequence. Further clinical trial research should be conducted to verify these herbal drug interactions. Education on herbal drug interactions and communication with patients on their use of herbal products is also important. PMID- 26417312 TI - Classification of oxidative stress based on its intensity. AB - In living organisms production of reactive oxygen species (ROS) is counterbalanced by their elimination and/or prevention of formation which in concert can typically maintain a steady-state (stationary) ROS level. However, this balance may be disturbed and lead to elevated ROS levels called oxidative stress. To our best knowledge, there is no broadly acceptable system of classification of oxidative stress based on its intensity due to which proposed here system may be helpful for interpretation of experimental data. Oxidative stress field is the hot topic in biology and, to date, many details related to ROS-induced damage to cellular components, ROS-based signaling, cellular responses and adaptation have been disclosed. However, it is common situation when researchers experience substantial difficulties in the correct interpretation of oxidative stress development especially when there is a need to characterize its intensity. Careful selection of specific biomarkers (ROS modified targets) and some system may be helpful here. A classification of oxidative stress based on its intensity is proposed here. According to this classification there are four zones of function in the relationship between "Dose/concentration of inducer" and the measured "Endpoint": I - basal oxidative stress (BOS); II - low intensity oxidative stress (LOS); III - intermediate intensity oxidative stress (IOS); IV - high intensity oxidative stress (HOS). The proposed classification will be helpful to describe experimental data where oxidative stress is induced and systematize it based on its intensity, but further studies will be in need to clear discriminate between stress of different intensity. PMID- 26417313 TI - Platismatia glaucia and Pseudevernia furfuracea lichens as sources of antioxidant, antimicrobial and antibiofilm agents. AB - The antioxidative, antimicrobial and antibiofilm potentials of acetone, ethyl acetate and methanol extracts of lichen species Platismatia glauca and Pseudevernia furfuracea were evaluated. The phytochemical analysis by GC, GC/MS and NMR revealed caperatic acid, atraric acid, atranorin and chloroatranorin as the predominant compounds in Platismatia glauca. Atraric acid, olivetoric acid, atranorin and chloroatranorin were the major constituents in Pseudevernia furfuracea. The strong antioxidant capacities of the Platismatia glauca and Pseudevernia furfuracea extracts were assessed by their total phenolic and flavonoid contents and DPPH scavenging activities. The methanol extracts of both species exhibited the strongest antioxidant activities with the highest IC50 value for Pseudevernia furfuracea (95.33 ug/mL). The lichen extracts demonstrated important antibacterial activities against 11 bacterial strains with detectable MIC values from 0.08 mg/mL to 2.5 mg/mL for Platismatia glauca and from 0.005 mg/mL to 2.5 mg/mL for Pseudevernia furfuracea. While the antibacterial activities of Pseudevernia furfuracea were solvent-independent, the acetone and ethyl acetate extracts of Platismatia glauca showed higher antibacterial activities compared to its methanol extract. The methanol extracts of both species demonstrated significant antifungal activities against 9 fungal strains with detectable MIC values from 0.04 mg/mL to 2.5 mg/mL. The best antifungal activities were determined against Candida species in Pseudevernia furfuracea extracts with remarkable MIC values which were lower than the MIC values of the positive contol fluconazole. The acetone and ethyl acetate extracts of Platismatia glauca showed better antibiofilm activities on Staphylococcus aureus and Proteus mirabilis with BIC value at 0.63 mg/mL then its methanol extract. On the other hand, the methanol extract of Pseudevernia furfuracea was more potent with BIC value at 1.25 mg/mL on Staphylococcus aureus and 0.63 mg/mL on Proteus mirabilis compared to other types of extracts. Our study indicates a possible use of lichens Platismatia glauca and Pseudevernia furfuracea as natural antioxidants and preservatives in food, pharmaceutical and cosmetic industry. PMID- 26417314 TI - Epigenetics in diagnosis, prognostic assessment and treatment of cancer: an update. AB - Cancer cells contain multiple genetic and epigenetic changes. The relative specificity of many epigenetic changes for neoplastic cells has allowed the identification of diagnostic, prognostic and predictive biomarkers for a number of solid tumors and hematological malignancies. Moreover, epigenetically-acting drugs are already in routine use for cancer and numerous additional agents are in clinical trials. Here, we review recent progress in the development and application of epigenetic strategies for the diagnosis, risk stratification and treatment of cancer. PMID- 26417316 TI - Antimicrobial and antioxidative activities in the bark extracts of Sonneratia caseolaris, a mangrove plant. AB - The present study deals with the phytochemical contents, antimicrobial and antioxidative activities of bark tissue of Sonneratia caseolaris, a mangrove plant from Sundarban estuary, India. Phytochemical analyses revealed the presence of high amounts of phenolics, flavonoids, tannins, alkaloids and saponins. Antimicrobial efficacies of various extracts of S. caseolaris were assessed by disc diffusion method against two Gram-positive (Bacillus subtilis and Bacillus coagulans), two Gram-negative (Escherichia coli and Proteus vulgaris) bacteria and one fungus (Saccharomyces cerevisiae). The methanolic extract among others showed significant minimum inhibitory concentration (MIC) values. The antioxidant activity as indicated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity of the bark tissue extract from the species was found to be quite appreciable. The extracts were found to retain their antimicrobial activities despite pH and thermal treatments, thus indicating the stability of their activity even at extreme conditions. The antioxidant activity was also found to be considerably stable after thermal treatments. The components of the tissue extracts were subjected to separation using thin layer chromatography (TLC). The constituents with antimicrobial and antioxidative properties were identified using TLC bioautography by agar-overlay and DPPH spraying methods respectively. A number of bioactive constituents with antimicrobial and radical scavenging properties were observed on the developed bioautography plate. The fractions with antimicrobial properties were isolated from the reference TLC plates and subjected to gas chromatography-mass spectrometry (GC-MS) analysis for partial characterization and identification of the metabolites that might be responsible for the activities. The study suggests Sonneratia caseolaris bark as a potential source of bioactive compounds with stable antimicrobial and antioxidative properties and can be used as natural antimicrobial/antioxidative agents in clinical, pharmaceutical and food processing industries. PMID- 26417317 TI - Suppressive effects of Mimosa pudica (L.) constituents on the production of LPS induced pro-inflammatory mediators. AB - The present study deals with the isolation of fourteen compounds from the active ethyl acetate (MPE) extract of M. pudica (L.) whole plant and their subsequent evaluation for the nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1beta) inhibitory activities in lipopolysaccharide (LPS) stimulated RAW 264.7 and J774A.1 cells. Among the tested compounds, L-mimosine (12; IC50 = 19.23 to 21.15 uM), crocetin (4; IC50 = 23.45 to 25.57 uM), crocin (14; IC50 = 27.16 to 31.53 uM) and jasmonic acid (11; IC50 = 21.32 to 29.42 uM) were identified as potent NO inhibitor when tested on the macrophages. Similarly, towards TNF-alpha and IL-1beta inhibition, including these four compounds, and ethyl gallate (3), gallic acid (10) and caffeic acid (7) were found to be more active with half maximal concentration, 17.32 to 62.32 uM whereas the other compounds depicted moderate and mild effects (IC50 = 59.32 to 95.01 uM). Also, at a dose of 40 mg/Kg, L-mimosine (12), jasmonic acid (11), crocin (14) and its de esterified form, crocetin (4) were found to significantly (p < 0.05 and 0.001) reduce 60.7 %, 48.9 %, 48.4 % and 43.6 % respectively of TNF-de-esterified production in female Sprague Dawley rats. However, in case of IL-1beta, with the same dose (40 mg/Kg), jasmonic acid (11) exhibited significant reduction with 54.2 % followed by crocin (14) (50.2 %) and crocetin (4) (39.8 %) while L mimosine (12) was found to reduce only 16.3 %. Based on the results, it can be estimated that these compounds imparting greatly to anti-inflammatory effects of M. pudica in vitro as well as in vivo through reduction of LPS-induced pro inflammatory mediators which affirm the ethno-pharmacological use of this plant for prevention of inflammatory-related disorders. PMID- 26417318 TI - Synthesis and antibacterial activity of a new derivative of the Meldrun acid: 2,2 dimethyl-5-(4H-1,2,4-triazol-4-ylaminomethylene)-1,3-dioxane-4,6-dione (C9H10N4O4). AB - The discovery of new substances with proven antimicrobial activity is the current study goal of various researchers. Usage of synthetic products has grown considerably in the past few years due to processing agility, and capability of going through previous chemical modifications in order to enhance its biological activity. Widespread careless use of antimicrobials has made the number of resistant microorganisms rise significantly, thus demanding more efficient drugs to fight them. One of these synthetic candidates for this purpose is the substance 2,2-Dimethyl-5-(4H-1,2,4-triazol-4-ylaminomethylene)-1,3-dioxane-4,6 dione (C9H10N4O4), aminomethylene derivative from Meldrum's acid. This substance, alone and in association with common antibiotics, were evaluated in vitro for antimicrobial activity, and had their minimum inhibitory concentration (MIC) towards Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 10536 and Pseudomonas aeruginosa ATCC 15442, as well as multiresistant strains Escherichia coli 27, Staphylococcus aureus 358 and Pseudomonas aeruginosa 03 determined. The antimicrobial modulation action tests of the aminoglycosides with C9H10N4O4 were performed according to the microdilution method, and resulted in observation of a positive synergic effect. PMID- 26417319 TI - Combined anti-ages and antioxidant activities of different solvent extracts of Solanum elaeagnifolium Cav (Solanacea) fruits during ripening and related to their phytochemical compositions. AB - Oxidative stress and advanced glycation end products (AGEs) are known as key factors for the development of diabetic complications such as retinopathy, cataract as well as atherosclerosis and neurodegenerative diseases, including Alzheimer's diseases. In this context, natural products have been previously identified as promising sources for antioxidant and anti-glycation compounds. The current study focuses on the evaluation of antioxidant and glycation inhibitory activities of different solvent extracts of Solanum elaeagnifolium Cav (Solanaceae) fruits at different ripening stages. The results showed that antioxidant and anti-AGEs activities were significantly influenced by solvents polarities and ripening stages of S. elaeagnifolium Cav. With one exception, methanolic extract of overripe S. elaeagnifolium Cav fruit showed important protective effects against cellular oxidative stress. The aqueous extract showed the highest ABTS(+) scavenging ability. Principal component analysis showed that total phenolic and flavonoid contents correlated well with observed antioxidants and anti-glycation activities. These results bring attention to the possible use of S. elaeagnifolium Cav as a valuable source of bioactive compounds exhibiting antioxidant effects and potentially alleviating diabetic complications. PMID- 26417315 TI - Hepatitis C virus infection: establishment of chronicity and liver disease progression. AB - Hepatitis C virus (HCV) often causes persistent infection, and is an important factor in the etiology of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). There are no preventive or therapeutic vaccines available against HCV. Treatment strategies of HCV infection are likely to improve with recently discovered direct antiviral agents (DAAs). However, a proportion of patients still progress to liver failure and/or HCC despite having been cured of the infection. Thus, there is a need for early diagnosis and therapeutic modalities for HCV related end stage liver disease prevention. HCV genome does not integrate into its host genome, and has a predominantly cytoplasmic life cycle. Therefore, HCV mediated liver disease progression appears to involve indirect mechanisms from persistent infection of hepatocytes. Studying the underlying mechanisms of HCV mediated evasion of immune responses and liver disease progression is challenging due to the lack of a naturally susceptible small animal model. We and other investigators have used a number of experimental systems to investigate the mechanisms for establishment of chronic HCV infection and liver disease progression. HCV infection modulates immune systems. Further, HCV infection of primary human hepatocytes promotes growth, induces phenotypic changes, modulates epithelial mesenchymal transition (EMT) related genes, and generates tumor initiating stem-like cells (TISCs). HCV infection also modulates microRNAs (miRNAs), and influences growth by overriding normal death progression of primary human hepatocytes for disease pathogenesis. Understanding these ob-servations at the molecular level should aid in developing strategies for additional effective therapies against HCV mediated liver disease progression. PMID- 26417320 TI - Scientific validation of cardioprotective attribute by standardized extract of Bombyx mori against doxorubicin-induced cardiotoxicity in murine model. AB - Doxorubicin (DOX) is an excellent antineoplastic agent used for the treatment of hematological and solid malignancies. The aqueous extract of Bombyx mori (BMAE) contains amino acids and some flavonoids with obvious cardioprotective effect. The aim of this study was to investigate the possible protective effect of BMAE against DOX-induced cardiotoxicity and its underlying mechanisms on murine model. The metabolic profiling of BMAE was carried out by Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS) and the amino acid profiling by HPLC method using fluorescence detector (HPLC-FLD). The biochemical parameter like caspase-3, tumor necrosis factor-alpha (TNF-alpha), interleukin -6 (IL-6), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) and malondialdehyde (MDA) were studied. Tissue damage was further evaluated by histopathological studies. The metabolic profiling of BMAE exhibited presence of quercetin 7-O-beta-D glucoside, kaempferol 7-O-beta-D-glucopyranoside, coumaric acid glucoside, 2 hydroxy-nonadecanoic acid and 9,12-dihydroxy stearic acid as important constituents. The amino acid profile by HPLC-FLD showed presence of 17 amino acids. The BMAE showed prominent free radical scavenging activity when assessed by the H2O2 and super-oxide method. The results of present investigation showed protection against DOX-induced oxidative stress (lipid peroxidation), by reverting activities of apoptotic markers (caspase-3 and TNF-alpha), cardiac markers (CK-MB and LDH activities) as well as pro-inflammatory marker IL-6 followed by oral administration of BMAE. In addition, results of histopathology also supported well the above results. It was observed that BMAE protects DOX induced cardiotoxicity by virtue of its antioxidants possibly by flavonoids and amino acids. PMID- 26417321 TI - Antidiabetic activity of 3-hydroxyflavone analogues in high fructose fed insulin resistant rats. AB - Synthetic 3-hydroxyflavone analogues (JY-1, JY-2, JY-3, JY-4), were tested for antidiabetic activity in high-fructose-diet-fed (66 %, for 6 weeks) insulin resistant Wistar rats (FD-fed rats). The fasting blood glucose, insulin, creatinine and AGEs were decreased to near normal upon treatment with test compounds. Insulin resistance markers such as HOMA-IR, K-ITT, plasma triglycerides, lipids, endogenous antioxidant defense and glycogen were restored in FD-fed rats after treatment with 3-hydroxyflavones. It is known that insulin resistance is partly because of oxidative stress and hence antioxidant activity was determined. They exhibited significant in vitro DPPH and ABTS radical scavenging activity (IC50: 10.66-66.63 uM). Test compounds inhibited ROS and NO production in RAW 264.7 cells (IC50: 10.39-42.63 uM) and they were found as potent as quercetin. Further, the test compounds inhibited lipid peroxidation at low concentrations (IC50: 99.61-217.47 uM). All test compounds at concentrations 100-200 uM protected calf thymus DNA-damage by Fenton reaction. In addition, test compounds inhibited protein glycation in different in vitro antiglycation assays. JY-2 showed maximum potency in all the stages of glycation which was comparable to the standard quercetin and aminoguanidine. Test compounds also enhanced the glucose uptake by L6 myotubes at an EC50 much lower than that of quercetin. Thus the synthetic 3-hydroxyflavones were found to have good antidiabetic activity by pleotropic and multimodal suppression of insulin resistance and enhancement of glucose uptake by skeletal muscles. These compounds are non-toxic at the doses tested. Further, the combined antioxidant and antiglycation activities of these molecules have complementary benefits in management of diabetes. PMID- 26417323 TI - Anti-inflammatory effect of selagin-7-O-(6''-O-acetyl-)-beta-D-glycoside isolated from Cancrinia discoidea on lipopolysaccharide-induced mouse macrophage RAW 264.7 cells. AB - Selagin-7-O-(6''-O-acetyl-)-beta-D-glycoside, a new flavone glycoside isolated from Cancrinia discoidea, is known to exhibit anti-inflammatory activity in vivo. This study aimed to investigate the protection of this flavone glycoside on inflammation in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. The effects of selagin-7-O-(6''-O-acetyl-)-beta-D-glycoside on inflammatory cytokines and signaling pathways were analyzed by enzyme-linked immunosorbent assay, reverse transcription-polymerase chain reaction, and western blot. Results show that selagin-7-O-(6''-O-acetyl-)-beta-D-glycoside protected LPS-induced macrophage RAW 264.7 cells from injury. The flavone glycoside markedly inhibited the LPS-induced production of tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 and increased interleukin-10 release in a concentration-dependent manner. Furthermore, treatment with the flavone glycoside decreased nitric oxide and prostaglandin E2 in LPS-challenged RAW 264.7 cells. These decreases were associated with the down-regulation of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), and nuclear factor kappa B (NF-kappaB) activity. These findings suggest that the anti-inflammatory effects of selagin-7-O-(6''-O-acetyl )-beta-D-glycoside were associated with the adjustment of inflammatory cytokines, and attributed to the down-regulation of NF-kappaB and consequent suppression of the expression of iNOS and COX-2. PMID- 26417322 TI - Endoplasmic reticulum membrane potassium channel dysfunction in high fat diet induced stress in rat hepatocytes. AB - In a previous study we reported the presence of a large conductance K(+) channel in the membrane of endoplasmic reticulum (ER) from rat hepatocytes. The channel open probability (Po) appeared voltage dependent and reached to a minimum 0.2 at +50 mV. Channel activity in this case was found to be totally inhibited at ATP concentration 2.5 mM, glibenclamide 100 uM and tolbutamide 400 uM. Existing evidence indicates an impairment of endoplasmic reticulum functions in ER stress condition. Because ER potassium channels have been involved in several ER functions including cytoprotection, apoptosis and calcium homeostasis, a study was carried out to consider whether the ER potassium channel function is altered in a high fat diet model of ER stress. Male Wistar rats were made ER stress for 2 weeks with a high fat diet. Ion channel incorporation of ER stress model into the bilayer lipid membrane allowed the characterization of K(+) channel. Our results indicate that the channel Po was significantly increased at voltages above +30 mV. Interestingly, addition of ATP 7.5 mM, glibenclamide 400 uM and tolbutamide 2400 uM totally inhibited the channel activities, 3-fold, 4-fold and 6-fold higher than that in the control groups, respectively. Our results thus demonstrate a modification in the ER K(+) channel gating properties and decreased sensitivity to drugs in membrane preparations coming from ER high fat model of ER stress, an effect potentially linked to a change in ER K(+) channel subunits in ER stress condition. Our results may provide new insights into the cellular mechanisms underlying ER dysfunctions in ER stress. PMID- 26417324 TI - Neuroprotection by diarylpropionitrile in mice with spinal cord injury. AB - The initial impact of spinal cord injury (SCI) often results in inflammation leading to irreversible damage with consequent loss of locomotor function. Minimal recovery is achieved once permanent damage has occurred. Using a mouse model of SCI we observed a transitory increase followed by a rapid decline in gene expression and protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of cellular anti-oxidative genes. Immediate treatment with diarylpropionitrile (DPN), a non-steroidal selective estrogen receptor beta ligand, resulted in a significant increase in Nrf2 levels, and reduction of inflammation and apoptosis compared to untreated SCI animals. Furthermore, DPN treatment improved locomotor function within 7 days after induction of SCI. DPN acted through activation of PI3K/ Akt pathway, known to be involved in down regulation of apoptosis and up-regulation of cell survival in injured tissues. These findings suggest that immediate activation of cellular anti-oxidative stress mechanisms should provide protection against irreversible tissue damage and its profound detrimental effect on locomotor function associated with SCI. PMID- 26417325 TI - In vitro control of plant pathogenic Xanthomonas spp. using Poncirus trifoliata Rafin. AB - The secondary metabolites such as essential oil and pure compounds (limonin and imperatorin) from Poncirus trifoliata Rafin were tested for in vitro control of phytopathogenic bacteria of Xanthomonas spp. In vitro studies showed that the oil had inhibitory effect on Xanthomonas campestris pv. compestris KC94-17-XCC, Xanthomonas campestris pv. vesicatoria YK93-4-XCV, Xanthomonas oryzae pv. oryzae KX019-XCO and Xanthomonas sp. SK12 with their inhibition zones and minimum inhibitory concentration (MIC) values ranging from 13.1~22.1 mm and 62.5~125 MUg/ml, respectively. Limonin and imperatorin also had in vitro antibacterial potential (MIC: 15.62~62.5 MUg/ml) against all the tested Xanthomonas spp. Furthermore, the SEM studies demonstrated that limonin and imperatorin caused morphological changes of Xanthomonas sp. SK12 at the minimum inhibitory concentration (15.62 MUg/ml). These results of this study support the possible use of essential oil and natural compounds from P. Trifoliata in agriculture and agro-industries to control plant pathogenic microorganisms. PMID- 26417326 TI - Renin inhibitors in diabetes and hypertension: an update. AB - The coexistence of hypertension and diabetes increases the incidence of cardiovascular events and long-term morbidity and mortality. Blood pressure should be controlled with the most appropriate drugs as well as tight blood glucose control in patients with diabetes and hypertension. RAAS (Renin Angiotensin Aldosterone System) blockers have an important role in the treatment of these patients, in this sense, ACEi and ARB remained the major treatment option in hypertension guidelines. The most recent RAAS blocker to be approved by the FDA was aliskiren in 2007, a renin inhibitor. Studies showed that aliskiren is as effective as other antihypertensive drugs and has a safety profile similar to placebo. The potent renin inhibitor aliskiren directly inhibits the RAAS system at its rate limiting step and differently from other RAAS blockers; it decreases plasma renin activity (PRA). Although the relationship of increased PRA levels and cardiovascular risk has been shown, it is unclear if the PRA decrease provided by aliskiren has an impact on clinical outcomes and cardiovascular endpoints. On the other hand, large trials like ASPIRE, AVANT-GARDE, ALTITUDE, ASTRONAUT, which investigated the combination of aliskiren with other RAAS blockers, failed to show the expected outcomes or resulted with an increased incidence of adverse effects, which raised more questions. As a result of the ALTITUDE trial, combination of aliskiren with an ACEi or ARB is not recommended in patients with hypertension and diabetes, or at least moderate renal dysfunction. Trials designed to prove aliskiren's efficacy in new indications like diabetes, may face similar problems related to dual RAAS blockade because in the majority of cases, the optimal treatment is achieved with an ACEi or ARB. In this conjuncture, the increase in adverse events seen with aliskiren might be related to dual RAAS blockade rather than aliskiren directly. For instance, it is unclear whether the adverse event incidence would be the same, less, or higher if ALTITUDE was designed to investigate ACEi and ARB combination without aliskiren. In fact, every new molecular entity and mechanism of action faces the same barriers. For the time being, differentiating points like PRA lowering effects as an add-on therapy to calcium channel blockers or hydrochlorothiazide, and the populations that might have additional benefit, should be carefully investigated. PMID- 26417327 TI - Chemical stimulation of the lateral hypothalamus potentiated the sensitization to morphine in rats: involvement of orexin-1 receptor in the ventral tegmental area. AB - Orexin plays a crucial role in drug-seeking behavior. The lateral hypothalamus (LH) is a central region that produces orexin, and its projections to the ventral tegmental area (VTA) play an important role in reward and addiction-related behaviors. In this study, we investigated the role of LH stimulation and the involvement of the orexin-1 receptor (Ox1r) in the VTA in relation to morphine sensitization. In all animals, cannulae were implanted unilaterally into the LH and VTA to inject different doses of carbachol (62.5, 125 and 250 nmol/0.5 MUl saline) as a cholinergic agonist and SB334867 (1, 10 and 20 nmol/0.3 ul DMSO) as a selective Ox1r antagonist for three consecutive days (sensitization period) respectively. These drugs were injected five minutes before administration of an ineffective dose of morphine (0.5 mg/kg; sc) during the sensitization period. In all groups, the sensitization period occurred in a separate room from which the conditioning occurred. After this period, all groups exceeded five days under the conditioned place preference (CPP) paradigm without any treatment. For evaluation of morphine sensitization, place preference was induced by ineffective dose of morphine (0.5 mg/kg) and the CPP score was represented by the difference in time spent in drug- and saline-paired compartments. The results revealed that concurrent intra-LH administration of carbachol (125 nmol/0.5 ul saline) and an ineffective dose of morphine (0.5 mg/kg) significantly induce CPP. Additionally, the blockade of Ox1r in the VTA by SB334867 can attenuate the conditioning score induced by concurrent administration of carbachol and an ineffective dose of morphine. Our findings suggest that LH stimulation potentiates the effect of an ineffective dose of morphine, and induces morphine sensitization. It seems that the chemical stimulation of LH potentiates sensitization to morphine through the orexinergic system in the VTA in rats. PMID- 26417328 TI - Immune mediated liver failure. AB - Liver failure is a clinical syndrome of various etiologies, manifesting as jaundice, encephalopathy, coagulopathy and circulatory dysfunction, which result in subsequent multiorgan failure. Clinically, liver failure is classified into four categories: acute, subacute, acute-on-chronic and chronic liver failure. Massive hepatocyte death is considered to be the core event in the development of liver failure, which occurs when the extent of hepatocyte death is beyond the liver regenerative capacity. Direct damage and immune-mediated liver injury are two major factors involved in this process. Increasing evidence has suggested the essential role of immune-mediated liver injury in the pathogenesis of liver failure. Here, we review the evolved concepts concerning the mechanisms of immune mediated liver injury in liver failure from human and animal studies. Both innate and adaptive immunity, especially the interaction of various immune cells and molecules as well as death receptor signaling system are discussed. In addition, we highlight the concept of "immune coagulation", which has been shown to be related to the disease progression and liver injury exacerbation in HBV related acute-on-chronic liver failure. PMID- 26417329 TI - Role of tight junctions in signal transduction: an update. AB - Tight junctions (TJs), which are the most apically located of the intercellular junctional complexes, have a barrier function and a fence function. Recent studies show that they also participate in signal transduction mechanisms. TJs are modulated by intracellular signaling pathways including protein kinase C, mitogen-activated protein kinase, and NF-kappaB, to affect the epithelial barrier function in response to diverse stimuli. TJs are also regulated by various cytokines, growth factors, and hormones via signaling pathways. To investigate the regulation of TJ molecules via signaling pathways in human epithelial cells under normal and pathological conditions, we established a novel model of human telomerase reverse transcriptase-transfected human epithelial cells. In this review, we describe the recent progress in our understanding of the role of TJs for signal transduction under normal conditions in upper airway epithelium, pancreatic duct epithelial cells, hepatocytes, and endometrial epithelial cells, and in pathological conditions including cancer and infection. PMID- 26417331 TI - Recent studies on rosmarinic acid and its biological and pharmacological activities. PMID- 26417330 TI - Clinical pharmacology of atypical antipsychotics: an update. AB - This review will concentrate on the clinical pharmacology, in particular pharmacodynamic data, related to atypical antipsychotics, clozapine, risperidone, paliperidone, olanzapine, que!tiapine, amisulpride, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone and cariprazine. A summary of their acute pharmacokinetics properties are also reported. Four new second-generation antipsychotics are available: iloperidone, asenapine, lurasidone and in the next future cariprazine. Similar to ziprasidone and aripiprazole, these new agents are advisable for the lower propensity to give weight gain and metabolic abnormalities in comparison with older second-generation antipsychotics such as olanzapine or clozapine. Actually lurasidone seems to be best in terms of minimizing unwanted alterations in body weight and metabolic variables. Therapeutic drug monitoring is not strictly necessary for all of the new antipsychotic drugs because there are no unequivocal data supporting a relationship between plasma drug levels and clinical outcomes or side effects. The exception can be represented by clozapine for which plasma levels of 350-420 ng/ml are reported to be associated with an increased probability of a good clinical response. Also for olanzapine an established therapeutic range (20-50 ng/ml) is proposed to yield an optimal response and minimize side effects. PMID- 26417332 TI - Gebel-criteria for risk assessment in nanotoxicology. PMID- 26417333 TI - The post GWAS era: strategies to identify gene-gene and gene-environment interactions in urinary bladder cancer. PMID- 26417334 TI - Thermography based breast cancer detection using texture features and minimum variance quantization. AB - In this paper, we present a system based on feature extraction techniques and image segmentation techniques for detecting and diagnosing abnormal patterns in breast thermograms. The proposed system consists of three major steps: feature extraction, classification into normal and abnormal pattern and segmentation of abnormal pattern. Computed features based on gray-level co-occurrence matrices are used to evaluate the effectiveness of textural information possessed by mass regions. A total of 20 GLCM features are extracted from thermograms. The ability of feature set in differentiating abnormal from normal tissue is investigated using a Support Vector Machine classifier, Naive Bayes classifier and K-Nearest Neighbor classifier. To evaluate the classification performance, five-fold cross validation method and Receiver operating characteristic analysis was performed. The verification results show that the proposed algorithm gives the best classification results using K-Nearest Neighbor classifier and a accuracy of 92.5%. Image segmentation techniques can play an important role to segment and extract suspected hot regions of interests in the breast infrared images. Three image segmentation techniques: minimum variance quantization, dilation of image and erosion of image are discussed. The hottest regions of thermal breast images are extracted and compared to the original images. According to the results, the proposed method has potential to extract almost exact shape of tumors. PMID- 26417335 TI - Synthesis of novel antimicrobial aryl himachalene derivatives from naturally occurring himachalenes. AB - Five new 2,9,9-trimethyl-6,7,8,9-tetrahydro-benzocyclohepten-5-ylidene-amine derivatives (16a-16e) were synthesized from alpha-dehydro-ar-himachalene (11) that was originally prepared from an isomeric mixture of alpha, beta and gamma himachalenes (10), the abundant sesquiterpenes of Cedrus deodara essential oil. In addition, different aryl himachalenes derivatives (9, 12, 14 and 15) were also formed from 11. The structures of the synthesized compounds were confirmed on the basis of their NMR, IR and mass spectral data. The prepared compounds were tested against a group of sixteen organisms including gram positive and gram negative bacterial and fungal strains. The introduction of a series of substituted imine groups into aryl himachalenes at 5(th) position (16a-16e) enhanced antimicrobial activity as compared to the aromatized derivatives (9, 12, 14 and 15) against gram-positive bacteria Bacillus subtilis, Micrococcus luteus and Staphylococcus aureus, and mycotoxigenic fungi Aspergillus parasiticus, A. ochraceous and A. sydowii. graphical Abstract, Figure 1(Fig. 1). PMID- 26417336 TI - Biological activities and chemical composition of lichens from Serbia. AB - The aim of this study is to investigate chemical composition of acetone extracts of the lichens Parmelia arseneana and Acarospora fuscata and in vitro antioxidant, antimicrobial, and anticancer activities of these extracts and gyrophoric acid isolated from A. fuscata. The HPLC-UV method was used for the identification of secondary metabolites. Stictic acid, norstictic acid, gyrophoric acid, usnic acid, atranorin and chloroatranorin were identified in the A. fuscata. In P. arseneana, we detected stictic acid, norstictic acid, usnic acid and atranorin, while gyrophoric acid was not identified. Antioxidant activity was evaluated by measuring the scavenging capacity of tested samples on DPPH and superoxide anion radicals, reducing the power of samples and determination of total phenolic compounds in extracts. As a result of the study, gyrophoric acid was found to have the largest DPPH radical scavenging activity with an IC50 value of 105.75 ug/ml. Moreover, the tested samples had an effective superoxide anion radical scavenging and reducing power. The total content of phenol in extracts was determined as pyrocatechol equivalent. The antimicrobial activity was estimated by determination of the minimal inhibitory concentration by the broth microdilution method. The most active was also gyrophoric acid, with minimum inhibitory concentration values ranging from 0.019 to 1.25 mg/ml. Anticancer activity was tested against LS174 (human colon carcinoma cell line), A549 (human lung carcinoma cell line), Fem-x (malignant melanoma cell line), and a chronic myelogeneous leukaemia K562 cell line using the MTT method. Extract of P. arseneana expressed the strongest anticancer activity against all cell lines with IC50 values ranging from 11.61 to 47.06 ug/ml. PMID- 26417337 TI - Drosophila melanogaster - an embryonic model for studying behavioral and biochemical effects of manganese exposure. AB - Embryonic animals are especially susceptible to metal exposure. Manganese (Mn) is an essential element, but in excess it can induce toxicity. In this study we used Drosophila melanogaster as an embryonic model to investigate biochemical and behavioral alterations due to Mn exposure. Flies were treated with standard medium supplemented with MnCl2 at 0.1 mM, 0.5 mM or 1 mM from the egg to the adult stage. At 0.5 mM and 1 mM Mn, newly ecloded flies showed significantly enhanced locomotor activity when assessed by negative geotaxis behavior. In addition, a significant increase in Mn levels (p < 0.0001) was observed, while Ca, Fe, Cu, Zn and S levels were significantly decreased. A significant drop in cell viability occurred in flies exposed to 1 mM Mn. There was also an induction of reactive oxygen species at 0.5 mM and 1 mM Mn (p < 0.05). At 1 mM, Mn increased Catalase (p < 0.005), Superoxide Dismutase (p < 0.005) and Hsp83 (p < 0.0001) mRNA expression, without altering Catalase or Superoxide Dismutase activity; the activity of Thioredoxin reductase and Glutatione-S-transferase enzymes was increased. Mn treatment did not alter ERK or JNK1/2 phosphorylation, but at 1 mM caused an inhibition of p38(MAPK) phosphorylation. Together these data suggest mechanisms of adaptation in the fly response to Mn exposure in embryonic life. PMID- 26417338 TI - Impact of urinary bladder cancer risk variants on prognosis and survival. PMID- 26417340 TI - Biomarker: the universe of chemically induced gene expression alterations in human hepatocyte. PMID- 26417339 TI - Probing the origins of aromatase inhibitory activity of disubstituted coumarins via QSAR and molecular docking. AB - This study investigated the quantitative structure-activity relationship (QSAR) of imidazole derivatives of 4,7-disubstituted coumarins as inhibitors of aromatase, a potential therapeutic protein target for the treatment of breast cancer. Herein, a series of 3,7- and 4,7-disubstituted coumarin derivatives (1 34) with R1 and R2 substituents bearing aromatase inhibitory activity were modeled as a function of molecular and quantum chemical descriptors derived from low-energy conformer geometrically optimized at B3LYP/6-31G(d) level of theory. Insights on origins of aromatase inhibitory activity was afforded by the computed set of 7 descriptors comprising of F10[N-O], Inflammat-50, Psychotic-80, H-047, BELe1, B10[C-O] and MAXDP. Such significant descriptors were used for QSAR model construction and results indicated that model 4 afforded the best statistical performance. Good predictive performance were achieved as verified from the internal (comprising the training and the leave-one-out cross-validation (LOO-CV) sets) and external sets affording the following statistical parameters: R (2) Tr = 0.9576 and RMSETr = 0.0958 for the training set; Q (2) CV = 0.9239 and RMSECV = 0.1304 for the LOO-CV set as well as Q (2) Ext = 0.7268 and RMSEExt = 0.2927 for the external set. Significant descriptors showed correlation with functional substituents, particularly, R1 in governing high potency as aromatase inhibitor. Molecular docking calculations suggest that key residues interacting with the coumarins were predominantly lipophilic or non-polar while a few were polar and positively-charged. Findings illuminated herein serve as the impetus that can be used to rationally guide the design of new aromatase inhibitors. PMID- 26417341 TI - Cancer research: from prognostic genes to therapeutic targets. PMID- 26417342 TI - Transcriptome based differentiation of harmless, teratogenetic and cytotoxic concentration ranges of valproic acid. PMID- 26417343 TI - The body-on-a-chip concept: possibilities and limitations. PMID- 26417344 TI - The rediscovery of HepG2 cells for prediction of drug induced liver injury (DILI). PMID- 26417345 TI - Integrated spatiotemporal-metabolic modelling bridges the gap between metabolism on the cellular level and organ function. PMID- 26417346 TI - Concepts of predictive toxicology. PMID- 26417347 TI - Human non-parenchymal liver cells for co-cultivation systems. PMID- 26417348 TI - Molecular characterization of carotenoid biosynthetic genes and carotenoid accumulation in Scutellaria baicalensis Georgi. AB - Scutellaria baicalensis has a wide range of biological activities and has been considered as an important traditional drug in Asia and North America for centuries. A partial-length cDNA clone encoding phytoene synthase (SbPSY) and full-length cDNA clonesencoding phytoene desaturase (SbPDS), xi-carotene desaturase (SbZDS), beta-ring carotene hydroxylase (SbCHXB), and zeaxanthin epoxidase (SbZEP)were identifiedin S. baicalensis. Sequence analyses revealed that these proteins share high identity and conserved domains with their orthologous genes. SbPSY, SbPDS, SbZDS, SbCHXB, and SbZEP were constitutively expressed in the roots, stems, leaves, and flowers of S.b aicalensis. SbPSY, SbPDS, and SbZDS were highly expressed in the stems, leaves, and flowers and showed low expression in the roots, where only trace amounts of carotenoids were detected. SbCHXB and SbZEP transcripts were expressed at relatively high levels in the roots, stems, and flowers and were expressed at low levels in the leaves, where carotenoids were mostly distributed. The predominant carotenoids in S.b aicalensiswere lutein and beta-carotene, with abundant amounts found in the leaves (517.19 and 228.37 MUg g(-1) dry weight, respectively). Our study on the biosynthesis of carotenoids in S. baicalensis will provide basic data for elucidating the contribution of carotenoids to the considerable medicinal properties of S. baicalensis. PMID- 26417349 TI - Dropwort (Filipendula hexapetala Gilib.): potential role as antioxidant and antimicrobial agent. AB - The aim of this study was to investigate the antioxidant activity of the methanolic extracts of Filipendula hexapetala Gilib. aerial parts (FHA) and roots (FHR) and their potential in different model systems, as well as antimicrobial activity. According to this, a number of assays were employed to evaluate the antioxidant and antimicrobial potential of F. hexapetala extracts. In addition, the antioxidant activity assays in different model systems were carried out, as well as pH, thermal and gastrointestinal stability studies. The phenolic compounds contents in FHA and FHR were also determined. The results showed that F. hexapetala extracts had considerable antioxidant activity in vitro and a great stability in different conditions. The extracts exhibited antimicrobial activity against most of the tested bacterial and fungal species. Also, the extracts contain high level of phenolic compounds, especially aerial parts extract. PMID- 26417350 TI - pH-sensitive, polymer modified, plasma stable niosomes: promising carriers for anti-cancer drugs. AB - The aim of this study was the design and evaluation of a novel plasma stable, pH sensitive niosomal formulation of Mitoxantrone by a modified ethanol injection method. Cholesterol hemisuccinate was added instead of cholesterol in order to produce pH-sensitivity property and using PEG-Poly (monomethyl itaconate)-CholC6 (PEG-PMMI-CholC6) copolymer introduced simultaneously pH-sensitivity and plasma stability properties in prepared niosomes. The pH-sensitivity and cytotoxicity of Mitoxantrone niosomes were evaluated in vitro in phosphate buffer with different pHs as well as using human ovarian cancer cell line (OVCAR-3), human breast cancer cell line (MCF-7) and human umbilical vein endothelial cells (HUVEC). Results showed that both cholesterol derivatives bearing formulations had pH sensitive property and were found to release their contents under mild acidic conditions rapidly. In addition, the PEG-PMMI-CholC6-based niosomes could reserve the pH-sensitivity after incubation in plasma. Both Mitoxantrone-loaded pH sensitive niosomes showed higher cytotoxicity than the conventional niosomes on OVCAR-3 and MCF-7 cell lines. However, both pH-sensitive niosomes exhibited lower cytotoxic effect on HUVEC cell line. Plasma stable, pH-sensitive niosomes could improve the cytotoxic effect and reduce the side effects of anti-tumor drugs. PMID- 26417351 TI - Butanolic fraction of Moringa oleifera Lam. (Moringaceae) attenuates isoprotrenol induced cardiac necrosis and oxidative stress in rats: an EPR study. AB - The preventive effect of Moringa oleifera polyphenolic fraction (MOPF) on cardiac damage was evaluated in isoproterenol (ISO) induced cardiotoxicity model of Wistar rats. Male rats in different groups were treated with MOPF orally at the dose of 50, 100 and 150 mg/kg/day for 28 days and were subsequently administered (s.c.) with ISO (85 mg/kg body weight) for the last two days. At the end of the experiment levels of serum troponin-T, creatine kinase-MB, lactate dehydrogenase, content of malondialdehyde (MDA), activities/levels of different cellular antioxidants were estimated in control and experimental groups. Additionally, scavenging potential to the hydroxyl radical of the fraction was measured by electron paramagnetic resonance (EPR). ISO administered rats showed significant increase in the levels of serum troponin-I, creatine kinase, lactate dehydrogenase, and heart tissue MDA content. Furthermore, marked reduction in the activities of antioxidants such as superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione levels were observed. EPR study showed an increase in signal intensity in ISO-induced rats. Triphenyl tetrazolium chloride (TTC) staining of heart section revealed a marked increase in infarcted area in ISO-induced rats. Histological features of the heart also indicated a disruption in the structure of cardiac myofibrils in these animals. MOPF (100 mg/kg body weight) pretreatment prevented all these adverse effects of ISO. Present results show that the rich polyphenolic content of Moringa oleifera significantly reduced the myocardial damage and decreased the oxidative stress, possibly through hydroxyl radical scavenging activity as evidenced from the EPR spectra. PMID- 26417352 TI - Evaluation of offspring sex ratio, sex hormones and antioxidant enzymes following exposure to methyl tertiary butyl ether in adult male Sprague-Dawley rats. AB - Methyl tertiary butyl ether (MTBE) is an oxygenated fuel additive which has been used widely in many parts of the world. This experiment was performed to determine the effect of MTBE on offspring sex ratio, sex hormones and antioxidant enzymes. A total of 20 adult Sprague-Dawley male rats were divided into four groups and received 0, 400, 800 and 1600 mg/kg/day MTBE by gavages for 30 consecutive days. At the end of the experiment, blood samples were taken for determination of sex hormones and antioxidant enzymes. Then, male rats were mated with healthy unexposed female rats and sex of offspring was determined after birth. Sex ratio was 0.48, 0.50, 0.43 and 0.50 in 0, 400, 800 and 1600 mg/kg/day MTBE groups, respectively (P = 0.91). There was significant decreasing trend for luteinizing hormone (LH) and testosterone in experimental groups (rs = -0.50, P = 0.030 and rs = -0.67, P = 0.002, respectively). No changes were observed for superoxide dismutase. However, decrease in glutathione peroxidase (GPX) was observed in all treatment groups compared with control which was significant in 400 mg/kg/day MTBE group (P = 0.016). The present study showed that paternal exposure to oral MTBE has no effect on offspring sex ratio; while, MTBE exposure could exert dose-dependent changes in serum testosterone and LH in treatment groups. The results of the present study, need to be clarified in the future studies. PMID- 26417353 TI - Ruta montana L. leaf essential oil and extracts: characterization of bioactive compounds and suppression of crown gall disease. AB - The aims of this study were to assess the antimicrobial efficacy of the leaf essential oil and the leaf extracts of R. montana against Botrytis cinerea, Fusarium oxysporum, Verticillium dahliae, Aspergillus oryzae and Fusarium solani. The oil (1.000 ug/disk) and the extracts (1.500 ug/disk) revealed a remarkable antifungal effect against the tested plant pathogenic fungi with a radial growth inhibition percentage of 40.0-80.0 % and 5.0-58.0 %, respectively along with their respective MIC values ranging from 100 to 1100 ug/mL and 250 to 3000 ug/mL. The oil had a strong detrimental effect on spore germination of all the tested plant pathogens along with the concentration as well as time-dependent kinetic inhibition of Fusarium oxysporum. Also, the oil exhibited a potent in vivo antifungal effect against Botrytis cinerea on tomato plants. Experiments carried out in plant revealed that the essential oil was slightly effective in suppression of gall formation induced by Agrobacterium tumefaciens on bitter almond. The results of this study indicate that the oil and extracts of R. montana leaves could become natural alternatives to synthetic fungicides to control certain important plant microbial diseases. The GC-MS analysis determined that 28 compounds, which represented 89.03 % of total oil, were present in the oil containing mainly 1-butene, methylcyclopropane, 2-butene and caryophyllene oxide. PMID- 26417354 TI - Rituximab therapy improves recalcitrant Pemphigus vulgaris. AB - Pemphigus is a severe life-threatening blistering disease associated with autoantibodies against cell adhesion proteins desmogleins 1 and 3. Patients with severe pemphigus commonly show high rates of relapse after conventional immunosuppressive therapy. The newly developed drug Rituximab showed impressing promises in the treatment of refractory pemphigus vulgaris (PV). In the present study the efficacy of a single course rituximab therapy in the treatment of PV was investigated. Eighteen patients with severe recalcitrant PV were recruited to this study. Pemphigus disease activity index (PDAI), anti-desmoglein 1 and anti desmoglein 3 antibody titers, and percent of CD20 positive cells were measured at baseline, 10 +/- 1, and 22 +/- 2 weeks after rituximab therapy. Rituximab was given intravenously at dose 375 mg/m(2) once weekly for 4 weeks. Rituximab therapy caused a dramatic reduction in the PDAI, accompanied by decreases in anti desmoglein 1 and anti-desmoglein 3 antibody titers over the follow-up course. The B-cell population decreased at the first follow-up, but returned to its baseline levels at the second follow-up. Rituximab therapy decreased the dose of immunosuppressive drugs required to control the disease. It seems that the rituximab may be effective and safe for treatment of refractory PV. PMID- 26417355 TI - Reduction of cytotoxicity of benzalkonium chloride and octenidine by Brilliant Blue G. AB - The irritative effects of preservatives found in ophthalmologic solution, or of antiseptics used for skin disinfection is a consistent problem for the patients. The reduction of the toxic effects of these compounds is desired. Brilliant Blue G (BBG) has shown to meet the expected effect in presence of benzalkonium chloride (BAK), a well known preservative in ophthalmic solutions, and octenidine dihydrochloride (Oct), used as antiseptic in skin and wound disinfection. BBG shows a significant protective effect on human corneal epithelial (HCE) cells against BAK and Oct toxicity, increasing the cell survival up to 51 % at the highest BAK or Oct concentration tested, which is 0.01 %, both at 30 min incubation. Although BBG is described as a P2x7 receptor antagonist, other selective P2x7 receptor antagonists, OxATP (adenosine 5'-triphosphate-2',3' dialdehyde) and DPPH (N'-(3,5-dichloropyridin-4-yl)-3-phenylpropanehydrazide), did not reduce the cytotoxicity of neither BAK nor Oct. Therefore we assume that the protective effect of BBG is not due to its action on the P2x7 receptor. Brilliant Blue R (BBR), a dye similar to BBG, was also tested for protective effect on BAK and Oct toxicity. In presence of BAK no significant protective effect was observed. Instead, with Oct a comparable protective effect was seen with that of BBG. To assure that the bacteriostatic effect is not affected by the combinations of BAK/BBG, Oct/BBG and Oct/BBR, bacterial growth inhibition was analyzed on different Gram-negative and Gram-positive bacteria. All combinations of BAK or Oct with BBG hinder growth of Gram-positive bacteria. The combinations of 0.001 % Oct and BBR above 0.025 % do not hinder the growth of B. subtilis. For Gram-negative bacteria, BBG and BBR reduce, but do not abolish, the antimicrobial effect of BAK nor of Oct. In conclusion, the addition of BBG at bacterial inhibitory concentrations is suggested in the ready-to-use ophthalmic preparations and antiseptic solutions. PMID- 26417356 TI - Evaluation on antioxidant properties of sixteen plant species from Jeju Island in Korea. AB - In this study, the antioxidant properties of 80 % ethanol extracts of 16 species of plants from Jeju Island in Korea were evaluated using various antioxidant assays, including the DPPH (1,1-Diphenyl-2-pricrylhydrazyl) radical scavenging, superoxide scavenging, xanthine oxidase inhibition and hydrogen peroxide scavenging activities. Among the 16 plant extracts tested, CN-13 showed strong antioxidant properties in the DPPH radical scavenging and hydrogen peroxide scavenging tests. The CN-13 ethanol extract was thus selected to be used for further experiments, and was separated into various fractions using four different organic solvents (n-hexane, methylene chloride, ethyl acetate and butanol). The ethyl acetate fraction of CN-13 extract evidenced strong DPPH radical scavenging properties as compared to the other fractions. The ethyl acetate fraction also strongly inhibited DNA-damage induced by hydrogen peroxide oxidative damage in a mouse lymphoma (L5178Y-R) cell line. Moreover, a correlation between the total phenolic content of the extract, and its antioxidant property was reported. PMID- 26417357 TI - Biodegradation and detoxification of textile azo dyes by bacterial consortium under sequential microaerophilic/aerobic processes. AB - Release of textile azo dyes to the environment is an issue of health concern while the use of microorganisms has proved to be the best option for remediation. Thus, in the present study, a bacterial consortium consisting of Providencia rettgeri strain HSL1 and Pseudomonas sp. SUK1 has been investigated for degradation and detoxification of structurally different azo dyes. The consortium showed 98-99 % decolorization of all the selected azo dyes viz. Reactive Black 5 (RB 5), Reactive Orange 16 (RO 16), Disperse Red 78 (DR 78) and Direct Red 81 (DR 81) within 12 to 30 h at 100 mg L(-1) concentration at 30 +/- 0.2 degrees C under microaerophilic, sequential aerobic/microaerophilic and microaerophilic/aerobic processes. However, decolorization under microaerophilic conditions viz. RB 5 (0.26 mM), RO 16 (0.18 mM), DR 78 (0.20 mM) and DR 81 (0.23 mM) and sequential aerobic/microaerophilic processes viz. RB 5 (0.08 mM), RO 16 (0.06 mM), DR 78 (0.07 mM) and DR 81 (0.09 mM) resulted into the formation of aromatic amines. In distinction, sequential microaerophilic/ aerobic process doesn't show the formation of amines. Additionally, 62-72 % reduction in total organic carbon content was observed in all the dyes decolorized broths under sequential microaerophilic/aerobic processes suggesting the efficacy of method in mineralization of dyes. Notable induction within the levels of azoreductase and NADH-DCIP reductase (97 and 229 % for RB 5, 55 and 160 % for RO 16, 63 and 196 % for DR 78, 108 and 258 % for DR 81) observed under sequential microaerophilic/aerobic processes suggested their critical involvements in the initial breakdown of azo bonds, whereas, a slight increase in the levels of laccase and veratryl alcohol oxidase confirmed subsequent oxidation of formed amines. Also, the acute toxicity assay with Daphnia magna revealed the nontoxic nature of the dye-degraded metabolites under sequential microaerophilic/aerobic processes. As biodegradation under sequential microaerophilic/aerobic process completely detoxified all the selected textile azo dyes, further efforts should be made to implement such methods for large scale dye wastewater treatment technologies. PMID- 26417358 TI - Effect of Momordica charantia fruit extract on vascular complication in type 1 diabetic rats. AB - Diabetes mellitus is one of the risk factors in the development of vascular complications. Decreased nitric oxide (NO) production and increased lipid peroxidation in diabetes mellitus are the dominant exaggerating factors. Mormodica charantia (MC) was proven to be useful in improving diabetes mellitus and its complications. In the present study, a total of 40 male Sprague-Dawley rats were used. Diabetes was induced by a single dose (50 mg/kg) of streptozotocin (STZ), intramuscularly. Following 4 weeks of STZ induction, the animals were equally divided into five groups (n = 8); Control group (Ctrl), control group treated with MC (Ctrl-MC), diabetic untreated group (DM-Ctrl), diabetic group treated with MC (DM-MC) and diabetic group treated with metformin 150 g/kg (DM-Met). Oral administration of the MC fruit extract (1.5 g/kg) was continued for 28 days. DM-MC group showed a significant decrease (P < 0.05) in blood pressure, total cholesterol and triglyceride levels compared to the DM-Ctrl group. Aortic tissue NO level was significantly increased and malondialdehyde level was decreased in the DM-MC group. Immunohistochemical staining showed an increase in eNOS expression in the endothelial lining of the DM-MC group. Similarly, morphological deterioration of the aortic tissues was reverted to normal. In summary, treatment with the MC fruit extract exerted the significant vasculoprotective effect in the type 1 diabetic rat model. PMID- 26417359 TI - Chemical composition of biomass generated in the guava tree pruning. AB - Psidium guajava L. (Myrtaceae) is a native plant of Central America and is now widely cultivated in many tropical regions of the world for the fruit production. In Mexico, in the guava orchards common practices to control fruit production are: water stress, defoliation and pruning. In this study, we report the chemical composition of the biomass (branches and leaves) generated in the pruning practices. The results ranged as follows: pH (4.98-5.88), soda solubility (39.01 70.49 %), ash (1.87-8.20 %); potassium and calcium were the major inorganic elements in ash. No heavy metals were detected in the studied samples; total solubility (15.21-46.60 %), Runkel lignin (17.77-35.26 %), holocellulose (26.56 69.49 %), alpha-cellulose (15.53-35.36 %), hemicelluloses (11.02-34.12 %), tannins in aqueous extracts (3.81-9.06 %), and tannins in ethanolic extracts (3.42-15.24 %). PMID- 26417360 TI - Comparative growth analysis of capsulated (Vi+) and acapsulated (Vi-) Salmonella typhi isolates in human blood. AB - Salmonella enterica serovar Typhi (S. Typhi) is a human restricted pathogen. It biosynthesizes a virulence capsular polysaccharide named as Vi antigen. S. Typhi regulates expression of genes involved in the biosynthesis of Vi antigen in response to osmolarity. Beside Vi-positive isolates, Vi-negative (acapsulated) isolates are also pathogenic. However, Vi-positive isolates are more prevalent. The present study was planned to investigate comparative growth of Vi-positive and Vi-negative S. Typhi isolates in an ex vivo human whole blood model. Four isolates of each type were tested for growth in human whole blood and in an enrichment medium (Tryptic soy broth-TSB) as a control. It was found that capsulated (Vi-positive) strains formed smooth circular colonies and grew with shorter lag and generation time than Vi-negative isolates. Overall growth pattern of S. Typhi isolates both in vitro and ex vivo conditions showed that Vi-positive isolates grew at a faster rate. Especially in human blood, the lag time of acapsulated isolates was almost doubled as compared to capsulated S. Typhi isolates. It was also observed that Vi-negative isolates reduced in number up to 81 % during the first 12 hours of incubation in human whole blood. Interestingly, both types of isolates had similar growth curve in TSB indicating that Vi capsule is dispensable for bacterial growth in vitro. This study shows for the first time that absence of capsular antigen retards the growth of Vi-negative isolates on initial contact with human blood, but with passage of time they adjust themselves according to the new environment. PMID- 26417361 TI - The effect of high intensity interval training on cardioprotection against ischemia-reperfusion injury in wistar rats. AB - The aims of the present study were to determine whether short term high intensity interval training (HIIT) could protect the heart against ischemia reperfusion (IR) injury; and if so, to evaluate how long the exercise-associated protection can be lasted. Sixty-three rats were randomly assigned into sedentary (n = 15), sham (n = 7), and exercise groups (n = 41). Rats in the exercise groups performed 5 consecutive days of HIIT on treadmill: 5 min warm up with 50 % VO2max, 6*2 min with 95-105 % VO2max (about 40 to 45 m/min), 5*2 min recovery with 65-75 % VO2max (about 28 to 32 m/min), and 3 min cool down with 50 % VO2max, all at 0 % grade. Animals exposed to an in vivo cardiac IR surgery, performed at days 1, 7, and 14 following the final exercise session. Ischemia-induced arrhythmias, myocardial infarct size (IS), plasma lactate dehydrogenase (LDH) and creatine kinase (CK) activities were measured in all animals. Compared to sedentary rats, exercised animals sustained less IR injury as evidenced by a lower size of infarction and lower levels of LDH and CK at day one and day 7 post exercise. In comparison of sedentary group, IS significantly decreased in EX-IR1 and EX-IR7 groups (50 and 35 %, respectively), but not in EX-IR14 group (19 %). The exercise-induced cardioprotection disappeared 14 days following exercise cessation. There were no significant changes in ischemia-induced arrhythmia between exercised and sedentary rats. The results clearly demonstrate that HIIT protects the heart against myocardial IR injury. This protective effect can be sustained for at least one week following the cessation of the training. PMID- 26417362 TI - The phycobilisomes: an early requisite for efficient photosynthesis in cyanobacteria. AB - Cyanobacteria trap light energy by arrays of pigment molecules termed "phycobilisomes (PBSs)", organized proximal to "reaction centers" at which chlorophyll perform the energy transduction steps with highest quantum efficiency. PBSs, composed of sequential assembly of various chromophorylated phycobiliproteins (PBPs), as well as nonchromophoric, basic and hydrophobic polypeptides called linkers. Atomic resolution structure of PBP is a heterodimer of two structurally related polypeptides but distinct specialised polypeptides- a and beta, made up of seven alpha-helices each which played a crucial step in evolution of PBPs. PBPs carry out various light dependent responses such as complementary chromatic adaptation. The aim of this review is to summarize and discuss the recent progress in this field and to highlight the new and the questions that remain unresolved. PMID- 26417363 TI - A sulfated polysaccharide of Ecklonia cava inhibits the growth of colon cancer cells by inducing apoptosis. AB - We investigated anticancer effects of the crude polysaccharides (CPs) isolated from Ecklonia cava enzymatic extracts using AMG, Viscozyme, Protamex, and Alcalase enzyme against a colon cancer cell line, CT26 cells. Among them, the CP of Protamex extract (PCP) contained the highest fucose and sulfated group contents and showed the highest growth inhibitory effect against CT-26 cells. In addition, PCP dose-dependently increased the formation of apoptotic body and the percentage of Sub-G1 DNA contents. Also, PCP activated caspase 9 and PARP as regulating the expressions of Bax and Bcl-2. Moreover, PPP2, a fraction purified from PCP showed the highest growth inhibitory effect against CT 26 cells with the increased fucose and sulfated group contents. The results demonstrate that the isolated SP containing plentiful fucose and sulfated group contents has the anticancer effect on colon cancer cells via regulation of Bcl-2/Bax signal pathway. PMID- 26417364 TI - Paper-based acetylcholinesterase inhibition assay combining a wet system for organophosphate and carbamate pesticides detection. AB - A dramatic increase in pesticide usage in agriculture highlights the need for on site monitoring for public health and safety. Here, a paper-based sensor combined with a wet system was developed for the simple and rapid screening of organophosphate (OP) and carbamate (CM) pesticides based on the inhibition of acetylcholinesterase (AChE). The paper-based sensor was designed as a foldable device consisting of a cover and detection sheets pre-prepared with indoxyl acetate and AChE, respectively. The paper-based sensor requires only the incubation of a sample on the test zone for 10 minutes, followed by closing of the foldable sheet to initiate the enzymatic reaction. Importantly, the buffer loading hole was additionally designed on the cover sheet to facilitate the interaction of the coated substrate and the immobilized enzyme. This subsequently facilitates the mixing of indoxyl acetate with AChE, resulting in the improved analytical performance of the sensor. The absence or decrease in blue color produced by the AChE hydrolysis of indoxyl acetate can be observed in the presence of OPs and CMs. Under optimized conditions and using image analysis, the limit of detection (LOD) of carbofuran, dichlorvos, carbaryl, paraoxon, and pirimicarb are 0.003, 0.3, 0.5, 0.6, and 0.6 ppm, respectively. The assay could be applied to determine OP and CM residues in spiked food samples. Visual interpretation of the color signal was clearly observed at the concentration of 5 mg/kg. Furthermore, a self-contained sample pre-concentration approach greatly enhanced the detection sensitivity. The paper-based device developed here is low cost, requires minimal reagents and is easy to handle. As such, it would be practically useful for pesticide screening by non-professional end-users. PMID- 26417365 TI - Growth, physiology and yield of durum wheat (Triticum durum) treated with sewage sludge under water stress conditions. AB - In arid and semi-arid areas, low soil fertility and water deficit considerably limit crop production. The use of sewage sludge as an organic amendment could contribute to the improvement of soil fertility and hence the agronomic production. The study aims to highlight the behaviour of durum wheat to the application of sewage sludge associated with water stress. The assessment focused on morphophysiological parameters of the wheat plant and yield. Under greenhouse conditions, the variety Mohamed Ben Bachir was treated by four water stress levels (100 %, 80 %, 50 % and 30 %). Each stress level comprised five fertilizer treatments: 20, 50 and 100 t/ha of dry sludge, 35 kg/ha of urea, and a control with no fertilization. Results revealed a significant loss in water content and chlorophyll a in leaves. Water stress negatively affected the development of wheat plants by reducing significantly seed yield, leaf area and biomass produced. Plant's responses to water stress manifested by an accumulation of proline and a decrease in total phosphorus. However, the increasing doses of sewage sludge limited the effect of water stress. Our findings showed an increase in the amount of chlorophyll pigments, leaf area, total phosphorus, biomass and yield. In addition, excessive accumulation of proline (1.11 +/- 1.03 ug/g DM) was recorded as a result of the high concentration of sludge (100 t/ha DM). The application of sewage sludge is beneficial for the wheat crop, but the high accumulation of proline in plants treated with high dose of sludge suggests to properly consider this fact. The application of sludge should be used with caution in soils where water is limited. Because the combined effect of these two factors could result in a fatal osmotic stress to crop development. PMID- 26417366 TI - Blood pressure percentiles by age and body mass index for adults. AB - Since no comprehensive study has been conducted on blood pressure (BP) percentiles established upon nationally representative sample population of adults, the present study aimed to construct the blood pressure percentiles by age, sex and body mass index (BMI) of the subjects. Analyses were based on data collected in 2011 from 8,425 adults aged 25 to 69 years old. Data on demographic characteristics, anthropometric measurements, and blood pressure was recorded for each subject. Linear Regression analysis was used to assess the adjusted relationship of age-sex-specific standard deviation scores of BMI, height, and weight with blood pressure. Four separate models for systolic blood pressure (SBP) and diastolic blood pressure (DBP) of men and women were constructed for BP percentiles according to age and BMI. Blood pressure increased with the rise in BMI and weight, but showed a negative correlation with height. SBP and DBP rose steadily with increasing age, but the rise in SBP was greater than DBP. Overweight and obese population, seem to fall into the category of hypertensive. The findings of present study show that BP percentiles are steadily increased by age and BMI. In addition, most obese or overweight adults are hypertensive. PMID- 26417367 TI - A Multilayer Naive Bayes Model for Analyzing User's Retweeting Sentiment Tendency. AB - Today microblogging has increasingly become a means of information diffusion via user's retweeting behavior. Since retweeting content, as context information of microblogging, is an understanding of microblogging, hence, user's retweeting sentiment tendency analysis has gradually become a hot research topic. Targeted at online microblogging, a dynamic social network, we investigate how to exploit dynamic retweeting sentiment features in retweeting sentiment tendency analysis. On the basis of time series of user's network structure information and published text information, we first model dynamic retweeting sentiment features. Then we build Naive Bayes models from profile-, relationship-, and emotion-based dimensions, respectively. Finally, we build a multilayer Naive Bayes model based on multidimensional Naive Bayes models to analyze user's retweeting sentiment tendency towards a microblog. Experiments on real-world dataset demonstrate the effectiveness of the proposed framework. Further experiments are conducted to understand the importance of dynamic retweeting sentiment features and temporal information in retweeting sentiment tendency analysis. What is more, we provide a new train of thought for retweeting sentiment tendency analysis in dynamic social networks. PMID- 26417368 TI - On Training Efficiency and Computational Costs of a Feed Forward Neural Network: A Review. AB - A comprehensive review on the problem of choosing a suitable activation function for the hidden layer of a feed forward neural network has been widely investigated. Since the nonlinear component of a neural network is the main contributor to the network mapping capabilities, the different choices that may lead to enhanced performances, in terms of training, generalization, or computational costs, are analyzed, both in general-purpose and in embedded computing environments. Finally, a strategy to convert a network configuration between different activation functions without altering the network mapping capabilities will be presented. PMID- 26417369 TI - Changes in Bone Mineral Density and Metabolic Parameters after Pulsatile Gonadorelin Treatment in Young Men with Hypogonadotropic Hypogonadism. AB - To assess the prevalence of osteoporosis in young men with hypogonadotropic hypogonadism (HH) and to investigate the changes of BMD and metabolic parameters, a total of 22 young male patients with HH and 20 healthy controls were enrolled in the study. BMD, biochemical, and hormonal parameters were measured in two groups. Osteoporosis was more prevalent in HH patients (45.45%) than the control subjects (10.00%) (P < 0.001). The patients with HH had lower BMD in lumbar spine 2-4, femoral neck, and total hip (P < 0.001, for all) and higher fasting insulin (P = 0.001), HOMA-IR (P = 0.002), and SHBG (P < 0.001) compared to the controls. After 6 months of pulsatile gonadorelin treatment, BMI (P = 0.021) and BMD in lumbar spine 2-4, femoral neck, and total hip (P = 0.002, P = 0.003, and P = 0.003, resp.) increased dramatically and total cholesterol (P = 0.034), fasting insulin (P = 0.025), HOMA-IR (P = 0.021), and SHBG (P = 0.001) decreased significantly in HH patients. The study shows a higher prevalence of osteoporosis in young men with HH. Long-term pulsatile gonadorelin treatment indicates a positive effect on BMD and metabolic parameters of HH patients. PMID- 26417370 TI - Evaluation of AgNORs in Oral Potentially Malignant Lesions. AB - Oral squamous cell carcinoma (OSCC) is usually preceded by detectable mucosal changes, as leukoplakias and erythroplakia. Histologically, these lesions can range from hyperkeratosis and acanthosis to epithelial dysplasia and even OSCC. The aim of this study was to investigate the proliferative activity, using AgNORs quantification proteins, in low- and high-risk oral epithelial dysplasia, OSCC, and nondysplastic epithelium (inflammatory fibrous hyperplasia). The sample was divided into 4 groups: G1: 10 cases of inflammatory fibrous hyperplasia (IFH), G2: 11 cases of low-risk epithelial dysplasia (LD), G3: 10 cases of high-risk epithelial dysplasia (HD), and G4: 11 cases of OSCC. The quantitative analysis was performed using an image processing software in photomicrographs at 1000x magnification. The one-way ANOVA was used for comparison of the mean AgNORs counts between the study groups. The mean AgNORs count was significantly higher (P <= 0.01) in OSCC when compared to IFH and the LD; however, it was not statistically different from HD. The mean number of LD was significantly lower than the HD and OSCC, with no difference related to IFH. AgNORs quantification can be an important and cheap method to help in the determination of the degree of epithelial dysplasia and, consequently, in the analysis of their potential for malignant transformation. PMID- 26417371 TI - Phenotypic and Molecular Characterisation of Extended-Spectrum Beta-Lactamase Producing Escherichia coli Obtained from Animal Fecal Samples in Ado Ekiti, Nigeria. AB - Production of extended-spectrum beta-lactamases (ESBLs) producing E. coli in animals and different methods of identifications from Ado Ekiti, Ekiti State, Nigeria, were investigated. Three hundred and fifty fecal samples, collected from apparently healthy cattle and pigs, were cultured and identified following standard procedures. ESBL phenotypic detection was carried out using combination disc test, double disc synergism test, and ESBL brilliance agar screening. Molecular detection of TEM, SHV, and CTX-M genes was carried out using standard molecular method. One hundred and fourteen E. coli isolates were recovered from the 350 samples processed, out of which 72 (63.2%) isolates were positive for ESBLs with multiple resistance to the antibiotics used. Eighty-one (71%) isolates were positive for ESBL by combination disc test, 90 (78.9%) were positive for double disc synergism test, and 93 (81.6%) were positive for ESBL brilliance agar. TEM and CTX-M genes were detected in 48 (42.1%) and 51 (44.7%) isolates, respectively. SHV gene was not detected in any of the isolates while TEM and CTX M were detected in 33 (28.9%) isolates. This study showed high resistance of E. coli to antibiotics, particularly to the third generation cephalosporins. Regular monitoring and regulated use of antibiotics in livestock should be encouraged. PMID- 26417372 TI - Topical Hypericum perforatum Improves Tissue Regeneration in Full-Thickness Excisional Wounds in Diabetic Rat Model. AB - Delayed wound healing process is one of the most important concerns in diabetes. Healing of wounds has four phases, namely, hemostasis, inflammation, proliferation, and remodeling. For a successful repair, all four factors must occur properly. Hence, we aimed to evaluate the healing effects of Hypericum perforatum (HP) on full-thickness diabetic skin wounds by using stereological methods. Forty-eight female diabetic rats were randomly divided into four groups (n = 12): gel base treated group, HP 5% gel treated group, HP 10% gel treated group, and the control group which received no treatment. A circular 1 cm(2) full thickness wound was created on the animal's neck and wound area was measured every three days. After sacrificing the animals, skin samples were fixed and prepared for stereological evaluations. Based on the results, HP treated group showed faster wound closure rate in comparison with control and vehicle groups (P < 0.05). In addition, numerical density of fibroblasts, volume density of collagen bundles, and mean diameter and volume densities of the vessels in HP group were significantly higher than control and vehicle groups. The results of this study showed that HP has the ability to improve tissue regeneration by enhancing fibroblast proliferation, collagen bundle synthesis, and revascularization. PMID- 26417373 TI - Acupoint Catgut Embedding for Obesity: Systematic Review and Meta-Analysis. AB - Acupoint catgut embedding (ACE) was applied widely to antiweight in China. The aim of this review is to estimate the effectiveness and safety of ACE on obesity. A literature search was conducted in PubMed, Cochrane Library, EBASE, CNKI, and so forth, using combination subject terms of obesity (or overweight, weight loss, etc.) and acupoint catgut embedding (or catgut implantation, catgut embedding). Improvement rate, reduction of body weight and body mass index (BMI), and so forth were analyzed. 43 studies were included for systematic review and meta analysis. Although with poor methodological quality, ACE was superior to manual acupuncture (MA), sham, and cupping in improvement rate and presented a better tendency (OR > 1) compared with drugs and electroacupuncture (EA). Mean values of weight loss by ACE were 1.14 kg, 1.26 kg, 1.79 kg, and 3.01 kg comparing with MA, drugs, EA, and sham, respectively. Mean of BMI reduced to 0.56 kg/m(2), 0.83 kg/m(2), 0.79 kg/m(2), and 1.63 kg/m(2) comparing with MA, drugs, EA, and sham. Less adverse effects were reported. Pooled outcomes presented a tendency of equal or superior effects to other interventions and fewer side effects. Future high quality trials with rigorous design and positive FDA approved drug as control are urgent to assess the effect of ACE for obesity. PROSPERO registration number is as follows: CRD42015016006. PMID- 26417374 TI - Effect of Tongxinluo on Nephrin Expression via Inhibition of Notch1/Snail Pathway in Diabetic Rats. AB - Podocyte injury is an important mechanism of diabetic nephropathy (DN). Accumulating evidence suggests that nephrin expression is decreased in podocyte in DN. Moreover, it has been demonstrated that tongxinluo (TXL) can ameliorate renal structure disruption and dysfunction in DN. However, the effect of TXL on podocyte injury in DN and its molecular mechanism is unclear. In order to explore the effect of TXL on podocyte injury and its molecular mechanism in DN, our in vivo and in vitro studies were performed. Our results showed that TXL increased nephrin expression in diabetic rats and in high glucose cultured podocyte. Meanwhile, TXL decreased ICN1 (the intracellular domain of notch), HES1, and snail expression in podocyte in vivo and in vitro. More importantly, we found that TXL protected podocyte from injury in DN. The results demonstrated that TXL inhibited the activation of notch1/snail pathway and increased nephrin expression, which may be a mechanism of protecting effect on podocyte injury in DN. PMID- 26417375 TI - Design and Formulation of Optimized Microemulsions for Dermal Delivery of Resveratrol. AB - The objective of this study was to formulate optimal formulations of microemulsions (MEs) and evaluate their feasibility for delivery of resveratrol into human skin ex vivo. Oil-in-water MEs were formulated using surfactant (S) PEG-8 caprylic/capric glycerides and cosurfactant (CoS) polyglyceryl-6 isostearate. Ethyl oleate was used as an oily phase. MEs were formulated using 5 : 1, 6 : 1, and 7 : 1 surfactant and cosurfactant (S : CoS) weight ratios. Pseudoternary phase diagrams were constructed and optimal compositions of MEs were obtained using Design Expert software. Mean droplet size for optimized ME formulations was determined to be 68.54 +/- 1.18 nm, 66.08 +/- 0.16 nm, and 66.66 +/- 0.56 nm for systems with S : CoS weight ratios 5 : 1, 6 : 1, and 7 : 1, respectively. Resveratrol loading resulted in mean droplet size increase. The distribution of droplet size between fractions changed during storage of formulated MEs. Results demonstrated the increase of number of droplets and relative surface area when S : CoS weight ratios were 6 : 1 and 7 : 1 and the decrease when S : CoS weight ratio was 5 : 1. The highest penetration of resveratrol into the skin ex vivo was determined from ME with S : CoS weight ratio 5 : 1. It was demonstrated that all MEs were similar in their ability to deliver resveratrol into the skin ex vivo. PMID- 26417376 TI - Bone Mineral Density and Fracture Risk Assessment to Optimize Prosthesis Selection in Total Hip Replacement. AB - The variability in patient outcome and propensity for surgical complications in total hip replacement (THR) necessitates the development of a comprehensive, quantitative methodology for prescribing the optimal type of prosthetic stem: cemented or cementless. The objective of the research presented herein was to describe a novel approach to this problem as a first step towards creating a patient-specific, presurgical application for determining the optimal prosthesis procedure. Finite element analysis (FEA) and bone mineral density (BMD) calculations were performed with ten voluntary primary THR patients to estimate the status of their operative femurs before surgery. A compilation model of the press-fitting procedure was generated to define a fracture risk index (FRI) from incurred forces on the periprosthetic femoral head. Comparing these values to patient age, sex, and gender elicited a high degree of variability between patients grouped by implant procedure, reinforcing the notion that age and gender alone are poor indicators for prescribing prosthesis type. Additionally, correlating FRI and BMD measurements indicated that at least two of the ten patients may have received nonideal implants. This investigation highlights the utility of our model as a foundation for presurgical software applications to assist orthopedic surgeons with selecting THR prostheses. PMID- 26417377 TI - Parametric Modeling of Human Gradient Walking for Predicting Minimum Energy Expenditure. AB - A mathematical model to predict the optimum gradient for a minimum energetic cost is proposed, based on previous results that showed a minimum energetic cost when gradient is -10%. The model focuses on the variation in mechanical energy during gradient walking. It is shown that kinetic energy plays a marginal role in low speed gradient walking. Therefore, the model considers only potential energy. A mathematical parameter that depends on step length was introduced, showing that the optimal gradient is a function of that parameter. Consequently, the optimal negative gradient depends on the individual step length. The model explains why recent results do not suggest a single optimal gradient but rather a range around -10%. PMID- 26417378 TI - Review of Modelling Techniques for In Vivo Muscle Force Estimation in the Lower Extremities during Strength Training. AB - BACKGROUND: Knowledge of the musculoskeletal loading conditions during strength training is essential for performance monitoring, injury prevention, rehabilitation, and training design. However, measuring muscle forces during exercise performance as a primary determinant of training efficacy and safety has remained challenging. METHODS: In this paper we review existing computational techniques to determine muscle forces in the lower limbs during strength exercises in vivo and discuss their potential for uptake into sports training and rehabilitation. RESULTS: Muscle forces during exercise performance have almost exclusively been analysed using so-called forward dynamics simulations, inverse dynamics techniques, or alternative methods. Musculoskeletal models based on forward dynamics analyses have led to considerable new insights into muscular coordination, strength, and power during dynamic ballistic movement activities, resulting in, for example, improved techniques for optimal performance of the squat jump, while quasi-static inverse dynamics optimisation and EMG-driven modelling have helped to provide an understanding of low-speed exercises. CONCLUSION: The present review introduces the different computational techniques and outlines their advantages and disadvantages for the informed usage by nonexperts. With sufficient validation and widespread application, muscle force calculations during strength exercises in vivo are expected to provide biomechanically based evidence for clinicians and therapists to evaluate and improve training guidelines. PMID- 26417380 TI - Deformation of Soft Tissue and Force Feedback Using the Smoothed Particle Hydrodynamics. AB - We study the deformation and haptic feedback of soft tissue in virtual surgery based on a liver model by using a force feedback device named PHANTOM OMNI developed by SensAble Company in USA. Although a significant amount of research efforts have been dedicated to simulating the behaviors of soft tissue and implementing force feedback, it is still a challenging problem. This paper introduces a kind of meshfree method for deformation simulation of soft tissue and force computation based on viscoelastic mechanical model and smoothed particle hydrodynamics (SPH). Firstly, viscoelastic model can present the mechanical characteristics of soft tissue which greatly promotes the realism. Secondly, SPH has features of meshless technique and self-adaption, which supply higher precision than methods based on meshes for force feedback computation. Finally, a SPH method based on dynamic interaction area is proposed to improve the real time performance of simulation. The results reveal that SPH methodology is suitable for simulating soft tissue deformation and force feedback calculation, and SPH based on dynamic local interaction area has a higher computational efficiency significantly compared with usual SPH. Our algorithm has a bright prospect in the area of virtual surgery. PMID- 26417379 TI - Comparative Sensitivity Analysis of Muscle Activation Dynamics. AB - We mathematically compared two models of mammalian striated muscle activation dynamics proposed by Hatze and Zajac. Both models are representative for a broad variety of biomechanical models formulated as ordinary differential equations (ODEs). These models incorporate parameters that directly represent known physiological properties. Other parameters have been introduced to reproduce empirical observations. We used sensitivity analysis to investigate the influence of model parameters on the ODE solutions. In addition, we expanded an existing approach to treating initial conditions as parameters and to calculating second order sensitivities. Furthermore, we used a global sensitivity analysis approach to include finite ranges of parameter values. Hence, a theoretician striving for model reduction could use the method for identifying particularly low sensitivities to detect superfluous parameters. An experimenter could use it for identifying particularly high sensitivities to improve parameter estimation. Hatze's nonlinear model incorporates some parameters to which activation dynamics is clearly more sensitive than to any parameter in Zajac's linear model. Other than Zajac's model, Hatze's model can, however, reproduce measured shifts in optimal muscle length with varied muscle activity. Accordingly we extracted a specific parameter set for Hatze's model that combines best with a particular muscle force-length relation. PMID- 26417381 TI - Kinematic, Dynamic, and Energy Characteristics of Diastolic Flow in the Left Ventricle. AB - Blood flow characteristics in the normal left ventricle are studied by using the magnetic resonance imaging, the Navier-Stokes equations, and the work-energy equation. Vortices produced during the mitral valve opening and closing are modeled in a two-dimensional analysis and correlated with temporal variations of the Reynolds number and pressure drop. Low shear stress and net pressures on the mitral valve are obtained for flow acceleration and deceleration. Bernoulli energy flux delivered to blood from ventricular dilation is practically balanced by the energy influx and the rate change of kinetic energy in the ventricle. The rates of work done by shear and energy dissipation are small. The dynamic and energy characteristics of the 2D results are comparable to those of a 3D model. PMID- 26417382 TI - Assessment of Knee Cartilage Stress Distribution and Deformation Using Motion Capture System and Wearable Sensors for Force Ratio Detection. AB - Knowledge about the knee cartilage deformation ratio as well as the knee cartilage stress distribution is of particular importance in clinical studies due to the fact that these represent some of the basic indicators of cartilage state and that they also provide information about joint cartilage wear so medical doctors can predict when it is necessary to perform surgery on a patient. In this research, we apply various kinds of sensors such as a system of infrared cameras and reflective markers, three-axis accelerometer, and force plate. The fluorescent marker and accelerometers are placed on the patient's hip, knee, and ankle, respectively. During a normal walk we are recording the space position of markers, acceleration, and ground reaction force by force plate. Measured data are included in the biomechanical model of the knee joint. Geometry for this model is defined from CT images. This model includes the impact of ground reaction forces, contact force between femur and tibia, patient body weight, ligaments, and muscle forces. The boundary conditions are created for the finite element method in order to noninvasively determine the cartilage stress distribution. PMID- 26417383 TI - Intracellular microlasers. AB - Optical microresonators1 which confine light within a small cavity are widely exploited for various applications ranging from the realization of lasers2 and nonlinear devices3, 4, 5 to biochemical and optomechanical sensing6, 7, 8, 9, 10, 11. Here we employ microresonators and suitable optical gain materials inside biological cells to demonstrate various optical functions in vitro including lasing. We explored two distinct types of microresonators: soft and hard, that support whispering-gallery modes (WGM). Soft droplets formed by injecting oil or using natural lipid droplets support intracellular laser action. The laser spectra from oil-droplet microlasers can chart cytoplasmic internal stress (~500 pN/MUm2) and its dynamic fluctuations at a sensitivity of 20 pN/MUm2 (20 Pa). In a second form, WGMs within phagocytized polystyrene beads of different sizes enable individual tagging of thousands of cells easily and, in principle, a much larger number by multiplexing with different dyes. PMID- 26417384 TI - Emerging Trends in Behavioral Genetic Studies of Child Temperament. AB - In this article, we describe three emerging trends in the application of behavioral genetic methods to the study of temperament. The trends-using multiple methods to assess temperament, considering contextual influences on temperament, and evaluating the structure of temperament-have been well studied in the phenotypic literature, but adding a behavioral genetic perspective can enrich our understanding of temperament. We review recent behavioral genetic research in each of these areas and discuss its implications. PMID- 26417385 TI - Rural-urban differences in the clinico-pathologic profiles of Jamaican men with prostate cancer. AB - BACKGROUND: Prostate cancer causes the highest number of cancer-related deaths in Jamaican men. It is not known whether rural-dwelling men present with worse disease than urban-dwelling men at initial presentation. Since rural and urban dwelling Jamaicans are predominantly of African descent and generally similar in respect of racial composition, if any significant variation in initial presentation were found, it would suggest that these are likely due to differences in awareness, access to care, and screening patterns. METHODS: The medical records of rural and urban-dwelling patients with prostate cancer were compared. Patients' age at presentation, initial prostate-specific antigen level, digital rectal examination findings, biopsy Gleason scores and initial treatment received were compared using bivariate and logistic regression analyses. RESULTS: In unadjusted analyses rural-dwelling men were older compared to urban-dwelling men (72 years versus 68.5 years, p = 0.035), had higher median PSA values (22.9 ng/ml versus 18 ng/ml, p = 0.001), higher local tumour stage (65.2 % versus 34.8 % T3 disease; 73.7 % versus 26.3 % T4 disease; p = 0.005), higher mean Gleason scores (p = 0.048) and more non-curative initial treatments. Local tumour stage was the only statistically significant difference between rural and urban dwelling men in logistic regression analysis with rural-dwelling men having a 70 % higher risk of locally-advanced disease (OR = 1.70, 95 % CI: 1.03-2.79; p = 0.038). CONCLUSION: Rural-dwelling men presented with more advanced prostate cancer compared to urban-dwelling men. As both rural and urban-dwelling men are of predominant African descent it is likely that these differences are due to differences in access to care, screening practice and awareness of the disease. PMID- 26417386 TI - Human papillomavirus types in non-cervical high-grade intraepithelial neoplasias and invasive carcinomas from San Luis Potosi, Mexico: a retrospective cross sectional study. AB - BACKGROUND: Viral infections and the burden of high-grade intraepithelial neoplasias (HIN) and invasive carcinomas (IC) associated to infections by human papillomavirus (HPV) types may be prevented by type-specific anti-HPV vaccines. This study determined the prevalence of HPV types in non-cervical HIN and IC diagnosed from 1999 to 2011 at a general hospital in San Luis Potosi, Mexico. METHODS: Review of the 67 formaldehyde-fixed paraffin-embedded non-cervical specimens initially diagnosed as HIN (n = 28) or IC (n = 39) confirmed the presence of tumor tissue in 63 of them and changed the diagnosis of 24 from HIN to low-grade intraepithelial neoplasias, that were excluded from the study. HPV DNA was detected with the SPF10-DNA enzyme immunoassay in the 39 cases included, and viral types in the HPV-positive tumors were identified with the INNO-LiPA linear probe array. RESULTS: Among the cases included, four HIN were located in the vagina (n = 3) and vulva (n = 1), and 35 IC in the oral cavity (n = 19), penis (n = 8), vagina (n = 7) and vulva (n = 1). There were 13 HPV-positive cases from the vagina (n = 7), vulva (n = 1), penis (n = 1) and oral cavity (n = 1). The viral types identified were the high-risk types HPV16 in the vagina (n = 3) and vulva (n = 3), HPV45 in the vagina (n = 2), HPV59 in the vagina (n = 1) and penis (n = 1), HPV33 in the vagina (n = 1),and HPV35 in the tongue(n = 1); and the low-risk types HPV54 in the vagina (n = 1), and HPV11 in the vulva (n = 1). CONCLUSIONS: Five high-risk viral types (HPV16, 45, 59, 33 and 35) and two low risk types (HPV11 and 54) infect one third of the non-cervical HIN and IC included. Most infections are by a single HPV high-risk type, the most prevalent one being HPV16. Vagina is the most frequent location of the HPV-positive tumors. Vaccination against HPV16 and HPV18 could have prevented around half of the HPV positive tumors. PMID- 26417387 TI - The DSM-5 diagnosis of nonsuicidal self-injury disorder: a review of the empirical literature. AB - With the presentation of nonsuicidal self-injury disorder (NSSID) criteria in the fifth version of the Statistical and Diagnostic Manual of Mental Disorders (DSM 5), empirical studies have emerged where the criteria have been operationalized on samples of children, adolescents and young adults. Since NSSID is a condition in need of further study, empirical data are crucial at this stage in order to gather information on the suggested criteria concerning prevalence rates, characteristics, clinical correlates and potential independence of the disorder. A review was conducted based on published peer-reviewed empirical studies of the DSM-5 NSSID criteria up to May 16, 2015. When the DSM-5 criteria were operationalized on both clinical and community samples, a sample of individuals was identified that had more general psychopathology and impairment than clinical controls as well as those with NSSI not meeting criteria for NSSID. Across all studies interpersonal difficulties or negative state preceding NSSI was highly endorsed by participants, while the distress or impairment criterion tended to have a lower endorsement. Results showed preliminary support for a distinct and independent NSSID diagnosis, but additional empirical data are needed with direct and structured assessment of the final DSM-5 criteria in order to reliably assess and validate a potential diagnosis of NSSID. PMID- 26417388 TI - The association of self-injurious behaviour and suicide attempts with recurrent idiopathic pain in adolescents: evidence from a population-based study. AB - BACKGROUND: While several population-based studies report that pain is independently associated with higher rates of self-destructive behaviour (suicidal ideation, suicide attempts, and self-injurious behaviour) in adults, studies in adolescents are rare and limited to specific chronic pain conditions. The aim of this study was to investigate the link between self-reported idiopathic pain and the prevalence and frequency of self-injury (SI) and suicide attempts in adolescents. METHODS: Data from a cross-sectional, school-based sample was derived to assess SI, suicide attempts, recurrent pain symptoms and various areas of emotional and behavioural problems via a self-report booklet including the Youth Self-Report (YSR). Adolescents were assigned to two groups (presence of pain vs. no pain) for analysis. Data from 5,504 students of 116 schools in a region of South Western Germany was available. A series of unadjusted and adjusted multinomial logistic regression models were performed to address the association of pain, SI, and suicide attempts. RESULTS: 929 (16.88%) respondents reported recurrent pain in one of three areas of pain symptoms assessed (general pain, headache, and abdominal pain). Adolescents who reported pain also reported greater psychopathological distress on all sub-scales of the YSR. The presence of pain was significantly associated with an increased risk ratio (RR) for SI (1-3 incidences in the past year: RR: 2.96; >3 incidences: RR: 6.04) and suicide attempts (one attempt: RR: 3.63; multiple attempts: RR: 5.4) in unadjusted analysis. Similarly, increased RR was observed when adjusting for sociodemographic variables. While controlling for psychopathology attenuated this association, it remained significant (RRs: 1.4-1.8). Sub-sequent sensitivity analysis revealed different RR by location and frequency of pain symptoms. CONCLUSIONS: Adolescents with recurrent idiopathic pain are more likely to report previous incidents of SI and suicide attempts. This association is likely mediated by the presence of psychopathological distress as consequence of recurrent idiopathic pain. However, the observed variance in dependent variables is only partially explained by emotional and behavioural problems. Clinicians should be aware of these associations and interview adolescents with recurrent symptoms of pain for the presence of self-harm, past suicide attempts and current suicidal thoughts. Future studies addressing the neurobiology underpinnings of an increased likelihood for self-injurious behaviour and suicide attempts in adolescents with recurrent idiopathic pain are necessary. PMID- 26417389 TI - Immigration as risk factor for non-suicidal self-injury and suicide attempts in adolescents in Germany. AB - BACKGROUND: Whereas non-suicidal self-injury (NSSI) and suicide attempts (SA) are rather common among adolescents, the description of risk factors has often failed to take migration into perspective. Our study aimed to describe immigration status in adolescents with regards to their lifetime history of NSSI and SA. METHODS: We carried out a population based study in a school community of ninth graders (N = 452, mean age 14.85, SD 0.58) in southern Germany. Data were collected via adolescent self report on sociodemographic variables and on NSSI and SA using the Self Harm Behavior Questionnaire. RESULTS: Adolescents born outside Germany showed an elevated rate of a lifetime history of NSSI and SA. When compared to German adolescents without a (family) history of migration (NSSI 19.16%, SA 3.24%), adolescents who were born in another country had an elevated risk for NSSI (42.86%, OR 3.36) and SA (17.86%, OR 6.78), which was higher than the risk of adolescents who had at least one parent who had emigrated from another country (NSSI 30.08%, OR 2.46 and SA 8.94%, OR 4.45). CONCLUSION: Our findings should inform intervention services and prevention programs for NSSI and suicidality in youth. Adopting such programs to include culturally sensible modules could improve the outcome in ethnically diverse adolescents. PMID- 26417390 TI - A cross-sectional matched sample study of nonsuicidal self-injury among young adults: support for interpersonal and intrapersonal factors, with implications for coping strategies. AB - BACKGROUND: Young adults are a high-risk group for nonsuicidal self-injury (NSSI). It is important to have a better understanding of these behaviors in order to facilitate effective research, intervention, and treatment. Models have been presented to explain these behaviors where emotion regulation, coping, and support play a role. Yet conflicting results have occurred based on demographic factors such as race and sex. While controlling for the observable demographic factors, this study sought to examine differences between individuals who currently engage in NSSI, engaged in NSSI in the past, and never engaged in NSSI related to emotions, coping strategies, interpersonal support, and ethnic identity and belonging. METHODS: Participants were selected from freshman students at two universities, in geographically different locations in the United States (N = 282). Participants in this study were matched on demographic factors: race, sex, and university. This led to demographically matched groups (current, past, never engagement in NSSI; n = 94 per group). Groups were compared on intrapersonal factors (i.e., emotions: depression and anxiety; coping strategies: adaptive and maladaptive; interpersonal support: family, friend, and significant other; and ethnic identity and belonging). Descriptive statistics and ANOVA with post hoc Scheffe were utilized to explicate differences between groups. RESULTS: Individuals who never engaged in NSSI reported significantly higher levels of ethnic belonging and interpersonal support and lower levels of depression and anxiety than both groups who engaged in NSSI. Individuals who never self-injured used less adaptive and maladaptive coping strategies than participants who self injured. Young adults who currently engaged in NSSI reported higher levels of depression and anxiety, higher levels of both types of coping, and perceived less support. CONCLUSIONS: It is important to understand the differences between individuals who self-injure in comparison to those who do not so that mental health clinicians can provide more effective services and preventative efforts. PMID- 26417391 TI - Research with adolescents who engage in non-suicidal self-injury: ethical considerations and challenges. AB - Non-suicidal self-injury (NSSI) has emerged as a significant psychiatric issue among youth. In addition to its high prevalence rates, NSSI is associated with a number of psychiatric issues and confers risk for varying degrees of physical injury. It is also a risk factor for attempted suicide. Thus, youth who engage in NSSI represent a vulnerable and high-risk population and researchers are likely to encounter a variety of ethical challenges when conducting NSSI research. Accordingly, it is critical that researchers be familiar with the major ethical issues involved in NSSI research and how to effectively account for and address them. This is important both prior to obtaining clearance from their Institutional Review Boards and when carrying out their research. To date, there is no consolidated resource to delineate the ethical challenges inherent to NSSI research and how these can be effectively navigated throughout the research process. The goals of this paper are to review international best practices in NSSI research across the various contexts within which it is studied, to offer guidelines for managing these issues, to identify areas in which variation in approaches prohibits decisive recommendations, and to generate questions in need of further consideration among scholars in this field. PMID- 26417392 TI - Nonsuicidal self-injury: a rapidly evolving global field. PMID- 26417393 TI - ExSTraCS 2.0: Description and Evaluation of a Scalable Learning Classifier System. AB - Algorithmic scalability is a major concern for any machine learning strategy in this age of 'big data'. A large number of potentially predictive attributes is emblematic of problems in bioinformatics, genetic epidemiology, and many other fields. Previously, ExS-TraCS was introduced as an extended Michigan-style supervised learning classifier system that combined a set of powerful heuristics to successfully tackle the challenges of classification, prediction, and knowledge discovery in complex, noisy, and heterogeneous problem domains. While Michigan-style learning classifier systems are powerful and flexible learners, they are not considered to be particularly scalable. For the first time, this paper presents a complete description of the ExS-TraCS algorithm and introduces an effective strategy to dramatically improve learning classifier system scalability. ExSTraCS 2.0 addresses scalability with (1) a rule specificity limit, (2) new approaches to expert knowledge guided covering and mutation mechanisms, and (3) the implementation and utilization of the TuRF algorithm for improving the quality of expert knowledge discovery in larger datasets. Performance over a complex spectrum of simulated genetic datasets demonstrated that these new mechanisms dramatically improve nearly every performance metric on datasets with 20 attributes and made it possible for ExSTraCS to reliably scale up to perform on related 200 and 2000-attribute datasets. ExSTraCS 2.0 was also able to reliably solve the 6, 11, 20, 37, 70, and 135 multiplexer problems, and did so in similar or fewer learning iterations than previously reported, with smaller finite training sets, and without using building blocks discovered from simpler multiplexer problems. Furthermore, ExS-TraCS usability was made simpler through the elimination of previously critical run parameters. PMID- 26417394 TI - Effect of ionizing radiation on the physical biology of head and neck squamous cell carcinoma cells. AB - Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer worldwide. Although there are numerous treatment options for HNSCC, such as surgery, cytotoxic chemotherapy, molecularly targeted systemic therapeutics, and radiotherapy, overall survival has not significantly improved in the last 50 years. This suggests a need for a better understanding of how these cancer cells respond to current treatments in order to improve treatment paradigms. Ionizing radiation (IR) promotes cancer cell death through the creation of cytotoxic DNA lesions, including single strand breaks, base damage, crosslinks, and double strand breaks (DSBs). As unrepaired DSBs are the most cytotoxic DNA lesion, defining the downstream cellular responses to DSBs are critical for understanding the mechanisms of tumor cell responses to IR. The effects of experimental IR on HNSCC cells beyond DNA damage in vitro are ill-defined. Here we combined label free, quantitative phase and fluorescent microscopy to define the effects of IR on the dry mass and volume of the HNSCC cell line, UM-SCC-22A. We quantified nuclear and cytoplasmic subcellular density alterations resulting from 8 Gy X-ray IR and correlated these signatures with DNA and gamma-H2AX expression patterns. This study utilizes a synergistic imaging approach to study both biophysical and biochemical alterations in cells following radiation damage and will aid in future understanding of cellular responses to radiation therapy. PMID- 26417395 TI - Studying Process and Proximal Outcomes of Supervision for Motivational Interviewing. PMID- 26417396 TI - Management and Reconstruction in the Breast Cancer Patient With a Fungating T4b Tumor. AB - BACKGROUND: A subset of women with locally advanced breast cancer presented with fungating tumor mass eroding and infiltrating the surrounding breast skin (T4b breast cancers). These patients often have chronic pain, large open wounds, frequent infections, malodorous drainage, social isolation, and general debilitation that present enormous therapeutic challenges. Because of the advanced nature of the disease, palliation, while minimizing recovery time and maximizing quality of life, is essential. METHODS: From 2009 to 2014, a total of 12 consecutive patients underwent resection of fungating T4b breast tumors and subsequent chest wall reconstruction. Demographic, socioeconomic, and clinical data were collected retrospectively. RESULTS: Fifty percent of women had distant metastases at the time of reconstruction, and 17% of women presented to the emergency department in a hemodynamically unstable condition in either hemorrhagic shock or septic shock, necessitating delay of reconstruction for up to 1 week. Mean wound size for reconstruction was 473 cm(2). Reconstructive procedures included split-thickness skin grafting and thoracoepigastric advancement, latissimus dorsi, trapezius, and extended transverse and vertical rectus abdominis flaps. Postoperative survival ranged from 98 to 172 days (mean = 127 days), with 9 patients currently living. Seventy-five percent of patients had improved pain and reduced wound care needs after reconstruction. Postoperative reconstruction-specific complications occurred in 33% of cases, with 1 patient requiring a second operating room visit. CONCLUSIONS: Women with fungating T4b breast cancer tumors often present with metastatic disease and have significant need for pain and wound palliation. The reconstructive techniques performed are reliable, efficacious in palliating pain, and reducing wound care needs and have low complication rates. PMID- 26417397 TI - Establishing the relationship of inhaler satisfaction, treatment adherence, and patient outcomes: a prospective, real-world, cross-sectional survey of US adult asthma patients and physicians. AB - BACKGROUND: Inhaled asthma medications are the mainstay of treatment for chronic asthma. However, nonadherence rates for long-term inhaler therapy among adults are estimated to exceed 50 %. Nonadherence is associated with unfavorable clinical outcomes and diminished quality of life. Research suggests that adherence is associated with patients' satisfaction with their treatment regimen and other factors, such as concomitant allergic rhinitis and tobacco use. METHODS: This prospective, cross-sectional survey of physicians and their patients evaluated the relationship between patient satisfaction with attributes of inhaler devices, treatment adherence, and clinical outcomes. Primary care and specialist physicians completed a physician-reported patient record form for patients with a confirmed asthma diagnosis. Patients for whom a physician reported form was completed were invited to complete a patient-reported form. Both surveys collected information about demographics, symptoms, exacerbation history, treatment, smoking status, comorbidities, type of inhaler device, and treatment adherence. Patients also indicated the degree to which they were satisfied with attributes of their currently prescribed inhaler device(s). Partial least squares path modeling quantified relationships between latent variables and clinical outcomes. RESULTS: A total of 243 patients were included in our analysis and 41 % had poorly controlled asthma. More favorable clinical outcomes were significantly associated with greater patient satisfaction with drug delivery (P = 0.002), higher medication adherence (P = 0.049), no history of tobacco use (P < 0.001), and absence of comorbid allergic rhinitis (P = 0.005). Attributes associated with device satisfaction included patient perceptions of consistency in the amount of drug delivery to the lungs, ease of use, and feedback about the number of remaining doses. CONCLUSIONS: Higher patient satisfaction with their asthma drug delivery inhaler device is a significant predictor of more favorable clinical outcomes while allergic rhinitis and smoking history were negatively associated with optimal control of asthma. These findings provide clinicians with opportunities to improve patients' clinical outcomes by tailoring choice of inhaler device therapy and providing education about the correct way to use the device to ensure optimal outcomes. Patients will likely benefit from medical therapy to manage comorbid allergic rhinitis and smoking cessation interventions. Patients unable to stop smoking may require alternative medical therapies to improve their clinical outcomes. PMID- 26417398 TI - Allergen immunotherapy on the way to product-based evaluation-a WAO statement. AB - Allergen immunotherapy (AIT) is widely used in clinical practice for patients with moderate to severe allergic rhinitis due to inhalant allergens and may be delivered via subcutaneous (SCIT) and sublingual routes (SLIT). However, the quality of evidence for individual AIT products is very heterogeneous, and extensions of overall conclusions ("class effects") on the efficacy and disease modifying effects to all AIT products are unjustified. In contrast, each product needs to be evaluated individually, based on available study results, to justify efficacy and specific claims on sustained and disease modifying effects per allergen and targeted patient group (children vs. adults, allergic rhinitis vs. asthma). WAO intends to support the current development to evidence-based AIT, which ultimately will lead to a more efficacious treatment of allergic patients and the appropriate recognition of AIT. PMID- 26417399 TI - Evaluation of genetic risk scores for prediction of dichotomous outcomes. AB - Substantial uncertainty exists as to whether combining multiple disease associated single nucleotide polymorphisms (SNPs) into a genotype risk score (GRS) can improve the ability to predict the risk of disease in a clinically relevant way. We calculated the ability of a simple count GRS to predict the risk of a dichotomous outcome under both multiplicative and additive models of combined effects. We then compared the results of these simulations with the observed results of published GRS measured within multiple epidemiologic cohorts. If the combined effect of each disease-associated SNP included in a GRS is multiplicative on the risk scale, then a count GRS score should be useful for risk prediction with as few as 10-20 SNPs. Adding additional SNPs to the GRS under this model dramatically improves risk prediction. By contrast, if the combined effect of each SNP included in a GRS is linearly additive on the risk scale, a simple count GRS is unlikely to provide clinically useful risk prediction. Adding additional SNPs to the GRS under this model does not improve risk prediction. The combined effect of SNPs included in several published GRS measured in several well-phenotyped epidemiologic cohort studies appears to be more consistent with a linearly additive effect. A simple count GRS is unlikely to be clinically useful for predicting the risk of a dichotomous outcome. Alternative methods for constructing GRS that attempt to identify and include SNPs that demonstrate multiplicative gene-gene or gene-environment interactive effects are needed. PMID- 26417400 TI - Genetic determinants of uterine fibroid size in the multiethnic NIEHS uterine fibroid study. AB - We conducted a follow-up association study across extended candidate chromosomal regions for uterine leiomyoma (UL), or fibroids, to search for loci influencing the size of UL in 916 premenopausal North American women participants to the NIEHS uterine fibroid study. Proportional odds models with adjustments for confounders were fitted to evaluate the association of a final set of 2,484 single nucleotide polymorphisms (SNPs) with the size of uterine fibroids measured by transabdominal and transvaginal ultrasounds. SNP association with UL size was tested in a case-only design comparing three categories of tumor size (small, medium and large tumors) and in a design that included UL-free controls as the lowest category of a four-level ordinal outcome to account for misclassifications due to small, undetected tumors. In the case-only design, rs2285789 in SORCS2 (sortilin-related VPS10 domain containing receptor 2) was the sole variant that remained significant after correction for multiple testing (Bonferroni-adjusted P=0.037). Several other SNPs, namely those located in MYT1L, TMCC1 and BRCA1, reached promising associations. In the design that included the controls, several genes of potential relevance to UL pathogenesis were associated (Bonferroni unadjusted P < 0.01) with tumor size, particularly LIFR-AS1 (leukemia inhibitory factor receptor alpha-antisense RNA 1), which showed the strongest association (Bonferroni-unadjusted P=0.0006) among the genes with regulated expression in UL. In conclusion, SORCS2, a known GWAS candidate for circulating IGF-I and IGFBP-3, may act through IGF-I signaling to affect the size of fibroids. Through down regulation of LIFR, LIFR-AS1 may mediate the inhibitory action of LIF (leukemia inhibitory factor), a cytokine involved in embryonic uterine development. Replication analyses are needed to substantiate our reported associations of SORCS2 and LIFR-AS1 with the size of fibroids. PMID- 26417401 TI - The SIRT1 promoter polymorphic site rs12778366 increases IL-6 related human mortality in the prospective study "Treviso Longeva (TRELONG)". AB - Studies on sirtuins (SIRT), a family of proteins with deacetylase activity, have provided convergent evidence of the key role of these enzymes in aging-linked physiological functions. The link between SIRT1 and longevity has emerged in model organism but few data are available in humans, in particular relying on longitudinal studies. Here, we assessed whether a genetic variant within SIRT1 gene promoter (rs12778366) was associated to human longevity. We analyzed 586 genomic DNA (gDNA) collected in the study "Treviso Longeva" (TRELONG), including elderly over 70 years of age from the municipality of Treviso, a town in the Northeast of Italy, with a 11-year follow-up. We genotyped SIRT1 rs12778366 by real-time polymerase chain reaction (RT-PCR) allelic discrimination assay. A cross-sectional analysis performed by comparing people over and under 85 years of age did not evidence association between rs12778366 and longevity. When we performed a longitudinal analysis considering mortality as dependent variable, we did not observe an association of rs12778366 with longevity in the whole population (corrected P-value = 0.33). However, when we stratified the TRELONG subjects according to circulating level of interleukin-6 (IL-6), a predictor of disability and mortality, we found that rs12778366 (TC+CC) carriers were at increased risk of mortality in comparison to the TT reference group (corrected P value = 0.03, HR 1.47). Our data do not support a major role of rs12778366 in human longevity, but the stratified analysis on IL-6 suggests that this variant may be involved in the detrimental effect of high circulating IL-6 in the elderly. PMID- 26417402 TI - Evaluations of life style factors and the severity of Gastroesophageal reflux disease; a case-control study. AB - The incidence of Gastroesophageal reflux disease (GERD) has increased remarkably worldwide. This study focuses on the background features of these patients and evaluates the two GERD sub types; none erosive (NERD) and erosive (ERD). In a case-control study, patients with reflux symptoms who had obtained a total score of 8-18 of the GERD questionnaire were included. Control group consisted of their families with lower scores and no reflux presentations. All demographic features were recorded. Then upper GI endoscopy performed and the cases divided into two sub groups: NERD and ERD. In the next step, all demographic data analyzed for these two subgroups. The data were analyzed using the SPSS software version 21. A number of 210 subjects included in each group (210 patients with GERD and 210 control group) with normal statistical distribution of age and gender. There was a significant relationship between GERD and BMI (P=0.001), eating fatty foods (P=0.0001), lying after meal (P=0.0001), drinking beverages with meal (0.0001), eating spicy food (0.006) and NSAIDs use (P=0.0001). Then the cases divided into two subgroups; NERD (n=146) and ERD (n=64). There were a significant relationship with eating salty-smoky food (P=0.005) and eating spicy food (P=0.011). The difference of BMI between NERD and ERD was remarkable but was not statistically significant. Our results showed that obesity is an important risk factor for GERD. Other possible risk factors such as NSAIDs use and certain foods and wrong habits like lying after meal should be addressed in future longitudinal surveys. PMID- 26417403 TI - Genetic variants in hypothalamic-pituitary-adrenal axis genes and breast cancer risk in Caucasians and African Americans. AB - Elevated circulating levels of the adrenal androgen dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are associated with increased breast cancer risk in prospective studies. Genetic variants in hypothalamic-pituitary-adrenal (HPA) axis genes may contribute to these circulating hormone levels, and consequently to breast cancer risk. No previous studies have examined the effects of genetic variants in HPA axis genes on breast cancer risk. We evaluated the associations of 49 single nucleotide polymorphisms (SNPs) in five HPA axis genes (NR3C1, NR3C2, CRH, CRHR1, and CRHBP) with the risk of breast cancer in the Women's Insights and Shared Experiences (WISE) Study of Caucasians (346 cases and 442 controls), as well as African Americans (149 cases and 246 controls). Of the 49 SNPs evaluated, one showed a nominal significant association (P for trend < 0.05) with breast cancer risk among Caucasians, and another two among African Americans. The age-adjusted additive odds ratio (OR) (95% confidence interval (95% CI)) of the SNP rs11747190[A] in the CRHBP gene for the risk of breast cancer among Caucasian women was 1.45 (1.09-1.94). The age-adjusted additive ORs (95% CIs) of two SNPs (CRHBP rs1700688[T] and CRHR1 rs17689471[C]) for the risk of breast cancer among African American women were 1.84 (1.13-2.98) and 2.48 (1.20-5.13), respectively. However, these SNPs did not show significant associations after correction for multiple testing. Our findings do not provide strong supportive evidence for the contribution of genetic variants in these HPA axis genes to the risk of developing breast cancer in either Caucasians or African Americans. PMID- 26417404 TI - Brief communication genotyping of Burkholderia pseudomallei revealed high genetic variability among isolates from a single population group. AB - Burkholderia pseudomallei is a soil dwelling Gram-negative bacteria predominates in Southeast Asia zone and the tropical part of Australia. Genetic diversity has been explored among various populations and environments worldwide. To date, little data is available on MLST profiling of clinical B. pseudomallei isolates in peninsular Malaysia. In this brief report, thirteen culture positive B. pseudomallei cases collected from a single population of Terengganu state in the Western Peninsular Malaysia and were confirmed by In-house TTS1-PCR. Isolates were subjected for multi-locus sequence typing (MLST) to explore their genotypic diversity and to investigate for possible clonal clustering of a certain sequence type. Patient's clinical information was examined to investigate for clinical correlation among the different genotypes. In spite of small sample set, MLST results indicated predictive results; considerable genotypic diversity, predominance and novelty among B. pseudomallei collected over a single geographically-located population in Malaysia. Massive genotypic heterogeneity was observed; 8 different sequence types with predominance of sequence type 54 and discovery of two novel sequence types. However, no clear pathogenomic or organ tropism clonal relationships were predicted. PMID- 26417405 TI - Targeting inflammation in type 2 diabetes by antibody-mediated Tyro-3, Axl, Mer receptor activation. PMID- 26417406 TI - Incretin physiology and pathophysiology from an Asian perspective. AB - Incretin hormones, such as glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, are secreted on oral nutrient ingestion and regulate postprandial glucose homeostasis by conveying the signal of intestinal glucose flux. In East Asians, the secretion of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 is not reduced in type 2 diabetes relative to normal glucose tolerance. Although the incretin effect is blunted in European patients with type 2 diabetes, a few East Asian studies showed no difference in the incretin effect between type 2 diabetes and normal glucose tolerance. Interestingly, the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors or glucagon-like peptide-1 receptor agonists was reported to be greater in Asians than in non-Asians. The difference in the treatment responses could be ascribed to a different pathophysiology of type 2 diabetes (lower insulin secretory function and less insulin resistance), lower body mass index, different genetic makeups, preserved incretin effect and different food compositions in East Asians compared with other ethnic groups. Based on the currently available data, incretin-based therapies appear to be safe and well tolerated in East Asians. Nevertheless, continuous pharmacovigilance is required. The characteristics of incretin biology and treatment responses to incretin-based therapies should be considered in developing ethnicity-specific treatment guidelines and making patient-centered decisions for patients with type 2 diabetes. PMID- 26417407 TI - Clinical characteristics of metabolic syndrome in Korea, and its comparison with other Asian countries. AB - Metabolic syndrome is referred to as syndrome X or insulin resistance syndrome, and is primarily composed of abdominal obesity, diabetes, glucose intolerance, dyslipidemia and high blood pressure. Asians have a lower frequency of obesity than Caucasians, but have an increasing tendency toward metabolic syndrome. Thus, metabolic syndrome poses a major challenge for public health professionals, and is set to become a social and economic problem in Asian populations. Most data on metabolic syndrome are based on studies from Western countries with only limited information derived from Asian populations. Recently, several studies were carried out on a large scale that represents the general Korean population. The prevalence of metabolic syndrome in Korean adults has varied depending on the study designs and different criteria, but shows a distinct increasing trend of metabolic syndrome driven by an increase in abdominal obesity and dyslipidemia. Given the rapid economic progression of Korea over the past 30 years along with a rise of the aged population, it is expected that the prevalence of metabolic syndrome will further increase. Therefore, a proactive strategy at the governmental level for metabolic syndrome prevention should be implemented, reducing abdominal obesity and dyslipidemia. Healthy dietary habits and regular exercise should be emphasized as a part of such a strategy. PMID- 26417408 TI - Fructose induces glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 and insulin secretion: Role of adenosine triphosphate-sensitive K(+) channels. AB - Adenosine triphosphate-sensitive K(+) (KATP) channels play an essential role in glucose-induced insulin secretion from pancreatic beta-cells. It was recently reported that the KATP channel is also found in the enteroendocrine K-cells and L cells that secrete glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), respectively. In the present study, we investigated the involvement of the KATP channel in fructose-induced GIP, GLP-1 and insulin secretion in mice. Fructose stimulated GIP secretion, but pretreatment with diazoxide, a KATP channel activator, did not affect fructose induced GIP secretion under streptozotocin-induced hyperglycemic conditions. Fructose significantly stimulated insulin secretion in Kir6.2 (+/+) mice, but not in mice lacking KATP channels (Kir6.2 (-/-) ), and fructose stimulated GLP-1 secretion in both Kir6.2 (+/+) mice and Kir6.2 (-/-) mice under the normoglycemic condition. In addition, diazoxide completely blocked fructose-induced insulin secretion in Kir6.2 (+/+) mice and in MIN6-K8 beta-cells. These results show that fructose-induced GIP and GLP-1 secretion is KATP channel-independent and that fructose-induced insulin secretion is KATP channel-dependent. PMID- 26417409 TI - Regardless of central obesity, metabolic syndrome is a significant predictor of type 2 diabetes in Japanese Americans. AB - AIMS/INTRODUCTION: The impact of metabolic syndrome (MetS) on the development of type 2 diabetes has been reported in different ethnic populations. However, whether central obesity is an essential component as a diagnostic criterion for MetS remains a controversial topic. The aim of the present study was to investigate the association between MetS and the incidence of type 2 diabetes with or without central obesity in a Japanese American population. MATERIALS AND METHODS: We examined whether MetS predicts incident type 2 diabetes among 928 Japanese American participants who did not have diabetes enrolled in an ongoing medical survey between 1992 and 2007. MetS was defined on the basis of American Heart Association/National Heart, Lung, and Blood Institute criteria. The average follow-up period was approximately 6.8 years. RESULTS: During the follow-up period, 116 new cases of diabetes were diagnosed. Compared to the participants without MetS, the hazard ratio (HR) for incident type 2 diabetes was significantly higher in participants with MetS, after adjustment for sex, age and impaired glucose tolerance (HR 1.64, 95% CI 1.11-2.42). The risk of type 2 diabetes was found to be significantly higher in participants with MetS but without central obesity (HR 2.07, 95% CI 1.25-3.41), as well as in participants with MetS and with central obesity (HR 2.46, 95% CI 1.51-4.01) than in participants with neither MetS nor central obesity, after adjustment for sex, age and impaired glucose tolerance. CONCLUSIONS: These results show that the presence of MetS, with or without central obesity, could independently predict the development of type 2 diabetes in Japanese Americans. PMID- 26417410 TI - Impact of population aging on trends in diabetes prevalence: A meta-regression analysis of 160,000 Japanese adults. AB - AIMS/INTRODUCTION: To provide age- and sex-specific trends, age-standardized trends, and projections of diabetes prevalence through the year 2030 in the Japanese adult population. MATERIALS AND METHODS: In the present meta-regression analysis, we included 161,087 adults from six studies and nine national health surveys carried out between 1988 and 2011 in Japan. We assessed the prevalence of diabetes using a recorded history of diabetes or, for the population of individuals without known diabetes, either a glycated hemoglobin level of >=6.5% (48 mmol/mol) or the 1999 World Health Organization criteria (i.e., a fasting plasma glucose level of >=126 mg/dL and/or 2-h glucose level of >=200 mg/dL in the 75-g oral glucose tolerance test). RESULTS: For both sexes, prevalence appeared to remain unchanged over the years in all age categories except for men aged 70 years or older, in whom a significant increase in prevalence with time was observed. Age-standardized diabetes prevalence estimates based on the Japanese population of the corresponding year showed marked increasing trends: diabetes prevalence was 6.1% among women (95% confidence interval [CI] 5.5-6.7), 9.9% (95% CI 9.2-10.6) among men, and 7.9% (95% CI 7.5-8.4) among the total population in 2010, and was expected to rise by 2030 to 6.7% (95% CI 5.2-9.2), 13.1% (95% CI 10.9-16.7) and 9.8% (95% CI 8.5-12.0), respectively. In contrast, the age-standardized diabetes prevalence using a fixed population appeared to remain unchanged. CONCLUSIONS: This large-scale meta-regression analysis shows that a substantial increase in diabetes prevalence is expected in Japan during the next few decades, mainly as a result of the aging of the adult population. PMID- 26417411 TI - Establishment of maturity-onset diabetes of the young-induced pluripotent stem cells from a Japanese patient. AB - Maturity-onset diabetes of the young (MODY) is a heterozygous monogenic diabetes; more than 13 disease genes have been identified. However, the pathogenesis of MODY is not fully understood, because the pancreatic beta-cells of the patients are inaccessable. Therefore, we attempted to establish MODY patient-derived induced pluripotent stem cells (MODY-iPS) cells to investigate the pathogenic mechanism of MODY by inducing pancreatic beta-cells. We established MODY5-iPS cells from a Japanese patient with MODY5 (R177X), and confirmed that MODY5-iPS cells possessed the characteristics of pluripotent stem cells. In the course of differentiation from MODY5-iPS cells into pancreatic beta-cells, we examined the disease gene, HNF1B messenger ribonucleic acid. We found that the amount of R177X mutant transcripts was much less than that of wild ones, but they increased after adding cycloheximide to the medium. These results suggest that these R177X mutant messenger ribonucleic acids are disrupted by nonsense-mediated messenger ribonucleic acid decay in MODY-iPS cells during the developmental stages of pancreatic beta-cells. PMID- 26417413 TI - Extent of weight reduction necessary for minimization of diabetes risk in Japanese men with visceral fat accumulation and glycated hemoglobin of 5.6-6.4. AB - AIMS/INTRODUCTION: Weight reduction improves glycemic control in obese men with glycated hemoglobin (HbA1c) of 5.6-6.4%, suggesting that it can prevent the development of diabetes in these patients. The aim of the present study was to quantify the amount of weight reduction necessary for minimization of diabetes risk in Japanese men with visceral fat accumulation. MATERIALS AND METHODS: The study participants were 482 men with an estimated visceral fat area of >=100 cm(2), HbA1c of 5.6-6.4%, fasting plasma glucose (FPG) of <126 mg/dL or casual plasma glucose <200 mg/dL. They were divided into two groups based on weight change at the end of the 3-year follow-up period (weight gain and weight loss groups). The weight loss group was classified into quartile subgroups (lowest group, 0 to <1.2%: second lowest group, >=1.2 to <2.5%: second highest group, >=2.5 to <4.3%: highest group, >=4.3% weight loss). The development of diabetes at the end-point represented a rise in HbA1c to >=6.5% or FPG >=126 mg/dL, or casual plasma glucose >=200 mg/dL. RESULTS: The cumulative incidence of diabetes at the end of the 3-year follow-up period was 16.2% in the weight gain group and 10.1% in the weight loss group (P not significant). The incidence of diabetes was significantly lower in the highest weight loss group (3.1%), but not in the second highest, the second lowest and the lowest weight loss groups (9.7, 10.1 and 18.3%), compared with the weight gain group. CONCLUSIONS: Minimization of the risk of diabetes in Japanese men with visceral fat accumulation requires a minimum of 4-5% weight loss in those with HbA1c of 5.6-6.4%. PMID- 26417412 TI - Correlation of serum testosterone with insulin resistance in elderly male type 2 diabetes mellitus patients with osteoporosis. AB - AIMS/INTRODUCTION: The present study was designed to investigate the correlations between the serum testosterone level and insulin sensitivity in elderly male type 2 diabetes patients with osteoporosis. MATERIALS AND METHODS: A total of 35 elderly male patients with type 2 diabetes (type 2 diabetes group), 30 elderly male type 2 diabetes patients combined with osteoporosis (DO group) and 30 healthy elderly men (normal control group) participated in the present study. The fasting plasma glucose, fasting insulin, testosterone (T) and estradiol (E2) were measured. The insulin sensitivity index (ISI), homeostasis model assessment of insulin resistance (HOMA-IR) and E2/T were calculated. Then, the correlations of serum testosterone level with ISI and HOMA-IR were analyzed by statistical methods. RESULTS: The HOMA-IR, E2 and E2/T of the type 2 diabetes group and DO group were significantly increased, whereas the bone mineral density, ISI, T and sex hormone binding globulin were decreased compared with those of the normal control group. Serum testosterone levels of the type 2 diabetes group and DO group were negatively correlated to the HOMA-IR (r = -0.496, -0.506; P < 0.05), whereas they were positively correlated to the fasting insulin (r = 0.281, 0.292; P < 0.05) and ISI (r = 0.364, 0.403; P < 0.05). CONCLUSIONS: The reduced level of serum testosterone in elderly male type 2 diabetes patients with osteoporosis might promote insulin resistance. PMID- 26417414 TI - Comparison of sitagliptin with nateglinide on postprandial glucose and related hormones in drug-naive Japanese patients with type 2 diabetes mellitus: A pilot study. AB - AIMS/INTRODUCTION: Dipeptidyl peptidase-4 inhibitors and glinides are effective in reducing postprandial hyperglycemia. However, little information is available on the comparative effects of the two drugs on the levels of postprandial glucose. The aim of the present study was to compare the effects of sitagliptin and nateglinide on meal tolerance tests in drug-naive patients with type 2 diabetes mellitus. MATERIALS AND METHODS: The study participants were 19 patients with type 2 diabetes mellitus, which was inadequately controlled by diet and exercise. An open-label, prospective, cross-over trial was carried out to compare the effects of single-dose sitagliptin and nateglinide on the postprandial glucose level and its related hormones during meal tests. RESULTS: The change in area under the curve (AUC) of glucose from 0 to 180 min (AUC0-180 min) during the meal test by nateglinide was similar to that by sitagliptin. As expected, the change in active glucagon like peptide-1 was significantly higher after a single dose of sitagliptin than nateglinide. Then, insulin secretion relative to glucose elevation (ISG) (DeltaISG0-180 min: DeltaAUC0-180 min insulin/AUC0-180 min glucose) was significantly enhanced by nateglinide compared with sitagliptin. Conversely, glucagon level (DeltaAUC0-180 min glucagon) was increased by administration of nateglinide, whereas the glucagon level was reduced by administration of sitagliptin. CONCLUSIONS: The effects of sitagliptin on postprandial glucose levels were similar to those of nateglinide in drug-naive type 2 diabetes patients. However, the induced changes in insulin, active glucagon-like peptide-1 and glucagon during meal loading suggest that reduction of postprandial hyperglycemia was achieved by the unique effect of each drug. PMID- 26417415 TI - Fear of hypoglycemia and its determinants in insulin-treated patients with type 2 diabetes mellitus. AB - The aim of the present study was to investigate the prevalence of fear of hypoglycemia, in association with severe hypoglycemia and social factors, in insulin-treated patients with type 2 diabetes mellitus. A questionnaire survey on hypoglycemia and patient-physician communication was carried out in 355 patients with insulin-treated type 2 diabetes mellitus patients at 16 hospitals and clinics. A fear of hypoglycemia was reported by 27.7% of patients. A stepwise logistic regression analysis found that severe hypoglycemia during the past 1 year was a significant determinant of fear of hypoglycemia (odds ratio 2.16, 95% confidence interval 1.06-4.41; P = 0.034), and age (odds ratio 1.02, 95% confidence interval 1.00-1.05, P = 0.038) and living alone (odds ratio 1.93, 95% confidence interval 1.00-3.73, P < 0.05) were significantly higher in patients with fear of hypoglycemia than in those without it. PMID- 26417416 TI - Irisin levels are associated with urotensin II levels in diabetic patients. AB - AIMS/INTRODUCTION: Irisin is a newly identified myokine that can promote energy expenditure. Previous studies showed that circulating urotensin II (UII) levels were increased in diabetes, and UII could inhibit the glucose transport in skeletal muscle in diabetic mice and aggravated insulin resistance. We presumed that irisin levels are associated with UII in diabetic patients. MATERIALS AND METHODS: A total of 71 patients with type 2 diabetes and 40 healthy subjects were recruited. Blood and urinary irisin concentrations were measured by using enzyme linked immunosorbent assay, and UII concentrations were measured by bioelectrical impedance analysis. Every participant's body composition was analyzed by bioelectrical impedance. RESULTS: The serum irisin levels were significantly lower in diabetic patients than that of controls, whereas serum UII levels were significantly higher in diabetic patients than that in that of controls. Serum irisin levels were negatively associated with circulating UII, hemoglobin A1c and the natural logarithm transformation of urinary albumin excretion, whereas serum irisin was positively associated with estimated glomerular filtration rate, and low-density lipoprotein cholesterol and urinary irisin were positively associated with urinary UII. Furthermore, circulating irisin is positively associated with muscle mass, whereas circulating UII is negatively associated with muscle mass in diabetic patients. Hemoglobin A1c and circulating UII are independent determinants of circulating irisin by multiple regression analysis. CONCLUSIONS: The present results provide the clinical evidence of an association between irisin and UII in diabetic patients. Hemoglobin A1c and circulating UII are independent determinants of circulating irisin. Our results hint that UII and high glucose might inhibit the release of irisin from skeletal muscle in diabetic patients. PMID- 26417417 TI - Impacts of the Great East Japan Earthquake on diabetic patients. AB - AIMS/INTRODUCTION: We investigated impacts of the Great East Japan Earthquake on diabetic patients and characterized those with disaster-susceptible diabetes. MATERIALS AND METHODS: We enrolled 497 diabetic patients who had been followed at hospitals in devastated areas. We collected metabolic parameters prospectively, 1 and 3 months after the earthquake, and retrospectively for pre-earthquake time points. Questionnaire surveys were carried out regarding earthquake-related damage and post-earthquake lifestyle alterations. Available data were analyzed to examine associations with post-earthquake glycosylated hemoglobin alterations. RESULTS: The mean glycosylated hemoglobin level of the participants was not elevated at 1 month, and was significantly decreased at 3 months as compared with the pre-earthquake glycosylated hemoglobin. There were no significant differences in earthquake-related damage or lifestyle alterations between the improved and worsened glycemic control groups according to the data obtained from the questionnaire survey. As reported, fasting serum C-peptide levels were significantly lower in the worsened glycemic control group (P < 0.05). Notably, plasma noradrenaline levels were significantly higher in the worsened glycemic control group (P < 0.05). Furthermore, at 1 month after the earthquake, the plasma noradrenaline level was significantly higher in the low C-peptide group (fasting serum C-peptide <1.0 ng/mL) than in the high C-peptide group (fasting serum C-peptide >=1.0 ng/mL), but this difference had disappeared by 3 months after the earthquake. These findings show that post-earthquake plasma noradrenaline levels were temporarily increased in the low C-peptide group. CONCLUSIONS: Sympathetic nerve activation might be elicited more easily in subjects with lower endogenous insulin secretory capacity, and could be involved in the mechanism underlying post-earthquake worsening of glycemic control. PMID- 26417418 TI - Case of ketoacidosis by a sodium-glucose cotransporter 2 inhibitor in a diabetic patient with a low-carbohydrate diet. AB - We present a case of a 32-year-old diabetic woman with Prader-Willi syndrome who developed severe ketoacidosis caused by a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a novel class of antihyperglycemic agents, during a strict low carbohydrate diet. At admission, a serum glucose level of 191 mg/dL was relatively low, though laboratory evaluations showed severe ketoacidosis. This is the first report of ketoacidosis caused by a SGLT2 inhibitor. It is necessary to not only pay attention when using a SGLT2 inhibitor in patients following a low carbohydrate diet, but also to start a low-carbohydrate diet in patients treated with a SGLT2 inhibitor because of a high risk for developing ketoacidosis. PMID- 26417419 TI - Protamine-containing insulin allergy and renal dysfunction in a patient with type 2 diabetes. AB - An 87-year-old woman with type 2 diabetes noticed a red itchy rash at the insulin injection sites 3 weeks after initiation of premixed insulin therapy. Laboratory data at that time showed marked eosinophilia and progression of renal dysfunction. Insulin treatment was discontinued, and antidiabetic oral drugs were used, as well as intravenous injection of dexamethasone. Her skin lesions disappeared, and both eosinophilia and renal dysfunction gradually improved. The results of skin prick tests and measurement of specific immunoglobulin E antibodies suggested that the insulin allergy was caused by protamine. Although cases of insulin allergy associated with renal dysfunction are rare, we must be aware, especially for elderly patients with poor renal function in the first application of insulin. PMID- 26417420 TI - Homeodomain interacting protein kinase 2 is downregulated through the peroxisome proliferator-activated receptor gamma signaling pathway in an insulin-resistant population. PMID- 26417421 TI - CHEMICAL SELECTIVITY OF NUCLEOBASE ADDUCTION RELATIVE TO IN VIVO MUTATION SITES ON EXON 7 FRAGMENT OF P53 TUMOR SUPPRESSOR GENE. AB - Damage to p53 tumor suppressor gene is found in half of all human cancers. Databases integrating studies of large numbers of tumors and cancer cell cultures show that mutation sites of specific p53 codons are correlated with specific types of cancers. If the most frequently damaged p53 codons in vivo correlate with the most frequent chemical damage sites in vitro, predictions of organ specific cancer risks might result. Herein, we describe LC-MS/MS methodology to reveal codons with metabolite-adducted nucleobases by LC-MS/MS for oligonucleotides longer than 20 base pairs. Specifically, we used a known carcinogen, benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) to determine the most frequently adducted nucleobases within codons. We used a known sequence of 32 base pairs (bp) representing part of p53 exon 7 with 5 possible reactive hot spots. This is the first nucleobase reactivity study of a double stranded DNA p53 fragment featuring more than 20 base pairs with multiple reactive sites. We reacted the 32 bp fragment with benzo[a]pyrene metabolite BPDE that undergoes nucleophilic substitution by DNA bases. Liquid chromatography-mass spectrometry (LC-MS/MS) was used for sequencing of oligonucleotide products from the reacted 32 bp fragment after fragmentation by a restriction endonuclease. Analysis of the adducted p53 fragment compared with unreacted fragment revealed guanines of codons 248 and 244 as most frequently targeted, which are also mutated with high frequency in human tumors. Codon 248 is mutated in non-small cell and small cell lung, head and neck, colorectal and skin cancer, while codon 244 is mutated in small cell lung cancer, all of which involve possible BDPE exposure. Results suggest the utility of this approach for screening of adducted p53 gene by drugs and environmental chemicals to predict risks for organ specific cancers. PMID- 26417422 TI - Efficient Chemoenzymatic Synthesis of an N-glycan Isomer Library. AB - Quantification, characterization and biofunctional studies of N-glycans on proteins remain challenging tasks due to complexity, diversity and low abundance of these glycans. The availability of structurally defined N-glycans (especially isomers) libraries is essential to help on solving these tasks. We reported herein an efficient chemoenzymatic strategy, namely Core Synthesis/Enzymatic Extension (CSEE), for rapid production of diverse N-glycans. Starting with 5 chemically prepared building blocks, 8 N-glycan core structures containing one or two terminal N-acetyl-D-glucosamine (GlcNAc) residue(s) were chemically synthesized via consistent use of oligosaccharyl thioethers as glycosylation donors in the convergent fragment coupling strategy. Each of these core structures was then extended to 5 to 15 N-glycan sequences by enzymatic reactions catalyzed by 4 robust glycosyltransferases. Success in synthesizing N-glycans with Neu5Gc and core-fucosylation further expanded the ability of enzymatic extension. High performance liquid chromatography with an amide column enabled rapid and efficient purification (>98% purity) of N-glycans in milligram scales. A total of 73 N-glycans (63 isomers) were successfully prepared and characterized by MS2 and NMR. The CSEE strategy provides a practical approach for "mass production" of structurally defined N-glycans, which are important standards and probes for Glycoscience. PMID- 26417423 TI - Protonation state of the Cu4S2 CuZ site in nitrous oxide reductase: redox dependence and insight into reactivity. AB - Spectroscopic and computational methods have been used to determine the protonation state of the edge sulfur ligand in the Cu4S2 CuZ form of the active site of nitrous oxide reductase (N2OR) in its 3CuICuII (1-hole) and 2CuI2CuII (2 hole) redox states. The EPR, absorption, and MCD spectra of 1-hole CuZ indicate that the unpaired spin in this site is evenly delocalized over CuI, CuII, and CuIV. 1-hole CuZ is shown to have a MU2-thiolate edge ligand from the observation of S-H bending modes in the resonance Raman spectrum at 450 and 492 cm-1 that have significant deuterium isotope shifts (-137 cm-1) and are not perturbed up to pH 10. 2-hole CuZ is characterized with absorption and resonance Raman spectroscopies as having two Cu-S stretching vibrations that profile differently. DFT models of the 1-hole and 2-hole CuZ sites are correlated to these spectroscopic features to determine that 2-hole CuZ has a MU2-sulfide edge ligand at neutral pH. The slow two electron (+1 proton) reduction of N2O by 1-hole CuZ is discussed and the possibility of a reaction between 2-hole CuZ and O2 is considered. PMID- 26417424 TI - MM Quadruply Bonded Complexes Supported by Vinylbenzoate Ligands: Synthesis, Characterization, Photophysical Properties and Application as Synthons. AB - From the reactions between M2(T i PB)4 compounds and meta and para - vinylbenzoic acids (2 equiv) in toluene at room temperature the compounds trans-M2(T i PB)2L2, where L = m-vinylbenzoate 1A (M = Mo) and 1B (M = W) and T i PB = 2,4,6 triisopropylbenzoate, and where L = p-vinylbenzoate 2A (M = Mo) and 2B (M = W) have been isolated. Compounds 1A and 2A have been shown to undergo Heck carbon carbon coupling reactions with phenyliodide to produce trans-Mo2(T i PB)2(O2CC6H4 m-CH=CH-C6H5)2,3A and trans-Mo2(T i PB)2(O2CC6H4-p-CH=CH-C6H5)2, 4A. The molybdenum compounds 1A and 2A have been structurally characterized by single crystal X-ray crystallography. All the new compounds have been characterized by 1H NMR, IR, UV-Visible absorption and emission spectroscopy, high resolution MALDITOF MS, fs- and ns- transient absorption spectroscopy and fs- time-resolved IR spectroscopy. Electronic structure calculations employing density functional theory, DFT, and time-dependent DFT have been employed to aid in the interpretation of spectral data. All compounds show intense absorptions in the visible region corresponding to M2delta to Lpi* charge transfer transitions. The lifetimes of the 1MLCT state fall in the range of 1 - 10 ps and for the molybdenum complexes the T1 states are 3deltadelta* with lifetimes ~50 MUs while for the tungsten complexes the T1 are 3 MLCT with lifetimes in the range of 3 - 10 ns. PMID- 26417425 TI - Graphene-DNAzyme Junctions: A Platform for Direct Metal Ion Detection with Ultrahigh Sensitivity. AB - Many metal ions are present in biology and in the human body in trace amounts. Despite numerous efforts, metal sensors with ultrahigh sensitivity (< a few picomolar) are rarely achieved. Here, we describe a platform method that integrates a Cu2+-dependent DNAzyme into graphene-molecule junctions and its application for direct detection of paramagnetic Cu2+ with femtomolar sensitivity and high selectivity. Since DNAzymes specific for other metal ions can be obtained through in vitro selection, the method demonstrated here can be applied to the detection of a broad range of other metal ions. PMID- 26417426 TI - Magnetic circular dichroism and computational study of mononuclear and dinuclear iron(IV) complexes. AB - High-valent iron(IV)-oxo species are key intermediates in the catalytic cycles of a range of O2-activating iron enzymes. This work presents a detailed study of the electronic structures of mononuclear ([FeIV(O)(L)(NCMe)]2+, 1, L = tris(3,5 dimethyl-4-methoxylpyridyl-2-methyl)amine) and dinuclear ([(L)FeIV(O)(MU O)FeIV(OH)(L)]3+, 2) iron(IV) complexes using absorption (ABS), magnetic circular dichroism (MCD) spectroscopy and wave-function-based quantum chemical calculations. For complex 1, the experimental MCD spectra at 2-10 K are dominated by a broad positive C-term band between 12000 and 18000 cm-1. As the temperature increases up to ~20 K, this feature is gradually replaced by a derivative-shaped signal. The computed MCD spectra are in excellent agreement with experiment, which reproduce not only the excitation energies and the MCD signs of key transitions but also their temperature-dependent intensity variations. To further corroborate the assignments suggested by the calculations, the individual MCD sign for each transition is independently determined from the corresponding electron donating and accepting orbitals. Thus, unambiguous assignments can be made for the observed transitions in 1. The ABS/MCD data of complex 2 exhibit ten features that are assigned as ligand-field transitions or oxo- or hydroxo-to metal charge transfer bands, based on MCD/ABS intensity ratios, calculated excitation energies, polarizations, and MCD signs. In comparison with complex 1, the electronic structure of the FeIV=O site is not significantly perturbed by the binding to another iron(IV) center. This may explain the experimental finding that complexes 1 and 2 have similar reactivities toward C-H bond activation and O atom transfer. PMID- 26417427 TI - Significant Improvement of Oxidase Activity through the Genetic Incorporation of a Redox-active Unnatural Amino Acid. AB - While nature employs various covalent and non-covalent strategies to modulate tyrosine (Y) redox potential and pKa to optimize enzyme activities, such approaches have not been systematically applied for the design of functional metalloproteins. Through the genetic incorporation of 3-methoxytyrosine (OMeY) into myoglobin, we recapitulated important features of cytochrome c oxidase (CcO) into this small soluble protein, which exhibits selective O2 reduction activity while generating small amount of reactive oxygen species (ROS). These results demonstrate that the electron donating ability of a tyrosine residue in the active site is important for CcO function. Moreover, we elucidated the structural basis for the genetic incorporation of OMeY into proteins, by solving the X-ray structure of OMeY specific aminoacyl-tRNA synthetase in complex with OMeY. PMID- 26417428 TI - Unified Approach to Prenylated Indole Alkaloids: Total Syntheses of (-)-17 Hydroxy-Citrinalin B, (+)-Stephacidin A, and (+)-Notoamide I. AB - A unified strategy for the synthesis of congeners of the prenylated indole alkaloids is presented. This strategy has yielded the first synthesis of the natural product (-)-17-hydroxy-citrinalin B as well as syntheses of (+) stephacidin A and (+)-notoamide I. An enolate addition to an in situ generated isocyanate was utilized in forging a key bicyclo[2.2.2]diazaoctane moiety, and in this way connected the two structural classes of the prenylated indole alkaloids through synthesis. PMID- 26417429 TI - Evolution and development of the adelphophagic, intracapsular Schmidt's larva of the nemertean Lineus ruber. AB - BACKGROUND: The life cycle of many animals includes a larval stage, which has diversified into an astonishing variety of ecological strategies. The Nemertea is a group of spiralians that exhibits a broad diversity of larval forms, including the iconic pilidium. A pelagic planktotrophic pilidium is the ancestral form in the Pilidiophora, but several lineages exhibit deviations of this condition, mostly as a transition to pelagic lecithotrophy. The most extreme case occurs, however, in the Pilidiophoran Lineus ruber, which exhibits an adelphophagic intracapsular pilidium, the so-called Schmidt's larva. RESULTS: We combined confocal laser scanning microscopy and gene expression studies to characterize the development and metamorphosis of the Schmidt's larva of L. ruber. The larva forms after gastrulation, and comprises a thin epidermis, a proboscis rudiment and two pairs of imaginal discs from which the juvenile will develop. The cells internalized during gastrulation form a blind gut and the blastopore gives rise to the mouth of the larva and juvenile. The Schmidt's larva eats other siblings that occupy the same egg capsule, accumulating nutrients for the juvenile. A gradual metamorphosis involves the differentiation of the juvenile cell types from the imaginal discs and the shedding of the larval epidermis. The expression of evolutionarily conserved anterior (foxQ2, six3/6, gsc, otx), endomesodermal (foxA, GATA456-a, twi-a) and posterior (evx, cdx) markers demonstrate that the juvenile retains the molecular patterning of the Schmidt's larva. After metamorphosis, the juveniles stay over 20 days within the egg masses, until they are fully mature and hatch. CONCLUSIONS: The evolution of the intracapsular Schmidt's larva involved the loss of the typical feeding structures of the planktotrophic pilidium and a precocious formation of the imaginal discs, as also observed in other pelagic lecithotrophic forms. However, no special adaptations are observed related to adelphophagy. As in planktotrophic pilidium, the molecular mechanism patterning the juvenile is only active in the imaginal discs and not during the early development of the larva, suggesting two separate molecular programs during nemertean embryogenesis. Our results illuminate the diversification of larval forms in the Pilidiophora and Nemertea, and thus on the developmental mechanisms underlying metazoan larval evolution. PMID- 26417430 TI - Skeletal muscle interleukin 15 promotes CD8(+) T-cell function and autoimmune myositis. AB - BACKGROUND: Interleukin 15 (IL-15) is thought to be abundant in the skeletal muscle under steady state conditions based on RNA expression; however, the IL-15 RNA level may not reflect the protein level due to post-transcriptional regulation. Although exogenous protein treatment and overexpression studies indicated IL-15 functions in the skeletal muscle, how the skeletal muscle cell uses IL-15 remains unclear. In myositis patients, IL-15 protein is up-regulated in the skeletal muscle. Given the supporting role of IL-15 in CD8(+) T-cell survival and activation and the pathogenic role of cytotoxic CD8(+) T cells in polymyositis and inclusion-body myositis, we hypothesize that IL-15 produced by the inflamed skeletal muscle promotes myositis via CD8(+) T cells. METHODS: Expression of IL-15 and IL-15 receptors at the protein level by skeletal muscle cells were examined under steady state and cytokine stimulation conditions. The functions of IL-15 in the skeletal muscle were investigated using Il15 knockout (Il15 (-/-) ) mice. The immune regulatory role of skeletal muscle IL-15 was determined by co-culturing cytokine-stimulated muscle cells and memory-like CD8(+) T cells in vitro and by inducing autoimmune myositis in skeletal-muscle specific Il15 (-/-) mice. RESULTS: We found that the IL-15 protein was not expressed by skeletal muscle cells under steady state condition but induced by tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) stimulation and expressed as IL-15/IL-15 receptor alpha (IL-15Ralpha) complex. Skeletal muscle cells expressed a scanty amount of IL-15 receptor beta (IL 15Rbeta) under either conditions and only responded to a high concentration of IL 15 hyperagonist, but not IL-15. Consistently, deficiency of endogenous IL-15 affected neither skeletal muscle growth nor its responses to TNF-alpha and IFN gamma. On the other hand, the cytokine-stimulated skeletal muscle cells presented antigen and provided IL-15 to promote the effector function of memory-like CD8(+) T cells. Genetic ablation of Il15 in skeletal muscle cells greatly ameliorated autoimmune myositis in mice. CONCLUSIONS: These findings together indicate that skeletal muscle IL-15 directly regulates immune effector cells but not muscle cells and thus presents a potential therapeutic target for myositis. PMID- 26417432 TI - Understanding the biosynthesis of platelets-derived extracellular vesicles. AB - Platelet-derived extracellular vesicles (PEVs) are described as sub-cellular vesicles released into circulation upon platelets shear stress, activation, injury, or apoptosis. They are considered as universal biomarkers in a wide range of physiological and pathological processes. They are of tremendous significance for the prediction, diagnosis, and observation of the therapeutic success of many diseases. Understanding their biosynthesis and therefore functional properties would contribute to a better understanding of the pathological mechanisms leading to various diseases in which their levels are raised and they are implicated. The review takes a critical look at the historical background of PEVs, their structural components, the mechanism of their formation, physiological, and exogenous stimuli inducing their release and their detection. It concludes by highlighting on the importance of undertaking in-depth studies into PEVs biosynthesis and subsequently gaining a better understanding of their biological role in general. PMID- 26417431 TI - MLBCD: a machine learning tool for big clinical data. AB - BACKGROUND: Predictive modeling is fundamental for extracting value from large clinical data sets, or "big clinical data," advancing clinical research, and improving healthcare. Machine learning is a powerful approach to predictive modeling. Two factors make machine learning challenging for healthcare researchers. First, before training a machine learning model, the values of one or more model parameters called hyper-parameters must typically be specified. Due to their inexperience with machine learning, it is hard for healthcare researchers to choose an appropriate algorithm and hyper-parameter values. Second, many clinical data are stored in a special format. These data must be iteratively transformed into the relational table format before conducting predictive modeling. This transformation is time-consuming and requires computing expertise. METHODS: This paper presents our vision for and design of MLBCD (Machine Learning for Big Clinical Data), a new software system aiming to address these challenges and facilitate building machine learning predictive models using big clinical data. RESULTS: The paper describes MLBCD's design in detail. CONCLUSIONS: By making machine learning accessible to healthcare researchers, MLBCD will open the use of big clinical data and increase the ability to foster biomedical discovery and improve care. PMID- 26417433 TI - Differences in antigen-specific CD4+ responses to opportunistic infections in HIV infection. AB - HIV-infected individuals with severe immunodeficiency are at risk of opportunistic infection (OI). Tuberculosis (TB) may occur without substantial immune suppression suggesting an early and sustained adverse impact of HIV on Mycobacterium tuberculosis (MTB)-specific cell mediated immunity (CMI). This prospective observational cohort study aimed to observe differences in OI specific and MTB-specific CMI that might underlie this. Using polychromatic flow cytometry, we compared CD4+ responses to MTB, cytomegalovirus (CMV), Epstein-Barr virus (EBV) and Candida albicans in individuals with and without HIV infection. MTB-specific CD4+ T-cells were more polyfunctional than virus specific (CMV/EBV) CD4+ T-cells which predominantly secreted IFN-gamma (IFN-gamma) only. There was a reduced frequency of IFN-gamma and IL-2 (IL-2)-dual-MTB-specific cells in HIV infected individuals, which was not apparent for the other pathogens. MTB specific cells were less differentiated especially compared with CMV-specific cells. CD127 expression was relatively less frequent on MTB-specific cells in HIV co-infection. MTB-specific CD4+ T-cells PD-1 expression was infrequent in contrast to EBV-specific CD4+ T-cells. The variation in the inherent quality of these CD4+ T-cell responses and impact of HIV co-infection may contribute to the timing of co-infectious diseases in HIV infection. PMID- 26417434 TI - Cooperative and alternate functions for STIM1 and STIM2 in macrophage activation and in the context of inflammation. AB - Calcium (Ca(2+)) signaling in immune cells, including macrophages, controls a wide range of effector functions that are critical for host defense and contribute to inflammation and autoimmune diseases. However, receptor-mediated Ca(2+) responses consist of complex mechanisms that make it difficult to identify the pathogenesis and develop therapy. Previous studies have revealed the importance of the Ca(2+) sensor STIM1 and store-operated Ca(2+)-entry (SOCE) for Fcgamma-receptor activation and IgG-induced inflammation. Here, we identify the closely related STIM2 as mediator of cell migration and cytokine production downstream of GPCR and TLR4 activation in macrophages and show that mice lacking STIM2 are partially resistant to inflammatory responses in peritonitis and LPS induced inflammation. Interestingly, STIM2 modulates the migratory behavior of macrophages independent from STIM1 and without a strict requirement for Ca(2+) influx. While STIM2 also contributes in part to FcgammaR activation, the C5a induced amplification of IgG-mediated phagocytosis is mainly dependent on STIM1. Blockade of STIM-related functions limits mortality in experimental models of AIHA and LPS-sepsis in normal mice. These results suggest benefits of Ca(2+) inhibition for suppression of exacerbated immune reactions and illustrate the significance of alternate functions of STIM proteins in macrophage activation and in the context of innate immune inflammation. PMID- 26417435 TI - BTK mutations selectively regulate BTK expression and upregulate monocyte XBP1 mRNA in XLA patients. AB - Mutations in the Bruton agammaglobulinemia tyrosine kinase (BTK) gene are responsible for X-linked agammaglobulinemia (XLA). Unfolded or misfolded proteins can trigger stress pathways in the endoplasmic reticulum (ER), known as unfolded protein response (UPR). The aim was to clarify the involvement of UPR in XLA pathophysiology. By reverse transcription-quantitative PCR, we evaluated the expression of BTK and 12 UPR-related genes in eight patients. Moreover, we assessed the BTK protein expression and pattern in the patients' monocytes by flow cytometry and fluorescence immunocytochemistry. We found a reduced BTK expression in patients with stop codon mutations (P < 0.02). However, missense mutations did not affect BTK expression. Flow cytometry showed a reduction of BTK in patients which was corroborated by an absent or nonfunctional protein synthesis revealed by immunocytochemistry. In contrast with the other UPR-related genes, X-box binding protein 1 (XBP1) was markedly upregulated in the patients (P < 0.01), suggesting Toll-like receptor (TLR) activation since BTK directly interacts with TLRs as a negative regulator and XBP1 can be activated in direct response to TLR ligation. Different BTK mutations can be identified by the BTK expression. Inasmuch as UPR-related genes were downregulated or unaltered in patients, we speculate the involvement of the TLRs-XBP1 axis in the XLA pathophysiology. Such data could be the basis for further studies of this novel pathomechanism concerning XLA. PMID- 26417436 TI - Amaranthus leucocarpus lectin recognizes a moesin-like O-glycoprotein and costimulates murine CD3-activated CD4(+) T cells. AB - The Galbeta1,3GalNAcalpha1,O-Ser/Thr specific lectin from Amaranthus leucocarpus (ALL) binds a ~70 kDa glycoprotein on murine T cell surface. We show that in the absence of antigen presenting cells, murine CD4(+) T cells activated by an anti CD3 antibody plus ALL enhanced cell proliferation similar to those cells activated via CD3/CD28 at 48 h of culture. Moreover, ALL induced the production of IL-4, IL-10, TNF-alpha, and TGF-beta in CD3-activated cells. Proteomic assay using two-dimensional electrophoresis and far-Western blotting, ALL recognized two prominent proteins associated to the lipid raft microdomains in CD3/CD28 activated CD4(+) T cells. By mass spectrometry, the peptide fragments from ALL recognized proteins showed sequences with 33% homology to matricin (gi|347839 NCBInr) and 41% identity to an unnamed protein related to moesin (gi|74186081 NCBInr). Confocal microscopy analysis of CD3/CD28-activated CD4(+) T cells confirmed that staining by ALL colocalized with anti-moesin FERM domain antibody along the plasma membrane and in the intercellular contact sites. Our findings suggest that a moesin-like O-glycoprotein is the ALL-recognized molecule in lipid rats, which induces costimulatory signals on CD4(+) T cells. PMID- 26417437 TI - IL-33 promotes MHC class II expression in murine mast cells. AB - Mast cells (MCs), recognized as tissue-resident cells of hematopoietic origin, are involved in cellular and pathological manifestations of allergic disorders including atopic dermatitis. IL-33, a member of the IL-1 cytokine family, activates Th2-type immune responses, and promotes the degranulation and maturation of MCs. However, it is uncertain whether IL-33 treatment induces mature mast cells to acquire the characteristics of the monocyte-dendritic cell lineage.We investigated the effect of IL-33 on the MHC class II expression and function of murine mast cells. IL-33-treated mature murine bone marrow-derived mast cells (BMMCs) were analyzed by FACS, real-time PCR, chromatin immunoprecipitation (ChIP) assay, and Western blotting. The morphology and degranulation activity of BMMCs and T-cell activation by BMMCs were also examined. BMMCs treated with IL-33 for 10 days induced cell surface expression of the MHC class II protein, whereas the expression of FcepsilonRI and c-kit was not affected by IL-33. The expression of CIITA, driven from pIII and pIV, was up regulated in IL-33-treated BMMCs. The amount of PU.1 mRNA and protein significantly increased in IL-33-treated BMMCs. The ChIP assay showed PU.1 binding to CIITA pIII, and enhanced histone acetylation due to IL-33 treatment. Syngeneic T cells were activated by co-culture with IL-33-treated BMMCs, although the expression of the co-stimulatory molecules, CD40, CD80, CD86, and PDL-1, was not detected. Mast cells express MHC class II after prolonged exposure to IL-33, probably due to enhanced recruitment of PU.1 to CIITA pIII, resulting in transactivation of CIITA and MHC class II. IL-33 is an important cytokine in allergic disorders. Mast cells have the ability to express MHC class II after prolonged exposure to IL-33 in a murine model. IL-33 holds a key to understanding the etiology of atopic dermatitis. PMID- 26417438 TI - Bacterial clearance reverses a skewed T-cell repertoire induced by Salmonella infection. AB - Salmonella typhimurium invades the spleen, liver, and peripheral lymph nodes and has recently been detected in the bone marrow and thymus, resulting in a reduced thymic size and a decline in the total number of thymic cells. A specific deletion of the double-positive cell subset has been characterized, yet the export of mature T cells to the periphery remains normal. We analyzed Salmonella pathogenesis regarding thymic structure and the T-cell maturation process. We demonstrate that, despite alterations in the thymic structure, T-cell development is maintained during Salmonella infection, allowing the selection of single positive T-cell clones expressing particular T-cell receptor beta chains (TCR Vbeta). Moreover, the treatment of infected mice with an antibiotic restored the normal thymic architecture and thymocyte subset distribution. Additionally, the frequency of TCR-Vbeta usage after treatment was comparable to that in non infected mice. However, bacteria were still recovered from the thymus after 1 month of treatment. Our data reveal that a skewed T-cell developmental process is present in the Salmonella-infected thymus that alters the TCR-Vbeta usage frequency. Likewise, the post-treatment persistence of Salmonella reveals a novel function of the thymus as a potential reservoir for this infectious agent. PMID- 26417439 TI - Atherosclerosis severity is not affected by a deficiency in IL-33/ST2 signaling. AB - Interleukin (IL)-33 is a cytokine of the IL-1 family, which signals through the ST2 receptor. Previous work demonstrated that the systemic administration of recombinant IL-33 reduces the development of atherosclerosis in apolipoprotein E deficient (ApoE(-/-)) mice by inducing a Th1-to-Th2 shift. The objective of our study was to examine the role of endogenous IL-33 and ST2 in atherosclerosis. ApoE(-/-), IL-33(-/-)ApoE(-/-), and ST2(-/-)ApoE(-/-) mice were fed with a cholesterol-rich diet for 10 weeks. Additionally, a group of ApoE(-/-) mice was injected with a neutralizing anti-ST2 or an isotype control antibody during the period of the cholesterol-rich diet. Atherosclerotic lesion development was measured by Oil Red O staining in the thoracic-abdominal aorta and the aortic sinus. There were no significant differences in the lipid-staining area of IL-33( /-)ApoE(-/-), ST2(-/-)ApoE(-/-), or anti-ST2 antibody-treated ApoE(-/-) mice, compared to ApoE(-/-) controls. The absence of IL-33 signaling had no major and consistent impact on the Th1/Th2 cytokine responses in the supernatant of in vitro-stimulated lymph node cells. In summary, deficiency of the endogenously produced IL-33 and its receptor ST2 does not impact the development of atherosclerosis in ApoE-deficient mice. PMID- 26417440 TI - Testing the role of the FcgammaRIIB immunoreceptor tyrosine-based inhibitory motif in regulation of the B cell immune response. AB - In vitro studies have demonstrated that the immunoreceptor tyrosine-based inhibitory motif (ITIM) of the inhibitory Fc receptor FcgammaRIIB is critical for mediating attenuation of signaling via immunoreceptor tyrosine-based activation motif (ITAM) containing receptors, such as the B cell antigen receptor (BCR), when FcgammaRIIB is co-cross-linked to these activation receptors. To test the role of the FcgammaRIIB ITIM motif in regulation of the B cell immune response in vivo, we constructed lines of transgenic mice expressing a form of FcgammaRIIB with an inactivating tyrosine (Y) to phenylalanine (F) mutation in the ITIM motif. Detailed studies of one of these lines, in which the mutant FcgammaRIIB was expressed on B cells and other cell types that normally express this receptor, were performed. No quantitative differences in germinal center (GC) B cell responses were observed between the mutant FcgammaRIIB transgenic line and control mice. However, serum antibody and antibody forming cell responses were often observed to be elevated in the ITIM mutant FcgammaRIIB transgenic mice as compared to controls, though not to the same extent as mice deficient in expression of FcgammaRIIB. Moreover, primary B cells from the ITIM mutant FcgammaRIIB line did not display the same level of augmented BCR signaling as primary FcgammaRIIB deficient B cells under conditions inducing co-cross-linking of FcgammaRIIB and the BCR. In total, these data suggest that a functional ITIM motif is not required for all in vivo inhibitory activity of this receptor. However, we also found that the transgenic ITIM mutant FcgammaRIIB receptor was expressed at abnormal levels in several hematopoietic lineages. Thus, confirmation of our findings will require the generation and analysis of mice in which an ITIM mutant form of FcgammaRIIB is expressed in vivo as is the endogenous receptor. PMID- 26417441 TI - Overexpression of Fkbp11, a feature of lupus B cells, leads to B cell tolerance breakdown and initiates plasma cell differentiation. AB - Systemic Lupus Erythematosus (SLE) is a severe systemic autoimmune disease, characterized by multi-organ damages, triggered by an autoantibody-mediated inflammation, and with a complex genetic influence. It is today accepted that adult SLE arises from the building up of many subtle gene variations, each one adding a new brick on the SLE susceptibility and contributing to a phenotypic trait to the disease. One of the ways to find these gene variations consists in comprehensive analysis of gene expression variation in a precise cell type, which can constitute a good complementary strategy to genome wide association studies. Using this strategy, and considering the central role of B cells in SLE, we analyzed the B cell transcriptome of quiescent SLE patients, and identified an overexpression of FKBP11, coding for a cytoplasmic putative peptidyl-prolyl cis/trans isomerase and chaperone enzyme. To understand the consequences of FKBP11 overexpression on B cell function and on autoimmunity's development, we created lentiviral transgenic mice reproducing this gene expression variation. We showed that high expression of Fkbp11 reproduces by itself two phenotypic traits of SLE in mice: breakdown of B cell tolerance against DNA and initiation of plasma cell differentiation by acting upstream of Pax5 master regulator gene. PMID- 26417442 TI - Decreased expression of CD200R3 on mouse basophils as a novel marker for IgG1 mediated anaphylaxis. AB - IgE-mediated mast cell activation is the trigger of anaphylaxis in humans, whereas it is known that not only IgE but also IgG can induce anaphylaxis in mice. In our preliminary experiments, the expression of a murine basophil identification marker, CD200R3, on antigen-sensitized basophils decreased following specific antigen challenge. Interestingly, this decrease did not always correspond with increased expression of the IgE-mediated basophil activation marker CD200R1. Since IgG as well as IgE plays a role in mouse anaphylaxis, we hypothesized that the observed decrease in CD200R3 on basophils was caused by IgG mediated cell activation. We attempted to establish whether CD200R3 is a marker of IgG-mediated basophil activation and if its expression is correlated with anaphylaxis in a mouse model. Mouse basophils were stimulated via Fc?Rs and/or FcgammaRs, and levels of CD200R1 and CD200R3 were analyzed by flow cytometry. Basophils derived from naive mice were challenged with a natural antigen, beta lactoglobulin, after passive sensitization with anti-beta-LG serum or IgG/IgG subclass-depleted antiserum. Systemic anaphylaxis was induced by i.v. injection of anti-FcgammaRIII/II monoclonal antibody, and CD200R3 expression on peripheral basophils was assessed. Stimulation via Fc?Rs induced a significant increase in CD200R1 expression but had only a small effect on that of CD200R3. However, anti FcgammaRIII/II stimulation reduced CD200R3 expression markedly. In passive sensitization experiments, down-regulation of CD200R3 induced by antigen challenge was strongly negated by the depletion of IgG or IgG1 from antiserum. Intravenous injection of anti-FcgammaRIII/II induced CD200R3 down-regulation on peripheral basophils, together with a drop in rectal temperature. Lowered CD200R3 expression on basophils is induced by IgG-mediated stimulation via FcgammaRs. Use of CD200R1 and CD200R3 as activation markers enables the evaluation of murine basophil activation mediated by IgE and IgG, respectively. PMID- 26417443 TI - IL-27 and TGFbeta mediated expansion of Th1 and adaptive regulatory T cells expressing IL-10 correlates with bacterial burden and disease severity in pulmonary tuberculosis. AB - CD4(+) T cell expression of IL-10 is an important mechanism controlling immunity to tuberculosis (TB). To identify the CD4(+) T cell subsets producing IL-10 in human TB, we enumerated the frequencies of IL-10 expressing CD4(+) T cell subsets following TB-antigen stimulation of cells from individuals with pulmonary (PTB) and latent TB (LTB). We first demonstrate that TB antigens induce an expansion of IL-10 expressing Th1 (IL-10(+), IFNgamma(+), T-bet(+)), Th2 (IL-10(+), IL-4(+), GATA-3(+)), Th9 (IL-10(+), IL-9(+), IL-4(-)), Th17 (IL-10(+), IL-17(+), IFNgamma( )), and natural and adaptive regulatory T cells [nTregs; IL-10(+), CD4(+), CD25(+), Foxp3(+) and aTregs; IL-10 single(+), CD4(+), CD25(-), Foxp3(-)] in PTB and LTB individuals, with frequencies being significantly higher in the former. However, only Th1 cells and adaptive Tregs expressing IL-10 exhibit a positive relationship with bacterial burdens and extent of disease in PTB. Finally, we show that IL-27 and TGFbeta play an important role in the regulation of IL-10(+) Th cell subsets. Thus, active PTB is characterized by an IL-27 and TGFbeta mediated expansion of IL-10 expressing CD4(+) T cell subsets, with IL-10(+) Th1 and IL-10(+) aTreg cells playing a potentially pivotal role in the pathogenesis of active disease. PMID- 26417444 TI - Peripheral basophil reactivity, CD203c expression by Cryj1 stimulation, is useful for diagnosing seasonal allergic rhinitis by Japanese cedar pollen. AB - Measuring specific IgE can yield direct, accurate, and objective data. Nevertheless, clinical symptoms of allergy are often inconsistent with these data. Recently, the expression of CD203c, a surface marker of basophils, has been reported as capable of distinguishing allergic patients. This study compared specific IgE in serum and skin tests against antigen to assess CD203c as a biomarker correlated with allergic rhinitis (AR). We asked 3,453 subjects whether they experienced any AR related symptom. All subjects were assessed for six specific IgEs for common aeroallergens. Skin tests were also conducted for six aeroallergens. We observed the reactivity of peripheral basophil by measuring the levels of CD203c by Cryj1 stimulation using flow cytometry. Of the 3,453 participants, 1,987 (57.5%) possessed Japanese cedar pollen (JCP) specific IgE in their serum. Among those 1,987 JCP specific IgE positive participants, 552 (27.8%) had not experienced any allergic symptom during the JCP season. The levels of CD203c in the peripheral basophil by Cryj1 stimulation were significantly higher in SAR-JCP subjects than in non-SAR-JCP subjects (Cryj1 0.5 ng/ml: 2.25 +/- 0.90% vs. 60.2 +/- 27.4%, p < 0.01, Cryj1 50 ng/ml: 1.89 +/- 0.90% vs. 68.0 +/- 21.2%, p < 0.01). Our results indicate that the levels of CD203c in peripheral basophils by Cryj1 stimulation is a more objective and reliable marker that better reflects the allergic reaction by SAR-JCP in vivo than measuring specific IgE in serum or skin tests. PMID- 26417445 TI - Neonatal microbial colonization in mice promotes prolonged dominance of CD11b(+)Gr-1(+) cells and accelerated establishment of the CD4(+) T cell population in the spleen. AB - To assess the microbial influence on postnatal hematopoiesis, we examined the role of early life microbial colonization on the composition of leukocyte subsets in the neonatal spleen. A high number of CD11b(+)Gr-1(+) splenocytes present perinatally was sustained for a longer period in conventionally colonized (CONV) mice than in mono-colonized (MC) and germfree (GF) mice, and the CD4(+) T cell population established faster in CONV mice. At the day of birth, compared to GF mice, the expression of Cxcl2 was up-regulated and Arg1 down-regulated in livers of CONV mice. This coincided with lower abundance of polylobed cells in the liver of CONV mice. An earlier peak in the expression of the genes Tjp1, Cdh1, and JamA in intestinal epithelial cells of CONV mice indicated an accelerated closure of the epithelial barrier. In conclusion, we have identified an important microbiota dependent neonatal hematopoietic event, which we suggest impacts the subsequent development of the T cell population in the murine spleen. PMID- 26417447 TI - Gold Nanoparticle Labeling Based ICP-MS Detection/Measurement of Bacteria, and Their Quantitative Photothermal Destruction. AB - Bacteria such as Salmonella and E. coli present a great challenge in public health care in today's society. Protection of public safety against bacterial contamination and rapid diagnosis of infection require simple and fast assays for the detection and elimination of bacterial pathogens. After utilizing Salmonella DT104 as an example bacterial strain for our investigation, we report a rapid and sensitive assay for the qualitative and quantitative detection of bacteria by using antibody affinity binding, popcorn shaped gold nanoparticle (GNPOPs) labeling, surfance enchanced Raman spectroscopy (SERS), and inductively coupled plasma mass spectrometry (ICP-MS) detection. For qualitative analysis, our assay can detect Salmonella within 10 min by Raman spectroscopy; for quantitative analysis, our assay has the ability to measure as few as 100 Salmonella DT104 in a 1 mL sample (100 CFU/mL) within 40 min. Based on the quantitative detection, we investigated the quantitative destruction of Salmonella DT104, and the assay's photothermal efficiency in order to reduce the amount of GNPOPs in the assay to ultimately to eliminate any potential side effects/toxicity to the surrounding cells in vivo. Results suggest that our assay may serve as a promising candidate for qualitative and quantitative detection and elimination of a variety of bacterial pathogens. PMID- 26417446 TI - Hyperoxia promotes polarization of the immune response in ovalbumin-induced airway inflammation, leading to a TH17 cell phenotype. AB - Previous studies have demonstrated that hyperoxia-induced stress and oxidative damage to the lungs of mice lead to an increase in IL-6, TNF-alpha, and TGF-beta expression. Together, IL-6 and TGF-beta have been known to direct T cell differentiation toward the TH17 phenotype. In the current study, we tested the hypothesis that hyperoxia promotes the polarization of T cells to the TH17 cell phenotype in response to ovalbumin-induced acute airway inflammation. Airway inflammation was induced in female BALB/c mice by intraperitoneal sensitization and intranasal introduction of ovalbumin, followed by challenge methacholine. After the methacholine challenge, animals were exposed to hyperoxic conditions in an inhalation chamber for 24 h. The controls were subjected to normoxia or aluminum hydroxide dissolved in phosphate buffered saline. After 24 h of hyperoxia, the number of macrophages and lymphocytes decreased in animals with ovalbumin-induced airway inflammation, whereas the number of neutrophils increased after ovalbumin-induced airway inflammation. The results showed that expression of Nrf2, iNOS, T-bet and IL-17 increased after 24 of hyperoxia in both alveolar macrophages and in lung epithelial cells, compared with both animals that remained in room air, and animals with ovalbumin-induced airway inflammation. Hyperoxia alone without the induction of airway inflammation lead to increased levels of TNF-alpha and CCL5, whereas hyperoxia after inflammation lead to decreased CCL2 levels. Histological evidence of extravasation of inflammatory cells into the perivascular and peribronchial regions of the lungs was observed after pulmonary inflammation and hyperoxia. Hyperoxia promotes polarization of the immune response toward the TH17 phenotype, resulting in tissue damage associated with oxidative stress, and the migration of neutrophils to the lung and airways. Elucidating the effect of hyperoxia on ovalbumin-induced acute airway inflammation is relevant to preventing or treating asthmatic patients that require oxygen supplementation to reverse the hypoxemia. PMID- 26417448 TI - Microbeads-Guided Reconstruction of 3D Osteocyte Network during Microfluidic Perfusion Culture. AB - Osteocytes reside as 3-dimensionally networked cells in the lacunocanalicular structure of bones, and function as the master regulators of homeostatic bone remodeling. We report here, for the first time to our best knowledge, the use of a biomimetic approach to reconstruct the 3D osteocyte network with physiological relevant microscale dimensions. In this approach, biphasic calcium phosphate microbeads were assembled with murine early osteocytes (MLO-A5) to provide an initial mechanical framework for 3D network formation and maintenance during long term perfusion culture in a microfluidic chamber. The microbead size of 20-25 MUm was used to: (1) facilitate a single cell to be placed within the interstitial space between the microbeads, (2) mitigate the proliferation of the entrapped cell due to its physical confinement in the interstitial site, and (3) control cell-to-cell distance to be 20-25 MUm as observed in murine bones. The entrapped cells formed a 3D cellular network by extending and connecting their processes through openings between the microbeads within 3 days of culture. The entrapped cells produced significant mineralized extracellular matrix to fill up the interstitial spaces, resulting in the formation of a dense tissue structure during the course of 3-week culture. We found that the time-dependent osteocytic transitions of the cells exhibited trends consistent with in vivo observations, particularly with high expression of Sost gene, which is a key osteocyte-specific marker for the mechanotransduction function of osteocytes. In contrast, cells cultured in 2D well-plates did not replicate in vivo trends. These results provide an important new insight in building physiologically relevant in vitro bone tissue models. PMID- 26417449 TI - Diffusion properties of inkjet printed ionic self-assembling polyelectrolyte hydrogels. AB - In the present work, Crank's model was used to characterize solute transport in inkjet printed polyelectrolyte gels. The diffusion of a small charged molecule (fluorescein), various size linear uncharged molecules (dextrans), and a globular protein (albumin) in printed PSS-PDDA with near stoichiometric composition happened respectively at about 10-8, 10-9, and 10-10 cm2/sec. Polyelectrolyte complexes printed with non-stoichiometric ratios were found to be non-equilibrium structures consisting of three populations of polymer chains: fully complexed chains, chains in partial electrostatic interaction with the complex, and chains in excess having minimal interaction with the complex. This structure may be multiple phases. The applicability of hydrodynamic and free volume models to describe transport in printed polyelectrolyte gels was discussed. PMID- 26417450 TI - Canadian Pediatric Weight Management Registry (CANPWR): baseline descriptive statistics and comparison to Canadian norms. AB - BACKGROUND: A pilot study was conducted to assess the feasibility of establishing a multi-site CANadian Pediatric Weight management Registry (CANPWR) containing individual, family and weight management program information. METHODS: Standardized baseline data were collected to characterize CANPWR participants (n = 310) in comparison to a sample of age-matched Canadian children measured in the nationally representative Canadian Health Measures Survey (CHMS; n = 3,788). This study compared demographic, anthropometric, cardiometabolic and lifestyle characteristics of participants (aged 6-17 years) in the CANPWR pilot study with those from the CHMS. RESULTS: Compared to CHMS respondents, CANPWR participants had higher BMI z-score, waist circumference, blood pressure, total cholesterol, LDL cholesterol, triglycerides and fasting glucose, and lower HDL cholesterol. They reported lower sugared drink consumption, were more likely to be non-white and had parents with lower education. CONCLUSIONS: The CANPWR cohort represents a group that has biological and behavioral profiles that place them at increased health risk and who differ significantly from typical Canadians of the same age. PMID- 26417451 TI - A protocol for developing an evaluation framework for an academic and private sector partnership to assess the impact of major food and beverage companies' investments in community health in the United States. AB - Public health leaders increasingly recognize the importance of multi-sector partnerships and systems approaches to address obesity. Public-private partnerships (PPP), which are joint ventures between government agencies and private sector entities, may help facilitate this process, but need to be delivered through comprehensive, transparent frameworks to maximize potential benefits and minimize potential risks for all partners. The City University of New York (CUNY) School of Public Health and the Healthy Weight Commitment Foundation (HWCF) propose to engage in a unique academic-private-sector research partnership to evaluate the impact and effectiveness of the food and beverage industry's investment in obesity and hunger prevention and reduction through community-level healthful eating and active living programs. The CUNY-HWCF academic-private partnership protocol described here incorporates best practices from the literature on PPP into the partnership's design. The CUNY-HWCF partnership design demonstrates how established guidelines for partnership components will actively incorporate and promote the principles of successful PPPs identified in various research papers. These identified principles of successful PPP, including mutuality (a reciprocal relationship between entities), and equality among partners, recognition of partners' unique strengths and roles, alignment of resources and expertise toward a common cause, and coordination and delegation of responsibilities, will be embedded throughout the design of governance, management, funding, intellectual property and accountability structures. The CUNY-HWCF partnership responds to the call for increased multi sector work in obesity prevention and control. This framework aims to promote transparency and the shared benefits of complementary expertise while minimizing shared risks and conflicts of interest. This framework serves as a template for future academic-private research partnerships. PMID- 26417452 TI - Endothelial Cell Loss after Phacoemulsification according to Different Anterior Chamber Depths. AB - Purpose. To compare the loss of corneal endothelial cells after phacoemulsification according to different anterior chamber depths (ACDs). Methods. We conducted a prospective study on 135 eyes with senile cataracts. Eyes with nuclear density grades of 2 to 4 were divided into three groups according to ACD: ACD I, 1.5 < ACD <= 2.5 mm; ACD II, 2.5 < ACD <= 3.5 mm; or ACD III, 3.5 < ACD <= 4.5 mm. Intraoperative mean cumulative dissipated energy (CDE) was measured. Clinical examinations included central corneal thickness (CCT) and endothelial cell count (ECC) preoperatively and 2 months postoperatively. Results. There were no significant differences in CDE among the ACD groups (P > 0.05). Endothelial cell loss was significantly higher in ACD I than in ACD III in grades 3 and 4 cataract density groups 2 months after phacoemulsification (P < 0.05). There were also more changes in CCT in all of the cataract density groups in the ACD I group compared to the ACD II and III groups 2 months postoperatively, but the difference was not statistically significant. Conclusions. Eyes with shallow ACDs, especially those with relatively hard cataract densities, can be vulnerable to more corneal endothelial cell loss in phacoemulsification surgery. PMID- 26417454 TI - Reproductive and Obstetric Factors Are Key Predictors of Maternal Anemia during Pregnancy in Ethiopia: Evidence from Demographic and Health Survey (2011). AB - Anemia is a major public health problem worldwide. In Ethiopia, a nationally representative and consistent evidence is lacking on the prevalence and determinants during pregnancy. We conducted an in-depth analysis of demographic and health survey for the year 2011 which is a representative data collected from all regions in Ethiopia. Considering maternal anemia as an outcome variable, predicting variables from sociodemographic, household, and reproductive/obstetric characteristics were identified for analyses. Logistic regression model was applied to identify predictors at P < 0.05. The prevalence of anemia among pregnant women was 23%. Maternal age, region, pregnancy trimester, number of under five children, previous history of abortion (termination of pregnancy), breastfeeding practices, and number of antenatal care visits were key independent predictors of anemia during pregnancy. In conclusion, the level of anemia during pregnancy is a moderate public health problem in Ethiopia. Yet, special preventive measures should be undertaken for pregnant women who are older in age and having too many under five children and previous history of abortion. Further evidence is expected to be generated concerning why pregnant mothers from the eastern part of the country and those with better access to radio disproportionately develop anemia more than their counterparts. PMID- 26417453 TI - Anti-VEGF Therapy and the Retina: An Update. AB - Ocular angiogenesis and macular oedema are major causes of sight loss across the world. Aberrant neovascularisation, which may arise secondary to numerous disease processes, can result in reduced vision as a result of oedema, haemorrhage, and scarring. The development of antivascular endothelial growth factor (anti-VEGF) agents has revolutionised the treatment of retinal vasogenic conditions. These drugs are now commonly employed for the treatment of a plethora of ocular pathologies including choroidal neovascularisation, diabetic macular oedema, and retinal vein occlusion to name a few. In this paper, we will explore the current use of anti-VEGF in a variety of retinal diseases and the impact that these medications have had on visual outcome for patients. PMID- 26417455 TI - How Predictable Is the Operative Time of Laparoscopic Surgery for Ovarian Endometrioma? AB - Endometriosis is a tricky albeit common disease whose management largely relies on laparoscopy. We have studied the operative times of laparoscopic endometrioma surgery in order to assess their predictability and possible predictors. One hundred forty-eight laparoscopies were included, with a median operative time of 70 minutes (mean 75.14; 95% CI: 70.03-80.24). Half of the cases had a duration within 15-20 minutes above or below the median (IQR: 55-93.75), but the whole dataset ranged from 20 to 180 minutes, and the standard deviation was relatively large (31.4). Surgical times were significantly related to technical (number and size of the cysts) and nontechnical factors (age, parity, dysmenorrhea, and family history). At multiple logistic regression, after adjusting for number and size of the cysts, surgical times below the first quartile were associated with older age (>30 years old: aOR: 3.590; 95% CI: 1.417-9.091) and parity (>=1 delivery: aOR: 3.409; 95% CI: 1.343-8.651). Longer times, above the third quartile, were instead predicted by a familial anamnesis of endometriosis (aOR: 3.639; 95% CI: 1.246-10.627). Our findings indicate highly variable surgical times, which are predicted by unexpected nontechnical factors. This is consistent with the complexity of endometriosis and its treatment. Productivity and efficiency in endometriosis surgery should focus on the quality of healthcare outcomes rather than on the time spent in the operating theatres. PMID- 26417456 TI - Analysis of AKAP7gamma Dimerization. AB - A-kinase anchoring proteins (AKAPs) constitute a family of scaffolding proteins that contribute to spatiotemporal regulation of PKA-mediated phosphorylation events. In particular, AKAP7 is a family of alternatively spliced proteins that participates in cardiac calcium dynamics. Here, we demonstrate via pull-down from transfected cells and by direct protein-protein association that AKAP7gamma self associates. Self-association appears to be an isoform specific phenomenon, as AKAP7alpha did not associate with itself or with AKAP7gamma. However, AKAP7gamma did associate with AKAP7delta, suggesting the long isoforms of the AKAP can form heterodimers. Surface plasmon resonance found that the AKAP7gamma self association occurs via two high affinity binding sites with K D values in the low nanomolar range. Mapping of the binding sites by peptide array reveals that AKAP7gamma interacts with itself through multiple regions. Photon counting histogram analysis (PCH) of AKAP7gamma-EGFP expressed in HEK-293 cells confirmed that AKAP7gamma-EGFP self-associates in a cellular context. Lastly, computational modeling of PKA dynamics within AKAP7gamma complexes suggests that oligomerization may augment phosphorylation of scaffolded PKA substrates. In conclusion, our study reveals that AKAP7gamma forms both homo- and heterodimers with the long isoforms of the AKAP and that this phenomenon could be an important step in mediating effective substrate phosphorylation in cellular microdomains. PMID- 26417457 TI - Coincidence Anticipation Timing Performance during an Acute Bout of Brisk Walking in Older Adults: Effect of Stimulus Speed. AB - This study examined coincidence anticipation timing (CAT) performance at slow and fast stimulus speeds before, during, and after an acute bout of walking in adults aged 60-76 years. Results from a series of repeated measures ANOVAs indicated significant rest versus exercise * stimulus speed * time interactions for absolute and variable errors (both P = 0.0001) whereby absolute and variable error scores, when stimulus speed was slow, improved as the duration of exercise increased. When stimulus speed was fast there were significantly greater absolute and variable errors at 18 minutes of the walking bout. There was also greater error at 18 minutes during walking compared to rest. These results suggest that, in a task involving walking and CAT, stimulus speeds plays an important role; specifically walking (exercise) enhances CAT performance at slow stimulus speeds but reduces CAT performance at fast stimulus speeds. The implications are that in everyday situations, where events require dual-task responses to be made at different speeds, for example, walking on the pavement whilst avoiding a crowd, compared to crossing a busy road, an understanding of how different stimulus speeds influence dual-task performance is extremely important, particularly in the older adult population. PMID- 26417458 TI - Age-Related Reduced Somatosensory Gating Is Associated with Altered Alpha Frequency Desynchronization. AB - Sensory gating (SG), referring to an attenuated neural response to the second identical stimulus, is considered as preattentive processing in the central nervous system to filter redundant sensory inputs. Insufficient somatosensory SG has been found in the aged adults, particularly in the secondary somatosensory cortex (SII). However, it remains unclear which variables leading to the age related somatosensory SG decline. There has been evidence showing a relationship between brain oscillations and cortical evoked excitability. Thus, this study used whole-head magnetoencephalography to record responses to paired-pulse electrical stimulation to the left median nerve in healthy young and elderly participants to test whether insufficient stimulus 1- (S1-) induced event-related desynchronization (ERD) contributes to a less-suppressed stimulus 2- (S2-) evoked response. Our analysis revealed that the minimum norm estimates showed age related reduction of SG in the bilateral SII regions. Spectral power analysis showed that the elderly demonstrated significantly reduced alpha ERD in the contralateral SII (SIIc). Moreover, it was striking to note that lower S1-induced alpha ERD was associated with higher S2-evoked amplitudes in the SIIc among the aged adults. Conclusively, our findings suggest that age-related decline of somatosensory SG is partially attributed to the altered S1-induced oscillatory activity. PMID- 26417459 TI - Restoration of Central Programmed Movement Pattern by Temporal Electrical Stimulation-Assisted Training in Patients with Spinal Cerebellar Atrophy. AB - Disrupted triphasic electromyography (EMG) patterns of agonist and antagonist muscle pairs during fast goal-directed movements have been found in patients with hypermetria. Since peripheral electrical stimulation (ES) and motor training may modulate motor cortical excitability through plasticity mechanisms, we aimed to investigate whether temporal ES-assisted movement training could influence premovement cortical excitability and alleviate hypermetria in patients with spinal cerebellar ataxia (SCA). The EMG of the agonist extensor carpi radialis muscle and antagonist flexor carpi radialis muscle, premovement motor evoked potentials (MEPs) of the flexor carpi radialis muscle, and the constant and variable errors of movements were assessed before and after 4 weeks of ES assisted fast goal-directed wrist extension training in the training group and of general health education in the control group. After training, the premovement MEPs of the antagonist muscle were facilitated at 50 ms before the onset of movement. In addition, the EMG onset latency of the antagonist muscle shifted earlier and the constant error decreased significantly. In summary, temporal ES assisted training alleviated hypermetria by restoring antagonist premovement and temporal triphasic EMG patterns in SCA patients. This technique may be applied to treat hypermetria in cerebellar disorders. (This trial is registered with NCT01983670.). PMID- 26417461 TI - An Influence of Birth Weight, Gestational Age, and Apgar Score on Pattern Visual Evoked Potentials in Children with History of Prematurity. AB - PURPOSE: The objective of our study was to examine a possible influence of gestational age, birth weight, and Apgar score on amplitudes and latencies of P100 wave in preterm born school-age children. MATERIALS AND METHODS: We examined the following group of school-age children: 28 with history of prematurity (mean age 10.56 +/- 1.66 years) and 25 born at term (mean age 11.2 +/- 1.94 years). The monocular PVEP was performed in all children. RESULTS: The P100 wave amplitudes and latencies significantly differ between preterm born school-age children and those born at term. There was an essential positive linear correlation of the P100 wave amplitudes with birth weight, gestational age, and Apgar score. There were the negative linear correlations of P100 latencies in 15-minute stimulation from O1 and Oz electrode with Apgar score and O1 and O2 electrode with gestational age. CONCLUSIONS: PVEP responses vary in preterm born children in comparison to term. Low birth weight, early gestational age, and poor baseline output seem to be the predicting factors for the developmental rate of a brain function in children with history of prematurity. Further investigations are necessary to determine perinatal factors that can affect the modified visual system function in preterm born children. PMID- 26417460 TI - Neural Plastic Effects of Cognitive Training on Aging Brain. AB - Increasing research has evidenced that our brain retains a capacity to change in response to experience until late adulthood. This implies that cognitive training can possibly ameliorate age-associated cognitive decline by inducing training specific neural plastic changes at both neural and behavioral levels. This longitudinal study examined the behavioral effects of a systematic thirteen-week cognitive training program on attention and working memory of older adults who were at risk of cognitive decline. These older adults were randomly assigned to the Cognitive Training Group (n = 109) and the Active Control Group (n = 100). Findings clearly indicated that training induced improvement in auditory and visual-spatial attention and working memory. The training effect was specific to the experience provided because no significant difference in verbal and visual spatial memory between the two groups was observed. This pattern of findings is consistent with the prediction and the principle of experience-dependent neuroplasticity. Findings of our study provided further support to the notion that the neural plastic potential continues until older age. The baseline cognitive status did not correlate with pre- versus posttraining changes to any cognitive variables studied, suggesting that the initial cognitive status may not limit the neuroplastic potential of the brain at an old age. PMID- 26417462 TI - Buschke-Lowenstein Tumour: Successful Treatment with Minimally Invasive Techniques. AB - We report a case of an 80-year-old female who presented with a four-year history of a growing mass in the perianal area with pain and bleeding during defaecation. Clinical examination revealed a locally destructive, cauliflower-like, verrucous mass measuring 10 * 12 cm in diameter. Histologic findings revealed a moderate degree of dysplasia of the epithelium with koilocytosis atypia, acanthosis, and parakeratosis, features that are consistent with Buschke-Lowenstein tumour. Polymerase-chain-reaction assay for human papillomavirus (HPV) showed an infection with HPV type 11. Full-thickness excision of involved skin was undertaken by cryotherapy and electrocautery over five months. The entire wound was left open to heal by secondary intention. After 3 years of follow-up, the patient has not experienced a recurrence, with excellent functional results, but the cosmetic results were satisfactory. These minimally invasive techniques can be safer and more cost-effective than surgery and the General Practitioner can play a key role in diagnosis. PMID- 26417463 TI - Different Cardiac Anomalies in Mother and Son with 4q-Syndrome. AB - We report a female patient with asymptomatic cor triatriatum sinister, associated with 4q34.3 deletion. Her child, carrying the same imbalance, suffers from tetralogy of Fallot. To the best of our knowledge, this is the first reported case of cor triatriatum associated with deletion of the long arm of the chromosome 4; furthermore, the majority of patients with chromosome 4 long arm syndrome have de novo deletions and only few familial cases have been reported so far. PMID- 26417465 TI - Enterococcus hirae Bacteremia Associated with Acute Pancreatitis and Septic Shock. AB - Infection with Enterococcus hirae has rarely been reported in humans but is not uncommon in mammals and birds. We describe a case of Enterococcus hirae bacteremia associated with acute pancreatitis, acute cholecystitis, and septic shock responsive to antibiotic therapy and supportive critical care management. Unique aspects of this case of Enterococcus hirae bacteremia are its association with acute pancreatitis and its geographical origin. To our knowledge, this is the first report of Enterococcus hirae bacteremia occurring in a patient in the United States. Although human infection with this organism appears to be rare, all cases reported to date describe bacteremia associated with severe and life threatening illness. Thus, physicians need to be cognizant of the clinical significance of this heretofore little recognized pathogen. PMID- 26417464 TI - MALT Lymphoma of the Bladder: A Case Report and Review of the Literature. AB - The presentation of a MALT lymphoma in the bladder is exceedingly rare. Furthermore, the optimal treatment of primary MALT confined to the bladder remains to be defined. Here, we report a case of a 65-year-old female with primary MALT lymphoma treated with definitive radiation therapy. The patient received a total dose of 30 Gy in 20 equal daily fractions to the bladder and tolerated the treatment well. In addition, we have extensively reviewed the relevant literature to better define the optimal management of this rare disease. In conclusion, primary MALT lymphoma of the bladder represents a rare malignancy with excellent prognosis if detected at an early stage. For early stage disease, definitive radiation represents an excellent treatment modality with a minimal side-effect profile. PMID- 26417467 TI - Posterior Cortical Atrophy Presenting with Superior Arcuate Field Defect. AB - An 80-year-old female with reading difficulty presented with progressive arcuate field defect despite low intraocular pressure. Over a 5-year period, the field defect evolved into an incongruous homonymous hemianopia and the repeated neuroimaging revealed progressive posterior cortical atrophy. Further neuropsychiatric assessment demonstrated symptoms and signs consistent with Benson's syndrome. PMID- 26417466 TI - Fetomaternal Hemorrhage following Placement of an Intrauterine Pressure Catheter: Report of a New Association. AB - Fetomaternal hemorrhage (FMH) can be associated with significant perinatal mortality. Our review of the literature did not identify any cases of FMH following placement of an intrauterine pressure catheter (IUPC). In our case, an IUPC was inserted in a patient undergoing induction of labor at term. Fetal bradycardia ensued shortly after placement, warranting an emergent cesarean delivery. Severe neonatal anemia was identified, and evaluation of maternal blood was consistent with massive FMH. This is the first reported association between FMH and IUPC placement. If this relationship is validated in future reports, appropriate changes in clinical practice may be warranted. PMID- 26417468 TI - Massive Localized Lymphedema Arising from Abdominal Wall: A Case Report and Review of the Literature. AB - Massive localized lymphedema (MLL) is a rare pseudosarcomatous lesion due to localized lymphatic obstruction from variable causes. It is most common on medial aspect of thigh and inguinal region. Abdominal localization is rare and may cause clinical diagnostic confusion with other malignant tumors due to its large size. We report a case of abdominal wall MLL of a 56-year-old male patient under clinical suspicion of well differentiated liposarcoma. The literature search and differential diagnosis will be addressed. In doubt cases, immunohistochemical stain or fluorescent in situ hybridization can help to separate this entity from the other mimickers. PMID- 26417469 TI - Severe Burns and Amputation of Both Arms in the First Psychotic Episode of a Schizophrenic Patient. AB - An alleged reduction of sensitivity to pain in people with schizophrenia has been reported, but the nature of this complex phenomenon has not been elucidated yet. Reports of insensitivity to burns from people with schizophrenia are extremely rare. We report the case of a 24-year-old man who set both of his arms on fire during the first break of paranoid schizophrenia. As a result of severe tissue damage, both of his limbs had to be amputated. Today, at the age of 59, the patient is physically and mentally rehabilitated and is adherent to treatment. Additionally, given the uncertainty about the true nature of the alleged hypoalgesia in schizophrenia, we postulate the need for a comprehensive phenomenological approach in the study of embodiment in people with this condition. PMID- 26417471 TI - Lornoxicam Side Effects May Lead to Surgical Mismanagement, in Case of Postoperative Intra-Abdominal Collection: A Case Report and Literature Review. AB - Postoperative collection is a known complication of abdominal surgery, especially after major surgery; however, minor surgical procedures may also be associated with this phenomenon. Utilization of nonsteroidal anti-inflammatory drugs, such as lornoxicam, and the adverse effects thereof, may affect the surgeon's judgment regarding the need for, and extent of, draining of these collections. Here I report the case of a 25-year-old male who presented with perforated acute retrocaecal subhepatic appendicitis complicated by pleural effusion and a small abdominal collection. The pleural effusion resolved almost completely over time. However, the patient showed incomplete recovery, as demonstrated by nausea, vomiting, and mood disturbance along with abdominal pain, tachycardia, and a persistent small abdominal collection. We initially suspected infection caused by a highly virulent type of bacteria and planned to perform percutaneous drainage. However, owing to skin erythematic changes, administration of lornoxicam was ceased, which resulted in complete recovery of the symptoms and consequently in avoidance of unnecessary invasive intervention to drain the abdominal collection. These findings suggest that the utilization and adverse effects of some painkillers for postoperative pain, such as lornoxicam, may affect the surgeon's judgment regarding the most appropriate surgical workup in cases of postoperative fluid collection. PMID- 26417470 TI - Right Heart Transvalvular Embolus with High Risk Pulmonary Embolism in a Recently Hospitalized Patient: A Case Report of a Therapeutic Challenge. AB - Thrombus-in-transit is not uncommon in pulmonary embolism but Right Heart Transvalvular Embolus (RHTVE) complicating this is rare. A 54-year-old obese male with recent hospitalization presented with severe dyspnea and collapse. Initial investigations revealed elevated d-dimer and troponin. CTA showed saddle pulmonary embolus and bedside echocardiogram revealed right ventricular (RV) pressure overload and dilatation (RV > 41 mm), McConnell's sign, and mobile echodensity attached to tricuspid valve. Patient was immediately resuscitated and promptly transferred for surgical embolectomy under cardiopulmonary bypass. A long segment of embolus traversing through the tricuspid valve and extensive bilateral pulmonary artery embolus were removed. IVC filter was placed for a persistent right lower extremity DVT. Hypercoagulable work-up was negative. Patient continued to do well after discharge on Coumadin. Open embolectomy offers great promises where there is no consensus in optimal management approach in such patients. Bedside echocardiogram is vital in risk stratification and deciding choice of advanced PE treatment. PMID- 26417472 TI - Extraperitoneally Ruptured, Everted, and Prolapsed Bladder: A Very Rare Complication of Pelvic Injury. AB - Traumatic rupture of the bladder with eversion and protrusion via the perineum is a rare complication of pelvic injury. We present a 36-year-old lady who sustained severe pelvic injury with a bleeding right-sided deep perineal laceration. She had closed reduction of pelvic fracture with pelvic banding and primary closure of perineal laceration at a private hospital. She subsequently had dehiscence of repaired perineal laceration with protrusion of fleshy mass from vulva and leakage of urine per perineum five weeks later. Examination revealed a fleshy mucosa-like mass protruding anteriorly with a bridge of tissue between it and right anterolateral vaginal wall. Upward pressure on this mass revealed the bladder neck and ureteric orifices. She had perineal and pelvic exploration with findings of prolapsed, completely everted bladder wall through a transverse anterior bladder wall rent via the perineum, and an unstable B1 pelvic disruption. She had repair of the ruptured, everted, and prolapsed bladder, double-plate and screw fixation of disrupted pelvis and repair of the pelvic/perineal defect. She commenced physiotherapy and ambulation a week after surgery. Patient now walks normally and is continent of urine. We conclude that the intrinsic urethral continent mechanism plays a significant role in maintaining continence in females. PMID- 26417473 TI - Psychopathology in Substance Use Disorder Patients with and without Substance Induced Psychosis. AB - Background. Substance-induced psychotic disorder (SIPD) is a diagnosis constructed to distinguish substance-induced psychotic states from primary psychotic disorders. A number of studies have compared SIPD persons with primary psychotic patients, but there is little data on what differentiates substance use disorder (SUD) individuals with and without SIPD. Here, we compared psychopathology, sociodemographic variables, and substance use characteristics between SUD patients with and without SIPD. Methods. A retrospective chart review was conducted on newly admitted patients at a rehabilitation centre between 2007 and 2012. Results. Of the 379 patients included in the study, 5% were diagnosed with SIPD (n = 19) and 95% were diagnosed with SUDs without SIPD (n = 360). More SIPD patients reported using cannabis and psychostimulants, and fewer SIPD patients reported using alcohol than SUDs patients without SIPD. SIPD patients scored higher on the "schizophrenia nuclear symptoms" dimension of the SCL-90R psychoticism scale and exhibited more ClusterB personality traits than SUD patients without SIPD. Discussion. These data are consistent with previous studies suggesting that psychopathology, substance type, and sociodemographic variables play important role in the development of SIPD. More importantly, the results highlight the need for paying greater attention to the types of self reported psychotic symptoms during the assessment of psychotomimetic effects associated with psychoactive substances. PMID- 26417474 TI - Pediatric Patient and Parental Anxiety and Impressions Related to Initial Gastrointestinal Endoscopy: A Japanese Multicenter Questionnaire Study. AB - Objective. To assess anxiety among pediatric patients and their parents related to initial gastrointestinal endoscopy. Methods. Patients aged <19 years undergoing initial gastrointestinal (GI) endoscopy and their parents were invited to complete a self-administered questionnaire related to endoscopy in 13 institutions in Japan. Results. The subjects were 128 children, aged 1 month to 17 years. Forty-eight patients (37.5%) underwent esophagogastroduodenoscopy (EGD), 32 (25%) underwent colonoscopy (CS), 39 (30.5%) underwent both EGD and CS, 3 (2.3%) underwent balloon enteroscopy (BE), 3 (2.3%) underwent capsule endoscopy (CE), and 3 (2.3%) underwent CE and other endoscopic procedures. In the preendoscopy questionnaire, the most common concerns of the patients and parents before undergoing the procedure were "Pain" (45% of the patients underwent EGD or BE via the oral approach, and 52% of the patients underwent CS or BE via the anal approach) and "Procedural accidents related to the endoscopy" (63% of parents). In the postendoscopy questionnaire, the most common difficulty that patients and parents actually experienced before and after undergoing the procedure was "Hunger." Conclusion. A preparatory intervention including an explanation regarding specific concerns before initial GI endoscopy, which this study revealed, could reduce anxiety experienced by both pediatric patients and parents. PMID- 26417475 TI - Human cadaveric dissection: a historical account from ancient Greece to the modern era. AB - The review article attempts to focus on the practice of human cadaveric dissection during its inception in ancient Greece in 3rd century BC, revival in medieval Italy at the beginning of 14th century and subsequent evolution in Europe and the United States of America over the centuries. The article highlights on the gradual change in attitude of religious authorities towards human dissection, the shift in the practice of human dissection being performed by barber surgeons to the anatomist himself dissecting the human body and the enactment of prominent legislations which proved to be crucial milestones during the course of the history of human cadaveric dissection. It particularly emphasizes on the different means of procuring human bodies which changed over the centuries in accordance with the increasing demand due to the rise in popularity of human dissection as a tool for teaching anatomy. Finally, it documents the rise of body donation programs as the source of human cadavers for anatomical dissection from the second half of the 20th century. Presently innovative measures are being introduced within the body donation programs by medical schools across the world to sensitize medical students such that they maintain a respectful, compassionate and empathetic attitude towards the human cadaver while dissecting the same. Human dissection is indispensable for a sound knowledge in anatomy which can ensure safe as well as efficient clinical practice and the human dissection lab could possibly be the ideal place to cultivate humanistic qualities among future physicians in the 21st century. PMID- 26417477 TI - Regional differences in the density of Langerhans cells, CD8-positive T lymphocytes and CD68-positive macrophages: a preliminary study using elderly donated cadavers. AB - To provide a better understanding of the local immune system in the face and external genitalia, i.e., the oral floor, lower lip, palpebral conjunctiva, anus and penis, we examined the distribution and density of CD1a-positve Langerhans cells, CD8-positive suppressor T lymphocytes and CD68-positive macrophages using specimens from 8 male elderly cadavers. The density of Langerhans cells showed an individual difference of more than (or almost) 10-fold in the lip (oral floor). In the oral floor, Langerhans cells were often spherical. Submucosal or subcutaneous suppressor lymphocytes, especially rich in the oral floor and penile skin, migrated into the epithelium at 4 sites, except for the anus. In the conjunctiva, macrophage migration into the epithelium was seen in all 8 specimens. The density of suppressor lymphocytes showed a significant correlation between the oral floor and the lip (r=0.78). In contrast, the anal and penile skins showed no positive correlation in the density of all three types of immunoreactive cells examined. Overall, irrespective of the wide individual differences, the oral floor and conjunctiva seemed to be characterized by a rich content of all three cell types, whereas the penile skin was characterized by an abundance of suppressor lymphocytes. Based on the tables, as mean value, the relative abundance of three different cell types were as follows; CD1a-positive Langerhans cells (anus), CD8-positive lymphocytes (penis), and CD68-positive macrophages (lip). The present observations suggest that the local immune response is highly site-dependent, with a tendency for tolerance rather than rejection. PMID- 26417478 TI - Nfic regulates tooth root patterning and growth. AB - Molecular interactions between epithelium and mesenchyme are important for root formation. Nuclear factor I-C (Nfic) has been identified as a key regulator of root formation. However, the mechanisms of root formation and their interactions between Hertwig's epithelial root sheath (HERS) and mesenchyme remain unclear. In this study, we investigated the role of Nfic in root patterning and growth during molar root development. The molars of Nfic knockout mice exhibited an enlarged pulp chamber and apical displacement of the pulpal floor, characteristic features of taurodontism, due to delayed furcation formation. In developing molar roots of mutant mice at P14, BrdU positive cells decreased in the apical mesenchyme of the elongation region whereas those cells increased in the dental papilla of the furcation region. Whereas cytokeratin 14 and laminin were localized in HERS cells of mutant molars, Smoothened (Smo) and Gli1 were downregulated in preodontoblasts. In contrast, cytokeratin 14 and Smo were localized in the cells of the furcation region of mutant molars. These results indicate that Nfic regulates cell proliferation in the dental mesenchyme and affects the fate of HERS cells in a site-specific manner. From the results, it is suggested that Nfic is required for root patterning and growth during root morphogenesis. PMID- 26417476 TI - Differentiation of adipose-derived stem cells into Schwann-like cells: fetal bovine serum or human serum? AB - Access to autologous Schwann cells is limited due to lack of donor site and its difficult isolation and culture. Therefore, one of the possible ways to obtain to Schwann cells is to differentiate mesenchymal stem cells into glial pathway using various materials and protocols. The aim of this study was to compare the effects of fetal bovine serum and human serum on Schwann cell differentiation of adipose derived stem cells to choose the best serum for use in future research. For this purpose, after isolation of human adipose-derived stem cells, it was characterized and differentiated into Schwann cell lineage using two protocols which one of them contained fetal bovine serum and the other human serum. At the end, morphological evaluation declared an increased detachment of cells in response to human serum. On the other side, immunocytochemistry showed that there was a significant increase in the number of cells expressing glial fibrillary acidic proteins and S100 in fetal bovine serum-treated group when compared to human serum-treated one (P<0.05). It was concluded that fetal bovine serum was more effective than allogeneic human serum in Schwann cell differentiation of adipose-derived stem cells. PMID- 26417479 TI - Morphological study of styloid process of the temporal bone and its clinical implications. AB - The objective of this study was to study the morphometry of the styloid process of temporal bone and prevalence of elongated styloid process. The morphology of elongated styloid process along with its embryological and clinical importance are discussed. The present study included 110 human dry skulls which were procured from the bone collections of the department of anatomy. The styloid process was observed macroscopically on both sides of all the skulls, the elongations if any were noted. All the styloids were measured for their length, thickness at different levels and interstyloid distance at various levels. Out of 110 specimens, only 5 skulls (4.5%) exhibited the elongated styloid process. Among them, 3 skulls (2.7%) had unilateral elongation and 2 skulls (1.8%) had bilateral elongation of the styloid process. The mean length of the styloid process was 17.8+/-9.3 mm and 18.2+/-5.6 mm for the right and left sides, respectively. The prevalence of elongated styloid process in the present study was 4.5%. The clinical anatomy of this congenital variant is important to the neurosurgeon and radiologist, while interpreting the computed tomogram and magnetic resonance image scans. The morphological knowledge of elongated styloid process is clinically important since the course of the vertebral artery may be distorted in such situations. PMID- 26417480 TI - Rectus and oblique muscles of eyeball: a morphometric study of Indian population. AB - During the strengthening and weakening procedures of intraocular muscles, distance of insertion from the sclerocorneal junction is an important determinant in the identification of muscles. During repositioning of the aponeurosis of the muscles, it is desired that the width should not change in order to avoid diversion of forces. Available anatomic studies on insertions of extraocular muscles are few, date back to early twentieth century and have been conducted on mostly white population. The present study is an attempt to document the insertions of recti and oblique muscles in Indian population. Forty eyeballs were removed from orbit. Insertion of recti and obliqui were cleaned and eyeballs were perfused with normal saline to regain the volume (hence shape and size) before recording observations. Insertion of recti and obliqui muscles were observed under various study parameters. The distance of insertion of recti from the limbus were found to be 7.3 mm, 8.06 mm, 8.71 mm, and 8.74 mm for medial, inferior, lateral, and superior rectus, respectively. The superior oblique was aponeurotic and found to be more variable in mode of insertion as compared to inferior oblique which had a fleshy and relatively constant insertion. The observations on insertion of recti and obliqui as obtained in present study differ from earlier studies to the tune of 1-1.5 mm. This may be attributed to adoption of method of reperfusion of eyeball before recording observations thus maintaining size close to in vivo. The observations are expected to be closer to actual. PMID- 26417481 TI - Role of cadaveric dissections in modern medical curricula: a study on student perceptions. AB - The shift from traditional medical curricula to newer teaching and learning approaches such as problem-based learning has often resulted in omission or significant reduction of cadaveric dissections as a method of learning anatomy. The objective of this study was to evaluate students' perception of dissection in a graduate-entry, problem-based learning-based medical curriculum. At the end of the musculoskeletal dissection program in second year, a Likert-type questionnaire was used to explore medical student perceptions of the perceived advantages and challenges of cadaveric dissections in comparison with other anatomy teaching methods. Overall, a majority of students had a positive perception of dissections. Students who attended dissections regularly had significantly more positive perceptions about their experience and were in agreement with statements such as "dissections make learning more interesting" and "I would be disadvantaged if I did not attend dissection classes." Non regular attendance was associated with statements about dissections such as "I do not like the smell," "time consuming," and "bored with the way it is carried out." A follow-up study after completion of the medical program revealed a significant improvement of positive perception about dissection. Student perceptions appear to favour a role for cadaveric dissection in learning anatomy in modern medical curricula. However, optimal and effective integration of dissections is important, with consideration given to its structure and extent of content weighed against logistics and availability of resources; while addressing negative perceptions of dissection-based teaching. PMID- 26417482 TI - Bone tumors in pre-modern skulls from human skeletal series of Joseon Dynasty. AB - To date, there are still very few reports on benign-tumor cases based on East Asian skeletal series, even though other regions and continents have been well represented. In our study on the Joseon Human Skeletal Series, we identified benign bone tumors in two skeletons (cases Nos. 75 and 96). Our radiological analyses showed both cases to be homogeneous sclerotic bone masses aligned with the cranial vault suture. In a subsequent series of differential diagnoses, we determined both cases to be osteoma, the most common bone-tumor type reported for archaeological samples. Our study is the osteoarchaeological basis for this, the first-ever report on benign bone neoplasm in a pre-modern East Asian population. PMID- 26417483 TI - An anomalous portal vein crossing the lesser sac and ending at the upper part of ductus venosus. AB - In serial sagittal sections of a fetus on week 9 (crown-rump length, 36 mm), we incidentally found absence of the usual portal vein through the hepatoduodenal ligament. Instead, an anomalous portal vein originated behind the pancreatic body, crossed the lesser sac and merged with the upper part of the ductus venosus. During the course across the lesser sac, the vein provided a deep notch of the liver caudate lobe (Spiegel's lobe). The hepatoduodenal ligament contained the hepatic artery, the common bile duct and, at the right posterior margin of the ligament, and a branch of the anomalous portal vein which communicated with the usual right branch of the portal vein at the hepatic hilum. The umbilical portion of the portal vein took a usual morphology and received the umbilical vein and gave off the ductus venosus. Although it seemed not to be described yet, the present anomalous portal vein was likely to be a persistent left vitelline vein. The hepatoduodenal ligament was unlikely to include the left vitelline vein in contrast to the usual concept. PMID- 26417484 TI - Absence of the lateral and third ventricles associated with holoprosencephaly. AB - We describe a 6-month-old boy suffering from motor and mental retardation. All radiological features were suggestive of holoprosencephaly with no identifiable lateral or third ventricles and fusion of the thalami. PMID- 26417485 TI - Electromyography in musculoskeletal pain: A reappraisal and practical considerations. AB - BACKGROUND: Patients with musculoskeletal pain (MSP) and local tenderness in the back and extremities are frequently referred to electromyography (EMG) laboratory to assess the integrity of the spinal nerve roots, peripheral nerves, and skeletal muscles. When focal muscle weakness and anatomical sensory deficits are clinically evident, this procedure is almost always abnormal. In some situations, when the presenting symptoms consist of local pain and tenderness without neuromuscular deficits, its diagnostic utility becomes questionable as illustrated in the present study. METHODS: EMG findings of 75 patients referred for evaluation of local MSP and tenderness in the neck and lower back and in the upper and lower extremities were reviewed. These patients were selected from a group of 200 patients referred for evaluation of unilateral local pain and tenderness in various parts of the body. All EMG procedures and clinical neurologic examination were performed by the author and all underwent magnetic resonance imaging of the affected parts of the body prior to the procedure. None of the 75 patients studied had concurrent medical disorders or had previous spinal root injuries or surgeries to the spine. RESULTS: All 75 patients in this study showed normal EMG of the affected extremities and normal peripheral nerve conduction study. Those with herniated disc in the cervical or lumbar spine presenting with local pain and tenderness in the neck and lower back but without neurologic deficits or clear radicular symptoms, had normal study also. The remaining 125 patients excluded from the study, had various EMG and peripheral nerve abnormalities that can be attributed to concurrent medical disorders and previous injuries to the spinal roots. CONCLUSIONS: Use of EMG in the diagnosis of local MSP, unless associated with clinical neurologic deficits, almost always yields negative results. The utility of this procedure is limited to pathology in the motor unit. It cannot assess the function of the sensory components of the spinal roots, small-diameter sensory nerves, and the sensory innervation of the spine via sinuvertebral nerve. Therefore, if the motor unit is anatomically and physiologically intact, the procedure is of little value in the diagnosis of MSP. Likewise, peripheral nerve conduction study is likely to be normal unless clear neurologic deficits are present. The present study illustrates that a good history and meticulous neurologic examination should be an integral part of an ideal electrodiagnostic procedure. PMID- 26417486 TI - Optical mesoscopy without the scatter: broadband multispectral optoacoustic mesoscopy. AB - Optical mesoscopy extends the capabilities of biological visualization beyond the limited penetration depth achieved by microscopy. However, imaging of opaque organisms or tissues larger than a few hundred micrometers requires invasive tissue sectioning or chemical treatment of the specimen for clearing photon scattering, an invasive process that is regardless limited with depth. We developed previously unreported broadband optoacoustic mesoscopy as a tomographic modality to enable imaging of optical contrast through several millimeters of tissue, without the need for chemical treatment of tissues. We show that the unique combination of three-dimensional projections over a broad 500 kHz-40 MHz frequency range combined with multi-wavelength illumination is necessary to render broadband multispectral optoacoustic mesoscopy (2B-MSOM) superior to previous optical or optoacoustic mesoscopy implementations. PMID- 26417487 TI - Optoacoustic detection of tissue glycation. AB - Oxidative-based diseases including diabetes, chronic renal failure, cardiovascular diseases and neurological disorders are accompanied by accumulation of advanced glycation endproducts (AGE). Therefore, AGE-associated changes in tissue optical properties could yield a viable pathological indicator for disease diagnostics and monitoring. We investigated whether skin glycation could be detected based on absorption changes associated with AGE accumulation using spectral optoacoustic measurements and interrogated the optimal spectral band for skin glycation determination. Glycated and non-glycated skin was optoacoustically measured at multiple wavelengths in the visible region. The detected signals were spectrally processed and compared to measurements of skin auto-fluorescence and to second harmonic generation multiphoton microscopy images. Optoacoustic measurements are shown to be capable of detecting skin glycolysis based on AGE detection. A linear dependence was observed between optoacoustic intensity and the progression of skin glycation. The findings where corroborated by autofluorescence observations. Detection sensitivity is enhanced by observing normalised tissue spectra. This result points to a ratiometric method for skin glycation detection, specifically at 540 nm and 620 nm. We demonstrate that optoacoustic spectroscopy could be employed to detect AGE accumulation, and possibly can be employed as a non-invasive quick method for monitoring tissue glycation. PMID- 26417488 TI - Photoacoustic imaging of salivary glands. AB - In this work, we utilized photoacoustic imaging (PAI) with co-registered ultrasound (US) to non-invasively assess salivary gland function in vivo. A significant increase in salivary gland oxygen saturation was observed on PAI within minutes after gustatory stimulation of healthy mice reflective of the hyperemic response associated with secretion of saliva. Good correlation was seen between PAI and Doppler sonography. Salivary adenoid cystic carcinomas showed higher oxygen saturation compared to surrounding salivary gland tissue. Our results demonstrate the potential clinical utility of PAI for visualization of salivary gland physiology and pathology. PMID- 26417489 TI - In vivo dual-modality photoacoustic and optical coherence tomography imaging of human dermatological pathologies. AB - Vascular abnormalities serve as a key indicator for many skin diseases. Currently available methods in dermatology such as histopathology and dermatoscopy analyze underlying vasculature in human skin but are either invasive, time-consuming, and laborious or incapable of providing 3D images. In this work, we applied for the first time dual-modality photoacoustic and optical coherence tomography that provides complementary information about tissue morphology and vasculature of patients with different types of dermatitis. Its noninvasiveness and relatively short imaging time and the wide range of diseases that it can detect prove the merits of the dual-modality imaging system and show the great potential of its clinical use in the future. PMID- 26417490 TI - Camera array based light field microscopy. AB - This paper proposes a novel approach for high-resolution light field microscopy imaging by using a camera array. In this approach, we apply a two-stage relay system for expanding the aperture plane of the microscope into the size of an imaging lens array, and utilize a sensor array for acquiring different sub apertures images formed by corresponding imaging lenses. By combining the rectified and synchronized images from 5 * 5 viewpoints with our prototype system, we successfully recovered color light field videos for various fast moving microscopic specimens with a spatial resolution of 0.79 megapixels at 30 frames per second, corresponding to an unprecedented data throughput of 562.5 MB/s for light field microscopy. We also demonstrated the use of the reported platform for different applications, including post-capture refocusing, phase reconstruction, 3D imaging, and optical metrology. PMID- 26417491 TI - Controlling local temperature in water using femtosecond optical tweezer. AB - A novel method of directly observing the effect of temperature rise in water at the vicinity of optical trap center is presented. Our approach relies on changed values of corner frequency of the optical trap that, in turn, is realized from its power spectra. Our two color experiment is a unique combination of a non heating femtosecond trapping laser at 780 nm, coupled to a femtosecond infrared heating laser at 1560 nm, which precisely controls temperature at focal volume of the trap center using low powers (100-800 uW) at high repetition rate. The geometric ray optics model quantitatively supports our experimental data. PMID- 26417492 TI - Magnetic resonance imaging appropriate for construction of subject-specific head models for diffuse optical tomography. AB - Subject-specific head models of which their geometry is based on structural magnetic resonance images are essential to accurately estimate the spatial sensitivity profiles for image reconstruction in diffuse optical tomography. T1 weighted magnetic resonance images, which are commonly used for structural imaging, are not sufficient for the threshold-based segmentation of the superficial tissues. Two types of pulse sequences, which provide a high contrast among the superficial tissues, are introduced to complement the segmentation to construct the subject-specific head models. The magnetic resonance images acquired by the proposed pulse sequences are robust to the threshold level and adequate for the threshold-based segmentation of the superficial tissues compared to the T1- and T2-weighted images. The total scan time of the proposed pulse sequences is less than one-fourth of that for the T2-weighted pulse sequence. PMID- 26417493 TI - InstantScope: a low-cost whole slide imaging system with instant focal plane detection. AB - We report the development of a high-throughput whole slide imaging (WSI) system by adapting a cost-effective optomechanical add-on kit to existing microscopes. Inspired by the phase detection concept in professional photography, we attached two pinhole-modulated cameras at the eyepiece ports for instant focal plane detection. By adjusting the positions of the pinholes, we can effectively change the view angle for the sample, and as such, we can use the translation shift of the two pinhole-modulated images to identify the optimal focal position. By using a small pinhole size, the focal-plane-detection range is on the order of millimeter, orders of magnitude longer than the objective's depth of field. We also show that, by analyzing the phase correlation of the pinhole-modulated images, we can determine whether the sample contains one thin section, folded sections, or multiple layers separated by certain distances - an important piece of information prior to a detailed z scan. In order to achieve system automation, we deployed a low-cost programmable robotic arm to perform sample loading and $14 stepper motors to drive the microscope stage to perform x-y scanning. Using a 20X objective lens, we can acquire a 2 gigapixel image with 14 mm by 8 mm field of view in 90 seconds. The reported platform may find applications in biomedical research, telemedicine, and digital pathology. It may also provide new insights for the development of high-content screening instruments. PMID- 26417494 TI - Reduction of distortion in photothermal microscopy and its application to the high-resolution three-dimensional imaging of nonfluorescent tissues. AB - A scheme for reducing image distortion in photothermal microscopy is presented. In photothermal microscopy, the signal shape exhibits twin peaks corresponding to the focusing or defocusing of the probe beam when a sample is scanned in the axial direction. This causes a distortion when imaging a structured sample in the axial plane. Here, we demonstrate that image distortion caused by the twin peaks is effectively suppressed by providing a small offset between two the focal planes of the pump and the probe beams. Experimental results demonstrate improvement in resolution, especially in the axial direction, over conventional optical microscopy-even with the focal offset. When a dry objective lens with a numerical aperture of 0.95 is used, the full width at half the maximum of the axial point spread function is 0.6 MUm, which is 50% (62%) smaller than the focal spot sizes of the pump (probe) beam. Herein, we present high-resolution three dimensional imaging of thick biological tissues based on the present scheme. PMID- 26417495 TI - Photoacoustic imaging of cerebral hypoperfusion during acupuncture. AB - Using acupuncture to treat cerebral hypoperfusion is a hot topic. However, there is a lack of effective tools to clarify the therapeutic effect of acupuncture on cerebral hypoperfusion. Here, we show in a mouse model of cerebral hypoperfusion that photoacoustic tomography (PAT) can noninvasively image cerebral vasculature and track total hemoglobin (HbT) concentration changes in cerebral hypoperfusion with acupuncture stimulation on the YangLingQuan (GB34) point. We measured the changes of HbT concentration and found that the HbT concentration in hypoperfusion regions was clearly lower than that in the control regions when the acupuncture was absent; however, it was significantly increased when the acupuncture was implemented on the GB34 point. We also observed the increase of vessel size and the generation of new vessels in cerebral hypoperfusion during acupuncture. Laser speckle imaging (LSI) was employed to validate some of the PAT findings. PMID- 26417496 TI - Validation of a partial coherence interferometry method for estimating retinal shape. AB - To validate a simple partial coherence interferometry (PCI) based retinal shape method, estimates of retinal shape were determined in 60 young adults using off axis PCI, with three stages of modeling using variants of the Le Grand model eye, and magnetic resonance imaging (MRI). Stage 1 and 2 involved a basic model eye without and with surface ray deviation, respectively and Stage 3 used model with individual ocular biometry and ray deviation at surfaces. Considering the theoretical uncertainty of MRI (12-14%), the results of the study indicate good agreement between MRI and all three stages of PCI modeling with <4% and <7% differences in retinal shapes along horizontal and vertical meridians, respectively. Stage 2 and Stage 3 gave slightly different retinal co-ordinates than Stage 1 and we recommend the intermediate Stage 2 as providing a simple and valid method of determining retinal shape from PCI data. PMID- 26417497 TI - Multimodal fiber source for nonlinear microscopy based on a dissipative soliton laser. AB - Recent developments in high energy femtosecond fiber lasers have enabled robust and lower-cost sources for multiphoton-fluorescence and harmonic-generation imaging. However, picosecond pulses are better suited for Raman scattering microscopy, so the ideal multimodal source for nonlinear microcopy needs to provide both durations. Here we present spectral compression of a high-power femtosecond fiber laser as a route to producing transform-limited picosecond pulses. These pulses pump a fiber optical parametric oscillator to yield a robust fiber source capable of providing the synchronized picosecond pulse trains needed for Raman scattering microscopy. Thus, this system can be used as a multimodal platform for nonlinear microscopy techniques. PMID- 26417498 TI - NIR light propagation in a digital head model for traumatic brain injury (TBI). AB - Near infrared spectroscopy (NIRS) is capable of detecting and monitoring acute changes in cerebral blood volume and oxygenation associated with traumatic brain injury (TBI). Wavelength selection, source-detector separation, optode density, and detector sensitivity are key design parameters that determine the imaging depth, chromophore separability, and, ultimately, clinical usefulness of a NIRS instrument. We present simulation results of NIR light propagation in a digital head model as it relates to the ability to detect intracranial hematomas and monitor the peri-hematomal tissue viability. These results inform NIRS instrument design specific to TBI diagnosis and monitoring. PMID- 26417499 TI - Novel catheter enabling simultaneous radiofrequency ablation and optical coherence reflectometry. AB - A novel radiofrequency ablation catheter has been developed with integrated custom designed optics, enabling real-time monitoring of radiofrequency ablation procedures through polarization-sensitive optical coherence reflectometry. The optics allow for proper tissue illumination through a view-port machined in the catheter tip, thus providing lesion depth control over the RF ablation treatment. The system was verified in an in-vitro model of swine myocardium. Optical performance and thermal stability was confirmed after more than 25 procedures, without any damage to the optical assembly induced by thermal stress or material degradation. The use of this catheter in RF ablation treatments may make possible to assess lesion depth during therapy, thus translating into a reduction of potential complications on the procedure. PMID- 26417500 TI - Specific imaging of atherosclerotic plaque lipids with two-wavelength intravascular photoacoustics. AB - The lipid content in plaques is an important marker for identifying atherosclerotic lesions and disease states. Intravascular photoacoustic (IVPA) imaging can be used to visualize lipids in the artery. In this study, we further investigated lipid detection in the 1.7-um spectral range. By exploiting the relative difference between the IVPA signal strengths at 1718 and 1734 nm, we could successfully detect and differentiate between the plaque lipids and peri adventitial fat in human coronary arteries ex vivo. Our study demonstrates that IVPA imaging can positively identify atherosclerotic plaques using only two wavelengths, which could enable rapid data acquisition in vivo. PMID- 26417501 TI - Strategy for accurate liver intervention by an optical tracking system. AB - Image-guided navigation for radiofrequency ablation of liver tumors requires the accurate guidance of needle insertion into a tumor target. The main challenge of image-guided navigation for radiofrequency ablation of liver tumors is the occurrence of liver deformations caused by respiratory motion. This study reports a strategy of real-time automatic registration to track custom fiducial markers glued onto the surface of a patient's abdomen to find the respiratory phase, in which the static preoperative CT is performed. Custom fiducial markers are designed. Real-time automatic registration method consists of the automatic localization of custom fiducial markers in the patient and image spaces. The fiducial registration error is calculated in real time and indicates if the current respiratory phase corresponds to the phase of the static preoperative CT. To demonstrate the feasibility of the proposed strategy, a liver simulator is constructed and two volunteers are involved in the preliminary experiments. An ex vivo porcine liver model is employed to further verify the strategy for liver intervention. Experimental results demonstrate that real-time automatic registration method is rapid, accurate, and feasible for capturing the respiratory phase from which the static preoperative CT anatomical model is generated by tracking the movement of the skin-adhered custom fiducial markers. PMID- 26417502 TI - In vivo imaging of activated microglia in a mouse model of focal cerebral ischemia by two-photon microscopy. AB - Microglia are brain resident macrophages rapidly responding to various stimuli to exert appropriate inflammatory responses. Although they have recently been exploited as an attractive candidate for imaging neuroinflammation, it is still difficult to visualize them at the cellular and molecular levels. Here we imaged activated microglia by establishing intracranial window chamber (ICW) in a mouse model of focal cerebral ischemia by using two-photon microscopy (TPM), in vivo. Intravenous injection of fluorescent antibodies allowed us to detect significantly elevated levels of Iba-1 and CD68 positive activated microglia in the ipsilateral compared to the contralateral side of the infarct. We further observed that indomethacin, a non-steroidal anti-inflammatory drug significantly attenuated CD68-positive microglial activation in ICW, which was further confirmed by qRT-PCR biochemical analyses. In conclusion, we believe that in vivo TPM imaging of ICW would be a useful tool to screen for therapeutic interventions lowering microglial activation hence neuroinflammation. PMID- 26417503 TI - Observation of sound-induced corneal vibrational modes by optical coherence tomography. AB - The mechanical stability of the cornea is critical for maintaining its normal shape and refractive function. Here, we report an observation of the mechanical resonance modes of the cornea excited by sound waves and detected by using phase sensitive optical coherence tomography. The cornea in bovine eye globes exhibited three resonance modes in a frequency range of 50-400 Hz. The vibration amplitude of the fundamental mode at 80-120 Hz was ~8 um at a sound pressure level of 100 dB (2 Pa). Vibrography allows the visualization of the radially symmetric profiles of the resonance modes. A dynamic finite-element analysis supports our observation. PMID- 26417504 TI - Non-contact measurement of oxygen saturation with an RGB camera. AB - A novel method (Sophia) is presented to track oxygen saturation changes in a controlled environment using an RGB camera placed approximately 1.5 m away from the subject. The method is evaluated on five healthy volunteers (Fitzpatrick skin phenotypes II, III, and IV) whose oxygen saturations were varied between 80% and 100% in a purpose-built chamber over 40 minutes each. The method carefully selects regions of interest (ROI) in the camera image by calculating signal-to noise ratios for each ROI. This allows it to track changes in oxygen saturation accurately with respect to a conventional pulse oximeter (median coefficient of determination, 0.85). PMID- 26417505 TI - Evaluation of burn severity in vivo in a mouse model using spectroscopic optical coherence tomography. AB - Clinical management of burn injuries depends upon an accurate assessment of the depth of the wound. Current diagnostic methods rely primarily on subjective visual inspection, which can produce variable results. In this study, spectroscopic optical coherence tomography was used to objectively evaluate burn injuries in vivo in a mouse model. Significant spectral differences were observed and correlated with the depth of the injury as determined by histopathology. The relevance of these results to clinical burn management in human tissues is discussed. PMID- 26417506 TI - Longitudinal far red gene-reporter imaging of cancer metastasis in preclinical models: a tool for accelerating drug discovery. AB - In this short communication, we demonstrate for the first time, the use of far red fluorescent gene reporter, iRFP to longitudinally and non-invasively track the in vivo process of lymphatic metastases from an orthotopic site of mammary implantation through lymphatic vessels and to draining lymph nodes. Potentially useful to accelerate cancer drug discovery as an in vivo screening tool to monitor the pharmacological arrest of metastasis, we show that the custom as well as commercial small animal imaging devices have adequate performance to detect the gene reporter in stably expressing metastatic cancer cells. PMID- 26417507 TI - Periscope for noninvasive two-photon imaging of murine retina in vivo. AB - Two-photon microscopy allows visualization of subcellular structures in the living animal retina. In previously reported experiments it was necessary to apply a contact lens to each subject. Extending this technology to larger animals would require fitting a custom contact lens to each animal and cumbersome placement of the living animal head on microscope stage. Here we demonstrate a new device, periscope, for coupling light energy into mouse eye and capturing emitted fluorescence. Using this periscope we obtained images of the RPE and their subcellular organelles, retinosomes, with larger field of view than previously reported. This periscope provides an interface with a commercial microscope, does not require contact lens and its design could be modified to image retina in larger animals. PMID- 26417508 TI - Design of high-performance adaptive objective lens with large optical depth scanning range for ultrabroad near infrared microscopic imaging. AB - We report on the theory and design of adaptive objective lens for ultra broadband near infrared light imaging with large dynamic optical depth scanning range by using an embedded tunable lens, which can find wide applications in deep tissue biomedical imaging systems, such as confocal microscope, optical coherence tomography (OCT), two-photon microscopy, etc., both in vivo and ex vivo. This design is based on, but not limited to, a home-made prototype of liquid-filled membrane lens with a clear aperture of 8mm and the thickness of 2.55mm ~3.18mm. It is beneficial to have an adaptive objective lens which allows an extended depth scanning range larger than the focal length zoom range, since this will keep the magnification of the whole system, numerical aperture (NA), field of view (FOV), and resolution more consistent. To achieve this goal, a systematic theory is presented, for the first time to our acknowledgment, by inserting the varifocal lens in between a front and a back solid lens group. The designed objective has a compact size (10mm-diameter and 15mm-length), ultrabroad working bandwidth (760nm - 920nm), a large depth scanning range (7.36mm in air) - 1.533 times of focal length zoom range (4.8mm in air), and a FOV around 1mm * 1mm. Diffraction-limited performance can be achieved within this ultrabroad bandwidth through all the scanning depth (the resolution is 2.22 MUm - 2.81 MUm, calculated at the wavelength of 800nm with the NA of 0.214 - 0.171). The chromatic focal shift value is within the depth of focus (field). The chromatic difference in distortion is nearly zero and the maximum distortion is less than 0.05%. PMID- 26417509 TI - Modal content of living human cone photoreceptors. AB - Decades of experimental and theoretical investigations have established that photoreceptors capture light based on the principles of optical waveguiding. Yet considerable uncertainty remains, even for the most basic prediction as to whether photoreceptors support more than a single waveguide mode. To test for modal behavior in human cone photoreceptors in the near infrared, we took advantage of adaptive-optics optical coherence tomography (AO-OCT, lambdac = 785 nm) to noninvasively image in three dimensions the reflectance profile of cones. Modal content of reflections generated at the cone inner segment and outer segment junction (IS/OS) and cone outer segment tip (COST) was examined over a range of cone diameters in 1,802 cones from 0.6 degrees to 10 degrees retinal eccentricity. Second moment analysis in conjunction with theoretical predictions indicate cone IS and OS have optical properties consistent of waveguides, which depend on segment diameter and refractive index. Cone IS was found to support a single mode near the fovea (<=3 degrees ) and multiple modes further away (>4 degrees ). In contrast, no evidence of multiple modes was found in the cone OSs. The IS/OS and COST reflections share a common optical aperture, are most circular near the fovea, show no orientation preference, and are temporally stable. We tested mode predictions of a conventional step-index fiber model and found that in order to fit our AO-OCT results required a lower estimate of the IS refractive index and introduction of an IS focusing/tapering effect. PMID- 26417510 TI - Pupil tracking optical coherence tomography for precise control of pupil entry position. AB - To maximize the collection efficiency of back-scattered light, and to minimize aberrations and vignetting, the lateral position of the scan pivot of an optical coherence tomography (OCT) retinal scanner should be imaged to the center of the ocular pupil. Additionally, several retinal structures including Henle's Fiber Layer (HFL) exhibit reflectivities that depend on illumination angle, which can be controlled by varying the pupil entry position of the OCT beam. In this work, we describe an automated method for controlling the lateral pupil entry position in retinal OCT by utilizing pupil tracking in conjunction with a 2D fast steering mirror placed conjugate to the retinal plane. We demonstrate that pupil tracking prevents lateral motion artifacts from impeding desired pupil entry locations, and enables precise pupil entry positioning and therefore control of the illumination angle of incidence at the retinal plane. We use our prototype pupil tracking OCT system to directly visualize the obliquely oriented HFL. PMID- 26417511 TI - Algorithm for mapping cutaneous tissue oxygen concentration using hyperspectral imaging. AB - The measurement of tissue oxygenation plays an important role in the diagnosis and therapeutic assessment of a large variety of diseases. Many different methods have been developed and are currently applied in clinical practice for the measurement of tissue oxygenation. Unfortunately, each of these methods has its own limitations. In this paper we proposed the use of hyperspectral imaging as new method for the assessment of the tissue oxygenation level. To extract this information from hyperspectral images a new algorithm for mapping cutaneous tissue oxygen concentration was developed. This algorithm takes into account and solves some problems related to setting and calculation of some parameters derived from hyperspectral images. The algorithm was tested with good results on synthetic images and then validated on the fingers of a hand with different blood irrigation states. The results obtained have proved the ability of hyperspectral imaging together with the developed algorithm to map the oxy- and deoxyhemoglobin distribution on the analyzed fingers. These are only preliminary results and other studies should be done before this approach to be used in the clinical setting for the diagnosis and monitoring of various diseases. PMID- 26417513 TI - Optical imaging of the prefrontal activity in joint attention experience. AB - Functional near-infrared spectroscopy (fNIRS) was used to measure the prefrontal activity in joint attention experience. 16 healthy adults participated in the experiment in which 42 optical channels were fixed over the anterior prefrontal cortex (aPFC), dorsolateral prefrontal cortex (DLPFC), inferior frontal gyrus (IFG) and a small anterior portion of the superior temporal gyrus (STG). Video stimuli were used to engender joint or non-joint attention experience in observers. Cortical hemodynamic response and functional connectivity were measured and averaged across all subjects for each stimulus condition. Our data showed the activation in joint attention located in the aPFC and DLPFC bilaterally, but dominantly in the left hemisphere. This observation, together with the previous findings on infants and children, provides a clear developmental scenario on the prefrontal activation associated with joint attention process. In the case of non-joint attention condition, only a small region of the right DLPFC was activated. Functional connectivity was observed to be enhanced, but differently in joint and non-joint attention condition. PMID- 26417512 TI - Bedside monitoring of patients with shock using a portable spatially-resolved near-infrared spectroscopy. AB - Clinical monitoring of shock mainly depends on blood-oxygen-indices obtained from invasive blood sample tests. The central internal jugular central vein oxygenation level (ScvO2) has been considered as a gold standard indicator for shock prediction. We developed a noninvasive spatially-resolved near-infrared spectroscopy (SR-NIRS) to measure tissue blood oxygen saturation (StO2) surrounding the region of taking blood sample for the ScvO2 test in 25 patients with shock. StO2 values were found to be highly correlated (r = 0.84, p < 0.001) with ScvO2 levels and the concordance coefficient of 0.80 is high. The results suggest the potential of noninvasive SR-NIRS for bedside shock monitoring. PMID- 26417514 TI - Rapid spontaneous Raman light sheet microscopy using cw-lasers and tunable filters. AB - We perform rapid spontaneous Raman 2D imaging in light-sheet microscopy using continuous wave lasers and interferometric tunable filters. By angularly tuning the filter, the cut-on/off edge transitions are scanned along the excited Stokes wavelengths. This allows obtaining cumulative intensity profiles of the scanned vibrational bands, which are recorded on image stacks; resembling a spectral version of the knife-edge technique to measure intensity profiles. A further differentiation of the stack retrieves the Raman spectra at each pixel of the image which inherits the 3D resolution of the host light sheet system. We demonstrate this technique using solvent solutions and composites of polystyrene beads and lipid droplets immersed in agar and by imaging the C-H (2800-3100cm( 1)) region in a C. elegans worm. The image acquisition time results in 4 orders of magnitude faster than confocal point scanning Raman systems, allowing the possibility of performing fast spontaneous Raman.3D-imaging on biological samples. PMID- 26417515 TI - In vivo microscopy of hemozoin: towards a needle free diagnostic for malaria. AB - Clinical diagnosis of malaria suffers from poor specificity leading to overtreatment with antimalarial medications. Alternatives, like blood smear microscopy or antigen-based tests, require a blood sample. We investigate in vivo microscopy as a needle-free malaria diagnostic. Two optical signatures, birefringence and absorbance, of the endogenous malaria by-product hemozoin were evaluated as in vivo optical biomarkers. Hemozoin birefringence was difficult to detect in highly scattering tissue; however, hemozoin absorbance was observed in increasingly complex biological environments and detectable over a clinically relevant range of parasitemia in vivo in a P. yoelii-infected mouse model of malaria. PMID- 26417516 TI - Ultrastructural features of collagen in thyroid carcinoma tissue observed by polarization second harmonic generation microscopy. AB - Changes in collagen ultrastructure between malignant and normal human thyroid tissue were investigated ex vivo using polarization second harmonic generation (SHG) microscopy. The second-order nonlinear optical susceptibility tensor component ratio and the degree of linear polarization (DOLP) of the SHG signal were measured. The ratio values are related to the collagen ultrastructure, while DOLP indicates the relative amount of coherent signal and incoherent scattering of SHG. Increase in ratio values and decrease in DOLP were observed for tumor tissue compared to normal thyroid, indicating higher ultrastructural disorder in tumor collagen. PMID- 26417517 TI - Diverse effects of a 445 nm diode laser on isometric contraction of the rat aorta. AB - The usefulness of visible lasers in treating vascular diseases is controversial. It is probable that multiple effects of visible lasers on blood vessels and their unclear mechanisms have hampered the usefulness of this therapy. Therefore, elucidating the precise actions and mechanisms of the effects of lasers on blood vessels would provide insight into potential biomedical applications. Here, using organ chamber isometric contraction measurements, western blotting, patch-clamp, and en face immunohistochemistry, we showed that a 445 nm diode laser contracted rat aortic rings, both by activating endothelial nitric oxide synthase and by increasing oxidative stress. In addition to the effects on the endothelium, the laser also directly relaxed and contracted vascular smooth muscle by inhibiting L type Ca(2+) channels and by activating protein tyrosine kinases, respectively. Thus, we conclude that exposure to 445 nm laser might contract and dilate blood vessels in the endothelium and smooth muscle via distinct mechanisms. PMID- 26417518 TI - Label-free surface-enhanced Raman spectroscopy for detection of colorectal cancer and precursor lesions using blood plasma. AB - Fecal based tests have limited diagnostic values in detecting adenomatous polyps, the precursor lesions to colorectal cancer (CRC). Surface enhanced Raman spectroscopy (SERS) using silver nanoparticles as substrate is a multiplexed analytical technique capable of detecting biomolecules with high sensitivity. This study utilizes SERS to analyze blood plasma for detecting both CRC and adenomatous polyps for the first time. Blood plasma samples are collected from healthy control subjects and patients diagnosed with adenomas and CRC. Using a real-time Raman system, SERS spectra for blood plasma samples are measured in 1 s. The collected SERS spectra are analyzed with partial least squares discriminant analysis. Classification of normal versus CRC plus adenomatous polyps achieved diagnostic sensitivity of 86.4% and specificity of 80%. The results suggest that blood plasma SERS analysis could be a potential screening test to detect both CRC and adenomas. PMID- 26417519 TI - Using functional near-infrared spectroscopy (fNIRS) to detect the prefrontal cortical responses to deception under different motivations. AB - In this study, functional near-infrared spectroscopy (fNIRS) was adopted to investigate the prefrontal cortical responses to deception under different motivations. By using a feigned memory impairment paradigm, 19 healthy adults were asked to deceive under the two different motivations: to obtain rewards and to avoid punishments. Results indicated that when deceiving for obtaining rewards, there was greater neural activation in the right inferior frontal gyrus (IFG) than the control condition. When deceiving for avoiding punishments, there was greater activation in the right inferior frontal gyrus (IFG) and the left middle frontal gyrus (MFG) than the control condition. In addition, deceiving for avoiding punishments led to greater neural activation in the left MFG than when deceiving for obtaining rewards. Furthermore, the results showed a moderate hit rate in detecting deception under either motivation. These results demonstrated that deception with different motivations led to distinct responses in the prefrontal cortex. fNIRS could provide a useful technique for the detection of deception with strategy of feigning memory impairment under different motivations. PMID- 26417520 TI - Three-dimensional, three-vector-component velocimetry of cilia-driven fluid flow using correlation-based approaches in optical coherence tomography. AB - Microscale quantification of cilia-driven fluid flow is an emerging area in medical physiology, including pulmonary and central nervous system physiology. Cilia-driven fluid flow is most completely described by a three-dimensional, three-component (3D3C) vector field. Here, we generate 3D3C velocimetry measurements by synthesizing higher dimensional data from lower dimensional measurements obtained using two separate optical coherence tomography (OCT)-based approaches: digital particle image velocimetry (DPIV) and dynamic light scattering (DLS)-OCT. Building on previous work, we first demonstrate directional DLS-OCT for 1D2C velocimetry measurements in the sub-1 mm/s regime (sub-2.5 inch/minute regime) of cilia-driven fluid flow in Xenopus epithelium, an important animal model of the ciliated respiratory tract. We then extend our analysis toward 3D3C measurements in Xenopus using both DLS-OCT and DPIV. We demonstrate the use of DPIV-based approaches towards flow imaging of Xenopus cerebrospinal fluid and mouse trachea, two other important ciliary systems. Both of these flows typically fall in the sub-100 MUm/s regime (sub-0.25 inch/minute regime). Lastly, we develop a framework for optimizing the signal-to-noise ratio of 3D3C flow velocity measurements synthesized from 2D2C measures in non orthogonal planes. In all, 3D3C OCT-based velocimetry has the potential to comprehensively characterize the flow performance of biological ciliated surfaces. PMID- 26417521 TI - Signal enhancement in multiphoton imaging by the use of coated glass substrates. AB - In nonlinear optical imaging of biological specimens, more than half of the generated luminescence signal is lost, when signal collection is performed in the epi-illuminated geometry. In this study, we enhanced the collected luminescence signal by the use of alternating multiply-coated layers of tantalum pentoxide (Ta2O5) and silicon dioxide (SiO2) on standard microscope cover glasses that has high transmission in the near-infrared wavelength region and high reflection of the visible, luminescence signal. Our coating is biocompatible, allows visual examination of the specimens and optimize collection of the luminescence signal. We demonstrated this approach on a number of specimens including sulforhodamine solution, fluorescence microspheres, and labeled 3T3 cells. In all cases, the use of coated cover glass enhanced signal, optimally by a factor of about 2. Image analysis of labeled 3T3 cells also shows signal enhancement did not contribute to additional photobleaching. Our results show that properly designed coated cover glass can enhance detected signal in multiphoton microscopy and result in improved image quality. PMID- 26417522 TI - Quantitative imaging of light-triggered doxorubicin release. AB - The efficacy of chemotherapy is related, in large part, to the concentration of drug that reaches tumor sites. Doxorubicin (DOX) is a common anti-cancer drug that is also approved for use in liposomal form for the treatment of ovarian cancer. We recently developed a porphyrin-phospholipid (PoP)-liposome system that enables on demand release of DOX from liposomes using near infrared irradiation to improve DOX bioavailability. Owing to its intrinsic fluorescence, it is possible, and desirable, to quantify DOX concentration and distribution, preferably noninvasively. Here we quantified DOX distribution following light triggered drug release in phantoms and an animal carcass using spatial frequency domain imaging. This study demonstrates the feasibility of non-invasive quantitative mapping of DOX distributions in target areas. PMID- 26417523 TI - Quantitative analysis of platelets aggregates in 3D by digital holographic microscopy. AB - Platelet spreading and retraction play a pivotal role in the platelet plugging and the thrombus formation. In routine laboratory, platelet function tests include exhaustive information about the role of the different receptors present at the platelet surface without information on the 3D structure of platelet aggregates. In this work, we develop, a method in Digital Holographic Microscopy (DHM) to characterize the platelet and aggregate 3D shapes using the quantitative phase contrast imaging. This novel method is suited to the study of platelets physiology in clinical practice as well as the development of new drugs. PMID- 26417524 TI - Automated choroidal neovascularization detection algorithm for optical coherence tomography angiography. AB - Optical coherence tomography angiography has recently been used to visualize choroidal neovascularization (CNV) in participants with age-related macular degeneration. Identification and quantification of CNV area is important clinically for disease assessment. An automated algorithm for CNV area detection is presented in this article. It relies on denoising and a saliency detection model to overcome issues such as projection artifacts and the heterogeneity of CNV. Qualitative and quantitative evaluations were performed on scans of 7 participants. Results from the algorithm agreed well with manual delineation of CNV area. PMID- 26417525 TI - Contrast-based sensorless adaptive optics for retinal imaging. AB - Conventional adaptive optics ophthalmoscopes use wavefront sensing methods to characterize ocular aberrations for real-time correction. However, there are important situations in which the wavefront sensing step is susceptible to difficulties that affect the accuracy of the correction. To circumvent these, wavefront sensorless adaptive optics (or non-wavefront sensing AO; NS-AO) imaging has recently been developed and has been applied to point-scanning based retinal imaging modalities. In this study we show, for the first time, contrast-based NS AO ophthalmoscopy for full-frame in vivo imaging of human and animal eyes. We suggest a robust image quality metric that could be used for any imaging modality, and test its performance against other metrics using (physical) model eyes. PMID- 26417527 TI - Fast time-lens-based line-scan single-pixel camera with multi-wavelength source. AB - A fast time-lens-based line-scan single-pixel camera with multi-wavelength source is proposed and experimentally demonstrated in this paper. A multi-wavelength laser instead of a mode-locked laser is used as the optical source. With a diffraction grating and dispersion compensating fibers, the spatial information of an object is converted into temporal waveforms which are then randomly encoded, temporally compressed and captured by a single-pixel photodetector. Two algorithms (the dictionary learning algorithm and the discrete cosine transform based algorithm) for image reconstruction are employed, respectively. Results show that the dictionary learning algorithm has greater capability to reduce the number of compressive measurements than the DCT-based algorithm. The effective imaging frame rate increases from 200 kHz to 1 MHz, which shows a significant improvement in imaging speed over conventional single-pixel cameras. PMID- 26417526 TI - Fast single photon avalanche photodiode-based time-resolved diffuse optical tomography scanner. AB - Resolution in diffuse optical tomography (DOT) is a persistent problem and is primarily limited by high degree of light scatter in biological tissue. We showed previously that the reduction in photon scatter between a source and detector pair at early time points following a laser pulse in time-resolved DOT is highly dependent on the temporal response of the instrument. To this end, we developed a new single-photon avalanche photodiode (SPAD) based time-resolved DOT scanner. This instrument uses an array of fast SPADs, a femto-second Titanium Sapphire laser and single photon counting electronics. In combination, the overall instrument temporal impulse response function width was 59 ps. In this paper, we report the design of this instrument and validate its operation in symmetrical and irregularly shaped optical phantoms of approximately small animal size. We were able to accurately reconstruct the size and position of up to 4 absorbing inclusions, with increasing image quality at earlier time windows. We attribute these results primarily to the rapid response time of our instrument. These data illustrate the potential utility of fast SPAD detectors in time-resolved DOT. PMID- 26417528 TI - Direct regularization from co-registered anatomical images for MRI-guided near infrared spectral tomographic image reconstruction. AB - Combining anatomical information from high resolution imaging modalities to guide near-infrared spectral tomography (NIRST) is an efficient strategy for improving the quality of the reconstructed spectral images. A new approach for incorporating image information directly into the inversion matrix regularization was examined using Direct Regularization from Images (DRI), which encodes the gray-scale data into the NIRST image reconstruction problem. This process has the benefit of eliminating user intervention such as image segmentation of distinct regions. Specifically, the Dynamic Contrast Enhanced Magnetic Resonance (DCE-MR) image intensity value differences within the anatomical image were used to implement an exponentially-weighted regularization function between the image pixels. The algorithm was validated using simulated reconstructions with noise, and the results showed that spatial resolution and robustness of the reconstructed images were significantly improved by appropriate choice of the regularization weight parameters. The proposed approach was also tested on in vivo breast data acquired in a recent clinical trial combining NIRST / MRI for cancer tumor characterization. Relative to the standard "no priors" diffuse recovery, the contrast of the tumor to the normal surrounding tissue increased from 2.4 to 3.6, and the difference between the tumor size segmented from DCE-MR images and reconstructed optical images decreased from 18% to 6%, while there was an overall decrease in surface artifacts. PMID- 26417529 TI - Pump-probe imaging of pigmented cutaneous melanoma primary lesions gives insight into metastatic potential. AB - Metastatic melanoma is associated with a poor prognosis, but no method reliably predicts which melanomas of a given stage will ultimately metastasize and which will not. While sentinel lymph node biopsy (SLNB) has emerged as the most powerful predictor of metastatic disease, the majority of people dying from metastatic melanoma still have a negative SLNB. Here we analyze pump-probe microscopy images of thin biopsy slides of primary melanomas to assess their metastatic potential. Pump-probe microscopy reveals detailed chemical information of melanin with subcellular spatial resolution. Quantification of the molecular signatures without reference standards is achieved using a geometrical representation of principal component analysis. Melanin structure is analyzed in unison with the chemical information by applying principles of mathematical morphology. Results show that melanin in metastatic primary lesions has lower chemical diversity than non-metastatic primary lesions, and contains two distinct phenotypes that are indicative of aggressive disease. Further, the mathematical morphology analysis reveals melanin in metastatic primary lesions has a distinct "dusty" quality. Finally, a statistical analysis shows that the combination of the chemical information with spatial structures predicts metastatic potential with much better sensitivity than SLNB and high specificity, suggesting pump probe microscopy can be an important tool to help predict the metastatic potential of melanomas. PMID- 26417530 TI - Intrinsic heating in optically trapped Au nanoparticles measured by dark-field spectroscopy. AB - Assessing the degree of heating present when a metal nanoparticle is trapped in an optical tweezers is critical for its appropriate use in biological applications as a nanoscale force sensor. Heating is necessarily present for trapped plasmonic particles because of the non-negligible extinction which contributes to an enhanced polarisability. We present a robust method for characterising the degree of heating of trapped metallic nanoparticles, using the intrinsic temperature dependence of the localised surface plasmon resonance (LSPR) to infer the temperature of the surrounding fluid at different incident laser powers. These particle specific measurements can be used to infer the rate of heating and local temperature of trapped nanoparticles. Our measurements suggest a considerable amount of a variability in the degree of heating, on the range of 414-673 K/W, for different 100 nm diameter Au nanoparticles, and we associated this with variations in the axial trapping position. PMID- 26417532 TI - CORRIGENDUM. AB - [This corrects the article on p. 13 in vol. 10, PMID: 25709858.]. PMID- 26417531 TI - Master slave en-face OCT/SLO. AB - Master Slave optical coherence tomography (MS-OCT) is an OCT method that does not require resampling of data and can be used to deliver en-face images from several depths simultaneously. As the MS-OCT method requires important computational resources, the number of multiple depth en-face images that can be produced in real-time is limited. Here, we demonstrate progress in taking advantage of the parallel processing feature of the MS-OCT technology. Harnessing the capabilities of graphics processing units (GPU)s, information from 384 depth positions is acquired in one raster with real time display of up to 40 en-face OCT images. These exhibit comparable resolution and sensitivity to the images produced using the conventional Fourier domain based method. The GPU facilitates versatile real time selection of parameters, such as the depth positions of the 40 images out of the set of 384 depth locations, as well as their axial resolution. In each updated displayed frame, in parallel with the 40 en-face OCT images, a scanning laser ophthalmoscopy (SLO) lookalike image is presented together with two B-scan OCT images oriented along rectangular directions. The thickness of the SLO lookalike image is dynamically determined by the choice of number of en-face OCT images displayed in the frame and the choice of differential axial distance between them. PMID- 26417534 TI - The effect of multiple micronutrient supplementation on quality of life in patients with symptomatic heart failure secondary to ischemic heart disease: a prospective case series clinical study. AB - Heart failure is a progressive cardiovascular disorder and, in most cases, begins with atherosclerosis and ischemic heart disease. The prognosis of patients with heart failure is poor, even with improvement on the management of all forms of ischemic heart disease. There have been studies on heart failure using a single nutrient or a combination of multiple nutrients. Results are mixed. The aim of this study was to assess the influence of multiple micronutrient supplementation using the quality of life measure on patients with heart failure secondary to ischemic heart disease. This prospective case series followed 12 patients for a period between 3 to 8 months, using the Minnesota Living with Heart Failure Questionnaire (MLHFQ) as the sole outcome measure. The primary outcome was a score change over time between the start and endpoint of treatment. Change in MLHFQ mean total score was 27.08 +/- 20.43 and mean symptoms score was 4.67 +/- 3.34. Paired t-test showed a difference between baseline and endpoint of treatment (P < 0.001), which was statistically significant. A high dose of multiple micronutrients may have beneficial effects on cardiac function in patients with symptomatic heart failure. This study indicates the need for long term controlled studies to test the efficacy and safety of this economic approach in managing heart failure. PMID- 26417533 TI - Proteomic approaches to identify circulating biomarkers in patients with abdominal aortic aneurysm. AB - Abdominal aortic aneurysm (AAA) is a common condition with high mortality when ruptured. Most clinicians agree that small AAAs are best managed by ultrasonographic surveillance. However, it has been stated in recent reviews that a serum/plasma biomarker that predicts AAA rupture risk would be a powerful tool in stratifying patients with small AAAs. Identification of such circulating biomarkers with traditional hypothesis driven studies has been unsuccessful. In this review we summarize six studies using different proteomic approaches to find new, potential plasma AAA biomarker candidates. In conclusion, by using proteomic approaches novel potential plasma biomarkers for AAA have been identified. PMID- 26417535 TI - Early Illustrations of Geste Antagoniste in Cervical and Generalized Dystonia. AB - BACKGROUND: Geste antagoniste, or sensory trick, is a voluntary maneuver that temporarily reduces the severity of dystonic postures or movements. We present a historical review of early reports and illustrations of geste antagoniste. RESULTS: In 1894, Brissaud described this phenomenon in Paris in patients with torticollis. He noted that a violent muscular contraction could be reversed by a minor voluntary action. He considered the improvement obtained by what he called "simple mannerisms, childish behaviour or fake pathological movements" was proof of the psychogenic origin of what he named mental torticollis. This concept was supported by photographical illustrations of the patients. The term geste antagoniste was used by Brissaud's pupils, Meige and Feindel, in their 1902 monograph on movement disorders. Other reports and illustrations of this sign were published in Europe between 1894 and 1906. Although not mentioned explicitly, geste antagoniste was also illustrated in a case report of generalized dystonia in Oppenheim's 1911 seminal description of dystonia musculorum deformans in Berlin. DISCUSSION: Brissaud-Meige's misinterpretation of the geste antagoniste unfortunately anchored the psychogenic origin of dystonia for decades. In New York, Herz brought dystonia back into the realm of organic neurology in 1944. Thereafter, it was given prominence by other authors, notably Fahn and Marsden in the 1970-1980s. Nowadays, neurologists routinely investigate for geste antagoniste when a dystonic syndrome is suspected, because it provides a further argument in favor of dystonia. The term alleviating maneuver was proposed in 2014 to replace sensory trick or geste antagoniste. This major sign is now part of the motor phenomenology of the 2013 Movement Disorder Society's classification of dystonia. PMID- 26417537 TI - Erratum for Vinuela A, Kang UJ. Reversibility of tardive dyskinesia syndrome. Tremor Other Hyperkinet Mov. 2014; 4. doi: 10.7916/D86Q1VXZ. PMID- 26417536 TI - Intermediate Phenotypes of ATP1A3 Mutations: Phenotype-Genotype Correlations. AB - BACKGROUND: ATP1A3-related disorders include rapid-onset dystonia-parkinsonism (RDP or DYT12), alternating hemiplegia of childhood (AHC), and CAPOS syndrome (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss). CASE REPORT: We report two cases with intermediate forms between RDP and AHC. Patient 1 initially presented with the AHC phenotype, but the RDP phenotype emerged at age 14 years. The second patient presented with levodopa responsive paroxysmal oculogyria, a finding never before reported in ATP1A3 related disorders. Genetic testing confirmed heterozygous changes in the ATP1A3 gene in both patients, one of them novel. DISCUSSION: Intermediate phenotypes of RDP and AHC support the concept that these two disorders are part of a spectrum. We add our cases to the phenotype-genotype correlations of ATP1A3-related disorders. PMID- 26417539 TI - Demographics and density estimates of two three-toed box turtle (Terrapene carolina triunguis) populations within forest and restored prairie sites in central Missouri. AB - Box turtles (Terrapene carolina) are widely distributed but vulnerable to population decline across their range. Using distance sampling, morphometric data, and an index of carapace damage, we surveyed three-toed box turtles (Terrapene carolina triunguis) at 2 sites in central Missouri, and compared differences in detection probabilities when transects were walked by one or two observers. Our estimated turtle densities within forested cover was less at the Thomas S. Baskett Wildlife Research and Education Center, a site dominated by eastern hardwood forest (d = 1.85 turtles/ha, 95% CI [1.13, 3.03]) than at the Prairie Fork Conservation Area, a site containing a mix of open field and hardwood forest (d = 4.14 turtles/ha, 95% CI [1.99, 8.62]). Turtles at Baskett were significantly older and larger than turtles at Prairie Fork. Damage to the carapace did not differ significantly between the 2 populations despite the more prevalent habitat management including mowing and prescribed fire at Prairie Fork. We achieved improved estimates of density using two rather than one observer at Prairie Fork, but negligible differences in density estimates between the two methods at Baskett. Error associated with probability of detection decreased at both sites with the addition of a second observer. We provide demographic data on three-toed box turtles that suggest the use of a range of habitat conditions by three-toed box turtles. This case study suggests that habitat management practices and their impacts on habitat composition may be a cause of the differences observed in our focal populations of turtles. PMID- 26417538 TI - Novel epitopes identified from efflux pumps of Mycobacterium tuberculosis could induce cytotoxic T lymphocyte response. AB - Overcoming drug-resistance is one of the major challenges to control tuberculosis (TB). The up-regulation of efflux pumps is one common mechanism that leads to drug-resistance. Therefore, immunotherapy targeting these efflux pump antigens could be promising strategy to be combined with current chemotherapy. Considering that CD8+ cytotoxic T lymphocytes (CTLs) induced by antigenic peptides (epitopes) could elicit HLA-restricted anti-TB immune response, efflux pumps from classical ABC family (Mycobacterium tuberculosis, Mtb) were chosen as target antigens to identify CTL epitopes. HLA-A2 restricted candidate peptides from Rv2937, Rv2686c and Rv2687c of Mycobacterium tuberculosis were predicted, synthesized and tested. Five peptides could induce IFN-gamma release and cytotoxic activity in PBMCs from HLA-A2(+) PPD(+) donors. Results from HLA-A2/K(b) transgenic mice immunization assay suggested that four peptides Rv2937-p168, Rv2937-p266, Rv2686c-p151, and Rv2686c-p181 could induce significant CTL response in vivo. These results suggested that these novel epitopes could be used as immunotherapy candidates to TB drug-resistance. PMID- 26417540 TI - Temporal and spatial strategies in an active place avoidance task on Carousel: a study of effects of stability of arena rotation speed in rats. AB - The active place avoidance task is a dry-arena task used to assess spatial navigation and memory in rodents. In this task, a subject is put on a rotating circular arena and avoids an invisible sector that is stable in relation to the room. Rotation of the arena means that the subject's avoidance must be active, otherwise the subject will be moved in the to-be-avoided sector by the rotation of the arena and a slight electric shock will be administered. The present experiment explored the effect of variable arena rotation speed on the ability to avoid the to-be-avoided sector. Subjects in a group with variable arena rotation speed learned to avoid the sector with the same speed and attained the same avoidance ability as rats in a group with a stable arena rotation speed. Only a slight difference in preferred position within the room was found between the two groups. No difference was found between the two groups in the dark phase, where subjects could not use orientation cues in the room. Only one rat was able to learn the avoidance of the to-be-avoided sector in this phase. The results of the experiment suggest that idiothetic orientation and interval timing are not crucial for learning avoidance of the to-be-avoided sector. However, idiothetic orientation might be sufficient for avoiding the sector in the dark. PMID- 26417541 TI - Humans differ in their personal microbial cloud. AB - Dispersal of microbes between humans and the built environment can occur through direct contact with surfaces or through airborne release; the latter mechanism remains poorly understood. Humans emit upwards of 10(6) biological particles per hour, and have long been known to transmit pathogens to other individuals and to indoor surfaces. However it has not previously been demonstrated that humans emit a detectible microbial cloud into surrounding indoor air, nor whether such clouds are sufficiently differentiated to allow the identification of individual occupants. We used high-throughput sequencing of 16S rRNA genes to characterize the airborne bacterial contribution of a single person sitting in a sanitized custom experimental climate chamber. We compared that to air sampled in an adjacent, identical, unoccupied chamber, as well as to supply and exhaust air sources. Additionally, we assessed microbial communities in settled particles surrounding each occupant, to investigate the potential long-term fate of airborne microbial emissions. Most occupants could be clearly detected by their airborne bacterial emissions, as well as their contribution to settled particles, within 1.5-4 h. Bacterial clouds from the occupants were statistically distinct, allowing the identification of some individual occupants. Our results confirm that an occupied space is microbially distinct from an unoccupied one, and demonstrate for the first time that individuals release their own personalized microbial cloud. PMID- 26417544 TI - Insight on the anatomy, systematic relationships, and age of the Early Cretaceous ankylopollexian dinosaur Dakotadon lakotaensis. AB - Knowledge regarding the early evolution within the dinosaurian clade Ankylopollexia drastically increased over the past two decades, in part because of an increase in described taxa from the Early Cretaceous of North America. These advances motivated the recent completion of extensive preparation and conservation work on the holotype and only known specimen of Dakotadon lakotaensis, a basal ankylopollexian from the Lakota Formation of South Dakota. That specimen (SDSM 8656) preserves a partial skull, lower jaws, a single dorsal vertebra, and two caudal vertebrae. That new preparation work exposed several bones not included in the original description and revealed that other bones were previously misidentified. The presence of extensive deformation in areas of the skull is also noted that influenced inaccuracies in prior descriptions and reconstructions of this taxon. In addition to providing an extensive re description of D. lakotaensis, this study reviews previously proposed diagnoses for this taxon, identifies two autapomorphies, and provides an extensive differential diagnosis. Dakotadon lakotaensis is distinct from the only other ankylopollexian taxon known from the Lakota Formation, Osmakasaurus depressus, in the presence of two prominent, anteroposteriorly oriented ridges on the ventral surfaces of the caudal vertebrae, the only overlapping material preserved between these taxa. The systematic relationships of D. lakotaensis are evaluated using both the parsimony and posterior probability optimality criteria, with both sets of analyses recovering D. lakotaensis as a non-hadrosauriform ankylopollexian that is more closely related to taxa from the Early Cretaceous (e.g., Iguanacolossus, Hippodraco, and Theiophytalia) than to more basally situated taxa from the Jurassic (e.g., Camptosaurus, Uteodon). This taxonomic work is supplemented by field work that relocated the type locality, confirming its provenance from unit L2 (lower Fuson Member equivalent) of the Lakota Formation. Those data, combined with recently revised ages for the members of the Lakota Formation based on charophyte and ostracod biostratigraphy, constrain the age of this taxon to the late Valanginian to early Barremian. PMID- 26417542 TI - Metatranscriptomic analysis of a high-sulfide aquatic spring reveals insights into sulfur cycling and unexpected aerobic metabolism. AB - Zodletone spring is a sulfide-rich spring in southwestern Oklahoma characterized by shallow, microoxic, light-exposed spring water overlaying anoxic sediments. Previously, culture-independent 16S rRNA gene based diversity surveys have revealed that Zodletone spring source sediments harbor a highly diverse microbial community, with multiple lineages putatively involved in various sulfur-cycling processes. Here, we conducted a metatranscriptomic survey of microbial populations in Zodletone spring source sediments to characterize the relative prevalence and importance of putative phototrophic, chemolithotrophic, and heterotrophic microorganisms in the sulfur cycle, the identity of lineages actively involved in various sulfur cycling processes, and the interaction between sulfur cycling and other geochemical processes at the spring source. Sediment samples at the spring's source were taken at three different times within a 24-h period for geochemical analyses and RNA sequencing. In depth mining of datasets for sulfur cycling transcripts revealed major sulfur cycling pathways and taxa involved, including an unexpected potential role of Actinobacteria in sulfide oxidation and thiosulfate transformation. Surprisingly, transcripts coding for the cyanobacterial Photosystem II D1 protein, methane monooxygenase, and terminal cytochrome oxidases were encountered, indicating that genes for oxygen production and aerobic modes of metabolism are actively being transcribed, despite below-detectable levels (<1 uM) of oxygen in source sediment. Results highlight transcripts involved in sulfur, methane, and oxygen cycles, propose that oxygenic photosynthesis could support aerobic methane and sulfide oxidation in anoxic sediments exposed to sunlight, and provide a viewpoint of microbial metabolic lifestyles under conditions similar to those seen during late Archaean and Proterozoic eons. PMID- 26417543 TI - A comparison of two gluteus maximus EMG maximum voluntary isometric contraction positions. AB - Background. The purpose of this study was to compare the peak electromyography (EMG) of the most commonly-used position in the literature, the prone bent-leg (90 degrees ) hip extension against manual resistance applied to the distal thigh (PRONE), to a novel position, the standing glute squeeze (SQUEEZE). Methods. Surface EMG electrodes were placed on the upper and lower gluteus maximus of thirteen recreationally active females (age = 28.9 years; height = 164 cm; body mass = 58.2 kg), before three maximum voluntary isometric contraction (MVIC) trials for each position were obtained in a randomized, counterbalanced fashion. Results. No statistically significant (p < 0.05) differences were observed between PRONE (upper: 91.94%; lower: 94.52%) and SQUEEZE (upper: 92.04%; lower: 85.12%) for both the upper and lower gluteus maximus. Neither the PRONE nor SQUEEZE was more effective between all subjects. Conclusions. In agreement with other studies, no single testing position is ideal for every participant. Therefore, it is recommended that investigators employ multiple MVIC positions, when possible, to ensure accuracy. Future research should investigate a variety of gluteus maximus MVIC positions in heterogeneous samples. PMID- 26417546 TI - Consequences of life history switch point plasticity for juvenile morphology and locomotion in the Tungara frog. AB - Many animals with complex life cycles can cope with environmental uncertainty by altering the timing of life history switch points through plasticity. Pond hydroperiod has important consequences for the fitness of aquatic organisms and many taxa alter the timing of life history switch points in response to habitat desiccation. For example, larval amphibians can metamorphose early to escape drying ponds. Such plasticity may induce variation in size and morphology of juveniles which can result in carry-over effects on jumping performance. To investigate the carry-over effects of metamorphic plasticity to pond drying, we studied the Tungara frog, Physalaemus pustulosus, a tropical anuran that breeds in highly ephemeral habitats. We conducted an outdoor field mesocosm experiment in which we manipulated water depth and desiccation and measured time and size at metamorphosis, tibiofibula length and jumping performance. We also conducted a complimentary laboratory experiment in which we manipulated resources, water depth and desiccation. In the field experiment, metamorphs from dry-down treatments emerged earlier, but at a similar size to metamorphs from constant depth treatments. In the laboratory experiment, metamorphs from the low depth and dry-down treatments emerged earlier and smaller. In both experiments, frogs from dry-down treatments had relatively shorter legs, which negatively impacted their absolute jumping performance. In contrast, reductions in resources delayed and reduced size at metamorphosis, but had no negative effect on jumping performance. To place these results in a broader context, we review past studies on carry-over effects of the larval environment on jumping performance. Reductions in mass and limb length generally resulted in lower jumping performance across juvenile anurans tested to date. Understanding the consequences of plasticity on size, morphology and performance can elucidate the linkages between life stages. PMID- 26417547 TI - PopAlu: population-scale detection of Alu polymorphisms. AB - Alu elements are sequences of approximately 300 basepairs that together comprise more than 10% of the human genome. Due to their recent origin in primate evolution some Alu elements are polymorphic in humans, present in some individuals while absent in others. We present PopAlu, a tool to detect polymorphic Alu elements on a population scale from paired-end sequencing data. PopAlu uses read pair distance and orientation as well as split reads to identify the location and precise breakpoints of polymorphic Alus. Genotype calling enables us to differentiate between homozygous and heterozygous carriers, making the output of PopAlu suitable for use in downstream analyses such as genome-wide association studies (GWAS). We show on a simulated dataset that PopAlu calls Alu elements inserted and deleted with respect to a reference genome with high accuracy and high precision. Our analysis of real data of a human trio from the 1000 Genomes Project confirms that PopAlu is able to produce highly accurate genotype calls. To our knowledge, PopAlu is the first tool that identifies polymorphic Alu elements from multiple individuals simultaneously, pinpoints the precise breakpoints and calls genotypes with high accuracy. PMID- 26417548 TI - Epidemiological Studies of Substance Dependence and Abuse in Adults. AB - Drug and alcohol use disorders account for a high and potentially preventable proportion of overall disability and mortality. This article reviews published data on the distribution of alcohol and drug abuse and dependence in the USA. Published data shows that alcohol use disorders are more prevalent than illegal drug use disorders, although the persistence of both disorders was similar over a three-year follow-up period. Significant variability exists within sex, racial/ethnic, and age groups. Men, Native Americans, and young adults, aged 18 to 25, are at a higher risk of substance dependence. Environmental correlates of disorder include early environmental factors, political environment, and social contextual factors. Systematically identifying, and measuring variability across demographic populations, will guide prevention and intervention efforts. Future research will expand understanding of the complex interplay between individual and environmental factors that serve to initiate and sustain alcohol and drug use disorders. PMID- 26417549 TI - EEG Abnormalities in Children with Speech and Language Impairment. AB - INTRODUCTION: Epilepsy, a chronic condition of recurrent seizures, affects language, but the extent and nature of the language disturbance varies widely according to the type, severity, and cause of the epilepsy. There is paucity of literature on the electroencephalographic abnormalities in children with speech and language impairment. The present study was therefore planned to find the association of epileptiform EEG abnormalities in children with speech and language impairment and if present, their localization and lateralization to the language areas of the brain that are present predominantly in the left hemisphere. MATERIALS AND METHODS: The study was conducted on Paediatric patients having speech and language impairment (n=94, age-2 to 8 years) selected on the basis of detailed history and neurologic examination. Video Electroencephalography (EEG) was performed as per American Clinical Neurophysiology Society guidelines using 16 channel RMS computerized EEG machine for a minimum of 40 minutes to capture both wakefulness and sleep along with activation procedures like hyperventilation (if feasible) and photic stimulation. EEG was reviewed for any abnormal EEG background, benign variants, interictal epileptiform discharges and ictal discharges. RESULTS: In our cohort, 19.7% boys and 22.2% girls presented with seizures in their infancy and this gender difference was found to be statistically significant (p<0.05). EEG was abnormal in 47.9% children (45 out of 94) with no significant gender difference. Epileptiform EEG was seen in 73.6% of children with history of seizures and 41.3% of children without history of seizures (p<0.05). The EEG abnormities included: abnormal background (64.5%), presence of generalized interictal epileptiform discharges (57.8%), focal epileptiform discharges (20%) exclusively from left hemisphere and multifocal interictal epileptiform discharges (33.3%), each occurring in isolation or associated with other abnormities. CONCLUSION: In the current study, it is definite that presence of generalized abnormalities in EEG are seen in higher frequency and focal interictal epileptiform discharges are solely seen in left hemisphere in children with speech and language impairment. Although, there is no distinct pattern of EEG abnormalities in such patients, we recommend a routine EEG in them and also brain imaging to complement the EEG findings. PMID- 26417545 TI - Intrinsically disordered caldesmon binds calmodulin via the "buttons on a string" mechanism. AB - We show here that chicken gizzard caldesmon (CaD) and its C-terminal domain (residues 636-771, CaD136) are intrinsically disordered proteins. The computational and experimental analyses of the wild type CaD136 and series of its single tryptophan mutants (W674A, W707A, and W737A) and a double tryptophan mutant (W674A/W707A) suggested that although the interaction of CaD136 with calmodulin (CaM) can be driven by the non-specific electrostatic attraction between these oppositely charged molecules, the specificity of CaD136-CaM binding is likely to be determined by the specific packing of important CaD136 tryptophan residues at the CaD136-CaM interface. It is suggested that this interaction can be described as the "buttons on a charged string" model, where the electrostatic attraction between the intrinsically disordered CaD136 and the CaM is solidified in a "snapping buttons" manner by specific packing of the CaD136 "pliable buttons" (which are the short segments of fluctuating local structure condensed around the tryptophan residues) at the CaD136-CaM interface. Our data also show that all three "buttons" are important for binding, since mutation of any of the tryptophans affects CaD136-CaM binding and since CaD136 remains CaM-buttoned even when two of the three tryptophans are mutated to alanines. PMID- 26417550 TI - Hirschsprung's Disease in Neonates with Special Reference to Calretinin Immunohistochemistry. AB - BACKGROUND: Hirschsprung's disease is a classic example of a complex genetic disease, characterized by the lack of enteric ganglia in the submucosal and myenteric plexuses, along variable portions of the distal gut. The diagnosis of Hirschsprung's disease is based on a combination of clinical features, radiological appearance of the bowel and histological features in Haematoxylin & Eosin stained sections of intestinal biopsies. Calretinin Immunohistochemistry is emerging to be one of the newer methods. AIMS AND OBJECTIVES: This study was undertaken to ascertain 1) clinical profile; 2) mode of presentation; 3) to evaluate the role of Calretinin immunostain in the diagnosis of Hirschsprung's Disease. MATERIALS AND METHODS: This prospective and observational study was conducted in the Department of Pathology IPGME&R from July 2013 to September 2014. Eighty nine patients, clinically and radiologically diagnosed with Hirschsprung's disease underwent surgery and were included in the study. The data of every patient including age, sex and presenting symptoms were recorded. Eventually, histopathological examination & immunohistochemistry were done. RESULTS: Total number of cases studied was 89 which aged between 0 days to 28 days. Overall sensitivity in our study to diagnose presence or absence of ganglion cells by calretinin immunohistochemistry was 100% and the specificity is 97.44% with positive and negative predictive value of 84.62 % and 100 % respectively. CONCLUSION: Calretinin immunohistochemistry holds several advantages, and it's simple and not doubtful; and it is either positive or negative. PMID- 26417551 TI - Stevens Johnson Syndrome-Toxic Epidermal Necrolysis Overlap Secondary to Interaction Between Methotrexate and Etoricoxib: A Case Report. AB - Rheumatoid arthritis (RA) is an autoimmune disease affecting about 1% of people, with the highest incidence between 40 and 70 years. Methotrexate is an anti folate analogue that has good efficacy and safety in the treatment of RA. Methotrexate (MTX) and non-steroidal anti inflammatory drugs are often concomitantly administered in clinical practice for the treatment of RA. In this case report, a 57-year-old female was treated with oral methotrexate 7.5 mg per week for a diagnosed case of RA. Since her pain persisted after completing six weeks of treatment with methotrexate, oral etoricoxib 60 mg once daily was added to the treatment regimen. Six weeks later, the patient complained of oral ulcerations and blisters on all fours limbs and trunk. The patient was re evaluated and was diagnosed with Stevens-Johnson syndrome-Toxic epidermal necrolysis (SJS-TEN) overlap. This case highlights the possible pharmacokinetic interaction between methotrexate and etoricoxib that has a significant clinical implication. PMID- 26417553 TI - Is Endoscopy Really Necessary in My Case? A Four Year Retrospective Study. AB - INTRODUCTION: About 40% of the general population report dyspepsia at some time in their life making it a fairly common disease. Uncomplicated dyspepsia refers to patients whose dyspepsia is not accompanied by alarm features or associated with NSAIDS usage. AIM: To assess the need for UGI Endoscopy and find out the patterns of different endoscopic presentations in patients presenting with uncomplicated dyspepsia. MATERIALS AND METHODS: Our study conducted in KR Hospital, Mysore, Department of General Surgery is a retrospective endoscopic study of 1450 patients with uncomplicated dysepsia. RESULTS: A significant 64% of the patients presenting with uncomplicated dyspepsia were found to have findings on endoscopy. The most common age range for positive endoscopic findings was 40 50 years in our hospital. Malignancy was diagnosed in 2.5% patients. CONCLUSION: We recommend upper GI endoscopy in patients presenting with uncomplicated dyspepsia for patients above 40 years of age in our hospital. PMID- 26417552 TI - Spontaneous Soft Tissue Haematomas- A Rare Presentation of Chronic Myeloid Leukemic (CML). AB - Spontaneous soft tissue haematomas are rarely found in haematological malignancies. Chronic myeloid leukemia (CML) is a myeloproliferative disorder which rarely present with thrombo-haemorrhagic phenomenon. It is a malignant clonal disorder of pleuripotent stem cells that results in increase in myeloid, erythroid and platelets cells in peripheral blood and marked myeloid hyperplasia in bone marrow. It is characterized by the presence of Philadelphia chromosome (Ph) with BCR - ABL 1 fusion gene. This gene is responsible for the formation of 210 KDa chimeric proteins with enhanced tyrosine kinase activity which leads to the abnormal bone marrow cell proliferation and to the clinical and morphologic manifestations of leukemia. Cutaneous and mucous membrane bleeding is common in CML whereas bleeding in deep soft tissue is rarely found because of qualitative and quantitative platelet abnormalities. Here, we report a case of CML (BCR-ABL rearrangement positive) who presented with large haematoma in the anterior as well as posterior compartment of left thigh and treated successfully with hydroxyurea and imatinib. PMID- 26417554 TI - Cd34 and Mast Cell Analysis in Normal Oral Mucosa and Different Grades of Oral Squamous Cell Carcinoma: A Comparative Study. AB - BACKGROUND: Oral Squamous Cell Carcinoma (OSCC) remains a serious health problem worldwide. Prognosis of OSCC is poor and long term survival rate still remains below 50%. Angiogenesis or neovascularisation plays an important role in tumour progression and metastasis. Mast cells have been implicated in promoting tumour angiogenesis, especially of digestive tract, little is known in OSCC. AIM & OBJECTIVE: To study the correlation between blood vessel density (BVD) and mast cell density (MCD) in different grades of OSCC. MATERIALS AND METHODS: METHODS: Thirty eight paraffin blocks of different grades of OSCC were retrieved from the department and sections were stained with CD34 followed by counterstaining with toluidine blue. The slides were then analysed using Leica Software (Version 4.5). RESULTS: Mean BVD and MCD were found to be increased in OSCC as compared to normal mucosa. Increase in BVD with co-current increase in MCD was also observed in different grades of OSCC. CONCLUSION: From our study, it was concluded that, mast cells play a major role in promoting tumour angiogenesis. But, as the grade of the tumour increases, other angiogenic factors may play a more significant role than mast cells in tumour progression. PMID- 26417555 TI - Class II Division 1 in New Dimension: Role of Posterior Transverse Interarch Discrepancy in Class II Division 1 Malocclusion During the Mixed Dentition Period. AB - INTRODUCTION: Posterior transverse discrepancy as seen in some cases of Class II Division 1 malocclusion in mixed dentition period can be related to typical skeletofacial characteristics. These features when studied early in the mixed dentition period give a clear view of the desired appropriate treatment plan in a particular case. AIM: The purpose of this study was to establish a simple method to determine the posterior (intermolar) transverse discrepancy and craniofacial skeletal features between the dental arches during the mixed dentition in a sample of Class II Division 1 patients to provide diagnostic and therapeutic guidance in the early approach. MATERIALS AND METHODS: A sample of 60 Class II Division 1 patients in mixed dention that were divided into 30 Class II Division 1 patients with posterior transverse interarch discrepancy {Class II (I) PTID group} and 30 Class II Division 1 patients without posterior transverse interarch discrepancy {Class II (I) NPTID group}. Thirty Class I subjects in mixed dentition were included as control. RESULTS: The skeletal features of the Class II group without PTID are those of the skeletal Class II associated with 'anatomic' mandibular retrusion (due to a micrognathic mandible) and those of the Class II group with PTID as skeletal Class II associated with only a 'functional' mandibular retrusion (due to a posteriorly displaced mandible of normal size). CONCLUSION: This study confirmed the role of occlusion in the control of maxillomandibular skeletal relationships.The treatment strategies could be planned on the basis of the transverse component of Class II Division 1 groups in the mixed dentition period. PMID- 26417556 TI - Amplification of Cellular Oncogenes in Solid Tumors. AB - The term gene amplification refers to an increase in copy number of a gene. Upregulation of gene expression through amplification is a general mechanism to increase gene dosage. Oncogene amplifications have been shown in solid human cancers and they are often associated with progression of cancer. Defining oncogene amplification is useful since it is used as a prognostic marker in clinical oncology nowadays, especially v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (HER2) targeted agents are used in breast cancer patients with high level of HER2 overexpression as a therapeutic approach. However, patients without HER2 overexpression do not appear to benefit from these agents. We concluded that determination of oncogene amplification in solid tumors is an important factor in treatment of human cancers with many unknowns. We have referred to PubMed and some databases to prepare this article. PMID- 26417557 TI - Estimation of 10-Year Risk of Coronary Heart Disease in Nepalese Patients with Type 2 Diabetes: Framingham Versus United Kingdom Prospective Diabetes Study. AB - BACKGROUND: Predicting future coronary heart disease (CHD) risk with the help of a validated risk prediction function helps clinicians identify diabetic patients at high risk and provide them with appropriate preventive medicine. AIM: The aim of this study is to estimate and compare 10-year CHD risks of Nepalese diabetic patients using two most common risk prediction functions: The Framingham risk equation and United Kingdom Prospective Diabetes Study (UKPDS) risk engine that are yet to be validated for Nepalese population. PATIENTS AND METHODS: We conducted a hospital-based, cross-sectional study on 524 patients with type 2 diabetes. Baseline and biochemical variables of individual patients were recorded and CHD risks were estimated by the Framingham and UKPDS risk prediction functions. Estimated risks were categorized as low, medium, and high. The estimated CHD risks were compared using kappa statistics, Pearson's bivariate correlation, Bland-Altman plots, and multiple regression analysis. RESULTS: The mean 10-year CHD risks estimated by the Framingham and UKPDS risk functions were 17.7 +/- 12.1 and 16.8 +/- 15 (bias: 0.88, P > 0.05), respectively, and were always higher in males and older age groups (P < 0.001). The two risk functions showed moderate convergent validity in predicting CHD risks, but differed in stratifying them and explaining the patients' risk profile. The Framingham equation predicted higher risk for patients usually below 70 years and showed better association with their current risk profile than the UKPDS risk engine. CONCLUSIONS: Based on the predicted risk, Nepalese diabetic patients, particularly those associated with increased numbers of risk factors, bear higher risk of future CHDs. Since this study is a cross-sectional one and uses externally validated risk functions, Nepalese clinicians should use them with caution, and preferably in combination with other guidelines, while making important medical decisions in preventive therapy of CHD. PMID- 26417558 TI - The Pattern of Psoriatic Arthritis in Kashmir: A 6-Year Prospective Study. AB - BACKGROUND: The prevalence, clinical presentation, and patterns of psoriatic arthritis (PsA) vary in different parts of the world. The scenario of PsA in west is different from that of Asia. Moreover, the oligoarticular type which was considered most prevalent earlier has been replaced by polyarticular type. AIM: The study was to the clinical profile of psoriasis patients associated with PsA in Kashmir valley of India. MATERIALS AND METHODS: This was a noninterventional, observational, prospective, hospital-based study involving 150 successive patients of PsA over a span of 6 years. Severity of the skin and nail involvement was assessed by Psoriasis Area and Severity Index (PASI) and Nail Psoriasis Severity Index (NAPSI), respectively. PsA was diagnosed by classification criteria for PsA. The number and pattern of swollen and tender joints was counted and classified by Moll and Wright's classification criteria. RESULTS: Plaque-type psoriasis was the most common clinical type, observed in 122 (81.33%) patients followed by erythrodermic psoriasis in 10 (6.66%) patients and pustular psoriasis in eight (5.33%) patients. PsA occurred between 30 and 40 years of age in 105 (70%) patients. The cutaneous involvement occurred before joint involvement in 113 (75.33%), while they occurred simultaneously in 30 (20%) cases and the PsA preceded the skin involvement in seven (4.66%) cases. Symmetrical polyarthritis was the commonest clinical presentation and was seen in 90 (60%) patients. Nail involvement due to psoriasis was present in 120 (80%) patients. Commonest nail change found was pitting and seen in 60 (40%) patients. CONCLUSION: The clinical pattern of PsA varies in different parts of the world. Knowledge of the clinical presentation of PsA in a given area is necessary for the successful management of this disease. PMID- 26417559 TI - Multidetector Computed Tomography and Magnetic Resonance Imaging Evaluation of Craniovertebral junction Abnormalities. AB - BACKGROUND: Craniovertebral junction (CVJ) abnormalities constitute an important group of treatable neurological disorders with diagnostic dilemma. Their precise diagnosis, identification of probable etiology, and pretreatment evaluation significantly affects prognosis and quality of life of patients. AIMS: The study was to classify various craniovertebral junction disorders according to their etiology and to define the importance of precise diagnosis for pretreatment evaluation with multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI). MATERIALS AND METHODS: This is a prospective observational study of 62 patients referred to our department between October 2012 and September 2014. All patients suspected to have a craniovertebral junction disorder were included in the study, from all age groups and both genders. Detailed clinical history was taken. Radiographs of cervical spine were collected if available. All patients were subjected to MDCT and/or MRI. RESULTS: In our study of 62 patients; 39 were males and 23 were females, with male to female ratio of 1.6:1. Most common age group was 2(nd) -3(rd) decade (19 patients, 30.64%). Developmental anomalies (33 patients, 53.22%) were the most common etiology group followed by traumatic (10 patients, 16.12%), degenerative (eight patients, 12.90%), infective (four patients, 6.45%), inflammatory and neoplastic (three patients each, 4.8%), and no cause found in one patient. CONCLUSIONS: CVJ abnormalities constitute an important group of treatable neurological disorders, especially in certain ethnic groups and are approached with much caution by clinicians. Thus, it is essential that radiologists should be able to make a precise diagnosis of craniovertebral junction abnormalities, classify them into etiological group, and rule out important mimickers on MDCT and/or MRI, as this information ultimately helps determine the management of such abnormalities, prognosis, and quality of life of patients. PMID- 26417560 TI - Hypoplasia of the Spleen: Review of Pathogenesis, Diagnosis, and Potential Clinical Implications. AB - CONTEXT: Splenic aplasia is seen when the spleen is congenitally absent, has been surgically removed, or becomes atrophic secondary to episodes of arterial/venous occlusion, which result in splenic infarction. This rare condition is caused by a heterogenous group of diseases, which may present a wide spectrum of clinical manifestations. Splenic hypoplasia is defined as reduction in splenic mass and or functions caused by incomplete splenic development or secondary parenchymal involution. Splenic infarction may be clinically silent and only discovered incidentally during abdominal exploration for other conditions. CASE REPORT: We present an unusual case of hypoplastic spleen with calcifications, which was preoperatively found during radiologic workup for gastric carcinoma. An 88-year old woman presented with coffee-ground emesis. Her past medical history was only significant for atrial fibrillation. Esophagogastroduodenoscopy demonstrated gastric carcinoma, for which a subtotal gastrectomy was planned. Preoperative computed tomography scan showed a hypoplastic spleen with calcifications in the left upper quadrant. Symptoms of immunologic deficiency were not present. During laparotomy, an atrophied and calcified spleen was identified and left in situ. The patient made an uneventful postoperative recovery. Splenic hypoplasia is an unique entity, which may be seen in the setting of atrial fibrillation and abdominal malignancy. CONCLUSION: Splenic hypoplasia may be detected incidentally during radiologic workup or abdominal exploration. Abdominal symptoms or immunologic deficiency are not always present. PMID- 26417561 TI - Double Right Coronary Artery Originating from Separate Ostia: A Report of Two Cases. AB - CONTEXT: Coronary artery anomalies are uncommon and most are incidental findings. Double right coronary artery (RCA) is a very rare coronary artery anomaly. CASE REPORT: We report two cases of double RCA incidentally found in electrocuted patients. Both cases showed double RCA arising from separate ostia. On microscopy, both right coronaries showed no significant pathology in the first case while in the second case, the posterior RCA showed features of obliterative arteritis. CONCLUSION: Although double coronary artery has been regarded as hemodynamically insignificant, it may be associated with atherosclerosis, acute coronary syndromes, and other anomalies. It is important to know the anatomic variants. Meticulous grossing and careful observation could unearth hidden anomalies. PMID- 26417562 TI - Hyperhomocysteinemia Association With Transient Global Amnesia: A Rare Case Report. AB - CONTEXT: Transient global amnesia (TGA) is an intriguing condition that classically presents with an abrupt onset of temporary complete anterograde amnesia and partial retrograde amnesia. Most individuals who experience such a form of amnesia usually have only one attack but recurrent attacks are possible. Most attacks last for a few minutes or few hours and the ability to lay down new memories may also be affected but gradually improves, leaving only a dense amnestic gap for the duration of the episode. There has been some discussion about the etiology behind TGA; however, there has yet to be a consensus with regard to any significant association. CASE REPORT: We report the case of a 65 year-old male presenting with a sudden onset of memory loss that is typical of TGA and who was found to have elevated homocysteine levels. There has only been one other case previously reported that discussed a possible correlation between hyperhomocysteinemia and TGA. It is yet to be determined if increased homocysteine level is a significant risk factor for attacks of TGA. CONCLUSION: Although it was first described more than half a century ago, it can still be misdiagnosed frequently as many physicians are not familiar with this condition. Furthermore, there are quite a few medical conditions that may cause sudden memory impairment, such as epilepsy and stroke, which make it difficult to distinguish them from this form of amnesia. The knowledge of these clinical identities is necessary for a high index of suspicion, which may lead to a meticulous medical evaluation as required for proper diagnosis. PMID- 26417563 TI - Myanmar: An Endemic Country for Oral Cancer. PMID- 26417564 TI - Erratum to: Diet, exercise or diet with exercise: comparing the effectiveness of treatment options for weight-loss and changes in fitness for adults (18-65 years old) who are overfat, or obese; systematic review and meta-analysis. AB - [This corrects the article DOI: 10.1186/s40200-015-0154-1.]. PMID- 26417565 TI - Evaluation of the reproducibility of the AO/ASIF classification for humeral shaft fractures. AB - OBJECTIVE: To evaluate the reproducibility of the AO/Asif classification for humeral shaft fractures. METHODS: Consecutive radiographs of the arm in both anteroposterior and lateral view from 60 patients with humeral shaft fractures were analyzed. Six observers who were familiar with the AO/Asif classification (three shoulder and elbow surgery specialists and three general orthopedists) were selected to make the analysis, which was done at three different times. The data were subjected to statistical analysis using the kappa coefficient. RESULTS: The intra and interobserver concordance was statistically significant in all the analyses. CONCLUSIONS: All the evaluators showed concordance between the three evaluations that was considered to be statistically significant. However, the highest values were found among the specialists. PMID- 26417567 TI - Evaluation of the results from non-arthroplastic treatment (arthroscopy) for shoulder arthrosis. AB - OBJECTIVES: To evaluate the functional results from patients with arthrosis who underwent an arthroscopic procedure, in an attempt to correlate these results with the patients' epidemiological profile, surgical technique used, possible complications and postoperative protocol. METHODS: Between 1998 and 2011, 31 patients (32 shoulders) with shoulder arthrosis underwent arthroscopic treatment performed by the Shoulder and Elbow Group of the Department of Orthopedics and Traumatology of Santa Casa de Sao Paulo. Primary or secondary cases of shoulder arthrosis under the age of 70 years, in which the rotator cuff was intact, were included. Furthermore, cases in which, despite an indication for an arthroplastic procedure, an attempt to perform an alternative procedure had been chosen, were also included. The following were evaluated: sex, age, dominance, comorbidities, length of time with complaint, associated lesions, etiology, previous treatment, operation performed, postoperative protocol and pre and postoperative active ranges of motion. The functional evaluation was conducted using the UCLA criteria, before and after the operation. The joint cartilage alterations were classified in accordance with Outerbridge and the arthrosis by means of Walch. RESULTS: There were statistically significant mean differences in the values for elevation, lateral rotation and medial rotation from before to after the operation (p < 0.001) and there was a tendency (p = 0.057) toward poor results with greater length of time with complaints before the surgery. The total gain in UCLA score did not have any statistically significant relationship with any of the other variables analyzed. CONCLUSION: Arthroscopic treatment of glenohumeral arthrosis provided functional improvement of the glenohumeral joint, with significant gains in elevation and lateral and medial rotation, and improvements in function and pain. Greater length of time with complaints was a factor strongly suggestive of worse results. PMID- 26417566 TI - Preliminary results from osteosynthesis using Ender nails by means of a percutaneous technique, in humeral diaphysis fractures in adults. AB - OBJECTIVE: To demonstrate the clinical and functional results from treatment of humeral diaphysis fractures using Ender nails. METHODS: Eighteen patients who underwent osteosynthesis of humeral diaphysis fractures using Ender nails were evaluated. In addition to the clinical and radiographic evaluations, patients with a minimum of one year of follow-up were assessed by means of the Constant, American Shoulder and Elbow Surgeons (ASES), Mayo Clinic and Simple Shoulder Value (SSV) functional scores, and in relation to the degree of satisfaction with the final result. The fixation technique used was by means of an anterograde percutaneous route. RESULTS: All the patients achieved fracture consolidation, after a mean of 2.9 months (ranging from 2 to 4 months). The mean Constant score was 85.7 (ranging from 54 to 100) and the mean ASES score was 95.9 (ranging from 76 to 100). All the patients achieved the maximum score on the Mayo Clinic scale. CONCLUSION: Fixation of humeral diaphysis fractures using Ender nails by means of a percutaneous technique was shown to be a method with promising preliminary results. PMID- 26417568 TI - Partial rotator cuff injury in athletes: bursal or articular? AB - A painful shoulder is a very common complaint among athletes, especially in the case of those in sports involving throwing. Partial lesions of the rotator cuff may be very painful and cause significant functional limitation to athletes' sports practice. The incidence of partial lesions of the cuff is variable (13 37%). It is difficult to make the clinical and radiological diagnosis, and this condition should be borne in mind in the cases of all athletes who present symptoms of rotator cuff syndrome, including in patients who are diagnosed only with tendinopathy. OBJECTIVE: To evaluate the epidemiological behavior of partial lesions of the rotator cuff in both amateur and professional athletes in different types of sports. METHODS: We evaluated 720 medical files on athletes attended at the shoulder service of the Discipline of Sports Medicine at the Sports Traumatology Center, Federal University of Sao Paulo. The majority of them were men (65%). Among all the patients, 83 of them were diagnosed with partial lesions of the rotator cuff, by means of ultrasonography or magnetic resonance, or in some cases using both. We applied the binomial test to compare the proportions found. RESULT: It was observed that intra-articular lesions predominated (67.6%) and that these occurred more frequently in athletes in sports involving throwing (66%). Bursal lesions occurred in 32.4% of the athletes, predominantly in those who did muscle building (75%). CONCLUSION: Intra articular lesions are more frequent than bursal lesions and they occur predominantly in athletes in sports involving throwing, while bursal lesions were more prevalent in athletes who did muscle building. PMID- 26417571 TI - Anatomical reconstruction of the anterior cruciate ligament: a logical approach. AB - We describe the surgical approach that we have used over the last years for anterior cruciate ligament (ACL) reconstruction, highlighting the importance of arthroscopic viewing through the anteromedial portal (AMP) and femoral tunnel drilling through an accessory anteromedial portal (AMP). The AMP allows direct view of the ACL femoral insertion site on the medial aspect of the lateral femoral condyle, does not require guides for anatomic femoral tunnel reaming, prevents an additional lateral incision in the distal third of the thigh (as would be unavoidable when the outside-in technique is used) and also can be used for double-bundle ACL reconstruction. PMID- 26417569 TI - Magnetic resonance study on the anatomical relationship between the posterior proximal region of the tibia and the popliteal artery. AB - OBJECTIVE: To analyze and describe the distance from the popliteal artery to three specific areas of the proximal region of the tibia, with the knee extended, by means of magnetic resonance. METHODS: Images of 100 knees of patients who underwent magnetic resonance examinations were analyzed. The location of the popliteal artery was measured in three different areas of the posterior proximal region of the tibia. The first measurement was made at the level of the knee joint (tibial plateau). The second was 9 mm distally to the tibial plateau. The third was at the level of the anterior tuberosity of the tibia (ATT). RESULTS: The distances between the popliteal artery and the tibial plateau and ATT region were significantly greater in males than in females. The distances between the popliteal artery and the regions 9 mm distally to the tibial plateau and the ATT were significantly greater in the age group over 36 years than in the group <=36 years. CONCLUSION: Knowledge of the anatomical position of the popliteal artery, as demonstrated through magnetic resonance studies, is of great relevance in planning surgical procedures that involve the knee joint. In this manner, devastating iatrogenic injuries can be avoided, particularly in regions that are proximal to the tibial plateau and in young patients. PMID- 26417570 TI - Gluteal pain in athletes: how should it be investigated and treated? AB - Gluteal pain is a frequent symptom in athletes, and defining it etiologically is a challenge for orthopedists. In the present study, using an anatomical approach to the posterior region of the pelvis and the proximal femur, divided into four quadrants, systematized investigation is proposed with the aim of optimizing the treatment and accelerating athletes' return to their sport, through correct diagnosis. PMID- 26417572 TI - Disordered ripples are a common feature of genetically distinct mouse models relevant to schizophrenia. AB - We present results from a novel comparative approach to the study of mechanisms of psychiatric disease. Previous work examined neural activity patterns in the hippocampus of a freely behaving mouse model associated with schizophrenia, the calcineurin knockout mouse. Here we examined a genetically distinct mouse that exhibits a similar set of behavioral phenotypes associated with schizophrenia, a transgenic model expressing a putative dominant-negative DISC1 (DN-DISC1). Strikingly, the principal finding of the earlier work is replicated in the DN DISC1 mice, that is, a selective increase in the numbers of sharp-wave ripple events in the local hippocampal LFP, while at the same time other LFP patterns such as theta and gamma are unaffected. Sharp-wave ripples are thought to arise from hippocampal circuits, and reflect the coordinated activity of the principal excitatory cells of the hippocampus, in specific patterns that represent reactivated memories of previous experiences and imagined future experiences that predict behavior. These findings suggest that multiple genetic alterations could converge on distinct patterns of aberrant neurophysiological function to give rise to common behavioral phenotypes in psychiatric disease. PMID- 26417573 TI - A potential osteoporosis target in the FAS ligand/FAS pathway of osteoblast to osteoclast signaling. PMID- 26417574 TI - Achieving tissue specific levels of angiogenesis: Not(ch) a big deal! PMID- 26417575 TI - Overcoming the hurdles of using PET/CT for target volume delineation in curative intent radiotherapy of non-small cell lung cancer. PMID- 26417576 TI - Comparison of self-reported and measured range of motion in total knee arthroplasty patients. AB - Total knee arthroplasty (TKA) is an established method used in the treatment of end-stage knee osteoarthritis. Range of motion (ROM) and relief from pain show success of TKA. One of the most important aims of this treatment is to achieve an adequate ROM. Numerous outcome instruments and patient-reported questionnaires are in use to evaluate of TKA patients. For this purpose, disease-specific questionnaires and self-reported ROM and function evaluation tools are also being developed. The most important criteria in musculoskeletal care is assessing the joint mobility of the patient's. Joint mobility can be measured with visual estimates, universal goniometer, X-ray radiography, digital gravity goniometers and applications found in smart phones. Apart from the reliability and validity of the method, obtaining the same results from different examiners is very important. The clinical follow-up of patients is an important part of postoperative care after TKA. The follow-up interval and duration remain dependent on the physician's anticipation of the clinical progress of the individual patient. Long-term surveillance of joint arthroplasty is necessary, but it has also become increasingly burdensome as greater numbers of TKAs are performed, and in younger populations. Patient self-reported questionnaires and self-goniometric measurement are used by many investigators to decrease this burden on the surgeon or staff, and in combination with telemedicine radiographs might be a reasonable option to routine clinic visits. They could reasonably be expected to lower the burden on both the patient and the clinician without eliminating contact and thus sacrificing quality of care. At the same time, it would reduce the financial burden too. Self-reported measured ROM can use in the routine follow-ups to reduce surgeons, physiotherapist and other staff. PMID- 26417577 TI - The potential utility of patient-reported range of motion after total knee arthroplasty. PMID- 26417578 TI - Lung metastasectomy: an experience-based therapeutic option. PMID- 26417579 TI - Pulmonary lobectomies for patients with cognitive impairment: the importance of postoperative respiratory care. AB - BACKGROUND: Patients with cognitive impairment (CI) may have an increased risk of complications after major thoracic surgery. However, little is known about this risk and the corresponding management. METHODS: Clinical data of patients who underwent pulmonary lobectomy via open thoracotomy between January 2006 and December 2008 in our institution were retrospectively reviewed. RESULTS: Overall, 1,325 patients who underwent pulmonary lobectomy via open thoracotomy were analyzed retrospectively, in which five patients were diagnosed with CI. Sputum retention was common and led to significant hypoxemia in all five patients. Four patients were re-intubated due to severe respiratory dysfunction, and three underwent tracheotomy 7 days after intubation due to respiratory infection. Regarding to duration of chest tube placement, length of hospital stay, morbidity rate, and hospital cost, CI patients were significant higher compared with cognitively normal patients undergoing lobectomy via open thoracotomy. CONCLUSIONS: Patients with CI may have difficulties in expectoration after pulmonary lobectomy, and develop multiple respiratory complications, thus increasing hospital stay. Efficacious sputum and airway clearance is critical in these patients. PMID- 26417580 TI - Esophageal electric fields are predictive of atrial cardioversion success-a finite element analysis. AB - BACKGROUND: Atrial fibrillation (AF) is a debilitating cardiac arrhythmia, one potential treatment of which is external cardioversion. Studies have shown external cardioversion success is affected by electrode placement and that esophageal electric fields (EEFs) during low strength shocks have the potential to be used in determining patient-specific optimal electrode placements during animal experiments. The objective of this study was to determine the relationship between EEFs and atrial defibrillation thresholds (ADFTs) during computer simulations using an anatomically realistic computer model of a human torso. METHODS: Over 600 electrode placements were simulated during which EEFs were compared to ADFTs. RESULTS: There was no single optimal electrode placement with multiple electrode placements resulting in similarly low ADFTs. There was over 40% difference in the ADFTs between the most and least optimal electrode configurations. There was no correlation between EEFs and ADFTs for all electrode placements, but a strong negative correlation when small shifts from clinically relevant electrode placements were performed. CONCLUSIONS: These results suggest a small shifts protocol from clinically relevant electrode placements has the potential to increase the probability of successful cardioversion on the first shock and reduce the cumulative number of shocks and energy to which patients are exposed. PMID- 26417582 TI - Risk-reducing strategies for repair of complex ascending aortic false aneurysms. AB - Late presentation of aortic false aneurysm following repair of acute type A aortic dissection occurs in 10% to 24% of cases. This condition is associated with high mortality if left untreated. Herein we describe a combination of surgical strategies that we believe may be used effectively to reduce the surgical risk of these complex operations. PMID- 26417581 TI - Are anticoagulant independent mechanical valves within reach-fast prototype fabrication and in vitro testing of innovative bi-leaflet valve models. AB - BACKGROUND: Exploration for causes of prosthetic valve thrombogenicity has frequently focused on forward or post-closure flow detail. In prior laboratory studies, we uncovered high amplitude flow velocities of short duration close to valve closure implying potential for substantial shear stress with subsequent initiation of blood coagulation pathways. This may be relevant to widely accepted clinical disparity between mechanical and tissue valves vis-a-vis thrombogenicity. With a series of prototype bi-leaflet mechanical valves, we attempt reduction of closure related velocities with the objective of identifying a prototype valve with thrombogenic potential similar to our tissue valve control. This iterative design approach may find application in preclinical assessment of valves for anticoagulation independence. METHODS: Tested valves included: prototype mechanical bi-leaflet BVs (n=56), controls (n=2) and patented early prototype mechanicals (n=2) from other investigators. Pulsatile and quasi steady flow systems were used for testing. Projected dynamic valve area (PDVA) was measured using previously described novel technology. Flow velocity over the open and closing periods was determined by volumetric flow rate/PDVA. For the closed valve interval, use was made of data obtained from quasi-steady back pressure/flow tests. Performance was ranked by a proposed thrombogenicity potential index (TPI) relative to tissue and mechanical control valves. RESULTS: Optimization of the prototype valve designs lead to a 3-D printed model (BV3D). For the mitral/aortic site, BV3D has lower TPI (1.10/1.47) relative to the control mechanical valve (3.44/3.93) and similar to the control tissue valve (ideal TPI <=1.0). CONCLUSIONS: Using unique technology, rapid prototyping and thrombogenicity ranking, optimization of experimental valves for reduced thrombogenic potential was expedited and simplified. Innovative mechanical valve configurations were identified that merit consideration for further development which may bring the anti-coagulation independent mechanical valve within reach. PMID- 26417583 TI - Robotic-assisted right inferior lobectomy. PMID- 26417584 TI - Robotic thymectomy in patients with myasthenia gravis by vascular skeletonization. PMID- 26417586 TI - Discontinuing epidermal growth factor receptor-tyrosine kinase inhibitor during second-line chemotherapy: is the evidence strong enough? PMID- 26417585 TI - If no difference in effectiveness is found between two treatments it may be because the treatments are similarly ineffective. PMID- 26417587 TI - Is fixation an option for comminuted femoral head fracture? AB - Femoral head fracture (Pepkin fracture) is a serious injury that is usually caused by trauma with more incidences in young age. There is no definitive treatment suggested in literature for Pepkin fracture. In this work, a case with class IV Pipkin fracture is presented. Fixation of the fracture was done and the outcomes of the surgical procedure immediately and 6 years after surgery are documented. PMID- 26417588 TI - Professor Shi-Wen Wu: One City, One Doctor-building up the national DMD registry network. PMID- 26417589 TI - Prof. Hong Zhao, ATM's Associate Editor-in-Chief, honored with Beijing's 10 Outstanding Young Doctors Award. PMID- 26417590 TI - Human Genes Encoding Transcription Factors and Chromatin-Modifying Proteins Have Low Levels of Promoter Polymorphism: A Study of 1000 Genomes Project Data. AB - The expression level of each gene is controlled by its regulatory regions, which determine the precise regulation in a tissue-specific manner, according to the developmental stage of the body and the necessity of a response to external stimuli. Nucleotide substitutions in regulatory gene regions may modify the affinity of transcription factors to their specific DNA binding sites, affecting the transcription rates of genes. In our previous research, we found that genes controlling the sensory perception of smell and genes involved in antigen processing and presentation were overrepresented significantly among genes with high SNP contents in their promoter regions. The goal of our study was to reveal functional features of human genes containing extremely small numbers of SNPs in promoter regions. Two functional groups were found to be overrepresented among genes whose promoters did not contain SNPs: (1) genes involved in gene-specific transcription and (2) genes controlling chromatin organization. We revealed that the 5'-regulatory regions of genes encoding transcription factors and chromatin modifying proteins were characterized by reduced genetic variability. One important exception from this rule refers to genes encoding transcription factors with zinc-coordinating DNA-binding domains (DBDs), which underwent extensive expansion in vertebrates, particularly, in primate evolution. Hence, we obtained new evidence for evolutionary forces shaping variability in 5'-regulatory regions of genes. PMID- 26417591 TI - Epitope Fingerprinting for Recognition of the Polyclonal Serum Autoantibodies of Alzheimer's Disease. AB - Autoantibodies (aAb) associated with Alzheimer's disease (AD) have not been sufficiently characterized and their exact involvement is undefined. The use of information technology and computerized analysis with phage display technology was used, in the present research, to map the epitope of putative self-antigens in AD patients. A 12-mer random peptide library, displayed on M13 phages, was screened using IgG from AD patients with two repetitions. Seventy-one peptides were isolated; however, only 10 were positive using the Elisa assay technique (Elisa Index > 1). The results showed that the epitope regions of the immunoreactive peptides, identified by phage display analysis, were on the exposed surfaces of the proteins. The putative antigens MAST1, Enah, MAO-A, X11/MINT1, HGF, SNX14, ARHGAP 11A, APC, and CENTG3, which have been associated with AD or have functions in neural tissue, may indicate possible therapeutic targets. PMID- 26417593 TI - Corrigendum to "Characterization of Bone Marrow Mononuclear Cells on Biomaterials for Bone Tissue Engineering In Vitro". PMID- 26417592 TI - Intra-Amniotic LPS Induced Region-Specific Changes in Presynaptic Bouton Densities in the Ovine Fetal Brain. AB - RATIONALE: Chorioamnionitis has been associated with increased risk for fetal brain damage. Although, it is now accepted that synaptic dysfunction might be responsible for functional deficits, synaptic densities/numbers after a fetal inflammatory challenge have not been studied in different regions yet. Therefore, we tested in this study the hypothesis that LPS-induced chorioamnionitis caused profound changes in synaptic densities in different regions of the fetal sheep brain. MATERIAL AND METHODS: Chorioamnionitis was induced by a 10 mg intra amniotic LPS injection at two different exposure intervals. The fetal brain was studied at 125 days of gestation (term = 150 days) either 2 (LPS2D group) or 14 days (LPS14D group) after LPS or saline injection (control group). Synaptophysin immunohistochemistry was used to quantify the presynaptic density in layers 2-3 and 5-6 of the motor cortex, somatosensory cortex, entorhinal cortex, and piriforme cortex, in the nucleus caudatus and putamen and in CA1/2, CA3, and dentate gyrus of the hippocampus. RESULTS: There was a significant reduction in presynaptic bouton densities in layers 2-3 and 5-6 of the motor cortex and in layers 2-3 of the entorhinal and the somatosensory cortex, in the nucleus caudate and putamen and the CA1/2 and CA3 of the hippocampus in the LPS2D compared to control animals. Only in the motor cortex and putamen, the presynaptic density was significantly decreased in the LPS14 D compared to the control group. No changes were found in the dentate gyrus of the hippocampus and the piriforme cortex. CONCLUSION: We demonstrated that LPS-induced chorioamnionitis caused a decreased density in presynaptic boutons in different areas in the fetal brain. These synaptic changes seemed to be region-specific, with some regions being more affected than others, and seemed to be transient in some regions. PMID- 26417594 TI - Circulating S100B and Adiponectin in Children Who Underwent Open Heart Surgery and Cardiopulmonary Bypass. AB - BACKGROUND: S100B protein, previously proposed as a consolidated marker of brain damage in congenital heart disease (CHD) newborns who underwent cardiac surgery and cardiopulmonary bypass (CPB), has been progressively abandoned due to S100B CNS extra-source such as adipose tissue. The present study investigated CHD newborns, if adipose tissue contributes significantly to S100B serum levels. METHODS: We conducted a prospective study in 26 CHD infants, without preexisting neurological disorders, who underwent cardiac surgery and CPB in whom blood samples for S100B and adiponectin (ADN) measurement were drawn at five perioperative time-points. RESULTS: S100B showed a significant increase from hospital admission up to 24 h after procedure reaching its maximum peak (P < 0.01) during CPB and at the end of the surgical procedure. Moreover, ADN showed a flat pattern and no significant differences (P > 0.05) have been found all along perioperative monitoring. ADN/S100B ratio pattern was identical to S100B alone with the higher peak at the end of CPB and remained higher up to 24 h from surgery. CONCLUSIONS: The present study provides evidence that, in CHD infants, S100B protein is not affected by an extra-source adipose tissue release as suggested by no changes in circulating ADN concentrations. PMID- 26417596 TI - The Effects of TiO2 Nanodot Films with RGD Immobilization on Light-Induced Cell Sheet Technology. AB - Cell sheet technology is a new strategy in tissue engineering which could be possible to implant into the body without a scaffold. In order to get an integrated cell sheet, a light-induced method via UV365 is used for cell sheet detachment from culture dishes. In this study, we investigated the possibility of cell detachment and growth efficiency on TiO2 nanodot films with RGD immobilization on light-induced cell sheet technology. Mouse calvaria-derived, preosteoblastic (MC3T3-E1) cells were cultured on TiO2 nanodot films with (TR) or without (TN) RGD immobilization. After cells were cultured with or without 5.5 mW/cm(2) UV365 illumination, cell morphology, cell viability, osteogenesis related RNA and protein expression, and cell detachment ability were compared, respectively. Light-induced cell detachment was possible when cells were cultured on TR samples. Also, cells cultured on TR samples showed better cell viability, alongside higher protein and RNA expression than on TN samples. This study provides a new biomaterial for light-induced cell/cell sheet harvesting. PMID- 26417595 TI - Biomarkers of Brain Damage and Postoperative Cognitive Disorders in Orthopedic Patients: An Update. AB - The incidence of postoperative cognitive dysfunction (POCD) in orthopedic patients varies from 16% to 45%, although it can be as high as 72%. As a consequence, the hospitalization time of patients who developed POCD was longer, the outcome and quality of life were worsened, and prolonged medical and social assistance were necessary. In this review the short description of such biomarkers of brain damage as the S100B protein, NSE, GFAP, Tau protein, metalloproteinases, ubiquitin C terminal hydrolase, microtubule-associated protein, myelin basic protein, alpha-II spectrin breakdown products, and microRNA was made. The role of thromboembolic material in the development of cognitive decline was also discussed. Special attention was paid to optimization of surgical and anesthetic procedures in the prevention of postoperative cognitive decline. PMID- 26417597 TI - Posterior Cingulate Lactate as a Metabolic Biomarker in Amnestic Mild Cognitive Impairment. AB - Mitochondrial dysfunction represents a central factor within the pathogenesis of the Alzheimer's disease (AD) spectrum. We hypothesized that in vivo measurements of lactate (lac), a by-product of glycolysis, would correlate with functional impairment and measures of brain health in a cohort of 15 amnestic mild cognitive impairment (aMCI) individuals. Lac was quantified from the precuneus/posterior cingulate (PPC) using 2-dimensional J-resolved magnetic resonance spectroscopy (MRS). Additionally, standard behavioral and imaging markers of aMCI disease progression were acquired. PPC lac was negatively correlated with performance on the Wechsler logical memory tests and on the minimental state examination even after accounting for gray matter, cerebral spinal fluid volume, and age. No such relationships were observed between lac and performance on nonmemory tests. Significant negative relationships were also noted between PPC lac and hippocampal volume and PPC functional connectivity. Together, these results reveal that aMCI individuals with a greater disease progression have increased concentrations of PPC lac. Because lac is upregulated as a compensatory response to mitochondrial impairment, we propose that J-resolved MRS of lac is a noninvasive, surrogate biomarker of impaired metabolic function and would provide a useful means of tracking mitochondrial function during therapeutic trials targeting brain metabolism. PMID- 26417598 TI - The Cortisol Awakening Response in Patients with Poststroke Depression Is Blunted and Negatively Correlated with Depressive Mood. AB - It is important to reduce poststroke depression (PSD) to improve the stroke outcomes and quality of life in stroke patients, but the underlying mechanisms of PSD are not completely understood. As many studies implicate dysregulation of hypothalamic-pituitary-adrenal axis in the etiology of major depression and stroke, we compared the cortisol awakening response (CAR) of 28 admitted PSD patients with that of 23 age-matched caregiver controls. Saliva samples for cortisol measurement were collected immediately, 15, 30, and 45 min after awakening for two consecutive days. Depressive mood status in PSD patients was determined with Beck Depression Inventory and Hamilton Depression Rating Scale. Salivary cortisol levels of PSD patients did not rise significantly at any sampling time, showing a somewhat flat curve. Caregiver controls showed significantly higher CAR at 15 and 30 min after awakening compared to PSD patients even though the two groups did not differ at awakening or 45 min after awakening. Area-under-the-curve analysis revealed a significant negative correlation between the CAR and the degree of depression in PSD patients. Thus, our findings suggest that poststroke depression is closely related with dysfunctional HPA axis indicated by blunted CAR. PMID- 26417599 TI - Sustained Reduction of Cerebellar Activity in Experimental Epilepsy. AB - Clinical and experimental evidence suggests a role for the cerebellum in seizure control, while no data are available on cerebellar activity between seizures. We hypothesized that interictal regional activity of the deep cerebellar nuclei is reduced in epilepsy and tested this in an animal model by using DeltaFosB and cytochrome oxidase (COX) (immuno)histochemistry. The expression of these two markers of neuronal activity was analysed in the dentate nucleus (DN), interpositus nucleus (IN), and fastigial nucleus (FN) of the cerebellum of fully amygdala kindled rats that were sacrificed 48 hours after their last seizure. The DN and FN of kindled rats exhibited 25 to 29% less DeltaFosB immunopositive cells than their respective counterpart in sham controls (P < 0.05). COX expression in the DN and FN of kindled animals was reduced by 32 to 33% compared to respective control values (P < 0.05). These results indicate that an epileptogenic state is characterized by decreased activity of deep cerebellar nuclei, especially the DN and FN. Possible consequences may include a decreased activation of the thalamus, contributing to further seizure spread. Restoration of FN activity by low frequency electrical stimulation is suggested as a possible treatment option in chronic epilepsy. PMID- 26417600 TI - Role and Importance of IGF-1 in Traumatic Brain Injuries. AB - It is increasingly affirmed that most of the long-term consequences of TBI are due to molecular and cellular changes occurring during the acute phase of the injury and which may, afterwards, persist or progress. Understanding how to prevent secondary damage and improve outcome in trauma patients, has been always a target of scientific interest. Plans of studies focused their attention on the posttraumatic neuroendocrine dysfunction in order to achieve a correlation between hormone blood level and TBI outcomes. The somatotropic axis (GH and IGF 1) seems to be the most affected, with different alterations between the acute and late phases. IGF-1 plays an important role in brain growth and development, and it is related to repair responses to damage for both the central and peripheral nervous system. The IGF-1 blood levels result prone to decrease during both the early and late phases after TBI. Despite this, experimental studies on animals have shown that the CNS responds to the injury upregulating the expression of IGF-1; thus it appears to be related to the secondary mechanisms of response to posttraumatic damage. We review the mechanisms involving IGF-1 in TBI, analyzing how its expression and metabolism may affect prognosis and outcome in head trauma patients. PMID- 26417602 TI - Quantitative Anatomical Studies. PMID- 26417601 TI - Regeneration, Plasticity, and Induced Molecular Programs in Adult Zebrafish Brain. AB - Regenerative capacity of the brain is a variable trait within animals. Aquatic vertebrates such as zebrafish have widespread ability to renew their brains upon damage, while mammals have--if not none--very limited overall regenerative competence. Underlying cause of such a disparity is not fully evident; however, one of the reasons could be activation of peculiar molecular programs, which might have specific roles after injury or damage, by the organisms that regenerate. If this hypothesis is correct, then there must be genes and pathways that (a) are expressed only after injury or damage in tissues, (b) are biologically and functionally relevant to restoration of neural tissue, and (c) are not detected in regenerating organisms. Presence of such programs might circumvent the initial detrimental effects of the damage and subsequently set up the stage for tissue redevelopment to take place by modulating the plasticity of the neural stem/progenitor cells. Additionally, if transferable, those "molecular mechanisms of regeneration" could open up new avenues for regenerative therapies of humans in clinical settings. This review focuses on the recent studies addressing injury/damage-induced molecular programs in zebrafish brain, underscoring the possibility of the presence of genes that could be used as biomarkers of neural plasticity and regeneration. PMID- 26417603 TI - Fascioliasis: An Ongoing Zoonotic Trematode Infection. AB - Zoonotic trematode infections are an area of the neglected tropical diseases that have become of major interest to global and public health due to their associated morbidity. Human fascioliasis is a trematode zoonosis of interest in public health. It affects approximately 50 million people worldwide and over 180 million are at risk of infection in both developed and underdeveloped countries. The one health paradigm is an area that seeks to address the problem of zoonotic infections through a comprehensive and sustainable approach. This review attempts to address the major challenges in managing human and animal fascioliasis with valuable insights gained from the one health paradigm to global health and multidisciplinary integration. PMID- 26417604 TI - Gray and White Matter Volumes and Cognitive Dysfunction in Drug-Naive Newly Diagnosed Pediatric Epilepsy. AB - Epilepsy patients often have cognitive dysfunction even at early stages of disease. We investigated the relationship between structural findings and neuropsychological status in drug-naive newly diagnosed pediatric epilepsy patients. Thirty newly diagnosed pediatric epilepsy patients and 25 healthy control subjects aged 7~16 years were enrolled, who were assessed by the Korean version of the Wechsler Intelligence Scale for Children (K-WISC-III), the Stroop test, and the trail making test (TMT). Optimized voxel-based morphometry (VBM) was performed for both Gray Matter (GM) and White Matter (WM) volumes. Lower performance levels of verbal intelligence quotient, freedom from distractibility, and executive function were observed in epilepsy group. Interestingly, poor performance in these cognitive subdomains was correlated with regional VBM findings involving both GM and WM volumes, but with different patterns between groups. GM volumes revealed clear differences predominantly in the bilateral frontal regions. These findings indicate that certain cognitive functions may be affected in the early stage of epilepsy, not related to the long-standing epilepsy or medication, but more related to the neurocognitive developmental process in this age. Epilepsy can lead to neuroanatomical alterations in both GM and WM, which may affect cognitive functions, during early stages even before commencement of AED medication. PMID- 26417605 TI - Mutations Found in embCAB, embR, and ubiA Genes of Ethambutol-Sensitive and Resistant Mycobacterium tuberculosis Clinical Isolates from China. AB - To better understand the molecular mechanisms of Ethambutol (EMB) resistance, the mutant hot spot region of five genes (embB, embA, embC, embR, and ubiA) was amplified and sequenced in 109 EMB-resistant and 153 EMB-susceptible clinical isolates from China. Twenty-seven EMB-susceptible isolates were found to have nonsynonym mutations, 23 of which were in embB. The mutations occurred most frequently in embB (85.3%, 93) and were seldom in embC (2.8%, 3), embA (3.7%, 4), embR (3.7%, 4), and ubiA (8.3%, 9) in EMB-resistant isolates. For the embB gene, 63 isolates showed mutations at embB306, 20 at embB406, nine at embB497, and five at embB354 in EMB-resistant isolates. In addition, the particular mutants at embB406 and embB497 indicated both high levels of EMB resistance (MICs > 5 MUg/mL) and broad anti-TB drug resistance spectrums. Our data supported the facts that embB306 could be used as a marker for EMB resistance with a sensitivity of 57.8% and a specificity of 78.8%. PMID- 26417607 TI - Food Service Perspectives on National School Lunch Program Implementation. AB - OBJECTIVES: Explore barriers and facilitators to implementation of the new National School Lunch Program (NSLP) policy guidelines. METHODS: Interviews with eight food service directors using an interview guide informed by the Consolidated Framework for Implementation Research. RESULTS: Food service personnel; parents, teachers, school staff; and students were important stakeholders. Characteristics of the new NSLP policy guidelines were reported to create increased demands; resources alleviated some barriers. Directors reported increased food and labor costs, food sourcing challenges, decreased student participation, and organizational constraints as barriers to implementation. Creativity in menu planning facilitated success. CONCLUSIONS: Factors within the food service department, characteristics of implementing individuals and the new NSLP policy guidelines, and stakeholder involvement in the implementation process relate to successful implementation. PMID- 26417606 TI - The Bidirectional Relationship between Sleep and Immunity against Infections. AB - Sleep is considered an important modulator of the immune response. Thus, a lack of sleep can weaken immunity, increasing organism susceptibility to infection. For instance, shorter sleep durations are associated with a rise in suffering from the common cold. The function of sleep in altering immune responses must be determined to understand how sleep deprivation increases the susceptibility to viral, bacterial, and parasitic infections. There are several explanations for greater susceptibility to infections after reduced sleep, such as impaired mitogenic proliferation of lymphocytes, decreased HLA-DR expression, the upregulation of CD14+, and variations in CD4+ and CD8+ T lymphocytes, which have been observed during partial sleep deprivation. Also, steroid hormones, in addition to regulating sexual behavior, influence sleep. Thus, we hypothesize that sleep and the immune-endocrine system have a bidirectional relationship in governing various physiological processes, including immunity to infections. This review discusses the evidence on the bidirectional effects of the immune response against viral, bacterial, and parasitic infections on sleep patterns and how the lack of sleep affects the immune response against such agents. Because sleep is essential in the maintenance of homeostasis, these situations must be adapted to elicit changes in sleep patterns and other physiological parameters during the immune response to infections to which the organism is continuously exposed. PMID- 26417608 TI - Quantitative high-throughput gene expression profiling of human striatal development to screen stem cell-derived medium spiny neurons. AB - A systematic characterization of the spatio-temporal gene expression during human neurodevelopment is essential to understand brain function in both physiological and pathological conditions. In recent years, stem cell technology has provided an in vitro tool to recapitulate human development, permitting also the generation of human models for many diseases. The correct differentiation of human pluripotent stem cell (hPSC) into specific cell types should be evaluated by comparison with specific cells/tissue profiles from the equivalent adult in vivo organ. Here, we define by a quantitative high-throughput gene expression analysis the subset of specific genes of the whole ganglionic eminence (WGE) and adult human striatum. Our results demonstrate that not only the number of specific genes is crucial but also their relative expression levels between brain areas. We next used these gene profiles to characterize the differentiation of hPSCs. Our findings demonstrate a temporal progression of gene expression during striatal differentiation of hPSCs from a WGE toward an adult striatum identity. Present results establish a gene expression profile to qualitatively and quantitatively evaluate the telencephalic hPSC-derived progenitors eventually used for transplantation and mature striatal neurons for disease modeling and drug-screening. PMID- 26417609 TI - A marker-free system for highly efficient construction of vaccinia virus vectors using CRISPR Cas9. AB - The current method for creation of vaccinia virus (VACV) vectors involves using a selection and purification marker, however inclusion of a gene without therapeutic value in the resulting vector is not desirable for clinical use. The Cre-LoxP system has been used to make marker-free Poxviruses, but the efficiency was very low. To obtain a marker-free VACV vector, we developed marker gene excision systems to modify the thymidine kinase (TK) region and N1L regions using Cre-Loxp and Flp-FRET systems respectively. CRISPR-Cas9 system significantly resulted in a high efficiency (~90%) in generation of marker gene-positive TK mutant VACV vector. The marker gene (RFP) could be excised from the recombinant virus using Cre recombinase. To make a marker-free VV vector with double gene deletions targeting the TK and N1L gene, we constructed a donor repair vector targeting the N1L gene, which can carry a therapeutic gene and the marker (RFP) that could be excised from the recombinant virus using Flp recombinase. The marker-free system developed here can be used to efficiently construct VACV vectors armed with any therapeutic genes in the TK region or N1L region without marker genes. Our marker-free system platform has significant potential for development of new marker-free VACV vectors for clinical application. PMID- 26417610 TI - Inhibitory Control is Associated with Psychosocial, Cognitive, and Weight Outcomes in a Longitudinal Sample of Girls. AB - Early self-regulation abilities have been highlighted as a robust predictor of adaptive development, but the extant literature has typically focused on outcomes in different developmental domains separately. The aim of the current study was to expand upon this research by testing pathways from girls' inhibitory control at age 7, an aspect of self-regulation, to their psychosocial, cognitive, and weight outcomes from ages 9 to 15 (n=192). Results supported the hypothesis that greater inhibitory control is independently associated with better subsequent psychosocial, cognitive, and weight outcomes. These findings, combined with evidence that self-regulatory capacities are modifiable in early childhood, offer opportunities for interdisciplinary preventive interventions aiming to promote child health and well-being across domains and over time. PMID- 26417611 TI - Developments in Neurovascular Diseases and Treatments. PMID- 26417613 TI - Possible association between mandibular repositioning device for sleep apnea and osseous lytic lesion with fracture of the coronoid process of the mandible: A case report. AB - Mandibular repositioning devices (MRDs) increase the patency of the upper airway by repositioning the mandible forward, resulting in displacement of the oropharyngeal tissues preventing upper airway collapsibility. Mandibular anterior repositioning is counteracted by muscle force from the temporalis muscle. A 39 year-old man had an osteolytic lesion with fracture of the coronoid process of the mandible secondary to wearing a MRD for sleep apnea. Continuous stress generated on the coronoid process temporalis muscle resulted in osteolysis and fracture of the coronoid process on the patient's right side, resulting in swelling and limited ability to open his mouth. The patient was managed with intravenous antibiotics to control the osteomyelitis and surgical debridement, with removal of the coronoid process of the mandible. It is unclear why the fracture only occurred on the right side. Pathologic fracture of the coronoid process due to chronic stress and secondary osteomyelitis is a rare severe complication of treatment for obstructive sleep apnea syndrome with a MRD. PMID- 26417614 TI - A rare case of a broken dental bur perforating the medial orbital wall without damaging the eye. AB - Rotating instruments used in the fields of dentistry and oral surgery operate at high speeds. Therefore, if small particles are projected and strike the orbit, injuries of varying severity can occur. We report here a case in which a broken dental bur pierced into the orbit. The bur fortunately did not damage the eyeball and stopped after penetration of the medial orbital wall. The subject was a 27 year-old dental assistant and not wearing protective eyewear. A foreign body had penetrated the medial wall of the right orbit and the tip had reached the ethmoid sinus. The medial orbital wall was exposed subperiosteally after dissection of the medial canthal ligament, and the foreign body was removed. Although the importance of protective eyewear had been advocated, eye protection compliance differed by region and dental personnel. Eye protection use needs to increase in not only dentists but also other dental personnel. PMID- 26417615 TI - Evaluation of root canal configuration of maxillary and mandibular anterior teeth using cone beam computed tomography: An in-vivo study. AB - OBJECTIVE: Several studies demonstrate variability of root canal morphology of anterior teeth. This in-vivo study was designed to analyze and characterize root canal morphology of maxillary and mandibular anterior teeth using three dimensional imaging. METHOD AND MATERIALS: Patients who required CBCT radiographic examinations as part of their routine examination, diagnosis, and treatment planning were enrolled on the study. A total of 1,200 healthy, untreated, fully developed maxillary and mandibular incisors and canines were included. The following observations were recorded: (i) number of roots and their morphology; (ii) number of canals per root; and (iii) primary variations in the morphology of the root canal systems. RESULTS: Root canal morphology of maxillary teeth was consistent with a single canal extending from the pulp chamber to the apex in 98% of the cases. In contrast, in mandibular central and lateral incisors, the presence of a single canal represented 64.5% and 60.5% respectively. The second most common morphology was the presence of one canal leaving the pulp chamber, which divided into two within the root, and then merged to exit as one canal in 18% and 25.5% respectively. The presence of one canal leaving the pulp chamber and dividing short of the apex into two separate and distinct canals with separate apical foramina (variant 5) was recorded in 14.5% and 12% respectively. CONCLUSION: There was a low incidence of anatomical variation in maxillary anterior teeth. In contrast, mandibular anterior teeth presented with a high prevalence of two canals, especially central and lateral incisors. The reported data may help clinicians understand the variations in root canal morphology of anterior teeth in order to overcome problems associated with shaping and cleaning procedures. PMID- 26417612 TI - Inflammatory Signaling Involved in High-Fat Diet Induced Prostate Diseases. AB - High-Fat Diet (HFD) has emerged as an important risk factor not only for obesity and diabetes but also for urological disorders. Recent research provides ample evidence that HFD is a putative cause for prostatic diseases including prostate cancer. The mechanisms whereby these diseases develop in the prostate have not been fully elucidated. In this review we discuss signaling pathways intricately involved in HFD-induced prostate disease. We performed a search through PUBMED using key words "high fat diet" and "prostate". Our data and perspectives are included in this review along with research performed by various other groups. HFD is positively associated with an increased risk of benign prostatic hyperplasia (BPH) and prostate cancer. HFD induces oxidative stress and inflammation in the prostate gland, and these adverse influences transform it from a normal to a diseased state. Studies demonstrate that HFD accelerates the generation of reactive oxygen species by driving the NADPH oxidase system, exacerbating oxidative stress in the prostate. HFD also causes a significant increase in the levels of pro-inflammatory cytokines and gene products through activation of two important signaling pathways: the Signal Transducer and Activator of Transcription (STAT)-3 and Nuclear Factor-kappa B (NF-kappaB). Both these pathways function as transcription factors required for regulating genes involved in proliferation, survival, angiogenesis, invasion and inflammation. The crosstalk between these two pathways enhances their regulatory function. Through its influences on the NF-kappaB and Stat-3 signaling pathways, it appears likely that HFD increases the risk of development of BPH and prostate cancer. PMID- 26417616 TI - Full-mouth rehabilitation with monolithic CAD/CAM-fabricated hybrid and all ceramic materials: A case report and 3-year follow up. AB - Esthetic full-mouth rehabilitation represents a great challenge for clinicians and dental technicians. Computer-aided design/ computer-assisted manufacture (CAD/CAM) technology and novel ceramic materials in combination with adhesive cementation provide a reliable, predictable, and economic workflow. Polychromatic feldspathic CAD/CAM ceramics that are specifically designed for anterior indications result in superior esthetics, whereas novel CAD/CAM hybrid ceramics provide sufficient fracture resistance and adsorption of the occlusal load in posterior areas. Screw-retained monolithic CAD/CAM lithium disilicate crowns (ie, hybrid abutment crowns) represent a reliable and time- and cost-efficient prosthetic implant solution. This case report details a CAD/CAM approach to the full-arch rehabilitation of a 65-year-old patient with toothand implant-supported restorations and provides an overview of the applied CAD/CAM materials and the utilized chairside intraoral scanner. The esthetics, functional occlusion, and gingival and peri-implant tissues remained stable over a follow-up period of 3 years. No signs of fractures within the restorations were observed. PMID- 26417617 TI - Partial-prep bonded restorations in the anterior dentition: Long-term gingival health and predictability. A case report. AB - Bonded porcelain restorations are a predictable and durable treatment option that can restore not only the strength and function of the teeth but also the esthetic appearance. One important issue in adhesive dentistry is the preservation of sound enamel. Following biomimetic principles, employing minimally invasive applications and adhesive technologies is of paramount importance for successful restorations. While it is widely accepted that minimally invasive restorative techniques should be favored, there is still some controversy over the noninvasive approaches. The purpose of this article is to question the complete "no-prep veneer" concept due to the possible negative effects on periodontal health caused by excessive contour and overhangs of the ceramic restoration, and to propose a new method to assess the quality and longevity of veneers with a partial-prep concept. PMID- 26417618 TI - The association between dental proximal restorations and periodontal disease: A retrospective 10-18 years longitudinal study. AB - OBJECTIVE: Dental restorations may be plaque retentive. The aim of this study was to evaluate the long-term association between proximal restorations and the incidence and progression of periodontal disease in well-maintained patients. METHOD AND MATERIALS: Probing pocket depths (PPD), bleeding on probing (BOP), and radiographic status of proximal restorations were retrospectively retrieved from files of patients attending a specialist periodontal office. Ill-fitting margins were recorded. The association between these parameters was evaluated at baseline examination (T0), after cause-related therapy (T1) and after >= 10 years from T0 (T2), during which supportive periodontal therapy (SPT) was administered, using descriptive statistics, ANOVA-Bonferroni, and chi-square analyses. RESULTS: 1,301 teeth were examined. Mean PPD in unrestored surfaces was 3.7 +/- 1.7 mm, 3.1 +/- 1.3 mm, and 2.8 +/- 1 mm at T0, T1, and T2, respectively. Deeper pockets were found in restored surfaces at those time points with PPD values of 4.4 +/- 1.8 mm, 3.6 +/- 1.4 mm, and 3.2 +/- 1.1 mm, respectively (P < .001). Higher PPD values were found in restored surfaces exhibiting inadequate restorations when compared to restored surfaces with adequate restorations at all time points. These values were 4.9 +/- 1.9 mm, 4.1 +/- 1.5 mm, and 4 +/- 1.7 mm vs 4.3 +/- 1.8 mm, 3.6 +/- 1.4 mm, and 3.1 +/- 1.1 mm, respectively (P < .001). CONCLUSION: The present study confirmed that restorations might be detrimental to periodontal health. A significant association between the presence of proximal restorations and the incidence of periodontal disease was observed. This association was more pronounced for inadequate restorations while becoming less significant over time in patients receiving routine SPT. PMID- 26417619 TI - Effect of full-mouth disinfection on insulin sensitivity in type 2 diabetes patients with and without chronic periodontitis. AB - OBJECTIVE: To explore the effect of full-mouth disinfection (FMD) on glycemic control and insulin resistance in type 2 diabetes mellitus (DM). METHOD AND MATERIALS: Sixty dentate patients who were never-smokers with type 2 diabetes mellitus were recruited for the study. Based on clinical examination they were divided into two groups: one with chronic periodontitis and the other without chronic periodontitis. Periodontal parameters Plaque Index (PI), Gingival Index (GI), and probing pocket depth (PPD) were evaluated. Blood samples were assessed for the levels of fasting glucose (FG), insulin, and C-reactive protein (CRP), and insulin glucose ratio was calculated using a mathematical equation (HOMA-IR). All parameters were assessed at baseline, and at 3 months and 6 months after FMD. RESULTS: The results showed a significant reduction in PI, GI, PPD, FG, and HOMA IR from baseline to 6 months. The CRP levels were constant throughout the study period. CONCLUSION: Within the limitations of the present study it can be concluded that FMD contributes to significant reduction in insulin resistance, thereby improving the glycemic control in type 2 diabetes mellitus patients. PMID- 26417621 TI - Very late recurrence of renal cell carcinoma experiencing long-term response to sunitinib: a case report. AB - Renal cell carcinoma (RCC) is responsible for 4% of all neoplasms in adults and for 80% of all primary renal tumors. Metastatic RCC is resistant to all cytotoxic agents and generally prognosis is poor. However, the clinical behavior of RCC is unpredictable, and late recurrences of disease can occur even after several years from the initial surgical approach, so response to the currently available targeted agents is uncertain, due to the lack of reliable prognostic and predictive factors. We report the case of a patient who developed a metastatic recurrence of RCC 16 years after primary treatment, in spite of metastatic disease at diagnosis. At the time of relapse, the disease showed a surprisingly long-term response to Sunitinib, which is maintained after 74 months of treatment. This case report highlights the unpredictable behavior of RCC and underlines the presence of a subset of patients with metastatic RCC achieving long-term response to Sunitinib, despite poor clinical features. In this subset of patients, an important clinical question arises about the appropriate duration of treatment and the need to continue it indefinitely. PMID- 26417622 TI - Setting Expectations. PMID- 26417623 TI - Alcohol, Tobacco, Triggers, and Headache Disorders. PMID- 26417624 TI - Oral contraceptives: a good scare. PMID- 26417625 TI - Bevacizumab (AVASTIN) and age-related macular degeneration. Lower cost does not justify taking risks. AB - Intravitreal injection of ranibizumab, a VEGF inhibitor, is an option for patients with neovascular age-related macular degeneration (AMD). Because of its lower price, bevacizumab, a VEGF inhibitor closely related to ranibizumab and marketed for the treatment of various malignancies, is sometimes used off label for intravitreal injection in AMD. In 2011, the harm-benefit balance of bevacizumab in patients with AMD was uncertain. New data are available in 2015. In six randomised trials including a total of about 3200 patients, funded independently of the pharmaceutical industry, bevacizumab (1.25 mg per dose) was about as effective as ranibizumab (0.5 mg per injection): visual acuity stabilised or improved in 90% to 95% of patients after one to two years of treatment. During these trials, bevacizumab did not reduce the number of injections needed, as compared with ranibizumab. These trials confirmed the known adverse effect profile of bevacizumab, which is similar to that of ranibizumab and includes serious ocular as well as extraocular adverse effects, in particular cardiac disorders. Serious extraocular adverse events, especially gastrointestinal disorders, were more frequent with bevacizumab than with ranibizumab at one year (18% versus 14%). In early 2015, there are no bevacizumab products suitable for intravitreal injection. In 2011, cases of sight-threatening infectious endophthalmitis were reported in the United States, following contamination during syringe preparation for intravitreal administration. In practice, when treatment with a VEGF inhibitor is considered for AMD, it is more prudent to choose ranibizumab, despite its currently unacceptable price. PMID- 26417627 TI - Apixaban (Eliquis) in deep vein thrombosis and pulmonary embolism. Warfarin remains the standard therapy. AB - Not more effective than warfarin. The lower incidence of bleeding observed among patients selected for these trials must be weighed against the lack of either an antidote or a routine clotting test. PMID- 26417626 TI - Ranibizumab: reject such high (exorbitant) prices. PMID- 26417628 TI - Aflibercept (Eylea) and diabetic macular oedema. A first-choice VEGF inhibitor in case of marked visual loss. AB - Overall, VEGF inhibitors administered by intravitreal injection have a similar harm-benefit balance. However, a publicly funded trial has shown that aflibercept is more effective than ranibizumab and bevacizumab in patients with marked loss of visual acuity. PMID- 26417629 TI - Eltrombopag (Revolade ) and thrombocytopenia in patients with hepatitis C. Hepatotoxic drug; more harms than benefits. AB - Too many potentially life-threatening adverse effects, including hepatic decompensation and thromboembolic complications. PMID- 26417630 TI - INN common-stem: -olol. PMID- 26417631 TI - Drug-induced lesions of the oesophageal mucosa. AB - Lesions of the oesophageal mucosa are observed in various situations: most often with gastrooesophageal reflux disease, but also with infections, cancer, contact with a toxic substance, etc. When they are symptomatic, these lesions provoke burning sensations, dysphagia, regurgitation and sometimes dorsal pain. The changes to the oesophageal mucosa may take various forms: inflammation, erosion, ulceration or necrosis. Serious or even fatal complications can develop but are rare; they include oesophageal perforation, stricture and haemorrhage. Some oral drugs damage the oesophageal mucosa through direct contact. The symptoms often develop several hours after ingestion. The pain is of sudden onset. The resulting lesions are solitary or multiple ulcers that vary in depth and usually occur in the upper portion of the oesophagus. Various factors prolong contact between a drug and the oesophageal mucosa, in particular: swallowing the drug with insufficient liquid or just before lying down; capsule forms; and oesophageal abnormalities. The drugs most frequently implicated are tetracyclines, particularly doxycycline, bisphosphonates and various nonsteroidal anti inflammatory drugs (NSAIDs). Many drugs, used in various situations, provoke gastro-oesophageal reflux disease, sometimes causing mucosal lesions in the lower oesophagus: calcium-channel blockers, nitrates, exenatide and liraglutide, drugs with antimuscarinic effects, theophylline, etc. Some drugs affect all mucous membranes in the body, including the oesophageal mucosa, irrespective of their route of administration: cancer drugs, isotretinoin, and nicorandil. PMID- 26417632 TI - Lesions of the oesophageal mucosa and their causes. PMID- 26417633 TI - Baclofen and pregnancy: birth defects and withdrawal symptoms. AB - A comparison of 134 pregnant women who had taken baclofen in early pregnancy and 400 pregnant controls showed an increased risk of major malformations. Several infants exposed to baclofen until birth exhibited withdrawal symptoms. PMID- 26417634 TI - Parkinson's disease: initial treatment of motor disorders. AB - Parkinson's disease is characterised by three main symptoms: slowness and paucity of movements, rigidity, and resting tremor. Rapid improvement in these symptoms after levodopa administration supports the diagnosis of Parkinson's disease. It is important to inform the patient tactfully, allowing him or her to control the pace at which information on the diagnosis, symptoms and prognosis is conveyed. Patients with minimal discomfort or mild disability derive little benefit from drug therapy. Physiotherapy and physical exercises are sometimes useful. Previously untreated patients with marked functional impairment should receive medication. The choice is essentially between levodopa and ropinirole, and mainly depends on the patient's age. PMID- 26417635 TI - Prevention of deep vein thrombosis. First choice treatments. PMID- 26417636 TI - Breast cancer and duration of tamoxifen. AB - Two randomised trials have compared 5 years versus 10 years of tamoxifen therapy following surgery for hormone receptor-positive early breast cancer. Overall mortality, breast cancer-related mortality and the breast cancer recurrence rate were all lower when tamoxifen was continued for 10 years. Prolonging tamoxifen therapy increased the incidence of endometrial cancer and thromboembolic events. The value of tamoxifen therapy therefore decreases over time. PMID- 26417637 TI - Type 2 diabetes: Mediterranean diet delays need for drug therapy. AB - According to a trial in patients with recently diagnosed type 2 diabetes, adopting a "Mediterranean" diet seems to delay the need for glucose-lowering drugs by several years compared with a low-fat diet. PMID- 26417638 TI - Ischaemic stroke: decide rapidly. AB - A meta-analysis of individual data for 6756 patients showed that intravenous thrombolysis with alteplase improved survival without overt neurological deficits when started within 4.5 hours of the first symptoms of ischaemic stroke, at a cost of increased mortality due to cerebral haemorrhage during the week following thrombolysis. PMID- 26417639 TI - Discounted drug prices for hospitals: result in prescriptions for expensive drugs in the community. AB - Hospital prescribing has a major influence on community prescribing. In France, pharmaceutical companies can sell drugs to hospitals at dramatically reduced prices in the expectation of increasing sales in community pharmacies. PMID- 26417640 TI - Microphthalmia-associated transcription factor mutations are associated with white-spotted coat color in swamp buffalo. AB - A candidate gene analysis of the microphthalmia-associated transcription factor (MITF) gene was used in an attempt to identify the genetic basis for a white spotted coat color phenotype in the Asian swamp buffalo (Bubalus bubalis carabanensis). Ninety-three buffaloes-32 solid, 38 spotted and 23 white individuals-were Sanger-sequenced for all MITF exons as well as highly conserved intronic and flanking regions. MITF cDNA representing skin and iris tissue from six spotted, nine solid and one white buffaloes was also Sanger-sequenced to confirm detected mutations. Two independent loss-of-function mutations, a premature stop codon (c.328C>T, p.Arg110*) and a donor splice-site mutation (c.840+2T>A, p.Glu281_Leu282Ins8), both of which cause white-spotted coat color in swamp buffaloes, were identified. The nonsense mutation leads to a premature stop codon in exon 3, and likely removal of the resulting mRNA via nonsense mediated decay pathway, whereas the donor splice-site mutation leads to aberrant splicing of exon 8 that encodes part of a highly conserved region of MITF. The resulting insertion of eight amino acid residues is expected to perturb the leucine zipper part in the basic helix-loop-helix leucine zipper (bHLH-Zip) domain and will most likely influence dimerization and DNA binding capacity. Electrophoretic mobility shift assay was performed using mutant and wild-type MITF proteins and showed that the mutant MITF protein resulting from the splice site mutation decreased in vitro DNA binding capacity compared to wild-type MITF. White-spotted buffalo bulls are sacrificed in funeral ceremonies in Tana Toraja, Indonesia, because they are considered holy, and our results show that genetic variation causes a tie to the cultural use of these buffaloes. PMID- 26417641 TI - Phase unwrapping in 4D MR flow with a 4D single-step laplacian algorithm. AB - PURPOSE: To introduce and demonstrate a method for unwrapping 4D flow data by utilizing continuity constraints in all four available dimensions. MATERIALS AND METHODS: A Laplacian-based algorithm for unwrapping phase data was expanded to unwrap along the temporal dimension in addition to all three spatial dimensions. The method was tested on simulated blood flow under varying vessel diameters and velocity encoding (Venc ) values. The algorithm was also tested in the aorta of five volunteers, with wrapped data acquired with Venc = 80 cm/s and 40 cm/s. Unwrapping performance was measured visually and in comparison to a high Venc reference free of phase wrapping. Ten patients with aortic coarctations with clinical Venc values and lower-Venc reconstructions were corrected and scored by blinded reviewers on a 0-3 scale. RESULTS: Simulated data were completely unwrapped for most clinically relevant levels of velocity aliasing using the proposed method. In vivo data in the aorta were completely unwrapped for cases of moderate wrapping (Venc = 80 cm/s, peak velocities = ~160 cm/s), while residual aliasing remained for the more considerably aliased datasets (Venc = 40 cm/s). Improvements were seen in scoring (mean score improved by 1.1 and 2.2 for clinical and low-Venc datasets, respectively) by the blinded reviewers in the patient cohort for both standard and low-Venc reconstructions. CONCLUSION: A computationally fast, fully automated, easy to use, and parameter-free single step method for unwrapping 4D flow data is shown to be effective for use in most common clinical occurrences of velocity aliasing. PMID- 26417642 TI - Surgical Salvage of Thermal Ablation Failures for Renal Cell Carcinoma. AB - PURPOSE: Cryoablation and radio frequency ablation are attractive modalities for small renal masses in patients with substantial comorbidities. However, salvage extirpative therapy for local recurrence after thermal ablation can be challenging due to associated perinephric fibrosis. MATERIALS AND METHODS: Patients with thermal ablation refractory tumors requiring surgical salvage from 1997 to 2013 were identified and retrospectively reviewed. RESULTS: A total of 27 patients were treated surgically after cryoablation (18) or radio frequency ablation (9) failed. Subjective assessment indicated moderate/severe fibrosis in 22 cases (81%). Partial nephrectomy was preferred in all patients but was not possible in 12, primarily due to unfavorable tumor size/location. In the intended partial nephrectomy group (15) open surgery was performed in all patients and completed in 14, with the procedure aborted in 1 due to extensive perinephric fibrosis. Radical nephrectomy was planned in 12 patients, of whom 8 were treated laparoscopically with 1 requiring conversion to open. Median estimated blood loss was 225 ml. Overall 17 patients experienced no complications and 4 had minor complications. However, 6 patients experienced more significant complications (Clavien III-IVb). Since January 2008 partial nephrectomy was performed more frequently (12 of 17, or 71% vs 2 of 10, or 20% for previous cases, p=0.02). CONCLUSIONS: Surgical salvage after failed thermal ablation is feasible in most instances, and partial nephrectomy is often possible but can be challenging due to associated perinephric fibrosis. The difficulty of surgical salvage should be recognized as a potential limitation of the thermal ablation treatment strategy. Prospective studies of thermal ablation vs partial nephrectomy should be prioritized to provide higher quality data about the merits and limitations of each approach. PMID- 26417643 TI - Quantitative Proteomic Analysis of Differentially Expressed Proteins and Downstream Signaling Pathways in Chronic Bladder Ischemia. AB - PURPOSE: Growing evidence suggests that ischemia may contribute to aging associated bladder dysfunction and lower urinary tract symptoms. Our goal was to determine the effects of chronic ischemia on bladder proteomic profiles and characterize downstream signaling pathways. MATERIALS AND METHODS: Bilateral iliac artery atherosclerosis and chronic bladder ischemia were created in male Sprague Dawley(r) rats. At 8 weeks cystometrograms were obtained. Ischemic and control bladder tissues were then processed for label-free quantitative proteomic analysis. GO (Gene Ontology) and IPA (Ingenuity(r) Pathway Analysis) software were used to classify altered proteins in bladder ischemia. Western blot was done to confirm differentially expressed proteins. Tissue structure was examined by transmission electron microscopy. RESULTS: Chronic ischemia resulted in detrusor instability and noncompliance. Proteomic analysis revealed a total of 4,277 proteins in ischemic and 4,602 in control bladder tissues. In ischemic bladders 359 and 66 proteins were differentially expressed with a greater than twofold and fivefold change, respectively. On GO analysis differentially expressed proteins were associated with molecular signaling mechanisms underlying proteolysis and degenerative processes. Pathway and network analysis of ischemic tissues suggested that altered proteins are involved in ubiquitination, Nrf2 mediated oxidative stress response, cell death, glucose metabolism and cytoskeleton remodeling. Western blot verified changes in 4 representative proteins, including Nedd4l, Mpo, Ca3 and Fkbp5. Altered proteomic profile of the bladder was associated with widespread ultrastructural damage. CONCLUSIONS: Alterations of bladder proteomic profiles in ischemia may provide new insight into molecular pathways underlying bladder dysfunction and lower urinary tract symptoms in pelvic atherosclerosis. PMID- 26417645 TI - Renal Vascular Clamp Placement: A Potential Cause of Incomplete Hilar Control during Partial Nephrectomy. AB - PURPOSE: Previous benchtop studies have shown that robotic bulldog clamps provide incomplete vascular control of a Penrose drain. We determined the efficacy of robotic and laparoscopic bulldog clamps to ensure hemostasis on the human renal artery. The effect of clamp position on vascular control was also examined. MATERIALS AND METHODS: Fresh human cadaveric renal arteries were used to determine the leak point pressure of 7 bulldog clamps from a total of 3 manufacturers. Five trials were performed per clamp at 4 locations, including the fulcrum, proximal, middle and distal positions. Comparison was done using the Kruskal-Wallis test with p <0.05 considered significant. RESULTS: None of the bulldog clamps leaked at a pressure less than 215 mm Hg when applied at the proximal, middle or distal position. In general leak point pressure decreased as the artery was positioned more distal along the clamp. The exception was when the vessel was placed at the fulcrum position. At that position 80% to 100% of trials with the Klein laparoscopic, 100% with the Klein robotic (Klein Robotic, San Antonio, Texas) and 60% to 80% with the Scanlan robotic (Scanlan International, Saint Paul, Minnesota) clamp leaked at pressure below 215 mm Hg. CONCLUSIONS: Each vascular clamp adequately occluded flow at physiological pressure when placed at the proximal, middle or distal position. Furthermore, these results demonstrate that there is leakage at physiological pressure when the artery is placed at the fulcrum of certain clamp types. These results suggest that applying a bulldog clamp at the fulcrum could potentially lead to inadequate vessel occlusion and intraoperative bleeding. PMID- 26417644 TI - Perirenal Fat Promotes Renal Arterial Endothelial Dysfunction in Obese Swine through Tumor Necrosis Factor-alpha. AB - PURPOSE: Perirenal fat is associated with poor blood pressure control and chronic kidney disease but the underlying mechanisms remain elusive. We tested the hypothesis that perirenal fat impairs renal arterial endothelial function in pigs with obesity-metabolic derangements. MATERIALS AND METHODS: We studied 14 domestic pigs after 16 weeks of a high fat/high fructose diet (obesity-metabolic derangement group) or standard chow (lean group). Renal blood flow, glomerular filtration rate and visceral fat volumes were studied in vivo by computerized tomography. Renal arterial endothelial function was also studied ex vivo in organ baths. RESULTS: Pigs with obesity-metabolic derangements demonstrated increased body weight, blood pressure, cholesterol and intra-abdominal fat compared to lean pigs and perirenal fat volume was significantly larger. Renal blood flow and glomerular filtration rate were markedly elevated while urinary protein level was preserved. Ex vivo acetylcholine induced, endothelium dependent vasodilation of renal artery rings was substantially impaired in pigs with obesity-metabolic derangements compared to lean pigs. Endothelial function was further blunted in obesity-metabolic derangement and lean arterial rings by incubation with perirenal fat harvested from pigs with obesity-metabolic derangements but not from lean pigs. It was restored by inhibiting tumor necrosis factor-alpha. Perirenal fat from pigs with obesity-metabolic derangements also showed increased pro-inflammatory macrophage infiltration and tumor necrosis factor-alpha expression. CONCLUSIONS: In pigs with obesity-metabolic derangements perirenal fat directly causes renal artery endothelial dysfunction, which is partly mediated by tumor necrosis factor-alpha. PMID- 26417646 TI - An Increase in Gleason 6 Tumor Volume While on Active Surveillance Portends a Greater Risk of Grade Reclassification with Further Followup. AB - PURPOSE: We evaluated the relative risk of later grade reclassification and outcomes of patients in whom high volume Gleason 6 prostate cancer develops while on active surveillance. MATERIALS AND METHODS: A prospectively maintained database was used to identify patients on active surveillance between 1998 and 2013. Tumor volume was assessed based on the number of positive cores and proportion of core involvement. The chi-square and Fisher exact tests were used for analysis as appropriate. The primary end point was the development of grade reclassification, defined as grade only and/or grade and volume at the event biopsy. RESULTS: A total of 555 men met the study inclusion criteria. Mean followup was 46 months. Overall 70 patients demonstrated an increase in tumor volume at or after biopsy 2. Compared to those men never experiencing volume or grade reclassification, prostate specific antigen at diagnosis was not significantly different (p=0.95), but median prostate volume was smaller in patients who demonstrated volume reclassification (p <0.001). The incidence of pure volume reclassification was 6.8%, 6.1% and 7.8% at biopsy 2, 3 and 4, respectively. Men with volume reclassification were more likely to experience later grade reclassification than those without at 33.3% vs 9.3%, respectively (p <0.0001). CONCLUSIONS: While Gleason 6 prostate cancer has a favorable natural history, it appears that patients on active surveillance who experience volume reclassification are at substantially higher risk for grade reclassification. Thus, urologists should pay close attention to tumor core involvement, and monitoring should be adjusted accordingly for early volume reclassification in younger men and those in good health. PMID- 26417647 TI - Modulation of Lactobacillus casei bacteriophage A2 lytic/lysogenic cycles by binding of Gp25 to the early lytic mRNA. AB - The genetic switch of Lactobacillus casei bacteriophage A2 is regulated by the CI protein, which represses the early lytic promoter PR and Cro that abolishes expression from the lysogenic promoter PL . Lysogens contain equivalent cI and cro-gp25 mRNA concentrations, i.e., CI only partially represses P(R), predicting a lytic cycle dominance. However, A2 generates stable lysogens. This may be due to Gp25 binding to the cro-gp25 mRNA between the ribosomal binding site and the cro start codon, which abolishes its translation. Upon lytic cycle induction, CI is partially degraded, cro-gp25 mRNA levels increase, and Cro accumulates, launching viral progeny production. The concomitant concentration increase of Gp25 restricts cro mRNA translation, which, together with the low but detectable levels of CI late during the lytic cycle, promotes reentry of part of the cell population into the lysogenic cycle, thus explaining the low proportion of L. casei lysogens that become lysed (~ 1%). A2 shares its genetic switch structure with many other Firmicutes phages. The data presented may constitute a model of how these phages make the decision for lysis versus lysogeny. PMID- 26417648 TI - Patient specific hemodynamic response functions associated with interictal discharges recorded via simultaneous intracranial EEG-fMRI. AB - Simultaneous collection of scalp EEG and fMRI has become an important tool for studying the hemodynamic changes associated with interictal epileptiform discharges (IEDs) in persons with epilepsy, and has become a standard presurgical assessment tool in some centres. We previously demonstrated that performing EEG fMRI using intracranial electrodes (iEEG-fMRI) is of low risk to patients in our research centre, and offers unique insight into BOLD signal changes associated with IEDs recorded from very discrete sources. However, it is unknown whether the BOLD response corresponding to IEDs recorded by iEEG-fMRI follows the canonical hemodynamic response. We therefore scanned 11 presurgical epilepsy patients using iEEG-fMRI, and assessed the hemodynamic response associated with individual IEDs using two methods: assessment of BOLD signal changes associated with isolated IEDs at the location of the active intracranial electrode, and by estimating subject-specific impulse response functions to isolated IEDs. We found that the hemodynamic response associated with the intracranially recorded discharges varied by patient and by spike location. The observed shape and timing differences also deviated from the canonical hemodynamic response function traditionally used in many fMRI experiments. It is recommended that future iEEG fMRI studies of IEDs use a flexible hemodynamic response model when performing parametric tests to accurately characterize these data. PMID- 26417650 TI - Seminal plasma proteins and their relationship with percentage of morphologically normal sperm in 2-year-old Brahman (Bos indicus) bulls. AB - The objective was to determine the relationship between seminal plasma proteins and sperm morphology in Bos indicus bulls of the Brahman breed. Fifty-six 24 month-old Australian Brahman bulls were electroejaculated and samples were examined to determine the percentage of morphologically normal sperm (PNS24) and the seminal plasma protein composition was identified and quantified by 2-D gel electrophoresis. The total integrated optical density of 152 seminal plasma protein spots (SPPs) across all gels was determined using the PDQuest software version 8.0 (Bio Rad, USA). Using a single regression mixed model with the density of individual spots as a covariate for PNS24, 17 SPPs were significantly associated with PNS24 (p<0.05). A multiple regression analyses of these SPPs, using three models; non-parametric Tree Model, Generalized Additive Model, and a step-wise selection method were conducted, and 6 SPPs could be used to predict PNS24; four SPPs had positive and two had negative association with PNS24. Together these spots explained 35% of the phenotypic variation in PNS24. Using mass spectrometry (MALDI-ToF and TripleToF-MS) the SPPs with positive relationship contained mainly apolipoprotein A-I (1310), protein DJ-1 and glutathione peroxidase 3 (2308), phosphoglycerate kinase 1 (6402) and apolipoprotein A-I and secretoglobin family 1D member (8008). The SPPs inversely associated with PNS24 were clusterin/seminal plasma protein A3 (1411) and epididymal secretory protein E1 (8108). This is the first comprehensive report on the association between seminal plasma protein composition in Bos indicus Brahman bulls and sperm morphology. PMID- 26417651 TI - TESS3: fast inference of spatial population structure and genome scans for selection. AB - Geography and landscape are important determinants of genetic variation in natural populations, and several ancestry estimation methods have been proposed to investigate population structure using genetic and geographic data simultaneously. Those approaches are often based on computer-intensive stochastic simulations and do not scale with the dimensions of the data sets generated by high-throughput sequencing technologies. There is a growing demand for faster algorithms able to analyse genomewide patterns of population genetic variation in their geographic context. In this study, we present TESS3, a major update of the spatial ancestry estimation program TESS. By combining matrix factorization and spatial statistical methods, TESS3 provides estimates of ancestry coefficients with accuracy comparable to TESS and with run-times much faster than the Bayesian version. In addition, the TESS3 program can be used to perform genome scans for selection, and separate adaptive from nonadaptive genetic variation using ancestral allele frequency differentiation tests. The main features of TESS3 are illustrated using simulated data and analysing genomic data from European lines of the plant species Arabidopsis thaliana. PMID- 26417649 TI - Effects of dietary n-6:n-3 fatty acid ratio and vitamin E on semen quality, fatty acid composition and antioxidant status in boars. AB - The aim of the present study was to evaluate the effects of dietary n-6:n-3 fatty acid (FA) ratio and vitamin E on the semen quality, FA composition and antioxidant status of boars. Forty-eight Landrace boars were randomly distributed in a 3*2 factorial design with three n-6:n-3 FA ratios (14.4, 6.6 and 2.2) by the inclusion of three oil sources (soybean, fish/soybean, fish) and two vitamin E levels (200 and 400mg/kg). During the 8 weeks of treatment, semen parameters were evaluated. Serum, sperm and seminal plasma samples were taken at 0 and 8 weeks to monitor the FA composition and antioxidant status. Results showed that the 6.6 and 2.2 dietary ratios very effectively increased docosahexaenoic acid (DHA) and n-3 polyunsaturated fatty acid (PUFA) and decreased docosapentaenoic acid (DPA) and n-6:n-3 ratio in spermatozoa. The 6.6 dietary ratio contributed to a greater progressive sperm motility (P<0.05) than the 14.4 and 2.2 dietary ratio, and this ratio also enhanced the superoxide dismutase (SOD) and total antioxidant capacity (TAC) (P<0.05) in seminal plasma more significantly than the other two ratios at week 8. Compared with 200mg/kg supplementation of vitamin E, 400mg/kg supplementation of vitamin E increased the progressive sperm motility, SOD of sperm, TAC and SOD of seminal plasma and serum, and decreased sperm malondialdehyde (MDA) (P<0.05). In conclusion, the 6.6 dietary ratio and 400mg/kg vitamin E supplementation improve progressive sperm motility by modifying the sperm FA composition and antioxidant status. PMID- 26417652 TI - Close relationship between circumflex artery and left atrial appendage. PMID- 26417653 TI - Changes in referral protocols for cardiac surgery: do financial considerations come at a cost? AB - INTRODUCTION AND OBJECTIVES: The aim of this study was to determine whether changes to referral protocols for cardiac surgery have had an impact on waiting times, hospitalizations and mortality during the waiting period and during the first year of follow-up after surgery. METHODS: In this retrospective study of patients referred for cardiac surgery between January 1, 2008 and September 30, 2014, the study population was divided into two groups: those referred before (group A, January 1, 2008 to August 31, 2011) and after (group B, September 1, 2011 to September 30, 2014) the change in referral protocols. A telephone follow up was conducted. RESULTS: There were 864 patients referred for cardiac surgery, 557 in group A and 307 in group B. Patient characteristics were similar between groups. The mean waiting time for surgery was 10.6+/-18.5 days and 55.7+/-79.9 days in groups A and B, respectively (p=0.00). During the waiting period two patients (0.4%) were hospitalized in group A and 28 (9.1%) in group B (p=0:00); mortality was, respectively, 0% and 2.3% (p=0.00). During one-year follow-up 12.8% of group A patients and 16% of group B patients were hospitalized. Cardiovascular mortality in this period was around 5% in both groups (p>0.05). CONCLUSION: Changes to referral protocols for cardiac surgery had an impact on waiting times, on the number of hospitalizations and on mortality in this period. PMID- 26417654 TI - Infective endocarditis in an HIV-infected intravenous drug user. AB - Infective endocarditis is a common complication among injecting drug users. Disease risk among these patients is increased by the spread of HIV infection. In the following article, we discuss the exceptional clinical presentation of a 28 year-old patient who used intravenous drugs (heroin) for 10 years, had been infected with HIV for seven years and as a complication had developed Staphylococcus aureus infective endocarditis. The patient came to the hospital in serious condition, complaining of bodily pain, swelling of the legs and general weakness. During hospitalization, besides infective endocarditis, she was also diagnosed with anemia, toxic hepatitis, renal failure, ascites, sepsis, and pneumonia. A completely disrupted tricuspid valve, damaged aortic valve, and fibrosis of the mitral valve were detected. Echocardiographic and radiologic data showed that the patient's condition continued to deteriorate day by day, with significant progression of heart failure, ejection fraction decreasing from 45% to 10%, and development of myocarditis, hydrothorax and pericarditis. However, this progressive worsening of the patient's condition ceased when vancomycin was administered. To the authors' knowledge, this is the first such case described in the literature in which significant improvement was observed despite the patient's complex condition with associated complications. PMID- 26417655 TI - Looking into and beyond the heart. PMID- 26417656 TI - Psoriasis strikes back! Epicardial adipose tissue: another contributor to the higher cardiovascular risk in psoriasis. AB - For many years psoriasis was considered an inflammatory condition restricted to the skin. However, nowadays it is considered an immune-mediated, systemic inflammatory condition associated with numerous medical comorbidities, particularly cardiometabolic diseases, and overall cardiovascular mortality. Several studies have suggested that psoriasis may be an independent risk factor for atherosclerosis, indicating that psoriasis itself poses an intrinsic risk for cardiovascular disease, probably due to the disease's inflammatory burden. However, other causes beyond systemic inflammation and traditional cardiovascular risk factors may be implicated in cardiovascular disease in psoriasis. Recently, epicardial adipose tissue, an emerging cardiovascular risk factor, has been shown to be increased in psoriasis patients and to be associated with subclinical atherosclerosis, providing another possible link between psoriasis and atherosclerosis. The reason for the increase in epicardial adipose tissue in patients with psoriasis is unknown, but it is probably multifactorial, with genetic, immune-mediated and behavioral factors having a role. Thus, along with the increased prevalence of cardiometabolic risk factors and systemic inflammation in psoriasis, epicardial adipose tissue is probably another important contributor to the higher cardiovascular risk observed in psoriasis. PMID- 26417657 TI - Preparing giant unilamellar vesicles (GUVs) of complex lipid mixtures on demand: Mixing small unilamellar vesicles of compositionally heterogeneous mixtures. AB - Giant unilamellar vesicles (GUVs) are simple model membrane systems of cell-size, which are instrumental to study the function of more complex biological membranes involving heterogeneities in lipid composition, shape, mechanical properties, and chemical properties. We have devised a method that makes it possible to prepare a uniform sample of ternary GUVs of a prescribed composition and heterogeneity by mixing different populations of small unilamellar vesicles (SUVs). The validity of the protocol has been demonstrated by applying it to ternary lipid mixture of DOPC, DPPC, and cholesterol by mixing small unilamellar vesicles (SUVs) of two different populations and with different lipid compositions. The compositional homogeneity among GUVs resulting from SUV mixing is quantified by measuring the area fraction of the liquid ordered-liquid disordered phases in giant vesicles and is found to be comparable to that in GUVs of the prescribed composition produced from hydration of dried lipids mixed in organic solvent. Our method opens up the possibility to quickly increase and manipulate the complexity of GUV membranes in a controlled manner at physiological buffer and temperature conditions. The new protocol will permit quantitative biophysical studies of a whole new class of well-defined model membrane systems of a complexity that resembles biological membranes with rafts. PMID- 26417658 TI - Prevalence and risk factors for colonization with methicillin resistant Staphylococcus aureus and other Staphylococci species in hospitalized and farm horses in Israel. AB - Methicillin-resistant staphylococci (MRS), and specifically Methicillin-resistant Staphylococcus aureus (MRSA) colonization or infection have become a serious emerging condition in equine hospitals, with complex concerns regarding animals, personnel and public health. The objectives of this study were to evaluate the prevalence and risk factors for colonization by Staphylococci, MRS, and MRSA among horses in Israel. Nasal swabs were collected from horses at 17 riding stables (n=206), and from hospitalized horses admitted to a veterinary hospital (n=84). Species identification was performed by pta gene PCR, RFLP analysis and sequencing. MRS was identified by the presence of mecA. Genetic relatedness of MRSA isolates was determined by spa typing and MLST. SCCmec-type and pvl gene were determined. Univariable and multivariable statistical analysis were used to identify potential risk factors. Colonization with Staphylococci was found among 3.8% of farm horses and 50.6% of hospitalized horses (p<0.05). MRS isolates were not found in any of the farm horses, but were isolated from 21.6% of the horses at the veterinary hospital, comprising 42.8% of all hospital isolates. MRSA was found exclusively among hospitalized horses (7.2%). All MRSA isolates belonged to a unique single multi-drug-resistant clone, ST5-SCCmec V, pvl-negative, spa-type t535. Risk factors for colonization with MRS were pure bred, hospitalization and antibiotic use. This is the first surveillance study of Staphylococci in horses in Israel, and the first report on the presence of a unique MRSA strain among hospital horses, recognizing the veterinary hospital as a potential reservoir for MRSA, an antibiotic resistant pathogen with human relevance. PMID- 26417659 TI - Plasma IL-1Ra: linking hyperapoB to risk factors for type 2 diabetes independent of obesity in humans. AB - BACKGROUND/OBJECTIVE: Plasma apoB predicts the incidence of type 2 diabetes (T2D); however, the link between apoB-linpoproteins and risks for T2D remain unclear. Insulin resistance (IR) and compensatory hyperinsulinemia characterize prediabetes, and the involvement of an activated interleukin-1 (IL-1) family, mainly IL-1beta and its receptor antagonist (IL-Ra), is well documented. ApoB lipoproteins were reported to promote IL-1beta secretion in immune cells; however, in vivo evidence is lacking. We hypothesized that obese subjects with hyperapoB have an activated IL-1 system that explains hyperinsulinemia and IR in these subjects. SUBJECTS/METHODS: We examined 81 well-characterized normoglycemic men and postmenopausal women (?27 kg m(-2), 45-74 years, non-smokers, sedentary, free of chronic disease). Insulin secretion and sensitivity were measured by the gold-standard Botnia clamp, which is a combination of a 1-h intravenous glucose tolerance test (IVGTT) followed by 3-h hyperinsulinemic euglycemic clamp. RESULTS: Plasma IL-1beta was near detection limit (0.071-0.216 pg ml(-1)), while IL-1Ra accumulated at 1000-folds higher (77-1068 pg ml(-1)). Plasma apoB (0.34 1.80 g l(-1)) associated significantly with hypersinsulinemia (totalIVGTT: C peptide r=0.27, insulin r=0.22), IR (M/I=-0.29) and plasma IL-1Ra (r=0.26) but not with IL-1beta. Plasma IL-1Ra associated with plasma IL-1beta (r=0.40), and more strongly with hyperinsulinemia and IR than apoB, while the association of plasma IL-1beta was limited to second phase and total insulin secretion (r=0.23). Adjusting the association of plasma apoB to hyperinsulinemia and IR for IL-1Ra eliminated these associations. Furthermore, despite equivalent body composition, subjects with hyperapoB (?80th percentile, 1.14 g l(-1)) had higher C-peptide secretion and lower insulin sensitivity than those with low plasma apoB (?20th percentile, 0.78 g l(-1)). Adjustment for plasma IL-1 Ra eliminated all group differences. CONCLUSION: Plasma apoB is associated with hyperinsulinemia and IR in normoglycemic obese subjects, which is eliminated upon adjustment for plasma IL-1Ra. This may implicate the IL-1 family in elevated risks for T2D in obese subjects with hyperapoB. PMID- 26417661 TI - The shadow of the future promotes cooperation in a repeated prisoner's dilemma for children. AB - Cooperation among genetically unrelated individuals can be supported by direct reciprocity. Theoretical models and experiments with adults show that the possibility of future interactions with the same partner can promote cooperation via conditionally cooperative strategies such as tit-for-tat (TFT). Here, we introduce a novel implementation of the repeated Prisoner's Dilemma (PD) designed for children to examine whether repeated interactions can successfully promote cooperation in 10 and 11 year olds. We find that children cooperate substantially more in repeated PDs than in one-shot PDs. We also find that girls cooperate more than boys, and that children with more conduct problems cooperate less. Finally, we find that children use conditional cooperation strategies but that these strategies vary by gender and conduct problem rating. Specifically, girls and children with few conduct problems appear to follow an altruistic version of win stay, lose-shift (WSLS), attempting to re-establish cooperation after they had defected. Boys and children with more conduct problems appear to follow a Grim strategy, defecting for the duration after the partner defects. Thus we provide evidence that children utilize the power of direct reciprocity to promote cooperation in strategic interactions and that, by late elementary school, distinct strategies of conditional cooperation have emerged. PMID- 26417660 TI - Importance of the type of provider seen to begin health care for a new episode low back pain: associations with future utilization and costs. AB - RATIONALE, AIMS AND OBJECTIVE: Low back pain (LBP) care can involve many providers. The provider chosen for entry into care may predict future health care utilization and costs. The objective of this study was to explore associations between entry settings and future LBP-related utilization and costs. METHODS: A retrospective review of claims data identified new entries into health care for LBP. We examined the year after entry to identify utilization outcomes (imaging, surgeon or emergency visits, injections, surgery) and total LBP-related costs. Multivariate models with inverse probability weighting on propensity scores were used to evaluate relationships between utilization and cost outcomes with entry setting. RESULTS: 747 patients were identified (mean age = 38.2 (+/- 10.7) years, 61.2% female). Entry setting was primary care (n = 409, 54.8%), chiropractic (n = 207, 27.7%), physiatry (n = 83, 11.1%) and physical therapy (n = 48, 6.4%). Relative to primary care, entry in physiatry increased risk for radiographs (OR = 3.46, P = 0.001), advanced imaging (OR = 3.38, P < 0.001), injections (OR = 4.91, P < 0.001), surgery (OR = 4.76, P = 0.012) and LBP-related costs (standardized Beta = 0.67, P < 0.001). Entry in chiropractic was associated with decreased risk for advanced imaging (OR = 0.21, P = 0.001) or a surgeon visit (OR = 0.13, P = 0.005) and increased episode of care duration (standardized Beta = 0.51, P < 0.001). Entry in physical therapy decreased risk of radiographs (OR = 0.39, P = 0.017) and no patient entering in physical therapy had surgery. CONCLUSIONS: Entry setting for LBP was associated with future health care utilization and costs. Consideration of where patients chose to enter care may be a strategy to improve outcomes and reduce costs. PMID- 26417663 TI - Biofilm Formation of Staphylococcus aureus on Various Surfaces and Their Resistance to Chlorine Sanitizer. AB - This study investigated the effect of material types (polystyrene, polypropylene, glass, and stainless steel) and glucose addition on Staphylococcus aureus biofilm formation, and the relationship between biofilm formation measured by crystal violet (CV) staining and the number of biofilm cells determined by cell counts was studied. We also evaluated the efficacy of chlorine sanitizer on inhibiting various different types of S. aureus biofilms on the surface of stainless steel. Levels of biofilm formation of S. aureus were higher on hydrophilic surfaces (glass and stainless steel) than on hydrophobic surfaces (polypropylene and polystyrene). With the exception of biofilm formed on glass, the addition of glucose in broth significantly increased the biofilm formation of S. aureus on all surfaces and for all tested strains (P <= 0.05). The number of biofilm cells was not correlated with the biomass of the biofilms determined using the CV staining method. The efficacy of chlorine sanitizer against biofilm of S. aureus was not significantly different depending on types of biofilm (P > 0.05). Therefore, further studies are needed in order to determine an accurate method quantifying levels of bacterial biofilm and to evaluate the resistance of bacterial biofilm on the material surface. PRACTICAL APPLICATION: Biofilm formation of Staphylococcus aureus on the surface was different depending on the surface characteristics and S. aureus strains. There was low correlation between crystal violet staining method and viable counts technique for measuring levels of biofilm formation of S. aureus on the surfaces. These results could provide helpful information for finding and understanding the quantification method and resistance of bacterial biofilm on the surface. PMID- 26417662 TI - Integration of a transfected gene into the genome of Babesia bovis occurs by legitimate homologous recombination mechanisms. AB - This study examines the patterns of gene integration of gfp-bsd upon stable transfection into the T3Bo strain of Babesia bovis using a plasmid designed to integrate homologous sequences of the parasite's two identical ef-1alpha A and B genes. While the transfected BboTf-149-6 cell line displayed two distinct patterns of gene integration, clonal lines derived from this strain by cell sorting contained only single gfp-bsd insertions. Whole genome sequencing of two selected clonal lines, E9 and C6, indicated two distinct patterns of gfp-bsd insertion occurring by legitimate homologous recombination mechanisms: one into the expected ef-1alpha orf B, and another into the ef-1alpha B promoter. The data suggest that expression of the ef-1alpha orf B is not required for development of B. bovis in cultured erythrocyte stages. Use of legitimate homologous recombination mechanisms in transfected B. bovis supports the future use of transfection methods for developing efficient gene function assignment experiments using gene knockout techniques. PMID- 26417664 TI - Polymorphism of PXR gene associated with the increased risk of drug-induced liver injury in Indonesian pulmonary tuberculosis patients. AB - WHAT IS KNOWN AND OBJECTIVE: Tuberculosis is still a major infectious disease in Indonesia. Patients are treated mostly using fixed-dose combination treatment in primary public health facilities. The incidence of antituberculosis drug-induced liver injury (AT-DILI) is approximately 10% among Indonesian tuberculosis patients who used standard fixed combination regimens during the intensive phase of treatment. However, information regarding genetic polymorphism associated with the increase risk of drug-induced liver injury is still limited. The aim of this study was to investigate pregnane X receptor (PXR) gene polymorphisms as one of the risk factors of AT-DILI. METHODS: In this prospective cohort study, we recruited 106 adult patients diagnosed with pulmonary tuberculosis and treated with category I FDC (fixed-dose combination). The identification of SNP -25385C>T (rs3814055) was conducted by ARMS (amplification refractory mutation system). Hepatotoxicity was defined as ALT and/or AST levels above the normal threshold on the second, fourth and sixth months of monitoring during tuberculosis treatment. RESULTS AND DISCUSSION: The logistic regression analysis showed that patients with the TT genotype of PXR gene (rs3814055) significantly had a greater risk of AT-DILI (OR 8.89; 95% CI 1.36-57.93, P < 0.05), compared with those of wild-type CC genotype. WHAT IS NEW AND CONCLUSION: The result suggests that in Indonesian patients with tuberculosis, the risk of having AT-DILI was associated with TT genotype of the PXR gene. PMID- 26417665 TI - Mechanism of Polyphosphates Hydrolysis by Purified Polyphosphatases from the Dorsal Muscle of Silver Carp (Hypophthalmichthys Molitrix) as Detected by 31P NMR. AB - The dynamic hydrolysis of tetrasodium pyrophosphate (TSPP), sodium tripolyphosphate (STPP) and polyphosphate compound, which was catalyzed by purified pyrophosphatase (PPase) and myosin- tripolyphosphatase (TPPase) from the silver carp dorsal muscle, was studied using (31) P NMR spectroscopy. In the PPase + TSPP system, the pyrophosphate (PP) was hydrolyzed quickly and completely within 8 h and the hydrolysis rate of PP was 12.51%/h. In the TPPase + STPP system, the first-order hydrolysis of tripolyphosphate (TPP) was not yet complete after 48 h, and the derived PP accumulated progressively. Given the coexistence of PPase and TPPase, only 1.20% of TPP in STPP alone remained after 48 h. However, the generation rate of Pi in the polyphosphate compound (TSPP: STPP: sodium hexametaphosphate = 1: 8: 1) was 0.76%/h, which was less than 0.88%/h in STPP alone. In the presence of polyphosphatases, the decrease of PP or TPP content in the polyphosphate compound was not as rapid as that in TSPP or STPP alone due to the inhibitory effect of PP on TPPase and the effect of low system pH on PPase. The understanding of polyphosphates hydrolysis mechanism was capable of developing the advanced polyphosphate mixture in order to reduce the phosphate residue in fish products. PRACTICAL APPLICATION: Processors appreciate the proven value of phosphates to increase the yield and functionality of the fish meat products. Our studies showed that the hydrolysis rate of PP or TPP in the blend was slower than that of polyphosphate alone. Thus, it is likely that the addition of PP and TPP in a polyphosphate blend had a prolonged interaction with proteins in fish meat processing and the effectiveness of polyphosphates was enhanced. PMID- 26417666 TI - PATIENTS EXPERIENCES OF INVOLVEMENT IN CHOICE OF DIALYSIS MODE. AB - BACKGROUND: International guidelines recommend that patients choose dialysis mode based on their own values and preferences; thus, involvement is needed in dialysis choice. A literature review indicated a lack of knowledge concerning patient involvement in decision-making, especially concerning patients' experiences of the decision-making process just after making the decision and before starting dialysis. OBJECTIVES: To gather information about how patients experienced involvement in the decision-making process of renal substation therapy just after they have made the decision and before starting dialysis. METHODS: A qualitative method with a phenomenological and hermeneutic approach. The study was based on individual semi-structured interviews with nine adult patients with chronic kidney disease. A data-driven analysis based on systematic text condensation was used. FINDINGS: Patients are a significant part of the decision. Health care professionals contribute to the experience of being involved. Patients keep putting off the final choice. CONCLUSION: The patients found themselves involved in the choice of dialysis mode and have different views on what is needed to feel being involved. Information, interaction, and advice from health care professionals affect this experience. However, the experience of not having any symptoms caused patients to put off the final choice of dialysis mode. PMID- 26417667 TI - Sodium MRI radiofrequency coils for body imaging. AB - The proliferation of high-field whole-body systems, advances in gradient performance and refinement of signal-to-noise ratio (SNR)-efficient short-TE sequences suitable for sodium imaging have led to a resurgence of interest in sodium imaging for body applications. With this renewed interest has come increased demand for SNR-efficient sodium coils. Efficient coils can significantly increase SNR in sodium imaging, allowing higher resolutions and/or shorter scan times. In this work, we focus on body imaging applications of sodium MRI, and review developments in MRI radiofrequency (RF) coil topologies for sodium imaging. We first provide a brief discussion of RF coil design considerations in sodium imaging. This is followed by an overview of common coil topologies, their advantages and disadvantages, and examples of each. PMID- 26417668 TI - Increased visual cortical thickness in sight-recovery individuals. AB - Individuals who are born blind due to dense bilateral cataracts and who later regain vision due to cataract surgery provide a unique model to evaluate the effect of early sensory experience in humans. In recent years, several studies have started to assess the functional consequences of early visual deprivation in these individuals, revealing a number of behavioral impairments in visual and multisensory functions. In contrast, the extent to which a transient period of congenital visual deprivation impacts brain structure has not yet been investigated. The present study investigated this by assessing cortical thickness of occipital areas in a group of six cataract-reversal individuals and a group of six age-matched normally sighted controls. This analysis revealed higher cortical thickness in cataract-reversal individuals in the left calcarine sulcus, in the superior occipital gyrus and in the transverse occipital sulcus bilaterally. In addition, occipital cortical thickness correlated negatively with behavioral performance in an audio-visual task for which visual input was critical, and positively with behavioral performance in auditory tasks. Together, these results underscore the critical role of early sensory experience in shaping brain structure and suggest that increased occipital cortical thickness, while potentially compensatory for auditory sensory processing, might be maladaptive for visual recovery in cases of sight restoration. PMID- 26417669 TI - Feasibility and reproducibility of BOLD and TOLD measurements in the liver with oxygen and carbogen gas challenge in healthy volunteers and patients with hepatocellular carcinoma. AB - PURPOSE: To quantify baseline relaxation rates R2* and R1 in the abdomen, their changes after respiratory challenges, and their reproducibility in healthy volunteers and patients with hepatocellular carcinoma (HCC) at 1.5T and 3.0T. MATERIALS AND METHODS: R2* measurements were acquired in the liver in 8 volunteers and 27 patients with 34 HCCs using multiecho T2* at baseline and after respiratory challenges with 100% oxygen (O2 ) and carbogen (CB = 95%O2 /5%CO2 ). R1 was measured at 1.5T in one volunteer and 21 patients with 23 HCCs. Test retest coefficient of variation (CV) was assessed in 10 subjects. Intra- and interobserver variability of R2* and R1 measurements was assessed in 12 and 10 patients, respectively. Parameters for HCC, liver, and muscle were compared between baseline and after gas challenges. RESULTS: We observed that R2* and R1 imaging of HCCs with O2 and CB is feasible and reproducible (test-retest CV R2*<15%/R1 <5%; intra- and interobserver intraclass correlation coefficient R2*>0.88/R1 >0.7 and CV R2*<7%/R1 <3% at 1.5T). R2* measurements were observed to be less reproducible at 3.0T (CV<35%). There was a statistically significant decrease in R2* values in HCC before and after O2 (P = 0.02) and increase in R1 after O2 (P = 0.004). CB had no significant effect (P R2* = 0.47/R1 = 0.278). CONCLUSION: R2* measurements in HCC and liver parenchyma are more reproducible at 1.5T than at 3.0T, and with O2 than with CB challenge. We observed a decrease in R2* and an increase in R1 of HCCs from baseline in response to O2 challenge, as expected with increased tissue and blood oxygenation. PMID- 26417670 TI - Oxidative stress promotes benign prostatic hyperplasia. AB - BACKGROUND: Benign prostatic hyperplasia (BPH) is characterized by increased tissue mass in the transition zone of the prostate, which leads to obstruction of urine outflow and significant morbidity in the majority of older men. Plasma markers of oxidative stress are increased in men with BPH but it is unclear whether oxidative stress and/or oxidative DNA damage are causal in the pathogenesis of BPH. METHODS: Levels of 8-OH deoxyguanosine (8-OH dG), a marker of oxidative stress, were measured in prostate tissues from normal transition zone and BPH by ELISA. 8-OH dG was also detected in tissues by immunohistochemistry and staining quantitated by image analysis. Nox4 promotes the formation of reactive oxygen species. We therefore created and characterized transgenic mice with prostate specific expression of Nox4 under the control of the prostate specific ARR2PB promoter. RESULTS: Human BPH tissues contained significantly higher levels of 8-OH dG than control transition zone tissues and the levels of 8-OH dG were correlated with prostate weight. Cells with 8-OH dG staining were predominantly in the epithelium and were present in a patchy distribution. The total fraction of epithelial staining with 8-OH dG was significantly increased in BPH tissues by image analysis. The ARR2PB-Nox4 mice had increased oxidative DNA damage in the prostate, increased prostate weight, increased epithelial proliferation, and histological changes including epithelial proliferation, stromal thickening, and fibrosis when compared to wild type controls. CONCLUSIONS: Oxidative stress and oxidative DNA damage are important in the pathogenesis of BPH. PMID- 26417671 TI - A 3D map of the islet routes throughout the healthy human pancreas. AB - Islets of Langerhans are fundamental in understanding diabetes. A healthy human pancreas from a donor has been used to asses various islet parameters and their three-dimensional distribution. Here we show that islets are spread gradually from the head up to the tail section of the pancreas in the form of contracted or dilated islet routes. We also report a particular anatomical structure, namely the cluster of islets. Our observations revealed a total of 11 islet clusters which comprise of small islets that surround large blood vessels. Additional observations in the peripancreatic adipose tissue have shown lymphoid-like nodes and blood vessels captured in a local inflammatory process. Our observations are based on regional slice maps of the pancreas, comprising of 5,423 islets. We also devised an index of sphericity which briefly indicates various islet shapes that are dominant throughout the pancreas. PMID- 26417672 TI - Reasoning About Cultural and Genetic Transmission: Developmental and Cross Cultural Evidence From Peru, Fiji, and the United States on How People Make Inferences About Trait Transmission. AB - Using samples from three diverse populations, we test evolutionary hypotheses regarding how people reason about the inheritance of various traits. First, we provide a framework for differentiat-ing the outputs of mechanisms that evolved for reasoning about variation within and between (a) biological taxa and (b) culturally evolved ethnic categories from (c) a broader set of beliefs and categories that are the outputs of structured learning mechanisms. Second, we describe the results of a modified "switched-at-birth" vignette study that we administered among children and adults in Puno (Peru), Yasawa (Fiji), and adults in the United States. This protocol permits us to study perceptions of prenatal and social transmission pathways for various traits and to differentiate the latter into vertical (i.e., parental) versus horizontal (i.e., peer) cultural influence. These lines of evidence suggest that people use all three mechanisms to reason about the distribution of traits in the population. Participants at all three sites develop expectations that morphological traits are under prenatal influence, and that belief traits are more culturally influenced. On the other hand, each population holds culturally specific beliefs about the degree of social influence on non-morphological traits and about the degree of vertical transmission-with only participants in the United States expecting parents to have much social influence over their children. We reinterpret people's differentiation of trait transmission pathways in light of humans' evolutionary history as a cultural species. PMID- 26417673 TI - Neural basis of disgust perception in racial prejudice. AB - Worldwide racial prejudice is originated from in-group/out-group discrimination. This prejudice can bias face perception at the very beginning of social interaction. However, little is known about the neurocognitive mechanism underlying the influence of racial prejudice on facial emotion perception. Here, we examined the neural basis of disgust perception in racial prejudice using a passive viewing task and functional magnetic resonance imaging. We found that compared with the disgusted faces of in-groups, the disgusted faces of out-groups result in increased amygdala and insular engagement, positive coupling of the insula with amygdala-based emotional system, and negative coupling of the insula with anterior cingulate cortex (ACC)-based regulatory system. Furthermore, machine-learning algorithms revealed that the level of implicit racial prejudice could be predicted by functional couplings of the insula with both the amygdala and the ACC, which suggests that the insula is largely involved in racially biased disgust perception through two distinct neural circuits. In addition, individual difference in disgust sensitivity was found to be predictive of implicit racial prejudice. Taken together, our results suggest a crucial role of insula-centered circuits for disgust perception in racial prejudice. PMID- 26417674 TI - Dissociation of perception and action in audiovisual multisensory integration. AB - The 'temporal rule' of multisensory integration (MI) proposes that unisensory stimuli, and the neuronal responses they evoke, must fall within a window of integration. Ecological validity demands that MI should occur only for physically simultaneous events (which may give rise to non-simultaneous neural activations), and spurious neural response simultaneities unrelated to environmental multisensory occurrences must somehow be rejected. Two experiments investigated the requirements of simultaneity for facilitative MI. Experiment 1 employed an reaction time (RT)/race model paradigm to measure audiovisual (AV) MI as a function of AV stimulus-onset asynchrony (SOA) under fully dark adapted conditions for visual stimuli that were either rod- or cone-isolating. Auditory stimulus intensity was constant. Despite a 155-ms delay in mean RT to the scotopic vs. photopic stimulus, facilitative AV MI in both conditions occurred exclusively at an AV SOA of 0 ms. Thus, facilitative MI demands both physical and physiological simultaneity. Experiment 2 investigated the accuracy of simultaneity and temporal order judgements under the same stimulus conditions. Judgements of AV stimulus simultaneity or temporal order were significantly influenced by stimulus intensity, indicating different simultaneity requirements for these tasks. The possibility was considered that there are mechanisms by which the nervous system may take account of variations in response latency arising from changes in stimulus intensity in order to selectively integrate only those physiological simultaneities that arise from physical simultaneities. It was proposed that separate subsystems for AV MI exist that pertain to action and perception. PMID- 26417676 TI - THE ASSOCIATION BETWEEN MENSTRUAL CYCLE CHARACTERISTICS AND PERCEIVED BODY IMAGE: A CROSS-SECTIONAL SURVEY OF POLISH FEMALE ADOLESCENTS. AB - The increasing prevalence of negative body perceptions among adolescent girls and the tendency towards wishing to be thinner have become a cultural norm in Western culture. Adolescent girls are particularly vulnerable to developing a negative body image due to physical and sexual changes occurring during puberty. This study aimed to evaluate the association between different measures of body image perceptions and different phases of the menstrual cycle after controlling for weight status and other potential confounders in Polish adolescent girls aged 12 18 years. Three-hundred and thirty participants of a cross-sectional survey conducted in 2009, normally cycling and with no eating disorders, completed a background questionnaire and the Stunkard Figure Rating Scale, and their anthropometric measurements were collected. The dependent outcome variables were measures of body image (actual body image, ideal body image and ideal-self discrepancy) and dichotomous body image perception (satisfied versus dissatisfied) adjusted for other predictor factors: socio-demographic variables, menstrual history and cycle phases, and weight status. One-way ANOVA indicated that weight status, age at menarche and menstrual cycle phase were associated with actual body image and rate of ideal-self discrepancy. Ideal body image was associated with weight status and menstrual cycle phase. General logistic regression models were constructed to evaluate associations of body dissatisfaction and all potential predictor variables. The final selected model of the multiple logistic regression analysis using the backward elimination procedure revealed that adjusted for other factors, negative body image was significantly associated with different phases of the menstrual cycle (p trend=0.033) and increasing body weight status (p trend=0.0007). The likelihood of body dissatisfaction was greatest during the premenstrual phase of the menstrual cycle (OR=2.38; 95% CI 1.06, 5.32) and among girls in obesity class I (OR=8.04; 95% CI 2.37, 27.26). The study confirmed the association between body image dissatisfaction in adolescent girls and different phases of the menstrual cycle after controlling for weight status. The issue of negative body self-image is not only of cognitive, but also of practical value as understanding better the factors contributing to the formation of a negative body image may be instrumental in developing preventive health programmes targeted at young people. PMID- 26417675 TI - Lectin-induced agglutination method of urinary exosomes isolation followed by mi RNA analysis: Application for prostate cancer diagnostic. AB - BACKGROUND: Prostate cancer is the most common cancer in men. Prostate-specific antigen has, however, insufficient diagnostic specificity. Novel complementary diagnostic approaches are greatly needed. MiRNAs are small regulatory RNAs which play an important role in tumorogenesis and are being investigated as a cancer biomarker. In addition to their intracellular regulatory functions, miRNAs are secreted into the extracellular space and can be found in various body fluids, including urine. The stability of extracellular miRNAs is defined by association with proteins, lipoprotein particles, and membrane vesicles. Among the known forms of miRNA packaging, tumour-derived exosome-enclosed miRNAs is thought to reflect the vital activity of cancer cells. The assessment of the exosomal fraction of urinary miRNA may present a new and highly specific method for prostate cancer diagnostics; however, this is challenged by the absence of reliable and inexpensive methods for isolation of exosomes. METHODS: Prostate cancer (PC) cell lines and urine samples collected from 35 PC patients and 35 healthy donors were used in the study. Lectins, phytohemagglutinin, and concanavalin A were used to induce agglutination of exosomes. The efficiency of isolation process was evaluated by AFM and DLS assays. The protein content of isolated exosomes was analysed by western blotting. Exosomal RNA was assayed by automated electrophoresis and expression level of selected miRNAs was evaluated by RT-qPCR. The diagnostic potency of the urinary exosomal miRNA assessment was estimated by the ROC method. RESULTS: The formation of multi-vesicular agglutinates in urine can be induced by incubation with lectin at a final concentration of 2 mg/ml. These agglutinates contain urinary exosomes and may be pelleted by centrifugation with a relatively low G-force. The analysis of PC related miRNA in urinary exosomes revealed significant up-regulation of miR-574 3p, miR-141-5p, and miR-21-5p associated with PC. CONCLUSIONS: Lectin-induced aggregation is a low-cost and easily performed method for isolation of exosomes from urine. Isolated exosomes can be further analysed in terms of miRNA content. The miRNA profile of urinary exosomes reflects development of prostate cancer and may present a promising diagnostic tool. PMID- 26417677 TI - Baroreceptor activation therapy: The importance of targeting the right patient: who needs to be treated? PMID- 26417678 TI - Dependence on epiphytic bacteria for freezing protection in an Antarctic moss, Bryum argenteum. AB - Mosses are the dominant flora of Antarctica, but their mechanisms of survival in the face of extreme low temperatures are poorly understood. A variety of Bryum argenteum from 77 degrees S was previously shown to have strong ice-pitting activity, a sign of the presence of ice-binding proteins (IBPs) that mitigate freezing damage. Here, using samples that had been stored at -25(o) C for 10 years, it is shown that much if not all of the activity is due to bacterial ice binding proteins secreted on the leaves of the moss. Sequencing of the leaf metagenome revealed the presence of hundreds of genes from a variety of bacteria (mostly Actinobacteria and Bacteroidetes) that encode a domain (DUF3494) that is associated with ice binding. The frequency of occurrence of this domain is one to two orders of magnitude higher than it is in representative mesophilic bacterial metagenomes. Genes encoding 42 bacterial IBPs with N-terminal secretion signals were assembled. There appears to be a commensal relationship in which the moss provides sustenance to the bacteria in return for freezing protection. PMID- 26417679 TI - The anterior paraventricular thalamus modulates neuronal excitability in the suprachiasmatic nuclei of the rat. AB - The suprachiasmatic nucleus (SCN) in mammals is the master clock which regulates circadian rhythms. Neural activity of SCN neurons is synchronized to external light through the retinohypothalamic tract (RHT). The paraventricular thalamic nucleus (PVT) is a neural structure that receives synaptic inputs from, and projects back to, the SCN. Lesioning the anterior PVT (aPVT) modifies the behavioral phase response curve induced by short pulses of bright light. In order to study the influence of the aPVT on SCN neural activity, we addressed whether the stimulation of the aPVT can modulate the electrical response of the SCN to either retinal or RHT stimulation. Using in vitro and in vivo recordings, we found a large population of SCN neurons responsive to the stimulation of either aPVT or RHT pathways. Furthermore, we found that simultaneous stimulation of the aPVT and the RHT increased neuronal responsiveness and spontaneous firing rate (SFR) in neurons with a low basal SFR (which also have more negative membrane potentials), such as quiescent and arrhythmic neurons, but no change was observed in neurons with rhythmic firing patterns and more depolarized membrane potentials. These results suggest that inputs from the aPVT could shift the membrane potential of an SCN neuron to values closer to its firing threshold and thus contribute to integration of the response of the circadian clock to light. PMID- 26417680 TI - Natural resources and the spread of HIV/AIDS: Curse or blessing? AB - This paper answers two questions: "What impact have natural resources had on the spread of the HIV epidemic so far?" and "What role can natural resource rents play in order to finance the long-run response to HIV/AIDS?" Using a panel dataset covering 137 countries from 1990 until 2008, de Soysa and Gizelis (2013) provided evidence in Social Science & Medicine that oil-rich countries are more deeply affected by the HIV and TB epidemics. They concluded that government of resource-rich countries failed to implement effective public policies for dealing with the epidemics. In this paper, I show that their results are (1) not robust, (2) based on an inappropriate choice of dependent variable and (3) spurious because series are non-stationary. After correcting for these issues, I find no robust relationship between resource rents and the spread of HIV and TB. The paper concludes by emphasizing the potential of natural resources rents for financing the long-term liability brought about by the HIV/AIDS epidemic in sub Saharan Africa. PMID- 26417682 TI - DPF2 regulates OCT4 protein level and nuclear distribution. AB - The amount of transcription factor OCT4 is strictly regulated. A tight regulation of OCT4 levels is crucial for mammalian embryonic development and oncogenesis. However, the mechanisms underlying regulation of OCT4 protein expression and nuclear distribution are largely unknown. Here, we report that DPF2, a plant homeodomain (PHD) finger protein, is upregulated during H9 cell differentiation induced by retinoic acid. Endogenous interaction between DPF2 and OCT4 in P19 cells was revealed by an immunoprecipitation assay. GST-pull down assay proved that OCT4 protein in H9 cells and recombinant OCT4 can precipitate with DPF2 in vitro. In vitro ubiquitination assay demonstrated DPF2 might serve as an E3 ligase. Knock down of dpf2 using siRNA increased OCT4 protein level and stability in P19 cells. DPF2 siRNAs also up-regulates OCT4 but not NANOG in H9 cells. However, RA fails to downregulates OCT4 protein level in cells infected by lenitviruses containing DPF2 siRNA. Moreover, overexpression of both DPF2 and OCT4 in 293 cells proved the DPF2-OCT4 interaction. DPF2 but not PHD2 mutant DPF2 enhanced ubiquitination and degradation of OCT4 in 293 cells co-expressed DPF2 and OCT4. Both wild type DPF2 and PHD2 mutant DPF2 redistributes nuclear OCT4 without affecting DPF2-OCT4 interaction. Further analysis indicated that DPF2 decreases monomeric and mono-ubiquitinated OCT4, assembles poly-ubiquitin chains on OCT4 mainly through Ub-K48 linkage. These findings contribute to an understanding of how OCT4 protein level and nuclear distribution is regulated by its associated protein. PMID- 26417681 TI - Loss of calbindin-D28K is associated with the full range of tangle pathology within basal forebrain cholinergic neurons in Alzheimer's disease. AB - Basal forebrain cholinergic neurons (BFCN) are selectively vulnerable in Alzheimer's disease (AD). We have shown that most of the BFCN in the human brain contain the calcium-binding protein calbindin-D28K (CB), a large proportion lose their CB in the course of normal aging, and the BFCN which degenerate in AD lack CB. Here, we investigated the relationship between CB in the BFCN and the process of tangle formation in AD using antibodies to tau epitopes that appear early, intermediate or late in the process of tangle formation. Very small percentages (0%-3.7%) of CB-positive BFCN contained pretangles and/or tangles, and very small percentages (0%-5%) of the total BFCN pretangles and/or tangles were in CB immunoreactive neurons. The number of CB-positive BFCN which contained tau immunoreactivity was highest for the early epitope and lower for intermediate epitopes. A late appearing epitope was absent from CB-positive BFCN. Age-related loss of CB appears to coincide with tangle formation in the BFCN and is associated with the full range of tau pathology, including late appearing epitopes. PMID- 26417684 TI - Cecal inoculum peritonitis: An alternative model for sepsis vascular dysfunction study. AB - AIMS: Sepsis is a life threatening condition that is characterized by the loss of vascular reactivity. The factor(s) responsible for the diminished vascular function seen in sepsis are not well understood. The purpose of this study was to characterize the vascular dysfunction from the rat cecal inoculum (CI) sepsis model using cecal ligation and puncture (CLP), and lipopolysaccharide (LPS) sepsis as reference models. MATERIALS AND METHODS: Experiments were performed on isolated aorta from CI, CLP and LPS treated rats using a combination of pharmacological approaches. KEY FINDINGS: Phenylephrine (PE)-induced aortic contraction was significantly decreased in each model (p<0.05) and not normalized by L-NAME or indomethacin. The vascular response elicited in the CI model for acetylcholine (Ach) was more similar to that seen in the CLP than the LPS model. The removal of the endothelial layer increased sensitivity to L-NAME (p<0.05) in aortae from CI group. Inhibition of the large conductance Ca(2+)/voltage sensitive K(+) (BKCa) channel did not normalize PE hyporesponsiveness but did abolish sepsis-induced contractile oscillation. Inhibition of the voltage dependent Kv1.5 channel was not able to reverse the vascular hyporesponsiveness, however, inhibition of the ATP dependent (KATP) channel inhibition partially restored the contractile response (p<0.05). Elevation of VCAM expression and aortic structural alternation were observed in each model. SIGNIFICANCE: These results suggest that the CI model may be an additional tool that could be used to investigate the mechanisms of vascular hyporesponsiveness in sepsis. PMID- 26417685 TI - Isolation and characterization of (15Z)-lycopene thermally generated from a natural source. AB - (15Z)-Lycopene was prepared by thermal isomerization of (all-E)-lycopene derived from tomatoes, and isolated by using a series of chromatographies. The fine red crystalline powder of (15Z)-lycopene was obtained from 556 mg of (all-E)-lycopene with a yield of 0.6 mg (purity: reversed-phase HPLC, 97.2%; normal-phase HPLC, >=99.9%), and (1)H and (13)C NMR spectra of the isomer were fully assigned. More refined computational analyses that considered differences in the energy levels of the conformers involved in isomerization have also determined the stabilities of (15Z)-lycopene and other geometric isomers, along with the activation energies during isomerization from the all-E form. The fine control of conditions for HPLC separation and an advanced theoretical insight into geometric isomerization have led to the discovery of the 15Z-isomer generated from a natural source. PMID- 26417686 TI - Activin A in combination with OP9 cells facilitates development of Flk-1(+) PDGFRalpha(-) and Flk-1(+) PDGFRalpha(+) hematopoietic mesodermal cells from murine embryonic stem cells. AB - Lateral mesoderm-derived hemogenic endothelial cells are known to originate the definitive hematopoietic lineage in mouse embryogenesis. The developmental process of the definitive hematopoietic lineage can be recapitulated by inducing differentiation of mouse embryonic stem (ES) cells in a co-culture system with OP9 stromal cells. However, the signaling molecules that can modulate the development of the definitive hematopoietic lineage in the OP9 co-culture system have yet to be identified. Here we report that activin A enhanced the hematopoietic potential of endothelial cells derived from ES cells in the OP9 co culture system. Activin A in combination with OP9 cells augmented development of Flk-1(+) PDGFRalpha(+) early mesodermal cells and Flk-1(+) PDGFRalpha(-) lateral mesodermal cells from ES cells. These Flk-1(+) mesodermal cells further differentiated into CD41(+) endothelial cells, which preferentially possessed high hematopoietic potential. Furthermore, Flk-1(+) PDGFRalpha(+) cells but not Flk-1(+) PDGFRalpha(-) cells produced hematopoietic progenitors with a bimodal pattern when cultured as an aggregate with OP9 cells. Our results suggest that activin A in combination with OP9 cells facilitates differentiation of ES cells to Flk-1(+) mesodermal cells, which encompass various precursors that separately contribute to the development of hematopoietic lineages. PMID- 26417683 TI - Analysis of TMEFF2 allografts and transgenic mouse models reveals roles in prostate regeneration and cancer. AB - BACKGROUND: Previous results from our lab indicate a tumor suppressor role for the transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) in prostate cancer (PCa). Here, we further characterize this role and uncover new functions for TMEFF2 in cancer and adult prostate regeneration. METHODS: The role of TMEFF2 was examined in PCa cells using Matrigel(TM) cultures and allograft models of PCa cells. In addition, we developed a transgenic mouse model that expresses TMEFF2 from a prostate specific promoter. Anatomical, histological, and metabolic characterizations of the transgenic mouse prostate were conducted. The effect of TMEFF2 in prostate regeneration was studied by analyzing branching morphogenesis in the TMEFF2-expressing mouse lobes and alterations in branching morphogenesis were correlated with the metabolomic profiles of the mouse lobes. The role of TMEFF2 in prostate tumorigenesis in whole animals was investigated by crossing the TMEFF2 transgenic mice with the TRAMP mouse model of PCa and analyzing the histopathological changes in the progeny. RESULTS: Ectopic expression of TMEFF2 impairs growth of PCa cells in Matrigel or allograft models. Surprisingly, while TMEFF2 expression in the TRAMP mouse did not have a significant effect on the glandular prostate epithelial lesions, the double TRAMP/TMEFF2 transgenic mice displayed an increased incidence of neuroendocrine type tumors. In addition, TMEFF2 promoted increased branching specifically in the dorsal lobe of the prostate suggesting a potential role in developmental processes. These results correlated with data indicating an alteration in the metabolic profile of the dorsal lobe of the transgenic TMEFF2 mice. CONCLUSIONS: Collectively, our results confirm the tumor suppressor role of TMEFF2 and suggest that ectopic expression of TMEFF2 in mouse prostate leads to additional lobe-specific effects in prostate regeneration and tumorigenesis. This points to a complex and multifunctional role for TMEFF2 during PCa progression. PMID- 26417687 TI - Phosphorylation of Mycobacterium tuberculosis protein tyrosine kinase A PtkA by Ser/Thr protein kinases. AB - Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), has inflicted about one third of mankind and claims millions of deaths worldwide annually. Signalling plays an important role in Mtb pathogenesis and persistence, and thus represents attractive resource for drug target candidates. Here, we show that protein tyrosine kinase A (PtkA) can be phosphorylated by Mtb endogenous eukaryotic-like Ser/Thr protein kinases (eSTPKs). Kinase assays showed that PknA, PknD, PknF, and PknK can phosphorylate PtkA in dose- and time-dependent manner. Enzyme kinetics suggests that PknA has the highest affinity and enzymatic efficiency towards PtkA. Furthermore, protein-protein interaction assay in surrogate host showed that PtkA interacts with multi-eSTPKs in vivo, including PknA. Lastly, we show that PtkA phosphorylation by eSTPKs occurs on threonine residues and may effect tyrosine phosphorylation levels and thus PtkA activity in vitro. These results demonstrate that PtkA can serve as a substrate to many eSTPKs and suggests that's its activity can be regulated. PMID- 26417688 TI - Yhhu4488, a novel GPR40 agonist, promotes GLP-1 secretion and exerts anti diabetic effect in rodent models. AB - G protein-coupled receptor 40 (GPR40) is predominantly expressed in pancreatic beta-cells and activated by long-chain fatty acids. GPR40 has drawn considerable interest as a potential therapeutic target for type 2 diabetes mellitus (T2DM) due to its important role in enhancing glucose-stimulated insulin secretion (GSIS). Encouragingly, GPR40 is also proven to be highly expressed in glucagon like peptide-1 (GLP-1)-producing enteroendocrine cells afterwards, which opens a potential role of GPR40 in enhancing GLP-1 secretion to exert additional anti diabetic efficacy. In the present study, we discovered a novel GPR40 agonist, yhhu4488, which is structurally different from other reported GPR40 agonists. Yhhu4488 showed potent agonist activity with EC50 of 49.96 nM, 70.83 nM and 58.68 nM in HEK293 cells stably expressing human, rat and mouse GPR40, respectively. Yhhu4488 stimulated GLP-1 secretion from fetal rat intestinal cells (FRIC) via triggering endogenous calcium store mobilization and extracellular calcium influx. The effect of yhhu4488 on GLP-1 secretion was further confirmed in type 2 diabetic db/db mice. Yhhu4488 exhibited satisfactory potency in in vivo studies. Single administration of yhhu4488 improved glucose tolerance in SD rats. Chronic administration of yhhu4488 effectively decreased fasting blood glucose level, improved beta-cell function and lipid homeostasis in type 2 diabetic ob/ob mice. Taken together, yhhu4488 is a novel GPR40 agonist that enhances GLP-1 secretion, improves metabolic control and beta-cell function, suggesting its promising potential for the treatment of type 2 diabetes. PMID- 26417689 TI - Exposure to 3,3',5-triiodothyronine affects histone and RNA polymerase II modifications, but not DNA methylation status, in the regulatory region of the Xenopus laevis thyroid hormone receptor betaAlpha gene. AB - Thyroid hormones (THs) play a critical role in amphibian metamorphosis, during which the TH receptor (TR) gene, thrb, is upregulated in a tissue-specific manner. The Xenopus laevis thrb gene has 3 TH response elements (TREs) in the 5' flanking regulatory region and 1 TRE in the exon b region, around which CpG sites are highly distributed. To clarify whether exposure to 3,3',5-triiodothyronine (T3) affects histone and RNA polymerase II (RNAPII) modifications and the level of DNA methylation in the 5' regulatory region, we conducted reverse transcription-quantitative polymerase chain reaction, bisulfite sequencing and chromatin immunoprecipitation assay using X. laevis cultured cells and premetamorphic tadpoles treated with or without 2 nM T3. Exposure to T3 increased the amount of the thrb transcript, in parallel with enhanced histone H4 acetylation and RNAPII recruitment, and probably phosphorylation of RNAPII at serine 5, in the 5' regulatory and exon b regions. However, the 5' regulatory region remained hypermethylated even with exposure to T3, and there was no significant difference in the methylation status between DNAs from T3-untreated and -treated cultured cells or tadpole tissues. Our results demonstrate that exposure to T3 induced euchromatin-associated epigenetic marks by enhancing histone acetylation and RNAPII recruitment, but not by decreasing the level of DNA methylation, in the 5' regulatory region of the X. laevis thrb gene. PMID- 26417690 TI - AGPAT2 deficiency impairs adipogenic differentiation in primary cultured preadipocytes in a non-autophagy or apoptosis dependent mechanism. AB - AIMS: Mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) result in lipodystrophy, insulin resistance and diabetes. Autophagy is required for normal adipogenesis and adipose tissue development. The aim of this study was to determine whether impaired autophagy or excessive cell death underlie the adipogenic inability of Agpat2(-/-) mice preadipocytes. METHODS: Preadipocytes were isolated from interscapular brown adipose tissue (BAT) of Agpat2(-/-) and Agpat2(+/+) newborn mice and cultured/differentiated in vitro. Intracellular lipids were quantified by oil red O staining. Cell death was assessed by lactate dehydrogenase (LDH) activity. Apoptosis and autophagy regulatory factors were determined at the mRNA and protein level with Real-time PCR, immunoblot and immunofluorescence. RESULTS: Adipogenically induced Agpat2(-/-) preadipocytes had fewer lipid-loaded cells and lower levels of adipocyte markers than wild type preadipocytes. Before adipogenic differentiation, autophagy-related proteins (ATGs) ATG3, ATG5-ATG12 complex, ATG7 and LC3II were increased but autophagic flux was reduced, as suggested by increased p62 levels, in Agpat2(-/-) preadipocytes. Adipogenic induction increased LDH levels in the culture media in Agpat2(-/-) preadipocytes but no differences were observed in the activation of Caspase 3 or in markers of autophagic flux. CONCLUSIONS: AGPAT2 is required for in vitro adipogenesis of mouse preadipocytes. Autophagy defects or apoptosis are not involved in the adipogenic failure of Agpat2(-/-) preadipocytes. PMID- 26417691 TI - Angiopoietin-like 4 enhances metastasis and inhibits apoptosis via inducing bone morphogenetic protein 7 in colorectal cancer cells. AB - Angiopoietin-like 4 (ANGPTL4), a secretory glycoprotein, plays an important role in cancer metastasis. In the present study, we aim to investigate the roles and mechanisms of ANGPTL4 in the regulation of colorectal cancer metastasis. We found that expression level of ANGPTL4 was increased in colorectal cancer tissues, compared with that in normal tissues. Moreover, liver metastasis was significantly associated with higher expression of ANGPTL4. In vitro studies further showed that overexpression of ANGPTL4 enhanced cell migration, invasion and inhibited apoptosis. At the molecular level, ANGPTL4 overexpression resulted in an up-regulation of bone morphogenetic protein 7 (BMP7). Indeed, knockdown of BMP7 by small interfering RNA (siRNA) oligos reversed the roles of ANGPTL4 overexpression in HCT116 cells. Finally, in vivo studies further confirmed the metastatic roles of ANGPTL4 by inducing BMP7. Therefore, our study demonstrated that ANGPTL4 might promote metastasis and might inhibit apoptosis of colorectal cancer cells by up-regulation of BMP7. PMID- 26417693 TI - Ovarian infertility is associated with cardiovascular disease risk factors in later life: A Japanese cross-sectional study. AB - OBJECTIVES: This study aimed to clarify the association between ovarian infertility and cardiovascular disease risk factors in later life in Japanese women. STUDY DESIGN: The Japan Nurses' Health Study (JNHS) is a cohort study of Japanese women's health. Data from the JNHS baseline survey (n = 49,927) between 2001 and 2007 were used in a cross-sectional, retrospective analysis. A total of 44,601 women were classified into three categories: ovarian infertility group (n=1167), other infertility group (n = 4619), and no infertility group (n = 38,815). Logistic regression analysis compared with the no infertility group was performed. MAIN OUTCOME MEASURES: Age-adjusted odds ratios (ORs) and multivariable-adjusted ORs for hypertension, hypercholesterolemia, and diabetes mellitus (DM). RESULTS: The prevalence of obese women (BMI >= 25) who were < 45 years old in the ovarian infertility group was significantly higher compared with that in the other groups. Women in the ovarian infertility group were at risk for hypertension at >= 45 years old (age-adjusted OR: 1.65%, confidence interval [CI]: 1.23-2.21); for hypercholesterolemia at < 45 and >= 45 years old (age adjusted OR: 1.42, 95% CI: 1.06-1.88 at < 45 years; age-adjusted OR: 1.39, 95% CI: 1.06-1.81 at >= 45 years); and for DM at < 45 years old (age-adjusted OR: 2.92, 95% CI: 1.57-5.46). CONCLUSIONS: Japanese women with ovarian infertility (most women have polycystic ovary syndrome) are at high risk of hypertension from 45 years of age, hypercholesterolemia at all ages, and diabetes mellitus (DM) before 45 years old. PMID- 26417692 TI - The role and regulation of Moraxella catarrhalis-induced human beta-defensin 3 expression in human pulmonary epithelial cells. AB - BACKGROUND: Bacterial colonisation with Moraxella catarrhalis may partly sustain chronic inflammation in the lower airways of patients with chronic obstructive pulmonary disease (COPD). In addition, this bacterium causes infectious exacerbations of COPD, which often necessitate treatment with antibiotics. Antimicrobial peptides are the body's own antibiotic substances with bactericidal and bacteriostatic, as well as immunomodulatory function. In particular, human beta-defensin 3 (hBD-3) exerts an antimicrobial effect against an extraordinarily broad spectrum of pathogens. We therefore investigated the role of hBD-3 in infections of pulmonary epithelial cells with M. catarrhalis. METHODS: The antimicrobial activity of hBD-3 vs. M. catarrhalis was evaluated in an antimicrobial susceptibility assay. We analyzed hBD-3 secretion of M. catarrhalis infected pulmonary epithelial cells using ELISA. The role of M. catarrhalis specific virulence factors, toll-like receptors (TLR) 2 and 4, MAPK pathways, and transcription factors AP-1 and NF-kappaB in the induction and regulation of hBD-3 expression were explored with specific inhibitors, small interference RNA, Western Blot, and chromatin immunoprecipitation (ChIP) assays. RESULTS: HBD-3 exhibited a strong bactericidal effect against M. catarrhalis. M. catarrhalis induced hBD-3 expression in pulmonary epithelial cells, which was dependent on M. catarrhalis membranous lipoolygosaccharide (LOS), while the surface proteins UspA1 and UspA2 were not involved. Gene silencing of TLR2, but not TLR4, led to a reduced hBD-3 secretion after stimulation with M. catarrhalis or M. catarrhalis LOS. Inhibition of MAPKs ERK1/2 and JNK, but not p38, reduced hBD-3 secretion. HBD-3 expression was mediated through the recruitment of AP-1 to the hBD-3 gene promoter and was independent of NF-kappaB. CONCLUSION: The immune response of pulmonary epithelial cells towards M. catarrhalis involves secretion of hBD-3, which has a bactericidal effect against this pathogen. Binding of M. catarrhalis virulence factor LOS to TLR2 causes an ERK1/2- and JNK-dependent induction of AP 1-related transcription of the hBD-3 gene, resulting in the production and secretion of hBD-3. PMID- 26417694 TI - Homogeneous Immunochemical Assay on the Lateral Flow Strip for Measurement of DNase I Activity. AB - Deoxyribonuclease I (DNase I) is an important enzyme that cleaves both double stranded and single-stranded DNA at their phosphate backbone. DNase I is a useful biomarker. Previous studies have shown that patients with prostate cancer and systemic lupus erythematosus exhibit reduced DNase I activity, and patients with myocardial infarction exhibit increased DNase I activity. Current methods of measuring DNase I relies either on an immunochemical assay, which requires multiple washing steps, or on a single radial enzyme diffusion assay, which requires a long digestion time and an expensive fluorescence detection system. We have developed a lateral flow immunochemical assay for the measurement of DNase I activity on the test strip. The assay utilized a dually labeled double-stranded DNA as the reporter probe. The biotin-labeled terminal of the probe bound to the streptavidin immobilized on the lateral flow test strip, and the fluorescein labeled terminal bound to the antibody-conjugated gold nanoparticles, resulting in a visible test line. The presence of DNase I would cleave the reporter probe and lead to reduced test line intensity. Using the DNase I test strip, we have successfully measured the DNase I activity and determined the factors that influence the sensitivity and linear dynamic range of the assay. We have also investigated the conditions that inhibited the DNase I activity. The combined advantage of a wash-free assay format and colorimetric readout would make the lateral flow DNase I test strip a suitable platform for point-of-care diagnostics. PMID- 26417695 TI - Iron Status of Cats with Chronic Kidney Disease. AB - BACKGROUND: Iron deficiency is a proposed mechanism for the anemia that occurs in cats with chronic kidney disease (CKD). Minimal research investigating the iron status of these cats has been performed. OBJECTIVE: To compare indicators of iron status in cats with CKD versus healthy cats and cats with nonrenal illness (NRI). To compare indicators of iron status in anemic versus nonanemic cats with CKD. ANIMALS: Thiry-nine client or employee owned healthy cats, 40 cats with CKD and 34 cats with NRI included. METHODS: Exclusion criteria included prior iron or erythropoiesis stimulating agent administration, blood transfusion, or concurrent CKD and NRI. Complete blood counts, serum chemistries, serum iron concentrations, total iron binding capacity (TIBC), and ferritin concentrations were measured and percent transferrin saturation (TSAT) calculated on all cats. Data were analyzed using nonparametric statistical testing. RESULTS: No statistically significant differences were detected among groups for iron concentration (P = .50), ferritin concentration (P = .47), or TSAT (P = .19). TIBC was significantly lower in CKD (median 262 MUg/dL; IQR 233-302; range 165-488) versus healthy cats (median 316 MUg/dL; IQR 272-345, range 196-464); (P = .0030). When comparing anemic (hemoglobin <9.5 g/dL) versus nonanemic cats with CKD, TSAT was significantly lower (P = .033) in anemic (median 20.2%; IQR 17.8-34.5; range 17.6-35.9) compared to nonanemic (median 29.0%; IQR 25.5-44.1; range 11.5-94.4). No statistically significant differences found for ferritin concentration (P = .94), iron concentration (P = .21) or TIBC (P = .97). CONCLUSIONS AND CLINICAL IMPORTANCE: These results indicate that an iron deficient state exists in anemic cats with CKD and is more likely functional rather than absolute. PMID- 26417696 TI - Aspartic acid racemization reveals a high turnover state in knee compared with hip osteoarthritic cartilage. AB - OBJECTIVE: We investigated tissue turnover in healthy and osteoarthritic cartilage. We challenge long held views that osteoarthritis (OA) is dominated by a similar turnover process in all joints and present evidence that hip and knee cartilage respond very differently to OA. METHODS: d- and l-Aspartate (Asp) were quantified for whole cartilage, collagen and non-collagenous components of cartilage obtained at the time of joint replacement. We computed the Asp racemization ratio (Asp-RR = d/d + l Asp), reflecting the proportion of old to total protein, for each component. RESULTS: Compared with hip OA, knee OA collagen fibrils (P < 0.0001), collagen (P = 0.007), and non-collagenous proteins (P = 0.0003) had significantly lower age-adjusted mean Asp-RRs consistent with elevated protein synthesis in knee OA. Knee OA collagen had a mean hydroxyproline/proline (H/P) ratio of 1.2 consistent with the presence of type III collagen whereas hip OA collagen had a mean H/P ratio of 0.99 consistent with type II collagen. Based on Asp-RR, the relative age was significantly different in knee and hip OA (P < 0.0005); on average OA knees were estimated to be 30 yrs 'younger', and OA hips 10 yrs 'older' than non-OA. CONCLUSIONS: The metabolic response to OA was strikingly different by joint site. Knee OA cartilage evinced an anabolic response that appeared to be absent in hip OA cartilage. These results challenge the long held view that OA cartilage is capable of only minimal repair and that collagen loss is irreversible. PMID- 26417697 TI - Plasma bioavailability and regional brain distribution of polyphenols from apple/grape seed and bilberry extracts in a young swine model. AB - SCOPE: The pharmacokinetics, bioavailability, and regional brain distribution of polyphenols from apple-grape seed extract (AGSE) mixture and bilberry extract were studied after 3 weeks of dosing in weanling pigs. MATERIALS AND METHODS: Weanling piglets were treated for 3 weeks with extracts of (AGSE) or bilberry extracts, using a physiological (27.5 mg/kg) or supplement (82.5 mg/kg) dose. A 24-h pharmacokinetic study was conducted and brain tissue was harvested. Major flavan-3-ol and flavonol metabolites including catechin-O-beta-glucuronide, epicatechin-O-beta-glucuronide, 3'O-methyl-catechin-O-beta-glucuronide, 3'O methyl-epicatechin-O-beta-glucuronide, quercetin-O-beta-glucuronide, and O-methyl quercetin-O-beta-glucuronide were analyzed in plasma, urine, and regional brain extracts from AGSE groups. Anthocyanidin-O-galactosides and O-glucosides of delphinidin (Del), cyanidin (Cyn), petunidin (Pet), peonidin (Peo), and malvidin (Mal) were analyzed in plasma, urine, and brain extracts from bilberry groups. CONCLUSION: Significant plasma dose-dependence was observed in flavan-3-ol metabolites of the AGSE group and in Mal, Del and Cyn galactosides and Pet, Peo, and Cyn glucosides of the bilberry groups. In the brain, a significant dose dependence was found in the cerebellum and frontal cortex in all major flavan-3 ol metabolites. All anthocyanidin glycosides, except for delphinidin, showed a dose-dependent increase in the cerebellum. PMID- 26417698 TI - In ovo administration of copper nanoparticles and copper sulfate positively influences chicken performance. AB - BACKGROUND: Copper (Cu) is a key trace mineral involved in a variety of physiological processes, and is commonly used in poultry production. However, regardless of the inclusion level the majority of Cu is excreted with poultry faeces. We hypothesise that in ovo administration will allow for better utilisation of Cu during embryo development than when supplied post-natally with feed to growing chickens. Thus, the objective of this study was to evaluate effects of in ovo administration of NanoCu and copper sulfate (CuSO4 ) on broiler chicken performance. RESULTS: The study showed the positive influences of Cu nanoparticles and CuSO4 on broiler chickens performance. Body weight, at the end of the rearing period (day 42) was significantly higher in NanoCu (2206 g) and CuSO4 (2402 g) groups compared to the control group (2000 g). Both treatment groups had significantly lower feed conversion rate and mortality, and higher percentage of breast and leg muscles in the carcass versus control. CONCLUSION: The in ovo application of Cu colloids may ensure an efficient penetration of Cu into the embryonic tissue with long lasting effects on postnatal growth. The method may provide a successful alternative to using Cu as a feed additive. (c) 2015 Society of Chemical Industry. PMID- 26417699 TI - Prognostic value of residual pulmonary congestion at discharge assessed by lung ultrasound imaging in heart failure. AB - AIMS: Residual pulmonary congestion at discharge is associated with poor prognosis in heart failure (HF), but its quantification through physical examination is challenging. Ultrasound imaging of lung comets (B-lines) could improve congestion evaluation. The aim of this study was to assess the short-term prognostic value of B-lines after discharge from HF hospitalisation compared with other indices of haemodynamic congestion (BNP, E/e', and inferior vena cava diameter) or clinical status (NYHA class). METHODS AND RESULTS: Sixty consecutive HF inpatients underwent clinical examination, echocardiography, and lung ultrasound at discharge, independently of, and in addition to routine management by the attending physicians. The median B-line count was 8.5 (5-34). Three-month event-free survival for the primary endpoint (all-cause death or HF hospitalisation) was 27 +/- 10% in patients with >=30 B-lines and 88 +/- 5% in those with <30 B-lines (P < 0.0001). In a multivariable model, >=30 B-lines significantly predicted the combined endpoint (hazard ratio 5.66, 95% confidence interval 1.74-18.39, P = 0.04), along with NYHA >=III and inferior vena cava diameter, while other indirect measures of congestion (BNP and E/e' >=15) were not retained in the model; furthermore >=30 B-lines independently also predicted the secondary outcomes (HF hospitalisation and death). Importantly, B-line addition to NYHA class and BNP was associated with improved risk classification (integrated discrimination improvement 15%, P = 0.02; continuous net reclassification improvement 65%, P = 0.03). CONCLUSION: Residual pulmonary congestion at discharge, as assessed by a B-line count >=30, is a strong predictor of outcome. Lung ultrasonography may represent a useful tool to identify and monitor congestion and optimize therapy during and/or after hospitalisation for HF, which should be further validated in multicentre studies. PMID- 26417700 TI - Serum levels of phytoestrogens as biomarkers of intake in Mexican women. AB - Phytoestrogens have generated interest in human health in view of their potential effect to reduce the risk of developing chronic diseases. Serum levels of phytoestrogens have been proposed as an alternative to measure the exposure of phytoestrogens. We evaluated the use of serum as a biomarker of phytoestrogen's intake in healthy women. Phytoestrogens in serum (luteolin, kaempferol, equol, biochanin A, formononetin, quercetin, naringenin, coumestrol, secoisolariciresinol, genistein, matairesinol, enterolactone, enterodiol, daidzein, glycitein and resveratrol) were analyzed by HPLC-ESI-MS. Subjects were asked to recall all foods and beverages consumed the previous 24 h. Association of dietary intake and serum concentrations was performed by Spearman correlation. Correlations were found for naringenin (r = 0.47, p < 0.001), luteolin (r = 0.4 p < 0.001), genistein (r = 0.32, p < 0.01) enterolactone (r = 0.35, p = 0.0553), coumestrol (r = 0.26, p = 0.0835) and resveratrol (r = 0.29, p = 0.0517). Serum levels as biomarkers of intake along with a 24-h recall would be useful in order to investigate the relationship between phytoestrogens and health. PMID- 26417701 TI - Variability in quality of chest compressions provided during simulated cardiac arrest across nine pediatric institutions. AB - AIM: The variability in quality of CPR provided during cardiac arrest across pediatric institutions is unknown. We aimed to describe the degree of variability in the quality of CPR across 9 pediatric institutions, and determine if variability across sites would be affected by Just-in-Time CPR training and/or visual feedback during simulated cardiac arrest. METHODS: We conducted secondary analyses of data collected from a prospective, multi-center trial. Participants were equally randomized to either: (1) No intervention; (2) Real-time CPR visual feedback during cardiac arrest or (3) Just-in-Time CPR training. We report the variability in median chest compression depth and rate across institutions, and the variability in the proportion of 30-s epochs of CPR meeting 2010 American Heart Association guidelines for depth and rate. RESULTS: We analyzed data from 528 epochs in the no intervention group, 552 epochs in the visual feedback group, and 525 epochs in the JIT training group. In the no intervention group, compression depth (median range 22.2-39.2mm) and rate (median range 116.0-147.6 min(-1)) demonstrated significant variability between study sites (p<0.001). The proportion of compressions with adequate depth (0-11.5%) and rate (0-60.5%) also varied significantly across sites (p<0.001). The variability in compression depth and rate persisted despite use of real-time visual feedback or JIT training (p<0.001). CONCLUSION: The quality of CPR across multiple pediatric institutions is variable. Variability in CPR quality across institutions persists even with the implementation of a Just-in-Time training session and visual feedback for CPR quality during simulated cardiac arrest. PMID- 26417702 TI - Canadian Guidelines for the use of targeted temperature management (therapeutic hypothermia) after cardiac arrest: A joint statement from The Canadian Critical Care Society (CCCS), Canadian Neurocritical Care Society (CNCCS), and the Canadian Critical Care Trials Group (CCCTG). PMID- 26417703 TI - Hope and perceptions of parental role among parents assessed as maltreating their children. AB - The present study is anchored in the view that hope is a resource that fosters better coping and parenting. It examines the self-perceived hope and parental role of parents whom the welfare services in Israel have assessed as maltreating their children. The parents were recruited in 2010 through facilities for maltreated children. The study sample consisted of 262 parents (68.4% response rate), divided into those who had at least one child removed from home and those whose children were all at home. Both groups of parents reported moderately high basic and family hope and sense of pathways and agency, and moderate perceived parental role, with no significant group differences. Differences were found, however, in the role of hope in mediating between parents' sociodemographic features and their perceived parental role. The mediation was more substantial among the parents whose children were at home and differed in content. Only among parents whose children were at home did religiosity (beta = 0.20, P < 0.05) and living with a partner (beta = 0.18, P < 0.05) lead to greater hope, which increased the perceived parental role. Moreover, the findings underscore the lack of role of family hope and sense of agency among parents whose children were not at home. In both the groups, higher income led to greater hope (beta = 0.18, P < 0.05 for at home; beta = 0.16, P < 0.05 for in placement), which increased the self-perceived parental role but the mediation was effected differently. The findings suggest that professionals working with parents who maltreat their children can use the parents' hope as a resource to help them improve their parenting, especially where the child was removed from home. PMID- 26417705 TI - The impact of cardiopulmonary exercise testing on patients over the age of 80 undergoing elective colorectal cancer surgery. AB - AIM: Advanced age and occult cardiorespiratory disease are associated with increased morbidity and mortality following surgery. Cardiopulmonary exercise testing (CPET) may allow the identification of high-risk patients and facilitate planned postoperative critical care support. The aim of this study was to determine whether preoperative CPET in patients aged over 80 undergoing elective colorectal cancer resection was associated with improved outcome. METHOD: All patients aged 80 years and above undergoing elective colorectal cancer resection between 1 March 2011 and 1 September 2013 were retrospectively analysed. Referral for CPET testing was at the discretion of the operating surgeon. Postoperative critical care unit (CCU) admission was based upon the CPET results. RESULTS: Ninety-four patients were identified, of whom 48 underwent CPET testing. The CPET group were significantly older than the non-CPET group (85 vs 83 years, P = 0.04) and were more likely to have a planned admission to CCU postoperatively (P < 0.0001). Despite the increased use of CCU resources, the overall CCU length of stay (LOS) in the CPET group did not differ from the non-CPET group, but the non CPET group had a higher proportion of Level-3 care. There were no differences in the incidence of unplanned CCU admission between the CPET and the non-CPET group (P = 0.23). There were no differences in overall LOS between the two groups (P = 0.42). There was no difference in mortality (P = 0.11), overall complications (P = 0.53) or severe complications (P = 0.3). CONCLUSION: Preoperative CPET testing in patients aged over 80 undergoing elective colorectal cancer resection allows identification of higher-risk patients and mitigation of risk by preemptive admission to a CCU. This stratification allows equivalent results to be achieved in high- and low-risk elderly patients undergoing colorectal surgery. PMID- 26417706 TI - Startup of electrophoresis in a suspension of colloidal spheres. AB - The transient electrophoretic response of a homogeneous suspension of spherical particles to the step application of an electric field is analyzed. The electric double layer encompassing each particle is assumed to be thin but finite, and the effect of dynamic electroosmosis within it is incorporated. The momentum equation for the fluid outside the double layers is solved through the use of a unit cell model. Closed-form formulas for the time-evolving electrophoretic and settling velocities of the particles in the Laplace transform are obtained in terms of the electrokinetic radius, relative mass density, and volume fraction of the particles. The time scale for the development of electrophoresis and sedimentation is significantly smaller for a suspension with a higher particle volume fraction or a smaller particle-to-fluid density ratio, and the electrophoretic mobility at any instant increases with an increase in the electrokinetic particle radius. The transient electrophoretic mobility is a decreasing function of the particle volume fraction if the particle-to-fluid density ratio is relatively small, but it may increase with an increase in the particle volume fraction if this density ratio is relatively large. The particle interaction effect in a suspension on the transient electrophoresis is much weaker than that on the transient sedimentation of the particles. PMID- 26417704 TI - Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis. AB - The identification of small molecules that target specific CFTR variants has ushered in a new era of treatment for cystic fibrosis (CF), yet optimal, individualized treatment of CF will require identification and targeting of disease modifiers. Here we use genome-wide association analysis to identify genetic modifiers of CF lung disease, the primary cause of mortality. Meta analysis of 6,365 CF patients identifies five loci that display significant association with variation in lung disease. Regions on chr3q29 (MUC4/MUC20; P=3.3 * 10(-11)), chr5p15.3 (SLC9A3; P=6.8 * 10(-12)), chr6p21.3 (HLA Class II; P=1.2 * 10(-8)) and chrXq22-q23 (AGTR2/SLC6A14; P=1.8 * 10(-9)) contain genes of high biological relevance to CF pathophysiology. The fifth locus, on chr11p12-p13 (EHF/APIP; P=1.9 * 10(-10)), was previously shown to be associated with lung disease. These results provide new insights into potential targets for modulating lung disease severity in CF. PMID- 26417707 TI - Inflammatory response and endothelial dysfunction in the hearts of mice co exposed to SO2 , NO2 , and PM2.5. AB - SO2 , NO2 , and PM2.5 are typical air pollutants produced during the combustion of coal. Increasing evidence indicates that air pollution has contributed to the development and progression of heart-related diseases over the past decades. However, little experimental data and few studies of SO2 , NO2 , and PM2.5 co exposure in animals exist; therefore, the relevant mechanisms underlying this phenomenon are unclear. An important characteristic of air pollution is that co exposure persists at a low concentration throughout a lifetime. In the present study, we treated adult mice with SO2 , NO2 , and PM2.5 at various concentrations (0.5 mg/m3 SO2 , 0.2 mg/m3 NO2 6 h/d, with intranasal instillation of 1 mg/kg PM2.5 every other day during these exposures; or 3.5 mg/m3 SO2 , 2 mg/m3 NO2 6 h/d, and 10 mg/kg PM2.5 for 28 d). Blood pressure (BP), heart rate (HR), histopathological damage, and inflammatory and endothelial cytokines in the heart were assessed. The results indicate that co-exposure caused endothelial dysfunction by elevating endothelin-1 (ET-1) expression and repressing the endothelial nitric oxide synthase (eNOS) level as well as stimulating the inflammatory response by increasing the levels of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Additionally, these alterations were confirmed by histological staining. Furthermore, we observed decreased BP and increased HR after co-exposure. Our results indicate that co-exposure to SO2 , NO2 , and PM2.5 may be a major risk factor for cardiac disease and may induce injury to the hearts of mammals and contribute to heart disease. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1996-2005, 2016. PMID- 26417709 TI - Relative age effect: implications for effective practice. AB - Physical and psychological differences related to birthdate amongst athletes of the same selection year have been characterised as the "relative age effects" (RAEs). RAEs have been identified in a variety of sports, both at youth and adult level, and are linked with dropout of athletes and a reduction of the talent pool. This study examined the existence, mechanisms and possible solutions to RAEs using qualitative methodology. Seven experts in the field of talent identification and development were interviewed. Inductive analysis of the data showed that, while there was mixed evidence for the existence of RAEs across sports, the eradication of RAEs was attributed to controllable features of the development environment. The factors reported included the structure of "categories" used to group athletes within the sport (e.g. age, weight, size, skills), recognition and prioritisation of long-term development over "short term win focus." Education of relevant parties (e.g. coaches, scouts, clubs) about RAEs and the nature of "talent" within a long-term context was suggested, along with careful consideration of the structure of the development environment (e.g. delayed selection, provision for late developers, focus on skills not results, use of challenge). Implications for research and practice are discussed. PMID- 26417708 TI - Deoxynivalenol, but not E. coli lipopolysaccharide, changes the response pattern of intestinal porcine epithelial cells (IPEC-J2) according to its route of application. AB - The porcine intestinal epithelium is a primary target for mycotoxin deoxynivalenol (DON) and lipopolysaccharides (LPS). Although epithelial cells are exposed to these toxins mainly from the luminal-chyme compartment an exposure from the blood side resulting from systemic absorption cannot be excluded. Thus, we investigated the effect of DON and LPS, alone or combined, on porcine intestinal epithelial cells IPEC-J2 on a transcriptional, translational and functional level when administered either from apical or basolateral. IPEC-J2 cells were cultured on 12-well inserts in complete medium at 5% CO2 and 39 degrees C and subjected to following treatments: control (CON), 2000 ng/mL DON, 1 MUg/mL LPS or DON+LPS for 72 h, either from apical or basolateral. Transepithelial electrical resistance (TEER), protein and IL-8 content were measured and microarray analysis, qRT-PCR (IL-8, zonula occludens-1 ZO-1, beta actin), Western Blot (ZO-1, beta-actin) and immunofluorescence (ZO-1) were performed. Data of at least three independent experiments were analysed with ANOVA and Dunnett's post hoc test. Basolateral DON resulted in significantly lower cell counts (p<0.05) with larger cells (p<0.01), whereas apical DON reduced total (p<0.001) and specific protein content (IL-8 content CON vs. DON: 2378 pg/3 mL vs. 991 pg/3 mL; p<0.001). Transcripts of beta-actin and ZO-1 were significantly upregulated in response to DON, irrespective of direction, whereas IL-8 mRNA remained unaffected. However, ZO-1 spatial distribution in the tight junction and its function (TEER) were detrimentally affected by basolateral DON only. In conclusion, direction of DON exposure affected IPEC-J2 differently on a translational and functional level, but was mainly inconsequential on a transcriptional level. PMID- 26417710 TI - Left-colon antegrade enema (LACE): Long-term experience with the Macedo-Malone approach. AB - AIMS: We evaluated the long-term results with a left antegrade continence enema (LACE) approach: "Macedo-Malone (MM) procedure" to define parameters such as clinical durability of the technique and patients' compliance with the method. METHODS: We reviewed the medical records of all patients that underwent the MM procedure in our institution since 2001 and conducted a telephonic interview to investigate the use of the enema and satisfaction with the procedure. RESULTS: Thirty-five MM procedures were performed, but eight patients lost to follow-up were excluded. Fifteen patients (55%) were female. Myelomeningocele was the clinical diagnoses in 25 (93%). Mean age at surgery was 9 years (3-27 years) and mean follow-up was 75 months (median: 56 months). The indication for LACE was clinically intractable constipation with fecal leakage. Most patients still used the stoma regularly to do the enema (74%). Mean washout time was 27 min (2-90 min). The revision rate due to stenosis was 22.2% (6/27) and all underwent suprafascial revision. We performed one classical MACE by infrafascial approach as a salvage procedure. Overall reoperation rate was 25.8% and fecal continence was 89%. There were no reports of leakage through the stoma. Among patients who still used the stoma, 74% were satisfied with surgery and would strongly recommend the procedure to another patient. CONCLUSIONS: The MM procedure is a straightforward procedure, which can be performed in 15-20 min, avoids additional entero-entero anastomosis, precludes the use of the appendix, and has shown comparable results to either "classical" MACE or other LACE variants. Neurourol. Urodynam. 36:111-115, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26417711 TI - Reducing anxiety during conscious surgery - A patient survey. PMID- 26417713 TI - A Survey on Turkish nursing students' perception of clinical learning environment and its association with academic motivation and clinical decision making. AB - BACKGROUND: Nursing education is a process that includes theoretical and practical learning and requires the acquisition of theoretical knowledge and skill. Nursing students need a good clinical practice environment in order to apply their knowledge and skills due to the fact that the clinical practice settings play an important role in the nursing profession. OBJECTIVES: This study was carried out in an effort to explore nursing students' perception of the clinical learning environment and its association with academic motivation and clinical decision making. DESIGN: A descriptive survey design was used. SETTING: This study was conducted in Giresun University in Turkey. PARTICIPANTS: Participants were second-, third- and fourth-year undergraduate students (n=222) in the Bachelor of Nursing Science Degree in the academic spring term of 2014 2015. METHODS: The data was collected using the 'Clinical Learning Environment Scale', the 'Academic Motivation, and the 'The Clinical Decision Making in Nursing Scale'. RESULTS: Of the respondents in this study, 45% of the students were second class, 30.6% of the students were third class and 24.3% of the students were fourth class. There was a statistically significant positive correlation found between the clinical learning environment and the nursing students' academic motivation (r=0.182, p<.05). However, there was no correlation between the clinical learning environment and clinical decision making (r=0.082, p>.05). CONCLUSION: One of the prerequisites for the training of qualified students is to provide nursing students with a qualified clinical environment. It was found that nursing students' academic motivation increased as the quality of their clinical learning environment improved. PMID- 26417714 TI - Northern Ireland and 'The Troubles', outlining an innovative approach to nursing/midwifery student teaching and module evaluation. AB - This discussion paper outlines an approach to developing and evaluating an educative programme primarily delivered by lay 'citizen trainers' in educating student nurses, and student midwives to the impact of and experience of extended and extensive civil unrest within their communities ('the Troubles' ). This is drawn from experience within the Northern Ireland 'Troubles' and all of the citizen trainers were directly affected physically/psychologically. The programme was intended to both educate but primarily to help facilitate student nurses and student midwives to better understanding to experience and context and to more effective care delivery to those affected by/damaged by 'the Troubles'. Evaluation of the teaching and learning by the students was significantly positive. PMID- 26417715 TI - Identification of active elementary flux modes in mitochondria using selectively permeabilized CHO cells. AB - Metabolic compartmentation is a key feature of mammalian cells. Mitochondria are the powerhouse of eukaryotic cells, responsible for respiration and the TCA cycle. We accessed the mitochondrial metabolism of the economically important Chinese hamster ovary (CHO) cells using selective permeabilization. We tested key substrates without and with addition of ADP. Based on quantified uptake and production rates, we could determine the contribution of different elementary flux modes to the metabolism of a substrate or substrate combination. ADP stimulated the uptake of most metabolites, directly by serving as substrate for the respiratory chain, thus removing the inhibitory effect of NADH, or as allosteric effector. Addition of ADP favored substrate metabolization to CO2 and did not enhance the production of other metabolites. The controlling effect of ADP was more pronounced when we supplied metabolites to the first part of the TCA cycle: pyruvate, citrate, alpha-ketoglutarate and glutamine. In the second part of the TCA cycle, the rates were primarily controlled by the concentrations of C4 dicarboxylates. Without ADP addition, the activity of the pyruvate carboxylase malate dehydrogenase-malic enzyme cycle consumed the ATP produced by oxidative phosphorylation, preventing its accumulation and maintaining metabolic steady state conditions. Aspartate was taken up only in combination with pyruvate, whose uptake also increased, a fact explained by complex regulatory effects. Isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase were identified as the key regulators of the TCA cycle, confirming existent knowledge from other cells. We have shown that selectively permeabilized cells combined with elementary mode analysis allow in-depth studying of the mitochondrial metabolism and regulation. PMID- 26417716 TI - Characteristics of FDG-PET findings in the diagnosis of systemic juvenile idiopathic arthritis. AB - OBJECTIVE: To examine and delineate inflammatory focus in patients with juvenile idiopathic arthritis (JIA), (18)F-Fluoro-deoxy-glucose (FDG)-positron emission tomography (PET) ((18)F-FDG-PET) was applied to patients with JIA, and the images of these patients were compared. METHODS: Sixty-eight children (59 with systemic JIA (s-JIA) and 9 with polyarticular JIA) were included. The diagnosis of JIA was done to meet the International League of Associations for Rheumatology (ILAR) criteria. After 6-h fasting, whole-body positron emission tomography (PET) scans were acquired 60 min after intravenous injection of 3-5 MBq/kg (18)F-FDG. The interpretation of (18)F-FDG uptake was based on visual characteristics. RESULTS: Two types of PET images were outstanding in s-JIA; one was (18)F-FDG uptake in red bone marrow, such as the spine, pelvis, and long bones as well as spleen (12 cases), and other type was the uptake in the major joints, such as hips, elbows, wrists, knees, and ankles (8 cases). The former findings were correlated with elevated levels of inflammatory markers, while the latter were with significantly increased levels of MMP-3 (p < 0.05). CONCLUSION: There was a noticeable accumulation of (18)F-FDG uptake in bone marrow of s-JIA patients which may indicate the inflammatory focus of this disease and play an important role in the pathogenic basis of arthritis and systemic inflammation of s-JIA. PMID- 26417712 TI - 123I-MIBG scintigraphy and 18F-FDG-PET imaging for diagnosing neuroblastoma. AB - BACKGROUND: Neuroblastoma is an embryonic tumour of childhood that originates in the neural crest. It is the second most common extracranial malignant solid tumour of childhood.Neuroblastoma cells have the unique capacity to accumulate Iodine-123-metaiodobenzylguanidine (123I-MIBG), which can be used for imaging the tumour. Moreover, 123I-MIBG scintigraphy is not only important for the diagnosis of neuroblastoma, but also for staging and localization of skeletal lesions. If these are present, MIBG follow-up scans are used to assess the patient's response to therapy. However, the sensitivity and specificity of 123I-MIBG scintigraphy to detect neuroblastoma varies according to the literature.Prognosis, treatment and response to therapy of patients with neuroblastoma are currently based on extension scoring of 123I-MIBG scans. Due to its clinical use and importance, it is necessary to determine the exact diagnostic accuracy of 123I-MIBG scintigraphy. In case the tumour is not MIBG avid, fluorine-18-fluorodeoxy glucose ((18)F-FDG) positron emission tomography (PET) is often used and the diagnostic accuracy of this test should also be assessed. OBJECTIVES: PRIMARY OBJECTIVES: 1.1 To determine the diagnostic accuracy of 123I-MIBG (single photon emission computed tomography (SPECT), with or without computed tomography (CT)) scintigraphy for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old.1.2 To determine the diagnostic accuracy of negative 123I-MIBG scintigraphy in combination with (18)F FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old, i.e. an add-on test. SECONDARY OBJECTIVES: 2.1 To determine the diagnostic accuracy of (18)F-FDG PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old.2.2 To compare the diagnostic accuracy of 123I-MIBG (SPECT-CT) and (18)F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old. This was performed within and between included studies. 123I-MIBG (SPECT-CT) scintigraphy was the comparator test in this case. SEARCH METHODS: We searched the databases of MEDLINE/PubMed (1945 to 11 September 2012) and EMBASE/Ovid (1980 to 11 September 2012) for potentially relevant articles. Also we checked the reference lists of relevant articles and review articles, scanned conference proceedings and searched for unpublished studies by contacting researchers involved in this area. SELECTION CRITERIA: We included studies of a cross-sectional design or cases series of proven neuroblastoma, either retrospective or prospective, if they compared the results of 123I-MIBG (SPECT-CT) scintigraphy or (18)F-FDG-PET(-CT) imaging, or both, with the reference standards or with each other. Studies had to be primary diagnostic and report on children aged between 0 to 18 years old with a neuroblastoma of any stage at first diagnosis or at recurrence. DATA COLLECTION AND ANALYSIS: One review author performed the initial screening of identified references. Two review authors independently performed the study selection, extracted data and assessed the methodological quality.We used data from two-by-two tables, describing at least the number of patients with a true positive test and the number of patients with a false negative test, to calculate the sensitivity, and if possible, the specificity for each included study.If possible, we generated forest plots showing estimates of sensitivity and specificity together with 95% confidence intervals. MAIN RESULTS: Eleven studies met the inclusion criteria. Ten studies reported data on patient level: the scan was positive or negative. One study reported on all single lesions (lesion level). The sensitivity of 123I MIBG (SPECT-CT) scintigraphy (objective 1.1), determined in 608 of 621 eligible patients included in the 11 studies, varied from 67% to 100%. One study, that reported on a lesion level, provided data to calculate the specificity: 68% in 115 lesions in 22 patients. The sensitivity of 123I-MIBG scintigraphy for detecting metastases separately from the primary tumour in patients with all neuroblastoma stages ranged from 79% to 100% in three studies and the specificity ranged from 33% to 89% for two of these studies.One study reported on the diagnostic accuracy of (18)F-FDG-PET(-CT) imaging (add-on test) in patients with negative 123I-MIBG scintigraphy (objective 1.2). Two of the 24 eligible patients with proven neuroblastoma had a negative 123I-MIBG scan and a positive (18)F-FDG PET(-CT) scan.The sensitivity of (18)F-FDG-PET(-CT) imaging as a single diagnostic test (objective 2.1) and compared to 123I-MIBG (SPECT-CT) (objective 2.2) was only reported in one study. The sensitivity of (18)F-FDG-PET(-CT) imaging was 100% versus 92% of 123I-MIBG (SPECT-CT) scintigraphy. We could not calculate the specificity for both modalities. AUTHORS' CONCLUSIONS: The reported sensitivities of 123-I MIBG scintigraphy for the detection of neuroblastoma and its metastases ranged from 67 to 100% in patients with histologically proven neuroblastoma.Only one study in this review reported on false positive findings. It is important to keep in mind that false positive findings can occur. For example, physiological uptake should be ruled out, by using SPECT-CT scans, although more research is needed before definitive conclusions can be made.As described both in the literature and in this review, in about 10% of the patients with histologically proven neuroblastoma the tumour does not accumulate 123I-MIBG (false negative results). For these patients, it is advisable to perform an additional test for staging and assess response to therapy. Additional tests might for example be (18)F-FDG-PET(-CT), but to be certain of its clinical value, more evidence is needed.The diagnostic accuracy of (18)F-FDG-PET(-CT) imaging in case of a negative 123I-MIBG scintigraphy could not be calculated, because only very limited data were available. Also the detection of the diagnostic accuracy of index test (18)F-FDG-PET(-CT) imaging for detecting a neuroblastoma tumour and its metastases, and to compare this to comparator test 123I-MIBG (SPECT-CT) scintigraphy, could not be calculated because of the limited available data at time of this search.At the start of this project, we did not expect to find only very limited data on specificity. We now consider it would have been more appropriate to use the term "the sensitivity to assess the presence of neuroblastoma" instead of "diagnostic accuracy" for the objectives. PMID- 26417718 TI - Two bent-shaped pi-organogelators: synthesis, fluorescence, self-assembly and detection of volatile acid vapours in gel films and in gel-gel states. AB - Two novel bent-shaped pi-organogelators 6a and 6b having different terminal pyridine rings as responsive sites were designed, synthesized and fully characterized. A subtle difference in the position of the N atom at the pyridine ring greatly affected their fluorescence and gelation properties. 6b showed remarkably stronger fluorescence both in solution and in the solid state as compared to 6a. Theoretical calculation revealed a clear discrepancy in the electron distribution between them. Furthermore, driven by pi-pi stacking interaction and hydrophobic interaction, both 6a and 6b can gelate several organic solvents with different polarities. Rheological studies, spectroscopic tests and powder X-ray diffraction showed that 6a displayed a closer stacking mode leading to stronger gel robustness. The xerogel films of 6a and 6b were prepared and utilized to detect acid vapours. Both of them can fulfil the detection of acid vapours through a distinct fluorescence change which could be seen by the naked eye under a UV lamp, but with different sensing modes. A rare gel to gel transformation was also observed upon exposure to acid vapours accompanied by a morphological change. PMID- 26417719 TI - Unique prototropy of meso-alkylidenyl carbaporphyrinoid possessing one meso exocyclic double bond. AB - Generic synthesis, identification of structural identity, unique prototropy and spectroscopic properties of meso-alkylidenyl-thia(m-benzi)porphyrinoid containing one exocyclic double bond at the meso-position were presented. PMID- 26417717 TI - Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren. AB - We report that the DNA methylation profile of a child's neonatal whole blood can be significantly influenced by his or her mother's neonatal blood lead levels (BLL). We recruited 35 mother-infant pairs in Detroit and measured the whole blood lead (Pb) levels and DNA methylation levels at over 450,000 loci from current blood and neonatal blood from both the mother and the child. We found that mothers with high neonatal BLL correlate with altered DNA methylation at 564 loci in their children's neonatal blood. Our results suggest that Pb exposure during pregnancy affects the DNA methylation status of the fetal germ cells, which leads to altered DNA methylation in grandchildren's neonatal dried blood spots. This is the first demonstration that an environmental exposure in pregnant mothers can have an epigenetic effect on the DNA methylation pattern in the grandchildren. PMID- 26417720 TI - Physical Therapist-Delivered Pain Coping Skills Training and Exercise for Knee Osteoarthritis: Randomized Controlled Trial. AB - OBJECTIVE: To investigate whether a 12-week physical therapist-delivered combined pain coping skills training (PCST) and exercise (PCST/exercise) is more efficacious and cost effective than either treatment alone for knee osteoarthritis (OA). METHODS: This was an assessor-blinded, 3-arm randomized controlled trial in 222 people (73 PCST/exercise, 75 exercise, and 74 PCST) ages >=50 years with knee OA. All participants received 10 treatments over 12 weeks plus a home program. PCST covered pain education and training in cognitive and behavioral pain coping skills, exercise comprised strengthening exercises, and PCST/exercise integrated both. Primary outcomes were self-reported average knee pain (visual analog scale, range 0-100 mm) and physical function (Western Ontario and McMaster Universities Osteoarthritis Index, range 0-68) at week 12. Secondary outcomes included other pain measures, global change, physical performance, psychological health, physical activity, quality of life, and cost effectiveness. Analyses were by intent-to-treat methodology with multiple imputation for missing data. RESULTS: A total of 201 participants (91%), 181 participants (82%), and 186 participants (84%) completed week 12, 32, and 52 measurements, respectively. At week 12, there were no significant between-group differences for reductions in pain comparing PCST/exercise versus exercise (mean difference 5.8 mm [95% confidence interval (95% CI) -1.4, 13.0]) and PCST/exercise versus PCST (6.7 mm [95% CI -0.6, 14.1]). Significantly greater improvements in function were found for PCST/exercise versus exercise (3.7 units [95% CI 0.4, 7.0]) and PCST/exercise versus PCST (7.9 units [95% CI 4.7, 11.2]). These differences persisted at weeks 32 (both) and 52 (PCST). Benefits favoring PCST/exercise were seen on several secondary outcomes. Cost effectiveness of PCST/exercise was not demonstrated. CONCLUSION: This model of care could improve access to psychological treatment and augment patient outcomes from exercise in knee OA, although it did not appear to be cost effective. PMID- 26417721 TI - Coping with patients suffering from overactive bladder: experiences of family caregivers in Hong Kong. AB - This article examines the experiences of family caregivers working with patients affected by overactive bladder (OAB) in Hong Kong. Chronic diseases create physical and emotional burdens not only for patients but also for family caregivers, who often experience physical and emotional burnout and social impairment. Extensive literature has pertained to caregiver experiences in western and non-western settings; however, few studies have addressed the livelihoods and experiences of family caregivers of patients with OAB in ethnic Chinese communities. Because of the increasing prevalence of OAB worldwide, this study investigated the experiences of such caregivers in Hong Kong, examining their emotional and social needs. A qualitative research design with individual semistructured interviews was adopted, and snowball sampling was used to recruit 35 family caregivers who were referred by patients with OAB. The participants were interviewed individually from May to August 2013. A phenomenological approach was adopted in the data analysis. The data revealed that all participants had unpleasant experiences in caring for family members with OAB. A sense of powerlessness, helplessness, confusion and guilt, as well as grievances and social withdrawal, was prevalent, causing great physical and emotional suffering and subsequent physical and emotional burnout. These negative experiences were often caused by confusion regarding caretaking duties. The negative emotions of the participants and their family members also caused a lack of communication and mutual understanding about the disease, causing care-giving to be even more confusing and difficult. Furthermore, because of traditional Chinese cultural values and gender expectations, male participants experienced the triple burden of employment, domestic duties and care-giving. More holistic social and healthcare support services should be provided for care-giving family members of patients with OAB patients, empowering such caregivers to attend to family members and care for their own emotional well-being. PMID- 26417722 TI - Evaluation of glottic view through Air-Q Intubating Laryngeal Airway in the supine and lateral position and assessing it as a conduit for blind endotracheal intubation in children in the supine position. AB - INTRODUCTION: We assessed the feasibility of blind orotracheal intubation in children using the Air-QILA as a conduit in supine position and the glottic view grading by fiberoptic bronchoscope (FOB) through it both in supine and lateral positions. METHODS: After ethical approval and consent, 60 children were enrolled in the study. In the operating room, after attaching standard monitors to all children, anesthesia was induced with sevoflurane (2-8%) in oxygen (100%). Once the children became sedated, an i.v. access was established and injection glycopyrrolate (10 MUg . kg(-1)), fentanyl (2 MUg . kg(-1)), and atracurium (0.5 mg . kg(-1)) were administered. After 3 min, the Air-QILA was placed in supine position and glottic view was assessed by using FOB, in supine and right lateral decubitus position. In all children, gradings of glottic view in two different positions were noted. After that all children were turned supine, and orotracheal intubation was done blindly through the Air-QILA. The success rate, insertion time of the Air-QILA, and endotracheal intubation were noted. RESULTS: The Air QILA placement was successful in 57 children in first attempt and three children required second attempt. However, blind endotracheal intubations through the Air QILA were successful in 38 children in first attempt and 12 children required second attempt. In the remaining 10 children, where blind endotracheal intubation through the Air-QILA remained unsuccessful, conventional laryngoscopy was performed. In supine and lateral positions, Grade 1 glottic view was seen in 41 and 38 of total 60 patients, respectively. Turning of all children from supine to lateral decubitus position resulted in the deterioration of grading of glottic view in eight children and improvement in two children (P = 0.001). CONCLUSION: The Air-QILA is an easy to place supraglottic airway device with excellent airway seal and low airway morbidity. It may be useful as a conduit for blind orotracheal intubation in supine position and can be used as an effective alternative to FOB in low resource settings. PMID- 26417723 TI - Brain extracellular matrix retains connectivity in neuronal networks. AB - The formation and maintenance of connectivity are critically important for the processing and storage of information in neuronal networks. The brain extracellular matrix (ECM) appears during postnatal development and surrounds most neurons in the adult mammalian brain. Importantly, the removal of the ECM was shown to improve plasticity and post-traumatic recovery in the CNS, but little is known about the mechanisms. Here, we investigated the role of the ECM in the regulation of the network activity in dissociated hippocampal cultures grown on microelectrode arrays (MEAs). We found that enzymatic removal of the ECM in mature cultures led to transient enhancement of neuronal activity, but prevented disinhibition-induced hyperexcitability that was evident in age-matched control cultures with intact ECM. Furthermore, the ECM degradation followed by disinhibition strongly affected the network interaction so that it strongly resembled the juvenile pattern seen in naive developing cultures. Taken together, our results demonstrate that the ECM plays an important role in retention of existing connectivity in mature neuronal networks that can be exerted through synaptic confinement of glutamate. On the other hand, removal of the ECM can play a permissive role in modification of connectivity and adaptive exploration of novel network architecture. PMID- 26417725 TI - Novel method to leukoreduce murine blood for transfusion: how to reduce animal usage. AB - BACKGROUND: Basic research on the pathomechanisms of transfusion-related adverse events depends on murine transfusion models, in which leukoreduction (LR) is a prevalent standard. The commonly used neonatal LR filter (LRF) is associated with considerable animal numbers. A more efficient method would help support the guiding principles of "replacement, reduction, refinement" (3Rs). STUDY DESIGN AND METHODS: Blood from C57BL/6 and C57BL/6-Tg(UBC-GFP)30Scha/J mice was leukoreduced using (1) a neonatal LRF, (2) a syringe LRF, or (3) CD45 microbeads. Product quality was assessed according to US Food and Drug Administration (FDA) standards. White blood cell numbers were analyzed by flow cytometry; hemoglobin concentrations and hematocrit were measured and in vivo posttransfusion recoveries were determined after 2 weeks of storage. RESULTS: Using the neonatal filter, a LR of 99.56% was achieved with wastage of 12.4 mL in comparison to 99.68% and 1-mL hold-up volume with the syringe filter and 99.11 +/- 0.24% LR and 0.1-mL wastage using microbeads. All techniques achieved FDA quality standards, apart from posttransfusion recovery rate, which was only reached by the microbeads-based technique. CONCLUSION: LR with CD45 microbeads not only reduces animal usage but also provides a more efficacious method regarding posttransfusion red blood cell recovery and, hence, provides a promising alternative to commonly used methods. PMID- 26417724 TI - Melanin production through novel processing of proopiomelanocortin in the extracellular compartment of the auricular skin of C57BL/6 mice after UV irradiation. AB - The production of melanin is regulated by alpha-melanocyte-stimulating hormone (alpha-MSH), which is produced from proopiomelanocortin (POMC). Keratinocytes release POMC along with lower levels of alpha-MSH and ACTH. To clarify the mechanism of melanogenesis after ultraviolet (UV)-irradiation, this study focused on the expression of POMC and POMC-derived peptides after UV-irradiation. Western blot analysis and immunoassays indicated that both POMC and alpha-MSH-like immunoreactivity (alpha-MSH-LI) increased after UV-irradiation. However, other POMC-derived products were very low. In hypophysectomized mice, alpha-MSH-LI increased to the same level as in control mice after UV-irradiation. Structural analysis revealed that the major alpha-MSH-LI product was ACTH(1-8). Furthermore, ACTH(1-8) competed with [(125)I]-alpha-MSH for receptor binding and increased melanin production via a melanocortin-1 receptor. These results suggested that melanin was produced through ACTH(1-8) after UV-irradiation. Trypsin-like enzymatic activity, which is responsible for POMC activation, increased after UV irradiation and was identified as tryptase. In mast cell-deficient mice, which do not produce tryptase, alpha-MSH-LI levels were unchanged after UV-irradiation. The present study demonstrates the production of ACTH(1-8) from POMC by tryptase, which is a novel peptide-processing mechanism in the extracellular compartment of the skin. PMID- 26417726 TI - SUN4 is essential for nuclear remodeling during mammalian spermiogenesis. AB - One of the more dramatic examples of cellular reorganization occurs during spermiogenesis in which a roughly spherical spermatid is transformed into a mature sperm cell. A highlight of this process involves nuclear remodeling whereby the round spermatid nucleus is sculpted into an elongated and polar structure. This transformation in nuclear architecture features chromatin condensation, changes in the composition and organization of the nuclear lamina and redistribution and elimination of nuclear pore complexes. The manchette, a cytoplasmic microtubule-based structure is thought to play a crucial role in the remodeling process. Here we show that SUN4, a spermatid nuclear membrane protein has an essential function in coupling the manchette to the nuclear periphery. In the absence of SUN4, manchette microtubules appear highly disorganized and the nucleus itself fails to elongate. Consequently, mice deficient in SUN4 display globozoospermia with associated infertility. PMID- 26417728 TI - Probing hydrogen bonding orbitals: resonant inelastic soft X-ray scattering of aqueous NH3. AB - To probe the influence of hydrogen bonding on the electronic structure of ammonia, gas phase and aqueous NH3 have been investigated using soft X-ray absorption (XAS), resonant inelastic soft X-ray scattering (RIXS), and electronic structure calculations including dynamical effects. Strong spectral differences in the XAS scans as well as in the RIXS spectra between gas phase and aqueous NH3 are attributed to orbital mixing with the water orbitals, dipole-dipole interactions, differences in vibronic coupling, and nuclear dynamics on the time scale of the RIXS process. All of these effects are consequences of hydrogen bonding and the impact of the associated orbitals, demonstrating the power of XAS and RIXS as unique tools to study hydrogen bonding in liquids. PMID- 26417729 TI - Novel retinopathy in related Gordon setters: a clinical, behavioral, electrophysiological, and genetic investigation. AB - PURPOSE: To conduct ophthalmic, behavioral, electrophysiological, and genetic testing on two related Gordon setters presented for day blindness and compare findings with those of nine related and unrelated Gordon setters. METHODS: All dogs underwent comprehensive ophthalmic examination. Maze testing was conducted under different light intensities. Rod and cone function was assessed electroretinographically. DNA samples were screened for five canine retinal disease gene mutations. RESULTS: Ophthalmic examination was unremarkable in all dogs. There was no notable difference between day blind dogs and the reference population in scotopic and mesopic maze tests. Day blind dogs performed worse in the photopic maze with slower course completion time and more obstacle collisions. Electroretinography revealed extinguished cone function in day blind dogs and depressed rod responses in all but two reference dogs. One reference population dog presented with day blindness 1 year after initial examination. Mutations that cause achromatopsia (in CNGB3) and cone-rod dystrophies (in ADAM9 and IQCB1) were not detected in any dog tested, although five reference dogs were carriers of the mutation in C2orf71 that causes rod-cone degeneration 4 (rcd4) in Gordon setters and in polski owczarek nizinny dogs. CONCLUSIONS: This report describes a novel retinopathy in related Gordon setters that has clinical signs and vision testing results consistent with achromatopsia but electroretinographic results suggestive of cone-rod dystrophy. The majority of Gordon setters in this study had low rod responses on electroretinography but it is unclear whether this was indicative of rod dysfunction or normal for the breed. Longer-term observation of affected individuals is warranted. PMID- 26417731 TI - Classification in psychiatry: from a symptom based to a cause based model? AB - The assumption that eventually the classification in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM) will incorporate aspects of causation uncovered by research in neuroscience is examined in view of the National Institute of Mental Health's NIMH Research Domain Criteria (RDoC) project. I argue that significant advantages of maintaining the classification system, focussed on grouped descriptions of symptoms, are often undervalued or not considered. In this paper I will challenge the standard view that the transition from the purely symptom based approach is an inevitable and desirable change. PMID- 26417730 TI - Work-related factors, job satisfaction and intent to leave the current job among United States nurses. AB - AIMS AND OBJECTIVES: To examine the relationships of work-related factors (e.g., autonomy, work schedule, supervisory and peer support) to nurses' job satisfaction and intent to leave their current position. BACKGROUND: Low job satisfaction and high turnover of nurses are major problems for health care. To improve nurse retention, work-related factors associated with job satisfaction and intent to leave should be investigated. DESIGN: A cross-sectional secondary data analysis. METHODS: Data were obtained in 2004 from Wave 3 of the Nurses' Worklife and Health Study. A random sample of 5000 actively licenced nurses in Illinois and North Carolina (two U.S. states) were sent the survey in wave 1, of which 1641 actively working bedside nurses participated in wave 3. We examined associations of various work-related factors with job satisfaction and intent to leave the current position. RESULTS: Nurses who were dissatisfied with their job reported significantly higher psychological demands and lower autonomy than nurses who were satisfied. Nurses were significantly less satisfied with their jobs when they worked longer hours with inadequate breaks or sick days. Lack of support from peers and supervisors was also related to significantly lower odds of job satisfaction. For intention to leave, nurses who said they planned to leave their current job reported significantly lower autonomy and less support from their peers than nurses who intended to stay. CONCLUSION: A variety of modifiable work-related factors were significantly related to job satisfaction and intention to leave the current job among nurses. Future research should focus on developing interventions that could mitigate these factors (e.g., by improving work schedules, increasing autonomy and/or nurse support). The impact of such interventions on job satisfaction and intention to leave the current position could then be evaluated. RELEVANCE TO CLINICAL PRACTICE: To increase nurse retention, improved schedules, autonomy and supportive work environments should be promoted. PMID- 26417727 TI - Groucho restricts rhomboid expression and couples EGFR activation with R8 selection during Drosophila photoreceptor differentiation. AB - Notch and EGFR signaling pathways play important roles in photoreceptor differentiation during Drosophila eye development. Notch signaling induces Enhancer of Split (E(spl)) proteins to repress atonal (ato) expression and restrict R8 photoreceptor cell fate. The R8 precursors express rhomboid (rho), which is required for the release of active EGFR ligand to activate EGFR signaling in surrounding cells for the subsequent stepwise recruitment. However, it is not clear about the mechanisms of transcriptional regulation of rho and how the lateral inhibition of Notch signaling and rho expression are coordinated. In this study, we show that inactivation of Groucho (Gro), an evolutionally conserved transcriptional corepressor, inhibits Ato upregulation, delays R8 determination, and promotes differentiation of R2-5 type of neurons. We demonstrate that these phenotypes are caused by a combination of the loss of Notch-mediated lateral inhibition and the precocious activation of EGFR signaling due to deregulated rho expression. Blocking EGFR signaling by Pnt-RNAi in conjunction with Gro-inactivation leads to lateral inhibition defects with deregulated Ato expression and R8 differentiation. We further show that inactivation of E(spl), which are the Gro binding transcription factors, causes deregulated rho expression and extra R8 cells within and posterior to the morphogenetic furrow (MF), and that E(spl) mediates the binding of Gro to the regulatory regions of both rho and ato genes in eye disc cells. Our results suggest that Gro inhibits rho expression in undifferentiated cells and represses the expression of both ato and rho in non-R8 precursors during initiation of photoreceptor differentiation in an E(spl)-dependent manner. The latter function of Gro provides novel insights into the mechanism that coordinates R8 specification with the restriction of initial rho expression to developing R8 cells. PMID- 26417732 TI - Words that heal. AB - The value of words in the healing process runs constant to the path of therapeutic treatment, the net of exchanges and relationships between brain chemistry and the right words in order to heal is subtle and intricate. Psychotherapy, a treatment with words, is shown to be a treatment that directly affects the brain and that is able to change it stably, even in its anatomical structure and function. According to Kandel (1999), a leading living scientist and Nobel Prize winner for medicine and physiology, American neurologist and psychiatrist, psychotherapy is a real cure, a biological treatment, as it produces behavioral changes through new words and new experiences. The article offers a brief overview of the use of the fantasy of argument, since the time of the classical rethoric of the sophists up to the new rethoric, to illustrate how the structure of the speech, and the dialectic ability of opposing different thoughts, closely resembles the way of thinking. Consequently the choice of words can be considered an instrument of great impact that is inserted in the stream of thoughts that determines the attitude of a person, and therefore, his/her actions. This happens whenever you communicate voluntarily, and not simply when interacting. The right choice of words remains a turning point in all of our relationships, not only in therapeutic situations, but in every other social relationship in life, family or friends. PMID- 26417733 TI - Person-centred psychopharmacotherapy: what is it? Each patient is a unique, responsive and responsible subject. AB - Modern psychopharmacotherapy is currently in contention both outside and within the field of psychiatry. Conventional psychopharmacology paradigms focusing just on a disease perspective, biological narrative and a "one fits all" treatment are often regarded as inadequate and disjunctive. A significant proportion of psychiatric patients achieve no improvement or only partial improvement in their symptoms, while many of them suffer adverse and even toxic effects of medications. Psychopharmacotherapy as a sole form of treatment may carry the wrong message that patients don't have to change their life style and don't have to learn any new skills, they just have to receive their medication on time because the only problem is in brain chemistry. Evidence-based psychopharmacotherapy and person-centered narrative psychopharmacotherapy are not competitors but a complementuary duality, as intimately connected as brain and soul. Narrative preserves individuality, distinctivenesss and therapeutic context, whereas quantitative methods and evidence-based guidelines offer a solid foundation for what is reliably and generally correct. The purpose of person centered psychopharmacotherapy is to empower the patients to control their disease, to re-author their problematic life story, to obtain full personal recovery and to regain control over their life. PMID- 26417734 TI - The Doctor Patient Relationship; what if Communication Skills are not used? A Maltese Story. AB - The doctor patient relationship is fundamental to the practice of medicine. In the UK, much work has been carried out to develop taining in communication skills for both doctors and medical students. Whereas it is true that controled trials of communication skills are now beginning to emerge in the primary care literature, it is also true that there is need for studies of communication skills on the hospital ward. One alternative form of evidence for the need of communication skills is that of anthropological studies of hospital wards. We here summarise the observations made in one such anthropological study which was carried out in a renal unit in Malta. The conclusion of these observations is that the inability of the doctors to utilise communication skills is that patients develop meaningful relationships with other groups of professionals, to the extent that they consider them as part of an extended family. Doctors remain isolated from all these relationships and only relate to patients from a position of power. PMID- 26417735 TI - The Concept of Body Language in the Medical Consultation. AB - In this paper we wish to argue that the human body is an instrument of communication that can be used by the individual. This can be shown by the use of phenomenology, as described by Husserl, and that indeed empathy, as described by phenomenology, can be seen as a link enabling two human bodies/persons to communicate. We then wish to show from neuroscience that empathy can itself be seen as a bodily function. We then will describe how the doctor-patient relationship in the consultation is an extremely important type of communication between two persons, and how teaching of consultation skills has developed. We will show that, once consultation skills teaching was established, then study of body language became an essential part of this teaching, as soon as the technology was developed, and finally we will demonstrate that it is now possible to confirm by observational and controlled trials that appropriate use of body language does indeed enhance the effectiveness of the consultation, including, we would suggest, by appropriate communication of empathy and understanding. PMID- 26417736 TI - Empathy among physicians, medical students and candidates. AB - BACKGROUND: Empathy is one of the crucial personality traits for all medical professionals, including physicians. The importance of empathy in doctor-patient relationship cannot be overestimated, as it is beneficial for both sides. Regrettably, there is evidence for the decline in this trait over the course of medical studies. SUBJECTS AND METHODS: The participants were 509 voluntary respondents: medical school candidates (16.1%), medical students (65%), medical trainees (9.8%), residents (6.3%) and specialists (2.8%). The Interpersonal Reactivity Index (IRI) was administered to them, which is a self-report tool measuring empathy. RESULTS: Gender difference in the IRI score was especially prominent - the mean score for female respondents was 59.83 points, while in men it was 51.16 point (p<0.001). The level of empathy did not differ significantly in the sub-groups divided with regards to the stage of their medical career. However, the total IRI score in women was the highest in the group of doctors, while in post-graduated males it was the lowest. Age of the respondents correlated positively with the perspective taking sub-scale and negatively with the fantasy and personal distress sub-scales. CONCLUSIONS: Empathy is a trait that is rarely being enhanced in medical students during their education. While empathy is crucial for the development of a satisfactory doctor-patient relationship, there is an urgent need to adopt educational programs aimed at reinforcing empathy in medical students. PMID- 26417737 TI - Islam, mental health and being a Muslim in the West. AB - The allegation that, 'Being Muslim means that you cannot be British' is often made. In view of this, we conducted a small survey (n=75) utilising purposive sampling on Muslims residing in the United Kingdom. Participants were recruited in a King's College London Islamic Society event in November 2014 in Guy's Hospital, London. 75/75 (100%) of the participants recruited responded. 69/75 (94%) of respondents either disagreed or strongly disagreed that, 'Being Muslim means that you cannot be British' (75/75 (100%) Muslim participants, 43/75 (57.3%) female participants, 32/75 (42.7%) male participants, mean Age 20.5 years, (Std. Dev. +/-2.5)). This paper broadly seeks to answer two related questions. Firstly, 'What is the relationship between Islam and the West?' and secondly, 'What is the relationship between Islam and mental health?' In relation to the former, the rise of radicalization over recent years and the Islamophobia that has ensued have brought Islam and Muslims under intense scrutiny. Hence we feel it is both timely and important to offer a brief background of Islam and its relevance to the Western world. In relation to the latter, for many people religion and mental health are deeply and intimately intertwined. For example, religion can enable a person to develop mental health resilience and Islam has been reported to be a protective factor against suicidal behaviour. We conclude our paper by illustrating how the two questions are interrelated. We do so by offering an autobiographical narrative from a Muslim healthcare professional residing in the UK who developed a mental health problem precipitated by war in the country of his origin. His narrative includes descriptions of the role Islam that played in his recovery as well as his attempts to reconcile seemingly disparate aspects of his identity. PMID- 26417738 TI - Traumatic events in childhood and their association with psychiatric illness in the adult. AB - INTRODUCTION: Child maltreatment is a well-known condition that is currently considered to be associated with the development of severe psychiatric conditions. Consequently, the authors decided to review the current literature in order to give a complete scenario of the situation in the world and to give recommendations about prevention and treatment as well as research goals. METHODS: An electronic search was conducted through the means of MEDLINE database in order to find the most up to date peer-reviewed papers, including only those papers published in 2015. RESULTS: 15 papers were included and analyzed the current situation in different countries: US (n.3), Australia (n.2), Ireland (n.2), Israel (n.2), China (n.2), Indonesia (n.1), Pakistan (n.1) and Norway (n.1). DISCUSSION: Even though sexual abuse has been studied extensively, both physical and emotional abuse and neglect appear to be more represented within the population of patients that had suffered from abuse. Psychiatric disorders (mainly personality disorders, depression and anxiety), interpersonal, social and legal outcomes are important consequences of child maltreatment. CONCLUSIONS: Interventions and strategies are needed at different levels, from prevention to treatment and further research is important in order to better understand the phenomenon. PMID- 26417739 TI - Assessing Parenting Capacity in Psychiatric Mother and Baby Units: A case report and review of literature. AB - AIMS AND HYPOTHESIS: This review aimed to improve infant risk assessments in the context of maternal mental illness by identifying key predictors of poor parenting outcomes. BACKGROUND: Inadequate parenting as a result of severe and persistent mental illness is a common reason for courts terminating parental rights. However, the current practice of parenting capacity assessments in the setting of perinatal psychiatry is fraught with risks and uncertainty. A well recognised flaw in the assessment process is the lack of valid and reliable tools that have been specifically validated for assessing parenting capacity in mothers with a history of mental illness and the potential risk of harm to their infant. To date, there is only one instrument available. METHODS: A systematic search of Medline, PsycInfo and Embase via the Ovid interface was conducted between September and December 2014. Citation snowball sampling was also used to identify further relevant studies. An additional search was performed in Google to access grey literature. RESULTS: A total of 38 citations were identified, of which 8 publications focusing on the populations of England, France and Belgium met the eligibility criteria of this review. Evidence from existing research suggests that poor parenting outcomes in maternal psychiatric illness are strongly associated with correlates of socio-economic inequalities. However, evidence regarding the long-term implications of such factors is weak as only one follow up study and no longitudinal studies were identified in this review. CONCLUSION: Our review suggests that the use of standardised empirically validated risk assessment tools would benefit the current practice of parenting assessments by improving the process by which collected information is analysed. This would enhance the accuracy of decision-making, and improve the safeguarding of the infant. Further research is needed on medium to long-term parenting outcomes, particularly regarding its relations to: the type of maternal psychiatric disorder; the quality of maternal relationships; previous attachment experience; psychiatric illness or behavioural disorder in the partner and neonatal/infant medical complications. This would more accurately reflect the dynamic nature of parenting and would help to determine the effectiveness of specific interventions addressing risk factors associated with poor parenting outcomes. PMID- 26417740 TI - A lot of mental illness starts in adolescence. Therefore should we shift some of the spending from adult to adolescent mental health services? AB - In May 2015 the UK elected a new government. In election campaigns, health is one of the most important areas of debate and over the preceding 12 months, the state of child and adolescent mental health services (CAMHS) had held a particularly high profile in the media and in political debate. Many had suggested that the rate of mental illness starting in adolescence is increasing and that service provision is not of sufficient quality or scale to meet this need. A brief review of the sources for these statistics reveals that whilst this may be true, there is a dearth of accurate and up to date data on the scale of the need for CAMHS or the extent to which it is being met. Nonetheless, members of all parties claimed to support improvements in mental health service provision for children and adolescents through increases in funding. A key question for policy makers has therefore become, from where any additional funding might be derived. One suggestion has been that funding be transferred from spending on adult mental health services. The exact practical nature of such a policy is yet to be explored in detail by government or stakeholders. The primary purpose of the present discussion is therefore to consider the possible ethical implications of such a policy in principle. The discussion forms part of a wider and evolving political and professional discourse on society's and government's attitude towards mental illness, towards the balance of individual and societal needs and towards the balance between preventative and supportive interventions to improve health. PMID- 26417741 TI - Poverty and mental health: What should we know as mental health professionals? AB - BACKGROUND: Social inequality as a social and economic phenomenon has become an issue of common interest in Europe and other societies worldwide, mainly after the recent global financial and economic crisis that occurred in 2008. The increasing gap observed between socioeconomically advantaged and disadvantaged people has caused intensive debates in politics, social sciences and in the field of public health. Today, poverty is considered as a major variable adversely influencing health. In this paper we will discuss the link between poverty and mental health. SUBJECTS AND METHODS: We conducted a literature search focusing on three main objectives: (I) to investigate the definition of "poverty"; (II) to determine the association between poverty and major mental health problems; and (III) to discuss the extent to which poverty could be both a cause and a consequence of mental health. RESULTS: We identified a total of 142 relevant papers, published between 1995 and 2014, only 32 were retained. Main findings are summarised in this paper. CONCLUSION: Poverty can be considered as a risk factor for mental illness. Yet the relation between poverty and mental health is complex, without direct causation, and bidirectional. As poverty has severe consequences not only on health but also on the whole society, combating poverty should be placed high on the political agenda. PMID- 26417742 TI - One of many lessons from the European Mental Health Integration Index. AB - The Mental Health Integration Index developed by the Economist Intelligence Unit describes and explores the challenges of European countries of integrating people with mental illness into society and employment, within the European Union's 28 Member States, plus Norway and Switzerland. Countries have been ranked according to estimation based on indicators of their degree of commitment to support those living with mental illness into society and employment. The Index is based on a list of indicators including the environment for those with mental illness, their access to medical help and services, their opportunities--specifically job related--and the governance of the system, including human rights issues and efforts to combat stigma. The indicators were developed in consultation with a panel of independent experts on mental health. Key findings of the research are that Germany's strong healthcare system and generous social provision put it at the top of the Index, with the UK and Scandinavian states not far behind. However, examples of best practice "islands of excellence" in integration are not limited to the leading countries and exists in all European Countries. The Index reveals also the discrepancy between perfect legislation and poor implementation of it in practice in many European countries. It proposes that the investment figure is a proxy for seriousness in establishing good policy and practice. According to the Index some reform plans including entire national mental health programmes are largely aspirational and are grossly under-funded. Moreover various levels of government responsible for the implementation of its component parts are largely ignoring its implementation. When we consider the legislation as an promise to professionals and people with mental health problems, this promise is largely unfulfilled. The is a need for strong leadership in mental health changes process, policy capacity and real financial investments in the way of The European countries to develop community based mental health services and system of care. PMID- 26417743 TI - Can clinical use of Social Media improve quality of care in mental Health? A Health Technology Assessment approach in an Italian mental health service. AB - Clinical use of modern Information and Communication Technologies such as Social Media (SM) can easily reach and empower groups of population at risk or affected by chronic diseases, and promote improvement of quality of care. In the paper we present an assessment of SM (i.e. e-mails, websites, on line social networks, apps) in the management of mental disorders, carried out in the Mental Health Service of Trento (Italy) according to Health Technology Assessment criteria. A systematic review of literature was performed to evaluate technical features, safety and effectiveness of SM. To understand usage rate and attitude towards new social technologies of patients and professionals, we performed a context analysis by a survey conducted over a group of 88 psychiatric patients and a group of 35 professionals. At last, we made recommendations for decision makers in order to promote SM for the management of mental disorders in a context of prioritization of investments in health care. PMID- 26417744 TI - Setting Up a Mental Health Clinic in the Heart of Rural Africa. AB - INTRODUCTION: The World Health Organization defines health as a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity (WHO 1948). In Africa, mental health issues often come last on the list of priorities for policy-makers & people's attitudes towards mental illness are strongly influenced by traditional beliefs in supernatural causes/remedies. The massive burden attributed to mental illness in these communities, poses a huge moral, cultural/economic challenge and requires a concerted and integrated approach involving policy makers, mental health Practitioners, the general public, service users and their families and other stake holders to reverse the trend. PROJECT OBJECTIVES: Improving community awareness of mental illness. Change the negative perception of mental illness by the community. Providing a screening/referral pathway for mental illnesses. Providing supervision of patient care. POTENTIAL RESULTS: Promote community participation on issues regarding mental health with a view to challenge existing traditional attitudes and beliefs, reduce stigma and promote health seeking behaviour. PMID- 26417745 TI - Mental Health Support Service for University Students. AB - SERVICE: The Mental Health Support Service provides substantial one to one practical support for students to enable them to manage their mental health and study to provide coordinated support and ensure compliance with the Equality Act 2010. RESOURCES: The service consists of a full time Mental Health Advisor and a part time Support Worker and is available all year round. Supervision is received from a Consultant Psychiatrist. ROLES: To liaise with students and professionals when a student is admitted to hospital/Crisis Teams. Close communication with other services such as Student Engagement, the International Office, the Chaplain and academics. NATIONAL TRENDS: Data from the Office of National Statistics between 2007 and 2011 have shown an increase in the number of student suicides since the start of the recession. SURVEY FEEDBACK: Feedback highlights that students benefit from the support and value the professional and welcoming attitude of the team. CONCLUSION: The service continues to provide good quality support to those who access it. Student feedback shows that they believe the support has helped them to stay at university and complete their degree. PMID- 26417746 TI - Could Carmelite Spirituality Promote Good Mental Health? A brief Tribute to Saint Teresa of Avila in the 500th anniversary of her birth. AB - Often it is overlooked that Christian Spirituality involves a personal relationship of a human being with God. It is of interest that both the Protestant Reformers and the exponents of the Catholic Counter Reformation agreed upon this. Two of the greatest exponents of the Counter-Reformation, both of whom were made Doctors of the Church because of their teaching on Prayer were Saint Teresa of Avila and Saint John of the Cross. This year is the 500th anniversary of the birth of Saint Teresa of Avila. Here, as a Catholic Psychiatrist, I argue that the teaching of both saints about the prayer life, properly understood, tends to improve self worth, and therefore must tend to help persons with mental health problems. PMID- 26417747 TI - Human resources and their possible forensic meanings. AB - Forensics (forensic--before the Forum) means the application of knowledge from different scientific fields in order to define facts in judicial and/or administrative procedures. Nowadays forensics, besides this, finds its application even in different economic processes. For example, forensics enters the commercial areas of business intelligence and of different security areas. The European Commission recognized the importance of forensics, and underscored the importance of development of its scientific infrastructure in member States. We are witnessing the rise of various tragedies in economic and other kinds of processes. Undoubtedly, the world is increasingly exposed to various forms of threats whose occurrences regularly involve people. In this paper we are proposing the development of a new approach in the forensic assessment of the state of human resources. We are suggesting that in the focus should be the forensic approach in the psychological assessment of awareness of the individual and of the critical infrastructure sector operator (CISO) in determining the level of actual practical, rather than formal knowledge of an individual in a particular field of expertise, or in a specific scientific field, and possible forensic meanings. PMID- 26417748 TI - Global strategies targeting the recruitment crisis in psychiatry: the Doctors Academy Future Excellence International Medical Summer School. AB - BACKGROUND: The World Health Organization has identified a chronic shortage of psychiatrists worldwide whereas the demand for mental health services is on the rise. Indeed mental health problems are projected to be a leading cause of morbidity by 2020 according to the Global Burden of Disease study. Bhugra et al, under the auspices of the Royal College of Psychiatrists and the World Psychiatry Association, spearheaded an international study across 22 countries and identified myriad factors that can influence career choices at pre-medical school, medical school and postgraduate levels. The enthusiasm and passion of mental health educators and the quality of psychiatry placements were identified as factors that can attract medical and students and graduates to a career in psychiatry. The Future Excellence International Medical Summer School (FEIMSS) is a 5-day event for medical students held yearly in Manchester, UK. FEIMSS is the largest event of its kind in the world; the 2013 cohort was comprised of 244 students from 40 countries representing 80 universities. AIMS: To improve the image of psychiatrists and the perception of psychiatry in general with 2 brief contact-based lectures from a consultant and an early-career psychiatrist. The lectures incorporated references to the humanities (literature, poetry, history, film, drama and art). METHODS: A mixed-methods study was conducted. Paper evaluation forms were hand-distributed to participants who attended the psychiatry talks. Items to constructs relevant to the talks were on a Likert-type scale. Participants were given the choice of anonymity. There was space for free text comments which were subjected to thematic analyses. RESULTS: 25/25 of the participants responded (response rate 100%). The heterogeneous sample was comprised of participants representing 11 countries from Japan to Kosovo. The written feedback was exceptionally positive. For the, 'The psychiatry talks were interesting' and, 'Attending FEIMMS improved my understanding and respect for other cultures' constructs, 23/25 (92%) of respondents agreed or strongly agreed. DISCUSSION: Notwithstanding the limitations of our evaluation--which to our knowledge is the first of its kind on such an ethnically eclectic sample--our results suggest that a brief contact-based intervention incorporating the humanities may positively influence the perceptions of psychiatry and psychiatrists that medical students from diverse cultural backgrounds have. We contend that FEIMSS provides a platform to recruit medical students into psychiatry from all over the world and enables them to develop cultural competency. PMID- 26417750 TI - "Dance and go on": a project of psychosocial rehabilitation on the road. AB - The project "Dance and go on" was created with the intention of bringing out of the Day Centre of the Department of Mental Health of Torre del Greco, the dance group "Dance That you go" active since 2009. Dancing Bachata becomes a rehabilitation tool to express emotions through the body and to open to the outside, on the territory (local society), overcoming the fear of being judged by others, the prejudice and the social stigma about mental illness. The rehabilitation activities of the dancing group allowed patients to improve their care of self, self-esteem, confidence in their capacities and an increase in their social relations. The strength and cohesion of the rehabilitation group has given to the patients the opportunity to believe in their own abilities, to accept themselves with their difficulties and to improve the relationship with their body in relation with each other. PMID- 26417749 TI - Cinematherapy and film as an educational tool in undergraduate psychiatry teaching: a case report and review of the literature. AB - Film possesses an extraordinary power and offers an unrivalled medium for entertainment and escapism. There are many films that revolve around a mental illness theme and the medical specialty that most commonly features in motion picture is psychiatry. Over the last few decades films have become increasingly used as an educational tool in the teaching of psychiatry topics such as mental state examination to undergraduate students. Above and beyond its utility in pedagogy, film also has the power to heal and the term cinematherapy has been coined to reflect this. Indeed, there are case studies of people with first-hand experience of psychopathology who report that watching films with a mental illness theme has contributed to their recovery. We provide a first person narrative from an individual with schizophrenia in which he expounds on the concepts of cinematherpy and metaphorical imagery in films which theme on psychosis. PMID- 26417751 TI - A holistic approach on the neurological benefits of music. AB - A holistic perspective on human beings allows health carers to achieve an understanding of all the physiological, psychological and social disturbances of the patient as a whole. Through this article we wish to focus on how music has holistic neurological benefits. Music-therapy interventions can be more accessible and even "self-managed" by the patient's relatives. They can reinforce social cohesion, family ties and patients' self-esteem and thus produce a better quality of life. Overall, it is important to consider the benefits that an evolutionary understanding of musical behaviour and a holistic clinical perspective of the role of music may bring for rehabilitation of a wide range of symptoms and conditions. PMID- 26417752 TI - 'Craziness' and creativity: Psychopathology and Poetry. AB - Not all poets have experienced psychopathology. Conversely, not all those who have experienced psychopathology become poets. The notion, nonetheless, of there being an association between 'craziness' and creativity, contentious though it may be, remains a seductive one. Poetry is both beneficial for the person who is composing or reciting it as well as the person who may be reading or listening to it. Poetry Therapy, which falls under the remit of Art Therapy, is increasingly being recognised as an effective form of adjunctive therapy for the treatment of mental health problems. The main aims of this paper are to explore (and to attempt to elucidate) if there is indeed a relationship between the artistic temperament and mental illness and to comment on the rise and recognition of Art Therapy. PMID- 26417753 TI - Clinical utilisation of the "G.T. MSRS", the rating scale for mixed states: 35 cases report. AB - The knowledge of the clinical features of the mixed states and of the symptoms of the "mixity" of mood disorders is crucial: to mis-diagnose or mis-treat patients with these symptoms may increase the suicide risk and make worse the evolution of mood disorders. The rating scale "G.T. MSRS" has been designed to improve the clinical effectiveness of both psychiatrists and GPs by enabling them to make an early "general" diagnosis of mixed states. This study presents some cases in which the "G.T. MSRS" scale has been used, in order to demonstrate its usefullness. PMID- 26417754 TI - Are there different genotypes in Bipolar II and Bipolar I disorder and if so, why then do we tend to observe Unipolar Depression converting to Bipolar II and then converting to Bipolar I? AB - We review the recent literature in order to establish the importance of a spectrum for bipolar affective disorder, and that unipolar depression, bipolar II and bipolar I are discrete entities that may however evolve in sequence. We discuss clinical, genetic and neurobiological data which illustrate the differences between bipolar I and bipolar II. To fit the data we suggest a series of multiple mood disorder genotypes, some of which evolve into other conditions on the bipolar spectrum. Thence we discuss the nature of the bipolar spectrum and demonstrate how this concept can be used as the basis of a staging model for bipolar disorder. PMID- 26417755 TI - Bipolar and Borderline Personality Disorders: a descriptive comparison of psychopathological aspects in patients discharged from an Italian Inpatient Unit using PANSS and BPRS. AB - BACKGROUND: There is current scientific debate in consideration of the possibility to consider the Borderline Personality Disorder (BPD) as a mood disorder within the bipolar spectrum furthermore, authors reported about the challenging differential diagnosis of BPD and Bipolar Disorder (BD). SUBJECTS AND METHODS: 32 patients hospitalized in the Inpatient Psychiatric Unit in Perugia, discharged with a diagnosis of BD or BPD, were included. Factor analyses of BPRS and PANSS items were performed. Association between socio-demographic, clinical and psychopathological variables was tested using bivariate analyses. RESULTS: Factor analysis identified 6 Factors, explaining 67.6% of the variance, interpreted as follow: 1) Euphoric Mania, 2) Psychosis, 3) Inhibited Depression, 4) Disorganization, 5) Psychosomatic features, and 6) Mixed features. Bivariate analyses identified statistically significant differences between BPD and BD according to: PANSS positive symptoms domain, BPRS total score, Euphoric Mania and Disorganization. No statistically significant differences came up on socio demographic and clinical aspects. CONCLUSION: Even though the sample is small, interesting findings came out from our investigation. Our findings are in line with the current literature. Euphoric mood, is one of the aspects which best differentiated BD from BPD. Higher scores in Disorganization, BPRS and PANSS positive symptoms in BD may be related to the fact that our sample is a group of patients from an acute inpatient unit, so the impact of the symptoms severity for BD may be remarkable. PMID- 26417756 TI - Overlapping phenomena of bipolar disorder and epilepsy--a common pharmacological pathway. AB - BACKGROUND: Studies and data on prevalence, recognition and clinical features of bipolar disorder (BD) in epilepsy remain limited. Still, there is a growing evidence of BD and epilepsy being frequent co-morbid conditions with some features suggesting shared pathophysiological mechanisms that include the episodic course of both conditions, the possible kindling mechanism and the efficacy of some antiepileptic drugs (AEDs) in BD. SUBJECTS AND METHODS: The aim of this paper is to review concepts of overlapping phenomena of bipolar disorder and epilepsy. A literature review of the theoretical bases of the relationship between BD and epilepsy is presented. CONCLUSIONS: The comorbidity of epilepsy and mood disorders was a subject of interest of many studies for decades. Bipolar disorder and epilepsy have a number of clinical, biochemical and pathophysiological features in common. Bipolar disorder in epilepsy, excluding the ictal or periictal symptoms, can be categorized using standardized measures. Standardized psychiatric interview procedures based on DSM criteria like SCID-I or MINI provide comprehensive way to diagnose mood disorders in patients with epilepsy. PMID- 26417757 TI - Diffusion-weighted imaging of the brain in bipolar disorder: a case report. AB - BACKGROUND: Some investigations strongly support a role of glial abnormalities in the pathophysiology of bipolar disorder. The degree of white matter axonal and myelination disruption is measured through the rate of water molecule diffusion. High ADC measures correspond to relatively unimpeded water diffusion, while low ADC measures reflect preserved myelinated axons. CASE REPORT: Parietal and occipital areas may be involved in the pathophysiology of bipolar disorder, particularly in cognition and perception, along with the prefrontal and temporal cortices for the disruption of emotional processing. In the literature the widespread alterations of the cortical white matter microstructure is documented. CONCLUSIONS: This case reports demonstrates the features of the increased mean ADC values in the left occipital lobe. Future DWI studies are expected to investigate the correlation of white matter changes with the functional impairment, which often persists during euthymia in bipolar disorder. PMID- 26417758 TI - The Cambridge-Perugia Inventory for assessment of Bipolar Disorder. AB - It is well known that Bipolar Disorder is a condition which is often under diagnosed or misdiagnosed. We propose an inventory of questions which will help assess the longitutinal history of the patient's illness, and to evaluate the presence of mixed affective states, rapid cycling, and comorbidities, all of which have an important bearing on prognosis. PMID- 26417759 TI - Recognising Bipolar Disorders in Primary Care. AB - Bipolar disorder, previously called 'Manic-depression', is a complex group of conditions characterised by recurrent changes in mood and energy. Crucially, the intensity and duration of these changes go beyond normal fluctuations and personality traits. Bipolar Disorder is a mental health disorder, but physical health manifestations (Smith 2013, Westman 2013, Fagiolini 2008, Young 2013) and complications are just as important. GPs have a key role in the recognition and management, in conjunction with secondary care colleagues. Diagnosis is often difficult and may take several years (Smith 2011, Angst 2005, Manning 2010), because patients usually seek help for anxiety, depression or fatigue, not hypomania/mania, which they may not recognise. Individuals with a first episode of mania are more likely to present directly to secondary care, sometimes via a third party alerting the emergency services. There is also debate around the classification, diagnosis and treatment of individuals with brief and milder mood changes ('bipolar spectrum disorder') (Faravelli 2009, Spence 2011). In the UK, the recent NICE Guidelines (2014) 1 only included Bipolar I and Bipolar II for these reasons. A particular challenge for GPs is that whilst most people who have Bipolar Disorder (and especially Bipolar II) are depressed, most people with depression within a Primary Care setting do not have Bipolar Disorder. Thus, a brief pragmatic screen is recommended in Primary care: ask about a family history of Bipolar Disorder and screen for a history of mania/hypomania in individuals with anxiety, depression or irritability, especially if there are recurrent episodes, suicidal thoughts or a previous suicide attempt. For suspected cases, formal diagnosis should not be made within Primary Care but individuals should be referred for Psychiatric assessment, ideally to a Mood Disorders specialist. PMID- 26417760 TI - The comorbidity between bipolar disorder and ADHD in a young adult: a focus on impulsivity. AB - Impulsivity is a complex behavioural feature of many psychiatric disorders, in particular of risk-taking behaviour, and is an important determinant of personality. Both ADHD and bipolar disorder express features of impulsivity. The concept of having two or more simultaneous psychiatric conditions is an increasingly recognised concept in the field of psychiatry, and is important clinically for management and prognosis. Consequently, the aim of this case presentation is to report about a young patient with both bipolar II and ADHD, in order to better understand which of the possible clinical phenotypes of these psychiatric conditions exist in comorbidity, mainly focusing on impulsive features because of the relevant challenge that this psychological aspect can represent in the clinical treatment of these patients. PMID- 26417761 TI - The developmental stages of Bipolar Disorder: a case report. AB - Bipolar disorder is a developing disorder; its early stages are sometimes misdiagnosed as anxiety or depressive disorders. At the same time, these disorders are often in comorbidity with bipolar disorder. This complex symptomatology can lead to misinterpretation and underdiagnosis of bipolar disorders, mainly at the earliest stages. Consequently, one of the most important challenges for clinicians is to recognize the non specific early symptoms with the aid of clinical information, for example a family history of bipolar disorder. Furthermore, it is well-known that comorbid anxiety disorders can lead to a worse prognosis in bipolar patients but it is not exactly clear to what extent. A deeper understanding of the relationship between these comorbidities and their stage of development will hopefully lead to better care of patients with bipolar disorder from a younger age. PMID- 26417762 TI - The Management of Patients with Depression In Primary Care: an Audit Review. AB - AIMS AND METHODS: The IAPT scheme was introduced in 2007 to implement the recommendations from NICE guidelines regarding psychological therapy for depression. This retrospective audit carried out across two General Practice Surgeries evaluates the care being given in relation to the standards of NICE guidelines. RESULTS: Initial audit found variable concordance, however after discussion of this at a local audit meeting and the displaying of posters and leaflets detailing the IAPT scheme this was improved on re-audit. CLINICAL IMPLICATIONS: Training should be provided to General Practitioners regarding the standards of care for patients with low mood or depression. In this training there should be an emphasis on the role of psychological therapy and details given of local resources. Posters and leaflets should be clearly displayed to allow patients to self-refer to IAPT. A close watch must be given to waiting times for the IAPT service as demands increase. PMID- 26417764 TI - Observing the Effects of Mindfulness-Based Meditation on Anxiety and Depression in Chronic Pain Patients. AB - BACKGROUND: People whose chronic pain limits their independence are especially likely to become anxious and depressed. Mindfulness training has shown promise for stress-related disorders. METHODS: Chronic pain patients who complained of anxiety and depression and who scored higher than moderate in Hamilton Depression Rating Scale (HDRS) and Hospital Anxiety and Depression Scale (HADS) as well as moderate in Quality of Life Scale (QOLS) were observed for eight weeks, three days a week for an hour of Mindfulness Meditation training with an hour daily home Mindfulness Meditation practice. Pain was evaluated on study entry and completion, and patients were given the Patients' Global Impression of Change (PGIC) to score at the end of the training program. RESULTS: Forty-seven patients (47) completed the Mindfulness Meditation Training program. Over the year-long observation, patients demonstrated noticeable improvement in depression, anxiety, pain, and global impression of change. CONCLUSION: Chronic pain patients who suffer with anxiety and depression may benefit from incorporating Mindfulness Meditation into their treatment plans. PMID- 26417763 TI - Depression, family and cellular immunity: Influence of family relationships and cellular immunity on the severity of depression. AB - BACKGROUND: Exposure to stress activates the hypothalamic-pituitary-adrenal axis through the release of catecholamines, which modify humoral and cellular immunity. On the one hand, this psycho-immunological theory makes it possible to forge links between immunity and depression. On the other hand, we know that family determinants are an important variable in the model of vulnerability to depression. Our study weighs the influence of cellular immunity and family relations on the severity of depression. SUBJECTS AND METHOD: 498 inpatients with major depressive disorder were enrolled in an open-label trial. In addition to a socio-demographic questionnaire, they completed Olsen's FACES III and the Beck Depression Inventory (BDI). Flow cytometry was used to assess lymphocyte subsets. RESULTS: In terms of immunity, there are correlations between the BDI and percentages of CD3 (p=0.015; r=-0.112), CD4 (p<0.000; r=-0.175), CD4/CD8 (p=0.045; r=-0.093) and CD16 and 56 (p=0.014; r=0.113). In terms of family relationships, there is a correlation between the BDI and family of origin, both for cohesion (p=0.007; r=-0.169) and adaptability (p=0.035; r=-0.133) measures. With respect to the relationship between family dynamics and immunity, there are correlations between adaptability in the family of origin and CD3 (p=0.04; r=0.094) and CD4 (p=0.044; r=0.093). A logistic regression model for family variables explained 11.4% of the BDI, compared to 12.7% for immune variables, while a model including the two explained 16%. CONCLUSIONS: While both the family and immunity can explain the BDI, it is surprising they have a greater effect in combination than individually. This suggests that the psycho-immunological theory should look at the relation between immunity and family life, notably in relation to the family of origin. PMID- 26417765 TI - Socio-economic cultural transformations and Depression in elderly people. AB - The socio-economic and cultural evolution in the last decades encouraged a significant process of transformation of the life conditions in advanced societies, particularly the average duration of the life of the elderly population, which since the second half of the past century has increased by about 60%, becoming from an average of fifty years to about eighty two for women and eighty for men. This phenomenon enables scholars and in particular demography scholars, to assume that in 2030 the number of elderly persons will reach about two billion worldwide. This development of an increasingly longer life expectancy, justifies the trust in the great progress that characterizes our society. The rapid growth of this segment of population, due to the improved living conditions and the related progress in science, technology and medicine, in addition to its positive aspects, also includes negative elements, which already affect the Welfare State and, more generally, the public administration that is called to fill the gaps that the transformation of the family and kinship networks have treated with indifference. The problems of the increasingly long lived, is not freed from new elements of negativity related to the physical and mental decline that leads to the development of new diseases in addition to those already present, ans is increasingly motivated to seek the best remedies to shorten or eliminate the diseases of the elderly. In this context, Depression assumes a central dimension which will surely be a central concern for the economic, social and health impact and for the multitude of changes that put in crisis many of the traditional institutions. This work aims to analyze through a careful review of the scientific literature, the causes of the spread of this disease, the diagnostic difficulties and possible solutions for prevention and care. PMID- 26417766 TI - Evaluation of the level of depression among medical students from Poland, Portugal and Germany. AB - BACKGROUND: Depression is a serious illness affecting health, family and professional life of many people of all sectors of society. It also concerns students, regardless of their geographical location. The Beck Depression Inventory (BDI) is a proper tool to brief check of the level of depression because it has high correlation with depression. The aim of this study was to assess and compare the level of depression among medical students from Poland, Portugal and Germany. SUBJECTS AND METHODS: Students from different countries were asked to fill in an electronic form containing the BDI. The form was created separately for each country, using official translation of the BDI, approved by the competent psychiatric association. Google Drive software was used for the electronic form, and Stat soft Statistica v10 software for statistical analysis. RESULTS: There were statistically significant differences (p<0.05) in terms of average score of the BDI and of the proportion of the scores more than 10 points of medical and technology students among kinds of studies and countries. The average score of the BDI of medical students: Poland: 13.76+/-9.99 points; Germany: 8.49+/-7.64 points; Portugal: 7.37+/-7.67 points. The average score of the BDI of technology students: Poland: 12.42+/-9.66 points; Germany: 10.51+/ 8.49 points; Portugal: 9.25+/-8.97 points. The proportion of the scores more than 10 points of medical students: Poland 56.32% (285/506) Germany 34.92% (154/441) Portugal 26.03% (82/315). The proportion of the scores more than 10 points of technology students: Poland 55.01% (368/669) Germany 43.82% (156/356) Portugal 37.57% (136/362). CONCLUSIONS: The highest depression score among medical and technology students according the BDI was found in Poland. A proper monitoring of depression is required, as well as rapid and appropriate help for those who suffer from it. PMID- 26417767 TI - Evaluation of the utility of Liebowitz Social Anxiety Scale and Barratt Impulsiveness Scale in the diagnosis of social anxiety, impulsivity and depression. AB - BACKGROUND: Often mental disorders are serious problems concerning psychological well-being. They require comprehensive and specialized psychiatric and psychological help, but there are no public methods of controlling your mental state. The aim of study was the evaluation of the utility of Liebowitz Social Anxiety Scale and Barratt Impulsiveness Scale in the diagnosis of social anxiety, impulsivity and depression. SUBJECTS AND METHODS: The study included 85 persons. The study group had 34 patients treated in an open ward of the Department of Psychiatry and Psychotherapy of Medical University of Silesia in Katowice. The control group included 51 persons without mental disorders. Three self-rating questionnaires were used: Beck Depression Inventory, Barratt Impulsiveness Scale and Liebowitz Social Anxiety Scale. Statistica v10 Statsoft software was used for statistical analysis. RESULTS: The analyzed groups had significant differences in terms of Beck Scale (U Mann-Whitney test p=0.000001). Average score in study group: 22.94+/-12.50; in control group: 7.15+/-6.44. Groups had significant differences in terms of Liebowitz Scale (U test Mann-Whitney test, p=0.000164). Average score in the study group: 60.41+/-30.30; in control group: 35.01+/-23.94. Groups had significant differences in terms of Barratt Scale (t-student test p=0.000601). Average in study group: 66.35+/-9,49; in control group: 59.54+/ 7.87. Significant positive correlation was observed between the results of Beck Scale and Liebowitz Scale (r=0.64465). Correlation was not observed between the results of the Liebowitz and Barrat (r=0.12091 and Beck and Barrat (r=0.21482). CONCLUSIONS: The intensity of the Liebowitz Social Anxiety Scale is directly proportional to the severity of depression according to the Beck Depression Inventory. The degree of impulsivity by Barrat Impulsiveness Scale does not correlate with the level of depression according to Beck Depression Inventory. The analyzed scales are relevant in the diagnosis of mental disorders. PMID- 26417768 TI - Symptom Frequency Characteristics of the Hamilton Depression Rating Scale of Major Depressive Disorder in Epilepsy. AB - BACKGROUND: Depressive disorders are common among patients with epilepsy (PWE). The aim of this study was to explore symptom frequencies of 17-item Hamilton Depression Rating Scale (HDRS-17) and recognize the clinical characteristics of Major Depressive Disorder in PWE. SUBJECTS AND METHODS: A sample of 40 adults outpatients with epilepsy and depression was diagnosed using SCID-I for DSM-IV-TR and HDRS-17. The total HDRS-17 score was analysed followed by the exploratory analysis based on the hierarchical model. RESULTS: The frequencies of HDRS-17 items varied widely in this study. Insomnia related items and general somatic symptoms items as well as insomnia and somatic factors exhibited constant and higher frequency. Feeling guilty, suicide, psychomotor retardation and depressed mood showed relatively lower frequencies. Other symptoms had variable frequencies across the study population. CONCLUSIONS: Depressive disorders are common among PWE. In the study group insomnia and somatic symptoms displayed highest values which could represent atypical clinical features of mood disorders in PWE. There is a need for more studies with a use of standardized approach to the problem. PMID- 26417769 TI - Recognising and Treating Depression in the Elderly. AB - INTRODUCTION: Depression is a major contributor to healthcare costs and is projected to be the leading cause of disease burden in middle and higher income countries by the year 2030. Depression in later life is associated with disability, increased mortality, and poorer outcomes from physical illness. Its prevalence remains high throughout lifetime, with almost 14% of older adults living in the community estimated to have clinically relevant symptoms of depression worldwide. DIAGNOSIS: Recognizing depression in the elderly is not always easy. Medical illnesses are a common trigger for depression. TREATMENT: Most depressed people welcome care, concern and support, but they may be frightened and may resist help. The treatment of depression demands patience and perseverance for the patient and physician. Sometimes several different treatments must be tried before full recovery. Each person has individual biological and psychological characteristics that require individualized care. PROGNOSIS: The prognosis for recovery is equal in young and old patients, although remission may take longer to achieve in older patients. FURTHER CARE: Depression is a highly treatable medical condition and is not a normal part of growing older. Therefore, it is crucial to understand and recognize the symptoms of the illness in the primary care. PMID- 26417770 TI - A systematic review of structural and functional MRI differences between psychotic and nonpsychotic depression. AB - BACKGROUND: Psychotic depression is widely accepted as a specific subtype of unipolar major depression. Magnetic resonance imaging studies have begun to investigate the neurobiological changes that differentiate this subtype of major depression from non-psychotic depression. Any differences may eventually be useful in aiding diagnosis patients for whom there is diagnostic uncertainty. This review collates the currently available evidence. SUBJECTS AND METHODS: A systematic search of the Medline, PubMed, Embase & Web of Science databases was used to identify all articles comparing structural grey matter or functional magnetic resonance imaging (MRI) differences between adults (18+) with previously diagnosed psychotic and nonpsychotic depression in predefined regions of interest (hippocampus, amygdala, cingulate, insula & frontal cortices). The results were collated and organised according to brain region. RESULTS: There is a paucity of studies addressing structural and functional changes differentiating these two disorders and recommendations regarding use of these modalities in diagnosis cannot be made. From the available studies decreases in frontal cortex grey matter volumes may differentiate psychotic from non-psychotic depression whilst further studies are required to confirm decreases in insula cortex volumes. fMRI studies show associations between altered activity in these two regions and cognitive impairments in patients with psychotic depression. The volumes of putative emotional processing regions including the amygdala, hippocampus and anterior cingulate show no difference between psychotic and nonpsychotic depression. CONCLUSIONS: Structural and functional changes in the higher associative regions of the frontal and insular cortices appear to differentiate psychotic and nonpsychotic depression to a greater degree than changes in putative emotional processing regions. The quality of the evidence both in terms of numbers of studies available and sample sizes involved is very poor but in regard to directing future study, understanding the neurobiology of psychotic depression may benefit from a more detailed assessment of these two regions. PMID- 26417771 TI - Sociodemographic and clinical features of patients with depressive disorder in Khartoum, Sudan. AB - BACKGROUND: It's known worldwide that depression is becoming a major health problem and its prevalence is increasing. The main objective of this study is to find out the prevalence of depression among patients attending a general psychiatric clinic, and study their sociodemographic and clinical features. METHODS: Files of patients attending a private psychiatric clinic in Khartoum in the period June 2005-June 2010 were reviewed. Only those with a diagnosis of depression were chosen, sociodemographic date and clinical features were documented and results were shown below. RESULTS AND DISCUSSION: Total numbers of patients with depression were 137 (11.4%). Females were more than males (56.2%), the majority are between ages 41-60 (40.9%), married (65%), (14.9%) had family history of psychiatric disorders and (52%) had a previous history of psychiatric treatment. Depressed mood is the commonest symptom (98.5%), loss of interest (91.9%), reduced energy (57%), guilt feelings (17.9%) and (35.8%) of our samples expressed suicidal ideations. The commonest type of somatic symptom is generalized aches and pain (30.7%), (18%) were psychotic. CONCLUSION: The present study is a retrospective descriptive study, based on a private psychiatric clinic sample. It provided a useful baseline for more comprehensive field based studies, to try to aid planning and development of services to meet the needs of the population. PMID- 26417772 TI - Suffering Depression in the Christian Church--One Person's Experience. AB - The author has suffered for several years from Anxiety and depression. Here she describes her experiences, both of depression and of her experience as a person suffering from depression within the Christian Church. PMID- 26417773 TI - Management of primary negative symptoms in schizophrenia: an one-year observational study. AB - Negative symptoms represent a separate symptom domain, with respect to depression, neurocognition, and social cognition and have a strong direct and indirect impact on real-life functioning. Furthermore, negative symptoms that do not improve following antipsychotic treatment are an important diagnostic and therapeutic challenge. We conducted a 12-month-study open-observational study to evaluate the efficacy of some atypical antipsychotics on negative symptoms, according to the following recommendations of Consensus Development Conference Attendees. In our study, we evaluated in an open-label study the efficacy of some second-generation antipsychotics (clozapine, quetiapine, olanzapine, aripiprazole, paliperidone) in 42 patients with schizophrenia or schizoaffective disorder (DSM-5 criteria) with 'persistent negative symptoms'. We used different rating scales (PANSS, CDSs, BNSS, BPRS), but mainly we focused on the new Brief Negative Symptoms Scale (BNSS) for negative symptoms. Our total data indicate an overall statistically significant reduction in all scales, although not clinically relevant. PMID- 26417774 TI - A comparative study between cognitive impairments of adults with schizophrenia and children with psychotic spectrum disorders: a literature review. AB - BACKGROUND: Cognitive impairments have been extensively reported for patients suffering from schizophrenia but a lot of questions persist about these troubles. Several domains of cognitive functions are impaired which result in daily life difficulties. Many arguments tend to show that children suffering from psychotic spectrum disorders present cognitive impairments also but things are not clearly defined. The aim of this review is to compare the cognitive impairments of children suffering from psychotic symptoms and adults suffering from schizophrenia in order to improve the understanding of the two clinical affections. A better understanding of the disease is necessary to improve the health care which currently give poor results. SUBJECTS AND METHODS: Besides the Diagnostic and Statistical Manual (DSM-5) and the French reference books, the present research has been conducted using PubMed, Medline, PsycINFO, PsycARTICLES and ScienceDirect. Literature about cognitive impairments of adults with schizophrenia and children with psychotic spectrum disorders is assessed and results are compared. RESULTS: Both children and adults suffer from cognitive impairments: language, memories, executive and motor functions and IQ are impaired. An important heterogeneity in the troubles has been observed and a poor knowledge in terms of onset time, evolution, intensity, impact on everyday life and therapeutic interest has been reported. CONCLUSION: Adults with schizophrenia and children suffering from psychotic spectrum disorders have similar cognitive impairments in many domains of cognition. The similarities in term of cognitive impairments highlighted in the present work should support new studies in order to adapt to children the current cognitive therapies which are mostly provided to adults. As the cognitive impairments are heterogeneous, each patient should receive a tailored neurocognitive exam which takes into account its abilities and weaknesses. PMID- 26417775 TI - Atypical Antipsychotics for Schizophrenia and/or Bipolar Disorder in Pregnancy: Current Recommendations and Updates in the NICE Guidelines. AB - BACKGROUND: The gold standard pharmacological agents used to treat schizophrenia and bipolar disorder in adults are antipsychotics. Atypical or second-generation antipsychotics have superseded or used as alternatives to typical first generation antipsychotics due to better tolerability and safety profile. However the efficacy and safety of these drugs are severely limited in pregnancy and/or women of childbearing potential. There are very few guidelines to guide the clinical management of schizophrenia and/or bipolar disorder in this subgroup. AIM: We aimed to review current evidence of atypical antipsychotics used in pregnancy where available, with considerations to its efficacy and safety to both the mother and fetus, in conjunction with the recently updated NICE guidelines. METHODS: The latest NICE CG192 guidelines on antenatal and postnatal mental health, published in December 2014 was reviewed and summarized, and the BNF approved list of atypical antipsychotics were identified. Clinically relevant MEDLINE-linked publications were searched and selected where available using the PubMed search engine to identify evidence for or against the use of atypical antipsychotics in pregnancy. RESULTS AND CONCLUSIONS: NICE CG192 improved clarity on the prediction, support and holistic management of mental illness in pregnancy and puerperium; however there were no specific recommendations in terms of pharmacological agents used to treat schizophrenia and/or bipolar disorder in this subgroup. Evidence from the literature on atypical antipsychotics yielded discordant results. Nonetheless, our report presents preliminary findings of certain antipsychotics which appear to be effective and safe in pregnancy. Future research would benefit from larger, prospective randomized controlled trials, and perhaps include newer atypical antipsychotics for consideration in this subgroup. PMID- 26417776 TI - Effects of hormones on cognition in schizophrenic male patients--preliminary results. AB - BACKGROUND: Schizophrenia is a prevalent neurodevelopmental disorder of an unknown etiology and a variable phenotypic expression. In the recent years, the impact of hormones on the course of schizophrenia has been investigated. This study is aimed at assessing the level of correlating serum levels of hormones in schizophrenic male patients with their cognitive functioning measured with neuropsychological tests. SUBJECTS AND METHODS: In the index group there were 15 medicated male schizophrenic patients. In the control group there were 15 age and education matched healthy men. All subjects underwent analysis of serum hormones level (TSH, testosterone, estradiol, FSH, LH, progesterone and prolactin) and a battery of tests (Trail Making Test A and B, Stroop Test, Verbal and Semantic Fluency Test). RESULTS: The mean serum levels of the following hormones were higher in the index group than in the control group: TSH (1.76 mIU/L vs 1.58 mIU/L; p=0.66), progesterone (0.85 ng/ml vs 0.69 ng/ml; p=0.22) and prolactin (558.71 uIU/ml vs 181 uIU/ml; p=0.025). The mean levels of estradiol (24.36 pg/ml vs 25.40 ng/ml; p=0.64), FSH (3.17 mIU/ml vs 5.72 mIU/ml; p=0.019), LH (3.85 mIU/ml vs 5.77 mIU/ml; p=0.056) and testosterone (2.90 ng/ml vs 5.38 ng/ml; p=0.003) were higher in the control group. In the index group there were significant negative correlations between FSH and semantic fluency (rho= 0.678606), progesterone and: TMT B (rho=-0.586763), Stroop 1 (rho=-0.701880) and Stroop 2 (rho=-0.601074) and prolactin and TMT A (rho=-0.579607). CONCLUSIONS: The preliminary results of our study show that serum levels of FSH and testosterone are significantly lower, whereas the level of prolactin is markedly higher, in schizophrenic male patients than in healthy men. There is an inverse correlation between serum levels of progesterone, FSH and prolactin and the results of certain cognitive functioning tests in schizophrenic men. PMID- 26417777 TI - Long term telemedicine study of compliance in paranoid schizophrenia. AB - BACKGROUND: Low compliance is one of the crucial problems of contemporary psychiatry. Relapses, deterioration of cognitive functioning, negative symptoms, neuroleptic resistance are the examples of many consequences of noncompliance in schizophrenia SUBJECTS AND METHODS: The study was designed to assess the compliance in the 200 patients diagnosed with paranoid schizophrenia, all in the state of symptomatic remission and on the stable neuroleptic treatment. The compliance was assessed using a telepsychiatric system, sending reminders: 1 hour before the planned dose to remind them that drug intake is approaching, and at the moment of intake to check if they took the drug. The confirmed drug intakes were counted by the telepsychiatric system. RESULTS: 158 patients completed the study period. The compliance in the first month of the treatment was 44.6% and decreased over the rest of the period to the level of 33.4%. 50% of the schizophrenic patients were compliant at a level lower than 37%. This group was considered the low compliance group, and in this group the compliance increased after 6 months from 9.3% to 10.3% (p<0.0001). CONCLUSIONS: The compliance in the group of schizophrenic patients in remission is very low. The telemedicine system improves the compliance in the patients with the worst compliance. PMID- 26417778 TI - In search of neural mechanisms of mirror neuron dysfunction in schizophrenia: resting state functional connectivity approach. AB - It has been repeatedly shown that schizophrenia patients have immense alterations in goal-directed behaviour, social cognition, and social interactions, cognitive abilities that are presumably driven by the mirror neurons system (MNS). However, the neural bases of these deficits still remain unclear. Along with the task related fMRI and EEG research tapping into the mirror neuron system, the characteristics of the resting state activity in the particular areas that encompass mirror neurons might be of interest as they obviously determine the baseline of the neuronal activity. Using resting state fMRI, we investigated resting state functional connectivity (FC) in four predefined brain structures, ROIs (inferior frontal gyrus, superior parietal lobule, premotor cortex and superior temporal gyrus), known for their mirror neurons activity, in 12 patients with first psychotic episode and 12 matched healthy individuals. As a specific hypothesis, based on the knowledge of the anatomical inputs of thalamus to all preselected ROIs, we have investigated the FC between thalamus and the ROIs. Of all ROIs included, seed-to-voxel connectivity analysis revealed significantly decreased FC only in left posterior superior temporal gyrus (STG) and the areas in visual cortex and cerebellum in patients as compared to controls. Using ROI-to ROI analysis (thalamus and selected ROIs), we have found an increased FC of STG and bilateral thalamus whereas the FC of these areas was decreased in controls. Our results suggest that: (1) schizophrenia patients exhibit FC of STG which corresponds to the previously reported changes of superior temporal gyrus in schizophrenia and might contribute to the disturbances of specific functions, such as emotional processing or spatial awareness; (2) as the thalamus plays a pivotal role in the sensory gating, providing the filtering of the redundant stimulation, the observed hyperconnectivity between the thalami and the STGs in patients with schizophrenia might explain the sequential overload with sensory inputs that leads to the abnormal cognitive processing. PMID- 26417779 TI - How does Schizophrenia occur and can delusions be protective to the person? A bird's eye view attempting to Integrate the Neurobiology and Psychology of Schizophrenia. AB - This short paper is an attempt to integrate what we know about the biological development of schizophrenia. It attempts to integrate Neurodevelomental, Dopamine, Glutamate, Salience and Psychological theories of the development of schizophrenia into a unitary whole, and thus to illustrate how these theories relate together. It is a summary of a much larger work, presently in preparation, done for the purposes of the present coference. It attempts to describe the biological development of schizophrenia, and thence the delusions and hallucinations which play a part in it symptomatically. PMID- 26417780 TI - Suicide and attempted suicide: epidemiological surveillance as a crucial means of a local suicide prevention project in Trento's Province. AB - The World Health Organization identifies suicide among the top 10 causes of death in many countries with an overall mortality rate of 16 per 100,000 inhabitants. Furthermore suicide attempts present a frequency 4-10 times greater than the suicidal events, representing also one of the main risk factors to lead to recurrent attempts of suicide. In 2008 the Autonomous Province of Trento launched a suicide prevention pogram called "Invitation to Life" which includes various interventions intended to counter the phenomenon of suicide in the region. Actually the epidemiological research upon the phenomenon of suicide in Trentino region is one of the main pillars of the project: it represents a fundamental requirement to identify risk and protective factors in the population in order to adopt more specific and effective preventive strategies. This article aims to present methods and instruments for epidemiological monitoring of suicide and attempted suicide which are applied in Trentino and to describe results after seven years from the beginning of the local prevention program "Invitation to life". PMID- 26417781 TI - Personality and psychotic symptoms as predictors of self-harm and attempted suicide. AB - BACKGROUND: Nonfatal suicidal behaviours (NSB), including suicide ideation, suicide plan and suicide attempt, constitute a serious problem for public healthcare services. Suicide gesture (SG) which refers to self-injurious behaviour with no intent to die, differs from NSB in a variety of important ways. The aim of this study was to investigate demographic and clinical characteristics of NSB and SG to examine whether self-injurers with intent to die differ significantly from self injurers without such intent. METHODS: All admissions for NSB and SG to the Psychiatric Inpatient Unit of University / General Hospital Santa Maria della Misericordia, Perugia, Umbria, Italy, from January 2015 to June 2015 were included in a medical record review. Basic descriptive statistics and distributional properties of all variables were first examined. Bivariate analyses were performed using Chi-square tests for group comparisons and t-test for independent samples used when appropriated. RESULTS: The study sample included 38 patients. Of these 23 had committed NSB (13.1%), 15 had commetted SG (8.5%). Number of married NSB was significantly higher than the number of married SG (p=0.08). We found a significant difference between NSB and SG related to the item of impulse control that was poorer in SG than NSB (p=0.010). BPRS items of hostility (p=0.082), suspiciousness (p=0.042) and excitement (p=0.02) were found to be significantly higher in SG than NSB. Borderline personality disorder (p=0.032) and Passive-Aggressive personality disorder (p=0,082) diagnosed by the means of the SCID-II, were more represented in SG than NSB (p=0.044). Schizoid personality disorder was significantly related to NSB (p=0.042). No others significant differences were found. CONCLUSIONS: NSB and SG are different for many psychopathological characteristics. These results confirm the importance of classifying individuals on the basis of the intent to die. Additional research is needed to understand and elucidate psychopatological and clinical characteristics of the different categories of self-injurers to find risk factors specific to suicide attempts. PMID- 26417783 TI - Suicide in adolescence: attempt to cure a crisis, but also the fatal outcome of certain pathologies. AB - BACKGROUND: Teen suicide is an alarming public health issue. The purpose of this paper is to better understand the reasons behind attempting/committing suicide. Our research focuses on adolescent psychopathology and on pathologies that are considered as adolescent suicide risk factors. SUBJECTS AND METHODS: We conducted literature-based research. The first part of this research was based on adolescent psychopathological traits, whilst the second concentrated on the most frequently made diagnoses in the case of adolescents who had attempted suicide. RESULTS: Adolescence is a period of life characterized by great instability, where everything is called into question. We can observe a high propensity towards taking action, which allows the adolescent to bypass certain questions that they cannot answer. This takes place against a background where the body, which is undergoing change, becomes the scene, the means and the purpose to answer these questions, once and for all, through suicide. Notwithstanding, the studies also show that, setting aside these psychopathological considerations that characterize every adolescent, certain diagnoses are commonly related to adolescent suicide and, as such, constitute risk factors. These pathologies are as follows: depression, adjustment disorder and personality disorder. We can, however, include some precisions as regards the frequency of these diagnoses, given that adolescence is inherently a period of life characterized by depression and that the future adult is obliged to adjust. CONCLUSIONS: Teen suicide is, therefore, conditioned by pathological behaviour, which is part of a necessary and normal transition, but one which is occasionally stimulated by certain pathological instabilities. PMID- 26417782 TI - Comparison of assessment and management of suicidal risk for acute psychiatric assessment between two state sponsored hospitals in England and Italy. AB - The risk of suicide is one of the most important risk factors looked into for acute psychiatric assessments that influences the management plan. The prevalence of suicide is on a rise across European countries; as a consequence, the different countries have created specific guidelines and policies in order to prevent suicides in the acute settings. These guidelines are based on both different cultural aspects as well as the different organization of the mental health system in the different countries. This paper wants to present the comparison between the guidelines of two European countries, England and Italy, in order to evaluate the systems, understand differences and common contact points. The different European countries could learn one from the other and a European shared point of view may be a way forward to create better understanding and preventing the risk of suicide across the population. PMID- 26417784 TI - Hormonal and developmental influences on adolescent suicide: a systematic review. AB - BACKGROUND: Teen suicide is a major public health problem. In the United States, it is the third cause of death among the 10-24 year olds. Adolescence involves numerous changes, whether physical, social, emotional or hormonal. At a neurobiological level, a teenager's nervous system is also affected and undergoes significant modifications. SUBJECTS AND METHODS: We conducted a systematic review of electronic literature published between January 1990 and August 2014 via MEDLINE, PubMED and PsychINFO to list articles concerning the risk of teen depression and suicide risks in adolescents as well as those relating to the adolescent's neuro-anatomical brain and the effect that puberty has on it. RESULTS AND DISCUSSION: When analyzing the various studies, it is clear that all support the idea that adolescence is a special period, both at neuroanatomical and biological levels. The risk of impulsiveness and depression is explained, anatomically, by a faster maturation of the limbic system, and biologically, by a higher sensitivity of the serotoninergic system and to glucocorticoids, which themselves are influenced by the specific hormonal environment during this period. Moreover and above all, adolescence is a vulnerable time for many reasons: physical, hormonal, social, cognitive, and emotional changes, self development, etc. We should not restrict it to structural neurological changes without taking into account the other factors or compartmentalize young people into a reductive model based on determinism. CONCLUSIONS: Adolescence is a time of change, transformation, and adaptation. The hormonal events that occur during this period have significant effects on brain development, neuro-cerebral chemistry, adolescent behavior and risks of depression. It is important to try to prevent suicide and depression in adolescents considering its entirety and complexity but also by paying attention to neuro-biological factors even if, at present, many research projects are currently underway to develop an appropriate drug therapy strategy. PMID- 26417786 TI - An economic analysis of different cannabis decriminalization scenarios. AB - BACKGROUND: Cannabis is the most widely used illegal drug in European countries. In countries with repressive cannabis policies, prevalence is not lower than in those with tolerant laws. Repressive policies not only have uncertain benefits but they are also expensive. Economists tend to believe that good public policies minimize social costs; that is, they help to improve collective wellbeing at a lower cost. METHOD: The paper draws on a review of international literature on cannabis legislative models around the world. After a description of some of the fundamental concepts of a market economy, several existing policy scenarios will be presented and analyzed from an economic perspective. Strength and weaknesses will be summarized for each alternative. RESULTS: In addition to consumption tolerance in countries such as the Netherlands, recent decriminalization of domestic markets in the Unites States and Uruguay present alternatives to reduce the negative impact of cannabis on society. Earlier initiation age and rise in consumption are unintended potential consequences of decriminalization that need to be addressed by public authorities when designing a liberalized cannabis policy environment. Price is a key variable that needs to be addressed to prevent a rise in consumption. CONCLUSION: Repressive cannabis policies are expensive and have limited impact on consumption. Consumption legalization significantly reduces expenses for repression and law enforcement, allowing for the allocation of more resources to other targets such as education and prevention. With legalization of supply along with consumption, repression and law enforcement costs are reduced even further. Moreover, a legal market would create employment and generate tax revenues that could be allocated to the prevention of increased consumption. Legalizing cannabis would not lead to a sudden rise in consumption, providing the duty imposed by the state kept the product at its current price. PMID- 26417785 TI - Relaxation and Impact on the Multidimensional Health Locus of Control: Interest of group psychoeducation for stress management in the context of liaison psychiatry within a General Hospital. AB - BACKGROUND: In this article we propose a model for caring for a group focusing on psychoeducation for stress management and learning relaxation designed for patients experiencing somatization and who were recruited during organic medicine consultations. We are developing an interest for this kind of group from a clinical and practical point of view and have sought to demonstrate the impact that this kind of care can have on health representations among these patients through using the MHLC (Multidimensional Health Locus of Control) questionnaire. SUBJECT AND METHODS: Participants in the stress management and relaxation groups completed the questionnaire at the beginning of the first session and at the end of the second and last session. We collected 94 usable questionnaires between January 2008 and December 2014 and processed the data using Student's t-test on paired samples. RESULTS: The results tend to demonstrate that psychoeducation for stress management and relaxation reduces internality scores in patients with high scores and the opposite for patients whose internality scores are low. DISCUSSION: Our research protocol does not enable us to distinguish between the respective influences of the psychoeducation group and the relaxation group. CONCLUSION: The psychoeducation groups for stress management and relaxation have an impact on health representations in patients experiencing somatization who would not have spontaneously sought out psychiatric consultations. PMID- 26417787 TI - Neuropsychiatric Manifestations of Colloid Cysts: a review of the literature. AB - Colloid cysts account for approximately 2% of primary brain tumours and the majority of cases are identified in the fourth and fifth decade. They are small, gelatinous neoplasms lined by a single layer of mucin-secreting columnar epithelium that are thought to arise from errors in folding of the primitive neuroepithelium. They develop in the rostral aspect of the third ventricle in the foramen of Monro in 99% of cases and despite their benign histology carry a poor prognosis, with a mortality greater than 10% in symptomatic cases. The location of colloid cysts within the ventricular system results in obstruction of the foramen of Monro as the cyst grows, disrupting the circulation of cerebrospinal fluid (CSF) and causing hydrocephalus. This is the mechanism behind the most common presenting symptoms of postural headache, nausea and vomiting - a clinical picture synonymous with hydrocephalus and intracranial pathology. In addition to these classical neurological symptoms, there is a high prevalence of psychiatric symptoms in the patient population, with symptoms ranging from anterograde amnesia to gustatory hallucination. These symptoms can occur with or without the presence of hydrocephalus, and are thought to be secondary to compression of connecting pathways between the mesocortices and subcortical limbic regions. These symptoms have been shown to be comparative in frequency to the classical symptoms, yet are rarely the reason for referral to a neurological or neurosurgical service for investigation. PMID- 26417788 TI - Psychiatric caregiver stress: clinical implications of compassion fatigue. AB - The capacity to work productively is a key component of health and emotional well being. People who work in health care can be exposed to the fatigue of care. Compassion fatigue has been described as an occupational hazard specific to clinical work related severe emotional distress. In our study, we have evaluated compassion fatigue in a mental health group (47 psychiatric staff) and its relationship with inpatients (237 inpatients) affected by some psychiatric disorders. At baseline, the more significant data indicate a high percentage of Job Burnout and Compassion Fatigue in psychiatric nurses (respectively, 39.28%, 28.57%). Significant Compassion Fatigue percentage is present also in psychologist group (36.36%). Finally, in psychiatrists, the exposure to patients increased vicarious trauma (28.57%), but not job burnout. After a year of participation in Balint Groups, the psychiatric staff presented an overall reduction in total mean score in any administered scale (CBI: p<0.0000045; sCFs: (Vicarious Trauma: p<0.0288; Job Burnout: p<0.000001)). Thus, compassion fatigue causes concern among mental health professionals, and Balint Groups may represent a therapeutic strategy to help health professionals to face difficulties in challenging work environments. PMID- 26417789 TI - A questionnaire to assess social stigma. AB - Psychiatric patients often suffer for two reasons: due to the illness and due to the social stigma of mental illness, that increases the uneasiness and psychic pain of the person suffering from serious psychiatric disorder. This unwell person is often the object of stigma because he is "different" from others, and he also can be margenalised by society. In this study we intend to assess whether these margenalising attitudes might be also present among mental health professionals who have presented psychic problems in a previous period of their life, against sick persons suffering of the same illness even if he is a mental health professional. Two questionnaires have been developed, one for professionals and another for the patients, with the aim of identifying these marginalising attitudes. We intend that this study shall be a multicenter, observational and international study, promoted by the Mental Health Dept. of Naples (ASL Naples 3 South, Italy). PMID- 26417790 TI - The psychosomatic spectrum: a clinical-analytic survey of the relationship between eating disorders and migraine. AB - OBJECTIVE: To evaluate if somatic symptoms of Eating Disorders and Migraine reflect similar aspects of personality and temperament. METHODS: The clinical notes of 27 migraineurs and of 26 ED outpatients were reviewed; 40 medical students of the University of Perugia were recruited as healthy controls. TCI, DMI, SCID-II and TAS-20 were used. STATISTICAL ANALYSIS: performed by logistic regression, a cluster analysis that gave the weight for the three groups, and a logistic regression of the cluster analysis. RESULTS: Patients showed medium scores in almost all the scales of the different tests. High scores in HA and low scores in NS characterized both migraine and ED patients. Logistic regression of the cluster analysis underscored that ED patients, migraineurs, and controls differed for HA (435.424, p<=0.0001), TAS-20 F2 (difficulty in describing feelings to others; 7.087, p=0.029), and the defense mechanism turning against object (6.702, p=0.035). DISCUSSION: The temperamental aspects of low NS and high HA represent the core symptoms of a spectrum composed of somatizing patients who use affective and behavioral strategies that are not functional enough in affective regulation. PMID- 26417791 TI - Can Violence cause Eating Disorders? AB - The origin and course of eating disorders and nutrition have a multifactorial etiology and should therefore take into consideration: psychological factors, evolutionary, biological and socio-cultural (Juli 2012). Among the psychological factors we will focus on violence (in any form) and in particular on the consequences that they have on women, which vary in severity. Recent studies show that women get sick more than men, both from depression and eating disorders, with a ratio of 2:1; this difference begins in adolescence and continues throughout the course of life (Niolu 2010). The cause of this difference remains unclear. Many studies agree that during adolescence girls have negative feelings more frequently and for a longer duration caused by stressful life events and difficult circumstances, such as abuse or violence. This results in an increased likelihood of developing a symptom that will be connected to eating disorders and/or depression. As far as the role of food is concerned in eating disorders, it has a symbolic significance and offers emotional comfort. Eating means to incorporate and assimilate, and even in an ideal sense, the characteristics of the foods become part of the individual. Feelings that lead to binges with food are normally a result of feelings related to abuse or violence and lead to abnormal behavior which leads to binging and the final result being that the person is left feeling guilty and ashamed. Research confirms that 30% of patients who have been diagnosed with eating disorders, especially bulimia, have a history of sexual abuse during childhood. Ignoring the significance of this factor can result in the unleashing of this disease as the patient uses the disorder as his expressive theater (Mencarelli 2008). Factors that contribute to the possibility of developing an eating disorder are both the age of the patient at the time of the abuse and the duration of the abuse. The psychological effects that follow may include dissociative symptoms and symptoms of an Eating Disorder. PMID- 26417792 TI - Psychiatric disorders associated with Cushing's syndrome. AB - BACKGROUND: Cushing's syndrome is the term used to describe a set of symptoms associated with hypercortisolism, which in most cases is caused by hypophysial microadenoma over-secreting adrenocorticotropic hormone. This endocrine disorder is often associated with psychiatric comorbidities. The most important include mood disorders, psychotic disorders, cognitive dysfunctions and anxiety disorders. SUBJECT AND METHODS: The aim of this article was to review the prevalence, symptoms and consequences of psychiatric disorders in the course of Cushing's syndrome. We therefore performed a literature search using the following keywords: Cushing's syndrome and psychosis, Cushing's syndrome and mental disorders, Cushing's syndrome and depression, Cushing's syndrome and anxiety. RESULTS: The most prevalent psychiatric comorbidity of Cushing's syndrome is depression. Psychiatric manifestations can precede the onset of full blown Cushing's syndrome and therefore be misdiagnosed. Despite the fact that treatment of the underlying endocrine disease in most cases alleviates psychiatric symptoms, the loss of brain volume persists. CONCLUSIONS: It is important to be alert to the symptoms of hypercortisolism in psychiatric patients to avoid misdiagnosis and enable them receiving adequate treatment. PMID- 26417793 TI - "Claw your way"--Machiavellianism among the medical community. AB - BACKGROUND: Machiavellianism is a personality trait characterized by emotional detachment and tendency to manipulate others to achieve one's own goal. It is presumed that people high in Machiavellianism would more likely choose business related occupations, whereas low Machiavellians would prefer helping professions, therefore medical professionals are expected to be low-Machs. SUBJECTS AND METHODS: This is a questionnaire study on 509 respondents: medical school candidates (16.1%), medical students (65%), medical trainees (9.8%), residents (6.3%) and specialists (2.8%) aimed at assessing the level of Machiavellianism, as measured with Mach-IV score, a self-report questionnaire. RESULTS: The overall mean Mach-IV score was 59.24+/-6.07. The highest mean Mach-IV score, 61.80+/ 6.94, was found in the group of medical school candidates. The lowest mean Mach IV score, 57.61+/-7.88, was reported in the group of registered specialists. Male gender was found to be positively correlated with the mean Mach-IV score, which in women was 58.97+/-6.08 and in men it was 60.16+/-6.01. There was a negative correlation between the mean Mach-IV score and the age of post-graduate participants. When we divided all participants into subgroups of "low Machs" (<60 points) and " high Machs" (>=60 points), we found that both subgroups were similarly numerous--49.5% and 50.5%, accordingly. The highest representation of "high Machs" was found in the subgroup of medical studies candidates (65.85%), then in the students (47.73%) and in the group of post-graduates (45.16%). Gender differences remained statistically significant--47.33% of women and 60.18% of men were "high Machs". CONCLUSIONS: Machiavellianism level among medical candidates, students and doctors is relatively high, however is gradually decreasing with the progress of career. PMID- 26417794 TI - Efficacy of LAI in first episode psychosis: an observational study--clinical reports. AB - The use of antipsychotics, especially second generation antipsychotics, represents the milestone treatment of "first episode of psychosis" (FEP). Although prodromal symptoms of psychosis have long been recognized, the clinical management of psychotic disorders conventionally begins at the first episode of frank psychosis, as it is well acknowledged that "duration of untreated psychosis" (DUP) is one of the main factor that negatively affects prognosis: a longer DUP is highly correlated to reduced response to treatment, poor clinical and social outcomes, and an overall worst prognosis. Long-acting injectable (LAI) formulations of antipsychotics have traditionally been used for those patients with psychosis with the most severe symptoms, poorest compliance, most hospitalizations and poorest outcomes; moreover it seems that psychiatrists tend to prescribe LAI at the latter stages of the disease. We retrospectively collected clinical and sociodemographic data regarding patients consecutively presenting with symptoms of FEP attending the Community Mental Health Service (CMHS) in Foggia from 1st June 2014 to 31st May 2015. We selected patients who attended the CMHS in Foggia with symptoms of FEP. Different scales were administered to assess symptoms severity, quality of life, side effects, adherence, and overall functionality. In our sample LAI treatment was found to be effective in treating symptoms associated to FEP, improved quality of life and it was associated with a clinically irrelevant incidence of extrapyramidal side effect. Considering that achieving a full symptoms remission in people affected by FEP is associated to better outcomes, and that DUP is associated to poor prognosis, LAIs could play an important role in improving overall recovery. PMID- 26417795 TI - A National Snapshot of Substance Misuse among Child and Adolescent Psychiatric Inpatients in Malta. AB - This paper reports on a patient record survey that was undertaken with the central aim of establishing reliable, baseline information to inform strategic planning and organisation of future CAMHS in Malta. The records of the total population of children and adolescents admitted into the psychatric hospital over a five year period were surveyed. Results showed that the characteristics and circumstances of children and adolescents with mental disorder and comorbid substance misuse in Malta are similar to those described in international studies. The survey emphasised the pressing need for further research into this sub group and also highlighted gaps in reliable data systems locally. PMID- 26417796 TI - HoNOSCA in an adolescent psychiatric inpatient unit: an exploration of outcome measures. AB - Routine Outcome Measures (ROM) are important tools, increasingly used to assess both patient progress and service-provider efficacy. The Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA) is a clinician- and patient rated ROM which summarises a patient's global functioning within behaviour, impairment, symptoms and social domains. Recent literature suggests that consistent disparity exists between the patients' self-ratings and the clinicians' ratings on HoNOSCA. We analysed HoNOSCA data for our own adolescent inpatient unit and report similar findings. Studies have also shown significant differences in both physical and mental health outcomes based on the patient clinician dynamic and effective communication. We thus investigated the predictive utility of the two HoNOSCA scores, and the disparity between them, with respect to other outcomes measures (CGAS, length of stay and improvement on HoNOSCA). HoNOSCA disparity scores were significantly associated with both patient- and clinician-rated HoNOSCA improvement scores. Moreover, higher admission HoNOSCA scores were associated with greater HoNOSCA improvement scores, for both patient and clinician ratings. We report admission and discharge HoNOSCA scores comparable to other child and adolescent psychiatric inpatient facilities. PMID- 26417797 TI - Personality characteristics of psychotic patients as possible motivating factors for participating in group psychotherapy. AB - BACKGROUND: This study aimed to examine the relationship between some personality characteristics of patients diagnosed with psychotic disorders and the quality of their engagement in psychodynamic group psychotherapy. Given that previous research has shown that self-stigma is significantly negatively associated with the engagement of patients, the measure of self-stigma was used as a correlate of patients' motivation to participate in group psychotherapy. SUBJECTS AND METHODS: A total of 48 outpatients (52.1% women; mean age 35.30 years) attending group psychodynamic psychotherapy completed The Inventory of Personality Organization, The Pathological Narcissism Inventory, The Measure of Parental Style, The Relationship Questionnaire, and The Internalized Stigma of Mental Illness scale. RESULTS: The findings showed that patients with higher levels of self-stigma have unhealthy attachments styles, perceived their mothers' parental style as indifferent and achieved greater scores on narcissistic vulnerability scale. They are also are prone to primitive psychological defences, have poorly integrated identity, and achieved lower scores on reality testing dimension. CONCLUSION: Taking into account the limitations of this study, these findings may contribute to improved understanding of the quality of participation and engagement of psychotic patients in group psychotherapy, and may help to develop more effective therapeutic approaches. PMID- 26417798 TI - The Use of Psychotropic Drug Therapy in Borderline Personality Disorder: a Case Report. AB - It is estimated that around 75% of patients with Borderline Personality Disorder (BPD) are prescribed psychotropic medication during their treatment course, although this is not recommended as first line therapy. In the UK, there are no guidelines to advise which drug treatments to use in BPD, however, numerous, but mostly small scale studies, show evidence that different medications target specific core symptoms. We report a case of a 25 year old woman with BPD, who has received treatment with five different psychotropic medications. We go on to assess not only the efficacy of these treatments in this individual case, but also whether the use of these treatments is in line with best evidence according to currently available research. PMID- 26417799 TI - Training in sleep medicine among European early career psychiatrists: a project from the European Psychiatric Association--Early Career Psychiatrists Committee. AB - INTRODUCTION: Sleep disorders have a proven association with psychiatric illness. Therefore, psychiatrists require appropriate training in diagnosing and treating sleep disorders. To date, there is no data available in Europe on training in sleep medicine for early career psychiatrists (ECP). AIMS: To identify the availability of training in sleep medicine for psychiatric trainees across Europe and to establish how confident doctors feel in treating these conditions. METHODS: European-wide survey carried out by the European Psychiatric Association (EPA)-Early Career Psychiatrists Committees. Representatives of ECPs from each participating European country filled in a questionnaire about availability of training in sleep medicine in their country. ECPs were also invited to fill out a questionnaire at the EPA congress in Nice in 2013. RESULTS: 55 participants from 27 European countries responded. Only 24% had sleep medicine training mandatorily included in their national training curriculum. A majority (60%) felt that the quality of the training they received was either average or below average. 88% felt either very or fairly confident in treating insomnia. However, when asked to select the correct management options for insomnia from a provided list of six, only 19% and 33% of respondents chose the two correct options. CONCLUSIONS: There is a clear gap between the level of confidence and the clinical judgements being made to treat insomnia among European ECPs. There is a definite need to improve the availability and structure of sleep medicine training for psychiatric trainees in Europe. PMID- 26417800 TI - Telepsychiatry in Polish patients' and doctors' opinion. AB - BACKGROUND: Telepsychiatry is a new method of medical care, using modern communication technologies and electronic informations. It consists of web pages, containing data about diseases and their treatment in the form of multimedia libraries with video- and audiobooks. This research concerns verification of knowledge and attitude to telepsychiatry amongst patients and psychiatrists. SUBJECTS AND METHODS: An anonymous survey was conducted amongst 105 psychiatrists aged 26-74, including 74 women and 31 men and 102 patients aged 21-79, including 61 women and 41 men. RESULTS: Research reveals that majority of patients never met with the concept of 'telepsychiatry' and do not know what it means. However, more than 50% of respondents answered positively to every question considering the utility of telepsychiatry. Furthermore according to 18% it is possible to replace eye-to-eye conversation by videoconferencing. Only 15% of doctors claim to have an extensive knowledge on telepsychiatry, and 10% do not know what it means. The vast majority of physicians perceive positive aspects of this method of medical care, but 63% would not want general insertion of telepsychiatry. Doctors are apprehensive of losing personal data and medical confidentiality, and of the necessity of legal changes as well. CONCLUSION: The obtained results allow us to conclude that Polish patients and doctors, regardless of their knowledge, age, gender or disease, perceive advantages of telepsychiatry. In connection with this, implementing this method into the Polish medical market makes sense and is in accordance with both patients' and doctors' opinion. Based on our research, we confirmed that there is a necessity of wider popularization of telepsychiatry in Polish therapeutics. PMID- 26417801 TI - Genetic of addiction: common and uncommon factors. AB - Epidemiological studies strongly suggest that genetic factors operate at all steps of addictions, including vulnerability to initiation, continued use, and propensity to become dependent. Several studies have been popular to investigate the relative contributions of genetic and environmental factors, including the availability of and exposure to a substance, and shared and unique environments. The genetic influence on addiction has proved to be substantial, and heritabilities for most addictive disorders are moderate to high. In this work we evaluate the current status of data that analyzed genetic contribution in addictions. PMID- 26417802 TI - Neurofeedback application in the treatment of autistic spectrum disorders (ASD). AB - The aim of this paper is to describe neurofeedback (NFB) treatment in Autistic spectrum disorder (ASD) children. There is no specific cure for autism and therapeutic guidelines are directed to improve the quality of life of people with autism by reducing the symptoms and by increasing their functioning. Neurofeedback is a computerized method based on tracking electrical activity of the brain (EEG) and giving a feedback about it. The method has been developed in neurophysiological labs of scientific institutes in USA and has been used very successfully for over last 20 years. It has proven its efficacy in practise, but also in scientific and clinical research. During 2010 and 2011 neurofeedback treatment was administered to 10 children (N=10, 7 males and 3 females) age range 4 to 7 years which have been diagnosed as autistic spectrum disorder (highly functional) with an unspecific impairment of speech development and trouble communicating. An evaluation of treatment was done according to estimation of changes in functioning (parents, teachers and therapists' ratings and all other experts that were monitoring the child before, during and after the treatment) and tracking of changes in electrophysiology. The results have shown most changes in behaviour (less aggressive, more cooperation, better communication), attention span and sensory motor skills. According to the assessment of parents, teachers, therapists and other experts all children have accomplished a certain degree of improvement in the level of daily functioning. Our experiences in usage of neurofeedback in Autistic spectrum disorder (ASD) children confirmed previous data that this method can be applied to this category of patients. PMID- 26417803 TI - Analisys of the therapeutic factors in the Therapeutic Community Podsused among the war related diagnosis and the others. AB - Therapeutic community/TC/ is a sociotherapeutic method that uses sociotherapeutic and psychotherapeutic techniques for various mental disorders. In Croatia, during and after the war many war veterans have been in treatment through TC and many of them still participate in it. Majority of them were diagnosed with PTSD diagnosis, but some of them also had other diagnosis, e.g. depression, paranoid delusion, etc. In this paper we describe principles of TC that we use in Croatia and we also try to find out which curative factors of TC are the most important for this population. We applied semistructured intervju based on Yalom book of practice and theory of psychotherapy to explore what factors do war veterans find the most important and relevant for their resilience and better coping with everyday issues. PMID- 26417804 TI - Development of vocational training systems for patients with intellectual disability in Poland. AB - BACKGROUND: The problem of employment of people with intellectual disabilities is present in many countries. The literature on this topic draws attention to the fact that the improvement of the situation in this area is conditioned by changes in government policies, practices of employers and adequate preparation to undertake professional duties by persons with intellectual disabilities. OBJECTIVE: The objective of this review was to explore the changes in vocational rehabilitation forms in Poland. RESULTS: As one of the ways to solve this problem since 1991 in Poland the so called Workshops of Vocational Therapy have been created. According to the regulations the Workshops were designed for adults with intellectual disabilities, aged over 16 years with a total incapacity of gaining an employment, for which occupational therapy was a form of social rehabilitation. The further step in this process was the establishment of Vocational Activation Centers, with which high hopes were associated. They were expected to be an intermediate link in the creation of career paths from rehabilitation forms ultimately to open labor market. In practice it turned out that the creation of these Centers in Poland has been too slow. CONCLUSIONS: This raised the necessity to change the attitude from the concept of matching the participant to work and to the new environment, which frequently ends as a trauma, to the concept of matching jobs to people. New initiatives and new rehabilitation programs are developed based on this attitude. PMID- 26417805 TI - Audit of memory clinic practice against CCG guidelines: West Suffolk Hospital. AB - INTRODUCTION: The memory service based in the West Suffolk has received increased funding to deliver a high quality service against standards set by the Clinical Commissioning Group (CCG). AIMS: This audit aims to examine if we are achieving the standards set by the local CCG and to identify areas to improve the quality of the service.We also aimed to assess information as to how many patients referred had dementia. If they had a dementia suitable for possible anti-dementia medication (such as dementia of Alzheimer's type, Alzheimer's mixed type or atypical or Lewy body/ Parkinson's dementia) to ascertain if they were being offered anti-dementia medication. METHODS: Retrospective analysis of 60 patients from the memory service were analysed. The first 10 patients referred in alternative months were selected for inclusion. Standards were based on targets set by the CCG in terms of time needed to assess, diagnose, communicate diagnosis to the GP and give post diagnostic advice. RESULTS: Patients in this memory service were being seen 37 days (on average) after referral. Most patients received a diagnosis at their initial assessment but some needed further investigation to establish the diagnosis or the specific type of diagnosis. The time for letters to be typed did not meet standards and letters were sent out on average 23 days after patients were being seen. Post diagnostic advice was delivered to most who received a diagnosis. CONCLUSIONS: Our service is offering timely diagnosis to those referred to the memory service in line with national guidelines. PMID- 26417806 TI - Psychogenic speech disorder--a case report. AB - BACKGROUND: Conversion (dissociative) disorder is a psychiatric disorder in which somatic symptoms or deficits are present in the absence of a definable organic cause. The etiology of this disorder is not yet fully understood. The most characteristic presentations are: pseudosensory syndromes, pseudoseizures, psychogenic movement disorders and pseudoparalysis. Psychogenic speech disorder is a rare form of conversion (dissociative) disorder. The aim of present case study is to complete the knowledge on this subject. SUBJECT AND METHODS: The article presents a case of a fifty year old woman who developed psychogenic disorder of speech after being degraded to a lower position at work. After excluding organic background of observed symptoms, the diagnosis of conversion (dissociative) disorder was stated and adequate therapy was implemented, within the capabilities of the Ward. RESULTS: Partial remission of presented symptoms was achieved as a result of psychopharmacotherapy and psychotherapy. CONCLUSIONS: Before stating the diagnosis of conversion (dissociative) disorder, possible somatic causes of the observed symptoms should be excluded. Special attention should be drawn to the importance of studying the psychological and family context of this case and the patient's difficulty to understand and accept that produced symptoms might be triggered by a psychogenic factor. PMID- 26417807 TI - Mental state and its psychophysical conditions in patients with acute leukaemia treated with bone marrow transplantation. AB - BACKGROUND: Acute leukaemia and bone marrow transplantation (BMT) as a method of its treatment are great psychological stressors, which are responsible for anxiety and depression in the group of patients. The aim of the study was to assess the patients' mental state and its psychophysical predictors before and after BMT. SUBJECT AND METHOD: The study was of a longitudinal and self descriptive character. The questionnaires: LOT-R, AIS, Mini-Mac, CECS, RSCL and HADS were filled by 60 patients with acute leukaemia before and after BMT. RESULTS: There were no essential statistical differences between the severity of anxiety and depression before and after BMT but the pattern and the power of various mental state predictors changed in the course of the hospitalization. Anxiety before transplantation was greater when the psychological stress and the strategy of "anxious preoccupation" were stronger and the strategy of "fighting spirit" and the level of generalized optimism were weaker. The factors explained 51% variations of anxiety before transplantation. After BMT 77% variations of anxiety were explained, which were associated with a high level of distress at the end of the hospitalization, higher level of anxiety before transplantation, weaker strategy of "fighting spirit" before transplantation and stronger strategy of "anxious preoccupation" after BMT. Before transplantation 36% variations of depression were explained and estimated as weaker "fighting spirit" and worse "global life quality". The essential predictors of depressive symptoms after transplantation, explained by 81% variations of depression, were weaker "fighting spirit" before transplantation, stronger "anxious preoccupation" after transplantation, worse "global life quality" after transplantation and higher level of anxious and depressive symptoms on admission to hospital. CONCLUSION: The psychological and pharmacological interventions, which reduce anxiety, depression and "anxious preoccupation" as well as enhance "fighting spirit", should be introduced before BMT to improve the patients' mental state. PMID- 26417808 TI - What evidence is there to show which antipsychotics are more diabetogenic than others? AB - BACKGROUND: The use of antipsychotic therapy has been proven to have an association with the incidence of diabetes mellitus. The use of atypical antipsychotics is shown to have a higher association, in contrast with typical antipsychotics. Olanzapine and Clozapine appear to have the highest rates of diabetes mellitus incidence, due to their tendency to affect glucose metabolism compared with other antipsychotic drugs. In this research the main goal is to understand which antipsychotic drugs are the most diabetogenic and to show the mechanisms involved in the glucose metabolism dysregulations with special focus on Olanzapine considering it is a very commonly prescribed and used drug especially among patients with schizophrenia. METHODS: Our study is a literature based research. For our research we reviewed 41 Pubmed published articles from 2005 to 2015. CONCLUSION: According to most of the literature, from all the antipsychotics, Clozapine followed by Olanzapine appear to be the atypical neuroleptics that most relate to metabolic syndrome and Diabetes. The basis for this metabolic dysregulations appears to be multifactorial in origin and a result of the drugs, environment and genes interaction. PMID- 26417809 TI - Critical Analysis of Psychiatrists' Opinion in GP Referral letter. AB - BACKGROUND: Primary and secondary care communication is the cornerstone of patient's care. Proper dialogue should be established. The shared care protocol was an attempt to try to fill gaps and build bridges. METHODS: A special form was designed to collect information about psychiatrists' opinion on GPs' referral letter to psychiatric services. It contained 14 items, each item was marked as essential, can be included or irrelevant. This form was sent electronically to psychiatrists in South Essex University NHS Trust. They are 98 in total. It was inputted on Excel data sheet and was analysed. RESULTS: 44 psychiatrists responded. All respondents agreed that reason for referral is essential. Concise description of the condition, risks and current medication were rated as essential in more than 90%. Past medical history, past psychiatric history and current physical health were essential in 79%. DISCUSSION: All professionals involved should participate in evaluating and refining communication. Psychiatrists' opinion in GPs letters is paramount as they are the recipients and their assessments and future management plan should be geared to address the GP's concerns. This is shown clearly by the psychiatrists agreeing that reason for referral should be included in all letters, followed by what the GP has already done and what risks the patient presents. CONCLUSION: Improving communication between health professionals, improves patient's care, saves time and money, and in addition prevents duplication of investigation and procedures. PMID- 26417810 TI - A Completed Cycle Audit of Psychiatric Discharge Summaries. AB - BACKGROUND: Patients discharge summaries are important as they record a vital miles stone in patients' care. Their accurate record improves patients' care and clarifies communication between different health professionals. METHODS: 60 Discharge summaries from different consultant psychiatrists' case load were audited. The results were analysed and presented with recommendations to improve them a format was suggested. A reaudit of 62 discharge summaries was carried out by the same team after three years in the same catchment area but the practice has changed to inpatient and community. RESULTS: Improvement in most of the areas audited occur in the reaudit which indicates the usefulness of audit in improving clinical practice which a pivotal part of clinical governance. DISCUSSION: This completed audit cycle has proven that clinical practice has been reviewed and methods of improving it have been implemented. It has been noted that more items were reviewed and added to the second cycle which should be condoned. CONCLUSION: Discharge summaries are important clinical documents in secondary and primary care communications. They are helpful for secondary care staff as they good references for people in out of hours services and Accident and Emergency. Good quality discharge summaries improve patients care and make it easy to manage clinical risk. PMID- 26417811 TI - Modern indications for the use of opipramol. AB - Opipramol is considered as a pharmacological agent that does not fit the classification taking into account the division of antidepressants, antipsychotics and anxiolytics. It has a structure related to tricyclic antidepressants but it has a different mechanism of action, i.e. binding to sigma1 and to sigma2 sites. It has been regarded as an effective drug in general anxiety disorders together with other agents like SSRI's, SNRI's, buspirone and pregabalin for many years. It can however also be indicated in other conditions, e.g. it may be used as a premedication in the evening prior to surgery, positive results are also observed in psychopharmacological treatment with opipramol in somatoform disorders, symptoms of depression can be significantly reduced in the climacteric syndrome. The latest data from literature present also certain dangers and side effects, which may result due to opipramol administration. Mania may be induced not only in bipolar patients treated with opipramol, but it can be an adverse drug reaction in generalized anxiety disorder. This analysis shows however that opipramol is an important drug still very useful in different clinical conditions. PMID- 26417812 TI - The Prevalence of Body Dysmorphic Disorder in Patients Undergoing Cosmetic Surgery: a Systematic Review. AB - Body dysmorphic disorder (BDD) is a somatoform disorder characterised by a distressing obsession with an imagined or slight appearance defect, which can significantly impair normal day-to-day functioning. Patients with BDD often first present, and are hence diagnosed, in cosmetic surgery settings. Several studies have investigated the prevalence rate of BDD in the general population or have done so for patients referring to cosmetic medical centers. To date, however, no review has been undertaken to compare the prevalence in the general community versus in a cosmetic surgery setting. Despite the lack of such a review it is a commonly held belief that BDD is more common in patients seeking cosmetic surgery. The current study aims to review the available literature in order to investigate whether BDD is indeed more prevalent in patients requesting cosmetic surgery, and if that is the case, to provide possible reasons for the difference in prevalence. In addition this review provides evidence on the effectiveness of cosmetic surgery as a treatment of BDD. PMID- 26417813 TI - Cortisol as an indicator of hypothalmic-pitituary-adrenal axis dysregulation in patients with panic disorder: a literature review. AB - Dysregulation of hypothalamic-pituitary-adrenal axis (HPA) is seen in numerous mental disorders. Data of HPA axis disturbance in panic disorder are inconsistent. In panic disorder HPA axis hyperactivity has been observed with elevated cortisol levels. However, hypocortisolism has also been noted. Salivary cortisol as a biomarker of HPA-axis activity has received special attention. The aim of this paper is to review the findings on cortisol levels in panic disorder. PMID- 26417814 TI - Impulsivity in anxiety disorders. A critical review. AB - BACKGROUND: Anxiety symptoms and disorders are common. High comorbidity between anxiety and other psychiatric disorders has been observed in community. Still, the relationship between impulsivity and anxiety disorders is controversial and not well explored. MATERIAL AND METHODS: The aim of this paper is to review measures of trait impulsivity in anxiety disorders. A literature review of the theoretical bases of the relationship between anxiety disorders and impulsivity is presented. RESULTS: Impulsivity is a key feature of numerous psychiatric disorders. Traditional conceptualizations suggest that impulsivity might display a negative relationship with anxiety. However, an association of impulsivity in patients with anxiety disorders is present. Some studies support proposition that anxiety may influence impulsivity in individuals with predisposition toward behavioural disinhibition. CONCLUSION: There is a link between anxiety and impulsivity in psychiatric patients characterized by problems with impulse control (e.g. pathological gambling, self-harming behaviour, eating disorders), mood disorders and anxiety disorders. Behavioural and pharmacological interventions for decreasing impulsivity may effectively be used in the treatment. PMID- 26417815 TI - Impulsivity and Panic Disorder: an exploratory study of psychometric correlates. AB - BACKGROUND: Impulsivity is associated with a wide variety of psychiatric disorders. However, the relationship between anxiety and impulsivity is not well explored. The objective of this study was to examine whether anxiety symptoms correlate with impulsivity in patients with panic disorder. SUBJECTS AND METHODS: We examined 21 psychotropic drug-naove patients with panic disorder recruited from the outpatient setting. The severity of Panic Disorder was assessed with Panic and Agoraphobia Scale (PAS)-clinical rating version. Impulsivity was evaluated with Barratt Impulsiveness Scale, 11th version (BIS-11). RESULTS: Our findings indicate the correlation between specific dimensions of impulsivity and selected subscales of Panic and Agoraphobia Scale. The positive correlation between attentional and non-planning dimensions of impulsivity, 'disability' and 'worries about health' in drug-naove patients with PD was observed. CONCLUSIONS: The findings corroborate with the prior reports of higher impulsivity trait among patients with anxiety disorders. PMID- 26417816 TI - Rapid-onset agranulocytosis in a patient treated with clozapine and lamotrigine. AB - BACKGROUND: Clozapine is the treatment of choice in drug-resistant schizophrenia. Lamotrigine is a mood stabiliser recommended as combined treatment strategy in clozapine-resistant patients. There are cases of late-onset agranulocytosis reported in literature. Some are associated with clozapine or lamotrigine, others with the combination of both. CASE REPORT: The article presents a case of rapid onset agranulocytosis in a 60-year old clozapine-resistant patient, in whom lamotrigine was introduced as potentiation strategy. Discontinuation of both substances and GCSF treatment resulted in normalization of the absolute neutrophil count. CONCLUSIONS: The case suggests a possibility of developing rapid-onset agranulocytosis in clozapine-resistant patients who require lamotrigine as augmentation strategy. This emphasises the significance of monitoring a patient's blood count and early management of any dyscrasias noticed. PMID- 26417817 TI - Psychological distress and social factors in patients with asthma and chronic obstructive lung disease. AB - Chronic respiratory diseases which embrace asthma and chronic obstructive pulmonary disease (COPD) are common in the population. In a large number of cases they are diagnosed very late. Statistics of deaths, especially in the case of COPD, are underestimated because morbidity and mortality can be affected by other comorbid conditions, for example cardiovascular disease. Asthma and COPD impair not only physical functioning of patients but also affect their psychological state. Mood disorders and cognitive function impairment are more often observed in this group than in the general population. It has been proven that the coexistence of psychological dysfunction significantly worsens the functioning of patients (affects, among others, their work, family and social lives) and has an impact on the course of the treatment of the somatic illness. First of all, patients with cognitive deficits have greater problems in applying treatment recommendations. Accordingly, it seems to be important to pay more attention to the problem of mental disorders in patients with obstructive lung diseases. There is a clear need for a multidisciplinary approach that will enable prevention, early detection and effective treatment of the psychological disorders in that group of patients. PMID- 26417818 TI - Need for a Comprehensive Sex and Relationship Education Programme for Adults with Learning Disability. AB - INTRODUCTION: Most people with learning disabilities (PWLD) have little understanding of the concept of sex and relationship. PWLD are vulnerable and more likely to be victims of sexual offending. Currently, the only formal access to sex and relationship education that PWLD have is in special need schools. BACKGROUND: The right to express their sexuality is frequently restricted or denied by restricted policies, negative attitudes and lack of awareness of their needs. AIMS: To provide a Comprehensive Sex and Relationship Education programme for PWLD. METHODOLOGY: These group/individual sessions will led by a sexuality support worker with experience in working with PWLD. They will be supported by members of the multidisciplinary team including, psychiatrist, psychologist, occupational therapists etc. CONCLUSION: Providing sex and relationship education PWLD would help them achieve a fulfilling and rewarding sexual experience and make them less vulnerable to sexual abuse. There should be greater emphasis to be placed on sex and relationship education in PWLD; preferably by qualified professionals. PMID- 26417819 TI - Medical Record Documentation in a Learning Disability In-patient Unit. AB - INTRODUCTION: Consistency in clinical structure and content is an important aspect of clinical practice. The rising demands on healthcare systems and associated costs require a much more efficient and transparent means of recording and accessing reliable clinical information in order to manage and deliver good quality care to patients. AIMS: The audit has been completed with an aim to highlight the local standards set for medical record documentation and to assess if the outlined standards are being met in a learning disability in-patient psychiatric setting, the Coppice. METHODOLOGY: Criteria based on GMC Good Medical practice guidelines (2013), RCPsych Good Psychiatric Practice (2009) and Records Management Policy. CONCLUSIONS: Good practice was maintained for most parameters. Mild inaccuracies were noted with date of birth/ward name, timing and signatures. RECOMMENDATIONS: This was presented locally and measures put in place to address the gaps. A re-audit should be performed within a year in order to complete the audit cycle and to ensure that the recommendations and action plan have been followed through. PMID- 26417821 TI - How can we make the current UK psychiatric training scheme truly trainee centred? AB - INTRODUCTION: UK Psychiatric training is popular worldwide and IMG from throughout the world come to UK. Psychiatric training has undergone significant changes but this has not reflected in the outcomes. There is a need to refocus on trainee centred teaching principles. CURRENT PSYCHIATRIC TRAINING: Current training scheme started in 2007 as run-through programme spanning six years. Till 2005, examinations decided the progression of trainees through the training scheme with development of Work Place Based Assessments. Following Tooke's report, training was uncoupled and examinations regained importance in deciding the progress of trainees to higher training. FACTORS AFFECTING PSYCHIATRIC TRAINING: EWTD, budget cuts, service priorities lead to a sense of lack of importance among trainees. Surveys focussing on clinical supervision pointed to the inadequacy and poor quality of supervision. Training has lost trainee centeredness. It is important to make the training maximally effective to deliver safer services. Trainees are major work forces and the future consultants who lead and manage services. CONCLUSION: Student centred teaching is a highly skilled educational process. Adapting these principles into psychiatric training could help trainees learn successfully. PMID- 26417822 TI - Evaluation of a Specialised Counselling Service for Perinatal Bereavement. AB - OBJECTIVES: We aimed to evaluate the outcomes of Petals: a charitable organisation in Cambridgeshire. Petals provides counselling for women and couples who have suffered perinatal bereavement, or trauma during pregnancy or birth. This paper attempts to evaluate the effect of counseling interventions at this difficult time. METHODS: Outcomes were recorded in 107 patients using the CORE (Clinical Outcomes in Routine Evaluation) system. CORE was developed to assess the effectiveness of psychological therapies. CORE-OM (CORE Outcome Measure) involves a questionnaire that assesses subjective well-being, symptoms/problems, function, and risk to self and others. The CORE-OM questionnaire was completed before and after the counselling sessions. RESULTS: The CORE-OM scores were summated into a global representation of severity. Severity decreased in all patients. Symptoms of psychological pathology were also decreased in all cases. CONCLUSION: Offering a free specialised counselling for parents suffering perinatal loss seems to be associated with an improvement in psychological outcomes. It is possible that it is more effective among a clinical population. However, we are uncertain of the natural history of the psychological problems this group of clients are experiencing. Having a control group would show how much of any natural improvement is due to the therapy; conversely, it is possible that without intervention these problems worsen with time, so a control group could actually amplify the effect. PMID- 26417820 TI - Pro Re Nata (PRN) prescription in an Inpatient Low Secure Learning Disability Unit. AB - INTRODUCTION: Pro Re Nata (PRN) prescribing in psychiatry is a common and valuable facility to be used in acutely distressed patients. It is open to misuse and PRN prescribing may be unnecessary/inappropriate. AIM: The aim of the audit is to ensure safe and effective prescription of PRN medication. AUDIT STANDARDS: The standards were set in congruence with the guidance from the local trust policy. METHODOLOGY: All of the inpatient records at Wood Lea clinic were studied over a 2 month period. CONCLUSIONS: Most of the standards against which the clinical notes were assessed gave evidence of good medical practice. Patient demographics demonstrated a 100% record of the NHS number but the patient's name and ward fell short. RECOMMENDATIONS: This was presented locally and measures put in place to address gaps. Re-audit should be performed within a year in order to complete the audit cycle and to ensure that recommendations/action plan have been followed through. PMID- 26417823 TI - Should measurement of cognition be part of recovery programs for patients with Psychotic Illness? AB - The recovery model of schizophrenia is central to the devlopment of community services for patients with schizophrenia. However often when applying the recovery model of psychosis, often formal identification of cognitive imparements is not carried out, nor are interventions to improve cognitive functioning offered in a targeted way. Here we discuss how these issues relate to each other and argue for the use of cognitive testing in order to elp recovery in schizophrenia. PMID- 26417824 TI - A review of the evidence for the use of metformin in the treatment of metabolic syndrome caused by antipsychotics. AB - BACKGROUND: Psychiatric patients requiring therapy with antipsychotics have a greater incidence of becoming overweight or obese compared with the general population. Many of these patients are often treated with second-generation (atypical) antipsychotics (SGAs), which are associated with weight gain, dyslipidaemia, and other metabolic derangements. The most important and first line of treatment for the metabolic syndrome is lifestyle changes including diet and exercise. However, other approaches like the use of medication (e.g. Metformin) have been also used, mainly when the lifestyle changes are difficult to achieve. Therefore, the treatment of antipsychotic-induced weight gain with metformin may be an option after the lifestyle and dietary changes fail. The use of metformin is still experimental and off license regarding the treatment of metabolic syndrome in Psychiatric patients, however we wished to assess the evidence for its use. METHODS: Our study is a literature based research. For our research we reviewed 12 Pubmed published articles from 2006 to 2013. CONCLUSION: Metformin have been reported to counteract effectively antipsychotic-induced body weight gain and has been demonstrated to improve glycaemic control and promote a moderate weight loss in both diabetic and non-diabetic subjects. Metformin use appears to be a benefit when started early in the course of treatment and mostly in young adults newly exposed to antipsychotic drugs. PMID- 26417825 TI - Factors influencing the levels of work engagement in physicians from Poland, Serbia and Bulgaria. AB - INTRODUCTION: Lowered work engagement and burnout are a growing problem in recent years, especially among physicians. Cynicism, lack of energy and decreased efficacy may lead to the occurrence of severe depression. These phenomena influence almost every aspect of affected person's life, both professional and extraprofessional, and decrease its quality. The aim of our study was to evaluate the influence of family life and other factors on levels of work engagement and risk of depression. MATERIALS AND METHODS: Our study was conducted on a group of 417 physicians from Poland, Serbia and Bulgaria using a paper questionnaire. The collected data was subjected to statistical analyses using Statsoft Statistica v. 10.0 software. RESULTS: There was no significant correlation between work engagement and sex or age. The highest score on work engagement was in Serbia (m=4.41; Mann-Whitney's U test with p<0.05). The highest score of BDI was in Bulgaria (m=14.73; Mann-Whitney's U test with p<0.05). There was no significant correlation exceeding r=0.5 between UWES and SWING scales. WHI+/WHI- ratio correlates significantly with a BDI scale (Spearman's r=-0.49; p<0.05). CONCLUSIONS: Family life of physicians seem to have minor or even no influence on their work engagement and risk of burnout. The negative influence of work on family life may increase the risk of depression, and that effect is not susceptible to either positive or negative interactions of family life with work. The country with the lowest expenditure on a healthcare have also the lowest levels of work engagement. PMID- 26417826 TI - PROMISE. Beyond frontiers. AB - The concepts underlying the PROMISE initiative are described. This initiative to implement more humane healthcare is now developing from a local initiativein Cambridge to a global movement. PMID- 26417827 TI - Teenage pregnancy: a psychopathological risk for mothers and babies? AB - INTRODUCTION: Teen pregnancy remains a public health problem of varying importance in developing and developed countries. There are risks and consequences for teen parents and the child on the medical and socioeconomic level. METHOD: We conducted a literature search on multiple databases, focusing on the risk and the consequences of teen pregnancy and childbearing. We used different combined keywords as teen pregnancy, teen mother, teenage parents, teenage childbearing, teenage mother depression. Our search included different type of journals to have access on different views (medical, psychological, epidemiologic). RESULTS: The teen mothers are more at risk for postnatal depression, school dropout and bad socioeconomic status. The babies and children are more at risk for prematurity and low birthweight and later for developmental delays and behavior disorders. CONCLUSIONS: Pregnancy in adolescence should be supported in an interdisciplinary way (gynecologist, psychologist, child psychiatrist, midwives, pediatrician). We need further studies that allow targeting patients most at risk and personalizing maximum support. PMID- 26417828 TI - Hypothalamus-Pituitary-Adrenal Axis, Hair Cortisol and the Metabolic Syndrome. AB - In this paper we discuss the possibility of using Hair Cortisol in Clinical Practice to monitor HPA status in patents at risk of developing the Metabolic Syndrome, and also its possible use to assess effectiveness of the effectiveness of treatment in patients with the Metabolic Syndrome. PMID- 26417829 TI - Palliative Care in Dementia. AB - The Dementias are common neurodegenerative diseases which gradually deteriorate and eventually become fatal. However, hospice care is usually made available to patients suffering from Cancer, while patients who suffer from other chronic conditions such as dementia are not usually offered such care. However the lessons which have been learnt regarding hospice palliative care could be applied with some modification to the care of patients with Dementia. This article attempts to discuss the present literature about palliative care in Dementia, in order to clarify the evidence which underlies the European Association for Palliative Care 'White paper defining optimal palliative care in older people with dementia'. PMID- 26417830 TI - Views from GP and Psychiatric trainees about getting experience in each other's specialty during training: A way to develop a shared culture? AB - The need to deliver holistic medical care that addresses both physical and mental health requirements has never been more important. The UK medical training system has been designed to provide all medical graduates with a broad experience of different medical specialities and psychiatry prior to entering specialist training. Furthermore there is a distinct crossover between Psychiatric and General Practice training, with programmes providing trainees with the opportunity to work alongside each other in the care of mental health patients. The video presentation will explain the UK medical training system in more detail, before going on to explore how the organisation of training may foster a shared culture among different specialities and how it could form a model for improving parity of esteem of medical and physical health care. In addition it will discuss the strengths and weaknesses of this system from a trainee perspective and will conclude with comments from eminent Psychiatrists whom have special interests in medical training and developingparity of mental and physical health care. PMID- 26417831 TI - 'Dar Kenn Ghal Sahhtek'--an eating disorder and obesity service in Malta. AB - This paper will describe the incidence of eating disorders, with particular focus on obesity and binge eating, within the Island of Malta. The development of and 'Dar Kenn Ghal Sahhtek', the first centre for eating disorders in Malta will then be recounted, and the effective therapeutic interventions provided in it will be described. One important function of this unit is the treatment of excessive obesity. Some epidemiological data on the Obese Patients in DKS, relating to the incidence of Binge Eating Disorder in the DKS patient group will be given. This data was collected during a collaboritive research project between the Psychiatry Department of Cambridge University and 'Dar Kenn Ghal Sahhtek'. PMID- 26417832 TI - Transcranial magnetic stimulation (TMS) in Attention Deficit Hyperactivity Disorder (ADHD). AB - Attention Deficit Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder, which affects children as well as adults and leads to significant impairment in educational, social and occupational functioning and has associated personal and societal costs. Whilst there are effective medications (mostly stimulants) as well as some psychobehavioural treatments that help alleviate symptoms of ADHD, there is still need to improve our understanding of its neurobiology as well as explore other treatment options. Transcranial Magnetic Stimulation (TMS) and repetitive transcranial magnetic stimulation (rTMS) are safe and non-invasive investigative and therapeutic tools respectively. In this short article, I will explore their potential for improving our understanding of the neurobiology of ADHD as well consider its as a possible treatment option. PMID- 26417833 TI - The girl who would not sit--case report. AB - A 21 year old girl presented with severe fear of contamination leading to 11 hours of cleaning per day and refusal to sit down anywhere except at home or in mother's car. She also had a moderate depressive episode secondary to social stressors and further isolation due to her lack of time to socialize as cleaning was her priority. She was supported according to the biopsychosocial model of care i.e. An antidepressant (Sertraline), 1:1 psychology and alternative housing away from precipitating and perpetuating stressors. She improved significantly over 6 months, but the cultural issues and stigma continued to hinder the longer term care plans. The importance of understanding the beliefs and customs of the Travellers' community is highlighted with this case report. PMID- 26417834 TI - Why hasn't studying perception in autism spectrum disorders helped us create a cognitive model? AB - There are a number of cognitive models of autism that aim to explain how mental processes are handled differently in the condition. These models make claims about the nature of cognitive function in people with autism, and suggest that these differences applied in social contexts lead to the characteristic behavioural patterns. However, it is difficult to study these cognitive differences directly because of the complexity of social situations. Studies of perceptual function are tempting as an alternative way to study cognition because it is far easier to control the conditions and the stimuli that participants are exposed to. This makes hypothesis generation and interpretation of results more objective and more convincing. However, the study of perception in autism hasn't been very productive in contributing towards a model of cognition in autism. In many areas there are studies reporting contradictory results, preventing arrival at a consensus about the largest unresolved issues in the area. These studies tend to be repeated multiple times, but continue to provide contradictory evidence that doesn't allow us to place confidence in any of the cognitive models. An approach to these issues is proposed, focusing on critical analysis of contradictory studies rather than the endless process of repetition. This allows previous studies to be interpreted more objectively and resolve conflicts, and guides the design of future studies in ways that avoid the pitfalls that have been identified. Both of these outcomes result in more productive work being done. The first example is in the study of motion perception in autism, where the use of non-identical stimuli has been problematic. On closer critical analysis, a fundamental aspect of the motion stimuli demonstrates that the contradictions might be expected based on the differences in stimuli used. Addressing this issue can move the field towards resolution. A second example is in the study of spatial frequency sensitivity. Here, poor study design has created results leading to an "eagle-eyed visual acuity" hypothesis of autism. Errors in the initial study are revealed, suggesting that the model should be abandoned. Finally, a general issue is the assumption of homogeneity of perceptual ability and genetics in autism, where the reality is that subgroups exist within the population of people with autism, and significant variation exists between them. The evidence for this is summarised and the issues that it creates explored. PMID- 26417835 TI - Effect of natriuretic peptides on cerebral artery blood flow in healthy volunteers. AB - The natriuretic peptides (NPs), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), have vasoactive functions that concern humans and most animals, but their specific effects on cerebral circulation are poorly understood. We therefore examined the responsiveness of cerebral arteries to different doses of the natriuretic peptides in animals and humans. We conducted a dose-response experiment in guinea pigs (in vitro) and a double-blind, three-way cross-over study in healthy volunteers (in vivo). In the animal experiment, we administered cumulative doses of NPs to pre-contracted segments of cerebral arteries. In the main study, six healthy volunteers were randomly allocated to receive two intravenous doses of ANP, BNP or CNP, respectively, over 20 min on three separate study days. We recorded blood flow velocity in the middle cerebral artery (VMCA) by transcranial Doppler. In addition, we measured temporal and radial artery diameters, headache response and plasma concentrations of the NPs. In guinea pigs, ANP and BNP but not CNP showed significant dose-dependent relaxation of cerebral arteries. In healthy humans, NP infusion had no effect on mean VMCA, and we found no difference in hemodynamic responses between the NPs. Furthermore, natriuretic peptides did not affect temporal and radial artery diameters or induce headache. In conclusion, natriuretic peptides in physiological and pharmacological doses do not affect blood flow velocity in the middle cerebral artery or dilate extracerebral arteries in healthy volunteers. PMID- 26417836 TI - Signal peptide-CUB-EGF domain-containing protein 1 (SCUBE1) levels in patients with overt and subclinical hyperthyroidism: effects of treatment. AB - BACKGROUND AND OBJECTIVES: Signal peptide-CUB-EGF domain-containing protein 1 (SCUBE1) has been shown to increase in parallel with platelet activation in acute ischaemic and thrombotic diseases. There has been no study evaluating SCUBE1 levels in patients with overt hyperthyroidism (OHyper) and subclinical hyperthyroidism (SHyper), conditions which are known to show impairment of both endothelial and platelet function. This study sought to evaluate SCUBE1 concentrations in patients with SHyper and OHyper, and assessed the effects of antithyroid drug (ATD) therapy on circulating SCUBE1 levels. DESIGN AND METHODS: Forty-five untreated patients with OHyper, 20 untreated patients with SHyper and 30 age- and sex-matched healthy controls were prospectively included in the study. Biochemical and hormonal parameters were evaluated in all patients before and after treatment. RESULTS: Compared with the control subjects, SCUBE1 levels were significantly increased in patients with SHyper and OHyper (P < 0.0001 and P = 0.002, respectively). SCUBE1 levels were not significantly different in patients with OHyper compared with patients with SHyper. There was no significant correlation between serum thyroid hormones and SCUBE1 levels. Plasma SCUBE1 levels decreased significantly in both OHyper and SHyper after ATD treatment (P < 0.05). CONCLUSIONS: Increased SCUBE1 levels in both SHyper and OHyper patients may reflect increased platelet activation and possible endothelial dysfunction, which might augment the risk for atherosclerotic and atherothrombotic complications. SCUBE1 may be used as a reliable marker of endothelial damage in hyperthyroidism, especially in the subclinical period. PMID- 26417837 TI - Intramolecular Conjugate Ene Reaction of gamma-Difluoromethyl- and gamma Trifluoromethyl-alpha,beta-Unsaturated gamma-Butyrolactones. AB - A general synthetic strategy to cis-fused bicyclic gamma-butyrolactones via the retro-Diels-Alder reaction/intramolecular conjugate ene cascade (RDA/ICE) reaction under the flash-vacuum pyrolysis of maleic anhydride adducts is developed. The reaction gave high yields of products with high stereoselectivity. The existence of the difluoromethyl or trifluoromethyl group at the gamma position of the in situ-generated homoalkenyl- or homoalkynyl-alpha,beta unsaturated gamma-butyrolactones was found to accelerate the rate of the intramolecular conjugate ene reaction leading to gamma-difluoromethylated and gamma-trifluoromethylated cis-fused bicyclic gamma-butyrolactones. PMID- 26417838 TI - Erratum: Theoretical analysis of excited states and energy transfer mechanism in conjugated dendrimers. PMID- 26417840 TI - Accuracy of plasma interleukin-18 and adiponectin concentrations in predicting metabolic syndrome and cardiometabolic disease risk in middle-age Brazilian men. AB - The aims of this cross-sectional study were to explore the ability of serum interleukin 18 (IL-18) and adiponectin to identify metabolic syndrome (MetS), and to verify their association with an index of central lipid overaccumulation (lipid accumulation product (LAP)) and cardiometabolic risk factors in a population of middle-aged Brazilian men. A group of 218 apparently healthy middle aged Brazilian men (age, 50.3 +/- 4.97 years) underwent anthropometric, clinical, sociodemographic, and standard serum biochemical assessments. LAP was calculated and the study participants were categorized into 3 groups according to serum IL 18 and adiponectin cut-points tertiles to verify the association of these biomarkers with cardiometabolic risk factors. The MetS group had more less active (p = 0.03) and obese (p < 0.01) individuals who exhibited higher IL-18 (p < 0.01) and lower adiponectin (p < 0.01) than did those in the group with no MetS. After adjustments (age, smoking, alcohol consumption, physical activity level, and total body fat), serum IL-18 >= 336.4 pg/mL was an independent factor for MetS occurrence and it was directly associated with LAP (>=51.28), central obesity, hypertriglyceridemia, and hypertension (p < 0.05), but not with high-density lipoprotein cholesterol (HDL-C). Serum adiponectin >= 7.02 MUg/mL was negatively associated with MetS occurrence, LAP, hypertriglyceridemia, and low HDL-C (p < 0.05), but not with central obesity and hypertension. In conclusion, both IL-18 and adiponectin demonstrated the ability to identify MetS in this population, with IL-18 being more accurate. The association of these biomamarkers with LAP and cardiometabolic risk factors highlights its relevance as a diagnostic tool. PMID- 26417841 TI - Predicted 10-year risk of cardiovascular disease among Canadian adults using modified Framingham Risk Score in association with dietary intake. AB - Initial risk assessment to estimate 10-year risk of cardiovascular disease (CVD) is completed by Framingham Risk Score (FRS). In 2012 2 modifications were added to FRS by the Canadian Cardiovascular Society: FRS is doubled in subjects aged 30 59 years who have CVD present in a first-degree relative before 55 years of age for men and 65 years of age for women; and cardiovascular age is calculated for each individual. Our aim was to implement these modifications and evaluate differences compared with traditional FRS. Further, we evaluated the association between dietary intake and 10-year risk. The Canadian Health Measures Survey data cycle 1 was used among participants aged 30-74 years (n = 2730). Descriptive and logistic regression analyses were conducted using STATA SE 11. Using modified FRS for predicting 10-year risk of CVD significantly increased the estimated risk compared with the traditional approach, 8.66% +/- 0.35% versus 6.06% +/- 0.18%, respectively. Greater impact was observed with the "cardiovascular age" modification in men versus women. The distribution of Canadians in low- (<10%) and high-risk (>=20%) categories of CVD show a significant difference between modified and traditional FRS: 67.4% versus 79.6% (low risk) and 13.7% versus 4.5% (high risk), respectively. The odds of having risk >=10% was significantly greater in low-educated, abdominally obese individuals or those with lower consumption of breakfast cereal and fruit and vegetable and greater potato and potato products consumption. In conclusion, the traditional FRS method significantly underestimates CVD risk in Canadians; thus, applying modified FRS is beneficial for screening. Additionally, fibre consumption from fruit and vegetable or breakfast cereals might be beneficial in reducing CVD risks. PMID- 26417842 TI - How does the VPD response of isohydric and anisohydric plants depend on leaf surface particles? AB - Atmospheric vapour pressure deficit (VPD) is the driving force for plant transpiration. Plants have different strategies to respond to this 'atmospheric drought'. Deposited aerosols on leaf surfaces can interact with plant water relations and may influence VPD response. We studied transpiration and water use efficiency of pine, beech and sunflower by measuring sap flow, gas exchange and carbon isotopes, thereby addressing different time scales of plant/atmosphere interaction. Plants were grown (i) outdoors under rainfall exclusion (OD) and in ventilated greenhouses with (ii) ambient air (AA) or (iii) filtered air (FA), the latter containing <1% ambient aerosol concentrations. In addition, some AA plants were sprayed once with 25 mM salt solution of (NH4 )2 SO4 or NaNO3 . Carbon isotope values (delta(13) C) became more negative in the presence of more particles; more negative for AA compared to FA sunflower and more negative for OD Scots pine compared to other growth environments. FA beech had less negative delta(13) C than AA, OD and NaNO3 -treated beech. Anisohydric beech showed linearly increasing sap flow with increasing VPD. The slopes doubled for (NH4 )2 SO4 - and tripled for NaNO3 -sprayed beech compared to control seedlings, indicating decreased ability to resist atmospheric demand. In contrast, isohydric pine showed constant transpiration rates with increasing VPD, independent of growth environment and spray, likely caused by decreasing gs with increasing VPD. Generally, NaNO3 spray had stronger effects on water relations than (NH4 )2 SO4 spray. The results strongly support the role of leaf surface particles as an environmental factor affecting plant water use. Hygroscopic and chaotropic properties of leaf surface particles determine their ability to form wicks across stomata. Such wicks enhance unproductive water loss of anisohydric plant species and decrease CO2 uptake of isohydric plants. They become more relevant with increasing number of fine particles and increasing VPD and are thus related to air pollution and climate change. Wicks cause a deviation from the analogy between CO2 and water pathways through stomata, bringing some principal assumptions of gas exchange theory into question. PMID- 26417843 TI - A shift in paradigm towards human biology-based systems for cholestatic-liver diseases. AB - Cholestatic-liver diseases (CLDs) arise from diverse causes ranging from genetic factors to drug-induced cholestasis. The so-called diseases of civilization (obesity, diabetes, metabolic disorders, non-alcoholic liver disease, cardiovascular diseases, etc.) are intricately implicated in liver and gall bladder diseases. Although CLDs have been extensively studied, there seem to be important gaps in the understanding of human disease. Despite the fact that many animal models exist and substantial clinical data are available, translation of this knowledge towards therapy has been disappointingly limited. Recent advances in liver cell culture such as in vivo-like 3D cultivation of human primary hepatic cells, human induced pluripotent stem cell-derived hepatocytes; and cutting-edge analytical techniques such as 'omics' technologies and high-content screenings could play a decisive role in deeper mechanistic understanding of CLDs. This Topical Review proposes a roadmap to human biology-based research using omics technologies providing quantitative information on mechanisms in an adverse outcome/disease pathway framework. With modern sensitive tools, a shift in paradigm in human disease research seems timely and even inevitable to overcome species barriers in translation. PMID- 26417844 TI - Prevalence of hypertriglyceridemic waist and association with risk of type 2 diabetes mellitus: a meta-analysis. AB - INTRODUCTION: A meta-analysis of studies assessing the prevalence of hypertriglyceridemic waist and an association with risk of type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: PubMed, EMBASE, Web of Science, CNKI, CQVIP and Wanfang databases were searched for studies of the prevalence of hypertriglyceridemic waist or association with risk of T2DM. Reference lists of each original article were also searched. A random-effects model was used to synthesize the combined prevalence and odds ratios. Publication bias and substantial heterogeneity were examined. RESULTS: Twenty-five eligible studies involving 93 194 participants (93 194 for prevalence and 34 199 for odds ratios): 17 articles of prevalence, and 8 of both prevalence and risk of T2DM. Prevalence of hypertriglyceridemic waist ranged from 4% to 47%, with pooled prevalence of 18% (95% CI 13-23%), overall: 18% (95% CI 13-23%) for men and 19% (95% CI 13-24%) for women. Odds ratios ranged from 2.8 to 9.6 for T2MD in overall, with pooled odds ratios of 4.18 (95% CI 3.55-4.92), overall: 3.55 (95% CI 2.93-4.31) for men and 4.18 (95% CI 3.43-5.09) for women. DISCUSSION/CONCLUSION: The prevalence of hypertriglyceridemic waist has reached an alarming level and is closely associated with increased risk of T2DM in the general population, particularly among women and among brown-skinned men and women. PMID- 26417845 TI - Managing synchronous liver metastases from colorectal cancer: a multidisciplinary international consensus. AB - An international panel of multidisciplinary experts convened to develop recommendations for managing patients with colorectal cancer (CRC) and synchronous liver metastases (CRCLM). A modified Delphi method was used. CRCLM is defined as liver metastases detected at or before diagnosis of the primary CRC. Early and late metachronous metastases are defined as those detected ?12months and >12months after surgery, respectively. To provide information on potential curability, use of high-quality contrast-enhanced computed tomography (CT) before chemotherapy is recommended. Magnetic resonance imaging is increasingly being used preoperatively to aid detection of subcentimetric metastases, and alongside CT in difficult situations. To evaluate operability, radiology should provide information on: nodule size and number, segmental localization and relationship with major vessels, response after neoadjuvant chemotherapy, non-tumoral liver condition and anticipated remnant liver volume. Pathological evaluation should assess response to preoperative chemotherapy for both the primary tumour and metastases, and provide information on the tumour, margin size and micrometastases. Although the treatment strategy depends on the clinical scenario, the consensus was for chemotherapy before surgery in most cases. When the primary CRC is asymptomatic, liver surgery may be performed first (reverse approach). When CRCLM are unresectable, the goal of preoperative chemotherapy is to downsize tumours to allow resection. Hepatic resection should not be denied to patients with stable disease after optimal chemotherapy, provided an adequate liver remnant with inflow and outflow preservation remains. All patients with synchronous CRCLM should be evaluated by a hepatobiliary multidisciplinary team. PMID- 26417846 TI - Investigation of the cingulate cortex in idiopathic generalized epilepsy. AB - OBJECTIVE: Studies using quantitative neuroimaging have shown subtle abnormalities in patients with idiopathic generalized epilepsy (IGE). These findings have several locations, but the midline parasagittal structures are most commonly implicated. The cingulate cortex is related and may be involved. The objective of the current investigation was to perform a comprehensive analysis of the cingulate cortex using multiple quantitative structural neuroimaging techniques. METHODS: Thirty-two patients (18 women, 30 +/- 10 years) and 36 controls (18 women, 32 +/- 11 years) were imaged by 3 Tesla magnetic resonance imaging (MRI). A volumetric three-dimensional (3D) sequence was acquired and used for this investigation. Regions-of-interest were selected and voxel-based morphometry (VBM) analyses compared the cingulate cortex of the two groups using Statistical Parametric Mapping (SPM8) and VBM8 software. Cortical analyses of the cingulate gyrus was performed using Freesurfer. Images were submitted to automatic processing using built-in routines and recommendations. Structural parameters were extracted for individual analyses, and comparisons between groups were restricted to the cingulate gyrus. Finally, shape analyses was performed on the anterior rostral, anterior caudal, posterior, and isthmus cingulate using spherical harmonic description (SPHARM). RESULTS: VBM analyses of cingulate gyrus showed areas of gray matter atrophy, mainly in the anterior cingulate gyrus (972 mm(3) ) and the isthmus (168 mm(3) ). Individual analyses of the cingulate cortex were similar between patients with IGE and controls. Surface-based comparisons revealed abnormalities located mainly in the posterior cingulate cortex (718.12 mm(2) ). Shape analyses demonstrated a predominance of anterior and posterior cingulate abnormalities. SIGNIFICANCE: This study suggests that patients with IGE have structural abnormalities in the cingulate gyrus mainly localized at the anterior and posterior portions. This finding is subtle and variable among patients. PMID- 26417848 TI - Effects of baffle configuration and tank size on spherical agglomerates of dimethyl fumarate in a common stirred tank. AB - To pave the way for technology transfer and scale up of the spherical agglomeration (SA) process for dimethyl fumarate, effects of the US, European and Kawashima type baffles and 0.5, 2.0 and 10 L-sized common stirred tank were studied. It was found that the particle size distribution varied significantly. However, the size-related properties such as dissolution profile and flowability of agglomerates from the same size cut after sieving could remain unchanged. The interior structure-related properties such as particle density and mechanical property of agglomerates upon baffle change and scale up from the same size cut were decayed and the agglomerates could become denser and stronger by prolonged maturation time. To maintain the same size distribution, agglomerates from any batch could have been separated and classified by sieving and then blended back together artificially by the desired weight% of each cut. PMID- 26417849 TI - Preparation and evaluation of lipid polymer nanoparticles for eradicating H. pylori biofilm and impairing antibacterial resistance in vitro. AB - The resistance of Helicobacter pylori to classical antimicrobial treatment has become increasingly common, whereupon biofilms are considered to play an important role in the resistance mechanism. Here 10.2% of amoxicillin (AMX) and a novel anti H. pylori adhesion material pectin sulfate (PECS) loaded lipid polymer nanoparticles (LPN) were prepared, with rhamnolipid and phospholipids as the outer mixed lipids layer (RHL-PC-LPN). The size of RHL-PC-LPN was around 200 nm, was negatively-charged, and showed sustained and complete drug release within 24h. In an in vitro study, H. pylori biofilm models were successfully established. RHL-PC-LPN, superior to PC-LPN (employing phospholipids only as the outer lipid layer), PECS+AMX (mixture of PECS and AMX) and AMX only, was proven to significantly eradicate H. pylori in the biofilm form. In accordance to our previous results, the RHL-PC-LPN group, together with the PC-LPN and PECS+AMX group, inhibited H. pylori from adhering to AGS cells. Investigating the underlying mechanisms contributing to the death of H. pylori caused by RHL-PC LPN, we found that LPN could lower the antibiotic minimal inhibition concentration (MIC) to biofilm form from 125 MUg/ml to 15.6 MUg/ml. Furthermore, FITC-ConA labeled extracellular polymeric substances (EPS) were decreased in the RHL-PC-LPN group observed by a laser scanning confocal microscope. Therefore, we conclude that employing the mixed lipids of rhamnolipid and phospholipids as the outer layer of nanoparticles and PECS as the inner core produces a system capable of significantly disrupting H. pylori biofilm by eliminating the EPS as well as inhibiting the adherence and colonization of bacteria. PMID- 26417847 TI - Spatiotemporal patterns of cortical fiber density in developing infants, and their relationship with cortical thickness. AB - The intrinsic relationship between the convoluted cortical folding and the underlying complex whiter matter fiber connections has received increasing attention in current neuroscience studies. Recently, the axonal pushing hypothesis of cortical folding has been proposed to explain the finding that the axonal fibers (derived from diffusion tensor images) connecting to gyri are significantly denser than those connecting to sulci in both adult human and non human primate brains. However, it is still unclear about the spatiotemporal patterns of the fiber density on the cortical surface of the developing infant brains from birth to 2 years of age, which is the most dynamic phase of postnatal brain development. In this paper, for the first time, we systemically characterized the spatial distributions and longitudinal developmental trajectories of the cortical fiber density in the first 2 postnatal years, via joint analysis of longitudinal structural and diffusion tensor imaging from 33 healthy infants. We found that the cortical fiber density increases dramatically in the first year and then keeps relatively stable in the second year. Moreover, we revealed that the cortical fiber density on gyral regions was significantly higher at 0, 1, and 2 years of age than that on sulcal regions in the frontal, temporal, and parietal lobes. Meanwhile, the cortical fiber density was strongly positively correlated with cortical thickness at several three-hinge junction regions of gyri. These results significantly advanced our understanding of the intrinsic relationship between the cortical folding, cortical thickness and axonal wiring during early postnatal stages. PMID- 26417850 TI - Atomic-level characterization of transport cycle thermodynamics in the glycerol-3 phosphate:phosphate antiporter. AB - Membrane transporters actively translocate their substrate by undergoing large scale structural transitions between inward- (IF) and outward-facing (OF) states ('alternating-access' mechanism). Despite extensive structural studies, atomic level mechanistic details of such structural transitions, and as importantly, their coupling to chemical events supplying the energy, remain amongst the most elusive aspects of the function of these proteins. Here we present a quantitative, atomic-level description of the functional thermodynamic cycle for the glycerol-3-phosphate:phosphate antiporter GlpT by using a novel approach in reconstructing the free energy landscape governing the IF<->OF transition along a cyclic transition pathway involving both apo and substrate-bound states. Our results provide a fully atomic description of the complete transport process, offering a structural model for the alternating-access mechanism and substantiating the close coupling between global structural transitions and local chemical events. PMID- 26417851 TI - Provision and consumption of alcohol-based hand rubs in European hospitals. AB - Hand hygiene is considered to be the most effective way of preventing microbial transmission and healthcare-associated infections. The use of alcohol-based hand rubs (AHRs) is the reference standard for effective hand hygiene. AHR consumption is a valuable surrogate parameter for hand hygiene performance, and it can be easily tracked in the healthcare setting. AHR availability at the point of care ensures access to optimal agents, and makes hand hygiene easier by overcoming barriers such as lack of AHRs or inconvenient dispenser locations. Data on AHR consumption and availability at the point of care in European hospitals were obtained as part of the Prevention of Hospital Infections by Intervention and Training (PROHIBIT) study, a framework 7 project funded by the European Commission. Data on AHR consumption were provided by 232 hospitals, and showed median usage of 21 mL (interquartile range (IQR) 9-37 mL) per patient-day (PD) at the hospital level, 66 mL/PD (IQR 33-103 mL/PD) at the intensive-care unit (ICU) level, and 13 mL/PD (IQR 6-25 mL/PD) at the non-ICU level. Consumption varied by country and hospital type. Most ICUs (86%) had AHRs available at 76-100% of points of care, but only approximately two-thirds (65%) of non-ICUs did. The availability of wall-mounted and bed-mounted AHR dispensers was significantly associated with AHR consumption in both ICUs and non-ICUs. The data show that further improvement in hand hygiene behaviour is needed in Europe. To what extent factors at the national, hospital and ward levels influence AHR consumption must be explored further. PMID- 26417852 TI - Association between activities related to routes of infection and clinical manifestations of melioidosis. AB - We sought associations between route of infection by Burkholderia pseudomallei and clinical manifestations in 330 cases of melioidosis in northeast Thailand using bivariate multivariable logistic regression models. Activities related to skin inoculation were negatively associated with bacteraemia, activities related to ingestion were associated with bacteraemia, and activities related to inhalation were associated with pneumonia. Our study suggests that route of infection is one of the factors related to clinical manifestations of melioidosis. PMID- 26417853 TI - Cluster of Fusarium solani isolations in a Bronchoscopy Unit. PMID- 26417854 TI - Pentoxifylline for intermittent claudication. AB - BACKGROUND: Intermittent claudication (IC) is a symptom of peripheral arterial disease (PAD) and is associated with high morbidity and mortality. Pentoxifylline, one of many drugs used to treat IC, acts by decreasing blood viscosity, improving erythrocyte flexibility and promoting microcirculatory flow and tissue oxygen concentration. Many studies have evaluated the efficacy of pentoxifylline in treating individuals with PAD, but results of these studies are variable. This is an update of a review first published in 2012. OBJECTIVES: To determine the efficacy of pentoxifylline in improving the walking capacity (i.e. pain-free walking distance and total (absolute, maximum) walking distance) of individuals with stable intermittent claudication, Fontaine stage II. SEARCH METHODS: For this update, the Cochrane Vascular Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2015) and the Cochrane Register of Studies (2015, Issue 3). SELECTION CRITERIA: All double-blind, randomised controlled trials (RCTs) comparing pentoxifylline versus placebo or any other pharmacological intervention in patients with IC Fontaine stage II. DATA COLLECTION AND ANALYSIS: Two review authors separately assessed included studies,. matched data and resolved disagreements by discussion. Review authors assessed the methodological quality of studies by using the Cochrane 'Risk of bias' tool and collected results related to pain-free walking distance (PFWD) and total walking distance (TWD). Comparison of studies was based on duration and dose of pentoxifylline. MAIN RESULTS: We included in this review 24 studies with 3377 participants. Seventeen studies compared pentoxifylline versus placebo. In the seven remaining studies, pentoxifylline was compared with flunarizine (one study), aspirin (one study), Gingko biloba extract (one study), nylidrin hydrochloride (one study), prostaglandin E1 (two studies) and buflomedil and nifedipine (one study). The quality of the evidence was generally low, with large variability in reported findings.. Most included studies did not report on random sequence generation and allocation concealment, did not provide adequate information to allow selective reporting to be judged and did not report blinding of assessors. Heterogeneity between included studies was considerable with regards to multiple variables, including duration of treatment, dose of pentoxifylline, baseline walking distance and participant characteristics; therefore, pooled analysis was not possible.Of 17 studies comparing pentoxifylline with placebo, 14 reported TWD and 11 reported PFWD; the difference in percentage improvement in TWD for pentoxifylline over placebo ranged from 1.2% to 155.9%, and in PFWD from -33.8% to 73.9%. Testing the statistical significance of these results generally was not possible because data were insufficient. Most included studies suggested improvement in PFWD and TWD for pentoxifylline over placebo and other treatments, but the statistical and clinical significance of findings from individual trials is unclear. Pentoxifylline generally was well tolerated; the most commonly reported side effects consisted of gastrointestinal symptoms such as nausea. AUTHORS' CONCLUSIONS: Given the generally poor quality of published studies and the large degree of heterogeneity evident in interventions and in results, the overall benefit of pentoxifylline for patients with Fontaine class II intermittent claudication remains uncertain. Pentoxifylline was shown to be generally well tolerated.Based on total available evidence, high-quality data are currently insufficient to reveal the benefits of pentoxifylline for intermittent claudication. PMID- 26417855 TI - Fertility and early pregnancy outcomes after conservative treatment for cervical intraepithelial neoplasia. AB - BACKGROUND: Cervical intra-epithelial neoplasia (CIN) typically occurs in young women of reproductive age. Although several studies have reported the impact that cervical conservative treatment may have on obstetric outcomes, there is much less evidence for fertility and early pregnancy outcomes. OBJECTIVES: To assess the effect of cervical treatment for CIN (excisional or ablative) on fertility and early pregnancy outcomes. SEARCH METHODS: We searched in January 2015 the following databases: the Cochrane Gynaecological Cancer Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library, Issue 12, 2014), MEDLINE (up to November week 3, 2014) and EMBASE (up to week 52, 2014). SELECTION CRITERIA: We included all studies reporting on fertility and early pregnancy outcomes (less than 24 weeks of gestation) in women with a history of CIN treatment (excisional or ablative) as compared to women that had not received treatment. DATA COLLECTION AND ANALYSIS: Studies were classified according to the treatment method used and the fertility or early pregnancy endpoint. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using a random-effects model and inter-study heterogeneity was assessed with I(2). Two review authors (MK, AM) independently assessed the eligibility of retrieved papers and risk of bias. The two review authors then compared their results and any disagreements were resolved by discussion. If still unresolved, a third review author (MA) was involved until consensus was reached. MAIN RESULTS: Fifteen studies (2,223,592 participants - 25,008 treated and 2,198,584 untreated) that fulfilled the inclusion criteria for this review were identified from the literature search. The meta-analysis demonstrated that treatment for CIN did not adversely affect the chances of conception. The overall pregnancy rate was higher for treated (43%) versus untreated women (38%; RR 1.29, 95% CI 1.02 to 1.64; 4 studies, 38,050 participants, very low quality), although the inter-study heterogeneity was considerable (P < 0.01). The pregnancy rates in treated and untreated women with an intention to conceive (88% versus 95%, RR 0.93, 95% CI 0.80 to 1.08; 2 studies, 70 participants, very low quality) and the number of women requiring more than 12 months to conceive (14% versus 9%, RR 1.45, 95% CI 0.89 to 2.37; 3 studies, 1348 participants, very low quality) were no different. Although the total miscarriage rate (4.6% versus 2.8%, RR 1.04, 95% CI 0.90 to 1.21; 10 studies, 39,504 participants, low quality) and first trimester miscarriage rate (9.8% versus 8.4%, RR 1.16, 95% CI 0.80 to 1.69, 4 studies, 1103 participants, low quality) was similar for treated and untreated women, CIN treatment was associated with an increased risk of second trimester miscarriage, (1.6% versus 0.4%, RR 2.60, 95% CI 1.45 to 4.67; 8 studies, 2,182,268 participants, low quality). The number of ectopic pregnancies (1.6% versus 0.8%, RR 1.89, 95% CI 1.50 to 2.39; 6 studies, 38,193 participants, low quality) and terminations (12.2% versus 7.4%, RR 1.71, 95% CI 1.31 to 2.22; 7 studies, 38,208 participants, low quality) were also higher in treated women.The results should be interpreted with caution. The included studies were often small with heterogenous design. Most of these studies were retrospective and of low or very low quality (GRADE assessment) and were therefore prone to bias. Subgroup analyses for the individual treatment methods and comparison groups and analysis to stratify for the cone length was not possible. AUTHORS' CONCLUSIONS: This meta analysis suggests that treatment for CIN does not adversely affect fertility, although treatment was associated with an increased risk of miscarriage in the second trimester. These results should be interpreted with caution as the included studies were non-randomised and many were of low or very low quality and therefore at high risk of bias. Research should explore mechanisms that may explain the increase in mid-trimester miscarriage risk and stratify this impact of treatment by the length of the cone and the treatment method used. PMID- 26417856 TI - Clinical, cytogenetic, and molecular findings in a patient with a 46,XX,del(18)(q22)/46,XX,idic(18)(q22) karyotype. AB - Pseudoisodicentric or asymmetrical dicentric chromosomes 18 are rare findings in clinical cytogenetics. So far, only 8 patients with breakpoints in 18q have been reported and in none of them breakpoints were narrowed down to the molecular level. Here, we describe a 17 months old girl with a perimembranous ventricular septal defect, cleft palate, and minor dysmorphism including hypertelorism, flat nose, frontal bossing and low set ears as well as mosaicism for a cell line with a pseudoisodicentric chromosome 18q and a second cell line with a terminal deletion of 11 Mb in 18q22.2->qter. SNP-array investigation revealed a symmetric breakpoint in 18q22.2 and most likely postzygotic formation from the maternal chromosome 18. Clinical findings in all patients reported so far as well as in the patient presented here were in part overlapping with the clinical phenotypes of trisomy 18 and partial monosomy 18q. PMID- 26417857 TI - Data and preprints. PMID- 26417858 TI - Gene signatures from pancreatic cancer tumor and stromal cells predict disease outcome. AB - Pancreatic cancers consist of a heterogeneous amalgam of assorted cell types, making it challenging to develop a classification system that groups these tumors according to common molecular features. A new study tackles this important issue using bioinformatics approaches to decipher gene expression signatures derived specifically from either tumor cells or nonmalignant stromal cells that predict patient outcome and may inform personalized treatments. PMID- 26417859 TI - Adeno-associated virus finds its disease. AB - Adeno-associated virus (AAV) vectors have been widely adopted for use in gene therapy. A new study raises concerns regarding this approach, reporting that chromosomal insertions of AAV serotype 2 seem to activate proto-oncogenes in human hepatocellular carcinoma. PMID- 26417860 TI - PRC1 proteins orchestrate three-dimensional genome architecture. AB - The three-dimensional organization of the genome has an important role in orchestrating gene expression, but its regulation is poorly understood. Now, a new study uncovers a major role for Polycomb components of the PRC1 complex in organizing physical networks of genes that are co-repressed to maintain pluripotency. PMID- 26417861 TI - How do emergency medicine residency core faculty obtain their ultrasound training for credentialing? PMID- 26417862 TI - A Quantitative Method for Microtubule Analysis in Fluorescence Images. AB - Microtubule analysis is of significant value for a better understanding of normal and pathological cellular processes. Although immunofluorescence microscopic techniques have proven useful in the study of microtubules, comparative results commonly rely on a descriptive and subjective visual analysis. We developed an objective and quantitative method based on image processing and analysis of fluorescently labeled microtubular patterns in cultured cells. We used a multi parameter approach by analyzing four quantifiable characteristics to compose our quantitative feature set. Then we interpreted specific changes in the parameters and revealed the contribution of each feature set using principal component analysis. In addition, we verified that different treatment groups could be clearly discriminated using principal components of the multi-parameter model. High predictive accuracy of four commonly used multi-classification methods confirmed our method. These results demonstrated the effectiveness and efficiency of our method in the analysis of microtubules in fluorescence images. Application of the analytical methods presented here provides information concerning the organization and modification of microtubules, and could aid in the further understanding of structural and functional aspects of microtubules under normal and pathological conditions. PMID- 26417863 TI - Urodynamic findings in women with refractory overactive bladder symptoms. AB - OBJECTIVES: To assess: (i) the correlation between overactive bladder symptoms and urodynamic findings in female patients; and (ii) the association of urinary symptoms with the presence of detrusor overactivity and/or bladder outlet obstruction. METHODS: The present retrospective study included female patients with overactive bladder symptoms who underwent urodynamic evaluation by a single physician. Patients with previous anti-incontinence surgery or neurogenic bladder were excluded. Spearman's correlation coefficients were calculated to correlate overactive bladder symptoms with the urodynamic findings. Univariate and multivariate logistic regression analyses were used to determine the independent factors for detrusor overactivity and bladder outlet obstruction. RESULTS: Overall, 1737 reports were analyzed. All patients had urgency with or without urgency urinary incontinence. Urgency, urgency urinary incontinence and nocturia correlated with detrusor overactivity. The severity of frequency, nocturia and slow stream correlated with bladder outlet obstruction. In contrast, stress urinary incontinence showed an inverse, but weak, correlation with bladder outlet obstruction. Stress urinary incontinence correlated moderately with urine leak. Storage symptoms showed an inverse, but weak, correlation with maximum cystometric capacity. Multivariate analysis data showed that age, urgency, urgency urinary incontinence and nocturia were independent predictors of detrusor overactivity, whereas the severity of frequency was a predictor of bladder outlet obstruction. CONCLUSION: As overactive bladder symptoms increase in severity, female patients tend to have a smaller bladder capacity and a higher incidence of detrusor overactivity. A significant number of these patients have bladder outlet obstruction. PMID- 26417864 TI - iTRAQ-based quantitative proteomic analysis of a toxigenic dinoflagellate Alexandrium catenella and its non-toxic mutant. AB - Paralytic shellfish toxins (PSTs) are a group of potent neurotoxic alkaloids produced by cyanobacteria and dinoflagellates. The PST biosynthesis gene cluster and several toxin-related proteins have been unveiled in cyanobacteria, yet little is known about dinoflagellates. Here, we compared the protein profiles of a toxin-producing dinoflagellate Alexandrium catenella (ACHK-T) and its non-toxic mutant (ACHK-NT), and characterized differentially displayed proteins using a combination of the iTRAQ-based proteomic approach and the transcriptomic database. Totally 3488 proteins were identified from A. catenella, and proteins involved in carbohydrate, amino acid and energy metabolism were the most abundant. Among them, 185 proteins were differentially displayed: proteins involved in amino acid biosynthesis, protein and carbohydrate metabolism and bioluminescence were more abundant in ACHK-T, while proteins participating in photosynthesis, fatty acid biosynthesis, and the processes occurring in peroxisome displayed higher abundances in ACHK-NT. Seven toxin-related proteins were identified but they varied insignificantly between the two strains. Different carbon and energy utilization strategies were potentially related to the toxin producing ability, and the regulation mechanism of PST biosynthesis was more complex in dinoflagellates. Our study provides the first comprehensive dataset on the dinoflagellate proteome and lays the groundwork for future proteomic study. PMID- 26417865 TI - The role of the pubococcygeus muscle in the urethrogenital reflex of male rats. AB - AIM: To determine the response of the pubococcygeus muscle (Pcm) during the urethrogenital reflex (UGR). METHODS: Urethane-anesthetized male rats (n = 20) were used to describe the gross anatomy of the Pcm (n = 3), the effect of the electrical stimulation of the Pcm on the urethral pressure (n = 3), and the reflex activity of the Pcm due to the mechanical stimulation of the urethra (n = 3) and during penile and urethrogenital reflexes (n = 11). The urethral pressure (UP) was recorded as a response to penile stimulation (brushing, extension, and occlusion) and during the UGR; the electromyographic activity of the Pcm was simultaneously evaluated. The role of the Pcm was assessed by measuring urethral pressure variables before and after denervation of this muscle. RESULTS: The Pcm is innervated by the caudal branch of the somatomotor branch of the pelvic nerve. The electrically induced contraction of the Pcm increased the UP. The mechanical stimulation of the urethra during the induced micturition caused the reflex activity of the Pcm. The different penile stimuli caused bursts of activity of the Pcm. During the UGR, the Pcm exhibited a tonic activity. The transection of the caudal branch of the Smb reduced the maximal UP during the penile stimulation. The same was true regarding the duration of the UGR, the pressure that triggers the UGR, and the highest pressure observed during the UGR. CONCLUSION: Our results suggest that the activation of the Pcm is relevant for the UGR in male rats. Neurourol. Urodynam. 36:80-85, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26417866 TI - Selection of voxel size and photon number in voxel-based Monte Carlo method: criteria and applications. AB - The voxel-based Monte Carlo method (VMC) is now a gold standard in the simulation of light propagation in turbid media. For complex tissue structures, however, the computational cost will be higher when small voxels are used to improve smoothness of tissue interface and a large number of photons are used to obtain accurate results. To reduce computational cost, criteria were proposed to determine the voxel size and photon number in 3-dimensional VMC simulations with acceptable accuracy and computation time. The selection of the voxel size can be expressed as a function of tissue geometry and optical properties. The photon number should be at least 5 times the total voxel number. These criteria are further applied in developing a photon ray splitting scheme of local grid refinement technique to reduce computational cost of a nonuniform tissue structure with significantly varying optical properties. In the proposed technique, a nonuniform refined grid system is used, where fine grids are used for the tissue with high absorption and complex geometry, and coarse grids are used for the other part. In this technique, the total photon number is selected based on the voxel size of the coarse grid. Furthermore, the photon-splitting scheme is developed to satisfy the statistical accuracy requirement for the dense grid area. Result shows that local grid refinement technique photon ray splitting scheme can accelerate the computation by 7.6 times (reduce time consumption from 17.5 to 2.3 h) in the simulation of laser light energy deposition in skin tissue that contains port wine stain lesions. PMID- 26417867 TI - Early Repolarization Pattern: Another Brick in the Wall of Vagal Tone. PMID- 26417868 TI - Relationship between J Waves and Vagal Activity in Patients Who Do Not Have Structural Heart Disease. AB - BACKGROUND: J waves are associated with increased vagal activity in patients with idiopathic ventricular fibrillation in several studies to date. However, the relationship between J waves and autonomic nervous activity in patients without structural heart disease remains under investigation. We investigated whether the presence of a J wave on the surface electrocardiogram (ECG) was related to increased vagal activity in patients without structural heart disease. METHODS: This retrospective study included 684 patients without structural heart disease who had undergone Holter ECG and surface ECG monitoring. Based on the presence of J waves on the surface ECG, patients were divided into two groups: those with J waves (group 1) and those without J waves (group 2). We compared heart rate variability (HRV), reflecting autonomic nervous activity, using 24-h Holter ECG between the groups. RESULTS: J waves were present in 92 (13.4%) patients. Heart rate (HR) in group 1 was significantly lesser than that in group 2 (P = 0.031). The ratio of low-frequency (LF) components to high-frequency (HF) components (LF/HF) in group 1 was significantly lower than that in group 2 (P = 0.001). The square root of the mean squared differences of successive NN intervals in group 1 was also significantly higher than that in group 2 (P = 0.047). In a multivariate regression analysis, male sex, HR, and LF/HF ratio remained independent determinants for the presence of J waves (P = 0.039, P = 0.036, and P < 0.001, respectively). CONCLUSION: In patients without structural heart disease, the presence of a J wave was associated with a slow HR, male sex, and increased vagal activity, independently. PMID- 26417869 TI - Isolated Left Ventricular Apical Hypoplasia with Right Ventricular Outflow Tract Obstruction: A Rare Combination. AB - Isolated left ventricular (LV) apical hypoplasia is a unusual and recently recognized congenital cardiac anomaly. A 19-year-old man was found to have an abnormal ECG and cardiac murmur identified during a routine health check since joining work. His ECG revealed normal sinus rhythm, right-axis deviation, poor R wave progression, and T wave abnormalities. On physical examination, a 2/6~3/6 systolic murmur was heard at the second intercostal space along the left sternal border. Subsequent echocardiography and cardiac magnetic resonance imaging confirmed the LV apical hypoplasia. Of note, we first found that LV apical hypoplasia was accompanied by RV outflow tract obstruction due to exaggerated rightward bulging of the basal-anterior septum during systole. A close follow-up was performed for the development of heart failure, pulmonary hypertension, and potentially tachyarrhythmia. PMID- 26417871 TI - Striving for optimal care: Updates in quality, value, and patient experience. AB - BACKGROUND: Hospitalists are playing a growing role in quality improvement efforts, and they are increasingly spearheading programs to improve patient experience and healthcare value. We aimed to summarize and critique recent research related to quality, value, and patient experience in the clinical practice of hospital medicine. METHODS: We reviewed articles published between January 2014 and February 2015, identified through a hand search of leading journals, continuing medical education collaborative journal reviews, Agency for Healthcare Research and Quality's Patient Safety network, and PubMed. The authors collectively selected 9 articles based on their relevance to hospital practice. We review their findings, strengths, and limitations and make recommendations for practice. This is a summary of an update we presented at the 2015 Hospital Medicine national meeting. RESULTS: Key findings include: a comprehensive hand off program was associated with improved patient safety; successful readmissions interventions were resource-intensive, multifaceted and increased patient capacity to handle illness; patient activation was correlated with lower resource use post-hospitalization; positive associations exist between patient experience and understanding of their hospitalization; hospitals and practitioners can adopt simple low-cost strategies to reduce the trauma of hospitalization; hospitalists frequently order low-value tests, most often to reassure themselves or their patients; broad-spectrum antibiotics are grossly overused in hospitalized patients leading to preventable harms including clostridium difficile colitis, and programs that support "self-stewardship" may help moderate this risk. CONCLUSIONS: Recent research provides important insights into readmissions prevention, patient experience and low-value test ordering, as well as introduces interventions that may mitigate the risks of handoffs and the overuse of broad spectrum antibiotics. PMID- 26417872 TI - Solution and air stable host/guest architectures from a single layer covalent organic framework. AB - We show that the surface-supported two-dimensional covalent organic framework (COF) known as COF-1 can act as a host architecture for C60 fullerene molecules, predictably trapping the molecules under a range of conditions. The fullerenes occupy the COF-1 lattice at the solution/solid interface, and in dried films of the COF-1/fullerene network that can be synthesized through either drop deposition of fullerene solution or by a dipstick-type synthesis in which the surface-supported COF-1 is briefly dipped into the fullerene solution. PMID- 26417870 TI - Potential causal associations between vitamin D and uric acid: Bidirectional mediation analysis. AB - Vitamin D deficiency, a major public-health worldwide, is associated with hyperuricemia but casual association is questioned. The study was conducted to determine potential causal associations between 25-hydroxy vitamin D (25(OH)D) and uric acid (UA). A cross-sectional study of the Electricity Generating Authority of Thailand (EGAT3) cohort was conducted. Subjects (n = 2,288) were used to genotype the group-specific component (GC) at rs2282679 and ATP-binding cassette subfamily G member 2 (ABCG2) at rs2231142. Mediation analysis with 1000 replication bootstrap was applied to construct causal pathways i.e., rs2282679 -> 25(OH)D -> UA and rs2231142 -> UA -> 25(OH)D: The mediator (i.e., 25(OH)D and UA) was firstly regressed on the studied gene (i.e., rs2282679 and rs2231142). A potential causal effect of C allele on UA through 25(OH)D was -0.0236 (95% CI: 0.0411, -0.0058), indicating every minor C allele resulted in decreasing the 25(OH)D and then significantly decreased the UA by 0.0236 unit. For the second pathway, the mediation effect was 0.0806 (95% CI: 0.0107, 0.1628); every T allele copy for rs2231142 increased UA and thus increased 25(OH)D by 0.0806 unit. Our study suggested potential causal associations between the GC gene and UA through the 25(OH)D mediator, and the ABCG2 and the 25(OH)D through the UA mediator but the absolute effects are very clinically small. PMID- 26417873 TI - Obituary--D. Gentry Steele (1941-2014). PMID- 26417874 TI - Rhodium(III)-Catalyzed Directed ortho-C-H Bond Functionalization of Aromatic Ketazines via C-S and C-C Coupling. AB - Described herein is a convenient and efficient method for sulfuration and olefination of aromatic ketazines via rhodium-catalyzed oxidative C-H bond activation. A range of substituted substrates are supported, and a possible mechanism is proposed according to experimental results of kinetic isotopic effect, reversibility studies, and catalysis of rhodacycle intermediate c1. PMID- 26417875 TI - Exploration of high-density protein microarrays for antibody validation and autoimmunity profiling. AB - High-density protein microarrays of recombinant human protein fragments, representing 12,412 unique Ensembl Gene IDs, have here been produced and explored. These protein microarrays were used to analyse antibody off-target interactions, as well as for profiling the human autoantibody repertoire in plasma against the antigens represented by the protein fragments. Affinity purified polyclonal antibodies produced within the Human Protein Atlas (HPA) were analysed on microarrays of three different sizes, ranging from 384 antigens to 21,120 antigens, for evaluation of the antibody validation criteria in the HPA. Plasma samples from secondary progressive multiple sclerosis patients were also screened in order to explore the feasibility of these arrays for broad-scale profiling of autoantibody reactivity. Furthermore, analysis on these near proteome-wide microarrays was complemented with analysis on HuProtTM Human Proteome protein microarrays. The HPA recombinant protein microarray with 21,120 antigens and the HuProtTM Human Proteome protein microarray are currently the largest protein microarray platforms available to date. The results on these arrays show that the Human Protein Atlas antibodies have few off-target interactions if the antibody validation criteria are kept stringent and demonstrate that the HPA-produced high-density recombinant protein fragment microarrays allow for a high-throughput analysis of plasma for identification of possible autoantibody targets in the context of various autoimmune conditions. PMID- 26417876 TI - Risk Factors for Chronic Renal Insufficiency Following Cardiac Transplantation. AB - Although previous publications have discussed kidney disease in nonrenal solid organ transplantation, none has reviewed thoroughly the potential predictors of long-term renal impairment in cardiac recipients. Thus, the purpose of this review article is to summarize the current state of knowledge on risk factors of chronic renal insufficiency in heart transplant patients. An English language Medline literature search (1946-April 2014) was conducted using the search terms renal insufficiency, kidney failure, kidney diseases, nephrotoxi$ ($ for truncation), creatinine, glomerular filtration rate, heart transplantation and organ transplantation. Additional references were identified from a review of literature citations. A total of 74 articles discussing key risk factors were included in the manuscript. The existing literature reveals that several recipient characteristics (age, female sex, pretransplant/early post-transplant kidney impairment, diabetes, and hypertension) increase the risk of renal insufficiency after transplantation. Current data also indicate that, while cyclosporine and tacrolimus are most likely major determinants of post-transplant kidney failure, the effects of calcineurin inhibitor doses and concentrations remain unclear. A small number of studies suggest that tacrolimus could possibly induce less nephrotoxicity than cyclosporine, but meta-analyses of randomized controlled trials show the opposite with comparable incidences of dialysis after cardiac transplantation. Finally, the role of genetic variations has only been explored to a limited extent in heart transplant patients. This growing body of evidence should ultimately lead to a better risk prediction regarding chronic renal insufficiency following cardiac transplantation and a more personalized tailoring of immunosuppressive regimens. PMID- 26417877 TI - Differences in the seasonality of Middle East respiratory syndrome coronavirus and influenza in the Middle East. PMID- 26417878 TI - Interim estimates of divergence date and vaccine strain match of human influenza A(H3N2) virus from systematic influenza surveillance (2010-2015) in Hangzhou, southeast of China. AB - OBJECTIVES: In the post-pandemic period 2010-2015, seasonal influenza A(H3N2) virus predominated in Hangzhou, southeast of China, with an increased activity and semi-annual seasons. This study utilized HA virus gene segment sequences to analyze the divergence date and vaccine strain match of human influenza A(H3N2) virus from systematic influenza surveillance in Hangzhou. METHODS: Virological and serological analyses of 124 representative A(H3N2) viruses from prospective studies of systematic surveillance samples were conducted to quantify the genetic and antigenic characteristics and their vaccine strain match. RESULTS: Bayesian phylogenetic inference showed that two separate subgroups 3C.3 and 3C.2 probably diverged from group 3C in early 2012 and then evolved into groups 3C.3a and 3C.2a, respectively, in the 2014/15 influenza season. Furthermore, high amino acid substitution rates of the HA1 subunit were found in A(H3N2) group 3C.2a variants, indicating that increased antigenic drift of A(H3N2) group 3C.2a virus is associated with a vaccine mismatch to the 2015/16 vaccine reference strain Switzerland/9715293/2013 (group 3C.3a). CONCLUSIONS: A portion of the group 3C.2a isolates are not covered by the current A(H3N2) vaccine strain. These findings offer insights into the emergence of group 3C.2a variants with epidemic potential in the imminent influenza seasons. PMID- 26417879 TI - Comparative proteomics of Shigella flexneri 2a strain 301 using a rabbit ileal loop model reveals key proteins for bacterial adaptation in host niches. AB - OBJECTIVES: Many studies focusing on changes in the host following Shigella spp invasion have been reported in recent years. However, the key factors required for the adaptation of these pathogens to host niches have usually been neglected. METHODS: In this study, a comparative proteomic analysis was performed to examine changes in the protein expression profile of Shigella flexneri within the host using a rabbit ileal loop model to reveal proteins that are associated with pathogenic adaptation. RESULTS: The protein expression profiles of bacteria isolated from the ileum and colon were very similar, although they differed slightly from that of bacteria isolated from the cecum. When compared with the sample in vitro, the expressions of seven proteins were found to be upshifted in vivo (OmpA, YgiW, MglB, YfiD, MetK, TktA, and AhpF), while two proteins were down regulated (ElaB and GlnH). CONCLUSIONS: The abundance of nine proteins changed in vivo, suggesting that these proteins may contribute to adaptation to the intestinal lumen. PMID- 26417880 TI - The epidemiology of hepatitis C virus in Afghanistan: systematic review and meta analysis. AB - OBJECTIVES: To characterize hepatitis C virus (HCV) epidemiology and inform public health research, policy, and programming priorities in Afghanistan. METHODS: Records of HCV incidence and prevalence were reviewed systematically and synthesized following PRISMA guidelines. Meta-analyses were implemented using a DerSimonian-Laird random effects model with inverse variance weighting to estimate HCV prevalence among various at risk populations. A risk of bias assessment was incorporated. RESULTS: The search identified one HCV incidence and 76 HCV prevalence measures. HCV incidence was only assessed among people who inject drugs (PWID), and was reported at 66.7 per 100 person-years. Meta-analyses estimated HCV prevalence at 0.7% among the general population (range 0-9.1%, 95% confidence interval (CI) 0.5-0.9%), 32.6% among PWID (range 9.5-70.0%, 95% CI 24.5-41.3%), and 2.3% among populations at intermediate risk (range 0.0-8.3%, 95% CI 1.3-3.7%). No data were available for other high risk populations such as hemodialysis, thalassemia, and hemophilia patients. CONCLUSIONS: HCV prevalence among the general population in Afghanistan is comparable to global levels. Data are needed for the level of infection among key clinical populations at high risk of infection. There is also an immediate need for expansion of harm reduction programs among PWID and prisoners. PMID- 26417881 TI - Metabolite profiling reveals temperature effects on the VOCs and flavonoids of different plant populations. AB - Temperature is one of the key factors in limiting the distribution of plants and controlling major metabolic processes. A series of simulated reciprocal transplant experiments were performed to investigate the effect of temperature on plant chemical composition. Polygonum minus of different lowland and highland origin were grown under a controlled environment with different temperature regimes to study the effects on secondary metabolites. We applied gas chromatography-mass spectrometry and liquid chromatography time-of-flight mass spectrometry to identify the chemical compounds. A total of 37 volatile organic compounds and 85 flavonoids were detected, with the largest response observed in the compositional changes of aldehydes and terpenes in highland plants under higher temperature treatment. Significantly less anthocyanidin compounds and larger amounts of flavonols were detected under higher temperature treatment. We also studied natural variation in the different plant populations growing under the same environment and identified compounds unique to each population through metabolite fingerprinting. This study shows that the origin of different plant populations influences the effects of temperature on chemical composition. PMID- 26417882 TI - An UPLC-MS detection method for the quantification of five antibiotics in human plasma. AB - BACKGROUND: An UPLC-MS detection method for the quantification of amikacin, flucloxacillin, meropenem, penicillin G and vancomycin was developed and validated. RESULTS: The calibration curves were found to be linear from 0.47 to 50 mg/l for amikacin, 1.28 to 135 mg/l for flucloxacillin, 0.75 to 80 mg/l for meropenem, 0.38 to 80 mg/l for penicillin G and 0.73 to 80 mg/l for vancomycin. Between- and within-run accuracy was ranged between 85 and 115%. Between and within imprecision expressed as CV was within 15%. CONCLUSION: The validated method was successfully applied to a PK study in very preterm and small for gestational age infants treated for nosocomial sepsis and/or meningitis. PMID- 26417883 TI - Protease activity of Per a 10 potentiates Th2 polarization by increasing IL-23 and OX40L. AB - Proteases are implicated in exacerbation of allergic diseases. In this study, the role of proteolytic activity of Per a 10 was evaluated on Th2 polarization. Intranasal administration of Per a 10 in mice led to allergic airway inflammation as seen by higher IgE levels, cellular infiltration, IL-17A, and Th2 cytokines, whereas, inactive (Delta)Per a 10 showed attenuated response. There was an increased OX40L expression on lung and lymph node dendritic cells in Per a 10 immunized group and on Per a 10 stimulated BMDCs. Reduction in CD40 expression without any change at transcript level in lungs of Per a 10 immunized mice suggested CD40 cleavage. BMDCs pulsed with Per a 10 showed reduced CD40 expression with lower IL-12p70 secretion as compared to heat inactivated Per a 10. IL-23, TNF-alpha, and IL-6 levels were significantly higher in Per a 10 stimulated BMDCs supernatant. In DC-T cell coculture studies, Per a 10 pulsed BMDCs showed higher levels of IL-4 and IL-13 that were reduced on blocking of either IL-23 or OX40L. In conclusion, the data suggests a critical role of protease activity of Per a 10 in promoting Th2 polarization by increasing IL-23 secretion and OX40L expression on dendritic cells. PMID- 26417884 TI - Predictive factors of adverse events after intravesical suburothelial onabotulinumtoxina injections for overactive bladder syndrome-A real-life practice of 290 cases in a single center. AB - AIMS: Patients often experience adverse events (AEs) after intravesical onabotulinumtoxinA (BoNT-A) treatment for overactive bladder refractory to antimuscarinic agents. We investigated the prevalence and predictive factors of AEs in such patients. METHODS: A total of 290 patients underwent intravesical BoNT-A (100 U) suburothelial injection. The age, gender, overactive bladder subtypes, medical co-morbidities, and neurological diseases of the patients were recorded. The maximum flow rate (Qmax ), voided volume, post-void residual (PVR) volume, and voiding efficiency (VE) at baseline were analyzed to identify adverse events within 3 months after treatment. RESULTS: Acute urinary retention (AUR) developed in 24 patients (8.3%), and urinary tract infection (UTI) occurred in 44 (15.2%) within 3 months of treatment. Large PVR volume (>200 ml) occurred in 81 (27.9%), 68 (24.3%), and 49 (18.4%) patients 1, 3, and 6 months after treatment, respectively. AUR developed significantly more often in men, patients >61 years old, those with a baseline Qmax <=15 ml/sec, PVR >=100 ml, and VE <90%. Patients older than 61 years had a higher incidence of large PVR 1 month after treatment. Female gender and a baseline PVR volume >=100 ml had a greater incidence of UTI. Age >61 years, low Qmax , low voiding efficiency, and large PVR at baseline were also risk factors for adverse events. CONCLUSION: AUR, UTI, and large PVR volume are common AEs after BoNT-A treatment. Patients with overactive bladders that are at risk of developing AEs after BoNT-A injection should be informed of the possible AEs. Neurourol. Urodynam. 36:142-147, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26417885 TI - Placebo and nocebo effects on itch: effects, mechanisms, and predictors. AB - Placebo and nocebo effects have been extensively studied in the field of pain and more recently also on itch. In accordance with placebo research on pain, expectancy learning via verbal suggestion or conditioning has shown to induce placebo and nocebo effects on itch, in which the combination of both procedures seems most promising. Moreover, itch can also be transferred 'contagiously' in which suggestion and social behavioural learning seem to play a role. With regard to predictors of placebo and nocebo responding on itch and contagious itch, preliminary evidence suggests a role for individual psychological characteristics and personality traits regarding negative outcome expectancies. Although findings on placebo and nocebo effects on itch seem comparable to pain, we have only just begun to understand the underlying mechanisms and predictors of placebo and nocebo effects on itch. PMID- 26417886 TI - Unified Protocol for Cobalt-Catalyzed Oxidative Assembly of Two Aryl Metal Reagents Using Oxygen as an Oxidant. AB - The first cobalt-catalyzed oxidative cross-coupling reaction of two aryl metal reagents is described. An equivalent amount of two aryl Grignard or lithium reagents, after mediation by an equivalent amount of simple ClTi(OEt)3, was facilely assembled under the catalysis of 1 mol % of CoCl2/10 mol % of DMPU using oxygen. The cross-couplings between various aryl metal reagents, especially between two structurally similar aryl Grignard reagents, proceeded smoothly and selectively and, thus, provided a highly general and efficient method for the construction of biaryl compounds. PMID- 26417887 TI - Selective recognition and extraction of KBr via cooperative interactions with a urea functionalized crown ether dual-host. AB - Selective solid-liquid extraction of KBr is demonstrated for the first time with a crown ether based pentafluorophenyl urea functionalized dual-host receptor. (1)H-NMR and ITC studies have been carried out to illustrate the effect of cooperativity towards the recognition of alkali metal salts. PMID- 26417889 TI - From Pakistan a line of hope for 'The Polio Eradication and Endgame Strategic Plan 2013-2018'. PMID- 26417890 TI - Magnetically-induced ferroelectricity in the (ND4)2[FeCl5(D2O)] molecular compound. AB - The number of magnetoelectric multiferroic materials reported to date is scarce, as magnetic structures that break inversion symmetry and induce an improper ferroelectric polarization typically arise through subtle competition between different magnetic interactions. The (NH4)2[FeCl5(H2O)] compound is a rare case where such improper ferroelectricity has been observed in a molecular material. We have used single crystal and powder neutron diffraction to obtain detailed solutions for the crystal and magnetic structures of (NH4)2[FeCl5(H2O)], from which we determined the mechanism of multiferroicity. From the crystal structure analysis, we observed an order-disorder phase transition related to the ordering of the ammonium counterion. We have determined the magnetic structure below TN, at 2 K and zero magnetic field, which corresponds to a cycloidal spin arrangement with magnetic moments contained in the ac-plane, propagating parallel to the c axis. The observed ferroelectricity can be explained, from the obtained magnetic structure, via the inverse Dzyaloshinskii-Moriya mechanism. PMID- 26417891 TI - Multivalent presentation of carbohydrates by 3(14)-helical peptide templates: synthesis, conformational analysis using CD spectroscopy and saccharide recognition. AB - A well defined 314-helical tetravalent beta-galactopeptide site-specific functionalised template (SSFT) 1 was prepared containing d-galactose units, with free anomeric carbons as the aldehyde tags, and was explored via ligation with different aminoxy sugars (alpha-/beta-d-glucose, alpha/beta-d-galactose, alpha-d mannose and beta-d-lactose) to get 314-helical carbohydrate-functionalised multivalent glycoconjugates 2-7. Preliminary recognition studies of tetramannosyl glycoconjugate 4 with a specific lectin (concanavalin A) using fluorescence anisotropy showed an increase in binding affinity and the multivalency effect was found to be increased by 6.5 times per glycan. PMID- 26417892 TI - Peri-operative management of the surgical patient with diabetes 2015: Association of Anaesthetists of Great Britain and Ireland. AB - Diabetes affects 10-15% of the surgical population and patients with diabetes undergoing surgery have greater complication rates, mortality rates and length of hospital stay. Modern management of the surgical patient with diabetes focuses on: thorough pre-operative assessment and optimisation of their diabetes (as defined by a HbA1c < 69 mmol.mol(-1) ); deciding if the patient can be managed by simple manipulation of pre-existing treatment during a short starvation period (maximum of one missed meal) rather than use of a variable-rate intravenous insulin infusion; and safe use of the latter when it is the only option, for example in emergency patients, patients expected not to return to a normal diet immediately postoperatively, and patients with poorly controlled diabetes. In addition, it is imperative that communication amongst healthcare professionals and between them and the patient is accurate and well informed at all times. Most patients with diabetes have many years of experience of managing their own care. The purpose of this guideline is to provide detailed guidance on the peri operative management of the surgical patient with diabetes that is specific to anaesthetists and to ensure that all current national guidance is concordant. PMID- 26417893 TI - The atomic and electronic structure of nitrogen- and boron-doped phosphorene. AB - First principles modeling of nitrogen- and boron-doped phosphorene demonstrates the tendency toward the formation of highly ordered structures. Nitrogen doping leads to the formation of -N-P-P-P-N- lines. Further transformation into -P-N-P-N lines across the chains of phosphorene occurs with increasing band gap and increasing nitrogen concentration, which coincides with the decreasing chemical activity of N-doped phosphorene. In contrast to the case of nitrogen, boron atoms prefer to form -B-B- pairs with the further formation of -P-P-B-B-P-P- patterns along the phosphorene chains. The low concentration of boron dopants converts the phosphorene from a semiconductor into a semimetal with the simultaneous enhancement of its chemical activity. Co-doping of phosphorene by both boron and nitrogen starts from the formation of -B-N- pairs, which provides flat bands and further transformation of these pairs into hexagonal BN lines and ribbons across the phosphorene chains. PMID- 26417888 TI - Brain size and limits to adult neurogenesis. AB - The walls of the cerebral ventricles in the developing embryo harbor the primary neural stem cells from which most neurons and glia derive. In many vertebrates, neurogenesis continues postnatally and into adulthood in this region. Adult neurogenesis at the ventricle has been most extensively studied in organisms with small brains, such as reptiles, birds, and rodents. In reptiles and birds, these progenitor cells give rise to young neurons that migrate into many regions of the forebrain. Neurogenesis in adult rodents is also relatively widespread along the lateral ventricles, but migration is largely restricted to the rostral migratory stream into the olfactory bulb. Recent work indicates that the wall of the lateral ventricle is highly regionalized, with progenitor cells giving rise to different types of neurons depending on their location. In species with larger brains, young neurons born in these spatially specified domains become dramatically separated from potential final destinations. Here we hypothesize that the increase in size and topographical complexity (e.g., intervening white matter tracts) in larger brains may severely limit the long-term contribution of new neurons born close to, or in, the ventricular wall. We compare the process of adult neuronal birth, migration, and integration across species with different brain sizes, and discuss how early regional specification of progenitor cells may interact with brain size and affect where and when new neurons are added. PMID- 26417894 TI - Evaluation of fatty acids in pregnancy: plasma or erythrocyte membrane? PMID- 26417895 TI - The controversy of infant formula: does it have a role in managing child malnutrition in fully weaned infants? PMID- 26417897 TI - Erratum. PMID- 26417896 TI - Response to the letter by Gedela. PMID- 26417898 TI - Quality of online information to support patient decision-making in breast cancer surgery. AB - BACKGROUND: Breast cancer patients commonly use the internet as an information resource. Our objective was to evaluate the quality of online information available to support patients facing a decision for breast surgery. METHODS: Breast cancer surgery-related queries were performed (Google and Bing), and reviewed for content pertinent to breast cancer surgery. The DISCERN instrument was used to evaluate websites' structural components that influence publication reliability and ability of information to support treatment decision-making. Scores of 4/5 were considered "good." RESULTS: 45 unique websites were identified. Websites satisfied a median 5/9 content questions. Commonly omitted topics included: having a choice between breast conservation and mastectomy (67%) and potential for 2nd surgery to obtain negative margins after breast conservation (60%). Websites had a median DISCERN score of 2.9 (range 2.0-4.5). Websites achieved higher scores on structural criteria (median 3.6 [2.1-4.7]), with 24% rated as "good." Scores on supporting decision-making questions were lower (2.6 [1.3-4.4]), with only 7% scoring "good." CONCLUSION: Although numerous breast cancer-related websites exist, most do a poor job providing women with essential information necessary to actively participate in decision-making for breast cancer surgery. Providing easily- accessible, high-quality online information has the potential to significantly improve patients' experiences with decision-making. PMID- 26417899 TI - Serum Soluble Semaphorin 4D is Associated with Left Atrial Diameter in Patients with Atrial Fibrillation. AB - BACKGROUND: The aim of this study was to evaluate the serum soluble semaphorin 4D (sSema4D) in patients with atrial fibrillation and to investigate the relationship of serum sSema4D with left atrial diameter (LAD). MATERIAL AND METHODS: We studied a total of 113 patients who were subdivided into paroxysmal and non-paroxysmal (included persistent and permanent) atrial fibrillation groups, respectively. Another 55 subjects without atrial fibrillation were enrolled as the healthy control group. Serum levels of soluble semaphorin 4D (Sema4D) were measured in all subjects using the enzyme-labeled immunosorbent assay method. We also evaluated the coagulation parameters and left atrial diameters. RESULTS: Patients with paroxysmal and non-paroxysmal atrial fibrillation had significantly higher sSema4D level compared with controls (8.50+/-2.19 ng/mL and 9.30+/-2.28 ng/mL vs. 6.56+/-1.27 ng/ml, P<0.05). Serum sSema4D concentrations were elevated in patients with non-paroxysmal atrial fibrillation compared to those with paroxysmal atrial fibrillation (P<0.001). The level of sSema4D was positively correlated with LAD (r=0.606, P<0.001). Multivariate logistic regression analysis revealed that serum sSema4D, LAD, male sex, heart rate, hypertension, and coronary artery disease were associated with atrial fibrillation (P<0.05). CONCLUSIONS: Serum sSema4D levels are increased in patients with atrial fibrillation and are independently associated with atrial remodeling. PMID- 26417900 TI - The discovery of Antarctic RNA viruses: a new game changer. AB - Antarctic ecosystems are dominated by micro-organisms, and viruses play particularly important roles in the food webs. Since the first report in 2009 (Lopez-Bueno et al. ), 'omic'-based studies have greatly enlightened our understanding of Antarctic aquatic microbial diversity and ecosystem function (Wilkins et al. ; Cavicchioli ). This has included the discovery of many new eukaryotic viruses (Lopez-Bueno et al. ), virophage predators of algal viruses (Yau et al. ), bacteria with resistance to phage (Lauro et al. ) and mechanisms of haloarchaeal evasion, defence and adaptation to viruses (Tschitschko et al. ). In this issue of Molecular Ecology, Lopez-Bueno et al. () report the first discovery of RNA viruses from an Antarctic aquatic environment. High sequence coverage enabled genome variation to be assessed for four positive-sense single stranded RNA viruses from the order Picornavirales. By examining the populations present in the water column and in the lake's catchment area, populations of 'quasispecies' were able to be linked to local environmental factors. In view of the importance of viruses in Antarctic ecosystems but lack of data describing them, this study represents a significant advance in the field. PMID- 26417902 TI - Site-Specific Antibody Labeling by Covalent Photoconjugation of Z Domains Functionalized for Alkyne-Azide Cycloaddition Reactions. AB - Antibodies are extensively used in research, diagnostics, and therapy, and for many applications the antibodies need to be labeled. Labeling is typically performed by using amine-reactive probes that target surface-exposed lysine residues, resulting in heterogeneously labeled antibodies. An alternative labeling strategy is based on the immunoglobulin G (IgG)-binding protein domain Z, which binds to the Fc region of IgG. Introducing the photoactivable amino acid benzoylphenylalanine (BPA) into the Z domain makes it possible for a covalent bond to be be formed between the Z domain and the antibody on UV irradiation, to produce a site-specifically labeled product. Z32 BPA was synthesized by solid phase peptide synthesis and further functionalized to give alkyne-Z32 BPA and azide-Z32 BPA for Cu(I) -catalyzed cycloaddition, as well as DBCO-Z32 BPA for Cu free strain-promoted cycloaddition. The Z32 BPA variants were conjugated to the human IgG1 antibody trastuzumab and site-specifically labeled with biotin or fluorescein. The fluorescently labeled trastuzumab showed specific staining of the membranes of HER2-expressing cells in immunofluorescence microscopy. PMID- 26417901 TI - A randomized DBPC trial to determine the optimal effective and safe dose of a SLIT-birch pollen extract for the treatment of allergic rhinitis: results of a phase II study. AB - BACKGROUND: Sublingual immunotherapy (SLIT) is a potential efficacious and safe treatment option for patients with respiratory, IgE-mediated allergic diseases. A combined tolerability, dose-finding study with a sublingual liquid birch pollen preparation (SB) was conducted. METHODS: Two hundred and sixty-nine adults with birch-pollen-induced AR were randomized to placebo, SB: 3333, 10,000, 20,000 or 40,000 AUN/ml. Differences in symptom scores following a titrated nasal provocation test (TNPT) at baseline and after 5 months of treatment were determined. Safety, tolerability, birch-pollen-specific immunoglobulin levels and peak nasal inspiratory flow (PNIF) were also measured (all measures determined outside the birch pollen season). RESULTS: In all treatment groups, an improvement in symptom scores after treatment compared to baseline was observed, with an additional stepwise improvement in the active groups compared to placebo, which was significant in high-dose groups (P = 0.008 and P < 0.001, respectively). For this primary endpoint, a significant linear dose-response curve was observed: the higher the dose, the better the improvement observed. Likewise, active treatment resulted in an increase in PNIF and serum IgG levels compared to placebo. The highest improvements were found in the 40,000 AUN/ml group. All active dosages resulted in more adverse reactions than placebo, which were mainly mild and well-controlled. CONCLUSIONS: A multicentre trial evaluated the dose-response and tolerability of SB. All active treatment groups showed better responses than placebo for both primary and secondary parameters. The results indicate that, within the studied dose range, SB 40,000 AUN/ml is the most optimal effective and safe dose (ClinicalTrials.gov: NCT01639768). PMID- 26417903 TI - Acylglycerophosphate acyltransferase 4 (AGPAT4) is a mitochondrial lysophosphatidic acid acyltransferase that regulates brain phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol levels. AB - The acylglycerophosphate acyltransferase/lysophosphatidic acid acyltransferase (AGPAT/LPAAT) family is a group of homologous acyl-CoA-dependent lysophospholipid acyltransferases. We performed studies to better understand the subcellular localization, activity, and in vivo function of AGPAT4/LPAATdelta, which we found is expressed in multiple mouse brain regions. Endogenous brain AGPAT4 and AGPAT4 overexpressed in HEK293 or Sf9 insect cells localizes to mitochondria and is resident on the outer mitochondrial membrane. Further fractionation showed that AGPAT4 is present specifically in the mitochondria and not in the mitochondria associated endoplasmic reticulum membrane (i.e. MAM). Lysates from Sf9 cells infected with baculoviral Agpat4 were tested with eight lysophospholipid species but showed an increased activity only with lysophosphatidic acid as an acyl acceptor. Analysis of Sf9 phospholipid species, however, indicated a significant 72% increase in phosphatidylinositol (PI) content. We examined the content of major phospholipid species in brains of Agpat4(-/-) mice and found also a >50% decrease in total levels of PI relative to wildtype mice, as well as significant decreases in phosphatidylcholine (PC) and phosphatidylethanolamine (PE), but no significant differences in phosphatidylserine, phosphatidylglycerol, cardiolipin, or phosphatidic acid (PA). A compensatory upregulation of Agpats 1, 2, 3, 5, and 9 may help to explain the lack of difference in PA. Our findings indicate that AGPAT4 is a mitochondrial AGPAT/LPAAT that specifically supports synthesis of brain PI, PC, and PE. This understanding may help to explain apparent redundancies in the AGPAT/LPAAT family. PMID- 26417904 TI - Experienced and anticipated discrimination reported by individuals in treatment for substance use disorders within the Netherlands. AB - Experiences and expectations of discrimination (anticipated discrimination) may delay treatment seeking among people with substance use disorders. In addition, experienced and anticipated discrimination can be a barrier to successful recovery and rehabilitation. The aim of this study was to study the level of experienced and anticipated (the expectation to be rejected) discrimination among individuals in treatment for substance use disorders as well as the association between both concepts of discrimination. In addition, the association of experienced and anticipated discrimination with clinical and social characteristics was investigated. A cross-sectional survey among individuals in treatment for substance use disorders in the Netherlands was carried out in 2012. Individuals in treatment (N = 186) completed a self-reported questionnaire about experienced and anticipated discrimination. Descriptive statistics and chi squared analyses were performed to investigate the level of experienced and anticipated discrimination and the association between both concepts. Linear regression analyses were used to investigate the association with clinical and social characteristics, such as occupational status and type of treatment. Individuals in treatment for substance use disorders reported high levels of experienced and anticipated discrimination. Respondents experienced most discrimination in family ties, intimate relationships and friendships. Experienced and anticipated discrimination were both positively correlated. Having complex substance use problems and a longer history of substance use problems was related to higher levels of experienced discrimination. In conclusion, experienced and anticipated discrimination were highly prevalent among individuals in treatment for substance use disorders. Attention in addiction treatment for adequate coping with discrimination may be needed in order to achieve successful social participation and rehabilitation of these individuals. PMID- 26417905 TI - Evaluating the Use of Twitter to Enhance the Educational Experience of a Medical School Surgery Clerkship. AB - OBJECTIVE: Although it has been suggested that social-networking services such as Twitter could be used as a tool for medical education, few studies have evaluated its use in this setting. We sought to evaluate the use of Twitter as a novel educational tool in a medical school surgery clerkship. We hypothesized that Twitter can enhance the educational experience of clerkship students. DESIGN: We performed a prospective observational study. We created a new Twitter account, and delivered approximately 3 tweets per day consisting of succinct, objective surgical facts. Students were administered pre- and postclerkship surveys, and aggregate test scores were obtained for participating students and historical controls. SETTING: Required third-year medical school surgery clerkship at the University of Michigan large tertiary-care academic hospital. PARTICIPANTS: Third year medical students. RESULTS: The survey response rate was 94%. Preclerkship surveys revealed that most (87%) students have smartphones, and are familiar with Twitter (80% have used before). Following completion of the clerkship, most students (73%) reported using the Twitter tool, and 20% used it frequently. Overall, 59% believed it positively influenced their educational experience and very few believed it had a negative influence (2%). However, many (53%) did not believe it influenced their clerkship engagement. Aggregate mean National Board of Medical Examiners Shelf Examination scores were not significantly different in an analysis of medical student classes completing the clerkship before or after the Twitter tool (p = 0.37). CONCLUSIONS: Most of today's learners are familiar with social media, and own the technology necessary to implement novel educational tools in this platform. Applications such as Twitter can be facile educational tools to supplement and enhance the experience of students on a medical school clerkship. PMID- 26417906 TI - Structural and Functional Characterization of the Hazelnut Allergen Cor a 8. AB - Nonspecific lipid transfer proteins (nsLTPs) are basic proteins, stabilized by four disulfide bonds, and are expressed throughout the plant kingdom. These proteins are also known as important allergens in fruits and tree nuts. In this study, the nsLTP from hazelnuts, Cor a 8, was purified and its crystal structure determined. The protein is stable at low pH and refolds after thermal denaturation. Molecular dynamics simulations were used to provide an insight into conformational changes of Cor a 8 upon ligand binding. When known epitope areas from Pru p 3 were compared to those of Cor a 8, differences were obvious, which may contribute to limited cross-reactivity between peach and hazelnut allergens. Differences in epitope regions may contribute to limited cross-reactivity between Cor a 8 and nsLTPs from other plant sources. The structure of Cor a 8 represents the first resolved structure of a hazelnut allergen. PMID- 26417908 TI - Heinz Lauener - Urban Folklore. PMID- 26417907 TI - C3-induced release of neurotrophic factors from Schwann cells - potential mechanism behind its regeneration promoting activity. AB - Previous studies revealed a peripheral nerve regeneration (PNR)(1) promoting activity of Clostridium botulinum C3(2) exoenzyme or a 26(mer) C-terminal peptide fragment covering amino acids 156-181 (C3(156-181)),(3) when delivered as one time injection at the lesion site. The current study was performed to 1) investigate if prolonged availability of C3 and C3(156-181) at the lesion site can further enhance PNR in vivo and to 2) elucidate effects of C3 and C3(156-181) on Schwann cells (SCs)(4)in vitro. For in vivo studies, 10 mm adult rat sciatic nerve gaps were reconstructed with the epineurial pouch technique or autologous nerve grafts. Epineurial pouches were filled with a hydrogel containing i) vehicle, ii) 40 MUM C3 or iii) 40 MUM C3(156-181). Sensory and motor functional recovery was monitored over 12 weeks and the outcome of PNR further analyzed by nerve morphometry. In vitro, we compared gene expression profiles (microarray analysis) and neurotrophic factor expression (western blot analysis) of untreated rat neonatal SCs with those treated with C3 or C3(156-181) for 72 h. Effects on neurotrophic factor expression levels were proven in adult human SCs. Unexpectedly, prolonged delivery of C3 and C3(156-181) at the lesion site did not increase the outcome of PNR. Regarding the potential mechanism underlying their previously detected PNR promoting action, however, 6 genes were found to be commonly altered in SCs upon treatment with C3 or C3(156-181). We demonstrate significant down-regulation of genes involved in glutamate uptake (Eaac1,(5)Grin2a(6)) and changes in neurotrophic factor expression (increase of FGF-2(7) and decrease of NGF(8)). Our microarray-based expression profiling revealed novel C3-regulated genes in SCs possibly involved in the axonotrophic (regeneration promoting) effects of C3 and C3(156-181). Detection of altered neurotrophic factor expression by C3 or C3(156-181) treated primary neonatal rat SCs and primary adult human SCs supports this hypothesis. PMID- 26417909 TI - Inhibition of Neutrophil Extracellular Trap Formation after Stem Cell Transplant by Prostaglandin E2. AB - RATIONALE: Autologous and allogeneic hematopoietic stem cell transplant (HSCT) patients are susceptible to pulmonary infections, including bacterial pathogens, even after hematopoietic reconstitution. We previously reported that murine bone marrow transplant (BMT) neutrophils overexpress cyclooxygenase-2, overproduce prostaglandin E2 (PGE2), and exhibit defective intracellular bacterial killing. Neutrophil extracellular traps (NETs) are DNA structures that capture and kill extracellular bacteria and other pathogens. OBJECTIVES: To determine whether NETosis was defective after transplant and if so, whether this was regulated by PGE2 signaling. METHODS: Neutrophils isolated from mice and humans (both control and HSCT subjects) were analyzed for NETosis in response to various stimuli in the presence or absence of PGE2 signaling modifiers. MEASUREMENTS AND MAIN RESULTS: NETs were visualized by immunofluorescence or quantified by Sytox Green fluorescence. Treatment of BMT or HSCT neutrophils with phorbol 12-myristate 13 acetate or rapamycin resulted in reduced NET formation relative to control cells. NET formation after BMT was rescued both in vitro and in vivo with cyclooxygenase inhibitors. Additionally, the EP2 receptor antagonist (PF-04418948) or the EP4 antagonist (AE3-208) restored NET formation in neutrophils isolated from BMT mice or HSCT patients. Exogenous PGE2 treatment limited NETosis of neutrophils collected from normal human volunteers and naive mice in an exchange protein activated by cAMP- and protein kinase A-dependent manner. CONCLUSIONS: Our results suggest blockade of the PGE2-EP2 or EP4 signaling pathway restores NETosis after transplantation. Furthermore, these data provide the first description of a physiologic inhibitor of NETosis. PMID- 26417910 TI - Incidence and Predictors of Left Ventricular Thrombus After Primary Percutaneous Coronary Intervention for Anterior ST-Segment Elevation Myocardial Infarction. AB - BACKGROUND: The role of warfarin in anterior ST-segment elevation myocardial infarction (STEMI) complicated by left ventricular (LV) dysfunction in patients treated with primary percutaneous coronary intervention (PCI) and dual antiplatelet therapy is unclear. Warfarin may prevent cardioembolic events but significantly increases bleeding in the setting of dual antiplatelet therapy. HYPOTHESIS: The incidence of LV thrombus in anterior STEMI patients treated with PCI is low, and clinical predictors might be valuable in determining patients at risk. METHODS: We performed a retrospective, single-center study of 687 consecutive patients with anterior STEMI treated with PCI from 2006 to 2013. Baseline variables were evaluated in 310 patients at high risk for LV thrombus based on echocardiographic criteria. Patients with definite, probable, and no LV thrombus were compared by ANOVA, chi(2), or t test where appropriate. Logistic regression analysis was performed. RESULTS: The incidence of LV thrombus was 15% (n = 47 probable/definite thrombus). Cardiac arrest was the only independent characteristic associated with increased risk of LV thrombus (odds ratio [OR]: 4.06, 95% confidence interval [CI]: 1.3-12.7). Trends were observed for a lower risk in cardiogenic shock (OR: 0.33, 95% CI: 0.10-1.05) and aspirin use at baseline (OR: 0.43, 95% CI: 0.17-1.1). Treatment variables associated with LV thrombus included unfractionated heparin use post-PCI (OR: 2.43, 95% CI: 1.16 5.1) and use of balloon angioplasty without stent. CONCLUSIONS: In contemporary practice with primary PCI, definite LV thrombus following anterior STEMI with LV dysfunction is challenging to predict. Further investigation is needed to determine if there is a subset of patients that should be treated with prophylactic warfarin. PMID- 26417912 TI - Celecoxib enhances [sorafenib + sildenafil] lethality in cancer cells and reverts platinum chemotherapy resistance. AB - The present studies sought to determine whether the lethality of the drug combination [sorafenib + sildenafil] could be enhanced by the anti-inflammatory agent celecoxib, using ovarian cancer and other tumor cell lines as models. Also, in a dose dependent fashion celecoxib enhanced [sorafenib + sildenafil] lethality in multiple ovarian cancer cell lines. In a dose dependent fashion celecoxib enhanced the ability of [sorafenib + sildenafil] to reduce expression of multiple chaperone proteins in parallel with lower levels of the drug efflux pumps ABCB1 and ABCG2. Over-expression of GRP78 and HSP27 maintained pump expression in the presence of drugs. Cell killing by the 3 drug combination was mediated by mitochondrial / caspase 9 -dependent apoptotic signaling and by RIP-1 / caspases 2 and 4 / AIF -dependent necroptotic signaling. Pre-treatment of intrinsically resistant primary ovarian cancer cells with [celecoxib + sorafenib + sildenafil] significantly enhanced tumor cell killing by a subsequent cisplatin exposure. Similar data were obtained in some cancer cell lines, but not all, using the related platinum containing drugs, oxaliplatin and carboplatin. As our prior publications have also validated in vivo the combinations of [celecoxib + sildenafil] and [sorafenib + sildenafil] as cytotoxic to multiple tumor cell types, combined with the present findings, we would argue that the combination of celecoxib/sorafenib/sildenafil should be explored in a new phase I trial in ovarian cancer. PMID- 26417911 TI - Gd3+-1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic-2-hydroxypropyl-beta cyclodextrin/Pluronic Polyrotaxane as a Long Circulating High Relaxivity MRI Contrast Agent. AB - A multivalent magnetic resonance imaging agent based on a 2-hydroxypropyl-beta cyclodextrin (HPCD):Pluronic F127 polyrotaxane carrier has been synthesized, and its blood pool contrast properties have been characterized. This Gd3+-DO3A HPCD/Pluronic polyrotaxane construct is shown to circulate for more than 30 min and provide >100-fold vascular enhancement relative to the monomeric Gd3+-DO3A HPCD control that is rapidly cleared via the kidney. The high r1 relaxivity at 37 degrees C (23.83 mM(-1) s(-1) at 1.5 T; 34.08 mM(-1) s(-1) at 0.5 T), extended blood circulation, well-known pharmacology of the polyrotaxane precursors, and absence of acute toxicity make it a highly attractive blood pool contrast agent candidate. PMID- 26417914 TI - DNA methylation of tumor suppressor protein-coding and non-coding genes in multiple myeloma. AB - Multiple myeloma is an incurable hematological malignancy arising from immortalized plasma cells in the bone marrow. DNA methylation refers to the catalytic addition of a methyl group to the cytosine ring of a CpG dinucleotide. Methylation of a promoter-associated CpG island, a cluster of CpG dinucleotides, may lead to silencing of the associated gene. In carcinogenesis, methylation of protein-coding or non-coding tumor suppressor genes/miRNAs is associated with transcriptional silencing, loss of tumor suppressor function and prognostic significance. This review first introduces pathogenesis of myeloma and DNA methylation in cancer. Then, it summarizes methylation of protein-coding tumor suppressor genes, especially, the latest genome-wide methylation studies in myeloma, followed by the latest findings of methylation of non-coding tumor suppressor miRNAs in myeloma. PMID- 26417913 TI - Synergistic Efficacy from Gene Therapy with Coreceptor Blockade and a beta2 Agonist in Murine Pompe Disease. AB - Pompe disease (glycogen storage disease type II; acid maltase deficiency) is a devastating myopathy resulting from acid alpha-glucosidase (GAA) deficiency in striated and smooth muscle. Despite the availability of enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), the limitations of ERT have prompted the preclinical development of gene therapy. Gene therapy has the advantage of continuously producing GAA, in contrast to ERT, which requires frequent injections of rhGAA. An adeno-associated viral (AAV) vector containing a muscle-specific promoter, AAV-MHCK7hGAApA, achieved high GAA expression in heart and skeletal muscle in mice with Pompe disease. However, elevated GAA activity was not sufficient to completely clear accumulated glycogen in skeletal muscle. The process of glycogen clearance from lysosomes might require improved trafficking of GAA to the lysosomes in skeletal muscle, previously achieved with the beta(2)-agonist clenbuterol that enhanced glycogen clearance in skeletal muscle without increasing GAA activity. Glycogen clearance was clearly enhanced by treatment with a nondepleting anti-CD4 monoclonal antibody (anti-CD4 mAb) along with muscle-specific GAA expression in cardiac muscle, but that treatment was not effective in skeletal muscle. Furthermore, anti-CD4 mAb treatment along with clenbuterol achieved synergistic therapeutic efficacy in both cardiac and skeletal muscle. This triple therapy increased both muscle strength and weight gain. Overall, triple therapy to enhance GAA trafficking and to suppress immune responses significantly improved the efficacy of muscle-targeted gene therapy in murine Pompe disease. PMID- 26417915 TI - Case Sequencing of Diagnostic Imaging Studies Performed Under General Anesthesia or Monitored Anesthesia Care During Nights and Weekends. AB - General anesthesia or monitored anesthesia care sometimes is provided in nonoperating room (OR) locations during nights and weekends (e.g., for magnetic resonance imaging [MRI] or computerized tomography [CT]). Rational and consistent scheduling and sequencing decisions for these diagnostic imaging procedures, including coordination with OR cases, cannot be done without knowing how long each case can wait to be started without risking a worsening of the patient's condition. We reviewed the medical records of the 81 patients who underwent diagnostic imaging procedures (78 = MRI, 3 = CT scan) under general anesthesia or monitored anesthesia care either on weekends or between 6 pm and 6 am at the University of Iowa Hospitals between March 2012 and February 2014. For 77.8% of patients, the indications could have changed clinical management within 4 hours (N = 63/81). Among the 63 imaging studies with potential immediate impact, there was documentation of results having been communicated to the treating team within 4 hours of the completion of imaging for 39 of the patients. Among the 39 patients, 15 promptly received medications or underwent procedures based on the imaging results. Thus, 15 of the 81 patients had a change in care (18.5%, 95% lower confidence limit = 11.2%). Our results are important since we showed previously that it is not possible to make rational and consistent decisions in case sequencing without knowing how long each case (including diagnostic imaging procedures) can wait to be started without a change in the patient's risk. The scheduled surgical procedure itself provides sufficient information to assess safe waiting times to start add-on cases (e.g., appendectomy). In contrast, MRI provides no context as to how potential findings will influence treatment. Our results show that the assumption cannot reasonably be made when sequencing cases that all imaging studies can or cannot wait longer than pending surgical procedures. Our results show that, for evidence-based OR management decision making, information to decide appropriate waiting should be obtained electronically or verbally for each imaging study. PMID- 26417916 TI - In Situ Analysis of Gas Generation in Lithium-Ion Batteries with Different Carbonate-Based Electrolytes. AB - Gas generation in lithium-ion batteries is one of the critical issues limiting their safety performance and lifetime. In this work, a set of 900 mAh pouch cells were applied to systematically compare the composition of gases generated from a serial of carbonate-based composite electrolytes, using a self-designed gas analyzing system. Among electrolytes used in this work, the composite gamma butyrolactone/ethyl methyl carbonate (GBL/EMC) exhibited remarkably less gassing because of the electrochemical stability of the GBL, which makes it a promising electrolyte for battery with advanced safety and lifetime. PMID- 26417917 TI - Siege of Leningrad Survivors Phenotyping and Biospecimen Collection. AB - BACKGROUND: Poor nutrition during the early stages of human development can lead to rare pathological conditions in adult life. The best-known and most severe historical cases of famine include the Dutch 'Hunger Winter,' the Finnish famine, the Chinese Great famine, and the siege of Leningrad. The siege of Leningrad (now Saint Petersburg) was one of the longest in history, lasting 872 days, from September 8, 1941 to January 27, 1944. There were 670,000 registered deaths of the civil population, in which 97% died due to starvation. The aim of the present study is to create a collection of biospecimens from extensively phenotyped siege of Leningrad survivors, who underwent starvation during the early periods of their lives, and from a matched control group. METHODS: A total 305 siege survivors and 51 age- and sex- matched control subjects were investigated in of an observational retroprospective cohort study in 2009-2011 at a baseline visit. After 3 years of follow-up, 252 siege survivors (182 females and 70 males; mean age 74.7 +/- 2.6 years) and 45 controls (32 females and 13 males; mean age 75.5 +/- 2.8 years) were examined. All siege survivors were exposed to the extreme dietary restriction and stress associated with the siege in their early childhood. All participants signed informed consent and were subject to questionnaires and physical examination, as well as various laboratory and instrumental tests. Anthropometry, blood measurement, cognitive and physiological testing, and vascular damage assessment were performed. RESULTS: Blood specimens of the extensively phenotyped siege survivors were collected and processed (blood plasma, blood serum, and flash-frozen PBMC); serum and urine were used for laboratory tests. CONCLUSIONS: We believe that data obtained from this unique collection of biospecimens can elucidate the mechanisms of healthy aging and emphasize the importance of reproductive health, counseling, and monitoring among people with eating disorders. PMID- 26417918 TI - Picosecond Dynamics of Excitonic Magnetic Polarons in Colloidal Diffusion-Doped Cd(1-x)Mn(x)Se Quantum Dots. AB - Spontaneous magnetization is observed at zero magnetic field in photoexcited colloidal Cd(1-x)Mn(x)Se (x = 0.13) quantum dots (QDs) prepared by diffusion doping, reflecting strong Mn(2+)-exciton exchange coupling. The picosecond dynamics of this phenomenon, known as an excitonic magnetic polaron (EMP), are examined using a combination of time-resolved photoluminescence, magneto photoluminescence, and Faraday rotation (TRFR) spectroscopies, in conjunction with continuous-wave absorption, magnetic circular dichroism (MCD), and magnetic circularly polarized photoluminescence (MCPL) spectroscopies. The data indicate that EMPs form with random magnetization orientations at zero external field, but their formation can be directed by an external magnetic field. After formation, however, external magnetic fields are unable to reorient the EMPs within the luminescence lifetime, implicating anisotropy in the EMP potential-energy surfaces. TRFR measurements in a transverse magnetic field reveal rapid (<5 ps) spin transfer from excitons to Mn(2+) followed by coherent EMP precession at the Mn(2+) Larmor frequency for over a nanosecond. A dynamical TRFR phase inversion is observed during EMP formation attributed to the large shifts in excitonic absorption energies during spontaneous magnetization. Partial optical orientation of the EMPs by resonant circularly polarized photoexcitation is also demonstrated. Collectively, these results highlight the extraordinary physical properties of colloidal diffusion-doped Cd(1-x)Mn(x)Se QDs that result from their unique combination of strong quantum confinement, large Mn(2+) concentrations, and relatively narrow size distributions. The insights gained from these measurements advance our understanding of spin dynamics and magnetic exchange in colloidal doped semiconductor nanostructures, with potential ramifications for future spin-based information technologies. PMID- 26417919 TI - Factors Leading to Rapid Response Team Interventions in Adult Medical-Surgical Patients. AB - The effectiveness of a Rapid Response Team Intervention (RRTI) in preventing transfer to a higher level of care and decreasing in-hospital mortality has not been firmly established. This retrospective exploratory study examined differences between medical-surgical patients who had an RRTI and those who did not. Results yielded 5 statistically significant differences (P <= .05) between the 2 groups as well as a large variation (range, 0-238 minutes; SD = 87.73 minutes) between time of documentation of RRTI criteria to time in calling an RRTI. PMID- 26417920 TI - Systematic Review of Control Measures to Reduce Hazardous Drug Exposure for Health Care Workers. AB - Because of their involvement in the transport, handling, preparation, administration, or disposal of hazardous medications, health care workers across multiple settings are at risk for adverse health consequences from exposure to these drugs. This review presents evidence-based strategies to mitigate the harmful exposures. These include engineering controls, full use of personal protective equipment, medical and environmental monitoring, hazard identification, and the need for a comprehensive hazardous drug control program that includes education and training for health care workers. PMID- 26417921 TI - Significant differences of monooxotungsten(IV) and dioxotungsten(VI) benzenedithiolates containing two intramolecular NHS hydrogen bonds from molybdenum analogues. AB - A monooxotungsten(iv) benzenedithiolate complex containing two intramolecular NHS hydrogen bonds, (NEt4)2[W(IV)O(1,2-S2-3-t-BuNHCOC6H3)2] (1-W), was synthesized via a ligand-exchange reaction between a new starting complex, (NEt4)2[W(IV)O(SC6F5)4], and a partially deprotonated dithiol. When dithiol was used in solution, the oxo ligand was protonated and removed to afford (NEt4)2[W(IV)(1,2-S2-3-t-BuNHCOC6H3)3]. The trans isomer, trans-1-W, was crystallized, and the molecular structure was determined via X-ray analysis. Trans-1-W was gradually isomerized by heating it in solution and it eventually achieved an approximately 1 : 1 mixture of trans/cis isomers after 48 days. However, a slightly excess amount of trans isomer remained, so the isomerization rate was considerably slower than that of the molybdenum analogue. In the presence of NEt4BH4, deuteration of the NH protons was observed in acetonitrile d3. The oxidation of both trans- and cis-1-W by Me3NO afforded the corresponding dioxotungsten(vi) complex, (NEt4)2[W(VI)O2(1,2-S2-3-t-BuNHCOC6H3)2] (2-W), as a single isomer. The contributions of the NHS hydrogen bonds to the bond distances, vibrational data, and electrochemical properties are described via comparisons with their molybdenum analogues. The results of this comparative study yielded insights into both tungsten and molybdenum enzymes. PMID- 26417922 TI - Formaldehyde as Tethering Organocatalyst: Highly Diastereoselective Hydroaminations of Allylic Amines. AB - Catalysts possessing sufficient activity to achieve intermolecular alkene hydroaminations under mild conditions are rare, and this likely accounts for the scarcity of asymmetric variants of this reaction. Herein, highly diastereoselective hydroaminations of allylic amines utilizing hydroxylamines as reagents and formaldehyde as catalyst are reported. This catalyst induces temporary intramolecularity, which results in high rate accelerations, and high diastereocontrol with either chiral allylic amines or chiral hydroxylamines. The reaction scope includes internal alkenes. Overall this work provides a new, stereocontrolled route to form complex vicinal diamines. PMID- 26417923 TI - The Growth of Palliative Care in U.S. Hospitals: A Status Report. AB - BACKGROUND: Palliative care is expanding rapidly in the United States. OBJECTIVE: To examine variation in access to hospital palliative care. METHODS: Data were obtained from the American Hospital Association (AHA) Annual SurveysTM for Fiscal Years 2012 and 2013, the National Palliative Care RegistryTM, the Dartmouth Atlas of Healthcare, the American Census Bureau's American Community Survey (ACS), web searches, and telephone interviews of hospital administrators and program directors. Multivariable logistic regression was used to examine predictors of hospital palliative care programs. RESULTS: Sixty-seven percent of hospitals with 50 or more total facility beds reported a palliative care program. Institutional characteristics were strongly associated with the presence of a hospital palliative care program. Ninety percent of hospitals with 300 beds or more were found to have palliative care programs as compared to 56% of hospitals with fewer than 300 beds. Tax status was also a significant predictor. Not-for-profit hospitals and public hospitals were, respectively, 4.8 times and 7.1 times more likely to have a palliative care program as compared to for-profit hospitals. Palliative care penetration was highest in the New England (88% of hospitals), Pacific (77% of hospitals), and mid-Atlantic (77% of hospitals) states and lowest in the west south central (43% of hospitals) and east south central (42% of hospitals) states. CONCLUSIONS: This study demonstrates continued steady growth in the number of hospital palliative care programs in the United States, with almost universal access to services in large U.S. hospitals and academic medical centers. Nevertheless access to palliative care remains uneven and depends on accidents of geography and hospital ownership. PMID- 26417925 TI - Comparative study of van der Waals corrections to the bulk properties of graphite. AB - Graphite is a stack of honeycomb (graphene) layers bound together by nonlocal, long-range van der Waals (vdW) forces, which are poorly described by density functional theory (DFT) within local or semilocal exchange-correlation functionals. Several approximations have been proposed to add a vdW correction to the DFT total energies (Stefan Grimme (D2 and D3) with different damping functions (D3-BJ), Tkatchenko-Scheffler (TS) without and with self-consistent screening (TS + SCS) effects). Those corrections have remarkly improved the agreement between our results and experiment for the interlayer distance (from 3.9 to 0.6%) [corrected] and high-level random-phase approximation (RPA) calculations for interlayer binding energy (from 69.5 to 1.5%). [corrected]. We report a systematic investigation of various structural, energetic and electron properties with the aforementioned vdW corrections followed by comparison with experimental and theoretical RPA data. Comparison between the resulting relative errors shows that the TS + SCS correction provides the best results; the other corrections yield significantly larger errors for at least one of the studied properties. If considerations of computational costs or convergence problems rule out the TS + SCS approach, we recommend the D3-BJ correction. Comparison between the computed pi(z)Gamma-splitting and experimental results shows disagreements of 10% or more with all vdW corrections. Even the computationally more expensive hybrid PBE0 has proved unable to improve the agreement with the measured splitting. Our results indicate that improvements of the exchange correlation functionals beyond the vdW corrections are necessary to accurately describe the band structure of graphite. PMID- 26417924 TI - Thioredoxins in cardiovascular disease. AB - Key thioredoxin (Trx) system components are nicotinamide adenine dinucleotide phosphate (NADPH), Trx reductase (TrxR), and Trx. TrxR catalyzes disulfide reduction in Trx with NADPH as cofactor. Because Trx is an antioxidant, oxidative stress results in an increase in Trx, which has a reduced disulfide component. If Trx is suppressed, oxidative stress in higher. In contrast a decrease in oxidative stress is associated with low Trx levels. Trx is involved in inflammation, apoptosis, embryogenesis, and cardiovascular disease (CVD). This review focuses on the Trx system in CVD. Abnormal Trx binding occurs in mouse familial combined hyperlipidemia; however, this has not been confirmed in humans. Congestive heart failure is a manifestation of many CVDs, which may be improved by attenuating oxidative stress through the suppression of Trx and decreased reactive oxygen species. Angiotensin II is associated with hypertension and other CVDs, and its receptor blockade results in decreased oxidative stress with reduced Trx levels. Inflammation is a major causative factor of CVDs, and myocarditis as an example, is associated with increased Trx levels. Vascular endothelial dysfunction has an association with CVD. This dysfunction is alleviated by hormone replacement therapy, which involves decreased oxidative stress and Trx levels. Diabetes mellitus has a major association with CVDs; increase in Trx levels may reflect insulin resistance. Identification of Trx system abnormalities may lead to innovative approaches to treat multiple CVDs and other pathologies. PMID- 26417926 TI - Femtosecond Laser Flap Creation for Laser In Situ Keratomileusis in the Setting of Previous Radial Keratotomy. AB - PURPOSE: The aim of the study was to report the outcomes of laser in situ keratomileusis (LASIK) in subjects with previous radial keratotomy (RK) using a novel femtosecond laser setting on a proprietary femtosecond laser platform. DESIGN: This was a retrospective, consecutive chart review of patients at a single private practice institution. METHODS: The medical records of 16 eyes of 8 subjects who underwent femtosecond-assisted LASIK for consecutive hyperopia after RK were retrospectively reviewed. The preoperative characteristics, intraoperative details, and postoperative outcomes were analyzed. RESULTS: All 16 eyes had successful femtosecond laser flap creation without significant intraoperative or postoperative complications. Uncorrected visual acuity significantly improved postoperatively (P = 0.0142) and remained stable through the final follow-up interval at 9 to 12 months postoperatively. None of the subjects lost any lines of best spectacle-corrected visual acuity in the postoperative period. CONCLUSIONS: The novel femtosecond laser technique described in this study can provide a safe and effective method for patients undergoing LASIK after previous RK. Future investigations are required to further validate the findings reported in this study. PMID- 26417927 TI - Visual Performance After Contralateral Implantation of Multifocal Intraocular Lenses With +3.0 and +4.0 Diopter Additions. AB - PURPOSE: To evaluate visual performance after contralateral implantation of AcrySof ReSTOR aspheric intraocular lenses (IOLs) with +3.0 and +4.0 diopter near additions. DESIGN: This was a retrospective case study conducted at Tokyo Dental College Suidobashi Hospital in Tokyo, Japan. METHODS: Eleven patients who were implanted with the SN6AD1 IOL and the SN6AD3 IOL contralaterally were included in this study. The distance, intermediate (1 m, 50 cm), and near (40 and 30 cm) uncorrected and corrected binocular visual acuity (VA), contrast sensitivity, depth of focus, and patient satisfaction were assessed more than 1 month postoperatively. RESULTS: Postoperatively, the mean uncorrected (corrected) binocular logarithm of the minimum angle of resolution VA levels were as follows: distance, -0.120 (-0.163); intermediate, 1 m, 0.226 (0.012) and 50 cm, 0.037 (0.006); and near, 40 cm, 0.067 (-0.040) and 30 cm, 0.091 (-0.053). The depth of focus had a smooth curve with double peaks. The mean contrast sensitivity was normal at all spatial frequencies. All patients were spectacle independent and expressed high satisfaction. CONCLUSIONS: Contralateral implantation of multifocal IOLs with +3.0 and +4.0 D additions takes advantage of the good uncorrected near VA provided by both IOLs and may be an option for patients who require a broader range of good uncorrected near VA. PMID- 26417928 TI - Neuro-Ophthalmology Annual Review. AB - PURPOSE: The purpose of this review was to update the practicing ophthalmologist on the English language neuro-ophthalmology literature from the past year. DESIGN: A review of English language literature from August 1, 2013, to August 1, 2014, was conducted. METHODS: The author searched PubMed from August 1, 2013, to August 1, 2014, limited to English language publications including original articles, review articles, and case reports and excluding letters to the editor, unpublished work, and abstracts. The following topics were searched: pupillary abnormalities, eye movement dysfunction, neuromuscular diseases, optic neuropathies, optic neuritis, demyelinating diseases including multiple sclerosis, lesions of the optic chiasm and posterior primary visual pathways, elevated intracranial pressure, tumors and aneurysms affecting the visual pathways, vascular diseases, higher visual function, and neuroimaging advances. The focus of this review is on clinically relevant literature in the past year for the practicing ophthalmologist. The aim was to highlight remarkable and interesting literature rather than exhaustively including all new neuro ophthalmological publications of the year. RESULTS: Initially, more than 11,000 articles were identified. One hundred were selected that met criteria specified above. CONCLUSIONS: This review updates the comprehensive ophthalmologist on neuro-ophthalmic topics. PMID- 26417929 TI - Cytotoxic T cell responses are enhanced by antigen design involving the presentation of MUC1 peptide on cholera toxin B subunit. AB - Induction of cytotoxic T lymphocytes (CTL) is critical to cancer vaccine based immunotherapy. Efforts to elicit CTLs against tumor MUC1 with peptide based vaccine have not been successful in clinical application. We have design a MUC1 vaccine by replacing B cell epitope of CTB with MUC1 VNTR peptide. Immunization with hybrid CTB-MUC1 plus aluminum hydroxide and CpG adujuvant (CTB-MUC1-Alum CpG) induce MUC1-specific CTLs in mice. Moreover, this vaccination can prevent tumor growth and reduce tumor burden in MUC1+B16 mice model. Meanwhile, CTB-MUC1 Alum-CpG vaccination can promote Th1 cells and CD8+ T cells inflate to tumor tissue. Our approach might be applicable to other cancer vaccine design. PMID- 26417930 TI - The G-protein-coupled bile acid receptor Gpbar1 (TGR5) suppresses gastric cancer cell proliferation and migration through antagonizing STAT3 signaling pathway. AB - Gpbar1 (TGR5), a membrane-bound bile acid receptor, is well known for its roles in regulation of energy homeostasis and glucose metabolism. Here we show that TGR5 is a suppressor of gastric cancer cell proliferation and migration through antagonizing STAT3 signaling pathway. We firstly show that TGR5 activation greatly inhibited proliferation and migration of human gastric cancer cells and strongly induced gastric cancer cell apoptosis. We then found that TGR5 activation antagonized STAT3 signaling pathway through suppressing the phosphorylation of STAT3 and its transcription activity induced by lipopolysaccharide (LPS) or interleukin-6. TGR5 overexpression with ligand treatment inhibited gene expression mediated by STAT3. It suggests that TGR5 antagonizes gastric cancer proliferation and migration at least in part by inhibiting STAT3 signaling. These findings identify TGR5 as a suppressor of gastric cancer cell proliferation and migration that may serve as an attractive therapeutic tool for human gastric cancer. PMID- 26417931 TI - MicroRNA-99a inhibits tumor aggressive phenotypes through regulating HOXA1 in breast cancer cells. AB - MicroRNAs (miRNAs) are key regulators of tumor progression. Based on microarray data, we identified miR-99a as a potential tumor suppressor in breast cancer. Expression of miR-99a is frequently down-regulated in breast cancer tissues relative to normal breast tissues. Reduced miR-99a expression was highly associated with lymph node metastasis and shorter overall survival of patients with breast cancer. Gain- and loss-of-function studies revealed that, miR-99a significantly inhibits breast cancer cell proliferation, migration, and invasion. An integrated bioinformatics analysis identified HOXA1 mRNA as the direct functional target of miR-99a, and this regulation was confirmed by luciferase reporter assay. Furthermore, we showed for the first time that HOXA1 expression is elevated in breast cancer tissues. Knockdown of HOXA1 significantly inhibited breast cancer cell proliferation, migration and invasion, and restoration of HOXA1 partially rescued the inhibitory effect of miR-99a in breast cancer cells. Collectively, our data indicate that miR-99a plays a tumor-suppressor role in the development of breast cancer, and could serve as a potential therapeutic target for breast cancer treatment. PMID- 26417934 TI - Early and mid-term outcomes of a novel Endovascular Aneurysm Sealing (EVAS) system in patients with infrarenal Abdominal Aortic Aneurysms. AB - BACKGROUND: Endovascular aneurysm sealing (EVAS) using the Nellix system is a promising technology for Abdominal Aortic Aneurysm (AAA) treatment. Long-term data is unavailable regarding the potential modifications of the EndoBags and their content, and the polymer behavior over time. We present our initial clinical experience with this sac anchoring endoprosthesis in 24 patients with a maximum 12 months follow-up. METHODS AND RESULTS: From December 2013 to March 2015, 24 patients with an infrarenal AAA were treated with the NellixTM System. Computed Tomography Angiography (CTA) scan control was performed at 30 days, and follow-up Magnetic Resonance Angiography (MRA) and ultrasounds were performed at 30 days, 6 and 12 months. Median and peak systolic velocities in the suprarenal aorta were measured preoperatively and during follow-up using phase contrast sequences and Argus (Siemens, Erlangen, Germany) software of the MRA. We achieved 100% technical success, 0% aneurysm-related mortality and 0% endoleaks. One patient (4%) experienced early acute thrombosis of a single Nellix stent, successfully treated with thrombolysis. Sac shrinkage occurred in 80% of cases with 12 months follow-up. CONCLUSIONS: Our preliminary clinical experience is promising, with 100% early technical success and satisfactory sealing of the aneurysm sac. Post-procedural controls during 1-year- follow-up revealed no morphologic changes of the aneurysm wall, stable device and endobag position, and gradual dissolution of the air initially trapped within the EndoBags. Aneurysmal sac shrinkage occurs and probably is due to the remodeling of the thrombus around the EndoBags and the dissipation of the air bubbles into the EndoBags. PMID- 26417932 TI - Wnt/beta-catenin, an oncogenic pathway targeted by H. pylori in gastric carcinogenesis. AB - A section of gastric cancers presents nuclear beta-catenin accumulation correlated with H. pylori infection. H. pylori stimulate Wnt/beta-catenin pathway by activating oncogenic c-Met and epidermal growth factor receptor (EGFR), or by inhibiting tumor suppressor Runx3 and Trefoil factor 1 (TFF1). H. pylori also trigger Wnt/beta-catenin pathway by recruiting macrophages. Moreover, Wnt/beta catenin pathway is found involved in H. pylori-induced gastric cancer stem cell generation. Recently, by using gastroids, researchers have further revealed that H. pylori induce gastric epithelial cell proliferation through beta-catenin. These findings indicate that Wnt/beta-catenin is an oncogenic pathway activated by H. pylori. Therefore, this pathway is a potential therapy target for H. pylori related gastric cancer. PMID- 26417933 TI - Nickel chloride (NiCl2)-caused inflammatory responses via activation of NF-kappaB pathway and reduction of anti-inflammatory mediator expression in the kidney. AB - Nickel (Ni) or Ni compounds target a number of organs and produce multiple toxic effects. Kidney is the major organ for Ni accumulation and excretion. There are no investigations on the Ni- or Ni compounds-induced renal inflammatory responses in human beings and animals at present. Therefore, we determined NiCl2-caused alteration of inflammatory mediators, and functional damage in the broiler's kidney by the methods of biochemistry, immunohistochemistry and quantitative real time polymerase chain reaction (qRT-PCR). Dietary NiCl2 in excess of 300 mg/kg caused the renal inflammatory responses that characterized by increasing mRNA expression levels of the pro-inflammatory mediators including tumor necrosis factor-alpha (TNF-alpha), cyclooxygenase-2 (COX-2), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-18 (IL-18) via the activation of nucleic factor kappaB (NF-kappaB), and decreasing mRNA expression levels of the anti-inflammatory mediators including interleukin-2 (IL-2), interleukin-4 (IL-4) and interleukin-13 (IL-13). Concurrently, NiCl2 caused degeneration, necrosis and apoptosis of the tubular cells, which was consistent with the alteration of renal function parameters including elevated alkaline phosphatase (AKP) activity, and reduced activities of sodium-potassium adenosine triphosphatase (Na(+)/K(+)-ATPase), calcium adenosine triphosphatase (Ca(2+) ATPase), lactic dehydrogenase (LDH), succinate dehydrogenase (SDH) and acid phosphatase (ACP) in the kidney. The above-mentioned results present that the activation of NF-kappaB pathway and reduction of anti-inflammatory mediator expression are main mechanisms of NiCl2-caused renal inflammatory responses and that the renal function is decreased or impaired after NiCl2-treated. PMID- 26417936 TI - The endovascular treatment of juxta-renal abdominal aortic aneurysm using fenestrated endograft: early and mid-term results. AB - AIM: To evaluate the early and mid term results of the endovascular treatment of juxta-renal abdominal aortic aneurysms (j-AAA) using fenestrated endograft (FEVAR). METHODS: Between 2008 to 2013 all consecutive patients underwent FEVAR using Cook-Zenith fenestrated endograft for treating j-AAA (proximal neck length <5mm) with renal aortic alpha/beta angle < 60 degrees , were prospectively collected in a database. Cardiovascular risk factors, co-morbidities, aortic- iliac morphological features, intra and post-procedural data were analyzed. Pre operative FEVAR planning was performed by a thoraco-abdominal computer tomography angiography (CTA) and the 3D/Center Lumen Line reconstructions (3Mensio). Follow up was conduced by duplex ultrasound (DUS)/ contrast enhancement DUS (CEUS) and/or CTA at 1,6,12-month and yearly thereafter. Early endpoints were: technical (TS) / clinical (CS) success, renal function worsening (>= 30% of pre- operative creatinine value) and type I/III endoleak. Mid term endpoints were: type I/III endoleak, target visceral vessels patency, j-AAA shrinkage, freedom from re intervention and survival. RESULTS: Twenty patients (M: 94.7%; mean age: 73.4+/ 5.9 years; ASA >=3: 100%) were enrolled. The mean neck length and j-AAA diameter were 2 +/- 1.4mm (range: 0-4mm) and 54.9 +/-5mm respectively. Eleven (55%) endograft with 2 fenestrations and a scallop, 8 (45%) with 3 fenestrations and a scallop and 1 (5%) with 1 fenestration and a scallop were implanted. Sixty-seven visceral vessels were re-vascularized. TS and CS were 100% and 95% respectively (1/20 30-day mortality). Peri-operative renal function worsening was observed in 15% of cases. The mean follow-up was 25+/-20 months (range: 2-72months). No type I/III endoleak or occlusion of target visceral vessels occurred. There was j-AAA shrinkage in 65% of patients and no cases of j-AAA enlargement were observed. There were no FEVAR-related re-interventions. Survival at 12, 24 and 36 months were 89.4%, 80.5% e 80.5% respectively. CONCLUSION: According to our results, the endovascular treatment for j-AAA, with alpha/beta angle < 60 degrees , is safe and effective. PMID- 26417935 TI - First experience with the new Sorin Crown PRT bioprosthetic aortic valve: early postoperative outcome and hemodynamic performance in 90 patients. AB - AIM: The Crown PRT (The Phospholipid Reduction Treatment) is a new stent bovine bioprosthesis for aortic valve replacement (AVR). Aim of this paper is to report the postoperative clinical and hemodynamic results after ninety consecutive implants. METHODS: After receiving CE mark in July 2014, two European university centers implanted the new Crown PRT (Sorin Group, Burnaby, Canada) for the first time. Up to now, ninety patients underwent aortic valve replacement, in isolated or combined procedures, for aortic stenosis or insufficiency. Intraoperative transesophageal echocardiogram was used to assess the prosthesis's function. In hospital outcomes and echocardiographic parameters were recorded. RESULTS: Age and Log Euroscore were 71.8+/-7.9 years and 10.2%+/-4.5 respectively. In-hospital mortality for isolated AVR was 0%; one patient died after a multiple procedure (overall 30-days mortality 1.1%). No adverse device effects were recorded. Intensive Care Unit stay was 2+/-5.8 days. At discharge, echocardiogram showed no paravalvular leaks and normal postoperative gradients. CONCLUSION: Our starting results showed that the Crown PRT is safe and reliable, with excellent hemodynamic performance. Further clinical results with a larger population and long term follow-up are needed to assess the versatility and the durability of this new device. PMID- 26417937 TI - Abdominal aortic aneurysm. AB - Endovascular repair of abdominal aortic aneurysm has become a milestone in the treatment of patients with abdominal aortic aneurysm.Technological improvement allows treatment in more and more complex cases. This review summarizes all grafts available in the market. At the best of our knowledge a complete review of most important trial on this topic are provided and at least technical tips and tricks for standard cases are recapitulated. PMID- 26417938 TI - Hydrogen peroxide-independent generation of superoxide catalyzed by soybean peroxidase in response to ferrous ion. AB - It is well documented that extracellular alkalization occurs in plants under the challenges by pathogenic microbes. This may eventually induce the pH-dependent extracellular peroxidase-mediated oxidative burst at the site of microbial challenges. By employing the purified proteins of horseradish peroxidase as a model, we have recently proposed a likely role for free Fe(2+) in reduction of ferric enzyme of plant peroxidases into ferrous intermediate and oxygen-bound form of enzyme known as Compound III which may eventually releases superoxide anion radical (O2(*-)), especially under alkaline condition, possibly contributing to the plant defense mechanism. In the present study, we employed the purified protein of soybean peroxidase (SBP) as an additional model, and examined the changes in the redox status of enzyme accompanying the generation of O2(*-) in response to Fe(2+) under alkaline condition. PMID- 26417940 TI - Anatomical and Morphological Features of the Fetal Human Pancreaticobiliary Ductal Union. AB - To investigate pancreaticobiliary ductal anatomy during developmental stages, gallbladders, common bile ducts, pancreatic ducts and their interface with the duodenum were studied in 36 human fetuses between 4-6 weeks postconceptual age were studied. For histological examination, sections were cut continuously from the paraffin-embedded tissue block and stained with hematoxylin and eosin. The expression of proliferating cell nuclear antigen in the gallbladder was examined with immunohistochemistry. Among 36 cases, three shapes of the greater duodenal papilla were found: hemispheroid (58.1%), circular cylinder (25%), and flat shape (16.9%). For the location of the greater duodenal papillas, more than half (69.4%) of the cases were in the middle descendant duodenum. Seven cases (19.4%) were in the lower descendant duodenum. Three cases (8.3%) were in the upper descendant duodenum, and one (2.9%) was in the distal descending part of duodenum. There were four types of the pancreaticobiliary ductal union: "Y" in 24 cases(66.7%), "U" in 4 cases (11.1%),"V" in 7 cases (19.4%), and pancreaticobiliary maljunction in 1 case (2.8%). For patients with congenital bile duct dilation and Biliary cancer, the positive cells of proliferating cell nuclear antigen were increased significantly (P < 0.05). Different types in pancreaticobiliary ductal union investigated in this study may provide clues for pathogenesis and clinical treatment of pancreaticobiliary maljunction. PMID- 26417939 TI - ADAM12 and PAPP-A: Candidate regulators of trophoblast invasion and first trimester markers of healthy trophoblasts. AB - Proper placental development and function is crucial for a healthy pregnancy, and there has been substantial research to identify markers of placental dysfunction for the early detection of pregnancy complications. Low first-trimester levels of a disintegrin and metalloproteinase 12 (ADAM12) and pregnancy-associated plasma protein-A (PAPP-A) have been consistently associated with the subsequent development of preeclampsia and fetal growth restriction. These molecules are both metalloproteinases secreted by the placenta that cleave insulin-like growth factor binding proteins (IGFBPs), although ADAM12 also has numerous other substrates. Recent work has identified ADAM12, and particularly its shorter variant, ADAM12S, as a regulator of the migration and invasion of trophoblasts into the lining of the uterus, a critical step in normal placental development. While the mechanisms underlying this regulation are not yet clear, they may involve the liberation of heparin-binding EGF-like growth factor (HB-EGF) and/or IGFs from IGFBPs. In contrast, there has been relatively little functional work examining PAPP-A or the IGFBP substrates of ADAM12 and PAPP-A. Understanding the functions of these markers and the mechanisms underlying their association with disease could improve screening strategies and enable the development of new therapeutic interventions. PMID- 26417941 TI - Diffusion of Benzene and Alkylbenzenes in n-Alkanes. AB - The translational diffusion constants, D, of benzene and a series of alkylbenzenes have been determined in four n-alkanes at room temperature using capillary flow techniques. The alkylbenzenes are toluene, ethylbenzene, 1 phenylpropane, 1-phenylpentane, 1-phenyloctane, 1-phenylundecane, 1 phenyltetradecane, and 1-phenylheptadecane. The n-alkanes are n-nonane, n-decane, n-dodecane, and n-pentadecane. Ratios of the solutes' D values are independent of solvent and in general agreement with the predictions of diffusion models for cylinders and lollipops. For the latter, an alkylbenzene's phenyl ring is the lollipop's candy; the alkyl chain is its handle. A model that considers the solutes to be spheres with volumes determined by the van der Waals increments of their constituent atoms is not in agreement with experiment. The diffusion constants of 1-alkene and n-alkane solutes in n-alkane solvents also are compared with the cylinder model; reasonably good agreement is found. The n-alkanes are relatively extended, and this appears to be the case for the alkyl chains of the 1-alkenes and alkylbenzenes as well. PMID- 26417943 TI - Synthetic and Structural Studies of Mixed Sodium Bis(trimethylsilyl)amide/Sodium Halide Aggregates in the Presence of eta(2)-N,N-, eta(3)-N,N,N/N,O,N-, and eta(4) N,N,N,N-Donor Ligands. AB - When n-hexane solutions of an excess of sodium bis(trimethylsilyl)amide (NaHMDS) are combined with cesium halide (halide = Cl, Br, or I) in the presence of the tetradentate donor molecule [tris[2-(dimethylamino)ethyl]amine] (Me6TREN), the isolation and characterization of a series of sodium amide/sodium halide mixed aggregates was forthcoming. Cesium halide was employed because it efficiently reacted with NaHMDS to produce a molecular, soluble source of sodium halide salt (which was subsequently captured by an excess of NaHMDS) via a methathetical reaction. These mixed sodium amide/sodium halide complexes are formally sodium sodiates, are deficient in halide with respect to the amide, and have the general formula [{Na5(MU-HMDS)5(MU5-X)}{Na(Me6TREN)}] [where X = Cl (1), Br (2), or I (3)]. The influence of the donor ligand was studied for the NaI/NaHMDS system, and when n-hexane solutions of this composition were treated with tridentate donors such as N,N,N',N",N"-pentamethyldiethylenetriamine (PMDETA) or N,N,N',N' tetramethyldiaminoethyl ether (TMDAE), solvent-separated ion-pair cocomplexes [Na5(MU-HMDS)5(MU5-I)](-)[Na3(MU-HMDS)2(PMDETA)2](+) (4) and [Na5(MU-HMDS)5(MU5 I)](-)[Na(TMDAE)2](+) (5) were isolated. However, upon reaction with bidentate proligands such as the chiral diamine (R,R)-N,N,N',N'-tetramethylcyclohexane-1,2 diamine [(R,R)-TMCDA] or N,N,N',N'-tetramethylethylenediamine (TMEDA), neutral complexes [Na4(MU-HMDS)3(MU4-I)(donor)2] [donor = (R,R)-TMCDA (6) and TMEDA (7)] were produced. To illustrate the generality of the latter reaction with other halides, [Na4(MU-HMDS)3(MU4-Br)(TMEDA)2] (8) was also prepared by employing NaBr in the synthesis instead of NaI. PMID- 26417942 TI - Behavioral associations with waterpipe tobacco smoking dependence among US young adults. AB - BACKGROUND AND AIMS: Waterpipe tobacco smoking (WTS) is increasingly prevalent in the United States, especially among young adults. We aimed to (1) adapt items from established dependence measures into a WTS dependence scale for US young adults (the US Waterpipe Dependence Scale), (2) determine the factor structure of the items and (3) assess associations between scale values and behavioral use characteristics known to be linked to dependence. DESIGN: Cross-sectional survey. SETTING: United States. PARTICIPANTS: A total of 436 past-year waterpipe tobacco users ages 18-30 years selected at random from a national probability-based panel. MEASUREMENTS: Participants responded to six tobacco dependence items adapted for WTS in US populations. Behavioral use characteristics included factors such as frequency of use and age of initiation. FINDINGS: Principal components analysis yielded an unambiguous one-factor solution. Approximately half (52.9%) of past-year waterpipe tobacco users received a score of 0, indicating that none of the six WTS dependence items were endorsed. Approximately one-quarter (25.4%) endorsed one dependence item and 22.7% endorsed two or more items. Higher WTS dependence scores were associated significantly with all five behavioral use characteristics. For example, compared with those who endorsed no dependence items, those who endorsed two or more had an adjusted odds ratio (AOR) of 3.90 [95% confidence interval (CI) = 1.56-9.78] for having had earlier age of initiation and an AOR of 32.75 (95% CI = 9.76-109.86) for more frequent WTS sessions. CONCLUSIONS: Scores on a six-item waterpipe tobacco smoking dependence scale (the US Waterpipe Dependence Scale) correlate with measures that would be expected to be related to dependence, such as amount used and age of initiation. PMID- 26417945 TI - Correction: Bacillus anthracis Diversity and Geographic Potential across Nigeria, Cameroon and Chad: Further Support of a Novel West African Lineage. PMID- 26417944 TI - Neuromodulation to the Rescue: Compensation of Temperature-Induced Breakdown of Rhythmic Motor Patterns via Extrinsic Neuromodulatory Input. AB - Stable rhythmic neural activity depends on the well-coordinated interplay of synaptic and cell-intrinsic conductances. Since all biophysical processes are temperature dependent, this interplay is challenged during temperature fluctuations. How the nervous system remains functional during temperature perturbations remains mostly unknown. We present a hitherto unknown mechanism of how temperature-induced changes in neural networks are compensated by changing their neuromodulatory state: activation of neuromodulatory pathways establishes a dynamic coregulation of synaptic and intrinsic conductances with opposing effects on neuronal activity when temperature changes, hence rescuing neuronal activity. Using the well-studied gastric mill pattern generator of the crab, we show that modest temperature increase can abolish rhythmic activity in isolated neural circuits due to increased leak currents in rhythm-generating neurons. Dynamic clamp-mediated addition of leak currents was sufficient to stop neuronal oscillations at low temperatures, and subtraction of additional leak currents at elevated temperatures was sufficient to rescue the rhythm. Despite the apparent sensitivity of the isolated nervous system to temperature fluctuations, the rhythm could be stabilized by activating extrinsic neuromodulatory inputs from descending projection neurons, a strategy that we indeed found to be implemented in intact animals. In the isolated nervous system, temperature compensation was achieved by stronger extrinsic neuromodulatory input from projection neurons or by augmenting projection neuron influence via bath application of the peptide cotransmitter Cancer borealis tachykinin-related peptide Ia (CabTRP Ia). CabTRP Ia activates the modulator-induced current IMI (a nonlinear voltage-gated inward current) that effectively acted as a negative leak current and counterbalanced the temperature-induced leak to rescue neuronal oscillations. Computational modelling revealed the ability of IMI to reduce detrimental leak-current influences on neuronal networks over a broad conductance range and indicated that leak and IMI are closely coregulated in the biological system to enable stable motor patterns. In conclusion, these results show that temperature compensation does not need to be implemented within the network itself but can be conditionally provided by extrinsic neuromodulatory input that counterbalances temperature-induced modifications of circuit-intrinsic properties. PMID- 26417946 TI - Grey-Theory-Based Optimization Model of Emergency Logistics Considering Time Uncertainty. AB - Natural disasters occur frequently in recent years, causing huge casualties and property losses. Nowadays, people pay more and more attention to the emergency logistics problems. This paper studies the emergency logistics problem with multi center, multi-commodity, and single-affected-point. Considering that the path near the disaster point may be damaged, the information of the state of the paths is not complete, and the travel time is uncertainty, we establish the nonlinear programming model that objective function is the maximization of time satisfaction degree. To overcome these drawbacks: the incomplete information and uncertain time, this paper firstly evaluates the multiple roads of transportation network based on grey theory and selects the reliable and optimal path. Then simplify the original model under the scenario that the vehicle only follows the optimal path from the emergency logistics center to the affected point, and use Lingo software to solve it. The numerical experiments are presented to show the feasibility and effectiveness of the proposed method. PMID- 26417947 TI - Correction: Reduced Topological Efficiency in Cortical-Basal Ganglia Motor Network of Parkinson's Disease: A Resting State fMRI Study. PMID- 26417948 TI - Functional Domains of ZFP809 Essential for Nuclear Localization and Gene Silencing. AB - Zinc finger protein 809 (ZFP809) is a member of the Kruppel-associated box containing zinc finger protein (KRAB-ZFP) family, and is highly expressed in mouse immature cells. ZFP809 is known to inhibit the expression of transduced genes driven by Moloney murine leukemia virus (MoMLV)-typed retroviral vectors by binding to the primer binding site (PBS) located downstream of the MLV-long terminal repeat (LTR) of the vectors and recruiting protein complexes that introduce epigenetic silencing marks such as histone modifications and DNA methylation at the MLV-LTR. However, it remains undetermined what domains of ZFP809 among the KRAB domain at N-terminus and the seven zinc fingers are critical for gene silencing. In this study, we assessed subcellular localization, gene silencing ability, and binding ability to the PBS of a series of truncated and mutated ZFP809 proteins. We revealed the essential role of the KRAB A box for all functions assessed, together with the accessory roles of a subset of zinc fingers. Our data also suggest that interaction between KAP1 and the KRAB A box of ZFP809 is critical in KAP1-dependent control of gene silencing for ZFP809 targets. PMID- 26417950 TI - Corticostriatal dynamics encode the refinement of specific behavioral variability during skill learning. AB - Learning to perform a complex motor task requires the optimization of specific behavioral features to cope with task constraints. We show that when mice learn a novel motor paradigm they differentially refine specific behavioral features. Animals trained to perform progressively faster sequences of lever presses to obtain reinforcement reduced variability in sequence frequency, but increased variability in an orthogonal feature (sequence duration). Trial-to-trial variability of the activity of motor cortex and striatal projection neurons was higher early in training and subsequently decreased with learning, without changes in average firing rate. As training progressed, variability in corticostriatal activity became progressively more correlated with behavioral variability, but specifically with variability in frequency. Corticostriatal plasticity was required for the reduction in frequency variability, but not for variability in sequence duration. These data suggest that during motor learning corticostriatal dynamics encode the refinement of specific behavioral features that change the probability of obtaining outcomes. PMID- 26417949 TI - Hospital Admission following Acute Kidney Injury in Kidney Transplant Recipients Is Associated with a Negative Impact on Graft Function after 1-Year. AB - The incidence and outcomes of acute kidney injury (AKI) in kidney transplantation are poorly known. Retrospective cohort analysis was performed on the data of all patients (>=3 months after transplantation and >=16 years of age) admitted to the hospital due to medical or surgical complications from 2007 to 2010. We analyzed 458 kidney transplant recipients, 55.2% men, median age 49 (IQR, 36-58) years, median of 12.5 (IQR, 3-35) months after kidney transplantation; admitted to the hospital due to medical or surgical complications. Most of the patients received a kidney from a deceased donor (62.2%), the primary cause for hospital admission was infection (60.7%) and 57 (12.4%) individuals were diagnosed with acute rejection (AR). The incidence of AKI was 82.3%: 31.9% stage 1, 29.3% stage 2 and 21.2% stage 3. Intensive care unit (ICU) admission (OR 8.90, 95% CI: 1.77-44.56 p = 0.008), infection (OR 5.73, 95% CI: 2.61-12.56, p<0.001) and the use of contrast media (OR 9.34, 95% CI: 2.04-42.70, p = 0.004) were the independent risk factors for AKI development. The mortality rate was 2.1% and all patients who died were diagnosed with AKI. Even after the exclusion of AR cases, at the end of 12 months, the individuals with AKI exhibited higher percent changes in creatinine values when compared with individuals without AKI (9.1% vs. -4.3%; p<0.001). According to KDIGO system, we found a high incidence of AKI among the complications of renal transplantation. As in other scenarios, AKI was associated with renal function loss at 1-year after the hospital discharge. PMID- 26417951 TI - Complications after Radiofrequency Ablation of 233 Hepatic Tumors. AB - OBJECTIVE: The only curative treatment for primary and secondary hepatic malignancies is surgery and liver transplantation. Thus, the majority of the patients are not candidates for resection, and there is a lack of organs. For these reasons, alternative treatment modalities such as radiofrequency ablation (RFA) are employed. The objective of this paper is to evaluate the incidence and types of complications related to open and percutaneous RFA. METHOD: This is a retrospective study of patients with hepatic malignancies treated by RFA. Tumor size, location, numbers of nodules, approach, histology and associated procedures were analyzed and correlated to complications. RESULTS: A total of 151 patients with primary and secondary hepatic malignancies were included: 58 with hepatocellular carcinoma (HCC), 68 with metastases from colorectal cancer and 25 with other types of tumors. Complications occurred in 24.5% of the patients, mostly (58.9%) in those with HCC. Ascites was the most common complication, followed by wound infection. The only two significant factors associated with complications were the presence of HCC (p = 0.0087) and two or more lesions (p = 0.0323). The mortality rate was 0.69%. CONCLUSION: RFA is a safe technique, but complications may occur and are multifactorial. Appropriate patient selection, early complication recognition and adequate treatment are essential. PMID- 26417952 TI - Real-time monitoring of rolling circle amplification using aggregation-induced emission: applications in biological detection. AB - We report that QATPE, an aggregation-induced emission-active tetraphenylethene dye, can be used as a non-sequence-specific ssDNA probe for real-time monitoring of all rolling circle amplification (RCA) reactions, thus making RCA more suitable for biosensing applications. PMID- 26417953 TI - The role of healthcare providers in the roll out of preexposure prophylaxis. AB - PURPOSE OF REVIEW: To review the most recent studies assessing the preparedness of healthcare practitioners to provide anti-HIV preexposure prophylaxis (PrEP) and suggest areas for future implementation research. RECENT FINDINGS: As PrEP is a biobehavioral intervention, healthcare providers are likely to play a critical role in implementing PrEP in care settings. Studies suggest that many specialized providers are aware of PrEP and support its provision as a public health intervention, though knowledge and acceptance are less among generalists. Therefore, utilization of PrEP by clinicians has been limited to a few early adopters. Concerns about the efficacy and long-term safety of PrEP, and perceived barriers to prescribing PrEP, could limit prescribing behaviors and intentions. Resistance to performing routine HIV risk assessments by clinicians is an additional barrier to implementing PrEP, although innovative tools to help clinicians routinely perform risk assessments, are being developed. SUMMARY: Interventions are needed to engage a broader array of healthcare providers in PrEP provision. Utilizing a framework based on diffusion of innovation theory, this review proposes strategies that can be implemented and evaluated to increase PrEP prescribing by healthcare providers. If resources are invested in training clinicians to provide PrEP, then these stakeholders could enhance the use of PrEP as part of a prevention package by primary providers. PMID- 26417954 TI - Tenofovir-based oral preexposure prophylaxis prevents HIV infection among women. AB - PURPOSE OF REVIEW: Despite tremendous promise as a female-controlled HIV prevention strategy, implementation of preexposure prophylaxis (PrEP) among women has been limited, in part because of disparate efficacy results from randomized trials in this population. This review synthesizes existing evidence regarding PrEP efficacy for preventing HIV infection in women and considerations for delivering PrEP to women. RECENT FINDINGS: In three efficacy trials, conducted among men and women, tenofovir-based oral PrEP reduced HIV acquisition in subgroups of women by 49-79% in intent-to-treat analyses, and by >85% when accounting for PrEP adherence. Two trials did not demonstrate an HIV prevention benefit from PrEP in women, but substantial evidence indicates those results were compromised by very low adherence to the study medication. Qualitative research has identified risk perception, stigma, and aspects of clinical trial participation as influencing adherence to study medication. Pharmacokinetic studies provide supporting evidence that PrEP offers HIV protection in women who are adherent to the medication. SUMMARY: Tenofovir-based daily oral PrEP prevents HIV acquisition in women. Offering PrEP as an HIV prevention option for women at high risk of HIV acquisition is a public health imperative and opportunities to evaluate implementation strategies for PrEP for women are needed. PMID- 26417956 TI - DPP-4 inhibitors and risk of infections: a meta-analysis of randomized controlled trials. AB - BACKGROUND: To evaluate the risk of infections in the treatment of type 2 diabetes patients with dipeptidyl-peptidase 4 (DPP-4) inhibitors. METHODS: A literature search was conducted through electronic databases. The inclusion criteria included study duration of no less than 12 weeks developed in type 2 diabetes patients, the use of a randomized control group receiving a DPP-4 inhibitor and the availability of outcome data for infections. Out of 2181 studies, 74 studies were finally included. RESULTS: The risk of overall infection for DPP-4 inhibitors treatment was comparable to placebo (odds ratio (OR) = 0.97, 95% confidence interval (CI), 0.91 to 1.04, p = 0.40), metformin treatment (OR = 1.22, 95% CI, 0.95 to 1.56, p = 0.12), sulphonylurea treatment (OR = 1.09, 0.93 to 1.29, p = 0.29), thiazolidinedione treatment (OR = 0.86, 95% CI, 0.65 to 1.14, p = 0.29) and alpha glucosidase inhibitor treatment (OR = 1.03, 95% CI, 0.33 to 3.22, p = 0.96). When compared different DPP-4 inhibitors with placebo treatment, risks of infections were comparable for alogliptin, linagliptin, sitagliptin, saxagliptin and vildagliptin. Compared with placebo or active comparator treatment, risks of infection in different systems for DPP-4 inhibitors were all comparable. CONCLUSIONS: The overall risk of infections of DPP-4 inhibitor was not increased compared with control groups. PMID- 26417957 TI - A Randomized Controlled Trial of Positioning for Lumbar Puncture in Young Infants. AB - OBJECTIVE: The lateral and sitting positions are those most widely used to perform lumbar puncture (LP) in infants. This study sought to compare LP success rates by position. Secondary outcomes were successful LP on the first attempt and rates of procedural complications. METHODS: Infants aged 1 to 90 days undergoing LP in our pediatric emergency department between June 1, 2012 and October 31, 2013 were randomized to 1 position or the other. Successful LP was defined as collection of cerebrospinal fluid with a red blood cell count of less than 10,000 cells/mm on either of the first 2 attempts. Electronic medical records were reviewed for patient information, cerebrospinal fluid results, and procedural complications. Providers completed a questionnaire detailing their previous LP experience and technique. Primary results were analyzed using the intention-to treat principle. RESULTS: We enrolled 168 infants. Of 167 with data eligible for analysis, 82 (49%) were randomized to the lateral position. There was no statistically significant difference in LP success rate between the lateral (77%, 63/82) and sitting (72%, 61/85) positions (difference, 5.1%; 95% confidence interval, -8.2%-18.3%). There were no significant differences in success on the first LP attempt or the rates of procedural complications. CONCLUSIONS: Among infants 1 to 90 days of age, this study found no difference in LP success between the lateral and sitting positions. PMID- 26417955 TI - Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing. AB - The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and elimination of bilirubin. Resultant indirect hyperbilirubinemia with jaundice can cause premature discontinuation of atazanavir. Risk for bilirubin-related discontinuation is highest among individuals who carry two UGT1A1 decreased function alleles (UGT1A1*28 or *37). We summarize published literature that supports this association and provide recommendations for atazanavir prescribing when UGT1A1 genotype is known (updates at www.pharmgkb.org). PMID- 26417958 TI - Determinants of Pediatric Psychiatry Length of Stay in 2 Urban Emergency Departments. AB - OBJECTIVES: Pediatric mental illness poses a significant burden with an overall prevalence of approximately 10%. Increasingly, children with mental disorders seek care in the emergency department (ED). However, the ED is not an ideal setting. Pediatric mental health patients receive limited treatment and experience significantly longer length of stay (LOS) than other patients seen in the ED. This study examines patient and hospital factors associated with LOS and prolonged LOS (PLOS). METHODS: This is a retrospective chart review of patients between the ages of 3 and 17 presenting at 2 participating urban EDs with a psychiatric diagnosis from May 2010 to May 2012. RESULTS: This study includes 939 patients with an average age of 14.1 years and a median LOS of 295 minutes. The diagnosis was the strongest predictor of LOS and PLOS. Patients with a psychotic disorder or suicide attempt or ideation experienced a longer LOS, 35% and 55% increases, respectively, and an increased odds of PLOS (odds ratio, 3.07 and 8.36, respectively). Patient sex, previous history of self-harm, and the daily census were associated with both a longer LOS and PLOS. Ethnicity, site of admission, and year of admission were only associated with LOS. CONCLUSIONS: Diagnosis-specific management factors are the primary determinant of LOS. However, some patient characteristics and hospital operational factors are also associated with LOS. Organizational reforms and an evaluation of the required human and material resources are necessary to improve access to and availability of pediatric mental health care. PMID- 26417959 TI - Bullying and Suicide Risk Among Pediatric Emergency Department Patients. AB - OBJECTIVES: This study aimed to describe the association between recent bullying victimization and risk of suicide among pediatric emergency department (ED) patients. METHODS: Patients presenting to 1 of 3 different urban pediatric EDs with either medical/surgical or psychiatric chief complaints completed structured interviews as part of a study to develop a suicide risk screening instrument, the Ask Suicide-Screening Questions. Seventeen candidate items and the criterion reference Suicidal Ideation Questionnaire were administered to patients ages 10 to 21 years. Bullying victimization was assessed by a single candidate item ("In the past few weeks, have you been bullied or picked on so much that you felt like you couldn't stand it anymore?"). RESULTS: A total of 524 patients completed the interview (34.4% psychiatric chief complaints; 56.9% female; 50.4% white, non Hispanic; mean [SD] age, 15.2 [2.6] years). Sixty patients (11.5%) reported recent bullying victimization, and of these, 33 (55.0%) screened positive for suicide risk on the Ask Suicide-Screening Questions or the previously validated Suicidal Ideation Questionnaire. After controlling for demographic and clinical variables, including a history of depression and drug use, the odds of screening positive for suicide risk were significantly greater in patients who reported recent bullying victimization (adjusted odds ratio, 3.19; 95% confidence interval, 1.66-6.11). After stratification by chief complaint, this association persisted for medical/surgical patients but not for psychiatric patients. CONCLUSIONS: Recent bullying victimization was associated with increased odds of screening positive for elevated suicide risk among pediatric ED patients presenting with medical/surgical complaints. Understanding this important correlate of suicide risk in pediatric ED patients may help inform ED-based suicide prevention interventions. PMID- 26417961 TI - A Cationic MOF with High Uptake and Selectivity for CO2 due to Multiple CO2 Philic Sites. AB - The reaction of N-rich pyrazinyl triazolyl carboxyl ligand 3-(4-carboxylbenzene) 5-(2-pyrazinyl)-1H-1,2,4-triazole (H2 cbptz) with MnCl2 afforded 3D cationic metal-organic framework (MOF) [Mn2 (Hcbptz)2 (Cl)(H2 O)]Cl?DMF?0.5 CH3 CN (1), which has an unusual (3,4)-connected 3,4T1 topology and 1D channels composed of cavities. MOF 1 has a very polar framework that contains exposed metal sites, uncoordinated N atoms, narrow channels, and Cl(-) basic sites, which lead to not only high CO2 uptake, but also remarkably selective adsorption of CO2 over N2 and CH4 at 298-333 K. The multiple CO2 -philic sites were identified by grand canonical Monte Carlo simulations. Moreover, 1 shows excellent stability in natural air environment. These advantages make 1 a very promising candidate in post-combustion CO2 capture, natural-gas upgrading, and landfill gas-purification processes. PMID- 26417962 TI - Molecular basis of alcoholic fatty liver disease: From incidence to treatment. AB - Alcoholic liver diseases have complex and multiple pathogenic mechanisms but still no effective treatment. Steatosis or alcoholic fatty liver disease (AFLD) has a widespread incidence and is the first step in the progression to more severe stages of alcoholic liver disease, with concomitant increases in morbidity and mortality rates. The ways in which this progression occurs and why some individuals are susceptible are still unanswered scientific questions. Research with animal models and clinical evidence have shown that it is a multifactorial disease that involves interactions between lipid metabolism, inflammation, the immune response and oxidative stress. Each of these pathways provides a better understanding of the pathogenesis of AFLD and contributes to the development of therapeutic strategies. This review emphasizes the importance of research on alcoholic steatosis based on incidence data, key pathogenic mechanisms and therapeutic interventions, and discusses perspectives on the progression of this disease. PMID- 26417963 TI - Nonidentical twins: Comparison of frequentist and Bayesian lasso for Cox models. AB - One important task in translational cancer research is the search for new prognostic biomarkers to improve survival prognosis for patients. The use of high throughput technologies allows simultaneous measurement of genome-wide gene expression or other genomic data for all patients in a clinical trial. Penalized likelihood methods such as lasso regression can be applied to such high dimensional data, where the number of (genomic) covariables is usually much larger than the sample size. There is a connection between the lasso and the Bayesian regression model with independent Laplace priors on the regression parameters, and understanding this connection has been useful for understanding the properties of lasso estimates in linear models (e.g. Park and Casella, 2008). In this paper, we study the lasso in the frequentist and Bayesian frameworks in the context of Cox models. For the Bayesian lasso we extend the approach by Lee et al. (2011). In particular, we impose the lasso penalty only on the genome features, but not on relevant clinical covariates, to allow the mandatory inclusion of important established factors. We investigate the models in high- and low-dimensional simulation settings and in an application to chronic lymphocytic leukemia. PMID- 26417964 TI - Impact of Fighting on Antibody Response to Hepatitis B Virus Vaccine in Mice. AB - Antibody responses to vaccines can be influenced by various behavioral and psychosocial factors. Few reports exist on the impact of fighting on antibody response to vaccines. This study unexpectedly found that fighting could significantly enhance antibody production in male mice immunized with hepatitis B virus (HBV) vaccines. To confirm the finding, a mouse-fighting model was established in which it was observed that only intense fighting, not mild fighting, enhanced the antibody response to HBV surface antigen in male mice, and that the frequency of fighting and active attacks during fighting showed no obvious relationship with the antibody levels in the male mice that experienced fighting. In addition, fighting can cause significant upregulation of CD80 in CD11c(+) cells in the spleen of male mice. These data suggest that fighting could influence the humoral immune response in individuals immunized with vaccines or infected with microbes. PMID- 26417966 TI - Understanding the cancer cell phenotype beyond the limitations of current omics analyses. AB - Efforts to understand the mechanistic principles driving cancer metabolism and proliferation have been lately governed by genomic, transcriptomic and proteomic studies. This paper analyzes the caveats of these approaches. As molecular biology's central dogma proposes a unidirectional flux of information from genes to mRNA to proteins, it has frequently been assumed that monitoring the changes in the gene sequences and in mRNA and protein contents is sufficient to explain complex cellular processes. Such a stance commonly disregards that post translational modifications can alter the protein function/activity and also that regulatory mechanisms enter into action, to coordinate the protein activities of pathways/cellular processes, in order to keep the cellular homeostasis. Hence, the actual protein activities (as enzymes/transporters/receptors) and their regulatory mechanisms ultimately dictate the final outcomes of a pathway/cellular process. In this regard, it is here documented that the mRNA levels of many metabolic enzymes and transcriptional factors have no correlation with the respective protein contents and activities. The validity of current clinical mRNA based tests and proposed metabolite biomarkers for cancer detection/prognosis is also discussed. Therefore, it is proposed that, to achieve a thorough understanding of the modifications undergone by proliferating cancer cells, it is mandatory to experimentally analyze the cellular processes at the functional level. This could be achieved (a) locally, by examining the actual protein activities in the cell and their kinetic properties (or at least kinetically characterize the most controlling steps of the pathway/cellular process); (b) systemically, by analyzing the main fluxes of the pathway/cellular process, and how they are modulated by metabolites, all which should contribute to comprehending the regulatory mechanisms that have been altered in cancer cells. By adopting a more holistic approach it may become possible to improve the design of therapeutic strategies that would target cancer cells more specifically. PMID- 26417968 TI - Palliation of unresectable cholangiocarcinoma: can we do more than merely drain? PMID- 26417965 TI - Emergency Hospital Care for Exacerbation of COPD: Is Inhaled Maintenance Therapy Modified? AB - BACKGROUND: The impact of hospital emergency care and inward admission for acute exacerbations of COPD on inhaled maintenance treatment is not well known. OBJECTIVE: Therefore, we evaluated the impact of short-stay emergency hospital care and inward admission for acute exacerbation of COPD (eCOPD) on inhaled maintenance treatment prescribed at discharge. DESIGN: Prospective observational cohort study of patients presenting with eCOPD at emergency departments in 16 hospitals of the Spanish healthcare system. The ethics committee at each hospital approved the study and patients provided an informed consent before inclusion. We classified the patients according to the severity of COPD: mild/moderate (FEV1 >= 50% predicted) or severe/very severe (FEV1 < 50% predicted) and need of inward hospitalisation. We analysed changes to maintenance treatment on discharge according to GOLD strategy. RESULTS: 1559 patients, 65% required hospitalisation. The most common maintenance treatment was inhaled corticoids (ICS) (80.9%) followed by long-acting beta-agonists (LABA) (75.4%). The most common combination was triple therapy (LABA+ LAMA+ICS) (56.2%) followed by LABA+ICS dual therapy (18.2%) regardless of the severity of COPD. In more than 60% of patients treatment was not changed at discharge. The most common change in treatment was a reduction when discharge was from emergency care and an increase after hospitalisation (-21.6% and +19.5% in severe/very severe COPD, respectively). CONCLUSIONS: Emergency hospital care for eCOPD does not usually induce changes in inhaled maintenance treatment for COPD regardless of the duration of the hospital stay. PMID- 26417967 TI - Epigenetic Control of Apolipoprotein E Expression Mediates Gender-Specific Hematopoietic Regulation. AB - Epigenetic alterations play a central role in the control of normal and malignant blood cell development. We demonstrate here that expression of a truncated DNA methyltransferase 3B isoform DNMT3B7, which has been shown to alter cellular epigenetic patterns, decreases the overall number of hematopoietic stem and progenitor cells (HSPCs), and markedly diminishes blood cell reconstitution within the female hormonal microenvironment. Gene expression profiling of HSPCs isolated from DNMT3B7 transgenic embryos identified Apolipoprotein E (Apoe) as overexpressed. The CpG island controlling Apoe expression had lower levels of modified cytosines in DNMT3B7 transgenic HSPCs, corresponding with the observed increase in gene expression. Furthermore, we observed that spleens and bone marrows of female mice transplanted with DNMT3B7 transgenic HSPCs express very high levels of Apoe. Finally, the introduction of Apoe-overexpressing HSPCs into male recipients decreased bone marrow engraftment, recapitulating our original observations in female recipients. Our work reveals a dynamic interplay between the intrinsic epigenetic changes in HSPCs and extrinsic endocrine factors acting on these cells to regulate the efficiency of HSPC engraftment and reconstitution. We have identified a novel mechanism by which gender-specific hormones modulate HSPC function, which could serve as a target for augmenting hematopoiesis in cases with limited HSC functionality. PMID- 26417969 TI - Farewell to the cap or is there still an indication? PMID- 26417970 TI - Show me how you remove small polyps and I'll tell you who you are. PMID- 26417971 TI - Hybrid biliary interventions for Roux-en-Y anatomy. PMID- 26417972 TI - Reply to Kobiela et al. PMID- 26417973 TI - Reply to Kobiela et al. PMID- 26417974 TI - Water exchange versus carbon dioxide insufflation in unsedated colonoscopy: less is more. PMID- 26417975 TI - Reply to Ishaq et al. PMID- 26417978 TI - [Not Available]. PMID- 26417979 TI - [Not Available]. PMID- 26417981 TI - Video comment on Saurabh Mukewar et al. PMID- 26417980 TI - Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. AB - This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). It addresses the diagnosis and management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH). Main Recommendations MR1. ESGE recommends immediate assessment of hemodynamic status in patients who present with acute upper gastrointestinal hemorrhage (UGIH), with prompt intravascular volume replacement initially using crystalloid fluids if hemodynamic instability exists (strong recommendation, moderate quality evidence). MR2. ESGE recommends a restrictive red blood cell transfusion strategy that aims for a target hemoglobin between 7 g/dL and 9 g/dL. A higher target hemoglobin should be considered in patients with significant co-morbidity (e. g., ischemic cardiovascular disease) (strong recommendation, moderate quality evidence). MR3. ESGE recommends the use of the Glasgow-Blatchford Score (GBS) for pre-endoscopy risk stratification. Outpatients determined to be at very low risk, based upon a GBS score of 0 - 1, do not require early endoscopy nor hospital admission. Discharged patients should be informed of the risk of recurrent bleeding and be advised to maintain contact with the discharging hospital (strong recommendation, moderate quality evidence). MR4. ESGE recommends initiating high dose intravenous proton pump inhibitors (PPI), intravenous bolus followed by continuous infusion (80 mg then 8 mg/hour), in patients presenting with acute UGIH awaiting upper endoscopy. However, PPI infusion should not delay the performance of early endoscopy (strong recommendation, high quality evidence). MR5. ESGE does not recommend the routine use of nasogastric or orogastric aspiration/lavage in patients presenting with acute UGIH (strong recommendation, moderate quality evidence). MR6. ESGE recommends intravenous erythromycin (single dose, 250 mg given 30 - 120 minutes prior to upper gastrointestinal [GI] endoscopy) in patients with clinically severe or ongoing active UGIH. In selected patients, pre-endoscopic infusion of erythromycin significantly improves endoscopic visualization, reduces the need for second-look endoscopy, decreases the number of units of blood transfused, and reduces duration of hospital stay (strong recommendation, high quality evidence). MR7. Following hemodynamic resuscitation, ESGE recommends early (<= 24 hours) upper GI endoscopy. Very early (< 12 hours) upper GI endoscopy may be considered in patients with high risk clinical features, namely: hemodynamic instability (tachycardia, hypotension) that persists despite ongoing attempts at volume resuscitation; in-hospital bloody emesis/nasogastric aspirate; or contraindication to the interruption of anticoagulation (strong recommendation, moderate quality evidence). MR8. ESGE recommends that peptic ulcers with spurting or oozing bleeding (Forrest classification Ia and Ib, respectively) or with a nonbleeding visible vessel (Forrest classification IIa) receive endoscopic hemostasis because these lesions are at high risk for persistent bleeding or rebleeding (strong recommendation, high quality evidence). MR9. ESGE recommends that peptic ulcers with an adherent clot (Forrest classification IIb) be considered for endoscopic clot removal. Once the clot is removed, any identified underlying active bleeding (Forrest classification Ia or Ib) or nonbleeding visible vessel (Forrest classification IIa) should receive endoscopic hemostasis (weak recommendation, moderate quality evidence). MR10. In patients with peptic ulcers having a flat pigmented spot (Forrest classification IIc) or clean base (Forrest classification III), ESGE does not recommend endoscopic hemostasis as these stigmata present a low risk of recurrent bleeding. In selected clinical settings, these patients may be discharged to home on standard PPI therapy, e. g., oral PPI once-daily (strong recommendation, moderate quality evidence). MR11. ESGE recommends that epinephrine injection therapy not be used as endoscopic monotherapy. If used, it should be combined with a second endoscopic hemostasis modality (strong recommendation, high quality evidence). MR12. ESGE recommends PPI therapy for patients who receive endoscopic hemostasis and for patients with adherent clot not receiving endoscopic hemostasis. PPI therapy should be high dose and administered as an intravenous bolus followed by continuous infusion (80 mg then 8 mg/hour) for 72 hours post endoscopy (strong recommendation, high quality evidence). MR13. ESGE does not recommend routine second-look endoscopy as part of the management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH). However, in patients with clinical evidence of rebleeding following successful initial endoscopic hemostasis, ESGE recommends repeat upper endoscopy with hemostasis if indicated. In the case of failure of this second attempt at hemostasis, transcatheter angiographic embolization (TAE) or surgery should be considered (strong recommendation, high quality evidence). MR14. In patients with NVUGIH secondary to peptic ulcer, ESGE recommends investigating for the presence of Helicobacter pylori in the acute setting with initiation of appropriate antibiotic therapy when H. pylori is detected. Re-testing for H. pylori should be performed in those patients with a negative test in the acute setting. Documentation of successful H. pylori eradication is recommended (strong recommendation, high quality evidence). MR15. In patients receiving low dose aspirin for secondary cardiovascular prophylaxis who develop peptic ulcer bleeding, ESGE recommends aspirin be resumed immediately following index endoscopy if the risk of rebleeding is low (e. g., FIIc, FIII). In patients with high risk peptic ulcer (FIa, FIb, FIIa, FIIb), early reintroduction of aspirin by day 3 after index endoscopy is recommended, provided that adequate hemostasis has been established (strong recommendation, moderate quality evidence). PMID- 26417982 TI - Video comment on Mohammad Yaghoobi et al. PMID- 26417983 TI - Video comment on Roger G. Blanks et al. PMID- 26417984 TI - Mesh size analysis of cellulose nanofibril hydrogels using solute exclusion and PFG-NMR spectroscopy. AB - The pore structure of TEMPO-mediated oxidized CNF hydrogels, chemically cross linked with water-soluble diamines, is studied. A solute exclusion method and pulsed-field-gradient NMR are used to estimate the mesh size distribution in the gel network in its hydrated state. Dextran fractions with the nominal molecular weights in the range of 10-2000 kDa are used as probes. The results show a nonuniform network structure, consisting of a group of large openings that contain ~50% of water, and regions with a more compact structure and smaller mesh units that restrict the diffusivity of the dextran molecules. A biexponential model is proposed for the NMR echo amplitude decay due to the probe diffusion into the gel network. A typical single exponential model does not fit the experimental data when the probe molecular size is comparable to the network mesh size. The results obtained with NMR, using the proposed biexponential model, are in very good agreement with those determined with solute exclusion. Precise mesh size estimation with solute exclusion using pore models is subject to restrictions, and vary with the assumed pore geometry. The average mesh size obtained using a spherical pore model, ~35 nm, in the compact regions of the hydrogel, is in good agreement with the theoretical value in a network of rodlike particles. Neglecting the wall effects leads to underestimation of the mesh size with both techniques. PMID- 26417985 TI - Alkali-Metal-Mediated Magnesiations of an N-Heterocyclic Carbene: Normal, Abnormal, and "Paranormal" Reactivity in a Single Tritopic Molecule. AB - Herein the sodium alkylmagnesium amide [Na4Mg2(TMP)6(nBu)2] (TMP=2,2,6,6 tetramethylpiperidide), a template base as its deprotonating action is dictated primarily by its 12 atom ring structure, is studied with the common N heterocyclic carbene (NHC) IPr [1,3-bis(2,6-diisopropylphenyl)imidazol-2 ylidene]. Remarkably, magnesiation of IPr occurs at the para-position of an aryl substituent, sodiation occurs at the abnormal C4 position, and a dative bond occurs between normal C2 and sodium, all within a 20 atom ring structure accommodating two IPr(2-). Studies with different K/Mg and Na/Mg bimetallic bases led to two other magnesiated NHC structures containing two or three IPr(-) monoanions bound to Mg through abnormal C4 sites. Synergistic in that magnesiation can only work through alkali-metal mediation, these reactions add magnesium to the small cartel of metals capable of directly metalating a NHC. PMID- 26417986 TI - Reply. PMID- 26417988 TI - Magnetic resonance elastography of the brain: An in silico study to determine the influence of cranial anatomy. AB - PURPOSE: Magnetic resonance elastography (MRE) of the brain has demonstrated potential as a biomarker of neurodegenerative disease such as dementia but requires further evaluation. Cranial anatomical features such as the falx cerebri and tentorium cerebelli membranes may influence MRE measurements through wave reflection and interference and tissue heterogeneity at their boundaries. We sought to determine the influence of these effects via simulation. METHODS: MRE associated mechanical stimulation of the brain was simulated using steady state harmonic finite element analysis. Simulations of geometrical models and anthropomorphic brain models derived from anatomical MRI data of healthy individuals were compared. Constitutive parameters were taken from MRE measurements for healthy brain. Viscoelastic moduli were reconstructed from the simulated displacement fields and compared with ground truth. RESULTS: Interference patterns from reflections and heterogeneity resulted in artifacts in the reconstructions of viscoelastic moduli. Artifacts typically occurred in the vicinity of boundaries between different tissues within the cranium, with a magnitude of 10%-20%. CONCLUSION: Given that MRE studies for neurodegenerative disease have reported only marginal variations in brain elasticity between controls and patients (e.g., 7% for Alzheimer's disease), the predicted errors are a potential confound to the development of MRE as a biomarker of dementia and other neurodegenerative diseases. Magn Reson Med 76:645-662, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26417987 TI - Biomodulatory metronomic therapy in stage IV melanoma is well-tolerated and may induce prolonged progression-free survival, a phase I trial. PMID- 26417989 TI - Genetic Variation of Sclerotinia sclerotiorum from Multiple Crops in the North Central United States. AB - Sclerotinia sclerotiorum is an important pathogen of numerous crops in the North Central region of the United States. The objective of this study was to examine the genetic diversity of 145 isolates of the pathogen from multiple hosts in the region. Mycelial compatibility groups (MCG) and microsatellite haplotypes were determined and analyzed for standard estimates of population genetic diversity and the importance of host and distance for genetic variation was examined. MCG tests indicated there were 49 different MCGs in the population and 52 unique microsatellite haplotypes were identified. There was an association between MCG and haplotype such that isolates belonging to the same MCG either shared identical haplotypes or differed at no more than 2 of the 12 polymorphic loci. For the majority of isolates, there was a one-to-one correspondence between MCG and haplotype. Eleven MCGs shared haplotypes. A single haplotype was found to be prevalent throughout the region. The majority of genetic variation in the isolate collection was found within rather than among host crops, suggesting little genetic divergence of S. sclerotiorum among hosts. There was only weak evidence of isolation by distance. Pairwise population comparisons among isolates from canola, dry bean, soybean and sunflower suggested that gene flow between host populations is more common for some crops than others. Analysis of linkage disequilibrium in the isolates from the four major crops indicated primarily clonal reproduction, but also evidence of genetic recombination for isolates from canola and sunflower. Accordingly, genetic diversity was highest for populations from canola and sunflower. Distribution of microsatellite haplotypes across the study region strongly suggest that specific haplotypes of S. sclerotiorum are often found on multiple crops, movement of individual haplotypes among crops is common and host identity is not a barrier to gene flow for S. sclerotiorum in the north central United States. PMID- 26417990 TI - Preterm Cord Blood Contains a Higher Proportion of Immature Hematopoietic Progenitors Compared to Term Samples. AB - BACKGROUND: Cord blood contains high number of hematopoietic cells that after birth disappear. In this paper we have studied the functional properties of the umbilical cord blood progenitor cells collected from term and preterm neonates to establish whether quantitative and/or qualitative differences exist between the two groups. METHODS AND RESULTS: Our results indicate that the percentage of total CD34+ cells was significantly higher in preterm infants compared to full term: 0.61% (range 0.15-4.8) vs 0.3% (0.032-2.23) p = 0.0001 and in neonates <32 weeks of gestational age (GA) compared to those >=32 wks GA: 0.95% (range 0.18 4.8) and 0.36% (0.15-3.2) respectively p = 0.0025. The majority of CD34+ cells co expressed CD71 antigen (p<0.05 preterm vs term) and grew in vitro large BFU-E, mostly in the second generation. The subpopulations CD34+CD38- and CD34+CD45- resulted more represented in preterm samples compared to term, conversely, Side Population (SP) did not show any difference between the two group. The absolute number of preterm colonies (CFCs/10microL) resulted higher compared to term (p = 0.004) and these progenitors were able to grow until the third generation maintaining an higher proportion of CD34+ cells (p = 0.0017). The number of colony also inversely correlated with the gestational age (Pearson r = -0.3001 p<0.0168). CONCLUSIONS: We found no differences in the isolation and expansion capacity of Endothelial Colony Forming Cells (ECFCs) from cord blood of term and preterm neonates: both groups grew in vitro large number of endothelial cells until the third generation and showed a transitional phenotype between mesenchymal stem cells and endothelial progenitors (CD73, CD31, CD34 and CD144)The presence, in the cord blood of preterm babies, of high number of immature hematopoietic progenitors and endothelial/mesenchymal stem cells with high proliferative potential makes this tissue an important source of cells for developing new cells therapies. PMID- 26417991 TI - Synthetic Double-Stranded RNA Poly(I:C) Aggravates IgA Nephropathy by Triggering IgA Class Switching Recombination through the TLR3-BAFF Axis. AB - BACKGROUND: Immunoglobulin class-switch recombination (CSR) is crucial for the expression of IgA, and it plays a vital role in the physiopathology of IgA nephropathy (IgAN). The aim of the study is to investigate the effect of polyriboinosinic:polyribocytidylic acid (poly(I:C)) in modulating toll-like receptor (TLR) 3-B-cell-activating factor belonging to the TNF family (BAFF) axis activation, which in turn promotes IgA CSR of IgAN patients and the IgAN rat model. METHODS: Blood samples and tonsillar tissue specimens were obtained from 24 patients with IgAN and 26 patients with chronic tonsillitis as control. We also used the IgAN rat model to investigate the relationship between viral infection and IgA CSR. RESULTS: Immunohistochemical and ELISA western blotting examination revealed that the TLR3/BAFF axis is activated in IgAN patients when compared to controls. Synthetic double-stranded RNA poly(I:C) stimulation upregulates the TACI/TLR3/TRIF/TRAF6 expression and promotes IgA CSR and BAFF productions in tonsil mononuclear cells. TLR3 or BAFF siRNA decreases IgA expression. In IgAN rat models, TLR3/BAFF signaling was highly activated. With 200 MUg poly(I:C) sodium salt into the left naris for 8 weeks, IgA was highly deposited on glomeruli. It also revealed that poly(I:C) activated TLR3/BAFF axis and IgA CSR in vivo. CONCLUSION: These data points toward the role of TLR3/BAFF axis in IgA CSR of IgAN, and the data also support the notion that mucosal immunization with virus infection results in impaired mucosal and systemic IgA responses. PMID- 26417992 TI - Impact of Frontal Lobe Function and Behavioral Changes on Health-Related Quality of Life in Patients with Parkinson's Disease: A Cross-Sectional Study from Southwest China. AB - BACKGROUND: Cognitive impairment may negatively impact the health-related quality of life (HRQoL) in patients with Parkinson's disease (PD). However, information on the effects of frontal lobe function and behavior changes on the HRQoL of the Chinese PD population is limited. Studies on the associations among frontal lobe function, behavioral changes and the HRQoL may help optimize the treatment and improve the HRQoL of PD patients. METHODS: A total of 309 PD patients were evaluated using the Frontal Assessment Battery, the Frontal Behavioral Inventory (FBI) and the PD Questionnaire 39-item version (PDQ-39). RESULTS: Patients with worse frontal lobe function were older (p < 0.001), had longer disease durations (p = 0.002), higher Unified Parkinson's Disease Rating Scale part III (UPDRS-III) scores (p < 0.001) and higher Hoehn and Yahr (H-Y) stages (p = 0.001), and exhibited significantly higher PDQ-39 summary index (SI; p = 0.001) compared with those who had better frontal lobe function. In addition, the disease duration (p = 0.008), UPDRS-III scores (p < 0.001), H-Y stage (p < 0.001), PDQ-39 SI and scores for each domain of the PDQ-39 (p < 0.001) were higher as the severity of frontal behavioral changes increased. The total FBI score (p < 0.001) was positively correlated with the PDQ-39 SI. CONCLUSIONS: Frontal behavioral changes were closely associated with poor HRQoL in Chinese PD patients. PMID- 26417994 TI - Satellite Based Assessment of Hydroclimatic Conditions Related to Cholera in Zimbabwe. AB - INTRODUCTION: Cholera, an infectious diarrheal disease, has been shown to be associated with large scale hydroclimatic processes. The sudden and sporadic occurrence of epidemic cholera is linked with high mortality rates, in part, due to uncertainty in timing and location of outbreaks. Improved understanding of the relationship between pathogenic abundance and climatic processes allows prediction of disease outbreak to be an achievable goal. In this study, we show association of large scale hydroclimatic processes with the cholera epidemic in Zimbabwe reported to have begun in Chitungwiza, a city in Mashonaland East province, in August, 2008. PRINCIPAL FINDINGS: Climatic factors in the region were found to be associated with triggering cholera outbreak and are shown to be related to anomalies of temperature and precipitation, validating the hypothesis that poor conditions of sanitation, coupled with elevated temperatures, and followed by heavy rainfall can initiate outbreaks of cholera. Spatial estimation by satellite of precipitation and global gridded air temperature captured sensitivities in hydroclimatic conditions that permitted identification of the location in the region where the disease outbreak began. DISCUSSION: Satellite derived hydroclimatic processes can be used to capture environmental conditions related to epidemic cholera, as occurred in Zimbabwe, thereby providing an early warning system. Since cholera cannot be eradicated because the causative agent, Vibrio cholerae, is autochthonous to the aquatic environment, prediction of conditions favorable for its growth and estimation of risks of triggering the disease in a given population can be used to alert responders, potentially decreasing infection and saving lives. PMID- 26417995 TI - Long Noncoding RNA H19 Promotes Osteoblast Differentiation Via TGF beta1/Smad3/HDAC Signaling Pathway by Deriving miR-675. AB - Long noncoding RNAs (lncRNAs) are emerging as important regulatory molecules at the transcriptional and post-transcriptional levels and may play essential roles in the differentiation of human bone marrow mesenchymal stem cell (hMSC). However, their roles and functions remain unclear. Here, we showed that lncRNA H19 was significantly upregulated after the induction of osteoblast differentiation. Overexpression of H19 promoted osteogenic differentiation of hMSCs in vitro and enhanced heterotopic bone formation in vivo, whereas knockdown of H19 inhibited these effects. Subsequently, we found that miR-675, encoded by exon1 of H19, promoted osteoblast differentiation of hMSCs and was partially responsible for the pro-osteogenic effect of H19. Investigating the underlying mechanism, we demonstrated that H19/miR-675 inhibited mRNA and protein expression of transforming growth factor-beta1 (TGF-beta1). The downregulation of TGF-beta1 subsequently inhibited phosphorylation of Smad3. Meanwhile, H19/miR-675 downregulated the mRNA and protein levels of histone deacetylase (HDAC) 4/5, and thus increased osteoblast marker gene expression. Taken together, our results demonstrated that the novel pathway H19/miR-675/TGF-beta1/Smad3/HDAC regulates osteogenic differentiation of hMSCs and may serve as a potential target for enhancing bone formation in vivo. PMID- 26417996 TI - An Advanced Sodium-Ion Battery Composed of Carbon Coated Na3V2(PO4)3 in a Porous Graphene Network. AB - A 3D hierarchical meso- and macroporous Na3V2(PO4)3-based hybrid cathode with connected Na ion/electron pathways is developed for ultra-fast charge and discharge sodium-ion batteries. It delivers an excellent rate capability (e.g., 86 mA h g(-1) at 100 C) and outstanding cycling stability (e.g., 64% retention after 10,000 cycles at 100 C), indicating its superiority in practical applications. PMID- 26417997 TI - Dysregulation of host cellular genes targeted by human papillomavirus (HPV) integration contributes to HPV-related cervical carcinogenesis. AB - Integration of human papillomavirus (HPV) viral DNA into the human genome has been postulated as an important etiological event during cervical carcinogenesis. Several recent reports suggested a possible role for such integration-targeted cellular genes (ITGs) in cervical carcinogenesis. Therefore, a comprehensive analysis of HPV integration events was undertaken using data collected from 14 publications, with 499 integration loci on human chromosomes included. It revealed that HPV DNA preferred to integrate into intragenic regions and gene dense regions of human chromosomes. Intriguingly, the host cellular genes nearby the integration sites were found to be more transcriptionally active compared with control. Furthermore, analysis of the integration sites in the human genome revealed that there were several integration hotspots although all chromosomes were represented. The ITGs identified were found to be enriched in tumor-related terms and pathways using gene ontology and KEGG analysis. In line with this, three of six ITGs tested were found aberrantly expressed in cervical cancer tissues. Among them, it was demonstrated for the first time that MPPED2 could induce HeLa cell and SiHa cell G1/S transition block and cell proliferation retardation. Moreover, "knocking out" the integrated HPV fragment in HeLa cell line decreased expression of MYC located ~500 kb downstream of the integration site, which provided the first experimental evidence supporting the hypothesis that integrated HPV fragment influence MYC expression via long distance chromatin interaction. Overall, the results of this comprehensive analysis implicated that dysregulation of ITGs caused by viral integration as possibly having an etiological involvement in cervical carcinogenesis. PMID- 26417998 TI - A prospective, randomized, double-blind comparison of an ablative fractional 2940 nm erbium-doped yttrium aluminum garnet laser with a nonablative fractional 1550 nm erbium-doped glass laser for the treatment of photoaged Asian skin. AB - BACKGROUND: As compared with ablative fractional CO2 laser, ablative fractional erbium-doped yttrium aluminum garnet (Er:YAG) laser is considered to be a more suitable treatment option for photoaged skin in Asians due to the lower incidence of postinflammatory hyperpigmentation. OBJECTIVE: To compare the efficacy and safety of ablative fractional Er:YAG laser (ablative fractional resurfacing [AFR]) and nonablative fractional 1550-nm Er:glass laser (non-AFR [NAFR]) in the treatment of photoaging. METHODS: This was a prospective, randomized, double blinded comparative study. In three sessions, at four-week intervals, 19 patients received Er:YAG AFR, and 15 patients received Er:glass NAFR. Pigmentation, uneven tone/erythema, wrinkles and overall features of photoaging were scored. Patient satisfaction, adverse effects and pain scores were recorded. Melanin and erythema indexes were measured. RESULTS: Reductions in pigmentation and uneven tone/erythema scores were significantly greater after Er:YAG AFR, while wrinkle score reduction was significantly greater after Er:glass NAFR. Physician and patient assessments for the overall features showed greater improvement in the Er:glass NAFR. Treatment-related pain or adverse events were less in the Er:YAG AFR. CONCLUSION: Both Er:YAG AFR and Er:glass NAFR are effective and safe and could be used in a complementary manner for treating photoaged Asian skin. PMID- 26417999 TI - Tracking Time Evolution of Collective Attention Clusters in Twitter: Time Evolving Nonnegative Matrix Factorisation. AB - Micro-blogging services, such as Twitter, offer opportunities to analyse user behaviour. Discovering and distinguishing behavioural patterns in micro-blogging services is valuable. However, it is difficult and challenging to distinguish users, and to track the temporal development of collective attention within distinct user groups in Twitter. In this paper, we formulate this problem as tracking matrices decomposed by Nonnegative Matrix Factorisation for time sequential matrix data, and propose a novel extension of Nonnegative Matrix Factorisation, which we refer to as Time Evolving Nonnegative Matrix Factorisation (TENMF). In our method, we describe users and words posted in some time interval by a matrix, and use several matrices as time-sequential data. Subsequently, we apply Time Evolving Nonnegative Matrix Factorisation to these time-sequential matrices. TENMF can decompose time-sequential matrices, and can track the connection among decomposed matrices, whereas previous NMF decomposes a matrix into two lower dimension matrices arbitrarily, which might lose the time sequential connection. Our proposed method has an adequately good performance on artificial data. Moreover, we present several results and insights from experiments using real data from Twitter. PMID- 26418000 TI - Influence of Cervical Muscle Fatigue on Musculo-Tendinous Stiffness of the Head Neck Segment during Cervical Flexion. AB - AIM: The aim of this study is to determine if the fatigue of cervical muscles has a significant influence on the head-neck segment musculo-tendinous stiffness. METHODS: Ten men (aged 21.2 +/- 1.9 years) performed four quick-release trials of flexion at 30 and 50% MVC before and after the induction of muscular fatigue on cervical flexors. Electromyographic activity was recorded on the sternocleidomastoids (SCM) and spinal erectors (SE), bilaterally. Musculo tendinous stiffness was calculated through the quick-release method adapted to the head-neck segment. RESULTS: We noticed a significant linear increase of the head-neck segment musculo-tendinous stiffness with the increase of exertion level both before (P < 0.0001) and after the fatigue procedure (P < 0.0001). However, this linear relationship was not different before and after the fatigue procedure. EMG analysis revealed a significant increase of the root mean square for the right SCM (P = 0.0002), the left SCM (P < 0.0001), the right SE (P < 0.0001), and the left SE (P < 0.0001) and a significant decrease of the median power frequency only for the right (P = 0.0006) and the left (P = 0.0003) SCM with muscular fatigue. DISCUSSION: We did not find significant changes in the head-neck segment musculo-tendinous stiffness with fatigue of cervical muscles. We found a significant increase in EMG activity in the SCM and the SE after the induction of fatigue of the SCM. Our findings suggest that with fatigue of cervical flexors, neck muscle activity is modulated in order to maintain the musculo-tendinous stiffness at a steady state. PMID- 26418002 TI - Religious Affiliation Modulates Weekly Cycles of Cropland Burning in Sub-Saharan Africa. AB - Vegetation burning is a common land management practice in Africa, where fire is used for hunting, livestock husbandry, pest control, food gathering, cropland fertilization, and wildfire prevention. Given such strong anthropogenic control of fire, we tested the hypotheses that fire activity displays weekly cycles, and that the week day with the fewest fires depends on regionally predominant religious affiliation. We also analyzed the effect of land use (anthrome) on weekly fire cycle significance. Fire density (fire counts.km-2) observed per week day in each region was modeled using a negative binomial regression model, with fire counts as response variable, region area as offset and a structured random effect to account for spatial dependence. Anthrome (settled, cropland, natural, rangeland), religion (Christian, Muslim, mixed) week day, and their 2-way and 3 way interactions were used as independent variables. Models were also built separately for each anthrome, relating regional fire density with week day and religious affiliation. Analysis revealed a significant interaction between religion and week day, i.e. regions with different religious affiliation (Christian, Muslim) display distinct weekly cycles of burning. However, the religion vs. week day interaction only is significant for croplands, i.e. fire activity in African croplands is significantly lower on Sunday in Christian regions and on Friday in Muslim regions. Magnitude of fire activity does not differ significantly among week days in rangelands and in natural areas, where fire use is under less strict control than in croplands. These findings can contribute towards improved specification of ignition patterns in regional/global vegetation fire models, and may lead to more accurate meteorological and chemical weather forecasting. PMID- 26418001 TI - Transcriptomic Analysis of the Anterior Silk Gland in the Domestic Silkworm (Bombyx mori) - Insight into the Mechanism of Silk Formation and Spinning. AB - Silk proteins are synthesized in the middle and posterior silk glands of silkworms, then transit into the anterior of the silk gland, where the silk fibers are produced, stored and processed. The mechanism of formation and spinning of the silk fibers has not been fully elucidated, and transcriptome analyses specific to the anterior silk gland have not been reported. In the present study, we explored gene expression profiles in five regions of silk gland samples using the RNA-Seq method. As a result, there were 959,979,570 raw reads obtained, of which 583,068,172 reads were mapped to the silkworm genome. A total of 7419 genes were found to be expressed in terms of reads per kilobase of exon model per million mapped reads >= 5 in at least one sample. The gene numbers and expression levels of the expressed genes differed between these regions. The differentially expressed genes were analyzed, and 282 genes were detected as up regulated in the anterior silk gland, compared with the other parts. Functions of these genes were addressed using the gene ontology and Kyoto Encyclopedia of Genes and Genomes databases, and seven key pathways were enriched. It suggested that the ion transportation, energy metabolism, protease inhibitors and cuticle proteins played essential roles in the process of silk formation and spinning in the anterior silk gland. In addition, 210 genes were found differently expressed between males and females, which should help to elucidate the mechanism of the quality difference in silk fibers from male and female silkworms. PMID- 26417993 TI - The Application of DNA Barcodes for the Identification of Marine Crustaceans from the North Sea and Adjacent Regions. AB - During the last years DNA barcoding has become a popular method of choice for molecular specimen identification. Here we present a comprehensive DNA barcode library of various crustacean taxa found in the North Sea, one of the most extensively studied marine regions of the world. Our data set includes 1,332 barcodes covering 205 species, including taxa of the Amphipoda, Copepoda, Decapoda, Isopoda, Thecostraca, and others. This dataset represents the most extensive DNA barcode library of the Crustacea in terms of species number to date. By using the Barcode of Life Data Systems (BOLD), unique BINs were identified for 198 (96.6%) of the analyzed species. Six species were characterized by two BINs (2.9%), and three BINs were found for the amphipod species Gammarus salinus Spooner, 1947 (0.4%). Intraspecific distances with values higher than 2.2% were revealed for 13 species (6.3%). Exceptionally high distances of up to 14.87% between two distinct but monophyletic clusters were found for the parasitic copepod Caligus elongatus Nordmann, 1832, supporting the results of previous studies that indicated the existence of an overlooked sea louse species. In contrast to these high distances, haplotype-sharing was observed for two decapod spider crab species, Macropodia parva Van Noort & Adema, 1985 and Macropodia rostrata (Linnaeus, 1761), underlining the need for a taxonomic revision of both species. Summarizing the results, our study confirms the application of DNA barcodes as highly effective identification system for the analyzed marine crustaceans of the North Sea and represents an important milestone for modern biodiversity assessment studies using barcode sequences. PMID- 26418003 TI - Heat Shock Protein 60 in Eggs Specifically Induces Tregs and Reduces Liver Immunopathology in Mice with Schistosomiasis Japonica. AB - BACKGROUND: Parasitic helminths need to suppress the host immune system to establish chronic infections. Paradoxically, immunosuppression induced by the worm also benefits the host by limiting excessive inflammation and tissue damage, which remains the major cause leading to serious morbidity and mortality. Regulatory T cells (Tregs) are key immune regulators of this mutualism. The successive rise in Tregs during schistosome infection plays a critical role in immunoregulation. We and others previously showed that Schistosoma japonicum (S. japonicum) egg antigens (SEA) induce Tregs both in vitro and in vivo. In addition, we identified that SjHSP60 derived from SEA significantly induces Tregs in vivo and in vitro. However, the contribution of SjHSP60 in SEA to Treg induction and the related mechanisms of the Treg induction have not yet been identified. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we showed that S. japonicum stress protein HSP60 (SjHSP60) was constitutively and extensively expressed in eggs of S. japonicum. SjHSP60 specially induced Tregs in vivo and in vitro without inducing other CD4+ T sub-populations including Th1, Th2 and Th17 cells. Furthermore, we showed that the SjHSP60-depleted SEA almost lost the ability in vitro and displayed a significant impaired ability to induce Tregs in vivo. Finally, our study illustrated that the mechanisms of SjHSP60-mediated induction of Tregs are through both conversion of CD4+CD25- T cells into CD4+CD25+Foxp3+ Tregs and expansion of preexisting CD4+CD25+Foxp3+ Tregs in a TLR4-dependent manner. CONCLUSIONS/SIGNIFICANCE: Collectively, our findings identify SjHSP60 as a major parasitic contributor of Treg induction in S. japonicum egg antigens, which not only contributes to the better understanding of the mechanism of immunoregulation during helminth infection, but also suggests its potential as a therapeutic target for control of immunopathology, allergic and autoimmune diseases. PMID- 26418004 TI - Urbanicity and Paediatric Bacteraemia in Ghana-A Case-Control Study within a Rural-Urban Transition Zone. AB - BACKGROUND: Systemic bacterial infections are a major cause of paediatric febrile illness in sub-Saharan Africa. Aim of this study was to assess the effects of social and geographical determinants on the risk of bacteraemia in a rural-urban transition zone in Ghana. METHODS: Children below 15 years of age with fever were recruited at an outpatient department in the suburban belt of Kumasi, Ghana's second largest city. Blood was taken for bacterial culture and malaria diagnostics. The socio-economic status of participants was calculated using Principle Component Analysis. A scale, based on key urban characteristics, was established to quantify urbanicity for all communities in the hospital catchment area. A case-control analysis was conducted, where children with and without bacteraemia were cases and controls, respectively. RESULTS: Bacteraemia was detected in 72 (3.1%) of 2,306 hospital visits. Non-typhoidal Salmonella (NTS; n = 24; 33.3%) and Salmonella typhi (n = 18; 25.0%) were the most common isolates. Logistic regression analysis showed that bacteraemia was negatively associated with urbanicity (odds ratio [OR] = 0.8; 95% confidence interval [CI]: 0.7-1.0) and socio-economic status (OR = 0.8; 95% CI: 0.6-0.9). Both associations were stronger if only NTS infections were used as cases (OR = 0.5; 95% CI: 0.3-0.8 and OR = 0.6; 95% CI: 0.4-1.0, respectively). CONCLUSIONS: The results of this study highlight the importance of individual as well as community factors as independent risk factors for invasive bacterial infection (IBI) and especially NTS. Epidemiological data support physicians, public health experts and policy makers to identify disease prevention and treatment needs in order to secure public health in the transitional societies of developing countries. PMID- 26418005 TI - Osteocalcin Is Not Associated with the Risk of Type 2 Diabetes: Findings from the EPIC-NL Study. AB - OBJECTIVE: To investigate whether total osteocalcin (tOC), uncarboxylated osteocalcin (ucOC) and percentage of uncarboxylated osteocalcin (%ucOC) are associated with the risk of type 2 diabetes. METHODS: This nested case control study included 1,635 participants, 833 incident diabetes cases and 802 non diabetic control participants, aged 21-70 years from the EPIC-NL cohort. Baseline concentrations of tOC, ucOC and %ucOC were assessed. During 10 years of follow up, diabetes cases were self-reported and verified against information from general practitioners or pharmacists. The association between the different forms of osteocalcin and diabetes risk was assessed with logistic regression adjusted for diabetes risk factors (waist circumference, age, sex, cohort, smoking status, family history of diabetes, hypertension, alcohol intake, physical activity and education) and dietary factors (total energy intake and energy adjusted intake of fat, fiber, protein and calcium). RESULTS: TOC concentration was not associated with diabetes risk, with an odds ratio (OR) of 0.97 (0.91-1.03) for each ng/ml increment after adjustment for diabetes risk factors and dietary factors. No association between ucOC and %ucOC and the risk of diabetes was observed either. In sex stratified analyses (P interaction = 0.07), higher %ucOC tended to be associated with an increased risk of type 2 diabetes in a multivariable model in women (OR 1.05 for each increment of 5% ucOC (1.00-1.11), Ptrend = 0.08), but not in men (OR 0.96 for each increment of 5% ucOC (0.88-1.04)). When waist circumference was replaced by body mass index, none of the osteocalcin forms were associated with the risk of type 2 diabetes in the final model among both women and men. CONCLUSIONS: Available evidence suggests that tOC, ucOC and %ucOC are each not associated with the risk of type 2 diabetes. However, more large-scale cohort studies are needed to clarify the presence of any association between the different forms of osteocalcin and the risk of type 2 diabetes. PMID- 26418006 TI - Cytidine Deaminase as a Molecular Predictor of Gemcitabine Response in Patients with Biliary Tract Cancer. AB - OBJECTIVE: Gemcitabine-based chemotherapy is regarded as the standard treatment for biliary tract cancer (BTC). Potential biomarkers for gemcitabine response include the activities of cytidine deaminase (CDA), human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (DCK), and ribonucleotide reductase M1 (RRM1). Here, we investigated whether single nucleotide polymorphisms (SNPs) in their encoding genes were associated with the efficacy of gemcitabine chemotherapy in treating BTC. METHODS: We retrospectively evaluated 11 SNPs in the CDA, hENT1, DCK, human concentrative nucleoside transporter 3 (hCNT3), and RRM1 genes in 80 patients with unresectable, metastatic, or recurrent BTC who were treated with gemcitabine plus cisplatin. RESULTS: After the results were adjusted for clinical predictors, the variant allele of rs1048977 in the CDA gene was associated with tumor response in a dominant model (OR, 0.23; 95% CI, 0.06-0.93; p = 0.039). No significant association was detected between the 11 SNPs and grade 3/4 toxicity. CONCLUSIONS: Our findings suggest that the polymorphism of CDA may be a potential predictive marker for the efficacy of gemcitabine-based chemotherapy in patients with BTC. PMID- 26418007 TI - Dual Energy CT Angiography of Peripheral Arterial Disease: Feasibility of Using Lower Contrast Medium Volume. AB - OBJECTIVE: One of the main drawbacks associated with Dual Energy Computed Tomography Angiography (DECTA) is the risk of developing contrast medium-induced nephropathy (CIN). The aim of the present study was firstly, to design an optimal CT imaging protocol by determining the feasibility of using a reduced contrast medium volume in peripheral arterial DECTA, and secondly, to compare the results with those obtained from using routine contrast medium volume. METHODS: Thirty four patients underwent DECTA for the diagnosis of peripheral arterial disease. They were randomly divided into two groups: Group 1 (routine contrast volume group) with n = 17, injection rate 4-5 ml/s, and 1.5 ml/kg of contrast medium, and Group 2 ((low contrast volume group), with n = 17, injection rate 4-5ml/s, and contrast medium volume 0.75 ml/kg. A fast kilovoltage-switching 64-slice CT scanner in the dual-energy mode was employed for the study. A total of 6 datasets of monochromatic images at 50, 55, 60, 65, 70 and 75 keV levels were reconstructed with adaptive statistical iterative reconstruction (ASIR) at 50%. A 4-point scale was the tool for qualitative analysis of results. The two groups were compared and assessed quantitatively for image quality on the basis of signal-to-noise ratio (SNR) and contrast-to-noise-ratio (CNR). Radiation and contrast medium doses were also compared. RESULTS: The overall mean CT attenuation and mean noise for all lower extremity body parts was significantly lower for the low volume contrast group (p<0.001), and varied significantly between groups (p = 0.001), body parts (p<0.001) and keVs (p<0.001). The interaction between group body parts was significant with CT attenuation and CNR (p = 0.002 and 0.003 respectively), and marginally significant with SNR (p = 0.047), with minimal changes noticed between the two groups. Group 2 (low contrast volume group) displayed the lowest image noise between 65 and 70 keV, recorded the highest SNR and CNR at 65 keV, and produced significantly lower results with respect to contrast medium volume and duration of contrast injection (p<0.001). The effect of radiation dose was not statistically significant between the two groups. CONCLUSIONS: DECTA images created at 65 keV and 50% ASIR with low contrast medium volume protocol, yielded results that were comparable to routine contrast medium volume, with acceptable diagnostic images produced during the evaluation of peripheral arteries. PMID- 26418008 TI - Structure and Sialyllactose Binding of the Carboxy-Terminal Head Domain of the Fibre from a Siadenovirus, Turkey Adenovirus 3. AB - The virulent form of turkey adenovirus 3 (TAdV-3), also known as turkey hemorrhagic enteritis virus (THEV), is an economically important poultry pathogen, while the avirulent form is used as a vaccine. TAdV-3 belongs to the genus Siadenovirus. The carboxy-terminal region of its fibre does not have significant sequence similarity to any other adenovirus fibre heads of known structure. Two amino acid sequence differences between virulent and avirulent TAdV-3 map on the fibre head: where virulent TAdV-3 contains Ile354 and Thr376, avirulent TAdV-3 contains Met354 and Met376. We determined the crystal structures of the trimeric virulent and avirulent TAdV-3 fibre head domains at 2.2 A resolution. Each monomer contains a beta-sandwich, which, surprisingly, resembles reovirus fibre head more than other adenovirus fibres, although the ABCJ-GHID topology is conserved in all. A beta-hairpin insertion in the C-strand of each trimer subunit embraces its neighbouring monomer. The avirulent and virulent TAdV 3 fibre heads are identical apart from the exact orientation of the beta-hairpin insertion. In vitro, sialyllactose was identified as a ligand by glycan microarray analysis, nuclear magnetic resonance spectroscopy, and crystallography. Its dissociation constant was measured to be in the mM range by isothermal titration calorimetry. The ligand binds to the side of the fibre head, involving amino acids Glu392, Thr419, Val420, Lys421, Asn422, and Gly423 binding to the sialic acid group. It binds slightly more strongly to the avirulent form. We propose that, in vivo, the TAdV-3 fibre may bind a sialic acid-containing cell surface component. PMID- 26418009 TI - Involvement of Prolyl Hydroxylase Domain Protein in the Rosiglitazone-Induced Suppression of Osteoblast Differentiation. AB - Rosiglitazone is a well-known anti-diabetic drug that increases insulin sensitivity via peroxisome proliferator-activated receptor gamma (PPARgamma) activation, but unfortunately it causes bone loss in animals and humans. A previous study showed that prolyl hydroxylase domain protein (PHD) plays a role in rosiglitazone-induced adipocyte differentiation. Based on the inverse relationship between adipocyte and osteoblast differentiation, we investigated whether PHD is involved in the effects of rosiglitazone on osteoblast differentiation. Rosiglitazone inhibited osteoblast differentiation in a concentration-dependent manner, and in parallel induced three PHD isoforms (PHD1, 2, and 3). PHD inhibitors and knockdown of each isoform prevented the inhibitory effects of rosiglitazone on osteoblast differentiation and increased the expression of Runx2, a transcription factor essential for osteoblastogenesis. MG 132, a proteasomal inhibitor also prevented the rosiglitazone-induced degradation of Runx2. Furthermore, both increased PHD isoform expressions and reduced osteoblast differentiation by rosiglitazone were prevented by PPARgamma antagonists, indicating these effects were mediated via PPARgamma activation. In vivo oral administration of rosiglitazone to female ICR mice for 8 weeks reduced bone mineral densities and plasma alkaline phosphatase (ALP) activity, and increased PHD expression in femoral primary bone marrow cells and the ubiquitination of Runx2. Together, this suggests that the rosiglitazone-induced suppression of osteoblast differentiation is at least partly induced via PPARgamma-mediated PHD induction and subsequent promotion of the ubiquitination and degradation of Runx2. PMID- 26418010 TI - Race Does Not Predict Melanocyte Heterogeneous Responses to Dermal Fibroblast Derived Mediators. AB - INTRODUCTION: Abnormal pigmentation following cutaneous injury causes significant patient distress and represents a barrier to recovery. Wound depth and patient characteristics influence scar pigmentation. However, we know little about the pathophysiology leading to hyperpigmentation in healed shallow wounds and hypopigmentation in deep dermal wound scars. We sought to determine whether dermal fibroblast signaling influences melanocyte responses. METHODS AND MATERIALS: Epidermal melanocytes from three Caucasians and three African Americans were genotyped for single nucleotide polymorphisms (SNPs) across the entire genome. Melanocyte genetic profiles were determined using principal component analysis. We assessed melanocyte phenotype and gene expression in response to dermal fibroblast-conditioned medium and determined potential mesenchymal mediators by proteome profiling the fibroblast-conditioned medium. RESULTS: Six melanocyte samples demonstrated significant variability in phenotype and gene expression at baseline and in response to fibroblast-conditioned medium. Genetic profiling for SNPs in receptors for 13 identified soluble fibroblast secreted mediators demonstrated considerable heterogeneity, potentially explaining the variable melanocyte responses to fibroblast-conditioned medium. DISCUSSION: Our data suggest that melanocytes respond to dermal fibroblast derived mediators independent of keratinocytes and raise the possibility that mesenchymal-epidermal interactions influence skin pigmentation during cutaneous scarring. PMID- 26418011 TI - Continuous Metabolic Syndrome Scores for Children Using Salivary Biomarkers. AB - BACKGROUND: Binary definitions of the metabolic syndrome based on the presence of a particular number of individual risk factors are limited, particularly in the pediatric population. To address this limitation, we aimed at constructing composite and continuous metabolic syndrome scores (cmetS) to represent an overall measure of metabolic syndrome (MetS) in a large cohort of metabolically at-risk children, focusing on the use of the usual clinical parameters (waist circumference (WC) and systolic blood pressure (SBP), supplemented with two salivary surrogate variables (glucose and high density lipoprotein cholesterol (HDLC). Two different approaches used to create the scores were evaluated in comparison. METHODS: Data from 8,112 Kuwaiti children (10.00 +/- 0.67 years) were used to construct two cmetS for each subject. The first cmetS (cmetS-Z) was created by summing standardized residuals of each variable regressed on age and gender; and the second cmetS (cmetS-PCA) was defined as the first principal component from gender-specific principal component analysis based on the four variables. RESULTS: There was a graded relationship between both scores and the number of adverse risk factors. The areas under the curve using cmetS-Z and cmetS PCA as predictors for severe metabolic syndrome (defined as the presence of >=3 metabolic risk factors) were 0.935 and 0.912, respectively. cmetS-Z was positively associated with WC, SBP, and glucose, but inversely associated with HDLC. Except for the lack of association with glucose, cmetS-PCA was similar to cmetS-Z in boys, but had minimum loading on HDLC in girls. Analysis using quantile regression showed an inverse association of fitness level with cmetS-PCA (p = 0.001 for boys; p = 0.002 for girls), and comparison of cmetS-Z and cmetS PCA suggested that WC and SBP were main contributory components. Significant alterations in the relationship between cmetS and salivary adipocytokines were demonstrated in overweight and obese children as compared to underweight and normal-weight children. CONCLUSION: We have derived continuous summary scores for MetS from a large-scale pediatric study using two different approaches, incorporating salivary measures as surrogate for plasma measures. The derived scores were viable expressions of metabolic risk, and can be utilized to study the relationships of MetS with various aspects of the metabolic disease process. PMID- 26418012 TI - Dynamic Data Visualization with Weave and Brain Choropleths. AB - This article introduces the neuroimaging community to the dynamic visualization workbench, Weave (https://www.oicweave.org/), and a set of enhancements to allow the visualization of brain maps. The enhancements comprise a set of brain choropleths and the ability to display these as stacked slices, accessible with a slider. For the first time, this allows the neuroimaging community to take advantage of the advanced tools already available for exploring geographic data. Our brain choropleths are modeled after widely used geographic maps but this mashup of brain choropleths with extant visualization software fills an important neuroinformatic niche. To date, most neuroinformatic tools have provided online databases and atlases of the brain, but not good ways to display the related data (e.g., behavioral, genetic, medical, etc). The extension of the choropleth to brain maps allows us to leverage general-purpose visualization tools for concurrent exploration of brain images and related data. Related data can be represented as a variety of tables, charts and graphs that are dynamically linked to each other and to the brain choropleths. We demonstrate that the simplified region-based analyses that underlay choropleths can provide insights into neuroimaging data comparable to those achieved by using more conventional methods. In addition, the interactive interface facilitates additional insights by allowing the user to filter, compare, and drill down into the visual representations of the data. This enhanced data visualization capability is useful during the initial phases of data analysis and the resulting visualizations provide a compelling way to publish data as an online supplement to journal articles. PMID- 26418013 TI - Correction: Thrombospondin-1 Production Is Enhanced by Porphyromonas gingivalis Lipopolysaccharide in THP-1 Cells. PMID- 26418014 TI - Genome Wide Identification of LIM Genes in Cicer arietinum and Response of Ca 2LIMs in Development, Hormone and Pathogenic Stress. AB - The eukaryotic lineage-specific LIM protein (LIN11, ISL1, and MEC3) family play pivotal role in modulation of actin dynamics and transcriptional regulation. The systematic investigation of this family has not been carried in detail and rare in legumes. Current study involves the mining of Cicer arietinum genome for the genes coding for LIM domain proteins and displayed significant homology with LIM genes of other species. The analysis led to the identification of 15 members, which were positioned on chickpea chromosomes. The phylogenetic and motif analysis suggested their categorization into two sub-families i.e., Ca-2LIMs and Ca-DA1/DAR, which comprised of nine and six candidates, respectively. Further sub categories of Ca-2LIMs were recognised as alphaLIM, betaLIM, deltaLIM and gammaLIM. The LIM genes within their sub-families displayed conserved genomic and motif organization. The expression pattern of Ca-2LIMs across developmental and reproductive tissues demonstrated strong correlation with established consensus. The Ca-2LIM belongs to PLIM and GLIM (XLIM) was found highly expressed in floral tissue. Others showed ubiquitous expression pattern with their dominance in stem. Under hormonal and pathogenic conditions these LIMs were found to up-regulate during salicylic acid, abscisic acid and Ascochyta rabiei treatment or infection; and down-regulated in response to jasmonic acid treatment. The findings of this work, particularly in terms of modulation of LIM genes under biotic stress will open up the way to further explore and establish the role of chickpea LIMs in plant defense response. PMID- 26418015 TI - Cardiorespiratory Adaptations during Concurrent Aerobic and Strength Training in Men and Women. AB - This study investigated the effects of endurance followed by strength training (ES, men n = 16; women n = 15), the reverse exercise order (SE, men n = 18, women n = 13) and concurrent endurance and strength training performed on alternating days (AD, men n = 21, women n = 18) on cardiorespiratory parameters. Peak oxygen consumption ([Formula: see text]O2peak) and oxygen consumption at sub-maximal power outputs ([Formula: see text]O2submax) of 50 to 175 Watts in men and 50 to 125 Watts in women were assessed during an incremental cycling test both before and after 24 weeks of training. Increases in [Formula: see text]O2peak in both men and women were statistically larger in AD (18+/-9% and 25+/-11%) compared to ES (7+/-9% and 12+/-12%, p = 0.002 and 0.009, respectively) and SE (7+/-9% and 10+/-8%, p = 0.005 and 0.008, respectively). No statistical group interaction was observed for [Formula: see text]O2submax in men, but in women [Formula: see text]O2submax was statistically lower at week 24 in ES compared to AD at 75 W ( 2+/-6% vs. +3+/-6%, p = 0.027) and 125 W (-4+/-5% vs. +2+/-5%, p = 0.010). These findings indicate that endurance and strength training performed on alternating days may optimize the adaptations in [Formula: see text]O2peak in both sexes, while performing ES training in women may optimize cardiorespiratory fitness at sub-maximal power outputs. PMID- 26418017 TI - Lateral Transorbital Endoscopic Access to the Hippocampus, Amygdala, and Entorhinal Cortex: Initial Clinical Experience. AB - BACKGROUND/AIMS: Transorbital approaches traditionally have focused on skull base and cavernous sinus lesions medial to the globe. Lateral orbital approaches to the temporal lobe have not been widely explored despite several theoretical advantages compared to open craniotomy. Recently, we demonstrated the feasibility of the lateral transorbital technique in cadaveric specimens with endoscopic visualization. We describe our initial clinical experience with the endoscope assisted lateral transorbital approach to lesions in the temporal lobe. METHODS: Two patients with mesial temporal lobe pathology presenting with seizures underwent surgery. The use of a transpalpebral or Stallard-Wright eyebrow incision enabled access to the intraorbital compartment, and a lateral orbital wall 'keyhole' opening permitted visualization of the anterior temporal pole. RESULTS: This approach afforded adequate access to the surgical target and surrounding structures and was well tolerated by the patients. To the best of our knowledge, this report constitutes the first case series describing the endoscope assisted lateral transorbital approach to the temporal lobe. We discuss the limits of exposure, the nuances of opening and closing, and comparisons to open craniotomy. CONCLUSION: Further prospective investigation of this approach is warranted for comparison to traditional approaches to the mesial temporal lobe. PMID- 26418018 TI - Lysophosphatidic Acid Mediates Activating Transcription Factor 3 Expression Which Is a Target for Post-Transcriptional Silencing by miR-30c-2-3p. AB - Although microRNAs (miRNAs) are small, non-protein-coding entities, they have important roles in post-transcriptional regulation of most of the human genome. These small entities generate fine-tuning adjustments in the expression of mRNA, which can mildly or massively affect the abundance of proteins. Previously, we found that the expression of miR-30c-2-3p is induced by lysophosphatidic acid and has an important role in the regulation of cell proliferation in ovarian cancer cells. The goal here is to confirm that ATF3 mRNA is a target of miR-30c-2-3p silencing, thereby further establishing the functional role of miR-30c-2-3p. Using a combination of bioinformatics, qRT-PCR, immunoblotting and luciferase assays, we uncovered a regulatory pathway between miR-30c-2-3p and the expression of the transcription factor, ATF3. Lysophosphatidic acids triggers the expression of both miR-30c-2-3p and ATF3, which peak at 1 h and are absent 8 h post stimulation in SKOV-3 and OVCAR-3 serous ovarian cancer cells. The 3' untranslated region (3'-UTR) of ATF3 was a predicted, putative target for miR-30c 2-3p, which we confirmed as a bona-fide interaction using a luciferase reporter assay. Specific mutations introduced into the predicted site of interaction between miR-30c-2-3p and the 3'-UTR of ATF3 alleviated the suppression of the luciferase signal. Furthermore, the presence of anti-miR-30c-2-3p enhanced ATF3 mRNA and protein after lysophosphatidic acid stimulation. Thus, the data suggest that after the expression of ATF3 and miR-30c-2-3p are elicited by lysophosphatidic acid, subsequently miR-30c-2-3p negatively regulates the expression of ATF3 through post-transcriptional silencing, which prevents further ATF3-related outcomes as a consequence of lysophosphatidic acid signaling. PMID- 26418016 TI - A Review of the Statistical and Quantitative Methods Used to Study Alcohol Attributable Crime. AB - Modelling the relationship between alcohol consumption and crime generates new knowledge for crime prevention strategies. Advances in data, particularly data with spatial and temporal attributes, have led to a growing suite of applied methods for modelling. In support of alcohol and crime researchers we synthesized and critiqued existing methods of spatially and quantitatively modelling the effects of alcohol exposure on crime to aid method selection, and identify new opportunities for analysis strategies. We searched the alcohol-crime literature from 1950 to January 2014. Analyses that statistically evaluated or mapped the association between alcohol and crime were included. For modelling purposes, crime data were most often derived from generalized police reports, aggregated to large spatial units such as census tracts or postal codes, and standardized by residential population data. Sixty-eight of the 90 selected studies included geospatial data of which 48 used cross-sectional datasets. Regression was the prominent modelling choice (n = 78) though dependent on data many variations existed. There are opportunities to improve information for alcohol-attributable crime prevention by using alternative population data to standardize crime rates, sourcing crime information from non-traditional platforms (social media), increasing the number of panel studies, and conducting analysis at the local level (neighbourhood, block, or point). Due to the spatio-temporal advances in crime data, we expect a continued uptake of flexible Bayesian hierarchical modelling, a greater inclusion of spatial-temporal point pattern analysis, and shift toward prospective (forecast) modelling over small areas (e.g., blocks). PMID- 26418019 TI - Left Ventricular Wall Stress-Mass-Heart Rate Product and Cardiovascular Events in Treated Hypertensive Patients: LIFE Study. AB - In the Losartan Intervention for End Point Reduction in Hypertension (LIFE) study, 4.8 years' losartan- versus atenolol-based antihypertensive treatment reduced left ventricular hypertrophy and cardiovascular end points, including cardiovascular death and stroke. However, there was no difference in myocardial infarction (MI), possibly related to greater reduction in myocardial oxygen demand by atenolol-based treatment. Myocardial oxygen demand was assessed indirectly by the left ventricular mass*wall stress*heart rate (triple product) in 905 LIFE participants. The triple product was included as time-varying covariate in Cox models assessing predictors of the LIFE primary composite end point (cardiovascular death, MI, or stroke), its individual components, and all cause mortality. At baseline, the triple product in both treatment groups was, compared with normal adults, elevated in 70% of patients. During randomized treatment, the triple product was reduced more by atenolol, with prevalences of elevated triple product of 39% versus 51% on losartan (both P<=0.001). In Cox regression analyses adjusting for age, smoking, diabetes mellitus, and prior stroke, MI, and heart failure, 1 SD lower triple product was associated with 23% (95% confidence interval 13%-32%) fewer composite end points, 31% (18%-41%) less cardiovascular mortality, 30% (15%-41%) lower MI, and 22% (11%-33%) lower all cause mortality (all P<=0.001), without association with stroke (P=0.34). Although losartan-based therapy reduced ventricular mass more, greater heart rate reduction with atenolol resulted in larger reduction of the triple product. Lower triple product during antihypertensive treatment was strongly, independently associated with lower rates of the LIFE primary composite end point, cardiovascular death, and MI, but not stroke. PMID- 26418020 TI - 17beta-Estradiol Attenuates Conduit Pulmonary Artery Mechanical Property Changes With Pulmonary Arterial Hypertension. AB - Pulmonary arterial hypertension (PAH), a rapidly fatal vascular disease, strikes women more often than men. Paradoxically, female PAH patients have better prognosis and survival rates than males. The female sex hormone 17beta-estradiol has been linked to the better outcome of PAH in females; however, the mechanisms by which 17beta-estradiol alters PAH progression and outcomes remain unclear. Because proximal pulmonary arterial (PA) stiffness, one hallmark of PAH, is a powerful predictor of mortality and morbidity, we hypothesized that 17beta estradiol attenuates PAH-induced changes in mechanical properties in conduit proximal PAs, which imparts hemodynamic and energetic benefits to right ventricular function. To test this hypothesis, female mice were ovariectomized and treated with 17beta-estradiol or placebo. PAH was induced in mice using SU5416 and chronic hypoxia. Extra-lobar left PAs were isolated and mechanically tested ex vivo to study both static and frequency-dependent mechanical behaviors in the presence or absence of smooth muscle cell activation. Our static mechanical test showed significant stiffening of large PAs with PAH (P<0.05). 17beta-Estradiol restored PA compliance to control levels. The dynamic mechanical test demonstrated that 17beta-estradiol protected the arterial wall from the PAH induced frequency-dependent decline in dynamic stiffness and loss of viscosity with PAH (P<0.05). As demonstrated by the in vivo measurement of PA hemodynamics via right ventricular catheterization, modulation by 17beta-estradiol of mechanical proximal PAs reduced pulsatile loading, which contributed to improved ventricular-vascular coupling. This study provides a mechanical mechanism for delayed disease progression and better outcome in female PAH patients and underscores the therapeutic potential of 17beta-estradiol in PAH. PMID- 26418021 TI - Effects of Intrinsic and Extrinsic Cardiac Nerves on Atrial Arrhythmia in Experimental Pulmonary Artery Hypertension. AB - Atrial arrhythmia, which includes atrial fibrillation (AF) and atrial flutter (AFL), is common in patients with pulmonary arterial hypertension (PAH), who often have increased sympathetic nerve activity. Here, we tested the hypothesis that autonomic nerves play important roles in vulnerability to AF/AFL in PAH. The atrial effective refractory period and AF/AFL inducibility at baseline and after anterior right ganglionated plexi ablation were determined during left stellate ganglion stimulation or left renal sympathetic nerve stimulation in beagle dogs with or without PAH. Then, sympathetic nerve, beta-adrenergic receptor densities and connexin 43 expression in atrial tissues were assessed. The sum of the window of vulnerability to AF/AFL was increased in the right atrium compared with the left atrium at baseline in the PAH dogs but not in the controls. The atrial effective refractory period dispersion was increased in the control dogs, but not in the PAH dogs, during left stellate ganglion stimulation. The voltage thresholds for inducing AF/AFL during anterior right ganglionated plexi stimulation were lower in the PAH dogs than in the controls. The AF/AFL inducibility was suppressed after ablation of the anterior right ganglionated plexi in the PAH dogs. The PAH dogs had higher sympathetic nerve and beta1 adrenergic receptor densities, increased levels of nonphosphorylated connexin 43, and heterogeneous connexin 43 expression in the right atrium when compared with the control dogs. The anterior right ganglionated plexi play important roles in the induction of AF/AFL. AF/AFL induction was associated with right atrium substrate remodeling in dogs with PAH. PMID- 26418023 TI - Another Piece to the Puzzle: Linking the Cardiac Nervous System to Atrial Fibrillation in Pulmonary Arterial Hypertension. PMID- 26418022 TI - Impact of Ivabradine on Central Aortic Blood Pressure and Myocardial Perfusion in Patients With Stable Coronary Artery Disease. AB - Treatment of hypertensive patients with beta-blockers reduces heart rate and decreases central blood pressure less than other antihypertensive drugs, implying that reducing heart rate without altering brachial blood pressure could increase central blood pressure, explaining the increased cardiovascular risk reported with beta-blocker. We describe a randomized, double-blind study to explore whether heart rate reduction with the If inhibitor ivabradine had an impact on central blood pressure. We included 12 normotensive patients with stable coronary artery disease, heart rate >=70 bpm (sinus rhythm), and stable background beta blocker therapy. Patients received ivabradine 7.5 mg BID or matched placebo for two 3-week periods with a crossover design and evaluation by aplanation tonometry. Treatment with ivabradine was associated with a significant reduction in resting heart rate after 3 weeks versus no change with placebo (-15.8+/-7.7 versus +0.3+/-5.8 bpm; P=0.0010). There was no relevant between-group difference in change in central aortic systolic blood pressure (-4.0+/-9.6 versus +2.4+/ 12.0 mm Hg; P=0.13) or augmentation index (-0.8+/-10.0% versus +0.3+/-7.6%; P=0.87). Treatment with ivabradine was associated with a modest increase in left ventricular ejection time (+18.5+/-17.8 versus +2.8+/-19.3 ms; P=0.074) and a prolongation of diastolic perfusion time (+215.6+/-105.3 versus -3.0+/-55.8 ms with placebo; P=0.0005). Consequently, ivabradine induced a pronounced increase in Buckberg index, an index of myocardial viability (+39.3+/-27.6% versus -2.5+/ 13.5% with placebo; P=0.0015). In conclusion, heart rate reduction with ivabradine does not increase central aortic blood pressure and is associated with a marked prolongation of diastolic perfusion time and an improvement in myocardial perfusion index. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2011-004779-35. PMID- 26418024 TI - High B-Type Natriuretic Peptide Hypertensives at Target Blood Pressure: Potential Role of beta-Blockers to Reduce Their Elevated Risk. PMID- 26418025 TI - Patent Foramen Ovale Closure in Obstructive Sleep Apnea Improves Blood Pressure and Cardiovascular Function. AB - Obstructive sleep apnea (OSA) is a frequent syndrome characterized by intermittent hypoxemia and increased prevalence of arterial hypertension and cardiovascular morbidity. In OSA, the presence of patent foramen ovale (PFO) is associated with increased number of apneas and more severe oxygen desaturation. We hypothesized that PFO closure improves sleep-disordered breathing and, in turn, has favorable effects on vascular function and arterial blood pressure. In 40 consecutive patients with newly diagnosed OSA, we searched for PFO. After initial cardiovascular assessment, the 14 patients with PFO underwent initial device closure and the 26 without PFO served as control group. Conventional treatment for OSA was postponed for 3 months in both groups, and polysomnographic and cardiovascular examinations were repeated at the end of the follow-up period. PFO closure significantly improved the apnea-hypopnea index (DeltaAHI -7.9+/-10.4 versus +4.7+/-13.1 events/h, P=0.0009, PFO closure versus control), the oxygen desaturation index (DeltaODI -7.6+/-16.6 versus +7.6+/-17.0 events/h, P=0.01), and the number of patients with severe OSA decreased significantly after PFO closure (79% versus 21%, P=0.007). The following cardiovascular parameters improved significantly in the PFO closure group, although remained unchanged in controls: brachial artery flow-mediated vasodilation, carotid artery stiffness, nocturnal systolic and diastolic blood pressure (-7 mm Hg, P=0.009 and -3 mm Hg, P=0.04, respectively), blood pressure dipping, and left ventricular diastolic function. In conclusion, PFO closure in OSA patients improves sleep-disordered breathing and nocturnal oxygenation. This translates into an improvement of endothelial function and vascular stiffening, a decrease of nighttime blood pressure, restoration of the dipping pattern, and improvement of left ventricular diastolic function. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01780207. PMID- 26418027 TI - Crystallographic, Electronic, and Magnetic Properties of Rock Salt Superstructure Sulfide Lu2CrS4 with Jahn-Teller Distortion. AB - A new chromium(II) sulfide, Lu2CrS4, with a novel structure was prepared by a solid-state reaction. The powder X-ray diffraction pattern could be indexed as a tetragonal system, with a = 7.46373(2) A, c = 22.6338(2) A, and space group I42d (No. 122). Rietveld analysis of the pattern provided the crystal structure consisting of CrS6 and LuS6 octahedra sharing edges and apexes and revealed a rock salt superstructure with new cation (vacancy) arrangements. The electrical resistivity indicates semiconducting behavior. The magnetic susceptibility and specific heat measurements showed that the Cr ions are in the high-spin d(4) configuration and that their magnetic moments ordered antiferromagnetically at 55 K. The basic antiferromagnetic structure was determined using powder neutron diffraction data at 10 K. The band structure calculations demonstrate that the densities of states of Cr 3d electrons split into two spin-up eg bands because of Jahn-Teller distortion. PMID- 26418026 TI - Changes in the Sterol Composition of the Plasma Membrane Affect Membrane Potential, Salt Tolerance and the Activity of Multidrug Resistance Pumps in Saccharomyces cerevisiae. AB - We investigated the impact of the deletions of genes from the final steps in the biosynthesis of ergosterol (ERG6, ERG2, ERG3, ERG5, ERG4) on the physiological function of the Saccharomyces cerevisiae plasma membrane by a combination of biological tests and the diS-C3(3) fluorescence assay. Most of the erg mutants were more sensitive than the wild type to salt stress or cationic drugs, their susceptibilities were proportional to the hyperpolarization of their plasma membranes. The different sterol composition of the plasma membrane played an important role in the short-term and long-term processes that accompanied the exposure of erg strains to a hyperosmotic stress (effect on cell size, pH homeostasis and survival of yeasts), as well as in the resistance of cells to antifungal drugs. The pleiotropic drug-sensitive phenotypes of erg strains were, to a large extent, a result of the reduced efficiency of the Pdr5 efflux pump, which was shown to be more sensitive to the sterol content of the plasma membrane than Snq2p. In summary, the erg4Delta and erg6Delta mutants exhibited the most compromised phenotypes. As Erg6p is not involved in the cholesterol biosynthetic pathway, it may become a target for a new generation of antifungal drugs. PMID- 26418028 TI - Assessment of Nutritional Status in Children With Cancer and Effectiveness of Oral Nutritional Supplements. AB - Malnutrition is a common consequence of cancer in children, but the most effective methods of nutrition intervention are under debate. We aimed to evaluate the nutritional status of children diagnosed with cancer, and to investigate the effect of oral nutritional supplements on anthropometric measurements, biochemical parameters, and outcome. A randomized clinical study of 45 newly diagnosed cancer patients was performed. Anthropometric and biochemical data and related factors were assessed at 0, 3, and 6 months after diagnosis. On initial anthropometric assessment, prevalence of malnutrition by weight or height was found to be lower as compared with body mass index (BMI), or weight for height (WFH), or arm anthropometry. Twenty-six of the patients (55%) received oral nutritional supplement. During the second 3 months after diagnosis, there was a statistically significant decrease in number of the patients with WFH <90th percentile and BMI <5th percentile (P = .003 and P = .04, respectively). Infectious complications occurred more frequently in malnourished patients during first 3 months, and survival of children who were malnourished at the 6th month was significantly lower than that of well-nourished children (P = .003). On laboratory assessment, serum prealbumin levels of the all subjects were below normal ranges, but no relation was found for serum prealbumin or albumin levels in patients who were malnourished or not at diagnosis. Nutritional intervention is necessary to promote normal development and increase functional status as a child receives intensive treatment. Protein- and energy-dense oral nutritional supplements are effective for preventing weight loss in malnourished children. PMID- 26418029 TI - Synthesis, crystal structure and properties of the new superconductors TaRuB and NbOsB. AB - Two new ternary compounds TaRuB and NbOsB were synthesized by arc-melting and annealing at 1500-1850 degrees C. They crystallize in orthorhombic primitive structures with space group Pbam. Magnetic susceptibility, electrical resistivity, and specific heat measurements reveal bulk superconductivity for metallic TaRuB with a T(c) ~ 4 K. Electronic structure calculations by DFT methods show that 4d and 5d transition-metal states dominate the density of states (DOS) at the Fermi level E(F) with a pronounced quasi one-dimensional behaviour along the [0 0 1] direction. Comparison of the calculated DOS at E(F) with specific heat data reveals a moderate electron-phonon coupling. Possible small boron vacancies could significantly reduce the DOS at E(F), hence decrease T(c) for samples annealed at higher temperatures. For NbOsB, the DOS(E(F)) is strongly reduced due to an increase of covalent bonding interactions between Os and B. Accordingly, a lower T(c) ~ 1 K is observed. PMID- 26418030 TI - Interview with Stephen B Baylin. AB - Stephen B Baylin is a codirector of the Cancer Biology Program at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and the Virginia and DK Ludwig Professor of Oncology and Medicine. Baylin attended Duke University, where he earned his medical degree and completed his internship and first year residency in internal medicine. He then worked for 2 years at the National Heart and Lung Institute of the NIH. In 1971, he joined the departments of oncology and medicine at Johns Hopkins University School of Medicine. His research interests include cellular biology and genetics of cancer, specifically epigenetics or genetic modifications other than those in DNA that can affect cell behavior, and silencing of tumor suppressor genes and tumor progression. His research has looked at the mechanisms through which variations in tumor cells derive, and cell differentiation in cancers such as medullary thyroid carcinoma and small-cell lung carcinoma. He has served on the American Association for Cancer Research Board of Directors, and is an associate editor of Cancer Research. He has also presented frequently at AACR conferences and chaired the special conference on 'DNA Methylation, Imprinting and the Epigenetics of Cancer'. He has authored or coauthored more than 370 publications. PMID- 26418031 TI - LPA Induces Colon Cancer Cell Proliferation through a Cooperation between the ROCK and STAT-3 Pathways. AB - Lysophosphatidic acid (LPA) plays a critical role in the proliferation and migration of colon cancer cells; however, the downstream signaling events underlying these processes remain poorly characterized. The aim of this study was to investigate the signaling pathways triggered by LPA to regulate the mechanisms involved in the progression of colorectal cancer (CRC). We have used three cell line models of CRC, and initially analyzed the expression profile of LPA receptors (LPAR). Then, we treated the cells with LPA and events related to their tumorigenic potential, such as migration, invasion, anchorage-independent growth, proliferation as well as apoptosis and cell cycle were evaluated. We used the Chip array technique to analyze the global gene expression profiling that occurs after LPA treatment, and we identified cell signaling pathways related to the cell cycle. The inhibition of these pathways verified the conclusions of the transcriptomic analysis. We found that the cell lines expressed LPAR1, -2 and -3 in a differential manner and that 10 MUM LPA did not affect cell migration, invasion and anchorage-independent growth, but it did induce proliferation and cell cycle progression in HCT-116 cells. Although LPA in this concentration did not induce transcriptional activity of beta-catenin, it promoted the activation of Rho and STAT-3. Moreover, ROCK and STAT-3 inhibitors prevented LPA-induced proliferation, but ROCK inhibition did not prevent STAT-3 activation. Finally, we observed that LPA regulates the expression of genes related to the cell cycle and that the combined inhibition of ROCK and STAT-3 prevented cell cycle progression and increased the LPA-induced expression of cyclins E1, A2 and B1 to a greater degree than either inhibitor alone. Overall, these results demonstrate that LPA increases the proliferative potential of colon adenocarcinoma HCT-116 cells through a mechanism involving cooperation between the Rho-ROCK and STAT3 pathways involved in cell cycle control. PMID- 26418033 TI - Myasthenia gravis Lambert-Eaton overlap syndrome. AB - INTRODUCTION: To assess whether a myasthenia gravis (MG) Lambert-Eaton overlap syndrome (MLOS) exists. METHODS: Case reports that met the universally accepted diagnostic criteria for MG and Lambert-Eaton myasthenic syndrome (LEMS) were sought through a PubMed search. Fifty-five possible cases of MLOS were identified. RESULTS: Thirty-nine cases met the diagnostic criteria for MG and LEMS. Analysis of clinical features showed that these patients have common MG and LEMS symptoms: oculo-bulbar paresis and good response to anti-cholinesterase for MG and limb weakness and decreased or absent reflexes for LEMS. All had the classical LEMS pattern in the repetitive nerve stimulation test: low compound muscle action potential amplitude and incremental response > 60% with brief exercise or at high rate of stimulation. Eight patients had combined positive acetylcholine receptor antibody (AChR-ab) or muscle-specific kinase-ab and voltage-gated calcium channel- ab tests. CONCLUSIONS: A myasthenia gravis Lambert Eaton overlap syndrome (MLOS) does exist. PMID- 26418034 TI - Aqueous foams stabilized by temperature-sensitive hairy polymer particles. AB - Submicrometer-sized polystyrene (PS) particles carrying poly[2 (diethylamino)ethyl methacrylate] (PDEA) hairs (PDEA-PS particles) were synthesized by free radical dispersion polymerization. The hydrophilicity hydrophobicity balance of the PDEA could be tuned by varying the temperature at near neutral pH (a lower critical solution temperature of PDEA at pH 6.86, 41 degrees C) and therefore these sterically-stabilized particles acted as temperature-sensitive stabilizers for aqueous foams. At 25 degrees C, where the PDEA hairs were hydrated and PDEA-PS particles were colloidally stable in aqueous media, foams were formed which coalesced with time and the size of the bubble increased. At 40 and 45 degrees C, where the PDEA hairs were partially non hydrated and PDEA-PS particles were close to flocculation or weakly flocculated, foams were formed and bubble coalescence and size increase speeds were slower than those observed at 25 degrees C. At and above 50 degrees C, where the PDEA hairs were non-hydrated and PDEA-PS particles were heavily flocculated in aqueous media, the more stable cream-like foams whose volume was almost the same for 1 week were formed. Scanning electron microscopy studies indicated that the particles mainly adsorbed at the air-water interface as monolayers at 25 degrees C and as multilayers at and above 40 degrees C. The foam stability and structure could be controlled by changing the temperature. PMID- 26418032 TI - Synergistic Proinflammatory Responses by IL-17A and Toll-Like Receptor 3 in Human Airway Epithelial Cells. AB - Viral respiratory infections activate the innate immune response in the airway epithelium through Toll-like receptors (TLRs) and induce airway inflammation, which causes acute exacerbation of asthma. Although increases in IL-17A expression were observed in the airway of severe asthma patients, the interaction between IL-17A and TLR activation in airway epithelium remains poorly understood. In this study, we demonstrated that IL-17A and polyI:C, the ligand of TLR3, synergistically induced the expression of proinflammatory cytokines and chemokines (G-CSF, IL-8, CXCL1, CXCL5, IL-1F9), but not type I interferon (IFN alpha1, -beta) in primary culture of normal human bronchial epithelial cells. Synergistic induction after co-stimulation with IL-17A and polyI:C was observed from 2 to 24 hours after stimulation. Treatment with cycloheximide or actinomycin D had no effect, suggesting that the synergistic induction occurred without de novo protein synthesis or mRNA stabilization. Inhibition of the TLR3, TLR/TIR domain-containing adaptor-inducing interferon beta (TRIF), NF-kappaB, and IRF3 pathways decreased the polyI:C- and IL-17A/polyI:C-induced G-CSF and IL-8 mRNA expression. Comparing the levels of mRNA induction between co-treatment with IL 17A/polyI:C and treatment with polyI:C alone, blocking the of NF-kappaB pathway significantly attenuated the observed synergism. In western blotting analysis, activation of both NF-kappaB and IRF3 was observed in treatment with polyI:C and co-treatment with IL-17A/polyI:C; moreover, co-treatment with IL-17A/polyI:C augmented IkappaB-alpha phosphorylation as compared to polyI:C treatment alone. Collectively, these findings indicate that IL-17A and TLR3 activation cooperate to induce proinflammatory responses in the airway epithelium via TLR3/TRIF mediated NF-kappaB/IRF3 activation, and that enhanced activation of the NF-kappaB pathway plays an essential role in synergistic induction after co-treatment with IL-17A and polyI:C in vitro. PMID- 26418035 TI - Z-Selective Hydrothiolation of Racemic 1,3-Disubstituted Allenes: An Atom Economic Rhodium-Catalyzed Dynamic Kinetic Resolution. AB - A Z-selective rhodium-catalyzed hydrothiolation of 1,3-disubstituted allenes and subsequent oxidation towards the corresponding allylic sulfones is described. Using the bidentate 1,4-bis(diphenylphosphino)butane (dppb) ligand, Z/E selectivities up to >99:1 were obtained. The highly atom-economic desymmetrization reaction tolerates functionalized aromatic and aliphatic thiols. Additionally, a variety of symmetric internal allenes, as well as unsymmetrically disubstituted substrates were well tolerated, thus resulting in high regioselectivities. Starting from chiral but racemic 1,3-disubstituted allenes a dynamic kinetic resolution (DKR) could be achieved by applying (S,S)-Me-DuPhos as the chiral ligand. The desired Z-allylic sulfones were obtained in high yields and enantioselectivities up to 96 % ee. PMID- 26418036 TI - Safety challenges of powered two-wheelers. PMID- 26418037 TI - Assessing proximal risks for acute traumatic events: the case-crossover design. PMID- 26418040 TI - Low-Dose, Long-Wave UV Light Does Not Affect Gene Expression of Human Mesenchymal Stem Cells. AB - Light is a non-invasive tool that is widely used in a range of biomedical applications. Techniques such as photopolymerization, photodegradation, and photouncaging can be used to alter the chemical and physical properties of biomaterials in the presence of live cells. Long-wave UV light (315 nm-400 nm) is an easily accessible and commonly used energy source for triggering biomaterial changes. Although exposure to low doses of long-wave UV light is generally accepted as biocompatible, most studies employing this wavelength only establish cell viability, ignoring other possible (non-toxic) effects. Since light exposure of wavelengths longer than 315 nm may potentially induce changes in cell behavior, we examined changes in gene expression of human mesenchymal stem cells exposed to light under both 2D and 3D culture conditions, including two different hydrogel fabrication techniques, decoupling UV exposure and radical generation. While exposure to long-wave UV light did not induce significant changes in gene expression regardless of culture conditions, significant changes were observed due to scaffold fabrication chemistry and between cells plated in 2D versus encapsulated in 3D scaffolds. In order to facilitate others in searching for more specific changes between the many conditions, the full data set is available on Gene Expression Omnibus for querying. PMID- 26418042 TI - Thermochromism of Cu(I) Tetrakisguanidine Complexes: Reversible Activation of Metal-to-Ligand Charge-Transfer Bands. AB - Tetranuclear, intensely blue-coloured Cu(I) complexes were synthesised in which two Cu2 X3 (-) units (X=Br or I) are bridged by a dicationic GFA (guanidino functionalised aromatic) ligand. The UV/Vis spectra show a large metal-to-ligand charge-transfer (MLCT) band around 638 nm. The tetranuclear "low-temperature" complexes are in a temperature-dependent equilibrium with dinuclear Cu(I) "high temperature" complexes, which result from the reversible elimination of two CuX groups. A massive thermochromism effect results from the extinction of the strong MLCT band upon CuX elimination with increasing temperature. For all complexes, quantum chemical calculations predict a small and method-dependent energy difference between the possible electronic structures, namely Cu(I) and dicationic GFA ligand (closed-shell singlet) versus Cu(II) and neutral GFA ligand (triplet or broken-symmetry state). The closed-shell singlet state is disfavoured by hybrid-DFT functionals, which mix in exact Hartree-Fock exchange, and is favoured by larger basis sets and consideration of a polar medium. PMID- 26418041 TI - Investigating the Mechanism of Hyperglycemia-Induced Fetal Cardiac Hypertrophy. AB - Hyperglycemia in diabetic mothers enhances the risk of fetal cardiac hypertrophy during gestation. However, the mechanism of high-glucose-induced cardiac hypertrophy is not largely understood. In this study, we first demonstrated that the incidence rate of cardiac hypertrophy dramatically increased in fetuses of diabetic mothers using color ultrasound examination. In addition, human fetal cardiac hypertrophy was successfully mimicked in a streptozotocin (STZ)-induced diabetes mouse model, in which mouse cardiac hypertrophy was diagnosed using type M ultrasound and a histological assay. PH3 immunofluorescent staining of mouse fetal hearts and in vitro-cultured H9c2 cells indicated that cell proliferation decreased in E18.5, E15.5 and E13.5 mice, and cell apoptosis in H9c2 cells increased in the presence of high glucose in a dose-dependent manner. Next, we found that the individual cardiomyocyte size increased in pre-gestational diabetes mellitus mice and in response to high glucose exposure. Meanwhile, the expression of beta-MHC and BMP-10 was up-regulated. Nkx2.5 immunofluorescent staining showed that the expression of Nkx2.5, a crucial cardiac transcription factor, was suppressed in the ventricular septum, left ventricular wall and right ventricular wall of E18.5, E15.5 and E13.5 mouse hearts. However, cardiac hypertrophy did not morphologically occur in E13.5 mouse hearts. In cultured H9c2 cells exposed to high glucose, Nkx2.5 expression decreased, as detected by both immunostaining and western blotting, and the expression of KCNE1 and Cx43 was also restricted. Taken together, alterations in cell size rather than cell proliferation or apoptosis are responsible for hyperglycemia-induced fetal cardiac hypertrophy. The aberrant expression of Nkx2.5 and its regulatory target genes in the presence of high glucose could be a principal component of pathogenesis in the development of fetal cardiac hypertrophy. PMID- 26418043 TI - Predicting Suicide Intent: The Roles of Experiencing or Committing Violent Acts. AB - According to the interpersonal theory of suicide (Joiner, 2005), repeated exposure to painful or provocative experiences is associated with lethal or nearly lethal suicide attempts. However, suicide research often focuses on suicide ideation or attempts, rather than intent. Using data from the Collaborative Psychiatric Epidemiological Surveys, we examined traumatic experiences, with a focus on repeated exposure to traumas, in individuals who described their suicide attempts as a strong intent to die versus a cry for help. Only repeated acts of committing violence were associated with high suicide intent, suggesting that individuals who engage in violence are at heightened risk for suicide. PMID- 26418044 TI - Auditory Training Effects on the Listening Skills of Children With Auditory Processing Disorder. AB - OBJECTIVES: Children with auditory processing disorder (APD) typically present with "listening difficulties,"' including problems understanding speech in noisy environments. The authors examined, in a group of such children, whether a 12 week computer-based auditory training program with speech material improved the perception of speech-in-noise test performance, and functional listening skills as assessed by parental and teacher listening and communication questionnaires. The authors hypothesized that after the intervention, (1) trained children would show greater improvements in speech-in-noise perception than untrained controls; (2) this improvement would correlate with improvements in observer-rated behaviors; and (3) the improvement would be maintained for at least 3 months after the end of training. DESIGN: This was a prospective randomized controlled trial of 39 children with normal nonverbal intelligence, ages 7 to 11 years, all diagnosed with APD. This diagnosis required a normal pure-tone audiogram and deficits in at least two clinical auditory processing tests. The APD children were randomly assigned to (1) a control group that received only the current standard treatment for children diagnosed with APD, employing various listening/educational strategies at school (N = 19); or (2) an intervention group that undertook a 3-month 5-day/week computer-based auditory training program at home, consisting of a wide variety of speech-based listening tasks with competing sounds, in addition to the current standard treatment. All 39 children were assessed for language and cognitive skills at baseline and on three outcome measures at baseline and immediate postintervention. Outcome measures were repeated 3 months postintervention in the intervention group only, to assess the sustainability of treatment effects. The outcome measures were (1) the mean speech reception threshold obtained from the four subtests of the listening in specialized noise test that assesses sentence perception in various configurations of masking speech, and in which the target speakers and test materials were unrelated to the training materials; (2) the Children's Auditory Performance Scale that assesses listening skills, completed by the children's teachers; and (3) the Clinical Evaluation of Language Fundamental-4 pragmatic profile that assesses pragmatic language use, completed by parents. RESULTS: All outcome measures significantly improved at immediate postintervention in the intervention group only, with effect sizes ranging from 0.76 to 1.7. Improvements in speech-in-noise performance correlated with improved scores in the Children's Auditory Performance Scale questionnaire in the trained group only. Baseline language and cognitive assessments did not predict better training outcome. Improvements in speech-in-noise performance were sustained 3 months postintervention. CONCLUSIONS: Broad speech-based auditory training led to improved auditory processing skills as reflected in speech-in-noise test performance and in better functional listening in real life. The observed correlation between improved functional listening with improved speech-in-noise perception in the trained group suggests that improved listening was a direct generalization of the auditory training. PMID- 26418045 TI - Everyday Listening Performance of Children Before and After Receiving a Second Cochlear Implant: Results Using the Parent Version of the Speech, Spatial, and Qualities of Hearing Scale. AB - OBJECTIVES: To evaluate change in individual children's performance in general areas of everyday listening following sequential bilateral implantation, and to identify the specific types of listening scenarios in which performance change occurred. The first hypothesis was that parent performance ratings for their child would be higher in the bilateral versus unilateral implant condition for each section of the speech, spatial and qualities of hearing scale for parents, viz.: speech perception, spatial hearing, and qualities of hearing. The second hypothesis was that the rating for the participant group would be higher in the bilateral condition for speech perception items involving group conversation or background noise, spatial hearing items, and qualities of hearing items focused on sound segregation or listening effort. DESIGN: Children receiving sequential bilateral implants at the Royal Victorian Eye and Ear Hospital and fulfilling selection criteria (primarily no significant cognitive or developmental delays, and oral English language skills of child and parent sufficient for completing assessments) were invited to participate in a wider project evaluating outcomes. The assessment protocol for older children included the speech, spatial, and qualities of hearing scale for parents. All children (n = 20; ages 4 to 15 years) whose parents completed the scale preoperatively and at 24-months postoperatively were included in this study. Ratings obtained preoperatively in the unilateral implant condition (or unilateral implant plus hearing aid for 4 participants) were compared with those obtained postoperatively in the bilateral implant condition. RESULTS: Bilateral ratings were significantly higher than unilateral ratings on the speech section for 12 children (W >= 7.0; p <= 0.03), on the spatial section for 13 children (W >= 15.0; p <= 0.03), and on the qualities of hearing section for 9 children (W >= 15.0; p <= 0.047). The difference between conditions was unrelated to time between implants or age at bilateral implantation (r <= 0.4; p >= 0.082). The median bilateral ratings for the participant group were higher for all eight speech perception items, including, as predicted, those involving group conversation and/or background noise (W >= 37.5; p <= 0.043). Also, as predicted, the median bilateral ratings for the participant group were higher for all six spatial hearing items (W >= 88.0; p <= 0.014), and for qualities of hearing items related to sound segregation (W >= 94.0; p <= 0.029), but not for those related to listening effort (W <= 92.0; p >= 0.112). CONCLUSIONS: Seventy-five percentage of parents perceived change in their child's daily listening performance postoperatively, and 25% perceived change across all three listening areas. For the overall participant group, the parents perceived a change in performance in the majority of specific listening scenarios, although change was limited in the qualities of hearing section, including no change in listening effort. Previous research suggests postoperative change was likely due to the headshadow effect and improved spatial hearing. Additional contributions may have been made by binaural summation, redundancy, and unmasking. For these participants, differences between device conditions may have been limited by their relatively old age at implantation, delay between implants, and limited bilateral experience. These results will provide valuable information to families during preoperative counseling and postoperative discussions about expected progress and evident benefit. PMID- 26418046 TI - Search for Allergens from the Pollen Proteome of Sunflower (Helianthus annuus L.): A Major Sensitizer for Respiratory Allergy Patients. AB - BACKGROUND: Respiratory allergy triggered by pollen allergens is increasing at an alarming rate worldwide. Sunflower pollen is thought to be an important source of inhalant allergens. Present study aims to identify the prevalence of sunflower pollinosis among the Indian allergic population and characterizes the pollen allergens using immuno-proteomic tools. METHODOLOGY: Clinico-immunological tests were performed to understand the prevalence of sensitivity towards sunflower pollen among the atopic population. Sera from selected sunflower positive patients were used as probe to detect the IgE-reactive proteins from the one and two dimensional electrophoretic separated proteome of sunflower pollen. The antigenic nature of the sugar moiety of the glycoallergens was studied by meta periodate modification of IgE-immunoblot. Finally, these allergens were identified by mass-spectrometry. RESULTS: Prevalence of sunflower pollen sensitization was observed among 21% of the pollen allergic population and associated with elevated level of specific IgE and histamine in the sera of these patients. Immunoscreening of sunflower pollen proteome with patient sera detected seven IgE-reactive proteins with varying molecular weight and pI. Hierarchical clustering of 2D-immunoblot data highlighted three allergens characterized by a more frequent immuno-reactivity and increased levels of IgE antibodies in the sera of susceptible patients. These allergens were considered as the major allergens of sunflower pollen and were found to have their glycan moiety critical for inducing IgE response. Homology driven search of MS/MS data of these IgE reactive proteins identified seven previously unreported allergens from sunflower pollen. Three major allergenic proteins were identified as two pectate lyases and a cysteine protease. CONCLUSION: Novelty of the present report is the identification of a panel of seven sunflower pollen allergens for the first time at immuno-biochemical and proteomic level, which substantiated the clinical evidence of sunflower allergy. Further purification and recombinant expression of these allergens will improve component-resolved diagnosis and therapy of pollen allergy. PMID- 26418048 TI - Recombinant hepatitis C viruses that might hamper accurate genotype classification and choice of treatment with direct-acting agents, southeastern France. PMID- 26418047 TI - Breast Cancer Cell Line Aggregate Morphology Does Not Predict Invasive Capacity. AB - To invade and metastasize to distant loci, breast cancer cells must breach the layer of basement membrane surrounding the tumor and then invade through the dense collagen I-rich extracellular environment of breast tissue. Previous studies have shown that breast cancer cell aggregate morphology in basement membrane extract correlated with cell invasive capacity in some contexts. Moreover, cell lines from the same aggregate morphological class exhibited similarities in gene expression patterns. To further assess the capacity of cell and aggregate morphology to predict invasive capacity in physiologically relevant environments, six cell lines with varied cell aggregate morphologies were assessed in a variety of assays including a 3D multicellular invasion assay that recapitulates cell-cell and cell-environment contacts as they exist in vivo in the context of the primary breast tumor. Migratory and invasive capacities as measured through a 2D gap assay and a 3D spheroid invasion assay reveal that breast cancer cell aggregate morphology alone is insufficient to predict migratory speed in 2D or invasive capacity in 3D. Correlations between the 3D spheroid invasion assay and gene expression profiles suggest this assay as an inexpensive functional method to predict breast cancer invasive capacity. PMID- 26418049 TI - Cortical control of facial expression. AB - The present Review deals with the motor control of facial expressions in humans. Facial expressions are a central part of human communication. Emotional face expressions have a crucial role in human nonverbal behavior, allowing a rapid transfer of information between individuals. Facial expressions can be either voluntarily or emotionally controlled. Recent studies in nonhuman primates and humans have revealed that the motor control of facial expressions has a distributed neural representation. At least five cortical regions on the medial and lateral aspects of each hemisphere are involved: the primary motor cortex, the ventral lateral premotor cortex, the supplementary motor area on the medial wall, and the rostral and caudal cingulate cortex. The results of studies in humans and nonhuman primates suggest that the innervation of the face is bilaterally controlled for the upper part and mainly contralaterally controlled for the lower part. Furthermore, the primary motor cortex, the ventral lateral premotor cortex, and the supplementary motor area are essential for the voluntary control of facial expressions. In contrast, the cingulate cortical areas are important for emotional expression, because they receive input from different structures of the limbic system. PMID- 26418050 TI - Conventions and nomenclature for double diffusion encoding NMR and MRI. AB - Stejskal and Tanner's ingenious pulsed field gradient design from 1965 has made diffusion NMR and MRI the mainstay of most studies seeking to resolve microstructural information in porous systems in general and biological systems in particular. Methods extending beyond Stejskal and Tanner's design, such as double diffusion encoding (DDE) NMR and MRI, may provide novel quantifiable metrics that are less easily inferred from conventional diffusion acquisitions. Despite the growing interest on the topic, the terminology for the pulse sequences, their parameters, and the metrics that can be derived from them remains inconsistent and disparate among groups active in DDE. Here, we present a consensus of those groups on terminology for DDE sequences and associated concepts. Furthermore, the regimes in which DDE metrics appear to provide microstructural information that cannot be achieved using more conventional counterparts (in a model-free fashion) are elucidated. We highlight in particular DDE's potential for determining microscopic diffusion anisotropy and microscopic fractional anisotropy, which offer metrics of microscopic features independent of orientation dispersion and thus provide information complementary to the standard, macroscopic, fractional anisotropy conventionally obtained by diffusion MR. Finally, we discuss future vistas and perspectives for DDE. PMID- 26418051 TI - Isomerization and fragmentation pathways of 1,2-azaborine. AB - The generation of 1,2-azaborine (4), the BN-analogue of ortho-benzyne, was recently achieved by elimination of tert-butyldimethylchlorosilane under the conditions of flash vacuum pyrolysis. The present investigation identifies by computational means pathways for the thermal isomerization and fragmentation of 1,2-azaborine. The computations were performed using single reference (hybrid/density functional, second order Moller-Plesset perturbation, and coupled cluster theories) as well as multiconfiguration methods (complete active space SCF based second order perturbation theory, multireference configuration interaction, and multiconfiguration coupled electron pair approximation) with basis sets up to polarized triple-zeta quality. The 1,2-azaborine is, despite the distortion of its molecular structure, the most stable C4H4BN isomer investigated. The formation of BN-endiyne isomers is highly unfavorable as the identified pathways involve barriers close to 80 kcal mol(-1). The concerted fragmentation to ethyne and 2-aza-3-bora-butadiyne even has a barrier close to 120 kcal mol(-1). The fragmentation of BN-enediynes has energetic requirements similar to enediynes. PMID- 26418052 TI - Correction: Investigating the Goldilocks Hypothesis: The Non-Linear Impact of Positive Trait Change on Well-Being. PMID- 26418053 TI - Mesostructured TiO2 Gated Periodic Mesoporous Organosilica-Based Nanotablets for Multistimuli-responsive Drug Release. AB - A multistimuli-responsive drug carrier is designed and successfully synthesized by self-assembly of thiol-modified periodic mesoporous organosilica (PMO) nanoparticles, coated gold nanoparticles (AuNPs), and mesostructured titanium dioxide (TiO2). Dye-loaded PMO-Au@TiO2 nanotablets are shown to respond to environmental changes (pH, temperature, and light) to achieve controlled release. PMID- 26418055 TI - A Ranking Approach for Probe Selection and Classification of Microarray Data with Artificial Neural Networks. AB - Acute leukemia classification into its myeloid and lymphoblastic subtypes is usually accomplished according to the morphology of the tumor. Nevertheless, the subtypes may have similar histopathological appearance, making screening procedures difficult. In addition, approximately one-third of acute myeloid leukemias are characterized by aberrant cytoplasmic localization of nucleophosmin (NPMc(+)), where the majority has a normal karyotype. This work is based on two DNA microarray datasets, available publicly, to differentiate leukemia subtypes. The datasets were split into training and test sets, and feature selection methods were applied. Artificial neural network classifiers were developed to compare the feature selection methods. For the first dataset, 50 genes selected using the best classifier was able to classify all patients in the test set. For the second dataset, five genes yielded 97.5% accuracy in the test set. PMID- 26418056 TI - Human Papillomavirus Genome-Wide Identification of T-Cell Epitopes for Peptide Vaccine Development Against Cervical Cancer: An Integration of Computational Analysis and Experimental Assay. AB - Human papillomavirus (HPV) has long been documented as the primary factor causing cervical cancer and other complications, and development of immunotherapeutic vaccines against HPV is thought to be an important approach in preventing women from HPV infections. It is known that the first step in vaccine development is to find potent T-cell epitopes in HPV proteins that can be effectively recognized and presented by the human leukocyte antigen (HLA) system. In the current study, we proposed a synthetic pipeline that integrates computational analysis and experimental assay to discover new peptide epitopes from HPV genome with high affinity to the HLA-A*0201, one of the most frequent HLA allele in Caucasian and Asian populations. In the procedure, a structure-based three-dimensional quantitative structure-activity relationship (3D-QSAR) methodology was described and several 3D-QSAR predictors were established using a set of activity-known HLA binders. The best predictor was then employed to perform extrapolation over the HPV genome to screen potential protein fragments with high HLA binding potency. Consequently, 10 peptides were suggested as promising candidates and their affinities toward HLA-A*0201 were assayed using a standard T2 cell surface stabilization test. Four peptides--LLITSNINA from protein E1 (BL50 = 7244 nM), VLLCVCLLI from protein E5 (BL50 = 9118 nM), VLLLWITAA from protein E5 (BL50 = 3388 nM), and LLMGTLGIV from protein E7 (BL50 = 5500 nM)--were identified as high affinity binders. Further, the structural basis and binding mode of HLA-A*0201 LLITSNINA complex was examined in detail, revealing a complicated network of nonbonded interactions across the complex interface that should render high stability and specificity for the interaction system. PMID- 26418054 TI - Providing Access to Genomic Variant Knowledge in a Healthcare Setting: A Vision for the ClinGen Electronic Health Records Workgroup. AB - The Clinical Genome Resource (ClinGen) is a National Institutes of Health (NIH) funded collaborative program that brings together a variety of projects designed to provide high-quality, curated information on clinically relevant genes and variants. ClinGen's EHR (Electronic Health Record) Workgroup aims to ensure that ClinGen is accessible to providers and patients through EHR and related systems. This article describes the current scope of these efforts and progress to date. The ClinGen public portal can be accessed at www.clinicalgenome.org. PMID- 26418057 TI - Polyclonal and monoclonal antibodies in renal transplant: an update. AB - PURPOSE OF REVIEW: There are several monoclonal and polyclonal antibodies used in renal transplantation today, this article will discuss several agents, their updates and newer agents. RECENT FINDINGS: Antithymocyte globulin and interleukin 2 (IL-2) receptor blocker continue to be used as induction agents. The risk of acute rejection was higher in IL-2 receptor blockers mainly in the first year, but graft survivals were similar in both groups long term. Belatacept is the only approved intravenous maintenance immunosuppressive therapy which provides the benefit of glomerular filtration rate preservation, but it was associated with a higher risk of acute rejection and post-transplant lymphoproliferative disorder. Bortezomib may help decrease donor-specific antibody levels, but there are limited data to support its use for desensitization or rejection. Eculizumab may help in antibody-mediated rejection in some cases but has not shown promising long-term effects in high-risk individuals. Newer agents have been continuously tested for improved efficacy and safety. SUMMARY: Transplantation is the standard of care for end-stage renal disease patients, but we still have a long way to go, as we need to improve long-term outcomes. The manipulation of the immune system is a delicate undertaking, with risks of adverse events; therefore, risk versus benefit needs to be carefully evaluated and treatment needs to be individualized. PMID- 26418058 TI - Nutrition, vitamin D, and health outcomes in hemodialysis: time for a feeding frenzy? AB - PURPOSE OF REVIEW: The role of nutrition and nutritional supplementation in dialysis recently has been reinvigorated, with small clinical trials exploring surrogate outcomes and larger epidemiologic studies generating treatment hypotheses requiring further study. The present review focuses on major aspects of nutrition and outcomes in hemodialysis patients: protein and calorie intake and nutritional vitamin D supplementation. RECENT FINDINGS: Building on data from small studies, two large, quasi-experimental cohort studies showed significant mortality benefits associated with oral nutritional supplements provided during dialysis, suggesting potential options for ameliorating the protein-energy wasting that is common in dialysis patients and associated with poor outcomes. Multiple cohort studies suggest, both in the general population and in dialysis, that higher 25(OH) vitamin D levels are associated with improved outcomes; however, no major mortality trials exist in dialysis, and the smaller, surrogate studies conducted to date have been disappointing, showing no consistent benefits in surrogate outcomes including inflammation and anemia, despite appropriate responses of vitamin D levels to repletion. SUMMARY: Nutritional interventions are attractive options for improving outcomes in dialysis patients. Nutritional protein supplements have considerable promise, but require further study, preferably in a large, generalizable pragmatic trial. Small nutritional vitamin D supplementation trials in dialysis have had disappointing results. In the absence of new data, there appears to be no role for routine assessment or repletion of 25(OH) vitamin D deficiency or insufficiency in dialysis. PMID- 26418059 TI - Acute kidney: improving the pathway of care for patients and across healthcare. AB - PURPOSE OF REVIEW: Acute kidney injury (AKI) is common, harmful and of global concern. There is a need to understand the pathway of the management of AKI in order to identify potential areas where care can be improved, for the individual and for healthcare systems. RECENT FINDINGS: There has been considerable focus on risk assessment and earlier detection using changes in serum creatinine. There is less understanding of optimal management, enhanced and long-term recovery, and education to support better care. Using Kidney Disease Improving Global Outcomes based criteria to improve the detection of AKI improves its detection, but requires supportive training and education to deliver better outcomes.Policy makers need to understand the personal and economic burden that results from AKI. There is a need to provide commissioning support, improvement methodologies, and registry initiatives with research investment to sustain progress in overall management. SUMMARY: There is clear evidence of harm related to AKI and a need to improve the reliability of care. The prevalence is high, with the potential to significantly improve short-term and long-term care by addressing all the elements in the pathway, at both patient and system level, assessing risk, detection, treatment, and recovery. PMID- 26418060 TI - Current status on the evaluation and management of the highly sensitized kidney transplant recipient. AB - PURPOSE OF REVIEW: In light of the recent changes to the kidney allocation system (KAS) and the observed increase in the rate of transplantation of the highly sensitized kidney transplant candidate, the evaluation and care of this population is a timely topic. RECENT FINDINGS: In its first year, the new KAS has already realized one goal of improving the chances of transplanting the most highly sensitized patients in the waiting list. This has brought to the forefront the need for recipient readiness in this special population, as well as the need for histocompatibility labs and kidney transplant programs to align themselves with each other, and also with the requirements of the United Network for Organ Sharing, and increase proficiency in testing and data interpretation. This manuscript is a review of the literature as well as practice patterns as they relate to the changes in KAS and the observed outcome since the activation of the new KAS, with the ultimate goal of aiding in the development of a more unified approach in the care of this specialized population which will allow for interdisciplinary and cross centre dialogue to optimize long term care and outcomes. SUMMARY: Here we will review the changes to the KAS as they affect the highly sensitized kidney transplant recipient, and additional considerations in the evaluation and management of these patients. PMID- 26418061 TI - Progression of Liver Fibrosis in HIV/HCV Co-Infection: A Comparison between Non Invasive Assessment Methods and Liver Biopsy. AB - OBJECTIVES: To evaluate the diagnostic performance of seven non-invasive tests (NITs) of liver fibrosis and to assess fibrosis progression over time in HIV/HCV co-infected patients. METHODS: Transient elastography (TE) and six blood tests were compared to histopathological fibrosis stage (METAVIR). Participants were followed over three years with NITs at yearly intervals. RESULTS: Area under the receiver operating characteristic curve (AUROC) for significant fibrosis (> = F2) in 105 participants was highest for TE (0.85), followed by FIB-4 (0.77), ELF-Test (0.77), APRI (0.76), Fibrotest (0.75), hyaluronic acid (0.70), and Hepascore (0.68). AUROC for cirrhosis (F4) was 0.97 for TE followed by FIB-4 (0.91), APRI (0.89), Fibrotest (0.84), Hepascore (0.82), ELF-Test (0.82), and hyaluronic acid (0.79). A three year follow-up was completed by 87 participants, all on antiretroviral therapy and in 20 patients who completed HCV treatment (9 with sustained virologic response). TE, APRI and Fibrotest did not significantly change during follow-up. There was weak evidence for an increase of FIB-4 (mean increase: 0.22, p = 0.07). 42 participants had a second liver biopsy: Among 38 participants with F0-F3 at baseline, 10 were progessors (1-stage increase in fibrosis, 8 participants; 2-stage, 1; 3-stage, 1). Among progressors, mean increase in TE was 3.35 kPa, in APRI 0.36, and in FIB-4 0.75. Fibrotest results did not change over 3 years. CONCLUSION: TE was the best NIT for liver fibrosis staging in HIV/HCV co-infected patients. APRI-Score, FIB-4 Index, Fibrotest, and ELF-Test were less reliable. Routinely available APRI and FIB-4 performed as good as more expensive tests. NITs did not change significantly during a follow-up of three years, suggesting slow liver disease progression in a majority of HIV/HCV co-infected persons on antiretroviral therapy. PMID- 26418062 TI - Clinical Characteristics of Preschool Children with Oppositional Defiant Disorder and Callous-Unemotional Traits. AB - There is a need to know whether callous-unemotional (CU) traits identify a more severe group of oppositional defiant children (ODD). The aim of this study is to ascertain cross-sectionally and longitudinally the specific contribution of CU levels and the presence of ODD in the psychological state of preschool children from the general population. A total of 622 children were assessed longitudinally at ages 3 and 5 with a semi-structured diagnostic interview and questionnaires filled out by parents and teachers. In multivariate models simultaneously including ODD diagnosis and CU levels, controlling by socioeconomic status, ethnicity, sex, severity of conduct disorder symptoms and other comorbidity, high CU scores were related to higher levels of aggression, withdrawn, externalizing and global symptomatology, functional impairment and higher probability of comorbid disorders and use of services. The contribution of CU traits on children's psychological state was not moderated by the presence/absence of ODD. Stability for CU traits and number of ODD-symptoms between ages 3 and 5 was statistically significant but moderate-low (intra-class correlation under .40). Assessment and identification of CU traits from preschool might help to identify a subset of children who could have socialization problems, not only among those with ODD but also among those without a diagnosis of conduct problems. PMID- 26418063 TI - The Experience of Treating Drooling with Repeated Botulinum Toxin Injections. AB - Botulinum toxin A (BTX-A) injections to the salivary glands are effective in the treatment of drooling, and complications are rare. However, there are only a few previous reports on the long-term use of BTX-A injections. This study retrospectively analyzes our experience of treating drooling with repeated BTX-A injections in patients with neurodegenerative diseases. All patients who received repeated BTX-A injections to the submandibular glands at Tampere University Hospital in 2004-2013 were included in the analysis. Six patients, aged from 6 to 21 years, were included in the study, and a total of 41 bilateral BTX-A injections were administered to their submandibular glands. The average number of injections per patient was 6 (range: 3-11). The average interval between the injections was 9.8 months (range: 4-18), and 95% (39/41) of the injections were performed with good response. The complication rate of the BTX-A injections was 2.4% (1/41), since one of the patients had swallowing problems after an injection. BTX-A injections to the submandibular glands are effective and have a low morbidity rate, and repeated injections can be recommended as long-term treatment of drooling. PMID- 26418064 TI - B-Cell Responses to Human Bocaviruses 1-4: New Insights from a Childhood Follow Up Study. AB - Human bocaviruses (HBoVs) 1-4 are recently discovered, antigenically similar parvoviruses. We examined the hypothesis that the antigenic similarity of these viruses could give rise to clinically and diagnostically important immunological interactions. IgG and IgM EIAs as well as qPCR were used to study ~2000 sera collected from infancy to early adolescence at 3-6-month intervals from 109 children whose symptoms were recorded. We found that HBoV1-4-specific seroprevalences at age 6 years were 80%, 48%, 10%, and 0%, respectively. HBoV1 infections resulted in significantly weaker IgG responses among children who had pre-existing HBoV2 IgG, and vice versa. Furthermore, we documented a complete absence of virus type-specific immune responses in six viremic children who had pre-existing IgG for another bocavirus, indicating that not all HBoV infections can be diagnosed serologically. Our results strongly indicate that interactions between consecutive HBoV infections affect HBoV immunity via a phenomenon called "original antigenic sin", cross-protection, or both; however, without evident clinical consequences but with important ramifications for the serodiagnosis of HBoV infections. Serological data is likely to underestimate human exposure to these viruses. PMID- 26418065 TI - Long-Term Cognitive and Behavioral Outcomes following Resolution of Sleep Disordered Breathing in Preschool Children. AB - This study aimed to determine the long term effects of resolution of SDB in preschool children, either following treatment or spontaneous recovery, on cognition and behavior. Children diagnosed with SDB at 3-5y (N = 35) and non snoring controls (N = 25), underwent repeat polysomnography (PSG) and cognitive and behavioral assessment 3 years following a baseline study. At follow-up, children with SDB were grouped into Resolved and Unresolved. Resolution was defined as: obstructive apnea hypopnea index (OAHI) <=1 event/h; no snoring detected on PSG; and no parental report of habitual snoring. 57% (20/35) of children with SDB received treatment, with SDB resolving in 60% (12/20). 43% (15/35) were untreated, of whom 40% (6/15) had spontaneous resolution of SDB. Cognitive reduced between baseline and follow-up, however this was not related to persistent disease, with no difference in cognitive outcomes between Resolved, Unresolved or Control groups. Behavioral functioning remained significantly worse in children originally diagnosed with SDB compared to control children, regardless of resolution. Change in OAHI did not predict cognitive or behavioral outcomes, however a reduction in nocturnal arousals, irrespective of full resolution, was associated with improvement in attention and aggressive behavior. These results suggest that resolution of SDB in preschool children has little effect on cognitive or behavioral outcomes over the long term. The association between sleep fragmentation and behavior appears independent of SDB, however may be moderated by concomitant SDB. This challenges the assumption that treatment of SDB will ameliorate associated cognitive and behavioural deficits and supports the possibility of a SDB phenotype. PMID- 26418066 TI - An exceptional overall survival using bevacizumab beyond progression in a patient with non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is the most common malignancy and the leading cause of cancer death worldwide. In this report, we describe a patient with NSCLC who was treated with continuation of Bevacizumab (Bev) beyond progression to first-line Bev-based chemotherapy. The prolonged treatment with Bev by continuing the inhibition of VEGF beyond first-progression has a strong rationale. Nevertheless, few data exist regarding the efficacy and safety of Bev beyond first line of chemotherapy progression in NSCLC patients. Further studies including a large number of patients are needed, in order to select patients who could benefit from this approach. PMID- 26418068 TI - The Effect of Human Serum Albumin and Hematocrit on the Cake Collapse Temperature of Lyophilized Red Blood Cells. AB - Freeze-drying, or lyophilization, has shown great promise in addressing many of the logistical challenges of storing and preserving red blood cells (RBCs). A crucial part of any RBC lyophilization protocol is the primary drying temperature, which affects the sample drying rate and the dried cake's ability to form a stable glassy solid. Primary drying is most efficient just below the temperature at which the porous structure of the cake begins to collapse, known as the cake collapse temperature. In this short report, we utilize freeze-drying microscopy to examine the effects of human serum albumin (HSA) and hematocrit on the cake collapse temperature. Increasing the hematocrit from 0% to 20% significantly raised the cake collapse temperature from - 37.8 degrees C to -34.8 degrees C. Addition of 5% HSA to a 20% hematocrit RBC suspension further increased the cake collapse temperature to -20.4 degrees C. These data provide a basis for future study of the relationship between cake collapse and overall cell survival, with the object of building a clinically-viable RBC lyophilization protocol. PMID- 26418067 TI - Interaction of extravillous trophoblast galectin-1 and mucin(s)-Is there a functional relevance? AB - In the course of embryo implantation extensive interaction of the trophoblast with uterine tissue is crucial for adequate trophoblast invasion. This interaction is highly controlled, and it has been pointed out that a specific glycocode and changes in glycosylation may be important for successful implantation and maintenance of pregnancy. Both uterine and trophoblast cells have been shown to express cell surface glycoconjugates and sugar binding proteins, such as mucins (MUC) and galectins (gals). An increasing number of studies have investigated potential candidates interacting in this process. However, knowledge about the biochemical nature of the interactions and their importance for trophoblast cell function, and, consequently, for pregnancy outcome are still lacking. This review is aimed at deliberating the possibility that mucins, as heavily glycosylated proteins, might be among the functionally relevant galectin ligands in human trophoblast, based on both published data and our original research. PMID- 26418070 TI - A strange family, or how a new pleolipovirus reveals its friends and relatives. AB - A new virus of halophilic Archaea is reported by Liu et al., and is remarkable in many ways. SNJ2 is the first temperate, pleomorphic virus (pleolipovirus) that integrates into the genome of its host. Analyses of the virus structure and its genome have provided an unexpected puzzle while at the same time solving another. On the one hand, the study shows a curious relationship exists between SNJ2 and an unrelated provirus (SNJ1) found as a plasmid in the same cell. The presence of SNJ1 appears to allow much higher levels of SNJ2 virus to be produced, although the mechanism involved remains unclear. On the other hand, the curious occurrence of a conserved cluster of pleolipovirus-related genes found widely distributed among haloarchaeal genomes and known for almost 10 years, now appears to correspond to SNJ2-related proviruses. PMID- 26418069 TI - Elements as Direct Feedstocks for Organic Synthesis: Fe/I2/O2 for Diamination of 2-Cyclohexenones with 2-Aminopyrimidine and 2-Aminopyridines. AB - Elements as feedstocks for organic synthesis, the trio of metallic iron, molecular iodine, and dioxygen, were found to be an excellent tool for oxidative regioselective diamination of conjugated enones with 2-aminopyrimidine (a guanidine surrogate) and 2-aminopyridines leading to unaromatized coupled products in moderate to good yields. PMID- 26418071 TI - Microdialysis as a Part of Invasive Cerebral Monitoring During Porcine Septic Shock. AB - BACKGROUND: Metabolic changes in critically ill patients with endotoxin-induced septic shock are measured primarily by techniques that afford organ-specific metabolic monitoring based on interstitial fluid samples. The present study was designed to evaluate the role of cerebral microdialysis (MD) as a part of invasive neuromonitoring during endotoxemia in a porcine model. MATERIALS AND METHODS: Continuous endotoxin infusion was administered to 7 female pigs and, in addition to hemodynamic monitoring and blood chemistry, interstitial lactate, pyruvate, glucose and glycerol concentrations in muscle, liver, and cerebral tissue were measured via in vivo MD for an observation period of 180 minutes. RESULTS: The cerebral concentrations of lactate and glycerol showed no significant increases, whereas the hepatic and muscular levels rose dramatically under endotoxemia. However, the lactate/pyruvate ratio and especially the lactate/glucose ratio showed a profound and significant increase in brain tissue as well. Cerebral perfusion pressure decreased from 77 to 50 mm Hg without reaching pathologic values. CONCLUSIONS: Although our results confirm the special protection of the brain during endotoxemia compared with other organs, early metabolic changes become evident by increasing lactate/pyruvate ratio and lactate/glucose ratio. MD appears to be a suitable additional technique in invasive neuromonitoring for obtaining early information about metabolic deterioration in the brain during septic shock. PMID- 26418072 TI - Combined use of simulation and digital technologies for teaching dermatologic surgery. PMID- 26418073 TI - HCV NS3 quasispecies in liver and plasma and dynamics of telaprevir-resistant variants in breakthrough patients assessed by UDPS: A case study. AB - BACKGROUND: The impact of pre-existing variants in hepatitis C virus (HCV) quasispecies, carrying resistance-associated mutations (RAMs), on the outcome of treatment with direct acting antiviral agents (DAA) is debated and it is complicated by the lack of knowledge of quasispecies distribution between the viral reservoir (liver) and the circulating compartment. OBJECTIVE: To evaluate NS3 protease heterogeneity and presence of RAMs on baseline plasma and liver biopsy samples. Plasma dynamics were also analyzed during therapy and after its suspension. Study design Ultra-deep pyrosequencing (UDPS) was performed in two HCV genotype 1a patients who received telaprevir (TVR)-based therapy and developed treatment failure due to TVR-resistance. RESULTS: In both patients the baseline diversity of NS3 quasispecies in plasma was higher than in liver (183.6*10(-4) vs 47.8*10(-4) and 246.0*10(-4) vs 55.0*10(-4) nt substitution/site, respectively, p<0.0001), but phylogenetic trees did not evidence compartmentalization between the two compartments. At baseline RAMs (i.e. V36A, T54A) were detected very low levels (range: 0.31-0.52%) in both specimen types. However, phylogenetic analyses revealed that the viral variants carrying these mutations at baseline were different from those that became fixed at breakthrough, when combined V36M+R155K, conferring high-level resistance to TVR, were observed. The frequency of resistance-associated variants declined after withdrawal of drug selective pressure. CONCLUSIONS: UDPS allowed extensive evaluation of quasispecies compartmentalization and of their dynamics after withdrawal of TVR. Plasma and liver NS3 quasispecies, including low level RAMs, do not show significant difference. PMID- 26418074 TI - Comparison of the clinical impact of endoscopic ultrasound-guided choledochoduodenostomy and hepaticogastrostomy for bile duct obstruction with duodenal obstruction. PMID- 26418075 TI - Co-heredity of silent CAP + 1570 T>C (HBB:c*96T>C) defect and severe beta-thal mutation: a cause of mild beta-thalassemia intermedia. AB - INTRODUCTION: During an intensive screening program aimed at identifying the healthy carriers of thalassemia and the couples at risk of bearing an affected fetus, a rare single nucleotide variation (SNV), CAP + 1570 T > C (HBB:c*96T > C), located 12 nucleotides upstream of the polyadenylation signal in 3'UTR of the beta globin gene was identified. It was previously reported as a beta+ thalassemia mutation and later as a plain polymorphism. METHODS: Genotype identification of globin gene mutations was carried out using sequencing analysis, GAP-PCR, and MLPA methods. RESULTS: CAP + 1570 T > C (HBB:c*96T > C) was found in 39 heterozygotes, in one case in homozygous state and in thirteen cases of co-inheritance of this nucleotide substitution with other mutations in globin genes. Carriers of this mutation showed a 'silent' phenotype without appreciable microcytosis and hypochromia, so they cannot be differentiated from noncarrier individuals. Compound heterozygotes for this mutation and severe beta thal mutations showed a variable phenotype ranging from beta-thal carrier to mild form of beta-thalassemia intermedia, revealing new aspects and allowing to better understand the clinical implications of this nucleotide substitution that can be classified as a silent beta-thalassemic defect. CONCLUSION: Data reported in this study indicate the need of investigating partner of beta-thalassemia carrier by complete sequencing analysis of beta-globin gene and of providing an appropriate genetic counseling for couples at risk undergoing prenatal diagnosis. PMID- 26418076 TI - Impact of serum Wisteria floribunda agglutinin positive Mac-2-binding protein and serum interferon-gamma-inducible protein-10 in primary biliary cirrhosis. AB - AIM: We aimed to examine the relationship between serum Wisteria floribunda agglutinin positive Mac-2-binding protein (WFA(+) -M2BP) levels and serum interferon-gamma-inducible protein-10 (IP-10) levels and liver histological findings for patients with primary biliary cirrhosis (PBC) compared with other laboratory fibrotic or inflammatory parameters. METHODS: A total of 57 PBC patients were analyzed. Receiver-operator curve (ROC) analysis was performed for calculating the area under the ROC (AUROC) for WFA(+) -M2BP, IP-10 and four serum fibrosis markers for the presence of liver cirrhosis (F4) or advanced fibrosis (F3 or F4). Similarly, ROC analysis of WFA(+) -M2BP, IP-10, aspartate aminotransferase and alanine aminotransferase for the presence of severe inflammation activity (A3) was performed. RESULTS: There were eight men and 49 women (median age, 59 years). As for histological findings, F4 was observed in five patients, F3 in 11, F2 in 17, F1 in 24 and F0 in zero, whereas A3 was observed in seven patients, A2 in 27, A1 in 19 and A0 in four. The WFA(+) -M2BP levels ranged from 0.5 cut-off index (COI) to 13.6 COI (median, 1.8), while serum IP-10 levels ranged 121.9-1835.9 pg/mL (median, 571.5). For predicting liver cirrhosis, WFA(+) -M2BP yielded the highest AUROC (0.97, P < 0.01). For predicting severe liver inflammation activity (A3), WFA(+) -M2BP and serum IP-10 yielded the highest AUROC with a level of 0.87. WFA(+) -M2BP levels significantly correlated with serum IP-10 levels (rs = 0.55, P < 0.0001). CONCLUSION: Serum WFA(+) -M2BP and serum IP-10 can be useful markers for predicting histological findings in PBC patients. PMID- 26418077 TI - Ethnic and socioeconomic disparities in dermatology. AB - Ethnic and socioeconomic disparities exist within healthcare. Specifically, minority group members experience more deleterious health outcomes than do majority group members. In this paper, we explore the factors that influence such variety, with a focus on the field of dermatology, in an attempt to understand the ways to improve minority group results. We also highlight how the prevalence of mental health issues within minority group and low socioeconomic status individuals can differentially influence dermatological disease states, such as the relationship between depression and psoriasis. PMID- 26418078 TI - C-H Oxidation of Ingenanes Enables Potent and Selective Protein Kinase C Isoform Activation. AB - Ingenol derivatives with varying degrees of oxidation were prepared by two-phase terpene synthesis. This strategy has allowed access to analogues that cannot be prepared by semisynthesis from natural ingenol. Complex ingenanes resulting from divergent C-H oxidation of a common intermediate were found to interact with protein kinase C in a manner that correlates well with the oxidation state of the ingenane core. Even though previous work on ingenanes has suggested a strong correlation between potential to activate PKCdelta and induction of neutrophil oxidative burst, the current study shows that the potential to activate PKCbetaII is of key importance while interaction with PKCdelta is dispensable. Thus, key modifications of the ingenane core allowed PKC isoform selectivity wherein PKCdelta-driven activation of keratinocytes is strongly reduced or even absent while PKCbetaII-driven activation of neutrophils is retained. PMID- 26418079 TI - Generally applicable limits on intakes of uranium based on its chemical toxicity and the radiological significance of intakes at those limits. AB - Uranium is chemically toxic and radioactive, and both considerations have to be taken into account when limiting intakes of the element, in the context of both occupational and public exposures. Herein, the most recent information available on the chemical toxicity and biokinetics of uranium is used to propose new standards for limiting intakes of the element. The approach adopted allows coherent standards to be set for ingestion and inhalation of different chemical forms of the element by various age groups. It also allows coherent standards to be set for occupational and public exposures (including exposures of different age groups) and for various exposure regimes (including short-term and chronic exposures). The proposed standards are more restrictive than those used previously, but are less restrictive than the Minimal Risk Levels proposed recently by the US Agency for Toxic Substances and Disease Registry. Having developed a set of proposed limits based solely on chemical toxicity considerations, the radiological implications of exposure at those proposed limits are investigated for natural, depleted and enriched uranium. PMID- 26418080 TI - High Mobility Ambipolar Diketopyrrolopyrrole-Based Conjugated Polymer Synthesized Via Direct Arylation Polycondensation. AB - A diketopyrrolopyrrole-based conjugated polymer, PDPP-4FTVT, which exhibits ambipolar transport behavior in air with hole and electron mobilities up to 3.40 and 5.86 cm(2) V(-1) s(-1), respectively, is synthesized via direct arylation polycondensation. Incorporation of F-atoms in beta-positions of thiophene rings dramatically improves the efficiency of direct arylation polycondensation. PMID- 26418082 TI - Pressure Control of Cuprophilic Interactions in a Luminescent Mechanochromic Copper Cluster. AB - For the development of applications based on mechanochromic luminescent materials, a comprehensive study of the mechanism responsible for the emission changes is required. We report the study of a mechanochromic copper iodide cluster under hydrostatic pressure, which allows control of crystal packing via modification of the intermolecular interactions. In situ single-crystal powder X ray diffraction analysis and emission measurements under pressure permit one to establish a direct correlation between the molecular structure and luminescence properties and, in particular, to demonstrate that cuprophilic interactions are responsible for the stimuli-responsive luminescence properties of such multinuclear coordination compounds. PMID- 26418083 TI - Diet-Quality Scores and Prevalence of Nonalcoholic Fatty Liver Disease: A Population Study Using Proton-Magnetic Resonance Spectroscopy. AB - Dietary pattern analysis is an alternative approach to examine the association between diet and nonalcoholic fatty liver disease (NAFLD). This study examined the association of two diet-quality scores, namely Diet Quality Index International (DQI-I) and Mediterranean Diet Score (MDS) with NAFLD prevalence. Apparently healthy Chinese adults (332 male, 465 female) aged 18 years or above were recruited through a population screening between 2008 and 2010 in a cross sectional population-based study in Hong Kong. DQI-I and MDS, as well as major food group and nutrient intakes were calculated based on dietary data from a food frequency questionnaire. NAFLD was defined as intrahepatic triglyceride content at >=5% by proton-magnetic resonance spectroscopy. Multivariate logistic regression models were used to examine the association between each diet-quality score or dietary component and prevalent NAFLD with adjustment for potential lifestyle, metabolic and genetic factors. A total of 220 subjects (27.6%) were diagnosed with NAFLD. DQI-I but not MDS was associated with the prevalence of NAFLD. A 10-unit decrease in DQI-I was associated with 24% increase in the likelihood of having NAFLD in the age and sex adjusted model (95% CI: 1.06-1.45, p = 0.009), and the association remained significant when the model was further adjusted for other lifestyle factors, metabolic and genetic factors [OR: 1.26 (95% CI: 1.03-1.54), p = 0.027]. Multivariate regression analyses showed an inverse association of the intake of vegetables and legumes, fruits and dried fruits, as well as vitamin C with the NAFLD prevalence (p<0.05). In conclusion, a better diet quality as characterized by a higher DQI-I and a higher consumption of vegetables, legumes and fruits was associated with a reduced likelihood of having NAFLD in Hong Kong Chinese. PMID- 26418084 TI - The metabolic and cardiovascular consequences of obesity in persons with HIV on long-term antiretroviral therapy. AB - OBJECTIVE: This study assessed the effect of obesity on metabolic and cardiovascular disease risk factors in HIV-infected adults on antiretroviral therapy with sustained virologic suppression. DESIGN: Observational, comparative cohort study with three group-matched arms: 35 nonobese and 35 obese HIV-infected persons on efavirenz, tenofovir and emtricitabine with plasma HIV-1 RNA less than 50 copies/ml for more than 2 years, and 30 obese HIV-uninfected controls. Patients did not have diabetes or known cardiovascular disease. METHODS: We compared glucose tolerance, serum lipids, brachial artery flow-mediated dilation, carotid intima-media thickness, and soluble inflammatory and vascular adhesion markers between nonobese and obese HIV-infected patients, and between obese HIV infected and HIV-uninfected patients, using Wilcoxon rank-sum tests and multivariate linear regression. RESULTS: The cohort was 52% men and 48% nonwhite. Nonobese and obese HIV-infected patients did not differ by clinical or demographic characteristics. Obese HIV-uninfected controls were younger than obese HIV-infected patients and less likely to smoke (P < 0.03 for both). Among HIV-infected patients, obesity was associated with greater insulin release, lower insulin sensitivity, and higher serum high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-alpha receptor 1 levels (P < 0.001), but similar lipid profiles, sCD14, sCD163, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1, and carotid intima-media thickness and flow mediated dilation. In contrast, Obese HIV-infected patients had adverse lipid changes, and greater circulating intercellular adhesion molecule 1, vascular cell adhesion molecule 1 and sCD14, compared with obese HIV-uninfected controls after adjusting for age and other factors. CONCLUSION: Obesity impairs glucose metabolism and contributes to circulating high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-alpha receptor 1 levels, but has few additive effects on dyslipidemia and endothelial activation, in Obese HIV infected adults on long-term antiretroviral therapy. PMID- 26418085 TI - Postautologous stem cell transplantation long-term outcomes in 26 HIV-positive patients affected by relapsed/refractory lymphoma. AB - OBJECTIVES: To describe survival data, CD4 T-cell long-term dynamics and the correlation between dynamics and events occurrence in 26 HIV-positive patients with refractory lymphoma in complete response after autologous stem cell transplantation (ASCT). DESIGN: Retrospective single-centre study. METHODS: Lymphoma relapse, second cancers and opportunistic infections were considered after ASCT. Group A included patients experiencing events after ASCT and group B the remaining patients. Overall survival, progression-free survival and event free survival probabilities were estimated by Kaplan-Meier method. The comparison of median CD4 T-cell count at cancer diagnosis with matched values was investigated by Wilcoxon signed-rank test and between group A and B by Mann Whitney U test. RESULTS: With a median of 6-year follow-up, the overall survival, the progression-free survival and the event-free survival at 10 years were 91, 86 and 36%. Compared with CD4 T-cell count at cancer diagnosis a higher amount was maintained over time after ASCT. Two patients experienced a lymphoma relapse at 4.3 and 3.1 years; five patients had secondary malignancies and nine patients opportunistic infections at a median time of 2.2 and 0.4 years from ASCT. At 6 and 12 months after ASCT, a significant difference in CD4 T-cell count was found between group A and B. CONCLUSION: ASCT has a dramatic impact on survival of HIV positive patients with refractory lymphoma. We support surveillance of opportunistic infections early after ASCT and of second cancers or lymphoma relapses later from ASCT. Both opportunistic infections and second malignancies were successfully managed and the only long-term death occurred due to lymphoma relapse. ASCT seems to contribute to immune recovery. PMID- 26418087 TI - An expanding universe of noncoding RNAs between the poles of basic science and clinical investigations. AB - The Keystone Symposium 'MicroRNAs and Noncoding RNAs in Cancer', Keystone, CO, USA, 7-12 June 2015 Since the discovery of RNAi, great efforts have been undertaken to unleash the potential biomedical applicability of small noncoding RNAs, mainly miRNAs, involving their use as biomarkers for personalized diagnostics or their usability as active agents or therapy targets. The research's focus on the noncoding RNA world is now slowly moving from a phase of basic discoveries into a new phase, where every single molecule out of many hundreds of cataloged noncoding RNAs becomes dissected in order to investigate these molecules' biomedical relevance. In addition, RNA classes neglected before, such as long noncoding RNAs or circular RNAs attract more attention. Numerous timely results and hypotheses were presented at the 2015 Keystone Symposium 'MicroRNAs and Noncoding RNAs in Cancer'. PMID- 26418088 TI - The Effect of Salinity on Egg Development and Viability of Schistocephalus solidus (Cestoda: Diphyllobothriidea). AB - Schistocephalus solidus plerocercoids commonly infect three-spined stickleback Gasterosteus aculeatus populations in brackish and freshwaters, but infections are typically absent from marine populations. Here we provide an experimental test of the salinity tolerance of S. solidus eggs, to determine the role of salinity in limiting the distribution of infection in coastal zones. We find that S. solidus eggs, derived from the in vitro culture of 3 different plerocercoids, developed normally in salinities of up to 12.50/00, but above this egg viability dropped rapidly, and no egg hatching was observed at salinities above 200/00. Our results are consistent with the distribution of infections in natural stickleback populations and add resolution to previous descriptive observations on salinity tolerance in S. solidus. They also demonstrate that S. solidus presents a novel disease challenge to marine populations of three-spined sticklebacks entering brackish and freshwater environments. PMID- 26418086 TI - HIV transmission biology: translation for HIV prevention. AB - Rigorous testing of new HIV-prevention strategies is a time-consuming and expensive undertaking. Thus, making well informed decisions on which candidate prevention approaches are most likely to provide the most benefit is critical to appropriately prioritizing clinical testing. In the case of biological interventions, the decision to test a given prevention approach in human trials rests largely on evidence of protection in preclinical studies. The ability of preclinical studies to predict efficacy in humans may depend on how well the model recapitulates key biological features of HIV transmission relevant to the question at hand. Here, we review our current understanding of the biology of HIV transmission based on data from animal models, cell culture, and viral sequence analysis from human infection. We summarize studies of the bottleneck in viral transmission; the characteristics of transmitted viruses; the establishment of infection; and the contribution of cell-free and cell-associated virus. We seek to highlight the implications of HIV-transmission biology for development of prevention interventions, and to discuss the limitations of existing preclinical models. PMID- 26418089 TI - [The political dimension of open access: knowledge as a public good or as a commodity?]. PMID- 26418090 TI - [Is disease merely illness?: Biomedicine, "parallel" forms of care and power]. AB - Following Giovanni Berlinguer's proposal that health/disease processes are one of the primary spies into the contradictions of a system, this article describes cases that occurred in central and peripheral capitalist contexts as well as in the so-called "real socialist" States that allow such a role to be seen. Secondly, we observe the processes and above all the interpretations developed in Latin America and especially Mexico regarding the role attributed to traditional medicine in the identity and sense of belonging of indigenous peoples, which emphasize the incompatibility of indigenous worldviews with biomedicine. To do so we analyze projects that were carried out under the notion of intercultural health, which in large part resulted in failure both in health and political terms. The almost entirely ideological content and perspective of these projects is highlighted, as is the scant relationship they hold with the reality of indigenous people. Lastly, the impact and role that the advance of these conceptualizations and health programs might have had in the disengagement experienced over the last nearly ten years in the ethnic movements of Latin America is considered. PMID- 26418091 TI - [Religion and health: the public intervention of Catholic religious agents trained in bioethics in the parliamentary debate on death with dignity in Argentina]. AB - This paper discusses from a sociological perspective one of Catholicism's fronts of public intervention in the development and enactment of health legislation. In particular we analyze the debate in parliamentary committees on the so-called "death with dignity" law (No. 26742), for which a group of bioethics experts was convened to counsel senators regarding the scope and limits of the law. The majority of the invited experts advocated a personalist bioethics perspective, which is a theological bioethics development of contemporary Catholicism. In the debate no representatives of other faiths were present, reinforcing the widely studied overlap between Catholicism and politics in Argentina. PMID- 26418092 TI - [Body, rights and comprehensive health: Analysis of the parliamentary debates on the Gender Identity and Assisted Fertilization Laws (Argentina, 2011-2013)]. AB - In this paper we present an analysis of the parliamentary debates of the Gender Identity Law (No. 26743) and the Assisted Fertilization Law (No. 26862) carried out in the Argentine National Congress between 2011 and 2013. Using a qualitative content analysis technique, the stenographic records of the debates were analyzed to explore the following questions: How was the public problem to which each law responds characterized? How was the mission of each law conceptualized? To what extent did those definitions call into question ideas of health and illness, in including in the public health system coverage for certain medical treatments of body optimization or modification? In the process of sanctioning both laws, the concepts of health and disease were put into dispute as moral categories. In this context, an expanded concept of comprehensive health arose, in which desires regarding reproduction and the body were included. PMID- 26418093 TI - [Women, addiction and rehabilitation: Reflections from the northwestern border of Mexico]. AB - Since the recognition of addiction as a mental illness, studies concerning treatment and therapeutic models have tended to focus on its psychiatric and psychological dimensions. The aim of this article is to highlight the centrality of the social dimension, not only as potential trigger of addictive behaviors and of stigma regarding these behaviors, but also as a variable that permeates diagnosis and treatment. The reflections are based on fieldwork carried out in rehabilitation centers for drug-consuming women in the border city of Tijuana, northwestern Mexico. The results show that the predominant therapeutic models in the city are based in and reproduce the traditional role of women. The social implications of this finding are analyzed, and it is suggested that these centers could be better utilized in the process of building a society with greater gender equality. PMID- 26418094 TI - [Cartography of psychoactive heterotopias: a look at the medical, legal and social discourses regarding drug use]. AB - This article traces a map of the social control of drugs through the politics of space, according to the Foucaultian concept of "heterotopia." Firstly, a brief genealogy of the use of psychotropic substances in different times and cultures is described, up to the introduction of the prohibitionist paradigm. Attention is paid to the way in which power has marked, separated and enclosed certain rituals and uses of pleasure in physical and symbolic sites. The itinerary is focused on the Spanish context to establish a dialogue between the various policies of space that have come into being and have overlapped in the construction and management of a problem which has been rendered an object to the gazes, mechanics and discourses of the medical, legal, and social fields. In this way, the intersections between the liminal spaces of drug use and the harm reduction paradigm are analyzed, including therapeutic strategies with prescribed drugs, from methadone programs to the new heroin programs. PMID- 26418095 TI - [Deaths due to motorcycle accidents and their association with variables related to social reproduction in a northeastern Brazilian state]. AB - The objective of this article was to identify the association between motorcycle deaths and variables related to Samaja's theory of social reproduction in the period 2000-2005 in the state of Pernambuco. An ecological, case-control study was carried out, with municipalities as the unit of analysis. Cases were defined as the 20% of municipalities with the highest local empirical Bayesian coefficients for mortality due to motorcycle accidents, and controls as the 40% with the lowest coefficients. The municipalities with the greatest chances of high coefficients for mortality due to motorcycle accidents showed high population growth factors and increases in the total fleet of motorcycles, with low population densities, low GDP per capita, and more than 20 motorcycles per thousand inhabitants. We conclude that the variables related to macro-policies proved to have greater force in explaining higher chances of motorcycle death. PMID- 26418096 TI - [Level of and change in road traffic mortality in Argentina, Chile, Colombia and Mexico, 2000-2011]. AB - The aim of this study was to estimate the effect of run-over fatalities and traffic collisions in life expectancy in Argentina, Chile, Colombia and Mexico, between 2000 and 2011. Years of life expectancy lost (YLEL) were calculated for the periods 2000-2002 and 2009-2011. The results show that road traffic deaths made up between 1% and 4% of all deaths in each country. In the first period, the highest level of mortality occurred in Colombia (YLEL=0.96) and the lowest in Argentina (YLEL=0.59). In all the countries studied except Argentina, the impact of these deaths on life expectancy was reduced in the second period. The main change took place in Colombia, reaching 0.72 YLEL in the second period. It is concluded that traffic-related deaths have a negative impact on health systems, victims, the productive sector, and society in general. From this point of view, the issue of road transit must be considered a matter of public health, requiring multi-sector intervention in the design of national and regional policies. PMID- 26418097 TI - [The perception of values in food commercials on the part of young people with and without eating disorders]. AB - Advertising uses stereotyped body images to promote physical ideals and unhealthy eating habits related to food products which are targeted especially at young people. The purpose of this study, carried out in Barcelona (Spain) in May 2013, was to test the perception of 139 young people of university age - with and without eating disorders - regarding 25 values in seven food commercials that did and did not use body image strategies. Results show that only the group of young people with eating disorders considered commercials using body image strategies to have a very negative influence on values such as health, well-being, family and effort. In contrast, the assessment of the two groups regarding the rest of the commercials greatly coincided. These results show that today?s university youth have accepted as normal a beauty canon based on the prevailing social and economic order, while young people in treatment for eating disorders have learned to denaturalize such messages. PMID- 26418098 TI - [Care work in the health sector based on the psychodynamics of work and the care perspective: An interview with Pascale Molinier]. AB - This interview with Pascale Molinier was carried out in Buenos Aires in October 2014, in the context of activities organized by the Health and Work Program at the Department of Community Health of the Universidad Nacional de Lanus, Argentina. The interview explores the relationship between work and subjectivation, examining the role of work in the structuring of the psyche, in the dynamics of pleasure and suffering, and in the construction of gender identities. "Feminized" work - that of nurses, caregivers and maids, among others - is examined from a "care" perspective, analyzing its intrinsic invisibility and impossibility of being quantified and measured, which makes it a challenge to management-based logic. PMID- 26418099 TI - Is It Possible to Draw a Risk Map for Obturator Nerve Injury During Pelvic Lymph Node Dissection? The Heilbronn Experience and a Review of the Literature. AB - OBJECTIVE: Obturator nerve injury (ONI) is a rare complication during pelvic lymph node dissection (PLND), in extraperitoneal laparoscopic radical prostatectomy (e-LRP), and/or extraperitoneal robotic-assisted laparoscopic radical prostatectomy (e-RALP). It is important to recognize ONI during the initial operation, maximizing the feasibility of simultaneous repair. Here we report our experience with ONI during e-LRP/e-RALP procedures and draw an injury risk map. MATERIALS AND METHODS: Between December 1999 and November 2014, 2531 e LRPs and 1027 e-RALPs were performed. Five patients (3 during e-LRP, 2 during e RALP) experienced ONI in the proximal part of the nerve. Obturator nerves were clipped during the 3 e-LRP cases. Clips were immediately removed, and patients received physiotherapy with medical treatments in the postoperative period. During e-RALP, two obturator nerves were transected and subsequently repaired using the robotic Da Vinci((r)) Surgical System (Intuitive Surgical, Inc., Sunnyvale, CA). ONI types were investigated in detail in these patients, and current published studies were analyzed in order to draw a risk map. RESULTS: Mean follow-up was 18.8 +/- 2.7 months. In total, 3558 cases (2531 e-LRPs, 1027 e RALPs) were performed. ONI occurred in 3 e-LRP (0.1%) and 2 e-RALP (0.1%) patients. Simultaneous repair was performed successfully in all cases, as clips were removed in e-LRP cases and obturator nerves were repaired using 6/0 polypropylene (Prolene((r)); Ethicon, Somerville, NJ) suture in e-RALP cases. There was no complication associated with obturator nerve functions such as adductor function and/or neurologic deficiency during long-term follow-up. In view of published studies in the literature, the proximal part of the obturator nerve is at highest risk for injury during PLND, representing 77.8% of reported cases of ONI. CONCLUSIONS: According to our ONI risk map, the proximal part of the obturator nerve is at higher risk for injury during PLND. Careful dissection and a good knowledge of pelvic anatomy are essential for preventing ONI. Successful ONI management can be performed simultaneously in experienced hands. PMID- 26418100 TI - Adsorption of poly acrylic acid onto the surface of calcite: an experimental and simulation study. AB - Macromolecular binding to minerals is of great importance in the formation of biofilms, and carboxylate functional groups have been found to play a pivotal role in the functioning of these macromolecules. Here we present both fluorescence time-resolved anisotropy measurements and simulation data on the conformational behaviour and binding of a poly acrylic acid polymer. In solution the polymer exhibits a pH dependent behaviour, with a coiled conformation at a low pH and extended conformation at higher pH values. The polymer is readily adsorbed on the surface of calcite, preferring to bind in an extended conformation, with the strength of the adsorption dependent on the pH and presence of counter ions. We discuss the reasons why the calculated adsorption free energy differs from that obtained from a Langmuir isotherm analysis, showing that they refer to different quantities. The enhanced binding of the extended conformations shows the importance of flexibility in the binding of macromolecules. PMID- 26418101 TI - Potent Antibacterial Activity of Copper Embedded into Silicone and Polyurethane. AB - A simple, easily up-scalable swell-encapsulation-shrink technique was used to incorporate small 2.5 nm copper nanoparticles (CuNPs) into two widely used medical grade polymers, polyurethane, and silicone, with no significant impact on polymer coloration. Both medical grade polymers with incorporated CuNPs demonstrated potent antimicrobial activity against the clinically relevant bacteria, methicillin-resistant Staphylococcus aureus and Escherichia coli. CuNP incorporated silicone samples displayed potent antibacterial activity against both bacteria within 6 h. CuNP-incorporated polyurethane exhibited more efficacious antimicrobial activity, resulting in a 99.9% reduction in the numbers of both bacteria within just 2 h. With the high prevalence of hospital-acquired infections, the use of antimicrobial materials such as these CuNP-incorporated polymers could contribute to reducing microbial contamination associated with frequently touched surfaces in and around hospital wards (e.g., bed rails, overbed tables, push plates, etc.). PMID- 26418102 TI - A Conversation With the Winner of the Clara Ford Nursing Excellence Award. PMID- 26418104 TI - Cardiac Assessment. AB - Heart disease remains the number one cause of mortality in both men and women in the United States and patients with heart failure are at high risk for hospitalization. Thirty-day readmission rates have become a benchmark for hospitals and home healthcare agency reimbursement. Physical exam and history taking are essential to evaluate patients with suspected or known heart disease, and to detect early symptoms of worsening heart failure. Home care clinicians have the opportunity to assess the patient in the home environment, identify significant changes in the patient's status, and form a plan of care for effective intervention to prevent the need for emergency department care or rehospitalization. In this second article of a four-part series, the subjective and objective assessment of the cardiovascular system exam is reviewed. PMID- 26418106 TI - Suicide Risk in Homebound Elderly Individuals What Home Care Clinicians Need to Know. AB - Suicide rates and risk increase with age. Older people are heavy users of in-home services. Many of the reasons that older adults need home care are serious risk factors for suicide. These include disability, physical illness, and other conditions that affect self-sufficiency. Home care providers are well positioned to identify elder suicide risk. This requires some understanding of suicidal behavior, the key risk factors for suicide in elders, the warning signs, and what to do if suicidality is encountered. The suicide prevention field has not recognized home care as a means of reaching suicidal elders. It is critical that this be corrected as elder suicides stand to rise as the elder population increases. PMID- 26418107 TI - Best Practice for After-Hours Hospice Symptom Management: A Literature Review. AB - Medicare-certified hospice home care agencies must provide a 24/7 on-call system to respond to patient and caregiver concerns. How these calls are handled impacts patient and family outcomes and satisfaction. Ideally, hospice nurses provide adequate caregiver education during routine visits to minimize the need for after hours calls. A literature review provided evidence that hospice nurse education and appropriate telephone support improves symptom management, enhances family support, provides a sense of security, reduces anxiety, and promotes comfort. PMID- 26418108 TI - Managing Sjogren's Syndrome. AB - There are approximately 4 million Americans diagnosed with Sjogren's Syndrome. This article discusses the epidemiology, pathophysiology, diagnostics, and implications for home care clinicians who may encounter patients with this syndrome. Chronic pain is discussed as well as interventions to manage symptoms such fatigue, dry eyes mouth and skin. PMID- 26418109 TI - Medication Discrepancies and Associated Risk Factors Identified in Home Health patients. AB - Medication discrepancies can place patients at increased risk for adverse drug events. We sought to determine the frequency, type, and reason for medication discrepancies in patients receiving home healthcare following hospital discharge. We conducted a retrospective, observational study of adults discharged from an academic medical center who received home healthcare following hospital discharge from one affiliated home healthcare agency. Medication discrepancies were identified by comparing the hospital discharge medication list to what the patient was taking at the first home healthcare visit. Almost all patients (66/70, 94%) had at least one medication discrepancy. The median number of discrepancies per patient was 5. Nearly half of the discrepancies were omissions (46%), in which the patient was not taking a medication on the discharge medication list. Increased age was significantly associated with fewer medication discrepancies overall (IRR = 0.99, p < 0.05). Higher health literacy was associated with more omissions (IRR = 1.85, p < 0.05). PMID- 26418110 TI - Retinopathy Overview. PMID- 26418111 TI - As U-500 Insulin Safety Concerns Mount, It's Time to Rethink Safe Use of Strengths Above U-100. PMID- 26418112 TI - Scabies Infestation. PMID- 26418113 TI - A Day in the Life of a Community Health Worker in Uganda. PMID- 26418114 TI - Communicating With Deaf Patients: What You Need to Know. PMID- 26418115 TI - Staying Within the Law: Home Healthcare Billing and Documentation. PMID- 26418116 TI - The Need for Increased Home-Based Primary Care Visits. PMID- 26418117 TI - Light-Controlled Histone Deacetylase (HDAC) Inhibitors: Towards Photopharmacological Chemotherapy. AB - Cancer treatment suffers from limitations that have a major impact on the patient's quality of life and survival. In the case of chemotherapy, the systemic distribution of cytotoxic drugs reduces their efficacy and causes severe side effects due to nonselective toxicity. Photopharmacology allows a novel approach to address these problems because it employs external, local activation of chemotherapeutic agents by using light. The development of photoswitchable histone deacetylase (HDAC) inhibitors as potential antitumor agents is reported herein. Analogues of the clinically used chemotherapeutic agents vorinostat, panobinostat, and belinostat were designed with a photoswitchable azobenzene moiety incorporated into their structure. The most promising compound exhibits high inhibitory potency in the thermodynamically less stable cis form and a significantly lower activity for the trans form, both in terms of HDAC activity and proliferation of HeLa cells. This approach offers a clear prospect towards local photoactivation of HDAC inhibition to avoid severe side effects in chemotherapy. PMID- 26418118 TI - Hierarchical Mesoporous/Macroporous Perovskite La0.5Sr0.5CoO3-x Nanotubes: A Bifunctional Catalyst with Enhanced Activity and Cycle Stability for Rechargeable Lithium Oxygen Batteries. AB - Perovskites show excellent specific catalytic activity toward both oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) in alkaline solutions; however, small surface areas of the perovskites synthesized by traditional sol-gel methods lead to low utilization of catalytic sites, which gives rise to poor Li-O2 batteries performance and restricts their application. Herein, a hierarchical mesporous/macroporous perovskite La0.5Sr0.5CoO3-x (HPN LSC) nanotube is developed to promote its application in Li-O2 batteries. The HPN LSC nanotubes were synthesized via electrospinning technique followed by postannealing. The as-prepared HPN-LSC catalyst exhibits outstanding intrinsic ORR and OER catalytic activity. The HPN-LSC/KB electrode displays excellent performance toward both discharge and charge processes for Li-O2 batteries, which enhances the reversibility, the round-trip efficiency, and the capacity of resultant batteries. The synergy of high catalytic activity and hierarchical mesoporous/macroporous nanotubular structure results in the Li-O2 batteries with good rate capability and excellent cycle stability of sustaining 50 cycles at a current density of 0.1 mA cm(-2) with an upper-limit capacity of 500 mAh g(-1). The results will benefit for the future development of high-performance Li-O2 batteries using hierarchical mesoporous/macroporous nanostructured perovskite type catalysts. PMID- 26418119 TI - Joint myocardial T1 and T2 mapping using a combination of saturation recovery and T2 -preparation. AB - PURPOSE: To develop a heart-rate independent breath-held joint T1 -T2 mapping sequence for accurate simultaneous estimation of coregistered myocardial T1 and T2 maps. METHODS: A novel preparation scheme combining both a saturation pulse and T2 -preparation in a single R-R interval is introduced. The time between these two pulses, as well as the duration of the T2 -preparation is varied in each heartbeat, acquiring images with different T1 and T2 weightings, and no magnetization dependence on previous images. Inherently coregistered T1 and T2 maps are calculated from these images. Phantom imaging is performed to compare the proposed maps with spin echo references. In vivo imaging is performed in ten subjects, comparing the accuracy and precision of the proposed technique to existing myocardial T1 and T2 mapping sequences of the same duration. RESULTS: Phantom experiments show that the proposed technique provides accurate quantification of T1 and T2 values over a wide-range (T1 : 260 ms to 1460 ms, T2 : 40 ms to 200 ms). In vivo imaging shows that the proposed sequence quantifies T1 and T2 values similar to a saturation-based T1 mapping and a conventional breath-hold T2 mapping sequence, respectively. CONCLUSION: The proposed sequence allows joint estimation of accurate and coregistered quantitative myocardial T1 and T2 maps in a single breath-hold. Magn Reson Med 76:888-896, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26418122 TI - Does vagotomy reduce the risk of Parkinson's disease? PMID- 26418120 TI - Correction: Short-term Forecasting of the Prevalence of Trachoma: Expert Opinion, Statistical Regression, versus Transmission Models. PMID- 26418123 TI - Metabolic routes along digestive system of licorice: multicomponent sequential metabolism method in rat. AB - This study was conducted to establish the multicomponent sequential metabolism (MSM) method based on comparative analysis along the digestive system following oral administration of licorice (Glycyrrhiza uralensis Fisch., leguminosae), a traditional Chinese medicine widely used for harmonizing other ingredients in a formulae. The licorice water extract (LWE) dissolved in Krebs-Ringer buffer solution (1 g/mL) was used to carry out the experiments and the comparative analysis was performed using HPLC and LC-MS/MS methods. In vitro incubation, in situ closed-loop and in vivo blood sampling were used to measure the LWE metabolic profile along the digestive system. The incubation experiment showed that the LWE was basically stable in digestive juice. A comparative analysis presented the metabolic profile of each prototype and its corresponding metabolites then. Liver was the major metabolic organ for LWE, and the metabolism by the intestinal flora and gut wall was also an important part of the process. The MSM method was practical and could be a potential method to describe the metabolic routes of multiple components before absorption into the systemic blood stream. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26418125 TI - The Risk of Acute Kidney Injury from Fluid Restriction and Hydroxyethyl Starch in Thoracic Surgery. AB - BACKGROUND: Fluid is restricted in thoracic surgery to reduce acute lung injury, and hydroxyethyl starches (HES) are often administered to reduce fluid amount. This strategy may contribute to the development of acute kidney injury (AKI). We evaluated the incidence, risk factors, and prognosis of AKI in thoracic surgery. We especially focused on whether fluid restriction/HES administration increased AKI. METHODS: This is a retrospective study of patients undergoing thoracic surgery in a tertiary care academic center. Postoperative AKI was diagnosed within 72 hours after surgery based on the Acute Kidney Injury Network criteria. Demographic, intraoperative, and postoperative data were compared between non-AKI and AKI groups. Logistic regression was used to model the association between risk factors and AKI. RESULTS: Final analysis included 1442 patients. Of these, 74 patients developed AKI (5.1%). Crystalloid restriction (<=3 mL.kg.h) was unrelated to AKI, regardless of preoperative renal functions (odds ratio [OR], 0.5; 95% confidence interval [CI] 0.2-1.4). AKI occurred more often when HES were administered to the patients with decreased renal function (OR, 7.6; 95% CI, 1.5 58.1) or having >2 risk factors with normal renal function (OR, 7.2; 95% CI, 3.6 14.1). Multivariate analysis revealed several risk factors: angiotensin converting enzyme inhibitor/angiotensin receptor blockers, open thoracotomy, pneumonectomy/esophagectomy, diabetes mellitus, cerebrovascular disease, low albumin level, and decreased renal function. CONCLUSIONS: Fluid restriction neither increased nor was a risk factor for AKI. HES should be administered with caution in high-risk patients undergoing thoracic surgery. PMID- 26418124 TI - Inhibition of Mitochondrial Fission Protein Reduced Mechanical Allodynia and Suppressed Spinal Mitochondrial Superoxide Induced by Perineural Human Immunodeficiency Virus gp120 in Rats. AB - BACKGROUND: Mitochondria play an important role in many cellular and physiologic functions. Mitochondria are dynamic organelles, and their fusion and fission regulate cellular signaling, development, and mitochondrial homeostasis. The most common complaint of human immunodeficiency virus (HIV)-sensory neuropathy is pain on the soles in patients with HIV, but the exact molecular mechanisms of HIV neuropathic pain are not clear. In the present study, we investigated the role of mitochondrial dynamin-related protein 1 (Drp1, a GTPase that mediates mitochondrial fission) in the perineural HIV coat glycoprotein gp120-induced neuropathic pain state. METHODS: Neuropathic pain was induced by the application of recombinant HIV-1 envelope protein gp120 into the sciatic nerve. Mechanical threshold was tested using von Frey filaments. The mechanical threshold response was assessed over time using the area under curves. Intrathecal administration of antisense oligodeoxynucleotide (ODN) against Drp1, mitochondrial division inhibitor-1 (mdivi-1), or phenyl-N-tert-butylnitrone (a reactive oxygen species scavenger) was given. The expression of spinal Drp1 was examined using western blots. The expression of mitochondrial superoxide in the spinal dorsal horn was examined using MitoSox imaging. RESULTS: Intrathecal administration of either antisense ODN against Drp1 or mdivi-1 decreased mechanical allodynia (a sensation of pain evoked by nonpainful stimuli) in the gp120 model. Intrathecal ODN or mdivi-1 did not change basic mechanical threshold in sham surgery rats. Intrathecal Drp1 antisense ODN decreased the spinal expression of increased Drp1 protein induced by peripheral gp120 application. Intrathecal phenyl-N-tert butylnitrone reduced mechanical allodynia. Furthermore, both intrathecal Drp1 antisense ODN and mdivi-1 reversed the upregulation of mitochondrial superoxide in the spinal dorsal horn in the gp120 neuropathic pain state. CONCLUSIONS: These data suggest that mitochondrial division plays a substantial role in the HIV gp120-related neuropathic pain state through mitochondrial reactive oxygen species and provides evidence for a novel approach to treating chronic pain in patients with HIV. PMID- 26418127 TI - Talking about Climate Change and Global Warming. AB - The increasing prevalence of social networks provides researchers greater opportunities to evaluate and assess changes in public opinion and public sentiment towards issues of social consequence. Using trend and sentiment analysis is one method whereby researchers can identify changes in public perception that can be used to enhance the development of a social consciousness towards a specific public interest. The following study assessed Relative search volume (RSV) patterns for global warming (GW) and Climate change (CC) to determine public knowledge and awareness of these terms. In conjunction with this, the researchers looked at the sentiment connected to these terms in social media networks. It was found that there was a relationship between the awareness of the information and the amount of publicity generated around the terminology. Furthermore, the primary driver for the increase in awareness was an increase in publicity in either a positive or a negative light. Sentiment analysis further confirmed that the primary emotive connections to the words were derived from the original context in which the word was framed. Thus having awareness or knowledge of a topic is strongly related to its public exposure in the media, and the emotional context of this relationship is dependent on the context in which the relationship was originally established. This has value in fields like conservation, law enforcement, or other fields where the practice can and often does have two very strong emotive responses based on the context of the problems being examined. PMID- 26418126 TI - Intraoperative Electroencephalogram Suppression Predicts Postoperative Delirium. AB - BACKGROUND: Postoperative delirium is a common complication associated with increased morbidity and mortality, longer hospital stays, and greater health care expenditures. Intraoperative electroencephalogram (EEG) slowing has been associated previously with postoperative delirium, but the relationship between intraoperative EEG suppression and postoperative delirium has not been investigated. METHODS: In this observational cohort study, 727 adult patients who received general anesthesia with planned intensive care unit admission were included. Duration of intraoperative EEG suppression was recorded from a frontal EEG channel (FP1 to F7). Delirium was assessed twice daily on postoperative days 1 through 5 with the Confusion Assessment Method for the intensive care unit. Thirty days after surgery, quality of life, functional independence, and cognitive ability were measured using the Veterans RAND 12-item survey, the Barthel index, and the PROMIS Applied Cognition-Abilities-Short Form 4a survey. RESULTS: Postoperative delirium was observed in 162 (26%) of 619 patients assessed. When we compared patients with no EEG suppression with those divided into quartiles based on duration of EEG suppression, patients with more suppression were more likely to experience delirium (chi(4) = 25, P < 0.0001). This effect remained significant after we adjusted for potential confounders (odds ratio for log(EEG suppression) 1.22 [99% confidence interval, 1.06-1.40, P = 0.0002] per 1-minute increase in suppression). EEG suppression may have been associated with reduced functional independence (Spearman partial correlation coefficient -0.15, P = 0.02) but not with changes in quality of life or cognitive ability. Predictors of EEG suppression included greater end-tidal volatile anesthetic concentration and lower intraoperative opioid dose. CONCLUSIONS: EEG suppression is an independent risk factor for postoperative delirium. Future studies should investigate whether anesthesia titration to minimize EEG suppression decreases the incidence of postoperative delirium. This is a substudy of the Systematic Assessment and Targeted Improvement of Services Following Yearlong Surgical Outcomes Surveys (SATISFY-SOS) surgical outcomes registry (NCT02032030). PMID- 26418128 TI - Home-based versus clinic-based specimen collection in the management of Chlamydia trachomatis and Neisseria gonorrhoeae infections. AB - BACKGROUND: Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are the most frequent causes of bacterial sexually transmitted infections (STIs). Management strategies that reduce losses in the clinical pathway from infection to cure might improve STI control and reduce complications resulting from lack of, or inadequate, treatment. OBJECTIVES: To assess the effectiveness and safety of home-based specimen collection as part of the management strategy for Chlamydia trachomatis and Neisseria gonorrhoeae infections compared with clinic based specimen collection in sexually-active people. SEARCH METHODS: We searched the Cochrane Sexually Transmitted Infections Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and LILACS on 27 May 2015, together with the World Health Organization International Clinical Trials Registry (ICTRP) and ClinicalTrials.gov. We also handsearched conference proceedings, contacted trial authors and reviewed the reference lists of retrieved studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) of home-based compared with clinic-based specimen collection in the management of C. trachomatis and N. gonorrhoeae infections. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for inclusion, extracted data and assessed risk of bias. We contacted study authors for additional information. We resolved any disagreements through consensus. We used standard methodological procedures recommended by Cochrane. The primary outcome was index case management, defined as the number of participants tested, diagnosed and treated, if test positive. MAIN RESULTS: Ten trials involving 10,479 participants were included. There was inconclusive evidence of an effect on the proportion of participants with index case management (defined as individuals tested, diagnosed and treated for CT or NG, or both) in the group with home-based (45/778, 5.8%) compared with clinic-based (51/788, 6.5%) specimen collection (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.60 to 1.29; 3 trials, I2 = 0%, 1566 participants, moderate quality). Harms of home-based specimen collection were not evaluated in any trial. All 10 trials compared the proportions of individuals tested. The results for the proportion of participants completing testing had high heterogeneity (I2 = 100%) and were not pooled. We could not combine data from individual studies looking at the number of participants tested because the proportions varied widely across the studies, ranging from 30% to 96% in home group and 6% to 97% in clinic group (low-quality evidence). The number of participants with positive test was lower in the home-based specimen collection group (240/2074, 11.6%) compared with the clinic-based group (179/967, 18.5%) (RR 0.72, 95% CI 0.61 to 0.86; 9 trials, I2 = 0%, 3041 participants, moderate quality). AUTHORS' CONCLUSIONS: Home-based specimen collection could result in similar levels of index case management for CT or NG infection when compared with clinic-based specimen collection. Increases in the proportion of individuals tested as a result of home-based, compared with clinic-based, specimen collection are offset by a lower proportion of positive results. The harms of home-based specimen collection compared with clinic-based specimen collection have not been evaluated. Future RCTs to assess the effectiveness of home-based specimen collection should be designed to measure biological outcomes of STI case management, such as proportion of participants with negative tests for the relevant STI at follow-up. PMID- 26418129 TI - Liquid Crystal Interfaces Programmed with Enzyme-Responsive Polymers and Surfactants. AB - Synthesis of biologically active peptide-polymer amphiphiles (PPAs), and characterization of assemblies formed by PPAs at the interfaces of liquid crystal (LC) microdroplets, is shown to permit the use of PPAs in strategies that can trigger ordering transitions in LC microdroplets in response to targeted biomolecular events. PMID- 26418131 TI - Reply. PMID- 26418132 TI - A clinical evaluation of skin disorders of lower limb amputation sites. AB - Amputee patients commonly experience skin problems that may result in social, mental, and economic difficulties. The purpose of this study was to evaluate the incidence of dermatological disorders and identify potential causes and symptomatic patterns among a population of lower limb amputees. Seventy lower limb amputees were enrolled. Complete examinations were performed by a dermatologist, who diagnosed and documented any skin disorders observed and recorded demographic characteristics of each patient. Mycological and bacteriological swabs were collected from the skin at the amputation site for culture analysis. In patients with suspected disease, patch tests were performed. Of the 70 patients, 58 (82.9%) were male and 12 (17.1%) female. Vascular insufficiency due to diabetes (n = 38, 54.3%) and trauma (n = 16, 22.9%) were the most common reasons for amputation. Skin problems were observed in 49 (70%) cases, and positive allergen reactions occurred in 16 (45.7%) of the 35 contact dermatitis cases. Fungal infection occurred in two patients and bacterial infection in seven. Seventy percent of the lower limb amputee patients in this cohort exhibited skin problems. This high percentage indicates that skin problems may reduce patients' quality of life. A multidisciplinary approach to the treatment of patients who have undergone amputation and early recognition and treatment of symptoms are therefore of critical importance. PMID- 26418130 TI - Chromatin Remodeling Factor Brg1 Supports the Early Maintenance and Late Responsiveness of Nestin-Lineage Adult Neural Stem and Progenitor Cells. AB - Insights from embryonic development suggest chromatin remodeling is important in adult neural stem cells (aNSCs) maintenance and self-renewal, but this concept has not been fully explored in the adult brain. To assess the role of chromatin remodeling in adult neurogenesis, we inducibly deleted Brg1--the core subunit of SWI/SNF-like Brg1/Brm-associated factor chromatin remodeling complexes--in nestin expressing aNSCs and their progeny in vivo and in culture. This resulted in abnormal adult neurogenesis in the hippocampus, which initially reduced hippocampal aNSCs and progenitor maintenance, and later reduced its responsiveness to physiological stimulation. Mechanistically, deletion of Brg1 appeared to impair cell cycle progression, which is partially due to elevated p53 pathway and p21 expression. Knockdown of p53 rescued the neurosphere growth defects caused by Brg1 deletion. Our results show that epigenetic chromatin remodeling (via a Brg1 and p53/p21-dependent process) determines the aNSCs and progenitor maintenance and responsiveness of neurogenesis. PMID- 26418134 TI - The road to the winner's circle begins at the ASHRM Annual Conference! AB - The saying "Time flies when you're having fun" is a time-honored expression that is part of our vernacular. Sometimes we say it in jest, tongue in cheek, when it seems a long day will never end! However, when we celebrate professional or personal anniversaries, when we look at our growing kids, or especially, when we look in the mirror, we marvel at how fast the years have flown by! PMID- 26418135 TI - Delivering safe and trusted healthcare-Patient-centered and value-based. PMID- 26418133 TI - Osteodystrophy in Cholestatic Liver Diseases Is Attenuated by Anti-gamma-Glutamyl Transpeptidase Antibody. AB - BACKGROUND: Cholestatic liver diseases exhibit higher levels of serum gamma glutamyl transpeptidase (GGT) and incidence of secondary osteoporosis. GGT has been identified as a novel bone-resorbing factor that stimulates osteoclast formation. The aim of this study was to elucidate the interaction of elevated GGT levels and cholestatic liver disease-induced bone loss. METHODS: Wistar rats were divided into three groups: sham-operated control (SO) rats, bile duct ligation (BDL) rats, and anti-GGT antibody-treated BDL rats (AGT). Serum GGT level was measured. Bone mineral density (BMD) was analyzed by dual-energy X-ray absorptiometry. Bone morphometric parameters and microarchitectural properties were determined by micro-computed tomography and histomorphometry of the distal metaphysis of femurs. Alterations of bone metabolism-related factors were evaluated by cytokine array. Effects of GGT on osteoblasts or stromal cells were evaluated by RT-PCR, enzyme activity, and mineralization ability. RESULTS: Serum levels of GGT were significantly elevated in the BDL-group. In the BDL group, BMD, bone mass percentage, and osteoblast number were significantly decreased, whereas osteoclast number was significantly increased. These alterations were markedly attenuated in the AGT group. The mRNA levels of vascular endothelial growth factor-A, LPS-induced CXC chemokine, monocyte chemoattractant protein-1, tumor necrosis factor-alpha interleukin-1beta and receptor activator of nuclear factor-kappa B ligand were upregulated, and those of interferon-gamma and osteoprotegerin were downregulated in the GGT-treated stromal cells. Furthermore, GGT inhibited mineral nodule formation and expression of alkaline phosphatase and bone sialo-protein in osteoblastic cells. CONCLUSION: Our results indicate that elevated GGT level is involved in hepatic osteodystrophy through secretion of bone resorbing factor from GGT-stimulated osteoblasts/bone marrow stromal cells. In addition, GGT also possesses suppressive effects on bone formation. Managing elevated GGT levels by anti-GGT antibody may become a novel therapeutic agent for hepatic osteodystrophy in chronic liver diseases. PMID- 26418136 TI - Where we've been, where we are, and where we are going: A 35-year perspective on healthcare risk management. AB - In celebration of ASHRM's 35-year anniversary, this article will explore the journey of healthcare risk management and the professionals practicing within its discipline over time and project the future of both the discipline and the profession. PMID- 26418137 TI - How is the effectiveness of root cause analysis measured in healthcare? AB - If a hundred healthcare executives were polled about their definitions of root cause analysis, there would be a hundred different answers. Herein lies the problem-understanding the intent and power of root cause analysis (RCA). For this reason, RCA is viewed as having either limited or phenomenal value to an organization. This article will seek to strip away the labels associated with RCA brands and focus on the processes, their results, and how they are communicated (or miscommunicated) to executive management. Effective RCA efforts can fail because of their inability to demonstrate their value to the bottom line of the organization. PMID- 26418138 TI - Business resilience: Reframing healthcare risk management. AB - The responsibility of risk management in healthcare is fractured, with multiple stakeholders. Most hospitals and healthcare systems do not have a fully integrated risk management system that spans the entire organizational and operational structure for the delivery of key services. This article provides insight toward utilizing a comprehensive Business Resilience program and associated methodology to understand and manage organizational risk leading to organizational effectiveness and operational efficiencies, with the fringe benefit of realizing sustainable operational capability during adverse conditions. PMID- 26418139 TI - The role of informed consent in patient complaints: Reducing hidden health system costs and improving patient engagement through shared decision making. AB - INTRODUCTION: Patient complaints about physicians are strongly associated with malpractice risk. Physicians at high risk for lawsuits tend to have poor communication skills and are more commonly the subject of patient complaints about communication issues. If a malpractice action does not arise, patient complaints nonetheless represent significant prelitigation transaction costs for the healthcare system that have not been previously quantified. Informed consent complaints represent a unique constellation of clinical communication skills clearly tied to malpractice risk. The goal of this study was to measure institutional resource consumption allocated to informed consent (IC) complaints, which are both costly and preventable. METHODS: We compared IC complaints to other complaints about medical care in a single medical center in the United States, estimating the absolute and relative burden of IC deficiencies within this healthcare system. RESULTS: Resource consumption for the resolution of IC complaints far exceeded their proportional representation of complaints, representing half of all complaints, while disproportionately absorbing two thirds of staff time devoted to complaint resolution. CONCLUSIONS: Complaint resolution represents an unrecognized remediable cost and an underappreciated opportunity for reducing waste in healthcare. We suggest that healthcare systems can reduce costs and elevate their patient-centered care practices by improving patient-provider communication during medical decision making via engagement strategies such as shared decision making. PMID- 26418140 TI - Case law update. PMID- 26418141 TI - Multiprobe devices for exercise transcutaneous oxymetry in patients complaining claudication: interest and limits of unusual probe positions. AB - BACKGROUND: Exercise transcutaneous oximetry (PtcO2) can argue for a vascular origin of exercise-related pain in atypical unusual localizations, such as lumbar, thigh or foot pain. We used five probes as a standard for treadmill PtcO2 tests. Recent commercially available devices now include up to eight probes. We aimed at analyzing the potential interest of positioning a 6th probe on the area of unusual localization during exercise PtcO2 tests. METHODS: We retrospectively analyzed our data with a 6-probes device, using as a standard: one probe on the chest, one on each buttock and one on each calf. The sixth probe was positioned either: in the lumbar median position (N.=342), on the anterior lower part of the thigh (N.=391) or on the dorsum of the foot (N.=155) in patients complaining exercise-induced pain including the back, thigh or foot respectively. Results on the sixth probe at the limb were compared to result of the standard adjacent probe. A positive test (abnormal result) was defined as a minimal value of the DROP-index lower than minus 15 mmHg. RESULTS: Prevalence of positive results on the 6th probe with negative results on the adjacent standard probe was 2.3% at the lumbar site, 3.8% at the thigh and 12.3% at the foot level. CONCLUSIONS: Atypical localizations are rarely but sometimes associated to isolated positive exercise PtcO2 results and may justify the use of more than five probes in some patients, specifically for foot pain. PMID- 26418142 TI - Endovascular therapy for visceral artery aneurysms. AB - BACKGROUND: The aim of this study was to report outcome and complications of endovascular therapy for visceral artery aneurysms (VAA). METHODS: Forty endovascular procedures for VAAs were performed in 33 patients between 2009 and 2014. RESULTS: The main indications was size (N.=15), bleeding (N.=14) and mycotic aneurysm (N.=3). The splenic artery was the most common artery of true aneurysms (11/16) and pseudo aneurysms due to pancreatitis (5/14). The median size of the true aneurysms was 24 mm (range 15-65). Two ruptures of true VAAs occurred in elderly. Five patients had eleven synchronous artery aneurysms at CT abdomen. Local anesthesia was used in 93%. Coil embolization were performed without (N.=15) and with (N.=14) other techniques. Nine aneurysms were excluded with stent grafts and patency rate was 88%. Coil embolization was complicated by five spleen infarctions, managed with splenectomy (N.=1) and drainage of abscess (N.=1). One patient died, unrelated to the VAA. CONCLUSIONS: Endovascular therapy of VAAs, irrespective of etiology, was an effective treatment option. PMID- 26418143 TI - Endovenous laser ablation of the great saphenous vein comparing 1920-nm and 1470 nm diode laser. AB - BACKGROUND: The aim of this study was to compare venous occlusion rates at a one year follow-up comparing 1920-nm versus 1470-nm endolaser. METHODS: Randomized prospective study with consecutive patients with varicose veins associated to great saphenous reflux. The 1470-nm laser ablation was performed in continuous mode, with power of 10 W, while for the 1920-nm it was set in 5 W. Follow-up data were collected at the 7-day, 30-day, 3-month, 6-month and 1-year visits, and involved clinical, ultrasound evaluation and measurement of occlusion length. RESULTS: Sixty seven patients were included, with 42 limbs operated in the 1470 nm group and 48 limbs in the 1920-nm group. There were no differences in relation to age, CEAP (Clinical, Etiologic, Anatomical and Pathological Classification), VCSS (Venous Clinical Severity Score) and saphenous diameter. The resulting LEED in 1920-nm group was 17.8+/-0.6 J/cm and vs. 24.7+/-0.8 J/cm in 1470-nm group (P<0.01). Closure rates were lower for the 1920-nm group: 90.9% vs. 96.8% (P=0.06) at 30 days, 87.5% vs. 96.3% at 6 months (P=0.03), and 87.5% vs. 94.7% (P=0.05) at one year. The 1920-nm group had less ecchymosis (18.7% vs. 52.4%), induration (12.4% vs. 38.1%) and days of analgesic use (1.4+/-0.2 vs. 2.4+/-0.4). CEAP and VCSS were reduced over time in both groups. CONCLUSIONS: Treatment with endolaser 1920-nm was feasible and with reduced complications. The use of low endoluminal energy resulted in lower vein occlusion rates comparing to the 1470 nn laser. Clinical outcome scores were similar between groups. PMID- 26418145 TI - Update on medical abortion: simplifying the process for women. AB - PURPOSE OF REVIEW: Medical abortion using mifepristone and misoprostol comprises a growing proportion of abortions performed in the United States. Simplifying the process of medical abortion can optimize use of resources and improve care for women. RECENT FINDINGS: Medical abortion using evidence-based protocols is effective through 70 days' gestation. The requirement of a follow-up office visit with a transvaginal ultrasound to ensure completion of medical abortion is safely and effectively replaced with self-administered low-sensitivity or semiquantitative urine pregnancy tests and remote communication with women. Most contraceptive options can be initiated the same day as mifepristone administration to improve contraceptive use after medical abortion. State legislatures continue to pass laws that threaten evidence-based medical abortion practices. Such efforts ultimately limit access to well-tolerated and effective medical abortion services. SUMMARY: Research supports simplification of the follow-up protocol for medical abortion, and provision of the contraceptive implant and progestin injectable for postabortion contraception the same day as mifepristone administration. With disregard to its documented safety and efficacy, legislative challenges persist as significant challenges to provision of evidence-based medical abortion. PMID- 26418146 TI - Speech in 10-Year-Olds Born With Cleft Lip and Palate: What Do Peers Say? AB - OBJECTIVE: The aim of this study was to explore how 10-year-olds describe speech and communicative participation in children born with unilateral cleft lip and palate in their own words, whether they perceive signs of velopharyngeal insufficiency (VPI) and articulation errors of different degrees, and if so, which terminology they use. Methods/Participants: Nineteen 10-year-olds participated in three focus group interviews where they listened to 10 to 12 speech samples with different types of cleft speech characteristics assessed by speech and language pathologists (SLPs) and described what they heard. The interviews were transcribed and analyzed with qualitative content analysis. RESULTS: The analysis resulted in three interlinked categories encompassing different aspects of speech, personality, and social implications: descriptions of speech, thoughts on causes and consequences, and emotional reactions and associations. Each category contains four subcategories exemplified with quotes from the children's statements. More pronounced signs of VPI were perceived but referred to in terms relevant to 10-year-olds. Articulatory difficulties, even minor ones, were noted. Peers reflected on the risk to teasing and bullying and on how children with impaired speech might experience their situation. The SLPs and peers did not agree on minor signs of VPI, but they were unanimous in their analysis of clinically normal and more severely impaired speech. CONCLUSIONS: Articulatory impairments may be more important to treat than minor signs of VPI based on what peers say. PMID- 26418147 TI - Age and Phonetic Influences on Velar Flutter as a Component of Nasal Turbulence in Children With Repaired Cleft Palate. AB - OBJECTIVE: The purpose of this study was to determine the influence of age and selected phonetic factors on velar flutter as a component of nasal turbulence in children with repaired cleft palate. PARTICIPANTS: A total of 30 children with repaired cleft palate with or without cleft lip ranging in age from 4 to 13 years (mean, 8.6 years; standard deviation, 2.4 years) who exhibited nasal turbulence characterized by velar flutter participated in the study. MEASURES: The headset of a nasometer was used to record the children producing multiple repetitions of consonant-vowel (CV) syllables that contrasted the stops /p/ and /t/ with the fricatives /f/ and /s/ and the high-front vowel /i/ with the low mid-central vowel /Lambda/. All targeted consonants were coded relative to the presence of flutter using both perceptual and spectral criteria. Percentages of syllables coded for flutter were calculated as a function of consonant and vowel types. Intra-and interjudge reliability of coding was high. RESULTS: Percentages of syllables with velar flutter ranged from a high of 100% to a low of 4% among the participants. A Spearman rank-order correlation between age and percentage of syllables with flutter was nonsignificant. Mantel-Haenszel tests for repeated measures indicated that flutter occurred more often during production of syllables containing /i/ (62%) when compared with /Lambda/ (50%) (P = .029). CONCLUSIONS: Velar flutter as a component of nasal turbulence varies widely among children with repaired cleft palate. CV syllables with high vowels appear to trigger velar flutter more often than syllables with low vowels. PMID- 26418144 TI - Regulation and Function of the Nucleotide Binding Domain Leucine-Rich Repeat Containing Receptor, Pyrin Domain-Containing-3 Inflammasome in Lung Disease. AB - Inflammasomes are specialized inflammatory signaling platforms that govern the maturation and secretion of proinflammatory cytokines, such as IL-1beta and IL 18, through the regulation of caspase-1-dependent proteolytic processing. Several nucleotide binding domain leucine-rich repeat-containing receptor (NLR) family members (i.e., NLR family, pyrin domain containing [NLRP] 1, NLRP3, and NLR family, caspase recruitment domain containing-4 [NLRC4]) as well as the pyrin and hemopoietic expression, interferon-inducibility, nuclear localization domain containing family member, absent in melanoma 2, can form inflammasome complexes in human cells. In particular, the NLRP3 inflammasome is activated in response to cellular stresses through a two-component pathway, involving Toll-like receptor 4 ligand interaction (priming) followed by a second signal, such as ATP-dependent P2X purinoreceptor 7 receptor activation. Emerging studies suggest that the NLRP3 inflammasome can exert pleiotropic effects in human diseases with potentially both pro- and antipathogenic sequelae. Whereas NLRP3 inflammasome activation can serve as a vital component of host defense against invading bacteria and pathogens, excessive activation of the inflammasome can lead to inflammation associated tissue injury in the setting of chronic disease. In addition, pyroptosis, an inflammasome-associated mode of cell death, contributes to host defense. Recent research has described the regulation and function of the NLRP3 inflammasome in various pulmonary diseases, including acute lung injury and acute respiratory distress syndrome, sepsis, respiratory infections, chronic obstructive pulmonary disease, asthma, pulmonary hypertension, cystic fibrosis, and idiopathic pulmonary fibrosis. The NLRP3 and related inflammasomes, and their regulated cytokines or receptors, may represent novel diagnostic or therapeutic targets in pulmonary diseases and other diseases in which inflammation contributes to pathogenesis. PMID- 26418148 TI - Facial Asymmetry in Children with Unicoronal Synostosis Who Have Undergone Craniofacial Reconstruction in Infancy. AB - OBJECTIVE: Quantitatively assess 3D spatially detailed soft-tissue facial asymmetry in children who had undergone craniofacial reconstruction for Unicoronal Synostosis (UCS), and compare the facial asymmetry to control patients. It was hypothesized that there would be no significant differences in the facial asymmetry between the groups. DESIGN: Clinical, retrospective follow up study. Methodological study. SETTING: Primary care center. PATIENTS/PARTICIPANTS: Twenty-two children with UCS were selected after review of records. INCLUSION CRITERIA: isolated UCS; surgically treated for UCS within the first 19 months of life, without secondary reconstruction; and DNA analysis for the Muenke mutation. An age- and sex-matched control group was employed. INTERVENTIONS: The UCS group had undergone bilateral craniotomy of the frontal bone with unilateral supraorbital rim advancement. MAIN OUTCOME MEASURE(S): Using 3D surface scanning, a detailed map of 3D asymmetry presenting the amount of asymmetry in the sagittal, vertical, and transverse directions was calculated for six facial subregions. RESULTS: The facial asymmetry in the UCS group was significantly larger than in the control group for all regions, to the largest extent in the sagittal direction (level of significance: 5%). The regions with the most pronounced asymmetry were cheeks (mean: 5.45 mm; SD: 1.83 mm), forehead (mean: 5.00 mm; SD: 1.57 mm), and eyes (mean: 4.26 mm; SD: 1.44 mm). CONCLUSIONS: Ninety percent of the UCS patients in the study had significant facial asymmetry throughout the facial area. The study demonstrates a methodology of facial asymmetry quantification well suited for soft-tissue surgical outcome evaluations and long-term follow-up studies in patients with craniofacial anomalies. PMID- 26418149 TI - Craniofacial Morphology in Midline Cervical Cleft: Case Report and Review of Literature. AB - Congenital midline cervical cleft is a rare anomaly of the neck. This paper presents the case of a boy diagnosed with this disorder in which a preliminary orthodontic treatment was implemented. The craniofacial anomalies associated with this malformation produced a defect that could only be successfully treated through the implementation of orthodontic and surgical treatments. In this case, congenital midline cervical cleft was accompanied by certain disorders within the facial structures of the skull, primarily mandibular retrusion, flattening of the contour of the mandibular base, and a steep angle between the cranial base and the mandibular plane. PMID- 26418150 TI - A Qualitative Study of Children's Perspectives on Their Peer Relationships in the Context of Living With a Craniofacial Anomaly. AB - OBJECTIVE: To gain understanding of perspectives on peer relationships from children with congenital craniofacial anomalies (CFA). DESIGN: This was qualitative research based in a phenomenological approach, using narratives that captured children's responses to open-ended and objective questions about peer relations and life with a CFA. Interviews were audio recorded and transcribed. Transcripts were coded according to thematic categories. SETTING: Children were patients at a reconstructive plastic surgery center in an urban hospital and medical school and were recruited from a regional support organization for families of children with CFA that was associated with the hospital. PATIENTS, PARTICIPANTS: Nine children with congenital CFA aged 9 to 14 years. MAIN OUTCOME MEASURES: Thematic coding categories were developed from the narratives using an open coding strategy; these categories focused on aspects of children's interactions with peers and their appraisals of the role of their CFA in their lives. RESULTS: Children reported satisfaction with most aspects of their peer relationships and expressed confidence in their ability to manage challenges. They acknowledged some difficulties with living with a CFA but tended to hold a balanced perspective on the impact of a CFA on their lives, and they expressed optimism about their future lives. CONCLUSIONS: This sample of children with CFA exhibited much resilience. Although they may not be representative of all children with CFA, they provide examples that can be used to generate hypotheses for future research. PMID- 26418151 TI - Update: Non-Invasive Positive Pressure Ventilation in Chronic Respiratory Failure Due to COPD. AB - Long-term non-invasive positive pressure ventilation (NPPV) has widely been accepted to treat chronic hypercapnic respiratory failure arising from different etiologies. Although the survival benefits provided by long-term NPPV in individuals with restrictive thoracic disorders or stable, slowly-progressing neuromuscular disorders are overwhelming, the benefits provided by long-term NPPV in patients with chronic obstructive pulmonary disease (COPD) remain under question, due to a lack of convincing evidence in the literature. In addition, long-term NPPV reportedly failed in the classic trials to improve important physiological parameters such as arterial blood gases, which might serve as an explanation as to why long-term NPPV has not been shown to substantially impact on survival. However, high intensity NPPV (HI-NPPV) using controlled NPPV with the highest possible inspiratory pressures tolerated by the patient has recently been described as a new and promising approach that is well-tolerated and is also capable of improving important physiological parameters such as arterial blood gases and lung function. This clearly contrasts with the conventional approach of low-intensity NPPV (LI-NPPV) that uses considerably lower inspiratory pressures with assisted forms of NPPV. Importantly, HI-NPPV was very recently shown to be superior to LI-NPPV in terms of improved overnight blood gases, and was also better tolerated than LI-NPPV. Furthermore, HI-NPPV, but not LI-NPPV, improved dyspnea, lung function and disease-specific aspects of health-related quality of life. A recent study showed that long-term treatment with NPPV with increased ventilatory pressures that reduced hypercapnia was associated with significant and sustained improvements in overall mortality. Thus, long-term NPPV seems to offer important benefits in this patient group, but the treatment success might be dependent on effective ventilatory strategies. PMID- 26418153 TI - Correction: How Long Is Too Long in Contemporary Peer Review? Perspectives from Authors Publishing in Conservation Biology Journals. PMID- 26418152 TI - Deficits in hippocampal-dependent transfer generalization learning accompany synaptic dysfunction in a mouse model of amyloidosis. AB - Elevated beta-amyloid and impaired synaptic function in hippocampus are among the earliest manifestations of Alzheimer's disease (AD). Most cognitive assessments employed in both humans and animal models, however, are insensitive to this early disease pathology. One critical aspect of hippocampal function is its role in episodic memory, which involves the binding of temporally coincident sensory information (e.g., sights, smells, and sounds) to create a representation of a specific learning epoch. Flexible associations can be formed among these distinct sensory stimuli that enable the "transfer" of new learning across a wide variety of contexts. The current studies employed a mouse analog of an associative "transfer learning" task that has previously been used to identify risk for prodromal AD in humans. The rodent version of the task assesses the transfer of learning about stimulus features relevant to a food reward across a series of compound discrimination problems. The relevant feature that predicts the food reward is unchanged across problems, but an irrelevant feature (i.e., the context) is altered. Experiment 1 demonstrated that C57BL6/J mice with bilateral ibotenic acid lesions of hippocampus were able to discriminate between two stimuli on par with control mice; however, lesioned mice were unable to transfer or apply this learning to new problem configurations. Experiment 2 used the APPswe PS1 mouse model of amyloidosis to show that robust impairments in transfer learning are evident in mice with subtle beta-amyloid-induced synaptic deficits in the hippocampus. Finally, Experiment 3 confirmed that the same transfer learning impairments observed in APPswePS1 mice were also evident in the Tg-SwDI mouse, a second model of amyloidosis. Together, these data show that the ability to generalize learned associations to new contexts is disrupted even in the presence of subtle hippocampal dysfunction and suggest that, across species, this aspect of hippocampal-dependent learning may be useful for early identification of AD-like pathology. PMID- 26418155 TI - Do Hybrid Trees Inherit Invasive Characteristics? Fruits of Corymbia torelliana X C. citriodora Hybrids and Potential for Seed Dispersal by Bees. AB - Tree invasions have substantial impacts on biodiversity and ecosystem functioning, and trees that are dispersed by animals are more likely to become invasive. In addition, hybridisation between plants is well documented as a source of new weeds, as hybrids gain new characteristics that allow them to become invasive. Corymbia torelliana is an invasive tree with an unusual animal dispersal mechanism: seed dispersal by stingless bees, that hybridizes readily with other species. We examined hybrids between C. torelliana and C. citriodora subsp. citriodora to determine whether hybrids have inherited the seed dispersal characteristics of C. torelliana that allow bee dispersal. Some hybrid fruits displayed the characteristic hollowness, resin production and resin chemistry associated with seed dispersal by bees. However, we did not observe bees foraging on any hybrid fruits until they had been damaged. We conclude that C. torelliana and C. citriodora subsp. citriodora hybrids can inherit some fruit characters that are associated with dispersal by bees, but we did not find a hybrid with the complete set of characters that would enable bee dispersal. However, around 20,000 hybrids have been planted in Australia, and ongoing monitoring is necessary to identify any hybrids that may become invasive. PMID- 26418154 TI - Relation between Intensity of Biocide Practice and Residues of Anticoagulant Rodenticides in Red Foxes (Vulpes vulpes). AB - Anticoagulant rodenticides (ARs) are commonly used to control rodent infestations for biocidal and plant protection purposes. This can lead to AR exposure of non target small mammals and their predators, which is known from several regions of the world. However, drivers of exposure variation are usually not known. To identify environmental drivers of AR exposure in non-targets we analyzed 331 liver samples of red foxes (Vulpes vulpes) for residues of eight ARs and used local parameters (percentage of urban area and livestock density) to test for associations to residue occurrence. 59.8% of samples collected across Germany contained at least one rodenticide, in 20.2% of cases at levels at which biological effects are suspected. Second generation anticoagulants (mainly brodifacoum and bromadiolone) occurred more often than first generation anticoagulants. Local livestock density and the percentage of urban area were good indicators for AR residue occurrence. There was a positive association between pooled ARs and brodifacoum occurrence with livestock density as well as of pooled ARs, brodifacoum and difenacoum occurrence with the percentage of urban area on administrative district level. Pig holding drove associations of livestock density to AR residue occurrence in foxes. Therefore, risk mitigation strategies should focus on areas of high pig density and on highly urbanized areas to minimize non-target risk. PMID- 26418156 TI - Seeing and Feeling Motion: Canonical Computations in Vision and Touch. AB - While the different sensory modalities are sensitive to different stimulus energies, they are often charged with extracting analogous information about the environment. Neural systems may thus have evolved to implement similar algorithms across modalities to extract behaviorally relevant stimulus information, leading to the notion of a canonical computation. In both vision and touch, information about motion is extracted from a spatiotemporal pattern of activation across a sensory sheet (in the retina and in the skin, respectively), a process that has been extensively studied in both modalities. In this essay, we examine the processing of motion information as it ascends the primate visual and somatosensory neuraxes and conclude that similar computations are implemented in the two sensory systems. PMID- 26418158 TI - Management of Home Parenteral Nutrition: A Prospective Multicenter Observational Study. AB - BACKGROUND: There are no specific Swiss home parenteral nutrition (HPN) data showing patient characteristics, quality of life (QoL) and complications. The goal of this study was to collect representative nationwide data on current adult HPN patients in Switzerland for international comparability and benchmarking. METHODS: This was a multicenter, nationwide, observational study. We conducted interviews for demographics, PN characteristics, QoL and complications. The data were assessed at baseline and after a follow-up of 3 months using a questionnaire. RESULTS: Thirty-three adult patients were included. The most common underlying diseases were cancer, radiation enteritis and state after bariatric surgery, and the most prevalent indication was short bowel syndrome. During the 3-month observation period, significant increase or stabilization of body weight occurred in the patients, physical activity scores improved from 34.0 to 39.4 and mental scores improved from 41.9 to 46.4. HPN dependency and traveling restrictions were of the greatest concern. Diarrhea, xerostomia and/or thirst were frequent complaints. CONCLUSION: Anthropometric parameters and QoL improved during the observational period in this HPN cohort. These Swiss HPN data are prerequisite for evaluation and comparison of HPN recommendations and best clinical practice, status of professional care instructions related to HPN effectiveness, quality of treatment and patient safety. PMID- 26418159 TI - Enantioselective Synthesis of Bicyclic delta-Lactones via N-Heterocyclic Carbene Catalyzed Cascade Reaction. AB - The N-heterocyclic carbene-catalyzed cascade reaction of enals with malonates to give bicyclic delta-lactones was developed. The cyclopentane- and cyclohexane fused delta-lactones with three continued stereocenters were obtained in high yields with excellent diastereo- and high enantioselectivities. PMID- 26418157 TI - Visualization of Active Glucocerebrosidase in Rodent Brain with High Spatial Resolution following In Situ Labeling with Fluorescent Activity Based Probes. AB - Gaucher disease is characterized by lysosomal accumulation of glucosylceramide due to deficient activity of lysosomal glucocerebrosidase (GBA). In cells, glucosylceramide is also degraded outside lysosomes by the enzyme glucosylceramidase 2 (GBA2) of which inherited deficiency is associated with ataxias. The interest in GBA and glucosylceramide metabolism in the brain has grown following the notion that mutations in the GBA gene impose a risk factor for motor disorders such as alpha-synucleinopathies. We earlier developed a beta glucopyranosyl-configured cyclophellitol-epoxide type activity based probe (ABP) allowing in vivo and in vitro visualization of active molecules of GBA with high spatial resolution. Labeling occurs through covalent linkage of the ABP to the catalytic nucleophile residue in the enzyme pocket. Here, we describe a method to visualize active GBA molecules in rat brain slices using in vivo labeling. Brain areas related to motor control, like the basal ganglia and motor related structures in the brainstem, show a high content of active GBA. We also developed a beta-glucopyranosyl cyclophellitol-aziridine ABP allowing in situ labeling of GBA2. Labeled GBA2 in brain areas can be identified and quantified upon gel electrophoresis. The distribution of active GBA2 markedly differs from that of GBA, being highest in the cerebellar cortex. The histological findings with ABP labeling were confirmed by biochemical analysis of isolated brain areas. In conclusion, ABPs offer sensitive tools to visualize active GBA and to study the distribution of GBA2 in the brain and thus may find application to establish the role of these enzymes in neurodegenerative disease conditions such as alpha synucleinopathies and cerebellar ataxia. PMID- 26418161 TI - Attitudes in China about Crops and Foods Developed by Biotechnology. AB - Transgenic Bt cotton has been planted in China since 1997 and, in 2009, biosafety certificates for the commercial production of Bt rice and phytase corn were issued by the Chinese government. The public attitude in China toward agricultural biotechnology and genetically modified (GM) crops and foods has received considerable attention worldwide. We investigated the attitudes of consumers, Bt cotton farmers and scientists in China regarding GM crops and foods and the factors influencing their attitudes. Data were collected using interview surveys of consumer households, farmer households and scientists. A discrete choice approach was used to elicit the purchase intentions of the respondents. Two separate probit models were developed to examine the effect of various factors on the choices of the respondents. Bt cotton farmers had a very positive attitude because Bt cotton provided them with significant economic benefits. Chinese consumers from developed regions had a higher acceptance and willingness to pay for GM foods than consumers in other regions. The positive attitude toward GM foods by the scientific community will help to promote biotechnology in China in the future. Our survey emphasized that educational efforts made by government officials, the media and scientists can facilitate the acceptance of GM technology in China. Further educational efforts will be critical for influencing consumer attitudes and decisions of government agencies in the future. More effective educational efforts by government agencies and public media concerning the scientific facts and safety of GM foods would enhance the acceptance of GM crops in China. PMID- 26418163 TI - Is Serum Serotonin Involved in the Bone Loss of Young Females with Anorexia Nervosa? AB - Recent experimental data suggest that circulating serotonin interacts with bone metabolism, although this is less clear in humans. This study investigated whether serum serotonin interferes with bone metabolism in young women with anorexia nervosa (AN), a clinical model of energy deprivation. Serum serotonin, markers of bone turnover [osteocalcin (OC), procollagen type I N-terminal propeptide (PINP), type I-C telopeptide breakdown products (CTX)], leptin, soluble leptin receptor (sOB-R), and insulin-like growth factor-1 (IGF-1) and its binding protein (IGFBP-3) were assessed. Whole body, spine, hip, and radius areal bone mineral density BMD (aBMD) were assessed by dual-energy X-ray absorptiometry in 21 patients with AN and 19 age-matched controls. Serum serotonin, leptin, IGF 1, IGFBP-3, OC, PINP, and aBMD at all sites, radius excepted, were significantly reduced in AN whereas CTX and sOB-R were increased compared with controls. Serum serotonin levels were positively correlated with weight, body mass index, whole body fat mass, leptin, and IGF-1, and negatively with CTX for the entire population. Low serum serotonin levels are observed in patients with AN. Although no direct link between low serum serotonin levels and bone mass was identified in these patients, the negative relationship between serotonin and markers of bone resorption found in all population nevertheless suggests the implication of serotonin in bone metabolism. Impact of low serum serotonin on bone in AN warrants further studies. PMID- 26418160 TI - Vascular Smooth Muscle Cells Stimulate Platelets and Facilitate Thrombus Formation through Platelet CLEC-2: Implications in Atherothrombosis. AB - The platelet receptor CLEC-2 is involved in thrombosis/hemostasis, but its ligand, podoplanin, is expressed only in advanced atherosclerotic lesions. We investigated CLEC-2 ligands in vessel walls. Recombinant CLEC-2 bound to early atherosclerotic lesions and normal arterial walls, co-localizing with vascular smooth muscle cells (VSMCs). Flow cytometry and immunocytochemistry showed that recombinant CLEC-2, but not an anti-podoplanin antibody, bound to VSMCs, suggesting that CLEC-2 ligands other than podoplanin are present in VSMCs. VSMCs stimulated platelet granule release and supported thrombus formation under flow, dependent on CLEC-2. The time to occlusion in a FeCl3-induced animal thrombosis model was significantly prolonged in the absence of CLEC-2. Because the internal elastic lamina was lacerated in our FeCl3-induced model, we assume that the interaction between CLEC-2 and its ligands in VSMCs induces thrombus formation. Protein arrays and Biacore analysis were used to identify S100A13 as a CLEC-2 ligand in VSMCs. However, S100A13 is not responsible for the above-described VSMC induced platelet activation, because S100A13 is not expressed on the surface of normal VSMCs. S100A13 was released upon oxidative stress and expressed in the luminal area of atherosclerotic lesions. Suspended S100A13 did not activate platelets, but immobilized S100A13 significantly increased thrombus formation on collagen-coated surfaces. Taken together, we proposed that VSMCs stimulate platelets through CLEC-2, possibly leading to thrombus formation after plaque erosion and stent implantation, where VSMCs are exposed to blood flow. Furthermore, we identified S100A13 as one of the ligands on VSMCs. PMID- 26418162 TI - A Survey of the Knowledge of Venous Thromboembolism Prophylaxis among the Medical Staff of Intensive Care Units in North China. AB - BACKGROUND: Guideline concordance for venous thromboembolism (VTE) prophylaxis in critically ill patients in intensive care units (ICUs) varies across different countries. OBJECTIVE: To explore how the medical staff of ICUs in China comprehend and practice VTE prophylaxis. METHOD: Questionnaires comprising 39 questions and including 4 dimensions of thromboprophylaxis were administered in ICUs in North China. RESULTS: In all, 52 ICUs at 23 tertiary hospitals in 7 Chinese provinces and municipalities were surveyed. A total of 2500 questionnaires were sent, and 1861 were returned, corresponding to a response rate of approximately 74.4%. Of all surveyed medical staff, 36.5% of physicians and 22.2% of nurses were aware of the guidelines in China, and 19.0% of physicians and 9.5% of nurses comprehended the 9th edition of the guidelines of the American College of Chest Physicians (ACCP). Additionally, 37.6% of the medical staff chose a prophylaxis method based on the related guidelines, and 10.3% could demonstrate the exact indication for mechanical pattern application. Worries about skin injury, difficulty with removal and discomfort during mechanical thromboprophylaxis were cited by more than 30% of nurses, which was significantly more frequent than for physicians (graduated compression stockings: 54.3% VS 34.1%, 60.7% VS 49%, and 59.4% VS 54%, p = 0.000; intermittent pneumatic compression: 31% VS 22.2%, 19.2% VS 13.9%, and 37.8% VS 27.2%, p = 0.000). CONCLUSIONS AND RELEVANCE: The knowledge of VTE prophylaxis among the medical staff of ICUs in North China remains limited, which may lead to a lack of standardization of VTE prophylaxis. Strengthened, standardized training may help medical staff to improve their comprehension of the relevant guidelines and may finally reduce the occurrence of VTE in ICUs and improve the prognosis of critically ill patients with VTE. PMID- 26418164 TI - Weight acceptance versus body dissatisfaction: Effects on stigma, perceived self esteem, and perceived psychopathology. AB - OBJECTIVE: It is unknown whether weight acceptance or body dissatisfaction impact anti-fat stigma. Therefore, this study utilized a 2*2 between-subject experimental design to examine of the relationship between body acceptance and stigmatization. METHOD: Participants were university undergraduates (N=394, 70% women, mean age=20.8 years, mean BMI=23.61 kg/m(2)) who were randomly assigned to read vignettes describing an obese or normal-weight target described as either accepting or not accepting of her weight. Participants completed measures of stigma (the Fat Phobia Scale (FPS), the modified Anti-fat Attitudes Scale (AFA)), perceived self-esteem (assessed with the modified Rosenberg Self-Esteem Scale (RSE)), and perceived psychopathology. RESULTS: Analyses revealed significant main effects for acceptance. Notably, targets who accepted their weight were less stigmatized on the FPS (F(1, 354)=66.82, p<.001) and the AFA willpower subscale (F(1, 373)=37.90, p<.001), and they were perceived as having better self esteem (F(1, 371)=166.16, p<.001) and fewer psychological problems (F(1, 381)=123.19, p<.001) than those who did not accept their weight. CONCLUSION: Results from this study suggest that size acceptance, even when practiced by obese targets, was significantly less stigmatized than body dissatisfaction and associated with better perceived self esteem and mental health. PMID- 26418165 TI - Single-Sided Deafness: The Effect of Cochlear Implantation on Quality of Life, Quality of Hearing, and Working Performance. AB - AIMS: To evaluate the effect of a cochlear implant (CI) on quality of life (QoL), quality of hearing (QoH), and working performance in patients with single-sided deafness (SSD). METHODS: Using specific questionnaires, we measured QoL, QoH, and working performance in 7 SSD patients scheduled for CI surgery of the affected ear. Sound localization and speech perception in noise were also assessed. All questionnaires and tests were performed before the CI surgery and at 6 and 12 months after CI activation. RESULTS: The QoL, QoH, sound localization, and speech perception in noise had improved statistically significantly after CI surgery. Communication with co-workers became easier, and the patients were less fatigued after the working day. CONCLUSIONS: CI clearly improves QoL, QoH, and working performance in patients with SSD. PMID- 26418166 TI - Stress reveals new destination for EGF receptor. PMID- 26418167 TI - Reply. PMID- 26418169 TI - How Severely Is DNA Quantification Hampered by RNA Co-extraction? AB - The optional RNase digest that is part of many DNA extraction protocols is often omitted, either because RNase is not provided in the kit or because users do not want to risk contaminating their laboratory. Consequently, co-eluting RNA can become a "contaminant" of unknown magnitude in a DNA extraction. We extracted DNA from liver, lung, kidney, and heart tissues and established that 28-52% of the "DNA" as assessed by spectrophotometry is actually RNA (depending on tissue type). Including an RNase digest in the extraction protocol reduced 260:280 purity ratios. Co-eluting RNA drives an overestimation of DNA yield when quantification is carried out using OD 260 nm spectrophotometry, or becomes an unquantified contaminant when spectrofluorometry is used for DNA quantification. This situation is potentially incompatible with the best practice guidelines for biobanks issued by organizations such as the International Society for Biological and Environmental Repositories, which state that biospecimens should be accurately characterized in terms of their identity, purity, concentration, and integrity. Consequently, we conclude that an RNase digest must be included in DNA extractions if pure DNA is required. We also discuss the implications of unquantified RNA contamination in DNA samples in the context of laboratory accreditation schemes. PMID- 26418168 TI - Total Saponin from Anemone flaccida Fr. Schmidt Prevents Bone Destruction in Experimental Rheumatoid Arthritis via Inhibiting Osteoclastogenesis. AB - Anemone flaccida Fr. Schmidt is used in the clinical compound prescription for the treatment of rheumatoid arthritis (RA) in China and has the traditional use of draining dampness, diminishing swelling, and relieving pain. Total saponins (TS) are the characteristic components and also the main active ingredients of A. flaccida. Previous reports indicated that TS possess anti-inflammatory and immunoregulatory properties; however, the effects of TS on bone destruction of RA have not been evaluated. In this study, our data first showed the therapeutic effects of TS on severity of arthritis and arthritis progression in collagen induced arthritis (CIA) rats. Then, by microfocal computed tomography (CT) quantification, TS significantly increased bone mineral density, bone volume fraction, and trabecular thickness and decreased trabecular separation of inflamed joints both at peri-articular and extra-articular locations. TS also diminished the level of the bone resorption marker CTX-I and simultaneously increased the bone formation marker osteocalcin in sera of CIA rats. Interestingly, TS prevented bone destruction by reducing the number of osteoclasts in inflamed joints, reducing the expression of receptor activator of nuclear factor-kappaF (RANK) ligand (RANKL) and RANK, increasing the expression of osteoprotegerin (OPG), at both mRNA and protein levels, and decreasing the ratio of RANKL to OPG in inflamed joints and sera of CIA rats. This was further confirmed in the co-culture system of human fibroblast-like synovial and peripheral blood mononuclear cells. In addition, TS inhibited the levels of pro inflammatory cytokines implicated in bone resorption, such as interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNFalpha), IL-6, IL-17, and IL-23 in sera and joints. These findings offer convincing evidence that TS attenuate RA partially by preventing both focal bone destruction and systemic bone loss. This anti-erosive effect results in part from inhibiting osteoclastogenesis by regulating the RANKL/RANK/OPG signaling pathway. The suppression of systemic and local pro-osteoclastogenic cytokines by TS was also highly effective. PMID- 26418170 TI - Law & Order, CSI, and NCIS: The Association Between Exposure to Crime Drama Franchises, Rape Myth Acceptance, and Sexual Consent Negotiation Among College Students. AB - Previous research has identified that exposure to the crime drama genre lowers rape myth acceptance and increases sexual assault prevention behaviors such as bystander intervention. However, recent content analyses have revealed marked differences in the portrayal of sexual violence within the top three crime drama franchises. Using a survey of 313 college freshmen, this study explores the influence of exposure to the three most popular crime drama franchises: Law & Order, CSI, and NCIS. Findings indicate that exposure to the Law & Order franchise is associated with decreased rape myth acceptance and increased intentions to adhere to expressions of sexual consent and refuse unwanted sexual activity; whereas exposure to the CSI franchise is associated with decreased intentions to seek consent and decreased intentions to adhere to expressions of sexual consent. Exposure to the NCIS franchise was associated with decreased intentions to refuse unwanted sexual activity. These results indicate that exposure to the specific content of each crime drama franchise may have differential results on sexual consent negotiation behaviors. PMID- 26418171 TI - What is the potential for context aware communication aids? AB - Use of voice output communication aids (VOCAs) can be a very effective strategy to assist people with speech impairments in communicating. Despite this, people who use communication aids often express frustration with VOCAs-desiring devices that are simpler, quicker and more effective to use. Whilst it is not possible to resolve all these issues with technology, it is argued that significant progress can be made. The use of contextual information is one development that could improve the simplicity and effectiveness of communication aid design. Improving the effectiveness of communication aids, including through the use of context support, is a goal of the NIHR Devices for Dignity Assistive Technology Theme. This discussion paper examines the potential for creating 'context aware' communication aids. Three projects in which the authors have been involved are described to illustrate different approaches to the use of contextual information. PMID- 26418172 TI - Genotyping of Toxoplasma gondii Directly from Human and Animal Biological Samples: From Partial Genotypes to a New Genotype. AB - Genotyping of Toxoplasma gondii is traditionally performed using DNA obtained from tachyzoites after isolation by bioassay in mice. In this study, genotyping of T. gondii was performed by multiplex nested polymerase chain reaction restriction fragment length polymorphism (Mn-PCR-RFLP) in DNA obtained from the lungs of experimentally infected mice, the hearts of naturally infected free range chickens, and human blood samples of newborns with congenital toxoplasmosis. The efficiency of Mn-PCR varied according to the marker. We obtained complete genotypes of all of the mice lung samples. In chickens, total or partial genotyping was performed on all of the 15 samples. Two complete genotypes were obtained, including one identified for the first time, and another previously described in different hosts including dogs, cats, and humans. In blood from infants, partial genotypes were obtained in 8 of the 12 samples. Mouse bioassay is the most efficient method to obtain DNA from T. gondii , but direct tissue genotyping enhances the likelihood of obtaining molecular information on T. gondii and is an effective tool as a complement to isolation in mice. In this study, we genotyped Toxoplasma gondii directly from human (blood samples of newborns with congenital toxoplasmosis) and free-range chickens (hearts) by Mn PCR-RFLP. We present partial and complete genotypes and provide technical and scientific information about T. gondii genotyping methods. PMID- 26418173 TI - Cognitive deficits and posttraumatic stress disorder in children: A diagnostic dilemma illustrated through a case study. AB - Studies investigating the neuropsychological functioning of children who experience trauma have predominantly focused on maltreated populations. This article presents a case study that details the longitudinal outcome of a girl who experienced a motor vehicle accident at 5 years of age. It highlights the clinical relevance of research investigating the neuropsychological impact of single-incident trauma on children. It illustrates difficulties clinicians face in discriminating between the effects of developmental delay, traumatic brain injury, attention-deficit/hyperactivity disorder, trauma, and posttraumatic stress symptoms or posttraumatic stress disorder, especially in children with compensable injuries. The state of the current literature is discussed, and directions for future research are provided. PMID- 26418174 TI - Structural and kinetic investigation of the hydride composite Ca(BH4)2 + MgH2 system doped with NbF5 for solid-state hydrogen storage. AB - Designing safe, compact and high capacity hydrogen storage systems is the key step towards introducing a pollutant free hydrogen technology into a broad field of applications. Due to the chemical bonds of hydrogen-metal atoms, metal hydrides provide high energy density in safe hydrogen storage media. Reactive hydride composites (RHCs) are a promising class of high capacity solid state hydrogen storage systems. Ca(BH4)2 + MgH2 with a hydrogen content of 8.4 wt% is one of the most promising members of the RHCs. However, its relatively high desorption temperature of ~350 degrees C is a major drawback to meeting the requirements for practical application. In this work, by using NbF5 as an additive, the dehydrogenation temperature of this RHC was significantly decreased. To elucidate the role of NbF5 in enhancing the desorption properties of the Ca(BH4)2 + MgH2 (Ca-RHC), a comprehensive investigation was carried out via manometric measurements, mass spectrometry, Differential Scanning Calorimetry (DSC), in situ Synchrotron Radiation-Powder X-ray Diffraction (SR-PXD), X-ray Absorption Spectroscopy (XAS), Anomalous Small-Angle X-ray Scattering (ASAXS), Scanning and Transmission Electron Microscopy (SEM, TEM) and Nuclear Magnetic Resonance (NMR) techniques. PMID- 26418175 TI - Qualitative Exploration of Sexual Experiences Among Adults on the Autism Spectrum: Implications for Sex Education. AB - CONTEXT: The increasing prevalence of autism since the 1990s has led to growing demand for sex education that meets the needs of persons on the autism spectrum. Yet there is a dearth of research documenting the firsthand experiences and perspectives of autistic individuals. METHODS: A thematic analysis was conducted of in-depth, Internet-facilitated interviews with 24 adults on the autism spectrum who were recruited from Internet community spaces between November 2012 and May 2013. Inclusion criteria were self-identification as a person on the autism spectrum, being a U.S. resident, being aged 18 or older, and having the ability to communicate orally or through writing. RESULTS: Participants were aged 18-61 and were living in the community at the time of interview, most with limited extrafamilial support. They were less likely than the general population to be heterosexual or gender-conforming and were more likely to have experienced romantic or sexual debut after age 18. Participants' most common concerns were courtship difficulties and sensory dysregulation in the context of partnered sexuality. These concerns were exacerbated by inadequate and inappropriate sex education experiences. Participants addressed challenges by using sensory barriers (e.g., latex gloves); planning when and how to have sex; negotiating alternatives to sexual scripts predicated on nondisabled experience; and practicing explicit and intentional communication. CONCLUSIONS: Individuals on the autism spectrum would benefit from sex education that normalizes differences (e.g., in identities and experiences of sexuality), is offered throughout young adulthood, addresses disability-relevant sensory and communication needs, and includes practicing neurotypical sociosexual norms. PMID- 26418176 TI - Sequence Adaptive Peptide-Polysaccharide Nanostructures by Biocatalytic Self Assembly. AB - Coassembly of peptides and polysaccharides can give rise to the formation of nanostructures with tunable morphologies. We show that in situ enzymatic exchange of a dipeptide sequence in aromatic peptide amphiphiles/polysaccharide coassemblies enables dynamic formation and degradation of different nanostructures depending on the nature of the polysaccharide present. This is achieved in a one-pot system composed of Fmoc-cysteic acid (CA) and Fmoc-lysine (K) plus phenylalanine amide (F) in the presence of thermolysin that, through dynamic hydrolysis and amide formation, gives rise to a dynamic peptide library composed of the corresponding Fmoc-dipeptides (CAF and KF). When the cationic polysaccharide chitosan is added to this mixture, selective amplification of the CAF peptide is observed giving rise to formation of nanosheets through coassembly. By contrast, upon addition of anionic heparin, KF is formed that gives rise to a nanotube morphology. The dynamic adaptive potential was demonstrated by sequential morphology changes depending on the sequence of polysaccharide addition. This first demonstration of the ability to access different peptide sequences and nanostructures, depending on the presence of biopolymers, may pave the way to biomaterials that can adapt their structure and function and may be of relevance in the design of materials able to undergo dynamic morphogenesis. PMID- 26418180 TI - Enantioselective palladium-catalyzed C-H functionalization of indoles using an axially chiral 2,2'-bipyridine ligand. AB - A palladium-catalyzed enantioselective C?H functionalization of indoles was achieved with an axially chiral 2,2'-bipyridine ligand, thus providing the desired indol-3-acetate derivatives with up to 98 % ee. Moreover, the reaction protocol was also effective for asymmetric O?H insertion reaction of phenols using alpha-aryl-alpha-diazoacetates. This represents the first successful application of bipyridine ligands with axial chirality in palladium-catalyzed carbene migratory insertion reactions. PMID- 26418177 TI - PepO, a CovRS-controlled endopeptidase, disrupts Streptococcus pyogenes quorum sensing. AB - Group A Streptococcus (GAS, Streptococcus pyogenes) is a human-restricted pathogen with a capacity to both colonize asymptomatically and cause illnesses ranging from pharyngitis to necrotizing fasciitis. An understanding of how and when GAS switches between genetic programs governing these different lifestyles has remained an enduring mystery and likely requires carefully tuned environmental sensors to activate and silence genetic schemes when appropriate. Herein, we describe the relationship between the Control of Virulence (CovRS, CsrRS) two-component system and the Rgg2/3 quorum-sensing pathway. We demonstrate that responses of CovRS to the stress signals Mg(2+) and a fragment of the antimicrobial peptide LL-37 result in modulated activity of pheromone signaling of the Rgg2/3 pathway through a means of proteolysis of SHP peptide pheromones. This degradation is mediated by the cytoplasmic endopeptidase PepO, which is the first identified enzymatic silencer of an RRNPP-type quorum-sensing pathway. These results suggest that under conditions in which the virulence potential of GAS is elevated (i.e. enhanced virulence gene expression), cellular responses mediated by the Rgg2/3 pathway are abrogated and allow individuals to escape from group behavior. These results also indicate that Rgg2/3 signaling is instead functional during non-virulent GAS lifestyles. PMID- 26418182 TI - Synthesis of bridged diketopiperazines by using the persistent radical effect and a formal synthesis of bicyclomycin. AB - A conceptually new and unified approach to diverse bridged diketopiperazines (DKPs) with widely variable ring sizes was developed by taking advantage of the persistent radical effect. This method enables synthesis of the core structures of bridged DKP alkaloids and was applied to a formal synthesis of the antibiotic bicyclomycin. PMID- 26418183 TI - B(C6F5)3 -catalyzed transfer of dihydrogen from one unsaturated hydrocarbon to another. AB - A transition-metal-free transfer hydrogenation of 1,1-disubstituted alkenes with cyclohexa-1,4-dienes as the formal source of dihydrogen is reported. The process is initiated by B(C6 F5 )3 -mediated hydride abstraction from the dihydrogen surrogate, forming a Bronsted acidic Wheland complex and [HB(C6 F5 )3 ](-) . A sequence of proton and hydride transfers onto the alkene substrate then yields the alkane. Although several carbenium ion intermediates are involved, competing reaction channels, such as dihydrogen release and cationic dimerization of reactants, are largely suppressed by the use of a cyclohexa-1,4-diene with methyl groups at the C1 and C5 as well as at the C3 position, the site of hydride abstraction. The alkene concentration is another crucial factor. The various reaction pathways were computationally analyzed, leading to a mechanistic picture that is in full agreement with the experimental observations. PMID- 26418181 TI - Optogenetic apoptosis: light-triggered cell death. AB - An optogenetic Bax has been designed that facilitates light-induced apoptosis. We demonstrate that mitochondrial recruitment of a genetically encoded light responsive Bax results in the release of mitochondrial proteins, downstream caspase-3 cleavage, changes in cellular morphology, and ultimately cell death. Mutagenesis of a key phosphorylatable residue or modification of the C-terminus mitigates background (dark) levels of apoptosis that result from Bax overexpression. The mechanism of optogenetic Bax-mediated apoptosis was explored using a series of small molecules known to interfere with various steps in programmed cell death. Optogenetic Bax appears to form a mitochondrial apoptosis induced channel analogous to that of endogenous Bax. PMID- 26418185 TI - Suicide by Shotgun in Southeastern Minnesota. AB - Suicide by shotgun is a common method of suicide with high regional variation. We sought to describe their distinct, challenging features and provide demographic and risk characteristics. We reviewed 228 gunshot wounds autopsied at Mayo Clinic from 1994 to 2014; of these, 75 (32.9%) were shotgun wounds. All were suicides and contact range. Ages ranged from 14 to 92 years old; of these, 97% were men. The majority involved the head (70.9%), were intraoral (48.2%), and had upward (73.2%) and backward (73.2%) directionality. Next most common was the chest (21.5%), with backward (94.1%) and downward (64.7%) directionality. Four involved multiple wounds. Wadding was recovered in 16 (21.3%) cases. Six (8.0%) had a survival period. Most (66.7%) took place at home. Seventy-one percent had a known psychiatric history; 32.4% had positive toxicology. Although contact range shotgun wounds cause severe destruction, entrance wound and other characteristic are identifiable with thorough scene, autopsy, and radiographic documentation. PMID- 26418187 TI - Bismuth Based Hybrid Perovskites A3Bi2 I9 (A: Methylammonium or Cesium) for Solar Cell Application. AB - Low-toxic bismuth-based perovskites are prepared for the possible replacement of lead perovskite in solar cells. The perovskites have a hexagonal crystalline phase and light absorption in the visible region. A power conversion efficiency of over 1% is obtained for a solar cell with Cs3 Bi2 I9 perovskite, and it is concluded that bismuth perovskites have very promising properties for further development in solar cells. PMID- 26418188 TI - Missing data in clinical trials for weight management. AB - In 2014, the US FDA approved liraglutide for weight management. The statistical review of the application presented various challenges related to the handling of missing data. The ability of the drug to cause weight loss was not in question. The challenge centered on obtaining a reliable estimate of the intention-to-treat effect to support the risk-benefit evaluation. Subjects in the trials that stopped treatment prior to the endpoint were encouraged to attend the primary endpoint visit. Data from the subjects that returned for a primary efficacy assessment played a significant role in the statistical review. They were used to illustrate shortcomings of the applicant's primary efficacy analysis and sensitivity analyses. They were also used in the FDA analyses to address missing data. The goal of this article is to illustrate challenges and considerations associated with the handling of missing data in clinical trials. PMID- 26418186 TI - Function and control of human invasive trophoblast subtypes: Intrinsic vs. maternal control. AB - The establishment of a functional placenta is pivotal for normal fetal development and the maintenance of pregnancy. In the course of early placentation, trophoblast precursors differentiate into highly invasive trophoblast subtypes. These cells, referred to as extravillous trophoblasts (EVTs), penetrate the maternal uterus reaching as far as the inner third of the myometrium. One of the most fundamental functions of EVTs is the transformation of spiral arteries to establish the uteroplacental blood circulation assuring an adequate nutrient and gas supply to the developing fetus. To achieve this, specialized EVT subpopulations interact with maternal immune cells, provoke elastolysis in the arterial wall and replace the endothelial cells lining the spiral arteries to induce intraluminal vascular remodeling. These and other trophoblast-mediated processes are tightly controlled by paracrine signals from the maternal decidua and furthermore underlie an intrinsic cell-type specific program. Various severe pregnancy complications such as preeclampsia or intrauterine growth retardation are associated with abnormal EVT function, shallow invasion, and decreased blood flow to the placenta. Hence a better understanding of human trophoblast invasion seems mandatory to improve therapeutic intervention. This approach, however, requires a profound knowledge of the human placenta, its various trophoblast subtypes and in particular a better understanding of the regulatory network that controls the invasive phenotype of EVTs. PMID- 26418189 TI - Additional sampling directions improve detection range of wireless radiofrequency probes. AB - PURPOSE: While MRI is enhancing our knowledge about the structure and function of the human brain, subject motion remains a problem in many clinical applications. Recently, the use of wireless radiofrequency markers with three one-dimensional (1D) navigators for prospective correction was demonstrated. This method is restricted in the range of motion that can be corrected, however, because of limited information in the 1D readouts. METHODS: Here, the limitation of techniques for disambiguating marker locations was investigated. It was shown that including more sampling directions extends the tracking range for head rotations. The efficiency of trading readout resolution for speed was explored. RESULTS: Tracking of head rotations was demonstrated from -19.2 to 34.4 degrees , -2.7 to 10.0 degrees , and -60.9 to 70.9 degrees in the x-, y-, and z directions, respectively. In the presence of excessive head motion, the deviation of marker estimates from SPM8 was reduced by 17.1% over existing three-projection methods. This was achieved by using an additional seven directions, extending the time needed for readouts by a factor of 3.3. Much of this increase may be circumvented by reducing resolution, without compromising accuracy. CONCLUSION: Including additional sampling directions extends the range in which markers can be used, for patients who move a lot. Magn Reson Med 76:913-918, 2016. (c) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 26418190 TI - Free Energy Calculations using a Swarm-Enhanced Sampling Molecular Dynamics Approach. AB - Free energy simulations are an established computational tool in modelling chemical change in the condensed phase. However, sampling of kinetically distinct substates remains a challenge to these approaches. As a route to addressing this, we link the methods of thermodynamic integration (TI) and swarm-enhanced sampling molecular dynamics (sesMD), where simulation replicas interact cooperatively to aid transitions over energy barriers. We illustrate the approach by using alchemical alkane transformations in solution, comparing them with the multiple independent trajectory TI (IT-TI) method. Free energy changes for transitions computed by using IT-TI grew increasingly inaccurate as the intramolecular barrier was heightened. By contrast, swarm-enhanced sampling TI (sesTI) calculations showed clear improvements in sampling efficiency, leading to more accurate computed free energy differences, even in the case of the highest barrier height. The sesTI approach, therefore, has potential in addressing chemical change in systems where conformations exist in slow exchange. PMID- 26418192 TI - Missed stroke in acute vertigo and dizziness: It is time for action, not debate. PMID- 26418193 TI - Corrigendum. PMID- 26418191 TI - Safety of guidewire-based measurement of fractional flow reserve and the index of microvascular resistance using intravenous adenosine in patients with acute or recent myocardial infarction. AB - AIMS: Coronary guidewire-based diagnostic assessments with hyperemia may cause iatrogenic complications. We assessed the safety of guidewire-based measurement of coronary physiology, using intravenous adenosine, in patients with an acute coronary syndrome. METHODS: We prospectively enrolled invasively managed STEMI and NSTEMI patients in two simultaneously conducted studies in 6 centers (NCT01764334; NCT02072850). All of the participants underwent a diagnostic coronary guidewire study using intravenous adenosine (140 MUg/kg/min) infusion for 1-2 min. The patients were prospectively assessed for the occurrence of serious adverse events (SAEs) and symptoms and invasively measured hemodynamics were also recorded. RESULTS: 648 patients (n=298 STEMI patients in 1 hospital; mean time to reperfusion 253 min; n=350 NSTEMI in 6 hospitals; median time to angiography from index chest pain episode 3 (2, 5) days) were included between March 2011 and May 2013. Two NSTEMI patients (0.3% overall) experienced a coronary dissection related to the guidewire. No guidewire dissections occurred in the STEMI patients. Chest symptoms were reported in the majority (86%) of patient's symptoms during the adenosine infusion. No serious adverse events occurred during infusion of adenosine and all of the symptoms resolved after the infusion ceased. CONCLUSIONS: In this multicenter analysis, guidewire-based measurement of FFR and IMR using intravenous adenosine was safe in patients following STEMI or NSTEMI. Self-limiting symptoms were common but not associated with serious adverse events. Finally, coronary dissection in STEMI and NSTEMI patients was noted to be a rare phenomenon. PMID- 26418194 TI - Wet Nanoindentation of the Solid Electrolyte Interphase on Thin Film Si Electrodes. AB - The solid electrolyte interphase (SEI) film formed at the surface of negative electrodes strongly affects the performance of a Li-ion battery. The mechanical properties of the SEI are of special importance for Si electrodes due to the large volumetric changes of Si upon (de)insertion of Li ions. This manuscript reports the careful determination of the Young's modulus of the SEI formed on a sputtered Si electrode using wet atomic force microscopy (AFM)-nanoindentation. Several key parameters in the determination of the Young's modulus are considered and discussed, e.g., wetness and roughness-thickness ratio of the film and the shape of a nanoindenter. The values of the Young's modulus were determined to be 0.5-10 MPa under the investigated conditions which are in the lower range of those previously reported, i.e., 1 MPa to 10 GPa, pointing out the importance of the conditions of its determination. After multiple electrochemical cycles, the polymeric deposits formed on the surface of the SEI are revealed, by force-volume mapping in liquid using colloidal probes, to extend up to 300 nm into bulk solution. PMID- 26418196 TI - Improvement of J(sc) in a Cu2ZnSnS4 Solar Cell by Using a Thin Carbon Intermediate Layer at the Cu2ZnSnS4/Mo Interface. AB - Back contact modification plays an important role in improving energy conversion efficiency of Cu2ZnSnS4 (CZTS) thin film solar cells. In this paper, an ultrathin carbon layer is introduced on molybdenum (Mo)-coated soda lime glass (SLG) prior to the deposition of CZTS precursor to improve the back contact and therefore enhance CZTS solar cell efficiency. By introducing this layer, the short circuit current (Jsc) and device conversion efficiency increase for both nonvacuum (sol gel) and vacuum (sputtering) methods. Specifically, for the sol-gel based process, Jsc increases from 13.60 to 16.96 mA/cm(2) and efficiency from 4.47% to 5.52%, while for the sputtering based process, Jsc increases from 17.50 to 20.50 mA/cm(2) and efficiency from 4.10% to 5.20%. Furthermore, introduction of this layer does not lead to any deterioration of either open circuit voltage (Voc) or fill factor (FF). PMID- 26418195 TI - Glyconanomaterials for Combating Bacterial Infections. AB - Bacterial infections constitute an increasing problem to human health in response to build-up of resistance to present antibiotics and sluggish development of new pharmaceuticals. However, a means to address this problem is to pinpoint the drug delivery to-and into-the bacteria. This results in a high local concentration of the drug, circumventing the increasingly high doses otherwise necessary. Combined with other effectors, such as covalent attachment to carriers, rendering the drugs less degradable, and the combination with efflux inhibitors, old drugs can be revived. In this context, glyconanomaterials offer exceptional potential, since these materials can be tailored to accommodate different effectors. In this Concept article, we describe the different advantages of glyconanomaterials, and point to their potential in antibiotic "revitalization". PMID- 26418199 TI - Correction. PMID- 26418197 TI - Another Frontier in Microbiome Research: Preterm Birth. PMID- 26418200 TI - Correction. PMID- 26418202 TI - Systematic Review of Outcomes After Noncardiac Surgery in Patients with Implanted Left Ventricular Assist Devices. AB - The number of patients supported with left ventricular assist devices (LVADs) is rising rapidly, and noncardiac surgery (NCS) in these patients presents unique challenges. Given the controversy regarding the safety and timing of elective NCS, we performed a systematic review examining the perioperative morbidity and mortality of NCS in stable patients with LVADs. The published literature was searched using strategies created by a medical librarian. All reports involving five or more patients with implanted LVAD undergoing NCS were eligible for inclusion. One hundred and sixty one patients who underwent 252 surgeries were included from seven studies. Cohort size ranged from 8 to 47 patients undergoing 12 to 67 NCS. Median age ranged from 50.1 to 68 years and 75 to 100% were male. Thirty day postoperative mortality ranged from 6.4 to 16.7%, although four studies reported no deaths. Due to the small number of included studies with relative few patients and widely heterogeneous reporting of outcomes a formal quantitative meta-analysis was not performed. Noncardiac surgery in patients with LVADs appears to be safe and feasible in select patients. Future studies should use standard study design and reporting parameters to facilitate the systematic examination of safety and outcomes for elective NCS in LVAD patients. PMID- 26418201 TI - Generation of Two Biological Wound Dressings as a Potential Delivery System of Human Adipose-Derived Mesenchymal Stem Cells. AB - Human adipose-derived mesenchymal stem cells (hADMSCs) are believed to be potential key factors for starting the regenerative process after tissue injury. However, an efficient method of delivering these regenerative cells to an external wound site is still lacking. Human amnion and pig skin have long been used as skin wound dressings for the treatment of burns and other skin lesions. Herein, we present the generation of two constructs using these two biomaterials as effective scaffolds for the culture of hADMSCs. It was found that hADMSCs seeded onto radiosterilized human amnion and pig skin are viable and proliferate. These cells are able to migrate over these scaffolds as demonstrated by using time-lapse microscopy. In addition, the scaffolds induce hADMSCs to secrete interleukin-10, an important negative regulator of inflammation, and interleukin 1beta, a proinflammatory protein. The interplay between these two proteins has been proven to be vital for a balanced restoration of all necessary tissues. Thus, radiosterilized human amnion and pig skin are likely suitable scaffolds for delivery of hADMSCs transplants that could promote tissue regeneration in skin injuries like patients with burn injuries. PMID- 26418203 TI - Convective Leakage Makes Heparin Locking of Central Venous Catheters Ineffective Within Seconds: Experimental Measurements in a Model Superior Vena Cava. AB - Central venous catheters (CVCs), placed in the superior vena cava (SVC) for hemodialysis or chemotherapy, are routinely filled while not in use with heparin, an anticoagulant, to maintain patency and prevent thrombus formation at the catheter tip. The heparin-locking procedure, however, places the patient at risk for systemic bleeding, as heparin is known to leak from the catheter into the blood stream. We provide evidence from detailed in vitro experiments that shows the driving mechanism behind heparin leakage to be convective-diffusive transport due to the pulsatile flow surrounding the catheter. This novel mechanism is supported by experimental planar laser-induced fluorescence (PLIF) and particle image velocimetry (PIV) measurements of flow velocity and heparin transport from a CVC placed inside a model SVC inside a pulsatile flow loop. The results predict an initial, fast (<10 s), convection-dominated phase that rapidly depletes the concentration of heparin in the near-tip region, the region of the catheter with side holes. This is followed by a slow, diffusion-limited phase inside the catheter lumen, where the concentration is still high, that is insufficient at replenishing the lost heparin concentration in the near-tip region. The results presented here, which are consistent with previous in vivo estimates of 24 hour leakage rates, predict that the concentration of heparin in the near-tip region is essentially zero for the majority of the interdialytic phase, rendering the heparin locking procedure ineffective. PMID- 26418204 TI - Predictors of Thromboembolic Events in Patients with Ventricular Assist Device. AB - Ventricular assist device patients (VAD) are at increased risk for thromboembolism. Biomarkers of hemolysis, such as lactate dehydrogenase (LDH) and poorly controlled international normalized ratio (INR) has been identified as predictors of thromboembolism. Patients aged 19 years and older who had a continuous flow VAD placed from 2006 to 2012 were included in this study (N = 115). We assessed the relationship of LDH elevation (>=600 IU/L) at different time points and thromboembolism. Over the 51.3 person-years of follow-up, a total of 23 first thromboembolic events occurred. Patients with elevated LDH on the day of VAD implantation had an increased risk for thromboembolism (hazard ratio [HR]: 4.72, 95% confidence interval [CI]: 1.44-15.4; p = 0.01). There was an increased risk of thromboembolism with early LDH elevation within the first month post-VAD (HR: 4.95, 95% CI: 1.69-14.4; p = 0.003) and estimated glomerular filtration rate <30 before VAD implantation (HR: 4.74, 95% CI: 1.12-20.1; p = 0.0346), whereas there was a decreased risk with good anticoagulation control (HR: 0.30, 95% CI: 0.10-0.86; p = 0.0247). Our study is the first to highlight the association between LDH elevation on the day of implantation and post-VAD thromboembolism. This study details the increased risk of thromboembolism with early LDH elevation and the importance of maintaining time in therapeutic INR range. PMID- 26418205 TI - Effects of Sevoflurane Inhalation During Cardiopulmonary Bypass on Pediatric Patients: A Randomized Controlled Clinical Trial. AB - The effects of sevoflurane inhalation during cardiopulmonary bypass (CPB) on postoperative courses and serum cardiac troponin I (cTnI) concentrations in pediatric patients undergoing cardiac surgery have not been extensively investigated. In this single-center, prospective, randomized trial, an anesthetic regimen containing 2% sevoflurane used throughout the CPB process was compared with a total intravenous anesthesia (TIVA) regimen. One hundred and three patients undergoing congenital heart defect repair with CPB were included in this prospective randomized controlled study. They were randomized into two groups: the sevoflurane group, who received 2% sevoflurane during CPB via an oxygenator, and the control group, who received only an oxygen-air mixture. The pre- and intra-operative parameters were comparable between the two groups. There was a slight but significant increase of arterial diastolic pressure in the sevoflurane group immediately after CPB compared with control patients (46.9 +/- 9.3 mm Hg vs. 43.6 +/- 8.9 mm Hg; p = 0.033). There was no death in either group. The postoperative ventilation time (in mean [95% confidence interval]) was shorter in the sevoflurane group than that in the control group (26.1 [19.2, 33.0] h vs. 37.7 [24.4, 50.9] h; p = 0.014). The postoperative ICU time, hospital days, and serial serum cTnI concentrations were not significantly different between the two groups. Inhalation of 2% sevoflurane during CPB is beneficial to the recovery of pediatric patients undergoing cardiac surgery but has no significant effect on postoperative cTnI release. PMID- 26418206 TI - Safety Management of a Clinical Process Using Failure Mode and Effect Analysis: Continuous Renal Replacement Therapies in Intensive Care Unit Patients. AB - The failure mode and effect analysis (FMEA) may improve the safety of the continuous renal replacement therapies (CRRT) in the intensive care unit. We use this tool in three phases: 1) Retrospective observational study. 2) A process FMEA, with implementation of the improvement measures identified. 3) Cohort study after FMEA. We included 54 patients in the pre-FMEA group and 72 patients in the post-FMEA group. Comparing the risks frequencies per patient in both groups, we got less cases of under 24 hours of filter survival time in the post-FMEA group (31 patients 57.4% vs. 21 patients 29.6%; p < 0.05); less patients suffered circuit coagulation with inability to return the blood to the patient (25 patients [46.3%] vs. 16 patients [22.2%]; p < 0.05); 54 patients (100%) versus 5 (6.94%) did not get phosphorus levels monitoring (p < 0.05); in 14 patients (25.9%) versus 0 (0%), the CRRT prescription did not appear on medical orders. As a measure of improvement, we adopt a dynamic dosage management. After the process FMEA, there were several improvements in the management of intensive care unit patients receiving CRRT, and we consider it a useful tool for improving the safety of critically ill patients. PMID- 26418207 TI - Renal Function Recovery with Total Artificial Heart Support. AB - Heart failure patients requiring total artificial heart (TAH) support often have concomitant renal insufficiency (RI). We sought to quantify renal function recovery in patients supported with TAH at our institution. Renal function data at 30, 90, and 180 days after TAH implantation were analyzed for patients with RI, defined as hemodialysis supported or an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m. Between January 2008 and December 2013, 20 of the 46 (43.5%) TAH recipients (age 51 +/- 9 years, 85% men) had RI, mean preoperative eGFR of 48 +/- 7 ml/min/1.73 m. Renal function recovery was noted at each follow-up interval: increment in eGFR (ml/min/1.73 m) at 30, 90, and 180 days was 21 +/- 35 (p = 0.1), 16.5 +/- 18 (p = 0.05), and 10 +/- 9 (p = 0.1), respectively. Six patients (30%) required preoperative dialysis. Of these, four recovered renal function, one remained on dialysis, and one died. Six patients (30%) required new-onset dialysis. Of these, three recovered renal function and three died. Overall, 75% (15 of 20) of patients' renal function improved with TAH support. Total artificial heart support improved renal function in 75% of patients with pre-existing significant RI, including those who required preoperative dialysis. PMID- 26418208 TI - Incidence of Hemolysis in Patients with Cardiogenic Shock Treated with Impella Percutaneous Left Ventricular Assist Device. AB - Impella assist devices have been increasingly used in cardiogenic shock (CS). This study aims to assess the incidence of hemolysis when Impella support is used longer than 6 hours in CS. We retrospectively studied all patients who required Impella between April 2009 and September 2013. Demographic data and hemolysis indicators were sampled and analyzed using paired t-test. A total of 118 devices were placed and 40 used longer than 6 hours. The average time of support was 86.63 hours, and the 30 and 90 days of survival were 65% and 60%, respectively. After 24 hours of support, the hemoglobin (Hb) decreased significantly despite 17% of patients receiving blood transfusion (p = 0.0001). By the time of removal, 65% of patients were transfused to maintain a Hb of 10 mg/dl (p = 0.0014). The lactate dehydrogenase (LDH) increased to 5,201 U/L (n = 22; p = 0.0096), the bilirubin to 5.6 mg/dl (p = 0.008), and the haptoglobin level was 15.4 mg/dl (n = 25). The cumulative incidence of hemolysis was 62.5%. Hemolysis is a common occurrence in patients with long-term Impella support for CS, evaluated by the persistent decline in Hb and haptoglobin as well as increase in LDH and bilirubin. Strict monitoring of hemolysis parameters at baseline and at frequent intervals is crucial. PMID- 26418209 TI - Distal Proctocolitis in Infants: Is It Always an Allergic Disease? PMID- 26418210 TI - Attrition in Long-Term Nutrition Research Studies: A Commentary by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Early Nutrition Research Working Group. AB - Long-term follow-up of randomised trials and observational studies provide the best evidence presently available to assess long-term effects of nutrition, and such studies are an important component in determining optimal infant feeding practices. Attrition is, however, an almost inevitable occurrence with increasing age at follow-up. There is a common assumption that studies with <80% follow-up rates are invalid or flawed, and this criticism seems to be more frequently applied to follow-up studies involving randomised trials than observational studies. In this article, we explore the basis and evidence for this "80% rule" and discuss the need for greater consensus and clear guidelines for analysing and reporting results in this specific situation. PMID- 26418211 TI - One Extra Gram of Protein to Preterm Infants From Birth to 1800 g: A Single Blinded Randomized Clinical Trial. AB - OBJECTIVE: The aim of the study was to evaluate the effect on growth and neurodevelopment of increasing amino acid (AA) during parenteral nutrition and protein intake during enteral nutrition in extremely low birth-weight infants starting from birth to day of reaching 1800 g body weight. METHODS: We randomized preterm infants with birth weight 500 to 1249 g either to a high AA/protein intake (HiP [high protein]: parenteral nutrition = 3.5 AA, enteral nutrition = 4.6 protein g . kg . day) or to a standard of care group (StP [standard protein]: parenteral nutrition = 2.5 AA, enteral nutrition = 3.6 protein g . kg . day). The primary outcome was weight gain from birth to 1800 g. RESULTS: TWO:: hundred twenty-six patients were screened, 164 completed the study and were analyzed (82 StP and 82 HiP). Cumulative AA/protein intake from birth to 1800 g was 178 +/- 42 versus 223 +/- 45 g/kg in the StP versus HiP group respectively, P < 0.0001.Blood urea was higher in HiP than in StP group both during parenteral and enteral nutrition (P = 0.004).Weight gain from birth to 1800 g was 12.3 +/- 1.6 in StP and 12.6 +/- 1.7 g . kg . day in HiP group (P = 0.294). We found no difference in any growth parameters neither during hospital stay nor at 2 years corrected age. Bayley III score at 24 months corrected age was 93.8 +/- 12.9 in StP group and 94.0 +/- 13.9 in the HiP group, P = 0.92. CONCLUSIONS: Increasing AA/protein intake both during parenteral and enteral nutrition does not improve growth and neurodevelopment of small preterm infants 500 to 1249 g birth weight. PMID- 26418212 TI - Identification and Management of Acute Malnutrition in Hospitalized Children: Developed Country Perspective. PMID- 26418213 TI - Pancreatitis Subtypes Survey in 852 Childhood-Onset Systemic Lupus Erythematosus Patients. AB - OBJECTIVE: Pancreatitis is a rare and a life-threatening systemic lupus erythematosus (SLE) manifestation in childhood-onset SLE (cSLE). The objective of this study was to systematically classify pancreatitis in cSLE according to the International Study Group of Pediatric Pancreatitis and determine the overall prevalence, clinical features, laboratory, and first episode outcomes. METHODS: A multicenter cohort study in 10 pediatric rheumatology centers, including 852 patients with cSLE. RESULTS: Pancreatitis was diagnosed in 22 of 852 (2.6%) patients with cSLE. It was classified as acute pancreatitis in 20 (91%), acute recurrent pancreatitis in 2 (9%), and none of them had chronic pancreatitis. None of them had gallstones, traumatic pancreatitis, or reported alcohol/tobacco use. The comparison of patients with pancreatitis (first episode) and without this complication revealed a shorter disease duration (1 [0-10] vs 4 [0-23] years, P < 0.0001) and higher median of Systemic Lupus Erythematosus Disease Activity Index 2000 (21 [0-41] vs 2 [0-45], P < 0.0001). The frequencies of fever (P < 0.0001), weight loss (P < 0.0001), serositis (P < 0.0001), nephritis (P < 0.0001), arterial hypertension (P < 0.0001), acute renal failure (P < 0.0001), macrophage activation syndrome (P < 0.0001), and death (P = 0.001) were also higher in patients with pancreatitis. The frequencies of intravenous methylprednisolone use (P < 0.0001) and the median of prednisone dose (55 [15-60] vs 11 [1-90] mg/day, P < 0.0001) were significantly higher in patients with pancreatitis. Of note, the 2 patients with acute recurrent pancreatitis had 2 episodes, with pain-free interval of 1 and 4 years. CONCLUSIONS: This was the first study characterizing pancreatitis using the International Study Group of Pediatric Pancreatitis standardized definitions in patients with cSLE showing that the predominant form is acute pancreatitis seen in association with glucocorticoid treatment and active severe disease. PMID- 26418214 TI - Liver Transplantation for Biliary Atresia: Is There a Difference in Outcome for Infants? AB - OBJECTIVES: Liver transplantation (LT) in children with biliary atresia (BA) is often performed because of poor bile drainage, complications of biliary cirrhosis, or recurrent cholangitis. Poor bile drainage after a Kasai hepatoportoenterostomy is the primary driver for LT in infancy. The aim of the present study was to compare the clinical characteristics and outcome of first isolated liver transplantation for infants with BA who underwent transplant before 2 years of age (transplanted at infancy [TAI]) with children transplanted later in life (age 2-<18 years = transplanted at childhood [TAC]). METHODS: Children with BA who underwent LT between 2002 and 2012 were identified from the United Network for Organ Sharing Standard Transplant Analysis and Research data set files. RESULTS: A total of 1818 children underwent first isolated liver transplantation for BA (TAI 1408 [77.4%]; TAC 410 [22.6%]). One and 5-year patient survival of the TAI and TAC patients was 95.2%, 93.8%, and 97.8 %, 97.1%, respectively (P < 0.01 for both periods). One and 5-year graft survival of the TAI and TAC patients was 87.6%, 84.6 % and 93.2%, 90.7%, respectively (P < 0.01 for both periods). Removal from the waitlist for disease progression or death was significantly higher for TAI compared with TAC (120 patients [6.3%] vs 21 [3.7%], P = 0.02). Cold ischemic time was found to be the prognostic factor for death after LT in TAI, whereas being on life support was a poor prognostic factor in TAC by multivariate risk factor analysis. CONCLUSIONS: The vast majority of transplants for BA occur in children <2 years of age. Younger patients with BA had significantly higher waitlist and posttransplant mortality. Given the consistently poorer outcomes, there is an urgent need to find methods to improve bile drainage after the Kasai hepatoportoenterostomy. PMID- 26418216 TI - An analytic linear accelerator source model for GPU-based Monte Carlo dose calculations. AB - Recently, there has been a lot of research interest in developing fast Monte Carlo (MC) dose calculation methods on graphics processing unit (GPU) platforms. A good linear accelerator (linac) source model is critical for both accuracy and efficiency considerations. In principle, an analytical source model should be more preferred for GPU-based MC dose engines than a phase-space file-based model, in that data loading and CPU-GPU data transfer can be avoided. In this paper, we presented an analytical field-independent source model specifically developed for GPU-based MC dose calculations, associated with a GPU-friendly sampling scheme. A key concept called phase-space-ring (PSR) was proposed. Each PSR contained a group of particles that were of the same type, close in energy and reside in a narrow ring on the phase-space plane located just above the upper jaws. The model parameterized the probability densities of particle location, direction and energy for each primary photon PSR, scattered photon PSR and electron PSR. Models of one 2D Gaussian distribution or multiple Gaussian components were employed to represent the particle direction distributions of these PSRs. A method was developed to analyze a reference phase-space file and derive corresponding model parameters. To efficiently use our model in MC dose calculations on GPU, we proposed a GPU-friendly sampling strategy, which ensured that the particles sampled and transported simultaneously are of the same type and close in energy to alleviate GPU thread divergences. To test the accuracy of our model, dose distributions of a set of open fields in a water phantom were calculated using our source model and compared to those calculated using the reference phase-space files. For the high dose gradient regions, the average distance-to-agreement (DTA) was within 1 mm and the maximum DTA within 2 mm. For relatively low dose gradient regions, the root-mean-square (RMS) dose difference was within 1.1% and the maximum dose difference within 1.7%. The maximum relative difference of output factors was within 0.5%. Over 98.5% passing rate was achieved in 3D gamma index tests with 2%/2 mm criteria in both an IMRT prostate patient case and a head-and-neck case. These results demonstrated the efficacy of our model in terms of accurately representing a reference phase-space file. We have also tested the efficiency gain of our source model over our previously developed phase-space-let file source model. The overall efficiency of dose calculation was found to be improved by ~1.3-2.2 times in water and patient cases using our analytical model. PMID- 26418215 TI - Caring Decisions: The Development of a Written Resource for Parents Facing End-of Life Decisions. AB - BACKGROUND: Written resources in adult intensive care have been shown to benefit families facing end of life (EoL) decisions. There are few resources for parents making EoL decisions for their child and no existing resources addressing ethical issues. The Caring Decisions handbook and website were developed to fill these gaps. AIM: We discuss the development of the resources, modification after reviewer feedback and findings from initial pilot implementation. DESIGN: A targeted literature review-to identify resources and factors that impact on parental EoL decision-making; development phase-guided by the literature and the researchers' expertise; consultation process-comprised a multi-disciplinary panel of experts and parents; pilot evaluation study-hard-copy handbook was distributed as part of routine care at an Australian Children's Hospital. SETTING/PARTICIPANTS: Twelve experts and parents formed the consultation panel. Eight parents of children with life-limiting conditions and clinicians were interviewed in the pilot study. RESULTS: Numerous factors supporting/impeding EoL decisions were identified. Caring Decisions addressed issues identified in the literature and by the multidisciplinary research team. The consultation panel provided overwhelmingly positive feedback. Pilot study parents found the resources helpful and comforting. Most clinicians viewed the resources as very beneficial to parents and identified them as ideal for training purposes. CONCLUSIONS: The development of the resources addressed many of the gaps in existing resources. The consultation process and the pilot study suggest these resources could be of significant benefit to parents and clinicians. PMID- 26418217 TI - WITHDRAWN: Adenotonsillectomy for obstructive sleep apnoea in children. PMID- 26418218 TI - Reaction of Laser-Ablated Uranium and Thorium Atoms with H2Se: A Rare Example of Selenium Multiple Bonding. AB - The compounds H2ThSe and H2USe were synthesized by the reaction of laser-ablated actinide metal atoms with H2Se under cryogenic conditions following the procedures used to synthesize H2AnX (An = Th, U; X = O, S). The molecules were characterized by infrared spectra in an argon matrix with the aid of deuterium substitution and electronic structure calculations at the density functional theory level. The main products, H2ThSe and H2USe, are shown to have a highly polarized actinide-selenium triple bond, as found for H2AnS on the basis of electronic structure calculations. There is an even larger back-bonding of the Se with the An than found for the corresponding sulfur compounds. These molecules are of special interest as rare examples of multiple bonding of selenium to a metal, particularly an actinide metal. PMID- 26418219 TI - Cardioprotective Actions of TGFbetaRI Inhibition Through Stimulating Autocrine/Paracrine of Survivin and Inhibiting Wnt in Cardiac Progenitors. AB - Heart failure due to myocardial infarction (MI) is a major cause of morbidity and mortality in the world. We found previously that A83-01, a TGFbetaRI inhibitor, could facilitate cardiac repair in post-MI mice and induce the expansion of a Nkx2.5 + cardiomyoblast population. This study aimed to investigate the key autocrine/paracrine factors regulated by A83-01 in the injured heart and the mechanism of cardioprotection by this molecule. Using a previously described transgenic Nkx2.5 enhancer-green fluorescent protein (GFP) reporter mice, we isolated cardiac progenitor cells (CPC) including Nkx2.5-GFP + (Nkx2.5+), sca1+, and Nkx2.5+/sca1 + cells. A83-01 was found to induce proliferation of these three subpopulations mainly through increasing Birc5 expression in the MEK/ERK dependent pathway. Survivin, encoded by Birc5, could also directly proliferate Nkx2.5 + cells and enhance cultured cardiomyocytes viability. A83-01 could also reverse the downregulation of Birc5 in postinjured mice hearts (n = 6) to expand CPCs. Moreover, the increased Wnt3a in postinjured hearts could decrease CPCs, which could be reversed by A83-01 via inhibiting Fzd6 and Wnt1-induced signaling protein 1 expressions in CPCs. Next, we used inducible alphaMHC-cre/mTmG mice to label cardiomyocytes with GFP and nonmyocytes with RFP. We found A83-01 preserved more GFP + myocytes (68.6% +/- 3.1% vs. 80.9% +/- 3.0%; p < .05, n = 6) and fewer renewed RFP + myocytes (0.026% +/- 0.005% vs. 0.062% +/- 0.008%; p < .05, n = 6) in parallel with less cardiac fibrosis in isoprenaline-injected mice treated with A83-01. TGFbetaRI inhibition in an injured adult heart could both stimulate the autocrine/paracrine activity of survivin and inhibit Wnt in CPCs to mediate cardioprotection and improve cardiac function. PMID- 26418220 TI - Urease and Dental Plaque Microbial Profiles in Children. AB - OBJECTIVE: Urease enzymes produced by oral bacteria generate ammonia, which can have a significant impact on the oral ecology and, consequently, on oral health. To evaluate the relationship of urease with dental plaque microbial profiles in children as it relates to dental caries, and to identify the main contributors to this activity. METHODS: 82 supragingival plaque samples were collected from 44 children at baseline and one year later, as part of a longitudinal study on urease and caries in children. DNA was extracted; the V3-V5 region of the 16S rRNA gene was amplified and sequenced using 454 pyrosequencing. Urease activity was measured using a spectrophotometric assay. Data were analyzed with Qiime. RESULTS: Plaque urease activity was significantly associated with the composition of the microbial communities of the dental plaque (Baseline P = 0.027, One Year P = 0.012). The bacterial taxa whose proportion in dental plaque exhibited significant variation by plaque urease levels in both visits were the family Pasteurellaceae (Baseline P<0.001; One Year P = 0.0148), especially Haemophilus parainfluenzae. No association was observed between these bacteria and dental caries. Bacteria in the genus Leptotrichia were negatively associated with urease and positively associated with dental caries (Bonferroni P<0.001). CONCLUSIONS: Alkali production by urease enzymes primarily from species in the family Pasteurellaceae can be an important ecological determinant in children's dental plaque. Further studies are needed to establish the role of urease-associated bacteria in the acid/base homeostasis of the dental plaque, and in the development and prediction of dental caries in children. PMID- 26418221 TI - Chronic maternal morphine alters calbindin D-28k expression pattern in postnatal mouse brain. AB - The distribution pattern of calbindin (CB)-D28k-expressing neurons results to be altered in several brain regions of chronic morphine exposed adult mice. In this study, the influence of chronic maternal exposure to morphine on the distribution pattern of CB-D28k-expressing neurons in the brain of mouse offspring was investigated. Females of CD-1 mice were daily administered with saline or morphine for 7 days before mating, during the whole gestation period, and until 21 day post-partum. Their offspring were sacrificed on postnatal day 18, and the brains were examined by histology using cresyl violet and by immunohistochemistry using a rabbit polyclonal anti-CB-D28k antibody. Histology revealed no significant differences in the distribution pattern and the number of neurons between the offspring forebrain of the control group of mice and the two groups of mice treated with different doses of morphine. However, immunohistochemical analysis revealed that the number of CB-D28k-immunoreactive neurons remarkably decreased in the cingulate cortex, in the layers II-IV of the parietal cortex and in all regions of the hippocampus, while it increased in the layers V-VI of the parietal cortex and in the subicular region of the offspring brain of morphine treated mice. Overall, our findings demonstrate that maternal exposure to morphine alters the pattern of CB-D28k-expressing neuron pattern in specific regions of murine developing brain, in a layer- and dose-dependent way, thus suggesting that these alterations might represent a mechanism by which morphine modifies the functional aspects of developing brain. PMID- 26418223 TI - Transcendent Pluralism: A Middle-Range Theory of Nonviolent Social Transformation Through Human and Ecological Dignity. AB - Transcendent pluralism is a middle-range theory that focuses on the emergence of human dignity within relationships among diverse peoples through nonviolent social transformation. The theory proposes that contemporary social problems that negatively influence health are rooted in human and ecological devaluation and that healing is needed through the advance of dignity. The theory has been developed through both deductive and inductive processes including 4 research studies. The theory of transcendent pluralism provides a framework for nurses seeking to advance dignity. This article provides an overview of the theory's development and components. PMID- 26418222 TI - High Intensity Exercise in Multiple Sclerosis: Effects on Muscle Contractile Characteristics and Exercise Capacity, a Randomised Controlled Trial. AB - INTRODUCTION: Low-to-moderate intensity exercise improves muscle contractile properties and endurance capacity in multiple sclerosis (MS). The impact of high intensity exercise remains unknown. METHODS: Thirty-four MS patients were randomized into a sedentary control group (SED, n = 11) and 2 exercise groups that performed 12 weeks of a high intensity interval (HITR, n = 12) or high intensity continuous cardiovascular training (HCTR, n = 11), both in combination with resistance training. M.vastus lateralis fiber cross sectional area (CSA) and proportion, knee-flexor/extensor strength, body composition, maximal endurance capacity and self-reported physical activity levels were assessed before and after 12 weeks. RESULTS: Compared to SED, 12 weeks of high intensity exercise increased mean fiber CSA (HITR: +21 +/- 7%, HCTR: +23 +/- 5%). Furthermore, fiber type I CSA increased in HCTR (+29 +/- 6%), whereas type II (+23 +/- 7%) and IIa (+23 +/- 6%,) CSA increased in HITR. Muscle strength improved in HITR and HCTR (between +13 +/- 7% and +45 +/- 20%) and body fat percentage tended to decrease (HITR: -3.9 +/- 2.0% and HCTR: -2.5 +/- 1.2%). Furthermore, endurance capacity (Wmax +21 +/- 4%, time to exhaustion +24 +/- 5%, VO2max +17 +/- 5%) and lean tissue mass (+1.4 +/- 0.5%) only increased in HITR. Finally self-reported physical activity levels increased 73 +/- 19% and 86 +/- 27% in HCTR and HITR, respectively. CONCLUSION: High intensity cardiovascular exercise combined with resistance training was safe, well tolerated and improved muscle contractile characteristics and endurance capacity in MS. TRIAL REGISTRATION: ClinicalTrials.gov NCT01845896. PMID- 26418224 TI - Molecularly imprinted polymers for the solid-phase extraction of four fluoroquilones from milk and lake water samples. AB - A method based on molecular crowding and ionic liquids as reaction solvents has been used for the synthesis of molecularly imprinted polymers. Levofloxacin was selected as the template, polymethyl methacrylate was the molecular crowding agent, and 1-butyl-3-methylimidazolium tetrafluoroborate (ionic liquid) was selected as the reaction solvent and porogen. The optimized proportion for the mixed porogen was dimethyl sulfoxide/ionic liquid/polymethyl methacrylate 1:1.6:5 in chloroform (150 mg mL(-1) ). The morphology and chemical composition of levofloxacin imprinted polymers were assessed by scanning electron microscopy and Fourier transform infrared spectroscopy. The absorption experiments demonstrated that the levofloxacin imprinted polymers possess high selective recognition property to levofloxacin and analogs, including enrofloxacin, ciprofloxacin and gatifloxacin, which all belong to fluoroquinolones. An extraction method using levofloxacin imprinted polymers as sorbent followed by high-performance liquid chromatography analysis was optimized for the determination of four fluoroquinolones in milk and lake water samples. Under the optimized conditions, good linearity was observed in a range of 5-1000 ng g(-1) with the limit of detection between 0.3 and 0.5 ng g(-1) for the four fluoroquinolones. The recoveries at three spiked levels ranged 82.4-98.3% with the relative standard deviation <=4.9. PMID- 26418225 TI - The end of RIPK1-RIPK3-MLKL-mediated necroptosis in acetaminophen-induced hepatotoxicity? PMID- 26418226 TI - Gender-specific associations of sleep duration with uncontrolled blood pressure in middle-aged patients. AB - OBJECTIVE: The present study was designed to evaluate the associations between sleep duration and uncontrolled blood pressure in a hospital-based sample of middle-aged adults. METHODS: Between March 2012 and December 2012, a cross sectional survey was conducted among the hypertensive outpatients of Anzhen Hospital and a community hospital in Beijing, China. Eligible participants were adults aged 35-55 years with an established diagnosis of hypertension and had been on standard antihypertensive drug treatment for at least 6 months. An interviewer-led questionnaire was used to collect the participants' demographic, lifestyle and dietary information, as well as medical histories. Usual sleep durations were categorized as <7 h, 7-8 h and >8 h per night. Logistic regression models were used to assess gender-specific associations between sleep duration and uncontrolled hypertension, with adjustment for age, gender, family history, diabetes, smoking, alcohol consumption and physical activity. RESULTS: A total of 3038 participants were finally investigated. Among them, 1569 (51.6%) patients had their blood pressure uncontrolled. In men, no significant association was found between sleep duration categories and uncontrolled hypertension. In women, compared with those sleeping <7 h, longer sleepers tended to have a lower risk of uncontrolled hypertension for sleeping 7-8 hours (odds ratio [OR] 0.537, 95% confidence interval [CI], 0.370-0.780) and sleeping >8 h (OR 0.316, 95% CI, 0.202 0.494), respectively. CONCLUSION: Modest associations between short sleep duration and uncontrolled hypertension were seen in middle-aged women but not in men in the hypertensive population. PMID- 26418227 TI - Dielectric Elastomer Based "Grippers" for Soft Robotics. AB - The use of few stiff fibers to control the deformation of dielectric elastomer actuators, in particular to break the symmetry of equi-biaxial lateral strain in the absence of prestretch, is demonstrated. Actuators with patterned fibers are shown to evolve into unique shapes upon electrical actuation, enabling novel designs of gripping actuators for soft robotics. PMID- 26418228 TI - Using Ion Imaging to Measure Velocity Distributions in Surface Scattering Experiments. AB - We present a new implementation of ion imaging for the study of surface scattering processes. The technique uses a combination of spatial ion imaging with laser slicing and delayed pulsed extraction. The scattering velocities of interest are parallel to the imaging plane, allowing speed and angular distributions to be extracted from a single image. The first results of direct scattering of N2 from a clean, single-crystal Au(111) surface are reported, and the speed resolution is shown to be competitive with current state-of-the-art time-of-flight methods for velocity measurements while providing simultaneous measurements of in-plane angular distributions. PMID- 26418229 TI - NUP98-HOXA9 bearing therapy-related myeloid neoplasm involves myeloid-committed cell and induces HOXA5, EVI1, FLT3, and MEIS1 expression. AB - INTRODUCTION: Chromosomal rearrangements involving NUP98 gene have been associated with human leukemias such as de novo AML, therapy-related AML (t-AML), myelodysplastic syndrome (MDS), and chronic myeloid leukemia (CML). Genetic fusion NUP98-HOXA9, caused by t(7;11)(p15;p15), is a recurrent cytogenetic alteration in de novo acute myeloid leukemia (AML) usually found in young Asian patients and its description in therapy-related myeloid neoplasms (t-MN) is rare. Only one Asian case with molecular demonstration of the NUP98-HOXA9 fusion has been reported in therapy-related leukemia. NUP98-HOXA9 leukemogenic mechanism is derived from the transcription factor activity of the chimeric protein, which enhances the expression of genes related to cellular differentiation arrest and proliferation. PATIENTS AND METHODS: We studied a Caucasian woman with a therapy related acute myeloid leukemia after Ewing's sarcoma. Molecular demonstration of the genetic fusion NUP98-HOXA9 was performed by RT-PCR, and gene expression was analyzed by real-time PCR, including four AML patients with MLL rearrangements for comparative analysis. Cytologic and flow cytometric analysis was also carried out. RESULTS: After cytologic and flow cytometric analysis diagnostics was therapy-related myeloid neoplasm (t-MN). The major component of blasts in the acute leukemia was with neutrophilic differentiation, but 13% erythroid lineage blasts were also found. Cytogenetic and FISH analysis revealed t(7;11)(p15;p15) and NUP98-HOXA9 fusion gene was demonstrated. Gene expression analysis showed upregulation of EVI1 and MEIS1 in the index patient, both of them previously related to a worst outcome. CONCLUSION: In this work, we include a detailed molecular, clinical, cytological, and cytometric study of the second t-AML bearing NUP98-HOXA9 genetic fusion. PMID- 26418230 TI - Integration of Sentence-Level Semantic Information in Parafovea: Evidence from the RSVP-Flanker Paradigm. AB - During text reading, the parafoveal word was usually presented between 2 degrees and 5 degrees from the point of fixation. Whether semantic information of parafoveal words can be processed during sentence reading is a critical and long standing issue. Recently, studies using the RSVP-flanker paradigm have shown that the incongruent parafoveal word, presented as right flanker, elicited a more negative N400 compared with the congruent parafoveal word. This suggests that the semantic information of parafoveal words can be extracted and integrated during sentence reading, because the N400 effect is a classical index of semantic integration. However, as most previous studies did not control the word-pair congruency of the parafoveal and the foveal words that were presented in the critical triad, it is still unclear whether such integration happened at the sentence level or just at the word-pair level. The present study addressed this question by manipulating verbs in Chinese sentences to yield either a semantically congruent or semantically incongruent context for the critical noun. In particular, the interval between the critical nouns and verbs was controlled to be 4 or 5 characters. Thus, to detect the incongruence of the parafoveal noun, participants had to integrate it with the global sentential context. The results revealed that the N400 time-locked to the critical triads was more negative in incongruent than in congruent sentences, suggesting that parafoveal semantic information can be integrated at the sentence level during Chinese reading. PMID- 26418231 TI - Validation and Extension of the Prolonged Mechanical Ventilation Prognostic Model (ProVent) Score for Predicting 1-Year Mortality after Prolonged Mechanical Ventilation. AB - RATIONALE: Prognostic models can inform management decisions for patients requiring prolonged mechanical ventilation. The Prolonged Mechanical Ventilation Prognostic model (ProVent) score was developed to predict 1-year mortality in these patients. External evaluation of such models is needed before they are adopted for routine use. OBJECTIVES: The goal was to perform an independent external validation of the modified ProVent score and assess for spectrum extension at 14 days of mechanical ventilation. METHODS: This was a retrospective cohort analysis of patients who received prolonged mechanical ventilation at the University of Iowa Hospitals. Patients who received 14 or more days of mechanical ventilation were identified from a database. Manual review of their medical records was performed to abstract relevant data including the four model variables at Days 14 and 21 of mechanical ventilation. Vital status at 1 year was checked in the medical records or the social security death index. Logistic regressions examined the associations between the different variables and mortality. Model performance at 14 to 20 days and 21+ days was assessed for discrimination by calculating the area under the receiver operating characteristic curve, and calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test. MEASUREMENTS AND MAIN RESULTS: A total of 180 patients (21+ d) and 218 patients (14-20 d) were included. Overall, 75% were surgical patients. One-year mortality was 51% for 21+ days and 32% for 14 to 20 days of mechanical ventilation. Age greater than 65 years was the strongest predictor of mortality at 1 year in all cohorts. There was no significant difference between predicted and observed mortality rates for patients stratified by ProVent score. There was near-perfect specificity for mortality in the groups with higher ProVent scores. Areas under the curve were 0.69 and 0.75 for the 21+ days and the 14 to 20 days cohorts respectively. P values for the Hosmer-Lemeshow statistics were 0.24 for 21+ days and 0.22 for 14 to 20 days. CONCLUSIONS: The modified ProVent model was accurate in our cohort. This supports its geographic and temporal generalizability. It can also accurately identify patients at risk of 1-year mortality at Day 14 of mechanical ventilation, but additional confirmation is required. Further studies should explore the implications of adopting the model into routine use. PMID- 26418232 TI - CHILDHOOD MALTREATMENT AND THE COURSE OF DEPRESSIVE AND ANXIETY DISORDERS: THE CONTRIBUTION OF PERSONALITY CHARACTERISTICS. AB - BACKGROUND: We investigated the effect of childhood maltreatment on predicting the 4-year course of depressive and anxiety disorders and the possible mediating role of personality characteristics in the association between childhood maltreatment and illness course. METHODS: Longitudinal data in a large sample of participants with baseline depressive and/or anxiety disorders (n = 1,474, 18-65 years) were collected in the Netherlands Study of Depression and Anxiety. At baseline, childhood maltreatment was assessed with a semistructured interview. Personality trait questionnaires (Neuroticism-Extroversion-Openness Five Factor Inventory, Mastery scale, and Leiden Index of Depression Sensitivity), recent stressful life events (List of Threatening Experiences Questionnaire), and psychosocial variables were administered. The Life Chart Interview was used to determine the time to remission of depressive and/or anxiety disorders. RESULTS: At baseline, 846 participants (57.4%) reported any childhood maltreatment. Childhood maltreatment had a negative impact on psychosocial functioning and was predictive of more unfavorable personality characteristics and cognitive reactivity styles (P < 0.001). Childhood maltreatment was a significant predictor of lower likelihood of remission of depressive and/or anxiety disorders (HR = 0.94, P < 0.001). High levels of neuroticism, hopelessness, external locus of control, and low levels of extraversion were mediating the relationship between childhood maltreatment and 4-year remission of depressive and anxiety disorders. CONCLUSIONS: Certain personality characteristics are key players in the mechanism linking childhood maltreatment to an adverse illness course of depressive and anxiety disorders. Early interventions--reducing neuroticism and hopelessness, and enhancing extraversion and locus of control--might contribute to a better prognosis in a "high-risk" group of depressive and anxiety disorders. PMID- 26418233 TI - Effectiveness of benzodiazepine premedication on recovery in day-case surgery: a systematic review with meta-analysis. AB - INTRODUCTION: Benzodiazepines are frequently used as a premedication. In day-case surgery, anesthetists are reluctant to administer benzodiazepines preoperatively for reasons of delayed recovery. However, premedication with benzodiazepines might be beneficial regarding postoperative somatic symptoms/complaints (i.e. time to recovery and postoperative side effects) and psychological phenomena. EVIDENCE ACQUISITION: A systematic review with meta-analysis was performed using all important search engines. Study methodological quality was assessed using risk of bias tables. Mean differences (MD) and odds ratios (OR) were used for continuous data (time to recovery and psychological phenomena) and categorical data (postoperative somatic symptoms) respectively. Random effects modelling was applied. Nineteen studies were included. Overall time to recovery was significantly delayed in patients receiving benzodiazepines (MD 1.75; 95% CI 0.82 to 2.69) although time to discharge was not significantly affected. Postoperative side effects were significantly reduced in patients receiving benzodiazepines (OR 0.47; 95% CI 0.36 to 0.63). Regarding psychological outcome, only anxiety could be statistically analyzed showing no statistical difference (MD 1.47; 95% CI 1.01 to 3.96). EVIDENCE SYNTHESIS: Although overall time to recovery was significantly prolonged by benzodiazepine premedication, withholding premedication in day-case surgery patients is not justified for such reason, as time to discharge was not negatively affected. Furthermore, benzodiazepines show to have beneficial effects on postoperative side effects. CONCLUSIONS: For a firm conclusion regarding psychological phenomena, more research is needed. Anaesthetists should take into account this new evidence when they apply their premedication regime in day-case surgery. PMID- 26418234 TI - Mechanical ventilation on ECMO: unfinished business. PMID- 26418235 TI - Prognostic and predictive immune gene signatures in breast cancer. AB - PURPOSE OF REVIEW: Here, we focus on molecular biomarkers derived from transcriptomic studies to summarize the recent advances in our understanding of the mechanisms associated with differential prognosis and treatment outcome in breast cancer. RECENT FINDINGS: Breast cancer is certainly immunogenic; yet it has been historically resistant to immunotherapy. In the past few years, refined immunotherapeutic manipulations have been shown to be effective in a significant proportion of cancer patients. For example, drugs targeting the PD-1 immune checkpoint have been proven to be an effective therapeutic approach in several solid tumors including melanoma and lung cancer. Very recently, the activity of such therapeutics has also been demonstrated in breast cancer patients. Pari passu with the development of novel immune modulators, the transcriptomic analysis of human tumors unveiled unexpected and paradoxical relationships between cancer cells and immune cells. SUMMARY: This review examines our understanding of the molecular pathways associated with intratumoral immune response, which represents a critical step for the implementation of stratification strategies toward the development of personalized immunotherapy of breast cancer. PMID- 26418236 TI - Matrix metalloproteinases -8 and -9 in the Airways, Blood and Urine During Exacerbations of COPD. AB - Matrix metalloproteinases (MMPs) are elevated in the airways and blood of COPD patients, contributing to disease pathogenesis and tissue remodelling. However, it is not clear if MMP levels in airways, blood and urine are related or if MMP levels are related to disease severity or presence of exacerbations requiring hospitalisation. Seventy-two patients requiring hospitalisation for COPD exacerbations had serum, urine and sputum MMP-8, -9 and active MMP-9 measured by ELISA and gelatin zymography on day one, five and four weeks later (recovery). Clinical history, spirometry, COPD Assessment Test and MRC dyspnoea score were obtained. Twenty-two stable COPD patients had MMP measurements one week apart. During exacerbations, serum and urine MMP-9 were slightly elevated by 17% and 30% compared with recovery values respectively (p = 0.001 and p = 0.026). MMP-8 was not significantly changed. These MMP levels related to serum neutrophil numbers but not to outcome of exacerbations, disease severity measures or smoking status. In clinically stable patients, serum MMP levels did not vary significantly over 7 days, whereas urine MMPs varied by up to nine fold for MMP-8 (p = 0.003). Sputum, serum and urine contained different MMP species and complexes. Median values for sputum active MMP-9 were significantly different from serum (p = 0.035) and urine (p = 0.024). Serum and urine MMPs are only modestly elevated during exacerbations of COPD and unlikely to be useful biomarkers in this clinical setting. Airway, serum and urine MMP levels are independent of each other in COPD patients. Further, MMP levels are variable between patients and do not reflect airflow obstruction. PMID- 26418237 TI - LTP enhances synaptogenesis in the developing hippocampus. AB - In adult hippocampus, long-term potentiation (LTP) produces synapse enlargement while preventing the formation of new small dendritic spines. Here, we tested how LTP affects structural synaptic plasticity in hippocampal area CA1 of Long-Evans rats at postnatal day 15 (P15). P15 is an age of robust synaptogenesis when less than 35% of dendritic spines have formed. We hypothesized that LTP might therefore have a different effect on synapse structure than in adults. Theta burst stimulation (TBS) was used to induce LTP at one site and control stimulation was delivered at an independent site, both within s. radiatum of the same hippocampal slice. Slices were rapidly fixed at 5, 30, and 120 min after TBS, and processed for analysis by three-dimensional reconstruction from serial section electron microscopy (3DEM). All findings were compared to hippocampus that was perfusion-fixed (PF) in vivo at P15. Excitatory and inhibitory synapses on dendritic spines and shafts were distinguished from synaptic precursors, including filopodia and surface specializations. The potentiated response plateaued between 5 and 30 min and remained potentiated prior to fixation. TBS resulted in more small spines relative to PF by 30 min. This TBS-related spine increase lasted 120 min, hence, there were substantially more small spines with LTP than in the control or PF conditions. In contrast, control test pulses resulted in spine loss relative to PF by 120 min, but not earlier. The findings provide accurate new measurements of spine and synapse densities and sizes. The added or lost spines had small synapses, took time to form or disappear, and did not result in elevated potentiation or depression at 120 min. Thus, at P15 the spines formed following TBS, or lost with control stimulation, appear to be functionally silent. With TBS, existing synapses were awakened and then new spines formed as potential substrates for subsequent plasticity. PMID- 26418238 TI - An Evaluation of Prediction Equations for the 6 Minute Walk Test in Healthy European Adults Aged 50-85 Years. AB - OBJECTIVE: This study compared actual 6 minute walk test (6MWT) performance with predicted 6MWT using previously validated equations and then determined whether allometric modelling offers a sounder alternative to estimating 6MWT in adults aged 50-80 years. METHODS: We compared actual 6MWT performance against predicted 6MWT in 125 adults aged 50-85 years (62 male, 63 female). In a second sample of 246 adults aged 50-85 years (74 male, 172 female), a new prediction equation for 6MWT performance was developed using allometric modelling. This equation was then cross validated using the same sample that the other prediction equations were compared with. RESULTS: Significant relationships were evident between 6MWT actual and 6MWT predicted using all of the commonly available prediction equations (all P<0.05 or better) with the exception of the Alameri et al prediction equation (P>0.05). A series of paired t-tests indicated significant differences between 6MWT actual and 6MWT predicted for all available prediction equations (all P<0.05 or better) with the exception of the Iwama et al equation (P = .540). The Iwama et al equation also had similar bias (79.8m) and a coefficient of variation of over 15%. Using sample 2, a log-linear model significantly predicted 6MWT from the log of body mass and height and age (P = 0.001, adjusted R2 = .526), predicting 52.6% of the variance in actual 6MWT. When this allometric equation was applied to the original sample, the relationship between 6MWT actual and 6MWT predicted was in excess of values reported for the other previously validated prediction equations (r = .706, P = 0.001). There was a significant difference between actual 6MWT and 6MWT predicted using this new equation (P = 0.001) but the bias, standard deviation of differences and coefficient of variation were all less than for the other equations. CONCLUSIONS: Where actual assessment of the 6MWT is not possible, the allometrically derived equation presented in the current study, offers a viable alternative which has been cross validated and has the least SD of differences and smallest coefficient of variation compared to any of the previously validated equations for the 6MWT. PMID- 26418239 TI - Aseptic Meningitis Caused by Coxiella Burnetii. AB - Acute Q fever can have multiple presentations but neurologic involvement is rare. We describe the case of a 16-year-old female with severe headache and aseptic meningitis with acute Coxiella burnetii infection. PMID- 26418240 TI - Safe and Effective Prophylaxis with Bimonthly Intravenous Pentamidine in the Pediatric Hematopoietic Stem Cell Transplant Population. AB - BACKGROUND: Without prophylaxis, Pneumocystis jiroveci pneumonia (PCP) develops in 5%-15% of pediatric hematopoietic stem cell transplant (HCT) patients with mortality above 50%. Trimethoprim-sulfamethoxazole is a standard PCP prophylaxis; pentamidine is frequently used as second-line prophylaxis because of trimethoprim sulfamethoxazole's potential for cytopenias. Monthly intravenous (IV) pentamidine has variable efficacy with PCP infection rates of 0%-10% in pediatric patients, and higher breakthrough rates in those younger than 2 years. We hypothesized that bimonthly (twice monthly) pentamidine might have equivalent safety and improved efficacy; therefore, we conducted a retrospective analysis of bimonthly pentamidine PCP prophylaxis. METHODS: We retrospectively reviewed records of all pediatric HCT patients who received bimonthly IV pentamidine between December 2006 and June 2013, and collected data regarding demographics, clinical course, prophylaxis rationale, laboratory values and adverse events. RESULTS: Between December 2006 and June 2013, 111 pediatric HCT patients received bimonthly IV pentamidine (574 doses, 8758 patient-days); 31 patients were younger than 2 years at initiation. In the majority (53% of courses), pentamidine was initiated because of cytopenias. Fourteen patients (12.6% of patients, 2.4% of doses) experienced a side-effect prompting discontinuation, including 3 patients with infusion-related hypotension/anaphylaxis and 3 with acute pancreatic dysfunction. No patients [0% (95% confidence interval: 0-3.2)] developed PCP during or after bimonthly IV pentamidine prophylaxis. CONCLUSIONS: Bimonthly IV pentamidine for PCP prophylaxis in the HCT pediatric population has comparable safety to monthly IV pentamidine and was highly effective, including in the very young. Bimonthly IV pentamidine should be considered in pediatric patients as second-line PCP prophylaxis. PMID- 26418241 TI - Evaluation of Immune Response to Measles Component of MMR Vaccine in Children with HIV Infection Receiving Antiretroviral Therapy. AB - BACKGROUND: Children with HIV (CLHIV) respond poorly to primary immunization with measles vaccine and those responding tend to lose protective titer of antibodies by 2-3 years old. Revaccinating CLHIV after immune reconstitution with antiretroviral therapy (ART) may result in good seroconversion, thereby conferring them protection from measles. The objective was to study prevalence of measles antibodies in CLHIV receiving ART before and after immunization with MMR vaccine. METHODS: CLHIV in the age 5-18 years receiving ART for >6 months and with CD 4 count >15% were included in this prospective study. Their serum was assayed for IgG measles antibodies by qualitative immune-enzymatic determination using enzyme linked immunosorbent assay. The subjects were then immunized with a single dose of MMR vaccine. A repeat venous sample was assayed for measles antibodies 8-12 weeks after immunization. RESULTS: Sixty-six subjects (46 males, 20 females, mean age 10.4 +/- 2.8 years) were enrolled. The mean duration of ART was 3.4 +/- 1.5 years and median CD4 count 716.5 MU/L (interquartile range: 563.3 950). At enrollment, 16 (24.2%) subjects tested positive, 8 (12.1%) equivocal and 42 (63.6%) negative for measles antibodies. After 8-12 weeks of immunization, 62 (93.3%) tested positive, 1 (1.5%) equivocal, and 3 (4.5%) negative. There was no difference among the seropositive and seronegative subjects postimmunization with respect to age, sex, duration of ART, nutritional status, CD4 count, or WHO clinical stage. No serious adverse reaction was observed to vaccination. CONCLUSIONS: MMR vaccine leads to an excellent seroconversion to measles component of vaccine in immune-reconstituted CLHIV. PMID- 26418242 TI - Trends in Pertussis Diagnostic Testing in the United States, 1990 to 2012. AB - BACKGROUND: Reports of pertussis have been increasing in the US since the 1990s, and pertussis diagnostics have evolved during that time. Here, we describe temporal changes in pertussis diagnostic practices in the US during 1990 to 2012 and discuss potential implications. METHODS: Pertussis cases reported through the National Notifiable Diseases Surveillance System during 1990 to 2012 were included in this analysis. Laboratory results were stratified by test type, case classification, age group and case-patient state of residence. RESULTS: This analysis included 291,290 cases with 64% (n = 186,766) reporting at least 1 pertussis laboratory result. Culture and direct fluorescent antibody were the primary results reported during the early 1990s; however, polymerase chain reaction (PCR) surpassed all other test types during the late 1990s and 2000s. By 2012, more than 91% of cases with known results were tested using PCR, either alone or in combination with another test type. Before 2005, Massachusetts reported 71% of serology results, but an increasing number of states reported serologic results during 2005 to 2012. When stratified by age group, overall testing trends persist. As of 2012, culture confirmation is used infrequently across all ages, whereas the use of serology increases with age and is most prevalent among adults aged >= 20 years. CONCLUSIONS: PCR has become the primary diagnostic method, and serologic assays now are used in a majority of states. Epidemiologic trends must be considered in the context of changing diagnostic tests, and modifications to surveillance case definitions should be considered to better reflect current testing practices. PMID- 26418243 TI - Salmonella Osteomyelitis in Previously Healthy Children: Report of 4 Cases and Review of the Literature. AB - Salmonella osteomyelitis in children is an uncommon condition, typically associated with hemoglobinopathies or other underlying disorders. Only few cases have been reported in children without predisposing factors. We describe 4 cases of Salmonella osteomyelitis in otherwise healthy children. Since treatment duration is expected to be prolonged, the practice of direct inoculation of aspirates into blood culture bottles appears to be essential for diagnosis and targeted therapy. PMID- 26418244 TI - Osteomyelitis Because of Mycobacterium Xenopi in an Immunocompetent Child. AB - We present the case of a 6-year-old, immunocompetent boy with chronic osteomyelitis of the calcaneus caused by Mycobacterium xenopi. Of note, typical histopathology was not visible on the first biopsy and developed only later over a period of 6 weeks, highlighting the difficult differential diagnosis of osteomyelitis caused by nontuberculous mycobacteria. PMID- 26418245 TI - Correction: Dynamic Changes of Post-Translationally Modified Forms of CXCL10 and Soluble DPP4 in HCV Subjects Receiving Interferon-Free Therapy. PMID- 26418246 TI - Coordinating Electron Transport Chains to an Electron Donor. AB - Two electron transport chains (2 and 3) featuring two fullerenes with different electron acceptor strengths have been synthesized, characterized, and coordinated to a light harvesting/electron donating zinc porphyrin. Electrochemical assays corroborate the redox gradients along the designed electron transport chains, and complementary absorption and fluorescence titrations prove the assembly of ZnP-2 and ZnP-3 hybrids. PMID- 26418247 TI - Genome Wide Association Analysis Reveals New Production Trait Genes in a Male Duroc Population. AB - In this study, 796 male Duroc pigs were used to identify genomic regions controlling growth traits. Three production traits were studied: food conversion ratio, days to 100 KG, and average daily gain, using a panel of 39,436 single nucleotide polymorphisms. In total, we detected 11 genome-wide and 162 chromosome wide single nucleotide polymorphism trait associations. The Gene ontology analysis identified 14 candidate genes close to significant single nucleotide polymorphisms, with growth-related functions: six for days to 100 KG (WT1, FBXO3, DOCK7, PPP3CA, AGPAT9, and NKX6-1), seven for food conversion ratio (MAP2, TBX15, IVL, ARL15, CPS1, VWC2L, and VAV3), and one for average daily gain (COL27A1). Gene ontology analysis indicated that most of the candidate genes are involved in muscle, fat, bone or nervous system development, nutrient absorption, and metabolism, which are all either directly or indirectly related to growth traits in pigs. Additionally, we found four haplotype blocks composed of suggestive single nucleotide polymorphisms located in the growth trait-related quantitative trait loci and further narrowed down the ranges, the largest of which decreased by ~60 Mb. Hence, our results could be used to improve pig production traits by increasing the frequency of favorable alleles via artificial selection. PMID- 26418248 TI - PKC-Dependent GlyT1 Ubiquitination Occurs Independent of Phosphorylation: Inespecificity in Lysine Selection for Ubiquitination. AB - Neurotransmitter transporter ubiquitination is emerging as the main mechanism for endocytosis and sorting of cargo into lysosomes. In this study, we demonstrate PKC-dependent ubiquitination of three different isoforms of the glycine transporter 1 (GlyT1). Incubation of cells expressing transporter with the PKC activator phorbol ester induced a dramatic, time-dependent increase in GlyT1 ubiquitination, followed by accumulation of GlyT1 in EEA1 positive early endosomes. This occurred via a mechanism that was abolished by inhibition of PKC. GlyT1 endocytosis was confirmed in both retinal sections and primary cultures of mouse amacrine neurons. Replacement of only all lysines in the N-and C-termini to arginines prevented ubiquitination and endocytosis, displaying redundancy in the mechanism of ubiquitination. Interestingly, a 40-50% reduction in glycine uptake was detected in phorbol-ester stimulated cells expressing the WT-GlyT1, whereas no significant change was for the mutant protein, demonstrating that endocytosis participates in the reduction of uptake. Consistent with previous findings for the dopamine transporter DAT, ubiquitination of GlyT1 tails functions as sorting signal to deliver transporter into the lysosome and removal of ubiquitination sites dramatically attenuated the rate of GlyT1 degradation. Finally, we showed for the first time that PKC-dependent GlyT1 phosphorylation was not affected by removal of ubiquitination sites, suggesting separate PKC-dependent signaling events for these posttranslational modifications. PMID- 26418250 TI - Impact of cyclin-dependent kinase CDK4 inhibition on eryptosis. AB - BACKGROUND/AIMS: The cyclin-dependent kinase 4 (CDK4) participates in the regulation of apoptosis of nucleated cells by altering transcriptional regulation of genes governing cell proliferation and cell death. Similar to apoptosis of nucleated cells, erythrocytes may enter eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine (PS) exposure at the cell surface. As mature erythrocytes lack nuclei, acute stimulation of eryptosis cannot result from altered gene expression. Eryptosis is triggered by isotonic cell shrinkage following Cl- removal (replacement with the impermeant organic anion gluconate) or by oxidative stress (exposure to 0.3 mM tertbutyl hydroperoxide [tBOOH]). The present study explored whether CDK4 is expressed in erythrocytes and whether the CDK4 inhibitors II (NSC625987) and III (ryuvidine) influence eryptosis. METHODS: Western blotting was utilized for determination of the presence of CDK4 protein in human erythrocytes, and FACS analysis to determine Fluo3 fluorescence (reflecting cytosolic Ca2+), annexin-V-binding (reflecting PS-exposure) and forward scatter (reflecting cell volume). RESULTS: CDK4 protein was present in human erythrocytes. Cl- removal was followed by decrease of forward scatter and increase of both annexin-V-binding and Fluo3 fluorescence, an effect significantly curtailed by CDK4 inhibitors II and III. Furthermore, CDK4 inhibition blunted enhanced PS-exposure elicited by tBOOH treatment. CONCLUSIONS: The present observations disclose the presence of CDK4 protein in human erythrocytes and the suppression of suicidal erythrocyte death by pharmacological inhibition of CDK4. PMID- 26418249 TI - Predicting Anticancer Drug Responses Using a Dual-Layer Integrated Cell Line-Drug Network Model. AB - The ability to predict the response of a cancer patient to a therapeutic agent is a major goal in modern oncology that should ultimately lead to personalized treatment. Existing approaches to predicting drug sensitivity rely primarily on profiling of cancer cell line panels that have been treated with different drugs and selecting genomic or functional genomic features to regress or classify the drug response. Here, we propose a dual-layer integrated cell line-drug network model, which uses both cell line similarity network (CSN) data and drug similarity network (DSN) data to predict the drug response of a given cell line using a weighted model. Using the Cancer Cell Line Encyclopedia (CCLE) and Cancer Genome Project (CGP) studies as benchmark datasets, our single-layer model with CSN or DSN and only a single parameter achieved a prediction performance comparable to the previously generated elastic net model. When using the dual layer model integrating both CSN and DSN, our predicted response reached a 0.6 Pearson correlation coefficient with observed responses for most drugs, which is significantly better than the previous results using the elastic net model. We have also applied the dual-layer cell line-drug integrated network model to fill in the missing drug response values in the CGP dataset. Even though the dual layer integrated cell line-drug network model does not specifically model mutation information, it correctly predicted that BRAF mutant cell lines would be more sensitive than BRAF wild-type cell lines to three MEK1/2 inhibitors tested. PMID- 26418251 TI - Astrocyte elevated gene-1 increases invasiveness of NSCLC through up-regulating MMP7. AB - BACKGROUND/AIMS: The aggressive manner of non-small cell lung cancer (NSCLC) cells accounts for the majority of the lethality of the disease. Recently, increased astrocyte elevated gene-1 (AEG-1) levels have been shown to closely correlate with poor prognosis of NSCLC, whereas the underlying mechanisms are not clear. METHODS: We examined the AEG-1 and matrix metalloproteinase 7 (MMP7) levels in NSCLC tissues, compared to the paired adjacent non-tumor lung tissue. We modulated AEG-1 levels in NSCLC cells, and examined its effects on MMP7 levels by RT-qPCR, on cellular protein by Western blot, and on secreted protein by ELISA. We also examined the cell invasiveness in AEG-1-modified NSCLC cells in a transwell cell migration assay. We used specific signal pathway inhibitors to treat AEG-1-modified NSCLC cells and examined its effects on MMP7. RESULTS: AEG-1 and MMP7 levels were both significantly increased in NSCLC tissues, compared to the paired adjacent non-tumor lung tissue. The AEG-1 and MMP7 levels were strongly correlated. Overexpression of AEG-1 in NSCLC cells significantly increased MMP7 levels and cell invasiveness, while AEG-1 depletion in NSCLC cells significantly decreased MMP7 levels and cell invasiveness. Application of a specific MAPK-p42/p44 inhibitor, but not application of specific inhibitors for MAPK-p38, PI3k/Akt, or JNK signaling pathways, to AEG-1-overexpressing NSCLC cells substantially abolished the AEG-1-mediated MMP7 up regulation. CONCLUSION: AEG-1 promotes NSCLC cell invasiveness through MAPK-p42/p44-dependent activation of MMP7. PMID- 26418252 TI - Stimulating effect of a newly synthesized sulfonamido-based gallate on articular chondrocytes in vitro. AB - BACKGROUND: The phenotype of chondrocyte is easy to be lost when expanded in vitro by a process defined "dedifferentiation". Traditional growth factors such as transforming growth factor (TGF-beta1) are effective in preventing of dedifferentiation, but high costs and loss of activity limited their use. It is of significance to find substitutes which can reduce dedifferentiation and preserve chondrocytes phenotype to ensure sufficient differentiated cells for further study. METHODS: We synthesized new type of sulfonamido-based gallates named ZXHA-C and investigated its effect on primary articular chondrocytes of rats. After preliminary screening by cytotoxicity test, ZXHA-C of 1.06 * 10-8, 1.06 * 10-7 and 1.06 * 10-6M were chosen for further studies. Cell proliferation, morphology, viability, GAG synthesis and cartilage specific gene expression were detected. Also the effects of ZXHA-C on Wnt/beta-catenin signaling pathway were investigated. RESULTS: ZXHA-C could significantly promote chondrocytes growth. And it could enhance ECM synthesis by up-regulating expression levels of cartilage specific markers like aggrecan, collagen II and Sox9. Expression of collagen I which marked chondrocytes dedifferentiation was also significantly down-regulated after treated by ZXHA-C. Further exploration of the molecular mechanism indicated that ZXHA-C activated the Wnt/beta-catenin signal pathway in chondrocytes, as evidenced by up-regulated gene expression of beta-catenin, Wnt 4, cyclin D1 and Frizzled-2 and decreased glycogen synthase kinase 3beta (GSK 3beta). Among the various concentrations, ZXHA-C of 1.06 * 10-7 M showed the best performance, which was close to positive control (group with TGF-beta1). CONCLUSION: ZXHA-C might be potential a novel agent for the maintenances of chondrocytes phenotype. PMID- 26418253 TI - Placental growth factor promotes metastases of non-small cell lung cancer through MMP9. AB - BACKGROUND/AIMS: Neovascularization and invasion coordinate cancer metastases in non-small cell lung cancer (NSCLC). However, the underlying molecular mechanisms are poorly understood. Recently, a substantial role of placental growth factor (PLGF) in cancer cell invasion has been acknowledged in several types of cancer, whereas a possible involvement of PLGF in the metastases of NSCLC has not been studied. METHODS: Here, we analyzed the levels of PLGF and matrix metalloproteinase 9 (MMP9) in NSCLC specimens. We modified either PLGF or MMP9 levels in a NSCLC cell line A549, and examined the effects on the levels of MMP9 and PLGF. The cell invasiveness was quantified in a transwell cell migration assay. Pathway inhibitors were applied to determine the molecular mechanisms underlying the control of MMP9 by PLGF. RESULTS: We found that PLGF and MMP9 levels both significantly increased in the NSCLC specimens and were strongly correlated. Overexpression of PLGF in NSCLC cells increased the levels of MMP9 and cell invasiveness, while inhibition of PLGF in NSCLC cells decreased the levels of MMP9 and cell invasiveness. However, modification of MMP9 levels in NSCLC cells did not alter the levels of PLGF. These data suggest that PLGF may regulate MMP9 in NSCLC cells, but not vice versa. Moreover, inhibition of MMP9 in PLGF-overexpressing NSCLC cells abolished the effects of PLGF on cell invasiveness, suggesting that PLGF increases cell invasion via MMP9. Furthermore, suppression of MAPK-p38, but not suppression of either MAPK-p42/p44, or PI3k, or JNK signaling, substantially abolished the effect of PLGF on MMP9, suggesting that PLGF may activate MMP9 via MAPK-p38 signaling pathway. CONCLUSION: PLGF stimulated cancer invasion may be mediated through its effects on MMP9 activation in NSCLC cells. PMID- 26418254 TI - The mechanism of radiosensitization by YM155, a novel small molecule inhibitor of survivin expression, is associated with DNA damage repair. AB - BACKGROUND/AIMS: Survivin, a member of the inhibitor of apoptosis protein family, is an attractive target for cancer therapy. We investigated the effects of YM155, a small molecule inhibitor of survivin expression, on the radiosensitivity of human non-small cell lung cancer (NSCLC) cell lines and elucidated a relationship between the cellular localization of survivin and DNA double-strand break repair. METHODS: The cellular distribution of survivin was determined by Western blotting of subcellular fractions and by immunofluorescent staining in A549 NSCLC cells. Radiation-induced DNA damage was evaluated based on histone H2AX phosphorylation and foci formation. The relationship between the cellular localization of survivin and DNA double-strand break repair was analyzed by Western blotting and co-immunoprecipitations. RESULTS: YM155 down-regulated survivin expression in NSCLC cells in a concentration- and time-dependent manner. An in vitro clonogenic survival assay revealed that YM155 increased the sensitivity of NSCLC cells to radiation. After irradiation, we observed a rapid accumulation of survivin in the nucleus. An immunofluorescent analysis of histone x03B3;-H2AX demonstrated that the inhibition of survivin expression by YM155 resulted in impaired DNA double strand break repair. Co-immunoprecipitation assays using nuclear extracts revealed an interaction between survivin, Ku70, x03B3;-H2AX, and DNA-PKcs. Furthermore, S2056 autophosphorylation of DNA-PKcs was reduced in survivin depleted cells. CONCLUSIONS: These results suggested that YM155 sensitized NSCLC cells to radiation, at least in part by inhibiting DNA repair and enhancing apoptosis via the down-regulation of survivin expression. YM155 pretreatment inhibited DNA-PKcs autophosphorylation at S2056. Nuclear survivin was involved in DNA double-strand break repair via interactions with members of the DNA double strand break repair machinery. PMID- 26418255 TI - The Underlying Social Dynamics of Paradigm Shifts. AB - We develop here a multi-agent model of the creation of knowledge (scientific progress or technological evolution) within a community of researchers devoted to such endeavors. In the proposed model, agents learn in a physical-technological landscape, and weight is attached to both individual search and social influence. We find that the combination of these two forces together with random experimentation can account for both i) marginal change, that is, periods of normal science or refinements on the performance of a given technology (and in which the community stays in the neighborhood of the current paradigm); and ii) radical change, which takes the form of scientific paradigm shifts (or discontinuities in the structure of performance of a technology) that is observed as a swift migration of the knowledge community towards the new and superior paradigm. The efficiency of the search process is heavily dependent on the weight that agents posit on social influence. The occurrence of a paradigm shift becomes more likely when each member of the community attaches a small but positive weight to the experience of his/her peers. For this parameter region, nevertheless, a conservative force is exerted by the representatives of the current paradigm. However, social influence is not strong enough to seriously hamper individual discovery, and can act so as to empower successful individual pioneers who have conquered the new and superior paradigm. PMID- 26418256 TI - Tissue Factor Noncoagulant Signaling: Mechanisms and Implications for Cell Migration and Apoptosis. AB - Tissue factor (TF) is a 47-kDa transmembrane glycoprotein and the main initiator of the blood coagulation cascade. Binding to its ligand factor VIIa (FVIIa) also initiates noncoagulant signaling with broad biological implications. In this review, we discuss how TF interacts with other cell-surface proteins, which affect biological functions such as cell migration and cell survival. A vast number of publications have demonstrated the importance of TF-induced activation of protease-activated receptors, but recently published research has indicated a more complicated picture. As it has been discovered that TF interacts with integrins and receptor tyrosine kinases, novel signaling mechanisms for the TF/FVIIa complex have been presented. The knowledge of these new aspects of TF signaling may, for instance, facilitate the development of new treatment strategies for cancer and acute coronary syndromes, two examples of diseases characterized by aberrant TF expression and signaling. PMID- 26418257 TI - The Sound of a Buk (Korean Traditional Drum) Attenuates Anaphylactic Reactions by the Activation of Estrogen Receptor-beta. AB - BACKGROUND: Anaphylaxis is associated with systemic vasodilation that causes low blood pressure and induces hypoxic brain damage. The sound of a Buk (Korean traditional drum) is similar to the human heart beat and affects blood pressure, heart rate, and the nervous system by increasing physiological excitation and sympathetic nervous system activity. So, this study focused on the effect of Buk music as a means of treating anaphylaxis. METHODS: Mice were given an intraperitoneal injection of compound 48/80 (6.5 mg/kg, a mast cell degranulator). After compound 48/80 injection, mice were exposed to Buk music and white noise for 5 min in a sound isolation booth. The mortality rate was checked over the next 40 min. Levels of hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in the serum and brain tissues were analyzed by Western blotting, quantitative real-time PCR, and ELISA methods. RESULTS: Exposure to Buk music significantly reduced compound 48/80-induced mortality and histamine release, as well as HIF-1alpha and VEGF levels compared with the compound 48/80 group or compound 48/80 and white noise group. Buk music also reduced levels of tumor necrosis factor-alpha, and significantly increased estrogen receptor-beta mRNA levels. CONCLUSION: These results indicate that Buk music has potential for the treatment of anaphylaxis. PMID- 26418258 TI - Diffusion of Hydration Water around Intrinsically Disordered Proteins. AB - Hydration water dynamics around globular proteins have attracted considerable attention in the past decades. This work investigates the hydration water dynamics around partially/fully intrinsically disordered proteins and compares it to that of the globular proteins via molecular dynamics simulations. The translational diffusion of the hydration water is examined by evaluating the mean square displacement and the velocity autocorrelation function, while the rotational diffusion is probed through the dipole-dipole time correlation function. The results reveal that the translational and rotational motions of water molecules at the surface of intrinsically disordered proteins/regions are less restricted as compared to those around globular proteins/ordered regions, which is reflected in their higher diffusion coefficient and lower orientational relaxation time. The restricted mobility of hydration water in the vicinity of the protein leads to a sublinear diffusion in a heterogeneous interface. A positive correlation between the mean number of hydrogen bonds and the diffusion coefficient of hydration water implies higher mobility of water molecules at the surface of disordered proteins, which is due to their higher number of hydrogen bonds. Enhanced hydration water mobility around disordered proteins/regions is also related to their higher hydration capacity, low hydrophobicity, and increased internal protein motions. Thus, we generalize that the intrinsically disordered proteins/regions are associated with higher hydration water mobility as compared to globular protein/ordered regions, which may help to elucidate their varied functional specificity. PMID- 26418259 TI - Oral Nutritional Supplements and Taste Adherence in Malnourished Adults Inpatients, Effect on Adhesion during Hospital Stance. AB - AIM: The aim of our study was to evaluate a hypercaloric sweet milk-based oral nutrition supplement in a prospective 3-day study designed to assess the taste preferences of this oral nutritional supplement (ONS) in malnourished inpatients and the influence on adherence in daily intake. METHODS: A total of 46 in patients with recent weight loss were included in this study. One flavor (chocolate, vanilla or strawberry) was administered each day in a random way to each patient during 3 consecutive days. In the first 3 days, patients were asked to fill 2 questionnaires intended for reflecting ONS tolerance and acceptance. RESULTS: Sweet was better for chocolate flavor (3.9 +/- 2.4 points) than for vanilla flavor (2.7 +/- 2.3 points; p < 0.02) and strawberry flavor (3.1 +/- 2.3 points; p < 0.01). Chocolate flavored ONSs were rated as having more aftertaste (3.4 +/- 2.1 points) than vanilla (2.4 +/- 2.1 points; p < 0.01) and strawberry (2.6 +/- 1.5 points; p < 0.03). Patients who chose chocolate took a total of 20.7 +/- 20.9 average bricks during hospitalization (1.95 +/- 0.2 per day), patients who chose vanilla took 18.6 +/- 21.0 bricks (1.90 +/- 0.7 per day) and finally patients who chose strawberry took 14.5 +/- 13.5 bricks during admission (1.78 +/ 0.1 per day; p < 0.01). CONCLUSIONS: The taste preferences of all the ONSs are similar although the consumption is high in chocolate flavored ONS during hospitalization. Sweetness may have influenced this finding. PMID- 26418261 TI - Mixed Wastewater Coupled with CO2 for Microalgae Culturing and Nutrient Removal. AB - Biomass, nutrient removal capacity, lipid productivity and morphological changes of Chlorella sorokiniana and Desmodesmus communis were investigated in mixed wastewaters with different CO2 concentrations. Under optimal condition, which was 1:3 ratio of swine wastewater to second treated municipal wastewater with 5% CO2, the maximum biomass concentrations were 1.22 g L-1 and 0.84 g L-1 for C. sorokiniana and D. communis, respectively. Almost all of the ammonia and phosphorus were removed, the removal rates of total nitrogen were 88.05% for C. sorokiniana and 83.18% for D. communis. Lipid content reached 17.04% for C. sorokiniana and 20.37% for D. communis after 10 days culture. CO2 aeration increased intracellular particle numbers of both microalgae and made D. communis tend to be solitary. The research suggested the aeration of CO2 improve the tolerance of microalgae to high concentration of NH4-N, and nutrient excess stress could induce lipid accumulation of microalgae. PMID- 26418260 TI - Initial Health Assessments and HIV Screening under the Affordable Care Act. AB - BACKGROUND: The Centers for Disease Control and Prevention (CDC) estimates that 156,300 (95% CI 144,100-165,900) Americans living with HIV in 2012 were unaware of their infection. To increase knowledge of HIV status, CDC guidelines seek to make HIV screening a routine part of medical care. This paper examines how routinely California primary care providers test for HIV and how providers' knowledge of California's streamlined testing requirements, use of sexual histories, and having an electronic medical record prompt for HIV testing, relate to test offers. METHODS: We surveyed all ten California health plans offered under health reform's Insurance Exchange (response rate = 50%) and 322 primary care providers to those plans (response rate = 19%) to assess use of HIV screening and risk assessments. RESULTS: Only 31.7% of 60 responding providers reported offering HIV tests to all or most new enrollees and only 8.8% offered an HIV test of blood samples all or most of the time despite the California law requiring that providers offer HIV testing of blood samples in primary care settings. Twenty-eight of the 60 providers (46.6%) were unaware that California had reduced barriers to HIV screening by eliminating the requirement for written informed consent and pre-test counseling. HIV screening of new enrollees all or most of the time was reported by 53.1% of the well-informed providers, but only 7.1% of the less informed providers, a difference of 46 percentage points (95% CI: 21.0%-66.5%). Providers who routinely obtained sexual histories were 29 percentage points (95% CI: 0.2%-54.9%) more likely to screen for HIV all or most of the time than those who did not ask sexual histories. CONCLUSION: Changing HIV screening requirements is important, but not sufficient to make HIV testing a routine part of medical care. Provider education to increase knowledge about the changed HIV testing requirements could positively impact testing rates. PMID- 26418263 TI - Audit of Research Data. PMID- 26418262 TI - Germinal Center Kinases SmKIN3 and SmKIN24 Are Associated with the Sordaria macrospora Striatin-Interacting Phosphatase and Kinase (STRIPAK) Complex. AB - The striatin-interacting phosphatase and kinase (STRIPAK) complex is composed of striatin, protein phosphatase PP2A and protein kinases that regulate development in animals and fungi. In the filamentous ascomycete Sordaria macrospora, it is required for fruiting-body development and cell fusion. Here, we report on the presence and function of STRIPAK-associated kinases in ascomycetes. Using the mammalian germinal center kinases (GCKs) MST4, STK24, STK25 and MINK1 as query, we identified the two putative homologs SmKIN3 and SmKIN24 in S. macrospora. A BLASTP search revealed that both kinases are conserved among filamentous ascomycetes. The physical interaction of the striatin homolog PRO11 with SmKIN3 and SmKIN24 were verified by yeast two-hybrid (Y2H) interaction studies and for SmKIN3 by co-Immunoprecipitation (co-IP). In vivo localization found that both kinases were present at the septa and deletion of both Smkin3 and Smkin24 led to abnormal septum distribution. While deletion of Smkin3 caused larger distances between adjacent septa and increased aerial hyphae, deletion of Smkin24 led to closer spacing of septa and to sterility. Although phenotypically distinct, both kinases appear to function independently because the double-knockout strain DeltaSmkin3/DeltaSmkin24 displayed the combined phenotypes of each single deletion strain. PMID- 26418264 TI - Identification of MicroRNAs in Zebrafish Spermatozoa. AB - MicroRNAs (miRNAs) participate in almost all biological processes. Plenty of evidences show that some testis- or spermatozoa-specific miRNAs play crucial roles in the process of gonad and germ cell development. In this study, the spermatozoa miRNA profiles were investigated through a combination of illumina deep sequencing and bioinformatics analysis in zebrafish. Deep sequencing of small RNAs yielded 11,820,680 clean reads. By mapping to the zebrafish genome, we identified 400 novel and 204 known miRNAs that could be grouped into 104 families. Furthermore, we selected the six highest expressions of known miRNAs to detect their expression patterns in different tissues by stem-loop quantitative real-time polymerase chain reaction. We found that among the six miRNAs, dre-miR 202-5p displayed specific and high expression in zebrafish spermatozoa and testis. Fluorescence in situ hybridization analysis indicated that dre-miR-202-5p was predominantly expressed in all kind of germ cells at different spermatogenetic stages, including spermatogonia and spermatozoa, but barely expressed in the germ cells in the ovary. This sex-biased expression pattern suggests that dre-miR-202-5p might be related to spermatogenesis and the functioning of spermatozoa. The identification of miRNAs in zebrafish spermatozoa and germ cells offers new insights into the spermatogenesis and spermatozoa in the teleost and other vertebrates. PMID- 26418265 TI - Pyridoxine deficiency in adult patients with status epilepticus. AB - An 8-year-old girl treated at our facility for superrefractory status epilepticus was found to have a low pyridoxine level at 5 MUg/L. After starting pyridoxine supplementation, improvement in the EEG for a 24-hour period was seen. We decided to look at the pyridoxine levels in adult patients admitted with status epilepticus. We reviewed the records on patients admitted to the neurological ICU for status epilepticus (SE). Eighty-one adult patients were identified with documented pyridoxine levels. For comparison purposes, we looked at pyridoxine levels in outpatients with epilepsy (n=132). Reported normal pyridoxine range is >10 ng/mL. All but six patients admitted for SE had low normal or undetectable pyridoxine levels. A selective pyridoxine deficiency was seen in 94% of patients with status epilepticus (compared to 39.4% in the outpatients) which leads us to believe that there is a relationship between status epilepticus and pyridoxine levels. PMID- 26418266 TI - Charge-transfer complex versus sigma-complex formed between TiO2 and bis(dicyanomethylene) electron acceptors. AB - A novel group of organic-inorganic hybrid materials is created by the combination of titanium dioxide (TiO2) nanoparticles with bis(dicyanomethylene) (TCNX) electron acceptors. The TiO2-TCNX complex is produced by the nucleophilic addition reaction between a hydroxy group on the TiO2 surface and TCNX, with the formation of a sigma-bond between them. The nucleophilic addition reaction generates a negatively-charged diamagnetic TCNX adsorbate that serves as an electron donor. The sigma-bonded complex characteristically shows visible-light absorption due to interfacial charge-transfer (ICT) transitions. In this paper, we report on another kind of complex formation between TiO2 and TCNX. We have systematically studied the structures and visible-light absorption properties of the TiO2-TCNX complexes, with changing the electron affinity of TCNX. We found that TCNX acceptors with lower electron affinities form charge-transfer complexes with TiO2 without the sigma-bond formation. The charge-transfer complexes show strong visible-light absorption due to interfacial electronic transitions with little charge-transfer nature, which are different from the ICT transitions in the sigma-bond complexes. The charge-transfer complexes induce efficient light-to current conversions due to the interfacial electronic transitions, revealing the high potential for applications to light-energy conversions. Furthermore, we demonstrate that the formation of the two kinds of complexes is selectively controlled by the electron affinity of TCNX. PMID- 26418267 TI - Depression or anxiety: which is best able to predict patterns of lateralisation for the processing of emotional faces? AB - Previous research has shown that both anxiety and depression are associated with strength of lateralisation for the processing of emotive faces, although these clinical measures have always been considered in separate studies. In the present study, we measure depression and anxiety, within the same non-clinical sample, and consider whether these variables can predict strength of lateralisation, measured using the chimeric faces test. There are two key findings from this study. First, for females only, anxiety is negatively associated with right hemispheric superiority for processing of negative emotional expressions. Second, there was only one finding for depression, showing a relationship with strength of lateralisation for the processing of fearful faces that differed according to sex. PMID- 26418268 TI - S-palmitoylation and the regulation of NCX1. PMID- 26418269 TI - Does ulnar nerve dislocation at the elbow cause neuropathy: What do we learn? PMID- 26418270 TI - The Informatics Challenges Facing Biobanks: A Perspective from a United Kingdom Biobanking Network. AB - The challenges facing biobanks are changing from simple collections of materials to quality-assured fit-for-purpose clinically annotated samples. As a result, informatics awareness and capabilities of a biobank are now intrinsically related to quality. A biobank may be considered a data repository, in the form of raw data (the unprocessed samples), data surrounding the samples (processing and storage conditions), supplementary data (such as clinical annotations), and an increasing ethical requirement for biobanks to have a mechanism for researchers to return their data. The informatics capabilities of a biobank are no longer simply knowing sample locations; instead the capabilities will become a distinguishing factor in the ability of a biobank to provide appropriate samples. There is an increasing requirement for biobanking systems (whether in-house or commercially sourced) to ensure the informatics systems stay apace with the changes being experienced by the biobanking community. In turn, there is a requirement for the biobanks to have a clear informatics policy and directive that is embedded into the wider decision making process. As an example, the Breast Cancer Campaign Tissue Bank in the UK was a collaboration between four individual and diverse biobanks in the UK, and an informatics platform has been developed to address the challenges of running a distributed network. From developing such a system there are key observations about what can or cannot be achieved by informatics in isolation. This article will highlight some of the lessons learned during this development process. PMID- 26418271 TI - An analysis of the outcomes of cervical cone biopsies performed in a low resource setting. AB - Following skills transfer to this low resource setting, we carried out a descriptive analysis of the outcomes of all cone biopsies performed for women with cervical intra-epithelial neoplasia 3 (CIN 3). We also compared two methods of cone biopsy. All the women had follow-up smear tests at 6 and 18 months. There were no cases of CIN 3 at follow-up. 80% had normal smears at 18 months and 20% had CIN 1. Compared with knife cone biopsy, women who had an electric knife (hand held diathermy blade) cone biopsy had a significantly smaller volume of mean blood loss (55.5mls +/- 15.9 vs 153.3ml +/- 40, p < 0.001). With appropriate skills transfer, women with CIN 3 in a low resource setting can be effectively treated with conisation procedures. The diathermy knife is preferred to cold knife because of its associated low blood loss. PMID- 26418272 TI - Enzymatic Polymerization of Furan-2,5-Dicarboxylic Acid-Based Furanic-Aliphatic Polyamides as Sustainable Alternatives to Polyphthalamides. AB - Furan-2,5-dicarboxylic acid (FDCA)-based furanic-aliphatic polyamides can be used as promising sustainable alternatives to polyphthalamides (semiaromatic polyamides) and be applied as high performance materials with great commercial interest. In this study, poly(octamethylene furanamide) (PA8F), an analog to poly(octamethylene terephthalamide) (PA8T), is successfully produced via Novozym 435 (N435)-catalyzed polymerization, using a one-stage method in toluene and a temperature-varied two-stage method in diphenyl ether, respectively. The enzymatic polymerization results in PA8F with high weight-average molecular weight (M(w)) up to 54000 g/mol. Studies on the one-stage enzymatic polymerization in toluene indicate that the molecular weights of PA8F increase significantly with the concentration of N435; with an optimal reaction temperature of 90 degrees C. The temperature-varied, two-stage enzymatic polymerization in diphenyl ether yields PA8F with higher molecular weights, as compared to the one-stage procedure, at higher reaction temperatures. MALDI-ToF MS analysis suggests that eight end groups are present in the obtained PA8F: ester/amine, ester/ester, amine/amine, acid/amine, ester/acid, acid/acid, ester/amide, and no end groups (cyclic). Compared to PA8T, the obtained PA8F possesses a similar Tg and similar crystal structures, a comparable Td, but a lower Tm. PMID- 26418273 TI - Regulation of alkane degradation pathway by a TetR family repressor via an autoregulation positive feedback mechanism in a Gram-positive Dietzia bacterium. AB - n-Alkanes are ubiquitous in nature and serve as important carbon sources for both Gram-positive and Gram-negative bacteria. Hydroxylation of n-alkanes by alkane monooxygenases is the first and most critical step in n-alkane metabolism. However, regulation of alkane degradation genes in Gram-positive bacteria remains poorly characterized. We therefore explored the transcriptional regulation of an alkB-type alkane hydroxylase-rubredoxin fusion gene, alkW1, from Dietzia sp. DQ12 45-1b. The alkW1 promoter was characterized and so was the putative TetR family regulator, AlkX, located downstream of alkW1 gene. We further identified an unusually long 48 bp inverted repeat upstream of alkW1 and demonstrated the binding of AlkX to this operator. Analytical ultracentrifugation and microcalorimetric results indicated that AlkX formed stable dimers in solution and two dimers bound to one operator in a positive cooperative fashion characterized by a Hill coefficient of 1.64 (+/- 0.03) [k(D) = 1.06 (+/- 0.16) MUM, k(D) ' = 0.05 (+/- 0.01) MUM]. However, the DNA-binding affinity was disrupted in the presence of long-chain fatty acids (C10-C24), suggesting that AlkX can sense the concentrations of n-alkane degradation metabolites. A model was therefore proposed where AlkX controls alkW1 expression in a metabolite dependent manner. Bioinformatic analysis revealed that the alkane hydroxylase gene regulation mechanism may be common among Actinobacteria. PMID- 26418274 TI - Leptin levels are reduced by intravenous ghrelin administration and correlated with cue-induced alcohol craving. AB - Increasing evidence supports the role of appetite-regulating pathways, including ghrelin and leptin, in alcoholism. This study tested the hypothesis that intravenous exogenous ghrelin administration acutely decreases endogenous serum leptin levels, and that changes in leptin levels negatively correlate with alcohol craving. This was a double-blind, placebo-controlled human laboratory study. Non-treatment-seeking, alcohol-dependent, heavy drinkers (n=45) were randomized to receive intravenous ghrelin or placebo, followed by a cue reactivity procedure, during which participants were exposed to neutral (juice) and alcohol trial cues. There was a main effect for intravenous ghrelin administration, compared with placebo, in reducing serum leptin levels (P<0.01). Post hoc analysis showed significant differences in serum leptin levels at the alcohol trial (P<0.05) that persisted at the end of the experiment (P<0.05). By contrast, there were no significant differences in serum leptin levels at the juice trial (P=not significant (NS)). The change of serum leptin level at the alcohol trial correlated with the increase in alcohol urge (P<0.05), whereas urge to drink juice was not correlated with the leptin change at the juice trial (P=NS). These findings provide preliminary evidence of ghrelin-leptin cross-talk in alcoholic individuals and suggest that their relationship may have a role in alcohol craving. PMID- 26418275 TI - Children with autism spectrum disorders, who improved with a luteolin-containing dietary formulation, show reduced serum levels of TNF and IL-6. AB - Autism spectrum disorders (ASDs) have been associated with brain inflammation as indicated by microglia activation, as well as brain expression and increased plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF). Here we report that serum levels of IL-6 and TNF were elevated (61.95 +/- 94.76 pg ml(-1) and 313.8 +/- 444.3 pg ml(-1), respectively) in the same cohort of patients with elevated serum levels of corticotropin-releasing hormone (CRH) and neurotensin (NT), while IL-9, IL-31 and IL-33 were not different from controls. The elevated CRH and NT levels did not change after treatment with a luteolin-containing dietary formulation. However, the mean serum IL-6 and TNF levels decreased significantly (P=0.036 and P=0.015, respectively) at the end of the treatment period (26 weeks) as compared with levels at the beginning; these decreases were strongly associated with children whose behavior improved the most after luteolin formulation treatment. Our results indicate that there are distinct subgroups of children within the ASDs that may be identifiable through serum levels of IL-6 and TNF and that these cytokines may constitute distinct prognostic markers for at least the beneficial effect of luteolin formulation. PMID- 26418276 TI - Effects of depressive symptoms and peripheral DAT methylation on neural reactivity to alcohol cues in alcoholism. AB - In alcohol-dependent (AD) patients, alcohol cues induce strong activations in brain areas associated with alcohol craving and relapse, such as the nucleus accumbens (NAc) and amygdala. However, little is known about the influence of depressive symptoms, which are common in AD patients, on the brain's reactivity to alcohol cues. The methylation state of the dopamine transporter gene (DAT) has been associated with alcohol dependence, craving and depression, but its influence on neural alcohol cue reactivity has not been tested. Here, we compared brain reactivity to alcohol cues in 38 AD patients and 17 healthy controls (HCs) using functional magnetic resonance imaging and assessed the influence of depressive symptoms and peripheral DAT methylation in these responses. We show that alcoholics with low Beck's Depression Inventory scores (n=29) had higher cue induced reactivity in NAc and amygdala than those with mild/moderate depression scores (n=9), though subjective perception of craving was higher in those with mild/moderate depression scores. We corroborated a higher DAT methylation in AD patients than HCs, and showed higher DAT methylation in AD patients with mild/moderate than low depression scores. Within the AD cohort, higher methylation predicted craving and, at trend level (P=0.095), relapse 1 year after abstinence. Finally, we show that amygdala cue reactivity correlated with craving and DAT methylation only in AD patients with low depression scores. These findings suggest that depressive symptoms and DAT methylation are associated with alcohol craving and associated brain processes in alcohol dependence, which may have important consequences for treatment. Moreover, peripheral DAT methylation may be a clinically relevant biomarker in AD patients. PMID- 26418278 TI - Understanding P450-mediated Bio-transformations into Epoxide and Phenolic Metabolites. AB - Adverse drug reactions are commonly the result of cytochrome P450 enzymes (CYPs) converting the drugs into reactive metabolites. Thus, information about the CYP bioactivation of drugs would not only provide insight into metabolic stability, but also into the potential toxicity. For example, oxidation of phenyl rings may lead to either toxic epoxides or safer phenols. Herein, we demonstrate that the potential to form reactive metabolites is encoded primarily in the properties of the molecule to be oxidized. While the enzyme positions the molecule inside the binding pocket (selects the site of metabolism), the subsequent reaction is only dependent on the substrate itself. To test this hypothesis, we used this observation as a predictor of drug inherent toxicity. This approach was used to successfully identify the formation of reactive metabolites in over 100 drug molecules. These results provide a new perspective on the impact of functional groups on aromatic oxidation of drugs and their effects on toxicity. PMID- 26418279 TI - Fingerprint Ridge Density as a Potential Forensic Anthropological Tool for Sex Identification. AB - In cases of partial or poor print recovery and lack of database/suspect print, fingerprint evidence is generally neglected. In light of such constraints, this study was designed to examine whether ridge density can aid in narrowing down the investigation for sex identification. The study was conducted on the right-hand index digit of 245 males and 246 females belonging to the Punjabis of Delhi region. Five ridge density count areas, namely upper radial, radial, ulnar, upper ulnar, and proximal, were selected and designated. Probability of sex origin was calculated, and stepwise discriminant function analysis was performed to determine the discriminating ability of the selected areas. Females were observed with a significantly higher ridge density than males in all the five areas. Discriminant function analysis and logistic regression exhibited 96.8% and 97.4% accuracy, respectively, in sex identification. Hence, fingerprint ridge density is a potential tool for sex identification, even from partial prints. PMID- 26418277 TI - Pathophysiology of major depressive disorder: mechanisms involved in etiology are not associated with clinical progression. AB - Meta-analyses support the involvement of different pathophysiological mechanisms (inflammation, hypothalamic-pituitary (HPA)-axis, neurotrophic growth and vitamin D) in major depressive disorder (MDD). However, it remains unknown whether dysregulations in these mechanisms are more pronounced when MDD progresses toward multiple episodes and/or chronicity. We hypothesized that four central pathophysiological mechanisms of MDD are not only involved in etiology, but also associated with clinical disease progression. Therefore, we expected to find increasingly more dysregulation across consecutive stages of MDD progression. The sample from the Netherlands Study of Depression and Anxiety (18-65 years) consisted of 230 controls and 2333 participants assigned to a clinical staging model categorizing MDD in eight stages (0, 1A, 1B, 2, 3A, 3B, 3C and 4), from familial risk at MDD (stage 0) to chronic MDD (stage 4). Analyses of covariance examined whether pathophysiological mechanism markers (interleukin (IL)-6, C reactive protein (CRP), cortisol, brain-derived neurotrophic factor and vitamin D) showed a linear trend across controls, those at risk for MDD (stages 0, 1A and 1B), and those with full-threshold MDD (stages 2, 3A, 3B, 3C and 4). Subsequently, pathophysiological differences across separate stages within those at risk and with full-threshold MDD were examined. A linear increase of inflammatory markers (CRP P=0.026; IL-6 P=0.090), cortisol (P=0.025) and decrease of vitamin D (P<0.001) was found across the entire sample (for example, from controls to those at risk and those with full-threshold MDD). Significant trends of dysregulations across stages were present in analyses focusing on at-risk individuals (IL-6 P=0.050; cortisol P=0.008; vitamin D P<0.001); however, no linear trends were found in dysregulations for any of the mechanisms across more progressive stages of full-threshold MDD. Our results support that the examined pathophysiological mechanisms are involved in MDD's etiology. These same mechanisms, however, are less important in clinical progression from first to later MDD episodes and toward chronicity. PMID- 26418280 TI - Gal-1 silenced trophoblast tumor cells (BeWo) show decreased syncytium formation and different miRNA production compared to non-target silenced BeWo cells. AB - Galectin-1 (gal-1), a member of the mammalian beta-galactoside-binding proteins, exerts biological effects by recognition of glycan ligands, including those involved in cell adhesion and growth regulation. In previous studies, we demonstrated that gal-1 induces cell differentiation processes on the membrane of choriocarcinoma cells BeWo, including the receptor tyrosine kinases (RTKs) REarranged during Transfection (RET), Janus Kinase 2 (JAK2) and Vascular endothelial growth factor receptor 3 (VEGFR3). Furthermore, Mitogen-Activated Protein Kinases (MAPK) and serine/threonine kinases were phosphorylated by gal-1. In addition, gal-1 in trophoblast cells in vitro induced syncytium formation especially after concentration dependent stimulation of the cells with this galectin. This is in contrast to MAPK-inhibitor U0126 that reduced syncytium formation of BeWo cells. The aim of this study was to analyze the syncytium formation abilities of BeWo cells that were gal-1 silenced. We found a significantly reduced syncytium formation rate in gal-1 silenced BeWo cells. In addition, these cells show a different miRNA expression profile. In summary, we found that gal-1 is a major trigger for fusion processes in BeWo cells. This function is accompanied by different regulation of miRNA synthesis in the BeWo cell culture model. PMID- 26418281 TI - Large-Area Polyimide/SWCNT Nanocable Cathode for Flexible Lithium-Ion Batteries. AB - A large-area flexible polymer electrode is fabricated using a new type of polyimide/single-walled carbon nanotube (SWCNT) nanocable composite. SWCNTs serve as the current collector and conductive network, and polyimide nanoparticles anchored on carbon nanotubes act as active materials. The electrode shows superior rate performance, good cycling stability, and high flexibility. PMID- 26418282 TI - On analysis of longitudinal clinical trials with missing data using reference based imputation. AB - Reference-based imputation (RBI) methods have been proposed as sensitivity analyses for longitudinal clinical trials with missing data. The RBI methods multiply impute the missing data in treatment group based on an imputation model built using data from the reference (control) group. The RBI will yield a conservative treatment effect estimate as compared to the estimate obtained from multiple imputation (MI) under missing at random (MAR). However, the RBI analysis based on the regular MI approach can be overly conservative because it not only applies discount to treatment effect estimate but also posts penalty on the variance estimate. In this article, we investigate the statistical properties of RBI methods, and propose approaches to derive accurate variance estimates using both frequentist and Bayesian methods for the RBI analysis. Results from simulation studies and applications to longitudinal clinical trial datasets are presented. PMID- 26418283 TI - A semiflexible 64-channel receive-only phased array for pediatric body MRI at 3T. AB - PURPOSE: To design, construct, and validate a semiflexible 64-channel receive only phased array for pediatric body MRI at 3T. METHODS: A 64-channel receive only phased array was developed and constructed. The designed flexible coil can easily conform to different patient sizes with nonoverlapping coil elements in the transverse plane. It can cover a field of view of up to 44 * 28 cm(2) and removes the need for coil repositioning for body MRI patients with multiple clinical concerns. The 64-channel coil was compared with a 32-channel standard coil for signal-to-noise ratio and parallel imaging performances on different phantoms. With IRB approval and informed consent/assent, the designed coil was validated on 21 consecutive pediatric patients. RESULTS: The pediatric coil provided higher signal-to-noise ratio than the standard coil on different phantoms, with the averaged signal-to-noise ratio gain at least 23% over a depth of 7 cm along the cross-section of phantoms. It also achieved better parallel imaging performance under moderate acceleration factors. Good image quality (average score 4.6 out of 5) was achieved using the developed pediatric coil in the clinical studies. CONCLUSION: A 64-channel semiflexible receive-only phased array has been developed and validated to facilitate high quality pediatric body MRI at 3T. Magn Reson Med 76:1015-1021, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26418284 TI - Reduced integration and differentiation of the imitation network in autism: A combined functional connectivity magnetic resonance imaging and diffusion weighted imaging study. AB - OBJECTIVE: Converging evidence indicates that brain abnormalities in autism spectrum disorder (ASD) involve atypical network connectivity, but few studies have integrated functional with structural connectivity measures. This multimodal investigation examined functional and structural connectivity of the imitation network in children and adolescents with ASD, and its links with clinical symptoms. METHODS: Resting state functional magnetic resonance imaging and diffusion-weighted imaging were performed in 35 participants with ASD and 35 typically developing controls, aged 8 to 17 years, matched for age, gender, intelligence quotient, and head motion. RESULTS: Within-network analyses revealed overall reduced functional connectivity (FC) between distributed imitation regions in the ASD group. Whole brain analyses showed that underconnectivity in ASD occurred exclusively in regions belonging to the imitation network, whereas overconnectivity was observed between imitation nodes and extraneous regions. Structurally, reduced fractional anisotropy and increased mean diffusivity were found in white matter tracts directly connecting key imitation regions with atypical FC in ASD. These differences in microstructural organization of white matter correlated with weaker FC and greater ASD symptomatology. INTERPRETATION: Findings demonstrate atypical connectivity of the brain network supporting imitation in ASD, characterized by a highly specific pattern. This pattern of underconnectivity within, but overconnectivity outside the functional network is in contrast with typical development and suggests reduced network integration and differentiation in ASD. Our findings also indicate that atypical connectivity of the imitation network may contribute to ASD clinical symptoms, highlighting the role of this fundamental social cognition ability in the pathophysiology of ASD. PMID- 26418285 TI - Correlative Studies in Clinical Trials: A Position Statement From the International Thyroid Oncology Group. AB - OBJECTIVE: Patients with progressive thyroid cancer in distant metastatic sites represent a population with a need for new therapeutic options. Aspiring to improve the treatment of such patients, the objective of this position statement from the International Thyroid Oncology Group (ITOG) is to clarify the importance of incorporating high-quality correlative studies into clinical trials. PARTICIPANTS: ITOG was formed to develop and support high-quality multicenter and multidisciplinary clinical trials for patients with aggressive forms of thyroid cancer. The Correlative Sciences Committee of the ITOG focuses on the quality and types of correlative studies included in ITOG-associated clinical trials. EVIDENCE: This document represents expert consensus from ITOG regarding this issue based on extensive collective experience in clinical and translational trials informed by basic science. CONSENSUS PROCESS: The Correlative Studies Committee identified an international writing group representative of diverse specialties, including basic sciences. Drafts were reviewed by all members of the writing group, the larger committee, and the ITOG board. After consideration of all comments by the writing group and modification of the document, the final document was then approved by the authors and the ITOG board. CONCLUSIONS: High quality correlative studies, which include variety in the types of correlates, should be intrinsic to the design of thyroid cancer clinical trials to offer the best opportunity for each study to advance treatment for patients with advanced and progressive thyroid cancer. PMID- 26418286 TI - Serial GH Measurement After Intravenous Catheter Placement Alone Can Detect Levels Above Stimulation Test Thresholds in Children. AB - CONTEXT: GH stimulation testing is limited by poor specificity and reproducibility in identifying GH deficiency. Intravenous line placement (IVP) in pediatrics may be a stimulus for GH secretion. OBJECTIVE: The objective of the study was to determine whether the measurement of GH at baseline as well as 15 and 30 minutes after IVP detects additional patients with sufficient peak GH concentrations who are not identified by a subsequent insulin tolerance test (ITT). METHODS: The ITT protocol was modified to include GH measurement at the time of IVP (t = 0) and 15 (t = 15) and 30 (t = 30) minutes later. Insulin was administered at t = 30, and an ITT was performed as per standard protocols. Children were grouped according to the indication for ITT: initial evaluation of GH deficiency (group 1); and GH deficiency at transition to adulthood (group 2). RESULTS: Ninety-seven patients were included (76 in group 1, 21 in group 2). Of these, 27 (28%) had a peak GH concentration of 7 ng/mL or greater (19 in group 1, eight in group 2) either after IVP or ITT. Thirteen subjects (11 in group 1, two in group 2) had GH concentrations of 7 ng/mL or greater after IVP, without exceeding this on a subsequent ITT. Among the 11 group 1 patients, three of these GH peaks of 7 ng/mL or greater occurred at t = 0, 5 at t = 15, and 5 at t = 30, including one patient who had a peak GH of 7 ng/mL or greater at all three time points. CONCLUSION: Some children will not have a sufficient GH response to pharmacological stimuli but will have a robust response to IVP. We recommend GH measurement after IVP in children undergoing GH stimulation testing, particularly when there is a delay between IVP and the administration of the pharmacological stimulus. PMID- 26418288 TI - How Does Water Wet a Surface? AB - The adsorption and reactions of water on surfaces has attracted great interest, as water is involved in many physical and chemical processes at interfaces. On metal surfaces, the adsorption energy of water is comparable to the hydrogen bond strength in water. Therefore, the delicate balance between the water-water and the water-metal interaction strength determines the stability of water structures. In such systems, kinetic effects play an important role and many metastable states can form with long lifetimes, such that the most stable state may not reached. This has led to difficulties in the theoretical prediction of water structures as well as to some controversial results. The direct imaging using scanning tunneling microscopy (STM) in ultrahigh vacuum at low temperatures offers a reliable means of understanding the local structure and reaction of water molecules, in particular when interpreted in conjunction with density functional theory calculations. In this Account, a selection of recent STM results on the water adsorption and dissociation on close-packed metal surfaces is reviewed, with a particular focus on Ru(0001). The Ru(0001) surface is one where water adsorbs intact in a metastable state at low temperatures and where partially dissociated layers are formed at temperatures above ~150 K. First, we will describe the structure of intact water clusters starting with the monomer up to the monolayer. We show that icelike wetting layers do not occur on close packed metal surfaces but instead hydrogen bonded layers in the form of a mixture of pentagonal, hexagonal, and heptagonal molecular rings are observed. Second, we will discuss the dissociation mechanism of water on Ru(0001). We demonstrate that water adsorption changes from dissociative to molecular as a function of the oxygen preadsorbed on Ru. Finally, we briefly review recent STM experiments on bulk ice (Ih and Ic) and water adsorption on insulating thin films. We conclude with an outlook illustrating the manipulation capabilities of STM in respect to probe the proton and hydrogen dynamics in water clusters. PMID- 26418287 TI - Epigenetic Alterations in Human Liver From Subjects With Type 2 Diabetes in Parallel With Reduced Folate Levels. AB - OBJECTIVE: Epigenetic variation may contribute to the development of complex metabolic diseases such as type 2 diabetes (T2D). Hepatic insulin resistance is a hallmark of T2D. However, it remains unknown whether epigenetic alterations take place in the liver from diabetic subjects. Therefore, we investigated the genome wide DNA methylation pattern in the liver from subjects with T2D and nondiabetic controls and related epigenetic alterations to gene expression and circulating folate levels. RESEARCH DESIGN AND METHODS: Liver biopsies were obtained from 35 diabetic and 60 nondiabetic subjects, which are part of the Kuopio Obesity Surgery Study. The genome-wide DNA methylation pattern was analyzed in the liver using the HumanMethylation450 BeadChip. RNA expression was analyzed from a subset of subjects using the HumanHT-12 Expression BeadChip. RESULTS: After correction for multiple testing, we identified 251 individual CpG sites that exhibit differential DNA methylation in liver obtained from T2D compared with nondiabetic subjects (Q < .05). These include CpG sites annotated to genes that are biologically relevant to the development of T2D such as GRB10, ABCC3, MOGAT1, and PRDM16. The vast majority of the significant CpG sites (94%) displayed decreased DNA methylation in liver from subjects with T2D. The hypomethylation found in liver from diabetic subjects may be explained by reduced folate levels. Indeed, subjects with T2D had significantly reduced erythrocyte folate levels compared with nondiabetic subjects. We further identified 29 genes that displayed both differential DNA methylation and gene expression in human T2D liver including the imprinted gene H19. CONCLUSIONS: Our study highlights the importance of epigenetic and transcriptional changes in the liver from subjects with T2D. Reduced circulating folate levels may provide an explanation for hypomethylation in the human diabetic liver. PMID- 26418289 TI - WITHDRAWN: Ceramic inlays for restoring posterior teeth. PMID- 26418290 TI - Conductive Nanowires Templated by Molecular Brushes. AB - In this paper, we report the fabrication of conductive nanowires using polymer bottle brushes as templates. In our approach, we synthesized poly(2 dimethylamino)ethyl methacrylate methyl iodide quaternary salt brushes by two step atom transfer radical polymerization, loaded them with palladium salt, and reduced them in order to form metallic nanowires with average lengths and widths of 300 and 20 nm, respectively. The obtained nanowires were deposited between conductive gold pads and were connected to them by sputtering of additional pads to form an electric circuit. We connected the nanowires in an electric circuit and demonstrated that the conductivity of these nanowires is around 100 S.m(-1). PMID- 26418291 TI - Kinesin-5: A Team Is Just the Sum of Its Parts. AB - How the cell builds a spindle remains an open question. In this issue of Developmental Cell, Shimamoto, Forth, and Kapoor (2015) show that kinesin-5 motor ensembles can exert sliding forces that scale with microtubule overlap length. This behavior could allow microtubule architecture-dependent modulation of force and contribute to spindle self-organization. PMID- 26418292 TI - Spore No More: Quality Control during Bacterial Development. AB - In this issue of Developmental Cell, Tan et al. (2015) describe an elegant mechanism functioning during sporulation in Bacillus subtilis. Their findings suggest that quality control purges unfit spores via programmed cell death, providing further insight into the utility of this phenomenon in unicellular organisms. PMID- 26418293 TI - The Role of Cell Plasticity in Tissue Repair: Adaptive Cellular Reprogramming. AB - It is becoming clear that a radical change of cell identity of differentiated cells in vivo, triggered by injury or other adversity, provides an essential route to recovery for many different mammalian tissues. This process, which we term adaptive cellular reprogramming, promotes regeneration in one of two ways: by providing a transient class of repair cells or by directly replacing cells lost during tissue damage. Controlling adaptive changes in cell fate in vivo in order to promote the body's own cell therapy, particularly by pharmacology rather than genetics, is likely to become an increasingly active area of future work. PMID- 26418294 TI - Temporal-Spatial Resolution Fate Mapping Reveals Distinct Origins for Embryonic and Adult Microglia in Zebrafish. AB - Microglia are CNS resident macrophages, and they play important roles in neural development and function. Recent studies have suggested that murine microglia arise from a single source, the yolk sac (YS), yet these studies lack spatial resolution to define the bona fide source(s) for microglia. Here, using light induced high temporal-spatial resolution fate mapping, we challenge this single source view by showing that microglia in zebrafish arise from multiple sources. The embryonic/larval microglia originate from the rostral blood island (RBI) region, the equivalent of mouse YS for myelopoiesis, whereas the adult microglia arise from the ventral wall of dorsal aorta (VDA) region, a tissue also producing definitive hematopoiesis in mouse. We further show that the VDA-region-derived microglia are Runx1 dependent, but cMyb independent, and developmentally regulated differently from the RBI region-derived microglia. Our study establishes a new paradigm for investigating the development and function of distinct microglia populations. PMID- 26418295 TI - Microtubules Negatively Regulate Insulin Secretion in Pancreatic beta Cells. AB - For glucose-stimulated insulin secretion (GSIS), insulin granules have to be localized close to the plasma membrane. The role of microtubule-dependent transport in granule positioning and GSIS has been debated. Here, we report that microtubules, counterintuitively, restrict granule availability for secretion. In beta cells, microtubules originate at the Golgi and form a dense non-radial meshwork. Non-directional transport along these microtubules limits granule dwelling at the cell periphery, restricting granule availability for secretion. High glucose destabilizes microtubules, decreasing their density; such local microtubule depolymerization is necessary for GSIS, likely because granule withdrawal from the cell periphery becomes inefficient. Consistently, microtubule depolymerization by nocodazole blocks granule withdrawal, increases their concentration at exocytic sites, and dramatically enhances GSIS in vitro and in mice. Furthermore, glucose-driven MT destabilization is balanced by new microtubule formation, which likely prevents over-secretion. Importantly, microtubule density is greater in dysfunctional beta cells of diabetic mice. PMID- 26418297 TI - Lost in Translation: The Patient-Physician Relationship in the Molecular Era. PMID- 26418296 TI - Measuring Pushing and Braking Forces Generated by Ensembles of Kinesin-5 Crosslinking Two Microtubules. AB - The proper organization of the microtubule-based mitotic spindle is proposed to depend on nanometer-sized motor proteins generating forces that scale with a micron-sized geometric feature, such as microtubule overlap length. However, it is unclear whether such regulation can be achieved by any mitotic motor protein. Here, we employ an optical-trap- and total internal reflection fluorescence (TIRF)-based assay to show that ensembles of kinesin-5, a conserved mitotic motor protein, can push apart overlapping antiparallel microtubules to generate a force whose magnitude scales with filament overlap length. We also find that kinesin-5 can produce overlap-length-dependent "brake-like" resistance against relative microtubule sliding in both parallel and antiparallel geometries, an activity that has been suggested by cell biological studies but had not been directly measured. Together, these findings, along with numerical simulations, reveal how a motor protein can function as an analog converter, "reading" simple geometric and dynamic features in cytoskeletal networks to produce regulated force outputs. PMID- 26418298 TI - Usability of the Clinical Care Classification System for Representing Nursing Practice According to Specialty. AB - This study examined the ability of the Clinical Care Classification system to represent nursing record data across various nursing specialties. The data comprised nursing care plan records from December 1998 to October 2008 in a medical center. The total number of care plan documentation we analyzed was 2 060 178, and we used a process of knowledge discovery in datasets for data analysis. The results showed that 75.42% of the documented diagnosis terms could be mapped using the Clinical Care Classification system. However, a difference in nursing terminology emerged among various nursing specialties, ranging from 0.1% for otorhinolaryngology to 100% for colorectal surgery and plastic surgery. The top five nursing diagnoses were identified as knowledge deficit, acute pain, infection risk, falling risk, and bleeding risk, which were the most common health problems in an acute care setting but not in non-acute care settings. Overall, we identified a total of 21 established nursing diagnoses, which we recommend adding to the Clinical Care Classification system, most of which are applicable to emergency and intensive care specialties. Our results show that Clinical Care Classification is useful for documenting patient's problems in an acute setting, but we suggest adding new diagnoses to identify health problems in specialty settings. PMID- 26418299 TI - Accounting for Intraligand Interactions in Flexible Ligand Docking with a PMF Based Scoring Function. AB - We analyzed the frequency with which intraligand contacts occurred in a set of 1300 protein-ligand complexes [ Plewczynski et al. J. Comput. Chem. 2011 , 32 , 742 - 755 .]. Our analysis showed that flexible ligands often form intraligand hydrophobic contacts, while intraligand hydrogen bonds are rare. The test set was also thoroughly investigated and classified. We suggest a universal method for enhancement of a scoring function based on a potential of mean force (PMF-based score) by adding a term accounting for intraligand interactions. The method was implemented via in-house developed program, utilizing an Algo_score scoring function [ Ramensky et al. Proteins: Struct., Funct., Genet. 2007 , 69 , 349 - 357 .] based on the Tarasov-Muryshev PMF [ Muryshev et al. J. Comput.-Aided Mol. Des. 2003 , 17 , 597 - 605 .]. The enhancement of the scoring function was shown to significantly improve the docking and scoring quality for flexible ligands in the test set of 1300 protein-ligand complexes [ Plewczynski et al. J. Comput. Chem. 2011 , 32 , 742 - 755 .]. We then investigated the correlation of the docking results with two parameters of intraligand interactions estimation. These parameters are the weight of intraligand interactions and the minimum number of bonds between the ligand atoms required to take their interaction into account. PMID- 26418300 TI - A Programmed DNA Marker Based on Bis(4-ethynyl-1,8-naphthalimide) and Three Methane-Bridged Thiazole Orange. AB - Two large conjugated naphthalimide derivatives with or without three-methane bridged thiazole orange (TO3; i.e., compounds 1 a and 2 a, respectively) were designed and synthesized. The fluorescence of the naphthalimide group in compound 1 a at lambda=532 nm initially decreased and that for the TO3 group at lambda=655 nm increased sequentially upon adding Salmon testes (St) DNA. In contrast, without the TO3 group, the fluorescence intensity of compound 2 a monotonously decreased in response to the addition of DNA. The non-monotonic change in the fluorescence for compound 1 a could be divided into two linear sections with two different wavelengths in the range of 0 4.0 (range = 2.5-7.0). The results of multiple linear regression predicting maternal sensitivity, R(2) = .26, indicated that greater improvements in child-rearing attitudes over the course of treatment predicted higher levels of maternal sensitivity, beta = .33, whereas improvements in posttraumatic stress symptoms over the course of treatment did not, beta = -.10. Mothers' attitudes regarding parenting during the perinatal period may be a mechanism by which intervention fosters healthy mother-infant relationship dynamics. Thus, parenting attitudes are a worthy target of intervention in vulnerable families. PMID- 26418309 TI - Prolonged Abusive Chest Compressions in an Infant: An Occult Form of Child Abuse: Review of Hemodynamics. AB - This is the case of a 4-month-old male infant whose mother sought medical care because of poor feeding and low-grade temperature. The infant had no external evidence of abuse, but chest radiographs showed multiple bilateral rib fractures. There were no retinal hemorrhages. Investigation revealed that the father had repeatedly squeezed the child to unconsciousness. The cardiopulmonary effects of this form of abuse are restriction of respiration and reduced cardiac output. This is an unusual case of occult child abuse. PMID- 26418310 TI - Insulin-like growth factor I in cats: validation of an enzyme-linked immunosorbent assay and determination of biologic variation. AB - BACKGROUND: Insulin-like growth factor I (IGF-I) measurements are used in veterinary medicine for diagnosing growth hormone disorders. IGF-I assays are subject to interference by IGF-binding proteins (IGFBP) which may not be efficiently removed by standard extraction methods. Adding excess IGF-II during analysis may improve accuracy. OBJECTIVES: The purpose of the study was to validate a commercial human IGF-I ELISA which uses excess IGF-II for feline samples and to evaluate biologic variation. METHODS: Precision was determined by calculating the coefficient of variation (CV). Accuracy was determined by recovery after removal of IGFBP, addition of IGF-I, and linear dilution after the addition of IGFBP. Biologic variation was determined by repeated sampling in 7 cats. RESULTS: There was interference by IGFBP in the high measuring range, resulting in falsely low IGF-I concentrations. This was overcome by the addition of high concentrations of IGF-II. Untreated serum had a measured/expected ratio of 98-115% compared to serum where IGFBP had been removed. Recovery after the addition of IGF-I was 83-112%. Inter- and intra-assay CVs ranged from 2.4% to 5.0% which is within the minimum acceptance criteria based on biologic variation. The reference interval of IGF-I was wide (90-1207 ng/mL) and there was a significant association between body weight and ln IGF-I (P < .000001). CONCLUSIONS: This human ELISA is suitable for feline samples, but interfering IGFBP can cause falsely low concentrations. It is recommended to dilute samples such that IGF-I is < 28 ng/mL on the standard curve to grant for sufficient IGF II for binding of interferent IGFBP. PMID- 26418311 TI - Intranasal Administration of Lentiviral miR-135a Regulates Mast Cell and Allergen Induced Inflammation by Targeting GATA-3. AB - Mast cell (MC) degranulation is the foundation of the acute phase of allergic rhinitis (AR). Previously, downregulation of GATA binding protein 3 (GATA-3) was shown to suppress MC activation in an AR mouse model. Binding of microRNA-135a (miR-135a) to GATA-3 was also observed, and overexpression of this miRNA decreased GATA-3 mRNA and protein expression. However, the effects of miR-135a on MCs during AR are currently unknown. In the present study, we utilized a lentiviral (LV) vector to intranasally administer miR-135a to ovalbumin (OVA) sensitized AR mice. Following miR-135a treatment, the total serum IgE concentration observed during AR was significantly reduced. In the nasal mucosa, the expression of T-box expressed in T cells (T-bet) was higher, whereas that of GATA-3 was lower in the AR mice following miRNA treatment. Notably, during AR, the ratio of type 1 T-helper cells (Th1) to type 2 (Th2) cells in the spleen is unbalanced, favoring Th2. However, administering miR-135a to the AR mice appeared to balance this ratio by increasing and decreasing the percentage of Th1 and Th2 cells, respectively. MiR-135a also appeared to strongly suppress the infiltration of eosinophils and MCs into the nasal mucosa, and it was specifically localized in the MCs, suggesting that its influence is modulated through regulation of GATA 3 in these cells. Additional work identifying the full therapeutic potential of miR-135a in the treatment of AR and diseases involving allergen-induced inflammation is warranted. PMID- 26418312 TI - A Self-Assembled Albumin-Based Nanoprobe for In Vivo Ratiometric Photoacoustic pH Imaging. AB - A photoacoustic nanoprobe is self-assembled from human serum albumin and two types of dye molecules, one is inert to pH and the other is pH sensitive. This probe and the quantitative ratiometric photoacoustic pH imaging method are shown to have high safety, be easy-to-operate, and have depth-independent accuracy for real-time in vivo pH imaging of entire tumors. These features make them promising for future cancer prognosis and therapeutic planning. PMID- 26418314 TI - One Million Quantum States of Benzene. AB - In this study, we compute all of the dynamically relevant vibrational quantum states of benzene, using an "exact" quantum dynamics (EQD) methodology. Benzene (C6H6), in addition to being a very large molecule for EQD (12 atoms, 30 vibrational modes), also has a very large number of vibrational states-around 10(6) in all, lying within 6500 cm(-1) of the ground state. The EQD methodology developed here uses a phase space picture to optimize the truncation of a harmonic oscillator basis-not only with respect to the molecular system of interest but also with respect to the targeted spectral range. By employing several such EQD calculations, targeted to different spectral ranges, a "hybridized" data set is constructed that provides the most accurate results everywhere. In particular, more than 500,000 states are converged to 15 cm(-1) or better. PMID- 26418313 TI - Clinical and Cognitive Characteristics Associated with Mathematics Problem Solving in Adolescents with Autism Spectrum Disorder. AB - Mathematics achievement in autism spectrum disorder (ASD) has been understudied. However, the ability to solve applied math problems is associated with academic achievement, everyday problem-solving abilities, and vocational outcomes. The paucity of research on math achievement in ASD may be partly explained by the widely-held belief that most individuals with ASD are mathematically gifted, despite emerging evidence to the contrary. The purpose of the study was twofold: to assess the relative proportions of youth with ASD who demonstrate giftedness versus disability on applied math problems, and to examine which cognitive (i.e., perceptual reasoning, verbal ability, working memory) and clinical (i.e., test anxiety) characteristics best predict achievement on applied math problems in ASD relative to typically developing peers. Twenty-seven high-functioning adolescents with ASD and 27 age- and Full Scale IQ-matched typically developing controls were assessed on standardized measures of math problem solving, perceptual reasoning, verbal ability, and test anxiety. Results indicated that 22% of the ASD sample evidenced a mathematics learning disability, while only 4% exhibited mathematical giftedness. The parsimonious linear regression model revealed that the strongest predictor of math problem solving was perceptual reasoning, followed by verbal ability and test anxiety, then diagnosis of ASD. These results inform our theories of math ability in ASD and highlight possible targets of intervention for students with ASD struggling with mathematics. PMID- 26418316 TI - CLASSIFICATION OF ANXIETY DISORDERS COMORBID WITH MAJOR DEPRESSION: COMMON OR DISTINCT INFLUENCES ON RISK? AB - BACKGROUND: Anxiety and depression display frequent comorbidity. Individuals with comorbid disorders also often have more extreme symptomatology than those with single disorders. This correlation between comorbidity and severity poses an interesting question: Are comorbid forms of anxiety and depression essentially just more severe versions of the pure disorders? METHODS: In a large major depression (MD) case-control sample of individuals from the China, Oxford and VCU Experimental Research on Genetic Epidemiology project, we examined the patterns of lifetime anxiety comorbidity (including generalized anxiety disorder--GAD, panic disorder, and five phobia subtypes) among MD cases (N = 5,864) in this population. Binary and multinomial logistic regression was used to estimate associations between risk factors and outcomes including MD as well as latent class membership, which were compared using continuation ratios. RESULTS: We found a five-class solution to fit best, and each resulting class had a distinct pattern of association with the tested risk factors. The use of continuation ratios suggests that a class characterized by high endorsement of GAD is comparable to a more severely affected "pure MD" group. The other three classes (characterized by agoraphobia, various specific phobias, and by high endorsement of all comorbid anxiety disorders, respectively) appear to differ meaningfully from MD alone. CONCLUSIONS: Risk for MD resulting from environmental and psychosocial factors may also predispose individuals to GAD, and less consistently, other anxiety disorders. Presentations of MD with certain phobias display distinguishably different patterns of risk, however, and are therefore likely qualitatively distinct. PMID- 26418318 TI - Declining Dioxin Concentrations in the Rhone River Basin, France, Attest to the Effectiveness of Emissions Controls. AB - Emission-control policies have been implemented in Europe and North America since the 1990s for polychlorodibenzodioxins (PCDDs) and furans (PCDFs). To assess the effect of these policies on temporal trends and spatial patterns for these compounds in a large European river system, sediment cores were collected in seven depositional areas along the Rhone River in France, dated, and analyzed for PCDDs and PCDFs. Results show concentrations increase in the downstream direction and have decreased temporally at all sites during the last two decades, with an average decrease of 83% from 1992 to 2010. The time for a 50% decrease in concentrations (t1/2) averaged 6.9+/-2.6 and 9.1+/-2.9 years for the sum of measured PCDDs and PCDFs, respectively. Congener patterns are similar among cores and indicate dominance of regional atmospheric deposition and possibly weathered local sources. Local sources are clearly indicated at the most downstream site, where concentrations of the most toxic dioxin, TCDD, are about 2 orders of magnitude higher than at the other six sites. The relatively steep downward trends attest to the effects of the dioxin emissions reduction policy in Europe and suggest that risks posed to aquatic life in the Rhone River basin from dioxins and furans have been greatly reduced. PMID- 26418317 TI - Perceived Parenting Mediates Serotonin Transporter Gene (5-HTTLPR) and Neural System Function during Facial Recognition: A Pilot Study. AB - This study examined changes in prefrontal oxy-Hb levels measured by NIRS (Near Infrared Spectroscopy) during a facial-emotion recognition task in healthy adults, testing a mediational/moderational model of these variables. Fifty-three healthy adults (male = 35, female = 18) aged between 22 to 37 years old (mean age = 24.05 years old) provided saliva samples, completed a EMBU questionnaire (Swedish acronym for Egna Minnen Betraffande Uppfostran [My memories of upbringing]), and participated in a facial-emotion recognition task during NIRS recording. There was a main effect of maternal rejection on RoxH (right frontal activation during an ambiguous task), and a gene * environment (G * E) interaction on RoxH, suggesting that individuals who carry the SL or LL genotype and who endorse greater perceived maternal rejection show less right frontal activation than SL/LL carriers with lower perceived maternal rejection. Finally, perceived parenting style played a mediating role in right frontal activation via the 5-HTTLPR genotype. Early-perceived parenting might influence neural activity in an uncertain situation i.e. rating ambiguous faces among individuals with certain genotypes. This preliminary study makes a small contribution to the mapping of an influence of gene and behaviour on the neural system. More such attempts should be made in order to clarify the links. PMID- 26418319 TI - Serum levels of endocan correlate with the presence and severity of pre eclampsia. AB - BACKGROUND: Endocan, a cysteine-rich dermatan sulfate proteoglycan expressed by endothelial cells, is seemed to be a new biomarker for endothelial dysfunction. Pre-eclampsia (PE) is characterized by the new onset of hypertension, proteinuria after 20 weeks of gestation, placental vascular remodeling, systemic vascular inflammation and endothelial dysfunction. The aim of this study was to investigate the relationship of PE and its severity with serum endocan levels. METHODS: A cross-sectional study was performed. Serum was collected from women with PE and normotensive controls. Serum endocan and tumor necrosis factor alpha (TNF-alpha) concentrations were measured by a specific enzyme linked immunosorbent assay. RESULTS: Patients with PE had significantly higher median (interquartile range) endocan and mean TNF-alpha concentrations than controls [20.04 (12.26) ng/mL vs 15.55 (6.19) ng/mL, p < 0.001 for endocan; 26.49 +/- 12.14 pg/mL vs 14.62 +/- 5.61 pg/mL, p < 0.001 for TNF-alpha; respectively]. Serum endocan concentrations were positively correlated with systolic blood pressure (r = 0.618, p < 0.001), diastolic blood pressure (r = 0.608, p < 0.001), the amount of 24-h proteinuria (r = 0.786, p < 0.001) and TNF-alpha (r = 0.474, p < 0.001) in women with PE. In subgroup analysis, patients with severe PE had significantly higher endocan concentrations than those with mild PE. Receiver operating characteristic analysis of endocan was used to identify the patients with PE and also discriminating between mild and severe PE. CONCLUSION: Serum endocan concentrations were significantly elevated in women with PE versus normotensive controls, and concentrations seem to be associated with the severity of the disease. PMID- 26418320 TI - An analysis of clinical characteristics and prognosis for patients with serum alpha-fetoprotein-positive gastric cancer. AB - AIM: The aim of this analysis was to investigate the clinical characteristics and prognosis of patients with serum alpha-fetoproteinpositive gastric cancer (AFPGC) in order to improve the diagnosis and treatment. METHODS: A retrospective analysis was performed on the clinical characteristics and survival data of patients with gastric cancer in our hospital between March 2007 and September 2012, to compare the clinical characteristics of patients with serum AFPGC to those of patients with serum AFP-negative gastric cancer. A Cox regression model was used to explore the prognosis factors for gastric cancer. RESULTS: The 106 patients with serum AFPGC accounted for 8.5% (106/1253) of all the patients during the same period. There were poorer differentiation (64.2% vs. 54.0%), later clinical stage (83.1% vs. 48.6% at III+IV stage), larger tumor volume (78.3% vs. 57.9% with diameter>5 cm), and higher incidence of liver metastases (14.2% vs. 2.8%) and lymph node metastasis (76.4% vs. 52.7%) in patients with serum AFPGC than in those with serum AFP-negative gastric cancer (P<0.05). The 1 , 3-, and 5-year survival rates in patients with serum AFPGC were 52.8%, 31.3%, and 19.8%, respectively, with a median survival time of 14 months, and those in patients with serum alpha-fetoprotein-negative gastric cancer were 78.3%, 54.8%, and 36.8%, respectively, with a median survival time of 40 months. Multivariate Cox regression analysis showed that serum AFP positive (RR=2.70, 95% CI:1.50~4.87) was one of the risk factors of prognosis for patients with gastric cancer. CONCLUSION: It is more malignant in patients with serum AFPGC than in those with serum alpha-fetoprotein-negative gastric cancer. There are later clinical stage, poorer differentiation, larger tumor volume, and higher incidence of metastasis to the liver and lymph nodes in patients with serum AFPGC, with low survival rate and poor prognosis. PMID- 26418321 TI - Effect observation of anti epileptic drugs on serum folic acid and vitamin B12 of epileptic patients. AB - AIM: Comparative analysis of the effect of antiepileptic drugs on the epileptic (tonic clonic seizure type) patient's serum folate and vitamin B12 concentrations. METHODS: Consecutively, 84 cases from September 2010 to September 2014 from the Department of Internal Medicine of our hospital were considered to diagnose as epilepsy nerve. Among which, 49 cases received anti epileptic drug treatment (treatment group), 35 cases received treatment without anti epileptic drugs (non-treatment group); At the same period, 42 nonepileptic patients (control group) underwent the analysis of the difference of serum folate and vitamin B12 concentrations of among the three groups of patients before the test, and at the end of test with the contrast analysis of difference of clinical efficiency and thrombosis rate. RESULTS: Serum folic acid level of patients in the treatment group decreased significantly after test, vitamin B12 level was significantly higher, the differences were statistically significant (P<0.05), but folic acid and vitamin B12 concentration of non-treatment group and the control group did not change, and the differences were not statistically significant (P>0.05). Clinical efficiency of treatment group patients was significantly higher than that of the non-treatment group; the incidence of thrombosis was significantly lower than that of the non-treatment group, and the difference was statistically significant (P<0.05). CONCLUSION: Antiepileptic drugs can significantly improve clinical efficacy of the epilepsy tonic clonic seizure type patients, which may be related to the decrease of serum levels of folate and vitamin B12-increased concentration. PMID- 26418322 TI - Focal cerebral ischemia and neurovascular protection: a bench-to-bedside update. AB - PURPOSE OF REVIEW: To date, many pharmacological approaches, or combination of approaches, have been applied to experimental models of focal cerebral ischemia (FCI), but their translation to clinically effective agents has proved unsuccessful. To date, only thrombolysis with recombinant tissue-type plasminogen activator, or other 'clot-breaking' or 'clot-removal' approaches, have proved effective for acute stroke. This review, therefore, focuses on the 'vascular' phenomena involved in the development of FCI. RECENT FINDINGS: Recent advances in the experimental literature on FCI describe the microvascular characteristics of the ischemic penumbra, the consequences of cortical spreading depression on impairing cerebral perfusion, and the potential neuroprotective mechanisms of ischemic preconditioning via antithrombotic effects on the neurovascular unit. SUMMARY: This review provides a perspective about the neurovascular components contributing to the pathophysiology of FCI, and some relevant clinical strategies available on the horizon that hold promise for improved cerebral perfusion in FCI. PMID- 26418324 TI - Recent research advances in eosinophilic esophagitis. AB - PURPOSE OF REVIEW: Eosinophilic esophagitis (EoE) is a chronic allergic disease triggered by food allergens with an increasing prevalence. This review highlights recent research advances in EoE with a focus on the literature of the past 18 months. RECENT FINDINGS: The incidence of EoE in the black population is higher than previously suggested. A novel locus spanning CAPN14 is associated with EoE. Diagnostic tests utilizing an analysis of EoE-specific transcriptome have been improved. Standardized EoE symptom score systems have been established. Treatment trials show the promise and limitations of allergen avoidance, antiinflammatory reagents, and anti-interleukin-13 antibodies. Insights into disease mechanisms highlight the role of invariant natural killer T cells and group 2 innate immune cells. Epithelial barrier protein desmoglein 1, bone morphogenetic protein antagonist follistatin, neurotrophic tyrosine kinase receptor type 1, and CAPN14 have been defined as new potential therapeutic targets in EoE as regulators of the inflammatory interleukin-13-axis. The role of IgG4 in the disease mechanisms has been suggested. SUMMARY: Genetic predisposition influenced by environmental factors increases EoE susceptibility. Research identifying the critical events leading to allergen sensitization and the esophagus-specific responses that drive EoE is evolving, and will lead to a better understanding of EoE and new therapeutic approaches for the disease. PMID- 26418323 TI - Epigenetics in allergic diseases. AB - PURPOSE OF REVIEW: Allergic diseases are among the most prevalent chronic diseases of childhood, affecting more than 7 million children in the United States. Epidemiological evidence supports the idea that the inception of allergic diseases is typically before the preschool years, even when chronic symptoms do not emerge until adulthood. The role of epigenetic mechanisms (particularly DNA methylation) in allergic disease is under active investigation because these mechanisms are known to be at the interface of gene regulation, environmental stimuli, and developmental processes, all of which are essential for the pathogenesis for asthma and allergy. This article specifically reviews genome wide DNA methylation studies in allergic disease. RECENT FINDINGS: Differential DNA methylation at specific regions appears to be associated with concurrent allergic disease. A few studies have identified methylation signatures predictive of disease. SUMMARY: DNA methylation signatures have been shown to be associated with several allergic disease phenotypes, typically concurrently with disease. The few that have been found to precede diagnosis are especially interesting because they highlight an early trajectory to disease. PMID- 26418325 TI - Pathogenesis of Adrenal Aldosterone-Producing Adenomas Carrying Mutations of the Na(+)/K(+)-ATPase. AB - Aldosterone-producing adenoma (APA) is a major cause of primary aldosteronism, leading to secondary hypertension. Somatic mutations in the gene for the alpha1 subunit of the Na(+)/K(+)-ATPase were found in about 6% of APAs. APA-related alpha1 subunit of the Na(+)/K(+)-ATPase mutations lead to a loss of the pump function of the Na(+)/K(+)-ATPase, which is believed to result in membrane depolarization and Ca(2+)-dependent stimulation of aldosterone synthesis in adrenal cells. In addition, H(+) and Na(+) leak currents via the mutant Na(+)/K(+)-ATPase were suggested to contribute to the phenotype. The aim of this study was to investigate the cellular pathophysiology of adenoma-associated Na(+)/K(+)-ATPase mutants (L104R, V332G, G99R) in adrenocortical NCI-H295R cells. The expression of these Na(+)/K(+)-ATPase mutants depolarized adrenal cells and stimulated aldosterone secretion. However, an increase of basal cytosolic Ca(2+) levels in Na(+)/K(+)-ATPase mutant cells was not detectable, and stimulation with high extracellular K(+) hardly increased Ca(2+) levels in cells expressing L104R and V332G mutant Na(+)/K(+)-ATPase. Cytosolic pH measurements revealed an acidification of L104R and V332G mutant cells, despite an increased activity of the Na(+)/H(+) exchanger. The possible contribution of cellular acidification to the hypersecretion of aldosterone was supported by the observation that aldosterone secretion of normal adrenocortical cells was stimulated by acetate induced acidification. Taken together, mutations of the Na(+)/K(+)-ATPase depolarize adrenocortical cells, disturb the K(+) sensitivity, and lower intracellular pH but, surprisingly, do not induce an overt increase of intracellular Ca(2+). Probably, the autonomous aldosterone secretion is caused by the concerted action of several pathological signaling pathways and incomplete cellular compensation. PMID- 26418328 TI - Body Plethysmography is Not Helpful for COPD Diagnosis, Determination of Severity, Phenotyping, nor Response to Therapy. PMID- 26418327 TI - Quantitative Analysis of Vortical Blood Flow in the Thoracic Aorta Using 4D Phase Contrast MRI. AB - INTRODUCTION: Phase contrast MRI allows for the examination of complex hemodynamics in the heart and adjacent great vessels. Vortex flow patterns seem to play an important role in certain vascular pathologies. We propose two- and three-dimensional metrics for the objective quantification of aortic vortex blood flow in 4D phase contrast MRI. MATERIALS AND METHODS: For two-dimensional vorticity assessment, a standardized set of 6 regions-of-interest (ROIs) was defined throughout the course of the aorta. For each ROI, a heatmap of time resolved vorticity values [Formula: see text] was computed. Evolution of minimum, maximum, and average values as well as opposing rotational flow components were analyzed. For three-dimensional analysis, vortex core detection was implemented combining the predictor-corrector method with lambda2 correction. Strength, elongation, and radial expansion of the detected vortex core were recorded over time. All methods were applied to 4D flow MRI datasets of 9 healthy subjects, 2 patients with mildly dilated aorta, and 1 patient with aortic aneurysm. RESULTS: Vorticity quantification in the 6 standardized ROIs enabled the description of physiological vortex flow in the healthy aorta. Helical flow developed early in the ascending aorta (absolute vorticity = 166.4+/-86.4 s-1 at 12% of cardiac cycle) followed by maximum values in mid-systole in the aortic arch (240.1+/-45.2 s-1 at 16%). Strength, elongation, and radial expansion of 3D vortex cores escalated in early systole, reaching a peak in mid systole (strength = 241.2+/ 30.7 s-1 at 17%, elongation = 65.1+/-34.6 mm at 18%, expansion = 80.1+/-48.8 mm2 at 20%), before all three parameters similarly decreased to overall low values in diastole. Flow patterns were considerably altered in patient data: Vortex flow developed late in mid/end-systole close to the aortic bulb and no physiological helix was found in the aortic arch. CONCLUSIONS: We have introduced objective measures for quantification of vortical flow in 4D phase contrast MRI. Vortex blood flow in the thoracic aorta could be consistently described in all healthy volunteers. In patient data, pathologically altered vortex flow was observed. PMID- 26418329 TI - Enhanced Intracellular Delivery and Tissue Retention of Nanoparticles by Mussel Inspired Surface Chemistry. AB - Nanomaterials have been broadly studied for intracellular delivery of diverse compounds for diagnosis or therapy. Currently it remains challenging for discovering new biomolecules that can prominently enhance cellular internalization and tissue retention of nanoparticles (NPs). Herein we report for the first time that a mussel-inspired engineering approach may notably promote cellular uptake and tissue retention of NPs. In this strategy, the catechol moiety is covalently anchored onto biodegradable NPs. Thus, fabricated NPs can be more effectively internalized by sensitive and multidrug resistant tumor cells, as well as some normal cells, resulting in remarkably potentiated in vitro activity when an antitumor drug is packaged. Moreover, the newly engineered NPs afford increased tissue retention post local or oral delivery. This biomimetic approach is promising for creating functional nanomaterials for drug delivery, vaccination, and cell therapy. PMID- 26418330 TI - A CASE OF ACCIDENTAL OCULAR INJURY FROM COSMETIC LASER BURN. AB - PURPOSE: To report the clinical course of a patient sustaining a ocular laser injury from 1,064-nm Nd:YAG cosmetic laser machine. METHOD AND PATIENT: A 31-year old beauty parlor aesthetician was operating an Nd:YAG cosmetic laser machine of 1,064 nm wavelength. However, the probe was held in the opposite direction, and on firing, the laser shot fired into her left eye. The patient heard a "pop" sound followed by immediate floaters and blurring of vision. Her clinical course was followed for 6 weeks, with investigations including optical coherence tomography, fluorescein angiogram, and Humphrey's visual field examination performed. RESULTS: Optical coherence tomography taken over the injured area showed thickened retina and preretinal hyperreflectivities. Fluorescein angiogram showed hypofluorescence superonasal to the disk with late staining of vessels. Humphrey's visual field showed a dense scotoma emanating from the blind spot. The lesion eventually scarred down, and the patient's vision recovered. DISCUSSION: The eye is the most susceptible body part to laser light injury. A review of reported laser accidents revealed the majority to be ocular injuries. The retina is particularly vulnerable, as laser light with wavelength between 400 nm and 1,400 nm is focused by the cornea and lens onto the retina, increasing the retinal irradiance as a result. Most injuries were parafoveal, suggesting that most injuries occurred during laser beam alignment. The prognosis is generally favorable. As laser use becomes more widespread and its application increasingly heterogeneous, regulation of laser use and monitoring of laser safety are crucial but at the same time challenging. PMID- 26418326 TI - RF9 Acts as a KISS1R Agonist In Vivo and In Vitro. AB - RF9, a reported antagonist of the mammalian gonadotropin-inhibitory hormone receptor, stimulates gonadotropin secretion in mammals. Recent studies have suggested that the stimulatory effect of RF9 on gonadotropin secretion relies on intact kisspeptin receptor (KISS1R) signaling, but the underlying mechanisms remain to be elucidated. Using Chinese Hamster Ovary cells stably transfected with KISS1R, we show that RF9 binds specifically to KISS1R, with a Kd of 1.6 * 10(-5)M, and stimulates an increase in intracellular calcium and inositol phosphate accumulation in a KISS1R-dependent manner, with EC50 values of 3.0 * 10(-6)M and 1.6 * 10(-7)M, respectively. RF9 also stimulated ERK phosphorylation, with a time course similar to that of kisspeptin-10. RFRP-3, the putative endogenous ligand for NPFFR1, did not stimulate inositol phosphate accumulation or pERK, nor did it alter responses to of kisspeptin-10 or RF9. In agreement with these in vitro data, we found that RF9 stimulated a robust LH increase in Npffr1( /-) mice, similar to that in wild-type littermates, whereas the stimulatory effect of RF9 was markedly reduced in Kiss1r(-/-) and double Kiss1r(-/-)/Npfrr1( /-) mice. The stimulatory effect of RF9 on LH secretion was restored by the selective rescue of Kiss1r expression in GnRH neurons, in Kiss1r(-/-T) mice. Taken together, our study demonstrates that RF9 acts primarily as a KISS1R agonist, but not as an allosteric modulator, to stimulate LH secretion. Our findings raise questions regarding the utility of RF9 for assessing NPFF1R function and de-emphasize a predominant role of this signaling system in central regulation of reproduction. PMID- 26418331 TI - RECURRENCE OF VITELLIFORM LESIONS ASSOCIATED WITH TEMPORARY VISION LOSS IN BEST VITELLIFORM MACULAR DYSTROPHY. AB - PURPOSE: To describe visual acuity changes associated with several cycles of accumulation, disappearance, and reaccumulation of vitelliform material in Best disease, with fundus photographs, fluorescein angiograms, and optical coherence tomography images documenting these stages. METHODS: Case report with 70 months of follow-up using fundus photography, fluorescein angiography, and optical coherence tomography to image the retina. A non-Hispanic white 33-year-old man with Best disease (positive for a mutation in the BEST1 gene, namely p.Tyr167Cys:c.500A>G). RESULTS: The patient had a history of choroidal neovascularization (CNV) followed by scarring of the macula with sustained vision loss of ~20/250 in the left eye when he was in his twenties. He subsequently presented in his thirties with acute vision loss in the right eye 3 times during a 70-month follow-up period. Each episode of vision loss in the right eye was preceded by several months of reaccumulation of vitelliform material in the macula apparent on fundus photographs, fluorescein angiograms, and optical coherence tomography, but no evidence of CNV on presentation. Each of the three episodes of vision loss in the right eye was followed by spontaneous gradual improvement in visual acuity over the next several months, correlating with decreasing amounts of the vitelliform material on clinical examination and fundus photographs. After the third documented recovery of visual acuity, at a time of stable vision, the patient developed CNV in the right eye, treated with intravitreal ranibizumab. CONCLUSION: This case demonstrates that vitelliform material can reaccumulate and resorb several times in Best disease, with temporary visual acuity decline after each episode of vitelliform material accumulation. There is a need for continued vigilance for the development of CNV in patients presenting with acute vision loss, although this patient developed CNV at a time of stable vision. PMID- 26418332 TI - Measurement of Postmortem 1,5-anhydroglucitol in Vitreous Humor for Forensic Diagnosis. AB - In forensic diagnosis, postmortem blood glucose is known to be susceptible to change after death. However, the 1,5-anhydroglucitol (1,5-AG) concentrations in plasma and cerebrospinal fluid (CSF) reflect the mean blood glucose level for a short period of time. In this study, we compared the postmortem 1,5-AG concentrations in vitreous humor and CSF in 47 subjects to evaluate the utility of this concentration in the vitreous humor for forensic diagnosis. The postmortem 1,5-AG concentrations in vitreous humor (mean+/-SD: 20.2 +/- 8.7 MUg/mL) and CSF (16.8 +/- 8.7 MUg/mL) did not differ significantly and showed a strong correlation (r(2) = 0.87, p < 0.01). These results suggest that the vitreous humor 1,5-AG concentration provides useful information on the antemortem blood glucose level, in addition to the HbA1c value and the CSF 1,5-AG concentration. PMID- 26418333 TI - Flow-induced focal adhesion remodeling mediated by local cytoskeletal stresses and reorganization. AB - Cells respond to fluid shear stress through dynamic processes involving changes in actomyosin and other cytoskeletal stresses, remodeling of cell adhesions, and cytoskeleton reorganization. In this study we simultaneously measured focal adhesion dynamics and cytoskeletal stress and reorganization in MDCK cells under fluid shear stress. The measurements used co-expression of fluorescently labeled paxillin and force sensitive FRET probes of alpha-actinin. A shear stress of 0.74 dyn/cm(2) for 3 hours caused redistribution of cytoskeletal tension and significant focal adhesion remodeling. The fate of focal adhesions is determined by the stress state and stability of the linked actin stress fibers. In the interior of the cell, the mature focal adhesions disassembled within 35-40 min under flow and stress fibers disintegrated. Near the cell periphery, the focal adhesions anchoring the stress fibers perpendicular to the cell periphery disassembled, while focal adhesions associated with peripheral fibers sustained. The diminishing focal adhesions are coupled with local cytoskeletal stress release and actin stress fiber disassembly whereas sustaining peripheral focal adhesions are coupled with an increase in stress and enhancement of actin bundles. The results show that flow induced formation of peripheral actin bundles provides a favorable environment for focal adhesion remodeling along the cell periphery. Under such condition, new FAs were observed along the cell edge under flow. Our results suggest that the remodeling of FAs in epithelial cells under flow is orchestrated by actin cytoskeletal stress redistribution and structural reorganization. PMID- 26418334 TI - Survival impact of the Australian National Bowel Cancer Screening Programme. AB - BACKGROUND: The Australian National Bowel Cancer Screening Program (NBCSP) has been offering age-based faecal occult blood testing since 2006. With the rapid expansion of this programme, the NBCSP will ultimately offer biennial screening to all 50-74 years old by 2020. Participation rates remain low. Previous reports have described an increased proportion of earlier stage cancers in patients with NBCSP-detected tumours. METHODS: Data on consecutive patients enrolled into a prospective, comprehensive, multidisciplinary database at six Victorian hospitals were examined. Clinicopathologic and outcome data were compared for NBCSP and symptomatic presentation patients. RESULTS: We identified 3743 patients that presented with colorectal cancer (CRC) at participating hospitals since May 2006. Of 1930 patients aged between 50 and 70 years, 141 (7.3%) had a NBCSP detected cancer, 1441 (74.7%) presented with symptoms and 266 (13.8%) were diagnosed through screening outside of the NBCSP. Based on the American Society of Anaesthesiology score, the NBCSP patients were fitter. They had an earlier stage of diagnosis and were more likely to be female and less likely to have lymphovascular invasion or to present as an emergency. NBCSP detected patients had a lower rate of recurrence (HR 0.17, P = 0.0001) and fewer deaths (HR 0.19, P = 0.005). CONCLUSIONS: Patients with NBCSP-detected CRC have a markedly reduced risk of CRC recurrence and death compared with patients with a symptomatic presentation. The dominant driver of this appears to be earlier stage at diagnosis. Increased promotion of the impact of the NBCSP, including data related to the survival impact, should be undertaken to increase participation rates and achieve further survival gains. PMID- 26418336 TI - Synthesis and spectral investigation of some new hetaryl-substituted hydroquinolinone derivatives. PMID- 26418335 TI - Temporal cAMP Signaling Selectivity by Natural and Synthetic MC4R Agonists. AB - The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor expressed in the brain, where it controls energy balance through pathways including alpha melanocyte-stimulating hormone (alpha-MSH)-dependent signaling. We have reported that the MC4R can exist in an active conformation that signals constitutively by increasing cAMP levels in the absence of receptor desensitization. We asked whether synthetic MC4R agonists differ in their ability to increase intracellular cAMP over time in Neuro2A cells expressing endogenous MC4R and exogenous, epitope tagged hemagglutinin-MC4R-green fluorescent protein. By analyzing intracellular cAMP in a temporally resolved Forster resonance energy transfer assay, we show that withdrawal of alpha-MSH leads to a quick reversal of cAMP induction. By contrast, the synthetic agonist melanotan II (MTII) induces a cAMP signal that persists for at least 1 hour after removal of MTII from the medium and cannot be antagonized by agouti related protein. Similarly, in mHypoE-42 immortalized hypothalamic neurons, MTII, but not alpha-MSH, induced persistent AMP kinase signal, which occurs downstream of increased cAMP. By using a fluorescence recovery after photobleaching assay, it appears that the receptor exposed to MTII continues to signal after being internalized. Similar to MTII, the synthetic MC4R agonists, THIQ and BIM-22511, but not LY2112688, induced prolonged cAMP signaling after agonist withdrawal. However, agonist-exposed MC4R desensitized to the same extent, regardless of the ligand used and regardless of differences in receptor intracellular retention kinetics. In conclusion, alpha-MSH and LY2112688, when compared with MTII, THIQ, and BIM-22511, vary in the duration of the acute cAMP response, showing distinct temporal signaling selectivity, possibly linked to specific cell compartments from which cAMP signals may originate. PMID- 26418337 TI - Toward Highly Sensitive Polymer Photodetectors by Molecular Engineering. AB - Modified 3,4-ethylenedioxythiophene is employed as the conjugated side chain in conjugated polymers, which can significantly depress the dark current of the polymer photodetectors with little associated decrease in photovoltaic properties, thus enhanceing the detectivities. This approach can be applied to a variety of conjugated polymers covering a photoresponse range from UV to NIR. PMID- 26418338 TI - Silymarin Constituent 2,3-Dehydrosilybin Triggers Reserpine-Sensitive Positive Inotropic Effect in Perfused Rat Heart. AB - 2,3-dehydrosilybin (DHS) is a minor flavonolignan component of Silybum marianum seed extract known for its hepatoprotective activity. Recently we identified DHS as a potentially cardioprotective substance during hypoxia/reoxygenation in isolated neonatal rat cardiomyocytes. This is the first report of positive inotropic effect of DHS on perfused adult rat heart. When applied to perfused adult rat heart, DHS caused a dose-dependent inotropic effect resembling that of catecholamines. The effect was apparent with DHS concentration as low as 10 nM. Suspecting direct interaction with beta-adrenergic receptors, we tested whether DHS can trigger beta agonist-dependent gene transcription in a model cell line. While DHS alone was unable to trigger beta agonist-dependent gene transcription, it enhanced the effect of isoproterenol, a known unspecific beta agonist. Further tests confirmed that DHS could not induce cAMP accumulation in isolated neonatal rat cardiomyocytes even though high concentrations (>= 10 MUM) of DHS were capable of decreasing phosphodiesterase activity. Pre-treatment of rats with reserpine, an indole alkaloid which depletes catecholamines from peripheral sympathetic nerve endings, abolished the DHS inotropic effect in perfused hearts. Our data suggest that DHS causes the inotropic effect without acting as a beta agonist. Hence we identify DHS as a novel inotropic agent. PMID- 26418340 TI - Correction: Acceleration of the Glycolytic Flux by Steroid Receptor Coactivator-2 Is Essential for Endometrial Decidualization. PMID- 26418339 TI - Exploring Muscle Activation during Nordic Walking: A Comparison between Conventional and Uphill Walking. AB - Nordic Walking (NW) owes much of its popularity to the benefits of greater energy expenditure and upper body engagement than found in conventional walking (W). Muscle activation during NW is still understudied, however. The aim of the present study was to assess differences in muscle activation and physiological responses between NW and W in level and uphill walking conditions. Nine expert Nordic Walkers (mean age 36.8+/-11.9 years; BMI 24.2+/-1.8 kg/m2) performed 5 minute treadmill trials of W and NW at 4 km/h on inclines of 0% and 15%. The electromyographic activity of seven upper body and five leg muscles and oxygen consumption (VO2) were recorded and pole force during NW was measured. VO2 during NW was 22.3% higher at 0% and only 6.9% higher at 15% than during W, while upper body muscle activation was 2- to 15-fold higher under both conditions. Lower body muscle activation was similarly increased during NW and W in the uphill condition, whereas the increase in erector spinae muscle activity was lower during NW than W. The lack of a significant increase in pole force during uphill walking may explain the lower extra energy expenditure of NW, indicating less upper body muscle activation to lift the body against gravity. NW seemed to reduce lower back muscle contraction in the uphill condition, suggesting that walking with poles may reduce effort to control trunk oscillations and could contribute to work production during NW. Although the difference in extra energy expenditure between NW and W was smaller in the uphill walking condition, the increased upper body muscle involvement during exercising with NW may confer additional benefit compared to conventional walking also on uphill terrains. Furthermore, people with low back pain may gain benefit from pole use when walking uphill. PMID- 26418341 TI - Simvastatin and vitamin D for migraine prevention: A randomized, controlled trial. AB - OBJECTIVE: The aim of this work was to assess efficacy and tolerability of simvastatin plus vitamin D for migraine prevention in adults with episodic migraine. METHODS: We performed a randomized, double-blind, placebo-controlled trial with a 12-week baseline period and 24-week intervention period in 57 adults with episodic migraine. Participants were randomly assigned to simvastatin 20 mg tablets twice-daily plus vitamin D3 1,000 international units capsules twice daily or matching placebo tablets and capsules. RESULTS: Compared to placebo, participants using simvastatin plus vitamin D3 demonstrated a greater decrease in number of migraine days from the baseline period to intervention weeks 1 to 12: a change of -8.0 (interquartile range [IQR]: -15.0 to -2.0) days in the active treatment group versus +1.0 (IQR: -1.0 to + 6.0) days in the placebo group, p < 0.001; and to intervention weeks 13 to 24: a change of -9.0 (IQR: -13 to -5) days in the active group versus +3.0 (IQR: -1.0 to + 5.0) days in the placebo group, p < 0.001. In the active treatment group, 8 patients (25%) experienced 50% reduction in the number of migraine days at 12 weeks and 9 (29%) at 24 weeks postrandomization. In comparison, only 1 patient (3%) in the placebo group (p = 0.03) experienced such a reduction. Adverse events were similar in both active treatment and placebo groups. INTERPRETATION: The results demonstrate that simvastatin plus vitamin D is effective for prevention of headache in adults with episodic migraine. Given statins' ability to repair endothelial dysfunction, this economical approach may also reduce the increased risk for vascular diseases among migraineurs. PMID- 26418343 TI - Ionic Switch Induced by a Rectangular-Hexagonal Phase Transition in Benzenammonium Columnar Liquid Crystals. AB - We demonstrate switching of ionic conductivities in wedge-shaped liquid crystalline (LC) ammonium salts. A thermoreversible phase transition between the rectangular columnar (Colr) and hexagonal columnar (Colh) phases is used for the switch. The ionic conductivities in the Colh phase are about four orders of magnitude higher than those in the Colr phase. The switching behavior of conductivity can be ascribed to the structural change of assembled ionic channels. X-ray experiments reveal a highly ordered packing of the ions in the Colr phase, which prevents the ion transport. PMID- 26418342 TI - Inhibition of EHMT2 Induces a Robust Antiviral Response Against Foot-and-Mouth Disease and Vesicular Stomatitis Virus Infections in Bovine Cells. AB - The genetic regulatory network controlling the innate immune system is well understood in many species. However, the role of the epigenetic mechanisms underlying the expression of immunoregulatory genes is less clear, especially in livestock species. Histone H3 lysine 9 dimethylation (H3K9me2) is an epigenetic modification associated with transcriptional silencing within the euchromatin regions. Euchromatic histone-lysine N-methyltransferase 2 (EHMT2; also known as G9a) is a crucial enzyme responsible for regulating the dynamics of this epigenetic modification. It has been shown that histone modifications play a role in regulating type I interferon (IFN) response. In the present study, we investigated the role of EHMT2 in the epigenetic regulation of bovine antiviral innate immunity and explored its therapeutic potential against viral infections. We evaluated the effects of pharmacological and RNAi-mediated inhibition of EHMT2 on the transcription of IFN-beta and other IFN-inducible antiviral genes, as well as its effect on foot-and-mouth disease virus (FMDV) and vesicular stomatitis virus (VSV) replication in bovine cells. We show that treatment of primary bovine cells with the synthetic EHMT2 inhibitor (UNC0638) either before or shortly after virus infection resulted in a significant increase in transcript levels of bovine IFN-beta (boIFN-beta; 300-fold) and other IFN-inducible genes, including IFN stimulated gene 15 (ISG-15), myxovirus resistance 1 (Mx-1), Mx-2, RIG-I, 2',5' oligoadenylate synthetase 1 (OAS-1), and protein kinase R (PKR). Expression of these factors correlated with a significant decrease in VSV and FMDV viral titers. Our data confirm the involvement of EHMT2 in the epigenetic regulation of boIFN-beta and demonstrate the activation of a general antiviral state after EHMT2 inhibition. PMID- 26418344 TI - PbS Quantum-Dot Depleted Heterojunction Solar Cells Employing CdS Nanorod Arrays as the Electron Acceptor with Enhanced Efficiency. AB - Depleted heterojunction (DH) solar cells have shown great potential in power conversion. A 3-D DH structure was first designed and fabricated through a layer by-layer spin-coating technique to increase the interfacial contact of p-type PbS quantum dots (QDs) and n-type CdS nanorod arrays. As a result, a decent power conversion efficiency of 4.78% in this structure was achieved, which is five times the efficiency of a planar heterojunction structure of a similar thickness. In the 3-D DH structure, n-type CdS nanorod arrays (NRs) were grown vertically as electron acceptors, on which p-type PbS quantum dots were deposited as absorbing materials in a layer-by-layer spin-coating fashion. The results are discussed in view of effective transportation of electrons through CdS NRs than the hopping transportation in large nanoparticle-based CdS film, the enlarged interfacial area, and shortened carrier diffusion distance. PMID- 26418345 TI - Exploring the reciprocal relationship between caregiver burden and the functional health of frail older adults in China: A cross-lag analysis. AB - The present study aimed to investigate the reciprocal relationship between caregiver burden and care recipient dependence in activities of daily living (ADLs) from the perspective of frail older adults and their family caregivers in China. Data were derived from a sample of 469 older adult-caregiver dyads that participated in both the 2010 and 2013 waves of the panel study Family Caregivers for the Frail and Very Elderly: Well-Being and Needs in Shanghai. A two-wave cross-lag analysis was used to examine the proposed model. ADL dependence in 2010 was a significant predictor of caregiver burden in 2013. Furthermore, caregiver burden in 2010 was a significant predictor of ADL dependence in 2013. This finding confirms the dyadic model of caregiver burden and care recipient well being. Implications for interventions and policy to help frail older adults and their family caregivers are discussed. PMID- 26418346 TI - Hierarchical Polymer-Carbon Nanotube Hybrid Mesostructures by Crystallization Driven Self-Assembly. AB - Multistep crystallization-driven self-assembly has great potential to enable the construction of sophisticated hybrid mesostructures. During the assembly procedure, each step modifies the properties of the overall structure. Here, we demonstrate the flexibility and efficiency of this approach by preparing polymer carbon nanotube (CNT) hybrid mesostructures. We started by growing polyferrocenyldimethylsilane (PFS) homopolymer crystals onto multiwalled CNTs. This first step facilitated the redispersion of the coated CNTs in both polar (2 propanol) and nonpolar (decane) solvents. In the second step of hybrid construction, a unimer solution of a PFS block copolymer was added into the PFS CNT solution. The PFS coating on the CNT initiated the growth of elongated micelles, resulting in structures that resembled hairy caterpillars. PFS-b-P2VP (P2VP = poly-2-vinylpyridine) micelles were grown from the surface of PFS-CNT hybrids in 2-propanol, and PFS-b-PI (PI = polyisoprene) micelles were grown from these hybrids in decane. These micelles, by transmission electron microscopy were seen to have an unusual wavy kinked structure, very different from the uniform smooth structures normally formed by both block copolymers. For hybrids with PFS b-PI micelles, cross-linking of the micelle coronas locked the whole structure in place and allowed us to use the partial oxidation of PFS components to grow metal nanoparticles in the core of these micelles. We finally investigated the influence of the corona-forming block used to grow the micelles on the wettability of films made from these mesostructures. Films formed with CNT hybrids grafted with PFS-b-PI micelles were superhydrophobic (contact angle, 152 degrees ). In contrast, the surface of the films was much more hydrophilic (contact angle, 54 degrees ) when they were prepared from CNT hybrids grafted with PFS-b-P2VP micelles. PMID- 26418347 TI - Preoperative vascular access evaluation for haemodialysis patients. AB - BACKGROUND: Haemodialysis treatment requires reliable vascular access. Optimal access is provided via functional arteriovenous fistula (fistula), which compared with other forms of vascular access, provides superior long-term patency, requires few interventions, has low thrombosis and infection rates and cost. However, it has been estimated that between 20% and 60% of fistulas never mature sufficiently to enable haemodialysis treatment. Mapping blood vessels using imaging technologies before surgery may identify vessels that are most suitable for fistula creation. OBJECTIVES: We compared the effect of conducting routine radiological imaging evaluation for vascular access creation preoperatively with standard care without routine preoperative vessel imaging on fistula creation and use. SEARCH METHODS: We searched Cochrane Kidney and Transplant's Specialised Register to 14 April 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that enrolled adult participants (aged >= 18 years) with chronic or end-stage kidney disease (ESKD) who needed fistulas (both before dialysis and after dialysis initiation) that compared fistula maturation rates relating to use of imaging technologies to map blood vessels before fistula surgery with standard care (no imaging). DATA COLLECTION AND ANALYSIS: Two authors assessed study quality and extracted data. Dichotomous outcomes, including fistula creation, maturation and need for catheters at dialysis initiation, were expressed as risk ratios (RR) with 95% confidence intervals (CI). Continuous outcomes, such as numbers of interventions required to maintain patency, were expressed as mean differences (MD). We used the random-effects model to measure mean effects. MAIN RESULTS: Four studies enrolling 450 participants met our inclusion criteria. Overall risk of bias was judged to be low in one study, unclear in two, and high in one.There was no significant differences in the number of fistulas that were successfully created (4 studies, 433 patients: RR 1.06, 95% CI 0.95 to 1.28; I2 = 76%); the number of fistulas that matured at six months (3 studies, 356 participants: RR 1.11, 95% CI 0.98 to 1.25; I2 = 0%); number of fistulas that were used successfully for dialysis (2 studies, 286 participants: RR 1.12, 95% CI 0.99 to 1.28; I2 = 0%); the number of patients initiating dialysis with a catheter (1 study, 214 patients: RR 0.66, 95% CI 0.42 to 1.04); and in the rate of interventions required to maintain patency (1 study, 70 patients: MD 14.70 interventions/1000 patient-days, 95% CI -7.51 to 36.91) between the use of preoperative imaging technologies compared with standard care (no imaging). AUTHORS' CONCLUSIONS: Based on four small studies, preoperative vessel imaging did not improve fistula outcomes compared with standard care. Adequately powered prospective studies are required to fully answer this question. PMID- 26418348 TI - Do emotions or gender drive our actions? A study of motor distractibility. AB - People's interaction with the social environment depends on the ability to attend social cues with human faces being a key vehicle of this information. This study explores whether directing the attention to gender or emotion of a face interferes with ongoing actions. In two experiments, participants reached for one of two possible targets by relying on one of two features of a face, namely, emotion (Experiment 1) or gender (Experiment 2) of a non-target stimulus (a task relevant distractor). Participants' reaching movements deviated toward the task relevant distractor in both experiments. However, when attending to the gender of the face the distractor effect was modulated by both gender (task-relevant feature) and emotion (task-irrelevant feature), with the largest movement deviation being observed toward angry male faces. Endogenous allocation of attention toward faces elicits a competing motor response to the ongoing action and the emotional content of the face contributes to this process at a more automatic and implicit level. PMID- 26418349 TI - The relationship between chitotriosidase activity and tuberculosis. AB - Chitotriosidase, secreted by activated macrophages, is a biomarker of activated macrophages. In this study, we explored whether chitotriosidase could be adopted as a biomarker to evaluate the curative effect on tuberculosis (TB). Five counties were randomly selected out of 122 counties/cities/districts in Hunan Province, China. Our cases were all TB patients who were newly diagnosed or had been receiving treatment at the Centers for Disease Control (CDCs) of these five counties between April and August in 2009. Healthy controls were selected from a community health facility in the Kaifu district of Changsha City after frequency matching of gender and age with the cases. Chitotriosidase activity was evaluated by a fluorometric assay. Categorical variables were analysed with the chi 2 test. Measurement data in multiple groups were tested with analysis of variance and least significant difference (LSD). Correlation between chitotriosidase activity and the degree of radiological extent (DRE) was examined by Spearman's rank correlation test. The average chitotriosidase activity levels of new TB cases, TB cases with different periods of treatment (6 months) and the control group were 54.47, 34.77, 21.54, 12.73 and 10.53 nmol/h.ml, respectively. Chitotriosidase activity in TB patients declined along with the continuity of treatment. The chitotriosidase activity of both smear-positive and the smear-negative pulmonary TB patients decreased after 6 months' treatment to normal levels (P < 0.05). Moreover, chitotriosidase activity was positively correlated with DRE (r = 0.607, P < 0.001). Our results indicate that chitotriosidase might be a marker of TB treatment effects. However, further follow-up study of TB patients is needed in the future. PMID- 26418351 TI - Group B streptococcus infections of soft tissue and bone in California adults, 1995-2012. AB - Group B streptococcus (GBS) is an increasing cause of disease in adults. We present long-term trends in incidence of overall infections and identify characteristics of patients with GBS cellulitis, bone and joint infections. Active, population-based surveillance was conducted from 1995-2012 in three California counties and the data were analysed retrospectively. All cases had isolation of GBS from a normally sterile site. Cases of cellulitis were classified based on clinical diagnosis. GBS bone or joint infection was defined as isolation of GBS from a bone or joint or a diagnosis of osteomyelitis or septic arthritis. Medical charts were reviewed for demographic and clinical information. There were 3917 cases of GBS; the incidence of disease increased from 5.8 to 8.3 cases/100 000 persons (P < 0.001) from 1995 to 2012. In adults aged ?40 years, the overall incidence of GBS increased from 8.5 to 14.2 cases/100 000 (P < 0.001) persons during the study period. The incidence of cellulitis increased from 1.6 to 3.8 cases/100 000 (P < 0.001), bone infection increased from 0.7 to 2.6 cases/100 000 (P < 0.001), and the incidence of joint infection remained approximately constant at an average rate of 1.0 case/100 000. The highest incidence rates were observed in men, persons aged ?80 years, non Hispanic blacks and Hispanics. Diabetes was the most common underlying condition (51.2% cellulitis cases, 76.3% bone infections, 29.8% joint infections). PMID- 26418350 TI - Determination of cut-off cycle threshold values in routine RT-PCR assays to assist differential diagnosis of norovirus in children hospitalized for acute gastroenteritis. AB - Norovirus (NV) is an important cause of acute gastroenteritis in children, but is also frequently detected in asymptomatic children, which complicates the interpretation of NV detection results in both the clinical setting and population prevalence studies. A total of 807 faecal samples from children aged <5 years hospitalized for acute gastroenteritis were collected in Thai Binh, Vietnam, from January 2011 to September 2012. Real-time RT-PCR was used to detect and quantify NV-RNA in clinical samples. A bimodal distribution of cycle threshold (Ct) values was observed in which the lower peak was assumed to represent cases for which NV was the causal agent of diarrhoea, whereas the higher peak was assumed to represent cases involving an alternative pathogen other than NV. Under these assumptions, we applied finite-mixture modelling to estimate a threshold of Ct <21.36 (95% confidence interval 20.29-22.46) to distinguish NV-positive patients for which NV was the likely cause of diarrhoea. We evaluated the validity of the threshold through comparisons with NV antigen ELISA results, and comparisons of Ct values in patients co-infected with rotavirus. We conclude that the use of an appropriate cut-off value in the interpretation of NV real-time RT-PCR results may improve differential diagnosis of enteric infections, and could contribute to improved estimates of the burden of NV disease. PMID- 26418352 TI - Our panel of experts highlight the most important research articles across the spectrum of topics relevant to the field of regenarative medicine. PMID- 26418353 TI - Study of Environment Lifestyle and Fibroids (SELF): Advancing the Field of Fibroid Epidemiology. PMID- 26418354 TI - Did Socioeconomic Inequality in Self-Reported Health in Chile Fall after the Equity-Based Healthcare Reform of 2005? A Concentration Index Decomposition Analysis. AB - OBJECTIVE: Chile, a South American country recently defined as a high-income nation, carried out a major healthcare system reform from 2005 onwards that aimed at reducing socioeconomic inequality in health. This study aimed to estimate income-related inequality in self-reported health status (SRHS) in 2000 and 2013, before and after the reform, for the entire adult Chilean population. METHODS: Using data on equivalized household income and adult SRHS from the 2000 and 2013 CASEN surveys (independent samples of 101 046 and 172 330 adult participants, respectively) we estimated Erreygers concentration indices (CIs) for above average SRHS for both years. We also decomposed the contribution of both "legitimate" standardizing variables (age and sex) and "illegitimate" variables (income, education, occupation, ethnicity, urban/rural, marital status, number of people living in the household, and healthcare entitlement). RESULTS: There was a significant concentration of above average SRHS favoring richer people in Chile in both years, which was less pronounced in 2013 than 2000 (Erreygers corrected CI 0.165 [Standard Error, SE 0.007] in 2000 and 0.047 [SE 0.008] in 2013). To help interpret the magnitude of this decline, adults in the richest fifth of households were 33% more likely than those in the poorest fifth to report above average health in 2000, falling to 11% in 2013. In 2013, the contribution of illegitimate factors to income-related inequality in SRHS remained higher than the contribution of legitimate factors. CONCLUSIONS: Income-related inequality in SRHS in Chile has fallen after the equity-based healthcare reform. Further research is needed to ascertain how far this fall in health inequality can be attributed to the 2005 healthcare reform as opposed to economic growth and other determinants of health that changed during the period. PMID- 26418355 TI - Different Severity and Severity Predictors in Early-Onset and Late-Onset Asthma: A Taiwanese Population-Based Study. AB - BACKGROUND: Late-onset asthma has been shown to be more severe than early-onset asthma in clinic-based studies. However, population-based studies are scarce, and the predictors of severity have been less studied. OBJECTIVES: To determine asthma severity and severity predictors regarding age at onset. METHODS: A cross sectional questionnaire survey was conducted among parents of children from 94 schools in Taiwan in 2004. Asthma severity was defined as short-acting beta2 agonist (SABA), inhaled corticosteroid (ICS) and health care use in the last year. Information on age at onset, demographics, heredity and home exposure was collected. Ordered logistic or logistic regression was used for determining the associations between risk factors and severity. RESULTS: Participants aged 26-50 years were included, resulting in 21,057 (67.8%) participants. Among them, 449 reported ever having had physician-diagnosed asthma, and 381 of those subjects answered the question on age at asthma onset. The risks of rescue SABA, ICS and health care use were generally higher among late-onset (13-50 years) than early onset (0-12 years) asthmatics. Use of SABA and health care increased from childhood-onset, adolescent- or young adult-onset to adult-onset asthma. Allergic rhinitis was positively associated with SABA use (OR, 9.08; 95% CI, 1.06-77.99) and ICS use (OR, 5.08; 95% CI, 1.47-17.52) in early-onset asthma. Dehumidifier use was negatively associated with SABA use (OR, 0.50; 95% CI, 0.29-0.87) and ICS use (OR, 0.38; 95% CI, 0.19-0.78) in late-onset asthma. CONCLUSIONS: In adults, late-onset asthma was more severe than early-onset asthma. Severity, as indicated by SABA and ICS use, was positively associated with allergic rhinitis in early onset asthma and negatively associated with dehumidifier use in late-onset asthma. PMID- 26418356 TI - The European antibody network's practical guide to finding and validating suitable antibodies for research. AB - Antibodies are widely exploited as research/diagnostic tools and therapeutics. Despite providing exciting research opportunities, the multitude of available antibodies also offers a bewildering array of choice. Importantly, not all companies comply with the highest standards, and thus many reagents fail basic validation tests. The responsibility for antibodies being fit for purpose rests, surprisingly, with their user. This paper condenses the extensive experience of the European Monoclonal Antibody Network to help researchers identify antibodies specific for their target antigen. A stepwise strategy is provided for prioritising antibodies and making informed decisions regarding further essential validation requirements. Web-based antibody validation guides provide practical approaches for testing antibody activity and specificity. We aim to enable researchers with little or no prior experience of antibody characterization to understand how to determine the suitability of their antibody for its intended purpose, enabling both time and cost effective generation of high quality antibody-based data fit for publication. PMID- 26418357 TI - A Longitudinal Study of Post-Traumatic Growth and Psychological Distress in Colorectal Cancer Survivors. AB - The stability of post-traumatic growth over time and the relationship between post-traumatic growth and traditional distress outcomes remains unclear. We tracked post-traumatic growth in a population-based sample of colorectal cancer patients from soon after diagnosis to five years subsequently to assess the heterogeneity of a post-traumatic growth response to cancer over time and describe the simultaneous and longitudinal relationships between post-traumatic growth and psychological distress. 1966 colorectal patients who were five months post diagnosis were assessed six times over a five year period. There was considerable heterogeneity associated with both psychological distress and benefit finding scores over time. However, both for benefit finding and psychological distress, the variation in individual scores suggested an underlying positive linear trend and both lagged and lagged change components. Specifically, benefit finding and psychological distress are mutual leading indicators of each other. First, benefit finding served as a leading indicator of distress, in that increases in reported benefit finding from year to year predicted higher future increases in psychological distress. As well, in an inverse relationship, psychological distress served as a leading indicator of benefit finding, such that increases in reported distress from year to year predicted lower future increases in benefit finding. Post-traumatic growth may reflect patients coping efforts to enhance perceptions of wellbeing in response to escalating cancer-related threats, acting as harbinger of increasing trajectories of psychological distress. This explanation is consistent with a cognitive dissonance response in which threats to the integrity of the self then lead to a tendency to accentuate positive aspects of the self. PMID- 26418358 TI - Time to Onset of Sustained Postoperative Pain Relief (SuPPR): Evaluation of a New Systems-Level Metric for Acute Pain Management. PMID- 26418359 TI - Perceptual Inference in Chronic Pain: An Investigation Into the Economy of Action Hypothesis. AB - OBJECTIVE: The experience of chronic pain critically alters one's ability to interact with their environment. One fundamental issue that has received little attention, however, is whether chronic pain disrupts how one perceives their environment in the first place. The Economy of Action hypothesis purports that the environment is spatially scaled according to the ability of the observer. Under this hypothesis it has been proposed that the perception of the world is different between those with and without chronic pain. Such a possibility has profound implications for the investigation and treatment of pain. The present investigation tested the application of this hypothesis to a heterogenous chronic pain population. METHODS: Individuals with chronic pain (36; 27F) and matched pain-free controls were recruited. Each participant was required to judge the distance to a series of target cones, to which they were to subsequently walk. In addition, at each distance, participants used Numerical Rating Scales to indicate their perceived effort and perceived pain associated with the distance presented. RESULTS: Our findings do not support the Economy of Action hypothesis: there were no significant differences in distance estimates between the chronic pain and pain-free groups (F1,60=0.927; P=0.340). In addition, we found no predictive relationship in the chronic pain group between anticipated pain and estimated distance (F1,154=0.122, P=0.727), nor anticipated effort (1.171, P=0.281) and estimated distance (F1,154=1.171, P=0.281). DISCUSSION: The application of the Economy of Action hypothesis and the notion of spatial perceptual scaling as a means to assess and treat the experience of chronic pain are not supported by the results of this study. PMID- 26418360 TI - The Dutch Central Sensitization Inventory (CSI): Factor Analysis, Discriminative Power, and Test-Retest Reliability. AB - OBJECTIVES: A standardized assessment of central sensitization can be performed with the Central Sensitization Inventory (CSI), an English questionnaire consisting of 25 items relating to current health symptoms. The aim of this study was to translate the CSI into Dutch, to perform a factor analysis to reveal the underlying structure, examine its discriminative power, and test-retest reliability. METHODS: The CSI was first translated into Dutch. A factor analysis was conducted on CSI data of a large group of chronic pain patients (n=368). The ability to discriminate between chronic pain patients (n=188) and pain-free controls (n=49) was determined and the test-retest reliability for chronic pain patients (n=36) and controls (n=45) with a time interval of 3 weeks was evaluated. RESULTS: The exploratory factor analysis resulted in a 4-factor model based on 20 items, representing the domains "General disability and physical symptoms" (Cronbach alpha=0.80), "Higher central sensitivity"(Cronbach alpha=0.78), "Urological and dermatological symptoms"(Cronbach alpha=0.60), and "Emotional distress"(Cronbach alpha=0.80). Furthermore, a parsimonious second order factor model was found, where the factor "General central sensitization" was underlying the 4 first-order factors. Chronic pain patients scored significantly worse on all 4 factors. The test-retest reliability was excellent values in both chronic pain patients (ICC=0.88) and controls (ICC=0.91). DISCUSSION: The original CSI was translated into Dutch and did not reveal any problems during data acquisition. The domains represented by the 4 factors may be useful in setting up specific patient profiles and treatment targets. To conclude, the Dutch CSI revealed 4 distinguishable domains, showed good internal consistency for the total score and 3 out of 4 domains, good discriminative power, and excellent test-retest reliability. PMID- 26418361 TI - TGFbeta Pathway Inhibition Redifferentiates Human Pancreatic Islet beta Cells Expanded In Vitro. AB - In-vitro expansion of insulin-producing cells from adult human pancreatic islets could provide an abundant cell source for diabetes therapy. However, proliferation of beta-cell-derived (BCD) cells is associated with loss of phenotype and epithelial-mesenchymal transition (EMT). Nevertheless, BCD cells maintain open chromatin structure at beta-cell genes, suggesting that they could be readily redifferentiated. The transforming growth factor beta (TGFbeta) pathway has been implicated in EMT in a range of cell types. Here we show that human islet cell expansion in vitro involves upregulation of the TGFbeta pathway. Blocking TGFbeta pathway activation using short hairpin RNA (shRNA) against TGFbeta Receptor 1 (TGFBR1, ALK5) transcripts inhibits BCD cell proliferation and dedifferentiation. Treatment of expanded BCD cells with ALK5 shRNA results in their redifferentiation, as judged by expression of beta-cell genes and decreased cell proliferation. These effects, which are reproducible in cells from multiple human donors, are mediated, at least in part, by AKT-FOXO1 signaling. ALK5 inhibition synergizes with a soluble factor cocktail to promote BCD cell redifferentiation. The combined treatment may offer a therapeutically applicable way for generating an abundant source of functional insulin-producing cells following ex-vivo expansion. PMID- 26418363 TI - Highly efficient exciton harvesting and charge transport in ternary blend solar cells based on wide- and low-bandgap polymers. AB - We have designed highly efficient ternary blend solar cells based on a wide bandgap crystalline polymer, poly(3-hexylthiophene) (P3HT), and a low-bandgap polymer, poly[(4,4'-bis(2-ethylhexyl)dithieno[3,2-b:2'3'-d]silole)-2,6-diyl-alt (2,1,3-benzothiadiazole)-4,7-diyl] (PSBTBT), and a fullerene derivative (PCBM). By using highly crystalline P3HT, high fill factors were obtained even for ternary blend solar cells, suggesting efficient charge transport due to large P3HT crystalline domains. In such large crystalline domains, some P3HT excitons could not diffuse into the interface with PCBM but can be collected in PSBTBT domains by efficient energy transfer because of large spectral overlap between the P3HT fluorescence and the PSBTBT absorption. Consequently, all the P3HT excitons can contribute to the photocurrent generation at the P3HT/PCBM interface and/or PSBTBT domains mixed with PCBM in the ternary blends. As a result, P3HT/PSBTBT/PCBM ternary blend solar cells exhibit a power conversion efficiency of 5.6%, which is even higher than those of both individual binary devices of P3HT/PCBM and PSBTBT/PCBM. PMID- 26418362 TI - Acute-Onset Tinnitus Is Associated with Contralateral Hearing in Sudden Deafness. AB - OBJECTIVE: We aimed to evaluate the prognostic factors for acute-onset tinnitus associated with unilateral idiopathic sudden sensorineural hearing loss (ISSNHL) and to assess the relationship between these factors and the final recovery. METHODS: A total of 770 patients with unilateral ISSNHL were enrolled retrospectively and their medical records reviewed. Patients were classified into two groups according to the presence of acute-onset tinnitus at the initial examination. Patient characteristics and the results of pure-tone audiometry were compared between the two groups initially and 3 months later. RESULTS: A total of 70.9% (n = 546) of patients had tinnitus initially. There was no significant difference in the mean hearing thresholds of the affected ear irrespective of accompanying tinnitus. In contrast, patients with tinnitus in the affected ear tended to have significantly better mean hearing thresholds in the nonaffected ear (p < 0.05). The logistic regression analysis revealed that better mean hearing thresholds in the nonaffected ear were associated with tinnitus occurrence (p < 0.05). Better hearing thresholds in the nonaffected ear, younger age, absence of dizziness, low-tone hearing loss, and combined intratympanic dexamethasone injection were associated with full recovery (p < 0.05). However, tinnitus was not an independent risk factor for full recovery. CONCLUSION: Better contralateral hearing was associated with both an increased incidence of concurrent tinnitus and a better final recovery. However, tinnitus was not related to full recovery. PMID- 26418364 TI - Charge Blinking Statistics of Semiconductor Nanocrystals Revealed by Carbon Nanotube Single Charge Sensors. AB - We demonstrate the relation between the optical blinking of colloidal semiconductor nanocrystals (NCs) and their electrical charge blinking for which we provide the first experimental observation of power-law statistics. To show this, we harness the performance of CdSe/ZnS NCs coupled with carbon nanotube field-effect transistors (CNTFETs), which act as single charge-sensitive electrometers with submillisecond time resolution, at room temperature. A random telegraph signal (RTS) associated with the NC single-trap charging is observed and exhibits power-law temporal statistics (tau(-alpha), with alpha in the range of ~1-3), and a Lorentzian current noise power spectrum with a well-defined 1/f(2) corner. The spectroscopic analysis of the NC-CNTFET devices is consistent with the charging of NC defect states with a charging energy of Ec >= 200 meV. These results pave the way for a deeper understanding of the physics and technology of nanocrystal-based optoelectronic devices. PMID- 26418366 TI - Evaluation of beam delivery and ripple filter design for non-isocentric proton and carbon ion therapy. AB - This study aims at selecting and evaluating a ripple filter design compatible with non-isocentric proton and carbon ion scanning beam treatment delivery for a compact nozzle. The use of non-isocentric treatments when the patient is shifted as close as possible towards the nozzle exit allows for a reduction in the air gap and thus an improvement in the quality of scanning proton beam treatment delivery. Reducing the air gap is less important for scanning carbon ions, but ripple filters are still necessary for scanning carbon ion beams to reduce the number of energy steps required to deliver homogeneous SOBP. The proper selection of ripple filters also allows a reduction in the possible transverse and depth dose inhomogeneities that could appear in non-isocentric conditions in particular. A thorough review of existing ripple filter designs over the past 16 years is performed and a design for non-isocentric treatment delivery is presented. A unique ripple filter quality index (QIRiFi) independent of the particle type and energy and representative of the ratio between energy modulation and induced scattering is proposed. The Bragg peak width evaluated at the 80% dose level (BPW80) is proposed to relate the energy modulation of the delivered Bragg peaks and the energy layer step size allowing the production of homogeneous SOBP. Gate/Geant4 Monte Carlo simulations have been validated for carbon ion and ripple filter simulations based on measurements performed at CNAO and subsequently used for a detailed analysis of the proposed ripple filter design. A combination of two ripple filters in a series has been validated for non-isocentric delivery and did not show significant transverse and depth-dose inhomogeneities. Non-isocentric conditions allow a significant reduction in the spot size at the patient entrance (up to 350% and 200% for protons and carbon ions with range shifter, respectively), and therefore in the lateral penumbra in the patients. PMID- 26418367 TI - Hepatic Arterial Phase in Gadoxetic Acid-Enhanced Liver Magnetic Resonance Imaging: Analysis of Respiratory Patterns and Their Effect on Image Quality. AB - OBJECTIVE: The aims of this study were to objectively evaluate patient respiration and breathing change after contrast injection and to assess its potential impact on image quality for the hepatic arterial phase in gadoxetic acid-enhanced magnetic resonance imaging. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and the requirement for informed consent was waived. One hundred fifty-four patients underwent gadoxetic acid-enhanced liver magnetic resonance imaging with a 13 second breath-hold hepatic arterial phase. During the acquisition of precontrast and hepatic arterial phases, the respiratory motion signal was acquired and graded on a 4-point scale based on the SD of the respiratory waveform, with the highest grade indicating the worst breath-hold. Breath-holding grades 3 and 4 for the hepatic arterial phases were considered as breath-holding difficulty during the hepatic arterial phase. Gadoxetic acid-related dyspnea was defined as when the SD value of respiratory waveform during the hepatic arterial phase was 200 greater than that of the precontrast image. Then, the precontrast and hepatic arterial phase images were evaluated with respect to overall image quality and motion artifact using a 5-point scale, with the highest score indicating the worst image quality. In the hepatic arterial phase, the correlation between breath-holding degree and image quality parameters was evaluated using Pearson correlation. The differences in mean image quality scores between patients with and without gadoxetic acid-related dyspnea were evaluated using Student t test. RESULTS: Based on the analysis of the respiratory waveforms, the incidence of breath-holding difficulty during the hepatic arterial phase was 23.4% (33/154), and the incidence of gadoxetic acid-related dyspnea was 6.5% (10/154). By image analysis, the incidence of a degraded hepatic arterial phase (overall image quality score >=4) was 5.2% (8/154). During the hepatic arterial phase, the breath-holding degree correlated with overall image quality and motion artifacts (r = 0.564 and 0.578, respectively). Patients with gadoxetic acid-related dyspnea showed significantly worse image qualities of the hepatic arterial phase than patients without gadoxetic acid-related dyspnea (all, P < 0.001), although image qualities for the precontrast image were not statistically significant between the 2 groups (all, P > 0.05). CONCLUSIONS: The objective analysis of respiratory patterns during a breath-hold is feasible and useful for evaluating gadoxetic acid-related dyspnea and its effect on image quality analysis. PMID- 26418368 TI - Changes in Maximal Strength, Velocity, and Power After 8 Weeks of Training With Pneumatic or Free Weight Resistance. AB - Because free weight (FW) and pneumatic (PN) resistance are characterized by different inertial properties, training with either resistance could afford unique strength, velocity, and power adaptations. Eighteen resistance-trained men completed baseline tests to determine their FW and PN bench press 1 repetition maximum (1RM). During the FW session, 4 explosive repetitions were performed at loads of 15, 30, 45, 60, 75, and 90% 1RM to assess force, velocity, and power. Participants were then assigned to a FW or PN training group, which involved three 90-minute sessions per week for 8 weeks. Both intervention groups completed identical periodized programs with the exception of the resistance used to perform all bench press movements. Free weight participants significantly increased their FW and PN 1RM (10.4 and 9.4%), and maximum (any load) force (9.8%), velocity (11.6%), and power (22.5%). Pneumatic-trained participants also exhibited increases in FW and PN 1RM (11.6 and 17.5%), and maximum force (8.4%), velocity (13.6%), and power (33.4%). Both interventions improved peak barbell velocity at loads of 15 and 30% 1RM; however, only the PN-trained individuals displayed improvements in peak force and power at these same loads. Training with PN resistance may offer advantages if attempting to improve power at lighter relative loads by affording an opportunity to consistently achieve higher accelerations and velocities (F = ma), in comparison with FW. Exploiting the inertial properties of the resistance, whether mass, elastic or PN, could afford an opportunity to develop mixed-method training strategies and/or elicit unique neuromuscular adaptations to suit the specific needs of athletes from sports characterized by varying demands. PMID- 26418369 TI - Effects of 4 Weeks of High-Intensity Interval Training and beta-Hydroxy-beta Methylbutyric Free Acid Supplementation on the Onset of Neuromuscular Fatigue. AB - This study investigated the effects of high-intensity interval training (HIIT) and beta-hydroxy-beta-methylbutyric free acid (HMB) supplementation on physical working capacity at the onset of neuromuscular fatigue threshold (PWC(FT)). Thirty-seven participants (22 men, 15 women; 22.8 +/- 3.4 years) completed an incremental cycle ergometer test (graded exercise test [GXT]); electromyographic amplitude from the right vastus lateralis was recorded. Assessments occurred preceding (PRE) and after 4 weeks of supplementation (POST). Participants were randomly assigned to control (C, n = 9), placebo (P, n = 14), or supplementation (S, n = 14) groups. Both P and S completed 12 HIIT sessions, whereas C maintained normal diet and activity patterns. The PWC(FT) (W) was determined using the maximal perpendicular distance (D(MAX)) method. Electromyographic amplitude (MUVrms) over time was used to generate a cubic regression. Onset of fatigue (TF) was the x-value of the point on the regression that was at D(MAX) from a line between the first and last data points. The PWC(FT) was estimated using TF and GXT power-output increments. The 2-way analysis of variance (ANOVA) (group * time) resulted in a significant interaction for PWC(FT) (F = 6.69, p = 0.004). Post hoc analysis with 1-way ANOVA resulted in no difference in PWC(FT) among groups at PRE (F = 0.87, p = 0.43); however, a difference in PWC(FT) was shown for POST (F = 5.46, p = 0.009). Post hoc analysis among POST values revealed significant differences between S and both P (p = 0.034) and C (p = 0.003). No differences (p = 0.226) were noted between P and C. Paired samples t-tests detected significant changes after HIIT for S (p < 0.001) and P (p = 0.016), but no change in C (p = 0.473). High-intensity interval training increased PWC(FT), but HMB with HIIT was more effective than HIIT alone. Furthermore, it seems that adding HMB supplementation with HIIT in untrained men and women may further improve endurance performance measures. PMID- 26418365 TI - LncRNA-Hh Strengthen Cancer Stem Cells Generation in Twist-Positive Breast Cancer via Activation of Hedgehog Signaling Pathway. AB - Cancer stem cells (CSCs) are a subpopulation of neoplastic cells with self renewal capacity and limitless proliferative potential as well as high invasion and migration capacity. These cells are commonly associated with epithelial mesenchymal transition (EMT), which is also critical for tumor metastasis. Recent studies illustrate a direct link between EMT and stemness of cancer cells. Long non-coding RNAs (lncRNAs) have emerged as important new players in the regulation of multiple cellular processes in various diseases. To date, the role of lncRNAs in EMT-associated CSC stemness acquisition and maintenance remains unclear. In this study, we discovered that a set of lncRNAs were dysregulated in Twist positive mammosphere cells using lncRNA microarray analysis. Multiple lncRNAs associated canonical signaling pathways were identified via bioinformatics analysis. Especially, the Shh-GLI1 pathway associated lncRNA-Hh, transcriptionally regulated by Twist, directly targets GAS1 to stimulate the activation of hedgehog signaling (Hh). The activated Hh increases GLI1 expression, and enhances the expression of SOX2 and OCT4 to play a regulatory role in CSC maintenance. Thus, the mammosphere-formation efficiency (MFE) and the self-renewal capacity in vitro, and oncogenicity in vivo in Twist-positive breast cancer cells are elevated. lncRNA-Hh silence in Twist-positive breast cells attenuates the activated Shh-GLI1 signaling and decreases the CSC-associated SOX and OCT4 levels, thus reduces the MFE and tumorigenesis of transplanted tumor. Our results reveal that lncRNAs function as an important regulator endowing Twist induced EMT cells to gain the CSC-like stemness properties. PMID- 26418370 TI - Kinematics and Kinetics of Squats, Drop Jumps and Imitation Jumps of Ski Jumpers. AB - Squats, drop jumps, and imitation jumps are commonly used training exercises in ski jumping to enhance maximum force, explosive force, and sport-specific skills. The purpose of this study was to evaluate the kinetics and kinematics of training exercises in ski jumping and to find objective parameters in training exercises that most correlate with the competition performance of ski jumpers. To this end, barbell squats, drop jumps, and imitation jumps were measured in a laboratory environment for 10 elite ski jumpers. Force and motion data were captured, and the influence of maximum vertical force, force difference, vertical take-off velocity, knee moments, knee joint power, and a knee valgus/varus index was evaluated and correlated with their season jump performance. The results indicate that, especially for the imitation jumps, a good correlation exists between the vertical take-off velocity and the personal jump performance on the hill (R = 0.718). Importantly, however, the more the athletes tended toward a valgus knee alignment during the measured movements, the worse their performance (R = 0.729 imitation jumps; R = 0.685 squats). Although an evaluation of the athletes' lower limb alignment during competitive jumping on the hill is still required, these preliminary data suggest that performance training should additionally concentrate on improving knee alignment to increase ski jumping performance. PMID- 26418371 TI - New Aggregation-Induced Emitters: Tetraphenyldistyrylbenzenes. AB - The synthesis of five novel distyrylbenzene (DSB) derivatives, featuring a central tetraphenylbenzene core, is reported. The targets show aggregation induced emission (AIE), which, however, is substituent-dependent. For the pure hydrocarbon and derivatives that do not carry (+M) or (-M) substituents, classic AIE behavior is observed, that is, the DSBs are non-fluorescent in solution, but are highly fluorescent in cold matrices, upon aggregate formation in poor solvents and in the solid, crystalline state. If aldehyde or dibutylamino groups are attached in the para-position of the DSB unit, non-classic AIE-phores result. These are fluorescent both in dilute solution as well as in the solid state. Prolonged irradiation of the targets leads to benzotetraphene derivatives by a double cyclization. PMID- 26418372 TI - REMD Simulations Reveal the Dynamic Profile and Mechanism of Action of Deleterious, Rescuing, and Stabilizing Perturbations to NBD1 from CFTR. AB - Cystic Fibrosis (CF) is a lethal, genetic disease caused by mutations to the CFTR chloride channel. The most common CF causing mutation is the deletion of F508 from the first Nucleotide Binding Domain (F508del-NBD1). This mutation leads to a thermally unstable domain and a misfolded, nonfunctioning CFTR. Replica Exchange MD simulations were used to simulate seven NBD1 constructs including wt and F508del-NBD1 both alone and in the presence of known rescuing mutations as well as F508del-NBD1 in complex with a known small (ligand) stabilizer. Analyzing the resulting trajectories suggests that differences in the biochemical properties of the constructs result from local and coupled differences in their dynamic profiles. A comparative analysis of these profiles as well as of the resulting trajectories reveals how the different perturbations exert their deleterious, rescuing, and stabilizing effects on NBD1. These simulations may therefore be useful for the design and mechanism-of-action analysis of new NBD1 stabilizers. PMID- 26418373 TI - Form follows function or does it? PMID- 26418374 TI - Deletion of FAST (Fas-activated serine/threonine phosphoprotein) ameliorates immune complex arthritis in mice. PMID- 26418375 TI - Research on Evidence-Based Practice. PMID- 26418377 TI - Erratum. PMID- 26418376 TI - Ionogels of Sugar Surfactant in Ethylammonium Nitrate: Phase Transition from Closely Packed Bilayers to Right-Handed Twisted Ribbons. AB - In the simplest ionic liquid, ethylammonium nitrate (EAN), ionogels with high mechanical strength were prepared from a surfactant with a disaccharide polar head. Phase structures from closely packed bilayers to right-handed twisted ribbons were determined via freeze-fracture transmission electron microscopy (FF TEM) observations. The phase transition mechanism was investigated deeply and systematically. The temperature contributes to suitable tail chain conformations of surfactant molecules for adapting to different self-assembled structures including right-handed twisted ribbons and bilayers. Two different arrays were revealed for different bilayers by the small-angle X-ray scattering (SAXS) measurements. The rheological and tribological properties of the ionogels were investigated. The better lubricating property and antiwear capability of the ionogels compared to the EAN may be attributed to the structure characteristics and the good thixotropic properties. PMID- 26418378 TI - New Perspectives of the Pathophysiology and Management in Heart Failure. PMID- 26418379 TI - Hereditary Renal Hypouricemia Type 1 and Autosomal Dominant Polycystic Kidney Disease. AB - BACKGROUND: Renal hypouricemia (RHUC) is a heterogeneous inherited disorder characterized by impaired tubular uric acid (UA) transport with severe complications, such as acute kidney injury. Type 1 is caused by a mutation in the SLC22A12 gene (URAT1) and type 2 in the SLC2A9 gene (GLUT9). In this article, the authors present a coexpression functional characterization of variants responsible for RHUC type 1 in a Czech family with polycystic kidney disease (PKD). METHODS: The serum UA concentration in the proband was 1.1 mg/dL and was expressed as an increase in the fractional excretion of UA (43%). The URAT1 allelic variants were prepared and their urate uptake and subcellular localization were studied by Xenopus oocytes expression system. Linkage analysis using a panel of 4 CA-repeat flanking markers for chromosome 16 and a panel of 3 CA-repeat flanking markers for chromosome 4 was performed, which carry the PKD1 and PKD2 genes, respectively. RESULTS: Coexpression results showed that p.G366R and p.R477H suppressed urate transport by wild types. Colocalization studies showed an accumulation of URAT1 in the endoplasmic reticulum of the p.G366R variant and mainly retention of wild-type protein by variants p.G366R and p.R477H. CONCLUSIONS: The findings suggest that not only loss-of-function mutation of URAT1 but also the dominant-negative effect cause RHUC through loss of UA absorption, partly due to protein misfolding caused by accumulation of URAT1 protein in the endoplasmic reticulum. PMID- 26418381 TI - Association Between Body Composition and Bone Mineral Density in Men on Hemodialysis. AB - Studies have revealed complex interactions between bone and fat, however there are few studies about this crosstalk in patients with chronic kidney disease. This study investigated possible relationship between bone mineral density (BMD) and body composition in patients who underwent hemodialysis. Twenty patients were enrolled in a cross-sectional study (47.0 [42.3-56.8] years, body mass index 26.0 +/- 4.2 kg/m, dialysis vintage of 48.5 [26.7-95.7] months). Body composition and BMD were assessed by dual-energy X-ray absorptiometry. Leptin and parathormone levels were analyzed using Multiplex kits (R&D System Inc). Low bone mass in the femoral neck was reported in 54.8% of patients. Total BMD and total T-score were positively correlated with lean mass (r = 0.46, P = 0.04; r = 0.47, P = 0.04, respectively), but not with leptin or body fat mass. In conclusion, lean body mass is probably important to maintain bone health in male patients who underwent hemodialysis. PMID- 26418382 TI - Augmented Hebbian reweighting accounts for accuracy and induced bias in perceptual learning with reverse feedback. AB - Using an asymmetrical set of vernier stimuli (-15", -10", -5", +10", +15") together with reverse feedback on the small subthreshold offset stimulus (-5") induces response bias in performance (Aberg & Herzog, 2012; Herzog, Eward, Hermens, & Fahle, 2006; Herzog & Fahle, 1999). These conditions are of interest for testing models of perceptual learning because the world does not always present balanced stimulus frequencies or accurate feedback. Here we provide a comprehensive model for the complex set of asymmetric training results using the augmented Hebbian reweighting model (Liu, Dosher, & Lu, 2014; Petrov, Dosher, & Lu, 2005, 2006) and the multilocation integrated reweighting theory (Dosher, Jeter, Liu, & Lu, 2013). The augmented Hebbian learning algorithm incorporates trial-by-trial feedback, when present, as another input to the decision unit and uses the observer's internal response to update the weights otherwise; block feedback alters the weights on bias correction (Liu et al., 2014). Asymmetric training with reversed feedback incorporates biases into the weights between representation and decision. The model correctly predicts the basic induction effect, its dependence on trial-by-trial feedback, and the specificity of bias to stimulus orientation and spatial location, extending the range of augmented Hebbian reweighting accounts of perceptual learning. PMID- 26418380 TI - Exposure to High-Risk Medications is Associated With Worse Outcomes in Older Veterans With Chronic Pain. AB - BACKGROUND: Chronic pain is common, costly and leads to significant morbidity in older adults, yet there are limited data on medication safety. The authors sought to evaluate the association of incident high-risk medication in the elderly (HRME) with mortality, emergency department (ED) or hospital care among older adults with chronic pain. METHODS: A retrospective Veterans Health Administration cohort study was conducted examining older veterans with chronic pain diagnoses and use of incident HRME (opioids, skeletal muscle relaxants, antihistamines and psychotropics). Outcomes evaluated included all-cause mortality, ED visits or inpatient hospital care. Descriptive statistics summarized variables for the overall cohort, the chronic pain cohort and those with and without HRME. Separate generalized linear mixed-effect regression models were used to examine the association of incident HRME on each outcome, controlling for potential confounders. RESULTS: Among 1,807,404 veterans who received Department of Veterans Affairs care in 2005 to 2006, 584,066 (32.3%) had chronic pain; 45,945 veterans with chronic pain (7.9%) had incident HRME exposure. The strongest significant associations of incident HRME were for high-risk opioids with all cause hospitalizations (odds ratio [OR] 2.08, 95% confidence interval [CI] 1.95 2.23), skeletal muscle relaxants with all-cause ED visits (OR 2.62, 95% CI 2.52 2.73) and mortality (OR 0.80, 95% CI 0.74-0.86), antihistamines with all-cause ED visits (OR 2.82 95% CI 2.72-2.95) and psychotropics with all-cause hospitalizations (OR 2.15, 95% CI 1.96-2.35). CONCLUSIONS: Our data indicate that incident HRME is associated with clinically important adverse outcomes in older veterans with chronic pain and highlight the importance of being judicious with prescribing certain classes of drugs in this vulnerable population. PMID- 26418383 TI - [The ENGAGE AF-TIMI 48 study]. PMID- 26418384 TI - [The PROMISE study]. PMID- 26418385 TI - [What meta-analyses teach us: pros and cons]. AB - The exponential increase in publications focusing on important clinical issues represents a major challenge for patients, physicians, and decision-makers, despite the braggadocio of many experts. Meta-analysis, when conducted within the context of a systematic review, offers an efficient and potent tool to summarize the clinical evidence accrued on a specific clinical question. Despite their many strengths, which include statistical precision, external validity, and the opportunity to analyze subgroups and moderators, meta-analyses also have many limitations. In addition, they are criticized because potentially an exercise in "mega-silliness", mixing "apples and oranges", unable to improve the quality of primary studies (in keeping with the say "garbage in-garbage out"), and focusing on an "average patient" who is only hypothetical. Yet, it is evident that meta analyses will continue to play a key role in informing decision making whenever the best approach is not self-evident. Thus, it is mandatory to know their main features in order to use them critically and constructively, without being dominated nor scared. PMID- 26418386 TI - [About paroxysmal atrial fibrillation and difficulties in clinical practice. Dubito ergo sum]. AB - The differences in terms of cardioembolic risk of permanent and paroxysmal atrial fibrillation are reviewed. On the basis of the available literature, the authors suggest that their equivalence reported in the recent guideline for the management of patients with atrial fibrillation represents an oversimplification. PMID- 26418387 TI - [Cardiovascular risk in polycystic kidney disease]. AB - Hypertension is common and occurs in the majority of autosomal dominant polycystic kidney disease (ADPKD) patients prior to loss of kidney function. Hypertension relates to progressive kidney enlargement, and is a significant independent risk factor for progression to end-stage renal disease. The pathogenesis of hypertension in ADPKD is complex and depends on many factors that influence each other. High expression of PKD1 and PKD2 genes is present in the cilia of tubular epithelial cells, in endothelial cells and in vascular smooth muscle cells. Decreased or absent polycystin-1 or -2 expression is associated with abnormal vascular structure and function. PKD1/PKD2 deficiency results in reduced nitric oxide levels, altered endothelial response to shear stress with attenuation in vascular relaxation. Activation of the renin-angiotensin aldosterone system occurs in ADPKD due to decreased nitric oxide production as well as bilateral cyst expansion and intra-renal ischemia. With increasing cyst size, further activation of the renin-angiotensin-aldosterone system occurs, blood pressure increases and a vicious cycle ensues with enhanced cyst growth and hypertension ultimately leading to end-stage renal disease. Inhibition of the angiotensin-aldosterone system is possible with angiotensin-converting enzyme inhibitors and seems to be the first-line treatment for hypertension in these subjects. As suggested by the HALT-PKD study, an aggressive blood pressure control is safe and recommended and is associated with preservation of kidney function and a reduction in total kidney volume over time. A collaborative multidisciplinary approach between nephrologists and cardiologists is necessary for the monitoring of kidney and heart complications. PMID- 26418388 TI - [The heart-friendly diet]. AB - The importance of proper diet in primary and secondary cardiovascular prevention is now quite clear: several recent studies, e.g. on fat and saturated fat intake, on sodium, and on dietary cholesterol, are being discussed by the lay press and by professionals. This paper reviews the most solid published evidence on diet and cardiovascular risk, to provide clinicians (namely, cardiologists) with a useful tool to be discussed with patients. Where evidence was strong enough, we discussed the cardiovascular actions of specific nutrients and of dietary patterns. Particular attention was paid to dietary fat, carbohydrates (in terms of glycemic index), and functional, polyphenol-rich foods. Of note, we critically review the available evidence in light of the Italian dietary patterns, to draw practical conclusions applicable to this country. PMID- 26418389 TI - [Cardiac involvement in Churg-Strauss syndrome]. AB - Churg-Strauss syndrome, recently renamed eosinophilic granulomatosis with polyangiitis (EGPA), is a rare form of systemic vasculitis, characterized by disseminated necrotizing vasculitis with extravascular granulomas occurring among patients with asthma and tissue eosinophilia. EGPA is classified as a small and medium-sized vessel vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA) and the hypereosinophilic syndrome. Typical clinical features include asthma, sinusitis, transient pulmonary infiltrates and neuropathy. Blood eosinophils are often >1500/ul or more than 10% on the differential leukocyte count. Blood eosinophils should always be tested in unexplained cardiac disorders, and may normalize even after low doses of corticosteroids. ANCA are positive in 40-60% of cases, mainly anti-myeloperoxidase. Heart involvement occurs in approximately 15-60% of EGPA patients, especially those who are ANCA negative. Any cardiac structure can be involved, and patients present with myocarditis, heart failure, pericarditis, arrhythmia, coronary arteritis, valvulopathy, intracavitary cardiac thrombosis. Although cardiovascular involvement is usually an early manifestation, it can also occur later in the course of the disease. A significant proportion of patients with cardiac involvement is asymptomatic. In the absence of symptoms and major ECG abnormalities, cardiac involvement may be detected in nearly 40% of the patients. All patients with EGPA should be studied not only with a detailed history of cardiac symptoms and ECG, but also with echocardiography; if abnormalities are detected, a cardiac magnetic resonance study should be performed. Coronary angiography and endomyocardial biopsy should be reserved to selected cases. Heart involvement carries a poor prognosis and causes 50% of the deaths of these patients. It is often insidious and underestimated. Optimal therapy is therefore important and based on high-dose corticosteroids plus immunosuppressive agents, particularly cyclophosphamide in case of myocardial inflammation. Thus, early diagnosis of cardiac involvement and subsequent therapy may prevent progression of cardiac disease. At present, the role of troponin and brain natriuretic peptide in monitoring and therapy remains unclear. Orthotopic heart transplantation is feasible in case of severe disease, even if the experience is limited in -EGPA, and optimal post-transplantation immunosuppressive strategy has yet to be defined. PMID- 26418390 TI - [Quality indicators for the assessment of ST-segment elevation acute myocardial infarction (STEMI) networks. How hospital discharge records could be integrated with Emergency medical services data: the Emilia-Romagna STEMI network experience]. AB - BACKGROUND: The assessment of the regional network for ST-segment elevation acute myocardial infarction (STEMI) is fundamental for quality assurance. Since 2011 all Italian Health Authorities, in addition to hospital discharge records (HDR), must provide a standardized information flow (ERD) about emergency department (ED) and emergency medical system (EMS) activities. The aim of this study was to evaluate whether data integration of ERD with HDR may allow the development of appropriate quality indicators. METHODS: Patients admitted to coronary care units (CCU) for STEMI between January 1 to December 31, 2013, were identified from the regional HDR database. All data were linked to those of the regional ERD database. Four quality indicators were defined: 1) rates of EMS activation, 2) rates of EMS direct transfer to the catheterization laboratory (Cath-lab), 3) transfer rates from a Spoke to a Hub hospital with angioplasty facilities, and 4) median time spent in ED. RESULTS: In 2013, 2793 patients with STEMI were admitted to the CCU. Of these, 1684 patients (60%) activated EMS and were transported to Spoke or Hub hospitals; 955 (57%) entered directly in CCU/Cath-lab; 677 were transferred directly to a Hub hospital ED without being admitted to a Spoke hospital. The median ED time in Hub hospital was 47 min (IQR 24-136) and in Spoke hospital 53 min (IQR 30-131). CONCLUSIONS: The integration among administrative data banks (i.e., HDR with ERD) allowed the assessment of the regional STEMI network and the identification of potentially useful quality indicators. Their easy availability should enable comparisons with local, national and international standards, and may favor quality improvement. PMID- 26418391 TI - [Acute results of left ventricular endocardial pacing for cardiac resynchronization therapy obtained with a transapical approach]. AB - Although cardiac resynchronization therapy (CRT) is considered a milestone in the treatment of patients affected with chronic congestive heart failure, reduced left ventricular ejection fraction and enlarged QRS, up to 30% of patients can be considered clinical non-responders to this treatment. In these patients, optimization of atrioventricular and interventricular intervals could be of some help, but results of trials are not univocal on the benefit of this procedure. In the last years, left ventricular endocardial pacing for CRT has emerged as a possible solution in non-responders. Several studies have demonstrated its feasibility and safety, and some reports suggest its incremental efficacy in comparison with traditional epicardial pacing, both obtained transvenously or surgically. We describe the cases of two patients already implanted with a CRT device who came to our attention for clinical non-responsiveness to CRT and who have been successfully treated with the addition of a left endocardial lead. A brief literature review on this topic is also reported. PMID- 26418392 TI - [Sequential spontaneous coronary artery dissection in a female patient on oral ephedrine]. AB - Spontaneous coronary artery dissection (SCAD) is an infrequent, but not rare, cause of acute coronary syndrome. It mainly affects young women, often with few or no traditional cardiovascular risk factors. In the case described, a 57-year old woman experienced a first episode of SCAD involving a distal branch of the circumflex coronary artery--treated conservatively--followed, after a few hours, by a second episode of SCAD involving the left anterior descending coronary artery, complicated by hemodynamic instability and treated with emergency angioplasty. During the previous months, the patient was taking a slimming drug containing ephedrine. Dual spontaneous coronary dissection of different type and involving two different vessels, which occurred in the same patient within a few hours, testifies the heterogeneity of the clinical picture of this syndrome and of the therapeutic approach. PMID- 26418393 TI - [Syncope: an untreated symptom with a lifesaving intervention]. AB - We report the case of a 61-year-old woman referred to our center for cardiac evaluation after a syncope, with echocardiographic findings of a papillary fibroelastoma on the edge of the non-coronary aortic cusp. The three-dimensional transesophageal approach provided a unique understanding of the size and shape of the mass and it favorably directed the surgeon towards treatment with conservative surgery. PMID- 26418394 TI - Silver-Mediated Oxidative Trifluoromethylation of Alcohols to Alkyl Trifluoromethyl Ethers. AB - The development of an efficient and practical method for the preparation of alkyl trifluoromethyl ethers is urgently demanding. The silver-mediated oxidative O trifluoromethylation of primary, secondary, and tertiary alcohols with TMSCF3 under mild reaction conditions is established to provide a novel approach to a broad range of alkyl trifluoromethyl ethers. Further, this method is applied to the late-stage O-trifluoromethylation of complex natural products and prescribed pharmaceutical agents. PMID- 26418395 TI - Organized Aggregation of Porphyrins in Lipid Bilayers for Third Harmonic Generation Microscopy. AB - Nonlinear optical microscopy has become a powerful tool for high-resolution imaging of cellular and subcellular composition, morphology, and interactions because of its high spatial resolution, deep penetration, and low photo-damage to tissue. Developing specific harmonic probes is essential for exploiting nonlinear microscopic imaging for biomedical applications. We report an organized aggregate of porphyrins (OAP) that formed within lipidic nanoparticles showing fingerprint spectroscopic properties, structure-associated second harmonic generation, and superradiant third harmonic generation. The OAP facilitated harmonic microscopic imaging of living cells with significantly enhanced contrast. The structure dependent switch between harmonic (OAP-intact) and fluorescence (OAP-disrupted) generation enabled real-time multi-modality imaging of the cellular fate of nanoparticles. Robustly produced under various conditions and easily incorporated into pre-formed lipid nanovesicles, OAP provides a biocompatible nanoplatform for harmonic imaging. PMID- 26418396 TI - Priming for novel object associations: Neural differences from object item priming and equivalent forms of recognition. AB - The neural substrates of associative and item priming and recognition were investigated in a functional magnetic resonance imaging study over two separate sessions. In the priming session, participants decided which object of a pair was bigger during both study and test phases. In the recognition session, participants saw different object pairs and performed the same size-judgement task followed by an associative recognition memory task. Associative priming was accompanied by reduced activity in the right middle occipital gyrus as well as in bilateral hippocampus. Object item priming was accompanied by reduced activity in extensive priming-related areas in the bilateral occipitotemporofrontal cortex, as well as in the perirhinal cortex, but not in the hippocampus. Associative recognition was characterized by activity increases in regions linked to recollection, such as the hippocampus, posterior cingulate cortex, anterior medial frontal gyrus and posterior parahippocampal cortex. Item object priming and recognition recruited broadly overlapping regions (e.g., bilateral middle occipital and prefrontal cortices, left fusiform gyrus), even though the BOLD response was in opposite directions. These regions along with the precuneus, where both item priming and recognition were accompanied by activation, have been found to respond to object familiarity. The minimal structural overlap between object associative priming and recollection-based associative recognition suggests that they depend on largely different stimulus-related information and that the different directions of the effects indicate distinct retrieval mechanisms. In contrast, item priming and familiarity-based recognition seemed mainly based on common memory information, although the extent of common processing between priming and familiarity remains unclear. Further implications of these findings are discussed. PMID- 26418397 TI - Dishonest Academic Conduct: From the Perspective of the Utility Function. AB - Dishonest academic conduct has aroused extensive attention in academic circles. To explore how scholars make decisions according to the principle of maximal utility, the author has constructed the general utility function based on the expected utility theory. The concrete utility functions of different types of scholars were deduced. They are as follows: risk neutral, risk averse, and risk preference. Following this, the assignment method was adopted to analyze and compare the scholars' utilities of academic conduct. It was concluded that changing the values of risk costs, internal condemnation costs, academic benefits, and the subjective estimation of penalties following dishonest academic conduct can lead to changes in the utility of academic dishonesty. The results of the current study suggest that within scientific research, measures to prevent and govern dishonest academic conduct should be formulated according to the various effects of the above four variables. PMID- 26418398 TI - To jab, or not to jab. PMID- 26418399 TI - Differentiating between red legs and cellulitis and reviewing treatment options. AB - Red legs (RL) is a chronic inflammatory condition often misdiagnosed as cellulitis. Antibiotic therapy is not required and does not resolve the symptoms. The main causes of RL are chronic dermatological and venous disease, including chronic oedema. Raising awareness of this condition among health professionals could prevent misdiagnosis and unnecessary costly and potentially harmful antibiotic therapy. The aim of this paper is to highlight the differential diagnoses and management of red legs, and the author also includes an example through a case history. PMID- 26418400 TI - Reviewing the importance of the cold chain in the distribution of vaccines. AB - Vaccination is an effective public health measure to prevent and control a number of infectious diseases. However, since vaccines are biological products and are sensitive to both heat and cold, they need to be maintained within a narrow range of temperatures, often referred to as the 'cold-chain'. This range, which is between +2 degrees C and +8 degrees C with a target +5 degrees C, does not allow for refreezing or storage at room temperature. This paper discusses the importance of the cold chain, what should be done both to maintain it, and the actions to be taken, should a break be noted. It is important to note the product information supplied with vaccines, which is taken from the summary of product characteristics that forms part of the licensing requirements for each vaccine, and which will state how it should be stored. Using a vaccine that has not been stored according to these instructions constitutes off-label use, for which the individual practitioner must take responsibility. It also emphasises the fragile nature of many public health interventions, maintenance of which require constant vigilance and close cooperation between many groups and individuals. PMID- 26418401 TI - Caring for stoma patients with arthritis and mental incapacities. AB - Mental incapacities in the form of dementia, Parkinson's disease, Huntington's disease, and the physical incapacities of arthritis are difficult hurdles for an older patient who has to undergo stoma surgery, irrespective of the stoma being temporary or permanent. The loss of intellectual and physical function can cause significant deterioration in the patient's ability to carry out day-to-day activities and can also manifest itself in changes in social behaviour. Caring for these patients in the community will require the nurse to adjust the patient's care accordingly, and provide a holistic and more individualised care package that includes the support of the carer or spouse. This article discusses the ways in which community nurses can help the older stoma patient and carer. PMID- 26418402 TI - Role of district and community nurses in bereavement care: a qualitative study. AB - BACKGROUND: The district nurse is one of the main providers of palliative care, which includes bereavement care. However, previous evidence shows a lack of education and training, as well as time management, as important factors in the delivery of bereavement care. AIM: This qualitative study aimed to explore the provision of bereavement care from a district nurse's perspective. METHOD: Data were collected from five participants using semi-structured interviews, and thematically analysed to produce the findings. The interviews were conducted within the author's and participants' working environments to maintain a professional stance between both parties. FINDINGS: The results suggest an awareness of bereavement care, but a lack of training and education into the theoretical aspects of the care. Knowing the types and stages of bereavement would be beneficial, both in the delivery and the identification of the most effective time to refer on. CONCLUSION: Bereavement care was understood to be part of the district nurse role, but the findings suggest that some nurses get too involved and no end date could be standardised, as each case is dependent on need. More experience of bereavement care and exposure increased awareness to its importance and improved confidence toward its delivery. PMID- 26418403 TI - Reviewing education challenges and solutions for health professionals in community care. AB - The biggest asset of the NHS is its staff. Health professionals working in the community are faced with a number of challenges to maintain and develop their knowledge and skills in their clinical practice. NHS England's Five Year Forward View describes the need for change, identifying the necessity to reshape care delivery, harnessing technology, and driving down variations in quality and safety of care. This article explores some of the challenges faced by community health-care providers and reviews possible solutions to meet community health care needs for now as well as the future. PMID- 26418405 TI - Facing death: 'in our unconscious, we are immortal'. PMID- 26418404 TI - Understanding the Code: keeping accurate records. AB - In his continuing series looking at the legal and professional implications of the Nursing and Midwifery Council's revised Code of Conduct, Richard Griffith discusses the elements of accurate record keeping under Standard 10 of the Code. This article considers the importance of accurate record keeping for the safety of patients and protection of district nurses. The legal implications of records are explained along with how district nurses should write records to ensure these legal requirements are met. PMID- 26418406 TI - Providing meaningful support to patients with asthma. PMID- 26418407 TI - Community nursing: the linchpin of quality care. PMID- 26418408 TI - Validation of the Canada Acute Coronary Syndrome Risk Score for Hospital Mortality in the Gulf Registry of Acute Coronary Events-2. AB - BACKGROUND: Several risk scores have been developed for acute coronary syndrome (ACS) patients, but their use is limited by their complexity. The new Canada Acute Coronary Syndrome (C-ACS) risk score is a simple risk-assessment tool for ACS patients. This study assessed the performance of the C-ACS risk score in predicting hospital mortality in a contemporary Middle Eastern ACS cohort. HYPOTHESIS: The C-ACS score accurately predicts hospital mortality in ACS patients. METHODS: The baseline risk of 7929 patients from 6 Arab countries who were enrolled in the Gulf RACE-2 registry was assessed using the C-ACS risk score. The score ranged from 0 to 4, with 1 point assigned for the presence of each of the following variables: age >=75 years, Killip class >1, systolic blood pressure <100 mm Hg, and heart rate >100 bpm. The discriminative ability and calibration of the score were assessed using C statistics and goodness-of-fit tests, respectively. RESULTS: The C-ACS score demonstrated good predictive values for hospital mortality in all ACS patients with a C statistic of 0.77 (95% confidence interval [CI]: 0.74-0.80) and in ST-segment elevation myocardial infarction and non-ST-segment elevation acute coronary syndrome patients (C statistic: 0.76, 95% CI: 0.73-0.79; and C statistic: 0.80, 95% CI: 0.75-0.84, respectively). The discriminative ability of the score was moderate regardless of age category, nationality, and diabetic status. Overall, calibration was optimal in all subgroups. CONCLUSIONS: The new C-ACS score performed well in predicting hospital mortality in a contemporary ACS population outside North America. PMID- 26418410 TI - Assessing Bleeding Risk With the HAS-BLED Score: Balancing Simplicity, Practicality, and Predictive Value in Bleeding-Risk Assessment. PMID- 26418409 TI - The HAS-BLED Score for Predicting Major Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: A Systematic Review and Meta-analysis. AB - Our objective was to compare the diagnostic accuracy between the HAS-BLED score and any of HEMORR2 HAGES, ATRIA, CHADS2 , or CHA2 DS2 -VASc scores in anticoagulated patients with atrial fibrillation. We systematically searched the Cochrane Library, MEDLINE, PubMed, and Embase databases for relevant studies. Data were extracted and analyzed according to predefined clinical endpoints. Eleven studies were identified. Discrimination analysis demonstrates that HAS BLED has no significant C-statistic differences for bleeding risk prediction compared with ATRIA or HEMORR2 HAGES, but it has significant differences compared with CHADS2 or CHA2 DS2 -VASc. The significant positive net reclassification improvement and integrated discrimination improvement values also show that HAS BLED is superior to that of any of HEMORR2 HAGES, ATRIA, CHADS2 , or CHA2 DS2 VASc scores. According to calibration analysis of HAS-BLED, it overpredicts the risk of bleeding in the low (risk ratio [RR]: 1.16, 95% confidence interval [CI]: 0.63-2.13, P = 0.64) risk stratification but underpredicts that in the moderate (RR: 0.66, 95% CI: 0.51-0.86, P = 0.002) and high (RR: 0.88, 95% CI: 0.70-1.10, P = 0.27) risk stratifications. The HAS-BLED score not only performs better than the HEMORR2 HAGES and ATRIA bleeding scores, but it also is superior to the CHADS2 and CHA2 DS2 -VASc stroke scores for bleeding prediction. The HAS-BLED score should be the optimal choice to assess major bleeding risk in clinical practice. PMID- 26418411 TI - Smart Muscle-Driven Self-Cleaning of Biomimetic Microstructures from Liquid Crystal Elastomers. AB - Muscle-driven actuation of biomimetic microfibrillar structures is achieved using integrative soft-lithography on a backing splayed liquid-crystal elastomer (LCE). Variation in the backing LCE layer thickness yields different modes of thermal deformation from a pure bend to a twist-bend. Muscular motion and dynamic self cleaning of gecko toe pads are mimicked via this mechanism. PMID- 26418412 TI - Pharmacokinetics and Urinary Excretion Mechanism of Orteronel (TAK-700), A Novel 17,20-Lyase Inhibitor, in Animals. AB - Orteronel is newly identified as a selective 17,20-lyase inhibitor for an agent for castration resistant prostate cancer. The absorption and disposition of [(14)C]orteronel were investigated in rats and monkeys. Orteronel was extensively excreted into rat and monkey urine in an unchanged form after oral administration. The unbound based renal clearances in rats and monkeys were greater than the respective glomerular filtration rates (GFR), suggesting that urinary tubular secretion plays an important role in the renal excretion of orteronel. Therefore, the uptake of [(14)C]orteronel was investigated using rat kidney slices to estimate the contribution of carrier-mediated transport on the urinary tubular secretion. The uptake study using rat kidney slices suggested that the transport of orteronel from the blood circulation to the kidney was mediated by a digoxin sensitive transport system represented by Oatp4c1 and non saturable components. Furthermore, the saturable component accounted for a limited fraction of the total renal uptake by rat kidney slices. These results suggested that non-saturable uptake mainly contributed to the renal excretion of orteronel in rats. PMID- 26418413 TI - Acotiamide Hydrochloride, a Therapeutic Agent for Functional Dyspepsia, Enhances Acetylcholine-induced Contraction via Inhibition of Acetylcholinesterase Activity in Circular Muscle Strips of Guinea Pig Stomach. AB - Acotiamide is a first-in-class prokinetic drug approved in Japan for the treatment of functional dyspepsia. Given that acotiamide enhances gastric motility in conscious dogs and rats, we assessed the in vitro effects of this drug on the contraction of guinea pig stomach strips and on acetylcholinesterase (AChE) activity in stomach homogenate following fundus removal. We also investigated the serotonin 5-HT4 receptor agonist mosapride, dopamine D2 receptor and AChE inhibitor itopride, and representative AChE inhibitor neostigmine. Acotiamide (0.3 and 1 MUM) and itopride (1 and 3 MUM) significantly enhanced the contraction of gastric body strips induced by electrical field stimulation (EFS), but mosapride (1 and 10 MUM) did not. Acotiamide and itopride significantly enhanced the contraction of gastric body and antrum strips induced by acetylcholine (ACh), but not that induced by carbachol (CCh). Neostigmine also significantly enhanced the contraction of gastric body strips induced by ACh, but not that by CCh. In contrast, mosapride failed to enhance contractions induced by either ACh or CCh in gastric antrum strips. Acotiamide exerted mixed inhibition of AChE, and the percentage inhibition of acotiamide (100 MUM) against AChE activity was markedly reduced after the reaction mixture was dialyzed. In contrast, itopride exerted noncompetitive inhibition on AChE activity. These results indicate that acotiamide enhances ACh-dependent contraction in gastric strips of guinea pigs via the inhibition of AChE activity, and that it exerts mixed and reversible inhibition of AChE derived from guinea pig stomach. PMID- 26418414 TI - Pharmacokinetic Study of a Diclofenac Sodium Capsule Filled with Enteric-coated Pellets in Healthy Chinese Volunteers by Liquid Chromatography-electrospray Ionization-tandem Mass Spectrometry. AB - The pharmacokinetic study of a diclofenac sodium capsule filled with enteric coated pellets (abbreviated as CAPSULE) in healthy Chinese subjects was evaluated using liquid chromatography-electrospray ionization-tandem mass spectrometry with simple sample preparation. In a cross-over study, 12 healthy male volunteers were given 50 mg CAPSULE and diclofenac sodium enteric-coated tablet (abbreviated as TABLET, used as a control dosage form) at fasting. The Cmax, AUC0-t, and Tmax of CAPSULE were 1.01+/-0.52 MUg/mL, 1.54+/-0.18 MUg.h/mL, and 1.50+/-1.31 h, respectively. When compared with TABLET, the pharmacokinetic study showed that although this CAPSULE exhibited similar AUC (only 10% lower), it presented lower maximum plasma concentration, faster absorption and shorter time to reach maximum concentration. When compared with the previous study in Germany, obvious variations on Tmax were found in Chinese subjects taking CAPSULE, but not TABLET. The results indicated that individual difference should be paid attention when prescribing CAPSULE to Chinese patients. PMID- 26418415 TI - Relationship between Tregitopes Structure and Binding with Major Histocompatibility Complex Class I. AB - Epitopes of T-cells (tregitopes) are linear sequences of amino acids present in many animal and human proteins. Tregitopes suppress the immunological response and could play a significant regulatory role in the pathogenesis of autoimmune diseases. They modulate T-cell response activated by the antigens of the major histocompatibility complex class I (MHC-I).The aim of this study was an attempt to determine the correlation between physicochemical properties and structures of tregitopes and their binding strength with MHC-I. 21 amino acid sequences of immunoglobulin G with verified or similar to tregitopes function were selected. The analysis of the binding strength with MHC-I was carried out on 41 various alleles since MHC-I can be coded by numerous alleles. The first phase of study attempted to find a correlation between the half minimal inhibitory concentration (LogIC50) calculated for MHC-I and physicochemical properties. From formulated arithmetic statements, only one allowed to determine significant correlation with LogIC50 with reference to alleles A*02:01 and A*02:06. The correlations for the alleles were linear and sigmoid, respectively (p<0.001). The presence of the repeated amino acids was confirmed in the sequences of the studied compounds. These amino acids are connected with stronger binding or lack of the binding with MHC-I expressed by LogIC50. The study shows the translation from the classification (cloud) model to the linear one. The significant linear dependence between chemical structure of tregitopes and their LogIC50 calculated for MHC-I was displayed. The presented method can be used in screening of new sequences that have regulatory properties for regulatory T-cells. PMID- 26418416 TI - Correction: Analysis of Response Elements Involved in the Regulation of the Human Neonatal Fc Receptor Gene (FCGRT). PMID- 26418417 TI - CT segmentation of dental shapes by anatomy-driven reformation imaging and B spline modelling. AB - Dedicated imaging methods are among the most important tools of modern computer aided medical applications. In the last few years, cone beam computed tomography (CBCT) has gained popularity in digital dentistry for 3D imaging of jawbones and teeth. However, the anatomy of a maxillofacial region complicates the assessment of tooth geometry and anatomical location when using standard orthogonal views of the CT data set. In particular, a tooth is defined by a sub-region, which cannot be easily separated from surrounding tissues by only considering pixel grey intensity values. For this reason, an image enhancement is usually necessary in order to properly segment tooth geometries. In this paper, an anatomy-driven methodology to reconstruct individual 3D tooth anatomies by processing CBCT data is presented. The main concept is to generate a small set of multi-planar reformation images along significant views for each target tooth, driven by the individual anatomical geometry of a specific patient. The reformation images greatly enhance the clearness of the target tooth contours. A set of meaningful 2D tooth contours is extracted and used to automatically model the overall 3D tooth shape through a B-spline representation. The effectiveness of the methodology has been verified by comparing some anatomy-driven reconstructions of anterior and premolar teeth with those obtained by using standard tooth segmentation tools. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26418418 TI - Correction: The Absence of CYP3A5*3 Is a Protective Factor to Anticonvulsants Hypersensitivity Reactions: A Case-Control Study in Brazilian Subjects. PMID- 26418419 TI - Comprehensive Identification of Sexual Dimorphism-Associated Differentially Expressed Genes in Two-Way Factorial Designed RNA-Seq Data on Japanese Quail (Coturnix coturnix japonica). AB - Japanese quail (Coturnix coturnix japonica) reach sexual maturity earlier, breed rapidly and successfully, and cost less and require less space than other birds raised commercially. Given the value of this species for food production and experimental use, more studies are necessary to determine chromosomal regions and genes associated with gender and breed-differentiation. This study employed Trinity and edgeR for transcriptome analysis of next-generation RNA-seq data, which included 4 tissues obtained from 3 different breeding lines of Japanese quail (random bred control, heavy weight, low weight). Differentially expressed genes shared between female and male tissue contrast groups were analyzed to identify genes related to sexual dimorphism as well as potential novel candidate genes for molecular sexing. Several of the genes identified in the present study as significant sex-related genes have been previously found in avian gene expression analyses (NIPBL, UBAP2), and other genes found differentially expressed in this study and not previously associated with sex-related differences may be considered potential candidates for molecular sexing (TERA, MYP0, PPR17, CASQ2). Additionally, other genes likely associated with neuronal and brain development (CHKA, NYAP), as well as body development and size differentiation (ANKRD26, GRP87) in quail were identified. Expression of homeobox protein regulating genes (HXC4, ISL1) shared between our two sex-related contrast groups (Female Brain vs. Male Brain and Ovary vs. Testis) indicates that these genes may regulate sex-specific anatomical development. Results reveal genetic features of the quail breed and could allow for more effective molecular sexing as well as selective breeding for traits important in commercial production. PMID- 26418421 TI - Extended Suspect and Non-Target Strategies to Characterize Emerging Polar Organic Contaminants in Raw Wastewater with LC-HRMS/MS. AB - An integrated workflow based on liquid chromatography coupled to a quadrupole time-of-flight mass spectrometer (LC-QTOF-MS) was developed and applied to detect and identify suspect and unknown contaminants in Greek wastewater. Tentative identifications were initially based on mass accuracy, isotopic pattern, plausibility of the chromatographic retention time and MS/MS spectral interpretation (comparison with spectral libraries, in silico fragmentation). Moreover, new specific strategies for the identification of metabolites were applied to obtain extra confidence including the comparison of diurnal and/or weekly concentration trends of the metabolite and parent compounds and the complementary use of HILIC. Thirteen of 284 predicted and literature metabolites of selected pharmaceuticals and nicotine were tentatively identified in influent samples from Athens and seven were finally confirmed with reference standards. Thirty four nontarget compounds were tentatively identified, four were also confirmed. The sulfonated surfactant diglycol ether sulfate was identified along with others in the homologous series (SO4C2H4(OC2H4)xOH), which have not been previously reported in wastewater. As many surfactants were originally found as nontargets, these compounds were studied in detail through retrospective analysis. PMID- 26418420 TI - Experimental Infection of Sheep at 45 and 60 Days of Gestation with Schmallenberg Virus Readily Led to Placental Colonization without Causing Congenital Malformations. AB - BACKGROUND: Main impact of Schmallenberg virus (SBV) on livestock consists in reproductive disorders, with teratogenic effects, abortions and stillbirths. SBV pathogenesis and viral placental crossing remain currently poorly understood. Therefore, we implemented an experimental infection of ewes, inoculated with SBV at 45 or 60 days of gestation (dg). METHODOLOGY: "Mourerous" breed ewes were randomly separated in three groups: eight and nine ewes were subcutaneously inoculated with 1 ml of SBV infectious serum at 45 and 60 dg, respectively (G45 and G60). Six other ewes were inoculated subcutaneously with sterile phosphate buffer saline as control group. All SBV inoculated ewes showed RNAemia consistent with previously published studies, they seroconverted and no clinical sign was reported. Lambs were born at term via caesarian-section, and right after birth they were blood sampled and clinically examined. Then both lambs and ewes were euthanatized and necropsied. PRINCIPAL FINDINGS/SIGNIFICANCE: No lambs showed any malformation suggestive of SBV infection and none of them had RNAemia or anti-SBV antibodies prior to colostrum uptake. Positive SBV RNA detection in organs was rare in both G45 and G60 lambs (2/11 and 1/10, respectively). Nevertheless most of the lambs in G45 (9/11) and G60 (9/10) had at least one extraembryonic structure SBV positive by RTqPCR. The number of positive extraembryonic structures was significantly higher in G60 lambs. Time of inoculation (45 or 60 dg) had no impact on the placental colonization success rate but affected the frequency of detecting the virus in the offspring extraembryonic structures by the time of lambing. SBV readily colonized the placenta when ewes were infected at 45 or 60 dg but infection of the fetuses was limited and did not lead to congenital malformations. PMID- 26418422 TI - Toxicity of Tributyltin in Juvenile Common Carp (Cyprinus Carpio): Physiological Responses, Hepatic Gene Expression, and Stress Protein Profiling. AB - In this study, the effects of tributyltin (TBT) on biochemical parameters (antioxidant responses and Na(+) -K(+) -ATPase) in different tissues were investigated by using juvenile common carp (Cyprinus Carpio) as well as growth and ion regulation-related genes expression and stress-related proteins profiling in fish liver. Oxidative stress indices and Na(+) -K(+) -ATPase showed tissues specific responses in fish exposed to different TBT concentrations. All tested genes related to GH/IGF-I axis and ion-regulation were significantly induced in the TBT group with lower concentrations (except for the igfbp3 in 10 MUg/L) and were inhibited in 20 MUg/L. In addition, the profiling of two proteins Hsp 70 and MT were increasing in a dose-dependent manner under TBT stress. In short, TBT induced biochemical and molecular responses in different tissues were reflected in the measured parameters in the test. On the basis of TBT residue levels in the natural environment, more long-term experiments at lower concentrations will be necessary in the future. PMID- 26418424 TI - A Tribute to Martin D. Brasier: Palaeobiologist and Astrobiologist (April 12, 1947-December 16, 2014). PMID- 26418425 TI - Is disulphide/thiol ratio related to blood pressure in masked hypertension? AB - Dynamic thiol/disulphide homeostasis plays a critical role in numerous intracellular enzymatic pathways including antioxidant defence and detoxification. In this study, we sought to investigate dynamic thiol/disulphide homeostasis in patients with masked hypertension (MHT) and its relationship with blood pressure. Forty patients (23 men, 17 women) with newly diagnosed MHT and not yet on medical therapy, and 40 healthy volunteers (21 men, 19 women) were enrolled. Blood thiol/disulphide homeostasis was measured in both groups. Serum native and total thiol levels were measured using the novel, fully automated colorimetric method developed by Erel et al. Serum disulphide level was calculated as (serum total thiol - serum native thiol)/2. Native and total thiol levels (p = 0.001) and native thiol/total thiol ratio (p = 0.023) were found to be lower in patients with MHT when compared to those of the control group. Disulphide level and ratios of disulphide/native thiol and disulphide/total thiol were higher in patients with MHT than in the control group (p = 0.001). A positive correlation of systolic blood pressure (SBP) and diastolic blood pressure (DBP) was observed with disulphide/native thiol ratio (p < 0.001). Stepwise multivariable regression analysis showed disulphide/native thiol ratio to be an independent risk factor of SBP and DBP, and SBP to be an independent risk factor of disulphide/thiol ratio (p = 0.001). In this study, we found that dynamic thiol/disulphide homeostasis shifted towards disulphide formation due to thiol oxidation in patients with MHT. Prospective randomised controlled studies are required to elucidate whether abnormal thiol/disulphide status lies in the pathogenesis of MHT or is a consequence of MHT. PMID- 26418423 TI - Lack of CD151/integrin alpha3beta1 complex is predictive of poor outcome in node negative lobular breast carcinoma: opposing roles of CD151 in invasive lobular and ductal breast cancers. AB - BACKGROUND: The proposed involvement of CD151 in breast cancer (BCa) progression is based on findings from studies in invasive ductal carcinoma (IDC). The IDC and invasive lobular carcinoma (ILC) represent distinct disease entities. Here we evaluated clinical significance of CD151 alone and in association with integrin alpha3beta1 in patients with ILC in context of the data of our recent IDC study. METHODS: Expression of CD151 and/or integrin alpha3beta1 was evaluated in ILC samples (N=117) using immunohistochemistry. The findings were analysed in relation to our results from an IDC cohort (N=182) demonstrating a prognostic value of an expression of CD151/integrin alpha3beta1 complex in patients with HER2-negative tumours. RESULTS: Unlike in the IDCs, neither CD151 nor CD151/alpha3beta1 complex showed any correlation with any of the ILC characteristics. Lack of both CD151 and alpha3beta1 was significantly correlated with poor survival (P=0.034) in lymph node-negative ILC N(-) cases. The CD151( )/alpha3beta1(-) patients had 3.12-fold higher risk of death from BCa in comparison with the rest of the ILC N(-) patients. CONCLUSIONS: Biological role of CD151/alpha3beta1 varies between ILC and IDC. Assessment of CD151/alpha3beta1 might help to identify ILC N(-) patients with increased risk of distant metastases. PMID- 26418426 TI - High genetic variation in resting-stage production in a metapopulation: Is there evidence for local adaptation? AB - Local adaptation is a key process for the maintenance of genetic diversity and population diversification. A better understanding of the mechanisms that allow (or prevent) local adaptation constitutes a key in apprehending how and at what spatial scale it occurs. The production of resting stages is found in many taxa and reflects an adaptation to outlast adverse environmental conditions. Daphnia magna (Crustacea) can alternate between asexual and sexual reproduction, the latter being linked to dormancy, as resting stages can only be produced sexually. In this species, on a continental scale, resting-stage production is locally adapted--that is, it is induced when the photoperiod indicates the imminence of habitat deterioration. Here, we aimed to explore whether selection is strong enough to maintain local adaptation at a scale of a few kilometers. We assessed life-history traits of 64 D. magna clones originating from 11 populations of a metapopulation with permanent and intermittent pool habitats. We found large within- and between-population variation for all dormancy-related traits, but no evidence for the hypothesized higher resting-stage production in animals from intermittent habitats. We discuss how gene flow, founder events, or other forms of selection might interfere with the process of local adaptation. PMID- 26418428 TI - Does Sarcopenia Impact Complications and Overall Survival in Patients Undergoing Radical Nephrectomy for Stage III and IV Kidney Cancer? AB - PURPOSE: To investigate the association of sarcopenia (muscle mass wasting) with complications and survival in patients undergoing radical nephrectomy for advanced kidney cancer. PATIENTS AND METHODS: We identified 137 patients with stage III and IV kidney cancer who underwent radical nephrectomy between 2008 and 2012. Preoperative cross-sectional imaging was used to measure total psoas area (TPA) at the level of L3 and controlled for height (m(2)). Sarcopenia was identified as TPA in the lowest gender-specific quartile. Patient characteristics and postoperative complications were compared between sarcopenic and nonsarcopenic patients. Kaplan-Meier survival curve estimates were generated for overall and gender-specific survival. RESULTS: Preoperative cross-sectional imaging was available for 128 patients (93%, 85 men and 43 women). Mean TPA for men was 5.49 cm(2)/m(2) versus 4.27 cm(2)/m(2) for women (P < 0.05). Sarcopenia was associated with risk of Clavien grade III or higher complication (P = 0.03) and node-positive disease (P = 0.01). Median follow-up was 48.3 months. Kaplan Meier estimates of overall and gender-specific survival were similar between sarcopenic and nonsarcopenic patients. CONCLUSION: Sarcopenia appears to be associated with risk of major complication after radical nephrectomy for advanced kidney cancer. It was not related to overall survival, however. This preoperative imaging tool may be helpful in preoperative counseling and preparation. PMID- 26418429 TI - Full-Thickness Astigmatic Keratotomy Combined With Small-Incision Lenticule Extraction to Treat High-Level and Mixed Astigmatism. AB - PURPOSE: To explore the clinical effects of combined full-thickness astigmatic keratotomy and small-incision lenticule extraction (SMILE) in patients who are inoperable using SMILE alone. METHODS: We included 13 eyes of 9 patients with high-level or mixed astigmatism who underwent full-thickness astigmatic keratotomy followed by SMILE (secondarily) to correct the residual refractive error. RESULTS: Six months after SMILE, the spherical equivalent was reduced from -4.83 +/- 3.26 D to -0.17 +/- 0.38 D (P < 0.001), and the astigmatism was reduced from 5.12 +/- 0.96 D to 0.21 +/- 0.22 D (P < 0.001). The uncorrected and corrected (CDVA) distance visual acuities improved from 1.07 +/- 0.62 to 0.02 +/- 0.13 (P < 0.001) and from 0.08 +/- 0.14 to -0.01 +/- 0.14 (P = 0.002), respectively. The CDVA improved by 1 or 2 Snellen lines in 8 cases (61.5%), and there was no loss in CDVA. All procedures were completed without intraoperative or postoperative complications. CONCLUSIONS: This combined procedure was effective and safe for the treatment of high-level or mixed astigmatism. PMID- 26418427 TI - Possible Further Evidence of Low Genetic Diversity in the El Sidron (Asturias, Spain) Neandertal Group: Congenital Clefts of the Atlas. AB - We present here the first cases in Neandertals of congenital clefts of the arch of the atlas. Two atlases from El Sidron, northern Spain, present respectively a defect of the posterior (frequency in extant modern human populations ranging from 0.73% to 3.84%), and anterior (frequency in extant modern human populations ranging from 0.087% to 0.1%) arch, a condition in most cases not associated with any clinical manifestation. The fact that two out of three observable atlases present a low frequency congenital condition, together with previously reported evidence of retained deciduous mandibular canine in two out of ten dentitions from El Sidron, supports the previous observation based on genetic evidence that these Neandertals constituted a group with close genetic relations. Some have proposed for humans and other species that the presence of skeletal congenital conditions, although without clinical significance, could be used as a signal of endogamy or inbreeding. In the present case this interpretation would fit the general scenario of high incidence of rare conditions among Pleistocene humans and the specific scenariothat emerges from Neandertal paleogenetics, which points to long-term small and decreasing population size with reduced and isolated groups. Adverse environmental factors affecting early pregnancies would constitute an alternative, non-exclusive, explanation for a high incidence of congenital conditions. Further support or rejection of these interpretations will come from new genetic and skeletal evidence from Neandertal remains. PMID- 26418430 TI - New Method for Removing Thermosensitive Acrylic Punctal Plugs From Lacrimal Puncta. AB - PURPOSE: This study explored a new method for removing thermosensitive acrylic punctal plugs from lacrimal puncta. METHODS: A total of 14 dry eye patients (14 eyes), who required the removal of thermosensitive acrylic punctal plugs from the lacrimal puncta because of serious complications, were recruited. Among the 14 patients, lacrimal punctal granuloma formation occurred in 3 patients, tearing occurred in 6 patients, canaliculitis occurred in 3 patients, and chronic inflammation of the ocular surface occurred in 2 patients. The plugs were removed using a new method. Briefly, after local anesthesia was administered, a small lid clamp was used to flip the eyelid outward. After the application of the lid clamp, the plug could be removed without the use of any additional tools if the lacrimal punctum was large enough. If the lacrimal punctum was not large enough, microforceps were used to expand the lacrimal punctum before the application of the lid clamp. If the plug still could not be removed after the expansion of the lacrimal punctum, we moved the small lid clamp from the distal side of the lacrimal ductule to the lacrimal punctum. RESULTS: Using this method, the plug was successfully removed in all of the patients. CONCLUSIONS: This is a simple and effective method for removing thermosensitive acrylic punctal plugs from lacrimal puncta. CLINICAL TRIAL REGISTRATION-URL: : http://www.clinicaltrials.gov. Unique identifier: ChiCTR-IPR-14005476. PMID- 26418431 TI - Descemet Membrane Endothelial Keratoplasty for a Decompensated Penetrating Keratoplasty Graft in the Presence of a Long Glaucoma Tube. AB - PURPOSE: To describe specific maneuvers and technical modifications to the standardized "no-touch" technique of Descemet membrane endothelial keratoplasty (DMEK) to successfully handle the presence of a glaucoma drainage device (GDD) tube in the anterior chamber of an eye with a failed primary penetrating keratoplasty (PK) graft. METHODS: A 42-year-old male patient underwent DMEK because of a failed primary PK graft in his phakic right eye. The patient was then evaluated at 3 and at 6 months after surgery. RESULTS: A modified no-touch DMEK technique proved a feasible treatment option for a decompensated primary PK graft in the presence of a long GDD tube. CONCLUSIONS: With specific technical modifications DMEK can be successfully performed in eyes with decompensated primary PK grafts in the presence of a long GDD tube. The very thin DMEK graft allows positioning between the GDD tube and the failed PK graft, leaving the tube in place. PMID- 26418432 TI - Nocardia asteroides Keratitis Resistant to Amikacin. AB - PURPOSE: To describe 2 cases of Nocardia keratitis resistant to topical compounded amikacin therapy. METHODS: A 24-year-old woman presented with a corneal infiltrate. Cultures were taken, and topical moxifloxacin was administered. Corneal biopsy was performed when clinical status deteriorated, which confirmed infection with Nocardia. The patient was administered topical compounded amikacin. When clinical status further deteriorated, she was switched to compounded trimethoprim-sulfamethoxazole, which resulted in rapid resolution. Separately, a 22-year-old woman presented with contact lens-related keratitis that grew Nocardia asteroides. Corneal cultures and drug sensitivity testing revealed a strain of N. asteroides resistant to amikacin and imipenem, but sensitive to tobramycin. After a protracted clinical course, the keratitis ultimately responded to topical tobramycin leaving the patient with a pericentral corneal scar. CONCLUSIONS: Nocardia keratitis is an atypical infection for which standard management algorithms exist. However, atypical cases require that these patients be followed closely for the response to therapy. PMID- 26418434 TI - Dry Eye Signs and Symptoms Persist During Systemic Neutralization of IL-1beta by Canakinumab or IL-17A by Secukinumab. AB - PURPOSE: To evaluate whether inhibition of the proinflammatory cytokines IL-1beta or IL-17A by canakinumab or secukinumab, respectively, influence the signs and symptoms of dry eye. METHODS: In a randomized, double-masked, placebo-controlled, outpatient clinical trial, 72 patients with moderate to severe dry eye were randomly assigned in a 1:1:1 ratio to treatment with a single intravenous dose of canakinumab, of secukinumab, or of placebo. Signs and symptoms of dry eye were evaluated on the treatment day and 1 week, 4 weeks, and 8 weeks after treatment. The prespecified primary efficacy endpoint was corneal staining in the study eye 4 weeks after treatment. Secondary endpoints included tear production (Schirmer test), tear film breakup time, conjunctival redness, the ocular surface disease index (OSDI), the frequency of a desire for a topical ocular lubricant, and visual acuity. RESULTS: Of the 71 patients included in the analysis of safety, the rate of adverse events was similar between treatment groups. The course of corneal staining scores from baseline to 4 weeks, respectively, were for canakinumab 1.46 to 1.33 (P = 0.62 compared with placebo), for secukinumab 1.46 to 1.23 (P = 0.22), and for placebo 1.68 to 1.42. There were no changes in the other measures of efficacy beyond what was within the range expected for stochastic day-to-day variation. CONCLUSIONS: The results suggest that the inhibition of IL-1beta or IL-17A obtained by systemic administration of neutralizing drugs does not influence the severity of dry eye. PMID- 26418435 TI - Novel Treatment for Hemorrhagic Descemet Detachment After Canaloplasty. AB - PURPOSE: To describe a case of hemorrhagic Descemet membrane detachment after canaloplasty and to discuss its management using alteplase, a tissue plasminogen activator (TPA). METHODS: Interventional case report. RESULTS: A 60-year-old woman with advanced pseudoexfoliation glaucoma developed severe hemorrhagic Descemet detachment after canaloplasty. Initial anterior chamber and pre-Descemet washout yielded no improvement. On the fifth postoperative day, the patient received a novel pre-Descemet treatment using a TPA with an anterior chamber air bubble. The intracorneal blood clot quickly dissolved intraoperatively with the Descemet membrane almost completely reattached on postoperative day 1. CONCLUSIONS: Hemorrhagic Descemet detachment is a rare and serious complication of canaloplasty. The use of pre-Descemet TPA dissolves the intracorneal blood clot and helps reattach Descemet membrane, allowing quick rehabilitation of patient's vision and preserving integrity of the cornea. PMID- 26418433 TI - Expression of NeuGc on Pig Corneas and Its Potential Significance in Pig Corneal Xenotransplantation. AB - PURPOSE: Pigs expressing neither galactose-alpha1,3-galactose (Gal) nor N glycolylneuraminic acid (NeuGc) take xenotransplantation one step closer to the clinic. Our aims were (1) to document the lack of NeuGc expression on corneas and aortas and cultured endothelial cells [aortic endothelial cells (AECs); corneal (CECs)] of GTKO/NeuGcKO pigs, and (2) to investigate whether the absence of NeuGc reduced human antibody binding to the tissues and cells. METHODS: Wild-type (WT), GTKO, and GTKO/NeuGcKO pigs were used for the study. Human tissues and cultured cells were negative controls. Immunofluorescence staining was performed using anti-Gal and anti-NeuGc antibodies, and human IgM and IgG binding to tissues was determined. Flow cytometric analysis was used to determine Gal and NeuGc expression on cultured CECs and AECs and to measure human IgM/IgG binding to these cells. RESULTS: Both Gal and NeuGc were detected on WT pig corneas and aortas. Although GTKO pigs expressed NeuGc, neither humans nor GTKO/NeuGcKO pigs expressed Gal or NeuGc. Human IgM/IgG binding to corneas and aortas from GTKO and GTKO/NeuGcKO pigs was reduced compared with binding to WT pigs. Human antibody binding to GTKO/NeuGcKO AECs was significantly less than that to GTKO AECs, but there was no significant difference in binding between GTKO and GTKO/NeuGcKO CECs. CONCLUSIONS: The absence of NeuGc on GTKO aortic tissue and AECs is associated with reduced human antibody binding, and possibly will provide a better outcome in clinical xenotransplantation using vascularized organs. For clinical corneal xenotransplantation, the absence of NeuGc expression on GTKO/NeuGcKO pig corneas may not prove an advantage over GTKO corneas. PMID- 26418436 TI - Five-Year Incidence and Predictors for Pterygium in a Rural Community in China: The Yunnan Minority Eye Study. AB - PURPOSE: To determine the 5-year cumulative incidence of pterygium and its associated predictors in the Bai Chinese population in a rural community. METHODS: This population-based study included 2133 subjects aged 50 years or older in 2010 and was repeated in 2015 with 1520 subjects (71.3%) participating in the follow-up examination. Participants with pterygium in either eye in 2010 were excluded from the analysis related to incidence. Anterior segment examination was performed without pupil dilation using a slit lamp, and pterygium was defined as a raised fleshy triangular fibrovascular tissue growth of the conjunctiva encroaching onto the clear cornea. RESULTS: The 5-year cumulative incidence of pterygium was 6.8% [95% confidence interval (CI), 5.2-8.4] and was significantly higher in women compared with men (8.8% vs. 3.8%; P = 0.003). The age-specific incidence was 7.7%, 6.5%, and 5.6% in those aged 50-59, 60-69, 70 years, or older at the baseline, respectively. Outdoor occupation was the only predictor, which remained to be significantly associated with a higher incidence of pterygium in multivariate analysis (odds ratio = 2.52, 95% CI, 1.27-4.95). The predictive effect of outdoor occupation on incident pterygium was moderate with an area under the curve in the receiver operating characteristic analysis of 0.59 (95% CI, 0.53-0.66). CONCLUSIONS: The incidence of pterygium in this rural cohort was higher compared to a previous report in Chinese in urban areas. The findings are important for health policy makers to project future burden of pterygium and make proper decisions on health resource allocation. PMID- 26418437 TI - Body Plethysmography is Helpful for COPD Diagnosis, Determination of Severity, Phenotyping, and Response to Therapy. PMID- 26418438 TI - Lethal bacterial trap: Cationic surface for endodontic sealing. AB - Insoluble antibacterial cationic nanoparticles have been previously shown to have potent and long-lasting antibacterial properties. Our tested hypothesis was that root canal pathogens will be attracted to and eliminated when exposed to epoxy resin-based surfaces incorporating cationic nanoparticles. In our research, an epoxy resin-based surface incorporating quaternary ammonium polyethyleneimine (QPEI) nanoparticles was evaluated. Surface characterization was performed using atomic force microscopy and X-ray photoelectron spectra. The surface anti Enterococcus faecalis effect was evaluated in an anti-gravitational model. Cell membrane potential, viability, biofilm thickness, and biomass were tested using flow cytometry and confocal laser scanning microscopy. Additionally, the antibiofilm activity of the bacterial supernatant was assessed. The surface characterization showed QPEI nanoparticle embedment on the modified sealer. The epoxy resin-based surface incorporating the QPEI nanoparticles actively attracted bacteria, causing membrane destabilization, and bacterial death. The supernatant of bacteria pre-exposed to QPEI showed an antibacterial effect. In conclusion, the tested epoxy resin-based surface incorporating QPEI nanoparticles traps and kills bacteria. The nanoparticles attracted bacteria, reducing their viability, and promoting cell death. PMID- 26418439 TI - Enhanced mucosal healing with curcumin in animal oral ulcer model. AB - OBJECTIVES/HYPOTHESIS: Oral ulcers are very common and can compromise the quality of life of patients with pain. The objective of this study was to evaluate mucosal healing with curcumin in an animal oral ulcer model. STUDY DESIGN: Experimental study. METHODS: Twenty New Zealand white rabbits were used. Round filter paper 6 mm in diameter was soaked with 15 MUl 50% acetic acid and applied over the upper labial gingiva, creating a uniform circular ulcer. After creation of an oral ulcer, curcumin, the active substance in tumeric, was applied twice over the ulcer in the experimental group but not in the control group. The ulcer area was calculated by maximal (D) and minimal (d) diameter : pi * D * d/4. All animals were weighed, and the area was measured on days 0, 7, and 14. On days 7 and 14, half of the animals were sacrificed and gingival specimens were acquired. RESULTS: Curcumin treatment exhibited accelerated healing such that the gross appearance of the ulcer demonstrated a recognizable difference in wound healing between the curcumin-treated and control groups with time. Weight loss was observed after the creation of oral ulcer in the control group. However, the curcumin-treated group gained weight with time, resulting in a significant weight difference. On day 14, epithelial regeneration was completed in the treated group but incomplete in the control group. CONCLUSION: Topical application of curcumin enhanced the wound-healing process of oral ulcer in the animal model, which implicate that curcumin can be used as an effective and safe medical tool in the treatment of oral ulcer. LEVEL OF EVIDENCE: NA. PMID- 26418440 TI - Injectable and Self-Healing Dynamic Hydrogels Based on Metal(I) Thiolate/Disulfide Exchange as Biomaterials with Tunable Mechanical Properties. AB - Despite numerous strategies involving dynamic covalent bonds to produce self healing hydrogels with similar frequency-dependent stiffness to native tissues, it remains challenging to use biologically relevant thiol/disulfide exchange to confer such properties to polymeric networks. Herein, we report a new method based on Metal(I) [Au(I) or Ag(I)] capping to protect thiolates from aerial oxidation without preventing thiolate/disulfide exchange. Dynamic hydrogels were readily prepared by injecting simultaneously aqueous solutions of commercially available HAuCl4 and 4-arm thiol-terminated polyethylene glycol [(PEGSH)4], resulting in a network containing a mixture of Au(I)-thiolate (Au-S) and disulfide bonds (SS). While the dynamic properties of the hydrogel were closely dependent on the pH, the mechanical properties could be easily tuned by adjusting (PEGSH)4 concentration and amount of Au-S, as judged by dynamic rheology studies. Permanent Au-S/SS exchange at physiological pH conferred self-healing behavior and frequency-dependent stiffness to the hydrogel. In addition, in vitro studies confirmed that Au-based dynamic material was not cytotoxic to human dermal fibroblasts, demonstrating its potential use as a medical device. Dynamic hydrogels obtained using Ag(I) ions demonstrated that the exchange reaction was not affected by the nature of the Metal(I) capping. Finally, this efficient thiolate capping strategy offers a simple way to produce injectable and self healing dynamic hydrogels from virtually any thiol-containing polymers. PMID- 26418441 TI - Can we ease the financial burden of colonoscopy? Using real-time endoscopic assessment of polyp histology to predict surveillance intervals. AB - BACKGROUND: Polyps identified at colonoscopy are predominantly diminutive (<5 mm) with a small risk (>1%) of high-grade dysplasia or carcinoma; however, the cost of histological assessment is substantial. AIM: The aim of this study was to determine whether prediction of colonoscopy surveillance intervals based on real time endoscopic assessment of polyp histology is accurate and cost effective. METHODS: A prospective cohort study was conducted across a tertiary care and private community hospital. Ninety-four patients underwent colonoscopy and polypectomy of diminutive (<=5 mm) polyps from October 2012 to July 2013, yielding a total of 159 polyps. Polyps were examined and classified according to the Sano-Emura classification system. The endoscopic assessment (optical diagnosis) of polyp histology was used to predict appropriate colonoscopy surveillance intervals. The main outcome measure was the accuracy of optical diagnosis of diminutive colonic polyps against the gold standard of histological assessment. RESULTS: Optical diagnosis was correct in 105/108 (97.2%) adenomas. This yielded a sensitivity, specificity and positive and negative predictive values (with 95%CI) of 97.2% (92.1-99.4%), 78.4% (64.7-88.7%), 90.5% (83.7-95.2%) and 93% (80.9-98.5%) respectively. Ninety-two (98%) patients were correctly triaged to their repeat surveillance colonoscopy. Based on these findings, a cut and discard approach would have resulted in a saving of $319.77 per patient. CONCLUSION: Endoscopists within a tertiary care setting can accurately predict diminutive polyp histology and confer an appropriate surveillance interval with an associated financial benefit to the healthcare system. However, limitations to its application in the community setting exist, which may improve with further training and high-definition colonoscopes. PMID- 26418443 TI - CONE DENSITY LOSS ON ADAPTIVE OPTICS IN EARLY MACULAR TELANGIECTASIA TYPE 2. AB - PURPOSE: To determine whether cone photoreceptors are impaired early in macular telangiectasia type 2 (MacTel 2) progression. METHODS: Eight patients with MacTel 2 lacking intraretinal cavitation underwent multimodal retinal imaging including adaptive optics. Cone packing metrics were determined in 5 sampling windows at different eccentricities from the fovea. Results were compared with a previously established normative database. RESULTS: In MacTel 2 eyes, cone density was significantly lower than normal at all eccentricities (P < 0.0001). Mean cone spacing and mean percentage of hexagonally organized cone photoreceptors were respectively significantly larger and lower than normal at all eccentricities (P = 0.0488 and P < 0.0001). In MacTel 2 patients, adaptive optics showed an irregular patchy disturbance of the cone mosaic corresponding to some fragmentation of the interdigitation zone on optical coherence tomography. The ellipsoid zone remained intact in the studied area. CONCLUSION: Adaptive optics showed that the macular cone density was lower than normal even outside the telangiectasia in MacTel 2 lacking intraretinal cavitation, although the ellipsoid zone remained intact on optical coherence tomography. These findings do not indicate that the cone density loss is causative of the disease as it might be secondary to Muller cell or rod loss in this area. However, cone density assessment could become a useful parameter to monitor disease progression. PMID- 26418442 TI - EVALUATION OF MULTIPLE DEXAMETHASONE INTRAVITREAL IMPLANTS IN PATIENTS WITH MACULAR EDEMA ASSOCIATED WITH RETINAL VEIN OCCLUSION. AB - BACKGROUND: Limited data have evaluated multiple injections of the dexamethasone 700 MUg implant (DEX) (Ozurdex; Allergan, Inc.) for cystoid macular edema (CME) secondary to retinal vein occlusion (RVO) over an extended regimen. METHODS: This retrospective study evaluated patients treated with DEX for CME associated with RVO. Each patient had ophthalmologic evaluation, optical coherence tomography (OCT), and 4 weeks to 6 weeks follow-up intervals. Retreatment criterion was fluid on OCT. Outcome measures included best-corrected visual acuity, intraocular pressure (IOP), central macular thickness on OCT, fluid resolution on OCT, and required treatment for elevated IOP and cataract. RESULTS: Thirty-one patients had 82 DEX injections, with 19 patients having >=2, 12 having >=3, 10 having >=4, 6 having >=5, and 4 having >=6 DEX injections. All patients were followed at least 12 weeks and had a mean follow-up period of 344.94 days. Fourteen patients (45%) developed ocular hypertension (>=22 mmHg), and 40% of phakic patients required cataract surgery. Mean interval of OCT fluid resolution was 52 days (range, 28-245; SD, +/-8), and mean retreatment interval was 119 days (range, 42 309; SD, +/-9). No patients required glaucoma surgery or developed endophthalmitis. CONCLUSION: This study suggests that repeated, as needed, DEX injections for CME associated with RVO may be performed. Patients should be monitored and treated for ocular hypertension and cataract progression. PMID- 26418444 TI - TREATMENT OF PERSISTENTLY OPEN MACULAR HOLES WITH HEAVY SILICONE OIL (DENSIRON 68) VERSUS C2F6. A PROSPECTIVE RANDOMIZED STUDY. AB - PURPOSE: To compare the efficacy of a mixture of silicone oil and perfluorohexyloctane (Densiron 68) with C2F6 gas endotamponade in the retreatment of persistently open full-thickness macular holes. METHODS: In this prospective randomized study, 21 consecutive patients who were unsuccessfully operated on for large idiopathic full-thickness macular hole were randomly assigned to undergo a second vitrectomy with 20% perfluoroethane gas (C2F6, Group A) or with Densiron 68 tamponade (Group B). PRIMARY OUTCOMES: Endpoint (12 months) full-thickness macular hole closure rate by spectral domain optical coherence tomography and logMAR corrected distance visual acuity. SECONDARY OUTCOMES: postoperative adverse events. RESULTS: The mean diameter of macular holes before the second pars plana vitrectomy was 680.3 +/- 120.8 MUm and 740.5 +/- 105.3 MUm in Groups A and B, respectively (P = 0.237); mean preoperative corrected distance visual acuity was 0.96 +/- 0.36 logMAR and 1.12 +/- 0.35 logMAR, respectively (P = 0.315). Endpoint full-thickness macular hole closure was obtained in 30% of patients (3/10) in Group A and in 82% (9/11) in Group B (P = 0.030). Corrected distance visual acuities were, respectively, 0.80 +/- 0.25 logMAR and 0.55 +/- 0.20 logMAR, with significant intergroup difference (P = 0.019); corrected distance visual acuity increased in Group B only (P = 0.003). No differences in complications were found. CONCLUSION: The results indicate that Densiron 68 tamponade could be a useful, safe, and more efficacious method than gas tamponade to retreat persisting macular holes. PMID- 26418445 TI - VOLUMETRIC ASSESSMENT OF THE RESPONSIVENESS OF PIGMENT EPITHELIAL DETACHMENTS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION TO INTRAVITREAL BEVACIZUMAB. AB - PURPOSE: To determine baseline factors that can predict the response of pigment epithelial detachments (PEDs) in neovascular age-related macular degeneration to treatment with intravitreal bevacizumab (IVB). METHODS: Patients with newly diagnosed neovascular age-related macular degeneration and PED who were treated exclusively with IVB were included. Response to treatment was defined by change in PED volume (determined using spectral-domain optical coherence tomography). PEDs were classified as either predominantly serous or fibrovascular. Multivariable regression and receiver operating characteristic analyses were performed. RESULTS: A total of 48 eyes were identified (mean follow-up time 73 weeks). Overall, the response to the first IVB treatment was predictive of the response to treatment at the final visit (P = 0.015). Serous PEDs had a greater decrease in volume at the final visit (P = 0.008). With respect to both PED types, a decrease in PED volume of 21% after the first IVB treatment was predictive of an overall decrease in volume of 30% at the final visit (sensitivity 83%, specificity 76%). CONCLUSION: In neovascular age-related macular degeneration, serous PEDs respond more favorably to IVB than fibrovascular PEDs. Overall, for both types of PED, the response to the first treatment is predictive of the final response to treatment. Taken together, the results would suggest that if there is less than 21% reduction in PED volume after the first IVB treatment, and/or the PED is predominantly fibrovascular, then switching to another antivascular endothelial growth factor agent should be considered. PMID- 26418446 TI - CORRELATION OF INCREASED INTRAVITREOUS WNT3A WITH VASCULAR ENDOTHELIAL GROWTH FACTOR IN PROLIFERATIVE DIABETIC RETINOPATHY. AB - PURPOSE: To investigate Wnt3a and vascular endothelial growth factor (VEGF) levels in the vitreous fluid of patients with proliferative diabetic retinopathy (PDR) and to examine their correlation with PDR activity. METHODS: Vitreous samples from 45 eyes with PDR and 28 eyes with nondiabetic macular disease were collected. Active PDR was present in 24 patients and inactive PDR in 21 patients, according to retinal neovascularization. The Wnt3a and VEGF level of vitreous fluid samples were measured by enzyme-linked immunosorbent assay. RESULTS: Comparison revealed that mean intravitreal levels of Wnt3a increased significantly in PDR eyes compared with control eyes (13.55 ng/mL vs. 1.57 ng/mL, P < 0.001). The mean VEGF concentrations in the vitreous fluid of patients with PDR were also higher than those in nondiabetic controls, with the values being 723.21 pg/mL and 20.81 pg/mL, respectively (P < 0.001). In addition, vitreous concentrations of Wnt3a and VEGF were significantly higher in active PDR than in eyes with inactive PDR (P = 0.016 and P = 0.008, respectively). Furthermore, a significant positive correlation was detected between Wnt3a and VEGF levels in the vitreous. CONCLUSION: Intravitreous levels of Wnt3a and VEGF in patients with PDR are increased and correlated mutually. Wnt3a may be an important player in the development of diabetic retinopathy and its activity in vitreous fluid can be biomarker of PDR. PMID- 26418447 TI - SUPPLEMENTAL SCLERAL BUCKLE IN VITRECTOMY FOR THE REPAIR OF RHEGMATOGENOUS RETINAL DETACHMENT: A Systematic Review of Literature and Meta-Analysis. AB - PURPOSE: To evaluate the effect of supplemental scleral buckle (SB) in pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment. METHODS: MEDLINE, EMBASE, and CENTRAL were searched to identify studies comparing PPV with supplemental SB (PPV + SB) to PPV alone for the repair of rhegmatogenous retinal detachment. The outcome measures were primary and final reattachment rates, and postoperative complications. Odds ratio with 95% confidence interval in random effects for the comparison of outcomes between PPV + SB and PPV alone was calculated. RESULTS: Ten studies consisting of 1,704 patients were included. Meta-analysis showed that the overall primary reattachment rate was significantly higher in PPV + SB than PPV alone (odds ratio, 1.70; 95% confidence interval, 1.21-2.39; P = 0.002). The final reattachment rate was equally high in both groups. Postoperative development of epiretinal membrane was more frequent in PPV + SB than in PPV alone (odds ratio, 1.89; 95% confidence interval, 1.30-2.76; P = 0.001), whereas no significant difference in postoperative development of macular edema, proliferative vitreoretinopathy, or elevation of intraocular pressure was found. CONCLUSION: Supplemental SB increases the primary reattachment rate in PPV for rhegmatogenous retinal detachment, although final reattachment rate was equally high with or without SB. PMID- 26418448 TI - Thru-the-Trocar Administration of Dexamethasone Intravitreal Implant During 23-G Pars Plana Vitrectomy: A Small Case Series. PMID- 26418449 TI - Vascularized Drusen: Slowly Progressive Type 1 Neovascularization Mimicking Drusenoid Retinal Pigment Epithelium Elevation. PMID- 26418450 TI - Perfluoro-n-octane Assisted Free Internal Limiting Membrane Flap Technique for Recurrent Macular Hole. PMID- 26418451 TI - Rosin Surfactant QRMAE Can Be Utilized as an Amorphous Aggregate Inducer: A Case Study of Mammalian Serum Albumin. AB - Quaternary amine of diethylaminoethyl rosin ester (QRMAE), chemically synthesized biocompatible rosin based cationic surfactant, has various biological applications including its use as a food product additive. In this study, we examined the amorphous aggregation behavior of mammalian serum albumins at pH 7.5, i.e., two units above their isoelectric points (pI ~5.5), and the roles played by positive charge and hydrophobicity of exogenously added rosin surfactant QRMAE. The study was carried out on five mammalian serum albumins, using various spectroscopic methods, dye binding assay, circular dichroism and electron microscopy. The thermodynamics of the binding of mammalian serum albumins to cationic rosin modified surfactant were established using isothermal titration calorimetry (ITC). It was observed that a suitable molar ratio of protein to QRMAE surfactant enthusiastically induces amorphous aggregate formation at a pH above two units of pI. Rosin surfactant QRMAE-albumins interactions revealed a unique interplay between the initial electrostatic and the subsequent hydrophobic interactions that play an important role towards the formation of hydrophobic interactions-driven amorphous aggregate. Amorphous aggregation of proteins is associated with varying diseases, from the formation of protein wine haze to the expansion of the eye lenses in cataract, during the expression and purification of recombinant proteins. This study can be used for the design of novel biomolecules or drugs with the ability to neutralize factor(s) responsible for the aggregate formation, in addition to various other industrial applications. PMID- 26418453 TI - The effects of familial risk and parental resolution on parenting a child with mild intellectual disability. AB - The current study investigated the manner by which family risk moderates the links between parental state of resolution with a child's diagnosis and both parent-child interaction and parental stress. The sample included 72 families with 4-7-year-old children (M=5.53, SD=0.73) diagnosed with mild intellectual disability. Parents reported on their resolution state and parental stress, and parent-child interactions were videotaped and analyzed. Results indicated that in families where mothers or fathers were unresolved rather than resolved, mother child interactions were less positive only in the context of high family risk. The father-child interaction was not found to be affected by family risk and parental resolution. Interestingly, mothers in low family risk situations who were resolved reported the lowest level of parental stress, suggesting a "double buffer" effect, whereas fathers with high family risk who were unresolved experienced the highest levels of parental stress, suggesting a "double risk" effect. PMID- 26418452 TI - Deletion of Estrogen Receptor Beta in Osteoprogenitor Cells Increases Trabecular but Not Cortical Bone Mass in Female Mice. AB - Although the role of ERalpha in regulating bone metabolism has been extensively studied, ERbeta has been largely dismissed as a relevant modulator of bone mass. Previous studies examining ERbeta utilized a germline knockout mouse expressing transcript variants of ERbeta and displaying systemic hormonal changes that confounded interpretation of the skeletal phenotype. Thus, we used a conditional ERbeta mouse model to achieve deletion of ERbeta specifically in early osteoprogenitor cells using the Prx1-Cre driver. We observed marked increases in the trabecular bone volume fraction (of 58% [p < 0.003] and 93% [p < 0.0003] in 6 and 12-week-old female ERbeta(Prx1-CKO) mice, respectively) but no changes in cortical bone. Serum estradiol and IGF-I levels were unaltered in ERbeta(Prx1 CKO) mice. Bone formation and resorption indices by histomorphometry and serum assays were unchanged in these mice, suggesting that alterations in bone turnover may have occurred early in development. However, the ratio of colony-forming unit osteoblasts (CFU-OBs) to CFU-fibroblasts (CFU-Fs) was increased in bone marrow cultures from ERbeta(Prx1-CKO) compared with control mice, indicating increased differentiation of osteoblast precursor cells into osteoblasts in ERbeta(Prx1 CKO) mice. Detailed quantitative polymerase chain reaction analyses of 128 genes in 16 prespecified pathways revealed significant downregulation of 11 pathways in ERbeta(Prx1-CKO) mice. Thus, deletion of ERbeta specifically in osteoblast lineage cells, in the absence of all splice variants, increases trabecular bone mass and modulates multiple pathways related to bone metabolism. These findings suggest that pharmacological inhibition of ERbeta in bone may provide a novel approach to treat osteoporosis. PMID- 26418454 TI - Feasibility of bioelectrical impedance analysis in persons with severe intellectual and visual disabilities. AB - BACKGROUND: Body composition measurements provide important information about physical fitness and nutritional status. People with severe intellectual and visual disabilities (SIVD) have an increased risk for altered body composition. Bioelectrical impedance analysis (BIA) has been evidenced as a reliable and non invasive method to asses body composition in healthy persons and various patient populations; however, currently, there is no feasible method available to determine body composition in people with SIVD. In this study, therefore, we aimed to assess the feasibility of BIA measurements in persons with SIVD. METHODS: In 33 participants with SIVD and Gross Motor Functioning Classification System (GMFCS) Scale I, II, III, or IV, two BIA measurements were sequentially performed employing Resistance and Reactance in Ohm and fat-free mass (FFM) in kg as outcome variables, utilizing the Bodystat((r)) QuadScan 4000. Feasibility was considered sufficient if >= 80% of the first measurement was performed successfully. Agreement between two repeated measurements was determined by using the paired t-test and Intraclass Correlation Coefficient (ICC; two way random, absolute agreement). Bland-Altman analyses were utilized to determine limits of agreement (LOAs) and systematic error. Agreement was considered acceptable if LOAs were <10% of the mean of the first measurement. RESULTS: The first BIA measurements were completed successfully in 88% of the participants. The paired t test demonstrated no significant differences in Resistance, Reactance, and FFM between BIA Measurements 1 and 2 (P=0.140, 0.091, and 0.866). ICC was 0.965 (95% CI: 0.922-0.984) for Resistance; 0.858 (95% CI: 0.705-0.934) for Reactance; and 0.992 (95% CI: 0.982-0.996) for FFM. LOAs expressed as a percentage of the mean of Measurement 1 were 6.1% for Resistance, 17.6% for Reactance, and 3.8% for FFM. CONCLUSIONS: The results of this study suggest that BIA measurements seem to be feasible in persons with SIVD. Although these results require confirmation in a more extensive sample of persons with SIVD, the findings of this study are an important first step in the assessment of applicability of BIA measurements for non-invasive monitoring of physical fitness and nutritional status of persons with SIVD. PMID- 26418457 TI - Single-Crystal-Like Organic Thin-Film Transistors Fabricated from Dinaphtho[2,3 b:2',3'-f]thieno[3,2-b]thiophene (DNTT) Precursor-Polystyrene Blends. AB - High-mobility short-channel organic thin-film transistors fabricated using a dinaphtho[2,3-b:2',3'-f]thieno[3,2-b]-thio--phene (DNTT) precursor (5,14-N- phenylmaleimide DNTT, endo-isomer-rich fraction) and polystyrene (PS) blends are reported. The DNTT grains are "single-crystal"-like and the field-effect mobility of the devices ranges up to 4.7 cm(2) V(-1) s(-1). The PS layer functions as a hydrophobic passivation layer on the Si/SiO2 substrate. PMID- 26418455 TI - BMPER Promotes Epithelial-Mesenchymal Transition in the Developing Cardiac Cushions. AB - Formation of the cardiac valves is an essential component of cardiovascular development. Consistent with the role of the bone morphogenetic protein (BMP) signaling pathway in cardiac valve formation, embryos that are deficient for the BMP regulator BMPER (BMP-binding endothelial regulator) display the cardiac valve anomaly mitral valve prolapse. However, how BMPER deficiency leads to this defect is unknown. Based on its expression pattern in the developing cardiac cushions, we hypothesized that BMPER regulates BMP2-mediated signaling, leading to fine tuned epithelial-mesenchymal transition (EMT) and extracellular matrix deposition. In the BMPER-/- embryo, EMT is dysregulated in the atrioventricular and outflow tract cushions compared with their wild-type counterparts, as indicated by a significant increase of Sox9-positive cells during cushion formation. However, proliferation is not impaired in the developing BMPER-/- valves. In vitro data show that BMPER directly binds BMP2. In cultured endothelial cells, BMPER blocks BMP2-induced Smad activation in a dose-dependent manner. In addition, BMP2 increases the Sox9 protein level, and this increase is inhibited by co-treatment with BMPER. Consistently, in the BMPER-/- embryos, semi quantitative analysis of Smad activation shows that the canonical BMP pathway is significantly more active in the atrioventricular cushions during EMT. These results indicate that BMPER negatively regulates BMP-induced Smad and Sox9 activity during valve development. Together, these results identify BMPER as a regulator of BMP2-induced cardiac valve development and will contribute to our understanding of valvular defects. PMID- 26418456 TI - TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype. AB - OBJECTIVE: Mutations in TPM3, encoding Tpm3.12, cause a clinically and histopathologically diverse group of myopathies characterized by muscle weakness. We report two patients with novel de novo Tpm3.12 single glutamic acid deletions at positions DeltaE218 and DeltaE224, resulting in a significant hypercontractile phenotype with congenital muscle stiffness, rather than weakness, and respiratory failure in one patient. METHODS: The effect of the Tpm3.12 deletions on the contractile properties in dissected patient myofibers was measured. We used quantitative in vitro motility assay to measure Ca(2+) sensitivity of thin filaments reconstituted with recombinant Tpm3.12 DeltaE218 and DeltaE224. RESULTS: Contractility studies on permeabilized myofibers demonstrated reduced maximal active tension from both patients with increased Ca(2+) sensitivity and altered cross-bridge cycling kinetics in DeltaE224 fibers. In vitro motility studies showed a two-fold increase in Ca(2+) sensitivity of the fraction of filaments motile and the filament sliding velocity concentrations for both mutations. INTERPRETATION: These data indicate that Tpm3.12 deletions DeltaE218 and DeltaE224 result in increased Ca(2+) sensitivity of the troponin-tropomyosin complex, resulting in abnormally active interaction of the actin and myosin complex. Both mutations are located in the charged motifs of the actin-binding residues of tropomyosin 3, thus disrupting the electrostatic interactions that facilitate accurate tropomyosin binding with actin necessary to prevent the on state. The mutations destabilize the off-state and result in excessively sensitized excitation-contraction coupling of the contractile apparatus. This work expands the phenotypic spectrum of TPM3-related disease and provides insights into the pathophysiological mechanisms of the actin-tropomyosin complex. PMID- 26418459 TI - Identification of Astrotactin2 as a Genetic Modifier That Regulates the Global Orientation of Mammalian Hair Follicles. AB - Planar cell polarity (PCP) signaling controls the global orientation of surface structures, such as hairs and bristles, in both vertebrates and invertebrates. In Frizzled6(-/-) (Fz6(-/-)) mice, hair follicle orientations on the head and back are nearly random at birth, but reorient during early postnatal development to eventually generate a nearly parallel anterior-to-posterior array. We report the identification of a naturally occurring exon 5 deletion in Astrotactin2 (Astn2) that acts as a recessive genetic modifier of the Fz6(-/-) hair patterning phenotype. A genetically engineered Astn2 exon 5 deletion recapitulates the modifier phenotype. In Fz6(-/-);Astn2(ex5del/del) mice, hair orientation on the back is subtly biased from posterior-to-anterior, leading to a 180-degree orientation reversal in mature mice. These experiments suggest that Astn2, an endosomal membrane protein, modulates PCP signaling. PMID- 26418460 TI - Interferon-gamma-Induced Nitric Oxide Synthase-2 Contributes to Blood/Brain Barrier Dysfunction and Acute Mortality in Experimental Streptococcus pneumoniae Meningitis. AB - The proinflammatory cytokine interferon-gamma (IFNgamma) recently was shown to play a crucial role in experimental pneumococcal meningitis (PM) pathogenesis, and we aimed in this study to investigate IFNgamma-driven nitric oxide synthase-2 (NOS2)-mediated pathogenesis of murine PM. We demonstrate that costimulation of toll-like receptors and IFNgamma receptors was synergistic for NOS2 expression in cultured murine microglia. Using an experimental PM model, wild-type mice treated with anti-IFNgamma antibody, as well as IFNgamma and NOS2 gene knockout (GKO) mice, were inoculated intracerebroventricularly with 10(3) colony-forming units of Streptococcus pneumoniae (WU2 strain). Mice were monitored daily during a 200 h disease course to assess survival rate and blood-brain barrier (BBB) permeability measured at 48 h. IFNgamma deficiency was protective in PM, with an approximate 3-fold increase in survival rates in both antibody-treated and IFNgamma GKO mice compared to controls (P < 0.01). At 48 h postinoculation, brain NOS2 mRNA expression was significantly increased in an IFNgamma-dependent manner. Mortality was significantly delayed in NOS2 GKO mice compared to controls (P < 0.01), and BBB dysfunction was reduced by 54% in IFNgamma GKO mice and abolished in NOS2 GKO. These data suggest that IFNgamma-dependent expression of NOS2 in the brain contributes to BBB breakdown and early mortality in murine PM. PMID- 26418461 TI - Surface Plasmon Polariton Cross-Coupling Enhanced Forward Emission from Insulator Metal-Capped ZnO Films. AB - Increasing light extraction efficiency in the forward direction is being extensively pursued due to its crucial role in realizing top-emitting organic and inorganic light emitting devices. Various surface plasmon polariton (SPP)-based strategies for emission enhancement and light extraction have been developed to improve the top-emitting efficiency of these devices. However, the role of surface roughness of both semiconductor film and metal electrode in improving the emission efficiency of a practical device has not been thoroughly studied yet. In this work, the influence of surface roughness of a top metal electrode on the photoluminescence enhancement of a ZnO thin film is investigated experimentally and numerically based on an insulator-metal-semiconductor system. It is found that the generic surface roughness of the metal electrode plays an encouraging role in increasing the forward-emission intensity by facilitating cross-coupling of SPPs on the two opposite sides of the metal layer. More importantly, the forward emission can be further enhanced by capping a high-index polymer layer on the metal electrode to bridge the momentum mismatch between the two SPPs modes. The experimental observations are well explained by the SPPs cross-coupling mechanism that models the radiation power of a dipolar emitter underneath the metal electrode as a function of the metal surface roughness. Our work opens up the possibility of using cross-coupling of SPPs as an effective means to fabricate high-brightness top-emitting devices without the need of complicated nanoscale patterning. PMID- 26418458 TI - Chemical, Thermal and Spectroscopic Methods to Assess Biodegradation of Winery Distillery Wastes during Composting. AB - The objective of this work was to study the co-composting process of wastes from the winery and distillery industry with animal manures, using the classical chemical methods traditionally used in composting studies together with advanced instrumental methods (thermal analysis, FT-IR and CPMAS 13C NMR techniques), to evaluate the development of the process and the quality of the end-products obtained. For this, three piles were elaborated by the turning composting system, using as raw materials winery-distillery wastes (grape marc and exhausted grape marc) and animal manures (cattle manure and poultry manure). The classical analytical methods showed a suitable development of the process in all the piles, but these techniques were ineffective to study the humification process during the composting of this type of materials. However, their combination with the advanced instrumental techniques clearly provided more information regarding the turnover of the organic matter pools during the composting process of these materials. Thermal analysis allowed to estimate the degradability of the remaining material and to assess qualitatively the rate of OM stabilization and recalcitrant C in the compost samples, based on the energy required to achieve the same mass losses. FT-IR spectra mainly showed variations between piles and time of sampling in the bands associated to complex organic compounds (mainly at 1420 and 1540 cm-1) and to nitrate and inorganic components (at 875 and 1384 cm 1, respectively), indicating composted material stability and maturity; while CPMAS 13C NMR provided semi-quantitatively partition of C compounds and structures during the process, being especially interesting their variation to evaluate the biotransformation of each C pool, especially in the comparison of recalcitrant C vs labile C pools, such as Alkyl /O-Alkyl ratio. PMID- 26418462 TI - Ultrafast Photoinduced Symmetry-Breaking Charge Separation and Electron Sharing in Perylenediimide Molecular Triangles. AB - We report on a visible-light-absorbing chiral molecular triangle composed of three covalently linked 1,6,7,12-tetra(phenoxy)perylene-3,4:9,10 bis(dicarboximide) (PDI) units. The rigid triangular architecture reduces the electronic coupling between the PDIs, so ultrafast symmetry-breaking charge separation is kinetically favored over intramolecular excimer formation, as revealed by femtosecond transient absorption spectroscopy. Photoexcitation of the PDI triangle dissolved in CH2Cl2 gives PDI(+*)-PDI(-*) in tauCS = 12.0 +/- 0.2 ps. Fast subsequent intramolecular electron/hole hopping can equilibrate the six possible energetically degenerate ion-pair states, as suggested by electron paramagnetic resonance/electron-nuclear double resonance spectroscopy, which shows that one-electron reduction of the PDI triangle results in complete electron sharing among the three PDIs. Charge recombination of PDI(+*)-PDI(-*) to the ground state occurs in tauCR = 1.12 +/- 0.01 ns with no evidence of triplet excited state formation. PMID- 26418464 TI - A Cross Sectional Analysis of Gonococcal and Chlamydial Infections among Men-Who Have-Sex-with-Men in Cape Town, South Africa. AB - BACKGROUND: Men-who-have-sex-with-men (MSM) are at high risk of HIV and sexually transmitted infection (STI) transmission. Asymptomatic STIs are common in MSM and remain undiagnosed and untreated where syndromic management is advocated. Untreated STIs could be contributing to high HIV rates. This study investigated symptomatic (SSTI) and asymptomatic STIs (ASTIs) in MSM in Cape Town. METHODS: MSM, 18 years and above, were enrolled into this study. Participants underwent clinical and microbiological screening for STIs. Urine, oro-pharyngeal and anal swab specimens were collected for STI analysis, and blood for HIV and syphilis screening. A psychosocial and sexual questionnaire was completed. STI specimens were analysed for Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) infection. RESULTS: 200 MSM were recruited with a median age of 32 years (IQR 26 39.5). Their median number of sex partners within the last year was 5 (IQR 2-20). 155/200 (78%) reported only male sex partners while 45/200 (23%) reported sex with men and women. 77/200 (39%) reported transactional sex. At enrolment, 88/200 (44%) were HIV positive and 8/112 (7%) initially HIV-negative participants seroconverted during the study. Overall, 47/200 (24%) screened positive for either NG or CT. There were 32 MSM (16%) infected with NG and 7 (3.5%) of these men had NG infections at two anatomical sites (39 NG positive results in total). Likewise, there were 23 MSM (12%) infected with CT and all these men had infections at only one site. Eight of the 47 men (17%) were infected with both NG and CT. ASTI was more common than SSTI irrespective of anatomical site, 38 /200 (19%) versus 9/200 (5%) respectively (p<0.001). The anus was most commonly affected, followed by the oro-pharynx and then urethra. Asymptomatic infection was associated with transgender identity (OR 4.09 CI 1.60-5.62), >=5 male sex partners in the last year (OR 2.50 CI 1.16-5.62) and transactional sex (OR 2.33 CI 1.13-4.79) but not with HIV infection. CONCLUSIONS: Asymptomatic STI was common and would not have been detected using a syndromic management approach. Although molecular screening for NG/CT is costly, in our study only four MSM needed to be screened to detect one case. This supports dual NG/CT molecular screening for MSM, which, in the case of confirmed NG infections, may trigger further culture-based investigations to determine gonococcal antimicrobial susceptibility in the current era of multi-drug resistant gonorrhoea. PMID- 26418465 TI - Exploring Regional Variation in Roost Selection by Bats: Evidence from a Meta Analysis. AB - BACKGROUND AND AIMS: Tree diameter, tree height and canopy closure have been described by previous meta-analyses as being important characteristics in roost selection by cavity-roosting bats. However, size and direction of effects for these characteristics varied greatly among studies, also referred to as heterogeneity. Potential sources of heterogeneity have not been investigated in previous meta-analyses, which are explored by correlating additional covariates (moderator variables). We tested whether effect sizes from 34 studies were consistent enough to reject the null hypothesis that trees selected by bats did not significantly differ in their characteristics from randomly selected trees. We also examined whether heterogeneity in tree diameter effect sizes was correlated to moderator variables such as sex, bat species, habitat type, elevation and mean summer temperature. METHODS: We used Hedges' g standardized mean difference as the effect size for the most common characteristics that were encountered in the literature. We estimated heterogeneity indices, potential publication bias, and spatial autocorrelation of our meta-data. We relied upon meta-regression and multi-model inference approaches to evaluate the effects of moderator variables on heterogeneity in tree diameter effect sizes. RESULTS: Tree diameter, tree height, snag density, elevation, and canopy closure were significant characteristics of roost selection by cavity-roosting bats. Size and direction of effects varied greatly among studies with respect to distance to water, tree density, slope, and bark remaining on trunks. Inclusion of mean summer temperature and sex in meta-regressions further explained heterogeneity in tree diameter effect sizes. CONCLUSIONS: Regional differences in roost selection for tree diameter were related to mean summer temperature. Large diameter trees play a central role in roost selection by bats, especially in colder regions, where they are likely to provide a warm and stable microclimate for reproductive females. Records of summer temperature fluctuations inside and outside tree cavities that are used by bats should be included in future research. PMID- 26418463 TI - Associations Between Physical Fitness Indices and Working Memory in Breast Cancer Survivors and Age-Matched Controls. AB - BACKGROUND: This study examined the effects of cardiorespiratory fitness, heart rate recovery, and physical activity on working memory in breast cancer survivors and age-matched controls. METHOD: Using a case-control design, 32 women who had received a breast cancer diagnosis and completed primary treatment within the past 36-months (11 radiation only; 21 chemotherapy) and 30 age-matched women with no previous cancer diagnosis completed a n-back continuous performance task commonly used as an assessment of working memory. In addition, cardiorespiratory fitness and heart rate recovery were measured during a submaximal graded exercise test and physical activity was measured using 7-days of accelerometer monitoring. RESULTS: Breast cancer survivors who had received chemotherapy had poorer heart rate recovery (p = .010) and engaged in less physical activity than women who had received radiation only (p = .004) or non-cancer controls (p = .029). Cancer treatment (radiation; chemotherapy) predicted differences in reaction times on the 1-back working memory task (p = .029). However, more rapid heart rate recovery predicted shorter reaction times on the 1-back task in the age-matched control group (p = .002). All participants with greater cardiorespiratory fitness displayed greater accuracy independent of disease status on the 1-back task (p = .017). No significant group differences in reaction times were observed for 2 back target trials between breast cancer survivors and controls. However, greater total physical activity predicted shorter reaction times in breast cancer survivors (radiation, chemotherapy) on the 2-back task (p = .014). In addition, all participants who exhibited more rapid heart rate recovery demonstrated better greater accuracy regardless of disease status (p = .013). CONCLUSION: These findings support differences in physical activty participation, heart rate recovery, and 1- and 2-back working memory reaction times between breast cancer survivors and age-matched controls. Greater cardiorespiratory fitness, heart rate recovery, and physical activity were positively associated with better working memory performance across conditions. PMID- 26418466 TI - Mammalian Brains Are Made of These: A Dataset of the Numbers and Densities of Neuronal and Nonneuronal Cells in the Brain of Glires, Primates, Scandentia, Eulipotyphlans, Afrotherians and Artiodactyls, and Their Relationship with Body Mass. AB - Comparative studies amongst extant species are one of the pillars of evolutionary neurobiology. In the 20th century, most comparative studies remained restricted to analyses of brain structure volume and surface areas, besides estimates of neuronal density largely limited to the cerebral cortex. Over the last 10 years, we have amassed data on the numbers of neurons and other cells that compose the entirety of the brain (subdivided into cerebral cortex, cerebellum, and rest of brain) of 39 mammalian species spread over 6 clades, as well as their densities. Here we provide that entire dataset in a format that is readily useful to researchers of any area of interest in the hope that it will foster the advancement of evolutionary and comparative studies well beyond the scope of neuroscience itself. We also reexamine the relationship between numbers of neurons, neuronal densities and body mass, and find that in the rest of brain, but not in the cerebral cortex or cerebellum, there is a single scaling rule that applies to average neuronal cell size, which increases with the linear dimension of the body, even though there is no single scaling rule that relates the number of neurons in the rest of brain to body mass. Thus, larger bodies do not uniformly come with more neurons--but they do fairly uniformly come with larger neurons in the rest of brain, which contains a number of structures directly connected to sources or targets in the body. PMID- 26418467 TI - Occupant injury in rollover crashes - Contribution of planar impacts with objects and other vehicles. AB - Planar impacts with objects and other vehicles may increase the risk and severity of injury in rollover crashes. The current study compares the frequency of injury measures (MAIS 2+, 3+, and 4+; fatal; AIS 2+ head and cervical spine; and AIS 3+ head and thorax) as well as vehicle type distribution (passenger car, SUV, van, and light truck), crash kinematics, and occupant demographics between single vehicle single event rollovers (SV Pure) and multiple event rollovers to determine which types of multiple event rollovers can be pooled with SV Pure to study rollover induced occupant injury. Four different types of multiple event rollovers were defined: single and multi-vehicle crashes for which the rollover is the most severe event (SV Prim and MV Prim) and single and multi-vehicle crashes for which the rollover is not the most severe event (SV Non-Prim and MV Non-Prim). Information from real world crashes was obtained from the National Automotive Sampling System - Crashworthiness Data System (NASS-CDS) for the period from 1995 through 2011. Belted, contained or partially ejected, adult occupants in vehicles that completed 1-16 lateral quarter turns were assigned to one of the five rollover categories. The results showed that the frequency of injury in non-primary rollovers (SV Non-Prim and MV Non-Prim) involving no more than one roof inversion is substantially greater than in SV Pure, but that this disparity diminishes for crashes involving multiple inversions. It can further be concluded that for a given number of roof inversions, the distribution of injuries and crash characteristics in SV Pure and SV Prim crashes are sufficiently similar for these categories to be considered collectively for purposes of understanding etiologies and developing strategies for prevention. PMID- 26418469 TI - The Utility of Hybrid SPECT/CT Lung Perfusion Scintigraphy in Pulmonary Embolism Diagnosis. AB - BACKGROUND: Pulmonary embolism (PE) is diagnosed either by ventilation/perfusion (V/Q) scintigraphy or pulmonary CT angiography. One of the imaging methods used in nuclear medicine is hybrid SPECT/CT scintigraphy. OBJECTIVES: The aim of this study was to evaluate the utility of SPECT/CT(Q) scintigraphy in the diagnosis of PE and to compare SPECT/CT(Q) with planar(Q) and SPECT(Q) methods. METHODS: The study group consisted of 109 consecutive patients suspected of having PE referred for performing lung scintigraphy. The inclusion criteria were: performance of perfusion planar, SPECT and SPECT/CT scans; availability of clinical data covering a 6-month follow-up period, and D-dimer level testing. The number of eligible patients was 84. PE was reported in patients with at least 1 segmental or 2 subsegmental perfusion defects without parenchymal abnormalities on CT scans. PE was excluded when there was a normal perfusion pattern or perfusion defects were caused by lung parenchymal abnormalities or were not arranged in accordance with the pulmonary vasculature. RESULTS: Twenty-six patients (31%) had a final diagnosis of PE. The sensitivity and specificity values of each method were as follows: planar(Q) 73 and 43%, SPECT(Q) 88 and 47% and SPECT/CT(Q) 100 and 83%. SPECT/CT(Q) yielded a significantly higher diagnostic accuracy than planar(Q) (p < 0.001) and SPECT(Q) (p < 0.001) scans. CONCLUSIONS: We conclude that hybrid SPECT/CT(Q) imaging has a high diagnostic efficacy in the diagnosis of PE. Lung perfusion scintigraphy performed with a hybrid SPECT/CT device has a significantly higher sensitivity and specificity than scanning performed with the planar or SPECT technique. PMID- 26418470 TI - A Meta-Analytic Review of Stand-Alone Interventions to Improve Body Image. AB - OBJECTIVE: Numerous stand-alone interventions to improve body image have been developed. The present review used meta-analysis to estimate the effectiveness of such interventions, and to identify the specific change techniques that lead to improvement in body image. METHODS: The inclusion criteria were that (a) the intervention was stand-alone (i.e., solely focused on improving body image), (b) a control group was used, (c) participants were randomly assigned to conditions, and (d) at least one pretest and one posttest measure of body image was taken. Effect sizes were meta-analysed and moderator analyses were conducted. A taxonomy of 48 change techniques used in interventions targeted at body image was developed; all interventions were coded using this taxonomy. RESULTS: The literature search identified 62 tests of interventions (N = 3,846). Interventions produced a small-to-medium improvement in body image (d+ = 0.38), a small-to medium reduction in beauty ideal internalisation (d+ = -0.37), and a large reduction in social comparison tendencies (d+ = -0.72). However, the effect size for body image was inflated by bias both within and across studies, and was reliable but of small magnitude once corrections for bias were applied. Effect sizes for the other outcomes were no longer reliable once corrections for bias were applied. Several features of the sample, intervention, and methodology moderated intervention effects. Twelve change techniques were associated with improvements in body image, and three techniques were contra-indicated. CONCLUSIONS: The findings show that interventions engender only small improvements in body image, and underline the need for large-scale, high-quality trials in this area. The review identifies effective techniques that could be deployed in future interventions. PMID- 26418472 TI - Straddle injury with anal sphincter and rectal rupture in a young girl Case report. AB - As a result of increasing sport or car accident, straddle injuries in pediatric age are becoming increasingly frequent. Mild lesions of the external genitalia and urinary apparatus, are mainly observed in blunt trauma, whereas more severe lesions are reported in penetrating injuries; however, ano-rectal involvement alone, has been reported very rarely and especially in penetrating trauma. We describe herein a case of straddle trauma occurring in a 14yr old girl involved in a car accident. The girl reported anal sphincter rupture and rectal wall tear with a blunt mechanism. No other involvement of genitourinary apparatus was observed. The diagnostic and surgical approach of this rare consequence of a straddle, blunt injury are described and commented. KEY WORDS: Anal sphincter rupture, Emergency laparoscopy, Perineal trauma, Rectal lesion, Straddle injury. PMID- 26418473 TI - Molecular pathways activation in coronary artery bypass surgery: which role for pump avoidance? AB - In this study, we review current knowledge regarding molecular pathways activation and their possible mechanisms in the perioperative period of coronary artery bypass surgery (CABG). We also highlight the role of off-pump CABG as a possible way to better understand these biological changes.We show that, after both on-pump and off-pump CABG, there is a marked and protracted activation of several molecular pathways indicating increased inflammatory status, haemostasis activation, as well as increased oxidative stress and unfavourable endothelial milieu. These changes persist for days and even weeks after surgery. Interestingly, a relatively limited number of these pathways show a more pronounced activation in case of cardiopulmonary bypass use, and these markers are mainly associated with oxidative stress activation; on the contrary, the vast majority of the pathways has a similar course both in on and off-pump procedures. Surgical stress accounts for more protracted and marked molecular pathway perturbations overall, being the effect of cardiopulmonary, if any, limited to the very early hours after surgery. The near future of the translational research in coronary bypass surgery is to develop therapeutic strategies aimed at reducing this response, that is largely unrelated to cardiopulmonary bypass use, in order to reduce perioperative complications and to speed up patients' recovery. PMID- 26418471 TI - Microsphere-based gradient implants for osteochondral regeneration: a long-term study in sheep. AB - BACKGROUND: The microfracture technique for cartilage repair has limited ability to regenerate hyaline cartilage. AIM: The current study made a direct comparison between microfracture and an osteochondral approach with microsphere-based gradient plugs. MATERIALS & METHODS: The PLGA-based scaffolds had opposing gradients of chondroitin sulfate and beta-tricalcium phosphate. A 1-year repair study in sheep was conducted. RESULTS: The repair tissues in the microfracture were mostly fibrous and had scattered fissures with degenerative changes. Cartilage regenerated with the gradient plugs had equal or superior mechanical properties; had lacunated cells and stable matrix as in hyaline cartilage. CONCLUSION: This first report of gradient scaffolds in a long-term, large animal, osteochondral defect demonstrated potential for equal or better cartilage repair than microfracture. PMID- 26418474 TI - Cobalt(II) amido complexes derived from a monodentate arylamido ligand featuring a highly electron-withdrawing C6F5 substituent. AB - A series of cobalt(ii) complexes of a highly electron-withdrawing amido ligand, [N(C6F5)(C6H3Pr(i)2-2,6)](-) (L), were synthesized and structurally characterized. Mononuclear [CoL(Cl)(TMEDA)] (3) and heterobimetallic [CoL2(MU Cl)Li(THF)3] (4) were obtained by direct metathetical reactions of anhydrous CoCl2 with one molar equivalent of [LiL(TMEDA)] (1) (TMEDA = Me2NCH2CH2NMe2) and [LiL(THF)3] (2), respectively. Complex 3 underwent facile ligand substitution reactions with LiMe and NaN3, yielding the corresponding mixed-ligand complexes [CoL(X)(TMEDA)] (X = Me 5, N36). Treatment of 3 with NaOMe led to the heterobimetallic complex [CoL2(MU-OMe)Na(TMEDA)] (7). The solid-state structures of complexes 1-7 were established by X-ray diffraction analysis. PMID- 26418475 TI - Toll-like receptors as targets for allergen immunotherapy. AB - PURPOSE OF REVIEW: Toll-like receptors (TLRs) are novel and promising targets for allergen immunotherapy. Bench studies suggest that TLR agonists reduce Th2 responses and ameliorate airway hyper-responsiveness. In addition, clinical trials are at initial phases to evaluate the safety and efficacy of TLR agonists for the allergen immunotherapy of patients with allergic rhinitis and asthma. (Figure is included in full-text article.) RECENT FINDINGS: To date, two allergy vaccine-containing TLR agonists have been investigated in clinical trials; Pollinex Quattro and AIC. The former contains monophosphoryl lipid, a TLR4 agonist and the latter contains, CpG motifs activating the TLR9 cascade. Preseasonal subcutaneous injection of both of these allergy vaccines has been safe and efficacious in control of nasal symptoms of patients with allergic rhinitis. CRX-675 (a TLR4 agonist), AZD8848 (a TLR7 agonist), VTX-1463 (a TLR8 agonist) and 1018 ISS and QbG10 (TLR9 agonists) are currently in clinical development for allergic rhinitis and asthma. SUMMARY: TLR agonists herald promising results for allergen immunotherapy of patients with allergic rhinitis and asthma. Future research should be directed at utilizing these agents for immunotherapy of food allergy (for instance, peanut allergy) as well. PMID- 26418476 TI - Brief Report: Inhibition of miR-145 Enhances Reprogramming of Human Dermal Fibroblasts to Induced Pluripotent Stem Cells. AB - MicroRNA (miRNAs) are short noncoding RNA molecules involved in many cellular processes and shown to play a key role in somatic cell induced reprogramming. We performed an array based screening to identify candidates that are differentially expressed between dermal skin fibroblasts (DFs) and induced pluripotent stem cells (iPSCs). We focused our investigations on miR-145 and showed that this candidate is highly expressed in DFs relative to iPSCs and significantly downregulated during reprogramming process. Inhibition of miR-145 in DFs led to the induction of "cellular plasticity" demonstrated by: (a) alteration of cell morphology associated with downregulation of mesenchymal and upregulation of epithelial markers; (b) upregulation of pluripotency-associated genes including SOX2, KLF4, C-MYC; (c) downregulation of miRNA let-7b known to inhibit reprogramming; and (iv) increased efficiency of reprogramming to iPSCs in the presence of reprogramming factors. Together, our results indicate a direct functional link between miR-145 and molecular pathways underlying reprogramming of somatic cells to iPSCs. PMID- 26418477 TI - Topologically Associating Domains: An invariant framework or a dynamic scaffold? AB - Metazoan genomes are organized into regions of topologically associating domains (TADs). TADs are demarcated by border elements, which are enriched for active genes and high occupancy architectural protein binding sites. We recently demonstrated that 3D chromatin architecture is dynamic in response to heat shock, a physiological stress that downregulates transcription and causes a global redistribution of architectural proteins. We utilized a quantitative measure of border strength after heat shock, transcriptional inhibition, and architectural protein knockdown to demonstrate that changes in both transcription and architectural protein occupancy contribute to heat shock-induced TAD dynamics. Notably, architectural proteins appear to play a more important role in altering 3D chromatin architecture. Here, we discuss the implications of our findings on previous studies evaluating the dynamics of TAD structure during cellular differentiation. We propose that the subset of variable TADs observed after differentiation are representative of cell-type specific gene expression and are biologically significant. PMID- 26418478 TI - Surrogate endpoints for clinical trials in primary sclerosing cholangitis: Review and results from an International PSC Study Group consensus process. AB - Primary sclerosing cholangitis (PSC) is a rare, but serious, cholestatic disease for which, to date, no effective therapy exists to halt disease progression toward end-stage liver disease. Clinical trial design to study drugs that improve prognosis is hampered by the relatively low event rate of clinically relevant endpoints. To overcome this shortcoming, there is an urgent need to identify appropriate surrogate endpoints. At present, there are no established surrogate endpoints. This article provides a critical review and describes the results of a consensus process initiated by the International PSC Study Group to delineate appropriate candidate surrogate endpoints at present for clinical trials in this frequently dismal disease. The consensus process resulted in a shortlist of five candidates as surrogate endpoints for measuring disease progression: alkaline phosphatase (ALP); transient elastography (TE); histology; combination of ALP+histology; and bilirubin. Of these, histology, ALP, and TE came out as the most promising. However, the expert panel concluded that no biomarker currently exceeds level 3 validation. Combining multiple endpoints is advisable. CONCLUSION: At present, there are insufficient data to support level 2 validation for any surrogate endpoint in PSC. Concerted efforts by all stakeholders are highly needed. Novel, promising noninvasive biomarkers are under study and should be incorporated as exploratory endpoints in clinical trials. PMID- 26418479 TI - Update on medical and regulatory issues pertaining to compounded and FDA-approved drugs, including hormone therapy. AB - OBJECTIVE: We review the historical regulation of drug compounding, concerns about widespread use of non-Food and Drug Admiistration (FDA)-approved compounded bioidentical hormone therapies (CBHTs), which do not have proper labeling and warnings, and anticipated impact of the 2013 Drug Quality and Security Act (DQSA) on compounding. METHODS: US government websites were searched for documents concerning drug compounding regulation and oversight from 1938 (passage of Federal Food, Drug, and Cosmetic Act [FDCA]) through 2014, including chronologies, Congressional testimony, FDA guidelines and enforcements, and reports. The FDCA and DQSA were reviewed. PubMed and Google were searched for articles on compounded drugs, including CBHT. RESULTS: Congress explicitly granted the FDA limited oversight of compounded drugs in a 1997 amendment to the FDCA, but the FDA has encountered obstacles in exercising that authority. After 64 patient deaths and 750 adversely affected patients from the 2012 meningitis outbreak due to contaminated compounded steroid injections, Congress passed the DQSA, authorizing the FDA to create a voluntary registration for facilities that manufacture and distribute sterile compounded drugs in bulk and reinforcing FDCA regulations for traditional compounding. Given history and current environment, concerns remain about CBHT product regulation and their lack of safety and efficacy data. CONCLUSIONS: The DQSA and its reinforcement of S503A of the FDCA solidifies FDA authority to enforce FDCA provisions against compounders of CBHT. The new law may improve compliance and accreditation by the compounding industry; support state and FDA oversight; and prevent the distribution of misbranded, adulterated, or inconsistently compounded medications, and false and misleading claims, thus reducing public health risk. PMID- 26418480 TI - Impact of Rett Syndrome Mutations on MeCP2 MBD Stability. AB - Rett syndrome causing missense mutations in the methyl-CpG-binding domain (MBD) of methyl CpG-binding protein 2 (MeCP2) were investigated both in silico and in vitro to reveal their effect on protein stability. It is demonstrated that the vast majority of frequently occurring mutations in the human population indeed alter the MBD folding free energy by a fraction of a kcal/mol up to more than 1 kcal/mol. While the absolute magnitude of the change of the free energy is small, the effect on the MBD functionality may be substantial since the folding free energy of MBD is about 2 kcal/mol only. Thus, it is emphasized that the effect of mutations on protein integrity should be evaluated with respect to the wild-type folding free energy but not with the absolute value of the folding free energy change. Furthermore, it was observed that the magnitude of the effect is correlated neither with the burial of the mutation sites nor with the basic amino acid physicochemical property change. Mutations that strongly perturb the immediate structural features were found to have little effect on folding free energy, while very conservative mutations resulted in large changes of the MBD stability. This observation was attributed to the protein's ability to structurally relax and reorganize to reduce the effect of mutation. Comparison between in silico and in vitro results indicated that some Web servers perform relatively well, while the free energy perturbation approach frequently overpredicts the magnitude of the free energy change especially when a charged amino acid is involved. PMID- 26418481 TI - Association between trabecular bone score and risk factors for fractures in Korean female patients with rheumatoid arthritis. AB - OBJECTIVE: To identify the association between trabecular bone score (TBS) and other known risk factors for fractures in rheumatoid arthritis (RA) patients. METHODS: One hundred female RA patients aged >=50 years were enrolled. The following risk factors for fracture were selected: prevalent vertebral fracture (VF), bone mineral density (BMD), TBS, and 10-year probability of major osteoporotic fracture by FRAX(r) (MOF-FRAX scores). The associations between risk factors were identified, and accuracy of TBS, BMD, and FRAX scores to detect the prevalent VF, the strongest risk factor for future fracture, were assessed. RESULTS: Twenty-six patients were revealed to have moderate to severe VFs. There was a modest negative correlation between MOF-FRAX score and TBS (r = -0.367, p < 0.01), while there was no correlation between MOF-FRAX score and L-spine BMD (r = -0.050, p = 0.62). The areas under curves (AUCs) were 0.818, 0.683, and 0.518 for the MOF-FRAX score, TBS, and L-spine BMD, respectively. Among patients with glucocorticoids (GC) use (n = 57), AUCs were 0.762, 0.758, and 0.448 for their MOF-FRAX score, TBS, and L-spine BMD, respectively. CONCLUSIONS: TBS showed better correlation with MOF-FRAX score than BMD, and it was superior to BMD in identifying prevalent VFs in RA patients, especially who are in use of GCs. PMID- 26418482 TI - Effects of Ambient Air and Temperature on Ionic Gel Gated Single-Walled Carbon Nanotube Thin-Film Transistor and Circuits. AB - Single-walled carbon nanotube thin-film transistor (SWCNT TFT) and circuits were fabricated by fully inkjet printing gold nanoparticles as source/drain electrodes, semiconducting SWCNT thin films as channel materials, PS-PMMA-PS/EMIM TFSI composite gel as gate dielectrics, and PEDOT/PSS as gate electrodes. The ionic gel gated SWCNT TFT shows reversible conversion from p-type transistor behavior in air to ambipolar features under vacuum due to reversible oxygen doping in semiconducting SWCNT thin films. The threshold voltages of ionic gel gated SWCNT TFT and inverters are largely shifted to the low value (0.5 V for p region and 1.0 V for n-region) by vacuum annealing at 140 degrees C to exhausively remove water that is incorporated in the ionic gel as floating gates. The vacuum annealed ionic gel gated SWCNT TFT shows linear temperature dependent transconductances and threshold voltages for both p- and n-regions. The strong temperature dependent transconductances (0.08 MUS/K for p-region, 0.4 MUS/K for n region) indicate their potential application in thermal sensors. In the other hand, the weak temperature dependent threshold voltages (-1.5 mV/K for p-region, 1.1 mV/K for n-region) reflect their excellent thermal stability. PMID- 26418483 TI - Hole spin relaxation in InAs/GaAs quantum dot molecules. AB - We calculate the spin-orbit induced hole spin relaxation between Zeeman sublevels of vertically stacked InAs quantum dots. The widely used Luttinger-Kohn Hamiltonian, which considers coupling of heavy- and light-holes, reveals that hole spin lifetimes (T1) of molecular states significantly exceed those of single quantum dot states. However, this effect can be overcome when cubic Dresselhaus spin-orbit interaction is strong. Misalignment of the dots along the stacking direction is also found to be an important source of spin relaxation. PMID- 26418484 TI - Force-Field Based Quasi-Chemical Method for Rapid Evaluation of Binary Phase Diagrams. AB - We present the Pair Configurations to Molecular Activity Coefficients (PAC-MAC) method. The method is based on the pair sampling technique of Blanco (Fan, C. F.; Olafson, B. D.; Blanco, M.; Hsu, S. L. Application of Molecular Simulation to Derive Phase Diagrams of Binary Mixtures. Macromolecules 1992, 25, 3667-3676) with an extension that takes the packing of the molecules into account by a free energy model. The intermolecular energy is calculated using classical force fields. PAC-MAC is able to predict activity coefficients and corresponding vapor liquid equilibrium diagrams at least 4 orders of magnitude faster than molecular simulations. The accuracy of the PAC-MAC method is tested by comparing the results with experimental data and with the results of the COSMO-SAC model (Lin, S.-T.; Sandler, S. I. A Priori Phase Equilibrium Prediction from a Segment Contribution Solvation Model. Ind. Eng. Chem. Res. 2002, 41, 899-913). PAC-MAC (using the OPLS-aa force field) is shown to be comparable in accuracy to COSMO SAC, at the considerable advantage that PAC-MAC in principle does not require quantum calculation, provided proper force fields to be available. PMID- 26418486 TI - Evaluation of mobile smartphones app as a screening tool for environmental noise monitoring. AB - Noise is a global occupational and environmental health hazard with considerable social and physiological impact and, therefore, there is a need for regular measurements to boost monitoring and regulations of environmental noise levels in our communities. This necessitates a readily available, inexpensive, and easy to use noise measuring device. We aimed to test the sensitivity and validity of mobile "smart" phones for this purpose. This was a comparative analysis of a cross sectional study done between January 2014 and February 2015. Noise levels were measured simultaneously at different locations within Abuja Nigeria at day and night hours in real time environments. A sound level meter (SLM) (Extech407730 Digital Soundmeter, serial no.: 2310135, calibration no: 91037) and three smartphones (Samsung Galaxy note3, Nokia S, and Techno Phantom Z running on Android "Apps" Androidboy1) were used. Statistical calculations were done with Pearson correlation, T-test and Consistency within American National Standards Institute acceptable standard errors. Noise level readings for both daytime and night with the SLM and the mobile phones showed equivalent values. All noise level meters measured were <100dB. The daytime readings were nearly identical in six locations and the maximum difference in values between the SLM and Smartphone instruments was 3db, noted in two locations. Readings in dBA showed strong correlation (r = 0.9) within acceptable error limits for Type 2 SLM devices and no significant difference in the values (p = 0.12 & 0.58) for both day and night. Sensitivity of the instrument yielded 92.9%. The androidboy1 "app" performance in this study showed a good correlation and comparative high sensitivity to the Standard SLM (type 2 SLM device). However there is the need for further studies. PMID- 26418487 TI - Exploration of the Chiral Recognition of Sugar-Based Diindolylmethane Receptors: Anion and Receptor Structures. AB - In this study, we have conducted a systematic investigation of the chiral recognition of carboxylic anions by D-glucuronic acid/diindolylmethane receptors. We investigate the influence of the anion structure on chiral recognition in the diindolylmethane/glucuronic acid-based receptor 1 a. We found that presence of an additional hydrogen-bond donor at the alpha position to the carboxylic function is essential for effective chiral differentiation in these systems. Furthermore, we present a synthetic procedure that allows for the synthesis of sugar-decorated receptors that possess a modified substituent at the anomeric position. Four new receptors 1 b-e have been synthesized, and their chiral-discrimination ability toward model carboxylates is studied. The obtained results show that the chiral recognition of these receptors can be fine-tuned by incorporation of a proper substituent into the receptor structure. PMID- 26418485 TI - Discovery of Indoline-2-carboxamide Derivatives as a New Class of Brain-Penetrant Inhibitors of Trypanosoma brucei. AB - There is an urgent need for new, brain penetrant small molecules that target the central nervous system second stage of human African trypanosomiasis (HAT). We report that a series of novel indoline-2-carboxamides have been identified as inhibitors of Trypanosoma brucei from screening of a focused protease library against Trypanosoma brucei brucei in culture. We describe the optimization and characterization of this series. Potent antiproliferative activity was observed. The series demonstrated excellent pharmacokinetic properties, full cures in a stage 1 mouse model of HAT, and a partial cure in a stage 2 mouse model of HAT. Lack of tolerability prevented delivery of a fully curative regimen in the stage 2 mouse model and thus further progress of this series. PMID- 26418488 TI - Does the Acute Care Spinal Cord Injury Setting Predict the Occurrence of Pressure Ulcers at Arrival to Intensive Rehabilitation Centers? AB - OBJECTIVE: The objective of this study was to evaluate the impact of acute care in specialized spinal cord injury (SCI) trauma centers on the prevalence of pressure ulcers (PU) upon arrival at a functional rehabilitation center after a traumatic SCI. DESIGN: This is a retrospective cohort study among 123 patients with traumatic SCI referred to intensive functional rehabilitation between January 1, 2009, and December 31, 2011. Group 1 (n = 90) was referred from a level 1 specialized SCI trauma center and group 2 (n = 33) was referred from seven trauma centers not specialized in SCI. RESULTS: The total prevalence of patients with PU at admission to functional rehabilitation was 33.3% (26.7% in group 1 and 51.5% in group 2, P = 0.017). There were also more patients with multiple PU in group 2 (24.2% vs. 2.2%, P = 0.0001). A binary logistic regression showed a significant relationship between the occurrence of PU and the type of acute care facility as well as the ASIA (American Spinal Injury Association) Impairment Scale grade. Receiving acute care at the specialized SCI trauma center was associated with a decrease in the number of patients developing one and multiple PU. CONCLUSIONS: These results highlight the importance of specialized SCI trauma centers in acute care of patients with traumatic SCI in reducing PU at their admission to functional rehabilitation settings. PMID- 26418490 TI - Avascular Necrosis of the Femoral Head Masquerading as Iliopsoas Bursitis: Imaging With Ultrasound and Magnetic Resonance. PMID- 26418489 TI - Effectiveness of Individualized Home-Based Exercise on Turning and Balance Performance Among Adults Older than 50 yrs: A Randomized Controlled Trial. AB - OBJECTIVE: This study evaluated the effectiveness of an individualized home-based exercise program that included specific turning exercises in improving turning performance in adults identified as having unsteadiness during turning. DESIGN: A single-blind (assessors) randomized controlled trial was conducted with 68 community-dwelling Malaysians aged 50 yrs and older, who had abnormal turning performance (outside of age and sex, normal limits on the Step/Quick Turn Test [180-degree turn task on the NeuroCom Balance Master with long plate]). The intervention group received a 16-wk home exercise program that included two turning exercises, whereas the control group maintained their usual activities. RESULTS: Significant group * time effects were found using two-way repeated measures analysis of variance for turning and balance/mobility measures. The intervention group significantly improved relative to the control group for (1) sway when turning 180 degrees Step/Quick Turn, F1,65 = 8.070, P = 0.006; (2) time to perform 180-degree turn Step/Quick Turn, F1,65 = 8.216, P = 0.006; (3) Timed Up and Go (single task), F1,65 = 6.647, P = 0.012; (4) Timed Up and Go (dual task), F1,65 = 8.301, P = 0.005; and (5) static stance sway, F1,65 = 10.491, P = 0.002. CONCLUSIONS: An individualized home exercise program that included specific exercises to improve turning ability was effective in improving turning performance in adults older than 50 yrs. PMID- 26418491 TI - Experience of Remotely Receiving and Delivering Resident Didactic Lectures. PMID- 26418492 TI - Focal Cingulum Injury by Minor and Direct Head Trauma: A Diffusion Tensor Tractography Study. PMID- 26418498 TI - Is adding a new class of cones to the retina sufficient to cure color-blindness? AB - New genetic methods have made it possible to substitute cone pigments in the retinas of adult nonhuman primates. Doing so influences the animals' visual abilities, demonstrating that the gene therapy was effective. However, we argue that no studies conducted so far have unambiguously demonstrated that the experimental animals have also acquired the ability to make new color distinctions. Simply put, it has been shown that animals that underwent the gene treatment can now-in addition to finding a red ball on a grayish background-find a green ball on a grayish background. However, it has not been shown that the animals can distinguish a red ball from a green one. For most people, that essential ability would be the primary reason for wanting to undergo a treatment for color-blindness in the first place, for instance, because their color blindness currently prevents them from pursuing a career as a pilot or firefighter. It is important to point out such possible limitations of gene therapy for color-blindness to avoid unwarranted expectations in both clinicians and patients. To explain the origin of our concerns, we simulate how replacing the pigment of some cones is expected to influence the outcomes on the behavioral test used so far. The simulations show that this test does not provide conclusive evidence that the animals acquired the ability to make new chromatic distinctions. In our view, it is therefore premature to claim that human color blindness can be cured through gene therapy. We propose a test that would provide more conclusive evidence of fundamentally altered color vision after gene therapy. PMID- 26418499 TI - Differential item functioning analysis of the Vanderbilt Expertise Test for cars. AB - The Vanderbilt Expertise Test for cars (VETcar) is a test of visual learning for contemporary car models. We used item response theory to assess the VETcar and in particular used differential item functioning (DIF) analysis to ask if the test functions the same way in laboratory versus online settings and for different groups based on age and gender. An exploratory factor analysis found evidence of multidimensionality in the VETcar, although a single dimension was deemed sufficient to capture the recognition ability measured by the test. We selected a unidimensional three-parameter logistic item response model to examine item characteristics and subject abilities. The VETcar had satisfactory internal consistency. A substantial number of items showed DIF at a medium effect size for test setting and for age group, whereas gender DIF was negligible. Because online subjects were on average older than those tested in the lab, we focused on the age groups to conduct a multigroup item response theory analysis. This revealed that most items on the test favored the younger group. DIF could be more the rule than the exception when measuring performance with familiar object categories, therefore posing a challenge for the measurement of either domain-general visual abilities or category-specific knowledge. PMID- 26418500 TI - Inhibition of Phosphate-Induced Vascular Smooth Muscle Cell Osteo-/Chondrogenic Signaling and Calcification by Bafilomycin A1 and Methylamine. AB - BACKGROUND/AIMS: Excessive phosphate concentrations trigger vascular calcification, an active process promoted by osteoinduction of vascular smooth muscle cells (VSMCs) with increased expression and activity of transcription factor RUNX2 (Core-binding factor alpha1, CBFA1), alkaline phosphatase (ALPL), TGFbeta1, transcription factor NFAT5, and NFAT5-sensitive transcription factor SOX9. The osteoinductive signaling and vascular calcification of hyperphosphatemic klotho-hypomorphic mice could be reversed by treatment with NH4Cl, effects involving decrease of TGFbeta1 and inhibition of NFAT5-dependent osteoinductive signaling. Known effects of NH4Cl include alkalinization of acidic cellular compartments. The present study explored whether osteo-/chondrogenic signaling could be influenced by alkalinization of acidic cellular compartments following inhibition of the vacuolar H+ ATPase with bafilomycin A1 or following dissipation of the pH gradient across the membranes of acidic cellular compartments with methylamine. METHODS: Primary human aortic smooth muscle cells (HAoSMCs) were treated with high phosphate to trigger osteo-/chondrogenic signaling and calcification in the absence or presence of bafilomycin A1 or methylamine. Calcium content was determined using a QuantiChrom Calcium assay, ALP activity by a colorimetric assay and transcript levels by quantitative RT PCR. RESULTS: High phosphate increased significantly the calcium deposition, CBFA1 and ALPL mRNA expression as well as alkaline phosphatase activity in HAoSMCs, all effects ameliorated by both, bafilomycin A1 and methylamine. High phosphate further significantly up-regulated the mRNA levels of TGFB1, NFAT5 and SOX9, effects significantly blunted by additional treatment with bafilomycin A1 or methylamine. Treatment of HAoSMCs with human TGFbeta1 protein or high phosphate up-regulated NFAT5, SOX9, CBFA1 and ALPL mRNA expression to similarly high levels which could not be further increased by combined treatment with high phosphate and TGFbeta1. Bafilomycin A1 failed to reverse the osteo-/chondrogenic signaling triggered by high phosphate together with TGFbeta1. CONCLUSIONS: Inhibition of the vacuolar H+ ATPase or dissipation of the pH gradient across the membranes of acidic cellular compartments both disrupt osteo-/chondrogenic signaling and calcium deposition in VSMCs, observations supporting the hypothesis that vascular calcification requires acidic cellular compartments. PMID- 26418501 TI - Thrombosis of multiple angiolipomas due to acenocumarol treatment. PMID- 26418502 TI - [PRIER II. The Emilia-Romagna Research and Innovation Programme]. AB - The Emilia-Romagna Programme for Research and Innovation "PRIER" was born in 2005 with the aim of increasing cultural and operational conditions for the development of clinical research, useful both to the Regional Health Service (SSR) and to the private sectors of pharmaceutical and biomedical areas. In this context, the PRIER had from the beginning a double connotation: a space where the SSR can explore issues related to the development of its own research capacity; and a context where new possible ways of relating and comparison with the pharmaceutical and biomedical industry are tested. Over the years the activities of PRIER were defined by: initiatives to strengthen the system of research in SSR; development of tools to monitor activities of the research; production of clinical-organizational recommendations for the governance of innovation. In 2013 a new area of discussion and a common interest have been identified on the subject of clinical registries. In particular, it wanted to build a path of work able to identify all the possible critical and relevant points (points to consider), indispensable, necessary or useful to the construction and use of clinical registries, taking into account the points of view of all actors involved. The course began with defining the rules of the game and continued with workshops that allowed to analyse together the matter. At the end of the second workshop it was decided to make the work carried out visible: first, not to miss the opportunity offered by the past but recent discussion; secondly, to facilitate the discussion both on the issue of registers and to the adopted methodology, which sees the different actors (public and private ones) to reason together in a context for once not influenced by necessities of negotiation and government resources. PMID- 26418503 TI - [Taxonomy and definition of clinical registries]. AB - In order to assess the needs of knowledge about surveillance and registries in Italy and to prepare a proposal for the advancement of monitoring and recording capacity, a working group led by the Italian Association of Epidemiology and composed by the University of Turin, the Institute of Health and Agenas, carried out a survey of definitions and approaches used in public health and consulted the main Italian experts in surveillance and registries. Some of the reflections developed in this project are presented, to assess to which extent they are adaptable to the prospects the program PRIER aims to. Different aspects of the issue are analyzed: from the frame work necessary to identify information needs and how to improve the ability to measure and types of definitions and taxonomies of the registers, to the implications of the choices about what to include in registries on regulation of the instruments and investment priorities for new registries and surveillance. PMID- 26418504 TI - [Considerations on limits and profits of registries]. AB - The article collects the summary of the discussion occurred in the setting of PRIER II, in the session dedicated to the taxonomy of registries. Shown below, some specific contributions by health professionals working at the regional departments, which deal with registries, as well as the contribution on the same subject by specialists working at some pharmaceutical companies. In particular, after the presentation summarized in the article by prof. Giuseppe Costa1, the contributions, respectively by a representative of the Emilia-Romagna Region, of a health and hospital service and by the PRIER II workgroup, are following. Finally, a collective work with all participants to the working group took place to focus on all the issues considered to be crucial in defining clinical registries. At the same discussion table, institutional representatives of the regulatory national and regional branch were also invited to take into consideration the points of view of all public and private registry users, in particular in their benefits, limits and purposes. Going through the discussion on a specific check list and deepening a number of statements identified by the working group, a list of key points, essential to characterize each clinical registry, was produced. PMID- 26418505 TI - [Health registries: methodological issues]. AB - Health registries and observational studies are different entities, and although several registries are conceived as observational cohort studies, or provide the data that are needed for cohort or case-control studies, this is not always true: many registries have specific aims that imply methodological standards that differ completely from those of an observational study. Of course, whenever a Registry is conceived with the aim of conducting an observational study, this will dictate its methods. The difference between a registry and the simple assembling and analysis of routine clinical data must be stressed as well: a registry may require that collection of data from different administrative sources, or of original data not available elsewhere, and must guarantee the quality and completeness of the information it contains. It has been repeatedly suggested that the huge databases of health information that are currently assembled by most health governing bodies should be exploited directly for evaluations of appropriateness and effectiveness. This is extremely dangerous, because the inherent potential biases already affecting all observational studies may completely undermine their validity if the currently accepted methodological standards are relaxed. Similarly, the use of observational studies for the assessment of the effectiveness of health technologies must be considered with caution. PMID- 26418506 TI - [Considerations on what we can (and what we should not) ask to registries]. AB - This article presents a summary of the discussion which took place during the works of PRIER II in the session dedicated to the methodology of registries. Following a thorough analysis of the possible methods and the limits which deal with the collection of clinical data through the registries, the different points of view were compared, perhaps the most relevant, related to this activity. All this has been done by taking advantage by the possibility to observe aspects from different points of view. In particular, the exercise considered those who have to deal with the methodological aspects of the registries as an operator of public health or as a private operator who creates services for companies. The final goal, again, was to line up a few essential points accompanied by reasoning and comments useful to anyone who wants to address the issue of registries from the methodological point of view. PMID- 26418507 TI - [Use of data: legal and ethical aspects]. AB - Health care professionals and organizations, in carrying out their activities, consistently handle information related to identified or identifiable (even indirectly) natural persons, therefore "personal data". The application of Legislative Decree 30 June 2003 n. 196--the Code concerning the protection of personal data--as integrated by the pronunciations of the authority tasked with the application of such a complex legislation, the Authority for the Protection of Personal Data, consequently follows. The aforementioned legislation is seldom fully applied even 12 years after its publication, and even so not properly or with the adequate level of care. As a consequence, the data processed is often not adequately safeguarded, and compliance is hindered at an organisational level: this is particularly true with reference to the state of the art in medical technology, which is characterized by the utilization of ICT technologies such as the ones used with clinical registries and the Electronic Health Record. This chapter shows that, even when processing personal data that is of a sensitive nature, and at the same time of great importance, it is possible to reconcile the need to access and manage information with the protection of the individuals to whom such information refers to. This possibility is however closely linked to the awareness of the issues involved, awareness that in turn comes from an indispensable knowledge of the different aspects of that complex legislation. PMID- 26418509 TI - Free-Standing T-Nb2O5/Graphene Composite Papers with Ultrahigh Gravimetric/Volumetric Capacitance for Li-Ion Intercalation Pseudocapacitor. AB - Free-standing electrodes with high gravimetric/volumetric capacitance will open up potential applications in miniaturized consumer electronics. Herein, we report a simple synthesis technology of free-standing orthorhombic Nb2O5 (T Nb2O5)/graphene composite papers for Li-intercalating pseudocapacitive electrodes. Through a facile polyol-mediated solvothermal reaction, the Nb2O5 nanodots are homogeneously decorated onto the surface of reduced graphite oxide (rGO), which can form a homogeneous Nb2O5/rGO colloidal suspension that can be easily fabricated into flexible composite papers. The heat-treated T Nb2O5/graphene composite papers exhibit a nanoporous layer-stacked structure with good ionic-electric conductive pathways, high T-Nb2O5 loading of 74.2%, and high bulk density of 1.55 g cm(-3). Such T-Nb2O5/graphene composite papers show a superior pseudocapacitor performance as free-standing electrodes, as evidenced by an ultrahigh gravimetric/volumetric capacitance (620.5 F g(-1) and 961.8 F cm(-3) at 1 mV s(-1)) and excellent rate capability. Furthermore, an organic electrolyte based asymmetric supercapacitor is assembled based on T-Nb2O5/graphene composite papers, which can deliver a high energy density of 47 W h kg(-1) and power density of 18 kW kg(-1). PMID- 26418510 TI - Retrieval flexibility and reinstatement in the developing hippocampus. AB - Episodic memory improves during childhood and this improvement has been associated with age differences in hippocampal function, but previous research has not manipulated the possible underlying mechanisms. We tested the hypothesis that age-related differences in hippocampal activation may reflect changes in retrieval flexibility. We expected these activation differences to be observed most prominently in the anterior hippocampus. Functional magnetic resonance imaging (fMRI) data were collected from children ages 8 and 10, and adults (N = 63) during an associative recognition task that required participants to recognize pairs of pictures which either appeared in the same location as during encoding (Same location), or in a flipped location, such that each picture switched their location with the other member of the pair (Flipped location). Recognition of same-location pairs placed lower demands on flexible retrieval compared to recognition of flipped-location pairs. Behaviorally, 8-year-olds exhibited the strongest correct recognition gains for same-location compared to flipped-location pairs, and females unexpectedly outperformed males across all ages. When we examined correct recognition, adults recruited the hippocampal head more strongly for flipped- versus same-location pairs compared to both groups of children; in contrast both adults and 10-year-olds recruited the hippocampal tail more strongly for flipped- versus same-location pairs compared to 8-year-olds. This pattern was stronger in the left hippocampus and for females. Moreover hippocampal discrimination between recognized and forgotten items in the same location condition was stronger in 8-year-olds compared to adults, and was stronger in the flipped-location condition in adults compared to 8-year-olds; this pattern was stronger in the left hippocampus. Individual differences in this discrimination contrast for flipped-location trials in the head and body predicted performance on an index of creative thinking. Overall, these results lend new support to the idea that hippocampal development may reflect change in retrieval flexibility with implications for additional forms of flexible cognition. PMID- 26418511 TI - Comprehensive investigation in patients affected by globozoospermia. PMID- 26418512 TI - Nicotine-Mediated Ca(2+)-Influx Induces IL-8 Secretion in Oral Squamous Cell Carcinoma Cell. AB - Cigarette smoking is one of the most important risk factors for the development of various diseases. Nicotine is the most extensively investigated component of cigarette smoke, and a comprehensive analysis of the genes induced by nicotine stimulation revealed that interleukin-8 (IL-8) was induced in oral squamous cell carcinoma cell (OSCC). Based on this background, the signaling mechanisms of nicotine-mediated IL-8 induction in OSCC was investigated. Augmented IL-8 secretion by Ca9-22 cells was blocked by the NF-kappaB inhibitor L-1-4' tosylamino-phenylethyl-chloromethyl ketone (TPCK) and the nicotinic acetylcholine receptor (nAChR)-specific inhibitor alpha-bungarotoxin (alphaBtx). The downstream signaling pathway was further examined by pre-incubating the cells with inhibitors against mitogen-activated protein kinase (MEK), protein kinase C (PKC), and Ca(2+)/calmodulin-dependent kinase II (CaMK II). Only the CaMK II inhibitor was found to exert an inhibitory effect on nicotine-mediated IL-8 secretion. Pre-treatment of the Ca9-22 cells with the Ca(2+) chelator BAPTA-AM drastically inhibited IL-8 secretion. Although nicotine stimulation induced the phosphorylation of the NF-kappaB p65 subunit, pre-treatment with BAPTA-AM was found to inhibit this activity significantly. CaMK II-dependent p65 phosphorylation was confirmed by pre-incubation of the cells with CaMK II inhibitor. The results from this study indicate that the binding of nicotine to nAChR induces Ca(2+) influx, which results in the activation and phosphorylation of CaMK II and NF-kappaB p65, respectively. Nicotine-mediated IL-8 induction should be a trigger for the initiation of various diseases. PMID- 26418513 TI - Prevalence of erectile dysfunction in a cohort of Italian hypertensive subjects. AB - The aim of this study was to evaluate the prevalence of erectile dysfunction (ED) in a cohort of Italian hypertensive men and the association with clinical and biochemical data. The study involved 270 consecutive hypertensive subjects aged 40-70 years evaluated in Italian Hypertension Centers of six hospitals from Liguria and Piedmont. ED was assessed through the self-administered questionnaire of the International Index of Erectile Function. Clinical history with ongoing drug treatment, various clinical parameters, biochemical data and evidence about the presence of subclinical target organ damage was collected. Twenty-seven subjects refused to answer the questionnaire (10%). Among the 243 remained subjects, 123 presented ED (50.6%). ED was highly related to age, systolic blood pressure, pulse pressure, smoking status, statin therapy and kidney function. The addition of a thiazide diuretic to an inhibitor of the renin-angiotensin system significantly increased the prevalence of ED. The prevalence of ED increased in relation with the number of hypotensive drug classes taken by the patients. ED was highly prevalent in this cohort of Italian hypertensive subjects and was associated with other cardiovascular risk factors, such as age, smoking status and kidney function. The role of ED as an early marker of cardiovascular disease is discussed. PMID- 26418514 TI - Uptake of Pharmaceuticals Influences Plant Development and Affects Nutrient and Hormone Homeostases. AB - The detection of a range of active pharmaceutical ingredients (APIs) in the soil environment has led to a number of publications demonstrating uptake by crops, however very few studies have explored the potential for impacts on plant development as a result of API uptake. This study investigated the effect of carbamazepine and verapamil (0.005-10 mg/kg) on a range of plant responses in zucchini (Cucurbita pepo). Uptake increased in a dose-dependent manner, with maximum leaf concentrations of 821.9 and 2.2 mg/kg for carbamazepine and verapamil, respectively. Increased carbamazepine uptake by zucchini resulted in a decrease in above (<60%) and below (<30%) ground biomass compared to the controls (p < 0.05). At soil concentrations >4 mg/kg the mature leaves suffered from burnt edges and white spots as well as a reduction in photosynthetic pigments but no such effects were seen for verapamil. For both APIs, further investigations revealed significant differences in the concentrations of selected plant hormones (auxins, cytokinins, abscisic acid and jasmonates), and in the nutrient composition of the leaves in comparison to the controls (p < 0.05). This is some of the first research to demonstrate that the exposure of plants to APIs is likely to cause impacts on plant development with unknown implications. PMID- 26418515 TI - Copper Complex in Poly(vinyl chloride) as a Nitric Oxide-Generating Catalyst for the Control of Nitrifying Bacterial Biofilms. AB - In this study, catalytic generation of nitric oxide by a copper(II) complex embedded within a poly(vinyl chloride) matrix in the presence of nitrite (source of nitric oxide) and ascorbic acid (reducing agent) was shown to effectively control the formation and dispersion of nitrifying bacteria biofilms. Amperometric measurements indicated increased and prolonged generation of nitric oxide with the addition of the copper complex when compared to that with nitrite and ascorbic acid alone. The effectiveness of the copper complex-nitrite-ascorbic acid system for biofilm control was quantified using protein analysis, which showed enhanced biofilm suppression when the copper complex was used in comparison to that with nitrite and ascorbic acid treatment alone. Confocal laser scanning microscopy (CLSM) and LIVE/DEAD staining revealed a reduction in cell surface coverage without a loss of viability with the copper complex and up to 5 mM of nitrite and ascorbic acid, suggesting that the nitric oxide generated from the system inhibits proliferation of the cells on surfaces. Induction of nitric oxide production by the copper complex system also triggered the dispersal of pre established biofilms. However, the addition of a high concentration of nitrite and ascorbic acid to a pre-established biofilm induced bacterial membrane damage and strongly decreased the metabolic activity of planktonic and biofilm cells, as revealed by CLSM with LIVE/DEAD staining and intracellular adenosine triphosphate measurements, respectively. This study highlights the utility of the catalytic generation of nitric oxide for the long-term suppression and removal of nitrifying bacterial biofilms. PMID- 26418516 TI - Fast and Noninvasive Characterization of Suspicious Lesions Detected at Breast Cancer X-Ray Screening: Capability of Diffusion-weighted MR Imaging with MIPs. AB - PURPOSE: To evaluate the ability of a diagnostic abbreviated magnetic resonance (MR) imaging protocol consisting of maximum intensity projections (MIPs) from diffusion-weighted imaging with background suppression (DWIBS) and unenhanced morphologic sequences to help predict the likelihood of malignancy on suspicious screening x-ray mammograms, as compared with an abbreviated contrast material enhanced MR imaging protocol and a full diagnostic breast MR imaging protocol. MATERIALS AND METHODS: This prospective institutional review board-approved study included 50 women (mean age, 57.1 years; range, 50-69 years), who gave informed consent and who had suspicious screening mammograms and an indication for biopsy, from September 2014 to January 2015. Before biopsy, full diagnostic contrast enhanced MR imaging was performed that included DWIBS (b = 1500 sec/mm(2)). Two abbreviated protocols (APs) based on MIPs were evaluated regarding the potential to exclude malignancy: DWIBS (AP1) and subtraction images from the first postcontrast and the unenhanced series (AP2). Diagnostic indexes of both methods were examined by using the McNemar test and were compared with those of the full diagnostic protocol and histopathologic findings. RESULTS: Twenty-four of 50 participants had a breast carcinoma. With AP1 (DWIBS), the sensitivity was 0.92 (95% confidence interval [CI]: 0.73, 0.98), the specificity was 0.94 (95% CI: 0.77, 0.99), the negative predictive value (NPV) was 0.92 (95% CI: 0.75, 0.99), and the positive predictive value (PPV) was 0.93 (95% CI: 0.75, 0.99). The mean reading time was 29.7 seconds (range, 4.9-110.0 seconds) and was less than 3 seconds (range, 1.2-7.6 seconds) in the absence of suspicious findings on the DWIBS MIPs. With the AP2 protocol, the sensitivity was 0.85 (95% CI: 0.78, 0.95), the specificity was 0.90 (95% CI: 0.72, 0.97), the NPV was 0.87 (95% CI: 0.69, 0.95), the PPV was 0.89 (95% CI: 0.69, 0.97), and the mean reading time was 29.6 seconds (range, 6.0-100.0 seconds). CONCLUSION: Unenhanced diagnostic MR imaging (DWIBS mammography), with an NPV of 0.92 and an acquisition time of less than 7 minutes, could help exclude malignancy in women with suspicious x-ray screening mammograms. The method has the potential to reduce unnecessary invasive procedures and emotional distress for breast cancer screening participants if it is used as a complement after the regular screening clarification procedure. PMID- 26418517 TI - Association of the Number of Years Since Menopause with Metabolic Syndrome and Insulin Resistance in Chinese Urban Women. AB - BACKGROUND: This study aimed to assess the prevalence of metabolic syndrome (MetS) and the association of years since menopause with MetS and Insulin Resistance (IR) in Chinese women. METHOD: A total of 4436 Chinese subjects aged 40-80 years participated in the study; 790 were premenopausal women, and 3646 were postmenopausal women. IR was arbitrarily defined as a homeostasis model assessment-IR index (HOMA-IR) value above the 75th percentile of normal glucose tolerance (NGT). MetS was defined according to the International Diabetes Federation consensus definition. To test whether there was an association between the number of years since menopause and MetS, multivariate logistic analysis was conducted. Premenopausal women were used as a comparison group in regression analyses. RESULTS: After adjustment for age, body mass index (BMI), and gamma glutamyltransferase (GGT), more years since menopause was highly associated with an increased risk of MetS (p for trend <0.05) ; the number of years since menopause was not correlated with fasting insulin and HOMA-IR. Postmenopausal women with 10 to 14 years since menopause had the highest risk (odds ratio [OR], 2.10; 95% confidence interval [CI], 1.52-2.89, p < .05) of MetS, high triglycerides (TG; OR, 1.80; 95% CI, 1.34-2.42, p < .05) and high glucose (OR, 1.52; 95% CI, 1.14-2.05, p < .05) and low high-density lipoprotein cholesterol (HDL-C; OR, 1.38; 95% CI, 1.18-2.32, p < .05). Postmenopausal women with more than 15 years since menopause had the highest risk of abdominal obesity (OR, 1.69; 95% CI, 1.05-2.71, p < .05). CONCLUSION: In China, more years since menopause was highly associated with an increased risk of MetS. Menopausal history may help identify women with increased risk of developing MetS. PMID- 26418518 TI - Conicity Index and Waist-to-Hip Ratio Are Superior Obesity Indices in Predicting 10-Year Cardiovascular Risk Among Men and Women. AB - BACKGROUND: Central obesity has been recognized as a main risk factor for cardiovascular (CV) events. Three popular central obesity indices are waist circumference, waist-to-hip ratio (WHR), and waist-to-height ratio; abdominal volume index and conicity index are 2 recent novel obesity indices. The main aim of this study is to determine the performance of these indices to best predict 10 year CV events. HYPOTHESIS: Some obesity indices can be used to predict cardiovascular risk. METHODS: In total, 3199 subjects (age range, 40-79 years) were enrolled in this cross-sectional study. The American College of Cardiology/American Heart Association and Framingham risk score tools were used to estimate the 10-year CV events. Receiver operating characteristic curve analysis was used to determine the optimal discriminator(s) among the central obesity measures in the estimation of a 10-year risk of CV events >=7.5%, >=10%, and >=20% separately. RESULTS: Among the 5 central obesity indices, conicity index showed the most discriminatory power in estimation of a 10-year CV risk. In men, based on the American College of Cardiology/American Heart Association tool, the areas under the curve (AUCs) were from 0.671 to 0.682 based on the 3 above thresholds, whereas with the Framingham tool, AUCs were from 0.651 to 0.659. In women, all AUCs were >0.7. Our results also showed WHR to be an almost comparable discriminator of CV disease risk in the Iranian study population. CONCLUSION: Conicity index and WHR had a more discriminatory accuracy for 10-year CV events compared with the other obesity indices. PMID- 26418520 TI - Design Principles for Heteroatom-Doped Carbon Nanomaterials as Highly Efficient Catalysts for Fuel Cells and Metal-Air Batteries. AB - Oxygen reduction reaction/oxygen evolution reaction (ORR/OER) catalytic activities of p-orbital heteroatom-doped carbon nanomaterials are demonstrated to correlate to the combination of the electron affinity and electronegativity of doping elements, which serves as an activity descriptor for the entire family of p-block element dopants. Such a descriptor has predictive power and enables effective design of new bifunctional catalysts with enhanced ORR/OER activities. PMID- 26418519 TI - Chemical composition and cytotoxicity of the essential oil from different parts of Datura metel L. AB - The essential oil from different parts of Datura metel L. were extracted using hydrodistillation and GC-MS was used to analyse the essential oil. The main components of flowers were ketone (23.61%) and ethyl palmitate (15.84%). The main components of leaves were ketone (18.84%) and phytol (18.71%). Ketone (39.45%) and phytol (31.32%) were the major components of petioles. Palmitic acid (30.60%) and ethyl linoleate (21.56%) were the major components of seeds. The major ingredient of roots was palmitic acid (52.61%). The main ingredients of the stems were palmitic acid (38.38%) and ethyl linoleate (17.38%). All the different parts of essential oil were screened for cytotoxicity. The roots and stems showed the inhibitory effects against HepG-2 with IC50 levels of 613.88 and 341.12 mg/L. The leaves and roots showed the inhibitory effects against HeLa with IC50 levels of 267.76 and 348.35 mg/L. All the six parts have inhibitory effects against SGC 7901 cell lines. PMID- 26418525 TI - Scientific Program of 33rd World Congress of Endourology & SWL Program Book. PMID- 26418521 TI - Transcriptome Characteristics and X-Chromosome Inactivation Status in Cultured Rat Pluripotent Stem Cells. AB - Rat pluripotent stem cells, embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs) as mouse and human ones have a great potential for studying mammalian early development, disease modeling, and evaluation of regenerative medicine approaches. However, data on pluripotency realization and self-renewal maintenance in rat cells are still very limited, and differentiation protocols of rat ESCs (rESCs) and iPSCs to study development and obtain specific cell types for biomedical applications are poorly developed. In this study, the RNA-Seq technique was first used for detailed transcriptome characterization in rat pluripotent cells. The rESC and iPSC transcriptomes demonstrated a high similarity and were significantly different from those in differentiated cells. Additionally, we have shown that reprogramming of rat somatic cells to a pluripotent state was accompanied by X-chromosome reactivation. There were two active X chromosomes in XX rESCs and iPSCs, which is one of the key attributes of the pluripotent state. Differentiation of both rESCs and iPSCs led to X chromosome inactivation (XCI). The dynamics of XCI in differentiating rat cells was very similar to that in mice. Two types of facultative heterochromatin described in various mammalian species were revealed on the rat inactive X chromosome. To explore XCI dynamics, we established a new monolayer differentiation protocol for rESCs and iPSCs that may be applied to study different biological processes and optimized for directed derivation of specific cell types. PMID- 26418522 TI - Chlorotoxin: Structure, activity, and potential uses in cancer therapy. AB - Chlorotoxin is a disulfide-rich stable peptide from the venom of the Israeli scorpion Leiurus quinquestriatus, which has potential therapeutic applications in the treatment of cancer. Its ability to preferentially bind to tumor cells has been harnessed to develop an imaging agent to help visualize tumors during surgical resection. In addition, chlorotoxin has attracted interest as a vehicle to deliver anti-cancer drugs specifically to cancer cells. Given its interesting structural and biological properties, chlorotoxin also has the potential to be used in a variety of other biotechnology and biomedical applications. Here, we review the structure, activity and potential applications of chlorotoxin as a drug design scaffold. PMID- 26418526 TI - What does end stage in neuromuscular diseases mean? Key approach-based transitions. AB - PURPOSE OF REVIEW: To revise the definition of end stage in the setting of neuromuscular disease (NMD), to understand the implications for the patient, family and healthcare team, and to address the obstacles involved in the lack of definition. RECENT FINDINGS: Unlike several conditions such as cancer, kidney or liver disease, the literature reveals no clear definition or categorization for NMD. Many articles mention end stage without defining it. Many years ago an expert consensus panel defined it based on functional criteria (forced vital capacity values and hypercapnic events). Only for amyotrophic lateral sclerosis/motoneurone disease has a wider criteria been proposed. As a consequence, the management of this heterogeneous group of disorders is often fragmented compared with the well organized palliative care program for cancer patients. SUMMARY: Better end-stage NMD definitions should help to identify the goals of care, but a broad range in time and intensity of deterioration make a valid definition difficult for end-stage NMD. Respiratory care, life-prolonging therapies, and structured care planning should be seen as complementary rather than dichotomous. This article emphasized the relevance of an integrated approach through the whole trajectories of NMD patients considering key transitions. PMID- 26418527 TI - The contribution of undergraduate palliative care education: does it influence the clinical patient's care? AB - PURPOSE OF REVIEW: The aim of this 2-year systematic review is to understand how learner assessment and curriculum evaluation of education in palliative care is being undertaken and to examine whether current undergraduate education influences the clinical patient's care. RECENT FINDINGS: Almost half of the 30 studies reviewed used a qualitative approach to evaluate learning experiences. Only three of them were controlled studies and a further one was a cohort study.When students openly express themselves, they agree that there is 'something' deep as regards the core or the essence of medical practice or nursing. They feel that they become better professionals and better prepared for the patients, not only in terms of end of life care, but also as regards care, irrespective of the phase of the disease.The inclusion of palliative care in undergraduate education is a way of providing knowledge, skill, and competences about palliative care (especially communication) and also improving attitudes toward caring in advanced disease and at the end of life. Different methods of experiential learning, even brief experiences, which bring students into close contact with palliative care clinical cases or patients, are providing better results. SUMMARY: From research studies, there is only indirect evidence that palliative care training at university leads to better clinical care of patients. In the future, long-term cohort or controlled studies might answer that question. PMID- 26418528 TI - If you want to understand the invisible, look carefully at the visible. PMID- 26418529 TI - Early History of Chronic Obstructive Pulmonary Disease 1808-1980. AB - COPD has become a more popular research area in the last 3 decades, yet the first clear descriptions of acute and chronic bronchitis were in 1808. This brief history, comprehensively referenced, leads us through the early developments in respiratory physiology and their applications. It emphasises the early history of chronic bronchitis and emphysema in the 19(th) and early 20(th) centuries, long before the dominant effects of cigarette smoking emerged. This remains relevant to developing countries today. PMID- 26418533 TI - Outcomes of patients with intestinal failure after the development and implementation of a multidisciplinary team. PMID- 26418531 TI - Aspects of mental health dysfunction among survivors of childhood cancer. AB - BACKGROUND: Some previous studies have reported that survivors of childhood cancer are at an increased risk of developing long-term mental health morbidity, whilst others have reported that this is not the case. Therefore, we analysed 5 year survivors of childhood cancer using the British Childhood Cancer Survivor Study (BCCSS) to determine the risks of aspects of long-term mental health dysfunction. PROCEDURE: Within the BCCSS, 10 488 survivors completed a questionnaire that ascertained mental health-related information via 10 questions from the Short Form-36 survey. Internal analyses were conducted using multivariable logistic regression to determine risk factors for mental health dysfunction. External analyses were undertaken using direct standardisation to compare mental health dysfunction in survivors with UK norms. RESULTS: This study has shown that overall, childhood cancer survivors had a significantly higher prevalence of mental health dysfunction for 6/10 questions analysed compared to UK norms. Central nervous system (CNS) and bone sarcoma survivors reported the greatest dysfunction, compared to expected, with significant excess dysfunction in 10 and 6 questions, respectively; the excess ranged from 4.4-22.3% in CNS survivors and 6.9-15.9% in bone sarcoma survivors. Compared to expected, excess mental health dysfunction increased with attained age; this increase was greatest for reporting 'limitations in social activities due to health', where the excess rose from 4.5% to 12.8% in those aged 16-24 and 45+, respectively. Within the internal analyses, higher levels of educational attainment and socio-economic classification were protective against mental health dysfunction. CONCLUSIONS: Based upon the findings of this large population-based study, childhood cancer survivors report significantly higher levels of mental health dysfunction than those in the general population, where deficits were observed particularly among CNS and bone sarcoma survivors. Limitations were also observed to increase with age, and thus it is important to emphasise the need for mental health evaluation and services across the entire lifespan. There is evidence that low educational attainment and being unemployed or having never worked adversely impacts long term mental health. These findings provide an evidence base for risk stratification and planning interventions. PMID- 26418534 TI - Pancreatic enzyme supplements are not effective for relieving abdominal pain in patients with chronic pancreatitis: Meta-analysis and systematic review of randomized controlled trials. PMID- 26418532 TI - Redox Modulation of PTEN Phosphatase Activity by Hydrogen Peroxide and Bisperoxidovanadium Complexes. AB - PTEN is a dual-specificity protein tyrosine phosphatase. As one of the central tumor suppressors, a thorough regulation of its activity is essential for proper cellular homeostasis. The precise implications of PTEN inhibition by reactive oxygen species (e.g. H2 O2 ) and the subsequent structural consequences remain elusive. To study the effects of PTEN inhibition, bisperoxidovanadium (bpV) complexes serve as important tools with the potential for the treatment of nerve injury or cardiac ischemia. However, their mode of action is unknown, hampering further optimization and preventing therapeutic applications. Based on protein crystallography, mass spectrometry, and NMR spectroscopy, we elucidate the molecular basis of PTEN inhibition by H2O2 and bpV complexes. We show that both molecules inhibit PTEN via oxidative mechanisms resulting in the formation of the same intramolecular disulfide, therefore enabling the reactivation of PTEN under reductive conditions. PMID- 26418535 TI - Domperidone prescribing practices exposed patients to cardiac risk despite a 'black box' warning: A Canadian tertiary care centre study. PMID- 26418537 TI - PEGylated Silk Nanoparticles for Anticancer Drug Delivery. AB - Silk has a robust clinical track record and is emerging as a promising biopolymer for drug delivery, including its use as nanomedicine. However, silk-based nanomedicines still require further refinements for full exploitation of their potential; the application of "stealth" design principals is especially necessary to support their evolution. The aim of this study was to develop and examine the potential of PEGylated silk nanoparticles as an anticancer drug delivery system. We first generated B. mori derived silk nanoparticles by driving beta-sheet assembly (size 104 +/- 1.7 nm, zeta potential -56 +/- 5.6 mV) using nanoprecipitation. We then surface grafted polyethylene glycol (PEG) to the fabricated silk nanoparticles and verified the aqueous stability and morphology of the resulting PEGylated silk nanoparticles. We assessed the drug loading and release behavior of these nanoparticles using clinically established and emerging anticancer drugs. Overall, PEGylated silk nanoparticles showed high encapsulation efficiency (>93%) and a pH-dependent release over 14 days. Finally, we demonstrated significant cytotoxicity of drug loaded silk nanoparticles applied as single and combination nanomedicines to human breast cancer cells. In conclusion, these results, taken together with prior silk nanoparticle data, support a viable future for silk-based nanomedicines. PMID- 26418536 TI - The Prevalence and Characteristics of Primary Headache and Dream-Enacting Behaviour in Japanese Patients with Narcolepsy or Idiopathic Hypersomnia: A Multi Centre Cross-Sectional Study. AB - BACKGROUND: Because the prevalence and characteristics of primary headache have yet to be thoroughly studied in patients with hypersomnia disorders, including narcolepsy and idiopathic hypersomnia, we examined these parameters in the Japanese population. METHODS: In a multicentre cross-sectional survey, among 576 consecutive outpatients with sleep disorders, 68 narcolepsy patients and 35 idiopathic hypersomnia patients were included. Additionally, 61 healthy control subjects participated. Semi-structured headache questionnaires were administered to all participants. RESULTS: The patients with narcolepsy (52.9%) and idiopathic hypersomnia (77.1%) more frequently experienced headache than the healthy controls (24.6%; p<0.0001). The prevalence rates were 23.5%, 41.2% and 4.9% for migraine (p<0.0001) and 16.2%, 23.5% and 14.8% (p = 0.58) for tension-type headache among the narcolepsy patients, the idiopathic hypersomnia patients and the control subjects, respectively. Those who experienced migraine more frequently experienced excessive daytime sleepiness, defined as an Epworth Sleepiness Scale score of >=10, than those who did not experience headache among the patients with narcolepsy (93.8% vs. 65.6%, p = 0.040) and idiopathic hypersomnia (86.7% vs. 37.5%, p = 0.026). Dream-enacting behaviour (DEB), as evaluated by the rapid eye movement sleep disorders questionnaire, was more frequently observed in the narcolepsy patients than in the idiopathic hypersomnia patients and the control subjects. An increased DEB frequency was observed in the narcolepsy patients with migraines compared to those without headache. CONCLUSIONS: Migraines were frequently observed in patients with narcolepsy and idiopathic hypersomnia. DEB is a characteristic of narcolepsy patients. Further studies are required to assess the factors that contribute to migraines in narcolepsy and idiopathic hypersomnia patients. PMID- 26418538 TI - Dual-Energy Computed Tomography-How Accurate Is Gemstone Spectrum Imaging Metal Artefact Reduction? Its Application to Orthopedic Metal Implants. AB - OBJECTIVE: To assess the accuracy and suitability of dual-energy computed tomography (DECT) in scanning metals used in orthopedic implants. MATERIALS AND METHODS: Four metal phantoms (Cobalt Chrome, Titanium Grade 5, Stainless Steel 316, and Stainless Steel 630), commonly used materials in orthopedic implants, were scanned by conventional, polychromatic CT as well as Gemstone Spectrum Imaging (GSI) DECT, with and without metal artefact reduction software (MARS). Scans were assessed for artefact based on Hounsfield unit values; and surfaces generated, based on a Canny edge detection algorithm. Two separate metal implants were also scanned and assessed for dimensional accuracy. RESULTS: Conventional, polychromatic CT, and GSI DECT (without MARS) scans displayed major beam hardening in the presence of all four metals. The GSI DECT with MARS showed very clear and reproducible boundaries with minimal noise surrounding the metal phantoms. However, geometric analysis found overestimation of the dimensions, volume, and surface area for most of the metal phantoms. Titanium displayed the least artefact, compared to the other metals, in all scan scenarios. CONCLUSIONS: Although metal artefact reduction using GSI DECT looks superior to conventional CT, when measured objectively, it was shown to overestimate geometries and skew dimensions. The GSI DECT with MARS should be used with caution, especially when assessing questions of implant shape or wear. PMID- 26418539 TI - Superolateral Hoffa's Fat Pad Edema in Collegiate Volleyball Players. AB - OBJECTIVE: Superolateral Hoffa's fat pad (SHFP) edema is a previously described magnetic resonance (MR) finding located between the patellar tendon and the lateral femoral condyle. The purpose of our study was to determine the prevalence and clinical significance of SHFP edema in female collegiate volleyball players. MATERIALS AND METHODS: Sixteen female collegiate volleyball players were consented for bilateral knee evaluations which consisted of history, physical examination and MR imaging. Each MR study was reviewed for the presence of SHFP edema, and 6 patellar maltracking measurements were done. These were tibial tuberosity-trochlear groove distance, patellar translation, lateral patellofemoral angle, trochlear depth, trochlear sulcus angle, and lateral trochlear inclination angle. RESULTS: A total of 16 athletes, 32 knees (16 girls; age range, 18-22 years; mean, 19.9) were enrolled in the study. Sixteen knees (50%) in 8 athletes had SHFP edema, with 100% bilaterality; 16 knees in 8 athletes had no evidence of SHFP edema (50%). Functional outcomes and physical examination findings were within normal limits for all athletes with no difference noted between SHFP edema-positive and -negative individuals. There was a statistically significant difference in the tibial tuberosity-trochlear groove distance, patellar translation, and patellofemoral angle (P value of < 0.001, 0.03 and 0.01, respectively) between the SHFP edema-positive and -negative individuals. CONCLUSIONS: Elite female volleyball athletes have a very high prevalence of SHFP edema, which is always bilateral. Although the exact etiology of SHFP edema remains inconclusive, it could potentially be a sensitive indicator of subtle patellar maltracking which cannot be distinguished by history and physical examination findings. Given the very high prevalence of SHFP edema and this being an asymptomatic finding, there is likely little clinical significance of this in majority of high-performance athletes. PMID- 26418541 TI - Ossification of the Posterior Longitudinal Ligament: Imaging Findings in the Era of Cross-Sectional Imaging. AB - Imaging appearance and classification systems of ossification of the posterior longitudinal ligament (OPLL) on computed tomography and magnetic resonance imaging will be reviewed. Computed tomography evaluation most accurately demonstrates OPLL length and thickness, whereas magnetic resonance imaging has the advantage of demonstrating abnormal signal in the cord. Neurologic symptoms are most common in the cervical spine and are related to the degree of spinal stenosis and presence of cord edema. Surgical treatment usually involves cases of cervical OPLL and includes anterior or posterior decompression. PMID- 26418540 TI - Semiquantitative and Quantitative Analyses of Dynamic Contrast-Enhanced Magnetic Resonance Imaging of Thyroid Nodules. AB - OBJECTIVE: This study was aimed to determine the utility of quantitative dynamic contrast-enhanced magnetic resonance imaging (MRI) in differentiating benign and malignant lesions in patients with known thyroid gland lesions scheduled for resection. METHODS: Patients scheduled for resection of a thyroid mass were prospectively enrolled. Dynamic contrast-enhanced MRI scans of the neck were performed before surgery. After resection, patients were divided into benign and malignant groups. Quantitative and semiquantitative MRI kinetic measurements of benign and malignant lesions were compared and analyzed. RESULTS: Twelve benign and 9 malignant lesions were identified in 19 patients. Mean Ktrans, Ve, and Kep for benign lesions were 1.69 +/- 1.59 min, 0.44 +/- 0.21 min, and 4.51 +/- 2.96 min, respectively; for the malignant lesions, 0.96 +/- 0.57 min, 0.45 +/- 0.19 min, and 3.57 +/- 3.53 min, respectively (P = 0.1886, 0.8036, and 0.3028, respectively). Tpeak, ERmax, slopemax, and iAUGC60 for benign lesions were 7.00 +/- 8.09 seconds, 293.27 +/- 141.25 seconds, 76.45 +/- 65.80 seconds, and 63.46 +/- 46.84, respectively; for malignant lesions, 8.11 +/- 8.55 seconds, 227.6 +/- 113.37 seconds, 81.17 +/- 109.71 seconds, and 43.69 +/- 26.19, respectively (P = 0.7525, 0.4941, 0.4474, and 0.3028, respectively). CONCLUSIONS: Dynamic contrast enhanced MRI pattern of kinetics was not significantly different for benign and malignant lesions of the thyroid using quantitative or semiquantitative methods. PMID- 26418542 TI - Pulmonary Leptospirosis With Diffuse Alveolar Hemorrhage: High-Resolution Computed Tomographic Findings in 16 Patients. AB - OBJECTIVE: The aim of this study was to evaluate the high-resolution computed tomographic (HRCT) findings from patients with leptospirosis and diffuse alveolar hemorrhage (DAH). MATERIALS AND METHODS: We retrospectively reviewed HRCT findings from 16 patients diagnosed as having leptospirosis causing DAH. The patient sample was composed of 13 men and 3 women aged 22 to 53 years (mean age, 34.5 years). Diagnosis was established with confirmation of leptospirosis infection by serologic microagglutination test. Histopathological study was performed in 8 patients. Two chest radiologists analyzed the HRCT images and reached decisions by consensus. RESULTS: The predominant HRCT findings were ground-glass opacities and airspace nodules (both n = 12, 75%), ground-glass nodules (n = 9, 56.25%), consolidations (n = 7, 43.75%), "crazy-paving" pattern (n = 3, 18.75%), and interlobular septal thickening without ground-glass opacity (n = 3, 18.75%). Bilateral pleural effusion was an associated finding in 2 (12.5%) patients. Analysis of the axial distribution of the lesions revealed diffuse distribution in 11 (68.75%) patients and peripheral lung zone predominance in 5 (31.25%) patients. Abnormalities were bilateral in all 16 (100%) patients. Analysis of the craniocaudal distribution of the lesions revealed lower zone predominance in 9 (56.25%) patients, diffuse distribution in 5 (31.25%) patients, middle zone predominance in 1 (6.25%) patient, and upper zone predominance in 1 (6.25%) patient. CONCLUSIONS: The most frequent HRCT findings in patients with leptospirosis causing DAH were ground-glass opacities, airspace nodules, ground-glass nodules, and consolidations. The lesions showed symmetrical distribution with lower zone predominance in most cases. PMID- 26418543 TI - The intraabdominal pressure A real indicator of the tension free principle during anterior wall repair procedure after incisional hernias. AB - AIM: Incisional hernias represent a late onset complication of any type of laparotomy, with a relatively high incidence, and reported in 2% to 11% of all laparotomies. MATERIAL AND METHODS: We performed a prospective longitudinal study that included a total number of 102 patients. The following parameters were monitored: patient history clinical findings, time of hospitalization, laboratory test results, types of surgery. Intra-abdominal pressure variations were measured using a specialized kit. RESULTS: Obesity was present in 69 of the patients (67.64%). Mesh plasty was most frequently used (80.39%). The inset of the mesh was performed in onlay position (40.19%), retromuscular (29.98%) or complete defect substitution (11.76%). The correlation between the type of abdominal wall plasty, variations on the Borg dyspnea scal and likewise the correlation between the VAS (visual analogue scale) pain scale and the abdominal wall plasty procedures proved to be highly statistically significant: p< 0.001. Furthermore, the intra-abdominal pressure varied with the type of abdominoplasty carried out, reviewing the tension free principle. The most important parameter was the intra abdominal pressure recorded at the end of the abdominoplasty, which showed significant correlations with the tension free plasties (retromuscular mesh and substitution mesh). CONCLUSIONS: The tension free methods, reflected by the intra abdominal pressure variation, were associated with a lower degree of dyspnea, low postoperative pain and less hospitalization time. KEY WORDS: Borg scale, Incisional hernia, Intra-abdominal pressure, Onlay, Visual analogue scale. PMID- 26418544 TI - What is the best imaging modality for diagnosing a large vestibular aqueduct? PMID- 26418545 TI - Staphylococcus aureus protects its immune-evasion proteins against degradation by neutrophil serine proteases. AB - Neutrophils store large quantities of neutrophil serine proteases (NSPs) that contribute, via multiple mechanisms, to antibacterial immune defences. Even though neutrophils are indispensable in fighting Staphylococcus aureus infections, the importance of NSPs in anti-staphylococcal defence is yet unknown. However, the fact that S. aureus produces three highly specific inhibitors for NSPs [the extracellular adherence proteins (EAPs) Eap, EapH1 and EapH2], suggests that these proteases are important for host defences against this bacterium. In this study we demonstrate that NSPs can inactivate secreted virulence factors of S. aureus and that EAP proteins function to prevent this degradation. Specifically, we find that a large group of S. aureus immune-evasion proteins is vulnerable to proteolytic inactivation by NSPs. In most cases, NSP cleavage leads to functional inactivation of virulence proteins. Interestingly, proteins with similar immune-escape functions appeared to have differential cleavage sensitivity towards NSPs. Using targeted mutagenesis and complementation analyses in S. aureus, we demonstrate that all EAP proteins can protect other virulence factors from NSP degradation in complex bacterial supernatants. These findings show that NSPs inactivate S. aureus virulence factors. Moreover, the protection by EAP proteins can explain why this antibacterial function of NSPs was masked in previous studies. Furthermore, our results indicate that therapeutic inactivation of EAP proteins can help to restore the natural host immune defences against S. aureus. PMID- 26418547 TI - (19)F NMR study of ligand dynamics in carboxylate-bridged diiron(II) complexes supported by a macrocyclic ligand. AB - A series of asymmetrically carboxylate-bridged diiron(ii) complexes featuring fluorine atoms as NMR spectroscopic probes, [Fe2(PIM)(Ar(4F-Ph)CO2)2] (10), [Fe2(F2PIM)(Ar(Tol)CO2)2] (11), and [Fe2(F2PIM)(Ar(4F-Ph)CO2)2] (12), were prepared and characterized by X-ray crystallography, Mossbauer spectroscopy, and VT (19)F NMR spectroscopy. These complexes are part of a rare family of syn N donor diiron(ii) compounds, [Fe2(X2PIM)(RCO2)2], that are structurally very similar to the active site of the hydroxylase enzyme component of reduced methane monooxygenase (MMOHred). Solution characterization of these complexes demonstrates that they undergo intramolecular carboxylate rearrangements, or carboxylate shifts, a dynamic feature relevant to the reactivity of the diiron centers in bacterial multicomponent monooxygenases. PMID- 26418546 TI - In-Depth Duodenal Transcriptome Survey in Chickens with Divergent Feed Efficiency Using RNA-Seq. AB - Since the feed cost is a major determinant of profitability in poultry industry, how to improve feed efficiency through genetic selection is an intriguing subject for breeders and producers. As a more suitable indicator assessing feed efficiency, residual feed intake (RFI) is defined as the difference between observed and expected feed intake based on maintenance and growth. However, the genetic mechanisms responsible for RFI in chickens are still less well appreciated. In this study, we investigated the duodenal transcriptome architecture of extreme RFI phenotypes in the six brown-egg dwarf hens (three per group) using RNA sequencing technology. Among all mapped reads, an average of 75.62% fell into annotated exons, 5.50% were located in introns, and the remaining 18.88% were assigned to intergenic regions. In total, we identified 41 promising candidate genes by differential expression analysis between the low and high RFI groups. Furthermore, qRT-PCR assays were designed for 10 randomly chosen genes, and nine (90.00%) were successfully validated. Functional annotation analyses revealed that these significant genes belong to several specific biological functions related to digestibility, metabolism and biosynthesis processes as well as energy homeostasis. We also predicted 253 intergenic coding transcripts, and these transcripts were mainly involved in fundamental biological regulation and metabolism processes. Our findings provided a pioneering exploration of biological basis underlying divergent RFI using RNA-Seq, which pinpoints promising candidate genes of functional relevance, is helpful to guide future breeding strategies to optimize feed efficiency and assists in improving the current gene annotation in chickens. PMID- 26418548 TI - Blast Wave Exposure to the Extremities Causes Endothelial Activation and Damage. AB - Extremity injury is a significant burden to those injured in explosive incidents and local ischaemia can result in poor functionality in salvaged limbs. This study examined whether blast injury to a limb resulted in a change in endothelial phenotype leading to changes to the surrounding tissue.The hind limbs of terminally anaesthetized rabbits were subjected to one of four blast exposures (high, medium, low, or no blast). Blood samples were analyzed for circulating endothelial cells pre-injury and at 1, 6, and 11 h postinjury as well as analysis for endothelial activation pre-injury and at 1, 6, and 12 h postinjury. Post mortem tissue (12 h post-injury) was analysed for both protein and mRNA expression and also for histopathology. The high blast group had significantly elevated levels of circulating endothelial cells 6 h postinjury. This group also had significantly elevated tissue mRNA expression of IL-6, E-selection, TNF alpha, HIF-1, thrombomodulin, and PDGF. There was a significant correlation between blast dose and the degree of tissue pathology (hemorrhage, neutrophil infiltrate, and oedema) with the worst scores in the high blast group. This study has demonstrated that blast injury can activate the endothelium and in some cases cause damage that in turn leads to pathological changes in the surrounding tissue. For the casualty injured by an explosion the damaging effects of hemorrhage and shock could be exacerbated by blast injury and vice versa so that even low levels of blast become damaging, all of which could affect tissue functionality and long-term outcomes. PMID- 26418551 TI - Correction: Assessing Mitochondrial DNA Variation and Copy Number in Lymphocytes of ~2,000 Sardinians Using Tailored Sequencing Analysis Tools. PMID- 26418549 TI - Serum Neurofilament Light Chain Levels Are Associated with Clinical Characteristics and Outcome in Patients with Cervical Artery Dissection. AB - BACKGROUND: Serum neurofilament light chain (sNfL) levels represent a promising marker of neuroaxonal injury. They are elevated in several neurological conditions, but their importance in cerebrovascular diseases remains unclear. In a proof of concept study, we compared sNfL levels with clinical characteristics and outcome in patients with cervical artery dissection (CeAD). METHODS: A total of 49 non-traumatic CeAD patients were included. sNfL levels were measured by high-sensitivity electrochemiluminescence immunoassay. Levels were compared with regard to (i) type of presenting symptoms (local symptoms only (n = 8), transient ischemic attack (TIA; n = 10) or ischemic stroke (n = 31)), (ii) stroke severity quantified by National Institute of Health Stroke Scale (NIHSS), (iii) time interval between onset of symptoms and blood sampling and (iv) 3-month outcome as measured by the modified Rankin Scale score. Analyses were performed using univariate and multivariate linear and ordinal regression models. RESULTS: CeAD patients presenting with stroke had significantly higher sNfL levels (median 108.9 pg/ml, interquartile range (37.8-427.7)) than patients with TIA (16.4 pg/ml (8.7-36.3), p = 0.002) or local symptoms (23.4 pg/ml (17.8-30.8), p = 0.0007). Among stroke patients, sNfL levels were positively associated with both NIHSS (p = 0.0002) and time between stroke onset and serum sampling (p = 1.9 * 10-6). Higher sNfL levels were associated with unfavorable outcome at 3 months (OR 4.67, 95% CI 1.69-12.95, p = 0.003). However, this association lost significance after adjustment for NIHSS. The highest sNfL level was observed in a TIA patient who had ischemic stroke 1 day after serum sampling for sNfL measurement. CONCLUSION: sNfL levels were increased in CeAD patients presenting with stroke, correlated with clinical severity and were influenced by the time point of blood sampling. The prognostic meaning of sNfL in CeAD deserves further testing. PMID- 26418550 TI - Efficient Driving of Piezoelectric Transducers Using a Biaxial Driving Technique. AB - Efficient driving of piezoelectric materials is desirable when operating transducers for biomedical applications such as high intensity focused ultrasound (HIFU) or ultrasound imaging. More efficient operation reduces the electric power required to produce the desired bioeffect or contrast. Our preliminary work [Cole et al. Journal of Physics: Condensed Matter. 2014;26(13):135901.] suggested that driving transducers by applying orthogonal electric fields can significantly reduce the coercivity that opposes ferroelectric switching. We present here the experimental validation of this biaxial driving technique using piezoelectric ceramics typically used in HIFU. A set of narrow-band transducers was fabricated with two sets of electrodes placed in an orthogonal configuration (following the propagation and the lateral mode). The geometry of the ceramic was chosen to have a resonance frequency similar for the propagation and the lateral mode. The average (+/- s.d.) resonance frequency of the samples was 465.1 (+/- 1.5) kHz. Experiments were conducted in which each pair of electrodes was driven independently and measurements of effective acoustic power were obtained using the radiation force method. The efficiency (acoustic/electric power) of the biaxial driving method was compared to the results obtained when driving the ceramic using electrodes placed only in the pole direction. Our results indicate that the biaxial method increases efficiency from 50% to 125% relative to the using a single electric field. PMID- 26418552 TI - Anharmonic Franck-Condon Factors for the X(2)B1 <- X(1)A1 Photoionization of Ketene. AB - The X(2)B1 <- X(1)A1 photoelectron spectra of ketene and its doubly deuterated isotopologue have been computed from correlated vibrational wave functions as determined from vibrational configuration interaction theory relying on multidimensional Born-Oppenheimer potential energy surfaces being obtained from explicitly correlated coupled-cluster calculations. Duschinsky effects were accounted for in all cases. Excellent agreement with available experimental data was achieved. PMID- 26418554 TI - Cerebral oximetry: the standard monitor of the future? AB - PURPOSE OF REVIEW: There is an increasing interest in the application of near infrared spectroscopy (NIRS) as a monitoring tool in noncardiac surgery. This review summarizes the latest developments and current evidence for the use of NIRS in the noncardiac intraoperative setting. RECENT FINDINGS: Unanticipated intraoperative physiological disturbances and a substantial interpatient variability in the limits of cerebral autoregulation, pose our patients at risk for adverse cerebral outcome, if the brain is not monitored specifically. In addition to a means to monitor the brain, NIRS has been shown to allow an estimate of overall organ oxygenation. Preliminary data suggest a relationship between cerebral desaturation and both neurologic and major organ morbidity. SUMMARY: NIRS offers noninvasive monitoring of cerebral and overall organ oxygenation in a wide range of clinical scenarios. There is an increasing evidence that the optimized cerebral oxygenation is associated with improved outcomes in both neurologic and major organ morbidity in a variety of surgical settings. PMID- 26418553 TI - Altered Right Ventricular Kinetic Energy Work Density and Viscous Energy Dissipation in Patients with Pulmonary Arterial Hypertension: A Pilot Study Using 4D Flow MRI. AB - INTRODUCTION: Right ventricular (RV) function has increasingly being recognized as an important predictor for morbidity and mortality in patients with pulmonary arterial hypertension (PAH). The increased RV after-load increase RV work in PAH. We used time-resolved 3D phase contrast MRI (4D flow MRI) to derive RV kinetic energy (KE) work density and energy loss in the pulmonary artery (PA) to better characterize RV work in PAH patients. METHODS: 4D flow and standard cardiac cine images were obtained in ten functional class I/II patients with PAH and nine healthy subjects. For each individual, we calculated the RV KE work density and the amount of viscous dissipation in the PA. RESULTS: PAH patients had alterations in flow patterns in both the RV and the PA compared to healthy subjects. PAH subjects had significantly higher RV KE work density than healthy subjects (94.7+/-33.7 mJ/mL vs. 61.7+/-14.8 mJ/mL, p = 0.007) as well as a much greater percent PA energy loss (21.1+/-6.4% vs. 2.2+/-1.3%, p = 0.0001) throughout the cardiac cycle. RV KE work density and percent PA energy loss had mild and moderate correlations with RV ejection fraction. CONCLUSION: This study has quantified two kinetic energy metrics to assess RV function using 4D flow. RV KE work density and PA viscous energy loss not only distinguished healthy subjects from patients, but also provided distinction amongst PAH patients. These metrics hold promise as imaging markers for RV function. PMID- 26418555 TI - Large databases in anaesthesiology. AB - PURPOSE OF REVIEW: The purpose of this study is to review the current state of large database research in anaesthesiology and to describe the evolution of the National Anesthesia Clinical Outcomes Registry (NACOR) in the USA. RECENT FINDINGS: The Anesthesia Quality Institute of the American Society of Anesthesiologists was created to develop a national anaesthesia registry for the USA. NACOR and the companion Anesthesia Incident Reporting System are now 5 years old and in daily use by hundreds of US practices. The 30 million cases in NACOR are an emerging source for 'big data' research in anaesthesiology. SUMMARY: The Information Age is bringing new capabilities for large database research to the specialty of anaesthesiology, driven by the formation of registries capable of capturing a large fraction of all cases performed. PMID- 26418556 TI - Synthesis of Fused Polycyclic Indoles by Bronsted Acid-Catalyzed Intramolecular Alkylation of Indoles with Alcohols. AB - An efficient methodology for the synthesis of a series of new fused polyclyclic indoles has been developed by Bronsted acid-catalyzed intramolecular Friedel Crafts reactions of properly designed indolyl alcohols. PMID- 26418557 TI - Research into Policy: A Brief History of Mitochondrial Donation. PMID- 26418558 TI - Mitigation of copper toxicity by DNA oligomers in green paramecia. AB - Impact of transition metals which catalyze the generation of reactive oxygen species (ROS), on activation of cell death signaling in plant cells have been documented to date. Similarly in green paramecia (Paramecium bursaria), an aquatic protozoan species harboring symbiotic green algae in the cytoplasm, toxicities of various metallic ions have been documented. We have recently examined the effects of double-stranded GC-rich DNA fragments with copper-binding nature and ROS removal catalytic activity as novel plant cell-protecting agents, using the suspension-cultured tobacco cells. Here, we show that above DNA oligomers protect the cells of green paramecia from copper-induced cell death, suggesting that the phenomenon firstly observed in tobacco cells is not limited only within higher plants but it could be universally observable in wider range of organisms. PMID- 26418559 TI - Monte Carlo Dosimetry of the 60Co BEBIG High Dose Rate for Brachytherapy. AB - INTRODUCTION: The use of high-dose-rate brachytherapy is currently a widespread practice worldwide. The most common isotope source is 192Ir, but 60Co is also becoming available for HDR. One of main advantages of 60Co compared to 192Ir is the economic and practical benefit because of its longer half-live, which is 5.27 years. Recently, Eckert & Ziegler BEBIG, Germany, introduced a new afterloading brachytherapy machine (MultiSource(r)); it has the option to use either the 60Co or 192Ir HDR source. The source for the Monte Carlo calculations is the new 60Co source (model Co0.A86), which is referred to as the new BEBIG 60Co HDR source and is a modified version of the 60Co source (model GK60M21), which is also from BEBIG. OBJECTIVE AND METHODS: The purpose of this work is to obtain the dosimetry parameters in accordance with the AAPM TG-43U1 formalism with Monte Carlo calculations regarding the BEBIG 60Co high-dose-rate brachytherapy to investigate the required treatment-planning parameters. The geometric design and material details of the source was provided by the manufacturer and was used to define the Monte Carlo geometry. To validate the source geometry, a few dosimetry parameters had to be calculated according to the AAPM TG-43U1 formalism. The dosimetry studies included the calculation of the air kerma strength Sk, collision kerma in water along the transverse axis with an unbounded phantom, dose rate constant and radial dose function. The Monte Carlo code system that was used was EGSnrc with a new cavity code, which is a part of EGS++ that allows calculating the radial dose function around the source. The spectrum to simulate 60Co was composed of two photon energies, 1.17 and 1.33 MeV. Only the gamma part of the spectrum was used; the contribution of the electrons to the dose is negligible because of the full absorption by the stainless-steel wall around the metallic 60Co. The XCOM photon cross-section library was used in subsequent simulations, and the photoelectric effect, pair production, Rayleigh scattering and bound Compton scattering were included in the simulation. Variance reduction techniques were used to speed up the calculation and to considerably reduce the computer time. The cut-off energy was 10 keV for electrons and photons. To obtain the dose rate distributions of the source in an unbounded liquid water phantom, the source was immersed at the center of a cube phantom of 100 cm3. The liquid water density was 0.998 g/cm3, and photon histories of up to 1010 were used to obtain the results with a standard deviation of less than 0.5% (k = 1). The obtained dose rate constant for the BEBIG 60Co source was 1.108+/-0.001 cGyh-1U-1, which is consistent with the values in the literature. The radial dose functions were compared with the values of the consensus data set in the literature, and they are consistent with the published data for this energy range. PMID- 26418560 TI - The Mechanoreflex and Hemodynamic Response to Passive Leg Movement in Heart Failure. AB - BACKGROUND: Sensitization of mechanosensitive afferents, which contribute to the exercise pressor reflex, has been recognized as a characteristic of patients with heart failure (HF); however, the hemodynamic implications of this hypersensitivity are unclear. OBJECTIVES: The present study used passive leg movement (PLM) and intrathecal injection of fentanyl to blunt the afferent portion of this reflex arc to better understand the role of the mechanoreflex on central and peripheral hemodynamics in HF. METHODS: Femoral blood flow (FBF), mean arterial pressure, femoral vascular conductance, HR, stroke volume, cardiac output, ventilation, and muscle oxygenation of the vastus lateralis were assessed in 10 patients with New York Heart Association class II HF at baseline and during 3 min of PLM both with fentanyl and without (control). RESULTS: Fentanyl had no effect on baseline measures but increased (control vs fentanyl, P < 0.05) the peak PLM-induced change in FBF (493 +/- 155 vs 804 +/- 198 DeltamL.min(-1)) and femoral vascular conductance (4.7 +/- 2 vs 8.5 +/- 3 DeltamL.min(-1).mm Hg)(-1) while norepinephrine spillover (103% +/- 19% vs 58% +/- 17%Delta) and retrograde FBF (371 +/- 115 vs 260 +/- 68 DeltamL.min(-1)) tended to be reduced (P < 0.10). In addition, fentanyl administration resulted in greater PLM-induced increases in muscle oxygenation, suggestive of increased microvascular perfusion. Fentanyl had no effect on the ventilation, mean arterial pressure, HR, stroke volume, or cardiac output response to PLM. CONCLUSIONS: Although movement-induced central hemodynamics were unchanged by afferent blockade, peripheral hemodynamic responses were significantly enhanced. Thus, in patients with HF, a heightened mechanoreflex seems to augment peripheral sympathetic vasoconstriction in response to movement, a phenomenon that may contribute to exercise intolerance in this population. PMID- 26418561 TI - Hip Abductor Muscle Weakness in Individuals with Gluteal Tendinopathy. AB - PURPOSE: This study aimed to compare hip abductor muscle strength between individuals with symptomatic, unilateral gluteal tendinopathy (GT), and asymptomatic controls. METHODS: Fifty individuals with GT age between 35 and 70 yr and 50 sex- and age-comparable controls were recruited from the community. Maximal isometric strength (torque normalized to body mass) of the hip abductors was recorded in the supine position using an instrumented manual muscle tester. A two-way mixed ANCOVA, with covariates of self-reported pain during testing and pain limiting maximum effort, was used to compare hip abductor strength of the symptomatic and asymptomatic hip between GT and control individuals. Data were expressed as mean and SD, with the pairwise comparisons expressed as mean differences and 95% confidence intervals. RESULTS: Individuals with GT demonstrated significantly lower hip abductor torque of both their symptomatic and asymptomatic hip than healthy controls (both P < 0.05), with mean strength deficits of 0.35 N.m.kg (32%) on the symptomatic hip and 0.25 N.m.kg (23%) on the asymptomatic hip. In individuals with GT, the symptomatic hip was significantly weaker than the asymptomatic hip with a mean strength deficit of 0.09 N.m.kg (11%) (P < 0.05). CONCLUSIONS: People with unilateral GT demonstrate significant weakness of the hip abductor muscles bilaterally when compared with healthy controls. Although it is not clear whether hip weakness precedes GT or is a consequence of the condition, the findings provide a basis to consider hip abductor muscle weakness in the treatment plan for management of GT. PMID- 26418563 TI - Topsoil and Deep Soil Organic Carbon Concentration and Stability Vary with Aggregate Size and Vegetation Type in Subtropical China. AB - The impact of reforestation on soil organic carbon (OC), especially in deep layer, is poorly understood and deep soil OC stabilization in relation with aggregation and vegetation type in afforested area is unknown. Here, we collected topsoil (0-15 cm) and deep soil (30-45 cm) from six paired coniferous forests (CF) and broad-leaved forests (BF) reforested in the early 1990s in subtropical China. Soil aggregates were separated by size by dry sieving and OC stability was measured by closed-jar alkali-absorption in 71 incubation days. Soil OC concentration and mean weight diameter were higher in BF than CF. The cumulative carbon mineralization (Cmin, mg CO2-C kg-1 soil) varied with aggregate size in BF and CF topsoils, and in deep soil, it was higher in larger aggregates than in smaller aggregates in BF, but not CF. The percentage of soil OC mineralized (SOCmin, % SOC) was in general higher in larger aggregates than in smaller aggregates. Meanwhile, SOCmin was greater in CF than in BF at topsoil and deep soil aggregates. In comparison to topsoil, deep soil aggregates generally exhibited a lower Cmin, and higher SOCmin. Total nitrogen (N) and the ratio of carbon to phosphorus (C/P) were generally higher in BF than in CF in topsoil and deep soil aggregates, while the same trend of N/P was only found in deep soil aggregates. Moreover, the SOCmin negatively correlated with OC, total N, C/P and N/P. This work suggests that reforested vegetation type might play an important role in soil OC storage through internal nutrient cycling. Soil depth and aggregate size influenced OC stability, and deep soil OC stability could be altered by vegetation reforested about 20 years. PMID- 26418564 TI - Direct Synthesis of Nitriles from Aldehydes Using an O-Benzoyl Hydroxylamine (BHA) as the Nitrogen Source. AB - The direct synthesis of nitriles from commercially available or easily prepared aldehydes has been achieved. O-(4-CF3-benzoyl)-hydroxylamine (CF3-BHA) was utilized as the nitrogen source to generate O-acyl oximes in situ with aldehydes, which can be converted to a nitrile with the assistance of a Bronsted acid. Several aliphatic, aromatic, and alpha,beta-unsaturated nitriles that contain different functional groups were prepared in high yields (up to 94% yield). This method has notable advantages, such as simple and mild conditions, high yields, and good functional group tolerance. PMID- 26418562 TI - Mitochondrial Gene Expression Profiles Are Associated with Maternal Psychosocial Stress in Pregnancy and Infant Temperament. AB - BACKGROUND: Gene-environment interactions mediate through the placenta and shape the fetal brain development. Between the environmental determinants of the fetal brain, maternal psychosocial stress in pregnancy has been shown to negatively influence the infant temperament development. This in turn may have adverse consequences on the infant neurodevelopment extending throughout the entire life span. However little is known about the underlying biological mechanisms of the effects of maternal psychosocial stress in pregnancy on infant temperament. Environmental stressors such as maternal psychosocial stress in pregnancy activate the stress response cascade that in turn drives the increase in the cellular energy demand of vital organs with high metabolic rates such as, in pregnancy, the placenta. Key players of the stress response cascade are the mitochondria. RESULTS: Here, we tested the expression of all 13 protein-coding genes encoded by the mitochondria in 108 placenta samples from the Stress in Pregnancy birth cohort, a study that aims at determining the influence of in utero exposure to maternal psychosocial stress in pregnancy on infant temperament. We showed that the expression of the protein-coding mitochondrial encoded gene MT-ND2 was positively associated with indices of maternal psychosocial stress in pregnancy including Prenatal Perceived Stress (beta = 0.259; p-regression = 0.004; r2-regression = 0.120), State Anxiety (beta = 0.218; p-regression = 0.003; r2-regression = 0.153), Trait Anxiety (beta = 0.262; p regression = 0.003; r2-regression = 0.129) and Pregnancy Anxiety Total (beta = 0.208; p-regression = 0.010; r2-regression = 0.103). In the meantime MT-ND2 was negatively associated with the infant temperament indices of Activity Level (beta = -0.257; p-regression = 0.008; r2-regression = 0.165) and Smile and Laughter (beta = -0.286; p-regression = 0.036; r2-regression = 0.082). Additionally, MT ND6 was associated with the maternal psychosocial stress in pregnancy index of Prenatal Perceived Stress (beta = -0.231; p-regression = 0.004; r2-regression = 0.120), while MT-CO2 was associated with the maternal psychosocial stress in pregnancy indices of State Anxiety (beta = 0.206; p-regression = 0.003; r2 regression = 0.153) and Trait Anxiety (beta = 0.205; p-regression = 0.003; r2 regression = 0.129). CONCLUSIONS: Our data support the role of mitochondria in responding to maternal psychosocial stress in pregnancy, as assessed in placenta, while also suggesting an important role for the mitochondria in the infant temperament development. PMID- 26418530 TI - The Clots in Legs Or sTockings after Stroke (CLOTS) 3 trial: a randomised controlled trial to determine whether or not intermittent pneumatic compression reduces the risk of post-stroke deep vein thrombosis and to estimate its cost effectiveness. AB - BACKGROUND: Venous thromboembolism (VTE) is a common cause of death and morbidity in stroke patients. There are few data concerning the effectiveness of intermittent pneumatic compression (IPC) in treating patients with stroke. OBJECTIVES: To establish whether or not the application of IPC to the legs of immobile stroke patients reduced their risk of deep vein thrombosis (DVT). DESIGN: Clots in Legs Or sTockings after Stroke (CLOTS) 3 was a multicentre, parallel-group, randomised controlled trial which allocated patients via a central randomisation system to IPC or no IPC. A technician blinded to treatment allocation performed compression duplex ultrasound (CDU) of both legs at 7-10 days and 25-30 days after enrolment. We followed up patients for 6 months to determine survival and later symptomatic VTE. Patients were analysed according to their treatment allocation. SETTING: We enrolled 2876 patients in 94 UK hospitals between 8 December 2008 and 6 September 2012. PARTICIPANTS: INCLUSION CRITERIA: patients admitted to hospital within 3 days of acute stroke and who were immobile on the day of admission (day 0) to day 3. EXCLUSION CRITERIA: age < 16 years; subarachnoid haemorrhage; and contra-indications to IPC including dermatitis, leg ulcers, severe oedema, severe peripheral vascular disease and congestive cardiac failure. INTERVENTIONS: Participants were allocated to routine care or routine care plus IPC for 30 days, or until earlier discharge or walking independently. MAIN OUTCOME MEASURES: The primary outcome was DVT in popliteal or femoral veins, detected on a screening CDU, or any symptomatic DVT in the proximal veins, confirmed by imaging, within 30 days of randomisation. The secondary outcomes included death, any DVTs, symptomatic DVTs, pulmonary emboli, skin breaks on the legs, falls with injury or fractures and duration of IPC use occurring within 30 days of randomisation and survival, symptomatic VTE, disability (as measured by the Oxford Handicap Scale), quality of life (as measured by the European Quality of Life-5 Dimensions 3 Level questionnaire) and length of initial hospital stay measured 6 months after randomisation. RESULTS: We allocated 1438 patients to IPC and 1438 to no IPC. The primary outcome occurred in 122 (8.5%) of 1438 patients allocated to IPC and 174 (12.1%) of 1438 patients allocated to no IPC, giving an absolute reduction in risk of 3.6% [95% confidence interval (CI) 1.4% to 5.8%] and a relative risk reduction of 0.69 (95% CI 0.55 to 0.86). After excluding 323 patients who died prior to any primary outcome and 41 who had no screening CDU, the primary outcome occurred in 122 of 1267 IPC participants compared with 174 of 1245 no-IPC participants, giving an adjusted odds ratio of 0.65 (95% CI 0.51 to 0.84; p = 0.001). Secondary outcomes in IPC compared with no-IPC participants were death in the treatment period in 156 (10.8%) versus 189 (13.1%) (p = 0.058); skin breaks in 44 (3.1%) versus 20 (1.4%) (p = 0.002); and falls with injury in 33 (2.3%) versus 24 (1.7%) (p = 0.221). Among patients treated with IPC, there was a statistically significant improvement in survival to 6 months (hazard ratio 0.86, 95% CI 0.73 to 0.99; p = 0.042), but no improvement in disability. The direct cost of preventing a DVT was L1282 per event (95% CI L785 to L3077). CONCLUSIONS: IPC is an effective and inexpensive method of reducing the risk of DVT and improving survival in immobile stroke patients. FUTURE RESEARCH: Further research should test whether or not IPC improves survival in other groups of high risk hospitalised medical patients. In addition, research into methods to improve adherence to IPC might increase the benefits of IPC in stroke patients. TRIAL REGISTRATION: Current Controlled Trials ISRCTN93529999. FUNDING: The start-up phase of the trial (December 2008-March 2010) was funded by the Chief Scientist Office of the Scottish Government (reference number CZH/4/417). The main phase of the trial was funded by the National Institute for Health Research Health Technology Assessment programme (reference number 08/14/03). Covidien Ltd (Mansfield, MA, USA) lent its Kendall SCDTM Express sequential compression system controllers to the 105 centres involved in the trial and donated supplies of its sleeves. It also provided logistical help in keeping our centres supplied with sleeves and training materials relevant to the use of their devices. Recruitment and follow-up were supported by the National Institute for Health Research-funded UK Stroke Research Network and by the Scottish Stroke Research Network, which was supported by NHS Research Scotland. PMID- 26418565 TI - In-Depth Dissection of the P133R Mutation in Steroid 5beta-Reductase (AKR1D1): A Molecular Basis of Bile Acid Deficiency. AB - Human steroid-5beta-reductase (aldo-keto reductase 1D1, AKR1D1) stereospecifically reduces Delta(4)-3-ketosteroids to 5beta-dihydrosteroids and is essential for steroid hormone metabolism and bile acid biosynthesis. Genetic defects in AKR1D1 cause bile acid deficiency that leads to life threatening neonatal hepatitis and cholestasis. The disease-associated P133R mutation caused significant decreases in catalytic efficiency with both the representative steroid (cortisone) and the bile acid precursor (7alpha-hydroxycholest-4-en-3 one) substrates. Pro133 is a second shell residue to the steroid binding channel and is distal to both the cofactor binding site and the catalytic center. Strikingly, the P133R mutation caused over a 40-fold increase in Kd values for the NADP(H) cofactors and increased the rate of release of NADP(+) from the enzyme by 2 orders of magnitude when compared to the wild type enzyme. By contrast the effect of the mutation on Kd values for steroids were 10-fold or less. The reduced affinity for the cofactor suggests that the mutant exists largely in the less stable cofactor-free form in the cell. Using stopped-flow spectroscopy, a significant reduction in the rate of the chemical step was observed in multiple turnover reactions catalyzed by the P133R mutant, possibly due to the altered position of NADPH. Thus, impaired NADPH binding and hydride transfer is the molecular basis for bile acid deficiency in patients with the P133R mutation. Results revealed that optimal cofactor binding is vulnerable to distant structural perturbation, which may apply to other disease-associated mutations in AKR1D1, all of which occur at conserved residues and are unstable. PMID- 26418567 TI - Early bone response to machined, sandblasting acid etching (SLA) and novel surface-functionalization (SLAffinity) titanium implants: characterization, biomechanical analysis and histological evaluation in pigs. AB - The purpose of the present study was to examine early tissue response and osseointegration in the animal model. The surface morphologies of SLAffinity were characterized using scanning electron microscopy and atomic force microscopy. The microstructures were examined by X-ray diffraction, and hardness was measured by nanoindentation. Moreover, the safety and toxicity properties were evaluated using computer-aided programs and cell cytotoxicity assays. In the animal model, implants were installed in the mandibular canine-premolar area of 12 miniature pigs. Each pig received three implants: machine, sandblasted, large grit, acid etched, and SLAffinity-treated implants. The results showed that surface treatment did affect bone-to-implant contact (BIC) significantly. At 3 weeks, the SLAffinity-treated implants were found to present significantly higher BIC values than the untreated implants. The SLAffinity treatments enhanced osseointegration significantly, especially at early stages of bone tissue healing. As described above, the results of the present study demonstrate that the SLAffinity treatment is a reliable surface modification method. PMID- 26418566 TI - Apamin Boosting of Synaptic Potentials in CaV2.3 R-Type Ca2+ Channel Null Mice. AB - SK2- and KV4.2-containing K+ channels modulate evoked synaptic potentials in CA1 pyramidal neurons. Each is coupled to a distinct Ca2+ source that provides Ca2+ dependent feedback regulation to limit AMPA receptor (AMPAR)- and NMDA receptor (NMDAR)-mediated postsynaptic depolarization. SK2-containing channels are activated by Ca2+ entry through NMDARs, whereas KV4.2-containing channel availability is increased by Ca2+ entry through SNX-482 (SNX) sensitive CaV2.3 R type Ca2+ channels. Recent studies have challenged the functional coupling between NMDARs and SK2-containing channels, suggesting that synaptic SK2 containing channels are instead activated by Ca2+ entry through R-type Ca2+ channels. Furthermore, SNX has been implicated to have off target affects, which would challenge the proposed coupling between R-type Ca2+ channels and KV4.2 containing K+ channels. To reconcile these conflicting results, we evaluated the effect of SK channel blocker apamin and R-type Ca2+ channel blocker SNX on evoked excitatory postsynaptic potentials (EPSPs) in CA1 pyramidal neurons from CaV2.3 null mice. The results show that in the absence of CaV2.3 channels, apamin application still boosted EPSPs. The boosting effect of CaV2.3 channel blockers on EPSPs observed in neurons from wild type mice was not observed in neurons from CaV2.3 null mice. These data are consistent with a model in which SK2-containing channels are functionally coupled to NMDARs and KV4.2-containing channels to CaV2.3 channels to provide negative feedback regulation of EPSPs in the spines of CA1 pyramidal neurons. PMID- 26418569 TI - Strain behavior and lattice dynamics in Ni50Mn35In15. AB - The lattice dynamics in the polycrystalline shape-memory Heusler alloy Ni50Mn35In15 have been studied by means of resonant ultrasound spectroscopy (RUS). RUS spectra were collected in a frequency range 100-1200 kHz between 10 and 350 K. Ni50Mn35In15 exhibits a ferromagnetic transition at 313 K in the austenite phase and a martensitic transition at 248 K accompanied by a change of the magnetic state. Furthermore it displays a paramagnetic to ferrimagnetic transition within the martensitic phase. We determined the temperature dependence of the shear modulus and the acoustic attenuation of Ni50Mn35In15 and compared it with magnetization data. Following the structural softening, which accompanies the martensitic transition as a pretransitional phenomenon, a strong stiffening of the lattice is observed at the martensitic magneto-structural transition. Only a weak magnetoelastic coupling is evidenced at the Curie temperatures both in austenite and martensite phases. The large acoustic damping in the martensitic phase compared with the austenitic phase reflects the motion of the twin walls, which freezes out in the low temperature region. PMID- 26418568 TI - Multiple Cosmic Sources for Meteorite Macromolecules? AB - The major organic component in carbonaceous meteorites is an organic macromolecular material. The Murchison macromolecular material comprises aromatic units connected by aliphatic and heteroatom-containing linkages or occluded within the wider structure. The macromolecular material source environment remains elusive. Traditionally, attempts to determine source have strived to identify a single environment. Here, we apply a highly efficient hydrogenolysis method to liberate units from the macromolecular material and use mass spectrometric techniques to determine their chemical structures and individual stable carbon isotope ratios. We confirm that the macromolecular material comprises a labile fraction with small aromatic units enriched in (13)C and a refractory fraction made up of large aromatic units depleted in (13)C. Our findings suggest that the macromolecular material may be derived from at least two separate environments. Compound-specific carbon isotope trends for aromatic compounds with carbon number may reflect mixing of the two sources. The story of the quantitatively dominant macromolecular material in meteorites appears to be made up of more than one chapter. PMID- 26418570 TI - Cost-effectiveness of RAS screening before monoclonal antibodies therapy in metastatic colorectal cancer based on FIRE3 Study. AB - The surprising results published by FIRE-3 revealed that the overall survival (OS) of RAS wild-type metastatic colorectal cancer (mCRC) patients treated with Cetuximab(Cmab) and FOLFIRI combination was prolonged to 33.1 months. The substantial increase in testing and treatment costs, however, impose a considerable health burden on patients and society. Hence the study was aimed to assess the cost-effectiveness of RAS screening before monoclonal antibodies (mAbs) therapy based on FIRE-3 study. Four groups were analyzed: group 1, patients with KRAS testing treated with Cmab and FOLFIRI; group 2, patients with RAS testing treated with Cmab and FOLFIRI; group 3, patients with KRAS testing treated with bevacizumab(Bmab) and FOLFIRI; group 4, patients with RAS testing treated with Bmab and FOLFIRI. A Markov model comprising 3 health states (progression-free survival, progressive disease and death) was built. The costs were calculated from a Chinese payer perspective, and survival was reported in quality-adjusted life-months (QALMs). Average total lifetime costs ranged from $104,682.44 (RAS-Bmab) to $136,867.44 (RAS-Cmab), while the survival gained varied from 16.88 QALMs in RAS-Bmab to 21.85 QALMs in RAS-Cmab. The cost per QALM was $6,263.86 for RAS-Cmab, $6,145.84 for KRAS-Bmab, $6,201.57 for RAS-Bmab and $6,960.70 for KRAS-Cmab respectively. The KRAS-Cmab strategy was dominated by the other 3 groups. The first-treatment cost of RAS-Cmab was the most influential one to the model. In all, the RAS screening prior to Cmab treatment in mCRC seems to be a cost-effective strategy in the time of monoclonal antibodies (mAbs) therapy with the most gained QALMs. PMID- 26418571 TI - RENACER study: Assessment of 12-month efficacy and safety of 168 certolizumab PEGol rheumatoid arthritis-treated patients from a Spanish multicenter national database. AB - OBJECTIVE: To assess effectiveness and safety of certolizumab PEGol (CZP) in rheumatoid arthritis (RA) patients after 12 months of treatment and to detect predictors of response. METHODS: Observational longitudinal prospective study of RA patients from 35 sites in Spain. Variables (baseline, 3- and 12-month assessment): sociodemographics, previous Disease Modifying Anti-Rheumatic Drug (DMARD) and previous Biological Therapies (BT) use; TJC, SJC, ESR, CRP, DAS28, SDAI. Response variables: TJC, SJC, CRP, ESR, and steroids dose reductions, EULAR Moderate/Good Response, SDAI response and remission, DAS28 remission. Safety variables: discontinuation due to side-effects. Descriptive, comparative and Logistic regression analyses were performed. RESULTS: We included 168 patients: 79.2% women, mean age 54.5 years (+/-13.2 SD), mean disease duration 7.5 years (+/-7.3 SD). Mean number of prior DMARD: 1.4 (+/-1.2 SD), mean number of prior BT was 0.8 (+/-1.1). Mean time on CZP was 9.8 months (+/-3.4 SD). A total of 71.4% were receiving CZP at 12-month assessment. Baseline predictors of response: lower prior number DMARD; low number prior BT; higher CRP, ESR, TJC, SJC, DAS28 and SDAI (p < 0.05) scores. A 25/46.4% Moderate/Good Response, a 20% SDAI remission, and a 44% DAS28 remission were observed. We observed 48 discontinuations (28.6%), 31 due to partial or complete ineffectiveness, and 17 due to side-effects. CONCLUSIONS: CZP showed benefit in severe RA patients, with significant reduction of all effectiveness parameters, despite the high prevalence of previous BT exposure in our series. We found CRP, ESR, prior DMARD/BT number, TJC, SJC, DAS28, and SDAI as baseline predictors of response. CZP was mostly well tolerated. PMID- 26418573 TI - High-Performance and Omnidirectional Thin-Film Amorphous Silicon Solar Cell Modules Achieved by 3D Geometry Design. AB - High-performance thin-film hydrogenated amorphous silicon solar cells are achieved by combining macroscale 3D tubular substrates and nanoscaled 3D cone like antireflective films. The tubular geometry delivers a series of advantages for large-scale deployment of photovoltaics, such as omnidirectional performance, easier encapsulation, decreased wind resistance, and easy integration with a second device inside the glass tube. PMID- 26418572 TI - Ruthenium Catalyzed Diastereo- and Enantioselective Coupling of Propargyl Ethers with Alcohols: Siloxy-Crotylation via Hydride Shift Enabled Conversion of Alkynes to pi-Allyls. AB - The first enantioselective carbonyl crotylations through direct use of alkynes as chiral allylmetal equivalents are described. Chiral ruthenium(II) complexes modified by Josiphos (SL-J009-1) catalyze the C-C coupling of TIPS-protected propargyl ether 1a with primary alcohols 2a-2o to form products of carbonyl siloxy-crotylation 3a-3o, which upon silyl deprotection-reduction deliver 1,4 diols 5a-5o with excellent control of regio-, anti-diastereo-, and enantioselectivity. Structurally related propargyl ethers 1b and 1c bearing ethyl and phenyl-substituents engage in diastereo- and enantioselective coupling, as illustrated in the formation of adducts 5p and 5q, respectively. Selective mono tosylation of diols 5a, 5c, 5e, 5f, 5k, and 5m is accompanied by spontaneous cyclization to deliver the trans-2,3-disubstituted furans 6a, 6c, 6e, 6f, 6k, and 6m, respectively. Primary alcohols 2a, 2l, and 2p were converted to the siloxy crotylation products 3a, 3l, and 3p, which upon silyl deprotection-lactol oxidation were transformed to the trans-4,5-disubstituted gamma-butyrolactones 7a, 7l, and 7p. The formation of 7p represents a total synthesis of (+)-trans whisky lactone. Unlike closely related ruthenium catalyzed alkyne-alcohol C-C couplings, deuterium labeling studies provide clear evidence of a novel 1,2 hydride shift mechanism that converts metal-bound alkynes to pi-allyls in the absence of intervening allenes. PMID- 26418575 TI - Water-Centered Interpretation of Intrinsic pPII Propensities of Amino Acid Residues: In Vitro-Driven Molecular Dynamics Study. AB - Amino acid residues of unfolded peptides in water sample only a few basins in the Ramachandran plot, including prominent polyproline II-like (pPII) conformations. Dynamics of guest residues, X, in GXG peptides in water were recently reported to be dominated by pPII and beta-strand-like (beta) conformations, resulting in an enthalpy-entropy compensation at ~300 K. Using molecular dynamics (MD) in explicit solvent, we here examine pPII and beta conformational ensembles of 15 guest residues in GXG peptides, quantify local orientation of water around their side chains through novel water orientation plots, and study their hydration and hydrogen bonding properties. We show that pPII and beta ensembles are characterized by distinct water orientations: pPII ensembles are associated with an increased population of water oriented in parallel to the side chain surface whereas beta ensembles exhibit more heterogeneous water orientations. The backbone hydration is significantly higher in pPII than in beta ensembles. Importantly, pPII to beta hydration differences and the solvent accessible surface area of Cbeta hydrogens both correlate with experimental pPII propensities. We propose that pPII conformations are stabilized by a local, hydrogen-bonded clathrate-like water structure and that residue-specific intrinsic pPII propensities reflect distinct abilities of side chains to template this water structure. PMID- 26418574 TI - Efficacy of probiotic treatment with Bifidobacterium longum 536 for induction of remission in active ulcerative colitis: A randomized, double-blinded, placebo controlled multicenter trial. AB - BACKGROUND AND AIM: We conducted a randomized, double-blinded, placebo-controlled trial to investigate the efficacy of Bifidobacterium longum 536 (BB536) supplementation for induction of remission in Japanese patients with active ulcerative colitis (UC). METHODS: Fifty-six patients with mild to moderate UC were enrolled. Three patients had pancolitis, 36 had left-sided colitis, and 17 had proctitis. Patients were randomly treated with 2-3 * 10(11) freeze-dried viable BB536 (28 patients) or placebo (28 patients) for 8 weeks. RESULTS: In total, 63% of patients receiving BB536 showed clinical remission (UC disease activity index [UCDAI] <=2) at week 8 compared to 52% of those receiving placebo (P = 0.395). We observed a significant decrease of UCDAI scores (3.8 +/- 0.4 at baseline to 2.6 +/- 0.4 at week 8) in the BB536 group (P < 0.01), whereas there was no significant decrease in the placebo group (P = 0.88). There was also a significant decrease in the Rachmilewitz endoscopic index (EI) and the Mayo subscore at week 8 in the BB536 group, whereas there was no significant decrease in the placebo group. A single patient in the BB536 group complained of a mild side-effect, but no other adverse effects were observed. CONCLUSION: Supplementation with BB536 was well tolerated and reduced UCDAI scores, EI and Mayo subscores after 8 weeks in Japanese patients with mild to moderately active UC. PMID- 26418577 TI - Evaluation of a passive optical based end of service life indicator (ESLI) for organic vapor respirator cartridges. AB - A passive visual end of service life indicator (ESLI) for certain organic vapors has been attached to the inside wall of an organic vapor respirator cartridge. The opposite side of the ESLI touches activated carbon inside the cartridge. During use, organic vapors moving through the cartridge adsorb into both the carbon and the ESLI. The cartridge body is clear so that when vapor concentrations meet a certain threshold, the user may observe the progressive development of an indicator bar down the side of the ESLI. The cartridge is deemed ready to change when any part of the indicator bar touches a marked end line. The performance of the ESLI was observed when the cartridge was tested against a variety of organic vapors, exposure concentrations above the minimum indication level, humidities, temperatures, flow rates, and mixtures. In all cases, the ESLI indicated end of service life with more than 10% cartridge service life remaining (which is a NIOSH test criteria). The results were also compared to mathematical predictions of cartridge service life. PMID- 26418576 TI - RNA-Seq Reveals Acute Manganese Exposure Increases Endoplasmic Reticulum Related and Lipocalin mRNAs in Caenorhabditis elegans. AB - Manganese (Mn) is an essential nutrient; nonetheless, excessive amounts can accumulate in brain tissues causing manganism, a severe neurological condition. Previous studies have suggested oxidative stress, mitochondria dysfunction, and impaired metabolism pathways as routes for Mn toxicity. Here, we used the nematode Caenorhabditis elegans to analyze gene expression changes after acute Mn exposure using RNA-Seq. L1 stage animals were exposed to 50 mM MnCl2 for 30 min and analyzed at L4. We identified 746 up- and 1828 downregulated genes (FDR corrected p < 0.05; two-fold change) that included endoplasmic reticulum related abu and fkb family genes, as well as six of seven lipocalin-related (lpr) family members. These were also verified by qRT-PCR. RNA interference of lpr-5 showed a dramatic increase in whole body vulnerability to Mn exposure. Our studies demonstrate that Mn exposure alters gene transcriptional levels in different cell stress pathways that may ultimately contribute to its toxic effects. PMID- 26418578 TI - Gadolinium(III)-Chelated Silica Nanospheres Integrating Chemotherapy and Photothermal Therapy for Cancer Treatment and Magnetic Resonance Imaging. AB - The combination of therapy and diagnosis has been emerging as a promising strategy for cancer treatment. To realize chemotherapy, photothermal therapy, and magnetic resonance imaging (MRI) in one system, we have synthesized a new magnetic nanoparticle (Gd@SiO2-DOX/ICG-PDC) integrating doxorubicin (DOX), indocyanine green (ICG), and gadolinium(III)-chelated silica nanospheres (Gd@SiO2) with a poly(diallyldimethylammonium chloride) (PDC) coating. PDC coating serves as a polymer layer to protect from quick release of drugs from the nanocarriers and increase cellular uptake. The DOX release from Gd@SiO2-DOX/ICG PDC depends on pH and temperature. The process will be accelerated in the acidic condition than in a neutral pH 7.4. Meanwhile, upon laser irradiation, the photothermal effects promote DOX release and improve the therapeutic efficacy compared to either DOX-loaded Gd@SiO2 or ICG-loaded Gd@SiO2. Moreover, MRI results show that the Gd@SiO2-PDC nanoparticles are safe T1-type MRI contrast agents for imaging. The Gd@SiO2-PDC nanoparticles loaded with DOX and ICG can thus act as a promising theranostic platform for multimodal cancer treatment. PMID- 26418579 TI - Design, Synthesis, and Conformational Analysis of Proposed beta-Turn Mimics from Isoxazoline-Cyclopentane Aminols. AB - Constrained aminols from oxazanorbornene derivatives have the geometrical features to be used as beta-turn inducers. Four different stereoisomers were prepared and spectroscopically characterized (MD calculations, NMR-titration and VT-NMR experiments). Temperature coefficients in DMSO are indicative for the existence of an intramolecular hydrogen bond. Chirooptical properties revealed a beta-turn arrangement of all the synthesized compounds, where, depending on the absolute configuration of the cyclopentane spacer, they can be labeled as left- or right-handed turns. PMID- 26418580 TI - Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice. AB - Defects in multidrug resistance 3 gene (MDR3), which encodes the canalicular phospholipid flippase, cause a wide spectrum of cholangiopathy phenotypes in humans. Mice deficient in Mdr2 (murine ortholog of MDR3) develop liver diseases that closely reproduce the biochemical, histological, and clinical features of human cholangiopathies such as progressive familial intrahepatic cholestasis and primary sclerosing cholangitis. We hypothesized that modulating bile acid metabolism by the gut hormone fibroblast growth factor 19 (FGF19) may represent a novel approach for treating cholangiopathy and comorbidities. We introduced adeno associated virus carrying the gene for either the endocrine hormone FGF19 or engineered FGF19 variant M70 to 12-week old Mdr2-deficient mice with fully established disease. Effects on serum levels of liver enzymes, liver histology, and bile acid homeostasis were evaluated. FGF19 and M70 rapidly and effectively reversed liver injury, decreased hepatic inflammation, attenuated biliary fibrosis, and reduced cholecystolithiasis in Mdr2-deficient mice. Mechanistically, FGF19 and M70 significantly inhibited hepatic expression of Cyp7a1 and Cyp27a1, which encode enzymes responsible for the rate-limiting steps in the classic and alternate bile acid synthetic pathways, thereby reducing the hepatic bile acid pool and blood levels of bile acids. Importantly, prolonged exposure to FGF19, but not M70, led to the formation of hepatocellular carcinomas in the Mdr2-deficient mice. Furthermore, M70 ameliorated the hepatosplenomegaly and ductular proliferation that are associated with cholangiopathy. CONCLUSION: These results demonstrate the potential for treating cholangiopathy by safely harnessing FGF19 biology to suppress bile acid synthesis. PMID- 26418582 TI - Molecular Mechanism of Wide Photoabsorption Spectral Shifts of Color Variants of Human Cellular Retinol Binding Protein II. AB - Color variants of human cellular retinol binding protein II (hCRBPII) created by protein engineering were recently shown to exhibit anomalously wide photoabsorption spectral shifts over ~200 nm across the visible region. The remarkable phenomenon provides a unique opportunity to gain insight into the molecular basis of the color tuning of retinal binding proteins for understanding of color vision as well as for engineering of novel color variants of retinal binding photoreceptor proteins employed in optogenetics. Here, we report a theoretical investigation of the molecular mechanism underlying the anomalously wide spectral shifts of the color variants of hCRBPII. Computational modeling of the color variants with hybrid molecular simulations of free energy geometry optimization succeeded in reproducing the experimentally observed wide spectral shifts, and revealed that protein flexibility, through which the active site structure of the protein and bound water molecules is altered by remote mutations, plays a significant role in inducing the large spectral shifts. PMID- 26418581 TI - Global Identification of Protein Post-translational Modifications in a Single Pass Database Search. AB - Bottom-up proteomics database search algorithms used for peptide identification cannot comprehensively identify post-translational modifications (PTMs) in a single-pass because of high false discovery rates (FDRs). A new approach to database searching enables global PTM (G-PTM) identification by exclusively looking for curated PTMs, thereby avoiding the FDR penalty experienced during conventional variable modification searches. We identified over 2200 unique, high confidence modified peptides comprising 26 different PTM types in a single-pass database search. PMID- 26418583 TI - Coexistence of Fetal Cardiac Malformation and Maternal Drug-Induced Lupus: Is Lamotrigine Safe? AB - Lamotrigine (LTG) is a widely used second-generation antiepileptic drug for long term therapy of epileptic patients. Although LTG monotherapy during pregnancy is assumed to be relatively safe, teratogenic effects related to LTG has been reported previously. The presence of fetal malformations and maternal drug induced lupus erythematosus concurrently in a pregnant women using LTG have not been reported before. We herein report a term infant with coarctation of aorta and ventricular septal defect, who was born to a mother treated with LTG for epilepsy before conception and throughout pregnancy. The mother was diagnosed with drug-induced lupus erythematosus at the 36th gestational week, and the symptoms resolved after discontinuation of the drug. Fetal cardiac anomalies should be searched in mothers who were exposed to LTG during pregnancy. PMID- 26418584 TI - Living with lipoedema: reviewing different self-management techniques. AB - At present, there is no proven cure for lipoedema. Nevertheless, much can be done to help improve symptoms and prevent progression. Many of these improvements can be achieved by patients using self-management techniques. This article describes the range of self-management techniques that community nurses can discuss with patients, including healthy eating, low-impact exercise, compression garments, self-lymphatic drainage, and counselling. PMID- 26418585 TI - Using compression hosiery to prevent rebound swelling. AB - The management of chronic oedema often consists of a programme of compression bandaging to reduce swelling and improve skin changes and limb shape, followed by patient self-care management in compression hosiery. Occasionally, patients experience rebound swelling and require further episodes of bandaging. In such cases, a thorough assessment of the causes of the rebound swelling should be carried out so that they can be eliminated. By evidencing three case studies, this article demonstrates that Haddenham Custom Goldpunkt garments can be useful in preventing rebound swelling, making it a cost- and resource-effective method of managing stubborn chronic oedema and lymphoedema. PMID- 26418586 TI - Lymphoedema nurse. PMID- 26418589 TI - Chronic Oedema. Moving forward together. PMID- 26418590 TI - Not letting lymphoedema get the better of me. PMID- 26418591 TI - Assessing the effect of chronic oedema with associated ulceration. AB - Chronic oedema is a common problem in the UK and, given the country's ageing population, the numbers are predicted to rise. In an epidemiological study carried out in Derby, England, researchers found the prevalence of chronic oedema to be 3.99 in every 1000 people, with the prevalence increasing to 10.31 in those aged 65-74 years. Often, patients with untreated chronic oedema will develop an ulceration that can lead to further costs and hospital admissions. The cost of treating chronic wounds has been estimated at L2.3 billion-L3.1 billion a year. It is therefore surprising that given the number of patients living with these problems, there is still a lack of knowledge and skill among nurses when assessing patients with chronic oedema and associated ulceration. This article offers advice for nurses when assessing leg ulcers in patients with chronic oedema, detailing the visual skin changes most frequently seen in these patients. The article also discusses some of the treatment options available, briefly covering the advantages and disadvantages of each option. PMID- 26418592 TI - Contextual factors determine the use of allocentric information for reaching in a naturalistic scene. AB - Numerous studies have demonstrated that humans incorporate allocentric information when reaching toward visual targets. So far, it is unclear how this information is integrated into the movement plan when multiple allocentric cues are available. In this study we investigated whether and how the extent of spatial changes and the task relevance of allocentric cues influence reach behavior. To this end, we conducted two experiments where we presented participants three-dimensional-rendered images of a naturalistic breakfast scene on a computer screen. The breakfast scene included multiple objects (allocentric cues) with a subset of objects functioning as potential reach targets (i.e., they were task-relevant). Participants freely viewed the scene and after a short delay, the scene reappeared with one object missing (target) and other objects being shifted left- or rightwards. Afterwards, participants were asked to reach toward the target position on a gray screen while fixating the screen center. We found systematic deviations of reach endpoints in the direction of object shifts which varied with the number of objects shifted, but only if these objects served as potential reach targets. Our results suggest that the integration of allocentric information into the reach plan is determined by contextual factors, in particular by the extent of spatial cue changes and the task-relevance of allocentric cues. PMID- 26418594 TI - [Treatment of obsessive-compulsive disorder: drugs, psychotherapy or combined treatments?]. AB - Serotonin reuptake inhibitors (SRIs) and cognitive-behavioral psychotherapy (CBT) are first-line treatments for obsessive-compulsive disorder (OCD). However, little is known concerning whether combining both treatments ab initio is more effective than either monotherapy alone. A review of the available literature, which is poor, shows that combining ab initio CBT and SRI has not been found to be clearly superior of either therapy alone, except for patients with severe depression (who could be treated effectively with pharmacotherapy alone) and for children and adolescents. Another promising area of research is combined sequential treatment, that is the addition of CBT in subjects not responding to SRIs alone. More research is clearly needed in order to achieve a personalized treatment plan for every OCD patient. PMID- 26418593 TI - Molecular Characterization of LjABCG1, an ATP-Binding Cassette Protein in Lotus japonicus. AB - LjABCG1, a full-size ABCG subfamily of ATP-binding cassette proteins of a model legume, Lotus japonicus, was reported as a gene highly expressed during the early stages of nodulation, but have not been characterized in detail. In this study we showed that the induction of LjABCG1 expression was remarkable by methyl jasmonate treatment, and reporter gene experiments indicated that LjABCG1 was strongly expressed in the nodule parenchyma and cell layers adjacent to the root vascular tissue toward the nodule. LjABCG1 was suggested to be localized at the plasma membrane based on the fractionation of microsomal membranes as well as separation via aqueous two-phase partitioning. The physiological functions of LjABCG1 in symbiosis and pathogenesis were analyzed in homologous and heterologous systems. LjABCG1 knock-down L. japonicus plants did not show clear phenotypic differences in nodule formation, and not in defense against Pseudomonas syringae, either. In contrast, when LjABCG1 was expressed in the Arabidopsis pdr8-1 mutant, the penetration frequency of Phytophthora infestans, a potato late blight pathogen, was significantly reduced in LjABCG1/pdr8-1 than in pdr8-1 plants. This finding indicated that LjABCG1, at least partially, complemented the phenotype of pdr8 in Arabidopsis, suggesting the multiple roles of this protein in plant-microbe interactions. PMID- 26418595 TI - [Early attachement relationships and epigenetic customization]. AB - Recently, new findings in epigenetic science switched the focus from the observation of physiological intragenomic dynamics to the idea of an environmental co-construction of phenotypic expression. In psichodynamic field, objectual relations and attachement theoreticians emphasized the interpersonal dimension of individual development, focusing the attention on the relational matrix of self organization. The construction of stable affective-behavioral traits throughout different parenting styles has actually found a coincidence in ethological studies, which have explored the epigenetic processes underlying the relationship between caregiving and HPA stress responsiveness. An adequate parenting style seems to support affective regulation throughout psychobiological hidden moderators, which would tend to rebalance the physiological systems homeostasis; an unconfident attachment style would promote, on the other hand, the allostatic load rise. Sites of longlife epigenetic susceptibility have also been identified in humans; although associated with risk of maladaptive developing in adverse environmental conditions, they seem to confer protection under favorable conditions. This persisting possibility of reorganization of stable traits throughout lifetime, which seems to be activated by a relevant environmental input, grant to significant relationships, and to therapeutical one as well, an implicit reconditioning potential which could result into the configuration of new stable affective-behavioral styles. PMID- 26418596 TI - [Osteoporosis and major depression: open debate on a bidirectional relationship]. AB - Osteoporosis and depression are two chronic diseases that affect large population groups with great impact on morbidity, mortality and quality of life. Existing studies of the relationship between depression and osteoporosis have been heterogeneous in their design and use of diagnostic instruments for depression, which might have contributed to the different results on the comorbidity of these two conditions. Moreover, the direction of the causative link is still controversial and the etiology remains unclear. Definitely, limited data suggest that osteoporosis may enhance depressive symptoms, while far more studies have shown that depression adversely affects bone density and increases fracture risk. Thus the correlation of these diseases is still under research. This review comments on a plausible causative relationship and underlying mechanisms that might elucidate the link between two very common diseases. We describe the possible impact of osteoporosis on moods and the effect of depression on bone health. In particular, we focus on the role of the hypothalamic-pituitary adrenocortical and sympathoadrenal axes, of the parathyroid hormone and cytokines. We also describe the effect of the antidepressant drugs as well as lifestyles that may explain this effect. PMID- 26418597 TI - [The onset of affective disorder: impact of duration of untreated psychosis on global functioning]. AB - AIM: Observational study on a young sample at the onset of affective disorder seeking help to a dedicated service, with the aim to evaluate the age of onset, the duration of untreated psychosis (DUP), and the functional outcome at 2-year follow-up. METHODS: For 57 young people at First Episode Psychosis (FEP) of Affective Disorder, consecutively recruited to SMILE service, were collected socio-demographic and clinical (DUP, psychiatric history, age of onset) data and psychopathological (BPRS e SCL-90), perceived distress (GHQ-12) and functioning (VGF) evaluations. RESULTS: Two years after the access to SMILE service, the sample showed a functional improvement, with a duration of untreated psychosis (DUP) of 120,9 weeks and a mean age of onset of 21 years. More than 50% of the sample reported a family psychiatric history; this subgroup showed a higher substance use and a longer DUP compared to young people with a negative family psychiatric history. DISCUSSION AND CONCLUSIONS: This study confirms the problem of the diagnostic delay of young people at FEP of Affective Disorder and underlines the role of family psychiatric history. Our results support the need of a specialized service to improve the early detection, identification and treatment of mental disorders. PMID- 26418598 TI - [Murder of the doctor]. AB - AIM: To examine possible risk factors for the doctor to be killed by the patient in the clinical practice by examining a series of murders that involved physicians. METHODS: This aim has been achieved through a retrospective review on clinical cases of doctors killed by patients within the period between 1988 and 2013, in Italy. RESULTS: In this period 18 Italian doctors have been killed in the workplace, with a rate of 0.3/100,000. In 7 cases, the murder resulted in the context of doctor-dissatisfaction; in 7 cases the murder was committed by a psychiatric patient; 1 case in the context of a stalking; 3 cases occurred in a workplace which was not safe enough. Four categories of at-risk contexts have been identified. One category includes a murder in the context of a doctor dissatisfaction, perceived by patient. The second category concerns murders committed by patients suffering from mental illness. A third category includes homicides in a workplace which is not safe. The last category comprises the murder in the context of stalking. CONCLUSIONS: These categories identify specific dangerous situations for physicians, in which are highlighted elements that have played a crucial role in the murder and for which special precautions are suggested preventive. PMID- 26418599 TI - ["Socialization in real environment" in the rehabilitative interventions of a Psychiatric Unit of Lombardia Region: history, methodology, activities, and critical aspects]. AB - INTRODUCTION: The activities of rehabilitation and social reintegration related to work placement have been an important component in the rehabilitation practices of the Psychiatry Unit n. 20 (UOP 20) of the Spedali Civili Hospital of Brescia because of a deeply rooted culture of industrial work among the inhabitants of the served area. METHODS: Through the analysis of the individualized tools and the routines adopted to satisfy the needs for rehabilitation and risocialization, with reference to the axis "work", of people followed by the UOP 20, the methods of definition and realization of the paths of Socialization in Real Environment (SAR) have been developed. RESULTS: A research conducted over a period of six years highlighted the therapeutic significance of SAR rehabilitation pathways. We found a general improvement in the quality of life of patients followed and the possibility of access to real work market for some of them through the empowerment of individuals and communities and the constant and long-lasting commitment of service and local communities to the integration and implementation of resources (both of patients and of life contexts). DISCUSSION: Local experience is compared with the broader landscape of the interventions on employment in people with psychiatric disorders to highlight similarities and differences in order to facilitate the building of a common language and to promote the continuous improvement of rehabilitative practices and interventions. PMID- 26418600 TI - Cerebral perfusional effects of 1-year rivastigmine treatment in Alzheimer disease: a case report. AB - It is described the case of a 74-years-old woman with probable Alzheimer Disease who showed good clinical response to rivastigmine associated with relevant improvement of cerebral perfusion after 1 year of treatment. The single-photon emission computed tomography (SPECT) scan showed a significant improvement in cortical uptake of the tracer in temporo-parietal and frontal regions in comparison to the examination performed before the treatment. PMID- 26418601 TI - [In Process Citation]. PMID- 26418602 TI - "Egg-Box"-Assisted Fabrication of Porous Carbon with Small Mesopores for High Rate Electric Double Layer Capacitors. AB - Here we report a method to fabricate porous carbon with small mesopores around 2 4 nm by simple activation of charcoals derived from carbonization of seaweed consisting of microcrystalline domains formed by the "egg-box" model. The existence of mesopores in charcoals leads to a high specific surface area up to 3270 m(2) g(-1), with 95% surface area provided by small mesopores. This special pore structure shows high adaptability when used as electrode materials for an electric double layer capacitor, especially at high charge-discharge rate. The gravimetric capacitance values of the porous carbon are 425 and 210 F g(-1) and volumetric capacitance values are 242 and 120 F cm(-3) in 1 M H2SO4 and 1 M TEA BF4/AN, respectively. The capacitances even remain at 280 F g(-1) (160 F cm(-3)) at 100 A g(-1) and 156 F g(-1) (90 F cm(-3)) at 50 A g(-1) in the aqueous and organic electrolytes, demonstrating excellent high-rate capacitive performance. PMID- 26418603 TI - Analysis of Human and Porcine Skin in vivo/ex vivo for Penetration of Selected Oils by Confocal Raman Microscopy. AB - BACKGROUND: The subject of oil penetration into the skin is controversially discussed in the scientific literature. METHODS: Confocal Raman microscopy was used for analyzing oil penetration into the skin. The following methods were applied in the study: methods based on tracking specific peaks (method 1), the nonrestricted multiple least square fit (method 2), analyzing the lipid-to keratin peak ratio using the perpendicular drop-down cutoff procedure (method 3), and the Gaussian function-based deconvolution procedure (method 4). RESULTS: The results obtained using methods 1, 2 and 4 show that the investigated oils do not penetrate deeper than 11 um into human and porcine skin. Petrolatum has a prominent swelling effect on the stratum corneum (32% in vivo, 28% ex vivo), while the other oils exhibit no significant swelling effect. By using method 3, the penetration profile of oils, and especially of petrolatum, into the skin was interpreted incorrectly for various reasons that are addressed herein below. CONCLUSION: Predominantly remaining in the uppermost corneocyte layers of the stratum corneum, topically applied oils do not reach the viable cells of the stratum spinosum. To exclude any possible mistakes when using the lipid-keratin Raman peak (2,820-3,030 cm-1), the penetration analysis should be performed using the Gaussian function-based deconvolution procedure. PMID- 26418605 TI - Blood Pressure Characteristics in Moderate to Severe Renal Insufficiency. AB - BACKGROUND/AIMS: Ambulatory blood pressure monitoring (ABPM) in chronic kidney disease (CKD) patients has been extensively studied, but few investigations have attempted to relate ABPM with CKD stages. The objectives of this article were to compare ABPM parameters for the diagnosis and treatment determination of CKD with daytime clinic blood pressure (BP) measurements. We also investigated BP and renal injury in combined hypertension and CKD. We supposed ABPM was important in combined hypertension and CKD. METHODS: We compared ABPM in hypertension patients, including 152 patients with combined hypertension and CKD. Patients with combined hypertension and CKD were grouped according to severity into stages 1 through 3 (Stage 1-3) and stages 4 and 5 (Stage 4-5). RESULTS: In the Stage 4-5 group, systolic BP (SBP) (daytime, nighttime and 24 h mean), diastolic BP (DBP), pulse pressure and SBP standard deviations (SD) (daytime and 24 h) were higher. SBP and DBP loads were significantly higher in the Stage 4-5 group. The nighttime load was higher than the daytime load. Mean arterial pressure (MAP) was higher and heart rates (HR) were faster in the Stage 4-5 group. CONCLUSIONS: BP load should be a component employed in ABPM to determine cardiovascular risk stratification. MAP and HR might be associated with risk to develop end-stage renal disease. PMID- 26418606 TI - Memory and navigation: Compression of space varies with route length and turns. AB - For memory to be efficient and useful during recall, problem-solving, and planning, retrieval must be compressed in time. Evidence from rodents suggests that neural compression during replay of spatial memories varies widely, with a range of compression ratios reported from 6:1 to 64:1. Anecdotal evidence suggests that similar compression occurs during mental navigation in humans: we recall how to get from one place to another countless times almost every day of our lives, and this recall never takes as long as physically travelling those routes would take. In this experiment we sought to determine whether this behavioural compression could be measured during mental navigation in humans (spatial memory replay), and which factors might affect the compression of such spatial memories. To this end, thirty participants mentally navigated routes between two landmarks, which varied in length and number of turns, as we measured replay times and recorded ratings of familiarity, detail, and presence. A multi level model was used to determine which factors were associated with variation in compression. Route length and number of turns emerged from this model as significantly correlated with compression, such that longer routes were more compressed while compression was attenuated as the number of turns in a route increased. This suggests that compression during recall may be affected by specific features of a route, especially those that may act to segment the space or event being represented. PMID- 26418612 TI - Isotope Fractionation Associated with the Indirect Photolysis of Substituted Anilines in Aqueous Solution. AB - Organic micropollutants containing aniline substructures are susceptible to different light-induced transformation processes in aquatic environments and water treatment operations. Here, we investigated the magnitude and variability of C and N isotope fractionation during the indirect phototransformation of four para-substituted anilines in aerated aqueous solutions. The model photosensitizers, namely 9,10-anthraquinone-1,5-disulfonate and methylene blue, were used as surrogates for dissolved organic matter chromophores generating excited triplet states in sunlit surface waters. The transformation of aniline, 4 CH3-, 4-OCH3-, and 4-Cl-aniline by excited triplet states of the photosensitizers was associated with inverse and normal N isotope fractionation, whereas C isotope fractionation was negligible. The apparent 15N kinetic isotope effects (AKIE) were almost identical for both photosensitizers, increased from 0.9958+/-0.0013 for 4-OCH3-aniline to 1.0035+/-0.0006 for 4-Cl-aniline, and correlated well with the electron donating properties of the substituent. N isotope fractionation is pH-dependent in that H+ exchange reactions dominate below and N atom oxidation processes above the pKa value of the substituted aniline's conjugate acid. Correlations of C and N isotope fractionation for indirect phototransformation were different from those determined previously for the direct photolysis of chloroanilines and offer new opportunities to distinguish between abiotic degradation pathways. PMID- 26418607 TI - Use of an IL1-receptor antagonist to prevent the progression of tendinopathy in a rat model. AB - This study evaluated if inhibiting IL1-beta activity with an IL1-receptor antagonist (IL1-RA) will prevent pathologic changes commonly seen in tendinopathy. Thirty-six Sprague-Dawley retired-breeder rats were divided into three groups having weekly bilateral patellar tendon injections: CON (0.1 ml Saline), CAR (0.1 ml 2% carrageenan), IL1-RA (0.1 ml 2% CAR plus 0.94 mg of the IL1-RA, 2.5 mg/kg). Carrageenan was used to establish tendinopathy in two groups due to its ability to develop tendinopathy in prior studies. Animals were euthanized 3 weeks after initial injection. The CAR group demonstrated significantly (p < 0.05) shorter tendon lengths (8.61 +/- 0.38 mm) relative to CON (8.94 +/- 0.38 mm) that was prevented in the IL1-RA (9.02 +/- 0.30 mm) as well as significantly increased collagenase activity in the CAR (0.061 +/- 0.043) compared to CON (0.027 +/- 0.015) (p< 0.05). By histological evaluation, the CAR group demonstrated significantly greater inflammation than IL1-RA, and CON (p < 0.05). CAR showed a trend for increased cross-sectional area relative to CON that was absent in the IL1-RA. IL1-RA can effectively inhibit the development of mechanical, chemical, and histologic changes seen with carrageenan-induced tendonitis. PMID- 26418604 TI - Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review. AB - Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, rare lung disease resulting in chronic oto-sino-pulmonary disease in both children and adults. Many physicians incorrectly diagnose PCD or eliminate PCD from their differential diagnosis due to inexperience with diagnostic testing methods. Thus far, all therapies used for PCD are unproven through large clinical trials. This review article outlines consensus recommendations from PCD physicians in North America who have been engaged in a PCD centered research consortium for the last 10 years. These recommendations have been adopted by the governing board of the PCD Foundation to provide guidance for PCD clinical centers for diagnostic testing, monitoring, and appropriate short and long-term therapeutics in PCD patients. PMID- 26418613 TI - Interplay of Substrate Conductivity, Cellular Microenvironment, and Pulsatile Electrical Stimulation toward Osteogenesis of Human Mesenchymal Stem Cells in Vitro. AB - The influences of physical stimuli such as surface elasticity, topography, and chemistry over mesenchymal stem cell proliferation and differentiation are well investigated. In this context, a fundamentally different approach was adopted, and we have demonstrated the interplay of inherent substrate conductivity, defined chemical composition of cellular microenvironment, and intermittent delivery of electric pulses to drive mesenchymal stem cell differentiation toward osteogenesis. For this, conducting polyaniline (PANI) substrates were coated with collagen type 1 (Coll) alone or in association with sulfated hyaluronan (sHya) to form artificial extracellular matrix (aECM), which mimics the native microenvironment of bone tissue. Further, bone marrow derived human mesenchymal stem cells (hMSCs) were cultured on these moderately conductive (10(-4)-10(-3) S/cm) aECM coated PANI substrates and exposed intermittently to pulsed electric field (PEF) generated through transformer-like coupling (TLC) approach over 28 days. On the basis of critical analysis over an array of end points, it was inferred that Coll/sHya coated PANI (PANI/Coll/sHya) substrates had enhanced proliferative capacity of hMSCs up to 28 days in culture, even in the absence of PEF stimulation. On the contrary, the adopted PEF stimulation protocol (7 ms rectangular pulses, 3.6 mV/cm, 10 Hz) is shown to enhance osteogenic differentiation potential of hMSCs. Additionally, PEF stimulated hMSCs had also displayed different morphological characteristics as their nonstimulated counterparts. Concomitantly, earlier onset of ALP activity was also observed on PANI/Coll/sHya substrates and resulted in more calcium deposition. Moreover, real time polymerase chain reaction results indicated higher mRNA levels of alkaline phosphatase and osteocalcin, whereas the expression of other osteogenic markers such as Runt-related transcription factor 2, Col1A, and osteopontin exhibited a dynamic pattern similar to control cells that are cultured in osteogenic medium. Taken together, our experimental results illustrate the interplay of multiple parameters such as substrate conductivity, electric field stimulation, and aECM coating on the modulation of hMSC proliferation and differentiation in vitro. PMID- 26418614 TI - Contribution of Histopathologic Tissue Composition to Quantitative MR Spectroscopy and Diffusion-weighted Imaging of the Prostate. AB - PURPOSE: To determine associations of metabolite levels derived from magnetic resonance (MR) spectroscopic imaging (ie, hydrogen 1 [(1)H] MR spectroscopic imaging) and apparent diffusion coefficients (ADCs) from diffusion-weighted imaging with prostate tissue composition assessed by digital image analysis of histologic sections. MATERIALS AND METHODS: Institutional ethical review board approved this retrospective study and waived informed consent. Fifty-seven prostate cancer patients underwent an MR examination followed by prostatectomy. One hematoxylin and eosin-stained section of the resected prostate per patient was digitized and computationally segmented into nuclei, lumen, and combination of epithelial cytoplasm and stroma. On each stained section, regions of interest (ROIs) were chosen and matched to the corresponding ADC map and (1)H MR spectroscopic imaging voxels. ADC and two metabolite ratios (citrate [Cit], spermine [Spm], and creatine [Cr] to choline [Cho] and Cho to Cr plus Spm) were correlated with percentage areas of nuclei, lumen, and cytoplasm and stroma for peripheral zone (PZ), transition zone (TZ), and tumor tissue in both zones of the prostate by using a linear mixed-effect model and Spearman correlation coefficient (rho). RESULTS: ADC and (Cit + Spm + Cr)/Cho ratio showed positive correlation with percentage area of lumen (rho = 0.43 and 0.50, respectively) and negative correlation with percentage area of nuclei (rho = -0.29 and -0.26, respectively). The Cho/(Cr + Spm) ratio showed negative association with percentage area of lumen (rho = -0.40) and positive association with area of nuclei (rho = 0.26). Percentage areas of lumen and nuclei, (Cit + Spm + Cr)/Cho ratio, and ADC were significantly different (P < .001) between benign PZ (23.7 and 7.7, 8.83, and 1.58 * 10(-3) mm(2)/sec, respectively) and tumor PZ tissue (11.4 and 12.5, 5.13, and 1.20 * 10(-3) mm(2)/sec, respectively). These parameters were also significantly different between benign TZ (20.0 and 8.2, 6.50, and 1.26 * 10(-3) mm(2)/sec, respectively) and tumor TZ tissue (9.8 and 11.2, 4.36, and 1.03 * 10(-3) mm(2)/sec, respectively). CONCLUSION: The observed correlation of (Cit + Spm + Cr)/Cho ratio and ADC of the prostate with its tissue composition indicates that components of this composition, such as percentage luminal area, contribute to the value of these MR parameters. PMID- 26418616 TI - Tobacco industry interference with tobacco control policies in Poland: legal aspects and industry practices. AB - BACKGROUND: Since 2006, when Poland ratified the WHO Framework Convention on Tobacco Control (FCTC), there have been efforts to improve tobacco control regulation in the country. At the same time, at the European Union level, Poland took part in discussions over revision of the Tobacco Tax Directive and the Tobacco Products Directive. This study aims to explore the tobacco industry's tactics to interfere with the creation of those policies. METHODS: Analysis of 257 documents obtained through freedom of information request. RESULTS: We identified three means that the tobacco industry used to interfere with tobacco control policies: creating a positive attitude, expressing a will to be a part of the policymaking process, and exerting pressure. We found that those tactics have often been used unethically, with the industry providing the government with ready legislation proposals, overstating its contribution to the economy and the government revenues, misrepresenting the illicit cigarette problem and misusing scientific evidence. The industry also used legal threats, including use of bilateral trade agreements, against implementation of tobacco control measures. The companies lobbied together directly and through third parties, with the cigarette excise tax structure being the only area of disagreement among the companies. The industry also pushed the Polish government to challenge tobacco control policies in countries with stronger public policy standards, including UK display bans and the Australian plain-packaging law. CONCLUSIONS: From an object of regulation, the tobacco industry in Poland became a partner with the government in legislative work. Implementation of provisions of Article 5.3 of the WHO FCTC could prevent further industry interference. PMID- 26418615 TI - Hepatic Radiofrequency Ablation-induced Stimulation of Distant Tumor Growth Is Suppressed by c-Met Inhibition. AB - PURPOSE: To elucidate how hepatic radiofrequency (RF) ablation affects distant extrahepatic tumor growth by means of two key molecular pathways. MATERIALS AND METHODS: Rats were used in this institutional animal care and use committee approved study. First, the effect of hepatic RF ablation on distant subcutaneous in situ R3230 and MATBIII breast tumors was evaluated. Animals were randomly assigned to standardized RF ablation, sham procedure, or no treatment. Tumor growth rate was measured for 31/2 to 7 days. Then, tissue was harvested for Ki-67 proliferative indexes and CD34 microvascular density. Second, hepatic RF ablation was performed for hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and c-Met receptor expression measurement in periablational rim, serum, and distant tumor 24 hours to 7 days after ablation. Third, hepatic RF ablation was combined with either a c-Met inhibitor (PHA-665752) or VEGF receptor inhibitor (semaxanib) and compared with sham or drug alone arms to assess distant tumor growth and growth factor levels. Finally, hepatic RF ablation was performed in rats with c-Met-negative R3230 tumors for comparison with the native c-Met positive line. Tumor size and immunohistochemical quantification at day 0 and at sacrifice were compared with analysis of variance and the two-tailed Student t test. Tumor growth curves before and after treatment were analyzed with linear regression analysis to determine mean slopes of pre- and posttreatment growth curves on a per-tumor basis and were compared with analysis of variance and paired two-tailed t tests. RESULTS: After RF ablation of normal liver, distant R3230 tumors were substantially larger at 7 days compared with tumors treated with the sham procedure and untreated tumors, with higher growth rates and tumor cell proliferation. Similar findings were observed in MATBIII tumors. Hepatic RF ablation predominantly increased periablational and serum HGF and downstream distant tumor VEGF levels. Compared with RF ablation alone, RF ablation combined with adjuvant PHA-665752 or semaxanib reduced distant tumor growth, proliferation, and microvascular density. For c-Met-negative tumors, hepatic RF ablation did not increase distant tumor growth, proliferation, or microvascular density compared with sham treatment. CONCLUSION: RF ablation of normal liver can stimulate distant subcutaneous tumor growth mediated by HGF/c-Met pathway and VEGF activation. This effect was not observed in c-Met-negative tumors and can be blocked with adjuvant c-Met and VEGF inhibitors. PMID- 26418617 TI - A closer look at 'Cheap White' cigarettes. AB - BACKGROUND: Given the prominence of Cheap Whites in illicit tobacco discussions, we examined various definitions, market presence, brand proliferation, manufacturers, production locations, trademark ownership, prices and compliance with tax stamp and warning labels. METHODS: Data from peer-reviewed and grey literature, newspapers, trademark registries, governments/international organisation reports, and the tobacco industry were contrasted with two visual legal requirements (tax stamps and warning labels) and prices from the Tobacco Pack Surveillance System (TPackSS). RESULTS: Multiple sources identified 82 Cheap White brands and 53 manufacturers operating at least 82 production facilities. One-third of these manufacturers are in the free zones of Russia, Cyprus and the UAE. Two-thirds of the 37 Cheap White brands in the TPackSS had neither the correct health warning nor the required tax stamp in at least one country where they were purchased. Cheap Whites are on average less expensive than all other brands, but the price gap is often not as large as anecdotally reported. The cheapest Cheap White cigarettes purchased in one of the TPackSS countries irrespective of the presence of legal signs were still more expensive than the least expensive other brands satisfying both legal requirements. CONCLUSIONS: We confirmed that many Cheap White brands do not comply with the legal requirements in countries where they are sold, but also found that some of these cigarettes appear to be sold legally even outside their country of origin. The presence of untaxed Cheap Whites undermines tobacco tax policies, while the availability of legal cheap cigarettes is a public health concern. PMID- 26418618 TI - In Vitro and In Vivo Evaluation of Cidofovir as a Topical Ophthalmic Antiviral for Ocular Canine Herpesvirus-1 Infections in Dogs. AB - PURPOSE: The effects of cidofovir were investigated against canine herpesvirus-1 (CHV-1) in vitro and in dogs with experimentally induced recurrent ocular CHV-1 infection, a host-adapted pathogen animal model of ocular herpes simplex virus-1 (HSV-1) infection. METHODS: The cidofovir EC50 was determined for CHV-1 and HSV 1. A randomized, masked vehicle-controlled trial was performed using beagles with experimentally induced recurrent ocular CHV-1 infection. Dogs received 1 drop of 0.5% cidofovir solution or 0.9% sodium chloride solution (vehicle) in both eyes 2 times daily for 14 days. Dogs were monitored at intervals for 30 days by a clinical ophthalmic examination, in vivo confocal microscopy of the cornea and conjunctiva, ocular sample CHV-1 polymerase chain reaction assay, hemogram, and serum biochemistry panel. Clinical ocular disease scores were calculated and infiltrating leukocytes detected by in vivo confocal microscopy quantified. RESULTS: Cidofovir displayed similar in vitro antiviral activity against CHV-1 and HSV-1. Clinical ocular disease scores were significantly higher in the cidofovir group compared to the vehicle group. Marked conjunctival pigmentation and blepharitis were also detected in the cidofovir group, but not the vehicle group. Conjunctival and corneal leukocyte infiltration scores determined by in vivo confocal microscopy were significantly higher in the cidofovir group. Dogs administered cidofovir had significantly reduced durations of ocular viral shedding compared to the vehicle group. Hemogram and serum biochemistry panel values were unremarkable. CONCLUSIONS: Twice-daily application of topical 0.5% cidofovir ophthalmic solution reduced the duration of ocular viral shedding in dogs with experimentally induced recurrent ocular CHV-1 infection, but was associated with local ocular toxicity. PMID- 26418619 TI - Patterns of Feedback on the Bridge to Independence: A Qualitative Thematic Analysis of NIH Mentored Career Development Award Application Critiques. AB - BACKGROUND: NIH Mentored Career Development (K) Awards bridge investigators from mentored to independent research. A smaller proportion of women than men succeed in this transition. The aim of this qualitative study was to analyze reviewers' narrative critiques of K award applications and explore thematic content of feedback provided to male and female applicants. METHOD: We collected 88 critiques, 34 from 9 unfunded and 54 from 18 funded applications, from 70% (n = 26) of investigators at the University of Wisconsin-Madison with K awards funded between 2005 and 2009 on the first submission or after revision. We qualitatively analyzed text in the 5 critique sections: candidate, career development plan, research plan, mentors, and environment and institutional commitment. We explored thematic content within these sections for male and female applicants and for applicants who had received a subsequent independent research award by 2014. RESULTS: Themes revealed consistent areas of criticism for unfunded applications and praise for funded applications. Subtle variations in thematic content appeared for male and female applicants: For male applicants criticism was often followed by advice but for female applicants it was followed by questions about ability; praise recurrently characterized male but not female applicants' research as highly significant with optimism for future independence. Female K awardees that obtained subsequent independent awards stood out as having track records described as "outstanding." CONCLUSION: This exploratory study suggests that K award reviewer feedback, particularly for female applicants, should be investigated as a potential contributor to research persistence and success in crossing the bridge to independence. PMID- 26418620 TI - Characteristics and role of dynamic membrane layer in anaerobic membrane bioreactors. AB - A submerged anaerobic dynamic membrane bioreactor (AnDMBR) was operated for treatment of concentrated wastewater. The dynamic membrane (DM) or cake layer was characterized on its physicochemical and biological composition and the role of the DM layer in treatment and filtration performances was assessed. The results showed that the DM layer had an important role in organic matter removal. Both organic and inorganic materials, such as sludge particles, soluble microbial products (SMP), extracellular polymeric substances (EPS), and Ca, N, P, Mg precipitations contributed to the DM layer formation. Thus, effective retention of very small particles by the DM layer was achieved. The DM layer had higher microbial diversity and different microbial population composition in comparison to the bulk sludge. Overall, this study provided a better understanding about the DM layer structure in AnDMBRs, which might lead to increased applicability of this promising technology for the treatment of concentrated wastewaters. PMID- 26418622 TI - Speckle Tracking Echocardiography of the Right Atrium: The Neglected Chamber. AB - The right atrium (RA) plays a pivotal role in electromechanical and endocrine regulation of the heart. Its peculiar anatomical features and phasic mechanical function make it distinct from ventricles. Various invasive and noninvasive techniques have been used to elucidate RA structure and function. Of these modalities, echocardiography has distinct advantages over others. Several conventional measures of RA function through echocardiography have been described in the literature, but they are load dependent. A relatively new technique is speckle tracking-derived strain, which is relatively less dependent on loading conditions. Speckle tracking echocardiography tracks acoustic scatters (speckles) of myocardium frame-by-frame to calculate strain or deformation of the myocardium. Speckle tracking echocardiography has been used extensively for strain assessment of the right and left ventricle to detect subtle disease pathology, to gain mechanistic insight, as a marker of ischemic metabolic memory, as an endpoint in clinical trials, and as a functional assessment tool. The RA is a relatively neglected chamber, as it is mostly studied for assessment of atrial mass lesions, for electrophysiological studies, and in animal models for physiological assessment. However, its role in the systolic and diastolic function of the right heart, pulmonary vascular pathology, congenital heart diseases, and combined electromechanical activation phenomena has been less explored or unexplored. Speckle tracking echocardiography is an ideal tool for the assessment of the RA because of its regional and global functional characterization, angle independence, and high temporal resolution. PMID- 26418621 TI - Toward Additive-Free Small-Molecule Organic Solar Cells: Roles of the Donor Crystallization Pathway and Dynamics. AB - The ease with which small-molecule donors crystallize during solution processing is directly linked to the need for solvent additives. Donor molecules that get trapped in disordered (H1) or liquid crystalline (T1) mesophases require additive processing to promote crystallization, phase separation, and efficient light harvesting. A donor material (X2) that crystallizes directly from solution yields additive-free solar cells with an efficiency of 7.6%. PMID- 26418623 TI - Fingerprint analysis and multi-component determination of Zibu Piyin recipe by HPLC with DAD and Q-TOF/MS method. AB - Zibu Piyin recipe (ZBPYR), a traditional Chinese medicine formula, is used for curing dementia caused by diabetes. For quality control of ZBPYR, fingerprint analysis and qualitative analysis using high-performance liquid chromatography (HPLC) with a diode-array detector, and confirmation using HPLC coupled with electrospray ionisation quadrupole time-of-flight tandem mass spectrometry (HPLC Q-TOF-MS) were undertaken. HPLC fingerprint consisting of 34 common peaks was developed among 10 batches of ZBPYR, in which 7 common peaks were identified in comparison with the authentic standards and detected simultaneously. Furthermore, these seven compounds were verified by HPLC-Q-TOF-MS methods. The method can be applied to the quality control of ZBPYR. PMID- 26418625 TI - DNA 5-hydroxymethylation in human adipose tissue differs between subcutaneous and visceral adipose tissue depots. AB - BACKGROUND: A stable intermediate during DNA demethylation, 5 hydroxymethylcytosine (5-hmC), raises questions about its function and distribution. Therefore, we tested whether 5-hmC exists in human adipose tissue depots and correlates with clinical variables. MATERIALS & METHODS: We measured the % 5-hmC content in both subcutaneous adipose tissue and visceral adipose tissue (VAT) from 81 individuals by using ELISA technology. To test for associations with several clinical variables we used paired students t-tests and linear regression analyses. RESULTS: We observed an average % 5-hmC content of 0.47% +/- 0.093 in subcutaneous adipose tissue, while VAT (0.51% +/- 0.122) is higher hydroxymethylated (p = 0.005). In the total cohort we observed a positive association of % 5-hmC in VAT with age (p = 0.034) and a negative relationship with low density lipoprotein-cholesterol (p = 0.008). CONCLUSION: Our data suggest adipose tissue depot specific 5-hmC levels with higher levels in VAT. PMID- 26418627 TI - Granuloma Annulare Arising in Tumescent Anesthesia Injection Sites After Endovenous Ablation. PMID- 26418626 TI - Ellagic acid, a polyphenolic compound, selectively induces ROS-mediated apoptosis in cancerous B-lymphocytes of CLL patients by directly targeting mitochondria. AB - To investigate the effects ofellagic acid (EA) on the cytotoxicity, B-lymphocytes isolated from CLL patients and healthy individuals. Flow cytometric assay was used to measure the percentage of apoptosis versus necrosis, intracellular active oxygen radicals (ROS), mitochondrial membrane potential (MMP) and the caspase-3 activity and then mitochondria were isolated from both groups B-lymphocytes and parameters of mitochondrial toxicity was investigated. Based on our results EA decreased the percentage of viable cells and induced apoptosis. EA increased ROS formation, mitochondria swelling, MMP decrease and cytochrome c release in mitochondria isolated from CLL BUT NOT healthy B-lymphocytes while pre-treatment with cyclosporine A and Butylated hydroxyl toluene (BHT) prevented these effects. Our results suggest that EA can act as an anti cancer candidate by directly and selectively targeting mitochondria could induce apoptosis through mitochondria pathway with increasing ROS production which finally ends in cytochrome c release, caspase 3 activation and apoptosis in cancerous B-lymphocytes isolated from CLL patients. PMID- 26418628 TI - Treatment of Actinic Cheilitis. PMID- 26418629 TI - Results of a Multimodal Program During Hospitalization in Obese COPD Exacerbated Patients. AB - The objective of this study was to analyze the results of a multimodal therapeutic program during hospitalization in obese AECOPD patients. This was a randomized, single-blind clinical trial conducted at two university hospitals in Granada, Spain. Forty-nine patients hospitalized due to AECOPD were randomly allocated to a control group (CG), in which patients received standard care, or to an intervention group (IG), in which patients were included in a multimodal therapeutic program, added to the standard care. The main outcome measures were pulmonary, physical (strength and exercise capacity) and perceived (dyspnea, quality of life and psychological distress) variables. Within-group significant improvements (p < 0.05) were found in physical and perceived variables in the IG after the treatment. In the CG, a significant decrease was found in lower limb strength and a significant improvement in dyspnea and in three subscales of the EuroQol-5D questionnaire. The between-groups analysis showed significant differences after the treatment on lower limb strength and exercise capacity values (p < 0.05), in three of the EuroQol-5D subscales, and in the total score and the depression subscale of the Hospital Anxiety and Depression Scale. A multimodal therapeutic program has a beneficial effect on physical functioning and perceived variables in hospitalized obese patients with AECOPD. PMID- 26418630 TI - Electron-Proton Decoupling in Excited-State Hydrogen Atom Transfer in the Gas Phase. AB - Hydrogen-release by photoexcitation, excited-state-hydrogen-transfer (ESHT), is one of the important photochemical processes that occur in aromatic acids and is responsible for photoprotection of biomolecules. The mechanism is described by conversion of the initial state to a charge-separated state along the O(N)-H bond elongation, leading to dissociation. Thus ESHT is not a simple H-atom transfer in which a proton and a 1s electron move together. Here we show that the electron transfer and the proton-motion are decoupled in gas-phase ESHT. We monitor electron and proton transfer independently by picosecond time-resolved near infrared and infrared spectroscopy for isolated phenol-(ammonia)5 , a benchmark molecular cluster. Electron transfer from phenol to ammonia occurred in less than 3 picoseconds, while the overall H-atom transfer took 15 picoseconds. The observed electron-proton decoupling will allow for a deeper understanding and control of of photochemistry in biomolecules. PMID- 26418632 TI - Excavating abiotic stress-related gene resources of terrestrial macroscopic cyanobacteria for crop genetic engineering: dawn and challenge. AB - Genetically engineered (GE) crops with resistance to environmental stresses are one of the most important solutions for future food security. Numerous genes associated to plant stress resistance have been identified and characterized. However, the current reality is that only a few transgenic crops expressing prokaryotic genes are successfully applied in field conditions. These few prokaryotic genes include Agrobacterium strain CP4 EPSPS gene, Bacillus thuringiensis Cry1Ab gene and a bacterial chaperonin gene. Thus, the excavation of potentially critical genes still remains an arduous task for crop engineering. Terrestrial macroscopic cyanobacteria, Nostoc commune and Nostoc flagelliforme, which exhibit extreme resistance to desiccation stress, may serve as new prokaryotic bioresources for excavating critical genes. Recently, their marker gene wspA was heterologously expressed in Arabidopsis plant and the transgenics exhibited more flourishing root systems than wild-type plants under osmotic stress condition. In addition, some new genes associated with drought response and adaptation in N. flagelliforme are being uncovered by our ongoing RNA-seq analysis. Although the relevant work about the terrestrial macroscopic cyanobacteria is still underway, we believe that the prospect of excavating their critical genes for application in GE crops is quite optimistic. PMID- 26418631 TI - Heterogeneous composition of key metabolic gene clusters in a vent mussel symbiont population. AB - Chemosynthetic symbiosis is one of the successful systems for adapting to a wide range of habitats including extreme environments, and the metabolic capabilities of symbionts enable host organisms to expand their habitat ranges. However, our understanding of the adaptive strategies that enable symbiotic organisms to expand their habitats is still fragmentary. Here, we report that a single ribotype endosymbiont population in an individual of the host vent mussel, Bathymodiolus septemdierum has heterogeneous genomes with regard to the composition of key metabolic gene clusters for hydrogen oxidation and nitrate reduction. The host individual harbours heterogeneous symbiont subpopulations that either possess or lack the gene clusters encoding hydrogenase or nitrate reductase. The proportions of the different symbiont subpopulations in a host appeared to vary with the environment or with the host's development. Furthermore, the symbiont subpopulations were distributed in patches to form a mosaic pattern in the gill. Genomic heterogeneity in an endosymbiont population may enable differential utilization of diverse substrates and confer metabolic flexibility. Our findings open a new chapter in our understanding of how symbiotic organisms alter their metabolic capabilities and expand their range of habitats. PMID- 26418634 TI - Smooth Pursuit Eye Movement Deficits in Patients With Whiplash and Neck Pain are Modulated by Target Predictability. AB - STUDY DESIGN: This is a cross-sectional study. OBJECTIVE: The purpose of this study is to support and extend previous observations on oculomotor disturbances in patients with neck pain and whiplash-associated disorders (WADs) by systematically investigating the effect of static neck torsion on smooth pursuit in response to both predictably and unpredictably moving targets using video oculography. SUMMARY OF BACKGROUND DATA: Previous studies showed that in patients with neck complaints, for instance due to WAD, extreme static neck torsion deteriorates smooth pursuit eye movements in response to predictably moving targets compared with healthy controls. METHODS: Eye movements in response to a smoothly moving target were recorded with video-oculography in a heterogeneous group of 55 patients with neck pain (including 11 patients with WAD) and 20 healthy controls. Smooth pursuit performance was determined while the trunk was fixed in 7 static rotations relative to the head (from 45 degrees to the left to 45 degrees to right), using both predictably and unpredictably moving stimuli. RESULTS: Patients had reduced smooth pursuit gains and smooth pursuit gain decreased due to neck torsion. Healthy controls showed higher gains for predictably moving targets compared with unpredictably moving targets, whereas patients with neck pain had similar gains in response to both types of target movements. In 11 patients with WAD, increased neck torsion decreased smooth pursuit performance, but only for predictably moving targets. CONCLUSION: Smooth pursuit of patients with neck pain is affected. The previously reported WAD specific decline in smooth pursuit due to increased neck torsion seems to be modulated by the predictability of the movement of the target. The observed oculomotor disturbances in patients with WAD are therefore unlikely to be induced by impaired neck proprioception alone. LEVEL OF EVIDENCE: 3. PMID- 26418633 TI - Association Between Preinfarction Angina and Angiographic Findings in Non-ST Segment Elevation Myocardial Infarction. AB - BACKGROUND: The association between preinfarction angina and angiographic findings has not been elucidated in patients with non-ST-segment elevation myocardial infarction (NSTEMI). HYPOTHESIS: Patients with preinfarction angina have favorable angiographic findings. METHODS: This retrospective study analyzed 481 patients who underwent coronary angiography within 5 days of presenting NSTEMI. Preinfarction angina was defined as experiencing >=1 chest-pain episode within 7 days prior to admission. Infarct size was measured as the peak cardiac troponin I (cTnI) level, and large myocardial infarction (MI) was defined as a peak cTnI level >85th percentile value in the study population. Infarct-related artery (IRA) patency was defined as Thrombolysis In Myocardial Infarction grade 2 or 3 flow. Clinical and angiographic characteristics and in-hospital mortality were compared between patients with and without preinfarction angina. RESULTS: Among 481 patients, 200 (42%) had preinfarction angina. Preinfarction angina was associated with smaller infarct size, indicated by lower peak cTnI levels (P = 0.006) and lower incidence of large MI (P = 0.02), and IRA patency (P = 0.03). There was no significant difference in in-hospital mortality. On multivariate analysis, both preinfarction angina (odds ratio: 0.53, 95% confidence interval: 0.29-0.94, P = 0.03) and IRA patency (odds ratio: 0.30, 95% confidence interval: 0.17-0.52, P < 0.001) were independent negative predictors of large MI. CONCLUSION: Our study demonstrates that preinfarction angina is a predictor of smaller infarct size and infarct-related artery patency in NSTEMI patients, suggesting that NSTEMI patients presenting without preinfarction angina are at increased risk of developing a large MI. PMID- 26418636 TI - [Insulin treatment of adults with type 1 diabetes]. AB - Whereas insulin treatment of type 1 diabetes formerly was limited by the availability of one or a few types of insulin with suboptimal pharmacokinetic properties, insulin analogues with more fitting physiological action profiles have now been developed and ultimately near-physiological insulin treatment can be delivered with insulin pumps. Adjustments of insulin dosing can be rationally based on dosing algorithms. This requires frequent glucose measurements and knowledge about dietary carbohydrate content. Today, the treatment and its complexity are individualized according to needs and wishes of the patient. PMID- 26418637 TI - [Diagnosing neck mass in adults]. AB - Doctors are frequently presented to patients with a neck mass, and the condition might cause diagnostic challenges. In younger adults, a neck mass can typically be explained by congenital, inflammatory or infectious causes. The highest probability of neoplasms is found in patients above 40 years of age. When a malignant neoplasm in the neck is suspected, patients should be referred to an ear, nose and throat specialist. In cases of suspect signs of malignancy as defined by the Danish Health and Medicines Authority, patients should be referred to the integrated national cancer pathways. PMID- 26418635 TI - Altered miRNA expression in the cervix during pregnancy associated with lead and mercury exposure. AB - AIM: Toxic metals including lead and mercury are associated with adverse pregnancy outcomes. This study aimed to assess the association between miRNA expression in the cervix during pregnancy with lead and mercury levels. MATERIALS & METHODS: We obtained cervical swabs from pregnant women (n = 60) and quantified cervical miRNA expression. Women's blood lead, bone lead and toenail mercury levels were analyzed. We performed linear regression to examine the association between metal levels and expression of 74 miRNAs adjusting for covariates. RESULTS: Seventeen miRNAs were negatively associated with toenail mercury levels, and tibial bone lead levels were associated with decreased expression of miR-575 and miR-4286. CONCLUSION: The findings highlight miRNAs in the human cervix as novel responders to maternal chemical exposure during pregnancy. PMID- 26418638 TI - [Synchronous sigmoideum- and caecum volvulus]. AB - This case presents a synchronous sigmoid- and caecum volvulus in a 69-year old man with Parkinson's disease, hypertension and previous history of colonic volvulus. On admission the patient had abdominal pain, nausea, vomiting and constipation. The CT scan showed a sigmoid volvulus with a dilated caecum. The synchronous sigmoideum- and caecum volvulus was diagnosed intraoperatively. Total colectomy and ileostomy was performed. PMID- 26418639 TI - [Myoclonus as a side effect to citalopram treatment in a patient with liver cirrhosis]. AB - Side effects such as myoclonus and tremor are rare when treating with selective serotonin reuptake inhibitors (SSRIs). We present a case where a patient with known liver cirrho-sis and in treatment with citalopram developed myoclonus, tremor and gait difficulties. The symptoms were reduced when the SSRI dose was decreased. In patients with unexplained movement disorders the usage of SSRIs should be considered as a cause. Furthermore, treatment with SSRIs should be carefully assessed in patients with reduced liver function. PMID- 26418640 TI - [Median arcuate ligament syndrome]. AB - The median arcuate ligament syndrome is a rare entity and poorly described in Danish literature. The syndrome is a diagnosis of exclusion and is characterized by chronic abdominal pain, postprandial pain and weight loss. It is believed that the median arcuate ligament, being a fibrous structure of diaphragm, compresses the coeliac trunk thus causing stenosis and malperfusion of the gastrointestinal organs. Until recently, there has been some reluctance to consider intervention with revascularization or ligament release. Within the latest decade minimally invasive techniques, including laparoscopic release of the median arcuate ligament, have shown promising results. PMID- 26418642 TI - Surgery is not an innate talent: the dark side of duty-hour restrictions for residents. PMID- 26418641 TI - [Anorexia nervosa is frequently associated with psychiatric co-morbidity]. AB - Recent literature is explored focusing on the relationship between symptoms of anorexia nervosa (AN) and other psychiatric disorders and lines of treatment. In AN, restrictive subtype, anxiety and obsessive-compulsive disorders are the most frequent co-morbidities. In AN, bulimic subtype, depression, emotional instability/borderline and dependency disorders are most frequent. Psychopharmacological treatment could be tried in cases with AN and co-morbid depression, but otherwise the evidence base is lacking and pharmacological treatment relies on case stories and experience. PMID- 26418644 TI - Comparison of parental socio-demographic factors in children and adolescents presenting with internalizing and externalizing disorders. AB - OBJECTIVE: This study aimed to: (a) examine parental socio-demographic factors in children and adolescents referred to an outpatient service for internalizing and externalizing disorders, and (b) compare the demographic variables and diagnoses for the two diagnostic groups. METHODS: Parents of all children who were referred to the child and adolescent outpatient service were asked to participate. Following their informed consent, they completed a socio-demographic questionnaire for themselves and a Child Behaviour Checklist (CBCL) for their child. The CBCL scores and the diagnoses assigned by the psychiatrists were then recorded for each child. Diagnoses were classified as internalizing or externalizing based on the primary DSM-IV diagnosis assigned by the psychiatrists. Data for the two groups were compared for study variables using Pearson correlation, t-tests, one-way ANOVA and logistic regression. RESULTS: Children who had externalizing disorders tended to live with unemployed single parents who had lower education levels and lived in rented or assisted housing. Children with internalizing problems tended to live in owned homes with employed parents. There was no significant association between age or gender for either group. CONCLUSION: Previous literature has reported an association between low SES and more mental health problems; however, the relationship between different indicators of SES and diagnosis is not clear. Despite small numbers, our study revealed significant differences between the parental socio-demographic factors for externalizing compared with internalizing disorders. PMID- 26418645 TI - Role of iso-receptors in receptor-receptor interactions with a focus on dopamine iso-receptor complexes. AB - Intercellular and intracellular communication processes consist of signals and recognition/decoding apparatuses of these signals. In humans, the G protein coupled receptor (GPCR) family represents the largest family of cell surface receptors. More than 30 years ago, it has been proposed that GPCR could form dimers or higher-order oligomers (receptor mosaics [RMs] at the plasma membrane level and receptor-receptor interactions [RRIs] have been proposed as a new integrative mechanism for chemical signals impinging on cell plasma membranes). The basic phenomena involved in RRIs are allostery and cooperativity of membrane receptors, and the present paper provides basic information concerning their relevance for the integrative functions of RMs. In this context, the possible role of iso-receptor RM is discussed (with a special focus on dopamine receptor subtypes and on some of the RMs they form with other dopamine iso-receptors), and it is proposed that two types of cooperativity, namely, homotropic and heterotropic cooperativity, could allow distinguishing two types of functionally different RMs. From a general point of view, the presence of iso-receptors and their topological organization within RMs allow the use of a reduced number of signals for the intercellular communication processes, since the target cells can recognize and decode the same signal in different ways. This theoretical aspect is further analyzed here by means of an analogy with artificial information systems. Thus, it is suggested that the 'multiplexer' and 'demultiplexer' concepts could, at least in part, model the role of RMs formed by iso-receptors in the information handling by the cell. PMID- 26418646 TI - Adaptive regulation of glucose transport, glycolysis and respiration for cell proliferation. AB - The cell must utilise nutrients to generate energy as a means of sustaining its life. As the environment is not necessarily abundant in nutrients and oxygen, the cell must be able to regulate energy metabolism to adapt to changes in extracellular and intracellular conditions. Recently, several key regulators of energy metabolism have been reported. This review describes the recent advances in molecular regulation of energy metabolism, focusing mainly on glycolysis and its shunt pathways. Human diseases, such as cancer and neurodegenerative disorders, are also discussed in relation to failure of energy metabolism regulation. PMID- 26418647 TI - Vector competence of two Indian populations of Culex quinquefasciatus (Diptera: Culicidae) mosquitoes to three West Nile virus strains. AB - BACKGROUND & OBJECTIVES: Culex quinquefasciatus is one of the principal vectors of West Nile virus (WNV). The mosquito also acts as a bridge vector as it feeds on both birds and humans. In the background of the recent reports of WNV activity in Kerala and Assam with fatalities, a study was initiated to determine the growth kinetics and transmission mechanisms of three strains of WNV in two populations of Cx. quinquefasciatus. METHODS: Mosquitoes were infected by oral feeding and growth on different post-infection days was determined with the three strains. Horizontal transmission was determined by confirming sickness and mortality in infant mice after infected mosquito bite. F1 generation eggs, larvae, pupae and adults of experimentally infected mosquitoes were screened for WNV to determine vertical (transovarial) transmission. Trans-stadial transmission was determined by detecting WNV in adult mosquitoes emerged from infected larvae. RESULTS: Both the mosquito populations replicated and maintained WNV for a prolonged period with high titers (>= 5log10 PFU/ml). WNV could be detected in saliva from Days 2 to 32 post-infection. Horizontal transmission by both the populations could be established but no vertical transmission was observed. However, parenterally infected larvae transmitted WNV to adults. INTERPRETATION & CONCLUSION: WNV has been isolated from >10 mosquito species from India, however, vector competence of none of the species has been studied. The present study demonstrates efficient transmission of WNV by Cx. quinquefasciatus mosquitoes. With its country wide prevalence and high vector competence, the mosquitoes could create grave consequences especially when virulent strains with potential to cause acute flaccid paralysis and death are circulating. PMID- 26418648 TI - Fly ash based Bacillus thuringiensis var. israelensis formulation for use against Culex quinquefasciatus, the vector of filariasis in natural ecosystems. AB - BACKGROUND & OBJECTIVES: Fly ash is produced in huge quantities by the various thermal power stations in India. This thermal waste has been employed as a carrier material in the preparation of a biopesticidal water dispersible powder (WDP) formulation for use against mosquitoes. In the present investigation, this newly developed fly ash based WDP formulation was evaluated in natural breeding habitats of mosquito. METHODS: Fly ash based WDP formulation of Bacillus thuringiensis var. israelensis (VCRC B17) was evaluated for its efficacy and residual activity in aquatic habitats supporting breeding of Culex quinquefasciatus, the vector of lymphatic filariasis in Neyveli Township, Neyveli Lignite Corporation, India for a period of one month. RESULTS: At an application rate of 10 kg/ha, the WDP was effective for five days regardless of the habitat, and provided 80-100% reduction in larval abundance of Cx. quinquefasciatus. INTERPRETATION & CONCLUSION: The study indicates that for continued control of immature density and prevention of adult emergence, a weekly application of this formulation is necessary. This study also showed that fly ash based formulations can be used for immediate control of mosquitoes in different types of habitats and has also brought out a new avenue for the utilization of coal ash. PMID- 26418649 TI - Vector ecology of human schistosomiasis in south India and description of a new species of the genus Ferrissia (Mollusca: Gastropoda: Planorbidae). AB - BACKGROUND & OBJECTIVES: Vector ecology and taxonomy of snails is a prerequisite for controlling schistosomiasis in the tropics. The ecology of the freshwater limpet genus Ferrissia was investigated for detection of cercariae larvae in them, and taxonomic description of a new species of the genus Ferrissia. METHODS: This study was conducted in 15 perennial streams from five different hills of south India. To study the seasonal patterns, a stream from each hill was selected and sampled in three seasons. In each study site, triplicate sampling was done and specimens were collected from stream substrates as well as waste material submerged in stream. Microscopic examination was carried out for detecting cercariae larvae in limpets. RESULTS: Three freshwater limpets (F. tenuis, F. verruca and F. fivefallsiensis) were observed. Seasonality influenced the abundance of limpets. The highest abundance was observed during post-monsoon (December and January). The distribution of Ferrissia was observed at riffle in pebbles, leaf litter and wastes (polyethylene bags and snacks cover) submerged in water. No cercariae larvae were found from the body of limpets. In this study, we described a new species of Ferrissia fivefallsiensis. INTERPRETATION & CONCLUSION: Our results showed the distribution, habitat preference and seasonality of limpets, and recommend the detection of Schistosoma from limpets as well as human samples by use of molecular tools. PMID- 26418650 TI - Microfilarial periodicity of Wuchereria bancrofti in Assam, Northeast India. AB - BACKGROUND & OBJECTIVES: Wuchereria bancrofti has shown nocturnal periodicity in India and other endemic countries of the world except pacific regions where non periodic or diurnal sub-periodic forms have been reported. Presence of sub periodic form of W. bancrofti in Andaman and Nicobar Islands, India and a case report of sub- periodic form of W. bancrofti from Mysore, India provide basis for exploring the periodicity pattern of microfilaria of W. bancrofti prevalent in Assam, Northeastern region of India. State of Assam has unique geographical location as its Northeastern region shares international boundaries with Nepal, China, Bhutan, Myanmar and Bangladesh. Evolutionary association of W. bancrofti found in Assam is not known and possibility of its link with W. bancrofti form, prevalent in neighbouring countries may not be ruled out. Hence, this study was undertaken to know the microfilarial periodicity of W. bancrofti in Assam. METHODS: Ten microfilaria positive adult male individuals having moderate to high microfilaraemia were selected. Informed written consent from each participant was obtained. The presence of microfilaria was observed at two hourly intervals over a period of 24 h using 50 MUl of finger prick peripheral blood samples. Peripheral blood smears were processed, stained and examined under microscope and microfilaria counts were recorded. RESULTS: Data collected were calculated and analyzed using modified statistical method, and the periodicity curve was prepared. Typical nocturnal periodicity was observed at a peak time of 0003 hrs with a periodicity index of 136.2. INTERPRETATION & CONCLUSION: Analysis of the data revealed nocturnal periodicity of the W. bancrofti prevalent in the Assam with peak periodicity about one hour ahead of the other states in India. Findings will be helpful in evaluation and monitoring of ongoing MDA programme for elimination of LF in Assam. PMID- 26418651 TI - Potential urban distribution of Phlebotomus mascittii Grassi and Phlebotomus neglectus Tonn. (Diptera: Psychodidae) in 2021-50 in Budapest, Hungary. AB - BACKGROUND & OBJECTIVES: In the Carpathian Basin, the most northern populations of Phlebotomus (sandfly) species, including the two studied species (Phlebotomus mascittii and Phlebotomus neglectus), are reported from central Hungary. The most important limiting factor of the distribution of Phlebotomus species in the region is the annual minimum temperature which may be positively affected by the urban heat island and the climate change in the future. The main objective of the study is to prove and predict the overwintering possibility of Phlebotomus species in urban environment. METHODS: Based on the latest reports of occurrence of sandfly species, climate envelope model was built for the period 1961-90 and 2025-50 to project the potential urban distribution of the species. The climatic data were obtained from RegCM regional climate model and MODIS satellite images. RESULTS: The recent occurrence of the species in central Hungary indicates that Phlebotomus species can overwinter in non-heated shelters in built environment. INTERPRETATION & CONCLUSION: Jointly heat island and the increase of minimum temperature in winter due to climate change seem to be able to provide suitable environment for the studied species in urban areas to a great extent. PMID- 26418652 TI - Confirmation of Culex (Culex) tritaeniorhynchus summorosus (Diptera: Culicidae) as a separate species. AB - BACKGROUND & OBJECTIVES: Culex tritaeniorhynchus, a member of Cx. vishnui subgroup, is an important vector of Japanese encephalitis (JE) virus. Cx. tritaeniorhynchus summorosus considered as a variety or subspecies of Cx. tritaeniorhynchus, has been studied in detail to settle its taxonomic status. Surveys for the collection of Cx. tritaeniorhynchus from Chandigarh and adjoining areas have established the availability of Cx. summorosus from this area. METHODS: For the present investigation, collections have been made from Chandigarh and its adjoining areas (up to 60 km) for procuring the material. The detailed morphology including scanning electron microscopy of immatures (eggs and larvae) and adults of Cx. tritaeniorhynchus and Cx. summorosus has been studied and compared. Further, the interbreeding experiments of the two species were also conducted and efforts had been made to allow cross- breeding among the members of these two species. RESULTS: Comparison of egg, larval and adult morphology of Cx. summorosus with the parental species Cx. tritaeniorhynchus under the light and electron microscope, revealed significant differences. Moreover, these two species have also been found to be reproductively isolated as indicated by laboratory experiments. This settles the controversy on the status of Cx. summorosus and confirms its status as a distinct species. INTERPRETATION & CONCLUSION: The study establishes that the two species show considerable number of differences which are sufficient to consider them as separate species rather than subspecies or variant of Cx. tritaeniorhynchus. Furthermore, the absence of interbreeding between these two again confirms their separate specific status according to biological species concept. But, it is yet to ascertain whether Cx. summorosus is a vector of Japanese encephalitis like Cx. tritaeniorhynchus or not. PMID- 26418654 TI - Anopheline mosquitoes in District Ramgarh (Jharkhand), India. AB - BACKGROUND & OBJECTIVES: Jharkhand is one of the highly malaria endemic states in India and experiencing vast ecological and human-induced changes over the years. These changes have provided more favourable conditions for malaria transmission in the region. The present study was carried out to find out the distribution and prevalence of anopheline vector and non-vector species in District Ramgarh of Jharkhand state. METHODS: Daytime indoor resting adult female anopheline mosquitoes were collected from four subcentres comprising of eight study villages in District Ramgarh. The collections were made from fixed as well as random human dwellings and cattlesheds on fortnightly basis using manual aspiration method from January to December 2012. Mosquito identification was done by using standard identification keys. RESULTS: A total of 18,875 anophelines belonging to 19 species were collected. Of these, 61.87% were vector species (An. culicifacies, An. fluviatilis and An. annularis). Of total vector collection, 57.44% was observed in Gola block and 42.55% in Ramgarh. An. culicifacies was predominant species followed by An. fluviatilis and An. annularis in the study area. Out of 19, eight anopheline species exhibited successional changes in their composition over the period of years. Statistical analysis revealed positive correlation between meteorological variables and man hour density in case of An. culicifacies, whereas these were negatively correlated in case of An. fluviatilis and An. annularis. INTERPRETATION & CONCLUSION: The study revealed the prevalence of three recognised malaria vector species (An. culicifacies, An. fluviatilis and An. annularis) in high density throughout the year in this area, which indicates possibility of widening of malaria transmission window in the presence of malaria parasites. The shifting of anopheline species in Ramgarh also indicate alteration in ecological, environmental and sociological conditions, which necessitate routine monitoring on ecology and successional changes of vector species as well as malariological survey for management and adoption of appropriate vector control strategies in this area. PMID- 26418653 TI - Control of Aedes aegypti and Ae. albopictus, the vectors of dengue and chikungunya, by using pheromone C21 with an insect growth regulator: Results of multicentric trials from 2007-12 in India. AB - BACKGROUND & OBJECTIVES: Aedes mosquito control has gained much importance nowadays in view of rise in number of reported cases of dengue and chikungunya in India and other countries. In the present study, C21 attracticide (containing a pheromone and an insect growth regulator-IGR, developed by Defence Research and Development Establishment (DRDE), Gwalior, India was tested for its feasibility for surveillance and control of Aedes mosquito in a multicentric mode from October 2007 to June 2012 in urban (Delhi, and Bengaluru district, Karnataka) and suburban (Alappuzha district, Kerala) settings of the country in three phases. METHODS: Across the randomly selected households in each study area, two to four containers treated with attracticide (experimental) and untreated (control) were placed and monitored by trained surveillance workers on weekly/ fortnightly basis for determining the presence of eggs, larvae and pupae. Container positivity, percent larvae, egg and pupae collected were determined during different phases and analyzed statistically using SPSS 18.0. RESULTS: Container positivity was found statistically significant at Bengaluru and Alappuzha, Kerala while in Delhi, it was found non-significant. Eggs collected from experimental containers were significantly higher in comparison to control at all the locations except Delhi. Also larvae collected from control containers were significantly higher at all the locations except Bengaluru. Pupae collected from control containers remained significantly higher at all the locations as no pupal formation was recorded from experimental containers. INTERPRETATION & CONCLUSION: The use of C21 attracticide hampered pupal formation, thus inhibiting adult population in the study areas. The study established that C21 attracticide was efficacious in the field conditions and has potential for use in surveillance and management of dengue and chikungunya mosquitoes. PMID- 26418655 TI - Pattern and predictors of neurological morbidities among childhood cerebral malaria survivors in central Sudan. AB - BACKGROUND & OBJECTIVES: Cerebral malaria is considered a leading cause of neuro disability in sub-Saharan Africa among children and about 25% of survivors have long-term neurological and cognitive deficits or epilepsy. Their development was reported to be associated with protracted seizures, deep and prolonged coma. The study was aimed to determine the discharge pattern and to identify potential and informative predictors of neurological sequelae at discharge, complicating childhood cerebral malaria in central Sudan. METHODS: A cross-sectional prospective study was carried out during malaria transmission seasons from 2000 to 2004 in Wad Medani, Sinnar and Singa hospitals, central Sudan. Children suspected of having cerebral malaria were examined and diagnosed by a Pediatrician for clinical, laboratory findings and any neurological complications. Univariate and multiple regression model analysis were performed to evaluate the association of clinical and laboratory findings with occurrence of neurological complications using the SPSS. RESULTS: Out of 940 examined children, only 409 were diagnosed with cerebral malaria with a mean age of 6.1 +/ 3.3 yr. The mortality rate associated with the study was 14.2% (58) and 18.2% (64) of survivors (351) had neurological sequelae. Abnormal posture, either decerebration or decortication, focal convulsion and coma duration of >48 h were significant predictors for surviving from cerebral malaria with a neurological sequelae in children from central Sudan by Univariate analysis. Multiple logistic regression model fitting these variables, revealed 39.6% sensitivity for prediction of childhood cerebral malaria survivors with neurological sequelae (R2 = 0.396; p=0.001). INTERPRETATION & CONCLUSION: Neurological sequelae are common due to childhood cerebral malaria in central Sudan. Their prediction at admission, clinical presentation and laboratory findings may guide clinical intervention and proper management that may decrease morbidity and improve CM consequences. PMID- 26418656 TI - Oviposition and vertical dispersal of Aedes mosquitoes in multiple storey buildings in Colombo district, Sri Lanka. AB - BACKGROUND & OBJECTIVES: The Colombo City in Sri Lanka is experiencing tremendous development and construction of multiple storey buildings and high rise apartments. The change in housing types and microhabitats might have altered the flight and breeding behaviour of Aedes mosquito population. This study was carried out to determine the vertical dispersal and abundance of Aedes mosquitoes in multiple storey buildings in the Colombo district, with respect to abiotic factors such as rainfall, humidity and wind speed. Hence, this study is of paramount importance, particularly for planning and implementation of control measures against Aedes mosquitoes. METHODS: An ovitrap based study was carried out at four selected multiple storey buildings in four residential areas located in Colombo, Sri Lanka, from August to December 2013. Results were analyzed using four indices; ovitrap index, mean number of larvae, mean number of eggs and mean number of larvae per ovipaddle. RESULTS: The results implied that Aedes mosquitoes could be found in different elevations from ground floor to the highest floor (130 ft). There was a significant difference between height and ovitrap index (p<0.05), and height and mean number of larvae per recovered ovipaddle (p<0.05). The highest index value for mean number of eggs was observed as 3.492 +/- 0.655 at the 6th floor (60 ft high from ground level). At the same height (60 ft height) other indices (ovitrap index, mean number of larvae and mean number of larvae per ovipaddle) also displayed higher values, i.e. 13.19 +/- 2.98%, 1.366 +/- 0.527, and 2.070 +/- 0.421%, respectively. Abiotic factors such as wind speed, coastal nature, etc. displayed a significant effect to the vertical dispersal of Aedes mosquitoes (p<0.05). INTERPRETATION & CONCLUSION: The study suggested that Aedes mosquitoes are able to breed at any level of the buildings and not restricted by their height. The indices (mean number of larvae, mean number of eggs) representing the vertical dispersal with respect to abundance seemed to be statistically non-significant (p>0.05) with height which indicates high abundance of Aedes mosquitoes at higher floors. Abiotic factors also seemed to cause significant effect to the vertical dispersal of Aedes mosquitoes in high rise buildings. PMID- 26418657 TI - Seasonal prevalence and blood meal analysis of filarial vector Culex quinquefasciatus in coastal areas of Digha, West Bengal, India. AB - BACKGROUND & OBJECTIVES: Filariasis is one of the major vector-borne diseases causing serious health problem in the tropics and subtropics. The coastal areas of Digha are known to be a filariasis prone region of West Bengal, India. The filarial parasite Wuchereria bancrofti is transmitted by Culex quinquefasciatus, the established filarial vector in West Bengal, India. The present work was aimed to determine the abundance of different mosquito species; and the frequency, distribution and blood meal analysis of Cx. quinquefasciatus in coastal areas of Digha. METHODS: During the present study, a total of 11,537 mosquitoes [Cx. quinquefasciatus, Armigeres subalbatus, Anopheles barbirostris, An. annularis, An. subpictus, An. sundaicus, Aedes albopictus, and Cx. vishnui (group)] were collected by hand collection method from human habitations and cattlesheds of 10 villages of Digha, West Bengal, India. The seasonal prevalence of Cx. quinquefasciatus was studied. In each season, blood meals of 300 Cx. quinquefasciatus collected from human habitations were analysed during the study period. RESULTS: Cx. quinquefasciatus was found to be the dominant species (88.44% of the total collection) in the study area. It was most frequently found in and around human habitations than cattlesheds. Total man hour density calculation revealed that this species was most prevalent during the rainy season. Two-way ANOVA revealed that the abundance of Cx. quinquefasciatus varied with different seasons. Blood meal analysis showed that the filarial vector preferred human blood than that of other animals. INTERPRETATION & CONCLUSION: This study suggested Cx. quinquefasciatus as the dominant mosquito species in the study area; and the anthropophilic nature of Cx. quinquefasciatus might be the reason of increase in the intensity of filarial transmission in coastal areas of Digha. PMID- 26418658 TI - Molecular phylogenetic affiliation of Wolbachia and phage WO among Mansonia mosquitoes from Kerala, India. PMID- 26418659 TI - Deltamethrin induced functional mortality of Anopheles stephensi, the urban malaria vector, in relation to resistance development. PMID- 26418660 TI - Hepatitis A and dengue coinfection. PMID- 26418661 TI - Atypical eschar: An unusual cutaneous manifestation of scrub typhus. PMID- 26418662 TI - Cheek swelling: An unusual presentation of filariasis. PMID- 26418663 TI - Corrigendum. PMID- 26418664 TI - Prevalence of Restless Legs Syndrome in Adult ADHD and Its Subtypes. AB - In this observational cross-sectional study, 49 subjects were assessed for sleep disorders and for ADHD symptoms. Thirty-six received an ADHD diagnosis (29: combined type (ADHD-C); 7: inattentive type). An RLS and RLS symptoms prevalence of 34.5% was found, with a higher prevalence rate in the ADHD-C subgroup, although not significantly (p = 0.066). RLS symptoms were correlated with particularly hyperactivity-impulsivity (rho = 0.742; p: 0.000). ADHD patients with positive RLS scores reported higher scores on the ADHD-Rating scale compared with patients with negative RLS scores (Z: -2.968, p = 0.003), mainly due to higher hyperactivity-impulsivity scores (Z: -3.145; p = 0.002). Our findings show that clinicians need to be aware of RLS among adult ADHD patients, particularly those with severe hyperactivity-impulsivity symptoms. PMID- 26418665 TI - Rare-earth metal methylidene complexes with Ln3(MU3-CH2)(MU3-Me)(MU2-Me)3 core structure. AB - Trinuclear rare-earth metal methylidene complexes with a Ln3(MU3-CH2)(MU3-Me)(MU2 Me)3 structural motif were synthesized by applying three protocols. Polymeric [LuMe3]n (1-Lu) reacts with the sterically demanding amine H[NSiMe3(Ar)] (Ar = C6H3iPr2-2,6) in tetrahydrofuran via methane elimination to afford isolable monomeric [NSiMe3(Ar)]LuMe2(thf)2 (4-Lu). The formation of trinuclear rare-earth metal tetramethyl methylidene complexes [NSiMe3(Ar)]3Ln3(MU3-CH2)(MU3-Me)(MU2 Me)3(thf)3 (7-Ln; Ln = Y, Ho, Lu) via reaction of [LnMe3]n (1-Ln; Ln = Y, Ho, Lu) with H[NSiMe3(Ar)] is proposed to occur via an "intermediate" species of the type [NSiMe3(Ar)]LnMe2(thf)x and subsequent C-H bond activation. Applying Lappert's concept of Lewis base-induced methylaluminate cleavage, compounds [NSiMe3(Ar)]Ln(AlMe4)2 (5-Ln; Ln = Y, La, Nd, Ho) were converted into methylidene complexes 7-Ln (Ln = Y, Nd, Ho) in the presence of tetrahydrofuran. Similarly, tetramethylgallate complex [NSiMe3(Ar)]Y(GaMe4)2 (6-Y) could be employed as a synthesis precursor for 7-Y. The molecular composition of complexes 4-Ln, 5-Ln, 6 Y and 7-Ln was confirmed by elemental analyses, FTIR spectroscopy, (1)H and (13)C NMR spectroscopy (except for holmium derivatives) and single-crystal X-ray diffraction. The Tebbe-like reactivity of methylidene complex 7-Nd with 9 fluorenone was assessed affording oxo complex [NSiMe3(Ar)]3Nd3(MU3-O)(MU2 Me)4(thf)3 (8-Nd). The synthesis of 5-Ln yielded [NSiMe3(Ar)]2Ln(AlMe4) (9-Ln; Ln = La, Nd) as minor side-products, which could be obtained in moderate yields when homoleptic Ln(AlMe4)3 were treated with two equivalents of K[NSiMe3(Ar)]. PMID- 26418666 TI - Adjunctive Non-Surgical Therapy of Inflamed Periodontal Pockets During Maintenance Therapy Using Diode Laser: A Randomized Clinical Trial. AB - BACKGROUND: Numerous studies have documented the clinical outcomes of laser therapy for untreated periodontitis, but very few have reported on lasers treating inflamed pockets during maintenance therapy. The aim of this study is to compare the effectiveness of scaling and root planing (SRP) plus the adjunctive use of diode laser therapy to SRP alone on changes in the clinical parameters of disease and on the gingival crevicular fluid (GCF) inflammatory mediator interleukin-1beta (IL-1beta) in patients receiving regular periodontal maintenance therapy. METHODS: This single-masked and randomized, controlled, prospective study includes 22 patients receiving regular periodontal maintenance therapy who had one or more periodontal sites with a probing depth (PD) >= 5 mm with bleeding on probing (BOP). Fifty-six sites were treated with SRP and adjunctive laser therapy (SRP + L). Fifty-eight sites were treated with SRP alone. Clinical parameters, including PD, clinical attachment level (CAL), and BOP, and GCF IL-1beta levels were measured immediately before treatment (baseline) and 3 months after treatment. RESULTS: Sites treated with SRP + L and SRP alone resulted in statistically significant reductions in PD and BOP and gains in CAL. These changes were not significantly different between the two therapies. Similarly, differences in GCF IL-1beta levels between SRP + L and SRP alone were not statistically significant. CONCLUSION: In periodontal maintenance patients, SRP + L did not enhance clinical outcomes compared to SRP alone in the treatment of inflamed sites with >= 5 mm PD. PMID- 26418667 TI - Comparative modeling of exposure to airborne nanoparticles released by consumer spray products. AB - Consumer exposure to sprays containing nano-objects is a continuing concern as a potential health hazard. One potential hazard has been formulated in the overload hypothesis. It describes a volume fraction of the macrophages that is occupied by deposited nanoparticles that leads to reduced macrophage mobility. Subsequent chronic inflammation may then lead to severe health consequences including cancer. To calculate lung deposition of spherical particles, the Multiple-Path Particle Dosimetry (MPPD) model (ARA, Albuquerque, NM) provides different kinds of lung models and age settings. Using the MPPD v 2.11 software, we modeled several consumer-related exposure scenarios. Different body orientations and age groups were investigated. Moreover, a number of materials representing different densities were used, and the exposure calculated using MPPD is compared to the hazard derived from the overload hypothesis. Conditions leading to macrophage overload were found for exposures to high particle doses for prolonged times and repeated exposure. Such conditions are unlikely in the context of regular consumer exposure. The overload hypothesis assumes the particles to be inert and biopersistent, a condition that currently lacks a clear regulatory definition and is valid only for a few selected materials. Furthermore, because of material specific effects and the possibility of surface adsorption of hazardous chemicals, nano-objects in propellant sprays remain of concern for consumer health. PMID- 26418668 TI - Children (10-12 years age) of women with epilepsy have lower intelligence, attention and memory: Observations from a prospective cohort case control study. AB - OBJECTIVE: To compare the cognitive outcome of children of women with epilepsy (CWE) with matched controls (CWO). METHODS: CWE (10-12 years) under follow up in Kerala Registry of Epilepsy and Pregnancy (n=190) were evaluated with WISC-IV, Trail Making Test (TMT), Rey Auditory Verbal Learning Test (RAVLT) and compared with age and sex matched children of women without epilepsy - CWO (n=149) drawn from schools in the same region. The dosage was expressed as prescribed daily dose/daily-defined dose (PDD/DDD) ratio in order to make comparisons. RESULTS: The Full Scale IQ of CWE (77.9 +/- 14.6) was 8.5 points lower than that of CWO (86.4 +/- 13.4), which was statistically significant (p=0.001). They performed lower on TMT Part A & B and RAVLT. The FSIQ mean +/- SD; PDD/DDD ratio and number of monotherapy exposure for different anti-epileptic drugs were phenobarbital: (74.5 +/- 14; 1.1 +/- 0.8; 22), valproate: (82.8 +/- 12.4; 0.3 +/- 0.1; 36), carbamazepine: (82.2 +/- 13.9; 0.6 +/- 0.3; 41), phenytoin: (82.6 +/- 13.5; 0.8+/ 0.3; 11). The FSIQ for those exposed to phenobarbital was significantly (p=0.01) lower than others. The significant predictors of FSIQ differed at lower and higher ends of its spectrum. These predictors were low body mass index and low maternal education for FSIQ<80 and low maternal education, low maternal IQ and high anti-epileptic drug dosage for FSIQ<86. High anti-epileptic drug dosage, low maternal IQ, and low paternal education were the predictors for FSIQ<92. SIGNIFICANCE: The IQ, attention and memory were significantly lower for 10-12 year old CWE when compared to CWO. The important predictors of low FSIQ were antiepileptic drug dosage, maternal IQ, and parental education. PMID- 26418669 TI - Prenatal Organophosphorus Pesticide Exposure and Child Neurodevelopment at 24 Months: An Analysis of Four Birth Cohorts. AB - BACKGROUND: Organophosphorus pesticides (OPs) are used in agriculture worldwide. Residential use was common in the United States before 2001. OBJECTIVES: We conducted a pooled analysis of four birth cohorts (children's centers; n = 936) to evaluate associations of prenatal exposure to OPs with child development at 24 months. METHODS: Using general linear models, we computed site-specific and pooled estimates of the association of total dialkyl (SigmaDAP), diethyl (SigmaDEP), and dimethylphosphate (SigmaDMP) metabolite concentrations in maternal prenatal urine with mental and psychomotor development indices (MDI/PDI) and evaluated heterogeneity by children's center, race/ethnicity, and PON1 genotype. RESULTS: There was significant heterogeneity in the center-specific estimates of association for SigmaDAP and SigmaDMP and the MDI (p = 0.09, and p = 0.05, respectively), as well as heterogeneity in the race/ethnicity-specific estimates for SigmaDAP (p = 0.06) and SigmaDMP (p = 0.02) and the MDI. Strong MDI associations in the CHAMACOS population per 10-fold increase in SigmaDAP (beta = 4.17; 95% CI: -7.00, -1.33) and SigmaDMP (beta = -3.64; 95% CI: -5.97, -1.32) were influential, as were associations among Hispanics (beta per 10-fold increase in SigmaDAP = -2.91; 95% CI: -4.71, -1.12). We generally found stronger negative associations of SigmaDAP and SigmaDEP with the 24-month MDI for carriers of the 192Q PON1 allele, particularly among blacks and Hispanics. CONCLUSIONS: Data pooling was complicated by center-related differences in subject characteristics, eligibility, and changes in regulations governing residential use of OPs during the study periods. Pooled summary estimates of prenatal exposure to OPs and neurodevelopment should be interpreted with caution because of significant heterogeneity in associations by center, race/ethnicity, and PON1 genotype. Subgroups with unique exposure profiles or susceptibilities may be at higher risk for adverse neurodevelopment following prenatal exposure. CITATION: Engel SM, Bradman A, Wolff MS, Rauh VA, Harley KG, Yang JH, Hoepner LA, Barr DB, Yolton K, Vedar MG, Xu Y, Hornung RW, Wetmur JG, Chen J, Holland NT, Perera FP, Whyatt RM, Lanphear BP, Eskenazi B. 2016. Prenatal organophosphorus pesticide exposure and child neurodevelopment at 24 months: an analysis of four birth cohorts. Environ Health Perspect 124:822-830; http://dx.doi.org/10.1289/ehp.1409474. PMID- 26418670 TI - Short interferon and ribavirin treatment for HCV genotype 2 or 3 infection: NORDynamIC trial and real-life experience. AB - OBJECTIVE: Interferon-free therapy for hepatitis C virus (HCV) infection is costly, and therefore patients with advanced fibrosis are prioritized. Although coupled with considerable side effects, a large proportion of genotype 2/3 infected patients achieve a sustained virological response (SVR) following interferon-based therapy. The present study evaluates experimental clinical trial and verifying real-life data with the aim of identifying patients with a high likelihood of favorable outcome following short interferon-based treatment. MATERIAL AND METHODS: The impact of established response predictors, e.g. age, ITPA and IL28B genetic variants, IP-10, liver histopathology and early viral kinetics on outcome was evaluated among HCV genotype 2/3 infected patients enrolled in the NORDynamIC trial. Similarly outcome was evaluated among Finnish and Swedish real-life genotype 2/3 infected patients treated for 12-16 weeks in accordance with national guidelines. RESULTS: In the NORDynamIC trial, age < 40 years or achieving HCV RNA < 1000 IU/mL day 7 were highly predictive of favorable outcome following 12 weeks therapy. Among 255 Finnish real-life patients below the age of 40 years treated for 12 weeks with interferon and ribavirin, 87% of HCV genotype 2 and 79% of genotype 3 infected patients achieved SVR, and among 117 Swedish real-life patients treated for 12-16 weeks, 97% of HCV genotype 2 and 94% of genotype 3 infected achieved SVR. CONCLUSIONS: Short interferon-based therapy offers a high likelihood of achieving SVR for selected HCV genotype 2/3 infected patients, and is an acceptable option given that a thorough discussion of the side effects is provided prior to initiation. PMID- 26418671 TI - Ontogenetic changes in contribution of calcium sensitization and calcium entry to blood pressure maintenance of Wistar-Kyoto and spontaneously hypertensive rats. AB - BACKGROUND: Altered calcium sensitization (mediated by RhoA/Rho-kinase pathway) and enhanced calcium entry through L-type voltage-dependent calcium channels (L VDCCs) participate in blood pressure (BP) maintenance of adult spontaneously hypertensive rats (SHRs). This study aimed to evaluate ontogenetic changes of these two pathways in BP control of SHR and Wistar-Kyoto (WKY) aged 3, 5, 7, 13, 26 and 42 weeks. METHODS: BP response to acute administration of Rho-kinase inhibitor fasudil or L-VDCC blocker nifedipine and the expression of particular components of RhoA/Rho-kinase pathway were determined in young and adult animals. RESULTS: Fasudil-induced BP reduction was attenuated in young SHR compared with WKY, but was enhanced in adult SHR. In contrast, BP response to nifedipine was similar in 3-week-old SHR and WKY and it was augmented with age in SHR but not in WKY. Consequently, the ratio between fasudil-induced and nifedipine-induced BP changes was lower in all age groups of SHR compared with WKY. Fasudil effects on contractility of isolated arteries were attenuated in young but not in adult SHR. mRNA expression of selected Rho-GEFs (Arhgef1, Arhgef11 and Arhgef12) was decreased only in adult SHR, whereas p63RhoGEF and CPI-17 expression was reduced in both age groups of SHR. Active RhoA and phosphorylated CPI-17 were increased in adult but not in young SHR. CONCLUSION: The importance of RhoA/Rho-kinase pathway for BP/vascular tone control is attenuated in SHR from prehypertensive stages. Enhanced RhoA activation and/or CPI-17 phosphorylation might be counteracted by reduced expression of upstream activators of Rho-kinase (Rho GEFs) together with lower expression of CPI-17 (in downstream cascade of Rho kinase). PMID- 26418672 TI - pi-Conjugated Microporous Polymer Films: Designed Synthesis, Conducting Properties, and Photoenergy Conversions. AB - Conjugated microporous polymers are a unique class of polymers that combine extended pi-conjugation with inherent porosity. However, these polymers are synthesized through solution-phase reactions to yield insoluble and unprocessable solids, which preclude not only the evaluation of their conducting properties but also the fabrication of thin films for device implementation. Here, we report a strategy for the synthesis of thin films of pi-conjugated microporous polymers by designing thiophene-based electropolymerization at the solution-electrode interface. High-quality films are prepared on a large area of various electrodes, the film thickness is controllable, and the films are used for device fabrication. These films are outstanding hole conductors and, upon incorporation of fullerenes into the pores, function as highly efficient photoactive layers for energy conversions. Our film strategy may boost the applications in photocatalysis, energy storage, and optoelectronics. PMID- 26418674 TI - BRAF and RAS Mutations in Sporadic and Secondary Pyogenic Granuloma. AB - Pyogenic granuloma (PG) is a common benign vascular skin lesion presenting as a rapidly growing angiomatous papule. The pathogenesis of most sporadic PG and PG associated with port wine stains (PWS) remains elusive. We report that of 10 PG secondarily arisen on a PWS, 8 showed a BRAF c.1799T>A (p.(Val600Glu)) and 1 a NRAS c.182A>G (p.(Gln61Arg)) mutation. The GNAQ c.548G>A mutation was identified in the PG and in the respective underlying PWS, indicating that the PG originate from cells of the PWS. In contrast to PG, twelve papulonodular lesions, which had developed in the PWS of seven patients, showed a RAS and BRAF wildtype status. In sporadic PG we identified the BRAF c.1799T>A mutation in 3/25, a BRAF c.1391G>A mutation in 1/25 and a KRAS c.37G>C mutation in 1/25. Mutation-specific immunohistochemical detection of BRAF p.(Val600Glu) confirmed endothelial cells as carriers of the mutation in secondary and sporadic PG. Our study identifies the BRAF c.1799T>A mutation as a major driver mutation in the pathogenesis of particularly secondary PG. These data shed light on the hitherto undetermined genetic basis of PG and classify PG as a benign neoplasm.Journal of Investigative Dermatology accepted article preview online, 29 September 2015. doi:10.1038/jid.2015.376. PMID- 26418677 TI - The Impact of a 24 Month Housing First Intervention on Participants' Body Mass Index and Waist Circumference: Results from the At Home / Chez Soi Toronto Site Randomized Controlled Trial. AB - Research suggests that individuals experiencing homelessness have high rates of overweight and obesity. Unhealthy weights and homelessness are both associated with increased risk of poor health and mortality. Using longitudinal data from 575 participants at the Toronto site of the At Home/Chez Soi randomized controlled trial, we investigate the impact of receiving a Housing First intervention on the Body Mass Index (BMI) and waist circumference of participants with moderate and high needs for mental health support services. The ANCOVA results indicate that the intervention resulted in no significant change in BMI or waist circumference from baseline to 24 months. The findings suggest a need for a better understanding of factors contributing to overweight, obesity, and high waist circumference in populations who have histories of housing precarity and experience low-income in tandem with other concerns such as mental illness and addictions. TRIAL REGISTRATION: International Standard Randomized Control Trial Number Register ISRCTN42520374. PMID- 26418679 TI - Adding Spice to the Slog: Humanities in Medical Training. AB - Writing from personal experience, physician and author Danielle Ofri asks what evidence is needed to justify trying to humanize medical training via the power of literature. PMID- 26418678 TI - Do Instructional Videos on Sputum Submission Result in Increased Tuberculosis Case Detection? A Randomized Controlled Trial. AB - OBJECTIVE: We examined the effect of an instructional video about the production of diagnostic sputum on case detection of tuberculosis (TB), and evaluated the acceptance of the video. TRIAL DESIGN: Randomized controlled trial. METHODS: We prepared a culturally adapted instructional video for sputum submission. We analyzed 200 presumptive TB cases coughing for more than two weeks who attended the outpatient department of the governmental Municipal Hospital in Mwananyamala (Dar es Salaam, Tanzania). They were randomly assigned to either receive instructions on sputum submission using the video before submission (intervention group, n = 100) or standard of care (control group, n = 100). Sputum samples were examined for volume, quality and presence of acid-fast bacilli by experienced laboratory technicians blinded to study groups. RESULTS: Median age was 39.1 years (interquartile range 37.0-50.0); 94 (47%) were females, 106 (53%) were males, and 49 (24.5%) were HIV-infected. We found that the instructional video intervention was associated with detection of a higher proportion of microscopically confirmed cases (56%, 95% confidence interval [95% CI] 45.7 65.9%, sputum smear positive patients in the intervention group versus 23%, 95% CI 15.2-32.5%, in the control group, p <0.0001), an increase in volume of specimen defined as a volume >=3ml (78%, 95% CI 68.6-85.7%, versus 45%, 95% CI 35.0-55.3%, p <0.0001), and specimens less likely to be salivary (14%, 95% CI 7.9 22.4%, versus 39%, 95% CI 29.4-49.3%, p = 0.0001). Older age, but not the HIV status or sex, modified the effectiveness of the intervention by improving it positively. When asked how well the video instructions were understood, the majority of patients in the intervention group reported to have understood the video instructions well (97%). Most of the patients thought the video would be useful in the cultural setting of Tanzania (92%). CONCLUSIONS: Sputum submission instructional videos increased the yield of tuberculosis cases through better quality of sputum samples. If confirmed in larger studies, instructional videos may have a substantial effect on the case yield using sputum microscopy and also molecular tests. This low-cost strategy should be considered as part of the efforts to control TB in resource-limited settings. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201504001098231. PMID- 26418680 TI - Infant Growth and the Occurrence of Developmental Defects of Enamel in 12-Year Olds. AB - BACKGROUND/AIMS: To investigate the association between birth weight and infant growth during the first year of life and the occurrence of developmental defects of enamel (DDE) in permanent dentition. METHODS: A random sample of 668 12-year old students was recruited from a birth cohort. Permanent incisors and first molars were clinically examined for DDE using the modified FDI (DDE) index. Multivariable negative binomial regression was used to examine the association of growth trajectory (five categories) from birth to 12 months with the occurrence of DDE (any defects, demarcated opacities, diffuse opacities, and hypoplasia) in the permanent dentition. RESULTS: The response rate was 76.9% (n = 514). Four hundred and eighty-five children had complete records of growth- and health related data. In the unadjusted model, infants who had birth weights closer to the WHO average and rapid growth were more likely to have 'demarcated opacities' (p < 0.05), and the first 3 months of life was the 'critical period' to develop 'demarcated opacities' in permanent dentition. However, after adjusting for the confounders (gender, gestational age, mode of delivery, type of feeding, parental education, and health status), significant association with the occurrence of 'demarcated opacities' (p < 0.05) remained only for the children of trajectory V (heavier birth weights and rapid growth); no 'critical period' was found to be significantly associated with DDE. CONCLUSIONS: Infants with heavy birth weight and rapid growth during the first year of life were more vulnerable to the occurrence of DDE in terms of demarcated opacities in their permanent dentition. PMID- 26418682 TI - Introduction to the Special Issue. PMID- 26418681 TI - Multi-Etiological Nature of Tuberculosis-Like Lesions in Condemned Pigs at the Slaughterhouse. AB - Tuberculosis-like lesions (TBL) in pigs have been associated with microorganisms other than mycobacteria. In this work a histopathological and microbiological evaluation of TBL in pigs is shown. A total of 352 samples belonging to 171 pigs totally condemned at slaughterhouse due to generalized TBL were sampled and selected for analysis. Pyogranulomatous (56.2%) and granulomatous lesions (20.2%) were observed in all analysed organs. Most of the granulomas observed in both lymph nodes and lungs belonged to more advanced stages of development (stages III and IV) whereas in the liver and the spleen most of lesions belonged to intermediate stages (stages II and III). Different microorganisms were simultaneously detected from TBL in the 42.7% of the animals. Mycobacterium tuberculosis complex (MTC) (38%), coryneform bacteria (40.3%) and streptococci (28.1%) were the main groups of microorganisms detected after bacteriological analysis, with Trueperella pyogenes and Streptococcus suis as the most frequently isolated species. Mycobacteria belonging to MTC were the most frequently detected pathogens in granulomatous and pyogranulomatous lesions in submandibular lymph nodes (32.7%) and coryneform bacteria were the microorganisms more frequently isolated from lungs (25.9%) and spleen samples (37.2%). These results may provide new insights into the pathogenesis and diagnosis of this pathology. The importance of coryneform bacteria and streptococci in such processes must be evaluated in future studies. PMID- 26418683 TI - Superficial Head and Neck Anatomy for Dermatologic Surgery: Critical Concepts. AB - BACKGROUND: Thorough understanding of head and neck anatomy is useful and necessary for dermatologic surgery. OBJECTIVE: To highlight pertinent head and neck anatomic structures that are encountered during dermatologic surgery and correlate these with common surgical problems. METHODS: Important anatomic structures and regional cutaneous anatomy are discussed and illustrated. RESULTS: Several important anatomic structures exist within the head and neck that can influence surgical outcomes. CONCLUSION: Anatomic knowledge is helpful to the dermatologic surgeon to optimize reconstructive outcomes. PMID- 26418684 TI - Secondary Intention Healing and Purse-String Closures. AB - BACKGROUND: Secondary intention healing and purse-string closures are simple but extremely useful methods for the dermatologic surgeon to master. OBJECTIVE: To review the literature on the use of these two types of closures and offer recommendations based on our collective experiences. METHODS: A literature review was performed using the terms "secondary intention healing" and "purse-string closure." The evidence and recommendations from the resultant references were summarized in our article and synthesized with our own experiences. RESULTS: Twenty-eight sources were cited overall with fifteen related to secondary intention healing, eleven pertaining to purse-string closures, and one randomized, blind clinical trial comparing the two modalities. CONCLUSION: The art of dermatologic surgery often requires a tailored approach to the patient and can involve a spectrum of closures, from the simplest to most complex. This variety not only provides more reconstruction options, but are also necessary to keep dermatologic surgery cost-effective. Certain locations or situations are more amenable for these two types of closures than others. The use of secondary intention healing, either alone or in conjunction with purse-string closures, should be in every dermatologic surgeon's armamentarium. PMID- 26418685 TI - Suture Products and Techniques: What to Use, Where, and Why. AB - BACKGROUND: There are an increasing number of wound closure materials and suturing techniques described in the dermatologic and surgery literature. A dermatologic surgeon's familiarity with these materials and techniques is important to supplement his or her already established practices and improve surgical outcomes. OBJECTIVE: To perform a thorough literature review of wound closure materials (sutures, tissue adhesives, surgical tape, and staples) and suturing techniques and to outline how and when to use them. MATERIALS AND METHODS: A literature review was conducted using PubMed and other online search engines. Keywords searched included suture, tissue adhesive, tissue glue, surgical tape, staples, dermatologic suturing, and suturing techniques. RESULTS: Numerous articles outline the utility of various sutures, surgical adhesives, surgical tape, and staples in dermatologic surgery. In addition, there are various articles describing classic and novel suturing techniques along with their specific uses in cutaneous surgery. CONCLUSION: Numerous factors must be considered when choosing a wound closure material and suturing technique. These include wound tension, desire for wound edge eversion/inversion, desired hemostasis, repair type, patient's ability to care for the wound and return for suture removal, skin integrity, and wound location. Careful consideration of these factors and proper execution of suturing techniques can lead to excellent cosmetic results. PMID- 26418686 TI - Undermining and Hemostasis. AB - BACKGROUND: Undermining and hemostasis are basic surgical techniques that can have a significant impact on surgical outcomes. OBJECTIVE: To review the mechanisms and techniques of undermining and hemostasis, with an emphasis on the advantages and limitations of each modality. MATERIALS AND METHODS: The PubMed database was searched for articles with the keywords "undermining," "hemostasis," and "electrosurgery." RESULTS: Whether performing blunt, sharp, or electrosurgical techniques, undermining at the appropriate depth and width is necessary for tissue movement during closures. Both excessive and inadequate undermining can compromise surgical healing. Surgical hemostasis techniques include pressure, suture ligation, topical hemostatic agents, and electrosurgery. Dermatologic surgeons should select the appropriate amount and type of hemostasis for each procedure. Particular care should be taken in performing electrosurgery, given the potential for complications. CONCLUSION: Understanding and optimizing hemostasis and undermining will allow dermatologic surgeons to execute complex closures with minimal complications. PMID- 26418687 TI - Optimizing Design and Execution of Linear Reconstructions on the Face. AB - BACKGROUND: Linear closure (LC) is the most common reconstructive design for cutaneous defects. Successful performance of a LC is dependent on both appropriate surgical planning and technical execution. OBJECTIVE: To review the design and execution of LCs on the face. MATERIALS AND METHODS: A systematic evaluation of LCs is provided to guide a logical approach for the repair of cutaneous facial defects. RESULTS: Reproducibly excellent aesthetic and functional results may be achieved with strategies that reduce incisional tension, preserve free margin position, and restore skin contour. Cosmetic unit borders and relaxed skin tension lines may be used to further camouflage facial scars. A comprehensive knowledge of facial anatomy, biomechanical properties of the skin, and incisional tension vectors facilitates correct preoperative planning and intraoperative technique. CONCLUSION: Proper design and execution of LCs allow for enhanced cosmesis and permit the cutaneous surgeon to progress to more technically advanced surgical procedures such as cutaneous flaps. PMID- 26418688 TI - Nonfacial Reconstructive Techniques. AB - BACKGROUND: Nonfacial reconstruction encompasses several anatomic locations with varied topography, skin quality, and tissue reservoirs. Patients also have varied mobility concerns and wound care needs when managing wounds in these areas. MATERIALS AND METHODS: This article includes techniques and approaches from the dermatologic surgery, plastic surgery, and podiatric surgery literature in an effort to provide a comprehensive overview of the subject matter. RESULTS AND CONCLUSION: Functionally and esthetically acceptable reconstructions of nonfacial surgical wounds can be accomplished with a variety of techniques based on the characteristics of the wound and unique needs of the patient. PMID- 26418689 TI - Advancement Flaps. AB - BACKGROUND: Advancement flaps are random-pattern flaps frequently used in the reconstruction of surgical defects on the face after the removal of skin cancer. Proper design and meticulous execution is crucial in achieving reproducible esthetic results. OBJECTIVE: To review the design and execution of advancement flaps in facial reconstruction. MATERIALS AND METHODS: A review of the literature on the use of advancement flaps in facial reconstruction was performed and curated with the authors' experience. CONCLUSION: Many factors come into play when using local flaps to reconstruct surgical defects on the face. Close attention must be given to the tissue surrounding the surgical defect and any free margin in the area. Designing the flap closure lines along cosmetic unit junctions and or relaxed skin tension lines, preserving both the form and function of the surrounding structures, and using excellent surgical techniques during the closure will all together help in providing reproducibly outstanding results. PMID- 26418690 TI - Rotation Flaps-Principles and Locations. AB - BACKGROUND: The rotation flap is a classic method of tissue rearrangement. It is a simple yet effective tool for recruiting tissue from areas of laxity and redirecting vectors of tension to reconstruct wounds not amenable to primary closure. OBJECTIVE: This article presents the basic design principles and specific applications of the rotation flap in dermatologic surgery. METHODS: A Medline search of articles describing rotation flaps published prior to April 1, 2015 was performed, and several prominent texts in dermatologic surgery were reviewed. RESULTS: Information gathered from the above sources is combined with the clinical experience of the author and editors to present surgeons with a guide for planning and executing various rotation flaps. CONCLUSIONS: Mastering the technique of the rotation flap will allow a surgeon to repair a wide variety of cutaneous defects. PMID- 26418691 TI - Transposition Flaps: Principles and Locations. AB - BACKGROUND: Transposition flaps are frequently used to repair defects of the head and neck after tumor extirpation with Mohs micrographic surgery. OBJECTIVE: To review the basic principles underlying single-stage transposition flaps and also their utility relative to location on the head and neck. MATERIALS AND METHODS: A review of the literature on transposition flaps was performed with specific reference to the principles of single-stage transposition flaps, including rhomboid flaps and their variations, multilobed flaps, and the locations where transposition flaps are frequently executed on the head and neck. RESULTS: Numerous articles have been written with regard to the techniques for designing and executing transposition flaps. The primary advantages of transposition flaps include less undermining as compared to large sliding flaps and the superior ability to displace tension away from the defect and from free margins. Optimal cosmesis with these flaps can be achieved with appropriate sizing of flaps (or lobes), appropriate undermining, and meticulous suturing. CONCLUSION: The versatility of transposition flaps makes them optimal for repair of defects on the head and neck and utilization of the outlined key principles and techniques aid in achieving an aesthetic result. PMID- 26418692 TI - Best Reconstructive Techniques: Improving the Final Scar. AB - BACKGROUND: Abnormal cutaneous scarring is due to excessive growth of fibrous tissue in response to traumatic or iatrogenic tissue injury and may adversely affect a patient's quality of life. The success of a surgical procedure is often tied to the cosmetic outcome. OBJECTIVES: To provide a synthesis of available literature and provide guidelines for the management of cutaneous scars with laser technology. MATERIALS AND METHODS: An extensive review of the medical literature was conducted to assess optimal treatment methods for cutaneous scars based on scar features, location, and skin phototype. Recommendations and algorithms were described based on this review and our current clinical experience. RESULTS: Combination therapy with laser and non-laser modalities offers a safe and effective method for scar revision. CONCLUSION: Armed with an understanding of relevant available therapies, skillful dermatologic surgeons may drastically improve the final scar cosmesis. This review discusses current and emerging laser therapy approaches to scar revision. PMID- 26418695 TI - Simulation design for microalgal protein optimization. AB - A method for designing the operating parameters (surface light intensity, operating temperature and agitation rate) was proposed for microalgal protein production. Furthermore, quadratic model was established and validated (R(2) > 0.90) with experimental data. It was recorded that temperature and agitation rate were slightly interdependent. The microalgal protein performance could be estimated using the simulated experimental setup and procedure developed in this study. The results also showed a holistic approach for opening a new avenue on simulation design for microalgal protein optimization. PMID- 26418693 TI - KCa3.1-Dependent Hyperpolarization Enhances Intracellular Ca2+ Signaling Induced by fMLF in Differentiated U937 Cells. AB - Formylated peptides are chemotactic agents generated by pathogens. The most relevant peptide is fMLF (formyl-Met-Leu-Phe) which participates in several immune functions, such as chemotaxis, phagocytosis, cytokine release and generation of reactive oxygen species. In macrophages fMLF-dependent responses are dependent on both, an increase in intracellular calcium concentration and on a hyperpolarization of the membrane potential. However, the molecular entity underlying this hyperpolarization remains unknown and it is not clear whether changes in membrane potential are linked to the increase in intracellular Ca2+. In this study, differentiated U937 cells, as a macrophage-like cell model, was used to characterize the fMLF response using electrophysiological and Ca2+ imaging techniques. We demonstrate by means of pharmacological and molecular biology tools that fMLF induces a Ca2+-dependent hyperpolarization via activation of the K+ channel KCa3.1 and thus, enhancing fMLF-induced intracellular Ca2+ increase through an amplification of the driving force for Ca2+ entry. Consequently, enhanced Ca2+ influx would in turn lengthen the hyperpolarization, operating as a positive feedback mechanism for fMLF-induced Ca2+ signaling. PMID- 26418696 TI - Fiber-optic Monitoring of Spinal Cord Hemodynamics in Experimental Aortic Occlusion. AB - BACKGROUND: Spinal cord ischemia occurs frequently during thoracic aneurysm repair. Current methods based on electrophysiology techniques to detect ischemia are indirect, non-specific, and temporally slow. In this article, the authors report the testing of a spinal cord blood flow and oxygenation monitor, based on diffuse correlation and optical spectroscopies, during aortic occlusion in a sheep model. METHODS: Testing was carried out in 16 Dorset sheep. Sensitivity in detecting spinal cord blood flow and oxygenation changes during aortic occlusion, pharmacologically induced hypotension and hypertension, and physiologically induced hypoxia/hypercarbia was assessed. Accuracy of the diffuse correlation spectroscopy measurements was determined via comparison with microsphere blood flow measurements. Precision was assessed through repeated measurements in response to pharmacologic interventions. RESULTS: The fiber-optic probe can be placed percutaneously and is capable of continuously measuring spinal cord blood flow and oxygenation preoperatively, intraoperatively, and postoperatively. The device is sensitive to spinal cord blood flow and oxygenation changes associated with aortic occlusion, immediately detecting a decrease in blood flow (-65 +/- 32%; n = 32) and blood oxygenation (-17 +/- 13%, n = 11) in 100% of trials. Comparison of spinal cord blood flow measurements by the device with microsphere measurements led to a correlation of R = 0.49, P < 0.01, and the within-sheep coefficient of variation was 9.69%. Finally, diffuse correlation spectroscopy is temporally more sensitive to ischemic interventions than motor-evoked potentials. CONCLUSION: The first-generation spinal fiber-optic monitoring device offers a novel and potentially important step forward in the monitoring of spinal cord ischemia. PMID- 26418697 TI - Comparative Effectiveness of Calabadion and Sugammadex to Reverse Non depolarizing Neuromuscular-blocking Agents. AB - BACKGROUND: The authors evaluated the comparative effectiveness of calabadion 2 to reverse non-depolarizing neuromuscular-blocking agents (NMBAs) by binding and inactivation. METHODS: The dose-response relationship of drugs to reverse vecuronium-, rocuronium-, and cisatracurium-induced neuromuscular block (NMB) was evaluated in vitro (competition binding assays and urine analysis), ex vivo (n = 34; phrenic nerve hemidiaphragm preparation), and in vivo (n = 108; quadriceps femoris muscle of the rat). Cumulative dose-response curves of calabadions, neostigmine, or sugammadex were created ex vivo at a steady-state deep NMB. In living rats, the authors studied the dose-response relationship of the test drugs to reverse deep block under physiologic conditions, and they measured the amount of calabadion 2 excreted in the urine. RESULTS: In vitro experiments showed that calabadion 2 binds rocuronium with 89 times the affinity of sugammadex (Ka = 3.4 * 10 M and Ka = 3.8 * 10 M-). The results of urine analysis (proton nuclear magnetic resonance), competition binding assays, and ex vivo study obtained in the absence of metabolic deactivation are in accordance with an 1:1 binding ratio of sugammadex and calabadion 2 toward rocuronium. In living rats, calabadion 2 dose-dependently and rapidly reversed all NMBAs tested. The molar potency of calabadion 2 to reverse vecuronium and rocuronium was higher compared with that of sugammadex. Calabadion 2 was eliminated renally and did not affect blood pressure or heart rate. CONCLUSIONS: Calabadion 2 reverses NMB induced by benzylisoquinolines and steroidal NMBAs in rats more effectively, i.e., faster than sugammadex. Calabadion 2 is eliminated in the urine and well tolerated in rats. PMID- 26418698 TI - Survival after Perioperative Cardiopulmonary Resuscitation: Providing an Evidence Base for Ethical Management of Do-not-resuscitate Orders. AB - Automatic suspension of do-not-resuscitate (DNR) orders during general anesthesia does not sufficiently address a patient's right to self-determination and is a practice still observed among anesthesiologists today. To provide an evidence base for ethical management of DNR orders during anesthesia and surgery, the authors performed a systematic review of the literature to quantify the survival after perioperative cardiopulmonary resuscitation (CPR). Results show that the probability of surviving perioperative CPR ranged from 32.0 to 55.7% when measured within the first 24 h after arrest with a neurologically favorable outcome expectancy between 45.3 and 66.8% at follow-up, which suggests a viable survival of approximately 25%. Because CPR generally proves successful in less than 15% of out-of-hospital cardiac arrests, the altered outcome probabilities that the conditions in the operating room bring on warrant reevaluation of DNR orders during the perioperative period. By preoperatively communicating the evidence to patients, they can make better informed decisions while reducing the level of moral distress that anesthesiologists may experience when certain patients decide to retain their DNR orders. PMID- 26418699 TI - Evaluation of Vancomycin Prediction Methods Based on Estimated Creatinine Clearance or Trough Levels. AB - BACKGROUND: The aim of this study was to investigate whether vancomycin clearance (CLva) can be adequately predicted with CLva prediction methods. Additionally, other covariates influencing the CLva were investigated and predictivity of monitoring of only trough levels to 24-hour area under the curve (AUC24) was evaluated. METHODS: Routine vancomycin plasma levels were measured with a fluorescence polarization immunoassay. Pharmacokinetic (PK) parameters of individual patients, that is, CLva and volume of distribution, were determined with maximum a posteriori Bayesian estimation. CLva was calculated with the 3 prediction methods, which are solely based on creatinine clearance (CLcr) estimated with Cockcroft and Gault formula and was compared with the calculated CLva with maximum a posteriori Bayesian estimation. Prediction errors were calculated. Correlations between CLva and CLcr, creatinine, age, weight, sex, and neutropenia were made. Furthermore, correlations between trough levels and AUC24 were evaluated. RESULTS: A total of 171 patients were included. Prediction errors and absolute prediction errors of the 3 methods ranged from 28% to 80% and 39% to 83%, respectively. In the multivariate analysis, CLva was significantly associated with CLcr, creatinine, age, weight, sex, and neutropenia. Linear correlation between AUC24 and trough levels was R(2) 0.38. CONCLUSIONS: Large prediction errors make the CLva algorithms based on estimated plasma CLcr unsuitable for use in patient care. Additionally, other factors, which are not accounted for in the current algorithms, influence the CLva individually. Owing to low association of AUC24 and trough levels, the AUC24 cannot be predicted with through levels. For a reliable AUC24 guided vancomycin dosing, therapeutic drug monitoring is necessary. PMID- 26418700 TI - Risperidone and Venlafaxine Metabolic Ratios Strongly Predict a CYP2D6 Poor Metabolizing Genotype. AB - PURPOSE: To investigate the predictive value of the risperidone and venlafaxine metabolic ratios and CYP2D6 genotype. METHODS: The determination of risperidone, 9-hydroxyrisperidone, and venlafaxine, O-desmethylvenlafaxine, N desmethylvenlafaxine and CYP2D6 genotype was performed in 425 and 491 patients, respectively. The receiver operator characteristic method and the area under the receiver operator characteristic curve were used to illustrate the predictive value of risperidone metabolic ratio for the individual CYP2D6 genotype. To evaluate the proposed cutoff levels of >1 to identify individuals with a poor CYP2D6 genotype, the sensitivity, specificity, positive predictive values, and negative predictive values were calculated. RESULTS: Area under the receiver operator characteristic curve to predict poor metabolizers for risperidone/9 hydroxyrisperidone and N-desmethylvenlafaxine/O-desmethylvenlafaxine ratios was 93% and 99%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value (confidence interval) of a risperidone/9 hydroxyrisperidone ratio >1 to predict a CYP2D6 poor metabolizer genotype were 91% (76%-97%), 86% (83%-89%), 35% (26%-46%), and 99% (97%-100%), respectively. The corresponding measures for N-desmethylvenlafaxine/O-desmethylvenlafaxine were 93% (76%-97%), 87% (83%-89%), 40% (32%-51%), and 99% (98%-100%). CONCLUSIONS: Risperidone/9-hydroxyrisperidone and N-desmethylvenlafaxine/O desmethylvenlafaxine metabolic ratios >1 strongly predict individuals with poor metabolizer genotype, which could guide psychotropic drug treatment to avoid adverse drug reactions and to increase their therapeutic efficacy in patients prescribed these drugs. PMID- 26418701 TI - Nuclear Factor of Activated T Cells-Regulated Gene Expression as Predictive Biomarker of Personal Response to Calcineurin Inhibitors. AB - BACKGROUND: Calcineurin inhibitors (CNIs) represent the most widely used immunosuppressive agents in kidney transplantation. Both CNIs show a narrow therapeutic window; thus, monitoring is necessary to balance efficacy and toxicity. Several approaches have been undertaken to measure the biological effects of CNI-based immunosuppression. METHODS: A quantitative analysis of gene expression was established to calculate the functional effects of calcineurin inhibition, the assessment of nuclear factor of activated T cells (NFAT) regulated gene expression. This assay is based on the quantitative analysis of interleukin-2, interferon-gamma, and granulocyte macrophage colony-stimulating factor gene expression in whole blood samples collected at the time cyclosporine A/tacrolimus troughs (C0) and 2 hours after oral uptake (C2). RESULTS: In this comprehensive review, analytical aspects of the assay and also clinical benefits and limitations are presented and discussed. Several observational studies underline the beneficial effect of NFAT-regulated gene expression as biomarker of personal response on CNI therapy, especially in infectious complications, malignancies, and acute rejection episodes. Data are more comprehensive in cyclosporine A compared with tacrolimus therapy. However, results on prospective interventional studies are sparse. A randomized controlled study evaluating the opportunity for NFAT-guided immunosuppression is ongoing. CONCLUSIONS: NFAT regulated gene expression is a promising biomarker in CNI therapy concerning infectious complications, malignancies, and acute rejection. Prospective interventional studies and randomized controlled studies are ongoing to confirm the encouraging results. PMID- 26418703 TI - Graft-Derived Cell-Free DNA as a Marker of Transplant Graft Injury. AB - Although short-term success after solid organ transplantation is good, long-term graft and recipient survival are both not satisfactory. Despite therapeutic drug monitoring (TDM) of immunosuppressive drugs (ISDs), both excessive and insufficient immunosuppression still do occur. There is a need for new biomarkers that, when combined with TDM, can be used to provide more effective and less toxic, personalized immunosuppression to improve long-term survival. Currently used methods are insufficient to rapidly, cost-effectively, and directly interrogate graft integrity after solid organ transplantation. However, because organ transplants are also genome transplants, measurement of graft-derived circulating cell-free DNA (GcfDNA) has shown promise as a way to improve both graft and recipient outcomes after solid organ transplantation through the early detection of severe graft injury, enabling an early intervention. A newly developed droplet digital polymerase chain reaction (ddPCR) method has advantages over expensive high-throughput sequencing methods to rapidly quantify GcfDNA percentages and absolute amounts. This procedure does not require donor DNA and therefore can be applied to any organ donor/recipient pair. The droplet digital polymerase chain reaction method allows for the early, sensitive, specific, and cost-effective direct assessment of graft integrity and can be used to define individual responses to ISDs including the minimal ISD exposures necessary to prevent rejection. This is especially important in patients undergoing ISD switches due to ISD toxicity, infections, or malignancies. Although prospective, multicenter clinical trials in liver, heart, and kidney transplantation have not been completed, early results suggest that GcfDNA can be combined with TDM to guide changes in immunosuppression to provide more effective, and less toxic treatment. Personalized immunosuppression will shift emphasis in transplantation from reaction to prevention and could improve outcome at lower health care costs. PMID- 26418702 TI - Biomarkers in Transplantation--Proteomics and Metabolomics. AB - Modern multianalyte "omics" technologies allow for the identification of molecular signatures that confer significantly more information than measurement of a single parameter as typically used in current medical diagnostics. Proteomics and metabolomics bioanalytical assays capture a large set of proteins and metabolites in body fluids, cells, or tissues and, complementing genomics, assess the phenome. Proteomics and metabolomics contribute to the development of novel predictive clinical biomarkers in transplantation in 2 ways: they can be used to generate a diagnostic fingerprint or they can be used to discover individual proteins and metabolites of diagnostic potential. Much fewer metabolomics than proteomics biomarker studies in transplant patients have been reported, and, in contrast to proteomics discovery studies, new lead metabolite markers have yet to emerge. Most clinical proteomics studies have been discovery studies. Several of these studies have assessed diagnostic sensitivity and specificity. Nevertheless, none of these newly discovered protein biomarkers have yet been implemented in clinical decision making in transplantation. The currently most advanced markers discovered in proteomics studies in transplant patients are the chemokines CXCL-9 and CXCL-10, which have successfully been validated in larger multicenter trials in kidney transplant patients. These chemokines can be measured using standard immunoassay platforms, which should facilitate clinical implementation. Based on the published evidence, it is reasonable to expect that these chemokine markers can help guiding and individualizing immunosuppressive regimens, may be able to predict acute and chronic T-cell-mediated and antibody-mediated rejection, and may be useful tools for risk stratification of kidney transplant patients. PMID- 26418704 TI - Analytical Aspects of the Implementation of Biomarkers in Clinical Transplantation. AB - In response to the urgent need for new reliable biomarkers to complement the guidance of the immunosuppressive therapy, a huge number of biomarker candidates to be implemented in clinical practice have been introduced to the transplant community. This includes a diverse range of molecules with very different molecular weights, chemical and physical properties, ex vivo stabilities, in vivo kinetic behaviors, and levels of similarity to other molecules, etc. In addition, a large body of different analytical techniques and assay protocols can be used to measure biomarkers. Sometimes, a complex software-based data evaluation is a prerequisite for appropriate interpretation of the results and for their reporting. Although some analytical procedures are of great value for research purposes, they may be too complex for implementation in a clinical setting. Whereas the proof of "fitness for purpose" is appropriate for validation of biomarker assays used in exploratory drug development studies, a higher level of analytical validation must be achieved and eventually advanced analytical performance might be necessary before diagnostic application in transplantation medicine. A high level of consistency of results between laboratories and between methods (if applicable) should be obtained and maintained to make biomarkers effective instruments in support of therapeutic decisions. This overview focuses on preanalytical and analytical aspects to be considered for the implementation of new biomarkers for adjusting immunosuppression in a clinical setting and highlights critical points to be addressed on the way to make them suitable as diagnostic tools. These include but are not limited to appropriate method validation, standardization, education, automation, and commercialization. PMID- 26418705 TI - Long noncoding RNAs in human disease: emerging mechanisms and therapeutic strategies. PMID- 26418706 TI - [In Process Citation]. PMID- 26418707 TI - [In Process Citation]. PMID- 26418708 TI - [In Process Citation]. PMID- 26418709 TI - [Malign hypertension]. PMID- 26418710 TI - [The fasting regime prior to anaesthesia]. AB - In modern anaesthesiology fasting preoperatively has been introduced in order to minimise the incidence of aspiration to the lungs. Since the 1990's studies have confirmed the safety of the current fasting regime of six hours for solids and two hours for fluids. By allowing the intake of carbohydrate-rich fluids until two hours before induction of anaesthesia, it has been shown that the negative effects of fasting such as thirst, starvation and anxiety are minimised. In the future, ultrasound technology might be used to assess the gastric volume prior to induction of anaesthesia. PMID- 26418711 TI - [Pharmacological risk differentiation of patients in psychiatry can be used in medication review]. AB - Based on demands from The Danish Healthcare Quality Programme (DDKM), that all patients must have a medical review performed, a risk scoring tool has been developed. The purpose of this tool is to differentiate patients in three groups to assure that necessary resources are allocated to patients having most complications. The scoring tool has now been used in more than 5,000 adult psychiatric patients in Central Denmark Region. The intent of allocating the necessary resources most effectively, when performing a medical review, seems to have been attained. PMID- 26418712 TI - [Pontocerebellar hypoplasia is a rare cause of floppy infant syndrome]. AB - The hypotone neonate, floppy infant, often proves to be a diagnostic challenge, as the causes of floppy infant syndrome are many and often rare. In this case story a floppy girl was diagnosed with the rare, autosomal recessive disease pontocerebellar hypoplasia type I. The tests for the most common causes of floppy infant syndrome showed nothing abnormal, but an array comparative genomic hybridization test gave information of loss of heterozygosity. This helped to narrow the list of plausible diagnoses and eventually led to the diagnosis of pontocerebellar hypoplasia type I. PMID- 26418713 TI - [Bullous pemphigoid may also be seen in children]. AB - Bullous pemphigoid is most commonly seen in elderly patients, however, an increasing number of cases in children have been reported. In this article we present a case of a five-month-old boy who was admitted with red annular plaques over his entire body and vesicles and bullae on his hands and feet. Correct diagnosis was made by skin biopsy and after reviewing the literature high dose oral steroids therapy (1 mg/kg/day) was successfully initiated. The cause of the disease remains unknown. With correct treatment the prognosis is good with documented ten-year follow-up without relapse. PMID- 26418714 TI - [A historical perspective of Ebola virus]. AB - The 2014 Ebola fever outbreak was the first of its kind in West Africa. This epidemic, affecting multiple countries, by far exceeded any previous outbreak in case counts and geographical spread. But Ebola viruses are not new to Africa, as they have occurred in epidemic proportion in the central part of the continent since 1976. The objective of this article is to compare previous outbreaks with the ongoing epidemic in an effort to identify some of the factors which have con tributed to the size and scope of the existing outbreak. PMID- 26418715 TI - [Work-related MRSA CC398 carrier status had serious psychosocial consequences to a farmer]. AB - We describe a case of work-related methicillin-resistant Staphylococcus aureus (MRSA) CC398 carrier status in a 33-year-old male working at a pig farm. The case was complicated since his pregnant girlfriend had also MRSA CC398 carrier status. Although she remained without contact to farm animals the MRSA could not be eradicated. Conflicting messages from healthcare workers complicated the case and the psychological consequences became traumatizing to the patient and caused sick leave and psychotherapy. This case shows the importance of better information of MRSA CC398-positive patients in the future, especially for MRSA-exposed occupations. PMID- 26418716 TI - [Varicella zoster meningitis with associated vasculitis in a two-month post partum woman]. AB - Reactivation of varicella zoster virus occurs more often in the elderly or immunocompromised persons. During pregnancy increased anti-inflammatory cellular response promotes tolerance of foetal antigens. Post-partum a shift towards an inflammatory response may facilitate the reoccurrence of latent infections. Varicella-associated vasculitis can lead to ischaemic lesions in the brain. We report a case of a two-month post-partum woman suffering from headache, nausea, vomiting, photophobia and radicular pain with varicella zoster meningitis and an ischaemic lesion in the splenium of corpus callosum. PMID- 26418717 TI - The Quality of Surgical and Pneumonia Care in Minority-Serving and Racially Integrated Hospitals. AB - OBJECTIVE: To explore the association between quality of care for surgical and pneumonia patients and the racial/ethnic composition of hospitals' patients. DATA SOURCE: Our primary data were surgical and pneumonia processes of care indicators from the 2012 Medicare Hospital Compare Data. We merged this data with information from the 2011 American Hospital Association Annual Survey of Hospitals. We computed the racial and ethnic composition of hospital patients using 2008 data from the Healthcare Costs and Utilization Project. STUDY DESIGN: The sample included 1,198 acute care general hospitals from 11 states: AZ, CA, FL, IA, MA, MD, NC, NJ, NY, WA, and WI. We compared quality across minority serving, racially integrated, and majority-white hospitals using unconditional quantile regression models controlling for hospital and market characteristics. PRINCIPAL FINDINGS: We found quality differences between the lowest performing minority-serving, racially integrated, and majority-white hospitals. As we moved from 10th to 90th quantile, the quality differences between hospitals by patients' racial composition disappeared. In other words, the best minority serving and racially integrated hospitals performed as well as the best majority hospitals. CONCLUSIONS: Efforts to improve quality of care for patients in minority-serving and racially integrated hospitals should focus on the lowest performers. PMID- 26418718 TI - Phospho-kinase profile of colorectal tumors guides in the selection of multi kinase inhibitors. AB - Protein kinases play a central role in the oncogenesis of colorectal tumors and are attractive druggable targets. Detection of activated kinases within a tumor could open avenues for drug selection and optimization of new kinase inhibitors. By using a phosphokinase arrays with human colorectal tumors we identified activated kinases, including the Epidermal Growth Factor Receptor (EGFR), components of the PI3K/mTOR pathway (AKT and S6), and STAT, among others. A pharmacological screening with kinase inhibitors against these proteins helped us to identify a new kinase inhibitor, termed EC-70124 that showed the highest anti proliferative activity in cell lines. EC-70124 also inhibited cell migration and biochemical experiments demonstrated its effect targeting the PI3K/mTOR pathway. This drug also arrested cells at G2/M and induced apoptosis. Experiments in combination with standard chemotherapy used in the clinical setting indicated a synergistic effect. EC-70124 also reduced tumor growth in vivo and inhibited pS6 in the implanted tumors. In conclusion, by studying the kinase profile of colorectal tumors, we identified relevant activated pathways, and a new multi kinase compound with significant antitumor properties. PMID- 26418719 TI - PDGF activation in PGDS-positive arachnoid cells induces meningioma formation in mice promoting tumor progression in combination with Nf2 and Cdkn2ab loss. AB - The role of PDGF-B and its receptor in meningeal tumorigenesis is not clear. We investigated the role of PDGF-B in mouse meningioma development by generating autocrine stimulation of the arachnoid through the platelet-derived growth factor receptor (PDGFR) using the RCAStv-a system. To specifically target arachnoid cells, the cells of origin of meningioma, we generated the PGDStv-a mouse (Prostaglandin D synthase). Forced expression of PDGF-B in arachnoid cells in vivo induced the formation of Grade I meningiomas in 27% of mice by 8 months of age. In vitro, PDGF-B overexpression in PGDS-positive arachnoid cells lead to increased proliferation.We found a correlation of PDGFR-B expression and NF2 inactivation in a cohort of human meningiomas, and we showed that, in mice, Nf2 loss and PDGF over-expression in arachnoid cells induced meningioma malignant transformation, with 40% of Grade II meningiomas. In these mice, additional loss of Cdkn2ab resulted in a higher incidence of malignant meningiomas with 60% of Grade II and 30% of Grade III meningiomas. These data suggest that chronic autocrine PDGF signaling can promote proliferation of arachnoid cells and is potentially sufficient to induce meningiomagenesis. Loss of Nf2 and Cdkn2ab have synergistic effects with PDGF-B overexpression promoting meningioma malignant transformation. PMID- 26418720 TI - A nanostructure of functional targeting epirubicin liposomes dually modified with aminophenyl glucose and cyclic pentapeptide used for brain glioblastoma treatment. AB - The objectives of the present study were to develop functional targeting epirubicin liposomes for transferring drugs across the blood-brain barrier (BBB), treating glioblastoma, and disabling neovascularization. The studies were performed on glioblastoma cells in vitro and on glioblastoma-bearing mice. The results showed that the constructed liposomes had a high encapsulation efficiency for drugs (>95%), suitable particle size (109 nm), and less leakage in the blood component-containing system; were significantly able to be transported across the BBB; and exhibited efficacies in killing glioblastoma cells and in destroying glioblastoma neovasculature in vitro and in glioblastoma-bearing mice. The action mechanisms of functional targeting epirubicin liposomes correlated with the following features: the long circulation in the blood system, the ability to be transported across the BBB via glucose transporter-1, and the targeting effects on glioblastoma cells and on the endothelial cells of the glioblastoma neovasculature via the integrin beta3 receptor. In conclusion, functional targeting epirubicin liposomes could be used as a potential therapy for treating brain glioblastoma and disabling neovascularization in brain glioblastomas. PMID- 26418722 TI - Type I collagen fibrils: an inducer of invadosomes. PMID- 26418723 TI - Osteogenic differentiation of adipose derived stem cells on high and low aspect ratio micropatterns. AB - Adipose derived stem cells (ADSCs) were cultured on collagen-silk fibroin films with microchannel and micropillar patterns to investigate the effects of cell morphology changes on osteogenic differentiation. Channel and pillar micropatterned films were prepared from collagen type I and silk fibroin. While higher ADSC proliferation profiles were obtained on micropillar blend film, microchannel blend films, however, caused twice higher aspect ratio and effective orientation of cells. Alkaline phosphatase activity of ADSCs was several times higher on microchannel surface when the measured activities were normalized to cell number. Effective deposition of collagen type I and mineral by the cells were observed for patterned and unpatterned films, and these extracellular matrix components were oriented along the axis of the microchannels. In conclusion, the use of collagen-fibroin blend film with microchannel topography increased the aspect ratio and alignment of cells significantly, and was also effective in the differentiation of ADSCs into osteogenic lineage. PMID- 26418721 TI - IL-13 receptor alpha2 is a negative prognostic factor in human lung cancer and stimulates lung cancer growth in mice. AB - IL-13 receptor subunit alpha-2 (IL13Ralpha2) is associated with poor prognosis in some cancers. However, the role of IL13Ralpha2 in lung cancer remains unknown. We showed that IL13Ralpha2 overexpression was associated with late stages of disease progression and shorter disease-free survival (DFS) as well as overall survival (OS) in resected lung cancer patients. IL13Ralpha2 promoted the migration, invasion and anoikis resistance of lung cancer cells in vitro. Silencing of IL13Ralpha2 in lung cancer cells decreased invasion in vitro and lung metastasis in vivo. IL13Ralpha2 activated phosphatidylinositol 3 kinase (PI3K), Akt, and transcriptional coactivator with PDZ-binding motif (TAZ). Inhibition of PI3K attenuated activation of TAZ and its downstream target genes by IL13Ralpha2. We suggest that inhibition of IL13Ralpha2 is a potential therapeutic approach in lung cancer. PMID- 26418724 TI - Atomic Layer Deposition from Dissolved Precursors. AB - We establish a novel thin film deposition technique by transferring the principles of atomic layer deposition (ALD) known with gaseous precursors toward precursors dissolved in a liquid. An established ALD reaction behaves similarly when performed from solutions. "Solution ALD" (sALD) can coat deep pores in a conformal manner. sALD offers novel opportunities by overcoming the need for volatile and thermally robust precursors. We establish a MgO sALD procedure based on the hydrolysis of a Grignard reagent. PMID- 26418725 TI - Saturation-transfer effects and longitudinal relaxation times of (31) P metabolites in fibroglandular breast tissue at 7T. AB - PURPOSE: To investigate longitudinal relaxation times and saturation-transfer effects of phosphorous metabolites in breast fibroglandular tissue in vivo with (31) P MR spectroscopy at 7T. METHODS: Progressive saturation with adiabatic half passage excitation was used to determine T1 values of (31) P metabolites in a group of six healthy volunteers. Saturation-transfer experiments were performed in seven healthy volunteers by saturating at 0 ppm and 10 ppm with sinc-Gaussian pulses (90 ms; 10-ms pulse interval; B1 = 17 MUT) prior to excitation. Localization was performed by surface coils and one-dimensional chemical shift imaging. Data were analyzed via spectral fitting with the JMRUI software package, and T1 values were obtained by fitting the data to the signal equation. RESULTS: The determined longitudinal relaxation time values at 7T were as follows: phosphoethanolamine, 4.0 +/- 0.2 s; phosphocholine, 1.8 +/- 0.2 s; inorganic phosphate, 6.1 +/- 0.1 s; phosphodiesters, glycerophosphatidylethanolamine plus glycerophosphocholine, 2.1 +/- 0.1, and glycerophosphatidylethanolamine, 1.5 +/- 0.1s; gamma-ATP, 2.1 +/- 0.1 s; and alpha-ATP, 2.0 +/- 0.1 s. Saturation-transfer measurements with saturation pulses at 0 ppm showed a significant signal reduction in the phosphodiester 2-3 ppm range, whereas the gamma-ATP signal at 2.5 ppm was not affected significantly. CONCLUSION: Longitudinal relaxation times of phosphorous metabolites in fibroglandular tissue revealed relatively low T1 values for phosphodiesters. Saturation-transfer measurements showed that the phosphodiester signals were the only signals that were affected significantly, possibly indicating the presence of mobile phospholipids. Magn Reson Med 76:402 407, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26418726 TI - Synthesis and controlled growth of osmium nanoparticles by electron irradiation. AB - We have synthesised osmium nanoparticles of defined size (1.5-50 nm) on a B- and S-doped turbostratic graphitic structure by electron-beam irradiation of an organometallic osmium complex encapsulated in self-spreading polymer micelles, and characterised them by transmission electron microscopy (TEM), high-resolution TEM (HRTEM), and atomic force microscopy (AFM) on the same grid. Oxidation of the osmium nanoparticles after exposure to air was detected by X-ray photoelectron spectroscopy (XPS). PMID- 26418727 TI - Investigation of the Gas-Phase Photolysis and Temperature-Dependent OH Reaction Kinetics of 4-Hydroxy-2-butanone. AB - Hydroxyketones are key secondary reaction products in the atmospheric oxidation of volatile organic compounds (VOCs). The fate of these oxygenated VOCs is however poorly understood and scarcely taken into account in atmospheric chemistry modeling. In this work, a combined investigation of the photolysis and temperature-dependent OH radical reaction of 4-hydroxy-2-butanone (4H2B) is presented. The objective was to evaluate the importance of the photolysis process relative to OH oxidation in the atmospheric degradation of 4H2B. A photolysis lifetime of about 26 days was estimated with an effective quantum yield of 0.08. For the first time, the occurrence of a Norrish II mechanism was hypothesized following the observation of acetone among photolysis products. The OH reaction rate coefficient follows the Arrhenius trend (280-358 K) and could be modeled through the following expression: k4H2B(T) = (1.26 +/- 0.40) * 10(-12) * exp((398 +/- 87)/T) in cm(3) molecule(-1) s(-1). An atmospheric lifetime of 2.4 days regarding the OH + 4H2B reaction was evaluated, indicating that OH oxidation is by far the major degradation channel. The present work underlines the need for further studies on the atmospheric fate of oxygenated VOCs. PMID- 26418728 TI - Sugar recognition and protein-protein interaction of mammalian lectins conferring diverse functions. AB - Recent advances in structural analyses of mammalian lectins reveal atomic-level details of their fine specificities toward diverse endogenous and exogenous glycans. Local variations on a common scaffold can enable certain lectins to recognize complex carbohydrate ligands including branched glycans and O glycosylated peptides. Simultaneous recognition of both glycan and the aglycon moieties enhances the affinity and specificity of lectins such as CLEC-2 and PILRalpha. Attention has been paid to the roles of galectin and RegIII family of proteins in protein-protein interactions involved in critical biological functions including signal transduction and bactericidal pore formation. PMID- 26418730 TI - A Clinical Case of an SRY-Positive Intersex/Hermaphrodite Holstein Cattle. AB - A single-born, 15-month-old Holstein cattle, diagnosed as hermaphrodite, was investigated for estrous cycle, hormonal profiles, karyotype, presence of SRY, as well as anatomopathological and histological aspects. Normal continuous estrous cycles and basal testosterone levels were reported. Necropsy showed the presence of a female genital tract that mismatched a vulvar opening and a male pelvic urethra continued within a penis. Moreover, we observed islands of seminiferous tubules with the presence of germline cells, 2 pampiniform plexi, the corpus cavernosum, the penile urethra, the corpus spongiosum and the glans. Cytogenetic analyses of the blood cells showed an XX karyotype, while the molecular analyses revealed the presence of the SRY gene in several tissues, including blood. This is the first report in the scientific literature of an SRY-positive hermaphrodite Holstein cattle with continuous ovarian cycles. PMID- 26418729 TI - BOLD Response Selective to Flow-Motion in Very Young Infants. AB - In adults, motion perception is mediated by an extensive network of occipital, parietal, temporal, and insular cortical areas. Little is known about the neural substrate of visual motion in infants, although behavioural studies suggest that motion perception is rudimentary at birth and matures steadily over the first few years. Here, by measuring Blood Oxygenated Level Dependent (BOLD) responses to flow versus random-motion stimuli, we demonstrate that the major cortical areas serving motion processing in adults are operative by 7 wk of age. Resting-state correlations demonstrate adult-like functional connectivity between the motion selective associative areas, but not between primary cortex and temporo-occipital and posterior-insular cortices. Taken together, the results suggest that the development of motion perception may be limited by slow maturation of the subcortical input and of the cortico-cortical connections. In addition they support the existence of independent input to primary (V1) and temporo-occipital (V5/MT+) cortices very early in life. PMID- 26418731 TI - Hearing threshold distribution and effect of screening in a population-based German sample. AB - OBJECTIVE: To establish the status of hearing in adults in Germany and the effects of screening for noise, tinnitus, ear diseases, and general health on the distribution of hearing threshold levels (HTL) DESIGN: A cross-sectional epidemiological study conducted between 2010 and 2012 in two middle-sized cities. STUDY SAMPLE: A total of 1903 adults aged 18 to 97 years from a randomized sample drawn from the local registration offices and stratified for age and gender. RESULTS: Dispersion and distribution of HTL data observed in the population-based sample are well in line with international results. However, median HTL tend to be better than in most recent international studies. Screening for "otological normality" improves the median HTL overall by 3 dB in males and 1 dB in females. This effect is strongly age-dependent in males and far less pronounced in females. While by and large HTL medians of females in the screened sample meet the values expected by ISO 7029:2000, HTL medians of males in middle and higher age cohorts are better than expected, especially in the frequencies above 2 kHz. CONCLUSIONS: This study supports international findings that in males, the age related decrease in hearing sensitivity at high frequencies is smaller than described by ISO 7029:2000. PMID- 26418732 TI - End-Stage Kidney Disease Due to Fibrillary Glomerulonephritis and Immunotactoid Glomerulopathy - Outcomes in 66 Consecutive ANZDATA Registry Cases. AB - BACKGROUND: Fibrillary glomerulonephritis (FGN) and immunotactoid glomerulopathy (IG) are uncommon and characterised by non-amyloid fibrillary glomerular deposits. The aim of this study was to investigate characteristics and outcomes of patients undergoing renal replacement therapy (RRT) for end-stage kidney disease (ESKD) secondary to FGN and IG. METHODS: All ESKD patients who commenced RRT in Australia and New Zealand 1 January 1990 to 31 December 2010 were included. Outcomes were assessed by Kaplan-Meier, multivariate logistic regression analysis and multivariable Cox proportional-hazards survival analysis. RESULTS: Of 45,216 individuals with ESKD, 55 (0.12%) had FGN and 11 (0.02%) had IG. The median survival of FGN patients on dialysis (5.63 years, 95% CI 3.31 7.96) was not significantly different from patients with other ESKD causes (median 4.01 years, 95% CI 4.34-4.47; log-rank 1.32, p = 0.25), but was significantly longer than that of IG patients (median 2.93 years, 95% CI 0.00 6.17; log-rank 4.8, p = 0.03). Thirteen (24%) FGN patients received 13 renal allografts, 4 (36%) IG patients received 4 renal-allografts and 11,528 (26%) other ESKD patients received 12,278 renal-allografts. FGN patients experienced comparable outcomes to other ESKD patients for both 10-year patient survival (100 vs. 84%, p = 0.93) and renal-allograft survival (67 vs. 76%, p = 0.06). For IG, the median follow-up was 3.66 years with 75% patient survival and 100% renal allograft survival. One (8%) FGN patient and 1 (25%) IG patient experienced recurrent FGN and IG respectively in their allograft. CONCLUSION: Patients with FGN have comparable dialysis and renal transplant outcomes to patients with other causes of ESKD. IG patients have inferior survival on dialysis, although renal transplant outcomes are acceptable. Disease recurrence in renal-allografts was low for both FGN and IG. PMID- 26418733 TI - E-Waste and Harm to Vulnerable Populations: A Growing Global Problem. AB - BACKGROUND: Electronic waste (e-waste) is produced in staggering quantities, estimated globally to be 41.8 million tonnes in 2014. Informal e-waste recycling is a source of much-needed income in many low- to middle-income countries. However, its handling and disposal in underdeveloped countries is often unsafe and leads to contaminated environments. Rudimentary and uncontrolled processing methods often result in substantial harmful chemical exposures among vulnerable populations, including women and children. E-waste hazards have not yet received the attention they deserve in research and public health agendas. OBJECTIVES: We provide an overview of the scale and health risks. We review international efforts concerned with environmental hazards, especially affecting children, as a preface to presenting next steps in addressing health issues stemming from the global e-waste problem. DISCUSSION: The e-waste problem has been building for decades. Increased observation of adverse health effects from e-waste sites calls for protecting human health and the environment from e-waste contamination. Even if e-waste exposure intervention and prevention efforts are implemented, legacy contamination will remain, necessitating increased awareness of e-waste as a major environmental health threat. CONCLUSION: Global, national, and local levels efforts must aim to create safe recycling operations that consider broad security issues for people who rely on e-waste processing for survival. Paramount to these efforts is reducing pregnant women and children's e-waste exposures to mitigate harmful health effects. With human environmental health in mind, novel dismantling methods and remediation technologies and intervention practices are needed to protect communities. CITATION: Heacock M, Kelly CB, Asante KA, Birnbaum LS, Bergman AL, Brune MN, Buka I, Carpenter DO, Chen A, Huo X, Kamel M, Landrigan PJ, Magalini F, Diaz-Barriga F, Neira M, Omar M, Pascale A, Ruchirawat M, Sly L, Sly PD, Van den Berg M, Suk WA. 2016. E-waste and harm to vulnerable populations: a growing global problem. Environ Health Perspect 124:550-555; http://dx.doi.org/10.1289/ehp.1509699. PMID- 26418734 TI - Di-N-Methylation of Anti-Gram-Positive Aminoglycoside-Derived Membrane Disruptors Improves Antimicrobial Potency and Broadens Spectrum to Gram-Negative Bacteria. AB - The effect of di-N-methylation of bacterial membrane disruptors derived from aminoglycosides (AGs) on antimicrobial activity is reported. Di-N-methylation of cationic amphiphiles derived from several diversely structured AGs resulted in a significant increase in hydrophobicity compared to the parent compounds that improved their interactions with membrane lipids. The modification led to an enhancement in antibacterial activity and a broader antimicrobial spectrum. While the parent compounds were either modestly active or inactive against Gram negative pathogens, the corresponding di-N-methylated compounds were potent against the tested Gram-negative as well as Gram-positive bacterial strains. The reported modification offers a robust strategy for the development of broad spectrum membrane-disrupting antibiotics for topical use. PMID- 26418735 TI - A recursive vesicle-based model protocell with a primitive model cell cycle. AB - Self-organized lipid structures (protocells) have been proposed as an intermediate between nonliving material and cellular life. Synthetic production of model protocells can demonstrate the potential processes by which living cells first arose. While we have previously described a giant vesicle (GV)-based model protocell in which amplification of DNA was linked to self-reproduction, the ability of a protocell to recursively self-proliferate for multiple generations has not been demonstrated. Here we show that newborn daughter GVs can be restored to the status of their parental GVs by pH-induced vesicular fusion of daughter GVs with conveyer GVs filled with depleted substrates. We describe a primitive model cell cycle comprising four discrete phases (ingestion, replication, maturity and division), each of which is selectively activated by a specific external stimulus. The production of recursive self-proliferating model protocells represents a step towards eventual production of model protocells that are able to mimic evolution. PMID- 26418736 TI - Combined Tin-Containing Fluoride Solution and CO2 Laser Treatment Reduces Enamel Erosion in vitro. AB - The aim of this in vitro study was to evaluate the effect of combined CO2 laser and tin-containing fluoride treatment on the formation and progression of enamel erosive lesions. Ninety-six human enamel samples were obtained, stored in thymol solution and, after surface polishing, randomly divided into 6 different surface treatment groups (n = 16 in each group) as follows: no treatment, control (C); one CO2 laser irradiation (L1); two CO2 laser irradiations (L2); daily application of fluoride solution (F); combined daily fluoride solution + one CO2 laser irradiation (L1F), and combined daily fluoride solution + two CO2 laser irradiations (L2F). Laser irradiation was performed at 0.3 J/cm2 (5 us/226 Hz/10.6 um) on day 1 (L1) and day 6 (L2). The fluoride solution contained AmF/NaF (500 ppm F), and SnCl2 (800 ppm Sn) at pH 4.5. After surface treatment the samples were submitted to an erosive cycling over 10 days, including immersion in citric acid (2 min/0.05 M/pH = 2.3) 6 times daily and storage in remineralization solution (>=1 h) between erosive attacks. At the end of each cycling day, the enamel surface loss (micrometers) was measured using a 3D laser profilometer. Data were statistically analyzed by means of a 2-level mixed effects model and linear contrasts (alpha = 0.05). Group F (-3.3 +/- 2.0 um) showed significantly lower enamel surface loss than groups C (-27.22 +/- 4.1 um), L1 (-18.3 +/- 4.4 um) and L2 (-16.3 +/- 5.3 um) but higher than L1F (-1.0 +/- 4.4 um) and L2F (1.4 +/- 3.2 um, p < 0.05). Under the conditions of this in vitro study, the tin containing fluoride solution caused 88% reduction of enamel surface loss, while its combination with CO2 laser irradiation at 0.3 J/cm2 hampered erosive loss almost completely. PMID- 26418739 TI - A Novel Iterative CT Reconstruction Approach Based on FBP Algorithm. AB - The Filtered Back-Projection (FBP) algorithm and its modified versions are the most important techniques for CT (Computerized tomography) reconstruction, however, it may produce aliasing degradation in the reconstructed images due to projection discretization. The general iterative reconstruction (IR) algorithms suffer from their heavy calculation burden and other drawbacks. In this paper, an iterative FBP approach is proposed to reduce the aliasing degradation. In the approach, the image reconstructed by FBP algorithm is treated as the intermediate image and projected along the original projection directions to produce the reprojection data. The difference between the original and reprojection data is filtered by a special digital filter, and then is reconstructed by FBP to produce a correction term. The correction term is added to the intermediate image to update it. This procedure can be performed iteratively to improve the reconstruction performance gradually until certain stopping criterion is satisfied. Some simulations and tests on real data show the proposed approach is better than FBP algorithm or some IR algorithms in term of some general image criteria. The calculation burden is several times that of FBP, which is much less than that of general IR algorithms and acceptable in the most situations. Therefore, the proposed algorithm has the potential applications in practical CT systems. PMID- 26418738 TI - A Survey of the ATP-Binding Cassette (ABC) Gene Superfamily in the Salmon Louse (Lepeophtheirus salmonis). AB - Salmon lice, Lepeophtheirus salmonis (Kroyer, 1837), are fish ectoparasites causing significant economic damage in the mariculture of Atlantic salmon, Salmo salar Linnaeus, 1758. The control of L. salmonis at fish farms relies to a large extent on treatment with anti-parasitic drugs. A problem related to chemical control is the potential for development of resistance, which in L. salmonis is documented for a number of drug classes including organophosphates, pyrethroids and avermectins. The ATP-binding cassette (ABC) gene superfamily is found in all biota and includes a range of drug efflux transporters that can confer drug resistance to cancers and pathogens. Furthermore, some ABC transporters are recognised to be involved in conferral of insecticide resistance. While a number of studies have investigated ABC transporters in L. salmonis, no systematic analysis of the ABC gene family exists for this species. This study presents a genome-wide survey of ABC genes in L. salmonis for which, ABC superfamily members were identified through homology searching of the L. salmonis genome. In addition, ABC proteins were identified in a reference transcriptome of the parasite generated by high-throughput RNA sequencing (RNA-seq) of a multi-stage RNA library. Searches of both genome and transcriptome allowed the identification of a total of 33 genes / transcripts coding for ABC proteins, of which 3 were represented only in the genome and 4 only in the transcriptome. Eighteen sequences were assigned to ABC subfamilies known to contain drug transporters, i.e. subfamilies B (4 sequences), C (11) and G (2). The results suggest that the ABC gene family of L. salmonis possesses fewer members than recorded for other arthropods. The present survey of the L. salmonis ABC gene superfamily will provide the basis for further research into potential roles of ABC transporters in the toxicity of salmon delousing agents and as potential mechanisms of drug resistance. PMID- 26418740 TI - Encountering a cartwheeling princess: relational psychoanalytic therapy of a child with attachment difficulties and ADHD. AB - OBJECTIVE: This study was conducted to demonstrate the use and process of contemporary relational psychoanalytic child therapy to address the interpersonal implications of attention deficit hyperactivity disorder and interlinked insecure attachment processes. METHOD: This therapy case study explicates the seven-month therapeutic process of a seven-year-old girl child highlighting the need for the child therapist to balance interventions aimed at both the internal and external world of the child. In essence, this account traces therapeutic scenarios of both painful and joyful material by means of paying close attention to the entwined transference and countertransference dynamics as well as creatively and authentically engaging with the child's way of making sense of self-states, others and even medication. RESULTS: Key features of this account include the foundational role of assessment and the compelling mediating role of a puppet as a co-therapist within the analytic space between psychotherapist and patient. CONCLUSION: Uniquely, as an inclusive psychoanalytic therapy, relational psychoanalytic child therapy reconfigures internal object relations of the child while simultaneously ushering changes into their familial and school context by utilising the mutuality established between the child and therapist as a central pivot. PMID- 26418741 TI - Controlling nonspecific trypsin cleavages in LC-MS/MS-based shotgun proteomics using optimized experimental conditions. AB - Trypsin has traditionally been used for enzymatic digestion during sample preparation in shotgun proteomics. The stringent specificity of trypsin is essential for accurate protein identification and quantification. But nonspecific trypsin cleavages are often observed in LC-MS/MS-based shotgun proteomics. To explore the extent of nonspecific trypsin cleavages, a series of biological systems including a standard protein mixture, Saccharomyces cerevisiae, human serum, human cancer cell lines and mouse brain were examined. We found that nonspecific trypsin cleavages commonly occurred in various trypsin digested samples with high frequency. To control these nonspecific trypsin cleavages, we optimized fundamental parameters during sample preparation with mouse brain homogenates. These parameters included denaturing agents and protein storage time, trypsin type, enzyme-to-substrate ratio, as well as protein concentration during digestion. The optimized experimental conditions significantly decreased the ratio of partially tryptic peptides in total identifications from 28.4% to 2.8%. Furthermore, the optimized digestion protocol was applied to the study of N glycoproteomics, and the proportions of partially tryptic peptides in enriched mixtures were also sharply reduced. Our work demonstrates the importance of controlling nonspecific trypsin cleavages in both shotgun proteomics and glycoproteomics and provides a better understanding and standardization for routine proteomics sample treatment. PMID- 26418737 TI - Evolution of Extensively Drug-Resistant Tuberculosis over Four Decades: Whole Genome Sequencing and Dating Analysis of Mycobacterium tuberculosis Isolates from KwaZulu-Natal. AB - BACKGROUND: The continued advance of antibiotic resistance threatens the treatment and control of many infectious diseases. This is exemplified by the largest global outbreak of extensively drug-resistant (XDR) tuberculosis (TB) identified in Tugela Ferry, KwaZulu-Natal, South Africa, in 2005 that continues today. It is unclear whether the emergence of XDR-TB in KwaZulu-Natal was due to recent inadequacies in TB control in conjunction with HIV or other factors. Understanding the origins of drug resistance in this fatal outbreak of XDR will inform the control and prevention of drug-resistant TB in other settings. In this study, we used whole genome sequencing and dating analysis to determine if XDR-TB had emerged recently or had ancient antecedents. METHODS AND FINDINGS: We performed whole genome sequencing and drug susceptibility testing on 337 clinical isolates of Mycobacterium tuberculosis collected in KwaZulu-Natal from 2008 to 2013, in addition to three historical isolates, collected from patients in the same province and including an isolate from the 2005 Tugela Ferry XDR outbreak, a multidrug-resistant (MDR) isolate from 1994, and a pansusceptible isolate from 1995. We utilized an array of whole genome comparative techniques to assess the relatedness among strains, to establish the order of acquisition of drug resistance mutations, including the timing of acquisitions leading to XDR-TB in the LAM4 spoligotype, and to calculate the number of independent evolutionary emergences of MDR and XDR. Our sequencing and analysis revealed a 50-member clone of XDR M. tuberculosis that was highly related to the Tugela Ferry XDR outbreak strain. We estimated that mutations conferring isoniazid and streptomycin resistance in this clone were acquired 50 y prior to the Tugela Ferry outbreak (katG S315T [isoniazid]; gidB 130 bp deletion [streptomycin]; 1957 [95% highest posterior density (HPD): 1937-1971]), with the subsequent emergence of MDR and XDR occurring 20 y (rpoB L452P [rifampicin]; pncA 1 bp insertion [pyrazinamide]; 1984 [95% HPD: 1974-1992]) and 10 y (rpoB D435G [rifampicin]; rrs 1400 [kanamycin]; gyrA A90V [ofloxacin]; 1995 [95% HPD: 1988-1999]) prior to the outbreak, respectively. We observed frequent de novo evolution of MDR and XDR, with 56 and nine independent evolutionary events, respectively. Isoniazid resistance evolved before rifampicin resistance 46 times, whereas rifampicin resistance evolved prior to isoniazid only twice. We identified additional putative compensatory mutations to rifampicin in this dataset. One major limitation of this study is that the conclusions with respect to ordering and timing of acquisition of mutations may not represent universal patterns of drug resistance emergence in other areas of the globe. CONCLUSIONS: In the first whole genome-based analysis of the emergence of drug resistance among clinical isolates of M. tuberculosis, we show that the ancestral precursor of the LAM4 XDR outbreak strain in Tugela Ferry gained mutations to first-line drugs at the beginning of the antibiotic era. Subsequent accumulation of stepwise resistance mutations, occurring over decades and prior to the explosion of HIV in this region, yielded MDR and XDR, permitting the emergence of compensatory mutations. Our results suggest that drug-resistant strains circulating today reflect not only vulnerabilities of current TB control efforts but also those that date back 50 y. In drug-resistant TB, isoniazid resistance was overwhelmingly the initial resistance mutation to be acquired, which would not be detected by current rapid molecular diagnostics employed in South Africa that assess only rifampicin resistance. PMID- 26418742 TI - Loss of Endometrial Plasticity in Recurrent Pregnancy Loss. AB - Menstruation drives cyclic activation of endometrial progenitor cells, tissue regeneration, and maturation of stromal cells, which differentiate into specialized decidual cells prior to and during pregnancy. Aberrant responsiveness of human endometrial stromal cells (HESCs) to deciduogenic cues is strongly associated with recurrent pregnancy loss (RPL), suggesting a defect in cellular maturation. MeDIP-seq analysis of HESCs did not reveal gross perturbations in CpG methylation in RPL cultures, although quantitative differences were observed in or near genes that are frequently deregulated in vivo. However, RPL was associated with a marked reduction in methylation of defined CA-rich motifs located throughout the genome but enriched near telomeres. Non-CpG methylation is a hallmark of cellular multipotency. Congruently, we demonstrate that RPL is associated with a deficiency in endometrial clonogenic cell populations. Loss of epigenetic stemness features also correlated with intragenic CpG hypomethylation and reduced expression of HMGB2, coding high mobility group protein 2. We show that knockdown of this sequence-independent chromatin protein in HESCs promotes senescence and impairs decidualization, exemplified by blunted time-dependent secretome changes. Our findings indicate that stem cell deficiency and accelerated stromal senescence limit the differentiation capacity of the endometrium and predispose for pregnancy failure. PMID- 26418743 TI - Determining composition of micron-scale protein deposits in neurodegenerative disease by spatially targeted optical microproteomics. AB - Spatially targeted optical microproteomics (STOMP) is a novel proteomics technique for interrogating micron-scale regions of interest (ROIs) in mammalian tissue, with no requirement for genetic manipulation. Methanol or formalin-fixed specimens are stained with fluorescent dyes or antibodies to visualize ROIs, then soaked in solutions containing the photo-tag: 4-benzoylbenzyl-glycyl hexahistidine. Confocal imaging along with two photon excitation are used to covalently couple photo-tags to all proteins within each ROI, to a resolution of 0.67 um in the xy-plane and 1.48 um axially. After tissue solubilization, photo tagged proteins are isolated and identified by mass spectrometry. As a test case, we examined amyloid plaques in an Alzheimer's disease (AD) mouse model and a post mortem AD case, confirming known plaque constituents and discovering new ones. STOMP can be applied to various biological samples including cell lines, primary cell cultures, ex vivo specimens, biopsy samples, and fixed post-mortem tissue. PMID- 26418744 TI - Extrinsic and intrinsic signals converge on the Runx1/CBFbeta transcription factor for nonpeptidergic nociceptor maturation. AB - The generation of diverse neuronal subtypes involves specification of neural progenitors and, subsequently, postmitotic neuronal differentiation, a relatively poorly understood process. Here, we describe a mechanism whereby the neurotrophic factor NGF and the transcription factor Runx1 coordinate postmitotic differentiation of nonpeptidergic nociceptors, a major nociceptor subtype. We show that the integrity of a Runx1/CBFbeta holocomplex is crucial for NGF dependent nonpeptidergic nociceptor maturation. NGF signals through the ERK/MAPK pathway to promote expression of Cbfb but not Runx1 prior to maturation of nonpeptidergic nociceptors. In contrast, transcriptional initiation of Runx1 in nonpeptidergic nociceptor precursors is dependent on the homeodomain transcription factor Islet1, which is largely dispensable for Cbfb expression. Thus, an NGF/TrkA-MAPK-CBFbeta pathway converges with Islet1-Runx1 signaling to promote Runx1/CBFbeta holocomplex formation and nonpeptidergic nociceptor maturation. Convergence of extrinsic and intrinsic signals to control heterodimeric transcription factor complex formation provides a robust mechanism for postmitotic neuronal subtype specification. PMID- 26418745 TI - FAM150A and FAM150B are activating ligands for anaplastic lymphoma kinase. AB - Aberrant activation of anaplastic lymphoma kinase (ALK) has been described in a range of human cancers, including non-small cell lung cancer and neuroblastoma (Hallberg and Palmer, 2013). Vertebrate ALK has been considered to be an orphan receptor and the identity of the ALK ligand(s) is a critical issue. Here we show that FAM150A and FAM150B are potent ligands for human ALK that bind to the extracellular domain of ALK and in addition to activation of wild-type ALK are able to drive 'superactivation' of activated ALK mutants from neuroblastoma. In conclusion, our data show that ALK is robustly activated by the FAM150A/B ligands and provide an opportunity to develop ALK-targeted therapies in situations where ALK is overexpressed/activated or mutated in the context of the full length receptor. PMID- 26418747 TI - Manganese(I)-Catalyzed C-H Aminocarbonylation of Heteroarenes. AB - A versatile manganese(I) catalyst was employed in C-H aminocarbonylation reactions of heteroarenes with aryl as well as with alkyl isocyanates using a removable directing group approach. Detailed experimental mechanistic studies were suggestive of an organometallic C-H manganesation step, followed by a rate determining migratory insertion. PMID- 26418746 TI - Enteric pathogens deploy cell cycle inhibiting factors to block the bactericidal activity of Perforin-2. AB - Perforin-2 (MPEG1) is an effector of the innate immune system that limits the proliferation and spread of medically relevant Gram-negative, -positive, and acid fast bacteria. We show here that a cullin-RING E3 ubiquitin ligase (CRL) complex containing cullin-1 and betaTrCP monoubiquitylates Perforin-2 in response to pathogen associated molecular patterns such as LPS. Ubiquitylation triggers a rapid redistribution of Perforin-2 and is essential for its bactericidal activity. Enteric pathogens such as Yersinia pseudotuberculosis and enteropathogenic Escherichia coli disarm host cells by injecting cell cycle inhibiting factors (Cifs) into mammalian cells to deamidate the ubiquitin-like protein NEDD8. Because CRL activity is dependent upon NEDD8, Cif blocks ubiquitin dependent trafficking of Perforin-2 and thus, its bactericidal activity. Collectively, these studies further underscore the biological significance of Perforin-2 and elucidate critical molecular events that culminate in Perforin-2 dependent killing of both intracellular and extracellular, cell-adherent bacteria. PMID- 26418748 TI - Changes in the gene expression of co-cultured human fibroblast cells and osteosarcoma cells: the role of microenvironment. AB - BACKGROUND: The progression of malignant tumors does not depend exclusively on the autonomous properties of cancer cells; it is also influenced by tumor stroma reactivity and is under strict microenvironmental control. By themselves, stromal cells are not malignant, and they maintain normal tissue structure and function. However, through intercellular interactions or by paracrine secretions from cancer cells, normal stromal cells acquire abnormal phenotypes that sustain cancer cell growth and tumor progression. In their dysfunctional state, fibroblast and immune cells produce chemokines and growth factors that stimulate cancer cell growth and invasion. In our previous work, we established an in vitro model based on a monolayer co-culture system of healthy human fibroblasts (HFs) and human osteosarcoma cells (the MG-63 cell line) that simulates the microenvironment of tumor cells and healthy cells. The coexistence between MG-63 cells and HFs allowed us to identify the YKL-40 protein as the main marker for verifying the influence of tumor cells grown in contact with healthy cells. METHODS: In this study, we evaluated the interactions of HFs and MG-63 cells in a transwell co-culture system over 24 h, 48 h, 72 h, and 96 h. We analyzed the contributions of these populations to the tumor microenvironment during cancer progression, as measured by multiple markers. We examined the effect of siRNA knockdown of YKL-40 by tracking the subsequent changes in gene expression within the co-culture. We validated the expression of several genes, focusing on those involved in cancer cell invasion, inflammatory responses, and angiogenesis: TNF alpha, IL-6, MMP-1, MMP-9, and VEGF. We compared the results to those from a transwell co-culture without the YKL-40 knockdown. RESULTS: In a pro-inflammatory environment promoted by TNF alpha and IL-6, siRNA knockdown of YKL-40 caused a down-regulation of VEGF and MMP-1 expression in HFs. CONCLUSIONS: These findings demonstrated that the tumor microenvironment has an influence on the gene expression of healthy surrounding tissues and on the process of tumorigenicity and it is emerging as attractive targets for therapeutic strategies. PMID- 26418749 TI - Flcn-deficient renal cells are tumorigenic and sensitive to mTOR suppression. AB - Deficiency of tumor suppressor FLCN leads to the activation of the mTOR signaling pathway in human BHD-associated renal cell carcinomas (RCC). We have previously developed a renal distal tubule-collecting duct-Henle's loop-specific Flcn knockout (KO) mouse model (Flcnflox/flox/Ksp-Cre). This mouse model can only survive for three weeks after birth due to the development of polycystic kidney and uremia. Whether these cystic solid hyperplasia changes seen in those KO mice are tumorigenic or malignant is unknown. In this study, we demonstrated that genetic disruption of Flcn in mouse kidney distal tubule cells could lead to tumorigenic transformation of these cells to develop allograft tumors with an aggressive histologic phenotype. Consistent with previous reports, we showed that the mTOR pathway plays an important role in the growth of these Flcn-deficient allograft and human UOK 257-1 xenograft tumors. We further demonstrated that the mTOR inhibitor, sirolimus, suppresses the tumor's growth, suggesting that mTOR inhibitors might be effective in control of FLCN-deficient RCC, especially in BHD renal tumorigenesis. PMID- 26418752 TI - Colonoscopic reduction of colo-colic intussusception in an adult with immunoglobulin A vasculitis (Henoch-Schonlein purpura). PMID- 26418751 TI - A strategy to combine pathway-targeted low toxicity drugs in ovarian cancer. AB - Serous Ovarian Cancers (SOC) are frequently resistant to programmed cell death. However, here we describe that these programmed death-resistant cells are nonetheless sensitive to agents that modulate autophagy. Cytotoxicity is not dependent upon apoptosis, necroptosis, or autophagy resolution. A screen of NCBI yielded more than one dozen FDA-approved agents displaying perturbed autophagy in ovarian cancer. The effects were maximized via combinatorial use of the agents that impinged upon distinct points of autophagy regulation. Autophagosome formation correlated with efficacy in vitro and the most cytotoxic two agents gave similar effects to a pentadrug combination that impinged upon five distinct modulators of autophagy. However, in a complex in vivo SOC system, the pentadrug combination outperformed the best two, leaving trace or no disease and with no evidence of systemic toxicity. Targeting the autophagy pathway in a multi-modal fashion might therefore offer a clinical option for treating recalcitrant SOC. PMID- 26418754 TI - Synthesis and Properties of C(2h)-Symmetric BN-Heteroacenes Tailored through Aromatic Central Cores. AB - The 2-fold successive electrophilic borylation on one aromatic central core led to a series of C(2h)-symmetric BN-heteroacenes in excellent yields. For the first time, we introduced trimethylsilyl (TMS) as either leaving group or oriented group for efficiently improving the preparation of BN-embedded polycyclic aromatic hydrocarbons (PAHs). The physical properties of the as-synthesized BN heteroacenes in either solid state or solution can be finely tuned through the position isomerization or the fused ring numbers of the aromatic central core. PMID- 26418753 TI - Biocompatibility of common polyimides with human endothelial cells for a cardiovascular microsensor. AB - The cardiovasculature is an emerging niche for polyimide microdevices, yet the biocompatibility of polyimides with human endothelial cells has not been reported in the literature. In this study, we have evaluated an experimental polyimide based pressure sensor for biological safety to determine its suitability for intravascular operation by using an in vitro model of human endothelium, following ISO 10993-5 protocols for extract tests and direct contact tests. First, SV-HCEC cells were incubated with extracts derived from common microfabrication polyimides utilized in the transducer (PMDA-ODA, BPDA-PPD, and a proprietary thermoplastic adhesive), and then labeled with selective probes to evaluate the effect of the polyimides on mitochondria and cell viability. Flow cytometry analysis showed that incubation of SV-HCECs with polyimide extracts resulted in no significant change in mitochondrial membrane potential (detected by JC-1) or apoptotic (annexin V) and necrotic (propidium iodide) cell death, when compared to incubation with extracts of high-density polyethylene (HDPE) and untreated cells used as negative controls. Second, primary human endothelial cells were incubated in direct contact with the completed sensor and then labeled with selective probes for live-dead analysis (calcein-AM, ethidium homodimer-1). Endothelial cells showed no loss of viability when compared to negative controls. Combined, the studies show no significant change in early markers of stress or more strict markers of viability in endothelial cells treated with the polyimides tested. We conclude that these common microfabrication polyimides and the derived sensor are not cytotoxic to human endothelial cells, the primary cell type that cardiovascular sensors will contact in vivo. PMID- 26418750 TI - Colorectal cancer-related mutant KRAS alleles function as positive regulators of autophagy. AB - The recent interest to modulate autophagy in cancer therapy has been hampered by the dual roles of this conserved catabolic process in cancer, highlighting the need for tailored approaches. Since RAS isoforms have been implicated in autophagy regulation and mutation of the KRAS oncogene is highly frequent in colorectal cancer (CRC), we questioned whether/how mutant KRAS alleles regulate autophagy in CRC and its implications. We established two original models, KRAS humanized yeast and KRAS-non-cancer colon cells and showed that expression of mutated KRAS up-regulates starvation-induced autophagy in both. Accordingly, KRAS down-regulation inhibited autophagy in CRC-derived cells harboring KRAS mutations. We further show that KRAS-induced autophagy proceeds via up-regulation of the MEK/ERK pathway in both colon models and that KRAS and autophagy contribute to CRC cell survival during starvation. Since KRAS inhibitors have proven difficult to develop, our results suggest using autophagy inhibitors as a combined/alternative therapeutic approach in CRCs with mutant KRAS. PMID- 26418755 TI - Decarboxylative Alkylcarboxylation of alpha,beta-Unsaturated Acids Enabled by Copper-Catalyzed Oxidative Coupling. AB - A facile and general method for copper-catalyzed decarboxylative alkylcarboxylation of cinnamic acids with dimethyl 2,2'-azobis(2 methylpropionate) has been developed. The scope and versatility of the reaction was demonstrated, and a broad range of substrates bearing electron-donating and withdrawing groups on the aromatic rings were all compatible with this reaction to provide desired beta,gamma-unsaturated esters in moderate to good yields. Moreover, alpha,beta-unsaturated acids with a carbonyl group on the gamma position of acrylic acids also smoothly proceeded to furnish the desired products in good yields. PMID- 26418756 TI - GNPAT variant is not associated with severe iron overload in Irish C282Y homozygotes. PMID- 26418758 TI - MicroRNAs as regulators of beta-cell function and dysfunction. AB - In the last decade, there has been an explosion in both the number of and knowledge about miRNAs associated with both type 1 and type 2 diabetes. Even though we are presently in the initial stages of understanding how this novel class of posttranscriptional regulators are involved in diabetes, recent studies have demonstrated that miRNAs are important regulators of the islet transcriptome, controlling apoptosis, differentiation and proliferation, as well as regulating unique islet and beta-cell functions and pathways such as insulin expression, processing and secretion. Furthermore, a large number of miRNAs have been linked to diabetogenic processes induced by elevated levels of glucose, free fatty acids and inflammatory cytokines. Thus, miRNAs are novel therapeutic targets with the potential of protecting the beta-cell, and there is proof of principle that miRNA antagonists, so-called antagomirs, are effective in vivo for other disorders. miRNAs are exported out of cells in exosomes, raising the intriguing possibility of cell-to-cell communication between distant tissues via miRNAs and that miRNAs can be used as biomarkers of beta-cell function, mass and survival. The purpose of this review is to provide a status on how miRNAs control beta-cell function and viability in health and disease. PMID- 26418759 TI - Thrombotic thrombocytopenic purpura: from diagnosis to therapy. AB - PURPOSE OF REVIEW: Thrombotic thrombocytopenic purpura (TTP) is a rare but challenging disease for intensive care specialists. Patients with acute TTP frequently require admission to the intensive care unit because of organ dysfunctions due to the disease or because of the risk of sudden aggravation at the onset of the disease. This review aims at describing recent evolutions in the diagnosis and for the management of TTP for the use of intensive care specialists. RECENT FINDINGS: The use of A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats (ADAMTS13) activity along with clinico-biological features to define TTP by most researchers' teams has led to easier interpretation of the literature. The main issues in TTP treatment in 2015 remain the indication and timing of introduction of anti-CD20 antibody rituximab for the treatment of inaugural TTP and the preemptive use of rituximab in asymptomatic patients with decreasing ADAMTS13 activity. SUMMARY: The classification of thrombotic microangiopathies has evolved from a clinical to a pathophysiological definition. TTP is characterized by a severe ADAMTS13 deficiency that can be documented in vitro, along with anti-ADAMTS13 antibodies in most adult cases. Plasmapheresis and immunosuppressive therapy with steroids remain the standard of care for acute inaugural TTP. Anti-CD20 monoclonal antibody rituximab is safe and indicated in relapsing and/or refractory TTP. Its indication in inaugural TTP remains to be evaluated but is nevertheless recommended by experts. Novel therapies for TTP are still in preclinical phases. PMID- 26418757 TI - Association Between Atrial Fibrillation and Costs After Myocardial Infarction: A Community Study. AB - BACKGROUND: The authors sought to estimate incremental economic impact of atrial fibrillation (AF) and the timing of its onset in myocardial infarction (MI) patients. HYPOTHESIS: Concurrent AF and its timing are associated with higher costs in MI patients. METHODS: This retrospective cohort study included incident MI patients from Olmsted County, Minnesota, treated between November 1, 2002, and December 31, 2010. We compared inflation-adjusted standardized costs accumulated between incident MI and end of follow-up among 3 groups by AF status and timing: no AF, new-onset AF (within 30 days after index MI), and prior AF. Multivariate adjustment of median costs accounted for right-censoring in costs. RESULTS: The final study cohort had 1389 patients, with 989 in no AF, 163 in new-onset AF, and 237 in prior AF categories. Median follow-up times were 3.98, 3.23, and 2.55 years, respectively. Mean age at index was 67 years, with significantly younger patients in the no AF group (64 years vs 76 and 77 years, respectively; P < 0.001). New-onset and prior AF patients had more comorbid conditions (hypertension, heart failure, and chronic obstructive pulmonary disease). After accounting for differences in baseline characteristics, we found adjusted median (95% confidence interval) costs of $73 000 ($69 000-$76 000) for no AF; $85 000 ($81 000-$89 000) for new-onset AF; and $97 000 ($94 000-$100 000) for prior AF. Inpatient costs composed the largest share of total median costs (no AF, 82%; new onset AF, 84%; prior AF, 83%). CONCLUSIONS: Atrial fibrillation frequently coexists with MI and imposes incremental costs, mainly attributable to inpatient care. Timing of AF matters, as prior AF was found to be associated with higher costs than new-onset AF. PMID- 26418761 TI - Pediatric blunt abdominal trauma: current management. AB - PURPOSE OF REVIEW: Nonoperative management of pediatric blunt abdominal injury has changed significantly in the last few years. RECENT FINDINGS: Improved resource utilization in the diagnosis of pediatric abdominal injury has been described. Hemodynamic status, rather than grade of injury, now guides care. Stable patients spend less time in the hospital, return to school upon discharge, and are allowed lower hemoglobin levels prior to transfusion. ICUs are reserved for those with recent or ongoing bleeding, previously unstable patients, or children with concomitant injuries necessitating ICU. Risk factors for failure and evidence for adjuncts to nonoperative management are emerging. Operative management of certain pancreatic injuries may have more favorable outcomes than nonoperative management. SUMMARY: Sufficient evidence has become available to radically change the management of pediatric abdominal injury, which is being incorporated into new evidence-based management algorithms. PMID- 26418760 TI - Endpoints in resuscitation. AB - PURPOSE OF REVIEW: Shock occurs because of a failure to deliver adequate oxygen to meet the metabolic demands of the body resulting in metabolic acidosis, inflammation, and coagulopathy. Resuscitation is the process of treating shock in an attempt to restore normal physiology. Various hemodynamic, metabolic, and regional endpoints have been described to evaluate the degree of shock and guide resuscitation efforts. We will briefly describe these endpoints, and propose damage control resuscitation as an additional endpoint. RECENT FINDINGS: Serum lactate, base deficit, and pH are well established endpoints of resuscitation that provide valuable information when trended over time; however, a single value is inadequate to determine adequacy of resuscitation. Rapid normalization of central venous oxygen concentration has been associated with improved survival, and bedside transthoracic echocardiography can be a reliable assessment of volume status. In hypovolemic/hemorrhagic shock, early hypotensive, or controlled resuscitation strategies have been associated with improved survival, and hemostatic strategies guided by thrombelastography using a balanced transfusion approach result in improved hemostasis. SUMMARY: Numerous endpoints are available; however, no single endpoint is universally applicable. Damage control resuscitation strategies have demonstrated improved survival, hemostasis, and less early death from exsanguination, suggesting that hemorrhage control should be an additional endpoint in resuscitation. PMID- 26418763 TI - MetaPhlAn2 for enhanced metagenomic taxonomic profiling. PMID- 26418762 TI - Widespread nuclease contamination in commonly used oxygen-scavenging systems. PMID- 26418764 TI - What if stem cells turn into embryos in a dish? AB - Recent studies show that pluripotent stem cells can undergo self-organized development in vitro into structures that mimic the body plan of the post implantation embryo. Modeling human embryogenesis in a dish opens up new possibilities for the study of early development and developmental disorders, but it may also raise substantial ethical concerns. PMID- 26418766 TI - Diving deeper to predict noncoding sequence function. PMID- 26418765 TI - Voltage sensors: challenging, but with potential. PMID- 26418767 TI - Photochemical Hydrogen Doping Induced Embedded Two-Dimensional Metallic Channel Formation in InGaZnO at Room Temperature. AB - The photochemical tunability of the charge-transport mechanism in metal-oxide semiconductors is of great interest since it may offer a facile but effective semiconductor-to-metal transition, which results from photochemically modified electronic structures for various oxide-based device applications. This might provide a feasible hydrogen (H)-radical doping to realize the effectively H-doped metal oxides, which has not been achieved by thermal and ion-implantation technique in a reliable and controllable way. In this study, we report a photochemical conversion of InGaZnO (IGZO) semiconductor to a transparent conductor via hydrogen doping to the local nanocrystallites formed at the IGZO/glass interface at room temperature. In contrast to thermal or ionic hydrogen doping, ultraviolet exposure of the IGZO surface promotes a photochemical reaction with H radical incorporation to surface metal-OH layer formation and bulk H-doping which acts as a tunable and stable highly doped n type doping channel and turns IGZO to a transparent conductor. This results in the total conversion of carrier conduction property to the level of metallic conduction with sheet resistance of ~16 Omega/?, room temperature Hall mobility of 11.8 cm(2) V(-1) sec(-1), the carrier concentration at ~10(20) cm(-3) without any loss of optical transparency. We demonstrated successful applications of photochemically highly n-doped metal oxide via optical dose control to transparent conductor with excellent chemical and optical doping stability. PMID- 26418768 TI - Superthin Abdominal Wall Glove-Like Flap Combined With Vacuum-Assisted Closure Therapy for Soft Tissue Reconstruction in Severely Burned Hands or With Infection. AB - Severe burn and infection to hands always involves the deep structures, such as tendons, joints, and bones. These wounds cannot be closed immediately and therefore creates a high risk for complication. We presented 9 cases with deep dermal burns to the dorsal of the hand (6 electrical burns and 3 thermal crush injuries) with wound infections in 2 cases. The vacuum-assisted closure system was used continuously until the flap reconstruction was performed. A random pattern and superthin abdominal wall skin flap-like glove was designed. The flap was transferred to the defected portion of the dorsum of the hand and resected from the abdominal wall about 3 weeks later. The flaps in 8 of the patients treated by this technique survived completely and partial necrosis of the distal flap occurred in 1 patient. The defect resolved after operative treatment and the function of the hands and fingers were successfully salvaged. All patients resulted in having a satisfactory aesthetic outcome with no or minor discomfort at the abdominal donor area. Integration of the vacuum-assisted closure system and the superthin abdominal wall glove-like flap reconstruction appeared to be successful and should be considered in patients with severely burned hands. PMID- 26418770 TI - A New Method to Control Tendon Tension in the Transfer of Extensor Indicis Proprius to Extensor Pollicis Longus Rupture. AB - This study evaluated the outcomes of extensor indicis proprius (EIP) transfer based on varying degrees of thumb extension after EIP transfer and elongation of the EIP. A total of 24 cases with extensor pollicis longus (EPL) ruptures who underwent EIP to EPL transfer were analyzed prospectively. The EIP transfer was performed with neutral wrist positioning. In group I (12 cases), EIP and EPL were sutured on the thumb in neutral state at interphalangeal joint, and the mean EIP elongation of this group measured 0.2 cm (range, -0.5 to 0.5 cm). In group II (12 cases), EIP and EPL were sutured on the thumb in full extension state at interphalangeal joint, and the mean EIP elongation measured 0.7 cm (range, 0.5 1.5 cm). The mean follow-up period was 13.5 months. The 2 groups were compared based on thumb motion, grip strength, pinch power, and the Disabilities of the Arm, Shoulder, and Hand questionnaire score. Extension of the thumb at the interphalangeal joint was -5.2 degrees in group I and 7.2 degrees in group II, demonstrating statistically significant differences. No significant differences were found between the 2 groups in other parameters. In EIP transfer, thumb in extension after transfer and EIP elongation is recommended for restoring thumb extension at the interphalangeal joint. PMID- 26418769 TI - Flexor Tenosynovitis Due to Tuberculosis in Hand and Wrist: Is Tenosynovectomy Imperative? AB - The treatment of flexor tenosynovitis in the hand and wrist due to tuberculosis is controversial. Although some authors recommend the antituberculous chemotherapy, the others recommend the surgical treatment. In this article, 12 patients with synovial tuberculosis of the flexor aspect of the hand and the wrist were evaluated with respect to diagnosis and treatment modalities. None of the patients had a history of tuberculosis, concomitant disease, immunosuppressive drug use, drug abuse, and human immunodefficiency virus positivity. A chest x-ray and family screening were performed in all of the cases, none had evidence of tuberculosis in the lung. The biopsy, histopathological examination, acid-fast bacillus staining, and BACTEC tuberculosis culture were performed. Antituberculous chemotherapy was initiated in patients diagnosed with tuberculosis by either histological or microbiological examinations. The patients did not undergo any further surgery after biopsy procedures. The lesions regressed totally in all patients after 3 months of treatment. Carpal tunnel syndrome symptoms and signs recruited at five months of treatment. In patients with flexor tuberculosis tenosynovitis, it is possible to achieve good results by applying only medical therapy after a biopsy, and without the need for further surgery. PMID- 26418771 TI - Operative Treatment of Lymphedema Using Suction-Assisted Lipectomy. AB - BACKGROUND: Surgical management of lymphedema includes removal of affected tissues (excisional procedures), or operations that create new lymphatic connections (physiologic procedures). The purpose of this study was to determine the efficacy of one type of excisional procedure, suction-assisted lipectomy, for extremity lymphedema. METHODS: Patients treated in our Lymphedema Program between 2007 and 2015 with liposuction that had postoperative follow-up were reviewed. The diagnosis of lymphedema was made by history/physical examination and confirmed with lymphoscintigraphy. Patient sex, age, type of lymphedema (primary or secondary), location of disease, infection history, volume of lipoaspirate, and reduction of extremity volume were recorded. RESULTS: Fifteen patients were included, mean age was 45 years (range, 17-71). Six patients had secondary upper extremity lymphedema, and 9 patients had lower limb disease. Eight patients had a history of repeated cellulitis involving the lymphedematous extremity. Mean lipoaspirate volume was 1612 mL (range, 1200-2800) for the upper extremity and 2902 mL (range, 2000-4800) for the lower limb. Postoperative follow-up averaged 3.1 years. The mean reduction in excess extremity volume was 73% (range, 48% to 94%), and patients reported improvement in their quality of life. CONCLUSIONS: Suction-assisted lipectomy is an effective technique to reduce extremity volume for patients with lymphedema. PMID- 26418772 TI - Indocyanine Green Lymphographic Signs of Lymphatic Collateral Formation in Lower Extremity Lymphedema After Cancer Resection. AB - Indocyanine green lymphography has recently been used to assess lymphatic vessel function in lymphedema patients. Postoperative collateral lymphatic vessels toward ipsilateral axillary lymph nodes are rarely seen above the umbilical level in lower lymphedema patients. Between January 2012 and December 2014, we performed indocyanine green lymphography of 192 limbs in 96 lower extremity lymphedema cases. As a result, dermal back flow appeared in 95 cases, with 38 in the lower abdominal area and 31 in the genital area. We confirmed 3 cases of superficial lymphatic collateral ways extending above the umbilical level to the axillary lymph nodes. All 3 cases had similarity in lower abdominal edema, so excessive lymphatic fluid in the lower abdomen was assumed to be the cause. Lymphatic collateral ways from abdomen to axillary lymph nodes in this study was likely to be designed to prevent the progress of lymphedema. PMID- 26418773 TI - An Application of Keystone Perforator Island Flap for Closure of Lumbosacral Myelomeningocele Defects. AB - Myelomeningocele, also known as spina bifida, is the commonest form of neural tube defect in which both meninges and spinal cord herniate through a large vertebral defect. It may be located at any spinal level; however; lumbosacral involvement is most common. After birth, the closure of spinal lesion is preferably undertaken in the first 48 hours to minimize the risk of injury and central nervous system infection. Relatively small skin defects overlying the dural repair may be directly closed. However, larger defects require reconstructive closure. Numerous methods of reconstruction have been described, such as split skin graft, local flaps or lumbosacral fasciocutaneous flaps, muscle flaps using latissimus dorsi, gluteal or paraspinous muscles, and perforator flaps namely superior gluteal artery perforators, and dorsal intercostal artery perforator flaps. At Monash Health, Victoria, we have used the keystone perforator island flaps to reconstruct lumbosacral myelomeningocele defects on 5 newborns between January 2008 and January 2014. This article evaluates the short-term and long-term outcomes of these patients who were followed up for 10 to 66 months. PMID- 26418774 TI - Preoperative Imaging for Thoracic Branch of Supraclavicular Artery Flap: A Comparative Study of Contrast-Enhanced Ultrasound With Three-Dimensional Reconstruction and Color Duplex Ultrasound. AB - OBJECTIVE: The thoracic branch of supraclavicular artery (TBSA) flap has been widely used to reconstruct face and neck defects. However, the branches of the supraclavicular artery (SCA) exhibit considerable anatomical variations. The aim of this study was to evaluate and compare the role of contrast-enhanced ultrasound (CEUS) with 3-dimensional (3D) reconstruction and regular color duplex ultrasonography (CDUS) in the preoperative assessment of TBSA flap. METHODS: From May 2009 to October 2013, 20 patients (involving 26 flaps) receiving anterior chest flaps for lower face and neck reconstruction underwent both CDUS and CEUS with 3D reconstruction preoperatively for detecting the TBSAs. The number of TBSAs, their caliber, peak systolic velocity (PSV), and course were recorded. In case of an absent TBSA, the second and third perforators of the internal mammary artery were detected. The preoperative imaging data were compared with the intraoperative findings to evaluate the value of CDUS and CEUS with 3D reconstruction for planning and performing the TBSA flaps. All patients were followed up for more than 1 year. RESULTS: A total of 37 TBSAs in 16 flaps were found by CDUS with a mean caliber of 0.6 +/- 0.1 mm and a mean PSV of 13.1 +/- 1.6 cm/s, whereas 48 TBSAs in 20 flaps were found by CEUS with a mean caliber of 0.8 +/- 0.2 mm and a mean PSV of 12.5 +/- 2.1 cm/sec. In 18 flaps with TBSA PSV above 10 cm/s, pedicled TBSA flaps were performed, whereas pedicled or free internal mammary artery flaps were chosen as alternative for the remaining 8 flaps. All 48 TBSAs were found intraoperatively and their origin from the SCA confirmed, indicating specificity and positive predictive value of both CDUS and CEUS were 100% in localizing TBSA preoperatively, whereas sensitivity and negative predictive value of CEUS were higher than using CDUS. CONCLUSIONS: The branches of SCA have marked anatomical variations. CEUS with 3D reconstruction has advantages over CDUS for the preoperative assessment of the donor-site vascular supply of TBSA flaps. PMID- 26418775 TI - Reverse-Flow Lateral Tarsal Island Flap for Covering the Great Toe Donor Site of Wraparound Flap. AB - BACKGROUND: Coverage of the great toe donor site of wraparound flap remains a challenge. This report presents the results of using an innervated pedicled reverse-flow lateral tarsal island flap for covering the great toe donor site of wraparound flap. PATIENTS AND METHODS: Between 2005 and 2010, 11 reverse-flow lateral tarsal island flaps were used to cover the great toe donor site of wraparound flap in 11 patients. This pedicled flap designed on the lateral tarsal area of foot was based distally on the dorsalis pedis artery; the lateral dorsal pedal cutaneous nerve was incorporated into the reverse-flow lateral tarsal island flap and coapted with the first plantar digital nerve. The donor sites of reverse-flow lateral tarsal island flap were covered with inguinal full-thickness skin grafts. RESULTS: All flaps achieved primary healing except for two that suffered from mild venous insufficiency which was managed by conservative intervention. All skin grafts covering the donor site of reverse-flow lateral tarsal island flap healed uneventfully. The mean follow-up was 24 months (range, 18-48 months). The mean hallux metatarsophalangeal-interphalangeal scale score was 92 points (range, 85-97 points) at 6 months postoperatively. The static 2 point discrimination of the reverse-flow lateral tarsal island flap ranged from 6 to 14 mm (mean 10 mm). None of the patients were restricted in standing or walking during follow-up. CONCLUSIONS: The reverse-flow lateral tarsal island flap based distally on the dorsalis pedis artery has a constant pedicle that is sufficiently long. This innervated pedicle flap is a reliable option to cover the great toe donor site of wraparound flap with satisfactory functional and cosmetic results and acceptable donor site morbidity. PMID- 26418776 TI - The Pacman Perforator-Based V-Y Advancement Flap for Reconstruction of Pressure Sores at Different Locations. AB - BACKGROUND: Many procedures have been proposed for the treatment of pressure sores, and V-Y advancement flaps are widely used to repair a defect. Unfortunately, the degree of mobility of a V-Y advancement flap is dependent on the laxity of the underlying subcutaneous tissue. This is an important disadvantage of traditional V-Y advancement flap and limits its use.We used V-Y advancement flaps as perforator-based to overcome mobility restriction problem, with a further modification (Pacman-like shape) to improve the covering surface area of the flap. METHODS: Between January 2012 and December 2014, the authors used 37 V-Y Pacman perforator-based flaps in 33 consecutive patients for coverage of defects located at sacral (n = 21), ischial (n = 13), trochanter (n = 1) regions. There were 27 male and 6 female patients with a mean age of 49.9 years (range, 15-74 years). RESULTS: All flaps survived completely (92.3%) except 3 in which one of them had undergone total necrosis due to hematoma and the other 2 had partial necrosis. No venous congestion was observed. The mean follow-up period was 14.9 months (range, 2-38 months). No flap surgery-related mortality or recurrence of pressure sores was noted. CONCLUSIONS: The V-Y Pacman perforator based advancement flaps are safe and very effective for reconstruction of pressure sores at various regions. The advantage of our modification procedure include shorter operative time, lesser pedicle dissection, low donor site morbidity, good preservation of muscle, and offers remarkable excursion to the V Y flap, which make the V-Y Pacman perforator-based flaps an excellent choice for large pressure sore coverage. PMID- 26418777 TI - The Versatile Extended Thoracodorsal Artery Perforator Flap for Breast Reconstruction. AB - BACKGROUND: The thoracodorsal artery perforator (TAP) flap is a versatile tool that can be used to reconstruct the breast. The authors use preoperative perforator mapping using color Doppler ultrasonography and present a safe, efficient harvesting technique to demonstrate reliable use of the TAP flap in reconstructive surgery. METHODS: A multicenter, retrospective review was performed on all patients undergoing TAP flap reconstruction from August 2011 to November 2014. Data were collected from patient records as well as outpatient interviews. RESULTS: A total of 106 TAP flaps were performed in 97 patients. The flaps were raised with either 1 perforator (42/106), 2 perforators (55/106), or three perforators (9/106), and turned as a propeller in 99 of 106 (93%) flaps or buried as a turnover in 7 of 106 (7%) of flaps. The mean operative time was 200 minutes (range, 60-485). Major complications occurred in 10 of 106 (10%) cases and included hematoma (1/108), venous congestion (2/108), and partial flap necrosis (7/108). The reconstructive goal was achieved in 103 of 106 (97%) flaps. CONCLUSIONS: The TAP flap is a pedicled, fasciocutaneous flap that can be used for total breast reconstruction as well as breast conserving surgery. This large, multicenter series describes our techniques of preoperative perforator mapping and a fast, reliable harvest. Reconstructive goals are accomplished in the great majority of patients. PMID- 26418778 TI - Primary Buttonhole Mastopexy and Nipple-Sparing Mastectomy: A Preliminary Report. AB - BACKGROUND: Patients undergoing nipple-sparing mastectomy and immediate-implant based reconstruction occasionally require a mastopexy based on their breast size and degree of ptosis. Previous reports have shown the feasibility of mastopexy nipple-sparing mastectomy in selected patients to raise the nipple up to 5 cm. Major mastopexy with nipple transposition more than 6 cm in conjunction with nipple-sparing mastectomy for therapeutic indications has not been described. The authors review their experience with primary buttonhole mastopexy performed in conjunction with nipple-sparing mastectomy. METHODS: Between 2008 and 2014, 16 patients (32 breasts) underwent bilateral primary mastopexy and nipple-sparing mastectomy with immediate staged implant-based reconstruction. The Passot buttonhole technique was used for the mastopexy in all patients, raising the nipple from 7 to 12 cm. Tumor-related data, risk factors, breast size, degree of ptosis, expander size, fill volume, selection criteria, and complications are discussed. RESULTS: The average follow-up period was 33 months (range, 14 to 80 months). There were no tumor recurrences, and all patients completed their reconstruction. Two patients required removal of the expander and delayed reconstruction because of infection and implant exposure due to nipple-areola loss. The reasons for nipple-areola loss and technical modifications to enhance skin viability by retaining a thin layer of subareolar breast tissue for removal during the second-stage implant exchange are discussed. CONCLUSIONS: Primary mastopexy using the buttonhole technique performed together with nipple-sparing mastectomy is a safe procedure with predictable results in patients with very large or ptotic breasts requiring lifts greater than 6 cm. The success of the combined procedure depends on preserving a thin layer of subareolar breast tissue and removing it at the time of implant exchange. PMID- 26418779 TI - Getting a Valid Survey Response From 662 Plastic Surgeons in the 21st Century. AB - INTRODUCTION: Web-based surveys save time and money. As electronic questionnaires have increased in popularity, telephone and mailed surveys have declined. With any survey, a response rate of 75% or greater is critical for the validity of any study. We wanted to determine which survey method achieved the highest response among academic plastic surgeons. METHODS: All American Association of Plastic Surgeons members were surveyed regarding authorship issues. They were randomly assigned to receive the questionnaire through 1 of 4 methods: (A) emailed with a link to an online survey; (B) regular mail; (C) regular mail + $1 bill, and (D) regular mail + $5 bill. Two weeks after the initial mailing, the number of responses was collected, and nonresponders were contacted to remind them to participate. The study was closed after 10 weeks. Survey costs were calculated based on the actual cost of sending the initial survey, including stationary, printing, postage (groups B-D), labor, and cost of any financial incentives. Cost of reminders to nonresponders was calculated at $5 per reminder, giving a total survey cost. RESULTS: Of 662 surveys sent, 54 were returned because of incorrect address/email, retirement, or death. Four hundred seventeen of the remaining 608 surveys were returned and analyzed. The response rate was lowest in the online group and highest in those mailed with a monetary incentive. CONCLUSIONS: Despite the convenience and low initial cost of web-based surveys, this generated the lowest response. We obtained statistically significant response rates (79% and 84%) only by using postal mail with monetary incentives and reminders. The inclusion of a $1 bill represented the greatest value and cost-effective survey method, based on cost per response. PMID- 26418780 TI - Digital Sympathectomy in Patients With Scleroderma: An Overview of the Practice and Referral Patterns and Perceptions of Rheumatologists. AB - PURPOSE: Periarterial sympathectomy is a treatment option for patients with systemic sclerosis (SSc) suffering from digital vasculopathy. Despite potential benefits of ulcer healing, pain improvement, and amputation prevention, this operation appears to be infrequently performed. The aims of our study are as follows: (1) to assess national digital sympathectomy rates in patients with SSc and (2) to improve our understanding of referring physicians' perceptions of operative management and access to hand surgeons. Our hypothesis is that rheumatologists' practices largely influence their referral patterns for digital sympathectomy. METHODS: To determine the rates and demographics of hospitalized patients with SSc who had undergone digital sympathectomy, we queried the Nationwide Inpatient Sample from 2006 to 2010. Additionally, we mailed a self administered survey to a national sample of 500 board-certified rheumatologists to elicit their practice patterns and perceptions of digital sympathectomy. Using logistic regression, we analyzed potential predictor variables associated with rheumatologists performing the following: (1) routinely counseling patients about digital sympathectomy and (2) expressing the desire to refer these patients for operative evaluation. RESULTS: Of 348,539 hospitalizations associated with a diagnosis of SSc, only 0.2% were for digital sympathectomy. Our questionnaire revealed that only 50% of rheumatologists routinely counseled, whereas 67% expressed the desire to refer. Factors associated with increased rheumatologists' interest in surgical management for patients with SSc included positive perception of the operation's efficacy, comfort with postoperative management, and interdisciplinary relationship with a hand surgeon. DISCUSSION: Critical components to increasing appropriate utilization of digital sympathectomy include enhancing rheumatologists' understanding of the operation, comfort with postoperative management, and promoting strong, interdisciplinary relationships with hand surgeons. Increasing education and awareness, as well as establishing a solid referral network of hand surgeons may thereby improve patient access to digital sympathectomy. PMID- 26418781 TI - Mjolnir. PMID- 26418782 TI - Pericranial Flap for Inner Lining in Nasal Reconstruction. AB - INTRODUCTION: The general principle in nasal reconstruction is to reconstruct the 3 layers of skin, cartilage, and mucosa. Reconstructing the inner lining remains a challenge especially when adjacent tissues are not available after tumor resection. The galea and pericranial flaps (PFs) are widely used in anterior skull base reconstructive surgery.We evaluated the use of the PF for the inner nasal lining in an anatomical cadaver study and present its clinical application in patients with benign and malignant tumors of the nose and anterior skull base. METHODS: Four fresh cadavers were injected with red-colored silicone for determining the pattern of vascularization of supraorbital (SOA) and supratrochlear (STA) arteries of each PF. Four surgical cases (2 nasocranial meningiomas, 1 nasal melanoma, and 1 nasal squamous cell carcinoma) received PF for reconstruction of inner lining. RESULTS: The median distances between the superior orbital rim and the division of the deep and superficial branches of STA and SOA were 8 +/- 3.3 mm and 8 +/- 3.7 mm, respectively. The maximum measured distance was 11 mm. The SOA provided the longest axial vascularization (70.7 +/- 13. 9 mm) compared with STA (35 +/- 10.4 mm). Median length of PF for subtotal nasal reconstruction including tip and columella were 70 +/- 5 mm and 22.5 +/- 3.5 mm, respectively.Three cases were successfully reconstructed with PF up to the distal border of the upper lateral cartilage. In 1 patient, distal necrosis of tip and columella occurred. CONCLUSIONS: The blood supply of the PF is mainly based on the SOA arteries. Thus, superficial dissection must end 15 mm above the orbital rim to ensure the survival of the flap. Pericranial flap can be applied for inner lining in combined nasocranial, septal, and nasal defects with extension down to the distal border of the upper lateral cartilage. Vascularization is reliable in flaps up to a length of 70 mm. PMID- 26418783 TI - Reconstruction of a Large External Hemipelvectomy Defect After Chordoma Resection Using a 5-Component Chimeric Rotational Flap. PMID- 26418784 TI - Donor Site Aesthetic Enhancement With Preoperative Botulinum Toxin in Forehead Flap Nasal Reconstruction. AB - BACKGROUND: Donor site scarring after forehead flap nasal reconstruction is acceptable. However, as aesthetic outcomes standards for cosmetic and reconstructive surgery merge, we aim to enhance results. We recently demonstrated the cosmetic benefit of botulinum toxin type A (BTX-A) for cleft lip cheiloplasty outcomes. We hypothesize that similar mechanism(s) benefit forehead flap donor scars. METHODS: A single surgeon performed 26 forehead flap reconstructions. Indications were cancer (n = 17), trauma (n = 3), and congenital deformity (n = 6). In this split-scar study half the forehead was pretreated with BTX-A and half with normal saline after random assignment. Photographs were evaluated at most recent follow-up. Scar evaluation was based on photographs by 3 plastic surgeons using a composite subjective visual analogue score (VAS). RESULTS: Photographic follow-up was 27 months (range, 10-60 months). Botulinum toxin type A was assigned to the upper forehead in 16 cases and lower forehead in 10 cases. Intrarater reliability among 4 evaluators of 104 VAS scores was 78.1%. Upper forehead VAS (7.9 +/- 1.2) was not different than lower forehead VAS (7.9 +/- 1.2) regardless of treatment (P = 0.62). The VAS score of BTX-A-treated scars (8.5 +/- 1.0) was significantly higher than the control (7.3 +/- 1.1; P < 0.0001). Among 104 individual comparisons (26 patients * 4 observers), there were 73 instances (70.2%) where the experimental VAS score was higher than the control. CONCLUSIONS: Preoperative BTX-A injection is feasible and enhances donor site scar appearance after forehead flap nasal reconstruction in an Asian population. PMID- 26418785 TI - Breast Reconstruction Using the Geometrically Modified Profunda Artery Perforator Flap From the Posteromedial Thigh Region: Combining the Benefits of Its Predecessors. AB - BACKGROUND: Occasionally, the deep inferior epigastric perforator flap is unavailable for autologous breast reconstruction. Alternative options, such as gluteal artery perforator flaps, the transverse upper gracilis flap, and the profunda artery perforator (PAP) flap, have been well documented. In our initial experience, the PAP flap was associated with limitations at the donor site. Therefore, a geometrically modified PAP flap was evaluated. METHODS: Forty geometrically modified PAP flap reconstructions were performed on 30 patients. Our modification comprised flap harvest from a more cranial area, hereby adding abundant inferior gluteal tissue to the flap while sparing superior thigh tissue. Patient characteristics, anatomical variables, and clinical outcome were prospectively evaluated. RESULTS: Mean patient age was 44 years, and mean body mass index (BMI) was 23.3 kg/m. Mean flap size was 32 * 12 cm, and mean weight was 385 g. Mean number of suitable perforators (diameter >= 0.5 mm) in the adductor magnus area was 1.7 per thigh. All flaps survived completely. Wound dehiscence at the donor site occurred after 4 unilateral reconstructions. Transient lymphedema of the leg occurred after 4 other unilateral reconstructions. Other wound morbidity or systemic complications did not occur. Secondary breast surgery for symmetry and volume was indicated after 16 reconstructions. Preoperative bra size was unchanged or larger in 36 reconstructions. Scar position in the crease was achieved after 39 reconstructions. Sensibility changes of the posteromedial thigh region were not observed. CONCLUSIONS: The geometrically modified PAP flap ensures in-the-crease scar positioning and provides sufficient tissue to restore preoperative bra size. PMID- 26418786 TI - Effects of High-Voltage Electrical Stimulation in Improving the Viability of Musculocutaneous Flaps in Rats. AB - BACKGROUND: The musculocutaneous flap of the transverse rectus abdominis muscle is a technique used for breast reconstruction, and one of the complications of this procedure is tissue necrosis. The objective of the study is to determine the effect of high-voltage electrical stimulation (HVES) in the transverse rectus abdominis muscle flap in rats. METHODS: Fourteen rats underwent surgery for obtaining the flap. The rats were distributed into 2 homogeneous groups: group 1 underwent both surgery and the use of HVES, whereas group 2 underwent just the surgery (control). Electrical stimulation was applied immediately after surgery and for 2 consecutive days. The percentage of necrotic area was analyzed using the Image J software, and blood flow was assessed by infrared thermography in different regions of the flap, divided into 4 zones according to the proximity of the pedicle of the inferior epigastric artery. RESULTS: The results were analyzed using a Student t test, where group 1 experienced a necrotic area of 26.2%, and group 2 had an area of 54.5%. Regarding the temperature, the 2 groups showed increase in the minimum and maximum temperature on the fourth postoperative day. CONCLUSION: The HVES appeared to have a positive influence on the viability of the flap. PMID- 26418788 TI - Validation of Videoconference With Smartphones in Telemedicine Facial Trauma Care: Analysis of Concordance to On-Site Evaluation. AB - BACKGROUND: The continental size of some countries and heterogeneous hospital network prevents patients who live in remote areas from getting adequate initial assessment of facial trauma. The authors present an alternative model for trauma assessment by videoconference via smartphones and analyze the concordance between telemedicine and face-to-face management. METHODS: Fifty patients with either a confirmed or suspected diagnosis of facial trauma were independently evaluated by 2 teams of physicians: Face-to-face and telemedicine-based. The face-to-face team attended patients at bedside (physical examination and computed tomography scan analysis). The telemedicine team consisted of a general surgery resident on duty in the emergency room and a plastic surgeon researcher remotely communicating via smartphones. Both teams answered a questionnaire, which contained data concerning patient's epidemiology, physical examination, computed tomography (CT) scan findings, and treatment option to be followed. Data were analyzed and compared regarding the similarity of answers. RESULTS: The sample studied was consistent with the literature, showing a predominance of young males. Traffic accidents and personal violence were the main causes of trauma. The concurrency of answers for physical examination findings was considered substantial (kappa = 0.720). For CT scan findings, it was almost perfect (kappa = 0.899); for defining the treatment option, it was almost perfect (kappa = 0.891). High concurrency of face CT scan findings was observed after we calculated the positive predictive value (89.9%), negative predictive value (99.3%), sensitivity (94.2%), specificity (98.8%), and accuracy (98.3%). CONCLUSIONS: The proposed model to facial assessment trauma by videoconference via smartphones is feasible, showing high concordance level with face-to-face assessment. PMID- 26418787 TI - Changes in Skin Vascularity in a Murine Model for Postmastectomy Radiation. AB - BACKGROUND: Postmastectomy radiation causes persistent injury to the breast microvasculature, and the prevailing assumption is that longer delays before breast reconstruction allow for recovery of blood supply. This study uses a murine model to examine the effects of radiation on skin vascularity to help determine when radiation-induced effects on the microvasculature begin to stabilize. STUDY DESIGN: Isogenic Lewis rats were divided into 2 groups: radiation therapy (XRT) (n = 24) and control (n = 24). The XRT rats received a breast cancer therapy human dose-equivalent of radiation to the groin, whereas control rats received no radiation. Animals were sacrificed at 4, 8, 12, and 16 weeks after completion of radiation. The vasculature was injected with Microfil, and groin skin was harvested for radiomorphometric analysis by microcomputed tomography. One-way analysis of variance with post hoc Tukey tests was used to determine significance between groups. RESULTS: Augmentation in vascularity was observed in the XRT group at 4 weeks after radiation compared to the control group (P = 0.045). Vessel number was decreased at 12 weeks (P = 0.002) and at 16 weeks (P = 0.001) in the XRT rats compared to control rats. Vessel separation in the XRT group was higher than that in the control group at 12 weeks (P = 0.009) and 16 weeks (P = 0.001). There was no change in vessel number and separation between weeks 12 and 16. CONCLUSIONS: A period of augmented skin vascularity is seen after radiation injury followed by decreased vascularity which demonstrates stabilization at approximately 12 weeks in this murine model. This model can be used to further study breast flap vascularity and the optimization of the timing of delayed breast reconstruction. PMID- 26418789 TI - An Updated View of the Integrated Plastic Surgery Match. AB - BACKGROUND: Plastic surgery is one the most competitive residency programs. Data on match trends for plastic surgery residencies and traits of successful applicants are necessary for individuals applying into this highly desirable specialty. AIM: Analyze recent trends in the independent and integrated match as well as to describe attributes of successful applicants. METHODS: Data from National Resident Matching Program and San Francisco Match Program for 2007 to 2014 were compiled and analyzed. Statistical analysis and figure creation were performed using the R software package. For bivariate associations, chi or Fisher's exact test was used. RESULTS: The number of available integrated plastic surgery positions through National Resident Matching Program has increased since 2007, whereas the number of independent residencies offered through the SF Match has steadily decreased. The average Step 2 scores, The number of research presentations, publications, abstracts, and the percent of students ranking plastic surgery only have increased. In a break from previous trends, percent of applicants with Alpha Omega Alpha (AOA) membership and mean Step 1 board scores decreased. United States medical school applicants who matched were more likely to be AOA members and graduates from a top 40 medical school. There was no significant association between having an additional academic degree and successfully matching into integrated plastic surgery. CONCLUSIONS: Integrated plastic surgery residency programs continue to be highly competitive, with overall increasing research experience, but slightly lower Step 1 scores and AOA membership than that in previous years. If the trend of decreasing independent and increasing integrated positions continues, the applicant only interested in plastic surgery may find the integrated pathway a more feasible option. PMID- 26418790 TI - Comment on the Chaput et al Study, Professional Burnout Among Plastic Surgery Residents: Can it be Prevented? Outcomes of a National Survey. PMID- 26418791 TI - Intraoperative Hemifacial Composite Flap Perfusion Assessment Using Spatial Frequency Domain Imaging: A Pilot Study in Preparation for Facial Transplantation. AB - BACKGROUND: Vascularized composite allotransplantation represents an important advancement in the field of reconstructive microsurgery and has continued to increase in popularity. The significant clinical morbidity associated with flap failure represents an important barrier to even more widespread use of these techniques. Early identification of vascular compromise has been associated with a higher salvage rate, yet most surgeons rely only on clinical assessment intraoperatively. Spatial frequency domain imaging (SFDI) presents a noncontact, objective measurement of tissue oxygenation over a large field of view. This study aims to evaluate the use of SFDI technology in hemifacial composite flap compromise as could occur during facial transplant. METHODS: Six composite hemifacial flaps were created in three 35-kg Yorkshire pigs and continuously imaged using SFDI before, during, and after 15-minute selective vascular pedicle occlusion. Arterial and venous clamping trials were performed for each flap. Changes in oxyhemoglobin concentration, deoxyhemoglobin concentration, and total hemoglobin were quantified over time. RESULTS: The SFDI successfully measured changes in oxygenation parameters in all 6 composite tissue flaps. Significant changes in oxyhemoglobin, deoxyhemoglobin, and total hemoglobin were seen relative to controls. Early and distinct patterns of alteration were noted in arterial and in venous compromise relative to one another. CONCLUSIONS: The need for noninvasive, reliable assessment of composite tissue graft viability is apparent, given the morbidity associated with flap failure. The results of this study suggest that SFDI technology shows promise in providing intraoperative guidance with regard to pedicle vessel integrity during reconstructive microsurgery. PMID- 26418793 TI - Reconstruction of a Large External Hemipelvectomy Defect After Chordoma Resection Using a 5-Component Chimeric Rotational Flap: Reply. PMID- 26418792 TI - The Surgical Treatment of Robin Sequence. AB - BACKGROUND: We present an outcomes analysis of the surgical treatment of Robin sequence including all infants and comorbid conditions treated by tongue-lip adhesion (TLA) or mandibular distraction osteogenesis (MDO). METHODS: A 19-year single-institution, multisurgeon retrospective review of all syndromic and nonsyndromic neonates with Robin sequence treated with TLA (1994-2004) or MDO (2004-2013) was performed. Comorbid conditions were recorded in all patients. Outcomes include incidence of tracheostomy, improvement in obstructive breathing, and surgical complications. Need for repeat distraction and conversion from TLA to MDO were included as secondary end-points. Polysomnography data were recorded preoperatively at 1 month and 1 year as a measure of airway improvement. RESULTS: Seventy-four MDO patients and 15 TLA patients during the study period met inclusion criteria. There was no significant difference in mean age at intervention (32.1 +/- 29.0 vs 35.5 +/- 32.1 days), birth weight (2.9 +/- 0.7 vs 3.2 +/- 0.6 kg), prematurity (23.0 vs 35.7%), or intrauterine growth restriction (31.1 vs 15.4%). Central nervous system anomalies (24.3% vs 0.0%; P < 0.04) and gastrostomy tubes (66.2% vs 33.3%; P < 0.03) were present more frequently in MDO patients versus TLA patients. Rates of other organ system anomalies were similar between the groups. The success rate was significantly higher in the MDO group (90.5% vs 60.0%; P < 0.008). Postoperative tracheostomies occurred in 8.1% of the MDO group and 33.3% of the TLA group (P < 0.02). Preoperative apnea-hyponea index was similar between the two groups (38.3 vs 38.1). The apnea-hyponea index was significantly improved in the MDO group at 1 month (4.0 vs 21.7; P < 0.002) and 1 year (5.7 vs 20.5; P < 0.005). Surgical complications were statistically less in the MDO group (20.3 vs 53.3%; P < 0.02). CONCLUSIONS: In the heterogeneous population of Robin sequence, MDO demonstrates superior outcomes measures at 1 month and 1 year compared to TLA. Fewer complications occurred in the MDO group compared to the TLA. PMID- 26418794 TI - Systematic Reviews in Craniofacial Trauma-Strengths and Weaknesses. AB - BACKGROUND: Despite substantial advances in the management of craniofacial trauma, numerous clinical questions remain. These are increasingly being answered using systematic reviews (SRs). However, caution is warranted as their validity and role in influencing clinical practice has been called into question. METHODS: A PubMed search was performed in October 2014 to identify SRs published up to and including September 2014 in 35 scientific journals. Two authors independently reviewed the literature and extracted data from included studies. Discrepancies were resolved by consensus. Assessment of multiple systematic reviews (AMSTAR) was used to determine the quality of SRs. RESULTS: The initial search retrieved 3080 articles of which 3051 articles were excluded after screening title and abstract. After full-text review of the remaining 29 articles, 3 additional articles were excluded, thus, leaving 26 SRs for final analysis. Regression analysis demonstrated that the overall number of published SRs increased significantly throughout the period analyzed (P = 0.022). The median AMSTAR score of all SRs was 4.5, consistent with a "poor-to-fair" quality. The interobserver agreement was high, as evidenced by a mean kappa of 0.91. Although there appeared to be a trend toward an increase in AMSTAR score by year over the period analyzed, this failed to reach statistical significance in terms of median (P = 0.36) or absolute (P = 0.26) counts. CONCLUSIONS: A tremendous opportunity exists for improvements in the quality of SRs focusing on craniofacial trauma. In addition to familiarizing authors with quality criteria for SRs, adoption of strict reporting criteria by scientific journals may result in long-term improvements in the quality of reporting. PMID- 26418795 TI - Speech Outcomes After Clinically Indicated Posterior Pharyngeal Flap Takedown. AB - BACKGROUND: Velopharyngeal insufficiency affects as many as one in three patients after cleft palate repair. Correction using a posterior pharyngeal flap (PPF) has been shown to improve clinical speech symptomatology; however, PPFs can be complicated by hyponasality and obstructive sleep apnea. The goal of this study was to assess if speech outcomes revert after clinically indicated PPF takedown. METHODS: The cleft-craniofacial database of the Children's Hospital of Pittsburgh at the University of Pittsburgh Medical Center was retrospectively queried to identify patients with a diagnosis of velopharyngeal insufficiency treated with PPF who ultimately required takedown. Using the Pittsburgh Weighted Speech Score (PWSS), preoperative scores were compared to those after PPF takedown. Outcomes after 2 different methods of PPF takedown (PPF takedown alone or PPF takedown with conversion to Furlow palatoplasty) were stratified and cross-compared. RESULTS: A total of 64 patients underwent takedown of their PPF. Of these, 18 patients underwent PPF takedown alone, and 46 patients underwent PPF takedown with conversion to Furlow Palatoplasty. Patients averaged 12.43 (range, 3.0 22.0)(SD: 3.93) years of age at the time of PPF takedown, and 58% were men. Demographics between groups were not statistically different. The mean duration of follow-up after surgery was 38.09 (range, 1-104) (SD, 27.81) months. For patients undergoing PPF takedown alone, the mean preoperative and postoperative PWSS was 3.83 (range, 0.0-23.0) (SD, 6.13) and 4.11 (range, 0.0-23.0) (SD, 5.31), respectively (P = 0.89). The mean change in PWSS was 0.28 (range, -9.0 to 7.0) (SD, 4.3). For patients undergoing takedown of PPF with conversion to Furlow palatoplasty, the mean preoperative and postoperative PWSS was 6.37 (range, 0-26) (SD, 6.70) and 3.11 (range, 0.0-27.0) (SD, 4.14), respectively (P < 0.01). The mean change in PWSS was -3.26 (range, -23.0 to 4.0) (SD, 4.3). For all patients, the mean preoperative PWSS was 5.66 (range, 0.0-26) (SD, 6.60) and 3.39 (range, 0.0-27) (SD, 4.48), respectively (P < 0.05). The mean change in PWSS was -2.26 (range, -23.0 to 7) (SD, 5.7). There was no statistically significant regression in PWSS for either surgical intervention. Two patients in the PPF takedown alone cohort demonstrated deterioration in PWSS that warranted delayed conversion to Furlow palatoplasty. Approximately 90% of patients, who undergo clinically indicated PPF takedown alone, without conversion to Furlow Palatoplasty, will show no clinically significant reduction in speech. CONCLUSIONS: Although there is concern that PPF takedown may degrade speech, this study finds that surgical takedown of PPF, when clinically indicated, does not result in a clinically significant regression of speech. PMID- 26418796 TI - Do Wound Cultures Give Information About the Microbiology of Blood Cultures in Severe Burn Patients? AB - BACKGROUND: Blood stream infection (BSI) and the subsequent development of sepsis are among the most common infection complications occurring in severe burn patients. This study was designed to evaluate the relationship between the burn wound flora and BSI pathogens. METHODS: Documentation of all bacterial and fungal wound and blood isolates from severe burn patients hospitalized in the burn unit and intensive care unit was obtained from medical records retrieved retrospectively from a computerized, hospital-wide database over a 13-year period. All data were recorded in relation to the Ryan score. RESULTS: Of 195 severe burn patients, 88 had at least 1 BSI episode. Transmission of the same pathogen from wound to blood was documented in 30% of the patients, with a rising BSI frequency as the Ryan score increased. There were a total of 263 bacteremic episodes in 88 study patients, 44% of blood isolates were documented previously in wound cultures, and transmission of the same pathogen from wound to blood was noted in 65% of bacteremic patients. CONCLUSIONS: When there is clinical suspicion of sepsis, appropriate empirical systemic antibiotic therapy should be broad spectrum and should rely on the susceptibility of the organisms from recent cultures of the burn wound surface, until the blood cultures results are completed. PMID- 26418797 TI - Status of Microsurgical Simulation Training in Plastic Surgery: A Survey of United States Program Directors. AB - PURPOSE: Various simulation models for microsurgery have been developed to overcome the limitations of Halstedian training on real patients. We wanted to assess the status of microsurgery simulation in plastic surgery residency programs in the United States. METHODS: Data were analyzed from responses to a survey sent to all plastic surgery program directors in the United States, asking for type of simulation, quality of facilities, utilization by trainees, evaluation of trainee sessions, and perception of the relevance of simulation. RESULTS: The survey response rate was 50%. Of all programs, 69% provide microsurgical simulation and 75% of these have a laboratory with microscope and 52% provide live animal models. Half share facilities with other departments. The quality of facilities is rated as good or great in 89%. Trainee utilization is once every 3 to 6 months in 82% of programs. Only in 11% is utilization monthly. Formal evaluation of simulation sessions is provided by 41% of programs. All program directors agree simulation is relevant to competence in microsurgery, 60% agree simulation should be mandatory, and 43% require trainees to complete a formal microsurgery course prior to live surgery. DISCUSSION: There seems to be consensus that microsurgical simulation improves competence, and the majority of program directors agree it should be mandatory. Developing and implementing standardized simulation modules and assessment tools for trainees across the nation as part of a comprehensive competency-based training program for microsurgery is an important patient safety initiative that should be considered. Organizing with other departments to share facilities may improve their quality and hence utilization. PMID- 26418798 TI - Improvement of Split Skin Graft Quality Using a Newly Developed Collagen Scaffold as an Underlayment in Full Thickness Wounds in a Rat Model. AB - INTRODUCTION: Frequently, full thickness skin defects were treated through split skin graft (SSG) transplantation. However, this is usually associated with a reduction of skin quality and scarring. In this context, a newly developed collagen cell carrier (CCC) has been evaluated as an underlayment in SSG transplantations in a rat model. MATERIALS AND METHODS: Twenty-eight standardized full thickness skin defects were generated on the back of 28 adult male Lewis rats. The wounds were randomized and treated with SSG transplantation solitarily (n = 14) or SSG transplantation using CCC as an underlayment (n = 14). For skin quality analysis, a histological evaluation was performed 3 months postoperative in regard to epidermal cell count and epidermal and dermal thickness. RESULTS: Wounds treated with SSG and CCC demonstrated a thicker epidermis and significantly higher epidermal cell count compared to SSG solitarily. At the time of evaluation, epidermal thickness of SSG and CCC was comparable to untreated, healthy skin (no statistically significant differences). DISCUSSION: As split skin grafting is frequently associated with skin quality reduction, the presented results reveal the beneficial effects of CCC in terms of skin graft quality improvement. This may offer unique opportunities in wound management and encourages further evaluation of CCC in surgical applications and regenerative medicine. PMID- 26418799 TI - Botulinum Toxin Use in Pediatric Plastic Surgery. AB - Botulinum toxin has increasingly become a prevalent treatment option for a wide range of conditions, many of which have their roots in plastic surgery and have been well studied. In adults, chronic headache, hyperhidrosis, and facial muscular hypertrophy have been effectively treated with botulinum toxin, and emerging studies have begun looking at its efficacy in children, as well. Successful treatment of spasticity and muscular contraction has allowed for the creation of safety profiles and dosage guidelines for botulinum toxin usage in children. The expanded indications for its use have since flourished in all arenas of pediatric care, including plastic surgery. Recent studies have described the use of botulinum toxin as an adjunct to the treatment of congenital torticollis and cleft lip. This review discusses the various applications of botulinum toxin for pediatric patients in the field of plastic surgery. PMID- 26418800 TI - Strategies for the Optimal Individualized Surgical Management of Craniofacial Fibrous Dysplasia. AB - BACKGROUND: The surgical management of craniofacial fibrous dysplasia is controversial. The purpose of this study was to report the surgical outcomes of individualized management of craniofacial fibrous dysplasia of a single institution. METHODS: Data from patients (n = 20) with craniofacial fibrous dysplasia, who were surgically treated between 2007 and 2014, were analyzed. Surgical approach (radical or conservative surgery) was individualized according to age, craniofacial anatomical site (zones I to IV of Chen and Noordhoff), functional issues, aesthetic impairment, patients/parents' preferences, and surgical team experience. The surgical outcomes (radical surgery group versus conservative surgery group) were compared based on the age at the time of the procedure, the length of hospital stay, reoperation, recurrence and complication rates, and the Whitaker grading system. RESULTS: Significant (all P < 0.05) differences were observed in patients with craniofacial fibrous dysplasia who were treated with radical excision (65%) compared with those treated with limited reduction burring (35%), according to age (19.22 years versus 12.57 years), the length of hospital stay (3.56 days versus 1.29 days), recurrence (15% versus 71%), and number of subsequent procedures (1 intervention versus 2.4 interventions), respectively. The radical surgery group presented a significantly (P < 0.05) lower initial Whitaker outcome score than the conservative surgery group (1.89 and 2.57, respectively). Similar (all P > 0.05) final Whitaker outcome scores (1.56 versus 1.71) and surgical complication rates (11% versus 14%) were recorded between the treatment groups. CONCLUSIONS: Based on clinical experience and surgical outcomes presented in this study, the surgical approach of craniofacial fibrous dysplasia should be tailored to individual patient's needs. PMID- 26418803 TI - Autologous Fat Grafting With Combined Three-Dimensional and Mirror-Image Analyses for Progressive Hemifacial Atrophy. AB - BACKGROUND: Autologous fat grafting (AFG) has been widely used to treat progressive hemifacial atrophy (PHA). However, objective and quantitative analyses in patients with PHA are complicated because of multidimensional atrophy and fat absorption. This study aimed to introduce a new method to predict volumetric deficiency of soft tissues and objectively evaluate the survival of grafted fat with 3-dimensional (3D) and mirror-image analysis (MIA). METHODS: Thirty-one patients with PHA were classified into 2 groups based on the location of the facial midsagittal plane (FMP), which was established through our proposed method using nasion (point a), anterior nasal spine (point b), and pogonion (point c). The included cases with centered FMP were treated using serial AFG and followed up for 12 to 15 months. Images were obtained preoperatively (pre-OP) and postoperatively at 2 time points (3 months and 12 months). Three-dimensional computed tomography (CT) was performed before the first surgery to locate the FMP and predict the volumetric deficiency of soft tissues with MIA. Three months after the first surgery, 3D laser scanning was conducted to evaluate the volume of surviving fat. Patient characteristics, satisfaction, and soft tissue augmentation results were analyzed. RESULTS: Twenty-seven cases (9 men and 18 women) with PHA were included and treated using serial AFG (mean number of operation, 3.1 times). The mean age was 22.1 years. With 3D CT or 3D laser scanning camera and MIA, we obtained the mean deficient volume of the affected area (30.48 mm) and the mean volume of the total fat injection (133.61 mm). The mean fat absorption ratio was 47.92%. The mean satisfaction score immediately obtained at first postoperative (score = 4.3) was higher than that at 3 months postoperatively (score = 4.1) and 12 months postoperatively (score = 4.0). No complications and donor-site morbidity were noted. CONCLUSION: The facial symmetry of patients with centered FMP can be successfully restored using serial AFG alone. The combined 3D and MIA can be used to predict the volumetric deficiency of soft tissues and objectively evaluate the survival of grafted fat. PMID- 26418804 TI - Reconstruction of a Nose Bitten and Eaten by a Dog: A Ten-Year Follow-up of a Bitten-Off Nose Replantation Performed on an Eleven-Year-Old Boy. AB - The nose is one of the most important aesthetic units of the face. After a traumatic amputation, replantation is undoubtedly the procedure of choice, although, technically, very challenging. We report the 10-year follow-up of a partially digested nose replantation after a dog-bite in an 11-year-old boy using supermicrosurgery technique. Our report confirms that the microsurgical replantation of the nose can lead to an acceptable aesthetic result, with the sufficient growth of the replanted part in the following years. Besides the patient did not report sensibility disorders. The nose replantation in our opinion is the best reconstructive option to achieve an optimal aesthetic and functional outcome. PMID- 26418805 TI - A Standardized Method of Isolating Adipose-Derived Stem Cells for Clinical Applications. AB - White adipose tissue is the most abundant and accessible source of stem cells in the adult human body. In this paper, we present a standardised and safe method of isolating and maximizing the number of adipose-derived stem cells (ASCs) from conventional liposuction for clinical applications, which was carried out through both mechanical (centrifuge) and enzymatic (collagenase) means. Isolated cells were characterized through flow cytometry assay. Gathered data showed a greater amount (9.06 * 10(5) ASCs from 100 mL of adipose tissue) of isolated ASCs compared to previous protocol, also with high (99%) cell vitality; the procedure we presented is easy and fast (80 minutes), allowing collecting a significative number of mesenchymal stem cells, which can be used for clinical purposes, such as wound healing. PMID- 26418806 TI - Differences in the Postoperative Outcomes According to the Primary Treatment Options Chosen by Patients With Carpal Tunnel Syndrome: Conservative Versus Operative Treatment. AB - PURPOSE: We prospectively analyzed the differences in the preoperative status and final outcomes between patients with or without the motivation for prompt surgery after a recent diagnosis of carpal tunnel syndrome (CTS). METHODS: One hundred fifty-six patients were enrolled and followed up from a cohort of 220 patients who were diagnosed with CTS between 2011 and 2013. Basic demographic factors, including the occupational features, were investigated in group 1 (n = 52, conservative treatment followed by surgery) and group 2 (n = 100, surgery immediately after diagnosis). The preoperative electrodiagnosis, clinical items by Graham, Disabilities of the Arm, Shoulder, and Hand (DASH) outcomes questionnaire, Boston Carpal Tunnel Questionnaire scores, and grip/pinch strengths were evaluated, and the degree of improvements was compared. RESULTS: The onset period of the symptoms or signs, as well as the time from the diagnosis to surgery, was significantly longer in group 1 than in group 2. In group 1, nonprofessional, simple, and repetitive jobs were more prevalent; however, the professional category was more common in group 2. The preoperative distributions among the electrodiagnostic grades were not different in both groups. Most of the clinical items by Graham were more definitively improved in group 2. DASH improvement at the final follow-up was meaningfully more in group 2 (34 +/- 5.3) than in group 1 (29 +/- 6.5). Boston Carpal Tunnel Questionnaire showed a similar trend regarding the DASH score (preoperative, improvement at the final follow-up) with statistical significance. The increase in grip/pinch strength was also greater in group 2. CONCLUSIONS: Most patients, who refused/delayed surgery as the initial treatment for CTS, were not improved by conservative options. Eventually, carpal tunnel release was performed; however, the overall outcomes were inferior compared with those of the groups who agreed to operative treatment as the initial option. PMID- 26418807 TI - Characterization and exposure measurement for indium oxide nanofibers generated as byproducts in the LED manufacturing environment. AB - This article aimed to elucidate the physicochemical characteristics and exposure concentration of powder and airborne particles as byproducts generated from indium tin oxide thin film process by an electron beam evaporation method during maintenance in light-emitting diode manufacturing environment. The chemical composition, size, shape, and crystal structure of powder and airborne particles as byproducts were investigated using a scanning electron microscope equipped with energy dispersive spectrometer, and an X-ray diffractometer. The number and mass concentration measurements of airborne particles were performed by using an optical particle counter of direct-reading aerosol monitor and an inductively coupled plasma-mass spectrometry after sampling, respectively. The airborne particles are composed of oxygen and indium. On the other hand, the powder byproducts consist mostly of oxygen and indium, but tin was found as a minor component. The shapes of the airborne and powder byproducts were fiber type. The length and diameter of fibrous particles were approximately 500-2,000 nm and 30 50 nm, respectively. The powder byproducts indicated indium oxide nanofibers with a rhombohedral structure. On the other hand, the indium oxide used as a source material in the preparation of ITO target showed spherical morphology with a body centered cubic structure, and it was the same as that of the pure crystalline indium oxide powder. During maintenance, the number concentrations ranged from 350-75,693 particles/ft(3), and arithmetic mean+/-standard deviation and geometric mean+/-geometric standard deviation were 11,624+/-15,547 and 4,846+/ 4.12 particles/ft(3), respectively. Meanwhile, under the same conditions, the airborne mass concentrations of the indium based on respirable particle size (3.5 um cut-point 50%) were 0.09-0.19 ug/m(3). Physicochemical characteristics of nanoparticle can affect toxicity so the fact that shape and crystal structure have changed is important. Thus, nanoparticle occupational toxicology greatly needs observations like this. PMID- 26418808 TI - Fucoxanthin Inhibits the Inflammation Response in Paw Edema Model through Suppressing MAPKs, Akt, and NFkappaB. AB - Undaria pinnatifida is a well-known traditional Korean food with a variety of biological activities. Carrageenan (carr) is commonly used to induce paw edema in animal models. This study was designed to elucidate the processes underlying the anti-inflammatory effect of fucoxanthin isolated from the sporophyll of U. pinnatifida in carr-induced paw edema in ICR mice. Fucoxanthin significantly decreased carr-induced increased nitric oxide levels in the plasma of mice with carr-induced paw edema. Fucoxanthin protected catalase (CAT) and superoxide dismutase (SOD) activity against disruption in mice with carr-induced paw edema. In addition, fucoxanthin repressed carr-induced activation of inducible nitric oxide synthase, cyclooxygenase-2, and nuclear factor kappa B, as well as carr induced phosphorylation of mitogen-activated protein kinase, extracellular signal regulated kinase, c-Jun N-terminal kinase, p38, and protein kinase B/Akt. These results suggest that fucoxanthin may have therapeutic potential as a treatment for patients with inflammatory diseases. PMID- 26418809 TI - Coexisting Membranous Nephropathy and IgA Nephropathy. AB - We herein present a case of a 14-year-old boy with the histological features of coexisting membranous nephropathy (MN) and IgA nephropathy (IgAN). Asymptomatic hematuria/proteinuria was initially detected in school urinary screening, with treatments including oral corticosteroids leading to complete remission. Cases of coexisting MN and IgAN are very rare among the pediatric population; however, the overlap of these two nephropathies does not always imply a deleterious clinical outcome in pediatric cases. PMID- 26418810 TI - Evidence of Notch-Hesr-Nrf2 Axis in Muscle Stem Cells, but Absence of Nrf2 Has No Effect on Their Quiescent and Undifferentiated State. AB - Nrf2 is a master regulator of oxidative stresses through the induction of anti oxidative genes. Nrf2 plays roles in maintaining murine hematopoietic stem cells and fly intestinal stem cells. The canonical Notch signaling pathway is also crucial for maintaining several types of adult stem cells including muscle stem cells (satellite cells). Here, we show that Dll1 induced Nrf2 expression in myogenic cells. In addition, primary targets of Notch signaling, Hesr1 and Hesr3, were involved in the up-regulation of Nrf2 mRNA and expression of its target genes. In vitro, Nrf2 had anti-myogenic and anti-proliferative effects on primary myoblasts. In vivo, although Nrf2-knockout mice showed decreased expression of its target genes in muscle stem cells, adult muscle stem cells of Nrf2-knockout mice did not exhibit the phenotype. Taken together, in muscle stem cells, the Notch-Hesr-Nrf2 axis is a pathway potentially inducing anti-oxidative genes, but muscle stem cells either do not require Nrf2-mediated anti-oxidative gene expression or they have a complementary system compensating for the loss of Nrf2. PMID- 26418811 TI - Expanding Functionality of Commercial Optical Coherence Tomography Systems by Integrating a Custom Endoscope. AB - Optical coherence tomography (OCT) is a useful imaging modality for detecting and monitoring diseases of the gastrointestinal tract and other tubular structures. The non-destructiveness of OCT enables time-serial studies in animal models. While turnkey commercial research OCT systems are plenty, researchers often require custom imaging probes. We describe the integration of a custom endoscope with a commercial swept-source OCT system and generalize this description to any imaging probe and OCT system. A numerical dispersion compensation method is also described. Example images demonstrate that OCT can visualize the mouse colon crypt structure and detect adenoma in vivo. PMID- 26418812 TI - Layer-by-Layers of Polymeric Micelles as a Biomimetic Drug-Releasing Network. AB - Mucin networks are lubricous biofunctional coats formed through the continuous deposition of mucin glycoproteins. Previously, we demonstrated the synthesis of a mucin mimic using biotinylated-filomicelles crosslinked via streptavidin using a layer-by-layer approach. These networks recreate the fibrous nature of mucin and can serve as a drug-releasing network. In this work, the ability to vary the network properties by blending filomicelles with spherical micelles is demonstrated. In addition, the deposition of a dense polymer coating on the mucin network was shown to act as a barrier to control diffusion and improved the structural stability under simulated oral chemical conditions. These biomimetic coatings can be utilized as a delivery system, providing a tunable drug release for oral applications. PMID- 26418814 TI - Highly Regioselective Palladium-Catalyzed Carboxylation of Allylic Alcohols with CO2. AB - Various allylic alcohols were carboxylated in the presence of a catalytic amount of PdCl2 and PPh3 using ZnEt2 as a stoichiometric transmetalation agent under a CO2 atmosphere (1 atm). This carboxylation proceeded in a highly regioselective manner to afford branched carboxylic acids predominantly. The beta,gamma unsaturated carboxylic acid thus obtained was successfully converted into an optically active gamma-butyrolactone, a known intermediate of (R)-baclofen. PMID- 26418813 TI - Effectiveness of a Home-Based Counselling Strategy on Neonatal Care and Survival: A Cluster-Randomised Trial in Six Districts of Rural Southern Tanzania. AB - BACKGROUND: We report a cluster-randomised trial of a home-based counselling strategy, designed for large-scale implementation, in a population of 1.2 million people in rural southern Tanzania. We hypothesised that the strategy would improve neonatal survival by around 15%. METHODS AND FINDINGS: In 2010 we trained 824 female volunteers to make three home visits to women and their families during pregnancy and two visits to them in the first few days of the infant's life in 65 wards, selected randomly from all 132 wards in six districts in Mtwara and Lindi regions, constituting typical rural areas in Southern Tanzania. The remaining wards were comparison areas. Participants were not blinded to the intervention. The primary analysis was an intention-to-treat analysis comparing the neonatal mortality (day 0-27) per 1,000 live births in intervention and comparison wards based on a representative survey in 185,000 households in 2013 with a response rate of 90%. We included 24,381 and 23,307 live births between July 2010 and June 2013 and 7,823 and 7,555 live births in the last year in intervention and comparison wards, respectively. We also compared changes in neonatal mortality and newborn care practices in intervention and comparison wards using baseline census data from 2007 including 225,000 households and 22,243 births in five of the six intervention districts. Amongst the 7,823 women with a live birth in the year prior to survey in intervention wards, 59% and 41% received at least one volunteer visit during pregnancy and postpartum, respectively. Neonatal mortality reduced from 35.0 to 30.5 deaths per 1,000 live births between 2007 and 2013 in the five districts, respectively. There was no evidence of an impact of the intervention on neonatal survival (odds ratio [OR] 1.1, 95% confidence interval [CI] 0.9-1.2, p = 0.339). Newborn care practices reported by mothers were better in intervention than in comparison wards, including immediate breastfeeding (42% of 7,287 versus 35% of 7,008, OR 1.4, CI 1.3-1.6, p < 0.001), feeding only breast milk for the first 3 d (90% of 7,557 versus 79% of 7,307, OR 2.2, 95% CI 1.8-2.7, p < 0.001), and clean hands for home delivery (92% of 1,351 versus 88% of 1,799, OR 1.5, 95% CI 1.0-2.3, p = 0.033). Facility delivery improved dramatically in both groups from 41% of 22,243 in 2007 and was 82% of 7,820 versus 75% of 7,553 (OR 1.5, 95% CI 1.2-2.0, p = 0.002) in intervention and comparison wards in 2013. Methodological limitations include our inability to rule out some degree of leakage of the intervention into the comparison areas and response bias for newborn care behaviours. CONCLUSION: Neonatal mortality remained high despite better care practices and childbirth in facilities becoming common. Public health action to improve neonatal survival in this setting should include a focus on improving the quality of facility-based childbirth care. TRIAL REGISTRATION: ClinicalTrials.gov NCT01022788. PMID- 26418815 TI - Novel sirtuin inhibitory warheads derived from the N(epsilon)-acetyl-lysine analog L-2-amino-7-carboxamidoheptanoic acid. AB - Built upon the catalytic mechanism-based pan-SIRT1/2/3 inhibitory warhead L-2 amino-7-carboxamidoheptanoic acid (L-ACAH, a close structural analog of N(epsilon)-acetyl-lysine) that our laboratory discovered recently, in the current study, its carboxamide NH2-ethylated analog was found to be a ~2.4-6.6-fold stronger SIRT1/2/3 inhibitory warhead than L-ACAH. Carboxamide NH2-dodecylated and carboxymethylated analogs of L-ACAH were also identified as potent SIRT6 and SIRT5 inhibitory warheads, respectively. PMID- 26418817 TI - Human Rights Texts: Converting Human Rights Primary Source Documents into Data. AB - We introduce and make publicly available a large corpus of digitized primary source human rights documents which are published annually by monitoring agencies that include Amnesty International, Human Rights Watch, the Lawyers Committee for Human Rights, and the United States Department of State. In addition to the digitized text, we also make available and describe document-term matrices, which are datasets that systematically organize the word counts from each unique document by each unique term within the corpus of human rights documents. To contextualize the importance of this corpus, we describe the development of coding procedures in the human rights community and several existing categorical indicators that have been created by human coding of the human rights documents contained in the corpus. We then discuss how the new human rights corpus and the existing human rights datasets can be used with a variety of statistical analyses and machine learning algorithms to help scholars understand how human rights practices and reporting have evolved over time. We close with a discussion of our plans for dataset maintenance, updating, and availability. PMID- 26418816 TI - Scalable Production of Recombinant Membrane Active Peptides and Its Potential as a Complementary Adjunct to Conventional Chemotherapeutics. AB - The production of short anticancer peptides in recombinant form is an alternative method for costly chemical manufacturing. However, the limitations of host toxicity, bioactivity and column purification have impaired production in mass quantities. In this study, short cationic peptides were produced in aggregated inclusion bodies by double fusion with a central protein that has anti-cancer activity. The anticancer peptides Tachiplicin I (TACH) and Latarcin 1 (LATA) were fused with the N- and C-terminus of the MAP30 protein, respectively. We successfully produced the recombinant TACH-MAP30-LATA protein and MAP30 alone in E. coli that represented 59% and 68% of the inclusion bodies. The purified form of the inclusion bodies was prepared by eliminating host cell proteins through multiple washing steps and semi-solubilization in alkaline buffer. The purified active protein was recovered by inclusive solubilization at pH 12.5 in the presence of 2 M urea and refolded in alkaline buffer containing oxides and reduced glutathione. The peptide-fusion protein showed lower CC50 values against cancer cells (HepG2, 0.35+/-0.1 MUM and MCF-7, 0.58+/-0.1 MUM) compared with normal cells (WRL68, 1.83+/-0.2 MUM and ARPE19, 2.5+/-0.1 MUM) with outstanding activity compared with its individual components. The presence of the short peptides facilitated the entry of the peptide fusion protein into cancer cells (1.8 to 2.2-fold) compared with MAP30 alone through direct interaction with the cell membrane. The cancer chemotherapy agent doxorubicin showed higher efficiency and selectivity against cancer cells in combination with the peptide- fusion protein. This study provides new data on the mass production of short anticancer peptides as inclusion bodies in E. coli by fusion with a central protein that has similar activity. The product was biologically active against cancer cells compared with normal cells and enhanced the activity and selective delivery of an anticancer chemotherapy agent. PMID- 26418818 TI - Unexpectedly Stable (Chlorocarbonyl)(N-ethoxycarbonylcarbamoyl)disulfane, and Related Compounds That Model the Zumach-Weiss-Kuhle (ZWK) Reaction for Synthesis of 1,2,4-Dithiazolidine-3,5-diones. AB - The Zumach-Weiss-Kuhle (ZWK) reaction provides 1,2,4-dithiazolidine-3,5-diones [dithiasuccinoyl (Dts)-amines] by the rapid reaction of O-ethyl thiocarbamates plus (chlorocarbonyl)sulfenyl chloride, with ethyl chloride and hydrogen chloride being formed as coproducts, and carbamoyl chlorides or isocyanates generated as yield-diminishing byproducts. However, when the ZWK reaction is applied with (N ethoxythiocarbonyl)urethane as the starting material, heterocyclization to the putative "Dts-urethane" does not occur. Instead, the reaction directly provides (chlorocarbonyl)(N-ethoxycarbonylcarbamoyl)disulfane, a reasonably stable crystalline compound; modified conditions stop at the (chlorocarbonyl)[1-ethoxy (N-ethoxycarbonyl)formimidoyl]disulfane intermediate. The title (chlorocarbonyl)(carbamoyl)disulfane cannot be converted to the elusive Dts derivative, but rather gives (N-ethoxycarbonyl)carbamoyl chloride upon thermolysis, or (N-ethoxycarbonyl)isocyanate upon treatment with tertiary amines. Additional transformations of these compounds have been discovered, providing entries to both known and novel species. X-ray crystallographic structures are reported for the title (chlorocarbonyl)(carbamoyl)disulfane; for (methoxycarbonyl)(N-ethoxycarbonylcarbamoyl)disulfane, which is the corresponding adduct after quenching in methanol; for [1-ethoxy-(N ethoxycarbonyl)formimidoyl](N'-methyl-N'-phenylcarbamoyl)disulfane, which is obtained by trapping the title intermediate with N-methylaniline; and for (N ethoxycarbonylcarbamoyl)(N'-methyl-N'-phenylcarbamoyl)disulfane, which is a short lived intermediate in the reaction of the title (chlorocarbonyl)(carbamoyl)disulfane with excess N-methylaniline. The new chemistry and structural information reported herein is expected to contribute to accurate modeling of the ZWK reaction trajectory. PMID- 26418819 TI - Predictive Factors Affecting Long-Term Outcome of Unilateral Lateral Rectus Recession. AB - BACKGROUND: There are few long-term outcome reports of unilateral lateral rectus (LR) recession for exotropia including a large number of subjects. Previous reports on unilateral LR recession commonly show extremely low rates of initial overcorrection and large exodrifts after surgery suggesting that the surgical dose may be increased. However, little is known of the long-term outcome of a large unilateral LR recession for exotropia. OBJECTIVES: To determine long-term outcomes and predictive factors of recurrence after a large unilateral LR recession in patients with exotropia. DATA EXTRACTION: Retrospective analysis was performed on 92 patients aged 3 to 17 years who underwent 10 mm unilateral LR recession for exotropia of <= 25 prism diopters (Delta) with prism and alternate cover testing and were followed up for more than 2 years after surgery. Final success rates within 10Delta of exophoria/tropia and 5Delta of esophoria/tropia at distance in the primary position, improvement in stereopsis and the predictive factors for recurrence were evaluated. RESULTS: At 24 months after surgery, 54% of patients had ocular alignment meeting the defined criteria of success, 45% had recurrence and 1% had overcorrection. After a mean follow-up of 39 months, 36% showed success, 63% showed recurrence and 1% resulted in overcorrection. The average time of recurrence was 23.4+/-14.7 months (range, 1-60 months) and the rate of recurrence per person-year was 23% after unilateral LR recession. Predictive factors of recurrence were a larger preoperative near angle of deviation (>16Delta) and larger initial postoperative exodeviation (>5Delta) at distance. CONCLUSIONS: Long-term outcome of unilateral LR recession for exotropia showed low success rates with high recurrence, thus should be reserved for patients with a small preoperative near angle of exodeviation. PMID- 26418820 TI - Asymmetric Construction of 3,4-Diamino Pyrrolidines via Chiral N,O-Ligand/Cu(I) Catalyzed 1,3-Dipolar Cycloaddition of Azomethine Ylides with beta Phthalimidonitroethene. AB - A series of chiral N,O-ligands derived from a 1,2-dihydroimidazo[1,2-a]quinolone motif have been evaluated for the asymmetric 1,3-dipolar cycloaddition of azomethine ylides with a novel dipolarophile beta-phthalimidonitroethene. A newly designed DHIPOH ligand 7c bearing 1-methyl and 4-iodo substituents was found to have significant "synergistic steric effects" and consequently afforded the corresponding 4-nitro-3-aminopyrrolidines with excellent diastereo- (dr up to 98:2) and enantio selectivities (ee up to 99%). Subsequent Raney Ni-catalyzed reduction and deprotection of phthalyl led to the structurally and biologically important 3,4-diaminopyrrolidines in a straightforward and efficient pathway. PMID- 26418821 TI - An update on Curcuma as a functional food in the control of cancer and inflammation. AB - PURPOSE OF REVIEW: Curcumin, commonly known as turmeric, is a spice that comes from the root Curcuma longa. The present article presents an update of new studies of curcumin activities as tested in anticancer models from 2011 to 2015. RECENT FINDINGS: Evidence from in-vitro and in-vivo research, together with clinical trials conducted over the past few decades, substantiates the potential of curcumin as an anticancer and anti-inflammatory agent. The development of formulations of curcumin in the form of nanoparticles, liposomes, micelles, or phospholipid complexes to enhance its bioavailability and efficacy are still in the early stages. Clinical trials with curcumin indicate safety, tolerability, and nontoxicity. However, the efficacy is questionable, based on the small numbers of patients in each study. SUMMARY: The laboratory and the clinical studies until 2011 were summarized in a review published in this journal. An update of the new studies and knowledge from 2011 to March 2015 focuses on new ways to overcome its low bioavailability and data from clinical trials. PMID- 26418822 TI - Gluten-free and casein-free diets in the therapy of autism. AB - PURPOSE OF REVIEW: The purpose of this study is to discuss the role of gluten free and casein-free diets in the treatment of autism. RECENT FINDINGS: In a recent UK survey, more than 80% of parents of children with autism spectrum disorder reported some kind of dietary intervention for their child (gluten-free and casein-free diet in 29%). When asked about the effects of the gluten-free and casein-free diet, 20-29% of the parents reported significant improvements on the autism spectrum disorder core dimensions. The findings of this study suggest additional effects of a gluten-free and casein-free diet on comorbid problems of autism such as gastrointestinal symptoms, concentration, and attention. The findings of another recent investigation suggested that age and certain urine compounds may predict the response of autism symptoms to a gluten-free and casein free diet. Although these results need to be replicated, they highlight the importance of patient subgroup analysis. Intervention trials evaluating the effects of a gluten-free and casein-free diet on autistic symptoms have so far been contradictory and inconclusive. SUMMARY: Most investigations assessing the efficacy of a gluten-free and casein-free diet in the treatment of autism are seriously flawed. The evidence to support the therapeutic value of this diet is limited and weak. A gluten-free and casein-free diet should only be administered if an allergy or intolerance to nutritional gluten or casein is diagnosed. PMID- 26418823 TI - Micronutrient deficiencies in inflammatory bowel disease. AB - PURPOSE OF REVIEW: Malnutrition, protein-energy, and micronutrient deficiencies are common among patients with inflammatory bowel disease (IBD). The deficiencies are a manifestation of the complicated disease and a cause of morbidity. The present review summarizes recent advances and evidence-based knowledge regarding micronutrients in relation to patients with IBD. RECENT FINDINGS: Micronutrient deficiencies occur in more than half of patients with IBD. Most common are deficiencies of iron, B12, vitamin D, vitamin K, folic acid, selenium, zinc, vitamin B6, and vitamin B1. Deficiencies are more common in Crohn's disease than in ulcerative colitis, and more in active disease than at times of remission. Micronutrient deficiency is associated with prolonged and complicated course of disease. Iron deficiency is the most common cause for anemia. Definite diagnosis of B12 deficiency cannot be established by serum levels alone. Vitamin D and vitamin K deficiencies are thought to be associated with heightened inflammatory state. The relationship of these deficiencies with bone disease is controversial. The present review focuses on the significance, epidemiology, treatment options, and recommendations regarding micronutrient deficiencies in IBD. SUMMARY: Micronutrient deficiencies are common and have clinical significance. High suspicion for micronutrient deficiencies is advocated so that treatable causes of morbidity are treated appropriately and late and irreversible sequlae are prevented. PMID- 26418825 TI - Map of Visual Activity in the Infant Brain Sheds Light on Neural Development. AB - A new study reveals that despite their limited visual acuity, 7-week-old babies have a surprisingly advanced visual cortex, including the ability to integrate visual and vestibular motion information. Read the accompanying Research Article. PMID- 26418824 TI - Osteoporosis and sarcopenia: two diseases or one? AB - PURPOSE OF REVIEW: This article reviews recently published evidence for common pathways explaining bone and muscle wasting in normal ageing and pathological conditions. RECENT FINDINGS: Numerous studies support the concept of a bone muscle unit, where constant cross-talking between the two tissues takes place, involving molecules released by the skeletal muscle secretome, which affects bone, and osteokines secreted by the osteoblasts and osteocytes, which, in turn, impact muscle cells. SUMMARY: New chemical entities aiming at concomitantly treating osteoporosis and sarcopenia could be developed by targeting pathways that centrally regulate bone and muscle or emerging pathways that facilitate the communication between the two tissues. PMID- 26418826 TI - Anemia in Chronic Obstructive Pulmonary Disease and the Potential Role of Iron Deficiency. AB - The purpose of this review is to evaluate the role of anemia on patient outcomes in chronic obstructive pulmonary disease (COPD), the potential contribution that low iron stores may play in this process, and possible treatment considerations. A review of research studies found that anemia is associated with declining functional outcomes, increased health care utilization and costs, and increased mortality in COPD. Associations exist between reduced iron intake and progression of COPD and in reduction of iron status with declining lung function. Currently data are limited on the effects of either treating anemia or utilizing iron supplementation in anemic COPD patients. If iron supplementation might therefore reverse some of the declines that patients experience, then routine screening and treatment may turn out to be an effective, simple and inexpensive intervention. Iron supplementation models utilized in other inflammatory-related disease states were reviewed as a possible starting point to evaluate treatment options in COPD. Future research can be directed to establish best practice standards for the use of iron supplementation in COPD. PMID- 26418827 TI - Slip of Spreading Viscoplastic Droplets. AB - The spreading of axisymmetric viscoplastic droplets extruded slowly on glass surfaces is studied experimentally using shadowgraphy and swept-field confocal microscopy. The microscopy furnishes vertical profiles of the radial velocity using particle image velocimetry (PIV) with neutrally buoyant tracers seeded in the fluid. Experiments were conducted for two complex fluids: aqueous solutions of Carbopol and xanthan gum. On untreated glass surfaces, PIV demonstrates that both fluids experience a significant amount of effective slip. The experiments were repeated on glass that had been treated to feature positive surface charges, thereby promoting adhesion between the negatively charged polymeric constituents of the fluids and the glass surface. The Carbopol and xanthan gum droplets spread more slowly on the treated surface and to a smaller radial distance. PIV demonstrated that this reduced spreading was associated with a substantial reduction in slip. For Carbopol, the effective slip could be eliminated entirely to within the precision of the PIV measurements; the reduction in slip was less effective for xanthan gum, with a weak slip velocity remaining noticeable. PMID- 26418828 TI - Engineering the Organophosphorus Acid Anhydrolase Enzyme for Increased Catalytic Efficiency and Broadened Stereospecificity on Russian VX. AB - The enzyme organophosphorus acid anhydrolase (OPAA), from Alteromonas sp. JD6.5, has been shown to rapidly catalyze the hydrolysis of a number of toxic organophosphorus compounds, including several G-type chemical nerve agents. The enzyme was cloned into Escherichia coli and can be produced up to approximately 50% of cellular protein. There have been no previous reports of OPAA activity on VR {Russian VX, O-isobutyl S-[2-(diethylamino)ethyl] methylphosphonothioate}, and our studies reported here show that wild-type OPAA has poor catalytic efficacy toward VR. However, via application of a structurally aided protein engineering approach, significant improvements in catalytic efficiency were realized via optimization of the small pocket within the OPAA's substrate-binding site. This optimization involved alterations at only three amino acid sites resulting in a 30-fold increase in catalytic efficiency toward racemic VR, with a strong stereospecificity toward the P(+) enantiomer. X-ray structures of this mutant as well as one of its predecessors provide potential structural rationales for their effect on the OPAA active site. Additionally, a fourth mutation at a site near the small pocket was found to relax the stereospecificity of the OPAA enzyme. Thus, it allows the altered enzyme to effectively process both VR enantiomers and should be a useful genetic background in which to seek further improvements in OPAA VR activity. PMID- 26418830 TI - Charge Detection Mass Spectrometry with Almost Perfect Charge Accuracy. AB - Charge detection mass spectrometry (CDMS) is a single-particle technique where the masses of individual ions are determined from simultaneous measurement of each ion's mass-to-charge ratio (m/z) and charge. CDMS has many desirable features: it has no upper mass limit, no mass discrimination, and it can analyze complex mixtures. However, the charge is measured directly, and the poor accuracy of the charge measurement has severely limited the mass resolution achievable with CDMS. Since the charge is quantized, it needs to be measured with sufficient accuracy to assign each ion to its correct charge state. This goal has now been largely achieved. By reducing the pressure to extend the trapping time and by implementing a novel analysis method that improves the signal-to-noise ratio and compensates for imperfections in the charge measurement, the uncertainty has been reduced to less than 0.20 e rmsd (root-mean-square deviation). With this unprecedented precision peaks due to different charge states are resolved in the charge spectrum. Further improvement can be achieved by quantizing the charge (rounding the measured charge to the nearest integer) and culling ions with measured charges midway between the integral values. After ions with charges more than one standard deviation from the mean are culled, the fraction of ions assigned to the wrong charge state is estimated to be 6.4 * 10(-5) (i.e., less than 1 in 15 000). Since almost all remaining ions are assigned to their correct charge state, the uncertainty in the mass is now almost entirely limited by the uncertainty in the m/z measurement. PMID- 26418829 TI - Effects of particle size and binding affinity for small interfering RNA on the cellular processing, intestinal permeation and anti-inflammatory efficacy of polymeric nanoparticles. AB - BACKGROUND: Silencing of excessive secreted tumour necrosis factor (TNF)-alpha from macrophages might be an effective therapy of ulcerative colitis (UC), which acquires improvements on small interfering RNA (siRNA) delivery vectors. Thus, in the present study, the effects of particle size and binding affinity of four polymeric nanoparticles on siRNA delivery for the treatment of UC were evaluated. METHODS: Galactosylated trimethyl chitosan-cysteine (GTC) nanoparticles of varying particle size and binding affinity for siRNA were prepared and TNF-alpha siRNA was encapsulated. Their cellular transport was investigated in murine macrophages and Caco-2 cell monolayers were utilized to analysis the intestinal permeation. Finally, in vivo anti-inflammatory efficacy was assessed in a mouse model of UC. RESULTS: Although marginal effects of particle size on the in vitro gene silencing efficiency were detected, GTC nanoparticles with a particle size of 450 nm and stronger binding affinity for siRNA showed reduced intestinal epithelial permeability and enhanced in vivo anti-inflammatory efficacy compared to those with a particle size of 200 nm. By contrast, the delivery processes were significantly affected by the binding affinity for siRNA, where smaller GTC nanoparticles (200 nm) with moderate siRNA binding strength exhibited remarkable cytoplasmic distribution and sufficient intracellular release of siRNA, as well as a sustained in vitro and in vivo gene silencing effect. CONCLUSIONS: Nanoparticles with a particle size of 450 nm or balanced binding affinity for siRNA might be preferable for the treatment of ulcerative colitis. PMID- 26418831 TI - Carbon Monoxide-Induced Stability and Atomic Segregation Phenomena in Shape Selected Octahedral PtNi Nanoparticles. AB - The chemical and morphological stability of size- and shape-selected octahedral PtNi nanoparticles (NP) were investigated after different annealing treatments up to a maximum temperature of 700 degrees C in a vacuum and under 1 bar of CO. Atomic force microscopy was used to examine the mobility of the NPs and their stability against coarsening, and X-ray photoelectron spectroscopy to study the surface composition, chemical state of Pt and Ni in the NPs, and thermally and CO induced atomic segregation trends. Exposing the samples to 1 bar of CO at room temperature before annealing in a vacuum was found to be effective at enhancing the stability of the NPs against coarsening. In contrast, significant coarsening was observed when the sample was annealed in 1 bar of CO, most likely as a result of Ni(CO)4 formation and their enhanced mobility on the support surface. Sample exposure to CO at room temperature prior to annealing led to the segregation of Pt to the NP surface. Nevertheless, oxidic PtOx and NiOx species still remained at the NP surface, and, irrespective of the initial sample pretreatment, Ni surface segregation was observed upon annealing in a vacuum at moderate temperature (T < 300 degrees C). Interestingly, a distinct atomic segregation trend was detected between 300 and 500 degrees C for the sample pre-exposed to CO; namely, Ni surface segregation was partially hindered. This might be attributed to the higher bonding energy of CO to Pt as compared to Ni. Annealing in the presence of 1 bar CO also resulted in the initial surface segregation of Ni (T < 400 degrees C) as long as PtOx and NiOx species were available on the surface as a result of the higher affinity of Ni for oxygen. Above 500 degrees C, and regardless of the sample pretreatment, the diffusion of Pt atoms to the NP surface and the formation of a Ni-Pt alloy are observed. PMID- 26418832 TI - Early-Onset Vemurafenib-Induced DRESS Syndrome. AB - Vemurafenib is a BRAF inhibitor indicated in metastatic or unresectable melanoma in patients with BRAF mutations. Vemurafenib is frequently toxic, but the toxicity is often not serious. The third case of vemurafenib-induced drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is reported herein. The case is unusual in that the onset was early, with symptoms emerging as of day 8 of treatment. Treatment of DRESS syndrome is not currently based on precise recommendations, but systemic corticosteroid therapy is effective in serious cases. Severe toxidermias under vemurafenib are exceptional; immediate discontinuation of treatment upon diagnosis is imperative. Switching from vemurafenib to dabrafenib then seems to constitute an interesting therapeutic alternative, since its efficacy is the same but with fewer cutaneous adverse reactions. This case highlights the importance of awareness of the risk of DRESS syndrome associated with vemurafenib and monitoring for warning signs from treatment initiation. PMID- 26418833 TI - Asbestos exposure and laryngeal cancer mortality. AB - OBJECTIVES/HYPOTHESIS: Occupational exposure to asbestos occurs in many workplaces and is well known to cause asbestosis, lung cancer, and mesothelioma. However, the link between asbestos exposure and other malignancies was not confirmed. The aim of the current meta-analysis was to provide a summary measure of risk for laryngeal cancer associated with occupational asbestos exposure. STUDY DESIGN: Systematic review and meta-analysis. METHODS: Electronic databases were searched for studies characterizing the association between asbestos and laryngeal cancer. Standardized mortality rate (SMR) with its 95% confidence interval (CI) of each study was combined using a fixed or random effect model. RESULTS: Significantly increased SMR for laryngeal cancer was observed when subjects were exposed to asbestos (SMR = 1.69, 95% CI = 1.45-1.97, P < .001), with little evidence of heterogeneity among studies (Q = 15.39, P = .803, I(2) = 0.0%). Effect estimates were larger for cohorts controlling for male subjects, Europe and Oceania, mining and textile industries, exposure to crocidolite, long study follow-up (>25 years), and SMR for lung cancer > 2.0. Publication bias was not detect by Begg test (P = .910) and Egger test (P = .340). CONCLUSIONS: Our study supports the association of exposure to asbestos with an increased risk of laryngeal cancer mortality among male workers. LEVEL OF EVIDENCE: NA Laryngoscope, 126:1169-1174, 2016. PMID- 26418834 TI - Candida albicans in cystic fibrosis: "Opening statements presented, let the trial begin". PMID- 26418835 TI - Strategies for Providing Constructive Feedback to Students. PMID- 26418836 TI - Authentic Engagement in High-Enrollment Graduate Courses: Pathophysiology Consumers Become Content Creators. AB - The challenge to educate increasing numbers of nursing students at all levels in both online and in-class environments calls for innovative instructional strategies that may include technology-based assignments to help students apply knowledge to clinical situations. This article describes a case study assignment created for a graduate-level pathophysiology course that required students to create digitally enhanced patient stories. Nursing students enrolled in the online and in-class sections of the course worked together using commonly available learning technology tools to create content that bridged pathophysiology concepts and clinical practice. PMID- 26418837 TI - Voice Simulation in Nursing Education. AB - The goal of this study was to improve prelicensure nursing students' attitudes toward and self-efficacy related to delivering nursing care to patients with auditory hallucinations. Based on the Hearing Voices That Are Distressing curriculum, 87 participants were instructed to complete 3 tasks while wearing headphones delivering distressing voices. Comparing presimulation and postsimulation results, this study suggests that the simulation significantly improved attitudes toward patients with auditory hallucinations; however, self efficacy related to caring for these patients remained largely unchanged. PMID- 26418838 TI - Prebriefing in Simulation-Based Learning Experiences. PMID- 26418839 TI - The behavioral characteristics of Sotos syndrome. AB - In this study we describe the levels of clinically significant behavior in participants with Sotos syndrome relative to three matched contrast groups in which the behavioral phenotype is well documented (Autism Spectrum Disorder, ASD; Prader-Willi, and Down syndromes). Parents and carers of 38 individuals with Sotos syndrome (mean age = 17.3; SD = 9.36), completed questionnaires regarding self-injury, aggression, repetitive behavior, autism spectrum phenomenology, overactivity, impulsivity and mood, interest and pleasure. Individuals with Sotos syndrome showed an increased risk of self-injurious behavior, physical aggression, and destruction of property relative to the Down syndrome group but not a greater risk of stereotyped behavior. Impulsivity and levels of activity were also significantly higher relative to those with Down syndrome and comparable to those with ASD. A large proportion of participants met the cut off score for ASD (70.3%) and Autism (32.4%) on the Social Communication Questionnaire. Social impairments were particularly prominent with repetitive behavior and communication impairments less characteristic of the syndrome. Interestingly, preference for routine and repetitive language were heightened in individuals with Sotos syndrome and the repetitive behavior profile was strikingly similar to that observed in individuals with Prader-Willi syndrome. These findings build upon previous research and provide further evidence of the behavioral phenotype associated with Sotos syndrome. PMID- 26418840 TI - Polymorphism in Thermoelectric As2Te3. AB - Metastable beta-As2Te3 (R3m, a = 4.047 A and c = 29.492 A at 300 K) is isostructural to layered Bi2Te3 and is known for similarly displaying good thermoelectric properties around 400 K. Crystallizing glassy-As2Te3 leads to multiphase samples, while beta-As2Te3 could indeed be synthesized with good phase purity (97%) by melt quenching. As expected, beta-As2Te3 reconstructively transforms into stable alpha-As2Te3 (C2/m, a = 14.337 A, b = 4.015 A, c = 9.887 A, and beta = 95.06 degrees ) at 480 K. This beta -> alpha transformation can be seen as the displacement of part of the As atoms from their As2Te3 layers into the van der Waals bonding interspace. Upon cooling, beta-As2Te3 displacively transforms in two steps below T(S1) = 205-210 K and T(S2) = 193-197 K into a new beta'-As2Te3 allotrope. These reversible and first-order phase transitions give rise to anomalies in the resistance and in the calorimetry measurements. The new monoclinic beta'-As2Te3 crystal structure (P2(1)/m, a = 6.982 A, b = 16.187 A, c = 10.232 A, beta = 103.46 degrees at 20 K) was solved from Rietveld refinements of X-ray and neutron powder patterns collected at low temperatures. These analyses showed that the distortion undergone by beta-As2Te3 is accompanied by a 4-fold modulation along its b axis. In agreement with our experimental results, electronic structure calculations indicate that all three structures are semiconducting with the alpha-phase being the most stable one and the beta'-phase being more stable than the beta-phase. These calculations also confirm the occurrence of a van der Waals interspace between covalently bonded As2Te3 layers in all three structures. PMID- 26418841 TI - Six-Year Survival of a Mini Dental Implant-Retained Overdenture in a Child with Ectodermal Dysplasia. AB - Patients with ectodermal dysplasia (ED) experience several problems caused by abnormal development and functioning of the head and neck region. In addition to developmental nasal cartilage abnormalities and absence of sweat glands, hair, and eyebrows, edentulism or developmental disorders of teeth (cone-shaped teeth) are commonly observed in these types of patients. ED is also characterized by underdeveloped alveolar ridges, a decreased occlusal vertical dimension, reduced salivary secretion, and dry oral mucosa, which make prosthetic rehabilitation difficult. Few studies of intraosseous dental implant-retained prostheses have described adverse effects on craniofacial growth and esthetic and functional disadvantages, while some researchers have described the advantages of this treatment option as an alternative option in these cases. Due to the associated alveolar bone deficiency, dental mini-implant therapy may be a treatment option for these patients; however, there are isolated cases in the literature regarding the rehabilitation of ED patients with mini-implant-supported overdentures. This clinical report describes the rehabilitation of a 6-year-old child with ED using a maxillary removable partial prosthesis and a mini-implant-retained mandibular overdenture. The clinical and radiographic findings of this prosthetic rehabilitation during the 6-year follow-up are also presented. PMID- 26418842 TI - Further support for the association of GNPAT variant rs11558492 with severe iron overload in hemochromatosis. PMID- 26418844 TI - Suitable biopsy site for detection of esophageal eosinophilia in eosinophilic esophagitis suspected cases. AB - BACKGROUND AND AIM: Esophageal eosinophilia (EE) is the most important finding for the diagnosis of eosinophilic esophagitis. We conducted the present retrospective study to clarify the most suitable site of the esophagus to examine for EE detection. METHODS: We enrolled 4999 subjects who underwent upper gastrointestinal endoscopy screening examinations as part of a detailed health check-up. When endoscopic esophageal abnormalities characteristic of eosinophilic esophagitis were observed, two or three biopsy specimens were obtained from the middle or lower esophagus, and endoscopic findings of fixed rings, exudates, furrows, edema, stricture, and crepe paper esophagus in biopsied sites were analyzed. RESULTS: Thirty-five subjects underwent histological examination for EE, of whom 20 showed positive findings in biopsied specimens. Higher grade endoscopic findings of exudates, furrows, and edema were observed in cases with EE in comparison to the 15 without EE, whereas statistically significant higher grade endoscopic findings of exudates, furrows, and edema were also observed in biopsied sites with EE in comparison to those without EE. In addition, a positive finding of EE in biopsied specimens from the lower esophagus was significantly more frequently noted as compared to those from the middle esophagus. Multiple logistic regression analysis showed that a lower esophagus biopsy site and severe exudates were significant factors related to a positive EE finding in biopsied specimens. CONCLUSION: The most suitable conditions for detection of EE are a lower esophagus biopsy site and the presence of exudates in cases suspicious of eosinophilic esophagitis shown by endoscopy. PMID- 26418843 TI - Use of asthma control indicators in measuring inhaled corticosteroid effectiveness in asthmatic smokers: a systematic review. AB - OBJECTIVE: The objective of this review is to explore how current research measures the effectiveness of inhaled corticosteroids (ICS) in smokers with asthma. DATA SOURCES: PubMed, CINAHL and PsycINFO databases were searched for combinations of terms relating to asthma, tobacco use and ICS effectiveness. STUDY SELECTIONS: The search was limited to articles published between 2004 and 2015, in English language. Studies met inclusion criteria if reporting the use of guideline-based asthma control indicators to measure the therapeutic effects of ICS or ICS combination therapies. This review did not exclude articles based on study design. Data were extracted and summarized to describe how indicators were measured across studies in order to characterize and describe the effects of ICS in smokers. RESULTS: Thirteen studies were included in this review. Six of these 13 studies used only one indicator to measure asthma control in smokers and ICS was found to improve asthma in only one of six of these studies. Of studies evaluating combination therapy, three of four studies reported a therapeutic benefit to smokers. In these studies of combination therapy multiple indicators of control were measured to assess drug effects. CONCLUSIONS: To assess the therapeutic benefit of ICS drugs in smokers, multiple indicators should be measured to determine if current therapy is improving asthma control. Asthma therapy should then be adjusted based on the patient's current asthma status. The development of clinical treatment guidelines for asthmatic smokers may help clinicians make best-practice, evidence-based recommendations in order to optimize care for these patients. PMID- 26418845 TI - What Is the Role of Pyridinium in Pyridine-Catalyzed CO2 Reduction on p-GaP Photocathodes? AB - Experimental evidence suggests that pyridinium plays an important role in photocatalytic CO2 reduction on p-GaP photoelectrodes. Pyridinium reduction to pyridinyl has been previously proposed as an essential mechanistic step for this reaction. However, theoretical calculations suggest that this step is not feasible in solution. Here, cluster models and accurate periodic boundary condition calculations are used to determine whether such a reduction step could occur by transfer of photoexcited electrons from the p-GaP photocathode and whether this transfer could be catalyzed by pyridinium adsorption on the p-GaP surface. It is found that both the transfer of photoexcited electrons to pyridinium and pyridinium adsorption are not energetically favored, thus making very unlikely pyridinium reduction to the pyridinyl radical and the proposed mechanisms requiring this reduction step. Given this conclusion, an alternative and energetically viable pathway for pyridinium reduction on p-GaP photoelectrodes is proposed. This pathway leads to the formation of adsorbed species that could react to form adsorbed dihydropyridine, which was proposed previously to play the role of the active catalyst in this system. PMID- 26418846 TI - Dehydropericyclic Reactions: Symmetry-Controlled Routes to Strained Reactive Intermediates. AB - The conceptual dehydrogenation of pericyclic reactions yields dehydropericyclic processes, which usually lead to strained or reactive intermediates. This is a simple scheme for inventing new chemical reactions. Computational results on two novel dehydropericyclic reactions are presented here. Conjugated enynes undergo a singlet-state photoisomerization that transposes the methylene carbon. We previously suggested excited-state closure to 1,2-cyclobutadiene followed by thermal ring opening. CCSD(T)//DFT computations show two minima of similar energy corresponding to 1,2-cyclobutadiene, one chiral and closed shell and the second a planar diradical. The chiral structure has a low barrier to ring opening and may best explain results on enyne photoisomerization. The first examples of 1,3-diyne + yne cycloadditions to give o-benzynes were reported in 1997. Computations on intramolecular versions of this tridehydro (-3H2) Diels-Alder reaction support a concerted mechanism for the parent triyne (1,3,8-nonatriyne); however, a slight electronic advantage in the concerted path may be outweighed by the difference in entropy of activation for sequential vs simultaneous formation of two new ring bonds. PMID- 26418847 TI - Health, safety, and environmental management system operation in contracting companies: A case study. AB - Systematic and cooperative interactions among parent industry and contractors are necessary for a successful health, safety, and environmental management system (HSE-MS). This study was conducted to evaluate the HSE-MS performance in contracting companies in one of the petrochemical industries in Iran during 2013. Managers of parent and contracting companies participated in this study. The data collection forms included 7 elements of an integrated HSE-MS (leadership and commitment; policy and strategic objectives; organization, resources, and documentation; evaluation and risk management; planning; implementation and monitoring; auditing and reviewing). The results showed that mean percentage of the total scores in seven elements of HSE-MS was 85.7% and 87.0% based on self report and report of parent company, respectively. In conclusion, this study showed that HSE-MS was desirably functioning; however, improvement to ensure health and safety of workers is still required. PMID- 26418848 TI - Turn-On Ratiometric Fluorescent Probe for Selective Discrimination of Cr(3+) from Fe(3+) in Aqueous Media for Living Cell Imaging. AB - Pyrene-based turn-on ratiometric fluorescent probe 1 demonstrates high sensitivity and exceptional selectivity toward Cr(3+) in the presence of other metals, including Fe(3+) in aqueous media. Interaction of Cr(3+) with probe 1 brings pyrene moieties close enough to have better aligned pi-pi stacking, thus enhancing the excimer peak many fold. On the other hand, the interaction of Fe(3+) with probe 1 brings forth a negligible difference in stacking, resulting in an insignificant change in fluorescence intensity. Exceptional selectivity of probe 1 with Cr(3+) over Fe(3+) and other metals has been confirmed by theoretical studies in addition to experimental results. Imaging of HeLa cells observed by confocal fluorescence microscopy reveals that probe 1 can be used to monitor Cr(3+) in live cells to map its subcellular distribution. PMID- 26418849 TI - Securement of the Indwelling Urinary Catheter: A Prevalence Study. AB - PURPOSE: The aims of this study were 4-fold: (1) to examine the proportion of indwelling urinary catheters that were secured in an acute care setting; (2) to determine the proportion of secured catheters that were secured correctly; (3) to examine the association of catheter securement with type of unit, age, sex, and location of insertion; and (4) to determine the proportion of units with catheter securement products available on the unit. DESIGN: Descriptive prevalence study. SUBJECTS AND SETTING: All medical and surgical units (n = 21) were surveyed for inpatients with indwelling urinary catheters in 1 urban tertiary care hospital in Western Canada. Critical care and pediatric units were excluded. METHODS: During a 6-hour period, 6 RNs data collectors recorded presence and accuracy of catheter securement, area where the participant was catheterized, and availability of securement products on unit. Data were collected using a data form designed for the study. RESULTS: Seventy-two of 370 inpatients had indwelling catheters on the day of the study. Of these, 61% (44/72) participated. The overall prevalence of catheter securement was 18% (8/44). Seven of the 8 secured catheters were secured correctly. The primary method of securement was a commercial adhesive device (6/8; 75%). Securement products were stocked on 47% of medicine units and 92% of surgical units. CONCLUSION: Findings are consistent with other studies and indicate that catheter securement practices are inadequate despite several guidelines published on catheter care. PMID- 26418850 TI - Functional amyloids in bacteria. AB - The term amyloidosis is used to refer to a family of pathologies altering the homeostasis of human organs. Despite having a name that alludes to starch content, the amyloid accumulations are made up of proteins that polymerize as long and rigid fibers. Amyloid proteins vary widely with respect to their amino acid sequences but they share similarities in their quaternary structure; the amyloid fibers are enriched in beta-sheets arranged perpendicular to the axis of the fiber. This structural feature provides great robustness, remarkable stability, and insolubility. In addition, amyloid proteins specifically stain with certain dyes such as Congo red and thioflavin-T. The aggregation into amyloid fibers, however, it is not restricted to pathogenic processes, rather it seems to be widely distributed among proteins and polypeptides. Amyloid fibers are present in insects, fungi and bacteria, and they are important in maintaining the homeostasis of the organism. Such findings have motivated the use of the term "functional amyloid" to differentiate these amyloid proteins from their toxic siblings. This review focuses on systems that have evolved in bacteria that control the expression and assembly of amyloid proteins on cell surfaces, such that the robustness of amyloid proteins are used towards a beneficial end. PMID- 26418851 TI - Cell immobilization of Streptomyces coelicolor : effect on differentiation and actinorhodin production. AB - Streptomycetes are mycelium-forming bacteria that produce two thirds of the clinically relevant secondary metabolites. Despite the fact that secondary metabolite production is activated at specific developmental stages of the Streptomyces spp. life cycle, different streptomycetes show different behaviors, and fermentation conditions need to be optimized for each specific strain and secondary metabolite. Cell-encapsulation constitutes an interesting alternative to classical fermentations, which was demonstrated to be useful in Streptomyces, but development under these conditions remained unexplored. In this work, the influence of cell-encapsulation in hyphae differentiation and actinorhodin production was explored in the model Streptomyces coelicolor strain. Encapsulation led to a delay in growth and to a reduction of mycelium density and cell death. The high proportion of viable hyphae duplicated extracellular actinorhodin production in the encapsulated cultures with respect to the non encapsulated ones. PMID- 26418852 TI - Phenotypic comparison of clinical and plant-beneficial strains of Pantoea agglomerans. AB - Certain strains of Pantoea are used as biocontrol agents for the suppression of plant diseases. However, their commercial registration is hampered in some countries because of biosafety concerns. This study compares clinical and plant beneficial strains of P. agglomerans and related species using a phenotypic analysis approach in which plant-beneficial effects, adverse effects in nematode models, and toxicity were evaluated. Plant-beneficial effects were determined as the inhibition of apple fruit infection by Penicillium expansum and apple flower infection by Erwinia amylovora. Clinical strains had no general inhibitory activity against infection by the fungal or bacterial plant pathogens, as only one clinical strain inhibited P. expansum and three inhibited E. amylovora. By contrast, all biocontrol strains showed activity against at least one of the phytopathogens, and three strains were active against both. The adverse effects in animals were evaluated in the plant-parasitic nematode Meloidogyne javanica and the bacterial-feeding nematode Caenorhabditis elegans. Both models indicated adverse effects of the two clinical strains but not of any of the plant beneficial strains. Toxicity was evaluated by means of hemolytic activity in blood, and genotoxicity with the Ames test. None of the strains, whether clinical or plant-beneficial, showed any evidence of toxicity. PMID- 26418853 TI - A phylogenetic approach to the early evolution of autotrophy: the case of the reverse TCA and the reductive acetyl-CoA pathways. AB - In recent decades, a number of hypotheses on the autotrophic origin of life have been presented. These proposals invoke the emergence of reaction networks leading from CO or CO2 to the organic molecules required for life. It has also been suggested that the last (universal) common ancestor (LCA or LUCA) of all extant cell lineages was a chemolitho-autotrophic thermophilic anaerobe. The antiquity of some carbon fixation pathways, the phylogenetic basal distribution of some autotrophic organisms, and the catalytic properties of iron-sulfur minerals have been advanced in support of these ideas. Here we critically examine the phylogenetic distribution and evolution of enzymes that are essential for two of the most ancient autotrophic means of metabolism: the reductive tricarboxylic acid (rTCA) cycle and the reductive acetyl-CoA pathway. Phylogenetic analysis of citryl-CoA synthetase and of citryl-CoA lyase, key enzymatic components of the rTCA cycle, and of CO dehydrogenase/acetyl-CoA synthase, a key enzyme in the reductive acetyl-CoA pathway, revealed that all three enzymes have undergone major lateral transfer events and therefore cannot be used as proof of the LCA's metabolic abilities nor as evidence of an autotrophic origin of life. PMID- 26418854 TI - Succession of the gut microbiota in the cockroach Blattella germanica. AB - The cockroach gut harbors a wide variety of microorganisms that, among other functions, collaborate in digestion and act as a barrier against pathogen colonization. Blattabacterium, a primary endosymbiont, lives in the fat body inside bacteriocytes and plays an important role in nitrogen recycling. Little is known about the mode of acquisition of gut bacteria or their ecological succession throughout the insect life cycle. Here we report on the bacterial taxa isolated from different developmental instars of the cockroach Blattella germanica. The bacterial load in the gut increased two orders of magnitude from the first to the second nymphal stage, coinciding with the incorporation of the majority of bacterial taxa, but remained similar thereafter. Pyrosequencing of the hypervariable regions V1-V3 of the 16S rRNA genes showed that the microbial composition differed significantly between adults and nymphs. Specifically, a succession was observed in which Fusobacterium accumulated with aging, while Bacteroides decreased. Blattabacterium was the only symbiont found in the ootheca, which makes the vertical transmission of gut bacteria an unlikely mode of acquisition. Scanning electron microscopy disclosed a rich bacterial biofilm in third instar nymphs, while filamentous structures were found exclusively in adults. PMID- 26418855 TI - A multiplex PCR for the simultaneous detection of Tenacibaculum maritimum and Edwardsiella tarda in aquaculture. AB - A specific and sensitive multiplex PCR (mPCR) method was developed as a useful tool for the simultaneous detection of two important flatfish pathogens in marine aquaculture, Tenacibaculum maritimum and Edwardsiella tarda. In fish tissues, the average detection limit for these mPCR-amplified organisms was 2 * 10 5 +/- 0.2 CFU/g and 4 * 10 5 +/- 0.3 CFU/g, respectively. These values are similar or even lower than those previously obtained using the corresponding single PCR. Moreover, mPCR did not produce any nonspecific amplification products when tested against 36 taxonomically related and unrelated strains belonging to 33 different bacterial species. Large amounts of DNA from one of the target bacterial species in the presence of low amounts from the other did not have a significant effect on the amplification sensitivity of the latter. PMID- 26418856 TI - CDC Report on the Potential Exposure to Anthrax. AB - The Centers for Disease Control and Prevention (CDC) conducted an internal review of an incident that involved an unintentional release of potentially viable anthrax within its Roybal Campus, in Atlanta, Georgia. On June 5, 2014, a laboratory scientist in the Bioterrorism Rapid Response and Advanced Technology (BRRAT) laboratory prepared extracts from a panel of eight bacterial select agents, including Bacillus anthracis (B. anthracis), under biosafety level (BSL) 3 containment conditions. These samples were being prepared for analysis using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, a technology that can be used for rapid bacterial species identification. PMID- 26418857 TI - Graded Exercise Testing in a Pediatric Weight Management Center: The DeVos Protocol. AB - BACKGROUND: In this article, we describe a protocol used to test the functional capacity of the obese pediatric patient and describe the peak oxygen consumption (VO2peak) of patients seeking treatment at a pediatric weight management center. METHODS: One hundred eleven (mean age, 12.5 +/- 3.0 years) patients performed a multistage exercise test on a treadmill, of which 90 (81%) met end-test criteria and provided valid VO2peak data. Peak VO2 was expressed: (1) in absolute terms (L.min(-1)); (2) as the ratio of the volume of oxygen consumed per minute relative to total body mass (mL.kg(-1).min(-1)); and (3) as the ratio of the volume of oxygen consumed per minute relative to fat-free mass (mL.FFM.kg( 1).min(-1)). RESULTS: Mean BMI z-score was 2.4 +/- 0.3 and the mean percent body fat was 36.5 +/- 9.7%. Absolute VO2peak (L.min(-1)) was significantly different between sexes; however, relative values were similar between sexes. Mean VO2peak was 25.7 +/- 4.8 mL.kg(-1).min(-1) with a range of 13.5-36.7 mL.kg(-1).min(-1). CONCLUSIONS: Obese youth seeking treatment at a stage 3 pediatric weight management center exhibit low VO2peak. The protocol outlined here should serve as a model for similar programs interested in the submaximal and peak responses to exercise in obese pediatric patients. PMID- 26418858 TI - Transformation Pathways of the Recalcitrant Pharmaceutical Compound Carbamazepine by the White-Rot Fungus Pleurotus ostreatus: Effects of Growth Conditions. AB - The widely used anticonvulsant pharmaceutical carbamazepine is recalcitrant in many environmental niches and thus poses a challenge in wastewater treatment. We followed the decomposition of carbamazepine by the white-rot fungus Pleurotus ostreatus in liquid culture compared to solid-state fermentation on lignocellulosic substrate where different enzymatic systems are active. Carbamazepine metabolites were identified using liquid chromatography-high resolution mass spectrometry (LC-Q-TOF-MS). In liquid culture, carbamazepine was only transformed to 10,11-epoxy carbamazepine and 10,11-dihydroxy carbamazepine as a dead-end product. During solid-state fermentation, carbamazepine metabolism resulted in the generation of an additional 22 transformation products, some of which are toxic. Under solid-state-fermentation conditions, 10,11-epoxy carbamazepine was further metabolized via acridine and 10,11-dihydroxy carbamazepine pathways. The latter was further metabolized via five subpathways. When (14)C-carbonyl-labeled carbamazepine was used as the substrate, (14)C-CO2 release amounted to 17.4% of the initial radioactivity after 63 days of incubation. The proposed pathways were validated using metabolites (10,11-epoxy carbamazepine, 10,11-dihydroxy carbamazepine, and acridine) as primary substrates and following their fate at different time points. This work highlights the effect of growth conditions on the transformation pathways of xenobiotics. A better understanding of the fate of pollutants during bioremediation treatments is important for establishment of such technologies. PMID- 26418859 TI - A Systematic Review of Reporting Tools Applicable to Sexual and Reproductive Health Programmes: Step 1 in Developing Programme Reporting Standards. AB - BACKGROUND: Complete and accurate reporting of programme preparation, implementation and evaluation processes in the field of sexual and reproductive health (SRH) is essential to understand the impact of SRH programmes, as well as to guide their replication and scale-up. OBJECTIVES: To provide an overview of existing reporting tools and identify core items used in programme reporting with a focus on programme preparation, implementation and evaluation processes. METHODS: A systematic review was completed for the period 2000-2014. Reporting guidelines, checklists and tools, irrespective of study design, applicable for reporting on programmes targeting SRH outcomes, were included. Two independent reviewers screened the title and abstract of all records. Full texts were assessed in duplicate, followed by data extraction on the focus, content area, year of publication, validation and description of reporting items. Data was synthesized using an iterative thematic approach, where items related to programme preparation, implementation and evaluation in each tool were extracted and aggregated into a consolidated list. RESULTS: Out of the 3,656 records screened for title and abstracts, full texts were retrieved for 182 articles, out of which 108 were excluded. Seventy-four full text articles corresponding to 45 reporting tools were retained for synthesis. The majority of tools were developed for reporting on intervention research (n = 15), randomized controlled trials (n = 8) and systematic reviews (n = 7). We identified a total of 50 reporting items, across three main domains and corresponding sub-domains: programme preparation (objective/focus, design, piloting); programme implementation (content, timing/duration/location, providers/staff, participants, delivery, implementation outcomes), and programme evaluation (process evaluation, implementation barriers/facilitators, outcome/impact evaluation). CONCLUSIONS: Over the past decade a wide range of tools have been developed to improve the reporting of health research. Development of Programme Reporting Standards (PRS) for SRH can fill a significant gap in existing reporting tools. This systematic review is the first step in the development of such standards. In the next steps, we will draft a preliminary version of the PRS based on the aggregate list of identified items, and finalize the tool using a consensus process among experts and user-testing. PMID- 26418860 TI - Association between ST8SIA2 and the Risk of Schizophrenia and Bipolar I Disorder across Diagnostic Boundaries. AB - BACKGROUND: Findings from family studies and recent genome-wide association studies have indicated overlap in the risk genes between schizophrenia and bipolar disorder (BD). After finding a linkage between the ST8SIA2 (ST8 alpha-N acetyl-neuraminide alpha-2, 8-sicalyltransferase 2 gene) locus (15q26) and mixed families with schizophrenia and BD, several studies have reported a significant association between this gene and schizophrenia or BD. We investigated the genetic association between ST8SIA2 and both schizophrenia and BD in the Korean population. METHODS: A total of 582 patients with schizophrenia, 339 patients with BD, and 502 healthy controls were included. Thirty-one tag single nucleotide polymorphisms (SNPs) across the ST8SIA2 region and three other SNPs showing significant associations in previous studies were genotyped. The associations were evaluated by logistic regression analysis using additive, dominant, and recessive genetic models. RESULTS: Fourteen of 34 SNPs showed a nominally significant association (p < 0.05) with at least one diagnostic group. These association trends were strongest for the schizophrenia and combined schizophrenia and bipolar I disorder (BD-I) groups. The strongest association was observed in rs11637898 for schizophrenia (p = 0.0033) and BD-I (p = 0.0050) under the dominant model. The association between rs11637898 and the combined schizophrenia and BD-I group (p = 0.0006, under the dominant model) remained significant after correcting for multiple testing. DISCUSSION: We identified a possible role of ST8SIA2 in the common susceptibility of schizophrenia and BD-I. However, no association trend was observed for bipolar II disorder. Further efforts are needed to identify a specific phenotype associated with this gene crossing the current diagnostic categories. PMID- 26418861 TI - The Thiazide-Sensitive Co-Transporter Promotes the Development of Sodium Retention in Mice with Diet-Induced Obesity. AB - BACKGROUND/AIMS: Intravascular volume expansion due to sodium retention is involved in the pathogenesis of obesity-related hypertension. Institution of high fat diet (HFD) feeding leads to an initial state of positive sodium balance due to enhanced tubular reabsorption of sodium, but which tubular sodium transporters are responsible for this remains undefined. METHODS: C57/Bl6 mice were fed control or HFD for 3 weeks. Blood pressures were recorded by tail cuff method. Sodium transporter expression and phosphorylation were determined by Western blotting. In vivo activity of NCC was determined using natriuretic responses to hydrochlorothiazide. Expression of NCC mRNA was determined using qPCR. RESULTS: At 3 weeks HFD mice had significant weight gains compared to control mice, but blood pressures were not yet elevated. There were no changes in expression or phosphorylation of the bumetanide-sensitive cotransporter, NKCC2, or in expression of subunits of the amiloride-sensitive ion channel, ENaC. However, there were significant increases in mRNA and protein expression of the thiazide sensitive co-transporter, NCC, in kidneys from HFD mice. Consistent with this, HFD mice had increased in vivo activity of NCC. CONCLUSIONS: Increased expression of NCC promotes the sodium loading response to institution of HFD feeding before onset of hypertension. PMID- 26418863 TI - Stylized Facts in Brazilian Vote Distributions. AB - Elections, specially in countries such as Brazil, with an electorate of the order of 100 million people, yield large-scale data-sets embodying valuable information on the dynamics through which individuals influence each other and make choices. In this work we perform an extensive analysis of data sets available for Brazilian proportional elections of legislators and city councilors throughout the period 1970-2014, which embraces two distinct political regimes: a military regime followed by a democratic one. We perform a comparative analysis of elections for legislative positions, in different states and years, through the distribution p(v) of the number of candidates receiving v votes. We show the impact of the different political regimes on the vote distributions. Although p(v) has a common shape, with a scaling behavior, quantitative details change over time and from one electorate to another. In order to interpret the observed features, we propose a multi-species model consisting in a system of nonlinear differential equations, with values of the parameters that reflect the heterogeneity of candidates. In its simplest setting, the model can not explain the cutoff, formed by the most voted candidates, whose success is determined mainly by their peculiar, intrinsic characteristics, such as previous publicity. However, the modeling allows to interpret the scaling of p(v), yielding a predictor of the degree of feedback in the interactions of the electorate. Knowledge of the feedback is relevant beyond the context of elections, since a similar interactivity may occur for other social contagion processes in the same population. PMID- 26418862 TI - Elastography Study of Hamstring Behaviors during Passive Stretching. AB - INTRODUCTION: The mechanical properties of hamstring muscles are usually inferred from global passive torque/angle relationships, in combination with adjoining tissues crossing the joint investigated. Shear modulus measurement provides an estimate of changes in muscle-tendon stiffness and passive tension. This study aimed to assess the passive individual behavior of each hamstring muscle in different stretching positions using shear wave elastography. METHODS/RESULTS: The muscle shear modulus of each hamstring muscle was measured during a standardized slow passive knee extension (PKE, 80% of maximal range of motion) on eighteen healthy male volunteers. Firstly, we assessed the reliability of the measurements. Results were good for semitendinosus (ST, CV: 8.9%-13.4%), semimembranosus (SM, CV: 10.3%-11.2%) and biceps femoris long-head (BF-lh, CV: 8.6%-13.3%), but not for biceps femoris short-head (BF-sh, CV: 20.3%-44.9%). Secondly, we investigated each reliable muscle in three stretch positions: 70 degrees , 90 degrees and 110 degrees of hip flexion. The results showed different values of shear modulus for the same amount of perceived stretch, with the highest measurements in the high-flexed hip situation. Moreover, individual muscles displayed different values, with values increasing or BF-lh, SM and ST, respectively. The inter-subject variability was 35.3% for ST, 27.4% for SM and 30.2% for BF-lh. CONCLUSION: This study showed that the hip needs to be high flexed to efficiently tension the hamstrings, and reports a higher muscle-tendon stress tolerance at 110 degrees of hip angle. In addition muscles have different passive behaviors, and future works will clarify if it can be linked with rate of injury. PMID- 26418864 TI - Sun Protection Behavior in Organ Transplant Recipients in Queensland, Australia. AB - BACKGROUND: Organ transplant recipients (OTRs) have a high risk of skin cancer, and excessive sun exposure is a major contributing factor. OBJECTIVE: To document the prevalence of sun protection and associated factors in OTRs in Queensland, Australia. METHODS: Cross-sectional study of the frequency of wearing hats, long sleeves and using sunscreens among OTRs and factors associated with regular use. Adjusted prevalence ratios (PRs) and 95% confidence intervals (CIs) were estimated using Poisson regression models. RESULTS: Among 446 OTRs, 66, 49 and 39% wore a hat, sunscreen and long sleeves, respectively, mostly when outdoors. 52% regularly practiced multiple sun protection measures while 19% did not. Sunburn-prone skin (PR = 1.43, 95% CI = 1.06-1.93) and frequent whole-body skin examinations (PR = 1.48, 95% CI = 1.19-1.84) were independently associated with regular use of multiple sun protection measures. CONCLUSION: Findings are consistent with sun-conscious OTRs also having more regular skin screening and that having frequent skin examinations promotes sun-protective habits. PMID- 26418865 TI - Multiple breath washout: From Renaissance to Enlightenment? PMID- 26418866 TI - Value of Information: A Tool to Improve Research Prioritization and Reduce Waste. AB - In a Guest Editorial, Cosetta Minelli and Gianluca Baio explain how VOI analysis can prioritize research projects by identifying uncertainty in existing knowledge and then estimating expected benefits from reducing that uncertainty. PMID- 26418867 TI - Activated Protein C-Resistance Determination and Vascular Access Thrombosis in Populations with High Prevalence of Factor V Leiden. AB - BACKGROUND/AIMS: Factor V Leiden heterozygosity occurs in 3-8% of the general European and US populations. Activated protein C resistance (APC-R)--a non molecular laboratory test--can efficiently demonstrate the presence of this mutation and can be performed on most coagulation analyzers. On the other hand, fistula or graft thrombosis is a common and costly complication in hemodialysis patients. Our aim was to establish the value of APC-R determination in hemodialysis patients by assessing the risk of access thrombosis in patients with increased APC-R. METHODS: A total of 133 patients (81 men, mean age 64.5 +/- 14.9 years and 52 women, mean age 63.6 +/- 15 years) were selected. Participants were divided into 2 groups: those with access thrombosis (54 patients, 40.6%) and those with no access thrombosis (79 patients, 59.4%), and they were tested for the most common congenital or acquired thrombophilia risk factors. RESULTS: Overall, 12 patients (9%) had an increased APC-R and 10 of them had at least 1 episode of access thrombosis (83.3%). Univariate analysis to estimate crude odds ratio (OR) showed an OR of 8.8 (95% CI 1.8-41.8) times higher risk for access thrombosis in these patients. No significant differences were found after adjusting for age, hypertension, diabetes mellitus, coronary artery disease, cerebrovascular disease, peripheral arterial disease and malignancy. Sex was also a factor influencing thrombosis, presenting a higher OR for women (OR 2.2, 95% CI 1.1-4.4). CONCLUSION: This study revealed a significant association between access thrombosis and increased APC-R in hemodialysis patients. This indicates that the determination of APC-R should be considered--especially, in populations with a high prevalence of Factor V Leiden--as proper anticoagulant therapy in these patients may reduce the risk of access thrombosis. PMID- 26418868 TI - Impact of McKenzie Method Therapy Enriched by Muscular Energy Techniques on Subjective and Objective Parameters Related to Spine Function in Patients with Chronic Low Back Pain. AB - BACKGROUND: The high incidence and inconsistencies in diagnostic and therapeutic process of low back pain (LBP) stimulate the continuing search for more efficient treatment modalities. Integration of the information obtained with various therapeutic methods and a holistic approach to the patient seem to be associated with positive outcomes. The aim of this study was to analyze the efficacy of combined treatment with McKenzie method and Muscle Energy Technique (MET), and to compare it with the outcomes of treatment with McKenzie method or standard physiotherapy in specific chronic lumbar pain. MATERIAL AND METHODS: The study included 60 men and women with LBP (mean age 44 years). The patients were randomly assigned to 1 of 3 therapeutic groups, which were further treated with: 1) McKenzie method and MET, 2) McKenzie method alone, or 3) standard physiotherapy for 10 days. The extent of spinal movements (electrogoniometry), level of experienced pain (Visual Analogue Scale and Revised Oswestry Pain Questionnaire), and structure of the spinal discs (MRI) were examined prior to the intervention, immediately thereafter, and 3 months after the intervention. RESULTS: McKenzie method enriched with MET had the best therapeutic outcomes. The mobility of cervical, thoracic, and lumbar spine normalized at levels corresponding to 87.1%, 66.7%, and 95% of respective average normative values. Implementation of McKenzie method, both alone and combined with MET, was associated with a significant decrease in Oswestry Disability Index, significant alleviation of pain (VAS), and significantly reduced size of spinal disc herniation. CONCLUSIONS: The combined method can be effectively used in the treatment of chronic LBP. PMID- 26418869 TI - Ex-Situ Kinetic Investigations of the Formation of the Poly-Oxo Cluster U38. AB - The ex-situ qualitative study of the kinetic formation of the poly-oxo cluster U38 , has been investigated after the solvothermal reaction. The resulting products have been characterized by means of powder XRD and scanning electron microscopy (SEM) for the solid phase and UV/Vis, X-ray absorption near edge structure (XANES), extended X-ray absorption fine structure (EXAFS), and NMR spectroscopies for the supernatant liquid phase. The analysis of the different synthesis batches, stopped at different reaction times, revealed the formation of spherical crystallites of UO2 from t=3 h, after the formation of unknown solid phases at an early stage. The crystallization of U38 occurred from t=4 h at the expense of UO2 , and is completed after t=8 h. Starting from pure uranium(IV) species in solution (t=0-1 h), oxidation reactions are observed with a U(IV) /U(VI) ratio of 70:30 for t=1-3 h. Then, the ratio is inversed with a U(IV) /U(VI) ratio of 25/75, when the precipitation of UO2 occurs. Thorough SEM observations of the U38 crystallites showed that the UO2 aggregates are embedded within. This may indicate that UO2 acts as reservoir of uranium(IV), for the formation of U38 , stabilized by benzoate and THF ligands. During the early stages of the U38 crystallization, a transient crystallized phase appeared at t=4 h. Its crystal structure revealed a new dodecanuclear moiety (U12 ), based on the inner hexanuclear core of {U6 O8 } type, decorated by three additional pairs of dinuclear U2 units. The U12 motif is stabilized by benzoate, oxalates, and glycolate ligands. PMID- 26418870 TI - Technique, Results, and Complications Related to Robot-Assisted Stereoelectroencephalography. AB - BACKGROUND: Robot-assisted stereoelectroencephalography (SEEG) may represent a simplified, precise, and safe alternative to the more traditional SEEG techniques. OBJECTIVE: To report our clinical experience with robotic SEEG implantation and to define its utility in the management of patients with medically refractory epilepsy. METHODS: The prospective observational analyses included all patients with medically refractory focal epilepsy who underwent robot-assisted stereotactic placement of depth electrodes for extraoperative brain monitoring between November 2009 and May 2013. Technical nuances of the robotic implantation technique are presented, as well as an analysis of demographics, time of planning and procedure, seizure outcome, in vivo accuracy, and procedure-related complications. RESULTS: One hundred patients underwent 101 robot-assisted SEEG procedures. Their mean age was 33.2 years. In total, 1245 depth electrodes were implanted. On average, 12.5 electrodes were implanted per patient. The time of implantation planning was 30 minutes on average (range, 15 60 minutes). The average operative time was 130 minutes (range, 45-160 minutes). In vivo accuracy (calculated in 500 trajectories) demonstrated a median entry point error of 1.2 mm (interquartile range, 0.78-1.83 mm) and a median target point error of 1.7 mm (interquartile range, 1.20-2.30 mm). Of the group of patients who underwent resective surgery (68 patients), 45 (66.2%) gained seizure freedom status. Mean follow-up was 18 months. The total complication rate was 4%. CONCLUSION: The robotic SEEG technique and method were demonstrated to be safe, accurate, and efficient in anatomically defining the epileptogenic zone and subsequently promoting sustained seizure freedom status in patients with difficult-to-localize seizures. PMID- 26418873 TI - In Reply: A Survey of Chronic Pain Due to Spinal Dural Arteriovenous Fistulae. PMID- 26418875 TI - Commentary: Endoscopic Third Ventriculostomy in 250 Adults With Hydrocephalus: Patient Selection, Outcomes, and Complications. PMID- 26418876 TI - Imaging of carbonic anhydrase IX with an 111In-labeled dual-motif inhibitor. AB - We developed a new scaffold for radionuclide-based imaging and therapy of clear cell renal cell carcinoma (ccRCC) targeting carbonic anhydrase IX (CAIX). Compound XYIMSR-01, a DOTA-conjugated, bivalent, low-molecular-weight ligand, has two moieties that target two separate sites on CAIX, imparting high affinity. We synthesized [111In]XYIMSR-01 in 73.8-75.8% (n = 3) yield with specific radioactivities ranging from 118 - 1,021 GBq/MUmol (3,200-27,600 Ci/mmol). Single photon emission computed tomography of [111In]XYIMSR-01 in immunocompromised mice bearing CAIX-expressing SK-RC-52 tumors revealed radiotracer uptake in tumor as early as 1 h post-injection. Biodistribution studies demonstrated 26% injected dose per gram of radioactivity within tumor at 1 h. Tumor-to-blood, muscle and kidney ratios were 178.1 +/- 145.4, 68.4 +/- 29.0 and 1.7 +/- 1.2, respectively, at 24 h post-injection. Retention of radioactivity was exclusively observed in tumors by 48 h, the latest time point evaluated. The dual targeting strategy to engage CAIX enabled specific detection of ccRCC in this xenograft model, with pharmacokinetics surpassing those of previously described radionuclide-based probes against CAIX. PMID- 26418877 TI - The Vacuolar ATPase a2-subunit regulates Notch signaling in triple-negative breast cancer cells. AB - Triple Negative Breast Cancer (TNBC) is a subtype of breast cancer with poor prognosis for which no targeted therapies are currently available. Notch signaling has been implicated in breast cancer but the factors that control Notch in TNBC are unknown. Because the Vacuolar ATPase has been shown to be important in breast cancer invasiveness, we investigated the role of a2-subunit isoform of Vacuolar ATPase (a2V) in regulating Notch signaling in TNBC. Confocal microscopy revealed that among all the 'a' subunit isoforms, a2V was uniquely expressed on the plasma membrane of breast cancer cells. Both a2V and NOTCH1 were elevated in TNBC tumors tissues and cell lines. a2V knockdown by siRNA as well as V-ATPase inhibition by Bafilomycin A1 (Baf A1) in TNBC cell lines enhanced Notch signaling by increasing the expression of Notch1 intracellular Domain (N1ICD). V-ATPase inhibition blocked NICD degradation by disrupting autophagy and lysosomal acidification as demonstrated by accumulation of LC3B and diminished expression of LAMP1 respectively. Importantly, treatment with Baf A1 or anti-a2V, a novel neutralizing antibody against a2V hindered cell migration of TNBC cells. Our findings indicate that a2V regulates Notch signaling through its role in endolysosomal acidification and emerges as a potential target for TNBC. PMID- 26418879 TI - TTK activates Akt and promotes proliferation and migration of hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is one of the most malignant cancers with poor clinical outcome. The protein kinase human monopolar spindle 1 (hMps1/TTK) gene expression is significantly increased in HCCs. However, its contributions to hepatocarcinogenesis remain unclear. In this study, we found that TTK was overexpressed in 77.63% (118/152) HCC specimens. Elevated TTK expression positively correlated with large tumor size and presence of the portal vein tumor thrombus (PVTT). Demethylation in its promoter increased TTK expression in HCC. In vitro assays revealed that TTK not only promoted cell proliferation and anchorage-independent growth, but also cell migration. Subsequent investigations revealed that TTK activated Akt/mTOR pathway in a p53 dependent manner. We also found that TTK specific kinase inhibitor AZ3146 could decrease HCC cell growth. In conclusion, TTK contributes to HCC tumorigenesis via promoting cell proliferation and migration. It may serve as a novel biomarker and a potential target in HCC cancer therapy. PMID- 26418878 TI - The metastasis suppressor, NDRG1, inhibits "stemness" of colorectal cancer via down-regulation of nuclear beta-catenin and CD44. AB - N-myc downstream-regulated gene 1 (NDRG1), has been identified as an important metastasis suppressor for colorectal cancer (CRC). In this study, we investigated: (1) the effects of NDRG1 on CRC stemness and tumorigenesis; (2) the molecular mechanisms involved; and (3) the relationship between NDRG1 expression and colorectal cancer prognosis. Our investigation demonstrated that CRC cells with silenced NDRG1 showed more tumorigenic ability and stem cell-like properties, such as: colony and sphere formation, chemoresistance, cell invasion, high expression of CD44, and tumorigenicity in vivo. Moreover, NDRG1 silencing reduced beta-catenin expression on the cell membrane, while increasing its nuclear expression. The anti-tumor activity of NDRG1 was demonstrated to be mediated by preventing beta-catenin nuclear translocation, as silencing of this latter molecule could reverse the effects of silencing NDRG1 expression. NDRG1 expression was also demonstrated to be negatively correlated to CRC prognosis. In addition, there was a negative correlation between NDRG1 and nuclear beta-catenin and also NDRG1 and CD44 expression in clinical CRC specimens. Taken together, our investigation demonstrates that the anti-metastatic activity of NDRG1 in CRC occurs through the down-regulation of nuclear beta-catenin and suggests that NDRG1 is a significant therapeutic target. PMID- 26418880 TI - Suppressor of Ty homolog-5, a novel tumor-specific human telomerase reverse transcriptase promoter-binding protein and activator in colon cancer cells. AB - The human telomerase reverse transcriptase (hTERT) promoter promotes differential hTERT gene expression in tumor cells and normal cells. However, information on the mechanisms underlying the differential hTERT transcription and induction of telomerase activity in tumor cells is limited. In the present study, suppressor of Ty homolog-5 (SPT5), a protein encoded by the SUPT5H gene, was identified as a novel tumor-specific hTERT promoter-binding protein and activator in colon cancer cells. We verified the tumor-specific binding activity of SPT5 to the hTERT promoter in vitro and in vivo and detected high expression levels of SUPT5H in colorectal cancer cell lines and primary human colorectal cancer tissues. SUPT5H was more highly expressed in colorectal cancer cases with distant metastasis than in cases without distant metastasis. Inhibition of endogenous SUPT5H expression by SUPT5H gene-specific short hairpin RNAs effectively attenuated hTERT promoter driven green fluorescent protein (GFP) expression, whereas no detectable effects on CMV promoter-driven GFP expression in the same cells were observed. In addition, inhibition of SUPT5H expression not only effectively repressed telomerase activity, accelerated telomere shortening, and promoted cell senescence in colon cancer cells, but also suppressed cancer cell growth and migration. Our results demonstrated that SPT5 contributes to the up-regulation of hTERT expression and tumor development, and SUPT5H may potentially be used as a novel tumor biomarker and/or cancer therapeutic target. PMID- 26418881 TI - The effective bioengineering method of implantation decellularized renal extracellular matrix scaffolds. AB - End stage renal disease (ESRD) is a progressive loss of kidney function with a high rate of morbidity and mortality. Transplantable organs are hard to come by and hold a high risk of recipient immune rejection. We intended to establish a more effective and faster method to decellularize and recellularize the kidney scaffold for transplant and regeneration. We successfully produced renal scaffolds by decellularizing rat kidneys with 0.5% sodium dodecyl sulfate (SDS), while still preserving the extracellular matrix (ECM) 3D architecture, an intact vascular tree and biochemical components. We recellularized the kidney scaffolds with mouse embryonic stem (ES) cells that then populated and proliferated within the glomerular, vascular, and tubular structures. After in vivo implantation, these recellularized scaffolds were easily reperfused, tolerated blood pressure and produced urine with no blood leakage. Our methods can successfully decellularize and recellularize rat kidneys to produce functional renal ECM scaffolds. These scaffolds maintain their basic components, retain intact vasculature and show promise for kidney regeneration. PMID- 26418882 TI - Biomarkers of Brain Structure and Function for Neurodegenerative Disorders: Are They Adequate for Go/No Go Decisions in Drug Development? AB - Given the high risk of developing drugs for neurodegenerative diseases if post phase I decisions to go into efficacy studies were made with quantitative knowledge of an agent's action in brain, the risks should be diminished. Furthermore, if biomarkers were compelling, they could be utilized during a lengthy trial as an early measure of futility. What follows is one perspective on the adequacy of current and emerging measures to be applied to such decision making. PMID- 26418883 TI - Strains Around Abutment Teeth with Different Attachments Used for Implant Assisted Distal Extension Partial Overdentures: An In Vitro Study. AB - PURPOSE: The aim of this study was to evaluate and compare strain around abutment teeth with different attachments used for implant-assisted distal extension partial overdentures (IADEPODs). MATERIALS AND METHODS: A mandibular Kennedy class I acrylic model (remaining teeth from first premolar to first premolar) was constructed. A conventional partial denture was constructed over the model (control, group 1). Two laboratory implants were then placed bilaterally in the first molar areas parallel to each other and perpendicular to the residual ridge. Three additional experimental partial overdentures (PODs) were constructed and connected to the implants using ball (group 2), magnetic (group 3), and Locator (group 4) attachments. Three linear strain gauges were bonded buccal, lingual, and distal to the first premolar abutment tooth at the right (loading) and the left (nonloading) sides. For each group, a universal testing device was used to apply a unilateral vertical static load (50 N) on the first molar area, and the strain was recorded using a multichannel digital strainometer. RESULTS: Significant differences between groups and between sites of strain gauges were detected. Strains recorded for all groups were compressive (negative) in nature. Group 1 demonstrated the highest strain, followed by group 3 and group 4; group 2 recorded the lowest strain. For group 2, the highest strain was recoded at the lingual nonloading side. For group 1, group 3, and group 4, the highest strain was recorded at the buccal loading side. CONCLUSION: Within the limitation of the present study, ball attachments used to retain IADEPODs to the implants were associated with lower strains around abutment teeth than Locator and magnetic attachments. The highest strain was recorded with conventional partial dentures. PMID- 26418884 TI - Serological Evidence of Infection by Leishmania (Leishmania) infantum (Synonym: Leishmania (Leishmania) chagasi) in Free-Ranging Wild Mammals in a Nonendemic Region of the State of Sao Paulo, Brazil. AB - Concerns about the interface between wildlife, domestic animals, and humans in the transmission of visceral leishmaniasis (VL) have been growing due to natural or anthropogenic environmental changes. In this context, investigations of the infection in wild mammals are important to assess their exposure to the vector and the parasite. A study of anti-Leishmania (Leishmania) infantum antibodies was carried out using the direct agglutination test (DAT) on 528 free-ranging wild mammals of 38 species from the region of Botucatu, state of Sao Paulo, Brazil, a municipality that has no records of the vector or of human or canine autochthony. Antibodies were detected, with a cutoff of 1:320, in 9/528 (1.7%; 95% confidence interval [CI] 0.6-2.8%) mammals of the species Callithrix jacchus, Lepus europaeus, Sphiggurus villosus, Nasua nasua, Eira barbara, and Galictis cuja, with high titers (>=1280) for the last three. These three are little-studied species, and previous records of the detection of anti-Leishmania spp. antibodies in Brazil exist only for coatis (N. nasua), whereas worldwide, infection by L. (L.) infantum has been confirmed only in hares (Le. europaeus). On the other hand, opossums and canids, the species most commonly reported to be naturally infected by L. (L.) infantum, were not seropositive. Fifty-eight (58/528; 10.9%) mammals were found to have antibody titers ranging from 20 to 160 and were not included among the seropositive animals due to the adopted cutoff. However, the possibility of infection in these animals should not be discarded, because there is no standard cutoff point for the different wild species. Our findings indicate the need for investigations into the exact role of the seropositive species in the epidemiology of VL and for effective epidemiological surveillance to prevent its expansion, because even in regions where there are no records of canine or human autochthonous cases, there may be parasite circulation among wild mammals. PMID- 26418885 TI - Assessment of ICD-9-based case definitions for influenza-like illness surveillance. AB - Population-based surveillance of influenza routinely relies on administrative medical encounter databases and ICD-9 codes. However, an assessment of the ICD-9 codes used for the Department of Defense (DoD) influenza-like illness (ILI) case definition has not been conducted since 2007. As coding practices may have changed over time, this analysis was done to determine the sensitivity, specificity, and positive predictive value (PPV) of the current ILI case definition and three alternative case definitions for the 2014-2015 influenza season. Influenza laboratory tests conducted on specimens from DoD beneficiaries during the 2014-2015 season were matched to ambulatory and inpatient medical encounters. The current DoD ILI case definition had high sensitivity (92%) but low specificity (30%) and moderate PPV (63%). A more specific ILI case definition utilizing only codes with greater than 75% influenza positivity for the matched laboratory test had high specificity (96%) and PPV (96%) and moderate sensitivity (62%). The current ILI case definition is sufficient for broad, sensitive population-based surveillance; however, an alternative case definition may be more appropriate when there is a need to maximize specificity. PMID- 26418886 TI - Incidence of syphilis, active component, U.S. Armed Forces, 1 January 2010 through 31 August 2015. AB - In 2014,the Centers for Disease Control and Prevention reported significant increases in cases of primary and secondary syphilis in the U.S.; among beneficiaries of the Military Health System, monthly surveillance reports tracking reportable medical events of syphilis have reflected similar increases. This analysis reports on incident cases and rates of syphilis among active component service members of the U.S. Armed Forces from 1 January 2010 through 31 August 2015. During the surveillance period, 2,976 cases of syphilis were diagnosed. Crude incidence rates increased from 30.9 cases per 100,000 person years (p-yrs) in 2010 to 47.4 cases per 100,000 p-yrs in 2015. Males accounted for 88.7% of cases. Incidence rates of syphilis were highest among service members who were black, non-Hispanic or who were aged 20-29 years. About one quarter of syphilis cases (24.4%; 727 cases) were diagnosed as HIV infected. Primary and secondary syphilis cases comprised 42% of all syphilis cases. Increasing rates of primary and secondary syphilis in active component service members reflect similar trends reported in the U.S. civilian population. PMID- 26418887 TI - Brief report: Rate of prescriptions by therapeutic classification, active component, U.S. Armed Forces, 2014. PMID- 26418888 TI - Bayesian spatiotemporal analysis of zero-inflated biological population density data by a delta-normal spatiotemporal additive model. AB - We evaluate the spatiotemporal changes in the density of a particular species of crustacean known as deep-water rose shrimp, Parapenaeus longirostris, based on biological sample data collected during trawl surveys carried out from 1995 to 2006 as part of the international project MEDITS (MEDiterranean International Trawl Surveys). As is the case for many biological variables, density data are continuous and characterized by unusually large amounts of zeros, accompanied by a skewed distribution of the remaining values. Here we analyze the normalized density data by a Bayesian delta-normal semiparametric additive model including the effects of covariates, using penalized regression with low-rank thin-plate splines for nonlinear spatial and temporal effects. Modeling the zero and nonzero values by two joint processes, as we propose in this work, allows to obtain great flexibility and easily handling of complex likelihood functions, avoiding inaccurate statistical inferences due to misclassification of the high proportion of exact zeros in the model. Bayesian model estimation is obtained by Markov chain Monte Carlo simulations, suitably specifying the complex likelihood function of the zero-inflated density data. The study highlights relevant nonlinear spatial and temporal effects and the influence of the annual Mediterranean oscillations index and of the sea surface temperature on the distribution of the deep-water rose shrimp density. PMID- 26418889 TI - Cationic Cobalt(III)-Catalyzed Aryl and Alkenyl C-H Amidation: A Mild Protocol for the Modification of Purine Derivatives. AB - A cationic cobalt(III)-catalyzed direct C-H amidation of unactivated (hetero)arenes and alkenes by using 1,4,2-dioxazol-5-ones as the amidating reagent has been developed. This transformation proceeds efficiently under external oxidant-free conditions with a broad substrate scope. Moreover, 6 arylpurine compounds, which often exhibit high potency in antimycobacterial, cytostatic, and anti-HCV activities, can be smoothly amidated, thus offering a mild protocol for their late stage functionalization. PMID- 26418891 TI - N-Acyl Amino Acid Ligands for Ruthenium(II)-Catalyzed meta-C-H tert-Alkylation with Removable Auxiliaries. AB - Acylated amino acid ligands enabled ruthenium(II)-catalyzed C-H functionalizations with excellent levels of meta-selectivity. The outstanding catalytic activity of the ruthenium(II) complexes derived from monoprotected amino acids (MPAA) set the stage for the first ruthenium-catalyzed meta functionalizations with removable directing groups. Thereby, meta-alkylated anilines could be accessed, which are difficult to prepare by other means of direct aniline functionalizations. The robust nature of the versatile ruthenium(II)-MPAA was reflected by challenging remote C-H transformations with tertiary alkyl halides on aniline derivatives as well as on pyridyl-, pyrimidyl-, and pyrazolyl-substituted arenes. Detailed mechanistic studies provided strong support for an initial reversible C-H ruthenation, followed by a SET-type C-Hal activation through homolytic bond cleavage. Kinetic analyses confirmed this hypothesis through an unusual second-order dependence of the reaction rate on the ruthenium catalyst concentration. Overall, this report highlights the exceptional catalytic activity of ruthenium complexes derived from acylated amino acids, which should prove instrumental for C-H activation chemistry beyond remote functionalization. PMID- 26418890 TI - Probing Structural Dynamics and Topology of the KCNE1 Membrane Protein in Lipid Bilayers via Site-Directed Spin Labeling and Electron Paramagnetic Resonance Spectroscopy. AB - KCNE1 is a single transmembrane protein that modulates the function of voltage gated potassium channels, including KCNQ1. Hereditary mutations in the genes encoding either protein can result in diseases such as congenital deafness, long QT syndrome, ventricular tachyarrhythmia, syncope, and sudden cardiac death. Despite the biological significance of KCNE1, the structure and dynamic properties of its physiologically relevant native membrane-bound state are not fully understood. In this study, the structural dynamics and topology of KCNE1 in bilayered lipid vesicles was investigated using site-directed spin labeling (SDSL) and electron paramagnetic resonance (EPR) spectroscopy. A 53-residue nitroxide EPR scan of the KCNE1 protein sequence including all 27 residues of the transmembrane domain (45-71) and 26 residues of the N- and C-termini of KCNE1 in lipid bilayered vesicles was analyzed in terms of nitroxide side-chain motion. Continuous wave-EPR spectral line shape analysis indicated the nitroxide spin label side-chains located in the KCNE1 TMD are less mobile when compared to the extracellular region of KCNE1. The EPR data also revealed that the C-terminus of KCNE1 is more mobile when compared to the N-terminus. EPR power saturation experiments were performed on 41 sites including 18 residues previously proposed to reside in the transmembrane domain (TMD) and 23 residues of the N- and C termini to determine the topology of KCNE1 with respect to the 1-palmitoyl-2 oleoyl-sn-glycero-3-phosphocholine (POPC)/1-palmitoyl-2-oleoyl-sn-glycero-3 phospho-(1'-rac-glycerol) (POPG) lipid bilayers. The results indicated that the transmembrane domain is indeed buried within the membrane, spanning the width of the lipid bilayer. Power saturation data also revealed that the extracellular region of KCNE1 is solvent-exposed with some of the portions partially or weakly interacting with the membrane surface. These results are consistent with the previously published solution NMR structure of KCNE1 in micelles. PMID- 26418892 TI - Effectiveness of Influenza Vaccination for Individuals with Chronic Obstructive Pulmonary Disease (COPD) in Low- and Middle-Income Countries. AB - Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death globally. In addition to the mortality associated with it, people with COPD experience significant morbidity, making this set of conditions a major public health concern. Infections caused by influenza virus are a preventable cause of morbidity and vaccination has been shown to be effective. The evidence of their benefit in persons with COPD mainly comes from high-income countries where influenza vaccination is used in routine practice, but little is known about the effectiveness, cost-effectiveness, and scalability of vaccination in low- and middle-income countries. We therefore systematically reviewed and present evidence related to vaccination against influenza in persons with COPD with a special focus on studies from low- and middle-income countries (LMICs). Available data from 19 studies suggest that the use of influenza vaccine in persons with COPD is beneficial, cost-effective, and may be relevant for low- and middle income countries. Wider implementation of this intervention needs to take into account the health care delivery systems of LMICs and use of prevalent viral strains in vaccines to be most cost effective. PMID- 26418894 TI - Interpenetration of a 3D Icosahedral M@Ni12 (M=Al, Ga) Framework with Porphyrin Reminiscent Boron Layers in MNi9 B8. AB - Two ternary borides MNi9 B8 (M=Al, Ga) were synthesized by thermal treatment of mixtures of the elements. Single-crystal X-ray diffraction data reveal AlNi9 B8 and GaNi9 B8 crystallizing in a new type of structure within the space group Cmcm and the lattice parameters a=7.0896(3) A, b=8.1181(3) A, c=10.6497(4) A and a=7.0897(5) A, b=8.1579(4) A, c=10.6648(7) A, respectively. The boron atoms build up two-dimensional layers, which consist of puckered [B16 ] rings with two tailing B atoms, whereas the M atoms reside in distorted vertices-condensed [Ni12 ] icosahedra, which form a three-dimensional framework interpenetrated by boron porphyrin-reminiscent layers. An unusual local arrangement resembling a giant metallo-porphyrin entity is formed by the [B16 ] rings, which, due to their large annular size of approximately 8 A, chelate four of the twelve icosahedral Ni atoms. An analysis of the chemical bonding by means of the electron localizability approach reveals strong covalent B-B interactions and weak Ni-Ni interactions. Multi-center dative B-Ni interaction occurs between the Al-Ni framework and the boron layers. In agreement with the chemical bonding analysis and band structure calculations, AlNi9 B8 is a Pauli-paramagnetic metal. PMID- 26418893 TI - Definitive Hematopoiesis in the Yolk Sac Emerges from Wnt-Responsive Hemogenic Endothelium Independently of Circulation and Arterial Identity. AB - Adult-repopulating hematopoietic stem cells (HSCs) emerge in low numbers in the midgestation mouse embryo from a subset of arterial endothelium, through an endothelial-to-hematopoietic transition. HSC-producing arterial hemogenic endothelium relies on the establishment of embryonic blood flow and arterial identity, and requires beta-catenin signaling. Specified prior to and during the formation of these initial HSCs are thousands of yolk sac-derived erythro-myeloid progenitors (EMPs). EMPs ensure embryonic survival prior to the establishment of a permanent hematopoietic system, and provide subsets of long-lived tissue macrophages. While an endothelial origin for these HSC-independent definitive progenitors is also accepted, the spatial location and temporal output of yolk sac hemogenic endothelium over developmental time remain undefined. We performed a spatiotemporal analysis of EMP emergence, and document the morphological steps of the endothelial-to-hematopoietic transition. Emergence of rounded EMPs from polygonal clusters of Kit(+) cells initiates prior to the establishment of arborized arterial and venous vasculature in the yolk sac. Interestingly, Kit(+) polygonal clusters are detected in both arterial and venous vessels after remodeling. To determine whether there are similar mechanisms regulating the specification of EMPs with other angiogenic signals regulating adult-repopulating HSCs, we investigated the role of embryonic blood flow and Wnt/beta-catenin signaling during EMP emergence. In embryos lacking a functional circulation, rounded Kit(+) EMPs still fully emerge from unremodeled yolk sac vasculature. In contrast, canonical Wnt signaling appears to be a common mechanism regulating hematopoietic emergence from hemogenic endothelium. These data illustrate the heterogeneity in hematopoietic output and spatiotemporal regulation of primary embryonic hemogenic endothelium. PMID- 26418895 TI - The efficacy and safety of Endostar combined with chemoradiotherapy for patients with advanced, locally recurrent nasopharyngeal carcinoma. AB - PURPOSE: To evaluate the short-term efficacy and safety of recombinant human endostatin (Endostar) combined with chemoradiotherapy for the treatment of advanced, locally recurrent nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Between March 2010 and October 2013, a total of 22 patients with stage rIII-IVb locally recurrent NPC underwent salvage radiotherapy with Endostar in Sun Yat-Sen University Cancer Center. Intensity-modulated radiotherapy (IMRT) was delivered. Platinum-based chemotherapy was used in a neoadjuvant protocol. Endostar was continuously administered intravenously (105 mg/m2) for 14 days (Days 1-14) from the first day of treatment during a 21-day cycle. Tumor response and treatment toxicities were observed. RESULTS: Until January 2014, the median follow-up time was 13 months (range, 4-41 months). All patients completed the planned radiotherapy. A complete response was achieved in 20 patients, and a partial response was achieved in 2 patients. The incidence of grade 3-5 late radiation injury in this study was 50% (11/22) and that of nasopharyngeal mucosal necrosis was 31.8% (7/22). CONCLUSIONS: Endostar combined with chemoradiotherapy may be effective in decreasing both the incidence of nasopharyngeal mucosal necrosis. Studies with a larger sample size and longer follow-up are warranted. PMID- 26418896 TI - Heme oxygenase-1 in macrophages controls prostate cancer progression. AB - Innate immune cells strongly influence cancer growth and progression via multiple mechanisms including regulation of epithelial to mesenchymal transition (EMT). In this study, we investigated whether expression of the metabolic gene, heme oxygenase-1 (HO-1) in tumor microenvironment imparts significant effects on prostate cancer progression.We showed that HO-1 is expressed in MARCO-positive macrophages in prostate cancer (PCa) xenografts and human prostate cancers. We demonstrated that macrophage specific (LyzM-Cre) conditional deletion of HO-1 suppressed growth of PC3 xenografts in vivo and delayed progression of prostate intraepithelial neoplasia (PIN) in TRAMP mice. However, initiation and progression of cancer xenografts in the presence of macrophages lacking HO-1 resulted in loss of E-cadherin, a known marker of poor prognosis as well as EMT. Application of CO, a product of HO-1 catalysis, increased levels of E-cadherin in the adherens junctions between cancer cells. We further showed that HO-1-driven expression of E-cadherin in cancer cells cultured in the presence of macrophages is dependent on mitochondrial activity of cancer cells.In summary, these data suggest that HO-1-derived CO from tumor-associated macrophages influences, in part, E-cadherin expression and thus tumor initiation and progression. PMID- 26418897 TI - The pan-HER family tyrosine kinase inhibitor afatinib overcomes HER3 ligand heregulin-mediated resistance to EGFR inhibitors in non-small cell lung cancer. AB - Afatinib is a second generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) characterized as an irreversible pan-human EGFR (HER) family inhibitor. Afatinib remains effective for a subpopulation of patients with non small cell lung cancer (NSCLC) with acquired resistance to first generation EGFF TKIs such as erlotinib. Heregulin activates HER3 in an autocrine fashion and causes erlotinib resistance in NSCLC. Here we examine whether afatinib is effective against heregulin-overexpressing NSCLCs harboring EGFR activating mutations. Afatinib but not erlotinib decreased EGFR mutant NSCLC PC9HRG cell proliferation in vitro and in mouse xenografts. Afatinib inhibited phosphorylation of the cell signaling pathway proteins HER3, EGFR, HER2, and HER4, likely by prevention of trans-phosphorylation as HER3 kinase activity is inadequate for auto-phosphorylation. Afatinib, unlike erlotinib, inhibited AKT activation, resulting in elevated apoptosis in PC9HRG cells. Clinically, a subpopulation of 33 patients with EGFR mutations and NSCLC who had received first generation EGFR-TKIs exhibited elevated plasma heregulin levels compared to healthy volunteers; one of these achieved a response with afatinib therapy despite having previously developed erlotinib resistance. Afatinib can overcome heregulin-mediated resistance to erlotinib in EGFR mutant NSCLC. Further studies are necessary to determine whether heregulin can predict afatinib efficacy after development offirst generation EGFR-TKI resistance. PMID- 26418898 TI - Induction of methionine adenosyltransferase 2A in tamoxifen-resistant breast cancer cells. AB - We previously showed that S-adenosylmethionine-mediated hypermethylation of the PTEN promoter was important for the growth of tamoxifen-resistant MCF-7 (TAMR-MCF 7) cancer cells. Here, we found that the basal expression level of methionine adenosyltransferase 2A (MAT2A), a critical enzyme for the biosynthesis of S adenosylmethionine, was up-regulated in TAMR-MCF-7 cells compared with control MCF-7 cells. Moreover, the basal expression level of MAT2A in T47D cells, a TAM resistant estrogen receptor-positive cell line was higher compared to MCF-7 cells. Immunohistochemistry confirmed that MAT2A expression in TAM-resistant human breast cancer tissues was higher than that in TAM-responsive cases. The promoter region of human MAT2A contains binding sites for nuclear factor-kappaB, activator protein-1 (AP-1), and NF-E2-related factor 2 (Nrf2), and the activities of these three transcription factors were enhanced in TAMR-MCF-7 cells. Both the protein expression and transcriptional activity of MAT2A in TAMR-MCF-7 cells were potently suppressed by NF-kappaB inhibition but not by c-Jun/AP-1 or Nrf2 knock down. Interestingly, the expression levels of microRNA (miR)-146a and -146b were diminished in TAMR-MCF-7 cells, and miR-146b transduction decreased NF-kappaB mediated MAT2A expression. miR-146b restored PTEN expression via the suppression of PTEN promoter methylation in TAMR-MCF-7 cells. Additionally, miR-146b overexpression inhibited cell proliferation and reversed chemoresistance to 4 hydroxytamoxifen in TAMR-MCF-7 cells. PMID- 26418899 TI - BPTF promotes tumor growth and predicts poor prognosis in lung adenocarcinomas. AB - BPTF, a subunit of NURF, is well known to be involved in the development of eukaryotic cell, but little is known about its roles in cancers, especially in non-small-cell lung cancer (NSCLC). Here we showed that BPTF was specifically overexpressed in NSCLC cell lines and lung adenocarcinoma tissues. Knockdown of BPTF by siRNA significantly inhibited cell proliferation, induced cell apoptosis and arrested cell cycle progress from G1 to S phase. We also found that BPTF knockdown downregulated the expression of the phosphorylated Erk1/2, PI3K and Akt proteins and induced the cleavage of caspase-8, caspase-7 and PARP proteins, thereby inhibiting the MAPK and PI3K/AKT signaling and activating apoptotic pathway. BPTF knockdown by siRNA also upregulated the cell cycle inhibitors such as p21 and p18 but inhibited the expression of cyclin D, phospho-Rb and phospho cdc2 in lung cancer cells. Moreover, BPTF knockdown by its specific shRNA inhibited lung cancer growth in vivo in the xenografts of A549 cells accompanied by the suppression of VEGF, p-Erk and p-Akt expression. Immunohistochemical assay for tumor tissue microarrays of lung tumor tissues showed that BPTF overexpression predicted a poor prognosis in the patients with lung adenocarcinomas. Therefore, our data indicate that BPTF plays an essential role in cell growth and survival by targeting multiply signaling pathways in human lung cancers. PMID- 26418900 TI - Proton pump inhibitors enhance the effects of cytotoxic agents in chemoresistant epithelial ovarian carcinoma. AB - This study was designed to investigate whether proton pump inhibitors (PPI, V ATPase blocker) could increase the effect of cytotoxic agents in chemoresistant epithelial ovarian cancer (EOC). Expression of V-ATPase protein was evaluated in patients with EOC using immunohistochemistry, and patient survival was compared based on expression of V-ATPase mRNA from a TCGA data set. In vitro, EOC cell lines were treated with chemotherapeutic agents with or without V-ATPase siRNA or PPI (omeprazole) pretreatment. Cell survival and apoptosis was assessed using MTT assay and ELISA, respectively. In vivo experiments were performed to confirm the synergistic effect with omeprazole and paclitaxel on tumor growth in orthotopic and patient-derived xenograft (PDX) mouse models. Expression of V-ATPase protein in ovarian cancer tissues was observed in 44 patients (44/59, 74.6%). Higher expression of V-ATPase mRNA was associated with poorer overall survival in TCGA data. Inhibition of V-ATPase by siRNA or omeprazole significantly increased cytotoxicity or apoptosis to paclitaxel in chemoresistant (HeyA8-MDR, SKOV3-TR) and clear cell carcinoma cells (ES-2, RMG-1), but not in chemosensitive cells (HeyA8, SKOV3ip1). Moreover, the combination of omeprazole and paclitaxel significantly decreased the total tumor weight compared with paclitaxel alone in a chemoresistant EOC animal model and a PDX model of clear cell carcinoma. However, this finding was not observed in chemosensitive EOC animal models. These results show that omeprazole pretreatment can increase the effect of chemotherapeutic agents in chemoresistant EOC and clear cell carcinoma via reduction of the acidic tumor microenvironment. PMID- 26418901 TI - The Acute Physiology and Chronic Health Evaluation IV, a New Scoring System for Predicting Mortality and Complications of Severe Acute Pancreatitis. AB - OBJECTIVES: Severe acute pancreatitis is associated with significant morbidity/mortality; thus, the ability to predict hospital course is imperative. An updated version of the Acute Physiology and Chronic Health Evaluation II (APACHE), APACHE IV, has recently been validated. Unlike other versions, APACHE IV uses hepatobiliary parameters and accounts for multiple comorbid conditions and sedation. The intention of this study was to examine APACHE IV for predicting mortality and secondary outcomes for pancreatitis in a prospective cohort. In addition, we compared APACHE IV to APACHE II, Bedside Index for Severity in Acute Pancreatitis, and Ranson criterion. METHODS: We prospectively collected physiologic parameters for each scoring system in 266 patients with severe acute pancreatitis from August 2011 to April 2014. Prognostic value of each score was determined using the area under the receiver operating characteristic curve. RESULTS: Among 266 patients, 59% were men, 52% were white, and 36.5% had alcohol induced pancreatitis. Mortality occurred in 15 (5.6%), and an APACHE IV of 44 or greater predicted mortality in 100% of cases. The receiver operating characteristic curve for APACHE IV was 0.93 (confidence interval [CI], 0.88 0.97); APACHE II, 0.87 (CI, 0.80-0.94); Bedside Index for Severity in Acute Pancreatitis, 0.86 (CI, 0.78-0.94); and Ranson criterion, 0.90 (CI, 0.94-0.96). CONCLUSION: The APACHE IV is a valid means for predicting mortality and disease related complications in acute pancreatitis. PMID- 26418902 TI - Increased Serum Insulin Exposure Does Not Affect Age or Stage of Pancreatic Adenocarcinoma Diagnosis in Patients With Diabetes Mellitus. AB - OBJECTIVES: In considering whether medications that increase insulin levels accelerate pancreatic adenocarcinoma (PC) development, we hypothesized that PC patients with diabetes mellitus (DM) who used exogenous insulin or insulin stimulating medications should have an earlier age at diagnosis or present with more advanced disease. METHODS: Patients enrolled in our PC registry from June 1, 2003, to May 31, 2012, were stratified according to treatment solely with insulin, insulin-stimulating medications, or insulin-independent medications. Age at PC diagnosis, PC stage, and years between DM and PC diagnoses were analyzed among the cohorts. RESULTS: Of 122 DM patients (mean age, 67.4 +/- 10.2 years), the mean ages at PC diagnosis within the insulin-only (n = 40), insulin stimulating (n = 11), insulin-independent (n = 71), and non-DM (n = 321) cohorts were 68.7 +/- 10.5, 69.6 +/- 10.8, 66.3 +/- 9.7, and 65.5 +/- 10.5 years, respectively. No significant difference among the age at PC diagnosis was observed based on duration or type of DM treatment. There was no correlation between PC stage and increased insulin exposure. CONCLUSIONS: Anti-DM medications that increase exposure to insulin do not appear to accelerate PC development using outcomes of mean age at PC diagnosis, PC stage, or duration between DM and PC diagnoses. PMID- 26418903 TI - Early Predictors of Fluid Sequestration in Acute Pancreatitis: A Validation Study. AB - OBJECTIVES: The primary aim of this retrospective study was to externally validate predictors of increased fluid sequestration at 48 hours (FS48) in acute pancreatitis (AP). METHODS: Patients admitted between January 10 and February 13 with a diagnosis of AP were evaluated. The FS48 was calculated as difference between total fluid input and output in the first 48 hours. Predictors of FS48, such as young age, alcoholic etiology, hemoconcentration, hyperglycemia, and systemic inflammatory response syndrome (SIRS), and outcomes in AP, such as increased length of stay, acute fluid collection(s), necrosis, and persistent organ failure (POF), were defined in accordance with the previous study. Linear regression analysis was performed to evaluate the association between predictors and outcome. RESULTS: Two hundred twenty-seven AP patients (mean age, 48 years; 54% men) with a median FS48 of 4.2 L were evaluated. Age younger than 40 years, alcoholic etiology, hemoconcentration, and SIRS independently predicted increased FS48 (P < 0.05). Increased FS48 was associated with persistent SIRS and POF (P < 0.01). There was a significant trend between number of predictors and FS (P < 0.001). The presence of 4 predictors or more was associated with higher rates of persistent SIRS and POF (P < 0.01). CONCLUSIONS: Our study validated 4 of 5 predictors of increased FS48 from the previous study. Presence of 4 predictors or more and increased FS48 are both associated with persistent SIRS and POF. PMID- 26418904 TI - Evaluation of the Added Value of Diffusion-Weighted Imaging to Conventional Magnetic Resonance Imaging in Pancreatic Neuroendocrine Tumors and Comparison With 68Ga-DOTANOC Positron Emission Tomography/Computed Tomography. AB - OBJECTIVES: The aims of this study were to investigate the added value of diffusion-weighted imaging (DWI) in pancreatic neuroendocrine tumor (pNET) evaluation and to compare magnetic resonance imaging (MRI) to Ga-DOTANOC positron emission tomography/computed tomography (PET/CT) results. METHODS: Morphological MRI (T2-weighted [T2-w] + contrast-enhanced [CE] T1-w) and DWI (T2-w + DWI) and Ga-DOTANOC PET/CT in 25 patients/30 pNETs were retrospectively evaluated. Per patient and per-lesion detection rates (pDR and lDR, respectively) were calculated. Apparent diffusion coefficient values were compared among pNET and surrounding and normal pancreas (control group, 18 patients). Apparent diffusion coefficient and standardized uptake value (SUV) values were compared among different grading and staging groups. RESULTS: No statistically significant differences in PET/CT and MRI session detection rates were found (morphological MRI and DW-MRI, 88% pDR and 87% lDR; combined evaluation, 92% pDR and 90% lDR; Ga DOTANOC PET/CT, 88% pDR and 80% lDR). Consensus reading (morphological/DW-MRI + PET/CT) improved pDR and lDR (100%). Apparent diffusion coefficient mean value was significantly lower compared with surrounding and normal parenchyma (P < 0.01). The apparent diffusion coefficient and SUV values of pNETs among different grading and staging groups were not statistically different. CONCLUSIONS: Conventional MRI, DW-MRI + T2-w sequences, and Ga-DOTANOC PET/CT can be alternative tools in pNET detection. Diffusion-weighted MRI could be valuable in patients with clinical suspicion but negative conventional imaging findings. However, the consensus reading of the 3 techniques seems the best approach. PMID- 26418905 TI - Correlation Between RAB27B and p53 Expression and Overall Survival in Pancreatic Cancer. AB - OBJECTIVES: RAB27B is a member of the Rab family GTPases involved in vesicle trafficking, and p53 has recently been implicated in regulating the exosome secretion pathway. Because exosome secretion plays an important role in modulating tumor microenvironment and invasive growth, we hypothesized that RAB27B and p53 expression might be associated with the aggressive behavior in pancreatic ductal adenocarcinoma, one of the most deadly human malignancies. METHODS: We determined protein expression of RAB27B and p53 in 260 pancreatic tissues (186 malignant and 74 normal or benign) by immunohistochemistry analysis on tissue microarray and their correlation with patients' clinical parameters and overall survival. RESULTS: We found that a high RAB27B protein expression (RAB27B) was significantly associated with perineural and vascular invasion, as well as distant metastasis. Patients with a high RAB27B expression had significantly poorer overall survival in both univariate and multivariate analyses. A significant correlation between RAB27B and p53 expression was observed. CONCLUSIONS: Our data indicate that RAB27B expression is an independent prognostic marker for pancreatic ductal adenocarcinoma and suggest that RAB27B regulated exosome secretion pathway represents a novel therapeutic target in pancreatic cancer. PMID- 26418906 TI - Extracorporeal Shock Wave Lithotripsy for Chinese Patients With Pancreatic Stones: A Prospective Study of 214 Cases. AB - OBJECTIVES: This study aims to evaluate prospectively the safety and efficacy of extracorporeal shock wave lithotripsy (ESWL) in Chinese patients. METHODS: A total of 214 patients with painful chronic pancreatitis and pancreatic stones who underwent ESWL followed by endoscopic retrograde cholangiopancreatography from March 2011 to February 2012 in Changhai Hospital were enrolled. The main pancreatic duct clearance rate and complications were recorded prospectively. Symptoms, weight, quality of life, and pancreatic function were assessed before and after ESWL and endotherapy. RESULTS: A total of 473 ESWL procedures were performed in 214 patients. Stones were fragmented in all cases. Complete clearance of main pancreatic duct stones and successful endoscopic decompression were achieved in 155 (72.4%) and 188 (90.8%) of 214 patients, respectively. Complications were observed after 20 sessions (20 of 473, 4.23%). Follow-up (n = 195) after 18.5 +/- 3.3 months showed that complete and partial pain relief were achieved in 71.3% and 24.0% of the patients, respectively. The scores for the quality of life (5.8 +/- 1.7 vs 8.1 +/- 1.2, P < 0.05) and mental health from the Medical Outcomes Study 36-Item Short-Form General Health Survey questionnaire (62.2 +/- 21.5 vs 68.5 +/- 16.4, P < 0.05) improved after ESWL. CONCLUSIONS: Thus, ESWL is a safe and effective method to treat Chinese patients with pancreatic stones. This procedure can significantly improve the success rate of endotherapy. PMID- 26418907 TI - Stimulation of Central alpha2 Receptors Attenuates Experimental Necrotizing Pancreatitis. AB - OBJECTIVES: Severe necrotizing pancreatitis (SNP) is a disease with relevant morbidity and mortality until today. No specific therapy is in sight. Central alpha2 agonists such as clonidine and dexmedetomidine are known to have anti inflammatory effects though the cholinergic anti-inflammatory pathway and are implemented in the clinical routine as adjunct sedative drugs. Their potential effect on SNP has not yet been tested. METHODS: Severe necrotizing pancreatitis was induced in male Wistar rats. Four treatment groups received either clonidine or dexmedetomidine before (prophylactic) or after induction of SNP (therapeutic). After 12 hours, pancreatic morphologic injury, systemic proinflammatory high mobility group box 1 protein, and pancreatic and pulmonary myeloperoxidase levels were evaluated. RESULTS: Severe necrotizing pancreatitis was fully established 12 hours after induction. "Prophylactic" and "therapeutic" administration of clonidine and dexmedetomidine reduced pancreatic morphologic injury (P < 0.05 vs SNP), serum proinflammatory high-mobility group box 1 protein (P < 0.0001 vs SNP), as well as pancreatic and pulmonary myeloperoxidase levels (P < 0.01 vs SNP). CONCLUSIONS: Prophylactic and therapeutic applications of the central alpha2 agonists clonidine and dexmedetomidine are effective to attenuate local and systemic injury in experimental SNP and should be evaluated in the clinical setting. PMID- 26418908 TI - Eotaxin-3 (CCL26) Expression in Human Pancreatic Myofibroblasts. AB - OBJECTIVES: Eosinophil infiltration is a histological feature of autoimmune pancreatitis (AIP). However, little is known about the mechanisms underlying eosinophilic infiltration. In this study, we aimed to investigate the expression of the eosinophil chemotactic protein, eotaxin-3, in human pancreatic myofibroblasts. METHODS: Enzyme-linked immunosorbent assays and quantitative polymerase chain reactions were used to quantify eotaxin-3 protein and messenger RNA levels, respectively. RESULTS: Eotaxin-3 expression was induced by T helper type 2 cytokines, interleukin-4 (IL-4) and IL-13, in time- and dose-dependent manners. Both IL-4 and IL-13 induced the rapid phosphorylation of STAT6 (signal transducer and activator of transcription 6), and STAT6-specific small interfering RNA significantly blocked IL-4- and IL-13-induced eotaxin-3 expression, indicating involvement of STAT6 signaling pathways in eotaxin-3 induction. In contrast, SOCS (suppressor of cytokine signaling) protein-specific small interfering RNA experiments suggested that the SOCS family proteins are negative regulators of IL-4- and IL-13-induced eotaxin-3 expression in pancreatic myofibroblasts. Interferon-gamma significantly inhibited IL-4- and IL-13-induced eotaxin-3 expression, and this response was mediated by STAT1 activation. CONCLUSIONS: Pancreatic myofibroblasts may be a cellular source of eotaxin-3 in the pancreas. The T helper type 2 cytokines, IL-4 and IL-13, are critical factors for the induction of eotaxin-3 in the pancreas. PMID- 26418909 TI - Association and Intragenic Single-Nucleotide Polymorphism Interactions of the XRCC1 Polymorphisms for Pancreatic Cancer Susceptibility. AB - OBJECTIVES: X-ray repair cross-complementing group 1 (XRCC1) gene is an important candidate gene for influencing human cancer risks. This study examined the main and interactive effect of 9 single-nucleotide polymorphisms (SNPs) (Arg194Trp, Arg280His, Arg399Gln, c.1254C>T, c.1517G>C, c.1471G>A, C310T, 539del542, and T1915C) of XRCC1 in contribution to pancreatic cancer (PC). METHODS: A total of 298 PC patients and 298 healthy controls were enrolled. Selected SNPs in XRCC1 were genotyped. The generalized multifactor dimensionality reduction method investigated gene-gene interactions. RESULTS: Single-locus analyses showed that, in the codominant model, the GO genotype of 539del542 might have a higher risk for PC (odds ratio [OR], 1.47; 95% confidence interval [95% CI], 1.05-2.08). For T1915C polymorphism, the TC and CC genotypes both had a higher risk for PC (OR, 1.76; 95% CI, 1.25-2.48; OR, 1.83; 95% CI, 1.05-3.19, respectively); and a similar result was observed in the dominant model (OR, 1.77; 95% CI, 1.28-2.46). A tendency of association between Arg280His and PC was also detected in the dominant model (OR, 0.70; 95% CI, 0.48-1.00). Furthermore, the generalized multifactor dimensionality reduction method showed that the 4-locus model was significant, involving Arg280His, 539del542, T1915C, and c.1517G>C (P < 0.05). CONCLUSIONS: Thus, XRCC1 polymorphisms may contribute to the risk of PC independently or in an interactive manner. PMID- 26418910 TI - Metamizol Relieves Pain Without Interfering With Cerulein-Induced Acute Pancreatitis in Mice. AB - OBJECTIVES: Animal models are essential to understand the pathogenesis of acute pancreatitis (AP) and to develop new therapeutic strategies. Although it has been shown that cerulein-induced AP is associated with pain in experimental animals, most experiments are carried out without any pain-relieving treatment because researchers are apprehensive of an interference of the analgetic agent with AP associated inflammation. In light of the growing ethical concerns and the legal tightening regarding animal welfare during experiments, this attitude should be changed. METHODS: Acute pancreatitis was induced by cerulein in the C57BL/6J and FVB/N mouse inbred strains. One group received vehicle only, and the other was treated with metamizol as analgetic agent. Pain sensation and parameters of AP were analyzed as well as the effect of metamizol in the pancreas and its actions in the brain. RESULTS: We report that oral administration of metamizol protects cerulein-treated mice from abdominal pain without influencing the clinical and histopathological course of the disease. In addition, it could be shown that metamizol reduces the central pain response. CONCLUSIONS: This study reveals that oral administered metamizol has no influence on the cerulein-induced AP and can be given as an analgesic to increase animal welfare in experiments with induced AP. PMID- 26418911 TI - Time Trend of Outcomes for Severe Acute Pancreatitis After Publication of Japanese Guidelines Based on a National Administrative Database. AB - OBJECTIVES: This study aimed to investigate the recent time trend of outcomes for severe acute pancreatitis after publication of Japanese guidelines based on a national administrative database. METHODS: A total of 10,400 patients with severe acute pancreatitis were referred to 1021 hospitals between 2010 and 2012 in Japan. We collected patients' data from the administrative database to compare in hospital mortality (within 28 days and overall), length of stay (LOS), and medical costs during hospitalization. The study periods were categorized into 3 groups according to fiscal year: 2010 (n = 2698), 2011 (n = 3842), and 2012 (n = 3860). RESULTS: In-hospital mortality within 28 days and overall in-hospital mortality were significantly decreased according to fiscal year (6.3% [2010] vs 5.7% [2011] vs 4.5% [2012], P = 0.005; 7.6% vs 7.1% vs 5.6%, P = 0.002, respectively). However, mean LOS and medical costs were not different between fiscal years (27.0 vs 27.1 vs 26.9 days, P = 0.218; 13,998.0 vs 14,156.4 vs 14,319.2 USD, P = 0.232, respectively). CONCLUSIONS: This study shows that mortality of severe acute pancreatitis was reduced according to the time course, whereas LOS or medical costs were stable after publication of the Japanese guidelines. PMID- 26418912 TI - Diagnostic Differentiation of Pancreatic Neuroendocrine Tumor From Other Neoplastic Solid Pancreatic Lesions During Endoscopic Ultrasound-Guided Fine Needle Aspiration. AB - OBJECTIVES: To identify factors differentiating pancreatic neuroendocrine tumors (PNETs) from non-PNET neoplastic solid pancreatic lesions (SPLs) and assess the accuracy of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). METHODS: This is a retrospective study at a tertiary center of consecutive patients referred for EUS from 2004 to 2011. The main outcomes were pretest predictors and accuracy of EUS-FNA for diagnosis of PNET. RESULTS: Among a total of 1108 EUS-FNAs for pancreatic lesions, 672 patients (PNET = 91, non-PNET neoplastic-SPLs = 581) had neoplastic-SPLs. The sensitivity, specificity, and accuracy of EUS-FNA for diagnosis of PNETs were 98.9%, 100%, and 99.9%, respectively. The mean needle-passes were 3.0/patient. The EUS volume (mean/year per endosonographer) in preceding 3 years significantly correlated with fewer needle passes (rs: [-0.26]; P = 0.02).Multivariate analysis demonstrated that patients with PNET when compared to non-PNET neoplastic-SPLs were younger (odds ratio [OR], 3.23; 95% confidence interval [95% CI], 1.19-9.09; P = 0.001), have 2 or more pancreatic lesions (OR, 5.63; 95% CI, 1.74-18.2; P = 0.005), and lower CA 19-9 values (OR, 10.0; 95% CI, 3.13-33.3; P = 0.001). Further, PNETs were less likely to have weight loss (OR, 0.40; 95% CI, 0.17-0.90; P = 0.03), current smoking (OR, 0.47; 95% CI, 0.22-0.98; P < 0.05), pancreatic ductal dilation (OR, 0.28; 95% CI, 0.13-0.60; P = 0.002), or imaging evidence of arterial invasion (OR, 0.22; 95% CI, 0.07-0.71; P = 0.01). CONCLUSIONS: Although pre-FNA findings can reliably characterize, EUS-FNA is highly accurate for the diagnosis of PNETs. PMID- 26418913 TI - Effects of Caffeine and Lycopene in Experimentally Induced Diabetes Mellitus. AB - OBJECTIVES: Diabetes mellitus (DM) is a global epidemic with increasing prevalence. The disease is chronic in nature, and patients must use antidiabetic drugs or insulin during their lifespan. Because of the difficulty of using injectable insulin preparations, patients and practitioners prefer to use oral antidiabetic drugs for prophylaxis and treatment. There are, however, numerous adverse effects of antidiabetic drugs and rapidly increasing attention is being paid to new nutraceutical drugs with fewer adverse effects. The purpose of this study was to evaluate the effects of caffeine and lycopene on streptozotocin (STZ)-induced DM in rats. METHODS: Caffeine and lycopene were administered to the study groups by oral gavages for 1 month whereafter experimental diabetes was induced in 90 rats in 6 groups. RESULTS: There were no pathological effects of lycopene and caffeine on the pancreas. Marked vacuolization and degeneration were observed in STZ-treated groups. Caffeine and lycopene decreased the pathological findings and lowered the blood and urine glucose levels in the rats with STZ induced DM, whereas these compounds increased serum insulin levels. CONCLUSIONS: This study showed that caffeine and lycopene provided protective effects against experimentally induced DM. The protective effects of lycopene were observed to be much greater than those of caffeine. PMID- 26418915 TI - The impact of environmental and biological factors on paraoxonase 1 and gamma glutamyltranspeptydase activities in the blood of smelters. AB - Disorders of paraoxonase and gamma-glutamyltranspeptydase activities can induce development of the atherosclerotic process. The aim of the study was to examine the effect of occupational exposure to heavy metals, tobacco smoke and alcohol consumption on the activities of paraoxonase and gamma-glutamyltranspeptydase as well as glutathione concentration. We have observed reduced paraoxonase activity and higher gamma-glutamyltranspeptydase activity in serum of smelters when compared to control groups. In the blood of smoking smelters was demonstrated a negative correlation between paraoxonase activity and BMI value as well as between paraoxonase activity and tobacco smoke and consumption of 40% alcohol. Also, negative correlation was found for the activity of paraoxonase and glutathione concentration as well as gamma-glutamyltranspeptydase activity. Higher gamma-glutamyltranspeptydase activity and lower paraoxonase activity in the serum of smelters exposed to heavy metals and tobacco smoke can cause disorders in functioning of the body. PMID- 26418916 TI - Does breastfeeding increase risk of early childhood caries? AB - According to the WHO, "breastfeeding is the normal way of providing young infants with the nutrients they need for healthy growth and development. Exclusive breastfeeding is recommended up to 6 months of age, with continued breastfeeding along with appropriate complementary foods up to two years of age or beyond". However, several studies have reported prolonged and unrestricted breastfeeding as a potential risk factor for primary tooth caries (ECC). On-demand breastfeeding, particularly while lying down at night, would seem to cause ECC because milk remains in the baby's mouth for long periods of time. There is lack of evidence that human milk is cariogenic; other factors, such as oral hygiene, may be more influential in caries development than on-demand breastfeeding. Moreover the biomechanics of breastfeeding differs from those of bottle feeding and milk is expressed into the soft palate and swallowed without remaining on teeth. Indeed we cannot forget that the main factor influencing caries development in infants is the presence of bacteria streptococcus mutans that thrives in a combination of sugars, small amounts of saliva and a low pH. Today the question is open and recently Chaffee, Felines, Vitolo et al. [2014] have found that breastfeeding for 24 months or longer increases the prevalence of severe early childhood caries in low-income families in Porto Alegre, Brazil. These results do not claim that prolonged breastfeeding is the cause of tooth decay; we can expect an association with food for infants often rich in refined sugars, which cause the reduction of the protective effect of saliva on the deciduous teeth enamel. In Japan, Kato, Yorifuji, Yamakawa et al. [2015] have found that infants who had been breastfed for at least 6 or 7 months, both exclusively and partially, were at elevated risk of dental caries at the age of 30 months compared with those who had been exclusively fed with formula. The authors themselves say, however, that further studies with more elaborate methods of assessment of breastfeeding may be necessary to determine the cariogenic nature of breastfeeding. In the meantime, given the many benefits of breastfeeding, the practice should continue to be strongly encouraged. Dental professionals should encourage parents to start proper oral hygiene with their children as soon as the first tooth erupts, and they should keep the intake of sugary beverages to a minimum. PMID- 26418917 TI - Serotype diversity of Streptococcus mutans and caries activity in children in Argentina. AB - AIM: The purpose of this study was to analyse the serotype distribution of S. mutans and their association with caries activity in school children from Cordoba, Argentina. MATERIALS AND METHODS: Clinical examination was performed in 133 children. The dmft+DMFT and Significant Caries (SiC) indices were calculated to identify individuals with high caries activity. After DNA extractions of S. mutans strains, serotypes were determined by PCR amplifications. The median caries activity of each serotype group was compared using a non-parametric Kruskall-Wallis test. RESULTS: We obtained S. mutans strains from stimulated saliva of 94 children. The mean dmft+DMFT was 4.14 and the mean SiC index was 8.65. Serotype c was the most frequent (53.2%), followed by e (31.9%), f (8.5%) and k (6.4%). The comparison between the SiC and Non-Sic groups showed significant differences in the frequency of serotypes c and k. The median caries activity was non-significant in the different serotypes. CONCLUSION: The difference between the serotype frequencies detected in Argentina compared to those of other countries could be related with contrasting dietary habits. The results obtained in the present study would increase the knowledge about the epidemiology of dental caries in children from Argentina. PMID- 26418918 TI - CPP-ACP and CPP-ACFP versus fluoride varnish in remineralisation of early caries lesions. A prospective study. AB - AIM: To evaluate the effects of novel casein phosphopeptide (CPP) formulations CPP-amorphous calcium phosphate (CCP- ACP) and CPP-amorphous calcium fluoride phosphate (CPP-ACFP) versus fluoride varnish on the remineralisation of enamel white spot lesions (WSLs) over a 12-week follow-up period. MATERIALS AND METHODS: STUDY DESIGN: Double-blind prospective study. Eligibility criteria were patients between 6 and 14 years old and have WSLs on their permanent teeth. We evaluated 786 WSLs. Participants were divided randomly into three groups. Groups A and B were instructed to daily topical application of GC Tooth Mouse (CPP-ACP) or Mi Paste Plus (CPP-ACFP), Group C received a monthly professional application of Duraphat fluoride varnish. WSLs were categorised according to the International Caries Detection and Assessment System (ICDAS II; grades 0-3) and assessed by laser fluorescence (DIAGNOdent) at baseline and at 4, 8 and 12 weeks. Changes in mineralisation before and after treatment were analysed using two-way analysis of variance, with post hoc Bonferroni's non-parametric tests for multiple comparisons. RESULTS: DIAGNOdent values were significantly reduced in Group B at 4 weeks, and in Groups A and C at 8 weeks. Mean values in Group B were lower than in Groups A and C at 4 weeks, and lower than Group C at 8 weeks. CPP-ACFP appeared to have a specific effect on smooth-surface caries, but no significant effect on caries in pits and fissures. CONCLUSION: At 4 weeks, CPP-ACFP is superior to fluoride varnish at remineralising smooth-surface WSLs. CPP-ACP is not superior to fluoride varnish by any of the measures studied. PMID- 26418919 TI - The reasons for extractions of primary teeth in Turkish children. AB - AIM: The aim of this study was to determine the current reasons for primary teeth extractions in Turkish children and their relative importance. MATERIALS AND METHODS: STUDY DESIGN: retrospective evaluation of patients by analysing dental records of children aged 2-13 years, receiving treatment in different regions in Turkey over a period of five years (2007-2012). Patient's age, gender, any significant medical finding, type of tooth extracted and the reason for the extraction were the parameters evaluated. RESULTS: It resulted that 2,508 primary teeth belonging to 1,755 children aged of 2-13 years were extracted. Extraction due to caries (57,4%) was found to be the most common reason. STATISTICS: Chi square tests were performed for statistical analysis. Although no differences in the types of teeth extracted were observed between genders, striking differences were noted in the different age groups. CONCLUSION: From this study it can be concluded that caries and subsequent pulpal pathology are the most common reasons for extraction of primary teeth in Turkey. Primary molars were the most common tooth type extracted. Preventive programmes for preschool children should be given importance. PMID- 26418914 TI - Elucidation of the CHO Super-Ome (CHO-SO) by Proteoinformatics. AB - Chinese hamster ovary (CHO) cells are the preferred host cell line for manufacturing a variety of complex biotherapeutic drugs including monoclonal antibodies. We performed a proteomics and bioinformatics analysis on the spent medium from adherent CHO cells. Supernatant from CHO-K1 culture was collected and subjected to in-solution digestion followed by LC/LC-MS/MS analysis, which allowed the identification of 3281 different host cell proteins (HCPs). To functionally categorize them, we applied multiple bioinformatics tools to the proteins identified in our study including SignalP, TargetP, SecretomeP, TMHMM, WoLF PSORT, and Phobius. This analysis provided information on the presence of signal peptides, transmembrane domains, and cellular localization and showed that both secreted and intracellular proteins were constituents of the supernatant. Identified proteins were shown to be localized to the secretory pathway including ones playing roles in cell growth, proliferation, and folding as well as those involved in protein degradation and removal. After combining proteins predicted to be secreted or having a signal peptide, we identified 1015 proteins, which we termed as CHO supernatant-ome (CHO-SO), or superome. As a part of this effort, we created a publically accessible web-based tool called GO-CHO to functionally categorize proteins found in CHO-SO and identify enriched molecular functions, biological processes, and cellular components. We also used a tool to evaluate the immunogenicity potential of high-abundance HCPs. Among enriched functions were catalytic activity and structural constituents of the cytoskeleton. Various transport related biological processes, such as vesicle mediated transport, were found to be highly enriched. Extracellular space and vesicular exosome associated proteins were found to be the most enriched cellular components. The superome also contained proteins secreted from both classical and nonclassical secretory pathways. The work and database described in our study will enable the CHO community to rapidly identify high-abundance HCPs in their cultures and therefore help assess process and purification methods used in the production of biologic drugs. PMID- 26418920 TI - Management of impacted dilacerated maxillary incisor with strategic positioning of a straightwire appliance. AB - AIM: To describe the orthodontic management of root dilaceration of an impacted maxillary tooth following trauma to its deciduous predecessors, to show the clinical management of root dilaceration of a maxillary central incisor and describe how the dilacerated tooth was successfully moved into alignment in a young patient with a proper multidisciplinary approach, using the simple and effective straightwire technique. CASE REPORT: After surgical exposure and orthodontic traction, the impacted dilacerated tooth was brought to alignment in the arch. The patient's chewing and speech function, and aesthetics were restored. The radiograph shows that the root is finally straight and relatively well developed. This approach avoids extraction and prosthetic rehabilitation of the dilacerated tooth. PMID- 26418921 TI - The care of traumatic dental injuries in primary schools in Southern Nigeria. AB - AIM: To assess the standards of care given to children who sustain traumatic dental injuries (TDI) in Nigerian primary schools. MATERIALS AND METHODS: STUDY DESIGN: cross-sectional study. Public and private schools were selected from the Southern geopolitical zones in Nigeria. An interviewer-administered questionnaire was used to obtain information on the presence or absence of a school clinic, trained nurse, records and first aid box from the head teachers. The record of past traumatic dental injury, cause of the injury and treatment measures were also obtained. STATISTICS: the information obtained were analysed using SPSS version 20. RESULTS: There were 90 private and 90 public primary schools; 61 (34.1%) schools had school clinics. Forty-two (23.9%) of the schools had school nurses (7 public and 35 private schools), and 27 (64.3%) of them had been trained to treat dental emergencies. Only 14 (7.8%) of the schools had records of dental injuries, and luxation injuries (31.6%) was the commonest injury. Children who sustained injuries in the school premises were sent home in 59 (38.7%) schools, while 36 (22.5%) and 37 (23.1%) schools were referred to physicians and dentists, respectively. CONCLUSION: Many schools do not have school clinics/sick bays or are poorly equipped to handle dental emergencies. Sending children home or to health centres without first aid could affect the prognosis of dental injuries, since timely intervention is of utmost importance for a successful outcome. PMID- 26418923 TI - New techniques for producing aesthetic, direct full-crown composite resin restorations for primary molars: a 24-month follow-up study of eight cases. AB - AIM: Although the demand for aesthetic restoration of primary molars has increased, techniques for producing aesthetic, direct full-crown restorations using light-cured composite resin for primary molars and the associated clinical outcome are not well established. The aim of this study was to describe the use of new techniques to produce aesthetic, direct full-crown restorations using light-cured composite resin for primary molars. The authors evaluate the clinical outcomes of the restoration method and investigate whether this technique could be used as an alternative to conventional methods. MATERIALS AND METHODS: Two new techniques, the resin block and the clear matrix, were studied by treating 8 teeth. The occlusal surface of stainless steel crowns was used for impression taking to facilitate accurate reproduction of the anatomic structure, and the aesthetic restoration was obtained simply and consistently. RESULTS: At the 24 month follow-up evaluation, these new direct techniques were completely satisfactory. Marginal discoloration was observed in one tooth treated with the clear matrix technique, and a small partial wear was observed in another tooth treated with the resin block. CONCLUSION: The new techniques for restoration resulted in functional and aesthetic reproduction of occlusal morphology. Therefore, these techniques could be considered a practical alternative to conventional methods. PMID- 26418922 TI - Inflammatory dentigerous cyst of mandibular first premolar associated with endodontically treated primary first molar: a rare case report. AB - AIM: Inflammatory dentigerous cysts usually occur in the mixed dentition. It has been reported that inflammatory lesions from the root area of a deciduous tooth bring about the development of dentigerous cysts around the unerupted permanent tooth bud. Endodontic treatment is a common and successful procedure for periapical inflammation in children. An inflammatory dentigerous cyst can occur in conjunction with endodontically treated primary tooth. CASE REPORT: This article reports a case of 6 years and 6 months old boy, with a single, well defined, unilocular, radiolucent area enclosing the first right unerupted mandibular premolar, accidentally discovered on the panoramic radiograph. The first right primary molar had received a root canal treatment 18 months prior. Clinical findings combined with radiographic and microscopic examinations confirmed the diagnosis of inflammatory dentigerous cyst. As treatment, enucleation of the cyst with removal of the involved permanent tooth was chosen and a removable partial denture was supplied to the patient after surgery. The 5 year follow-up revealed good healing of the bony lesion and displaced teeth. CONCLUSION: This case presented a severe and rare complication of endodontically treated primary tooth, and the recommendation includes: (1) early diagnosis of dentigerous cysts, which is essential to prevent extensive treatment; (2) more information on the adverse side effects of an endodontic treatment should be given to patients and parents; (3) patients should be informed about the importance of follow-ups and radiographic follow-up should be routinised. PMID- 26418924 TI - In vitro assessment of retention and microleakage in pit and fissure sealants following enamel pre-etching with sodium hypochlorite deproteinisation. AB - AIM: The purpose of this study was to assess and compare the rate of sealant retention and microleakage after placement on etched enamel with and without prior deproteinisation. MATERIALS AND METHODS: STUDY DESIGN: 75 freshly extracted third molars were randomly assigned to either of two pit and fissure treatment methods. Samples from both groups were etched with 37% phosphoric acid gel for 15 seconds, followed by placement of a sealant, and then subjected to thermocycling for evaluation of sealant retention. After that, specimens were immersed in rhodamine B, sectioned longitudinally, and examined under a confocal laser scanning microscope for assessment of microleakage. Collected data were statistically analysed using chi-square and Fisher exact tests with an alpha level of 0.05. RESULTS: The rate of sealant retention was similar between the two study groups (P = 0.073), but the rate of sealant microleakage was significantly lower in the enamel deproteinisation group (P < 0.001) than in the control group. CONCLUSION: Based on these findings, we recommend the deproteinisation method prior to enamel acid etching to obtain better clinical results with sealants. PMID- 26418925 TI - Early treatment of Class III malocclusion with RME and facial mask: evaluation of dentoalveolar effects on digital dental casts. AB - AIM: To analyse the dental effects on digital dental casts in subjects with Class III malocclusion treated with bonded Rapid Maxillary Expansion and Facial Mask (RME/FM). MATERIALS AND METHODS: A study group sample (SG) of 29 subjects (13 females and 16 males) and mean age of 7.4 years (SD 1.2 years) was selected. A bonded RME was placed and activated 1/4 of a turn per day until overcorrection of the transverse width. At the end of expansion, patients were given FMs and treated at least to a positive overjet. The SG was compared with a control group (CG) of 21 prepubertal subjects (9 females; 12 males) presenting with normal occlusion and mean age of 7.9 years (SD 1.6 years). For each subject of the SG and CG initial (pretreatment, T1) and final (post-treatment, T2) digital dental casts were available. Significant in between-group differences were tested with the Student's t-test. RESULTS: The transverse dimension of the upper arch was significantly greater in SG vs. CG (IMAW: +2.6 mm; ICAW: +3.1 mm). Anterior arch length and arch depth were significantly smaller in SG when compared with CG (AAL: -3.2 mm, AD: -3.4 mm) at the end of therapy. CONCLUSION: The orthopaedic treatment with bonded RME/FM produced in subjects treated in the deciduous or early mixed dentition a significant expansion of the maxillary arch and mesialisation of the posterior teeth with a reduction of the arch depth. PMID- 26418926 TI - New approach in paediatric dentistry: ultrasonic nondestructive evaluation of restorative dental materials. Experimental study. AB - AIM: The ultrasonic inspection is a non invasive method which is very developed in the industrial field, for the non-destructive evaluation of materials, and in the medical field, for the ultrasound diagnostic analysis. In paediatric dentistry the most widely used non- destructive evaluation is the X-ray technique. Radiographs are valuable aids in the oral health care of infants, children, adolescents, allowing dentists to diagnose and treat oral diseases that cannot be detected during a visual clinical examination. The aim of this in vitro study was to analyse the ultrasonic non-destructive evaluation (UT-NDE) technique to inspect both dental materials internal structure and the form and position of internal defects in order to obtain a diagnostic method, free of ionising radiations, in paediatric dentistry. Moreover the ultrasonic inspection (UT) could be a rapid method of diagnosis in uncooperative paediatric patients. MATERIALS AND METHODS: Study Design: Experimental samples were manufactured with the characteristics of a large composite or glass ionomer cement paediatric dental restoration, in terms of either size or operative technique used. Characteristics of the common restorations were analysed and reproduced in vitro, using the same operative conditions, also adding operative defects into some samples. All the samples were subjected to an innovative UT test using the pulse echo immersion scanning technique. Both C-scans and full volume scans were carried out during the experimental programme. To enhance the data obtained from the UT scan, a digital system (Ecus Inspection software) for signal detection, archiving, processing and displaying was used. RESULTS: UT images showed the presence of internal defects in the dental materials. It was also possible to inspect very thin discontinuity such as the one represented by the fluid resin. STATISTICS: In order to execute the statistical analysis, the values of electric voltage measured in five higher white points and in five higher grey points of the pictures pixels, were measured for each sample. Then, the average values and the standardised data were calculated. CONCLUSION: n In conclusion, the ultrasonic test could be a diagnostic non-invasive method in paediatric patients, capable to evaluate the quality of the restorative teeth filling, showing internal little defects. In vivo application of this diagnostic method should be developed. PMID- 26418927 TI - Prevalence of dental anomalies in children with cleft lip and unilateral and bilateral cleft lip and palate. AB - AIM: To examine the prevalence of different types of dental anomalies in children with nonsyndromic cleft lip, unilateral cleft lip-palate, and bilateral cleft lip palate. MATERIALS AND METHODS: A sample of 90 patients (aged 4-20 years) affected by isolated cleft lip, unilateral and bilateral cleft lip and palate was examined. Cleft patients were classified into one of three groups according to cleft type: (1) Unilateral Cleft Lip-Palate, (2) Bilateral Cleft Lip-Palate, and (3) Cleft Lip. Intraoral exams, panoramic radiographs and dental casts, were used to analyse the prevalence of the various dental anomalies included in this study. RESULTS: There were no statistically significant differences between patients with cleft lip, unilateral cleft lip and palate and bilateral cleft lip and palate. The congenital absence of the cleft-side lateral incisor was observed in 40% of the sample, and a total of 30% patients showed supernumerary teeth at the incisors region. Second premolar agenesis was found in 4.4% of patients, whereas in 18.9% of the sample there was an ectopic dental eruption. Lateral or central incisors rotation was noted in 31.1% of the sample, while shape anomaly, lateral incisor microdontia, and enamel hypoplasia were detected respectively in 25.6%, 5.6% and 18.9% of cleft patients. CONCLUSION: High prevalence of different dental anomalies in children with cleft lip and unilateral and bilateral cleft lip and palate has been confirmed. This study, in particular, shows the presence of ectopic and rotated teeth in the cleft area. PMID- 26418928 TI - Gingival fibromatosis: a case report. AB - AIM: Gingival Fibromatosis is characterised by a large increase in the gingival dimension which extends above the dental crowns, covering them partially or completely. The causes of the disease may have a genetic origin, in which case gingival hyperplasia may occur in isolation or be part of a syndrome, or acquired origin, which comes from specific drugs administered systemically. A form of gingival fibromatosis of idiopathic origin has been described. The therapy involves mainly the surgical removal of the hyperplastic gingival tissue, although in these cases recurrences are frequent. CASE REPORT: A 9 years old male patient came to observation at the Clinic of Pediatric Dentistry of the Tor Vergata Polyclinic of Rome. After Primary Gingival Fibromatosis was diagnosed, the therapeutic choice was to wait and postpone gingivectomy at the end of the development phase. PMID- 26418929 TI - Evaluation of words in child-paediatric dentist communication. AB - AIM: Aim of the present study is to demonstrate which words are widely used by children and a paediatric dentist during different dental procedures in conjunction with behaviour shaping in paediatric dentistry. MATERIALS AND METHODS: Twenty children aged between 3.5 and 10.5 (10 F, 10 M) visiting the clinic of Yeditepe University were enrolled for the study. An audio recorder was hidden in the operatory room, the paediatric dentist was blind. The procedure was randomised as for each child only one appointment was recorded (one patient-one appointment-one procedure). Age, gender, appointment type, details of procedure performed were recorded. At the end of every session, records were investigated regarding verbal communication. RESULTS: The paediatric dentist used a total of 5,005 words during the trial with minimum of 13 and max of 518 words in a session (mean 211.8 +/- 153.1). There were no significant differences in the words used by the child and the practitioner regarding gender, session, and duration of being acquainted with (p>0.05). Regarding age groups, preschoolers (3.5-6 yrs old) significantly used more words than the schoolers (7- 10.5 yrs old) (p<0.05). CONCLUSION: Paediatric dentists should be careful and selective in communication with children as well as using an age-appropriate language. PMID- 26418930 TI - Effect of audiovisual eyeglasses during dental treatment in 5-8 year-old children. AB - AIM: To evaluate the effect of Audiovisual (AV) eyeglasses on pain and anxiety levels during restorative treatment in 5-8 year-olds Thai children. MATERIALS AND METHODS: STUDY DESIGN: Forty-two children with bilateral carious molars were recruited and randomly divided into 2 groups according to the sequence of AV eyeglasses used. Group I was a group which received treatment without wearing AV eyeglasses in the first visit and wearing the eyeglasses in a second visit. Group II was vice versa. Treatments were done in 2 visits, 1 to 4 weeks apart. Self reporting pain using the Faces Pain Scale-Revised (FPS-R), face, legs, activity, crying and consolability scale (FLACC) and heart rate (HR), were measured to assess pain and anxiety levels, respectively. Besides baseline, all variables were measured at the following periods: 1) pre-operation, 2) rubber dam placement, 3) the first use of high speed hand piece, and 4) five minutes interval during the remaining treatment. RESULTS: There was no significant difference in gender (p=0.204) and treatment arch (p=0.292) using Chi-square test at p<0.05, previous dental experience (p=0.381) and treatment received (p=0.835) using Fisher's exact test at p<0.05, age (p=0.384, T-test at p<0.05), and treatment time (1st visit: p=0.465, 2nd visit: p=0.89, Mann- Whitney U test at p<0.05) between 2 groups. AV eyeglasses effectively reduced HR in pre-operation (p=0.043, T test at p<0.05) and FLACC scores in pre-operation (p=0.018, Mann Whitney U test at p<0.05) and during the first use of high speed hand piece (p=0.047, Mann-Whitney U test at p<0.05). However, HR were decreased during rubber dam placement (p=0.002, T test at p<0.0), the first use of high speed hand piece (p=0.049, T test at p<0.05) and during remaining treatment (p=0.035, T test at p<0.05) in second visit as compared with the first visit with or without wearing the eyeglasses. CONCLUSION: AV eyeglasses successfully reduced HR and physical distress during pre-operation and the first use of high speed hand piece. It could be used as an adjunctive distraction technique during dental treatment in children. PMID- 26418932 TI - [Poems from the clinic--afterwards]. PMID- 26418931 TI - The mandibular permanent second molars and their risk of impaction: a retrospective study. AB - AIM: The aim of this retrospective study is promote a better understanding of the impaction of teeth 37 and 47 by means of clinical and statistical data from the point of view of early interceptive treatment. MATERIALS AND METHODS: STUDY DESIGN: 478 patients of the Orthodontic School of "La Sapienza" University of Rome (Italy) were studied to assess the eruption of teeth 37 and 47 on at least two good-quality panorex using angular measurements and Nolla's index from January 2008 to December 2013. Data were analysed using ANOVA and Tukey HSD test (P < 0.05). RESULTS: The data obtained on the possible correlations between the examined teeth and the four reference angles show that at t0, the angular variation of teeth 36 or 46 is constant when the teeth are at the end of their eruptive process, while for teeth 37 and 47, this variation is always constant. At t0, the first and the second molars of both quadrants, during eruption showed a similar behaviour. At t1, the four teeth examined in the patients sample showed a model of development analogous to that exhibited at t0. STATISTICS: a constant variation (t0-t1) is present among the differences in the development of the 36 and the two angular values, while difference in development of the 37 and that of the angular value is constant only in relationship to the difference in development of the mandibular first molar of the same quadrant. The variations between the difference in development of the 47 and in angular value (t0-t1) are constant only when related to the developing 46. The analytic variance of gradience (vargrad) data confirm peculiar behaviour of the first one, according to both mandibular molars, during their eruptive development. CONCLUSIONS: Adoption of universally recognised radiographic predictive methods allows assessment of the case and allows the specialist to plan a suitable treatment to prevent or intercept the molar impaction, with a perspective of a less invasive and shorter therapy. Although rare, impaction of teeth 37 and 47 often requires a complex, multidisciplinary approach. PMID- 26418933 TI - [HbA1c is not enough in screening for impaired glucose metabolism. Glucose tolerance tests are also needed, as shown in Swedish prospective epidemiological study]. AB - An HbA1c threshold of >= 42 mmol/mol has been proposed to diagnose prediabetes. The sensitivity, specificity and positive predictive value of the proposed threshold for detection of individuals with prediabetes was examined in a study of 573 randomly selected individuals from Vara and Skovde. In addition, the utility of the FINDRISC questionnaire and of a fasting glucose test in combination with three short questions concerning BMI, heredity for type 2 diabetes and known hypertension was examined. Results from an oral glucose tolerance test were used as reference. The sensitivity of HbA1c and FINDRISC to detect individuals with IGT was 16 and 26 per cent respectively. Questions regarding BMI, heredity and hypertension together with a fasting glucose test yielded a sensitivity of 50%, but a lower specificity and positive predictive value. We conclude that HbA1c inefficiently detected individuals with impaired glucose tolerance and that oral glucose tolerance tests can still preferably be recommended. PMID- 26418934 TI - [Good results of stent treatment in perforated duodenal ulcer]. AB - Despite modern treatment of ulcer disease perforations still occur and constitute a life threatening complication. Standard treatment is surgical closure. We have introduced stent treatment as a minimal invasive alternative, mainly in elderly and co-morbid patients. During a 4-year period (2009-2012) ten patients with perforated duodenal ulcer were treated with a covered duodenal stent at South Alvsborg Hospital. These patients were retrospectively compared with all patients (n = 19) treated with surgical closure at the same hospital during the same time period. Stent treatment shows good clinical results indicating fewer complications than surgical treatment even if the patients had a slightly higher ASA score. In this series stent treatment is shown to be a safe and effective alternative for treating perforated duodenal ulcers, even in old and co-morbid patients. PMID- 26418935 TI - [Glucose impairment despite normal HbA1c or fasting plasma glucose]. PMID- 26418936 TI - [No support for lipid therapy as an effective antidote in acute intoxication. A systematic literature review and analysis of 114 case reports]. AB - Lipid rescue is increasingly used as treatment of various types of poisoning despite weak scientific evidence. Some experimental studies have confirmed a positive effect, but others have failed. Clinical studies are lacking, wherefore we decided to do a systematic review of all published human cases. Case reports were searched for in PubMed and Web of Science and thereafter examined by two experts according to an assessment form grading the probability for a causal connection between lipid rescue and improved symptoms. A total of 114 case reports were identified. No correlation was found between the ratings of the cases and the fat solubility of the respective toxins. The findings do not support the predication that lipid rescue is an effective antidote, not even in cases involving local anaesthetics. In view of the potentially negative effects of lipid rescue, it seems reasonable to strictly limit its indication to life threatening situations where conventional therapies have failed. PMID- 26418937 TI - [Mimicking sounds--our first language?]. PMID- 26418938 TI - [Antidepressants--life-saving or life-threatening?]. PMID- 26418939 TI - ["Take responsibility for people who have undergone bariatric surgery". Guidelines are lacking and follow-up needs radical improvement]. PMID- 26418941 TI - [The birth, life and death of value-based health care. The last "pseudo innovation"?]. PMID- 26418940 TI - [The poet Brodsky passed through the purgatory of Soviet psychiatry]. PMID- 26418942 TI - [In Process Citation]. PMID- 26418943 TI - [A better follow-up of obesity surgery needed]. PMID- 26418944 TI - [Considering time]. PMID- 26418945 TI - ErbB4 Activated p38gamma MAPK Isoform Mediates Early Cardiogenesis Through NKx2.5 in Human Pluripotent Stem Cells. AB - Activation of ErbB4 receptor signaling is instrumental in heart development, lack of which results in embryonic lethality. However, mechanism governing its intracellular signaling remains elusive. Using human pluripotent stem cells, we show that ErbB4 is critical for cardiogenesis whereby its genetic knockdown results in loss of cardiomyocytes. Phospho-proteome profiling and Western blot studies attribute this loss to inactivation of p38gamma MAPK isoform which physically interacts with NKx2.5 and GATA4 transcription factors. Post cardiomyocyte formation p38gamma/NKx2.5 downregulation is followed by p38alpha/MEF2c upregulation suggesting stage-specific developmental roles of p38 MAPK isoforms. Knockdown of p38gamma MAPK similarly disrupts cardiomyocyte formation in spite of the presence of NKx2.5. Cell fractionation and NKx2.5 phosphorylation studies suggest inhibition of ErbB4-p38gamma signaling hinders NKx2.5 nuclear translocation during early cardiogenesis. This study reveals a novel pathway that directly links ErbB4 and p38gamma to the transcriptional machinery of NKx2.5-GATA4 complex which is critical for cardiomyocyte formation during mammalian heart development. PMID- 26418946 TI - Pulmonary arterial wall thickness as a promising echocardiographic follow-up parameter in severe pediatric pulmonary hypertension. PMID- 26418947 TI - Continuous and pulsed hydrogen-deuterium exchange and mass spectrometry characterize CsgE oligomerization. AB - We report the use of hydrogen-deuterium amide exchange coupled to mass spectrometry (HDX-MS) to study the interfaces of and conformational changes accompanying CsgE oligomerization. This protein plays an important role in enteric bacteria biofilm formation. Biofilms provide protection for enteric bacteria from environmental extremes and raise concerns about controlling bacteria and infectious disease. Their proteinaceous components, called curli, are extracellular functional amyloids that initiate surface contact and biofilm formation. The highly regulated curli biogenesis involves a major subunit, CsgA, a minor subunit CsgB, and a series of other accessory proteins. CsgE, possibly functioning as oligomer, is a chaperonin-like protein that delivers CsgA to an outer-membrane bound oligomeric CsgG complex. No higher-order structure, or interfaces and dynamics of its oligomerization, however, are known. In this work, we determined regions involved in CsgE self-association by continuous HDX, and, on the basis of that, prepared a double mutant W48A/F79A, derived from interface alanine scan, and verified that it exists as monomer. Using pulsed HDX and MS, we suggest there is a structural rearrangement occurring during the oligomerization of CsgE. PMID- 26418948 TI - Utilities of Electronic Medical Records to Improve Quality of Care for Acute Kidney Injury: Past, Present, Future. AB - Electronic health records (EHRs) have become an integrated part of medical practice in most clinical settings around the world. Appropriate use of EHR potentially improves patient care while poorly designed EHR can cause harm. In recent years, EHR has been used as a platform to identify patients who have or may develop acute kidney injury (AKI). The benefit of using EHR for a rule-based classification of AKI has been controversial. While some reports indicate improvement in the process of care provided to AKI patients, other studies do not show significant changes in the outcomes. Utilities of EHR in AKI should go beyond a rule-based detection of the AKI as a syndrome. There are several different potential applications for such tools including AKI forecasting models and clinical decision support systems, to improve the quality of care and outcome of the patients with AKI. Both clinical and investigative interest in the field is growing among clinicians, administrators and scientists. Appropriate utilization of intelligent EHR can provide timely, appropriate and accurate information to the clinicians in order to improve the quality of care provided to critically ill patients and assist investigators to generate new knowledge. In this review paper, we discuss the past and present states of EHR role in the field of AKI. We also share our views regarding the future potentials and directions of these devices. PMID- 26418949 TI - Reply to comment by Ho on "genetic characterization, nickel tolerance, biosorption, kinetics, and uptake mechanism of a bacterium isolated from electroplating industrial effluent". PMID- 26418950 TI - Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM. AB - The outcome of cancer therapy strongly depends on the complex network of cell signaling pathways, including transcription factor activation following drug exposure. Here we assessed whether and how the MAP kinase (MAPK) cascade and its downstream target, the transcription factor AP-1, influence the sensitivity of malignant glioma cells to the anticancer drugs temozolomide (TMZ) and nimustine (ACNU). Both drugs induce apoptosis in glioma cells at late times following treatment. Activation of the MAPK cascade precedes apoptosis, as shown by phosphorylation of Jun kinase (JNK) and c-Jun, a main component of AP-1. Pharmacological inhibition and siRNA mediated knockdown of JNK and c-Jun reduced the level of apoptosis in LN-229 glioma cells treated with TMZ or ACNU. Analyzing the underlying molecular mechanism, we identified the pro-apoptotic gene BIM as a critical target of AP-1, which is upregulated following TMZ and ACNU. Importantly, shRNA mediated downregulation of BIM in the malignant glioma cell lines LN-229 and U87MG led to an attenuated cleavage of caspase-9 and, consequently, reduced the level of apoptosis following TMZ and ACNU treatment. Overall, we identified JNK/c-Jun activation and BIM induction as a late pro apoptotic response of glioma cells treated with alkylating anticancer drugs. PMID- 26418951 TI - Cytokine-induced killer cells efficiently kill stem-like cancer cells of nasopharyngeal carcinoma via the NKG2D-ligands recognition. AB - Cancer stem cells (CSCs) are considered to be the root cause for cancer treatment failure. Thus, there remains an urgent need for more potent and safer therapies against CSCs for curing cancer. In this study, the antitumor activity of cytokine induced killer (CIK) cells against putative CSCs of nasopharyngeal carcinoma (NPC) was fully evaluated in vitro and in vivo. To visualize putative CSCs in vitro by fluorescence imaging, and image and quantify putative CSCs in tumor xenograft-bearing mice by in vivo bioluminescence imaging, NPC cells were engineered with CSC detector vector encoding GFP and luciferase (Luc) under control of Nanog promoter. Our study reported in vitro intense tumor-killing activity of CIK cells against putative CSCs of NPC, as revealed by percentage analysis of side population cells, tumorsphere formation assay and Nanog-promoter GFP-Luc reporter gene strategy plus time-lapse recording. Additionally, time lapse imaging firstly illustrated that GFP-labeled or PKH26-labeled putative CSCs or tumorspheres were usually attacked simultaneously by many CIK cells and finally killed by CIK cells, suggesting the necessity of achieving sufficient effector-to-target ratios. We firstly confirmed that NKG2D blockade by anti-NKG2D antibody significantly but partially abrogated CIK cell-mediated cytolysis against putative CSCs. More importantly, intravenous infusion of CIK cells significantly delayed tumor growth in NOD/SCID mice, accompanied by a remarkable reduction in putative CSC number monitored by whole-body bioluminescence imaging. Taken together, our findings suggest that CIK cells demonstrate the intense tumor killing activity against putative CSCs of NPC, at least in part, by NKG2D-ligands recognition. These results indicate that CIK cell-based therapeutic strategy against CSCs presents a promising and safe approach for cancer treatment. PMID- 26418952 TI - Dendritic cell vaccination with a toll-like receptor agonist derived from mycobacteria enhances anti-tumor immunity. AB - Dendritic cell (DC)-based vaccines are considered useful in cancer immunotherapy, and the interaction of DC and adjuvants is important in the design of the next generation vaccines. In this study, whether DC combined with Rv2299c derived from mycobacteria could improve anti-tumor immune responses in a colon cancer mouse model was evaluated. MC38 cell lines were injected subcutaneously to establish colon-cancer-bearing mice and the following four groups were evaluated: PBS control, tumor antigen (TA) loaded-DC, Rv2299c, and a combination of TA-loaded-DC and Rv2299c. The combination treatment with TA-loaded-DC and Rv2299c exhibited greater inhibition of tumor growth compared to other groups. These effects were associated with the reduction of suppressor cells, such as myeloid-derived suppressor cells and regulatory T cells, and the induction of effector cells, such as CD4+ T cells and CD8+ T cells, in spleen, and with the activation of cytotoxic T Lymphocytes and NK cells. These results suggest that TA-loaded-DC vaccination with Rv2299c derived from mycobacteria enhanced anti-tumor immunity in a mouse colon cancer model by inhibiting the generation of immune-suppressive cells and recovering numbers of effector cells, and demonstrated superior polarization of the Th1/Th2 balance in favor of the Th1 immune response. PMID- 26418953 TI - Molecular inimitability amongst tumors: implications for precision cancer medicine in the age of personalized oncology. AB - Tumor sequencing has revolutionized oncology, allowing for detailed interrogation of the molecular underpinnings of cancer at an individual level. With this additional insight, it is increasingly apparent that not only do tumors vary within a sample (tumor heterogeneity), but also that each patient's individual tumor is a constellation of unique molecular aberrations that will require an equally unique personalized therapeutic regimen. We report here the results of 439 patients who underwent Clinical Laboratory Improvement Amendment (CLIA) certified next generation sequencing (NGS) across histologies. Among these patients, 98.4% had a unique molecular profile, and aside from three primary brain tumor patients with a single genetic lesion (IDH1 R132H), no two patients within a given histology were molecularly identical. Additionally, two sets of patients had identical profiles consisting of two mutations in common and no other anomalies. However, these profiles did not segregate by histology (lung adenocarcinoma-appendiceal cancer (KRAS G12D and GNAS R201C), and lung adenocarcinoma-liposarcoma (CDK4 and MDM2 amplification pairs)). These findings suggest that most advanced tumors are molecular singletons within and between histologies, and that tumors that differ in histology may still nonetheless exhibit identical molecular portraits, albeit rarely. PMID- 26418954 TI - EGFRvIII does not affect radiosensitivity with or without gefitinib treatment in glioblastoma cells. AB - BACKGROUND: Glioblastomas (GBM) are often characterized by an elevated expression of the epidermal growth factor receptor variant III (EGFRvIII). We used GBM cell lines with native EGFRvIII expression to determine whether this EGFR variant affects radiosensitivity with or without EGFR targeting. METHODS: Experiments were performed with GBM cell lines lacking (LN229, U87MG, U251, CAS-1) or endogenously expressing EGFRvIII (BS153, DKMG). The two latter cell lines were also used to establish sublines with a low (-) or a high proportion (+) of cells expressing EGFRvIII. EGFR signaling and the cell cycle were analyzed using Western blot and flow cytometry; cell survival was assessed by colony forming assay and double-strand break repair capacity by immunofluorescence. RESULTS: DKMG and BS153 parental cells with heterogeneous EGFRvIII expression were clearly more radiosensitive compared to other GBM cell lines without EGFRvIII expression. However, no significant difference was observed in cell proliferation, clonogenicity or radiosensitivity between the EGFRvIII- and + sublines derived from DKMG and BS153 parental cells. Expression of EGFRvIII was associated with decreased DSB repair capacity for BS153 but not for DKMG cells. The effects of EGFR targeting by gefitinib alone or in combination with irradiation were also found not to depend on EGFRvIII expression. Gefitinib was only observed to influence the proliferation of EGFRvIII- BS153 cells. CONCLUSION: The data indicate that EGFRvIII does not alter radiosensitivity with or without anti-EGFR treatment. PMID- 26418955 TI - Mesenchymal Stromal Cells for Treatment of Acute Steroid-Refractory Graft Versus Host Disease: Clinical Responses and Long-Term Outcome. AB - Acute graft-versus-host disease (aGvHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Steroid resistant aGvHD is associated with poor outcome, and no commonly accepted salvage therapy is available for its treatment. Here, we report 58 adult patients treated with mesenchymal stromal cells (MSCs) as salvage therapy for steroid-refractory aGvHD. Third-party MSCs expanded in platelet lysate-containing medium were transfused at a median dose of 0.99 * 10(6) cells per kg b.wt. A median of two MSC infusions were administered to each patient. Median time between the onset of aGvHD and the first infusion of MSCs was 12 days (range, 6-62 days). Most patients (79%) had grade IV aGvHD. Five patients showed complete response, five showed very good partial response, 17 showed partial response, and 31 showed no response. The estimated probability of survival after 1 year was 19%, and median survival was 69 days. Overall survival was not significantly different from that of a historical cohort of patients receiving alternative salvage therapy and no MSC infusions. In conclusion, MSC treatment on top of conventional immunosuppression was associated with an overall response rate of 47% but improved outcome in terms of survival remains to be shown. PMID- 26418956 TI - The Na+/Ca2+ Exchanger 1 (NCX1) Variant 3 as the Major Extrusion System in Renal Distal Tubular Transcellular Ca2+-Transport. AB - BACKGROUND/AIMS: Fine-tuning of renal calcium (Ca(2+)) reabsorption takes place in the late distal convoluted and connecting tubules (DCT2/CNT) of the kidney via transcellular Ca(2+) transport. Here, Ca(2+) enters the cell at the apical side via the epithelial Ca(2+) channel transient receptor potential vanilloid 5 and is subsequently extruded at the basolateral side by the concerted actions of the plasma membrane Ca(2+) ATPases and the Na(+)/Ca(2+) exchanger 1 (NCX1). NCX1 is responsible for ~ 70% of basolateral Ca(2+) extrusion. The aim of this study was to determine the predominant NCX1 variant in the kidney and its role in Ca(2+) transport. METHODS: DCT2/CNT specific tubules were used to show the abundance of NCX1 specific isoforms. Renal NCX1 variants were cloned from mouse kidney tissue. Human Embryonic Kidney 293(T) cells were transiently transfected with NCX1.3, and Fura-2 measurements and 45Ca(2+) uptake assays were performed to determine several characteristics of NCX1.3 in the reverse mode. RESULTS: NCX1.3 was demonstrated to be the predominant NCX1 variant in the DCT2/CNT, next to NCX1.2 and NCX1.7. NCX1.3 could be inhibited by SN-6, an NCX-specific inhibitor, whereas stimulation of the cAMP/PKA or PKC-mediated pathway did not affect Ca(2+) influx as measured in the reverse mode. Lowering intracellular Ca(2+) concentrations resulted in a decreased Ca(2+) uptake. CONCLUSION: NCX1.3 is the predominant NCX variant in the DCT2/CNT tubules. Its function is dependent on intracellular Ca(2+) concentrations. PMID- 26418959 TI - Brain Activation for Knee Movement Measured Days Before Second Anterior Cruciate Ligament Injury: Neuroimaging in Musculoskeletal Medicine. AB - BACKGROUND: Anterior cruciate ligament (ACL) injury has multifactorial causes encompassing mechanical, hormonal, exposure, and anatomical factors. Alterations in the central nervous system also play a role, but their influence after injury, recovery, and recurrent injury remain unknown. Modern neuroimaging techniques can be used to elucidate the underlying functional and structural alterations of the brain that predicate the neuromuscular control adaptations associated with ACL injury. This knowledge will further our understanding of the neural adaptations after ACL injury and rehabilitation and in relation to future injury risk. In this paper, we describe the measurement of brain activation during knee extension flexion after ACL injury and reconstruction and 26 days before a contralateral ACL injury. METHODS: Brain functional magnetic resonance imaging data for an ACL-injured participant and a matched control participant were collected and contrasted. RESULTS: Relative to the matched control participant, the ACL injured participant exhibited increased activation of motor planning, sensory processing, and visual-motor control areas. A similar activation pattern was present for the contralateral knee that sustained a subsequent injury. CONCLUSIONS: Bilateral neuroplasticity after ACL injury may contribute to risk of second injury, or aspects of neurophysiology may be predisposing factors to primary injury. CLINICAL IMPLICATIONS: Sensory-visual-motor function and motor learning adaptations may provide targets for rehabilitation. PMID- 26418958 TI - Joint Kinetics and Kinematics During Common Lower Limb Rehabilitation Exercises. AB - CONTEXT: Unilateral body-weight exercises are commonly used to strengthen the lower limbs during rehabilitation after injury, but data comparing the loading of the limbs during these tasks are limited. OBJECTIVE: To compare joint kinetics and kinematics during 3 commonly used rehabilitation exercises. DESIGN: Descriptive laboratory study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 9 men (age = 22.1 +/- 1.3 years, height = 1.76 +/- 0.08 m, mass = 80.1 +/- 12.2 kg) participated. INTERVENTION(S): Participants performed the single-legged squat, forward lunge, and reverse lunge with kinetic data captured via 2 force plates and 3-dimensional kinematic data collected using a motion-capture system. MAIN OUTCOME MEASURE(S): Peak ground reaction forces, maximum joint angles, and peak sagittal-joint moments. RESULTS: We observed greater eccentric and concentric peak vertical ground reaction forces during the single-legged squat than during both lunge variations (P <= .001). Both lunge variations demonstrated greater knee and hip angles than did the single-legged squat (P < .001), but we observed no differences between lunges (P > .05). Greater dorsiflexion occurred during the single-legged squat than during both lunge variations (P < .05), but we noted no differences between lunge variations (P = .70). Hip-joint moments were greater during the forward lunge than during the reverse lunge (P = .003) and the single-legged squat (P = .011). Knee-joint moments were greater in the single-legged squat than in the reverse lunge (P < .001) but not greater in the single-legged squat than in the forward lunge (P = .41). Ankle-joint moments were greater during the single-legged squat than during the forward lunge (P = .002) and reverse lunge (P < .001). CONCLUSIONS: Appropriate loading progressions for the hip should begin with the single-legged squat and progress to the reverse lunge and then the forward lunge. In contrast, loading progressions for the knee and ankle should begin with the reverse lunge and progress to the forward lunge and then the single-legged squat. PMID- 26418960 TI - Effect of ferromagnetic ordering on phonons in KCo2Se2. AB - Results of the density functional theory studies of the phonon dynamics in the ternary layered cobalt diselenide are reported. The partial phonon densities of states due to vibrations of K, Co, and Se atoms are analysed in detail. They indicate that phonons associated with the dynamics of Co and Se ions within the [Co2Se2] structural blocks span the entire spectral range extending to 260 cm( 1), whereas phonons from the K-sublattice remain limited to the frequency range of 80-150 cm(-1). The phonons conform with structural features of the quasi-2D layered structure of KCo2Se2. Ferromagnetic order in the Co-sublattice is shown to determine to a great extent the phonon densities of states, the Raman and infrared spectra of KCo2Se2. The in-planar magnetic interactions are responsible for pronounced softening of the high-frequency phonon modes and lead to disappearance of the low-frequency Raman-active mode of the E g symmetry. The observed behavior of the Raman-active and infrared-active modes suggests rather strong spin-phonon coupling in KCo2Se2. Results of the present investigations allow to clarify the origin of substantial differences between dynamical properties of the ferromagnetic Co-based and the paramagnetic Ni-based ternary layered dichalcogenides, both adopting the ThCr2Si2-type structure. PMID- 26418957 TI - A new balancing act: The many roles of melatonin and serotonin in plant growth and development. AB - Melatonin and serotonin are indoleamines first identified as neurotransmitters in vertebrates; they have now been found to be ubiquitously present across all forms of life. Both melatonin and serotonin were discovered in plants several years after their discovery in mammals, but their presence has now been confirmed in almost all plant families. The mechanisms of action of melatonin and serotonin are still poorly defined. Melatonin and serotonin possess important roles in plant growth and development, including functions in chronoregulation and modulation of reproductive development, control of root and shoot organogenesis, maintenance of plant tissues, delay of senescence, and responses to biotic and abiotic stresses. This review focuses on the roles of melatonin and serotonin as a novel class of plant growth regulators. Their roles in reproductive and vegetative plant growth will be examined including an overview of current hypotheses and knowledge regarding their mechanisms of action in specific responses. PMID- 26418961 TI - Interleukin-2, Ipilimumab, and Anti-PD-1: Clinical Management and the Evolving Role of Immunotherapy for the Treatment of Patients With Metastatic Melanoma. AB - Treatment of metastatic melanoma has changed dramatically in the past 5 years with the approval of six new agents (vemurafenib, dabrafenib, trametinib, ipilimumab, pembrolizumab, and nivolumab) by the US Food and Drug Administration (FDA). This review will compare the immunotherapies recently approved by the FDA (ipilimumab, nivolumab and pembrolizumab) with the long-approved immunotherapy, interleukin-2. Additional consideration will be given to the evolving landscape, including the opportunities for combination regimens. Immunotherapies have distinct mechanisms of action and unique response kinetics that differ from conventional cytotoxic and targeted therapies, and have a range of adverse events that can be safely managed by experienced health care providers. Data suggest immunotherapies can result in long-term survival in a proportion of patients. This dynamic and evolving field of immunotherapy for melanoma will continue to offer challenges in terms of optimal patient management for the foreseeable future. PMID- 26418962 TI - Irradiation Enhances the Ability of Monocytes as Nanoparticle Carrier for Cancer Therapy. AB - The tumor-homing ability of monocytes renders them a potential cellular delivery system for alternative cancer therapies, although their migratory ability can be impaired following reagent uptake. Approaches that enhance monocyte tumor homing and promote their migration will improve the clinical value of these cells as cellular carriers. Previous studies have shown that irradiation (IR) can promote macrophage aggregation in hypoxic regions. To investigate whether IR enhances the infiltration of bone marrow-derived monocytes (BMDMs) into tumors, the infiltration of BMDMs from GFP-transgenic mice in a murine prostate adenocarcinoma TRAMP-C1 model was examined by fluorescence microscopy. IR did not increase the number of BMDMs that infiltrated initially, but did increase monocyte retention within IR-treated tumors for up to 2 weeks. We also showed that BMDMs can take up various imaging and therapeutic agents, although the mobility of BMDMs decreased with increasing load. When BMDMs were differentiated in IR-treated tumor-conditioned medium (IR-CM) in vitro, the nanoparticle load mediated inhibition of migration was attenuated. These IR-CM-differentiated BMDMs delivered polymer vesicles encapsulating doxorubicin to radiation therapy (RT) induced hypoxic tumor regions, and enhanced the efficacy of RT. The prolonged retention of monocytes within irradiated tumor tissues and the ability of IR-CM to enhance the migratory ability of cargo-laden BMDMs suggest that monocytes pre conditioned by IR-CM can potentially act as cellular carriers for targeted therapy following conventional RT. PMID- 26418963 TI - Endoplasmic reticulum: Where nucleotide sugar transport meets cytokinin control mechanisms. AB - The endoplasmic reticulum (ER) is a multifunctional eukaryotic organelle where the vast majority of secretory proteins are folded and assembled to achieve their correct tertiary structures. The lumen of the ER and Golgi apparatus also provides an environment for numerous glycosylation reactions essential for modifications of proteins and lipids, and for cell wall biosynthesis. These glycosylation reactions require a constant supply of cytosolically synthesized substrate precursors, nucleotide sugars, which are transported by a group of dedicated nucleotide sugar transporters (NST). Recently, we have reported on the identification of a novel ER-localized NST protein, ROCK1, which mediates the transport of UDP-linked acetylated hexosamines across the ER membrane in Arabidopsis. Interestingly, it has been demonstrated that the activity of ROCK1 is important for the regulation of cytokinin-degrading enzymes, cytokinin oxidases/dehydrogenases (CKX), in the ER and, thus, for cytokinin responses. In this addendum we will address the biochemical and cellular activity of the ROCK1 transporter and its phylogenetic relation to other NST proteins. PMID- 26418965 TI - Method for the Synthesis of Dibenzo[g,p]Chrysenes: Domino Friedel-Crafts-Type Cyclization of Difluoroethenes Bearing Two Biaryl Groups. AB - Dibenzo[g,p]chrysenes were readily synthesized via the superacid- or TiF4 mediated domino Friedel-Crafts-type cyclization of 1,1-difluoroethenes bearing two biaryl groups, which were easily prepared via the Suzuki-Miyaura coupling of 1,1-difluoro-2,2-diiodoethene or 1-(biphenyl-2-yl)-1-bromo-2,2-difluoroethene. Using this approach, the activation of both vinylic and aromatic C-F bonds was successfully achieved to make new C-C bonds. PMID- 26418964 TI - A Sensitive and Biodegradable Pressure Sensor Array for Cardiovascular Monitoring. AB - An array of highly sensitive pressure sensors entirely made of biodegradable materials is presented, designed as a single-use flexible patch for application in cardiovascular monitoring. The high sensitivity in combination with fast response time is unprecedented when compared to recent reports on biodegradable pressure sensors (sensitivity three orders of magnitude higher), as illustrated by pulse wave velocity measurements, toward hypertension detection. PMID- 26418967 TI - A Model to Estimate Frozen Tissue Collection Targets in Biobanks to Support Cancer Research. AB - Human biospecimens are used in 40% of cancer research publications. Tumor biobanks are an important source for these biospecimens and support both prospective and retrospective research studies. Supporting retrospective research requires tumor tissue biobanks to accrue an adequate inventory, or stock, of cases comprising tumor biospecimens and associated treatment and outcomes data. We propose a model to establish appropriate targets for stocks of frozen tissue biospecimens in tumor biobanks, sufficient to support cancer research needs. Our model considers national levels of investment in academic cancer research relative to research use of cases described in publication output, and scales this to the local context of the BC Cancer Agency Tumour Tissue Repository (TTR) as an example. Adjustment factors are then applied to correct for the primary intended user base of the biobank, as well as variables intrinsic to all biobanking operations and case collection. On this basis we estimate a current target stock for the TTR of approximately 4500 cases. Local research demand derived from case release data can then be applied to fine-tune accrual targets and refine the biobank's relative portfolio of cases from different tumor sites. We recognize that current targets will need regular remodeling as research demands change over time and that our initial model has some limitations related to the need to extrapolate from available research and biobank utilization data, and does not incorporate biospecimen/case contributions within the context of a network. However, we believe the lack of models to estimate inventory targets for tumor biobanks and to better balance research demand with biospecimen supply, contributes to the hesitation of funders to provide support, and also the problems of sustainability faced by many biobanks. Creating tangible inventory targets will improve biobank efficiency, sustainability, and may also encourage increased and stable funding. PMID- 26418966 TI - Novel 3-Substituted 7-Phenylpyrrolo[3,2-f]quinolin-9(6H)-ones as Single Entities with Multitarget Antiproliferative Activity. AB - A series of chemically modified 7-phenylpyrrolo[3,2-f]quinolinones was synthesized and evaluated as anticancer agents. Among them, the most cytotoxic (subnanomolar GI50 values) amidic derivative 5f was shown to act as an inhibitor of tubulin polymerization (IC50, 0.99 MUM) by binding to the colchicine site with high affinity. Moreover, 5f induced cell cycle arrest in the G2/M phase of the cell cycle in a concentration dependent manner, followed by caspase-dependent apoptotic cell death. Compound 5f also showed lower toxicity in nontumoral cells, suggesting selectivity toward cancer cells. Additional experiments revealed that 5f inhibited the enzymatic activity of multiple kinases, including AURKA, FLT3, GSK3A, MAP3K, MEK, RSK2, RSK4, PLK4, ULK1, and JAK1. Computational studies showed that 5f can be properly accommodated in the colchicine binding site of tubulin as well as in the ATP binding clefts of all examined kinases. Our data indicate that the excellent antiproliferative profile of 5f may be derived from its interactions with multiple cellular targets. PMID- 26418969 TI - Structural phase transitions in trigonal Selenium induce the formation of a disordered phase. AB - Arguments based on the Mermin-Wagner theorem suggest that the quasi-1D trigonal phase of Se should be unstable against long wavelength perturbations. Consisting of parallel Se-Se chains, this essentially fragile solid undergoes a partial transition to a monoclinic structure (consisting of 8-membered rings) at low temperatures (~50 K), and to a distorted trigonal phase at moderate pressures (~3GPa). Experimental investigations on sub-millimeter-sized single crystals provide clear evidence that these transitions occur via a novel and counter intuitive route. This involves the reversible formation of an intermediate, disordered structure that appears as a minority phase with increasing pressure as well as with decreasing temperature. The formation of the disordered state is indicated by: (a) a 'Boson-peak' that appears at low temperatures in the specific heat and resonance Raman data, and (b) a decrease in the intensity of Raman lines over a relatively narrow pressure range. We complement the experimental results with a phenomenological model that illustrates how a first order structural transition may lead to disorder. Interestingly, nanocrystals of trigonal Se do not undergo any structural transition in the parameter space studied; neither do they exhibit signs of disorder, further underlining the role of disorder in this type of structural transition. PMID- 26418968 TI - CD151 promotes alpha3beta1 integrin-dependent organization of carcinoma cell junctions and restrains collective cell invasion. AB - Integrins function in collective migration both as major receptors for extracellular matrix and by crosstalk to adherens junctions. Despite extensive research, important questions remain about how integrin signaling mechanisms are integrated into collective migration programs. Tetraspanins form cell surface complexes with a subset of integrins and thus are good candidates for regulating the balance of integrin functional inputs into cell-matrix and cell-cell interactions. For example, tetraspanin CD151 directly associates with alpha3beta1 integrin in carcinoma cells and promotes rapid alpha3beta1-dependent single cell motility, but CD151 also promotes organized adherens junctions and restrains collective carcinoma cell migration on 2D substrates. However, the individual roles of CD151s integrin partners in CD151s pro-junction activity in carcinoma cells were not well understood. Here we find that CD151 promotes organized carcinoma cell junctions via alpha3beta1 integrin, by a mechanism that requires the a3b1 ligand, laminin-332. Loss of CD151 promotes collective 3D invasion and growth in vitro and in vivo, and the enhanced invasion of CD151-silenced cells is alpha3 integrin dependent, suggesting that CD151 can regulate the balance between alpha3beta1s pro-junction and pro-migratory activities in collective invasion. An analysis of human cancer cases revealed that changes in CD151 expression can be linked to either better or worse clinical outcomes depending on context, including potentially divergent roles for CD151 in different subsets of breast cancer cases. Thus, the role of the CD151-alpha3beta1 complex in carcinoma progression is context dependent, and may depend on the mode of tumor cell invasion. PMID- 26418970 TI - Airborne signals of communication in sagebrush: a pharmacological approach. AB - When plants receive volatiles from a damaged plant, the receivers become more resistant to herbivory. This phenomenon has been reported in many plant species and called plant-plant communication. Lab experiments have suggested that several compounds may be functioning as airborne signals. The objective of this study is to identify potential airborne signals used in communication between sagebrush (Artemisia tridentata) individuals in the field. We collected volatiles of one branch from each of 99 sagebrush individual plants. Eighteen different volatiles were detected by GC-MS analysis. Among these, 4 compounds; 1.8-cineol, beta caryophyllene, alpha-pinene and borneol, were investigated as signals of communication under natural conditions. The branches which received either 1,8 cineol or beta-caryophyllene tended to get less damage than controls. These results suggested that 1,8-cineol and beta-caryophyllene should be considered further as possible candidates for generalized airborne signals in sagebrush. PMID- 26418971 TI - Epidemiology of Pelvic Fractures in Germany: Considerably High Incidence Rates among Older People. AB - Epidemiological data about pelvic fractures are limited. Until today, most studies only analyzed inpatient data. The purpose of this study was to estimate incidence rates of pelvic fractures in the German population aged 60 years or older, based on outpatient and inpatient data. We conducted a retrospective population-based observational study based on routine data from a large health insurance company in Germany. Age and sex-specific incidence rates of first fractures between 2008 and 2011 were calculated. We also standardized incidence rates with respect to age and sex in the German population. Multiple Poisson regression models were used to evaluate the association between the risk of first pelvic fracture as outcome and sex, age, calendar year and region as independent variables. The total number of patients with a first pelvic fracture corresponded to 8,041 and during the study period 5,978 insured persons needed inpatient treatment. Overall, the standardized incidence rate of all first pelvic fractures was 22.4 [95% CI 22.0-22.9] per 10,000 person-years, and the standardized incidence rate of inpatient treated fractures 16.5 [16.1-16.9]. Our adjusted regression analysis confirmed a significant sex (RR 2.38 [2.23-2.55], p < 0.001, men as reference) and age effect (higher risk with increasing age, p < 0.001) on first fracture risk. We found a slight association between calendar year (higher risk in later years compared to 2008, p = 0.0162) and first fracture risk and a further significant association with region (RR 0.92 [0.87-0.98], p = 0.006, Westfalen-Lippe as reference). The observed incidences are considerably higher than incidences described in the international literature, even if only inpatient treated pelvic fractures are regarded. Besides which, non-inclusion of outpatient data means that a relevant proportion of pelvic fractures are not taken into account. Prevention of low energy trauma among older people remains an important issue. PMID- 26418973 TI - Polymer-Layer-Free Alignment for Fast Switching Nematic Liquid Crystals by Multifunctional Nanostructured Substrate. AB - A novel polymer-layer-free system for liquid-crystal alignment is demonstrated by various shaped indium tin oxide (ITO) patterns. Liquid crystals are aligned along the ITO line pattern and secondary sputtering lithography can change the shape of the ITO line pattern. Different shapes can control the direction and size of the pretilt angle. This effect eliminates defects and reduces the response time. PMID- 26418972 TI - Hodgkin lymphoma cell lines bind to platelets. Incubation with platelets induces CD15 and P-selectin dependent adhesion of the cell lines to Human Umbilical Vein Endothelial cells (HUVEC). AB - Hodgkin's lymphoma is believed to spread in an orderly fashion within the lymphatic compartment. In a minority of cases, after reaching the spleen, the neoplasm disseminates, reminiscent of metastasis. In the spleen, the Hodgkin-Reed Sternberg tumor cells come across platelets in the blood vessels and mainly in the splenic red pulp. Based on this knowledge, we investigated the possibility of platelets inducing cell adhesion in Hodgkin's lymphoma cell lines. We showed that L428 and KMH-2 cells strongly adhere to thrombin-activated platelets. Cell adhesion to platelets is partially dependent on CD15 antigens (Lewis(X)), mainly sialyl-CD15, and P-selectin. KMH-2, as compared to L428 cells, showed increased binding due to its differential high expression of the sialyl-CD15. As a consequence of incubation with platelets, KMH-2 cells also produced increased amounts of tumor necrosis factors alpha (TNFalpha) followed by enhanced binding to human vascular endothelial cells (HUVEC). Incubation of both cell lines with activated platelets also induced activation of AP-1 transcription complex. Our findings are consistent with the concept that platelets play a critical role in the dissemination of HRS cells in HL, predominantly in the spleen, by increasing cell adhesion and thus promoting their proliferative and migratory properties beyond the lymphatic system. PMID- 26418974 TI - Self-Sealing and Puncture Resistant Breathable Membranes for Water-Evaporation Applications. AB - Breathable and waterproof membranes that self-seal damaged areas are prepared by modifying a poly(ether ester) membrane with an amphiphilic polymer co-network. The latter swells in water and the gel closes punctures. Damaged composite membranes remain water tight up to pressures of at least 1.6 bar. This material is useful for applications where water-vapor permeability, self-sealing properties, and waterproofness are desired, as demonstrated for a medical cooling device. PMID- 26418975 TI - Tensions Between Policy and Practice in Finnish Biobank Legislation. AB - In 2012 a new biobanking law came into effect in Finland which, according to some, is one of the most comprehensive and broad national biobanking legislations in the world to date. The law covers both clinical and research collections and provides institutions with great flexibility in terms of transferring existing collections into a biobank. The law also includes provisions for individuals whose samples are stored in the biobank to request information regarding the studies in which the sample has been used. However, this provision also compels biobanks to provide an account of the significance of the research findings to their individual health. This legal provision has created tension between policy and practice in that most biobanks will struggle to interpret and apply this provision in practice. The relationship between the rights and needs to conduct research using biobank material and individual rights of access is sometimes unclear and fraught with interpretational challenges. The derivation of national interpretations of European Directives and Conventions gives rise to what I call interpretive regulatory dissonance. This is expected to be a challenge for harmonizing European and global biobanking activities in the future. PMID- 26418976 TI - [Establishment of hemophilia A patient-specific inducible pluripotent stem cells with urine cells]. AB - OBJECTIVE To generate hemophilia A (HA) patient-specific inducible pluripotent stem cells (iPSCs) and induce endothelial differentiation. METHODS Tubular epithelial cells were isolated and cultured from the urine of HA patients. The iPSCs were generated by forced expression of Yamanaka factors (Oct4, Sox2, c-Myc and Klf4) using retroviruses and characterized by cell morphology, pluripotent marker staining and in vivo differentiation through teratoma formation. Induced endothelial differentiation of the iPSCs was achieved with the OP9 cell co culture method. RESULTS Patient-specific iPSCs were generated from urine cells of the HA patients, which could be identified by cell morphology, pluripotent stem cell surface marker staining and in vivo differentiation of three germ layers. The teratoma experiment has confirmed that such cells could differentiate into endothelial cells expressing the endothelial-specific markers CD144, CD31 and vWF. CONCLUSION HA patient-specific iPSCs could be generated from urine cells and can differentiate into endothelial cells. This has provided a new HA disease modeling approach and may serve as an applicable autologous cell source for gene correction and cell therapy studies for HA. PMID- 26418977 TI - [Association of chromosome 17q copy number variation with overall survival of patients with hepatocellular carcinoma and screening of potential target genes]. AB - OBJECTIVE To assess the association of copy number variations (CNVs) in chromosome 17q with the overall survival(OS) of patients with hepatocellular carcinoma(HCC), and to screen for target genes contained in the OS-related CNVs. METHODS A total of 174 HCC cases were enrolled. For 66 patients, the follow-up data was available. High-resolution Agilent Hu-244A array comparative genomic hybridization (aCGH) and Affymetrix U133 Plus 2.0 expression arrays were used to detect CNVs and gene expression of genes from the 17q region, respectively. The association of CNVs and OS was assessed with Log-rank test, Kaplan-Meier survival analysis, and Cox proportional hazards models. The gene expression in HCCs with 17q gain, HCCs without, and non-tumor liver tissues were compared with a Mann Whitney U test. RESULTS Univariate association analysis showed that copy number gain in 17q25.1-25.3 was significantly associated with reduced OS (Log-rank test, P = 0.00002), and HCC cases with 17q25.1-25.3 gain had a 4.76-fold (95%CI: 2.31 9.81) increased hazard ratio (HR) for death from HCC, as compared to those without the gain. Multivariate Cox proportional hazards regression model revealed 17q25.1-25.3 gain to be an independent prognostic marker for poor OS (HR = 3.17, 95%CI: 1.39-7.26, P = 0.006). The expression levels of 18 genes in 17q25.1-25.3 including SLC9A3R1, GRB2, and TK1 were significantly increased in HCCs with gain than in those without (all P < 0.01) and non-tumor liver tissues (all P < 0.01). CONCLUSION The association of 17q25.1-25.3 gain with reduced OS has indicated that it is a prognostic marker for poor patient survival in HCC, for which SLC9A3R1, GRB2, and TK1 are candidate genes. PMID- 26418978 TI - [Drug resistance of colon cancer cells to 5-fluorouracil mediated by microRNA 21]. AB - OBJECTIVE To explore downstream regulatory pathway of microRNA-21 (miR-21) in colon cancer cells (RKO) through detecting miR-21 and its target PDCD4, and the influence of miR-21 regulation on the sensitivity of RKO cells to 5-fluorouracil (5-FU). METHODS 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine the effect of 5-FU on the viability of RKO cells with knockout of miR-21 or high expression of PDCD4. Real-time was used to determine the expression of PDCD4, ABCC5 and CD44 in RKO cell after knockout of miR-21. RESULTS MTT assay reveals that the IC50 of 5-FU in RKO-WT cells (52.82 +/ 0.06 umol/L) was about 67% higher than in miR-21 knockout cells (32.23 +/- 0.05 umol/L) (P < 0.05), and the apoptosis ratio elevated after knockout of miR-21. High expression of PDCD4, a target gene of miR-21, can negatively regulate the expression of ABC transporter ABCC5 and the stem cell marker CD44. CONCLUSION MiR 21 can mediate the drug resistance to 5-FU by inhibiting its target PDCD4, which can regulate the expression of ABCC5 and CD44 genes. PMID- 26418979 TI - [Pathway-focused correlation study of genome-wide methylation status with visual memory]. AB - OBJECTIVE To explore the biological processes and pathways associated with memory function which may be regulated by gene promoter methylation. METHODS The genome wide promoter methylation statuses in 9 healthy individuals were analyzed with a Multiplex HG18 CpG Promoter chip. Genes with promoter methylation statuses strongly correlated with both immediate and delayed visual memory function were preceded for pathway and physical interactions analysis. RESULTS Sixty nine genes have been correlated with both immediate and delayed visual memory functions. Twenty two pathways, with a Q-value of < 0.05, were identified by the pathway and physical interactions analysis, which included energy metabolism, axon guidance, tyrosine kinase activity, anterograde synaptic vesicle transport, and leukocyte migration and differentiation. CONCLUSION Pathways related with memory function may be regulated by DNA methylation. PMID- 26418980 TI - [Influence of genetic polymorphisms and non-genetic factors on the maintenance dose of warfarin]. AB - OBJECTIVE To assess the influence of genetic polymorphisms and non-genetic factors on warfarin maintenance dose variations in order to provide guidance for personalized use of warfarin. METHODS Two hundred patients from outpatient and inpatient with stable international normalized ratio(INR) were recruited. Clinical data and blood samples were collected. Genotypes of 4 genes involved in warfarin metabolic pathways were determined with Sanger sequencing. Based on statistical analysis of warfarin maintenance dosage, a mathematical model was established. RESULTS Among non-genetic factors, the age and height have significant influence in warfarin dosage. The dosage is negatively correlated with age but positively correlated with height. The difference in dosage for between the 20-year-old group and 60-year-old group has reached 1.81 mg/day, and that for between the 140 cm in height and 180 cm in height groups has reached 1.06 mg/day. VKORC1 -1639G/A, CYP2C9 430C/T, CYP2C9 1075A/C and CYP4F2 V433M polymorphisms have significant influence on stable warfarin dosage. The dosage for patients with wild type and mutant genotypes has varied from 0.35 mg/day to 0.84 mg/day. CONCLUSION Non-genetic factors and genetic polymorphisms play important roles in personalized variations of warfarin maintenance dose. The establishment of mathematical models considering multiple factors is helpful in evaluating the safety and effectiveness of warfarin dosage. PMID- 26418981 TI - [Application of quantitative fluorescence PCR for the prenatal diagnosis of common fetal chromosomal aneuploidies]. AB - OBJECTIVE To assess the value of quantitative fluorescence PCR (QF-PCR) for the prenatal diagnosis of common fetal chromosomal aneuploidies. METHODS A total of 2436 amniotic fluid samples were collected at 18 to 22 gestational weeks. Multiplex QF-PCR was performed with fluorescence-labeled primers specific for 32 polymorphic short tandem repeat (STR) sites on chromosomes 21, 18, 13, X and Y. The PCR products were assayed by capillary electrophoresis. All samples were also assayed by karyotyping. RESULTS Seventy-six (3.12%) samples were diagnosed as chromosomal aneuploidies by QF-PCR, among which 51 were trisomy 21, 12 were trisomy 18, 2 were trisomy 13, and 1 was triploidy. The results were all consistent with those of karyotyping. Ten samples were suspected as sex chromosomal aneuploidies, among which 9 were confirmed, except for 1 case with X structural abnormality. In addition, karyotyping has diagnosed 24 (0.99%) cases of structural abnormalities, only one of which was suspected by QF-PCR with partial abnormal STR results. Two (0.08%) samples were found to be mosaic by karyotyping, one of which was suggested by QF-PCR with cut-off ratios of STR markers. CONCLUSION QF-PCR is reliable for the diagnosis of numerical abnormalities of chromosomes 21, 18, 13, X and Y. The method can serve as an effective technique for rapid prenatal screening of common chromosome aneuploidies in fetus. PMID- 26418982 TI - [Bioinformatics analysis of differently expressed microRNAs in anxiety disorder]. AB - OBJECTIVE To identify differentially expressed microRNA (miRNA) in peripheral blood mononuclear cells (PBMCs) of anxiety patients and predict their target genes and function by bioinformatics analysis. METHODS The miRNA expression profiles were determined using an Affymetrix array. To validate the results, real time quantitative polymerase chain reaction (qRT-PCR) analysis in a larger cohort was employed. The targets of the differentially expressed miRNAs were predicted by Target Scan, miRBD, and DIANA-microT-CDS, and the results were analyzed by gene ontology (GO) and KEGG pathway analysis using FunNet. RESULTS MicroRNA microarray chip analysis has identified 7 miRNAs were detected with significant changes in expression in PBMCs of anxiety patients. qRT-PCR analysis has confirmed that the expression levels of 5 miRNAs (has-miR-4484, has-miR-4505, has miR-4674, has-miR-501-3p and has-miR-663) were up-regulated. Intersecting the genes by Target Scan, miRBD, and DIANA-microT-CDS has predicted 195 targets. GO analysis showed that biological processes regulated by the predicted target genes have included diverse terms. Some terms, e.g., nervous system development, nerve growth factor receptor signaling pathway, neuron migration, dendrite development, regulation of neuron projection development, midbrain development, regulation of excitatory postsynaptic membrane potential, gliogenesis, dendrite morphogenesis, etc. have direct relationship with the central nervous system and brain functions. Pathway analysis showed that a significant enrichment in several pathways related to neuronal brain functions such as glutamatergic synapse, axon guidance, calcium signaling pathway, MAPK signaling pathway, GnRH signaling pathway, Wnt signaling pathway, gap junction, long-term potentiation and VEGF signaling pathway, etc. Among the five microRNAs, has-miR-4484, has-miR-4505, has miR-4674 and has-miR-501-3p may have more important regulatory functions. CONCLUSION Five miRNAs (has-miR-4484, has-miR-4505, has-miR-4674, has-miR-501-3p and has-miR-663) are up-regulated in PBMCs of anxiety patients and may be closely involved in the pathogenesis of anxiety disorder. PMID- 26418983 TI - [Analysis of UPB1 gene mutation in a family affected with beta-ureidopropinoase deficiency]. AB - OBJECTIVE To detect potential mutation in a Chinese family affected with beta ureidopropinoase deficiency. METHODS Genomic DNA was extracted from peripheral blood samples. All exons and flanking intron regions of the UPB1 gene were amplified by PCR and detected by direct sequencing. RESULTS A homozygous mutation c.977G>A was identified in exon 9 of the UPB1 gene in the proband. Both parents of the proband had heterozygous change of the same site. CONCLUSION The c.977G>A mutation of the UPB1 gene is responsible for the pathogenesis of the disease in the infant. PMID- 26418984 TI - [Polymorphisms of killer cell immunoglobulin-like receptor and its ligand HLA-I gene among northern Chinese Han population]. AB - OBJECTIVE To investigate the distribution of killer cell immunoglobulin-like receptors (KIR) and their specific ligands human leukocyte antigen-I (HLA-I) gene in northern China. METHODS One hundred and eighty-four unrelated northern Chinese Han individuals were recruited. Genotypes of the KIR and HLA-ABC genes were studied by sequence-specific primer polymerase chain reaction (SSP-PCR). RESULTS Sixteen KIR genes were detected among the 184 unrelated individuals. In all individuals, the four framework genes were present. The frequencies for those carrying the remaining 12 KIR genes have ranged from 16.3% to 99.5%. Twenty-four KIR genotypes were identified, for which half were detected in a single individual. A new genotype comprised of KIR2DL3, 3DL1, 2DP1 and the framework genes was detected in one subject. Respectively, 12, 27 and 11 specificities of HLA alleles were identified on the HLA-A, B, C loci. CONCLUSION The distribution of polymorphisms of KIR and its ligand HLA-ABC genes among northern Chinese Han population have been ascertained. The frequencies of 9 KIR/HLA combinations in the above population have been determined for the first time. PMID- 26418985 TI - [Genetic study of the Penta E locus and identification of rare alleles]. AB - OBJECTIVE To study the genetic polymorphisms of Penta E locus in Fujian Han population. METHODS Polymorphisms of the Penta E locus in 851 unrelated individuals were analyzed using polymerase chain reaction-short tandem repeat (PCR-STR). The mutation rate of rare alleles was analyzed in 494 paternity identification cases (in a total of 674 meiosis). RESULTS Twenty-six alleles were identified for the Penta E locus, with their frequencies ranging from 0.0006 to 0.1528. There were 7 rare alleles, among which Penta E-28.4 ([AAAGA]29) was identified for the first time. Genetic parameters of the Penta E locus in Fujian Han population were obtained, including PIC= 0.91, PE= 0.817, PD= 0.986, and mutation rate= 0.0015. CONCLUSION The Penta E locus is highly polymorphic and has a low mutation rate in Fujian Han population. It also has a good prospect in genetics applications. DNA sequencing is a good method for identifying rare alleles. PMID- 26418986 TI - [Molecular genetic study of a family featuring cardiac conduction block]. AB - OBJECTIVE To explore the genetic mechanism for a family affected with cardiac conduction block. METHODS Affected family members were screened for potential mutations of known candidate genes. As no pathogenic mutation was found, two patients and one healthy member from the family were further analyzed by exomic sequencing followed by Sanger sequencing. The pathogenicity of suspected mutation was analyzed using bioinformatics software. RESULTS Sequencing of the full exome has identified a c.G1725T mutation in the CLCA2 gene. Sanger sequencing has detected the same mutation in all five patients, but not in the normal member from the family. Bioinformatics analysis indicated that the mutation has resulted in substitution of the 575th amino acid cysteine (C) by tryptophan (W). The site is highly conserved and becomes pathogenic with the mutation. CONCLUSION The heterozygous c.G1725T mutation in exon 11 of the CLCA2 gene probably underlies the disease and fit the autosomal dominant pattern of inheritance. PMID- 26418987 TI - [Congenital central hypoventilation syndrome: analysis of PHOX2B gene mutation in a case]. AB - OBJECTIVE To report on the phenotype of an infant with central hypoventilation syndrome (CCHS) and result of PHOX2B gene mutation analysis for the purpose of genetic counseling and prenatal diagnosis. METHODS Clinical data of an infant with CCHS was collected and analyzed. Potential mutation of PHOX2B gene was analyzed by amplified fragment length polymorphism (amp-FLP) and DNA sequencing. RESULTS The patient had typical clinical features of CCHS including frequent hypoventilation during sleeping, hypoxemia and hypercapnia which could be corrected by continuous ventilatory support. She also had repeated bruising and was difficult-to-wean, but without any cardiac, pulmonary, neuromuscular or brainstem lesions. DNA sequencing and amp-FLP of the PHOX2B gene showed that the patient has carried a polyalanine expansion repeat mutation (PARM) in exon 3. A 27 bp duplication was confirmed in the repeat sequence of 20 alanines by cloned and sequenced. This has led to an expansion of the repeat tract to 29 alanines. The genotype was therefore 20/29. CONCLUSION A patient with CCHS has been described. Mutation screening of PHOX2B gene can be used as an important support for diagnosis and genetic counseling for such patients. PMID- 26418989 TI - [Phenotypic and genetic analysis of a child featuring multiple malformations due to chromosome 18p deletion]. AB - OBJECTIVE To analyze a neonate with multiple malformations and to correlate its genotype with phenotype. METHODS The karotypes of the child and her parents were subjected to G-banding chromosome analysis, and array comparative genomic hybridization (array-CGH) was used for fine mapping of the aberrant region. RESULTS The karyotype of the child was ascertained as 46,XX,del(18)(p11.2). Array CGH has identified a 9.8 Mb deletion at 18p11.32-p11.22. The patient has presented features such as holoprosencephaly, choanal atresia, heart defect, and craniofacial dysmorphisms. CONCLUSION The de novo 18p deletion probably underlies the main clinical manifestations of the child. PMID- 26418988 TI - [Phenotypic and genetic analysis of a child with blepharophimosis, ptosis, epicanthus inverses syndrome and tetralogy of Fallot]. AB - OBJECTIVE To determine the genetic cause of a child with blepharophimosis, ptosis, and epicanthus inverses syndrome and tetralogy of Fallot, and to correlate the phenotype with the genotype. METHODS Routine G-banding has been previously performed on the patient and her parents. Chromosome microarray analysis (CMA) was performed for the three individuals and the fetus. RESULTS Chromosomal analysis has suggested normal karyotypes for the child and her parents. However, a de novo 8.9 Mb deletion on chromosome 3q22.1-q23 was detected by CMA. The deleted region has encompassed 74 genes including 41 disease-related genes, and this is also the most frequent region involved in interstitial 3q deletion. Patients with deletion of this region often have a common feature of dysplasia of eyelids, as well as a spectrum of other anomalies according to different breakpoints, including microcephaly, skeletal anomalies, congenital heart defects, cranial anomalies, intellectual disability and developmental delay. The patient's phenotype was in accordance with such spectrum. Her parents and sib did not show this variation by CMA. CONCLUSION The de novo interstitial deletion of 3q22.1-q23 probably underlies the main clinical manifestation in this child. CMA can provide more detailed information and allow further investigation of the genotype-phenotype correlation. PMID- 26418990 TI - [Lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia with P53 deletion and TCR-delta rearrangement in a case]. AB - OBJECTIVE To study the morphology, immunology, cyto- and molecular genetics of a patient with lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM), deletion of P53 gene and rearrangement of clonal T cell receptors-delta (TCR delta) gene. METHODS The cell morphology and immunocytochemistry were analyzed by bone marrow testing and biopsy. Cellular immunology was analyzed by flow cytometry. Genetic analysis was carried out by chromosome karyotyping, fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR). Immunoglobulin M (IgM) in serum and urine was assayed by immunofixation electrophoresis. And the effect of chlorambucil therapy was evaluated. RESULTS Bone marrow biopsy suggested that the patient was of B lymphocyte type and had abnormal increase of lymphocytoid plasma cells, which were CD38 and CD138 positive. The patient had a normal male karyotype. FISH and PCR analysis of peripheral blood samples suggested deletion of P53 gene and rearrangement of TCR delta gene. Immunofixation electrophoresis has detected IgM-kappa in both serum and urine. The patient showed partial response to chlorambucil. CONCLUSION In addition to typical clinical features, bone marrow examination, flow cytometry, histochemistry and immunophenotyping, testing for P53 gene deletion and lymphocyte gene rearrangement can facilitate the diagnosis and treatment of LPL/WM. PMID- 26418991 TI - [8p11 myeloproliferative syndrome with CEP110-FGFR1 fusion in a patient]. AB - OBJECTIVE To explore the clinical and laboratory features of a patient with 8p11 myeloproliferative syndrome (EMS) and CEP110-FGFR1 fusion. METHODS Combined bone marrow cytology, fluorescence in situ hybridization, fusion gene detection was used to analyze the patient. RESULTS Clinically, the patient had many features similar to those with chronic myelomonocytic leukemia, which included hyperleukocytosis, marked eosinophilia, monocytosis, myeloid hyperplasia and hyperplasia. Fluorescence in situ hybridization analysis for FGFR1 gene rearrangement was positive. Further study of the mRNA also confirmed an in-frame fusion between exon 38 of the CEP110 gene and exon 9 of FGFR1 gene. CONCLUSION EMS with CEP110-FGFR1 fusion is a very rare and distinct myeloproliferative neoplasm. FISH and molecular studies may improve its diagnosis. PMID- 26418992 TI - [Application of multiplex ligation-dependent probe amplification technique in prenatal diagnosis of alpha-thalassemia]. AB - OBJECTIVE To assess the application value of multiplex ligation-dependent probe amplification (MLPA) for the detection of gene deletion and prenatal diagnosis of alpha-thalassemia. METHODS MLPA was applied for 2 cases with alpha-thalassemia phenotype by whole blood cell counting and hemoglobin component detection but were ruled out by regular molecular diagnosis. Potential gene deletions and point mutations of alpha-thalassemia gene were detected with regular Gap-polymerase chain reaction (Gap-PCR) and reverse dot blotting (RDB) in 89 cases where one or both partners were carriers of alpha-thalassemia mutations. Meanwhile, MLPA was used for detecting alpha-globin gene deletion among the 89 samples. RESULTS For the 2 cases with alpha-thalassemia phenotype, no alpha globin gene deletion was detected by MLPA, but were subsequently confirmed as iron-deficiency anemia. The results of MLPA and Gap-PCR detection for the 88 cases were consistent, except for 1 fetal sample (chorionic villi) which could not be diagnosed by Gap-PCR and was confirmed to be - SEA/alphaalpha by MLPA. CONCLUSION MLPA can be applied to prenatal diagnosis of alpha-thalassemia as an effective supplement to Gap-PCR to reduce both misdiagnosis and missed diagnosis and improve the accuracy of prenatal diagnosis. PMID- 26418993 TI - [Genetic analysis and prenatal diagnosis of Xp deletion in a family with Duchenne/Becker muscular dystrophy]. AB - OBJECTIVE To delineate a deletional mutation of the Dystrophin gene on the short arm of chromosome X in a family affected with Duchenne/Becker muscular dystrophy. METHODS G-banded karyotyping, multiple ligation probe amplification (MLPA), array based comparative genomic hybridization(array-CGH) and whole genome exon high throughput sequencing were employed to delineate the mutation in the family. RESULTS GTG banding has demonstrated deletion of the terminal part of the short arm of chromosome X in the fetus. The same deletion was also found in its mother and maternal grandmother. MLPA analysis has revealed removal of exons 52 to 79 of the Dystrophin gene. A 30 Mb deletion in Xp22.33-p21.1 and a 10 Mb duplication in Xq27.2-q28 were identified by array-CGH and whole genome exon high-throughput sequencing. CONCLUSION The Xp deletion has led to deletion of exons 52 to 79 of the Dystrophin gene in the family. The female carriers also had certain features of Turner syndrome due to the same deletion. PMID- 26418994 TI - [Prenatal diagnosis of five cases of monochorionic-diamniotic twins discordant for karyotype analysis]. AB - OBJECTIVE To explore the mechanism and diagnostic method for monochorionic diamniotic twins discordant for karyotype analysis. METHODS Dual amniocentesis was performed on five pairs of monochorionic-diamniotic twins, which all consisted of a normal twin and one with multiple malformations revealed by ultrasound. Karyotype analysis was performed on amniocytes derived from each of the twins. Zygosity was also determined with DNA extracted from amniocytes with 16 polymorphic microsatellite markers. RESULTS Three cases of 45,X, one case of 47,XX,+9 and one case of 47,XY,+18 were detected among the abnormal twins, while the normal fetuses all had a normal karyotype. DNA analysis suggested that, in all cases, the twins have shared the 16 polymorphic microsatellite markers, which confirmed their monozygosity. CONCLUSION Monochorionic-diamniotic twins may be discordant for karyotyping, for which anaphase lagging, chromosomal non disjunction and trisomy rescue may be the underlying reasons. As a simple method, dual amniocentesis can be used to obtain amniotic fluid samples for karyotype analysis and determination of zygosity for such twins. PMID- 26418995 TI - [Molecular mechanism of 101A>G and 845G>A mutations of RHD gene responsible for a weak RhD]. AB - OBJECTIVE: To explore the molecular basis for an individual with a rare weak D phenotype. METHODS: Regular serological assaying and indirect antiglobulin testing (IAT) were performed to characterize the RhD blood group. Mutations of the RHD gene were screened by polymerase chain reaction (PCR), reverse transcription PCR and DNA sequencing. Amplified cDNA product was TA cloned and subjected to haplotype analysis. RESULTS: The RhD blood group of the proband was determined as weak D. The result of PCR amplification showed that all of the 10 exons of the RHD gene were present. Heterozygote status of 101A/G and 845A/G were determined by gDNA and cDNA sequencing. After TA cloning and haplotype sequencing, two alleles 101A>G mutation (weak D 101G ) and 845G>A mutation (weak D type 15) were revealed. CONCLUSION: 101A>G and 845G>A mutations are responsible for the low expression of RhD antigen on the red blood cells of the proband, which has resulted in a weak D phenotype. PMID- 26418996 TI - [Study of molecular mechanism for a blood sample with A3 phenotype]. AB - OBJECTIVE To explore the molecular mechanism for a blood sample with mixed-field hemagglutination upon determination of ABO blood group. METHODS Serological techniques were employed to identify the erythrocyte phenotype. The A and B antigens were detected by flow cytometry. The preliminary genotype of ABO gene was assayed with sequence-specific primer-polymerase chain reaction (PCR-SSP). Exons 6 and 7 of the ABO gene were amplified with PCR and analyzed by direct sequencing. Haplotypes of the ABO gene were analyzed by cloning sequencing as well. RESULTS The serological reaction pattern has supported an O phenotype when all the tubes were centrifuged for the first time. However, a mixed-field hemagglutination of red blood cells (RBCs) with anti-A antibodies was present after the tube was centrifuged five times later. A antigens were detected on the surface of partial red blood cells of the sample by flow cytometry. PCR- SSP results have shown that the preliminary ABO genotype was A/O. Analysis of the fragments of exons 6 and 7 of the ABO gene has indicated that heterozygosis lied as follows: 261G/A, 425T/T, 467C/T, 646A/T, 681A/G, 745C/T, 771C/T, 829A/G, conjecturing the genotype to be A307/O02, which was confirmed by haplotype sequence analysis. Compared with A101 allele, A307 allele has two missense mutations, 467C> T and 745C> T, which have resulted in substitutions Pro156Leu and Arg249Trp in the A glycosyltransferase polypeptide chain. CONCLUSION A variant allele (A307) has been identified for the first time in mainland China, which is responsible for the formation of A3 phenotype. PMID- 26418997 TI - [Association of TNF-alpha and IL-13 genes polymorphisms with bronchial asthma]. AB - OBJECTIVE To assess the association of polymorphisms of TNF-alpha gene (rs1799724, rs1800630, rs1799964 and rs769178) and IL-13 gene (rs2158177 and rs1295687) with susceptibility to asthma among ethnic Chinese in Qingdao region. METHODS For 400 asthma patients and 200 healthy subjects, above polymorphisms were detected with a SNaPshot method. RESULTS For rs2158177, the frequency of genotype of GG in the asthma group was significantly lower than the control group (2.8% vs. 5%, OR = 0.31, 95%CI: 0.12-0.82, P = 0.021). No significant difference was detected in the genotypic frequencies for the remaining 5 polymorphisms between the two groups (All P > 0.05). CONCLUSION The study has indicated that rs2158177 polymorphism of the IL-13 gene is associated with asthma in ethnic Han Chinese from Qingdao. No association has been found between polymorphisms of TNF alpha gene with susceptibility to asthma. PMID- 26418998 TI - [Association of single nucleotide polymorphisms of susceptibility genes of type 2 diabetes mellitus with liability to gout among ethnic Han Chinese males from coastal region of Shandong]. AB - OBJECTIVE To assess the association of single nucleotide polymorphisms (SNPs) of susceptibility genes of type 2 diabetes mellitus (T2DM) with liability to gout among ethnic Han Chinese males from coastal region of Shandong province. METHODS Seven SNPs within the susceptibility genes of T2DM, including rs10773971(G/C) and rs4766398(G/C) of WNT5B gene, rs10225163(G/C) of JAZF1 gene, rs2069590(T/A) of BDKRB2 gene, rs5745709(G/A) of HGF gene, rs1991914(C/A) of OTOP1 gene and rs2236479(G/A) of COL18A1 gene, were typed with a custom-made Illumina GoldenGate Genotyping assay in 480 male patients with gout and 480 male controls. Potential association was assessed with the chi-square test. RESULTS No significant difference was detected for the 7 selected SNPs in terms of genotypic and allelic frequencies (P > 0.05). When age and body mass index (BMI) were adjusted, the 7 genetic variants still showed no significant association with gout. CONCLUSION The genotypes of the 7 selected SNPs are not associated with gout in ethnic Han Chinese male patients from the coastal region of Shandong province. However, the results need to be replicated in larger sets of patients collected from other regions and populations. PMID- 26418999 TI - [Associations of Crohn's disease with DR4 and DR5 gene polymorphisms]. AB - OBJECTIVE: To assess the associations of death receptor DR4 and DR5 gene polymorphisms with Crohn's disease (CD). METHODS: A total of 295 CD patients and 490 healthy controls were recruited. Three single nucleotide polymorphisms (SNPs) of the DR4 (rs13278062, rs20575) and DR5 (rs1047266) genes were determined with a SNaPshot method. Unconditional logistic regression analysis was carried out for determining the allelic and genotypic differences of the three SNPs between CD patients and the controls, as well as the influence of the DR4 and DR5 gene polymorphisms on the clinical features of CD patients. Linkage disequilibrium and haplotype analysis were calculated by haplotype 4.2 and R language software. A gene-gene interaction model was established to analyze whether the three SNPs can exert a synergistic effect on the susceptibility to CD. RESULTS: The mutant allele (T) and genotype (GT+TT) of DR4 (rs13278062) were increased among CD patients compared to the controls (37.12% vs. 32.04%, P = 0.040, 95%CI: 1.010 1.550; 62.71% vs. 54.90%, P = 0.032, 95%CI: 1.028-1.855, respectively). However, the allelic and genotypic frequencies of DR4 (rs20575) and DR5 (rs1047266) did not differ between the two groups (all P > 0.05). Based on the Montreal Classification Standards, the CD patients were stratified by locations and behaviors of the disease. After multiple comparison correction (P < 0.0125), compared to ileocolonic CD patients respectively, the mutant allele (T) and genotype (GT+TT) of the rs13278062 polymorphism were significantly increased in colonic CD patients (41.04% vs. 25.64%, P = 0.002, 95%CI: 0.315-0.778; 66.04% vs. 41.03%, P = 0.001, 95%CI: 0.196-0.655, respectively) and terminal ileum CD patients (41.44% vs. 25.64%, P = 0.002, 95%CI: 0.311-0.762; 74.77% vs. 41.03%, P < 0.001, 95%CI: 0.126-0.437, respectively). In comparison to penetrating CD patients, the mutant allele (T) and genotype (GT+TT) of DR4 (rs13278062) were significantly decreased in stricturing CD patients (32.29% vs. 48.91%, P = 0.007, 95%CI: 0.300-0.828; 57.29% vs. 86.96%, P = 0.001, 95%CI: 0.078-0.520, respectively). A similar conclusion was drawn for the mutant genotype (GT+TT) of DR4 (rs13278062) in non-stricturing, non-penetrating CD patients (58.82% vs. 86.96%, P = 0.001, 95%CI: 0.086-0.536). Haplotype analysis indicated that the CT haplotype formed by rs20575 and rs13278062 was increased in CD patients compared to the controls (37.1% vs. 31.8%, P = 0.029, OR=1.279, 95%CI: 1.022-1.600). The outcome of a gene-gene interaction model indicated that the mutant genotype (GT+TT) of DR4 (rs13278062) and mutant genotype (CT+TT) of DR5 (rs1047266) may play a negatively synergistic role in CD patients (B = - 0.483, OR = 0.617, P = 0.030). CONCLUSION: The rs13278062 polymorphism of the DR4 gene not only can confer an increased risk for CD, but may also influence the location of the lesions and the disease behaviors. The CT haplotype formed by rs20575 and rs13278062 may be an independent risk factor for CD. Furthermore, the mutant genotype (GT+TT) of DR4 (rs13278062) and mutant genotype (CT+TT) of DR5 (rs1047266) may exert a negative synergistic effect on CD. PMID- 26419000 TI - [Advances in research of SCARB2 functions and related disorders]. AB - SCARB2 (scavenger receptor class B, member 2) is a lysosomal membrane glucoprotein, which is encoded by SCARB2 gene. It takes vital parts in the physiological and pathological processes including the transportation of beta glucocerebrosidase to the lysosome, infection of EV71 and load-induced cardiac myocyte hypertrophy. This article has reviewed the molecular structure and functions of SCARB2 gene and its protein, as well as their relationship with diseases. PMID- 26419001 TI - [Progress of molecular genetics research on rheumatoid arthritis]. AB - Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disorder that principally attacks flexible joints and synovia. The precise pathogenesis of RA remains unclear, and genetic factors probably play an important role in its etiology. In addition to genes from human leukocyte antigen (HLA) region, such as HLA-DRB, genes from non-HLA region, such as TIM-3, PTPN22, TRAF1/C5, STAT4, CCR5, PADI4 and FCGR2A may also contribute to its susceptibility. The advance in molecular genetics research on RA is reviewed here. PMID- 26419002 TI - [Progress in research on imprinted gene associated with male infertility]. AB - The connection between male infertility and abnormal methylation of imprinted genes has attracted much attention. Some imprinted genes, e.g., H19, MEG3, MEST and SNRPN, are known to be related with male infertility. Abnormal imprinted information may influence sperm concentration, motility and morphology, but the mechanism is still unclear. Sperm genomic imprinting reconstruction and erase respectively occur at the time of spermatogenesis and before embryo transfer. Many studies have shown that the probability of imprinting disorder syndrome of offspring born through assisted reproductive technology (ART) was significantly higher, leading to the worry about the safety of ART and speculation that the operation and in vitro environment may affect sperm imprinted information, which in turn may lead to imprinting diseases in the offspring. However, above connection still lacks convincing evidence. This paper has conducted a literature review of recent literature and explored the impact of abnormal methylation of imprinted genes on male fertility and the offspring. PMID- 26419003 TI - [Infantile spastic paraplegia in two cases from a pedigree]. PMID- 26419004 TI - [A pedigree affected with Huntington disease]. PMID- 26419005 TI - [A pedigree affected with congenital polydactyly]. PMID- 26419006 TI - Thermal Pretreatment Improves Viability of Cryopreserved Human Endothelial Cells. AB - A high survival rate of cryopreserved cells requires optimal cooling and thawing rates in the presence of a cryoprotective agent (CPA) or a combination of CPAs in adequate concentrations. One of the most widely used CPAs, dimethyl sulfoxide (Me2SO), however is toxic at high concentrations and has detrimental effects on cellular functions. Additional processing steps are necessary to remove the CPA after thawing, which make the process expensive and time consuming. Therefore it is of great interest to develop new cryoprotective strategies to replace the currently used CPAs or to reduce their concentration. The aim of this study was to investigate if thermal activation of human pulmonary microvascular endothelial cells (HPMEC ST-1.6R), prior to cryopreservation, could improve their post-thaw viability since the resulting heat shock protein expression acts as an intrinsic cellular protection mechanism. The results of this study suggest that both heat and cold shock pretreatments improve cryopreservation outcome of the HPMEC ST 1.6R cells. By re-cultivating cells after heat shock treatment before cryopreservation, a significant increase in cellular membrane integrity and adherence capacity could be achieved. However a combination of thermal activation and cryopreservation with alternative CPAs such as ectoine and L-proline could not further enhance the cell viability. The results of this study showed that pretreatment of endothelial cells with thermal activation could be used to reduce the Me2SO concentration required in order to preserve cell viability after cryopreservation. PMID- 26419007 TI - Adolescents' emotional engagement in friends' problems and joys: Associations of empathetic distress and empathetic joy with friendship quality, depression, and anxiety. AB - Although empathetic distress (i.e., taking on a friend's emotional distress as one's own) has been examined as a "cost of caring" especially common among girls, relations with adjustment remain untested. The current study tested associations of empathetic distress with friendship quality, depression, and anxiety. Adolescents (N = 300, ages 12-18) reported on their perceived experience of empathetic distress following a conversation with a friend about problems. The study also considered youths' emotional engagement in friends' positive life events, referred to as empathetic joy. Results indicated that girls reported greater empathetic distress and empathetic joy compared with boys. Findings also suggest that although empathetic distress may have positive implications for youths' friendship adjustment, this may come at the expense of emotional well being. In contrast, empathetic joy was associated with greater positive friendship quality and fewer internalizing symptoms. PMID- 26419008 TI - Intravitreal ranibizumab for choroidal neovascularization secondary to gyrate atrophy in a young patient: a multimodal imaging analysis. AB - PURPOSE: To present a case of choroidal neovascularization (CNV) due to gyrate atrophy (GA) treated with intravitreal ranibizumab. METHODS: A 35-year-old man presented with sudden loss of vision and central scotoma in the right eye, as well as progressive night vision deterioration over the past several years in both eyes. His best-corrected visual acuity (BCVA) was 6/60 in the right eye and 6/5 in the left eye. Funduscopy revealed bilateral confluent areas of chorioretinal atrophy and optical coherence tomography showed subretinal fluid consistent with CNV development in the right eye, which was confirmed by fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA). The left eye was normal. The patient had a family history of GA. Elevated levels of plasma ornithine were detected, establishing the diagnosis. RESULTS: The patient received a regimen of 3 monthly off-label intravitreal ranibizumab injections in the right eye. At the 6-month follow-up, no subretinal fluid was noticed and BCVA was 6/48. No other injections were performed, but the patient was advised to start an arginine-restricted diet and take vitamin B6 (pyridoxine) 300 mg daily. The BCVA was preserved and chorioretinal atrophy had not progressed on funduscopy, FFA, or ICGA 1 year later. CONCLUSIONS: Intravitreal ranibizumab can offer promising anatomical and functional results, maintaining visual acuity in patients with CNV secondary to GA, especially if used in combination with arginine-restricted diet and vitamin B6 supplementation. PMID- 26419009 TI - [Progress on biotherapy of hepatocellular carcinoma]. PMID- 26419010 TI - [Advances in gene therapy of liver cancer]. PMID- 26419011 TI - [Logistic regression analysis of risk factors of hepatogenous diabetes in patients with liver cirrhosis]. PMID- 26419012 TI - [Congenital hepatic fibrosis with polycystic kidney diseases: case report]. PMID- 26419013 TI - [Primary hepatic amyloidosis with gastrointestinal bleeding: case report]. PMID- 26419014 TI - [Current status of clinical applications of the artificial liver support system]. PMID- 26419015 TI - [Recent progress in identifying and characterizing factors influencing the natural history of chronic hepatitis C]. PMID- 26419016 TI - [Advances in understanding the role of microRNA-regulated hepatitis B virus X protein in the pathogenesis of hepatitis B virus-induced hepatocellular carcinoma]. PMID- 26419017 TI - [6 goals and 6 procedures for reducing mercury load caused by amalgam - a plea for a national exit plan]. PMID- 26419018 TI - [The goals and responsibilities of "Military Medicine Evenings"]. PMID- 26419019 TI - [100 years ago]. PMID- 26419020 TI - Proceedings of the 24th International Information Processing in Medical Imaging Conference, IPMI 2015, June 28-July 3, 2015, Isle of Skye, United Kingdom. PMID- 26419021 TI - Missouri Medicine 2015 member guide and directory. PMID- 26419022 TI - [THE STATE OF HEPATIC AND SPLANCHNIC BLOOD FLOW IN VARIOUS TYPES OF COMPLICATED PANCREATIC PSEUDOCYSTS]. AB - Investigations were conducted in 37 patients, suffering complicated pancreatic pseudocysts. In accordance to data of ultrasound Doppler flowmetry for the blood flow along portal vein, a. hepatis communis, a. mesenterica superior in complicated pancreatic pseudocysts compensatory--adaptive reactions on level of hepatic--spanchnic blood flow are directed towards restriction of the blood inflow through the portal vein system. This is accompanied by the common peripheral vascular resistence raising in basin of a. mesenterica superior, which have depended upon the patients' state severity, caused by reduction of the volume blood flow in a certan vascular collector. The oxygen debt of the liver in these patients is compensated by the volume blood flow enhancement along a. hepatis communis. PMID- 26419023 TI - [ROLE OF MICROFLORA OF THE ABDOMINAL CAVITY EXUDATE IN THE ENDOGENIC INTOXICATION OCCURRENCE IN PATIENTS, SUFFERING COMPLICATED ACUTE CHOLECYSTITIS WITH CONCURRENT CARDIAC INSUFFICIENCY OF ISCHEMIC GENESIS]. AB - While complicated acute cholecystitis (ACH) course the focus of infection constitutes one of the main causes of the endogenic intoxication (EI) occurrence, what leads to ischemic and hypoxic myocardial damage. There were presented the treatment results analysis in 213 patients, ageing 60 years old and older, managed for an ACH, complicated by peritonitis, paravesical abscess, with concurrent cardiac insufficiency of ischemic genesis, to whom laparoscopic cholecytectomy (LCHE) was conducted. Microflora of the abdominal cavity exudates in the patients, suffering an ACH of various severity, was studied. More rapid regression of inflammatory process, the EI severity and the ischemic-hypoxic myocardial affection reduction, positive impact on hemodynamics, reduction of myocardial ischemia severity were noted while local affection, when bacteriophages for treatment were applied. PMID- 26419024 TI - [DISSEMINATION BY H. PYLORI IN PATIENTS, SUFFERING VARIOUS FORMS OF CHOLECYSTITIS]. AB - Comparative analysis of dissemination by H. pylori of the bile portions in patients of a control group, suffering an acute calculous cholecystitis (ACCH), was performed. Dissemination of H. pylori in a control group was significantly less, than in a bile portions of patients, suffering ACCH. While analyzing the rate and degree of dissemination by H. pylori of the gastic and gallbladder mucosa biopsies of patients, suffering chronic non-calculous cholecystitis, associated with duodenogastric reflux and gastroduodenitis, bacteria were revealed trustworthy more often and in more number, than in a gallbladder mucosa in patients, suffering ACCH. PMID- 26419025 TI - [MINIINVASIVE TECHNOLOGIES IN TREATMENT OF POSTOPERATIVE ABDOMINAL HERNIAS]. AB - Methods and results of treatment of 119 patients, suffering postoperative abdominal hernia, were analyzed. There was established, that application of laparoscopic miniinvasive technologies permits to improve the results of treatment in patients in comparison with those after open operative interventions, due to shortening of the operation duration, better visualization during viscerolysis conduction, shortening of rehabilitation period, the patients postoperative quality of life improvement. PMID- 26419026 TI - [APPLICATION OF FISTULA PLUG WITH THE FIBRIN ADHESIVE IN TREATMENT OF RECTAL FISTULAS]. AB - Results of surgical treatment of 21 patients, suffering high transsphincteric and extrasphincteric rectal fistulas, were studied. In patients of Group I the fistula passage was closed, using fistula plug obturator; and in patients of Group II--by the same, but preprocessed by fibrin adhesive. The fistula aperture germeticity, prophylaxis of rude cicatrices development in operative wound zone, promotion of better fixation of bioplastic material were guaranteed, using fistula plug obturator with preprocessing, using fibrin adhesive. PMID- 26419027 TI - [PREDICTING FACTORS OF THE LIFE SPAN IN PATIENTS, SUFFERING METASTATIC COLORECTAL CANCER AND SYNCHRONOUS HEPATIC AFFECTION AFTER SURGICAL TREATMENT]. AB - The results of treatment of 125 patients, suffering metastatic hepatic affection in colorectal cancer (pT1--4N0--2M1--in colonic cancer and pT1--3N0--2M1--in cancer recti), to whom in 2008-2015 yrs a one-staged (Group 1) or two-staged (Group II) surgical treatment was done. In affection of 4 regional lymph nodes and more (pN2) late results were less favorable, than in pN1 or pN0, not depending from surgical approach choosed. In 48 (38.4%) patients with one syndromal hepatic metastatic focus, the indices of general three-year and five year cumulative survival were the best, than in other groups--82 and 63% (p = 0.001) accordingly; in monolobar affection--68 and 49%, and in bilobar--23 and 0%, not depending from method of surgical treatment (p < 0.001) choosed. Predictive factors were established, which impact negatively the indices of general survival in patients, suffering metastatic hepatic affection in colorectal cancer: hepatic metastatic foci number 4 and more, bilobar hepatic metastatic affection. PMID- 26419028 TI - [LAPAROSCOPIC HERNIOPLASTY IN INCARCERATED INGUINAL HERNIAS]. AB - The results of laparoscopic hernioplasty, using TAPP method and operation of Lichtenstein in 80 patients, suffering incarcerated inguinal hernia, were analyzed. While achievement of similar good and excellent immediate and late results, laparoscopic procedure has several advantages and may be used as a method of choice for treatment of inguinal hernia. PMID- 26419029 TI - [MORPHOMETRIC AND HISTOLOGICAL CHANGES OF TISSUES IN PATIENTS, WHO UNDERWENT OPERATIONS FOR POSTOPERATIVE ABDOMINAL HERNIAS]. AB - The impact of hernioplasty on postoperative morphometric and histological changes in tissues of patients, suffering postoperative abdominal hernias (POAH), was studied. For POAH 135 patients were operated, in 85 of them (the main group)- combined methods of hernial gate plasty in accordance to procedures proposed, and in 50 (control group)--classical methods of hernial gate were applied. The most favorable course of the wound process of the inflammatory, changes reduction and stabilization of the tissues reaction on implant already on the 7th postoperative day was noted after application of a sub lay method in original modification. PMID- 26419030 TI - [LONGITUDINAL SEGMENTAL SHIFT OF THE LEFT VENTRICULUS WALLS IN PATIENTS, SUFFERING THE AORTAL VALVE STENOSIS]. AB - In patients, suffering the aortal valve (AV) stenosis, the shift of middle and apical parts of all left ventriculus (LV) walls and basal parts of anterior- septa, anterior, posterior and inferior walls almost do not differ from those in norm. The shift of basal parts of inferior--septal and lateral walls had a tendency for lowering in comparison with such in norm. It is possible, that this phenomenon of the initial lowering of the movement amplitude in basal parts of inferior--septa and lateral walls of LV in patients, suffering the AV stenosis with preserved fraction of ejection, precedes to disorders of its hemodynamics and constitutes a predictor of the heart ejection reduction. So far, early revealing of the LV dysfunction play an important role in determination of terms of the operative intervention conduction in patients, suffering the AV stenosis. PMID- 26419031 TI - [NEGATIVE IMPACT OF CHROMOSOME 22Q11 MICRODELETION ON RESULTS OF TREATMENT IN PATIENTS, SUFFERING CONONTRUNCAL FAILURES OF HEART AND MAIN AORTO-PULMONARY COLLATERAL ARTERIES]. AB - Dependence of results of surgical treatment in 42 patients, suffering conotruncal failures and main aorto-pulmonary collateral arteries from presence of the chromosome 22q11 deletion syndrome, was analyzed. While presence of the chromosome 22q11 deletion syndrome duration of treatment of patients in intensive therapy unit and artificial pulmonary ventilation are longer, pressure in a pulmonary artery system after radical operative failures correction is higher, general lethality is bigger, than while the chromosome 22q11 deletion syndrome absence. The data obtained must be taken into account while determining tactics of treatment in patients with confirmed diagnosis of the chromosome 22q11 deletion syndrome. PMID- 26419032 TI - [SURGICAL TECHNIQUE OF A RENAL ARTERY CONTROL WHILE REMOVAL OF TUMORAL THROMBI FROM VENA CAVA INFERIOR]. AB - Efficacy and safety of a renal artery ligation after thrombectomy in comparison with those while using a standard surgical technique were studied. Possibility of performance and safety of thrombectomy without preliminary ligation of renal artery was proved. The results did not depend on level of intravenous tumoral spread and were significantly better, than while application of standard approaches to renal artery because of absence of embolic complications. PMID- 26419033 TI - [EXPERIENCE OF APPLICATION OF THE GENE INDUCTOR OF VASCULAR ENDOTHELIUM GROWTH FACTOR IN TREATMENT OF PATIENTS, SUFFERING ATHEROSCLEROTIC ISCHEMIA OF THE LOWER EXTREMITIES TISSUES]. AB - The results of examination of patients, suffering chronic ischemia of the lower extremities (LE) stages IIB - III (according to Fontaine), in whom preparation Neovasculgen was used in complex of medicinal therapy, were presented. In terms of follow-up before 12 months the distance, which the patients passed before the pain occurrence, have enhanced by 92.2%, and the ankle-brachial index--by 30.9%. Complications while application of the preparation were absent. Due to the treatment conducted there were LE saved and the patients' quality of life improved. PMID- 26419034 TI - [THE CHOICE OF SURGICAL TREATMENT METHOD FOR THE DEEP VEINS THROMBOSIS IN SYSTEM OF VENA CAVA INFERIOR]. AB - There were analyzed the results of examination and treatment of 455 patients, suffering deep veins thrombosis in a system of vena cava inferior, of whom 175 (38.5%) were operated on. Inclusion of ultrasound duplex scanning, roentgencontrast phlebography, multispiral computer tomography with intravenous contrasting, radionuclide phleboscintigraphy into complex of clinic-instrumental examination of the patients gives possibility to estimate the disorders of the main trunk and collateral venous blood flow in the deep veins thrombosis, as well as to substantiate indications and choice of the operative treatment method. PMID- 26419035 TI - [EFFICACY OF SURGICAL TREATMENT OF VARICOSE DISEASE, DEPENDING ON ADSORPTION RHEOLOGIC PROPERTIES OF BLOOD]. AB - Physico-chemical adsorption-rheological properties of venous blood in patients, suffering varicose disease of the lower extremities, and their impact on efficacy of various methods of surgical treatment were studied. Conduction of endovasal laser coagulation in combination with crossectomy have promoted enhancement of operative treatment efficacy in patients in initial terms of observation (in 1 week), in 1 month a complete occlusion of the vein was noted more rarely. Efficacy of a small--power laser ablation with irradiation power of 10 W and less in 4 weeks postoperatively is higher, than of surgical treatment with a laser irradiation power 15 W. In a varicose disease of the lower extremities there were observed the raising of the blood volume toughness, superficial relaxation and superficial stress on background of reduction of the toughness--elasticity module, superficial toughness and superficial elasticity. Crossectomy conduction did not influence the integral dynamics of adsorption--rheological properties of venous blood, but in 1 month after endovasal laser coagulation a normalization of physicchemical parameters of blood was noted. Application of laser irradiation of the 10 W power and less promotes inhibition of the relaxation properties of venous blood; a prognostic meaning owes initial value of the blood volume toughness. PMID- 26419036 TI - [IMPACT OF PERINATAL TACTICS ON THE POSTOPERATIVE PERIOD COURSE IN SURGICAL ELIMINATION OF AORTAL COARCTATION IN NEWBORN BABIES]. AB - The results of perinatal management and surgical treatment of 30 newborn babies, owing antenatally diagnosed isolated aortal coarctation (AC) and 40 newborn babies, in whom this diagnosis was not established antenatally, were analyzed. Application of antenatal diagnosis and optimization of the patients' perinatal management algorithm have permitted to reduce the treatment duration in the intensive therapy division of cardiosurgical department. In newborn babies, to whom the diagnosis of AC was established antenatally, a trustworthy reduced duration of postoperative pulmonary artificial ventilation was revealed in comparison with such in patients, in whom this diagnosis was not established antenatally. PMID- 26419037 TI - [BIOMECHANICAL SUBSTANTIATION OF ONE-AXIS DEFORMITY OF ADIPOSE-CUTANEOUS FLAPS OF TEMPORAL AND ZYGOMATIC AREAS WHILE PERFORMANCE OF UPPER RHYTIDOPLASTY]. AB - The urgency of the problem of determining the biomechanical features adipose cutaneous grafts due to a significant increase in the frequency of performing cosmetic surgery and the lack of a unified concept for such interventions. In 32 women aged 35 to 65 years, which will eliminate the excess soft tissues in the implementation ritidectomy and other surgical interventions, isolated patches of adipose-cutaneous flaps to determine the mechanisms of its plastic deformation. Based on the analysis of biomechanical research targeted the optimal stretching the boundaries of adipose-cutaneous flaps zygomatic--to (0.45 +/- 0.021) cm and temporal--by (0.0165 +/- 0.002) cm refer to areas that allowed to perform surgery with preservation of natural topographoanatomic relations persons in the performance of the upper ritidectomy. PMID- 26419038 TI - [MODERN METHODS OF PROGNOSTICATION OF THE RECURRENCES OCCURRENCE AFTER SURGICAL TREATMENT OF THE MAMMARY GLAND BENIGN TUMORS]. AB - Modern schemes of the recurrences predicting after surgical treatment of benign tumors of mammary gland (BTMG) were estimated. In accordance to data of retrospective investigation obtained, the recurrences occurrence rate through a five-year period of observation have constituted 2.3%. While doing prospective observation, the recurrences after treatment have occurred in 12 (24.0%) patients, suffering phylloid histologic form of tumor. The BTMG recurrences were noted predominantly in women--carriers of mutant alleles with polymorphism rs8190924 of gene GSR and AA rs3763511--of gene DKK4. Nethertheless, there are no data, which confirm the recurrence occurrence risk to be considered genetically determinated, the possibilities ratio for this kind of polymorphism have costituted 12.0 (trustworthy interval 95% 0.8 - 14.9). PMID- 26419039 TI - [THE ROLE OF TUMORAL STROMA IN PREDICTING OF THE SEVERITY COURSE IN PATIENTS, SUFFERING MAMMARY GLAND CANCER WITH P53 HYPEREXPRESSION]. AB - There was revealed, that the survival indices in mammary gland cancer (MGC) patients in similar stage of the disease, in the same tumor histology, and in a mutant gene p53 hyperexpression, to whom identical complex treatment was conducted, are rhythmic, what witnesses a necessity to search for additional predicting factors. Predicting role of tumoral stroma in patients, suffering MGC with p53 hyperexpression, was studied. PMID- 26419040 TI - [THE METHOD OF COLPOPOIESIS IN AN URINARY BLADDER EXTROPHY]. AB - Complex of extrophy--epispadias--a rare inborn malformation of genitourinary system, abdominal wall muscles and pelvic bones. The observation was adduced, concerning an urinary bladder extrophy in a girl in combination with vaginal agenesia after noneffective primarily--postponed closure of urinary bladder, osteotomy (in the age of 4 yrs old), with consequent ureterosygmostomy. In the patient there was conducted a reconstructive operation for vagina creation, using nonfunctioning bladder, right-sided nephrectomy for severe ureterohydronephrosis, reconstruction of anterior abdominal wall and external genitalia. PMID- 26419041 TI - [COMPARISON OF THE OCCURRENCE RATE OF NAUSEA AND VOMITING AFTER TRANSCUTANEOUS NEPHROLITHOTRIPSY: SEVOFLURANE OR PROPOFOL]. AB - Impact of various kinds of general anesthesia while performing transcutaneous endoscopic interventions on kidneys on postoperative occurrence and rate of nausea and vomiting were studied. Propofol and sevofluran were used for support of general anesthesia conduction. There was established, that if optimal depth of anesthesia is maintained (bispectral index 40 - 60 units), the rate of nausea and vomiting occurrence do not depend on the kind of anesthesia applied--total intravenous or the inhalation one. PMID- 26419042 TI - [IMPACT OF THE UPPER URINARY WAYS DRAINAGE METHOD ON RESTORATION OF RENAL FUNCTION IN PATIENTS, SUFFERING ACUTE OBSTRUCTIVE PYELONEPHRITIS]. AB - Renal function was studied, using radionuclide renography, in 142 patients, suffering acute obstructive pyelonephritis, in 73 of whom transcutaneous nephrostomy was applied and in 69--the ureter's stenting, for the urine passage restoration. The investigation was peformed in 1 month and 1 year after miniinvasive treatment. After comparison of the investigation results there was established, that after transcutaneous nephrostomy, using miniinvasive technologies, the affected kidney's functional inhibition was trustworthy less, than after stenting. Because of better preservation of renal function, the transcutaneous nephrostomy conduction in patients, suffering an acute obstructive pyelonephritis, constitutes a less invasive method, than the ureter's stenting. PMID- 26419043 TI - [ESTIMATION OF CLINICAL EFFICACY OF MODIFIED LASER VAPORISATION FOR BENIGN PROSTATIC HYPERPLASIA]. AB - The clinical efficiency of the method modified technique of laser vaporization of the prostate in patients with benign prostatic hyperplasia were analysed. Clinical efficacy method modified technique of laser vaporization according to IPSS, Q(max) and V(res) was higher than the laser vaporization and did not differ from TURP in patients with prostate volume of 80 ml. In patients with prostate volume over 80 ml modified technique of laser vaporization clinical efficacy was higher than prostatectomia. PMID- 26419044 TI - [METABOLIC INTOXICATION IN THERMIC TRAUMA]. AB - In 76 injured persons with deep and superficial burns, having area from 3 to 65% of the total body surface and ageing 5-16 yrs old, there was investigated the impact of early surgical treatment on the metabolic intoxication severity in accordance to content of the oxidatively modified proteins carbonyl groups in the blood serum, and of a ceruloplasmin, what was considered as integral express index of the organism antioxidant system state. Changes of these indices in ambustial disease of middle severity have witnessed a sufficiently compensated reaction of organism: of severe and extremely severe one--there were noted a deficiency of the organism antioxidant defense; and in stages of toxemia and septicotoxemia--attrition of the organism oxidant reserves and danger of the septic complications occurrence. Conduction of early surgical intervention have guaranteed maintenance of a ceruloplasmin content in stages of toxemia and septicotoxemia on the level of healthy persons, relief of the ambustial disease course, absence of critical metabolic intoxication and carbonyl stress, reduction of the septic complications rate in 1.5 times. PMID- 26419045 TI - [An Analysis of the Controversy on the Psychoprophylaxis Method in the Japanese Medical Journal "Obstetrics and Gynecology," 1954-1957]. AB - The methods of painless childbirth are generally divided into two kinds: "with drugs" and "without drugs." In Japan, the full-scale initiation of these two types of painless childbirth methods in clinical practice started in the early 1950s. The practice of the psychoprophylaxis method (PPM)--one of the painless childbirth methods "without drugs"--started in 1953. Japanese obstetricians had discussed the practicability of PPM for painless childbirth and had doubted the scientific nature and originality of PPM as a viable method. Therefore, they published a series of articles in the Japanese medical journal "Obstetrics and Gynecology" from 1954 to 1957. Two representative obstetricians developed this controversy. Naotaro KUJI, the director of the Central Maternity Hospital of the Japanese Red Cross Society and the chief practitioner of PPM, emphasized that PPM was a more practical method, considering the Japanese medical legal situation where midwives were prohibited to use drugs. On the other hand, Kakuichi ANDO, the chief professor of the Department of Obstetrics and Gynecology of Keio University and the team leader of the practitioners of painless childbirth "with drugs," doubted the practicability of PPM. In the course of these discussions, both groups of obstetricians gradually came to a consensus to use the concept of "pain relief" in labor, instead of "painless" childbirth. They also agreed to adopt methods "with drugs" and "without drugs," including PPM, according to the presented case. PMID- 26419046 TI - [Details and Background on the Origins of Modern Female Doctors in the Meiji Era: Research on the Minutes of the Central Board of Health (see text) in Hosokawa Junjiro's (see text) Monographs Goen-Sosho (see text) and Materials of the Bureau of Hygiene (see text)]. AB - This research is based on materials of the Bureau of Hygiene (see text) and the minutes of the Central Board of Health (see text) contained in Hosokawa Junjiro's (see text) monograph Goen Sosho (see text). It showed that the movement toward allowing the qualification of modern female doctors in Japan was going on in various parts of Japan from 1881 or earlier. This history shows the presence of many female doctors in the Edo Period. At an extraordinary meeting of the Central Board of Health, an advisory body of the Bureau of Hygiene, the qualification of female doctors was approved of in 1881. This was based on an article in the yororyo law (see text) about female doctors contained in the ancient laws of Japan. As a result, the Department of the Interior allowed female doctors in June, 1884. At this time, five females took the national examination for medical practitioners. The following year, Ogino Ginko (see text) became the first modern female doctor in Japan. Owing to the yororyou law about female doctors, and the efforts of many other females who wanted to become doctors, the first modern female doctors in Japan came into being. PMID- 26419047 TI - [Premature Death Problems of the Meiji Emperor's Infants, According to the Two Submissions of 1883 and 1888]. AB - The Meiji Emperor had fifteen children; five princes and ten princesses, but ten of them died of a meningitis-like disease in their infancy. People were concerned about the circumstances in which the lineage of the emperor's family was in a critical situation. They investigated the conditions regarding the children's upbringing and reported on the matter to higher officials in 1883 and 1888. But the author concludes that conditions did not change for the better because of those efforts. PMID- 26419048 TI - Looking forward. The University of New Mexico Hospital's memorial service to their patients who have died. PMID- 26419049 TI - Defining your own success: An introduction. PMID- 26419050 TI - Talking the talk: The keys to effective workplace communication. PMID- 26419051 TI - The RAS-ACS: Recruiting medical students and training future leaders. PMID- 26419052 TI - Teaching in the OR: New lessons for training surgical residents. PMID- 26419053 TI - Feedback fundamentals in surgical education: Tips for success. PMID- 26419054 TI - Political advocacy in surgery: The case for individual engagement. PMID- 26419055 TI - Surgeons and social media: Threat to professionalism or an essential part of contemporary surgical practice? PMID- 26419056 TI - No quality without access: ACS and NIH collaborate to ensure access to optimal care. PMID- 26419057 TI - The importance of detailed documentation in ICD-10. PMID- 26419058 TI - Resources for optimal patient care: EBDS and patient education programs. PMID- 26419059 TI - PACES trial: Evaluating the effectiveness of eflornithine and sulindac in preventing colon adenomas. PMID- 26419060 TI - Addressing surgeon fatigue and sleep deprivation. PMID- 26419061 TI - Dr. Henri Ford performs first separation of conjoined twins in Haiti. PMID- 26419062 TI - NTDB data points: A hot mess: Clothing-related burn injuries. PMID- 26419063 TI - [BIOINFORMATICS COMPARISON OF HUMAN AND PLANT PHOSPHATOMES]. AB - The study presents the results of bioinformatic comparison of protein phosphatases from higher plants and human phosphatom (150 sequences). Based on sequence and profile comparison with known catalytic domains, 204 plant homologues from Physcomitrella patens and Arabidopsis thaliana where selected. Clustering of joint group of plant and mammalian protein phosphatases revealed fundamental differences in plant and human phosphatomes. At the same time, it was shown significant differences in the set of protein phosphatases in P. patens, A. thaliana, and such monocots as Orysa saliva and Zea mays. PMID- 26419064 TI - HIGH FREQUENCY GENETIC TRANSFORMATION OF CICHORIUM INTYBUS L. USING nptII GENE AS A SELECTIVE MARKER. AB - Cichorium intybus L. is an important vegetable crop used as salad (leaf form) and for the production of coffee substitutes (root form). At the same time these plants can also be used in biotechnologies for synthesis of pharmaceutical proteins. Here we report the possibility of high frequency Agrobacterium rhizogenes- or A. tumefaciens-mediated transformation of C. intybus L. for construction of transgenic "hairy" roots and plants. The used plasmids contained target human interferonifn-alpha2b gene, Mycobacterium tuberculosis ESAT6:Ag85B antigene esxA::fbpB(DeltaTMD) fused gene and human telomerase reverse transcriptase h Tert gene. Using of nptII gene as a selective one was preferable to the bar gene for chicory. In this case the frequency of transgenic plants or "hairy" roots formation was significantly higher. Cultivation of explants on the medium with Basta in concentration 1-2 mg/l have led to plants death or to significant reduction of number of shoots formed. Frequency of "hairy" roots formation varied from 5.9 to 42.3% after A. rhizogenes-mediated transformation. Frequency of regeneration of transgenic plants varied from 10 to 86% after A. tumefaciens-mediated transformation. Both A. rhizogenes- and A. tumefaciens mediated transformation frequency depended on the type of explants, roots or cotyledons, and vector used. Usage of A. tumefaciens carrying pCB064 plasmid (target esxA:fbpB(DeltaTMD) fused gene and nptII selective gene) resulted in the most effective regeneration of transgenic plants with regeneration frequency up to 86%. In the case of chicory A. rhizogenes-mediated transformation the highest regeneration frequency up to 42.3% was demonstrated using p CB161 vector with ifn alpha2b target gene and nptII selective gene. PMID- 26419065 TI - DOES THE PATTERN OF CLONAL EVOLUTION IN THE KARYOTYPE OF PATIENTS WITH ACUTE MYELOID LEUKEMIA AND MYELODYSPLASTIC SYNDROMES DEPEND ON THE TYPE OF THE PRIMARY CHROMOSOMAL ABERRATIONS? AB - The aim of our study was to define if the type of primary chromosomal aberrations (CA) of the karyotype of patients with Acute myeloid leukemia (AML) and Myelodysplastic syndromes (MDS) determines the way and the rate of karyotype development. Conventional cytogenetic analysis was carried out on 248 AML and 105 MDS patients at diagnosis. Clonal evolution (CE) was found in 40% (51 of 128) of AML patients and in 47.5% (19 of 40) of MDS patients having CA in their karyotype. The first pattern we established was for the most frequent CA which initiate CE in 28 patients with a complex karyotype. These CA were non-balansed rearrangements in the following regions: 5q, 7q, 11q, 3q, monosomy 5, monosomy 7. The second pattern of CE was regarding the most frequent aneuploidias (+8, +11, +21, -Y, and the third pattern concerned balanced CA. We found significant difference in the distribution of karyotypes in different stages of progression between the first and the other two groups (p < 0.001). No statistical difference was found between the patterns in the second and the third group CA (p > 0.5). PMID- 26419066 TI - OPTIMISATION OF TOTAL RNA EXTRACTION FROM BOVINE OOCYTES AND EMBRYOS FOR GENE EXPRESSION STUDIES AND EFFECTS OF CRYOPROTECTANTS ON TOTAL RNA EXTRACTION. AB - Gene expression is required for understanding bovine oocytes meiotic maturation as well as the potential of embryonic development. In the present study a standardized reagent protocol for total RNA extraction was designed for bovine oocytes and embryos, which is considered specific and less expensive. For such purpose oocytes (n = 795) recovered from about 80 ovaries were divided in three groups: Group 1 modified Trizol (MTP, n = 355); Group 2 Guanidinium thiocyanate protocol (GNTC, n = 140) and Group 3 Commercial Kit protocol (CKP, n = 60). Oocytes belonging to group 1 (n = 100) and 3 (n = 20) were subjected to vitrification using two cryoprotectants 1,2 propandiol (PROH) or Dimethylsulfoxide (DMSO). The 240 remaining oocytes were divided into 3 groups in which 100 were used, in fresh, for in vitro fertilization, and 140 oocytes were vitrified using PROH (n = 70) and DMSO (n = 70) as cryoprotectants, being then fertilized in vitro after thawing. Embryos were used nine days after fertilization. Gene amplification (SDHA, (GAPDH and DNMT1) was performed in oocytes, and gene quantification (DNMT1) in in vitro produced embryos at the stage of blastocyst (n = 10). Efficiency of the extraction was further compared. The purity of all samples to different protocols ranged from 1.10 to 1.25 for GNTC protocol; from 2.05 to 2.63 for the CKP and from 1.50 to 2.11 for the developed MTP, being the last one nearest to the expected purity levels for RNA samples (1.7 to 2.0). On average, for 30 fresh oocytes, from spectrophotometer readings, total RNA concentration was 127.8 +/- 9.3 ng MUl(-1) for MTP, against 46.4 +/- 9.5 ng MUl(-1) from CKP and 476 +/- 12.9 ng MUl(-1) for GNTC protocol. Using the MTP to evaluate RNA in 30 vitrified/thawed oocytes, resulted in a total RNA concentration of 61.3 +/- 3.3 ng MUl(-1) and 40.0 MU 12.4 ng MU(-1), respectively for DMSO and PROH. Regarding total RNA concentration and purity, in blastocyst stage, more purity was observed in DMSO as compared to PROH (1.8 vs 1.2) (p < 0.05). Better results were also observed on the MTP for gene amplification when compared with the other protocols. For gene quantification, the proposed protocol quantified DNMT1 gene with PCR efficiency (0.933) after normalization against GAPDH and SDHA. Amplification and quantification of genes proved specificity and efficiency of the MTP over the other protocols. PMID- 26419067 TI - ZNF527 GENE rs386809049 ANALYSIS IN POPULATION OF UKRAINE. AB - It was shown that some mutations in a number of zinc finger protein (Znf) genes cause intellectual disability (ID). In our study in two affected siblings with ID exome analysis revealed the homozygous coding sequence (cds) indel rs386809049 in the ZNF527 gene. The c.806_808 deletion CAT and insertion TGTGCA (rs386809049) results in substitution of Pro269 and Tyr270 to Leu, Cys and Asn, located in the interdomain region of Zinc finger protein 527. The analyses of site orthologs revealed that Pro269 and Tyr270 amino acid positions are conserved across mammalian species, indicating that there may be an evolutionarily conserved function. To evaluate the ZNF527 gene involvement in intellectual disability pathogenesis analysis of rs386809049 polymorphism in 300 individuals from general population of Ukraine was performed. The following genotypes distribution was detected: CAT/CAT (67.7%), CAT/TGTGCA (31%) and TGTGCA/TGTGCA (1.3%). As far as we know this is the flirt published data on rs386809049 distribution in the populations. The ZNFS27 TGTGCA (polymorphic) allele frequency was 16.8% and CAT(wild type)--83.2% in the general population of Ukraine. Such a high polymorphic allele frequency allows us to suggest that analyzed rs386809049 polymorphism in ZNF527 gene cannot be the major cause of intellectual disability. PMID- 26419068 TI - [GENE POOL SIMILARITIES AND DIFFERENCES BETWEEN UKRAINIANS AND RUSSIANS OF SLOBOZHANSHINA ON Y-CHROMOSOME DATA]. AB - The results of the study of Y-chromosomal polymorphisms of Russian and Ukrainian population are presented for Slobozhanshina--contemporary border region, former "Wild Field" boundary, which was inhabited in XVII-XVIII centuries by both the Russians from the north and Ukrainians from the west. In general, Ukrainian and Russian populations of Slobozhanshchina genetically are very close, their set and frequency range of Y-chromosome haplogroups are typical for the Eastern Europe. But a detailed analysis of highly informative Y-chromosome markers showed that after 3,5 centuries of coexistence on the same historical territory, the both nations retain the ethnic specificity of their gene pools: Ukrainian populations are similar to the rest of Ukraine, and Russian populations are similar to the south of the European part of Russia. The genetic differences may be due to the spatial characteristics of marriage migration and the predominant ethnic environment. PMID- 26419069 TI - [PREIMPLANTATION DEVELOPMENT OF HUMAN EMBRYOS WITH NUMERICAL CHROMOSOME ABNORMALITIES IN VITRO]. AB - The study was focused on morphokynetic characteristics of in vitro cultured human embryos that were considered to be aneuploid or euploid according to the preimplantation genetic screening results. Among all the embryos examined only 34.2% were chromosomally balanced, while others possessed isolated or combined chromosome abnormalities. Although morphological features of cleaving pathologic and euploid embryos did not differ significantly, on the fifth day of culture chromosomally balanced specimen formed "expanded" blastocyst twice as frequently as abnormal ones. Moreover, development of 38.4% of aneuploid embryos was compromised before the initiation of cavitation. Thus, prolonged embryo culture advances selection of samples with the highest implantation potential for the transfer on the basis of the morphokynetic characteristics and helps to avoid additional genetic testing. PMID- 26419071 TI - [INITIAL EXPERIENCE OF TRANSVAGINAL EXTRACTION OF THE KIDNEY FOLLOWING LAPAROSCOPIC NEPHRECTOMY IN OUR DEPARTMENT]. AB - PURPOSE: We report the detailed technique and results of transvaginal extraction of the kidney following laparoscopic nephrectomy. PATIENTS AND METHODS: From August 2013 onward, we planned to perform transvaginal extraction of the kidney following laparoscopic nephrectomy in a total of 6 female patients. Of the 6 patients, 5 underwent the procedure. After completion of the primary laparoscopic nephrectomy and entrapping the removed kidney, the patients were placed in the supine lithotomy position. A transverse posterior colpotomy was created transvaginally at the apex of the posterior fornix. An opening was made in the peritoneum bluntly with the fingers under laparoscopic view. After the drawstring of the entrapped specimen was delivered into the vagina, the specimen was extracted intact via the vagina. When the vaginal wall was too tight for a large specimen, the incision was extended on the affected side. After removal of the specimen, the peritoneum was sutured laparoscopically, and the posterior colpotomy incision was repaired transvaginally. RESULTS: Transvaginal extraction was successful in 5 patients. The mean operative time for the vaginal extraction procedure was 59 minutes. Blood loss was minimal. The mean specimen weight was 447 g (range 271 to 655 g). No intraoperative complications occurred. Postoperatively, one case needed intermittent catheterization for a few days because of temporal dysfunction of the bladder. CONCLUSIONS: Transvaginal extraction is an efficacious and minimally morbid technique for removing the intact kidney after laparoscopic nephrectomy. PMID- 26419072 TI - [CLINICOPATHOLOGICAL STUDY OF PROSTATE BIOPSY IN PATIENTS RECEIVING DUTASTERIDE FOR BENIGN PROSTATIC HYPERPLASIA]. AB - OBJECTIVE: Dutasteride is a 5-alpha reductase inhibitor used to treat benign prostatic hyperplasia. Dutasteride lowers prostate-specific antigen (PSA) levels, which may lead to delays in the diagnosis and treatment of prostate cancer (PCa). This study investigated patients who underwent prostate biopsy (PBx) while receiving dutasteride to investigate whether this agent affects the diagnosis and treatment of PCa. PATIENTS AND METHODS: PBx was performed on six patients receiving dutasteride for > 3 months at our medical institutions between January 2010 and June 2013. No patients underwent PBx before dutasteride administration. We performed PBx both for patients with high initial PSA levels and for those with elevated PSA levels with or without initial PSA decline after dutasteride administration. We also investigated clinicopathological findings. RESULTS: Mean age at the start of administration was 69.5 +/- 5.9 years (range, 59-77 years), mean duration of administration was 14.1 +/- 7.4 months (range, 4.0-23.5 months), mean prostate volume at the start of administration was 70.4 +/- 30.7 ml (range, 18.8-104.6 ml), and mean PSA level at the start of administration was 7.7 +/- 3.3 ng/ml (range, 4.9-14.2 ng/ml). PSA density was 0.098 +/- 0.045 ng/ml/cm3 (range, 0.042-0.181 ng/ml/cm3), and PSA level at PBx was 5.4 +/- 2.7 ng/ml (range, 2.5 10.7 ng/ml). We detected three PCa patients, and clinical stage in each case was cT1cN0M0. Radical retropubic prostatectomy was performed in two cases, and androgen-deprivation therapy was performed in one case. CONCLUSION: All PCa were detected in the early clinical stage. No delays in detection or treatment of PCa were seen in any cases. Careful observation of PSA levels is simple and useful for detecting PCa in patients under dutasteride administration. PMID- 26419073 TI - [TREATMENT OUTCOME OF OBSTRUCTIVE PYELONEPHRITIS DUE TO URETERAL CALCULI WITH DISSEMINATED INTRAVASCULAR COAGULOPATHY]. AB - OBJECTIVES: Because obstructive pyelonephritis secondary to ureteral stones can easily cause sepsis and concomitant disseminated intravascular coagulation (DIC), it is a potentially lethal disease. However, the optimal treatment for such severe patients has yet to be established. In this study, we aimed at clarifying the effectiveness of emergent drainage and DIC treatments for patients with septic DIC due to obstructive pyelonephritis. In additon, we also evaluated the impact of recombinant human thrombomodullin (rTM) for severe patients with DIC. MATERIALS AND METHODS: From September 2006 to May 2013, 31 patients with obstructive pyelonephritis secondary to ureteral stones who met the acute DIC criteria from the Japanese Association of Acute Medicine were treated at our institution. All patients received emergent drainage of urinary tract and anti DIC treatment, as well as administration of antibiotics and adequate volume infusion. To evaluate the impact of rTM, patients received rTM were compared with those managed by other DIC therapeutic agents. RESULTS: The mean patients' age was 73 years old, and 27 patients (87.1%) were in a state of septic shock. All patients, except for one patient (3.2%) who died 6 days after drainage, could recover from sepsis and comcomitant DIC. Interestingly, thrombocyte count, creatinine, and SOFA Score in rTM group were recovered faster than those in no rTM group (p = 0.017, 0.0038, and 0.0006, respectively). CONCLUSIONS: These results indicate that most patients with DIC caused by obstractive pyelonephritis can be successfully managed by emergency drainage and anti-DIC treatment. In addition, rTM may be effective for the treatment of such severe patients by improving organ failure associated with disordered coagulation. PMID- 26419074 TI - [THE IMPACT OF LOWER URINARY TRACT SYMPTOMS ON GENERIC HEALTH-RELATED QUALITY OF LIFE IN MALE PATIENTS WITHOUT CO-MORBIDITY]. AB - PURPOSE: We investigated the impact of lower urinary tract symptoms (LUTS) on generic health-related quality of life (HRQOL) in male patients without co morbidity. PATIENTS AND METHOD: From 2003 to 2011, a total 567 men who presented out urological department completed the questionnaires including International Prostate Symptom Score (IPSS), incontinence-frequency score (IFS) from the UCLA prostate cancer index, MOS 36-Item Short-Form Health Survey (SF-36). Among 230 patients with no coexisting morbidity, the relations between each LUTS score of IPSS indices and IFS and 8 domain scores of SF-36 were analyzed by Pearson's product-moment correlation and stepwise multiple regression analysis. RESULT: Univariate analysis showed that the IFS had a significant correlation with all of 8 domain scores of SF-36, and also the IPSS item scores of urgency, nocturia and straining correlated significantly with multiple domain scores of SF-36. In multiple regression analysis, the proportionate contributions of LUTS to each SF 36 domain scores were low (R2 was 10% or less). Incontinence was considered as the most influential factor that had a negative impact on HRQOL in 7 SF-36 domains of physical functioning, role-physical, bodily pain, general health perception, vitality, social functioning and mental health. Additionally, nocturia, straining and urgency were significantly associated with deficit of HRQOL in 4 SF-36 domains (role-physical, general health perception, role emotional, mental health), 2 domains (bodily pain, social functioning) and 1 domain (role-emotional) of SF-36, respectively. CONCLUSION; Among LUTS, incontinence, nocturia and straining were the most important symptoms in association with the negative impact on generic HRQOL measured by SF-36. PMID- 26419075 TI - [PRIMARY MEDIASTINAL GERM CELL TUMOR ARISING IN A PATIENT WITH NEUROFIBROMATOSIS TYPE 1]. AB - Neurofibromatosis type 1 (NF1) is a distinct genetic disorder due to the NF1 gene mutation which induces the aberrant activation of the RAS-signaling. Because RAS related proteins function as oncogenic factors, NF1 patients frequently develop malignant tumors, especially of neural crest origin, such as peripheral nerve sheath. In addition, malignant tumors of the pancreas, colorectum, and lung have been reported to frequently arise in NF1 patients. However, the association between germ cell tumor and NF1 has not been clarified yet. A 29-year-old male with dyspnea was referred to our hospital because of the large mass in the anterior mediastinum and cervical lymph node swelling. The diagnosis was extragonadal germ cell tumor with cervical lymph node metastasis, and complete remission was obtained by multidisciplinary treatment consisted of combination chemotherapy and surgical resection. To our acknowledgement, this is the first case of extragonadal germ cell tumor in NF1 patients. We discuss the relevance between activation of the RAS-signaling and the development of germ cell tumor. PMID- 26419076 TI - [A CASE OF SOLITARY ADRENAL TUMOR METASTASIZED FROM RECTAL CANCER]. AB - Solitary adrenal metastasis of rectal cancer is comparatively rare condition and it is difficult to be diagnosed because it doesn't have any characteristic symptoms. We report a case of this type of adrenal tumor that could be figured out by tumor markers and the analysis of CT scan image. A 67-year-old man visited our department with the right adrenal tumor. He has a past medical history of rectal cancer and a low anterior resection was performed in 2011. After the surgery, he received adjuvant chemotherapy for 6 months. There has been no finding of recurrence or metastasis after chemotherapy. However, his follow-up abdominal CT in 2013 showed the right adrenal tumor which was 23 mm in diameter. Serum CEA level has also increased to 4.1 ng/ml, but there was no abnormal finding with hormonal study. The tumor size and CEA level gradually increased up to 46 mm in size and 10.4 ng/ml during 6 months. Enhanced CT also showed 39% at rate of absolute percentage wash out, which was not the finding of typical functional adrenal tumor. Based on these findings, we diagnosed that the origin of this adrenal tumor should be solitary metastasis of the rectal cancer. For the treatment of surgical procedure, we performed laparoscopic right adrenalectomy. The pathological finding showed adenocarcinoma, the origin of which was the previous rectal cancer. Six months have passed since the surgery, but CEA level still has remained normal range and neither finding of recurrence nor metastasis has been found. PMID- 26419077 TI - [A CASE OF HEPATIC METASTASECTOMY FOR RENAL PELVIS CARCINOMA]. AB - A 68-year-old woman presented with asymptomatic gross hematuria. Computed tomography (CT) scan revealed noninvasive tumor in the right ureteropelvic junction. After diagnosis with right pelvis carcinoma by ureteroscopy, she underwent laparoscopic nephroureterectomy in Aug. 2008. Six months later, hepatic metastasis was detected. Three courses of combination chemotherapy consisting of gemcitabine and cisplatin (GC) were conducted, and then partial response (PR) was achieved. In Aug. 2009, radical metastasectomy for liver metastasis was performed. More than four years and five months after hepatectomy, the patient has achieved a high quality of life. PMID- 26419078 TI - [A CASE OF GRANULOCYTIC SARCOMA IN THE BILATERAL URETER]. AB - A 61-year-old female presented with the complaints of fever and left back pain. She had previously undergone bone marrow transplantation for acute myeloid leukemia and achieved remission. Abdominal computed tomography (CT) revealed left hydronephrosis and suspected tumor lesions in the right upper ureter and left lower ureter. Ureteroscopy was performed for a diagnosis. A yellowish tumor was detected in the left lower ureter, and tissue biopsy was performed. Two weeks after the examination, abdominal CT revealed ascites and retroperitoneal dissemination. The results of the ascites cytology showed infiltration by leukemia cells, and the patient was diagnosed as having recurrent leukemia. A week later, she died. The ureteral tumor was diagnosed as a granulocytic sarcoma. Granulocytic sarcoma, a condition characterized by mass formation outside the bone marrow by granulocytic cells, is classified as a myeloid sarcoma, occurring in an estimated 2-8% of patients with myeloid leukemia. The possibility of granulocytic sarcoma should be considered when treating patients with a history of leukemia. PMID- 26419079 TI - [THREE CASE REPORTS OF METACHRONOUS BILATERAL TESTICULAR TUMOR: INVESTIGATION OF SEXUAL FUNCTION AND FERTILITY]. AB - The sexual dysfunction and infertility after treatment of bilateral germ cell tumors (GCT) becomes the serious problem. Therefore andrological aspects as well as cancer curability should be considered in planning of bilateral GCT treatment. Here we report 3 cases of metachronous bilateral GCT treated with different regimens, and discuss from the viewpoint of preservation of sexual function. Case presentations: (1) A 38-year-old man underwent right-sided orchitectomy for a right testicular tumor at the age of 26 years. Pathological diagnosis was seminoma and clinical stage was T1N0M0S2. 12 years later, contralateral testicular tumor developed. Left-sided orchitectomy was performed. Pathological diagnosis was seminoma and clinical stage was T1N0M0S2. He has been followed up for 4 years after the second operation without any evidence of tumor recurrence. Endocrinological examination show low testosterone level, and high LH and FSH levels. Erection and ejaculation are impossible but he does not request androgen replacement therapy. (2) A 21-year-old man underwent right-sided orchitectomy for a right testicular seminoma at the age of 20 years (T1 N0M0S0). 1 year later, contralateral seminoma (T1N0M0S0) developed and left-sided organ-preserving operation was performed. Histologic specimens showed seminoma and intratubular malignant germ cells (ITMGC) in surrounding seminiferous tubules. 2 cycles of BEP was added after the operation. He has been followed up for 5 years without any evidence of tumor recurrence. Endocrinological examination shows normal levels of testosterone and LH, but FSH is slightly high. Erection and ejaculation are possible. (3) A 36-year-old man underwent right-sided orchitectomy for a right testicular embryonal carcinoma at the age of 30 years. Clinical T1N0M0S1 was confirmed. 6 years later, he noticed the induration at his left testis. The result of fine needle aspiration cytology was embryonal carcinoma. At first, organ-preserving operation after chemotherapy was planned. However, he refused the operation considering the possibility of erectile dysfunction and infertility. As a result, he received only chemotherapy (3 cycles of BEP), and has been free of the disease for 11 years after chemotherapy. The level of testosterone, LH, and FSH are all normal. Erection and ejaculation are possible. PMID- 26419080 TI - [A CASE OF UROTHELIAL CARCINOMA OF THE URINARY BLADDER WITH SQUAMOUS DIFFERENTIATION RESPONDING TO PACLITAXEL AND CARBOPLATIN NEOADJUVANT CHEMOTHERAPY]. AB - A 42-year-old man was referred to our hospital for macrohematuria. Computer tomography and magnetic resonance imaging revealed right hydronephrosis and a retroperitoneal mass, located next to right side of the bladder. Cystoscopy showed a protruded lesion covered with normal mucosa at the right lateral wall. The patient underwent transurethral resection of the bladder tumor and biopsies of the bladder wall. Histological examination showed squamous cell carcinoma. Neoadjuvant chemotherapy using paclitaxel and carboplatin (TC) was performed. A total cystectomy, right nephroureterectomy and construction of the ileal conduit were performed after one course of systemic chemotherapy. Histological examination showed urothelial carcinoma with squamous cell differentiation. Unexpectedly, a small amount of CIS was detected only in the vicinity of the TUR scar. The patient received 2 cycles of TC chemotherapy as adjuvant chemotherapy. Unfortunately, 11 months later, local recurrence and liver metastasis were detected. He died 17 months after the surgery. PMID- 26419081 TI - [LEIOMYOSARCOMA ARISING FROM OVARIAN VEIN WITH RIGHT HYDRONEPHROSIS: A CASE REPORT]. AB - The patient was a 37-year-old woman who had suffered from repeated pyelonephritis. Computed tomography (CT) of the abdomen revealed a 1.9 cm retroperitoneal mass with compression of the right ureter and hydronephrosis. The patient visited our medical center and admitted. The patient underwent a simple total excision of the mass and end-to-end ureteral anastomosis. The tumor involved right ovarian vein and right ureter. Histopathological diagnosis was leiomyosarcoma of the ovarian vein. At 12 months after operation, local recurrence of surroundings tissue of the right ureter and gallbladder, and inferior vena cava invasion is found. Thus, the patient underwent a right nephroureterectomy with partly resection of the inferior vena cava and en block excision of the gallbladder. While CT revealed no recurrence three months after the operation, adjuvant postoperative combination chemotherapy with gemcitabine and docetaxel was administered. Nine cases of this leiomyosarcoma arising from ovarian vein have been reported in the literature. Leiomyosarcoma arising from ovarian vein with hydronephrosis is a second example. PMID- 26419082 TI - [How relevant is the risk of losing evidence due to delayed blood sampling? Conclusions from the evaluation of blood analysis results]. AB - If the order of a judge to take a blood sample can only be obtained with a marked delay after the incident, evidence proving that a suspect had been driving under the influence of alcohol or drugs of abuse may be lost. The evaluation of blood analysis results from the Institute of Legal Medicine in Frankfurt/Main from the years 2012-2014 shows that in 1.6 to 11.6% of positive cases, the drug concentrations were near the legal limits (20.2% of alcohol-positive and 7.5% of illicit drugs-positive samples). A loss of evidence can thus be expected in a large number of cases when the time between the police check of a driver and the collection of a blood sample increases. Blood concentrations of alcohol and drugs of abuse, especially tetrahydrocannabinol, cocaine, methamphetamine, and morphine, may already have dropped significantly after a delay of only half an hour. These delays are typically due to the time elapsing until the order to take a blood sample has been obtained from a judge and a medical doctor becomes available and arrives at the police station to draw a blood sample. The recommendation of medicolegal experts is to keep the time between police check of a suspect and blood sampling as short as possible. In routine cases, a realistic maximum of one hour should not be exceeded. PMID- 26419083 TI - [Projection of prisoner numbers]. AB - The past and future development of occupancy rates in prisons is of crucial importance for the judicial administration of every country. Basic factors for planning the required penal facilities are seasonal fluctuations, minimum, maximum and average occupancy as well as the present situation and potential development of certain imprisonment categories. As the prisoner number of a country is determined by a complex set of interdependent conditions, it has turned out to be difficult to provide any theoretical explanations. The idea accepted in criminology for a long time that prisoner numbers are interdependent with criminal policy must be regarded as having failed. Statistical and time series analyses may help, however, to identify the factors having influenced the development of prisoner numbers in the past. The analyses presented here, first describe such influencing factors from a criminological perspective and then deal with their statistical identification and modelling. Using the development of prisoner numbers in Hesse as an example, it has been found that modelling methods in which the independent variables predict the dependent variable with a time lag are particularly helpful. A potential complication is, however, that for predicting the number of prisoners the different dynamics in German and foreign prisoners require the development of further models. PMID- 26419084 TI - [Drying time for human saliva]. AB - In a case of aggravated extortion under threat of force, the medicolegal expert was asked to give an opinion on the drying time of human saliva. Fresh traces of saliva were applied to composite stones similar to those at the scene of the crime and their drying behavior was examined in a climate test chamber. Air temperature and air humidity during the experiment corresponded to the values of the measuring station located nearest to the crime scene. After one hour and 40 minutes no salivary spots were discernible on the stones any more. Depending on various influence factors, the traces could have originated both at the time of the offence and within a time window of up to 3 hours before. PMID- 26419085 TI - [Sudden death of a 16-year-old girl with WPW syndrome: a case report]. AB - The Wolff-Parkinson-White syndrome is a usually benign heart disease with accessory pathways. Circling excitations arise between atria and ventricles which can lead to cardiac arrhythmias. Cases of sudden cardiac death are rare (0.2 %). Risk factors for sudden cardiac death in patients with WPW syndrome are old age, several accessory pathways, male sex and previous syncopes. A 16-year-old girl was found lying dead in her bed. The evening before, she didn't feel well and complained about abdominal pain. The girl had known epilepsy and Wolff- Parkinson White syndrome. The macroscopic and histological findings are presented and discussed with reference to the pertinent literature. PMID- 26419086 TI - [Archaeology and criminology--Strengths and weaknesses of interdisciplinary cooperation]. AB - Interdisciplinary cooperation of archaeology and criminology is often focussed on the scientific methods applied in both fields of knowledge. In combination with the humanistic methods traditionally used in archaeology, the finding of facts can be enormously increased and the subsequent hermeneutic deduction of human behaviour in the past can take place on a more solid basis. Thus, interdisciplinary cooperation offers direct and indirect advantages. But it can also cause epistemological problems, if the weaknesses and limits of one method are to be corrected by applying methods used in other disciplines. This may result in the application of methods unsuitable for the problem to be investigated so that, in a way, the methodological and epistemological weaknesses of two disciplines potentiate each other. An example of this effect is the quantification of qualia. These epistemological reflections are compared with the interdisciplinary approach using the concrete case of the "Eulau Crime Scene". PMID- 26419087 TI - [Fatal skiing accidents: a forensic analysis taking the example of Salzburg]. AB - The rising popularity of Alpine skiing in recent years has led to an increase of skiing accidents, some with fatal outcome. In this paper, all fatal skiing accidents from the autopsy material of the Institute of Forensic Medicine of the Paris Lodron University Salzburg were evaluated and compared with statistical data of the Alpine Police. In the wintertime of 2005/2006 until 2013/2014, 22 deadly skiing accidents were autopsied. The age of the male and female victims ranged between 12 and 71 years. The main cause of death was craniocerebral and chest trauma. A relevant blood alcohol concentration was detected in only one case. Together with trauma-biomechanical and technical experts, forensic medicine serves as a necessary clarification interface between the investigating authorities and the judiciary. Determining the cause and manner of death as well as reconstructing the accident is the main task of the forensic pathologist. The present study shows that in the county of Salzburg, only a small percentage of fatal skiing accidents is evaluated from a forensic and trauma-biomechanical point of view. Thus the possibilities of an interdisciplinary accident analysis are not always fully utilized. PMID- 26419089 TI - [Fatal electric accident due to adverse error situation]. AB - Despite wearing high-impedance shoes, a young male died while trying to connect a garden pump (230 V). The cause of death could easily be determined on the basis of testimonies of eye-witnesses and an electric mark on the body. Histological and electron microscopic examinations showed metallisation of the electric mark (pure iron). Intensive investigative efforts were needed, however, to reproduce the current path, which resulted from three different coactive failures. The electrotechnical characteristics of the case and the resulting current path are described. PMID- 26419088 TI - [Human frontal inclination of the skull as a trait of sexual dimorphism- terminology and quantification]. AB - The skull presents a variety of morphological traits suitable for sex discrimination due to the degree of their development. The vertical frontal inclination has been established. as another marker of sex discrimination, as a steep forehead is considered as a female and a receding frontal inclination as a male attribute. In the literature, there are many different ways to define the morphognostic term "frontal inclination" and "forehead profile" respectively. As part of the project "Digital Forensic Osteology" definitions of the frontal inclination commonly found in the literature have been tested with regard to their applicability to virtual skulls based on post-mortem CT data. The actual angle measurements were carried out automatically using software developed by the authors of this article. For the investigations, profile images of skulls generated from volume-rendered CT data were used in which anthropometric measuring points had been set manually. With the help of discriminant analysis it was tested whether sex discrimination on virtual skulls based on defined variables can be carried out with sufficient sensitivity. The measurement accuracy of the defined variables on the volume-rendered images turned out to be good. No significant sex differences regarding the tested variables were found. Using all the four selected variables the sensitivity for female skulls was only about 66%, whereas for male skulls it was not much higher than the rate of coincidence (53%). The results of this pilot study suggest that apart from extending the sample size the inclusion of additional variables based on strict consideration of validity and reliability criteria should be critically tested. PMID- 26419090 TI - [In vitro characterization of glucuronosyl- and sulfotransferases involved in the conjugation of ethanol]. AB - Ethyl glucuronide (EtG) and ethyl sulfate (EtS) are minor metabolites of ethanol; for some years, both compounds have been used as direct biomarkers of alcohol consumption in forensic and clinical settings as well as in traffic medicine. Drinking experiments showed individual variations of the formation of EtG and EtS. At present, our knowledge on enzymes involved in the conjugation of ethanol is incomplete and partly inconsistent. The purpose of the present study was to characterize those enzymes that are capable of catalyzing glucuronidation and sulfation of ethanol including some potential inhibitors. Following optimization of incubation conditions, the formation rates of EtG and EtS from ethanol via recombinant glucuronosyltransferases (UGTs, hepatic) and sulfotransferases (SULTs, hepatic, intestinal), the kinetics and the inhibitory potential of polyphenols such as quercetin, kaempferol and resveratrol were determined. Analysis was performed following either solid phase extraction due to severe ion suppression of EtG or direct injection of the EtS-containing incubation mixture by high-pressure liquid chromatography/tandem mass spectrometry. Deuterated analogues were used as internal standards. All UGTs were capable of metabolizing ethanol through glucuronidation; UGT1A9 and UGT2B7 exhibited the highest formation rates. All SULTs showed ethanol-sulfating activity with SULT1A1 being most active. Data for all enzymes could best be described by Michaelis-Menten kinetics. All polyphenols inhibited the conjugation of ethanol except UGT2B 15. Inhibition was reversible and competitive for most enzymes; mechanism-based inhibition was evident for UGT2B7 and SULT2A1 with regard to quercetin and for SULT1E1 with regard to kaempferol. These results suggest an influence on the formation rates of EtG and EtS by common food ingredients beside known polymorphisms of UGT and SULT family members. Further studies should be conducted to achieve a better understanding of the extent and significance of this influence. PMID- 26419091 TI - [Alleged suicide by insulin]. AB - A 26-year-old man, who was on probation, was found dead in his home by his mother. Insulin vials and 2 insulin pens, which the man's stepfather (an insulin dependent diabetic) had been missing for over a week, were found next to the deceased. The circumstances suggested suicide by an injected insulin overdose. At the time of the autopsy, the corpse showed already marked signs of autolysis. Clinical chemical tests confirmed the injection of insulin, but indicated hyperglycemia at the time of death. Toxicological analyses revealed that the man had consumed amphetamine, cannabinoids, and tramadol in the recent past. Histological examination finally revealed extensive bronchopneumonia as the cause of death. The most plausible explanation for the results of the autopsy and the additional examinations was an injection of insulin as a failed attempt of self treatment. It is conceivable that the man had discovered by a rapid test that he was a diabetic, but had decided not to go to a doctor to avoid disclosure of parole violation due to continued drug abuse. He may have misinterpreted the symptoms caused by his worsening bronchitis and the developing bronchopneumonia as symptoms of a diabetic metabolic status and may have felt compelled to treat himself with insulin. PMID- 26419092 TI - [Death after the intake of amphetamine/ecstasy: two case reports]. AB - Synthetic amphetamines such as 3,4-methylenedioxy-N-methylamphetamine (MDMA, Ecstasy) have become recreational drugs in German discotheques because of their euphoric and mood-brightening effects. However, their consumption involves considerable risks, which may even be lethal under certain circumstances. A 19 year-old man was taken to a university hospital for suspected intoxication with a narcotic drug, where he died the next day. As cause of death "fulminant liver failure" was diagnosed. In blood from the femoral vein, MDMA was found in a concentration of 4.27 mg/l. Histological examination showed acute necrosis of the liver and parenchymatous bleeding. The second case is that of a 39-year-old man who collapsed at his workplace and died in hospital shortly afterwards. In his rucksack, a small bag with 1.6 g of amphetamine was found. Analysis of blood from the femoral vein showed an amphetamine concentration of 1.08 mg/l. PMID- 26419093 TI - [Translational Research and Anesthesiology]. PMID- 26419094 TI - [Comparison of Seven Intubation Devices in Difficult Airway Model]. AB - BACKGROUND: The efficacy in tracheal intubation may differ between different video-optical devices, in particular in patients with difficult airways. The purpose of this study was to evaluate the efficacy of video-laryngoscopes and fiberoptic bronchoscope (FOB) in tracheal intubation on a mannequin with several difficult airways, including limited mouth opening, cervical spine rigidity and tongue edema. METHODS: Residents performed tracheal intubation on a mannequin using Macintosh laryngoscope (Mac), rigid indirect-optical intubation devices and FOB. The laryngeal view, the success rate of tracheal intubation, and the time to intubate trachea were recorded. RESULTS: With limited mouth opening and cervical spine rigidity, video-optical intubation devices showed a significantly higher success rate of tracheal intubation than the Mac or FOB. In contrast, with tongue edema, the success rate of tracheal intubation was lower when Mac-type videolaryngoscopes were used. CONCLUSIONS: Videolaryngoscopes can generally be useful in patients with all difficult airways, but may be difficult in some circumstances (such as tongue edema). The FOB provided good laryngeal view in all cases, but the success rate of tracheal intubation was low and the time to intubate trachea was long. PMID- 26419095 TI - [Exposure to 1 % Sevoflurane for 6 Hours Enhances Proliferation of Human Colon Cancer Cells]. AB - BACKGROUND: Sevoflurane is one of the commonly used volatile anesthetics in cancer patients. The protective effect of sevoflurane preconditioning has raised concerns about whether sevoflurane could act advantageously for survival even of cancer cells. Therefore, we investigated the effects of sevoflurane on proliferation in colon cancer cell lines. METHODS: HCT116 and HT29 cells were plated in 96-well plates at a density of 1 x 10(4) cells/well and incubated overnight. On the next day, cells were exposed to 1% or 2% sevoflurane for 6 hr. After 24 hr recovery, we performed MTT assay. The absorbance of the formazan product was measured at a wavelength of 570 nm using 650 nm as the reference. In addition, to investigate the role of adenosine triphosphate-sensitive potassium (K(ATP)) channels, we conducted the same experiment under co-administration of K(ATP) inhibitor, glibenclamide. RESULTS: Only 1% sevoflurane significantly enhanced cell proliferation compared to the control in HCT116 and HT29 cells. Enhanced proliferation by sevoflurane was completely blocked by co-administration with glibenclamide in HCT116 cells. CONCLUSIONS: We had shown that 1% sevoflurane for 6 hr potentially enhances cell proliferation via K(ATP) channels in cancer cells. PMID- 26419096 TI - [The Effect of Preoperative Oral Rehydration on Hemodynamic Changes during Induction of Anesthesia and Intraoperative Fluid Management]. AB - BACKGROUND: Preoperative oral rehydration solution (ORS) prevents dehydration before surgery. Therefore taking enough ORS possibly reduces the hemodynamic changes during induction of anesthesia, and reduces the amount of fluid needed during anesthesia. METHODS: Forty patients undergoing elective surgery were randomly assigned to two groups: drinking 1,500 ml ORS 6 to 2 hours before anesthesia (ORS group) and nothing by mouth from 6 hours before anesthesia (Control group). Anesthesia induction was performed using propofol and remifentanil. To evaluate the hemodynamic changes, hemodynamic parameters including heart rate, blood pressure, cardiac index (CI), and stroke volume variation (SVV) were recorded before induction, after propofol administration, and after remifentanil administration. Total urine volume and the amount of fluid were also recorded at the end of the anesthesia. RESULTS: In ORS group, CI showed a significantly higher value after propofol administration (P = 0.046). SVV was significantly lower (P < 0.0001) and total amount of fluid during anesthesia was significantly reduced (P < 0.0001) in ORS group. CONCLUSIONS: Preoperative oral rehydration increases circulating blood volume, it keeps high CI during induction of anesthesia, and reduces the amount of intraoperative fluid. PMID- 26419098 TI - [Two Cases of Fetuses with Difficult Airway that Survived by the EXIT (Ex Utero Intrapartum Treatment) Procedure]. AB - We successfully managed two fetuses complicated with suspected airway obstruction after birth by the EXIT (ex utero intrapartum treatment) procedure, whose placental circulation was maintained till their airway was secured during the cesarean section. The first fetus was suspected to have airway obstruction due to a large neck mass. At 36 weeks of gestation, the EXIT procedure was undertaken performing the tracheal intubation successfully by laryngoscope. The second fetus with micrognathia was expected to have airway obstruction after birth. The EXIT procedure was undertaken at 35 weeks of gestation. The tracheal intubation by laryngoscope or by stylet scope was impossible, and the airway was secured by tracheostomy. The direct roles of anesthesiologists in the EXIT procedure are to let the uterus relax enough, deal with bleeding, and manage the fetal airway. The EXIT procedure is a specialized operation in which various specialists are involved, and a variety of judgments are necessary within a short time. Therefore, all concerned personnel should discuss previously to make a concensus on the processes during the procedure. The organization may be also an important role of the anesthesiologists in the EXIT procedure. PMID- 26419097 TI - [Effects of Anesthetics on Perioperative Short-term Outcomes in Patients Undergoing Thoracic Surgery with One-lung Ventilation]. AB - BACKGROUND: The present study was designed to evaluate the postoperative values such as body temperature (BT), white blood cells (WBC), P/F ratio and C-reactive protein (CRP) associated with propofol or sevoflurane in patients undergoing thoracic surgery with one-lung ventilation. METHODS: We retrospectively reviewed outcomes of patients undergoing video-associated thoracic surgery of the esophagus (VATS-E) with propofol (group P, n = 71) or sevoflurane (group S, n = 34). Data were taken at 1 POD and 2 POD in ICU. In addition, data of WBC and CRP were taken just before the operation and on 5 POD. Statistical analyses used t value and two-way ANOVA with statistic significance as P < 0.05. RESULTS: There was no significant difference between the two groups and we could not find the correlation between anesthetics and each factor. CONCLUSIONS: Propofol and sevoflurane had similar effect on BT, WBC, P/F ratio and CRP in patients undergoing thoracic surgery with one-lung ventilation. PMID- 26419099 TI - [Use and Safety of Preoperative Oral Rehydration Therapy Using a Jelly Type Oral Rehydration Solution]. AB - BACKGROUND: Traditionally, perioperative nutritional management centered on fluid therapy, but in recent years, with the spread of enhanced recovery after surgery (ERAS) protocols, the utility of oral rehydration therapy (ORT) has been reported. There are few reports, however, on the safety of using jelly type oral rehydration solutions for ORT. We examined the effects of OS-1 jelly on gastric fluid and investigated its safety. METHODS: A total of 147 patients (age range, 4 91 years), scheduled for elective surgery at our institution for whom ORT was indicated, were enrolled in this study. If the surgery was scheduled for the morning, patients were given two bottles of 200 g OS-1 jelly during the previous evening meal. If surgery was scheduled for the afternoon, two additional 200 g bottles were given to the patient with the morning meal on the day of surgery. Patients were allowed to drink water until two hours before the surgery. Gastric fluid was aspirated with a gastric tube after anesthesia induction, after which, volume and pH were measured. RESULTS: In all cases, gastric content was aspirated as a liquid, not a jelly. The volume and pH were 11.4 +/- 14.6 ml and 2.8 +/- 2.2, respectively. No major difference was seen in comparison with the data for OS-1 liquid. No postoperative aspiration pneumonia or reflux of gastric contents at the time of anesthesia induction was seen in any of the patients. CONCLUSIONS: From the present findings, if the time of water intake is strictly controlled, preoperative rehydration therapy using jelly-type oral rehydration solution is thought to be safe and comparable to liquid solution regarding its effects on gastric fluid. PMID- 26419100 TI - [Ultrasound Analysis of the Anatomical Relationships between Vertebral Arteries and Internal Jugular Veins in Adults]. AB - BACKGROUND: Accidental puncture of a vertebral artery can occur through the internal jugular vein during central venous catheterization. METHODS: We evaluated the anatomical relationships between vertebral arteries and internal jugular veins in one hundred adult patients under general anesthesia using echo image. RESULTS: The vertebral artery could be observed in all patients under the level of cricoid cartilage. Vertebral arteries ran in an outward direction toward the caudal side (3.9 mm lateral and 14.6 mm deep from the internal jugular vein : median). Mean width of vertebral artery was 4.2 mm. Because the width of central venous catheter guide wire is approx. 1 mm, accidental puncture of a vertebral artery can occur through the internal jugular vein during central venous catheterization. By the use of ultrasound analysis, the vertebral artery could be observed completely. CONCLUSIONS: It is important to identify the location of vertebral arteries under the level of cricoid cartilage and avoid the tap toward the lateral side. We can avoid accidental puncture of vertebral artery by taking care of these points. PMID- 26419101 TI - [A Clinical Comparison of Continuous Sciatic Nerve Block and Epidural Anesthesia for Postoperative Pain Control in Patients with Fracture of the Foot]. AB - BACKGROUND: Epidural analgesia provides good pain relief for patients with fracture of the foot Ultrasound-guided peripheral nerve block offers safety and efficacy without affecting the leg. METHODS: We compared the continuous sciatic nerve block with the continuous epidural anesthesia regarding postoperative pain after the open reduction and internal fixation (ORIF) of the ankle fracture or calcaneal bone fracture. RESULTS: Fifteen patients were included in the epidural group (group E), and 17 patients in the sciatic nerve block group (group S). The postoperative pain scores were significantly lower in group S 3 hours and 12 hours after the procedure, and tended to be lower in other periods. Perioperative periods were uneventful in both groups. CONCLUSIONS: Continuous sciatic nerve block developed good postoperative analgesia in ORIF of ankle fracture or calcaneal bone fracture compared with continuous epidural anesthesia. PMID- 26419102 TI - [Difficult Airway Management of a Patient with the Ossification of Anterior Longitudinal Ligament]. AB - We report a case of difficult airway management (DAM) with the ossification of anterior longitudinal ligament (OALL). A 66-year-old man complained of pharyngeal discomfort. He was diagnosed with OALL, and planned to have a surgery under general anesthesia. We expected DAM due to the limitation of cervical mobility and airway obstruction caused by OALL. We succeeded in awake intubation with video laryngoscope and tracheal tube introducer. PMID- 26419103 TI - [A Case of Postoperative Paraplegia Caused by Idiopathic Spinal Cord Infarction following Hepatectomy under Both General and Epidural Anesthesia]. AB - A 73-year-old woman (height : 155 cm, weight : 55 kg) was scheduled to undergo a laparotomic hepatectomy and radiofrequency ablation for hepatocellular carcinoma. Her medical history did not include any relevant conditions such as cardiovascular or neurological disorders. A thoracic epidural catheter was introduced at T8-9 before the induction of anesthesia with intravenous propofol. General anesthesia was maintained with the inhalation of oxygen, air, and desflurane, and the continuous infusion of remifentanil. Several intraoperative episodes of mild hypotension occurred, each of which was successfully treated with intravenous ephedrine, but otherwise her anesthetic course was uneventful, and she recovered from the anesthesia smoothly. Her postoperative pain was well controlled with continuous epidural infusion of levobupivacaine and fentanyl, and she could walk by herself on postoperative day (POD) 1. However, she suffered weakness in her lower extremities on POD2 and subsequently fell into complete paraplegia with sensory loss below the T4 level on POD3. A magnetic resonance imaging scan taken on POD4 showed an idiopathic spinal cord infarction (SCI) involving levels T1 through T4, although no epidural abnormalities, e.g., hematomas, were detected. Immediate treatment with methylprednisolone, ozagrel, and edaravone failed to resolve her symptoms. We suggest that it is of great importance to consider SCI as a differential diagnosis as soon as possible in cases of unanticipated postoperative paraplegia. PMID- 26419104 TI - [Anesthesia for Patients with Obstructive Sleep Apnea Syndrome Associated with Severe Obesity]. AB - A 41-year-old woman with concomitant severe obesity, obstructive sleep apnea syndrome, and asthma was scheduled for endoscopic cholecystectomy. She was 165.8 cm tall and weighed 141.2 kg, with BMI of 51.4. We were concerned with difficulty in ventilation and intubation at the time of anesthesia induction and intra- and post-operative ventilatory failure. After sedation with fentanyl and droperidol together with intraoral local anesthesia with lidocaine (Xylocaine Viscous), the intubating laryngeal mask (ILMA) was inserted while awake, and after the confirmation of adequate ventilation, the bronchoscope was inserted into the guide. Although she received no nerve block, she did not choke at the time of intubation. Because of airway pressure elevation during surgery, volume controlled ventilation was changed to pressure-controlled ventilation, and, because of a worsening P/F ratio, the recruitment procedure was performed during surgery, with a consequent improvement in the ratio. Although the use of the reservoir and NPPV equipment after extubation was considered, her respiratory status was stable, and she returned to her room with oxygen mask. PMID- 26419105 TI - [Desflurane Anesthesia in a Morbidly Obese Patient with Severe Obstructive Sleep Apnea]. AB - A 33-year-old morbidly obese patient (body mass index = 59.5 kg x m(-2)) with severe obstructive sleep apnea was scheduled to undergo osteosynthesis of right radial, ulnar and femoral fractures under general anesthesia. Awake intubation under conscious sedation using fantanyl and midazolam was performed by the Pentax AWS Airwayscope. By using desflurane under continuous infusion of remifentanil 0.2-0.5 MUg x kg(-1) x min(-1), BIS values were maintained between 40 and 60 during the surgery. Although duration of surgery was long (430 minutes), the times from discontinuation of the anesthetic drug to eye opening and extubation were 82 seconds and 8.5 minutes, respectively. Respiratory depression was minimal during postoperative period. In this case desflurane was safely used in a morbidly obese patient with severe obstructive sleep apnea. PMID- 26419106 TI - [A Case of a Severely Burned Patient with Suspected Takotsubo Cardiomyopathy Who Underwent Immediate Excision and Skin Grafting under General Anesthesia]. AB - An 88-year-old woman was severely burned on her thigh, leg, arm, buttocks, chest and abdomen in the bathroom and was emergently admitted to our hospital. The burn index was 10.8 and the prognostic burn index (PBI) was 99. The reports of echocardiography, cardiac biomarkers and electrocardiogram showed left ventricular dysfunction with apical akinesis, which was suspected as Takotsubo cardiomyopathy. To avoid poor prognosis because of severe PBI, immediate excision and skin grafting were performed under general anesthesia 23 hours after the burn onset. More infusion and transfusion than the expected amounts were needed during anesthesia and the postoperative 4 days because of cardiac failure and septic shock, which were overcome 14 days after the surgery. The complete early excision was impossible due to cardiac failure, and that the unexcised burn scar exacerbated infection and prevented her from survival. PMID- 26419107 TI - [Anesthetic Management of a Patient Complicated with Marfan Syndrome and Suffering from Stanford Type A Aortic Dissection during Pregnancy]. AB - We report a case of a 36-year-old woman at 34 weeks of gestation complicated with Marfan syndrome who underwent Bentall type aortic replacement surgery due to Stanford type A aortic dissection after undergoing caesarean section. Since this patient exhibited severe hypotension before coming to the operating room, it was very difficult to determine whether the cardiac surgery or caesarean section should be performed first. In this case, the caesarean section was performed first, followed by Bentall's surgery. Although intra-aortic balloon pumping and percutaneous cardiopulmonary support were required after weaning from the cardiopulmonary bypass, she was discharged on post-operative day (POD) 40 and the baby was discharged on POD 60, without signs of cerebral palsy. Unfortunately, this patient died on POD 57, due to heart failure. We discuss how to determine the priority of surgeries for patients who require emergency surgery for cardiovascular disease during pregnancy. PMID- 26419108 TI - [Anesthetic Management of an Adult Patient Complicated with Tricuspid Atresia Maladapted for Fontan Operation Who Underwent Laparoscopic Cholecystectomy]. AB - With the advance of diagnosis and therapeutic management for congenital heart disease, increasing numbers of the non-cardiac surgery were performed on patients with post-cardiac surgery, such as the radical operations and Fontan operation. However, there are adult patients who have not received Fontan operation lacking indication. We experienced a case of adult surgical patient for laparoscopic cholecystectomy complicated with tricuspid atresia who was not indicated for Fontan surgery. A 28-year-old man diagnosed with cholecystolithiasis was scheduled for laparoscopic cholecystectomy. He had undergone bidirectional Glenn and Blalock-Taussig shunt, but not undergone Fontan surgery for hypoplasia of the pulmonary artery and low left ventricular function. To reduce the influence of intraabdominal pressue on hemodynamics, the insufflations pressure was maintained at 8 mmHg during pneumoperitoneum. To assist ventricular function, dopamine and carperitide were administered perioperatively. We should carefully manage such a patient during perioperative period by understanding the hemodynamic state and considering the influence of pneumoperitoneum and posture. PMID- 26419109 TI - [Anesthetic Management for Laparoscopic Surgery in a Very Elderly Patient with Severe Mitral Regurgitation]. AB - A 90-year-old woman with severe mitral regurgitation underwent laparoscopic cholecystectomy. In her anesthetic management, we used FloTrac system and monitored arterial pressure-based cardiac index (CI), stroke volume (SV), and stroke volume variation (SVV) continuously as the indicators of intraoperative hemodynamics. Although the blood pressure fluctuated highly in Fowler position especially, we could control hemodynamics appropriately by intermittent volume infusion and adjusting administration of cardiovascular agents under monitoring these indicators. In a very elderly patient with severe mitral regurgitation, anesthesia and operation may cause severe circulatory disturbances. Therefore, it is important to select proper monitoring as stated above and maintain hemodynamics with the utmost care and attention. PMID- 26419110 TI - [Persistent Disturbance of Consciousness after Clipping of an Unruptured Cerebral Aneurysm due to Pseudohypoxic Brain Swelling]. AB - A patient developed persistent disturbance of consciousness after uneventful clipping of an unruptured cerebral aneurysm under general anesthesia. Pseudohypoxic brain swelling (PHBS) was suspected because computerized tomography (CT) and magnetic resonance imaging (MRI) revealed diffuse brain swelling, especially in the bilateral basal ganglia and thalami. Steroid pulse therapy in addition to antiedematous drugs and anticonvulsant improved the consciousness. Anesthesiologists should pay attention to PHBS in a case of persistent disturbance of consciousness after uneventful craniotomy. PMID- 26419111 TI - [Two Separate Instances of Anesthetic Management in a Patient Initially Diagnosed with Stiff-person Syndrome]. AB - In this case report, we describe separate instances of general anesthetic management administered to a patient during treatment for two unrelated conditions. The patient, a 57-year-old woman who had been experiencing walking difficulties for about four years, fell down because of muscle rigidity and spasms and fractured her humerus. She was subsequently diagnosed with stiff person syndrome. The fracture was treated conservatively, but three weeks later the alignment of the humerus became worse and the patient was scheduled to undergo an open reduction and internal fixation under general anesthesia (GA). Anesthesia was induced using propofol and fentanyl, and rocuronium was given for the tracheal intubation. The operation was completed successfully while anesthesia was maintained using sevoflurane and remifentanil without incident Four months later, the patient developed paraneoplastic syndrome stemming from breast cancer, and underwent a resection of the cancer under GA. The patient received propofol for the laryngeal mask insertion, and sevoflurane and pentazocine for maintenance of anesthesia. She was discharged from the hospital without any respiratory or airway problems. We used sevoflurane for maintenance of anesthesia on both occasions, and rocuronium for the first tracheal intubation. The patient's hemodynamics were stable during the operation. No prolonged effect of the muscle relaxant or any autonomic reactions were observed. The patient was fully conscious and in good respiratory condition after both surgeries, and was extubated in the operating room. There were no perioperative complications. PMID- 26419112 TI - [Anesthetic Management for a Patient with Fibromyalgia]. AB - A 22-year-old female with fibromyalgia (FM) was scheduled for tonsillectomy under general anesthesia. Her medication included pregabalin 300 mg x day(-1) and dantrolene 50 mg x day(-1). Anesthesia was maintained with sevoflurane remifentanil-fentanyl. Intravenous injection of fentanyl 20 MUg x hr(-1) and droperidol 100 MUg x hr(-1) was continued for 24 hours. On the first postoperative day, she reported that she had slept well and had no pain. There are some perioperative problems in a patient with FM. Therefore, anesthetic managements for a patient with FM is worth reporting. PMID- 26419113 TI - [A Case of Liver Contusion during Spinal Operation for Idiopathic Scoliosis]. AB - A 20-year-old man diagnosed as idiopathic scoliosis with Cobb angle 146 degrees was scheduled for two-stage operations. Anterior dissection of the thoracic vertebra in the left lateral decubitus position, and the placement of pedicle screws in the prone position were performed as the first-stage operation. During surgery, the patient developed liver contusion with ascites, probably due to hepatic compression placed between vertebrae and operating table in the prone position. In the second operation for posterior spinal fusion, the occurrence of liver contusion was prevented by performing abdominal ultrasonography before and after surgery, and monitoring AST/ALT during anesthesia as the indicators of liver contusion. Intraoperative management for organ protection is required during anesthesia in patients with idiopathic scoliosis associated with thoracic deformity. PMID- 26419114 TI - [Perioperative Management of a Patient with Hereditary Angioedema: A Case Report]. AB - Hereditary angioedema (HAE) is a very rare disease that occurs in about 1 in 50,000 to 150,000 people. HAE is caused by low levels or inproper function of the plasma protein C1 inhibitor (C1-INH) which regulates activation of the complement system and the coagulation system. The typical symptom of HAE is regional swellings without pain nor itching, usually triggered by physical trauma or emotional stress. Unlike allergic edema, HAE attacks do not respond to antihistamines, corticosteroids noradrenaline. The swelling attacks against face and throat are potentially life-threatening, and should be treated as a medical emergency. We report a patient with HAE who underwent radical cystectomy of the upper gum under general anesthesia. Because the oral surgery with tracheal intubation is known to be a risk factor of laryngeal edema in a patient with HAE, she was given C1-INH before operation to prevent laryngeal edema according to HAE Guideline 2010 by the Japanese Association for Complement Research. Her pharynx and larynx were checked with Airwayscope before intubation and with bronchofiberscope before extubation, but no edema was recognized. Postoperatively, she was given C1-INH on the next morning again. She was discharged seven days after operation without any complications. PMID- 26419115 TI - [Anesthetic Management of a Patient with Langerhans Cell Histiocytosis during Cesarean section]. AB - Langerhans cell histiocytosis is a rare disease, associated with histiocyte increases, and granuloma, in various organs. About 160 patients are reported in Japan. A pregnant patient with a pulmonary Langerhans cell histiocytosis underwent cesarean section under spinal anesthesia. She had repeated pneumothorax with bilateral pulmonary cysts rapidly becoming worse during pregnancy. She was treated with continuous oxygen after 28 weeks of the pregnancy. On 34 weeks of the pregnancy, spinal anesthesia with 0.5% hyperbaric bupivacaine (2 ml) and fentanyl (25 MUg) for cesarean section was performed, and provided excellent analgesia without any side-effects. PMID- 26419116 TI - [Successful Management of Cardiopulmonary Bypass Using Heparin in a Patient with Previous History of Heparin-induced Thrombocytopenia]. AB - Anti-coagulant management of cardiopulmonary bypass for the patient complicated with heparin-induced thrombocytopenia (HIT) is difficult. A woman of late 50's with a previous history of HIT was scheduled for mitral valve replacement, tricuspid valvuloplasty and coronary artery bypass graft. We knew that heparin antibody was negative by serologic and functional assay before the operation. According to the HIT guideline, we planned to use heparin only during cardiopulmonary bypass and to use argatroban for other catheters. Although the platelet count continued decreasing up to the 5th postoperative day unless the transfusion of platelets, heparin antibody was negative on the first postoperative day. But, it was thought that HIT would develop from 5 days to 10 days after using heparin. Therefore, we had to examine heparin antibody on the 5th postoperative day at least for the patients with a history of HIT. In the future, it is important to observe the patient carefully and examine heparin antibody. PMID- 26419117 TI - [Treatment of Tension Pneumothorax during Total Right Breast Extirpation and Reconstruction with a Flap of the Latissimus Dorsi Muscle]. AB - A patient developed tension pneumothorax during surgery. A 56-year-old woman with right breast cancer and axillary gland metastasis, was to undergo total right breast extirpation/axillary gland dissection, flap collection from the latissimus dorsi muscle, and reconstruction with this flap. During total right breast extirpation/axillary gland dissection, there were no problems, but the arterial blood oxygen saturation (SpO2) fell after the start of flap collection. After the start of reconstruction, SpO2 was reduced again. In the right lung field, no respiratory sound was heard, and chest X-ray showed right tension pneumothorax. A right thoracic drain was inserted and surgery was completed as scheduled. Thoracic CT did not reveal any abnormal findings, such as a brassiere, the day after surgery. PMID- 26419118 TI - Multi-Level, Multi Time-Scale Fluorescence Intermittency of Photosynthetic LH2 Complexes: A Precursor of Non-Photochemical Quenching? AB - The light harvesting complex LH2 is a chromoprotein that is an ideal system for studying protein dynamics via the spectral fluctuations of the emission of its intrinsic chromophores. We have immobilized these complexes in a polymer film and studied the fluctuations of the fluorescence intensity from individual complexes over 9 orders of magnitude in time. Combining time-tagged detection of single photons with a change-point analysis has allowed the unambigeous identification of the various intensity levels due to the huge statistical basis of the data set. We propose that the observed intensity level fluctuations reflect conformational changes of the protein backbone that might be a precursor of the mechanism from which nonphotochemical quenching of higher plants has evolved. PMID- 26419125 TI - Race equality initiative leaves nowhere to hide. PMID- 26419119 TI - Serum uric acid: a new therapeutic target for nonalcoholic fatty liver disease. AB - INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is a major, worldwide public health problem. NAFLD is recognized as a major cause of liver-related morbidity and mortality. However, physicians are currently limited by available treatment options. Recently, numerous studies have reported a correlation between serum uric acid (SUA) and NAFLD with numerous clinical and experimental studies demonstrating a significant correlation. This review will focus on the role of SUA in the development of NAFLD and its potential role as a new target for therapeutic intervention. AREAS COVERED: This review discusses SUA as a significant independent factor in the development of NAFLD. Moreover, we introduce the causal relationship between SUA, metabolic syndrome, and NAFLD. We discuss two major theories of insulin resistance and inflammasomes as potential explanations of the mechanistic link between SUA and NAFLD. In addition, we review current and emerging therapeutic medications to control appropriate SUA levels. EXPERT OPINION: There is an urgent need to develop novel, safe and effective therapies for the growing NAFLD epidemic. Reduction of SUA may be a promising potential treatment for patients with NAFLD. Clinical studies are required to determine the therapeutic effect of attenuation of hyperuricemia in humans with NAFLD. PMID- 26419126 TI - Stepping back into the operating theatres of bygone times. PMID- 26419127 TI - CPD requirement could remain at 35 hours in bid to reduce costs. PMID- 26419129 TI - RCN director spearheads campaign to protect paid time off for union reps. PMID- 26419130 TI - Survey reveals specialist talent not being nurtured. [Corrected]. PMID- 26419128 TI - Staff concerns about pay are 'falling on deaf ears'. PMID- 26419131 TI - Experts' letter to CNO highlights key issues for safe staffing guidance. PMID- 26419132 TI - Military nurse closer to home. PMID- 26419133 TI - Rejected immigration requests causing 'desperate' staff shortages. PMID- 26419134 TI - A helping hand for Hollywood. PMID- 26419135 TI - Cambridge trust rated inadequate. PMID- 26419136 TI - New online resource for budding school nurses. PMID- 26419138 TI - Why nurses should think twice before using terms of endearment. PMID- 26419144 TI - Pain. PMID- 26419145 TI - 'We're beating the BME bias'. PMID- 26419146 TI - Race and the NHS--a chance for change. PMID- 26419147 TI - Be aware and beat the odds. PMID- 26419157 TI - Change4Life. PMID- 26419158 TI - St John Ambulance First Aid. PMID- 26419160 TI - Support Alzheimer's patients in petition against cheap headlines. PMID- 26419161 TI - Short-term pain of union action may bring long-term gain for all. PMID- 26419164 TI - We can do more to reduce anxiety surrounding breastfeeding. PMID- 26419162 TI - Direct care target an admirable aim, but Mr Hunt won't help us achieve it. PMID- 26419165 TI - Snapshot of a career reveals how much the NHS has changed. PMID- 26419168 TI - How to measure tracheostomy tube cuff pressure. PMID- 26419169 TI - Disability discrimination in healthcare services and employment. AB - This article discusses the meaning and philosophical basis of disability discrimination in health care. It focuses on aspects of language that influence discourse about disability and affect the experiences of people with disabilities. Reference is made to the experiences of those who have an autism spectrum condition, with a specific focus on three NHS employees with Asperger syndrome, in relation to disability discrimination. The implications for nurses and nursing are discussed. Recommendations are made for awareness raising and training. PMID- 26419170 TI - The PEARL programme: caring for adults living with dementia. AB - Caring for people living with dementia in care homes requires training in best dementia care practice and person-centred care. This article describes the main interventions and processes that have been adopted by Four Seasons Health Care, an independent provider of residential care homes and care homes with nursing in the UK, to develop its homes into centres of excellence for dementia care. It provides an overview of the PEARL (Positively Enriching And enhancing Residents Lives) programme, which has been found to reduce antipsychotic medication use, depression scores and pain, and improve patient wellbeing. PMID- 26419171 TI - Assessing sexual health in mental health service users. AB - This article encourages the reader to consider sexuality and sexual health as essential to a full nursing assessment. It discusses the reasons why nurses should be more open in consultations with mental health service users in regard to sexual health. A step-by-step model that assists nurses in their interventions with service users on issues of sexuality is explored, and each stage of the model is explained. Although predominantly directed at mental health nurses, the main principles in this article could be adapted and applied to other care contexts, such as adult nursing. PMID- 26419172 TI - Concept mapping. PMID- 26419173 TI - Not so 'hard to reach'. PMID- 26419175 TI - The long road to equality. PMID- 26419176 TI - A chance to sell yourself. PMID- 26419177 TI - Remember to take notes... and ask plenty of questions. PMID- 26419178 TI - Daunting, yes. But great fun too. PMID- 26419179 TI - Welcome to our tough, rewarding profession--we're rooting for you. PMID- 26419180 TI - Budget early for success. PMID- 26419181 TI - Perfect planning for general practice placements. PMID- 26419182 TI - A crash course in grief. PMID- 26419183 TI - RCN Membership: what's in it for you? PMID- 26419184 TI - Making the most of the student-mentor clinical partnership. PMID- 26419185 TI - Take a good look at yourself. PMID- 26419186 TI - 'It is great to work with such a top team'. PMID- 26419187 TI - Musculoskeletal injuries in physical education versus non-physical education teachers: a prospective study. AB - Physical education (PE) teachers have a physically demanding job, putting them at a considerable risk for musculoskeletal injuries. To structurally develop tailored injury prevention programmes for PE teachers, a clear understanding of the extent, characteristics and underlying factors of their musculoskeletal injuries compared to referents is necessary. Therefore, the current study prospectively followed 103 PE teachers and 58 non-PE teachers, who registered musculoskeletal injuries and time of exposure to sports participation during one school year. Pearson chi(2)-tests and independent samples t-tests determined significant differences between PE and non-PE teachers regarding demographics and variables possibly related to injury occurrence. PE teachers had 1.23 and non-PE teachers 0.78 injuries/teacher/school year. This difference was significantly different after adjustment for hours spent weekly on intracurricular teaching during the career and for injury history during the preceding six months (P = 0.009; OR = 0.511; 95% CI = 0.308-0.846). PE teachers' most affected body parts were the knee and the back. PE teachers had a more extensive injury history (P < 0.001), a higher work- (P < 0.001) and sport index (P < 0.001), practiced more sports (P < 0.002) and taught more extracurricular sports (P = 0.001). Future injury prevention programmes should take account for the great injury history and heavy physical load in PE teachers. PMID- 26419188 TI - Highly Reliable Silver Nanowire Transparent Electrode Employing Selectively Patterned Barrier Shaped by Self-Masked Photolithography. AB - The transparent electrode based on silver nanowire (AgNW) networks is one promising alternative of indium tin oxide film in particular for advanced flexible and printable electronics. However, the widespread application of AgNW electrode is hindered by its poor long-term reliability. Although the reliability can be improved by applying traditional overcoating layer or the core-shell structure, the transmittance or conductivity is inevitably undermined. In this paper, a novel patterned barrier of photoresist in situ assembled on the nanowire surface realized the reliability enhancement by simply employing AgNWs themselves as the mask in the photolithography process. The patterned barrier selectively covered the nanowires, while keeping the high transmittance and conductivity unchanged and improving the adhesion of AgNW networks on substrate. After 720 h storage in 85 degrees C/85% relative humidity (RH) environment, the resistance of electrode with patterned barrier only increased by 0.72 times. This study proposes a new way, i.e., the in situ patterned barrier containing light sensitive substance, to selectively protect AgNW networks, which can be expanded to various metallic networks including nanowires, nanorods, nanocables, electrospun nanofibers, and so on. PMID- 26419189 TI - Monitoring the Response of the Human Urinary Metabolome to Brief Maximal Exercise by a Combination of RP-UPLC-MS and (1)H NMR Spectroscopy. AB - The delineation of exercise biochemistry by utilizing metabolic fingerprinting has become an established strategy. We present a combined RP-UPLC-MS and (1)H NMR strategy, supplemented by photometric assays, to monitor the response of the human urinary metabolome to short maximal exercise. Seventeen male volunteers performed two identical sprint sessions on separate days, consisting of three 80 m maximal runs. Using univariate and multivariate analyses, we followed the fluctuation of 37 metabolites at 1, 1.5, and 2 h postexercise. 2 Hydroxyisovalerate, 2-hydroxybutyrate, 2-oxoisocaproate, 3-methyl-2-oxovalerate, 3-hydroxyisobutyrate, 2-oxoisovalerate, 3-hydroxybutyrate, 2-hydroxyisobutyrate, alanine, pyruvate, and fumarate increased 1 h postexercise and then returned toward baseline. Lactate and acetate were higher than baseline at 1 and 1.5 h. Hypoxanthine and inosine remained above baseline throughout the postexercise period. Urate decreased at 1 h and increased at 1.5 h before returning to baseline. Valine, isoleucine, succinate, citrate, trimethylamine, trimethylamine N-oxide, tyrosine, and formate decreased at 1 h and/or 1.5 h postexercise and then returned to baseline. Creatinine gradually decreased over the sampling period. Glycine, 4-aminohippurate, and hippurate remained below baseline throughout the postexercise period. Our findings show that even one-half minute of maximal exercise elicited major perturbations in human metabolism, several of which persisted for at least 2 h. PMID- 26419190 TI - The importance of triaging in determining the quality of output from high throughput screening. PMID- 26419191 TI - Minimal systemic and high faecal exposure to cadazolid in patients with severe Clostridium difficile infection. AB - Cadazolid is under development as an oral treatment for Clostridium difficile infection (CDI), which is the most common infectious cause of antibiotic associated diarrhoea. Low systemic cadazolid exposures were previously reported in healthy subjects following both single and multiple oral dosing. The main objective of this study was to investigate systemic cadazolid exposure in patients with severe CDI with potential disrupted lining of the gastrointestinal tract. A single 3000 mg oral dose of cadazolid was administered to six patients with microbiologically-confirmed severe CDI. Plasma and faeces were collected up to 144 h post-dose for determination of cadazolid concentrations. Safety assessments were conducted over the 144-h investigational period. Cadazolid was well tolerated in patients with severe CDI, with no reported drug-related adverse events. Cadazolid systemic exposure following a single 3000 mg oral dose was very low, with a peak plasma concentration (C(max)) of 2.64 ng/mL and an area under the concentration-time curve (AUC(0-144)) of 125 ng*h/mL. The median peak daily faecal cadazolid concentration was 5675 times the C. difficile MIC(90) of 0.25 mg/L. In subjects with severe CDI, cadazolid systemic exposure was very low following a single high oral dose. Cadazolid plasma concentrations were similar in magnitude to those previously reported for healthy subjects, whereas total systemic exposure was ca. 5-6 times higher, but was still low. Peak daily faecal cadazolid concentrations were 5675 times the 0.25 mg/L C. difficile MIC(90), and on Day 4 five of the six patients presented a daily faecal cadazolid concentration >=1651 times the MIC(90) [ClinicalTrial.gov ID: NCT02053181]. PMID- 26419192 TI - Spontaneous electric fields in solid carbon monoxide. AB - Reflection-absorption infrared spectroscopy (RAIRS) is shown to provide a means of observing the spontelectric phase of matter, the defining characteristic of which is the occurrence of a spontaneous and powerful static electric field within a film of material. The presence of such a field is demonstrated here through the study of longitudinal-transverse optical splitting in RAIR spectra in films of carbon monoxide, based upon the deposition temperature dependence of this splitting. Analysis of spectral data, in terms of the vibrational Stark effect, allows the measurement of the polarization of spontelectric films, showing for example that solid carbon monoxide at 20 K may maintain a spontelectric field of 3.78 * 10(7) V m(-1), representing a polarization of 3.34 * 10(-4) cm(-2). We comment on the astrophysical implications of polarized carbon monoxide ices, on the surface of cosmic grains in star-forming regions. PMID- 26419193 TI - Psychiatry is a clinical neuroscience, but how do we move the field? PMID- 26419194 TI - A method comparison of a food frequency questionnaire to measure folate, choline, betaine, vitamin C and carotenoids with 24-h dietary recalls in women of reproductive age. AB - BACKGROUND/OBJECTIVES: The objective of this study was to conduct a method comparison of a modified food frequency questionnaire (FFQ), designed to estimate usual dietary intake of selected micronutrients and antioxidants including folate, choline, betaine, vitamin C and carotenoids (alpha-carotene, beta carotene, lutein, lycopene and beta-cryptoxanthin) with 24-h dietary recalls (24 HR) in women of reproductive age. SUBJECTS/METHODS: Sixty-four British women of reproductive age (18-40 years) were recruited in Oxford, UK and provided complete dietary data for analysis. METHODS: We compared micronutrient estimates from the FFQ against estimates derived from three multiple-pass, 24-HR interviews, by evaluating Pearson's correlation coefficients and Bland-Altman plots. RESULTS: Median intakes of most nutrients were higher when measured by FFQ compared with 24-HR. Strong correlation coefficients were observed for folate (r=0.80) and choline (r=0.68), whereas moderate correlation coefficients were observed for vitamin C (0.50) and lycopene (0.43). Weak correlation coefficients were observed for betaine (0.39) and other carotenoids (r=0.26-0.38). Bland-Altman plots indicated that there was a large amount of variability in the FFQ estimates of nutrient intakes compared to those using 24-HR, particularly for carotenoids. CONCLUSIONS: The findings indicate that this FFQ estimated higher mean intakes for most nutrients. Pearson's correlation coefficients were comparable with previous research; however, the Bland-Altman plots suggest a high variability in mean nutrient estimates between the FFQ and 24-h. We recommend further investigation of the validity of this FFQ before use. PMID- 26419195 TI - Body mass index, body fat and risk factor of relapse in anorexia nervosa. AB - BACKGROUND/OBJECTIVES: Preliminary studies have reported an association between poor long-term outcome and lower total body fat percentage in weight-restored inpatients treated for anorexia nervosa (AN). A possible link between poor long term outcome and higher trunk fat percentage has also been hypothesized. The aim was to assess the association between percentage and distribution of body fat at inpatient discharge and the maintenance of normal weight at 1-year follow-up in a sample of weight-restored females with AN. SUBJECTS/METHODS: Fifty-four short term weight-restored (body mass index (BMI; in kg/m(2)) ?18.5) adult females with AN treated in a specialist inpatient unit underwent dual-energy X-ray absorptiometry to determine total body fat and trunk fat percentages. Patients were contacted regularly following discharge, and at the end of the year clinical outcome was dichotomized as either 'full, good or fair' (a group that includes individuals with a BMI ?18.5 kg/m(2)) or 'poor' (BMI<18.5 kg/m(2)), using the modified Morgan-Russell criteria. RESULTS: No significant differences were found between 'full, good or fair' and 'poor' outcome groups in either total body fat or trunk fat percentages. Only lower BMI at inpatient discharge was associated with poor clinical outcome in the year following inpatient treatment. CONCLUSIONS: In short-term weight-restored adult females with AN, BMI, but not body fat percentage or distribution, at inpatient discharge is associated with long-term normal weight maintenance. PMID- 26419196 TI - Unprocessed red meat and processed meat consumption and risk of stroke in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC). AB - BACKGROUND/OBJECTIVES: High intakes of unprocessed red or processed meat may increase the risk of stroke. We aimed to examine the association between unprocessed red meat, processed meat and total red meat consumption and risk of total stroke and ischaemic stroke. SUBJECTS/METHODS: Cox proportional hazards regression analyses were conducted based on the data for 41,020 men and women aged 29-69 years at baseline. RESULTS: During a mean follow-up of 13.8 years, 674 incident cases of stroke (531 ischaemic strokes, 79 haemorrhagic strokes, 42 subarachnoid haemorrhages and 22 mixed or unspecified events) were identified. After multiple adjustment, unprocessed red meat, processed meat and total red meat consumption were not correlated with incidence of total stroke or ischaemic stroke in either men or women. The hazard ratios (HRs) for unprocessed red meat and processed meat and risk of total stroke comparing the highest with the lowest quintiles were, respectively, 0.81 (95% confidence interval (CI) 0.54-1.21; P trend=0.15) and 0.92 (95% CI 0.64-1.32; P-trend=0.82) in men and 1.21 (95% CI 0.79-1.85; P-trend=0.10) and 0.81 (95% CI 0.51-1.27; P-trend=0.17) in women. The HRs for unprocessed red meat and processed meat and risk of ischaemic stroke were, respectively, 0.80 (95% CI 0.51-1.25; P-trend=0.51) and 0.86 (95% CI 0.57 1.29; P-trend=0.77) in men and 1.24 (95% CI 0.74-2.05; P-trend=0.13) and 0.82 (95% CI 0.47-1.42; P-trend=0.31) in women. CONCLUSIONS: In the Spanish European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, unprocessed red meat and processed meat consumption were not associated with risk of stroke in men or women. PMID- 26419197 TI - Breast milk composition and infant nutrient intakes during the first 12 months of life. AB - BACKGROUND/OBJECTIVES: The objective of this study was to quantify human milk supply and intake of breastfed infants up to age 12 months. In addition, human milk composition was quantified per energetic macronutrient and fatty-acid composition in a subsample of lactating mothers. SUBJECTS/METHODS: One hundred and seventy-four Italian breastfed children were followed using test-weighing and 3-day food protocols from birth to age 12 months. From a subsample of 30 mothers breast milk samples were collected at child ages one (T1), two (T2), three (T3) and six (T6) months, and were analyzed for the amount of protein, digestible carbohydrates, total lipids and fatty-acid composition. RESULTS: One hundred and forty-two (82%) filled in at least one 3-day food protocol within the first 12 months of life and complied with test-weighing of all milk feeds. The number of valid food protocols declined from 126 infants at 1 month to 77 at 12 months of age. Only galactose, non-protein nitrogen and protein decreased significantly from age 1 to age 6 months of lactation. Maternal body mass index and age affected fatty-acid levels in human milk. Median human milk intake decreased from 625 ml at T1, over 724 ml at T3 to 477 ml/day at T6. Average energy and %energy from protein intake per day increased from 419 kcal (s.d. 99) and 8.4% (1.0) at T1, respectively, to 860 kcal (145) and 16.1% (2.6) at T12. CONCLUSIONS: These data provide a reference range of nutrient intakes in breastfed infants and may provide guidance for defining optimal nutrient intakes for infants that cannot be fully breastfed. PMID- 26419198 TI - Similar protective immunity induced by an inactivated enterovirus 71 (EV71) vaccine in neonatal rhesus macaques and children. AB - During the development of enterovirus 71 (EV71) inactivated vaccine for preventing human hand, foot and mouth diseases (HFMD) by EV71 infection, an effective animal model is presumed to be significant and necessary. Our previous study demonstrated that the vesicles in oral regions and limbs potentially associated with viremia, which are the typical manifestations of HFMD, and remarkable pathologic changes were identified in various tissues of neonatal rhesus macaque during EV71 infection. Although an immune response in terms of neutralizing antibody and T cell memory was observed in animals infected by the virus or stimulated by viral antigen, whether such a response could be considered as an indicator to justify the immune response in individuals vaccinated or infected in a pandemic needs to be investigated. Here, a comparative analysis of the neutralizing antibody response and IFN-gamma-specific T cell response in vaccinated neonatal rhesus macaques and a human clinical trial with an EV71 inactivated vaccine was performed, and the results showed the identical tendency and increased level of neutralizing antibody and the IFN-gamma-specific T cell response stimulated by the EV71 antigen peptide. Importantly, the clinical protective efficacy against virus infection by the elicited immune response in the immunized population compared with the placebo control and the up-modulated gene profile associated with immune activation were similar to those in infected macaques. Further safety verification of this vaccine in neonatal rhesus macaques and children confirmed the potential use of the macaque as a reliable model for the evaluation of an EV71 candidate vaccine. PMID- 26419199 TI - Enhancement of long-lasting immunoprotective effect against Androctonus australis hector envenomation using safe antigens: Comparative role of MF59 and Alum adjuvants. AB - Envenomation is a public health problem in many regions of the world. The only available treatment is the serotherapy that has limited efficiency due to the delay of its administration. The goal of this study is to provide a new and more efficient alternative to this treatment. A comparative study of the effects of two adjuvants in their ability to enhance the efficiency of the detoxified and safe antigens to produce a long lasting immunoprotection is undertaken using Aluminum Hydroxide adjuvant (Alum) or the water-in-oil MF59 adjuvant mixed with Androctonus australis hector (Aah) detoxified venom, and compare their effects on the immune system. Immunization schedule was performed with two groups of rabbits, which were injected with attenuated venom and Alum or MF59 adjuvant preparations, once a month during three months. Blood samples were collected each week for cell count, evaluation of myeloperoxidase (MPO) and eosinoperoxydase (EPO) activities and antibody titer. After four months from the last immunization, rabbits were challenged with increased doses of native Aah venom. Results showed that MF59 effect was immediate in the first 24h post-immunization by activating the recruitment of lymphocytes, monocytes and neutrophils, while Alum adjuvant effect seems to be delayed, and appeared in the second week after immunization. An important cell infiltration was observed with Alum preparation, due to its specific local depot effect. However, immunized animals with MF59 preparation challenged with the native venom showed a protective effect against its toxicity until 6 LD50 compared to those immunized with Alum preparation which are only protected at 4 LD50. One week after challenge, only immunized animals with Alum preparation present an increase in cell infiltration, MPO and EPO activities. These results are correlated with the ability of MF59 adjuvant to induce a potent immunoprotective effect against Aah venom compared to Alum adjuvant. PMID- 26419201 TI - Mechanism-Driven Elaboration of an Enantioselective Bromocyclopropanation Reaction of Allylic Alcohols. AB - A stereoselective bromocyclopropanation of allylic alcohols using dibromomethylzinc bromide is described. Spectroscopic studies to monitor the formation of transient intermediates not only led to the development of a more atom-economical halocyclopropanation reaction, but also highlighted the unique role of ether additives in the process. The desired bromo-substituted cyclopropanes were isolated in high yields and excellent diastereo- as well as enantioselectivities using readily available reagents. PMID- 26419200 TI - Simultaneous MR imaging for tissue engineering in a rat model of stroke. AB - In situ tissue engineering within a stroke cavity is gradually emerging as a novel therapeutic paradigm. Considering the varied lesion topology within each subject, the placement and distribution of cells within the lesion cavity is challenging. The use of multiple cell types to reconstruct damaged tissue illustrates the complexity of the process, but also highlights the challenges to provide a non-invasive assessment. The distribution of implanted cells within the lesion cavity and crucially the contribution of neural stem cells and endothelial cells to morphogenesis could be visualized simultaneously using two paramagnetic chemical exchange saturation transfer (paraCEST) agents. The development of sophisticated imaging methods is essential to guide delivery of the building blocks for in situ tissue engineering, but will also be essential to understand the dynamics of cellular interactions leading to the formation of de novo tissue. PMID- 26419203 TI - Foxp3-expressing sensitized Teff cells prolong survival of corneal allograft in corneal allograft transplantation mouse model. AB - OBJECTIVE: The study aimed to investigate whether Foxp3-expressing sensitized Teff cells could inhibit allograft rejection in corneal allograft transplantation mouse model. METHODS: Foxp3-expressing sensitized Teff cells were constructed by transfection of retroviral expression plasmid expressing Foxp3 into the sensi Teff cells from a Balb/c mouse immunized by C57BL/6(H2b) mouse splenocytes. Balb/c mice were randomly divided into 5 groups: Four groups received tail vein injection of Foxp3-expressing sensitized Teff cells, or Foxp3-expressing Teff cells, or Treg cells or no intervention 1 day prior to corneal allograft transplantation. C57BL/6(H2b) was the donor mouse. The last group received corneal autograft transplantation. Corneal allograft survival time and percentage of CD4(+) T cells were detected. ELISPOT and Footpad swelling test were used to measure IL-2 and IFN-gamma, and delayed-type hypersensitivity (DTH) response, respectively. RESULTS: Mice that had received an injection of Foxp3-expressing sensitized T cells prior to an allograft corneal transplantation, showed significantly longer survival time of corneal allograft, decreased percentage of CD4(+) T cells, IL-2 and IFN-gamma, and alleviated footpad swelling than the mice that had received either Foxp3-Teff or Treg cells. CONCLUSION: Foxp3-sensi-Teff cell treatment that prolongs corneal allograft survival in the mouse model, might partly through suppressing CD4(+) T cells, IL-2 and IFN-gamma. PMID- 26419204 TI - Enhanced light absorption by mixed source black and brown carbon particles in UK winter. AB - Black carbon (BC) and light-absorbing organic carbon (brown carbon, BrC) play key roles in warming the atmosphere, but the magnitude of their effects remains highly uncertain. Theoretical modelling and laboratory experiments demonstrate that coatings on BC can enhance BC's light absorption, therefore many climate models simply assume enhanced BC absorption by a factor of ~1.5. However, recent field observations show negligible absorption enhancement, implying models may overestimate BC's warming. Here we report direct evidence of substantial field measured BC absorption enhancement, with the magnitude strongly depending on BC coating amount. Increases in BC coating result from a combination of changing sources and photochemical aging processes. When the influence of BrC is accounted for, observationally constrained model calculations of the BC absorption enhancement can be reconciled with the observations. We conclude that the influence of coatings on BC absorption should be treated as a source and regionally specific parameter in climate models. PMID- 26419205 TI - Research of methods to detect genomic mutations induced by CRISPR/Cas systems. AB - The indel-forming non-homologous end joining (NHEJ) pathway repairs double strand breaks in mammalian genomes, resulting in mutation formation following genome editing. Common techniques employed to identify these mutations include the amplified fragment length polymorphism (AFLP) and SURVEYOR assays, which are time consuming, laborious, and only offer a low level of sensitivity. An alternative to these approaches, which is examined in this study, is based on the quantitative PCR high-resolution melting (qPCR-HRM) curve analysis technique and offers simple implementation, is capable of handling large sample sizes, takes no more than 90 min, and produces sensitive results. Using the newly discovered RNA guided CRISPR/Cas systems, the IL2RG and EMX1 genes were edited in the human 293T cell line in order to compare the mutation detection accuracies of the aforementioned methods. Genomic mutations were simulated by mixing mutated DNA fragments with normal fragments along a concentration gradient. The results of this comparative study showed that the HRM approach was both reproducible and accurate. PMID- 26419206 TI - Psychotic experiences and risk of self-injurious behaviour in the general population: a systematic review and meta-analysis. AB - BACKGROUND: Recent studies suggest that psychotic experiences (PE) in the general population are associated with an increased risk of self-injurious behaviour. Both the magnitude of this association and the level of adjustment for confounders vary among studies. A meta-analysis was performed to integrate the available evidence. The influence of possible confounders, including variably defined depression, was assessed. METHOD: A systematic review and meta-analysis was conducted including general population studies reporting on the risk of self injurious behaviour in individuals with PE. Studies were identified by a systematic search strategy in Pubmed, PsycINFO and Embase. Reported effect sizes were extracted and meta-analytically pooled. RESULTS: The risk of self-injurious behaviour was 3.20 times higher in individuals with PE compared with those without. Subanalyses showed that PE were associated with self-harm, suicidal ideation as well as suicidal attempts. All studies had scope for considerable residual confounding; effect sizes adjusted for depression were significantly smaller than effect sizes unadjusted for depression. In the longitudinal studies, adjustment for psychopathology resulted in a 74% reduction in excess risk. CONCLUSIONS: PE are associated with self-injurious behaviour, suggesting they have potential as passive markers of suicidality. However, the association is confounded and several methodological issues remain, particularly how to separate PE from the full range of connected psychopathology in determining any specific association with self-injurious behaviour. Given evidence that PE represent an indicator of severity of non-psychotic psychopathology, the association between PE and self-injurious behaviour probably reflects a greater likelihood of self injurious behaviour in more severe states of mental distress. PMID- 26419207 TI - Assessment and care of visuospatial disorientation in a mixed dementia patient: a case study using objective measurements. AB - We present a case of a mixed dementia patient with visuospatial disorientation and a developmental disability. The patient was a 69-year-old man who was hospitalized for resistance to care, wandering, and a sleep disorder. He was in the advanced stages of dementia and had severe visual impairment due to cataracts. We used an integrated circuit monitoring system and Actiwatch to measure the distance moved per day and sleep-rest cycle, respectively. We administered a coloured paper test to assess the colour most easily recognized by the patient, which was red. We found that displaying his name in large red letters by his door enabled the patient to read his name. We also moved him to a private room next to the day room. The distance moved per day decreased significantly after the implementation of the care plan. However, after the room change, large urine spills were often observed in the bathroom, indicating visuospatial problems. We placed red adhesive tape onto the toilet bowl to make it more visible, which solved the urine spill problem. This case study demonstrates the efficacy of using simple assessment techniques to identify the remaining abilities of a dementia patient and taking simple steps to address the behavioural and psychological symptoms of dementia. PMID- 26419208 TI - Nucleic-acid recognition interfaces: how the greater ability of RNA duplexes to bend towards the surface influences electrochemical sensor performance. AB - The influence of RNA versus DNA on the performance of electrochemical biosensors where redox-labelled nucleic acid duplexes bend towards the electrode surface has been assessed. Faster electron transfer was observed for duplexes containing RNA, suggesting duplexes with RNA are more flexible. These data are of particular importance for microRNA biosensors. PMID- 26419209 TI - Millisecond single-molecule localization microscopy combined with convolution analysis and automated image segmentation to determine protein concentrations in complexly structured, functional cells, one cell at a time. AB - We present a single-molecule tool called the CoPro (concentration of proteins) method that uses millisecond imaging with convolution analysis, automated image segmentation and super-resolution localization microscopy to generate robust estimates for protein concentration in different compartments of single living cells, validated using realistic simulations of complex multiple compartment cell types. We demonstrate its utility experimentally on model Escherichia coli bacteria and Saccharomyces cerevisiae budding yeast cells, and use it to address the biological question of how signals are transduced in cells. Cells in all domains of life dynamically sense their environment through signal transduction mechanisms, many involving gene regulation. The glucose sensing mechanism of S. cerevisiae is a model system for studying gene regulatory signal transduction. It uses the multi-copy expression inhibitor of the GAL gene family, Mig1, to repress unwanted genes in the presence of elevated extracellular glucose concentrations. We fluorescently labelled Mig1 molecules with green fluorescent protein (GFP) via chromosomal integration at physiological expression levels in living S. cerevisiae cells, in addition to the RNA polymerase protein Nrd1 with the fluorescent protein reporter mCherry. Using CoPro we make quantitative estimates of Mig1 and Nrd1 protein concentrations in the cytoplasm and nucleus compartments on a cell-by-cell basis under physiological conditions. These estimates indicate a ~4-fold shift towards higher values in the concentration of diffusive Mig1 in the nucleus if the external glucose concentration is raised, whereas equivalent levels in the cytoplasm shift to smaller values with a relative change an order of magnitude smaller. This compares with Nrd1 which is not involved directly in glucose sensing, and which is almost exclusively localized in the nucleus under high and low external glucose levels. CoPro facilitates time-resolved quantification of protein concentrations in single functional cells, and enables the distributions of concentrations across a cell population to be measured. This could be useful in investigating several cellular processes that are mediated by proteins, especially where changes in protein concentration in a single cell in response to changes in the extracellular chemical environment are subtle and rapid and may be smaller than the variability across a cell population. PMID- 26419210 TI - Evaluation of fracture resistance of endodontically treated teeth restored with composite resin along with fibre insertion in different positions in vitro. AB - This study was carried out to compare the different techniques of placement of polyethylene fibre (Ribbond) on reinforcement of endodontically treated teeth with MOD cavities in vitro. Forty extracted human premolars were randomly assigned to four groups (n = 10). Teeth in Groups I-IV received root canal treatment and a MOD cavity preparation, with gingival cavosurface margin 1.5 mm in coronal to cementoenamel junction. Group I served as no fibre group, Group II as occlusal fibre group, Group III as base fibre group and Group IV as dual-fibre group (occlusal and base both). Subsequent to restoring with composite resin and thermocycling, a vertical compressive force was applied at a cross-head speed of 0.5 mm min(-1) using universal testing machine until fracture. Data were analysed using one-way analysis of variance and Tukey's post hoc tests. Fracture resistance was significantly highest in dual-fibre group (P < 0.001) as compared with other groups. The highest favourable fracture rate was observed in the base fibre group (70%). This study concluded that the use of polyethylene fibre inserted over or under the restoration significantly increased the fracture strength of the root canal-treated teeth and maximum fracture resistance was observed when cavity was restored using dual-fibre technique. PMID- 26419211 TI - Enhanced detection of quantum dots labeled protein by simultaneous bismuth electrodeposition into microfluidic channel. AB - In this study, we propose an electrochemical immunoassay into a disposable microfluidic platform, using quantum dots (QDs) as labels and their enhanced detection using bismuth as an alternative to mercury electrodes. CdSe@ZnS QDs were used to tag human IgG as a model protein and detected through highly sensitive stripping voltammetry of the dissolved metallic component (cadmium in our case). The modification of the screen printed carbon electrodes (SPCEs) was done by a simple electrodeposition of bismuth that was previously mixed with the sample containing QDs. A magneto-immunosandwich assay was performed using a micromixer. A magnet placed at its outlet in order to capture the magnetic beads used as solid support for the immunoassay. SPCEs were integrated at the end of the channel as detector. Different parameters such as bismuth concentration, flow rate, and incubation times, were optimized. The LOD for HIgG in presence of bismuth was 3.5 ng/mL with a RSD of 13.2%. This LOD was about 3.3-fold lower than the one obtained without bismuth. Furthermore, the sensitivity of the system was increased 100-fold respect to experiments carried out with classical screen printed electrodes, both in presence of bismuth. PMID- 26419212 TI - Intergenomic interactions between mitochondrial and Y-linked genes shape male mating patterns and fertility in Drosophila melanogaster. AB - Under maternal inheritance, mitochondrial genomes are prone to accumulate mutations that exhibit male-biased effects. Such mutations should, however, place selection on the nuclear genome for modifier adaptations that mitigate mitochondrial-incurred male harm. One gene region that might harbor such modifiers is the Y-chromosome, given the abundance of Y-linked variation for male fertility, and because Y-linked modifiers would not exert antagonistic effects in females because they would be found only in males. Recent studies in Drosophila revealed a set of nuclear genes whose expression is sensitive to allelic variation among mtDNA- and Y-haplotypes, suggesting these genes might be entwined in evolutionary conflict between mtDNA and Y. Here, we test whether genetic variation across mtDNA and Y haplotypes, sourced from three disjunct populations, interacts to affect male mating patterns and fertility across 10 days of early life in D. melanogaster. We also investigate whether coevolved mito-Y combinations outperform their evolutionarily novel counterparts, as predicted if the interacting Y-linked variance is comprised of modifier adaptations. Although we found no evidence that coevolved mito-Y combinations outperformed their novel counterparts, interactions between mtDNA and Y-chromosomes affected male mating patterns. These interactions were dependent on male age; thus male reproductive success was shaped by G * G * E interactions. PMID- 26419213 TI - Evidence of a dissociation pattern in default mode subnetwork functional connectivity in schizophrenia. AB - The default mode network (DMN) is suggested to play a pivotal role in schizophrenia; however, the dissociation pattern of functional connectivity of DMN subsystems remains uncharacterized in this disease. In this study, resting state fMRI data were acquired from 55 schizophrenic patients and 53 matched healthy controls. DMN connectivity was estimated from time courses of independent components. The lateral DMN exhibited decreased connectivity with the unimodal sensorimotor cortex but increased connectivity with the heteromodal association areas in schizophrenics. The increased connectivity between the lateral DMN and right control network was significantly correlated with negative and anergia factor scores in the schizophrenic patients. The anterior and posterior DMNs exhibited increased and decreased connectivity with the right control and lateral visual networks, respectively, in schizophrenics. The altered DMN connectivity may underlie the hallucinations, delusions, thought disturbances, and negative symptoms involved in schizophrenia. Furthermore, DMN connectivity patterns could be used to differentiate patients from controls with 76.9% accuracy. These findings may shed new light on the distinct role of DMN subsystems in schizophrenia, thereby furthering our understanding of the pathophysiology of schizophrenia. Elucidating key disease-related DMN subsystems is critical for identifying treatment targets and aiding in the clinical diagnosis and development of treatment strategies. PMID- 26419214 TI - How Sensitive is the Amide I Vibration of the Polypeptide Backbone to Electric Fields? AB - Site-selective isotopic labeling of amide carbonyls offers a nonperturbative means to introduce a localized infrared probe into proteins. Although this strategy has been widely used to investigate various biological questions, the dependence of the underlying amide I vibrational frequency on electric fields (or Stark tuning rate) has not been fully determined, which prevents it from being used in a quantitative manner in certain applications. Herein, through the use of experiments and molecular dynamics simulations, the Stark tuning rate of the amide I vibration of an isotopically labeled backbone carbonyl in a transmembrane alpha-helix is determined to be approximately 1.4 cm(-1) /(MV/cm). This result provides a quantitative basis for using this vibrational model to assess local electric fields in proteins, among other applications. For instance, by using this value, we are able to show that the backbone region of a dipeptide has a surprisingly low dielectric constant. PMID- 26419215 TI - Effects of therapeutic positioning on vital parameters in patients with central neurological disorders: a randomised controlled trial. AB - AIMS AND OBJECTIVES: To investigate the effects of positioning on heart rate, breathing frequency and blood pressure in postacute, severely disabled patients with central neurological disorders. BACKGROUND: Positioning patients is part of the regular nursing routine in the care for severely disabled patients. Positioning can be done in a conventional way or in Lagerung in Neutralstellung (Engl.: positioning in neutral), which has recently been shown to have better effects on the passive range of motion and comfort than conventional positioning. While it is thought that positioning influences vital parameters, so far no study has investigated this for a clinically relevant observation period, and no study has compared different positioning concepts in this respect. DESIGN: A multicentre, randomised, controlled, single-blind clinical trial. METHODS: Two hundred and eighteen patients were randomly assigned to positioning in neutral or conventional positioning. For two hours, they were lying in one of five positions (supine, 30 degrees and 90 degrees side lying on the right or left side) according to the respective positioning concept. Heart rate, breathing frequency and blood pressure were measured before and after positioning in a supine lying position (i.e. not positioned according to any concept). It was investigated if the interventions influence vital parameters and whether there are differences between positioning in neutral and conventional positioning, or between the different positions. RESULTS: In neither of the groups did heart rate, breathing frequency and blood pressure change significantly after the intervention compared to before (p <= 0.01). CONCLUSION: Positioning does not influence heart rate, breathing frequency and blood pressure when patients are lying for a clinically feasible length of two hours. RELEVANCE TO CLINICAL PRACTICE: This study shows that nurses can apply both positioning concepts according to their patients' preferences or to address problems like pressure sore prevention. There is no risk of influencing basic vital parameters. PMID- 26419216 TI - Seed priming with polyethylene glycol regulating the physiological and molecular mechanism in rice (Oryza sativa L.) under nano-ZnO stress. AB - The present study was designed to highlight the impact of seed priming with polyethylene glycol on physiological and molecular mechanism of two cultivars of Oryza sativa L. under different levels of zinc oxide nanorods (0, 250, 500 and 750 mg L(-1)). Plant growth parameters were significantly increased in seed priming with 30% PEG under nano-ZnO stress in both cultivars. Whereas, this increase was more prominent in cultivar Qian You No. 1 as compared to cultivar Zhu Liang You 06. Significant increase in photosynthetic pigment with PEG priming under stress. Antioxidant enzymes activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) as well as malondialdehyde (MDA) contents were significantly reduced with PEG priming under nano-ZnO stress. Gene expression analysis also suggested that expression of APXa, APXb, CATa, CATb, CATc, SOD1, SOD2 and SOD3 genes were down regulated with PEG priming as compared to non-primed seeds under stress. The ultrastructural analysis showed that leaf mesophyll and root cells were significantly damaged under nano-ZnO stress in both cultivars but the damage was prominent in Zhu Liang You 06. However, seed priming with PEG significantly alleviate the toxic effects of nano-ZnO stress and improved the cell structures of leaf and roots in both cultivars. PMID- 26419217 TI - Prospective food diaries demonstrate breastfeeding characteristics in a UK birth cohort. AB - Breastfeeding duration and exclusive breastfeeding rates are universally below those recommended by World Health Organization. Due to limitations and challenges associated with researching breastfeeding characteristics, the times when exclusivity is likely to be lost and when women are most likely to discontinue breastfeeding have not yet been identified. Prospective food diaries allow reliable description of the dynamics of breastfeeding to be made to help identify these key time periods. Food diaries detailing intake from birth until the cessation of breastfeeding were analysed for 718 infants recruited into a national arm of an international multicentre birth cohort study (EuroPrevall). Analyses included linear regression analysis and Kaplan-Meier time course analysis. Breastfeeding and exclusive breastfeeding cessation rates for younger mothers (<25 years) are high in the first few weeks after delivery but slow markedly in the period 10-12 weeks after delivery. Cessation rates are consistent from 0 to 26 weeks in older mothers. This difference in feeding patterns led to significant differences between the two different age groups at 26 weeks for breastfeeding (P = 0.006) and exclusive breastfeeding at 8 weeks (P = 0.009). Forty-nine per cent of younger mothers (<25 years) stopped breastfeeding before their infant was 3 weeks old. To increase breastfeeding duration, further work is required to investigate the attitudes and perceptions associated with such high breastfeeding cessation rates in younger mothers during these very early post natal weeks. PMID- 26419218 TI - A familial pericentric inversion of chromosome 11 associated with a microdeletion of 163 kb and microduplication of 288 kb at 11p13 and 11q22.3 without aniridia or eye anomalies. AB - Interstitial deletions of 11p13 involving MPPED2, DCDC5, DCDC1, DNAJC24, IMMP1L, and ELP4 are previously reported to have downstream transcriptional effects on the expression of PAX6, due to a downstream regulatory region (DRR). Currently, no clear genotype-phenotype correlations have been established allowing for conclusive information regarding the exact location of the PAX6 DRR, though its location has been approximated in mouse models to be within the Elp4 gene. Of the clinical reports currently published examining patients with intact PAX6 genes but harboring deletions identified in genes downstream of PAX6, 100% indicate phenotypes which include aniridia, whereas approximately half report additional eye deformities, autism, or intellectual disability. In this clinical report, we present a 12-year-old male patient, his brother, and mother with pericentric inversions of chromosome 11 associated with submicroscopic interstitial deletions of 11p13 and duplications of 11q22.3. The inversions were identified by standard cytogenetic analysis; microarray and FISH detected the chromosomal imbalance. The patient's phenotype includes intellectual disability, speech abnormalities, and autistic behaviors, but interestingly neither the patient, his brother, nor mother have aniridia or other eye anomalies. To the best of our knowledge, these findings in three family members represent the only reported cases with 11p13 deletions downstream of PAX6 not demonstrating phenotypic characteristics of aniridia or abnormal eye development. Although none of the deleted genes are obvious candidates for the patient's phenotype, the absence of aniridia in the presence of this deletion in all three family members further delineates the location of the DRR for PAX6. PMID- 26419220 TI - Children with PIMD in interaction with peers with PIMD or siblings. AB - BACKGROUND: The complex disabilities of children with profound intellectual and multiple disabilities (PIMD) impede their presentation of peer directed behaviours. Interactions with typically developing peers have been observed to be more frequent than those with peers with PIMD. The typically developing peers with whom people with PIMD have frequent contact are their siblings. In this study, the amount of peer directed behaviours was compared between an interaction with a sibling and an interaction with a peer with PIMD. In addition, the attention directing strategies of the siblings, and how these affect the presentation of peer directed behaviours, were examined. METHOD: Thirteen children and young people with PIMD, who had a typically developing sibling, were identified. For each of these thirteen children, a peer with PIMD and a sibling were selected. The child with PIMD was observed together with a peer with PIMD and together with a sibling. In both conditions, video observations were conducted. A coding scheme for the peer directed behaviours of the children and young people with PIMD and a coding scheme for the attention directing behaviours of the siblings were used. Descriptive, comparative and sequential analyses were conducted. RESULTS: Significantly, more peer directed behaviours of the children with PIMD were observed in the condition with the sibling (30.76%) compared with that of the condition with the peer with PIMD (13.73%). The siblings presented attention directing behaviours in 30% of the time; the most frequently used was nonverbal behaviour. When the siblings presented a combination of verbal and nonverbal attention directing behaviours, they elicited multiple peer directed behaviours in the children and young people with PIMD. CONCLUSIONS: Persons with PIMD interact more with their siblings compared with their peers with PIMD. Interacting with siblings may probably be more motivating and encouraging. Presenting a combination of verbal and nonverbal behaviours attracts more attention of the persons with PIMD. PMID- 26419219 TI - PucC and LhaA direct efficient assembly of the light-harvesting complexes in Rhodobacter sphaeroides. AB - The mature architecture of the photosynthetic membrane of the purple phototroph Rhodobacter sphaeroides has been characterised to a level where an atomic-level membrane model is available, but the roles of the putative assembly proteins LhaA and PucC in establishing this architecture are unknown. Here we investigate the assembly of light-harvesting LH2 and reaction centre-light-harvesting1-PufX (RC LH1-PufX) photosystem complexes using spectroscopy, pull-downs, native gel electrophoresis, quantitative mass spectrometry and fluorescence lifetime microscopy to characterise a series of lhaA and pucC mutants. LhaA and PucC are important for specific assembly of LH1 or LH2 complexes, respectively, but they are not essential; the few LH1 subunits found in DeltalhaA mutants assemble to form normal RC-LH1-PufX core complexes showing that, once initiated, LH1 assembly round the RC is cooperative and proceeds to completion. LhaA and PucC form oligomers at sites of initiation of membrane invagination; LhaA associates with RCs, bacteriochlorophyll synthase (BchG), the protein translocase subunit YajC and the YidC membrane protein insertase. These associations within membrane nanodomains likely maximise interactions between pigments newly arriving from BchG and nascent proteins within the SecYEG-SecDF-YajC-YidC assembly machinery, thereby co-ordinating pigment delivery, the co-translational insertion of LH polypeptides and their folding and assembly to form photosynthetic complexes. PMID- 26419221 TI - Functional characterization of a glucosyltransferase gene, LcUFGT1, involved in the formation of cyanidin glucoside in the pericarp of Litchi chinensis. AB - Anthocyanins generate the red color in the pericarp of Litchi chinensis. UDP glucose: flavonoid 3-O-glycosyltransferase (UFGT, EC. 2.4.1.91) stabilizes anthocyanidin by attaching sugar moieties to the anthocyanin aglycone. In this study, the function of an UFGT gene involved in the biosynthesis of anthocyanin was verified through heterologous expression and virus-induced gene silencing assays. A strong positive correlation between UFGT activity and anthocyanin accumulation capacity was observed in the pericarp of 15 cultivars. Four putative flavonoid 3-O-glycosyltransferase-like genes, designated as LcUFGT1 to LcUFGT4, were identified in the pericarp of litchi. Among the four UFGT gene members, only LcUFGT1 can use cyanidin as its substrate. The expression of LcUFGT1 was parallel with developmental anthocyanin accumulation, and the heterologously expressed protein of LcUFGT1 displayed catalytic activities in the formation of anthocyanin. The LcUFGT1 over-expression tobacco had darker petals and pigmented filaments and calyxes resulting from higher anthocyanin accumulations compared with non-transformed tobacco. In the pericarp with LcUFGT1 suppressed by virus induced gene silencing, pigmentation was retarded, which was well correlated with the reduced-LcUFGT1 transcriptional activity. These results suggested that the glycosylation-related gene LcUFGT1 plays a critical role in red color formation in the pericarp of litchi. PMID- 26419222 TI - Habitat-associated skew of clone abundance in the Pseudomonas aeruginosa population. AB - The population structure of the cosmopolitan Pseudomonas aeruginosa was investigated by genotyping 2921 isolates from 1448 independent habitats with a custom-made 58 binary marker microarray. Of 323 identified clone types, 109 clones made up 82% of the population. The 20 most frequent clones had an absolute share of 44% indicating that the P. aeruginosa population is dominated by few epidemic clonal complexes. The frequency distribution of common clones was different between inanimate habitats and human niches. The three most abundant clones in the environment were rare among isolates from human infection. Conversely, disease-associated isolates either belonged to ubiquitous clones such as C and PA14 or to clones that were uncommon in the environment. The P. aeruginosa population consists of major clones that are just as versatile in their habitat and geographic origin as the whole species and of minor clones with preference for a peculiar niche. PMID- 26419223 TI - Regrouping of pigs by body weight at weaning does not affect growth performance, carcass quality or uniformity at slaughter of heavy weight pigs. AB - We studied the influence of pen uniformity at weaning (7.5 +/- 0.6 kg vs. 7.5 +/- 1.2 kg body weight (BW +/- SD)) and sex on growth performance during the nursery (7.5 to 27.3 kg BW) and the fattening (27.1 to 130.5 kg BW) phases and carcass quality of barrows and castrated females (CF). During the nursery phase, pigs from the more uniform pens had lower feed efficiency (P = 0.05) than pigs from the less uniform pens. Also, barrows had higher average daily feed intake (ADFI) (P < 0.05) and average daily gain (P < 0.001) and better feed efficiency (P < 0.001) than CF. During the fattening phase, initial pen uniformity did not affect growth performance of the pigs but barrows tended (P = 0.08) to have higher ADFI and worse feed efficiency than CF. Trimmed primal cut yield tended to be higher for the more uniform pigs and better for barrows than for CF (P = 0.09). It is concluded that regrouping of the pigs at weaning according to uniformity of BW did not affect growth performance or carcass quality of the pigs at slaughter. Castrated females might be used as an alternative to barrows for the production of carcasses destined to the dry-cured industry. PMID- 26419224 TI - Engineering excitonic dynamics and environmental stability of post-transition metal chalcogenides by pyridine functionalization technique. AB - Owing to their strong photon emission, low excitonic binding energies, and nearly ideal band offset values for water splitting reactions, direct gap quasi-2D gallium chalcogenides are potential candidates for applications in energy harvesting, optoelectronics, and photonics. Unlike other 2D materials systems, chemical functionalization of gallium chalcogenides is still at its seminal stages. Here, we propose vapor phase pyridine intercalation technique to manipulate optical properties of gallium chalcogenides. After functionalization, the excitonic dynamics of quasi-2D GaSe change significantly as evidenced by an increase in integrated PL intensity and emergence of a new emission feature that is below the band edge. Based on our DFT calculations, we attribute these to formation of bound exciton complexes at the trap sites introduced by chemical reaction between pyridine and GaSe. On the contrary, pyridine functionalization does not impact the optical properties of GaTe, instead treats GaTe surface to prevent oxidization of tellurium atoms. Overall, results suggest novel ways to control properties of gallium chalcogenides on demand and unleash their full potential for a range of applications in photonics and optoelectronics. PMID- 26419225 TI - Genetic risk for atrial fibrillation could motivate patient adherence to warfarin therapy: a cost effectiveness analysis. AB - BACKGROUND: Atrial fibrillation (AF) increases risk of stroke, and although this stroke risk can be ameliorated by warfarin therapy, some patients decline to adhere to warfarin therapy. A prospective clinical study could be conducted to determine whether knowledge of genetic risk for AF could increase adherence to warfarin therapy for patients who initially declined therapy. As a prelude to a potential prospective clinical study, we investigated whether the use of genetic information to increase adherence could be cost effective. METHODS: Markov model assessed costs and utilities of two care strategies for AF patients who declined warfarin therapy. In the usual care strategy patients received aspirin. In the test strategy genetic risk for AF was assessed (genotype of the 4q25 locus) and some patients with a positive genetic test (>=1 risk allele) were assumed to adhere to warfarin therapy. The remaining patients received aspirin. The incremental cost-effectiveness ratio (ICER) was the ratio of the costs differential and the quality adjusted life-years (QALYs) differential for the two strategies. RESULTS: We found that the 4q25 genetic testing strategy, compared with the usual care strategy (aspirin therapy), would be cost-effective (ICER $ 47,148) if 2.1 % or more of the test positive patients were to adhere to warfarin therapy. The test strategy would become a cost saving strategy if 5.3 % or more of the test positive patients were to adhere to warfarin therapy. If 20 % of test positive patients were to adhere to warfarin therapy in a hypothetical cohort of 1000 patients, 7 stroke events would be prevented and 3 extra-cranial major bleeding events would be caused over 5 years, resulting in a cost savings of ~ $250,000 and a net gain of 9 QALYs. DISCUSSION: A clinical study to assess the impact of patient knowledge of genetic risk of AF on adherence to warfarin therapy would be merited because even a modest increase in patient adherence would make a genetic testing strategy cost-effective. CONCLUSION: Providing patients who declined warfarin therapy with information about their genetic risk of AF would be cost effective if this genetic risk information resulted in modest increases in adherence. PMID- 26419226 TI - Interventions for preventing, delaying the onset, or decreasing the burden of frailty: an overview of systematic reviews. AB - BACKGROUND: Many systematic reviews have evaluated the effectiveness of interventions to prevent, delay, or decrease frailty symptoms, but no effort has been made to identify, map, and synthesize the findings from reviews across the full spectrum of interventions. Our objectives are to (1) synthesize findings from all existing systematic reviews evaluating interventions for preventing, delaying the onset, or decreasing the burden of frailty symptoms; (2) examine different conceptualizations of frailty that have been used in the development and implementation of interventions; and (3) inform policy by convening a stakeholder dialogue with Canadian health-system leaders. METHODS/DESIGN: We will conduct an overview of systematic reviews to identify and synthesize all of the systematic reviews addressing interventions to preventing, delaying the onset, or decreasing the burden of frailty symptoms. To identify relevant systematic reviews, we will conduct database searches for published and grey literature as well as contact key experts and search reference lists of included reviews. Two reviewers will independently review all search results for inclusion and then conceptually map, extract key findings (including the conceptualization/definition of frailty used) and assess the methodological quality of all included reviews. We will then synthesize the findings by producing a 'gap map' (i.e. mapping reviews in a matrix according to the interventions and outcomes assessed), and narratively synthesize the key messages across reviews related to type of interventions. DISCUSSION: Following the completion of the synthesis, we will use the findings to develop an evidence brief that mobilizes the best available evidence about the problem related to preventing, delaying the onset, or decreasing the burden of frailty symptoms in older adults, policy and programmatic options to address the problem and implementation considerations. The evidence brief will then be used as the input into a stakeholder dialogue, which will engage 18-22 Canadian health-system leaders (including policymakers, health providers, researchers, and other stakeholders) in 'off-the-record' deliberations to inform future actions and policymaking. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015022082. PMID- 26419227 TI - Nanoparticle-rich diesel exhaust-induced liver damage via inhibited transactivation of peroxisome proliferator-activated receptor alpha. AB - Diesel exhaust emission contains a high amount of nano-sized particles and is considered to be systemically distributed in the body. However, few studies about the effects of nanoparticle rich-diesel exhaust (NR-DE) on liver have been reported. The present investigation focuses on the effects of NR-DE on livers in rats, especially concerning inflammation and lipid metabolism. Male F344 rats were exposed to fresh air or low (24 +/- 7 ug/m3 ), medium (39 +/- 4 ug/m3 ) and high (138 +/- 20 ug/m3 ) concentrations of NR-DE for 1, 2, or 3 months (5 hours/day, 5 days/week). Exposure to both medium and high concentrations of NR-DE for one month increased plasma asparate aminotransferase and alanine aminotransferase activities, while only high concentrations increased plasma interleukin-6 and hepatic nuclear factor kappa B (NFkappaB), suggesting that activation of hepatic inflammatory signaling took place. Although these exposures elevated peroxisome proliferator-activated receptor (PPAR) alpha levels or its binding activity to the response element, neither activated PPARalpha-target genes such as beta-oxidative enzymes nor inhibited NFkappaB elevation. Thus, NR DE may contain some materials that inhibit PPARalpha activation in relation to lipid metabolism and inflammation. Taken together, NR-DE exposure at one month may cause inflammation; however, this finding may not be observed after a longer exposure period. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1985-1995, 2016. PMID- 26419228 TI - Atypical bromethalin intoxication in a dog: pathologic features and identification of an isomeric breakdown product. AB - BACKGROUND: Definitive post mortem confirmation of intoxication by the neurotoxic rodenticide bromethalin can be challenging. Brain lesions are not specific and detection of bromethalin and its metabolites are unpredictable due to rapid photodegradation and inconsistent behavior in tissues. CASE PRESENTATION: A 2 year-old dog presented with rapid onset of severe muscle tremors and death within hours after a known ingestion of a reportedly low dosage of bromethalin and subsequent decontamination using activated charcoal. Marked meningeal hemorrhages and multifocal myelin sheath vacuolation were observed in the brain. A marked reactive astrocytosis and neuronal hypoxia/necrosis were identified using immunohistochemistry (IHC) for glial fibrillary acidic protein (GFAP) and for neuron specific protein (NeuN). Bromethalin exposure and tissue absorption was confirmed by identification of one of two isomeric 543.7 molecular weight (MW) breakdown products in the patient's adipose and kidney samples using gas chromatography (GC) combined with tandem quadrupole mass spectrometry (MS/MS). CONCLUSIONS: The severity of clinical signs and subsequent death of this dog was not expected with the low dosage of bromethalin reportedly ingested, and the use of activated charcoal possibly precipitated a hypernatremic status. Meningeal hemorrhages are atypical of bromethalin intoxication, and might have been caused by hyperthermia, secondary to tremors or hypernatremia. Identification of one of two isomeric breakdown products in the adipose tissue and kidney provides an additional molecule to the toxicologic testing regime for bromethalin intoxication. PMID- 26419229 TI - Clostridium punense sp. nov., an obligate anaerobe isolated from healthy human faeces. AB - An obligately anaerobic, rod-shaped (0.5-1.0 * 2.0-10.0 MUm), Gram-stain-positive bacterium, occurring mainly singly or in pairs, and designated BLPYG-8T, was isolated from faeces of a healthy human volunteer aged 56 years. Cells were non motile. Oval, terminal spores were formed that swell the cells. The strain was affiliated with the genus Clostridium sensu stricto (Clostridium rRNA cluster I) as revealed by 16S rRNA gene sequence analysis. Strain BLPYG-8T showed 97.3 to 97.4 % 16S rRNA gene sequence similarity with Clostridium sulfidigenes DSM 18982T, Clostridium subterminale DSM 6970T and Clostridium thiosulfatireducens DSM 13105T. DNA-DNA hybridization and phenotypic analysis showed that the strain was distinct from its closest relatives, C. sulfidigenes DSM 18982T, C. subterminale DSM 6970T, C. thiosulfatireducens DSM 13105T with 54.2, 53.9 and 53.3 % DNA-DNA relatedness, respectively. Strain BLPYG-8T grew in PYG broth at temperatures between 20 and 40 degrees C (optimum 37 degrees C). The strain utilized a range of amino acids as well as carbohydrates as a source of carbon and energy. Glucose fermentation resulted in the formation of volatile fatty acids mainly acetic acid, n-butyric acid and organic acids such as succinic and lactic acid. The DNA G+C content of strain BLPYG-8T was 44.1 mol%. The major fatty acids (>10 %) were C14 : 0, iso-C15 : 0, C16 : 1omega7c and C16 : 0. Phylogenetic analysis and specific phenotypic characteristics and/or DNA G+C content differentiated the strain from its closest relatives. On the basis of these data, strain BLPYG-8T represents a novel species of the genus Clostridium, for which the name Clostridium punense sp. nov. is proposed. The type strain is BLPYG-8T ( = DSM 28650T = CCUG 64195T = MCC 2737T). PMID- 26419230 TI - Text message interventions for follow up of infants born to mothers positive for Chagas disease in Tucuman, Argentina: a feasibility study. AB - BACKGROUND: Diagnosis of congenital Chagas disease occurs at 9 months of age, making effective treatment challenging due to loss to follow-up. Mobile health (mHealth) has been utilized to improve communication and treatment adherence in many chronic diseases, although no studies of mHealth in Trypanosoma cruzi infected individuals have been conducted. Text message interventions, a subset of mHealth, has shown to improve appointment attendance and is relatively simple to set up, thus making it an ideal mechanism to facilitate communication with individuals in low-resource settings. OBJECTIVE: The aim of this study is to understand the acceptability, utilization, and barriers of an SMS-based appointment reminder to confirm a post-partum home visit to women in Tucuman, Argentina and whether these factors differ in urban and rural populations. METHODS: Women that tested positive for Chagas disease were invited to receive SMS reminders of their follow-up 4-week postpartum home visit. Demographic information and SMS contact preferences were collected at hospital discharge, and variables on mHealth utilization and barriers were recorded at follow-up. RESULTS: 77 (70.6%) of women possessed a cell phone for personal use. All eligible women owned phones compatible with SMS messages. The appointment reminder SMS was widely accepted with 64/72 (88.9%) enrolled women receiving the SMS message and 58/64 (90.6%) replying. Ninety-two percent of women stated that the text message was a useful reminder for the follow-up home visit. Women living in rural areas were less likely to own a cell phone for personal use and were significantly less likely to have internet access on their phone than women living in urban areas (RR 0.30, 95% CI 0.10-0.89). Furthermore, women from rural areas faced barriers to mHealth uptake such as change of phone number and response to messages from the hospital team at higher rates than women from urban areas, although these differences were not statistically significant. CONCLUSIONS: There is generally widespread acceptance and utilization of mHealth among this group of women with access to cell phones. However, there are still many barriers to overcome before mHealth interventions attain complete penetration in a population, most notably the issue of cell phone for personal use. PMID- 26419231 TI - Neurodevelopmental outcome of extremely low birth weight infants at 24 months corrected age: a comparison between Griffiths and Bayley Scales. AB - BACKGROUND: The availability of accurate assessment tools for the early detection of infants at risk for adverse neurodevelopmental outcomes is a major issue. The purpose of this study is to compare the outcomes of the Bayley Scales (Bayley-II vs Bayley-III) in a cohort of extremely low birth weight infants at 24 months corrected age, to define which edition shows the highest agreement with the Griffiths Mental Development Scales Revised. METHODS: We performed a single centre cohort study. We prospectively enrolled infants with a birth weight of 401 1000 g and/or gestational age < 28 weeks. Exclusion criteria were the presence of neurosensory disabilities and/or genetic abnormalities. Infants underwent neurodevelopmental evaluation at 24 months corrected age using the Griffiths and either the Bayley-II (birth years 2003-2006) or the Bayley-III (birth years 2007 2010). RESULTS: A total of 194 infants were enrolled. Concordance was excellent between the Griffiths and the Bayley-III composite scores for both cognitive language and motor abilities (weighted K = 0.80 and 0.81, respectively) but poorer for the Bayley-II (weighted K = 0.63 and 0.50, respectively). The Youden's Index revealed higher values for the Bayley-III than for the Bayley-II (75.9 vs 69.6%). Compared with the Griffiths, the Bayley-III found 3% fewer infants as being severely impaired in cognitive-language abilities and 7.8% fewer infants as being mildly impaired in motor skills while the Bayley-II showed, compared with the Griffiths, higher rates of severely impaired children both for cognitive language and motor abilities (14.1 and 15.3% more infants respectively). DISCUSSION: Our study suggests that the Bayley-III, although having a higher agreement with the Griffiths compared to the Bayley-II, slightly tends to underestimate neurodevelopmental impairment compared with the Griffiths, whereas the Bayley-II tends to overestimate it. CONCLUSIONS: On the basis of these findings, we recommend the use of multiple measures to assess neurodevelopmental outcomes of extremely low birth weight infants at 24 months. PMID- 26419232 TI - Cryptic speciation in the Triatoma sordida subcomplex (Hemiptera, Reduviidae) revealed by chromosomal markers. AB - BACKGROUND: Chagas disease vectors (Hemiptera-Reduviidae) comprise more than 140 blood-sucking insect species of the Triatominae subfamily. The largest genus is Triatoma, subdivided in several complexes and subcomplexes according to morphology, ecology and genetic features. One of them is the sordida subcomplex, involving four species: Triatoma sordida, T. guasayana, T. garciabesi and T. patagonica. Given the great morphological similarity of these species, their taxonomic identification, evolutionary relationships and population differentiation have been controversial for many years and even today remain under discussion. METHODS: We simultaneously analyzed two chromosomal markers, C heterochromatin distribution and 45S ribosomal genes chromosomal position, of 139 specimens from several sordida subcomplex populations from Argentina, Bolivia, Brazil and Paraguay, collected both in nature and from several established insectaries. Our results were compared with COI sequences deposited in GenBank. RESULTS: We recognized five chromosomal taxa with putative hybrids, which each differ in at least one chromosome marker. Most of them present significant differences in their mtDNA sequences. CONCLUSION: The chromosomal taxa here show a significant chromosome differentiation involving changes in the C heterochromatin content and in the ribosomal clusters position. This paper identifies several erroneously classified populations by morphological methods, delimits the geographical distribution of each taxon and proposes the existence of a new cryptic species, widely distributed in Argentina. We also suggest that sordida sibling species involve closely related as well as evolutionary distant species. Taxonomic status of each chromosomal taxon is discussed considering phenotypic and genetic results previously published. PMID- 26419234 TI - Relational Aggression, Victimization and Self-Concept: Testing Pathways from Middle Childhood to Adolescence. AB - When studying adolescent development, it is important to consider two key areas that are salient for teens, which are self-concept and peer relations. A secondary analysis of the National Institute of Health and Human Development Study of Early Child Care and Youth Development was conducted to examine the prospective bidirectional associations between self-concept and peer relations. To date, how social development broadly and peer relations in particular (e.g., relational aggression and victimization) affect self-concept domains is not fully understood. Using a large sample (N = 1063; 532 girls; M = 11.14 years; SD = .59) with multiple informants, the present study examined whether fifth grade relational aggression and sixth grade relational victimization was associated with adolescent self-concept in three key domains (i.e., academic, sports, physical appearance). A significant direct effect emerged, such that relational aggression in middle childhood was associated with decreases in academic self concept and increases in sports self-concept in adolescence. Analyses also revealed that having higher levels of domain specific self-concept led to decreases in relational aggression across the transition to adolescence. The findings highlight the importance of examining bidirectional prospective associations between relational aggression, relational victimization, and domain specific self-concept. Implications for future research and clinical intervention are discussed. PMID- 26419235 TI - Primary malignant lymphoma combined with clinically "silent" pheochromocytoma in the same adrenal gland. AB - An increased number of adrenal tumors are now diagnosed due to the increased number of abdominal CT scans being performed. We present the first case of malignant lymphoma combined with clinically "silent" pheochromocytoma in the same adrenal gland. An abdominal CT scan demonstrates unilateral adrenal lesion which suggests pheochromocytoma or adrenal carcinoma. Laboratory examinations revealed a slight increase of 24-h urine vanillylmandelic acid and 24-h urinary methanephrine excretion. Histological examination revealed two intermingled tumor cell proliferations-diffuse B cell lymphoma and pheochromocytoma.Unexpected coexistence of catecholamine-producing tumor with the other adrenal lesion can lead to serious complications of diagnosis and treatment. The adequate preparation for surgery can protect patient from threatening catecholamine crisis. PMID- 26419236 TI - PNPLA3 rs738409 Polymorphism Associated with Hepatic Steatosis and Advanced Fibrosis in Patients with Chronic Hepatitis C Virus: A Meta-Analysis. AB - BACKGROUND/AIMS: The recognition of a correlation between patatin-like phospholipase domain containing-protein 3 (PNPLA3) rs738409 (C>G) and the severity of liver steatosis or fibrosis in chronic hepatitis C (CHC) has not reached a consensus. This meta-analysis sought to investigate with accuracy the association between the PNPLA3 rs738409 (C>G) polymorphism and liver steatosis and advanced fibrosis in CHC patients. METHODS: We performed a comprehensive literature search from the PubMed, Embase, Web of Science, and Google Scholar databases up to December 31, 2014. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Statistical analyses were performed using Stata 12.0 software. RESULTS: The meta-analysis revealed the severity of liver fibrosis was significantly higher in CHC patients with PNPLA3 rs738409 GG in Caucasians (versus CC+CG OR, 2.29; 95% CI, 1.57 to 3.35; p<0.05) but not Asian populations. In Caucasians, liver steatosis was also more severe in CHC patients with rs738409 GG (versus CC+CG; OR, 4.33; 95% CI, 2.59 to 7.22; p<0.05). The sensitivity analysis indicated the results of this meta-analysis were stable and no publication bias was detected. CONCLUSIONS: PNPLA3 rs738409 (C>G) was associated with the risk of both advanced liver fibrosis and steatosis in patients with CHC, especially among Caucasian populations. PMID- 26419237 TI - Leukocyte telomere length and diabetes status, duration, and control: the 1999 2002 National Health and Nutrition Examination Survey. AB - BACKGROUND: Studies investigating the association between telomere length and diabetes have been inconsistent, and there are few data available investigating the associations of telomere length with diabetes duration and control. We evaluated the relationship of leukocyte telomere length with diabetes, and the relationship of leukocyte telomere length with diabetes duration and poor glucose control among people with diabetes. METHODS: We used data from the 1999-2002 National Health and Nutrition Examination Survey, a representative sample of the US civilian non-institutionalized population. In 3921 participants, leukocyte telomere length was measured and diabetes status was determined based on a previous diagnosis, hemoglobin A1c >= 6.5 %, or fasting glucose >= 126 mg/dL. RESULTS: The odds ratios (95 % confidence intervals) of diabetes associated with the first, second, and third quartile of leukocyte telomere length, compared to the highest quartile, was 2.09 (1.46-2.98), 1.74 (1.30-2.31), and 1.08 (0.76 1.54), respectively (p-trend < 0.01), in unadjusted models and 0.74 (0.48-1.14), 0.91 (0.61-1.34), and 0.87 (0.59-1.29), respectively (p-trend = 0.20), in multivariable adjusted models. Among participants with diabetes, unadjusted and adjusted leukocyte telomere length was not associated with diabetes duration or glucose control based on an hemoglobin A1c < 7 or < 8 % (all p > 0.05). CONCLUSIONS: In this study of the US general population, leukocyte telomere length was not associated with diabetes status, diabetes duration, or diabetes control. PMID- 26419239 TI - Looking for a standardized approach in the surgical treatment of hyperhidrosis. PMID- 26419240 TI - Circadian Insights into Motivated Behavior. AB - For an organism to be successful in an evolutionary sense, it and its offspring must survive. Such survival depends on satisfying a number of needs that are driven by motivated behaviors, such as eating, sleeping, and mating. An individual can usually only pursue one motivated behavior at a time. The circadian system provides temporal structure to the organism's 24 hour day, partitioning specific behaviors to particular times of the day. The circadian system also allows anticipation of opportunities to engage in motivated behaviors that occur at predictable times of the day. Such anticipation enhances fitness by ensuring that the organism is physiologically ready to make use of a time-limited resource as soon as it becomes available. This could include activation of the sympathetic nervous system to transition from sleep to wake, or to engage in mating, or to activate of the parasympathetic nervous system to facilitate transitions to sleep, or to prepare the body to digest a meal. In addition to enabling temporal partitioning of motivated behaviors, the circadian system may also regulate the amplitude of the drive state motivating the behavior. For example, the circadian clock modulates not only when it is time to eat, but also how hungry we are. In this chapter we explore the physiology of our circadian clock and its involvement in a number of motivated behaviors such as sleeping, eating, exercise, sexual behavior, and maternal behavior. We also examine ways in which dysfunction of circadian timing can contribute to disease states, particularly in psychiatric conditions that include adherent motivational states. PMID- 26419238 TI - Novel MASP1 mutations are associated with an expanded phenotype in 3MC1 syndrome. AB - BACKGROUND: 3MC1 syndrome is a rare autosomal recessive disorder characterized by intellectual disability, short stature and distinct craniofacial, umbilical, and sacral anomalies. Five mutations in MASP1, encoding lectin complement pathway enzymes MASP-1 and MASP-3, have thus far been reported to cause 3MC1 syndrome. Only one previously reported mutation affects both MASP-1 and MASP-3, while the other mutations affect only MASP-3. METHODS: We evaluated six unrelated individuals with 3MC1 syndrome and performed Sanger sequencing for all coding exons of MASP1. We also measured complement lectin and alternative pathway activities in an affected individual's serum. RESULTS: We found two novel splice site mutations, c.1012-2A > G in one and c.891 + 1G > T in two probands, and three novel missense mutations, c.1451G > A (p.G484E), c.1657G > A (p.D553N), and c.1987G > T (p.D663Y). Missense mutations affect only MASP-3, while splice site mutations affect both MASP-1 and MASP-3. In a proband who is homozygous for c.891 + 1G > T, we detected a total lack of lectin complement pathway activity and a 2.5-fold lower alternative pathway activity. The phenotype observed in patients whose both MASP-1 and MASP-3 are affected and in those whose only MASP-3 is affected does not appear to be different. We observed structural brain abnormalities, neonatal tooth, a vascular anomaly and a solid lesion in liver as novel phenotypic features of 3MC1 syndrome. CONCLUSION: Novel mutations and additional phenotypic features expand the genotypic and phenotypic spectrum of 3MC1 syndrome. Although patients with MASP-1 dysfunction in addition to disrupted MASP-3 have an altered complement system, their disease phenotype is not different from those having only MASP-3 dysfunction. PMID- 26419241 TI - Distress from Motivational Dis-integration: When Fundamental Motives Are Too Weak or Too Strong. AB - Past research has shown that satisfying different kinds of fundamental motives contributes to well-being. More recently, advances in motivational theory have shown that z is also tied to the integration of different motives. In other words, well-being depends not only on maximizing effectiveness in satisfying specific motives, but also on ensuring that motives work together such that no individual motive is too weak or too strong. In this chapter, we review existing research to show that specific forms of psychological distress can be linked to specific types of motivational imbalance or dis-integration. Such disintegration can arise from either excessive weakness of a specific motive or the excessive strength and/or dominance of a specific motive, thereby inhibiting other motives. Possible neural correlates and avenues of intervention are discussed. PMID- 26419242 TI - Integrating Qualitative and Quantitative Tools for the Detection and Identification of Lectins in Major Human Diseases. AB - Lectins are the (glyco)proteins that recognize and bind to specific sugar moieties without altering their structure. Galectins are mammalian lectins characterized by the presence of conserved 134 amino acids carbohydrate recognition domain and specificity for beta-galactosides. The involvement of lectins in diverse biological spectrum, especially some deadly human diseases like cancer, neurological disorders and cardiovascular disorders has proclaimed them as one of the important components of glycobiology, thereby seeking the methods of their detection and identification heavily desirable. In the present manuscript, we have provided a comprehensive outline of various methods of detection and identification of lectins employed till date, with their needs and usage varying according to the level of infrastructure of laboratories and around the world. In addition, a vision for some quick, highly sensitive and advanced methods for lectin detection and identification for diagnostic and therapeutic of various diseases is also provided. PMID- 26419243 TI - Post-concussion syndrome (PCS) in a youth population: defining the diagnostic value and cost-utility of brain imaging. AB - PURPOSE: Approximately 90% of concussions are transient, with symptoms resolving within 10-14 days. However, a minority of patients remain symptomatic several months post-injury, a condition known as post-concussion syndrome (PCS). The treatment of these patients can be challenging. The goal of our study was to assess the utility and cost-effectiveness of neurologic imaging two or more weeks post-injury in a cohort of youth with PCS. METHODS: We conducted a retrospective study of 52 pediatric patients with persistent post-concussion symptoms after 3 months. We collected demographics and neuroimaging results obtained greater than 2 weeks post-concussion. Neuroimaging ordered in the first 2 weeks post concussion was excluded, except to determine the rate of re-imaging. Descriptive statistics and corresponding cost data were collected. RESULTS: Of 52 patients with PCS, 23/52 (44%) had neuroimaging at least 2 weeks after the initial injury, for a total of 32 diagnostic studies. In summary, 1/19 MRIs (5.3%), 1/8 CTs (13%), and 0/5 x-rays (0%) yielded significant positive findings, none of which altered clinical management. Chronic phase neuroimaging estimated costs from these 52 pediatric patients totaled $129,025. We estimate the cost to identify a single positive finding was $21,000 for head CT and $104,500 for brain MRI. CONCLUSIONS: In this cohort of pediatric PCS patients, brain imaging in the chronic phase (defined as more than 2 weeks after concussion) was pursued in almost half the study sample, had low diagnostic yield, and had poor cost effectiveness. Based on these results, outpatient management of pediatric patients with long-term post-concussive symptoms should rarely include repeat neuroimaging beyond the acute phase. PMID- 26419244 TI - Microbial availability of mercury: effective detection and organic ligand effect using a whole-cell bioluminescent bioreporter. AB - A luxCDABE-based genetically engineered bacterial bioreporter (Escherichia coli ARL1) was used to detect bioavailable ionic mercury (Hg(II)) and investigate the effects of humic acids and ethylenediaminetetraacetic acid (EDTA) on the bioavailability of mercury in E. c oli. Results showed that the E. c oli ARL1 bioreporter was sensitive to mercury, with a detection limit of Hg(II) of 0.5 ug/L and a linear dose/response relationship up to 2000 ug Hg(II)/L. Humic acids and EDTA decreased the Hg(II)-induced bioluminescent response of strain ARL1, suggesting that the two organic ligands reduced the bioavailability of Hg(II) via complexation with Hg(II). Compared with traditional chemical methods, the use of E. c oli ARL1 is a cost-effective, rapid, and reliable approach for measuring aqueous mercury at very low concentrations and thus has potential for applications in field in situ monitoring. PMID- 26419245 TI - Biological toxicity of cellulose nanocrystals (CNCs) against the luxCDABE-based bioluminescent bioreporter Escherichia coli 652T7. AB - The aim of this study was to evaluate the biological toxicity of cellulose nanocrystals (CNCs) using the constitutively bioluminescent luxCDABE-based bioreporter Escherichia coli 652T7. The effects of CNCs on E. c oli 652T7 biotoxicity were investigated at different CNC concentrations, reaction times, and IC50 values. CNC toxicity was also compared with and without ultrasonic dispersion to establish dispersibility effects. The results demonstrated that CNCs were not significantly toxic at concentrations at or below 250 mg/L. At concentrations higher than 300 mg/L, toxicity increased linearly as CNC concentrations increased up to 2000 mg/L. IC50 calculations demonstrated an increase in cytotoxicity as CNC exposure times increased, and elevated dispersibility of the CNCs were shown to increase cytotoxicity effects. These results suggest that CNCs can impact microbial populations if elevated concentration thresholds are met. PMID- 26419246 TI - The relationship between perioperative administration of inhaled corticosteroid and postoperative respiratory complications after pulmonary resection for non small-cell lung cancer in patients with chronic obstructive pulmonary disease. AB - OBJECTIVES: Inhaled corticosteroid (ICS) treatment has been shown to increase the risk of respiratory complications in patients with stable chronic obstructive pulmonary disease (COPD). However, the effects of perioperative ICS treatment on postoperative respiratory complications after lung cancer surgery have not been elucidated. The aim of this study was to investigate whether perioperative ICS treatment would increase the risk of postoperative respiratory complications after lung cancer surgery in patients with COPD. METHODS: We retrospectively analyzed 174 consecutive COPD patients with non-small-cell lung cancer (NSCLC) who underwent lobectomy or segmentectomy between January 2007 and December 2014. Subjects were grouped based on whether or not they were administered perioperative ICS treatment. Postoperative cardiopulmonary complications were compared between the groups. RESULTS: There were no statistically significant differences in the incidence of postoperative respiratory complications (P = 0.573) between the perioperative ICS treatment group (n = 16) and the control group (n = 158). Perioperative ICS treatment was not significantly associated with postoperative respiratory complications in the univariate or multivariate analysis (odds ratio [OR] = 0.553, 95% confidence interval [CI] = 0.069-4.452, P = 0.578; OR = 0.635, 95% CI = 0.065-6.158, P = 0.695, respectively). Kaplan-Meier analysis showed that there were no statistically significant differences in the postoperative respiratory complications-free durations between the groups (P = 0.566), even after propensity score matching (P = 0.551). CONCLUSION: There was no relationship between perioperative ICS administration and the incidences of postoperative respiratory complications after surgical resection for NSCLC in COPD patients. PMID- 26419247 TI - A novel biodegradable external mesh stent improved long-term patency of vein grafts by inhibiting intimal-medial hyperplasia in an experimental canine model. AB - OBJECTIVES: Increased hemodynamic stress on vein grafts used in the arterial system is associated with vein graft disease. We determined whether a novel biodegradable external mesh stent could inhibit medial-intimal hyperplasia by suppressing hemodynamic stress on vein grafts and improve long-term patency. METHODS: Twenty-four beagles underwent bilateral femoral interposition grafting using reversed femoral veins. Vein grafts were externally supported by a novel poly L-lactide-epsilon-caprolactone copolymer (P(LA/CL)) biodegradable mesh stent or a nonabsorbable mesh stent. Vein grafts with no reinforcement were used as controls. The grafts were harvested 6 and 12 months after implantation for morphometric and immunohistochemical assessment. RESULTS: The endoluminal circumferential vein graft length was smaller in the P(LA/CL) and nonabsorbable groups (17.2 +/- 2.9 and 19.0 +/- 0.3 mm, respectively), than that in the control group (25.0 +/- 2.6 mm, P < 0.01) at 12 months. The mean intimal-medial thickness was thinner in P(LA/CL) and nonabsorbable stent groups (0.18 +/- 0.05 and 0.16 +/ 0.05 mm, respectively), than that in the control group (0.30 +/- 0.08 mm, P < 0.01). Differences in the intimal-medial thickness among the groups were associated with the magnitude of cellular proliferating activity. The graft patency ratio (100 %) was higher in the P(LA/CL) group than that in the nonabsorbable and control groups (72.2 and 63.6%, respectively, P < 0.05). CONCLUSIONS: The biodegradable P(LA/CL) external mesh stent improved vein graft patency for 12 months and prevented vein graft dilatation and intimal hyperplasia associated with suppressed neointimal layer cellular proliferating activity. PMID- 26419248 TI - Avoidable perioperative mortality at the University Teaching Hospital, Lusaka, Zambia: a retrospective cohort study. AB - PURPOSE: Perioperative mortality has fallen in both high- and low-income countries over the last 50 years. An evaluation of avoidable perioperative mortality can provide valuable lessons to improve care; however, there is relatively little recent data from the Least Developed Countries in the world. We aimed to compare recent avoidable perioperative mortality in Lusaka, Zambia, with historical data from 1987. METHODS: We conducted a retrospective cohort study by identifying perioperative deaths within days of surgery and comparing the operating room and mortuary registers for the 2012 calendar year. Multiple independent raters from anesthesiology and surgery/obstetrics gynecology reviewed case notes, when available, to identify avoidable causes of death. RESULTS: Of the 18,010 surgical patients in 2012, 114 were identified as having died perioperatively within six days of surgery. Fifty-nine files were available for further analysis (52% of identified perioperative deaths). Eighteen (30%) of these cases were assessed as avoidable, 19 cases (32%) probably avoidable, 14 cases (24%) unavoidable, and eight cases (14%) unclear. Thirty-one (53%) cases had surgical factors contributing to death, 19 (32%) cases had anesthesia factors, and 18 (30%) cases had systems factors. Most of the avoidable deaths were attributed to multiple factors. Key factors leading to the avoidable deaths were delays in surgery, lack of the availability of blood, and poor postoperative care. CONCLUSIONS: Most deaths were avoidable, suggesting that patient outcomes in low-resource settings can be improved within current resources. The multifactorial nature of avoidability implies that an interprofessional approach is required to improve the quality of care. PMID- 26419249 TI - Cadmium (Cd) Localization in Tissues of Cotton (Gossypium hirsutum L.), and Its Phytoremediation Potential for Cd-Contaminated Soils. AB - Phytoremediation using economically valuable, large biomass, non-edible plants is a promising method for metal-contaminated soils. This study investigated cotton's tolerance for Cd and remediation potential through analyzing Cd bioaccumulation and localization in plant organs under different soil Cd levels. Results showed cotton presents good tolerance when soil Cd concentration <=20.26 mg kg(-1). Cotton had good Cd accumulation ability under low soil Cd levels (<1.26 mg kg( 1)), with a TF value (the ratio of Cd concentration in stem to root) above 1. Energy dispersive X-ray microanalysis indicated cotton leaf transpiration played a key role in extracting soil Cd, while roots and stems were the main compartments of Cd storage. Cd complexation to other organic constituents in root and stem cell sap could be a primary detoxifying strategy. Therefore, cotton is a potential candidate for phytoremediation of Cd-contaminated soils. PMID- 26419250 TI - Cognitive behavioural therapy shows promise in heart failure patients with depression. PMID- 26419251 TI - Health of adolescents is targeted in new UN strategy. PMID- 26419252 TI - Delayed hospital admission until active labour may help prevent unnecessary caesarean delivery. PMID- 26419254 TI - Diagnostic performance and radiation dose of lower extremity CT angiography using a 128-slice dual source CT at 80 kVp and high pitch. AB - BACKGROUND: Multi-detector computed tomography (MDCT) angiography is now used for the diagnosing patients with peripheral arterial disease. The dose of radiation is related to variable factors, such as tube current, tube voltage, and helical pitch. PURPOSE: To assess the diagnostic performance and radiation dose of lower extremity CT angiography (CTA) using a 128-slice dual source CT at 80 kVp and high pitch in patients with critical limb ischemia (CLI). MATERIAL AND METHODS: Twenty-eight patients (mean, 64.1 years; range, 39-80 years) with CLI were enrolled in this retrospective study and underwent CTA using a 128-slice dual source CT at 80 kVp and high pitch and subsequent intra-arterial digital subtraction angiography (DSA), which was used as a reference standard for assessing diagnostic performance. RESULTS: For arterial segments with significant disease (>50% stenosis), overall sensitivity, specificity, and accuracy of lower extremity CTA were 94.8% (95% CI, 91.7-98.0%), 91.5% (95% CI, 87.7-95.2%), and 93.1% (95% CI, 90.6-95.6%), respectively, and its positive and negative predictive values were 91.0% (95% CI, 87.1-95.0%), and 95.1% (95% CI, 92.1 98.1%), respectively. Mean radiation dose delivered to lower extremities was 266.6 mGy.cm. CONCLUSION: Lower extremity CTA using a 128-slice dual source CT at 80 kVp and high pitch was found to have good diagnostic performance for the assessment of patients with CLI using an extremely low radiation dose. PMID- 26419255 TI - Inter- and intraobserver agreement in detection of testicular microlithiasis with ultrasonography. AB - BACKGROUND: Ultrasonography of the testis is a well-established diagnostic tool in detection of testicular microlithiasis (TML). Operator-dependent diagnostic variation related to skill, knowledge, and operator consistency are factors that influence detection of TML. PURPOSE: To determine inter- and intraobserver agreement for detection of TML using ultrasonography for a group of physicians with no or limited experience compared to a group of experience senior radiologists. MATERIAL AND METHODS: Between May and September 2014 a total of six observers evaluated 34 patients scrotal ultrasonography recorded from September to December 2013. The observers were blinded to patient history and previous ultrasonography. Three of the observers had no or limited experience with detection of TML, and three of the observers had more than 15 years of experience. Each observer reviewed all the scrotal ultrasonography recordings twice with a time interval of 3 months. RESULTS: The inter-observer agreement showed substantial agreement and up to almost perfect agreement (kappa = 0.86). Both the experienced and less experienced observers had a higher agreement in detecting and grading TML in their second reading. CONCLUSION: The ultrasonography grading system of TML in this study showed to be reproducible, with an inter- and intraobserver agreement ranging between substantial agreement and up to almost perfect agreement with many years of experience not necessarily being essential. PMID- 26419256 TI - Heat-Treatment-Responsive Proteins in Different Developmental Stages of Tomato Pollen Detected by Targeted Mass Accuracy Precursor Alignment (tMAPA). AB - Recently, we have developed a quantitative shotgun proteomics strategy called mass accuracy precursor alignment (MAPA). The MAPA algorithm uses high mass accuracy to bin mass-to-charge (m/z) ratios of precursor ions from LC-MS analyses, determines their intensities, and extracts a quantitative sample versus m/z ratio data alignment matrix from a multitude of samples. Here, we introduce a novel feature of this algorithm that allows the extraction and alignment of proteotypic peptide precursor ions or any other target peptide from complex shotgun proteomics data for accurate quantification of unique proteins. This strategy circumvents the problem of confusing the quantification of proteins due to indistinguishable protein isoforms by a typical shotgun proteomics approach. We applied this strategy to a comparison of control and heat-treated tomato pollen grains at two developmental stages, post-meiotic and mature. Pollen is a temperature-sensitive tissue involved in the reproductive cycle of plants and plays a major role in fruit setting and yield. By LC-MS-based shotgun proteomics, we identified more than 2000 proteins in total for all different tissues. By applying the targeted MAPA data-processing strategy, 51 unique proteins were identified as heat-treatment-responsive protein candidates. The potential function of the identified candidates in a specific developmental stage is discussed. PMID- 26419258 TI - Concentration Effects on the Entropy of Electrochemical Lithium Deposition: Implications for Li(+) Solvation. AB - The solvation behavior of Li(+) in ethylene carbonate and dimethylcarbonate upon dilution has been investigated by electrochemical microcalorimetry. We measured the heat effects at a Li electrode upon electrochemical Li deposition and dissolution from Li(+) solutions of varying concentration. The exchanged heat is correlated to the entropy of lithium deposition and therefore reveals information about the solvation of Li(+). Lithium deposition from electrolytes with lower concentrations showed less entropy gain than deposition from electrolytes with higher concentrations. This can be fully explained by the entropy of dilution of the Li(+) ions. From our data we further concluded that the inner coordination shell of the Li(+) ions does not significantly change between 0.01 and 1 M Li(+) concentration. The results also suggest that contact ion pairs, which are probably present in the electrolyte, show a similar solvation behavior as regular lithium ions. PMID- 26419257 TI - CSAR Benchmark Exercise 2013: Evaluation of Results from a Combined Computational Protein Design, Docking, and Scoring/Ranking Challenge. AB - Community Structure-Activity Resource (CSAR) conducted a benchmark exercise to evaluate the current computational methods for protein design, ligand docking, and scoring/ranking. The exercise consisted of three phases. The first phase required the participants to identify and rank order which designed sequences were able to bind the small molecule digoxigenin. The second phase challenged the community to select a near-native pose of digoxigenin from a set of decoy poses for two of the designed proteins. The third phase investigated the ability of current methods to rank/score the binding affinity of 10 related steroids to one of the designed proteins (pKd = 4.1 to 6.7). We found that 11 of 13 groups were able to correctly select the sequence that bound digoxigenin, with most groups providing the correct three-dimensional structure for the backbone of the protein as well as all atoms of the active-site residues. Eleven of the 14 groups were able to select the appropriate pose from a set of plausible decoy poses. The ability to predict absolute binding affinities is still a difficult task, as 8 of 14 groups were able to correlate scores to affinity (Pearson-r > 0.7) of the designed protein for congeneric steroids and only 5 of 14 groups were able to correlate the ranks of the 10 related ligands (Spearman-rho > 0.7). PMID- 26419259 TI - Mesenchymal stem cells-conditioned medium protects PC12 cells against 2,5 hexanedione-induced apoptosis via inhibiting mitochondria-dependent caspase 3 pathway. AB - Studies suggested that the conditioned medium of mesenchymal stem cells (MSC-CM) inhibited the increased apoptosis in various cells. However, there are no reports underlying the protection of MSC-CM against 2,5-hexanedione (HD)-induced apoptosis in neural cells. In the present study, the viability was observed in PC12 cells that received HD alone or with MSC-CM by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide assay. Apoptosis was estimated by Hoechst 33342 staining and flow cytometry. Mitochondrial transmembrane potential was examined by rhodamine 123. Moreover, we investigated the expression of Bax and Bcl-2, cytochrome c translocation, and caspase 3 activity by real-time polymerase chain reaction, Western blot, and immunochemistry. Nerve growth factor (NGF) was examined in MSCs and MSC-CM. Our results showed that MSC-CM promoted cell survival and reduced apoptosis in HD-exposed PC12 cells. Moreover, MSC-CM significantly reversed disturbance of Bax and Bcl-2, ameliorated disruption of mitochondrial transmembrane potential, and reduced release of cytochrome c and activity of caspase 3 in HD-exposed PC12 cells. In the meantime, NGF was detected in MSCs and MSC-CM. These findings demonstrate that MSC-CM protects against HD induced apoptosis in PC12 cells via inhibiting mitochondrial pathway. Our results indicate that NGF in MSC-CM may be involved in the protection of MSC-CM against HD-induced apoptosis. Our study clarifies the protection of MSC-CM on HD neurotoxicity and its underlying mechanism. PMID- 26419260 TI - Genotoxic and oxidative stress potential of nanosized and bulk zinc oxide particles in Drosophila melanogaster. AB - Zinc oxide nanoparticles (ZnONP) are manufactured on a large scale and can be found in a variety of consumer products, such as sunscreens, lotions, paints and food additives. Few studies have been carried out on its genotoxic potential and related mechanisms in whole organisms. In the present study, the in vivo genotoxic activity of ZnONP and its bulk form was assayed using the wing-spot test and comet assay in Drosophila melanogaster Additionally, a lipid peroxidation analysis using the thiobarbituric acid assay was also performed. Results obtained with the wing-spot test showed a lack of genotoxic activity of both ZnO forms. However, when both particle sizes were tested in the comet assay using larvae haemocytes, a significant increase in DNA damage was observed for ZnONP treatments but only at the higher dose applied. In addition, the lipid peroxidation assay showed significant malondialdehyde (MDA) induction for both ZnO forms, but the induction of MDA for ZnONP was higher for the ZnO bulk, suggesting that the observed DNA strand breaks could be induced by mediated oxidative stress. The overall data suggest that the potential genotoxicity of ZnONP in Drosophila can be considered weak according to the lack of mutagenic and recombinogenic effects and the induction of primary DNA damage only at high toxic doses of ZnONP. This study is the first assessing the genotoxic and oxidative stress potential of nano and bulk ZnO particles in Drosophila. PMID- 26419261 TI - Mechanisms of chromium hexavalent-induced apoptosis in rat testes. AB - Hexavalent chromium (CrVI)-containing compounds, present in industrial settings and in the environment, are known as carcinogens and mutagens. The present study is designed to test the hypothesis that oxidative stress mediates CrVI-induced apoptosis in testis. Male Wistar rats received an intraperitoneal injection of potassium dichromate at doses of 1 and 2 mg kg-1. Superoxide anion production was assessed by the determination of the reduction of cytochrome c and iodonitrotetrazolium, lipid peroxidation (LPO), metallothioneins (MTs), and catalase (CAT) activity. Apoptosis was evaluated by DNA fragmentation detected by agarose gel electrophoresis. Germinal cells apoptosis was detected by toluidine blue staining. The expression of Bax and Bcl-2 proteins (Pts) was also investigated. After 15 days of treatment, an increase of LPO and MT levels occurred, while CAT activity was decreased. Testicular tissues of treated rats showed pronounced degradation of the DNA into oligonucleotides as seen in the typical electrophoretic DNA ladder pattern. Intense apoptosis was observed in germinal cells of Cr-exposed rats. Bax Pt expression was induced in spermatogonia and spermatocytes cells of CrVI-treated rats. In contrast, Bcl-2 Pt was occasionally observed in germ cells of CrVI-exposed rats. These results clearly suggest that CrVI subacute treatment causes oxidative stress in rat testis leading to apoptosis. PMID- 26419262 TI - Identifying present challenges to reliable future transdermal drug delivery products. AB - Transdermal systems have become an accepted means of drug delivery, offering clinical benefits over other dosage forms. Although transdermal delivery has been very successful as a controlled release technology platform, there are a number of challenges that prevent this delivery route from achieving its fullest commercial potential. Additionally, beginning in 1997, transdermal drug delivery companies aligned with life science industries to deliver large molecules, peptides and proteins through the skin, which is difficult due to the skin barrier properties. A number of methods and technologies have been conceived to overcome the skin barrier. Among these are mechanical, chemical and thermal permeation enhancement techniques. These methods are briefly discussed as well as future directions for transdermal therapies. PMID- 26419264 TI - Analyzing the potential for incorrect haplotype calls with different pharmacogenomic assays in different populations: a simulation based on 1000 Genomes data. AB - AIM: Many currently available pharmacogenomic assays and algorithms interrogate a set of 'tag' polymorphisms for inferring haplotypes. We wanted to test the accuracy of such haplotype inferences across different populations. MATERIALS & METHODS: We simulated haplotype inferences made by existing pharmacogenomic assays for seven important pharmacogenes based on full genome data of 2504 persons in the 1000 Genomes dataset. RESULTS: A sizable fraction of samples did not match any of the haplotypes in the star allele nomenclature systems. We found no clear population bias in the accuracy of results of simulated assays. CONCLUSION: Haplotype nomenclatures and inference algorithms need to be improved to adequately capture pharmacogenomic diversity in human populations. PMID- 26419271 TI - Psychological, endocrine, and neural correlates of attentional bias in subclinical depression. AB - BACKGROUND: Our knowledge with respect to psychological, endocrine, and neural correlates of attentional bias in individuals with high vulnerability to developing depression - the subclinically depressed, still remains limited. DESIGN: The study used a 2 * 2 mixed design. METHODS: Attentional bias toward happy and sad faces in healthy (N = 26) and subclinically depressed individuals (N = 22) was assessed via a neuroimaging dot-probe attention task. Participants also completed trait and state psychological measures and provided saliva samples for cortisol analysis. RESULTS: The subclinical group showed attentional bias toward happy faces; past use of problem-focused coping strategies when dealing with a personally relevant stressor as well as state levels of anxiety, together, contributed to this bias. In the control group, the happy attentional bias was positively correlated with activity in the right caudate. In the subclinical group, the bias was negatively associated with the left fusiform gyrus and positively with the left inferior parietal lobule and bilateral putamen. We observed group differences in association between cortisol levels during the task and neural activity during happy attentional bias processing within the key regions involved in attention. CONCLUSIONS: The attentional bias toward happy faces may reflect an active coping attempt by the subclinical participants. PMID- 26419272 TI - Sections 3 and 37 of the Mental Health Act 1983 - a comparison. PMID- 26419263 TI - Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis. AB - INTRODUCTION: Recombinant human erythropoietin (rhEPO) is a first-line therapeutic for the anemia of chronic kidney disease, cancer chemotherapy, AIDS (Zidovudine therapy), and lower-risk myelodysplastic syndrome. However, rhEPO frequently elevates hypertension, is costly, and may affect cancer progression. Potentially high merit therefore exists for defining new targets for anti-anemia agents within erythropoietin (EPO) and EPO receptor (EPOR) regulatory circuits. AREAS COVERED: EPO production by renal interstitial fibroblasts is subject to modulation by several regulators of hypoxia-inducible factor 2a (HIF2a) including Iron Response Protein-1, prolyl hydroxylases, and HIF2a acetylases, each of which holds potential as anti-anemia drug targets. The cell surface receptor for EPO (EPOR) preassembles as a homodimer, together with Janus Kinase 2 (JAK2), and therefore it remains attractive to develop novel agents that trigger EPOR complex activation (activating antibodies, mimetics, small-molecule agonists). Additionally, certain downstream transducers of EPOR/JAK2 signaling may be druggable, including Erythroferrone (a hepcidin regulator), a cytoprotective Spi2a serpin, and select EPOR-associated protein tyrosine phosphatases. EXPERT OPINION: While rhEPO (and biosimilars) are presently important mainstay erythropoiesis-stimulating agents (ESAs), impetus exists for studies of novel ESAs that fortify HIF2a's effects, act as EPOR agonists, and/or bolster select downstream EPOR pathways to erythroid cell formation. Such agents could lessen rhEPO dosing, side effects, and/or costs. PMID- 26419274 TI - Highly luminescent gold nanoparticles: effect of ruthenium distance for nanoprobes with enhanced lifetimes. AB - The photophysical properties of gold nanoparticles, AuNPs, with sizes of 13, 50 and 100 nm in diameter, coated with surface-active ruthenium complexes have been studied to investigate the effect of the distance of the ruthenium luminescent centre from the gold surface. Luminescence lifetimes of the three ruthenium probes, RuS1, RuS6 and RuS12, with different length spacer units between the surface active groups and the ruthenium centre were taken. The metal complexes were attached to AuNP13, AuNP50 and AuNP100 via thiol groups using a method of precoating the nanoparticles with a fluorinated surfactant. The luminescence lifetime of the longer spacer unit complex, RuS12, was enhanced by 70% upon attachment to the AuNP when compared to the increase of the short and medium linker unit complexes, RuS1 (20%) and (RuS6 40%) respectively. The effect of the surfactant in the lifetime increase of the ruthenium coated AuNPs was shown to be larger for the medium spacer probe, RuS6. There was no effect of the change of the size of the AuNPs from 13 to 50 or 100 nm. PMID- 26419273 TI - Clinical negligence in hospitals in France and England. AB - This article arose from the back-to-back presentations by Michael Kelly and Patrice Metayer to the Anglo-French Medical Society in 2013 on the French and English legal systems handling a case of alleged clinical negligence as it proceeds from complaint to settlement or judgment in the two jurisdictions. Both systems have a hospital-based first stage with various avenues being available for amicable resolution, the French version being more regulated and prescribed than the English one. In both jurisdictions fewer than 5% cases go down the criminal route. Before the court is involved, in England there is an elaborate lawyer-controlled phase involving negotiations between the two sides and their experts which is expensive but often leads to pre-trial settlement for significant sums of money. Medical experts are central to all of this. In England they are largely unregulated and entirely advisory in an open market, in France they are both regulated and supervised by judges, being placed on official lists. These experts take a major inquisitorial role in a Debate between the two sides, combining the functions of Single Joint Expert (SJE), arbiter and mentor. If agreement is not reached, a second Debate before a different Expert is arranged. In both countries fewer than 5% cases reach a court for a hearing before a judge. In England a trial is an elaborate lengthy, expensive adversarial contest where all of the issues are rehearsed in full with factual and expert evidence, whereas in France in a contested case the judge reviews the reports of the two Debates with the lawyers who were involved (and not the experts, factual witnesses or parties). PMID- 26419275 TI - Peroxidase-like oxidative activity of a manganese-coordinated histidyl bolaamphiphile self-assembly. AB - A peroxidase-like catalyst was constructed through the self-assembly of histidyl bolaamphiphiles coordinated to Mn(2+) ions. The prepared catalyst exhibited oxidation activity for the organic substrate o-phenylenediamine (OPD) in the presence of hydrogen peroxide (H2O2). The histidyl bolaamphiphiles of bis(N-alpha amido-histidine)-1,7-heptane dicarboxylates self-assembled to make spherical structures in an aqueous solution. Subsequent association of Mn(2+) ions with the histidyl imidazoles in the self-assembly produced catalytic active sites. The optimal Mn(2+) ion concentration was determined and coordination of the Mn(2+) ion with multiple histidine imidazoles was investigated using spectroscopy analysis. The activation energy of the produced catalysts was 55.0 kJ mol(-1), which was comparable to other peroxidase-mimetic catalysts. A detailed kinetics study revealed that the prepared catalyst followed a ping-pong mechanism and that the turnover reaction was promoted by increasing the substrate concentration. Finally, application of the prepared catalyst for glucose detection was demonstrated through cascade enzyme catalysis. This study demonstrated a facile way to prepare an enzyme-mimetic catalyst through the self-assembly of an amphiphilic molecule containing amino acid segments. PMID- 26419277 TI - A comparison of exposure to risk factors for giardiasis in non-travellers, domestic travellers and international travellers in a Canadian community, 2006 2012. AB - The purpose of this study is to determine how demographic and exposure factors related to giardiasis vary between travel and endemic cases. Exposure and demographic data were gathered by public health inspectors from giardiasis cases reported from the Region of Waterloo from 2006 to 2012. Logistic regression models were fit to assess differences in exposure to risk factors for giardiasis between international travel-related cases and Canadian acquired cases while controlling for age and sex. Multinomial regression models were also fit to assess the differences in risk profiles between international and domestic travel related cases and endemic cases. Travel-related cases (both international and domestic) were more likely to go camping or kayaking, and consume untreated water compared to endemic cases. Domestic travel-related cases were more likely to visit a petting zoo or farm compared to endemic cases, and were more likely to swim in freshwater compared to endemic cases and international travel-related cases. International travellers were more likely to swim in an ocean compared to both domestic travel-related and endemic cases. These findings demonstrate that travel-related and endemic cases have different risk exposure profiles which should be considered for appropriately targeting health promotion campaigns. PMID- 26419278 TI - A rare variant (c.863G>T) in exon 7 of SMN1 disrupts mRNA splicing and is responsible for spinal muscular atrophy. AB - Proximal spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by deletion or mutation of SMN1 (survival motor neuron 1). SMN exon 7 splicing is regulated by a number of exonic and intronic regulatory sequences and the trans-factors that bind them. Variants located in or near these regulated regions should be evaluated to determine their effect on splicing. We identified the rare variant c.863G>T (r.835_*3del, p.Gly279Glufs*5) in exon 7 of SMN1 in three patients affected with type I or type II SMA. Most of the SMN1 transcripts exhibited complete loss of exon 7 in vivo. The ex vivo splicing assay demonstrated that the variant disrupts inclusion of exon 7 (~85%) in the SMN1 mRNA; replacement with various bases yielded a variety of splicing effects in SMN1 and SMN2 pre-mRNA. The c.863G>T (r.835_*3del, p.Gly279Glufs*5) variant is located in a region that includes binding sites for multiple splicing factors including Tra2beta1. Thus, the variant disrupts Tra2beta1 binding, but does not affect binding of hnRNP A1. These findings demonstrate how rare variants influence pre-mRNA splicing of SMN and reveal the functional influence of c.863G>T (r.835_*3del, p.Gly279Glufs*5) variant in patients with SMA. PMID- 26419279 TI - D117N in Cypher/ZASP may not be a causative mutation for dilated cardiomyopathy and ventricular arrhythmias. AB - Dilated cardiomyopathy (DCM) and malignant ventricular arrhythmias are important causes of congestive heart failure, heart transplantation, and sudden cardiac death in young patients. Cypher/ZASP is a cytoskeletal protein localized in the sarcomeric Z-line that has a pivotal role in maintaining adult cardiac structure and function. The putative mutation p.(D117N) in Cypher/ZASP has been suggested to cause systolic dysfunction, dilated left ventricle with hypertrabeculated myocardium, and intraventricular conduction disturbance, based on two reported sporadic cases. In two unrelated Bedouin families, one with pediatric DCM and the other with DCM and ventricular arrhythmias at young adulthood searching for the causative mutation by exome sequencing we identified the p.(D117N) variant in Cypher/ZASP. However, p.(D117N) did not segregate as the causative mutation in these families, i.e. it was not present in some patients and was found in several individuals who had no clinical manifestations. Furthermore, the carrier frequency in the Bedouin population of origin is estimated to be 5.2%, which is much higher than the incidence of idiopathic DCM in this population. Thus, our data support the notion that the p.(D117N) variant in Cypher/ZASP is not a causative mutation in the families tested by us. The results also indicates that at least in some cases, the p.(D117N) in Cypher/ZASP is not a causative mutation and the role of D117N in Cypher/ZASP in cardiac pathologies should be further clarified and re-evaluated. PMID- 26419280 TI - Corrigendum: Enhanced role of eddies in the Arctic marine biological pump. PMID- 26419281 TI - Hypothalamic overexpression of mutant huntingtin causes dysregulation of brown adipose tissue. AB - Expression of mutant huntingtin (htt) protein has been shown to cause metabolic imbalance in animal models of Huntington disease (HD). The pathways involved are not fully understood but dysfunction of both the hypothalamus and brown adipose tissue (BAT) has been implicated. Here we show that targeted expression of mutant HTT in the hypothalamus leads to loss of the A13 dopaminergic cell group located in the zona incerta and reduced mRNA expression of neuropeptide Y1 receptor in the hypothalamus. Furthermore, this is accompanied by downregulation of uncoupling protein 1 expression and PPARgamma coactivator-1 alpha in BAT and a rapid body weight gain. Taken together, our data might provide a mechanistic link between expression of mutant HTT, reduced activity of a hypothalamic dopaminergic pathway and dysfunction of BAT and in part explain the development of an obese phenotype in HD mouse models. PMID- 26419282 TI - Mode-resolved frequency comb interferometry for high-accuracy long distance measurement. AB - Optical frequency combs have developed into powerful tools for distance metrology. In this paper we demonstrate absolute long distance measurement using a single femtosecond frequency comb laser as a multi-wavelength source. By applying a high-resolution spectrometer based on a virtually imaged phased array, the frequency comb modes are resolved spectrally to the level of an individual mode. Having the frequency comb stabilized against an atomic clock, thousands of accurately known wavelengths are available for interferometry. From the spectrally resolved output of a Michelson interferometer a distance is derived. The presented measurement method combines spectral interferometry, white light interferometry and multi-wavelength interferometry in a single scheme. Comparison with a fringe counting laser interferometer shows an agreement within <10(-8) for a distance of 50 m. PMID- 26419283 TI - Antigen exposure in the late light period induces severe symptoms of food allergy in an OVA-allergic mouse model. AB - The mammalian circadian clock controls many physiological processes that include immune responses and allergic reactions. Several studies have investigated the circadian regulation of intestinal permeability and tight junctions known to be affected by cytokines. However, the contribution of circadian clock to food allergy symptoms remains unclear. Therefore, we investigated the role of the circadian clock in determining the severity of food allergies. We prepared an ovalbumin food allergy mouse model, and orally administered ovalbumin either late in the light or late in the dark period under light-dark cycle. The light period group showed higher allergic diarrhea and weight loss than the dark period group. The production of type 2 cytokines, IL-13 and IL-5, from the mesenteric lymph nodes and ovalbumin absorption was higher in the light period group than in the dark period group. Compared to the dark period group, the mRNA expression levels of the tight junction proteins were lower in the light period group. We have demonstrated that increased production of type 2 cytokines and intestinal permeability in the light period induced severe food allergy symptoms. Our results suggest that the time of food antigen intake might affect the determination of the severity of food allergy symptoms. PMID- 26419284 TI - Pancreatic Cancer: Promises and Failures of Target Therapies. AB - Currently, few efficient therapies are available to battle pancreatic cancer. Mechanisms underlying this cancer are not well known and researchers are trying to identify new therapeutic targets. Here, we present a review of new treatments and their results in recent years. PMID- 26419285 TI - Understanding Particle Formation: Solubility of Free Fatty Acids as Polysorbate 20 Degradation Byproducts in Therapeutic Monoclonal Antibody Formulations. AB - The purpose of this work was to determine the aqueous solubilities at 2-8 degrees C of the major free fatty acids (FFAs) formed by polysorbate 20 (PS20) degradation and identify possible ways to predict, delay, or mitigate subsequent particle formation in monoclonal antibody (mAb) formulations. The FFA solubility limits at 2-8 degrees C were determined by titrating known amounts of FFA in monoclonal antibody formulations and identifying the FFA concentration leading to visible and subvisible particle formation. The solubility limits of lauric, myristic, and palmitic acids at 2-8 degrees C were 17 +/- 1 MUg/mL, 3 +/- 1 MUg/mL, and 1.5 +/- 0.5 MUg/mL in a formulation containing 0.04% (w/v) PS20 at pH 5.4 and >22 MUg/mL, 3 +/- 1 MUg/mL, and 0.75 +/- 0.25 MUg/mL in a formulation containing 0.02% (w/v) PS20 at pH 6.0. For the first time, a 3D correlation between FFA solubility, PS20 concentration, and pH has been reported providing a rational approach for the formulator to balance these with regard to potential particle formation. The results suggest that the lower solubilities of the longer chain FFAs, generated from degradation of the stearate, palmitate, and myristate fraction of PS20, is the primary cause of seeding and subsequent FFA precipitation rather than the most abundant lauric acid. PMID- 26419286 TI - Transgenerational Adaptation to Pollution Changes Energy Allocation in Populations of Nematodes. AB - Assessing the evolutionary responses of long-term exposed populations requires multigeneration ecotoxicity tests. However, the analysis of the data from these tests is not straightforward. Mechanistic models allow the in-depth analysis of the variation of physiological traits over many generations, by quantifying the trend of the physiological and toxicological parameters of the model. In the present study, a bioenergetic mechanistic model has been used to assess the evolution of two populations of the nematode Caenorhabditis elegans in control conditions or exposed to uranium. This evolutionary pressure resulted in a brood size reduction of 60%. We showed an adaptation of individuals of both populations to experimental conditions (increase of maximal length, decrease of growth rate, decrease of brood size, and decrease of the elimination rate). In addition, differential evolution was also highlighted between the two populations once the maternal effects had been diminished after several generations. Thus, individuals that were greater in maximal length, but with apparently a greater sensitivity to uranium were selected in the uranium population. In this study, we showed that this bioenergetics mechanistic modeling approach provided a precise, certain, and powerful analysis of the life strategy of C. elegans populations exposed to heavy metals resulting in an evolutionary pressure across successive generations. PMID- 26419287 TI - Atomic layer deposition on 2D transition metal chalcogenides: layer dependent reactivity and seeding with organic ad-layers. AB - This commmunication presents a study of atomic layer deposition of Al2O3 on transition metal dichalcogenide (TMD) two-dimensional films which is crucial for use of these promising materials for electronic applications. Deposition of Al2O3 on pristine chemical vapour deposited MoS2 and WS2 crystals is demonstrated. This deposition is dependent on the number of TMD layers as there is no deposition on pristine monolayers. In addition, we show that it is possible to reliably seed the deposition, even on the monolayer, using non-covalent functionalisation with perylene derivatives as anchor unit. PMID- 26419288 TI - Interactions of Histone Acetyltransferase p300 with the Nuclear Proteins Histone and HMGB1, As Revealed by Single Molecule Atomic Force Spectroscopy. AB - One of the important properties of the transcriptional coactivator p300 is histone acetyltransferase (HAT) activity that enables p300 to influence chromatin action via histone modulation. p300 can exert its HAT action upon the other nuclear proteins too--one notable example being the transcription-factor-like protein HMGB1, which functions also as a cytokine, and whose accumulation in the cytoplasm, as a response to tissue damage, is triggered by its acetylation. Hitherto, no information on the structure and stability of the complexes between full-length p300 (p300FL) (300 kDa) and the histone/HMGB1 proteins are available, probably due to the presence of unstructured regions within p300FL that makes it difficult to be crystallized. Herein, we have adopted the high-resolution atomic force microscopy (AFM) approach, which allows molecularly resolved three dimensional contour mapping of a protein molecule of any size and structure. From the off-rate and activation barrier values, obtained using single molecule dynamic force spectroscopy, the biochemical proposition of preferential binding of p300FL to histone H3, compared to the octameric histone, can be validated. Importantly, from the energy landscape of the dissociation events, a model for the p300-histone and the p300-HMGB1 dynamic complexes that HAT forms, can be proposed. The lower unbinding forces of the complexes observed in acetylating conditions, compared to those observed in non-acetylating conditions, indicate that upon acetylation, p300 tends to weakly associate, probably as an outcome of charge alterations on the histone/HMGB1 surface and/or acetylation-induced conformational changes. To our knowledge, for the first time, a single molecule level treatment of the interactions of HAT, where the full-length protein is considered, is being reported. PMID- 26419289 TI - Increased frequency of co-existing JAK2 exon-12 or MPL exon-10 mutations in patients with low JAK2(V617F) allelic burden. AB - The frequency of co-existing JAK2(V617F)/MPL and JAK2(V617F)/JAK2 exon-12 mutations has not been previously investigated in MPNs. Poor survival was reported in primary myelofibrosis with low JAK2(V617F) allelic burden. However, mutational status of JAK2 exon-12 or MPL were not reported in these patients. This study developed a cost-effective multiplex high resolution melt assay that screens for mutations in JAK2 gene exons-12 and -14 ((V617F)) and MPL gene exon 10. Co-existing mutations with JAK2(V617F) were detected in 2.9% (6/208; two JAK2 exon-12 and four MPL exon-10) patient specimens with known JAK2(V617F) (allelic burden range: 0.1-96.8%). Co-existing mutations were detected in specimens with < 12% JAK2(V617F) allelic burden. Current WHO guidelines do not recommend further testing once JAK2(V617F) mutation is detected in MPNs. The findings, however, indicate that quantification of JAK2(V617F) allele burden may be clinically relevant in MPNs and in those with low allelic burden additional testing for JAK2 exon-12 and MPL exon-10 mutation should be pursued. PMID- 26419290 TI - Microneedles: bench to bedside. AB - Microneedles are tiny micron-sized structures, made of a variety of materials, used to minimally disrupt the outermost layer of the skin for enhancing the delivery of therapeutic molecules across the skin. They are sufficiently long enough just to breach the stratum corneum barrier but too short to reach the nerve endings that perceive pain. Treating the skin using microneedles results in the creation of aqueous microchannels that promote delivery of molecules practically of any size. Small molecules, proteins, vaccines and diagnostic agents can be delivered using microneedles. This technology that has started with microstructures made of metal and silicon has now undergone significant advances in the last decade and currently there are microneedle products in the market. PMID- 26419292 TI - The electronic structures and photophysical properties of platinum complexes with C^N^N ligands: the influence of the carborane substituent. AB - Carboranes have attracted increasing interest in the scientific community due to their remarkable structures and strong electron-withdrawing abilities. In this article, four platinum complexes [(C^N^N)PtC[triple bond, length as m dash]CPh](1), [(C^N^N)PtC[triple bond, length as m-dash]C-TPA](2), [(C^N^N)PtC[triple bond, length as m-dash]C-TAB](3), [(C^N^N)PtC[triple bond, length as m-dash]C-CB](4) (where TPA = triphenylamine, TAB = triarylboryl, CB = o carborane) have been calculated via density functional theory (DFT) and time dependent density functional theory (TDDFT) methods to mainly explore the influence of carborane substituents on electronic structures, photophysical properties and radiative decay processes. The calculated results reveal that 2 with electron-donating triphenylamine has a low radiative decay rate constant and a red-shifted emission band, but 3 and 4 containing electron-withdrawing triarylboryl and o-carborane exhibit the opposite properties, especially 4 is supposed to have the highest phosphorescence quantum yield with the smallest nonradiative decay rate constant. These findings successfully illustrated the structure-property relationship and the designed complex 4 with carborane can serve as a highly efficient phosphorescent material in the future. PMID- 26419291 TI - Quantifying the value of biomarkers for predicting mortality. AB - PURPOSE: In light of widespread interest in the prognostic value of biomarkers, we apply three discrimination measures to evaluate the incremental value of biomarkers--beyond self-reported measures--for predicting all-cause mortality. We assess whether all three measures--area under the receiver-operating characteristic curve, continuous net reclassification improvement, and integrated discrimination improvement--lead to the same conclusions. METHODS: We use longitudinal data from a nationally representative sample of older Taiwanese (n = 639, aged 54 or older in 2000, examined in 2000 and 2006, with mortality follow up through 2011). We estimate age-specific mortality using a Gompertz hazard model. RESULTS: The broad conclusions are consistent across the three discrimination measures and support the inclusion of biomarkers, particularly inflammatory markers, in household surveys. Although the rank ordering of individual biomarkers varies across discrimination measures, the following is true for all three: interleukin-6 is the strongest predictor, the other three inflammatory markers make the top 10, and homocysteine ranks second or third. CONCLUSIONS: The consistency of most of our findings across metrics should provide comfort to researchers using discrimination measures to evaluate the prognostic value of biomarkers. However, because the degree of consistency varies with the level of detail inherent in the research question, we recommend that researchers confirm results with multiple discrimination measures. PMID- 26419293 TI - Effect of cariprazine across the symptoms of mania in bipolar I disorder: Analyses of pooled data from phase II/III trials. AB - Bipolar I disorder is a chronic disorder characterized by episodic recurrences of mania, depression, and mixed affective states interspersed with periods of full or partial remission; subsyndromal residual symptoms between episodes are common and disabling. Cariprazine, an atypical antipsychotic, is a potent dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors. Post hoc analyses of pooled data from 3 positive trials were conducted to evaluate the effect of cariprazine 3-12 mg/d on the symptoms of mania in inpatients (18-65 years) with bipolar I disorder and a current manic episode. Analyses were based on the pooled intent-to-treat (ITT) population (placebo=429; cariprazine=608). Mean change from baseline to the end of treatment on individual Young Mania Rating Scale (YMRS) items was analysed using a mixed-effects model for repeated measures (MMRM); categorical symptom severity shifts were analysed using logistic regression. Statistically significant improvement in mean change was seen for cariprazine versus placebo on all 11 YMRS items (p<0.0001); significantly more cariprazine- versus placebo-treated patients had mild/no symptoms at the end of treatment on 11 YMRS items (p<0.0001) and concurrently on the 4 YMRS core symptoms (irritability, speech, content, and disruptive-aggressive behaviour) (p<0.0001). Significantly more cariprazine- versus placebo-treated patients shifted from a Moderate/Worse or Marked/Worse Symptoms categories to Mild/No Symptoms on all 11 (p<0.0001) and 9 of 11 YMRS items (p<0.05), respectively. Results suggest that cariprazine treatment improved mania across YMRS symptoms; a significant percentage of cariprazine- versus placebo-treated patients had mild/no symptoms at the end of treatment. PMID- 26419295 TI - Is Smoking a Predictor for Acute Mountain Sickness? Findings From a Meta Analysis. AB - AIM: Studies of the potential association between cigarette smoking and acute mountain sickness (AMS) have reached contradictory conclusions. Our aim was to perform a meta-analysis of studies across a range of populations to ascertain better the true relationship between cigarette smoking and AMS. MATERIALS AND METHODS: We used the PRISMA protocol to identify and screen eligible studies of smoking and AMS. Databases including Pubmed and Google Scholar were searched, using the terms "smoking" and "acute mountain sickness." We conducted a meta analysis of the selected studies in order to evaluate causal inference, evaluate potential biases, and investigate possible sources of heterogeneity across studies. RESULTS: We identified 3907 publications, of which 29 were eligible for inclusion by reporting smoking status and AMS. Of these, eight publications were excluded because they were duplicative or were lacking quantitative data. The 21 studies analyzed included 16 566 subjects. These fell into two groups: occupational/military (n = 8) or volunteers/trekkers/mixed (n = 13). Study heterogeneity was high (X (2) = 55.5, P < .001). Smoking was not statistically associated with increased risk of AMS: pooled OR = 0.88 (95% CI = 0.74-1.05). Stratification yielded similar risk estimates among the occupational/military studies versus all others and studies at relatively higher and lower altitudes. CONCLUSIONS: Overall, smoking was not statistically significantly associated with AMS: there is no consistent effect of cigarette smoking acting as either a protective factor against or a risk factor for AMS. IMPLICATIONS: This is the first quantitative assessment of published studies on smoking and AMS, which shows smoking to be neither a risk, nor protective. Studies specifically focusing on smoking as a risk factor, should guide further research on this issue. Although all smokers should be strongly advised to quit, studies on risk factors for AMS focusing on other exposures could shed light on the full range of risks for AMS. PMID- 26419294 TI - Alterations in brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in the brain regions of a learned helplessness rat model and the antidepressant effects of a TrkB agonist and antagonist. AB - Role of brain-derived neurotrophic factor (BDNF)-TrkB signaling in a learned helplessness (LH) model of depression was investigated. LH rats showed a reduction of BDNF in the medial prefrontal cortex (mPFC), CA3, and dentate gyrus (DG) of the hippocampus, whereas LH rats showed an increase in BDNF in the nucleus accumbens (NAc). Furthermore, levels of proBDNF, a BDNF precursor, were higher in the mPFC, but lower in the NAc, of LH rats. A single bilateral infusion of a TrkB agonist 7,8-DHF, but not a TrkB antagonist ANA-12, into the infralimbic (IL) of mPFC, DG, and CA3, but not the prelimbic (PrL) of mPFC, exerted antidepressant effects in LH rats. In contrast, a single bilateral infusion of ANA-12, but not 7,8-DHF, into the core and shell of NAc exerted antidepressant like effects in LH rats, with more potent effects observed for the NAc core than for NAc shell. Interestingly, a single administration of 7,8-DHF (10mg/kg, i.p.) significantly improved a decreased phosphorylation of TrkB in the mPFC, CA3, and DG of LH rats. Additionally, ANA-12 (0.5mg/kg, i.p.) significantly improved an increased phosphorylation of TrkB in the NAc of LH rats. In conclusion, these results suggest that LH causes depression-like behavior by altering BDNF in the brain regions, and that proBDNF-BDNF processing and transport may be altered in the mPFC-NAc circuit of LH rats. Therefore, TrkB agonists might exert antidepressant effects by stimulating TrkB in the IL, CA3, and DG, while TrkB antagonists might exert antidepressant effects by blocking TrkB in the NAc. PMID- 26419297 TI - [G. Bleu and D. Subtil in reply to the correspondence by D. Riethmuller on their article entitled: Assessment of vacuum-assisted delivery in a frank breech presentation. Gynecol Obstet Fertil 2015;43:123-7]. PMID- 26419296 TI - Feasibility of a self-rehabilitation program for the upper limb for stroke patients in Benin. AB - INTRODUCTION: Stroke is a major cause of disability and represents a very high cost in developing countries. Self-rehabilitation programs represent a new and original treatment for stroke patients, likely to reduce upper limb impairments and improve activity and participation. The goal of this study is to evaluate the feasibility of a self-rehabilitation protocol in Benin. METHODS: Twelve chronic stroke patients carried out the upper limb self-rehabilitation program (3 hours/day, 5 days/week for 2 weeks). The performance of these patients was evaluated before and after the self-rehabilitation program, by measuring the number of exercises that patients were able to achieve during a three-hour session, and by assessing their gross manual dexterity. RESULTS: Twelve patients were effectively able to complete the entire program. The number of unimanual exercises and self-mobilizations performed during a three-hour session as well as the score of the Box and Block test were improved by the self-rehabilitation program (P<0.05). DISCUSSION AND CONCLUSION: Self-rehabilitation programs are feasible and inexpensive as they do not involve a therapist. It is then a promising approach in stroke rehabilitation, particularly in developing countries, where rehabilitation costs are usually supported by patients. PMID- 26419298 TI - Glucocorticoid pharmacogenetics in pediatric idiopathic nephrotic syndrome. AB - Idiopathic nephrotic syndrome represents the most common type of primary glomerular disease in children: glucocorticoids (GCs) are the first-line therapy, even if considerable interindividual differences in their efficacy and side effects have been reported. Immunosuppressive and anti-inflammatory effects of these drugs are mainly due to the GC-mediated transcription regulation of pro- and anti-inflammatory genes. This mechanism of action is the result of a complex multistep pathway that involves the glucocorticoid receptor and several other proteins, encoded by polymorphic genes. Aim of this review is to highlight the current knowledge on genetic variants that could affect GC response, particularly focusing on children with idiopathic nephrotic syndrome. PMID- 26419306 TI - ACR BI-RADS Use in Low-Income Countries: An Analysis of Diagnostic Breast Ultrasound Practice in Uganda. PMID- 26419305 TI - In vitro-in vivo correlation for complex non-oral drug products: Where do we stand? AB - In vitro-in vivo correlation (IVIVC) is a predictive mathematical model describing the relationship between an in vitro property and a relevant in vivo response of drug products. Since the U.S. Food and Drug Administration (FDA) published a regulatory guidance on the development, evaluation, and applications of IVIVC for extended release (ER) oral dosage forms in 1997, IVIVC has been one of the most important issues in the field of pharmaceutics. However, even with the aid of the FDA IVIVC Guidance, only very limited Abbreviated New Drug Application (ANDA) submission for ER oral drug products included adequate IVIVC data to enable the completion of bioequivalence (BE) review within first review cycle. Establishing an IVIVC for non-oral dosage forms has remained extremely challenging due to their complex nature and the lack of in vitro release methods that are capable of mimicking in vivo drug release conditions. This review presents a general overview of recent advances in the development of IVIVC for complex non-oral dosage forms (such as parenteral polymeric microspheres/implants, and transdermal formulations), and briefly summarizes the knowledge gained over the past two decades. Lastly this review discusses possible directions for future development of IVIVC for complex non-oral dosage forms. PMID- 26419307 TI - From Gatekeeper to Steward: The Evolving Concept of Radiologist Accountability for Imaging Utilization. PMID- 26419308 TI - Thyroid Ultrasound Reporting Lexicon: White Paper of the ACR Thyroid Imaging, Reporting and Data System (TIRADS) Committee. AB - Ultrasound is the most commonly used imaging technique for the evaluation of thyroid nodules. Sonographic findings are often not specific, and definitive diagnosis is usually made through fine-needle aspiration biopsy or even surgery. In reviewing the literature, terms used to describe nodules are often poorly defined and inconsistently applied. Several authors have recently described a standardized risk stratification system called the Thyroid Imaging, Reporting and Data System (TIRADS), modeled on the BI-RADS system for breast imaging. However, most of these TIRADS classifications have come from individual institutions, and none has been widely adopted in the United States. Under the auspices of the ACR, a committee was organized to develop TIRADS. The eventual goal is to provide practitioners with evidence-based recommendations for the management of thyroid nodules on the basis of a set of well-defined sonographic features or terms that can be applied to every lesion. Terms were chosen on the basis of demonstration of consistency with regard to performance in the diagnosis of thyroid cancer or, conversely, classifying a nodule as benign and avoiding follow-up. The initial portion of this project was aimed at standardizing the diagnostic approach to thyroid nodules with regard to terminology through the development of a lexicon. This white paper describes the consensus process and the resultant lexicon. PMID- 26419309 TI - Health Resources and Services Agency Issues New National Practitioner Data Bank Guidebook. PMID- 26419310 TI - Integrating a Community Hospital-Based Radiology Department With an Academic Medical Center. PMID- 26419311 TI - Proton Beam Therapy Basics. PMID- 26419312 TI - Intestinal immune function, antioxidant status and tight junction proteins mRNA expression in young grass carp (Ctenopharyngodon idella) fed riboflavin deficient diet. AB - This study investigated the effects of riboflavin on intestinal immunity, tight junctions and antioxidant status of young grass carp (Ctenopharyngodon idella). Fish were fed diets containing graded levels of riboflavin (0.63-10.04 mg/kg diet) for 8 weeks. The study indicated that riboflavin deficiency decreased lysozyme, acid phosphatase, copper/zinc superoxide dismutase, glutathione reductase and glutathione peroxidase activities, and contents of complement component 3 and reduced glutathione in the intestine of fish (P < 0.05). Meanwhile, riboflavin deficiency increased reactive oxygen species, malondialdehyde and protein carbonyl contents and catalase activity (P < 0.05) in the intestine of fish. Furthermore, real-time polymerase chain reaction analysis was used to investigate mRNA expression patterns and found that the mRNA levels of interleukin 10 and transforming growth factor beta1, Occludin, zonula occludens 1, Claudin-b and Claudin-c, inhibitor protein kappaBalpha, target of rapamycin, ribosomal S6 protein kinase 1 and NF-E2-related factor 2, copper/zinc superoxide dismutase, glutathione peroxidase and glutathione reductase were decreased (P < 0.05) in the intestine of fish fed riboflavin-deficient diet. Conversely, the mRNA levels of tumor necrosis factor alpha, interleukin 1beta, interleukin 8, nuclear factor kappa B p65, Ikappa B kinase beta, Ikappa B kinase gamma, Kelch-like-ECH-associated protein 1b, p38 mitogen-activated protein kinase, myosin light chain kinase and Claudin-12 were increased (P < 0.05) in the intestine of fish fed riboflavin-deficient diet. In conclusion, riboflavin deficiency decreased immunity and structural integrity of fish intestine. The optimum riboflavin level for intestinal acid phosphatase activity of young grass carp was estimated to be 6.65 mg/kg diet. PMID- 26419313 TI - Structure and gelation properties of casein micelles doped with curcumin under acidic conditions. AB - In this study, the ability of micellar casein (MC) to interact with curcumin during acidification and to produce acid gel was investigated. Steady-state fluorescence spectroscopy of curcumin variation and fluorescence quenching of caseins upon binding with curcumin molecules were evidenced. Increasing the temperature from 20 to 35 degrees C enhanced MC-curcumin interactions as reflected by the increase in the binding constant from 0.6 +/- 0.3 * 10(4) to 6.6 +/- 0.6 * 10(4) M(-1). From changes in entropy, enthalpy and Gibbs free energy, hydrophobic interactions were proposed as major binding forces. Static fluorescence MC quenching was demonstrated for the MC-curcumin complex during acidification. From pH 7.4 to pH 5.0, the binding site numbers varied in the range from 1.25 +/- 0.05 to 1.49 +/- 0.05 and the binding constant kb varied from 3.9 +/- 0.4 * 10(4) to 7.5 +/- 0.7 * 10(4) M(-1). Small angle X-ray scattering profiles demonstrated that the MC internal structure was unchanged upon curcumin binding. The zeta-potential value of curcumin-doped MC indicated that curcumin did not modify the global charge of MC particles. Acid gelation studied by oscillation rheology and static multiple light scattering at 20 and 35 degrees C led to a similar behavior for native and curcumin-doped MC suspensions. For the first time, it was demonstrated that the colloidal and functional properties of MC were unchanged when doped with curcumin during acidification. PMID- 26419315 TI - Exploration of graphene oxide as an intelligent platform for cancer vaccines. AB - We explored an intelligent vaccine system via facile approaches using both experimental and theoretical techniques based on the two-dimensional graphene oxide (GO). Without extra addition of bio/chemical stimulators, the microsized GO imparted various immune activation tactics to improve the antigen immunogenicity. A high antigen adsorption was acquired, and the mechanism was revealed to be a combination of electrostatic, hydrophobic, and pi-pi stacking interactions. The "folding GO" acted as a cytokine self-producer and antigen reservoir and showed a particular autophagy, which efficiently promoted the activation of antigen presenting cells (APCs) and subsequent antigen cross-presentation. Such a "One but All" modality thus induced a high level of anti-tumor responses in a programmable way and resulted in efficient tumor regression in vivo. This work may shed light on the potential use of a new dimensional nano-platform in the development of high-performance cancer vaccines. PMID- 26419318 TI - Nanoporous Materials Can Tune the Critical Point of a Pure Substance. AB - Molecular simulations and NMR relaxometry experiments demonstrate that pure benzene or xylene confined in isoreticular metal-organic frameworks (IRMOFs) exhibit true vapor-liquid phase equilibria where the effective critical point may be reduced by tuning the structure of the MOF. Our results are consistent with vapor and liquid phases extending over many MOF unit cells. These results are counterintuitive since the MOF pore diameters are approximately the same length scale as the adsorbate molecules. As applications of these materials in catalysis, separations, and gas storage rely on the ability to tune the properties of adsorbed molecules, we anticipate that the ability to systematically control the critical point, thereby preparing spatially inhomogeneous local adsorbate densities, could add a new design tool for MOF applications. PMID- 26419319 TI - Abnormal behaviours during pramipexole treatment for Cotard's syndrome: a case report. AB - Cotard's syndrome is a relatively rare condition that involves a delusion of negation in which an individual believes he or she has lost his or her soul, is dead, or is without functional body systems. This syndrome is observed in various neuropsychiatric disorders but most commonly in mood disorders. Pramipexole has often been used in the adjunctive treatment of both bipolar and unipolar depression, and it is known to cause rare but serious adverse effects such as compulsive behaviours in the treatment of Parkinson's disease. Here we report a case of Cotard's syndrome in treatment-resistant major depression associated with abnormal behaviours that might be caused by pramipexole. In the present case, the patient's abnormal behaviours gradually disappeared about 2 months after the discontinuation of pramipexole. The hypoperfusion in the bilateral parieto occipital lobe found on single-photon emission computed tomography suggests the presence of Lewy body disease pathology. Nonetheless, the patient's abnormal behaviours disappeared after the discontinuation of pramipexole, indicating that they are mainly attributable to pramipexole treatment. However, the possible existence of Lewy body pathology could facilitate the emergence of abnormal behaviours after treatment with pramipexole. The patient's abnormal behaviours, such as eating other patients' food and taking her medicine before the scheduled time, might differ from typical compulsive behaviours induced by pramipexole (such as pathological gambling and hypersexuality), but they could be regarded as disinhibition. Therefore, we should follow up on the clinical course of this case carefully through neuroimaging investigation and neurocognitive assessment. PMID- 26419317 TI - Heat-shock pretreatment reduces expression and release of TSLP from keratinocytes under Th2 environment. AB - BACKGROUND: Atopic dermatitis is a chronic, relapsing inflammatory disease of the skin. Current therapy is not curative, and recalcitrant disease is a big stress and challenge for parents and physicians. This study explored the potential role of heat-shock protein 70 (HSP-70) and its anti-inflammatory effects on keratinocyte under TH2 environment. METHODS: Human keratinocyte cell line (HaCa T) was stimulated with IL-4, IL-13, and TNF-alpha to synthesize and secrete thymic stromal lymphopoietin (TSLP), an important cytokine of immunopathogenesis in atopic dermatitis. Heat shock was performed by immersing the cell-contained flash into a water bath of 45 degrees C for 20 min. Cell viability, TSLP expression, and secretion of HaCa T cells were measured and compared. Possible regulatory mechanisms influencing the expression of TSLP, such as the STAT6 and NF-kappaB signal pathways, were investigated. RESULTS: Heat-shock treatment induced intracellular HSP-70 expression in HaCa T cells without affecting cell viability. The induced expression and secretion of TSLP in HaCa T cells were suppressed by heat shock. The NF-kappaB signal pathway was inhibited by heat shock, leading to decreased TSLP expression and secretion. CONCLUSION: Heat stress-induced HSPs can significantly reduce the production and secretion of TSLP from HaCaT cells under Th2 environment. Thus, the evidence highlights the potential role of HSP-70 for atopic dermatitis in the future. PMID- 26419316 TI - Ethanol Enhances TGF-beta Activity by Recruiting TGF-beta Receptors From Intracellular Vesicles/Lipid Rafts/Caveolae to Non-Lipid Raft Microdomains. AB - Regular consumption of moderate amounts of ethanol has important health benefits on atherosclerotic cardiovascular disease (ASCVD). Overindulgence can cause many diseases, particularly alcoholic liver disease (ALD). The mechanisms by which ethanol causes both beneficial and harmful effects on human health are poorly understood. Here we demonstrate that ethanol enhances TGF-beta-stimulated luciferase activity with a maximum of 0.5-1% (v/v) in Mv1Lu cells stably expressing a luciferase reporter gene containing Smad2-dependent elements. In Mv1Lu cells, 0.5% ethanol increases the level of P-Smad2, a canonical TGF-beta signaling sensor, by ~ 2-3-fold. Ethanol (0.5%) increases cell-surface expression of the type II TGF-beta receptor (TbetaR-II) by ~ 2-3-fold from its intracellular pool, as determined by I(125) -TGF-beta-cross-linking/Western blot analysis. Sucrose density gradient ultracentrifugation and indirect immunofluorescence staining analyses reveal that ethanol (0.5% and 1%) also displaces cell-surface TbetaR-I and TbetaR-II from lipid rafts/caveolae and facilitates translocation of these receptors to non-lipid raft microdomains where canonical signaling occurs. These results suggest that ethanol enhances canonical TGF-beta signaling by increasing non-lipid raft microdomain localization of the TGF-beta receptors. Since TGF-beta plays a protective role in ASCVD but can also cause ALD, the TGF beta enhancer activity of ethanol at low and high doses appears to be responsible for both beneficial and harmful effects. Ethanol also disrupts the location of lipid raft/caveolae of other membrane proteins (e.g., neurotransmitter, growth factor/cytokine, and G protein-coupled receptors) which utilize lipid rafts/caveolae as signaling platforms. Displacement of these membrane proteins induced by ethanol may result in a variety of pathologies in nerve, heart and other tissues. PMID- 26419320 TI - Femoral nerve blocks for fractured neck of femur patients: A 'feel good solution' but a 'short-term fix'? AB - OBJECTIVE: Femoral nerve blocks (FNBs) are commonly administered to patients with a fractured neck of femur (NOF). FNBs reduce complications associated with opioids and are effective for up to 24 h. However, the recognised 'gold standard' time to definitive treatment (surgery) in the patient with a fractured NOF is within 48 h. This leaves a significant period of time in which the patient has no effective analgesia, and might require opioids to alleviate pain. The present study explored the number of NOF patients who received a FNB: their wait for definitive treatment (surgery) and how much opioid analgesia was administered in the preoperative phase. METHODS: A retrospective review of electronic patient records was conducted over a 6 month period in 2012. Patients who presented to the ED with a fractured NOF, received a FNB and were transferred to surgery in the same hospital were included in the sample. RESULTS: The median time from FNBs to surgery was 37.5 h. When patients waited more than 20 h for surgery, the volume of opioid received increased significantly (P <= 0.001). CONCLUSION: Even when patients' time to surgery was within the 'gold standard', patients received increasing doses of opioids 20 h after the administration of the FNB. While patients continue to wait extended periods for surgery, the practice of administering a single injection FNB needs to be challenged. ED clinicians might consider FNB infusions rather than single injection FNBs for patients with a fractured NOF. PMID- 26419321 TI - Evidence supporting vertical transmission of Salmonella in dairy cattle. AB - We set out to investigate whether Salmonella enterica could be recovered from various tissues of viable neonatal calves immediately following parturition. Eleven samples were aseptically collected from each of 20 calves and consisted of both left and right subiliac and prescapular lymph nodes (LN), mesenteric LN, spleen and liver, as well as intestinal tissue (including luminal contents) from the small intestine, caecum, spiral colon and rectum. In addition, a faecal sample was collected from 19 of the dams. Salmonella was recovered from at least one sample from 10 of the 20 neonates. Across all calves, Salmonella was recovered from 12.7% of all samples and from LN in particular, Salmonella was recovered from 10.0%, 5.0%, and 5.0% of subiliac, prescapular, and mesenteric LN, respectively. Within calves, Salmonella was recovered from 0% to 73% of samples and across tissues, estimates of Salmonella prevalence were greatest in the caecum (30%) but was never recovered from the right pre-scapular LN. These data provide evidence of vertical transmission from a dam to her fetus such that viable calves are born already infected and thereby not requiring faecal-oral exposure for transmission. This new knowledge ought to challenge - or at least add to - existing paradigms of Salmonella transmission dynamics within cattle herds. PMID- 26419322 TI - Nitric oxide is involved in brassinosteroid-induced alternative respiratory pathway in Nicotiana benthamiana seedlings' response to salt stress. AB - Recent studies reported that brassinosteroids (BRs) can induce plant tolerance to different environmental stresses via the nitric oxide (NO) signaling pathway. Previous reports have indicated that alternative oxidase (AOX) plays an important role in plants under various stresses. The mechanisms governing how NO is involved as a signal molecule which connects BR with AOX in regulating stress tolerance are still unknown. Recently, we found that Nicotiana benthamiana seedlings which were pretreated with BR have more tolerance to salt stress, accompanied with an increase of CN-resistant respiration. Our results suggested that pretreatment with 0.1 MUM brassinolide (BL, the most active brassinosteroid) alleviated salt-induced oxidative damage and increased the NbAOX1 transcript level. Application of 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-1 oxyl-3-oxide (cPTIO, an NO scavenger) or virus-induced gene silencing of nitrate reductase (NR) and nitric oxide synthase (NOS)-like enzyme compromised the BRs induced alternative respiratory pathway. Furthermore, pretreatment with specific chemical inhibitors of NR and NOS or gene silencing experiments decreased plant resistance to salt stress which also compromised BRs-induced salt stress tolerance. In conclusion, NO is involved in BRs-induced AOX capability which plays essential roles in salt tolerance in N. benthamiana seedlings. PMID- 26419323 TI - The effects of environmental enrichment and transport stress on the weights of lymphoid organs, cell-mediated immune response, heterophil functions and antibody production in laying hens. AB - The effects of environmental enrichment and transport stress on the immune system were investigated in laying hens. A total of 48 1-day-old chickens were used, half of the chickens were reared in conventional cages (RCC) and the rest in enriched cages (REC). Transport stress was applied in the 17th week. Liver weight decreased, spleen and bursa of Fabricius weights, white blood cell count, CD4+ and CD8+ cell proportions increased due to the transport. Environmental enrichment significantly increased antibody production and tended to increase monocyte percentage and CD8+ cell proportion. The effect of transport on, heterophil (H) and lymphocyte (L) percentages was not significant in RCC chickens. While heterophil percentage and H:L ratio increased, lymphocyte percentage decreased in REC chickens subjected to transport. Transport stress increased heterophil functions both in REC and RCC chickens, but the increase was higher in REC hens than in RCC hens. In conclusion, although environmental enrichment did not neutralize the effect of transport on lymphoid organs, it activated the non-specific immune system, cellular and the humoral branches of the specific immune system by increasing heterophil functions, CD8+ cells and antibody production, respectively. Therefore, environmental enrichment suggested for improving animal welfare may also be beneficial to improve the immune system of birds exposed to stress. PMID- 26419324 TI - Do the levels of tumor makers or proinflammatory cytokines in mid-trimester cervical fluid predict early-stage cervical shortening? AB - AIM: In the present study, we aimed to assess the biomarkers in mid-trimester cervical fluid that can predict early stage cervical shortening. MATERIAL AND METHODS: We obtained cervical swab specimens from 96 gravidas, after which the cervical length was measured, at approximately 20 weeks of gestation. Cervical length was measured again at 4 weeks after the initial examination. Cervical shortening was noted in 20 women between 20 and 24 weeks of gestation (group A), whereas no cervical shortening was noted in 76 women (group B). We evaluated the use of the levels of tumor markers, proinflammatory cytokines, and matrix metalloproteinase-8 (MMP-8) as candidate biomarkers. CA-125 and carcinoembryonic antigen levels were determined by using an automatic immunoassay system in both groups. Furthermore, IL-1beta, IL-8, tumor necrosis factor-alpha, and MMP-8 levels were measured using an enzyme-linked immunosorbent assay. RESULTS: The levels of inflammatory cytokines and MMP-8 did not differ between the two groups, and were not correlated with cervical length or the change in cervical length. Although CA-125 and carcinoembryonic antigen levels were higher in group A, they were not statistically significant (P = 0.304 and 0.092, respectively). CONCLUSION: Early stage cervical shortening in mid-trimester was not associated with an increase in the levels of tumor markers or proinflammatory cytokines in cervical fluid. PMID- 26419325 TI - Occurrence, activity and contribution of anammox in some freshwater extreme environments. AB - Anaerobic ammonium oxidation (anammox) widely occurs in marine ecosystems, and it plays an important role in the global nitrogen cycle. But in freshwater ecosystems its occurrence, distribution and contribution, especially in extreme environments, are still not well known. In this study, anammox process was investigated in some extreme environments of freshwater ecosystems, such as those with high (above 75 degrees C) and low (below -35 degrees C) temperature, high (pH > 8) and low (pH < 4) pH and eutrophy (the concentration of NH4 (+) -N > 300 mg kg(-1) ). The polymerase chain reaction (PCR) screening results showed that anammox bacteria were widespread in the examined sediments from freshwater extreme environments. Quantitative PCR showed that the abundance of anammox bacteria ranged from 6.94 * 10(4) to 8.05 * 10(6) hydrazine synthase (hzsB) gene copies g(-1) dry soil. (15) N-labelled incubation experiments indicated the occurrence of anammox in all examined sediments and the potential anammox rates ranged from 0.02 to 6.24 nmol N g(-1) h(-1) , with a contribution of 3.45-58.74% of the total N2 production. In summary, these results demonstrate the occurrence of anammox in these extreme environments, inferring that anammox may harbour a wide ecological niche in the freshwater ecosystems. PMID- 26419327 TI - To ask, or not to ask: the hesitation process described by district nurses encountering women exposed to intimate partner violence. AB - AIMS AND OBJECTIVES: To improve the understanding of district nurses' experiences of encountering women exposed to intimate partner violence. BACKGROUND: Intimate partner violence is a public health issue that influences all aspects of affected women's lives; it is thus of great relevance to identify intimate partner violence. District nurses in primary health care in Sweden encounter women of all ages and are therefore in a unique position to identify intimate partner violence and provide nursing care. However, studies indicate that several barriers have kept nurses from identifying intimate partner violence. Consequently deeper understanding of district nurses' encounters with women exposed to intimate partner violence is needed. DESIGN: A qualitative study using grounded theory method. METHODS: Interviews with 11 district nurses in primary health care in Sweden. RESULTS: The hesitation process is central in these encounters. Several barriers to asking and factors that facilitated asking impacted the hesitation process. Under the influence of these factors, district nurses moved from being unaware that identifying intimate partner violence was their professional responsibility, to becoming ambivalent about asking, to starting to prepare themselves to ask about intimate partner violence. The presence of factors that facilitated asking finally made district nurses feel prepared, and then they decided to ask women about intimate partner violence. CONCLUSIONS: The concept of managing the hesitation process could be used to be incorporated in continuing education and training. Barriers and facilitators concerning organisational factors found in this study may be specific to the Swedish health care system, but the concept of the hesitation process is applicable in similar contexts and perhaps to other issues about which it is difficult to ask. RELEVANCE TO CLINICAL PRACTICE: This study illuminates the importance of a supportive work environment in reducing district nurses' hesitation to ask about intimate partner violence and to propose continuing education, training and supervision for district nurses regarding intimate partner violence. PMID- 26419326 TI - A novel PIGN mutation and prenatal diagnosis of inherited glycosylphosphatidylinositol deficiency. AB - Glycosylphosphatidylinositol (GPI) anchors tether proteins to the extracellular face of eukaryotic plasma membranes. Defects in the human GPI anchor biosynthetic pathway cause inherited GPI deficiencies (IGDs) characterized by multiple congenital anomalies: dysmorphic faces, developmental delay, hypotonia, and epilepsy. We report the case of a 6-year-old boy with severe psychomotor developmental delay, epilepsy, and decreased granulocyte surface expression of GPI-anchored protein that suggested autosomal recessive GPI deficiency. The case underwent target exome sequencing to screen for IGDs. Target exome sequencing of the proband identified an apparently homozygous c.808T > C (p.Ser270Pro) mutation in PIGN, a gene involved in the GPI anchor biosynthetic pathway. As his parents were expecting another child, genetic carrier screening was conducted for the parents. Direct sequencing of the parents identified a heterozygous c.808T > C PIGN mutation in the father but none in the mother. To identify the mother's mutation, we performed semi-quantitative real-time PCR of the PIGN exons and long PCR, identifying a microdeletion in PIGN (del exons 2-14). The proband had inherited this microdeletion from his mother. Prenatal diagnosis of the fetus revealed that it was a heterozygous carrier of the mother's pathogenic allele. Here, we report a sporadic case of inherited GPI deficiency with a PIGN mutation and the first case of prenatal diagnosis for GPI deficiency. PMID- 26419328 TI - Ablative fractional laser resurfacing with topical paromomycin as adjunctive treatment for a recalcitrant cutaneous leishmaniasis wound. AB - BACKGROUND AND OBJECTIVE: Leishmaniasis is a vector borne disease that can cause disease manifestations that range from localized skin ulceration to lethal visceral disease. With increased global travel, cutaneous leishmaniasis (CL) is becoming more common in developed nations. However, current treatment options are limited. STUDY DESIGN: We report a 16-year-old female who presented with several non-tender, non-healing CL wounds on her bilateral upper and lower extremities. Ablative fractional laser resurfacing (AFR) was used in conjunction with topical paromomycin via laser-assisted delivery to treat the largest non-healing CL wound on the patient's distal lower extremity. RESULTS: Upon follow-up after two treatments with AFR, the patient's wound healed completely without evidence of infection and with minimal scarring. CONCLUSION: AFR with laser-assisted delivery of topical paromomycin represents a novel treatment option for resistant, non healing CL wounds. The technique may prove additionally useful for concurrent mitigation of scarring related to CL. PMID- 26419329 TI - The drug situation in Europe: an overview of data available on illicit drugs and new psychoactive substances from European monitoring in 2015. AB - AIM: A central task for the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) is to produce an annual report of the latest data available on drug demand and drug supply in Europe. This paper is intended to facilitate a better understanding of, and easier access to, the main quantitative European level data sets available in 2015. METHODS: The European reporting system formally covers all 28 European Union (EU) Member States, Norway and Turkey and incorporates multiple indicators alongside an early warning system (EWS) on uncontrolled new psychoactive substances (NPS). While epidemiological information is based largely on registries, surveys and other routine data reported annually, the EWS collects case-based data on an ongoing basis. The 2015 reporting exercise is centred primarily on a set of standardized reporting tools. RESULTS: The most recent data provided by European countries are presented, including data on drug use, drug-related morbidity and mortality, treatment demand, drug markets and new psychoactive substances, with data tables provided and methodological information. A number of key results are highlighted for illustrative purposes. Drug prevalence estimates from national surveys since 2012 (last year prevalence of use among the 15-34 age band) range from 0.4% in Turkey to 22.1% in France for cannabis, from 0.2% in Greece and Romania to 4.2% in the United Kingdom for cocaine, from 0.1% in Italy and Turkey to 3% in the Czech Republic and the United Kingdom for ecstasy, and from 0.1% or less in Romania, Italy and Portugal to 2.5% in Estonia for amphetamine. Declining trends in new HIV detections among people who inject drugs are illustrated, in addition to presentation of a breakdown of NPS reported to the EU early warning system, which have risen exponentially from fewer than 20 a year between 2005 and 2008, to 101 reported in 2014. CONCLUSIONS: Structured information is now available on patterns and trends in drug consumption in Europe, which permits triangulation of data from different sources and consideration of methodological limitations. Opioid drugs continue to place a burden on the drug treatment system, although both new heroin entrants and injecting show declines. More than 450 new psychoactive substances are now monitored by the European early warning system with 31 new synthetic cathinones and 30 new synthetic cannabinoid receptor agonists notified in 2014. PMID- 26419331 TI - Yeast nitrogen catabolite repression is sustained by signals distinct from glutamine and glutamate reservoirs. AB - Nitrogen catabolite repression (NCR) is a wide transcriptional regulation program enabling baker's yeast to downregulate genes involved in the utilization of poor nitrogen sources when preferred ones are available. Nowadays, glutamine and glutamate, the major nitrogen donors for biosyntheses, are assumed to be key metabolic signals regulating NCR. NCR is controlled by the conserved TORC1 complex, which integrates nitrogen signals among others to regulate cell growth. However, accumulating evidence indicate that the TORC1-mediated control of NCR is only partial, arguing for the existence of supplementary regulatory processes to be discovered. In this work, we developed a genetic screen to search for new players involved in NCR signaling. Our data reveal that the NADP-glutamate dehydrogenase activity of Gdh1 negatively regulates NCR-sensitive gene transcription. By determining the total, cytoplasmic and vacuolar pools of amino acids, we show that there is no positive correlation between glutamine/glutamate reservoirs and the extent of NCR. While our data indicate that glutamine could serve as initial trigger of NCR, they show that it is not a sufficient signal to sustain repression and point to the existence of yet unknown signals. Providing additional evidence uncoupling TORC1 activity and NCR, our work revisits the dogmas underlying NCR regulation. PMID- 26419330 TI - Limited dissemination of the wastewater treatment plant core resistome. AB - Horizontal gene transfer is a major contributor to the evolution of bacterial genomes and can facilitate the dissemination of antibiotic resistance genes between environmental reservoirs and potential pathogens. Wastewater treatment plants (WWTPs) are believed to play a central role in the dissemination of antibiotic resistance genes. However, the contribution of the dominant members of the WWTP resistome to resistance in human pathogens remains poorly understood. Here we use a combination of metagenomic functional selections and comprehensive metagenomic sequencing to uncover the dominant genes of the WWTP resistome. We find that this core resistome is unique to the WWTP environment, with <10% of the resistance genes found outside the WWTP environment. Our data highlight that, despite an abundance of functional resistance genes within WWTPs, only few genes are found in other environments, suggesting that the overall dissemination of the WWTP resistome is comparable to that of the soil resistome. PMID- 26419332 TI - The structure of Legionella pneumophila LegK4 type four secretion system (T4SS) effector reveals a novel dimeric eukaryotic-like kinase. AB - Bacterial pathogens subvert signalling pathways to promote invasion and/or replication into the host. LegK1-4 proteins are eukaryotic-like serine/threonine kinases that are translocated by the Dot/Icm type IV secretion system (T4SS) of several Legionella pneumophila strains. We present the crystal structures of an active fragment of the LegK4 protein in apo and substrate-bound states. The structure of LegK4(1-445) reveals a eukaryotic-like kinase domain flanked by a novel cap domain and a four-helix bundle. The protein self-assembles through interactions mediated by helices alphaF and alphaG that generate a dimeric interface not previously observed in a protein kinase. The helix alphaG is displaced compared to previous kinase structures, and its role in stabilization of the activation loop is taken on by the dimerisation interface. The apo-form of the protein has an open conformation with a disordered P-loop but a structured activation segment in absence of targeted phosphorylation. The nucleotide-binding site of LegK4 contains an unusual set of residues that mediate non-canonical interactions with AMP-PNP. Nucleotide binding results in limited changes in the active site, suggesting that LegK4 constitutive kinase activity does not depend on phosphorylation of the activation loop but on the stabilizing effects of the dimer. PMID- 26419333 TI - Extracellular vesicles are rapidly purified from human plasma by PRotein Organic Solvent PRecipitation (PROSPR). AB - Extracellular vesicles (EVs) such as exosomes and microvesicles mediate intercellular communication and regulate a diverse range of crucial biological processes. Host cells that are damaged, infected or transformed release biomarker containing EVs into the peripheral circulation, where they can be readily accessed for use in diagnostic or prognostic testing. However, current methods of EV isolation from blood plasma are complex and often require relatively large sample volumes, hence are inefficient for widespread use in clinical settings. Here, we report a novel and inexpensive method of rapidly isolating EVs from small volumes of human blood plasma by PRotein Organic Solvent PRecipitation (PROSPR). PROSPR encompasses a rapid three-step protocol to remove soluble proteins from plasma via precipitation in cold acetone, leaving the lipid encapsulated EVs behind in suspension. This generates higher purity EVs that can then be obtained from filtration or classical ultracentrifugation methods. We foresee that PROSPR-based purification of EVs will significantly accelerate the discovery of new disease biomarkers and the characterization of EVs with potential for clinical applications. PMID- 26419334 TI - Photon Harvesting in Sunscreen-Based Functional Nanoparticles. AB - The ultraviolet light component in the solar spectrum is known to cause several harmful effects, such as allergy, skin ageing, and skin cancer. Thus, current research attention has been paid to the design and fundamental understanding of sunscreen-based materials. One of the most abundantly used sunscreen molecules is Avobenzone (AB), which exhibits two tautomers. Here, we highlight the preparation of spherically shaped nanoparticles from the sunscreen molecule AB as well as from sunscreen-molecule-encapsulated polymer nanoparticles in aqueous media and study their fundamental photophysical properties by steady-state and time resolved spectroscopy. Steady-state studies confirm that the AB molecule is in the keto and enol forms in tetrahydrofuran, whereas the enol form is stable in the case of both AB nanoparticles and AB-encapsulated poly(methyl methacrylate) (PMMA) nanoparticles. Thus, the keto-enol transformation of AB molecules is restricted to a nanoenvironment. An enhancement of photostability in both the nanoparticle and PMMA-encapsulated forms under UV light irradiation is observed. The efficient excited energy transfer (60 %) from AB to porphyrin molecules opens up further prospects in potential applications as light-harvesting systems. PMID- 26419335 TI - Transcriptome analysis of hormone-induced gene expression in Brachypodium distachyon. AB - Brachypodium distachyon is a new model plant closely related to wheat and other cereals. In this study, we performed a comprehensive analysis of hormone regulated genes in Brachypodium distachyon using RNA sequencing technology. Brachypodium distachyon seedlings were treated with eight phytohormones (auxin, cytokinine, brassinosteroid, gibberelline, abscisic acid, ethylene, jasmonate and salicylic acid) and two inhibitors, Brz220 (brassinosteroid biosynthesis inhibitor) and prohexadione (gibberelline biosynthesis inhibitor). The expressions of 1807 genes were regulated in a phytohormone-dependent manner. We compared the data with the phytohormone responses that have reported in rice. Transcriptional responses to hormones are conserved between Bracypodium and rice. Transcriptional regulation by brassinosteroid, gibberellin and ethylene was relatively weaker than those by other hormones. This is consistent with the data obtained from comprehensive analysis of hormone responses reported in Arabidopsis. Brachypodium and Arabidopsis also shared some common transcriptional responses to phytohormones. Alternatively, unique transcriptional responses to phytohormones were observed in Brachypodium. For example, the expressions of ACC synthase genes were up-regulated by auxin treatment in rice and Arabidopsis, but no orthologous ACC synthase gene was up-regulated in Brachypodium. Our results provide information useful to understand the diversity and similarity of hormone regulated transcriptional responses between eudicots and monocots. PMID- 26419337 TI - Selection of pairings reaching evenly across the data (SPREAD): A simple algorithm to design maximally informative fully crossed mating experiments. AB - We present a novel algorithm for the design of crossing experiments. The algorithm identifies a set of individuals (a 'crossing-set') from a larger pool of potential crossing-sets by maximizing the diversity of traits of interest, for example, maximizing the range of genetic and geographic distances between individuals included in the crossing-set. To calculate diversity, we use the mean nearest neighbor distance of crosses plotted in trait space. We implement our algorithm on a real dataset of Neurospora crassa strains, using the genetic and geographic distances between potential crosses as a two-dimensional trait space. In simulated mating experiments, crossing-sets selected by our algorithm provide better estimates of underlying parameter values than randomly chosen crossing sets. PMID- 26419336 TI - Ancestral whole-genome duplication in the marine chelicerate horseshoe crabs. AB - Whole-genome duplication (WGD) results in new genomic resources that can be exploited by evolution for rewiring genetic regulatory networks in organisms. In metazoans, WGD occurred before the last common ancestor of vertebrates, and has been postulated as a major evolutionary force that contributed to their speciation and diversification of morphological structures. Here, we have sequenced genomes from three of the four extant species of horseshoe crabs Carcinoscorpius rotundicauda, Limulus polyphemus and Tachypleus tridentatus. Phylogenetic and sequence analyses of their Hox and other homeobox genes, which encode crucial transcription factors and have been used as indicators of WGD in animals, strongly suggests that WGD happened before the last common ancestor of these marine chelicerates >135 million years ago. Signatures of subfunctionalisation of paralogues of Hox genes are revealed in the appendages of two species of horseshoe crabs. Further, residual homeobox pseudogenes are observed in the three lineages. The existence of WGD in the horseshoe crabs, noted for relative morphological stasis over geological time, suggests that genomic diversity need not always be reflected phenotypically, in contrast to the suggested situation in vertebrates. This study provides evidence of ancient WGD in the ecdysozoan lineage, and reveals new opportunities for studying genomic and regulatory evolution after WGD in the Metazoa. PMID- 26419339 TI - Polysorbate 20 Degradation in Biopharmaceutical Formulations: Quantification of Free Fatty Acids, Characterization of Particulates, and Insights into the Degradation Mechanism. AB - Polysorbate 20 (PS20), a commonly used surfactant in biopharmaceuticals, showed degradation upon long-term (~18-36 months) storage of two monoclonal antibody (mAb, mAb-A, and mAb-B) drug products at 2-8 degrees C. The PS20 degradation resulted in the accumulation of free fatty acids (FFA), which ultimately precipitated to form particles upon long-term storage. This study documents the development, qualification, and application of a method for FFA quantification in soluble and insoluble fraction of protein formulation. The method was applied to the quantification of capric acid, lauric acid, myristic acid, palmitic/oleic acid, and stearic acid in placebo as well as active protein formulations on stability. Quantification of FFA in both the soluble and insoluble fraction of mAb-A and mAb-B provided a better mechanistic understanding of PS20 degradation and the dynamics of subsequent fatty acid particle formation. Additionally, the use of this method for monitoring and quantitation of the FFA on real time storage stability appears to aid in identifying batches with higher probability for particulate formation upon extended storage at 5 degrees C. PMID- 26419338 TI - Microguards and micromessengers of the genome. AB - The regulation of gene expression is of fundamental importance to maintain organismal function and integrity and requires a multifaceted and highly ordered sequence of events. The cyclic nature of gene expression is known as 'transcription dynamics'. Disruption or perturbation of these dynamics can result in significant fitness costs arising from genome instability, accelerated ageing and disease. We review recent research that supports the idea that an important new role for small RNAs, particularly microRNAs (miRNAs), is in protecting the genome against short-term transcriptional fluctuations, in a process we term 'microguarding'. An additional emerging role for miRNAs is as 'micromessengers' through alteration of gene expression in target cells to which they are trafficked within microvesicles. We describe the scant but emerging evidence that miRNAs can be moved between different cells, individuals and even species, to exert biologically significant responses. With these two new roles, miRNAs have the potential to protect against deleterious gene expression variation from perturbation and to themselves perturb the expression of genes in target cells. These interactions between cells will frequently be subject to conflicts of interest when they occur between unrelated cells that lack a coincidence of fitness interests. Hence, there is the potential for miRNAs to represent both a means to resolve conflicts of interest, as well as instigate them. We conclude by exploring this conflict hypothesis, by describing some of the initial evidence consistent with it and proposing new ideas for future research into this exciting topic. PMID- 26419340 TI - Kinetics and Mechanisms of Ciprofloxacin Oxidation on Hematite Surfaces. AB - Adsorption of antibiotics at mineral surfaces has been extensively studied over the past 20 years, yet much remains to be learned on their interfacial properties and transformation mechanisms. In this study, interactions of Ciprofloxacin (CIP), a fluoroquinolone antibiotic with two sets of synthetic nanosized hematite particles, with relatively smooth (H10, 10-20 nm in diameter) and roughened (H80, 80-90 nm in diameter) surfaces, were studied by means of liquid chromatography (LC), mass spectrometry (MS), and spectroscopy (vibration and X-ray photoelectron). Attenuated Total Reflectance Fourier Transform Infrared (ATR FTIR) spectroscopy provides evidence for inner-sphere bidentate complex formation of CIP at hematite surfaces in 0.01 M NaCl, irrespective of pH and particle size. ATR-FTIR spectroscopy also revealed that the sorbed mother CIP molecule decayed to other surface species over a period of at least 65 h. This was supported by the detection of three daughter products in the aqueous phase by LC/MS. The appearance of NH3(+) groups during the course of these experiments, revealed by cryogenic XPS, provides further evidence that CIP oxidation proceeds through an opening of piperazine ring via N-dealkylation. Additional in vacuo FTIR experiments under temperature-programmed desorption also showed that oxidation of sorbed byproducts were effectively degraded beyond 450 degrees C, a result denoting considerably strong (inter)molecular bonds of both mother and daughter products. This work also showed that rougher, possibly multidomainic particles (H80) generated slower rates of CIP decomposition but occurring through more complex schemes than at smoother particle surfaces (H10). This work thus uncovered key aspects of the binding of an important antibiotic at iron oxide surfaces, and therefore provided additional constraints to our growing understanding of the fate of emerging contaminants in the environment. PMID- 26419341 TI - Palladium-catalyzed cross-coupling reaction of azides with isocyanides. AB - An efficient palladium-catalyzed cross-coupling reaction of azides with isocyanides is developed, providing a general synthetic route to unsymmetric carbodiimides with excellent yields. This method shows a broad substrate scope, including not only aryl azides, but also unactivated benzyl and alkyl azides. Furthermore, from readily available substrates, Pd-catalyzed coupling with a tandem amine insertion cascade to obtain unsymmetric trisubstituted guanidines has been achieved in a one-pot fashion. PMID- 26419342 TI - A novel mutation in CEBPA gene in a patient with acute myeloid leukemia. PMID- 26419343 TI - Genetic parameters and signatures of selection in two divergent laying hen lines selected for feather pecking behaviour. AB - BACKGROUND: Feather pecking (FP) in laying hens is a well-known and multi factorial behaviour with a genetic background. In a selection experiment, two lines were developed for 11 generations for high (HFP) and low (LFP) feather pecking, respectively. Starting with the second generation of selection, there was a constant difference in mean number of FP bouts between both lines. We used the data from this experiment to perform a quantitative genetic analysis and to map selection signatures. METHODS: Pedigree and phenotypic data were available for the last six generations of both lines. Univariate quantitative genetic analyses were conducted using mixed linear and generalized mixed linear models assuming a Poisson distribution. Selection signatures were mapped using 33,228 single nucleotide polymorphisms (SNPs) genotyped on 41 HFP and 34 LFP individuals of generation 11. For each SNP, we estimated Wright's fixation index (FST). We tested the null hypothesis that FST is driven purely by genetic drift against the alternative hypothesis that it is driven by genetic drift and selection. RESULTS: The mixed linear model failed to analyze the LFP data because of the large number of 0s in the observation vector. The Poisson model fitted the data well and revealed a small but continuous genetic trend in both lines. Most of the 17 genome-wide significant SNPs were located on chromosomes 3 and 4. Thirteen clusters with at least two significant SNPs within an interval of 3 Mb maximum were identified. Two clusters were mapped on chromosomes 3, 4, 8 and 19. Of the 17 genome-wide significant SNPs, 12 were located within the identified clusters. This indicates a non-random distribution of significant SNPs and points to the presence of selection sweeps. CONCLUSIONS: Data on FP should be analysed using generalised linear mixed models assuming a Poisson distribution, especially if the number of FP bouts is small and the distribution is heavily peaked at 0. The FST-based approach was suitable to map selection signatures that need to be confirmed by linkage or association mapping. PMID- 26419344 TI - In vitro methods for screening transdermal formulations. AB - This article provides a review of the critical in vitro assays utilized in transdermal drug development. In vitro assays such as percutaneous absorption testing and dissolution (drug release) testing are powerful tools for screening potential transdermal compounds and drug quality control, respectively. Several 2D single-cell cultures and 3D human skin equivalents are available for screening compounds with low irritation and sensitization potential. The role of each assay and its limitations and challenges will be further discussed below. PMID- 26419345 TI - Relationship between strenuous exercise and cardiac "morbimortality": Benefits outweigh the potential risks. PMID- 26419346 TI - Concise access to iminophosphonamide stabilized heteroleptic germylenes: chemical reactivity and structural investigation. AB - The influence of a sterically demanding iminophosphonamide ligand, [(2,6 iPr2C6H3N)P(Ph2)(NtBu)]H (LH), on the synthesis and stability of a heteroleptic germylene monochloride, [(2,6-iPr2C6H3N)P(Ph2)(NtBu)]GeCl (1), and its reaction chemistry has been discussed. Complex 1 behaves as a Lewis base to form an adduct with Fe(CO)4, namely [(2,6-iPr2C6H3N)P(Ph2)(NtBu)]Ge(Cl)Fe(CO)4 (2). Reaction of 1 with KOtBu or AgOSO2CF3 affords Ge(ii) compounds, [(2,6 iPr2C6H3N)P(Ph2)(NtBu)]GeR (R = OtBu (3), OSO2CF3 (4)). Treatment of complex 1 with elemental sulfur or selenium leads to heavier analogues of germaacid chlorides, [(2,6-iPr2C6H3N)P(Ph2)(NtBu)]Ge(E)Cl (E = S (5), Se (6)). Similarly, compound 3 on reaction with elemental sulfur or selenium produces heavier analogues of germaesters, [(2,6-iPr2C6H3N)P(Ph2)(NtBu)]Ge(E)OtBu (E = S (7), Se (8)). Complexes 1-8 were characterized using multinuclear NMR and EI-MS, and solid state structures of complexes 1-3, 5 and 8 have been elucidated using single crystal X-ray diffraction. PMID- 26419348 TI - The intersection of global health with cancer control. PMID- 26419347 TI - Studies of trypanosomiasis in the Luangwa valley, north-eastern Zambia. AB - BACKGROUND: The present study, conducted in Zambia's Luangwa valley where both animal African trypanosomiasis (AAT) and human African trypanosomiasis (HAT) are endemic, combined the use of microscopy and molecular techniques to determine the presence of trypanosome species in cattle, goats and tsetse flies. METHODS: This study was conducted between 2008 and 2010 in Petauke, Chama and Isoka districts, north-eastern Zambia. A total of 243 cattle, 36 goats and 546 tsetse flies, were examined for presence of trypanosome species using microscopy, PCR and loop mediated isothermal amplification (LAMP). RESULTS: There was poor agreement among the test methods used for detection of trypanosomes species in animal blood and tsetse flies. Trypanosomes were observed in 6.1 % (95 % CI: 3.3-8.9 %) of the animals sampled by microscopy, 7.5 % (95 % CI: 4.4-10.6 %) by PCR and 18.6 % (95 % CI: 13.6-23.6 %) by PFR-LAMP. PFR-LAMP was more sensitive for detecting Trypanozoon than KIN-PCR. The highest occurrence of AAT was recorded in cattle from Petauke (58.7 %, 95 % CI: 44.7-72.7 %) while the lowest was from Isoka (5.4 %, 95 % CI: 0.8-10.0 %). Infection of both cattle and goats with Trypanosoma congolense and T. vivax was associated with clinical AAT. CONCLUSION: When selecting molecular techniques for AAT surveillance in endemic regions, the KIN PCR and species-specific PCR may be recommended for screening animal or tsetse fly samples for T. congolense and T. vivax, respectively. On the other hand, species-specific PCR and/or LAMP might be of greater value in the screening of animal and human body fluids as well as tsetse fly samples for Trypanozoon. PMID- 26419349 TI - Global Task Force on Radiotherapy for Cancer Control. PMID- 26419350 TI - The verdict is in: the time for effective solutions to the global cancer burden is now. PMID- 26419351 TI - Expanding global access to radiotherapy: the European Society for Radiotherapy and Oncology perspective. PMID- 26419352 TI - Radiotherapy in southeast Asia: room to grow. PMID- 26419353 TI - Expanding global access to radiotherapy: the IAEA perspective. PMID- 26419354 TI - Expanding global access to radiotherapy. AB - Radiotherapy is a critical and inseparable component of comprehensive cancer treatment and care. For many of the most common cancers in low-income and middle income countries, radiotherapy is essential for effective treatment. In high income countries, radiotherapy is used in more than half of all cases of cancer to cure localised disease, palliate symptoms, and control disease in incurable cancers. Yet, in planning and building treatment capacity for cancer, radiotherapy is frequently the last resource to be considered. Consequently, worldwide access to radiotherapy is unacceptably low. We present a new body of evidence that quantifies the worldwide coverage of radiotherapy services by country. We show the shortfall in access to radiotherapy by country and globally for 2015-35 based on current and projected need, and show substantial health and economic benefits to investing in radiotherapy. The cost of scaling up radiotherapy in the nominal model in 2015-35 is US$26.6 billion in low-income countries, $62.6 billion in lower-middle-income countries, and $94.8 billion in upper-middle-income countries, which amounts to $184.0 billion across all low income and middle-income countries. In the efficiency model the costs were lower: $14.1 billion in low-income, $33.3 billion in lower-middle-income, and $49.4 billion in upper-middle-income countries-a total of $96.8 billion. Scale-up of radiotherapy capacity in 2015-35 from current levels could lead to saving of 26.9 million life-years in low-income and middle-income countries over the lifetime of the patients who received treatment. The economic benefits of investment in radiotherapy are very substantial. Using the nominal cost model could produce a net benefit of $278.1 billion in 2015-35 ($265.2 million in low-income countries, $38.5 billion in lower-middle-income countries, and $239.3 billion in upper middle-income countries). Investment in the efficiency model would produce in the same period an even greater total benefit of $365.4 billion ($12.8 billion in low income countries, $67.7 billion in lower-middle-income countries, and $284.7 billion in upper-middle-income countries). The returns, by the human-capital approach, are projected to be less with the nominal cost model, amounting to $16.9 billion in 2015-35 (-$14.9 billion in low-income countries; -$18.7 billion in lower-middle-income countries, and $50.5 billion in upper-middle-income countries). The returns with the efficiency model were projected to be greater, however, amounting to $104.2 billion (-$2.4 billion in low-income countries, $10.7 billion in lower-middle-income countries, and $95.9 billion in upper-middle income countries). Our results provide compelling evidence that investment in radiotherapy not only enables treatment of large numbers of cancer cases to save lives, but also brings positive economic benefits. PMID- 26419355 TI - Characterization of DNA aptamers generated against the soft-shelled turtle iridovirus with antiviral effects. AB - BACKGROUND: Soft-shelled turtle iridovirus (STIV) causes severe systemic disease in farmed soft-shelled turtles (Trionyx sinensis). More efficient methods of controlling and detecting STIV infections are urgently needed. METHODS: In this study, we generated eight single-stranded DNA (ssDNA) aptamers against STIV using systematic evolution of ligands by exponential enrichment (SELEX). RESULTS: The aptamers formed representative stem-loop secondary structures. Electrophoretic mobility shift assays and fluorescent localization showed that the selected aptamers had high binding affinity for STIV. Aptamer QA-36 had the highest calculated binding affinity (K d ) of 53.8 nM. Flow cytometry and fluorescence microscopy of cell-aptamer interactions demonstrated that QA-12 was able to recognize both STIV-infected cells and tissues with a high level of specificity. Moreover, the selected aptamers inhibited STIV infection in vitro and in vivo, with aptamer QA-36 demonstrating the greatest protective effect against STIV and inhibiting STIV infection in a dose-dependent manner. DISCUSSION: We generated DNA aptamers that bound STIV with a high level of specificity, providing an alternative means for investigating STIV pathogenesis, drug development, and medical therapies for STIV infection. CONCLUSIONS: These DNA aptamers may thus be suitable antiviral candidates for the control of STIV infections. PMID- 26419357 TI - Evidence for disrupted gray matter structural connectivity in posttraumatic stress disorder. AB - Posttraumatic stress disorder (PTSD) is characterized by atrophy within the prefrontal-limbic network. Graph analysis was used to investigate to what degree atrophy in PTSD is associated with impaired structural connectivity within prefrontal limbic network (restricted) and how this affects the integration of the prefrontal limbic network with the rest of the brain (whole-brain). 85 male veterans (45 PTSD neg, 40 PTSD pos) underwent volumetric MRI on a 3T MR. Subfield volumes were obtained using a manual labeling scheme and cortical thickness measurements and subcortical volumes from FreeSurfer. Regression analysis was used to identify regions with volume loss. Graph analytical Toolbox (GAT) was used for graph-analysis. PTSD pos had a thinner rostral anterior cingulate and insular cortex but no hippocampal volume loss. PTSD was characterized by decreased nodal degree (orbitofrontal, anterior cingulate) and clustering coefficients (thalamus) but increased nodal betweenness (insula, orbitofrontal) and a reduced small world index in the whole brain analysis and by orbitofrontal and insular nodes with increased nodal degree, clustering coefficient and nodal betweenness in the restricted analysis. PTSD associated atrophy in the prefrontal limbic network results in an increased structural connectivity within that network that negatively affected its integration with the rest of the brain. PMID- 26419356 TI - Positive Emotions Program for Schizophrenia (PEPS): a pilot intervention to reduce anhedonia and apathy. AB - BACKGROUND: Recent literature has distinguished the negative symptoms associated with a diminished capacity to experience (apathy, anhedonia) from symptoms associated with a limited capacity for expression (emotional blunting, alogia). The apathy-anhedonia syndrome tends to be associated with a poorer prognosis than the symptoms related to diminished expression. The efficacy of drug-based treatments and psychological interventions for these symptoms in schizophrenia remains limited. There is a clear clinical need for new treatments. METHODS: This pilot study tested the feasibility of a program to reduce anhedonia and apathy in schizophrenia and assessed its impact on 37 participants meeting the ICD-10 criteria for schizophrenia or schizoaffective disorders. Participants were pre- and post-tested using the Scale for the Assessment of Negative Symptoms (SANS) and the Calgary Depression Scale for Schizophrenia (CDSS). They took part in eight sessions of the Positive Emotions Program for Schizophrenia (PEPS)--an intervention that teaches participants skills to help overcome defeatist thinking and to increase the anticipation and maintenance of positive emotions. RESULTS: Thirty-one participants completed the program; those who dropped out did not differ from completers. Participation in the program was accompanied by statistically significant reductions in the total scores for Avolition-Apathy and Anhedonia-Asociality on the SANS, with moderate effect sizes. Furthermore, there was a statistically significant reduction of depression on the CDSS, with a large effect size. Emotional blunting and alogia remain stable during the intervention. DISCUSSION: Findings indicate that PEPS is both a feasible intervention and is associated with an apparently specific reduction of anhedonia and apathy. However, these findings are limited by the absence of control group and the fact that the rater was not blind to the treatment objectives. CONCLUSIONS: PEPS is a promising intervention to improve anhedonia and apathy which need to be tested further in a controlled study. TRIAL REGISTRATION NUMBER: ISRCTN registry ISRCTN74048461, registered 18 may 2015. PMID- 26419359 TI - Para- and perirenal ultrasonographic fat thickness is associated with 24-hours mean diastolic blood pressure levels in overweight and obese subjects. AB - BACKGROUND: Renal sinus fat (RSF) has been recognized as a risk factor for arterial hypertension. This study was addressed to examine whether also para- and perirenal fat accumulation is associated to higher 24-h mean systolic (SBP) and/or diastolic blood pressure (DBP) levels in overweight and obese subjects. METHODS: A cohort of 42 overweight and obese patients, 29 women and 13 men, aged 25-55 years, not treated with any kind of drug, was examined. Body mass index (BMI), waist circumference (WC), fasting insulin and glucose serum levels, insulin resistance (assessed by using the homeostasis model assessment [HOMAIR]), and 24-h aldosterone urine levels were measured. Ambulatory blood pressure monitoring (ABPM) was measured with 15 min intervals from 7.0 a.m. to 11.0 a.m. and with 30 min intervals from 23.0 to 7.0 for consecutive 24 h, starting from 8:30 AM. Measurement of para- and perirenal fat thickness was performed by ultrasounds by a duplex Doppler apparatus. RESULTS: Para- and perirenal ultrasonographic fat thickness (PUFT) was significantly and positively correlated with WC (p < 0.01), insulin (p < 0.01), HOMAIR (p < 0.01), and 24-h mean DBP levels (p < 0.05). 24-h mean DBP was also significantly and positively correlated with 24-h aldosterone urine concentrations (p < 0.001). A multivariate analysis by multiple linear regression was performed; the final model showed that the association of 24-h mean DBP as dependent variable with PUFT (multiple R = 0.34; p = 0.026) and daily aldosterone production (multiple R = 0.59; p = 0.001) was independent of other anthropometric, hormone and metabolic parameters. DISCUSSION AND CONCLUSIONS: This study shows a positive independent association between PUFT and mean 24-h diastolic blood pressure levels in overweight and obese subjects, suggesting a possible direct role of PUFT in increasing daily diastolic blood pressure. PMID- 26419360 TI - Epidemiology of hepatitis A virus in Africa among persons aged 1-10 years: a systematic review protocol. AB - BACKGROUND: Africa is considered an area of high endemicity for hepatitis A virus infection. However, in the past two decades, tremendous progress has been made in improving water sources and sanitation which are risk factors for hepatitis A virus infection. Recent studies suggest that several African countries could be in epidemiological transitions due to the evident socio-economic development. As a result, there may be a decrease in the exposure to and infection with hepatitis A virus at an early age. Understanding and mapping the shifting epidemiology is vital in developing control measures against the disease. We are conducting a comprehensive systematic review study to document the current burden of hepatitis A virus infection in Africa. METHODS: Our population of interest is children between 1 and 10 years in any African country. We will select cross-sectional, case-control, and cohort studies that have tested hepatitis A virus infection by serological confirmation of antibodies against the virus. We will search for eligible studies published without language restrictions from PubMed, Scopus, Africa-wide, Web of Science, and WHOLIS as well as the reference lists of the relevant articles. Two authors will independently review the search outputs, select eligible articles, and extract pre-defined study outcomes. Inconsistencies will be resolved by discussion and consensus among the authors. Data will be extracted using a standardised data collection form. Trends in the prevalence and/or incidence will be evaluated by urban and rural setting if sufficient data is available. Where there is sufficient homogeneity between studies, meta analysis will also be conducted, otherwise the results will be presented in a narrative format. DISCUSSION: The systematic review will generate up-to-date information on the current burden of hepatitis A virus in Africa. This information may have implications on policy for hepatitis A vaccination on individual African countries. SYSTEMATIC REVIEW REGISTRATION: CRD42015023764. PMID- 26419358 TI - Prevalence of chronic periodontitis in an obese population: a preliminary study. AB - BACKGROUND: Chronic periodontitis (CP) is a global public health issue. Studies have suggested CP could be linked to obesity due to their similar pathophysiological pathway. The aim of this study is to determine the prevalence of CP and to assess the predictors for CP among the obese Malaysian population. METHODS: This is a cross-sectional study on obese participants. Obesity is defined as an individual who has Body Mass Index (BMI) >= 27.5 kg/m(2). A convenience sampling method was used. A total of 165 paricipants were recruited. This study involved answering questionnaires, obtaining biometric and clinical measurements of Visible plaque index (VPI), Gingival bleeding index (GBI), Probing pocket depth (PPD) and Clinical attachment loss (CAL). Data analysis was carried out using SPSS statistical software (SPSS Inc., version 20, US). RESULTS: A total of 165 participants; 67 (40.6%) males and 98 (59.4%) females participated in the study. Mean age of the participants was 43.9 (+/- 8.9). The prevalence of CP among the obese population was found to be 73.9%. Out of this, 43 and 55% were categorised as moderate and severe CP respectively. Around 64% of participants had sites with CAL >= 4 mm and participants with sites with PPD >= 4 mm were reported to be 25%. Around 83% of the participants had sites with GBI >= 30 and 92% of participants had sites with VPI >= 20%. GBI and VPI were found to have significantly higher odds for CP. CONCLUSION: Prevalence of CP was high among obese Malaysians. GBI and VPI were potential predictors for CP in this obese population. PMID- 26419361 TI - Resection of metachronous pancreatic cancer 4 years after pancreaticoduodenectomy for stage III pancreatic adenocarcinoma. AB - Pancreatic adenocarcinoma frequently recurs in patients even after resection with curative intent. The majority of these are early recurrences and are associated with metastatic disease, thus not amenable to repeat resection. Here we report a patient who underwent completion pancreatectomy for a metachronous pancreatic adenocarcinoma. This patient initially presented with painless jaundice and computed tomography (CT) revealed a mass in the head of the pancreas. Brushings obtained at endoscopic retrograde cholangiopancreatography (ERCP) were positive for adenocarcinoma. This patient then underwent a Whipple procedure and final pathology demonstrated stage III pancreatic ductal adenocarcinoma. Adjuvant therapy included gemcitabine and erlotinib. This patient was followed with physical examinations and serial laboratory and imaging studies. There was no evidence of disease for four years at which time and sharp elevation in CA-19-9 was found. Subsequent imaging revealed a mass in the remnant pancreas. Curative intent completion pancreatectomy was then performed which confirmed the presence of pancreatic adenocarcinoma. This was followed by adjuvant Gemcitabine based chemotherapy and chemoradiation. One year later the patient is alive with no evidence of disease. Thus, in highly selected patients with recurrent or metachronous pancreatic cancer, repeat pancreatectomy can be considered, but the course of treatment should be considered in a multidisciplinary setting. PMID- 26419362 TI - Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms. AB - Tylosis (hyperkeratosis palmaris et plantaris) is characterised by focal thickening of the skin of the hands and feet and is associated with a very high lifetime risk of developing squamous cell carcinoma of the oesophagus. This risk has been calculated to be 95% at the age of 65 in one large family, however the frequency of the disorder in the general population is not known and is likely to be less than one in 1,000,000. Oesophageal lesions appear as small (2-5 mm), white, polyploid lesions dotted throughout the oesophagus and oral leukokeratosis has also been described. Although symptoms of oesophageal cancer can include dysphagia, odynophagia, anorexia and weight loss, there may be an absence of symptoms in early disease, highlighting the importance of endoscopic surveillance in these patients. Oesophageal cancer associated with tylosis usually presents in middle to late life (from mid-fifties onwards) and shows no earlier development than the sporadic form of the disease. Tylosis with oesophageal cancer is inherited as an autosomal dominant trait with complete penetrance of the cutaneous features, usually by 7 to 8 years of age but can present as late as puberty. Mutations in RHBDF2 located on 17q25.1 have recently been found to be causative. A diagnosis of tylosis with oesophageal cancer is made on the basis of a positive family history, characteristic clinical features, including cutaneous and oesophageal lesions, and genetic analysis for mutations in RHBDF2. The key management goal is surveillance for early detection and treatment of oesophageal dysplasia. Surveillance includes annual gastroscopy with biopsy of any suspicious lesion together with quadratic biopsies from the upper, middle and lower oesophagus. This is coupled with dietary and lifestyle modification advice and symptom education. Symptomatic management of the palmoplantar keratoderma includes regular application of emollients, specialist footwear and early treatment of fissures and super-added infection, particularly tinea pedis. More specific treatment for the thick skin is available in the form of oral retinoids, which are very effective but commonly produce side effects, including nasal excoriation and bleeding, hypercholesterolaemia, and abnormal liver function tests. Genetic counselling can be offered to patients and family members once a family history has been established. The prognosis of tylosis with oesophageal cancer is difficult to determine due to the limited number of affected individuals. In the last 40 years of surveillance, five out of six cases of squamous oesophageal cancer in the Liverpool family were detected endoscopically and were surgically removed. Four of five patients had stage 1 disease at presentation and remain alive and well more than 8 years later. This suggests that the presence of a screening program improves prognosis for these patients. PMID- 26419363 TI - Vitamin D supplementation improves well-being in patients with frequent respiratory tract infections: a post hoc analysis of a randomized, placebo controlled trial. AB - BACKGROUND: The aim of this study was to test the hypothesis that vitamin D supplementation improves well-being in patients with frequent respiratory tract infections (RTIs). We performed a post hoc analysis of a randomized, placebo controlled and double-blind study in which patients with frequent RTIs were randomized to placebo or vitamin D (4000 IE/day for 1 year, n = 124). At the last visit of the study, patients were asked to perform a general assessment of their well-being during the study. RESULTS: The majority of patients, both placebo- and vitamin D treated, stated that they had felt 'better' during the study; 52% in the placebo group and 70% in the vitamin D group, relative risk 1.3 (95% CI 1.0 1.8; p = 0.06, Fisher's exact test). Statement of better well-being was associated with an increase in 25-hydroxyvitamin D (25-OHD) levels (p < 0.001). In contrast, worse well-being was associated with unchanged 25-OHD levels. Notably, a 25-OHD level above 100 nmol/L at the study end was associated with a higher chance of having a better well-being (p < 0.01). Four patients on anti depressive treatment could terminate their antidepressant medication during the study. These patients had a significant increase in 25-OHD levels from low levels at study-start. CONCLUSION: Vitamin D supplementation to patients with frequent RTIs might be beneficial, not only for infections, but also for their general well-being. However, given the post hoc design of this study, these findings need to be confirmed in additional clinical trials before firm conclusions can be drawn. TRIAL REGISTRATION: http://www.clinicaltrials.gov (NCT01131858), registered March 22, 2010. PMID- 26419364 TI - Slowly progressive Lemierre's syndrome with orbital pain and exophthalmos. AB - Lemierre's syndrome is an oropharyngeal bacterial infection characterized by rapidly progressive septic thrombophlebitis of the internal jugular vein. A lack of appropriate antibiotic therapy can be life-threatening. We describe the case of a 39-year-old man with Lemierre's syndrome who presented with long-lasting orbital pain and acute exophthalmos 6 weeks after initial infection. This report is to help clinicians consider the diagnosis of Lemierre's syndrome when encountering a patient with long-lasting orbital pain and acute exophthalmos. Neck ultrasonography is useful for detecting thrombophlebitis of the internal jugular vein in Lemierre's syndrome patients. PMID- 26419366 TI - High-throughput screening identified inherited genetic variations in the EGFR pathway contributing to skin toxicity of EGFR inhibitors. AB - AIM: To identify genomic variants in the EGFR pathway and in cytokines predisposing to skin toxicity from EGFR inhibitors. PATIENTS & METHODS: In 126 patients with cancer and EGFR inhibitor therapy skin toxicity was quantified and EGFR and inflammatory pathway genes were analyzed by deep sequencing. RESULTS: We found 1437 SNPs in the 382-kb target region. Three SNPs in EGFR intron 1 were found exclusively in patients without skin rash. Another EGFR intron 23 SNP was associated with skin rash, overall survival and IL8 plasma concentrations. Moreover, carriers of the PIK3R1 326I variant were predisposed to skin rash and better survival. CONCLUSION: Comprehensive pathway-based resequencing revealed some new but only moderately strong genomic predictors of skin toxicity. PMID- 26419373 TI - The pack size effect: Influence on consumer perceptions of portion sizes. AB - Larger portions as well as larger packs can lead to larger prospective consumption estimates, larger servings and increased consumption, described as 'portion-size effects' and 'pack size effects'. Although related, the effects of pack sizes on portion estimates have received less attention. While it is not possible to generalize consumer behaviour across cultures, external cues taken from pack size may affect us all. We thus examined whether pack sizes influence portion size estimates across cultures, leading to a general 'pack size effect'. We compared portion size estimates based on digital presentations of different product pack sizes of solid and liquid products. The study with 13,177 participants across six European countries consisted of three parts. Parts 1 and 2 asked participants to indicate the number of portions present in a combined photographic and text-based description of different pack sizes. The estimated portion size was calculated as the quotient of the content weight or volume of the food presented and the number of stated portions. In Part 3, participants stated the number of food items that make up a portion when presented with packs of food containing either a small or a large number of items. The estimated portion size was calculated as the item weight times the item number. For all three parts and across all countries, we found that participants' portion estimates were based on larger portions for larger packs compared to smaller packs (Part 1 and 2) as well as more items to make up a portion (Part 3); hence, portions were stated to be larger in all cases. Considering that the larger estimated portions are likely to be consumed, there are implications for energy intake and weight status. PMID- 26419375 TI - IgG N-Glycosylation Galactose Incorporation Ratios for the Monitoring of Classical Galactosaemia. AB - Classical galactosaemia (OMIM #230400) is a rare disorder of carbohydrate metabolism caused by deficiency of the galactose-1-phosphate uridyltransferase enzyme (EC 2.7.7.12). The cause of the long-term complications, including neurological, cognitive and fertility problems in females, remains poorly understood. The relatively small number of patients with galactosaemia and the lack of validated biomarkers pose a substantial challenge for determining prognosis and monitoring disease progression and responses to new therapies. We report an improved method of automated robotic hydrophilic interaction ultra performance liquid chromatography N-glycan analysis for the measurement of IgG N glycan galactose incorporation ratios applied to the monitoring of adult patients with classical galactosaemia. We analysed 40 affected adult patients and 81 matched healthy controls. Significant differences were noted between the G0/G1 and G0/G2 incorporation ratios between galactosaemia patients and controls (p < 0.001 and <0.01, respectively). Our data indicate that the use of IgG N glycosylation galactose incorporation analysis may be now applicable for monitoring patient dietary compliance, determining prognosis and the evaluation of potential new therapies. PMID- 26419376 TI - A Review of Recent Literature on Trauma Among Individuals Living with HIV. AB - Persons living with HIV (PLWH) report disproportionately high levels of exposure to traumatic events in childhood and adulthood. Traumatic experiences are associated with negative health and behavioral outcomes. Current research in this area seeks to further explicate the myriad health effects of trauma on PLWH and the pathways through which trauma operates. In this paper, we review articles published in English between January 2014 and June 2015 that examine traumatic experiences among PLWH, including intimate partner violence (IPV), domestic abuse, child abuse, and other forms of violence. A selection of studies examining trauma among PLWH and its associations with mental health, antiretroviral medication adherence, clinical outcomes, HIV disclosure, and sexual risk behaviors were included. Studies describing trauma coping strategies and interventions were also included. We conclude with recommendations for care of trauma-exposed PLWH and directions for future research. PMID- 26419377 TI - Are pelvic anatomical structures in danger during arthroscopic acetabular labral repair? Definition of safe bone depth. AB - PURPOSE: The purpose of this study was to evaluate safe depth for suture anchor insertion during acetabular labral repair and to determine the neighbouring structures at risk during drilling and anchor insertion. METHODS: Ten human cadaveric hips (six males and four females) were obtained. Acetabular labral surface was prepared and marked for right hips as 12, 1 and 3 o'clock positions, for left hips 12, 11 and 9 o'clock positions. Those were defined as anterior, anterior-superior and superior zones, respectively. These labral positions were drilled at defined zones. After measurements, depth of the bone at 10 degrees and 20 degrees drill angles on zones was compared statistically. RESULTS: Acetabular bone widths at investigated labral insertion points did not statistically differ. A total of 14 injuries in 60 penetrations occurred (23.3 %) with free drill penetrations, and no injuries occurred with stopped drill penetrations. The bone depth was gradually decreasing from 10 degrees to 20 degrees drill angles and from anterior to superior inserting zones without significant importance. The risk of perforation to the pelvic cavity started with 20 mm drill depth, and the mean depth for all insertions was calculated as 31.7 mm (SD 2.6). CONCLUSIONS: It is anatomically possible that some pelvic structures sustain iatrogenic injury during acetabular drilling for anchor placement. Being aware of mean pelvic vault is important in which drilling after excessive pincer rim trimming could easily decrease the depth of acetabular bone without a standard. Careful drilling by using stopped drill bit is crucial to prevent iatrogenic injury. PMID- 26419378 TI - Arthroscopic-assisted plate fixation for displaced large-sized comminuted greater tuberosity fractures of proximal humerus: a novel surgical technique. AB - PURPOSE: The purpose of the present study was to describe the use of a novel hybrid surgical technique-arthroscopic-assisted plate fixation-and evaluate its clinical and anatomical outcomes in the management of large, displaced greater tuberosity (GT) fractures with comminution. METHODS: From 2009 to 2011, this novel technique was performed in 11 patients [2 men and 9 women; median age, 64 years (range 41-83 years)] with large, comminuted GT fractures, with fragment displacements of >5 mm. The preoperative mean posterior and superior migration of the fractured fragment, as measured on computed tomography (CT), was 19.5 and 5.5 mm, respectively. Two patients had shoulder fracture-dislocation, and three had associated undisplaced surgical neck fracture. The mean duration between injury and surgery was 4 days. The mean follow-up duration was 26 months. RESULTS: At the final follow-up, the mean postoperative ASES, UCLA and SST scores were 84, 29, and 8, respectively. The mean range of motion was as follows: forward flexion, 138 degrees ; abduction, 135 degrees ; external rotation at the side, 19 degrees ; and internal rotation, up to the L2 level. The mean posterior and superior displacements of fracture fragments on postoperative CT scan [0.7 +/- 0.8 mm (range 0-2.1 mm) and 2.8 +/- 0.5 mm (range 3.4-5.3 mm), respectively] were significantly improved (p < 0.05). On arthroscopy, a partial articular-side supraspinatus tendon avulsion lesion was identified in 10 of 11 patients (91 %), and 1 of these patients had a partial tear of the biceps and 1 had a partial subscapularis tear, respectively (9 %). Intraoperatively, 1 anchor pullout and 1 anchor protrusion through the humeral head were noted and corrected. Postoperatively, the loss of reduction in the fracture fragment was noted in 1 patient at 4 weeks, after corrective reduction and fixation surgery. CONCLUSIONS: The novel arthroscopic-assisted anatomical plate fixation technique was found to be effective in reducing large-sized, displaced, comminuted GT fractures and in allowing concurrent management of intra-articular pathologies and early functional rehabilitation. Compared with the conventional plate fixation or arthroscopic suture anchor fixation technique, arthroscopic-assisted plate fixation enabled accurate restoration of the medial footprint of the GT fracture and provided an effective buttress to the large-sized GT fracture fragments. LEVEL OF EVIDENCE: Retrospective clinical study, Level IV. PMID- 26419379 TI - Regional differences in temperature course after knee arthroplasty. AB - PURPOSE: During wound healing after surgery, physiological inflammation leads to an increase in soft tissue perfusion. This is reflected by a characteristic temperature course in the skin. Although local surgical trauma also influences soft tissue perfusion, no data have been available on the regional temperature distribution after knee arthroplasty to date. This study aims at testing the hypothesis that the greatest regional difference in the temperature course is on the site of the maximum surgical trauma (medially) after knee arthroplasty implantation. This is to our knowledge the first study to present regional differences in the temperature course after TKA which would limit the diagnostic value of thermography. METHODS: Forty-two subjects who were to receive a surface replacement of the knee joint due to primary varus gonarthrosis were included in the study. In all cases, a medial parapatellar approach was chosen. Patients who underwent lateral release or a release of the lateral ligament structures were excluded. In all patients, a thermographic temperature determination was carried out on the operated knee joint every day up to the seventh post-operative day. RESULTS: On the medial side, there was no significant change in temperature between day one 34.9 degrees +/- 0.2 degrees (34.6-35.3 degrees C) and seven after surgery. Thereafter, the temperature remained constant here up to the seventh day after the operation. In contrast to this, on the lateral side there was an increase in skin temperature from the second 35.0 +/- 0.2 degrees C (34.7 35.4 degrees C) to the fifth 34.6 degrees +/- 0.2 degrees (34.1-34.9 degrees C) post-operative day (p = 0.002). Thereafter, the temperature remained constant here up to the seventh day after the operation. CONCLUSION: This study refutes the hypothesis that the greatest regional difference in the temperature course is on the site of maximum surgical trauma (medially) after knee arthroplasty implantation. It is shown to the contrary that there is the least regional difference in the temperature course on the site of maximum surgical trauma (medially) after total knee arthroplasty implantation. It is on the site of the minimal trauma (laterally) where marked differences in the temperature course appeared. The normal temporary temperature increase typical of physiological wound healing could only be shown at a distance from the site of soft tissue preparation. This may be the result of a local compromise of perfusion. Consequently, the post-operative diagnostic application of thermography remains limited to regions distant from the surgical site. This may prevent misinterpretation of post-operative thermographic measurements for scientific or clinical reasons. LEVEL OF EVIDENCE: II. PMID- 26419380 TI - High prevalence of multiple-antibiotic-resistant (MAR) Escherichia coli in river bed sediments of the Apies River, South Africa. AB - This study aimed at investigating the presence of antibiotic-resistant Escherichia coli in river bed sediments of the Apies River, Gauteng, South Africa, in order to better inform health management decisions designed to protect users of the river. Overall, 180 water and sediment samples were collected at 10 sites along the Apies River from January to February 2014. E. coli was enumerated using the Colilert(r) 18/Quanti-Tray(r) 2000 (IDEXX). Isolates were purified by streaking on eosin methylene blue agar followed by the indole test. Pure E. coli isolates were tested for resistance to nine antibiotics by the Kirby-Bauer disc diffusion method. Over 98% of the isolates were resistant to at least one of the antibiotics tested. The highest resistance was observed against nitrofurantoin (sediments) and ampicillin (water). Over 80% of all resistant isolates showed multiple antibiotic resistance (resistance to >=3 antibiotics). The abundance of E. coli in the sediments not only adds to the evidence that sediments are a reservoir for bacteria and possibly other pathogens including antibiotic resistant bacteria but also suggests that antibiotic-resistant genes could be transferred to pathogens due to the high prevalence of multiple-antibiotic resistant (MAR) strains of E. coli observed in the sediment. Using untreated water from the Apies River following resuspension for drinking and other household purposes could pose serious health risks for users. Our results suggest that river bed sediments could serve as reservoirs for MAR bacteria including pathogens under different climatic conditions and their analysis could provide information of public health concerns. PMID- 26419381 TI - Mercury concentrations and health risk assessment for two fish species, Barbus grypus and Barbus luteus, from the Maroon River, Khuzestan Province, Iran. AB - The purposes of this study are to investigate the concentration of mercury in edible muscle tissues of two popular edible fish species: the Shirbot (Barbus grypus) and Hemri (Barbus luteus), from the Maroon River, Khuzestan Province, Iran, and to assess the risk of their toxicity on human health. We collected 20 samples of each species from the river, and after biometry and determination of their age and sex, concentration of total mercury (assumed to be about 100% methylmercury) was measured. For B. grypus, mercury averaged 0.16 +/- 0.02 MUg g( 1) wet weight, and for B. luteus, it averaged 0.08 +/- 0.02 MUg g(-1) wet weight. Although mercury has been reported to accumulate with age, length, and trophic level in many studies, we did not find a significant correlation among age, sex, length, and mercury content in either of these omnivorous species. Mercury levels (maximum 0.37 MUg g(-1) wet weight) were below international standards. Consumption of these fish would not pose a serious health hazard to Iranian consumers at the average national consumption of 17.53 g day(-1). However, high end consumers eating more than 250 g week(-1) and pregnant women should be attentive in choosing fish low in mercury, for example, B. luteus rather than B. grypus. PMID- 26419382 TI - Sequence and structure-based comparative analysis to assess, identify and improve the thermostability of penicillin G acylases. AB - Penicillin acylases are enzymes employed by the pharmaceutical industry for the manufacture of semi-synthetic penicillins. There is a continuous demand for thermostable and alkalophilic enzymes in such applications. We have carried out a computational analysis of known penicillin G acylases (PGAs) in terms of their thermostable nature using various protein-stabilizing factors. While the presence of disulfide bridges was considered initially to screen putative thermostable PGAs from the database, various other factors such as high arginine to lysine ratio, less content of thermolabile amino acids, presence of proline in beta turns, more number of ion-pair and other non-bonded interactions were also considered for comparison. A modified consensus approach designed could further identify stabilizing residue positions by site-specific comparison between mesostable and thermostable PGAs. A most likely thermostable enzyme identified from the analysis was PGA from Paracoccus denitrificans (PdPGA). This was cloned, expressed and tested for its thermostable nature using biochemical and biophysical experiments. The consensus site-specific sequence-based approach predicted PdPGA to be more thermostable than Escherichia coli PGA, but not as thermostable as the PGA from Achromobacter xylosoxidans. Experimental data showed that PdPGA was comparatively less thermostable than Achromobacter xylosoxidans PGA, although thermostability factors favored a much higher stability. Despite being mesostable, PdPGA being active and stable at alkaline pH is an advantage. Finally, several residue positions could be identified in PdPGA, which upon mutation selectively could improve the thermostability of the enzyme. PMID- 26419383 TI - Control of carbon flux to glutamate excretion in Klebsiella pneumoniae: the role of the indigenous plasmid and its encoded isocitrate dehydrogenase. AB - Klebsiella pneumoniae (NCTC, CL687/80) harbors a large indigenous plasmid (p(C3)), which in addition to encoding for citrate utilization, proline synthesis and glutamate excretion, it uniquely carries the structural gene (icd); encoding isocitrate dehydrogenase (ICDH). Flux analysis revealed that ICDH, despite its role in the generation of NADPH required for glutamate dehydrogenase, is not rate limiting (controlling) in central metabolism as evidenced by a negative flux control coefficient and an adverse effect of overexpression (14-fold) on glutamate excretion. More significantly, however, this paper presents, for the first time, clear evidence that the accumulation of glutamate and its subsequent excretion is associated with the C3 plasmid-encoded regulatory elements, which trigger a shift-down in the activity of alpha-ketoglutarate dehydrogenase, both in the K. pneumoniae parental strain as well as in the E. coli exconjugants strains. This finding opens the door for the exploitation of regulatory elements as a tool for manipulating flux in microbial cell factories. PMID- 26419384 TI - What is new about diet in hepatic encephalopathy. AB - There is a relationship between hepatic encephalopathy (HE) protein malnutrition and muscle wasting. Muscle may play an alternative role in ammonia detoxification. Molecular mechanisms responsible for muscle depletion are under investigation. Specific nutrients may interact to reverse the molecular pathways involved in muscle wasting at an early stage. Training exercises have also been proposed to improve skeletal muscle mass. However, these data refer to small groups of patients. The amelioration of muscle mass may potentially help to prevent HE. The pathogenesis of HE is associated with modifications of the gut microbiota and diet is emerging to play a relevant role in the modulation of the gut milieu. Vegetarian and fibre-rich diets have been shown to induce beneficial changes on gut microbiota in healthy people, with reduction of Bacteroides spp., Enterobacteriaceae, and Clostridium cluster XIVa bacteria. By way of contrast, it has been suggested that a high-fat or protein diet may increase Firmicutes and reduce Bacteroidetes phylum. Milk-lysozyme and milk-oligosaccharides have also been proposed to induce a "healthy" microbiota. At present, no studies have been published describing the modification of the gut microbiota in cirrhotic patients with HE as a response to specific diets. New research is needed to evaluate the potentiality of foods in the modulation of gut microbiota in liver disease and HE. PMID- 26419385 TI - Idalopirdine - a small molecule antagonist of 5-HT6 with therapeutic potential against obesity. AB - 5HT6 receptor antagonists offer the potential for safe and effective drugs against obesity, because they can reduce weight without causing serious side effects in the cardiovascular system. Also, their anorexic effect is associated with reduced food intake via an enhancement of satiety. In the present study we investigated the anorexic effect of idalopirdine (LuAE58054) in a model of obesity induced by high-fat diet. To induce obesity in rats, the animals were treated with feed with a fat content of 40 %. Body weight was controlled and the amount of food and water consumed was determined. The influence of the test compound on the lipid profile and glucose level was measured, as well as locomotor activity in home cages on the 20th day of the treatment. LuAE58054, at 5 mg kg(-1)/day i.p., was significantly anorectic in this model of obesity. Animals treated with LuAE58054 weighed 8 and 9.2 % less than the control obese animals on the 12th and 21st days, respectively. It significantly reduced food intake and the amount of peritoneal fat in animals, and reduced the level of triglycerides in plasma. LuAE58054 did not have a statistically significant effect on the spontaneous activity of diet-induced obese rats. The present study clearly demonstrates the effectiveness of LuAE58054 in reducing body weight. This compound is in phase III of clinical trials for the treatment of cognitive deficits associated with Alzheimer's disease and schizophrenia. It is a 5HT6 receptor antagonist and is, therefore, free of those unacceptable side effects that preclude chronic use of anti-obesity drugs with other mechanisms of action. The search for an effective and safe anti-obesity drug is essential for an increasingly obese population; therefore, the anorectic action of LuAE58054 is important and there is a need for more research in this direction. PMID- 26419386 TI - Doppler flowmetry of the superior mesenteric artery and portal vein: impact for the early prediction of necrotizing enterocolitis in neonates. AB - PURPOSE: Necrotizing enterocolitis (NEC) is a serious gastrointestinal disorder in newborns. Early diagnosis and rapid treatment is essential for seeking good outcome for neonates. The aim of our study was to evaluate intestinal blood flow in superior mesenteric artery (SMA) and portal vein (PV) in neonates with suspected or confirmed NEC and investigate the prognostic cut-off values to develop NEC. METHODS: Doppler flowmetry of SMA and PV was performed for 62 newborns. Resistive (RI) and pulsatility (PI) indexes were measured in SMA as well as Volumetric blood flow (Vflow) in PV. ROC curves were applied to estimate sensitivity and specificity and to identify cut-off values. RESULTS: There were 93.5% preterm neonates. 29 patients (46.8%) were diagnosed with NEC and 33 (53.2%) formed a control group. 96.3% NEC patients had RI >0.75 with sensitivity of 96.3% and specificity of 90.9% (OR 260). 88.9% NEC patients had PI >1.85 with sensitivity of 88.9% and specificity of 78.8% (OR 29). Portal Vflow lower than 37 ml/min was present in 89.7% patients with NEC (OR 11.7). CONCLUSION: Intestinal blood flow Dopplerography can be a useful tool for diagnosing and predicting NEC. PMID- 26419389 TI - Meta-analysis of real-time fMRI neurofeedback studies using individual participant data: How is brain regulation mediated? AB - An increasing number of studies using real-time fMRI neurofeedback have demonstrated that successful regulation of neural activity is possible in various brain regions. Since these studies focused on the regulated region(s), little is known about the target-independent mechanisms associated with neurofeedback guided control of brain activation, i.e. the regulating network. While the specificity of the activation during self-regulation is an important factor, no study has effectively determined the network involved in self-regulation in general. In an effort to detect regions that are responsible for the act of brain regulation, we performed a post-hoc analysis of data involving different target regions based on studies from different research groups. We included twelve suitable studies that examined nine different target regions amounting to a total of 175 subjects and 899 neurofeedback runs. Data analysis included a standard first- (single subject, extracting main paradigm) and second-level (single subject, all runs) general linear model (GLM) analysis of all participants taking into account the individual timing. Subsequently, at the third level, a random effects model GLM included all subjects of all studies, resulting in an overall mixed effects model. Since four of the twelve studies had a reduced field of view (FoV), we repeated the same analysis in a subsample of eight studies that had a well-overlapping FoV to obtain a more global picture of self-regulation. The GLM analysis revealed that the anterior insula as well as the basal ganglia, notably the striatum, were consistently active during the regulation of brain activation across the studies. The anterior insula has been implicated in interoceptive awareness of the body and cognitive control. Basal ganglia are involved in procedural learning, visuomotor integration and other higher cognitive processes including motivation. The larger FoV analysis yielded additional activations in the anterior cingulate cortex, the dorsolateral and ventrolateral prefrontal cortex, the temporo-parietal area and the visual association areas including the temporo-occipital junction. In conclusion, we demonstrate that several key regions, such as the anterior insula and the basal ganglia, are consistently activated during self-regulation in real-time fMRI neurofeedback independent of the targeted region-of-interest. Our results imply that if the real-time fMRI neurofeedback studies target regions of this regulation network, such as the anterior insula, care should be given whether activation changes are related to successful regulation, or related to the regulation process per se. Furthermore, future research is needed to determine how activation within this regulation network is related to neurofeedback success. PMID- 26419391 TI - How prior expectations shape multisensory perception. AB - The brain generates a representation of our environment by integrating signals from a common source, but segregating signals from different sources. This fMRI study investigated how the brain arbitrates between perceptual integration and segregation based on top-down congruency expectations and bottom-up stimulus bound congruency cues. Participants were presented audiovisual movies of phonologically congruent, incongruent or McGurk syllables that can be integrated into an illusory percept (e.g. "ti" percept for visual "ki" with auditory /pi/). They reported the syllable they perceived. Critically, we manipulated participants' top-down congruency expectations by presenting McGurk stimuli embedded in blocks of congruent or incongruent syllables. Behaviorally, participants were more likely to fuse audiovisual signals into an illusory McGurk percept in congruent than incongruent contexts. At the neural level, the left inferior frontal sulcus (lIFS) showed increased activations for bottom-up incongruent relative to congruent inputs. Moreover, lIFS activations were increased for physically identical McGurk stimuli, when participants segregated the audiovisual signals and reported their auditory percept. Critically, this activation increase for perceptual segregation was amplified when participants expected audiovisually incongruent signals based on prior sensory experience. Collectively, our results demonstrate that the lIFS combines top-down prior (in)congruency expectations with bottom-up (in)congruency cues to arbitrate between multisensory integration and segregation. PMID- 26419388 TI - Interacting parallel pathways associate sounds with visual identity in auditory cortices. AB - Spatial and non-spatial information of sound events is presumably processed in parallel auditory cortex (AC) "what" and "where" streams, which are modulated by inputs from the respective visual-cortex subsystems. How these parallel processes are integrated to perceptual objects that remain stable across time and the source agent's movements is unknown. We recorded magneto- and electroencephalography (MEG/EEG) data while subjects viewed animated video clips featuring two audiovisual objects, a black cat and a gray cat. Adaptor-probe events were either linked to the same object (the black cat meowed twice in a row in the same location) or included a visually conveyed identity change (the black and then the gray cat meowed with identical voices in the same location). In addition to effects in visual (including fusiform, middle temporal or MT areas) and frontoparietal association areas, the visually conveyed object-identity change was associated with a release from adaptation of early (50-150ms) activity in posterior ACs, spreading to left anterior ACs at 250-450ms in our combined MEG/EEG source estimates. Repetition of events belonging to the same object resulted in increased theta-band (4-8Hz) synchronization within the "what" and "where" pathways (e.g., between anterior AC and fusiform areas). In contrast, the visually conveyed identity changes resulted in distributed synchronization at higher frequencies (alpha and beta bands, 8-32Hz) across different auditory, visual, and association areas. The results suggest that sound events become initially linked to perceptual objects in posterior AC, followed by modulations of representations in anterior AC. Hierarchical what and where pathways seem to operate in parallel after repeating audiovisual associations, whereas the resetting of such associations engages a distributed network across auditory, visual, and multisensory areas. PMID- 26419390 TI - Left ventral occipitotemporal activation during orthographic and semantic processing of auditory words. AB - The present fMRI study investigated the hypothesis that activation of the left ventral occipitotemporal cortex (vOT) in response to auditory words can be attributed to lexical orthographic rather than lexico-semantic processing. To this end, we presented auditory words in both an orthographic ("three or four letter word?") and a semantic ("living or nonliving?") task. In addition, a auditory control condition presented tones in a pitch evaluation task. The results showed that the left vOT exhibited higher activation for orthographic relative to semantic processing of auditory words with a peak in the posterior part of vOT. Comparisons to the auditory control condition revealed that orthographic processing of auditory words elicited activation in a large vOT cluster. In contrast, activation for semantic processing was only weak and restricted to the middle part vOT. We interpret our findings as speaking for orthographic processing in left vOT. In particular, we suggest that activation in left middle vOT can be attributed to accessing orthographic whole-word representations. While activation of such representations was experimentally ascertained in the orthographic task, it might have also occurred automatically in the semantic task. Activation in the more posterior vOT region, on the other hand, may reflect the generation of explicit images of word-specific letter sequences required by the orthographic but not the semantic task. In addition, based on cross-modal suppression, the finding of marked deactivations in response to the auditory tones is taken to reflect the visual nature of representations and processes in left vOT. PMID- 26419392 TI - What Is the Return on Investment for Implementation of a Crew Resource Management Program at an Academic Medical Center? AB - Crew Resource Management (CRM) training has been used successfully within hospital units to improve quality and safety. This article presents a description of a health system-wide implementation of CRM focusing on the return on investment (ROI). The costs included training, programmatic fixed costs, time away from work, and leadership time. Cost savings were calculated based on the reduction in avoidable adverse events and cost estimates from the literature. Between July 2010 and July 2013, roughly 3000 health system employees across 12 areas were trained, costing $3.6 million. The total number of adverse events avoided was 735-a 25.7% reduction in observed relative to expected events. Savings ranged from a conservative estimate of $12.6 million to as much as $28.0 million. Therefore, the overall ROI for CRM training was in the range of $9.1 to $24.4 million. CRM presents a financially viable way to systematically organize for quality improvement. PMID- 26419393 TI - Topical applications of vitamin D on implant surface for bone-to-implant contact enhance: a pilot study in dogs part II. AB - OBJECTIVE: The aim of this study was to evaluate the effect of topical application of vitamin D over implant surface, placed immediately to the extraction, throughout histological and histomorphometric analysis of peri implant tissue. MATERIAL AND METHODS: Six American foxhound dogs were used in the study. Mandibular premolar distal roots were extracted. Twenty-four immediate conical C1 implants (MIS, Barlev, Israel) were randomly assigned to the distal site on each site of the mandible in three groups: (Group CI) 12 titanium implants alone; (Test Group DI) 12 titanium implants supplemented with vitamin D. Prior to implanting, test implants (DI) were submerged in vitamin D 10% solution. No treatment was applied at control implants (CI). After 12 weeks, animals were sacrificed. Block sections were obtained and processed for mineralized ground sectioning. Bone-to-implant contact (Total BIC and BIC%), new bone formation (NBF), interthread bone (ITB), and histological linear measurements (HLM) were analyzed. RESULTS: At 12 weeks, all implants were clinically stable and histologically osseointegrated. BIC evaluation showed Total BIC mean and SD values for DI (48.96 +/- 2.14), CI (44.56 +/- 1.75) (P < 0.05), BIC% DI (43.59 +/ 0.98), and CI (42.67 +/- 9.26) (P > 0.05). For interthread bone formation, values were as follows: DI (15.21 +/- 3.87), CI (14.79 +/- 1.45) (P > 0.05), no statistically differences. Regarding peri-implant new bone formation, no statistically differences could be found between the two groups DI (31.87 +/- 1.23), CI (27.18 +/- 2.38) (P > 0.05). For linear measurements, test group (DI) showed statistically significant less buccal crestal bone loss (CBL) DI (0.37 +/- 0.12)*, CI (1.26 +/- 0.8) (P < 0.05), and vitamin D implants showed less lingual junctional epithelium DI (1.58 +/- 0.43)*, CI (2.18 +/- 0.48) (P < 0.05). No differences were observed in the buccal mucosa. CONCLUSION: With the limitation of animal studies, topical application of vitamin D on dental implants could reduce crestal bone loss and increase 10% more bone-to-implant contact at 12-week follow-up period. PMID- 26419394 TI - Computer aided mammography yields no clear benefit, research finds. PMID- 26419395 TI - Melt electrospinning of poly(lactic acid) and polycaprolactone microfibers by using a hand-operated Wimshurst generator. AB - A conventional melt electrospinning setup usually needs a large, heavy high voltage power supply and cannot work without a plug (electricity supply). In this article, we report a new melt electrospinning setup based on a small hand operated Wimshurst generator, which can avoid electrical interference between the high-voltage spinning system and the heating system, and make the setup very portable and safe. Poly(lactic acid) (PLA) and polycaprolactone (PCL) fibers with diameters of 15-45 MUm were fabricated successfully by using this apparatus. Experimental parameters such as the rotational speed of the generator handle (a half turn to two turns per second) and the spinning distance (2-14 cm) were investigated. In addition, PLA and PCL fibers were directly melt-electrospun onto a pork liver, and the temperature and adhesiveness of the deposited fibers were studied. The results indicate that the apparatus and melt-electrospun polymer microfibers may be used in dressing for wound healing. PMID- 26419396 TI - Reduction of Saccharomyces cerevisiae Pom34 protein level by SESA network is related to membrane lipid composition. AB - Various pathways block initiation of translation of the bulk of mRNAs in response to membrane stress, amino acid starvation and unfolded proteins. In contrast, SESA, a network of proteins comprising Smy2, Eap1, Scp160 and Asc1, is a novel inhibitor of translation initiation of specific mRNAs. SESA binds POM34 mRNA in response to failure in spindle pole body (SPB) duplication process and inhibits its initiation of translation. We herein report that Pom34 protein level is reduced also in cells with altered membrane lipid composition upon treatment with various chemicals and show that SESA-induced downregulation of Pom34 is crucial for viability of cells with a disturbed nuclear envelope. Thus, we propose that SESA's action in SPB duplication process is dependent on the alteration of membrane lipid composition to facilitate the insertion process. PMID- 26419397 TI - Single Unit Cell Bismuth Tungstate Layers Realizing Robust Solar CO2 Reduction to Methanol. AB - Solar CO2 reduction into hydrocarbons helps to solve the global warming and energy crisis. However, conventional semiconductors usually suffer from low photoactivity and poor photostability. Here, atomically-thin oxide-based semiconductors are proposed as excellent platforms to overcome this drawback. As a prototype, single-unit-cell Bi2WO6 layers are first synthesized by virtue of a lamellar Bi-oleate intermediate. The single-unit-cell thickness allows 3-times larger CO2 adsorption capacity and higher photoabsorption than bulk Bi2WO6. Also, the increased conductivity, verified by density functional theory calculations and temperature-dependent resistivities, favors fast carrier transport. The carrier lifetime increased from 14.7 to 83.2 ns, revealed by time-resolved fluorescence spectroscopy, which accounts for the improved electron-hole separation efficacy. As a result, the single-unit-cell Bi2WO6 layers achieve a methanol formation rate of 75 MUmol g(-1) h(-1), 125-times higher than that of bulk Bi2WO6. The catalytic activity of the single-unit-cell layers proceeds without deactivation even after 2 days. This work will shed light on designing efficient and robust photoreduction CO2 catalysts. PMID- 26419398 TI - Acute and chronic toxicity of neonicotinoids to nymphs of a mayfly species and some notes on seasonal differences. AB - Mayfly nymphs are among the most sensitive taxa to neonicotinoids. The present study presents the acute and chronic toxicity of 3 neonicotinoids (imidacloprid, thiacloprid, and thiamethoxam) to a mayfly species (Cloeon dipterum) and some notes on the seasonality of the toxicity of imidacloprid to C. dipterum and 5 other invertebrate species. Imidacloprid and thiamethoxam showed equal acute and chronic toxicity to a winter generation of C. dipterum, whereas thiacloprid was approximately twice as toxic. The acute and chronic toxicity of imidacloprid was much higher for the C. dipterum summer generation than for the winter one. The acute toxicity differs by a factor of 20 for the 96-h 50% effective concentration (EC50) and by a factor of 5.4 for the chronic 28-d EC50. Temperature had only a slight effect on the sensitivity of C. dipterum to imidacloprid because we only found a factor of 1.7 difference in the 96-h EC50 between tests performed at 10 degrees C and 18 degrees C. The difference in sensitivity between summer and overwintering generations was also found for 3 other insect species. The results indicate that if the use and environmental fate of the 3 neonicotinoids are comparable, replacing imidacloprid by another neonicotinoid might not reduce the environmental impact on the mayfly nymph C. dipterum. The results also show the importance of reporting which generation is tested because sensitivity values of insects in the summer might be underestimated by the experiments performed with neonicotinoids and an overwintering population. PMID- 26419400 TI - Assignment of Empirical Mode Decomposition Components and Its Application to Biomedical Signals. AB - OBJECTIVES: Empirical mode decomposition (EMD) is a frequently used signal processing approach which adaptively decomposes a signal into a set of narrow band components known as intrinsic mode functions (IMFs). For multi-trial, multivariate (multiple simultaneous recordings), and multi-subject analyses the number and signal properties of the IMFs can deviate from each other between trials, channels and subjects. A further processing of IMFs, e.g. a simple ensemble averaging, should determine which IMFs of one signal correspond to IMFs from another signal. When the signal properties have similar characteristics, the IMFs are assigned to each other. This problem is known as correspondence problem. METHODS: From the mathematical point of view, in some cases the correspondence problem can be transformed into an assignment problem which can be solved e.g. by the Kuhn-Munkres algorithm (KMA) by which a minimal cost matching can be found. We use the KMA for solving classic assignment problems, i.e. the pairwise correspondence between two sets of IMFs of equal cardinalities, and for pairwise correspondences between two sets of IMFs with different cardinalities representing an unbalanced assignment problem which is a special case of the k cardinality assignment problem. RESULTS: A KMA-based approach to solve the correspondence problem was tested by using simulated, heart rate variability (HRV), and EEG data. The KMA-based results of HRV decomposition are compared with those obtained from a hierarchical cluster analysis (state-of-the-art). The major difference between the two approaches is that there is a more consistent assignment pattern using KMA. Integrating KMA into complex analysis concepts enables a comprehensive exploitation of the key advantages of the EMD. This can be demonstrated by non-linear analysis of HRV-related IMFs and by an EMD-based cross-frequency coupling analysis of the EEG data. CONCLUSIONS: The successful application to HRV and EEG analysis demonstrates that our solutions can be used for automated EMD-based processing concepts for biomedical signals. PMID- 26419399 TI - Systemic Amyloid A Amyloidosis in Island Foxes (Urocyon littoralis): Severity and Risk Factors. AB - Systemic amyloid A (AA) amyloidosis is highly prevalent (34%) in endangered island foxes (Urocyon littoralis) and poses a risk to species recovery. Although elevated serum AA (SAA) from prolonged or recurrent inflammation predisposes to AA amyloidosis, additional risk factors are poorly understood. Here we define the severity of glomerular and medullary renal amyloid and identify risk factors for AA amyloidosis in 321 island foxes necropsied from 1987 through 2010. In affected kidneys, amyloid more commonly accumulated in the medullary interstitium than in the glomeruli (98% [n= 78 of 80] vs 56% [n= 45], respectively;P< .0001), and medullary deposition was more commonly severe (19% [n= 20 of 105]) as compared with glomeruli (7% [n= 7];P= .01). Univariate odds ratios (ORs) of severe renal AA amyloidosis were greater for short- and long-term captive foxes as compared with free-ranging foxes (ORs = 3.2, 3.7, respectively; overall P= .05) and for females as compared with males (OR = 2.9;P= .05). Multivariable logistic regression revealed that independent risk factors for amyloid development were increasing age class (OR = 3.8;P< .0001), San Clemente Island subspecies versus San Nicolas Island subspecies (OR = 5.3;P= .0003), captivity (OR = 5.1;P= .0001), and nephritis (OR = 2.3;P= .01). The increased risk associated with the San Clemente subspecies or captivity suggests roles for genetic as well as exogenous risk factors in the development of AA amyloidosis. PMID- 26419402 TI - DLL4 loss-of-function heterozygous mutations cause Adams-Oliver syndrome. PMID- 26419401 TI - A longitudinal twin study on Tojikomori and depressive symptoms in Japanese elderly. AB - BACKGROUND: Genetic factors associated with Tojikomori (being housebound without any limitations in physical functioning or mental problems) are unclear. We performed a twin study to help clarify the causes of Tojikomori and investigate the association between Tojikomori and depressive symptoms. METHODS: Participants were members of the Osaka University Aged Twin Registry. A total of 157 twin pairs (314 individuals) who provided data in 2008 and 2012 were included. Depressive symptoms were measured by the Geriatric Depression Scale short version (GDS). Social Activities Scores (SAS) were measured with questions assessing the frequency of going out and contact with others. Activities of daily living were assessed with the Barthel index. Structural equation modelling analysis was used to evaluate the relative importance of genes and environments for the phenotypes measured. RESULTS: In the first analysis, for SAS (2012), 25% of the variance was explained by additive genetic effects, and 75% was explained by unique environmental (including error) effects. For the GDS (2012), 28% of the variance was explained by additive genetic effects, and 72% was explained by unique environmental (including error) effects. In the second analysis, 25% of the total variance in SAS (2012) was explained by additive genetic factors, which influenced GDS scores (2008 and 2012). However, only 10% of the total variance in GDS scores (2012) was explained by additive genetic factors that influenced SAS (2008 and 2012). CONCLUSIONS: Tojikomori was influenced by genetic factors in the elderly Japanese subjects. The association between Tojikomori and depressive symptoms was explained by genetic and environmental factors that are common to both phenotypes. Depressive symptoms were a cause of future Tojikomori and were affected by additive genetic factors. Genetic factors of Tojikomori were not a major cause of future depressive symptoms. PMID- 26419403 TI - Exercise-induced hypoxia secondary to an atrial septal defect and cor triatriatum dexter. AB - A 14-year-old boy presented to us with a diagnosis of severe asthma and oxygen desaturation of 76% on a 6-minute-walk test. A contrast echocardiogram revealed echocontrast in the left and right atria simultaneously. A secundum atrial septal defect and partial cor triatriatum dexter were diagnosed, and the atrial defect was closed by cardiac catheterisation. PMID- 26419404 TI - Five-day stability of thawed plasma: solvent/detergent-treated plasma comparable with fresh-frozen plasma and plasma frozen within 24 hours. AB - BACKGROUND: Plasma stored refrigerated for up to 5 days after thawing is common practice in many US hospitals. Therefore, clotting factor activities in fresh frozen plasma (FFP), plasma frozen within 24 hours (PF24), and solvent/detergent treated plasma (SDP), thawed and stored at 1 to 6 degrees C for up to 5 days, were investigated. STUDY DESIGN AND METHODS: Five A, B, O, and AB units of FFP, PF24, and SDP were thawed and maintained for 5 days at 1 to 6 degrees C. The activity of factor (F)V, FVII, FVIII, protein S (PS), and ADAMTS13 was determined in each unit at baseline and every 24 hours thereafter for 5 days. RESULTS: After thaw, mean values of the variables tested were within the normal range in all three plasma products although, in SDP, FVIII activity was significantly lower (p = 0.0039). After 5 days of storage all factors significantly declined except for ADAMTS13 activity, which was stable. Mean FVIII and ADAMTS13 activity was comparable in all three plasma products and within the normal range, mean FV activity was significantly lower in FFP and PF24 (p<0.0001) compared to SDP, and mean FVII activity was significantly lower in PF24 (p<0.03) than in FFP or SDP. Mean PS activity was below the normal range in all three plasma products with the lowest values in SDP (p = 0.0001). CONCLUSION: Over 5 days of refrigerated storage the changes in the measured coagulation factors in FFP, PF24, and SDP are comparable. Clinical follow-up is needed to assess whether slightly lower PS levels in SDP are clinically important. PMID- 26419405 TI - Intrapartum fetal heart rate patterns preceding terminal bradycardia in infants (>34 weeks) with poor neurological outcome: A regional population-based study in Japan. AB - AIM: Intrapartum fetal bradycardia necessitates immediate operative delivery. Our aim was to investigate the hypothesis that some non-reassuring fetal heart rate (FHR) patterns were present before the onset of terminal bradycardia in infants who developed subsequent brain damage. MATERIAL AND METHODS: From a population based study of 65,197 deliveries, 190 stillbirths, 115 neonatal deaths, and 136 neurologically high-risk infants were registered by the Miyazaki Perinatal Conference. There were 15 cases of neurologically high-risk infants born at >34 weeks of gestation exhibiting intrapartum terminal bradycardia. Focusing on the brain-damaged infants, we retrospectively analyzed FHR patterns for at least 1 h prior to the bradycardia. RESULTS: Brain damage (cerebral palsy [n = 11] and mental retardation [n = 2]) was diagnosed at 2 years old in 13 out of 15 neurologically high-risk infants. Two infants had bradycardia on admission. In the remaining 11 infants, FHR patterns were reassuring in six (55%) and non reassuring in five (45%), including late decelerations (n = 4) and variable decelerations (n = 2). Clinically relevant factors in the non-reassuring group included intrauterine infection (n = 3), malpresentation with umbilical cord coiling (n = 1), and unknown causes (n = 1). Clinically relevant features in the reassuring group included cord prolapse (n = 1), vaginal breech delivery (n = 1), shoulder dystocia (n = 1), rupture of membranes (n = 1), and unknown causes (n = 2). CONCLUSION: More than half of the brain-damaged infants born at >34 weeks of gestation who exhibited intrapartum terminal bradycardia had unremarkable FHR patterns before abrupt-onset bradycardia. For those with non-reassuring patterns preceding bradycardia, intrauterine infection was the major sentinel event. PMID- 26419406 TI - Paenibacillus ripae sp. nov., isolated from bank side soil. AB - A Gram-stain-variable, rod-shaped, non-motile and endospore-forming bacterium, designated strain HZ1T, was isolated from a sample of bank side soil from Hangzhou city, Zhejiang province, PR China. On the basis of 16S rRNA gene sequence analysis, strain HZ1T was closely related to members of the genus Paenibacillus, sharing the highest levels of sequence similarity with Paenibacillus agarexedens DSM 1327T (94.4 %), Paenibacillus sputi KIT00200-70066 1T (94.4 %). Growth occurred at 15-42 degrees C (optimum 30-37 degrees C), pH 5.0-9.5 (optimum pH 7.0-8.0) and NaCl concentrations of up to 6.0 % (w/v) were tolerated (optimum 0.5 %). The dominant respiratory quinone was MK-7 and the DNA G+C content was 40.1 mol%. The major fatty acids were anteiso-C15 : 0 and iso-C16 : 0. The major polar lipids of strain HZ1T were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and several unknown lipids. The diagnostic diamino acid found in the cell-wall peptidoglycan was meso diaminopimelic acid. Based on its phenotypic and chemotaxonomic characteristics and phylogenetic data, strain HZ1T represents a novel species of the genus Paenibacillus, for which the name Paenibacillus ripae sp. nov. (type strain HZ1T = CCTCC AB 2014276T = LMG 28639T) is proposed. PMID- 26419407 TI - Cleft palate in a patient with the nested 22q11.2 LCR C to D deletion. PMID- 26419408 TI - Lipid droplet distribution of immature canine oocytes in relation to their size and the reproductive stage. AB - This study investigated the distribution of lipid droplets (LD) in immature canine oocytes in relation to their size and the reproductive stage. Oocytes were collected from the ovaries of bitches at different estrous stages, divided according to their size (110-120 um; >120 um), and stained with Nile Red to detect lipid droplet distribution. At the follicular phase most of the oocytes displayed a diffuse pattern of LD distribution, whereas at anestrus and luteal phase oocytes showed LD mainly in a peripheral/ perinuclear LD distribution. A significantly higher intensity of LD has been recorded in the oocytes > 120 um compared to those of smaller size (110 - 120 um) at all stages of the estrous cycle. At follicular phase, oocytes > 120 um displayed LD intensity similar to that of oocytes > 120 um at luteal phase and higher compared to the oocytes of the other groups. PMID- 26419409 TI - Physical assessment techniques performed by Italian registered nurses: a quantitative survey. AB - AIMS AND OBJECTIVES: The aims of the study were to describe which of the core techniques of the physical assessment are regularly performed by a sample of Italian nurses, and to investigate the potential predictors of a more complete examination. BACKGROUND: Physical examination is among the essential tasks of nursing professionals, who are requested to perform a correct and complete physical assessment. DESIGN: Cross-sectional survey. METHODS: The study was performed between August 2013 and January 2014 in 17 Italian regions. A total of 1182 questionnaires were collected. RESULTS: Most participants were females (age range 41-50 years), and worked in Internal Medicine, Intensive Care and Surgical hospital units. Of the 30 core techniques that are currently taught and performed according to the Italian Baccalaureate degree requirements, 20 were routinely performed, 6 were seldom used and 4 were learnt but almost never performed (auscultation of lung, heart and bowel sounds and spine inspection). Graduate and postgraduate nurses, working in Intensive Care Units and Nursing Homes, were more prone than the others to carry out a more complete physical assessment. CONCLUSIONS: The skills to perform a physical assessment are suboptimal among this sample of Italian nurses. Health and educational providers should pose more attention and efforts to provide nurses with an acceptable training in physical examination practice. RELEVANCE TO CLINICAL PRACTICE: This study describes the specific physical techniques performed by nurses in real practice and provides information on which skills require more attention in nursing educational programmes. PMID- 26419410 TI - Metabolic changes in rat urine after acute paraquat poisoning and discriminated by support vector machine. AB - Paraquat is quick-acting and non-selective, killing green plant tissue on contact; it is also toxic to human beings and animals. In this study, we developed a urine metabonomic method by gas chromatography-mass spectrometry to evaluate the effect of acute paraquat poisoning on rats. Pattern recognition analysis, including both partial least squares discriminate analysis and principal component analysis revealed that acute paraquat poisoning induced metabolic perturbations. Compared with the control group, the levels of benzeneacetic acid and hexadecanoic acid of the acute paraquat poisoning group (intragastric administration 36 mg/kg) increased, while the levels of butanedioic acid, pentanedioic acid, altronic acid decreased. Based on these urinary metabolomics data, support vector machine was applied to discriminate the metabolomic change of paraquat groups from the control group, which achieved 100% classification accuracy. In conclusion, metabonomic method combined with support vector machine can be used as a useful diagnostic tool in paraquat-poisoned rats. PMID- 26419411 TI - Evaluating the treatment effects model for estimation of cross-sectional associations between risk factors and cardiovascular biomarkers influenced by medication use. AB - PURPOSE: In cross-sectional observational data, evaluation of biomarker-to exposure associations is often complicated by nonrandom medication use. Traditional approaches often lead to biased estimates, consistent with known results involving confounding by indication. More sophisticated, yet easy to implement approaches such as inverse probability weighting and censored normal regression can address medication use in certain settings but have poor performance when medication use depends on off-medication biomarker values. More sophisticated approaches are necessary. METHODS: Heckman's treatment effects model resembles the process that gives rise to cross-sectional data. In this study, we conduct a variety of simulation studies to illustrate why traditional approaches are inappropriate when medication use depends on underlying biomarker values. We illustrate how Heckman's model can accommodate this feature. We also apply the models to data from the Multi-Ethnic Study of Atherosclerosis. RESULTS: Inverse probability weighting and censored normal regression are sensitive to how strongly medication use is associated with untreated biomarker values (the untreated value acts as an unmeasured predictor of medication use in this context). Heckman's model can often adequately remove bias and is robust to certain forms of model misspecification but relies on knowing important predictors of medication use, even when they are independent of the biomarker. The advantages of Heckman's model can be negated if the effect of medication on biomarker values is proportionate to the underlying biomarker. CONCLUSIONS: If predictors of medication use are measured, data are cross-sectional, and effects are approximately additive, then Heckman's model is more accurate relative to alternative approaches. PMID- 26419413 TI - 25 MHz clock continuous-variable quantum key distribution system over 50 km fiber channel. AB - In this paper, a practical continuous-variable quantum key distribution system is developed and it runs in the real-world conditions with 25 MHz clock rate. To reach high-rate, we have employed a homodyne detector with maximal bandwidth to 300 MHz and an optimal high-efficiency error reconciliation algorithm with processing speed up to 25 Mbps. To optimize the stability of the system, several key techniques are developed, which include a novel phase compensation algorithm, a polarization feedback algorithm, and related stability method on the modulators. Practically, our system is tested for more than 12 hours with a final secret key rate of 52 kbps over 50 km transmission distance, which is the highest rate so far in such distance. Our system may pave the road for practical broadband secure quantum communication with continuous variables in the commercial conditions. PMID- 26419414 TI - Non-antibiotic 12-membered macrolides: design, synthesis and biological evaluation in a cigarette-smoking model. AB - The 14-membered macrolide erythromycin A expresses three distinct biological properties, including antibacterial activity, gastrointestinal motor-stimulating activity and anti-inflammatory and/or immunomodulatory effects. Although low dose, long-term therapy using 14- and 15-membered macrolides displaying anti inflammatory and/or immunomodulatory activity effectively treats diffuse panbronchiolitis and chronic sinusitis, bacterial resistance may emerge. To address this issue, we developed the 12-membered non-antibiotic macrolide (8R,9S) 8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A (EM900) that promotes monocyte to macrophage differentiation, a marker for anti-inflammatory and/or immunomodulatory effects, without possessing antibacterial activity. In this article, we report that the new macrolide derivative (8R,9S) -de(3'-N-methyl)-3' N-(p-chlorobenzyl)-de(3-O-cladinosyl)-3-dehydro-8,9-dihydro-6,9-epoxy-8,9 anhydropseudoerythromycin A 12,13-carbonate (EM939) exhibited stronger promotive activity for monocyte to macrophage differentiation than that of the parent compound EM900 in addition to reduced cytotoxicity toward THP-1 cells and antibacterial inactivity. In a cigarette-smoking model used to simulate chronic obstructive pulmonary disease (COPD), the EM900 derivatives significantly attenuated lung and alveolar inflations, functionally and histologically, via oral administration. Because of these marked therapeutic effects, non-antibiotic EM900 derivatives may become central to the treatment of chronic inflammatory diseases such as COPD. PMID- 26419415 TI - Increased resistance rate to ceftazidime among blood culture isolates of ESBL producing Escherichia coli in a university-affiliated hospital of China. PMID- 26419416 TI - High population densities of Macrolophus pygmaeus on tomato plants can cause economic fruit damage: interaction with Pepino mosaic virus? AB - BACKGROUND: The zoophytophagous predator Macrolophus pygmaeus Rambur (Hemiptera: Miridae) is a successful biocontrol agent against several pest species in protected tomato crops. This predator is considered to be harmless for the crop. However, in recent years, Heteroptera feeding punctures on tomato fruit in Belgian and Dutch greenhouses have been misinterpreted as Pepino mosaic virus (PepMV) symptoms. In this study, three hypotheses were tested: (1) M. pygmaeus causes fruit damage that increases with population density and surpasses economic thresholds; (2) the presence of prey or alternative prey reduces the damage; (3) an infection of the tomato plants by PepMV triggers or aggravates M. pygmaeus fruit damage. RESULTS: At increasing M. pygmaeus densities, the severity of fruit damage increased from a few dimples towards yellowish discoloration and deformed fruits. A correlation with an infection with PepMV was found. The severity of the symptoms was independent of the presence of prey. A minimum economic density threshold was estimated at 0.32 M. pygmaeus per leaf. CONCLUSION: M. pygmaeus can cause economic damage to tomato fruits at densities common in practice. An infection of the plants with PepMV enhances fruit symptoms significantly. Interacting plant defence responses are most likely the key to explaining this, although confirmation is required. (c) 2015 Society of Chemical Industry. PMID- 26419417 TI - Logical error rate in the Pauli twirling approximation. AB - The performance of error correction protocols are necessary for understanding the operation of potential quantum computers, but this requires physical error models that can be simulated efficiently with classical computers. The Gottesmann-Knill theorem guarantees a class of such error models. Of these, one of the simplest is the Pauli twirling approximation (PTA), which is obtained by twirling an arbitrary completely positive error channel over the Pauli basis, resulting in a Pauli channel. In this work, we test the PTA's accuracy at predicting the logical error rate by simulating the 5-qubit code using a 9-qubit circuit with realistic decoherence and unitary gate errors. We find evidence for good agreement with exact simulation, with the PTA overestimating the logical error rate by a factor of 2 to 3. Our results suggest that the PTA is a reliable predictor of the logical error rate, at least for low-distance codes. PMID- 26419419 TI - Bandgap- and Radial-Position-Dependent Mn-Doped Zn-Cu-In-S/ZnS Core/Shell Nanocrystals. AB - This paper presents a mechanistic study on the doping of Zn-Cu-In-S/ZnS core/shell quantum dots (QDs) with Mn by changing the Zn-Cu-In-S QD bandgap and dopant position inside the samples (Zn-Cu-In-S core and ZnS shell). Results show that for the Mn:Zn-Cu-In-S/ZnS system, a Mn-doped emission can be obtained when the bandgap value of the QDs is larger than the energy of Mn-doped emission. Conversely, a bandgap emission is only observed for the doped system when the bandgap value of QDs is smaller than the energy gap of the Mn-doped emission. In the Zn-Cu-In-S/Mn:ZnS systems, doped QDs show dual emissions, consisting of bandgap and Mn dopant emissions, instead of one emission band when the value of the host bandgap is larger than the energy of the Mn-doped emission. These findings indicate that the emission from Mn-doped Zn-Cu-In-S/ZnS core/shell QDs depends on the bandgap of the QDs and the dopant position inside the core/shell material. The critical bandgap of the host materials is estimated to have the same value as the energy of the Mn d-d transition. Subsequently, the mechanism of photoluminescence properties of the Mn:Zn-Cu-In-S/ZnS and Zn-Cu-In-S/Mn:ZnS core/shell QD systems is proposed. Control experiments are then carried out by preparing Mn-doped Zn(Cu)-In-S QDs with various bandgaps, and the results confirm the reliability of the suggested mechanism. Therefore, the proposed mechanism can aid the design and synthesis of novel host materials in fabricating doped QDs. PMID- 26419418 TI - Cognitive tutoring induces widespread neuroplasticity and remediates brain function in children with mathematical learning disabilities. AB - Competency with numbers is essential in today's society; yet, up to 20% of children exhibit moderate to severe mathematical learning disabilities (MLD). Behavioural intervention can be effective, but the neurobiological mechanisms underlying successful intervention are unknown. Here we demonstrate that eight weeks of 1:1 cognitive tutoring not only remediates poor performance in children with MLD, but also induces widespread changes in brain activity. Neuroplasticity manifests as normalization of aberrant functional responses in a distributed network of parietal, prefrontal and ventral temporal-occipital areas that support successful numerical problem solving, and is correlated with performance gains. Remarkably, machine learning algorithms show that brain activity patterns in children with MLD are significantly discriminable from neurotypical peers before, but not after, tutoring, suggesting that behavioural gains are not due to compensatory mechanisms. Our study identifies functional brain mechanisms underlying effective intervention in children with MLD and provides novel metrics for assessing response to intervention. PMID- 26419420 TI - Dynamic scaling for the growth of non-equilibrium fluctuations during thermophoretic diffusion in microgravity. AB - Diffusion processes are widespread in biological and chemical systems, where they play a fundamental role in the exchange of substances at the cellular level and in determining the rate of chemical reactions. Recently, the classical picture that portrays diffusion as random uncorrelated motion of molecules has been revised, when it was shown that giant non-equilibrium fluctuations develop during diffusion processes. Under microgravity conditions and at steady-state, non equilibrium fluctuations exhibit scale invariance and their size is only limited by the boundaries of the system. In this work, we investigate the onset of non equilibrium concentration fluctuations induced by thermophoretic diffusion in microgravity, a regime not accessible to analytical calculations but of great relevance for the understanding of several natural and technological processes. A combination of state of the art simulations and experiments allows us to attain a fully quantitative description of the development of fluctuations during transient diffusion in microgravity. Both experiments and simulations show that during the onset the fluctuations exhibit scale invariance at large wave vectors. In a broader range of wave vectors simulations predict a spinodal-like growth of fluctuations, where the amplitude and length-scale of the dominant mode are determined by the thickness of the diffuse layer. PMID- 26419421 TI - Isolation and Crystallographic Characterization of Gd3N@D2(35)-C88 through Non Chromatographic Methods. AB - While several nonchromatographic methods are available for the isolation and purification of endohedral fullerenes of the type M3N@Ih-C80, little work has been done that would allow other members of the M3N@C2n family to be isolated with minimal chromatography. Here, we report that Gd3N@D2(35)-C88 can be isolated from the multitude of endohedral and empty cage fullerenes present in carbon soot obtained by electric-arc synthesis using Gd2O3-doped graphite rods. The procedure developed utilizes successive precipitation with the Lewis acids CaCl2 and ZnCl2 followed by treatment with amino-functionalized silica gel. The structure of the product was identified by single-crystal X-ray diffraction. PMID- 26419423 TI - Leadership by example: saying no to health industry board membership. PMID- 26419422 TI - Structure-Affinity Relationship Analysis of Selective FKBP51 Ligands. AB - The FK506-binding protein 51 (FKBP51) is a promising drug target for the treatment of stress-related psychiatric or metabolic disorders. Just recently, the first selective ligands for FKBP51 were reported based on an induced fit mechanism, but they are too large for a further drug development process. We therefore designed and synthesized a novel series of selective ligands to explore the requirements necessary for binding to the induced-fit conformation. All ligands of this series show no binding toward the structurally very similar antitarget FKBP52. With the cocrystal structure of the best ligand in this novel series we confirmed the induced fit mechanism. Furthermore, the structure affinity relationship provides information about beneficial structural features, which is valuable for the development of improved FKBP51-directed drugs. PMID- 26419424 TI - Copper-catalyzed electrophilic amination of sodium sulfinates at room temperature. AB - By using O-benzoyl hydroxylamines as amine sources, the first convenient copper catalyzed electrophilic amination of sodium sulfinates has been realized. Even with 2 mol% catalyst loading, the protocol provided an efficient and straightforward synthesis of a broad range of functional sulfonamides under ambient reaction conditions without an additional base and ligand. Based on the control experiments, a plausible mechanism was proposed. PMID- 26419425 TI - SAMSVM: A tool for misalignment filtration of SAM-format sequences with support vector machine. AB - Sequence alignment/map (SAM) formatted sequences [Li H, Handsaker B, Wysoker A et al., Bioinformatics 25(16):2078-2079, 2009.] have taken on a main role in bioinformatics since the development of massive parallel sequencing. However, because misalignment of sequences poses a significant problem in analysis of sequencing data that could lead to false positives in variant calling, the exclusion of misaligned reads is a necessity in analysis. In this regard, the multiple features of SAM-formatted sequences can be treated as vectors in a multi dimension space to allow the application of a support vector machine (SVM). Applying the LIBSVM tools developed by Chang and Lin [Chang C-C, Lin C-J, ACM Trans Intell Syst Technol 2:1-27, 2011.] as a simple interface for support vector classification, the SAMSVM package has been developed in this study to enable misalignment filtration of SAM-formatted sequences. Cross-validation between two simulated datasets processed with SAMSVM yielded accuracies that ranged from 0.89 to 0.97 with F-scores ranging from 0.77 to 0.94 in 14 groups characterized by different mutation rates from 0.001 to 0.1, indicating that the model built using SAMSVM was accurate in misalignment detection. Application of SAMSVM to actual sequencing data resulted in filtration of misaligned reads and correction of variant calling. PMID- 26419426 TI - A new chiral uranyl phosphonate framework consisting of achiral building units generated from ionothermal reaction: structure and spectroscopy characterizations. AB - The ionothermal reactions of uranyl nitrate and 1,3-pbpH4 (1,3-pbpH4 = 1,3 phenylenebis(phosphonic acid) ligand in ionic liquids of [C4mim][Dbp], [C4mpyr][Br], and [Etpy][Br], respectively, afforded three new uranyl phosphonates, namely [C4mim][(UO2)2(1,3-pbpH)(1,3-pbpH).Hmim] (1), [UO2(1,3 pbpH2)H2O.mpr] (2), and [Etpy][UO2(1,3-pbpH2)F] (3). Compound 1 exhibits a rare example of a chiral uranyl phosphonate 3D framework structure built from achiral building units of tetragonal bipyramidal uranium polyhedra and 1,3-pbp ligands. The structure adopts a network with channels extending along the b axis, which are filled with C4mim(+) and protonated 1-methylimidazole. In sharp contrast, compounds 2 & 3 both show pillared topology composed of uranyl pentagonal bipyramid polyhedra and phosphonate ligands. The layers are neutral in compound 2 with N-methylpyrrole molecules in the interlayer space, while compound 3 adopts anionic layer, and the charge is compensated with N-ethyl-pyridinium cations between the layers. Although compounds 1, 2, and 3 were synthesized under identical conditions with sole variation of the ionic liquid species, the resulting structures show a rich diversity in the local coordination environment of uranyl ions, the protonation of the phosphonate ligand, the conformation of ionic liquid ions, and the overall arrangement of the structure. All compounds were characterized by absorption, temperature dependent fluorescence, as well as infrared and Raman spectroscopies. PMID- 26419427 TI - Role of Locoregional Therapy and Predictors for Dropout in Patients with Hepatocellular Carcinoma Listed for Liver Transplantation. AB - PURPOSE: To identify factors associated with removal from the liver transplantation waitlist because of death, deterioration of condition, or exceeding Milan criteria in patients with hepatocellular carcinoma (HCC), with emphasis on the role of locoregional therapy (LRT), defined as percutaneous thermal ablation and drug-eluting embolic chemoembolization, as bridge therapy. MATERIALS AND METHODS: All patients listed for liver transplant at a single institution with exception points for HCC during 2004-2012 were evaluated. The most common cause of cirrhosis was hepatitis C (68%; 121/177). Seventy-one percent (125/177) of patients underwent liver transplantation, and 83% (147/177) underwent at least 1 LRT procedure. Of the 52 patients who did not undergo liver transplantation, 31 (60%) of livers were removed because of progression of HCC. RESULTS: The likelihood of transplant was higher for patients who received LRT (odds ratio [OR], 2.9; confidence interval [CI], 2.2-7.2) and lower for patients with multifocal tumors (OR, 0.25; CI, 0.12-0.52) and with larger tumors (OR, 0.94; CI, 0.90-0.98). Time on the waitlist (OR, 0.99; CI, 0.99-1.0) was not found to correlate with removal. LRT increased the likelihood of liver transplantation, specifically for patients with prolonged wait times. Patients who demonstrated complete response (CR) to LRT on the first follow-up imaging study were more likely to undergo liver transplantation. CONCLUSIONS: LRT increased the likelihood of a patient with HCC achieving liver transplant, particularly in patients facing prolonged waiting times. CR after LRT significantly increased the likelihood of liver transplantation. PMID- 26419428 TI - Transdermal delivery of biopharmaceuticals: dream or reality? AB - The skin being the largest organ of the body presents a potential route for administration of drugs. Passive transdermal products such as gels, creams and patches deliver drugs effectively across the skin. However, this approach is limited to lipophilic molecules with low molecular weights. Passive transdermal delivery of proteins and peptides which are hydrophilic with high molecular weights is negligible. This led to the development of various ways of surmounting the skin barrier so as to make this route feasible for peptide and protein delivery. The current article reviews various active transdermal technologies with special emphasis on microneedle mediated delivery. Microneedles, especially dissolvable microneedles present an excellent platform for protein and peptide delivery. Significant advances have been made in the past decade in this area. Published literature shows a broad spectrum of molecules being delivered successfully via microneedles. However, success in clinic will give a boost to all the efforts and advances made in this field so far. PMID- 26419429 TI - Is audit the answer? Formally including research and audit in emergency medicine practice better equips us for future clinical and political challenges. PMID- 26419430 TI - A crossbred reference population can improve the response to genomic selection for crossbred performance. AB - BACKGROUND: Breeding goals in a crossbreeding system should be defined at the commercial crossbred level. However, selection is often performed to improve purebred performance. A genomic selection (GS) model that includes dominance effects can be used to select purebreds for crossbred performance. Optimization of the GS model raises the question of whether marker effects should be estimated from data on the pure lines or crossbreds. Therefore, the first objective of this study was to compare response to selection of crossbreds by simulating a two-way crossbreeding program with either a purebred or a crossbred training population. We assumed a trait of interest that was controlled by loci with additive and dominance effects. Animals were selected on estimated breeding values for crossbred performance. There was no genotype by environment interaction. Linkage phase and strength of linkage disequilibrium between quantitative trait loci (QTL) and single nucleotide polymorphisms (SNPs) can differ between breeds, which causes apparent effects of SNPs to be line-dependent. Thus, our second objective was to compare response to GS based on crossbred phenotypes when the line origin of alleles was taken into account or not in the estimation of breeding values. RESULTS: Training on crossbred animals yielded a larger response to selection in crossbred offspring compared to training on both pure lines separately or on both pure lines combined into a single reference population. Response to selection in crossbreds was larger if both phenotypes and genotypes were collected on crossbreds than if phenotypes were only recorded on crossbreds and genotypes on their parents. If both parental lines were distantly related, tracing the line origin of alleles improved genomic prediction, whereas if both parental lines were closely related and the reference population was small, it was better to ignore the line origin of alleles. CONCLUSIONS: Response to selection in crossbreeding programs can be increased by training on crossbred genotypes and phenotypes. Moreover, if the reference population is sufficiently large and both pure lines are not very closely related, tracing the line origin of alleles in crossbreds improves genomic prediction. PMID- 26419431 TI - Caffeine's influence on object recognition and working-memory in prepubertal mice and its modulation by gender. AB - OBJECTIVE: This study investigated the effects of intraperitoneal injection of caffeine on Y-maze working-memory and novel object recognition (NOR) in prepubertal mice. METHODOLOGY: Y-maze spontaneous alternation and a novel object recognition test (consisting of acclimation, acquisition and test phases) were performed. Mice received a single dose of caffeine (10, 20, 40, 80 and 120mgkg( 1) i.p.) or vehicle, 30min before Y-maze exploration. For the NOR test, caffeine was given 30min before training and another dose 30min before test phase. RESULTS: NOR time (acquisition phase) increased significantly in males at all doses of caffeine and decreased in females at 10, 20 and 40mg/kg compared to vehicle; during the test phase, novel object exploration time decreased significantly in males and increased in females at 10 and 20mg/kg only to decrease again at 120mg/kg. Recognition index decreased in males and increased in females while, males showed poor discrimination between novel and familiar objects compared to vehicle; while females showed increased discrimination between novel and familiar object at 10, 20,40 and 80mg/kg and a decrease at 120mg/kg. Y-maze spontaneous alternation improved significantly in males at 10 and 40mg/kg and decreased at 20 and 120mg/kg in females. CONCLUSION: The findings suggest that acute caffeine injection improves non-spatial memory retention in female mice but not in males; spatial working-memory is however improved in males but not in females. PMID- 26419432 TI - A 26-hour system of highly sensitive whole genome sequencing for emergency management of genetic diseases. AB - While the cost of whole genome sequencing (WGS) is approaching the realm of routine medical tests, it remains too tardy to help guide the management of many acute medical conditions. Rapid WGS is imperative in light of growing evidence of its utility in acute care, such as in diagnosis of genetic diseases in very ill infants, and genotype-guided choice of chemotherapy at cancer relapse. In such situations, delayed, empiric, or phenotype-based clinical decisions may meet with substantial morbidity or mortality. We previously described a rapid WGS method, STATseq, with a sensitivity of >96 % for nucleotide variants that allowed a provisional diagnosis of a genetic disease in 50 h. Here improvements in sequencing run time, read alignment, and variant calling are described that enable 26-h time to provisional molecular diagnosis with >99.5 % sensitivity and specificity of genotypes. STATseq appears to be an appropriate strategy for acutely ill patients with potentially actionable genetic diseases. PMID- 26419434 TI - Strategies to implement evidence into practice to improve palliative care: recommendations of a nominal group approach with expert opinion leaders. AB - BACKGROUND: In the past decades, many new insights and best practices in palliative care, a relatively new field in health care, have been published. However, this knowledge is often not implemented. The aim of this study therefore was to identify strategies to implement improvement activities identified in a research project within daily palliative care practice. METHODS: A nominal group technique was used with members of the IMPACT consortium, being international researchers and clinicians in cancer care, dementia care and palliative care. Participants identified and prioritized implementation strategies. Data was analyzed qualitatively using inductive coding. RESULTS: Twenty international clinicians and researchers participated in one of two parallel nominal group sessions. The recommended strategies to implement results from a research project were grouped in five common themes: 1. Dissemination of results e.g. by publishing results tailored to relevant audiences, 2. Identification and dissemination of unique selling points, 3. education e.g. by developing e learning tools and integrating scientific evidence into core curricula, 4. Stimulation of participation of stakeholders, and 5. consideration of consequences e.g. rewarding services for their implementation successes but not services that fail to implement quality improvement activities. DISCUSSION: The added value of this nominal group study lies in the prioritisation by the experts of strategies to influence the implementation of quality improvement activities in palliative care. Efforts to ensure future use of scientific findings should be built into research projects in order to prevent waste of resources. PMID- 26419433 TI - Impact of long-term steroid therapy on epicardial and pericardial fat deposition: a cardiac MRI study. AB - BACKGROUND: Increased cardiac fat has been identified as a risk factor for coronary artery disease. Metabolic syndrome is associated with increased cardiac fat deposition. Steroids are known to imitate some effects of metabolic syndrome and are frequently used in patients with rheumatic disorders. Primary aim was to evaluate the impact of long-term steroid use on cardiac fat deposition in patients with rheumatic disorders. In addition, we sought to investigate if this effect might be dose-dependent. METHODS: Patients were enrolled as follows: (1) rheumatic disorder; and (2) long-term steroid therapy, and (3) underwent cardiovascular magnetic resonance (CMR) imaging. Patients were stratified in a high-dose (>7.5 mg prednisone equivalent/day for at least 6 months) and a low dose steroid group (<7.5 mg prednisone equivalent/day) and compared to steroid naive controls without rheumatic disorders. RESULTS: 122 patients were included (n = 61 steroid patients, n = 61 controls). N = 36 were classified as high-dose, n = 25 as low-dose steroid group. Steroid patients showed larger epicardial 5.7 [3.5-9.1] cm(2) and pericardial 13.0 [6.1-26.8] cm(2) areas of fat than controls 4.2 [1.3-5.8] cm(2)/6.4 [1.6-15.4] cm(2), p < 0.001, p < 0.01, respectively. High dose steroid patients had more epi- and pericardial fat both than controls: 7.2 [4.2-11.1] cm(2) vs. 4.4 [1.0-6.0] cm(2), p < 0.001; 18.6 [8.9-38.2] cm(2) vs. 10.7 [4.7-26.8] cm(2), p < 0.05, and patients in the low-dose steroid group (p < 0.01, p < 0.001, respectively). CONCLUSION: The present data suggest increased cardiac fat deposition in steroid-treated patients with rheumatic disorders. Furthermore, this accumulation of cardiac fat seems to be dose-dependent, pointing towards a cumulative effect of steroids. PMID- 26419435 TI - Isolation and characterization of twelve polymorphic microsatellite loci for Hypochaeris catharinensis (Asteraceae) and cross-amplification in related species. PMID- 26419436 TI - Development and characterization of eighty-one microsatellite markers in Indian white shrimp, Fenneropenaeus indicus, through cross-amplification. PMID- 26419437 TI - Identification of novel insertion-deletion markers for Dongxiang wild rice (Oryza rufipogon Griff.) using high-throughput sequencing technology. PMID- 26419439 TI - Understanding and safeguarding patient dignity in intensive care. AB - BACKGROUND: Dignity has been highlighted in previous research as one of the most important ethical concerns in nursing care. According to Eriksson, dignified caring is related to treating the patient as a unique human being and respecting human value. Intensive care unit patients are vulnerable to threatened dignity, and maintaining dignity may be challenging as a consequence of critical illness. OBJECTIVES: The aim is to highlight how nurses in an intensive care setting understand patient dignity, what threatens patient dignity and how nurses can safeguard patient dignity. Research design and participants: Data materials were collected through a survey questionnaire which contained open questions about patient dignity, and the text was analysed using hermeneutic reading and text interpretation. Totally, 25 nurses employed in an intensive care unit in Finland participated in the study. Ethical considerations: The study follows the guidelines for good scientific practice by the Finnish Advisory Board on Research Integrity and the ethical principles according to the Declaration of Helsinki. FINDINGS: Findings revealed that nurses recognize the patients' absolute dignity by regarding them as unique human beings. The nurses also recognize the importance of shared humanity in preserving patient dignity. Intensive care patients' dignity is threatened by negative attitudes and when their integrity is not being protected. Dignity is also threatened when patients and nurses are not part of the patients' care and patient care decisions, when patients receive care against their will and because of the acute nature of intensive care. PMID- 26419438 TI - Moral sensitivity and moral distress in Iranian critical care nurses. AB - BACKGROUND: Moral sensitivity is the foremost prerequisite to ethical performance; a review of literature shows that nurses are sometimes not sensitive enough for a variety of reasons. Moral distress is a frequent phenomenon in nursing, which may result in paradoxes in care, dealing with patients and rendering high-quality care. This may, in turn, hinder the meeting of care objectives, thus affecting social healthcare standards. RESEARCH OBJECTIVE: The present research was conducted to determine the relationship between moral sensitivity and moral distress of nurses in intensive care units. RESEARCH DESIGN: This study is a descriptive-correlation research. Lutzen's moral sensitivity questionnaire and Corley Moral Distress Questionnaire were used to gather data. Participants and research context: A total of 153 qualified nurses working in the hospitals affiliated to Shahid Beheshti University of Medical Sciences were selected for this study. Subjects were selected by census method. Ethical considerations: After explaining the objectives of the study, all the participants completed and signed the written consent form. To conduct the study, permission was obtained from the selected hospitals. FINDINGS: Nurses' average moral sensitivity grade was 68.6 +/- 7.8, which shows a moderate level of moral sensitivity. On the other hand, nurses also experienced a moderate level of moral distress (44.8 +/- 16.6). Moreover, there was no meaningful statistical relationship between moral sensitivity and moral distress (p = 0.26). DISCUSSION: Although the nurses' moral sensitivity and moral distress were expected to be high in the intensive care units, it was moderate. This finding is consistent with the results of some studies and contradicts with others. CONCLUSION: As moral sensitivity is a crucial factor in care, it is suggested that necessary training be provided to develop moral sensitivity in nurses in education and practical environments. Furthermore, removing factors that contribute to moral distress may help decrease it in nurses. PMID- 26419440 TI - A Radiation Oncologist's Guide to Contouring the Lacrimal Gland. PMID- 26419441 TI - Dental amalgam artifact: Adverse impact on tumor visualization and proton beam treatment planning in oral and oropharyngeal cancers. AB - PURPOSE: We evaluated the incidence and impact of dental filling artifacts on the definition of clinical target volume (CTV) for oropharyngeal/oral cavity cancers receiving radiation therapy. We performed phantom proton beam dosimetric analyses using a low-density composite filling to investigate artifact reduction and dose distribution. METHODS AND MATERIALS: We reviewed oral cavity/oropharynx radiation treatment plans between 2010 and 2012. Plans were evaluated for artifacts and impact on CTV visualization. We constructed a head and neck phantom, obtaining planning computed tomography images at baseline (native tooth) and for each filling (composite and metal amalgam) interchanged into a tooth adjacent to the tumor. We performed uniform scanning proton plans with each filling, evaluating for planning target volume (PTV) coverage and overall dose distribution. RESULTS: A total of 110 treatment plans were reviewed (71 oropharynx, 39 oral cavity). Artifacts were identified in 81 plans (73.6%), including 53 oropharynx (74.6%) and 28 oral cavity (71.8%). Artifacts obscured the CTV in 77 cases (95%), including 49 of 53 oropharynx cases (92.5%) and all 28 oral cavity cases. On phantom testing, the metal amalgam obscured the tumor while the composite did not. Hounsfield unit (HU) values (range, mean) for the tumor were: baseline ( 484.0 to 700.0 HU, 104 HU), composite (-728.5 to 1038.0 HU, 105 HU), metal amalgam (-1023.0 to 807.0 HU, 90.74 HU). The percent of planning target volume receiving 95% of prescription dose of the PTV was baseline (100%), composite (100%), and metal amalgam (92.3%). PTV dose ranges were baseline (98%-106%), composite (98%-107%), and metal amalgam (66%-111%). PTV coverage and dose distributions of the composite and native tooth plans were identical. CONCLUSIONS: A high incidence of artifacts was found on the planning scans of oral/oropharyngeal cancer patients, adversely impacting CTV visualization. In our phantom model, metal amalgam impacted tumor and tissue density. The PTV was underdosed with the metal amalgam compared with the composite filling. A potential solution involves exchanging metal fillings with composite before proton treatment planning for improved tumor visualization and dosimetry. PMID- 26419442 TI - Results of the 2014 Survey of the Association of Directors of Radiation Oncology Programs (ADROP). AB - BACKGROUND: In 2014, the Association of Directors of Radiation Oncology Programs (ADROP) conducted an in-depth survey of program directors along several axes. We report the results of this survey and compare the major findings with those of the 2007 ADROP survey. METHODS AND MATERIALS: The survey was written and approved by ADROP leadership in 2012, announced online through broadcasts throughout 2013 and early 2014, and closed in mid-2014. The results based on question groups related to (1) hours spent in activities, (2) budget and nonprogram resources, (3) physics/biology didactics, (4) mock exams/didactics/research, (5) electives, (6) students, and (7) resources/challenges were tabulated. Descriptive comparisons with the 2007 survey were performed. RESULTS: There was 26% participation (23/88 programs). Major areas of time commitment were faculty and site organization, maintenance, and corrections (70 hours/year) and didactics/conferences and rounds (200 hours/year). The median program director protected time was 23% (range 0%-50%). All responding programs (100%) had biology and physics courses and assigned directors, but only approximately 20% of respondents had a threshold grade in these courses for graduation. Major resources desired were templates of goals/objectives by disease site, competency evaluations by level, journal club repository, and software for contouring, oral examination preparation, grant writing, publication writing, oral presentation, and effective teaching. Major activity challenges were Accreditation Council for Graduate Medical Education external review and time commitment. CONCLUSIONS: Overall, the 2014 results are similar to those of the 2007 survey. The average time commitment remains considerably higher than the 10% minimum required in the current ACGME program requirements. The survey results may guide ADROP membership in centralizing some of the identified resources needed. PMID- 26419443 TI - Dosimetric effect of photon beam energy on volumetric modulated arc therapy treatment plan quality due to body habitus in advanced prostate cancer. AB - PURPOSE: The purpose of this study was to dosimetrically compare 6- and 10-MV photon beam energies in high-risk prostate cancer patients of various body habitus using a volumetric modulated arc therapy (VMAT) radiation delivery technique. The objectives of the study were to evaluate whether dosimetric differences exist and to investigate whether differences are dependent on patient body habitus. METHODS AND MATERIALS: Forty patients with various body habitus who had previously received treatment to the prostate and pelvic lymph nodes with VMAT techniques were chosen. Patients were planned in the Pinnacle(3) treatment planning system with double or triple SmartArc plans with 6- and 10-MV photon energies. All patients were optimized with the same planning objectives and normalized such that 95% of the planning target volume (PTV) received the prescription dose. Patients were evaluated for PTV and organ at risk (OAR) parameters for the bladder, rectum, small bowel, penile bulb, and sigmoid colon. Metrics used for comparison were D2%, D98%, homogeneity, conformity, and dose falloff for the PTV and D(2%), D(mean), V(80%), V(60%), and V(40%) for OARs. Statistical differences were evaluated with a paired-sample Wilcoxon signed rank test with a significance level of .05. RESULTS: For the PTV, there were no statistically significant differences in D(mean), D(2cc), conformation number, and homogeneity index values, but the dose falloff parameters, R50 and R25, showed a median improvement of 6.7% (P<.01) and 6.2% (P<.01), respectively, with 10 MV. A correlation between patient anterior-posterior distance (d(AP)) and percentage reduction in R50 of 0.436% per centimeter (P<.01) was determined. For OARs, statistically significant reductions in dose metrics were found in the small bowel and bladder, but increases in the D(2cc) of 3.5% in the penile bulb (P<.01) and 0.2% in the rectum (P=.02) were shown with 10 MV. The use of 10 MV also demonstrated a statistically significant reduction in the total number of monitor units of 15.9% (P<.01) compared with 6 MV. CONCLUSIONS: The study showed that 10 MV provides a faster dose falloff than 6 MV for patients whose prostate and pelvic lymph nodes are treated using a VMAT technique irrespective of body habitus; however, the improvement in dose falloff is dependent on body habitus and increases as the patient body habitus increases. PMID- 26419444 TI - Four dimensional magnetic resonance imaging optimization and implementation for magnetic resonance imaging simulation. AB - PURPOSE: Precise radiation therapy for abdominal lesions is complicated by respiratory motion and suboptimal soft tissue contrast from 4-dimensional (4D) computed tomography, whereas 4D magnetic resonance imaging MRI (4DMRI) provides superior tissue discrimination. This work evaluates a novel 4DMRI algorithm for motion management in radiation therapy. METHODS AND MATERIALS: Respiratory triggered, T2-weighted, single-shot 4DMRI was evaluated for an open 1.0T magnetic resonance simulation platform. An in-house programmable platform was devised that translated objects for a variety of breathing patterns. Coronal 4DMRIs were acquired to evaluate the impact of number of phases on excursion and scan time. The impact of breathing period and regularity on scan time was assessed. A novel clinical 4D prototype phantom was scanned to characterize excursion and absolute volume differences between phase acquisitions. Optimized parameters were applied to abdominal 4DMRIs of 5 volunteers and 2 abdominal cancer patients on an institutional review board-approved protocol. Duty cycle, scan time, and waveform analysis were evaluated. Maximum intensity projection datasets were analyzed. RESULTS: Two- to 5-fold acquisition time increase was measured for 10-phase versus 2-phase phantom experiments. Regular breathing patterns yielded higher duty cycles than irregular (48.5% and 35.9%, respectively, P < .001), whereas faster breathing rates yielded shorter 4DMRI acquisition times. Volumes of a hypodense target were underestimated 4% to 5% for 2 and 4 phases compared with 10 phases. Better agreement was obtained for 6- and 8-phase acquisitions (~3% different from 10 phase). Internal target volume centroids on minimum and maximum images across all phases were <2 mm different across all 10 phases, although slight target excursion variations (up to 4 mm) were observed. In humans, a strong negative association between breathing rate and acquisition time (Pearson's r = -0.68, P < .05) was observed. Eight-phase acquisition times ranged from 7 to 15 minutes, depending on the patient. CONCLUSION: 4DMRI has been optimized and implemented. Irregular breathing patterns and slow breathing rate adversely impacted 4DMRI efficiency; thus, interventions such as biofeedback may be desirable. PMID- 26419445 TI - Transferrin Receptor 1 in Chronic Hypoxia-Induced Pulmonary Vascular Remodeling. AB - BACKGROUND: Iron is associated with the pathophysiology of several cardiovascular diseases, including pulmonary hypertension (PH). In addition, disrupted pulmonary iron homeostasis has been reported in several chronic lung diseases. Transferrin receptor 1 (TfR1) plays a key role in cellular iron transport. However, the role of TfR1 in the pathophysiology of PH has not been well characterized. In this study, we investigate the role of TfR1 in the development of hypoxia-induced pulmonary vascular remodeling. METHODS: PH was induced by exposing wild-type (WT) mice and TfR1 hetero knockout mice to hypoxia for 4 weeks and evaluated via assessment of pulmonary vascular remodeling, right ventricular (RV) systolic pressure, and RV hypertrophy. In addition, we assessed the functional role of TfR1 in pulmonary artery smooth muscle cells in vitro. RESULTS: The morphology of pulmonary arteries did not differ between WT mice and TfR1 hetero knockout mice under normoxic conditions. In contrast, TfR1 hetero knockout mice exposed to 4 weeks hypoxia showed attenuated pulmonary vascular remodeling, RV systolic pressure, and RV hypertrophy compared with WT mice. In addition, the depletion of TfR1 by RNA interference attenuated human pulmonary artery smooth muscle cells proliferation induced by platelet-derived growth factor-BB (PDGF-BB) in vitro. CONCLUSIONS: These results suggest that TfR1 plays an important role in the development of hypoxia-induced pulmonary vascular remodeling. PMID- 26419446 TI - Educational attainment and health transitions over the life course: testing the potential mechanisms. AB - BACKGROUND: It has been shown that higher education associates with health outcomes, but the less is known about the specific mechanisms mediating this association. We examined whether higher education would associate with long-term health transitions from childhood to adulthood and whether health behaviors, self esteem, social support and work-related health hazards could mediate or confound this association. METHODS: The participants were from a population-based sample of 3596 men and women from the Young Finns study aged 3-18 years at the beginning of the study in 1980, and who responded to repeated surveys of educational attainment and self-rated health in four study phases from 1997 to 2012. The associations were tested using multistate Markov models for the health-state transition intensities. RESULTS: Our results suggested that a 1-year difference in education was related to a 16% higher transition probability from mediocre to good self-rated health over the 5-year follow-up. Depressive symptoms and job strain seemed to partly mediate or confound the association, but self-esteem and social support did not. CONCLUSIONS: These results suggest that educational attainment is associated with good self-rated health transitions from childhood to adulthood, and multiple processes rather than a single underlying mechanism are likely to drive the educational differences in self-rated health. PMID- 26419447 TI - Therapeutic Potential of alpha7 Nicotinic Acetylcholine Receptors. AB - Progress in the fields of neuroscience and molecular biology has identified the forebrain cholinergic system as being important in many higher order brain functions. Further analysis of the genes encoding the nicotinic acetylcholine receptors (nAChRs) has highlighted, in particular, the role of alpha7 nAChRs in these higher order brain functions as evidenced by their peculiar physiologic and pharmacological properties. As this receptor has gained the attention of scientists from academia and industry, our knowledge of its roles in various brain and bodily functions has increased immensely. We have also seen the development of small molecules that have further refined our understanding of the roles of alpha7 nAChRs, and these molecules have begun to be tested in clinical trials for several indications. Although a large body of data has confirmed a role of alpha7 nAChRs in cognition, the translation of small molecules affecting alpha7 nAChRs into therapeutics has to date only progressed to the stage of testing in clinical trials. Notably, however, most recent human genetic and biochemical studies are further underscoring the crucial role of alpha7 nAChRs and associated genes in multiple organ systems and disease states. The aim of this review is to discuss our current knowledge of alpha7 nAChRs and their relevance as a target in specific functional systems and disease states. PMID- 26419448 TI - Rho Kinases in Health and Disease: From Basic Science to Translational Research. AB - Rho-associated kinases ROCK1 and ROCK2 are key regulators of actin cytoskeleton dynamics downstream of Rho GTPases that participate in the control of important physiologic functions, S including cell contraction, migration, proliferation, adhesion, and inflammation. Several excellent review articles dealing with ROCK function and regulation have been published over the past few years. Although a brief overview of general molecular, biochemical, and functional properties of ROCKs is included, an effort has been made to produce an original work by collecting and synthesizing recent studies aimed at translating basic discoveries from cell and experimental models into knowledge of human physiology, pathophysiological mechanisms, and medical therapeutics. This review points out the specificity and distinct roles of ROCK1 and ROCK2 isoforms highlighted in the last few years. Results obtained from genetically modified mice and genetic analysis in humans are discussed. This review also addresses the involvement of ROCKs in human diseases and the potential use of ROCK activity as a biomarker or a pharmacological target for specific inhibitors. PMID- 26419449 TI - Approaches used by parents to keep their children safe at home: a qualitative study to explore the perspectives of parents with children aged under five years. AB - BACKGROUND: Childhood unintentional injury represents an important global health problem. Many unintentional injuries experienced by children aged under 5 years occur within the home and are preventable. The aim of this study was to explore the approaches used by parents of children under five in order to help prevent unintentional injuries in the home and the factors which influence their use. Understanding how parents approach risk-management in the home has important implications for injury practitioners. METHODS: A multi-centre qualitative study using semi-structured interviews. A thematic approach was used to analyse the data. Sixty five parents of children aged under 5 years, from four study areas were interviewed: Bristol, Newcastle, Norwich and Nottingham. RESULTS: Three main injury prevention strategies used by parents were: a) Environmental such as removal of hazards, and use of safety equipment; b) parental supervision; and c) teaching, for example, teaching children about safety and use of rules and routine. Strategies were often used in combination due to their individual limitations. Parental assessment of injury risk, use of strategy and perceived effectiveness were fluid processes dependent on a child's character, developmental age and the prior experiences of both parent and child. Some parents were more proactive in their approach to home safety while others only reacted if their child demonstrated an interest in a particular object or activity perceived as being an injury risk. CONCLUSION: Parents' injury prevention practices encompass a range of strategies that are fluid in line with the child's age and stage of development; however, parents report that they still find it challenging to decide which strategy to use and when. PMID- 26419450 TI - Population pharmacokinetics and pharmacodynamics of busulfan with GSTA1 polymorphisms in patients undergoing allogeneic hematopoietic stem cell transplantation. AB - AIM: A population pharmacokinetic (PPK) analysis was conducted to describe the influence of GSTA1 polymorphisms on intravenous busulfan in adults undergoing allogeneic hematopoietic stem cell transplantation. PATIENTS & METHODS: A PPK model was developed from 36 patients by a one-compartment model with first-order elimination. RESULTS: The typical value of clearance and volume of distribution were 11.0 l/h and 42.4 l, respectively. Clearance decreased by 15% and area under the concentration-time curves (AUCs) increased with GSTA1 variants compared with wild-type (both p < 0.05). Subtherapeutic AUCs were seen only in wild-type patients. CONCLUSION: To our knowledge, this is the first PPK study to suggest that GSTA1 polymorphisms in adults are associated with busulfan PK. PMID- 26419452 TI - Metabolomic charactetization of yeast cells after dehydration stress. AB - In this study, we analyzed the metabolite features of the yeasts Saccharomyces cerevisiae, Naumovia castellii, and Saccharomyces mikatae. The three species are closely related genetically but differ in their tolerance of desiccation stress. Specifically, we determined whether certain metabolites correlated with cell viability after stress imposition. The metabolomics profiles of these strains were compared before cell desiccation and after cell rehydration. In S. mikatae, the presence of lysine or glutamine during rehydration led to a 20% increase in survival whereas during dehydration the levels of both amino acids in this yeast were drastically reduced. PMID- 26419451 TI - RIFM fragrance ingredient safety assessment, isoamyl salicylate, CAS registry number 87-20-7. AB - The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization potential, as well as, environmental safety. Repeated dose toxicity was determined using to have the most conservative systemic exposure derived NOAEL of 47 mg/kg/day. A dietary 13-week subchronic toxicity study conducted in rats on a suitable read across analog resulted in a MOE of 2350 while considering 10.3% absorption from skin contact and 100% from inhalation. A MOE of >100 is deemed acceptable. PMID- 26419453 TI - Identification of a class B acid phosphatase in Haemophilus parasuis. AB - An acid phosphatase activity was detected in the supernatant of Haemophilus parasuis, a Gram-negative pleomorphic bacillus and the causative agent of Glasser's disease in pigs. To identify the gene responsible for the secreted activity, a genomic library of H. parasuis strain ER-6P was produced in Escherichia coli. Screening of the library allowed identification of two homologs to known phosphatases: PgpB and AphA. PgpB was predicted to be located in the bacterial membrane through six transmembrane domains while AphA was predicted to have a signal peptide. The aphA gene was cloned and expressed in E. coli. Characterization of H. parasuis AphA indicated that this protein belongs to the class B nonspecific acid phosphatases. AphA contained sequence signatures characteristic of this family of phosphatases and its activity was inhibited by EDTA. The optimal pH of recombinant AphA differed from that of the phosphatase activity found in H. parasuis supernatants. In addition, the phosphatase activity from H. parasuis supernatants was not inhibited by EDTA, indicating that H. parasuis AphA does not account for the phosphatase activity observed in the supernatants. Our results demonstrate the presence of a class B acid phosphatase (AphA) in H. parasuis and suggest that the bacterium would also secrete another, as yet unidentified phosphatase. PMID- 26419454 TI - Molecular epidemiology of methicillin-resistant Staphylococcus aureus in a university hospital in northwestern Spain. AB - Continuous monitoring of methicillin-resistant Staphylococcus aureus (MRSA) is necessary to understand the clonal evolution of successful lineages. In this study, we identified the MRSA clones circulating in a Spanish hospital during a 2 year period, assessed their relationship with antimicrobial resistance profiles, and investigated the presence of the emerging community-associated and livestock associated MRSA lineages (CA-MRSA, LA-MRSA). CC5-MRSA-IV isolates were the most frequently recovered, which supports the previously reported prevalence of this clone in Spanish hospitals. We observed ST125 isolates that harbored specific cassette chromosome recombinase (ccr) gene elements of the staphylococcal cassette chromosome mec (SCCmec) types IV and VI. That clone, which was first detected only recently, has increased resistance to erythromycin. Furthermore, 94% of the infections were caused by non-multiresistant isolates. Neither CA-MRSA nor LA-MRSA isolates were observed. These findings, along with related events over the last decade, suggest the establishment of a clonal endemic population in the Spanish clinical environment. PMID- 26419455 TI - Significance of tagI and mfd genes in the virulence of non-typeable Haemophilus influenzae. AB - Non-typeable Haemophilus influenzae (NTHi) is an opportunist pathogen well adapted to the human upper respiratory tract and responsible for many respiratory diseases. In the human airway, NTHi is exposed to pollutants, such as alkylating agents, that damage its DNA. In this study, we examined the significance of genes involved in the repair of DNA alkylation damage in NTHi virulence. Two knockout mutants, tagI and mfd, encoding N3-methyladenine-DNA glycosylase I and the key protein involved in transcription-coupled repair, respectively, were constructed and their virulence in a BALB/c mice model was examined. This work shows that N3 methyladenine-DNA glycosylase I is constitutively expressed in NTHi and that it is relevant for its virulence. PMID- 26419456 TI - Endophytic and rhizospheric bacterial communities isolated from the medicinal plants Echinacea purpurea and Echinacea angustifolia. AB - In this work we analyzed the composition and structure of cultivable bacterial communities isolated from the stem/leaf and root compartments of two medicinal plants, Echinacea purpurea (L.) Moench and Echinacea angustifolia (DC.) Hell, grown in the same soil, as well as the bacterial community from their rhizospheric soils. Molecular PCR-based techniques were applied to cultivable bacteria isolated from the three compartments of the two plants. The results showed that the two plants and their respective compartments were characterized by different communities, indicating a low degree of strain sharing and a strong selective pressure within plant tissues. Pseudomonas was the most highly represented genus, together with Actinobacteria and Bacillus spp. The presence of distinct bacterial communities in different plant species and among compartments of the same plant species could account for the differences in the medicinal properties of the two plants. PMID- 26419457 TI - A glucuronoxylan-specific xylanase from a new Paenibacillus favisporus strain isolated from tropical soil of Brazil. AB - A new xylanolytic strain, Paenibacillus favisporus CC02-N2, was isolated from sugarcane plantation fields in Brazil. The strain had a xylan-degrading system with multiple enzymes, one of which, xylanase Xyn30A, was identified and characterized. The enzyme is a single-domain xylanase belonging to family 30 of the glycosyl hydrolases (GH30). Xyn30A shows high activity on glucuronoxylans, with a Vmax of 267.2 U mg-1, a Km of 4.0 mg/ml, and a kcat of 13,333 min-1 on beechwood xylan, but it does not hydrolyze arabinoxylans. The three-dimensional structure of Xyn30A consists of a common (beta/alpha)8 barrel linked to a side chain-associated beta-structure, similar to previously characterized GH30 xylanases. The hydrolysis products from glucuronoxylan were methylglucuronic-acid substituted xylooligomers (acidic xylooligosaccharides). The enzyme bound to insoluble xylan but not to crystalline cellulose. Our results suggest a specific role for Xyn30A in xylan biodegradation in natural habitats. The enzyme is a good candidate for the production of tailored xylooligosaccharides for use in the food industry and in the biotechnological transformation of biomass. PMID- 26419458 TI - Physical rehabilitation interventions for adult patients with critical illness across the continuum of recovery: an overview of systematic reviews protocol. AB - BACKGROUND: Patients admitted to the intensive care unit with critical illness often experience significant physical impairments, which typically persist for many years following resolution of the original illness. Physical rehabilitation interventions that enhance restoration of physical function have been evaluated across the continuum of recovery following critical illness including within the intensive care unit, following discharge to the ward and beyond hospital discharge. Multiple systematic reviews have been published appraising the expanding evidence investigating these physical rehabilitation interventions, although there appears to be variability in review methodology and quality. We aim to conduct an overview of existing systematic reviews of physical rehabilitation interventions for adult intensive care patients across the continuum of recovery. METHODS/DESIGN: This protocol has been developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) guidelines. We will search the Cochrane Systematic Review Database, Database of Abstracts of Reviews of Effectiveness, Cochrane Central Register of Controlled Trials, MEDLINE, Excerpta Medica Database and Cumulative Index to Nursing and Allied Health Literature databases. We will include systematic reviews of randomised controlled trials of adult patients, admitted to the intensive care unit and who have received physical rehabilitation interventions at any time point during their recovery. Data extraction will include systematic review aims and rationale, study types, populations, interventions, comparators, outcomes and quality appraisal method. Primary outcomes of interest will focus on findings reflecting recovery of physical function. Quality of reporting and methodological quality will be appraised using the PRISMA checklist and the Assessment of Multiple Systematic Reviews tool. DISCUSSION: We anticipate the findings from this novel overview of systematic reviews will contribute to the synthesis and interpretation of existing evidence regarding physical rehabilitation interventions and physical recovery in post critical illness patients across the continuum of recovery. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015001068. PMID- 26419459 TI - Long-term Outcomes in Steroid-refractory Ulcerative Colitis Treated with Tacrolimus Alone or in Combination with Purine Analogues. AB - BACKGROUND AND AIMS: Tacrolimus is recommended for the treatment of steroid refractory ulcerative colitis (UC). Concomitantly started purine analogues (PAs) are used for the maintenance of remission, though their therapeutic relevance remains uncertain. Here we studied the role of PAs in the long-term outcome of steroid-refractory UC after tacrolimus treatment. METHODS: In five centres, charts of tacrolimus-treated UC patients with a steroid-refractory moderate to severe course were reviewed. Long-term efficacy was determined by colectomy rates and clinical remission in cases of colectomy-free survival for 3 months. RESULTS: We identified 156 patients (median age 34 years) with a median Lichtiger score of 12 (4-17) and pancolitis (E3) in 65% (101). The Kaplan-Meier curve for colectomy free survival after month 3 showed a benefit in the PA group (p = 0.02). In patients treated with PA clinical remission was achieved in 82% (65/79) vs 67% (39/58) in those not treated with PA (p = 0.02). Time to colectomy was 2 years (median, 0.7-5.8) in the PA group and 0.8 years (0.3-4.7) in the group not treated with PAs (p = 0.02). Time to relapse was 1.2 years (median, 0.3-6.2) in patients with PA treatment and 0.5 years (0.3-3.9) in those without PA treatment (p = 0.05). Overall, clinical remission was achieved in 67% (104/156) of patients. Colectomy was performed in 29% (45/156) 0.5 years (median, 0.04-5.79) after initiation of tacrolimus. Ten (6%) patients had to stop tacrolimus due to adverse events and two (without PA treatment) died. CONCLUSIONS: Our study supports the efficacy of tacrolimus in steroid-refractory UC. Purine analogues appear to be beneficial for the long-term outcome of these patients. PMID- 26419461 TI - Extensive Neuroendocrine Adenocarcinoma in Ulcerative Colitis. PMID- 26419460 TI - DNA Methylation Profiling in Inflammatory Bowel Disease Provides New Insights into Disease Pathogenesis. AB - BACKGROUND AND AIMS: Inflammatory bowel diseases (IBDs) are heterogeneous disorders with complex aetiology. Quantitative genetic studies suggest that only a small proportion of the disease variance observed in IBD is accounted for by genetic variation, indicating a potential role for differential epigenetic regulation in disease aetiology. The aim of this study was to assess genome-wide DNA methylation changes specifically associated with ulcerative colitis (UC), Crohn's disease (CD) and IBD activity. METHODS: DNA methylation was quantified in peripheral blood mononuclear cells (PBMCs) from 149 IBD cases (61 UC, 88 CD) and 39 controls using the Infinium HumanMethylation450 BeadChip. Technical and functional validation was performed using pyrosequencing and the real-time polymerase chain reaction. Cross-tissue replication of the top differentially methylated positions (DMPs) was tested in colonic mucosa tissue samples obtained from paediatric IBD cases and controls. RESULTS: A total of 3196 probes were differentially methylated between CD cases and controls, while 1481 probes were differentially methylated between UC cases and controls. There was considerable (45%) overlap between UC and CD DMPs. The top-ranked IBD-associated PBMC differentially methylated region (promoter region of TRIM39-RPP2) was also significantly hypomethylated in colonic mucosa from paediatric UC patients. In addition, we confirmed TRAF6 hypermethylation using pyrosequencing and found reduced TRAF6 gene expression in PBMCs of IBD patients. CONCLUSIONS: Our data provide new insights into differential epigenetic regulation of genes and molecular pathways, which may contribute to the pathogenesis and activity of IBD. PMID- 26419462 TI - Risk factors of acute myocardial infarction in middle-aged and adolescent people (< 45 years) in Yantai. AB - BACKGROUND: Yantai is a developed medium-sized coastal city in Eastern China, having a population of 1.6845 million. With the development of economy, some middle-aged and adolescent people (< 45 years) devote themselves to work and suffer from greater stress, which makes them ignore their own health. Moreover, they have unhealthy lifestyles and lack the knowledge of cardiovascular risk factors. OBJECTIVES: To identify the risk factors for first acute myocardial infarction in middle-aged and adolescent people in Yantai, a developed medium sized coastal city in Eastern China. METHODS: A total of 154 consecutive patients with first acute myocardial infarction (< 45 years), were enrolled in case group, and 462 patients without myocardial infarction were enrolled in control group. Three controls with the same sex and age were matched to each case. The risk factors were identified with univariate and multivariate analysis. RESULTS: Unhealthy food habit (eating seafood and meanwhile drinking beer), hypertension, current smokers, self-perceived stress, diabetes mellitus, obesity, sleep insufficience, hypercholesterolaemia and fatigue were independent risk factors for first acute myocardial infarction (P < 0.05). CONCLUSIONS: Besides those recognized risk factors for cardiovascular disease (hypertension, hypercholesterolemia, diabetes mellitus and smoking), eating seafood and meanwhile drinking beer, self-perceived stress, sleep insufficience, obesity and fatigue were also the risk factors for first acute myocardial infarction in middle-aged and adolescent people in Yantai. PMID- 26419463 TI - Disease proportions and drug prescribing pattern observed in a free health camp organized at Dhorphirdi Village Development Committee of Western Nepal. AB - BACKGROUND: Health camp is generally organized to provide health care services to the people deprived of health care facilities. The aim of this project was to assess the proportions of disease among attendees of health camp and study the drug prescribing pattern in a free health camp. METHODS: A case study was performed from 1 day health camp to determine the proportions of disease and drug prescribing pattern. Data collection was performed using log book maintained in the health camp and patient's demographic details, disease diagnosed and drug prescribed was obtained from same log book. RESULTS: A total of 317 patients were included in the study. The majority of the patients were in the range of 41-50 years. On the basis of study on ethnicity, Brahmins and Chettris, were found to be predominant ethnic groups with gastrointestinal disorders as the major disease. The total number of medications prescribed was 510, with non-steroidal anti-inflammatory drugs (NSAIDs) and antipeptic ulcer drugs being commonly prescribed. The average number of drugs per prescription and the percentage of antibiotics prescribed were 1.6 and 21.4%, respectively. It was observed that 96.8% of prescription was by generic names. Likewise, 100% of prescription included drugs from essential drug list. CONCLUSION: Majority of the patients were of working age group. Headache and fever were found to be the most prevalent cases and NSAIDs were the most commonly prescribed medications. The drug prescribing pattern of the free health camp complied with WHO recommended prescribing indicators. PMID- 26419464 TI - Primary erythromelalgia: a review. AB - Primary erythromelalgia (PE ORPHA90026) is a rare autosomal dominant neuropathy characterized by the combination of recurrent burning pain, warmth and redness of the extremities. The incidence rate of PE ranges from 0.36 to 1.1 per 100,000 persons. Gender ratio differs according to different studies and no evidence showed a gender preference. Clinical onset of PE is often in the first decade of life. Burning pain is the most predominant symptom and is usually caused and precipitated by warmth and physical activities. Reported cases of PE contain both inherited and sporadic forms. Genetic etiology of PE is mutations on SCN9A, the encoding gene of a voltage-gated sodium channel subtype Nav1.7. Diagnosis of PE is made upon clinical manifestations and screening for mutations on SCN9A. Exclusion of several other treatable diseases/secondary erythromelalgia is also necessary because of the lack of biomarkers specifically for PE. Differential diagnoses can include Fabry disease, cellulites, Raynaud phenomenon, vasculitis and so on. Diagnostic methods often involve complete blood count, imaging studies and thermograph. Treatment for PE is unsatisfactory and highly individualized. Frequently used pain relieving drugs involve sodium channel blockers such as lidocaine, carbamazepine and mexiletine. Novel drugs such as PF-05089771 and TV 45070 could be promising in ameliorating pain symptoms due to their Nav1.7 selectivity. Patients' symptoms often worsen over time and many patients develop ulcerations and gangrenes caused by excessive exposure to low temperature in order to relieve pain. This review mainly focuses on PE and the causative gene SCN9A--its mutations and their effects on Nav1.7 channels' electrophysiological properties. We propose a genotype-channelopathy-phenotype correlation network underlying PE etiology which could provide guidance for future therapeutics. PMID- 26419465 TI - Dynamic alteration of serum testosterone with aging: a cross-sectional study from Shanghai, China. AB - BACKGROUND: Level of the testosterone in a man's life span is very important. Studies on the serum testosterone concentrations in different age groups of healthy men were controversial. The aim of this study was to investigate dynamic changes of serum reproductive hormones with aging in healthy Chinese male and to compare its correlation with age. METHODS: Total of 1,093 healthy Chinese men from Shanghai aged from 20 to 87 years old was enrolled in the study. Concentrations of serum total testosterone (T), luteinizing hormone (LH) and sex hormone binding globulin (SHBG) were quantified by EIA. Testosterone secretion index (TSI) and free testosterone index (FTI) were then calculated. Data were analyzed by SPSS program. Non-parametric tests and univariate linear regression analyses were used. RESULTS: The 1,039 male participants were grouped into 12 groups by 5-year apart for each group. Significant differences in T, LH, SHBG, FTI and TSI were found between the 12 different age groups. Average of serum total T was 15.36 +/- 4.86 nmol/L; LH was 4.76 +/- 2.76 IU/L, SHBG was 32.61 +/- 17.24 nmol/L. Compared to age 20 ~ 24 group, serum T level of age 35 ~ 39, 40 ~ 44, 45 ~ 49, 50 ~ 54, and 55 ~ 59 was significantly decreased (p < 0.05). Intriguingly, however, serum T level of age 60 or older did not significantly reduced compared to the age of 20 ~ 24 group. Serum LH and SHBG were positively correlated with aging (p <0.01), while TSI and FTI were negatively correlated with aging (p <0.01). In addition, BMI was negatively and significantly correlated with levels of T (r = -0.585, p < 0.001), LH (r = -0.090, p < 0.001), SHBG (r = - 1.817, p < 0.001), and TSI (r = - 0.104, p < 0.001), but positively and significantly correlated with FTI level (r = 0.011, p < 0.001). CONCLUSION: Serum total testosterone fluctuated with aging in adult men, and FTI and TSI decreased gradually with aging. While age was not significantly correlated with T level, BMI was significantly and negatively correlated with T level, suggesting body weight may affect testosterone level. PMID- 26419466 TI - Prebiotic and Probiotic Regulation of Bone Health: Role of the Intestine and its Microbiome. AB - Recent advances in our understanding of how the intestinal microbiome contributes to health and disease have generated great interest in developing strategies for modulating the abundance of microbes and/or their activity to improve overall human health and prevent pathologies such as osteoporosis. Bone is an organ that the gut has long been known to regulate through absorption of calcium, the key bone mineral. However, it is clear that modulation of the gut and its microbiome can affect bone density and strength in a variety of animal models (zebrafish, rodents, chicken) and humans. This is demonstrated in studies ablating the microbiome through antibiotic treatment or using germ-free mouse conditions as well as in studies modulating the microbiome activity and composition through prebiotic and/or probiotic treatment. This review will discuss recent developments in this new and exciting area. PMID- 26419468 TI - Research Progress on the Antitumor Effects of Rhein: Literature Review. AB - BACKGROUND: Rhein (1,8-dihydroxy-3-carboxyanthraquinone) is a monomer of anthraquinone derivatives mainly found in Polygonaceae plants such as Rhubarb, and Cuspidatum, widely used in the traditional Chinese medicine with many pharmacological activities, such as antitumor, anti-inflammatory and antifibrotic effects, and regulation of glucose and lipid metabolism. OBJECTIVE: To conclude the role of Rhein in cancer control and its mechanisms for its futher deep research and potential clinical application. METHOD: All kinds of reports previously related to Rhein from PubMed datebase were collected, integrated and analyzed. RESULTS: Rhein could control many cancer cells by regulating their proliferation and apoptosis, invasion and migration, especially intrinsic and extrinsic apoptosis pathways induced by Rhein plays the core role in cancer control. For good inhibitory role in NF-kappaB pathway, the Ras/Raf/MEK (MAPK)/ERK and PTEN/PI3K/AKT/mTOR pathways are other two key pathways regulated by Rhein with its role in antiphosphorylation of ERK, PI3K and AKT to control many cancers' development which frequently dysregulated in cancer, involved in the activation, proliferation, invasion, and migration of cancer cells. CONCLUSION: Rhein is a potential cancer treatment agent. PMID- 26419467 TI - A Mechanism-Based Approach to the Management of Osteoarthritis Pain. AB - Pain from osteoarthritis (OA) affects millions of people worldwide, yet treatments are limited to acetaminophen, NSAIDs, physical therapy, and ultimately, surgery when there is significant disability. In recent years, our understanding of pain pathways in OA has developed considerably. Though joint damage and inflammation play a significant role in pain generation, it is now understood that both central and peripheral nervous system mechanisms exacerbate symptoms. Evolving management strategies for OA address central factors (e.g., sleep difficulties, catastrophizing, and depression) with treatments such as cognitive behavioral therapy and exercise. In addition, emerging data suggest that antibodies against peripheral signaling neuropeptides, such as nerve growth factor-1 (NGF-1), may significantly alleviate pain. However, concerns regarding potential adverse effects, such as rapidly progressive OA, still remain. A nuanced understanding is essential if we are to make headway in developing more effective treatments for OA. PMID- 26419469 TI - Implication of Unfolded Protein Response and Autophagy in the Treatment of BRAF Inhibitor Resistant Melanoma. AB - The continuous activation of the mitogen-activated protein kinase signaling cascade, typified by the BRAFV600E mutation, is one of the key alterations in melanoma. Accordingly, two BRAF inhibitors (BRAFi), vemurafenib and dabrafenib are utilized to treat melanoma and resulted in an excellent clinical outcome. However, the clinical success is not long-lasting, and the BRAFi resistance and disease progression inevitably occurs in nearly all patients. Endoplasmic reticulum stress-induced unfolded protein response and autophagy have emerged as potential pro-survival mechanisms adopted by melanoma cells in response to BRAFi. In this review, we discuss the role of unfolded protein response and autophagy that are implicated in the development of BRAFi-resistant melanoma and the corresponding strategy aiming at overcoming the intractable clinical problem. PMID- 26419470 TI - Opportunistic screening for osteoporosis using the sagittal reconstruction from routine abdominal CT for combined assessment of vertebral fractures and density. AB - SUMMARY: Opportunistic osteoporosis screening using abdominal CT scans obtained for other purposes has the potential to increase detection of those at increased risk for fragility fractures. We sought to combine the tasks of density measurement and vertebral fracture assessment on the sagittal view. We confirm that this represents a robust approach and recommend its implementation in clinical practice. INTRODUCTION: Opportunistic osteoporosis screening at routine abdominal CT has been proposed by measuring axial (transverse) L1 trabecular attenuation and by sagittal reconstruction for vertebral fracture assessment. We sought to combine this dual evaluation on the sagittal reconstruction alone to improve efficiency. METHODS: Routine contrast-enhanced abdominal CT scans performed for any indication on 571 consecutive adults age 60 years or older (mean age 70.7 years) were retrospectively analyzed. These were performed at a single center over a 3-month period. L1 trabecular attenuation was measured using an ovoid region-of-interest on both the transverse and sagittal series. The sagittal reconstruction was also analyzed for moderate-to-severe vertebral compression fractures using the Genant visual semi-quantitative method. Likely osteoporosis was defined by a moderate-to-severe fracture and/or sagittal L1 trabecular attenuation of <=110 Hounsfield units (HU) (previously found to be >90% specific for osteoporosis on our calibrated GE CT scanners at 120 kV(p)). Correlation was made with hip and spine dual X-ray absorptiometry (DXA). RESULTS: Mean absolute difference in L1 trabecular attenuation between transverse and sagittal reconstructions was 6.7 HU (+/-5.7) or 6.2%. The transverse and sagittal HU measurements were in agreement (i.e., both measurements above or below this threshold) in 94.5% of cases at the 110-HU cutoff. A total of 243 (42.3%) patients had likely osteoporosis by CT criteria, of which only 48 (19.8%) had previous DXA screening. CONCLUSION: Assessment of the sagittal view alone at routine abdominal CT for both vertebral fractures and trabecular bone mineral density provides a rapid and effective opportunistic screen for detecting individuals at increased risk for fragility fractures. PMID- 26419472 TI - Introduction: Regulatory B Cell Special Issue-making all the pieces fit. PMID- 26419476 TI - Establishment from the snout and kidney of goldfish, Carassius auratus, of two new cell lines and their susceptibility to infectious pancreatic necrosis virus. AB - Goldfish Carassius auratus are commonly used in scientific research and have a significant economic value in the pet trade. In this study, two cell lines were established from the snout and kidney tissue of goldfish, in order to create a biological monitoring tool for viral diseases. Cell lines were optimally maintained at 25 degrees C in M199 medium supplemented with 15-20 % fetal bovine serum. Chromosomal analysis indicated that both cell lines remained diploid, with a mean chromosomal count of 100. Results of viral inoculation assays revealed that both cell lines shared similar patterns of viral susceptibility and production to infectious pancreatic necrosis virus (IPNV). The viral titers of IPNV in goldfish snout cell line (GFSe) and goldfish kidney cell line (GFKf) reached 10(6.8) and 10(5.9) TCID50/0.1 mL, respectively, within 7 days. The cytopathic effect could be observed when Cyprinid herpesvirus 2 was inoculated into these cells; however, the CPE disappeared after four passages. No CPE was observed in the cells infected by spring viremia carp virus or grass carp reovirus. These newly established cell lines will be a useful diagnostic tool for viral diseases in this fish species and also for the isolation and study of goldfish viruses in future. PMID- 26419477 TI - Molecular signatures that are distinctive characteristics of the vertebrates and chordates and supporting a grouping of vertebrates with the tunicates. AB - Members of the phylum Chordata and the subphylum Vertebrata are presently distinguished solely on the basis of morphological characteristics. The relationship of the vertebrates to the two non-vertebrate chordate subphyla is also a subject of debate. Analyses of protein sequences have identified multiple conserved signature indels (CSIs) that are specific for Chordata or for Vertebrata. Five CSIs in 4 important proteins are specific for the Vertebrata, whereas two other CSIs are uniquely found in all sequenced chordate species including Ciona intestinalis and Oikapleura dioica (Tunicates) as well as Branchiostoma floridae (Cephalochordates). The shared presence of these molecular signatures by all vertebrates/chordate species, but in no other animal taxa, strongly indicates that the genetic changes represented by the identified CSIs diagnose monophyletic groups. Two other discovered CSIs are uniquely shared by different vertebrate species and by either one (Ciona intestinalis) or both tunicate (Ciona and Oikapleura) species, but they are not found in Branchiostoma or other animal species. Specific presence of these CSIs in different vertebrates and either one or both tunicate species provides strong independent evidence that the vertebrate species are more closely related to the urochordates (tunicates) than to the cephalochordates. PMID- 26419471 TI - Effect of osteoporosis medications on fracture healing. AB - Antiosteoporotic medications are often used to concurrently treat a patient's fragility fractures and underlying osteoporosis. This review evaluates the existing literature from animal and clinical models to determine these drugs' effects on fracture healing. The data suggest that these medications may enhance bone healing, yet more thorough prospective studies are warranted. Pharmacologic agents that influence bone remodeling are an essential component of osteoporosis management. Because many patients are first diagnosed with osteoporosis when presenting with a fragility fracture, it is critical to understand how osteoporotic medications influence fracture healing. Vitamin D and its analogs are essential for the mineralization of the callus and may also play a role in callus formation and remodeling that enhances biomechanical strength. In animal models, antiresorptive medications, including bisphosphonates, denosumab, calcitonin, estrogen, and raloxifene, do not impede endochondral fracture healing but may delay repair due to impaired remodeling. Although bisphosphonates and denosumab delay callus remodeling, they increase callus volume and result in unaltered biomechanical properties. Calcitonin increases cartilage formation and callus maturation, resulting in improved biomechanical properties. Parathyroid hormone, an anabolic agent, has demonstrated promise in animal models, resulting in accelerated healing with increased callus volume and density, more rapid remodeling to mature bone, and improved biomechanical properties. Clinical data with parathyroid hormone have demonstrated enhanced healing in distal radius and pelvic fractures as well as postoperatively following spine surgery. Strontium ranelate, which may have both antiresorptive and anabolic properties, affects fracture healing differently in normal and osteoporotic bone. While there is no effect in normal bone, in osteoporotic bone, strontium ranelate increases callus bone formation, maturity, and mineralization; forms greater and denser trabeculae; and improves biomechanical properties. Further clinical studies with these medications are needed to fully understand their effects on fracture healing in order to simultaneously treat fragility fractures and underlying osteoporosis. PMID- 26419478 TI - TNF-alpha: a treatment target or cause of sarcoidosis? AB - Sarcoidosis is a systemic granulomatous disease that affects numerous organs, commonly manifesting at the lungs and skin. While corticosteroids remain the first line of treatment, tumour necrosis factor alpha (TNF-alpha) inhibitors have been investigated as one potential steroid sparing treatment for sarcoidosis. TNF alpha is one of many components involved in the formation of granulomas in sarcoidosis. While there have been larger scale studies of biologic TNF-alpha inhibition in systemic sarcoidosis, studies in cutaneous disease are limited. Paradoxically, in some patients treated with biologic TNF-alpha inhibitors for other diseases, treatment can induce the development of sarcoidosis. In the light of this complexity, we discuss the role of TNF-alpha in granuloma formation, the therapeutic role of TNF-alpha inhibition and immunologic abnormalities following treatment with these TNF-alpha inhibitors including drug-specific alterations involving interferon-gamma, lymphotoxin-alpha, TNF receptor 2 (TNFR2) and T regulatory cells. PMID- 26419479 TI - Cross-dehydrogenative coupling of alpha-C(sp(3))-H of ethers/alkanes with C(sp(2))-H of heteroarenes under metal-free conditions. AB - Here we have developed an effective metal-free dehydrogenative coupling method wherein alpha-oxyalkyl and alkyl radicals were generated from various ethers and alkanes to undergo coupling with a variety of electron-deficient heteroarenes such as un/substituted iso-quinolones, quinolines, pyridines, pyrazines and pyrimidines. The persulfate-acetone-water system was optimized for the dehydrogenative coupling with cyclic ethers which gave moderate to excellent yields of alpha-oxyalkyl containing heteroarenes. We have also optimized the conditions for coupling with cyclic alkanes and alicyclic ethers and demonstrated by conducting the reactions with a variety of electron-deficient heteroarenes. Further, the present method is also applicable to electron deficient arenes like naphthoquinones and moreover, it didn't require any external acid. PMID- 26419480 TI - Forensic uses of research biobanks: should donors be informed? AB - Occasional reports in the literature suggest that biological samples collected and stored for scientific research are sometimes accessed and used for a variety of forensic purposes. However, donors are almost never informed about this possibility. In this paper we argue that the possibility of forensic access may constitute a relevant consideration at least to some potential research subjects in deciding whether to participate in research. We make the suggestion that if some type of forensic access to research collections is likely to be perceived by the subjects as a reason against donating their biological materials, there are good ethical reasons to make this type of access impossible or at least severely restricted. We also provide an ethical argument for the claim that, if a total ban on this type of forensic access cannot be achieved, potential research subjects should be informed about the extent to which this type of forensic access is possible. PMID- 26419481 TI - [Patients' need for consultation after a geriatric assessment in family practice : Survey]. AB - BACKGROUND: During a doctor-patient consultation patients usually seek information by disclosing their reasons for requesting the encounter. Geriatric assessment allows a proactive examination of patients' overall health and function and provides an opportunity to broach issues beyond the initial purposes of the consultation. OBJECTIVES: The study aimed at investigating older patients' information seeking behavior following a geriatric assessment and the kind of topics they wished to discuss, taking a variety of patient and health-related factors into account. MATERIAL AND METHODS: A total of 317 patients (>= 70 years) underwent a geriatric assessment in 40 general practices. Subsequently they obtained a list of the problems uncovered and rated the relevance and information needs for each problem. Analyses consisted of determining the prevalence of information need for each health topic and identifying predictors in a mixed model (multilevel regression analysis). RESULTS: The 317 patients presented with a median of 11 health problems (interquartile range, IQR 8-14) and 80 % of the patients had information needs concerning only a few of the problems. High information needs were present for physical complaints and for vaccination issues. Little information seeking behavior was evident for unhealthy lifestyles, falls, limitations in daily activities and psychosocial problems. In the mixed model the personal relevance and the type of health problem both had a significant and independent effect on information seeking behavior. CONCLUSION: A geriatric assessment generates a moderate need for information. It provides physicians with an opportunity to focus on those health problems that are important to older patients but not usually addressed in normal consultations. This particularly applies to limitations in daily activities and psychosocial problems. PMID- 26419482 TI - Outcome after operative treatment of proximal humeral fractures in elderly patients. AB - BACKGROUND: The proximal humeral fracture (PHF) (5 %) of the elderly is the third most common fracture after proximal femoral and distal radius fractures. Proximal femoral fractures often lead to a loss of autonomy. OBJECTIVES: The aim of this study is to show how PHF changes the patient's autonomy and the coping with everyday life as well as which factors influence the outcome 1 year (y) after surgery. MATERIALS AND METHODS: Data of 62 patients with surgical treatment of a PHF >= 60 y was prospectively collected. With a telephone interview Short Form (SF) 12 (physical and mental health; PH, MH), Barthel Index (BI), range of motion, pain, and satisfaction was observed after 3 and 12 months. The dependence of outcome on different factors was investigated. RESULTS: The mean age was 73.3 y (median 73, 60-94). Mortality after 3 months was 3 % and after 1 y 11 %. The PH before the injury (47.9) was significantly better than after 3 months (37.1) and after 1 y (42.6). The MH showed no difference. The BI before the injury (92) was significantly better than after 3 months (86), but the same after 1 y (91). After 1 y > 50 % were able to abduct and flex the arm > 90 degrees . More than two thirds were able to perform everyday life activities for body care and nutrition after 1 y. Approximately, 73 % of the patients had little or no pain, and 84 % were satisfied with the result after 1 y. Good score values before the fracture resulted in better outcome. Higher severity in fracture led to a higher level of pain. DISCUSSION: A surgically treated PHF in the elderly does not lead to a relevant impairment in quality of life. Despite the lack of complete retrieval of range of motion patients achieve a good to very good result in coping with everyday life. PMID- 26419483 TI - Noninvasive Tuberculosis Screening in Free-Living Primate Populations in Gombe National Park, Tanzania. AB - Recent advances in noninvasive detection methods for mycobacterial infection in primates create new opportunities for exploring the epidemiology of tuberculosis in free-living species. Chimpanzees (Pan troglodytes schweinfurthii) and baboons (Papio anubis) in Gombe National Park, Tanzania, were screened for infection with pathogens of the Mycobacterium tuberculosis Complex using Fecal IS6110 PCR; none was positive. This study demonstrates the feasibility of large-scale mycobacterial screening in wild primates. PMID- 26419484 TI - [Blood exposure accidents: knowledge and practices of hospital health workers in Mali]. AB - This is a prospective study conducted in December 2012 among 128 at the Nianankoro Fomba Hospital in Segou in order to assess their knowledge and practices on Blood Exposure Accidents (BEA). The average age of caregivers was 35.4 +/- 9 years (range: 22-59 years). The nurses were predominant with 37.5%. The definition of BEA was mastered by 43.8%. The main transmissible infectious agents (HIV, HBV and HCV) were ignored by 76.6%. Questioning revealed that during the treatment, 78.9% wore gloves and 36.0% recapped needles after use. The concept of washing and disinfection after BEA was known by 68.8%. The disinfectant applied was correct for 21.9% of the cases, the time of application for 69.5%. Consulting a referring physician after BEA was mandatory for 32% of them. The time limit of 48 hours delay for the declaration of BEA was experienced by 51.3%. Among staff interviewed 82 caregivers (64.1%) experienced at least one BEA. Students and nursing students were most at risk. Needle pricks were the most frequent (73.2%). BEA is a major problem in the Segou Nianankoro Fomba Hospital. Compliance with standard precautions is not of common practice. Post-exposure care is not widely known. The experienced cases show poor management of BEA in the structure. PMID- 26419485 TI - First reported case of intraocular Gnathostoma spinigerum in Cambodia. AB - A live intraocular nematode was identified from a 37 year-old man presented with iritis, pain, redness, lacrimation, swelling, vision loss and intermittent blindness during many hours per day of the left eye. By using slit lamp examination, a worm was removed from iris in an ophthalmology outpatient department setting and sent to the Medical Microbiology Laboratory, Institut Pasteur du Cambodge. Gnathostoma spinigerum was identified, based on its typical morphology via microscopic examination. Based on our diagnosis, the patient was treated by oral albendazole and responded well to this therapy. PMID- 26419486 TI - [Anopheles gambiae, major malaria vector in Logbessou, a peri-urban area of Douala (Cameroon)]. AB - An entomological survey was carried out from August to November 2013, in order to determine the vector system of a building site for social housing in a coastal periurban district of Douala (Cameroon). Mosquito larvae were collected and adult endophilic mosquitoes captured on volunteers, for a total sample of 4897 mosquitoes. Morpho-taxonomic techniques alongside molecular techniques enabled the identification of 4 species, all aggressive to humans: Cx. pipiens (22.3%), Ae. albopictus (0.3%), An. coluzzii and An. gambiae (77.4%). The overall average biting rate recorded was 41.73 bites/person/night (b/p/n). An. gambiae s.l. represents 90.82% of this aggressive fauna, followed by Cx. pipiens (8.58%) and Ae. albopictus (0.6%). The detection of CSP showed that An. gambiae was responsible for 100% of P. falciparum transmission. The overall mean Entomological Inoculation Rate (EIR) was 3.94 ib/p/n. Female An. gambiae mortality rates were 14.47%, 82.5% and 100% respectively with DDT, permethrin and deltamethrin. The proliferation of An. gambiae in this area during raining season, at the detriment of An. coluzzii Coetze & Wilkerson and An. melas Theobald known to be major malaria vectors in island and coastal areas of Africa, may owe to the forest that still colonises this coastal peri-urban locality. Residents should therefore make use of deltamethrin based protective measures. PMID- 26419488 TI - The cis-Diammineplatinum(II) Complex of Curcumin: A Dual Action DNA Crosslinking and Photochemotherapeutic Agent. AB - [Pt(cur)(NH3)2](NO3) (1), a curcumin-bound cis-diammineplatinum(II) complex, nicknamed Platicur, as a novel photoactivated chemotherapeutic agent releases photoactive curcumin and an active platinum(II) species upon irradiation with visible light. The hydrolytic instability of free curcumin reduces upon binding to platinum(II). Interactions of 1 with 5'-GMP and ct-DNA indicated formation of platinum-bound DNA adducts upon exposure to visible light (lambda=400-700 nm). It showed apoptotic photocytotoxicity in cancer cells (IC50 ~ 15 MUM), thus forming (?)OH, while remaining passive in the darkness (IC50 >200 MUM). A comet assay and platinum estimation suggest Pt-DNA crosslink formation. The fluorescence microscopic images showed cytosolic localization of curcumin, thus implying possibility of dual action as a chemo- and phototherapeutic agent. PMID- 26419487 TI - The effect of pregabalin and celecoxib on the analgesic requirements after laparoscopic cholecystectomy: a randomized controlled trial. AB - PURPOSE: Early postoperative pain is a common complaint after elective laparoscopic cholecystectomy. The use of non-opioid medications as a part of multimodal analgesia has been increasingly advocated in the management of acute post-surgical pain. This randomized, double-blinded, placebo-controlled study evaluated the efficacy of pregabalin, celecoxib, and their combination in the management of acute postoperative pain in patients undergoing elective laparoscopic cholecystectomy. METHODS: One hundred ASA I/II patients scheduled to undergo elective laparoscopic cholecystectomy were assigned to receive two perioperative doses, 12 h apart, of either pregabalin alone, celecoxib alone, their combination, or a placebo. Standard anesthetic protocol was followed. The primary outcomes were postoperative pain at rest and with movement. Secondary outcomes were fentanyl requirements and side effects, which were assessed at 1, 2, 4, 8, 12, and 24 h following surgery. Patient satisfaction with pain relief was recorded at discharge. Differences in main outcomes were analyzed using an intention-to-treat approach. RESULTS: There was no statistically significant difference (p > 0.05) between the four groups in terms of outcomes such as rest pain, movement pain, postoperative fentanyl requirements, or changes in anxiety scores. Patients who had only celecoxib had significantly higher satisfaction with pain management (p = 0.013). Patients who had only pregabalin were at three times-higher odds of having drowsiness (p = 0.040) and four-times-higher odds of having lightheadedness (p = 0.019) when compared with the placebo group. CONCLUSIONS: Pregabalin, celecoxib alone, or in combination offers no analgesic superiority over standard opioid care in the treatment of postoperative pain following laparoscopic cholecystectomy. PMID- 26419489 TI - Deciphering mechanisms of malathion toxicity under pulse exposure of the freshwater cladoceran Daphnia magna. AB - The organophosphate pesticide (OP) malathion is highly toxic to freshwater invertebrates, including the cladoceran Daphnia magna, a widely used test organism in ecotoxicology. To assess whether toxic effects of malathion are driven primarily by exposure concentration or exposure duration, D. magna was pulse exposed to equivalent integrated doses (duration * concentration): 3 h * 16 MUg/L, 24 h * 2 MUg/L, and 48 h * 1 MUg/L. After recovery periods of 3 h, 24 h, and 48 h, the toxicity of malathion on different biological levels in D. magna was examined by analyzing the following endpoints: survival and immobilization; enzyme activities of acetylcholinesterase (AChE), carboxylesterase (CbE), and glutathione S-transferase (GST); and AChE gene expression. The results showed no difference in survival among equivalent integrated doses. Adverse sublethal effects were driven by exposure concentration rather than pulse duration. Specifically, short pulse exposure to a high concentration of malathion resulted in more immobilized daphnids, lower AChE and CbE activities, and a higher transcript level of AChE gene compared with long pulse exposure to low concentration. The expression of the AChE gene was up-regulated, indicating a compensatory mechanism to cope with enzyme inhibition. The study shows the need for obtaining a better understanding of the processes underlying toxicity under realistic exposure scenarios, so this can be taken into account in environmental risk assessment of pesticides. PMID- 26419490 TI - First magenetic resonance imaging studies on aluminium maltolate-treated aged New Zealand rabbits: an Alzheimer's animal model. AB - BACKGROUND: Alzheimer's disease is a devastative neurodegenerative disorder. To date, there has been no animal model that could unravel the complete disease pathology. Magnetic resonance imaging has played a pivotal role in the quantitative assessment of brain tissue atrophy for a few decades. In particular, temporal lobe atrophy and ventricular dilatation have been found to be sensitive in Alzheimer's disease. METHODS: The present study focused on the replication of these crucial pathological events to enable disease progression to be diagnosed at an early stage and stopped through the use of potential therapeutic strategies. RESULT: The objective of this study was to show temporal lobe atrophy and ventricular dilatation in aluminium maltolate-treated aged New Zealand rabbit, and our study was able to demonstrate this for the first time. CONCLUSION: The present study makes this animal model a substantial one for further molecular level studies and opens up new targets for potential therapeutic strategies. PMID- 26419491 TI - Mindfulness-based stress reduction for long-term physical conditions: A systematic review. AB - OBJECTIVE: To identify whether mindfulness-based stress reduction is effective in improving physical health outcomes for long-term physical conditions. METHOD: A systematic review of the literature (retrieved from MEDLINE, PubMed and PsycINFO). RESULTS: Fifteen studies were included in the review. None of the studies assessed as having a low risk of bias demonstrated significant improvements in physical health status although there was some emerging evidence that mindfulness-based stress reduction may be useful in pain conditions. There was some preliminary evidence that it may also be effective in improving primary insomnia and irritable bowel syndrome. Small to moderate effect sizes were also found for asthma, pain, tinnitus, fibromyalgia and somatization disorders. CONCLUSION: Although there is some preliminary support for the use of mindfulness based stress reduction in physical health conditions, further research is required before it could be considered an effective intervention for improving physical health outcomes. PMID- 26419492 TI - Developing a Workflow Composite Score to Measure Clinical Information Logistics. A Top-down Approach. AB - BACKGROUND: Availability and usage of individual IT applications have been studied intensively in the past years. Recently, IT support of clinical processes is attaining increasing attention. The underlying construct that describes the IT support of clinical workflows is clinical information logistics. This construct needs to be better understood, operationalised and measured. OBJECTIVES: It is therefore the aim of this study to propose and develop a workflow composite score (WCS) for measuring clinical information logistics and to examine its quality based on reliability and validity analyses. METHODS: We largely followed the procedural model of MacKenzie and colleagues (2011) for defining and conceptualising the construct domain, for developing the measurement instrument, assessing the content validity, pretesting the instrument, specifying the model, capturing the data and computing the WCS and testing the reliability and validity. RESULTS: Clinical information logistics was decomposed into the descriptors data and information, function, integration and distribution, which embraced the framework validated by an analysis of the international literature. This framework was refined selecting representative clinical processes. We chose ward rounds, pre- and post-surgery processes and discharge as sample processes that served as concrete instances for the measurements. They are sufficiently complex, represent core clinical processes and involve different professions, departments and settings. The score was computed on the basis of data from 183 hospitals of different size, ownership, location and teaching status. Testing the reliability and validity yielded encouraging results: the reliability was high with r(split-half) = 0.89, the WCS discriminated between groups; the WCS correlated significantly and moderately with two EHR models and the WCS received good evaluation results by a sample of chief information officers (n = 67). These findings suggest the further utilisation of the WCS. CONCLUSION: As the WCS does not assume ideal workflows as a gold standard but measures IT support of clinical workflows according to validated descriptors a high portability of the WCS to other hospitals in other countries is very likely. The WCS will contribute to a better understanding of the construct clinical information logistics. PMID- 26419493 TI - Tangential cell migration during layer formation of chick optic tectum. AB - The laminated structure of the optic tectum is formed by radial and tangential cell migration during development. Studies of developing chick optic tectum have revealed two streams of tangential cell migration in the middle and superficial layers, which have distinctive origins, migratory paths, modes of migration, and destinations. We will review the process of the two types of tangential migrations, in order to elucidate their roles in the formation of the optic tectum layers. PMID- 26419494 TI - Civilian deaths from weapons used in the Syrian conflict. PMID- 26419495 TI - 'When operating a cafeteria, sales come before nutrition' - finding barriers and facilitators to serving reduced-sodium meals in worksite cafeterias. AB - OBJECTIVE: The present study was conducted to examine barriers to and facilitators of serving reduced-sodium meals (RSM) in worksite cafeterias. DESIGN: We conducted in-depth interviews with key stakeholders in food catering companies. SETTING: Food catering companies at various customer sites in South Korea. SUBJECTS: A total of nineteen interviews with twenty-five participants from ten catering companies were conducted. Sixteen on-site dietitians and nine managers from the catering companies' headquarters participated in the interviews. RESULTS: Four main themes emerged from the interviews. First, key stakeholders' psychosocial characteristics (perception, intention and knowledge) are important in serving RSM in worksite cafeterias. Second, skills and techniques related to measuring sodium content and preparing RSM were emphasized by the interviewees. Third, the lack of various delicious low-sodium menus is a barrier to serving RSM. Lastly, a number of environmental factors were addressed, which include social support for reduced-sodium diets (a facilitator) and pressure to maintain profit margins (a barrier), that contribute to serving meals with less salt. Based on these factors, various recommendations for future sodium reduction policies and programmes were suggested. CONCLUSIONS: It is important to implement population-wide sodium reduction as a means of preventing CVD and stroke. The study provided important facilitators of and barriers to serving RSM in worksite cafeterias, which could be helpful in developing environmental interventions that promote low-sodium diets. PMID- 26419496 TI - Adolescence as a Sensitive Period of Brain Development. AB - Most research on sensitive periods has focussed on early sensory, motor, and language development, but it has recently been suggested that adolescence might represent a second 'window of opportunity' in brain development. Here, we explore three candidate areas of development that are proposed to undergo sensitive periods in adolescence: memory, the effects of social stress, and drug use. We describe rodent studies, neuroimaging, and large-scale behavioural studies in humans that have yielded data that are consistent with heightened neuroplasticity in adolescence. Critically however, concrete evidence for sensitive periods in adolescence is mostly lacking. To provide conclusive evidence, experimental studies are needed that directly manipulate environmental input and compare effects in child, adolescent, and adult groups. PMID- 26419497 TI - Povidone-iodine pleurodesis for congenital chylothorax of the newborn. PMID- 26419498 TI - Optimal visualization of the fetal four-chamber and outflow tract views with transabdominal ultrasound in the morbidly obese: Are we there yet? AB - BACKGROUND: To compare optimal visualization of the four-chamber and outflow tract views of the fetal heart on sonographic examination between morbidly obese (body mass index [BMI] >= 40 kg/m(2) ) and nonobese (BMI < 25 kg/m(2) ) pregnant women. METHODS: In this retrospective cohort study, we included records and images from 509 pregnant women who had first undergone sonographic examination between 18 and 36 weeks' fetal gestational age. RESULTS: Compared with the nonobese women, morbidly obese women had lower optimal visualization of the four chamber and outflow-tract heart views: four-chamber view, morbidly obese, 83/186 (44.6%), versus nonobese, 283/323 (87.6%), and outflow-tract view, morbidly obese, 80/186 (43%) versus nonobese, 258/290 (89%); p < 0.0001 for each comparison. Similar outcomes were observed when the results from each subcategory of morbidly obese women (ie, BMI 40-49.9, 50-59.9, and >=60 kg/m(2) ) were compared with that from nonobese women; p < 0.0001 for each comparison. These outcomes remained the same regardless of whether this comparison was made among those who had their examination before or at 19 weeks' or more gestational age. Among the morbidly obese women, there was no difference in optimal visualization of the four-chamber or outflow-tract views regardless of whether the examination was performed at <23 weeks' or at >=23 weeks' gestational age: four-chamber view <23 weeks, 44.8% (78/174), versus four-chamber view >=23 weeks, 41.7% (5/12); p = 0.8, and outflow-tract view <23 weeks, 43.1% (75/174), versus outflow-tract view >=23 weeks, 41.7% (5/12); p = 0.9. After controlling for maternal age and race, the odds of visualizing the four-chamber and outflow-tract views in the morbidly obese were reduced compared with those in their nonobese counterparts: odds ratio (OR) for four-chamber, 0.13; 95% confidence interval (CI), 0.08-0.21, and OR for outflow-tract, 0.11; 95% CI, 0.07-0.17. CONCLUSIONS: Optimal visualization of the fetal four-chamber and outflow-tract views was achieved in less than 50% of morbidly obese women, compared with almost 90% in nonobese women. PMID- 26419499 TI - Effect of birth ball on labor pain relief: A systematic review and meta-analysis. AB - AIM: To critically evaluate the available evidence related to the impact of using a birth ball on labor pain relief. METHODS: The Cochrane library, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE/PubMed and Scopus were searched from their inception to January 2015 using keywords: (Birth* OR Swiss OR Swedish OR balance OR fitness OR gym* OR Pezzi OR sport* OR stability) AND (ball*) AND (labor OR labour OR Obstetric). All available randomized controlled trials involving women using a birth ball for pain relief during labor were considered. The search resulted in 341 titles and abstracts, which were narrowed down to eight potentially relevant articles. Of these, four studies met the inclusion criteria. Pain intensity on a 10 cm visual analogue scale was used as the main outcome measure. Risk of bias was assessed using the Cochrane Risk of Bias tool. Comprehensive Meta-Analysis Version 2 was used for statistical analysis. RESULTS: Four RCTs involving 220 women were included in the systematic review. One study was excluded from the meta-analysis because of heterogeneous interventions and a lack of mean and standard deviation results of labor pain score. The meta-analysis showed that birth ball exercises provided statistically significant improvements to labor pain (pooled mean difference -0.921; 95% confidence interval -1.28, -0.56; P = 0.0000005; I(2) = 33.7%). CONCLUSION: The clinical implementation of a birth ball exercise could be an effective tool for parturient women to reduce labor pain. However, rigorous RCTs are needed to evaluate the effect of the birth ball on labor pain relief. PMID- 26419500 TI - Long-term survival in microcephalic osteodysplastic primordial dwarfism type I: Evaluation of an 18-year-old male with g.55G>A homozygous mutation in RNU4ATAC. PMID- 26419501 TI - Demographic and psychosocial correlates of sexual activity in older Chinese people. AB - AIMS AND OBJECTIVES: This study examines sexual activity and associated psychosocial factors in older Chinese people. BACKGROUND: Sexuality continues to play a pivotal role in our lives even as we grow old. There is, however, very limited research on the topic in older populations. DESIGN: Cross-sectional survey. METHODS: A representative sample of 688 older Chinese people (>60 years old) were individually interviewed on their demographic characteristics; their interest in, knowledge of and perceived control over sexual activities; and their engagement in sexual activity. RESULTS: The results show that 51.32% of men and 41.26% of women reported engaging in some form of sexual activity. Sexual intercourse and caressing were commonly reported. A multiple regression analysis also showed that a higher level of sexual activity was associated with being younger, living with a spouse, having a strong interest in sex, having sufficient knowledge of elder sexuality and a high perceived control over sex. Distinct predictive factors in each gender were observed. A high level of perceived control was associated with a higher level of sexual activity in males but not females. A series of binary logistic regression analyses were conducted to determine the demographic and psychosocial correlates of sexual activity. With the exception of the use of objects (sex toys), sexual activities were consistently associated with being younger; living with a spouse; and having high levels of interest, knowledge and perceived control. CONCLUSIONS: A sizable amount of older Chinese people engage in varying degrees of sexual activity, and most are still interested in sex. RELEVANCE TO CLINICAL PRACTICE: Frontline health professionals need to be aware of the growing needs for sex education in older persons, particular attention should be paid to discuss the limitations brought about by various chronic conditions associated with ageing and their relevance to elder sexuality. PMID- 26419502 TI - Thermocrinis jamiesonii sp. nov., a thiosulfate-oxidizing, autotropic thermophile isolated from a geothermal spring. AB - An obligately thermophilic, chemolithotrophic, microaerophilic bacterium, designated strain GBS1T, was isolated from the water column of Great Boiling Spring, Nevada, USA. Thiosulfate was required for growth. Although capable of autotrophy, growth of GBS1T was enhanced in the presence of acetate, peptone or Casamino acids. Growth occurred at 70-85 degrees C with an optimum at 80 degrees C, at pH 6.50-7.75 with an optimum at pH 7.25, with 0.5-8 % oxygen with an optimum at 1-2 % and with <= 200 mM NaCl. The doubling time under optimal growth conditions was 1.3 h, with a final mean cell density of 6.2 +/- 0.5 * 107 cells ml- 1. Non-motile, rod-shaped cells 1.4-2.4 * 0.4-0.6 MUm in size occurred singly or in pairs. The major cellular fatty acids (>5 % of the total) were C20 : 1omega9c, C18 : 0, C16 : 0 and C20 : 0. Phylogenetic analysis of the GBS1T 16S rRNA gene sequence indicated an affiliation with Thermocrinis ruber and other species of the genus Thermocrinis, but determination of 16S rRNA gene sequence similarity ( <= 97.10 %) and in silico estimated DNA-DNA hybridization values ( <= 18.4 %) with the type strains of recognized Thermocrinis species indicate that the novel strain is distinct from described species. Based on phenotypic, genotypic and phylogenetic characteristics, a novel species, Thermocrinis jamiesonii sp. nov., is proposed, with GBS1T ( = JCM 19133T = DSM 27162T) as the type strain. PMID- 26419503 TI - Effects of dietary lysozyme levels on growth performance, intestinal morphology, non-specific immunity and mRNA expression in weanling piglets. AB - The aim of the present study was to determine the effect of dietary lysozyme levels on growth performance, gut health and non-specific immunity of weanling piglets. A total of 150 weanling piglets were allocated to six treatments. The piglets were fed the same basel diet supplemented with 0, 30, 60, 90 and 120 mg/kg lysozyme as well as antibiotics for 28 days. From day 14 to day 28 of dietary treatment, piglets fed 90 mg/kg lysozyme had greater average daily gain than piglets fed control diet. During the whole experimental period, piglets fed 120 mg/kg lysozyme tended to have greater average daily gain than piglets fed control diet. Compared with piglets fed control diet, piglets fed diets containing antibiotics and 90 mg/kg lysozyme had greater villus height to crypt depth ratio in duodenum and jejunum. Additionally, dietary supplementation of 60 and 90 mg/kg lysozyme as well as antibiotics enhanced the phagocytic activity of peritoneal macrophages in piglets. In conclusion, dietary lysozyme can accelerate the growth of weanling piglets by improving gut health and non-specific immunity and supplementing 90 mg/kg lysozyme is as effective as antibiotics (20 mg/kg colistin sulphate + 50 mg/kg kitasamycin) in improving the growth performance of weanling piglets. PMID- 26419504 TI - Use of a small particle solid-core packing for improved efficiency and rapid measurement of sirolimus and everolimus by LC-MS/MS. AB - Measurement of whole blood sirolimus and everolimus is required in order to optimize patient treatment following solid organ transplant. Assay by LC-MS/MS is increasingly preferred; however efficient use of the instrument and short turnaround times are crucial. Use of a 1.6 um solid-core packing HPLC column (Cortecs) gave significant increases in efficiency, sensitivity and throughput compared with an existing method, following simple protein precipitation of small volume (20 MUL) whole blood samples. Sirolimus, everolimus and the stable isotopic internal standard ((13) C2 D4 - everolimus) eluted at around 0.8 min, and total analytical run time was 2.2 min, saving almost 4 min per sample compared with an existing method. Within-assay imprecision (CV) was 3.3-8.5%, and between-assay imprecision was 2.2-10.8%. Retrospective assay of external quality assurance samples and comparison of patient samples assayed in parallel showed only small differences (between +6.8 and -1.9%) in results using the Cortecs column when compared with the existing method. No significant interferences or ion suppression were observed. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26419505 TI - In vivo quantification of hyperoxic arterial blood water T1. AB - Normocapnic hyperoxic and hypercapnic hyperoxic gas challenges are increasingly being used in cerebrovascular reactivity (CVR) and calibrated functional MRI experiments. The longitudinal arterial blood water relaxation time (T1a) change with hyperoxia will influence signal quantification through mechanisms relating to elevated partial pressure of plasma-dissolved O2 (pO2) and increased oxygen bound to hemoglobin in arteries (Ya) and veins (Yv). The dependence of T1a on Ya and Yv has been elegantly characterized ex vivo; however, the combined influence of pO2, Ya and Yv on T1a in vivo under normal ventilation has not been reported. Here, T1a is calculated during hyperoxia in vivo by a heuristic approach that evaluates T1 -dependent arterial spin labeling (ASL) signal changes to varying gas stimuli. Healthy volunteers (n = 14; age, 31.5 +/- 7.2 years) were scanned using pseudo-continuous ASL in combination with room air (RA; 21% O2/79% N2), hypercapnic normoxic (HN; 5% CO2/21% O2/74% N2) and hypercapnic hyperoxic (HH; 5% CO2/95% O2) gas administration. HH T1a was calculated by requiring that the HN and HH cerebral blood flow (CBF) change be identical. The HH protocol was then repeated in patients (n = 10; age, 61.4 +/- 13.3 years) with intracranial stenosis to assess whether an HH T1a decrease prohibited ASL from being performed in subjects with known delayed blood arrival times. Arterial blood T1a decreased from 1.65 s at baseline to 1.49 +/- 0.07 s during HH. In patients, CBF values in the affected flow territory for the HH condition were increased relative to baseline CBF values and were within the physiological range (RA CBF = 36.6 +/- 8.2 mL/100 g/min; HH CBF = 45.2 +/- 13.9 mL/100 g/min). It can be concluded that hyperoxic (95% O2) 3-T arterial blood T1aHH = 1.49 +/- 0.07 s relative to a normoxic T1a of 1.65 s. PMID- 26419506 TI - Do CHA2 DS2 VASc and HAS-BLED scores influence 'real-world' anticoagulation management in atrial fibrillation? 1556 patient registry from the reference cardiology centre. AB - INTRODUCTION: Although recommendations for the antithrombotic management of atrial fibrillation (AF) are based on strong evidence, the European guidelines are not fully implemented into practice. OBJECTIVES: The objective of this study is to analyse antithrombotic treatment in AF in Poland after the publication of the European Society of Cardiology Guidelines in 2012. PATIENTS AND METHODS: We retrospectively studied 1556 patients with AF from the Reference Cardiology University Centre in Poland in 2012-2014. RESULTS: CHA2 DS2 VASc and HAS-BLED scores were 3.5 +/- 1.7 and 2.4 +/- 1.1. Anti-vitamin K agent were prescribed in 59%, with non-vitamin K antagonist oral anticoagulants in 12%, acetylsalicylic acid (ASA) alone in 18%. Older patients (p < 0.0001) and with paroxysmal AF were less likely to receive oral anticoagulation (OAC, p < 0.0001). The risk of stroke according to CHA2 DS2 VASc score was higher in patients who did not receive OAC (p < 0.0001). The use of OAC increased with increasing CHA2 DS2 VASc score but was less frequent in score >= 4. The risk of bleeding was higher in patients without OAC (p < 0.0001). The odds of non-vitamin K antagonist oral anticoagulants use were lower for older patients, patients with ischaemic heart disease, chronic heart failure, anaemia, HAS-BLED >= 3 and valvular AF. ASA was given in 39% of the patients, especially in paroxysmal AF (p < 0.0001). The odds of ASA alone were higher for older patients, with ischaemic heart disease and history of myocardial infarction (p < 0.0001). The odds of use of ASA as the only treatment were 5.5 times higher for HAS-BLED >= 3 (p < 0.0001). CONCLUSIONS: Antithrombotic management in AF is well implemented in Polish conditions, but we show the lack of pattern concerning who is being treated with OAC and ASA when it comes to the risk of stroke and bleeding. PMID- 26419507 TI - Doxorubicin-poly (ethylene glycol)-alendronate self-assembled micelles for targeted therapy of bone metastatic cancer. AB - In order to increase the therapeutic effect of doxorubicin (DOX) on bone metastases, a multifunctional micelle was developed by combining pH-sensitive characteristics with bone active targeting capacity. The DOX loaded micelle was self-assembled by using doxorubicin-poly (ethylene glycol)-alendronate (DOX-hyd PEG-ALN) as an amphiphilic material. The size and drug loading of DOX loaded DOX hyd-PEG-ALN micelle was 114 nm and 24.3%. In pH 5.0 phosphate buffer solution (PBS), the micelle released DOX significantly faster than in pH 7.4 PBS. In addition, with the increase of incubation time, more red DOX fluorescence was observed in tumor cells and trafficked from cytoplasm to nucleus. The IC50 of DOX loaded DOX-hyd-PEG-ALN micelle on A549 cells was obviously lower than that of free DOX in 48 h. Furthermore, the in vivo image experimental results indicated that a larger amount of DOX was accumulated in the bone metastatic tumor tissue after DOX loaded DOX-hyd-PEG-ALN micelle was intravenously administered, which was confirmed by histological analysis. Finally, DOX loaded DOX-hyd-PEG-ALN micelle effectively delayed the tumor growth, decreased the bone loss and reduced the cardiac toxicity in tumor-bearing nude mice as compared with free DOX. In conclusion, DOX loaded DOX-hyd-PEG-ALN micelle had potential in treating bone metastatic tumor. PMID- 26419508 TI - Activating somatic mutations outside the SH2-domain of STAT3 in LGL leukemia. PMID- 26419510 TI - Pathogen infection drives patterns of nutrient resorption in citrus plants. AB - Nutrient resorption processes in the plants infected by pathogen remain poorly understood. Huanglongbing (HLB) is a destructive disease of citrus. HLB-pathogen 'Candidatus Liberibacter asiaticus' grows specifically in the phloem of hosts and may cause problems in the plant vascular system after infection. Therefore, it brings a great concern about the phloem nutrient transport and nutrient intra cycling in HLB-affected plants. We investigated the effects of 'Ca. L. asiaticus' infection on nitrogen (N) and phosphorus (P) concentrations and resorption in different citrus species (i.e. Citrus reticulata, Citrus limon and Citrus maxima). HLB-pathogen infection had distinctive impacts on nutrient resorption in different species. P resorption efficiency substantially decreased in infected C. reticulata plants relative to the healthy plants in summer, which may account for the marked decrease in the average fruit yield. P resorption was more efficient in infected C. limon plants than in the healthy plants. However, for C. maxima plants, HLB had no significant effects on N:P ratio in live leaves and resorption efficiency as well as on fruit yield. Keeping efficient internal nutrient cycling can be a strategy of citrus species being tolerant to HLB. PMID- 26419511 TI - Nanocatalysts Fabricated by a Dealloying Method. AB - Two types of nanomaterials with different morphologies are described in this article: nanoporous metals and titanate nanowires. Both materials are fabricated by a dealloying method. In the former case, the catalytic properties of nanoporous gold and palladium are exemplified by many chemical transformations. The reactions proceed without any support, stabilizer, or ligands. The catalyst can be easily recovered by a simple separation process and reused many times without significant loss of catalytic activity. In the latter case, the dealloying of Ti-Al alloy is described as a new fabrication method for producing ultrafine titanate nanowires. This method does not require high-temperature conditions, which is advantageous for the construction of fine structures. The key to this process is achieving a fine dispersion of intermetallic TiAl3 nanocrystals in the Al matrix in the mother alloy. The resulting nanowires exhibit remarkable Sr(2+) ion-exchange properties. PMID- 26419509 TI - Osteolytic lesions, cytogenetic features and bone marrow levels of cytokines and chemokines in multiple myeloma patients: Role of chemokine (C-C motif) ligand 20. AB - The relationship between bone marrow (BM) cytokine and chemokine levels, cytogenetic profiles and skeletal involvement in multiple myeloma (MM) patients is not yet defined. This study investigated a cohort of 455 patients including monoclonal gammopathy of uncertain significance (MGUS), smoldering MM and symptomatic MM patients. Skeletal surveys, positron emission tomography (PET)/computerized tomography (CT) and magnetic resonance imaging (MRI) were used to identify myeloma bone disease. Significantly higher median BM levels of both C C motif Ligand (CCL)3 and CCL20 were found in MM patients with radiographic evidence of osteolytic lesions as compared with those without, and in all MM patients with positive PET/CT scans. BM levels of CCL3, CCL20, Activin-A and Dickkopf-1 (DKK-1) were significantly higher in patients with high bone disease as compared with patients with low bone disease. Moreover, CCL20 BM levels were significant predictors of osteolysis on X-rays by multivariate logistic analysis. On the other hand, DKK-1 levels were related to the presence of MRI lesions independently of the osteolysis at the X-rays. Our data define the relationship between bone disease and the BM cytokine and chemokine patterns highlighting the tight relationship between CCL20 BM levels and osteolysis in MM. PMID- 26419512 TI - Protocatechuic acid ameliorates neurocognitive functions impairment induced by chronic intermittent hypoxia. AB - Chronic intermittent hypoxia (CIH) is a serious consequence of obstructive sleep apnoea (OSA) and has deleterious effects on central neurons and neurocognitive functions. This study examined if protocatechuic acid (PCA) could improve learning and memory functions of rats exposed to CIH conditions and explore potential mechanisms. Neurocognitive functions were evaluated in male SD rats by step-through passive avoidance test and Morris water maze assay following exposure to CIH or room air conditions. Ultrastructure changes were investigated with transmission electron microscopy, and neuron apoptosis was confirmed by TUNEL assays. Ultrastructure changes were investigated with transmission electron microscope and neuron apoptosis was confirmed by TUNEL assays. The effects of PCA on oxidative stress, apoptosis, and brain IL-1beta levels were investigated. Expression of Bcl-2, Bax, Cleaved Caspase-3, c-fos, SYN, BDNF and pro-BDNF were also studied along with JNK, P38 and ERK phosphorylation to elucidate the molecular mechanisms of PCA action. PCA was seen to enhance learning and memory ability, and alleviate oxidative stress, apoptosis and glial proliferation following CIH exposure in rats. In addition, PCA administration also decreased the level of IL-1beta in brain and increased the expression of BDNF and SYN. We conclude that PCA administration will ameliorate CIH-induced cognitive dysfunctions. PMID- 26419513 TI - Quantifying the Electron Donor and Acceptor Abilities of the Ketimide Ligands in M(N?C(t)Bu2)4 (M = V, Nb, Ta). AB - Addition of 4 equiv of Li(N?C(t)Bu2) to VCl3 in THF, followed by addition of 0.5 equiv of I2, generates the homoleptic V(IV) ketimide complex, V(N?C(t)Bu2)4 (1), in 42% yield. Similarly, reaction of 4 equiv of Li(N?C(t)Bu2) with NbCl4(THF)2 in THF affords the homoleptic Nb(IV) ketimide complex, Nb(N?C(t)Bu2)4 (2), in 55% yield. Seeking to extend the series to the tantalum congener, a new Ta(IV) starting material, TaCl4(TMEDA) (3), was prepared via reduction of TaCl5 with Et3SiH, followed by addition of TMEDA. Reaction of 3 with 4 equiv of Li(N?C(t)Bu2) in THF results in the isolation of a Ta(V) ketimide complex, Ta(Cl)(N?C(t)Bu2)4 (5), which can be isolated in 32% yield. Reaction of 5 with Tl(OTf) yields Ta(OTf)(N?C(t)Bu2)4 (6) in 44% yield. Subsequent reduction of 6 with Cp*2Co in toluene generates the homoleptic Ta(IV) congener Ta(N?C(t)Bu2)4 (7), although the yields are poor. All three homoleptic group 5 ketimide complexes exhibit squashed tetrahedral geometries in the solid state, as determined by X-ray crystallography. This geometry leads to a d(x(2)-y(2))(1) ((2)B1 in D(2d)) ground state, as supported by DFT calculations. EPR spectroscopic analysis of 1 and 2, performed at X- and Q-band frequencies (~9 and 35 GHz, respectively), further supports the (2)B1 ground-state assignment, whereas comparison of 1, 2, and 7 with related group 5 tetra(aryl), tetra(amido), and tetra(alkoxo) complexes shows a higher M-L covalency in the ketimide-metal interaction. In addition, a ligand field analysis of 1 and 2 demonstrates that the ketimide ligand is both a strong pi-donor and strong pi-acceptor, an unusual combination found in very few organometallic ligands. PMID- 26419514 TI - DNA Microenvironment Monitored by Controlling Redox Blinking. AB - The rate of a bimolecular reaction between a fluorophore and a freely diffusing molecule in the solvent depends on the accessibility of the fluorophore for collision with the molecule. We previously reported that the observation of blinking, caused by the formation of R6G in the excited triplet state ((3) R6G*) and its quenching reaction with O2 , allowed us to monitor the DNA conformational changes between a duplex and a hairpin. However, the small molecular size of O2 hampered sensitive monitoring of the microenvironment changes around R6G. In this study, we control redox blinking by adding a reductant ascorbic acid 2-phosphate (VcP), which converts (3) R6G* into the radical anion form R6G(.-) , and by adding a bulky oxidant FeDTPA. The bimolecular electron-transfer rate between R6G(.-) and bulky FeDTPA was more strongly affected by microenvironment changes around R6G, compared with that between (3) R6G* and the smaller O2 . This allowed us to monitor subtle DNA conformational changes caused by a single different nucleotide. PMID- 26419515 TI - Towards a table-top microscope for nanoscale magnetic imaging using picosecond thermal gradients. AB - Research advancement in magnetoelectronics is challenged by the lack of a table top magnetic measurement technique with the simultaneous temporal and spatial resolution necessary for characterizing magnetization dynamics in devices of interest, such as magnetic memory and spin torque oscillators. Although magneto optical microscopy provides superb temporal resolution, its spatial resolution is fundamentally limited by optical diffraction. To address this challenge, we study heat rather than light as a vehicle to stroboscopically transduce a local magnetic moment into an electrical signal while retaining picosecond temporal resolution. Using this concept, we demonstrate spatiotemporal magnetic microscopy using the time-resolved anomalous Nernst effect (TRANE). Experimentally and with supporting numerical calculations, we find that TRANE microscopy has temporal resolution below 30 ps and spatial resolution determined by the area of thermal excitation. Based on these findings, we suggest a route to exceed the limits imposed by far-field optical diffraction. PMID- 26419516 TI - Death due to coronary artery anomaly with coexistence of Chiari network. AB - Coronary artery anomalies rarely detected in autopsy series and angiograms can be a component of complex malformations, besides, can be also associated with sudden cardiac death. Presented case was 22-year-old male, who had suddenly fainted during a football match played on artificial turf, he was transferred into the hospital, however had died during intensive care therapy. He had been evaluated by local prosecutor, and sent to our center for autopsy. At autopsy, internal macroscopic examination revealed absence of the right coronary artery. A total of two coronary artery ostia were observed. One of them originated from the left aortic sinus, and the other one stemmed from 8 mm above the sinotubular line. Besides, Chiari network formation was seen in the right atrium. This case with coronary artery anomaly associated with formation of Chiari network was discussed from the perspective of forensic medicine in the light of the literature information. PMID- 26419517 TI - [Determination of body fluid based on analysis of nucleic acids]. AB - Recent methodological approaches of molecular genetics allow isolation of nucleic acids (DNA and RNA) from negligible forensic samples. Analysis of these molecules may be used not only for individual identification based on DNA profiling but also for the detection of origin of the body fluid which (alone or in mixture with other body fluids) forms the examined biological trace. Such an examination can contribute to the evaluation of procedural, technical and tactical value of the trace. Molecular genetic approaches discussed in the review offer new possibilities in comparison with traditional spectrum of chemical, immunological and spectroscopic tests especially with regard to the interpretation of mixtures of biological fluids and to the confirmatory character of the tests. Approaches based on reverse transcription of tissue specific mRNA and their subsequent polymerase chain reaction (PCR) and fragmentation analysis are applicable on samples containing minimal amounts of biological material. Methods for body fluid discrimination based on examination of microRNA in samples provided so far confusing results therefore further development in this field is needed. The examination of tissue specific methylation of nucleotides in selected gene sequences seems to represent a promising enrichment of the methodological spectrum. The detection of DNA sequences of tissue related bacteria has been established and it provides satisfactory results mainly in combination with above mentioned methodological approaches. PMID- 26419518 TI - Truncus arteriosus communis with survival to the age of 46 years: case report. AB - Truncus arteriosus communis is an uncommon congenital cardiovascular malformation characterized by a single arterial trunk that arises from the base of the heart and gives rise to the coronary, pulmonary and systemic arteries. The prognosis in truncus arteriosus is very poor without surgical correction. The median age at death without surgery ranges from 2 weeks to 3 months, with 85 % mortality by age 1 year. The authors report the autopsy findings of a 46 year old man with truncus arteriosus communis without surgical intervention who died at the hospital shortly after admission. PMID- 26419519 TI - A color test for the convenient identification of an ingested surface activating agent. AB - Color tests are easy, simple and inexpensive methods for the qualitative identification of chemicals. A color test was applied to the stomach contents of a forensic autopsy case. The result of the test, using bromophenol blue reagent, indicated the ingestion of a commercial cleaning product containing a cationic surface activating agent. Our findings suggest that forensic investigators should consider the additives used in commercial chemical products, such as surface activating agents, when determining the cause of death. PMID- 26419520 TI - Problems with the junior doctors' contract: how did we get here? PMID- 26419521 TI - Implementing systems medicine within healthcare. AB - The cause of a complex disease cannot be pinpointed to a single origin; rather, a highly complex network of many factors that interact on different levels over time and space is disturbed. This complexity requires novel approaches to diagnosis, treatment, and prevention. To foster the necessary shift to a pro active systems medicine, proof-of-concept studies are needed. Here, we highlight several systems approaches that have been shown to work within the field of respiratory medicine, and we propose the next steps for broader implementation. PMID- 26419522 TI - Host-parasite coevolution in populations of constant and variable size. AB - BACKGROUND: The matching-allele and gene-for-gene models are widely used in mathematical approaches that study the dynamics of host-parasite interactions. Agrawal and Lively (Evolutionary Ecology Research 4:79-90, 2002) captured these two models in a single framework and numerically explored the associated time discrete dynamics of allele frequencies. RESULTS: Here, we present a detailed analytical investigation of this unifying framework in continuous time and provide a generalization. We extend the model to take into account changing population sizes, which result from the antagonistic nature of the interaction and follow the Lotka-Volterra equations. Under this extension, the population dynamics become most complex as the model moves away from pure matching-allele and becomes more gene-for-gene-like. While the population densities oscillate with a single oscillation frequency in the pure matching-allele model, a second oscillation frequency arises under gene-for-gene-like conditions. These observations hold for general interaction parameters and allow to infer generic patterns of the dynamics. CONCLUSION: Our results suggest that experimentally inferred dynamical patterns of host-parasite coevolution should typically be much more complex than the popular illustrations of Red Queen dynamics. A single parasite that infects more than one host can substantially alter the cyclic dynamics. PMID- 26419523 TI - Deforestation, drainage network, indigenous status, and geographical differences of malaria in the State of Amazonas. AB - BACKGROUND: Malaria is a major public health problem worldwide. In Brazil, an average of 420,000 cases of malaria have been reported annually in the last 12 years, of which 99.7 % occurred in the Amazon region. This study aimed to analyse the distribution of malaria in the State of Amazonas and the influence of indigenous malaria in this scenario, to evaluate the correlation between incidence rates and socio-economic and environmental factors, and to evaluate the performance of health surveillance services. METHODS: This ecological study used secondary data obtained from the SIVEP-MALARIA malaria surveillance programme. The relationship between demographic, socio-economic and environmental factors, the performance of health surveillance services and the incidence of malaria in Amazonas, a multiple linear regression model was used. RESULTS: The crude rate of malaria in Amazonas was 4142.72 cases per 100,000 inhabitants between 2003 and 2012. The incidence rates for the indigenous and non-indigenous populations were 12,976.02 and 3749.82, respectively, with an indigenous population attributable fraction of only 8 %. The results of the linear regression analysis indicated a negative correlation between the two socio-economic indicators (municipal human development index (MHDI) and poverty rate) and the incidence of malaria in the period. With regard to the environmental indicators (average annual deforestation rate and percentage of areas under the influence of watercourses), the correlation with the incidence rate was positive. CONCLUSIONS: The findings underscore the importance of implementing economic and social development policies articulated with strategic actions of environmental protection and health care for the population. PMID- 26419524 TI - Mothers' decision-making during times of stress as a lone parent: a qualitative study. AB - INTRODUCTION: Little empirical evidence exists to identify the impact that a partner's absence or presence has on the mother's decision-making and her consequential help-seeking behaviour when her child is unwell. METHODS: This study used a qualitative design in three phases using focus groups and interviews to explore Army mothers' help-seeking behaviour as a lone parent when their child was unwell during the out-of-hours period. Thirty-one parents from a British Army garrison were interviewed. RESULTS: The findings demonstrated that Army life created a combination of stressors for Army mothers, which altered their help seeking behaviour when their child was unwell. When their partner was available, mothers contacted health services as a last resort, once all other avenues had been exhausted. However, in contrast, in their partners' absence, they were contacted as a first resort. CONCLUSION: An algorithm was generated from the findings, which illustrates the importance of ascertaining whether the mother is alone at the time of the consultation. Increased emotional vulnerability intensified the need for reassurance and affected a mother's decision-making ability. Primary healthcare staff should ascertain whether mothers are currently lone parents at an early stage of their assessment, as this may influence the entire consultation. PMID- 26419525 TI - Gestation under chronic constant light leads to extensive gene expression changes in the fetal rat liver. AB - Recent reports account for altered metabolism in adult offspring from pregnancy subjected to abnormal photoperiod, suggesting fetal programming of liver physiology. To generate a pipeline of subsequent mechanistic experiments addressing strong candidate genes, here we investigated the effects of constant gestational light on the fetal liver transcriptome. At 10 days of gestation, dams were randomized in two groups (n = 7 each): constant light (LL) and normal photoperiod (12 h light/12 h dark; LD). At 18 days of gestation, RNA was isolated from the fetal liver and subjected to DNA microarray (Affymetrix platform for 28,000 genes). Selected differential mRNAs were validated by quantitative PCR (qPCR), while integrated transcriptional changes were analyzed with Ingenuity Pathway Analysis and other bioinformatics tools. Comparison of LL relative to LD fetal liver led to the following findings. Significant differential expression was found for 3,431 transcripts (1,960 upregulated and 1,471 downregulated), with 393 of them displaying >= 1.5-fold change. We validated 27 selected transcripts by qPCR, which displayed fold-change values highly correlated with microarray (r(2) = 0.91). Different markers of nonalcoholic fatty liver disease were either upregulated (e.g., Ndn and Pnpla3) or downregulated (e.g., Gnmt, Bhmt1/2, Sult1a1, Mpo, and Mat1a). Diverse pathways were altered, including hematopoiesis, coagulation cascade, complement system, and carbohydrate and lipid metabolism. The microRNAs 7a-1, 431, 146a, and 153 were upregulated, while the abundant hepatic miRNA 122 was downregulated. Constant gestational light induced extensive modification of the fetal liver transcriptome. A number of differentially expressed transcripts belong to fundamental functional pathways, potentially contributing to long-term liver disease. PMID- 26419526 TI - Regional inequalities in self-rated health and disability in younger and older generations in Turkey: the contribution of wealth and education. AB - BACKGROUND: In Turkey, large regional inequalities were found in maternal and child health. Yet, evidence on regional inequalities in adult health in Turkey remains fragmentary. This study aims to assess regional and rural/urban inequalities in the prevalence of poor self-rated health and in disability among adult populations in Turkey, and to measure the contribution of education and wealth of individual residents. The central hypothesis was that geographical inequalities in adult health exist even when the effect of education and wealth were taken into account. METHODS: We analyzed data of the 2002 World Health Survey for Turkey on 10791 adults aged 20 years and over. We measured respondents' rating of their own general health and the prevalence of five types of physical disability. Logistic regression was used to estimate how much these two health outcomes varied according to urban/rural place of residence, region, education level and household wealth. We stratified the analyses by gender and age (<50 and >=50 years). RESULTS: Both health outcomes were strongly associated with educational level (especially for older age group) and with household wealth (especially for younger age group). Both health outcomes also varied according to region and rural/urban place of residence. Higher prevalence rates were observed in the East region (compared to West) with odd ratios varying between 1.40-2.76. After controlling for education and wealth, urban/rural differences in health disappeared, while regional differences were observed only among older women. The prevalence of poor self-rated health was higher for older women in the Middle (OR = 1.69), Black Sea (OR = 1.53) and East (OR = 2.06) regions. CONCLUSION: In Turkey, substantial geographical inequalities in self-reported adult health do exist, but can mostly be explained by differences in socioeconomic characteristics of residents. The regional disadvantage of older women in the East, Middle and Black Sea may have resulted from life-long exposure to gender discrimination under a patriarchal ideology. Yet, not geographic inequalities, but the more fundamental socioeconomic inequalities, are of key public health concern, also in Turkey. PMID- 26419528 TI - National Survey of Neurologists for Transient Ischemic Attack Risk Stratification Consensus and Appropriate Treatment for a Given Level of Risks. AB - BACKGROUND: Patients with a new transient ischemic attack (TIA) have a 5% subsequent stroke risk within 7 days. The Canadian TIA Score accurately determines the risk of subsequent stroke risk; however, it is unclear if physicians will use this new scale or how it will be used. Our objectives were to assess: (1) anticipated use; (2) component face validity; (3) risk strata for stroke within 7 days; and (4) actions required, for a given risk for subsequent stroke based on the proposed Canadian TIA Score. METHODS: After a rigorous development process (sample selection, key informant interviews, development of questionnaire following Dillman Tailored Design technique, cognitive interviews, and pilot-testing), a survey questionnaire was administered to a random sample of 300 neurologists selected from all neurologists listed in a national medical directory. The surveys were distributed using a modified Dillman technique. RESULTS: From a total of 265 eligible surveys, we received 140 (52.8%) completed surveys; 7 of 13 components comprising the Canadian TIA Score were rated as "very important" or "important" by survey respondents. Risk categories for subsequent stroke were defined as: minimal risk: less than 1%; low risk: 2%-4.9%; high risk: 5%-10%; critical risk: more than 10% risk of subsequent stroke within 7 days. Most (87.1%) of the neurologists would use a validated Canadian TIA Score. CONCLUSIONS: Neurologists appear ready to use a validated Canadian TIA Score in their clinical practice. Risk strata are definable, which may allow physicians to determine immediate actions, based on subsequent stroke risk. PMID- 26419527 TI - Protocol Deviations before and after Treatment with Intravenous Tissue Plasminogen Activator in Community Hospitals. AB - BACKGROUND: Protocol deviations before and after tissue plasminogen activator (tPA) treatment for ischemic stroke are common. It is unclear if patient or hospital factors predict protocol deviations. We examined predictors of protocol deviations and the effects of protocol violations on symptomatic intracerebral hemorrhage (sICH). METHODS: We used data from the Increasing Stroke Treatment through Interventional Behavior Change Tactics trial, a cluster-randomized, controlled trial evaluating the efficacy of a barrier assessment and educational intervention to increase appropriate tPA use in 24 Michigan community hospitals, to review tPA treatments between 2007 and 2010. Protocol violations were defined as deviations from the standard tPA protocol, both before and after treatment. Multilevel logistic regression models were fitted to determine if patient and hospital variables were associated with pretreatment or post-treatment protocol deviations. RESULTS: During the study, 557 patients (mean age 70, 52% male, median National Institutes of Health Stroke Scale score 12) were treated with tPA. Protocol deviations occurred in 233 (42%) patients: 16% had pretreatment deviations, 35% had post-treatment deviations, and 9% had both. The most common protocol deviations included elevated post-treatment blood pressure, antithrombotic agent use within 24 hours of treatment, and elevated pretreatment blood pressure. Protocol deviations were not associated with sICH, stroke severity, or hospital factors. Older age was associated with pretreatment protocol deviations (adjusted odds ratio [OR], .52; 95% confidence interval [CI], .30-.92). Pretreatment deviations were associated with post-treatment deviations (adjusted OR, 3.20; 95% CI, 1.91-5.35). CONCLUSIONS: Protocol deviations were not associated with sICH. Aside from age, patient and hospital factors were not associated with protocol deviations. PMID- 26419529 TI - Causes of Excessive Daytime Sleepiness in Patients with Acute Stroke--A Polysomnographic Study. AB - BACKGROUND: Sleep disorders are common in stroke patients. Sleep-disordered breathing (SDB), which is present in up to 72% of stroke patients, is the most frequent cause of excessive daytime sleepiness (EDS) in common population. The aim of this study was to assess the frequency of EDS in stroke patients and to analyze the impact of SDB, stroke severity, and location of stroke on EDS in the acute phase of stroke. METHODS: We enrolled 102 patients with the clinical diagnosis of acute stroke. Baseline clinical characteristics were recorded on admission. An Epworth sleepiness scale score higher than 9 was considered as EDS. To detect SDB, we performed standard overnight polysomnography within 4 +/- 2 days after the stroke onset. RESULTS: EDS was present in 21 patients (20.6%). In a population with EDS, we found a significantly higher number of obstructive apneic pauses, central apneic pauses, as well as significantly higher values of respiratory disturbance index (RDI), RDI during nonrapid eye movement sleep, desaturation index, and significant decrease of REM sleep duration. RDI (odds ratio [OR], 1.031; 95% confidence interval [CI], 1.007-1.056; P = .01) and duration of REM sleep (OR, .922; 95% CI, .853-.997; P = .042) were the only independent variables significantly associated with EDS in a binary multivariate regression model. CONCLUSION: SDB is a common, significant, and treatable cause of EDS in acute stroke patients. We suppose that examination in sleep laboratories is reasonable in all stroke patients with EDS, although the impact of SDB therapy on EDS and overall outcome in acute stroke remains unknown. PMID- 26419530 TI - The effect of oleic acid on the synthesis of Fe(3-x)O4 nanoparticles over a wide size range. AB - This work reports on the effect of the oleic acid concentration on the magnetic and structural properties of Fe3-xO4 nanoparticles synthesized by thermal decomposition of Fe(acac)3 in benzyl-ether. This method allows the synthesis of highly monodisperse particles ranging from 7 to 100 nm in size by only varying the concentration of oleic acid in the reaction mixture. The structural and magnetic characterization reveal homogeneous particles in composition, with narrow particle size distribution, which are single-phase magnetite with almost bulk-like values of the saturation magnetization of about 90-99 emu g(-1) at low temperatures and show the characteristic anomaly in the zero field-cooling magnetization curves associated with the Verwey transition for nanoparticles bigger than about 7 nm. In addition, the analyses of aliquots of the reaction mixtures by Fourier transform infrared spectroscopy at various stages shed light on the nucleation and growth processes of the particles. PMID- 26419531 TI - Cultivation of stable, reproducible microbial communities from different fecal donors using minibioreactor arrays (MBRAs). AB - BACKGROUND: Continuous-flow culture models are one tool for studying complex interactions between members of human fecal microbiotas because they allow studies to be completed during an extended period of time under conditions where pH, nutrient availability, and washout of waste products and dead cells can be controlled. Because many of the existing well-validated continuous-flow models are large and complex, we were interested in developing a simpler continuous-flow system that would allow microbial community dynamics to be examined in higher throughput while still maintaining complex microbial communities. To this end, we developed minibioreactor arrays (MBRAs), small volume bioreactors (15 ml) that allow simultaneous cultivation of up to 48 microbial communities in a single anaerobic chamber. RESULTS: We used MBRA to characterize the microbial community dynamics of replicate reactors inoculated from three different human fecal donors and reactors seeded with feces pooled from these three donors. We found that MBRA could be used to efficiently cultivate complex microbial communities that were a subset of the initial fecal inoculum (15-25 % of fecal OTUs initially observed). After an initial acclimation period of approximately 1 week, communities in each reactor stabilized and exhibited day-to-day variation similar to that observed in stable mouse fecal communities. Replicate reactors were predominately populated by shared core microbial communities; variation between replicate reactors was primarily driven by shifts in abundance of shared operational taxonomic units (OTUs). Consistent with differences between fecal donors, MBRA communities present in reactors seeded with different fecal samples had distinct composition and structure. CONCLUSIONS: From these analyses, we conclude that MBRAs can be used to cultivate communities that recapitulate key features of human fecal communities and are a useful tool to facilitate higher-throughput studies of the dynamics of these communities. PMID- 26419532 TI - Evaluation of the use of clinical decision support and online resources for pharmacogenomics education. AB - AIM: To assess impact and value of using clinical decision support (CDS) to drive providers toward online pharmacogenomics education. MATERIALS & METHODS: CDS was used to target prescribers of codeine/tramadol, send an educational email, display alert/inbox and provide links to an online resource. Providers were surveyed to assess impact. RESULTS: Of the methods used to target providers, educational email was more effective (7.2%). Survey response rate was 29.2% (n = 528/1817). Of respondents, 57.4% reported opening the email and 27.1% accessed the online resource. Of those accessing the resource, 89% found it useful and learned something new about pharmacogenomics. CONCLUSION: The impact of using CDS to target pharmacogenomics education was limited. However, providers accessing the online resource found it useful and educational. PMID- 26419534 TI - Intensive care in a private hospital: An option for emergency medicine trainees? PMID- 26419533 TI - Motives for dish choices during home meal preparation: results from a large sample of the NutriNet-Sante study. AB - BACKGROUND: Although culinary practices have strongly evolved over time, few data are available on contemporary dish choices during meal preparation. We therefore sought to determine individual motives when choosing dishes to be prepared during weekdays and on weekends. METHODS: The importance of 27 criteria related to dish choices was assessed in 53,025 participants in the NutriNet-Sante study. Dimensions of dish choice motives were investigated using exploratory factor analysis. Mean ratings of motives during weekdays and on weekends were compared using Student's t-test. Association between socio-demographic and cooking practice characteristics, and dish choice motives were evaluated using logistic regression models. RESULTS: Five dimensions of dish choice motives emerged: healthy diet (explained variance: 48.3%), constraints (19.0%), pleasure (12.1%), specific diets (11.0%) and organization (9.6%). The healthy diet factor was the most important on weekdays (mean rating 3.93) and weekends (3.90). Pleasure (3.61) had a higher score than constraints (3.54) on weekends (p < 0.0001) while the opposite was observed on weekdays (3.42 vs 3.77, respectively) (p < 0.0001). Organization was more important on weekdays (2.89) than on weekends (2.75) (p < 0.0001). Dish choice motives appeared to be significantly associated with socio demographic and cooking practice characteristics. CONCLUSION: This study highlighted factors involved in dish choices in meal preparation on weekdays and weekends, as well as individual characteristics which determine motives for dish choices. From a public health perspective, these findings might help to develop appropriate strategies for promoting home meal preparation. PMID- 26419535 TI - Root causes for delayed hospital discharge in patients with ST-segment Myocardial Infarction (STEMI): a qualitative analysis. AB - BACKGROUND: The majority of patients who suffer a ST-segment myocardial infarction (STEMI) are hospitalized for longer than 48 h. With the advent of reperfusion therapy, the benefits of such extended hospitalization has been questioned. The goal of this qualitative study was to identify the root causes for prolonged hospitalization in STEMI patients in order to refine future interventions to optimize the length of hospitalization. METHODS: Practitioners involved in the discharge process for STEMI patients at a single tertiary care STEMI center underwent semi-structured interviews focused on three fictional patient cases. Data were transcribed and analyzed for key themes by thematic analysis. RESULTS: Interviews were conducted with 17 practitioners (5 Attending Physicians, 4 Internal Medicine Residents, 4 Cardiology Residents, 4 Nursing Staff). The key themes were patient factors, provider factors, and transitions to outpatient care. Patient factors included concerns that early discharge would limit dose titration of medications, the educational experience of the patient, and prevent monitoring for complications. Provider factors included past clinical experience with STEMI complications, in turn impacting discharging behaviour. Transitions of care factors were difficulty in establishing reliable follow-up plans and home care services. CONCLUSIONS: Several themes were identified that influence the timing of discharge post STEMI. The majority of these issues are not incorporated into currently available post STEMI risk stratification tools. Future quality improvement interventions to reduce STEMI length of stay should focus on in-patient and out-patient strategies to address these unique clinical situations. PMID- 26419536 TI - Causes of end stage renal failure among haemodialysis patients in Khartoum State/Sudan. AB - BACKGROUND: End stage renal failure (ESRF) has become a major health problem in Sub Saharan Africa (SSA). There were limited data about causes of ESRF in the Sudan. METHODS: This is a cross sectional hospital based descriptive study. The subjects of the study are ESRF adults' patients on regular haemodialysis treatment in 15 haemdoialysis centres in Khartoum State-Sudan. Clinical and epidemiological data were obtained from 1583 patients. The medical files of each patient were reviewed to identify the cause of ESRF. Concerning the causes of ESRF, diabetes was diagnosed based on the past medical history and result of the glucose tolerance test, hypertension was diagnosed based on past history of hypertension based on blood pressure of more than 140/90 mmHg, glomerulonephritis was diagnosed based on results of previous kidney biopsies and on clinical grounds, polycystic kidney disease and obstructive uropathy were diagnosed based on abdominal ultrasound and other imaging modalities, sickle cell anaemia was diagnosed based on the result of haemoglobin electrophoresis, systemic lupus erythematosus was diagnosed based on the clinical criteria in addition to lab results of auto antibodies, and analgesic nephropathy was diagnosed based on past medical history of chronic analgesic drugs usage with no other identifiable risk factors. We included all ESRF patients on regular haemodialysis treatment. We excluded ESRF patients less than 18 years old. RESULTS: The results showed that the mean age of ESRF Patients was 49 +/- 15.8 (years) and 63.4% were male and 76.3% were unemployed. The mean duration of haemodialysis is 4.38 +/- 4.24 (years). The most common cause of ESRF in our patients was hypertension (34.6%) followed by chronic glomerulonephritis (17.6%), diabetes mellitus (12.8%), obstructive uropathy (9.6 %), autosomal dominant poly cystic kidney disease (ADPKD) (4.7%), chronic pyelonephritis (4.6%), analgesic nephropathy (3.5%). However in (10.7%) no cause was found. In patient aged less than 40 years old the leading cause of ESRF was glomerulonephritis (29.3%) followed by hypertension (25%). In patient aged between 40 to 60 years old the leading cause of ESRF was hypertension (38.5%) followed by diabetes mellitus (14%). In patient aged older than 60 years the leading cause of ESRF was hypertension (38.4%) followed by diabetes mellitus (23.3%). CONCLUSIONS: ESRF in Sudan affects the economically productive age group; unemployment rate among ESRF patients is high. The study showed that hypertension is a leading cause of ESRF in Sudan followed by chronic glomerulonephritis. Hypertension and diabetes mellitus are the leading causes of ESRF among patients over 40 years old. PMID- 26419538 TI - In vitro/in vivo correlations in transdermal product development. AB - As per the US FDA's guidance for industry entitled 'Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations', in vitro-in vivo correlations (IVIVC) can be used to establish a dissolution test as a surrogate for human bioequivalence studies and certain scale-up and postapproval changes. However, at the present time, establishment of a transdermal IVIVC is not used to support biowaiver claims in late phases of clinical development or postapproval changes (major formulation changes, i.e., >10% changes in inactive ingredients) to the best of the authors' knowledge. The value of developing an IVIVC for percutaneous drugs lies mainly in facilitating permeation testing of transdermal drug candidates and formulation performance optimization at much lower cost as compared with carrying out multiple in vivo studies. The present article will introduce the concept of transdermal IVIVC, outlining certain limitations to its applicability, in vitro and in vivo methods, regulatory product development requirements and the most common approaches to establish an IVIVC for a transdermal drug. Additionally, this article will also summarize some challenges and recent advancements in this field, along with selected academic examples of transdermal IVIVCs. PMID- 26419539 TI - Palladium(II) complexes featuring a mixed phosphine-pyridine-iminophosphorane pincer ligand: synthesis and reactivity. AB - An original mixed ligand (labelled L) of formula PPh2-CH2-Pyr-CH2-N[double bond, length as m-dash]PPh3, combining a pyridine core with phosphine and iminophosphorane, was synthesised. Its coordination with palladium(II) centers was studied. With [Pd(COD)Cl2], a cationic complex [LPdCl](Cl) 1, where L is coordinated in the pincer mode, was obtained. Chloride abstraction with silver salt in the presence of pyridine generated the dicationic complex [LPd(py)](BF4)2 (2). When reacting with a base such as potassium hexamethyldisilazane (KHMDS), 1 gave the neutral complex 3 [L*PdCl], wherein the benzylic position alpha to phosphine was selectively deprotonated, which induced dearomatisation of the pyridine ring. A similar complex [L*Pd(CH3)] (4) was obtained upon a reaction of [Pd(CH3)2(TMEDA)] and Lvia the departure of methane. Neutral complexes with the deprotonated ligand such as 3 yielded in the presence of deuterated methanol the corresponding deuterated complex, showing that the protonation is reversible with this ligand. Finally, upon attempting to dealkylate complex 4 using B(C6F5)3, an unexpected zwitterionic borated complex 5, resulting from the formation of a C-B bond in the benzylic position with restoration of the aromatic character of the pyridine, was isolated. Interestingly, when the metal was introduced after the ligand interacted with the borane reagent, another palladium complex formed, namely, [LPdMe][MeB(C6F5)3], originating from methyl abstraction. PMID- 26419537 TI - Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF 16/FOXO target gene expression. AB - BACKGROUND: Many neurodegenerative diseases are associated with protein misfolding/aggregation. Treatments mitigating the effects of such common pathological processes, rather than disease-specific symptoms, therefore have general therapeutic potential. RESULTS: Here we report that the anti-epileptic drug ethosuximide rescues the short lifespan and chemosensory defects exhibited by C. elegans null mutants of dnj-14, the worm orthologue of the DNAJC5 gene mutated in autosomal-dominant adult-onset neuronal ceroid lipofuscinosis. It also ameliorates the locomotion impairment and short lifespan of worms expressing a human Tau mutant that causes frontotemporal dementia. Transcriptomic analysis revealed a highly significant up-regulation of DAF-16/FOXO target genes in response to ethosuximide; and indeed RNAi knockdown of daf-16 abolished the therapeutic effect of ethosuximide in the worm dnj-14 model. Importantly, ethosuximide also increased the expression of classical FOXO target genes and reduced protein aggregation in mammalian neuronal cells. CONCLUSIONS: We have revealed a conserved neuroprotective mechanism of action of ethosuximide from worms to mammalian neurons. Future experiments in mouse neurodegeneration models will be important to confirm the repurposing potential of this well-established anti-epileptic drug for treatment of human neurodegenerative diseases. PMID- 26419540 TI - Competencies in Occupational and Environmental Health Nursing. PMID- 26419541 TI - Ebola Update. AB - The Ebola virus disease first appeared in 1976 in the Sudan and the Democratic Republic of Congo. The most recent outbreak occurred in West Africa in March 2014 and quickly spread in surrounding countries. Ebola spreads through direct contact with the body fluids of an infected individual. The incubation period for Ebola is 2 to 21 days. Individuals are infectious when symptomatic. Identifying individuals at high risk for Ebola in the United States includes early recognition of symptoms and a history of travel to an Ebola-affected area. Multiple diagnostic tests exist and should include a complete blood count and a comprehensive metabolic profile. Standard, contact, and droplet precautions are advised when taking care of patients with Ebola. Appropriate personal protective equipment as recommended by the Centers for Disease Control and Prevention should be worn. No vaccine or antiviral drug has been approved, but vaccine trials are under way. Occupational health nurses play a key role in educating employees about this disease. PMID- 26419542 TI - Health Effects of Vanpooling to Work. AB - Shared commutes to work, such as vanpooling, benefit the environment and provide economic gain for riders in terms of fuel costs, parking fees, and personal vehicle wear and tear. Although ride sharing is commonly believed to promote health through stress reduction, published evidence on this topic is limited, and findings vary. This study explored the perceived health and well-being of vanpoolers using a qualitative, descriptive design. Five focus groups of vanpoolers and two individual interviews with drivers were conducted (N=40 participants). Stress, change in sleep patterns, and interpersonal relationships emerged as major themes. Employee insights about the impact of vanpooling on work productivity and how employer commitment to the vanpool program influences the vanpool experience also were important findings. PMID- 26419543 TI - Formaldehyde Level in Anatomy Laboratory Teaching Room and Risk for Cancer. PMID- 26419544 TI - AAOHN Competencies. AB - The AAOHN Competency document is one of the core documents that define occupational health nursing practice. This article provides a description of the process used to update the competencies, as well as a description of the new competencies. PMID- 26419545 TI - Nanobiotechnological Approaches Against Multidrug Resistant Bacterial Pathogens: An Update. AB - Multiple drug resistant bacteria remain the greatest challenge in public health care. Globally, infections produced by such resistant strains are on the rise. Recent advent of genetic tolerance to antibiotics in many pathogens such as multiple drug resistant Staphylococcus aureus is a matter of concern, prompting researchers and pharmaceutical companies to search for new molecules and unconventional antibacterial agents. Recent advances in nanotechnology offer new opportunities to develop formulations based on metallic nanoparticles with different shapes and sizes and variable antimicrobial properties. This article is an extensive literature review that covers the latest approaches in the development of new and unconventional antibacterial agents using nanobiotechnological approaches which will better equip scientists and clinicians to face the challenges in view of dwindling stocks of effective and potent antimicrobial agents and formulations. PMID- 26419546 TI - Fumonisins: oxidative stress-mediated toxicity and metabolism in vivo and in vitro. AB - Fumonisins (FBs) are widespread Fusarium toxins commonly found as corn contaminants. FBs could cause a variety of diseases in animals and humans, such as hepatotoxic, nephrotoxic, hepatocarcinogenic and cytotoxic effects in mammals. To date, almost no review has addressed the toxicity of FBs in relation to oxidative stress and their metabolism. The focus of this article is primarily intended to summarize the progress in research associated with oxidative stress as a plausible mechanism for FB-induced toxicity as well as the metabolism. The present review showed that studies have been carried out over the last three decades to elucidate the production of reactive oxygen species (ROS) and oxidative stress as a result of FBs treatment and have correlated them with various types of FBs toxicity, indicating that oxidative stress plays critical roles in the toxicity of FBs. The major metabolic pathways of FBs are hydrolysis, acylation and transamination. Ceramide synthase, carboxylesterase FumD and aminotransferase FumI could degrade FB1 and FB2. The cecal microbiota of pigs and alkaline processing such as nixtamalization can also transform FB1 into metabolites. Most of the metabolites of FB1 were less toxic than FB1, except its partial (pHFB1) metabolites. Further understanding of the role of oxidative stress in FB-induced toxicity will throw new light on the use of antioxidants, scavengers of ROS, as well as on the blind spots of metabolism and the metabolizing enzymes of FBs. The present review might contribute to reveal the toxicity of FBs and help to protect against their oxidative damage. PMID- 26419548 TI - Deciding what really matters. AB - England's chief nursing officer (CNO) Jane Cummings has called for senior nurses and other healthcare professionals to engage with the development of a strategy to follow Compassion in Practice ( page 7 ). PMID- 26419547 TI - Trans-scleral diode laser cyclophotocoagulation for refractory glaucoma after high-risk penetrating keratoplasty. AB - To analyze the intraocular pressure reduction, number of anti-glaucoma medications needed, and post-operative complications of trans-scleral diode laser cyclophotocoagulation (DCPC) in patients with high-risk penetrating keratoplasty (PKP) and secondary refractory glaucoma. Prospective interventional, longitudinal, non-comparative series of cases, including 16 eyes of 15 patient's post-PKP on maximal anti-glaucoma medical therapy with intraocular pressures above 22 mmHg. All patients received 18 shots, 360 degrees peri-limbal (avoiding the long posterior ciliary nerves and arteries at 3 and 9 o'clock positions) of trans-scleral DCPC (2000 mW, time: 2.0 s/shot). There was a 55.5 % reduction (total of 14.0 mmHg) of the mean pre-operative IOP (31.5 mmHg) after the first diode laser application (p = 0.0020). Re-treatment was required in 31.2 % of eyes over a mean period of 10.7 months. In these five eyes, the mean pre-operative IOP was 40.4 mmHg, which decreased to 15.0 mmHg post-therapy, and a mean IOP reduction of 25.4 mmHg (p = 0.0218). There was a 51.0 % reduction in the mean number of medications used after the first, and a 57.1 % reduction after a second laser application. The incidence of failure (IOP >= 22 mmHg or need of additional medical therapy) from initial intervention to loss of follow-up was 1.3 % per person-month. DCPC effectively reduces the intraocular pressure and the number of anti-glaucoma medications with few complications in patients after high-risk PKP and secondary glaucoma. Only, one-third of the eyes needed a second intervention to control the intraocular pressure. Post-DCPC complications were limited to phthisis bulbi and endothelial dysfunction, one eye each. Please check and confirm the author names and initials are correct. Also, kindly confirm the details in the metadata are correct. PMID- 26419549 TI - Providers to face monthly monitoring over agency spends. AB - MONITOR AND the NHS Trust Development Authority have published rules to help NHS providers cut the cost of employing agency staff. PMID- 26419550 TI - Films show loud music interferes with smooth operation of theatres. AB - LOUD MUSIC played in operating theatres hinders the ability of nurses to hear instructions, a study has shown. PMID- 26419551 TI - Standards for pain management unveiled by college forum. AB - THE RCN has launched a knowledge and skills framework to help nursing teams assess and manage pain. PMID- 26419554 TI - Chief nurse welcomes topics for next nursing strategy. AB - ENGLAND'S CHIEF nurse Jane Cummings is urging nurses to advise her on the focus of the next nursing strategy. PMID- 26419553 TI - L5 million initiative to cut staff absence announced. AB - A DRIVE to improve NHS staff health will fail unless one of the main causes of stress, namely lack of staff, is tackled, say unions. PMID- 26419555 TI - Online health records offer patients chance to correct their notes. AB - PATIENTS WILL be able by 2018 to access their entire health records electronically and add their own notes, the health secretary has announced. PMID- 26419556 TI - Political influence. AB - SENIOR NURSES in Northern Ireland are to be trained in political influencing to help them understand better the political landscape of the country, and how they can help to shape policy on behalf of nurses and nursing. PMID- 26419557 TI - Chief nursing officer for Ireland aims to 'bring nurses together'. AB - WHEN IRELAND'S chief nursing officer (CNO) Siobhan O'Halloran was appointed to her post two years ago this month, she was determined to join nurses together, not just between the different nursing branches but geographically too. PMID- 26419558 TI - Benefits of a narrative culture. AB - LOOKING BACK over the past 20 years, the healthcare challenges we faced then are similar to those we face now. They may be heightened, but they still concern quality and safety, healthcare equity, cost constraints, and regulatory requirements. PMID- 26419565 TI - Vantage point - A 'wicked' problem. AB - SENIOR NURSES everywhere are facing a 'wicked' problem, wicked in the sense that it seems to defy resolution. The problem is this: the national shortage of nurses, particularly of those at band 5, is forcing us to use agency nurses so that we have enough staff to provide patient care safely. PMID- 26419566 TI - Community question. AB - THE BED manager scanned the whiteboard in the busy office of an acute psychiatric ward. 'What about this man, WL?' she asked. 'He's been in for nearly two weeks. Can he go on weekend leave?' The nurse in charge was sceptical, but an urgent admission was imminent, and there was no room. So WL was informed that he was ready for a trial period at home, and his bed was swiftly changed for the new arrival. Such is life in the inner-city psychiatric ward, where demand relentlessly exceeds supply. PMID- 26419568 TI - Beat (Beat Eating Disorders). AB - This charity website provides a comprehensive range of information on eating disorders. There is an overview section about different types of eating disorders, which is in clear and easily understood terms, giving readers the option to seek more detailed information. PMID- 26419569 TI - Deprivation of liberty. PMID- 26419570 TI - Emotional wellbeing. PMID- 26419571 TI - Social network. AB - The Better Care Exchange is a social network for health and social care professionals that enables information and knowledge sharing on good practice and better integrated care, and the implementation of Better Care Fund plans. PMID- 26419572 TI - Consultations. PMID- 26419573 TI - Inspiring undergraduates towards a career in community nursing. AB - This article is based on the findings of a literature review commissioned by the Queen's Nursing Institute Scotland as part of its commitment to promote an evidence-based educational policy. An analysis of the literature suggests that there is potential to expand the provision of community placements beyond traditional clinical areas and these placements should be identified and overseen in collaboration with managers, mentors and higher education institutions to ensure a consistent approach and a positive learning experience. This may inspire undergraduate nurses to pursue a career in community nursing. Currently, there is little evidence to support models. High-quality evaluation research is required to ensure that new models are developed using a sound evidence base. PMID- 26419574 TI - Nurse practitioners changing health behaviours: one patient at a time. AB - In 2005, legislation was enacted allowing nurse practitioners (NPs) to practise in British Columbia, Canada. Although substantial human and financial resources had been dedicated to the implementation of the role, no evaluation has been conducted to date. As part of a larger multiphase, mixed-methods study design, which evaluated the integration of NPs into the British Columbia healthcare system, this article describes findings related to changes that result for patients and the implications for the healthcare system when NPs become part of the care process. Using survey and interview data, themes that emerged were patient satisfaction, access to care, and behavioural changes. Findings suggest that patients are satisfied with the care they receive from NPs and that NPs make positive changes to health behaviour. PMID- 26419575 TI - Revalidation: implications for senior nurses. AB - Revalidation replaces the current triennial self-declaration system of maintaining nurse registration. It involves a third-party affirmation process designed to improve public and patient confidence that nurses remain up to date by undertaking relevant professional development activities. While revalidation is ultimately the responsibility of individual nurses, senior nurses have an important facilitating role in ensuring that registrants can remain on the register and so continue to practise. This article outlines, from a practical perspective, the senior nurse's role and responsibilities in supporting registrants through each stage of the revalidation process. PMID- 26419576 TI - 'I wanted to be boss'. AB - The ability to decide what has to be done now and what can wait has served Royal Blackburn Hospital matron for medicine and the medical admissions unit Lesley Gaw well in the three decades that she's been scaling the leadership ladder. But it could all have been so different, as Jennifer Trueland discovered when she met the innovative nurse manager. PMID- 26419577 TI - Benefits of a Dual Chemical and Physical Activation: Direct aza-Michael Addition of Anilines Promoted by Solvent Effect under High Pressure. AB - The unique combination of hexafluoroisopropanol (HFIP) employed as solvent and hyperbaric conditions (10-15 kbar) allows unprecedented 1,4-addition of poor nucleophiles, such as aromatic amines, onto sluggish (cumbersome) Michael acceptors without any promoter or workup. PMID- 26419578 TI - Very Late Thrombosis of a Bioresorbable Scaffold. PMID- 26419579 TI - The "De Winter Pattern" Can Progress to ST-segment Elevation Acute Coronary Syndrome. Response. PMID- 26419580 TI - Guidelines on the Management of Implantable Cardioverter-defibrillators at the End of Life. Response. PMID- 26419581 TI - Circadian aspects of myocardial infarction among young STEMI patients. PMID- 26419582 TI - Current developments in cell- and biomaterial-based approaches for stroke repair. AB - INTRODUCTION: Stroke is one of the most devastating diseases and a leading cause of mortality worldwide. So far, clinical management of stroke involves surgical clot retrieval or thrombolytic treatment inducing reperfusion of the occluded vessels in the cerebral infarcted area, which is dependent on early intervention following insult. New treatment strategies involve the promotion of angiogenesis and neuroplasticity, stimulation of endogenous neurogenesis, remyelinization, and immunomodulation by means of cell transplantation and sustained drug delivery. AREAS COVERED: This review describes different types of stem cells (endogenous and exogenous neural progenitors, pluripotent stem cell derivatives, mesenchymal stem cells [MSCs], olfactory ensheathing cells) and biomaterials, their routes of administration, means of noninvasive imaging, and the prerequisites and hurdles for the successful translation of the cell therapies to the clinic. EXPERT OPINION: Neural precursors (NPs) derived from pluripotent stem cells, unlike MSCs, can not only remodel the CNS by promoting neuroplasticity, angiogenesis, and immunomodulation, but also replace damaged cells. To transfer NPs into the clinic, step by step guidelines for researchers are identified and discussed. PMID- 26419583 TI - Daily intake of fermented milk with Lactobacillus casei strain Shirota reduces the incidence and duration of upper respiratory tract infections in healthy middle-aged office workers. AB - PURPOSE: Although several studies have demonstrated the efficacy of probiotics for preventing upper respiratory tract infections (URTIs) in at-risk populations, including children and the elderly, few studies have investigated the efficacy of probiotics in healthy adults living normal, everyday lives. Thus, we tried to evaluate the effects of Lactobacillus casei strain Shirota-fermented milk (LcS FM) on the incidence of URTIs in healthy middle-aged office workers. METHODS: In a randomized controlled trial, 96 eligible male workers aged 30-49 years consumed LcS-FM containing 1.0 * 1011 viable LcS cells or control milk (CM) once daily for 12 weeks during the winter season. URTI episodes were evaluated by a physician via a questionnaire of URTI symptoms. RESULTS: The incidence of URTIs during the intervention period was significantly lower in the LcS-FM group than in the CM group (22.4 vs. 53.2 %, P = 0.002). The time-to-event analysis showed that the LcS-FM group had a significantly higher URTI-free rate than the CM group over the test period (log-rank test: chi 2 11.25, P = 0.0008). The cumulative number of URTI episodes and cumulative days with URTI symptoms per person was lower in the LcS-FM group, and the duration per episode was shorter. Inhibition of both reductions in NK cell activity in peripheral blood mononuclear cells and increases in salivary cortisol levels was observed in the LcS-FM group. CONCLUSION: The results suggest that the daily intake of fermented milk with LcS may reduce the risk of URTIs in healthy middle-aged office workers, probably through modulation of the immune system. PMID- 26419584 TI - Waist circumference, trunk and visceral fat cutoff values for detecting hyperinsulinemia and insulin resistance in children: the Healthy Growth Study. PMID- 26419585 TI - Food intake and inflammation in European children: the IDEFICS study. AB - PURPOSE: This cross-sectional study assesses the relationship between consumption frequencies of food items and high-sensitivity C-reactive protein (hs-CRP) in European children. METHODS: Out of the baseline sample (N = 16.228) of the IDEFICS study, 6.403 children (1.315 boys aged 2 to <6, 1.908 boys aged 6 to <10, 1.204 girls aged 2 to <6 and 1.976 girls aged 6 to <10 years) had hs-CRP measured and the Children's Eating Habits Questionnaire filled, including a food frequency questionnaire. Logistic regression adjusted for body mass index z-score, education of the mother, breast-feeding and self-reported hours of physical activity in a sport club per week was conducted. RESULTS: Mean frequency intake of raw vegetable was lower in boys (p = 0.022 in young and p = 0.020 in old) and older girls (p = 0.026) with high hs-CRP concentration, while in younger girls (p = 0.008) the same occurred with the cooked vegetables. The probability of having higher hs-CRP concentration was significantly associated with having low consumption frequency of vegetables (p = 0.004 in older boys, raw vegetables; and p = 0.0032 in younger girls, cooked vegetables). Also, honey/jam intake decreased the probability of having higher concentration of hs-CRP, whereas soft drinks with sugar, mayonnaise and cereals milled increased this probability. CONCLUSIONS: Out of all food items associated with hs-CRP, frequency intake of vegetables presented more associations across all the analysis. Findings suggest that a high-frequency intake of vegetables is inversely related to an inflammatory status in children. More studies are needed to assess the association between diet and inflammation. PMID- 26419587 TI - Erratum to: Decreasing Recurrence Rates for Ductal Carcinoma In Situ: Analysis of 2996 Women Treated with Breast-Conserving Surgery Over 30 Years. PMID- 26419586 TI - Betaine is as effective as folate at re-synthesizing methionine for protein synthesis during moderate methionine deficiency in piglets. AB - PURPOSE: Both folate and betaine (synthesized from choline) are nutrients used to methylate homocysteine to reform the amino acid methionine following donation of its methyl group; however, it is unclear whether both remethylation pathways are of equal importance during the neonatal period when remethylation rates are high. Methionine is an indispensable amino acid that is in high demand in neonates not only for protein synthesis, but is also particularly important for transmethylation reactions, such as creatine and phosphatidylcholine synthesis. The objective of this study was to determine whether supplementation with folate, betaine, or a combination of both can equally re-synthesize methionine for protein synthesis when dietary methionine is limiting. METHODS: Piglets were fed a low methionine diet devoid of folate, choline, and betaine, and on day 6, piglets were supplemented with either folate, betaine, or folate + betaine (n = 6 per treatment) until day 10. [1-13C]-phenylalanine oxidation was measured as an indicator of methionine availability for protein synthesis both before and after 2 days of supplementation. RESULTS: Prior to supplementation, piglets had lower concentrations of plasma folate, betaine, and choline compared to baseline with no change in homocysteine. Post-supplementation, phenylalanine oxidation levels were 20-46 % lower with any methyl donor supplementation (P = 0.006) with no difference among different supplementation groups. Furthermore, both methyl donors led to similarly lower concentrations of homocysteine following supplementation (P < 0.05). CONCLUSIONS: These data demonstrate an equal capacity for betaine and folate to remethylate methionine for protein synthesis, as indicated by lower phenylalanine oxidation. PMID- 26419588 TI - AMPKalpha is essential for acute exercise-induced gene responses but not for exercise training-induced adaptations in mouse skeletal muscle. AB - Exercise training increases skeletal muscle expression of metabolic proteins improving the oxidative capacity. Adaptations in skeletal muscle by pharmacologically induced activation of 5'-AMP-activated protein kinase (AMPK) are dependent on the AMPKalpha2 subunit. We hypothesized that exercise training induced increases in exercise capacity and expression of metabolic proteins, as well as acute exercise-induced gene regulation, would be compromised in muscle specific AMPKalpha1 and -alpha2 double-knockout (mdKO) mice. An acute bout of exercise increased skeletal muscle mRNA content of cytochrome c oxidase subunit I, glucose transporter 4, and VEGF in an AMPK-dependent manner, whereas cluster of differentiation 36 and fatty acid transport protein 1 mRNA content increased similarly in AMPKalpha wild-type (WT) and mdKO mice. During 4 wk of voluntary running wheel exercise training, the AMPKalpha mdKO mice ran less than WT. Maximal running speed was lower in AMPKalpha mdKO than in WT mice but increased similarly in both genotypes with exercise training. Exercise training increased quadriceps protein content of ubiquinol-cytochrome c reductase core protein 1 (UQCRC1), cytochrome c, hexokinase II, plasma membrane fatty acid-binding protein, and citrate synthase activity more in AMPKalpha WT than in mdKO muscle. However, analysis of a subgroup of mice matched for running distance revealed that only UQCRC1 protein content increased more in WT than in mdKO mice with exercise training. Thus, AMPKalpha1 and -alpha2 subunits are important for acute exercise-induced mRNA responses of some genes and may be involved in regulating basal metabolic protein expression but seem to be less important in exercise training-induced adaptations in metabolic proteins. PMID- 26419590 TI - Effects of acute exercise on lipid content and dietary lipid uptake in liver and skeletal muscle of lean and diabetic rats. AB - Insulin resistance is associated with ectopic lipid accumulation. Physical activity improves insulin sensitivity, but the impact of exercise on lipid handling in insulin-resistant tissues remains to be elucidated. The present study characterizes the effects of acute exercise on lipid content and dietary lipid partitioning in liver and skeletal muscle of lean and diabetic rats by use of magnetic resonance spectroscopy (MRS). After baseline measurements, rats were randomized to exercise or no-exercise groups. A subset of animals was subjected to MRS directly after 1 h of treadmill running for measurement of total intrahepatocellular lipid (IHCL) and intramyocellular lipid (IMCL) content (n=7 lean and diabetic rats). The other animals were administered 13C-labeled lipids orally after treadmill visit (with or without exercise) followed by MRS measurements after 4 and 24 h to determine the 13C enrichment of IHCL and IMCL (n=8 per group). Total IHCL and IMCL content were fivefold higher in diabetic vs. lean rats (P<0.001). Exercise did not significantly affect IHCL content but reduced IMCL by 25+/-7 and 33+/-4% in lean and diabetic rats (P<0.05), respectively. Uptake of dietary lipids in liver and muscle was 2.3-fold greater in diabetic vs. lean rats (P<0.05). Prior exercise did not significantly modulate dietary lipid uptake into muscle, but in liver of both lean and diabetic rats, lipid uptake was 44% reduced after acute exercise (P<0.05). In conclusion, IMCL but not IHCL represents a viable substrate source during exercise in both lean and diabetic rats, and exercise differentially affects dietary lipid uptake in muscle and liver. PMID- 26419589 TI - Dominant negative FADD dissipates the proapoptotic signalosome of the unfolded protein response in diabetic embryopathy. AB - Endoplasmic reticulum (ER) stress and caspase 8-dependent apoptosis are two interlinked causal events in maternal diabetes-induced neural tube defects (NTDs). The inositol-requiring enzyme 1alpha (IRE1alpha) signalosome mediates the proapoptotic effect of ER stress. Diabetes increases tumor necrosis factor receptor type 1R-associated death domain (TRADD) expression. Here, we revealed two new unfolded protein response (UPR) regulators, TRADD and Fas-associated protein with death domain (FADD). TRADD interacted with both the IRE1alpha-TRAF2 ASK1 complex and FADD. In vivo overexpression of a FADD dominant negative (FADD DN) mutant lacking the death effector domain disrupted diabetes-induced IRE1alpha signalosome and suppressed ER stress and caspase 8-dependent apoptosis, leading to NTD prevention. FADD-DN abrogated ER stress markers and blocked the JNK1/2 ASK1 pathway. Diabetes-induced mitochondrial translocation of proapoptotic Bcl-2 members mitochondrial dysfunction and caspase cleavage were also alleviated by FADD-DN. In vitro TRADD overexpression triggered UPR and ER stress before manifestation of caspase 3 and caspase 8 cleavage and apoptosis. FADD-DN overexpression repressed high glucose- or TRADD overexpression-induced IRE1alpha phosphorylation, its downstream proapoptotic kinase activation and endonuclease activities, and apoptosis. FADD-DN also attenuated tunicamycin-induced UPR and ER stress. These findings suggest that TRADD participates in the IRE1alpha signalosome and induces UPR and ER stress and that the association between TRADD and FADD is essential for diabetes- or high glucose-induced UPR and ER stress. PMID- 26419591 TI - The role of HE4 for prediction of recurrence in epithelial ovarian cancer patients-results from the OVCAD study. AB - Patients with epithelial ovarian cancer (EOC) are at high risk of tumor recurrence. Human epididymis protein 4 (HE4) has been shown to be overexpressed in EOC. The primary aim of our study was to evaluate the role of HE4 in predicting recurrence in EOC patients. Furthermore, we assessed the role of HE4 in predicting recurrence after second-line chemotherapy. We retrospectively analyzed data of 92 out of 275 primary EOC patients of the multicenter project "Ovarian Cancer: Diagnosis of a silent killer" (OVCAD). The concentrations of HE4 and CA125 were determined preoperatively and 6 months after the end of platinum based first-line chemotherapy (FU) using ELISA and Luminex technique, respectively. The role of HE4 and CA125 for prediction of recurrence was determined using receiver operating characteristics (ROC) curves. Out of 92 patients included, 70 (76 %) were responders and 22 (23 %) non-responders in terms of response to platinum-based first-line chemotherapy. Median HE4 concentrations at follow-up (FU) differed between responders and non-responders (60.5 vs. 237.25 pM, p = 0.0001), respectively. The combined use of HE4 and CA125 at FU with cut-off values of 49.5 pM and 25 U/ml for HE4 and CA125, respectively, for predicting recurrence within 12 months after first-line chemotherapy performed better than HE4 or CA125 alone (area under the curve (AUC) 0.928, 95 % confidence intervals (CI) 0.838-1, p < 0.001). HE4 at FU could predict recurrence within 6 months after second-line chemotherapy (AUC 0.719, 95 % CI 0.553-0.885, p = 0.024). The combination of both elevated biomarkers revealed significantly worse estimated median progression-free survival (PFS; hazard ratio (HR) 8.14, 95 % CI 3.75-17.68, p < 0.001) and slightly worse PFS in those in whom only one biomarker was elevated (HR 1.46, 95 % CI 0.72-2.96, p = 0.292) compared to those patients in whom no biomarker was elevated. For the estimated median overall survival (OS), our analysis revealed similar results. HE4 in combination with CA125 performed better than CA125 and HE4 alone in predicting recurrence within 12 months after first-line chemotherapy. PMID- 26419592 TI - Developing strategies to predict photodynamic therapy outcome: the role of melanoma microenvironment. AB - Melanoma is among the most aggressive and treatment-resistant human skin cancer. Photodynamic therapy (PDT), a minimally invasive therapeutic modality, is a promising approach to treating melanoma. It combines a non-toxic photoactivatable drug called photosensitizer with harmless visible light to generate reactive oxygen species which mediate the antitumor effects. The aim of this review was to compile the available data about PDT on melanoma. Our comparative analysis revealed a disconnection between several hypotheses generated by in vitro therapeutic studies and in vivo and clinical assays. This fact led us to highlight new preclinical experimental platforms that mimic the complexity of tumor biology. The tumor and its stromal microenvironment have a dynamic and reciprocal interaction that plays a critical role in tumor resistance, and these interactions can be exploited for novel therapeutic targets. In this sense, we review two strategies used by photodynamic researchers: (a) developing 3D culture systems which mimic tumor architecture and (b) heterotypic cultures that resemble tumor microenvironment to favor therapeutic regimen design. After this comprehensive review of the literature, we suggest that new complementary preclinical models are required to better optimize the clinical outcome of PDT on skin melanoma. PMID- 26419594 TI - BMP10 inhibited the growth and migration of gastric cancer cells. AB - Bone morphogenetic protein 10 (BMP10), a novel member of BMP family, has been identified as an important regulator for angiogenesis. Dysregulation of BMP has been observed in several cancer types. However, its roles in gastric cancer (GC) remain unknown. In this study, the expression of BMP10 was found to be down regulated in GC samples. Forced expression of BMP10 in GC cells inhibited its growth and migration, while knocking down the expression of BMP10 in GC cells promoted cell growth, migration, and metastasis. BMP10 was shown to negatively regulated beta-catenin/TCF signaling by up-regulating Axin protein level. Taken together, the present study revealed the suppressive function of BMP10 in gastric cancer. PMID- 26419593 TI - Antimetastatic effect of fluvastatin on breast and hepatocellular carcinoma cells in relation to SGK1 and NDRG1 genes. AB - Metastasis occurs due to migration of the cells from primary tumor toward other tissues by gaining invasive properties. Since metastatic invasion shows a strong resistance against conventional cancer treatments, the studies on this issue have been focused. Within this context, inhibition of migration and determination of the relationships at the gene level will contribute to treatment of metastatic cancer cases. We have aimed to demonstrate the impact of TGF-beta1 and fluvastatin on human breast cancer (MCF-7) and human hepatocellular carcinoma (Hep3B) cell cultures via Real-Time Cell Analyzer (RTCA) and to test the expression levels of some genes (NDRG1, SGK1, TWIST1, AMPKA2) and to compare their gene expression levels according to RTCA results. Both of cell series were applied TGF-beta1 and combinations of TGF-beta1/fluvastatin. Primer and probes were synthesized using Universal Probe Library (UPL, Roche) software, and expression levels of genes were tested via qPCR using the device LightCycler 480 II (Roche). Consequently, fluvastatin dose-dependently inhibited migration induced by TGF-beta1 in both groups. This inhibition was accompanied by low level of SGK1 messenger RNA (mRNA) and high levels of NDRG1 and AMPKA2 mRNA. Thus, we conclude that fluvastatin plays an important role in reducing resistance to chemotherapeutics and preventing metastasis. PMID- 26419595 TI - Analgesic-antitumor peptide inhibits the migration and invasion of HepG2 cells by an upregulated VGSC beta1 subunit. AB - Analgesic-antitumor peptide (AGAP), one of the scorpion toxin polypeptides, has been shown to have an antitumor activity. Recombinant AGAP (rAGAP) was shown to affect the migration and invasion of HepG2 cells via a voltage-gated sodium channel (VGSC) beta1 subunit. The VGSC beta1 subunit was validated as a cell adhesion molecule (CAM) in human hepatocellular carcinoma (HCC) cell lines. rAGAP suppresses the migration and invasion of HepG2 cells but has no significant effect of human liver HL7702 cells without beta1 subunit expression. rAGAP inhibits the migration and invasion of the cells when the VGSC beta1 subunit is overexpressed in HL7702 cells. To explain these findings, VGSC beta1 subunit messenger RNA (mRNA) and protein levels were measured. The beta1 subunit protein level was upregulated in a dose-dependent manner following treatment with rAGAP while there was no significant change in the mRNA level, so rAGAP might be an active component of the VGSC beta1 subunit. PMID- 26419596 TI - Altered serum fatty acid composition in geriatric depression. AB - Fatty acids (FA), mainly polyunsaturated (PUFA) of n-3 or n-6 types, may influence neuropsychobiological processes. Decreased levels of n-3 PUFA have been shown to be related to major depression and supplementation of n-3 PUFA seems to contribute to improved depression treatment outcome. The profiles of serum FA profiles in patients with geriatric depression have not been thoroughly studied yet. The present study investigated the FA profiles of patients with geriatric depression and of mentally healthy elderly individuals. Serum FA profiles of 36 inpatients with geriatric depression who fulfilled DSM-IV criteria for unipolar major depression were compared with those of 37 control subjects. Patients with geriatric depression, irrespective of gender, exhibited lower total FAs, as well as significantly lower concentrations of total n-3 PUFA and eicosapentaenoic acid, though the groups did not differ with regard to Body Mass Index. The findings of the present study point to an association between lower FA serum levels and geriatric depression. Further investigations with larger samples and dietetic interventions may provide deeper insights into the role of eicosapentaenoic acid and total n-3 PUFA in the development and treatment of geriatric depression. PMID- 26419599 TI - Polarizable Force Field with a sigma-Hole for Liquid and Aqueous Bromomethane. AB - Bromomethane (CH3Br) is an acutely toxic environmental pollutant that contributes to ozone depletion. Molecular simulation could be a valuable tool for studying its partitioning and transport in the environment if an accurate molecular model was available. The generalized Amber force field (GAFF), OPLS (optimized potentials for liquid simulations) force field, and CHARMM general force field (CGenFF) were tested for their ability to model the physical properties of liquid bromomethane. The OPLS force field was in fairly good agreement with experiment, while CGenFF and GAFF were significantly in error. The Br Lennard-Jones parameters of the GAFF and CGenFF models were reparameterized, but their radial distribution functions still have significant deviations from those calculated by ab initio molecular dynamics (AIMD). A Drude polarizable force field for bromomethane was parametrized with an off-center positively charged site to represent the C-Br sigma-hole. This model is in good agreement with the bulk physical properties and the AIMD RDFs. The modest solubility of bromomethane was reproduced by this model, with dispersion interactions being the dominant water solute interaction. The water-solute electrostatic interactions are a smaller factor in solubility. This model predicts bromomethane to have a 13 kJ mol(-1) surface excess potential at the water-vapor interface. PMID- 26419597 TI - Driving and attention deficit hyperactivity disorder. AB - Adults with attention deficit hyperactivity disorder (ADHD) suffer from various impairments of cognitive, emotional and social functioning, which can have considerable consequences for many areas of daily living. One of those areas is driving a vehicle. Driving is an important activity of everyday life and requires an efficient interplay between multiple cognitive, perceptual, and motor skills. In the present study, a selective review of the literature on driving-related difficulties associated with ADHD is performed, seeking to answer whether individuals with ADHD show increased levels of unsafe driving behaviours, which cognitive (dys)functions of individuals with ADHD are related to driving difficulty, and whether pharmacological treatment significantly improves the driving behaviour of individuals with ADHD. The available research provides convincing evidence that individuals with ADHD have different and more adverse driving outcomes than individuals without the condition. However, it appears that not all individuals with ADHD are affected uniformly. Despite various cognitive functions being related with driving difficulties, these functions do not appear helpful in detecting high risk drivers with ADHD, nor in predicting driving outcomes in individuals with ADHD, since impairments in these functions are defining criteria for the diagnoses of ADHD (e.g., inattention and impulsivity). Pharmacological treatment of ADHD, in particular stimulant drug treatment, appears to be beneficial to the driving difficulties experienced by individuals with ADHD. However, additional research is needed, in particular further studies that address the numerous methodological weaknesses of many of the previous studies. PMID- 26419598 TI - Molecular diversity of spirooxindoles. Synthesis and biological activity. AB - Spirooxindoles are important synthetic targets possessing extended biological activity and drug discovery applications. This review focuses on the various strategies for the enantioselective synthesis of spirocyclic oxindoles relying on reports over the past decade and from earlier work. The spirooxindoles in this review are separated into three structural classes, and then further categorized into the method type from which the spirocycle is generated. PMID- 26419600 TI - Commonly-occurring polymorphisms in the COMT, DRD1 and DRD2 genes influence different aspects of motor sequence learning in humans. AB - Performing sequences of movements is a ubiquitous skill that involves dopamine transmission. However, it is unclear which components of the dopamine system contribute to which aspects of motor sequence learning. Here we used a genetic approach to investigate the relationship between different components of the dopamine system and specific aspects of sequence learning in humans. In particular, we investigated variations in genes that code for the catechol-O methyltransferase (COMT) enzyme, the dopamine transporter (DAT) and dopamine D1 and D2 receptors (DRD1 and DRD2). COMT and the DAT regulate dopamine availability in the prefrontal cortex and the striatum, respectively, two key regions recruited during learning, whereas dopamine D1 and D2 receptors are thought to be involved in long-term potentiation and depression, respectively. We show that polymorphisms in the COMT, DRD1 and DRD2 genes differentially affect behavioral performance on a sequence learning task in 161 Caucasian participants. The DRD1 polymorphism predicted the ability to learn new sequences, the DRD2 polymorphism predicted the ability to perform a previously learnt sequence after performing interfering random movements, whereas the COMT polymorphism predicted the ability to switch flexibly between two sequences. We used computer simulations to explore potential mechanisms underlying these effects, which revealed that the DRD1 and DRD2 effects are possibly related to neuroplasticity. Our prediction-error algorithm estimated faster rates of connection strengthening in genotype groups with presumably higher D1 receptor densities, and faster rates of connection weakening in genotype groups with presumably higher D2 receptor densities. Consistent with current dopamine theories, these simulations suggest that D1 mediated neuroplasticity contributes to learning to select appropriate actions, whereas D2-mediated neuroplasticity is involved in learning to inhibit incorrect action plans. However, the learning algorithm did not account for the COMT effect, suggesting that prefrontal dopamine availability might affect sequence switching via other, non-learning, mechanisms. These findings provide insight into the function of the dopamine system, which is relevant to the development of treatments for disorders such as Parkinson's disease. Our results suggest that treatments targeting dopamine D1 receptors may improve learning of novel sequences, whereas those targeting dopamine D2 receptors may improve the ability to initiate previously learned sequences of movements. PMID- 26419601 TI - Yolk hormones influence in ovo chemosensory learning, growth, and feeding behavior in domestic chicks. AB - In this study, we assessed whether prenatal exposure to elevated yolk steroid hormones can influence in ovo chemosensory learning and the behavior of domestic chicks. We simulated a maternal environmental challenge by experimentally enhancing yolk progesterone, testosterone, and estradiol concentrations in hen eggs prior to incubation. The embryos from these hormones-treated eggs (HO) as well as sham embryos (O) that had received the vehicle-only were exposed to the odor of fish oil (menhaden) between embryonic Days 11 and 20. An additional group of control embryos (C) was not exposed to the odor. All chicks were tested following hatching for their feeding preferences between foods that were or were not odorized with the menhaden odor. In the 3-min choice tests, the behavior of O chicks differed significantly according to the type of food whereas C and HO chicks showed no preference between odorized and non-odorized food. Our result suggests weaker response in HO chicks. In addition, HO chicks showed impaired growth and reduced intake of an unfamiliar food on the 24-h time scale compared to controls. Our data suggest that embryonic exposure to increased yolk hormone levels can alter growth, chemosensory learning, and the development of feeding behaviors. PMID- 26419604 TI - A novel astrovirus species in the gut of yaks with diarrhoea in the Qinghai Tibetan Plateau, 2013. AB - The yak (Bos grunniens) is an iconic symbol in the high-altitude region of the Qinghai-Tibetan Plateau. Diarrhoea is a common disease in yaks, resulting in major economic losses. To investigate the diversity of viral species, we reported the metagenomics-derived virome in a pooled faecal sample of 20 diarrhoeic yaks. The nine viruses found in the pooled diarrhoeic samples, in order of abundance of nucleic acid sequence, were influenza A virus, bovine viral diarrhoea virus (BVDV), rotavirus, ungulate tetraparvovirus 1 (bovine hokovirus), astrovirus (AstV), bovine enterovirus, hepatitis E virus, kobuvirus and woodchuck hepatitis virus. Compared with healthy yaks, only AstV had a significantly higher prevalence rate in diarrhoeal samples, indicating a correlation with the clinical symptoms of diarrhoea in yaks. To further investigate the molecular characterization of yak AstV, a near-full genome was obtained from a diarrhoeic sample. It was 6243 bp in length and shared 46.4-66.2 % similarity with other related bovine AstVs from faeces. Phylogenetic analysis of the genome demonstrated that the yak AstV fell within the bovine AstVs cluster, but was located in a unique lineage, suggesting a novel AstV species was identified in yaks. Interestingly, the ORF2 region of yak AstV had closer similarity and genetically relationship with deer AstV strain CcAstV-2 than that of the bovine AstVs. Further analysis showed that one possible interspecies recombination event occurred in ORF2. In summary, this study expanded our understanding of the viral communities of diarrhoeal yaks and identified a novel AstV that was associated with diarrhoea in yaks. PMID- 26419602 TI - Platelets and plasma stimulate sheep rotator cuff tendon tenocytes when cultured in an extracellular matrix scaffold. AB - The addition of platelet-rich plasma (PRP) to rotator cuff repair has not translated into improved outcomes after surgery. However, recent work stimulating ligament healing has demonstrated improved outcomes when PRP or whole blood is combined with an extracellular matrix carrier. The objective of this study was to evaluate the effect of three components of blood (plasma, platelets, and macrophages) on the in vitro activity of ovine rotator cuff cells cultured in an extracellular matrix environment. Tenocytes were obtained from six ovine infraspinatus tendons and cultured over 14 days in an extracellular matrix scaffold with the following additives: (1) plasma (PPP), (2) plasma and platelets (PAP), (3) plasma and macrophages (PPPM), (4) plasma, platelets and macrophages (PAPM), (5) phosphate buffered saline (PBS), and (6) PBS with macrophages (PBSM). Assays measuring cellular metabolism (AlamarBlue), proliferation (Quantitative DNA assay), synthesis of collagen and cytokines (SIRCOL, TNF-alpha and IL-10 ELISA, and MMP assay), and collagen gene expression (qPCR) were performed over the duration of the experiment, as well as histology at the conclusion. Plasma was found to stimulate cell attachment and spreading on the scaffold, as well as cellular proliferation. Platelets also stimulated cell proliferation, cellular metabolism, transition of cells to a myofibroblast phenotype, and contraction of the scaffolds. The addition of macrophages did not have any significant effect on the sheep rotator cuff cells in vitro. In vivo studies are needed to determine whether these changes in cellular function will translate into improved tendon healing. PMID- 26419605 TI - Reliability and validity of the Nurse Practitioners' Roles and Competencies Scale. AB - AIMS AND OBJECTIVES: The objective of this study was to test the reliability and construct validity of the Nurse Practitioners' Roles and Competencies Scale. BACKGROUND: The role of nurse practitioners has attracted international attention. The advanced nursing role played by nurse practitioners varies with national conditions and medical environments. To date, no suitable measurement tool has been available for assessing the roles and competencies of nurse practitioners in Asian countries. DESIGN: Secondary analysis of data from three studies related to nurse practitioners' role competencies. METHODS: We analysed data from 563 valid questionnaires completed in three studies to identify the factor structure of the Nurse Practitioners' Roles and Competencies Scale. To this end, we performed exploratory factor analysis using principal component analysis extraction with varimax orthogonal rotation. The internal consistency reliabilities of the overall scale and its subscales were examined using Cronbach's alpha coefficient. RESULTS: The scale had six factors: professionalism, direct care, clinical research, practical guidance, medical assistance, as well as leadership and reform. These factors explained 67.5% of the total variance in nurse practitioners' role competencies. Cronbach's alpha coefficient for the overall scale was 0.98, and those of its subscales ranged from 0.83-0.97. CONCLUSION: The internal consistency reliability and construct validity of the Nurse Practitioners' Roles and Competencies Scale were good. The high internal consistency reliabilities suggest item redundancy, which should be minimised by using item response theory to enhance the applicability of this questionnaire for future academic and clinical studies. RELEVANCE TO CLINICAL PRACTICE: The Nurse Practitioners' Roles and Competencies Scale can be used as a tool for assessing the roles and competencies of nurse practitioners in Taiwan. Our findings can also serve as a reference for other Asian countries to develop the nurse practitioner role. PMID- 26419606 TI - Maternal nutritional status (as measured by height, weight and BMI) in Bangladesh: trends and socio-economic association over the period 1996 to 2007. AB - OBJECTIVE: To analyse trends in maternal nutritional status in Bangladesh over a 12-year period and to examine the associations between nutritional status and socio-economic variables. DESIGN: Maternal nutritional status indicators were height, weight and BMI. Socio-economic variables used were region, residency, education and occupation of the mothers and their husbands, house type, and possession score in the household. SETTING: Bangladesh Demographic and Health Surveys (1996, 2000, 2004 and 2007) were the source of data. SUBJECTS: A total of 16 278 mothers were included. RESULTS: All of the socio-economic variables showed significant associations with maternal nutritional status indicators. Regional variation was found to be present; all three indicators were found to be lowest in the Sylhet division. Upward trends in maternal height, weight and BMI were evident from no possessions to four possessions in households, and for no education to higher education of women and their husbands. Bangladeshi mothers measured in 2007 were found to be on average 0.34 cm taller and 3.36 kg heavier than mothers measured in 1996. Between 1996 and 2007 maternal underweight fell from nearly 50 % to just over 30 % while overweight and obesity increased from about 3 % to over 9 % (WHO cut-offs) or from 7 % to nearly 18 % (Asian cut-offs). CONCLUSIONS: The study reveals that over the 12-year period in Bangladesh there has been a substantial reduction in maternal underweight accompanied by a considerable increase in obesity. It is also evident that malnutrition in Bangladesh is a multidimensional problem that warrants a proper policy mix and programme intervention. PMID- 26419608 TI - Comparison of emission estimates for non-CO2 greenhouse gases from livestock and poultry in Korea from 1990 to 2010. AB - It has often been claimed that non-carbon dioxide greenhouse gases (NCGGs), such as methane, nitrous oxide and fluorinated greenhouse gases, are significant contributors to climate change. Here we nvestigate emission estimates of methane and nitrous oxide from livestock and poultry production, which is recognized as a major source of those NCGGs, in Korea over the period of 1990 through 2010. Based on the data on livestock and poultry populations, emission estimates of methane and nitrous oxide are first derived based on the Tier 1 approach. Then, the Tier 2 approach is adopted to obtain emission estimates of methane and nitrous oxide from cattle, which are known to be the largest sources of these NCGGs and account for about 70% of emissions from livestock and poultry in Korea. The result indicates that the Tier 2 estimates of methane and nitrous oxide emissions from enteric fermentation and manure management are significantly different from the Tier 1 estimates over the analysis period. PMID- 26419607 TI - Inhibition of Beta-Amyloid Fibrillation by Luminescent Iridium(III) Complex Probes. AB - We report herein the application of kinetically inert luminescent iridium(III) complexes as dual inhibitors and probes of beta-amyloid fibrillogenesis. These iridium(III) complexes inhibited Abeta1-40 peptide aggregation in vitro, and protected against Abeta-induced cytotoxicity in neuronal cells. Furthermore, the complexes differentiated between the aggregated and unaggregated forms of Abeta1 40 peptide on the basis of their emission response. PMID- 26419610 TI - BAP1 promotes breast cancer cell proliferation and metastasis by deubiquitinating KLF5. AB - The transcription factor KLF5 is highly expressed in basal-like breast cancer and promotes breast cancer cell proliferation, survival, migration and tumour growth. Here we show that, in breast cancer cells, KLF5 is stabilized by the deubiquitinase (DUB) BAP1. With a genome-wide siRNA library screen of DUBs, we identify BAP1 as a bona fide KLF5 DUB. BAP1 interacts directly with KLF5 and stabilizes KLF5 via deubiquitination. KLF5 is in the BAP1/HCF-1 complex, and this newly identified complex promotes cell cycle progression partially by inhibiting p27 gene expression. Furthermore, BAP1 knockdown inhibits tumorigenicity and lung metastasis, which can be rescued partially by ectopic expression of KLF5. Collectively, our findings not only identify BAP1 as the DUB for KLF5, but also reveal a critical mechanism that regulates KLF5 expression in breast cancer. Our findings indicate that BAP1 could be a potential therapeutic target for breast and other cancers. PMID- 26419611 TI - Post-movement processing in visual oddball task - Evidence from intracerebral recording. AB - OBJECTIVE: To identify intracerebral sites activated after correct motor response during cognitive task and to assess associations of this activity with mental processes. METHODS: Intracerebral EEG was recorded from 205 sites of frontal, temporal and parietal lobes in 18 epileptic patients, who responded by button pressing together with mental counting to target stimuli in visual oddball task. RESULTS: Post-movement event-related potentials (ERPs) with mean latency 295 +/- 184 ms after movement were found in all subjects in 64% of sites investigated. Generators were consistently observed in mesiotemporal structures, anterior midcingulate, prefrontal, and temporal cortices. Task-variant nonspecific and target specific post-movement ERPs were identified, displaying no significant differences in distribution among generating structures. Both after correct and incorrect performances the post-performance ERPs were observed in frontal and temporal cortices with latency sensitive to error commission in several frontal regions. CONCLUSION: Mesiotemporal structures and regions in anterior midcingulate, prefrontal and temporal cortices seem to represent integral parts of network activated after correct motor response in visual oddball task with mental counting. Our results imply equivalent involvement of these structures in task-variant nonspecific and target specific processes, and suggest existence of common nodes for correct and incorrect responses. SIGNIFICANCE: Our results contribute to better understanding of neural mechanisms underlying goal-directed behavior. PMID- 26419612 TI - Bradysomnia in Parkinson's disease. AB - OBJECTIVE: Polysomnography studies in Parkinson's disease (PD) patients show altered sleep microstructure with decreased level of arousability, indicating impaired sleep-wake dynamics in PD. The aim of this study was to investigate dynamical aspects of sleep EEG in PD as compared to healthy controls. METHODS: In this retrospective, controlled study, we applied a previously established mathematical model of sleep EEG analysis (state space model) to PD patients and age- and gender-matched healthy volunteers (N=64). Dynamical aspects of sleep were quantified by measuring the spectral variability of the sleep EEG (by means of state space velocity). RESULTS: State space analysis revealed preserved global sleep-wake architecture in PD patients, but the velocity of sleep stage transitions was significantly reduced as compared to healthy controls. Correlation analysis revealed a strong association of state space velocity with arousal scores and daily dopamine agonist intake. CONCLUSIONS: Quantitative analysis of spectral sleep EEG variability (state space velocity) revealed reduced sleep-wake dynamics in PD patients as compared to control subjects. SIGNIFICANCE: We propose state space velocity as an objective and quantitative measure for altered sleep microstructure and as a potential biomarker of sleep alterations in PD, not accessible by conventional sleep analysis. PMID- 26419613 TI - Donor Properties of a New Class of Guanidinate Ligands Possessing Ketimine Backbones: A Comparative Study Using Iron. AB - Addition of 1 equiv of LiN?C(t)Bu2 or LiN?Ad (Ad = 2-adamantyl) to the aryl carbodiimide C(NDipp)2 (Dipp = 2,6-diisopropylphenyl) readily generates the lithium ketimine-guanidinates Li(THF)2[(X)C(NDipp)2] (X = N?C(t)Bu2 (1-(t)Bu), N?Ad (1-Ad)) in excellent yields. These new ligands can be readily metalated with iron to give the N,N'-bidentate chelates [{(X)C(NDipp)2}FeBr]2 (X = N?C(t)Bu2 (5 (t)Bu), N?Ad (5-Ad)), in which the ketimines behave as noncoordinating backbone substituents. In an effort to understand the potential electronic contributions of the ketimine group to the ligand architecture, a thorough structural and electronic study was conducted comparing the features and properties of 5-(t)Bu and 5-Ad to their guanidinate and amidinate analogues [{(X)C(NDipp)2}FeBr]2 (X = (i)Pr2N (6), (t)Bu (7)). Solid-state structural analyses indicate little electronic contribution from the N-ketimine nitrogen atom, while solution-phase electronic absorption spectra of 5-(t)Bu and 5-Ad are qualitatively similar to the amidinate complex 7. Yet, electrochemical measurements do show the donor properties of the ketimine-guanidinate in 5-(t)Bu to be intermediate between its guanidinate and amidinate counterparts in 6 and 7. Preliminary reactivity studies also show that the reduction chemistry of 5-(t)Bu diverges significantly from that of 6 and 7. Treatment of 5-(t)Bu with excess magnesium or 1 equiv of KC8 leads to the formation of the Fe(I)-Fe(I) complex [{MU-((t)Bu2C?N)C(NDipp)2}2Fe2] (11), which possesses an exceedingly short Fe?Fe bond (2.1516(5) A), while neither 6 nor 7 forms dinuclear complexes upon reduction. This result demonstrates that ketimine-guanidinates do not simply behave as amidinate variants but can contribute to distinctive metal chemistry of their own. PMID- 26419614 TI - Phase diagrams of dune shape and orientation depending on sand availability. AB - New evidence indicates that sand availability does not only control dune type but also the underlying dune growth mechanism and the subsequent dune orientation. Here we numerically investigate the development of bedforms in bidirectional wind regimes for two different conditions of sand availability: an erodible sand bed or a localized sand source on a non-erodible ground. These two conditions of sand availability are associated with two independent dune growth mechanisms and, for both of them, we present the complete phase diagrams of dune shape and orientation. On an erodible sand bed, linear dunes are observed over the entire parameter space. Then, the divergence angle and the transport ratio between the two winds control dune orientation and dynamics. For a localized sand source, different dune morphologies are observed depending on the wind regime. There are systematic transitions in dune shape from barchans to linear dunes extending away from the localized sand source, and vice-versa. These transitions are captured fairly by a new dimensionless parameter, which compares the ability of winds to build the dune topography in the two modes of dune orientation. PMID- 26419615 TI - A typology of people who tamper with pharmaceutical opioids: responses to introduction of a tamper-resistant formulation of controlled-release oxycodone. AB - PURPOSE: In April 2014, a tamper-resistant controlled-release oxycodone formulation was released in Australia. We aimed to determine whether there are latent classes of people who tamper with pharmaceutical opioids based on frequency of opioid and illicit drug use, the demographic and clinical profiles of these groups, and if there were changes in use and harms following the introduction. METHODS: A prospective cohort of 606 people who regularly tamper with pharmaceutical opioids was interviewed January to March 2014 (Wave 1) and May to August 2014 (Wave 2). Latent class analysis identified groups based on non prescribed opioid, illicit drug and prescribed opioid substitution therapy (OST) use at Wave 1. Regression models examined whether group membership predicted use and harms at Wave 2. RESULTS: Four groups were identified: frequent OST group (39%), mixed OST/heroin group (7%), infrequent pharmaceutical opioid and heroin group (44%) and frequent oxycodone group (25%). Compared with the frequent OST group, the infrequent pharmaceutical opioid/heroin group was more likely to report non-everyday pain and risky alcohol use, and the frequent oxycodone group had higher odds of homelessness. At Wave 2, oxycodone use decreased across groups (odds ratios (OR) <= 0.18, p < 0.001, particularly for the frequent oxycodone group: OR <= 0.05, p < 0.001), with reductions in days of use (g >= 0.35, p < 0.050). Non-prescribed pharmaceutical opioid use, illicit drug use and harms remained stable or decreased. CONCLUSIONS: Despite heterogeneity among people who tamper with pharmaceutical opioids, the tamper-resistant formulation was followed by reductions in oxycodone tampering among high-frequency and low-frequency users. There was no evidence of increased use of other opioids or illicit drugs. PMID- 26419616 TI - An unusually simple HP1 gene set in Hymenopteran insects. AB - The heterochromatin protein 1 (HP1) gene family includes a set of paralogs in higher eukaryotes that serve fundamental roles in heterochromatin structure and maintenance, and other chromatin-related functions. At least 10 full and 16 partial HP1 genes exist among Drosophila species, with multiple gene gains, losses, and sub-functionalizations within this insect group. An important question is whether this diverse set of HP1 genes and their dynamic evolution represent the standard rule in eukaryotic groups. Here we have begun to address this question by bio-informatically identifying the HP1 family genes in representative species of the insect order Hymenoptera, which includes all ants, bees, wasps, and sawflies. Compared to Drosophila species, Hymenopterans have a much simpler set of HP1 genes, including one full and two partial HP1s. All 3 genes appear to have been present in the common ancestor of the Hymenopterans and they derive from a Drosophila HP1B-like gene. In ants, a partial HP1 gene containing only a chromoshadow domain harbors amino acid changes at highly conserved sites within the PxVxL recognition region, suggesting that this gene has undergone sub-functionalization. In the jewel wasp Nasonia vitripennis, the full HP1 and partial chromoshadow-only HP1 are expressed in both germ line and somatic tissues. However, the partial chromodomain-only HP1 is expressed exclusively in the ovary and testis, suggesting that it may have a specialized chromatin role during gametogenesis. Our findings demonstrate that the HP1 gene family is much simpler and evolutionarily less dynamic within the Hymenopterans compared to the much younger Drosophila group, a pattern that may reflect major differences in the range of chromatin-related functions present in these and perhaps other insect groups. PMID- 26419617 TI - Involvement of Notch-1 in Resistance to Regorafenib in Colon Cancer Cells. AB - Regorafenib, an oral small-molecule multi kinase inhibitor, is able to block Vascular Endothelial Growth Factor Receptors (VEGFR-1, 2, and 3), Platelet Derived Growth Factor Receptors (PDGF), Fibroblast Growth Factor (FGF) receptor 1, Raf, TIE-2, and the kinases KIT, RET, and BRAF. Different studies have displayed its antitumor activity in several cancer models (both in vitro and in vivo), particularly in colorectal and gastrointestinal stromal cancers. The mechanism of resistance to regorafenib is largely unknown. In our investigation, we have generated regorafenib-resistant SW480 cells (Reg-R-SW480 cells) by culturing such cells with increasing concentration of regorafenib. Examination of intracellular signaling found that Akt signaling was activated in Reg-R-SW480 cells but not in wild-type SW480 cells, after regorafenib treatment as measured by Western Blot. The Notch pathway is a fundamental signaling system in the development and homeostasis of tissues since it regulates different cellular process such as proliferation, differentiation, and apoptosis and it can be a potential driver of resistance to a wide array of targeted therapies. In this study, we found that Notch-1 was significantly up-regulated in resistant tumor cells as well as HES1 and HEY. Additionally, inhibition of Notch-1 in resistant cells partially restored sensitivity to regorafenib treatment in vitro. Collectively, these data suggest a key role of Notch-1 in mediating the resistant effects of regorafenib in colorectal cancer cells, and also provide a rationale to improve the therapeutic efficacy of regorafenib. PMID- 26419618 TI - ZnO@SnO2 engineered composite photoanodes for dye sensitized solar cells. AB - Layered multi-oxide concept was applied for fabrication of photoanodes for dye sensitized solar cells based on ZnO and SnO2, capitalizing on the beneficial properties of each oxide. The effect of different combinations of ZnO@SnO2 layers was investigated, aimed at exploiting the high carrier mobility provided by the ZnO and the higher stability under UV irradiation pledged by SnO2. Bi-oxide photoanodes performed much better in terms of photoconversion efficiency (PCE) (4.96%) compared to bare SnO2 (1.20%) and ZnO (1.03%). Synergistic cooperation is effective for both open circuit voltage and photocurrent density: enhanced values were indeed recorded for the layered photoanode as compared with bare oxides (Voc enhanced from 0.39 V in case of bare SnO2 to 0.60 V and Jsc improved from 2.58 mA/cm(2) pertaining to single ZnO to 14.8 mA/cm(2)). Improved functional performances of the layered network were ascribable to the optimization of both high chemical capacitance (provided by the SnO2) and low recombination resistance (guaranteed by ZnO) and inhibition of back electron transfer from the SnO2 conduction band to the oxidized species of the electrolyte. Compared with previously reported results, this study testifies how a simple electrode design is powerful in enhancing the functional performances of the final device. PMID- 26419619 TI - Predicting time to castration resistance in hormone sensitive prostate cancer by a personalization algorithm based on a mechanistic model integrating patient data. AB - BACKGROUND: Prostate cancer (PCa) is a leading cause of cancer death of men worldwide. In hormone-sensitive prostate cancer (HSPC), androgen deprivation therapy (ADT) is widely used, but an eventual failure on ADT heralds the passage to the castration-resistant prostate cancer (CRPC) stage. Because predicting time to failure on ADT would allow improved planning of personal treatment strategy, we aimed to develop a predictive personalization algorithm for ADT efficacy in HSPC patients. METHODS: A mathematical mechanistic model for HSPC progression and treatment was developed based on the underlying disease dynamics (represented by prostate-specific antigen; PSA) as affected by ADT. Following fine-tuning by a dataset of ADT-treated HSPC patients, the model was embedded in an algorithm, which predicts the patient's time to biochemical failure (BF) based on clinical metrics obtained before or early in-treatment. RESULTS: The mechanistic model, including a tumor growth law with a dynamic power and an elaborate ADT-resistance mechanism, successfully retrieved individual time-courses of PSA (R(2) = 0.783). Using the personal Gleason score (GS) and PSA at diagnosis, as well as PSA dynamics from 6 months after ADT onset, and given the full ADT regimen, the personalization algorithm accurately predicted the individual time to BF of ADT in 90% of patients in the retrospective cohort (R(2) = 0.98). CONCLUSIONS: The algorithm we have developed, predicting biochemical failure based on routine clinical tests, could be especially useful for patients destined for short-lived ADT responses and quick progression to CRPC. Prospective studies must validate the utility of the algorithm for clinical decision-making. PMID- 26419620 TI - Evaluating attention in delirium: A comparison of bedside tests of attention. AB - AIM: Impaired attention is a core diagnostic feature for delirium. The present study examined the discriminating properties for patients with delirium versus those with dementia and/or no neurocognitive disorder of four objective tests of attention: digit span, vigilance "A" test, serial 7s subtraction and months of the year backwards together with global clinical subjective rating of attention. METHODS: This as a prospective study of older patients admitted consecutively in a general hospital. Participants were assessed using the Confusion Assessment Method, Delirium Rating Scale-98 Revised and Montreal Cognitive Assessment scales, and months of the year backwards. Pre-existing dementia was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders fourth edition criteria. RESULTS: The sample consisted of 200 participants (mean age 81.1 +/- 6.5 years; 50% women; pre-existing cognitive impairment in 126 [63%]). A total of 34 (17%) were identified with delirium (Confusion Assessment Method +). The five approaches to assessing attention had statistically significant correlations (P < 0.05). Discriminant analysis showed that clinical subjective rating of attention in conjunction with the months of the year backwards had the best discriminatory ability to identify Confusion Assessment Method-defined delirium, and to discriminate patients with delirium from those with dementia and/or normal cognition. Both of these approaches had high sensitivity, but modest specificity. CONCLUSION: Objective tests are useful for prediction of non delirium, but lack specificity for a delirium diagnosis. Global attentional deficits were more indicative of delirium than deficits of specific domains of attention. Geriatr Gerontol Int 2016; 16: 1028-1035. PMID- 26419621 TI - Dynamic DNA architectures: spontaneous DNA strand exchange and self-sorting driven by perylene bisimide interactions. AB - Three differently bay-substituted perylene bisimides together with the conventional unsubstituted chromophore were synthetically incorporated as homodimers in DNA double strands. If preannealed DNA duplexes with two different perylene bisimide homodimers are mixed together they undergo spontaneous DNA strand exchange. The dynamic self-sorting forms DNA architectures preferentially with perylene bisimide heterodimers and can be controlled by the electronic density in the chromophores. PMID- 26419622 TI - Revival of cytokine therapy in heart failure? PMID- 26419623 TI - Vulnerable plaque imaging: updates on new pathobiological mechanisms. AB - Early identification of vulnerable, rupture-prone atherosclerotic plaques with the optimal goal of cardiovascular event prevention is a field of vigorous research. Despite the advances in imaging modalities and the in vivo identification of many characteristics of vulnerability, few of these plaques actually rupture and even fewer lead to clinical events, questioning the predictive value of the above techniques in clinical practice. Factors causing the higher local vulnerability of the culprit plaque within a prothrombotic environment of widespread inflammation are generally unknown. Newly recognized local features, including microcalcifications and biomechanical factors, seem to contribute. In this review article, we target on new mechanisms, implicated in vulnerable plaque formation and rupture, analysing their potential clinical value. PMID- 26419624 TI - Genetic variants and disease: correlate or cause? PMID- 26419625 TI - Atrial fibrillation in heart failure: what should we do? AB - Heart failure (HF) and atrial fibrillation (AF) are two conditions that are likely to dominate the next 50 years of cardiovascular (CV) care. Both are increasingly prevalent and associated with high morbidity, mortality, and healthcare cost. They are closely inter-related with similar risk factors and shared pathophysiology. Patients with concomitant HF and AF suffer from even worse symptoms and poorer prognosis, yet evidence-based evaluation and management of this group of patients is lacking. In this review, we evaluate the common mechanisms for the development of AF in HF patients and vice versa, focusing on the evidence for potential treatment strategies. Recent data have suggested that these patients may respond differently than those with HF or AF alone. These results highlight the clear clinical need to identify and treat according to best evidence, in order to prevent adverse outcomes and reduce the huge burden that HF and AF are expected to have on global healthcare systems in the future. We propose an easy-to-use clinical mnemonic to aid the initial management of newly discovered concomitant HF and AF, the CAN-TREAT HFrEF + AF algorithm (Cardioversion if compromised; Anticoagulation unless contraindication; Normalize fluid balance; Target initial heart rate <110 b.p.m.; Renin-angiotensin aldosterone modification; Early consideration of rhythm control; Advanced HF therapies; Treatment of other CV disease). PMID- 26419626 TI - CD1a+ survivin+ dendritic cell infiltration in dermal lesions of systemic sclerosis. AB - INTRODUCTION: Proto-oncogene survivin is a member of the inhibitor of apoptosis (IAP) family of proteins. The presence of serous antibodies against survivin in patients with systemic sclerosis has been previously reported; however, there are few reports regarding the pathophysiological relationship between survivin and systemic sclerosis. We herein investigated the expression and function of survivin in SSc patients. METHODS: We performed immunohistochemistry analyses to determine the expression of XIAP, cIAP and survivin in skin lesions from patients with SSc and non-SSc. The expression levels of survivin in peripheral blood mononuclear cells (PBMCs) obtained from SSc patients and healthy controls were evaluated using RT-PCR and flow cytometry. Additionally, the function of survivin was verified with overexpression experiments using monocyte-derived dendritic cells (Mo-DCs). RESULTS: The expression patterns of both XIAP and cIAP were similar, while only the survivin expression differed between the SSc and non-SSc skin lesions. Survivin-overexpressing cells were detected in the SSc dermis frequently. The positive rate of survivin in SSc dermis (64.3%, 9/14) was higher than that in non-SSc dermis (11.2%, 1/9). Furthermore, survivin+ cells expressed CD1a, one of the DC markers. Real-time PCR and FACS analyses revealed that the survivin-WT (wild type) expression levels in PBMCs, in particular CD14+ monocytes, from SSc patients were higher than that from healthy controls. Additionally, the overexpression experiments showed that survivin-WT overexpressing CD1a+ Mo-DCs have the characteristics of promoting cell cycle progression and decreasing apoptotic cells. CONCLUSIONS: These findings suggest that dermal survivin+ CD1a+ cell infiltration may be a potential biomarker of SSc skin lesions. PBMCs and monocytes from SSc patients also overexpressed survivin; therefore, dermal survivin+ DC may be derived from peripheral blood monocytes. Additionally, survivin may be involved in dermal CD1a+ DC proliferation through cell cycle activation and resistance to apoptosis. Survivin may be an important molecule for the pathogenesis of SSc. PMID- 26419628 TI - Intraspecific lineage divergence and its association with reproductive trait change during species range expansion in central Eurasian wild wheat Aegilops tauschii Coss. (Poaceae). AB - BACKGROUND: How species ranges form in landscapes is a matter of long-standing evolutionary interest. However, little is known about how natural phenotypic variations of ecologically important traits contribute to species range expansion. In this study, we examined the phylogeographic patterns of phenotypic changes in life history (seed production) and phenological (flowering time) traits during the range expansion of Aegilops tauschii Coss. from the Transcaucasus and Middle East to central Asia. RESULTS: Our comparative analyses of the patterns of natural variations for those traits and their association with the intraspecific lineage structure showed that (1) the eastward expansion to Asia was driven by an intraspecific sublineage (named TauL1b), (2) high seed production ability likely had an important role at the initial dispersal stage of TauL1b's expansion to Asia, and (3) the phenological change to early flowering phenotypes was one of the key adaptation events for TauL1b to further expand its range in Asia. CONCLUSIONS: This study provides for the first time a broad picture of the process of Ae. tauschii's eastward range expansion in which life history and phenological traits may have had respective roles in its dispersal and adaptation in Asia. The clear association of seed production and flowering time patterns with the intraspecific lineage divergence found in this study invites further genetic research to bring the mechanistic understanding of the changes in these key functional traits during range expansion within reach. PMID- 26419627 TI - Rare presentation of four primary pediatric cardiac tumors. AB - Pediatric cardiac tumors are extremely rare and usually benign. We selected four unique cases of pediatric cardiac tumors from a 15-year period at our institution. The four chosen cases represent unique, rare primary tumors of the heart. Our selection includes a case of Rosai Dorfman disease without systemic involvement, which is, to our knowledge, the second case of isolated cardiac Rosai Dorfman disease in a child. We present a case of subtotal replacement of myocardium by granulocytic sarcoma with minimal bone marrow involvement, representing the first reported case in a child manifested as hypertrophic cardiomyopathy, as well as a case of a primary synovial sarcoma arising from the atrioventricular (AV) node, representing the fourth reported pediatric case of a cardiac synovial sarcoma, and it is the first to arise from the AV node. Finally, we present a primary congenital infantile fibrosarcoma of the heart, which is, to our knowledge, the first confirmed cardiac congenital infantile fibrosarcoma. These four cases represent the need for continued inclusion of rare cardiac conditions in a clinician's differential diagnosis. Furthermore, they present the need for more in-depth molecular and genomic analysis of pediatric cardiac tumors in order to identify their etiopathogenesis. PMID- 26419630 TI - Insights into the regulation of bacteriophage endolysin: multiple means to the same end. AB - Antibiotics are the molecules of choice to treat bacterial infections. However, because of the rapid emergence of drug-resistant bacteria, alternative modes of combating infections are being envisaged. Bacteriophages, which infect and lyse bacterial cells, may function as effective antimicrobial agents. Most bacteriophages produce their own peptidoglycan hydrolase called endolysin or lysin, which breaks down the cell wall of bacteria and aids in the release of newly assembled virions. Here, we discuss several findings that help us in understanding how endolysins are regulated. We observe that there is no common mechanism that is followed in all cases. Many different modes of activity regulation have been observed in endolysins, including regulation of protein expression, translocation across the cell membrane and post-translational modifications. These processes not only demonstrate how endolysins are made dependent on other accessory proteins and non-protein factors for their synthesis, translocation across the cytoplasmic membrane and activity, but also show how autoregulation helps in maintaining the enzyme in an inactive form. Various regulatory mechanisms that are discussed are particularly applicable to endolysins. Nevertheless, a detailed study of these methods opens new avenues of investigation in the area of protein translocation systems and the novel ways of enzyme activation and regulation in bacteria. PMID- 26419629 TI - Sunlight inhibits growth and induces markers of programmed cell death in Plasmodium falciparum in vitro. AB - BACKGROUND: Plasmodium falciparum is responsible for the majority of global malaria deaths. During the pathogenic blood stages of infection, a rapid increase in parasitaemia threatens the survival of the host before transmission of slow maturing sexual parasites to the mosquito vector to continue the life cycle. Programmed cell death (PCD) may provide the parasite with the means to control its burden on the host and thereby ensure its own survival. Various environmental stress factors encountered during malaria may induce PCD in P. falciparum. This study is the first to characterize parasite cell death in response to natural sunlight. METHODS: The 3D7 strain of P. falciparum was cultured in vitro in donor erythrocytes. Synchronized and mixed-stage parasitized cultures were exposed to sunlight for 1 h and compared to cultures maintained in the dark, 24 h later. Mixed-stage parasites were also subjected to a second one-hour exposure at 24 h and assessed at 48 h. Parasitaemia was measured daily by flow cytometry. Biochemical markers of cell death were assessed, including DNA fragmentation, mitochondrial membrane polarization and phosphatidylserine externalization. RESULTS: Sunlight inhibited P. falciparum growth in vitro. Late-stage parasites were more severely affected than early stages. However, some late-stage parasites survived exposure to sunlight to form new rings 24 h later, as would be expected during PCD whereby only a portion of the population dies. DNA fragmentation was observed at 24 and 48 h and preceded mitochondrial hyperpolarization in mixed stage parasites at 48 h. Mitochondrial hyperpolarization likely resulted from increased oxidative stress. Although data suggested increased phosphatidylserine externalization in mixed-stage parasites, results were not statistically significant. CONCLUSION: The combination of biochemical markers and the survival of some parasites, despite exposure to a lethal stimulus, support the occurrence of PCD in P. falciparum. PMID- 26419631 TI - Electro-acupuncture decreases 5-HT, CGRP and increases NPY in the brain-gut axis in two rat models of Diarrhea-predominant irritable bowel syndrome(D-IBS). AB - BACKGROUND: To examine whether electro-acupuncture (EA) could decrease 5 hydroxytryptamine (5-HT) and calcitonin gene-related peptide (CGRP), and increase neuro-peptide Y (NPY) in the brain-gut axis (BGA) in D-IBS using rat models. METHODS: Rats were randomly exposed to unpredictable chronic stress for 3 weeks followed by 1-hour acute restraint stress (CAS) after 7 days of rest, or daily gavage of Senna decoction (6 g/kg) plus chronic restraint stress (for a duration of 2 h, starting from 1 h prior to the gavage) for 2 weeks (ISC). The content of 5-HT, CGRP and NPY in the distal colon, spinal cord, hypothalamus was examined at the end of the treatment. RESULTS: 1. The two rat models exhibited similar characteristics, e.g., increased number of fecal pellets expelled in 1 h, decreased sacchar-intake, decreased CRD, elevated 5-HT, CGRP content and decreased NPY in the distal colon, spinal cord, hypothalamus (P < 0.05 vs. that in healthy control rats). 2. A series of equations was developed based on correlation regression analysis. The analysis results demonstrated that 5-HT mediates the changes in hypothalamus, spinal cord and colon. 5-HT and CGRP in spinal cord was closely correlated with general behavior evaluation and other transmitters in BGA. CONCLUSION: 1. In comparison to 5-HT, CGRP and NPY (particularly in the spinal cord) had closer relationship with the D-IBS symptoms induced by either stress factors or Senna decotion. 2. EA treatment could restore the brain-gut axis to balanced levels. PMID- 26419633 TI - A Highly Sensitive Fluorescent Sensor for Palladium and Direct Imaging of Its Ecotoxicity in Living Model Organisms. AB - Rhodamine is an ideal platform for fluorescence probes owing to its spiro-lactam framework and excellent photochemical properties. Herein, a novel rhodamine-based palladium fluorescent chemosensor, Rd-Eb, showing a fast response time (3 min), high sensitivity for palladium species over other ions, and a low detection limit (1.91*10(-7) m), was synthesized. It can act as an obvious colorimetric as well as a fluorescent "off/on" sensor for Pd(2+) . In addition, it is also an excellent sensor for in vivo imaging of Pd(2+) in zebra fish and Daphnia magna, illuminating the impact of palladium on organisms at different growth stages with respect to biological toxicology. PMID- 26419632 TI - Prenatal drug exposures sensitize noradrenergic circuits to subsequent disruption by chlorpyrifos. AB - We examined whether nicotine or dexamethasone, common prenatal drug exposures, sensitize the developing brain to chlorpyrifos. We gave nicotine to pregnant rats throughout gestation at a dose (3mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1mg/kg) that produces minimally-detectable inhibition of brain cholinesterase activity. In a parallel study, we administered dexamethasone to pregnant rats on gestational days 17-19 at a standard therapeutic dose (0.2mg/kg) used in the management of preterm labor, followed by postnatal chlorpyrifos. We evaluated cerebellar noradrenergic projections, a known target for each agent, and contrasted the effects with those in the cerebral cortex. Either drug augmented the effect of chlorpyrifos, evidenced by deficits in cerebellar beta-adrenergic receptors; the receptor effects were not due to increased systemic toxicity or cholinesterase inhibition, nor to altered chlorpyrifos pharmacokinetics. Further, the deficits were not secondary adaptations to presynaptic hyperinnervation/hyperactivity, as there were significant deficits in presynaptic norepinephrine levels that would serve to augment the functional consequence of receptor deficits. The pretreatments also altered development of cerebrocortical noradrenergic circuits, but with a different overall pattern, reflecting the dissimilar developmental stages of the regions at the time of exposure. However, in each case the net effects represented a change in the developmental trajectory of noradrenergic circuits, rather than simply a continuation of an initial injury. Our results point to the ability of prenatal drug exposure to create a subpopulation with heightened vulnerability to environmental neurotoxicants. PMID- 26419634 TI - Alcohol Use Disorder and Heavy Episodic Drinking in Rural Communities in Cambodia: Risk Factors and Community-Perceived Strategies. AB - Alcohol misuse is increasing in Southeast Asia. We investigated the extent of and risk factors for alcohol use disorder (AUD) and heavy episodic drinking (HED) in a rural community in Cambodia. We also attempted to explore the communities' perception of alcohol misuse and elicited potential community-based strategies to address the alcohol problem. A mixed-methods study design was used, combining a cross-sectional questionnaire survey with qualitative interviews (focus group discussions and key informant interviews). AUD and HED were measured using the AUDs Identification Test Alcohol Consumption questionnaire. The prevalence of AUD and HED was high: 25% and 31%, respectively. Male sex, younger age, and increasing income were significant risk factors. The communities were well aware of the harmful effects of alcohol, expressed the importance of implementing community-based measures, and proposed various community-led solutions. Evidence based strategies that are culturally appropriate, accepted, and driven by communities are urgently needed. PMID- 26419635 TI - Health Literacy in Taiwan: A Population-Based Study. AB - Data on health literacy (HL) in the population is limited for Asian countries. This study aimed to test the validity of the Mandarin version of the European Health Literacy Survey Questionnaire (HLS-EU-Q) for use in the general public in Taiwan. Multistage stratification random sampling resulted in a sample of 2989 people aged 15 years and above. The HLS-EU-Q was validated by confirmatory factor analysis with excellent model data fit indices. The general HL of the Taiwanese population was 34.4 +/- 6.6 on a scale of 50. Multivariate regression analysis showed that higher general HL is significantly associated with the higher ability to pay for medication, higher self-perceived social status, higher frequency of watching health-related TV, and community involvement but associated with younger age. HL is also associated with health status, health behaviors, and health care accessibility and use. The HLS-EU-Q was found to be a useful tool to assess HL and its associated factors in the general population. PMID- 26419636 TI - Validation of WHOQOL-BREF in Malayalam and Determinants of Quality of Life Among People With Type 2 Diabetes in Kerala, India. AB - Quality of life (QOL) is an important health outcome in people with chronic conditions like diabetes and WHOQOL-BREF is a popular instrument used worldwide to assess QOL. However, QOL varies considerably from society to society depending on the culture of the person. Hence, the WHOQOL-BREF was translated to the local language, Malayalam. This article attempts to establish reliability, construct and discriminant validity of the translated WHOQOL-BREF, and determinants of QOL among people with type 2 diabetes. A cross-sectional study was undertaken among 200 patients with diabetes attending a primary care center in a rural area of Kerala, India. The translated version of WHOQOL-BREF was found to be internally consistent (Cronbach's alpha = .86) and demonstrated discriminant and construct validity. Education was found to be an independent determinant of QOL in the physical, psychological, and environmental domains. Thus, the translated version had good psychometric properties and education was an independent determinant of QOL in 3 of 4 domains. PMID- 26419637 TI - New synthesis of phenyl-isothiocyanate C-functionalised cyclams. Bioconjugation and (64)Cu phenotypic PET imaging studies of multiple myeloma with the te2a derivative. AB - Azamacrocyclic bifunctional chelating agents (BCAs) are essential for the development of radiopharmaceuticals in nuclear medicine and we wish to prove that their bioconjugation by a function present on a carbon atom of the macrocyclic skeleton is a solution of choice to maintain their in vivo inertness. Based on our very recent methodology using a bisaminal template and selective N-alkylation approach, a new synthesis of conjugable C-functionalised teta, te2a and cb-te2a has been developed. These chelators have indeed a growing interest in nuclear medicine for positron emission tomography (PET) and radioimmunotherapy (RIT) where they show in several cases better complexation properties than dota or dota like macrocycles, especially with (64)Cu or (67)Cu radioisotopes. Chelators are bearing an isothiocyanate grafting function introduced by C-alkylation to avoid as much as possible a critical decrease of their chelating properties. The synthesis is very efficient and yields the targeted ligands, teta-Ph-NCS, te2a-Ph NCS and cb-te2a-Ph-NCS without fastidious work-up and could be easily extended to other cyclam based-BCAs. The newly synthetised te2a-Ph-NCS has been conjugated to an anti mCD138 monoclonal antibody (mAb) to evaluate its in vivo behavior and potentiality as BCA and to explore a first attempt of PET-phenotypic imaging in multiple myeloma (MM). Mass spectrometry analysis of the immunoconjugate showed that up to 4 chelates were conjugated per 9E7.4 mAb. The radiolabeling yield and specific activity post-purification of the bioconjugate 9E7.4-CSN-Ph-te2a were 95 +/- 2.8% and 188 +/- 27 MBq mg(-1) respectively and the immunoreactivity of (64)Cu-9E7.4-CSN-Ph-te2a was 81 +/- 7%. Animal experiments were carried out on 5T33-Luc(+) tumor bearing mice, either in subcutaneous or orthotopic. To achieve PET imaging, mice were injected with (64)Cu-9E7.4-CNS-Ph-te2a and acquisitions were conducted 2 and 20 h post-injection (PI). A millimetric bone uptake was localised in a sacroiliac of a MM orthotopic tumor. Nonspecific uptakes were observed at 2 h PI but, unlike for the tumor, a significant decrease was observed at 20 h PI which improves the contrast of the images. PMID- 26419642 TI - A Comprehensive Assessment Tool for Patient Registry Software Systems: The CIPROS Checklist. AB - BACKGROUND: Patient registries are an important instrument in medical research. Often their structure is complex and their implementation uses composite software systems to meet the wide spectrum of challenges. OBJECTIVES: For the implementation of a registry, there is a wide range of commercial, open source, and self-developed systems available and a minimal standard for the critical appraisal of their architecture is needed. METHODS: We performed a systematic review of the literature to define a catalogue of relevant criteria to construct a minimal appraisal standard. RESULTS: The CIPROS list is developed based on 64 papers which were found by our systematic review. The list covers twelve sections and contains 72 items. CONCLUSIONS: The CIPROS list supports developers to assess requirements on existing systems and strengthens the reporting of patient registry software system descriptions. It can be a first step to create standards for patient registry software system assessments. PMID- 26419644 TI - Effect of intra-abdominal administration of ligustrazine nanoparticles nano spray on postoperative peritoneal adhesion in rat model. AB - AIM: We aimed to evaluate the preventive effect of the ligustrazine nanoparticles nano spray (LNNS) for postoperative peritoneal adhesions in female rat models. MATERIAL AND METHODS: Fifty Wistar female rats weighting 250-300 g were randomly assigned to seven equal groups. All animals in the seven groups underwent midline laparotomy and ceca were abraded with sterile rasp. Group 1 underwent sham operations without treatment. In group 2, a postoperative peritoneal adhesion model was created, but no medication was given. In group 3, a postoperative peritoneal adhesion model was treated with LNNS, 2.5 mg/kg. In group 4, a postoperative peritoneal adhesion model was treated with LNNS, 5 mg/kg. In group 5, a postoperative peritoneal adhesion model was treated with LNNS, 10 mg/kg. In group 6, a postoperative peritoneal adhesion model was treated with polylactic acid (PLA) nanoparticle. In group 7, a postoperative peritoneal adhesion model was treated with ligustrazine, 2.5 mg/kg. Ten days after surgery, macroscopic and pathologic assessments were performed, and peritoneal fluid samples were collected in each group. The levels of tumor necrosis factor-alpha, tissue plasminogen activator and plasminogen activator inhibitor-1 in peritoneal fluid were determined by enzyme-linked immunosorbent assay. RESULTS: The adhesion score and extent of groups 4 and 5 was lower than that of group 2 in macroscopic assessment (P < 0.05). A comparison of tumor necrosis factor-alpha and tissue plasminogen activator level in the peritoneal fluid also demonstrated significant differences among groups 2, 4 and 5 (P < 0.05). The levels of plasminogen activator inhibitor-1 in peritoneal fluid in the LNNS groups were decreased compared to group 1. CONCLUSION: We suggest that LNNS could reduce peritoneal adhesion formation and it could be applied as a novel intervention for postoperative peritoneal adhesion. PMID- 26419646 TI - W-DARE: a three-year program of participatory action research to improve the sexual and reproductive health of women with disabilities in the Philippines. AB - BACKGROUND: In many contexts, women with disability have less access to sexual and reproductive health information, screening, prevention, and care services than women without disability. Women with disability are also known to be more likely to experience physical and sexual violence than women without disability. In the Philippines, health service providers often have little awareness of the sexual and reproductive experiences of women with disability and limited capacity to provide services in response to their needs. Very limited data are available to inform development of disability-inclusive sexual and reproductive health, and violence prevention and response, services in the country. This paper presents the protocol for W-DARE (Women with Disability taking Action on REproductive and sexual health), a three-year program of participatory action research that aims to improve the sexual and reproductive health of women with disability in the Philippines. DESIGN: W-DARE is a disability-inclusive program that will use mixed methods to 1) increase understanding of factors influencing the sexual and reproductive health of women with disability, and 2) develop, implement and evaluate local interventions to increase supply of and demand for services. W DARE will generate data on the prevalence of disability in two districts; the wellbeing and community participation of people with and without disability, and identify barriers to community; and describe the sexual and reproductive health needs and experiences, and service-related experiences of women with disability. These data will inform the development and evaluation of interventions aiming to improve access to sexual and reproductive health services, and violence prevention and response services, for women with disability. Local women with disabilities, their representative organisations, and SRH service providers will be involved as members of the research team across all stages of the research. DISCUSSION: This three-year study will provide evidence about factors undermining the sexual and reproductive health of women with disability in a lower-middle income country, and provide new insights about what may be effective in increasing access to services in settings of limited resources. Findings will be relevant across Asia and the Pacific. Analysis of the program will also provide evidence about disability-inclusion in participatory action research approaches. PMID- 26419645 TI - VMAT-SBRT planning based on an average intensity projection for lung tumors located in close proximity to the diaphragm: a phantom and clinical validity study. AB - The aim of the this study was to validate the use of an average intensity projection (AIP) for volumetric-modulated arc therapy for stereotactic body radiation therapy (VMAT-SBRT) planning for a moving lung tumor located near the diaphragm. VMAT-SBRT plans were created using AIPs reconstructed from 10 phases of 4DCT images that were acquired with a target phantom moving with amplitudes of 5, 10, 20 and 30 mm. To generate a 4D dose distribution, the static dose for each phase was recalculated and the doses were accumulated by using the phantom position known for each phase. For 10 patients with lung tumors, a deformable registration was used to generate 4D dose distributions. Doses to the target volume obtained from the AIP plan and the 4D plan were compared, as were the doses obtained from each plan to the organs at risk (OARs). In both phantom and clinical study, dose discrepancies for all parameters of the dose volume (D(min), D(99), D(max), D(1) and D(mean)) to the target were <3%. The discrepancies of D(max) for spinal cord, esophagus and heart were <1 Gy, and the discrepancy of V20 for lung tissue was <1%. However, for OARs with large respiratory motion, the discrepancy of the D(max) was as much as 9.6 Gy for liver and 5.7 Gy for stomach. Thus, AIP is clinically acceptable as a planning CT image for predicting 4D dose, but doses to the OARs with large respiratory motion were underestimated with the AIP approach. PMID- 26419649 TI - Multi-slice MRI with the dynamic multi-coil technique. AB - To date, spatial encoding for MRI is based on linear X, Y and Z field gradients generated by dedicated X, Y and Z wire patterns. We recently introduced the dynamic multi-coil technique (DYNAMITE) for the generation of magnetic field shapes for biomedical MR applications from a set of individually driven localized coils. The benefits for B0 magnetic field homogenization have been shown, as well as proof of principle of radial and algebraic MRI. In this study the potential of DYNAMITE MRI is explored further and the first multi-slice MRI implementation in which all gradient fields are purely DYNAMITE based is presented. The obtained image fidelity is shown to be virtually identical to that of a conventional MRI system with dedicated X, Y and Z gradient coils. Comparable image quality is a milestone towards the establishment of fully functional DYNAMITE MRI (and shim) systems. PMID- 26419647 TI - Transoral laser microsurgery for the treatment of oropharyngeal cancer: the Dalhousie University experience. AB - OBJECTIVE: The optimal treatment strategy for oropharyngeal squamous cell carcinoma is highly debated. However, growing evidence supports the use of minimally invasive techniques, such as transoral laser microsurgery (TLM), as a first-line treatment modality for these carcinomas. The purpose of our study was to assess the efficacy and safety of TLM for the treatment of primary and recurrent oropharyngeal carcinomas. METHODS: All patients with oropharyngeal carcinoma undergoing TLM at the QEII Health Sciences Centre in Halifax, Nova Scotia were identified within a prospective database monitoring TLM outcomes. Kaplan-Meier survival analysis was used to evaluate the following end points at 36 months: local control (LC), disease-specific survival (DSS), and disease-free survival (DFS). Safety endpoints included complications following surgery and long term morbidity related to TLM. RESULTS: Between 2003 and 2014, 39 patients with oropharyngeal carcinoma underwent TLM resection. Twenty-eight (72%) patients had primary carcinoma, nine (23%) were radiation/chemoradiation (RT/CRT) failures, and two (5%) had second primaries following previous RT/CRT. Three patients had stage I disease, 8 stage II, 5 stage III, and 23 stage IV disease. HPV status was available for 26 patients, of which 23 (88%) had HPV positive disease. Kaplan-Meier estimates of 36-month LC, DSS, and DFS for primary oropharyngeal carcinomas were 85.5% (SE 10.6%), 85.7% (SE 13.2%) and 77.7% (SE 12.5%) respectively. Thirty-six-month outcomes for RT/CRT failures were 66.76% (SE 15.7%) for LC and 55.6% (SE 16.6%) for DSS and DFS. Three patients developed complications following surgery. CONCLUSIONS: Observed 36-month efficacy and safety outcomes support the use of TLM for the treatment of primary and recurrent oropharyngeal carcinoma. PMID- 26419650 TI - Randomised control trial of humidified high flow nasal cannulae versus standard oxygen in the emergency department. AB - OBJECTIVES: The aim of the study was to determine if oxygen delivered through humidified high flow nasal cannulae (HHFNC) reduced the need for escalation in ventilation management and work of breathing in the ED patients presenting with acute undifferentiated shortness of breath compared with standard oxygen therapy. METHODS: This was an unblinded randomised control trial conducted at two hospital EDs in Sydney, Australia. Eligible patients presenting with shortness of breath were randomised to HHFNC or standard oxygen therapy. Primary outcomes were the need to escalate ventilation therapy or a reduction in respiratory rate of 20% or more within 2 h of commencement. RESULTS: One hundred patients were enrolled in the trial. The intervention group receiving HHFNC was associated with a higher proportion of patients with a reduced respiratory rate at 2 h (66.7% vs 38.5%, P = 0.005) and a lower proportion of patients requiring escalation in ventilation therapy (4.2% vs 19%, P = 0.02) compared with standard oxygen therapy. CONCLUSIONS: The use of high flow nasal cannula oxygenation was associated with improved respiratory state in selected patients presenting to the ED with acute undifferentiated shortness of breath. PMID- 26419643 TI - Developmental regulation of fear learning and anxiety behavior by endocannabinoids. AB - The developing brain undergoes substantial maturation into adulthood and the development of specific neural structures occurs on differing timelines. Transient imbalances between developmental trajectories of corticolimbic structures, which are known to contribute to regulation over fear learning and anxiety, can leave an individual susceptible to mental illness, particularly anxiety disorders. There is a substantial body of literature indicating that the endocannabinoid (eCB) system critically regulates stress responsivity and emotional behavior throughout the life span, making this system a novel therapeutic target for stress- and anxiety-related disorders. During early life and adolescence, corticolimbic eCB signaling changes dynamically and coincides with different sensitive periods of fear learning, suggesting that eCB signaling underlies age-specific fear learning responses. Moreover, perturbations to these normative fluctuations in corticolimbic eCB signaling, such as stress or cannabinoid exposure, could serve as a neural substrate contributing to alterations to the normative developmental trajectory of neural structures governing emotional behavior and fear learning. In this review, we first introduce the components of the eCB system and discuss clinical and rodent models showing eCB regulation of fear learning and anxiety in adulthood. Next, we highlight distinct fear learning and regulation profiles throughout development and discuss the ontogeny of the eCB system in the central nervous system, and models of pharmacological augmentation of eCB signaling during development in the context of fear learning and anxiety. PMID- 26419648 TI - Usual blood pressure, peripheral arterial disease, and vascular risk: cohort study of 4.2 million adults. AB - OBJECTIVES: To determine the subgroup specific associations between usual blood pressure and risk of peripheral arterial disease, and to examine the relation between peripheral arterial disease and a range of other types of vascular disease in a large contemporary cohort. DESIGN: Cohort study. SETTING: Linked electronic health records from 1990 to 2013 in the United Kingdom. PARTICIPANTS: 4,222,459 people aged 30-90 years, registered at a primary care practice for at least one year and with a blood pressure measurement. MAIN OUTCOME MEASURES: Time to first diagnosis of new onset peripheral arterial disease and time to first diagnosis of 12 different vascular events. RESULTS: A 20 mm Hg higher than usual systolic blood pressure was associated with a 63% higher risk of peripheral arterial disease (hazard ratio 1.63, 95% confidence interval 1.59 to 1.66). The strength of the association declined with increasing age and body mass index (P<0.001 for interaction) but was not modified by sex or smoking status. Peripheral arterial disease was associated with an increased risk of 11 different vascular events, including ischaemic heart disease (1.68, 1.58 to 1.79), heart failure (1.63, 1.52 to 1.75), aortic aneurysm (2.10, 1.79 to 2.45), and chronic kidney disease (1.31, 1.25 to 1.38), but not haemorrhagic stroke. The most common initial vascular event among those with peripheral arterial disease was chronic kidney disease (24.4% of initial events), followed by ischaemic heart disease (18.5% of initial events), heart failure (14.7%), and atrial fibrillation (13.2%). Overall estimates from this cohort were consistent with those derived from traditional studies when we pooled the findings in two meta-analyses. CONCLUSIONS: Raised blood pressure is a strong risk factor for peripheral arterial disease in a range of patient subgroups. Furthermore, clinicians should be aware that those with established peripheral arterial disease are at an increased risk of a range of other vascular events, including chronic kidney disease, ischaemic heart disease, heart failure, atrial fibrillation, and stroke. PMID- 26419651 TI - Emergent roles for intercellular adhesion molecule-1 in the restructuring of the blood-testis barrier during spermatogenesis in the mammal. AB - Mammalian spermatogenesis is comprised of a series of molecular, cellular, and morphological events that underscore the movement of developing germ cells across the blood-testis barrier. These events involve the restructuring of tight junctions, basal ectoplasmic specializations, gap junctions, and desmosomes, which constitute blood-testis barrier function. Previous studies show that preleptotene/leptotene spermatocytes traverse the blood-testis barrier while transiently trapped within an intermediate compartment, which sequesters primary spermatocytes away from basal and adluminal compartments of the seminiferous epithelium. Preleptotene/leptotene spermatocytes enter the adluminal compartment when stable junctions ahead of spermatocytes disassemble, while new junctions assemble behind them. While there is enormous restructuring of the seminiferous epithelium, the mechanism of germ cell movement is incompletely understood. In this perspective, the significance of intercellular adhesion molecule-1 in the restructuring of the blood-testis barrier during spermatogenesis in the mammal is discussed. PMID- 26419653 TI - Foodborne illness among factory workers, Gweru, Zimbabwe, 2012: a retrospective cohort study. AB - BACKGROUND: On the 20th September 2012 the Gweru district medical officer (DMO) reported a sudden increase in the number of factory workers complaining of symptoms suggestive of gastrointestinal illness. We conducted a retrospective cohort study to determine factors associated with illness among factory workers. METHODS: A retrospective cohort study was conducted from September to October 2012 among 98 randomly selected factory workers. Interviewer administered questionnaires were used to evaluate possible risk factors from which food attack rates, relative risks (RR) and adjusted odds ratios (AOR) were calculated using Epi info version 3.5.1. Bacteriological examination of food samples was performed. In addition rectal swabs and specimens from food handlers and patients were collected for analysis. RESULTS: Of the 98 workers interviewed, 87/98 (89%) were males. Consumption of beef stew (AOR = 9.28, 95% CI 2.78-30.91) was independently associated with foodborne illness. Klebsiella spp. were isolated from beef stew and stool specimen of patients. Watery diarrhoea 51/98 (52%), fatigue 48/98 (49%) and abdominal cramps 41/98 (42%) were the most presenting symptoms. CONCLUSIONS: Klebsiella spp. was the aetiological agent for the food borne illness at the factory and this resulted from consumption of contaminated beef stew by the workers. As a result of this evidence, the implicated beef was withdrawn from the canteen and the menu cycle was revised to minimise exposure to the same food. Food handlers training in food safety and hygiene and regular canteen inspections for quality assurance were recommended and adopted. No further food borne illness has been reported from the factory. PMID- 26419652 TI - A retrospective analysis of ethnic and gender differences in alcohol consumption among emergency department patients: a cross-sectional study. AB - BACKGROUND: Previous studies of alcohol use have recognized several trends in consumption patterns among gender and age yet few have examined ethnic differences. This study examines the intra- and inter-ethnic differences in alcohol consumption among a population of patients seen in the emergency department. METHODS: This is a cross-sectional study conducted in the emergency department in a large urban setting. Information on drinking behavior and ethnicity was collected using the Computerized Alcohol Screening and Brief Intervention (CASI) tool. We explored differences in drinking patterns using a multivariate multinomial logistic regression model. RESULTS: We analyzed the drinking habits of 2,444 patients surveyed between November 2012 and May 2014. The results indicate that when compared to non-Hispanic whites, Asians have the lowest odds of drinking within normal limits or excessively, followed by other Latinos, and Mexicans. Age and gender consistently showed statistically significant associations with alcohol-use. The odds of drinking within normal limits or excessively are inversely associated with age and were lower among females. The predicted probabilities show a marked gender-specific difference in alcohol use both between and within ethnic/racial groups. They also highlight an age-related convergence in alcohol use between men and women within ethnic groups. DISCUSSION: The results of this study show intra-racial/ethnic variability associated with sex and education. The highlighted differences within and between ethnic groups reinforce the need to use refined categories when examining alcohol use among minorities. CONCLUSION: The results of this study confirm some alcohol consumption trends among ethnic minorities observed in literature. It provides empirical evidence of the marked gender differences and highlights an age-related convergence for gender-specific alcohol use. Health care personnel should be aware of these differences when screening and counseling. PMID- 26419654 TI - All-cause mortality effects of replacing sedentary time with physical activity and sleeping using an isotemporal substitution model: a prospective study of 201,129 mid-aged and older adults. AB - BACKGROUND: Sedentary behaviour, sleeping, and physical activity are thought to be independently associated with health outcomes but it is unclear whether these associations are due to the direct physiological effects of each behaviour or because, across a finite 24-hour day, engagement in one behavior requires displacement of another. The aim of this study was to examine the replacement effects of sedentary behaviour (total sitting, television/computer screen time combined), sleeping, standing, walking, and moderate-to-vigorous physical activity on all-cause mortality using isotemporal substitution modelling. METHODS: Longitudinal analysis (4.22 +/- 0.9 years follow-up/849,369 person years) of 201,129 participants of the 45 and Up study aged >=45 years from New South Wales, Australia. RESULTS: Seven thousand four hundred and sixty deaths occurred over follow-up. There were beneficial associations for replacing total sitting time with standing (per-hour HR: 95 % CI: 0.95, 0.94-0.96), walking (0.86, 0.81-0.90), moderate-to-vigorous physical activity (0.88, 0.85-0.90), and sleeping in those sleeping <= 7 h/day (0.94, 0.90-0.98). Similar associations were noted for replacing screen time. Replacing one hour of walking or moderate to-vigorous physical activity with any other activity class was associated with an increased mortality risk by 7-18%. Excluding deaths in the first 24 months of the follow up and restricting analyses to those who were healthy at baseline did not materially change the above observations. CONCLUSION: Although replacing sedentary behaviour with walking and moderate-to-vigorous physical activity are associated with the lowest mortality risk, replacements with equal amounts of standing and sleeping (in low sleepers only) are also linked to substantial mortality risk reductions. PMID- 26419655 TI - Time trends and epidemiological patterns of perinatal lamb mortality in Norway. AB - BACKGROUND: Perinatal mortality is a major cause of loss in the sheep industry. Our aim was to explore time trends in crude population stillbirth and neonatal mortality rates in Norway. We used data on 6,435,715 lambs from flocks enrolled in the Norwegian Sheep Recording System (NSRS) from 2000 through 2010 for descriptive analysis of trends. Longitudinal patterns of mortality rates were compared for lambs within different levels of variables suspected to be associated with perinatal loss. RESULTS: There was an approximately linear increase in the annual proportion of stillborn lambs during the study period, from 3.3 % in 2000 to 4.7 % in 2010. In the same time period, average litter size of ewes in NSRS flocks increased from 2.00 to 2.19. However, a steady rise in stillbirth rate was observed within each litter size group, suggesting a gradually increasing impact on stillbirth risk of other, yet unidentified, factors. Average flock size increased during the study period. The highest stillbirth rates were found in the largest and smallest flocks. Early neonatal mortality rates (0-5 days of life) varied from year to year (minimum 2.2 %, maximum 3.2 %) and were invariably higher among triplets and quadruplets than among singletons and twins. Annual fluctuations were parallel within the various litter sizes. A significant overall decreasing trend was present within all litter sizes with the exception of singletons. Weather data for the prime lambing months (April and May) 2000-2010 indicated a relationship between low temperatures and high neonatal mortality rates. At the flock level, there was a significant positive correlation between stillbirths and early neonatal mortality rates (r = 0.13), between stillbirth rates in two consecutive years (r = 0.43) and between early neonatal mortality rates in two consecutive years (r = 0.40). CONCLUSIONS: The substantial increase in ovine stillbirth rate in recent years in Norway was to some extent related to a corresponding increase in the proportion of lambs in triplet or larger litters; however, other factors apparently have contributed. Early neonatal mortality rate exhibited year-to-year variations, partly following temperature fluctuations, which is somewhat unexpected, considering that lambing mainly occurs indoors in Norway. PMID- 26419656 TI - Homo and heteropolymetallic Group 4 molecular nitrides. AB - Treatment of [{Ti(eta(5)-C5Me5)(MU-NH)}3(MU3-N)] (1) with zirconium or hafnium tetrachloride adducts [MCl4(thf)2] affords complexes [Cl3M{(MU3-N)(MU3 NH)2Ti3(eta(5)-C5Me5)3(MU3-N)}] (M = Zr (2), Hf (3)). Titanium chloride complexes [Cl2Ti{(MU3-N)2(MU3-NH)Ti3(eta(5)-C5Me5)3(MU3-N)}] (4) and [(Me2NH)ClTi{(MU3 N)3Ti3(eta(5)-C5Me5)3(MU3-N)}] (5) are obtained by reaction of 1 with [TiCl4 x(NMe2)x] (x = 2, 3). The dimethylamine ligand in 5 is displaced by pyridine to give the analogue complex [(py)2ClTi{(MU3-N)3Ti3(eta(5)-C5Me5)3(MU3-N)}] (6). Treatment of the titanium chloride complexes 4 and 5 with sodium cyclopentadienide or lithium bis(trimethylsilyl)amide reagents leads to the cube type nitrido derivatives [RTi{(MU3-N)3Ti3(eta(5)-C5Me5)3(MU3-N)}] (R = eta(5) C5H5 (7), N(SiMe3)2 (8)). The reaction of the zirconium trichloride complex 2 with [Tl(C5H5)] yields exclusively the dichloride-monocyclopentadienyl derivative [(eta(5)-C5H5)Cl2Zr{(MU3-N)(MU3-NH)2Ti3(eta(5)-C5Me5)3(MU3-N)}] (9). However, the treatment of 2 with excess [Na(C5H5)] causes further chloride replacement in 9 and subsequent cyclopentadiene elimination to give [(eta(5)-C5H5)Zr{(MU3 N)3Ti3(eta(5)-C5Me5)3(MU3-N)}] (10) via intermediates [(eta(5)-C5H5)2ClZr{(MU3 N)Ti3(eta(5)-C5Me5)3(MU-NH)2(MU3-N)}] (11) and [(eta(5)-C5H5)ClZr{(MU3-N)2(MU3 NH)Ti3(eta(5)-C5Me5)3(MU3-N)}] (12). Treatment of 2 or 9 with [Mg(C5H5)2] leads to the magnesium derivative [(eta(5)-C5H5)Mg(MU-Cl)2(eta(5)-C5H5)Zr{(MU4-N)(MU3 N)(MU3-NH)Ti3(eta(5)-C5Me5)3(MU3-N)}] (13), which can be visualized as a result of the incorporation of one [Mg(eta(5)-C5H5)Cl] moiety to complex 12. In contrast to the metathesis process with [M(C5H5)x] derivatives and subsequent C5H6 eliminations, the reaction of 2 with potassium pentamethylcyclopentadienide in toluene produces the paramagnetic derivative [K(MU-Cl)3Zr{(MU3-N)(MU3 NH)2Ti3(eta(5)-C5Me5)3(MU3-N)}] (14) and C10Me10. Complex 14 reacts with one equivalent of 18-crown-6 or cryptand-222 to give the molecular complex [(18-crown 6)K(MU-Cl)3Zr{(MU3-N)(MU3-NH)2Ti3(eta(5)-C5Me5)3(MU3-N)}] (15) or the ion pair [K(crypt-222)][Cl3Zr{(MU3-N)(MU3-NH)2Ti3(eta(5)-C5Me5)3(MU3-N)}] (16). The X-ray crystal structures of 2, 8, 13 and 15 have been determined. PMID- 26419657 TI - Prevalence and determinants of symptoms of common mental disorders in retired professional Rugby Union players. AB - The primary aim of this study was to determine the prevalence of symptoms of common mental disorders (CMD) (distress, anxiety/depression, sleeping disturbance, adverse nutrition behaviour, adverse alcohol behaviour and smoking) among retired professional Rugby Union players. The secondary aim was to explore the associations between stressors (life events, Rugby Union career dissatisfaction) and the health conditions under study. Therefore, cross sectional analyses were conducted on baseline questionnaires from an ongoing prospective cohort study of retired professional Rugby Union players. An electronic questionnaire was established using validated questionnaires to assess symptoms of CMD and stressors. The electronic questionnaire was subsequently distributed to retired players by the national Rugby Union players' associations in France, Ireland and South Africa. Among 295 retired professional Rugby Union players (mean age of 38 years), prevalence rates were 25% for distress, 28% for anxiety/depression, 29% for sleeping disturbance, 62% for adverse nutrition behaviour, 15% for smoking and 24% for adverse alcohol behaviour. A higher number of life events were associated with distress (OR = 1.2; 95% CI 1.1-1.4), anxiety/depression (OR = 1.6; 95% CI 1.2-2.1), sleeping disturbance (OR = 1.6; 95% CI 1.2-2.1) and adverse nutrition behaviour (OR = 1.8; 95% CI 1.3-2.5). A higher level of dissatisfaction of the player's Rugby Union career was associated with distress (OR = 0.9; 95% CI 0.8-1.0), sleeping disturbance (OR = 0.9; 95% CI 0.9-1.0), smoking (OR = 0.9; 95% CI 0.9-1.0) and adverse nutrition behaviour (OR = 0.9; 95% CI 0.8-0.9). In conclusion, our study suggests that prevalence of symptoms of CMD is high among retired professional Rugby Union players, being associated with both a higher number of life events and a higher level of Rugby Union career dissatisfaction. PMID- 26419658 TI - RALA-mediated delivery of FKBPL nucleic acid therapeutics. AB - AIMS: RALA is a novel 30 mer bioinspired amphipathic peptide that is showing promise for gene delivery. Here, we used RALA to deliver the FK506-binding protein like - FKBPL gene (pFKBPL) - a novel member of the immunophilin protein family. FKBPL is a secreted protein, with overexpression shown to inhibit angiogenesis, tumor growth and stemness, through a variety of intra- and extracellular signaling mechanisms. We also elucidated proangiogenic activity and stemness after utilizing RALA to deliver siRNA (siFKBPL). MATERIALS & METHODS: The RALA/pFKBPL and RALA/siFKBPL nanoparticles were characterized in terms of size, charge, stability and toxicity. Overexpression and knockdown of FKBPL was assessed in vitro and in vivo. RESULTS: RALA delivered both pFKBPL and siFKBPL with less cytotoxicity than commercially available counterparts. In vivo, RALA/pFKBPL delivery retarded tumor growth, and prolonged survival with an associated decrease in angiogenesis, while RALA/siFKBPL had no effect on tumor growth rate or survival, but resulted in an increase in angiogenesis and stemness. CONCLUSION: RALA is an effective delivery system for both FKBPL DNA and RNAi and highlights an alternative therapeutic approach to harnessing FKBPL's antiangiogenic and antistemness activity. PMID- 26419659 TI - Response Surface Optimization for Decaffeination and Theophylline Production by Fusarium solani. AB - Coffee processing industries generate caffeine-containing waste that needs to be treated and decaffeinated before being disposed. Five fungal isolates obtained on caffeine-containing mineral media were tested for their ability to utilize caffeine at high concentrations. An isolate identified as Fusarium solani could utilize caffeine as a sole source of carbon and nitrogen up to 5 g/l and could degrade it to an extent of 30-53 % in 120 h. Sucrose that was added as an auxiliary substrate (5 g/l) enhanced the biodecaffeination of caffeine to 88 % in 96 h. The addition of co- substrate (sucrose) not only resulted in higher biodecaffeination efficiency, but also reduced the incubation period from the initial 120 to 96 h. Theophylline and 3-methyl xanthine were obtained as the major metabolites of decaffeination at 96 and 120 h, respectively. Response surface methodology used to optimize the process parameters for maximum biodecaffeination as well as theophylline production showed that a pH of 5.8, temperature of 24 degrees C and inoculum size of 4.8 * 10(5) spores/ml have resulted in a complete biodecaffeination of caffeine as well as the production of theophylline with a yield of 33 % (w/w). Results thus show that a viable and sustainable process can be developed for the detoxification of caffeine along with the recovery of theophylline, a commercially important chemical. PMID- 26419660 TI - Isolation and Characterization of Bacteria That Use Furans as the Sole Carbon Source. AB - Five bacterial strains were isolated from wastewater treatment facilities which were able to use furfural as the sole carbon source. Based on 16S rRNA phylogenetic analysis, these strains were identified as Cupriavidus pinatubonensis (designated ALS1280), Pigmentiphaga sp. (ALS1172), Pseudomonas sp. BWDY (ALS1279), Pseudomonas mendocina (ALS1131), and Pseudomonas putida (ALS1267). In all cases, growth under oxygenated conditions on furfural was accompanied by the transient accumulation of 2-furoic acid (furoate) with no furfuryl alcohol observed. ALS1267 and ALS1279 were also able to metabolize 5 (hydroxymethyl)furfural. The five isolates and their phylogenetic near neighbors were compared for furfural dehydrogenase activity and tolerance to furfural and furoate in defined and complex media. P. putida ALS1267 was the most tolerant to furans and tolerated 17 mM furfural or 195 mM furoate before its growth rate was reduced by 50 % in a defined medium. This strain also had the greatest specific growth rate on furfural (0.6/h at 27-30 degrees C) and showed the highest specific activity of furfural dehydrogenase (170 mIU/mg) of any furfural utilizing strain that has been characterized to date. PMID- 26419661 TI - Commentary: Vitamin D: prime mover or fellow traveller? PMID- 26419662 TI - Vocal response inhibition is enhanced by anodal tDCS over the right prefrontal cortex. AB - Stopping outright (reactive inhibition) and slowing down (proactive inhibition) are types of response inhibition which have mainly been investigated in the manual effector system. This study compared reactive inhibition across manual and vocal effector systems, examined the effects of excitatory anodal transcranial direct current stimulation (anodal tDCS) over the right prefrontal cortex (right PFC) and looked at the relationship between reactive and proactive inhibition. We hypothesised (1) that vocal reactive inhibition would be less effective than manual reactive inhibition as evidenced by longer stop signal reaction times; (2) that anodal tDCS would enhance both vocal and manual reactive inhibitions and (3) that proactive and reactive inhibitions would be positively related. We tested 14 participants over two sessions (one session with anodal tDCS and one session with sham stimulation) and applied stimulation protocol in the middle of the session, i.e. only during the second of three phases. We used a stop signal task across two stop conditions: relevant and irrelevant stop conditions in which stopping was required or ignored, respectively. We found that reactive inhibition was faster during and immediately after anodal tDCS relative to sham. We also found that greater level of proactive inhibition enhanced reactive inhibition (indexed by shorter stop signal reaction times). These results support the hypothesis that the right-PFC is part of a core network for reactive inhibition and supports previous contention that proactive inhibition is possibly modulated via preactivating the reactive inhibition network. PMID- 26419663 TI - The nature of constant and cyclic force production: unintentional force-drift characteristics. AB - We explored unintentional changes in forces during performance of constant and cyclic force-production tasks (F-tasks) after visual feedback removal. Based on earlier studies, we expected all force parameters to drop exponentially with time. We also explored possible role of working memory in the force drop phenomena. Healthy subjects performed constant or cyclic isometric F-tasks with the index finger under visual feedback. The cyclic task was paced by a metronome. Removing visual feedback resulted in a consistent force drop in constant F-tasks and a qualitatively similar drift in the mean force in the cyclic F-task. Both were slow with characteristic times of about 10-20 s. In contrast, force amplitude in the cyclic F-task increased quickly (within 1-2 s). When the subjects were asked to stop producing force for 5 s after the visual feedback disappeared and then resume force production, no downward force drift was seen in constant F-tasks, while in cyclic F-tasks, the drift of the mean force was present and an exaggerated increase in force amplitude was also observed. We conclude that while working memory limitations may influence cyclic F-tasks, their role in determining the force drift in constant F-tasks is limited. The results of both experiments are interpreted within the referent configuration hypothesis supplemented with an idea of unintentional drift of referent coordinates (RC-back-coupling) induced by differences between the referent and actual body configurations. PMID- 26419665 TI - Circulating Levels of Uric Acid and Risk for Metabolic Syndrome. AB - : Hyperuricemia leads to insulin resistance, whereas insulin resistance decreases renal excretion of uric acid, both mechanisms link elevated serum uric acid with metabolic syndrome. The aim of this study is to evaluate the probability for the development of metabolic syndrome in low-income young adults with hyperuricaemia. METHODS: We evaluated 103 patients less than 40 years of age, from a low-income population, and without history of cardiovascular disease, in all of them the presence of metabolic syndrome was assessed in accordance with the International Diabetes Federation criteria. In all patients, fasting serum uric acid levels were measured; hyperuricaemia was defined as serum uric acid values 6.5 mg/dl in men and 5.1 mg/dl in women. Statistical analysis was performed with odds ratio. RESULTS: 83 of our patients (80.5%) suffered metabolic syndrome, the odds ratio for the presence of metabolic syndrome in patients with hyperuricaemia was 5.1 (p=0.002, I.C 1.8- 14.5). When patients were evaluated by gender a significantly association between hyperuricaemia and metabolic syndrome was found in women (odds ratio 3.6, p=0.048, C.I. 1.0-12.9), and men (odds ratio 10.2, p= 0.015, IC 1.5-13.2). When uric acid was correlated with the components of metabolic syndrome, we only found a positive correlation with waist circumference (r=0.483). CONCLUSION: Our results showed a significant association between hyperuricemia and metabolic syndrome in low-income young adults in Mexico. DR is associated with estimated risk of CVD in type 2 diabetic patients. PMID- 26419664 TI - Effects of prolonged patellar tendon vibration on force steadiness in quadriceps femoris during force-matching task. AB - The quadriceps femoris (QF) muscle group plays an essential role in human movement, such as standing, walking and running. The ability to maintain a steady force during physical activity of the human lower limb is important for mobility, postural control and balance. Although prolonged mechanical vibration of the muscle-tendon unit can moderate the efficacy of synaptic input from Ia afferent onto the alpha-motor neuron pathway, the effect of prolonged tendon vibration on fluctuations of knee extensor force has received little attention. The purpose of the present study was to examine the effects of prolonged patellar tendon vibration on the force steadiness of the QF muscle. Nine healthy men performed a submaximal force-matching task involving isometric knee extension before and after patellar tendon vibration or quiet seated rest (n = 7, control condition) for 30 min. The target force was 2.5, 10 and 30 % of maximal voluntary contraction (MVC). Surface electromyography (EMG) of the four QF synergists was recorded and normalized to EMG amplitude during the MVC. The knee extension force and the EMG amplitude of vastus medialis during the MVC were significantly reduced after the vibration, but did not significantly decrease in the control condition. Fluctuations of force and normalized EMG of individual QF muscles at each submaximal force level did not significantly change after the vibration. We conclude that prolonged patellar tendon vibration does not influence the force steadiness of the QF muscle during an isometric force-matching task. PMID- 26419666 TI - One-Pot Synthesis of Polysubstituted Spirofluorene-Indene via Ru(II)-Catalyzed [3 + 2] Annulation and Intramolecular Friedel-Crafts Cyclization. AB - Ru(II)-catalyzed one-pot synthesis of polysubstituted spirofluorene-indenes via [3 + 2] annulation and then intramolecular Friedel-Crafts alkylation has been achieved. The simple method provides a broad scope of aryl ketones and internal alkynes, achieving PAHs skeletons in moderate to good yields. PMID- 26419667 TI - Maternal and Peer Regulation of Adolescent Emotion: Associations with Depressive Symptoms. AB - Emotion socialization by close relationship partners plays a role in adolescent depression. In the current study, a microsocial approach was used to examine how adolescents' emotions are socialized by their mothers and close friends in real time, and how these interpersonal emotion dynamics are related to adolescent depressive symptoms. Participants were 83 adolescents aged 16 to 17 years who participated in conflict discussions with their mothers and self-nominated close friends. Adolescents' positive and negative emotions, and mothers' and peers' supportive regulation of adolescent emotions, were coded in real time. Two multilevel survival analyses in a 2-level Cox hazard regression framework predicted the hazard rate of (1) mothers' supportive regulation of adolescents' emotions, and (2) peers' supportive regulation of adolescents' emotions. The likelihood of maternal supportiveness, regardless of adolescent emotions, was lower for adolescents with higher depressive symptoms. In addition, peers were less likely to up-regulate adolescent positive emotions at higher levels of adolescent depressive symptoms. The results of the current study support interpersonal models of depression and demonstrate the importance of real-time interpersonal emotion processes in adolescent depressive symptoms. PMID- 26419669 TI - Not Throwing Baby Out with the Bathwater. PMID- 26419668 TI - A randomized double-blind, non-inferiority Phase II trial, comparing dapaconazole tosylate 2% cream with ketoconazole 2% cream in the treatment of Pityriasis versicolor. AB - OBJECTIVES: The objective of this research was to evaluate the efficacy of a new antifungal imidazole, dapaconazole tosylate, in the treatment of Pityriasis versicolor (PV). DESIGN AND METHODS: Sixty patients with clinical and mycological diagnosis of PV were randomly assigned to receive either 1 g dapaconazole tosylate 2% cream or 1 g ketoconazole 2% cream. Treatments were applied once a day for 28 days. A dermatologist evaluated efficacy and safety daily, and weekly laboratorial tests were performed. The primary end point was a clinical and mycological cure of lesions after 28 days of treatment. The secondary end point was the time to clinical healing assessed by Kaplan-Meier analysis and Log-rank testing. RESULTS: Fifty-three patients adhered to protocol rules. Clinical and mycological cure was achieved in 84.6% (22/26) and 92.6% (25/27) of patients treated with ketoconazole and dapaconazole, respectively (difference [effect size] = 8.0%, Standard error of difference: 8.69%, 95% CI: -6.3 to 22.3%). Median time to healing was 23.5 and 21 days for ketoconazole and dapaconazole, respectively (p = 0.126). Adverse events occurred only in ketoconazole-treated patients (13%; 4/30). CONCLUSION: Dapaconazole tosylate is non-inferior to ketoconazole when used at a dose of 20 mg/day for 28 consecutive days for the treatment of PV. Dapaconazole also demonstrated a good safety profile. PMID- 26419671 TI - When a Tree Falls in the Woods: The Gravitropic Response in Poplar. PMID- 26419670 TI - Discovery of a Unique Clp Component, ClpF, in Chloroplasts: A Proposed Binary ClpF-ClpS1 Adaptor Complex Functions in Substrate Recognition and Delivery. AB - Clp proteases are found in prokaryotes, mitochondria, and plastids where they play crucial roles in maintaining protein homeostasis (proteostasis). The plant plastid Clp machinery comprises a hetero-oligomeric ClpPRT proteolytic core, ATP dependent chaperones ClpC and ClpD, and an adaptor protein, ClpS1. ClpS1 selects substrates to the ClpPR protease-ClpC chaperone complex for degradation, but the underlying substrate recognition and delivery mechanisms are currently unclear. Here, we characterize a ClpS1-interacting protein in Arabidopsis thaliana, ClpF, which can interact with the Clp substrate glutamyl-tRNA reductase. ClpF and ClpS1 mutually stimulate their association with ClpC. ClpF, which is only found in photosynthetic eukaryotes, contains bacterial uvrB/C and YccV protein domains and a unique N-terminal domain. We propose a testable model in which ClpS1 and ClpF form a binary adaptor for selective substrate recognition and delivery to ClpC, reflecting an evolutionary adaptation of the Clp system to the plastid proteome. PMID- 26419672 TI - Leaf Growth Directionality Is Divergent and Involves a Conserved MicroRNA Regulatory Module. PMID- 26419673 TI - Cyclic fatigue resistance of D-RaCe, ProTaper, and Mtwo nickel-titanium retreatment instruments after immersion in sodium hypochlorite. AB - OBJECTIVES: The aim of this study was to investigate the effect of immersion in sodium hypochlorite (NaOCl) on cyclic fatigue resistance of three different rotary nickel-titanium (NiTi) retreatment files. MATERIAL AND METHODS: A total of 90 new ProTaper, D-RaCe, and Mtwo retreatment files were tested. Thirty files of the same brand were randomly assigned to two groups (n = 15). Group 1 was no immersion (control group) and 16 mm of group 2 instruments were immersed in 5 % NaOCl at 37 degrees C for 5 min. All instruments were then tested for cyclic fatigue. Resistance to cyclic fatigue was determined by counting the numbers of cycles to failure in a 60 degrees curve with a 5-mm radius, recording the time in seconds to fracture. Data were analyzed by two-way analysis of variance. RESULTS: Resistance to cyclic fatigue decreased significantly for D-RaCe retreatment files after immersion in NaOCl. ProTaper and Mtwo retreatment files were not affected from immersion to NaOCl. D-RaCe retreatment instruments showed better cyclic fatigue resistance than ProTaper and Mtwo retreatment instruments, and the difference was statistically significant (p < 0.05). There was no significant difference between ProTaper and Mtwo retreatment instrument groups (p > 0.05). CONCLUSIONS: D-RaCe retreatment instruments had the highest cyclic fatigue resistance among retreatment files tested in this study, but immersion to NaOCl decreased the cyclic fatigue resistance of D-RaCe retreatment instrument. CLINICAL RELEVANCE: It should be considered that cyclic fatigue resistance of D RaCe can decrease in contact with NaOCl during the removal of canal filling material. PMID- 26419674 TI - Efficiency of powered systems for interproximal enamel reduction (IER) and enamel roughness before and after polishing-an in vitro study. AB - OBJECTIVE: This aims to evaluate the efficiency of three different powered interproximal enamel reduction (IER) systems and to assess enamel roughness before and after polishing using different polishing times. MATERIAL AND METHODS: Four metal strips of the G5 ProLign Set (swissdentacare, SDC, Grancia, Switzerland), four segmental discs of the ASR-Set 4594 and two sonic tips of the SonicLine Set (both Gebr. Basseler GmbH & Co. KG, Komet, Lemgo, Germany) were evaluated. Human extracted incisors served as the medium. Enamel reduction was determined in five intervals of 15 s each. Polishing was performed for 15 and 30 s using the manufacturers' recommended polishing systems. Enamel roughness (Ra) was quantitatively assessed by confocal laser scanning microscopy (CLSM). RESULTS: Significant differences in terms of enamel reduction were found among the working ends of all tested systems. The time needed to remove 0.1, 0.2 and 0.3 mm of enamel was determined. Surface analysis showed significantly higher mean Ra values for nine out of ten working ends before polishing. This was still the case for five working ends after 15 s and for two after 30 s of polishing. CONCLUSION: The graining and the system used have a significant influence on enamel reduction. The time needed for polishing depends on the last working end used; a polishing time of 30 s is not always appropriate. CLINICAL RELEVANCE: Knowledge about the cutting efficiency of powered IER working ends might help the clinician to estimate better the amount of enamel reduction during the stripping process. PMID- 26419675 TI - Microbiological effects and recolonization patterns after adjunctive subgingival debridement with Er:YAG laser. AB - OBJECTIVES: The objective of this study was to assess the microbiological effects and recolonization patterns after non-surgical periodontal treatment protocol based on the adjunctive use of erbium-doped yttrium aluminium garnet (Er:YAG) laser. MATERIAL AND METHODS: Patients diagnosed with chronic periodontitis were randomly assigned to two different treatment protocols: test, full-mouth subgingival ultrasonic instrumentation followed by Er-YAG laser application 1 week later to sites with initial probing pocket depth >=4.5 mm; and control, full mouth ultrasonic subgingival instrumentation within 1 week. Clinical (at sampled sites) and microbiological (culture-based) parameters were recorded at baseline and 3 and 12 months. Microbiological variables included total counts, frequency of detection, proportions and counts of target species. RESULTS: Results from 19 test and 21 control patients were compared. Minor changes were observed for total colony-forming units, with no differences between groups. For the frequency of detection, a limited and similar impact in both groups was observed for the most prevalent (over 80 %) periodontal pathogens (Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum). For proportions, reductions in P. gingivalis occurred at 3 months, both in the test and control groups (from 16.3 to 10 % and 16 to 14.8 %, respectively), although these differences were not statistically significant. At 12 months, the test group showed a statistically significant greater reduction in probing depth for the sampled sites. CONCLUSIONS: The adjunctive use of Er:YAG laser when compared with conventional ultrasonic debridement did not provide a microbiological added benefit. CLINICAL RELEVANCE: Even though some clinical benefits with the adjunctive laser application were identified when comparing both treatment protocols, there were no differences in microbiological outcomes or in the bacterial recolonization patterns. PMID- 26419677 TI - Implantable wireless battery recharging system for bladder pressure chronic monitoring. AB - This paper presents an implantable wireless battery recharging system design for bladder pressure chronic monitoring. The wireless recharging system consists of an external 15 cm-diameter 6-turn powering coil and a silicone-encapsulated implantable rectangular coil with a dimension of 7 mm * 17 mm * 2.5 mm and 18 turns, which further encloses a 3 mm-diameter and 12 mm-long rechargeable battery, two ferrite rods, an ASIC, and a tuning capacitor. For a constant recharging current of 100 MUA, an RF power of 700 MUW needs to be coupled into the implantable module through the tuned coils. Analyses and experiments confirm that with the two coils aligned coaxially or with a 6 cm axial offset and a tilting angle of 30 degrees , an external power of 3.5 W or 10 W is required, respectively, at an optimal frequency of 3 MHz to cover a large implant depth of 20 cm. PMID- 26419676 TI - Transungual permeation: current insights. AB - Nail disorders are beyond cosmetic concern; besides discomfort in the performance of daily chores, they disturb patients psychologically and affect their quality of life. Fungal nail infection (onychomycosis) is the most prevalent nail-related disorder affecting a major population worldwide. Overcoming the impenetrable nail barrier is the toughest challenge for the development of efficacious topical ungual formulation. Sophisticated techniques such as iontophoresis and photodynamic therapy have been proven to improve transungual permeation. This article provides an updated and concise discussion regarding the conventional approach and upcoming novel approaches focused to alter the nail barrier. A comprehensive description regarding preformulation screening techniques for the identification of potential ungual enhancers is also described in this review while highlighting the current pitfalls for the development of ungual delivery. PMID- 26419678 TI - Ivabradine reduces myocardial stunning in patients with exercise-inducible ischaemia. AB - Ivabradine is an effective treatment for angina in patients with stable coronary artery disease (CAD) and for heart failure. Experiments in a canine model have shown that ivabradine reduces both acute left ventricular (LV) dysfunction and post-ischaemic stunning. Aim of this study was to investigate the effect of ivabradine on LV dysfunction and stunning in patients with CAD and exercise inducible ischaemia. Fifteen patients with ejection fraction >40 % and heart rate >70 bpm were enrolled. After pharmacologic washout, echocardiography was performed at rest, at peak treadmill exercise and during recovery until return to baseline. After 2 weeks of ivabradine (7.5 mg bid) stress echocardiography was repeated at the same workload achieved during washout. Peak global and segmental (ischaemic vs. remote normal segments) LV longitudinal strain (LS) was assessed by 2D speckle tracking analysis. At washout, LS was significantly impaired in ischaemic compared to remote segments at peak stress and for several minutes during recovery. After ivabradine a smaller, albeit still significant, impairment of LS in ischaemic segments was observed at peak whilst no difference with remote segments was present during recovery. Furthermore, the average global LS value improved significantly after treatment. In conclusion, ivabradine reduces both acute LV dysfunction and stunning in patients with CAD and exercise-inducible ischaemia. We hypothesise that this mechanism might contribute to reduce chronic LV dysfunction in patients with CAD. In this setting the drug might limit the development of hibernating myocardium which is believed to result from repeated episodes of ischaemia and stunning. PMID- 26419679 TI - Assessing risk factors for early hip osteoarthritis in activity-related hip pain: a Delphi study. AB - OBJECTIVE: Hip pain and injury as a result of activity can lead to the development of early hip osteoarthritis (OA) in susceptible individuals. Our understanding of the factors that increase susceptibility continues to evolve. The ability to clearly identify individuals (and cohorts) with activity-related hip pain who are at risk of early hip OA is currently lacking. The purpose of this study was to gain expert consensus on which key clinical measures might help predict the risk of early hip OA in individuals presenting with activity-related hip pain. The agreed measures would constitute a standardised approach to initial clinical assessment to help identify these individuals. METHODS: This Dephi study used online surveys to gain concordance of expert opinion in a structured process of 'rounds'. In this study, we asked 'What outcome measures are useful in predicting hip OA in activity-related hip pain?' The Delphi panel consisted of experts from sport and exercise medicine, orthopaedics, rheumatology, physiotherapy and OA research. RESULTS: The study identified key clinical measures in the history, examination and investigations (plain anteroposterior radiograph and femoroacetabular impingement views) that the panel agreed would be useful in predicting future risk of hip OA when assessing activity-related hip pain. The panel also agreed that certain investigations and tests (eg, MR angiography) did not currently have a role in routine assessment. There was a lack of consensus regarding the role of MRI, patient-reported outcome measures (PROMs) and certain biomechanical and functional assessments. CONCLUSIONS: We provide a standardised approach to the clinical assessment of patients with activity-related hip pain. Assessment measures rejected by the Delphi panel were newer, more expensive investigations that currently lack evidence. Assessment measures that did not reach consensus include MRI and PROMs. Their role remains ambiguous and would benefit from further research. PMID- 26419680 TI - Cost-effectiveness and budget impact of Empirical vitamin D therapy on unintentional falls in older adults in the UK. AB - OBJECTIVES: To evaluate the health outcomes and economics associated with the current guidance relating to the prevention of falls in the elderly through vitamin D supplementation. SETTING: UK. PARTICIPANTS: UK population aged 60 years and above. INTERVENTIONS: A Markov health state transition model simulated patient transitions between key fall-related outcomes using a 5-year horizon and annual cycles to assess the costs and benefits of empirical treatment with colecalciferol 800 iu daily. PRIMARY AND SECONDARY OUTCOME MEASURES: Costs and health outcomes attributable to fall prevention following vitamin D supplementation. RESULTS: Our model shows that treating the UK population aged 60 years and above with 800 iu colecalciferol would, over a 5-year period: (1) prevent in excess of 430,000 minor falls; (2) avoid 190,000 major falls; (3) prevent 1579 acute deaths; (4) avoid 84,000 person-years of long-term care and (5) prevent 8300 deaths associated with increased mortality in long-term care. The greatest gains are seen among those 75 years and older. Based on reduction in falls alone, the intervention in all adults aged 65+ is cost-saving and leads to increased quality adjusted life years. Treating all adults aged 60+ incurs an intervention cost of L2.70bn over 5 years, yet produces a -L3.12bn reduction in fall-related costs; a net saving of L420M. Increasing the lower bound age limit by 5-year increments increases budget impact to -L1.17bn, -L1.75bn, and -L2.06bn for adults 65+, 70+ and 75+, respectively. CONCLUSIONS: This study shows that treatment of the elderly UK population with colecalciferol 800 iu daily would be associated with reductions in mortality and substantial cost-savings through fall prevention. PMID- 26419681 TI - Multicentre, randomised, placebo-controlled trial of extract of Japanese herbal medicine Daikenchuto to prevent bowel dysfunction after adult liver transplantation (DKB 14 Study). AB - INTRODUCTION: This multicentre randomised controlled clinical trial will aim to determine the ability of an extract (TJ-100) of Daikenchuto (traditional Japanese herbal medicine; Kampo) to prevent bowel dysfunction in at least 110 patients after liver transplantation (LT). METHODS AND ANALYSIS: The following co-primary end points will be evaluated on postoperative day 7: total oral and enteral caloric intake, abdominal distension and abdominal pain. The secondary end points will comprise sequential changes of total oral and enteral caloric intake after LT, sequential changes in numeric rating scales for abdominal distension and pain, elapsed time to the first postoperative passage of stool, quality of life assessment using the Gastrointestinal Symptom Rating Scale score (Japanese version), postoperative liver function, liver regeneration rate, incidence of bacteraemia and bacterial strain, trough level of immunosuppressants, occurrence of acute cellular rejection, discharge or not within 2 months after LT, sequential changes of portal venous flow to the graft and ascites discharge. The two arms of the study will comprise 55 patients per arm. ETHICS AND DISSEMINATION: The study has been conducted according to the CONSORT statement. All participants signed a written consent form, and the study has been approved by the institutional review board of each participating institute and conducted in accordance with the Declaration of Helsinki of 1996. The findings will be disseminated through scientific and professional conferences, and in peer reviewed journals. TRIAL REGISTRATION NUMBER: The DKB 14 Study was registered in the University Hospital Medical Information Network Clinical Trial Registration (UMIN-CTR), Japan (registration number: UMIN000014326) during 2014. PMID- 26419682 TI - Gallstone is correlated with an increased risk of idiopathic sudden sensorineural hearing loss: a retrospective cohort study. AB - OBJECTIVES: This study aims to test the hypothesis that gallstone disease (GSD) is a risk factor for the development of idiopathic sudden sensorineural hearing loss (ISSNHL). Research has shown risks of cardiovascular and cerebrovascular events in patients with GSD; however, well-conducted English studies on the association between GSD and the development of ISSNHL are lacking. DESIGN AND SETTING: Retrospective cohort study using the Taiwan Longitudinal Health Insurance Database. PARTICIPANTS: We compared 26,449 patients diagnosed with GSD between 1 January 2001 and 31 December 2007, with 52,898 age-matched, gender matched and comorbidities propensity scores-matched controls. OUTCOME MEASURED: We followed each patient until the end of 2011 and evaluated the incidence of ISSNHL for at least 4 years after the initial GSD diagnosis. RESULTS: The incidence of ISSNHL was 1.42 times higher in the GS cohort than in the non-GS cohort (9.27 vs 6.52/10,000 person-years). Using Cox proportional hazard regressions, the adjusted HR was 1.44 (95% CI 1.19 to 1.74). In the cohort of patients with GSD who needed a cholecystectomy, 37 patients suffered from ISSNHL. Among those patients, 31 (83.7%) patients sustained ISSNHL before cholecystectomy and 6 (16.2%) patients sustained ISSNHL after cholecystectomy. CONCLUSIONS: A diagnosis of GSD may be an independent risk for ISSNHL. This finding suggests that an underlying vascular and inflammatory mechanism may contribute to the development of ISSNHL. Physicians may want to counsel patients with GSD to seek medical attention if they have hearing impairments, because patients may be at an increased risk of developing ISSNHL. PMID- 26419683 TI - The challenge of vaccinating adults: attitudes and beliefs of the Canadian public and healthcare providers. AB - OBJECTIVES: Vaccine coverage for recommended vaccines is low among adults. The objective of this study was to assess the knowledge, attitudes, beliefs and behaviours of adults and healthcare providers related to four vaccine-preventable diseases and vaccines (diphtheria-tetanus-pertussis, zoster, pneumococcus and influenza). DESIGN: We undertook a survey and focus groups of Canadian adults and healthcare providers (doctors, nurses, pharmacists). A total of 4023 adults completed the survey and 62 participated in the focus groups; 1167 providers completed the survey and 45 participated in the focus groups. RESULTS: Only 46.3% of adults thought they were up-to-date on their vaccines; 30% did not know. In contrast, 75.6% of providers reported being up-to-date. Only 57.5% of adults thought it was important to receive all recommended vaccines (compared to 87.1 91.5% of providers). Positive attitudes towards vaccines paralleled concern about the burden of illness and confidence in the vaccines, with providers being more aware of disease burden and confident in vaccine effectiveness than the public. Between 55.0% and 59.7% of adults reported willingness to be vaccinated if recommended by their healthcare provider. However, such recommendations were variable; while 77.4% of the public reported being offered and 52.8% reported being recommended the influenza vaccine by their provider, only 10.8% were offered and 5.6% recommended pertussis vaccine. Barriers and facilitators to improved vaccine coverage in adults, such as trust-mistrust of health authorities, pharmaceutical companies and national recommendations, autonomy versus the public good and logistical issues (such as insufficient time and lack of vaccination status tracking), were identified by both the public and providers. CONCLUSIONS: Despite guidelines for adult vaccination, there are substantial gaps in knowledge and attitudes and beliefs among both the public and healthcare providers that lead to low vaccine coverage. A systematic approach that involves education, elimination of barriers and establishing and improving infrastructure for adult immunisation is required. PMID- 26419684 TI - Tracking Biases: An Update to the Validity and Reliability of Alcohol Retail Sales Data for Estimating Population Consumption in Scotland. AB - AIMS: To highlight the importance of monitoring biases when using retail sales data to estimate population alcohol consumption. METHODS: Previously, we identified and where possible quantified sources of bias that may lead to under- or overestimation of alcohol consumption in Scotland. Here, we update findings by using more recent data and by quantifying emergent biases. RESULTS: Underestimation resulting from the net effect of biases on population consumption in Scotland increased from -4% in 2010 to -7% in 2013. CONCLUSION: Biases that might impact on the validity and reliability of sales data when estimating population consumption should be routinely monitored and updated. PMID- 26419685 TI - Coccidioidomycosis in Biopsies with Presumptive Diagnosis of Malignancy in Dogs: Report of Three Cases and Comparative Discussion of Published Reports. AB - Coccidioidomycosis is a respiratory fungal infection with occasional systemic dissemination. The disseminated coccidioidomycosis is considered a multifaceted disease. In medicine, disseminated coccidioidomycosis is included within a group of infectious diseases that have been referred as the great imitators. In many cases, malignancies are included in the presumptive diagnosis. In veterinary medicine, disseminated coccidioidomycosis is common in dogs. Nonetheless, despite of being a diagnostic dilemma, disseminated coccidioidomycosis is underestimated and frequently not included into differentials, even in endemic zones. Herein, we describe three cases of granulomatous inflammation caused by Coccidioides spp. which were masquerading malignancies in dogs (0.39 %). The presumptive diagnoses in these cases were osteosarcoma, lymphoma and neurofibroma, respectively. A PCR assay employing tissues in paraffin blocks resulted positive for C. posadasii in one of these cases. A comparative discussion on the ambiguous clinic-pathological presentation of disseminated coccidioidomycosis in dogs and humans is included. PMID- 26419686 TI - Coffee inhibits nuclear factor-kappa B in prostate cancer cells and xenografts. AB - Chronic inflammation contributes to prostate cancer and the transcription factor Nuclear Factor-kappa B (NF-kappaB) is constitutively active in most such cancers. We examine the effects of coffee on NF-kappaB and on the regulation of selected genes in human-derived prostate cancer cells (PC3) and in PC3 xenografts in athymic nude mice. PC3 cells stably transduced with an NF-kappaB-luciferase reporter were used both in vitro and for xenografts. NF-kappaB activity was measured by reporter assays, DNA binding and in vivo imaging. Gene expression was measured in PC3 cells, xenografts and tumor microenvironment by low-density arrays. Western blotting of activated caspases was used to quantify apoptosis. Coffee inhibited TNFalpha-induced NF-kappaB activity and DNA-binding in PC3 cells. Furthermore, coffee increased apoptosis and modulated expression of a number of inflammation- and cancer-related genes in TNFalpha-treated PC3 cells. In vivo imaging revealed a 31% lower NF-kappaB-luciferase activation in the xenografts of the mice receiving 5% coffee compared to control mice. Interestingly, we observed major changes in gene expression in the PC3 cells in xenografts as compared to PC3 cells in vitro. In PC3 xenografts, genes related to inflammation, apoptosis and cytoprotection were down-regulated in mice receiving coffee, and coffee also affected the gene expression in the xenograft microenvironment. Our data demonstrate that coffee inhibits NF-kappaB activity in PC3 cells in vitro and in xenografts. Furthermore, coffee modulates transcription of genes related to prostate cancer and inflammation. Our results are the first to suggest mechanistic links between coffee consumption and prostate cancer in an experimental mouse model. PMID- 26419688 TI - Intramolecular Excimer Formation Dynamics of 1,3-Bis-(1-pyrenyl)propane within 1 Butyl-3-methylimidazolium Hexafluorophosphate and Its Polyethylene Glycol Mixtures. AB - Mixtures of ionic liquid with polyethylene glycol (PEG) have shown interesting features as solubilizing media. Intramolecular excimer formation dynamics of 1,3 bis-(1-pyrenyl)propane [1Py(3)1Py] is investigated within mixtures of a common and popular ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF6]) with PEGs of average molecular weight (MW) 200 (PEG200), average MW 400 (PEG400), number-average MW Mn 570-630 (PEG600), and number-average MW Mn 950 1050 (PEG1000) over the complete composition range at a 10 degrees interval in the temperature range 10-90 degrees C. Irrespective of the composition of the medium and the temperature, excited-state intensity decay of the excimer fluorescence best fits to a three-exponential decay function, suggesting the presence of one excited-state monomer and two kinetically distinguishable excimers where both excimers are populated simultaneously by the excited monomer with no interconversion between the two excimers. In neat PEGs for temperatures <= 50 degrees C, intensity decay data of monomer fluorescence best fits to a single-exponential decay function, which implies the dissociation of both excimers back to the monomer to be insignificant. As the temperature is increased, the fits become closer to a double-exponential decay function, implying dissociation of one of the excimers to become significant. In neat [bmim][PF6], while a double-exponential decay function is required to fit the monomer excited-state intensity decay data at lower temperatures, three exponentials are required to satisfactorily fit the data at higher temperatures, suggesting both excimers significantly dissociate back to the monomer at higher temperatures within the ionic liquid. Within long-chain PEG-containing ([bmim][PF6] + PEG) mixtures, PEG as opposed to [bmim][PF6] controls the excimer formation dynamics by supposedly wrapping around the excimer, thus hindering dissociation back to the monomer. The overall rate constant of the excimer formation within ([bmim][PF6] + PEG) mixtures is found to scale better with the microviscosity rather than the bulk viscosity of the mixtures. PMID- 26419689 TI - Few-Volt Operation of Printed Organic Ferroelectric Capacitor. AB - The fabrication of single-crystalline thin-film arrays for an organic ferroelectric small molecule is achieved by a simple solution process without additional thermal annealing. Based on a cooperative proton tautomerism through a hydrogen-bonding network, films show the polarity switching with an operating voltage of less than 5 V at room temperature. This approach provides a low-cost and eco-friendly fabrication of ferroelectric devices. PMID- 26419690 TI - Effect of ceftriaxone and cefepime on high-dose methotrexate clearance. AB - Numerous drug interactions with methotrexate have been identified, which can lead to serious life-threatening effects. Up to 90% of methotrexate is excreted unchanged in the urine with primary excretion dependent on organic anion transport in the renal proximal tubule. The two pathways responsible for methotrexate secretion are organic anion transport 1 and primarily organic anion transport 3. Penicillins undergo tubular secretion via organic anion transport, and cephalosporins are believed to also possess a similar risk when administered with methotrexate; however, there are no human studies observing this interaction with cephalosporins and methotrexate. Ceftriaxone undergoes biliary clearance and has low affinity for the same organic anion transports as methotrexate; therefore, ceftriaxone has a low potential to interact with methotrexate. Cefepime is primarily secreted by organic cation transport N2, and also has a low potential to interact with methotrexate. This case report describes the pharmacokinetic effect of concomitant beta-lactam therapy in a patient receiving high-dose methotrexate. PMID- 26419691 TI - Impact of oncology pharmacist-managed oral anticancer therapy in patients with chronic myelogenous leukemia. AB - BACKGROUND: Studies have identified non-adherence as one of the major contributing factors to treatment failure in chronic myelogenous leukemia (CML) patients receiving imatinib. Published literature has demonstrated a unique role of oncology pharmacists, as part of a multidisciplinary team, in contributing to overall positive outcomes for patients. STUDY OBJECTIVE: To evaluate the impact of an oncology pharmacist-managed oral anticancer therapy program on oral medication adherence in CML patients versus usual care. METHODS: Electronic refill history and medical records of patients diagnosed with CML treated with oral tyrosine kinase inhibitors (TKIs) managed by oncology pharmacists during a 6 year period, were retrospectively reviewed. Imatinib adherence rate, as the primary endpoint, was compared with the rate for those in the usual care group within the same organization. The secondary endpoints were descriptive to characterize pharmacist interventions for all TKIs. RESULTS: A total of 56 patients including 45 who were treated with imatinib, were evaluated. The group managed by oncology pharmacists resulted in a higher percentage of imatinib adherence rate compared to usual care (88.6% vs 65.8%, p = 0.0046). A total of 3432 pharmacist encounters were reviewed, and 567 interventions of six categories including side effect monitoring/management (n = 95; 16.8%); drug interaction detection (n = 109; 19.2%); TKI dose adjustment (n = 82; 14.5%); laboratory monitoring (n = 200; 35.3%); non-CML related drug choice (n = 74; 13.1%); and copay assistance (n = 7; 1.2%), were documented. This resulted in a mean of 10.1 interventions per patient. CONCLUSIONS: Our oncology pharmacist-managed oral anticancer therapy program significantly improved TKI adherence rates in CML patients. We attribute the success of our program to consistent follow-up by utilizing routine phone, and secure email follow-ups, that allowed our oncology pharmacists to build a close and trustworthy relationship with patients and families. PMID- 26419692 TI - Cytarabine syndrome despite corticosteroid premedication in an adult undergoing induction treatment for acute myelogenous leukemia. AB - Cytarabine syndrome is a rare clinical condition characterized by fever, malaise, myalgia, arthralgia, and/or rash that occurs after receipt of cytarabine. Our patient developed fever, malaise, and diffuse body pain shortly following cytarabine initiation despite receiving prophylactic dexamethasone. The patient's discomfort was treated with intravenous morphine and her other symptoms were controlled with a higher dose of dexamethasone. Although the exact cause is not fully understood, cytarabine syndrome is hypothesized to be an immune-mediated response following cytarabine-induced apoptosis that results in a rapid increase in proinflammatory cytokines. While there is no standard therapy for cytarabine syndrome, corticosteroids appear to play a role in the treatment and prevention of the condition by suppressing the proinflammatory response. Since our case describes the development of cytarabine syndrome despite dexamethasone, clinicians should monitor for this adverse event if patients begin exhibiting characteristics of this syndrome. PMID- 26419687 TI - The complexity of the Nrf2 pathway: beyond the antioxidant response. AB - The NF-E2-related factor 2 (Nrf2)-mediated signalling pathway provides living organisms an efficient and pivotal line of defensive to counteract environmental insults and endogenous stressors. Nrf2 coordinates the basal and inducible expression of antioxidant and Phase II detoxification enzymes to adapt to different stress conditions. The stability and cellular distribution of Nrf2 is tightly controlled by its inhibitory binding protein Kelch-like ECH-associated protein 1. Nrf2 signalling is also regulated by posttranslational, transcriptional, translational and epigenetic mechanisms, as well as by other protein partners, including p62, p21 and IQ motif-containing GTPase activating protein 1. Many studies have demonstrated that Nrf2 is a promising target for preventing carcinogenesis and other chronic diseases, including cardiovascular diseases, neurodegenerative diseases and pulmonary injury. However, constitutive activation of Nrf2 in advanced cancer cells may confer drug resistance. Here, we review the molecular mechanisms of Nrf2 signalling, the diverse classes of Nrf2 activators, including bioactive nutrients and other chemicals, and the cellular functions and disease relevance of Nrf2 and discuss the dual role of Nrf2 in different contexts. PMID- 26419693 TI - Salt-Free Reduction of Nonprecious Transition-Metal Compounds: Generation of Amorphous Ni Nanoparticles for Catalytic C-C Bond Formation. AB - A salt-free procedure for the generation of a wide variety of metal(0) particles, including Fe, Co, Ni, and Cu, was achieved using 2,3,5,6-tetramethyl-1,4 bis(trimethylsilyl)-1,4-diaza-2,5-cyclohexadiene (1), which reduced the corresponding metal precursors under mild conditions. Notably, Ni particles formed in situ from the treatment of Ni(acac)2 (acac = acetylacetonate) with 1 in toluene exhibited significant catalytic activity for reductive C-C bond-forming reactions of aryl halides in the presence of excess amounts of 1. By examination of high-magnification transmission electron microscopy images and electron diffraction patterns, we concluded that amorphous Ni nanoparticles (Ni aNPs) were essential for the high catalytic activity. PMID- 26419694 TI - Heat and oxidative stress alter the expression of orexin and its related receptors in avian liver cells. AB - Orexins (A and B) or hypocretins (1 and 2) are hypothalamic orexigenic neuropeptides that are involved in the regulation of several physiological processes in mammals. Recently, orexin has been shown to activate the hypothalamic-pituitary-adrenal (HPA) stress axis and emerging evidences identify it as a stress modulator in mammals. However, the regulation of orexin system by stress itself remains unclear. Here, we investigate the effects of heat, 4 Hydroxynonenal (4-HNE) and hydrogen peroxide (H2O2) stress on the hepatic expression of orexin (ORX) and its related receptors (ORXR1/2) in avian species. Using in vivo and in vitro models, we found that heat stress significantly down regulated ORX and ORXR1/2 mRNA and protein abundances in quail liver and LMH cells. H2O2, however, decreased ORX protein and increased ORX mRNA levels in a dose dependent manner (P<0.05). The absence of correlation between orexin mRNA and protein levels suggests that H2O2 treatment modulates post-transcriptional mechanisms. 4-HNE had a biphasic effect on orexin system expression, with a significant up-regulation at low doses (10 and 20MUM) and a significant down regulation at a high dose (30MUM). Taken together, our data indicated that hepatic orexin system could be a molecular signature in the heat and oxidative stress response. PMID- 26419695 TI - Energy metabolism of hyperthyroid gilthead sea bream Sparus aurata L. AB - Thyroid hormones, in particular 3,5,3'-triiodothyronine or T3, are involved in multiple physiological processes in mammals such as protein, fat and carbohydrate metabolism. However, the metabolic actions of T3 in fish are still not fully elucidated. We therefore tested the effects of T3 on Sparus aurata energy metabolism and osmoregulatory system, a hyperthyroid-induced model that was chosen. Fish were implanted with coconut oil depots (containing 0, 2.5, 5.0 and 10.0MUg T3/g body weight) and sampled at day 3 and 6 post-implantation. Plasma levels of free T3 as well as glucose, lactate and triglyceride values increased with increasing doses of T3 at days 3 and 6 post-implantation. Changes in plasma and organ metabolite levels (glucose, glycogen, triglycerides, lactate and total alpha amino acid) and enzyme activities related to carbohydrate, lactate, amino acid and lipid pathways were detected in organs involved in metabolism (liver) and osmoregulation (gills and kidney). Our data implicate that the liver uses amino acids as an energy source in response to the T3 treatment, increasing protein catabolism and gluconeogenic pathways. The gills, the most important extruder of ammonia, are fuelled not only by amino acids, but also by lactate. The kidney differs significantly in its substrate preference from the gills, as it obtained metabolic energy from lactate but also from lipid oxidation processes. We conclude that in S. aurata lipid catabolism and protein turnover are increased as a consequence of experimentally induced hyperthyroidism, with secondary osmoregulatory effects. PMID- 26419696 TI - Plasma levels of follicle-stimulating and luteinizing hormones during the reproductive cycle of wild and cultured Senegalese sole (Solea senegalensis). AB - The intensive culture of the Senegalese sole (Solea senegalensis) is hampered by the low or null fertilization rates exhibited by the first generation (F1) of reared males. To investigate the regulation of the reproductive processes in this species by the pituitary gonadotropins follicle-stimulating and luteinizing hormones (Fsh and Lh, respectively), we developed a highly sensitive and specific enzyme-linked immunosorbent assay (ELISA) for Lh measurements. Quantification of the Fsh and Lh plasma levels in cultured sole using the Lh ELISA developed here, and a previously developed ELISA for Fsh, indicated that in both males and females circulating Fsh steadily increased during autumn and winter and prior to the major spawning in spring, whereas an Lh surge occurred specifically during spawning. The increase in Fsh was associated with a rise of plasma levels of the steroid hormones testosterone (T), 11-ketotestosterone (11-KT) and estradiol 17beta (E2), but that of Lh was concomitant with a strong decline of the levels of E2 in females and of 11-KT in males, possibly reflecting a rapid steroidogenic shift promoting the final maturation of gametes. Comparison of the plasma levels of gonadotropins and steroids between wild and F1 fish during autumn and spring revealed that F1 males showed significantly lower plasma Lh titres compared to wild males, whereas the levels of T and 11-KT were similar or more elevated in the F1 fish. These data suggest that an impaired Lh secretion during spawning, and perhaps altered Lh-mediated mechanisms in the testis, may be underlying causes for the low reproductive performance of Senegalese sole F1 males. PMID- 26419697 TI - Developmental expression of estrogen receptor beta in the brain of prairie voles (Microtus ochrogaster). AB - Here, for the first time, the expression of estrogen receptor beta (ERbeta) is characterized in the brains of the highly prosocial prairie vole (Microtus ochrogaster). ERbeta immunoreactivity was compared in weanlings (postnatal Day 21) and adult males and females. The results indicate several major findings. First, unlike ERalpha, ERbeta expression is not sexually dimorphic. Second, the adult pattern of ERbeta-IR is established at the time of weaning, as there were no age-dependent effects on distribution. Finally, ERbeta does not appear to be as widely distributed in voles compared with rats and mice. High levels of ERbeta IR were observed in several regions/nuclei within the medial pre-optic area, ventrolateral pre-optic nuclei, and in the hypothalamus, especially in the paraventricular and supraoptic nuclei. The visualization of ERbeta in prairie voles is important as the socially monogamous prairie vole functions as a human relevant model system for studying the expression of social behavior and social deficit disorders. Future studies will now be able to determine the effect of treatments on the expression and/or development of ERbeta in this highly social species. PMID- 26419698 TI - Synergistic effect of exogeneous and endogeneous electrostimulation on osteogenic differentiation of human mesenchymal stem cells seeded on silk scaffolds. AB - Bioelectrical regulation of bone fracture healing is important for many cellular events such as proliferation, migration, and differentiation. The aim of this study was to investigate the osteogenic differentiation potential of human mesenchymal stem cells (hMSCs) cultivated on silk scaffolds in response to different modes of electrostimulation (e.g., exogeneous and/or endogeneous). Endogeneous electrophysiology was altered through the use of monensin (10 nM) and glibenclamide (10 MUM), along with external electrostimulation (60 kHz; 100-500 mV). Monensin enhanced the expression of early osteogenic markers such as alkaline phosphatase (ALP) and runt-related transcription factor 2 (RUNX-2). When exogeneous electrostimulation was combined with glibenclamide, more mature osteogenic marker upregulation based on bone sialoprotein expression (BSP) and mineralization was found. These results suggest the potential to exploit both exogeneous and endogeneous biophysical control of cell functions towards tissue specific goals. PMID- 26419699 TI - Ultra-processed foods have the worst nutrient profile, yet they are the most available packaged products in a sample of New Zealand supermarkets--CORRIGENDUM. PMID- 26419700 TI - Music, empathy and cultural understanding. AB - In the age of the Internet and with the dramatic proliferation of mobile listening technologies, music has unprecedented global distribution and embeddedness in people's lives. It is a source of intense experiences of both the most intimate and solitary, and public and collective, kinds - from an individual with their smartphone and headphones, to large-scale live events and global simulcasts; and it increasingly brings together a huge range of cultures and histories, through developments in world music, sampling, the re-issue of historical recordings, and the explosion of informal and home music-making that circulates via YouTube. For many people, involvement with music can be among the most powerful and potentially transforming experiences in their lives. At the same time, there has been increasing interest in music's communicative and affective capacities, and its potential to act as an agent of social bonding and affiliation. This review critically discusses a considerable body of research and scholarship, across disciplines ranging from the neuroscience and psychology of music to cultural musicology and the sociology and anthropology of music, that provides evidence for music's capacity to promote empathy and social/cultural understanding through powerful affective, cognitive and social factors; and explores ways in which to connect and make sense of this disparate evidence (and counter-evidence). It reports the outcome of an empirical study that tests one aspect of those claims, demonstrating that 'passive' listening to the music of an unfamiliar culture can significantly change the cultural attitudes of listeners with high dispositional empathy; presents a model that brings together the primary components of the music and empathy research into a single framework; and considers both some of the applications, and some of the shortcomings and problems, of understanding music from the perspective of empathy. PMID- 26419701 TI - Significant factors for work attractiveness and how these differ from the current work situation among operating department nurses. AB - AIMS AND OBJECTIVES: The aim was to examine significant factors for work attractiveness and how these differ from the current work situation among operating department nurses. A second objective was to examine the associations between age, gender, length of employment, work engagement, work ability, self rated health indicators and attractiveness of the current work situation. BACKGROUND: The attractiveness of work is rarely taken into account in research on nurse retention. To expand this knowledge, it is relevant to examine factors that make work attractive and their associations with related concepts. DESIGN: Correlational, cross-sectional survey using a convenience sample. METHODS: Questionnaires were answered by 147 nurses in four operating departments in Sweden. Correlation and regression analyses were conducted. RESULTS: The nurses rated the significance of all factors of work attractiveness higher than they rated those factors in their current work situation; salary, organisation and physical work environment had the largest differences. The most significant attractive factors were relationships, leadership and status. A statistically significant positive correlation between work engagement and attractive work was found. In the multiple regression model, the independent variables work engagement and older age significantly predicted work attractiveness. CONCLUSIONS: Several factors should be considered in the effort to increase work attractiveness in operating departments and thereby to encourage nurse retention. Positive aspects of work seem to unite work engagement and attractive work, while work ability and self-rated health indicators are other important dimensions in nurse retention. RELEVANCE TO CLINICAL PRACTICE: The great discrepancies between the significance of attractive factors and the current work situation in salary, organisation and physical work environment suggest ways in which work attractiveness may be increased. To discover exactly what needs to be improved may require a deeper look into the construct of the examined factors. PMID- 26419702 TI - Quantifying barcodes of dendritic spines using entropy-based metrics. AB - Spine motility analysis has become the mainstay for investigating synaptic plasticity but is limited in its versatility requiring complex, non automatized instrumentations. We describe an entropy-based method for determining the spatial distribution of dendritic spines that allows successful estimation of spine motility from still images. This method has the potential to extend the applicability of spine motility analysis to ex vivo preparations. PMID- 26419703 TI - Estimation of genetic parameters for carcass defects of Japanese Black cattle in Kagoshima. AB - Cattle exhibit a range of carcass defects, including blood splash (BLS), intramuscular edema (INE), muscle steatosis (MUS), bruising (BR), trim loss (TRL) and others (OTH). These defects lower the carcass value and can result in significant economic loss to producers. We estimated the incidence, relationship with inbreeding coefficients and genetic parameters of carcass defects in Japanese Black cattle using 561 619 carcass records from Kagoshima, Japan during April 1988 through March 2011. The defect incidence ranged from 0.22% for TRL to 5.73% for BR. The incidence of MUS and BR increased from 1.21% to 6.57% and from 1.06% to 9.31%, respectively. The incidence of INE peaked at 7.44% in 1999 and decreased thereafter. We observed a positive linear relationship between the defect incidence and the inbreeding coefficients in MUS, BR and TRL (P < 0.01). The heritabilities estimated by univariate animal model with Gibbs sampling for BLS, INE, MUS, BR and TRL were 0.24, 0.06, 0.18, 0.05 and 0.02, respectively. The contribution of farm variance to phenotypic variance was negligible (0.01 to 0.04). Significant genetic correlations of TRL were estimated with MUS (0.63) and BR (0.63). Our results suggest that genetic factors contribute to the incidence of BLS and MUS. PMID- 26419704 TI - Kidney-specific Sonoporation-mediated Gene Transfer. AB - Sonoporation can deliver agents to target local organs by systemic administration, while decreasing the associated risk of adverse effects. Sonoporation has been used for a variety of materials and in a variety of organs. Herein, we demonstrated that local sonoporation to the kidney can offer highly efficient transfer of oligonucleotides, which were systemically administrated to the tubular epithelium with high specificity. Ultrasonic wave irradiation to the kidney collapsed the microbubbles and transiently affected the glomerular filtration barrier and increased glomerular permeability. Oligonucleotides were passed through the barrier all at once and were absorbed throughout the tubular epithelium. Tumor necrosis factor alpha (TNFalpha), which plays a central role in renal ischemia-reperfusion injury, was targeted using small interfering RNA (siRNA) with renal sonoporation in a murine model. The reduction of TNFalpha expression after single gene transfer significantly inhibited the expression of kidney injury markers, suggesting that systemic administration of siRNA under temporary and local sonoporation could be applicable in the clinical setting of ischemic acute kidney injury. PMID- 26419708 TI - The contribution of allied health professionals. PMID- 26419706 TI - Metabolome analysis reveals the effect of carbon catabolite control on the poly(gamma-glutamic acid) biosynthesis of Bacillus licheniformis ATCC 9945. AB - Poly(gamma-glutamic acid) (PGA) is a polymer composed of L- and/or D-glutamic acids that is produced by Bacillus sp. Because the polymer has various features as water soluble, edible, non-toxic and so on, it has attracted attention as a candidate for many applications such as foods, cosmetics and so on. However, although it is well known that the intracellular metabolism of Bacillus sp. is mainly regulated by catabolite control, the effect of the catabolite control on the PGA producing Bacillus sp. is largely unknown. This study is the first report of metabolome analysis on the PGA producing Bacillus sp. that reveals the effect of carbon catabolite control on the metabolism of PGA producing Bacillus licheniformis ATCC 9945. Results showed that the cells cultivated in glycerol containing medium showed higher PGA production than the cells in glucose containing medium. Furthermore, metabolome analysis revealed that the activators of CcpA and CodY, global regulatory proteins of the intracellular metabolism, accumulated in the cells cultivated in glycerol-containing and glucose-containing medium, respectively, with CodY apparently inhibiting PGA production. Moreover, the cells seemed to produce glutamate from citrate and ammonium using glutamine synthetase/glutamate synthase. Pulsed addition of di-ammonium hydrogen citrate, as suggested by the metabolome result, was able to achieve the highest value so far for PGA production in B. licheniformis. PMID- 26419707 TI - Electronic Topological Transition in Ag2Te at High-pressure. AB - Recently, Ag2Te was experimentally confirmed to be a 3D topological insulator (TI) at ambient pressure. However, the high-pressure behaviors and properties of Ag2Te were rarely reported. Here, a pressure-induced electronic topological transition (ETT) is firstly found in Ag2Te at 1.8 GPa. Before ETT, the positive pressure coefficient of bulk band-gap, which is firstly found in TIs family, is found by both first-principle calculations and in situ high-pressure resistivity measurements. The electrical resistivity obtained at room temperature shows a maximum at 1.8 GPa, which is nearly 3.3 times to that at ambient pressure. This result indicates that the best bulk insulating character and topological nature in Ag2Te can be obtained at this pressure. Furthermore, the high-pressure structural behavior of Ag2Te has been investigated by in situ high-pressure synchrotron powder X-ray diffraction technique up to 33.0 GPa. The accurate pressure-induced phase transition sequence is firstly determined as P21/c -> Cmca -> Pnma. It is worth noting that the reported isostructural P21/c phase is not existed, and the reported structure of Cmca phase is corrected by CALYPSO methodology. The second high-pressure structure, a long puzzle to previous reports, is determined as Pnma phase. A pressure-induced metallization in Ag2Te is confirmed by the results of temperature-dependent resistivity measurements. PMID- 26419705 TI - A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration. AB - The leading edge of migrating cells contains rapidly translocating activated integrins associated with growing actin filaments that form 'sticky fingers' to sense extracellular matrix and guide cell migration. Here we utilized indirect bimolecular fluorescence complementation to visualize a molecular complex containing a Mig-10/RIAM/lamellipodin (MRL) protein (Rap1-GTP-interacting adaptor molecule (RIAM) or lamellipodin), talin and activated integrins in living cells. This complex localizes at the tips of growing actin filaments in lamellipodial and filopodial protrusions, thus corresponding to the tips of the 'sticky fingers.' Formation of the complex requires talin to form a bridge between the MRL protein and the integrins. Moreover, disruption of the MRL protein-integrin talin (MIT) complex markedly impairs cell protrusion. These data reveal the molecular basis of the formation of 'sticky fingers' at the leading edge of migrating cells and show that an MIT complex drives these protrusions. PMID- 26419709 TI - Prevention of surgical site infection: compliance is key. PMID- 26419710 TI - The application of epic3 guidelines: the complexity of practice. AB - Healthcare-associated infection (HCAI) is a major patient safety concern and is associated with morbidity, mortality and increased healthcare costs. Prevention and control requires a multi-modal approach, but the individual's accountability and rigorous application of standard infection prevention and control behaviours is at its core. The third instalment of the epic3 guidance ( Loveday et al, 2014a ) provided the evidence and advanced the importance of hand-hygiene behaviour, the use of non-sterile gloves and environmental cleanliness. This discussion considers some of the recommendations made in these areas of practice and some of the underlying complexities. Producing guidelines based on the best available evidence and transforming them into policies can be a useful adjunct to communicating the necessary standards. However, policies often erase the complexity of implementation. To strive for the best possible standard is an understandable and laudable objective, but organisations need to be mindful of the difficulties and obstacles that stand in their way, particularly in an era where the philosophy of 'zero tolerance' is gaining popularity. PMID- 26419711 TI - Letter to the Editor. AB - The editorial in BJN 24(15) written by BJN Editor in Chief, Ian Peate, challenged the Nursing and Midwifery Council's (NMC) Chief Executive and Registrar's assertion that the progress her organisation has achieved over the past 12 months is something to be 'delighted' about. The NMC responded and their letter is below. If you would like to comment on the issue email us: bjn@markallengroup.com. PMID- 26419712 TI - Sepsis: contemporary issues and implications for nursing. PMID- 26419713 TI - A multicentred cohort evaluation of a chitosan gelling fibre dressing. AB - A multicentre cohort evaluation was undertaken by 15 clinicans in 11 centres across Staffordshire community care on chitosan gelling fibre dressing (Kytocel((r))). The aim of this evaluation was to examine whether the new fibre dressing improved healing outcomes for patients with chronic non-healing wounds of 6 weeks or more, observations were made regarding tissue type, fluid handling, haemostasis in bleeding friable wounds and increased granulation. Quality of life observations regarding leaking, strikethrough, pain, wear time and malodour were observed over a 4-week period or until healed. A total of 18 patients took part; 13 women and 5 men, with a mean age of 60.7 years. Fifteen (83%) had wounds in excess of 12 weeks and nine (50%) received care within wound clinics compared to home visits. Eleven (61%) patients' wounds healed within 4 weeks. A number of quality-of-life issues were addressed successfully, namely reduction in malodour and fluid handling. Sixteen (89%) rated the dressing's overall performance as very good to good. PMID- 26419714 TI - Infection Prevention and Control Award: BJN RUNNER UP. PMID- 26419715 TI - The impact of nurse prescribing on the clinical setting. AB - AIM: To investigate the impact nurse prescribing has on the organisation, patient and health professional, and to identify factors associated with the growth of nurse prescribing. METHODS: Systematic search and narrative review. Data obtained through CINAHL, PubMed, Science direct, Online Computer Library Centre (OCLC), databases/websites, and hand searching. English peer-reviewed quantitative, qualitative and mixed-method articles published from September 2009 through to August 2014 exploring nurse prescribing from the perspective of the organisation, health professional and patient were included. Following a systematic selection process, studies identified were also assessed for quality by applying Cardwell's framework. RESULTS: From the initial 443 citations 37 studies were included in the review. Most studies were descriptive in nature. Commonalities addressed were stakeholders' views, prescribing in practice, jurisdiction, education and benefits/barriers. CONCLUSIONS: Prescriptive authority for nurses continues to be a positive addition to clinical practice. However, concerns have emerged regarding appropriate support, relationships and jurisdictional issues. A more comprehensive understanding of nurse and midwife prescribing workloads is required to capture the true impact and cost-effectiveness of the initiative. PMID- 26419716 TI - Technology and the issues facing nursing assessment. AB - This article describes an investigation into the use of technology and the issues nurses face undertaking nursing assessment. It reports qualitative, descriptive research involving interviews with ten ward nurses from three hospitals in New Zealand. Thematic analysis of the data revealed three key issues: the impact of technology, the influence of early warning systems and nurse autonomy. Results show how clinical decision making around nursing assessment is influenced by technology and the Early Warning Score. These clinical decisions may not always be informed by critical thinking in complex healthcare environments. The article concludes that nurse autonomy, while supported and endorsed in theory, is frequently in conflict with hospital risk-management policies and the use of prescriptive algorithms. PMID- 26419717 TI - Learning not blaming: the Government response. AB - In this second of a two-part column, John Tingle discusses the Government's response to the consultation on the Freedom to Speak Up review, the report Investigating Clinical Incidents in the NHS, and The Report of the Morecambe Bay Investigation. PMID- 26419718 TI - Focus on people, not the system: improving the NHS in England. AB - Emeritus professor Alan Glasper, from the University of Southampton, discusses the launch of the latest Department of Health initiative to make the NHS more people-focused, rather than system-focused. PMID- 26419719 TI - Patient information: confidentiality and the electronic record. AB - The rise of the electronic record now allows nurses to access a large archive of patient information that was more difficult to obtain when records consisted of manually held paper files. There have been several instances where curiosity and, occasionally, more malicious motivations have led nurses to access these records and read the notes of a celebrity or a person they know. In this article, Richard Griffith considers whether nurses' accessing and reading of the record of someone who is not in their care is in breach of their duty of confidentiality. PMID- 26419720 TI - The importance of education for a new primary care workforce. PMID- 26419721 TI - Examining the role of personal traumas in a nurse's work life. AB - In this monthly column, Aysha Mendes discusses the impact a nurse's personal traumas can have on his or her nursing practice, professional and personal experience of caring, and on patients and their families. PMID- 26419722 TI - Writing for publication: from staff nurse to nurse consultant. PMID- 26419723 TI - Learning from patients using the goldfish bowl model. PMID- 26419724 TI - Targeting substrate-site in Jak2 kinase prevents emergence of genetic resistance. AB - Emergence of genetic resistance against kinase inhibitors poses a great challenge for durable therapeutic response. Here, we report a novel mechanism of JAK2 kinase inhibition by fedratinib (TG101348) that prevents emergence of genetic resistance. Using in vitro drug screening, we identified 211 amino-acid substitutions conferring resistance to ruxolitinib (INCB018424) and cross resistance to the JAK2 inhibitors AZD1480, CYT-387 and lestaurtinib. In contrast, these resistant variants were fully sensitive to fedratinib. Structural modeling, coupled with mutagenesis and biochemical studies, revealed dual binding sites for fedratinib. In vitro binding assays using purified proteins showed strong affinity for the substrate-binding site (Kd = 20 nM) while affinity for the ATP site was poor (Kd = ~8 MUM). Our studies demonstrate that mutations affecting the substrate-binding pocket encode a catalytically incompetent kinase, thereby preventing emergence of resistant variants. Most importantly, our data suggest that in order to develop resistance-free kinase inhibitors, the next-generation drug design should target the substrate-binding site. PMID- 26419726 TI - Notch signaling dynamics in the adult healthy prostate and in prostatic tumor development. AB - BACKGROUND: The Notch signaling pathway has been implicated in prostate development, maintenance and tumorigenesis by its key role in cell-fate determination, differentiation and proliferation. Therefore, we proposed to analyze Notch family members transcription and expression, including ligands (Dll1, 3, 4 and Jagged1 and 2), receptors (Notch1-4) and effectors (Hes1, 2, 5 and Hey1, 2, L), in both normal and tumor bearing mouse prostates to better understand the dynamics of Notch signaling in prostate tumorigenesis. METHODS: Wild type mice and transgenic adenocarcinoma of the mouse prostate model (TRAMP) mice were sacrificed at 18, 24 or 30 weeks of age and the prostates collected and processed for either whole prostate or prostate cell specific populations mRNA analysis and for protein expression analysis by immunohistochemistry and immunofluorescence. RESULTS: We observed that Dll1 and Dll4 are expressed in the luminal compartment of the mouse healthy prostate, whereas Jagged2 expression is restricted to the basal and stromal compartment. Additionally, Notch2 and Notch4 are normally expressed in the prostate luminal compartment while Notch2 and Notch3 are also expressed in the stromal layer of the healthy prostate. As prostate tumor development takes place, there is up-regulation of Notch components. Particularly, the prostate tumor lesions have increased expression of Jagged1 and 2, of Notch3 and of Hey1. We have also detected the presence of activated Notch3 in prostatic tumors that co-express Jagged1 and ultimately the Hey1 effector. CONCLUSIONS: Taken together our results point out the Notch axis Jagged1-2/Notch3/Hey1 to be important for prostate tumor development and worthy of additional functional studies and validation in human clinical disease. PMID- 26419727 TI - Environmental roles of microbial amino acid racemases. AB - Enzymes catalysing the stereo-chemical inter-conversion of amino acids are known as amino acid racemases. In bacteria, these enzymes are fundamental to synthesize the D-Ala and D-Glu that are critical components of the peptidoglycan. In addition to this structural function in cell wall assembly, D-amino acids produced by microbial amino acid racemases have been described as relevant constituents in other prokaryotic structures (e.g. capsule, non-ribosomal peptides) and have been associated to growth fitness and to processes such as biofilm development, spore germination and signalling. The recent discovery of broad spectrum racemases able to produce and release several D-amino acids to the environment suggests that these enzymes might have a great impact in microbial ecology. Consequently, new data on the biochemistry and regulation of racemases is key to understand the biological significance of D-enantiomers in nature, in particular their effect on microbial social networks. This review summarizes current knowledge on the environmental roles of bacterial racemases with an emphasis on the potential roles of the new broad spectrum enzymes in natural environments. PMID- 26419728 TI - In situ detection of salicylate in Ocimum basilicum plant leaves via reverse iontophoresis. AB - The quantitative analysis of salicylate provides useful information for the evaluation of metabolic processes in plants. We report a simple, noninvasive method to measure salicylate in situ in Ocimum basilicum leaves using reverse iontophoresis in combination with cyclic voltammetry at disposable screen-printed electrodes and the concentration of salicylate in basil leaves was found to be 3 mM. PMID- 26419725 TI - The complexity of epigenetic diseases. AB - Over the past 30 years, a plethora of pathogenic mutations affecting enhancer regions and epigenetic regulators have been identified. Coupled with more recent genome-wide association studies (GWAS) and epigenome-wide association studies (EWAS) implicating major roles for regulatory mutations in disease, it is clear that epigenetic mechanisms represent important biomarkers for disease development and perhaps even therapeutic targets. Here, we discuss the diversity of disease causing mutations in enhancers and epigenetic regulators, with a particular focus on cancer. PMID- 26419729 TI - 17p11.2 and Xq28 duplication detected in a girl diagnosed with Potocki-Lupski syndrome. AB - BACKGROUND: Potocki-Lupski syndrome is a microduplication syndrome associated with duplication at 17p11.2. Features include facial dysmorphism, moderate to mild cognitive impairment and behavioural abnormalities including autism spectrum disorders. CASE PRESENTATION: We describe a patient from Sri Lanka that was referred for genetic assessment at 4 years of age due to subtle facial dysmorphism and expressive language impairment. She was diagnosed with Potocki Lupski syndrome through multiplex ligation probe amplification. She carried two duplications; one in 17p11.2 consistent with Potocki-Lupski, and one in Xq including the region for X-linked intellectual disability. CONCLUSION: Despite the absence of expected behavioural symptoms, many features of this patient are in accordance with Potocki-Lupski syndrome. This is the first diagnosed patient in Sri Lanka. PMID- 26419730 TI - Lipopeptide biosurfactant viscosin enhances dispersal of Pseudomonas fluorescens SBW25 biofilms. AB - Pseudomonads produce several lipopeptide biosurfactants that have antimicrobial properties but that also facilitate surface motility and influence biofilm formation. Detailed studies addressing the significance of lipopeptides for biofilm formation and architecture are rare. Hence, the present study sets out to determine the specific role of the lipopeptide viscosin in Pseudomonas fluorescens SBW25 biofilm formation, architecture and dispersal, and to relate viscA gene expression to viscosin production and effect. Initially, we compared biofilm formation of SBW25 and the viscosin-deficient mutant strain SBW25DeltaviscA in static microtitre assays. These experiments demonstrated that viscosin had little influence on the amount of biofilm formed by SBW25 during the early stages of biofilm development. Later, however, SBW25 formed significantly less biofilm than SBW25DeltaviscA. The indication that viscosin is involved in biofilm dispersal was confirmed by chemical complementation of the mutant biofilm. Furthermore, a fluorescent bioreporter showed that viscA expression was induced in biofilms 4 h prior to dispersal. Subsequent detailed studies of biofilms formed in flow cells for up to 5 days revealed that SBW25 and SBW25DeltaviscA developed comparable biofilms dominated by well-defined, mushroom shaped structures. Carbon starvation was required to obtain biofilm dispersal in this system. Dispersal of SBW25 biofilms was significantly greater than of SBW25DeltaviscA biofilms after 3 h and, importantly, carbon starvation strongly induced viscA expression, in particular for cells that were apparently leaving the biofilm. Thus, the present study points to a role for viscosin-facilitated motility in dispersal of SBW25 biofilms. PMID- 26419731 TI - Video-based on-ward supervision for final year medical students. AB - BACKGROUND: Constructive feedback is an essential element of the educational process, helping trainees reach their maximum potential and increasing their skill level. Video-based feedback has been described as highly effective in various educational contexts. The present study aimed to evaluate the feasibility and acceptability of video-based, on-ward supervision for final year students in a clinical context with real patients. METHODS: Nine final year medical students (three male, six female; aged 25.1 +/- 0.7 years) and eight patients (five male, three female; aged 59.3 +/- 16.8 years) participated in the pilot study. Final year students performed routine medical procedures at bedside on internal medicine wards at the University of Heidelberg Medical Hospital. Students were filmed and were under supervision. After performing the procedures, an oral feedback loop was established including student, patient and supervisor feedback on communicative and procedural aspects of skills performed. Finally, students watched their video, focusing on specific teachable moments mentioned by the supervisor. Written evaluations and semi-structured interviews were conducted that focused on the benefits of video-based, on-ward supervision. Interviews were analysed qualitatively, using open coding to establish recurring themes and overarching categories to describe patients' and students' impressions. Descriptive, quantitative analysis was used for questionnaire data. RESULTS: Supervised, self-chosen skills included history taking (n = 6), physical examination (n = 1), IV cannulation (n = 1), and ECG recording (n = 1). The video based, on-ward supervision was well accepted by patients and students. Supervisor feedback was rated as highly beneficial, with the video material providing an additional opportunity to focus on crucial aspects and to further validate the supervisor's feedback. Students felt the video material would be less beneficial without the supervisor's feedback. The setting was rated as realistic, with filming not influencing behaviour. CONCLUSION: Video-based, on-ward supervision may be a powerful tool for improving clinical medical education. However, it should be regarded as an additional tool in combination with supervisors' oral feedback. Acceptance was high in both students and patients. Further research should address possibilities of efficiently combining and routinely establishing these forms of feedback in medical education. PMID- 26419732 TI - Anticholinergic Exposure During Rehabilitation: Cognitive and Physical Function Outcomes in Patients with Delirium Superimposed on Dementia. AB - OBJECTIVES: We examined the association between anticholinergic medication exposure and subsequent cognitive and physical function in patients with delirium superimposed on dementia during rehabilitation. We also examined length of stay and discharge disposition by anticholinergic medication exposure. DESIGN: In this secondary analysis we used control group data from an ongoing randomized clinical trial. SETTING/PARTICIPANTS: Participants with delirium and dementia were enrolled at admission to post-acute care. These 99 participants had a mean age of 86.11 (+/-6.83) years; 67.6% were women; 98% were Caucasian; and 33% were positive for at least one APOE e4 allele. MEASURES: We obtained daily measures of cognitive and physical function using: Digit Span; memory, orientation and attention items from the Montreal Cognitive Assessment; CLOX; the Confusion Assessment Method; and the Barthel Index. Anticholinergic medication exposure was measured weekly using the Anticholinergic Cognitive Burden Scale. RESULTS: Using multilevel models for time we found that greater use of clinically relevant anticholinergic medications in the previous week reduced cognitive and physical function, as measured by Digit Span Backwards and the Barthel index, in the current week. There was no effect of anticholinergic medication use on delirium severity, and APOE status did not moderate any outcomes. Greater use of clinically relevant anticholinergic medications was related to longer length of stay but not discharge disposition. CONCLUSIONS: For vulnerable older adults, anticholinergic exposure represents a potentially modifiable risk factor for poor attention, working memory, physical function, and greater length of stay during rehabilitation. PMID- 26419733 TI - Age-Related Macular Degeneration-Associated Genes in Alzheimer Disease. AB - OBJECTIVES: Given the clinical and pathological similarities between age-related macular degeneration (AMD) and Alzheimer disease (AD), to assess whether AMD associated single nucleotide polymorphisms (SNPs), including those from complement-related genes, are associated with AD. DESIGN: A case-control association study-type design. SETTING: A UK tertiary care dementia clinic. PARTICIPANTS: 322 cognitively normal participants and 258 cases with a clinical diagnosis of AD. MEASUREMENTS: Polymorphisms in the following genes were studied: CFH, ARMS2, C2/CFB, C3, CFI/PLA2G12a, SERPING1, TLR3, TLR4, CRP, APOE, and TOMM40. Haplotypes were analysed for CFH, TOMM40, and APOE. Univariate analysis was performed for each genetic change and case-comparator status, and then correction for multiple testing performed. RESULTS: The presence of an epsilon4 APOE allele was significantly associated with AD. No association was evident between CFH SNPs or haplotypes, or other AMD-associated SNPs tested, and AD. The exceptions were TOMM40 SNPs, which were associated with AD even after correction for multiple comparisons. The associations disappeared, however, when entered into a regression model including APOE genotypes. CONCLUSIONS: The results for most SNPs tested, as well as CFH haplotypes, are novel. The functional effects of abnormal complement activity in AD's pathogenesis may be contradictory, but methodological reasons may underlie the lack of association-for example, genetic changes other than SNPs being involved. PMID- 26419734 TI - Risk of Hospitalization for Hypoglycemia in Older Patients with Diabetes Using Antipsychotic Drugs. AB - OBJECTIVE: Antipsychotics may disrupt metabolic regulation in patients with diabetes mellitus. The risk of hypoglycemia in older users of antipsychotics with diabetes is largely unknown. Therefore, we investigated the association between the use of antipsychotic drugs and hypoglycemia requiring hospital admission in older patients with diabetes. METHODS: In a nested case-control study using community pharmacy records linked to hospital admission data in the Netherlands (1998-2008), a cohort of 68,314 patients at least 65 years with diabetes was studied. Cases were patients from the study cohort with a first hospital admission for hypoglycemia; up to five comparison subjects were selected for each case. Exposure to antipsychotic drugs was the primary determinant of interest. Logistic regression analysis was performed to estimate the strength of the association between antipsychotic drug use and hypoglycemia, taking into account potential confounders. RESULTS: Eight hundred fifteen patients were admitted to hospital for hypoglycemia. Current use of antipsychotic drugs was associated with an increased risk of hypoglycemia compared with non-use (adjusted OR: 2.26; 95% CI: 1.45-3.52; Wald chi(2) = 13.08, df = 1, p <=0.001), especially in the first 30 days of treatment (adjusted OR: 7.65; 95% CI: 2.50-23.41; Wald chi(2) = 12.72, df = 1, p <=0.001) and with higher doses (adjusted OR: 8.20; 95% CI: 3.09-21.75; Wald chi(2) = 17.90, df = 1, p <=0.001). CONCLUSION: Use of antipsychotic drugs by older patients with diabetes mellitus was associated with an increased risk of hospitalization for hypoglycemia. Our findings suggest that glucose levels should be monitored closely after initiation of antipsychotic drugs. PMID- 26419735 TI - Effectiveness of the Modified Instrumental Reminiscence Intervention on Psychological Well-Being Among Community-Dwelling Chinese Older Adults: A Randomized Controlled Trial. AB - OBJECTIVE: The current study aimed to examine the effectiveness of the Instrumental Reminiscence Intervention-Hong Kong (IRI-HK) on alleviating depressive symptoms and improving life satisfaction in Chinese older adults living in empty nests (i.e., living alone or with a spouse only) in the community. METHODS: A longitudinal, randomized, controlled design was adopted. Experimental and wait-list control groups were provided with the IRI-HK immediately and 12 weeks after the baseline assessment, respectively. Participants were 114 older adults living in empty nests and recruited via local elderly community centers. This high-risk population with detectable depressive symptoms were randomized into experimental (N = 46) and control (N = 68) groups. The IRI-HK is a group reminiscence intervention modified with cultural adaptations for Chinese older adults. It emphasizes the use of problem-focused coping strategies and comprises six intervention sessions and two follow-up sessions. Participants' depressive symptoms and life satisfaction were measured by the Chinese version of the Geriatric Depression Scale-Short Form and the Life Satisfaction Scale-Chinese, respectively. RESULTS: Findings from this study showed a significant difference in depressive symptoms between groups after the intervention, F(1,77) = 35.62, p <0.001. Life satisfaction of the experimental group after the second follow-up was found to be significantly higher than that of the control group, F(1,68) = 5.67, p <0.05. CONCLUSION: The IRI-HK was a successful cultural adaption suitable for use in the Chinese context. It was found to be an effective intervention for alleviating depressive symptoms in older adults living in empty nests in the community. PMID- 26419736 TI - The iron component of particulate matter is antiapoptotic: A clue to the development of lung cancer after exposure to atmospheric pollutants? AB - The classification of outdoor air pollution as carcinogenic for humans strengthens the increasing concern about particulate matter (PM). We previously demonstrated that PM exposure produces an antiapoptotic effect resulting from polycyclic aromatic hydrocarbons (PAH) and water-soluble components. In this study, we investigated transition metallic compounds, particularly iron, in order to decipher their underlying molecular mechanisms that prevent apoptosis. Human bronchial epithelial cells were exposed for 4 h to different PM samples with established antiapoptotic effect (e.g. PM-AW) or not (e.g. PM-VS) or to their metallic components (Fe, Mn, Zn and Al) before apoptosis induction by the calcium ionophore A23187 or Staurosporine. PM-AW, Fe, Mn and Al significantly reduced induced apoptosis. The antiapoptotic effect of Fe was enhanced by benzo(a)pyrene, a typical PAH compound, but was totally reversed by the iron chelator, deferiprone. Furthermore, particles and iron triggered cellular ROS generation and prevented the depletion in glutathione levels observed during A23187-induced apoptosis. In contrast to benzo(a)pyrene, PM-AW and Fe rapidly activated NRF2, subsequently upregulated several target genes (HO1, NQO1 and GPX1) and modulated some genes which control cell death (BCL2, BAX and p53). The key role of the NRF2 pathway in the antiapoptotic effect mediated by Fe and PM was demonstrated using siRNA technology. Our results suggest that the iron component participates in the antiapoptotic effect of PM by activating a NRF2-dependent antioxidant process. As resisting to cell death is one of the hallmarks of cancer cells, these findings provide additional clues for understanding the development of lung cancer after atmospheric pollution exposure. PMID- 26419737 TI - Association of matrix metalloproteinase-10 polymorphisms with susceptibility to pelvic organ prolapse. AB - AIM: The aim of this study was to explore the correlation between genetic mutations in matrix metalloproteinase-10 (MMP-10) and susceptibility to pelvic organ prolapse (POP). MATERIAL AND METHODS: From September 2011 to December 2013, 263 subjects were recruited, including 91 patients with POP (case group) and 172 non-POP patients (control group). Total MMP-10 concentrations in serum were measured by enzyme-linked immunosorbent assay. The genotyping of MMP-10 was achieved by quantitative real-time polymerase chain reaction. All data were analyzed with SPSS 18.0. RESULTS: We found that parity, menopause, history of total hysterectomy, and family history of POP were all significantly higher in the POP group than in the control group (P = 0.017, P = 0.046, P = 0.0029 and P < 0.001, respectively). Serum MMP-10 levels were obviously higher in the POP group than in the control group (P < 0.05). In addition, there was a statistically significant difference between the two groups in the distribution frequency of the MMP-10 (rs17435959G/C) genotype (P < 0.05). However, the distribution frequency of the MMP-10 (rs17293607C/T) genotype between the two groups showed no significant differences (P > 0.05). Furthermore, the patients with parity > 2 and postmenopausal women had elevated serum MMP-10 levels, and the patients with parity > 2 and postmenopausal women who carried the G/C + C/C genotype in the MMP 10 gene had an increased risk of POP. CONCLUSION: We support the view that the rs17435959 polymorphism of the MMP-10 gene may be associated with an increased risk of POP. PMID- 26419738 TI - A reconstruction approach in wavelet domain for fluorescent molecular tomography via rotated sources illumination. AB - BACKGROUND: Fluorescent molecular tomography (FMT) aims at reconstructing the spatial map of optical and fluorescence parameters from fluence measurements. Basically, solving large-scale matrix equations is computationally expensive for image reconstruction of FMT. Despite the reconstruction quality can be improved with more sources, it may result in higher computational costs for reconstruction. This article presents a novel method in the wavelet domain with rotated sources illumination. METHODS: We use the finite element method for the computation of the forward model. The global inverse problem is solved based on wavelet in conjunction with principal component analysis. The iterative reconstruction is implemented with sources rotated in a certain angle. The original excitation light sources are used to reconstruct the image in the first iteration. Then, upon the sources are rotated by a certain angle, they are employed for the next iteration of reconstruction. RESULTS: Simulation results demonstrate that our method can considerably reduce the time taken for the computation of inverse problem in FMT. Furthermore, the approach proposed is also shown to largely outperform the traditional method in terms of the precision of inverse solutions. CONCLUSIONS: Our method has the capability to locate the inclusions. The proposed method can significantly speed up the reconstruction process with the high reconstruction quality. PMID- 26419739 TI - Is an insecure job better for health than having no job at all? A systematic review of studies investigating the health-related risks of both job insecurity and unemployment. AB - BACKGROUND: Though previous research repeatedly found that being employed is better for health than having no job at all, evidence suggests that employment is not always beneficial for health. With especially job insecurity reflecting a contemporary health risk for the employed, a systematic review was performed to assess if insecure employment can be as detrimental for health as unemployment, and to determine whether these associations vary according to different health measures and among men and women. METHODS: The literature search was conducted in the databases Medline, Embase and PsychInfo. In order to allow a more accurate comparison between the two risk factors, studies were included if the data for job insecurity and unemployment was ascertained from the same sample, and contained a quantitative analysis for both exposures towards one (or more) health outcome(s). RESULTS: Out of 375 articles, in total, 13 studies were included in the systematic review. In 24 analyses contrasting the health-related associations between job insecurity and unemployment, 16 statistically significant associations were found for each exposure. According to the different health outcomes used, job insecurity and unemployment were strongly related to mental health, whereas job insecurity was more strongly associated with somatic symptoms. Unemployment showed stronger relations with worse general health and mortality. In 4 out of 16 gender-stratified analyses, significant associations between job insecurity/unemployment and health were found for men but not for women. Beyond that, associations were significant or insignificant in both gender groups. CONCLUSIONS: Though there were moderate differences across the health outcomes, overall, it was found that job insecurity can pose a comparable threat to health than unemployment. Policy interventions should therefore not only consider health risks posed by unemployment, but should also aim at the reduction of insecure employment. PMID- 26419741 TI - Relationship between polyunsaturated fatty acid levels in maternal diets and human milk in the first month post-partum. AB - BACKGROUND: The present study evaluated the relationship between dietary fatty acid (FA) intakes and human milk FA levels. METHODS: Healthy lactating women (n = 514) from Northern China participated in the study. Dietary intake was assessed with a 24-h dietary recall questionnaire and evaluated using golden key maternal nutrition software (Wincome, Shanghai, China) and China Food Composition 2009. Human milk FA composition was determined by gas chromatography. RESULTS: The maternal daily median intakes of linoleic acid (LA), alpha-linolenic acid (ALA) and arachidonic acid (AA) were 19.93 g, 3.08 g and 16.33 mg, respectively. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intakes were below the recommended levels. FA levels in 100 g of human milk were 0.363 g LA, 0.038 g gamma-linolenic acid (GLA), 0.052 g dihomo gamma-linolenic acid (DGLA), 0.144 g ALA, 0.079 g AA, 0.007 g EPA, 0.018 g docosatetraenoic acid (DTA) and 0.048 g DHA. Multiple linear regression analysis revealed that human milk DGLA levels were negatively correlated with dietary LA intake (beta = -0.223, P = 0.030), and human milk GLA and DTA levels were negatively correlated with dietary ALA intake (beta = -2.189, P = 0.031; beta = -2.252, P = 0.027) after adjusting for possible confounding factors. CONCLUSIONS: The results of the present study suggest the presence of competitive interactions between n-3 fatty acids (ALA) and n-6 fatty acids (GLA and DTA). PMID- 26419740 TI - Heterogeneity of aquaporin-4 localization and expression after focal cerebral ischemia underlies differences in white versus grey matter swelling. AB - INTRODUCTION: Ischemic stroke, a major cause of mortality, is frequently accompanied by life-threatening cerebral edema. Aquaporin-4 (Aqp4), an astrocytic transmembrane water channel, is an important molecular contributor to cerebral edema formation. Past studies of Aqp4 expression and localization after ischemia examined grey matter exclusively. However, as white matter astrocytes differ developmentally, physiologically, and molecularly from grey matter astrocytes, we hypothesized that functionally important regional heterogeneity exists in Aqp4 expression and subcellular localization following cerebral ischemia. RESULTS: Subcellular localization of Aqp4 was compared between cortical and white matter astrocytes in postmortem specimens of patients with focal ischemic stroke versus controls. Subcellular localization and expression of Aqp4 was examined in rats subjected to experimental stroke. Volumetric analysis was performed on the cortex and white matter of rats subjected to experimental stroke. Following cerebral ischemia, cortical astrocytes exhibited reduced perivascular Aqp4 and unchanged Aqp4 protein abundance. In contrast, white matter astrocytes exhibited increased perivascular and plasmalemmal Aqp4 and a 2.2- to 6.2-fold increase in Aqp4 isoform abundance. Ischemic white matter swelled by approximately 40 %, while cortex swelled by approximately 9 %. CONCLUSIONS: The findings reported here raise the possibility that cerebral white matter may play a heretofore underappreciated role in the formation of cerebral edema following ischemia. PMID- 26419743 TI - Trait and state binge eating predispose towards cocaine craving. AB - Binge eating (BE) and drug seeking share similar behavioral features, including loss of control over consumption and compulsive seeking of the craved substance. Previous studies in animal models have demonstrated a complex interaction between 'state' BE, produced by intermittent access to a palatable diet, and 'trait' BE, a phenotypical proneness towards overeating. In the present study, we examined the relationship between state and trait BE and cocaine seeking. We used Otsuka Long Evans Tokushima Fatty rats, a genetic model for obesity that demonstrates BE like behavior, and Long Evans Tokushima Otsuka controls. They received a schedule of limited access to a palatable diet (3 days/week or 5 days/week access to Ensure for a month). Next, they underwent cocaine self-administration training (1 mg/kg, 1 hour/day for 10 days) followed by extinction sessions (7 days). We found that the degree of BE-like behavior and the state and trait BE combination predicted cocaine craving patterns. Lower levels of dopamine D2 receptors in the prefrontal cortex were correlated with increased drug craving. Moreover, restricted access to an attractive diet was found to be a risk factor for heightened cocaine craving, particularly in trait binge eaters, as rats on the 3 days/week access schedule persistently failed to cease cocaine seeking throughout extinction. Hence, we postulate a joint role of state and trait BE as risk factors for heightened cocaine craving. PMID- 26419742 TI - Myocardial SPECT Images in Incident Hemodialysis Patients Without Ischemic Heart Disease. AB - Cardiovascular disease is the leading cause of death in dialysis patients and is significantly associated with poor survival in incident dialysis patients. However, little is known about the pathogenesis of cardiovascular disease in these populations. (123) I-15-(p-iodophenyl)-3(R,S)- methylpentadecanoic acid (BMIPP) imaging is useful for detection of ischemic heart disease. We examined imaging characteristics to identify potential pathologies of cardiac disease, other than ischemic heart disease. The subjects were 42 incident dialysis patients without histories of ischemic heart disease such as acute coronary syndrome. All the patients underwent BMIPP imaging in addition to a screening examination. Patients with positive findings in BMIPP imaging underwent myocardial perfusion imaging within 2 weeks after BMIPP imaging to evaluate the possibility of ischemic heart disease. Twenty-two patients were BMIPP-positive and 10 of these patients had negative findings on perfusion imaging and were defined as mismatch cases. Compared with patients who were BMIPP- and perfusion positive, the mismatch cases had higher parathyroid hormone (PTH), serum albumin, and alkaline phosphatase levels. The mismatch cases also formed the largest proportion in the highest PTH tertile. A histologic examination of a mismatch case with no stenotic lesions in the coronary artery revealed the presence of cardiac hypertrophy and fibrosis. These findings suggest that a perfusion metabolism mismatch may be present in incident dialysis patients without a history of ischemic heart disease. This mismatch is associated with PTH, which suggests potential involvement of uremic cardiomyopathy in the pathology of cardiac disease in these patients. PMID- 26419745 TI - Advanced Cd(II) complexes as high efficiency co-sensitizers for enhanced dye sensitized solar cell performance. AB - This work reports on two new complexes with the general formula [Cd3(IBA)3(Cl)2(HCOO)(H2O)]n (1) and {[Cd1.5(IBA)3(H2O)6].3.5H2O}n (2), which can be synthesized by the reaction of Cd(II) with rigid linear ligand 4-HIBA containing imidazolyl and carboxylate functional groups [4-HIBA = 4-(1H-imidazol 1-yl)benzoic acid]. Single-crystal X-ray diffraction analyses indicate that complex 1 is a 2D "wave-like" layer structure constructed from trinuclear units and complex 2 is just a mononuclear structure. Surprisingly, both complexes 1 and 2 appear as a 3D supramolecular network via intermolecular hydrogen bonding interactions. What's more, due to their strong UV-visible absorption, 1 and 2 can be employed as co-sensitizers in combination with N719 to enhance dye-sensitized solar cell (DSSC) performance. Both of them could overcome the deficiency of the ruthenium complex N719 absorption in the region of ultraviolet and blue-violet, and the charge collection efficiency is also improved when 1 and 2 are used as co sensitizers, which are all in favor of enhancing the performance. The DSSC devices using co-sensitizers of 1/N719 and 2/N719 show an overall conversion efficiency of 8.27% and 7.73% with a short circuit current density of 17.48 mA cm(-2) and 17.39 mA cm(-2), and an open circuit voltage of 0.75 V and 0.74 V, respectively. The overall conversion efficiency is 27.23% and 18.92% higher than that of a device solely sensitized by N719 (6.50%). Consequently, the prepared complexes are high efficiency co-sensitizers for enhancing the performance of N719 sensitized solar cells. PMID- 26419744 TI - Cardiac rehabilitation. PMID- 26419746 TI - Treatment of industrial effluents by electrochemical generation of H2O2 using an RVC cathode in a parallel plate reactor. AB - Electrochemical techniques have been used for the discolouration of synthetic textile industrial wastewater by Fenton's process using a parallel plate reactor with a reticulated vitreous carbon (RVC) cathode. It has been shown that RVC is capable of electro-generating and activating H2O2 in the presence of Fe(2+) added as catalyst and using a stainless steel mesh as anode material. A catholyte comprising 0.05 M Na2SO4, 0.001 M FeSO4.7H2O, 0.01 M H2SO4 and fed with oxygen was used to activate H2O2.The anolyte contained only 0.8 M H2SO4. The operating experimental conditions were 170 mA (2.0 V < DeltaECell < 3.0 V) to generate 5.3 mM H2O2. Synthetic effluents containing various concentrations (millimolar - mM) of three different dyes, Blue Basic 9 (BB9), Reactive Black 5 (RB5) and Acid Orange 7 (AO7), were evaluated for discolouration using the electro-assisted Fenton reaction. Water discolouration was measured by UV-VIS absorbance reduction. Dye removal by electrolysis was a function of time: 90% discolouration of 0.08, 0.04 and 0.02 mM BB9 was obtained at 14, 10 and 6 min, respectively. In the same way, 90% discolouration of 0.063, 0.031 and 0.016 mM RB5 was achieved at 90, 60 and 30 min, respectively. Finally, 90% discolouration of 0.14, 0.07 and 0.035 mM AO7 was achieved at 70, 40 and 20 min, respectively. The experimental results confirmed the effectiveness of electro-assisted Fenton reaction as a strong oxidizing process in water discolouration and the ability of RVC cathode to electro-generate and activate H2O2 in situ. PMID- 26419747 TI - Abstracts of the V International Congress of Histology and Tissue Engineering - XVII Congress of the Spanish Society of Histology and Tissue Engineering. 12-14 September, 2013, Logrono, Spain. PMID- 26419748 TI - A novel method for expediting the development of patient-reported outcome measures and an evaluation of its performance via simulation. AB - BACKGROUND: Developing valid and reliable patient-reported outcome measures (PROMs) is a critical step in promoting patient-centered health care, a national priority in the U.S. Small populations or rare diseases often pose difficulties in developing PROMs using traditional methods due to small samples. METHODS: To overcome the small sample size challenge while maintaining psychometric soundness, we propose an innovative Ordinal Bayesian Instrument Development (OBID) method that seamlessly integrates expert and participant data in a Bayesian item response theory (IRT) with a probit link model framework. Prior distributions obtained from expert data are imposed on the IRT model parameters and are updated with participants' data. The efficiency of OBID is evaluated by comparing its performance to classical instrument development performance using actual and simulation data. RESULTS AND DISCUSSION : The overall performance of OBID (i.e., more reliable parameter estimates, smaller mean squared errors (MSEs) and higher predictive validity) is superior to that of classical approaches when the sample size is small (e.g. less than 100 subjects). Although OBID may exhibit larger bias, it reduces the MSEs by decreasing variances. Results also closely align with recommendations in the current literature that six subject experts will be sufficient for establishing content validity evidence. However, in the presence of highly biased experts, three experts will be adequate. CONCLUSIONS: This study successfully demonstrated that the OBID approach is more efficient than the classical approach when the sample size is small. OBID promises an efficient and reliable method for researchers and clinicians in future PROMs development for small populations or rare diseases. PMID- 26419749 TI - Individual time course of pre- and postsynaptic PET imaging may improve differential diagnosis of Parkinson's disease and multiple system atrophy: a case report. AB - BACKGROUND: Many in vivo studies have shown a difference in pre- and/or postsynaptic imaging between Parkinson's disease and multiple system atrophy; however, time course differences in pre- and postsynaptic imaging between Parkinson's disease and multiple system atrophy have not been rigorously investigated. CASE PRESENTATION: We report serial positron emission tomography images of both dopamine transporters and dopamine D2 receptors, obtained from a Japanese patient with Parkinson's disease who underwent positron emission tomography scanning at ages 71, 72, 74, and 75 years, and another Japanese patient with multiple system atrophy who underwent positron emission tomography scanning at ages 65, 66, and 67 years. Volumes-of-interest were placed on the striatal subregions. The percentage decreases between the first and last images showed that dopamine transporter availability decreased with disease progression in both patients, but that dopamine D2 receptor availability decreased only in the patient with multiple system atrophy. A partial correlation analysis between dopamine transporter and dopamine D2 receptor availability, controlling for the effects of striatal subregional differences, revealed a positive correlation in the patient with multiple system atrophy (r = 0.893, P = 0.0002), but no significant correlation in the patient with Parkinson's disease (r = -0.036, P = 0.89). CONCLUSIONS: The time course of pre- and postsynaptic imaging can be considerably different between Parkinson's disease and multiple system atrophy, and may be useful in improving the accuracy of discrimination between Parkinson's disease and multiple system atrophy. PMID- 26419750 TI - Physicochemical properties affect the synthesis, controlled delivery, degradation and pharmacokinetics of inorganic nanoporous materials. AB - Controlling size, shape and uniformity of porous constructs remains a major focus of the development of porous materials. Over the past two decades, we have seen significant developments in the fabrication of new, porous-ordered structures using a wide range of materials, resulting in properties well beyond their traditional use. Porous materials have been considered appealing, due to attractive properties such as pore size length, morphology and surface chemistry. Furthermore, their utilization within the life sciences and medicine has resulted in significant developments in pharmaceutics and medical diagnosis. This article focuses on various classes of porous materials, providing an overview of principle concepts with regard to design and fabrication, surface chemistry and loading and release kinetics. Furthermore, predictions from a multiscale mathematical model revealed the role pore length and diameter could have on payload release kinetics. PMID- 26419751 TI - Occurrence of diarrhoea and intestinal pathogens in non-medicated nursery pigs. AB - BACKGROUND: Intestinal disease in nursery pigs is the most common cause of antibiotic usage in pigs in Denmark. The decision to initiate batch medication of intestinal diseases in nursery pigs is typically made by the stock personnel based on clinical assessments of pigs and counting of diarrhoeic faecal pools on the pen floor. The target population of this study was batches of nursery pigs (10-66 days after weaning) where the stock personnel assessed the pigs to be without signs of intestinal disease and therefore did not needed treatment. The objective was to determine the within-herd prevalence of diarrhoea, and to determine the prevalence of Escherichia coli F4 and F18, Lawsonia intracellularis and Brachyspira pilosicoli by quantitative PCR in pigs with and without diarrhoea. RESULTS: The overall apparent prevalence of diarrhoeic pigs across sixteen herds was 32.6 % (CI 95 % 27.9-37.3). The prevalence of diarrhoea increased (p <= 0.001) with age of the pigs (days after weaning) with an odds ratio of 1.04 (CI 95 % 1.02-1.05) per extra day. Diarrhoeic pools were observed in 51 % of the pens. L. intracellularis, B. pilosicoli, E. coli F4 and F18 were detected in 20, 17, 13 and 11 % of the 256 faecal samples analysed by quantitative PCR respectively. There was no association between detection of pathogens and diarrhoea status of the individual pigs and between detection of pathogens in a pen and diarrhoea floor pools. In 51 % of the samples from diarrhoeic pigs, pathogens were not detected. Only 5 % of the 3060 pigs examined had clinical signs of diseases other than diarrhoea. CONCLUSIONS: One-third of non-medicated nursery pigs had diarrhoea when clinically examined even though they were assessed as healthy by stock personnel. Diarrhoeic status of the pigs and diarrhoeic pools in pen was a poor indicator of intestinal infections with E. coli F4 and F18, L. intracellularis and B. pilosicoli and subclinical infections were common. Therefore, clinical examination and counting of diarrhoea pools should be supported by microbiological testing as decision tools for initiation of batch treatments of intestinal infections in nursery pigs. PMID- 26419752 TI - The influence of neighbourhood green space on children's physical activity and screen time: findings from the longitudinal study of Australian children. AB - OBJECTIVE: It is often hypothesised that neighbourhood green space may help prevent well-known declines in physical activity and increases in sedentary behaviour that occur across childhood. As most studies in this regard are cross sectional, the purpose of our study was to use longitudinal data to examine whether green space promotes active lifestyles as children grow older. METHODS: Data came from participants (n = 4983; age = 4-5) of the Longitudinal Study of Australian Children, a nationally representative study on health and child development. Physical activity and screen time were measured biennially (2004 2012) using questionnaires and time use diaries. Quantity of neighbourhood green space was objectively measured using Australian Bureau of Statistics mesh block data for each participant's statistical area level 2. Multilevel regression was used to test for associations between physical activity and screen time with green space quantity, adjusting for socio-economic confounders. RESULTS: Boys living in areas with 10% more neighbourhood green space had a: 7% (95% CI = 1.02, 1.13) greater odds of choosing physically active pastimes; 8% (95 % CI = 0.85, 1.00) lower odds of not enjoying physical activity; 2.3 min reduction in weekend television viewing (95% CI = -4.00, -0.69); and 7% (95% CI = 1.02; 1.12) and 9% (95% CI = 1.03; 1.15) greater odds of meeting physical activity guidelines on weekdays and weekends, respectively. No statistically (or practically) significant results were observed for girls. CONCLUSION: Current provisions of neighbourhood green space may be more amenable to promoting active lifestyles among boys than girls. Research is needed to explore what types of green space promote active lifestyles in all children. PMID- 26419753 TI - Highlight: Unpicking the Secrets of the "Great Speciator". PMID- 26419754 TI - Fluorogenic Thorium Sensors Based on 2,6-Pyridinedicarboxylic Acid-Substituted Tetraphenylethenes with Aggregation-Induced Emission Characteristics. AB - A novel fluorescent sensor based on tetraphenylethene (TPE) modified with 2,6 pyridinedicarboxylic acid (PDA) that shows aggregation-induced emission (AIE) characteristics for thorium recognition with remarkable fluoresence enhancement response has been synthesized. This sensor is capable of visually distinguishing Th(4+) among lanthanides, transition metals, and alkali metals under UV light. Th(4+) can be detected by the naked eye at ppb levels owing to the AIE phenomenon. The sensor showed high selectivity for Th(4+) compared to all other metals tested, and this recognition displayed good anti-interference qualities. This study represents the first application of a AIE fluorescence sensor in actinide metal recognition and it has potential applications in environmental systems for thorium ion detection. PMID- 26419756 TI - Introducing a static receptor to compete with a dynamic combinatorial library in template binding. AB - We show herein that establishing a competition between a static receptor and components of dynamic combinatorial libraries to bind an appropriately selected template can be used to determine association constants by HPLC analysis after freezing of the equilibrium. PMID- 26419760 TI - Enrichment, Distribution of Vanadium-Containing Protein in Vanadium-Enriched Sea Cucumber Apostichopus japonicus and the Ameliorative Effect on Insulin Resistance. AB - Sea cucumbers are a potential source of natural organic vanadium that may improve insulin resistance. In this work, vanadium was accumulated rapidly in blood, body wall, and intestine by sea cucumber Apostichopus japonicus. Furthermore, water soluble vanadium-containing proteins, the main form of the organic vanadium, were tentatively accumulated and isolated by a bioaccumulation experiment. It was also designed to evaluate the beneficial effect of vanadium-containing proteins (VCPs) from sea cucumber rich in vanadium on the development of hyperglycemia and insulin resistance in C57BL/6J mice fed with a high-fat high-sucrose diet (HFSD). HFSD mice treated with VCPs significantly decreased fasting blood glucose, serum insulin, and HOMA-IR values as compared to HFSD mice, respectively. Serum adiponectin, resistin, TNF-alpha, and leptin levels in insulin-resistant mice were dramatically reduced by a VCP supplement. These results show an ameliorative effect on insulin resistance by treatment with VCPs. Such compound seems to be a valuable therapy to achieve and/or maintain glycemic control and therapeutic agents in the treatment arsenal for insulin resistance and type 2 diabetes. PMID- 26419761 TI - Some Elements in Thyroid Tissue are Associated with More Advanced Stage of Thyroid Cancer in Korean Women. AB - Excessive exposure to heavy metals including cadmium and lead is known to have adverse effects on various types of cancer. The aim of the present study was to evaluate the associations between blood and tissue levels of heavy metals and trace elements and different stages of thyroid cancer in Korean women. Ninety-two Korean women undergoing thyroidectomy were included in this study. Blood and thyroid tissue levels of cadmium, lead, mercury, selenium, and zinc were measured, and histopathological results, cancer tumor node metastasis (TNM) stage, and cancer multifocality were assessed. The tissue levels of cadmium, selenium, and zinc were significantly higher in patients with TNM stages 3 and 4 compared to those in stage 1. The tissue level of cadmium was greater in patients with higher tumor stage (>=T2) than those with lower stage (T1). Also, the tissue levels of cadmium and zinc were higher in multifocal group than in unifocal group. A logistic multiple regression analysis showed that the odds ratio (OR) for advanced tumor stage group (>=T2) increased in those with higher tissue cadmium level after adjustment (OR = 1.397, 95 % CI = 1.078-1.811). The accumulation of cadmium in thyroid tissue may be one of important etiologic factors for the thyroid cancer progression and aggravation in Korean women. PMID- 26419762 TI - Plazomicin: an investigational therapy for the treatment of urinary tract infections. AB - INTRODUCTION: Living in the ever-expanding era of multidrug-resistant (MDR), extensively drug-resistant (XDR), and even pandrug-resistant Gram-negative microorganisms, the medical community is facing the approaching fear of the "End of Antibiotics." Plazomicin is a next-generation aminoglycoside designed to evade all clinically relevant aminoglycoside-modifying enzymes, the main mechanism of aminoglycoside resistance. A newer aminoglycoside active against several MDR-XDR microorganisms is herein presented and discussed. AREAS COVERED: Herein, the authors present the currently available information on plazomicin. This includes the current knowledge concerning plazomicin's: mechanisms of action, in vitro activity and interactions, its pharmacokinetics, its clinical efficacy in complicated urinary tract infections (cUTIs) and acute pyelonephritis, and its toxicity issues. EXPERT OPINION: Plazomicin was developed to evade all clinically relevant aminoglycoside-modifying enzymes. Unfortunately, ribosomal enzymatic modification by ribosomal 16S-rRNA methyltransferases confers broad-spectrum high level aminoglycoside resistance. Still, plazomicin demonstrates high activity against the Enterobacteriaceae including extended spectrum beta lactamase and most carbapenemase producers, as well as several of the non-fermenters. When compared to levofloxacin, the in vivo activity of plazomicin in complicated urinary tract infections (cUTIs) and in acute pyelonephritis in humans was very promising. Furthermore, regarding safety, no clinically significant effects on renal, vestibular, or cochlear function have been observed both at Phase I and II studies in humans, with mild to moderate adverse events being dose related. However, the authors believe that the real position of plazomicin in the MDR-XDR world will be revealed once pending Phase III studies are completed. PMID- 26419755 TI - Vitamin D deficiency and essential hypertension. AB - Essential hypertension (EH) results when the balance between vasoconstriction and vasodilation is shifted in favor of vasoconstriction. This balance is controlled by the interaction of genetic and epigenetic factors. When there is an unstable balance, vitamin D deficiency as an epigenetic factor triggers a shift to the side of vasoconstriction. In this article, we critically analyze clinical findings on the effect of vitamin D on blood pressure, combined with progress in molecular mechanisms. We find that vitamin D repletion exerts a clinically significant antihypertensive effect in vitamin D-deficient EH patients. Of note, a few trials reported no antihypertensive effect from vitamin D due to suboptimal study design. Short-term vitamin D supplementation has no effect on blood pressure in normotensive subjects. This could explain the mixed results and may provide a theoretical basis for future trials to identify beneficial effects of vitamin D in intervention for EH. PMID- 26419763 TI - Osteoarticular infection caused by MDR Pseudomonas aeruginosa: the benefits of combination therapy with colistin plus beta-lactams. AB - OBJECTIVES: In the era of emergence of MDR Pseudomonas aeruginosa, osteoarticular infections (OIs) add more difficulties to its treatment. The role of beta-lactams (BLs) is questioned and older drugs need to be reconsidered. The objective of this study was to describe our experience in the management of OIs caused by MDR P. aeruginosa and evaluate different therapeutic options. METHODS: This was a retrospective analysis of a prospectively collected cohort (2004-13) of patients with OI caused by MDR P. aeruginosa. We created two groups: (i) Group A (more difficult to treat), prosthetic joint infections (PJIs) and osteoarthritis (OA) managed with device retention; and (ii) Group B (less difficult to treat), OA managed without device retention. Antibiotic treatment was administered according to clinician criteria: monotherapy/combined therapy; and BL used by intermittent bolus (IB)/continuous infusion. RESULTS: Of 34 patients, 15 (44.1%) had PJI and 19 (55.9%) had OA (8 related to an orthopaedic device). Twenty-three cases (68%) were caused by XDR P. aeruginosa. The initial management included removal of an orthopaedic device in 14 cases, together with antibiotic [alone, 19 (55.9%; 4 colistin, 14 BL-IB and 1 BL continuous infusion); and in combination, 15 (44.1%; 5 BL-IB and 10 BL continuous infusion)]. The overall cure rate was 50% (39% and 63% in Groups A and B, respectively), ranging from 31.6% with monotherapy to 73.3% with combined therapy (P = 0.016), with special interest within Group A (cure rate with combined therapy 71.4%, P = 0.049). After rescue therapy, which included removal of remaining devices, the cure rate reached 85.3%. CONCLUSIONS: We suggest that the BL/colistin combination is an optimized therapy for OI caused by MDR P. aeruginosa, together with an appropriate surgical treatment. PMID- 26419764 TI - Plasticity-related genes in brain development and amygdala-dependent learning. AB - Learning about motivationally important stimuli involves plasticity in the amygdala, a temporal lobe structure. Amygdala-dependent learning involves a growing number of plasticity-related signaling pathways also implicated in brain development, suggesting that learning-related signaling in juveniles may simultaneously influence development. Here, we review the pleiotropic functions in nervous system development and amygdala-dependent learning of a signaling pathway that includes brain-derived neurotrophic factor (BDNF), extracellular signaling-related kinases (ERKs) and cyclic AMP-response element binding protein (CREB). Using these canonical, plasticity-related genes as an example, we discuss the intersection of learning-related and developmental plasticity in the immature amygdala, when aversive and appetitive learning may influence the developmental trajectory of amygdala function. We propose that learning-dependent activation of BDNF, ERK and CREB signaling in the immature amygdala exaggerates and accelerates neural development, promoting amygdala excitability and environmental sensitivity later in life. PMID- 26419765 TI - Manipulation of combustion waves in carbon-nanotube/fuel composites by highly reactive Mg nanoparticles. AB - Manipulating the interface of micro/nanostructured materials and chemical fuels can change the fundamental characteristics of combustion waves that are generated during a reaction. In this study, we report that Mg/MgO nanoparticles actively amplify the propagation of combustion waves at the interface of multi-walled carbon nanotubes (MWCNTs) and chemical fuels. Fuel/MWCNT and fuel/MWCNT-Mg/MgO composite films were prepared by a facile synthetic method. We present complete physiochemical characterization of these composite films and evaluate the propagating velocities and real-time surface temperatures of combustion waves. Mg/MgO nanoparticles at the interface enhanced the reaction front velocity by 41%. The resulting explosive reactions supplied additional thermal energy to the chemical fuel, accelerating flame propagation. Furthermore, the surface temperatures of the composites with Mg/MgO nanoparticles were much lower, indicating how the transient heat from the reaction would ignite the unreacted fuels at lower surface temperatures despite not reaching the necessary activation energy for a chain reaction. This mechanism contributed to thermopower waves that amplified the output voltage. Furthermore, large temperature gradients due to the presence of nanoparticles increased charge transport inside the nanostructured material, due to the increased thermoelectric effects. This manipulation could contribute to the active control of interfacially driven combustion waves along nanostructured materials, yielding many potential applications. PMID- 26419767 TI - Novel Approach for Developing Dual-Phase Ceramic Membranes for Oxygen Separation through Beneficial Phase Reaction. AB - A novel method based on beneficial phase reaction for developing composite membranes with high oxygen permeation flux and favorable stability was proposed in this work. Various Ce0.8Sm0.2O2-delta (SDC) + SrCO3+Co3O4 powders with different SDC contents were successfully fabricated into membranes through high temperature phase reaction. The X-ray diffraction (XRD) measurements suggest that the solid-state reaction between the SDC, SrCO3 and Co3O4 oxides occurred at the temperature for membrane sintering, leading to the formation of a highly conductive tetragonal perovskite phase SmxSr1-xCoO3-delta. The morphology and elemental distribution of the dual-phase membranes were characterized using back scattered scanning electron microscopy and energy dispersive X-ray spectroscopy (BSEM-EDX). The oxygen bulk diffusivity and surface exchange properties of the materials were investigated via the electrical conductivity relaxation technique, which supported the formation of conductive phases. The SDC+20 wt % SrCO3+10.89 wt % Co3O4 membrane exhibited the highest permeation flux among the others, reaching 0.93 mL cm(-2) min(-1) [STP = standard temperature and pressure] under an air/helium gradient at 900 degrees C for a membrane with a thickness of 0.5 mm. In addition, the oxygen permeation flux remained stable during the long-time test. The results demonstrate the beneficial phase reaction as a practical method for the development of high-performance dual-phase ceramic membranes. PMID- 26419766 TI - Improvement in Social Competence Using a Randomized Trial of a Theatre Intervention for Children with Autism Spectrum Disorder. AB - The efficacy of a peer-mediated, theatre-based intervention on social competence in participants with autism spectrum disorder (ASD) was tested. Thirty 8-to-14 year-olds with ASD were randomly assigned to the treatment (n = 17) or a wait list control (n = 13) group. Immediately after treatment, group effects were seen on social ability, (d = .77), communication symptoms (d = -.86), group play with toys in the company of peers (d = .77), immediate memory of faces as measured by neuropsychological (d = .75) and ERP methods (d = .93), delayed memory for faces (d = .98), and theory of mind (d = .99). At the 2 month follow-up period, group effects were detected on communication symptoms (d = .82). The results of this pilot clinical trial provide initial support for the efficacy of the theatre based intervention. PMID- 26419768 TI - Safety Profile of Oral Iron Chelator Deferiprone in Chinese Children with Transfusion-Dependent Thalassaemia. AB - There is a lack of knowledge regarding the incidence of serious adverse drug reactions (ADR) to the oral iron chelator deferiprone in Chinese children with transfusion-dependent thalassaemia. In this retrospective population-based cohort study, paediatric thalassaemia patients in Hong Kong were screened for serious and medically important adverse events related to deferiprone therapy using diagnosis codes, laboratory data and hospital admissions. Potential ADRs were assessed by reviewing concomitant medications, diagnoses and laboratory data and evaluated using standardised causality assessment. Eighty-seven patients contributing 169.8 person-years were included. Thirty ADRs were identified in 21 patients. Most ADRs (56.0%) occurred in the first three months of therapy. Neutropenia occurred in 11 patients (12.6%; incidence rate 6.5 per 100 patient years) and severe neutropenia (agranulocytosis) was observed in 5 patients (5.7%, incidence rate 2.9 per 100 patient-years). Other identified ADRs involve severe arthropathy, elevated liver enzymes and mild thrombocytopenia. In conclusion, the safety profile of DFP therapy in Chinese children suffering from transfusion dependent thalassaemia is in line with previous studies of non-Chinese children. However, unlike previous studies, we observed a relatively high incidence of agranulocytosis and neutropenia in patients with simultaneous combined therapy. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy. Further prospective clinical and pharmacogenetic studies are required to better evaluate this important safety signal. KEY POINTS: * Half of the identified ADRs related to deferiprone therapy occurred during the first three months of treatment. * A relatively high incidence of agranulocytosis and neutropenia. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy. PMID- 26419769 TI - reSpect: software for identification of high and low abundance ion species in chimeric tandem mass spectra. AB - Most shotgun proteomics data analysis workflows are based on the assumption that each fragment ion spectrum is explained by a single species of peptide ion isolated by the mass spectrometer; however, in reality mass spectrometers often isolate more than one peptide ion within the window of isolation that contribute to additional peptide fragment peaks in many spectra. We present a new tool called reSpect, implemented in the Trans-Proteomic Pipeline (TPP), which enables an iterative workflow whereby fragment ion peaks explained by a peptide ion identified in one round of sequence searching or spectral library search are attenuated based on the confidence of the identification, and then the altered spectrum is subjected to further rounds of searching. The reSpect tool is not implemented as a search engine, but rather as a post-search engine processing step where only fragment ion intensities are altered. This enables the application of any search engine combination in the iterations that follow. Thus, reSpect is compatible with all other protein sequence database search engines as well as peptide spectral library search engines that are supported by the TPP. We show that while some datasets are highly amenable to chimeric spectrum identification and lead to additional peptide identification boosts of over 30% with as many as four different peptide ions identified per spectrum, datasets with narrow precursor ion selection only benefit from such processing at the level of a few percent. We demonstrate a technique that facilitates the determination of the degree to which a dataset would benefit from chimeric spectrum analysis. The reSpect tool is free and open source, provided within the TPP and available at the TPP website. Graphical Abstract ?. PMID- 26419770 TI - Mapping of Fab-1:VEGF Interface Using Carboxyl Group Footprinting Mass Spectrometry. AB - A proof-of-concept study was performed to demonstrate that carboxyl group footprinting, a relatively simple, bench-top method, has utility for first-pass analysis to determine epitope regions of therapeutic mAb:antigen complexes. The binding interface of vascular endothelial growth factor (VEGF) and the Fab portion of a neutralizing antibody (Fab-1) was analyzed using carboxyl group footprinting with glycine ethyl ester (GEE) labeling. Tryptic peptides involved in the binding interface between VEGF and Fab-1 were identified by determining the specific GEE-labeled residues that exhibited a reduction in the rate of labeling after complex formation. A significant reduction in the rate of GEE labeling was observed for E93 in the VEGF tryptic peptide V5, and D28 and E57 in the Fab-1 tryptic peptides HC2 and HC4, respectively. Results from the carboxyl group footprinting were compared with the binding interface identified from a previously characterized crystal structure (PDB: 1BJ1). All of these residues are located at the Fab-1:VEGF interface according to the crystal structure, demonstrating the potential utility of carboxyl group footprinting with GEE labeling for mapping epitopes. Graphical Abstract ?. PMID- 26419771 TI - 3D ToF-SIMS Analysis of Peptide Incorporation into MALDI Matrix Crystals with Sub micrometer Resolution. AB - The analytical sensitivity in matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is largely affected by the specific analyte-matrix interaction, in particular by the possible incorporation of the analytes into crystalline MALDI matrices. Here we used time-of-flight secondary ion mass spectrometry (ToF-SIMS) to visualize the incorporation of three peptides with different hydrophobicities, bradykinin, Substance P, and vasopressin, into two classic MALDI matrices, 2,5-dihydroxybenzoic acid (DHB) and alpha-cyano-4 hydroxycinnamic acid (HCCA). For depth profiling, an Ar cluster ion beam was used to gradually sputter through the matrix crystals without causing significant degradation of matrix or biomolecules. A pulsed Bi3 ion cluster beam was used to image the lateral analyte distribution in the center of the sputter crater. Using this dual beam technique, the 3D distribution of the analytes and spatial segregation effects within the matrix crystals were imaged with sub-MUm resolution. The technique could in the future enable matrix-enhanced (ME)-ToF SIMS imaging of peptides in tissue slices at ultra-high resolution. Graphical Abstract ?. PMID- 26419772 TI - Analysis of Parent/Nitrated Polycyclic Aromatic Hydrocarbons in Particulate Matter 2.5 Based on Femtosecond Ionization Mass Spectrometry. AB - Particulate matter 2.5 (PM2.5), collected from ambient air in Fukuoka City, was analyzed by gas chromatography combined with multiphoton ionization mass spectrometry using an ultraviolet femtosecond laser (267 nm) as the ionization source. Numerous parent polycyclic aromatic hydrocarbons (PPAHs) were observed in a sample extracted from PM2.5, and their concentrations were determined to be in the range from 30 to 190 pg/m(3) for heavy PPAHs. Standard samples of nitrated polycyclic aromatic hydrocarbons (NPAHs) were examined, and the limits of detection were determined to be in the picogram range. The concentration of NPAH adsorbed on PM2.5 in the air was less than 900-1300 pg/m(3). Graphical Abstract ?. PMID- 26419773 TI - Reply to Uramoto et al. PMID- 26419774 TI - Intraoperative ultrasound elastography has little diagnostic benefit for deeper tumours of the lung. PMID- 26419775 TI - Food waste volume and origin: Case studies in the Finnish food service sector. AB - We carried out a project to map the volume and composition of food waste in the Finnish food service sector. The amount, type and origin of avoidable food waste were investigated in 51 food service outlets, including schools, day-care centres, workplace canteens, petrol stations, restaurants and diners. Food service outlet personnel kept diaries and weighed the food produced and wasted during a one-week or one-day period. For weighing and sorting, the food waste was divided into two categories: originally edible (OE) food waste was separated from originally inedible (OIE) waste, such as vegetable peelings, bones and coffee grounds. In addition, food waste (OE) was divided into three categories in accordance with its origins: kitchen waste, service waste and customer leftovers. According to the results, about 20% of all food handled and prepared in the sector was wasted. The findings also suggest that the main drivers of wasted food are buffet services and overproduction. PMID- 26419776 TI - Mother and adolescent expressed emotion and adolescent internalizing and externalizing symptom development: a six-year longitudinal study. AB - In expressed emotion (EE) theory, it is held that high EE household environments enhance adolescent psychopathological distress. However, no longitudinal study has been conducted to examine if either the mother's EE or the adolescent's perception of EE predicts adolescent internalizing and externalizing symptom dimensions (an EE effect model) or vice versa (psychopathological effect model) together in one model. To unravel the reciprocal influences of maternal and adolescent perceived EE to adolescent internalizing and externalizing symptom dimensions, we tested two (i.e., one for internalizing and one for externalizing) cross-lagged panel models. In this study, it was found that both internalizing and externalizing symptom dimensions predicted the adolescent's perception of maternal EE as well as the mother's own rated EE criticism over time. The findings of this study should give both researchers and therapists a reason to reevaluate only using the EE effects model assumption in future EE studies. PMID- 26419777 TI - Role of macrophages in Wallerian degeneration and axonal regeneration after peripheral nerve injury. AB - The peripheral nervous system (PNS) has remarkable regenerative abilities after injury. Successful PNS regeneration relies on both injured axons and non-neuronal cells, including Schwann cells and immune cells. Macrophages are the most notable immune cells that play key roles in PNS injury and repair. Upon peripheral nerve injury, a large number of macrophages are accumulated at the injury sites, where they not only contribute to Wallerian degeneration, but also are educated by the local microenvironment and polarized to an anti-inflammatory phenotype (M2), thus contributing to axonal regeneration. Significant progress has been made in understanding how macrophages are educated and polarized in the injured microenvironment as well as how they contribute to axonal regeneration. Following the discussion on the main properties of macrophages and their phenotypes, in this review, we will summarize the current knowledge regarding the mechanisms of macrophage infiltration after PNS injury. Moreover, we will discuss the recent findings elucidating how macrophages are polarized to M2 phenotype in the injured PNS microenvironment, as well as the role and underlying mechanisms of macrophages in peripheral nerve injury, Wallerian degeneration and regeneration. Furthermore, we will highlight the potential application by targeting macrophages in treating peripheral nerve injury and peripheral neuropathies. PMID- 26419778 TI - Ectopic Expression of WRINKLED1 Affects Fatty Acid Homeostasis in Brachypodium distachyon Vegetative Tissues. AB - Triacylglycerol (TAG) is a storage lipid used for food purposes and as a renewable feedstock for biodiesel production. WRINKLED1 (WRI1) is a transcription factor that governs fatty acid (FA) synthesis and, indirectly, TAG accumulation in oil-storing plant tissues, and its ectopic expression has led to TAG accumulation in vegetative tissues of different dicotyledonous plants. The ectopic expression of BdWRI1 in the grass Brachypodium distachyon induced the transcription of predicted genes involved in glycolysis and FA biosynthesis, and TAG content was increased up to 32.5-fold in 8-week-old leaf blades. However, the ectopic expression of BdWRI1 also caused cell death in leaves, which has not been observed previously in dicotyledonous plants such as Arabidopsis (Arabidopsis thaliana). Lipid analysis indicated that the free FA content was 2-fold elevated in BdWRI1-expressing leaf blades of B. distachyon. The transcription of predicted genes involved in beta-oxidation was induced. In addition, linoleic FA treatment caused cell death in B. distachyon leaf blades, an effect that was reversed by the addition of the FA biosynthesis inhibitor cerulenin. Taken together, ectopic expression of BdWRI1 in B. distachyon enhances FA biosynthesis and TAG accumulation in leaves, as expected, but also leads to increased free FA content, which has cytotoxic effects leading to cell death. Thus, while WRI appears to ubiquitously affect FA biosynthesis and TAG accumulation in diverse plants, its ectopic expression can lead to undesired side effects depending on the context of the specific lipid metabolism of the respective plant species. PMID- 26419779 TI - Targeting VEGF-A with a vaccine decreases inflammation and joint destruction in experimental arthritis. AB - OBJECTIVES: Inflammation and angiogenesis are two tightly linked processes in arthritis, and therapeutic targeting of pro-angiogenic factors may contribute to control joint inflammation and synovitis progression. In this work, we explored whether vaccination against vascular endothelial growth factor (VEGF) ameliorates collagen-induced arthritis (CIA). METHODS: Anti-VEGF vaccines were heterocomplexes consisting of the entire VEGF cytokine (or a VEGF-derived peptide) linked to the carrier protein keyhole limpet hemocyanin (KLH). Two kinds of vaccines were separately tested in two independent experiments of CIA. In the first, we tested a kinoid of the murine cytokine VEGF (VEGF-K), obtained by conjugating VEGF-A to KLH. For the second, we selected two VEGF-A-derived peptide sequences to produce heterocomplexes (Vpep1-K and Vpep2-K). DBA/1 mice were immunized with either VEGF-K, Vpep1-K, or Vpep2-K, before CIA induction. Clinical and histological scores of arthritis, anti-VEGF, anti-Vpep Ab titers, and anti VEGF Abs neutralizing capacity were determined. RESULTS: Both VEGF-K and Vpep1-K significantly ameliorated clinical arthritis scores and reduced synovial inflammation and joint destruction at histology. VEGF-K significantly reduced synovial vascularization. None of the vaccines reduced anti-collagen Ab response in mice. Both VEGF-K and Vpep1-K induced persistently high titers of anti-VEGF Abs capable of inhibiting VEGF-A bioactivity. CONCLUSION: Vaccination against the pro-angiogenic factor VEGF-A leads to the production of anti-VEGF polyclonal Abs and has a significant anti-inflammatory effect in CIA. Restraining Ab response to a single peptide sequence (Vpep1) with a peptide vaccine effectively protects immunized mice from joint inflammation and destruction. PMID- 26419780 TI - Illness intrusiveness and subjective well-being in patients with glioblastoma. AB - Glioblastoma (GBM) is the most common adult CNS malignancy but its impact on quality of life (QOL) is poorly understood. In other patient populations, illness intrusiveness (the extent to which disease and treatment disrupts valued activities and interests) is associated with low subjective well-being, after controlling for disease and treatment variables. In this cross-sectional cohort study, we examined the relations among illness intrusiveness, disease burden, and subjective well-being in GBM. 73 GBM patients completed validated self-report measures of depression, positive affect, illness intrusiveness, and health related QOL. Responses were compared to data from six other cancer groups using repeated measures analyses of variance. Hierarchical multiple-regression analyses tested the hypothesis that illness intrusiveness accounts for well-being after controlling for the effects of disease burden. GBM patients reported less positive affect, more depression, and more illness intrusiveness than people with other cancers. Illness intrusiveness correlated with depression and (low) positive affect. Associations among cancer symptoms, depression, and positive affect decreased when illness intrusiveness was added to regression equations. Good performance status and high cancer-symptom burden were associated with illness intrusiveness and depression. GBM patients report greater distress, lower positive affect, and more illness intrusiveness than people with other cancers. Subjective well-being is mediated in part by illness intrusiveness in this population. In addition to medical treatment, efforts to help patients remain engaged in valued activities and interests may help preserve QOL after the diagnosis of a GBM. PMID- 26419781 TI - Erratum to: Survival prediction in high-grade gliomas using CT perfusion imaging. PMID- 26419782 TI - 3D RuO2 Microsupercapacitors with Remarkable Areal Energy. AB - Large areal capacitance electrodes made of ruthenium oxide on highly porous gold current collectors are realized by an attractive approach. The hybrid structure exhibits a capacitance in excess of 3 F cm(-2) and an areal energy density for all-solid-state microsupercapacitors that is comparable to those of microbatteries. PMID- 26419783 TI - The developmental inter-relationships between activity, novelty preferences, and delay discounting in male and female rats. AB - Increased locomotion, novelty-seeking, and impulsivity are risk factors associated with substance use. In this study, the inter-relationships between activity, novelty preferences, and delay discounting, a measure of impulsivity, were examined across three stages: juvenile/early adolescence (postnatal Day [P] 15, 19, and 42 for activity, novelty, and impulsivity, respectively), adolescent/late adolescent (P28, 32, 73), and adult (P90, 94, 137) in male and female rats. Our estimates of impulsive choice, where animals were trained to criterion, revealed an age * sex interaction where early adolescent females had the lowest levels of impulsivity. The relationships of activity and novelty to impulsivity significantly changed across age within each sex. Early adolescent males with high activity, but low novelty preferences, were more impulsive; however, low activity and high novelty preferences were related to high impulsivity in adult males. Female activity gradually increased across age, but did not show a strong relationship with impulsivity. Novelty preferences are moderately related to impulsivity into adulthood in females. These data show that males and females have different developmental trajectories for these behaviors. Males show greater sensation-seeking (e.g., activity) and risky behavior (e.g., novelty preferences) earlier in life, whereas these behaviors emerge during adolescence in females. PMID- 26419784 TI - A thoracodorsal artery perforator chimeric free flap for prevention of microvascular pedicle compression in lower extremity reconstruction. AB - BACKGROUND: Chimeric flaps are often used in reconstructive fields for multiple defects, different functional defects, and extensive defects. In this article, we present the results of the use of thoracodorsal artery perforator (TDAp) chimeric flaps including a latissimus dorsi (LD) or serratus anterior (SA) muscle to prevent pedicle compression for lower extremity reconstruction. METHODS: Nineteen TDAp chimeric flaps were used to prevent pedicle compression. Seven were female and 12 male. Patients' age ranged from 32 to 73 years. After harvesting TDAp skin flap, LD or SA muscle could be harvested along with the thoracodorsal vessels. Skin flap was incorporated into the main defect and muscle cuffs were positioned along the vascular pedicle. RESULTS: In 11 cases, there were two components, a skin flap and a muscle flap, and the other 8 were three components, a skin flap and two muscle flaps. The dimensions of the skin flaps ranged from 8 * 5 to 18 * 10 cm, and the muscle flaps ranged from 3 * 2 cm to 8 * 6 cm. The recipient vessel was anterior tibial artery or dorsalis pedis artery. All flap survived. Five cases suffered minor complications including donor site wound disruption, skin flap wound disruption, partial loss of the skin flap, and partial loss of the SA muscle flap. The mean follow-up was 13.9 months. All the patients were able to wear shoes without debulking procedures. CONCLUSION: The TDAp chimeric flaps including LD or SA muscle flaps were useful for covering the vascular pedicle and relieved vascular compression during lower extremity reconstruction. (c) 2015 Wiley Periodicals, Inc. Microsurgery, 38:46-50, 2018.. PMID- 26419787 TI - Nutritional status, tooth wear and quality of life in Brazilian schoolchildren. AB - OBJECTIVE: To evaluate the correlation among nutritional status, tooth wear and quality of life in Brazilian schoolchildren. DESIGN: The study followed a cross sectional design. Nutritional status was measured via anthropometry using BMI and tooth wear was measured using the Dental Wear Index; both these assessments were carried out by a trained recorder according to standard criteria. A modified version of the Child Oral Impacts on Daily Performances was used to assess quality of life. SETTING: City of Bauru, in Brazil. SUBJECTS: A cluster sample of 396 schoolchildren (194 boys and 202 girls) aged 7-10 years. RESULTS: The anthropometric assessment showed similar situations for both sexes regarding underweight (31.40 % in boys and 30.20 % in girls) and overweight/obesity (33.96 % in boys and 33.17 % in girls). The underweight children showed a greater severity of tooth wear in the primary teeth (OR=0.72; CI 0.36, 1.42), although in the permanent dentition the obese children had a greater severity of tooth wear (OR=1.42; 95 % CI 0.31, 6.55). The tooth wear was correlated with age for both dentitions. CONCLUSIONS: Tooth wear in the primary and permanent dentition may be related to nutritional status. Tooth wear and obesity did not have a significant impact on the schoolchildren's perception of quality of life. PMID- 26419788 TI - Changing nomenclature for PBC: From 'cirrhosis' to 'cholangitis'. PMID- 26419785 TI - Purification and characterization of tenerplasminin-1, a serine peptidase inhibitor with antiplasmin activity from the coral snake (Micrurus tener tener) venom. AB - A plasmin inhibitor, named tenerplasminin-1 (TP1), was isolated from Micrurus tener tener (Mtt) venom. It showed a molecular mass of 6542Da, similarly to Kunitz-type serine peptidase inhibitors. The amidolytic activity of plasmin (0.5nM) on synthetic substrate S-2251 was inhibited by 91% following the incubation with TP1 (1nM). Aprotinin (2nM) used as the positive control of inhibition, reduced the plasmin amidolytic activity by 71%. Plasmin fibrinolytic activity (0.05nM) was inhibited by 67% following incubation with TP1 (0.1nM). The degradation of fibrinogen chains induced by plasmin, trypsin or elastase was inhibited by TP1 at a 1:2, 1:4 and 1:20 enzyme:inhibitor ratio, respectively. On the other hand, the proteolytic activity of crude Mtt venom on fibrinogen chains, previously attributed to metallopeptidases, was not abolished by TP1. The tPA clot lysis assay showed that TP1 (0.2nM) acts like aprotinin (0.4nM) inducing a delay in lysis time and lysis rate which may be associated with the inhibition of plasmin generated from the endogenous plasminogen activation. TP1 is the first serine protease plasmin-like inhibitor isolated from Mtt snake venom which has been characterized in relation to its mechanism of action, formation of a plasmin:TP1 complex and therapeutic potential as anti-fibrinolytic agent, a biological characteristic of great interest in the field of biomedical research. They could be used to regulate the fibrinolytic system in pathologies such as metastatic cancer, parasitic infections, hemophilia and other hemorrhagic syndromes, in which an intense fibrinolytic activity is observed. PMID- 26419789 TI - Dr Ninan T Mathew--A tribute (1937-2015). PMID- 26419786 TI - Gold(I)-Catalyzed Enantioselective Desymmetrization of 1,3-Diols through Intramolecular Hydroalkoxylation of Allenes. AB - A gold(I)-catalyzed enantioselective desymmetrization of 1,3-diols was achieved by intramolecular hydroalkoxylation of allenes. The catalyst system 3-F dppe(AuCl)2/(R)-C8-TRIPAg proved to be specifically efficient to promote the desymmetrizing cyclization of 2-aryl-1,3-diols, which have proven challenging substrates in previous reports. Multisubstituted tetrahydrofurans were prepared in good yield with good enantioselectivity and diastereoselectivity by this method. PMID- 26419790 TI - Do interictal microembolic signals play a role in higher cortical dysfunction during migraine aura? AB - INTRODUCTION: The aim of this study was to evaluate the prevalence and clinical impact of interictal microembolic signals (MES) in patients suffering from migraine with higher cortical dysfunction (HCD), such as language and memory impairment, during an aura. PATIENTS AND METHODS: This study was carried out on 34 migraineurs with language and memory impairment during aura (HCD group), 31 migraineurs with only visual or visual and somatosensory symptoms during aura (Control group I), and 34 healthy controls (Control group II). We used a Doppler instrument to detect microemboli. Demographic data, disease features and the detection of MES between these groups, as well as the predictors of HCD during the aura, were analyzed. RESULTS: The duration of aura was longer and the frequency of aura was higher among patients with language and memory impairment during aura compared to Control group I. MES was detected in 29.4% patients from the HCD group, which was significantly higher compared to 3.2% in Control group I and 5.9% in Control group II. Regarding the absence or presence of MES, demographic and aura features were not different in the HCD subgroups. A longer duration of aura, the presence of somatosensory symptoms during the aura and the presence of interictal MES were independent predictors of HCD during the aura. CONCLUSION: The present findings indicate that HCD and MES are related in patients with migraine with aura. Further research is needed to better understand the exact pathophysiological mechanism. PMID- 26419791 TI - Treatment of older people with dementia in surgical wards from the viewpoints of the patients and close relatives. AB - AIMS AND OBJECTIVES: The aim of this study was to describe the treatment of older people with dementia in surgical wards from the viewpoints of the patients and their close relatives. BACKGROUND: Little is known about the impact of the increasing number of older people with dementia on the treatment of patients in acute care. DESIGN: A qualitative, descriptive design was used. METHOD: The data were collected using unstructured interviews, which were then subjected to inductive content analysis. RESULTS: Support from close relatives was significant for the mental and social wellbeing of older dementia patients during their hospital stay. People with dementia felt insecure in their relatives' absence, and missed them. For the relatives, the patients' hospital stay was emotionally heavy. The relatives desired more emotional support from the nursing staff. The participating patients hoped that the nursing staff would spend more time discussing their cases with them. One of the factors that hindered good care of an older person with dementia was use of restraint. Relatives felt that use of restraints violated patients' dignity. CONCLUSIONS: To improve the treatment of the people with dementia, the close relatives need to participate in planning the nature of care for the patients. RELEVANCE TO CLINICAL PRACTICE: The results are applicable for efforts to improve the abilities of nursing staff, physicians and close relatives in the treatment of older people with dementia in acute care settings. PMID- 26419792 TI - DAMP production by human islets under low oxygen and nutrients in the presence or absence of an immunoisolating-capsule and necrostatin-1. AB - In between the period of transplantation and revascularization, pancreatic islets are exposed to low-oxygen and low-nutrient conditions. In the present study we mimicked those conditions in vitro to study the involvement of different cell death processes, release of danger-associated molecular patterns (DAMP), and associated in vitro immune activation. Under low-oxygen and low-nutrient conditions, apoptosis, autophagy and necroptosis occur in human islets. Necroptosis is responsible for DAMP-release such as dsDNA, uric acid, and HMGB1. The sensors of the innate immune system able to recognize these DAMPs are mainly TLR, NOD receptors, and C-type lectins. By using cell-lines with a non-functional adaptor molecule MyD88, we were able to show that the islet-derived DAMPs signal mainly via TLR. Immunoisolation in immunoprotective membranes reduced DAMP release and immune activation via retention of the relative large DAMPs in the capsules. Another effective strategy was suppressing necroptosis using the inhibitor nec-1. Although the effect on cell-survival was minor, nec-1 was able to reduce the release of HMGB1 and its associated immune activation. Our data demonstrate that in the immediate post-transplant period islets release DAMPs that in vitro enhance responses of innate immune cells. DAMP release can be reduced in vitro by immunoisolation or intervention with nec-1. PMID- 26419793 TI - Effects of ethanol, molasses and Lactobacillus plantarum on the fermentation quality, in vitro digestibility and aerobic stability of total mixed ration silages in the Tibetan plateau of China. AB - In Tibet, it is common practice to make and relocate total mixed ration (TMR) silages before feeding due to the uneven distribution of forages temporally and spatially. This study was conducted to investigate the effects of Lactobacillus plantarum (L), molasses (M) or ethanol (E) on the fermentation quality and aerobic stability of local adaptive TMR silage. After 45 days of ensiling, pH and ammonia nitrogen in inoculated TMR silages were significantly lower than control. During the first 6 days of the aerobic exposure test, a small fluctuation in lactic acid concentration for all TMR silages was observed, and then silages with ethanol continued this trend, while lactic acid in silage without ethanol sharply decreased until the end of the aerobic exposure period. Meanwhile, pH gradually increased along the aerobic exposure; silages treated with ethanol showed lower pH after 9 days of aerobic exposure. The population of yeast gradually increased during 6 days of aerobic exposure, after that an accelerated rise was observed in TMR silages without ethanol. The combinational beneficial effect of L. plantarum and ethanol was found in combined addition of ethanol and Lactobacillus plantarum silages (EL), indicated by intermediate fermentation quality and higher aerobic stability. PMID- 26419795 TI - Yoga for Self-Care and Burnout Prevention Among Nurses. AB - The promotion of self-care and the prevention of burnout among nurses is a public health priority. Evidence supports the efficacy of yoga to improve physical and mental health outcomes, but few studies have examined the influence of yoga on nurse-specific outcomes. The purpose of this pilot-level randomized controlled trial was to examine the efficacy of yoga to improve self-care and reduce burnout among nurses. Compared with controls (n = 20), yoga participants (n = 20) reported significantly higher self-care as well as less emotional exhaustion and depersonalization upon completion of an 8-week yoga intervention. Although the control group demonstrated no change throughout the course of the study, the yoga group showed a significant improvement in scores from pre- to post-intervention for self-care (p < .001), mindfulness (p = .028), emotional exhaustion (p = .008), and depersonalization (p = .007) outcomes. Implications for practice are discussed. PMID- 26419797 TI - Global Tuberculosis. AB - Tuberculosis (TB) infections remain a common but deadly disease. TB control in health care and correctional settings presents numerous public health challenges for occupational and correctional health nurses. PMID- 26419798 TI - The visual perception of natural motion: abnormal task-related neural activity in DYT1 dystonia. AB - Although primary dystonia is defined by its characteristic motor manifestations, non-motor signs and symptoms have increasingly been recognized in this disorder. Recent neuroimaging studies have related the motor features of primary dystonia to connectivity changes in cerebello-thalamo-cortical pathways. It is not known, however, whether the non-motor manifestations of the disorder are associated with similar circuit abnormalities. To explore this possibility, we used functional magnetic resonance imaging to study primary dystonia and healthy volunteer subjects while they performed a motion perception task in which elliptical target trajectories were visually tracked on a computer screen. Prior functional magnetic resonance imaging studies of healthy subjects performing this task have revealed selective activation of motor regions during the perception of 'natural' versus 'unnatural' motion (defined respectively as trajectories with kinematic properties that either comply with or violate the two-thirds power law of motion). Several regions with significant connectivity changes in primary dystonia were situated in proximity to normal motion perception pathways, suggesting that abnormalities of these circuits may also be present in this disorder. To determine whether activation responses to natural versus unnatural motion in primary dystonia differ from normal, we used functional magnetic resonance imaging to study 10 DYT1 dystonia and 10 healthy control subjects at rest and during the perception of 'natural' and 'unnatural' motion. Both groups exhibited significant activation changes across perceptual conditions in the cerebellum, pons, and subthalamic nucleus. The two groups differed, however, in their responses to 'natural' versus 'unnatural' motion in these regions. In healthy subjects, regional activation was greater during the perception of natural (versus unnatural) motion (P < 0.05). By contrast, in DYT1 dystonia subjects, activation was relatively greater during the perception of unnatural (versus natural) motion (P < 0.01). To explore the microstructural basis for these functional changes, the regions with significant interaction effects (i.e. those with group differences in activation across perceptual conditions) were used as seeds for tractographic analysis of diffusion tensor imaging scans acquired in the same subjects. Fibre pathways specifically connecting each of the significant functional magnetic resonance imaging clusters to the cerebellum were reconstructed. Of the various reconstructed pathways that were analysed, the ponto-cerebellar projection alone differed between groups, with reduced fibre integrity in dystonia (P < 0.001). In aggregate, the findings suggest that the normal pattern of brain activation in response to motion perception is disrupted in DYT1 dystonia. Thus, it is unlikely that the circuit changes that underlie this disorder are limited to primary sensorimotor pathways. PMID- 26419800 TI - Chris Marshall 1949-2015. PMID- 26419799 TI - Regional brain hypometabolism is unrelated to regional amyloid plaque burden. AB - In its original form, the amyloid cascade hypothesis of Alzheimer's disease holds that fibrillar deposits of amyloid are an early, driving force in pathological events leading ultimately to neuronal death. Early clinicopathological investigations highlighted a number of inconsistencies leading to an updated hypothesis in which amyloid plaques give way to amyloid oligomers as the driving force in pathogenesis. Rather than focusing on the inconsistencies, amyloid imaging studies have tended to highlight the overlap between regions that show early amyloid plaque signal on positron emission tomography and that also happen to be affected early in Alzheimer's disease. Recent imaging studies investigating the regional dependency between metabolism and amyloid plaque deposition have arrived at conflicting results, with some showing regional associations and other not. We extracted multimodal neuroimaging data from the Alzheimer's disease neuroimaging database for 227 healthy controls and 434 subjects with mild cognitive impairment. We analysed regional patterns of amyloid deposition, regional glucose metabolism and regional atrophy using florbetapir ((18)F) positron emission tomography, (18)F-fluordeoxyglucose positron emission tomography and T1-weighted magnetic resonance imaging, respectively. Specifically, we derived grey matter density and standardized uptake value ratios for both positron emission tomography tracers in 404 functionally defined regions of interest. We examined the relation between regional glucose metabolism and amyloid plaques using linear models. For each region of interest, correcting for regional grey matter density, age, education and disease status, we tested the association of regional glucose metabolism with (i) cortex-wide florbetapir uptake; (ii) regional (i.e. in the same region of interest) florbetapir uptake; and (iii) regional florbetapir uptake while correcting in addition for cortex wide florbetapir uptake. P-values for each setting were Bonferroni corrected for 404 tests. Regions showing significant hypometabolism with increasing cortex-wide amyloid burden were classic Alzheimer's disease-related regions: the medial and lateral parietal cortices. The associations between regional amyloid burden and regional metabolism were more heterogeneous: there were significant hypometabolic effects in posterior cingulate, precuneus, and parietal regions but also significant positive associations in bilateral hippocampus and entorhinal cortex. However, after correcting for global amyloid burden, few of the negative associations remained and the number of positive associations increased. Given the wide-spread distribution of amyloid plaques, if the canonical cascade hypothesis were true, we would expect wide-spread, cortical hypometabolism. Instead, cortical hypometabolism appears to be linked to global amyloid burden. Thus we conclude that regional fibrillar amyloid deposition has little to no association with regional hypometabolism. PMID- 26419801 TI - Translating the effects of mTOR on secretory senescence. AB - Cellular senescence is often accompanied by the production of secreted proteins that mediate the diverse effects of senescence on the tissue microenvironment. The mammalian target of rapamycin (mTOR), a master regulator of protein synthesis, is now shown to control the senescence-associated secretory phenotype by modulating gene transcription and mRNA translation and stabilization. PMID- 26419802 TI - STIMATE reveals a STIM1 transitional state. AB - Decreases in endoplasmic reticulum calcium content are sensed by resident STIM proteins, which can activate plasma membrane Orai channels to facilitate Ca(2+) entry. The role of STIMATE, a previously unknown component of the store-operated calcium entry complex, has now been identified and defined. PMID- 26419803 TI - Corrigendum: Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation. PMID- 26419804 TI - Erratum: mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. PMID- 26419805 TI - A tunable azine covalent organic framework platform for visible light-induced hydrogen generation. AB - Hydrogen evolution from photocatalytic reduction of water holds promise as a sustainable source of carbon-free energy. Covalent organic frameworks (COFs) present an interesting new class of photoactive materials, which combine three key features relevant to the photocatalytic process, namely crystallinity, porosity and tunability. Here we synthesize a series of water- and photostable 2D azine-linked COFs from hydrazine and triphenylarene aldehydes with varying number of nitrogen atoms. The electronic and steric variations in the precursors are transferred to the resulting frameworks, thus leading to a progressively enhanced light-induced hydrogen evolution with increasing nitrogen content in the frameworks. Our results demonstrate that by the rational design of COFs on a molecular level, it is possible to precisely adjust their structural and optoelectronic properties, thus resulting in enhanced photocatalytic activities. This is expected to spur further interest in these photofunctional frameworks where rational supramolecular engineering may lead to new material applications. PMID- 26419806 TI - Electrocatalytic O2-Reduction by Synthetic Cytochrome c Oxidase Mimics: Identification of a "Bridging Peroxo" Intermediate Involved in Facile 4e(-)/4H(+) O2-Reduction. AB - A synthetic heme-Cu CcO model complex shows selective and highly efficient electrocatalytic 4e(-)/4H(+) O2-reduction to H2O with a large catalytic rate (>10(5) M(-1) s(-1)). While the heme-Cu model (FeCu) shows almost exclusive 4e( )/4H(+) reduction of O2 to H2O (detected using ring disk electrochemistry and rotating ring disk electrochemistry), when imidazole is bound to the heme (Fe(Im)Cu), this same selective O2-reduction to water occurs only under slow electron fluxes. Surface enhanced resonance Raman spectroscopy coupled to dynamic electrochemistry data suggests the formation of a bridging peroxide intermediate during O2-reduction by both complexes under steady state reaction conditions, indicating that O-O bond heterolysis is likely to be the rate-determining step (RDS) at the mass transfer limited region. The O-O vibrational frequencies at 819 cm(-1) in (16)O2 (759 cm(-1) in (18)O2) for the FeCu complex and at 847 cm(-1) (786 cm(-1)) for the Fe(Im)Cu complex, indicate the formation of side-on and end on bridging Fe-peroxo-Cu intermediates, respectively, during O2-reduction in an aqueous environment. These data suggest that side-on bridging peroxide intermediates are involved in fast and selective O2-reduction in these synthetic complexes. The greater amount of H2O2 production by the imidazole bound complex under fast electron transfer is due to 1e(-)/1H(+) O2-reduction by the distal Cu where O2 binding to the water bound low spin Fe(II) complex is inhibited. PMID- 26419809 TI - Diversity of fig glands is associated with nursery mutualism in fig trees. AB - PREMISE OF THE STUDY: Fig trees (Moraceae) have remarkable enclosed inflorescences called figs or syconia. The flowers are pollinated by host specific fig wasps that enter the fig to lay their eggs. This nursery pollination system is one of the most studied of tropical mutualism interactions, but the source of the volatiles that attract fig wasps to their specific host figs has not been confirmed. The fragrance is the basis of host selection and, therefore, of reproductive isolation among sympatric Ficus species. This study locates and characterizes the glands likely to be responsible for pollinator attraction and also protection from herbivory in the figs of nine Ficus species representing all the major lineages within the genus. METHODS: Figs with receptive pistillate flowers were examined using light and scanning electron microscopy. Tests for histolocalization of substances were employed to detect glandular activity throughout the figs. KEY RESULTS: A great diversity of glands is found throughout the fig, and for the first time, the sites producing fragrances are identified. Scent glands are present on the ostiolar bracts and the outer layers of the fig receptacle. Laticifers and phenolic-producing idioblasts, epidermis, and trichomes associated with fig protection occur on the ostiolar bracts, the fig receptacle, and floral tissues. CONCLUSIONS: The volatiles produced by glands on the ostiolar bracts are candidate sources for the long-distance attraction of pollinator fig wasps. Scent glands on the outer layers of the receptacle may also play a role in chemical perception of the figs or may be related to their protection. The high cost to the plants if the figs are eaten and the temperature conditions required for nursery pollination are likely the factors that led to the selection of phenolic glands and laticifers during the group's evolution. PMID- 26419807 TI - Interactions between chronic ethanol consumption and thiamine deficiency on neural plasticity, spatial memory, and cognitive flexibility. AB - BACKGROUND: Many alcoholics display moderate to severe cognitive dysfunction accompanied by brain pathology. A factor confounded with prolonged heavy alcohol consumption is poor nutrition, and many alcoholics are thiamine deficient. Thus, thiamine deficiency (TD) has emerged as a key factor underlying alcohol-related brain damage (ARBD). TD in humans can lead to Wernicke Encephalitis that can progress into Wernicke-Korsakoff syndrome and these disorders have a high prevalence among alcoholics. Animal models are critical for determining the exact contributions of ethanol (EtOH)- and TD-induced neurotoxicity, as well as the interactions of those factors to brain and cognitive dysfunction. METHODS: Adult rats were randomly assigned to 1 of 6 treatment conditions: chronic EtOH treatment (CET) where rats consumed a 20% v/v solution of EtOH over 6 months; severe pyrithiamine-induced TD (PTD-moderate acute stage); moderate PTD (PTD early acute stage); moderate PTD followed by CET (PTD-CET); moderate PTD during CET (CET-PTD); and pair-fed (PF) control. After recovery from treatment, all rats were tested on spontaneous alternation and attentional set-shifting. After behavioral testing, brains were harvested for determination of mature brain derived neurotrophic factor (BDNF) and thalamic pathology. RESULTS: Moderate TD combined with CET, regardless of treatment order, produced significant impairments in spatial memory, cognitive flexibility, and reductions in brain plasticity as measured by BDNF levels in the frontal cortex and hippocampus. These alterations are greater than those seen in moderate TD alone, and the synergistic effects of moderate TD with CET lead to a unique cognitive profile. However, CET did not exacerbate thalamic pathology seen after moderate TD. CONCLUSIONS: These data support the emerging theory that subclinical TD during chronic heavy alcohol consumption is critical for the development of significant cognitive impairment associated with ARBD. PMID- 26419808 TI - Ikaros mediates the DNA methylation-independent silencing of MCJ/DNAJC15 gene expression in macrophages. AB - MCJ (DNAJC15) is a mitochondrial protein that regulates the mitochondrial metabolic status of macrophages and their response to inflammatory stimuli. CpG island methylation in cancer cells constitutes the only mechanism identified for the regulation of MCJ gene expression. However, whether DNA methylation or transcriptional regulation mechanisms are involved in the physiological control of this gene expression in non-tumor cells remains unknown. We now demonstrate a mechanism of regulation of MCJ expression that is independent of DNA methylation. IFNgamma, a protective cytokine against cardiac inflammation during Lyme borreliosis, represses MCJ transcription in macrophages. The transcriptional regulator, Ikaros, binds to the MCJ promoter in a Casein kinase II-dependent manner, and mediates the repression of MCJ expression. These results identify the MCJ gene as a transcriptional target of IFNgamma and provide evidence of the dynamic adaptation of normal tissues to changes in the environment as a way to adapt metabolically to new conditions. PMID- 26419810 TI - Pollen structure and development in Nymphaeales: insights into character evolution in an ancient angiosperm lineage. AB - PREMISE OF THE STUDY: A knowledge of pollen characters in early-diverging angiosperm lineages is essential for understanding pollen evolution and the role of pollen in angiosperm diversification. In this paper, we report and synthesize data on mature pollen and pollen ontogeny from all genera of Nymphaeales within a comparative, phylogenetic context and consider pollen evolution in this early diverging angiosperm lineage. We describe mature pollen characters for Euryale, Barclaya, and Nymphaea ondinea, taxa for which little to no structural data exist. METHODS: We studied mature pollen for all nymphaealean genera using light, scanning electron, and transmission electron microscopy. We reviewed published reports of nymphaealean pollen to provide a comprehensive discussion of pollen characters in water lilies. KEY RESULTS: Nymphaeales exhibit diversity in key pollen characters, including dispersal unit size, ornamentation, aperture morphology, and tapetum type. All Nymphaeales pollen are tectate-columellate, exhibiting one of two distinct patterns of infratectal ultrastructure-a thick infratectal space with robust columellae or a thin infratectal space with thin columellae. All genera have pollen with a lamellate endexine that becomes compressed in the proximal, but not distal wall. This endexine ultrastructure supports the operculate hypothesis for aperture origin. Nymphaeaceae pollen exhibit a membranous granular layer, which is a synapomorphy of the family. CONCLUSIONS: Variation in pollen characters indicates that significant potential for lability in pollen development was present in Nymphaeales at the time of its divergence from the rest of angiosperms. Structural and ontogenetic data are essential for interpreting pollen characters, such as infratectum and endexine ultrastructure in Nymphaeales. PMID- 26419811 TI - Floral anatomy and vegetative development in Ceratophyllum demersum: a morphological picture of an "unsolved" plant. AB - PREMISE OF THE STUDY: The phylogenetic position of Ceratophyllum is still controversial in recent molecular analyses of angiosperms, with various suggestions of a sister group relation to all other angiosperms, eudicots, monocots, eudicots + monocots, and magnoliids. Therefore, the morphological characters of Ceratophyllum are important for resolving the phylogeny of angiosperms. In this study, we observed the detailed developmental anatomy of all lateral organs and their configurations to elucidate the floral development and phyllotactic pattern of Ceratophyllum demersum. METHODS: We observed fixed shoots of C. demersum with scanning electron microscopy and serial sections of the samples with light microscopy. KEY RESULTS: Bract primordia arise first, followed by the stamen primordia in staminate flowers. Both bracts and stamens initiate unidirectionally, first on the abaxial side of the floral apex and later on the adaxial side, most likely due to the contact pressure imposed by the leaf primordium at the superior node. In pistillate flowers, bract primordia on the abaxial side were also initiated first. The configuration of buds at one node showed six patterns and each pattern included at least one vegetative bud, and flower buds were always accompanied by vegetative buds at the same node. CONCLUSIONS: The initiation pattern of organs in the outer whorls of C. demersum flowers is distorted by mechanical pressure, resulting in the phyllotactic variation of staminate flowers. Vegetative buds are the main axillary buds with floral buds as accessory buds, which suggests that the shoot of C. demersum has been modified from a decussate phyllotaxis. PMID- 26419813 TI - Think Stoma Nurse: a tool to trigger referral to specialist care. AB - This article describes the initial development and subsequent evolution of a simple referral assessment tool for stoma care. The first author's personal experience identified that there was widespread inconsistency in perceptions of local multidisciplinary teams as to when it was appropriate to refer to specific specialist nursing teams. This resulted in both inappropriate and delayed referrals. A 'Think Specialist Nurse' initiative was developed across the author's trust, building on the traffic light template from the 'ThinkGlucose' tool, to facilitate referrals to clinical nurse specialists. The stoma-care specific tool, 'Think Stoma Nurse', has subsequently evolved beyond its initial audience, and has been adapted into materials aimed at patients and carers. PMID- 26419814 TI - Stoma Care Nurse of the Year: BJN AWARD RUNNER UP. AB - Gill Little, National Nurse Manager SecuriCare (Medical), entered Helen, Lyn, Tara and Gillian into the Stoma Care Nurse of the Year category. Here, she explains the reasons behind her nomination. PMID- 26419812 TI - Infants born large-for-gestational-age display slower growth in early infancy, but no epigenetic changes at birth. AB - We evaluated the growth patterns of infants born large-for-gestational-age (LGA) from birth to age 1 year compared to those born appropriate-for-gestational-age (AGA). In addition, we investigated possible epigenetic changes associated with being born LGA. Seventy-one newborns were classified by birth weight as AGA (10(th)-90(th) percentile; n = 42) or LGA (>90(th) percentile; n = 29). Post natal follow-up until age 1 year was performed with clinical assessments at 3, 6, and 12 months. Genome-wide DNA methylation was analysed on umbilical tissue in 19 AGA and 27 LGA infants. At birth, LGA infants had greater weight (p < 0.0001), length (p < 0.0001), ponderal index (p = 0.020), as well as greater head (p < 0.0001), chest (p = 0.044), and abdominal (p = 0.007) circumferences than AGA newborns. LGA infants were still larger at the age of 3 months, but by age 6 months there were no more differences between groups, due to higher length and weight increments in AGA infants between 0 and 6 months (p < 0.0001 and p = 0.002, respectively). Genome-wide analysis showed no epigenetic differences between LGA and AGA infants. Overall, LGA infants had slower growth in early infancy, being anthropometrically similar to AGA infants by 6 months of age. In addition, differences between AGA and LGA newborns were not associated with epigenetic changes. PMID- 26419815 TI - Stoma accessories and quality of life. PMID- 26419817 TI - ASCN welcomes delegates to its annual conference. PMID- 26419816 TI - Psychosocial impact of intestinal failure: a familial perspective. AB - Intestinal failure is a complicated long-term condition that can have profound physical and psychosocial consequences for a patient's life. Hospitalisation can be long, with many distressing and unpleasant medical procedures being endured. Patients often have to deal with large volumes of unmanageable faecal fluid from stomas or fistulae and usually require home parenteral nutrition (HPN) for the remainder of their life. The literature focuses on how patients often have to tolerate long periods of suffering, which can be the basis for significant emotional anguish. It also addresses how the condition can contribute to myriad psychosocial difficulties, which can have devastating effects on their body image and quality of life. However, there is a lack of information regarding the effects of this condition on the family, who not only have to provide ongoing support for the patient, but also have to attempt to function normally while coping with their own fears and emotions. This article reviews the experiences of two patients, father and daughter, living with intestinal failure; it discusses their experiences and reveals how they cope with the physical aspects. It also addresses how the condition can effect psychosocial disturbances, not only for them but for those living closely with them. The article addresses ways that nurses could develop their relationship with the patient, enabling them to recognise and act early on signs of emotional malady. PMID- 26419818 TI - Meeting the needs of new ostomists: a patient evaluation survey. AB - Nottingham University Hospitals (NUH) NHS Trust provides a care pathway for patients undergoing stoma formation surgery, with the stoma care nurse specialists providing ongoing support for patients, alongside the rest of the multidisciplinary team, from the preoperative consultation through to their community follow-up. In the past, the community service offered has not always been well-received and the whole pathway has not been evaluated in depth to date. This article reports on a patient evaluation survey of the stoma care pathway at NUH. The results showed that overall patients are very complimentary of the service offered to them by the stoma care team. They highly commend the stoma care nurse specialist. Two areas for amendment in the pathway have been identified: information provision and the length of time available for the stoma care nurse specialist to spend one-to-one with each patient. The results of this survey will aid the team in implementing positive changes to the stoma care pathway. PMID- 26419820 TI - Transmembrane prostatic acid phosphatase (TMPAP) delays cells in G1 phase of the cell cycle. AB - BACKGROUND: Prostate adenocarcinoma is the most common form of prostate cancer. We have previously shown in a murine model that prostatic acid phosphatase (PAP) deficiency leads to increased cell proliferation and development of prostate adenocarcinoma. The association between PAP and prostate cancer has been reported. Indeed, high PAP enzymatic activity is detected in the serum of patients with metastatic disease while its expression is reduced in prostate cancer tissue. However, the molecular mechanisms behind the onset of the disease remains poorly understood. We previously identified a novel transmembrane prostatic acid phosphatase (TMPAP) isoform, which interacts with snapin. TMPAP is expressed on the plasma membrane, as well as endosomal/lysosomal and exosomal membrane vesicles by means of a tyrosine-based lysosomal targeting motif (Yxxphi). METHODS: We used stable overexpression of the secreted isoform (SPAP) and TMPAP in LNCaP cells, live cell imaging, microarray and qRT-PCR analyses, and fluid phase uptake of HRP and transferrin. RESULTS: Our results indicate that the stable overexpression of TMPAP, but not SPAP in LNCaP cells reduces cell growth while increasing endo/exocytosis and cell size. Specifically, cells overexpressing TMPAP accumulate in the G1 phase of the cell cycle, and show altered gene expression profile. CONCLUSIONS: Our data suggests that TMPAP may function as a non-canonical tumor suppressor by delaying cell growth in G1 phase of the cell cycle. PMID- 26419821 TI - Fast switching from isotropic liquids to nematic liquid crystals: rotaxanes as smart fluids. AB - We examine a solution of rod-like piston-rotaxanes, which can switch their length by external excitation (for example optically) from a short state of length L to a long state of length qL. We show that this solution can exhibit a number of different behaviours. In particular it can rapidly switch from an isotropic to a nematic liquid crystalline state. There is a minimum ratio q* = 1.13 for which transitions from a pure isotropic state to a pure nematic state are possible. We present a phase-switching diagram, which gives the six possible behaviours for this system. It turns out that a large fraction of the phase switching diagram is occupied by the transition from a pure isotropic to a pure nematic state. PMID- 26419819 TI - Preclinical models of pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDA) is one of the most difficult human malignancies to treat. The 5-year survival rate of PDA patients is 7% and PDA is predicted to become the second leading cancer-related cause of death in the USA. Despite intensive efforts, the translation of findings in preclinical studies has been ineffective, due partially to the lack of preclinical models that faithfully recapitulate features of human PDA. Here, we review current preclinical models for human PDA (eg human PDA cell lines, cell line-based xenografts and patient derived tumour xenografts). In addition, we discuss potential applications of the recently developed pancreatic ductal organoids, three-dimensional culture systems and organoid-based xenografts as new preclinical models for PDA. PMID- 26419822 TI - Response to: 'Baseline differences in SAVOR trial'-- prespecified vs. post hoc analysis--a potential source of bias. PMID- 26419823 TI - The yield of screening symptomatic contacts of multidrug-resistant tuberculosis cases at a tertiary hospital in Addis Ababa, Ethiopia. AB - BACKGROUND: Early detection and treatment of multidrug-resistant tuberculosis (MDR-TB, resistant to isoniazid and rifampicin) is an urgent global priority. Identifying and tracing close contacts of patients with MDR-TB could be a feasible strategy to achieve this goal. However, there is limited experience with contact tracing among patients with drug-resistant tuberculosis both globally and in Ethiopia. Here we present our findings on the extent of screening symptomatic contacts and its yield in a tertiary hospital in a major urban setting in Ethiopia. RESULTS: Symptomatic household contacts were identified in 29 (5.7%) of 508 index cases treated at the hospital. There were a total of 155 family members in the households traced of whom 16 (10%) had confirmed MDR-TB. At least one confirmed MDR-TB cases was identified in 15 (51.7%) of the 29 traced households. CONCLUSIONS: Tracing symptomatic contacts of MDR-TB cases could be a high yield strategy for early detection and treatment of MDR-TB cases in the community. The approach should be promoted for wider adoption and dissemination. Larger scale studies should be done to determine its effectiveness and sustainability in similar settings. PMID- 26419824 TI - Mifepristone and misoprostol compared with misoprostol alone for induction of labor in intrauterine fetal death: A randomized trial. AB - AIM: To assess whether mifepristone and misoprostol are more beneficial than misoprostol alone for the induction of labor in women with intrauterine fetal death. METHODS: A randomized double blind placebo-controlled parallel group superiority trial was conducted. One hundred and ten women who had experienced fetal death at or later than 20 weeks of gestation were randomized by computer generated random number sequence to receive 200 mg of mifepristone or matched placebo tablets orally. Misoprostol was administered vaginally to women of both groups after 36-48 h. The main outcomes studied were the fetal-placental delivery rate within 24 hours of commencement of the first dose of misoprostol without additional intervention and the induction-delivery interval. RESULTS: Successful delivery occurred significantly more frequently in women who received mifepristone prior to misoprostol than in women who received only misoprostol (92.5% [49/53] compared with 71.2% [37/52] respectively; P = 0.001). The mean induction-delivery interval was also significantly shorter when using mifepristone plus misoprostol than using misoprostol alone (9.8 h, standard deviation, 4.4 compared with 16.3 h standard deviation, 5.7, respectively; P < 0.001). CONCLUSION: Use of a combination of mifepristone and misoprostol significantly improved the rate of successful delivery and shortened the induction-delivery interval in women who had experienced fetal death compared with the use of misoprostol alone. PMID- 26419825 TI - Similarities in murine infection and immune response to Borrelia bissettii and Borrelia burgdorferi sensu stricto. AB - In 1982, Borrelia burgdorferi sensu stricto (ss) was identified as the aetiological agent of Lyme disease. Since then an increasing number of Borrelia burgdorferi sensu lato (sl) species have been isolated in the United States. To date, many of these species remain understudied despite mounting evidence associating them with human illness. Borrelia bissettii is a spirochaete closely related to B. burgdorferi that has been loosely associated with human illness. Using an experimental murine infection model, we compared the infectivity and humoral immune response with a North American isolate of B. bissettii and B. burgdorferi using culture, molecular and serological methods. The original B. bissettii cultures were unable to infect immunocompetent mice, but were confirmed to be infectious after adaptation in immunodeficient animals. B. bissettii infection resulted in spirochaete burdens similar to B. burgdorferi in skin, heart and bladder whereas significantly lower burdens were observed in the joint tissues. B. bissettii induced an antibody response similar to B. burgdorferi as measured by both immunoblotting and the C6 ELISA. Additionally, this isolate of B. bissettii was sequenced on the Ion Torrent PGM, which successfully identified many genes orthologous to mammalian virulence factors described in B. burgdorferi. Similarities seen between both infections in this well-characterized murine model contribute to our understanding of the potential pathogenic nature of B. bissettii. Infection dynamics of B. bissettii, and especially the induced humoral response, are similar to B. burgdorferi, suggesting this species may contribute to the epidemiology of human borreliosis. PMID- 26419826 TI - Recovering the superficial microvascular pattern via diffuse reflection imaging: phantom validation. AB - BACKGROUND: Diffuse reflection imaging could potentially be used to recover the superficial microvasculature under cutaneous tissue and the associated blood oxygenation status with a modified imaging resolution. The aim of this work is to deliver a new approach of local off-axis scanning diffuse reflection imaging, with the revisit of the modified Beer-Lambert Law (MBLL). METHODS: To validate this, the system is used to recover the micron-scale subsurface vessel structure interiorly embedded in a skin equivalent tissue phantom. This vessel structure is perfused with oxygenated meta-hemoglobin solution. RESULTS: Our preliminary results confirm that the thin vessel structure can be mapped into a 2-D planar image. The distributions of oxygenated hemoglobin concentration ([Formula: see text]) and deoxygenated hemoglobin concentration ([Formula: see text]) can be co registerated through the MBLL upon the CW spectroscopy, the scattering issue is addressed in the reformed MBLL. The recovered pattern matches to the estimation from the simultaneous optical coherence tomography studies. CONCLUSIONS: With further modification, this system may serve as the first prototype to investigate the superficial microvasculature in the expotential skin cancer loci, or a micro lesion of vascular dermatosis. PMID- 26419827 TI - Perceptions and intentions relating to seeking help for depression among medical undergraduates in Sri Lanka: a cross-sectional comparison with non-medical undergraduates. AB - BACKGROUND: This study attempts to understand whether medical undergraduates in Sri Lanka would seek help for depression. This was done by examining their perceptions and intentions relating to seeking help for depression, using the responses of non-medical undergraduates as the baseline for comparison. METHOD: Medical (n = 620) and non-medical undergraduates (n = 4050) at the University of Colombo responded to a questionnaire which included a vignette about a depressed undergraduate, a depression measure, an open-ended question examining their intentions to seek help if affected by the problem described in the vignette, and scales examining their perceptions about the helpfulness of various help-seeking options for dealing with the problem. The latter items were also administered among mental health professionals to assess expert opinion on dealing with depression. Logistic regression models were used to examine if medical undergraduates differed from non-medical undergraduates in their rates of depression, help-seeking perceptions and help-seeking intentions. These models were also used to examine if being depressed was associated with differences in the help-seeking perceptions and intentions of medical undergraduates. RESULTS: Medical and non-medical undergraduates did not differ in their odds of being depressed. Overall, the medical undergraduates were more likely to appraise professional help positively. However, they did not differ from non-medical undergraduates in relation to their intentions to seek such help if affected by the problem personally. They were also more likely to indicate their intentions to seek help from parents and family. Furthermore, medical undergraduates who screened positive for Major Depression were less likely to appraise some of the recommended professional and informal help-seeking options as being 'helpful', with only 50 % considering that it was 'unhelpful' to deal with the problem alone. There was also no difference in their help-seeking intentions as compared to those screening negative for Major Depression. DISCUSSION AND CONCLUSIONS: Although medical training seems to be associated with better help-seeking beliefs, interventions are needed to improve these medical undergraduates' intentions to personally seek professional help for depression. It is concerning that medical undergraduates who are depressed might be less likely to consider it beneficial to seek help and instead, deal with the problem alone. PMID- 26419829 TI - The idiopathic preterm delivery methylation profile in umbilical cord blood DNA. AB - BACKGROUND: Preterm delivery is the leading cause of neonatal morbidity and mortality. Two-thirds of preterm deliveries are idiopathic. The initiating molecular mechanisms behind spontaneous preterm delivery are unclear. Umbilical cord blood DNA samples are an easy source of material to study the neonatal state at birth. DNA methylation changes can be exploited as markers to identify spontaneous preterm delivery. To identify methylation differences specific to idiopathic preterm delivery, we assessed genome-wide DNA methylation changes in 24 umbilical cord blood samples (UCB) using the 450 K Illumina methylation array. After quality control, conclusions were based on 11 term and 11 idiopathic preterm born neonates. The differentially methylated positions (DMPs) specific for preterm/term delivery, neonatal sex, use of oxytocin and mode of initiation of labor were calculated by controlling the FDR p value at 0.05. RESULTS: The analysis identifies 1855 statistically significant DMPs between preterm and term deliveries of which 508 DMPs are also attributable to clinical variables other than preterm versus term delivery. 1347 DMPs are unique to term vs preterm delivery, of which 196 DMPs do not relate to gestational age as such. Pathway analysis indicated enrichment of genes involved in calcium signalling, myometrial contraction and relaxation pathways. The 1151 DMPs that correlate with advancing gestational age (p < 0.05) include 161 DMPs that match with two previously reported studies on UCB methylation. Additionally, 123 neonatal sex specific DMPs, 97 DMPs specific to the induction of labour and 42 DMPs specific to the mode of initiation of labor were also identified. CONCLUSION: This study identifies 196 DMPs in UCB DNA of neonates which do not relate to gestational age or any other clinical variable recorded and are specific to idiopathic preterm delivery. Furthermore, 161 DMPs from our study overlap with previously reported studies of which a subset is also reported to be differentially methylated at 18 years of age. A DMP on MYL4, encoding myosin light chain 4, is a robust candidate for the identification of idiopathic preterm labour as it is identified by all 3 independent studies. PMID- 26419830 TI - 7-Ketocholesterol-induced lysosomal dysfunction exacerbates vascular smooth muscle cell calcification via oxidative stress. AB - Vascular calcification is known to reduce the elasticity of aorta. Several studies have suggested that autophagy-lysosomal pathway (ALP) in vascular smooth muscle cells (VSMCs) is associated with vascular calcification. A major component of oxidized low-density lipoproteins, 7-ketocholesterol (7-KC), has been reported to promote inorganic phosphorus (Pi)-induced vascular calcification and induce ALP. The aim of this study was to unravel the relationship between ALP and the progression of calcification by 7-KC. Calcification of human VSMCs was induced by Pi stimulation in the presence or absence of 7-KC. FACS analysis showed that 7-KC induced apoptosis at a high concentration (30 MUM), but not at a low concentration (15 MUM). Interestingly, 7-KC promoted calcification in VSMCs regardless of apoptosis. Immunoblotting and immunostaining showed that 7-KC inhibits not only the fusion of autophagosomes and lysosomes but also causes a swell of lysosomes with the reduction of cathepsin B and D. Moreover, lysosomal protease inhibitors exacerbated the apoptosis-independent calcification by 7-KC although inhibition of autophagosome formation by Atg5 siRNA did not. Finally, the 7-KC-induced progression of calcification was alleviated by the treatment with antioxidant. Taken together, our data showed that 7-KC promotes VSMC calcification through lysosomal-dysfunction-dependent oxidative stress. PMID- 26419831 TI - Preoperative and Intraoperative Factors for Early Failure of Native Arteriovenous Fistulas. AB - The aim of the study was to assess the potential predictive factors for early arteriovenous fistula (AVF) failure following the fistula first initiative. We retrospectively reviewed the data of 159 end-stage renal disease (ESRD) patients who underwent AVF creation. The preoperative factors such as demographic, comorbidity condition, laboratory parameters and medication, and intraoperative or surgical-related factors were assessed. In multivariate logistic regression analysis, significant predictive factors of early AVF failure were female gender (odds ratio (95% confidence interval): 2.63 (1.19-5.81); P = 0.017), higher body mass index (P = 0.038), and lower hemoglobin level (P = 0.048), while adjusting for preoperative factors or all factors. For adjusting of intraoperative factors, reduced venous diameter (P = 0.056) tended to be associated with early AVF failure. In conclusion, female gender, higher body mass index and lower hemoglobin level predicted the occurrence of early AVF failure in ESRD patients. PMID- 26419828 TI - Cortical tau load is associated with white matter hyperintensities. AB - INTRODUCTION: Cerebral white matter lesions (WML), visualized as white matter hyperintensities (WMH) on T2-weighted MRI, encompass structural damage and loss of integrity of the cerebral white matter (WM) and are commonly assumed to be associated with small vessel disease (SVD). However, it has been suggested that WM damage may also be the result of degenerative axonal loss that is secondary to cortical Alzheimer's disease (AD) pathologies i.e., hyperphosphorylated tau (HPtau) and amyloid-beta (Abeta). Here we investigate the influence of HPtau, Abeta and SVD on WMH severity. RESULTS: 36 human post-mortem right fixed cerebral hemispheres (mean age 84.4 +/- 7.7 years; male: 16, female: 20) containing varying amounts of AD-pathology (AD: 23, controls: 13) underwent T2- weighted MRI with WMH assessed according to the age related white matter change scale (ARWMC). After dissection, using tissue samples from the frontal, temporal, parietal and occipital regions from the right hemisphere, we quantitatively assessed cortical HPtau and Abeta pathology burden by measuring the percentage area covered by AT8 immunoreactivity (HPtau-IR) and 4G8 immunoreactivity (Abeta-IR), and assessed the severity of WM SVD by calculating the sclerotic index (SI) of WM arteries/arterioles. HPtau-IR, Abeta-IR, and SI were compared with ARWMC scores. HPtau-IR, Abeta-IR and WM ARWMC scores were all significantly higher in AD cases compared to controls, while SI values were similar between groups. ARWMC scores correlated with HPtau-IR, Abeta-IR and SI in various regions, however, linear regression revealed that only HPtau-IR was a significant independent predictor of ARWMC scores. CONCLUSIONS: Here we have shown that increasing cortical HPtau burden independently predicted the severity of WMH indicating its potentially important role in the pathogenesis of WM damage. Moreover, our findings suggest that in AD patients the presence of WMH may indicate cortical AD-associated pathology rather than SVD. Further studies are warranted to elucidate the pathological processes that lead to WM damage and to clarify if WMH may serve as a general biomarker for cortical AD-associated pathology. PMID- 26419832 TI - Thrombolytic therapy for pulmonary embolism. AB - BACKGROUND: Thrombolytic therapy (powerful anticoagulation drugs) is usually reserved for patients with clinically serious or massive pulmonary embolism (PE). Evidence suggests that thrombolytic agents may dissolve blood clots more rapidly than heparin and reduce the death rate associated with PE. However, there are still concerns about the possible risk of adverse effects of thrombolytic therapy, such as major or minor haemorrhages. This is the second update of the Cochrane review first published in 2006. OBJECTIVES: To assess the effects of thrombolytic therapy in patients with acute pulmonary embolism. SEARCH METHODS: For this update the Cochrane Vascular Group searched their Specialised Register (last searched September 2014) and the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (last searched Issue 8, 2014). We also searched individual trial collections and private databases, along with bibliographies of relevant articles. We handsearched relevant medical journals. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared thrombolytic therapy followed by heparin versus heparin alone, heparin plus placebo or surgical intervention in patients with acute PE. We did not include trials comparing two different thrombolytic agents or different doses of the same thrombolytic drug. DATA COLLECTION AND ANALYSIS: Two authors (BD and QH) assessed the eligibility and quality of trials and extracted data. MAIN RESULTS: We identified 18 trials with a total of 2197 participants for inclusion in the review. We were not able to include one study in the meta-analysis because it had no data to extract. Most of the studies carried a high risk of bias because of high or unclear risk relating to randomisation and blinding. Meta-analysis showed that, compared with heparin alone, or heparin plus placebo, thrombolytics plus heparin can reduce the odds of death (odds ratio (OR) 0.57, 95% confidence interval (CI) 0.37 to 0.87, P = 0.02, low quality evidence) and recurrence of PE (OR 0.51; 95% CI 0.29 to 0.89, P = 0.02, low quality evidence). The effects of death weakened when we excluded four studies at high risk of bias from analysis: OR 0.66, 95% CI 0.42 to 1.06, P = 0.08. The incidence of major and minor haemorrhagic events was higher in the thrombolytics group than in the control group, and this difference was statistically significant (OR 2.90, 95% CI 1.95 to 4.31, P < 0.001, low quality evidence; OR 3.09, 95% CI 1.58 to 6.06, P = 0.001, very low quality evidence, respectively). Length of hospital stay (mean difference (MD) -1.35, 95% CI -4.27 to 1.58) and quality of life were similar between the two treatment groups. Stroke was reported in one study and occurred more often in the thrombolytics group than in the control group, although the confidence interval was wide (OR 12.10, 95% CI 1.57 to 93.39). Limited information from a small number of trials indicated that thrombolytics may improve haemodynamic outcomes, perfusion lung scanning, pulmonary angiogram assessment, echocardiograms, pulmonary hypertension, coagulation parameters, clinical outcomes and survival time to a greater extent than heparin alone. However, the heterogeneity of the studies and small number of participants involved warrant caution when interpreting results. Similarily, fewer patients from the thrombolytics group required escalation of treatment. None of the included studies reported on post-thrombotic syndrome or compared the cost of the different treatments. AUTHORS' CONCLUSIONS: There is low quality evidence that thrombolytics reduce death following acute pulmonary embolism compared with heparin. Furthermore, thrombolytic therapies included in the review were heterogeneous. Thrombolytic therapy may be helpful in reducing the recurrence of pulmonary emboli but may cause more major and minor haemorrhagic events and stroke. More high quality double blind RCTs assessing safety and cost effectiveness are required. PMID- 26419833 TI - Heavy metals and its chemical speciation in sewage sludge at different stages of processing. AB - The analysis of heavy metal concentrations and forms in sewage sludge constitutes an important issue in terms of both health and environmental hazards the metals pose. The total heavy metals concentration enables only the assessment of its contamination. Hence the knowledge of chemical forms is required to determine their environmental mobility and sludge final disposal. Heavy metals speciation was studied by using four-stage sequential extraction BCR (Community Bureau of Reference). This study was aimed at determining the total concentration of selected heavy metals (Zn, Cu, Ni, Pb, Cd, Cr and Hg) and their chemical forms (except for Hg) in sludge collected at different stages of its processing at two municipal Wastewater Treatment Plants in southern Poland. Metals contents in sludge samples were determined by using flame atomic absorption spectrometry (FAAS) and electrothermal atomic absorption spectrometry (ETAAS). This study shows that Zn and Cu appeared to be the most abundant in sludge, while Cd and Hg were in the lowest concentrations. The sewage sludge revealed the domination of immobile fractions over the mobile ones. The oxidizable and residual forms were dominant for all the heavy metals. There was also a significant difference in metals speciation between sludges of different origin which was probably due to differences in wastewater composition and processes occurring in biological stage of wastewater treatment. The results indicate a negligible capability of metals to migrate from sludge into the environment. Our research revealed a significant impact of thickening, stabilization and hygienization on the distribution of heavy metals in sludge and their mobility. PMID- 26419834 TI - A critical review of in vitro dosimetry for engineered nanomaterials. AB - A major obstacle in the development of accurate cellular models for investigating nanobio interactions in vitro is determination of physiologically relevant measures of dose. Comparison of biological responses to nanoparticle exposure typically relies on administered dose metrics such as mass concentration of suspended particles, rather than the effective dose of particles that actually comes in contact with the cells over the time of exposure. Adoption of recently developed dosimetric methodologies will facilitate determination of effective dose delivered to cells in vitro, thereby improving the accuracy and reliability of in vitro screening data, validation of in vitro with in vivo data, and comparison across multiple datasets for the large variety of nanomaterials currently in the market. PMID- 26419835 TI - Highly Efficient Organocatalyzed Conversion of Oxiranes and CO2 into Organic Carbonates. AB - Invited for the cover of this issue is the group of Arjan Kleij at the Institute of Chemical Research of Catalonia (ICIQ). The image shows how naturally occurring compounds such as tannic acid can be used to devise highly efficient CO2 conversion catalysis. The Full Paper itself is available at 10.1002/cssc.201500710. PMID- 26419836 TI - Dimethyl Sulfide-Dimethyl Ether and Ethylene Oxide-Ethylene Sulfide Complexes Investigated by Fourier Transform Microwave Spectroscopy and Ab Initio Calculation. AB - The ground-state rotational spectra of the dimethyl sulfide-dimethyl ether (DMS DME) and the ethylene oxide-ethylene sulfide (EO-ES) complexes were observed by Fourier transform microwave spectroscopy, and a-type and c-type transitions were assigned for the normal, (34)S, and three (13)C species of the DMS-DME and a-type and b-type transitions for the normal, (34)S, and two (13)C species of the EO-ES complexes. The transition frequencies measured for both the complexes were analyzed by using an S-reduced asymmetric-top rotational Hamiltonian. The rotational parameters thus derived for the DMS-DME were found to be consistent with a structure of Cs symmetry with the DMS bound to the DME by two C-H(DMS)...O and one S...H-C(DME) hydrogen bonds. Some high-Ka lines were found to be split, and we have interpreted these splittings in terms of internal rotations of the two methyl groups of the DMS and of the "free", i.e., outer group, of the DME. Some forbidden transitions were also observed in cases where Ka = 3 levels were involved, for the DMS-DME complex in the internal-rotation E state. The barrier height, V3, to internal rotation of the CH3 in the DME thus derived is smaller than that of the DME monomer, while the V3 of the CH3 groups in the DMS is nearly the same as that of the DMS monomer. For the EO-ES complex, the observed data were interpreted in terms of an antiparallel structure of Cs symmetry with the EO bound to the ES by two C-H(ES)...O and two S...H-C(EO) hydrogen bonds. An attempt was also made to observe a-type transitions of the DMS dimer without success. We have applied a natural bond orbital analysis to the DMS-DME and EO-ES to calculate the stabilization energy CT (= DeltaEsigmasigma*), which was correlated closely with the binding energy as found for other related complexes. PMID- 26419837 TI - Endoscopic Z-plasty for Treatment of Supraglottic Stenosis: A New Technique. PMID- 26419838 TI - Predictors of Nodal Metastasis in Parotid Malignancies: A National Cancer Data Base Study of 22,653 Patients. AB - OBJECTIVE: (1) To identify predictors of nodal disease in parotid malignancies using various clinical and pathologic variables. (2) To examine the effect of nodal disease on overall survival (OS) in parotid cancers STUDY DESIGN: Retrospective database review. SETTING: National Cancer Data Base (1998-2012). SUBJECTS AND METHODS: We identified all cases of primary parotid malignancies in the United States between 1998 and 2012 in the National Cancer Data Base. Eight histopathologies, constituting >80% of all cases, were examined for nodal metastasis and survival. RESULTS: We identified 22,653 cases of primary parotid cancer. Eight major histologies were studied, with mucoepidermoid carcinoma (31%), acinic cell carcinoma (18%), adenocarcinoma (14%), and adenoid cystic carcinoma (9%) being most common. Regional nodal disease incidence was 24.4% overall and varied by histopathology. Salivary ductal carcinoma had the highest incidence of both nodal metastasis and occult lymph node metastasis. Overall, N0 patients lived significantly longer than N+ (5-year OS, 79% vs 40%; P < .001). Low-grade disease had significantly better survival than high-grade (5-year OS, 88% vs 69%; P < .001). Occult nodal disease was found in 10.2% and varied by histopathology. CONCLUSION: Regional lymph node metastasis significantly decreases survival in many parotid malignancies. High-grade cancers had higher incidences of regional disease than did low grade. Adenocarcinoma had the highest mortality when regional disease was present. Incidence of occult disease varied by histology, but incidence was <10% for all low-grade disease. High T stage and grade are significant independent predictors of nodal disease for most histopathologies. PMID- 26419839 TI - Cisplatin-Induced Ototoxicity and the Effects of Intratympanic Diltiazem in a Mouse Model. AB - OBJECTIVE: To evaluate whether the calcium-channel blocker diltiazem has protective effects against cisplatin-induced ototoxicity in a mouse model. STUDY DESIGN: Original basic science in vivo investigation. SETTING: Academic setting: Otolaryngology-Head and Neck Surgery laboratory at University of Connecticut Health Center. SUBJECTS: Thirty-nine female CBA/J mice. METHODS: Pure tone- or click-evoked auditory brainstem responses (ABRs) were recorded in CBA/J mice to determine auditory thresholds. All mice had baseline ABRs recorded. They were then given a single cisplatin bolus (14 mg/kg), followed by 5 consecutive days of intratympanic diltiazem or saline control. Follow-up thresholds were recorded on days 7, 14, and 21 postcisplatin. Tone-evoked ABRs evaluated the otoprotective effect of 2-mg/kg diltiazem in 9 mice, and dose effect was examined in response to click-evoked ABR with 2- or 4-mg/kg diltiazem in 2 groups of 15 mice. RESULTS: Saline-treated ears had significantly elevated tone-evoked auditory thresholds when compared with diltiazem-treated ears (P = .038) on day 7 postcisplatin only. Click-evoked ABR thresholds were significantly elevated in saline-treated ears versus diltiazem-treated ears for the 2-mg/kg group (P = .001) and 4-mg/kg group (P = .011) on days 7, 14, and 21 postcisplatin. CONCLUSION: Intratympanic diltiazem has significant protective effects against cisplatin ototoxicity at 2 and 4 mg/kg. This is the first in vivo study to demonstrate that diltiazem offers a potentially novel therapy for cisplatin-induced ototoxicity. PMID- 26419840 TI - Medicolegal Aspects of Iatrogenic Dysphonia and Recurrent Laryngeal Nerve Injury. AB - OBJECTIVE: To examine aspects of litigation involving iatrogenic dysphonia and injury to the recurrent laryngeal nerve in the adult population. STUDY DESIGN: Legal database review. SETTING: Medicolegal judicial system. SUBJECTS AND METHODS: Jury verdicts and settlement reports listing voice impairment or recurrent laryngeal nerve dysfunction as a primary injury in adult patients were identified in the Westlaw Database. Reports were examined for plaintiff demographics, defendant specialty, procedure performed, rates of settlements and verdicts, monetary awards, primary plaintiff symptoms, and common allegations. RESULTS: A total of 123 jury verdict and settlement reports were identified. General surgeons (24%), otolaryngologists (20%), and anesthesiologists (18%) were involved in the majority of cases. The procedure causing the alleged injury was primarily thyroidectomy (34%), followed by intubation (18%) and spinal instrumentation (10%). The majority of cases (70%) were decided in favor of the defendant. Where monetary awards were recorded, settlements and jury verdicts in favor of the plaintiff ranged between $4250 and $3,000,000, with a mean of $788,713. In addition to voice disturbances, complaints of dyspnea and dysphagia were commonly listed alleged injuries. The only factors associated with plaintiff verdicts were general surgery specialty (odds ratio, 6.3; 95% confidence interval, 1.7-23.2) and claims of loss of consortium (odds ratio, 8.5; 95% confidence interval, 1.2-60.7). CONCLUSION: Dysphonia is a common complication in a number of procedures across multiple specialties. Although the majority of cases are decided in favor or the defendant, payments awarded can be considerable. Awareness of factors involved in these medical malpractice cases can help limit physician liability. PMID- 26419841 TI - Differential Effects of HRAS Mutation on LTP-Like Activity Induced by Different Protocols of Repetitive Transcranial Magnetic Stimulation. AB - BACKGROUND: Costello syndrome (CS) is a rare congenital disorder due to a G12S amino acid substitution in HRAS protoncogene. Previous studies have shown that Paired Associative Stimulation (PAS), a repetitive brain stimulation protocol inducing motor cortex plasticity by coupling peripheral nerve stimulation with brain stimulation, leads to an extremely pronounced motor cortex excitability increase in CS patients. Intermittent Theta Burst Stimulation (iTBS) represents a protocol able to induce motor cortex plasticity by trains of stimuli at 50 Hz. In healthy subjects PAS and iTBS produce similar after-effects in motor cortex excitability. Experimental models showed that HRAS-dependent signalling pathways differently affect LTP induced by different patterns of repetitive synaptic stimulation. OBJECTIVE: We aimed to compare iTBS-induced after-effects on motor cortex excitability with those produced by PAS in CS patients and to observe whether HRAS mutation differentially affects two different forms of neuromodulation protocols. METHODS: We evaluated in vivo after-effects induced by PAS and iTBS applied over the right motor cortex in 4 CS patients and in 21 healthy age-matched controls. RESULTS: Our findings confirmed HRAS-dependent extremely pronounced PAS-induced after-effects and showed for the first time that iTBS induces no change in MEP amplitude in CS patients whereas both protocols lead to an increase of about 50% in controls. CONCLUSIONS: CS patients are characterized by an impairment of iTBS-related LTP-like phenomena besides enhanced PAS-induced after-effects, suggesting that HRAS-dependent signalling pathways have a differential influence on PAS- and iTBS-induced plasticity in humans. PMID- 26419842 TI - Chemoenzymatic collective synthesis of optically active hydroxyl(methyl)tetrahydronaphthalene-based bioactive terpenoids. AB - Starting from succinic anhydride and 2-methylanisole, a chemoenzymatic collective formal/total synthesis of several optically active tetrahydronaphthalene based bioactive natural products has been presented via advanced level common precursors; the natural product and antipode (-)/(+)-aristelegone B. Regioselective benzylic oxidations, stereoselective introduction of hydroxyl groups at the alpha-position of ketone moiety in syn-orientation, efficient enzymatic resolutions with high enantiomeric purity, stereoselective reductions, samarium iodide induced deoxygenations and tandem acylation-Wittig reactions without racemization and/or eliminative aromatization were the key features. An attempted diastereoselective synthesis of (+/-)-vallapin has also been described. PMID- 26419843 TI - Tumor associated PD-L1 expression pattern in microscopically tumor positive sentinel lymph nodes in patients with melanoma. AB - BACKGROUND: Characterization of PD-L1 expression within clinically/radiologically negative but microscopically tumor positive sentinel lymph nodes (SLN) is important to our understanding of the relevance of this immune checkpoint pathway for adjuvant therapy. METHODS: Patients included had primary cutaneous melanoma, Breslow thickness of 2.01-4.0 or >4 mm with or without tumor ulceration (T3a, T3b, T4a, T4b). All patients had microscopically tumor positive SLN. Hematoxylin and eosin (H&E) staining was performed, followed by PD-L1 immunohistochemical (IHC) staining using a preliminary IHC assay with anti-PD-L1 antibody clone 22C3. The slides were separately evaluated by two pathologists (JY and CG). Samples containing metastatic melanoma lesions were scored separately for PD-L1 expression in intratumoral and peritumoral locations, by utilizing two scoring methods. RESULTS: Twenty-four patients where metastatic melanoma presence in the SLN was confirmed by H&E review of the cut sections were included in the final analysis of PD-L1 expression. SLN tumor size ranged from 1 to 2 mm. For three patients, the melanin content was too high to confidently assign a PD-L1 score. For the remaining 21 patients, all had some evidence of either intratumoral or peritumoral PD-L1 expression. The frequency of intratumoral tumor-associated PD L1 expression was: 0 % of tumor cells (3 pts, 14 %); <1 % (5 pts, 24 %); 1-10 % (6 pts, 29 %) and >10 % (7 pts, 33 %). CONCLUSIONS: Tumor-associated PD-L1 expression is readily detectable within melanoma micrometastases in the SLN of the majority of patients. These results support the testing of a therapeutic role for PD1/PD-L1 inhibition in the adjuvant setting, targeting melanoma micrometastases. PMID- 26419844 TI - Implementing a home-based exercise program for patients with advanced, incurable diseases after discharge and their caregivers: lessons we have learned. AB - BACKGROUND: Palliative care (PC) patients experience loss of physical function which usually impedes mobility, autonomy and quality of life. We aimed at examining the feasibility of a home-based exercise program for patients with advanced, incurable diseases after discharge. RESULTS: This was a single-arm pilot study (WHO-ICTRP: DRKS00005048). The 12-week home-based program comprised strength, balance, flexibility and endurance components. Patients with a presumed life expectancy of 6-12 months were recruited during a 6-months period on a specialized PC and a radiation therapy ward. We chose the De Morton Mobility Index as primary outcome. Secondary outcomes were quality of life, 6-min walk test and others. A total of 145 patients were screened, 103 (98%) out of 105 patients on the specialized PC ward could not be included, mostly because of a low performance status [n = 94; 90%; Eastern Cooperative Oncology Group (ECOG) >2]. The only two eligible patients declined to participate. Eleven out of 40 patients (28%) were eligible on the radiation therapy ward. However, only one patient (9%) participated but dropped out 2 days later (upcoming surgery). Distance to the hospital (n = 3; 30%) and considering additional tasks as "too much" (n = 3; 30%) were most common reasons for non-participation. CONCLUSIONS: Establishing a home-based exercise program for inpatients after discharge was not feasible mainly due to non-eligibility and lack of demand. For future trials, we suggest that choosing (1) outpatients with (2) an ECOG of <=2 and (3) an estimated survival of >=9 months could enhance participation in home-based exercise programs. PMID- 26419845 TI - Endoscopic ultrasound-guided sampling of solid pancreatic masses: 22-gauge aspiration versus 25-gauge biopsy needles. AB - BACKGROUND: Biopsy needles have recently been developed to obtain both cytological and histological specimens during endoscopic ultrasound (EUS). We conducted this study to compare 22-gauge (G) fine needle aspiration (FNA) needles, which have been the most frequently used, and new 25G fine needle biopsy (FNB) needles for EUS-guided sampling of solid pancreatic masses. METHODS: We conducted a retrospective cohort study of all EUS-guided sampling performed between June 2010 and October 2013. During the study period, 76 patients with pancreatic masses underwent EUS-guided sampling with a 22G FNA needle (n = 38) or a 25G FNB needle (n = 38) for diagnosis. An on-site cytopathologist was not present during the procedure. Technical success, the number of needle passes, cytological diagnostic accuracy, cytological sample quality (conventional smear and liquid-based preparation), histological diagnostic accuracy, and complications were reviewed and compared. RESULTS: There were no significant differences in technical success (100% for both), the mean number of needle passes (5.05 vs. 5.55, P = 0.132), or complications (0% for both) between the 22G FNA group and the 25G FNB group. The 22G FNA and 25G FNB groups exhibited comparable outcomes with respect to cytological diagnostic accuracy (97.4% vs. 89.5%, P = 0.358) and histological diagnostic accuracy (34.2% vs. 52.6%, P = 0.105). In the cytological sample quality analysis, the 25G FNB group exhibited higher scores for the amount of diagnostic cellular material present (22G FNA: 0.92 vs. 25G FNB: 1.32, P = 0.030) and the retention of appropriate architecture (22G FNA: 0.97 vs. 25G FNB: 1.42, P = 0.010) in the liquid-based preparation. The 25G FNB group showed a better histological diagnostic yield for specific tumor discrimination compared with the 22G FNA group (60 % vs. 32.4%, P = 0.018). CONCLUSIONS: Use of the 25G FNB needle was technically feasible, safe, efficient, and comparable to use of the standard 22G FNA needle in patients with solid pancreatic masses in the absence of an on-site cytopathologist. The cytological sample quality in the liquid-based preparation and the histological diagnostic yield for specific tumor discrimination of EUS-guided sampling using a 25G FNB needle were significantly higher than those using a 22G FNA needle. PMID- 26419847 TI - Phosphodiesterase 4 inhibitors for the treatment of chronic obstructive pulmonary disease: a review of current and developing drugs. AB - INTRODUCTION: Phosphodiesterase (PDE) inhibitors modulate lung inflammation and cause bronchodilation by increasing intracellular cyclic adenosine 3', 5' monophosphate in airway smooth muscle and inflammatory cells. Roflumilast is the only approved PDE-4 inhibitor (PDE4I) for use in chronic obstructive pulmonary disease (COPD). Its beneficial clinical effects occur preferentially in patients with chronic bronchitis and frequent COPD exacerbations. Use of roflumilast as adjunctive or alternate therapy to other COPD medications reduces exacerbations and modestly improves lung function. AREAS COVERED: This article reviews the current role of PDE4I in COPD treatment emphasizing roflumilast's clinical efficacy and adverse effects. This article also reviews developing PDE4Is in early clinical trials and in preclinical studies. EXPERT OPINION: After decades of research in drug development, PDE4Is are a welcomed addition to the COPD therapeutic armamentarium. In its current clinical role, the salubrious clinical effects of PDE4I in reducing exacerbations and stabilizing the frequent exacerbator phenotype have to be cautiously balanced with numerous adverse effects. Developing drugs may provide similar or better clinical benefits while minimizing adverse effects by changing the mode of drug delivery to inhaled formulations, combining dual PDE isoenzyme inhibitors (PDE1/4I and PDE3/4I) and by forming hybrid molecules with other bronchodilators (muscarinic receptor antagonist/PDE4I and beta2-agonist/PDE4I). PMID- 26419848 TI - How to manage pasireotide, when using as medical treatment for Cushing's disease. PMID- 26419849 TI - Rescue in vitro maturation (IVM) of immature oocytes in stimulated cycles in women with low functional ovarian reserve (LFOR). AB - Rescue in vitro maturation (IVM) is currently not a routine procedure in association with in vitro fertilization (IVF). We compared in a prospectively cohort study of 10 patients with normal functional ovarian reserve (NFOR) and of 25 with low functional ovarian reserve (LFOR), defined by abnormally high FSH and/or abnormally low AMH levels), IVM dynamics of immature oocytes. Following controlled ovarian hyperstimulation in IVF cycles, only immature oocytes underwent rescue IVM (for up to 48 h). Oocyte maturation dynamics, fertilization rates, embryo development, and pregnancy rates were then compared between NFOR and LFOR patients. Though proportion of MI and GV oocytes reaching MII stages within 48 h and rate of maturation of MI oocytes did not differ, in women with LFOR significantly more GV oocytes reached MII stage within 24 h (30.4 vs. 66.9 %; P = 0.013), while fertilization rates and embryo generation numbers were similar between both groups. Rescue IVM, thus, produced 1.5 additional embryos for transfer in women with LFOR and 1.6 in patients with NFOR, a highly significant difference in relative improvement in available embryo numbers for LFOR (+60.0 %) and NFOR women (+16.5 %). Rescue IVM, thus, not only demonstrates different time dynamics between women with LFOR and NFOR but also disproportionate efficacy in improving available embryo numbers for transfer in favor of LFOR patients. 1/7 patients, who reached embryo transfer with only embryos produced via rescue IVF conceived and delivered, proving that rescue IVF in women with LFOR also improves pregnancy and delivery chances. Because of the small number of embryos LFOR patients produce, every additional embryo is of considerable potential clinical significance for them, suggesting that rescue IVM in women with LFOR should become routine practice. PMID- 26419850 TI - Elevated 1-hour plasma glucose levels are associated with dysglycemia, impaired beta-cell function, and insulin sensitivity: a pilot study from a real world health care setting. PMID- 26419846 TI - Understanding the molecular basis of autism in a dish using hiPSCs-derived neurons from ASD patients. AB - Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social cognition, language development, and repetitive/restricted behaviors. Due to the complexity and heterogeneity of ASD and lack of a proper human cellular model system, the pathophysiological mechanism of ASD during the developmental process is largely unknown. However, recent progress in induced pluripotent stem cell (iPSC) technology as well as in vitro neural differentiation techniques have allowed us to functionally characterize neurons and analyze cortical development during neural differentiation. These technical advances will increase our understanding of the pathogenic mechanisms of heterogeneous ASD and help identify molecular biomarkers for patient stratification as well as personalized medicine. In this review, we summarize our current knowledge of iPSC generation, differentiation of specific neuronal subtypes from iPSCs, and phenotypic characterizations of human ASD patient-derived iPSC models. Finally, we discuss the current limitations of iPSC technology and future directions of ASD pathophysiology studies using iPSCs. PMID- 26419851 TI - [(18)F]FDG PET/CT outperforms [(18)F]FDG PET/MRI in differentiated thyroid cancer. AB - PURPOSE: To evaluate the diagnostic potential of PET/MRI with [(18)F]FDG in comparison to PET/CT in patients with differentiated thyroid cancer suspected or known to have dedifferentiated. METHODS: The study included 31 thyroidectomized and remnant-ablated patients who underwent a scheduled [(18)F]FDG PET/CT scan and were then enrolled for a PET/MRI scan of the neck and thorax. The datasets (PET/CT, PET/MRI) were rated regarding lesion count, conspicuity, diameter and characterization. Standardized uptake values were determined for all [(18)F]FDG positive lesions. Histology, cytology, and examinations before and after treatment served as the standards of reference. RESULTS: Of 26 patients with a dedifferentiated tumour burden, 25 were correctly identified by both [(18)F]FDG PET/CT and PET/MRI. Detection rates by PET/CT and PET/MRI were 97 % (113 of 116 lesions) and 85 % (99 of 113 lesions) for malignant lesions, and 100 % (48 of 48 lesions) and 77 % (37 of 48 lesions) for benign lesions, respectively. Lesion conspicuity was higher on PET/CT for both malignant and benign pulmonary lesions and in the overall rating for malignant lesions (p < 0.001). There was a difference between PET/CT and PET/MRI in overall evaluation of malignant lesions (p < 0.01) and detection of pulmonary metastases (p < 0.001). Surgical evaluation revealed three malignant lesions missed by both modalities. PET/MRI additionally failed to detect 14 pulmonary metastases and 11 benign lesions. CONCLUSION: In patients with thyroid cancer and suspected or known dedifferentiation, [(18)F]FDG PET/MRI was inferior to low-dose [(18)F]FDG PET/CT for the assessment of pulmonary status. However, for the assessment of cervical status, [(18)F]FDG PET/MRI was equal to contrast-enhanced neck [(18)F]FDG PET/CT. Therefore, [(18)F]FDG PET/MRI combined with a low-dose CT scan of the thorax may provide an imaging solution when high-quality imaging is needed and high-energy CT is undesirable or the use of a contrast agent is contraindicated. PMID- 26419853 TI - Editor's Comment. PMID- 26419852 TI - Subacute haematotoxicity after PRRT with (177)Lu-DOTA-octreotate: prognostic factors, incidence and course. AB - PURPOSE: In peptide receptor radionuclide therapy (PRRT), the bone marrow (BM) is one of the dose-limiting organs. The accepted dose limit for BM is 2 Gy, adopted from (131)I treatment. We investigated the incidence and duration of haematological toxicity and its risk factors in patients treated with PRRT with (177)Lu-DOTA(0)-Tyr(3)-octreotate ((177)Lu-DOTATATE). Also, absorbed BM dose estimates were evaluated and compared with the accepted 2 Gy dose limit. METHODS: The incidence and duration of grade 3 or 4 haematological toxicity (according to CTCAE v3.0) and risk factors were analysed. Mean BM dose per unit (gigabecquerels) of administered radioactivity was calculated and the correlations between doses to the BM and haematological risk factors were determined. RESULTS: Haematological toxicity (grade 3/4) occurred in 34 (11 %) of 320 patients. In 15 of the 34 patients, this lasted more than 6 months or blood transfusions were required. Risk factors significantly associated with haematological toxicity were: poor renal function, white blood cell (WBC) count <4.0 * 10(9)/l, age over 70 years, extensive tumour mass and high tumour uptake on the OctreoScan. Previous chemotherapy was not associated. The mean BM dose per administered activity in 23 evaluable patients was 67 +/- 7 mGy/GBq, resulting in a mean BM dose of 2 Gy in patients who received four cycles of 7.4 GBq (177)Lu DOTATATE. Significant correlations between (cumulative) BM dose and platelet and WBC counts were found in a selected group of patients. CONCLUSION: The incidence of subacute haematological toxicity after PRRT with (177)Lu-DOTATATE is acceptable (11 %). Patients with impaired renal function, low WBC count, extensive tumour mass, high tumour uptake on the OctreoScan and/or advanced age are more likely to develop grade 3/4 haematological toxicity. The BM dose limit of 2 Gy, adopted from (131)I, seems not to be valid for PRRT with (177)Lu DOTATATE. PMID- 26419855 TI - Ultralight anisotropic foams from layered aligned carbon nanotube sheets. AB - In this work, we present large scale, ultralight aligned carbon nanotube (CNT) structures which have densities an order of magnitude lower than CNT arrays, have tunable properties and exhibit resiliency after compression. By stacking aligned sheets of carbon nanotubes and then infiltrating with a pyrolytic carbon (PyC), resilient foam-like materials were produced that exhibited complete recovery from 90% compressive strain. With density as low as 3.8 mg cm(-3), the foam structure is over 500 times less dense than bulk graphite. Microscopy revealed that PyC coated the junctions among CNTs, and also increased CNT surface roughness. These changes in the morphology explain the transition from inelastic behavior to foam like recovery of the layered CNT sheet structure. Mechanical and thermal properties of the foams were tuned for different applications through variation of PyC deposition duration while dynamic mechanical analysis showed no change in mechanical properties over a large temperature range. Observation of a large and linear electrical resistance change during compression of the aligned CNT/carbon (ACNT/C) foams makes strain/pressure sensors a relevant application. The foams have high oil absorption capacities, up to 275 times their own weight, which suggests they may be useful in water treatment and oil spill cleanup. Finally, the ACNT/C foam's high porosity, surface area and stability allow for demonstration of the foams as catalyst support structures. PMID- 26419854 TI - Association of Vitamin D With Stress Fractures: A Retrospective Cohort Study. AB - Vitamin D is an essential, fat-soluble nutrient that is a key modulator of bone health. Despite the gaining popularity throughout published medical studies, no consensus has been reached regarding a serum vitamin D level that will guarantee adequate skeletal health in a patient with an increased functional demand. The purpose of the present investigation was to examine the serum concentrations of vitamin D in patients with confirmed stress fractures. A total of 124 patients were included in our retrospective cohort study. Of the 124 patients, 53 had vitamin D levels measured within 3 months of diagnosis. An association was seen in patients with a stress fracture and vitamin D level measured, as 44 (83.02%) of the 53 patients had a serum 25-hydroxyvitamin D level <40 ng/mL. Although an association was seen at our institution in patients with stress fractures and a serum vitamin D concentration <40 ng/mL, a larger and prospective investigation is warranted to further understand the effect of vitamin D level and stress fracture prevention in an active, nonmilitary population. PMID- 26419856 TI - Influence of adiponectin gene variants and plasma fatty acids on systemic inflammation state association-A cross-sectional population-based study, Sao Paulo, Brazil. AB - SCOPE: Interactions between adiponectin genetic variants and plasma fatty acid profile can modulate plasma inflammatory biomarker concentration and the risk for metabolic diseases. The aim of this study was to investigate the interaction between single nucleotide polymorphisms of the adiponectin gene and plasma fatty acid profile in modulating the odds for systemic inflammation in a cross sectional population-based study. METHODS AND RESULTS: Inflammatory patterns comprised 11 inflammatory biomarkers. Among participants of the Health Survey of Sao Paulo, 262 adults (19-59 years) met the inclusion criteria. Anthropometric parameters, blood pressure, plasma inflammatory biomarker concentration, and fatty acid profile were measured and five single nucleotide polymorphisms of the adiponectin gene (rs2241766, rs1501299, rs16861209, rs17300539, and rs266729) genotyped. Individuals in the upper 50th percentile for plasma araquidonic acid, n-3 highly unsaturated fatty acid and estimated delta-5-desaturase activity, had reduced odds of being in the inflammatory cluster (OR (95% CI) = 0.55 (0.32 0.95), 0.50 (0.28-0.88) and 0.48 (0.28-0.83), respectively). Gene-plasma fatty acid profile interaction was found between rs2241766 and n-3 (p = 0.019), rs16861209 and araquidonic acid and docosapentaenoic acid (p = 0.044, p = 0.037, respectively), and rs17300539 and saturated fatty acid (p = 0.019). CONCLUSION: Plasma fatty acid profile can interact with adiponectin gene variants to modulate the risk for systemic inflammatory state. PMID- 26419857 TI - Implications of free breathing motion assessed by 4D-computed tomography on the delivered dose in radiotherapy for esophageal cancer. AB - The aim of this study was to assess the effect of breathing motion on the delivered dose in esophageal cancer 3-dimensional (3D)-conformal radiotherapy (3D CRT), intensity-modulated radiotherapy (IMRT), and volumetric modulated arc therapy (VMAT). We assessed 16 patients with esophageal cancer. All patients underwent 4D-computed tomography (4D-CT) for treatment planning. For each of the analyzed patients, 1 3D-CRT, 1 IMRT, and 1 VMAT (RapidArc-RA) plan were calculated. Each of the 3 initial plans was recalculated on the 4D-CT (for the maximum free inspiration and maximum free expiration) to assess the effect of breathing motion. We assessed the minimum dose (Dmin) and mean dose (Dmean) to the esophagus within the planning target volume, the volume changes of the lungs, the Dmean and the total lung volume receiving at least 40Gy (V40), and the V30, V20, V10, and V5. For the heart we assessed the Dmean and the V25. Over all techniques and all patients the change in Dmean as compared with the planned Dmean (planning CT [PCT]) to the esophagus was 0.48% in maximum free inspiration (CT_insp) and 0.55% in maximum free expiration (CT_exp). The Dmin CT_insp change was 0.86% and CT_exp change was 0.89%. The Dmean change of the lungs (heart) was in CT_insp 1.95% (2.89%) and 3.88% (2.38%) in CT_exp. In all, 4 patients had a clinically relevant change of the dose (>= 5% Dmean to the heart and the lungs) between inspiration and expiration. These patients had a very cranially or caudally situated tumor. There are no relevant differences in the delivered dose to the regions of interest among the 3 techniques. Breathing motion management could be considered to achieve a better sparing of the lungs or heart in patients with cranially or caudally situated tumors. PMID- 26419858 TI - Identification of dual-tropic HIV-1 using evolved neural networks. AB - Blocking the binding of the envelope HIV-1 protein to immune cells is a popular concept for development of anti-HIV therapeutics. R5 HIV-1 binds CCR5, X4 HIV-1 binds CXCR4, and dual-tropic HIV-1 can bind either coreceptor for cellular entry. R5 viruses are associated with early infection and over time can evolve to X4 viruses that are associated with immune failure. Dual-tropic HIV-1 is less studied; however, it represents functional antigenic intermediates during the transition of R5 to X4 viruses. Viral tropism is linked partly to the HIV-1 envelope V3 domain, where the amino acid sequence helps dictate the receptor a particular virus will target; however, using V3 sequence information to identify dual-tropic HIV-1 isolates has remained difficult. Our goal in this study was to elucidate features of dual-tropic HIV-1 isolates that assist in the biological understanding of dual-tropism and develop an approach for their detection. Over 1559 HIV-1 subtype B sequences with known tropisms were analyzed. Each sequence was represented by 73 structural, biochemical and regional features. These features were provided to an evolved neural network classifier and evaluated using balanced and unbalanced data sets. The study resolved R5X4 viruses from R5 with an accuracy of 81.8% and from X4 with an accuracy of 78.8%. The approach also identified a set of V3 features (hydrophobicity, structural and polarity) that are associated with tropism transitions. The ability to distinguish R5X4 isolates will improve computational tropism decisions for R5 vs. X4 and assist in HIV-1 research and drug development efforts. PMID- 26419859 TI - An evaluation study of a gender-specific smoking cessation program to help Hong Kong Chinese women quit smoking. AB - BACKGROUND: There is a lack of population-based smoking cessation interventions targeting woman smokers in Hong Kong, and in Asia generally. This study aimed to evaluate the effectiveness of a gender-specific smoking cessation program for female smokers in Hong Kong. METHODS: To evaluate the effectiveness of the service, a total of 457 eligible smokers were recruited. After the baseline questionnaire had been completed, a cessation counseling intervention was given by a trained counselor according to the stage of readiness to quit. Self-reported seven-day point prevalence of abstinence and reduction of cigarette consumption (>=50 %) and self-efficacy in rejecting tobacco were documented at one week and at two, three and six months. RESULTS: The 7-day point prevalence quit rate was 28.4 % (130/457), and 21.9 % (100/457) had reduced their cigarette consumption by at least 50 % at the six-month follow-up. The average daily cigarette consumption was reduced from 8.3 at baseline to 6.3 at six months. Moreover, both internal and external stimuli of anti-smoking self-efficacy increased from baseline to six months. CONCLUSIONS: The study provides some evidence for the effectiveness of the gender-specific smoking cessation program for female smokers. Furthermore, helping smokers to improve their self-efficacy in resisting both internal and external stimuli of tobacco use can be a way of enhancing the effectiveness of a smoking cessation intervention. PMID- 26419860 TI - Design of chemical space networks using a Tanimoto similarity variant based upon maximum common substructures. AB - Chemical space networks (CSNs) have recently been introduced as an alternative to other coordinate-free and coordinate-based chemical space representations. In CSNs, nodes represent compounds and edges pairwise similarity relationships. In addition, nodes are annotated with compound property information such as biological activity. CSNs have been applied to view biologically relevant chemical space in comparison to random chemical space samples and found to display well-resolved topologies at low edge density levels. The way in which molecular similarity relationships are assessed is an important determinant of CSN topology. Previous CSN versions were based on numerical similarity functions or the assessment of substructure-based similarity. Herein, we report a new CSN design that is based upon combined numerical and substructure similarity evaluation. This has been facilitated by calculating numerical similarity values on the basis of maximum common substructures (MCSs) of compounds, leading to the introduction of MCS-based CSNs (MCS-CSNs). This CSN design combines advantages of continuous numerical similarity functions with a robust and chemically intuitive substructure-based assessment. Compared to earlier version of CSNs, MCS-CSNs are characterized by a further improved organization of local compound communities as exemplified by the delineation of drug-like subspaces in regions of biologically relevant chemical space. PMID- 26419861 TI - Indian endocrinologists start debate on diabetes drug. PMID- 26419862 TI - High Burden of HBV-Infection and Atypical HBV Strains among HIV-infected Cameroonians. AB - AIM: To investigate the prevalence and genotypic profile of overt and occult hepatitis-B infection (OBI) among HIV-infected individuals in Cameroon. METHODS: 212 HIV-infected Cameroonians, aged 37.6 [IQR: 32.6-46.6] followed-up at the University Health Centre in Yaounde, were tested for HBsAg, anti-HBs, anti-HBc IgG/IgM, HBV-DNA and anti-HCV IgG. HBV positive cases were tested for Hepatitis Delta virus (HDV) using anti-HDV IgG and HDV-RNA. Liver function was assessed by alanine and aspartate aminotransaminases. OBI was defined as negative-HBsAg and detectable HBV-DNA. In occult or overt HBVinfected participants, HBV reverse transcriptase (RT)/surface (S) sequences were analyzed for drug resistance, immuneescape mutants, and phylogeny. RESULTS: Overall, 78.3% (166/212) participants had past/ongoing HBV-exposure, with 39.1% (83/212) carrying "HBcAbpositive alone". Prevalence of overt HBV (positive-HBsAg) was 11.8% (25/212), prevalence of HBV and HDV was respectively 6.9% (12/175) and 12% (3/25). Phylogeny of HBV-RT/S revealed the co-circulation of genotypes A and E. All HBV-coinfected participants harbored HBV strains with at least one immune escape mutation. Of note, one HBV variant carried the vaccine-escape mutation G145R that hinders HBsAg neutralization by antibodies. For the first time, a novel 9 aa-deletion (s115-s123), located in the HBsAg "a" determinant, was found concomitantly with OBI. A stop codon in the S region (associated with increased risk of hepatocellular carcinoma) was found in six cases. CONCLUSION: High prevalence of overt/occult HBV-infection and circulating atypical strains highlight the importance of HBV-surveillance among HIV-infected Cameroonians and strategies to detect OBI in highly endemic countries. PMID- 26419863 TI - Elective free flap revision in the head and neck cancer patient: Indications and outcomes. AB - Elective free flap revision among head and neck cancer patients remains poorly characterized. This study evaluates patients who underwent flap revision and their surgical outcomes. Patients who underwent tumor extirpation with free flap reconstruction were identified over a 5-year period. Elective flap revision was defined as debulking or redraping of the original free flap for functional or cosmetic reasons. Patient demographics, surgical indications, and outcomes were reviewed. One hundred and eighty-six patients were identified, and 19 (10.2%) underwent flap revision. Revision of oral cavity flaps (n = 9, 47.4%) was performed to address excessive flap bulk compromising lip competence, speech, swallowing, mastication, or placement of a dental prosthesis. Revision of flaps resurfacing the face or neck (n = 10, 52.6%) was performed to address facial ptosis after facial nerve sacrifice, facial asymmetry, or soft tissue redundancy. Revisions were performed at an average of 7.3 months postoperatively and there was no age or gender bias toward undergoing flap revision. Patients whose flap skin paddles were used to resurface the facial or neck skin were significantly more likely to undergo elective revision than patients with an external paddle designed for flap monitoring (p < 0.01). We identified a 10% elective revision rate for head and neck free flaps in cancer patients, approximately half of which were performed to improve oral cavity function and half of which were performed to address facial ptosis or asymmetry. While there was no age or gender preference for flap revision, extensive facial or neck resurfacing was significantly associated with eventual flap revision. PMID- 26419864 TI - Paving the COWpath: Learning and visualizing clinical pathways from electronic health record data. AB - OBJECTIVE: Clinical pathways translate best available evidence into practice, indicating the most widely applicable order of treatment interventions for particular treatment goals. We propose a practice-based clinical pathway development process and a data-driven methodology for extracting common clinical pathways from electronic health record (EHR) data that is patient-centered, consistent with clinical workflow, and facilitates evidence-based care. MATERIALS AND METHODS: Visit data of 1,576 chronic kidney disease (CKD) patients who developed acute kidney injury (AKI) from 2009 to 2013 are extracted from the EHR. We model each patient's multi-dimensional clinical records into one-dimensional sequences using novel constructs designed to capture information on each visit's purpose, procedures, medications and diagnoses. Analysis and clustering on visit sequences identify distinct types of patient subgroups. Characterizing visit sequences as Markov chains, significant transitions are extracted and visualized into clinical pathways across subgroups. RESULTS: We identified 31 patient subgroups whose extracted clinical pathways provide insights on how patients' conditions and medication prescriptions may progress over time. We identify pathways that show typical disease progression, practices that are consistent with guidelines, and sustainable improvements in patients' health conditions. Visualization of pathways depicts the likelihood and direction of disease progression under varied contexts. DISCUSSION AND CONCLUSIONS: Accuracy of EHR data and diversity in patients' conditions and practice patterns are critical challenges in learning insightful practice-based clinical pathways. Learning and visualizing clinical pathways from actual practice data captured in the EHR may facilitate efficient practice review by healthcare providers and support patient engagement in shared decision making. PMID- 26419865 TI - Evolvability Is an Evolved Ability: The Coding Concept as the Arch-Unit of Natural Selection. AB - Physical processes that characterize living matter are qualitatively distinct in that they involve encoding and transfer of specific types of information. Such information plays an active part in the control of events that are ultimately linked to the capacity of the system to persist and multiply. This algorithmicity of life is a key prerequisite for its Darwinian evolution, driven by natural selection acting upon stochastically arising variations of the encoded information. The concept of evolvability attempts to define the total capacity of a system to evolve new encoded traits under appropriate conditions, i.e., the accessible section of total morphological space. Since this is dependent on previously evolved regulatory networks that govern information flow in the system, evolvability itself may be regarded as an evolved ability. The way information is physically written, read and modified in living cells (the "coding concept") has not changed substantially during the whole history of the Earth's biosphere. This biosphere, be it alone or one of many, is, accordingly, itself a product of natural selection, since the overall evolvability conferred by its coding concept (nucleic acids as information carriers with the "rulebook of meanings" provided by codons, as well as all the subsystems that regulate various conditional information-reading modes) certainly played a key role in enabling this biosphere to survive up to the present, through alterations of planetary conditions, including at least five catastrophic events linked to major mass extinctions. We submit that, whatever the actual prebiotic physical and chemical processes may have been on our home planet, or may, in principle, occur at some time and place in the Universe, a particular coding concept, with its respective potential to give rise to a biosphere, or class of biospheres, of a certain evolvability, may itself be regarded as a unit (indeed the arch-unit) of natural selection. PMID- 26419871 TI - Outcome of Burns Treated With Autologous Cultured Proliferating Epidermal Cells: A Prospective Randomized Multicenter Intrapatient Comparative Trial. AB - Standard treatment for large burns is transplantation with meshed split skin autografts (SSGs). A disadvantage of this treatment is that healing is accompanied by scar formation. Application of autologous epidermal cells (keratinocytes and melanocytes) may be a suitable therapeutic alternative, since this may enhance wound closure and improve scar quality. A prospective, multicenter randomized clinical trial was performed in 40 adult patients with acute full thickness burns. On two comparable wound areas, conventional treatment with SSGs was compared to an experimental treatment consisting of SSGs in combination with cultured autologous epidermal cells (ECs) seeded in a collagen carrier. The primary outcome measure was wound closure after 5-7 days. Secondary outcomes were safety aspects and scar quality measured by graft take, scar score (POSAS), skin colorimeter (DermaSpectrometer) and elasticity (Cutometer). Wound epithelialization after 5-7 days was significantly better for the experimental treatment (71%) compared to the standard treatment (67%) (p = 0.034, Wilcoxon), whereas the take rates of the grafts were similar. No related adverse events were recorded. Scar quality was evaluated at 3 (n = 33) and 12 (n = 28) months. The POSAS of the observer after 3 and 12 months and of the patient after 12 months were significantly better for the experimental area. Improvements between 12% and 23% (p <= 0.010, Wilcoxon) were detected for redness, pigmentation, thickness, relief, and pliability. Melanin index at 3 and 12 months and erythema index at 12 months were closer to normal skin for the experimental treatment than for conventional treatment (p <= 0.025 paired samples t-test). Skin elasticity showed significantly higher elasticity (p = 0.030) in the experimental area at 3 months follow-up. We showed a safe application and significant improvements of wound healing and scar quality in burn patients after treatment with ECs versus SSGs only. The relevance of cultured autologous cells in treatment of extensive burns is supported by our current findings. PMID- 26419872 TI - Newly graduated nurses' occupational commitment and its associations with professional competence and work-related factors. AB - AIMS AND OBJECTIVES: To explore newly graduated nurses' occupational commitment and its associations with their self-assessed professional competence and other work-related factors. BACKGROUND: As a factor affecting nurse turnover, newly graduated nurses' occupational commitment and its associations with work-related factors needs exploring to retain adequate workforce. Nurses' commitment has mainly been studied as organisational commitment, but newly graduated nurses' occupational commitment and its association with work-related factors needs further studying. DESIGN: This study used descriptive, cross-sectional, correlation design. METHODS: A convenience sample of 318 newly graduated nurses in Finland participated responding to an electronic questionnaire. Statistical software, NCSS version 9, was used in data analysis. Frequencies, percentages, ranges, means and standard deviations summarised the data. Multivariate Analyses of Variance estimated associations between occupational commitment and work related variables. IBM SPSS Amos version 22 estimated the model fit of Occupational Commitment Scale and Nurse Competence Scale. RESULTS: Newly graduated nurses' occupational commitment was good, affective commitment reaching the highest mean score. There was a significant difference between the nurse groups in favour of nurses at higher competence levels in all subscales except in limited alternatives occupational commitment. Multivariate analyses revealed significant associations between subscales of commitment and competence, turnover intentions, job satisfaction, earlier professional education and work sector, competence counting only through affective dimension. CONCLUSION: The association between occupational commitment and low turnover intentions and satisfaction with nursing occupation was strong. Higher general competence indicated higher overall occupational commitment. RELEVANCE TO CLINICAL PRACTICE: Managers' recognition of the influence of all dimensions of occupational commitment in newly graduated nurses' professional development is important. Follow-up studies of newly graduated nurses' commitment, its relationship with quality care, managers' role in enhancing commitment and evaluation of the impact of interventions on improving commitment need further studying. PMID- 26419873 TI - Robustness of cell cycle control and flexible orders of signaling events. AB - The highly robust control of cell cycles in eukaryotes enables cells to undergo strictly ordered G1/S/G2/M phases and respond adaptively to regulatory signals; however the nature of the robustness remains obscure. Specifically, it is unclear whether events of signaling should be strictly ordered and whether some events are more robust than others. To quantitatively address the two questions, we have developed a novel cell cycle model upon experimental observations. It contains positive and negative E2F proteins and two Cdk inhibitors, and is parameterized, for the first time, to generate not only oscillating protein concentrations but also periodic signaling events. Events and their orders reconstructed under varied conditions indicate that proteolysis of cyclins and Cdk complexes by APC and Skp2 occurs highly robustly in a strict order, but many other events are either dispensable or can occur in flexible orders. These results suggest that strictly ordered proteolytic events are essential for irreversible cell cycle progression and the robustness of cell cycles copes with flexible orders of signaling events, and unveil a new and important dimension to the robustness of cell cycle control in particular and to biological signaling in general. PMID- 26419874 TI - Relationship between serum cortisol levels and some physiological parameters following reining training session in horse. AB - The changes of cortisol, red blood cells (RBC), hemoglobin (Hb), hematocrit (Hct), heart rate (HR), respiratory rate (RR) and rectal temperature (RT) were evaluated after a reining training session in eight Quarter Horses. All parameters were measured before exercise (T0), immediately after exercise (T1), 1 h after exercise (T2), 2 h after exercise (T3) and 24 h after exercise (T4). One way analysis of variance (ANOVA) for repeated measures, followed Bonferroni's post hoc test, showed a significant effect of the reining training session (P < 0.0001) on cortisol, RBC, Hb, Hct, HR, RR and RT. Simple linear regression analysis showed the positive correlation (P < 0.05) between cortisol changes and variations of studied parameters in T1, T3 and T4. Exercise-induced cortisol concentrations reflect the physiological response of reining training, suggesting that the changes observed are useful to assess the performance in reining horses and their reining training adaptability. PMID- 26419875 TI - High-Frequency Variation of Purine Biosynthesis Genes Is a Mechanism of Success in Campylobacter jejuni. AB - Phenotypic variation is prevalent in the zoonotic pathogen Campylobacter jejuni, the leading agent of enterocolitis in the developed world. Heterogeneity enhances the survival and adaptive malleability of bacterial populations because variable phenotypes may allow some cells to be protected against future stress. Exposure to hyperosmotic stress previously revealed prevalent differences in growth between C. jejuni strain 81-176 colonies due to resistant or sensitive phenotypes, and these isolated colonies continued to produce progeny with differential phenotypes. In this study, whole-genome sequencing of isolated colonies identified allelic variants of two purine biosynthesis genes, purF and apt, encoding phosphoribosyltransferases that utilize a shared substrate. Genetic analyses determined that purF was essential for fitness, while apt was critical. Traditional and high-depth amplicon-sequencing analyses confirmed extensive intrapopulation genetic variation of purF and apt that resulted in viable strains bearing alleles with in-frame insertion duplications, deletions, or missense polymorphisms. Different purF and apt alleles were associated with various stress survival capabilities under several niche-relevant conditions and contributed to differential intracellular survival in an epithelial cell infection model. Amplicon sequencing revealed that intracellular survival selected for stress-fit purF and apt alleles, as did exposure to oxygen and hyperosmotic stress. Putative protein recognition direct repeat sequences were identified in purF and apt, and a DNA-protein affinity screen captured a predicted exonuclease that promoted the global spontaneous mutation rate. This work illustrates the adaptive properties of high-frequency genetic variation in two housekeeping genes, which influences C. jejuni survival under stress and promotes its success as a pathogen. IMPORTANCE: C. jejuni is an important cause of bacterial diarrheal illness. Bacterial populations have many strategies for stress survival, but phenotypic variation due to genetic diversity has a powerful advantage: no matter how swift the change in environment, a fraction of the population already expresses the survival trait. Nonclonality is thus increasingly viewed as a mechanism of population success. Our previous work identified prominent resistant/sensitive colonial variation in C. jejuni bacteria in response to hyperosmotic stress; in the work presented here, we attribute that to high-frequency genetic variation in two purine biosynthesis genes, purF and apt. We demonstrated selective pressure for nonlethal mutant alleles of both genes, showed that single-cell variants had the capacity to give rise to diverse purF and apt populations, and determined that stress exposure selected for desirable alleles. Thus, a novel C. jejuni adaptive strategy was identified, which was, unusually, reliant on prevalent genetic variation in two housekeeping genes. PMID- 26419876 TI - Ontogenetic Differences in Dietary Fat Influence Microbiota Assembly in the Zebrafish Gut. AB - Gut microbiota influence the development and physiology of their animal hosts, and these effects are determined in part by the composition of these microbial communities. Gut microbiota composition can be affected by introduction of microbes from the environment, changes in the gut habitat during development, and acute dietary alterations. However, little is known about the relationship between gut and environmental microbiotas or about how host development and dietary differences during development impact the assembly of gut microbiota. We sought to explore these relationships using zebrafish, an ideal model because they are constantly immersed in a defined environment and can be fed the same diet for their entire lives. We conducted a cross-sectional study in zebrafish raised on a high-fat, control, or low-fat diet and used bacterial 16S rRNA gene sequencing to survey microbial communities in the gut and external environment at different developmental ages. Gut and environmental microbiota compositions rapidly diverged following the initiation of feeding and became increasingly different as zebrafish grew under conditions of a constant diet. Different dietary fat levels were associated with distinct gut microbiota compositions at different ages. In addition to alterations in individual bacterial taxa, we identified putative assemblages of bacterial lineages that covaried in abundance as a function of age, diet, and location. These results reveal dynamic relationships between dietary fat levels and the microbial communities residing in the intestine and the surrounding environment during ontogenesis. IMPORTANCE: The ability of gut microbiota to influence host health is determined in part by their composition. However, little is known about the relationship between gut and environmental microbiotas or about how ontogenetic differences in dietary fat impact gut microbiota composition. We addressed these gaps in knowledge using zebrafish, an ideal model organism because their environment can be thoroughly sampled and they can be fed the same diet for their entire lives. We found that microbial communities in the gut changed as zebrafish aged under conditions of a constant diet and became increasingly different from microbial communities in their surrounding environment. Further, we observed that the amount of fat in the diet had distinct age-specific effects on gut community assembly. These results reveal the complex relationships between microbial communities residing in the intestine and those in the surrounding environment and show that these relationships are shaped by dietary fat throughout the life of animal hosts. PMID- 26419877 TI - Unique Organization of Extracellular Amylases into Amylosomes in the Resistant Starch-Utilizing Human Colonic Firmicutes Bacterium Ruminococcus bromii. AB - Ruminococcus bromii is a dominant member of the human gut microbiota that plays a key role in releasing energy from dietary starches that escape digestion by host enzymes via its exceptional activity against particulate "resistant" starches. Genomic analysis of R. bromii shows that it is highly specialized, with 15 of its 21 glycoside hydrolases belonging to one family (GH13). We found that amylase activity in R. bromii is expressed constitutively, with the activity seen during growth with fructose as an energy source being similar to that seen with starch as an energy source. Six GH13 amylases that carry signal peptides were detected by proteomic analysis in R. bromii cultures. Four of these enzymes are among 26 R. bromii proteins predicted to carry dockerin modules, with one, Amy4, also carrying a cohesin module. Since cohesin-dockerin interactions are known to mediate the formation of protein complexes in cellulolytic ruminococci, the binding interactions of four cohesins and 11 dockerins from R. bromii were investigated after overexpressing them as recombinant fusion proteins. Dockerins possessed by the enzymes Amy4 and Amy9 are predicted to bind a cohesin present in protein scaffoldin 2 (Sca2), which resembles the ScaE cell wall-anchoring protein of a cellulolytic relative, R. flavefaciens. Further complexes are predicted between the dockerin-carrying amylases Amy4, Amy9, Amy10, and Amy12 and two other cohesin-carrying proteins, while Amy4 has the ability to autoaggregate, as its dockerin can recognize its own cohesin. This organization of starch-degrading enzymes is unprecedented and provides the first example of cohesin-dockerin interactions being involved in an amylolytic system, which we refer to as an "amylosome." IMPORTANCE: Fermentation of dietary nondigestible carbohydrates by the human colonic microbiota supplies much of the energy that supports microbial growth in the intestine. This activity has important consequences for health via modulation of microbiota composition and the physiological and nutritional effects of microbial metabolites, including the supply of energy to the host from short-chain fatty acids. Recent evidence indicates that certain human colonic bacteria play keystone roles in degrading nondigestible substrates, with the dominant but little-studied species Ruminococcus bromii displaying an exceptional ability to degrade dietary resistant starches (i.e., dietary starches that escape digestion by host enzymes in the upper gastrointestinal tract because of protection provided by other polymers, particle structure, retrogradation, or chemical cross-linking). In this report, we reveal the unique organization of the amylolytic enzyme system of R. bromii that involves cohesin-dockerin interactions between component proteins. While dockerins and cohesins are fundamental to the organization of cellulosomal enzyme systems of cellulolytic ruminococci, their contribution to organization of amylases has not previously been recognized and may help to explain the starch-degrading abilities of R. bromii. PMID- 26419878 TI - Reply to "Statins may decrease the Fatality Rate of MERS Infection". PMID- 26419879 TI - A Phase-Variable Surface Layer from the Gut Symbiont Bacteroides thetaiotaomicron. AB - The capsule from Bacteroides, a common gut symbiont, has long been a model system for studying the molecular mechanisms of host-symbiont interactions. The Bacteroides capsule is thought to consist of an array of phase-variable polysaccharides that give rise to subpopulations with distinct cell surface structures. Here, we report the serendipitous discovery of a previously unknown surface structure in Bacteroides thetaiotaomicron: a surface layer composed of a protein of unknown function, BT1927. BT1927, which is expressed in a phase variable manner by ~1:1,000 cells in a wild-type culture, forms a hexagonally tessellated surface layer. The BT1927-expressing subpopulation is profoundly resistant to complement-mediated killing, due in part to the BT1927-mediated blockade of C3b deposition. Our results show that the Bacteroides surface structure is capable of a far greater degree of structural variation than previously known, and they suggest that structural variation within a Bacteroides species is important for productive gut colonization. IMPORTANCE: Many bacterial species elaborate a capsule, a structure that resides outside the cell wall and mediates microbe-microbe and microbe-host interactions. Species of Bacteroides, the most abundant genus in the human gut, produce a capsule that consists of an array of polysaccharides, some of which are known to mediate interactions with the host immune system. Here, we report the discovery of a previously unknown surface structure in Bacteroides thetaiotaomicron. We show that this protein based structure is expressed by a subset of cells in a population and protects Bacteroides from killing by complement, a component of the innate immune system. This novel surface layer protein is conserved across many species of the genus Bacteroides, suggesting an important role in colonization and host immune modulation. PMID- 26419880 TI - Live Imaging of Host-Parasite Interactions in a Zebrafish Infection Model Reveals Cryptococcal Determinants of Virulence and Central Nervous System Invasion. AB - The human fungal pathogen Cryptococcus neoformans is capable of infecting a broad range of hosts, from invertebrates like amoebas and nematodes to standard vertebrate models such as mice and rabbits. Here we have taken advantage of a zebrafish model to investigate host-pathogen interactions of Cryptococcus with the zebrafish innate immune system, which shares a highly conserved framework with that of mammals. Through live-imaging observations and genetic knockdown, we establish that macrophages are the primary immune cells responsible for responding to and containing acute cryptococcal infections. By interrogating survival and cryptococcal burden following infection with a panel of Cryptococcus mutants, we find that virulence factors initially identified as important in causing disease in mice are also necessary for pathogenesis in zebrafish larvae. Live imaging of the cranial blood vessels of infected larvae reveals that C. neoformans is able to penetrate the zebrafish brain following intravenous infection. By studying a C. neoformans FNX1 gene mutant, we find that blood-brain barrier invasion is dependent on a known cryptococcal invasion-promoting pathway previously identified in a murine model of central nervous system invasion. The zebrafish-C. neoformans platform provides a visually and genetically accessible vertebrate model system for cryptococcal pathogenesis with many of the advantages of small invertebrates. This model is well suited for higher-throughput screening of mutants, mechanistic dissection of cryptococcal pathogenesis in live animals, and use in the evaluation of therapeutic agents. IMPORTANCE: Cryptococcus neoformans is an important opportunistic pathogen that is estimated to be responsible for more than 600,000 deaths worldwide annually. Existing mammalian models of cryptococcal pathogenesis are costly, and the analysis of important pathogenic processes such as meningitis is laborious and remains a challenge to visualize. Conversely, although invertebrate models of cryptococcal infection allow high-throughput assays, they fail to replicate the anatomical complexity found in vertebrates and, specifically, cryptococcal stages of disease. Here we have utilized larval zebrafish as a platform that overcomes many of these limitations. We demonstrate that the pathogenesis of C. neoformans infection in zebrafish involves factors identical to those in mammalian and invertebrate infections. We then utilize the live-imaging capacity of zebrafish larvae to follow the progression of cryptococcal infection in real time and establish a relevant model of the critical central nervous system infection phase of disease in a nonmammalian model. PMID- 26419881 TI - The 1977 H1N1 Influenza Virus Reemergence Demonstrated Gain-of-Function Hazards. PMID- 26419883 TI - Reply to "The 1977 H1N1 Influenza Virus Reemergence Demonstrated Gain-of-Function Hazards". PMID- 26419882 TI - Insufficient Acidification of Autophagosomes Facilitates Group A Streptococcus Survival and Growth in Endothelial Cells. AB - Group A streptococcus (GAS) is an important human pathogen, and its invasion via blood vessels is critically important in serious events such as bacteremia or multiorgan failure. Although GAS was identified as an extracellular bacterium, the internalization of GAS into nonphagocytic cells may provide a strategy to escape from immune surveillance and antibiotic killing. However, GAS has also been reported to induce autophagy and is efficiently killed within lysosome-fused autophagosomes in epithelial cells. In this study, we show that GAS can replicate in endothelial cells and that streptolysin O is required for GAS growth. Bacterial replication can be suppressed by altering GAS gene expression in an acidic medium before internalization into endothelial cells. The inhibitory effect on GAS replication can be reversed by treatment with bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase. Compared with epithelial cells in which acidification causes autophagy-mediated clearance of GAS, there was a defect in acidification of GAS-containing vesicles in endothelial cells. Consequently, endothelial cells fail to maintain low pH in GAS-containing autophagosomes, thereby permitting GAS replication inside LAMP-1- and LC3 positive vesicles. Furthermore, treatment of epithelial cells with bafilomycin A1 resulted in defective GAS clearance by autophagy, with subsequent bacterial growth intracellularly. Therefore, low pH is a key factor for autophagy-mediated suppression of GAS growth inside epithelial cells, while defective acidification of GAS-containing vesicles results in bacterial growth in endothelial cells. IMPORTANCE: Previous reports showed that GAS can induce autophagy and is efficiently killed within lysosome-fused autophagosomes in epithelial cells. In endothelial cells, in contrast, induction of autophagy is not sufficient for GAS killing. In this study, we provide the first evidence that low pH is required to prevent intracellular growth of GAS in epithelial cells and that this mechanism is defective in endothelial cells. Treatment of GAS with low pH altered GAS growth rate and gene expression of virulence factors and resulted in enhanced susceptibility of GAS to intracellular lysosomal killing. Our findings reveal the existence of different mechanisms of host defense against GAS invasion between epithelial and endothelial cells. PMID- 26419884 TI - ABA signalling is fine-tuned by antagonistic HAB1 variants. AB - Group A protein type 2C phosphatases (PP2Cs) are negative regulators of abscisic acid (ABA) signalling and plant adaptation to stress. However, our knowledge of the regulation of PP2C activity is limited. Here we report that the PP2C HAB1 undergoes alternative splicing to produce two splice variants, which encode HAB1.1 and HAB1.2, that play opposing roles in ABA-mediated seed germination and ABA-mediated post-germination developmental arrest. HAB1.2 is predominately formed in the presence of ABA and prevents seed germination and post-germinative growth. HAB1.2 interacts with OST1, but cannot inhibit OST1 kinase activity; thus, it functions as a positive regulator of ABA signalling. We also identified an RNA-recognition motif-containing protein, RBM25, as a potential regulator of HAB1 alternative splicing and molecular diversity. Our results reveal a mechanism for turning ABA signalling on and off and for plant adaptation to abiotic stress. PMID- 26419885 TI - Bio-inspired electron-delivering system for reductive activation of dioxygen at metal centres towards artificial flavoenzymes. AB - Development of artificial systems, capable of delivering electrons to metal-based catalysts for the reductive activation of dioxygen, has been proven very difficult for decades, constituting a major scientific lock for the elaboration of environmentally friendly oxidation processes. Here we demonstrate that the incorporation of a flavin mononucleotide (FMN) in a water-soluble polymer, bearing a locally hydrophobic microenvironment, allows the efficient reduction of the FMN by NADH. This supramolecular entity is then capable of catalysing a very fast single-electron reduction of manganese(III) porphyrin by splitting the electron pair issued from NADH. This is fully reminiscent of the activity of natural reductases such as the cytochrome P450 reductases with kinetic parameters, which are three orders of magnitude faster compared with other artificial systems. Finally, we show as a proof of concept that the reduced manganese porphyrin activates dioxygen and catalyses the oxidation of organic substrates in water. PMID- 26419886 TI - How does cigarette smoking cause acute pancreatitis? AB - INTRODUCTION: Acute Pancreatitis (AP) is an emerging health problem world-wide and it is a major cause of admissions for gastrointestinal disease in many countries. Amongst the more common causes (alcohol and gallstones), recent evidence has emerged indicating that smoking is an independent risk factor for AP. However, the mechanisms involved in smoking-induced AP have not been completely elucidated. This review puts together all the published evidence in literature to present the clinical and laboratory evidence relating smoking to the causation of AP. DISCUSSION: The two main metabolites from cigarette smoke, namely nicotine and NNK are able to induce functional and histological changes within the pancreas consistent with AP. The major mechanisms involved include their action on acinar cells and zymogen secretion through pathways involving CCK and the nicotinic preganglionic receptors. Effects on the pancreatic microvasculature may be mediated through the nitric oxide pathway. There is indirect evidence to suggest that nicotine and acrolein may lead to CFTR dysfunction thereby influencing ductal secretion. However, direct evidence for this effect is needed. The effect of cigarette smoke metabolites on stellate cells and the islets warrants further investigation in the context of pathogenesis of AP. CONCLUSION: Using a step-wise approach, the review revisits the effects of the various metabolites of cigarette smoke on the constituents of the pancreas (exocrine, endocrine, neurohormonal, stellate cells, ductal system) and highlights their proven, and potential, mechanisms in triggering off an attack of AP. PMID- 26419887 TI - Alcohol use initiation is associated with changes in personality trait trajectories from early adolescence to young adulthood. AB - BACKGROUND: Recent work has demonstrated the codevelopment of personality traits and alcohol use characteristics from early adolescence to young adulthood. Few studies, however, have tested whether alcohol use initiation impacts trajectories of personality over this time period. We examined the effect of alcohol use initiation on personality development from early adolescence to young adulthood. METHODS: Participants were male (nmen = 2,350) and female (nwomen = 2,618) twins and adoptees from 3 community-based longitudinal studies conducted at the Minnesota Center for Twin and Family Research. Data on personality traits of Positive Emotionality (PEM; Well-being), Negative Emotionality (NEM; Stress Reaction, Alienation, and Aggression), and Constraint (CON; Control and Harm Avoidance)-assessed via the Multidimensional Personality Questionnaire (MPQ)-and age of first drink were collected for up to 4 waves spanning ages 10 to 32. RESULTS: Alcohol use initiation was associated with significant decreases in levels of Well-being and CON traits, most notably Control; and significant increases in levels of all NEM traits, particularly Aggression. In general, the effects of alcohol use initiation on personality traits were moderated by gender and enhanced among those with earlier age of first drink. CONCLUSIONS: From early adolescence to young adulthood, alcohol use initiation predicts deviations from normative patterns of personality maturation. Such findings offer a potential mechanism underlying the codevelopment of personality traits and alcohol use characteristics during this formative period of development. PMID- 26419888 TI - Osteogenic Differentiation Evaluation of an Engineered Extracellular Matrix Based Tissue Sheet for Potential Periosteum Replacement. AB - Due to the indispensable role of periosteum in bone defect healing and regeneration, a promising method to enhance osteogenesis of bone grafts by using an engineered biomimetic periosteum would be highly beneficial. The stromal microenvironment of periosteum is composed of various highly organized extracellular matrix (ECM) fibers, so an aligned natural ECM sheet, derived from the human dermal fibroblast cell sheet, may be advantageous when applied for artificial periosteum fabrication. Human mesenchymal stem cells (hMSCs) have been used to replace the osteoprogenitor cell population in native periosteum due to hMSCs' great osteogenic potential and fast in vitro expansion capacity. The objective of this work is to investigate if the natural ECM sheet and the substrate alignment can promote in vitro osteogenesis of hMSCs. The conventional cell culture substrates collagen I-coated polydimethylsiloxane (PDMS) and tissue culture plastic (TCP) were used as controls. It was found that the ECM sheet significantly increased alkaline phosphatase activity and calcium deposition. The enhanced osteogenic potential was further confirmed by increased bone-specific gene expression. The ECM sheet can bind significantly higher amounts of growth factors including ANG-1, TGF-beta1, bFGF, and VEGF, as well as calcium phosphate nanoparticles, which contributed to high osteogenesis of the hMSCs on ECM sheet. However, the alignment of the substrates did not show significant influence on osteogenic activity and growth factor binding. These results demonstrated the great potential of hMSC-seeded ECM sheet as a biomimetic periosteum to improve critical sized bone regeneration. PMID- 26419889 TI - Germ plasm localisation of the HELICc of Vasa in Drosophila: analysis of domain sufficiency and amino acids critical for localisation. AB - Formation of the germ plasm drives germline specification in Drosophila and some other insects such as aphids. Identification of the DEAD-box protein Vasa (Vas) as a conserved germline marker in flies and aphids suggests that they share common components for assembling the germ plasm. However, to which extent the assembly order is conserved and the correlation between functions and sequences of Vas remain unclear. Ectopic expression of the pea aphid Vas (ApVas1) in Drosophila did not drive its localisation to the germ plasm, but ApVas1 with a replaced C-terminal domain (HELICc) of Drosophila Vas (DmVas) became germ-plasm restricted. We found that HELICc itself, through the interaction with Oskar (Osk), was sufficient for germ-plasm localisation. Similarly, HELICc of the grasshopper Vas could be recruited to the germ plasm in Drosophila. Nonetheless, germ-plasm localisation was not seen in the Drosophila oocytes expressing HELICcs of Vas orthologues from aphids, crickets, and mice. We further identified that glutamine (Gln) 527 within HELICc of DmVas was critical for localisation, and its corresponding residue could also be detected in grasshopper Vas yet missing in the other three species. This suggests that Gln527 is a direct target of Osk or critical to the maintenance of HELICc conformation. PMID- 26419890 TI - Social cognition and the cerebellum: A meta-analytic connectivity analysis. AB - This meta-analytic connectivity modeling (MACM) study explores the functional connectivity of the cerebellum with the cerebrum in social cognitive processes. In a recent meta-analysis, Van Overwalle, Baetens, Marien, and Vandekerckhove (2014) documented that the cerebellum is implicated in social processes of "body" reading (mirroring; e.g., understanding other persons' intentions from observing their movements) and "mind" reading (mentalizing, e.g., inferring other persons' beliefs, intentions or personality traits, reconstructing persons' past, future, or hypothetical events). In a recent functional connectivity study, Buckner et al. (2011) offered a novel parcellation of cerebellar topography that substantially overlaps with the cerebellar meta-analytic findings of Van Overwalle et al. (2014). This overlap suggests that the involvement of the cerebellum in social reasoning depends on its functional connectivity with the cerebrum. To test this hypothesis, we explored the meta-analytic co-activations as indices of functional connectivity between the cerebellum and the cerebrum during social cognition. The MACM results confirm substantial and distinct connectivity with respect to the functions of (a) action understanding ("body" reading) and (b) mentalizing ("mind" reading). The consistent and strong connectivity findings of this analysis suggest that cerebellar activity during social judgments reflects distinct mirroring and mentalizing functionality, and that these cerebellar functions are connected with corresponding functional networks in the cerebrum. PMID- 26419891 TI - Unravelling polar lipids dynamics during embryonic development of two sympatric brachyuran crabs (Carcinus maenas and Necora puber) using lipidomics. AB - Embryogenesis is an important stage of marine invertebrates with bi-phasic life cycles, as it conditions their larval and adult life. Throughout embryogenesis, phospholipids (PL) play a key role as an energy source, as well as constituents of biological membranes. However, the dynamics of PL during embryogenesis in marine invertebrates is still poorly studied. The present work used a lipidomic approach to determine how polar lipid profiles shift during embryogenesis in two sympatric estuarine crabs, Carcinus maenas and Necora puber. The combination of thin layer chromatography, liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry allowed us to achieve an unprecedented resolution on PL classes and molecular species present on newly extruded embryos (stage 1) and those near hatching (stage 3). Embryogenesis proved to be a dynamic process, with four PL classes being recorded in stage 1 embryos (68 molecular species in total) and seven PL classes at stage 3 embryos (98 molecular species in total). The low interspecific difference recorded in the lipidomic profiles of stage 1 embryos appears to indicate the existence of similar maternal investment. The same pattern was recorded for stage 3 embryos revealing a similar catabolism of embryonic resources during incubation for both crab species. PMID- 26419892 TI - Accounting for patient size in the optimization of dose and image quality of pelvis cone beam CT protocols on the Varian OBI system. AB - OBJECTIVE: The purpose of this study was to develop size-based radiotherapy kilovoltage cone beam CT (CBCT) protocols for the pelvis. METHODS: Image noise was measured in an elliptical phantom of varying size for a range of exposure factors. Based on a previously defined "small pelvis" reference patient and CBCT protocol, appropriate exposure factors for small, medium, large and extra-large patients were derived which approximate the image noise behaviour observed on a Philips CT scanner (Philips Medical Systems, Best, Netherlands) with automatic exposure control (AEC). Selection criteria, based on maximum tube current-time product per rotation selected during the radiotherapy treatment planning scan, were derived based on an audit of patient size. RESULTS: It has been demonstrated that 110 kVp yields acceptable image noise for reduced patient dose in pelvic CBCT scans of small, medium and large patients, when compared with manufacturer's default settings (125 kVp). Conversely, extra-large patients require increased exposure factors to give acceptable images. 57% of patients in the local population now receive much lower radiation doses, whereas 13% require higher doses (but now yield acceptable images). CONCLUSION: The implementation of size based exposure protocols has significantly reduced radiation dose to the majority of patients with no negative impact on image quality. Increased doses are required on the largest patients to give adequate image quality. ADVANCES IN KNOWLEDGE: The development of size-based CBCT protocols that use the planning CT scan (with AEC) to determine which protocol is appropriate ensures adequate image quality whilst minimizing patient radiation dose. PMID- 26419893 TI - Racemic cobalt phosphonates incorporating flexible bis(imidazole) co-ligands. AB - By incorporating flexible bis(imidazol-1-ylmethyl)benzene (bix) co-ligands, four new racemic cobalt phosphonates with formulae Co3(3-ppap)2(1,4-bix)2(H2O)4.4H2O (1), Co3(3-ppap)2(1,3-bix)2(H2O)4.5H2O (2), Co3(3-ppap)2(1,2-bix)2(H2O)4.4H2O (3) and Co3(ppa)2(1,2-bix)2.4H2O (4) are isolated, where 3-ppapH3 represents 3-phenyl 3-((phosphonomethyl)amino)propanoic acid and ppaH3 is 2-phenyl-2 (phosphonomethylamino)acetic acid. Compounds 1-3 crystallize in the monoclinic space group P21/c and show two-dimensional structures in which the Co3(3-ppap)2 chains are bridged by 1,4-bix, 1,3-bix and 1,2-bix ligands in trans-modes, respectively. Within the chain, a racemic dimer of Co2(3-ppap)2(2-) is found, where the Co atoms are doubly bridged by O-P-O units from the (S)- and (R)-3 ppap(3-) ligands. The dimers are connected by another crystallographically independent Co atom through O-P-O linkages to form an infinite racemic chain. The packing modes of the layers in 1-3 are quite different, however, which are ABAB in the cases of 1 and 3 while ABCDABCD in the case of 2, attributed to the positional isomerism of the bix co-ligands. Compound 4 displays a chain structure in which the 1,2-bix bridges the Co atoms in cis-mode within the chain. Magnetic properties are investigated for all compounds. PMID- 26419895 TI - Validation of a German version of the International Hip Outcome Tool (G-iHOT33) according to the COSMIN checklist: how much improvement is clinically relevant? AB - PURPOSE: The evaluation of the subjective health-related quality of life is especially for young, active patients with hip joint disorders important. The MAHORN study group has recently developed the "International Hip Outcome Tool" (iHOT33), a self-administered patient-reported outcome tool, which includes questions on the patient's symptoms, functional and sports limitations as well as social, emotional, and occupational limitations. The purpose of this study was to adapt and validate a German version of the iHOT33 according to the COSMIN checklist. METHODS: To validate the G-iHOT33, we conducted a prospective multicenter cohort study on patients with hip disorders and a score >=4 on the modified Tegner Activity Scale. The patients completed the G-iHOT33 questionnaire twice at intervals of at least 2 weeks. In addition, we recorded the Hip Outcome Score (HOS), a modified Tegner Activity Scale (TAS), the EuroQol-5D (EQ5-D), and a subjective assessment of the limitations. Evaluation of psychometric properties was conducted following the COSMIN checklist for validation of health status measurement instruments. The methodical testing for reliability included internal consistency, test-retest reliability, and measurement error. For testing of validity, we analyzed construct validity, hypotheses testing, interpretability, and responsiveness. RESULTS: Between December 2013 and December 2014, eighty three consecutive patients completed both questionnaires and were available for data analysis. Cronbach's alpha was 0.97 (95% CI 0.96, 0.99) confirming internal consistency and test-retest reliability of the G-iHOT-33 was high with an ICC = 0.88 (95% CI 0.80, 0.99). All a priori hypotheses were confirmed, further, no floor- or ceiling-effects occurred. The G-iHOT33 showed good responsiveness with a minimal important change (MIC) of 10 points. CONCLUSIONS: The German translation of the iHOT-33 (G-iHOT-33) is a viable tool for the evaluation of active patients with a hip disorder. Following the complete COSMIN checklist, we could prove that G-iHOT33 is a reliable, valid, and responsive PRO measurement tool. We could show that the minimal important change, a change of health condition the patient discerns is 10 points in the G-iHOT33 scale. This is the first study providing results on psychometric properties of the iHOT33 subscales. Level of evidence 1b validating cohort study. PMID- 26419894 TI - Neuropathogenesis of Chikungunya infection: astrogliosis and innate immune activation. AB - Chikungunya, "that which bends up" in the Makonde dialect, is an emerging global health threat, with increasing incidence of neurological complications. Until 2013, Chikungunya infection had been largely restricted to East Africa and the Indian Ocean, with cases within the USA reported to be from foreign travel. However, in 2014, over 1 million suspected cases were reported in the Americas, and a recently infected human could serve as an unwitting reservoir for the virus resulting in an epidemic in the continental USA. Chikungunya infection is increasingly being associated with neurological sequelae. In this study, we sought to understand the role of astrocytes in the neuropathogenesis of Chikungunya infection. Even after virus has been cleared form the circulation, astrocytes were activated with regard to TLR2 expression. In addition, white matter astrocytes were hypertrophic, with increased arbor volume in gray matter astrocytes. Combined, these would alter the number and distribution of synapses that each astrocyte would be capable of forming. These results provide the first evidence that Chikungunya infection induces morphometric and innate immune activation of astrocytes in vivo. Perturbed glia-neuron signaling could be a major driving factor in the development of Chikungunya-associated neuropathology. PMID- 26419896 TI - Double mobility cup total hip arthroplasty in patients at high risk for dislocation: a single-center analysis. AB - INTRODUCTION: Double mobility cup systems (DMCS) have gained increasing acceptance, especially in patients at high risk for dislocation. The aim of this investigation was to analyze the frequency and indications of the DMCS use in our praxis and to evaluate dislocation and cup revision rates after a minimum follow up of 2 years. MATERIALS AND METHODS: All patients implanted with a DMCS from May 2008 to August 2011 were identified from our institutional database of primary and revision THA procedures. Patient demographics, including ASA score, were recorded, along with details of the surgical procedures, indications for DMCS use, and post-operative clinical course and any complications. Radiographs were analyzed for implant positioning and radiological signs of loosening. RESULTS: 1046 primary THA were implanted, of these 39 (4 %) primary DMCS. Indications were severe neuromuscular disease (SND) (14), hip abductor degeneration (HAD) (9), cognitive dysfunction (CD) (8) and others. 345 revision THA were performed, of these 50 (14 %) revision DMCS. Indications were recurrent dislocations (27), multiple prior hip surgeries (13), HAD (5), CD (3) and others. Overall dislocation rate was 2/89 (2 %); both in revision THA. Overall cup revision rate was 5/89 (6 %): 3 septic, 1 periprosthetic acetabular fracture, 1 "intraprosthetic dissociation". 67 patients were available for the standardized questionnaire at a median follow-up of 43 months (range 25-78). 19 patients were not available for two-year follow-up: 17 died and two were lost to follow-up. CONCLUSIONS: This study supports the use of DMCS constructs in primary and revision hip arthroplasty for specific high-risk patients. We continue to indicate DMCS in this patient group. We do caution against extending indications for DMCS to lower risk patient groups due to unknown issues surrounding wear and component longevity. PMID- 26419897 TI - Arthroscopic Capsular Repair for Symptomatic Hip Instability After Previous Hip Arthroscopic Surgery. AB - BACKGROUND: Management of the hip capsule has been a topic of recent debate in hip arthroscopic surgery. Postoperative instability after hip arthroscopic surgery has been reported and can lead to poor outcomes. PURPOSE: To determine the outcome of patients diagnosed with symptomatic instability after hip arthroscopic surgery at a minimum of 12 months and 24 months after revision surgery for capsular repair. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: In a cohort of approximately 1100 patients who underwent hip arthroscopic surgery, 33 patients (33 hips) developed symptomatic instability requiring a revision surgery. Two patients suffered anterior dislocations following their initial surgery. Radiographs were reviewed to evaluate for acetabular dysplasia. Three patients were lost to follow-up and 10 patients were excluded as they were <1 year out from the revision surgery. A total of 20 patients (18 female, 2 male) completed a preoperative and postoperative modified Harris Hip Score (mHHS) and Hip Outcome Score (HOS) at a minimum of 12 months. Eleven of these patients had a minimum follow-up of 24 months. All patients filled out a Likert scale of perceived improvement in physical ability at final follow-up. RESULTS: The mean age of the patients was 29.7 years (range, 15.2-55.5 years). The mean lateral center-edge angle was 25 degrees , and the mean acetabular index was 7 degrees before revision. All patients underwent interportal capsulotomy during the index arthroscopic procedure. After their index arthroscopic procedures, patients had minimal improvement at a mean of 19.1 months postoperatively on the mHHS (from 57.1 to 57.6; P = .423), HOS-Activities of Daily Living (ADL) (from 62.7 to 66.4; P = .260), and HOS-Sports (from 42.0 to 39.1; P = .800). For the patients with a minimum 1-year follow-up after revision surgery (n = 20; mean follow-up, 21.3 months), the mean mHHS (from 57.6 preoperatively to 85.8 at final follow-up; P < .001), HOS-ADL (from 66.4 to 85.7; P < .001), and HOS-Sports (from 39.1 to 79.8; P < .001) all improved significantly. The results were similar when looking at only the patients with a minimum 2-year follow-up after revision surgery (n = 11; mean follow-up, 26.1 months); the mean mHHS (from 56.0 preoperatively to 91.5 at final follow-up; P = .001), HOS-ADL (from 68.3 to 89.9; P = .009), and HOS-Sports (from 35.7 to 87.9; P = .001) all improved significantly. When comparing patients with isolated capsular repair to those with additional procedures performed, there were no differences between the groups (all P > .05). At final follow-up, all but 1 patient had improved overall physical ability levels. CONCLUSION: Revision hip arthroscopic surgery for capsular repair in patients with symptomatic instability after hip arthroscopic surgery provides good functional outcomes at a minimum of 1 and 2 years postoperatively. PMID- 26419898 TI - Host specificity in Sporisorium reilianum is determined by distinct mechanisms in maize and sorghum. AB - Smut fungi are biotrophic plant pathogens that exhibit a very narrow host range. The smut fungus Sporisorium reilianum exists in two host-adapted formae speciales: S. reilianum f. sp. reilianum (SRS), which causes head smut of sorghum, and S. reilianum f. sp. zeae (SRZ), which induces disease on maize. It is unknown why the two formae speciales cannot form spores on their respective non-favoured hosts. By fungal DNA quantification and fluorescence microscopy of stained plant samples, we followed the colonization behaviour of both SRS and SRZ on sorghum and maize. Both formae speciales were able to penetrate and multiply in the leaves of both hosts. In sorghum, the hyphae of SRS reached the apical meristems, whereas the hyphae of SRZ did not. SRZ strongly induced several defence responses in sorghum, such as the generation of H2 O2 , callose and phytoalexins, whereas the hyphae of SRS did not. In maize, both SRS and SRZ were able to spread through the plant to the apical meristem. Transcriptome analysis of colonized maize leaves revealed more genes induced by SRZ than by SRS, with many of them being involved in defence responses. Amongst the maize genes specifically induced by SRS were 11 pentatricopeptide repeat proteins. Together with the microscopic analysis, these data indicate that SRZ succumbs to plant defence after sorghum penetration, whereas SRS proliferates in a relatively undisturbed manner, but non-efficiently, on maize. This shows that host specificity is determined by distinct mechanisms in sorghum and maize. PMID- 26419899 TI - Silver-catalyzed regioselective [3+2] cycloaddition of arene-diazonium salts with 2,2,2-trifluorodiazoethane (CF3CHN2): a facile access to 2-aryl-5 trifluoromethyltetrazoles. AB - A silver-catalyzed regioselective [3+2] cycloaddition reaction of arenediazonium salts with 2,2,2-trifluorodiazoethane (CF3CHN2) is reported. Under mild conditions, a series of 2-aryl substituted 5-trifluoromethyltetrazoles were obtained in moderate to excellent yields with wide functional group compatibility. Furthermore, this cycloaddition reaction could also be performed in a one-pot diazotization/cycloaddition sequence from commercially available aniline derivatives. PMID- 26419900 TI - Long-lasting analgesic effect of transcranial direct current stimulation in treatment of chronic endometriosis pain. AB - Approximately 10-20% of women of reproductive age suffer from endometriosis, with 70-90% of these women reporting chronic pain symptoms that persist during their menstrual cycle. We are presenting a case in which a novel form of noninvasive brain stimulation called transcranial direct current stimulation was used as an intervention in a 32-year-old woman with persistent, chronic pain symptoms caused by endometriosis for 20 years. Ten daily, 20-min sessions of 2-mA anodal transcranial direct current stimulation were applied over the left primary motor cortex. Acutely, visual analog scale pain symptoms were reduced by 60%. There were also significant decreases in modules of the Endometriosis Health Profile. At the 4-month follow-up, the patient still expressed an overall decrease in pain symptoms of 30%. PMID- 26419901 TI - Suppressing cAMP response element-binding protein transcription shortens the duration of status epilepticus and decreases the number of spontaneous seizures in the pilocarpine model of epilepsy. AB - OBJECTIVE: Current epilepsy therapies directed at altering the function of neurotransmitter receptors or ion channels, or release of synaptic vesicles fail to prevent seizures in approximately 30% of patients. A better understanding of the molecular mechanism underlying epilepsy is needed to provide new therapeutic targets. The activity of cyclic AMP (cAMP) response element-binding protein (CREB), a major transcription factor promoting CRE-mediated transcription, increases following a prolonged seizure called status epilepticus. It is also increased in the seizure focus of patients with medically intractable focal epilepsy. Herein we explored the effect of acute suppression of CREB activity on status epilepticus and spontaneous seizures in a chronic epilepsy model. METHODS: Pilocarpine chemoconvulsant was used to induce status epilepticus. To suppress CREB activity, a transgenic mouse line expressing an inducible dominant negative mutant of CREB (CREB(IR) ) with a serine to alanine 133 substitution was used. Status epilepticus and spontaneous seizures of transgenic and wild-type mice were analyzed using video-electroencephalography (EEG) to assess the effect of CREB suppression on seizures. RESULTS: Our findings indicate that activation of CREB(IR) shortens the duration of status epilepticus. The frequency of spontaneous seizures decreased in mice with chronic epilepsy during CREB(IR) induction; however, the duration of the spontaneous seizures was unchanged. Of interest, we found significantly reduced levels of phospho-CREB Ser133 upon activation of CREB(IR) , supporting prior work suggesting that binding to the CRE site is important for CREB phosphorylation. SIGNIFICANCE: Our results suggest that CRE transcription supports seizure activity both during status epilepticus and in spontaneous seizures. Thus, blocking of CRE transcription is a novel target for the treatment of epilepsy. PMID- 26419902 TI - Expression of serine proteinase P186 of Arthrobotrys oligospora and analysis of its nematode-degrading activity. AB - The nematode-trapping fungi possess a unique capability of predating and invading nematodes. As a representative nematode-trapping fungus, Arthrobotrys oligospora has been widely used to study the interactions between nematode-trapping fungi and their hosts. Serine proteinase is one of the important virulence factors during process of invasion of the nematode-trapping fungi into nematodes. In this study, using reverse transcription polymerase chain reaction, we amplified the gene sequence of serine proteinase 186 from A. oligospora, cloned it into pPIC9K vector and expressed it in the yeast Pichia pastoris. The expressed recombinant serine proteinase186 (reP186) was purified via Ni-affinity chromatography. The in vitro nematode-degrading activity of reP186 was analyzed. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blot analysis revealed that reP186 with molecular weight of 33 kDa was successfully obtained. ReP186 was capable of degrading a series of protein substrates including casein, gelatin, bovine serum albumin, denatured collagen and nematode cortical layer. The reP186 exhibited the maximal activity at pH 8.0 and 55 degrees C and was highly sensitive to the inhibitor, phenylmethanesulfonylfluoride. Treatment of Caenorhabditis elegans and Haemonchus contortus with reP186 for 12, 24 and 36 h, respectively, resulted in 62, 88 and 100 % of killing rates for C. elegans, and 52, 65 and 84 % of killing rates for H. contortus, respectively, indicating a relatively strong nematode degrading bioactivity of reP186. PMID- 26419904 TI - Commentary on Kim Miller. PMID- 26419903 TI - Rosiglitazone use and associated adverse event rates in Canada: an updated analysis. AB - BACKGROUND: We previously reported on the change in the use of rosiglitazone containing products (RCP) and adverse event reporting rates in Canadian patients between 2004 and 2010. The present study extends this analysis to include the January 2011 to December 2012 time period. METHODS: RCP utilization rates were obtained from IMS Health Brogan's longitudinal de-identified patient database, LRx. GlaxoSmithKline's global adverse events database was used to extract adverse events (AE), serious adverse events (SAE), and cardiac adverse events (CAE) reported in Canadian patients receiving RCP from April 2004 to December 2012. The patient utilization information from the LRx database was used to estimate rates per 100,000 patients. RESULTS: An estimated 182,841 patients were dispensed RCP prescriptions between April 2004 and December 2012. The total number of patients using RCP decreased by 85% from 2011 to 2012. From its peak use in 2007, the number of patients filling a prescription decreased 97%. A total of 1069 AEs were reported during the study period, of which 32 AE's were reported from Jan 2011 to Dec 2012. The average monthly reporting rates of AE's, SAE's and CAE's over 2011 2012 were 10.8/100,000 patients, 9.1/100,000 patients and 5.0/100,000 patients, respectively. CONCLUSIONS: The utilization of RCP in Canada has significantly declined. The significance of the adverse event rate information presented is uncertain and must be evaluated within the context of the well known factors that can influence AE reporting rates, as well as limitations to the methods used to estimate these reporting rates. PMID- 26419905 TI - Recruiting community health centers into pragmatic research: Findings from STOP CRC. AB - BACKGROUND: Challenges of recruiting participants into pragmatic trials, particularly at the level of the health system, remain largely unexplored. As part of Strategies and Opportunities to STOP Colon Cancer in Priority Populations (STOP CRC), we recruited eight separate community health centers (consisting of 26 individual safety net clinics) into a large comparative effectiveness pragmatic study to evaluate methods of raising the rates of colorectal cancer screening. METHODS: In partnership with STOP CRC's advisory board, we defined criteria to identify eligible health centers and applied these criteria to a list of health centers in Washington, Oregon, and California affiliated with Oregon Community Health Information Network, a 16-state practice-based research network of federally sponsored health centers. Project staff contacted centers that met eligibility criteria and arranged in-person meetings of key study investigators with health center leadership teams. We used the Consolidated Framework for Implementation Research to thematically analyze the content of discussions during these meetings to identify major facilitators of and barriers to health center participation. RESULTS: From an initial list of 41 health centers, 11 met the initial inclusion criteria. Of these, leaders at three centers declined and at eight centers (26 clinic sites) agreed to participate (73%). Participating and nonparticipating health centers were similar with respect to clinic size, percent Hispanic patients, and percent uninsured patients. Participating health centers had higher proportions of Medicaid patients and higher baseline colorectal cancer screening rates. Common facilitators of participation were perception by center leadership that the project was an opportunity to increase colorectal cancer screening rates and to use electronic health record tools for population management. Barriers to participation were concerns of center leaders about ability to provide fecal testing to and assure follow-up of uninsured patients, limited clinic capacity to prepare mailings required by the study protocol, discomfort with randomization, and concerns about delaying program implementation at some clinics due to the research requirements. CONCLUSION: Our findings address an important research gap and may inform future efforts to recruit community health centers into pragmatic research. PMID- 26419906 TI - Pigments influence the tolerance of Pseudomonas aeruginosa PAO1 to photodynamically induced oxidative stress. AB - Pseudomonas aeruginosa is an opportunistic pathogen known to be resistant to different classes of antibiotics and disinfectants. P. aeruginosa also displays a certain degree of tolerance to photodynamic therapy (PDT), an alternative antimicrobial approach exploiting a photo-oxidative stress induced by exogenous photosensitizers and visible light. To evaluate whether P. aeruginosa pigments can contribute to its relative tolerance to PDT, we analysed the response to this treatment of isogenic transposon mutants of P. aeruginosa PAO1 with altered pigmentation. In general, in the presence of pigments a higher tolerance to PDT induced photo-oxidative stress was observed. Hyperproduction of pyomelanin makes the cells much more tolerant to stress caused by either radicals or singlet oxygen generated by different photosensitizers upon photoactivation. Phenazines, pyocyanin and phenazine-1-carboxylic acid, produced in different amounts depending on the cultural conditions, are able to counteract both types of PDT elicited reactive oxygen species. Hyperproduction of pyoverdine, caused by a mutation in a quorum-sensing gene, rendered P. aeruginosa more tolerant to a photosensitizer that generates mainly singlet oxygen, although in this case the observed tolerance to photo-oxidative stress cannot be exclusively attributed to the presence of the pigment. PMID- 26419907 TI - Versatile and Amplified Biosensing through Enzymatic Cascade Reaction by Coupling Alkaline Phosphatase in Situ Generation of Photoresponsive Nanozyme. AB - The alkaline phosphatase (ALP) biocatalysis followed by the in situ enzymatic generation of a visible light responsive nanozyme is coupled to elucidate a novel amplification strategy by enzymatic cascade reaction for versatile biosensing. The enzymatic hydrolysis of o-phosphonoxyphenol (OPP) to catechol (CA) by ALP is allowed to coordinate on the surface of TiO2 nanoparticles (NPs) due to the specificity and high affinity of enediol ligands to Ti(IV). Upon the stimuli by CA generated from ALP, the inert TiO2 NPs is activated, which demonstrates highly efficient oxidase mimicking activity for catalyzing the oxidation of the typical substrate of 3,3',5,5'-tetramethylbenzidine (TMB) under visible light (lambda >= 400 nm) irradiation utilizing dissolved oxygen as an electron acceptor. On the basis of the cascade reaction of ALP and the nanozyme of CA coordinated TiO2 (TiO2-CA) NPs, we design exquisitely colorimetric biosensors for probing ALP activity and its inhibitor of 2, 4-dichlorophenoxyacetic acid (2,4-DA). Quantitative probing of ALP activity in a wide linear range from 0.01 to 150 U/L with the detection limit of 0.002 U/L is realized, which endows the methodology with sufficiently high sensitivity for potentially practical applications in real samples of human serum (ALP level of 40-190 U/L for adults). In addition, a novel immunoassay protocol by taking mouse IgG as an example is validated using the ALP/nanozyme cascade amplification reaction as the signal transducer. A low detection limit of 2.0 pg/mL is attained for mouse IgG, which is 4500-fold lower than that of the standard enzyme-linked immuno-sorbent assay (ELISA) kit. Although only mouse IgG is used as a proof-of-concept in our experiment, we believe that this approach is generalizable to be readily extended to other ELISA systems. This methodology opens a new horizon for amplified and versatile biosensing including probing ALP activity and following ALP-based ELISA immunoassays. PMID- 26419909 TI - Efficacy of Low-Density Lipoprotein Apheresis in Salvaging Critical Limb Ischemia Induced by Acute Thrombotic Occlusion on Peripheral Artery Disease. PMID- 26419908 TI - Clinical presentation and outcome by age categories in acute heart failure: results from an international observational cohort. AB - AIMS: To assess, according to age groups, patients' characteristics according to region of origin, the chronic therapeutic management, prognostic utility of clinical variables, and natriuretic peptides. METHODS AND RESULTS: The GREAT registry consisted of patients identified as presenting with acute heart failure at the emergency department. Four groups of patients were defined according to age: the young patient group (<65 years); 'middle-old' (65-74 years), 'old-old' (75-84 years) and the 'oldest-old' (85-94 years). Follow-up at 1 year was performed via personal contact or national data registries at 1 year. Dataset consisted of 14 758 patients aged up to 95 years, with the 'oldest-old' group being more prevalent in North America and Western Europe. The 30-day mortality rate were, respectively, 8.1%, 8.9%, 10.3%, and 16.3% among the four age groups and 1-year mortality rates were, respectively, 3.1%, 17.1%, 24.7%, and 39.9%. Chronic heart failure treatment was less frequently administered with age (percentage of the 'fully treated' group was 14% in the 'young' compared with 2% in the 'oldest-old' patient group). Reduced left ventricular ejection fraction was present in 70%, 62.3%, 52.5%, and 46.8% among the four age groups, respectively. The prognostic utility of most variables for short- and long-term outcome was attenuated with age, with the exception of natriuretic peptides. CONCLUSION: This study found a large heterogeneity in age among geographic regions and that the eldest are less likely to be treated in accordance with recommendations of current heart failure guidelines. Natriuretic peptide concentrations retained prognostic value in patients across age strata. PMID- 26419910 TI - Towards universal health coverage for reproductive health services in Ethiopia: two policy recommendations. AB - Reproductive health services are crucial for maternal and child health, but universal health coverage is still not within reach in most societies. Ethiopia's goal of universal health coverage promises access to all necessary services for everyone while providing protection against financial risk. When moving towards universal health coverage, health plans and policies require contextualized knowledge about baseline indicators and their distributions. To understand more about the factors that explain coverage, we study the relationship between socioeconomic and geographic factors and the use of reproductive health services in Ethiopia, and further explore inequalities in reproductive health coverage. Based on these findings, we discuss the normative implications of these findings for health policy. Using population-level data from the Ethiopian Demographic and Health Survey (2011) in a multivariate logistic model, we find that family planning and use of antenatal care are associated with higher wealth, higher education and being employed. Skilled attendance at birth is associated with higher wealth, higher education, and urban location. There is large variation between Addis Ababa (the capital) and other administrative regions. Concentration indices show substantial inequalities in the use of reproductive health services. Decomposition of the concentration indices indicates that difference in wealth is the most important explanatory factor for inequality in reproductive health coverage, but other factors, such as urban setting and previous health care use, are also associated with inequalities. When aiming for universal health coverage, this study shows that different socioeconomic factors as well as health-sector factors should be addressed. Our study re-confirms the importance of a broader approach to reproductive health, and in particular the importance of inequality in wealth and geography. Poor, non-educated, non-employed women in rural areas are multidimensionally worse off. The needs of these women should be addressed through elimination of out-of-pocket costs and revision of the formula for resource allocation between regions as Ethiopia moves towards universal health coverage. PMID- 26419911 TI - Is immune system-related hypertension associated with ovarian hormone deficiency? AB - NEW FINDINGS: What is the topic of this review? This review summarizes recent data on the role of ovarian hormones and sex in inflammation-related hypertension. What advances does it highlight? The adaptive immune system has recently been implicated in the development of hypertension in males but not in females. The role of the immune system in the development of hypertension in women and its relationship to ovarian hormone production are highlighted. The immune system is known to contribute to the development of high blood pressure in males. However, the role of the immune system in the development of high blood pressure in females and the role of ovarian hormones has only recently begun to be studied. In animal studies, both the sex of the host and the T cell are critical biological determinants of susceptibility and resistance to hypertension induced by angiotensin II. In women, natural menopause is known to result in significant changes in the expression of genes regulating the immune system. Likewise, in animal models, ovariectomy results in hypertension and an upregulation in T-cell tumour necrosis factor-alpha-related genes. Oestrogen replacement results in decreases in inflammatory genes in the brain regions involved in blood pressure regulation. Together, these studies suggest that the response of the adaptive immune system to ovarian hormone deficiency is a significant contributor to hypertension in women. PMID- 26419912 TI - An analysis of child protection 'standard operating procedures for research' in higher education institutions in the United Kingdom. AB - BACKGROUND: Interest in children's agency within the research process has led to a renewed consideration of the relationships between researchers and children. Child protection concerns are sometimes not recognised by researchers, and sometimes ignored. Yet much research on children's lives, especially in health, has the potential to uncover child abuse. University research guidance should be in place to safeguard both researchers and the populations under scrutiny. The aim of this study was to examine university guidance on protecting children in research contexts. METHODS: Child protection Standard Operating Procedures (SOPs) were requested from institutions with Research Assessment Exercise (2008) profiles in the top two quartiles according to published league tables. Procedures were included if they applied across the institution and if they were more extensive than stating the university's general application of the UK Disclosure and Barring Service process. A typology for scoring the SOPs was designed for this study based on the authors' previous work. The typology and the raw data scoring were reviewed independently by each of the team members and collectively agreed. The raw scores were charted and analysed using descriptive statistics. RESULTS: SOPs for research conduct amongst vulnerable groups were sought from 83 institutions. Forty HEIs provided policies which met the inclusion criteria. The majority did not mention children, young people or vulnerable adults as a whole, although children in nurseries and young people in universities were addressed. Only three institutions scored over 50 out of a possible 100. The mean score was 17.4. More than half the HEIs made no reference to vetting/barring schemes in research, only eight universities set out a training programme on child protection. Research was often not mentioned in the SOPs and only six mention children in research, with only two fully recognising the extent of child protection in research. DISCUSSION: There is potential for researchers to recognise and respond to maltreatment of children who participate in research. However, the majority of HEIs do not have an overt culture of safeguarding. There is confusion over what are the roles and responsibilities of HEIs in relation to research that involves children. CONCLUSIONS: The policies that are meant to support and guide research practice, so that children are protected, are in the most part non-existent or poorly developed. PMID- 26419913 TI - Stem cell treatment for acute myocardial infarction. AB - BACKGROUND: Cell transplantation offers a potential therapeutic approach to the repair and regeneration of damaged vascular and cardiac tissue after acute myocardial infarction (AMI). This has resulted in multiple randomised controlled trials (RCTs) across the world. OBJECTIVES: To determine the safety and efficacy of autologous adult bone marrow stem cells as a treatment for acute myocardial infarction (AMI), focusing on clinical outcomes. SEARCH METHODS: This Cochrane review is an update of a previous version (published in 2012). We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 2), MEDLINE (1950 to March 2015), EMBASE (1974 to March 2015), CINAHL (1982 to March 2015) and the Transfusion Evidence Library (1980 to March 2015). In addition, we searched several international and ongoing trial databases in March 2015 and handsearched relevant conference proceedings to January 2011. SELECTION CRITERIA: RCTs comparing autologous bone marrow-derived cells with no cells in patients diagnosed with AMI were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all references, assessed the risk of bias of the included trials and extracted data. We conducted meta-analyses using random effects models throughout. We analysed outcomes at short-term (less than 12 months) and long-term (12 months or more) follow-up. Dichotomous outcomes are reported as risk ratio (RR) and continuous outcomes are reported as mean difference (MD) or standardised MD (SMD). We performed sensitivity analyses to evaluate the results in the context of the risk of selection, performance and attrition bias. Exploratory subgroup analysis investigated the effects of baseline cardiac function (left ventricular ejection fraction, LVEF) and cell dose, type and timing of administration, as well as the use of heparin in the final cell solution. MAIN RESULTS: Forty-one RCTs with a total of 2732 participants (1564 cell therapy, 1168 controls) were eligible for inclusion. Cell treatment was not associated with any changes in the risk of all-cause mortality (34/538 versus 32/458; RR 0.93, 95% CI 0.58 to 1.50; 996 participants; 14 studies; moderate quality evidence), cardiovascular mortality (23/277 versus 18/250; RR 1.04, 95% CI 0.54 to 1.99; 527 participants; nine studies; moderate quality evidence) or a composite measure of mortality, reinfarction and re hospitalisation for heart failure (24/262 versus 33/235; RR 0.63, 95% CI 0.36 to 1.10; 497 participants; six studies; moderate quality evidence) at long-term follow-up. Statistical heterogeneity was low (I(2) = 0% to 12%). Serious periprocedural adverse events were rare and were generally unlikely to be related to cell therapy. Additionally, cell therapy had no effect on morbidity, quality of life/performance or LVEF measured by magnetic resonance imaging. Meta-analyses of LVEF measured by echocardiography, single photon emission computed tomography and left ventricular angiography showed evidence of differences in mean LVEF between treatment groups although the mean differences ranged between 2% and 5%, which are accepted not to be clinically relevant. Results were robust to the risk of selection, performance and attrition bias from individual studies. AUTHORS' CONCLUSIONS: The results of this review suggest that there is insufficient evidence for a beneficial effect of cell therapy for AMI patients. However, most of the evidence comes from small trials that showed no difference in clinically relevant outcomes. Further adequately powered trials are needed and until then the efficacy of this intervention remains unproven. PMID- 26419916 TI - Foreword. PMID- 26419914 TI - Approximation of head and neck cancer volumes in contrast enhanced CT. AB - BACKGROUND: Tumor volume may serve as a predictor of response to radiochemotherapy (RCT) in head and neck squamous cell carcinoma (HNSCC). Computer assisted tumor volumetry requires time-consuming slice-by-slice manual or semi-automated segmentation. We questioned how accurately primary tumor and suspect cervical lymph node (LN) volumes can be approximated by the maximum tumor diameters in three dimensions. METHODS: In contrast-enhanced diagnostic CT scans of 74 patients with incident advanced HNSCC, manual slice-by-slice segmentation volumetry of primary tumor, total- and largest suspect cervical LN served as the reference method. In the same scans, maximum orthogonal diameters were measured using the distance measurement tool in standard visualization software in axial and coronal sections. From these diameters, approximate volumes were calculated using the cubic and ellipsoid formula. A second segmentation volumetry was performed in contrast enhanced radiotherapy-planning CT scans obtained prior to primary concurrent RCT 24 days (+/- 13 days) following the initial diagnostic CT scans. Intraclass correlation coefficients and Bland-Altman analyses were used to compare results. RESULTS: Slice-by-slice manual segmentation volumetry of primary and LN volumes revealed a lognormal distribution and ranged from 0 to 86 ml and 0 to 129 ml, respectively. Volume approximations in diagnostic CT scans with the ellipsoid formula resulted in an -8 % underestimation of tumor volumes (95 % CI 14 % to -1 %; p = 0.022) and an -18 % underestimation of suspect cervical LN volumes (95 % CI -25 % to -12 %; p = 0.001). Inter rater intraclass correlation for primaries was 0.95 (95 % CI +0.92 to +0.97; p = 0.001), and intra rater intraclass correlation was 0.99 (95 % CI +0.98 to +0.99; p = 0.001). The cubic formula resulted in pronounced overestimation of primary and LN volumes. Primary tumor volumes obtained by the second segmentation volumetry in radiotherapy planning CT scans obtained on average 24 days following the initial volumetry resulted in larger primary tumor volumes (mean bias +28 %, 95 % CI +14 % to +41 %; p = 0.001). Tumor volume increase correlated with time between the diagnostic and planning CTs (r = 0.24, p = 0.05) and was approximately 1 % per day. DISCUSSION: Ellipsoid approximations of tumor and lymph node volumes in HNSCC using maximum orthogonal diameters underestimates volumes based on segmentation in multiple slices. Due to time difference and safety margins, segmented volumes in radiotherapy-planning CT scans tend to be larger than in diagnostic CT scans. CONCLUSION: Ellipsoid approximations of tumor and lymph node volumes in HNSCC are easily available from diagnostic CT scans. Volume estimates are applicable over a wide range of tumor and LN sizes and may be useful in clinical decision-making and oncologic research. PMID- 26419915 TI - Diverse regulatory factors associate with flowering time and yield responses in winter-type Brassica napus. AB - BACKGROUND: Flowering time, plant height and seed yield are strongly influenced by climatic and day-length adaptation in crop plants. To investigate these traits under highly diverse field conditions in the important oilseed crop Brassica napus, we performed a genome-wide association study using data from diverse agroecological environments spanning three continents. METHODS: A total of 158 European winter-type B.napus inbred lines were genotyped with 21,623 unique, single-locus single-nucleotide polymorphism (SNP) markers using the Brassica 60 K SNP Illumina(r) Infinium consortium array. Phenotypic associations were calculated in the panel over the years 2010-2012 for flowering time, plant height and seed yield in 5 highly diverse locations in Germany, China and Chile, adding up to 11 diverse environments in total. RESULTS: We identified 101 genome regions associating with the onset of flowering, 69 with plant height, 36 with seed yield and 68 cross-trait regions with potential adaptive value. Within these regions, B.napus orthologs for a number of candidate adaptation genes were detected, including central circadian clock components like CIRCADIAN CLOCK- ASSOCIATED 1 (Bna.CCA1) and the important flowering-time regulators FLOWERING LOCUS T (Bna.FT) and FRUITFUL (Bna.FUL). DISCUSSION: Gene ontology (GO) enrichment analysis of candidate regions suggested that selection of genes involved in post transcriptional and epigenetic regulation of flowering time may play a potential role in adaptation of B. napus to highly divergent environments. The classical flowering time regulators Bna.FLC and Bna.CO were not found among the candidate regions, although both show functional variation. Allelic effects were additive for plant height and yield, but not for flowering time. The scarcity of positive minor alleles for yield in this breeding pool points to a lack of diversity for adaptation that could restrict yield gain in the face of environmental change. CONCLUSIONS: Our study provides a valuable framework to further improve the adaptability and yield stability of this recent allopolyploid crop under changing environments. The results suggest that flowering time regulation within an adapted B. napus breeding pool is driven by a high number of small modulating processes rather than major transcription factors like Bna.CO. In contrast, yield regulation appears highly parallel, therefore yield could be increased by pyramiding positively associated haplotypes. PMID- 26419917 TI - What potential is there for liposomal-based nanotherapy for the treatment of Type 1 diabetes? PMID- 26419918 TI - Early communication deficits in the Shank1 knockout mouse model for autism spectrum disorder: Developmental aspects and effects of social context. AB - Alterations in SHANK genes were repeatedly reported in autism spectrum disorder (ASD). ASD is a group of neurodevelopmental disorders diagnosed by persistent deficits in social communication/interaction across multiple contexts, with restricted/repetitive patterns of behavior. To date, diagnostic criteria for ASD are purely behaviorally defined and reliable biomarkers have still not been identified. The validity of mouse models for ASD therefore strongly relies on their behavioral phenotype. Here, we studied communication by means of isolation induced pup ultrasonic vocalizations (USV) in the Shank1 mouse model for ASD by comparing Shank1(-/-) null mutant, Shank1(+/-) heterozygous, and Shank1(+/+) wildtype littermate controls. The first aim of the present study was to evaluate the effects of Shank1 deletions on developmental aspects of communication in order to see whether ASD-related communication deficits are due to general impairment or delay in development. Second, we focused on social context effects on USV production. We show that Shank1(-/-) pups vocalized less and displayed a delay in the typical inverted U-shaped developmental USV emission pattern with USV rates peaking on postnatal day (PND) 9, resulting in a prominent genotype difference on PND6. Moreover, testing under social conditions revealed even more prominently genotype-dependent deficits regardless of the familiarity of the social context. As communication by definition serves a social function, introducing a social component to the typically nonsocial test environment could therefore help to reveal communication deficits in mouse models for ASD. Together, these results indicate that SHANK1 is involved in acoustic communication across species, with genetic alterations in SHANK1 resulting in social communication/interaction deficits. Autism Res 2016, 9: 696-709. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26419919 TI - The Predictive Power of the Annellation Theory: The Case of the C26H16 Cata Condensed Benzenoid Polycyclic Aromatic Hydrocarbons. AB - The Annellation Theory was applied to establish the locations of maximum absorbance for the p and beta bands in the UV-vis spectra of eight benzenoid cata condensed polycyclic aromatic hydrocarbons (PAHs) with molecular formula C26H16 and no available syntheses procedures. In this group of eight isomers, there are seven compounds with potential carcinogenic properties due to geometrical constraints. In addition, crude oil and asphaltene absorption spectra exhibit similar properties, and the PAHs in heavier crude oils and asphaltenes are known to be the source of the color of heavy oils. Therefore, understanding the electronic bands of PAHs is becoming increasingly important. The methodology was validated using information for the remaining 29 isomers with available UV-vis spectra. The results satisfactorily agree with the results from semiempirical calculations made using the ZINDO/S approach. The locations of maximum absorbance for the p and beta bands in the UV-vis spectra of the eight C26H16 cata-condensed isomers dibenzo[c,m]tetraphene, naphtho[1,2-c]chrysene, dibenzo[c,f]tetraphene, benzo[f]picene, naphtho[2,1-a]tetraphene, naphtho[2,1-c]tetraphene, dibenzo[c,l]chrysene, and naphtho[1,2-a]tetraphene were established for the first time. PMID- 26419920 TI - Developing Research Knowledge and Competence in Master's Students: Individualizing Group Research Projects. PMID- 26419921 TI - Lewis acid-promoted [2 + 2] cycloadditions of alkenes with aryl ketenes. AB - A method for the [2 + 2] cycloaddition of aryl ketenes and alkenes is presented. The process involves the in situ generation of a ketene in the presence of a Lewis acid. The utility of products is demonstrated towards the synthesis of a common scaffold found in several natural product families. PMID- 26419922 TI - Pharmacokinetic considerations in the treatment of multiple sclerosis with interferon-beta. AB - INTRODUCTION: Interferon-beta (IFNbeta) is well established as a disease modifying treatment for patients with multiple sclerosis. Several preparations of the biopharmaceutical are available differing in protein structure, formulation, dose as well as frequency and route of administration. Recently, a pegylated form of IFNbeta has been marketed. AREAS COVERED: Following a PubMed database search, we provide an overview of what is presently known about the pharmacokinetics (PK) of IFNbeta including its absorption, distribution, metabolism and elimination. Also, we discuss the association with clinically relevant issues such as treatment efficacy, adverse events and anti-drug antibodies. EXPERT OPINION: IFNbeta has a bioavailability of ~ 30% after subcutaneous or intramuscular administration, shows peak serum concentrations within several hours, has a half life of < 1 day and is eliminated by a renal and hepatic pathway. PK parameters do not substantially differ between the types of IFNbeta and routes of administration; only pegylation of IFNbeta results in substantially increased and prolonged PK. Although no clinical dose-effect relationship could be established, there is an association of IFNbeta dose with magnetic resonance imaging outcome parameters. Furthermore, there is an association of IFNbeta serum levels with the occurrence of adverse events and anti-drug antibodies. PMID- 26419923 TI - Trends in Authorship Patterns in High-Impact Radiology Publications, 1980-2013. AB - RATIONALE AND OBJECTIVES: Concerns have been raised about authorship inflation in medical literature. The purpose of this study was to determine how the number of authors per radiology article has changed over time with regard to study type and geographic factors. MATERIALS AND METHODS: We collected data on study type, authorship count, and the country of the corresponding author for a sample of articles published in Radiology, American Journal of Roentgenology, and European Radiology in 1980, 1990, 2000, and 2013. Only original research and review articles were considered. We computed trends in the mean number of authors per article for each journal and compared authorship trends between study types and geographic region. The study did not involve human subjects and was therefore exempt from institutional board review at our institution. RESULTS: A total of 682 articles were reviewed, of which 572 were original research articles (83.9%) and 110 review articles (16.1%). The overall number of authors per article doubled from 3.6 in 1980 to 7.3 in 2013 (P < .001). From 1990 to 2013, the largest absolute increase in authorship count was in Radiology (4.4-8.1, 84.1%, P < .001). The largest increase in authorship occurred in original research articles (3.7-7.8, 111%, P < .001). Although authorship counts were greatest in Asia over most study period, growth in authorship count was highest in Europe. CONCLUSIONS: Authorship count has dramatically increased in radiology journals in the last 3 decades, particularly in original research articles and in Europe. PMID- 26419924 TI - Selective and sensitive determination of protoberberines by capillary electrophoresis coupled with molecularly imprinted microextraction. AB - In this work, we developed a novel molecularly imprinted solid-phase microextraction with capillary electrophoresis method for the selective extraction and determination of protoberberines in complicated samples. The imprinted monolith was prepared in a micropipette tip-based device by using acrylamide as the functional monomer, ethyleneglyoldimethacrylate as the cross linker and dimethylsulfoxide as the porogen, and exhibited an imprinting factor of 2.41 to berberine, 2.36 to palmatine and 2.38 to jatrorrhizine. Good capillary electrophoresis separation was achieved by using 20 mM phosphate buffer at pH 7 as running buffer with the addition of organic modifier of 10% methanol. Parameters such as sample pH value, sample flow rate and sample volume were investigated for imprinted monolith-based solid-phase microextraction. An imprinted solid-phase microextraction with capillary electrophoresis method was developed, the method showed a wide linear range (0.3-50 MUg/mL), good linearity (R2 >= 0.9947) and good reproducibility (relative standard deviations <= 0.73%), the limit of detection was as low as 0.1 MUg/mL, which was lower than some reported methods based on capillary electrophoresis for protoberberines. The method has been applied for determination of three common protoberberines in Cortex Phellodendri Chinensis, by using a molecularly imprinted monolith as the selective sorbent, most of the matrices in the Cortex Phellodendri Chinensis sample were removed and three protoberberines were selectively enriched and well determined. PMID- 26419925 TI - Risk of Intestinal Malignancy in Patients With Short Bowel Syndrome. AB - BACKGROUND: Postresection intestinal adaptation is an augmented self-renewal process that might increase the risk of malignant transformation in the intestine. Furthermore, patients with short bowel syndrome (SBS) have other characteristics that might increase this risk. Our aim was to determine the incidence of new intestinal malignancy in SBS patients. METHODS: We reviewed the records of 500 adult SBS patients identified from 1982-2013. There were 199 men and 301 women ranging in age from 19-91 years. Follow-up from the time of diagnosis of SBS ranged from 12-484 months. A total of 186 (37%) patients were followed >5 years. RESULTS: The cause of SBS was postoperative in 35% of patients, malignancy/radiation in 19%, mesenteric vascular disease in 17%, Crohn's disease in 16%, and other in 13%. Twenty-eight (6%) patients received growth stimulatory medications. Fifteen percent of patients had a prior total colectomy. Twenty-eight (6%) patients underwent intestinal transplantation, and 115 (23%) patients had a previous abdominal malignancy, including colorectal cancer in 43 patients. Thirty-six (7%) received radiation therapy. Recurrent colon cancer was found in 2 patients, one at a stoma and the other with lung metastases. New colon cancer was found in 1 patient (0.2%), a 62-year-old woman with long-standing Crohn's disease. CONCLUSION: The incidence of colon cancer in this heterogenous group of patients with SBS was similar to that of the normal population. This suggests that the risk of developing a new colon cancer in patients with SBS is not increased. PMID- 26419926 TI - Review of a two-year methicillin-resistant Staphylococcus aureus screening program and cost-effectiveness analysis in Singapore. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) poses an increasingly large disease and economic burden worldwide. The effectiveness of screening programs in the tropics is poorly understood. The aims of this study are: (i) to analyze the factors affecting MRSA colonization at admission and acquisition during hospitalization and (ii) to evaluate the cost-effectiveness of a screening program which aims to control MRSA incidence during hospitalization. METHODS: We conducted a retrospective case-control study of patients admitted to the Communicable Disease Centre (CDC) in Singapore between Jan 2009 and Dec 2010 when there was an ongoing selective screening and isolation program. Risk factors contributing to MRSA colonization on admission and acquisition during hospital stay were evaluated using a logistic regression model. In addition, a cost effectiveness analysis was conducted to determine the cost per disability adjusted life year (DALY) averted due to implementing the screening and isolation program. RESULTS: The average prevalence rate of screened patients at admission and the average acquisition rate at discharge during the study period were 12.1 and 4.8 % respectively. Logistic regression models showed that older age (adjusted odds ratio (OR) 1.03, 95 % CI 1.02-1.04, p < 0.001) and dermatological conditions (adjusted OR 1.49, 95 % CI 1.11-1.20, p = 0.008) were independently associated with an increased risk of MRSA colonization at admission. Age (adjusted OR 1.02, 95 % CI 1.01-1.03, p = 0.002) and length of stay in hospital (adjusted OR 1.04, 95 % CI 1.03-1.06, p < 0.001) were independent factors associated with MRSA acquisition during hospitalization. The screening and isolation program reduced the acquisition rate by 1.6 % and was found to be cost saving. For the whole study period, the program cost US$129,916, while it offset hospitalization costs of US$103,869 and loss of productivity costs of US$50,453 with -400 $/DALY averted. DISCUSSION: This study is the first to our knowledge that evaluates the cost-effectiveness of screening and isolation of MRSA patients in a tropical country. Another unique feature of the analysis is the evaluation of acquisition rates among specific types of patients (dermatological, HIV and infectious disease patients)and the comparison of the cost-effectiveness of screening and isolation between them. CONCLUSIONS: Overall our results indicate high MRSA prevalence that can be cost effectively reduced by selective screening and isolation programs in Singapore. PMID- 26419928 TI - Promyelocytic leukemia zinc finger mediates glucocorticoid-induced cell cycle arrest in the chondroprogenitor cell line ATDC5. AB - Glucocorticoids (GCs) affect the proliferation of growth plate chondrocytes. In this study, we investigated the role of the GC-inducible promyelocytic leukemia zinc finger (PLZF) gene in chondrocyte differentiation by using the chondrogenic cell line ATDC5. PLZF overexpression suppressed cell cycle progression (p < 0.01) and promoted differentiation into hypertrophic chondrocytes by inducing mRNA expression of alkaline phosphatase (p < 0.01), and the cyclin-dependent kinase (CDK) inhibitor p21 (p < 0.01). In contrast, PLZF knockdown impaired differentiation into hypertrophic chondrocytes and promoted cell cycle progression (p < 0.01). Treatment with the GC analogue dexamethasone (10(-6) M) suppressed cell cycle progression in ATDC5 cells. PLZF shRNA attenuated dexamethasone-induced cell cycle arrest (p < 0.01) by downregulating the mRNA expression of the CDK inhibitors p21 and p57 (p < 0.01). These results clearly indicated that PLZF promoted differentiation into hypertrophic chondrocytes and mediated dexamethasone-induced cell cycle arrest by regulating CDK inhibitors. PMID- 26419927 TI - Fingolimod induces neuroprotective factors in human astrocytes. AB - BACKGROUND: Fingolimod (FTY720) is the first sphingosine-1-phosphate (S1P) receptor modulator approved for the treatment of multiple sclerosis. The phosphorylated active metabolite FTY720-phosphate (FTY-P) interferes with lymphocyte trafficking. In addition, it accumulates in the CNS and reduces brain atrophy in multiple sclerosis (MS), and neuroprotective effects are hypothesized. METHODS: Human primary astrocytes as well as human astrocytoma cells were stimulated with FTY-P or S1P. We analyzed gene expression by a genome-wide microarray and validated induced candidate genes by quantitative PCR (qPCR) and ELISA. To identify the S1P-receptor subtypes involved, we applied a membrane impermeable S1P analog (dihydro-S1P), receptor subtype specific agonists and antagonists, as well as RNAi silencing. RESULTS: FTY-P induced leukemia inhibitory factor (LIF), interleukin 11 (IL11), and heparin-binding EGF-like growth factor (HBEGF) mRNA, as well as secretion of LIF and IL11 protein. In order to mimic an inflammatory milieu as observed in active MS lesions, we combined FTY-P application with tumor necrosis factor (TNF). In the presence of this key inflammatory cytokine, FTY-P synergistically induced LIF, HBEGF, and IL11 mRNA, as well as secretion of LIF and IL11 protein. TNF itself induced inflammatory, B-cell promoting, and antiviral factors (CXCL10, BAFF, MX1, and OAS2). Their induction was blocked by FTY-P. After continuous exposure of cells to FTY-P or S1P for up to 7 days, the extent of induction of neurotrophic factors and the suppression of TNF-induced inflammatory genes declined but was still detectable. The induction of neurotrophic factors was mediated via surface S1P receptors 1 (S1PR1) and 3 (S1PR3). CONCLUSIONS: We identified effects of FTY-P on astrocytes, namely induction of neurotrophic mediators (LIF, HBEGF, and IL11) and inhibition of TNF-induced inflammatory genes (CXCL10, BAFF, MX1, and OAS2). This supports the view that a part of the effects of fingolimod may be mediated via astrocytes. PMID- 26419929 TI - C1q/TNF-Related Protein 9 (CTRP9) attenuates hepatic steatosis via the autophagy mediated inhibition of endoplasmic reticulum stress. AB - C1q/TNF-Related Protein (CTRP) 9, the closest paralog of adiponectin, has been reported to protect against diet-induced obesity and non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism has not been fully elucidated. We explored the protective effect of CTRP9 against hepatic steatosis and apoptosis, and identified the mechanisms through autophagy and endoplasmic reticulum (ER) stress using in vitro and in vivo experiments. Treating HepG2 cells with human recombinant CTRP9 significantly ameliorated palmitate- or tunicamycin-induced dysregulation of lipid metabolism, caspase 3 activity and chromatin condensation, which lead to reduction of hepatic triglyceride (TG) accumulation. CTRP9 treatment induced autophagy markers including LC3 conversion, P62 degradation, Beclin1 and ATG7 through AMPK phosphorylation in human primary hepatocytes. Furthermore, CTRP9 decreased palmitate- or tunicamycin-induced ER stress markers, such as eIF2alpha, CHOP and IRE-1, in HepG2 cells. Compound C, an AMPK inhibitor, and 3 methyladenine (3 MA), an autophagy inhibitor, canceled the effects of CTRP9 on ER stress, apoptosis and hepatic steatosis. In the livers of HFD-fed mice, adenovirus-mediated CTRP9 overexpression significantly induced AMPK phosphorylation and autophagy, whereas suppressed ER stress markers. In addition, both SREBP1-mediated lipogenic gene expression and apoptosis were significantly attenuated, which result in improvement in hepatic steatosis by overexpression of CTRP9. These results demonstrate that CTRP9 alleviates hepatic steatosis through relief of ER stress via the AMPK-mediated induction of autophagy. PMID- 26419930 TI - Positive skeletal effect of two ingredients of Psoralea corylifolia L. on estrogen deficiency-induced osteoporosis and the possible mechanisms of action. AB - Estrogen replacement therapy (ERT) is utilized as a major regime for treatment of postmenopausal osteoporosis at present. However, long-term supplement of estrogen may cause uterine hyperplasia and hypertension leading to a high risk of endometrial cancer and breast cancer. Psoralea corylifolia L. has long been used as tonic and food additives in many countries. Previous studies had found two ingredients in P. corylifolia L.: bavachin and bakuchiol exhibited osteoblastic activity. The present study was designed to investigate the protective effect of bakuchiol and bavachin on ovariectomy-induced bone loss and explore the possible mechanism. In vivo, bakuchiol and bavachin could prevented estrogen deficiency induced bone loss in ovariectomized rats without uterotrophic activity. In vitro studies suggested that bakuchiol and bavachin induced primary human osteoblast differentiation by up-regulating the Wnt signalling pathway. This study suggests that such a bone-protective role makes them a promising and safe estrogen supplement for the ERT. PMID- 26419931 TI - The function of miR-199a-5p/Klotho regulating TLR4/NF-kappaB p65/NGAL pathways in rat mesangial cells cultured with high glucose and the mechanism. AB - Anti-aging protein Klotho may confer a renal protective effect via attenuating the nuclear factor-kappaB (NF-kappaB) p65 pathways activity. Besides, miR-199a-5p can promote gastric cancer by inhibition of Klotho protein expression. But little is known regarding to the role of miR-199a-5p/Klotho in regulating NF-kappaB p65 pathways in the pathogenesis of diabetic kidney disease (DKD). Thus, we explored Klotho and miR-199a-5p in terms of Toll-like receptor-4 (TLR4)/NF-kappaB p65/neutrophil gelatinase associated lipocalin (NGAL) signaling pathways in high glucose cultured mesangial cells (MCs). We found that high glucose increased miR 199a-5p expression, accompanied by the significantly decreased Klotho expression at both mRNA and protein. High glucose also activated TLR4/NF-kappaB p65/NGAL signaling pathways and promoted the downstream fibrosis and inflammatory reaction. Additionally, inhibition of miR-199a-5p or exogenous addition of Klotho restrained the activity of TLR4/NF-kappaB p65/NGAL signaling pathways, which in turn suppressed the inflammation and fibrosis in high glucose cultured MCs. This study provides a new basis to elucidate the protection mechanism of anti-aging protein Klotho in diabetic kidney. For the first time, our study prompts that miR 199a-5p can be used as a new therapeutic targets for DKD. PMID- 26419932 TI - miR-96 suppresses renal cell carcinoma invasion via downregulation of Ezrin expression. AB - BACKGROUND: The present study examined the role of microRNA (miR)-96 in renal cell carcinoma (RCC) invasion. METHODS: The expression of miR-96 was detected by quantitative reverse transcription-polymerase chain reaction in human RCC cell lines with high (Caki-1) and low (786-O) metastatic potential. Invasive ability and Ezrin expression were assessed in Caki-1 and 786-O cells transfected with a miR-96 mimic or inhibitor using wound healing assays, Transwell assays and western blotting. Expression of miR-96 and Ezrin was also examined in primary RCC samples from 17 patients with metastatic disease and 46 patients who maintained remission during a follow-up period of 37 months. RESULTS: miR-96 expression was significantly lower in Caki-1compared to786-O cells. The invasive ability of Caki 1 and 786-O cells increased following transfection of cells with miR-96 inhibitor, whereas it decreased following transfection with miR-96 mimic. Ezrin levels were negatively correlated with miR-96 in RCC, and inhibition of Ezrin expression suppressed the miR-96-induced change in invasive ability. The negative correlation between miR-96 and metastasis/Ezrin expression was also observed in human RCC specimens. CONCLUSIONS: These results suggest that miR-96 suppresses RCC invasion by modulating Ezrin expression. PMID- 26419933 TI - A brain mass in a patient with Behcet's disease: a case report. AB - INTRODUCTION: This case report describes an uncommon presentation of Behcet's disease which manifested as neuro-Behcet's disease. Although it is not the first reported case in the medical literature, it is a possible differential in a patient presenting with a brain tumor. Since the diagnosis of neuro-Behcet's disease depends largely on the clinical picture and medical history, it should be considered prior to opting for invasive diagnostic methods. CASE PRESENTATION: Our patient is a 36-year-old white man from Kuwait. He presented with acute onset of headache, vomiting, and right-sided weakness. Magnetic resonance imaging of his brain showed a mass in the brain stem. He then revealed that he had a history of recurrent painful oral and genital ulcers for the past 10 years, which suggested a diagnosis of Behcet's disease. A brain biopsy was recommended by a neurosurgeon at the time, but the patient refused the procedure. After initiating steroid therapy, the mass began to regress and, eventually, was undetectable on subsequent imaging of his brain. CONCLUSIONS: This case of neuro-Behcet's disease reflects the need to consider this diagnosis in a patient of less than 40 years of age presenting with a suspected brain tumor. This may delay the need for invasive diagnostic methods, especially if such methods are not desired by the patient. In the management of suspected neuro-Behcet's disease, initiating steroid therapy and measuring the response is a reasonable option before seeking a definitive diagnosis via brain biopsy. If the response to steroids is minimal then a brain biopsy should be performed. PMID- 26419935 TI - Combined use of anterolateral thigh flap and pharyngeal flap for reconstruction of extensive soft-palate defects. AB - BACKGROUND: Functional reconstruction of extensive soft-palate defects is challenging for microsurgeons. The versatility of the combination of a free anterolateral thigh flap and a superiorly based pharyngeal flap for oncologic soft-palate reconstruction was investigated. METHODS: The combination of flaps was used for immediate reconstruction after total or subtotal resection of the soft palate in five consecutive patients from 2006 to 2011. RESULTS: All flaps survived completely. Palatal fistula and miniplate infection each developed in one patient but healed conservatively. Follow-up period ranged from 21 to 66 months. All patients tolerated a regular diet without significant aspiration or nasal regurgitation. Speech intelligibility was excellent in all patients, and none required a palatal prosthesis. CONCLUSIONS: The combination of an anterolateral thigh flap and a superiorly based pharyngeal flap is a versatile option for reconstructing extensive soft-plate defects. This method is simple and achieves reproducible results with limited donor-site morbidity. (c) 2015 Wiley Periodicals, Inc. Microsurgery 36:291-296, 2016. PMID- 26419934 TI - A systematic review of community-to-facility neonatal referral completion rates in Africa and Asia. AB - BACKGROUND: An estimated 2.8 million neonatal deaths occur annually worldwide. The vulnerability of newborns makes the timeliness of seeking and receiving care critical for neonatal survival and prevention of long-term sequelae. To better understand the role active referrals by community health workers play in neonatal careseeking, we synthesize data on referral completion rates for neonates with danger signs predictive of mortality or major morbidity in low- and middle-income countries. METHODS: A systematic review was conducted in May 2014 of the following databases: Medline-PubMed, Embase, and WHO databases. We also searched grey literature. In addition, an investigator group was established to identify unpublished data on newborn referral and completion rates. Inquiries were made to the network of research groups supported by Save the Children's Saving Newborn Lives project and other relevant research groups. RESULTS: Three Sub-Saharan African and five South Asian studies reported data on community-to-facility referral completion rates. The studies varied on factors such as referral rates, the assessed danger signs, frequency of home visits in the neonatal period, and what was done to facilitate referrals. Neonatal referral completion rates ranged from 34 to 97 %, with the median rate of 74 %. Four studies reported data on the early neonatal period; early neonatal completion rates ranged from 46 to 97 %, with a median of 70 %. The definition of referral completion differed by studies, in aspects such as where the newborns were referred to and what was considered timely completion. CONCLUSIONS: Existing literature reports a wide range of neonatal referral completion rates in Sub-Saharan Africa and South Asia following active illness surveillance. Interpreting these referral completion rates is challenging due to the great variation in study design and context. Often, what qualifies as referral and/or referral completion is poorly defined, which makes it difficult to aggregate existing data to draw appropriate conclusions that can inform programs. Further research is necessary to continue highlighting ways for programs, governments, and policymakers to best aid families in low-resource settings in protecting their newborns from major health consequences. PMID- 26419936 TI - Self-Assembly of Tetraphenylalanine Peptides. AB - Three different tetraphenylalanine (FFFF) based peptides that differ at the N- and C-termini have been synthesized by using standard procedures to study their ability to form different nanoassemblies under a variety of conditions. The FFFF peptide assembles into nanotubes that show more structural imperfections at the surface than those formed by the diphenylalanine (FF) peptide under the same conditions. Periodic DFT calculations (M06L functional) were used to propose a model that consists of three FFFF molecules defining a ring through head-to-tail NH3(+)???(-)OOC interactions, which in turn stack to produce deformed channels with internal diameters between 12 and 16 A. Depending on the experimental conditions used for the peptide incubation, N-fluorenylmethoxycarbonyl (Fmoc) protected FFFF self-assembles into a variety of polymorphs: ultra-thin nanoplates, fibrils, and star-like submicrometric aggregates. DFT calculations indicate that Fmoc-FFFF prefers a parallel rather than an antiparallel beta-sheet assembly. Finally, coexisting multiple assemblies (up to three) were observed for Fmoc-FFFF-OBzl (OBzl = benzyl ester), which incorporates aromatic protecting groups at the two peptide terminals. This unusual and noticeable feature is attributed to the fact that the assemblies obtained by combining the Fmoc and OBzl groups contained in the peptide are isoenergetic. PMID- 26419937 TI - An integrated dose-finding tool for phase I trials in oncology. AB - In the past 25 years, the 3+3 design has been the most popular approach for planning phase I dose-finding trials in oncology. During the same time period, major development of more efficient model-based designs has been made by statistical researchers aiming to improve the clinical practice of dose finding in oncology. Despite the effort, 3+3 is still the most frequently used designs in practice. Part of the reason is due to the lack of software tools that allow comparison of different designs, including 3+3 and other model-based methods, in a head-to-head and easy-to-use fashion. To this end, we introduce NextGen-DF, a next-generation tool for designing oncology dose-finding trials that allows for construction, comparison, and calibration of multiple designs via internet, in real time, and independent of computer operating systems. Through NextGen-DF, we present massive and user-generated comparison results based on over 4 million simulated trials, which clearly indicate the inferiority of 3+3. To our knowledge, the reported crowd-sourcing results are the largest and most objective comparison across major dose-finding methods to date. NextGen-DF is expected to improve patient care and drug development by providing safer and more efficient designs for phase I oncology trials. NextGen-DF is available at www.compgenome.org/NGDF. PMID- 26419943 TI - Graduate nurses' knowledge of the functions and limitations of pulse oximetry. AB - AIMS AND OBJECTIVES: To examine nursing graduates' knowledge of functions and limitations of pulse oximetry. BACKGROUND: Pulse oximetry is a technology ubiquitous in its use in modern clinical settings. Although the technology's ability to accurately reflect hypoxaemia in patients has been established, its contribution to improving patient outcomes is less certain. In addition, experienced nurses have previously demonstrated poor understanding of the limitations of the technology. Pregraduate education has been identified as a potential source of knowledge deficit and has been recommended by authors as an important target of investigation. DESIGN: Cross-sectional, comparative, multicentre study. METHOD: A previously published and validated tool was used with the addition of eight clinical scenario questions which were validated by an expert panel. Convenience sampling was used to select participants to form one cohort of newly graduated nurses (Cohort 1: n = 210) and a second cohort of nurses completing their intensive postgraduate clinical year (Cohort 2: n = 97). RESULTS: Significant deficits relating to the theoretical factors that affect pulse oximetry application and interpretation were identified. Results suggest some knowledge is negatively correlated with clinical experience and that pregraduate university education appears to influence the ability to effectively apply pulse oximetry knowledge to clinical scenarios. CONCLUSIONS: This study provides insight into pulse oximetry knowledge acquisition and deficits of graduate nurses which may inform pre- and postgraduate nurse education. In particular, it suggests that some pulse oximetry knowledge and clinical application of knowledge is not enhanced by clinical experience but rather is currently gained through pregraduate experiences. RELEVANCE TO CLINICAL PRACTICE: Inappropriate utilisation and interpretation of pulse oximetry places patients at risk of mismanagement and undetected deterioration. Improvement in pregraduate education around the appropriate use of pulse oximetry may reduce clinical costs, reduce incidents of failure to rescue and improve patient outcomes. PMID- 26419944 TI - North Americans are eating more fat and less carbohydrate, study finds. PMID- 26419938 TI - A ROS-Activatable Agent Elicits Homologous Recombination DNA Repair and Synergizes with Pathway Compounds. AB - We designed ROS-activated cytotoxic agents (RACs) that are active against AML cancer cells. In this study, the mechanism of action and synergistic effects against cells coexpressing the AML oncogenes MLL-AF9 fusion and FLT3-ITD were investigated. One RAC (RAC1) had an IC50 value of 1.8+/-0.3 MUm, with ninefold greater selectivity for transformed cells compared to untransformed cells. Treatment induced DNA strand breaks, apoptosis, and cell cycle arrest. Proteomics and transcriptomics revealed enhanced expression of the pentose phosphate pathway, DNA repair, and pathways common to cell stress. Western blotting confirmed repair by homologous recombination. Importantly, RAC1 treatment was synergistic in combination with multiple pathway-targeting therapies in AML cells but less so in untransformed cells. Together, these results demonstrate that RAC1 can selectively target poor prognosis AML and that it does so by creating DNA double-strand breaks that require homologous recombination. PMID- 26419945 TI - Ginkgo biloba leaf extract induces DNA damage by inhibiting topoisomerase II activity in human hepatic cells. AB - Ginkgo biloba leaf extract has been shown to increase the incidence in liver tumors in mice in a 2-year bioassay conducted by the National Toxicology Program. In this study, the DNA damaging effects of Ginkgo biloba leaf extract and many of its constituents were evaluated in human hepatic HepG2 cells and the underlying mechanism was determined. A molecular docking study revealed that quercetin, a flavonoid constituent of Ginkgo biloba, showed a higher potential to interact with topoisomerase II (Topo II) than did the other Ginkgo biloba constituents; this in silico prediction was confirmed by using a biochemical assay to study Topo II enzyme inhibition. Moreover, as measured by the Comet assay and the induction of gamma-H2A.X, quercetin, followed by keampferol and isorhamnetin, appeared to be the most potent DNA damage inducer in HepG2 cells. In Topo II knockdown cells, DNA damage triggered by Ginkgo biloba leaf extract or quercetin was dramatically decreased, indicating that DNA damage is directly associated with Topo II. DNA damage was also observed when cells were treated with commercially available Ginkgo biloba extract product. Our findings suggest that Ginkgo biloba leaf extract- and quercetin-induced in vitro genotoxicity may be the result of Topo II inhibition. PMID- 26419946 TI - Cell Magnetic Targeting System for Repair of Severe Chronic Osteochondral Defect in a Rabbit Model. AB - The aim of this study was to investigate a cell delivery system for repair of severe chronic osteochondral defects using magnetically labeled mesenchymal stem cells (m-MSCs), with the aid of an external magnetic device, through the accumulation of a small number of m-MSCs into a desired area and to detect the suitable number of autologous m-MSCs needed for repair of the defect. Twenty-six male Japanese white rabbits aged 6 months were used. An osteochondral defect was created bilaterally at the weight-bearing surface of the medial femoral condyle of the rabbits' knees (3 mm diameter; 4 mm depth). At 4 weeks after creation of the defect, autogenic transplantation of the m-MSCs into the defect area was performed, followed by 10-min exposure to an external magnetic device, where animals were divided into four groups: high (1 * 10(6) m-MSCs), medium (2 * 10(5) m-MSCs), low (4 * 10(4) m-MSCs), and control (PBS injection). At 4 and 12 weeks posttransplantation of m-MSCs, repaired tissue was assessed histologically using the Fortier score with toluidine blue staining. Transplantation of a low number of m-MSCs was not enough to improve osteogenesis and chondrogenesis, but the medium and high groups improved repair of the chronic defect with chondrogenic tissues and showed histologically significantly better results than the control and low groups. The use of a magnetic targeting system for delivering m-MSCs has the potential to overcome the clinical hurdles for repair of the severe chronic osteochondral defect. Furthermore, this system is predicted to produce good clinical outcomes for humans, not only to repair osteochondral defects but also to repair a variety of damaged tissues. PMID- 26419947 TI - Reference ranges of hematology and lymphocyte subsets in healthy Korean native cattle (Hanwoo) and Holstein dairy cattle. AB - There are no accurate reference ranges for hematology parameters and lymphocyte subsets in Korean native beef cattle (Hanwoo). This study was performed to establish reliable reference ranges of hematology and lymphocyte subsets using a large number of Hanwoo cattle (n = 350) and to compare differences between Hanwoo and Holstein dairy cattle (n = 334). Additionally, age-related changes in lymphocyte subsets were studied. Bovine leukocyte subpopulation analysis was performed using mono or dual color flow cytometry. The leukocyte subpopulations investigated in healthy cattle included: CD2(+) cells, sIgM(+) cells, MHC class II(+) cells, CD3(+) CD4(+) cells, CD3(+) CD8(+) cells, and WC1(+) cells. Although Hanwoo and Holstein cattle are the same species, results showed several differences in hematology and lymphocyte subsets between Hanwoo and Holstein cattle. This study is the first report to establish reference ranges of hematology and lymphocyte subsets in adult Hanwoo cattle. PMID- 26419949 TI - Subducting seamounts control interplate coupling and seismic rupture in the 2014 Iquique earthquake area. AB - To date, the parameters that determine the rupture area of great subduction zone earthquakes remain contentious. On 1 April 2014, the Mw 8.1 Iquique earthquake ruptured a portion of the well-recognized northern Chile seismic gap but left large highly coupled areas un-ruptured. Marine seismic reflection and swath bathymetric data indicate that structural variations in the subducting Nazca Plate control regional-scale plate-coupling variations, and the limited extent of the 2014 earthquake. Several under-thrusting seamounts correlate to the southward and up-dip arrest of seismic rupture during the 2014 Iquique earthquake, thus supporting a causal link. By fracturing of the overriding plate, the subducting seamounts are likely further responsible for reduced plate-coupling in the shallow subduction zone and in a lowly coupled region around 20.5 degrees S. Our data support that structural variations in the lower plate influence coupling and seismic rupture offshore Northern Chile, whereas the structure of the upper plate plays a minor role. PMID- 26419948 TI - Transcriptomic changes following synthesis of a Populus full-sib diploid and allotriploid population with different heterozygosities driven by three types of 2n female gamete. AB - Diploid gametes are usually applied to produce triploids of Populus [originating from first-division restitution (FDR), second-division restitution (SDR), and postmeiotic restitution (PMR) 2n eggs]. Three types of 2n gametes transmitted different parental heterozygosities in Populus. Failed spindle formation and no chromosomal separation to opposite poles during meiosis I mean that FDR 2n gametes carry nonsister chromatids that are potentially heterozygous. By contrast, SDR 2n gametes result from failed sister chromatid separation in meiosis II, and therefore, they carry sister chromatid that are potentially homozygous. Completely homozygous 2n gametes can arise from the PMR mechanism. The alteration of gene expression resulting from allopolyploidization is a prominent feature in plants. We compared gene expression in the full-sib progeny of three allotriploid Populus populations (triploid-F, triploid-S, and triploid P) with that in its parent species, and their full-sib diploid F1 hybrid. Genome wide expression level dominance was biased toward the maternal in the diploid F1 hybrid and three allotriploid populations, whereas our data indicated important, but different, effects of the transmission of different heterozygosity by 2n female gametes in the expression patterns of allopolyploids. Because of the higher level of heterozygosity, the triploids had higher rates of non-additive and transgressive expression patterns in the triploid-F than in triploid-S and triploid-P. Compared with diploid F1, about 30-fold more genes (251) were differently expressed in the triploid-F than in the triploid-S (9) and triploid-P (8), respectively. These findings indicate that hybridization and polyploidization have immediate and distinct effects on the large-scale patterns of gene expression, and different effects on the transmission of heterozygosity by three 2n female gametes. PMID- 26419950 TI - Ultralow-threshold multiphoton-pumped lasing from colloidal nanoplatelets in solution. AB - Although multiphoton-pumped lasing from a solution of chromophores is important in the emerging fields of nonlinear optofluidics and bio-photonics, conventionally used organic dyes are often rendered unsuitable because of relatively small multiphoton absorption cross-sections and low photostability. Here, we demonstrate highly photostable, ultralow-threshold multiphoton-pumped biexcitonic lasing from a solution of colloidal CdSe/CdS nanoplatelets within a cuvette-based Fabry-Perot optical resonator. We find that colloidal nanoplatelets surprisingly exhibit an optimal lateral size that minimizes lasing threshold. These nanoplatelets possess very large gain cross-sections of 7.3 * 10(-14) cm(2) and ultralow lasing thresholds of 1.2 and 4.3 mJ cm(-2) under two-photon (lambdaexc=800 nm) and three-photon (lambdaexc=1.3 MUm) excitation, respectively. The highly polarized emission from the nanoplatelet laser shows no significant photodegradation over 10(7) laser shots. These findings constitute a more comprehensive understanding of the utility of colloidal semiconductor nanoparticles as the gain medium in high-performance frequency-upconversion liquid lasers. PMID- 26419951 TI - Opportunities and challenges of integrating ecological restoration into assessment and management of contaminated ecosystems. AB - Ecosystem restoration planning near the beginning of the site assessment and management process ("early integration") involves consideration of restoration goals from the outset in developing solutions for contaminated ecosystems. There are limitations to integration that stem from institutional barriers, few successful precedents, and limited availability of guidance. Challenges occur in integrating expertise from various disciplines and multiple, sometimes divergent interests and goals. The more complex process can result in timing, capacity, communication, and collaboration challenges. On the other hand, integrating the 2 approaches presents new and creative opportunities. For example, integration allows early planning for expanding ecosystem services on or near contaminated lands or waters that might otherwise have been unaddressed by remediation alone. Integrated plans can explicitly pursue ecosystem services that have market value, which can add to funds for long-term monitoring and management. Early integration presents opportunities for improved and productive collaboration and coordination between ecosystem restoration and contaminant assessment and management. Examples exist where early integration facilitates liability resolution and generates positive public relations. Restoration planning and implementation before the completion of the contaminated site assessment, remediation, or management process ("early restoration") can facilitate coordination with offsite restoration options and a regional approach to restoration of contaminated environments. Integration of performance monitoring, for both remedial and restoration actions, can save resources and expand the interpretive power of results. Early integration may aid experimentation, which may be more feasible on contaminated lands than in many other situations. The potential application of concepts and tools from adaptive management is discussed as a way of avoiding pitfalls and achieving benefits in early integration. In any case, there will be challenges with early integration of restoration concepts for contaminated ecosystems, but the benefits are likely to outweigh them. PMID- 26419953 TI - Nitrogen-doped graphene network supported copper nanoparticles encapsulated with graphene shells for surface-enhanced Raman scattering. AB - In this study, we demonstrated nitrogen-doped graphene network supported few layered graphene shell encapsulated Cu nanoparticles (NPs) (Cu@G-NGNs) as a sensing platform, which were constructed by a simple and scalable in situ chemical vapor deposition (CVD) technique with the assistance of a self-assembled three-dimensional (3D) NaCl template. Compared with pure Cu NPs and graphene decorated Cu NPs, the graphene shells can strengthen the plasmonic coupling between graphene and Cu, thereby contributing to an obvious improvement in the local electromagnetic field that was validated by finite element numerical simulations, while the 3D nitrogen-doped graphene walls with a large surface area facilitated molecule adsorption and the doped nitrogen atoms embedded in the graphene lattice can reduce the surface energy of the system. With these merits, a good surface enhanced Raman spectroscopy (SERS) activity of the 3D Cu@G-NGN painting film on glass was demonstrated using rhodamine 6G and crystal violet as model analytes, exhibiting a satisfactory sensitivity, reproducibility and stability. As far as we know, this is the first report on the in situ synthesis of nitrogen-doped graphene/copper nanocomposites and this facile and low-cost Cu based strategy tends to be a good supplement to Ag and Au based substrates for SERS applications. PMID- 26419952 TI - Post-chikungunya chronic arthralgia: Results from a retrospective follow-up study of 131 cases in Tolima, Colombia. PMID- 26419954 TI - Fabrication of Pd Nanoparticles Embedded C@Fe3O4 Core-Shell Hybrid Nanospheres: An Efficient Catalyst for Cyanation in Aryl Halides. AB - Isolated chemical reactors were fabricated by integrating catalytically active sites (Pd) with magnetic functionality (Fe3O4) along with carbon while preserving the constituents functional properties to realize the structure-property relationship of Pd by comparing the catalytic activity of spherical Pd NPs with cubical Pd NPs for cyanation in aryl halides using K4[Fe(CN)6] as a green cyanating agent to yield corresponding nitriles. The superior catalytic reactivity of the cubical Pd NPs is attributed to the larger number of {100} surface facets. The TEM images of reused catalyst shows the change in structure from cubical to spherical nanoparticles, attributed to the efficient leaching susceptibility of Pd {100} surface facets. The cubical Pd NPs on carbon@Fe3O4 is attractive in view of its high catalytic efficiency, easy synthesis, magnetic separability, environmental friendliness, high stability, gram scale applicability, and reusability. PMID- 26419956 TI - Acetabular dysplasia may be related to global joint hyperlaxity. AB - PURPOSE: Some patients with shoulder laxity complain of coxalgia without a history of trauma. We hypothesised that patients who have recurrent shoulder instability accompanied with generalised joint hyperlaxity tend to have acetabular dysplasia. METHODS: Pelvic radiographs of 26 young patients with hyperlaxity who had shoulder instability complaints without any history of hip joint trauma were evaluated by measuring their centre-edge angle (CEA) and acetabular angle (AA). In addition, Beighton generalised joint laxity tests were performed. All of the patients had shoulder pain and instability accompanied with hyperlaxity. We performed magnetic resonance imaging examination to show SLAP Bankart lesions and pelvis anteroposterior X-rays to detect acetabular dysplasia. RESULTS: The average age of the study group was 26 +/- 8.03 years (13-39). Six patients were female and 20 were male. When CEA (<22.6 degrees) was used as a criterion for acetabular dysplasia, the dysplasia rate of our patient group was 3.84 % for the right hip, 3.84 % for the left hip and 3.84 % overall. When AA (>42.2 degrees) was used as the dysplasia criterion, the dysplasia rate of patient group was 30.76 % for the right hip, 57.69 % for the left hip and 57.69 % overall. CONCLUSIONS: CEA values were significantly lower (p = 0.009) and AA values were significantly higher (p < 0.001) in our study group than the previously-reported average values of the Turkish population. We think that acetabular dysplasia is more frequent in patients with hyperlaxity; further studies are needed to test this idea. PMID- 26419957 TI - Midterm clinical results of osteochondral autograft transplantation for advanced stage Freiberg disease. AB - PURPOSE: We aimed to evaluate the midterm clinical results of osteochondral autograft transplantation (OAT) for advanced stage Freiberg disease. METHODS: This study included consecutive patients who underwent OAT for advanced stage Freiberg disease and were followed postoperatively for more than five years. In all cases, the autograft was harvested from the ipsilateral knee joint. Clinical evaluation was performed based on the American Orthopaedic Foot and Ankle Society Lesser Metatarsophalangeal-Interphalangeal Scale (AOFAS) score and visual analogue scale (VAS) score, which were done pre-operatively and at the most recent follow-up. Radiological evaluation was performed at two years after the operation. Furthermore, the most recent six patients underwent magnetic resonance imaging (MRI) five years after the operation to assess the configuration of the articular surface. RESULTS: A total of 13 patients (all female; mean age 16.7 years; range 10-38 years) were included and followed up for a mean duration of 67.2 months (range 60-100 months). The mean AOFAS significantly improved from a score of 66.9 +/- 5.3 (range 59-77) to 93.0 +/- 7.6 (range 82-100) (p < 0.0001). Likewise, the mean VAS significantly improved from a score of 72.7 +/- 10.3 (range 60-90) to 7.8 +/- 7.2 (range 0-20) (p < 0.0001). Radiographs at two years after the operation revealed no osteoarthritic change in all cases. MRI at five years after the operation showed consolidation of the transplanted autograft and smooth configuration of the articular surface in the six cases. CONCLUSIONS: OAT may be effective for advanced stage Freiberg disease. Further studies are necessary before this technique can become the standard operative treatment. PMID- 26419955 TI - Analysis of Proteins That Rapidly Change Upon Mechanistic/Mammalian Target of Rapamycin Complex 1 (mTORC1) Repression Identifies Parkinson Protein 7 (PARK7) as a Novel Protein Aberrantly Expressed in Tuberous Sclerosis Complex (TSC). AB - Many biological processes involve the mechanistic/mammalian target of rapamycin complex 1 (mTORC1). Thus, the challenge of deciphering mTORC1-mediated functions during normal and pathological states in the central nervous system is challenging. Because mTORC1 is at the core of translation, we have investigated mTORC1 function in global and regional protein expression. Activation of mTORC1 has been generally regarded to promote translation. Few but recent works have shown that suppression of mTORC1 can also promote local protein synthesis. Moreover, excessive mTORC1 activation during diseased states represses basal and activity-induced protein synthesis. To determine the role of mTORC1 activation in protein expression, we have used an unbiased, large-scale proteomic approach. We provide evidence that a brief repression of mTORC1 activity in vivo by rapamycin has little effect globally, yet leads to a significant remodeling of synaptic proteins, in particular those proteins that reside in the postsynaptic density. We have also found that curtailing the activity of mTORC1 bidirectionally alters the expression of proteins associated with epilepsy, Alzheimer's disease, and autism spectrum disorder-neurological disorders that exhibit elevated mTORC1 activity. Through a protein-protein interaction network analysis, we have identified common proteins shared among these mTORC1-related diseases. One such protein is Parkinson protein 7, which has been implicated in Parkinson's disease, yet not associated with epilepsy, Alzheimers disease, or autism spectrum disorder. To verify our finding, we provide evidence that the protein expression of Parkinson protein 7, including new protein synthesis, is sensitive to mTORC1 inhibition. Using a mouse model of tuberous sclerosis complex, a disease that displays both epilepsy and autism spectrum disorder phenotypes and has overactive mTORC1 signaling, we show that Parkinson protein 7 protein is elevated in the dendrites and colocalizes with the postsynaptic marker postsynaptic density-95. Our work offers a comprehensive view of mTORC1 and its role in regulating regional protein expression in normal and diseased states. PMID- 26419958 TI - Mutual positive effects between shrubs in an arid ecosystem. AB - One-way facilitation in plants has been found in many harsh environments and their role as structural forces governing species composition in plant communities is now well established. However, reciprocal positive effects benefiting two interacting species have seldom been reported and, in recent reviews, conceptually considered merely as facilitation when in fact there is room for adaptive strategies and evolutionary responses. We tested the existence of such reciprocal positive effects in an arid environment in SE Spain using spatial pattern analysis, a species removal experiment, and a natural experiment. We found that the spatial association between Maytenus senegalensis and Whitania frutescens, two shrub species of roughly similar size intimately interacting in our community, resulted in mutual benefit for both species. Benefits included improved water relations and nutritional status and protection against browsing, and did occur despite simultaneous competition for resources. Our data suggest two-way facilitation or, rather, a facultative mutualism among higher plant species, a process often overlooked which could be a main driver of plant community dynamics allowing for evolutionary processes. PMID- 26419960 TI - Subacute CNS Demyelination after Treatment with Nivolumab for Melanoma. AB - Immunotherapy with monoclonal antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1) has improved the survival of patients with metastatic melanoma. These agents carry a certain risk of adverse immune-related events. We present a patient with widely metastatic melanoma who was initially treated with ipilimumab and subsequently with nivolumab. After four infusions of nivolumab, he developed subacute multifocal central nervous system (CNS) demyelination. Nivolumab was discontinued and, despite immunosuppressive therapy, the largest lesion progressed significantly, whereas another lesion showed radiographic improvement. After further progression, the patient succumbed to his CNS lesions 4 months later. Autopsy revealed extensive demyelination, a mild multifocal T-cell-rich perivascular lymphoid infiltrate, abundant macrophages, and necrosis. There was no metastatic melanoma in the brain. CNS demyelination has not been described in association with nivolumab. We hypothesize that the combination therapy of ipilimumab and subsequent nivolumab accounted for the severity of the demyelinating process in this patient. This case, with comprehensive clinical, molecular, and neuropathologic characterization, illustrates the need for awareness of these potential CNS complications with the use of multiple checkpoint inhibitors. PMID- 26419959 TI - MicroRNA MIR21 and T Cells in Colorectal Cancer. AB - The complex interactions between colorectal neoplasia and immune cells in the tumor microenvironment remain to be elucidated. Experimental evidence suggests that microRNA MIR21 (miR-21) suppresses antitumor T-cell-mediated immunity. Thus, we hypothesized that tumor MIR21 expression might be inversely associated with T cell density in colorectal carcinoma tissue. Using 538 rectal and colon cancer cases from the Nurses' Health Study and the Health Professionals Follow-up Study, we measured tumor MIR21 expression by a quantitative reverse-transcription PCR assay. Densities of CD3(+), CD8(+), CD45RO (PTPRC)(+), and FOXP3(+) cells in tumor tissue were determined by tissue microarray immunohistochemistry and computer-assisted image analysis. Ordinal logistic regression analysis was conducted to assess the association of MIR21 expression (ordinal quartiles as a predictor variable) with T-cell density (ordinal quartiles as an outcome variable), adjusting for tumor molecular features, including microsatellite instability; CpG island methylator phenotype; KRAS, BRAF, and PIK3CA mutations; and LINE-1 methylation. We adjusted the two-sided alpha level to 0.012 for multiple hypothesis testing. Tumor MIR21 expression was inversely associated with densities of CD3(+) and CD45RO(+) cells (Ptrend < 0.0005). The multivariate odds ratio of the highest versus lowest quartile of MIR21 for a unit increase in quartile categories of CD3(+) or CD45RO(+) cells was 0.44 [95% confidence interval (CI), 0.28 to 0.68] or 0.41 (95% CI, 0.26-0.64), respectively. Our data support a possible role of tumor epigenetic deregulation by noncoding RNA in suppressing the antitumor T-cell-mediated adaptive immune response and suggest MIR21 as a potential target for immunotherapy and prevention in colorectal cancer. PMID- 26419962 TI - On the thermodynamically stable amorphous phase of polymer-derived silicon oxycarbide. AB - A model for the thermodynamic stability of amorphous silicon oxycarbide (SiCO) is presented. It builds upon the reasonably accepted model of SiCO which is conceived as a nanodomain network of graphene. The domains are expected to be filled with SiO2 molecules, while the interface with graphene is visualized to contain mixed bonds described as Si bonded to C as well as to O atoms. Normally these SiCO compositions would be expected to crystallize. Instead, calorimetric measurements have shown that the amorphous phase is thermodynamically stable. In this article we employ first-principles calculations to estimate how the interfacial energy of the graphene networks is favorably influenced by having mixed bonds attached to them. We analyze the ways in which this reduction in interfacial energy can stabilize the amorphous phase. The approach highlights how density functional theory computations can be combined with the classical analysis of phase transformations to explain the behavior of a complex material. In addition we discover a two-dimensional lattice structure, with the composition Si2C4O3 that is constructed from a single layer of graphene congruent with silicon and oxygen bonds on either side. PMID- 26419963 TI - Two-stage, acetic acid-aqueous ammonia, fractionation of empty fruit bunches for increased lignocellulosic biomass utilization. AB - Fractionation of EFB was conducted in two consecutive steps using a batch reaction system: hemicellulose hydrolysis using acetic acid (AA; 3.0-7.0 wt.%) at 170-190 degrees C for 10-20 min in the first stage, and lignin solubilization using ammonium hydroxide (5-20 wt.%) at 140-220 degrees C for 5-25 min in the second stage. The two-stage process effectively fractionated empty fruit bunches (EFB) in terms of hemicellulose hydrolysis (53.6%) and lignin removal (59.5%). After the two-stage treatment, the fractionated solid contained 65.3% glucan. Among three investigated process parameters, reaction temperature and ammonia concentration had greater impact on the delignification reaction in the second stage than reaction time. The two-stage fractionation processing improved the enzymatic digestibility to 72.9% with 15 FPU of cellulase/g of glucan supplemented with 70 pNPG of beta-glycosidase (Novozyme 188)/g-glucan, which was significantly enhanced from the equivalent digestibility of 28.3% for untreated EFB and 45.7% for AAH-fractionated solid. PMID- 26419961 TI - Efficacy of a Cancer Vaccine against ALK-Rearranged Lung Tumors. AB - Non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of the anaplastic lymphoma kinase (ALK) gene is treated with ALK tyrosine kinase inhibitors (TKI), but the treatment is successful for only a limited amount of time; most patients experience a relapse due to the development of drug resistance. Here, we show that a vaccine against ALK induced a strong and specific immune response that both prophylactically and therapeutically impaired the growth of ALK-positive lung tumors in mouse models. The ALK vaccine was efficacious also in combination with ALK TKI treatment and significantly delayed tumor relapses after TKI suspension. We found that lung tumors containing ALK rearrangements induced an immunosuppressive microenvironment, regulating the expression of PD-L1 on the surface of lung tumor cells. High PD-L1 expression reduced ALK vaccine efficacy, which could be restored by administration of anti PD-1 immunotherapy. Thus, combinations of ALK vaccine with TKIs and immune checkpoint blockade therapies might represent a powerful strategy for the treatment of ALK-driven NSCLC. PMID- 26419964 TI - Rapid and solvent-saving liquefaction of woody biomass using microwave-ultrasonic assisted technology. AB - A novel process to rapidly liquefy sawdust using reduced quantities of solvent, was successfully carried out via microwave-ultrasonic assisted technology (MUAT) in a sulphuric acid/polyethylene glycol 400-glycerol catalytic system. The influences of some key parameters on the liquefaction yield were investigated. The results showed that compared with traditional liquefaction, the introduction of MUAT allowed the solvent dosage to be halved and shortened the liquefaction time from 60 to 20 min. The liquefaction yield reached 91% under the optimal conditions. However, the influence on the yield of some parameters such as catalyst concentration, was similar to that of traditional liquefaction, indicating that the application of MUAT possibly only intensified heat and mass transfer rather than altering either the degradation mechanism or pathway. The introduction of MUAT as a process intensification technology has good industrial application potential for woody biomass liquefaction. PMID- 26419965 TI - Clinically Confirmed Stroke With Negative Diffusion-Weighted Imaging Magnetic Resonance Imaging: Longitudinal Study of Clinical Outcomes, Stroke Recurrence, and Systematic Review. AB - BACKGROUND AND PURPOSE: We sought to establish whether the presence (versus absence) of a lesion on magnetic resonance imaging (MRI) with diffusion weighting (DWI-MRI) at presentation with acute stroke is associated with worse clinical outcomes at 1 year. METHODS: We recruited consecutive patients with a nondisabling ischemic stroke and performed DWI-MRI. Patients were followed up at 1 year to establish stroke recurrence (clinical or on MRI), cognitive impairment (Addenbrooke Cognitive Assessment Revised,<88) and modified Rankin Scale. RESULTS: A median of 4 days post stroke, one third (76/264; 29%) of patients did not have a DWI lesion (95% confidence interval, 23%-35%). There was no statistically significant difference between those with and without a DWI lesion with respect to age or vascular risk factors. Patients without a lesion were more likely to be women or have previous stroke. At 1 year, 11 of 76 (14%) patients with a DWI-negative index stroke had a clinical diagnosis of recurrent stroke or transient ischemic attack, 33% had cognitive impairment (Addenbrooke Cognitive Assessment Revised<88), and 40% still had modified Rankin Scale>1, no different from DWI-positive patients; DWI-positive patients were more likely to have a new lesion on MRI (14%), symptomatic or asymptomatic, than DWI-negative patients (2%; P=0.02). Our data were consistent with 6 other studies (total n=976), pooled proportion of DWI-negative patients was 21% (95% confidence interval, 12%-32%). CONCLUSIONS: Nearly one third of patients with nondisabling stroke do not have a relevant lesion on acute DWI-MRI. Patients with negative DWI-MRI had no better prognosis than patients with a lesion. DWI-negative stroke patients should receive secondary prevention. PMID- 26419966 TI - Reflux of Anterior Spinal Artery Predicts Recurrent Posterior Circulation Stroke in Bilateral Vertebral Artery Disease. AB - BACKGROUNDS AND PURPOSE: Predictive value of reflux of anterior spinal artery for recurrent posterior circulation ischemia in bilateral vertebral arteries steno occlusive disease was evaluated. METHODS: We retrospectively reviewed 55 patients with symptomatic posterior circulation stroke caused by bilateral stenotic (>70%) lesions of the vertebral artery. We investigated any correlation of clinical and angiographic characteristics including collateral flow patterns, with recurrent stroke. Risk factors for poor 3-month functional outcome were also evaluated. RESULTS: Recurrent posterior circulation stroke was observed in 15 (27.3%) patients. Multivariable analysis using Cox proportional hazards model showed anterior spinal artery reflux as a significant risk factor for stroke recurrence (adjusted hazard ratio, 19.3 [95% confidence interval, 5.35-69.9]; P<0.001). Anterior spinal artery reflux was also correlated with poor functional outcome (modified Rankin Scale score, 3-6; adjusted odds ratio, 7.41 [95% confidence interval, 1.24-44.4]; P=0.028). CONCLUSIONS: In patients with symptomatic bilateral vertebral artery occlusive disease, anterior spinal artery reflux predicted recurrent posterior circulation stroke and poor functional outcome. PMID- 26419967 TI - Location, Infarct Load, and 3-Month Outcomes of Delayed Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage is a serious disease with high case fatality and morbidity. Delayed cerebral infarction (DCI) is an important surrogate marker. How location and infarct load affected outcomes was unclear. We aimed to assess the effects of load and location of DCI on outcomes of aneurysmal subarachnoid hemorrhage at 3 months. METHODS: We prospectively enrolled patients with subarachnoid hemorrhage presenting to an academic neurosurgical unit in Hong Kong during a 3-year period. DCI was defined by new hypoattenuation on computed tomography at 4 to 6 weeks, which was not present in the postaneurysm-treatment computed tomography at 24 to 48 hours. DCI was assessed for location according to cerebral artery territories and load semiquantitatively. Cognitive and functional outcome assessments were carried out 3 months after ictus. RESULTS: One hundred twenty-six patients with subarachnoid hemorrhage consented for this study. DCI occurred in 56 (44%) patients and was associated with poorer cognitive and functional outcomes (Montreal Cognitive Assessment, Mini-Mental State Examination, modified Rankin Scale, and Lawton Instrumental Activity of Daily Living) at 3 months. In patients with DCI, the presence of perforator zone infarct was associated with poorer cognitive and functional outcomes, and cortical middle cerebral artery infarct was associated with poorer modified Rankin Scale. After adjustment for age, admission World Federation of Neurosurgical Societies Grade and mode of aneurysm treatment, both middle cerebral artery cortical infarct load and perforator infarct load were independently associated with poor cognitive outcomes (Montreal Cognitive Assessment and Mini-Mental State Examination) and modified Rankin Scale. CONCLUSIONS: Middle cerebral artery cortical and perforator zone infarct loads are potential surrogate marker to assess the severity of delayed cerebral ischemia. PMID- 26419968 TI - Differences Between US and UK Adults in Stroke Preparedness: Evidence From Parallel Population-Based Community Surveys. AB - BACKGROUND AND PURPOSE: Although time-dependent treatment is available, most people delay contacting emergency medical services for stroke. Given differences in the healthcare system and public health campaigns, exploring between-country differences in stroke preparedness may identify novel ways to increase acute stroke treatment. METHODS: A survey was mailed to population-based samples in Ingham County, Michigan, US (n=2500), and Newcastle upon Tyne, UK (n=2500). Surveys included stroke perceptions and stroke/nonstroke scenarios to assess recognition and response to stroke. Between-country differences and associations with stroke preparedness were examined using t tests and linear mixed models. RESULTS: Overall response rate was 27.4%. The mean age of participants was 55 years, and 58% were female. US participants were better in recognizing stroke (70% versus 63%, d=0.27) and were more likely to call emergency medical services (55% versus 52%, d=0.11). After controlling for demographics and comorbidities, US participants remained more likely to recognize stroke but were not more likely to respond appropriately. A greater belief that medical treatment can help with stroke and understanding of stroke was associated with improved stroke recognition and response. CONCLUSIONS: Overall, stroke recognition and response were moderate. US participants were modestly better at recognizing stroke, although there was little difference in response to stroke. Future stroke awareness interventions could focus more on stroke outcome expectations and developing a greater understanding of stroke among the public. PMID- 26419969 TI - Poor Collateral Circulation Assessed by Multiphase Computed Tomographic Angiography Predicts Malignant Middle Cerebral Artery Evolution After Reperfusion Therapies. AB - BACKGROUND AND PURPOSE: Collateral circulation (CC) has been associated with recanalization, infarct volume, and clinical outcome in patients undergoing acute reperfusion therapies. However, its relationship with the development to malignant middle cerebral artery infarction (mMCAi) has not been evaluated. Our aim was to determine the impact of CC using multiphase computed tomographic angiography (during the acute stroke phase in the prediction of mMCAi. METHODS: Patients with consecutive acute stroke with <4.5 hours who were evaluated for reperfusion therapies and presented with an M1-MCA or terminal internal carotid artery occlusion by CTA were included. CC was evaluated on 6 grades by multiphase CTA according to the University of Calgary CC Scale; CC status was defined as poor (grades, 0-3) or good (grades, 4-5). The mMCAi was defined according to clinical and radiological criteria. Recanalization was assessed with transcranial Doppler at 24 hours and final Thrombolysis in Brain Ischemia score>=2b in patients undergoing endovascular reperfusion treatment. RESULTS: Eighty-two patients were included. Mean age was 65.1+/-13.83 years, median baseline National Institutes of Health Stroke Scale score was 18 (interquartile range, 13-20), and 67.9% M1 and 32.1% terminal internal carotid artery occlusions. Fifty-three patients received endovascular reperfusion treatment. Fifteen patients developed mMCAi. In the univariate analysis, patients with mMCAi had lower CC scores (2.29 versus 3.71; P=0.001). Endovascular reperfusion treatment was associated with lower rate of mMCAi development than only intravenous reperfusion treatment (9.4% versus 29.6%; P=0.028). Patients with poor CC had higher risk of developing mMCAi (13% versus 2%; P=0.001). On the multivariate analysis adjusted by age, vessel occlusion, baseline National Institutes of Health Stroke Scale, and recanalization, the presence of poor CC by multiphase CTA was the only independent predictor of mMCAi (P=0.048; odds ratio, 9.72; 95% confidence interval, 1.387-92.53). CONCLUSIONS: CC assessment by multiphase CTA independently predicts malignant MCA infarction progression. In patients with persistent occlusion after reperfusion therapies, the presence of poor CC may improve the early mMCAi detection and management. PMID- 26419970 TI - The pathway for serial proton supply to the active site of nitrogenase: enhanced density functional modeling of the Grotthuss mechanism. AB - Nitrogenase contains a well defined and conserved chain of water molecules leading to the FeMo cofactor (FeMo-co, an [Fe7MoCS9] cluster with bidentate chelation of Mo by homocitrate) that is the active site where N2 and other substrates are sequentially hydrogenated using multiple protons and electrons. The function of this chain is proposed to be a proton wire, serially translocating protons to triply-bridging S3B of FeMo-co, where, concomitant with electron transfer to FeMo-co, an H atom is generated on S3B. Density functional simulations of this proton translocation mechanism are reported here, using a large 269-atom model that includes all residues hydrogen bonded to and surrounding the water chain, and likely to influence proton transfer: three carboxylate O atoms of obligatory homocitrate are essential. The mechanism involves the standard two components of the Grotthuss mechanism, namely H atom slides that shift H3O(+) from one water site to the next, and HOH molecular rotations that convert backward (posterior) OH bonds in the water chain to forward (anterior) OH bonds. The topography of the potential energy surface for each of these steps has been mapped. H atom slides pass through very short (ca. 2.5 A) O-H-O hydrogen bonds, while HOH rotations involve the breaking of O-HO hydrogen bonds, and the occurrence of long (up to 3.6 A) separations between contiguous water molecules. Both steps involve low potential energy barriers, <7 kcal mol(-1). During operation of the Grotthuss mechanism in nitrogenase there are substantial displacements of water molecules along the chain, occurring as ripples. These characteristics of the 'Grotthuss two-step', coupled with a buffering ability of two carboxylate O atoms of homocitrate, and combined with density functional characterisation of the final proton slide from the ultimate water molecule to S3B (including electron addition), have been choreographed into a complete mechanism for serial hydrogenation of FeMo-co. The largest potential barrier is estimated to be 14 kcal mol(-1). These results are discussed in the context of reactivity data for nitrogenase, and the occurrence of a comparable water chain in cytochrome-c oxidase. Further investigation of the low-frequency conformational dynamics of the nitrogenase proteins, coupling proton transfer with other events in the nitrogenase cycle, is briefly canvassed. PMID- 26419971 TI - Pharmacovigilance Considerations for Biosimilars in the USA. AB - In 2015, five or more biosimilars may be approved in the USA. Because no two biologic medicines are identical, postapproval safety monitoring will be critical to detect potential differences in safety signals between a biosimilar, its reference product, and other biosimilars. Postapproval safety monitoring in the USA uses two signal detection systems: spontaneous reporting systems (SRSs) and active surveillance (AS) systems. Both depend on accurate identification of the specific product(s) dispensed or administered to patients, which may be compromised when products from multiple manufacturers share common drug nomenclature or coding. Product identification can present challenges across different healthcare settings, including inpatient and ambulatory care. Common oral-dosage drugs are predominantly dispensed directly to patients by pharmacists, whereas most injectable drugs, including biologics, are administered to patients by healthcare professionals in outpatient clinics or hospitals. Thus, the effectiveness of SRS and AS mechanisms in both pharmacy and medical channels must be given greater consideration as biotechnology matures. In this article, we describe these systems and their limitations. We identify challenges and opportunities for product-specific safety surveillance of biologics in both the pharmacy and medical settings and provide recommendations to improve biologic safety surveillance under the current and future systems envisioned in the Drug Quality and Security Act. As biosimilars are integrated into existing pharmacovigilance systems, distinguishable nonproprietary names and codes for all biologics, as well as other opportunities to improve traceability (e.g., increased use of barcodes), must be considered to ensure patient safety and confidence in this new class of drugs. PMID- 26419973 TI - First-principles study of terpyrrole as a potential hydrogen cyanide sensor: DFT calculations. AB - The sensitivity of terpyrrole (TPy; used as a polypyrrole model) to toxic hydrogen cyanide (HCN) adsorption was studied by using DFT to perform geometry optimization and to calculate the adsorption energy of HCN on TPy as well as orbital properties. The interaction of terpyrrole with HCN was studied for different relative orientations of the molecules. The adsorption energy, charge analysis, and the density of states were used to evaluate the ability of TPy to sense HCN in these different relative orientations. The adsorption energy was calculated to be -3.9 and -3.1 kcal mol(-1) for two possible relative orientations. Frontier molecular orbitals and energies indicated that some hybridization occurs during the adsorption of HCN on TPy when the molecules have appropriate relative orientations, resulting in an increase in conductivity. Considering the changes in the HOMO-LUMO energy gap that were calculated to occur during HCN adsorption, it is clear that TPy is sensitive to HCN adsorption, suggesting that TPy has the potential to act as an HCN sensor. Graphical abstract HCN adsorption on TPy. PMID- 26419972 TI - Molecular docking and molecular dynamics studies reveal structural basis of inhibition and selectivity of inhibitors EGCG and OSU-03012 toward glucose regulated protein-78 (GRP78) overexpressed in glioblastoma. AB - Glioblastoma (GBM), a malignant form of brain tumor, has a high mortality rate. GRP78, one of the HSP70 protein family members, is overexpressed in GBM. GRP78 is the key chaperone protein involved in the unfolded protein response. Upregulated GRP78 expression in cancer cells inhibits apoptosis and promotes chemoresistance. GRP78 has an ATPase domain, a substrate-binding domain, and a linker region. ATP competitive inhibitors such as EGCG and OSU-03012 inhibit GRP78 activity and reduce its expression in GBM. However, there is a lack of structural data on the binding modes of these inhibitors to GRP78 ATPase domain. Further, the mode of selectivity of these inhibitors toward GRP78 also is unknown. Toward this end, molecular docking was performed with AutoDock Vina and confirmation obtained by docking using ROSIE. The stability and MM-PBSA binding energy of GRP78-inhibitor complexes as well as energetic contribution of individual residues was analyzed by 50 ns molecular dynamics run with GROMACS. MSA by ClustalW2 identified unique amino acid residues in the ATPase domain of GRP78 which were different from the residues present in other HSP70 proteins. Important and unique amino acid residues of GRP78 such as Ile61, Glu293, Arg297, and Arg367 played a major role in the intermolecular interactions with these inhibitors. The interactions with unique residues of GRP78 as compared with those of HSP70-1A provided the basis for selectivity. It was found that the binding affinity and specificity/selectivity of EGCG toward GRP78 was higher than that toward HSP70 1A, and selectivity was even better than OSU-03012. OSU-03012 was predicted to bind to GRP78. Analyses from MD runs showed tight binding and stability of complexes, and the highest number of hydrogen bonds during the trajectory runs were comparable to those found in the docking studies. Energetic contribution of individual inhibitor-interacting residues showed that energy values of Ile61 and Glu293 were among the most negative. These studies are, to the best of our knowledge, the first studies characterizing EGCG and OSU-03012 interactions with GRP78 on a structural basis and provide a significant insight into their binding modes, selectivity, and structural stability. PMID- 26419974 TI - Accurate Gaussian basis sets for atomic and molecular calculations obtained from the generator coordinate method with polynomial discretization. AB - Accurate Gaussian basis sets for atoms from H to Ba were obtained by means of the generator coordinate Hartree-Fock (GCHF) method based on a polynomial expansion to discretize the Griffin-Wheeler-Hartree-Fock equations (GWHF). The discretization of the GWHF equations in this procedure is based on a mesh of points not equally distributed in contrast with the original GCHF method. The results of atomic Hartree-Fock energies demonstrate the capability of these polynomial expansions in designing compact and accurate basis sets to be used in molecular calculations and the maximum error found when compared to numerical values is only 0.788 mHartree for indium. Some test calculations with the B3LYP exchange-correlation functional for N2, F2, CO, NO, HF, and HCN show that total energies within 1.0 to 2.4 mHartree compared to the cc-pV5Z basis sets are attained with our contracted bases with a much smaller number of polarization functions (2p1d and 2d1f for hydrogen and heavier atoms, respectively). Other molecular calculations performed here are also in very good accordance with experimental and cc-pV5Z results. The most important point to be mentioned here is that our generator coordinate basis sets required only a tiny fraction of the computational time when compared to B3LYP/cc-pV5Z calculations. PMID- 26419975 TI - Effect of oocyte dysmorphisms on intracytoplasmic sperm injection cycle outcomes in normal ovarian responders. AB - AIM: The aim of this study was to identify the influence of oocyte dysmorphisms on clinical outcomes after intracytoplasmic sperm injection cycle in normal responders. MATERIAL AND METHODS: In the prospective study, morphology of 1999 metaphase II oocytes retrieved from 316 intracytoplasmic sperm injection cycles was evaluated from March 2011 to March 2013 at Royan Institute. Controlled ovarian stimulation was performed by long standard agonist protocol. Oocyte morphology was assessed before sperm injection by one embryologist. The associations between fertilization rate, embryo quality and the independent variables were analyzed using odds ratio (OR) calculated with unconditional logistic regression test. RESULTS: From all retrieved oocytes, 1543 (77.1%) showed at least one morphologic aberration. Presence of cytoplasmic vacuoles and high cytoplasmic viscosity were associated with a significant decrease in the fertilization rate (OR: 0.5; P = 0.004 and OR: 0.6; P = 0.03, respectively). The results showed that oocyte morphology did not affect embryo quality. The number of gonadotrophin injections used showed a direct relation with presence of large perivitelline space. No significant difference was observed among four groups (women with total normal morphologic oocytes [group 1], women with total extracytoplasmic dysmorphic oocytes [group 2], women with total cytoplasmic dysmorphic oocytes [group 3] and women with total oocytes containing multiple dysmorphic features [group 4]) in terms of implantation and clinical pregnancy rates. CONCLUSIONS: Metaphase II oocyte morphology had minor impacts on fertilization rate, pronuclear morphology and embryo quality in women with normal ovarian response. PMID- 26419977 TI - Differential Development of Inflammation and Insulin Resistance in Different Adipose Tissue Depots Along Aging in Wistar Rats: Effects of Caloric Restriction. AB - The prevalence of insulin resistance and type 2 diabetes increases with aging and these disorders are associated with inflammation. Insulin resistance and inflammation do not develop at the same time in all tissues. Adipose tissue is one of the tissues where inflammation and insulin resistance are established earlier during aging. Nevertheless, the existence of different fat depots states the possibility of differential roles for these depots in the development of age associated inflammation and insulin resistance. To explore this, we analyzed insulin signaling and inflammation in epididymal, perirenal, subcutaneous, and brown adipose tissues during aging in Wistar rats. Although all tissues showed signs of inflammation and insulin resistance with aging, epididymal fat was the first to develop signs of inflammation and insulin resistance along aging among white fat tissues. Subcutaneous adipose tissue presented the lowest degree of inflammation and insulin resistance that developed latter with age. Brown adipose tissue also presented latter insulin resistance and inflammation but with lower signs of macrophage infiltration. Caloric restriction ameliorated insulin resistance and inflammation in all tissues, being more effective in subcutaneous and brown adipose tissues. These data demonstrate differential susceptibility of the different adipose depots to the development of age-associated insulin resistance and inflammation. PMID- 26419976 TI - Preparing for an Aging World: Engaging Biogerontologists, Geriatricians, and the Society. AB - Although the demographic revolution has produced hundreds of millions people aged 65 and older, a substantial segment of that population is not enjoying the benefits of extended healthspan. Many live with multiple chronic conditions and disabilities that erode the quality of life. The consequences are also costly for society. In the United States, the most costly 5% of Medicare beneficiaries account for approximately 50% of Medicare's expenditures. This perspective summarizes a recent workshop on biomedical approaches to best extend healthspan as way to reduce age-related dysfunction and disability. We further specify the action items necessary to unite health professionals, scientists, and the society to partner around the exciting and palpable opportunities to extend healthspan. PMID- 26419978 TI - Global Multimorbidity Patterns: A Cross-Sectional, Population-Based, Multi Country Study. AB - BACKGROUND: Population ageing challenges health care systems due to the high prevalence and impact of multimorbidity in older adults. However, little is known about how chronic conditions present in certain multimorbidity patterns, which could have great impact on public health at several levels. The aim of our study was to identify and describe multimorbidity patterns in low-, middle-, and high income countries. METHODS: We analyzed data from the Collaborative Research on Ageing in Europe project (Finland, Poland, and Spain) and the World Health Organization's Study on Global Ageing and Adult Health (China, Ghana, India, Mexico, Russia, and South Africa). These cross-sectional studies obtained data from 41,909 noninstitutionalized adults older than 50 years. Exploratory factor analysis was performed to detect multimorbidity patterns. Additional adjusted binary logistic regressions were performed to identify associations between sociodemographic factors and multimorbidity. RESULTS: Overall multimorbidity prevalence was high across countries. Hypertension, cataract, and arthritis were the most prevalent comorbid conditions. Two or three multimorbidity patterns were found per country. Several patterns were identified across several countries: "cardio-respiratory" (angina, asthma, and chronic obstructive pulmonary disease), "metabolic" (diabetes, obesity, and hypertension), and "mental-articular" (arthritis and depression). CONCLUSIONS: A high prevalence of multimorbidity occurs in older adults across countries, with low- and middle-income countries gradually approaching the figures of richer countries. Certain multimorbidity patterns are present in several countries, which suggest that common underlying etiopathogenic factors may play a role. Deeper understanding of these patterns may lead to the development of preventive actions to diminish their prevalence and also give rise to new, comprehensive approaches for the management of these co-occurring conditions. PMID- 26419980 TI - [Improving the reperfusion therapy for patients with ST-segment elevation myocardial infarction according to the new guideline]. PMID- 26419981 TI - [Guideline on the diagnosis and therapy of ST-segment elevation myocardial infarction]. PMID- 26419982 TI - [Chinese expert consensus on clinical application of selective cholesterol absorption inhibitor (2015)]. PMID- 26419979 TI - Brain Amyloid Deposition Is Associated With Lower Instrumental Activities of Daily Living Abilities in Older Adults. Results From the MAPT Study. AB - BACKGROUND: Brain amyloid deposition is one of the key pathological hallmarks underlying the cognitive changes associated with Alzheimer's disease. Growing interest has been given to the earliest clinical manifestations of amyloid plaques. However, the relationship between amyloid status and activities of everyday function remains largely unknown. In the present study, we examined the relationship between instrumental activities of daily living performance (using the ADL-PI score) and amyloid status in older adults. METHODS: Cross-sectional analyses of data from the Multidomain Alzheimer Preventive Trial (MAPT) were performed. Volunteers underwent a brain 18F-AV45 positron emission tomography examination. Bivariate analysis and regression models were conducted to study the relationships between brain amyloid deposition and the total ADL-PI score. RESULTS: We included 271 participants (women = 60%; age = 76+/-4 years). Amyloid positron emission tomography was positive (standard uptake value >=1.17) for 103 participants (38%). The ADL-PI score was lower in amyloid positive participants than in their amyloid negative counterparts (38.8 vs 40.3, p = .007). This association was also confirmed in regression models adjusted for age, gender, and familial history of Alzheimer's disease (odds ratio = 0.94; 95% confidence interval 0.89-0.99; p = .02). This finding was consistent in cognitively normal individuals and in those with mild cognitive impairment, using the clinical dementia rating scale. CONCLUSIONS: This study highlighted an association between early functional limitations and brain amyloid deposition in elderly subjects. These symptoms could be the clinical manifestations of amyloid plaques even in the absence of overt dementia. Further prospective studies are warranted for examining the evolution of ADL-PI score over the course of Alzheimer's disease. PMID- 26419983 TI - [Long-term outcomes of patients with unprotected left main coronary artery disease post revascularization]. AB - OBJECTIVE: To compare the long-term real-world outcomes of consecutive patients with unprotected left main coronary artery disease (ULMCA) underwent percutaneous coronary intervention (PCI) with drug-eluting stents (DES) and coronary artery bypass grafting (CABG). METHODS: Consecutive patients with ULMCA (defined as stenosis >= 50%) undergoing DES implantation or CABG between January 2003 to July 2009 in Beijing Anzhen Hospital were enrolled. The follow-up period extended through August 2013. The end points of the study were death, cardiac death, repeat revascularization, myocardial infarction (MI), stroke, the composite of cardiac death, MI or stroke and MACCE (major adverse cardiac and cerebrovascular events, the composite of cardiac death, MI, stroke or repeat revascularization). RESULTS: From January 2003 to July 2009, 922 ULMCA patients were enrolled in this study (465 PCI patients, and 457 CABG patients). The median follow-up was 7.1 years (interquartile range 5.3 to 8.2 years). The crude relative risk was as follows: overall death rate (13.0% (41/465) vs. 22.1% (72/457), P = 0.009), stroke rate (5.8% (11/465) vs. CABG 18.9% (46/457), P < 0.001) were significantly lower whereas the rate of repeat revascularization (32.3% (110/465) vs. CABG 19.2% (58/457), P < 0.001) was significantly higher in PCI group than in CABG group. MI rate was similar between PCI and CABG group (13.9% (33/465) vs. 6.7% (26/457), P = 0.196). MACCE rate was also similar between the 2 groups (42.9% (145/465) vs. 42.5% (142/457), P = 0.122). After multivariate adjusting, there was no significant difference in rates of death, MI and a composite of serious outcomes (cardiac death, MI, or stroke) between the 2 groups. Rates of MACCE were significantly higher in the PCI group (P = 0.009) due to increased rate of repeat revascularization (P < 0.001). However, stroke rate was still significantly higher in CABG group (P = 0.001) after multivariate adjusting. CONCLUSION: During a follow-up up to 8.2 years, the survival rate is similar between the PCI and the CABG group in patients with ULMCA disease. The rate of repeat revascularization is significantly higher and stroke rate is significantly lower in the PCI group compared to CABG group. PMID- 26419984 TI - [Total cholesterol mediates the effect of ABO blood group on coronary heart disease]. AB - OBJECTIVE: To find a potential link among ABO blood group, lipid profiles and coronary artery disease (CAD) and to estimate the effect size of connection using mediation analysis model. METHODS: A total of 898 consecutive patients undergoing coronary angiography were enrolled, and divided into CAD group and non-CAD group according to angiographic findings. According to ABO blood group, patients were divided into O blood group and non-O blood group, as well as A blood group and non-A blood group. Baseline characteristics among various groups were compared and the association of ABO blood group, CAD and lipid profile was explored. RESULTS: Subjects of blood type A had higher concentration of total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) compared with that of non-A type (TC: (4.43 +/- 1.12) mmol/L vs. (4.18 +/- 1.09) mmol/L, LDL-C: (2.79 +/- 0.99) mmo/L vs. (2.59 +/- 1.01) mmol/L, all P < 0.01). TC and LDL-C were significantly higher while high density lipoprotein cholesterol (HDL-C) and ApoA I levels were significantly lower in CAD group than in non-CAD group (TC: (4.36 +/- 1.05) mmol/L vs. (4.13 +/- 1.16) mmol/L, LDL-C: (2.61 +/- 0.87) mmol/L vs. (2.47 +/- 0.94) mmol/L; ApoA I: (1.38 +/- 0.29) mmol/L vs. (1.45 +/- 0.33) mmol/L; all P < 0.01). After adjustment for traditional cardiovascular risk factors, blood group A and TC remained significantly associated with the risk of CAD (OR = 1.88, 95% CI 1.280-2.774, P < 0.01; OR = 1.03, 95% CI 1.018-1.033, P < 0.01, respectively). Specially, mediation analysis indicated that 10.5% of the effect of A blood group on CAD was mediated by TC levels (P < 0.01). CONCLUSION: Our data indicate that there is an association between ABO blood group, TC levels and risk of CAD. Around 10.5% of the effect of A blood group on CAD is mediated by TC levels. PMID- 26419985 TI - [Activated clotting time post therapeutic anticoagulation with unfractionated heparin in patients undergoing elective percutaneous coronary intervention]. AB - OBJECTIVE: To investigate the activated clotting time (ACT) level after administration of guideline-recommended dose of unfractionated heparin (UFH) and to confirm the importance of ACT monitoring in percutaneous coronary intervention (PCI). METHODS: We performed a retrospective study on 1 062 patients undergoing elective PCI in Peking Union Medical College Hospital from May 1, 2011 to December 31, 2012. All patients were administrated weight-adjusted UFH (70-100 U/kg) based on PCI guideline of ACCF/AHA/SCAI. Patients were divided into 3 groups: ACT < 300 s (598 cases), ACT 300-350 s (183 cases) and ACT > 350 s (281 cases). ACT level and factors that may affect UFH anticoagulation were analyzed. RESULTS: (1) The mean age was (63.0 +/- 10.6) years and 751 (70.7%) patients were men. The mean weight was (70.5 +/- 11.7) kg, and the mean UFH dose used was (100.7 +/- 9.1) U/kg. (2) The median ACT was 285 (240-352) s after the UFH use. Pre-defined ACT target (300-350 s) was achieved only in 17.2% (183/1 062) patients. (3) Age, gender, height, weight, UFH/weight and the risk factors of coronary heart disease were similar among 3 groups (all P > 0.05). Multifactor linear correlation analysis showed that UFH/weight was related to ACT level (r = 0.07, P < 0.01), but other factors were not related to ACT level (all P > 0.05). (4) Among 598 patients with ACT < 300 s, 444 (74.2%) patients received additional UFH. No major bleeding events were observed in 1 062 patients. The incidence of minor bleeding and ischemic complications within 48 h after procedure were similar among 4 groups of ACT < 300 s with additional UFH, ACT < 300 s without additional UFH, ACT 300-350 s and ACT > 350 s (all P > 0.05). CONCLUSIONS: In this single-center study, only a small proportion of patients reached the ACT target after administration of weight-adjusted UFH. Our results supported the recommendation of ACT monitoring in current PCI guideline to improve efficacy and safety of UFH anticoagulation therapy. PMID- 26419986 TI - [Value of fractional flow reserve measurement in intracavitary therapy for patients with moderate renal artery stenosis]. AB - OBJECTIVE: To analyze the value of fractional flow reserve (FFR) measurement on endovascular therapy for patients with renal artery stenosis. METHODS: Clinical data of 9 patients underwent endovascular therapy due to moderate renal artery stenosis (50%-69%) in Anzhen hospital from May to September 2013 were retrospectively analyzed. Fractional flow reserve (FFR) were measured in patients with moderate stenosis in renal artery and abnormal glomerular filtration rate (GFR) or different between renal artery angiography and ultrasound before the procedure. Endovascular therapy was not applied for patients with FFR > 0.90, and the patients were subsequently followed up clinically. Endovascular therapy was applied in patients with FFR less than 0.90 or the pressure difference between the two ends of stenosis was more than 20 mmHg (1 mmHg = 0.133 kPa). Blood pressure, ultrasound and contrast-enhanced ultrasonography data were obtained at 1 and 3 months later, respectively. RESULTS: There were 6 patients diagnosed as severe renal artery stenosis (>= 70%) and the other 3 patients diagnosed as moderate renal artery stenosis by renal artery ultrasound before operation. Two patients with FFR > 0.90 were not undertaken the endovascular therapy. Seven patients with FFR < 0.90 underwent endovascular therapy. After renal artery stenting, renal stenosis was relieved immediately and the transstent blood flow was fluency in these 7 patients. There was significant difference in the FFR before and after operation (0.81 +/- 0.09 vs.0.94 +/- 0.03, P = 0.008). Among the patients underwent endovascular therapy, blood pressure was normal without medication in 2 patients and well controlled with 1 or 2 combined antihypertensive drugs in the rest 5 patients. CONCLUSION: In patients with moderate renal artery stenosis, fractional flow reserve measurement could be used as a useful index to guide intervention procedure and to evaluate the efficacy of endovascular therapy. PMID- 26419987 TI - [Association between clinical features and histopathological findings in patients with left ventricular non-compaction cardiomyopathy]. AB - OBJECTIVE: To investigate the association between clinical and histopathological features in patients with left ventricular non-compaction cardiomyopathy (LVNC). METHODS: Histopathological examinations were made on 11 LVNC recipient hearts from June 2004 to June 2014 in Fuwai Hospital, myocardial ultrastructure changes were detected using transmission electron microscopy. Association between clinical and pathological features were analyzed. RESULTS: Patients were (24 +/- 11) years old. There were 6 patients with mucus matrix LVNC, 3 patients with fibrous fatty infiltration, and 2 patients with cardiomyocytes proliferation. The gross morphological changes of LVNC hearts were characterized by numerous and prominent trabeculations with deep intratrabecular recesses in left ventricular myocardium. Ratios of the thicker noncompacted endocardial layer (N) and thin epicardial compacted layer (C) (N/C ratio) were >= 2.0, and the most serious lesions were located in the left ventricular apex, and followed by the left ventricular free wall. Histological microscopic examinations evidenced numerous matrix-like material and immature cardiomyocytes on endocardial tissue. Transmission electron microscopy revealed mitochondrial abnormalities on morphology, number, and distribution, underdeveloped cardiomyocytes and anomalies of intercalated disc structure, increased deposition of extracellular matrix-like substance and perinuclear glycogen. Pathological changes on cytoplasmic matrix and intercalated disc were present in all three tissue types of LVNC in this cohort and mitochondria hyperplasia was detected in patients with fibrous fatty infiltration. Heart weight >= 350 g is often associated with increased number of mitochondria. Increased cytoplasmic matrix was often detected in patients with LVEF >= 30% while intercalated disc anomalies were often detected in patients with LVEF < 30%. CONCLUSION: Histological changes were closely related clinical features in patients with LVNC. PMID- 26419988 TI - [Chronic transvenous pacemaker/implantable cardioverter defibrillator leads implantation induced pathological changes]. AB - OBJECTIVE: Widely pacemaker/implantable cardioverter defibrillator (ICD) implantation is also related to an increasing need for transvenous lead extraction. Understanding the location and extent of pathological changes, including adhesions and fibrous tissue formation along the course of chronic pacemaker/ICD leads, are essential for operators performing lead extraction operations in order to reduce the potential life threatening complications. METHODS: Three parts are included in the research, pathological examination on 83 extracted pacemaker/ICD leads using excimer laser technique from March 2008 to March 2011, autopsy examination of one died patient during lead extraction for lead-related infective endocarditis, and anatomical analysis on pacemaker/ICD leads from 10 patients died of other non-cardiac causes. RESULTS: Extensive encapsulated fibrous tissue around the leads and extensive adhesion/fibrosis along the course of the leads from venous entry site to the lead/myocardial interface could be detected on transvenous pacemaker/ICD leads. Since the tissue at the junction between superior vena cava (SVC) and right atrium (RA) is very thin, free of pericardium, thus, this is a common place for extensive adhesion/fibrosis and myocardial perforation/tear during lead extraction, which accounted for one death during extraction in our cohort. Extensive adhesion and fibrosis were also observed at the tricuspid valve and subvalvular structures. Leads implanted to the right ventricular apex were close to the epicardial surface and prone to perforation through myocardium. It is common to observe thrombus on the leads or at the interface between leads and myocardial tissue, especially at right atrial appendage (RAA) at the site of lead insertion. CONCLUSION: Extensive adhesions and fibrosis can be commonly seen along the course of pacemaker/ICD leads, and at SVC to RA junction, the tricuspid valve/subvalvular structures, and RA/RV lead interface. The tissue at SVC to RA junction is very thin, making it vulnerable for myocardial perforation/tear during lead extraction. Thrombus is commonly seen along the leads or at the lead tissue interface. PMID- 26419989 TI - [Value of patient health questionnaires (PHQ)-9 and PHQ-2 for screening depression disorders in cardiovascular outpatients]. AB - OBJECTIVE: To analyze the value of 2- and 9-question patient health questionnaires (PHQ-2 and PHQ-9) for screening status of depression in cardiovascular outpatients. METHODS: From June 2013 to January 2014, a total of 201 outpatients from psycho-cardiological outpatients departments were consecutively enrolled into this study. All patients were asked to complete PHQ-9 and the mental psychological assessment by qualified researchers trained by psychiatry according to the composite international diagnostic interviews (CIDI), 50 cases were retested to assess the retest reliability after one week. The PHQ-2 and PHQ-9 were validated with the CIDI as the reference criteria. RESULTS: According to the CIDI, 42 (21.3%) out of the 201 outpatients were diagnosed as depression. For PHQ-9 scale, a cutoff value of 10 presented satisfactory results with 87.1% sensitivity, 83.5% specificity, 58.7% positive predicting value, 95.6% negative predicting value and the area under the ROC curve (AUC) was 0.877 (SE = 0.032, 95% CI: 0.813-0.938). The Cronbach's alpha coefficients and test-retest reliability of the PHQ-9 were 0.809 and 0.882, respectively. Compared with CIDI, the cutoff value of the PHQ-2 was 3 with 85.7% sensitivity, 69.2% specificity, 57.1% positive predicting value, 93.6% negative predicting value, and the AUC was 0.806 (SE = 0.042, 95% CI: 0.774-0.889). The Cronbach's alpha coefficients and test-retest reliability of the PHQ-2 were 0.785 and 0.813, respectively. CONCLUSION: The PHQ-2 and PHQ-9 are reliable and efficient instruments for screening and especially excluding depression in cardiovascular outpatients. PMID- 26419990 TI - [Ad-hVEGF165 reverses homocysteine-induced endothelial dysfunction by regulating nitric oxide system]. AB - OBJECTIVE: To investigate the therapeutic effect of Ad-hVEGF165 on the endothelial cells dysfunction induced by homocysteine (Hcy) and related molecular mechanisms. METHODS: Human umbilical vein endothelial cells CRL-1730 were treated with Hcy at different concentrations (0, 0.05, 1.00 mmol/L) for 24 h. The same concentration of Hcy, Ad-Track and Ad-hVEGF165 were added to the cells in the following groups: blank group, Hcy0.05 group, Hcy1.00 group, Ad-Track group, Hcy0.05+Ad-Track group, Hcy1.00+Ad-Track group, Ad-hVEGF165 group, Hcy0.05+Ad hVEGF165 group, Hcy1.00+ Ad-hVEGF165 group for 48 h. The mRNA and protein expressions of eNOS and DDAH2 were detected by real-time PCR and Western blot. The correlations of mRNA and protein expressions between endothelial nitric oxide synthase (eNOS) and dimethylarginine dimthylaminohydrolase (DDAH)2 were evaluated by Pearson correlation analysis. RESULTS: Compared with blank group and Ad hVEGF165 group, the mRNA and protein expressions of eNOS were decreased in Hcy0.05 group and Hcy0.05+Ad-hVEGF165 group (both P < 0.05), and the mRNA and protein expressions of DDAH2 in cells treated with 0.05 mmol/L and 1.00 mmol/L Hcy were reduced as well (all P < 0.05). DDAH2 mRNA and protein expression are increased (all P < 0.05) in Ad-hVEGF165 group compared with the blank group and Ad-Track, Hcy0.05 + Ad-hVEGF165 and Hcy0.05 group compared with Hcy0.05+Ad-Track group, Hcy1.00+Ad-hVEGF165 and Hcy1.00 group compared with Hcy1.00+Ad-Track group. The mRNA and protein expressions of eNOS and DDAH2 were uncorrelated under the effect of Hcy (r = 0.057 and 0.449, both P > 0.05) and VEGF (r = 0.284 and 0.432, both P > 0.05). CONCLUSION: Recombinant adenovirus Ad-hVEGF165 could reverse Hcy-induced endothelial cells dysfunction via upregulating the expressions of eNOS and DDAH2. PMID- 26419991 TI - [Experimental studies on the role of GATA4 in the endocardial cushions development]. AB - OBJECTIVE: To investigate the role of GATA4 gene in the endocardial cushions development. METHODS: Target gene eukaryote expression vectors were constructed by pcDNA3.1(-) vector plasmid, and were identified by DNA sequence analysis. Recombinant plasmids were transfected into Hela cells with lipofectamine 2000, meanwhile Hela cells transfected with empty vector or those without transfection served as transfection control group and blank control group, respectively. Real time PCR and Western blot were performed to detect the relative expression of mRNA and protein of transcription factors GATA4, Sox9, Scleraxis and ECM proteins Aggrecan, Tenascin in each group. RESULTS: The relative mRNA expression of GATA4 in experimental group was significantly higher than in transfection control group and blank control group. GATA4 mRNA expression in Hela(GATA4), Hela(H436Y), Hela(Null) and Hela group was 310.83 +/- 2.39, 146.35 +/- 1.74, 0.94 +/- 0.32, 1.00 +/- 0.28, respectively (F = 72.508, P < 0.05). Western blot results were consistent with the results obtained by qRT-PCR. The relative mRNA and protein expressions of Sox9, Scleraxis, Aggrecan and Tenascin in both experimental groups were significantly higher than that in transfection control group and blank control group (P < 0.05), and above gene expressions were significantly downregulated in GATA4(H436Y) group, while they were similar between transfection control group and blank control group (all P > 0.05). CONCLUSIONS: GATA4 H436Y mutation reduces it's transcriptional activation, which might serve as a theoretical framework to demonstrate the roles of GATA4 gene in endocardial cushion development. PMID- 26419992 TI - [STAT signaling pathway mediates high glucose induced cardiac fibroblasts proliferation and collagen deposition in vitro]. AB - OBJECTIVE: To observe the signal transducers and activator of transcriptions (STATs) protein expression changes and investigate the functional role of STATs pathway in case of high glucose-induced cardiac fibroblasts (CFs) proliferation and collagen deposition in vitro. METHODS: Rat cardiac fibroblasts were isolated from 1- to 3-day-old SD rats, cells from the second to fourth passages were used for the experiment. CFs were cultured in Dulbecco's modified Eagle's medium, supplemented with 5.5 mmol/L glucose (NG), 5.5 mmol/L glucose plus 19.4 mmol/L mannose (OC) or 25 mmol/L glucose (HG) in the presence of absence of STAT1 inhibitor (fludarabine, FLU) and STAT3 inhibitor (S3I-201). After 24 h and 48 h culture in vitro, the proliferation of CFs was measured by 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. After 12 h and 24 h culture in vitro, the production of type I and III collagen was evaluated using real-time quantitative PCR and ELISA. After 0, 30, 60 and 120 min culture in vitro, the phosphorylated expression of STAT1 and STAT3 was analyzed by Western blot. RESULTS: CFs proliferation was significantly enhanced post 24 h and 48 h HG stimulation, and procollagen I and III mRNA expression was significantly upregulated post 12 h and 24 h HG stimulation. Deposition of collagen I and III was also significantly increased post 24 h and 72 h HG stimulation. STAT1 phosphorylation in CFs was increased after 120 min HG stimulation and STAT3 phosphorylation in CFs was increased post 60 min and 120 min HG stimulation. FLU and S3I-201 could inhibit HG-induced CFs proliferation and suppress of which was stimulated by FLU and S3I-201 could both suppress upregulated procollagen I and III mRNA expression and the deposition of collagen types I and III post HG stimulation. STAT1 phosphorylation inhibition resulted in less mRNA downregulation of procollagen type III than that of procollagen type I post 12 h HG stimulation. The STAT3 phosphorylation inhibition resulted in more significantly upregulated procollagen type III mRNA expression than procollagen type I mRNA expression at 12 h post HG stimulation. CONCLUSION: HG could enhance the protein expression of phosphorylated STAT1 and STAT3 in CFs, which are responsible for HG-induced increased CFs proliferation and collagen deposition in vitro. PMID- 26419993 TI - [Comparison of heart rate variability measurements between ballistocardiogram and electrocardiography]. AB - OBJECTIVE: To compare the heart rate variability (HRV) measurements between ballistocardiogram (BCG) and electrocardiography (ECG). METHODS: The signals of BCG and ECG of 21 patients were collected synchronously. JJ intervals of BCG and RR intervals of ECG were used to calculate the cardiac periods. The parameters of HRV analysis were calculated in time domain analysis, frequency domain analysis and nonlinear analysis. The results derived from BCG and ECG were compared. RESULTS: The parameters of HRV analysis calculated from BCG and ECG had high similarity. The correlation coefficients of SDNN, TP, LF, HF and SD2 between the BCG and ECG methods were high (r = 1). The correlation coefficients of rMSSD and SD2 were 0.99 and of PNN50 and LF/HF were 0.98 between the two methods. HRV analysis results derived from the two methods were similar (P > 0.05). CONCLUSION: HRV could also be measured reliably by calculating the JJ interval from BCG. PMID- 26419994 TI - [Levosimendan-induced liver damage in an elderly patient with heart failure]. PMID- 26419995 TI - [Anomalous origin of left main coronary artery from the pulmonary artery: a case report]. PMID- 26419996 TI - [Update on the new oral anticoagulants and prevention of coronary artery disease]. PMID- 26419997 TI - [Association between scientific view of health and bioethics]. PMID- 26419998 TI - [Research progress on association between red blood cell distribution width and cardiovascular disease]. PMID- 26420000 TI - Specific Accumulation of Lanthanum Carbonate in the Gastric Mucosal Histiocytes in a Dialysis Patient. PMID- 26419999 TI - Which heart failure patients profit from natriuretic peptide guided therapy? A meta-analysis from individual patient data of randomized trials. AB - AIMS: Previous analyses suggest that heart failure (HF) therapy guided by (N terminal pro-)brain natriuretic peptide (NT-proBNP) might be dependent on left ventricular ejection fraction, age and co-morbidities, but the reasons remain unclear. METHODS AND RESULTS: To determine interactions between (NT-pro)BNP guided therapy and HF with reduced [ejection fraction (EF) <=45%; HF with reduced EF (HFrEF), n = 1731] vs. preserved EF [EF > 45%; HF with preserved EF (HFpEF), n = 301] and co-morbidities (hypertension, renal failure, chronic obstructive pulmonary disease, diabetes, cerebrovascular insult, peripheral vascular disease) on outcome, individual patient data (n = 2137) from eight NT-proBNP guidance trials were analysed using Cox-regression with multiplicative interaction terms. Endpoints were mortality and admission because of HF. Whereas in HFrEF patients (NT-pro)BNP-guided compared with symptom-guided therapy resulted in lower mortality [hazard ratio (HR) = 0.78, 95% confidence interval (CI) 0.62-0.97, P = 0.03] and fewer HF admissions (HR = 0.80, 95% CI 0.67-0.97, P = 0.02), no such effect was seen in HFpEF (mortality: HR = 1.22, 95% CI 0.76-1.96, P = 0.41; HF admissions HR = 1.01, 95% CI 0.67-1.53, P = 0.97; interactions P < 0.02). Age (74 +/- 11 years) interacted with treatment strategy allocation independently of EF regarding mortality (P = 0.02), but not HF admission (P = 0.54). The interaction of age and mortality was explained by the interaction of treatment strategy allocation with co-morbidities. In HFpEF, renal failure provided strongest interaction (P < 0.01; increased risk of (NT-pro)BNP-guided therapy if renal failure present), whereas in HFrEF patients, the presence of at least two of the following co-morbidities provided strongest interaction (P < 0.01; (NT-pro)BNP guided therapy beneficial only if none or one of chronic obstructive pulmonary disease, diabetes, cardiovascular insult, or peripheral vascular disease present). (NT-pro)BNP-guided therapy was harmful in HFpEF patients without hypertension (P = 0.02). CONCLUSION: The benefits of therapy guided by (NT pro)BNP were present in HFrEF only. Co-morbidities seem to influence the response to (NT-pro)BNP-guided therapy and may explain the lower efficacy of this approach in elderly patients. PMID- 26420001 TI - EEG Topographic Mapping of Visual and Kinesthetic Imagery in Swimmers. AB - This study investigated differences in QEEG measures between kinesthetic and visual imagery of a 100-m swim in 36 elite competitive swimmers. Background information and post-trial checks controlled for the modality of imagery, swimming skill level, preferred imagery style, intensity of image and task equality. Measures of EEG relative magnitude in theta, low (7-9 Hz) and high alpha (8-10 Hz), and low and high beta were taken from 19 scalp sites during baseline, visual, and kinesthetic imagery. QEEG magnitudes in the low alpha band during the visual and kinesthetic conditions were attenuated from baseline in low band alpha but no changes were seen in any other bands. Swimmers produced more low alpha EEG magnitude during visual versus kinesthetic imagery. This was interpreted as the swimmers having a greater efficiency at producing visual imagery. Participants who reported a strong intensity versus a weaker feeling of the image (kinesthetic) had less low alpha magnitude, i.e., there was use of more cortical resources, but not for the visual condition. These data suggest that low band (7-9 Hz) alpha distinguishes imagery modalities from baseline, visual imagery requires less cortical resources than kinesthetic imagery, and that intense feelings of swimming requires more brain activity than less intense feelings. PMID- 26420003 TI - Scientific theory, the publishing crisis and the wisdom of editors. PMID- 26420002 TI - Endocannabinoids and related lipids in blood plasma following touch massage: a randomised, crossover study. AB - BACKGROUND: The endocannabinoid system is involved in the regulation of stress and anxiety. In a recent study, it was reported that short-term changes in mood produced by a pleasant ambience were correlated with changes in the levels of plasma endocannabinoids and related N-acylethanolamines (Schrieks et al. PLoS One 10: e0126421, 2015). In the present study, we investigated whether stress reduction by touch massage (TM) affects blood plasma levels of endocannabinoids and related N-acylethanolamines. RESULTS: A randomized two-session crossover design for 20 healthy participants was utilised, with one condition that consisted of TM and a rest condition as control. TM increased the perceived pleasantness rating of the participants, and both TM and rest reduced the basal anxiety level as assessed by the State scale of the STAI-Y inventory. However, there were no significant effects of either time (pre- vs. post-treatment measures) as main effect or the interaction time x treatment for the plasma levels of the endocannabinoids anandamide and 2-arachidonoylglycerol or for eight other related lipids. Four lipids showed acceptable relative reliabilities, and for two of these (linoleoyl ethanolamide and palmitoleoyl ethanolamide) a significant correlation was seen between the TM-related change in levels, calculated as (post-TM value minus pre-TM value) - (post-rest value minus pre rest value), and the corresponding TM-related change in perceived pleasantness. CONCLUSIONS: It is concluded that in the participants studied here, there are no overt effects of TM upon plasma endocannabinoid levels. Possible associations of related N-acylethanolamines with the perceived pleasantness should be investigated further. PMID- 26420012 TI - A numerical framework to investigate hemodynamics during endovascular mechanical recanalization in acute stroke. AB - Ischemic stroke, caused by embolism of cerebral vessels, inflicts high morbidity and mortality. Endovascular aspiration of the blood clot is an interventional technique for the recanalization of the occluded arteries. However, the hemodynamics in the Circle of Willis (CoW) are not completely understood, which results in medical misjudgment and complications during surgeries. In this study we establish a multiscale description of cerebral hemodynamics during aspiration thrombectomy. First, the CoW is modeled as a 1D pipe network on the basis of computed tomography angiography (CTA) scans. Afterwards, a vascular occlusion is placed in the middle cerebral artery and the relevant section of the CoW is transferred to a 3D computational fluid dynamic (CFD) domain. A suction catheter in different positions is included in the CFD simulations. The boundary conditions of the 3D domain are taken from the 1D domain to ensure system coupling. A Eulerian-Eulerian multiphase simulation describes the process of thrombus aspiration. The physiological blood flow in the 1D and 3D domains is validated with literature data. Further on, it is proved that domain reduction and pressure coupling at the boundaries are an appropriate method to reduce computational costs. Future work will apply the developed framework to various clinical questions. PMID- 26420011 TI - Persistent organic pollutants and non-alcoholic fatty liver disease in morbidly obese patients: a cohort study. AB - BACKGROUND: In animal experiments persistent organic pollutants (POPs) cause hepatosteatosis. In epidemiological studies POPs have positive associations with serum markers of nonalcoholic fatty liver disease (NAFLD) and together with obesity synergistic association with insulin resistance. Because insulin resistance and obesity are critical in NAFLD pathogenesis, we investigated the association of serum pollutant levels with liver histology and alanine aminotransferase (ALT) in morbidly obese. METHODS: Liver biopsies were from 161 participants of the Kuopio Obesity Surgery Study (KOBS) who underwent bariatric surgery 2005-2011. Liver histology was categorized as normal, steatosis and non alcoholic steatohepatitis (NASH). Liver phenotype at baseline and ALT at baseline and 12 months post-surgery were correlated to serum POP concentrations at respective time points. As lipophilic POPs concentrate to smaller fat volume during weight loss, serum levels before and 12 months after bariatric surgery were compared. RESULTS: Baseline serum concentration of PCB-118, beta-HCH and several PFAAs had an inverse association with lobular inflammation possibly due to changes in bile acid metabolism. ALT had negative associations with many POPs at baseline that turned positive at 12 months after major clinical improvements. There was an interaction between some POPs and sex at 12 months, and in stratified data positive associations were observed mainly in females but not in males. CONCLUSIONS: We found a negative association between serum concentrations of PCB-118, beta-HCH and several PFAAs with lobular inflammation at baseline. Positive POPs-ATL associations at 12 months among women suggest that increased POP concentrations may decrease the degree of liver recovery. PMID- 26420013 TI - Molecular-matched materials for anticancer drug delivery and imaging. AB - AIM: In this study, we aim to construct nanoformulation with high-cargo loading and controlled serum kinetics. MATERIALS & METHODS: Molecular-matched materials (MMMs) are established through the conjugation of the functional moiety to a molecule representative of the nanoparticle's core. Molecular-matched nanoemulsions and liposomes were prepared using MMMs. RESULTS: This technique based on MMMs even allows us to efficiently load either hydrophobic or hydrophilic moieties into a hydrophobic core of the nanoparticles. MMMs-based nanoparticles showed marked improvement in serum pharmacokinetics and anticancer effect. CONCLUSION: The desired performance can be achieved when the hydrophobic anchor of the PEG derivatives and the moiety conjugated to the therapeutic (or imaging) agents are molecularly identical to the core. PMID- 26420014 TI - Paternalism and autonomy: views of patients and providers in a transitional (post communist) country. AB - BACKGROUND: Patient autonomy is a fundamental, yet challenging, principle of professional medical ethics. The idea that individual patients should have the freedom to make choices about their lives, including medical matters, has become increasingly prominent in current literature. However, this has not always been the case, especially in communist countries where paternalistic attitudes have been interwoven into all relationships including medical ones. Patients' expectations and the role of the doctor in the patient-physician relationship are changing. Croatia, as a transitional country, is currently undergoing this particular process. METHODS: Qualitative research was conducted by means of six focus group discussions held in the years 2012 and 2013 in Croatia. Focus groups were held separately with each of the following: first year and final (6(th)) year medical students, physicians engaged in medical ethics education, physicians practicing in a clinical hospital, family medicine residents and individuals representing patients with chronic disease. This research specifically addresses issues related to patient autonomy, in particular, the principles of truth telling, confidentiality, and informed consent. All focus group discussions were audio taped and then transcribed verbatim and systematized according to acknowledged qualitative analysis methods. RESULTS AND DISCUSSION: Patient autonomy is much more than a simple notion defined as the patient's right to make treatment decisions independently. It has to be understood in context of the broader socio-cultural setting. At present, both patients and medical doctors in Croatia are increasingly appreciating the importance of promoting the principle of autonomy in medical decision-making. However, the current views of medical students, physicians and patients reveal inconsistencies. CONCLUSIONS: Knowing how to respect the various facets of patients' autonomy should be part of physician's professional duties, and also be reflected in his or her core clinical competencies. For this reason greater importance should be dedicated to patient autonomy issues in medical education in Croatia. PMID- 26420015 TI - Antioxidant and anti hyperglycemic role of wine grape powder in rats fed with a high fructose diet. AB - BACKGROUND: Metabolic syndrome is a growing worldwide health problem. We evaluated the effects of wine grape powder (WGP), rich in antioxidants and fiber, in a rat model of metabolic syndrome induced by a high fructose diet. We tested whether WGP supplementation may prevent glucose intolerance and decrease oxidative stress in rats fed with a high fructose diet. METHODS: Male Sprague Dawley rats weighing 180 g were divided into four groups according to their feeding protocols. Rats were fed with control diet (C), control plus 20 % WGP (C + WGP), 50 % high fructose (HF) or 50 % fructose plus 20 % WGP (HF + WGP) for 16 weeks. Blood glucose, insulin and triglycerides, weight, and arterial blood pressure were measured. Homeostasis model assessment (HOMA) index was calculated using insulin and glucose values. A glucose tolerance test was performed 2 days before the end of the experiment. As an index of oxidative stress, thiobarbituric acid reactive substances (TBARS) level was measured in plasma and kidney, and superoxide dismutase was measured in the kidney. RESULTS: Thiobarbituric acid reactive substances in plasma and renal tissue were significantly higher when compared to the control group. In addition, the area under the curve of the glucose tolerance test was higher in HF fed animals. Furthermore, fasting blood glucose, plasma insulin levels, and the HOMA index, were also increased. WGP supplementation prevented these alterations in rats fed with the HF diet. We did not find any significant difference in body weight or systolic blood pressure in any of the groups. CONCLUSIONS: Our results show that WGP supplementation prevented hyperglycemia, insulin resistance and reduced oxidative stress in rats fed with HF diet. We propose that WGP may be used as a supplement in human food as well. PMID- 26420016 TI - Evidence for abnormal cytokine expression in Gulf War Illness: A preliminary analysis of daily immune monitoring data. AB - BACKGROUND: Gulf War Illness (GWI) is a clinically heterogeneous chronic condition that affects many veterans of the 1990-1991 Persian Gulf War. One of the most prevalent and debilitating symptoms of GWI is abnormal fatigue. The mechanisms underlying GWI generally, and fatigue symptoms specifically, have yet to be conclusively identified, although immune system abnormalities are suspected to be involved. The first goal of this immune monitoring study was to determine if GWI is associated with higher absolute levels and daily variability of pro inflammatory immune factors. The second goal was to explore the relationship between day-to-day immune marker fluctuations and daily self-reported fatigue severity. METHODS: We recruited veterans with GWI and healthy veteran control (HV) participants to provide self-reported fatigue severity data and blood samples, over 25 consecutive days. We profiled inflammatory processes by using a longitudinal, daily immune-monitoring approach. For each day, serum cytokine and chemokine concentrations were determined using multiplex assays. RESULTS: Seven veterans with GWI and eight healthy veteran control (HV) participants completed the study protocol. We found that GWI was associated with higher variability in the expression of eotaxin-1 (p < 0.001). For GWI participants, higher fatigue severity days were associated with greater IL-1beta (p = 0.008) and IL-15 (p < 0.001). CONCLUSIONS: Our findings provide preliminary evidence that the immune system is involved in the pathophysiology of GWI. Longitudinal immune profiling approaches may be helpful in discovering targets for novel therapies in conditions such as GWI. PMID- 26420018 TI - Negotiating the dilemma of anaesthesia and sedation in NICUs. PMID- 26420019 TI - Arginine analogues incorporating carboxylate bioisosteric functions are micromolar inhibitors of human recombinant DDAH-1. AB - Dimethylarginine dimethylaminohydrolase (DDAH) is a key enzyme involved in the metabolism of asymmetric dimethylarginine (ADMA) and N-monomethyl arginine (NMMA), which are endogenous inhibitors of the nitric oxide synthase (NOS) family of enzymes. Two isoforms of DDAH have been identified in humans, DDAH-1 and DDAH 2. DDAH-1 inhibition represents a promising strategy to limit the overproduction of NO in pathological states without affecting the homeostatic role of this important messenger molecule. Here we describe the design and synthesis of 12 novel DDAH-1 inhibitors and report their derived kinetic parameters, IC50 and Ki. Arginine analogue 10a, characterized by an acylsulfonamide isosteric replacement of the carboxylate, showed a 13-fold greater inhibitory potential relative to the known DDAH-1 inhibitor, L-257. Compound 10a was utilized to study the putative binding interactions of human DDAH-1 inhibition using molecular dynamics simulations. The latter suggests that several stabilizing interactions occur in the DDAH-1 active-site, providing structural insights for the enhanced inhibitory potential demonstrated by in vitro inhibition studies. PMID- 26420020 TI - A brief history of pediatric urologic oncology as a subspecialty. PMID- 26420021 TI - Proteomic analysis reveals differentially secreted proteins in the urine from patients with clear cell renal cell carcinoma. AB - OBJECTIVE: The aim of this study was to evaluate the differentially secreted protein profile in the urine from patients with clear cell renal cell carcinoma (ccRCC) using mass spectrometry-based methods. Urine composition can reflect kidney physiology and can be used to detect markers for renal diseases. Moreover, characterization of the secretome is likely to assist in the investigation of new drugs for biological targets and diagnose the ccRCC at an early stage. METHODS AND MATERIALS: Urine samples from patients were divided according to Fuhrman degree (FI-IV), which was associated with the cellular differentiation as good prognosis (GP) and poor prognosis (PP). Healthy individuals were used as the control group (CG). We used both qualitative and quantitative mass spectrometry based analyses that involved the following approaches: 1-dimensional gel electrophoresis combined with liquid chromatography mass spectrometry in tandem (1DE LC-MS/MS), in-solution digestion combined with label-free 1-dimensional LC MS(E) (1D LC-MS(E)), and bidimensional gel electrophoresis combined with matrix assisted laser desorption/ionization time of flight in tandem (2DE MALDI-TOF/TOF) or combined with LC-MS/MS. RESULTS: All the strategies allowed the identification of 354 proteins from the CG, GP, and PP groups. Qualitative experiments using 1DE LC-MS/MS analysis detected different protein profiles, and 224 proteins were identified in all groups. The label-free MS(E) quantitative analysis identified 113 proteins and generated novel information on secreted protein profiles, including 49 up-secreted proteins in the urine from patients with ccRCC and 40 down-secreted proteins related to the CG. Proteins such as kininogen-1, uromodulin, apolipoprotein D, polyubiquitin, and CD59 glycoprotein were down secreted according to the groups CG>GP>PP. In contrast, apolipoprotein A, fibrinogen, and haptoglobin were up secreted in patient groups. The same expression profile observed for kininogen-1, apolipoprotein D, fibrinogen, and haptoglobin was corroborated by 2DE LC-MS/MS or 2DE MALDI-TOF/TOF analyses. These 2 strategies also showed 13 differentially secreted proteins among the 3 groups. CONCLUSIONS: The proteins kininogen-1, apolipoprotein D, fibrinogen, and haptoglobin presented similar quantitative protein profiles according to MS(E) and 2DE approaches. The latter proteins were up secreted and the former ones were down-regulated. The strategies used proved to be valuable in identifying proteins that were differentially secreted in urine from patients with RCC. PMID- 26420022 TI - There is a place for radical cystectomy and urinary diversion, including orthotopic bladder substitution, in patients aged 75 and older: Results of a retrospective observational analysis from a high-volume center. AB - INTRODUCTION: The incidence of cancer increases with age and owing to the changing demographics we are increasingly confronted with treating bladder cancer in old patients. We report our results in patients>75 years of age who underwent open radical cystectomy (RC) and urinary diversion. MATERIAL AND METHODS: From January 2000 to March 2013, a consecutive series of 224 old patients with complete follow-up who underwent RC and urinary diversion (ileal orthotopic bladder substitute [OBS], ileal conduit [IC], and ureterocutaneostomy [UCST]) were included in this retrospective single-center study. End points were the 90 day complication rates (Clavien-Dindo classification), 90-day mortality rates, overall and cancer-specific survival rates, and continence rates (OBS). RESULTS: Median age was 79.2 years (range: 75.1-91.6); 35 of the 224 patients (17%) received an OBS, 178 of the 224 patients (78%) an IC, and 11 of the 224 patients (5%) an UCST. The 90-day complication rate was 54.3% in the OBS (major: Clavien grade 3-5: 22.9%, minor: Clavien Grade 1-2: 31.4%), 56.7% in the IC (major: 27%, minor: 29.8%), and 63.6% in the UCST group (major: 36.4%, minor: 27.3%); P = 0.001. The 90-day mortality was 0% in the OBS group, 13% in the IC group, and 10% in the UCST group (P = 0.077). The Glasgow prognostic score was an independent predictor of all survival parameters assessed, including 90-day mortality. Median follow-up was 22 months. Overall and cancer-specific survivals were 90 and 98, 47 and 91, and 11 and 12 months for OBS, IC, and UCST, respectively. In OBS patients, daytime continence was considered as dry in 66% and humid in 20% of patients. Nighttime continence was dry in 46% and humid 26% of patients. CONCLUSION: With careful patient selection, oncological and functional outcome after RC can be good in old patients. Old age as the sole criterion should not preclude the indication for RC or the option of OBS. In old patients undergoing OBS, satisfactory continence results can be achieved. PMID- 26420023 TI - Efficient singlet oxygen generation from sugar pendant C60 derivatives for photodynamic therapy. AB - The amidation reaction between C60 with an activated ester group (1) and acetylated Glc (AcGlc) with an amino group (2) was performed to yield the target AcGlc-pendant C60 compound (3). The water soluble deacetylated compound, Glc pendant C60 compound (4), exhibited high photocytotoxicity against HeLa cells due to the more efficient singlet oxygen generation as compared with that of Glc pendant azafulleroids. PMID- 26420024 TI - Ammonia activates pacC and patulin accumulation in an acidic environment during apple colonization by Penicillium expansum. AB - Penicillium expansum, the causal agent of blue mould rot, causes severe post harvest fruit maceration simultaneously with the secretion of d-gluconic acid (GLA) and the mycotoxin patulin in colonized tissue. The factor(s) inducing patulin biosynthesis during colonization of the host acidic environment is unclear. During the colonization of apple fruit in vivo and growth in culture, P. expansum secretes pH-modulating GLA and ammonia. Although patulin and its possible opportunistic precursor GLA accumulate together during fungal development, ammonia is detected on the colonized tissue's leading edge and after extended culture, close to patulin accumulation. Here, we demonstrate ammonia induced transcript activation of the global pH modulator PacC and patulin accumulation in the presence of GLA by: (i) direct exogenous treatment of P. expansum growing on solid medium; (ii) direct exogenous treatment on colonized apple tissue; (iii) growth under self-ammonia production conditions with limited carbon; and (iv) analysis of the transcriptional response to ammonia of the patulin biosynthesis cluster. Ammonia induced patulin accumulation concurrently with the transcript activation of pacC and patulin biosynthesis cluster genes, indicating the regulatory effect of ammonia on pacC transcript expression under acidic conditions. Electrophoretic mobility shift assays using P. expansum PacC and antibodies to the different cleaved proteins showed that PacC is not protected against proteolytic signalling at pH 4.5 relative to pH 7.0, but NH4 addition did not further enhance its proteolytic cleavage. Ammonia enhanced the activation of palF transcript in the Pal pathway under acidic conditions. Ammonia accumulation in the host environment by the pathogen under acidic pH may be a regulatory cue for pacC activation, towards the accumulation of secondary metabolites, such as patulin. PMID- 26420017 TI - Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study. AB - BACKGROUND: Neonates who are in pain or are stressed during care in the intensive care unit (ICU) are often given sedation or analgesia. We investigated the current use of sedation or analgesia in neonatal ICUs (NICUs) in European countries. METHODS: EUROPAIN (EUROpean Pain Audit In Neonates) was a prospective cohort study of the management of sedation and analgesia in patients in NICUs. All neonates admitted to NICUs during 1 month were included in this study. Data on demographics, methods of respiration, use of continuous or intermittent sedation, analgesia, or neuromuscular blockers, pain assessments, and drug withdrawal syndromes were gathered during the first 28 days of admission to NICUs. Multivariable linear regression models and propensity scores were used to assess the association between duration of tracheal ventilation (TV) and exposure to opioids, sedatives-hypnotics, or general anaesthetics in neonates (O-SH-GA). This study is registered with ClinicalTrials.gov, number NCT01694745. FINDINGS: From Oct 1, 2012, to June 30, 2013, 6680 neonates were enrolled in 243 NICUs in 18 European countries. Mean gestational age of these neonates was 35.0 weeks (SD 4.6) and birthweight was 2384 g (1007). 2142 (32%) neonates were given TV, 1496 (22%) non-invasive ventilation (NIV), and 3042 (46%) were kept on spontaneous ventilation (SV). 1746 (82%), 266 (18%), and 282 (9%) neonates in the TV, NIV, and SV groups, respectively, were given sedation or analgesia as a continuous infusion, intermittent doses, or both (p<0.0001). In the participating NICUs, the median use of sedation or analgesia was 89.3% (70.0-100) for neonates in the TV group. Opioids were given to 1764 (26%) of 6680 neonates and to 1589 (74%) of 2142 neonates in the TV group. Midazolam was given to 576 (9%) of 6680 neonates and 536 (25%) neonates of 2142 neonates in the TV group. 542 (25%) neonates in the TV group were given neuromuscular blockers, which were administered as continuous infusions to 146 (7%) of these neonates. Pain assessments were recorded in 1250 (58%) of 2138, 672 (45%) of 1493, and 916 (30%) of 3017 neonates in the TV, NIV, and SV groups, respectively (p<0.0001). In the univariate analysis, neonates given O-SH-GA in the TV group needed a longer duration of TV than did those who were not given O-SH-GA (mean 136.2 h [SD 173.1] vs 39.8 h [94.7] h; p<0.0001). Multivariable and propensity score analyses confirmed this association (p<0.0001). INTERPRETATION: Wide variations in sedation and analgesia practices occur between NICUs and countries. Widespread use of O-SH-GA in intubated neonates might prolong their need for mechanical ventilation, but further research is needed to investigate the therapeutic and adverse effects of O-SH-GA in neonates, and to develop new and safe approaches for sedation and analgesia. FUNDING: European Community's Seventh Framework Programme. PMID- 26420025 TI - Polyol-enhanced dispersive liquid-liquid microextraction coupled with gas chromatography and nitrogen phosphorous detection for the determination of organophosphorus pesticides from aqueous samples, fruit juices, and vegetables. AB - Polyol-enhanced dispersive liquid-liquid microextraction has been proposed for the extraction and preconcentration of some organophosphorus pesticides from different samples. In the present study, a high volume of an aqueous phase containing a polyol (sorbitol) is prepared and then a disperser solvent along with an extraction solvent is rapidly injected into it. Sorbitol showed the best results and it was more effective on the extraction recoveries of the analytes than inorganic salts such as sodium chloride, potassium chloride, and sodium sulfate. Under the optimum extraction conditions, the method showed low limits of detection and quantification within the ranges of 12-56 and 44-162 pg/mL, respectively. Enrichment factors and extraction recoveries were in the ranges of 2799-3033 and 84-92%, respectively. The method precision was evaluated at a concentration of 10 ng/mL of each analyte, and relative standard deviations were found to be less than 5.9% for intraday (n = 6) and less than 7.8% for interday (n = 4). Finally, some aqueous samples were successfully analyzed using the proposed method and four analytes (diazinon, dimethoate, chlorpyrifos, and phosalone) were determined, some of them at ng/mL level. PMID- 26420026 TI - Sortilin-related receptor CNS expressed 2 (SorCS2) is localized to Bunina bodies in amyotrophic lateral sclerosis. AB - Sortilin-related receptor CNS expressed 2 (SorCS2) is one of the vacuolar protein sorting 10 family proteins (VPS10Ps) that have pleiotropic roles in protein trafficking and intracellular and intercellular signaling. Bunina bodies (BBs) are specifically detected in the lower motor neurons in patients with amyotrophic lateral sclerosis (ALS). BBs are immunolabeled with antibodies against cystatin C, transferrin and peripherin and are considered to originate from the endoplasmic reticulum, which is part of the protein sorting pathway. The present study investigated whether VPS10Ps are involved in the formation of BBs in ALS. We immunohistochemically examined the spinal cord from patients with ALS and control subjects using antibodies against VPS10Ps (sortilin, SorLA, SorCS1, SorCS2 and SorCS3). In normal controls, antibodies against VPS10Ps immunolabeled the cytoplasm of anterior horn cells in a fine granular pattern. In ALS, almost all BBs (95.1%) were strongly immunopositive for SorCS2, and immunoreativity for sortilin and SorLA was decreased in anterior horn cells. These findings suggest that VPS10Ps may be involved in the disease process of ALS. PMID- 26420027 TI - Hyperforin alleviates mood deficits of adult rats suffered from early separation. AB - In this study, we aimed to explore the effect of hyperforin (Hyp) on adult rats suffered from early separation. Wistar infant rats were randomly divided into three groups: control group (CON), early separation from parents group (ESP), and early separation from parents+treatment with 3mg/kg/day Hyp group (ESP+Hyp). Postnatal rats of ESP group and ESP+Hyp group were separated from their mothers for 6h every day on the 14th day after birth, and this separation lasted for 3 weeks, while rats of CON group had no separation. Hyperforin was intragastric administrated on the 21th day after birth, and lasted for 2 weeks in ESP+Hyp group. After separation, adult rats were evaluated by using the open field test (OFT), novelty suppressed feeding test (NSF) and forced swimming test (FST). In OFT, time spent in central grids was much shorter in ESP group compared with that of CON group. After treatment with hyperforin, time spent in central area was much longer compared with that of ESP group. In NSF, the feeding latency of ESP group was much longer than that of CON group. After treatment with hyperforin, the feeding latency was shorter compared with that of ESP group. In FST, score of ESP group was markedly higher than that of CON group. Interestingly, the score was obviously lower in ESP+Hyp group than that of ESP group. In conclusion, these results suggest that hyperforin is able to alleviate anxiety and remit depression in ESP rats. PMID- 26420028 TI - The expression levels of prolyl oligopeptidase responds not only to neuroinflammation but also to systemic inflammation upon liver failure in rat models and cirrhotic patients. AB - BACKGROUND: Liver failure in experimental animals or in human cirrhosis elicits neuroinflammation. Prolyl oligopeptidase (PREP) has been implicated in neuroinflammatory events in neurodegenerative diseases: PREP protein levels are increased in brain glial cells upon neuroinflammatory insults, but the circulating PREP activity levels are decreased in multiple sclerosis patients in a process probably mediated by bioactive peptides. In this work, we studied the variation of PREP levels upon liver failure and correlated it with several inflammatory markers to conclude on the relation of PREP with systemic and/or neuroinflammation. METHODS: PREP enzymatic activity and protein levels measured with immunological techniques were determined in the brain and plasma of rats with portacaval shunt (PCS) and after treatment with ibuprofen. Those results were compared with the levels of PREP measured in plasma from cirrhotic patients with or without minimal hepatic encephalopathy (MHE). Levels of several pro inflammatory cytokines and those of NO/cGMP homeostasis metabolites were measured in PCS rats and cirrhotic patients to conclude on the role of PREP in inflammation. RESULTS: In PCA rats, we found that PREP levels are significantly increased in the hippocampus, striatum and cerebellum, that in the cerebellum the PREP increase was significantly found in the extracellular space and that the levels were restored to those measured in control rats after administration of an anti-inflammatory agent, ibuprofen. In cirrhotic patients, circulatory PREP activity was found to correlate to systemic and neuroinflammatory markers and had a negative correlation with the severity of the disease, although no clear relation to MHE. CONCLUSIONS: These results support the idea that PREP levels could be used as indicators of cirrhosis severity in humans, and using other markers, it might contribute to assessing the level of neuroinflammation in those patients. This work reports, for the first time, that PREP is secreted to the extracellular space in the cerebellum most probably due to glial activation and supports the role of the peptidase in the inflammatory response. PMID- 26420030 TI - Decanuclear Ln10 Wheels and Vertex-Shared Spirocyclic Ln5 Cores: Synthesis, Structure, SMM Behavior, and MCE Properties. AB - The reaction of a Schiff base ligand (LH3) with lanthanide salts, pivalic acid and triethylamine in 1:1:1:3 and 4:5:8:20 stoichiometric ratios results in the formation of decanuclear Ln10 (Ln = Dy (1), Tb (2), and Gd (3)) and pentanuclear Ln5 complexes (Ln = Gd (4), Tb (5), and Dy (6)), respectively. The formation of Ln10 and Ln5 complexes are fully governed by the stoichiometry of the reagents used. Detailed magnetic studies on these complexes (1-6) have been carried out. Complex 1 shows a SMM behavior with an effective energy barrier for the reversal of the magnetization (Ueff) = 16.12(8) K and relaxation time (tauo) = 3.3*10(-5) s under 4000 Oe direct current (dc) field. Complex 6 shows the frequency dependent maxima in the out-of-phase signal under zero dc field, without achieving maxima above 2 K. Complexes 3 and 4 show a large magnetocaloric effect with the following characteristic values: -DeltaSm = 26.6 J kg(-1) K(-1) at T = 2.2 K for 3 and -DeltaSm = 27.1 J kg(-1) K(-1) at T = 2.4 K for 4, both for an applied field change of 7 T. PMID- 26420029 TI - First human case report of sepsis due to infection with Streptococcus suis serotype 31 in Thailand. AB - BACKGROUND: Streptococcus suis is a zoonotic pathogen that causes invasive infections in humans and pigs. It has been reported that S. suis infection in humans is mostly caused by serotype 2. However, human cases caused by other serotypes have rarely been reported. This is the first report of a human case of infection with S. suis serotype 31 in Thailand. CASE PRESENTATION: A 55-year-old male alcohol misuser with liver cirrhosis was admitted with sepsis to a hospital in the Central Region of Thailand. He had consumed a homemade, raw pork product prior to the onset of illness. He was alive after treatment with ceftriaxone and no complication occurred. An isolate from blood culture at the hospital was suspected as viridans group Streptococcus. It was confirmed at a reference laboratory as S. suis serotype 31 by biochemical tests, 16S rDNA sequencing, and multiplex polymerase chain reaction for serotyping, but it was untypable by the co-agglutination test with antisera against recognized S. suis serotypes, suggesting loss of capsular material. The absence of a capsule was confirmed by transmission electron microscopy. The isolate was confirmed to be sequence type 221, with 13 putative virulence genes that are usually found in serotype 2 strains. CONCLUSION: We should be aware of the emergence of S. suis infections caused by uncommon serotypes in patients with predisposing conditions. Laboratory capacity to identify S. suis in the hospital is needed in developing countries, which can contribute to enhanced surveillance, epidemiological control, and prevention strategies in the prevalent area. PMID- 26420031 TI - Exome sequencing in a patient with Catel-Manzke-like syndrome excludes the involvement of the known genes and reveals a possible candidate. AB - In the present study we describe the exome sequencing and analysis of a patient with Catel-Manzke-like phenotype showing bilateral hyperphalangism of the second finger and thumb clinodactyly due to a unilateral delta phalanx, associated with growth, cardiac and vertebral defects. The exome sequencing analysis excluded pathogenetic mutations in the genes known to cause syndromes with hyperphalangism and did not identify any alteration in the X-chromosome or de novo mutations in likely candidate genes. Under the assumption of an autosomal recessive mode of inheritance and based on the frequency of the single nucleotide variants found in homozygous or double heterozygous states and the results of computer prediction programs, only one gene, DNAH10, emerged as a candidate in the pathogenesis of the disease in our patient. However, the differences among the known biological functions of DNAH10 and the genes involved in the other syndromes with hyperphalangism, suggest caution in the interpretation of the results. PMID- 26420036 TI - Rapid and sensitive detection of carbapenemase activity in Acinetobacter baumannii using superficially porous liquid chromatography-tandem mass spectrometry. AB - BACKGROUND: The emergence and spread of carbapenem-resistant Acinetobacter baumannii poses a challenge for optimizing antibiotic therapies and preventing outbreaks. Traditional phenotypic assays such as the modified Hodge test (MHT) or polymerase chain reaction (PCR)-based detection of the carbapenemase genes are time-consuming and complicated. Therefore, new approaches for the efficient detection of carbapenemase-producing A. baumannii are urgently required. METHODS: In this study, we used the superficially porous liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay to measure carbapenem hydrolysis in a solution spiked with test strains of A. baumannii. The rate of carbapenem hydrolysis during incubation was expressed as the ratio of the carbapenem peak area of the test A. baumannii strains to the noncarbapenemase-producing A. baumannii ATCC 17978. This method can accurately measure the carbapenem hydrolysis rate and, therefore, can effectively identify carbapenemase-producing strains within 75 minutes. RESULTS: A total of 112 A. baumannii strains were used in this study, including 103 clinical isolates with 68 carbapenem-resistant strains and 35 carbapenem-susceptible strains, seven ATCC strains and two selected mutants. The results of the superficially porous LC-MS/MS assay showed higher detection sensitivity compared to the results of the MHT. CONCLUSION: Our results demonstrate the ability of the former method to routinely detect carbapenemase producing A. baumannii. PMID- 26420037 TI - Comparison of Capability of Human Bone Marrow Mesenchymal Stem Cells and Endometrial Stem Cells to Differentiate into Motor Neurons on Electrospun Poly(epsilon-caprolactone) Scaffold. AB - Human endometrial and bone marrow-derived mesenchymal stem cells can be differentiated into a number of cell lineages. Mesenchymal stem cells (MSCs) are potential candidates for cellular therapy. The differentiation of human bone marrow MSCs (hBM-MSCs) and endometrial stem cells (hEnSCs) into motor neuron-like cells has been rarely investigated previously; however, the comparison between these stem cells when they are differentiated into motor neuron-like cell is yet to be studied. The aim of this study was therefore to investigate and compare the capability of hBM-MSCs and hEnSCs cultured on tissue culture polystyrene (TCP) and poly epsilon-caprolactone (PCL) nanofibrous scaffold to differentiate into motor neuron-like cells in the presence of neural inductive molecules. Engineered hBM-MSCs and hEnSCs seeded on PCL nanofibrous scaffold were differentiated into beta-tubulin III, islet-1, Neurofilament-H (NF-H), HB9, Pax6, and choactase positive motor neurons by immunostaining and real-time PCR, in response to the signaling molecules. The data obtained from PCR and immunostaining showed that the expression of motor neuron markers of both hBM-MSCs and hEnSCs differentiated cells on PCL scaffold are significantly higher than that of the control group. The expression of these markers in hEnSCs differentiated cells was higher than that in hBM-MSCs. However, this difference was not statistically significant. In conclusion, differentiated hBM-MSCs and hEnSCs on PCL can provide a suitable three-dimensional situation for neuronal survival and outgrowth for regeneration of the central nervous system. Both cells may be potential candidates for cellular therapy in motor neuron disorders. However, differentiation of hEnSCs into motor neuron-like cells was better than hBM-MSCs. PMID- 26420038 TI - Postnatal epigenetic regulation of intestinal stem cells requires DNA methylation and is guided by the microbiome. AB - BACKGROUND: DNA methylation is an epigenetic mechanism central to development and maintenance of complex mammalian tissues, but our understanding of its role in intestinal development is limited. RESULTS: We use whole genome bisulfite sequencing, and find that differentiation of mouse colonic intestinal stem cells to intestinal epithelium is not associated with major changes in DNA methylation. However, we detect extensive dynamic epigenetic changes in intestinal stem cells and their progeny during the suckling period, suggesting postnatal epigenetic development in this stem cell population. We find that postnatal DNA methylation increases at 3' CpG islands (CGIs) correlate with transcriptional activation of glycosylation genes responsible for intestinal maturation. To directly test whether 3' CGI methylation regulates transcription, we conditionally disrupted two major DNA methyltransferases, Dnmt1 or Dnmt3a, in fetal and adult intestine. Deficiency of Dnmt1 causes severe intestinal abnormalities in neonates and disrupts crypt homeostasis in adults, whereas Dnmt3a loss was compatible with intestinal development. These studies reveal that 3' CGI methylation is functionally involved in the regulation of transcriptional activation in vivo, and that Dnmt1 is a critical regulator of postnatal epigenetic changes in intestinal stem cells. Finally, we show that postnatal 3' CGI methylation and associated gene activation in intestinal epithelial cells are significantly altered by germ-free conditions. CONCLUSIONS: Our results demonstrate that the suckling period is critical for epigenetic development of intestinal stem cells, with potential important implications for lifelong gut health, and that the gut microbiome guides and/or facilitates these postnatal epigenetic processes. PMID- 26420040 TI - A cross-sectional study of the magnitude, barriers, and outcomes of HIV status disclosure among women participating in a perinatal HIV transmission study, "the Nevirapine Repeat Pregnancy study". AB - BACKGROUND: HIV status disclosure is a difficult emotional task for HIV-infected persons and may create the opportunity for both social support and rejection. In this study, we evaluated the proportions, patterns, barriers and outcomes of HIV- 1 status disclosure among a group of women in Uganda. METHODS: An exit interview was conducted one year post-partum for 85 HIV-infected women who participated in a study of HIV-1 transmission rates among NVP-experienced compared with NVP-naive women in "The Nevirapine Repeat Pregnancy (NVP-RP) Study" at the Makerere University-Johns Hopkins University Research Collaboration, Kampala-Uganda, between June 2004 and June 2006. RESULTS: Of the 85 women interviewed, 99 % had disclosed their HIV status to at least one other person. Disclosure proportions ranged between 1 % to employer(s) and 69 % to a relative other than a parent. Only 38 % of the women had disclosed to their sex partners. Women with an HIV infected baby were more likely than those with an uninfected baby to disclose to their sex partner, OR 4.9 (95 % CI, 2.0 -11.2), and women were less likely to disclose to a partner if they had previously disclosed to another relative than if they had not, OR 0.19 (95 % CI, 0.14-0.52). The most common reasons for non disclosure included fear of separation from the partner and subsequent loss of financial support 34 %, and not living with the partner (not having opportunities to disclose) 26 %. While most women (67 %) reported getting social support following disclosure, 22 % reported negative outcomes (neglect, separation from their partners, and loss of financial support). Following disclosure of HIV status, 9 % of women reported that their partner (s) decided to have an HIV test. CONCLUSION: Results from this study show high overall HIV disclosure proportions and how this disclosure of HIV status can foster social support. However, proportions of disclosure specifically to male sex partners were low, which suggests the need for interventions aimed at increasing male involvement in perinatal care, along with supportive counseling. PMID- 26420042 TI - How To Form a Phosphate Anhydride Linkage in Nucleotide Derivatives. AB - The fundamental roles of nucleoside triphosphates and nucleotide cofactors such as NAD(+) in biochemistry are well known. In recent decades, continuing research has revealed the key role of 5'-capped RNA and 5',5'-dinucleoside polyphosphates in the regulation of vitally important physiological processes. Last but not least, the commercial potential of nucleoside triphosphate synthesis can hardly be overestimated. Nevertheless, despite decades of investigation and the obvious topicality of the research on the chemical synthesis of the nucleotide compounds containing phosphate anhydride linkages, none of the existing procedures can be considered an up-to-date "gold standard". However, there are a number of fruitful synthetic approaches to forming phosphate anhydride linkages in satisfactory yield. These are summarized in this concise review, organized by the type of active phosphorous intermediate and reagents used. PMID- 26420039 TI - Urokinase-type plasminogen activator receptor interaction with beta1 integrin is required for platelet-derived growth factor-AB-induced human mesenchymal stem/stromal cell migration. AB - INTRODUCTION: Mesenchymal stem cells (MSC) are well described for their role in tissue regeneration following injury. Migratory properties of endogenous or administrated MSC are critical for tissue repair processes. Platelet-derived growth factor (PDGF) is a chemotactic growth factor that elicits mesenchymal cell migration. However, it is yet to be elucidated if signaling pathways other than direct activation of PDGF receptor (PDGF-R) are involved in PDGF-induced cell migration. METHODS: Knocking down and co-immunoprecipitation approaches were used to evaluate urokinase-type plasminogen activator receptor (uPAR) requirement and its interactions with proteins involved in migration mechanisms, in human MSC induced to migrate under PDGF-AB effect. RESULTS: We demonstrated that uPAR activation and its association with beta1-integrin are required for PDGF-AB induced migration. This phenomenon takes place in MSC derived from bone marrow and from adipose tissue. CONCLUSIONS: We showed that PDGF-AB downstream signaling requires other effector molecules in MSC such as the uPA/uPAR system and beta1 integrin signaling pathway known for their role in migration. These findings provide new insights in molecular mechanisms of PDGF-AB-induced migration of human MSC that may be relevant to control MSC function and tissue remodeling after injury. PMID- 26420041 TI - 3D fibre deposition and stereolithography techniques for the design of multifunctional nanocomposite magnetic scaffolds. AB - Magnetic nanocomposite scaffolds based on poly(epsilon-caprolactone) and poly(ethylene glycol) were fabricated by 3D fibre deposition modelling (FDM) and stereolithography techniques. In addition, hybrid coaxial and bilayer magnetic scaffolds were produced by combining such techniques. The aim of the current research was to analyse some structural and functional features of 3D magnetic scaffolds obtained by the 3D fibre deposition technique and by stereolithography as well as features of multimaterial scaffolds in the form of coaxial and bilayer structures obtained by the proper integration of such methods. The compressive mechanical behaviour of these scaffolds was investigated in a wet environment at 37 degrees C, and the morphological features were analysed through scanning electron microscopy (SEM) and X-ray micro-computed tomography. The capability of a magnetic scaffold to absorb magnetic nanoparticles (MNPs) in water solution was also assessed. confocal laser scanning microscopy was used to assess the in vitro biological behaviour of human mesenchymal stem cells (hMSCs) seeded on 3D structures. Results showed that a wide range of mechanical properties, covering those spanning hard and soft tissues, can be obtained by 3D FDM and stereolithography techniques. 3D virtual reconstruction and SEM showed the precision with which the scaffolds were fabricated, and a good-quality interface between poly(epsilon-caprolactone) and poly(ethylene glycol) based scaffolds was observed for bilayer and coaxial scaffolds. Magnetised scaffolds are capable of absorbing water solution of MNPs, and a preliminary information on cell adhesion and spreading of hMSCs was obtained without the application of an external magnetic field. PMID- 26420043 TI - Hundreds of unnecessary surgeries were done by physician assistant in $150m fraud. PMID- 26420044 TI - Precise colloids with tunable interactions for confocal microscopy. AB - Model colloidal systems studied with confocal microscopy have led to numerous insights into the physics of condensed matter. Though confocal microscopy is an extremely powerful tool, it requires a careful choice and preparation of the colloid. Uncontrolled or unknown variations in the size, density, and composition of the individual particles and interactions between particles, often influenced by the synthetic route taken to form them, lead to difficulties in interpreting the behavior of the dispersion. Here we describe the straightforward synthesis of copolymer particles which can be refractive index- and density-matched simultaneously to a non-plasticizing mixture of high dielectric solvents. The interactions between particles are accurately tuned by surface grafting of polymer brushes using Atom Transfer Radical Polymerization (ATRP), from hard sphere-like to long-ranged electrostatic repulsion or mixed charge attraction. We also modify the buoyant density of the particles by altering the copolymer ratio while maintaining their refractive index match to the suspending solution resulting in well controlled sedimentation. The tunability of the inter-particle interactions, the low volatility of the solvents, and the capacity to simultaneously match both the refractive index and density of the particles to the fluid opens up new possibilities for exploring the physics of colloidal systems. PMID- 26420045 TI - Assessment of the psychometric properties of the Chinese Impact of Vision Impairment questionnaire in a population-based study: findings from the Singapore Chinese Eye Study. AB - PURPOSE: We investigated whether the Chinese impact of vision impairment (IVI) questionnaire is valid to generate reliable person estimates in a population based sample. METHODS: VRQoL was measured using the 32-item Chinese version of the IVI questionnaire in the Singapore Chinese Eye Study (2009-2011), a population-based study of the prevalence and risk factors for VI and eye diseases in Chinese Singaporeans. Rasch analysis was used to assess the Chinese IVI's response category functioning, precision, unidimensionality, targeting and differential item functioning. The ability of the Chinese IVI to discriminate participants along the spectrum of VI demonstrated criterion validity. RESULTS: Of the 3353 participants, 27.2 % (n = 912) had VI (presenting visual acuity <6/12, better eye). Response categories were collapsed from six to four to resolve disordered thresholds. The Chinese IVI initially demonstrated multidimensionality and was split into three scales: 'Reading and Accessing Information'; 'Mobility and Independence'; and 'Emotional Well-being'. All three scales were unidimensional and demonstrated excellent range-based precision (all reliability coefficients 0.97), following removal of three misfitting items. Mean person measures decreased with worsening VI (e.g. Reading: none (7.50 logits); mild (6.99 logits); moderate (6.44 logits); and severe (3.01 logits) VI; p < 0.001). CONCLUSIONS: A three-dimensional 29-item Chinese IVI is a valid tool to assess the impact of VI on VRQoL in a large population-based sample, comprising over a quarter of participants with VI. The 28-item English IVI is also likely to be valid for use in population-based studies; however, this must be demonstrated empirically in future studies. PMID- 26420046 TI - Initiation of medications for Parkinson's disease: a qualitative description. AB - AIMS AND OBJECTIVES: To understand experiences of people with Parkinson's disease to initiate medication therapy for Parkinson's disease. BACKGROUND: Nonadherence to medication regimens and reluctance to initiate medication therapy among people with Parkinson's disease has been documented in previous research. However, little is known about experiences and decisions of people with Parkinson's disease to initiate antiparkinsonian medications and their beliefs or levels of understanding of antiparkinsonian medications in the USA. DESIGN: An exploratory, descriptive qualitative study was employed. METHODS: Semi-structured interviews were conducted with 16 community-dwelling individuals with Parkinson's disease (69% male) and five family caregivers (40% male). Data analysis was performed using content analysis. RESULTS: Two domains emerged from the data: decision making to initiate antiparkinsonian medications as prescribed and reasons to delay initiation of levodopa to a later stage of Parkinson's disease. CONCLUSIONS: Acceptance of antiparkinsonian medications at the early stage of Parkinson's disease was influenced by the trusting relationship between participants and their health care provider. Fear of levodopa's long-term side effects led to acceptance of non-levodopa therapies first. Complementary and Alternative Medicine was used to manage Parkinson's disease symptoms among participants who delayed antiparkinsonian medication therapy. RELEVANCE TO CLINICAL PRACTICE: Nurses may have a role to assess individuals' beliefs and concerns about antiparkinsonian medication therapy and to provide adequate information to assist with the decision about Parkinson's disease symptom management. PMID- 26420047 TI - Potential of Submergedly Cultivated Mycelia of Ganoderma spp. as Antioxidant and Antimicrobial Agents. AB - The study aimed to evaluate the antiradical and antimicrobial (antibacterial and antifungal) potentials of ethanol mycelial extracts of selected Ganoderma species and strains and to define interand intraspecies diversity among Ganoderma species and strains. Ganoderma lucidum strains were good DPPH* scavengers (neutralizing up to 57.12% radicals), contrary to G. applanatum (20.35%) and G. carnosum (17.04%). High correlations between the activities and contents of total phenols in the extracts showed that these compounds were carriers of the activity. Results obtained by both discdiffusion and microdilution methods indicated that the extract of G. lucidum BEOFB 433 was the most potent antibacterial agent that inhibited growth of almost all bacterial species at a concentration of 1.0 mg/mL. Salmonella typhimurium was the most sensitive species to the mycelium extracts. Extracts of G. lucidum BEOFB 431 and BEOFB 434 showed the best antifungal activity since in concentration of 0.5 mg/mL inhibited the growth of Aspergillus glaucus (BEOFB 431) and the growth of A. glaucus and Trichoderma viride (BEOFB 434). Extracts of G. applanatum and G. lucidum BEOFB 431 had the strongest fungicidal effects, with lethal outcomes for A. glaucus and T. viride, respectively, being noted at a concentration of 1.17 mg/mL. Aspergillus niger was proved as the most resistant species. PMID- 26420048 TI - Bioremediation of Carbendazim, a Benzimidazole Fungicide Using Brevibacillus borstelensis and Streptomyces albogriseolus Together. AB - Excessive use of pesticides in agriculture has resulted in contamination of water resources, air, soil and disruption of biogeochemical cycles. These compounds adversely affect humans and animal health, helpful soil microbes and crop production as well. Biodegradation of pesticides by microbes exists in a number of habitats like soil, sediments, surface, ground water, and sludge, etc. In the present study, efforts were made to develop a microbial consortium comprising of Streptomyces albogriseolus and Brevibacillus borstelensis strains isolated earlier which are capable of degrading carbendazim, a benzimidazole fungicide and making it harmless. Both the strains Brevibacillus borstelensis and Streptomyces albogriseolus displayed growth even at higher concentrations (500MUg mL(-1)) of carbendazim. The consortium containing Brevibacillus borstelensis and Streptomyces albogriseolus reduced carbendazim concentration from 30 ug mL(-1) to 0.86 ug mL(-1) (nearly 97%) in 12hrs to 0.60 ug mL(-1) (~98%) in 20 hrs as determined by LCMS analysis. There was a significant reduction observed in carbendazim concentration than reduction obtained when individual strain was used. This study paves a way for further exploration of degradation mechanism at the genetic level to enhance the capability of microorganisms in consortia. PMID- 26420049 TI - Triptolide Induces Cell Apoptosis by Targeting H3K4me3 and Downstream Effector Proteins in KM3 Multiple Myeloma Cells. AB - As the principal active ingredient in the Chinese herb Tripterygium wilfordii Hook.F (TwHF), triptolide has been shown to have very strong antitumor properties. The trimethylation of lysine 4 on histone H3 (H3K4me3) has been proposed to promote gene expression, and the accumulation of H3K4me3 at the transcriptional start sites of oncogenes is involved in carcinogenesis. To identify the association between the reduction of H3K4me3 and the apoptosis of MM cells induced by triptolide, we investigated the global patterns of H3K4me3 occupancy in the MM cell genome. Combined analyses using ChIP-on-chip and western blotting showed that H3K4me3 were highly enriched on the gene promoters of c-Myc and VEGFA and were associated with the up-regulation of both genes. Treatment of KM3 cells with triptolide and siRNA targeting ASH2L reduced the expression of c Myc and VEGFA. These results suggest that triptolide can down-regulate c-Myc and VEGFA expression by blocking the accumulation of H3K4me3 on their promoters,and thus play an important role in anti-MM mechanism. PMID- 26420050 TI - Nutrition in Allogeneic Stem Cell Transplantion--Clinical Guidelines and Immunobiological Aspects. AB - Even though malnutrition is associated with an adverse prognosis after allogeneic stem cell transplantation, few studies have addressed the question what is the optimal nutritional support for these patients. There is a general agreement that the body weight, body mass index and nutritional intake can be used to guide the post-transplant nutritional support; enteral nutrition may then be tried but most patients will require parenteral nutrition. There is no scientific basis for further standardization of post-transplant nutritional support. The nutritional status with regard to amino acid as well as fatty acid metabolism and vitamin levels are important for immunoregulation. Several amino acids and their metabolites function as signaling molecules through their binding to specific receptors, and they are thereby become important both in dendritic cell differentiation and T cell activation and the metabolic switch that often occurs during the activation of immunocompetent cells. We review previous studies of nutritional support in allotransplant recipients and discuss possible molecular mechanisms involved in metabolic immunoregulation and the development of post transplant immune-mediated complications. PMID- 26420051 TI - Development of Personalized Molecular Therapy for Acute Myeloid Leukemia. AB - Acute myeloid leukemia (AML) is characterized by extensive clinical and biological heterogeneity. Despite vast advances in understanding the molecular pathology in AML during the last two decades few new AML therapeutics have been approved by the European Medicines Agency. Since 2005 only the epigenetic modulators decitabine and azacytidine, as well as histamine (plus interleukin- 2) have been approved against AML. None of these have outstanding efficiency, and decitabine and azacytdine have only been incorporated in frontline therapy of AML with limited enthusiasm. The majority of AML patients are frail and elderly, and lack of mild but effective agents for this patient cohort constitutes a major unmet need as overall survival remains poor. Along with the recent advancements in the molecular characterization of AML, numerous targeted therapies have been tested in clinical trials. In this review, we discuss the biological rationale for a selection of these novel therapeutic approaches, including epigenetic modifiers, agents targeting signalling pathways and inhibitors of nuclear cytoplasmic shuttling. Further we discuss some of the possible shortcomings in current trial design that could explain the apparent incoherence between our improved biological knowledge and the lack of progress in therapy development of AML. PMID- 26420052 TI - Features and outcomes of pediatric early T cell leukemia: King Hussein Cancer Center experience. PMID- 26420054 TI - Changes in levels of apoptosis in the walls of different segments of great saphenous varicose veins. AB - OBJECTIVE: Disordered programmed cell death may play a role in the development of superficial venous incompetence. We have determined the number of cells undergoing apoptosis and the alterations in the apoptotic level in the wall of different segments of the great saphenous varicose vein. METHODS: Twenty-one varicose great saphenous veins (VGSVs) (varicose group) and 12 normal great saphenous veins (GSVs) (control group) were collected, and the apoptosis level in the upper, middle, and lower segments were immunohistochemically stained with antibodies (anti-Bax and anti-Bcl-xl). Apoptosis was evaluated by the TUNEL assay and immunofluorescence staining. The morphology of apoptotic cells was observed with an electron microscope. RESULTS: Quantitative analysis showed that the apoptotic ratios in venous walls (intima and media) of the varicose group were significantly lower than the corresponding regions in the control group (all P < 0.05). A significantly higher apoptotic rates of the venous walls was observed in control group within the upper compared with the lower segment (P < 0.05). Significantly higher positive proteins expression rates of Bcl-xl/Bax were also detected in the VGSVs compared with the GSVs within the three segments, respectively (P < 0.01). Electron microscopic observations confirmed that endothelial and smooth muscle cells in varicose and normal vein walls exhibited apoptotic morphologic features, such as fuzzy mitochondrial cristae, medullary changes, and margination of the nuclear chromatin. CONCLUSION: VGSV walls were found to have a significant decrease in apoptotic rate compared with that of GSVs. The rate of apoptosis in the intima and media within the upper segment was increased more than the middle and lower segments in the GSVs. Our findings confirm that programmed cell death is down-regulated in primary varicose veins. PMID- 26420053 TI - Association of polymorphisms near the FOXC2 gene with the risk of varicose veins in ethnic Russians. AB - OBJECTIVE: To investigate the association of polymorphisms located near the FOXC2 gene with the risk of varicose veins in ethnic Russians. METHODS: Allele, genotype, and haplotype frequencies were determined in the sample of 474 patients with primary varicose veins and in the control group of 478 individuals without a history of chronic venous disease. RESULTS: Polymorphisms rs7189489, rs4633732, and rs1035550 showed the association with the increased risk of varicose veins, but none of the observed associations remained significant after correction for multiple testing. Haplotype analysis revealed the association of haplotype rs7189489 C-rs4633732 T-rs34221221 C-rs1035550 C-rs34152738 T-rs12711457 G with the increased risk of varicose veins (OR = 2.67, P = 0.01). CONCLUSIONS: Our results provide evidence that the studied polymorphisms do not play a major role in susceptibility to varicose veins development in the Russian population. PMID- 26420056 TI - How TK-TD and population models for aquatic macrophytes could support the risk assessment for plant protection products. AB - This case study of the Society of Environmental Toxicology and Chemistry (SETAC) workshop MODELINK demonstrates the potential use of mechanistic effects models for macrophytes to extrapolate from effects of a plant protection product observed in laboratory tests to effects resulting from dynamic exposure on macrophyte populations in edge-of-field water bodies. A standard European Union (EU) risk assessment for an example herbicide based on macrophyte laboratory tests indicated risks for several exposure scenarios. Three of these scenarios are further analyzed using effect models for 2 aquatic macrophytes, the free floating standard test species Lemna sp., and the sediment-rooted submerged additional standard test species Myriophyllum spicatum. Both models include a toxicokinetic (TK) part, describing uptake and elimination of the toxicant, a toxicodynamic (TD) part, describing the internal concentration-response function for growth inhibition, and a description of biomass growth as a function of environmental factors to allow simulating seasonal dynamics. The TK-TD models are calibrated and tested using laboratory tests, whereas the growth models were assumed to be fit for purpose based on comparisons of predictions with typical growth patterns observed in the field. For the risk assessment, biomass dynamics are predicted for the control situation and for several exposure levels. Based on specific protection goals for macrophytes, preliminary example decision criteria are suggested for evaluating the model outputs. The models refined the risk indicated by lower tier testing for 2 exposure scenarios, while confirming the risk associated for the third. Uncertainties related to the experimental and the modeling approaches and their application in the risk assessment are discussed. Based on this case study and the assumption that the models prove suitable for risk assessment once fully evaluated, we recommend that 1) ecological scenarios be developed that are also linked to the exposure scenarios, and 2) quantitative protection goals be set to facilitate the interpretation of model results for risk assessment. PMID- 26420057 TI - A Cs(x)WO3/ZnO nanocomposite as a smart coating for photocatalytic environmental cleanup and heat insulation. AB - A novel CsxWO3/ZnO smart coating was proposed to achieve multiple functions, such as heat insulation, photodecomposition of toxic NO gas, blocking of harmful UV light, etc. In this composite coating, CsxWO3 nanorods were used as a NIR and UV light shielding material while ZnO nanoparticles were utilized as a photocatalyst and a material to enhance visible light transmittance and block UV light. When the mass ratio of CsxWO3/ZnO was 1, the composite coating possessed a very good visible light transmittance of over 80% and an excellent UV-shielding ability. This novel coating showed heat insulation that is superior to the ITO coating and photocatalytic decontamination of NO gas that is superior to the standard TiO2 (P25). The proposed CsxWO3/ZnO smart coating is a promising material not only for energy saving but also for environmental cleanup. PMID- 26420055 TI - Use of Focus Groups to Inform a Youth Diabetes Prevention Model. AB - OBJECTIVE: To explore minority adolescents' perceptions of their diabetes risk, barriers and facilitators to adopting lifestyle changes, and ideas for adapting a youth diabetes prevention model. METHODS: The study was conducted at collaborating community sites in East Harlem, NY. Trained moderators facilitated focus groups, which were audio taped and transcribed. Participants were 21 Latino and African American adolescents aged 14-18 years with a family history of diabetes and no reported personal history of diabetes. The phenomenon of interest was youth input in adapting a diabetes prevention model. Two researchers independently coded transcripts, identified major themes, compared findings, and resolved differences through discussion and consensus. RESULTS: Dominant themes included (1) the impact of diabetes on quality of life within adolescents' personal networks; (2) conflict between changing diet and activity and their current lifestyle; (3) lifestyle choices being dictated by cost, mood, body image, and environment, not health; and (4) family, social, and environmental pressures reinforcing sedentary behaviors and unhealthy diets. CONCLUSIONS AND IMPLICATIONS: Themes from youth focus groups were framed in the context of an existing youth diabetes prevention conceptual model, with results informing expansion of the model and identification and organization of potential intervention components. PMID- 26420059 TI - Multiple Bonds between Main-Group Elements and Transition Metals. 136. "Polymerization" of an Organometal Oxide: The Unusual Behavior of Methyltrioxorhenium(VII) in Water. PMID- 26420058 TI - A diphtheria toxin resistance marker for in vitro and in vivo selection of stably transduced human cells. AB - We developed a selectable marker rendering human cells resistant to Diphtheria Toxin (DT). The marker (DT(R)) consists of a primary microRNA sequence engineered to downregulate the ubiquitous DPH2 gene, a key enzyme for the biosynthesis of the DT target diphthamide. DT(R) expression in human cells invariably rendered them resistant to DT in vitro, without altering basal cell growth. DT(R)-based selection efficiency and stability were comparable to those of established drug resistance markers. As mice are insensitive to DT, DT(R)-based selection can be also applied in vivo. Direct injection of a GFP-DT(R) lentiviral vector into human cancer cell-line xenografts and patient-derived tumorgrafts implanted in mice, followed by systemic DT administration, yielded tumors entirely composed of permanently transduced cells and detectable by imaging systems. This approach enabled high-efficiency in vivo selection of xenografted human tumor tissues expressing ectopic transgenes, a hitherto unmet need for functional and morphological studies in laboratory animals. PMID- 26420060 TI - Software development for estimating the concentration of radioactive cesium in the skeletal muscles of cattle from blood samples. AB - The 2011 earthquake severely damaged the Fukushima Daiichi Nuclear Power Plant (FNPP), resulting in the release of large quantities of radioactive material into the environment. The deposition of these radionuclides in rice straw as livestock feed led to the circulation of contaminated beef in the market. Based on the safety concern of the consumers, a reliable method for estimating concentrations of radioactive cesium in muscle tissue is needed. In this study, we analyzed the concentrations of radioactive cesium in the blood and skeletal muscle of 88 cattle, and detected a linear correlation between them. We then developed software that can be used to estimate radioactive cesium concentrations in muscle tissue from blood samples. Distribution of this software to the livestock production field would allow us to easily identify high-risk cattle, which would be beyond the safety regulation, before shipping out to the market. This software is planned to be released as freeware. This software would contribute to food safety, and aid the recovery of the livestock industry from the damage creacted by the 2011 Tohoku earthquake and tsunami. PMID- 26420061 TI - Lack of survival improvement with novel anti-myeloma agents for patients with multiple myeloma and central nervous system involvement: the Greek Myeloma Study Group experience. AB - Involvement of the central nervous system (CNS) is a rare complication of multiple myeloma (MM). Herein, we have described the incidence, characteristics, prognostic factors for post CNS-MM survival, and outcome of CNS-MM and explored the efficacy of novel agents (NA) (thalidomide, bortezomib, lenalidomide) in this setting. Between 2000 and 2013, 31 (0.9 %) out of 3408 newly diagnosed symptomatic MM patients, consecutively diagnosed and treated during the same period in 12 Greek centers, developed CNS-MM (M/F 15/16, median age 59 years, range 20-96 years; newly diagnosed/relapsed-refractory 2/29; median time to CNS MM diagnosis 29 months). Clinical and laboratory characteristics were retrospectively recorded. Twenty-six percent of patients had circulating plasma cells (PCs) or plasma cell leukemia (PCL) at CNS-MM and 39 % had skull-derived plasmacytomas, suggesting hematological and contiguous spread. Treatment for CNS MM was offered in 29/31 patients and 11/29 responded (NA 18/29, additional radiotherapy 9/28, intrathecal chemotherapy 13/29). The median post CNS-MM survival was 3 months (95 % CI 1.9-4.1) and did not differ between patients treated with NA and/or radiotherapy vs. others. In the multivariate analysis, prior treatment of MM with NA, extramedullary disease (EMD) during MM course (i.e., plasmacytomas, circulating PCs, or documented PCL) and abnormally high LDH at MM diagnosis were independent prognostic factors, whereas treatment of CNS-MM with NA did not predict for post CNS-MM survival. Despite the relatively limited number of patients due to the rarity of CNS-MM, our results suggest that NA do not seem to improve post CNS-MM survival. Patients with EMD display shortened post CNS-MM survival and should be followed thoroughly. PMID- 26420062 TI - A randomized clinical trial on the effectiveness of an intervention to treat psychological distress and improve quality of life after autologous stem cell transplantation. AB - Psychological distress contributes to impaired quality of life in hematological cancer patients. Stepped care treatment, in which patients start with the least intensive treatment most likely to work and only receive more intensive interventions if needed, could improve distress. We aimed to evaluate the outcome of stepped care treatment on psychological distress and physical functioning in patients treated with autologous stem cell transplantation for hematological malignancies. In the present study, we performed a randomized clinical trial with two treatment arms: stepped care and care as usual. Baseline assessment and randomization occurred during pre-transplant hospitalization. Stepped care was initiated after 6 weeks, consisting of (1) watchful waiting, (2) Internet-based self-help intervention, and (3) face-to-face counseling/ psychopharmacological treatment/ referral. Follow-up measurements were conducted at 13, 30, and 42 weeks after transplantation. Stepped care (n = 47) and care as usual (n = 48) were comparable on baseline characteristics. The uptake of the intervention was low: 24 patients started with step 1, 23 with step 2, and none with step 3. Percentages of distressed patients ranged from 4.1 to 9.7 %. Ten percent of patients received external psychological or psychiatric care. No statistically significant differences were found between stepped care and care as usual on psychological distress or physical functioning in intention to treat analyses, nor in per protocol analyses. The stepped care program was not effective in decreasing psychological distress. The low intervention uptake, probably related to the low levels of psychological distress, offers an explanation for this outcome. Future research should take into account patients' specific care needs. Netherlands Trial Registry identifier: NTR1770. PMID- 26420064 TI - Adsorption of Lead Ions from Aqueous Phase on Mesoporous Silica with P-Containing Pendant Groups. AB - Mesoporous silica materials with hydroxyphosphatoethyl pendant groups (POH-MS) were obtained by a two-step process: (1) block copolymer Pluronic P123-templated synthesis of mesoporous silica with diethylphosphatoethyl groups (DP-MS) by co condensation of diethylphosphatoethyl triethoxysilane (DPTS) and tetraethylorthosilicate (TEOS) under acidic conditions and (2) conversion of diethylphosphatoethyl into hydroxyphosphatoethyl groups upon suitable treatment with concentrated hydrochloric acid. The DP-MS samples obtained by using up to 20% of DPTS featured hexagonally ordered mesopores, narrow pore size distribution and high specific surface area. Conversion of DP-MS to mesoporous silica with hydroxyphosphatoethyl groups (POH-MS) resulted in the enlargement of the specific surface area, total porosity, and microporosity. High affinity of hydroxyphosphatoethyl groups toward lead ions (Pb(2+)) makes the POH-MS materials attractive sorbents for lead ions, which is reflected by high lead uptake reaching 272 mg of Pb(2+) per gram of POH-MS. This study shows that the simple and effective co-condensation strategy assures high loading of P-containing groups showing high affinity toward lead ions, which is of great importance for removal of highly toxic lead ions from contaminated water. PMID- 26420063 TI - [Direct oral anticoagulation and gastrointestinal bleeding: Interventional therapy management]. AB - BACKGROUND: More and more patients are being treated with direct oral anticoagulants (DOAC). Under treatment with DOACs gastrointestinal bleeding appears to occur more frequently, particularly in the lower gastrointestinal tract, compared to treatment with vitamin K antagonists (e.g. warfarin). OBJECTIVE: A possible approach should now be elaborated in a joint effort by gastroenterologists and cardiologists. MATERIAL AND METHODS: A selective literatue search was carried out and own experiences were also included. RESULTS: The decision to perform procoagulant therapy by slowly injecting 30-50 IU prothrombin complex concentrate (PPSB) per kg body weight intravenously depends on various factors and should be assessed critically. Specific antidotes are awaiting approval. After a bleeding episode potentially controllable and reversible triggers must be excluded (e.g. drug interactions and renal impairment). The risk of recurrent bleeding and the risk of thromboembolic events have to be weighed against each other before deciding to readminister an anticoagulant and its form. Dose reduction and changing to apixaban (in reduced dosage) are options for risk reduction and vitamin K antagonists can also be considered. DISCUSSION: It is still unclear what role specific antidotes will play. PMID- 26420066 TI - Benzophenone and its analogs bind to human glyoxalase 1. AB - Benzophenone is a popular photophore for photoaffinity-labeling. It is also an important framework for drug development; many drugs contain benzophenone or analogous frameworks. The current work reports that benzophenone and its analogs bind to human glyoxalase 1. The binding, however, has little effect on the catalytic activity of this enzyme. The implications of the finding in terms of both drug development and photoaffinity-labeling are discussed. PMID- 26420065 TI - PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells. AB - Tumour-initiating cells (TICs) are advocated to constitute the sustaining force to maintain and renew fully established malignancy; however, the molecular mechanisms responsible for these properties are elusive. We previously demonstrated that voltage-gated calcium channel alpha2delta1 subunit marks hepatocellular carcinoma (HCC) TICs. Here we confirm directly that alpha2delta1 is a HCC TIC surface marker, and identify let-7c, miR-200b, miR-222 and miR-424 as suppressors of alpha2delta1(+) HCC TICs. Interestingly, all the four miRNAs synergistically target PBX3, which is sufficient and necessary for the acquisition and maintenance of TIC properties. Moreover, PBX3 drives an essential transcriptional programme, activating the expression of genes critical for HCC TIC stemness including CACNA2D1, EpCAM, SOX2 and NOTCH3. In addition, the expression of CACNA2D1 and PBX3 mRNA is predictive of poor prognosis for HCC patients. Collectively, our study identifies an essential signalling pathway that controls the switch of HCC TIC phenotypes. PMID- 26420068 TI - All-metallagermoxane with an adamantanoid cage structure: [(Cp*Ru(CO)2Ge)4(MU O)6] (Cp* = eta(5)-C5Me5). AB - In an attempt to synthesize a zero valent germanium compound, we have carried out the reaction of [(Cp*RuCO)(GeCl2)]2, 1 with potassium metal that led to the formation of a metallagermoxane [(Cp*Ru(CO)2Ge)4(MU-O)6], 2. Compound 2 is the first example of a tetrametallagermoxane with an exo-{Cp*Ru(CO)2} fragment. DFT calculations were used to examine the key intermediates associated with the formation of 2. PMID- 26420067 TI - New SIRT1 activator from alkaline hydrolysate of total saponins in the stems leaves of Panax ginseng. AB - Two new dammarane-type triterpenes, namely ginsenoslaloside-I [3beta,12beta,24S trihydroxy-dammara-20(22)E,25-diene-3-O-beta-D-glucopyranoside, 1] and 20(S) ginsenoside-Rh1-6'-acetate (2), together with twelve known compounds (3-14) were isolated from the alkaline hydrolysate of total saponins of the stems-leaves of Panax ginseng C.A. Meyer. Their chemical structures were elucidated by extensive spectroscopic analyses and comparison with the reported data. All 14 compounds were evaluated for their anti-proliferative activities against two human cancer cell lines (HL-60 and Hep-G2) and promotion activities of SIRT1. Compound 6 exhibited significant inhibitory activity in a concentration-dependent manner against HL-60 and Hep-G2 with the IC50 values of 10.32 and 24.33MUM, respectively, and had comparable IC50 values with those of vinorelbine, a positive control agent. Meanwhile, compounds 1 and 6 were found to be a potential activator of SIRT1. The preliminary structure-activity relationship was also discussed based on the experimental data obtained. PMID- 26420069 TI - What factors control superficial lava dome explosivity? AB - Dome-forming eruption is a frequent eruptive style and a major hazard on numerous volcanoes worldwide. Lava domes are built by slow extrusion of degassed, viscous magma and may be destroyed by gravitational collapse or explosion. The triggering of lava dome explosions is poorly understood: here we propose a new model of superficial lava-dome explosivity based upon a textural and geochemical study (vesicularity, microcrystallinity, cristobalite distribution, residual water contents, crystal transit times) of clasts produced by key eruptions. Superficial explosion of a growing lava dome may be promoted through porosity reduction caused by both vesicle flattening due to gas escape and syn-eruptive cristobalite precipitation. Both processes generate an impermeable and rigid carapace allowing overpressurisation of the inner parts of the lava dome by the rapid input of vesiculated magma batches. The relative thickness of the cristobalite-rich carapace is an inverse function of the external lava dome surface area. Explosive activity is thus more likely to occur at the onset of lava dome extrusion, in agreement with observations, as the likelihood of superficial lava dome explosions depends inversely on lava dome volume. This new result is of interest for the whole volcanological community and for risk management. PMID- 26420070 TI - Bifidobacterium breve prevents necrotising enterocolitis by suppressing inflammatory responses in a preterm rat model. AB - Necrotising enterocolitis (NEC) is associated with inflammatory responses and barrier dysfunction in the gut. In this study, we investigated the effect of Bifidobacterium breve M-16V on factors related to NEC development using an experimental rat model. Caesarean-sectioned rats were given formula milk with or without B. breve M-16V by oral gavage thrice daily, and experimental NEC was induced by exposing the rats to hypoxic conditions. Naturally delivered rats that were reared by their mother were used as healthy controls. The pathological score of NEC and the expression of molecules related to inflammatory responses and the barrier function were assessed in the ileum. B. breve M-16V reduced the pathological scores of NEC and resulted in some improvement in survivability. B. breve M-16V suppressed the increased expression of molecules related to inflammation and barrier function that resulted from NEC induction. B. breve M 16V normalised Toll-like receptor (TRL)4 expression and enhanced TLR2 expression. Our data suggest that B. breve M-16V prevents NEC development by modulating TLR expressions and suppressing inflammatory responses in a rat model. PMID- 26420071 TI - HIV transmission law in the age of treatment-as-prevention. AB - Evidence that treating people with HIV early in infection prevents transmission to sexual partners has reframed HIV prevention paradigms. The resulting emphasis on HIV testing as part of prevention strategies has rekindled the debate as to whether laws that criminalise HIV transmission are counterproductive to the human rights-based public health response. It also raises normative questions about what constitutes 'safe(r) sex' if a person with HIV has undetectable viral load, which has significant implications for sexual practice and health promotion. This paper discusses a recent high-profile Australian case where HIV transmission or exposure has been prosecuted, and considers how the interpretation of law in these instances impacts on HIV prevention paradigms. In addition, we consider the implications of an evolving medical understanding of HIV transmission, and particularly the ability to determine infectiousness through viral load tests, for laws that relate to HIV exposure (as distinct from transmission) offences. We conclude that defensible laws must relate to appreciable risk. Given the evidence that the transmissibility of HIV is reduced to negligible level where viral load is suppressed, this needs to be recognised in the framing, implementation and enforcement of the law. In addition, normative concepts of 'safe(r) sex' need to be expanded to include sex that is 'protected' by means of the positive person being virally suppressed. In jurisdictions where use of a condom has previously mitigated the duty of the person with HIV to disclose to a partner, this might logically also apply to sex that is 'protected' by undetectable viral load. PMID- 26420072 TI - Survey of Japanese mothers of daughters eligible for human papillomavirus vaccination on attitudes about media reports of adverse events and the suspension of governmental recommendation for vaccination. AB - AIM: Following media reports of adverse medical events surrounding human papillomavirus (HPV) vaccination and the suspension of Japanese governmental recommendation, most adolescents have refrained from receiving the vaccine. This represents a national critical event, because the incidence of cervical cancer in Japan continues to increase. METHODS: We conducted an Internet survey to investigate why Japanese adolescent girls decline, continue or discontinue their HPV vaccination, how their mothers influence their decision, and the mothers' feelings about future HPV vaccination for their daughters. One thousand mothers with daughters 10-18 years of age were recruited for our questionnaire. RESULTS: Our results suggest that acceptance of the HPV vaccine was determined predominantly by the mother's perceptions of risk versus benefits, rather than the daughter's wishes. The mothers' knowledge of the benefits of the prophylactic HPV vaccine and their attitude toward cervical cancer screening influenced their decision whether to allow their daughter to receive future vaccinations. The tenor of survey responses of those mothers who were anti-vaccine changed significantly to the positive in response to a proposed scenario where the governmental recommendation for the HPV vaccine was reinstated, whereas a hypothetical educational intervention sheet did not significantly change their attitude. CONCLUSIONS: Promotion of the HPV vaccine through comprehensive education for both mothers and daughters, not only on the vaccine itself, but also about cervical cancer and screening, is required for any successful program to prevent cervical cancer. PMID- 26420074 TI - Detection and Occurrence of Indicator Organisms and Pathogens. AB - This review summarizes the literature pertaining to the occurrence and detection of indicator organisms and pathogens published during 2014. It is organized into the following sections: i) detection and quantification of fecal indicators and waterborne pathogens, ii) microbial source tracking (MST) using genotypic and phenotypic methods, iii) antibiotic resistant bacteria (ARB), iv) live vs. dead cell differentiation methods, and v) next generation sequencing (NGS). PMID- 26420073 TI - Detection, Occurrence and Fate of Emerging Contaminants in Agricultural Environments. AB - A total of 43 papers published in 2014 were reviewed ranging from detailed descriptions of analytical methods, to fate and occurrence studies, to measuring and predicting biological effects for a wide variety of emerging contaminants likely to occur in agricultural environments. New methods and studies on veterinary pharmaceuticals, natural and synthetics steroids, and antibiotic resistance genes in agricultural environments continue to expand our knowledge base on the occurrence and potential impacts of these compounds. This review is divided into the following sections: Introduction, Analytical Methods, Occurrence and Fate, Antibiotic Resistance Genes, and Risk Assessment. PMID- 26420076 TI - Physico-Chemical Processes. AB - This review is on the research literature published in 2014 related to the physico-chemical processes for water and wastewater treatment. The review is divided into six sections, including coagulation/flocculation, filtration, sedimentation, oxidation, flotation, sorption process. PMID- 26420075 TI - Wastewater Collection Systems. AB - This chapter presents a review of the literature published in 2014 on topics relating to wastewater collection systems. It presents advances in noteworthy research and industry experiences selected from major literature sources. This review is divided into the following sections: sewer system planning; sewer condition assessment/rehabilitation; pump stations and system design; operation and maintenance; and regulatory issues/ integrated planning. PMID- 26420078 TI - Biological Fixed Film. AB - The review includes literatures published in the year of 2014 regarding the uses of biofilm and bioreactor to treat wastewater. Topics considered are: biofilm formation and factors that impact biofilm formation; extracellular polymeric substance from biofilms; biofilm consortia and quorum sensing; biofilm reactors and biofilm in bioelectrochemical systems. PMID- 26420077 TI - Activated Sludge and other Aerobic Suspended Culture Processes. AB - This is a literature review for the year 2014 and contains information specifically associated with suspended growth processes including activated sludge and sequencing batch reactors. This review is a subsection of the treatment systems section of the annual literature review. The review encompasses modeling and kinetics, nutrient removal, system design and operation. Compared to past reviews, many topics show increase in activity in 2014. These include, nitrogen and phosphorus control, fate and effect of xenobiotics, industrial wastes treatment, and some new method for the determination of activated sludge. These topics are referred to the degradation of constituents in activated sludge. Other sections include population dynamics, process microbiology of activated sludge, modeling and kinetics. Many of the subsections in the industrial wastes: converting sewage sludge into fuel gases, thermos-alkali hydrolysis of Waste Activated Sludge (WAS), sludge used as H2 S adsorbents were also mentioned in this review. PMID- 26420079 TI - Membrane Processes. AB - This review, for literature published in 2014, contains information related to membrane processes for municipal and industrial applications. This review is a subsection of the Treatment Systems section of the annual Water Environment Federation literature review and covers the following topics: pretreatment, membrane bioreactor (MBR) configuration, design, nutrient removal, operation, industrial treatment, fixed film and anaerobic membrane systems, reuse, microconstituents removal, membrane technology advances, membrane fouling, and modeling. Other sub-sections of the Treatment Systems section that might relate to this literature review include: Biological Fixed-Film Systems, Activated Sludge and Other Aerobic Suspended Culture Processes, Anaerobic Processes, Water Reclamation and Reuse. The following sections might also have related information on membrane processes: Industrial Wastes, Hazardous Wastes, and Fate and Effects of Pollutants. PMID- 26420080 TI - Anaerobic Process. AB - A review of the literature published in 2014 on the focus of Anaerobic Process. It is divided into the following sections. *Pretreatment *Organic waste *multiple stage co-digestion *Process Methodology and Technology. PMID- 26420082 TI - Disinfection Processes. AB - A review of the literature published in 2014 on topics relating to disinfection processes is presented. This review is divided into the following sections: disinfection methods, disinfection byproducts, and microbiology and microbial communities. PMID- 26420081 TI - Wetlands for Wastewater Treatment. AB - This paper provides a review of the treatment technologies, which utilize natural processes or passive components in wastewater treatment. In particular, this paper primarily focuses on wetland systems and their applications in wastewater treatment (as an advanced treatment unit or decentralized system), nutrient and pollutant removal (single and multiple pollutants, and metals), and emerging pollutant removal (pharmaceuticals). A summary of studies involving the plant (vegetation) effects, wetland design and modeling, hybrid and innovative systems, storm water treatment and pathogen removal is also included. PMID- 26420083 TI - Biosolids and Sludge Management. AB - This review section covers journal articles and conference papers related to biosolids and sludge management that were published in 2014. The literature review has been divided into the following sections: * Biosolids regulations and management issues; * ;Biosolids characteristics, quality and measurement including microconstituents and pathogens; * Sludge treatment technologies including pretreatment and sludge minimization, conditioning and dewatering, digestion, composting and innovative technologies; * Disposal and reuse including combustion/ incineration, land application and non- agricultural use; * Odor and air emissions; and * Energy issues. PMID- 26420084 TI - Gaseous Emissions from Wastewater Facilities. AB - A review of the literature published in 2014 on topics relating to gaseous emissions from wastewater facilities is presented. This review is divided into the following sections: odorant emissions from wastewater treatment plants (WWTPs); greenhouse gas (GHG) emissions from WWTPs; gaseous emissions from wastewater collection systems; physiochemical odor/emissions control methods; biological odor/emissions control methods; odor characterization/monitoring; and odor impacts/risk assessments. PMID- 26420085 TI - Modeling, Instrumentation, Automation, and Optimization of Water Resource Recovery Facilities. AB - A review of the literature published in 2014 on topics relating to water resource recovery facilities (WRRF) in the areas of modeling, instrumentation, automation and optimization of wastewater treatment is presented. Note that WEF has adopted 'WRRF' replacing such previous terms as publicly owned treatment works, wastewater treatment plant (WWTP), and other terms and officially instituted this change in its publications beginning in 2012. It is anticipated the replaced terms will remain in use by other publications and authors for some time. This review will strive to maintain consistency with this change but also avoid confusion where possible. PMID- 26420086 TI - Distributed Treatment Systems. AB - This section presents a review of the literature published in 2014 on topics relating to distributed treatment systems. This review is divided into the following sections with multiple subsections under each: constituent removal; treatment technologies; and planning and treatment system management. PMID- 26420087 TI - Sustainability. AB - This review on Sustainability covers selected 2014 publications on the focus of the following sections: * Sustainable water and wastewater utilities * Sustainable water resources management * Stormwater and green infrastructure * Sustainability in wastewater treatment * Life cycle assessment (LCA) applications * Sustainability and energy in wastewater industry, * Sustainability and asset management. PMID- 26420088 TI - Agricultural Waste. AB - The management and disposal of agricultural waste are drawn more and more attention because of the increasing yields and negative effects on the environment. However, proper treatments such as converting abundant biomass wastes into biogas through anaerobic digestion technology, can not only avoid the negative impacts, but also convert waste into available resources. This review summarizes the studies of nearly two hundred scholars from the following four aspects: the characterization, reuse, treatment, and management of agricultural waste. PMID- 26420089 TI - Automotive Wastes. AB - A review of the literature from 2014 related to automotive wastes is presented. Topics include solid wastes from autobodies and tires as well as vehicle emissions to soil and air as a result of the use of conventional and alternative fuels. Potential toxicological and health risks related to automotive wastes are also discussed. PMID- 26420090 TI - Chemical Waste and Allied Products. AB - This review of literature published in 2014 focuses on waste related to chemical and allied products. The topics cover the waste management practices, hospital waste, pesticide waste, chemical wastewater, pesticide wastewater and pharmaceutical wastewater. The other topics include aerobic treatment, anaerobic treatment, sorption and ozonation. PMID- 26420091 TI - Food-Processing Wastes. AB - Literature published in 2014 and early 2015 related to food processing wastes treatment for industrial applications are reviewed. This review is a subsection of the Treatment Systems section of the annual Water Environment Federation literature review and covers the following food processing industries and applications: general, meat and poultry, fruits and vegetables, dairy and beverage, and miscellaneous treatment of food wastes. PMID- 26420092 TI - Mine Drainage and Oil Sand Water. AB - Mine drainage from the mining of mineral resources (coal, metals, oil sand, or industrial minerals) remains as a persistent environmental problem. This review summarizes the scientific literature published in 2014 on the technical issues related to mine drainage or mine water in active and abandoned coal/hard rock mining sites or waste spoil piles. Also included in this review is the water from oil sand operations. This review is divided into the four sections: 1) mine drainage characterization, 2) prediction and environmental impact, 3) treatment technologies, 4) oil sand water. Many papers presented in this review address more than one aspect and different sections should not be regarded as being mutuallyexclusive or all-inclusive. PMID- 26420093 TI - Textiles. AB - A review of the literature published in 2014 on topics relating to the treatment alternatives for wastewater from the textile industries is presented. This review is divided into the following sections: a brief introduction on the implementation of the Best Available Techniques into textile industry, a review of the more promising treatment technologies distinguished into physico-chemical, biological and combined processes. PMID- 26420094 TI - Bioenergy from Biofuel Residues and Wastes. AB - This review includes works published in the general scientific literature during 2014 on the production of bioenergy and biofuel from waste residues generated during bioethanol and biodiesel production with a brief overview of current and emerging feedstocks. Anothersection of this review summarizes literature on culturing algae for biofuels including bioreactors and open pond cultivation systems with the utilization of inorganic and organic sources of nutrients. New methods applicable to the mass culture of algae are highlighted. Algal cell harvesting and oil extraction techniques tested and developed for algae are also discussed. PMID- 26420095 TI - Hazardous Waste Treatment Technologies. AB - The article reviews the scientific literature published in 2014 on physical, chemical, and biological treatment of hazardous contaminants and environmental bioremediation. PMID- 26420096 TI - Radioactive Wastes. AB - Papers reviewed herein present a general overview of radioactive waste activities around the world in 2014. These include safety assessments, decommission and decontamination of nuclear facilities, fusion facilities, transportation and management solutions for the final disposal of low and high level radioactive wastes (LLW and HLW), interim storage and final disposal options for spent fuel (SF), and tritiated wastes, with a focus on environmental impacts due to the mobility of radionuclides in water, soil and ecosystem alongwith other progress made in the management of radioactive wastes. PMID- 26420097 TI - Mixing and Transport. AB - This section covers research published during the calendar year 2014 on mixing and transport processes. The review covers mixing of anaerobic digesters, mixing of heat transfer, and environmental fate and transport. PMID- 26420098 TI - Stream, Lake, and Reservoir Management. AB - This review on stream, lake, and reservoir management covers selected 2014 publications on the focus of the following sections: * Biota * Climate effect * Models * Remediation and restoration * Reservoir operations * Stream, Lake, and Reservoir Management * Water quality. PMID- 26420099 TI - Contaminated Aquatic Sediments. AB - A review of the literature published in 2014 relating to the assessment, evaluation and remediation of contaminated aquatic sediments is presented. The review is divided into the following sections: policy and guidance, methodology, distribution, fate and transport, bioavailability, bioaccumulation, risk, toxicity and remediation. PMID- 26420100 TI - Nonpoint Source Pollution. AB - The article presents a comprehensive review of research advancing in 2014 on nonpoint source pollution (NPS). The topics presented relate to nonpoint source pollution (NPS) within agricultural and urban areas. NPS pollution from agricultural areas is the main focus in this review. Management of NPS in agricultural, urban and rural areas is presented. Modeling of NPS pollution in different watersheds with various modeling tools is reviewed. PMID- 26420101 TI - Fate of Environmental Pollutants. AB - This annual review covers the literature published in 2014 on topics related to the occurrence and fate of emerging environmental pollutants in wastewater. Due to the vast amount of literature published on this topic, I have discussed only a fraction of the quality research publications, up to maximum 15 relevant articles per section, due to limitation of space. The abstract search was carried out using Web of Science, and the abstracts were selected based on their relevance. In few cases, full-text articles were referred to better understand new findings. This review is divided into the following sections: biological agents, disinfection by-products (DBPs), halogenated compounds, pharmaceuticals and personal care products (PPCPs), and other emerging contaminants. PMID- 26420102 TI - Substratum-Associated Microbiota. AB - This review of literature on substratumassociated microbiota from 2014 highlights topics on benthic algae and bacteria from a range of aquatic environments, but focuses on freshwater habitats. Advances in pollution and toxin detection, assessment methods, and applications of new technologies are highlighted as are updates in taxonomy and systematics. Aspects of general ecology, water quality, nutrient cycling, trophic interactions, land use changes, biofuels, biofouling, and environmental challenges such as climate change, pollutants, tar sands and fracking, oil spills and nuisance blooms are presented. PMID- 26420103 TI - Effects of Pollution on Freshwater Organisms. AB - This review includes works published in the general scientific literature during 2014 on the effects of anthropogenic pollutants on freshwater organisms. It begins with two broad sections: research reviews and broad field studies and surveys. This is followed by reviews of research categorized in sections to reflect the pollutant class. These sections include wastewater, stormwater and non-point source pollution, nutrients, sediment cap materials and suspended clays, botanical extracts, surfactants, metals, persistent organic pollutants, pharmaceuticals, endocrine disruptors, pesticides, petroleum hydrocarbons and polycyclic aromatic hydrocarbons (PAHs), ionic liquids, and nanomaterials. The final section includes works describing innovations in the field of freshwater pollution research. PMID- 26420104 TI - Effects of Pollution on Marine Organisms. AB - This review covers selected 2014 articles on the biological effects of pollutants and human physical disturbances on marine and estuarine plants, animals, ecosystems and habitats. The review, based largely on journal articles, covers field and laboratory measurement activities (bioaccumulation of contaminants, field assessment surveys, toxicity testing and biomarkers) as well as pollution issues of current interest including endocrine disrupters, emerging contaminants, wastewater discharges, dredging and disposal, etc. Special emphasis is placed on effects of oil spills and marine debris due in part to the 2010 Deepwater Horizon oil blowout in the Gulf of Mexico and the 2011 Japanese tsunami. Several topical areas reviewed in the past (ballast water and ocean acidification) were dropped this year. The focus of this review is on effects, not pollutant fate and transport. There is considerable overlap across subject areas (e.g.some bioaccumulation papers may be cited in other topical categories). Please use keyword searching of the text to locate related but distributed papers. Use this review only as a guide and please consult the original papers before citing them. PMID- 26420105 TI - Health Effects Associated with Wastewater Treatment, Reuse, and Disposal. AB - A review of the literature published in 2014 on topics relating to public and environmental health risks associated with wastewater treatment, reuse, and disposal is presented. This review is divided into the following sections: wastewater management, microbial hazards, chemical hazards, wastewater reuse, wastewater treatment plants, wastewater disposal, and sludge and biosolids. PMID- 26420106 TI - Emerging Pollutants - Part I: Occurrence, Fate and Transport. AB - Part I: Occurrence, Fate, and Transport (this review) is a sequel of Emerging Pollutants. This review compiles research in 2014 for investigating emerging pollutants in wastewater and environmental sources of emerging pollutants. It investigates the occurrence, fate, transport of emerging pollutants in the environment. This review further discusses the monitoring approaches, modeling, and toxicological impacts of these compounds that are relevant to wastewater. PMID- 26420107 TI - Emerging Pollutants - Part II: Treatment. AB - Emerging contaminants are considered as some substances of actual or potential threat to human health or environment, which include endocrine disruptors, pharmaceutical, personal care products, nanoparticles, antibiotic resistance genes and chemicals used in packaging products, etc. The disposal and treatment of emerging contaminants has become a key problem in the field of water pollution control. The purpose of this review is to summarize published researches on emerging pollutants treatment in 2014. PMID- 26420108 TI - Thermal Effects. AB - This review focuses on the research literatures published in 2014 relating to topics of thermal effects in water pollution control. This review is divided into the following sections: anaerobic wastewater and sludge treatment, biological nitrogen and phosphorus removal, membrane biological treatment, sewage sludge pyrolysis, natural treatment, resource recovery, electrolysis, oxidation and adsorption treatment. PMID- 26420109 TI - Economics. AB - A review of literature during calendar year 2014 focused on environmental policies and sustainable development, and economic policies. This review is divided into these sections: sustainable development, irrigation, ecosystems and water management, climate change and disaster risk management, economic growth, water supply policies, water consumption, water price regulation, and water price valuation. PMID- 26420110 TI - Analytical Methods for Pesticide Residues in the Water Environment. AB - A review of literature published in 2014 focusing on analytical methods for pesticides in the water environment is presented here. The review includes publications on extraction methods and on analytical methods such as biochemical assays and immunoassays, electrochemical methods, chromatographic or mass spectrometric techniques, spectrophotometric techniques, fluorescence, and chemiluminescence techniques. PMID- 26420111 TI - [Comprehensive managements and focus on both prevention and therapy are essential to improve the outcome of patients with glucose metabolism abnormalities and atherosclerotic diseases]. PMID- 26420112 TI - [Biomarkers and individualized precise treatment of cardiovascular diseases]. PMID- 26420113 TI - [Role of bioactive small molecules in the progression of vascular calcification]. PMID- 26420114 TI - [Diastolic and therapeutic value of biomarkers in children with postural tachycardia syndrome]. PMID- 26420115 TI - [Research progress on the association between Corin-natriuretic peptides system and cardiovascular diseases]. PMID- 26420116 TI - [Update on the relationship between C-type natriuretic peptide and cardiovascular disease]. PMID- 26420117 TI - [Chinese guidelines on the management of glucose metabolism abnormalities and atherosclerosis cardiovascular diseases]. PMID- 26420118 TI - [Predictive value of baseline plasma midregional fragment of pro-adrenomedullin level on long-term outcome of postural tachycardia syndrome children treated with midodrine hydrochloride]. AB - OBJECTIVE: To explore the predictive value of baseline plasma midregional fragment of pro-adrenomedullin level (MR-proADM) on long-term survival of postural tachycardia syndrome (POTS) children treated with midodrine hydrochloride. METHODS: Fifty-three children (male 26, mean age (14.5 +/- 4.5) years old) with POTS were included in this study, and all of them were diagnosed as POTS in our department from December 2007 to January 2010. Fifty-three children with POTS were divided into two groups according to the baseline plasma content of MR-proADM. Group I consisted of 35 POTS children with plasma content of MR-proADM > 61.5 ng/L, and the group II consisted of 18 POTS children with plasma content of MR-proADM <= 61.5 ng/L. The mean follow-up time was (67 +/- 7) months. The orthostatic intolerance symptom score and the symptom free survival were compared between the 2 groups. RESULTS: At the 60 months follow-up, the symptom score of children in group I was significantly lower than that in group II (chi(2) = 4.985, P < 0.05). At 72 months follow up, the symptom score was similar between the 2 groups (chi(2) = 0.004, P > 0.05) while the symptom free survival of group I was significantly higher than that in group II (chi(2) = 4.566, P < 0.05). CONCLUSION: The baseline plasma MR-proADM level is value in predicting the long-term survival of POTS children treated with midodrine hydrochloride. PMID- 26420119 TI - [Plasma amino-terminal pro-brain natriuretic peptide level and affecting factors in a community-based healthy Chinese population]. AB - OBJECTIVE: To investigate the plasma level of amino-terminal pro-brain natriuretic peptide (NT-proBNP) and related influencing factors in a community based healthy population in Beijing area. METHODS: We measured plasma NT-proBNP level by fluoroimmunoassay between March 2012 and July 2012 from 1 034 healthy subjects (including 486 men and 548 women). Empiric method was used to determine the reference value and influencing factors were analyzed. RESULTS: Age and gender are important factors affecting the level of NT-proBNP in healthy subjects. NT-proBNP plasma level is significantly higher in women than in men within each age strata below 75 years old, i.e. < 45, 45-54, 55-64 and 65-74 years old (P = 0.005, 0.001, 0.001, 0.011 respectively), but NT-proBNP plasma level is similar between male and female older than 75 years (P = 0.504). NT proBNP level also increases with age irrespective of gender. Body mass index (BMI) is another independent influencing factor of NT-proBNP (P < 0.001), while estimated glomerular filtration rate is not influencing factor. The reference range of NT-proBNP is < 133 ng/L for men and < 289 ng/L for women aged < 55 years old, < 185 ng/L for men and < 333 ng/L for women aged between 55 and 64 years old, and < 465 ng/L for men and < 378 ng/L for women aged >= 75 years old. CONCLUSION: The major influencing factors of NT-proBNP level in the healthy population are age, gender and BMI. It essential to establish normal reference range of NT-proBNP according to these factors for Chinese population. PMID- 26420120 TI - [Potential role of microRNA-181b on atherosclerosis]. AB - OBJECTIVE: To observe the serum expression of miR-181b in atherosclerotic patients and the in vitro effects of miR-181b on vascular smooth muscle cell growth and migration. METHODS: Fifty patients (mean age: (78.1 +/- 8.9) years old) with carotid ultrasound examination evidenced atherosclerotic plaque were enrolled as the atherosclerosis group and 50 healthy (mean age: (72.5 +/- 10.7) years old) subjects serve as control group. Stem-loop real time RT-PCR was used to detect the serum expression of miR-181b. Importin-alpha3 was predicted to be a direct target of miR-181b by Targetscan and Pictar. Western-blot was employed to detect the in vitro effects of miR-181b on the expression of Importin-alpha3 in endothelial cells. Luciferase reporter assay was employed to testify the prediction. The effects of miR-181b on vascular smooth muscle cell growth, migration abilities were respectively examined by CCK8 assay and Matrigel migration assay. RESULTS: Compared with healthy controls, serum expression of miR 181b was significantly down-regulated in patients with atherosclerosis (31.69 +/- 0.96 vs. 82.28 +/- 5.95, P < 0.05); Importin-alpha3 was predicted and proved to be a direct target of miR-181b by Western-blot and luciferase reporter assay. The proliferation and migration of vascular smooth muscle cell were significantly downregulated by forced expression of miR-181b (1.57 +/- 0.18 vs. 2.66 +/- 0.16, P < 0.05; 8.7 +/- 1.1 vs. 21.4 +/- 2.3, P < 0.05), while these effects could be abolished by inhibition of miR-181b (2.88 +/- 0.09 vs. 2.04 +/- 0.11, P < 0.05; 15.2 +/- 1.5 vs. 8.4 +/- 1.3, P < 0.05). CONCLUSION: The serum miR-181b level was significantly reduced in patients with atherosclerosis. miR-181b may function as an atherosclerosis suppressor by interupting the NF-kappaB pathway in endothelial cells and inhibiting the proliferation and migration of vascular smooth muscle cells. PMID- 26420121 TI - [TPM1 gene mutation is associated with dilated cardiomyopathy in Kazaks in Xinjiang]. AB - OBJECTIVE: Detect the relationship between TPM1 gene mutations and dilated cardiomyopathy (DCM) of Kazaks and Hans in Xinjiang. METHODS: TPM1 gene was screened from 31 family members in a Kazak family with familiar DCM (FDCM), 100 patients with idiopathic DCM (IDCM, 50 Kazaks and 50 Hans), and in 100 healthy controls (50 Kazaks and 50 Hans). All the samples were the inpatients or outpatients of First Affiliated Hospital of Xinjiang University from 2012 to 2014. PCR was used to amplify 9 exons and nearby introns of the TPM1 gene. The amplified products were sequenced and compared with the standard sequence with CHROMAS software and BLAST software in Pubmed to identify mutation sites. The relationship between TPM1 gene mutations in the Kazak IDCM and healthy volunteers, between Han and Kazak IDCM and healthy volunteers was analyzed. Tropomyosin was qualitatively and quantitatively detected by ELISA in all subjects. RESULTS: A novel variant (c.524 G > T) was identified in two FDCM patients at exon 3, this mutation caused an amino acid substitution, Gln111His. The FDCM, IDCM from Kazak and Han, healthy volunteers from Kazak and Han were founded a rs1071646 (c.644C > A, Ala151Ala). There was a significant difference in the genotype distribution (chi(2) = 13.36, P = 0.001) and allele frequency (chi(2) = 10.25, P = 0.001) between Kazaks with IDCM and Kazak controls of rs1071646, while these parameters were similar between Han IDCM patients and Han controls (all P > 0.05). The tropomyosin content of Kazak and Han IDCM patients were significantly lower than Kazak and Han controls ((1 764.2 +/- 350.9) ng/L vs. (2 369.7 +/- 345.9) ng/L, P = 0.001). CONCLUSION: TPM1 gene of rs1071646 polymorphism is a possible independent risk factor for IDCM in Kazaks but not Han Chinese. PMID- 26420122 TI - [Impact of fenestration on early outcome in patients undergoing modified Fontan operation]. AB - OBJECTIVE: To compare the impact of fenestration on early outcome in patients undergoing modified Fontan operation. METHODS: Data from 90 consecutive patients underwent modified Fontan operation from November 2008 to June 2013 were retrospectively analyzed. Patients were divided into fenestrated group (49 patients) and non-fenestrated group (41 patients) and early outcome post operation was compared between the two groups. RESULTS: Anatomy, age, gender, body weight and disease classifications were similar between the two groups (all P > 0.05). Postoperative central venous pressure was (11.4 +/- 4.1) mmHg (1 mmHg = 0.133 kPa) in fenestrated group and (12.1 +/- 3.8) mmHg in non-fenestrated group (P = 0.894). The duration of chest tube drainage was (11.1 +/- 9.2) day in fenestrated group and (15.0 +/- 10.7) day in non-fenestrated group (P = 0.160). Volume of pleural drainage was 772.0 (411.5-1 971.5) ml in fenestrated group and 1 259.0 (571.0-2 647.5) ml in non-fenestrated group (P = 0.214). Duration of ICU stay was 24.0 (18.0-40.0) day in fenestrated group and 24.0 (19.0-36.0) day in non-fenestrated group (P = 0.751). The time of respirator use was 9.0 (6.0-15.0) hours in fenestrated group and 8.0 (6.0-16.0) hours in non-fenestrated group (P = 0.951). Duration of hospital stay was significantly longer in fenestrated group than in non-fenestrated group ((32.7 +/- 23.0) day vs. (27.8 +/- 12.6) day, P = 0.025). One patient (2.0%) died of low cardiac output syndrome in fenestrated group and 1 patient (2.4%) experienced hydropericardium in non-fenestrated group. The incidence rate of complications (P = 0.898) and mortality (P = 1.000) were similar between the two groups. CONCLUSION: Early outcome is similar for patients undergoing the modified Fontan operation with or without fenestration. PMID- 26420123 TI - [Impact of mesenchymal stem cells transplantation on myocardial myocardin-related transcription factor-A and bcl-2 expression in rats with experimental myocardial infarction]. AB - OBJECTIVE: To observe the impact of mesenchymal stem cells (BMSCs) transplantation on myocardial myocardin-related transcription factor-A (MRTF-A) and bcl-2 expression in rats with experimental myocardial infarction (MI). METHODS: Thirty rats were randomly divided into sham, MI and MI + BMSCs (1 * 10(6) injected into 4 infarct points immediately post coronary artery ligation) groups (n = 10 each).One week later, TUNEL was used to detect cardiomyocyte apoptosis, the myocardial expression of MRTF-A and bcl-2 was detected by laser scanning confocal microscope and Western blot. In vitro plasmid of MRTF-A and co transfection with plasmids of MRTF-A and bcl-2 or mutated bcl-2 transfection into cardiomyocyte was applied to evaluate the relationship between MRTF-A and bcl-2. RESULTS: The number of apoptotic cardiomyocytes in the sham group, MI group and MI + BMSCs group were (4.05 +/- 1.56)%, (62.38 +/- 8.41)% and (22.36 +/- 6.17)%, respectively (P < 0.05). The protein expression of MRTF-A and bcl-2 in the MI group were significantly lower than those in sham group, while significantly upregulated in MI + BMSCs group (P < 0.05 vs. MI). In cultured neonatal rat cardiomyocyte, the expression of bcl-2 protein was significantly upregulated after transfection with MRTF-A plasmid, and bcl-2-luciferase activity significantly increased after co-transfection with plasmids of MRTF-A and bcl-2 luciferase, however, the positive regulatory effect of MRTF-A was abolished after transfection with mutated bcl-2. CONCLUSION: Mesenchymal stem cells transplantation can effectively reduce cardiomyocyte apoptosis in this rat MI model, and upregulate the expression of MRTF-A. Consequent up-regulated bcl-2 expression might be involved in the beneficial effects of BMSCs transplantation in this model. PMID- 26420124 TI - [Impact and related mechanism of exogenous receptor activity modifying protein 1 on calcitonin gene-related peptide modified bone marrow mesenchymal stem cells on the migration of vascular smooth muscle cells in vitro]. AB - OBJECTIVE: To investigate the impact of calcitonin gene-related peptide (CGRP) modified bone marrow mesenchymal stem cell (MSC) on the migration of vascular smooth muscle cell (VSMC) and related mechanisms. METHODS: The MSC and VSMC were isolated from rats and cultured, CGRP was transfected to MSC with the high expression lentivirus vector, VSMC was transfected with high expression lentivirus vector of receptor activity modifying protein 1 (RAMP1) and the silence expression lentivirus vector of RAMP1. Then MSC was co-cultured with VSMC. Experimental groups were as follows: (1) Ang II group (MSC + VSMC + Ang II); (2) MSC(CGRP+) group (MSC(CGRP+) + VSMC + Ang II); (3) MSC(CGRP+) RAMP1(-) group (MSC(CGRP+) + VSMC(RAMP1-) + Ang II); (4) MSC(CGRP+) RAMP1(+) group (MSC(CGRP+) + VSMC(RAMP1+) + Ang II); (5) RAMP1(+) group (MSC + VSMC(RAMP1+) + Ang II). Transwell assay was applied to detect the migration of smooth muscle cells, Western blot was applied to detect the protein expression of cells in various groups. RESULTS: VSMC migration number was significantly lower in MSC(CGRP+) group compared with Ang II group (50.8 +/- 2.6 vs. 71.4 +/- 2.3, P < 0.05), but higher than in MSC(CGRP+) RAMP1(+) group (50.8 +/- 2.6 vs. 30.4 +/- 3.0, P < 0.05). When RAMP1 expression reduced in VSMC, compared with MSC(CGRP+) RAMP1(+) group, VSMC migration increased in the MSC(CGRP+) RAMP1(-) group compared to MSC(CGRP+)RAMP1(+) (69.0 +/- 5.6 vs. 30.4 +/- 3.0, P < 0.05) and was similar to Ang II group (69.0 +/- 5.6 vs. 71.4 +/- 2.3, P > 0.05) and RAMP1(+) group (71.6 +/- 3.4). According to the result of Western blot, P-P65 protein expression in MSC(CGRP+) group was lower than that in Ang II group (0.475 +/- 0.022 vs.0.642 +/- 0.035, P < 0.05). P-P65 protein expression in MSC(CGRP+)RAMP1( ) group was higher than that in MSC(CGRP+) RAMP1(+) group (0.670 +/- 0.030 vs. 0.373 +/- 0.041, P < 0.05), and there was no difference between MSC(CGRP+)RAMP1( ) group and Ang II group (P > 0.05). P-P65 protein expression was similar between RAMP1(+) group (0.643 +/- 0.039) and Ang II group (P > 0.05). CONCLUSIONS: CGRP inhibits VSMC migration through RAMP1. NF-kappaB and RAMP1 play crucial role in the inhibiting effects of CGRP on VSMC migration. Thus, RAMP1-CGRP signaling inhibits VSMC migration through NF-kappaB signal pathways. PMID- 26420125 TI - [Effects of norepinephrine on proliferation and apoptosis of neonatal cardiac fibroblasts in rats]. AB - OBJECTIVE: To investigate the effects of different concentrations of norepinephrine (NE) on proliferation and apoptosis of cultured cardiac fibroblasts (CFBs) from neonatal mice and to elucidate related mechanisms. METHODS: CFBs of Sprague-Dawley (SD) rats were isolated and cultured and divided into normal control group and different concentration of NE intervention groups (0.1, 1, 10, 50, and 100 umol/L). Water soluble tetrazolium-1 (WST-1) assay was carried out to detect the viability of CFBs. Morphology of apoptosis cells was evaluated by fluorescence microscope with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The expressions of collagen I, collagen III, pro-oncogene c-myc in CFBs were detected by reverse transcription-polymerase chain reaction (RT-PCR). The phospho-mitogen activated protein kinase (p-p38MAPK) and caspase3 protein levels were examined by Western blot. RESULTS: Proliferation was significantly increased in 1 umol/L and 10 umol/L groups compared with the normal control group (1.05 +/- 0.05 and 1.09 +/- 0.02 vs. 1.00 +/- 0.03, all P < 0.05).CFBs apoptosis was significantly enhanced in 50 umol/L and 100 umol/L groups ((22.69 +/- 2.18)% and (36.40 +/- 6.80)% vs.(4.50 +/- 1.08)%, all P < 0.05). Expression of Collagen I peaked in 10 umol/L group, expression of collagen III and c-myc increased dose-dependently in proportion to increasing NE concentrations (all P < 0.05 vs. control group). The expression of p-p38MAPK and caspase3 was also significantly upregulated in a dose-dependent manner in NE groups (all P < 0.05 vs. control group). CONCLUSIONS: Low concentration NE induces CFBs proliferation and high concentration NE promotes CFBs apoptosis. p38MAPK phosphorylation may be a major mediator of NE-induced effects on CFBs. PMID- 26420126 TI - [Relationship between central obesity and clustering of cardiovascular risk factors in adults of Jiangsu province]. AB - OBJECTIVE: To explore the relationship between central obesity and cardiovascular risk factors and their clustering in adults of Jiangsu province. METHODS: Multi stratified clustering sampling method was used to sample 8 400 residents aged 18 years and over from 14 diseases surveillance units in Jiangsu province from October to December 2010. Information was obtained with face-to-face interview, physical examination and laboratory testing. A total of 8 380 residents finished the study protocol and their data were analyzed. Central obesity was defined as waist circumference >= 85 cm in males or >= 80 cm in females. Following complex weighting of the samples, level and proportion of cardiovascular risk factors in group with different waist circumference were analyzed. RESULTS: The prevalence of central obesity among adults in Jiangsu province was 46.2%, the proportion of males and females was 46.4% and 46.1%, respectively (P > 0.05). The prevalence of center obesity varied significantly in residents with different age, area, education and occupation (all P < 0.01). The level of systolic blood pressure, diastolic blood pressure, fasting blood glucose, total cholesterol, triglyceride, high density lipoprotein cholesterol and low density lipoprotein cholesterol was also significantly different in residents with different degree of waist circumference (all P < 0.01). The prevalence of hypertension, diabetes, dyslipidemia and clustering of cardiovascular risk factors increased in proportion to increasing waist circumference (all P < 0.05). Multivariate logistic regression analysis showed that the risk of hypertension, diabetes, dyslipidemia and clustering of cardiovascular risk factors was 2.2 (OR = 2.2, 95% CI: 2.0-2.4) and 4.7 (OR = 4.7, 95% CI: 3.9-5.7); 2.1 (OR = 2.1, 95% CI: 1.7-2.5) and 3.8 (OR = 3.8, 95% CI: 3.2-4.5); 2.3 (OR = 2.3, 95% CI: 1.8-2.9) and 4.1 (OR = 4.1, 95% CI: 3.2-5.3); 3.4 (OR = 3.4, 95% CI: 2.9-3.9) and 8.0 (OR = 8.0, 95% CI: 6.2-10.2) fold higher in residents with mild and severe central obesity than residents without central obesity. CONCLUSIONS: The extent of central obesity positively correlates with the prevalence of cardiovascular risk factors and their clustering in adults of Jiangsu province. Comprehensive interventions on obesity serve as an important tool to reduce the cardiovascular risk in adult Jiangshu residents. PMID- 26420127 TI - [Meta-analysis of clinical trials of folic acid, vitamin B12 and B6 supplementation on plasma homocysteine level and risk of cardiovascular disease]. AB - OBJECTIVE: To evaluate the effects of folic acid, vitamin B(6) and B(12) supplementation on plasma homocysteine level and risk of cardiovascular disease. METHODS: The databases, including Embase, Pubmed, Ovid, Biosis, China National Knowledge Infra-structure (CNKI), Wanfang Data, VIP Database for Chinese Technical Periodical (VIP), Chinese Biomedical Literature Database (CMB), were searched to identify random control trials between February 1994 to February 2014 on the effect of folic acid, vitamin B(6) and B(12) supplementation on plasma homocysteine level and risk of cardiovascular disease. The screening, data extraction and quality assessment were conducted in accordance with the inclusion and exclusion criteria by two reviewers independently. The software Review Manager 5.2 was used. Funnel plots and Egger's regression test were applied to evaluate the publication bias. RESULTS: Data from 12 studies including 34 481 patients were analyzed using a fixed-effects model. Funnel plot and Egger's test (P > 0.10) confirmed the absence of publication bias. No statistically significant heterogeneity was detected on testing after excluding the sources of heterogeneity (chi-square test, I < 2 < 50%). Baseline homocysteine levels were similar between the placebo and folic acid, vitamin B(6) and B(12) groups (all P > 0.05). Mean homocysteine levels were significantly lower with folic acid, vitamin B(6) and B(12) therapy compared with placebo during follow-up (all P < 0.05). The pooled relative risks with 95% confidence intervals of outcomes for patients treated with folic acid, vitamin B(6) and B(12) supplementation compared with placebo were 0.98 (0.93-1.03) for cardiovascular event, 0.97 (0.87-1.07) for coronary artery disease, 1.00 (0.92-1.08) for myocardial infarction and 0.92 (0.82-1.03) for cardiovascular death. CONCLUSIONS: Folic aicd combined with vitamin B(6) and B(12) treatment significantly reduced plasma homocysteine level, but did not affect the risk of cardiovascular disease. Thus, folic acid combined with vitamin B(6) and B(12) should not be recommended as secondary prevention of cardiovascular diseases. PMID- 26420129 TI - [Research progress on etiology and imaging of atrial remodeling]. PMID- 26420128 TI - [Three cases of congenital quadricuspid aortic valve]. PMID- 26420130 TI - [Regulating effects of microRNAs on autophagy and the relationship with cardiovascular diseases]. PMID- 26420131 TI - A Conserved Structural Motif Mediates Retrograde Trafficking of Shiga Toxin Types 1 and 2. AB - Shiga toxin-producing Escherichia coli (STEC) produce two types of Shiga toxin (STx): STx1 and STx2. The toxin A-subunits block protein synthesis, while the B subunits mediate retrograde trafficking. STEC infections do not have definitive treatments, and there is growing interest in generating toxin transport inhibitors for therapy. However, a comprehensive understanding of the mechanisms of toxin trafficking is essential for drug development. While STx2 is more toxic in vivo, prior studies focused on STx1 B-subunit (STx1B) trafficking. Here, we show that, compared with STx1B, trafficking of the B-subunit of STx2 (STx2B) to the Golgi occurs with slower kinetics. Despite this difference, similar to STx1B, endosome-to-Golgi transport of STx2B does not involve transit through degradative late endosomes and is dependent on dynamin II, epsinR, retromer and syntaxin5. Importantly, additional experiments show that a surface-exposed loop in STx2B (beta4-beta5 loop) is required for its endosome-to-Golgi trafficking. We previously demonstrated that residues in the corresponding beta4-beta5 loop of STx1B are required for interaction with GPP130, the STx1B-specific endosomal receptor, and for endosome-to-Golgi transport. Overall, STx1B and STx2B share a common pathway and use a similar structural motif to traffic to the Golgi, suggesting that the underlying mechanisms of endosomal sorting may be evolutionarily conserved. PMID- 26420133 TI - In Silico Prediction of the Effects of Mutations in the Human Mevalonate Kinase Gene: Towards a Predictive Framework for Mevalonate Kinase Deficiency. AB - Mevalonate kinase (MVK) catalyses the phosphorylation of mevalonate. Deficiency of MVK is associated with two rare periodic fever syndromes, mevalonic aciduria (MA), a severe form and hyper-immunoglobulin-D syndrome (HIDS), a milder form. An in silico approach was used to analyse the physicochemical and structural effects of 47 disease-associated variants of MVK. A further 20 variants, which are present in human genome databases, were also analysed. Variants associated with MA are clustered into a "hotspot" consisting of residues 8-35 and 234-338 and tended to result in a prediction of severely reduced protein stability. Four of the uncharacterised variants, p.H24P, p.G198R, p. R253W, and p.G335S, were likely to be associated with MA. This method could be used as the basis for initial predictions of severity when new MVK variants are discovered. PMID- 26420132 TI - A rare variant association test in family-based designs and non-normal quantitative traits. AB - Rare variant studies are now being used to characterize the genetic diversity between individuals and may help to identify substantial amounts of the genetic variation of complex diseases and quantitative phenotypes. Family data have been shown to be powerful to interrogate rare variants. Consequently, several rare variants association tests have been recently developed for family-based designs, but typically, these assume the normality of the quantitative phenotypes. In this paper, we present a family-based test for rare-variants association in the presence of non-normal quantitative phenotypes. The proposed model relaxes the normality assumption and does not specify any parametric distribution for the marginal distribution of the phenotype. The dependence between relatives is modeled via a Gaussian copula. A score-type test is derived, and several strategies to approximate its distribution under the null hypothesis are derived and investigated. The performance of the proposed test is assessed and compared with existing methods by simulations. The methodology is illustrated with an association study involving the adiponectin trait from the UK10K project. PMID- 26420134 TI - Design of Randomized, double-blind, Evaluation in secondary Stroke Prevention comparing the EfficaCy and safety of the oral Thrombin inhibitor dabigatran etexilate vs. acetylsalicylic acid in patients with Embolic Stroke of Undetermined Source (RE-SPECT ESUS). AB - RATIONALE: Cryptogenic ischemic strokes constitute 20-30% of ischemic strokes, the majority of which are embolic strokes of undetermined source. The standard preventive treatment in these patients is usually acetylsalicylic acid. AIM: The Randomized, double-blind, Evaluation in secondary Stroke Prevention comparing the EfficaCy and safety of the oral Thrombin inhibitor dabigatran etexilate vs. acetylsalicylic acid in patients with Embolic Stroke of Undetermined Source (RE SPECT ESUS) is designed to determine whether the oral thrombin inhibitor dabigatran, taken within three-months after embolic stroke of undetermined source, is superior to acetylsalicylic acid for prevention of recurrent stroke and to characterize the safety of dabigatran in this setting. DESIGN: Prospective, randomized, double-blind, multicenter trial in approximately 6000 patients and 550 centers with embolic stroke of undetermined source. Subjects are randomized to dabigatran or acetylsalicylic acid and treated for an expected minimum of six-months and up to approximately three-years. It is an event-driven trial aiming for 353 adjudicated primary outcome events. STUDY OUTCOMES: The primary efficacy outcome is time to first recurrent stroke (ischemic, hemorrhagic, or unspecified). Key secondary outcomes are time to first ischemic stroke and time to first occurrence in the composite outcome of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death. The primary safety outcome is major hemorrhage, including symptomatic intracranial hemorrhage. DISCUSSION: Acetylsalicylic acid is the most common antithrombotic given to patients with embolic strokes of undetermined source to reduce recurrence risk. This trial will determine whether anticoagulation with dabigatran is more effective than acetylsalicylic acid, and acceptably safe. PMID- 26420142 TI - Species Delimitation's Coming of Age. PMID- 26420143 TI - Exosomal doxorubicin reduces the cardiac toxicity of doxorubicin. AB - AIM: To test the efficacy and toxicity of exosomal doxorubicin (exoDOX) compared with free doxorubicin. MATERIALS & METHODS: The cytotoxic effects of exoDOX were tested in vitro and in nude mice by measuring the tumor volume. The toxic effects were evaluated by measuring the bodyweight and through histopathologic analyses. The biodistribution of DOX was assessed by MS. RESULTS: In vitro and in vivo studies showed that exosomes did not decrease the efficacy of DOX. Surprisingly, exoDOX showed no cardiotoxicity as observed in DOX-treated mice and MS studies confirmed that the accumulation of exoDOX in the heart was reduced by approximately 40%. CONCLUSION: We demonstrated that exoDOX was less toxic than DOX through its altered biodistribution. PMID- 26420144 TI - [Primary aldosteronism: new insights into familial forms]. AB - Primary aldosteronism (PA) is characterized by autonomic aldosterone production, usually leading to severe hypertension and hypokalaemia. PA is a heterogeneous condition caused by sporadic adrenal adenoma, bilateral adrenal hyperplasia or rare familial forms. Familial aldosteronism type 1 is caused by a hybrid gene that codes for an ACTH-sensitive form of aldosterone synthase. Familial aldosteronism type 3 was recently recognized as a new form of PA caused by mutation in KCNJ5. The clinical manifestations vary from life-threatening PA and pronounced adrenal hyperplasia to milder forms. In addition to germline mutations in KCNJ5, somatic KCNJ5 mutations are present in about 40% of aldosterone producing adrenal adenomas. Mutations in three other genes are also regularly observed. All these mutations cause increased aldosterone synthase activity, eventually leading to PA. In patients under 20 with PA, familial forms must be excluded before proceeding to adrenalectomy. PMID- 26420145 TI - [Ankle sprain during a volleyball game]. AB - A 27-year old woman was admitted to the emergency room after her left ankle rolled inward during a volleyball game. On physical examination a bony prominence on the lateral side of the left foot was noticeable, without neurovascular injury. An X-ray (anterior-posterior view) showed a subtalar dislocation without associated fractures. PMID- 26420146 TI - [Group A streptococcal-associated arthritis in children]. AB - Group A streptococcal (GAS) infection can cause septic arthritis (SA), acute rheumatic fever (ARF) and post-streptococcal reactive arthritis (PSRA). Differentiating between these three entities can have important consequences for both therapy and prognosis. SA is diagnosed by means of clinical, biochemical and microbiological parameters. With respect to ARF and PSRA, evidence of a recent GAS infection should be established, in combination with several other major or minor criteria. Currently there is ongoing scientific debate as to whether PSRA and ARF are two different disease entities or belong to the same spectrum. PSRA presents earlier after GAS pharyngitis than ARF, is normally less responsive to NSAIDs, has a longer duration and is often accompanied by skin abnormalities. However, there are also many similarities. In this report we describe three children suffering from GAS-associated arthritis and discuss the symptoms, diagnosis and therapy. PMID- 26420147 TI - [Referred with the working diagnosis 'pneumothorax: could it be another diagnosis?]. AB - BACKGROUND: Patients who are referred to an emergency department (ED) often have a working diagnosis. Hospital physicians may be inclined to accept this diagnosis and incorrectly link the findings of investigations to it. This may lead to an incorrect definitive diagnosis and therapy. CASE DESCRIPTION: We present the case of a 36-year-old female who was referred to the ED with a pneumothorax seen on chest x-ray. Findings from history-taking, physical examination and a second chest x-ray taken on the ED were diagnosed as being consistent with pneumothorax and a chest-drain was inserted. However, further investigation showed that she had Swyer-James-Mcleod syndrome which could have been treated conservatively. CONCLUSION: This patient was given a chest drain after the working diagnosis of pneumothorax was made. Due to the definite diagnosis of Swyer-James-Mcleod the indication for chest drainage may have been incorrect. If a diagnosis of pneumothorax is suspected, but diagnostic findings suggest otherwise, further investigations should be performed before a chest drain is inserted. PMID- 26420148 TI - [Psychopathology during and after pregnancy]. AB - This article describes two patients with psychosocial problems during and after pregnancy. The first woman suffers from an obsessive-compulsive disorder and developed postnatal depression after her first pregnancy. Her second pregnancy was marked by uncertainty, anxiety and stress. Her caregivers noticed her problems and referred her to a Psychiatry-Obstetrics-Paediatrics(POP)-team, who provided her with successful treatment. The second woman had physical symptoms, which were largely ascribed to antenatal depression and were effectively treated using antidepressants and cognitive behavioural therapy. Although these patients experienced different problems in different situations, the impact on the woman, partner and child(ren) was tremendous in both cases. This article makes clear that early screening and treatment of symptoms of anxiety and depression are relevant during and after pregnancy. Vigilance and screening by midwives, family doctors and gynaecologists help in early recognition and ultimately in earlier treatment, either medicinal and/or using psychotherapy, which may reduce or even prevent harmful consequences. PMID- 26420149 TI - [Unplanned readmissions of frail elderly patients: a retrospective analysis of admissions in a teaching hospital]. AB - OBJECTIVE: To assess the prevalence and predictors of readmission in patients of 65 years or older. DESIGN: Retrospective data analysis. METHOD: We used a dossier analysis to identify the number of readmissions and patient characteristics of all patients aged 65 years or older admitted to the Radboud University Medical Centre between 29 September 2013 and 4 October 2014. We also used data from the Dutch hospital safety tool (VMS) screening bundle for frail elderly patients. Predictors for readmission were investigated using logistic regression analysis. RESULTS: The readmission rate within 30 days of discharge was 10.9% (95% CI 10.2 11.7) of all admissions of elderly patients. The most common symptom associated with readmission was dyspnea (24.9%). Diseases with an increased risk for readmission were: heart failure (OR=2.6; 95% CI 1.9 - 3.7), chronic obstructive pulmonary disease (OR=2.2; 95% CI 1.5 - 3.2), renal insufficiency (OR=1.8; 95% CI 1.3 - 2.6) and cancer (OR=1.5; 95% CI 1.1 - 2.1). Total burden of disease and functional limitations accounted jointly for 49% of the variance in readmissions. Repeated readmissions could be less well predicted (explained variance: 14%); the use of more than 3 drugs (OR=1.07; 95% CI 1.02 - 1.13) and a low body mass index (OR=0.94; 95% CI 0.88 - 0.99) were predictors for multiple readmissions. CONCLUSION: Elderly patients suffering from dyspnea have the highest risk for readmission. Patients with heart failure, COPD, renal failure, cancer, functional loss or malnutrition require extra attention on transition from hospital to home in order to lower the number of unnecessary readmissions. PMID- 26420162 TI - Sociocultural Factors and Parent-Therapist Agreement on Explanatory Etiologies for Youth Mental Health Problems. AB - Sociocultural factors were examined in relationship to parent-therapist agreement on beliefs about the etiology of mental health problems in a sample of youth receiving outpatient mental health services (n = 277 parents). When examined individually, racial/ethnic match was unrelated, but higher parental affinity to mainstream American culture, higher parent education level, and greater similarity in parent and therapist scores on affinity to mainstream American culture were all significantly associated with greater parent-therapist co endorsement of etiological explanations, while higher parental affinity to an alternative/indigenous culture was significantly associated with lower co endorsement. When examined simultaneously in one model, only parent education level remained significantly associated. Findings suggest a complex relationship between sociocultural factors and that attention to parent cultural affinity and parent education level may facilitate parent-therapist agreement on beliefs about child problem causes. PMID- 26420163 TI - Treatment of Acute Cough Due to the Common Cold: Multi-component, Multi-symptom Therapy is Preferable to Single-Component, Single-Symptom Therapy--A Pro/Con Debate. AB - Acute viral upper respiratory tract infection, or, the common cold, affects essentially every human being, and cough is reported as its most frequent associated symptom. Billions of dollars are spent worldwide annually by individuals seeking relief from this multi-symptom syndrome. Thousands of non prescription, over-the-counter products are available worldwide, aimed at relieving the various bothersome symptoms induced by the common cold. Differences of opinion exist as to whether optimal therapy for cough associated with the common cold consists of multi-component, multi-symptom cough/cold preparations, or, whether single-component medications, aimed at relief of specific symptoms, represent the optimal therapeutic approach. The 5th American Cough Conference, held in Washington, D.C. in June, 2015, provided an ideal forum for discussion and debate of this issue between two internationally recognized experts in the field of the common cold and its treatment. PMID- 26420165 TI - Robots and type 1 diabetes. PMID- 26420164 TI - Adherence to Anti-tuberculosis treatment and treatment outcomes among tuberculosis patients in Alamata District, northeast Ethiopia. AB - BACKGROUND: Non-adherence to tuberculosis (TB) treatment can result in an emergence of new strains, prolonged infectiousness, drug resistance and poor treatment outcomes. Thus, assessment of the level of adherence to anti-TB treatment, treatment outcomes and identifying factors associated with non adherence and poor treatment outcomes are vital for improving TB treatment adherence and treatment outcomes in the study area. The main objectives of the current study were to assess the level of adherence to anti-TB treatment among patients taking anti-TB drug treatment and to identify factors associated with non-adherence. Whereas, the secondary objectives were to assess treatment outcomes and factors associated with poor treatment outcomes among TB patients previously treated at the health institutions of Alamata District, northeast Ethiopia. METHODS: In a health facility-based cross-sectional study, TB patients who were taking anti-TB drug treatment were interviewed using a structured questionnaire to evaluate level of adherence to anti-TB treatment. TB treatment outcomes were evaluated using data generated from a record review of previous TB patients who were treated at health facilities of Alamata District from January 2007 to June 2012. Adherence data and treatment outcomes data were computerized separately using Epi-Data version 3.1 and analyzed using STATA version 10.0. RESULTS: Between November 2012 and January 2013, 116 (58.0%) male TB patients and 84 (42.0%) female TB patients were interviewed, of whom 77.5% were new cases, 23.5% were smear-positive pulmonary TB (SPPTB) cases, 26.5% were smear-negative PTB (SNPTB) cases and 50.0% were extra pulmonary (EPTB) cases. The overall adherence rate to anti-TB treatment was 88.5%. The main reasons for the non adherent patients were forgetting to take medication, being away from home, drug side effects, being unable to go to the health facilities on the date of appointment and being hospitalized. In the TB treatment outcomes component of the current study, records of 4,275 TB patients were reviewed and the overall treatment success rate was 90.1%. Two-hundred fifteen (5.0%) patients had unsuccessful treatment outcomes, of whom 76 (35.3%) defaulted, 126 (58.6%) died and 13 (6.1%) had treatment failure. Significant predictors of unsuccessful treatment outcomes were being positive for human immunodeficiency virus (HIV) infection [adjusted odds ratio (aOR) = 2.1, 95% CI 1.5-3.0], being SPPTB case (aOR = 3.4, 95% CI 2.4-4.8), being SNPTB case (aOR = 2.0, 95% CI 1.5-2.8)], and being re-treatment cases (aOR = 2.6, 95% CI 1.5-3.7). CONCLUSION: In the present study area, there was a high level of adherence to anti-TB treatment and also a high TB treatment success rate. However, still further effort like health education to patient or family is needed to reduce those factors which affect adherence and treatment success rates in order to ensure higher rates of adherence and treatment success than the currently observed in the present study area. PMID- 26420166 TI - Ceftazidime-avibactam for the treatment of complicated urinary tract infections and complicated intra-abdominal infections. AB - Treatment of complicated urinary tract infections and complicated intra-abdominal infections is increasingly difficult due to the rising prevalence of multidrug resistant Gram-negative bacteria. Ceftazidime-avibactam is a combination of the established third-generation cephalosporin ceftazidime with avibactam, a novel non-beta-lactam beta-lactamase inhibitor, which restores the activity of ceftazidime against many beta-lactamase-producing Gram-negative bacteria, including extended-spectrum beta-lactamases and Klebsiella pneumoniae carbapenemases. Clinical and nonclinical studies supporting the safety and efficacy of ceftazidime-avibactam include microbiological surveillance studies of clinically relevant pathogens, in vivo animal models of infection, pharmacokinetic/pharmacodynamic target attainment analyses, Phase I clinical pharmacology studies, and Phase II/III studies in the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including patients with ceftazidime-nonsusceptible Gram-negative infections. PMID- 26420167 TI - To Love is to Suffer: Older Adults' Daily Emotional Contagion to Perceived Spousal Suffering. AB - Objectives: For older adults coping with a spouse's chronic condition, greater marital satisfaction may not be entirely protective for psychological health. We examined marital satisfaction and gender as moderators of the association between perceived spousal suffering and daily emotional contagion. Based on empathy altruism and interdependent self-construal theories, we hypothesized that high marital satisfaction and being female would heighten daily emotional contagion, or within-person associations between perceived spouse suffering and distress to spouse suffering. Method: Forty-five older adults who had a spouse with a musculoskeletal condition completed daily interviews. Participants reported their marital satisfaction once in the laboratory and then daily perceptions of their spouse's physical suffering and their own distress to spouse suffering via phone at home for 7 days. Results: Consistent with hypotheses, there were significant within-person effects such that highly satisfied wives experienced heightened emotional contagion on days when they perceived higher than average spouse suffering. Unexpectedly, men who were high in marital satisfaction experienced heightened daily distress irrespective of their perceptions of level of spousal suffering. Discussion: Marital satisfaction can increase daily emotional contagion to spousal suffering among older couples dealing with chronic conditions. Wives' distress may be more dependent on perceiving high levels of partner suffering compared with husbands' distress. PMID- 26420168 TI - Do the classification of areas and distance matter to the assessment results of achieving the treatment targets among type 2 diabetes patients? AB - BACKGROUND: Type 2 diabetes is a major health concern all over the world. The prevention of diabetes is important but so is well-balanced diabetes care. Diabetes care can be influenced by individual and neighborhood socio-economic factors and geographical accessibility to health care services. The aim of the study is to find out whether two different area classifications of urban and rural areas give different area-level results of achieving the targets of control and treatment among type 2 diabetes patients exemplified by a Finnish region. The study exploits geo-referenced patient data from a regional primary health care patient database combined with postal code area-level socio-economic variables, digital road data and two grid based classifications of areas: an urban-rural dichotomy and a classification with seven area types. METHODS: The achievement of control and treatment targets were assessed using the patient's individual laboratory data among 9606 type 2 diabetes patients. It was assessed whether hemoglobin A1c (HbA1c) was controlled and whether the recommended level of HbA1c was achieved in patients by different area classes and as a function of distance. Chi square test and logistic regression analysis were used for testing. RESULTS: The study reveals that area-level inequalities exist in the care of type 2 diabetes in a detailed 7-class area classification but if the simple dichotomy of urban and rural is applied differences vanish. The patient's gender and age, area level education and the area class they belonged to were associated with achievements of control and treatment targets. Longer distance to health care services was not a barrier to good achievements of control or treatment targets. CONCLUSIONS: A more detailed grid-based area classification is better for showing spatial differences in the care of type 2 diabetes patients. Inequalities exist but it would be misleading to state that the differences are simply due to urban or rural location or due to distance. From a planning point of view findings suggest that detailed geo-coded patient information could be utilized more in resourcing and targeting the health care services to find the area-level needs of care and to improve the cost-efficient allocation of resources. PMID- 26420169 TI - Assessing the detection, reporting and investigation of adverse events in clinical trial protocols implemented in Cameroon: a documentary review of clinical trial protocols. AB - BACKGROUND: International guidelines recommend ethical and scientific quality standards for managing and reporting adverse events occurring during clinical trials to competent research ethics committees and regulatory authorities. The purpose of this study was to determine whether clinical trial protocols in Cameroon are developed in line with national requirements and international guidelines as far as detecting, reporting and investigating of adverse events is concerned. METHODS: It was a documentary review of all approved clinical trial protocols that were submitted at the Cameroon National Ethics Committee for evaluation from 1997 through 2012. Data were extracted using a preconceived and validated grid. Protocol review process targeted the title, abstract, objectives, methodology, resources, and the chapter on safety. RESULTS: In total, 106 (4.9 %) clinical trial protocols were identified from 2173 protocols seen in the archive and 104 (4.8 %) included for review. Seventy six (73.1 %) trials did not include the surveillance of adverse events as part of their objective. A total of 91 (87.5 %) protocols did not budget for adverse event surveillance, 76 (73.1 %) did not have a data safety management board (DSMB), 11(10.6 %) included insurance for participants, 47 (45.2 %) did not include a case definition for serious adverse events, 33 (31.7 %) described procedures to detect adverse events, 33 (31.7 %) described procedure for reporting and 22 (21.2 %) described procedure for investigating adverse events. DISCUSSIONS: Most clinical trial protocols in Cameroon are developed to focus on benefits and pay little attention to harms. The development of national guidelines can improve the surveillance of adverse events in clinical trial research conducted in Cameroon. Adverse events surveillance tools and a budget are critical for an adequate planning for adverse event surveillance when developing trial protocols. CONCLUSION: Clinical trial protocols submitted in the Cameroon National Ethics Committee do not adequately plan to assess adverse events in clinical trial protocols. In order to improve on the safety of participants and marketed drug, there is a need to develop national guidelines for clinical trials by the government, and to improve evaluation procedures and monitoring of ongoing trials by the ethics committee. PMID- 26420170 TI - The visual encoding of tool-object affordances. AB - The perception of tool-object pairs involves understanding their action relationships (affordances). Here, we sought to evaluate how an observer visually encodes tool-object affordances. Eye-movements were recorded as right-handed participants freely viewed static, right-handed, egocentric tool-object images across three contexts: correct (e.g. hammer-nail), incorrect (e.g. hammer-paper), spatial/ambiguous (e.g. hammer-wood), and three grasp-types: no hand, functional grasp-posture (grasp hammer-handle), non-functional/manipulative grasp-posture (grasp hammer-head). There were three areas of interests (AOI): the object (nail), the operant tool-end (hammer-head), the graspable tool-end (hammer handle). Participants passively evaluated whether tool-object pairs were functionally correct/incorrect. Clustering of gaze scanpaths and AOI weightings grouped conditions into three distinct grasp-specific clusters, especially across correct and spatial tool-object contexts and to a lesser extent within the incorrect tool-object context. The grasp-specific gaze scanpath clusters were reasonably robust to the temporal order of gaze scanpaths. Gaze was therefore automatically primed to grasp-affordances though the task required evaluating tool-object context. Participants also primarily focused on the object and the operant tool-end and sparsely attended to the graspable tool-end, even in images with functional grasp-postures. In fact, in the absence of a grasp, the object was foveally weighted the most, indicative of a possible object-oriented action priming effect wherein the observer may be evaluating how the tool engages on the object. Unlike the functional grasp-posture, the manipulative grasp-posture caused the greatest disruption in the object-oriented priming effect, ostensibly as it does not afford tool-object action due to its non-functional interaction with the operant tool-end that actually engages with the object (e.g., hammer head to nail). The enhanced attention towards the manipulative grasp-posture may serve to encode grasp-intent. Results here shed new light on how an observer gathers action-information when evaluating static tool-object scenes and reveal how contextual and grasp-specific affordances directly modulate visuospatial attention. PMID- 26420171 TI - Current trends in the development of porous polymer monoliths for the separation of small molecules. AB - Since their introduction, the main application area of porous polymer monoliths has been in the fast gradient separation of synthetic and natural polymers. On the other hand, it has proven to be difficult to prepare polymer monoliths providing column efficiency comparable with particulate and monolithic silica based stationary phases. During this decade, several experimental approaches were performed that aimed to improve this property of polymer monoliths. These protocols include variation in a polymerization time and preparation of monolithic stationary phases at limited conversion of the polymerization reaction, application of novel, highly ordered, nanomaterials, and/or hypercross linking surface modification controlling the cross-link density of prepared monoliths. By using some of these approaches, monolithic stationary phases with column efficiency reaching 200,000 plates/m for low-molecular-weight compounds have been prepared. This review deals with preparation of polymer monoliths for the separation of small molecules and summarizes recent development in this field. At first, it focuses on monolithic columns morphology and repeatability of their preparation. Then, recent results in individual experimental protocols are discussed. Finally, possible future steps leading to the preparation of more efficient monolithic stationary phases are outlined. PMID- 26420173 TI - A metal-mediated boron-centred isomerisation reaction via C-H activation. AB - A heterocyclic manganese complex (4) derived from a carbonyl-borylene coupling reaction undergoes isomerisation, during which the former borylene moiety migrates to the cyclopentadienyl ligand and inserts into a C-H bond. This reaction and a computational study of its mechanism are discussed. PMID- 26420174 TI - Combining marine macroecology and palaeoecology in understanding biodiversity: microfossils as a model. AB - There is growing interest in the integration of macroecology and palaeoecology towards a better understanding of past, present, and anticipated future biodiversity dynamics. However, the empirical basis for this integration has thus far been limited. Here we review prospects for a macroecology-palaeoecology integration in biodiversity analyses with a focus on marine microfossils [i.e. small (or small parts of) organisms with high fossilization potential, such as foraminifera, ostracodes, diatoms, radiolaria, coccolithophores, dinoflagellates, and ichthyoliths]. Marine microfossils represent a useful model system for such integrative research because of their high abundance, large spatiotemporal coverage, and good taxonomic and temporal resolution. The microfossil record allows for quantitative cross-scale research designs, which help in answering fundamental questions about marine biodiversity, including the causes behind similarities in patterns of latitudinal and longitudinal variation across taxa, the degree of constancy of observed gradients over time, and the relative importance of hypothesized drivers that may explain past or present biodiversity patterns. The inclusion of a deep-time perspective based on high-resolution microfossil records may be an important step for the further maturation of macroecology. An improved integration of macroecology and palaeoecology would aid in our understanding of the balance of ecological and evolutionary mechanisms that have shaped the biosphere we inhabit today and affect how it may change in the future. PMID- 26420172 TI - Deep sequencing analysis of transcriptomes in Aspergillus flavus in response to resveratrol. AB - BACKGROUND: Resveratrol has been reported as a natural phytoalexin that inhibits infection or the growth of certain fungi including Aspergillus flavus. Our previous research revealed that aflatoxin production in A. flavus was reduced in medium with resveratrol. To understand the molecular mechanism of the A. flavus response to resveratrol treatment, the high-throughput paired-end RNA-Seq was applied to analyze the transcriptomic profiles of A. flavus. RESULTS: In total, 366 and 87 genes of A. flavus were significantly up- and down- regulated, respectively, when the fungus was treated with resveratrol. Gene Ontology (GO) functional enrichment analysis revealed that 48 significantly differentially expressed genes were involved in 6 different terms. Most genes in the aflatoxin biosynthetic pathway genes cluster (#54) did not show a significant change when A. flavus was treated with resveratrol, but 23 of the 30 genes in the #54 cluster were down-regulated. The transcription of aflA and aflB was significantly suppressed under resveratrol treatment, resulting in an insufficient amount of the starter unit hexanoate for aflatoxin biosynthesis. In addition, resveratrol significantly increased the activity of antioxidative enzymes that destroy radicals, leading to decreased aflatoxin production. Moreover, stuA, fluG, flbC, and others genes involved in mycelial and conidial development were down regulated, which disrupted the cell's orderly differentiation and blocked conidia formation and mycelia development. The transcripts of laeA and veA were slightly inhibited by resveratrol, which may partly decrease aflatoxin production and depress conidia formation. CONCLUSIONS: Resveratrol can affect the expression of A. flavus genes that are related to developmental and secondary metabolic processes, resulting in decreased aflatoxin production and conidia formation and could also cause abnormal mycelia development. These results provide insight into the transcriptome of A. flavus in response to resveratrol and a new clew for further study in regulation of aflatoxin biosynthesis in A. flavus. PMID- 26420176 TI - Effect of nutritional support on clinical outcomes in perioperative malnourished patients: a meta-analysis. AB - Malnutrition is an independent risk factor for complications, mortality, wound healing, length of hospital stay, and costs. Associations between nutritional support and surgical patients remain controversial. Databases, including Pubmed, EMBASE, Web of Science, CNKI, VIP, and the Cochrane Library, were searched to find randomized controlled trials (RCTs) that assessed the effect of nutritional support on clinical outcomes in perioperative malnourished patients. The methodological quality of each included trial was assessed. A meta-analysis was conducted with Rev Man 5.2. Fifteen RCTs, involving 3831 patients, were included in this meta-analysis. Compared with control group, results showed that nutritional support was more effective in decreasing the incidence of infectious [relative risk (RR): 0.58; 95% CI: 0.50, 0.68; p<0.01] and non-infectious complications (RR: 0.74; 95% CI: 0.63, 0.88; p<0.01), and shortening the length of hospital stay [weighted mean difference (WMD): -2.64; 95% CI: -5.13, -0.16; p<0.05]. Moreover, the incidence of infectious complications in the immune nutrition group was significantly lower than that in the standard nutrition group (RR: 0.75; 95% CI: 0.58, 0.97; p<0.05). However, changes in hospital costs (WMD: 894; 95% CI: -1140, 2928; p>0.05) and postoperative mortality (RR: 0.77; 95% CI: 0.41, 1.44; p>0.05) between the nutritional support group and control group were not significantly different. In conclusion, perioperative nutritional support was superior in improving clinical outcomes in malnourished patients, which could significantly reduce the incidence of complications and effectively shorten the length of hospital stay. PMID- 26420175 TI - Cutoff value of HbA1c for predicting diabetes and prediabetes in a Chinese high risk population aged over 45. AB - OBJECTIVE: To evaluate the cutoff value of HbA1c for predicting diabetes and prediabetes in a Chinese high risk population aged over 45. METHODS: A total of 619 people aged over 45 without diabetes were randomly recruited to complete Finnish Diabetes Risk Score (FINDRISC) questionnaire. 208 high-risk individuals (defined by Diabetes Risk Score >=9) had OGTT and HbA1c determined at the same time. RESULTS: In a Chinese population aged over 45, the best cutoff value of HbA1c for detecting diabetes and prediabetes was 5.8% and 5.4% respectively. The area under the receiver operating characteristic (AUROC) curve of HbA1c for detecting diabetes was 0.85 (95% CI: 0.80-0.90) and prediabetes was 0.62 (95% CI: 0.54-0.70). The combined use of HbA1c and fasting blood glucose (FPG) had larger AUROC than HbA1c alone (0.88, 95%CI: 0.83-0.92 in detecting diabetes vs 0.75, 95% CI: 0.67-0.82 in prediabetes), and had a higher sensitivity in predicting diabetes and higher specificity and positive predictive value (PPV) in predicting prediabetes. However, the AUROC between HbA1c alone and combined use in predicting diabetes was not significantly different (p=0.173). CONCLUSIONS: FINDRISC is feasible tool to screen people who are at high risk of diabetes. The cutoff values of HbA1c to diagnose diabetes and prediabetes in a Chinese high risk population aged over 45 were 5.8% and 5.4%, respectively. The sensitivity and specificity of HbA1c for detecting diabetes and prediabetes was relatively low, so that the combined use of HbA1c and FPG may be more effective in prediction. PMID- 26420178 TI - Dietary or enteral medium-chain triglyceride usage in a Chinese general hospital. AB - OBJECTIVES: Medium chain triglycerides (MCTs) are of nutritional interest for their unique properties on ingestion, absorption and metabolism. However, dietary and enteral MCTs usage in hospitalized patients in China requires evaluation. METHODS: A retrospective analysis was conducted on 46 hospitalized patients who were administered MCTs therapy between January, 2012 and December, 2013 in Peking Union Medical College Hospital. The clinical parameters of subjects were evaluated 2 weeks after intervention. All indications and outcomes of MCTs therapy underwent evidence-based evaluation. A survey was conducted on a random sample of 77 doctors to clarify the awareness and knowledge of MCTs therapy among clinicians. RESULTS: Among 46 cases undergoing MCTs therapy, there were 21 with gastrointestinal dysfunction (with improvement in 15 cases), 15 with lymphatic anomalies (with improvement in 7 cases), 5 with dyslipidemia (with improvement in 3 cases), 4 with exocrine pancreatic insufficiency (with improvement in 2 cases) and 1 with epilepsy (without improvement). All indications were evidence -based. Although MCTs were being utilized in an increasing number of patients, the survey revealed poor knowledge of their physicochemical properties, medical indications and the therapeutic basis of their use among clinicians. CONCLUSIONS: MCTs therapy is of benefit in the management of gastrointestinal malabsorption, pancreatic exocrine insufficiency, intestinal lymphangiectasia and dyslipidemia. However, randomized controlled trials with adequate sample size and longer follow up are required to evaluate further their efficacy, and more educational programs are needed to ensure clinical competence for MCT therapy. PMID- 26420177 TI - Emerging malnutrition during hospitalisation independently predicts poor 3-month outcomes after acute stroke: data from a Chinese cohort. AB - OBJECTIVE: Questions exist regarding the causal relationship between malnutrition and stroke outcomes. This study aimed to determine whether nutritional status changes or malnutrition during hospitalisation could predict 3-month outcomes in acute stroke patients. METHODS: During a 10-month period, patients who suffered their first stroke within 7 days after stroke onset were included in this prospective multi-centre study. The demographic parameters, stroke risk and severity factors, malnutrition risk factors and dysphagia were recorded. Nutritional status was assessed by 3 anthropometric and 3 biochemical indices. Changes in nutritional status were defined by comparing the admission values with the 2-week values. A Modified Rankin Scale score of 3-6 was defined as a poor outcome at the 3-month follow-up. Univariate and multiple logistic regression analyses were used to investigate the power of nutritional status changes in predicting poor patient outcomes. RESULTS: Data from 760 patients were analysed. Poor outcomes were observed in 264 (34.7%) patients. Malnutrition prevalence was 3.8% at admission and 7.5% after 2-weeks in hospital, which could not predict 3 month outcome. Emerging malnutrition was observed in 36 patients (4.7%) during the 2-week hospitalisation period and independently predicted poor 3-month outcomes after adjusting for confounding factors (odds ratio 1.37, 95% confidence interval 1.03-1.83). CONCLUSIONS: Emerging malnutrition during hospitalisation independently predicted poor 3-month outcomes in acute stroke patients in this study. PMID- 26420179 TI - Glucose absorption in nephropathy patients receiving continuous ambulatory peritoneal dialysis. AB - OBJECTIVES: Peritoneal dialysis patients are at risk of glucose absorption from peritoneal dialysate, not only because of energy imbalance but also the toxic effects of high glucose. The current widely applied formulae may be not suitable for estimation of glucose absorption in continuous ambulatory peritoneal dialysis (CAPD) patients. This study examined the actual glucose absorption in a cohort of CAPD patients and compared the results with estimates from four current formulae. METHODS: We conducted a survey of glucose absorption of a cohort of 72 CAPD patients and compared actual dialysate glucose absorbed and estimates using K/DOQI formula, Grodstein formula, Bodnar formula, or a percentage estimate of 60%. RESULTS: The total dialysate glucose infused each day varied from 54.4 to 191 g/day with average of 102+/-27.9 g. The average of glucose absorbed was 65.7 g (ranging from 19.5 to 131 g) by actual measurements. The mean absorption rate was 64.4% (ranging from 30.6% to 92.4%). The glucose absorbed from dialysate accounted for 13.8% (ranging from 5.0% to 30.1%) of total energy intake. The average errors of absolute values between actual measurements and estimates were greater than 10 g or 20 g glucose (p<0.001). The average errors in percentages were greater than 20% or 40%, dependently on estimating methods. CONCLUSIONS: The applications of current estimating methods may have limitations. The actual measurement provides dietitians and doctors with more exact information of absorbed glucose and energy compared to the current estimating methods. PMID- 26420180 TI - Effect of vitamin B-12 and n-3 polyunsaturated fatty acids on plasma homocysteine, ferritin, C-reaction protein, and other cardiovascular risk factors: a randomized controlled trial. AB - OBJECTIVES: Vitamin B-12 and n-3 polyunsaturated fatty acids (PUFA) decrease blood homocysteine (Hcy) concentrations. However, the combined effect of these nutrients on Hcy and ferritin, and C-reactive protein is limited and inconclusive. The objective was to examine the synergistic effect of vitamin B-12 in combination of n-3 PUFA on plasma Hcy, ferritin, and other biochemical markers. METHODS: In a randomized controlled trial, thirty eligible subjects were randomly divided into three groups, and assigned to receive 1000 MUg of vitamin B 12, 2 g fish oil, or 1000 MUg vitamin B-12 and 2 g fish oil, respectively, for 8 weeks. Plasma phospholipids (PL) fatty acids and biochemical markers were determined. This study was registered under ClinicalTrials.gov Identifier: NCT01762072. RESULTS: Plasma PL 20:5n-3, 22:6n-3 and n-3 PUFA was increased after 4 and 8 week supplementation of fish oil, and vitamin B-12+fish oil. Plasma concentrations of triacylglycerol, uric acid, C-reactive protein, and ferritin were significantly decreased after 4 and 8 week supplementation of fish oil, and vitamin B-12+fish oil. In all groups, significant changes in plasma Hcy were observed during the study period. Vitamin B-12, fish oil, and vitamin B-12+fish oil supplementation lowered plasma Hcy concentrations by 22%, 19%, and 39%, respectively. CONCLUSIONS: The combination of vitamin B-12 and fish oil has a synergistic effect on lowering plasma concentrations of Hcy. PMID- 26420181 TI - Effects of supplementation with a combination of beta-hydroxy-beta-methyl butyrate, L-arginine, and L-glutamine on postoperative recovery of quadriceps muscle strength after total knee arthroplasty. AB - OBJECTIVES: Total knee arthroplasty (TKA) performed in knee osteoarthritis patients is reported to be immediately followed by a decrease in quadriceps muscle strength. We investigated the effects of supplementation with a combination beta-hydroxy-beta-methyl butyrate, L-arginine, and L-glutamine (HMB/Arg/Gln) on the postoperative recovery of quadriceps muscle strength in patients after TKA. METHODS: Study subjects were 23 patients (12 women; mean age: 70.5) who underwent TKA. The patients were randomly allocated into the control group or the group that consumed HMB/Arg/Gln supplementation (HMB/Arg/Gln group). HMB/Arg/Gln supplementation or control food were consumed for 5 days before the surgery and for 28 days after the surgery, and maximal quadriceps strength was measured at 7 days before the surgery, and at 14, 28 and 42 days after the surgery. During the study, total energy expenditure was measured using a lifestyle recording device. The two groups followed the rehabilitation in the same way. RESULTS: The maximal quadriceps strength was 1.1+/-0.62 Nm/Kg before surgery and 0.7+/-0.9 Nm/Kg after surgery 14 days in the control group (p=0.02), and 1.1+/-0.3 Nm/Kg before surgery and 0.9+/-0.4 Nm/Kg after surgery 14 days in the HMB/Arg/Gln group. Although the control group experienced a significant loss of muscle strength after the surgery, the HMB/Arg/Gln group did not. There was no significant difference in total energy expenditure between the two groups. CONCLUSIONS: Consuming HMB/Arg/Gln supplementation may suppress the loss of muscle strength after TKA. Intervention with exercise and nutrition appears to enable patients to maintain their quadriceps strength. PMID- 26420182 TI - Encapsulated green kiwifruit extract: a randomised controlled trial investigating alleviation of constipation in otherwise healthy adults. AB - OBJECTIVES: Previous clinical trials have shown bowel function is improved through consumption of whole kiwifruit (Actinidia deliciosa). This study investigated whether encapsulated kiwifruit extract (1 g/day) could alleviate constipation in otherwise healthy adults. METHODS: Forty adults with confirmed constipation entered this trial, of which 32 completed with >80% compliance. Two capsules were self-administered morning and evening for 2 periods, each of 3 weeks duration, separated by a 3+ week washout in a double blind, randomised, placebo controlled crossover. Inclusion criteria included constipation with <=3 bowel movements (BM) per week. Daily records of defecation frequency and stool characteristics were obtained throughout treatment, as well as a measurement of gastrointestinal symptoms rating scale (GSRS) and quality of life (QoL) before and after each intervention arm. RESULTS: There was no difference in total BM over 3 weeks (p>0.05) or mean BM during each of weeks 1, 2 and 3 (p>0.05) between the kiwifruit extract and placebo when assessed from a faecal diary. There was also no detectable difference in defecation related scores of BM ease of defecation, volume, consistency or BM type assessed using Bristol stool chart scores. Nor was there a significant change in GSRS or QoL between pre and post treatment measures, when compared to placebo (p>0.05). CONCLUSIONS: This trial showed that improvement in bowel function or comfort was not achieved through supplementation with 1 g/day freeze dried kiwifruit extract. Efficacy from prior kiwifruit powder and whole fruit trials indicate that investigating higher doses of encapsulated kiwifruit extract may be worthwhile. PMID- 26420183 TI - Determinants of dietary self-care behaviours among Taiwanese patients with type 2 diabetes. AB - The effects of patient characteristics on reported adherence to dietary self-care behaviours in 184 Taiwanese outpatients 40 years or older with type 2 diabetes was assessed. Patient characteristics included the presence of predisposing factors affecting diabetes adherence (knowledge and attitudes about the disease, self-efficacy, and the absence of psychological problems), enabling factors (understanding of diabetes and environmental factors affecting it), and reinforcing factors (presence of medical and social support) which were evaluated using a 72 item self-administered questionnaire with 8 subscales. Adherence was assessed by patients' reports of carrying out 7 self-care behaviours (following a diabetic meal plan, following the diabetes exchange system, eating meals providing the same amount of carbohydrate every day, counting carbohydrates, reducing dietary fat, consuming high fiber foods, and keeping a daily food record). Reported adherence ranged from 17% to 74%. No single predisposing, enabling, or reinforcing factor predicted adherence to all of the dietary self care behaviours. However, more self-efficacy, better understanding, and a better attitude toward diabetes were associated with performing five or more of the dietary self-care behaviours examined. With respect to specific self-care behaviours, women were more likely than men to count carbohydrates (OR=5.75) and reduce fat in their diets (OR=2.57). Patients who attended more nutrition education sessions were more likely to follow diabetes meal plans (OR=2.11) and the diabetes exchange system (OR=3.07). Efforts are needed to encourage providers to teach diabetes self-care behaviours to patients and to capitalize upon demographic and psychosocial characteristics that can enhance patient adherence. PMID- 26420184 TI - Diabetes self-care behaviours and clinical outcomes among Taiwanese patients with type 2 diabetes. AB - We examined the influences of patients' background characteristics on the frequency of performing five diabetes self-care behaviours that 185 Taiwanese outpatients reported. All patients had type 2 diabetes diagnosed for more than a year and attended an outpatient clinic at a large university hospital where they had received at least one dietitian-led individual nutrition education session and one nurse-led diabetes education session during the course of their care. Seventy nine percent of the patients regularly (defined as responses often or always on the questionnaire) took their medications and over half followed recommended meal plans and exercised, but fewer performed foot care (38%) or checked their blood glucose levels (20%) regularly. The associations between patients' demographics and disease-related characteristics and their performance of self-care behaviours were assessed with logistic regression. Although checking blood glucose levels and performing diabetes foot care were unrelated to any clinical outcome examined, patients who took their diabetes medications had lower hemoglobin A1c levels and fewer chronic complications than those who did not. Furthermore, patients who followed a diabetes meal plan also had lower hemoglobin A1c levels, and those who exercised regularly had healthier body mass indices (BMI) than those who did not. PMID- 26420185 TI - Low haemoglobin levels contribute to low grip strength independent of low-grade inflammation in Japanese elderly women. AB - Muscle strength declines with age. However, factors that contribute to such declines are not well documented and have not been extensively studied in elderly populations of Asian origin. Correlations of grip strength with a broad range of factors associated with declines in muscle strength were examined in 202 community-living elderly Japanese women. After adjustment for age, grip strength was positively correlated with body weight, height, serum albumin, haemoglobin, high-density lipoprotein cholesterol (HDL-C) and serum iron and inversely with serum copper, and log high-sensitivity C-reactive protein (hsCRP). Multiple linear regression analysis with grip strength as a dependent variable showed that 47.0% of variability of grip strength could be accounted for by height, age and haemoglobin in order of increasing R2. In conclusion, low haemoglobin may contribute to low muscle strength independently of age, anthropometric, nutritional, and inflammatory markers in the elderly, and may represent an important confounder of the association between grip strength and functional decline in community- living Japanese elderly women. PMID- 26420186 TI - Anaemia prevalence over time in Indonesia: estimates from the 1997, 2000, and 2008 Indonesia Family Life Surveys. AB - OBJECTIVE: To summarize anaemia prevalence data for children, women, and men using data from the second, third and fourth waves of the Indonesia Family Life Surveys (IFLS), which were conducted in 1997/8, 2000, and 2007/8, respectively. METHODS: Anaemia prevalence was determined for children 0 to 5 years, 5 to 12 years, 12 to 15 years, non-pregnant women at least 15 years, pregnant women at least 15 years, and men at least 15 years, based on haemoglobin adjusted for altitude and smoking status. RESULTS: Compared with 1997/8 estimates, anaemia prevalence estimates were lower in 2007/8 for all groups, with the greatest relative decline occurring in children 5 to 12 years (25.4%). Trend analysis found anaemia significantly declined over the survey years for all groups (chi2 p=0.005 for pregnant women, chi2 p<0.001 for all other groups). CONCLUSIONS: IFLS anaemia estimates for different population groups decreased between 1997/8 and 2007/8 and were consistent with estimates from Southeast Asia, and with other studies conducted in Indonesia. While the prevalence of anaemia consistently decreased in all groups, anaemia remains a moderate public health problem for children 0 to 5 years, children 5 to 12 years, and non-pregnant and pregnant women. PMID- 26420187 TI - Intake and major sources of dietary flavonoid in Korean adults: Korean National Health and Nutrition Examination Survey 2010-2012. AB - With an effort to investigate possible relationship between flavonoids and health, an accurate estimation of flavonoid intake is valuable. We estimated dietary flavonoid intake and identified the major food sources. Subjects were healthy adults aged >=19 y (n=11,474) who completed the 24-h dietary recall of the Korean National Health and Nutritional Examination Survey (2010-2012). The US Department of Agriculture and newly estimated or published values for typical Korean foods were combined into a Korean-targeted flavonoid database. The mean intake of total flavonoid was 107+/-1.47 mg/d, with a higher intake in women than in men after energy-adjustment. Quercetin, cyanidin, genistein, daidzein, epigallocatechin 3-gallate, epicatechin, hesperetin, and luteolin were identified as major flavonoid compounds. Across the age range studied, flavonols and flavones showed a reversed U-shape curve; flavan-3-ol and flavanones showed a decreasing pattern; and anthocyanidins and isoflavones showed an increasing pattern. Forty-five food items were identified as contributing >2% of at least one flavonoid compound's intake. Kimchi was the major food source of total flavonoids, followed by green tea, persimmons, and soybeans. Single food items accounting for more than 50% of the intake of a specific flavonoid included persimmons (cyanidin), green tea (epigallocatechin, epicatechin-3-gallate, and epigallocatechin 3-gallate), black tea (thearubigin), tangerines (hesperetin and naringenin), and onions (isorhamnetin). This study provides information on Korean flavonoid intake to enable international comparisons, along with insight into how the sources and intake of various flavonoids vary according to age and gender. This work should facilitate future investigations of the association between flavonoid intake and health. PMID- 26420188 TI - New data for vitamin D in Australian foods of animal origin: impact on estimates of national adult vitamin D intakes in 1995 and 2011-13. AB - OBJECTIVES: To assess the potential dietary supply of vitamin D to Australian adults by application of new data for Australian primary foods of animal origin. METHODS: New published analytical data on the vitamin D contents of Australian primary foods from animal products were obtained and assessed for reliability. Using food consumption data from Australian population dietary surveys for 1995 and 2011-2013, estimates were made of the likely average daily intakes of vitamin D equivalents from these sources by Australian adults. RESULTS: Meats, chicken, fish, eggs and dairy produce may alone have contributed about 4.2 MUg vitamin D equivalents per day to average Australian diets of adults >18 years in 1995 and 4.3 MUg in 2011-2013. CONCLUSIONS: Dietary vitamin D intake in Australia is likely to be higher than previously estimated because new data from improved analytical methods reveal the contributions to vitamin D supply from foods of animal origin. Absence of reliable vitamin D data for milk and milk products, and the gaps in vitamin D data for many commonly consumed seafood, poultry, eggs and processed animal products greatly limit estimation of dietary vitamin D intakes by Australians. PMID- 26420190 TI - The correlation between high body mass index and survival in patients with esophageal cancer after curative esophagectomy: evidence from retrospective studies. AB - OBJECTIVE: To investigate the predictive value of high body mass index (H-BMI) on the survival of patients with esophageal cancer (EC) after curative esophagectomy. METHODS: Studies were systematically identified to investigate the relationship between overweight and obese (H-BMI) and clinical outcomes in EC patients treated with curative esophagectomy. Measured clinical outcomes were disease-free survival (DFS) and overall survival (OS). The pooled hazard ratio (HR) with 95% confidence interval (CI) was estimated. Subgroup analyses were performed according to tumour type and body mass index (BMI). RESULTS: Fourteen studies with 4823 cases were included in the final pooled quantitative analysis. In EC patients overall, H-BMI was associated with improved DFS (HR, 0.83; 95% CI: 0.75-0.90) and OS (HR, 0.79; 95 % CI: 0.73-0.85), as compared with normal BMI. The results were consistent with those who were overweight. Among patients with esophageal adenocarcinoma (EAC), a better prognosis, as reflected by OS, was observed with H-BMI (HR, 0.81; 95% CI: 0.73-0.89). The same results were also observed in EAC patients who were obese and overweight. In contrast, among patients with esophageal squamous cell carcinoma (ESCC), H-BMI was associated with a worse prognosis, as reflected by DFS (HR, 2.26; 95% CI: 1.29-3.24). CONCLUSIONS: H-BMI has distinctly different impacts on the postoperative survival of EAC and ESCC patients. H-BMI is a potential predictor for better prognosis in EC patients overall, and particularly in EAC patients, treated with curative esophagectomy. However, in ESCC patients, H-BMI is a potential predictor for a worse prognosis of postoperative survival. PMID- 26420189 TI - BMI and all-cause mortality among Chinese and Caucasians: the People's Republic of China and the Atherosclerosis Risk in Communities Studies. AB - BACKGROUND: Lower ethnic-specific body mass index (BMI) cutpoints have been proposed for Asians and adapted in some countries. However, to our knowledge, no study has directly compared Asians to other ethnic groups to test differences in associations between BMI and all-cause mortality using common methods. OBJECTIVES: We estimated the association between BMI and all-cause mortality in Chinese Asians and Caucasian Americans to determine if lower Asian-specific BMI cutpoints are warranted. METHODS: Extant data of the People's Republic of China Study (1983-1997) including 5546 Chinese and the Atherosclerosis Risk in Communities Study (1987-2002) including 9932 Caucasians aged 45-64 years at baseline were used. All analyses were performed using Cox proportional regression models. RESULTS: Standardized mortality rates were 6.88 (95% confidence interval (CI): 5.75-8.24) and 5.50 (95% CI: 4.74-6.39) per 1000 person-years for Chinese and Caucasians, respectively. Standardized mortality probabilities by age 70 were similar across all BMI categories among Chinese. Furthermore, the probabilities were similar to those among Caucasians with BMI of 27.5-<32.5 kg/m2. The BMI associated with lowest mortality risk was almost identical between Chinese (25.1 kg/m2) and Caucasians (25.2 kg/m2). The analysis of categorical BMI did not reveal an increased mortality risk at any BMI category among Chinese. In contrast, compared to those with a BMI of 23.0-<25.0 kg/m2, risk was elevated by 35% among Caucasians with a BMI of 30.0-<32.5 kg/m2. CONCLUSIONS: These findings do not support different BMI cutpoints for Chinese than Caucasians on the basis of mortality rates. PMID- 26420191 TI - Interrelationship between glucose metabolism and undercarboxylated osteocalcin: a cross-sectional study in a community-dwelling population. AB - OBJECTIVE: Undercarboxylated osteocalcin (ucOC) produced from the bone was recently found to play a regulatory role in the insulin and adiponectin secretion. We performed a cross-sectional study to investigate the relationship between ucOC and diabetes mellitus (DM). METHODS: We included 1,870 subjects aged over 50 from participants of a health examination. According to the current medication and past history, 605 subjects had hypertension (HT), 316 had dyslipidemia (DL), and 182 had type 2 DM. Fasting blood samples were collected to measure concentrations of ucOC and the bone turnover marker, tartrate-resistant acid phosphatase 5b (TRACP5b) by ELISA. RESULTS: The serum ucOC level was significantly lower in DM(+) than DM(-) in both men and women. In a logistic regression analysis, a low level of ucOC was significantly associated with the presence of DM in both men and women after adjusting for age, BMI, serum creatinine, triglyceride, and TRACP5b. Multiple regression analysis showed a negative association of ucOC with HbA1c and fasting plasma glucose, and a positive association with the insulin level. In contrast, no association was found between TRACP5b and the indices above, suggesting that the effect of ucOC on the insulin secretion and the glycemic status was independent of bone turnover. CONCLUSIONS: The present cross-sectional study showed a significant association between ucOC and glucose metabolism after correction with bone turnover in a community-dwelling population both in men and women, indicating that ucOC may play an important role in the pathogenesis of DM through the pathways independent of bone metabolism. PMID- 26420192 TI - A meta-analysis combining parallel and cross-over randomized controlled trials to assess impact of iodine fortified foods on urinary iodine concentration among children. AB - The purpose of this analysis was to combine evidence from parallel and cross-over randomized controlled trials to assess the impact of iodine fortified foods on urinary iodine concentration (UIC) in children. A structured search for studies on iodine intervention studies on MEDLINE, Pro Quest, and the Cochrane Library from Jan, 1990 to Dec, 2012 was carried out. Carry-over effect was estimated by general linear model. We explored two methods to pool continuous outcomes in a meta-analysis by combining parallel and cross-over trial designs. The standard mean difference was calculated for net change in UIC. Fixed or random-effects models were used to summaries fortified food response data. Meta-regression and covariate meta-analysis were performed to explore the influ-ence of confounders on the net pooled effect on UIC. The overall pooled estimate, which combined parallel with cross-over trials in the absence of carry-over effect of UIC from 9 studies, showed a significant increase in the fortified group compared with the control group (n=3448; standard mean difference=2.02 MUg/L; 95% CI: 1.30, 2.73; I2=99%, tau2=1.81, p<0.01). Meta-regression analysis indicated that dose of the feeding was positively related to the effect size (regression coefficient=0.014; 95% CI: 0.003, 0.026; p<0.019). The net pooled effect size after removing the confounders was 1.59 (95% CI: 0.953, 2.23) MUg/L. There was an association between intakes of io-dine fortified foods and UIC in children. These results suggest that we can combine parallel with cross-over trials for meta-analysis for nutrients such as iodine when absorption is high. PMID- 26420193 TI - Standard values of rapid turnover proteins and zinc in Japanese children. AB - Measurement of rapid-turnover proteins has an established place in nutrition assessment and is partly dependent on the zinc metallo-enzymes involved. We investigated the reference values of rapid turnover proteins and zinc in Japanese children. This cross-sectional study was conducted at a single center. We collected data from children aged 0 to 12 years with inguinal hernia, umbilical hernia, or hydrocele of the spermatic cord, who had body mass index z scores of 2 to 2. The standard references (mean+/-2 SD) of transthyretin were 11.5-21.5 mg/dL in infants (<=1.5 years), 13.6-21.5 mg/dL in preschool children (1.6-6 years), and 12.3-23.4 mg/dL in preadolescent children (6.1-12 years). The standard references of retinol binding protein were 1.27-2.55 mg/dL, 1.28-2.54 mg/dL, and 1.27-2.44 mg/dL in each age group, respectively. Rapid turnover proteins did not differ significantly in each group. The transthyretin level was weakly correlated with aging (r=0.284, p=0.003) and estimated lean body mass (r=0.274, p=0.004). Retinol-binding protein was not correlated with aging and anthropometric parameters. We established reference values for rapid turnover proteins with known zinc status in Japanese children. These values were not, or only weakly, correlated with anthropometric parameters for assessing protein energy malnutrition. PMID- 26420194 TI - Is parental body weight related with their children's overweight and obesity in Gao Hang Town, Shanghai? AB - OBJECTIVES: This study aimed to evaluate the relationship between parental body weight and their children's overweight and obesity in school students in Gao Hang Town, Shanghai. METHODS: A cross-sectional study was performed in five primary schools in Gao Hang Town, Shanghai. Overall, 2,025 sets of parents and their children (7-13 years, 981 boys/1044 girls) were enrolled. Body mass index (BMI) and waist circumference for each child were measured. Age, gender, birth weight, and breastfeeding history was recorded for each child and the BMI of their parents was obtained by a self-completion questionnaire. Overweight (including obesity) was defined as a BMI of >=24.0 kg/m2 in parents and a BMI >=P85 in children according to age- and gender-specific percentiles. Re-sults: The total prevalence of overweight was higher in boys than in girls (35.5% vs 19.5%), while it was the same in fathers compared with mothers (50.6% vs 18.9%). The prevalence of overweight in boys showed a trend with increasing age, but remained stable versus age in girls. Parents were further divided into four subgroups as follows: I) both father and mother had a normal BMI; II) father overweight, mother normal weight; III) father normal weight, mother overweight; IV) both father and mother are overweight. The odds ratio of overweight was 2.26 for group II, 2.71 for group III, and 4.36 for group IV, respectively, compared with group I. Gender, paternal BMI, and maternal BMI were chosen as risk factors for children overweight. CONCLUSIONS: Parental BMI affects their offspring overweight and obesity in Chinese school students. PMID- 26420195 TI - Polychlorinated biphenyl and heavy metal exposures among fishermen in the Straits of Malacca: neurobehavioural performance. AB - The aim of this study was to determine the level of exposure to polychlorinated biphenyls (PCBs) and selected heavy metals among fishermen via dietary intake of fish and other seafood from the eastern coast along the Straits of Malacca. This study determined the neurobehavioural performances (based on neurobehavioural core test battery scores) of the fishermen and evaluated the correlations between scores of neurobehavioural core test battery and exposure factors. Ninety fishermen participated in the study. The total fish intakes of the fishermen were measured using a set of food frequency questionnaires. The PCBs contents in the seafood samples ranged between 0.2 and 0.6 pg/g fresh sample. The concentrations of mercury (Hg), arsenic (As), cadmium (Cd), and lead (Pb) in the seafood samples were 1.1-5.4, 0.3-4.4, 0.6-36.1, and 0.02-0.3 MUg/g fresh sample, respectively. The PCBs, Hg, As, Cd, and Pb exposures of the fishermen was estimated to be 2.8, 0.02, 4.5, 0.09, and 0.5 pg/kg body weight/day, respectively. PCB and heavy metal exposures through dietary intake of fish and seafood were within the tolerable daily limits. The results of neurobehavioural core test battery revealed that the neurobehavioural performances of the fishermen were not affected due to PCB and heavy metal intoxication. No correlations were found between the exposure and neurobehavioural performance among the fishermen. These data are useful for policy makers to assure the safety and quality of seafood in relation to sea pollution. Although the levels of exposure were low, periodic assessment of the quality of fish and fish products is required due to the polluted seawater. PMID- 26420196 TI - Effectiveness of a public dietitian-led diabetes nutrition intervention on glycemic control in a community setting in China. AB - OBJECTIVE: Diabetes mellitus requires lifelong treatment, most of which is accomplished in family and community settings. The present study was designed to identify the effectiveness of nutrition intervention provided by public dietitian on glycemic control in a community setting in China. METHODS: Two communities were selected and randomly assigned to a routine care group (59 subjects) and a public dietitian-led intervention group (58 subjects) who received diabetic nutrition management for one year. The main measures included fasting plasma glucose, HbA1c, weight, body mass index (BMI), lipid profile, and blood pressure. RESULTS: In the intervention group, there was significant improvement in fasting plasma glucose, HbA1c, cholesterol, and triglyceride levels relative to the control subjects (p<0.05). Over the 12-month period, there was a decrease in energy intake, including reductions in absolute amounts (grams) of protein and fat in the intervention group. The energy percent values of carbohydrate, protein, and fat were 50.7%, 17.0%, and 32.3%, respectively, at baseline and 53.0%, 17.1%, and 29.9% (within the recommended range) after the intervention. There were significant improvements in total energy, absolute amounts of fat and protein, and the energy percent values of carbohydrates and fat. In the control group, however, these values were similar before and after the intervention, and the energy percent values of fat were still above the recommended range. CONCLUSIONS: In a community setting, a diabetes nutrition intervention led by a public dietitian significantly improved the glycemic control of type 2 diabetic patients. PMID- 26420197 TI - Identifying barriers to the implementation of nutrition education in South Korea. AB - To improve the nutritional status of children and adolescents, it is critical to identify the barriers to the implementation of nutrition education in schools. We carried out a cross-sectional study by analyzing data from 121 subjects (45 nutrition teachers and 76 school dietitians). Among the personal, environmental and systematic barriers, the top four barriers to the implementation of nutrition education were heavy workload (4.28 points), lack of a systematic curriculum (4.12 points), lack of perception of nutrition education by school administrators and teachers (4.07 points), and lack of continuing education for nutrition teachers and school dietitians (4.05 points). Additionally, poor working conditions, such as low pay, were identified as significant barriers to nutrition education for school dietitians compared with nutrition teachers (4.33 vs 3.47 points, p<0.001). This research provides useful information for nutrition policy makers to promote nutrition education in schools in South Korea. PMID- 26420198 TI - The adherence of packaged food products in Hyderabad, India with nutritional labelling guidelines. AB - BACKGROUND: India is experiencing a nutrition transition with the consumption of processed foods rapidly increasing. Nutrition labels are essential if consumers are to understand the healthiness of these products. The Food Safety and Standards Authority of India have recently introduced regulation defining national nutrition labelling requirements and Codex Alimentarius recommends a global standard. OBJECTIVES: To quantify the adherence of the declared nutrients on Indian packaged foods with national and global requirements. METHODS: The presence or absence of data for seven required nutrients was recorded for all food products available for sale. Branches of three major retail chains and three smaller stores in Hyderabad, India between October and November, 2010 were surveyed. RESULTS: Data were collected for 4166 packaged products that fell into 14 different food groups. 52% of products displayed nutrient information on energy, protein, carbohydrate, sugar and total fat, meeting the minimum requirements of the Food Safety and Standards Authority of India. Only 27% met the minimum criteria defined by Codex which also requires the reporting of saturated fat and sodium. There was significant variation in compliance for leading brands, country of manufacture and food group (p<0.01 for all). CONCLUSIONS: The majority of Indian packaged foods do not meet national and international nutrient labelling guidelines. With the Indian population likely to consume much more packaged food over coming years full and effective food labelling will be essential. The failure of Indian legislation to require labelling of sodium and saturated fat may warrant review. PMID- 26420199 TI - Diets high in carbohydrate may not be appropriate for rs328 G carriers with the metabolic syndrome. AB - The objective of this study was to test how the genetic polymorphisms located within the lipoprotein lipase (LPL) locus would modulate the relationship between a diet high in carbohydrate and insulin resistance related traits in metabolic syndrome adults. A one year nutritional intervention study focusing on education to increase dietary intake of whole grain, vegetable and fruit, and to reduce the intake of sodium, simple sugar and dietary fat (especially cooking oil and pork lard) was conducted. Two districts in Shanghai, China were randomly selected to be the intervention and control group, and patients (n=235) with metabolic syndrome within these two districts were selected based on a multistage sampling method. Fasting glucose was reduced in rs328 CC homozygotes (p=0.028) but not G carriers (p=0.686) within the intervention group. Also an ancillary study with greater statistical power by combining the baseline measurements across both the intervention and control groups was conducted to test the cross-sectional statistical interactions between carbohydrate/fat and lipoprotein lipase genotypes for homeostasis model assessment of insulin resistance/insulin/fasting glucose. Increased carbohydrate intakes were positively associated with homeostasis model assessment of insulin resistance and insulin in rs328 G carriers but not CC homozygotes (p for interaction was 0.025). These results indicate that diet high in carbohydrate may not be suitable for metabolic syndrome rs328 G carriers, calling for the development of personalized dietary intervention for metabolic syndrome subjects. PMID- 26420200 TI - Diaceno[a,e]pentalenes: An Excellent Molecular Platform for High-Performance Organic Semiconductors. AB - Three diaceno[a,e]pentalene analogues with pendant sterically bulky di-tert butylphenyl groups have been designed and synthesized. With the extension of the conjugated molecular framework, the molecular arrangement is apparently tuned by the balance between the pi-extended surface and pendant alkyl or aryl substituents. Theoretical calculations of the morphologies were in good agreement with the experimental results. Ambient-stable field-effect transistors based on dianthraceno[a,e]pentalene (DAP) have been fabricated, which exhibited excellent hole mobilities (up to 6.55 cm(2) V(-1) s(-1)). Thus, this study has shown that diaceno[a,e]pentalenes are stable even with an extraordinarily large pi-surface area, and may thus serve as excellent molecular platforms for further exploring high-performance semiconducting materials. PMID- 26420201 TI - Phototropic solar tracking in sunflower plants: an integrative perspective. AB - BACKGROUND: One of the best-known plant movements, phototropic solar tracking in sunflower (Helianthus annuus), has not yet been fully characterized. Two questions are still a matter of debate. (1) Is the adaptive significance solely an optimization of photosynthesis via the exposure of the leaves to the sun? (2) Is shade avoidance involved in this process? In this study, these concepts are discussed from a historical perspective and novel insights are provided. SCOPE AND METHODS: Results from the primary literature on heliotropic growth movements led to the conclusion that these responses cease before anthesis, so that the flowering heads point to the East. Based on observations on 10-week-old plants, the diurnal East-West oscillations of the upper fifth of the growing stem and leaves in relation to the position of the sun (inclusive of nocturnal re orientation) were documented, and photon fluence rates on the leaf surfaces on clear, cloudy and rainy days were determined. In addition, the light-response curve of net CO2 assimilation was determined on the upper leaves of the same batch of plants, and evidence for the occurrence of shade-avoidance responses in growing sunflower plants is summarized. CONCLUSIONS: Only elongating, vegetative sunflower shoots and the upper leaves perform phototropic solar tracking. Photon fluence response and CO2 assimilation measurements cast doubt on the 'photosynthesis-optimization hypothesis' as the sole explanation for the evolution of these plant movements. We suggest that the shade-avoidance response, which maximizes light-driven CO2 assimilation, plays a major role in solar tracking populations of competing sunflower plants, and an integrative scheme of these growth movements is provided. PMID- 26420202 TI - Genetic variation facilitates seedling establishment but not population growth rate of a perennial invader. AB - BACKGROUND AND AIMS: Assessing the demographic consequences of genetic variation is fundamental to invasion biology. However, genetic and demographic approaches are rarely combined to explore the effects of genetic variation on invasive populations in natural environments. This study combined population genetics, demographic data and a greenhouse experiment to investigate the consequences of genetic variation for the population fitness of the perennial, invasive herb Lupinus polyphyllus. METHODS: Genetic and demographic data were collected from 37 L. polyphyllus populations representing different latitudes in Finland, and genetic variation was characterized based on 13 microsatellite loci. Associations between genetic variation and population size, population density, latitude and habitat were investigated. Genetic variation was then explored in relation to four fitness components (establishment, survival, growth, fecundity) measured at the population level, and the long-term population growth rate (lambda). For a subset of populations genetic variation was also examined in relation to the temporal variability of lambda. A further assessment was made of the role of natural selection in the observed variation of certain fitness components among populations under greenhouse conditions. KEY RESULTS: It was found that genetic variation correlated positively with population size, particularly at higher latitudes, and differed among habitat types. Average seedling establishment per population increased with genetic variation in the field, but not under greenhouse conditions. Quantitative genetic divergence (Q(ST)) based on seedling establishment in the greenhouse was smaller than allelic genetic divergence (F'(ST)), indicating that unifying selection has a prominent role in this fitness component. Genetic variation was not associated with average survival, growth or fecundity measured at the population level, lambda or its variability. CONCLUSIONS: The study suggests that although genetic variation may facilitate plant invasions by increasing seedling establishment, it may not necessarily affect the long-term population growth rate. Therefore, established invasions may be able to grow equally well regardless of their genetic diversity. PMID- 26420203 TI - Explanatory ecological factors for the persistence of desiccation-sensitive seeds in transient soil seed banks: Quercus ilex as a case study. AB - BACKGROUND AND AIMS: Dominant tree species in northern temperate forests, for example oak and beech, produce desiccation-sensitive seeds. Despite the potentially major influence of this functional trait on the regeneration and distribution of species under climate change, little is currently known about the ecological determinants of the persistence of desiccation-sensitive seeds in transient soil seed banks. Knowing which key climatic and microsite factors favour seed survival will help define the regeneration niche for species whose seeds display extreme sensitivity to environmental stress METHODS: Using the Mediterranean Holm oak (Quercus ilex) forest as a model system, an in situ time course monitoring of seed water status and viability was performed during the unfavourable winter season in two years with contrasting rainfall, at an instrumented site with detailed climate records. In parallel, the characteristics of the microhabitat and their influence on the post-winter water status and viability of seeds were investigated in a regional survey of 33 woodlands representative of the French distribution of the species. KEY RESULTS: Time course monitoring of seed water status in natural conditions confirmed that in situ desiccation is the main abiotic cause of mortality in winter. Critical water contents could be reached in a few days during drought spells. Seed dehydration rates were satisfactorily estimated using integrative climate proxies including vapour pressure deficit and potential evapotranspiration. Seed water status was therefore determined by the balance between water uptake after a rainfall event and water loss during dry periods. Structural equation modelling of microhabitat factors highlighted the major influence of canopy openness and resulting incident radiation on the ground. CONCLUSIONS: This study provides part of the knowledge required to implement species distribution models which incorporate their regeneration niche. It is an important step forward in evaluating the ecological consequences of increasing winter drought and environmental filtering due to climate change on the regeneration of the most dominant Mediterranean tree species. PMID- 26420204 TI - Attack modes and defence reactions in pathosystems involving Sclerotinia sclerotiorum, Brassica carinata, B. juncea and B. napus. AB - BACKGROUND AND AIMS: Sclerotinia stem rot (SSR, Sclerotinia sclerotiorum) is a damaging disease of oilseed brassicas world-wide. Host resistance is urgently needed to achieve control, yet the factors that contribute to stem resistance are not well understood. This study investigated the mechanisms of resistance to SSR. METHODS: Stems of 5-week-old Brassica carinata, B. juncea and B. napus of known resistance were infected via filter paper discs impregnated with S. sclerotiorum mycelium under controlled conditions. Transverse sections of the stem and portions of the stem surface were examined using optical and scanning electron microscopy. The association of anatomical features with the severity of disease (measured by mean lesion length) was determined. KEY RESULTS: Several distinct resistance mechanisms were recorded for the first time in these Brassica-pathogen interactions, including hypersensitive reactions and lignification within the stem cortex, endodermis and in tissues surrounding the lesions. Genotypes showing a strong lignification response 72 h post-infection (hpi) tended to have smaller lesions. Extensive vascular invasion by S. sclerotiorum was observed only in susceptible genotypes, especially in the vascular fibres and xylem. Mean lesion length was negatively correlated with the number of cell layers in the cortex, suggesting progress of S. sclerotiorum is impeded by more cell layers. Hyphae in the centre of lesions became highly vacuolate 72 hpi, reflecting an ageing process in S. sclerotiorum hyphal networks that was independent of host resistance. The infection process of S. sclerotiorum was analogous in B. carinata and B. napus. Infection cushions of the highly virulent isolate of S. sclerotiorum MBRS-1 were grouped together in dense parallel bundles, while hyphae in the infection cushions of a less aggressive isolate WW-3 were more diffuse, and this was unaffected by host genotype. CONCLUSIONS: A variety of mechanisms contribute to host resistance against S. sclerotiorum across the three Brassica species. These complex interactions between pathogen and host help to explain variable expressions of resistance often observed in the field. PMID- 26420205 TI - Disturbance and density-dependent processes (competition and facilitation) influence the fine-scale genetic structure of a tree species' population. AB - BACKGROUND AND AIMS: Disturbances, dispersal and biotic interactions are three major drivers of the spatial distribution of genotypes within populations, the last of which has been less studied than the other two. This study aimed to determine the role of competition and facilitation in the degree of conspecific genetic relatedness of nearby individuals of tree populations. It was expected that competition among conspecifics will lead to low relatedness, while facilitation will lead to high relatedness (selection for high relatedness within clusters). METHODS: The stand structure and spatial genetic structure (SGS) of trees were examined within old-growth and second-growth forests (including multi stemmed trees at the edge of forests) of Nothofagus pumilio following large-scale fires in Patagonia, Chile. Genetic spatial autocorrelations were computed on a spatially explicit sampling of the forests using five microsatellite loci. As biotic plant interactions occur among immediate neighbours, mean nearest neighbour distance (MNND) among trees was computed as a threshold for distinguishing the effects of disturbances and biotic interactions. KEY RESULTS: All forests exhibited a significant SGS for distances greater than the MNND. The old-growth forest genetic and stand structure indicated gap recolonization from nearby trees (significantly related trees at distances between 4 and 10 m). At distances smaller than the MNND, trees of the second-growth interior forest showed significantly lower relatedness, suggesting a fading of the recolonization structure by competition, whereas the second-growth edge forest showed a positive and highly significant relatedness among trees (higher among stems of a cluster than among stems of different clusters), resulting from facilitation. CONCLUSIONS: Biotic interactions are shown to influence the genetic composition of a tree population. However, facilitation can only persist if individuals are related. Thus, the genetic composition in turn influences what type of biotic interactions will take place among immediate neighbours in post-disturbance forests. PMID- 26420213 TI - Correlation of pelvic incidence with radiographical parameters for acetabular retroversion: a retrospective radiological study. AB - BACKGROUND: Pelvic incidence (PI) has been linked to several degenerative processes within the spinopelvic system. Acetabular retroversion is a recognised risk factor for osteoarthritis of the hip. We therefore hypothesised that these two factors might be part of a specific anatomical variant associated with degenerative changes. This study was performed to clarify this issue. METHODS: The pelvic incidence was measured on 589 computertomographical data sets acquired between 2008 and 2010. For 220 patients a 2D rendering in an antero-posterior view of the CT data set was performed to evaluate the parameters of acetabular retroversion. Those included the prominence of the ischial spine sign (PRISS), the cross-over sign (COS) and the posterior wall sign (PWS). Between 477 and 478 hips were evaluated depending on the parameter of retroversion. RESULTS: The mean pelvic incidence was significantly lower in hips positive for the PRISS and the PWS. However, there were no significant differences between hips positive or negative for the COS. DISCUSSION: As hypothesised, the lower PI values in PWS and PRISS positive hips suggest a link between PI and retroversion of the acetabulum. Whether this is of any clinical relevance remains, however, unknown. CONCLUSION: Acetabular retroversion is linked to PI. In hips where the prominence of the ischial spine sign and/or the posterior wall sign was present, the mean pelvic incidence value was lower. PMID- 26420212 TI - Conserved determinants of lentiviral genome dimerization. AB - BACKGROUND: Retroviruses selectively package two copies of their unspliced genomes by what appears to be a dimerization-dependent RNA packaging mechanism. Dimerization of human immunodeficiency virus Type-1 (HIV-1) genomes is initiated by "kissing" interactions between GC-rich palindromic loop residues of a conserved hairpin (DIS), and is indirectly promoted by long-range base pairing between residues overlapping the gag start codon (AUG) and an upstream Unique 5' element (U5). The DIS and U5:AUG structures are phylogenetically conserved among divergent retroviruses, suggesting conserved functions. However, some studies suggest that the DIS of HIV-2 does not participate in dimerization, and that U5:AUG pairing inhibits, rather than promotes, genome dimerization. We prepared RNAs corresponding to native and mutant forms of the 5' leaders of HIV-1 (NL4-3 strain), HIV-2 (ROD strain), and two divergent strains of simian immunodeficiency virus (SIV; cpz-TAN1 and -US strains), and probed for potential roles of the DIS and U5:AUG base pairing on intrinsic and NC-dependent dimerization by mutagenesis, gel electrophoresis, and NMR spectroscopy. RESULTS: Dimeric forms of the native HIV-2 and SIV leaders were only detectable using running buffers that contained Mg(2+), indicating that these dimers are more labile than that of the HIV-1 leader. Mutations designed to promote U5:AUG base pairing promoted dimerization of the HIV-2 and SIV RNAs, whereas mutations that prevented U5:AUG pairing inhibited dimerization. Chimeric HIV-2 and SIV leader RNAs containing the dimer-promoting loop of HIV-1 (DIS) exhibited HIV-1 leader-like dimerization properties, whereas an HIV-1NL4-3 mutant containing the SIVcpzTAN1 DIS loop behaved like the SIVcpzTAN1 leader. The cognate NC proteins exhibited varying abilities to promote dimerization of the retroviral leader RNAs, but none were able to convert labile dimers to non-labile dimers. CONCLUSIONS: The finding that U5:AUG formation promotes dimerization of the full-length HIV-1, HIV-2, SIVcpzUS, and SIVcpzTAN1 5' leaders suggests that these retroviruses utilize a common RNA structural switch mechanism to modulate function. Differences in native and NC dependent dimerization propensity and lability are due to variations in the compositions of the DIS loop residues rather than other sequences within the leader RNAs. Although NC is a well-known RNA chaperone, its role in dimerization has the hallmarks of a classical riboswitch. PMID- 26420215 TI - The PKC/NF-kappaB signaling pathway induces APOBEC3B expression in multiple human cancers. AB - Overexpression of the antiviral DNA cytosine deaminase APOBEC3B has been linked to somatic mutagenesis in many cancers. Human papillomavirus infection accounts for APOBEC3B upregulation in cervical and head/neck cancers, but the mechanisms underlying nonviral malignancies are unclear. In this study, we investigated the signal transduction pathways responsible for APOBEC3B upregulation. Activation of protein kinase C (PKC) by the diacylglycerol mimic phorbol-myristic acid resulted in specific and dose-responsive increases in APOBEC3B expression and activity, which could then be strongly suppressed by PKC or NF-kappaB inhibition. PKC activation caused the recruitment of RELB, but not RELA, to the APOBEC3B promoter, implicating noncanonical NF-kappaB signaling. Notably, PKC was required for APOBEC3B upregulation in cancer cell lines derived from multiple tumor types. By revealing how APOBEC3B is upregulated in many cancers, our findings suggest that PKC and NF-kappaB inhibitors may be repositioned to suppress cancer mutagenesis, dampen tumor evolution, and decrease the probability of adverse outcomes, such as drug resistance and metastasis. PMID- 26420214 TI - Kinetic Modeling and Constrained Reconstruction of Hyperpolarized [1-13C] Pyruvate Offers Improved Metabolic Imaging of Tumors. AB - Hyperpolarized [1-(13)C]-pyruvate has shown tremendous promise as an agent for imaging tumor metabolism with unprecedented sensitivity and specificity. Imaging hyperpolarized substrates by magnetic resonance is unlike traditional MRI because signals are highly transient and their spatial distribution varies continuously over their observable lifetime. Therefore, new imaging approaches are needed to ensure optimal measurement under these circumstances. Constrained reconstruction algorithms can integrate prior information, including biophysical models of the substrate/target interaction, to reduce the amount of data that is required for image analysis and reconstruction. In this study, we show that metabolic MRI with hyperpolarized pyruvate is biased by tumor perfusion and present a new pharmacokinetic model for hyperpolarized substrates that accounts for these effects. The suitability of this model is confirmed by statistical comparison with alternates using data from 55 dynamic spectroscopic measurements in normal animals and murine models of anaplastic thyroid cancer, glioblastoma, and triple negative breast cancer. The kinetic model was then integrated into a constrained reconstruction algorithm and feasibility was tested using significantly undersampled imaging data from tumor-bearing animals. Compared with naive image reconstruction, this approach requires far fewer signal-depleting excitations and focuses analysis and reconstruction on new information that is uniquely available from hyperpolarized pyruvate and its metabolites, thus improving the reproducibility and accuracy of metabolic imaging measurements. PMID- 26420216 TI - An Imbalance in TAZ and YAP Expression in Hepatocellular Carcinoma Confers Cancer Stem Cell-like Behaviors Contributing to Disease Progression. AB - Transcriptional coactivator with PDZ-binding motif (TAZ) and yes-associated protein (YAP) are equivalently placed downstream effectors of the Hippo pathway with oncogenic roles in human cancers. However, the expression profiles of TAZ/YAP differ depending on the cancer cell type, suggesting that these proteins have different roles during cancer progression, yet no studies have examined the biologic significance of the balance between TAZ and YAP expression levels. Here we examined the functional roles of TAZ/YAP in hepatocellular carcinoma progression. We found that TAZ, but not YAP, was predominantly expressed in HCC. TAZ knockdown under normal conditions attenuated cell growth in HCC cells; however, TAZ knockdown combined with 5-fluorouracil treatment significantly increased chemoresistance compared with control cells. Notably, TAZ knockdown induced compensatory YAP expression and was accompanied by upregulation of CD90, a HCC-specific cancer stem cell marker. Continuous treatment with 5-fluorouracil also induced YAP expression and promoted tumor formation in vivo. Conversely, double knockdown of TAZ/YAP reduced chemoresistance and tumorigenicity. Moreover, YAP knockdown aggravated HCC cell growth to a greater degree than TAZ knockdown, and YAP overexpression was strongly associated with poor prognoses in patients with HCC. Collectively, these studies demonstrate that TAZ and YAP exhibit different functional roles in cancer progression, and a shift to predominant YAP expression upon TAZ depletion conferred cancer stem cell-like properties including chemoresistance and tumorigenicity in HCC. Therefore, targeting of both TAZ/YAP will be required for a complete antitumor response in HCC. PMID- 26420217 TI - Modeling the effect of operator and passenger characteristics on the fatality risk of motorcycle crashes. AB - BACKGROUND: In Iran more than 25% of crash fatalities belong to motorcycle operators and passengers in the recent years, from which about 20% are related to passenger fatalities. METHODS: The aim of this study was to investigate the motorcycle operator and passenger characteristics as well as other contributory factors that may affect the fatality risk of motorcyclists involved in traffic crashes. To this end, motorcycle crash data between 2009 and 2012 was extracted from Iran traffic crash database and a logistic regression analysis was performed to obtain odds ratio estimates for each of the study variables. RESULTS: The fatality risk of motorcyclists has a direct relationship with the number of pillion passengers carried. Results also indicate that the amount of increase in the likelihood of having a fatality in a motorcycles crash is considerably higher when the operator is accompanied by a male passenger of the same age. Furthermore, results showed that if the crash is occurred in the darkness, on curves, in rural areas and on highways, then the crash would be more likely to be fatal. Moreover, the head-on collisions, older operators, unlicensed operators and not using a safety helmet were found to increase the likelihood of a fatality in a motorcycle crash. CONCLUSIONS: Preventative measures such as, imposing stricter rules regarding safety helmet usage and confining the number of pillion passengers to one, might be implemented to reduce the fatality risk in motorcycle crashes. In addition, more appropriate infrastructures for penalizing offending motorcyclists could also reduce the frequency of law violations such as not wearing helmet or riding without motorcycle license, which in turn, would result into a reduction in the fatality risk of motorcycle crashes. PMID- 26420218 TI - Albumin in chronic liver disease: structure, functions and therapeutic implications. AB - Human serum albumin is a critical plasma protein produced by the liver with a number of accepted clinical indications in chronic liver disease including management of circulatory and renal dysfunction in patients with ascites. Advanced cirrhosis is characterised by reduced albumin concentration as well as impaired albumin function as a result of specific structural changes and oxidative damage. Traditionally, the biologic and therapeutic role of albumin in liver disease was attributed to its oncotic effects but it is now understood that albumin has a wide range of other important physiologic functions such as immunomodulation, endothelial stabilisation, antioxidant effects and binding multiple drugs, toxins and other molecules. This review discusses the multifunctional properties of albumin and, in particular, the biologic and clinical implications of structural and functional changes of albumin that are associated with cirrhosis. Based on these insights, we explore the current and potential future therapeutic uses of albumin in liver disease. PMID- 26420219 TI - Determining exon connectivity in complex mRNAs by nanopore sequencing. AB - Short-read high-throughput RNA sequencing, though powerful, is limited in its ability to directly measure exon connectivity in mRNAs that contain multiple alternative exons located farther apart than the maximum read length. Here, we use the Oxford Nanopore MinION sequencer to identify 7,899 'full-length' isoforms expressed from four Drosophila genes, Dscam1, MRP, Mhc, and Rdl. These results demonstrate that nanopore sequencing can be used to deconvolute individual isoforms and that it has the potential to be a powerful method for comprehensive transcriptome characterization. PMID- 26420221 TI - 25OHD analogues and vacuum blood collection tubes dramatically affect the accuracy of automated immunoassays. AB - Variations in vitamin D quantification methods are large, and influences of vitamin D analogues and blood collection methods have not been systematically examined. We evaluated the effects of vitamin D analogues 25OHD2 and 3-epi 25OHD3 and blood collection methods on vitamin D measurement, using five immunoassay systems and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Serum samples (332) were selected from routine vitamin D assay requests, including samples with or without 25OHD2 or 3-epi 25OHD3, and analysed using various immunoassay systems. In samples with no 25OHD2 or 3-epi 25OHD3, all immunoassays correlated well with LC-MS/MS. However, the Siemens system produced a large positive mean bias of 12.5 ng/mL and a poor Kappa value when using tubes with clot activator and gel separator. When 25OHD2 or 3-epi 25OHD3 was present, correlations and clinical agreement decreased for all immunoassays. Serum 25OHD in VACUETTE tubes with gel and clot activator, as measured by the Siemens system, produced significantly higher values than did samples collected in VACUETTE tubes with no additives. Bias decreased and clinical agreement improved significantly when using tubes with no additives. In conclusion, most automated immunoassays showed acceptable correlation and agreement with LC-MS/MS; however, 25OHD analogues and blood collection tubes dramatically affected accuracy. PMID- 26420220 TI - Pre-differentiation of human neural stem cells into GABAergic neurons prior to transplant results in greater repopulation of the damaged brain and accelerates functional recovery after transient ischemic stroke. AB - INTRODUCTION: Despite attempts to prevent brain injury during the hyperacute phase of stroke, most sufferers end up with significant neuronal loss and functional deficits. The use of cell-based therapies to recover the injured brain offers new hope. In the current study, we employed human neural stem cells (hNSCs) isolated from subventricular zone (SVZ), and directed their differentiation into GABAergic neurons followed by transplantation to ischemic brain. METHODS: Pre-differentiated GABAergic neurons, undifferentiated SVZ-hNSCs or media alone were stereotaxically transplanted into the rat brain (n=7/group) 7 days after endothelin-1 induced stroke. Neurological outcome was assessed by neurological deficit scores and the cylinder test. Transplanted cell survival, cellular phenotype and maturation were assessed using immunohistochemistry and confocal microscopy. RESULTS: Behavioral assessments revealed accelerated improvements in motor function 7 days post-transplant in rats treated with pre differentiated GABAergic cells in comparison to media alone and undifferentiated hNSC treated groups. Histopathology 28 days-post transplant indicated that pre differentiated cells maintained their GABAergic neuronal phenotype, showed evidence of synaptogenesis and up-regulated expression of both GABA and calcium signaling proteins associated with neurotransmission. Rats treated with pre differentiated cells also showed increased neurogenic activity within the SVZ at 28 days, suggesting an additional trophic role of these GABAergic cells. In contrast, undifferentiated SVZ-hNSCs predominantly differentiated into GFAP positive astrocytes and appeared to be incorporated into the glial scar. CONCLUSION: Our study is the first to show enhanced exogenous repopulation of a neuronal phenotype after stroke using techniques aimed at GABAergic cell induction prior to delivery that resulted in accelerated and improved functional recovery. PMID- 26420222 TI - Smoking behaviors before and after implementation of a smoke-free legislation in Guangzhou, China. AB - BACKGROUND: According to the partial smoke-free legislation implemented on 1 September 2010 in Guangzhou, China, smoke-free did not cover all indoor areas. Some places have a full smoking ban (100 % smoke-free), other places have a partial smoking ban, and homes have no ban. This study aimed to compare the smoking behaviors before and after implementation of a smoke-free legislation. METHOD: A repeated cross-sectional survey was conducted on smoking-related behaviors with a total of 4,900 respondents before, and 5,135 respondents after the legislation was instituted. For each wave of the survey, a three-stage stratified sampling process was used to obtain a representative sample. Pearson's Chi-square test was used to determine differences of smoking prevalence and quit ratio between the two samples. Logistic regression models were used to examine the associations of a smoke-free legislation with smoking behaviors. RESULTS: The overall daily smoking rate declined significantly from 20.8 % to 18.2 % (p < 0.05), especially among those aged 15-24 years. The quit ratios increased significantly (from 14.5 % to 17.9 %), but remained low among 15-44 year olds. The overall self-reported smoking behaviors in locations with a full smoking ban decreased significantly from 36.4 % to 24.3 % with the greater drops occurring in cultural venues, public transport vehicles, and government offices. Smoking in places with partial smoking bans remained high (89.6 % vs. 90.4 %), although a slight decrease was observed in some of these areas. The implementation of a smoke-free legislation did not lead to more smoking in homes (91.0 % vs 89.4 %), but smoking in homes remained high. CONCLUSIONS: These findings highlight the urgent need for a comprehensive smoke-free legislation covering all public places in Guangzhou, simultaneously educational interventions and campaigns promoting voluntary changes in home smoking need to occur. PMID- 26420223 TI - Nurses' documentation of physiological observations in three acute care settings. AB - AIMS AND OBJECTIVES: To explore nurses' documentation of physiological observations in acute care; emergency department, medical and surgical units. BACKGROUND: In Australia, physiological observations include respiratory rate, oxygen saturation, heart rate, blood pressure, temperature and level of consciousness. There is a clear relationship between abnormal physiological observations and adverse events. Nurses have highest level of responsibility for accurate measurement, interpretation and documentation of physiological observations. DESIGN: A descriptive exploratory design was used and the study data were collected using a prospective point prevalence approach between 25 July 2012-22 August 2012. METHODS: The study was conducted in the emergency department, two 30-bed medical units and one 30-bed surgical unit of a 578 bed public health service in Melbourne, Australia. All adult patients aged >=18 years present during data collection periods were eligible for inclusion. Patients in the emergency department resuscitation area were excluded. Patient characteristics and physiological observations for the preceding 24 hours in ward patients or eight hours in emergency department patients were collected. RESULTS: One hundred and seventy-eight patients were included; 38 emergency department patients, 84 medical patients and 56 surgical patients. The median age was 72.5 years and 43.8% were males. The most frequently documented physiological observations were respiratory rate, oxygen saturation, heart rate and systolic blood pressure. The least frequently recorded physiological observations were temperature and conscious state. One or more abnormal physiological parameters was documented in 79.8% (n = 142) patients; evidence of reporting abnormalities was documented in 19.7% of patients (n = 28/142). When controlled for length of stay, physiological observations were more frequently documented in the emergency department. CONCLUSIONS: There was variability in the number of parameters documented and frequency of physiological observations documented by nurses. RELEVANCE TO CLINICAL PRACTICE: Physiological abnormalities that do not necessarily fulfil rapid response team activation criteria are common in acute care patients and provide nurses with an opportunity for early recognition of deteriorating patients. PMID- 26420224 TI - Genome-wide mRNA-seq profiling reveals predominant down-regulation of lipid metabolic processes in adipose tissues of Small Tail Han than Dorset sheep. AB - Small Tail Han and Dorset sheep are two different sheep with distinguished morphologies in fat depositions. In order to characterize their gene expression profiles, our present study took the advantages of RNA sequencing technology with the aims to identify important genes regulating the metabolisms in adipose tissues of two different sheep. In obtained high quality sequencing reads, 85.9 (Han) and 86.1% (Dorset) were uniquely aligned to Oar v3.1 sheep reference genome, and over 76% of bases in mapped reads corresponded to mRNA. Using R package EBSeq, we identified 602 differentially expressed genes. Using the 602 genes, GO analysis showed that 30 out of 56 significantly enriched biological processes were metabolism related, of which the most significant one was triglyceride biosynthetic process. The KEGG pathway analysis indicated the down regulation of several fat metabolic pathways. The predominant down-regulation of massive metabolic processes, particularly the lipid metabolism, in adipose tissues of Han sheep could explain, at least in part, the distinguished fat deposition between two different sheep, and our data constitute a basic picture of transcriptomes in these sheep for better understanding of underline biological mechanism in their lipid metabolisms. PMID- 26420225 TI - Comment on Lerchl study: "Tumor promotion in mice by exposure to radiofrequency electromagnetic fields still waiting evidence". PMID- 26420226 TI - Identification and proteomic analysis of osteoblast-derived exosomes. AB - Exosomes are nanometer-sized vesicles with the function of intercellular communication, and they are released by various cell types. To reveal the knowledge about the exosomes from osteoblast, and explore the potential functions of osteogenesis, we isolated microvesicles from supernatants of mouse Mc3t3 by ultracentrifugation, characterized exosomes by electron microscopy and immunoblotting and presented the protein profile by proteomic analysis. The result demonstrated that microvesicles were between 30 and 100 nm in diameter, round shape with cup-like concavity and expressed exosomal marker tumor susceptibility gene (TSG) 101 and flotillin (Flot) 1. We identified a total number of 1069 proteins among which 786 proteins overlap with ExoCarta database. Gene Oncology analysis indicated that exosomes mostly derived from plasma membrane and mainly involved in protein localization and intracellular signaling. The Ingenuity Pathway Analysis showed pathways are mostly involved in exosome biogenesis, formation, uptake and osteogenesis. Among the pathways, eukaryotic initiation factor 2 pathways played an important role in osteogenesis. Our study identified osteoblast-derived exosomes, unveiled the content of them, presented potential osteogenesis-related proteins and pathways and provided a rich proteomics data resource that will be valuable for further studies of the functions of individual proteins in bone diseases. PMID- 26420227 TI - Comment on "Reflex epileptic mechanisms in humans: Lessons about natural ictogenesis" by Peter Wolf. PMID- 26420228 TI - Reply to "Comment to 'Reflex epileptic mechanisms in humans: Lessons about natural ictogenesis' by Peter Wolf" by Stefano Meletti and Anna Elisabetta Vaudano. PMID- 26420229 TI - Early warning sign on computed tomography of the head. PMID- 26420230 TI - Ultrafast switching of an electrochromic device based on layered double hydroxide/Prussian blue multilayered films. AB - Electrochromic materials are the most important and essential components in an electrochromic device. Herein, we fabricated high-performance electrochromic films based on exfoliated layered double hydroxide (LDH) nanosheets and Prussian blue (PB) nanoparticles via the layer-by-layer assembly technique. X-ray diffraction and UV-vis absorption spectroscopy indicate a periodic layered structure with uniform and regular growth of (LDH/PB)n ultrathin films (UTFs). The resulting (LDH/PB)n UTF electrodes exhibit electrochromic behavior arising from the reversible K(+) ion migration into/out of the PB lattice, which induces a change in the optical properties of the UTFs. Furthermore, an electrochromic device (ECD) based on the (LDH/PB)n-ITO/0.1 M KCl electrolyte/ITO sandwich structure displays superior response properties (0.91/1.21 s for coloration/bleaching), a comparable coloration efficiency (68 cm(2) C(-1)) and satisfactory optical contrast (45% at 700 nm), in comparison with other inorganic material-based ECDs reported previously. Therefore, this work presents a facile and cost-effective strategy to immobilize electrochemically active nanoparticles in a 2D inorganic matrix for potential application in displays, smart windows and optoelectronic devices. PMID- 26420231 TI - The discovery of modular binding domains: building blocks of cell signalling. AB - Cell signalling - the ability of a cell to process information from the environment and change its behaviour in response - is a central property of life. Signalling depends on proteins that are assembled from a toolkit of modular domains, each of which confers a specific activity or function. The discovery of modular protein- and lipid-binding domains was a crucial turning point in understanding the logic and evolution of signalling mechanisms. PMID- 26420233 TI - Insights in Nanoparticle-Bacterium Interactions: New Frontiers to Bypass Bacterial Resistance to Antibiotics. AB - Nanotechnology has been revealed as a fundamental approach for antibiotics delivery. In this paper, recent findings demonstrating the superiority of nanocarried-antibiotics over "naked" ones and the ways by which nanoparticles can help to overwhelm bacterial drug resistance are reviewed. The second part of this paper sheds light on nanoparticle-bacterium interaction patterns. Finally, key factors affecting the effectiveness of nanoparticles interactions with bacteria are discussed. PMID- 26420232 TI - Targeting Polycomb systems to regulate gene expression: modifications to a complex story. AB - Polycomb group proteins are transcriptional repressors that are essential for normal gene regulation during development. Recent studies suggest that Polycomb repressive complexes (PRCs) recognize and are recruited to their genomic target sites through a range of different mechanisms, which involve transcription factors, CpG island elements and non-coding RNAs. Together with the realization that the interplay between PRC1 and PRC2 is more intricate than was previously appreciated, this has increased our understanding of the vertebrate Polycomb system at the molecular level. PMID- 26420234 TI - Molecular combing compared to Southern blot for measuring D4Z4 contractions in FSHD. AB - We compare molecular combing to Southern blot in the analysis of the facioscapulohumeral muscular dystrophy type 1 locus (FSHD1) on chromosome 4q35 qter (chr 4q) in genomic DNA specimens sent to a clinical laboratory for FSHD testing. A de-identified set of 87 genomic DNA specimens determined by Southern blot as normal (n = 71), abnormal with D4Z4 macrosatellite repeat array contractions (n = 7), indeterminate (n = 6), borderline (n = 2), or mosaic (n = 1) was independently re-analyzed by molecular combing in a blinded fashion. The molecular combing results were identical to the Southern blot results in 75 (86%) of cases. All contractions (n = 7) and mosaics (n = 1) detected by Southern blot were confirmed by molecular combing. Of the 71 samples with normal Southern blot results, 67 (94%) had concordant molecular combing results. The four discrepancies were either mosaic (n = 2), rearranged (n = 1), or borderline by molecular combing (n = 1). All indeterminate Southern blot results (n = 6) were resolved by molecular combing as either normal (n = 4), borderline (n = 1), or rearranged (n = 1). The two borderline Southern blot results showed a D4Z4 contraction on the chr 4qA allele and a normal result by molecular combing. Molecular combing overcomes a number of technical limitations of Southern blot by providing direct visualization of D4Z4 macrosatellite repeat arrays on specific chr 4q and chr 10q alleles and more precise D4Z4 repeat sizing. This study suggests that molecular combing has superior analytical validity compared to Southern blot for determining D4Z4 contraction size, detecting mosaicism, and resolving borderline and indeterminate Southern blot results. Further studies are needed to establish the clinical validity and diagnostic accuracy of these findings in FSHD. PMID- 26420235 TI - Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with erlotinib in patients with advanced solid tumors. AB - PURPOSE: Navitoclax (ABT-263), a novel, oral Bcl-2 inhibitor, enhances the antitumor effects of chemotherapy in vitro by lowering the apoptotic threshold. This phase I study (NCT01009073) evaluated the safety, pharmacokinetics, and preliminary antitumor activity of navitoclax combined with erlotinib in patients with advanced solid tumors. PATIENTS AND METHODS: An open-label dose escalation study included an arm evaluating navitoclax combined with erlotinib, which included a dose escalation cohort and a planned safety expansion cohort. Patients with documented cancers for whom erlotinib therapy was appropriate received erlotinib 150 mg orally once daily plus navitoclax 150 mg orally once daily, with navitoclax dose escalation via a continuous reassessment method model. RESULTS: Eleven patients were enrolled, including six patients with nonsmall cell lung cancer. Dose-limiting toxicities, most commonly diarrhea, were observed in 4 patients. Navitoclax dosing remained at 150 mg/day because the maximum tolerated dose was exceeded at this starting dose. The planned dose escalation did not occur; no recommended phase II dose (RPTD) was identified, and there was no safety expansion cohort. The most common treatment-related adverse events were diarrhea, nausea, vomiting, and decreased appetite. Pharmacokinetic analysis showed no apparent interactions between co-administered navitoclax and erlotinib. No objective responses were observed; the disease control rate was 27 % (95 % CI, 6-61 %). CONCLUSION: At the erlotinib and navitoclax doses administered, RPTD was not reached, but the safety profile of the combination was consistent with data from monotherapy studies. There were no apparent pharmacokinetic interactions between erlotinib and navitoclax. Three patients had stable disease. PMID- 26420236 TI - Risk factors for pegylated liposomal doxorubicin-induced palmar-plantar erythrodysesthesia over time: assessment of monocyte count and baseline clinical parameters. AB - PURPOSE: Pegylated liposomal doxorubicin (PLD) is widely used in relapsing ovarian carcinoma. Its original formulation is metabolized by the monocyte macrophage system. One of its main toxicities is the palmoplantar erythrodysesthesia (PPE) syndrome. To date, no predictive factors of PPE have been identified. METHODS: Data of patients (pts) treated with PLD between 2005 and 2014 were retrospectively collected. A case-control study was performed, comparing main baseline clinical and biological characteristics of pts experiencing PPE and those who did not, after at least three cycles of PLD. A pilot analysis of blood monocyte subpopulations (classical, intermediate and non classical) was performed by FACS in selected pts. RESULTS: Among 88 pts treated with PLD, 28 experienced PPE of any grade (31, 95 % CI 21-41). The first occurrence of PPE was at first cycle in only 11 % of pts, peaked at cycle 2 (32 %) and represented 57 % of cases after cycle 3. Baseline characteristics of pts with PPE were compared to 27 control pts who received at least 3 cycles. Older pts represented 61 % of pts with PPE and 15 % of pts without PPE (p = 0.04 by Chi square test). Monocyte count and inflammatory parameters were not associated with PPE. However, the analysis of monocyte subpopulations revealed a large inter patient variability. CONCLUSION: Contrary to most acute toxicities, PPE occurred more frequently after several cycles, suggesting a PLD body accumulation through repeated cycles. PPE was more frequent in pts older than 70 years. Monocyte subpopulations may have different roles on PLD metabolism and warrant further studies. PMID- 26420237 TI - The Urine Marker Test: An Alternative Approach to Supervised Urine Collection for Doping Control. AB - BACKGROUND: Urine sample collection for doping control tests is a key component of the World Anti-Doping Agency's fight against doping in sport. However, a substantial number of athletes experience difficulty when having to urinate under supervision. Furthermore, it cannot always be ensured that athletes are actually delivering their own urine. A method that can be used to alleviate the negative impact of a supervised urination procedure and which can also identify urine as coming from a specific athlete is the urine marker test. Monodisperse low molecular weight polyethylene glycols (PEGs) are given orally prior to urination. Urine samples can be traced to the donor by analysis of the PEGs previously given. OBJECTIVE: The objective of this study was to investigate the use of the urine marker during urine doping control testing. METHODS: Two studies investigated athletes' acceptance of this new method via two questionnaires (n = 253). Furthermore, a third study (n = 91) investigated whether ingestion of the marker can identify the urine as coming from a specific person and whether the marker interferes with the detection of prohibited substances. RESULTS AND CONCLUSIONS: The results indicate that this new method finds wide acceptance both from athletes who have only heard about the procedure and those who have actually tested the new method. Furthermore, the marker, which can identify urine as coming from a specific person, does not interfere with the detection of prohibited substances. PMID- 26420239 TI - Acute changes in cellular zinc alters zinc uptake rates prior to zinc transporter gene expression in Jurkat cells. AB - A coordinated network of zinc transporters and binding proteins tightly regulate cellular zinc levels. Canonical responses to zinc availability are thought to be mediated by changes in gene expression of key zinc transporters. We investigated the temporal relationships of actual zinc uptake with patterns of gene expression in membrane-bound zinc transporters in the human immortalized T lymphocyte Jurkat cell line. Cellular zinc levels were elevated or reduced with exogenous zinc sulfate or N,N,N',N-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), respectively. Excess zinc resulted in a rapid 44 % decrease in the rate of zinc uptake within 10 min. After 120 min, the expression of metallothionein (positive control) increased, as well as the zinc exporter, ZnT1; however, the expression of zinc importers did not change during this time period. Zinc chelation with TPEN resulted in a rapid twofold increase in the rate of zinc uptake within 10 min. After 120 min, the expression of ZnT1 decreased, while again the expression of zinc importers did not change. Overall, zinc transporter gene expression kinetics did not match actual changes in cellular zinc uptake with exogenous zinc or TPEN treatments. This suggests zinc transporter regulation may be the initial response to changes in zinc within Jurkat cells. PMID- 26420238 TI - Dose-Response Relationships of Resistance Training in Healthy Old Adults: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Resistance training (RT) is an intervention frequently used to improve muscle strength and morphology in old age. However, evidence-based, dose response relationships regarding specific RT variables (e.g., training period, frequency, intensity, volume) are unclear in healthy old adults. OBJECTIVES: The aims of this systematic review and meta-analysis were to determine the general effects of RT on measures of muscle strength and morphology and to provide dose response relationships of RT variables through an analysis of randomized controlled trials (RCTs) that could improve muscle strength and morphology in healthy old adults. DATA SOURCES: A computerized, systematic literature search was performed in the electronic databases PubMed, Web of Science, and The Cochrane Library from January 1984 up to June 2015 to identify all RCTs related to RT in healthy old adults. STUDY ELIGIBILITY CRITERIA: The initial search identified 506 studies, with a final yield of 25 studies. Only RCTs that examined the effects of RT in adults with a mean age of 65 and older were included. The 25 studies quantified at least one measure of muscle strength or morphology and sufficiently described training variables (e.g., training period, frequency, volume, intensity). STUDY APPRAISAL AND SYNTHESIS METHODS: We quantified the overall effects of RT on measures of muscle strength and morphology by computing weighted between-subject standardized mean differences (SMDbs) between intervention and control groups. We analyzed the data for the main outcomes of one-repetition maximum (1RM), maximum voluntary contraction under isometric conditions (MVC), and muscle morphology (i.e., cross-sectional area or volume or thickness of muscles) and assessed the methodological study quality by Physiotherapy Evidence Database (PEDro) scale. Heterogeneity between studies was assessed using I2 and chi2 statistics. A random effects meta-regression was calculated to explain the influence of key training variables on the effectiveness of RT in terms of muscle strength and morphology. For meta regression, training variables were divided into the following subcategories: volume, intensity, and rest. In addition to meta-regression, dose-response relationships were calculated independently for single training variables (e.g., training frequency). RESULTS: RT improved muscle strength substantially (mean SMDbs = 1.57; 25 studies), but had small effects on measures of muscle morphology (mean SMDbs = 0.42; nine studies). Specifically, RT produced large effects in both 1RM of upper (mean SMDbs = 1.61; 11 studies) and lower (mean SMDbs = 1.76; 19 studies) extremities and a medium effect in MVC of lower (mean SMDbs = 0.76; four studies) extremities. Results of the meta-regression revealed that the variables "training period" (p = 0.04) and "intensity" (p < 0.01) as well as "total time under tension" (p < 0.01) had significant effects on muscle strength, with the largest effect sizes for the longest training periods (mean SMDbs = 2.34; 50-53 weeks), intensities of 70-79% of the 1RM (mean SMDbs = 1.89), and total time under tension of 6.0 s (mean SMDbs = 3.61). A tendency towards significance was found for rest in between sets (p = 0.06), with 60 s showing the largest effect on muscle strength (mean SMDbs = 4.68; two studies). We also determined the independent effects of the remaining training variables on muscle strength. The following independently computed training variables are most effective in improving measures of muscle strength: a training frequency of two sessions per week (mean SMDbs = 2.13), a training volume of two to three sets per exercise (mean SMDbs = 2.99), seven to nine repetitions per set (mean SMDbs = 1.98), and a rest of 4.0 s between repetitions (SMDbs = 3.72). With regard to measures of muscle morphology, the small number of identified studies allowed us to calculate meta-regression for the subcategory training volume only. No single training volume variable significantly predicted RT effects on measures of muscle morphology. Additional training variables were independently computed to detect the largest effect for the single training variable. A training period of 50-53 weeks, a training frequency of three sessions per week, a training volume of two to three sets per exercise, seven to nine repetitions per set, a training intensity from 51 to 69% of the 1RM, a total time under tension of 6.0 s, a rest of 120 s between sets, and a rest of 2.5 s between repetitions turned out to be most effective. LIMITATIONS: The current results must be interpreted with caution because of the poor overall methodological study quality (mean PEDro score 4.6 points) and the considerable large heterogeneity (I2) = 80%, chi2 = 163.1, df = 32, p < 0.01) for muscle strength. In terms of muscle morphology, our search identified nine studies only, which is why we consider our findings preliminary. While we were able to determine a dose-response relationship based on specific individual training variables with respect to muscle strength and morphology, it was not possible to ascertain any potential interactions between these variables. We recognize the limitation that the results may not represent one general dose response relationship. CONCLUSIONS: This systematic literature review and meta analysis confirmed the effectiveness of RT on specific measures of upper and lower extremity muscle strength and muscle morphology in healthy old adults. In addition, we were able to extract dose-response relationships for key training variables (i.e., volume, intensity, rest), informing clinicians and practitioners to design effective RTs for muscle strength and morphology. Training period, intensity, time under tension, and rest in between sets play an important role in improving muscle strength and morphology and should be implemented in exercise training programs targeting healthy old adults. Still, further research is needed to reveal optimal dose-response relationships following RT in healthy as well as mobility limited and/or frail old adults. PMID- 26420240 TI - Does addition of low-level laser therapy (LLLT) in conservative care of knee arthritis successfully postpone the need for joint replacement? AB - The current study evaluates whether the addition of low-level laser therapy into standard conventional physical therapy in elderly with bilateral symptomatic tri compartmental knee arthritis can successfully postpone the need for joint replacement surgery. A prospective randomized cohort study of 100 consecutive unselected elderly patients with bilateral symptomatic knee arthritis with each knee randomized to receive either treatment protocol A consisting of conventional physical therapy or protocol B which is the same as protocol A with added low level laser therapy. The mean follow-up was 6 years. Treatment failure was defined as breakthrough pain which necessitated joint replacement surgery. After a follow-up of 6 years, patients clearly benefited from treatment with protocol B as only one knee needed joint replacement surgery, while nine patients treated with protocol A needed surgery (p < 0.05). We conclude low-level laser therapy should be incorporated into standard conservative treatment protocol for symptomatic knee arthritis. PMID- 26420241 TI - Extended minimally invasive lung resections: VATS bilobectomy, bronchoplasty, and pneumonectomy. AB - PURPOSE: The aim of the present study was to analyze feasibility, morbidity, mortality, and oncologic outcome of extended video-assisted thoracoscopic surgery (VATS) anatomic lung resections in a single-center experience. Extended resections include bilobectomies, bronchoplasties, and pneumonectomies. METHODS: The present study is a retrospective analysis of a prospectively maintained institutional database. Between 2009 and 2014, 390 patients were scheduled for anatomical VATS resections. VATS resection was completed in 370 patients giving an overall conversion rate of 5.1 %. Extended VATS resections were performed in 29 patients (7.8 %): bilobectomy in 8, bronchoplastic resection in 15 (2 bronchial sleeve resections, 11 wedge bronchoplasties, 2 simple bronchoplasties), and pneumonectomy in 6. RESULTS: Median operative time was 217 min (117-390 min). Median chest tube duration was 4 days (range, 2-50 days). Median length of hospital stay was 9 days (6-63 days). There was no in-hospital mortality. Major complications with need for reinterventions occurred in three patients (10.3 %): one air leakage from bronchial stump after pneumonectomy, one hematothorax after completion pneumonectomy, and one chylothorax. All complications were treated with VATS procedures. Minor complications included two persistent air leaks that were treated with an additional chest drain and resolved, one urinary tract infection, one atelectasis with need for bronchoscopy, and one pleural fluid collection with the need for drainage. After a median follow-up of 26 months, no local tumor recurrence occurred. Two patients had a second lung primary cancer and four patients with advanced tumor stages had distant recurrent disease. CONCLUSIONS: With growing experience, extended VATS resections are feasible in selected cases with low perioperative morbidity and mortality. PMID- 26420242 TI - The lower effectiveness of text-only health warnings in China compared to pictorial health warnings in Malaysia. AB - BACKGROUND: In 2009, China changed its health warnings on cigarette packs from side-only text warnings to two text-only warnings on 30% of the bottom of the front and back of the pack. Also in 2009, Malaysia changed from similar text warnings to pictorial health warnings consistent with Framework Convention on Tobacco Control (FCTC) Article 11 Guidelines. OBJECTIVE: To measure the impact of the change in health warnings in China and to compare the text-only health warnings to the impact of the pictorial health warnings introduced in Malaysia. METHODS: We measured changes in key indicators of warning effectiveness among a longitudinal cohort sample of smokers from Waves 1 to 3 (2006-2009) of the International Tobacco Control (ITC) China Survey and from Waves 3 to 4 (2008 2009) of the ITC Malaysia Survey. Each cohort consisted of representative samples of adult (>=18 years) smokers from six cities in China (n=6575) and from a national sample in Malaysia (n=2883). Generalised Estimating Equations (GEE) were used to examine the impact of the health warnings on subsequent changes in salience of warnings, cognitive and behavioural outcomes. FINDINGS: Compared to Malaysia, the weak text-only warning labels in China led to a significant change in only two of six key indicators of health warning effectiveness: forgoing cigarettes and reading the warning labels. The change to pictorial health warnings in Malaysia led to significant and substantial increases in five of six indicators (noticing, reading, forgoing, avoiding, thinking about quitting). CONCLUSIONS: The delay in implementing pictorial health warnings in China constitutes a lost opportunity for increasing knowledge and awareness of the harms of cigarettes, and for motivating smokers to quit. PMID- 26420243 TI - Predomination of IL-17-producing tryptase-positive/chymase-positive mast cells in azoospermic chronic testicular inflammation. AB - Chronic testicular inflammation and infection have been regarded as important factors in the pathogenesis of azoospermia. As key effector cells in innate and adaptive immune system, mast cells (MCs) were observed in inflammation and autoimmune disease. Furthermore, increased expression of tryptase-positive MCs has been reported in testicular disorders associated with male infertility/subfertility. However, little is known about the potential relationship between MCs and chronic testicular inflammation in azoospermic patients. Moreover, the preferential expression of MCs' subtypes in testis of these patients is still far from being understood. Thus, this study aimed to investigate characteristics of testicular MCs as well as their subtypes in azoospermic men with chronic testicular inflammation (AZI, n = 5) by immunohistochemical techniques. Our results showed significant increase of MCs in AZI, and more importantly, considerable numbers of tryptase-positive/chymase positive MCs could also be demonstrated in AZI, when compared to control groups representing azoospermia without chronic testicular inflammation (AZW, n = 5) and normal spermatogenesis (NT, n = 5) respectively. Most interestingly, immunofluorescence staining revealed autoimmune-associated interleukin (IL)-17 producing MCs in AZI, whereas co-expression of MC markers with tumour necrosis factor (TNF)-alpha, IL-10 and IL-1beta could not be detected. In conclusion, AZI is associated with significant increase of tryptase-positive/chymase-positive MCs expressing IL-17, and these MCs might contribute to the pathogenesis of AZI. PMID- 26420245 TI - Assessment of health-related quality of life of Bangladeshi patients with type 2 diabetes using the EQ-5D: a cross-sectional study. AB - BACKGROUND: The management of diabetes requires a fundamental change in the lifestyle of patients, and one of the important outcome criteria is the quality of life. We assessed the health-related quality of life (HR-QoL) and examined the factors associated with it in type 2 diabetes. METHODS: An analytical cross sectional study was conducted among 500 type 2 diabetes patients (age >25 years and duration of diabetes >1 year). They were selected conveniently from the Out Patient department of the Bangladesh Institute of Health Sciences Hospital. The HR-QoL was assessed using an adapted and validated Bangla version of the EQ-5D ((c) 1990 EuroQol Group. EQ-5DTM) questionnaire. It has five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression and two levels (problem and no problem) on each dimension. The responses to the EQ-5D were further translated into a single summary EQ-5D index using the UK TTO value set. RESULTS: Of the patients, 50.2% were female, and 49.4% were aged >55 years. Only 28.4% had completed higher secondary education, and 50.8% were from lower middle-income families. Around 78.8% either had overweight or were obese. About 50.4% had problems in mobility, 28.2% in self-care, 47.6% in usual activities, 72.8% in pain/discomfort, and 73.6% in anxiety/depression. Results of binary logistic regression analysis showed that age, gender, lower-middle income, and HbA1C were significantly (p < 0.05) associated with mobility. Self-care was significantly (p < 0.05) related to age, family history and duration of diabetes mellitus (DM). Gender, family history of DM, and lower-middle income had a significant (p < 0.05) association with usual activities. Pain was significantly (p < 0.05) associated with age, lower-middle income, and upper-middle income. Rural area, higher education, and HbA1C were significantly (p < 0.05) related to anxiety. Results of multiple linear regression analysis showed that age (p = 0.0001), female gender (p = 0.0001), and prescribed treatment (p = 0.048) were associated with the EQ-5D index. CONCLUSIONS: The large majority (73%) of the patients had problems in pain/discomfort and anxiety/depression; 50% had problems in mobility and usual activities; and three in ten in self-care. Age, female gender, income, education, family history and duration of DM, and prescribed treatment are important factors that are associated with the HR-QoL in type 2 diabetes. PMID- 26420244 TI - Perception of quality of care of patients with potentially severe diseases evaluated at a distinct quick diagnostic delivery model: a cross-sectional study. AB - BACKGROUND: Although hospital-based outpatient quick diagnosis units (QDU) are an increasingly recognized cost-effective alternative to hospitalization for the diagnosis of potentially serious diseases, patient perception of their quality of care has not been evaluated well enough. This cross-sectional study analyzed the perceived quality of care of a QDU of a public third-level university hospital in Barcelona. METHODS: One hundred sixty-two consecutive patients aged >= 18 years attending the QDU over a 9-month period were invited to participate. A validated questionnaire distributed by the QDU attending physician and completed at the end of the first and last QDU visit evaluated perceived quality of care using six subscales. RESULTS: Response rate was 98 %. Perceived care in all subscales was high. Waiting times were rated as 'short'/'very short' or 'better'/'much better' than expected by 69-89 % of respondents and physical environment as 'better'/'much better' than expected by 94-96 %. As to accessibility, only 3 % reported not finding the Unit easily and 7 % said that frequent travels to hospital for visits and investigations were uncomfortable. Perception of patient physician encounter was high, with 90-94 % choosing the positive extreme ends of the clinical information and personal interaction subscales items. Mean score of willingness to recommend the Unit using an analogue scale where 0 was 'never' and 10 'without a doubt' was 9.5 (0.70). On multivariate linear regression, age >65 years was an independent predictor of clinical information, personal interaction, and recommendation, while age 18-44 years was associated with lower scores in these subscales. No schooling predicted higher clinical information and recommendation scores, while university education had remarkable negative influence on them. Having >=4 QDU visits was associated with lower time to diagnosis and recommendation scores and malignancy was a negative predictor of time to diagnosis, clinical information, and recommendation. DISCUSSION: It is worthy of note that the questionnaire evaluated patient perception and opinions of healthcare quality including recommendation rather than simply satisfaction. It has been argued that perception of quality of care is a more valuable approach than satisfaction. In addition to embracing an affective dimension, satisfaction appears more dependent on patient expectations than is perception of quality. CONCLUSIONS: While appreciating that completing the questionnaire immediately after the visit and its distribution by the QDU physician may have affected the results, scores of perceived quality of care including recommendation were high. There were, however, significant differences in several subscales associated with age, education, number of QDU visits, and diagnosis of malignant vs. benign condition. PMID- 26420246 TI - Left anterior small thoracotomy for minimally invasive coronary artery bypass grafting. AB - Since the 1990 s, minimally invasive cardiac surgery has gained wide acceptance due to patient and economic demand. The advantages are less trauma, bleeding, wound infections, pain and faster recovery. Many studies showed that the outcomes are comparable with those of conventional sternotomy. Left anterior small thoracotomy (LAST) evolved into a routine and safe access in specialized centres for minimally invasive direct coronary artery bypass grafting. The 6-cm incision is localized above the fourth intercostal space, 3-4 cm lateral to the left sternal border and below the left mammilla. With a double-lumen tube, the left lung is deflated before entering the pleural space. The left internal mammary artery is harvested under direct vision with the use of special retractors. The anastomosis of the left anterior descending artery is performed on the beating heart as known from off-pump surgery. One chest tube is inserted. The intercostal space is closed with braided sutures to prevent lung herniation. Ropivacaine is used for local infiltration. The pectoral muscle, subcutaneous tissue and skin are closed with running sutures. Complications of the LAST approach are rare (conversion to sternotomy, re-thoracotomy, phrenic nerve palsy, wound infection and thoracic wall hernia) and well manageable. PMID- 26420247 TI - Carotid artery cannulation in aortic surgery: why not? PMID- 26420248 TI - Effect of orthodontic brackets and different wires on radiofrequency heating and magnetic field interactions during 3.0-T MRI: Author response. PMID- 26420250 TI - Gastric-Type Extremely Well-Differentiated Adenocarcinoma of the Stomach: A Challenge for Preoperative Diagnosis. AB - Gastric-type extremely well-differentiated adenocarcinoma (EWDA) is a rare type of gastric adenocarcinoma characterized by infiltration of well-formed mucinous glands with little or no nuclear atypia, which resemble foveolar epithelium or pyloric glands. Because of its high degree of differentiation, preoperative biopsy diagnosis of gastric-type EWDA is very difficult. We encountered a case of gastric-type EWDA, manifesting as a Borrmann type 4 lesion, in a 47-year-old man. Despite four repeated biopsies, the preoperative biopsy diagnosis was not conclusive due to the scarcity of diagnostic tumor cells and lack of knowledge regarding the unusual histologic findings of gastric-type EWDA. We herein describe the histologic findings of gastric-type EWDA in detail, with the aim of facilitating a preoperative biopsy diagnosis and understanding of this rare type of gastric adenocarcinoma. PMID- 26420249 TI - Reproducibility of brain metabolite concentration measurements in lesion free white matter at 1.5 T. AB - BACKGROUND: Post processing for brain spectra has a great influence on the fit quality of individual spectra, as well as on the reproducibility of results from comparable spectra. This investigation used pairs of spectra, identical in system parameters, position and time assumed to differ only in noise. The metabolite amplitudes of fitted time domain spectroscopic data were tested on reproducibility for the main brain metabolites. METHODS: Proton spectra of white matter brain tissue were acquired with a short spin echo time of 30 ms and a moderate repetition time of 1500 ms at 1.5 T. The pairs were investigated with one time domain post-processing algorithm using different parameters. The number of metabolites, the use of prior knowledge, base line parameters and common or individual damping were varied to evaluate the best reproducibility. RESULTS: The protocols with most reproducible amplitudes for N-acetylaspartate, creatine, choline, myo-inositol and the combined Glx line of glutamate and glutamine in lesion free white matter have the following common features: common damping of the main metabolites, a baseline using only the points of the first 10 ms, no additional lipid/macromolecule lines and Glx is taken as the sum of separately fitted glutamate and glutamine. This parameter set is different to the one delivering the best individual fit results. DISCUSSION: All spectra were acquired in "lesion free" (no lesion signs found in MR imaging) white matter. Spectra of brain lesions, for example tumors, can be drastically different. Thus the results are limited to lesion free brain tissue. Nevertheless the application to studies is broad, because small alterations in brain biochemistry of lesion free areas had been detected nearby tumors, in patients with multiple sclerosis, drug abuse or psychiatric disorders. CONCLUSION: Main metabolite amplitudes inside healthy brain can be quantified with a normalized root mean square deviation around 5 % using CH3 of creatine as reference. Only the reproducibility of myo-inositol is roughly twice as bad. The reproducibility should be similar using other references like internal or external water for an absolute concentration evaluation and are not influenced by relaxation corrections with literature values. PMID- 26420251 TI - IgG4-Related Disease Presented as a Mural Mass in the Stomach. AB - Isolated gastric IgG4-related disease (IgG4-RD) is a very rare tumefactive inflammatory condition, with only a few cases reported to date. A 48-year-old woman was incidentally found to have a subepithelial tumor in the stomach. Given a presumptive diagnosis of gastrointestinal stromal tumor or neuroendocrine tumor, she underwent wedge resection. The lesion was vaguely nodular and mainly involved the submucosa and proper muscle layer. Microscopically, all classical features of type I autoimmune pancreatitis including lymphoplasmacytic infiltration, storiform fibrosis, obliterative phlebitis, and numerous IgG4 positive plasma cells were seen. She had no evidence of IgG4-RD in other organs. Although very rare, IgG4-RD should be considered one of the differential diagnoses in the setting of gastric wall thickening or subepithelial mass-like lesion. Deep biopsy with awareness of this entity might avoid unnecessary surgical intervention. PMID- 26420252 TI - CD30-Positive T-Cell Lymphoproliferative Disease of the Oral Mucosa in Children: A Manifestation of Epstein-Barr Virus-Associated T-Lymphoproliferative Disorder. AB - Eosinophilic ulcer of the oral mucosa (EUOM) is a very rare, benign, self limiting ulcerative lesion of the oral cavity of unknown pathogenesis, and belongs to the same spectrum of CD30(+) T-cell lymphoproliferative disease (LPD) of the oral mucosa. The etiology and pathogenesis of the disease are unknown. We report two cases in children who were initially diagnosed with EUOM and CD30(+) T cell LPD, respectively. However, retrospective analysis revealed that a majority of infiltrated atypical T cells were positive for Epstein-Barr virus (EBV). The present cases suggest that the pathogenesis and etiology of EUOM or CD30(+) T cell LPD occurring in children are different from those in adults. EUOM or CD30(+) T-cell LPD in children is a manifestation of EBV-positive T-cell LPD, and should therefore be distinguished from the disease in adults. PMID- 26420253 TI - Serum angiopoietin-like protein 2 as a potential biomarker for diagnosis, early recurrence and prognosis in gastric cancer patients. AB - Chronic inflammation of gastric mucosa by Helicobacter pylori infection can initiate gastric carcinogenesis. As angiopoietin-like protein 2 (ANGPTL2) mediates inflammation and inflammation-associated carcinogenesis, we investigated the functional and clinical significance of ANGPTL2 in human gastric cancer (GC). SiRNA knockdown studies were performed for the functional assessment of ANGPTL2 in GC cell lines. ANGPTL2 expression was evaluated immunohistochemically in 192 tissue specimens from GC patients. In addition, we screened serum ANGPTL2 levels from 32 GC patients and 23 healthy controls; and validated these results in 194 serum samples from GC patients and 45 healthy controls by ELISA. ANGPTL2 knockdown caused anoikis and inhibited proliferation, invasion and migration in GC cells. ANGPTL2 expression was upregulated in GC tissues compared to normal gastric mucosa; and high ANGPTL2 expression was significantly associated with tumor progression, early recurrence (P = 0.003) and poor prognosis (P = 0.007). Serum ANGPTL2 in GC patients was significantly higher than for healthy controls (P < 0.05), and accurately distinguished GC patients from healthy control (AUC = 0.865). The validation step confirmed significantly higher serum ANGPTL2 levels in GC patients than healthy controls (P < 0.0001). Receiver operating characteristic curves yielded robust AUC value (0.831) accompanied by high sensitivity (73.0%) and specificity (82.2%) in distinguishing GC patients from healthy controls. High serum ANGPTL2, rather than its expression in matched tissues, was significantly associated with tumor progression, and emerged as an independent marker for recurrence (HR: 5.05, P = 0.0004) and prognosis (HR: 3.6, P = 0.01). Serum ANGPTL2 expression is a potential noninvasive biomarker for diagnosis, early recurrence and prognosis of GC patients. PMID- 26420254 TI - Pan-genomic analysis to redefine species and subspecies based on quantum discontinuous variation: the Klebsiella paradigm. AB - BACKGROUND: Various methods are currently used to define species and are based on the phylogenetic marker 16S ribosomal RNA gene sequence, DNA-DNA hybridization and DNA GC content. However, these are restricted genetic tools and showed significant limitations. RESULTS: In this work, we describe an alternative method to build taxonomy by analyzing the pan-genome composition of different species of the Klebsiella genus. Klebsiella species are Gram-negative bacilli belonging to the large Enterobacteriaceae family. Interestingly, when comparing the core/pan genome ratio; we found a clear discontinuous variation that can define a new species. CONCLUSIONS: Using this pan-genomic approach, we showed that Klebsiella pneumoniae subsp. ozaenae and Klebsiella pneumoniae subsp. rhinoscleromatis are species of the Klebsiella genus, rather than subspecies of Klebsiella pneumoniae. This pan-genomic analysis, helped to develop a new tool for defining species introducing a quantic perspective for taxonomy. PMID- 26420255 TI - Uveitis in Children: Diagnosis and Management. AB - Uveitis is a term used to describe inflammation of uvea, which is the middle layer of eye. It is an important cause of blindness in children in both developed and developing countries. Delayed diagnosis, inadequate treatment and risk of amblyopia are some of the factors that are unique to childhood uveitis and are responsible for significant morbidity seen with this disease. PMID- 26420257 TI - Cutting science budget would be "Neanderthal" behaviour, expert says. PMID- 26420256 TI - Changes in PH in exhaled breath condensate after specific bronchial challenge test in patients with chronic hypersensitivity pneumonitis: a prospective study. AB - BACKGROUND: The aim of this study was to investigate the influence of the specific inhalation challenge (SIC) on changes of pH values in exhaled breath condensate (EBC) in patients with hypersensitivity pneumonitis (HP). METHODS: A prospective study of 85 patients with suspected HP, of whom 63 were diagnosed with HP due to exposure to avian or fungal antigens. In all cases, EBC samples were collected before and after completion of the SIC and pH values were determined. RESULTS: Taken as a whole, patients with HP did not present changes in EBC pH after SIC. However, considering only patients with exposure to molds, those diagnosed with HP had a significantly more acid pH post-SIC than those with another diagnosis (p = 0.011). This fact is not observed in patients exposed to bird's antigens. A ROC curve showed that a reduction in EBC pH of 0.3 units or more after SIC in patients diagnosed with HP due to exposure to molds had a sensitivity of 30 % (CI: 12.8 to 54.3 %) and a specificity of 100 % (CI: 65.5 to 100 %). CONCLUSION: EBC pH may be useful in interpreting SIC results in patients with HP, especially in those patients exposed to molds. Further studies are now required to test the validity of these proposals. PMID- 26420258 TI - The region from phenylalanine-28 to lysine-50 of a yeast mitochondrial ATPase inhibitor (IF1) forms an alpha-helix in solution. AB - A mitochondrial ATPase inhibitor, IF1, is a 63 amino acid residue protein that regulates the activity of ATP synthase (F(1)F(o)-ATPase). In the present study, we constructed mutant IF1 proteins with proline residues inserted into a wide range of their primary structures to determine the location and function of alpha helix in the protein. A total of 11 yeast IF1 protein mutants were expressed and purified. Proline insertions in the region 28-50 reduced alpha-helical contents, indicating that the region formed a helix in solution. Oligomer formation of proline mutants at the C-terminal 38-60 region was markedly reduced, indicating that the region is required for oligomerization of the protein. Proline mutants at the N-terminal 18-39 region did not inhibit F(1)F(o)-ATPase, indicating that the region is required for ATPase inhibitory activity. Inhibition of a proline insertion mutant between residues 44 and 45 that lost a large portion of the alpha-helix was slower, although the maximal inhibition level of the mutant protein was comparable to that of wild-type IF1. The results suggest that the helix of yeast IF1 facilitates binding to F(1) by promoting initial interaction of the proteins. PMID- 26420259 TI - Effects of cellulase supplementation to corn soybean meal-based diet on the performance of sows and their piglets. AB - A total of 15 primiparous sows (Landrace * Yorkshire) and their litters were used in the current study to evaluate the efficacy of cellulase supplementation on the production performance of sows and piglets. Pigs were randomly allocated into one of three treatments with five replicates per treatment. The dietary treatments were as follows: (i) CON (corn-soybean meal-based control); (ii) EZ1 (CON + 0.05% cellulase); and (iii) EZ2 (CON + 0.10% cellulase). The supplementation of cellulase had no effect (P > 0.05) on body weight and feed intake of lactating sows. At weaning, back fat thickness loss decreased (P = 0.04) linearly in EZ1 and EZ2 treatments. The average daily gain (ADG) of piglets increased (linear P = 0.06, quadratic P = 0.04)) during days 14 to 21 as well as at days 21 to 25 (linear P = 0.03 and quadratic P = 0.01) with the increase in the level of supplemented enzyme. Dry matter and nitrogen digestibility increased (linear P = 0.01) in lactating sows fed EZ1 and EZ2 diet compared with CON. In conclusion, it is suggested that cellulase supplementation to corn-soybean meal based diet exerts beneficial effects to sows in reducing their back fat thickness loss at weaning and also helps to improve nutrient digestibility. It also helped to improve the ADG of piglets. PMID- 26420260 TI - Cdh2 stabilizes FGFR1 and contributes to primed-state pluripotency in mouse epiblast stem cells. AB - The cell adhesion molecule Cadherin 2 (Cdh2) plays important roles in somatic cell adhesion, proliferation and migration. Cdh2 is also highly expressed in mouse epiblast stem cells (mEpiSCs), but its function in these cells is unknown. To understand the function of Cdh2 in mEpiSCs, we compared the expression of pluripotency-related genes in mEpiSCs and mouse embryonic stem cells (mESCs) after either Cdh2 knockdown or Cdh2 over-expression. Introduction of specific siRNA against Cdh2 led to attenuation of pluripotency-related genes. Pluripotent gene expression was not recovered by over-expression of Cdh1 following Cdh2 knockdown. Western blot analysis and co-immunoprecipitation assays revealed that Cdh2 stabilizes FGFR1 in mEpiSCs. Furthermore, stable transfection of mESCs with Cdh2 cDNA followed by FGF2 supplementation accelerated cell differentiation. Thus, Cdh2 contributes to the establishment and maintenance of FGF signaling dependent self-renewal in mEpiSCs through stabilization of FGFR1. PMID- 26420262 TI - Effect of observation on lower limb prosthesis gait biomechanics: Preliminary results. AB - BACKGROUND: The Hawthorne effect, a subcategory of reactivity, causes human behavior to change when under observation. Such an effect may apply to gait variation of persons with prosthetics or orthotics devices. OBJECTIVES: This study investigated whether the presence of observers directly affects the gait pattern of users of lower limb prostheses. STUDY DESIGN: Within-subject intervention study. METHODS: Primary outcome measures were gait parameters of initial double support time and upper body lateral tilt angle, which were collected with a mobile sensor attached to the subjects' back. To make subjects feel unwatched, a certain amount of deception was necessary, and two different conditions were created and statistically compared against each other: one in which the subjects were initially unaware of the attention of observers and another one in which the same subjects were aware of a group of observers. RESULTS: Data from two subjects using trans-femoral prosthesis are reported. Findings included a change in step initial double support percentage by up to 14.2% (p = 0.019). Considerable changes were also noted in secondary outcome measures including speed, stride length, and stride symmetry. CONCLUSIONS: A reactivity effect of observation exists in prosthetics gait analysis. More comprehensive studies may be motivated by these preliminary findings. CLINICAL RELEVANCE: Results of this study suggest that users of lower limb prostheses walk differently when their gait is being assessed (e.g. in the prosthetist's office) than in situations without observers. This may in part explain the clinical experience that modifications of prosthetic fit or alignment provide only short term betterment. PMID- 26420261 TI - Xpert MTB/RIF assay can be used on archived gastric aspirate and induced sputum samples for sensitive diagnosis of paediatric tuberculosis. AB - BACKGROUND: Tuberculosis (TB) in children is neglected, mainly due to lack of sensitive diagnostic tools. Recently Xpert MTB/RIF assay has revolutionized the diagnostic field, but its usefulness in pediatric TB has not been reported from India and no report is available on its use on long term archived samples. METHODS: We recruited 130 pediatric patients with probable intrathoracic tuberculosis and their gastric aspirate (GA) and induced sputum (IS) samples on 2 consecutive days were collected between January 2009 and December 2012. All samples (n = 520) were subjected to smear examination, BACTEC-MGIT culture and in house multiplex PCR. An aliquot of each sample was stored at -80 degrees C and tested in Xpert MTB/RIF assay in 2013. RESULTS: Sample wise and patient wise detection rate of smear microscopy was 4.4 % and 10 %, while for BACTEC-MGIT culture this rate was 24.4 % and 46.9 %, respectively. Of the 130 day 1 GA samples, 31.5 % and 27.7 % day 2 GA samples were culture positive. Only 17.7 % GA samples were positive on both days. Of the 130 IS samples collected on day 1 and day 2, 15.4 % and 23.1 % samples were culture positive. A combination of GA and IS yielded best results. Combining both GA and IS, the overall sensitivity of Xpert MTB/RIF on smear and culture positive samples was 95.6 %. In smear negative and culture positive samples its sensitivity was 62.5 %. The duration of sample storage impacted the Xpert MTB/RIF test performance (p = 0.0001). In smear positive samples stored for 650-849 days, its sensitivity was 85.7 % and 77.1 % for IS and GA samples which dropped to 33.3 % and 50 %, respectively, if stored for more than 1050 days. DISCUSSION: Confirmatory diagnosis of tuberculosis particularly in children is a medical challenge. No laboratory or radiological test can reach to a satisfactory level of diagnostic sensitivity. However, in this study we found that combination of multiple samples and multiple diagnostic tests can give much better yield, though not optimum. In present study, combination of 2 gastric aspirates (GA) and 2 induced sputum (IS) samples collected on two consecutive days, and tested on three diagnostic methods yielded a significantly high detection rate. Despite long term storage, the overall sensitivity of Xpert MTB/RIF on smear and -culture positive samples remained very high. But after storing these samples under subfreezing conditions the sensitivity of Xpert MTB/RIF decreased significantly. This is expected because even if the sample is smear and culture positive, the count of surviving mycobacteria goes down, after several years this count can reach to a undetectable level. CONCLUSION: This report shows that smear and culture positive samples stored at subfreezing conditions for several years can be used in the Xpert MTB/RIF assay, while maintaining appreciable diagnostic test sensitivity and specificity. PMID- 26420263 TI - Prevalence of concomitant hypo-hyperdontia in a group of Turkish orthodontic patients. AB - AIM: Was to investigate hypodontia and supernumerary teeth, in the same individual, which is termed 'concomitant hypo-hyperodontia' (CHH) and the frequency of CHH in a large sample of non-syndromic orthodontic patients. METHODS: In this retrospective study, the records were reviewed of 1236 Turkish orthodontic patients treated between 1994 and 2003 at Marmara University, Paediatric Clinics. Data were collected and analysed for differences in the distribution of hypodontia and supernumerary teeth, sex, and malocclusion type. RESULTS: A total of 1236 orthodontic patients were included in this study. The mean age of children was 17.05 years (SD = 2.5). The prevalence of hypodontia was 7 % (82) and was more frequently found in girls. Concomitant hypo-hyperodontia was found in 9 children, involving 8 boys and 1 girl. The frequency of mesiodens in hypodontia patients with Class I, II, and Class III malocclusions was 3 (3 boys), 5 (5 boys) and 1 (1 girl), respectively. CHH prevalence was found 0.7 % (9 patients). The gender ratio was 0.2:1.1 for CHH. CONCLUSIONS: Supernumerary teeth may lead to some clinical problems including malocclusions, aesthetic and functional complaints, and also psychological problems. Early diagnosis of the condition and multidisciplinary approach for management of such cases is recommended. PMID- 26420264 TI - Effect on oral pH changes and taste perception in 10-14-year-old children, after calcium fortification of a fruit juice. AB - AIM: The aim was to determine the effect of calcium fortification of a commercially available mixed-fruit juice on oral pH changes and taste perception in a group of 10 to 14 year-old Indian children. METHOD: A controlled, blinded, non-randomised clinical trial was adopted, consisting of a sample of 100 healthy children (DMFT <3; age 10-14 years), who were exposed to three test juices one by one [Group A: original fruit juice (control group); Group B: calcium-fortified fruit juice and Group C: calcium + vitamin D fortified fruit juice]. Oral pH, collection of saliva and plaque sampling was undertaken, before and after the juice exposure by each subject at 0, 1, 5, 15, 30 and 45 min. The respective pH was measured with a digital pH meter. For taste perception, a scoring system was used after exposure of the juices to the subjects in a blind manner. The statistical evaluation was done using one-way ANOVA for salivary and plaque pH and Kruskal-Wallis test for buffer capacity and taste perception. RESULTS: There was a smaller drop in salivary and plaque pH (p < 0.5) and a significant reduction in perceived taste (p < 0.001) by the subjects after calcium modification of fruit juice. CONCLUSION: The calcium-modified mixed fruit juices was less acidogenic compared with the unfortified juice, and hence will be less cariogenic and erosive towards teeth. PMID- 26420265 TI - Eastern equine encephalitis virus in mice I: clinical course and outcome are dependent on route of exposure. AB - BACKGROUND: Eastern equine encephalitis virus (EEEV), an arbovirus, is an important human and veterinary pathogen belonging to one of seven antigenic complexes in the genus Alphavirus, family Togaviridae. EEEV is considered the most deadly of the mosquito-borne alphaviruses due to the high case fatality rate associated with clinical infections, reaching up to 75 % in humans and 90 % in horses. In patients that survive acute infection, neurologic sequelae are often devastating. Although natural infections are acquired by mosquito bite, EEEV is also highly infectious by aerosol. This fact, along with the relative ease of production and stability of this virus, has led it to being identified as a potential agent of bioterrorism. METHODS: To characterize the clinical course and outcome of EEEV strain FL93-939 infection, we compared clinical parameters, cytokine expression, viremia, and viral titers in numerous tissues of mice exposed by various routes. Twelve-week-old female BALB/c mice were infected by the intranasal, aerosol, or subcutaneous route. Mice were monitored for clinical signs of disease and euthanized at specified time points (6 hpi through 8 dpi). Blood and tissues were harvested for cytokine analysis and/or viral titer determination. RESULTS: Although all groups of animals exhibited similar clinical signs after inoculation, the onset and severity differed. The majority of those animals exposed by the aerosol route developed severe clinical signs by 4 dpi. Significant differences were also observed in the viral titers of target tissues, with virus being detected in the brain at 6 hpi in the aerosol study. CONCLUSION: The clinical course and outcome of EEEV infection in mice is dependent on route of exposure. Aerosol exposure to EEEV results in acute onset of clinical signs, rapid neuroinvasion, and 100 % mortality. PMID- 26420266 TI - On the Effect of Thermophysical Properties of Clothing on the Heat Strain Predicted by PHS Model. AB - Procedures and equations reported in ISO 9920 for the correction of basic thermophysical clothing properties taking into account pumping effect and air movement are very different from those used by the Predicted Heat Strain (PHS) model in ISO 7933. To study the effect of these differences on the assessment of hot environments using the PHS model, an analysis focusing on the modelling of the dynamic thermal insulation and the vapour resistance of the clothing reported in ISO 9920 and ISO 7933 standards will be discussed in this paper. The results are useful evidence to start a discussion on the best practice for dealing with clothing thermophysical properties and underline the need to harmonize the entire set of standards in the field of the Ergonomics of the Thermal Environment. ISO 7933 is presently under revision. PMID- 26420267 TI - Incidence of and risk factors for metachronous gastric cancer after endoscopic resection and successful Helicobacter pylori eradication: results of a large scale, multicenter cohort study in Japan. AB - BACKGROUND: A previous multicenter prospective randomized study from Japan showed that Helicobacter pylori eradication reduced the development of metachronous gastric cancer (MGC) after endoscopic resection for early gastric cancer. MGC risk, however, is not eliminated; yet few studies have evaluated its long-term incidence and risk factors. In this study, we investigated the incidence of and risk factors for MGC in patients who underwent endoscopic resection for early gastric cancer with successful H. pylori eradication. METHODS: A total of 594 patients who underwent endoscopic resection for early gastric cancer and successful H. pylori eradication at three institutions (National Cancer Center Hospital, University of Tokyo Hospital, and Wakayama Medical University Hospital) were analyzed retrospectively. Annual endoscopic surveillance was performed after initial endoscopic resection. MGC was defined as a gastric cancer newly detected at least 1 year after successful H. pylori eradication. RESULTS: Ninety-four MGCs were detected in 79 patients during the 4.5-year median follow-up period. Kaplan Meier analysis showed the cumulative incidence of MGC 5 years after successful H. pylori eradication was 15.0 %; the incidence of MGC calculated by use of the person-year method was 29.9 cases per 1000 person-years. Multivariate analysis using the Cox proportional hazards model revealed that male sex, severe gastric mucosal atrophy, and multiple gastric cancers before successful H. pylori eradication were independent risk factors for MGC. Eleven percent of MGCs (10 of 94) were detected more than 5 years after successful H. pylori eradication. CONCLUSION: Surveillance endoscopy for MGC in patients who have undergone endoscopic resection for early gastric cancer should be performed even after successful H. pylori eradication. PMID- 26420268 TI - Primary malignant mucosal melanoma of the upper lip: a case report and review of the literature. AB - BACKGROUND: Malignant melanoma of oral cavity is a rare condition, accounting for 0.5% of all oral malignancies and about 1-2% of all melanomas. Oral melanomas have extremely poor prognosis with 5 years survival rate of 12.3%. The poor prognosis compared to cutaneous melanoma may be attributed to delay in reporting by patient and diagnosis, and apt to become ulcerated due to repeated trauma. The 'chameleonic' presentation of a mainly asymptomatic condition, the rarity of these lesions, the poor prognosis and the necessity of a highly specialized treatment are factors that should be seriously considered by the involved health provider. CASE PRESENTATION: We present a case of 32 years old male of Han ethnicity with mucosal melanoma of upper lip, comparing his clinical presentation and histological findings at his first visit and following the recurrence. The patient complained of black discoloration on the left side of upper lip since 4 years which gradually increased in size and later involved the skin of the lip. Excision with 5 mm safety margin was performed but the patient presented with the similar lesion after three and half years of the treatment. So, again wide excision with 2 cm safety margin was performed followed by reconstruction of the lip. CONCLUSION: This case provides an example of aggressive behavior of mucosal melanoma and emphasizes on the fact that any pigmented lesion detected in the oral cavity may exhibit potential growth and should be submitted to biopsy to exclude malignancy. It also exemplifies of how the time of diagnosis and the evolution of a disease could be seriously influenced by patient's behavior. PMID- 26420270 TI - Toward an optimized treatment of intracellular bacterial infections: input of nanoparticulate drug delivery systems. AB - Intracellular pathogenic bacteria can lead to some of the most life-threatening infections. By evolving a number of ingenious mechanisms, these bacteria have the ability to invade, colonize and survive in the host cells in active or latent forms over prolonged period of time. A variety of nanoparticulate systems have been developed to optimize the delivery of antibiotics. Main advantages of nanoparticulate systems as compared with free drugs are an efficient drug encapsulation, protection from inactivation, targeting infection sites and the possibility to deliver drugs by overcoming cellular barriers. Nevertheless, despite the great progresses in treating intracellular infections using nanoparticulate carriers, some challenges still remain, such as targeting cellular subcompartments with bacteria and delivering synergistic drug combinations. Engineered nanoparticles should allow controlling drug release both inside cells and within the extracellular space before reaching the target cells. PMID- 26420276 TI - Response to "Letter to Congenital microtia in a neonate suspected of isotretinoin exposure one month before pregnancy: A case report". PMID- 26420269 TI - Neurostimulation for cognitive rehabilitation in stroke (NeuroCog): study protocol for a randomized controlled trial. AB - BACKGROUND: Stroke patients may present severe cognitive impairments, primarily related to executive functions. Transcranial direct current stimulation has shown promising results, with neuromodulatory and neuroplastic effects. This study is a double-blind, sham-controlled clinical trial aiming to compare the long-term effects of stimulation in two different cognitive regions after a stroke. METHODS/DESIGN: Sixty patients who suffer from chronic strokes will be randomized into one of four groups: dorsolateral prefrontal cortex, cingulo-opercular network, motor primary cortex and sham stimulation. Each group will receive transcranial direct current stimulation at an intensity of 2 mA for 20 minutes daily for 10 consecutive days. Patients will be assessed with a Dysexecutive Questionnaire, Semantic Fluency Test, categorical verbal fluency and Go-no go tests, Wechsler Adult Intelligence Scale, Rey Auditory-Verbal Learning Test, Letter Comparison and Pattern Comparison Tasks at baseline and after their tenth stimulation session. Those who achieve clinical improvement with neurostimulation will be invited to receive treatment for 12 months as part of a follow-up study. DISCUSSION: Long-term stimulation could be analyzed in regard to possible adaptive changes on plasticity after structural brain damage and if these changes are different in terms of clinical improvement when applied to two important cognitive centers. TRIALS REGISTRATION: Clinicaltrials.gov, NCT02315807 . 9 December 2014. PMID- 26420277 TI - Exploring brain functional plasticity in world class gymnasts: a network analysis. AB - Long-term motor skill learning can induce plastic structural and functional reorganization of the brain. Our previous studies detected brain structural plasticity related to long-term intensive gymnastic training in world class gymnasts (WCGs). The goal of this study was to investigate brain functional plasticity in WCGs by using network measures of brain functional networks. Specifically, we acquired resting-state fMRI data from 13 WCGs and 14 controls, constructed their brain functional networks, and compared the differences in their network parameters. At the whole brain level, we detected significantly decreased overall functional connectivity (FC) and decreased local and global efficiency in the WCGs compared to the controls. At the modular level, we found intra- and inter-modular reorganization in three modules, the cerebellum, the cingulo-opercular and fronto-parietal networks, in the WCGs. On the nodal level, we revealed significantly decreased nodal strength and efficiency in several non rich club regions of these three modules in the WCGs. These results suggested that functional plasticity can be detected in the brain functional networks of WCGs, especially in the cerebellum, fronto-parietal network, and cingulo opercular network. In addition, we found that the FC between the fronto-parietal network and the sensorimotor network was significantly negatively correlated with the number of years of training in the WCGs. These findings may help us to understand the outstanding gymnastic performance of the gymnasts and to reveal the neural mechanisms that distinguish WCGs from controls. PMID- 26420279 TI - The timing of language learning shapes brain structure associated with articulation. AB - We compared the brain structure of highly proficient simultaneous (two languages from birth) and sequential (second language after age 5) bilinguals, who differed only in their degree of native-like accent, to determine how the brain develops when a skill is acquired from birth versus later in life. For the simultaneous bilinguals, gray matter density was increased in the left putamen, as well as in the left posterior insula, right dorsolateral prefrontal cortex, and left and right occipital cortex. For the sequential bilinguals, gray matter density was increased in the bilateral premotor cortex. Sequential bilinguals with better accents also showed greater gray matter density in the left putamen, and in several additional brain regions important for sensorimotor integration and speech-motor control. Our findings suggest that second language learning results in enhanced brain structure of specific brain areas, which depends on whether two languages are learned simultaneously or sequentially, and on the extent to which native-like proficiency is acquired. PMID- 26420278 TI - Lesion-induced and activity-dependent structural plasticity of Purkinje cell dendritic spines in cerebellar vermis and hemisphere. AB - Neuroplasticity allows the brain to encode experience and learn behaviors, and also to re-acquire lost functions after damage. The cerebellum is a suitable structure to address this topic because of its strong involvement in learning processes and compensation of lesion-induced deficits. This study was aimed to characterize the effects of a hemicerebellectomy (HCb) combined or not with the exposition to environmental enrichment (EE) on dendritic spine density and size in Purkinje cell proximal and distal compartments of cerebellar vermian and hemispherical regions. Male Wistar rats were housed in enriched or standard environments from the 21st post-natal day (pnd) onwards. At the 75th pnd, rats were submitted to HCb or sham lesion. Neurological symptoms and spatial performance in the Morris water maze were evaluated. At the end of testing, morphological analyses assessed dendritic spine density, area, length, and head diameter on vermian and hemispherical Purkinje cells. All hemicerebellectomized (HCbed) rats showed motor compensation, but standard-reared HCbed animals exhibited cognitive impairment that was almost completely compensated in enriched HCbed rats. The standard-reared HCbed rats showed decreased density with augmented size of Purkinje cell spines in the vermis, and augmented both density and size in the hemisphere. Enriched HCbed rats almost completely maintained the spine density and size induced by EE. Both lesion-induced and activity-dependent cerebellar plastic changes may be interpreted as "beneficial" brain reactions, aimed to support behavioral performance rescuing. PMID- 26420280 TI - Elisabeth Holme. PMID- 26420281 TI - Quo vadis: the re-definition of "inborn metabolic diseases". PMID- 26420285 TI - Patient educational technologies and their use by patients diagnosed with localized prostate cancer. AB - BACKGROUND: Two urology practices in Calgary, Canada use patient educational technology (PET) as a core component of their clinical practice. The purpose of this study was to determine how patients interact with PET designed to inform them about their treatment options for clinically localized prostate cancer. METHODS: A PET library was developed with 15 unique prostate-related educational modules relating to diagnosis, treatment options, and potential side effects. The PET collected data regarding its use, and those data were used to conduct a retrospective analysis. Descriptive analyses were conducted and comparisons made between patients' utilization of the PET library during first and subsequent access; Pearson's Chi-Square was used to test for statistical significance, where appropriate. RESULTS: Every patient (n = 394) diagnosed with localized prostate cancer was given access to the PET library using a unique identifier. Of those, 123 logged into the library and viewed at least one module and 94 patients logged into the library more than once. The average patient initially viewed modules pertaining to their diagnosis. Viewing behavior significantly changed in subsequent logins, moving towards modules pertaining to treatment options, decision making, and post-surgical information. DISCUSSION: As observed through the longitudinal utilization of the PET library, information technology offers clinicians an opportunity to provide an interactive platform to meet patients' dynamic educational needs. Understanding these needs will help inform the development of more useful PETs. CONCLUSION: The informational needs of patients diagnosed with clinically localized prostate cancer changed throughout the course of their diagnosis and treatment. PMID- 26420286 TI - NPHS2 mutations account for only 15% of nephrotic syndrome cases. AB - BACKGROUND: Nephrotic syndrome is traditionally classified on the basis of the response to standard steroid treatment. Mutations in more than 24 genes have been associated with nephrotic syndrome in children, although the great majority of steroid-resistant cases have been attributed to mutations in three main genes: NPHS1, NPHS2 and WT1. The aims of this study were to identify mutations in these genes more frequently reported as mutated and to characterize each variation using different in silico prediction algorithms in order to understand their biological functions. METHODS: We performed direct sequence analysis of exons 8 and 9 of WT1, 8 exons of NPHS2 and 29 exons of NPHS1, including NPHS2 and NPHS1 intron-exon boundary sequences, as well as 700 bp of the 5' UTR from both genes in 27 steroid-resistant patients aged between 3 months and 18 years. RESULTS: Analysis of the NPHS2 gene revealed four missense mutations, one frameshift mutation and three variations in the 5' UTR. Four patients presented compound heterozygosis, and four other patients presented one heterozygous alteration only. WT1 and NPHS1 gene analysis did not reveal any mutations. DISCUSSION: This is the first study focusing on genetics of SRNS in Brazilian children. Identification of mutations is important because it could influence physicians' decision on patient treatment, as patients carrying mutations can be spared the side effects of immunosuppressive therapy and ultimately could be considered for kidney transplantation from a living donor. CONCLUSIONS: After molecular analysis of the genes more frequently reported as mutated in 27 steroid-resistant nephrotic syndrome patients, we identified NPHS2 mutations confirming the hereditary character of the kidney disease in only 14.8% of patients. Therefore, the next step is to perform a next generation sequencing based analysis of glomeluropathy-related panel of genes for the remaining patients in order to search for mutations in other genes related to steroid-resistant nephrotic syndrome. PMID- 26420288 TI - Significant LVOT obstruction after mitral valve in ring procedure. PMID- 26420287 TI - FDG-PET reveals improved cardiac regeneration and attenuated adverse remodelling following Sitagliptin + G-CSF therapy after acute myocardial infarction. AB - AIMS: Dual therapy comprising G-CSF for mobilization of bone marrow-derived progenitor cells (BMPCs), with simultaneous pharmacological inhibition of dipeptidylpeptidase-IV for enhanced myocardial recruitment of circulating BMPC via the SDF-1alpha/CXCR4-axis, has been shown to improve survival after acute myocardial infarction (AMI). Using an innovative method to provide non-invasive serial in vivo measurements and information on metabolic processes, we aimed to substantiate the possible effects of this therapeutic concept on cardiac remodelling after AMI using 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET). METHODS AND RESULTS: AMI was induced in C57BL/6 mice by performing surgical ligation of the left anterior descending artery in these mice. Animals were then treated with granulocyte-colony stimulating factor + Sitagliptin (GS) or placebo for a duration of 5 days following AMI. From serial PET scans, we verified that the infarct size in GS-treated mice (n = 13) was significantly reduced at Day 30 after AMI when compared with the mice receiving placebo (n = 10). Analyses showed a normalized FDG uptake on Day 6 in GS-treated mice, indicating an attenuation of the cardiac inflammatory response to AMI in treated animals. Furthermore, flow cytometry showed a significant increase in the anti-inflammatory M2-macrophages subpopulation in GS-treated animals. In comparing GS treated with placebo animals, those receiving GS-therapy showed a reduction in myocardial hypertrophy and left ventricular dilatation, which indicates the beneficial effect of GS treatment on cardiac remodelling. Remarkably, flow cytometry and immunohistochemistry showed an increase of myocardial c-kit positive cells in treated mice (n = 12 in both groups). CONCLUSION: Using the innovative method of micro-PET for non-invasive serial in vivo measurements of metabolic myocardial processes in mice, we were able to provide mechanistic evidence that GS therapy improves cardiac regeneration and reduces adverse remodelling after AMI. PMID- 26420289 TI - Perforated aortic valve aneurysm in infective endocarditis: from vegetation to aneurysm. PMID- 26420290 TI - Anomalous bilateral pulmonary veins with normal drainage into the left atrium. PMID- 26420291 TI - Incremental predictive value for obstructive coronary artery disease by combination of Duke Clinical Score and Agatston score. AB - AIMS: Recent study suggests that algorithms such as the Duke Clinical score (DCS) may overestimate the pretest probability. The Agatston score representing the grade of coronary artery calcification can be simply calculated from low radiation exposure ECG-gated plain CT. In this study, we investigated whether or not more superior diagnostic performance for obstructive coronary artery disease (CAD) can be obtained by combining DCS with the Agatston score. METHODS AND RESULTS: Of 3939 consecutive patients suspected of having stable angina without known CAD who underwent Coronary Computed Tomography Angiography (CCTA) as well as calculation of the DCS and Agatston score at our hospital, 3688 patients were selected as subjects. Obstructive CAD was defined as >50% diameter stenosis on CCTA; we investigated the diagnostic performance based on the area under the curve (AUC) of a receiver operating characteristic (ROC) curve, Net Reclassification Improvement (NRI), and Integrated Discrimination Improvement (IDI). The AUCs of ROCs prepared using the DCS alone and combination of the DCS and Agatston score were 0.7137 and 0.8057, respectively, showing that the diagnostic performance of the combination was significantly superior to DCS alone (P < 0.001). NRI was 0.8132 and IDI was 0.1374, showing that the diagnostic performance was improved by the combination of the DCS and Agatston score compared with DCS alone (P < 0.001). NRI (0.3522) and IDI (0.0287) were improved compared with those of the Agatston score alone (P < 0.001). CONCLUSION: The combination of the DCS and Agatston score improved the diagnostic performance for obstructive CAD compared with DCS alone and Agatston score. PMID- 26420292 TI - FDG-PET/CT for driveline infection in a patient with implantable left ventricular assist device. PMID- 26420293 TI - Double-orifice mitral valve in Ebstein's anomaly. PMID- 26420295 TI - Epigenetic analysis of regulatory T cells using multiplex bisulfite sequencing. PMID- 26420294 TI - Sirtuins in Cancer: a Balancing Act between Genome Stability and Metabolism. AB - Genomic instability and altered metabolism are key features of most cancers. Recent studies suggest that metabolic reprogramming is part of a systematic response to cellular DNA damage. Thus, defining the molecules that fine-tune metabolism in response to DNA damage will enhance our understanding of molecular mechanisms of tumorigenesis and have profound implications for the development of strategies for cancer therapy. Sirtuins have been established as critical regulators in cellular homeostasis and physiology. Here, we review the emerging data revealing a pivotal function of sirtuins in genome maintenance and cell metabolism, and highlight current advances about the phenotypic consequences of defects in these critical regulators in tumorigenesis. While many questions should be addressed about the regulation and context-dependent functions of sirtuins, it appears clear that sirtuins may provide a promising, exciting new avenue for cancer therapy. PMID- 26420296 TI - Expression Profile Analysis of miR-221 and miR-222 in Different Tissues and Head Kidney Cells of Cynoglossus semilaevis, Following Pathogen Infection. AB - Half-smooth tongue sole (Cynoglossus semilaevis) is an important marine commercial fish species in China, which suffers from widespread disease outbreaks. Recently, in this regard, our group identified immune-related microRNAs (miRNAs) of C. semilaevis following Vibrio anguillarum infection. Furthermore, miRNA microarray was utilized to characterize the immune roles of important miRNA candidates in response to bacterial infection. Therefore, in the present study, we characterized miR-221 and miR-222 and profiled their expression after challenge. Here, miR-221 and miR-222 precursors were predicted to have a typical hairpin structure. Both miRNAs were expressed in a broad range of tissues in C. semilaevis, while miR-221 and miR-222 were significantly differentially expressed in the immune tissues of C. semilaevis among three small RNA libraries [control group (CG), bacteria-challenged fish without obvious symptoms of infection (NOSG), and bacteria-challenged fish with obvious symptoms of infection (HOSG)]. In order to further characterize and understand the immune response of miR-221 and miR-222, therefore, we profiled miR-221 and miR-222 expression in selected immune tissues after challenge with V. anguillarum. Both miR-221 and miR 222 were upregulated in the liver and spleen, while different expression patterns were observed in the head kidney. In addition, in half-smooth tongue sole head kidney cell line after challenge with lipopolysaccharide (LPS), polyinosinic:polycytidylic acid (poly I:C), peptidoglycan (PGN), and red-spotted grouper nervous necrosis virus (RGNNV), both miR-221 and miR-222 showed significant difference in expression response to pathogen. Meanwhile, the target gene of miR-221 and miR-222 was predicted, which indicated that tumor necrosis factor receptor-associated factor 6 (TRAF6) and interleukin-1 beta (IL-1beta) were the target genes of miR-221 and miR-222, respectively. Collectively, these findings indicated that miR-221 and miR-222 have putative roles in innate immune response during C. semilaevis exposure to pathogens. Our findings could expand the knowledge of immune function of C. semilaevis miRNA and guide future studies on C. semilaevis immunity. PMID- 26420297 TI - Multimodality Imaging of Cancer Superoxide Anion Using the Small Molecule Coelenterazine. AB - PURPOSE: We evaluated the small molecule coelenterazine as a potential reporter of cancer-associated superoxide anion in cell culture and in mice. PROCEDURES: The superoxide anion concentrations of various cancer cell lines were quantified by coelenterazine chemiluminescence in vitro. Coelenteramide fluorescence was detected via flow cytometry and fluorescent microscopy. Coelenterazine was used for the in vivo detection of cancer-associated superoxide anion using the 4T1 breast adenocarcinoma mouse model. RESULTS: Various cell lines in culture demonstrated different superoxide anion concentrations, with a signal range of 3.15 +/- 0.06 to 11.80 +/- 0.24 times that of background. In addition to chemiluminescent detection of coelenterazine, we demonstrated fluorescent detection of coelenteramide within the cytoplasm of cells. 4T1 murine mammary adenocarcinoma tumors in mice demonstrated significantly higher 2.13 +/- 0.19 fold coelenterazine-based chemiluminescence than that of surrounding normal tissues. CONCLUSIONS: Collectively, our results indicate that coelenterazine can be used to assay superoxide anion concentrations in cultured cancer cells and in tumors growing in mice. PMID- 26420298 TI - Impaired processing of self-face recognition in anorexia nervosa. AB - Body image disturbances and massive weight loss are major clinical symptoms of anorexia nervosa (AN). The aim of the present study was to examine the influence of body changes and eating attitudes on self-face recognition ability in AN. Twenty-seven subjects suffering from AN and 27 control participants performed a self-face recognition task (SFRT). During the task, digital morphs between their own face and a gender-matched unfamiliar face were presented in a random sequence. Participants' self-face recognition failures, cognitive flexibility, body concern and eating habits were assessed with the Self-Face Recognition Questionnaire (SFRQ), Trail Making Test (TMT), Body Shape Questionnaire (BSQ) and Eating Disorder Inventory-2 (EDI-2), respectively. Subjects suffering from AN exhibited significantly greater difficulties than control participants in identifying their own face (p = 0.028). No significant difference was observed between the two groups for TMT (all p > 0.1, non-significant). Regarding predictors of self-face recognition skills, there was a negative correlation between SFRT and body mass index (p = 0.01) and a positive correlation between SFRQ and EDI-2 (p < 0.001) or BSQ (p < 0.001). Among factors involved, nutritional status and intensity of eating disorders could play a part in impaired self-face recognition. PMID- 26420299 TI - Perceived vulnerability to disease and antifat attitudes in a sample of children and teenagers. AB - PURPOSE: Perceived vulnerability to disease (beliefs about personal susceptibility to contracting an infectious disease) is usually related to the expression of prejudice towards different stigmatized groups. In this study, the relationship between this variable and the expression of the prejudice towards obese people was analyzed. METHOD: The sample comprised a total of 137 children and teenagers, aged between 12 and 17 years, from a Spanish high school who fulfilled several scales which measure perceived vulnerability to disease, antifat attitudes and perceived controllability of weight. Additionally, body mass index (BMI) was calculated by means of the participants' height and weight. RESULTS: Perceived infectability (one of the factors of the perceived vulnerability to disease scale) was negatively related to controllability of weight, and germ aversion (the second factor of the vulnerability scale), showed a positive relationship with the antipathy towards obese people. Finally, perceived controllability of weight was positively correlated with BMI. CONCLUSIONS: The implications of these results in the field of the study of the prejudice toward obese people are discussed. To our knowledge, no other studies have investigated the relationship between perceived vulnerability to disease and antifat attitudes in minors. Additionally, this is the first time that the measured BMI has been used instead of the self-reported one. PMID- 26420300 TI - Myhre syndrome: Clinical features and restrictive cardiopulmonary complications. AB - Myhre syndrome, a connective tissue disorder characterized by deafness, restricted joint movement, compact body habitus, and distinctive craniofacial and skeletal features, is caused by heterozygous mutations in SMAD4. Cardiac manifestations reported to date have included patent ductus arteriosus, septal defects, aortic coarctation and pericarditis. We present five previously unreported patients with Myhre syndrome. Despite varied clinical phenotypes all had significant cardiac and/or pulmonary pathology and abnormal wound healing. Included herein is the first report of cardiac transplantation in patients with Myhre syndrome. A progressive and markedly abnormal fibroproliferative response to surgical intervention is a newly delineated complication that occurred in all patients and contributes to our understanding of the natural history of this disorder. We recommend routine cardiopulmonary surveillance for patients with Myhre syndrome. Surgical intervention should be approached with extreme caution and with as little invasion as possible as the propensity to develop fibrosis/scar tissue is dramatic and can cause significant morbidity and mortality. PMID- 26420301 TI - Hepatitis B surface gene variants isolated from blood donors with overt and occult HBV infection in north eastern Egypt. AB - BACKGROUND: Major hydrophilic region in genomic HBV extending from aa99 to aa169, clustered with a highly conformational epitope, is critical to the antigenicity of hepatitis B surface antigen (HBsAg) and may affect the diagnosis of HBV in HBV screening test. So, this study aimed to characterize variants of S gene product of hepatitis B virus (HBV) isolated from patients with overt or occult HBV infection in north-eastern Egypt. METHODS: The study included sera of two different groups of volunteer blood donors (VBDs), 82 with overt HBV that were positive for HBsAg and anti-HBc and 343 donors negative for HBsAg eligible for donation. Of the latter group, only 44 were positive for anti-HBc. All anti-HBc positive sera were subjected to HBV DNA detection and partial sequence analysis targeting the HBV S gene. RESULTS: HBV DNA was detected in 22.7 % of HBsAg-/anti HBc + (10/44 patients) and in 90 % of HBsAg + donors (74/82 patients) with significant statistical difference (P = 0.0001). Phylogenetic analysis showed that HBV strains retrieved from both groups were of genotype D. Amino acid escape mutation T125M was detected in only 2 samples of the occult infection group and in none of the overt group (P = 0.01). Different amino acid substitutions were identified in overt infection group: S143L/T (16.2 %, 12/74) and P120T/S (2.7 %, 2/74). Q129R was significantly more frequent in cases with occult HBV infection (40 %, 4/10) than overt group (6.8 %, 5/74) (P = 0.01). CONCLUSIONS: HBV genotype D predominated both in patients with overt and occult HBV infection. Different profiles of amino acid substitutions in the major hydrophilic region were seen in these two groups in Egypt. PMID- 26420302 TI - Antibiotic use and resistance: a cross-sectional study exploring knowledge and attitudes among school and institution personnel in Tbilisi, Republic of Georgia. AB - BACKGROUND: The Republic of Georgia lacks regulations regarding drug prescriptions. In pharmacies, all drugs except psychotropic medication are sold legally without prescription anti-, including anti-tuberculosis agents. Due to the lack of adequate policies and regulations, the big share of responsibility regarding antibiotic education lies with the general public. This study examines public knowledge and attitudes toward antibiotic use and resistance in the Republic of Georgia among personnel from government schools and other public institutions. METHODS: This cross-sectional study was conducted in June 2011 using a quantitative questionnaire. Convenience sampling method was used. Participants included 250 individuals aged 21-80 years, from government schools and public institutions. Participants were from Tbilisi as well as the surrounding rural and urban areas. Respondents provided demographic data along with statements on knowledge and attitudes towards antibiotic use and resistance. Poisson and logistic regression models were used to study the relationship between knowledge, attitude outcomes and socio-demographic characteristics. RESULTS: The overall response rate was 75% (n = 187), of which 80% were female. Approximately 91% of respondents had used antibiotics at least once and 55% agreed that antibiotics speed up recovery from common colds. A number of respondents (55%) reported having received antibiotics without previously consulting a doctor and 62% reported having purchased antibiotics without a prescription. Respondents demonstrated some misunderstanding around the terms 'bacteria' and 'virus.' About 52% of participants agreed that antibiotics are effective against bacteria; however, 55% also agreed that antibiotics are effective against viruses. Trust in doctors was high at 80%. More knowledge was associated with a lower probability of having purchased antibiotics without medical consultation. CONCLUSIONS: The study findings demonstrate that respondents have several misconceptions and lack knowledge on proper antibiotic use and resistance. High proportion of people use antibiotics without a medical prescription or consultation, while having high trust in the medical personnel. We believe that the high level of trust in doctors shown by our respondents should be acknowledged by the Georgian government, health care providers and public health policy professionals. Furthermore, the information should be utilized in future educational and antibiotic resistance awareness raising campaigns. PMID- 26420303 TI - Efficacy of a pressure-sensing mattress cover system for reducing interface pressure: study protocol for a randomized controlled trial. AB - BACKGROUND: Interface pressure is a key risk factor in the development of pressure ulcers. Visual feedback of continuous interface pressure between the body and support surface could inform clinicians on repositioning strategies and play a key role in an overall strategy for the prevention and management of pressure ulcers. METHODS/DESIGN: A parallel two-group randomized controlled clinical trial will be conducted to study the effect of continuous pressure imaging on reducing interface pressure and on the incidence of pressure ulcers in vulnerable hospital patients. A total of 678 eligible consenting inpatients at risk of pressure ulcer development in a tertiary acute care institution will be randomly allocated to either having the ForeSite PTTM system with the liquid crystal display monitor turned on to provide visual feedback to the clinicians while also collecting continuous interface pressure data (intervention group) or to having the ForeSite PTTM system with monitor turned off (that is, not providing visual feedback) but still collecting continuous interface pressure data (control group), in a ratio of 1:1. Continuous interface pressure data will be collected in both groups for 3 days (72 h). Data collection will continue until discharge for a subset of approximately 60 patients. The primary outcome will be the differences in the two groups' interface pressure analysis. Interface pressure readings will be collected through hourly samplings of continuous interface pressure recordings. Secondary outcomes will be the differences between the two groups in pressure-related skin and soft tissue changes in areas at risk of pressure ulcer (obtained at baseline within 24 h of admission) and on the third day of the trial or at discharge and perceptions of the intervention by patients and clinicians (obtained on the third day or at discharge). DISCUSSION: This will be the first randomized controlled trial to investigate the effect of visual feedback with continuous interface pressure of vulnerable hospital patients across different care settings, and the association between interface pressure and development of pressure-related skin and soft tissue changes. The results could provide important information to guide clinical practice in the prevention and management of pressure ulcers. TRIALS REGISTRATION: ClinicalTrials.gov NCT02325388 (date of registration: 24 December 2014). PMID- 26420305 TI - Synthesis and self-assembly of carbamoylmethylphosphonate acrylamide-based diblock copolymers: new valuable thermosensitive materials. AB - We report the synthesis by RAFT polymerization of well-defined diblock copolymers bearing carbamoylmethylphosphonate moieties which proved to sorb gadolinium. These poly(diethyl-6-(acrylamido)hexylcarbamoylmethylphosphonate-b-acrylic acid) (P(CPAAm6C-b-AA)) copolymers were able to self-assemble as a function of temperature, above their cloud point value. PMID- 26420304 TI - Metabolomics in childhood diabetes. AB - Recent increases in the incidence of both type 1 (T1D) and type 2 diabetes (T2D) in children and adolescents point to the importance of environmental factors in the development of these diseases. Metabolomic analysis explores the integrated response of the organism to environmental changes. Metabolic profiling can identify biomarkers that are predictive of disease incidence and development, potentially providing insight into disease pathogenesis. This review provides an overview of the role of metabolomic analysis in diabetes research and summarizes recent research relating to the development of T1D and T2D in children. PMID- 26420306 TI - Antibacterial Mechanism of (-)-Nortrachelogenin in Escherichia coli O157. AB - (-)-Nortrachelogenin is a lignan belonging to group of polyphenolic compounds. Its biological properties in mammalian cells are well-studied; however, its biological effects in microorganisms remain poorly understood. Its efficacy against pathogenic bacteria, including antibiotic-resistant strains, was investigated and it was found that bacteria are highly susceptible to the antibacterial effects of this compound. To investigate the antibacterial mode of action(s) against Escherichia coli O157, its effect on the penetration of SYTOX green into bacterial cells was assayed. The penetration of SYTOX Green into a bacterial cell is a measure of permeability of the plasma membrane. An increase in fluorescence intensity using bis-(1,3-dibutylbarbituric acid) trimethine oxonol [DiBAC4(3)] and 3,3'-dipropylthiacarbocyanine iodide [DiSC3(5)] was also observed, indicating membrane depolarization. Potassium ion efflux from the cytosol into the extracellular matrix showed that cellular damage due to (-) nortrachelogenin treatment resulted in the loss of intracellular components. While cells were damaged by (-)-nortrachelogenin, large unilamellar vesicles containing fluorescein isothiocyanate-dextran were perturbed to migrate molecules between 3.3 and 4.8 nm. The release of calcein from giant unilamellar vesicles, occurring as a result of disruption in artificial membranes, was visualized. Taken together, our results indicate that (-)-nortrachelogenin exerts its antibacterial effect by disorganizing and perturbing the cytoplasmic membrane, demonstrating the potential of this compound as a candidate for antibiotic drug development. PMID- 26420309 TI - Pharmacist independent prescribing in critical care: results of a national questionnaire to establish the 2014 UK position. AB - OBJECTIVES: Clinical pharmacist practice is well established in the safe and effective use of medicines in the critically ill patient. In the UK, independent pharmacist prescribers are generally recognised as a valuable and desirable resource. However, currently, there are only anecdotal reports of pharmacist independent prescribing in critical care. The aim of this questionnaire was to determine the current and proposed future independent prescribing practice of UK clinical pharmacists working in adult critical care. METHODS: The questionnaire was distributed electronically to UK Clinical Pharmacy Association members (closed August 2014). KEY FINDINGS: There were 134 responses to the questionnaire (response rate at least 33%). Over a third of critical care pharmacists were practising independent prescribers in the specialty, and 70% intended to be prescribers within the next 3 years. Pharmacists with >=5 years critical care experience (P < 0.001) or worked in a team (P = 0.005) were more likely to be practising independent prescribers. Pharmacists reported significant positives to the use of independent prescribing in critical care both in patient care and job satisfaction. Independently, prescribing was routine in: dose adjustment for multi-organ failure, change in route or formulation, correction prescribing errors, therapeutic drug monitoring and chronic medication. The majority of pharmacist prescribers reported they spent <=5% of their clinical time prescribing and accounted for <=5% of new prescriptions in critical care patients. CONCLUSIONS: Most critical care pharmacists intend to be practising as independent prescribers within the next 3 years. The extent and scope of critical care pharmacist prescribing appear to be of relatively low volume and within niche prescribing areas. PMID- 26420310 TI - Hexaphenylbenzene-Stabilized Luminescent Silver Nanoclusters: A Potential Catalytic System for the Cycloaddition of Terminal Alkynes with Isocyanides. AB - A hexaphenylbenzene (HPB)-based derivative bearing thiol groups has been designed and synthesized that undergoes aggregation-induced emission enhancement in mixed aqueous media to form rodlike fluorescent aggregates. These rodlike aggregates behave as a "not quenched" probe for the detection of silver ions and further act as reactors and stabilizers for reducing-agent-free preparation of blue luminescent silver nanoclusters at room temperature. The utilization of fluorescent supramolecular aggregates for the preparation of Ag NCs in mixed aqueous media is unprecedented in the literature. Moreover, the wet chemical method that we are reporting in the present paper for the preparation of luminescent silver nanoclusters is better than the other methods reported in the literature. Further, these in situ generated Ag NCs showed exceptional catalytic activity in the preparation of pyrroles involving cocyclization of isocyanides and terminal alkynes. Interestingly, the catalytic efficiency of in situ generated Ag NCs was found to be better than the other catalytic systems reported in the literature. PMID- 26420308 TI - Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite's food vacuole and alter drug sensitivities. AB - Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, are the major determinant of chloroquine resistance in this lethal human malaria parasite. Here, we describe P. falciparum lines subjected to selection by amantadine or blasticidin that carry PfCRT mutations (C101F or L272F), causing the development of enlarged food vacuoles. These parasites also have increased sensitivity to chloroquine and some other quinoline antimalarials, but exhibit no or minimal change in sensitivity to artemisinins, when compared with parental strains. A transgenic parasite line expressing the L272F variant of PfCRT confirmed this increased chloroquine sensitivity and enlarged food vacuole phenotype. Furthermore, the introduction of the C101F or L272F mutation into a chloroquine-resistant variant of PfCRT reduced the ability of this protein to transport chloroquine by approximately 93 and 82%, respectively, when expressed in Xenopus oocytes. These data provide, at least in part, a mechanistic explanation for the increased sensitivity of the mutant parasite lines to chloroquine. Taken together, these findings provide new insights into PfCRT function and PfCRT-mediated drug resistance, as well as the food vacuole, which is an important target of many antimalarial drugs. PMID- 26420311 TI - Proximal humerus allograft prosthetic composites: technique, outcomes, and pearls and pitfalls. AB - The proximal humerus is the second most common location of primary bone sarcomas and a frequent location of benign locally aggressive primary osseous tumors. In contrast to other locations, tumors in this region impose significant challenges for local control and reconstruction. This is due to glenohumeral joint anatomic characteristics such as lack of intrinsic stability and dependence on dynamic and static stabilizers. In addition, the close proximity of the axillary nerve and axillary vascular bundle places these at risk of resection when attaining local control. Allograft prosthetic composites (APCs) of the proximal humerus are one of the methods for mobile reconstruction. This modality presents lower fracture rates when compared to osteoarticular allografts and lower rates of subluxation and instability than endoprosthesis. Recent literature documents a trend for superior functional outcome at comparable complication rates. APC reconstruction is an important tool in the orthopedic oncologist armamentarium. PMID- 26420313 TI - [Anniversary symposium of the Israeli-German Dermatological Society]. PMID- 26420312 TI - Autoinducer-2 regulates Pseudomonas aeruginosa PAO1 biofilm formation and virulence production in a dose-dependent manner. AB - BACKGROUND: Pseudomonas aeruginosa is an opportunistic pathogen that is the leading cause of iatrogenic infections in critically ill patients, especially those undergoing mechanical ventilation. In this study, we investigated the effects of the universal signaling molecule autoinducer-2 (AI-2) in biofilm formation of P. aeruginosa PAO1. RESULTS: The addition of 0.1 nM, 1 nM, and 10 nM exogenous AI-2 to P. aeruginosa PAO1 increased biofilm formation, bacterial viability, and the production of virulence factors. However, compared to the 10 nM AI-2 group, higher concentrations of AI-2 (100 nM and 1 MUM) reduced biofilm formation, bacterial viability, and the production of virulence factors. Consistent with the changes in morphology, gene expression analysis revealed that AI-2 up-regulated the expression of quorum sensing-associated genes and genes encoding virulence factors at lower concentrations and down-regulated these genes at higher concentrations. CONCLUSIONS: Our study demonstrated that exogenous AI-2 acted in a dose-dependent manner to regulate P. aeruginosa biofilm formation and virulence factors secretion via modulating the expression of quorum sensing associated genes and may be targeted to treat P. aeruginosa biofilm infections. PMID- 26420315 TI - [Greater emphasis should be placed on exercise program of rehabilitation for patients with coronary artery disease]. PMID- 26420316 TI - [Interpretation and assessment of Joint British Societies' consensus recommendations for the prevention of cardiovascular disease (JBS3)]. PMID- 26420314 TI - An empirical comparison of the OPQoL-Brief, EQ-5D-3 L and ASCOT in a community dwelling population of older people. AB - BACKGROUND: This study examined the relationships between a newly developed older person-specific non-preference-based quality of life (QoL) instrument (Older People's Quality of Life brief questionnaire (OPQoL-brief)) and two generic preference-based instruments (the EQ-5D-3L Level (EQ-5D-3 L) and the Adult Social Care Outcomes Toolkit (ASCOT) in a community-dwelling population of Australian older people receiving aged care services. METHODS: We formulated hypotheses about the convergent validity between the instruments (examined by Wilcoxon-Mann Whitney, Kruskal Wallis and Spearman's correlation tests) and levels of agreement (assessed using intra class correlation (ICC) and modified Bland-Altman plots based on normalized Z EQ-5D-3 L and ASCOT utilities and OPQoL-Brief summary scores). RESULTS: The utilities/summary scores for 87 participants (aged 65-93 years) were moderately but positively correlated. Moderate convergent validity was evident for a number of instrument dimensions with the strongest relationship (r = 0.57) between 'enjoy life' (OPQoL-Brief) and 'social contact' (ASCOT). The overall ICC was 0.54 and Bland-Altman scatter plots showed 3-6% of normalized Z scores were outside the 95% limits of agreement suggesting moderate agreement between all three instruments (agreement highest between the OPQoL-Brief and the ASCOT). CONCLUSIONS: Our results suggest that the OPQoL-Brief, the ASCOT and the EQ-5D_3L are suitable for measuring quality of life outcomes in community dwelling populations of older people. Given the different constructs underpinning these instruments, we recommend that choice of instrument should be guided by the context in which the instruments are being applied. Currently, the OPQoL-Brief is not suitable for use in cost-utility analyses as it is not preference-based. Given their different perspectives, we recommend that both the ASCOT and the EQ 5D are applied simultaneously to capture broader aspects of quality of life and health status within cost-utility analyses within the aged care sector. Future research directed towards the development of a new single preference-based instrument that incorporates both health status and broader aspects of quality of life within quality adjusted life year calculations for older people would be beneficial. PMID- 26420317 TI - [Chinese expert consensus on exercise-based rehabilitation for patients with coronary heart disease]. PMID- 26420318 TI - [Predictors of atrial fibrillation recurrence after catheter ablation in hypertrophic cardiomyopathy patients with atrial fibrillation]. AB - OBJECTIVE: To evaluate the efficacy of catheter ablation in Chinese hypertrophic cardiomyopathy (HCM) patients with atrial fibrillation (AF), and to determine the risk factors of AF recurrence. METHODS: This study enrolled 40 HCM patients with AF who underwent primary AF ablation at Beijing Anzhen Hospital from June 2005 to June 2013. Ablation strategy included bilateral pulmonary vein isolation (PVI) for paroxysmal AF (n = 27) and PVI plus left atrial roof, mitral isthmus and tricuspid isthmus linear ablations for persistent AF (n = 13). AF recurrence was followed-up by means of electrocardiography or Holter monitoring. Risk factors associated with AF recurrence were determined by a Cox regression model and the predictive power was evaluated by receiver operating characteristic (ROC) curve. RESULTS: After (34 +/- 18) months follow-up, 30% (12/40) cases remained in sinus rhythm off antiarrhythmic drug, most AF recurrence (18/28, 64.3%) occurred within 1 year post ablation. Multivariate Cox regression demonstrated that left atrial dimension (LAD, HR = 1.124, 95% CI 1.051-1.202, P = 0.001) and female gender (HR = 3.304, 95% CI 1.397-7.817, P = 0.007) were independent risk factors of AF recurrence. The cut-off value of LAD at 43.5 mm predicted AF recurrence with sensitivity of 93.5% and specificity of 60.0%. Every 1 mm enlargement in LAD was associated with an increased risk of arrhythmia recurrence (HR = 1.095, 95% CI 1.031-1.163, P = 0.003). CONCLUSIONS: AF ablation in Chinese HCM patients is safe and feasible. However, sinus rhythm maintenance rate is low at long-time follow up. Most of the recurrent AF occurs within 1 year post AF ablation procedure. Left atrial diameter and female gender are independent risk factors of AF recurrence. PMID- 26420319 TI - [Contribution of atrial activation to the segment of the typical atrial flutter wave: an electro-anatomic insight into the electrocardiogram morphology]. AB - OBJECTIVE: To investigate how the intra-cardiac activation was translates into the characterized flutter wave in patients with cavatricuspid isthmus-dependent counter-clockwise atrial flutter (CTI-AFL). METHODS: A total of 15 hospitalized CTI-AFL patients (mean age: (60 +/- 14) years old, 1 female) from October 2012 to February 2014 were enrolled in the study. The activation map was re-constructed during AFL rhythm for left atrium and right atrium using 3-dimensional mapping system. The flutter wave in surface electrocardiogram was analyzed in combination with the intra-cardiac activation. RESULTS: The mean left ventricular ejection fraction was (60.8 +/- 6.6)%, and the left atrial diameter was (39.0 +/- 3.4) mm. The mean tachycardia cycle length was (220 +/- 24) ms. The activation map was completed in all cases. In inferior leads, the flutter wave was divided into three parts: slowly downward part, sharp downward part and the terminal positive part. The three parts corresponded to the fixed activation part of the macro reentry. CONCLUSION: The distinctive flutter wave of CTI-AFL was determined by the unique macro-reentry activation in the right atrium. The activation of left atrium contributes to the downward part of the wave. PMID- 26420320 TI - [Left ventricular systolic synchrony assessed by phase analysis of gated myocardial perfusion imaging in patients with old myocardial infarction]. AB - OBJECTIVE: To assess the left ventricular (LV) systolic synchrony by phase analysis of gated myocardial perfusion imaging (GMPI) with SPECT/CT in patients with old myocardial infarction (OMI) and further to identify independent predictors for LV dyssynchrony. METHODS: Seventy-six OMI patients and seventy four healthy volunteers (control group) underwent resting GMPI from October 2010 to September 2013 in our hospital were included in this study. The left ventricular systolic synchrony parameters including phase histogram bandwidth (BW) and phase standard deviation (SD) were obtained by Cedars-Sinai quantitative gated SPECT (QGS) phase analysis technique, and LV cardiac function was also measured. The extent of myocardial perfusion defect was analyzed by the Quantitative Perfusion SPECT (QPS) software. The value of BW and SD were compared between OMI and the control groups, between LVEF <= 35% and LVEF > 35% groups in OMI patients. Dyssynchrony was defined when the BW exceeded the abnormality threshold derived from a normal control group (threshold = x +/- 2s for normal BW). RESULTS: (1) The BW ((91.3 +/- 58.6) degrees vs. (37.2 +/- 11.7) degrees ) and SD ((27.3 +/- 20.8) degrees vs. (11.8 +/- 5.4) degrees ) were significantly higher and the LVEF was significantly lower in OMI group than in the normal control group (all P < 0.01). In addition, BW ((136.0 +/- 52.9) degrees vs. (51.0 +/- 24.0) degrees ) and SD ((38.7 +/- 21.3) degrees vs. (17.1 +/- 14.0) degrees ) were significantly higher in patients with LVEF <= 35% than in patients with LVEF > 35% (all P < 0.001). (2) Dyssynchrony (BW > 60.6 degrees ) prevalence was 57.9% (44/76) in OMI patients. Compared with the synchrony group, LVEF was significantly lower, while the left ventricular end-diastolic volume, end systolic volume, summed motion score, summed thickening score and extent were significantly higher in dyssynchrony group (all P < 0.001). (3) Additionally, dyssynchrony prevalence was significantly higher in patients with LVEF <= 35% compared with patients with LVEF > 35% (91.7% (33/36) vs. 27.5% (11/40), P < 0.001). (4) Pearson correlation analysis showed that LVEF was negatively correlated with BW (r = -0.807, P < 0.001). (5) Multivariate logistic regression analysis revealed that the extent of myocardial perfusion defect was an independent predictor for dyssynchrony in OMI patients (OR = 1.076, 95% CI: 1.015 1.141, P = 0.015). CONCLUSIONS: GMPI phase analysis can reliably reflect left ventricular systolic synchrony. The left ventricular systolic dyssynchrony in OMI patients is significantly increased. Left ventricular dyssynchrony is closely related to LVEF. The extent of myocardial perfusion defect (Extent) is an independent predictor for left ventricular systolic dyssynchrony in OMI patients. PMID- 26420321 TI - [A qualitative research on the psychological experience of hospitalized patients with acute myocardial infarction]. AB - OBJECTIVE: To observe the psychological experience of patients with acute myocardial infarction (AMI) during hospitalization. METHODS: From November 2012 to February 2013, semi-structured interviews were conducted in 10 patients with AMI in the Cardiovascular Department of First Affiliated Hospital of Henan University of Science and Technology. Grounded theory approach was performed to analyze the collected data. RESULTS: The 6 themes and 3 secondary themes during their hospitalization were: helplessness and dependence when AMI was diagnosed fear of immediate death induced by AMI, confusion on various problems such as operation time, excretory after PCI and limited knowledge details, the feel of safety after PCI, the fear of AMI, and the worry about overtreatment. CONCLUSIONS: Hospitalized AMI patients have complicated psychological responses. Medical staff should provide targeted strategies and timely communication with AMI patients to reduce their psychological burden. PMID- 26420322 TI - [Effect of ethanol and its metabolites on acetylcholine-sensitive K(+) channel Kir3.1 protein expression of neonatal rat primary atrial cardiomyocytes]. AB - OBJECTIVE: To identify the effect of ethanol and its metabolite acetaldehyde on acetylcholine-sensitive K(+) channel Kir3.1 protein expression, and explore the potential role of this channel and acetaldehyde in arrhythmia caused by acute alcoholic intoxication. METHODS: Primary atrial cardiomyocytes were isolated from 150 newborn SD rats by typsin and type II collagenase, cultured and troponin I was determined by immunofluorescence. Cell survival in 200-800 mmol/L ethanol or 50-500 umol/L acetaldehyde treated cells for 24 hours was measured by CCK-8 assay to determine the concentration of ethanol and acetaldehyde for inducing apoptosis in cardiomyocytes. The highest non-apoptotic concentration (200 mmol/L) of ethanol and acetaldehyde (100 umol/L) was used in the main study. Kir3.1 protein expression was detected by Western blot. RESULTS: (1) Cellular immunofluorescence results showed that cultured cells are cardiomyocytes, and more than 90% of these cells are troponin I positive. (2) CCK-8 assay demonstrated that the survival rate of cardiomyocytes in the groups treated by ethanol over 400 mmol/L for 24 hours or acetaldehyde over 400 umol/L was significantly lower than that of the control group (P < 0.05), while the survival rate was similar in cardiomyocytes treated by ethanol less than 200 mmol/L or acetaldehyde less than 350 umol/L for 24 hours and the control group (P > 0.05). (3) Western-bolt assay revealed that ethanol and acetaldehyde treatment for 24 hours upregulated Kir3.1 protein expression in primary atrial cardiomyocytes of newborn SD rats by (44.52 +/- 23.07)% and (45.04 +/- 22.01)% respectively compared with the control group (all P < 0.01). CONCLUSIONS: Acute ethanol and acetaldehyde treatment could significantly upregulate the protein expression of acetylcholine-sensitive K(+) channel Kir3.1, this might serve as a potential mechanism for arrhythmia caused by acute alcoholic intoxication. PMID- 26420323 TI - [Nuclear factor-kappaB pathway mediates the effects of CD137 signaling on NFATc1 expression in mice vascular smooth muscle cells]. AB - OBJECTIVE: To observe whether CD137 signaling could affect the nuclear factor of activated T cells c1 (NFATc1) expression through nuclear factor-kappaB (NF kappaB) pathway in mice aortic vascular smooth muscle cells (VSMCs). METHODS: Adherence methods for tissues explants were used for primary culture of mouse aortic VSMCs. The mRNA expression of CD137 and NFATc1 was detected by real-time quantitative PCR (RT-qPCR). The VSMCs protein expression of IkappaB-alpha, NF kappaB p65, phospo-p65 and NFATc1 was determined by Western blot. The level of CD137 was measured by Flow Cytometry (FCM). RESULTS: (1) The mRNA and protein expression of CD137 in VSMCs was significantly upregulated at 24 h after co culture with TNF-alpha (10 ng/ml, all P < 0.05). (2) Compared with the control group, the level of p-NF-kappaB p65 in cytoplasm and nucleus was significantly increased (8.34 +/- 0.28 vs. 1, P < 0.05, and 2.64 +/- 0.42 vs. 1, P < 0.05) while the level of IkappaB-alpha was reduced (1 vs. 2.70 +/- 0.28, P < 0.05) after co-treatment with agonist-CD137 mAb, above effects were partly blocked by adding specific NF-kappaB inhibitor PDTC (30 umol/L: 1.15 +/- 0.14 vs. 8.34 +/- 0.28, P < 0.05, and 2.09 +/- 0.12 vs. 2.64 +/- 0.42, P < 0.05, and 1.78 +/- 0.74 vs. 1, P < 0.05). (3) The mRNA (2.07 +/- 0.09 vs. 1, P < 0.05) and protein (1.75 +/- 0.07 vs. 1, P < 0.05) expression of NFATc1 was significantly upregulated by agonist CD137mAb compared with the control group, and these effects could be reversed by PDTC (1.15 +/- 0.07 vs. 2.07 +/- 0.09, P < 0.05, and 0.90 +/- 0.11 vs. 1.75 +/- 0.07, P < 0.05). CONCLUSION: CD137 signaling could affect the NFATc1expression in VSMCs through NF-kappaB pathway. PMID- 26420324 TI - [MicroRNA-182 modulates high glucose-induced cardiomyocyte hypertrophy via targeting Rac1]. AB - OBJECTIVE: To investigate the role and signalling of microRNA(miR)-182 on regulating high glucose-induced cardiomyocyte hypertrophy. METHODS: The candidates of miR which might potentially be involved on targeting Rac1 were predicted by applying bioinformatics analysis. The expression of all related candidates miRs was verified by real-time reverse transcription-PCR (RT-PCR) in cardiac tissues of db/db mice and db/m mice. Then the relationship between candidates miR and Rac1 was investigated with Pearson relevant analysis. Neonatal mice cardiomyocytes were cultured and divided into 2 groups: normal glucose group and high glucose group. The level of selected miR and Rac1 in two groups was detected by RT-PCR. Neonatal mice cardiomyocytes were then randomly divided into 4 groups: normal glucose group, selected microRNA mimics control group, high glucose group, high glucose plus selected miR mimics control group. The morphology of cardiomyocyte in each group was detected under light microscope. Furthermore, Rac1, beta-MHC and alpha-SMA expressions were detected in cultured cardiomyocyte treated by high glucose for 48 h after transfecting selected miR mimics by RT-PCR and Western blot. RESULTS: A total of 6 miR candidates potentially targeting Rac1 were screened by bioinformatics, which were miR-182, miR-142-3p, miR-140, miR-101a, miR-429 and miR-200b. Among these candidates, miR 182 and miR-142-3p expression was significantly downregulated in cardiac tissues of db/db mice compared with db/m controls (P < 0.05). MiR-182 was negatively correlated with Rac1 by person analysis (r = -0.891 02). Downregulation of miR 182 and upregulation of Rac1, beta-MHC, alpha-SMA were found in high glucose induced cardiomyocyte. After transfection of miR-182 mimics, hypertrophic changes were significantly reduced and Rac1 as well beta-MHC expression was significantly downregulated in cardiomyocyte incubated with high glucose. CONCLUSION: MiR-182 might be involved in the regulation of high glucose-induced myocardial hypertrophy process via targeting Rac1. PMID- 26420325 TI - [Telmisartan reduces retina vessel endothelial cell apoptosis via upregulating retinal ACE2-Ang-(1-7)-Mas axis in spontaneous hypertensive rats]. AB - OBJECTIVE: To investigate the effects of angiotensin II (Ang II) antagonist telmisartan on retina vessel endothelial cell apoptosis and its impact on the ACE2-Ang-(1-7)-Mas axis in spontaneous hypertensive rats (SHR). METHODS: Thirty six SHR 16 week-old were randomly divided into 3 groups (n = 12 each): SHR, SHRT (telmisartan 10 mg . kg-1 . d-1 by gastric gavage) and SHRTA group (telmisartan 10 mg . kg-1 . d-1 by gastric gavage plus intravenous injection of A-779 0.5 mg . kg-1 . d-1), twelve WKY rats served as normotensive control group. Systolic blood pressure was measured at pre-treatment and 8 weeks later. After 8 weeks, rats were sacrificed, the expression of ACE2 and Mas in retina were analyzed by qRT PCR, Western blot and Immunohistochemistry, the Ang-(1-7) concentration in serum was measured by ELISA. Specimens were obtained and stained by hematoxylin and eosin, and the morphology of retina vessel was observed. Apoptosis of vessel endothelial cells were determined by using terminal deoxynucleotidyl transferase mediated dUTP nick end labeling method. RESULTS: The systolic blood pressure of SHR, SHRT and SHRTA groups at baseline were significantly higher than age-matched WKY group (all P < 0.01). Eight weeks later, the systolic blood pressure group was significantly lower in SHRT group than in the SHR group (P < 0.01), this effect was partly reversed in SHRTA group. The retinal ACE2 mRNA and protein expression was significantly lower in SHR group than in WKY and SHRT groups (P < 0.01), which was similar between SHRT group and SHRTA group (P > 0.05). The retinal Mas mRNA and protein expression were significantly lower in SHR group compared to WKY and SHRT groups (all P < 0.01), which was significantly lower in SHRTA group than in the SHRT group (P < 0.05). ELISA results showed that serum Ang-(1-7) protein level was significantly lower in SHR group than in WKY group and SHRT group (both P < 0.05), which was lower in SHRTA group compared to SHRT group. Retinal vessel endothelial cell apoptosis was higher in SHR group than in WKY group, which could be reduced by cotreatment with telmisartan and this beneficial effect could be reversed by A-779. CONCLUSION: Telmisartan can reduce retinal vessel endothelial cell apoptosis via upregulating the ACE2-Ang-(1-7)-Mas axis. PMID- 26420326 TI - [A case of transcatheter closure of inferior vena cava type atrial septal defect with patent ductus arteriosus occlusion device guided by 3D printing technology]. PMID- 26420328 TI - [Simultaneous transcatheter closure of right coronary artery fistula and percutaneous coronary intervention of left coronary artery disease: a case report]. PMID- 26420327 TI - [Prior transcatheter aortic valve implantation evaluation with 3D printing technology: a case report]. PMID- 26420329 TI - [Natural evolution of pericardial cyst in a 32-year-old male patient]. PMID- 26420330 TI - [Progress on transcatheter aortic valve implantation strategy for severe aortic regurgitation]. PMID- 26420331 TI - [Value of fractional flow reserve measurements in patients with coronary artery bifurcation lesions underwent percutaneous coronary intervention]. PMID- 26420332 TI - [Research advances on the therapeutic role of ezetimibe in atherosclerotic cardiovascular diseases]. PMID- 26420333 TI - Clinical course and complications following diagnostic bronchoalveolar lavage in critically ill mechanically ventilated patients. AB - BACKGROUND: Flexible, fibreoptic bronchoscopy (FFB) and bronchoalveolar lavage (BAL) have been used for diagnostic purposes in critically ill ventilated patients. The additional diagnostic value compared to tracheal aspirations in ventilator-associated pneumonia (VAP) has been questioned. Nevertheless, BAL can provide extra information for the differential diagnosis of respiratory disease and good antibiotic stewardship. These benefits should outweigh potential hazards caused by the invasiveness of this diagnostic technique. The focus of the present study was on the clinical course and complications of patients following BAL procedures up to 24 h. METHODS: Hundred sixty-four FFB guided BAL procedures for suspected pneumonia were analysed in an observational study. The clinical course of patients was monitored by respiratory and haemodynamic data before BAL, 1 and 24 h after BAL. Complications were defined and registered. Factors associated with complications were analysed by logistic regression. RESULTS: CLINICAL COURSE: a decrease in average pO2/FiO2 ratio 1 h after BAL from 29 kPa (218 mmHg) to 25 kPa (189 mmHg) (p < 0.05) was observed which fully recovered within 24 h. Respiratory complications: the incidence of procedure related hypo-oxygenation (SaO2 <= 88 %) and/or bronchospasm was 9 %; a decrease of >25 % PaO2/FiO2 ratio 1 h after BAL was found in 29 % of patients; no bleeding or pneumothorax were registered. Haemodynamic complications: there were no cases of hypertension and cardiac rhythm disturbances; haemodynamic instability within the first 24 h after BAL was recorded in 22 %; this was correlated with a cardiovascular diagnosis at admission (OR 2.9; 95 % CI 1.2 - 6.7) and the presence of cardiovascular co morbidity (OR 3.5; 95 % CI 1.5 - 8.3). The incidence of bacteraemia was 7 %. There was no case of procedure related death. DISCUSSION: Frequently occurring haemodynamic and respiratory instability but no cases of cardiac rhythm disturbances, bleeding, pneumothorax or procedure related death were attributable to diagnostic FFB and BAL. The procedures should be conducted under careful supervision by experienced physicians. Only a randomized controlled trial that compares diagnostic FFB and BAL with a non-invasive strategy could ultimately establish the safety profile and clinical utility of these procedures in critically ill ventilated patients. PMID- 26420334 TI - Randomised controlled trial of the effect of long-term selenium supplementation on plasma cholesterol in an elderly Danish population. AB - Although cross-sectional studies have shown a positive association between Se and cholesterol concentrations, a recent randomised controlled trial in 501 elderly UK individuals of relatively low-Se status found that Se supplementation for 6 months lowered total plasma cholesterol. The Danish PRECISE (PREvention of Cancer by Intervention with Selenium) pilot study (ClinicalTrials.gov ID: NCT01819649) was a 5-year randomised, double-blinded, placebo-controlled trial with four groups (allocation ratio 1:1:1:1). Men and women aged 60-74 years (n 491) were randomised to 100 (n 124), 200 (n 122) or 300 (n 119) MUg Se-enriched yeast or matching placebo-yeast tablets (n 126) daily for 5 years. A total of 468 participants continued the study for 6 months and 361 participants, equally distributed across treatment groups, continued for 5 years. Plasma samples were analysed for total and HDL-cholesterol and for total Se concentrations at baseline, 6 months and 5 years. The effect of different doses of Se supplementation on plasma lipid and Se concentrations was estimated by using linear mixed models. Plasma Se concentration increased significantly and dose dependently in the intervention groups after 6 months and 5 years. Total cholesterol decreased significantly both in the intervention groups and in the placebo group after 6 months and 5 years, with small and nonsignificant differences in changes in plasma concentration of total cholesterol, HDL cholesterol, non-HDL-cholesterol and total:HDL-cholesterol ratio between intervention and placebo groups. The effect of long-term supplementation with Se on plasma cholesterol concentrations or its sub-fractions did not differ significantly from placebo in this elderly population. PMID- 26420337 TI - Rapid quantitative analysis of adulterant Lonicera species in preparations of Lonicerae Japonicae Flos. AB - Lonicerae Japonicae Flos is often adulterated with Lonicerae Flos, which is derived from the other four Lonicera species, in both the crude drug and Lonicerae Japonicae Flos preparations. We proposed a methodology for the quantitative analysis of adulterant Lonicerae Flos in Lonicerae Japonicae Flos preparations. Taking macranthoidins A, B, dipsacoside B (saponins), sweroside (iridoids), and luteolin-7-O-d-glucoside (flavonoids) as markers, a method of ultra high performance liquid chromatography with triple quadrupole mass spectrometry was employed to determine their amounts in Lonicerae Flos, Lonicerae Japonicae Flos, and Lonicerae Japonicae Flos preparations. The proportion of adulterant Lonicerae Flos in Lonicerae Japonicae Flos preparations was estimated based on the saponin contents of Lonicerae Japonicae Flos and Lonicerae Flos. All analytes separated under isocratic elution in 12 min with acceptable linearity, precision, repeatability, and accuracy. Lonicerae Japonicae Flos was easily distinguished from Lonicerae Flos by the total amount of saponins (0.067 and > 45.8 mg/g for Lonicerae Japonicae Flos and Lonicerae Flos, respectively). Eighteen of twenty one Lonicerae Japonicae Flos preparation samples were adulterated with Lonicerae Flos in proportions of 11.3-100%. The developed ultra high performance liquid chromatography with triple quadrupole mass spectrometry method could be used for the identification of Lonicerae Japonicae Flos and the four species of Lonicerae Flos and for the analysis of Lonicerae Japonicae Flos preparations adulterated with Lonicerae Flos. PMID- 26420336 TI - Next Generation of SiFAlin-Based TATE Derivatives for PET Imaging of SSTR Positive Tumors: Influence of Molecular Design on In Vitro SSTR Binding and In Vivo Pharmacokinetics. AB - The Silicon-Fluoride-Acceptor (SiFA)-(18)F-labeling strategy has been shown before to enable the straightforward and efficient (18)F-labeling of complex biologically active substances such as proteins and peptides. Especially in the case of peptides, the radiolabeling proceeds kit-like in short reaction times and without the need of complex product workup. SiFA-derivatized, (18)F-labeled Tyr(3)-octreotate (TATE) derivatives demonstrated, besides strong somatostatin receptor (SSTR) binding, favorable in vivo pharmacokinetics as well as excellent tumor visualization by PET imaging. In this study, we intended to determine the influence of the underlying molecular design and used molecular scaffolds of SiFAlin-TATE derivatives on SSTR binding as well as on the in vivo pharmacokinetics of the resulting (18)F-labeled peptides. For this purpose, new SiFAlin-(Asp)n-PEG1-TATE analogs (where n = 1-4) were synthesized, efficiently radiolabeled with (18)F in a kit-like manner and obtained in radiochemical yields of 70-80%, radiochemical purities of >=97%, and nonoptimized specific activities of 20.1-45.2 GBq/MUmol within 20-25 min starting from 0.7-1.5 GBq of (18)F. In the following, the radiotracer's lipophilicities and stabilities in human serum were determined. Furthermore, the SSTR-specific binding affinities were evaluated by a competitive displacement assay on SSTR-positive AR42J cells. The obtained in vitro results support the assumption that aspartic acids are able to considerably increase the radiotracer's hydrophilicity and that their number does not affect the SSTR binding potential of the TATE derivatives. The most promising tracer (18)F-SiFAlin-Asp3-PEG1-TATE [(18)F]6 (LogD = -1.23 +/- 0.03, IC50 = 20.7 +/- 2.5 nM) was further evaluated in vivo in AR42J tumor-bearing nude mice via PET/CT imaging against the clinical gold standard (68)Ga-DOTATATE as well as the previously developed SiFAlin-TATE derivative [(18)F]3. The results of these evaluations showed that [(18)F]6-although showing very similar chemical and in vitro properties to [(18)F]3-exhibits not only a slowed renal clearance compared to [(18)F]3, but also a higher absolute tumor uptake compared to (68)Ga-DOTATATE, and furthermore enables excellent tumor visualization with high image resolution. These results emphasize the importance of systematic study of the influence of molecular design and applied structure elements of peptidic radiotracers, as these may considerably influence in vivo pharmacokinetics while not affecting other parameters such as radiochemistry, lipophilicity, serum stability, or receptor binding potential. PMID- 26420335 TI - A pain-inducing centipede toxin targets the heat activation machinery of nociceptor TRPV1. AB - The capsaicin receptor TRPV1 ion channel is a polymodal nociceptor that responds to heat with exquisite sensitivity through an unknown mechanism. Here we report the identification of a novel toxin, RhTx, from the venom of the Chinese red headed centipede that potently activates TRPV1 to produce excruciating pain. RhTx is a 27-amino-acid small peptide that forms a compact polarized molecule with very rapid binding kinetics and high affinity for TRPV1. We show that RhTx targets the channel's heat activation machinery to cause powerful heat activation at body temperature. The RhTx-TRPV1 interaction is mediated by the toxin's highly charged C terminus, which associates tightly to the charge-rich outer pore region of the channel where it can directly interact with the pore helix and turret. These findings demonstrate that RhTx binding to the outer pore can induce TRPV1 heat activation, therefore providing crucial new structural information on the heat activation machinery. PMID- 26420339 TI - Infant Feeding Websites and Apps: A Systematic Assessment of Quality and Content. AB - BACKGROUND: Internet websites and smartphone apps have become a popular resource to guide parents in their children's feeding and nutrition. Given the diverse range of websites and apps on infant feeding, the quality of information in these resources should be assessed to identify whether consumers have access to credible and reliable information. OBJECTIVE: This systematic analysis provides perspectives on the information available about infant feeding on websites and smartphone apps. METHODS: A systematic analysis was conducted to assess the quality, comprehensibility, suitability, and readability of websites and apps on infant feeding using a developed tool. Google and Bing were used to search for websites from Australia, while the App Store for iOS and Google Play for Android were used to search for apps. Specified key words including baby feeding, breast feeding, formula feeding and introducing solids were used to assess websites and apps addressing feeding advice. Criteria for assessing the accuracy of the content were developed using the Australian Infant Feeding Guidelines. RESULTS: A total of 600 websites and 2884 apps were screened, and 44 websites and 46 apps met the selection criteria and were analyzed. Most of the websites (26/44) and apps (43/46) were noncommercial, some websites (10/44) and 1 app were commercial and there were 8 government websites; 2 apps had university endorsement. The majority of the websites and apps were rated poor quality. There were two websites that had 100% coverage of information compared to those rated as fair or poor that had low coverage. Two-thirds of the websites (65%) and almost half of the apps (47%) had a readability level above the 8th grade level. CONCLUSIONS: The findings of this unique analysis highlight the potential for website and app developers to merge user requirements with evidence-based content to ensure that information on infant feeding is of high quality. There are currently no apps available to consumers that address a variety of infant feeding topics. To keep up with the rapid turnover of the evolving technology, health professionals need to consider developing an app that will provide consumers with a credible and reliable source of information about infant feeding, using quality assessment tools and evidence-based content. PMID- 26420343 TI - Electric control of topological phase transitions in Dirac semimetal thin films. AB - Dirac semimetals host three-dimensional (3D) Dirac fermion states in the bulk of crystalline solids, which can be viewed as 3D analogs of graphene. Owing to their relativistic spectrum and unique topological character, these materials hold great promise for fundamental-physics exploration and practical applications. Particularly, they are expected to be ideal parent compounds for engineering various other topological states of matter. In this report, we investigate the possibility to induce and control the topological quantum spin Hall phase in a Dirac semimetal thin film by using a vertical electric field. We show that through the interplay between the quantum confinement effect and the field induced coupling between sub-bands, the sub-band gap can be tuned and inverted. During this process, the system undergoes a topological phase transition between a trivial band insulator and a quantum spin Hall insulator. Consequently, one can switch the topological edge channels on and off by purely electrical means, making the system a promising platform for constructing topological field effect transistors. PMID- 26420338 TI - Emerging platforms using liquid biopsy to detect EGFR mutations in lung cancer. AB - Advances in target therapies for lung cancer have enabled detection of gene mutations, specifically those of EGFR. Assays largely depend on the acquisition of tumor tissue biopsy, which is invasive and may not reflect the genomic profile of the tumor at treatment due to tumor heterogeneity or changes that occur during treatment through acquired resistance. Liquid biopsy, a blood test that detects evidence of cancer cells or tumor DNA, has generated considerable interest for its ability to detect EGFR mutations. However, its clinical application is limited by complicated collection methods and the need for technique-dependent platforms. Recently, simpler techniques for EGFR mutant detection in urine or saliva samples have been developed. This review focuses on advances in liquid biopsy and discusses its potential for clinical implementation in lung cancer. PMID- 26420344 TI - Two new ent-kaurane-type diterpene glycosides from zucchini (Cucurbita pepo L.) seeds. AB - Two new ent-kaurane diterpene glycosides; 12alpha-(beta-d-glucopyranosyloxy) 7beta-hydroxykaurenolide (1) and 7beta-(beta-d-glucopyranosyloxy)-12alpha hydroxykaurenolide (2), a new steroid; (24S)-stigmasta-7,22E,25-trien-3-one (12), and known compounds (3-11, 13-14) were isolated from zucchini (Cucurbita pepo L.) seeds. The absolute structures of 1 and 2 were determined by acid hydrolysis and application of a modified Moscher's method. Furthermore, isolated compounds (1 14), and a derivative, 1a, were evaluated for their inhibitory effects on macrophage activation by an inhibitory assay of nitric oxide (NO) production. PMID- 26420345 TI - A 3-year follow-up after anterior colporrhaphy compared with collagen-coated transvaginal mesh for anterior vaginal wall prolapse: a randomised controlled trial. AB - OBJECTIVE: To compare the 1-year (previously published) and 3-year objective and subjective cure rates, and complications, related to the use of a collagen-coated transvaginal mesh for anterior vaginal wall prolapse against a conventional anterior repair. DESIGN: Randomised controlled study. SETTING: Six departments of obstetrics and gynaecology in Norway, Sweden, Finland, and Denmark. POPULATION: A total of 138 women, of 55 years of age or older, admitted for stage >=2 anterior vaginal wall prolapse. METHODS: The women scheduled for primary anterior vaginal wall prolapse surgery were randomised between conventional anterior colporrhaphy and surgery with a collagen-coated prolene mesh. All patients were evaluated using the Pelvic Organ Prolapse Quantification (POP-Q) assessment before and after surgery. Symptoms related to pelvic organ prolapse were evaluated using the Pelvic Floor Impact Questionnaire (PFIQ-7) and the Pelvic Floor Distress Inventory (PFDI-20). MAIN OUTCOME MEASURES: Objective cure, defined as POP-Q stage <2 prolapse at the 1- and 3-year follow-ups. Furthermore, mesh exposure and dyspareunia were also recorded. RESULTS: In total, 138 patients (70 from the mesh group versus 68 from the conventional anterior colporrhaphy group) out of 160 (86.3%) participated in the 3-year follow-up. POP-Q revealed an objective anatomic cure for 88.1 and 91.4%, respectively, in the mesh group at the 1- and 3 year follow-ups, compared with 39.9 and 41.2% in the colporrhaphy group. No difference between the groups was observed regarding PFIQ-7, PFDI-20, and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12) scores. The number of mesh exposures did not change during the study period and all exposures were minor. CONCLUSION: Our study demonstrates that although the objective outcome was superior in the mesh group, the use of mesh had no impact on the subjective outcome. TWEETABLE ABSTRACT: POP-Q deteriorates after anterior prolapse surgery but remains stable in women with mesh implantation. PMID- 26420346 TI - Twenty-One Novel EGFR Kinase Domain variants in Patients with Nonsmall Cell Lung Cancer. AB - Somatic sequence variants in the epidermal growth factor receptor (EGFR) kinase domain are associated with sensitivity to tyrosine kinase inhibitors (TKIs) in patients with nonsmall cell lung cancer (NSCLC). Patients exhibiting sequence variants in this domain that produce kinase activity enhancement, are more likely to benefit from TKIs than patients with EGFR wild-type disease. Although most NSCLC EGFR-related alleles are concentrated in a few positions, established protocols recommend sequencing EGFR exons 18-21. In this study, 21 novel somatic variants belonging to such exons in adult Argentinean patients affected with NSCLC are reported. Of these, 18 were single amino acid substitutions (SASs), occurring alone or in combination with another genetic alteration (complex cases), one was a short deletion, one was a short deletion-short insertion combination, and one was a duplication. New variants and different combinations of previously reported variants were also found. Moreover, two of the reported SASs occurred in previously unreported positions of the EGFR kinase domain. In order to characterize the new sequence variants, physicochemical, sequence and conformational analyses were also performed. A better understanding of sequence variants in NSCLC may facilitate the most appropriate treatment choice for this complex disease. PMID- 26420347 TI - Transfer of Copper from an Amyloid to a Natural Copper-Carrier Peptide with a Specific Mediating Ligand. AB - The oxidative stress that arises from the catalytic reduction of dioxygen by Cu(II/I)-loaded amyloids is the major pathway for neuron death that occurs in Alzheimer's disease. In this work, we show that bis-8(aminoquinoline) ligands, copper(II) specific chelators, are able to catalytically extract Cu(II) from Cu Abeta1-16 and then completely release Cu(I) in the presence of glutathione to provide a Cu(I)-glutathione complex, a biological intermediate that is able to deliver copper to apo forms of copper-protein complexes. These data demonstrate that bis-8(aminoquinolines) can perform the transfer of copper ions from the pathological Cu-amyloid complexes to regular copper-protein complexes. These copper-specific ligands assist GSH to recycle Cu(I) in an AD brain and consequently slow down oxidative damage that is due to copper dysregulation in Alzheimer's disease. Under the same conditions, we have shown that the copper complex of PBT2, a mono(8-hydroxyquinoline) previously used as a drug candidate, does not efficiently release copper in the presence of GSH. In addition, we report that GSH itself was unable to fully abstract copper ions from Cu-beta amyloid complexes. PMID- 26420348 TI - The pattern of CD44 and matrix metalloproteinase 9 expression is a useful predictor of ulcerative colitis-associated dysplasia and neoplasia. AB - Ulcerative colitis (UC)-associated neoplasia presumably evolves through a chronic inflammation-dysplasia-adenocarcinoma sequence in which a corporation of several factors takes place. The grade of dysplasia is important in further development of colorectal cancer. CD44 is a cell adhesion molecule and acts as a docking receptor for matrix metalloproteinase 9 (MMP-9). The aims of this study are to assess UC-associated dysplasia and to distinguish regenerative changes from premalignant ones through detecting pattern of CD44 and MMP-9 expression in different UC lesions. Fifty-four samples of UC and UC-associated carcinoma were collected and examined for the immunohistochemical expression of CD44 and MMP-9 in the colon mucosa. Correlation between their expression and the severity of dysplasia were also statistically analyzed. Homogenous membranous staining pattern of CD44 was detected in all cases of regenerative atypia (negative for dysplasia) and most of indefinite for dysplasia (IND) cases, whereas most dysplastic (low-grade and high-grade dysplasia) cases showed irregular staining pattern. CD44 expression pattern was significantly correlated with grade of dysplasia in UC (P = .0001); on the other hand, MMP-9 expression was significantly increased in the dysplastic and neoplastic cases than in nondysplastic cases (regenerative atypia and IND) (P = .0001). Significant correlation was found between irregular CD44 staining pattern and MMP-9 expression (P = .0001). Irregular staining pattern of CD44 together with increased MMP-9 expression in UC-associated dysplasia predicts advanced disease and aids in the differentiation of regenerative atypia from UC-associated dysplasia as well as grading of IND cases. PMID- 26420349 TI - Use of ultrasmall superparamagnetic iron oxide particles for imaging carotid atherosclerosis. AB - Based on the results of histopathological studies, inflammation within atherosclerotic tissue is now widely accepted as a key determinant of the disease process. Conventional imaging methods can highlight the location and degree of luminal stenosis but not the inflammatory activity of the plaque. Iron oxide based MRI contrast media particularly ultrasmall supermagnetic particles of iron oxide have shown potential in assessing atheromatous plaque inflammation and in determining efficacy of antiatherosclerosis pharmacological treatments. In this paper, we review current data on the use of ultrasmall superparamagnetic iron oxides in atherosclerosis imaging with focus on ferumoxtran-10 and ferumoxytol. The basic chemistry, pharmacokinetics and dynamics, potential applications, limitations and future perspectives of these contrast media nanoparticles are discussed. PMID- 26420350 TI - Effect of the type of silage on milk yield, intake and rumen metabolism of dairy cows grazing swards with low herbage mass. AB - The aim of this study was to evaluate the effect of herbage allowance (HA) and type of silage supplemented (TS) on milk yield, dry matter intake (DMI) and metabolism of dairy cows in early lactation. Thirty-six Holstein-Friesian dairy cows were allocated to four treatments derived from an arrangement of two HA (LHA = 17 or HHA = 25 kg of DM/cow/day) and two TS (grass (GS) or maize (MS)). Herbage allowance had no effect on DMI or milk yield. Rumen pH and NH3 -N concentration were not affected by HA. The efficiency of microbial protein synthesis in the rumen (microbial protein (MP)) was affected by HA with 21.5 and 23.9 g microbial nitrogen per kg ruminal digestible organic matter for LHA and HHA, respectively (P < 0.05). Supplementation with MS showed higher values of milk yield by 2.4 kg/cow/day (P < 0.001), milk protein content by 0.10 % (P < 0.023) and herbage DMI by 2.2 kg/cow/day, and showed lower values for milk urea compared to GS (P < 0.001). The former results suggest that TS had a greater effect on milk yield, total feed intake and energy intake than increase in herbage allowance; however, increase in HA had greater effects on MP than TS. PMID- 26420351 TI - Effects of a feeding intervention in patients with Alzheimer's disease and dysphagia. AB - AIMS AND OBJECTIVES: This study aimed to investigate the effects of a feeding intervention in patients with Alzheimer's disease with dysphagia. BACKGROUND: In patients with Alzheimer's disease, inadequate food and fluid intake can result in malnutrition, dehydration and increased morbidity and mortality. Patients may lose self-care abilities such as self-feeding. DESIGN: A prospective cohort study. METHODS: A three-month self-control feeding intervention was conducted prospectively in 30 nursing home residents with Alzheimer's disease with dysphagia. Pre- and post-intervention measures included the Kubota water swallow test, type and amount of food intake and assessment of nutritional status by triceps skinfold thickness, upper arm circumference, serum albumin and haemoglobin. We used the Edinburgh Feeding Evaluation in Dementia scale to evaluate eating compliance and the Mini- Mental State Examination to evaluate cognitive function. Pre- and post-intervention results were compared to evaluate the effects of nursing intervention. RESULTS: Patients' eating/feeding abilities improved overall, including significantly increased food intake (p < 0.001), decreased levels on the Kubota water swallow test (p < 0.001) and significant differences in skinfold thickness, arm circumference, serum albumin and haemoglobin (all p < 0.01), indicating improved nutritional status. Edinburgh Feeding Evaluation in Dementia scale scores decreased significantly, showing improved eating compliance. No changes were noted in cognition post-intervention. Among 22 patients who initially required feeding, five patients resumed self feeding after the intervention (p = 0.06). CONCLUSIONS: Results of this study show that a feeding intervention can improve food intake, eating compliance and nutritional status in patients with Alzheimer's disease with dysphagia and prevent further decline in swallowing function. RELEVANCE TO CLINICAL PRACTICE: The significant improvement in eating/feeding measures suggest that this feeding intervention model could be developed as a feeding skills programme to improve both the eating/feeding care by nursing staff and the eating/feeding abilities and nutritional status of Alzheimer's disease patients. PMID- 26420352 TI - Mothers' group participation: associations with social capital, social support and mental well-being. AB - AIM: To investigate the relationships between participation in mothers' groups and social capital, social support and mental well-being measures for mothers whose oldest child was 0-5 years. BACKGROUND: Evaluations of facilitated mothers' groups have found positive benefits for information sharing and support. Mothers' groups often continue as parent-led groups; however, little is known about the potential benefits of ongoing participation compared with non-participation. DESIGN: Cross-sectional survey. METHODS: Data were collected through a survey from March 2013-January 2014 in Perth, Western Australia. The data from a subgroup of mothers (N = 313) whose oldest child was 0-5 years of age were analysed using multivariable regression. Participation in mothers' groups in the previous 12 months was investigated for associations with social capital {Neighbourhood Cohesion Index (NCI); Families, Social Capital and Citizenship Survey (FSCCS) and Reciprocity}; social support {Medical Outcomes Study-Social Support Survey (MOS-SSS) and Parent Support Outside Home Scale (PSOHS)}; and mental well-being {Warwick Edinburgh Mental Well-Being Scale (WEMWBS)}. Participation was measured as three groups - locally, outside area of residence and non-participation. RESULTS: Mothers who participated in mothers' groups locally scored significantly higher than those who had not participated in mothers' group for 'social capital' (NCI, FSCCS, Reciprocity), 'social support' (MOS-SSS, PSOHS) and 'mental well-being' (WEMWBS). Mothers who participated in mothers' group outside the area scored significantly higher than those who had not participated in mothers' groups for one measure of 'social support' (PSOHS). CONCLUSIONS: Participation in mothers' group locally may provide support and social capital benefits for mothers of children aged 0-5 years, which may influence mental well-being. PMID- 26420353 TI - Histone Acetyltransferase GCN5 Regulates Osteogenic Differentiation of Mesenchymal Stem Cells by Inhibiting NF-kappaB. AB - As the most well-studied histone acetyltransferase (HAT) in yeast and mammals, general control nonderepressible 5 (GCN5) was documented to play essential roles in various developmental processes. However, little is known about its role in osteogenic differentiation of mesenchymal stem cells (MSCs). Here, we detected the critical function of GCN5 in osteogenic commitment of MSCs. In this role, the HAT activity of GCN5 was not required. Mechanistically, GCN5 repressed nuclear factor kappa B (NF-kappaB)-dependent transcription and inhibited the NF-kappaB signaling pathway. The impaired osteogenic differentiation by GCN5 knockdown was blocked by inhibition of NF-kappaB. Most importantly, the expression of GCN5 was decreased significantly in the bone tissue sections of ovariectomized mice or aged mice. Collectively, these results may point to the GCN5-NF-kappaB pathway as a novel potential molecular target for stem cell mediated regenerative medicine and the treatment of metabolic bone diseases such as osteoporosis. PMID- 26420354 TI - Deficiency in apolipoprotein A-I ablates the pharmacological effects of metformin on plasma glucose homeostasis and hepatic lipid deposition. AB - Recently, we showed that deficiency in apolipoprotein A-I (ApoA-I) sensitizes mice to diet-induced obesity, glucose intolerance and NAFLD. Here we investigated the potential involvement of ApoA-I in the pharmacological effects of metformin on glucose intolerance and NAFLD development. Groups of apoa1-deficient (apoa1(-/ )) and C57BL/6 mice fed western-type diet were either treated with a daily dose of 300 mg/kg metformin for 18 weeks or left untreated for the same period. Then, histological and biochemical analyses were performed. Metformin treatment led to a comparable reduction in plasma insulin levels in both C57BL/6 and apoa1(-/-) mice following intraperitoneal glucose tolerance test. However, only metformin treated C57BL/6 mice maintained sufficient peripheral insulin sensitivity to effectively clear glucose following the challenge, as indicated by a [(3)H]-2 deoxy-D-glucose uptake assay in isolated soleus muscle. Similarly, deficiency in ApoA-I ablated the effect of metformin on hepatic lipid deposition and NAFLD development. Gene expression analysis indicated that the effects of ApoA-I on metformin treatment may be independent of adenosine monophosphate-activated protein kinase (AMPK) activation and de novo lipogenesis. Interestingly, metformin treatment reduced mitochondrial oxidative phosphorylation function only in apoa1(-/-) mice. Our data show that the role of ApoA-I in diabetes extends to the modulation of the pharmacological actions of metformin, a common drug for the treatment of type 2 diabetes. PMID- 26420355 TI - Impaired endothelial calcium signaling is responsible for the defective dilation of mesenteric resistance arteries from db/db mice to acetylcholine. AB - We aimed at assessing the role of endothelial cell calcium for the endothelial dysfunction of mesenteric resistance arteries of db/db mice (a model of type 2 diabetes) and determine whether treatment with sulfaphenazole, improves endothelial calcium signaling and function. Pressure myography was used to study acetylcholine (ACh) -induced vasodilation. Intracellular calcium ([Ca(2+)]i) transients was measured by confocal laser scanning microscopy and smooth muscle membrane potential with sharp microelectrodes. The impaired dilation to ACh observed in mesenteric resistance arteries from db/db mice was improved by treatment of the mice with sulfaphenazole for 8 weeks. The impaired dilation to ACh was associated with decreased endothelial [Ca(2+)]i and smooth muscle hyperpolarization. Sulfaphenazole applied in vitro improved endothelial mediated dilation of arteries from db/db mice both in the absence and the presence of inhibitors of nitric oxide and cyclooxygenase. Sulfaphenazole also increased the percentage of endothelial cells with ACh induced increases of [Ca(2+)]i. The study shows that impaired endothelial [Ca(2+)]i control can explain the reduced endothelial function in arteries from diabetic mice and that sulfaphenazole treatment improves endothelial [Ca(2+)]i responses to ACh and consequently endothelium-dependent vasodilation. These observations provide mechanistic insight into endothelial dysfunction in diabetes. PMID- 26420356 TI - Beneficial effect of magnesium lithospermate B on cerebral ischemia-reperfusion injury in rats involves the regulation of miR-107/glutamate transporter 1 pathway. AB - Recent studies uncovered that glutamate accumulation following cerebral ischemia reperfusion (I/R) was related to the dysfunction of miR-107/glutamate transporter 1(GLT-1) pathway and magnesium lithospermate B (MLB) possesses the pharmacological activity of anti-excitotoxicity. This study aims to explore whether MLB is able to protect rat brain from excitatory neurotoxicity during I/R by modulating miR-107/GLT-1 pathway. Rats were subjected to 2h of cerebral ischemia following by 24h of reperfusion to establish an I/R injury model, which showed an increase in neurological deficit score, infarct volume and cellular apoptosis concomitant with glutamate accumulation, miR-107 elevation and GLT-1 down-regulation. Administration of MLB reduced I/R-induced cerebral injury accompanied by a reverse in glutamate accumulation, miR-107 and GLT-1 expression. Next, we examined the association of MLB with miR-107/GLT-1 pathway in a nerve cell hypoxia/reoxygenation (H/R) injury model. H/R treatment increased the nerve cells apoptosis concomitant with glutamate accumulation and miR-107 elevation, and suppressed GLT-1 expression, mimicking our in vivo findings. All these effects were reversed in the presence of MLB, confirming a strong correlation between MLB and miR-107/GLT-1 pathway. Based on these observations, we conclude that MLB is able to protect the rat brain from excitatory neurotoxicity during I/R through the regulation of miR-107/GLT-1 pathway. PMID- 26420361 TI - Depression: Evolutionary New Neural Circuitries Are Still Adjusting for Cognition. AB - Depression can be both normal and abnormal, and the balance of its expression determines the behavioral outcome/diagnosis. It is a complex pathophysiology based on a heterogeneous syndrome whose etiology is diverse as well. Within the context of a central nervous system, the nervous system blueprint can be found in single cells (sensory, motor, and integrative processes). These consolidated functions provide for novel coping strategies for survival. The maintenance and evolvement of this system into a central nervous system is based on conserving these functions, including chemical messengers and functionality in having specific cells medi-ate these primordial functions. Additionally, this neural coping strategy provides advantages for DNA. Thus, with different neural cells at work, pathways/networks would evolve, producing more complex behaviors and become a very critical phenomenon for future advances. This evolvement has taken over 1 billion years to de-velop. In so doing, as with any new programming (e.g., cognition), errors will occur. Given the widespread qual-ities of depression, it is surmised that this abnormality, and other psychiatric disorders, may emerge due to in-herent neural weaknesses related to cognition being a recent evolutionary development. PMID- 26420362 TI - High volumetric uptake of ammonia using Cu-MOF-74/Cu-CPO-27. AB - Cu-MOF-74 (also known as Cu-CPO-27) was identified as a sorbent having one of the highest densities of Cu(ii) sites per unit volume. Given that Cu(ii) in the framework can be thermally activated to yield a five-coordinate Cu(ii) species, we identified this MOF as a potential candidate for maximal volumetric uptake of ammonia. To that end, the kinetic breakthrough of ammonia in Cu-MOF-74/Cu-CPO-27 was examined under both dry and humid conditions. Under dry conditions the MOF exhibited a respectable performance (2.6 vs. 2.9 NH3 per nm(3) for the current record holder HKUST-1), and under 80% relative humidity, the MOF outperformed HKUST-1 (5.9 vs. 3.9 NH3 per nm(3), respectively). PMID- 26420363 TI - The Role of Flow-Independent Exhaled Nitric Oxide Parameters in the Assessment of Airway Diseases. AB - Nitric oxide (NO), the first gas known to act as a biological messenger, is one of the most widely studied free radical/gas in medicine, both for its biological function and therapeutic applications. The measurement of endogenous NO in exhaled air is widely used in the evaluation of lung disorders. Partitioning of exhaled nitric oxide (eNO) is of increasing interest because of the additional information about lung pathology and distal lung inflammation that can be obtained. Specifically, measuring exhaled NO at multiple flow rates allows assessment of the flow-independent NO parameters: alveolar NO concentration (CalvNO), bronchial NO flux (JNO), bronchial wall NO concentration (CWNO), and bronchial diffusing capacity of NO (DNO). Several studies have reported that there were different patterns of those parameters in different airway diseases and/or in different severities of the same disease, mostly in asthma. Specifically, while JNO seems to provide the same information as FeNO50, alveolar NO concentration appears to be an independent parameter that is putatively associated with increased distal lung inflammation and more severe disease. However, despite much research interest in partitioning exhaled NO, clinical usefulness has yet to be established. PMID- 26420364 TI - Vascular Biomarkers in Asthma and COPD. AB - Bronchial asthma and chronic obstructive pulmonary disease (COPD) remain a global health problem with significant morbidity and mortality. The changes in bronchial microvasculature that occurin asthma and COPD contribute to airway wall remodeling. Angiogenesis seems to be more prevalent in asthma and vasodilatation seemsmore relevant in COPD while vascular leak is present in both diseases. Recently, there has been increased interest in the vascular component of airway remodeling in chronic bronchial inflammation of asthma and COPD although its role in the progression of the diseases has not been fully elucidated. Various cells andmediators are involved in the vascular remodeling in asthma and COPD while proinflammatory cytokines and growth factors exert angiogenic and antiangiogenic effects. Vascular endothelial growth factor (VEGF) is a key regulator of blood vessel growth mainly in asthma but also in COPD. In asthmatic airways VEGF promotes proliferation and differentiation of endothelial cells and induces vascular leakage and permeability. It has also been involved in enhanced allergic sensitization, upregulated subsequent T-helper-2 type inflammatory responses, chemotaxis for monocytes and eosinophils, and airway oedema. Impaired VEGF signaling has been associated with emphysema in animal models. Studies on lung biopsies have shown a decreasing effect of anti-asthma drugs to the vascular component of airway remodeling. There is less available evidence on the effect of the currently used drugs on airway microvascular network in COPD. This review article explores the current knowledge regarding vascular biomarkers in asthma and COPD as well as the therapeutic implications of these mediators. PMID- 26420365 TI - Biomarkers in the Evaluation and Management of Idiopathic Pulmonary Fibrosis. AB - Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, debilitating disease of unknown etiology and a median survival from diagnosis of 3-5 years. Despite extensive research efforts, its etiology in humans still remains largely unknown, and no curative drug therapies are available. With a gradually increasing worldwide incidence, IPF still presents a major challenge in clinical research due to its appreciable heterogeneity among individual patients in disease course and the lack of easily reproducible surrogate markers for patient relevant outcomes. Currently clinicians and researchers apply a panel of functional, radiological and histopathological indices to stratify patients into distinct phenotypic patterns of disease progression. However, none of these indicators can reliably predict not only treatment responsiveness but more importantly disease behavior, thus allowing clinicians to promptly apply aggressive therapeutic approaches to prevent or ameliorate acute exacerbation. Furthermore, on the contrary to molecular biomarkers, physiologic prognosticators provide no insights into disease mechanism and thus are unlikely to identify distinct molecular phenotypes of the disease. In the dawn of the "fibromics" era the need for disease stratification based on molecular phenotypes and implementation of personalized medicine therapeutic approaches is still unmet. Molecular biomarkers lie in the core of personalized medicine and therefore represent the main focus of this review article. Limitations that hamper their widespread clinical applicability along with future perspectives on how to address these major caveats and launch IPF biomarkers to the same trajectory as to tumor biomarkers in oncology are also discussed. PMID- 26420366 TI - Phenotyping and Endotyping Asthma Based on Biomarkers. AB - Asthma is a chronic inflammatory airways disorder mainly characterized by heterogeneity. A phenotype is defined as a group of patients that present similar clinically observable characteristics, without establishing a direct etiologic relationship with a distinct pathophysiologic mechanism. An endotype, on the other hand, describes a subgroup that shares the same pathophysiologic processes that lead to the development, the progression and the presentation of a disease. A biomarker has been defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention. Several inflammatory phenotypes have been identified by the use of biomarkers. Most of them are based on the predominant type of cells in different biological fluids with sputum to be remained the most representative one. Eosinophilia represents the major characteristic of what we called classic atopic asthma. This particular phenotype usually responds well to corticosteroids, except for a small subgroup of severe asthma where even in the presence of eosinophils the ICS seem to have a less responsive role. Neutrophilic phenotype driven by the presence of neutrophils shows inadequate response to corticosteroid treatment, even in mild asthma. The major approach in order to define an endotype is driven by three main parameters. The statistical clustering approach, use of advanced statistical mathematics to create distinct patient clusters, the specific targeted immune therapies and finally the application of omics' approach. Both phenotypes and endotypes are trying to clarify mechanisms and processes that driven the complexity of asthma. Both concepts could identify approaches which could establish new targeted to specific biomarkers treatment therapies/strategies. PMID- 26420367 TI - Surfactant Proteins in Smoking-Related Lung Disease. AB - Pulmonary surfactant is a highly surface-active mixture of proteins and lipids that is synthesized and secreted in the alveoli by type II epithelial cells and is found in the fluid lining the alveolar surface. The protein part of surfactant constitutes two hydrophilic proteins (SP-A and SP-D) that regulate surfactant metabolism and have immunologic functions, and two hydrophobic proteins (SP-B and SP-C), which play a direct role in the organization of the surfactant structure in the interphase and in the stabilization of the lipid layers during the respiratory cycle. Several studies have shown that cigarette smoke seems to affect, in several ways, both surfactant homeostasis and function. The alterations in surfactants' biophysical properties caused by cigarette smoking, contribute to the development of several smoking related lung diseases. In this review we provide information on biochemical and physiological aspects of the pulmonary surfactant and on its possible association with the development of two major chronic diseases of the lung known to be related to smoking, i.e. chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Additional information on the possible role of surfactant protein alterations and/or dysfunction in the combination of these two conditions, recently described as combined pulmonary fibrosis and emphysema (CPFE) are also provided. PMID- 26420368 TI - Methodological Issues and Possible Clinical Implications for Exhaled Breath Condensate pH in Asthma. AB - Exhaled breath condensate (EBC) pH is a commonly studied biomarker which represents the acidity of the whole airway tract, including the lower and upper airways as well as oral cavity. Because neat, unprocessed EBC pH can be affected by environmental and end-tidal carbon dioxide, two further reproducible techniques have been developed to measure condensate acidity with several methodological, pathophysiological and environmental factors which may influence EBC pH. Airway acidification may contribute to various pathological features of asthma, therefore EBC pH may be a non-invasive, but unspecific clinical biomarker of this disorder. This review summarises the current knowledge on EBC pH in asthma focusing on methodological aspects and possible clinical applications. PMID- 26420369 TI - Cardiac Biomarkers in the Identification of Future Risk in Chronic Obstructive Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD) is a common and disabling disease and the third leading cause of global mortality behind ischemic heart disease and stroke. Acute exacerbations of COPD accelerate lung function decline affecting the quality of life of COPD patients and moreover, remain the major contributors to morbidity and mortality of these patients. Cardiovascular comorbidities are prevalent in COPD patients and of great importance since they have a negative impact on patients' health status. During the past few years there is an increasing interest in potential molecules that can be measured accurately and reproducibly and that can be used in COPD as biomarkers to predict clinical important outcomes such as exacerbations, hospitalizations and mortality. Such molecules have been successfully used in cardiovascular diseases and therefore, cardiac biomarkers have attracted attention for their potential use in COPD. The present review summarizes the available evidence for the use of the most important cardiac biomarkers in the evaluation of COPD severity, outcomes and management. PMID- 26420370 TI - Incidental Diagnosis of Asymptomatic Non-Small-Cell Lung Cancer: A Registry-Based Analysis. AB - INTRODUCTION: Clinical manifestation of non-small-cell lung cancer (NSCLC) mainly occurs at advanced stages. Thus, the scientific community is evaluating different screening programs in high-risk patients to detect NSCLC at an earlier stage to improve survival. However, up to now patient selection and modalities have been discussed controversially. In this analysis we aimed to focus on asymptomatic NSCLC patients, whose disease was detected coincidentally and to elaborate the significance and effect of incidentally detected NSCLC on survival. PATIENTS AND METHODS: Medical files of 1279 consecutive NSCLC patients diagnosed between 2001 and 2009 were retrospectively analyzed. Incidentally detected asymptomatic NSCLC patients were compared with patients with tumor-specific symptoms. RESULTS: In 117 of 1279 patients an asymptomatic diagnosis was ascertained by coincidence (9.1%). A smoking history of >= 30 pack-years was documented in 41 (58.6%) of 70 evaluable patients with incidentally detected NSCLC. Patients with incidentally diagnosed NSCLC were characterized by lower stages at diagnosis, a better performance status, and a higher proportion of previous or present other malignancies. Overall survival (OS) was significantly superior in patients with an asymptomatic diagnosis compared with patients with symptoms (median OS, 38.9 months vs. 16.1 months; P < .001). In a Cox proportional hazard model, incidental diagnosis proved to be an independent prognostic factor with regard to OS. CONCLUSION: Our findings point to the advantage of asymptomatic detection of NSCLC and might underline the benefit of screening programs. Further research on the detection of lung cancer in asymptomatic patients outside of existing screening criteria is warranted. PMID- 26420371 TI - Mesenchymal stem cells stabilize the blood-brain barrier through regulation of astrocytes. AB - INTRODUCTION: The blood-brain barrier (BBB) protects the brain against potentially neurotoxic molecules in the circulation, and loss of its integrity may contribute to disease progression in neurodegenerative conditions. Recently, the active role of reactive astrocytes in BBB disruption has become evident in the inflamed brain. In the present study, we investigated whether mesenchymal stem cell (MSC) treatment might modulate reactive astrocytes and thus stabilize BBB integrity through vascular endothelial growth factor A (VEGF-A) signaling in inflammatory conditions. METHODS: For the inflamed brain, we injected LPS using a stereotaxic apparatus and MSCs were injected into the tail vein. At 6 hours and 7 days after LPS injection, we analyzed modulatory effects of MSCs on the change of BBB permeability through VEGF-A signaling using immunochemistry and western blot. To determine the effects of MSCs on VEGF-A-related signaling in cellular system, we had used endothelial cells treated with VEGF-A and co-cultured astrocyte and BV 2 cells treated with lipopolysaccharide (LPS) and then these cells were co cultured with MSCs. RESULTS: In LPS-treated rats, MSCs restored Evans blue infiltration and the number of endothelial-barrier antigen (EBA) and P glycoprotein (p-gp)-expressing cells, which were significantly altered in LPS treated animals. Additionally, MSC administration following LPS treatment markedly increased the density of astrocytic filaments around vessels and reversed LPS-induced elevations in VEGF-A levels as well as endothelial nitric oxide synthase (eNOS)-dependent downregulation of tight junction proteins in the endothelium. Consequently, MSC treatment reduced neutrophil infiltration and enhanced survival of midbrain dopaminergic neurons in LPS-treated animals. In cellular system, MSC treatment led to a significant reversion of VEGF-A-induced eNOS and tight junction protein expression in endothelial cells, which led to increased EBA expressing cells. Additionally, MSC treatment significantly attenuated LPS-induced increased expressions of IL-1beta in microglia and VEGF-A in astrocytes with an increase in IL-10 levels. CONCLUSION: The present study indicated that MSCs may stabilize BBB permeability by modulating astrocytic endfeet and VEGF-A signaling, which may be relevant to the treatment of Parkinsonian diseases as a candidate for disease modifying therapeutics. PMID- 26420373 TI - Bottom-up, hard template and scalable approaches toward designing nanostructured Li2S for high performance lithium sulfur batteries. AB - Li2S with a high theoretical capacity of 1166 mA h g(-1) and the capability to pair with lithium free anodes has drawn much attention for lithium sulfur (Li-S) battery applications. However, the fast battery decay and the low capacity retention due to dissolution of intermediate polysulfides in electrolytes limit its development. Designing a nanosized and nanostructured host for Li2S through facile techniques is one of the ways to alleviate the dissolution and improve Li S battery performance; nevertheless, it is technically difficult to synthesize nanosized and nanostructured hosts for Li2S because Li2S is highly sensitive to moisture and oxygen. Herein, a novel technique, i.e., a bottom-up, hard template and scalable method, is proposed to engineer nanoLi2S composites with core-shell structures as cathodes of Li-S batteries. The size of the as-prepared nanostructured Li2S is around 100 nm. With the assistance of FETEM, HRTEM and EFTEM elemental mapping, an excellent core-shell structure has been confirmed and the outside carbon shell has a thickness of 20-50 nm, effectively retarding polysulfide outflow and dissolution. A high initial capacity of 915 mA h g(-1) at 0.2 C has been achieved upon electrochemical cycling and the battery still has exceptional capacity retention after prolonged 200 cycles with a limited decay of 0.18% per cycle. Also, at 0.5 C the electrode exhibits 60% capacity retention with a long life of 300 cycles. We attribute these good performances to the nano architecture constructed by the novel and facile method. PMID- 26420372 TI - Characteristics of Travelers to Asia Requiring Multidose Vaccine Schedules: Japanese Encephalitis and Rabies Prevention. AB - BACKGROUND: Japanese encephalitis (JE) and rabies are serious vaccine preventable diseases which are an important consideration for travelers to Asia. METHODS: Five Boston-area travel clinics collected demographic data, trip information, and interventions for travelers to Asia seen at pre-travel consultations from March 1, 2008, through July 31, 2010. We evaluated travelers for proportion vaccinated for JE and rabies, those traveling for >1 month, and whether travelers had adequate time to complete the JE series (clinic visit >=28 days before departure) and rabies pre-exposure prophylaxis (clinic visit >=21 days before departure). RESULTS: Among 15,440 travelers from five Boston Area Travel Medicine Network travel clinics, Asia was the most common destination region, visited by 5,582 (36%) of travelers. Among these travelers, 4,810 (86%) planned to travel to only one Asian subregion. Median trip duration was 17 days, with more than 20% traveling for >1 month. The most common destinations were South (41%), Southeast (26%), and East (23%) Asia. Of those traveling to South, Southeast, or East Asia, over one-third with trips >1 month had insufficient time to complete a series for either JE or rabies vaccine. Overall, only 10% of travelers were vaccinated (past and pre-travel visit) for either JE or rabies, with lowest percentages among travelers visiting friends and relatives. Most travelers received advice on vector precautions (96%) and rabies prevention, which included avoiding animal contact, washing wounds, and obtaining appropriate post-exposure prophylaxis (88%). CONCLUSION: Given the insufficient time for completion and relatively low vaccination rates, greater awareness of earlier pre-travel consultations, at least 4-6 weeks before travel, and accurate risk assessment for travelers are important. Effective counseling about vector avoidance, rabies, and animal bite prevention and management remains critical. PMID- 26420374 TI - The association of sleep-disordered breathing with high cerebral pulsatility might not be related to diffuse small vessel disease. A pilot study. AB - BACKGROUND: In a population-based sampling study conducted in community-dwelling older adults living in rural Ecuador, we aimed to assess the relation among sleep disordered breathing, cerebral pulsatility index, and diffuse small vessel disease. METHODS: Of 25 participants, 9 (36%) had moderate-to-severe sleep disordered breathing, characterized by an apnea/hypopnea index >=15 per hour, and 10 (40%) had moderate-to-severe white matter hyperintensities, graded according to the modified Fazekas scale. Mean (SD) pulsatility index in the middle cerebral artery was 1.18 (0.19) and positively correlated with the apnea/hypopnea index (R = .445, P = .03, [Pearson's correlation coefficient]). The middle cerebral artery pulsatility index was increased in persons with moderate-to-severe sleep disordered breathing compared with persons who had none-to-mild sleep-disordered breathing (mean [SD] 1.11 [0.12] vs. 1.3 [0.23], P = .01). No significant differences were found in the prevalence of moderate-to-severe white matter hyperintensities across groups of sleep-disordered breathing (P = .40) or in the mean apnea/hypopnea index across groups of persons with none-to-mild or moderate to-severe white matter hyperintensities (P = .16). CONCLUSIONS: This pilot study shows that moderate-to-severe sleep-disordered breathing correlates with cerebral pulsatility, but such association might be independent of diffuse small vessel disease. PMID- 26420375 TI - IL-18-induced expression of high-affinity IL-2R on murine NK cells is essential for NK-cell IFN-gamma production during murine Plasmodium yoelii infection. AB - Early production of pro-inflammatory cytokines, including IFN-gamma, is essential for control of blood-stage malaria infections. We have shown that IFN-gamma production can be induced among human natural killer (NK) cells by coculture with Plasmodium falciparum infected erythrocytes, but the importance of this response is unclear. To further explore the role of NK cells during malaria infection, we have characterized the NK-cell response of C57BL/6 mice during lethal (PyYM) or nonlethal (Py17XNL) P. yoelii infection. Ex vivo flow cytometry revealed that NK cells are activated within 24 h of Py17XNL blood-stage infection, expressing CD25 and producing IFN-gamma; this response was blunted and delayed during PyYM infection. CD25 expression and IFN-gamma production were highly correlated, suggesting a causal relationship between the two responses. Subsequent in vitro experiments revealed that IL-18 signaling is essential for induction of CD25 and synergizes with IL-12 to enhance CD25 expression on splenic NK cells. In accordance with this, Py17XNL-infected erythrocytes induced NK-cell CD25 expression and IFN-gamma production in a manner that is completely IL-18- and partially IL-12-dependent, and IFN-gamma production is enhanced by IL-2. These data suggest that IL-2 signaling via CD25 amplifies IL-18- and IL-12-mediated NK cell activation during malaria infection. PMID- 26420376 TI - Visible-light-accelerated oxygen vacancy migration in strontium titanate. AB - Strontium titanate is a model transition metal oxide that exhibits versatile properties of special interest for both fundamental and applied researches. There is evidence that most of the attractive properties of SrTiO3 are closely associated with oxygen vacancies. Tuning the kinetics of oxygen vacancies is then highly desired. Here we reported on a dramatic tuning of the electro-migration of oxygen vacancies by visible light illumination. It is found that, through depressing activation energy for vacancy diffusion, light illumination remarkably accelerates oxygen vacancies even at room temperature. This effect provides a feasible approach towards the modulation of the anionic processes. The principle proved here can be extended to other perovskite oxides, finding a wide application in oxide electronics. PMID- 26420378 TI - Neuronal circuits: Looking after your own. PMID- 26420379 TI - Highlights from SelectBio 2015: Academic Drug Discovery Conference, Cambridge, UK, 19-20 May 2015. AB - The SelectBio 2015: Academic Drug Discovery Conference was held in Cambridge, UK, on 19-20 May 2015. Building on the success of academic drug discovery events in the USA, this conference aimed to showcase the exciting new research emerging from academic drug discovery and to help bridge the gap between basic research and commercial application. At the event the authors heard from a number of speakers on a broad array of topics, from partnering models for academia and industry to novel drug discovery approaches across various therapeutic areas, with a few talks, such as those by Susanne Muller-Knapp (Structure Genomics Consortium, Oxford University, Oxford, UK) and Julian Blagg (Institute of Cancer Research, UK), covering both remits, by highlighting a number of such partnerships and then delving into some case studies. The conference concluded with a heated debate on whether phenotypic discovery should be favored over targeted discovery in academia and pharma, in a panel discussion chaired by Roland Wolkowicz (San Diego State University, USA). PMID- 26420380 TI - Recurrent duplications of 17q12 associated with variable phenotypes. AB - The ability to identify the clinical nature of the recurrent duplication of chromosome 17q12 has been limited by its rarity and the diverse range of phenotypes associated with this genomic change. In order to further define the clinical features of affected patients, detailed clinical information was collected in the largest series to date (30 patients and 2 of their siblings) through a multi-institutional collaborative effort. The majority of patients presented with developmental delays varying from mild to severe. Though dysmorphic features were commonly reported, patients do not have consistent and recognizable features. Cardiac, ophthalmologic, growth, behavioral, and other abnormalities were each present in a subset of patients. The newly associated features potentially resulting from 17q12 duplication include height and weight above the 95th percentile, cataracts, microphthalmia, coloboma, astigmatism, tracheomalacia, cutaneous mosaicism, pectus excavatum, scoliosis, hypermobility, hypospadias, diverticulum of Kommerell, pyloric stenosis, and pseudohypoparathryoidism. The majority of duplications were inherited with some carrier parents reporting learning disabilities or microcephaly. We identified additional, potentially contributory copy number changes in a subset of patients, including one patient each with 16p11.2 deletion and 15q13.3 deletion. Our data further define and expand the clinical spectrum associated with duplications of 17q12 and provide support for the role of genomic modifiers contributing to phenotypic variability. PMID- 26420382 TI - Increasing incidence of type 1 diabetes among Korean children and adolescents: analysis of data from a nationwide registry in Korea. AB - BACKGROUND: The incidence of type 1 diabetes mellitus (T1DM) in children and adolescents has increased worldwide. However, the epidemiology of T1DM among Korean youth has not been reported since 2001. We investigated the incidence of T1DM in Korean children and adolescents from 2012 to 2014 and compared it with data from 1995 to 2000. PATIENTS AND METHODS: Data were obtained from the National Health Insurance Service (NHIS) registry, and age- and sex-specific incidence rates were calculated per 100 000 population. RESULTS: In total, 706 patients (326 boys and 380 girls, aged <15 yr) with T1DM were registered in the NHIS during 2012-2014. The incidence rate per 100 000 population was 3.19 (95% confidence interval [CI] 2.96-3.43). We found incidence rates of 1.68, 3.16, and 4.46 in children 0-4, 5-9, and 10-14 yr, respectively. The T1DM incidence was 2.84 in boys and 3.56 in girls. A higher T1DM incidence was seen during 2012-2014 than from 1995-2000 (incidence rate ratio 2.33; p < 0.001). The incidence rate ratios between 1995-2000 and 2012-2014 were 2.31, 2.20, and 2.27 in children 0-4, 5-9, and 10-14 yr, respectively. The annual increase in T1DM incidence was 5.6% (95% CI 5.0-6.3%) between 1995 and 2014. CONCLUSIONS: We observed a significant increase in the T1DM incidence. This increase was higher in boys than in girls, and was highest in children aged 0-4 yr. Studies are needed to evaluate the long term epidemiological trend of T1DM incidence. PMID- 26420377 TI - Proliferation control in neural stem and progenitor cells. AB - Neural circuit function can be drastically affected by variations in the number of cells that are produced during development or by a reduction in adult cell number owing to disease. For this reason, unique cell cycle and cell growth control mechanisms operate in the developing and adult brain. In Drosophila melanogaster and in mammalian neural stem and progenitor cells, these mechanisms are intricately coordinated with the developmental age and the nutritional, metabolic and hormonal state of the animal. Defects in neural stem cell proliferation that result in the generation of incorrect cell numbers or defects in neural stem cell differentiation can cause microcephaly or megalencephaly. PMID- 26420383 TI - Design, synthesis and structure-activity relationship studies of novel phenoxyacetamide-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes. AB - The free fatty acid receptor 1 (FFA1) has attracted extensive attention as a novel antidiabetic target in the last decade. Several FFA1 agonists reported in the literature have been suffered from relatively high molecular weight and lipophilicity. We have previously reported the FFA1 agonist 1. Based on the common amide structural characteristic of SAR1 and NIH screened compound, we here describe the continued structure-activity exploration to decrease the molecular weight and lipophilicity of the compound 1 series by converting various amide linkers. All of these efforts lead to the discovery of the preferable lead compound 18, a compound with considerable agonistic activity, high LE and LLE values, lower lipophilicity than previously reported agonists, and appreciable efficacy on glucose tolerance in both normal and type 2 diabetic mice. PMID- 26420384 TI - Molecular modeling studies and synthesis of novel quinoxaline derivatives with potential anticancer activity as inhibitors of c-Met kinase. AB - In an effort to develop potent anti-cancer agents, we have synthesized some substituted quinoxaline derivatives. Reaction of 6-bromo-3-methylquinoxalin-2(1H) one 1 with aromatic aldehydes furnished the styryl derivatives 2a-e. Alkylation of 1 with ethyl chloroacetate produced the N-alkyl derivatives 3. Hydrazinolysis of the ester derivative 3 with hydrazine hydrate afforded the hydrazide derivative 4. In addition, chlorination of 1 with phosphorus oxychloride afforded the 2-chloro derivative 5 which was used as a key intermediate for the synthesis of substituted quinoxaline derivatives 6-8, N-pyrazole derivative 9, tetrazolo[1,5-a]quinoxaline derivative 10 and Schiff base derivatives 13, 15 via reaction with several nucleophiles reagents. Docking methodologies were used to predict their binding conformation to explain the differences of their tested biological activities. All the tested compounds were screened in vitro for their cytotoxic effect on three tumor cell lines. Some new quinoxaline derivatives were studied as inhibitors of c-Met kinase, a receptor associated with high tumor grade and poor prognosis in a number of human cancers. Compounds 2e, 4, 7a, 12a, 12b and 13 showed the highest binding affinity with CDOCKER energy score, while showed the lowest IC50 values against three types of cancer cell lines. It is worth to mention that, compounds 2e, 7a, 12b and 13 showed comparable inhibition activity to the reference drug, while compounds 4 and 12a showed a more potent inhibition activity than Doxorubicin. PMID- 26420385 TI - CARE OF A PATIENT'S VASCULAR ACCESS FOR HAEMODIALYSIS: A NARRATIVE LITERATURE REVIEW. AB - BACKGROUND: Patients requiring haemodialysis have diverse clinical needs impacting on the longevity of their vascular access and their quality of life. A clinical practice scenario is presented that raises the potential of unsafe cannulation of a patient's vascular access as a result of minimal patient empowerment. Vascular access care is the responsibility of everyone, including the patient and carer. AIM: The aim of this narrative literature review (1997 2014) is to explore the current understanding of what factors influence the care of vascular access for haemodialysis. METHOD: A narrative literature review allows the synthesis of the known literature pertinent to the research question into a succinct model or unique order to enable new understandings to emerge. The bio-ecological model was used to guide the thematic analysis of the literature. RESULTS: The narrative literature review revealed five themes related to care of vascular access: patient experience; relationships-empowerment and shared decision making; environment of healthcare; time; and quality of life as the outcome of care. CONCLUSION: The management of vascular access is complicated. Current available literature predominantly concentrates on bio-medical aspects of vascular access care. Contextualised vascular access care in the complex ecology of the patient and carer's lives has the potential to enhance nursing practice and patient outcomes. PMID- 26420386 TI - Islamist insurgency and the war against polio: a cross-national analysis of the political determinants of polio. AB - BACKGROUND: There is widespread agreement that civil war obstructs efforts to eradicate polio. It is suggested that Islamist insurgents have a particularly negative effect on vaccination programmes, but this claim is controversial. METHODS: We analyse cross-national data for the period 2003-14 using negative binomial regressions to investigate the relationship between Islamist and non Islamist insurgency and the global distribution of polio. The dependent variable is the annual number of polio cases in a country according to the WHO. Insurgency is operationalized as armed conflict between the state and an insurgent organization resulting in >=25 battle deaths per year according to the Uppsala Conflict Data Programme. Insurgencies are divided into Islamist and non-Islamist insurgencies. We control for other possible explanatory variables. RESULTS: Islamist insurgency did not have a significant positive relationship with polio throughout the whole period. But in the past few years - since the assassination of Osama bin Laden in 2011- Islamist insurgency has had a strong effect on where polio cases occur. The evidence for a relationship between non-Islamist insurgency and polio is less compelling and where there is a relationship it is either spurious or driven by ecological fallacy. CONCLUSIONS: Only particular forms of internal armed conflict - those prosecuted by Islamist insurgents - explain the current global distribution of polio. The variation over time in the relationship between Islamist insurgency and polio suggests that Islamist insurgent's hostility to polio vaccinations programmes is not the result of their theology, as the core tenets of Islam have not changed over the period of the study. Rather, our analysis indicates that it is a plausibly a reaction to the counterinsurgency strategies used against Islamist insurgents. The assassination of Osama bin Laden and the use of drone strikes seemingly vindicated Islamist insurgents' suspicions that immunization drives are a cover for espionage activities. PMID- 26420389 TI - Using self-assessments to enhance business continuity programmes. AB - Self-assessments have limitations and are no substitute for independent audits of a business continuity programme. Nevertheless, they can be an economical way to identify gaps, enhance the programme and create awareness. Self- assessments can also help prepare the programme and team members for an independent audit. In a resource-constrained environment, self-assessments can provide an opportunity to obtain measurable outputs about current state that can be tracked over time to capture improvement and maturity or identify deficiencies. Self-assessments can have a valuable place in any business continuity programme. PMID- 26420390 TI - The synergy needed for business resilience. AB - This paper discusses best practices on where to strategically connect risk management, business continuity, disaster recovery, crisis management, crisis communications, physical security, cyber security and emergency planning within the organisation. PMID- 26420387 TI - Calcium intake and risk of fracture: systematic review. AB - OBJECTIVE: To examine the evidence underpinning recommendations to increase calcium intake through dietary sources or calcium supplements to prevent fractures. DESIGN: Systematic review of randomised controlled trials and observational studies of calcium intake with fracture as an endpoint. Results from trials were pooled with random effects meta-analyses. DATA SOURCES: Ovid Medline, Embase, PubMed, and references from relevant systematic reviews. Initial searches undertaken in July 2013 and updated in September 2014. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials or cohort studies of dietary calcium, milk or dairy intake, or calcium supplements (with or without vitamin D) with fracture as an outcome and participants aged >50. RESULTS: There were only two eligible randomised controlled trials of dietary sources of calcium (n=262), but 50 reports from 44 cohort studies of relations between dietary calcium (n=37), milk (n=14), or dairy intake (n=8) and fracture outcomes. For dietary calcium, most studies reported no association between calcium intake and fracture (14/22 for total, 17/21 for hip, 7/8 for vertebral, and 5/7 for forearm fracture). For milk (25/28) and dairy intake (11/13), most studies also reported no associations. In 26 randomised controlled trials, calcium supplements reduced the risk of total fracture (20 studies, n=58,573; relative risk 0.89, 95% confidence interval 0.81 to 0.96) and vertebral fracture (12 studies, n=48,967. 0.86, 0.74 to 1.00) but not hip (13 studies, n=56,648; 0.95, 0.76 to 1.18) or forearm fracture (eight studies, n=51,775; 0.96, 0.85 to 1.09). Funnel plot inspection and Egger's regression suggested bias toward calcium supplements in the published data. In randomised controlled trials at lowest risk of bias (four studies, n=44,505), there was no effect on risk of fracture at any site. Results were similar for trials of calcium monotherapy and co-administered calcium and vitamin D. Only one trial in frail elderly women in residential care with low dietary calcium intake and vitamin D concentrations showed significant reductions in risk of fracture. CONCLUSIONS: Dietary calcium intake is not associated with risk of fracture, and there is no clinical trial evidence that increasing calcium intake from dietary sources prevents fractures. Evidence that calcium supplements prevent fractures is weak and inconsistent. PMID- 26420388 TI - TRPM2 protects against tissue damage following oxidative stress and ischaemia reperfusion. AB - TRPM channels are a subgroup of the transient receptor potential (TRP) channel superfamily whose members have important roles in cell proliferation and survival. TRPM2, the second subfamily member to be cloned, is expressed in many tissues including brain, heart, vasculature and haematopoietic cells. TRPM2 is activated by oxidative stress and several other extracellular signals including tumour necrosis factor alpha (TNF-alpha) and amyloid beta-peptide, which increase production of ADP-ribose (ADPR). ADPR binds to the TRPM2 C-terminal NUDT9-H domain, activating the channel. Early studies support the paradigm that TRPM2 activation induces cell death by sustained Ca(2+) influx or by enhancing cytokine production, aggravating inflammation and tissue injury. However, more recent data show that for a number of physiological processes, TRPM2 is protective. TRPM2 protects lungs from endotoxin-induced injury by reducing reactive oxygen species (ROS) production by phagocytes. It protects hearts from oxidative damage after ischaemia-reperfusion or hypoxia-reoxygenation by maintaining better mitochondrial bioenergetics and by decreasing ROS. Sustained Ca(2+) entry through TRPM2 is required to maintain cellular bioenergetics and protect against hypoxia reoxygenation injury. TRPM2 also protects neuroblastoma from moderate oxidative stress by decreasing ROS through increased levels of forkhead box transcription factor 3a (FOXO3a) and a downstream effector, superoxide dismutase 2. TRPM2 is important for tumour growth and cell survival through modulation of hypoxia inducible transcription factor expression, mitochondrial function and mitophagy. These findings in cardiac ischaemia and in neuroblastoma suggest that TRPM2 has a basic role in sustaining mitochondrial function and in cell survival that applies to a number of physiological systems and pathophysiological processes including ischaemia-reperfusion injury. PMID- 26420391 TI - Changing the paradigm of emergency response: The need for first-care providers. AB - There is a major gap in the security of the critical infrastructure - civilian medical response to atypical emergencies. Clear evidence demonstrates that, despite ongoing improvements to the first-responder system, there exists an inherent delay in the immediate medical care at the scene of an emergency. This delay can only be reduced through a societal shift in reliance on police and fire response and by extending the medical system into all communities. Additionally, through analysis of military data, it is known that immediately addressing the common injury patterns following a traumatic event will save lives. The predictable nature of these injuries, coupled with an unavoidable delay in the arrival of first responders, necessitates the need for immediate care on scene. Initial care is often rendered by bystanders, typically armed only with basic first-aid training based on medical emergencies and does not adequately address the traumatic injury patterns seen in disasters. Implementing an approach similar to the American Cardiac Arrest Act can improve outcomes to traumatic events. This paper analyses the latest data on active shooter incidents and proposes that the creation of a network of trauma-trained medic extenders would improve all communities' resilience to catastrophic disaster. PMID- 26420392 TI - Black sky: Exposing electricity as the Achilles' heel of resilience. AB - The national power grid is the most critical and the most vulnerable life-support infrastructure in modern society. Electricity serves as the essential element in sustaining every other sector of critical infrastructure including water, fuel and communications. Collective experience with responding to and recovering from widespread, long-duration power outages - known as black sky events - is nearly non-existent. Understanding these risks and weaknesses requires a collaborative planning effort with the public and private sectors to identify and protect critical nodes within the interdependent infrastructure to ensure that recovery from a catastrophic event is possible. This also requires a 'whole community' approach to planning and execution to facilitate a response on an unprecedented level. PMID- 26420393 TI - Initial response to a range of physical threats in an office environment. AB - The paper proposes that there are a number of low-probability, but not insignificant, physical threat scenarios relating to the office environment that warrant an initial response capability (in addition to fire evacuation drill). Explosive, contamination and intruder scenarios are included in the threats' scope. The term 'initial response' essentially refers to first actions relating to how and where to direct people to preserve life safety. Given the likelihood that an organisation would not have any emergency services support in the early stages of an incident, it follows that it is likely that the organisation would be 'on its own' to assess, decide and execute the initial response. Aside from any moral obligations, the paper proposes that there are potential legal obligations to compel an organisation to be so prepared. An important consideration explored is the feasibility of having an effective initial response capability. The relative simplicity and low cost of implementation and maintenance of a response is described. Lastly, the point is made that, aside from fire evacuation (which is a drill), all the other threat scenarios discussed require some decision making. It is not possible to be 100 per cent correct 100 per cent of the time. A decision support matrix is described with the objective of increasing the percentage chance of making the most appropriate decision most of the time. In particular, this is seen as an area for further discussion. PMID- 26420394 TI - Business continuity, emergency planning and special needs: How to protect the vulnerable. AB - Emergencies and disasters affect all segments of the population. Some segments are more at risk during the emergency response and recovery efforts owing to vulnerabilities that increase the risk of harm. These vulnerabilities are due to individuals' disabilities, which must be incorporated into emergency and business continuity planning. Some disabilities are obvious, such as impaired vision, hearing or mobility, while other are less evident, but equally disabling, such as cognitive disorders, geographical or language isolation, and numerous age-related factors. Taken together when creating emergency or business continuity plans, the issues identified as disabilities can be grouped by functionality and termed as special needs. This paper will detail the identification of special needs populations, explain how these persons are vulnerable during the emergency or disaster response and recovery process, and provide examples of how to partner with individuals within identified special needs populations to improve the planning process. PMID- 26420395 TI - Effective information management and assurance for a modern organisation during a crisis. AB - During a crisis, organisations face a major unpredictable event with potentially negative consequences. Effective information management and assurance can assist the organisation in making sure that they have the correct information in a secure format to make decisions to recover their operations. The main elements of effective information management and assurance are confidentiality, integrity and availability, combined with non-repudiation. Should an element of effective information management or assurance be removed it can have a detrimental effect on the other elements and render the information management and assurance practices of the organisation ineffectual. PMID- 26420396 TI - The hexagon hypothesis: Six disruptive scenarios. AB - This paper aims to bring a simple but effective and comprehensive approach to the development, delivery and monitoring of business continuity solutions. To ensure that the arguments and principles apply across the board, the paper sticks to basic underlying concepts rather than sophisticated interpretations. First, the paper explores what exactly people are defending themselves against. Secondly, the paper looks at how defences should be set up. Disruptive events tend to unfold in phases, each of which invites a particular style of protection, ranging from risk management through to business continuity to insurance cover. Their impact upon any business operation will fall into one of six basic scenarios. The hexagon hypothesis suggests that everyone should be prepared to deal with each of these six disruptive scenarios and it provides them with a useful benchmark for business continuity. PMID- 26420397 TI - Hedging against terrorism: Are US businesses prepared? AB - Private US companies face risks in connection with financial matters, but are not necessarily prepared to cope with risks that can seriously disrupt or even halt their operations, notably terrorist attacks and natural disasters. Enhancing the resilience of businesses when dealing with terrorism is especially challenging, as these groups or individuals can adapt tactics to exploit the vulnerabilities of companies they wish to target. Business managers need to formulate flexible preparedness plans that reduce risks from large-scale natural disasters as well as terrorist attacks. In doing so, they can take advantage of post-9/11 US government guidance for these endeavours as well as programmes that eliminate risks to private insurance entities so they can issue policies that cover terrorist strikes of high consequences. Just as business executives use hedging strategies in the world of finance, they also need operational hedging strategies as a means of exploiting as well as lowering the risks surrounding future uncertainties. Resources devoted to planning and hedging are investments that can increase the odds of businesses surviving and thriving, even if they experience high-impact terrorist attacks, threats or large-scale natural disasters, making suppliers, customers and stakeholders happy. The purpose of this paper is to give executives the incentive to take steps to do just that. PMID- 26420398 TI - Community resilience assessment and literature analysis. AB - Earlier and current disaster-related research emphasised the sociological/behavioural perspective. This led to a significant amount of literature devoted to descriptive context of natural, man-made and technological disasters and sequelae. This paper considers a next step involving a more expanded approach in research methodology. The phases include: (1) the development of a comprehensive database of ideas provided by authors of scholarly and scientific papers; (2) the development of computer-supported algorithms to prepare an array of scenarios representing relationships, gaps and inconsistencies in existing knowledge; (3) a process for evaluating the scenarios to determine a feasible and interesting next research strategy or programmatic action that will provide enhanced description of the problems as well as possible insights to their correction by interventions. The intent is to develop interventions as an essential component for better prevention, mitigation, rehabilitation, reconstruction and problem-solving affected by disaster events. To illustrate this approach, community resilience, a relatively new and important idea was studied. The phrase was used to describe relationships and omissions. The ideas associated with this central idea were considered in the building of a new instrument for evaluation of community vulnerability and readiness. This methodology addresses the time constraints realised by practitioners and investigators. The methods should eliminate tedious, clerical functions and focus on the intellectual functions representing optimal use of human energy. PMID- 26420399 TI - Using self-assessments to enhance business continuity programmes. AB - Self-assessments have limitations and are no substitute for independent audits of a business continuity programme. Nevertheless, they can be an economical way to identify gaps, enhance the programme and create awareness. Self- assessments can also help prepare the programme and team members for an independent audit. In a resource-constrained environment, self-assessments can provide an opportunity to obtain measurable outputs about current state that can be tracked over time to capture improvement and maturity or identify deficiencies. Self-assessments can have a valuable place in any business continuity programme. PMID- 26420400 TI - Novel Coumarin Substituted Water Soluble Cyclophosphazenes as "Turn-Off" Type Fluorescence Chemosensors for Detection of Fe(3+) ions in Aqueous Media. AB - In the present work, 3-[2-(diethylamino)ethyl]-7-oxy-4-methylcoumarin substituted cyclotriphosphazene (4) and cyclotetraphosphazene (5) derivatives were synthesized by the reactions of hexachlorocyclotriphosphazene (1) or octachlorocyclotetraphosphazene (2) with 3-[2-(diethylamino)ethyl]-7-hydroxy-4 methylcoumarin (3) for the first time. The quaternized cationic (6 and 7) and zwitterionic (8 and 9) derivatives of these compounds (4 and 5) were obtained by the reactions of dimethyl sulfate and 1,3-propanesultone, respectively. All newly synthesized cyclophosphazene compounds (4-9) were fully characterized by elemental analysis and general spectroscopic techniques such as FT-IR, (31)P-NMR, (1)H-NMR and MALDI-TOF mass. All these coumarin substituted cyclophosphazene compounds (4-9) were soluble in most of organic solvents and quaternized ionic and zwitterionic compounds (6-9) also showed excellent solubility in water. The fluorescence behaviors of novel cyclophosphazene compounds were investigated in methanol and water solutions. The chemosensor properties of newly synthesized water soluble quaternized ionic and zwitterionic cyclotriphosphazene and cyclotetraphosphazene derivatives (6-9) were investigated in aqueous media. These cyclophosphazene derivatives showed fluorescence chemosensor behavior with high selectivity for Fe(3+) ions in aqueous solution. PMID- 26420401 TI - Depressive episodes, symptoms, and trajectories in women recently diagnosed with breast cancer. AB - Depression carries serious psychosocial, physical, and economic consequences for cancer survivors. Study goals were to characterize patterns and predictors of depressive symptoms and major depressive episodes in recently diagnosed breast cancer patients. Consecutively recruited women (N = 460) completed a validated interview (CIDI) and questionnaire measure (CES-D) of depression within 4 months after invasive breast cancer diagnosis and at six additional assessments across 12 months. Outcomes were major depressive episodes, continuous symptom scores, and latent symptom trajectory classes. Across 12 months, 16.6 % of women met criteria for a major depressive episode. Unemployment predicted depressive episodes after other correlates were controlled. Distinct trajectory classes were apparent: an estimated 38 % of women had chronically elevated symptoms (High trajectory), 20 % recovered from elevated symptoms (Recovery), and 43 % had lower symptoms (Low and Very Low trajectories). Although 96 % of episodes occurred in the High or Recovery classes, 66 % of women in the High trajectory did not have an episode. Women in the Low (vs High) trajectory were more likely to be older, retired, more affluent, and have fewer comorbid diseases and briefer oncologic treatment. Women in the Recovery trajectory (vs High) were more likely to be married and more affluent and have fewer comorbid diseases. Assuming available therapeutic resources, assessment of both depressive symptoms and episodes over several months after diagnosis is important. Identification of patients at risk for persistently high depressive symptoms (e.g., younger, longer treatment course) opens targeted opportunities to prevent and promote rapid recovery from depression. PMID- 26420402 TI - Pneumocystis jiroveci pneumonia (PCP) in patients receiving neoadjuvant and adjuvant anthracycline-based chemotherapy for breast cancer: incidence and risk factors. AB - Opportunistic infection with Pneumocystis jiroveci pneumonia (PCP) has not been recognized as a significant complication of early-stage breast cancer treatment. However, we have observed an increase in PCP incidence among patients receiving chemotherapy for early-stage breast cancer. Herein we identify risk factors for and calculate incidence of PCP in this population. We identified all cases of PCP at Dana-Farber Cancer Institute/Brigham and Women's Hospital (DFCI/BWH) from 1/1/2000 to 12/31/2013 in patients with stage I-III breast cancer treated with an adriamycin/cyclophosphamide (AC)-containing regimen. Nineteen cases of PCP in non metastatic breast cancer patients were identified. All patients with PCP were diagnosed after receipt of either three or four cycles of AC chemotherapy on a dose-dense schedule. Patients who developed PCP were treated with median 16.4 mg prednisone equivalents/day as nausea prophylaxis for a median 64 days. The overall incidence of PCP among 2057 patients treated with neoadjuvant or adjuvant dose-dense AC for three or more cycles was 0.6 % (95 % confidence interval 0.3 1.0 %). No PCP was diagnosed in 1001 patients treated with non-dose-dense AC. There was one death from PCP. Women receiving dose-dense AC chemotherapy for early-stage breast cancer are at risk for PCP. Administering the same chemotherapy and corticosteroid dose over an 8-week versus 12-week non-dose-dense schedule appears to have created a novel infectious vulnerability. Replacing dexamethasone with alternative anti-emetics may mitigate this risk. PMID- 26420403 TI - Is a higher boost dose of radiation necessary after breast-conserving therapy for patients with breast cancer with final close or positive margins? AB - To determine rates of loco-regional recurrence (LRR), distant failure and overall survival for patients with breast cancer treated with breast-conserving therapy (BCT) with a close or positive surgical margin (C/PM) treated with standard dose boost radiation compared with a higher boost of radiation. We retrospectively studied 1476 patients with T1-T3 invasive breast cancer treated with BCT between 1992 and 2009. Median age was 57 years. Patients were divided into three groups: Group I included 1197 patients (81 %) with negative margins who received a standard boost (median 60 Gy) total dose to the lumpectomy cavity; Group II included 116 patients (8 %) with C/PM who received a standard boost (median 60 Gy); and Group III included 163 patients (11 %) with C/PM who received a higher boost (median 68 Gy). Biological subtypes (e.g., ER, PR, HER2/neu) were available for 858 patients (58 %) and were also assessed for any relationship to LRR rate. The Kaplan-Meier, Cox-regression, and log-rank tests were used to estimate rates of LRR and the significance of risk factors. Median follow-up was 8.6 years. The overall 5- and 10-year cumulative incidences of LRR were 2.1 % (95 % CI 0.8-2.1 %) and 4.5 % (95 % CI 3.4-6.0 %), respectively. The 5- and 10-year cumulative incidences of LRR for Group I (negative margins + standard boost) were 1.9 and 4.4 %; for Group II (C/PM + standard boost) were 3.9 and 7.0 %; and for Group III (C/PM + higher boost) were 2.9 and 3.8 %, respectively. No statistically significant differences in LRR rates were found among the three groups (p = 0.4). Similar results were obtained for distant failure (p = 0.3) and overall survival (p = 0.4). On multivariate analysis, tumor grade (p = 0.03), systemic-therapy (p = 0.005), node positivity (p = 0.05), young age (p = 0.001), and biological subtype (p = 0.04) were statistically significantly associated with higher LRR. Higher boost dose and margin positivity were not significant. Our data suggest that the 10-year risk of local recurrence for patients with close or positive margins receiving a standard boost was 7 % compared to 3.8 % for those receiving a higher boost; however, this difference was not significant. A higher boost dose did not significantly improve local control, nor did margins impact LRR risk in our cohort of patients. PMID- 26420405 TI - Endurance, resistance and resilience in the South African health care system: case studies to demonstrate mechanisms of coping within a constrained system. AB - BACKGROUND: South Africa is at present undertaking a series of reforms to transform public health services to make them more effective and responsive to patient and provider needs. A key focus of these reforms is primary care and its overburdened, somewhat dysfunctional and hierarchical nature. This comparative case study examines how patients and providers respond in this system and cope with its systemic demands through mechanisms of endurance, resistance and resilience, using coping and agency literatures as the theoretical lenses. METHODS: As part of a larger research project carried out between 2009 and 2010, this study conducted semi-structured interviews and observations at health facilities in three South African provinces. This study explored patient experiences of access to health care, in particular, ways of coping and how health care providers cope with the health care system's realities. From this interpretive base, four cases (two patients, two providers) were selected as they best informed on endurance, resistance and resilience. Some commentary from other respondents is added to underline the more ubiquitous nature of these coping mechanisms. RESULTS: The cases of four individuals highlight the complexity of different forms of endurance and passivity, emotion- and problem-based coping with health care interactions in an overburdened, under-resourced and, in some instances, poorly managed system. Patients' narratives show the micro-practices they use to cope with their treatment, by not recognizing victimhood and sometimes practising unhealthy behaviours. Providers indicate how they cope in their work situations by using peer support and becoming knowledgeable in providing good service. CONCLUSIONS: Resistance and resilience narratives show the adaptive power of individuals in dealing with difficult illness, circumstances or treatment settings. They permit individuals to do more than endure (itself a coping mechanism) their circumstances, though resistance and resilience may be limited. These are individual responses to systemic forces. To transform health care, mutually supportive interactions are required among and between both patients and providers but their nature, as micro-practices, may show a way forward for system change. PMID- 26420404 TI - Black breast cancer survivors experience greater upper extremity disability. AB - Over one-third of breast cancer survivors experience upper extremity disability. Black women present with factors associated with greater upper extremity disability, including: increased body mass index (BMI), more advanced disease stage at diagnosis, and varying treatment type compared with Whites. No prior research has evaluated the relationship between race and upper extremity disability using validated tools and controlling for these factors. Data were drawn from a survey study among 610 women with stage I-III hormone receptor positive breast cancer. The disabilities of the arm, shoulder and hand (QuickDASH) is an 11-item self-administered questionnaire that has been validated for breast cancer survivors to assess global upper extremity function over the past 7 days. Linear regression and mediation analysis estimated the relationships between race, BMI and QuickDASH score, adjusting for demographics and treatment types. Black women (n = 98) had 7.3 points higher average QuickDASH scores than White (n = 512) women (p < 0.001). After adjusting for BMI, age, education, cancer treatment, months since diagnosis, and aromatase inhibitor status, Black women had an average 4-point (95 % confidence interval 0.18-8.01) higher QuickDASH score (p = 0.04) than White women. Mediation analysis suggested that BMI attenuated the association between race and disability by 40 %. Even several years post-treatment, Black breast cancer survivors had greater upper extremity disability, which was partially mediated by higher BMIs. Close monitoring of high BMI Black women may be an important step in reducing disparities in cancer survivorship. More research is needed on the relationship between race, BMI, and upper extremity disability. PMID- 26420407 TI - [A Study on the Chinese Name of Smallpox]. AB - The Zhou hou fang (Handbook of Formulae) is the earliest known ancient medical book carrying the title of smallpox, called "lu chuan" (captive sore). Since then, various names had been applied to this disorder, including "sheng chuang" (holy sore), "tian chuang" (celestial sore), "wan dou chuang" (pea sore), "fu dou chuang" (bran sore), and "dou zhen" (pox-rash). This frequent changes of disease titles in its history is a significant mark of the evolution of TCM recognition on smallpox related to its treatment and prevention, and folk-social customs. It was not until the Republican period that the title of "pox-rash" was substituted by smallpox, a specific title for this viral infection. This is also the outcome showing the important position of TCM treatment and prevention for smallpox replaced by the preventive method of modern smallpox vaccination. PMID- 26420408 TI - [Patients' medical activities as viewed from medical case records of South Ridge]. AB - There are plenty of materials recorded in the medical case records of the South Ridge. Through these records, it is possible to understand the patients' idea of their confidence toward the doctors, changing of invited doctors, pharmacological views, religious behaviors for inviting doctors and giving prognosis, payment to the doctors and their activities of public benefits. All these can offer help to the overall understanding of therapeutic history. PMID- 26420406 TI - Risk factors associated with the occurrence of proximal humerus fractures in patients with rheumatoid arthritis: a custom strategy for preventing proximal humerus fractures. AB - To our knowledge, no prior report focused on the risk factors for proximal humerus fractures in patients with rheumatoid arthritis. The purpose of this study was to evaluate the association between potential risk factors and the occurrence of proximal humerus fractures in patients with rheumatoid arthritis. A total of 11,907 patients with rheumatoid arthritis were enrolled in our observational cohort rheumatoid arthritis study between 2000 and 2012. Self reported proximal humerus fractures were verified using the patients' medical records. Cox proportional hazard models were used to analyze the independent contribution of risk factors to the occurrence of proximal humerus fractures. During follow-up (mean 5.6 years), 92 proximal humerus fractures were verified in 91 patients. Multivariate Cox regression analyses estimated that the hazard ratios of sustaining a proximal humerus fracture were 1.37 for every 10-year increase in age [95 % confidence interval (CI) 1.10-1.70; P < 0.01], 1.95 for increases in serum C-reactive protein levels (mg/100 mL; 95 % CI 1.15-3.34; P < 0.05), 2.13 for a history of fractures (95 % CI 1.34-3.40; P < 0.01), 1.07 for the daily prednisolone dose (per mg; 95 % CI 1.01-1.13; P < 0.05), and 1.97 for oral bisphosphonate use (95 % CI 1.20-3.23; P < 0.01). Better control of rheumatoid arthritis with a smaller daily prednisolone dose in elderly patients with a history of fractures may be important for preventing proximal humerus fractures. PMID- 26420410 TI - [Studies on the doctor-patient relationship in early Chinese missionary hospitals]. AB - During the 19th century, missionary hospitals were set up by the missionaries in China, establishing a new doctor-patient relationship with doctors at the dominant position. In the early Chinese missionary hospitals, the doctor-patient relationship was relatively good, which could be seen from Chinese people's feelings of gratitude to the medical missionaries. The early missionary hospitals were totally controlled by the western Christians during the 1820-1860. Such good doctor-patient relationship was the results of common action of multiple factors, including Christianity, free medical charges, management idea based on humanism, the idea of the hospitals to avoid medical risks, family concept in traditional Chinese culture and so on. PMID- 26420409 TI - [Contention on the theory of processing techniques of Chinese materia medica in the Ming-Qing period]. AB - On the basis of the golden stage of development of processing techniques of medicinals in the Song dynasty, the theory and techniques of processing in the Ming-Qing dynasties developed and accomplished further. The knowledge of some physicians on the processing of common medicinal, such as Radix rehmannia and Radixophiopogonis, was questioned, with new idea of processing methods put forward and argued against those insisting traditional ones, marking the progress of the art of processing. By reviewing the contention of technical theory of medicinal processing in the Ming-Qing period, useful references can be provided for the inheritance and development of the traditional art of processing medicinals. PMID- 26420411 TI - [An introduction to the transmission of modern western medicine in southwestern borderland]. AB - Yunnan is located in the southwestern border of China, neighboring South Asia and Southeast Asia. Since the end ofthe 19th century, the western medicine was introduced into Yunnan Province along with the arrival of missionaries, exerting great influence on local medicine in Yunnan, even in inland China, and has become an integral part of Chinese modern medical history. Initially, the missionaries who knew only a little medical knowledge and treated the patients effectively during their missionary work with the western medicines they carried, so as to develop the believers. At the beginning of the 20th century, Catholic Church and Christian Church began to establish Church Hospitals in Yunnan, including the "Dafashi Hospital (French Consulate Hospital)" set up in 1901, and "Fudian Hospital (French Government Hospital)" established in 1902, and many Hospitals set up in Yunnan Province. The Church Hospitals also established medical schools and nurse schools all over Yunnan, which promoted modern medical education in Yunnan, and had profound influence on modern education of western medicine in this Provence. PMID- 26420412 TI - [On the formulation of TCM foreign exchange policy after the reform and opening up]. AB - The foreign exchange activities of traditional Chinese medicine are conducted under the guidance of the policy of the CPC and Chinese government. After the carrying out of the reform and opening-up policy, foreign exchange policy of TCM has experienced the process of growing up from nothing, from less to more, and from coarse to fine, which is closely related to our country's foreign policy, the cause of Chinese medicine development, and urgent need of international communication. In the three decades after the reform and opening-up policy, the formulation of foreign exchange policy of TCM can be divided into three stages: viz., inclusion in the framework of national foreign policy (1978-1985), embodiment in the policy of developing TCM cause (1986-1996), and appearance in the special policy of foreign exchange of Chinese medicine (since 1997). From the development process of these policies, the development of each policy gradually complies with the process of the development of the times, with its contents basically in line with the requirements of the times. The implementation of some policies promotes the foreign exchanges and cooperation of Chinese medicine. PMID- 26420413 TI - [Preliminary exploration on educational reform of general western medical history in medical colleges and universities under new situations and circumstances]. AB - With the appearance of the "biological-psychological-social" medical model, the purpose, value and significance of medicine are reviewed and reconsidered by the people, and the history of medicine becomes one of the core subjects in the medical humanist education, along with change of the teaching of general western medical history. Medical history is no longer the accumulation of the achievements of human knowledge and medical experience, the intellectual history of theorytransformation, and the history of reformation of medical technologies, but a concrete and colorful living situation, displayed by the scientists, physicians and normal peoplecommunity during the process of their consistent recognition and transformation on medicine. Therefore, the teaching of generalwestern medical history should adjust the compilation of teaching materials, update the educational concept, change the contents, methods of teaching and examination in order to lay stress on the cultural viewpoint and the function of humanity and quality of education. PMID- 26420414 TI - [Textual research on circulation of the Ming edition of Li Heng's Xiu zhen fang (Pocket Formulary)]. AB - Xiu zhen fang (Pocket Formulary) is a recipe book of the Ming Dynasty, inspired and managed by Zhu Su, compiled by Li Heng of liangyisuo (good physician house) in Zhou wangfu (Zhou's royal palace). The book was compiled and published twice during the reigns of the Hongwu and Yongle Emperors of the Ming Dynasty. Because of its high practicability, there were some editions in circulation, and the book was published several times only in the Ming Dynasty. At present, the earliest extanteditionwas the little character version of Yongle, and the version in the 4(th) year of Zhengde Emperor of the Ming Dynasty was a reprinting edition based on the Yongle edition, sharingthe same edition system. Most of the editions appeared after the reign of Zhengtong Emperor of the Ming Dynasty, titled by "kui ben (head version)" and "da quan (complete edition)" were the editionspublished in the local bookshops, which had rather distinct differences from the Yongle edition system not only in the its format but also in its contents. PMID- 26420415 TI - [Investigation on the number of ancient medical books collected in Haiyuan Private Library]. AB - Yang's Haiyuan Private Library in Liaocheng City, Shandong Province, is the only extant one among the four famous private libraries of the Qing dynasty in Northern China. Its collection is ample and graceful and especially rich in rare and secret versions, amounting to over 2 000 kinds, 200- thousand volumes. By sorting out 5 kinds of such collections from the Yang's family catalogue of Liaocheng in Shandong, plus 3 kinds of supplemented catalogue by Wang Shaozeng, the Catalogue of Haiyuan Private Library Collected in Shandong Provincial Library, and catalogues of modern scholars, it can be basically identified that the number of medical collections of Yang's Haiyuan Private Library is 87 kinds. Supposing all kinds contain 112 works, then Haiyuan Private Library totally has 1296 volumes according to the catalogues. PMID- 26420416 TI - [Establishment and development of National Institutes of Health of the United States]. AB - National Institutes of Health traces its root to a one-room laboratory created in 1887. Now it has become a federal agency including 27 institutes and centers, also one of the world biggest centers of biomedical research.Throughout the history of NIH, much experience is worth learning, for example: allocating persistent and sufficient funds, basing on basic research and adjusting its focus duly, expanding the scope of subsidizing and stressing talent cultivation. PMID- 26420417 TI - Relation of serum 25-hydroxyvitamin D status with skeletal muscle mass by sex and age group among Korean adults. AB - The objective of this study was to examine whether high serum 25-hydroxyvitamin D (25(OH)D) concentration was associated with high skeletal muscle mass, taking into account the effects of sex and age among the participants of the Korea National Health and Nutrition Examination Survey (KNHANES) aged 40 years or older. This was a cross-sectional study using data from the 2009 to 2010 KNHANES; a total of 8406 subjects (3671 men and 4735 women) were included. The appendicular skeletal muscle mass index (ASMMI, kg/m2) was estimated to measure the skeletal muscle mass. Hypovitaminosis was classified when the level of serum 25(OH)D was <20 ng/ml. The general linear model adjusted for confounding factors was used to determine differences in means of ASMMI by 25(OH)D status. The mean values of ASMMI were higher for men when compared with women. Women had a greater proportion of hypovitaminosis (71.1%) compared with men (53.2%). After adjusting for multiple factors, men were seen to have significant differences in ASMMI based on 25(OH)D status regardless of age, showing a lower mean value of ASSMI in those with hypovitaminosis. However, there was no difference in ASMMI by 25(OH)D status among women in both younger and older age groups. In conclusion, we found that there might be a positive relationship between 25(OH)D and skeletal muscle mass in men, indicating that interventions to improve 25(OH)D levels that are aimed at increasing muscle mass could be beneficial for men with more rapid decreased rate of skeletal muscle mass. PMID- 26420418 TI - Relief of obstructive jaundice from pancreatic cancer: the end of the plastic stent era? PMID- 26420419 TI - TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro. AB - OBJECTIVE: Cholestatic liver diseases in humans as well as bile acid (BA)-feeding and common bile duct ligation (CBDL) in rodents trigger hyperplasia of cholangiocytes within the portal fields. Furthermore, elevation of BA levels enhances proliferation and invasiveness of cholangiocarcinoma (CCA) cells in animal models, thus promoting tumour progression. TGR5 is a G-protein coupled BA receptor, which is highly expressed in cholangiocytes and postulated to mediate the proliferative effects of BA. DESIGN: BA-dependent cholangiocyte proliferation was examined in TGR5-knockout and wild type mice following cholic acid (CA) feeding and CBDL. TGR5-dependent proliferation and protection from apoptosis was studied in isolated cholangiocytes and CCA cell lines following stimulation with TGR5 ligands and kinase inhibitors. TGR5 expression was analysed in human CCA tissue. RESULTS: Cholangiocyte proliferation was significantly reduced in TGR5 knockout mice in response to CA-feeding and CBDL. Taurolithocholic acid and TGR5 selective agonists induced cholangiocyte proliferation through elevation of reactive oxygen species and cSrc mediated epidermal growth factor receptor transactivation and subsequent Erk1/2 phosphorylation only in wild type but not in TGR5-knockout-derived cells. In human CCA tissue TGR5 was overexpressed and the pathway of TGR5-dependent proliferation via epidermal growth factor receptor and extracellular signal-regulated kinase (ERK)1/2 activation also translated to CCA cell lines. Furthermore, apoptosis was inhibited by TGR5-dependent CD95 receptor serine phosphorylation. CONCLUSIONS: TGR5 is an important mediator of BA induced cholangiocyte proliferation in vivo and in vitro. Furthermore, TGR5 protects cholangiocytes from death receptor-mediated apoptosis. These mechanisms may protect cholangiocytes from BA toxicity under cholestatic conditions, however, they may trigger proliferation and apoptosis resistance in malignantly transformed cholangiocytes, thus promoting CCA progression. PMID- 26420420 TI - Endoplasmic reticulum protein 29 (ERp29) confers radioresistance through the DNA repair gene, O(6)-methylguanine DNA-methyltransferase, in breast cancer cells. AB - Resistance of cancer cells to radiotherapy is a major clinical problem in cancer treatment. Therefore, understanding the molecular basis of cellular resistance to radiotherapy and identification of novel targets are essential for improving treatment efficacy for cancer patients. Our previous studies have demonstrated a significant role of ERp29 in breast cancer cell survival against doxorubicin induced genotoxic stress. We here reported that ERp29 expression in the triple negative MDA-MB-231 breast cancer cells significantly increased cell survival against ionizing radiation. Methylation PCR array analysis identified that ERp29 expression increased promoter hypomethylation of the DNA repair gene, O(6) methylguanine DNA-methyltransferase (MGMT), by downregulating DNA methyltransferase 1. Knockdown of MGMT in the ERp29-transfected cancer cells increased radiosensitivity, leading to a decreased post-irradiation survival. In addition, radiation treatment in the MGMT-knockdown cells elevated phosphorylation of gamma-H2AX and cleavage of caspase 3, indicating that depletion of MGMT facilitates DNA double strands breaks and increases cell apoptosis. Hence, our studies prove a novel function of ERp29?MGMT in cancer cell survival against radiation. Targeting ERp29?MGMT axis may be useful for providing better treatment efficacy in combination with radiotherapy in breast cancer. PMID- 26420421 TI - Opposing Effects of NGF and proNGF on HIV Induced Macrophage Activation. AB - Macrophage and microglial activation by HIV in the central nervous system (CNS) triggers the secretion of soluble factors which damage neurons. Therapeutic approaches designed to restore cognitive function by suppressing this inflammatory activity have not yet been successful. Recent studies have indicated that the phenotype of macrophages is differentially controlled by the mature and pro form of nerve growth factor. These cells therefore may be highly responsive to the imbalance in pro versus mature neurotrophins often associated with neurodegenerative diseases. In this study we evaluated the interactions between neurotrophins and HIV induced macrophage activation. HIV stimulation of macrophages induced a neurotoxic phenotype characterized by the expression of podosomes, suppression of calcium spiking and increased neurotoxin production. The secretome of the activated macrophages revealed a bias toward anti-angiogenic like activity and increased secretion of MMP-9. Co-stimulation with NGF and HIV suppressed neurotoxin secretion, increased calcium spiking, suppressed podosome expression and reversed 86% of the proteins secreted in response to HIV, including MMP-9 and many growth factors. In contrast, co-stimulation of macrophages with proNGF not only failed to reverse the effects of HIV but increased the neurotoxic phenotype. These differential effects of proNGF and NGF on HIV activation provide a potential novel therapeutic avenue for controlling macrophage activation in response to HIV. PMID- 26420423 TI - Tele-health-care in the elderly living in nursing home: the first Sicilian multimodal approach. AB - BACKGROUND: The continued aging of the population is affecting the health of the industrialized countries, with an increasing burden for the healthcare system. Thus, during the last decade, we assisted to relevant progress in the medical treatment and rehabilitation techniques and devices, including the development of telemedicine for geriatric care. AIM: To demonstrate the effectiveness of a novel tele-health-care model allowing a better management of elderly living in nursing homes. METHODS: Fifty-nine elderly patients (19 males and 40 females; mean age 79.1 (+/-9.2), were randomly divided into two groups: the experimental group that performed a proper telemonitoring with a multimodal approach (including monitoring of the vital signs and neurological/psychological counseling), and the control group, which underwent standard in-home nursing care. Neurobehavioral symptoms and quality of life were assessed in both the groups at baseline, and after the telecare protocol's end. RESULTS: The experimental group had a statistically significant reduction in Geriatric Depression Scale (p < 0.01) and Brief Psychiatric Rating Scale (p < 0.05) scores, and an improvement in their quality of life. Moreover, mean blood pressure and heart rate were lower in the experimental than in the control group (p < 0.05), and admission to health care services was higher in the control than in the experimental group (p < 0.05). CONCLUSIONS: Telemedicine can be considered as an important tool in improving health and quality of life in the elderly living in nursing homes, and potentially reducing healthcare service access, hospitalization, and costs. PMID- 26420422 TI - The DNA structure and sequence preferences of WRN underlie its function in telomeric recombination events. AB - Telomeric abnormalities caused by loss of function of the RecQ helicase WRN are linked to the multiple premature ageing phenotypes that characterize Werner syndrome. Here we examine WRN's role in telomeric maintenance, by comparing its action on a variety of DNA structures without or with telomeric sequences. Our results show that WRN clearly prefers to act on strand invasion intermediates in a manner that favours strand invasion and exchange. Moreover, WRN unwinding of these recombination structures is further enhanced when the invading strand contains at least three G-rich single-stranded telomeric repeats. These selectivities are most pronounced at NaCl concentrations within the reported intranuclear monovalent cation concentration range, and are partly conferred by WRN's C-terminal region. Importantly, WRN's specificity for the G-rich telomeric sequence within this precise structural context is particularly relevant to telomere metabolism and strongly suggests a physiological role in telomeric recombination processes, including T-loop dynamics. PMID- 26420424 TI - Bullous pemphigoid and neurodegenerative diseases: a study in a setting of a Central European university dermatology department. AB - Bullous pemphigoid (BP) is an autoimmune blistering dermatosis of the elderly mediated by IgG and IgE antibodies to skin hemidesmosomal proteins, BP180 and/or BP230, that occur physiologically also in neuronal tissue. It was reported that BP is associated with neurodegenerative diseases (ND). We performed a retrospective study in a setting of a Central European university dermatology department on prevalence of ND in 94 BP patients. 26 out of 94 BP patients had at least one ND. ND included: Parkinson's disease, dementia, stroke, hear loss, tinnitus, blindness, vertigo, neurosyphilis, systemic sclerosis, and epilepsy. Since population aging is conceivably responsible for the rising number of BP cases as a result of immunosenescence-related phenomena, the plausible BP specific immunopathogenetic relationship between BP and ND deserves to be further experimentally explored. PMID- 26420425 TI - Assessment of the diagnostic efficacy of enolase as an indication of active infection of Schistosoma japonicum. AB - Schistosomiasis is a common zoonoses affecting humans. The atypical clinical symptoms, low morbidity, and low degree of infection impede diagnosis and assessment of epidemics. Detecting circulating antigens from adult worms in patients' body fluids should be diagnostically superior to examining eggs in feces. Herein, the excretory-secretory proteins of adult worms were analyzed by using 2-D protein electrophoresis and mass spectrometry. The Schistosoma japonicum enolase (Sj enolase) was identified as the most abundant excretory secretory antigen. Purified recombinant Sj enolase was prepared, and specific monoclonal and polyclonal antibodies were raised against it. A sandwich enzyme linked immunoassay (sandwich ELISA) was established that used the monoclonal antibody as a capture antibody and the polyclonal antibody as a detection antibody. The linear detection range was 0.7-1000 ng/ml (minimum 700 pg/ml). Sj enolase could be detected in the sera of infected rabbits and disappeared rapidly postpraziquantel treatment. The sensitivity and specificity of this sandwich ELISA to detect field serum samples of schistosomiasis were 84.61 and 95.83 %, respectively. The cross-reaction rates for clonorchiasis and paragonimiasis were 3.33 and 5 %, respectively. This ELISA assay was used to test 45 matching sera of schistosomiasis patients before treatment and at 3, 6, 9, and 12 months posttreatment. Among the sera, 88.89 % were positive before treatment. At 3, 6, 9, and 12 months postpraziquantel treatment, 93.33, 97.78, 100, and 100 % tested negative, respectively. Therefore, Sj enolase can be used to indicate active Schistosoma infection, and detecting serum Sj enolase is important for diagnosis and evaluating treatment effect. PMID- 26420426 TI - The reciprocal effect of pain catastrophizing and satisfaction with participation in the multidisciplinary treatment of patients with chronic back pain. AB - BACKGROUND: The aim of the study was to examine the reciprocity between pain catastrophizing, social participation and quality of life outcomes (pain intensity, pain disability, negative affectivity) in patients with low back pain in a multidisciplinary pain treatment. METHODS: Patients undergoing inpatient rehabilitation were surveyed at the beginning and two weeks after the end of rehabilitation. N = 262 low back pain patients participated (mean age: 52.2, 62.1 % female). A two-wave cross-lagged design and structural equation modeling were used to analyze data. RESULTS: We found evidence of reciprocal relations with regard to several outcomes. For example, pain catastrophizing at the beginning of treatment is associated with negative affectivity after rehabilitation, and the post-treatment value of pain catastrophizing is associated with pain disability and satisfaction with participation at the start of treatment. Pain disability and pain catastrophizing are predictors of lower treatment outcome while pain intensity and negative affectivity are not risk factors. Participation stands in a reciprocal relationship with some of the pain treatment outcomes. The surprising result, namely, that those patients more satisfied with social participation experience less improvement regarding catastrophizing, can be explained by ceiling effects and the Communal Coping Model. CONCLUSIONS: This study provides evidence of the importance of taking reciprocal relations among pain catastrophizing, social participation and other pain outcomes into account. Providers of multidisciplinary pain treatment need to play attention to patients at risk with high disability and catastrophizing thoughts. Pain treatment would benefit from closer integration of psychosocial measures to foster social participation. PMID- 26420427 TI - Analyses of acute kidney injury biomarkers by ultra-high performance liquid chromatography with mass spectrometry. AB - The newly developed acute kidney injury biomarkers are very important for the early and timely detection of kidney diseases. This review contains details of the analyses of several acute kidney injury biomarkers using ultra-high performance liquid chromatography-mass spectrometry in urine and plasma samples. In this review we attempt to discuss some aspects of the types of the biomarkers, patents, sample preparation, and the analyses. Besides, efforts were also made to discuss the possible uses of superficially porous (core-shell) columns in traditional and inexpensive high-performance liquid chromatography instruments. Additionally, the challenges and the future prospects are also highlighted. The present review will be useful for the academicians, scientists, and clinicians for the early detection of acute kidney injury biomarkers. PMID- 26420428 TI - Clinical application of amplicon-based next-generation sequencing to therapeutic decision making in lung cancer. AB - BACKGROUND: The clinical implementation of genomic profiling for lung cancer with high-throughput, multiplex tests is warranted to allow prioritization of appropriate therapies for individual patients. We have now applied such testing to detect actionable mutations that may inform treatment recommendations in lung cancer. PATIENTS AND METHODS: We prospectively applied amplicon sequencing panels that cover both mutational hotspots in 22 genes related to lung and colon tumorigenesis as well as 72 major variants of ALK, RET, ROS1, and NTRK1 fusion transcripts. We then determined the proportion of patients who received genotype directed therapy and their overall survival (OS). RESULTS: Tumor specimens from 110 patients with lung cancer recruited between July 2013 and March 2015 were analyzed. The most common genetic alterations were TP53 mutations in 42 patients, followed by EGFR mutations in 25, STK11 mutations in 12, and KRAS mutations in 10. Potentially actionable mutations were identified in 44 patients including 50% of those with adenocarcinoma and 14% of those with squamous cell carcinoma. The OS of patients with advanced or recurrent cancer who had an actionable mutation and received targeted therapy (median OS not achieved) was significantly longer than that of those with no mutation (18.1 months, P = 0.041) or of those with a mutation not so treated (6.1 months, P = 0.0027). CONCLUSIONS: Multiplex genomic testing was performed on formalin-fixed, paraffin-embedded tumor specimens with a success rate of >=95%. Such testing can assist physicians in matching patients with approved or experimental targeted treatments. CLINICAL TRIAL REGISTRATION: The University Medical Hospital Information Network (UMIN) Clinical Trials Registry under the identifier UMIN000014782. PMID- 26420429 TI - Glyma11g13220, a homolog of the vernalization pathway gene VERNALIZATION 1 from soybean [Glycine max (L.) Merr.], promotes flowering in Arabidopsis thaliana. AB - BACKGROUND: The precise timing of flowering is fundamental to successful reproduction, and has dramatic significance for crop yields. Although prolonged low temperatures are not required for flowering induction in soybean, vernalization pathway genes have been retained during the evolution of this species. Little information is currently available in regarding these genes in soybean. RESULTS: We were able to detect the expression of Glyma11g13220 in different organs at all monitored developmental stages in soybean. Glyma11g13220 expression was higher in leaves and pods than in shoot apexes and stems. In addition, Glyma11g13220 was responsive to photoperiod and low temperature in soybean. Furthermore, Glyma11g13220 was found to be a nuclear-localized protein. Over-expression of Glyma11g13220 in an Arabidopsis Columbia-0 (Col-0) background resulted in early flowering. Quantitative real-time PCR analysis revealed that transcript levels of flower repressor FLOWERING LOCUS C (FLC), and FD decreased significantly in transgenic Arabidopsis compared with wild-type Col-0, while the expression of VERNALIZATION INSENSITIVE 3 (VIN3) and FLOWERING LOCUS T (FT) noticeably increased. CONCLUSIONS: Our results suggest that Glyma11g13220, a homolog of Arabidopsis VRN1, is a functional protein. Glyma11g13220, which is responsive to photoperiod and low temperature in soybean, may participate in the vernalization pathway in Arabidopsis and help regulate flowering time. Arabidopsis VRN1 and Glyma11g13220 exhibit conserved as well as diverged functions. PMID- 26420433 TI - Mycobacterium gordonae-induced humidifier lung. AB - BACKGROUND: Nontuberculous mycobacteria are well known to be a cause of hot tub lung, however, to our knowledge, there exists no case report of humidifier lung induced by mycobacteria. CASE PRESENTATION: A case of a nonimmunocompromised female patient with Mycobacterium gordonae-induced humidifier lung is described. She spontaneously recovered after discontinuing ultrasonic humidifier use. When subjected to a provocation test, she demonstrated acute respiratory distress with signs and symptoms, consistent with hypersensitivity pneumonitis. Before and after the provocation test, water in the humidifier reservoir revealed only Mycobacterium gordonae by the microbiologic analyses. CONCLUSION: To our knowledge, this is the first report of humidifier lung induced by nontuberculous mycobacteria. Although nontuberculous mycobacteria are well-known to be agents of hot tub lung or metal working fluid lung, physicians should also consider the pathogen as a cause of hypersensitivity lung reaction associated with humidifier use. PMID- 26420434 TI - A lncRNA to repair DNA. AB - Long non-coding RNAs (lncRNAs) have emerged as regulators of various biological processes, but to which extent lncRNAs play a role in genome integrity maintenance is not well understood. In this issue of EMBO Reports, Sharma et al [1] identify the DNA damage-induced lncRNA DDSR1 as an integral player of the DNA damage response (DDR). DDSR1 has both an early role by modulating repair pathway choices, and a later function when it regulates gene expression. Sharma et al [1] thus uncover a dual role for a hitherto uncharacterized lncRNA during the cellular response to DNA damage. PMID- 26420435 TI - Possibility of monitoring granulation by analyzing the amount of hydroxypropylcellulose, a binder on the surface of granules, using ToF-SIMS. AB - The purpose of this study was to clarify the mechanism responsible for high-shear wet granulation using time-of-flight secondary ion mass spectrometry (ToF-SIMS), which can be used for surface chemical mapping. A total of 15 kinds of granules, including hydroxypropylcellulose (HPC) as a binder, were obtained in a model formulation using different granulation conditions, such as the amount of sprayed water and the granulation time. Surface chemical mapping of these granules was then performed using a ToF-SIMS analysis, which distinguishes each component by detecting the specific mass-to-charge ratio (m/z). As a result, we found that HPC got to appear on the surface of granule with proceeding wet granulation. By considering this result, we concluded that the distributions of HPC might be closely related to the progress of granule consolidation and growth in wet granulation. Therefore, the progress of granulation can likely be understood by measuring the content of HPC on the granule surface. PMID- 26420436 TI - A descriptive review of cardiac tumours in dogs and cats. AB - Cardiac tumours are uncommon in the canine and feline population and often an incidental finding. Common types include haemangiosarcoma (HSA), aortic body tumours (chemodectoma and paraganglioma) and lymphoma. These neoplasms can cause mild to severe, life-threatening clinical signs that are independent of the histological type and may be related to altered cardiovascular function or local haemorrhage/effusion into the pericardial space. Cardiac tumours may require symptomatic treatment aimed at controlling tumour bleeding and potential arrhythmias, and other signs caused by the mass effect. Additional treatment options include surgery, chemotherapy and radiotherapy. For all medical therapies, complete remission is unlikely and medical management, beyond adjunctive chemotherapy in HSA, requires further investigation but combination chemotherapy is recommended for lymphoma. The aim of this report is to summarize and critically appraise the current literature in a descriptive review. However, interpretation is limited by the lack of definitive diagnosis and retrospective nature of most studies. PMID- 26420437 TI - Estimation of Recent and Ancient Inbreeding in a Small Endogamous Tunisian Community Through Genomic Runs of Homozygosity. AB - Runs of homozygosity (ROHs) are extended genomic regions of homozygous genotypes that record populations' mating patterns in the past. We performed microarray genotyping on 15 individuals from a small isolated Tunisian community. We estimated the individual and population genome-wide level of homozygosity from data on ROH above 0.5 Mb in length. We found a high average number of ROH per individual (48.2). The smallest ROH category (0.5-1.49 Mb) represents 0.93% of the whole genome, while medium-size (1.5-4.99 Mb) and long-size ROH (>=5 Mb) cover 1.18% and 0.95%, respectively. We found that genealogical individual inbreeding coefficients (Fped ) based on three- to four-generation pedigrees are not reliable indicators of the current proportion of genome-wide homozygosity inferred from ROH (FROH ) either for 0.5 or 1.5 Mb ROH length thresholds, while identity-by-descent sharing is a function of shared coancestry. This study emphasizes the effect of reproductive isolation and a prolonged practice of consanguinity that limits the genetic heterogeneity. It also provides evidence of both recent and ancient parental relatedness contribution to the current level of genome-wide homozygosity in the studied population. These findings may be useful for evaluation of long-term effects of inbreeding on human health and for future applications of ROHs in identifying recessive susceptibility genes. PMID- 26420438 TI - Erratum to: A new transcriptional variant and small azurophilic granules in an acute promyelocytic leukemia case with NPM1/RARA fusion gene. PMID- 26420439 TI - Mild to moderate increase of serum calcitonin levels only in presence of large medullary thyroid cancer deposits. AB - Many open questions remain to be elucidated about the diagnosis, treatment and prognosis of medullary thyroid cancer (MTC). The most intriguing concerns the outcome of MTC patients after surgery. Great importance is usually given to serum calcitonin (Ct) and carcinoembryonic (CEA) levels. It is commonly believed that the higher are the levels of these tumor markers and their kinetics (double time and velocity of markers levels) the worst is the prognosis. However, this is not the rule, as there are huge MTC metastatic deposits characterized by low serum Ct and CEA levels, and this condition is not closely related to the outcome of the disease during post-surgical follow-up. A series is reported here of patients who have these characteristics, as well as a description of their prognosis and clinical outcome. PMID- 26420440 TI - Long latency between GAD-antibody detection and development of limbic encephalitis--a case report. AB - BACKGROUND: In the pathogenesis of limbic encephalitis other promoting factors besides the pure existence of autoantibodies are increasingly discussed to play a significant role. This is to our knowledge the first described patient in whom the presence of autoantibodies precedes the manifestation of limbic encephalitis for many years. CASE PRESENTATION: At the age of 38 years, in the serum of a patient with polyendocrine autoimmunity high titers of cytoplasmic islet cell antibodies and of anti-glutamate decarboxylase (GAD) 65 antibodies were observed as an incidential finding, GAD67 antibodies were negative at that time. After a latency of 18 years, she manifested with refractory temporal lobe epilepsy most likely due to autoimmune limbic encephalitis. After epilepsy onset, the patient underwent magnetic resonance imaging (MRI), electroencephalography, cerebrospinal fluid (CSF), serum and neuropsychological investigations during a follow-up period of 8 years. A pharmacoresistent epilepsy with seizure onset from the right temporal lobe and declarative memory deficits were observed affecting primarily the recall of verbal informations. MRI showed a slightly increased signal in the right amygdala without progression. GAD antibodies could be detected in serum (titre 1: 1000) and CSF (titre 1:1) by immunofluorescence. Both, GAD65 and GAD67 antibodies were observed in cell-based assays. CONCLUSIONS: It can be assumed that in addition to a pre-existing systemic T-cell response associated with the longstanding polyendocrine autoimmunity, a delayed intrathecal autoimmunity developed leading to limbic encephalitis. This change might be reflected by the development of GAD67 antibodies in our patient. Besides the contribution of this case report to a better understandig of the pathomechanisms for the development of central nervous system (CNS) autoimmunity, it also has a clinical impact as early treatment of GAD antibody-associated CNS disorders has a better prognosis. Therefore, vigilance for symptoms indicating GAD antibody-associated CNS autoimmunity is mandatory in patients with GAD antibody-associated endocrine dysfunction. PMID- 26420441 TI - Direct Evidence for Active Suppression of Salient-but-Irrelevant Sensory Inputs. AB - Researchers have long debated whether attentional capture is purely stimulus driven or purely goal driven. In the current study, we tested a hybrid account, called the signal-suppression hypothesis, which posits that stimuli automatically produce a bottom-up salience signal, but that this signal can be suppressed via top-down control processes. To test this account, we used a new capture-probe paradigm in which participants searched for a target shape while ignoring an irrelevant color singleton. On occasional probe trials, letters were briefly presented inside the search shapes, and participants attempted to report these letters. Under conditions that promoted capture by the irrelevant singleton, accuracy was greater for the letter inside the singleton distractor than for letters inside nonsingleton distractors. However, when the conditions were changed to avoid capture by the singleton, accuracy for the letter inside the irrelevant singleton was reduced below the level observed for letters inside nonsingleton distractors, an indication of active suppression of processing at the singleton location. PMID- 26420442 TI - Weight Discrimination and Risk of Mortality. AB - Discrimination based on weight is a stressful social experience linked to declines in physical and mental health. We examined whether this harmful association extends to risk of mortality. Participants in the Health and Retirement Study (HRS; N = 13,692) and the Midlife in the United States Study (MIDUS; N = 5,079) reported on perceived discriminatory experiences and attributed those experiences to a number of personal characteristics, including weight. Weight discrimination was associated with an increase in mortality risk of nearly 60% in both HRS participants (hazard ratio = 1.57, 95% confidence interval = [1.34, 1.84]) and MIDUS participants (hazard ratio = 1.59, 95% confidence interval = [1.09, 2.31]). This increased risk was not accounted for by common physical and psychological risk factors. The association between mortality and weight discrimination was generally stronger than that between mortality and other attributions for discrimination. In addition to its association with poor health outcomes, weight discrimination may shorten life expectancy. PMID- 26420443 TI - Synthesis of Phenylene Vinylene Macrocycles through Acyclic Diene Metathesis Macrocyclization and Their Aggregation Behavior. AB - A series of phenylene vinylene macrocycles (PVMs) bearing substituents with various sizes and electronic properties have been synthesized through a one-step acyclic diene metathesis macrocyclization approach and their aggregation behaviors have been investigated. In great contrast to the aggregation of the analogous phenylene ethynylene macrocycles, which aggregate only when substituted with electron-withdrawing groups, these PVMs undergo exceptionally strong aggregation, regardless of the electron-donating or -withdrawing characters of the substituents. The unusual aggregation behavior of the PVMs is further investigated with thermodynamic and computer modeling studies, which show a good agreement with the recently proposed direct through-space interaction model, rather than the polar/pi model. The high aggregation tendency of PVMs suggests the great potential of this novel class of shape-persistent macrocycles in a variety of applications, such as ion channels, host-guest recognition, and catalysis. PMID- 26420444 TI - Experimental measurement and Monte Carlo assessment of Argon-41 production in a PET cyclotron facility. AB - In a medical cyclotron facility, (41)Ar (t1/2 = 109.34 m) is produced by the activation of air due to the neutron flux during irradiation, according to the (40)Ar(n,gamma)(41)Ar reaction; this is particularly relevant in widely diffused high beam current cyclotrons for the production of PET radionuclides. While theoretical estimations of the (41)Ar production have been published, no data are available on direct experimental measurements for a biomedical cyclotron. In this work, we describe a sampling methodology and report the results of an extensive measurement campaign. Furthermore, the experimental results are compared with Monte Carlo simulations performed with the FLUKA code. To measure (41)Ar activity, air samples were taken inside the cyclotron bunker in sealed Marinelli beakers, during the routine production of (18)F with a 16.5 MeV GE-PETtrace cyclotron; this sampling thus reproduces a situation of absence of air changes. Samples analysis was performed in a gamma-ray spectrometry system equipped with HPGe detector. Monte Carlo assessment of the (41)Ar saturation yield was performed directly using the standard FLUKA score RESNUCLE, and off-line by the convolution of neutron fluence with cross section data. The average (41)Ar saturation yield per one liter of air of (41)Ar, measured in gamma-ray spectrometry, resulted to be 3.0 +/- 0.6 Bq/uA*dm(3) while simulations gave a result of 6.9 +/- 0.3 Bq/uA*dm(3) in the direct assessment and 6.92 +/- 0.22 Bq/uA*dm(3) by the convolution neutron fluence-to-cross section. PMID- 26420445 TI - Monte Carlo evaluation of the effect of inhomogeneities on dose calculation for low energy photons intra-operative radiation therapy in pelvic area. AB - The aim of this study was to evaluate the effect of inhomogeneities on dose calculation for low energy photons intra-operative radiation therapy (IORT) in pelvic area. A GATE Monte Carlo model of the INTRABEAM(r) was adapted for the study. Simulations were performed in the CT scan of a cadaver considering a homogeneous segmentation (water) and an inhomogeneous segmentation (5 tissues from ICRU44). Measurements were performed in the cadaver using EBT3 Gafchromic(r) films. Impact of inhomogeneities on dose calculation in cadaver was 6% for soft tissues and greater than 300% for bone tissues. EBT3 measurements showed a better agreement with calculation for inhomogeneous media. However, dose discrepancy in soft tissues led to a sub-millimeter (0.65 mm) shift in the effective point dose in depth. Except for bone tissues, the effect of inhomogeneities on dose calculation for low energy photons intra-operative radiation therapy in pelvic area was not significant for the studied anatomy. PMID- 26420446 TI - Measuring skin dose in CT examinations under complex geometries: Instruments, methods and considerations. AB - OBJECTIVE: To investigate skin dose in Computed Tomography (CT) and its dependence on scanning geometry. MATERIALS AND METHODS: Measurements of entrance surface air kerma (ESAK) in free air and entrance skin dose (ESD) on an anthropomorphic phantom were performed in a 64-slice CT scanner, using two different instruments: the Dose Profiler (DP) and the QED skin diode (QEDSD). Using DP and QEDSD, the ESAK rate profiles at the isocenter and at different distances from it, were measured using axial scans. Using DP and helical scans the ESAK rate profile in the Z-axis was acquired. The same profile was acquired with the QEDSD also, using many axial scans and manual table translation. ESD measurements were performed with the DP and QEDSD, in axial and helical scan mode. RESULTS: ESAK measurements with DP and QEDSD were in good agreement, for both point dose and profile measurements. The agreement was also good for ESD measurements but not for helical scans, due to variable X-ray beam overlapping and different tube angular positions at each scan start. It was observed that the ESD values at different Y-axis offsets were comparable to the respective ESAK values recorded at the same Y-axis offset distances without the phantom. CONCLUSIONS: Both DP and QEDSD were proven suitable for performing point ESD measurements. However, calculating the skin dose distribution in CT examinations is a very challenging task. A practical approach would be for CT scanners to provide a conservative estimate of the peak skin dose using the isocenter ESAK value. PMID- 26420447 TI - Did antepartum hypoxic insult caused by fetal vessel thrombosis influence the procalcitonin level in umbilical blood? A case report. AB - We report a case of marked elevation of the procalcitonin level in umbilical blood and neonatal blood at birth. The mother did not perceive fetal motion. Antepartum fetal heart rate monitoring showed a loss of variability and absence of acceleration. No fetal breathing movement, fetal movement, or fetal tone were observed by ultrasonography. The female neonate was delivered by cesarean section at 25 weeks of gestation, with birthweight 774 g. The umbilical arterial pH value at birth was 7.29. Mild elevation in interleukin-6 and tumor necrosis factor alpha in umbilical blood were observed. Cytochrome c showed a high level in umbilical and neonatal blood at birth. Placental histopathology revealed multiple fetal vessel thrombosis in the large stem villi and chorionic vessels. The neonate showed no infectious signs throughout the neonatal period. Computed tomography at 3 months of age revealed atrophy in the cerebrum and cerebellum. At 1 year after birth, the infant showed spastic quadriplegia. In this case, antepartum asphyxia due to fetal vessel thrombosis may have influenced the elevation of procalcitonin level in umbilical blood and neonatal blood at birth. PMID- 26420449 TI - Estimation of potassium and magnesium flows in animal production in Dianchi Lake basin, China. AB - The objectives of this study were to estimate and evaluate potassium (K) and magnesium (Mg) budgets and flows of animal production in the basin of Dianchi Lake, China. Feed sampling and farmer interviews were conducted in field surveys. The supplies of K and Mg from local and external feeds and the retention, production and excretion of animals were calculated individually for dairy cows, fattening pigs, breeding sows, and broilers and laying hens. The K and Mg flows on a regional level were estimated using the individual budgets. At the individual level, in dairy cattle, the K and Mg supplied from local feeds accounted for large parts of the total nutrient intakes, whereas in the other animal categories most of the K and Mg in the feeds depended on external resources. Our findings also suggested that excessive Mg intake resulted in high Mg excretion and low use efficiency in dairy cattle and fattening pigs. At the regional level, the K and Mg amounts of manure produced and applied in the area (K: 339 and Mg: 143 t/year) exceeded those used as local feeds. Our results imply the animal production potentially increased the K and Mg loads in the regional agriculture system. PMID- 26420448 TI - High specificity targeting and detection of human neuroblastoma using multifunctional anti-GD2 iron-oxide nanoparticles. AB - AIM: To develop biocompatible, tumor-specific multifunctional iron-oxide nanoconstructs targeting neuroblastoma, an aggressive pediatric malignancy. MATERIALS & METHODS: Clinical-grade humanized monoclonal antibody (hu14.18K322A), designed to target GD2 antigen on neuroblastoma with reduced nonspecific immune interactions, was conjugated to hydroxyethyl starch-coated iron-oxide nanoparticles. Targeting capability in vitro and in vivo was assessed by immunofluorescence, electron microscopy, analytical spectrophotometry, histochemistry and magnetic resonance R2* relaxometry. RESULTS: The biocompatible nanoconstructs demonstrated high tumor specificity in vitro and in vivo, and low background uptake in a mouse flank xenograft model. Specific accumulation in tumors enabled particle visualization and quantification by magnetic resonance R2* mapping. CONCLUSION: Our findings support the further development toward clinical application of this anti-GD2 iron-oxide nanoconstruct as diagnostic and therapeutic scaffold for neuroblastoma and potentially other GD2-positive malignancies. PMID- 26420452 TI - Functional Conservation of Both CDS- and 3'-UTR-Located MicroRNA Binding Sites between Species. PMID- 26420450 TI - A web-based intervention to promote applications for rehabilitation: a study protocol for a randomized controlled trial. AB - BACKGROUND: The German welfare system follows the principle "rehabilitation rather than pension," but more than the half of all disability pensioners did not utilize medical rehabilitation before their early retirement. A major barrier is the application procedure. Lack of information about the opportunity to utilize rehabilitation services restricts the chance to improve work ability and to prevent health-related early retirement by rehabilitation programs. The establishment of new access paths to medical rehabilitation services was, therefore, identified as a major challenge for rehabilitation research in a recent expertise. Thus, a web-based information guide was developed to support the application for a medical rehabilitation program. METHODS/DESIGN: For this study, the development of a web-based information guide was based on the health action process approach. Four modules were established. Three modules support forming an intention by strengthening risk perception (module 1), positive outcome expectancies (module 2) and self-efficacy (module 3). A fourth module aims at the realization of actual behavior by offering instructions on how to plan and to push the application process. The study on the effectiveness of the web-based information guide will be performed as a randomized controlled trial. Persons aged 40 to 59 years with prior sick leave benefits during the preceding year will be included. A sample of 16,000 persons will be randomly drawn from the registers of 3 pension insurance agencies. These persons will receive a questionnaire to determine baseline characteristics. Respondents of this first survey will be randomly allocated either to the intervention or the control group. Both study groups will then receive letters with general information about rehabilitation. The intervention group will additionally receive a link to the web-based information guide. After 1 year, a second survey will be conducted. Additionally, administrative data will be used to determine if participants apply for rehabilitation and finally start a rehabilitation program. The primary outcomes are the proportion of applied and utilized medical rehabilitation services. Secondary outcomes are cognitions on rehabilitation, self-rated work ability, health-related quality of life and perceived disability, as well as days with sick leave benefits and days of regular employment. DISCUSSION: The randomized controlled trial will provide highest ranked evidence to clarify whether theory-driven web-based information supports access to rehabilitation services for people with prior sickness benefits. TRIAL REGISTRATION: German Clinical Trials Register (Identifier: DRKS00005658 , 16 January 2014). PMID- 26420453 TI - Editorial: The public understanding of nursing--time for a step change? PMID- 26420451 TI - Adaptive Evolution Favoring KLK4 Downregulation in East Asians. AB - The human kallikrein (KLK) cluster, located at chromosome 19q13.3-13.4, encodes 15 serine proteases, including neighboring genes (KLK3, KLK2, KLK4, and KLK5) with key roles in the cascades of semen liquefaction, tooth enamel maturation, and skin desquamation. KLK2 and KLK3 were previously identified as targets of adaptive evolution in primates through different mechanisms linked to reproductive biology and, in humans, genome-wide scans of positive selection captured, a yet unexplored, evidence for KLK neutrality departure in East Asians. We perform a detailed evaluation of KLK3-KLK5 variability in the 1000 Genomes samples from East Asia, Europe, and Africa, which was sustained by our own sequencing. In East Asians, we singled out a 70-kb region surrounding KLK4 that combined unusual low levels of diversity, high frequency variants with significant levels of population differentiation (FST > 0.5) and fairly homogenous haplotypes given the large local recombination rates. Among these variants, rs1654556_G, rs198968_T, and rs17800874_A stand out for their location on putative regulatory regions and predicted functional effects, namely the introduction of several microRNA binding sites and a repressor motif. Our functional assays carried out in different cellular models showed that rs198968_T and rs17800874_A operate synergistically to reduce KLK4 expression and could be further assisted by rs1654556_G. Considering the previous findings that KLK4 inactivation causes enamel malformations in humans and mice, and that this gene is coexpressed in epidermal layers along with several substrates involved in either cell adhesion or keratinocyte differentiation, we propose KLK4 as another target of selection in East Asians correlated to tooth and epidermal morphological traits. PMID- 26420460 TI - Is the ventrogluteal site suitable for intramuscular injections in children under the age of three? AB - AIM: This study was conducted to determine whether the ventrogluteal site could be used for intramuscular injections in children under the age of 3 and to compare the subcutaneous and muscle layer thickness at the anterolateral, deltoid and ventrogluteal site in the different age groups and in both sexes. BACKGROUND: Although recent literature has reported that the ventrogluteal area can be an alternative site for intramuscular injections in children <=12 months of age, little research-based evidence has been found for the use of the ventrogluteal site in infants and toddlers. DESIGN: A descriptive study which took place between November 2013-August 2014. METHOD: A total of 142 children between the ages of 1-36 months were selected by random sampling and ultrasound measurements were made of subcutaneous and muscle thicknesses in the anterolateral, deltoid and ventrogluteal areas. Measurements were analysed using one-way anova and independent samples t-test. RESULTS: The subcutaneous tissue thicknesses in the deltoid, anterolateral and ventrogluteal areas in children between 1-12 months old (n = 56) were 5.20, 6.62 and 7.26 mm respectively, while in children between 13-24 months old (n = 42), these measurements were 4.35, 6.72 and 7.98 mm; in children between 25-36 months old (n = 44), the measurements were 5.92, 7.97 and 13.5 mm. The muscle thicknesses in the deltoid, anterolateral and ventrogluteal areas in children 1- 12 months old were 5.86, 9.10 and 8.17 respectively, while in children between 13-24 months old, the measurements were 7.71, 12.92 and 17.32 mm; in children 25-36 months old, the measurements were 9.28, 18.81 and 19.62 mm. CONCLUSION: This study found that the muscle in the ventrogluteal site is adequately developed, even in infants between the ages of 1-12 months and that in particular, in children 12-36 months old, the ventrogluteal site is even thicker than the anterolateral. PMID- 26420462 TI - N-heterocyclic carbene copper(I) catalysed N-methylation of amines using CO2. AB - The N-methylation of amines using CO2 and PhSiH3 as source of CH3 was efficiently performed using a N-heterocyclic carbene copper(i) complex. The methodology was found compatible with aromatic and aliphatic primary and secondary amines. Synthetic and computational studies have been carried out to support the proposed reaction mechanism for this transformation. PMID- 26420461 TI - Correlation between Echo-Tracking Parameters and In Vitro Measurements of Arterial Contraction and Relaxation in Rats Fed a High-Cholesterol Diet. AB - BACKGROUND: Echo-tracking (ET) is a new technique that allows the assessment of arterial function and stiffness. This study aimed to ascertain the utility of the echo-tracking (ET) technique to assess vascular stiffness in rats with hypercholesterolemia and atherosclerosis. MATERIAL AND METHODS: ET was used to measure the arterial stiffness of the aorta in cholesterol-fed Sprague-Dawley rats (group T1, n=10, for 4 weeks; group T2, n=10, for 12 weeks) and normal control rats (group C1, n=10; group C2, n=10). In vitro isometric tension experiments were used to measure the maximum contractile tension (MCT) and maximum relaxation percentage (MRR%) of aortic rings. Indicators of arterial stiffness and aortic MCT and MRR% were compared between groups using linear regression analysis. Light microscopic evaluation was used to demonstrate atherosclerotic changes in the aorta. RESULTS: The rat models were successfully induced; pathological examination of the aortas showed significant atherosclerosis in group T2, but not in groups C1, C2, or T1. The arterial stiffness parameters obtained using ET and aortic rings in vitro showed significant impairments in T1 and T2 rats compared with C1 and C2 controls (all P<0.05 vs. controls). In addition, these impairments were greater in the T2 group than in the T1 group (all P<0.05). Finally, MRR% correlated with the distensibility coefficient (r=0.396, P=0.012), arterial compliance (r=0.317, P=0.047), stiffness parameter b (r=-0.406, P=0.009) and one-point pulse wave beta (r=-0.434, P=0.005). CONCLUSIONS: These results suggest that ET could be used to evaluate the changes in arterial wall elasticity associated with atherosclerosis and hypercholesterolemia. PMID- 26420463 TI - Reduction of conventional dendritic cells during Plasmodium infection is dependent on activation induced cell death by type I and II interferons. AB - Dendritic cells (DCs) play critical roles in innate and adaptive immunity and in pathogenesis during the blood stage of malaria infection. The mechanisms underlying DC homeostasis during malaria infection are not well understood. In this study, the numbers of conventional DCs (cDCs) and plasmacytoid DCs (pDCs) in the spleens after lethal rodent malaria infection were examined, and were found to be significantly reduced. Concomitant with up-regulation of maturation associated molecules, activation of caspase-3 was significantly increased, suggesting induction of cell death. Studies using neutralizing antibody and gene deficient mice showed that type I and II interferons were critically involved in activation induced cell death of cDCs during malaria infection. These results demonstrate that DCs rapidly disappeared following IFN-mediated DC activation, and that homeostasis of DCs was significantly impaired during malaria infection. PMID- 26420464 TI - Secondary structure of expansion segment D1 in LSU rDNA from Arachnida and its phylogenetic application in Eriophyoid mites and in Acari. AB - An increasing number of researchers have applied secondary-structure based multiple alignments of rDNA genes in phylogeny. These studies mostly depended on a few valuable divergent domains in LSU and SSU rDNA. Yet other divergent domains, e.g. D1, were poorly investigated and rarely used. However, these domains might contain additional evolutionary data and play a vital role in DNA based phylogenetic study. Here, we investigated all available D1 sequences of Arachnida taxa and predicted corresponding secondary structures to help identify homologous positions in the D1 region. Long insertions were found exclusive to Eriophyoidea and folded into three newly proposed helices. Non-Acari taxa were all GC rich. In Acari, most Trombidiformes and all Mesostigmata (Parasitiformes) taxa were AT rich and Ixodida (Parasitiformes) GC rich; however there was no consistent base bias in Sarcoptiformes sequences. For Eriophyoid mites, genera Cecidophyopsis and Aceria were both well supported in MP, NJ, ME and ML tress based on D1 sequences, and clusters of Cecidophyopsis species were identical with former study. This demonstrated that the D1 region could act as a valuable molecular marker in phylogenetic reconstruction of Eriophyoidea. Additionally, D1 has been proven suitable in phylogenetic analysis at the family and genus level in Acari, but not in Opiliones. PMID- 26420465 TI - Digestion of glycogen by a glucosidase released by Trichomonas vaginalis. AB - Trichomonas vaginalis is a protozoan parasite that is the causative agent of trichomoniasis, a widespread sexually transmitted disease. In vitro culture of T. vaginalis typically employs a medium supplemented with either maltose or glucose and carbohydrates are considered essential for growth. Although the nature of the carbohydrates utilized by T. vaginalis in vivo is undefined, the vaginal epithelium is rich in glycogen, which appears to provide a source of carbon for the vaginal microbiota. Here, we show that T. vaginalis grows equally well in growth media supplemented with simple sugars or with glycogen. Analysis of conditioned growth medium by thin layer chromatography indicates that growth on glycogen is accompanied by glycogen breakdown to a mixture of products including maltose, glucose, and oligosaccharides. Enzymatic assays with conditioned growth medium show that glycogen breakdown is accomplished via the release of a glucosidase activity having the properties of an alpha-amylase into the growth medium. Furthermore, we find that released glucosidase activity increases upon removal of carbohydrate from the growth medium, indicating regulation of synthesis and/or secretion in response to environmental cues. Lastly, we show that addition of T. vaginalis glucosidase activity to a growth medium containing glycogen generates sufficient simple sugar to support the growth of lactobacilli which, themselves, are unable to degrade glycogen. Thus, not only does the glucosidase activity likely play an important role in allowing T. vaginalis to secure simple sugars for its own use, it has the potential to impact the growth of other members of the vaginal microbiome. PMID- 26420466 TI - Ultrafast Fabrication of Flexible Dye-Sensitized Solar Cells by Ultrasonic Spray Coating Technology. AB - This study investigates novel deposition techniques for the preparation of TiO2 electrodes for use in flexible dye-sensitized solar cells. These proposed new methods, namely pre-dye-coating and codeposition ultrasonic spraying, eliminate the conventional need for time-consuming processes such as dye soaking and high temperature sintering. Power conversion efficiencies of over 4.0% were achieved with electrodes prepared on flexible polymer substrates using this new deposition technology and N719 dye as a sensitizer. PMID- 26420467 TI - Recombinant bacterial lipoproteins as vaccine candidates. AB - Recombinant bacterial lipoproteins (RLP) with built-in immuno-stimulating properties for novel subunit vaccine development are reviewed. This platform technology offers the following advantages: easily converts antigens into highly immunogenic RLP using a fusion sequence containing lipobox; the lipid moiety of RLP is recognized as the danger signals in the immune system through the Toll like receptor 2, so both innate and adaptive immune responses can be induced by RLP; serves as an efficient and cost-effective bioprocess for producing RLP in Escherichia coli and the feasibility and safety of this core platform technology has been successfully demonstrated in animal model studies including meningococcal group B subunit vaccine, dengue subunit vaccine, novel subunit vaccine against Clostridium difficile-associated diseases and HPV-based immunotherapeutic vaccines. PMID- 26420468 TI - Wave-particle interaction in the Faraday waves. AB - Wave motion in disordered Faraday waves is analysed in terms of oscillons or quasi-particles. The motion of these oscillons is measured using particle tracking tools and it is compared with the motion of fluid particles on the water surface. Both the real floating particles and the oscillons, representing the collective fluid motion, show Brownian-type dispersion exhibiting ballistic and diffusive mean squared displacement at short and long times, respectively. While the floating particles motion has been previously explained in the context of two dimensional turbulence driven by Faraday waves, no theoretical description exists for the random walk type motion of oscillons. It is found that the r.m.s velocity ?MU(osc)?(rms) of oscillons is directly related to the turbulent r.m.s. velocity ?MU?(rms) of the fluid particles in a broad range of vertical accelerations. The measured ?MU(osc)?(rms) accurately explains the broadening of the frequency spectra of the surface elevation observed in disordered Faraday waves. These results suggest that 2D turbulence is the driving force behind both the randomization of the oscillons motion and the resulting broadening of the wave frequency spectra. The coupling between wave motion and hydrodynamic turbulence demonstrated here offers new perspectives for predicting complex fluid transport from the knowledge of wave field spectra and vice versa. PMID- 26420469 TI - What Online Communities Can Tell Us About Electronic Cigarettes and Hookah Use: A Study Using Text Mining and Visualization Techniques. AB - BACKGROUND: The rise in popularity of electronic cigarettes (e-cigarettes) and hookah over recent years has been accompanied by some confusion and uncertainty regarding the development of an appropriate regulatory response towards these emerging products. Mining online discussion content can lead to insights into people's experiences, which can in turn further our knowledge of how to address potential health implications. In this work, we take a novel approach to understanding the use and appeal of these emerging products by applying text mining techniques to compare consumer experiences across discussion forums. OBJECTIVE: This study examined content from the websites Vapor Talk, Hookah Forum, and Reddit to understand people's experiences with different tobacco products. Our investigation involves three parts. First, we identified contextual factors that inform our understanding of tobacco use behaviors, such as setting, time, social relationships, and sensory experience, and compared the forums to identify the ones where content on these factors is most common. Second, we compared how the tobacco use experience differs with combustible cigarettes and e cigarettes. Third, we investigated differences between e-cigarette and hookah use. METHODS: In the first part of our study, we employed a lexicon-based extraction approach to estimate prevalence of contextual factors, and then we generated a heat map based on these estimates to compare the forums. In the second and third parts of the study, we employed a text mining technique called topic modeling to identify important topics and then developed a visualization, Topic Bars, to compare topic coverage across forums. RESULTS: In the first part of the study, we identified two forums, Vapor Talk Health & Safety and the Stopsmoking subreddit, where discussion concerning contextual factors was particularly common. The second part showed that the discussion in Vapor Talk Health & Safety focused on symptoms and comparisons of combustible cigarettes and e-cigarettes, and the Stopsmoking subreddit focused on psychological aspects of quitting. Last, we examined the discussion content on Vapor Talk and Hookah Forum. Prominent topics included equipment, technique, experiential elements of use, and the buying and selling of equipment. CONCLUSIONS: This study has three main contributions. Discussion forums differ in the extent to which their content may help us understand behaviors with potential health implications. Identifying dimensions of interest and using a heat map visualization to compare across forums can be helpful for identifying forums with the greatest density of health information. Additionally, our work has shown that the quitting experience can potentially be very different depending on whether or not e-cigarettes are used. Finally, e-cigarette and hookah forums are similar in that members represent a "hobbyist culture" that actively engages in information exchange. These differences have important implications for both tobacco regulation and smoking cessation intervention design. PMID- 26420470 TI - A promising way to open an energy gap in bilayer graphene. AB - There has been huge research interest in the energy gap problem of monolayer and bilayer graphene due to their great potential in practical applications. Herein, based on first-principles calculations, we report a promising way to open a large band gap in bilayer graphene (BLG) by sandwiching it between two substrates, although this is not usually expected to occur due to the weak interlayer interactions dominated by van der Waals forces. Taking surface-functionalized boron-nitrides as substrates, we predict from first-principles calculations that BLG can have energy gaps ranging from 0.35 eV to 0.55 eV, depending on the substrates and stacking order. Compared to other methods of band-gap manipulation in BLG, the structural integrity of BLG is well-preserved in our study, and the predicted energy gap is suitable for electric devices. Since the proposed method is easily realized in experiments, our results will hopefully accelerate the application of graphene in semiconductor devices and promote the development of graphene technology. PMID- 26420471 TI - Measuring health-relevant businesses over 21 years: refining the National Establishment Time-Series (NETS), a dynamic longitudinal data set. AB - BACKGROUND: The densities of food retailers, alcohol outlets, physical activity facilities, and medical facilities have been associated with diet, physical activity, and management of medical conditions. Most of the research, however, has relied on cross-sectional studies. In this paper, we assess methodological issues raised by a data source that is increasingly used to characterize change in the local business environment: the National Establishment Time Series (NETS) dataset. DISCUSSION: Longitudinal data, such as NETS, offer opportunities to assess how differential access to resources impacts population health, to consider correlations among multiple environmental influences across the life course, and to gain a better understanding of their interactions and cumulative health effects. Longitudinal data also introduce new data management, geoprocessing, and business categorization challenges. Examining geocoding accuracy and categorization over 21 years of data in 23 counties surrounding New York City (NY, USA), we find that health-related business environments change considerably over time. We note that re-geocoding data may improve spatial precision, particularly in early years. Our intent with this paper is to make future public health applications of NETS data more efficient, since the size and complexity of the data can be difficult to exploit fully within its 2-year data licensing period. Further, standardized approaches to NETS and other "big data" will facilitate the veracity and comparability of results across studies. PMID- 26420472 TI - Computational Design of Oligopeptide Containing Poly(ethylene glycol) Brushes for Stimuli-Responsive Drug Delivery. AB - Stimuli-responsive biomaterials are used to facilitate drug and gene delivery by shielding the drug/gene during circulation times and selectively releasing the cargo at the desired target. Within stimuli-responsive materials, pH-responsive materials are exploited for delivery to specific organs, intracellular compartments, cancer cells, site of inflammation or infection as those sites are characterized by pH that is different from the blood pH. In this paper we use molecular dynamics (MD) simulations to design such pH-responsive biomaterials where the balance between the various intermolecular interactions (e.g., electrostatics, van der Waals) within the biomaterials allow biofunctional molecules to be reversibly shielded and exposed to the environment with change in pH. In our model the shielding aspect is imparted by a polyethylene glycol (PEG) brush and the pH-responsive component is a PEG-tethered oligopeptide that undergoes changes in conformations via protonation of residues upon changes in pH. Starting with a PEG-tethered peptide in a monodisperse short PEG brush, we first vary the composition and sequence of histidine (H), lysine (K), and glutamate (E) along the oligopeptide sequence to find the design parameters that maximize the shielding and exposure of the oligopeptide at pH ~ 7.0 and pH < 7.0, respectively. Then, we probe the effect of the PEG brush on the conformations of the oligopeptides by simulating PEG-tethered peptide in a bimodal PEG brush containing short PEG and long PEG chains. We characterize the intermolecular interactions involving the PEG, peptide, and solvent that influence the shielded and exposed conformations of the oligopeptides at the two different pHs. In a short monodisperse PEG brush, with a longer PEG-tethered peptide containing large blocks of histidines that undergo change in protonation state as a response to pH change, placed between a protonated lysine and deprotonated glutamate, the PEG brush exhibits maximum shielding and exposure with pH change. This change from shielded to exposed state is driven by electrostatic repulsion upon H protonation. The presence of long PEG chains in a bimodal PEG brush leads to dominating PEG-peptide attractive interactions that reduces the contrast in shielded and exposed conformations of the PEG-tethered peptide upon protonation of histidines. PMID- 26420473 TI - Preoperative transcutaneous electrical nerve stimulation for localizing superficial nerve paths. AB - During surgery, peripheral nerves are often seen to follow unpredictable paths because of previous surgeries and/or compression caused by a tumor. Iatrogenic nerve injury is a serious complication that must be avoided, and preoperative evaluation of nerve paths is important for preventing it. In this study, transcutaneous electrical nerve stimulation (TENS) was used for an in-depth analysis of peripheral nerve paths. This study included 27 patients who underwent the TENS procedure to evaluate the peripheral nerve path (17 males and 10 females; mean age: 59.9 years, range: 18-83 years) of each patient preoperatively. An electrode pen coupled to an electrical nerve stimulator was used for superficial nerve mapping. The TENS procedure was performed on patients' major peripheral nerves that passed close to the surgical field of tumor resection or trauma surgery, and intraoperative damage to those nerves was apprehensive. The paths of the target nerve were detected in most patients preoperatively. The nerve paths of 26 patients were precisely under the markings drawn preoperatively. The nerve path of one patient substantially differed from the preoperative markings with numbness at the surgical region. During surgery, the nerve paths could be accurately mapped preoperatively using the TENS procedure as confirmed by direct visualization of the nerve. This stimulation device is easy to use and offers highly accurate mapping of nerves for surgical planning without major complications. The authors conclude that TENS is a useful tool for noninvasive nerve localization and makes tumor resection a safe and smooth procedure. PMID- 26420474 TI - Long-term outcome of free fibula osteocutaneous flap and massive allograft in the reconstruction of long bone defect. AB - Reconstruction of massive bone defects in bone tumors with allografts has been shown to have significant complications including infection, delayed or nonunion of allograft, and allograft fracture. Resection compounded with soft tissue defects requires skin coverage. A composite osteocutaneous free fibula offers an optimal solution where the allografts can be augmented mechanically and achieve biological incorporation. Following resection, the cutaneous component of the free osteocutaneous fibula flaps covers the massive soft tissue defect. In this retrospective study, the long-term outcome of 12 patients, who underwent single stage limb reconstruction with massive allograft and free fibula osteocutaneous flaps instead of free fibula osteal flaps only, was evaluated. This study included 12 consecutive patients who had primary bone tumors and had follow-up for a minimum of 24 months. The mean age at the time of surgery was 19.8 years. A total of eight patients had primary malignant bone tumors (five osteosarcomas, two chondrosarcomas and one synovial sarcoma), and four patients had benign bone tumors (two giant-cell tumors, one aneurysmal bone cyst, and one neurofibromatosis). The mean follow-up for the 12 patients was 63 months (range 24-124 months). Out of the 10 patients, nine underwent lower-limb reconstruction and ambulated with partial weight bearing and full weight bearing at an average of 4.2 months and 8.2 months, respectively. In conclusion, augmentation of a massive allograft with free fibula osteocutaneous flap is an excellent alternative for reducing the long-term complication of massive allograft and concurrently addresses the soft tissue coverage. PMID- 26420476 TI - Resolving the conundrum of inbreeding depression but no inbreeding avoidance: Estimating sex-specific selection on inbreeding by song sparrows (Melospiza melodia). AB - Inbreeding avoidance among interacting females and males is not always observed despite inbreeding depression in offspring fitness, creating an apparent "inbreeding paradox." This paradox could be resolved if selection against inbreeding was in fact weak, despite inbreeding depression. However, the net magnitude and direction of selection on the degree to which females and males inbreed by pairing with relatives has not been explicitly estimated. We used long term pedigree data to estimate phenotypic selection gradients on the degree of inbreeding that female and male song sparrows (Melospiza melodia) expressed by forming socially persistent breeding pairs with relatives. Fitness was measured as the total numbers of offspring and grand offspring contributed to the population, and as corresponding expected numbers of identical-by-descent allele copies, thereby accounting for variation in offspring survival, reproduction, and relatedness associated with variation in parental inbreeding. Estimated selection gradients on the degree to which individuals paired with relatives were weakly positive in females, but negative in males that formed at least one socially persistent pairing. However, males that paired had higher mean fitness than males that remained socially unpaired. These analyses suggest that net selection against inbreeding may be weak in both sexes despite strong inbreeding depression, thereby resolving the "inbreeding paradox." PMID- 26420477 TI - Rare genomic rearrangement in a boy with Williams-Beuren syndrome associated to XYY syndrome and intriguing behavior. AB - Williams-Beuren syndrome (WBS) is caused by a hemizygous contiguous gene microdeletion of 1.55-1.84 Mb at 7q11.23 region. Approximately, 28 genes have been shown to contribute to classical phenotype of SWB with presence of dysmorphic facial features, supravalvular aortic stenosis (SVAS), intellectual disability, and overfriendliness. With the use of Microarray-based comparative genomic hybridization and other molecular cytogenetic techniques, is possible define with more accuracy partial or atypical deletion and refine the genotype phenotype correlation. Here, we report on a rare genomic structural rearrangement in a boy with atypical deletion in 7q11.23 and XYY syndrome with characteristic clinical signs, but not sufficient for the diagnosis of WBS. Cytogenetic analysis of G-banding showed a karyotype 47,XYY. Analysis of DNA with the technique of MLPA (Multiplex Ligation-dependent Probe Amplification) using kits a combination of kits (P064, P036, P070, and P029) identified an atypical deletion on 7q11.23. In addition, high resolution SNP Oligonucleotide Microarray Analysis (SNP-array) confirmed the alterations found by MLPA and revealed others pathogenic CNVs, in the chromosomes 7 and X. The present report demonstrates an association not yet described in literature, between Williams-Beuren syndrome and 47,XYY. The identification of atypical deletion in 7q11.23 concomitant to additional pathogenic CNVs in others genomic regions allows a better comprehension of clinical consequences of atypical genomic rearrangements. PMID- 26420475 TI - Gossypium barbadense genome sequence provides insight into the evolution of extra long staple fiber and specialized metabolites. AB - Of the two cultivated species of allopolyploid cotton, Gossypium barbadense produces extra-long fibers for the production of superior textiles. We sequenced its genome (AD)2 and performed a comparative analysis. We identified three bursts of retrotransposons from 20 million years ago (Mya) and a genome-wide uneven pseudogenization peak at 11-20 Mya, which likely contributed to genomic divergences. Among the 2,483 genes preferentially expressed in fiber, a cell elongation regulator, PRE1, is strikingly At biased and fiber specific, echoing the A-genome origin of spinnable fiber. The expansion of the PRE members implies a genetic factor that underlies fiber elongation. Mature cotton fiber consists of nearly pure cellulose. G. barbadense and G. hirsutum contain 29 and 30 cellulose synthase (CesA) genes, respectively; whereas most of these genes (>25) are expressed in fiber, genes for secondary cell wall biosynthesis exhibited a delayed and higher degree of up-regulation in G. barbadense compared with G. hirsutum, conferring an extended elongation stage and highly active secondary wall deposition during extra-long fiber development. The rapid diversification of sesquiterpene synthase genes in the gossypol pathway exemplifies the chemical diversity of lineage-specific secondary metabolites. The G. barbadense genome advances our understanding of allopolyploidy, which will help improve cotton fiber quality. PMID- 26420479 TI - Interleukin-29 induces receptor activator of NF-kappaB ligand expression in fibroblast-like synoviocytes via MAPK signaling pathways. AB - AIM: We previously reported that interleukin-29 (IL-29) was highly expressed in the blood and synovium of rheumatoid arthritis (RA) patients and contributed to synovial inflammation by induction of proinflammatory cytokine production. Given chronic inflammation can trigger the process of bone erosion, and receptor activator of nuclear factor-kappaB ligand (RANKL) plays a crucial role in bone erosion of RA, we hypothesize that IL-29 mediates bone erosion in RA by regulation of RANKL expression. Here, we investigated the effect of IL-29 on RANKL expression in RA fibroblast-like synoviocytes (FLS) and the relevant signaling pathways involved in it. METHODS: Primary fibroblast cells isolated from RA patients were stimulated by recombinant IL-29 in the presence or absence of anti-IL-29 antibody, and the expression levels of RANKL were assessed using real-time polymerase chain reaction and immunostaining. Furthermore, the IL-29 signaling pathway for regulation of RANKL was also examined by Western blotting assay. RESULTS: IL-29 upregulated RANKL expression in a dose-dependent manner, and blockade of IL-29 resulted in a significantly reduced RANKL expression in RA FLS. Incubation RA-FLS with IL-29 (100 ng/mL) led to phosphorylation of ERK (extracellular signal-regulated kinase), p38 and JNK (c-Jun N-terminal kinase). The expression of RANKL induced by IL-29 could be completely blocked by the inhibitors of mitogen-activated protein kinase (MAPK) signal pathway, including PD98059 (ERK inhibitor), SB203580 (p38 inhibitor) and SP600125 (JNK inhibitor). CONCLUSION: These findings indicate, for the first time, that IL-29 could directly induce RANKL expression in RA-FLS via MAPK signaling pathway, suggesting IL-29 might be a new target in the prevention of joint destruction in RA. PMID- 26420480 TI - Printable Bioelectronics To Investigate Functional Biological Interfaces. AB - Thin-film transistors can be used as high-performance bioelectronic devices to accomplish tasks such as sensing or controlling the release of biological species as well as transducing the electrical activity of cells or even organs, such as the brain. Organic, graphene, or zinc oxide are used as convenient printable semiconducting layers and can lead to high-performance low-cost bioelectronic sensing devices that are potentially very useful for point-of-care applications. Among others, electrolyte-gated transistors are of interest as they can be operated as capacitance-modulated devices, because of the high capacitance of their charge double layers. Specifically, it is the capacitance of the biolayer, being lowest in a series of capacitors, which controls the output current of the device. Such an occurrence allows for extremely high sensitivity towards very weak interactions. All the aspects governing these processes are reviewed here. PMID- 26420481 TI - The Kaposi Sarcoma Herpesvirus Latency-associated Nuclear Antigen DNA Binding Domain Dorsal Positive Electrostatic Patch Facilitates DNA Replication and Episome Persistence. AB - Kaposi sarcoma-associated herpesvirus (KSHV) has a causative role in several human malignancies. KSHV latency-associated nuclear antigen (LANA) mediates persistence of viral episomes in latently infected cells. LANA mediates KSHV DNA replication and segregates episomes to progeny nuclei. The structure of the LANA DNA binding domain was recently solved, revealing a positive electrostatic patch opposite the DNA binding surface, which is the site of BET protein binding. Here we investigate the functional role of the positive patch in LANA-mediated episome persistence. As expected, LANA mutants with alanine or glutamate substitutions in the central, peripheral, or lateral portions of the positive patch maintained the ability to bind DNA by EMSA. However, all of the substitution mutants were deficient for LANA DNA replication and episome maintenance. Mutation of the peripheral region generated the largest deficiencies. Despite these deficiencies, all positive patch mutants concentrated to dots along mitotic chromosomes in cells containing episomes, similar to LANA. The central and peripheral mutants, but not the lateral mutants, were reduced for BET protein interaction as assessed by co-immunoprecipitation. However, defects in BET protein binding were independent of episome maintenance function. Overall, the reductions in episome maintenance closely correlated with DNA replication deficiencies, suggesting that the replication defects account for the reduced episome persistence. Therefore, the electrostatic patch exerts a key role in LANA-mediated DNA replication and episome persistence and may act through a host cell partner(s) other than a BET protein or by inducing specific structures or complexes. PMID- 26420482 TI - Structural Basis for Ligand Recognition and Functional Selectivity at Angiotensin Receptor. AB - Angiotensin II type 1 receptor (AT1R) is the primary blood pressure regulator. AT1R blockers (ARBs) have been widely used in clinical settings as anti hypertensive drugs and share a similar chemical scaffold, although even minor variations can lead to distinct therapeutic efficacies toward cardiovascular etiologies. The structural basis for AT1R modulation by different peptide and non peptide ligands has remained elusive. Here, we report the crystal structure of the human AT1R in complex with an inverse agonist olmesartan (Benicar(TM)), a highly potent anti-hypertensive drug. Olmesartan is anchored to the receptor primarily by the residues Tyr-35(1.39), Trp-84(2.60), and Arg-167(ECL2), similar to the antagonist ZD7155, corroborating a common binding mode of different ARBs. Using docking simulations and site-directed mutagenesis, we identified specific interactions between AT1R and different ARBs, including olmesartan derivatives with inverse agonist, neutral antagonist, or agonist activities. We further observed that the mutation N111(3.35)A in the putative sodium-binding site affects binding of the endogenous peptide agonist angiotensin II but not the beta arrestin-biased peptide TRV120027. PMID- 26420483 TI - Ethosuximide Induces Hippocampal Neurogenesis and Reverses Cognitive Deficits in an Amyloid-beta Toxin-induced Alzheimer Rat Model via the Phosphatidylinositol 3 Kinase (PI3K)/Akt/Wnt/beta-Catenin Pathway. AB - Neurogenesis involves generation of new neurons through finely tuned multistep processes, such as neural stem cell (NSC) proliferation, migration, differentiation, and integration into existing neuronal circuitry in the dentate gyrus of the hippocampus and subventricular zone. Adult hippocampal neurogenesis is involved in cognitive functions and altered in various neurodegenerative disorders, including Alzheimer disease (AD). Ethosuximide (ETH), an anticonvulsant drug is used for the treatment of epileptic seizures. However, the effects of ETH on adult hippocampal neurogenesis and the underlying cellular and molecular mechanism(s) are yet unexplored. Herein, we studied the effects of ETH on rat multipotent NSC proliferation and neuronal differentiation and adult hippocampal neurogenesis in an amyloid beta (Abeta) toxin-induced rat model of AD like phenotypes. ETH potently induced NSC proliferation and neuronal differentiation in the hippocampus-derived NSC in vitro. ETH enhanced NSC proliferation and neuronal differentiation and reduced Abeta toxin-mediated toxicity and neurodegeneration, leading to behavioral recovery in the rat AD model. ETH inhibited Abeta-mediated suppression of neurogenic and Akt/Wnt/beta catenin pathway gene expression in the hippocampus. ETH activated the PI3K.Akt and Wnt.beta-catenin transduction pathways that are known to be involved in the regulation of neurogenesis. Inhibition of the PI3K.Akt and Wnt.beta-catenin pathways effectively blocked the mitogenic and neurogenic effects of ETH. In silico molecular target prediction docking studies suggest that ETH interacts with Akt, Dkk-1, and GSK-3beta. Our findings suggest that ETH stimulates NSC proliferation and differentiation in vitro and adult hippocampal neurogenesis via the PI3K.Akt and Wnt.beta-catenin signaling. PMID- 26420484 TI - Histone Deacetylase 3 Coordinates Deacetylase-independent Epigenetic Silencing of Transforming Growth Factor-beta1 (TGF-beta1) to Orchestrate Second Heart Field Development. AB - About two-thirds of human congenital heart disease involves second heart field derived structures. Histone-modifying enzymes, histone deacetylases (HDACs), regulate the epigenome; however, their functions within the second heart field remain elusive. Here we demonstrate that histone deacetylase 3 (HDAC3) orchestrates epigenetic silencing of Tgf-beta1, a causative factor in congenital heart disease pathogenesis, in a deacetylase-independent manner to regulate development of second heart field-derived structures. In murine embryos lacking HDAC3 in the second heart field, increased TGF-beta1 bioavailability is associated with ascending aortic dilatation, outflow tract malrotation, overriding aorta, double outlet right ventricle, aberrant semilunar valve development, bicuspid aortic valve, ventricular septal defects, and embryonic lethality. Activation of TGF-beta signaling causes aberrant endothelial-to mesenchymal transition and altered extracellular matrix homeostasis in HDAC3-null outflow tracts and semilunar valves, and pharmacological inhibition of TGF-beta rescues these defects. HDAC3 recruits components of the PRC2 complex, methyltransferase EZH2, EED, and SUZ12, to the NCOR complex to enrich trimethylation of Lys-27 on histone H3 at the Tgf-beta1 regulatory region and thereby maintains epigenetic silencing of Tgf-beta1 specifically within the second heart field-derived mesenchyme. Wild-type HDAC3 or catalytically inactive HDAC3 expression rescues aberrant endothelial-to-mesenchymal transition and epigenetic silencing of Tgf-beta1 in HDAC3-null outflow tracts and semilunar valves. These findings reveal that epigenetic dysregulation within the second heart field is a predisposing factor for congenital heart disease. PMID- 26420485 TI - Retinal Degeneration Slow (RDS) Glycosylation Plays a Role in Cone Function and in the Regulation of RDS.ROM-1 Protein Complex Formation. AB - The photoreceptor-specific glycoprotein retinal degeneration slow (RDS, also called PRPH2) is necessary for the formation of rod and cone outer segments. Mutations in RDS cause rod and cone-dominant retinal disease, and it is well established that both cell types have different requirements for RDS. However, the molecular mechanisms for this difference remain unclear. Although RDS glycosylation is highly conserved, previous studies have revealed no apparent function for the glycan in rods. In light of the highly conserved nature of RDS glycosylation, we hypothesized that it is important for RDS function in cones and could underlie part of the differential requirement for RDS in the two photoreceptor subtypes. We generated a knockin mouse expressing RDS without the N glycosylation site (N229S). Normal levels of RDS and the unglycosylated RDS binding partner rod outer segment membrane protein 1 (ROM-1) were found in N229S retinas. However, cone electroretinogram responses were decreased by 40% at 6 months of age. Because cones make up only 3-5% of photoreceptors in the wild-type background, N229S mice were crossed into the nrl(-/-) background (in which all rods are converted to cone-like cells) for biochemical analysis. In N229S/nrl(-/ ) retinas, RDS and ROM-1 levels were decreased by ~60% each. These data suggest that glycosylation of RDS is required for RDS function or stability in cones, a difference that may be due to extracellular versus intradiscal localization of the RDS glycan in cones versus rods. PMID- 26420488 TI - Biomarkers in Child Mental Health: a bio-psycho-social perspective is needed. PMID- 26420486 TI - ATM-dependent Phosphorylation of the Fanconi Anemia Protein PALB2 Promotes the DNA Damage Response. AB - The Fanconi anemia protein PALB2, also known as FANCN, protects genome integrity by regulating DNA repair and cell cycle checkpoints. Exactly how PALB2 functions may be temporally coupled with detection and signaling of DNA damage is not known. Intriguingly, we found that PALB2 is transformed into a hyperphosphorylated state in response to ionizing radiation (IR). IR treatment specifically triggered PALB2 phosphorylation at Ser-157 and Ser-376 in manners that required the master DNA damage response kinase Ataxia telangiectasia mutated, revealing potential mechanistic links between PALB2 and the Ataxia telangiectasia mutated-dependent DNA damage responses. Consistently, dysregulated PALB2 phosphorylation resulted in sustained activation of DDRs. Full-blown PALB2 phosphorylation also required the breast and ovarian susceptible gene product BRCA1, highlighting important roles of the BRCA1-PALB2 interaction in orchestrating cellular responses to genotoxic stress. In summary, our phosphorylation analysis of tumor suppressor protein PALB2 uncovers new layers of regulatory mechanisms in the maintenance of genome stability and tumor suppression. PMID- 26420487 TI - Innervating sympathetic neurons regulate heart size and the timing of cardiomyocyte cell cycle withdrawal. AB - Sympathetic drive to the heart is a key modulator of cardiac function and interactions between heart tissue and innervating sympathetic fibres are established early in development. Significant innervation takes place during postnatal heart development, a period when cardiomyocytes undergo a rapid transition from proliferative to hypertrophic growth. The question of whether these innervating sympathetic fibres play a role in regulating the modes of cardiomyocyte growth was investigated using 6-hydroxydopamine (6-OHDA) to abolish early sympathetic innervation of the heart. Postnatal chemical sympathectomy resulted in rats with smaller hearts, indicating that heart growth is regulated by innervating sympathetic fibres during the postnatal period. In vitro experiments showed that sympathetic interactions resulted in delays in markers of cardiomyocyte maturation, suggesting that changes in the timing of the transition from hyperplastic to hypertrophic growth of cardiomyocytes could underlie changes in heart size in the sympathectomized animals. There was also an increase in the expression of Meis1, which has been linked to cardiomyocyte cell cycle withdrawal, suggesting that sympathetic signalling suppresses cell cycle withdrawal. This signalling involves beta-adrenergic activation, which was necessary for sympathetic regulation of cardiomyocyte proliferation and hypertrophy. The effect of beta-adrenergic signalling on cardiomyocyte hypertrophy underwent a developmental transition. While young postnatal cardiomyocytes responded to isoproterenol (isoprenaline) with a decrease in cell size, mature cardiomyocytes showed an increase in cell size in response to the drug. Together, these results suggest that early sympathetic effects on proliferation modulate a key transition between proliferative and hypertrophic growth of the heart and contribute to the sympathetic regulation of adult heart size. PMID- 26420489 TI - The Effects of Interpreter Use on Agreement Between Clinician- and Self-Ratings of Functioning in Hispanic Integrated Care Patients. AB - This study explored whether concordance between self- and clinician- assessment of functioning differs when an interpreter is used in therapy versus when there is language congruence between the clinician and the patient, and whether concordance is affected by patient distress. Participants were 418 Spanish speaking patients seen at one of three primary care clinics. Patients were primarily Hispanic (94 %), uninsured (65 %), and female (84 %), and ranged in age from 18 to 73 years (M = 41.70, SD = 10.70). Pearson's correlation coefficients assessed the association between self- and clinician- reports of patient functioning with and without use of an interpreter. Fisher's z transformations assessed the significance of the difference between the correlation coefficients. Although interpreter use did not significantly disrupt communication of functioning when the patient was highly distressed, there was significant discordance in clinician and patient reports in patients experiencing milder levels of distress communicating by means of an interpreter. PMID- 26420490 TI - Disparities in Health Services Use Among Multiracial American Young Adults. AB - Addressing disparities in health services utilization remains critical for improving minority health; however, most studies do not report on the health service use of multiracial young adults (age 22-34). This study compares past year health service use of self-identified multiracial (two or more races) young adults with monoracial White young adults. Weighted survey data from Add Health (N = 7296) and multivariate logistic regression analyses were used. Compared to monoracial White young adults, Black-White multiracial [OR 0.40, 95 % CI (0.17 0.90)] and Black-Native American multiracial [OR 0.23, 95 % CI (0.09-0.63)] young adults are less likely to report primary care service use in the past year. Multiracial young adults have different health care service utilization than their White monoracial peers with Black-Native American young adults appearing to be particularly vulnerable to under-utilization of primary care services. It is important to examine multiracial subgroups when studying patterns of health services utilization. PMID- 26420492 TI - Caregiver Well-Being: Is it On Your Radar? PMID- 26420491 TI - A low-dose, dual-phase cardiovascular CT protocol to assess left atrial appendage anatomy and exclude thrombus prior to left atrial intervention. AB - Assessment of the left atrial appendage (LAA) for thrombus and anatomy is important prior to atrial fibrillation (AF) ablation and LAA exclusion. The use of cardiovascular CT (CCT) to detect LAA thrombus has been limited by the high incidence of pseudothrombus on single-pass studies. We evaluated the diagnostic accuracy of a two-phase protocol incorporating a limited low-dose delayed contrast-enhanced examination of the LAA, compared with a single-pass study for LAA morphological assessment, and transesophageal echocardiography (TEE) for the exclusion of thrombus. Consecutive patients (n = 122) undergoing left atrial interventions for AF were assessed. All had a two-phase CCT protocol (first-past scan plus a limited, 60-s delayed scan of the LAA) and TEE. Sensitivity, specificity, diagnostic accuracy, positive (PPV) and negative predictive values (NPV) were calculated for the detection of true thrombus on first-pass and delayed scans, using TEE as the gold standard. Overall, 20/122 (16.4 %) patients had filling defects on the first-pass study. All affected the full delineation of the LAA morphology; 17/20 (85 %) were confirmed as pseudo-filling defects. Three (15 %) were seen on late-pass and confirmed as true thrombi on TEE; a significant improvement in diagnostic performance relative to a single-pass scan (McNemar Chi square 17, p < 0.001). The sensitivity, specificity, diagnostic accuracy, PPV and NPV was 100, 85.7, 86.1, 15.0 and 100 % respectively for first-pass scans, and 100 % for all parameters for the delayed scans. The median (range) additional radiation dose for the delayed scan was 0.4 (0.2-0.6) mSv. A low-dose delayed scan significantly improves the identification of true LAA anatomy and thrombus in patients undergoing LA intervention. PMID- 26420493 TI - Reply to the Letter to the Editor by O'Caoimh et al. PMID- 26420494 TI - Pioneering a Nursing Home Quality Improvement Learning Collaborative: A Case Study of Method and Lessons Learned. AB - OBJECTIVES: To describe the development of a nursing home (NH) quality improvement learning collaborative (QILC) that provides Lean Six Sigma (LSS) training and infrastructure support for quality assurance performance improvement change efforts. DESIGN: Case report. SETTING/PARTICIPANTS: Twenty-seven NHs located in the Greater Rochester, NY area. INTERVENTION: The learning collaborative approach in which interprofessional teams from different NHs work together to improve common clinical and organizational processes by sharing experiences and evidence-based practices to achieve measurable changes in resident outcomes and system efficiencies. MEASUREMENTS: NH participation, curriculum design, LSS projects. RESULTS: Over 6 years, 27 NHs from urban and rural settings joined the QILC as organizational members and sponsored 47 interprofessional teams to learn LSS techniques and tools, and to implement quality improvement projects. CONCLUSIONS: NHs, in both urban and rural settings, can benefit from participation in QILCs and are able to learn and apply LSS tools in their team-based quality improvement efforts. PMID- 26420495 TI - Leucobacter zeae sp. nov., isolated from the rhizosphere of maize (Zea mays L.). AB - A novel yellow-pigmented, aerobic, rod-shaped, non-motile bacterium, designated strain CCMF41T, was isolated from rhizosphere soil of maize (Zea mays) collected in Wufeng District, Taichung, Taiwan. Strain CC-MF41T exhibited 16S rRNA gene sequence similarity of 97.5, 97.3, 97.2 and 97.1% to Leucobacter chironomi MM2LBT (and 'Leucobacter kyeonggiensis'F3-P9 and 'L. humi' Re-6, the names of which have not been validly published), Leucobactertardus K70/01T, L. komagatae IFO 15245T and 'Leucobacter margaritiformis' A23. However,CC-MF41T and 'L. margaritiformis' A23 formed a loosely bound phylogenetic lineage (with alow bootstrap value) associated with species of the genus Leucobacter. In DNA-DNA reassociation experiments, the relatedness of strain CC-MF41T to L. chironomi DSM 19883T was 57.1% (reciprocal value 29.1 %). The DNA G+C content of strain CC-MF41T was 72.1 mol% and the cell-wall peptidoglycan contained 2,4-diaminobutyric acid, alanine, glycine,glutamic acid and threonine. The major menaquinone was MK-11 and the predominant fatty acids were iso-C16 : 0, anteiso-C15 : 0 and anteiso-C17 : 0. The polar lipid profile of strain CCMF41T contained major amounts of diphosphatidylglycerol followed by an unidentified glycolipid, phosphatidylglycerol and an unknown phospholipid. Based on its phylogenetic,phenotypic and chemotaxonomic distinctiveness, strain CC-MF41T represents a novel species of Leucobacter, for which the name Leucobacter zeae sp. nov. is proposed. The type strain isCC-MF41T (=BCRC 80515T=LMG 27265T). PMID- 26420496 TI - Effect of co-ingestion of amino acids with rice on glycaemic and insulinaemic response. AB - Consumption of high glycaemic index (GI) and glycaemic response (GR) food such as white rice has been implicated in the development of type 2 diabetes. Previous studies have reported the ability of individual amino acids to reduce GR of carbohydrate-rich foods. Because of the bitter flavour of amino acids, they have rarely been used to reduce GR. We now report the use of a palatable, preformed amino acid mixture in the form of essence of chicken. In all, sixteen healthy male Chinese were served 68 or 136 ml amino acid mixture together with rice, or 15 or 30 min before consumption of white rice. Postprandial blood glucose and plasma insulin concentrations were measured at fasting and every 15 min after consumption of the meal until 60 min after the consumption of the white rice. Subsequent blood samples were taken at 30-min intervals until 210 min. The co ingestion of 68 ml of amino acid mixture with white rice produced the best results in reducing the peak blood glucose and GR of white rice without increasing the insulinaemic response. It is postulated that amino acid mixtures prime beta-cell insulin secretion and peripheral tissue uptake of glucose. The use of ready-to-drink amino acid mixtures may be a useful strategy for lowering the high-GI rice diets consumed in Asia. PMID- 26420497 TI - Mandatory implementation of NICE Guidelines for the care of bipolar disorder and other conditions in England and Wales. AB - BACKGROUND: Bipolar disorder is a common long-term mental health condition characterised by episodes of mania or hypomania and depression resulting in disability, early death, and high health and society costs. Public money funds the National Institute of Healthcare and Clinical Excellence (NICE) to produce clinical guidelines by systematically identifying the most up to date research evidence and costing its main recommendations for healthcare organisations and professionals to follow in England and Wales. Most governments, including those of England and Wales, need to improve healthcare but at reduced cost. There is evidence, particularly in bipolar disorder, that systematically following clinical guidelines achieves these outcomes. DISCUSSION: NICE clinical guidelines, including those regarding bipolar disorder, remain variably implemented. They give clinicians and patients a non-prescriptive basis for deciding their care. Despite the passing of the Health and Social Care Act in 2012 in England requiring all healthcare organisations to consider NICE clinical guidelines in commissioning, delivering, and inspecting healthcare services, healthcare organisations in the National Health Service may ignore them with little accountability and few consequences. There is no mechanism to ensure that healthcare professionals know or consider them. Barriers to their implementation include the lack of political and professional leadership, the complexity of the organisation of care and policy, mistrust of some processes and recommendations of clinical guidelines, and a lack of a clear implementation model, strategy, responsibility, or accountability. Mitigation to these barriers is presented herein. SUMMARY: The variability, safety, and quality of healthcare might be improved and its cost reduced if the implementation of NICE clinical guidelines, such as those for bipolar disorder, were made the minimum starting point for clinical decision-making and mandatory responsibilities of all healthcare organisations and professionals. PMID- 26420498 TI - Characterization of DNA variants in the human kinome in breast cancer. AB - Kinases play a key role in cancer biology, and serve as potential clinically useful targets for designing cancer therapies. We examined nucleic acid variations in the human kinome and several known cancer-related genes in breast cancer. DNA was extracted from fine needle biopsies of 73 primary breast cancers and 19 metastatic lesions. Targeted sequencing of 518 kinases and 68 additional cancer related genes was performed using the SOLiD sequencing platform. We detected 1561 unique, non-synonymous variants in kinase genes in the 92 cases, and 74 unique variants in 43 kinases that were predicted to have major functional impact on the protein. Three kinase groups--CMGC, STE and TKL--showed greater mutational load in metastatic compared to primary cancer samples, however, after correction for multiple testing the difference was significant only for the TKL group (P = 0.04). We also observed that a higher proportion of histologic grade 1 and 2 cases had high functional impact variants in the SCYL2 gene compared with grade 3 cases. Our findings indicate that individual breast cancers harbor a substantial number of potentially functionally important nucleotide variations in kinase genes, most of which are present in unique combinations and include both somatic and germline functional variants. PMID- 26420499 TI - Ultrasound Elastography for Differentiating Benign from Malignant Thickened Greater Omentum. AB - OBJECTIVES: To investigate whether ultrasound elastography (UE) is an effective non-invasive diagnostic procedure for evaluating benign and malignant thickened greater omentum. METHODS: Ultrasound elastographic images from 118 patients who underwent ultrasound-guided biopsy for thickened greater omentum from May 2012 to October 2013 were retrospectively analysed. The results were compared with the pathological findings from the biopsies, and evaluated by ROC curve analysis. RESULTS: A total of 93.6% of the benign thickened greater omentum had elasticity scoring of 1 or 2, whereas 93.0% of the malignant thickened greater omentum had elasticity scoring of 3 or 4. The elasticity strain ratios for malignant thickened greater omenta were higher than for benign thickened greater omenta using muscle or fat yielded as reference tissue (P < 0.01). The optimal cut-off point for elasticity strain ratios using fat as reference was 2.6. The sensitivity, specificity, accuracy, and positive and negative predictive values for determining elasticity strain ratios using fat as reference were 83.3%, 90.6%, 86.5%, 92.1%, and 80.6%, respectively, and for elasticity scoring were 95.2%, 96.9%, 95.9%, 97.6%, and 93.9%, respectively. CONCLUSIONS: UE using elasticity scoring or elasticity strain ratios is an effective new non-invasive method for differentiating benign from malignant thickened greater omentum. KEY POINTS: * Elasticity score is an objective method for differentiating greater omentum lesions. * Elasticity strain ratio is another method for differentiating greater omentum lesions. * Fat tissue is better than abdominal wall muscle as reference in elasticity imaging. * UE is a new effective, non-invasive method for diagnosing omental diseases. PMID- 26420501 TI - Junior doctors pledge to continue action unless Hunt improves offer. PMID- 26420500 TI - T2 black lesions on routine knee MRI: differential considerations. AB - The majority of abnormal findings or lesions on T2-weighted fast spin-echo (FSE) magnetic resonance imaging (MRI) are hyperintense due to increased perfusion or fluid content, such as infections, tumours or synovitis. Hypointense lesions on T2-weighted images (both fat-suppressed and non-fat-suppressed) are less common and can sometimes be overlooked. Such lesions have limited differential diagnostic possibilities, and include vacuum phenomenon, loose body, tenosynovial giant cell tumour, rheumatoid arthritis, haemochromatosis, gout, amyloid, chondrocalcinosis, hydroxyapetite deposition disease, lipoma arborescens, arthrofibrosis and iatrogenic lesions. These lesions often show characteristic appearances and predilections in the knee. In this article, the authors describe the MRI features of hypointense T2 lesions on routine knee MRI and outline a systematic diagnostic approach towards their evaluation. Key Points * Hypointense lesions on T2 images (T2 Dark Lesions) encompass limited diagnostic possibilities. * T2 Dark lesions often show characteristic appearances and predilections in the knee. * A systematic diagnostic approach will help radiologists make the correct diagnosis. PMID- 26420504 TI - Parameter Estimation for Gene Regulatory Networks from Microarray Data: Cold Shock Response in Saccharomyces cerevisiae. AB - We investigated the dynamics of a gene regulatory network controlling the cold shock response in budding yeast, Saccharomyces cerevisiae. The medium-scale network, derived from published genome-wide location data, consists of 21 transcription factors that regulate one another through 31 directed edges. The expression levels of the individual transcription factors were modeled using mass balance ordinary differential equations with a sigmoidal production function. Each equation includes a production rate, a degradation rate, weights that denote the magnitude and type of influence of the connected transcription factors (activation or repression), and a threshold of expression. The inverse problem of determining model parameters from observed data is our primary interest. We fit the differential equation model to published microarray data using a penalized nonlinear least squares approach. Model predictions fit the experimental data well, within the 95% confidence interval. Tests of the model using randomized initial guesses and model-generated data also lend confidence to the fit. The results have revealed activation and repression relationships between the transcription factors. Sensitivity analysis indicates that the model is most sensitive to changes in the production rate parameters, weights, and thresholds of Yap1, Rox1, and Yap6, which form a densely connected core in the network. The modeling results newly suggest that Rap1, Fhl1, Msn4, Rph1, and Hsf1 play an important role in regulating the early response to cold shock in yeast. Our results demonstrate that estimation for a large number of parameters can be successfully performed for nonlinear dynamic gene regulatory networks using sparse, noisy microarray data. PMID- 26420505 TI - Mathematical Model for MRSA Nasal Carriage. AB - An interesting biological phenomenon that is a factor for the spread of antibiotic-resistant strains, such as MRSA, is human nasal carriage. Here, we evaluate several biological hypotheses for this problem in an effort to better understand and narrow the scope of the dominant factors that allow these bacteria to persist in otherwise healthy individuals. First, we set up and analyze a simple PDE model created to generally mimic the interactions of the microbes and nasal immune response. This includes looking at different types of diffusion and chemotaxis terms as well as different boundary conditions. Then, using sensitivity analysis, we walk through several biological hypotheses and compare to the model's results looking for persistent infection scenarios indicated by the model's bacteria component surviving over time. PMID- 26420506 TI - Acute aortic dissection mimicking acute abdomen in a 14-year-old boy. AB - Aortic dissection is extremely rare in children. Although it usually presents with severe chest pain, atypical clinical presentations mimicking various illnesses may cause misdiagnosis. In this report, the case of a 14-year-old boy with symptoms suggestive of acute abdomen, which was finally diagnosed as aortic dissection, is discussed. PMID- 26420502 TI - Structural basis of glycan specificity in neonate-specific bovine-human reassortant rotavirus. AB - Strain-dependent variation of glycan recognition during initial cell attachment of viruses is a critical determinant of host specificity, tissue-tropism and zoonosis. Rotaviruses (RVs), which cause life-threatening gastroenteritis in infants and children, display significant genotype-dependent variations in glycan recognition resulting from sequence alterations in the VP8* domain of the spike protein VP4. The structural basis of this genotype-dependent glycan specificity, particularly in human RVs, remains poorly understood. Here, from crystallographic studies, we show how genotypic variations configure a novel binding site in the VP8* of a neonate-specific bovine-human reassortant to uniquely recognize either type I or type II precursor glycans, and to restrict type II glycan binding in the bovine counterpart. Such a distinct glycan-binding site that allows differential recognition of the precursor glycans, which are developmentally regulated in the neonate gut and abundant in bovine and human milk provides a basis for age-restricted tropism and zoonotic transmission of G10P[11] rotaviruses. PMID- 26420507 TI - Genetic dissection of the maize kernel development process via conditional QTL mapping for three developing kernel-related traits in an immortalized F2 population. AB - Kernel development is an important dynamic trait that determines the final grain yield in maize. To dissect the genetic basis of maize kernel development process, a conditional quantitative trait locus (QTL) analysis was conducted using an immortalized F2 (IF2) population comprising 243 single crosses at two locations over 2 years. Volume (KV) and density (KD) of dried developing kernels, together with kernel weight (KW) at different developmental stages, were used to describe dynamic changes during kernel development. Phenotypic analysis revealed that final KW and KD were determined at DAP22 and KV at DAP29. Unconditional QTL mapping for KW, KV and KD uncovered 97 QTLs at different kernel development stages, of which qKW6b, qKW7a, qKW7b, qKW10b, qKW10c, qKV10a, qKV10b and qKV7 were identified under multiple kernel developmental stages and environments. Among the 26 QTLs detected by conditional QTL mapping, conqKW7a, conqKV7a, conqKV10a, conqKD2, conqKD7 and conqKD8a were conserved between the two mapping methodologies. Furthermore, most of these QTLs were consistent with QTLs and genes for kernel development/grain filling reported in previous studies. These QTLs probably contain major genes associated with the kernel development process, and can be used to improve grain yield and quality through marker-assisted selection. PMID- 26420509 TI - Mass transfer in electromembrane extraction--The link between theory and experiments. AB - Electromembrane extraction was introduced in 2006 as a totally new sample preparation concept for the extraction of charged analytes present in aqueous samples. Electromembrane extraction is based on electrokinetic migration of the analytes through a supported liquid membrane and into a MUL-volume of acceptor solution under the influence of an external electrical field. To date, electromembrane extraction has mostly been used for the extraction of drug substances, amino acids, and peptides from biological fluids, and for organic micropollutants from environmental samples. Electromembrane extraction has typically been combined with chromatography, mass spectrometry, and electrophoresis for analyte separation and detection. At the moment, close to 125 research papers have been published with focus on electromembrane extraction. Electromembrane extraction is a hybrid technique between electrophoresis and liquid-liquid extraction, and the fundamental principles for mass transfer have only partly been investigated. Thus, although there is great interest in electromembrane extraction, the fundamental principle for mass transfer has to be described in more detail for the scientific acceptance of the concept. This review summarizes recent efforts to describe the fundamentals of mass transfer in electromembrane extraction, and aim to give an up-to-date understanding of the processes involved. PMID- 26420508 TI - Denticle-embedded ampullary organs in a Cretaceous shark provide unique insight into the evolution of elasmobranch electroreceptors. AB - Here, we report a novel type of dermal denticle (or placoid scale), unknown among both living and fossil chondrichthyan fishes, in a Cretaceous lamniform shark. By their morphology and location, these dermal denticles, grouped into clusters in the cephalic region, appear to have been directly associated with the electrosensory ampullary system. These denticles have a relatively enlarged (~350 MUm in diameter), ornamented crown with a small (~100 MUm) asterisk- or cross shaped central perforation connected to a multi-alveolate internal cavity. The formation of such a complex structure can be explained by the annular coalescence and fusion, around an ampullary vesicle, of several developmental units still at papillary stage (i.e. before mineralization), leading to a single denticle embedding an alveolar ampulla devoid of canal. This differs from larger typical ampullae of Lorenzini with a well-developed canal opening in a pore of the skin and may represent another adaptive response to low skin resistance. Since it has been recently demonstrated that ampullary organs arise from lateral line placodes in chondrichthyans, this highly specialized type of dermal denticle (most likely non-deciduous) may be derived from the modified placoid scales covering the superficial neuromasts (pit organs) of the mechanosensory lateral line system of many modern sharks. PMID- 26420510 TI - Changes in biochemical, hemodynamic, and dialysis adherence parameters in hemodialysis patients during Ramadan. AB - This paper aimed to study the effect of Ramadan fasting on biochemical and clinical parameters and compliance for dialysis. A prospective multicenter observational cross-sectional study comparing fasting with a non-fasting stable adult hemodialysis patients for demographic and biochemical parameters, compliance with dialysis, inter-dialytic weight gain, pre- and post-blood pressure, and frequency of intradialytic hypotensive episodes was carried out. Six hundred thirty-five patients, of whom 64.1% fasted, were studied. The fasters were younger (53.3 +/- 16.2 vs. 58.4 +/- 16.1 years; P = 0.001) but had similar duration on dialysis (P = 0.35). More fasters worked (22.0% vs. 14.6%; P = 0.001) and missed dialysis sessions during Ramadan. No differences were noted between groups in sex, diabetic status, or dialysis shift or day. There were no differences in the pre- and post-dialysis blood pressure; serum potassium, albumin or weight gain; diabetic status; sex; and dialysis shift time or days. However, serum phosphorous was significantly higher in the fasting group (2.78 +/ 1.8 vs. 2.45 +/- 1.6 mmol/L; P = 0.045). There were no intragroup differences in any of the parameters studied when comparing the findings during Ramadan with those in the month before Ramadan. Fasters were significantly younger and more likely to be working, to miss dialysis sessions, and to have higher serum phosphorous levels. No other differences were observed. PMID- 26420511 TI - Flexible nanoporous tunable electrical double layer biosensors for sweat diagnostics. AB - An ultra-sensitive and highly specific electrical double layer (EDL) modulated biosensor, using nanoporous flexible substrates for wearable diagnostics is demonstrated with the detection of the stress biomarker cortisol in synthetic and human sweat. Zinc oxide thin film was used as active region in contact with the liquid i.e. synthetic and human sweat containing the biomolecules. Cortisol detection in sweat was accomplished by measuring and quantifying impedance changes due to modulation of the double layer capacitance within the electrical double layer through the application of a low orthogonally directed alternating current (AC) electric field. The EDL formed at the liquid-semiconductor interface was amplified in the presence of the nanoporous flexible substrate allowing for measuring the changes in the alternating current impedance signal due to the antibody-hormone interactions at diagnostically relevant concentrations. High sensitivity of detection of 1 pg/mL or 2.75 pmol cortisol in synthetic sweat and 1 ng/mL in human sweat is demonstrated with these novel biosensors. Specificity in synthetic sweat was demonstrated using a cytokine IL-1beta. Cortisol detection in human sweat was demonstrated over a concentration range from 10-200 ng/mL. PMID- 26420512 TI - Metabolites and Changes in Antioxidant Activity of A-Type and B-Type Proanthocyanidin Dimers after Incubation with Rat Intestinal Microbiota. AB - Metabolism of B-type EC dimer, A-type EC dimer, A-type ECG dimer, and A-type EGCG dimer was compared in vitro after incubation with rat intestinal microbiota for 0 24 h. A "dimeric" catabolite (m/z 815.6) was detected in four procyanthocyanidin dimers. Although the early cleavage of the C4-C8 interflavan bond and the reductive cleavage of the C-ring occurred in both B-type and A-type dimers, the degradation routes of these two types of dimers might somewhat differ. A dimeric catabolite C1 and more low molecular weight phenolic acids were detected in the metabolites of A-type EC dimer, but not in B-type EC dimer. The antioxidant capabilities of the A-type dimers were enhanced significantly after incubation for 6 h, whereas the antioxidant capacity of B-type EC dimer decreased. The results suggested that changes in antioxidant activity of procyanidin dimers after bioconversion by rat intestinal microbiota were not only structure dependent but also incubation condition dependent. PMID- 26420513 TI - Pacific Populations, Metabolic Disease and 'Just-So Stories': A Critique of the 'Thrifty Genotype' Hypothesis in Oceania. AB - Pacific populations have long been observed to suffer a high burden of metabolic disease, including obesity, type 2 diabetes and gout. The 'Thrifty Genotype' hypothesis has frequently been used to explain this high prevalence of disease. Here, the 'Thrifty Genotype' hypothesis and the evolutionary background of Pacific populations are examined. We question its relevance not only in the Pacific region but more generally. Not only has the hypothesis not been explicitly tested, but most archaeological and anthropological data from the Pacific fundamentally do not support its application. PMID- 26420515 TI - Near-Infrared Phosphorus-Substituted Rhodamine with Emission Wavelength above 700 nm for Bioimaging. AB - Phosphorus has been successfully fused into a classic rhodamine framework, in which it replaces the bridging oxygen atom to give a series of phosphorus substituted rhodamines (PRs). Because of the electron-accepting properties of the phosphorus moiety, which is due to effective sigma*-pi* interactions and strengthened by the inductivity of phosphine oxide, PR exhibits extraordinary long-wavelength fluorescence emission, elongating to the region above 700 nm, with bathochromic shifts of 140 and 40 nm relative to rhodamine and silicon substituted rhodamine, respectively. Other advantageous properties of the rhodamine family, including high molar extinction coefficient, considerable quantum efficiency, high water solubility, pH-independent emission, great tolerance to photobleaching, and low cytotoxicity, stay intact in PR. Given these excellent properties, PR is desirable for NIR-fluorescence imaging in vivo. PMID- 26420516 TI - [Cancer pain management: Systematic review and critical appraisal of clinical practice guidelines]. AB - OBJECTIVE: Although several clinical practice guidelines have been developed in the last decades, cancer pain management is still deficient. The purpose of this work was to carry out a comprehensive and systematic literature review of current clinical practice guidelines on cancer pain management, and critically appraise their methodology and content in order to evaluate their quality and validity to cope with this public health issue. MATERIALS AND METHODS: A systematic review was performed in the main databases, using English, French and Spanish as languages, from 2008 to 2013. Reporting and methodological quality was rated with the Appraisal of Guidelines, Research and Evaluation II (AGREE-II) tool, including an inter-rater reliability analysis. Guideline recommendations were extracted and classified into several categories and levels of evidence, aiming to analyse guidelines variability and evidence-based content comprehensiveness. RESULTS: Six guidelines were included. A wide variability was found in both reporting and methodological quality of guidelines, as well as in the content and the level of evidence of their recommendations. The Scottish Intercollegiate Guidelines Network guideline was the best rated using AGREE-II, while the Sociedad Espanola de Oncologia Medica guideline was the worst rated. The Ministry of Health Malaysia guideline was the most comprehensive, and the Scottish Intercollegiate Guidelines Network guideline was the second one. CONCLUSIONS: The current guidelines on cancer pain management have limited quality and content. We recommend Ministry of Health Malaysia and Scottish Intercollegiate Guidelines Network guidelines, whilst Sociedad Espanola de Oncologia Medica guideline still needs to improve. PMID- 26420514 TI - Models and methods for in vitro testing of hepatic gap junctional communication. AB - Inherent to their pivotal roles in controlling all aspects of the liver cell life cycle, hepatocellular gap junctions are frequently disrupted upon impairment of the homeostatic balance, as occurs during liver toxicity. Hepatic gap junctions, which are mainly built up by connexin32, are specifically targeted by tumor promoters and epigenetic carcinogens. This renders inhibition of gap junction functionality a suitable indicator for the in vitro detection of nongenotoxic hepatocarcinogenicity. The establishment of a reliable liver gap junction inhibition assay for routine in vitro testing purposes requires a cellular system in which gap junctions are expressed at an in vivo-like level as well as an appropriate technique to probe gap junction activity. Both these models and methods are discussed in the current paper, thereby focusing on connexin32-based gap junctions. PMID- 26420517 TI - Attribution-Based Nocebo Effects. Perceived Effects of a Placebo Pill and a Sham Magnetic Field on Cognitive Performance and Somatic Symptoms. AB - BACKGROUND: Negative non-specific (nocebo-like) effects of medications and electromagnetic fields are often described as results of mistaken attribution. PURPOSE: The current study aimed to find empirical evidence supporting this theory. METHOD: Participants completed questionnaires assessing modern health worries, health anxiety, and somatosensory amplification, were assigned to one of three conditions (placebo pill with sedative information, sham magnetic field, or control), and completed a 14-min vigilance task. Changes in physiological arousal (heart rate, heart rate variability, and skin conductance) and reported symptoms were also measured. Finally, causal attributions concerning cognitive performance and reported symptoms were assessed. RESULTS: No increase in symptom reports and physiological arousal was measured in the two intervention groups. A perceived negative effect on cognitive performance was attributed to both sham conditions, and attributions were connected to modern health worries. A proportion of reported symptoms was ascribed to the placebo pill but not to the sham magnetic field. Symptom attributions were not related to any assessed psychological variables. CONCLUSIONS: An aroused physiological state is not necessary for the automatic causal attribution process. Negative effects attributed to medication and environmental factors can be regarded as unavoidable side effects of human cognitive-emotional functioning; they might be alleviated, but cannot be completely eradicated. PMID- 26420519 TI - The emergency medicine research priority setting partnership. PMID- 26420518 TI - How many preterm births in England are due to excision of the cervical transformation zone? Nested case control study. AB - BACKGROUND: Preterm births (as a proportion of all births) have been increasing in many countries. There is growing evidence of increased risk of preterm birth following excisional treatment of the cervix. We estimate the number of preterm births attributable to excisional treatments with a length of 10 mm or more in England. METHODS: Case-control study nested in a record linkage cohort of women with a histological sample at 13 hospitals in England. We combined observed age at first excisional treatment in our cohort with the weighted distribution of excision length from the case-control study to estimate the length distribution by age at first treatment among the cohort. The number of births after excision for each 5-year age group was estimated using national fertility data; published absolute risks of preterm (<37 gestational weeks) and very preterm birth (<32 weeks) were applied to these to estimate the number of preterm births per 100 women treated. Excess preterm births were estimated assuming all treatments were small. The attributable risk of preterm birth following excisional treatment in England was estimated. RESULTS: The majority of first excisional treatments at colposcopy were small (47.5%) or medium (39.1%), 9.5% were large and 4.1% were very large excisions. 4.0% of women treated before birth had more than one excisional treatment. Thus based on our cohort of 10,711 treated women and the length of treatment observed in the case control study we estimate an excess of 240 preterm births (including 57 very preterm) or 2.2 (including 0.5 very preterm) per 100 women treated. At a population level (for England) we estimate that 39,101 women aged 20-39 would be treated each year and that these treatments will lead to an excess of 840 preterm births (including 196 very preterm) in England each year. CONCLUSIONS: Assuming associations between preterm birth and treatment for cervical disease are causal; we estimate that an excess 840 (2.5%) preterm birth in England each year are due to excisional treatments of 10 mm or more. Those that go on to become pregnant should be closely monitored during antenatal period to reduce their risk of preterm birth. PMID- 26420520 TI - Integrative review of nurse-led follow-up after discharge from the ICU. AB - AIM AND OBJECTIVES: To analyse and synthesise the structure, content, types of outcome variables and advantages of nurse-led follow-up of adult patients after discharge from intensive care units. BACKGROUND: Follow-up service after discharge from the intensive care unit has been suggested as a way of supporting recovery of patients. Nevertheless, varieties exist in the understanding and content of nurse-led follow-up. DESIGN: An integrative review of nurse-led follow up inspired by the framework of Whittemore and Knafl. METHODS: An integrative method merged with the recommendations of the PRISMA statement was used to structure the review and findings. Online databases PubMed, CINAHL, ScienceDirect and Scopus were searched from the years 2003-2014. The retrieved articles were independently assessed by two reviewers. Critical appraisal was conducted using check lists from Johanna Briggs Institute. Emerging patterns were validated by all the authors throughout the entire process of analysis. RESULTS: Seventeen papers were included. Three patterns of nurse-led follow-up were identified: (1) Ward visits--in the immediate time after discharge from intensive care unit, (2) Ward visits and appointment(s) to an intensive care unit follow-up clinic and (3) follow-up visit to an intensive care unit and phone call(s) after discharge. Content of short-term nurse-led follow-up (1) ranged from clinical assessment to supporting patients in articulating their subjective health concerns. Long-term nurse-led follow-up (2, 3) included appointments, phone call(s) or information on where advice could be sought. Types of outcome variables were primarily descriptive. There were strong implications for patients' satisfaction with nurse led follow-up up to six months after discharge. CONCLUSION: Nurse-led follow-up might promote patients' health and enable use of adequate resources. RELEVANCE TO CLINICAL PRACTICE: The findings of this review could be used to design, and test, future interventions and their implementation. PMID- 26420521 TI - [History of incompability among medicinals of "Glycyrrhiza antagonistic to Sargassum, Euphorbia Pekinensis, Kansui, and Genkwa" and its modern recognition]. AB - The allegation of "Glycyrrhiza antagonistic to Sargassum, Euphorbia Pekinensis, Kansui, and Genkwa", being one of the hypotheses of "18 antagonisms" in TCM pharmacology, is referring to the antagonistic action among the Radix et Rhizoma Glycyrrhiza and Radix Euphorbiae Kansui, Radix Euphorbiae Pekinensis, Flos Genkwa, and Sargassum when compounded together in a single recipe. By reviewing its history concerted with modern knowledge, it can be found that the theory of "seven emotions" was originated from Shennong's Classic of Materia Medica; while the Variorum of the Classic of Materia Medica firstly and definitely records that Radix et Rhizoma Glycyrrhizae is forbidden to be used with Radix Kansui, Flos Genkwa, Radix Euphorbiae Pekinensis, Sargassum together in a single formula. It was summarized into a Chinese poetic sentence as above-mentioned later. In the works of later ages, including Chinese Pharmacopoeia, A Great Dictionary of Chinese Materia Medica, and China's Herbology, etc., all enhance the understanding of the prohibited combination of Radix et Rhizoma Glycyrrhizae and its incompatible herbs. Nevertheless, there are discrepancies between the results of modern experimental and clinical studies on this problem, which, needless to say, should be resolved by further investigations. PMID- 26420522 TI - [Evolution of the origin of strain of Shancigu (Rhizoma Pleionis)]. AB - Shancigu (Rhizome Pleionis) was first recorded in the Ben cao shiyi (Supplements to Chinese Materia Medica). The source of the strain of this medicinal was unclear because of its too simple description in the medical books in the Tang and Song dynasties. Its original plant could be Cremastra appendiculata (D.Don) Makino, Tulipa edulis (Miq.) Baker and so on. The original plant of Shanciguwas Tulipaedulis since the Ming dynasty to the Republican period. The name of "Guangcigu" began to appear in the Republican period because of the changes of its processing method. The original plants evolved into Cremastra appendiculata, Pleione bulbocodioides (Franch.) Rolfe and Pleione yunnanensis Rolfe, with Tulipa edulisas the original plant of Guangcigu (Bulbus of Tulipasedulis). It is found that only the Tulipaedulis is the unequivocal origin with the longest medicinal history through sorting out of the original plants of Shancigu. Hence, it is suggested that Tulipa edulis should be recovered as the original strain of Shancigu. PMID- 26420523 TI - [Medical application of the art of supplication before the Tang dynasty]. AB - Ample materials on diseases treated with supplication were seen on excavated texts, medical works from ancient time, and religious works before the Tang dynasty (including Tang dynasty). Since the breaking up of witchcraft from medicine, there are still supplication applied in the treatment and prevention of diseases, including those of internal medicine, external medicine, women's and children's diseases, disease of the sense organs, and infections. There are dual reasons for this phenomena, one being the diseases caused by spirit and ghostss; and the other being certain effectiveness of this art on some diseases not cured by other regular treatments, hence, its acceptance by secular people. PMID- 26420524 TI - [The significance of drawing on experience of experimental study on Chinese materia medica during the Republican period]. AB - During the period of the Republic of China, researches of experiments on Chinese materia medica developed extensively with the scientific process of Chinese medicine. Although the technology standard was relatively low and the reference value, limited. The experiences, positive or negative, obtained at that time still has reference significance to today's Chinese medicine scientific research. The notion that traditional Chinese medical and scientific research be conducted under the guidance of TCM theory; valuable experience contained in the ancient literature of traditional Chinese medicine be collected; and the transformation capacity of scientific research be elevated, has been accepted by modern TCM professionals. If you go back to the history, it can be seen that this notion was summarized through repeated practice during the critical moment of traditional Chinese medicine, which should be emphasized and its understanding deepened at any time. PMID- 26420525 TI - [Crisis and vitality: new evaluation of the development of the Chinese Medicine in the Republican period]. AB - By investigating the development process of the Republic of China with pluralistic perspective, it can be seen that contemporary TCM was undergoing the crises of theory, value, and survival, and rights which were a necessary steps when entering a new historical stage. The mainstream of the development of TCM during this period included fighting for its existence and self-strengthening, which had gained five achievements, including prevention of the attempts of abolishing TCM; involvement into the modern national political system; inheritance of the integrity of academic system; the formation of embryonic shape of new business, and the experience attained in the integration of Chinese and Western Medicine. All these manifested its strong vitality, though it was somewhat limited in its developmental level. It had laid down the basis for the embryonic stage of developmental model of Chinese medicine after the twentieth century. PMID- 26420526 TI - [Exploration on the appraisal of Chinese medical lawsuit cases in the Republican period]. AB - Since the doctor-patient relationship was increasingly tense during the Republican period, Chinese medical lawsuit cases happened frequently due to various sorts of dispute, and had become the focus in both medical and judiciary fields. During this period, the Chinese medical professionals were highly concerned about the rights of medical appraisal and opposed the appraisal made only by western medical professionals alone. Through the establishment of various sorts of appraisal units by professional community, academic groups, and medical colleges, endeavor were made to improve the appraisal level of professionalization and objectivity. PMID- 26420527 TI - [New merge of knowledge of the acu-moxibustion academic in the Republican period]. AB - During the republican period, western science and technology as well as western medicine spread quickly in China, and inevitably had a profound influence on the academic of acu-moxibustion. The confluence of Chinese and western medicine with the scientification of acu-moxibustion had left an obvious mark on the academic of acu-moxibustion. No matter whether the theory involves science of channels and collaterals, acupoints and methods of needling and moxibustion or the improvement of acu-moxibustion apparatus and new therpy methods, all carrying remarkable characteristic of new merge of knowledge, and providing solid foundation and valuable reference for the development of contemporary academic of acu moxibustion. PMID- 26420528 TI - [Development of external medicine and dermatology of TCM in the Republican period]. AB - The inheritance of the theory in external medicine in the Republican period was mainly derived from Wai ke zheng zong (Orthodox Manual of External Medicine) and Yi zong jin jian (Golden Mirror of Medicine) and the sorting out of medical plasters, pills, and powders from Wai ke shi san fang (Thirteen Recipes of External Medicine). Zhang Shanlei's Yang ke gang yao (Guidelines for Ulcerations), based on the five-year experience of Zhu's family, offers new experience and ideas for syndrome differentiation; Ding Ganren's diagnosis for external medicine is exquisite with many well known formulae prescribed by himself; Monographs on leprosy and syphilis were published by famous physicians. Departments of external medicine and anal diseases, and classes on external medicine and dermatology and venereal diseases were set up in TCM schools in Guangdong and Zhejiang provinces with teaching materials compiled. All these mark the development of external medicine in modern age. PMID- 26420529 TI - [Textual research on relationship between traditional Chinese medicine and medical prescriptions in the Sanskrit formulary Bower Manuscript excavated in Xinjiang]. AB - This paper introduces the Bower Manuscript in Sanskrit written on birch bark excavated in Xinjiang, which was bought in Kuqa by a British India army lieutenant Bower, hence its title. Then, it was researched, annotated, and published in 7 volumes by a German British lieutenant and orientalist Honer. The first three volumes are devoted to medical prescriptions. It is first verified that its "Dazi Xiangye San" is the "Dujuan Dachen San" in Tibetan medicine. By comparing it with other traditional medical systems, such as Chinese, Tibetan, Mongolian, and Uyghur medical systems, we found that Bower Manuscript is closer to Tibetan medicine and Mongolian medicine, while it has less relation with Chinese medicine and Uyghur medicine. However, it also exerts some influence on TCM. PMID- 26420530 TI - [Philological structure of Dan xi shou jing (Danxi's Hand Mirror)]. AB - Zhu Danxi, one of the four Major Schools of the Jin-Yuan Dynasties, had a lot of works circulated with its authorship in disarray. Part of the works were compiled by his disciples, while others were by his self-taught followers based on prior circulated Danxi's originals, plus some apocryphal so-called Danxi's works circulated posthumously. When sorting out Danxi's Hand Mirror, we found that some of its contents are closely related to Bei ji qian jin yao fang (Essential Prescriptions Worth a Thousand Gold for Emergencies), Qian jin yi fang (Supplements to Qian jin yao fang), Tai ping sheng hui fang (Peaceful Holy Benevolent Prescriptions), Zhu jie shang han lun (Annotated Treatises of Cold Pathogenic Disease), Shang han ming li lun (Elucidation of Cold Pathogenic Disease), Ge zhi yu lun (Treatise of Inquiring the Properties of Things), either by transcription or with an identical origin. By clearing their relationships, it can provide assistance to the research of the philological structure of Danxi's hand Mirror. PMID- 26420531 TI - [Research on TCM periodical Tong su yi shi yue kan (Popular Medical Monthly), a magazinepublished in Peking in the Republican period]. AB - The Popular Medical Monthly, a periodical inaugurated by the Aiyou Society in October, 1919, was the earliest TCM periodical published in Peking, the goal of which was to spread common medical knowledgeand hygienic ideas. It included discussion, translation, investigation, random talk, record, and corresponding, featuring popularizing medical and hygienic conception to the populace, upgrading people's knowledge on seasonal epidemic disases, etc. PMID- 26420532 TI - [An introduction to the Institute of History of Medicine in Medical School of Johns Hopkins University]. AB - The Institute of History of Medicine in Medical School of Johns Hopkins University is a well-known institute in the world. It includes the department of history of medicine, a historic collection, a library of history of medicine and an Editorial Board of the Bulletin of History of Medicine, embodying the tasks of teaching, researching and publication. The faculty members are active and outstanding in lots of fields of history of medicine. It leads the latest research on history of medicine with extensive research scope and active academic activities. PMID- 26420533 TI - Sarcoid-like reaction mimicking vaginal cancer recurrence. AB - A sarcoid-like reaction is a development of non-caseating granuloma in patients with underlying malignancy and represents a false positive finding on positron emission tomography/computed tomography (PET/CT). A sarcoid-like reaction is a benign condition; therefore, differentiating a sarcoid-like reaction from cancer recurrence is necessary. Only uterine and ovarian cancer related cases have been reported in the gynecological field and to the best of our knowledge, this is the first case of a sarcoid-like reaction in vaginal cancer. A 59-year-old vaginal cancer patient received concurrent chemoradiotherapy and achieved complete remission. Recurrence of vaginal cancer was suspected because of the elevation of serum squamous cell carcinoma antigen level. PET/CT revealed abnormal uptake at the bilateral mediastinal and hilar lymph nodes. A non-caseating granuloma was detected from the biopsy of the swollen lymph nodes. No evidence of cancer recurrence was observed. A sarcoid-like reaction should be considered when evaluating PET/CT in cancer patients to prevent unnecessary treatments. PMID- 26420534 TI - Graphene oxides and the angiogenic process. PMID- 26420542 TI - Identification of STAT3 and STAT5 proteins in the rat suprachiasmatic nucleus and the Day/Night difference in astrocytic STAT3 phosphorylation in response to lipopolysaccharide. AB - Signal transducers and activators of transcription (STAT) proteins regulate many aspects of cellular physiology from growth and differentiations to immune responses. Using immunohistochemistry, we show the daily rhythm of STAT3 protein in the rat suprachiasmatic nucleus (SCN), with low but significant amplitude peaking in the morning. We also reveal the strong expression of STAT5A in astrocytes of the SCN and the STAT5B signal in nonastrocytic cells. Administration of lipopolysaccharide (LPS) acutely induced phosphorylation of STAT3 on Tyr705 during both the day and the night and induced phosphorylation on Ser727 but only after the daytime application. The LPS-induced phospho-STAT3 (Tyr705) remained elevated for 24 hr after the daytime application but declined within 8 hr when LPS was applied at night. PMID- 26420544 TI - Proposal for a Domain Wall Nano-Oscillator driven by Non-uniform Spin Currents. AB - We propose a new mechanism and a related device concept for a robust, magnetic field tunable radio-frequency (rf) oscillator using the self oscillation of a magnetic domain wall subject to a uniform static magnetic field and a spatially non-uniform vertical dc spin current. The self oscillation of the domain wall is created as it translates periodically between two unstable positions, one being in the region where both the dc spin current and the magnetic field are present, and the other, being where only the magnetic field is present. The vertical dc spin current pushes it away from one unstable position while the magnetic field pushes it away from the other. We show that such oscillations are stable under noise and can exhibit a quality factor of over 1000. A domain wall under dynamic translation, not only being a source for rich physics, is also a promising candidate for advancements in nanoelectronics with the actively researched racetrack memory architecture, digital and analog switching paradigms as candidate examples. Devising a stable rf oscillator using a domain wall is hence another step towards the realization of an all domain wall logic scheme. PMID- 26420543 TI - Molecular detection and characterization of Babesia bovis, Babesia bigemina, Theileria species and Anaplasma marginale isolated from cattle in Kenya. AB - BACKGROUND: Infections with Babesia bovis, Babesia bigemina, Theileria species and Anaplasma marginale are endemic in Kenya yet there is a lack of adequate information on their genotypes. This study established the genetic diversities of the above tick-borne hemoparasites infecting cattle in Kenya. METHODS: Nested PCR and sequencing were used to determine the prevalence and genetic diversity of the above parasites in 192 cattle blood samples collected from Ngong and Machakos farms. B. bovis spherical body protein 4, B. bigemina rhoptry-associated protein 1a, A. marginale major surface protein 5, Theileria spp. 18S rRNA, T. parva p104 and T. orientalis major piroplasm surface protein were used as the marker genes. RESULTS: B. bovis, B. bigemina, T. parva, T. velifera, T. taurotragi, T. mutans and A. marginale were prevalent in both farms, whereas T. ovis, Theileria sp. (buffalo) and T. orientalis were found only in Ngong farm. Co-infections were observed in more than 50 % of positive samples in both farms. Babesia parasites and A. marginale sequences were highly conserved while T. parva and T. orientalis were polymorphic. Cattle-derived T. parva was detected in Machakos farm. However, cattle and buffalo-derived Theileria were detected in Ngong farm suggesting interactions between cattle and wild buffaloes. Generally, the pathogens detected in Kenya were genetically related to the other African isolates but different from the isolates in other continents. CONCLUSIONS: The current findings reaffirm the endemicity and co-infection of cattle with tick-borne hemoparasites, and the role of wildlife in pathogens transmission and population genetics in Kenya. PMID- 26420545 TI - Structural insights into the loss of catalytic competence in pectate lyase activity at low pH. AB - Pectate lyase, a family 1 polysaccharide lyase, catalyses cleavage of the alpha 1,4 linkage of the polysaccharide homogalacturonan via an anti beta-elimination reaction. In the Michaelis complex two calcium ions bind between the C6 carboxylate of the d-galacturonate residue and enzyme aspartates at the active centre (+1 subsite), they withdraw electrons acidifying the C5 proton facilitating its abstraction by the catalytic arginine. Here we show that activity is lost at low pH because protonation of aspartates results in the loss of the two catalytic calcium-ions causing a profound failure to correctly organise the Michaelis complex. PMID- 26420547 TI - Hypopituitarism in Neurocritical Patients: A Case Report. AB - BACKGROUND: Besides changes in pituitary hormones secretion observed during the acute phase of stroke as an adaptive response to injury or an effect of drugs, a true hypopituitarism due to ischemic and/or hemorrhagic damage at the hypothalamus and/or pituitary gland can develop after a stroke. CASE REPORT: We report a case of a 72-year-old woman showing clinical signs and laboratory data suggesting a secondary adrenal insufficiency following a recent acute brain ischemia. Cortisone therapy significantly improved this pituitary dysfunction. CONCLUSIONS: Clinicians must pay attention to the hypothalamic-pituitary axis in neurocritical patients because hormonal replacement therapy may be life-saving. PMID- 26420546 TI - Decreased Serotonin Levels and Serotonin-Mediated Osteoblastic Inhibitory Signaling in Patients With Ankylosing Spondylitis. AB - Evidence suggests that serotonin is an inhibitor of bone formation. We aimed to assess: 1) serum serotonin levels in patients with ankylosing spondylitis (AS), a prototype bone-forming disease, compared with patients with rheumatoid arthritis (RA) and healthy subjects; 2) the effect(s) of TNFalpha blockers on serum serotonin levels in patients with AS and RA; and 3) the effect(s) of serum of AS patients on serotonin signaling. Serum serotonin levels were measured in 47 patients with AS, 28 patients with RA, and 40 healthy subjects by radioimmunoassay; t test was used to assess differences between groups. The effect of serum on serotonin signaling was assessed using the human osteoblastic cell line Saos2, evaluating levels of phospho-CREB by Western immunoblots. Serotonin serum levels were significantly lower in patients with AS compared with healthy subjects (mean +/- SEM ng/mL 122.9 +/- 11.6 versus 177.4 +/- 24.58, p = 0.038) and patients with RA (mean +/- SEM ng/mL 244.8 +/- 37.5, p = 0.0004). Patients with AS receiving TNFalpha blockers had significantly lower serotonin levels compared with patients with AS not on such treatment (mean +/- SEM ng/mL 95.8 +/- 14.9 versus 149.2 +/- 16.0, p = 0.019). Serotonin serum levels were inversely correlated with pCREB induction in osteoblast-like Saos-2 cells. Serotonin levels are low in patients with AS and decrease even further during anti-TNFalpha treatment. Differences in serotonin levels are shown to have a functional impact on osteoblast-like Saos-2 cells. Therefore, serotonin may be involved in new bone formation in AS. PMID- 26420548 TI - Evaluation of Thyroid Hormone Status in Children with Steroid Resistant Nephrotic Syndrome: A North India Study. AB - BACKGROUND: Steroid resistant nephrotic syndrome (SRNS) has a chronic and progressive course. Limited data is available evaluating thyroid function parameters in SRNS patients. The aim of the present study was to evaluate the thyroid hormone status in Indian children with SRNS. MATERIALS & METHODS: The present cross-sectional study included 50 patients aged 1-12 years with SRNS. As per Up:Uc ratio divided into three groups: Group A) 16 patients of SRNS in complete remission Group B) 14 patients of SRNS in partial remission Group C) 20 patients of SRNS in relapse. Serum levels of FT3, FT4 and TSH were measured in all. RESULTS: 20% of the children (n=10) with SRNS had hypothyroidism (7 subclinical hypothyroidism and 3 with overt hypothyroidism). One child was found to be in complete remission, 4 in partial remission and 5 in relapse phase. TSH levels were found to be significantly elevated in children with relapse (p = 0.042). Serum albumin showed a significant negative correlation with Up:Uc ratio ( p < 0.0001) whereas total cholesterol showed a significant positive correlation (p < 0.001). On correlating TSH level with Up:Uc ratio a significant positive correlation ( p = 0.0098) was observed. CONCLUSION: Subclinical hypothyroidism in SRNS is temporary and may improve with remission. However prolonged proteinuria in SRNS patients may lead to progressive damage of the renal tubules and impaired absorption of Low Molecular Weight (LMW) proteins which may further exhaust the thyroid reserve and lead to overt hypothyroidism. Therefore thyroid examination should be routinely advocated in these children. PMID- 26420550 TI - Using the Program Evaluation Committee as a Dynamic Vehicle for Improvement in Psychiatry Training. PMID- 26420551 TI - The promise of open innovation in drug discovery: an industry perspective. PMID- 26420552 TI - Adhesive hydrophobicity of Cu2O nano-columnar arrays induced by nitrogen ion irradiation. AB - Low energy nitrogen ions are used in this work to manipulate wetting properties of the surface of the array of Cu2O nano-columns, which yields remarkable results. The nano-columnar thin films were grown on a highly conductive silicon surface by a sputter deposition technique. The films were irradiated at two different fluences of 5 * 10(15) and 1 * 10(16) ions per cm(2), respectively. With increasing fluence the shape of column tip changes, columns are bent and porous channels between columns are clogged up. While the surface of the pristine sample is hydrophilic, the irradiated surface turns into hydrophobic but having adhesion properties. We have analysed the structural and chemical properties of the surface in detail to understand the initial and modified wetting properties. Furthermore, the temporal evolutions of different droplet parameters are investigated to realize the interactions between the water droplet, the sample surface and the atmosphere. We envisage that such modified surfaces can be beneficial for transport of a small volume of liquids with minimum loss and spectroscopic studies, where a small amount of water droplet is available for measurements. PMID- 26420553 TI - Evaluation of Social Media Utilization by Latino Adolescents: Implications for Mobile Health Interventions. AB - BACKGROUND: Trends in social media use, including sending/receiving short message service (SMS) and social networking, are constantly changing, yet little is known about adolescent's utilization and behaviors. This longitudinal study examines social media utilization among Latino youths, and differences by sex and acculturation. OBJECTIVES: The purpose of this study was to examine Latino adolescents' social media utilization and behavior over a 16-month period, and to assess whether changes in use differed by sex and acculturation. METHODS: This study included 555 Latino youths aged 13-19 who completed baseline and 16-month follow-up surveys. Prevalence of social media utilization and frequency, by sex and acculturation categories, was examined using generalized estimating equations. RESULTS: Women are more likely to use SMS, but men are significantly more likely to SMS a girl/boyfriend (P=.03). The use of Internet by men and women to research health information increased over time. Facebook use declined over time (P<.001), whereas use of YouTube (P=.03) and Instagram (P<.001) increased, especially among women and more US acculturated youths. CONCLUSION: Social media is ubiquitous in Latino adolescents' lives and may be a powerful mode for public health intervention delivery. PMID- 26420555 TI - Overpaying morbidity adjusters in risk equalization models. AB - Most competitive social health insurance markets include risk equalization to compensate insurers for predictable variation in healthcare expenses. Empirical literature shows that even the most sophisticated risk equalization models-with advanced morbidity adjusters-substantially undercompensate insurers for selected groups of high-risk individuals. In the presence of premium regulation, these undercompensations confront consumers and insurers with incentives for risk selection. An important reason for the undercompensations is that not all information with predictive value regarding healthcare expenses is appropriate for use as a morbidity adjuster. To reduce incentives for selection regarding specific groups we propose overpaying morbidity adjusters that are already included in the risk equalization model. This paper illustrates the idea of overpaying by merging data on morbidity adjusters and healthcare expenses with health survey information, and derives three preconditions for meaningful application. Given these preconditions, we think overpaying may be particularly useful for pharmacy-based cost groups. PMID- 26420556 TI - Reduction of Eu(3+) due to a change of the topological structure of the BO3 unit in borate glass. AB - Adjusting and controlling an ion's chemical state has always been a focus of researchers' attention. Herein, an intense long-lasting phosphorescence of Eu(2+) is obtained without any sacrificial reductant. The remarkable self-reducing process and the unique luminescence properties stem from a variation of the topological structure of the BO3 triangle. PMID- 26420554 TI - Mode of allocation and social demographic factors correlate with impaired quality of life after liver transplantation. AB - BACKGROUND: Health-related Quality of life (HRQoL) is a major goal of clinical management after liver transplantation (LTx). There is still disagreement on the effects of social-demographic factors and changes in the allocation system on HRQoL. The aim of this study was to evaluate the impact of social-demographic factors, mode of organ-allocation, waiting time and hepatocellular carcinoma (HCC) on HRQoL after LTx. METHODS: HRQoL was assessed using the EORTC-QLQ-C30 questionnaire, which was sent to 238 recipients. Investigated parameters included age, sex, distance to transplant center, follow-up at hospital, size of hometown, highest education, marital status, having children, background liver disease, waiting time, mode of allocation, HCC, hospitalization after LTx and diagnosis of malignancy after LTx. All evaluated parameters were entered into multivariate linear regression analysis. RESULTS: Completed questionnaire were returned by 73% of the recipients. After LTx, the HRQoL-function scales increased over time. Age, marital status, highest education, completed professional training, working status, job position, duration of waiting time to LTx, distance to transplant center, place offollow, HU-statuts, mode of organ allocation and duration of hospitalization were associated with significantly worse function- and significantly lower symptom scales. HCC as a primary disease did not affect HRQoL. CONCLUSIONS: Low HRQoL correlated significantly with MELD-based organ allocation, more than 28-day hospitalization, divorced status, lower education- and non-working status, higher distance to transplant center, follow up at transplant center, HU-status, shorter waiting time to LTx and younger age. Improvement of HRQoL after LTx may require clinical management of pain, psychotherapy and financial support. PMID- 26420562 TI - Structure and energetics of graphene oxide isomers: ab initio thermodynamic analysis. AB - Graphene oxide (GO) holds significant promise for electronic devices and nanocomposite materials. A number of models were proposed for the GO structure, combining carboxyl, hydroxyl, carbonyl and epoxide groups at different locations. The complexity and variety of GO isomers, whose thermodynamic stability and formation kinetics depend on the applied conditions, make determination of the GO structure with atomistic precision challenging. We report high level theoretical investigation of multiple molecular configurations, which are anticipated in GO. We conclude that all oxygen containing groups at the GO surface are thermodynamically permitted, whereas the 'edge' positions are systematically more favorable than the 'center' and 'side' positions. We discuss a potentially novel type of chemical bond or bonding reinforcement in GO, which consists of a covalent bond and a strong electrostatic contribution from a polarized graphene plane. We observe and analyze significant modifications of the graphene geometry and electronic structure upon oxidation. The reported thermodynamic data guide experiments aimed at deciphering the GO chemical composition and structure, and form the basis for predicting GO properties required for nano-technological applications. PMID- 26420557 TI - Transcriptional responses and flavor volatiles biosynthesis in methyl jasmonate treated tea leaves. AB - BACKGROUND: Tea (Camellia sinensis) has long been consumed worldwide for its amazing flavor and aroma. Methyl jasmonate (MeJA), which acts as an effective elicitor among the plant kingdom, could mostly improve the quality of tea aroma by promoting flavor volatiles in tea leaves. Although a variety of volatile secondary metabolites that contribute to aroma quality have been identified, our understanding of the biosynthetic pathways of these compounds has remained largely incomplete. Therefore, information aboaut the transcriptome of tea leaves and, specifically, details of any changes in gene expression in response to MeJA, is required for a better understanding of the biological mechanisms of MeJA mediated volatiles biosynthesis. Moreover, MeJA treatment could exaggerate the responses of secondary metabolites and some gene expression which offer a better chance to figure out the mechanism. RESULTS: The results of two-dimensional gas chromatograph mass-spectrometry showed that the terpenoids content in MeJA treated tea leaves increased, especially linalool, geraniol, and phenylethyl alcohol. More importantly, we carried out RNA-seq to identify the differentially expressed genes (DEGs) related to volatiles biosynthesis pathways induced by MeJA treatment (0 h, 12 h, 24 h and 48 h) in tea leaves. We identified 19245, 18614, 11890 DEGs respectively in the MeJA_12h, MeJA_24 h and MeJA_48 h samples. The alpha-Lenolenic acid degradation pathway was firstly responded resulting in activating the JA-pathway inner tea leaves, and the MEP/DOXP pathway significantly exaggerated. Notably, the expression level of jasmonate O methyltransferase, which is associated with the central JA biosynthesis pathway, was increased by 7.52-fold in MeJA_24 h tea leaves. Moreover, the genes related to the terpenoid backbone biosynthesis pathway showed different expression patterns compared with the untreated leaves. The expression levels of 1-deoxy-D xylulose-phosphate synthase (DXS), all-trans-nonaprenyl-diphosphate synthase, geranylgeranyl reductase, geranylgeranyl diphosphate synthase (type II), hydroxymethylglutaryl-CoA reductase and 4-hydroxy-3-methylbut-2-enyl diphosphate reductase increased by approximately 2-4-fold. CONCLUSIONS: The results of two dimension gas-chromatography mass-spectrometry analysis suggested that exogenous application of MeJA could induce the levels of volatile components in tea leaves, especially the geraniol, linalool and its oxides. Moreover, the transcriptome analysis showed increased expression of genes in alpha-Lenolenic acid degradation pathway which produced massive jasmonic acid and quickly activated holistic JA pathway inner tea leaves, also the terpenoid backbones biosynthesis pathway was significantly affected after MeJA treatment. In general, MeJA could greatly activate secondary metabolism pathways, especially volatiles. The results will deeply increase our understanding of the volatile metabolites biosynthesis pathways of tea leaves in response to MeJA. PMID- 26420563 TI - Giant sialolith of submandibular gland duct treated by excision and ductal repair: a case report. PMID- 26420565 TI - Targeting tumor glycolysis by a mitotropic agent. AB - Metabolic reprogramming is one of the hallmarks of cancer. Altered metabolism in cancer cells is exemplified by enhanced glucose utilization, a biochemical signature that is clinically exploited for cancer diagnosis using positron emission tomography and computed tomography imaging. Accordingly, disrupting the glucose metabolism of cancer cells has been contemplated as a potential therapeutic strategy against cancer. Experimental evidences indicate that targeting glucose metabolism by inhibition of glycolysis or oxidative phosphorylation promotes anticancer effects. Yet, successful clinical translation of antimetabolites or energy blockers to treat cancer remains a challenge, primarily due to lack of efficacy and/or systemic toxicity. Recently, using nanotechnology, Marrache and Dhar have documented the feasibility of delivering a glycolytic inhibitor through triphenylphosphonium (TPP), a mitotropic agent that selectively targets mitochondria based on membrane potential. Furthermore, by utilizing gold nanoparticles the investigators also demonstrated the potential for simultaneous induction of photothermal therapy, thus facilitating an additional line of attack on cancer cells. The report establishes that specific inhibition of tumor glycolysis is achievable through TPP-dependent selective targeting of cancer cells. This nanotechnological approach involving TPP-guided selective delivery of an antiglycolytic agent complemented with photothermal therapy provides a new window of opportunity for effective and specific targeting of tumor glycolysis. PMID- 26420564 TI - Complications of otitis media - a potentially lethal problem still present. AB - INTRODUCTION: It is an erroneous but commonly held belief that intracranial complications (ICCs) of chronic and acute otitis media (COM and AOM) are past diseases or from developing countries. These problems remain, despite improvements in antibiotic care. OBJECTIVE: This paper analyzes the occurrence and clinical characteristics and course of the main ICCs of otitis media (OM). METHODS: Retrospective cohort study of 51 patients with ICCs from OM, drawn from all patients presenting with OM to the emergency room of a large inner-city tertiary care hospital over a 22-year period. RESULTS: 80% of cases were secondary to COM of which the incidence of ICC was 0.8%; 20% were due to AOM. The death occurrence was 7.8%, hearing loss in 90%, and permanent neurological sequelae in 29%. Patients were 61% male. In the majority, onset of ear disease had occurred during childhood. Delay of diagnosis of both the initial infection as well as the secondary ICC was significant. ICCs included brain abscess and meningitis in 78%, and lateral sinus thrombosis, empyema and otitic hydrocephalus in 13%, 8% and 1% of cases, respectively. Twenty-seven neurosurgical procedures and 43 otologic surgery procedures were performed. Two patients were too ill for surgical intervention. CONCLUSION: ICCs of OM, although uncommon, still occur. These cases require expensive, complex and long-term inpatient treatment and frequently result in hearing loss, neurological sequelae and mortality. It is important to be aware of this potentiality in children with COM, especially, and maintain a high index of suspicion in order to refer for otologic specialty care before such complications occur. PMID- 26420566 TI - Kinetic Insights into the Elongation Reaction of Actin Filaments as a Function of Temperature, Pressure, and Macromolecular Crowding. AB - Actin polymerization is an essential process in eukaryotic cells that provides a driving force for motility and mechanical resistance for cell shape. By using preformed gelsolin-actin nuclei and applying stopped-flow methodology, we quantitatively studied the elongation kinetics of actin filaments as a function of temperature and pressure in the presence of synthetic and protein crowding agents. We show that the association of actin monomers to the pointed end of double-stranded helical actin filaments (F-actin) proceeds via a transition state that requires an activation energy of 56 kJ mol(-1) for conformational and hydration rearrangements, but exhibits a negligible activation volume, pointing to a compact transition state that is devoid of packing defects. Macromolecular crowding causes acceleration of the F-actin elongation rate and counteracts the deteriorating effect of pressure. The results shed new light on the combined effect of these parameters on the polymerization process of actin, and help us understand the temperature and pressure sensitivity of actin polymerization under extreme conditions. PMID- 26420567 TI - Reliability and validity of CDAI and SDAI indices in comparison to DAS-28 index in Moroccan patients with rheumatoid arthritis. AB - BACKGROUND: Clinical disease activity index (CDAI) and simplified disease activity index (SDAI) are useful tools for the evaluation of disease activity in patients with rheumatoid arthritis (RA), but have not been comparatively validated in Moroccan population. Therefore, this study was designed to assess validity and reliability of CDAI and SDAI in comparison to disease activity score 28 joints (DAS-28) in Moroccan patients with RA. METHODS: Patients with RA were included in a cross-sectional study. Patient characteristics and RA were collected. The disease activity was assessed by DAS-28, CDAI and SDAI. Patients were splitted into groups of remission, low, moderate and high activity on the basis of predefined cut-offs for DAS-28, CDAI, and SDAI. A Spearman correlation between composite indexes and inter-group comparison of the indexes were performed. Using DAS-28 as a gold standard, the Receiver operator characteristic (ROC) curve was used to assess the performance of a screening test at different levels. RESULTS: The study was conducted with 103 patients of female predominance (87.4%). Mean age was 49.7 +/- 11.4 years. Median disease duration was in the order of 8 years [3-14]. There was an excellent correlation between DAS-28 and CDAI (r = 0.95, p <0.001), CDAI and SDAI (r = 0.90, p <0.001), and DAS-28 and SDAI (r = 0.92, p <0.001). There was a good inter-rater alignment between the DAS 28 and CDAI (Weighted kappa =0.743) and there was a moderate inter-rater alignment between the DAS-28 and SDAI (Weighted kappa =0.60), and also between the SDAI and CDAI (Weighted kappa = 0.589). There was no statistically significant difference between AUROC of CDAI and SDAI as both were performed equally well. DISCUSSION: This study is the first Moroccan case study to compare the performance of both CDAI and SDAI in evaluation of disease activity in patients with RA. Our study showed that there was a direct and excellent correlation between DAS-28 and CDAI, and SDAI and DAS-28. CONCLUSION: Our study shows a strong positive correlation between DAS-28, CDAI and SDAI. The cut-off values for CDAI and SDAI used in western literature can be used with minor modifications in Moroccan scenario. PMID- 26420568 TI - Work participation in adults with Marfan syndrome: Demographic characteristics, MFS related health symptoms, chronic pain, and fatigue. AB - Marfan syndrome (MFS) is a severe autosomal dominant connective tissue disorder that might influence peoples work ability. This cross sectional study aims to investigate work participation in adults with verified MFS diagnosis and to explore how the health related consequences of MFS and other factors might influence work participation. The prevalence of health problems in young adults compared to older adults with MFS was examined in association to work participation. A postal questionnaire including questions about work participation, demographic characteristics, MFS related health problems, chronic pain, and fatigue was sent to 117 adults with verified MFS (Ghent 1), and 62% answered. Fifty-nine percent were employed or students, significantly lower work participation than the General Norwegian Population (GNP), but higher than the Norwegian population of people with disability. Most young adults worked full time despite extensive health problems, but the average age for leaving work was low. Few had received any work adaptations prior to retiring from work. In multiple logistic regression analysis, only age, lower educational level and severe fatigue were significantly associated with low work participation; not MFS related health problems or chronic pain. Fatigue appears to be the most challenging health problem to deal with in work, but the covariance is complex. Focus on vocational guidance early in life, more appropriate work adaptations, and psychosocial support might improve the possibility for sustaining in work for adults with MFS. More research about work challenges in adults with MFS is needed. PMID- 26420569 TI - Identification of a major radiometabolite of [11C]PBB3. AB - INTRODUCTION: [(11)C]PBB3 is a clinically used positron emission tomography (PET) probe for in vivo imaging of tau pathology in the brain. Our previous study showed that [(11)C]PBB3 was rapidly decomposed to a polar radiometabolite in the plasma of mice. For the pharmacokinetic evaluation of [(11)C]PBB3 it is important to elucidate the characteristics of radiometabolites. In this study, we identified the chemical structure of a major radiometabolite of [(11)C]PBB3 and proposed the metabolic pathway of [(11)C]PBB3. METHODS: Carrier-added [(11)C]PBB3 was injected into a mouse for in vivo metabolite analysis. The chemical structure of a major radiometabolite was identified using LC-MS. Mouse and human liver microsomes and liver S9 samples were incubated with [(11)C]PBB3 in vitro. In silico prediction software was used to assist in the determination of the metabolite and metabolic pathway of [(11)C]PBB3. RESULTS: In vivo analysis showed that the molecular weight of a major radiometabolite of [(11)C]PBB3, which was called as [(11)C]M2, was m/z 390 [M+H(+)]. In vitro analysis assisted by in silico prediction showed that [(11)C]M2, which was not generated by cytochrome P450 enzymes (CYPs), was generated by sulfated conjugation mediated by a sulfotransferase. CONCLUSION: The major radiometabolite, [(11)C]M2, was identified as a sulfated conjugate of [(11)C]PBB3. [(11)C]PBB3 was metabolized mainly by a sulfotransferase and subsidiarily by CYPs. PMID- 26420570 TI - Drug-induced hypersensitivity syndrome by liposomal amphotericin-B: a case report. AB - BACKGROUND: Liposomal amphotericin-B (Ambisome((r))) is widely used antifungal drug for treatments of invasive fungal infections. The use of liposomal amphotericin-B is increasing in medical setting because of its tolerability and potent antifungal activity. CASE PRESENTATION: In a case of a 76 year-old Japanese female was admitted with subarachnoid hemorrhage, the ethnicity of the patient is Asian, we experienced that liposomal amphotericin-B was the culprit drug for Drug-induced hypersensitivity syndrome, also known as drug rash with eosinophilia and systemic symptoms in view of a clear temporal relationship between liposomal amphotericin-B administration and the onset of symptoms, the remission of the symptomatological pattern after liposomal amphotericin-B withdrawal. CONCLUSION: The present case report shows that prolonged liposomal amphotericin-B treatment can be associated with drug rash with eosinophilia and systemic symptoms. We recommend careful monitoring of neutrophil counts in a prolonged treatment course with liposomal amphotericin-B. PMID- 26420572 TI - Effects of inorganic acids and divalent hydrated metal cations (Mg(2+), Ca(2+), Co(2+), Ni(2+)) on gamma-AlOOH sol-gel process. AB - In-depth understanding of the sol-gel process plays an essential role in guiding the preparation of new materials. Herein, the effects of different inorganic acids (HCl, HNO3 and H2SO4) and divalent hydrated metal cations (Mg(2+), Ca(2+), Co(2+), Ni(2+)) on gamma-AlOOH sol-gel process were studied based on experiments and density functional theory (DFT) calculations. In these experiments, the sol originating from the gamma-AlOOH suspension was formed only with the addition of HCl and HNO3, but not with H2SO4. Furthermore, the DFT calculations showed that the strong adsorption of HSO4(-) on the surface of the gamma-AlOOH particles, and the hydrogen in HSO4(-) pointing towards the solvent lead to an unstable configuration of electric double layer (EDL). In the experiment, the gelation time sequence of gamma-AlOOH sol obtained by adding metal ions changed when the ionic strength was equal to or greater than 0.198 mol kg(-1). The DFT calculations demonstrated that the adsorption energy of hydrated metal ions on the gamma-AlOOH surface can actually make a difference in the sol-gel process. PMID- 26420571 TI - Protocol for a systematic review on the effect of demand generation interventions on uptake and use of modern contraceptives in LMIC. AB - BACKGROUND: Despite a global increase in contraception use, its prevalence remains low in low- and middle-income countries. One strategy to improve uptake and use of contraception, as an essential complement to policies and supply-side interventions, is demand generation. Demand generation interventions have reportedly produced positive effects on uptake and use of family planning services, but the evidence base remains poorly documented. To reduce this knowledge gap, we will conduct a systematic review on the impact of demand generation interventions on the use of modern contraception. The objectives of the review will be as follows: (1) to synthesize evidence on the impacts and costs of family planning demand generation interventions and on their effectiveness in improving modern contraceptive use and (2) to identify the indicators used to assess effectiveness, cost-effectiveness, and impacts of demand generation interventions. METHODS/DESIGN: We will systematically review the public health and health promotion literature in several databases (e.g., CINAHL, Medline, EMBASE) as well as gray literature. We will select articles from 1970 to 2015, in French and in English. The review will include studies that assess the impact of family planning programs or interventions on changes in contraception use. The studied interventions will be those with a demand generation component, even if a supply component is implemented. Two members of the team will independently search, screen, extract data, and assess the quality of the studies selected. Different tools will be used to assess the quality of the studies depending on the study design. If appropriate, a meta-analysis will be conducted. The analysis will involve comparing odd ratios (OR) DISCUSSION: The systematic review results will be disseminated to United Nations Population Fund program countries and will contribute to the development of a guidance document and programmatic tools for planning, implementing, and evaluating demand generation interventions in family planning. Improving the effectiveness of family planning programs is critical for empowering women and adolescent girls, improving human capital, reducing dependency ratios, reducing maternal and child mortality, and achieving demographic dividends in low- and middle-income countries. SYSTEMATIC REVIEW REGISTRATION: This protocol is registered in PROSPERO (CRD 42015017549). PMID- 26420573 TI - The effect of brain size evolution on feeding propensity, digestive efficiency, and juvenile growth. AB - One key hypothesis in the study of brain size evolution is the expensive tissue hypothesis; the idea that increased investment into the brain should be compensated by decreased investment into other costly organs, for instance the gut. Although the hypothesis is supported by both comparative and experimental evidence, little is known about the potential changes in energetic requirements or digestive traits following such evolutionary shifts in brain and gut size. Organisms may meet the greater metabolic requirements of larger brains despite smaller guts via increased food intake or better digestion. But increased investment in the brain may also hamper somatic growth. To test these hypotheses we here used guppy (Poecilia reticulata) brain size selection lines with a pronounced negative association between brain and gut size and investigated feeding propensity, digestive efficiency (DE), and juvenile growth rate. We did not find any difference in feeding propensity or DE between large- and small brained individuals. Instead, we found that large-brained females had slower growth during the first 10 weeks after birth. Our study provides experimental support that investment into larger brains at the expense of gut tissue carries costs that are not necessarily compensated by a more efficient digestive system. PMID- 26420576 TI - Propane sigma-Complexes on PdO(101): Spectroscopic Evidence of the Selective Coordination and Activation of Primary C-H Bonds. AB - Achieving selective C-H bond cleavage is critical for developing catalytic processes that transform small alkanes to value-added products. The present study clarifies the molecular-level origin for an exceptionally strong preference for propane to dissociate on the crystalline PdO(101) surface via primary C-H bond cleavage. Using reflection absorption infrared spectroscopy (RAIRS) and density functional theory (DFT) calculations, we show that adsorbed propane sigma complexes preferentially adopt geometries on PdO(101) in which only primary C-H bonds datively interact with the surface Pd atoms at low propane coverages and are thus activated under typical catalytic reaction conditions. We show that a propane molecule achieves maximum stability on PdO(101) by adopting a bidentate geometry in which a H-Pd dative bond forms at each CH3 group. These results demonstrate that structural registry between the molecule and surface can strongly influence the selectivity of a metal oxide surface in activating alkane C-H bonds. PMID- 26420575 TI - Long noncoding RNAs could be potential key players in the pathophysiology of Sjogren's syndrome. AB - Long noncoding RNAs (lncRNAs) are a recently discovered class of noncoding functional RNAs encoded by metazoan genomes. Recent studies suggest a larger regulatory role for lncRNAs in critical biological and disease processes. Mounting evidence on the role of lncRNAs in regulating key processes of the immune system prompted us to hypothesize the role of lncRNAs as key regulators of the pathophysiology of Sjogren's syndrome (SS). We used two similar approaches based on reanalysis of microarray expression datasets and curation of lncRNA protein coding gene interactions from literature to derive support for our hypothesis. We also discuss potential caveats to our approach and suggest approaches to validate the hypothesis. Our analysis suggests the potential larger and hitherto unknown role of lncRNA regulatory networks in modulating the expression of key genes involved in the pathogenesis of SS and thereby modulating the pathophysiology of SS. PMID- 26420574 TI - Amygdala and cingulate structure is associated with stereotype on sex-role. AB - Sex-role egalitarianism (SRE) is the belief that the sex of an individual should not influence the perception of his or her rights, abilities, obligations, and opportunities. Thus, low SRE reflects a more conservative stereotypical view on sex-role. Here we investigated anatomical correlates of individual differences in SRE in the present study. We used voxel-based morphometry, a questionnaire to determine an individual's SRE and associated psychological measures, and determined the association of SRE with gray matter structures and their cognitive nature in healthy individuals (375 men and 306 women; age, 20.6 +/- 1.8 years). We demonstrated that higher SRE was associated with smaller regional gray matter density (rGMD) in the anterior part of the posterior cingulate cortex (PCC) and higher rGMD in the right amygdala. Post-hoc analyses revealed psychological measures characterized by contentious interpersonal orientations, such as contentious achievement motivation, were associated with lower SRE and higher rGMD in the anterior part of PCC. Depressive tendencies were associated with lower SRE and higher rGMD in the right amygdala. These findings suggest that variations in stereotype on sex role have roots in the limbic brain structures linked to contentious interpersonal orientation (cingulate) and negative mood (amygdala). PMID- 26420577 TI - Optimisation of a treat-to-target approach in rheumatoid arthritis: strategies for the 3-month time point. AB - BACKGROUND: Treat-to-target (T2T) is a widely accepted management strategy for rheumatoid arthritis (RA) with a key decision point at 3 months after treatment initiation. At this time point, it remains unclear which patients will benefit from treatment adaptation or from continuation of existing treatment. METHODS: We performed a pooled analysis of patient-level clinical trial data of patients with RA. We used a diagnostic testing methodology and a probabilistic approach employing logistic regression to investigate which levels of response at 3 months can inform treatment decisions in regard to achieving the target at 6 months. RESULTS: To be at least 80% sensitive for achieving the low disease activity (LDA) target at 6 months, a change at 3 months in Simplified Disease Activity Index/Clinical Disease Activity Index (SDAI or CDAI) of 58% needs to be observed at 3 months. Higher changes are needed to sensitively predict remission (REM). Not reaching the (minor) SDAI 50% response level is afflicted with very low negative likelihood ratios (LRs) (0.28 for LDA and 0.07 for REM at 6 months). Experiencing (major) SDAI 85% response has substantial positive LRs of 9.2 for reaching LDA and 6.2 for reaching REM at 6 months. In logistic regression, the change at 3 months is significantly associated with reaching of the target at 6 months. CONCLUSIONS: The 3-month time point is a critical decision point. Not achieving minor responses at 3 months makes reaching of the treatment target at 6 months highly unlikely, while reaching major responses is highly predictive of reaching the treatment target. PMID- 26420578 TI - Response to: 'Role of nerve growth factor (NGF) and tropomyosin receptor kinase A (TrkA) in the pathogenesis of osteoarthritis. Might NGF be the link interwinding obesity and OA?' by Iannone et al. PMID- 26420579 TI - Mutation in MMP2 gene may result in scleroderma-like skin thickening. PMID- 26420580 TI - Influence of rice whole-crop silage diet on growth performance, carcass and meat characteristics and muscle-related gene expression in Japanese Black steers. AB - The present study investigated the influence of a diet largely comprising rice whole-crop silage (rWCS) on growth performance, carcass and meat characteristics, and expression of genes involved in muscle growth of Japanese Black steers. Steers were randomly separated into rWCS-fed (rWCS ad libitum and restricted feeding of concentrate) and concentrate-fed groups. Total digestible nutrient intake and daily gain (DG) decreased in rWCS-fed steers in comparison with concentrate-fed steers, whereas dressed carcass weight and final body weight did not significantly differ between the groups. Decreases in drip loss in the muscle of rWCS-fed steers may be caused by alpha-tocopherol and beta-carotene in muscle. Feeding large amounts of rWCS to steers may maintain quantitative productivity of beef steers equally to a concentrate-based diet, and improve the qualitative productivity. Results of gene expression suggest that activation of skeletal muscle growth in rWCS-fed steers may occur at the late fattening period owing to a decrease in myostatin and increase in myosin heavy chain gene expression. Preadipocyte factor-1 and myostatin genes may be strongly involved in the control of lipid accumulation. This rearing system would allow beef production to switch to rWCS-based diets from concentrate-based diets. PMID- 26420581 TI - The enigma of 'harmful' alcohol consumption: evidence from a mixed methods study involving female drinkers in Scotland. AB - BACKGROUND/AIMS: An appreciation of the drinking patterns of population subgroups may usefully inform tailored interventions. For this purpose, research has highlighted a need to better describe the drinking behaviour of UK women. This study aims to characterise the purchasing and consumption behaviour of female heavy, harmed, drinkers in contact with Scottish health services in two cities and to explore the factors that influence the link to harm. METHODS: Mixed methods study involving cross-sectional survey questionnaires and one-to-one interviews (5). The questionnaires documented (1) demographic data (including derived deprivation score), last week's (or 'typical' weekly) consumption (type, brand, volume, price, place of purchase), self-reported illnesses, and (2) Alcohol-Related Problem Questionnaire score. A total of 181 patients with serious health problems linked to alcohol were recruited within National Health Service (NHS) hospital clinics (in- and outpatient settings), in two Scottish cities during 2012. RESULTS: Median consumption was 157.6 UK units for the recorded week, with almost exclusive purchase from 'off-sale' retail outlets. Preferred drinks were white cider, vodka and white wine. Increasing problems was positively associated with drinking more in the week, being younger and belonging to Glasgow. CONCLUSION: For Scottish women, the current definition of 'harmful' consumption likely captures a fourfold variation in alcohol intake, with gender differences less apparent. While current alcohol-related harm is positively associated with dose and being younger, there is clear evidence of an influence of the less tangible 'Glasgow effect'. Future harm concerns are warranted by data relating to pattern, alcohol dose and cigarette use. PMID- 26420582 TI - Insomnia symptoms and mortality: a register-linked study among women and men from Finland, Norway and Lithuania. AB - Evidence on the association between insomnia symptoms and mortality is limited and inconsistent. This study examined the association between insomnia symptoms and mortality in cohorts from three countries to show common and unique patterns. The Finnish cohort comprised 6605 employees of the City of Helsinki, aged 40-60 years at baseline in 2000-2002. The Norwegian cohort included 6236 participants from Western Norway, aged 40-45 years at baseline in 1997-1999. The Lithuanian cohort comprised 1602 participants from the City of Palanga, aged 35-74 years at baseline in 2003. Mortality data were derived from the Statistics Finland and Norwegian Cause of Death Registry until the end of 2012, and from the Lithuanian Regional Mortality Register until the end of 2013. Insomnia symptoms comprised difficulties initiating sleep, nocturnal awakenings, and waking up too early. Covariates were age, marital status, education, smoking, alcohol, physical inactivity, obesity, diabetes, cardiovascular diseases, depression, shift work, sleep duration, and self-rated health. Cox regression analysis was used. Frequent difficulties initiating sleep were associated with all-cause mortality among men after full adjustments in the Finnish (hazard ratio 2.51; 95% confidence interval 1.07-5.88) and Norwegian (hazard ratio 3.42; 95% confidence interval 1.03-11.35) cohorts. Among women and in Lithuania, insomnia symptoms were not statistically significantly associated with all-cause mortality after adjustments. In conclusion, difficulties initiating sleep were associated with mortality among Norwegian and Finnish men. Variation and heterogeneity in the association between insomnia symptoms and mortality highlights that further research needs to distinguish between men and women, specific symptoms and national contexts, and focus on more chronic insomnia. PMID- 26420583 TI - Primary pulmonary neoplasia in cats: assessment of computed tomography findings and survival. AB - OBJECTIVE: To identify variables with a preoperative computed tomography scan that influence survival of cats undergoing surgical removal of a primary lung tumour. A secondary objective was to determine whether histologic type and or grade of feline pulmonary tumours affects long term survival. METHODS: Medical records were retrospectively reviewed for cats with preoperative computed tomography scans and surgical resection of primary lung tumours. Pulmonary carcinomas were reviewed for histologic diagnosis using two different approaches, histologic grade as well as major histologic pattern. RESULTS: Median survival time of all (n = 28) cats was 156 days. Median survival time for cats with lymph node enlargement was 65 days versus 498 days for cats without lymph node enlargement on preoperative computed tomography scan. Median survival time for cats with preoperative pleural effusion was 2 . 5 days versus 467 days for cats without pleural effusion. Cats with low or intermediate grade tumours had a median survival time of 730 days versus 105 days for cats with high grade tumours. CLINICAL SIGNIFICANCE: Cats with preoperative lymph node enlargement and pleural effusion have shorter survival times than cats without. PMID- 26420584 TI - Symbolism and ritual practices related to hunting in Maya communities from central Quintana Roo, Mexico. AB - BACKGROUND: Some Mayan peasant-hunters across the Yucatan Peninsula in Mexico still carry out a hunting ritual -Loojil Ts'oon, Loj Ts'oon or Carbine Ceremony- in which they renew the divine permission for hunting in order to continue deserving the gift of prey after a period of hunt. Thus they are granted access to game by the gods and the Lords of the Animals, particularly the spirit/evil wind call. This paper focuses on the acts within the Loojil Ts'oon -which is performed in the X-Pichil community and surrounding area- that make it unique among the hunting rituals performed in other parts of the Peninsula. METHODS: The Loojil Ts'oon hunting ritual was observed and registered in audiovisual format in two different occasions in X-Pichil (Friday 04/29/2011 and Friday 07/29/2011). Afterwards, we delivered digital videodisks (DVD) to hunters and their families and to the j-men (the magic-medic-ritual specialist) who participated in these ceremonies. This delivery produced confidence among participants to talk more openly and in-depth about the Loojil Ts'oon, revealing symbolic, psychological, and material details previously unknown to outsiders. Qualitative information was obtained through the ethnographic method using techniques such as participant observation and guided tours. Semi-structured interviews were carried out to obtain complementary information. RESULTS AND DISCUSSION: On one hand, we describe the preparation and cleansing of the "Sip soup", as well as its parading and distribution -delivery to the spirit/evil-wind Sip- on the streets of the community (highlingting the role of the rooster as a counter-gift). On the other hand, the cleansing of the jaws (of deer: Odocoileus virginianus, Mazama spp.; and peccaries: Tayassuidae) and their return to the Lords of Animals in the hills so that they may give these animals new life. CONCLUSIONS: By performing the Loojil Ts'oon, the act of killing an animal is legitimized. The kill transforms into an exchange to perpetuate life, in which gods and Lords of animals grant the hunter the solicited new game if he has completed his ritual duties and has not broken the prescribed hunting rules. The Loojil Ts'oon does not only represent the continuity and regeneration of animals, that is, fauna as a resource, but also of the whole hunting cycle. The hunter does so to maintain and recreate order and equilibrium in one's relationship with nature as a whole, with the rest of one's social group, and with oneself. Thus, hunting transcends the exclusively material dimension of a subsistence activity. PMID- 26420585 TI - Computer-Aided Diagnosis of Parkinson's Disease Using Enhanced Probabilistic Neural Network. AB - Early and accurate diagnosis of Parkinson's disease (PD) remains challenging. Neuropathological studies using brain bank specimens have estimated that a large percentages of clinical diagnoses of PD may be incorrect especially in the early stages. In this paper, a comprehensive computer model is presented for the diagnosis of PD based on motor, non-motor, and neuroimaging features using the recently-developed enhanced probabilistic neural network (EPNN). The model is tested for differentiating PD patients from those with scans without evidence of dopaminergic deficit (SWEDDs) using the Parkinson's Progression Markers Initiative (PPMI) database, an observational, multi-center study designed to identify PD biomarkers for diagnosis and disease progression. The results are compared to four other commonly-used machine learning algorithms: the probabilistic neural network (PNN), support vector machine (SVM), k-nearest neighbors (k-NN) algorithm, and classification tree (CT). The EPNN had the highest classification accuracy at 92.5% followed by the PNN (91.6%), k-NN (90.8%) and CT (90.2%). The EPNN exhibited an accuracy of 98.6% when classifying healthy control (HC) versus PD, higher than any previous studies. PMID- 26420586 TI - Ventilation heterogeneity and the benefits and challenges of multiple breath washout testing in patients with cystic fibrosis. AB - Multiple breath inert gas washout tests offer a simple and non-invasive method of measuring the effects of peripheral airway disease on ventilation efficiency, and have been the subject of intense research and commercial interest in the last decade. Although highly sensitive, these tests are not specific to disease in the small airways and are not suited to all patients with cystic fibrosis. They are harder to perform in subjects with more severe lung disease, with longer test time and poorer reproducibility in this population. The clinical advantages are more obvious in those with milder airways disease, where they are more sensitive to early changes than spirometry. In this population they are also quicker to complete and reproducible. A particular advantage in children is a stable range of normal which does not change during adolescence. Different inert gases give different washout results, and the technology to measure MBW is itself still evolving. Newer technologies such as hyperpolarised gas MRI are now helping us to understand how disease-related changes in lung ventilation influences inert gas washout. PMID- 26420587 TI - The Wnt inhibitor dickkopf-1: a link between breast cancer and bone metastases. AB - Breast cancer is the second leading cause of cancer death in women and metastasizes to bone in greater than 80 % of advanced-disease patients. Once breast cancer bone metastases are established, the disease is incurable and drives numerous complications that increase morbidity and diminish patients' quality of life. Many mechanisms have been implicated in bone metastases of breast cancer. The critical role of Wnt signalling pathway inhibition in initiating bone lesions has been demonstrated in a variety of bone diseases and tumours. Overexpression of dickkopf-1 (Dkk1) protein, a negative regulator of the Wnt/beta-catenin pathway, has been found in breast cancer cell lines that form osteolytic metastases preferentially and in serum from breast cancer patients with osteolytic bone metastases. Further understanding of the mechanistic role of Dkk1 as a link between primary breast tumours and secondary osteolytic bone metastases may facilitate development of anti-Dkk1 antibody therapeutic tools. PMID- 26420588 TI - Anthelmintic activity of trans-cinnamaldehyde and A- and B-type proanthocyanidins derived from cinnamon (Cinnamomum verum). AB - Cinnamon (Cinnamomum verum) has been shown to have anti-inflammatory and antimicrobial properties, but effects on parasitic worms of the intestine have not been investigated. Here, extracts of cinnamon bark were shown to have potent in vitro anthelmintic properties against the swine nematode Ascaris suum. Analysis of the extract revealed high concentrations of proanthocyanidins (PAC) and trans-cinnamaldehyde (CA). The PAC were subjected to thiolysis and HPLC-MS analysis which demonstrated that they were exclusively procyanidins, had a mean degree of polymerization of 5.2 and 21% of their inter-flavan-3-ol links were A type linkages. Purification of the PAC revealed that whilst they had activity against A. suum, most of the potency of the extract derived from CA. Trichuris suis and Oesophagostomum dentatum larvae were similarly susceptible to CA. To test whether CA could reduce A. suum infection in pigs in vivo, CA was administered daily in the diet or as a targeted, encapsulated dose. However, infection was not significantly reduced. It is proposed that the rapid absorption or metabolism of CA in vivo may prevent it from being present in sufficient concentrations in situ to exert efficacy. Therefore, further work should focus on whether formulation of CA can enhance its activity against internal parasites. PMID- 26420589 TI - Localization of Hippo signalling complexes and Warts activation in vivo. AB - Hippo signalling controls organ growth and cell fate by regulating the activity of the kinase Warts. Multiple Hippo pathway components localize to apical junctions in epithelial cells, but the spatial and functional relationships among components have not been clarified, nor is it known where Warts activation occurs. We report here that Hippo pathway components in Drosophila wing imaginal discs are organized into distinct junctional complexes, including separate distributions for Salvador, Expanded, Warts and Hippo. These complexes are reorganized on Hippo pathway activation, when Warts shifts from associating with its inhibitor Jub to its activator Expanded, and Hippo concentrates at Salvador sites. We identify mechanisms promoting Warts relocalization, and using a phospho specific antisera and genetic manipulations, identify where Warts activation occurs: at apical junctions where Expanded, Salvador, Hippo and Warts overlap. Our observations define spatial relationships among Hippo signalling components and establish the functional importance of their localization to Warts activation. PMID- 26420590 TI - Acute effects of calcium supplements on blood pressure and blood coagulation: secondary analysis of a randomised controlled trial in post-menopausal women. AB - Recent evidence suggests that Ca supplements increase the risk of cardiovascular events, but the mechanism(s) by which this occurs is uncertain. In a study primarily assessing the effects of various Ca supplements on blood Ca levels, we also investigated the effects of Ca supplements on blood pressure and their acute effects on blood coagulation. We randomised 100 post-menopausal women to 1 g/d of Ca or a placebo containing no Ca. Blood pressure was measured at baseline and every 2 h up to 8 h after their first dose and after 3 months of supplementation. Blood coagulation was measured by thromboelastography (TEG) in a subgroup of participants (n 40) up to 8 h only. Blood pressure declined over 8 h in both the groups, consistent with its normal diurnal rhythm. The reduction in systolic blood pressure was smaller in the Ca group compared with the control group by >5 mmHg between 2 and 6 h (P<=0.02), and the reduction in diastolic blood pressure was smaller at 2 h (between-groups difference 4.5 mmHg, P=0.004). Blood coagulability, assessed by TEG, increased from baseline over 8 h in the calcium citrate and control groups. At 4 h, the increase in the coagulation index was greater in the calcium citrate group compared with the control group (P=0.03), which appeared to be due to a greater reduction in the time to clot initiation. These data suggest that Ca supplements may acutely influence blood pressure and blood coagulation. Further investigation of this possibility is required. PMID- 26420591 TI - Clostridium luticellarii sp. nov., isolated from a mud cellar used for producing strong aromatic liquors. AB - A strictly anaerobic, Gram-stain-positive bacterium, designated FW431T, was isolated from a mud cellar used for producing strong aromatic Chinese liquors. The strain was able to produce butanoic acid, an important component of the aroma style of Chinese liquors. Cells of strain FW431T were straight or slightly curved rods with a polar endospore and peritrichous flagella. The major cellular fatty acids (>10 % of the total) were C16 : 0, C18 : 1omega9c and C18 : 0. Biolog assays indicated that the strain preferably metabolizes palatinose, l-fucose, beta-hydroxybutyric acid, l-rhamnose and alpha-ketobutyric acid among 95 carbon sources tested. FW431T was related most closely to Clostridium ljungdahlii DSM 13528T and Clostridium kluyveri DSM 555T based on 16S rRNA gene sequence similarities of 95.0 and 94.2 %, respectively. The DNA G+C content of the genomic DNA was 44.4 mol%. Based on the evidence presented here, FW431T ( = CGMCC 1.5201T = KCTC 15519T) is proposed as the type strain of a novel species, Clostridium luticellarii sp. nov. PMID- 26420592 TI - Cysteine Enhances Bioavailability of Copper to Marine Phytoplankton. AB - Emiliania huxleyi, a ubiquitous marine algae, was cultured under replete and Cu limiting conditions to investigate Cu uptake strategies involving thiols and associated redox reactions; comparisons to a model diatom, Thalassiosira pseudonana, were also drawn. Cu-limitation increased rates of cell surface reduction of Cu(II) to Cu(I) in E. huxleyi but not in T. pseudonana. Furthermore, Cu-limited E. huxleyi cells took up more Cu when cysteine was present compared to when no ligand was added, although a dependence on cysteine concentration was not observed. In contrast, Cu uptake by replete cells was dependent upon the relative abundance of inorganic species [Cu(I)']. We also show that cysteine can increase the bioavailability of Cu to Cu-limited cells, of both species, through the reductive release of Cu(I) from fairly strong Cu(II) ligands such as EDTA. Finally, support for a mechanism involving uptake of a Cys-Cu complex in E. huxleyi is drawn from the observation that Cu-limitation significantly enhances cysteine uptake by transporters that exhibit Michaelis-Menten kinetics. These Cu uptake strategies help explain the presence and distribution of dissolved thiols in surface seawater and have implications for the biogeochemical cycling of Cu in low Cu environments. PMID- 26420593 TI - Real-time characterization of risks of death associated with the Middle East respiratory syndrome (MERS) in the Republic of Korea, 2015. AB - BACKGROUND: An outbreak of the Middle East respiratory syndrome (MERS), comprising 185 cases linked to healthcare facilities, occurred in the Republic of Korea from May to July 2015. Owing to the nosocomial nature of the outbreak, it is particularly important to gain a better understanding of the epidemiological determinants characterizing the risk of MERS death in order to predict the heterogeneous risk of death in medical settings. METHODS: We have devised a novel statistical model that identifies the risk of MERS death during the outbreak in real time. While accounting for the time delay from illness onset to death, risk factors for death were identified using a linear predictor tied to a logit model. We employ this approach to (1) quantify the risks of death and (2) characterize the temporal evolution of the case fatality ratio (CFR) as case ascertainment greatly improved during the course of the outbreak. RESULTS: Senior persons aged 60 years or over were found to be 9.3 times (95% confidence interval (CI), 5.3 16.9) more likely to die compared to younger MERS cases. Patients under treatment were at a 7.8-fold (95% CI, 4.0-16.7) significantly higher risk of death compared to other MERS cases. The CFR among patients aged 60 years or older under treatment was estimated at 48.2% (95% CI, 35.2-61.3) as of July 31, 2015, while the CFR among other cases was estimated to lie below 15%. From June 6, 2015, onwards, the CFR declined 0.3-fold (95% CI, 0.1-1.1) compared to the earlier epidemic period, which may perhaps reflect enhanced case ascertainment following major contact tracing efforts. CONCLUSIONS: The risk of MERS death was significantly associated with older age as well as treatment for underlying diseases after explicitly adjusting for the delay between illness onset and death. Because MERS outbreaks are greatly amplified in the healthcare setting, enhanced infection control practices in medical facilities should strive to shield risk groups from MERS exposure. PMID- 26420594 TI - The prognostic role of pre-cystectomy hemoglobin levels in patients with invasive bladder cancer. AB - PURPOSE: To determine whether pre-treatment hemoglobin (Hb) levels in patients with bladder cancer impact on oncological outcomes after radical cystectomy (RC). METHODS: A consecutive, contemporary series of 246 patients undergoing RC and pelvic lymph node dissection for bladder cancer. Decreased Hb level was defined as <=12 g/dL. The Kaplan-Meier method was used to estimate recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS). The Fisher exact/Chi-square test was used to investigate differences between both groups. Uni- and multivariable Cox regression analysis addressed risk factors for recurrence, cancer-specific death and overall death. The median follow-up was 30 months (2-116). RESULTS: Of the 246 patients, 182 (74 %) had normal (>12 g/dL) and 64 decreased (<=12 g/dL) preoperative Hb (26 %). In univariable analysis, decreased Hb was associated with increased age, extravesical disease, hydronephrosis (all p < 0.001), node positive disease and positive resection margins (both p = 0.01). Subanalyzed for patients with organ-confined disease (defined as <=pT2bN0R0; N = 109), the 3-year RFS, CSS and OS was significantly lower in patients with decreased (34.9, 35.5 and 19.8 %) compared to normal Hb level (69.7, 86.3 and 77.6 %; p = 0.01/p = 0.002/p < 0.001). In multivariable analysis, RFS, CSS and OS were significantly lower in patients with decreased Hb (p = 0.007, p = 0.001 and p = 0.002), pathologically locally advanced tumor (>=pT3a; p = 0.023, p = 0.036 and p = 0.065) and nodal stage (p < 0.001, p = 0.006 and p = 0.001) and positive soft tissue surgical margins (p = 0.040, p = 0.004 and 0.012). CONCLUSIONS: Pre cystectomy Hb levels are associated with adverse histopathologic characteristics and provide additional prognostic information especially for patients with pathologically localized bladder cancer. PMID- 26420595 TI - PREDICT: model for prediction of survival in localized prostate cancer. AB - PURPOSE: Current models for prediction of prostate cancer-specific survival do not incorporate all present-day interventions. In the present study, a pre treatment prediction model for patients with localized prostate cancer was developed. METHODS: From 1989 to 2008, 3383 patients were treated with I-125 brachytherapy (n = 1694), external beam radiotherapy (>=74 Gy, n = 336) or radical prostatectomy (n = 1353). Pre-treatment parameters (clinical T-stage, biopsy grade, PSA and age) were related to the hazard of mortality by multivariate Cox proportional hazard analysis. The PRetreatment Estimation of the risk of Death In Cancer of the prosTate (PREDICT) model was developed. The predictive accuracy of the model was assessed by calibration and discrimination and compared to the Ash risk classification system. RESULTS: Of the 3383 patients analyzed, 2755 patients (81 %) were alive at the end of follow-up, 149 patients (4 %) died of prostate cancer and 365 patients (11 %) died of other causes, and for 114 patients (3 %) cause of death was unknown. Median follow-up time was 7.6 years. After correction for overoptimism, the c-statistic of the prediction model for prostate cancer-specific mortality was 0.78 (95 % CI 0.74-0.82), compared to 0.78 (95 % CI 0.75-0.81) for the risk classification system by Ash et al. The PREDICT model showed better calibration than the Ash risk classification system. CONCLUSIONS: The PREDICT model showed a good predictive accuracy and reliability. The PREDICT model might be a promising tool for physicians to predict disease specific survival prior to any generally accepted intervention in patients with localized prostate cancer. PMID- 26420596 TI - Extended versus limited pelvic lymph node dissection during bilateral nerve sparing radical prostatectomy and its effect on continence and erectile function recovery: long-term results and trifecta rates of a comparative analysis. AB - PURPOSE: To assess continence and erectile function (EF) recovery of extended pelvic lymph node dissection (ePLND) versus limited PLND (lPLND) after bilateral nerve-sparing radical prostatectomy (BNSRP). METHODS: Consecutive prostate cancer (PCa) patients undergoing BNSRP were stratified according to D'Amico into two groups: low-risk-PCa lPLND (obturator) and intermediate-/high-risk-PCa ePLND (obturator, external iliac artery, internal iliac artery, common iliac artery). Continence (no pad/one safety pad) and EF (IIEF-5 >= 17) recovery were assessed. Patients with phosphodiesterase type 5 inhibitors, neoadjuvant/adjuvant therapy, positive lymph nodes or positive surgical margins were excluded. RESULTS: From January 2007 to May 2012, a total 966 consecutive patients were included. Four hundred and sixty patients met the inclusion/exclusion criteria: 262 patients had ePLND and 198 patients had lPLND. Mean number of lymph nodes was 20.4 (range 10 65) and 4.7 (range 0-10), respectively (p < 0.001). Continence and spontaneous EF recovery after 12 months were 89.7 versus 93.4 % and 40.4 versus 47.5 %, respectively (all p > 0.05). Patient age at surgery (p = 0.001), preoperative EF (p < 0.001) and pathological tumor stage (p = 0.008), but not ePLND (p = 0.561), were independent predictors of EF recovery. No association was detected for continence recovery. Seven-year BCR-free survival for pT2 PCa was 100 and 94.8 % in lPLND and ePLND, respectively (p = 0.011). For pT3 PCa, this was 94.7 and 81.2 %, respectively (p = 0.287). At 2 years, the trifecta of continence, potency and recurrence freedom was achieved in 47.5 and 44.1 % in lPLND and ePLND, respectively (p = 0.451). CONCLUSIONS: ePLND is not associated with increased risk of postoperative incontinence or erectile dysfunction. Only patient age at surgery, preoperative EF and pathological tumor stage represent predictors of EF recovery. PMID- 26420597 TI - Is the smoke-free protections glass half full or half empty? PMID- 26420598 TI - Calcium intake and bone mineral density: systematic review and meta-analysis. AB - OBJECTIVE: To determine whether increasing calcium intake from dietary sources affects bone mineral density (BMD) and, if so, whether the effects are similar to those of calcium supplements. DESIGN: Random effects meta-analysis of randomised controlled trials. DATA SOURCES: Ovid Medline, Embase, Pubmed, and references from relevant systematic reviews. Initial searches were undertaken in July 2013 and updated in September 2014. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials of dietary sources of calcium or calcium supplements (with or without vitamin D) in participants aged over 50 with BMD at the lumbar spine, total hip, femoral neck, total body, or forearm as an outcome. RESULTS: We identified 59 eligible randomised controlled trials: 15 studied dietary sources of calcium (n=1533) and 51 studied calcium supplements (n=12,257). Increasing calcium intake from dietary sources increased BMD by 0.6-1.0% at the total hip and total body at one year and by 0.7-1.8% at these sites and the lumbar spine and femoral neck at two years. There was no effect on BMD in the forearm. Calcium supplements increased BMD by 0.7-1.8% at all five skeletal sites at one, two, and over two and a half years, but the size of the increase in BMD at later time points was similar to the increase at one year. Increases in BMD were similar in trials of dietary sources of calcium and calcium supplements (except at the forearm), in trials of calcium monotherapy versus co-administered calcium and vitamin D, in trials with calcium doses of >= 1000 versus <1000 mg/day and <= 500 versus >500 mg/day, and in trials where the baseline dietary calcium intake was <800 versus >= 800 mg/day. CONCLUSIONS: Increasing calcium intake from dietary sources or by taking calcium supplements produces small non-progressive increases in BMD, which are unlikely to lead to a clinically significant reduction in risk of fracture. PMID- 26420599 TI - Interaction type influences ecological network structure more than local abiotic conditions: evidence from endophytic and endolichenic fungi at a continental scale. AB - Understanding the factors that shape community assembly remains one of the most enduring and important questions in modern ecology. Network theory can reveal rules of community assembly within and across study systems and suggest novel hypotheses regarding the formation and stability of communities. However, such studies generally face the challenge of disentangling the relative influence of factors such as interaction type and environmental conditions on shaping communities and associated networks. Endophytic and endolichenic symbioses, characterized by microbial species that occur within healthy plants and lichen thalli, represent some of the most ubiquitous interactions in nature. Fungi that engage in these symbioses are hyperdiverse, often horizontally transmitted, and functionally beneficial in many cases, and they represent the diversification of multiple phylogenetic groups. We evaluated six measures of ecological network structure for >4100 isolates of endophytic and endolichenic fungi collected systematically from five sites across North America. Our comparison of these co occurring interactions in biomes ranging from tundra to subtropical forest showed that the type of interactions (i.e., endophytic vs. endolichenic) had a much more pronounced influence on network structure than did environmental conditions. In particular, endophytic networks were less nested, less connected, and more modular than endolichenic networks in all sites. The consistency of the network structure within each interaction type, independent of site, is encouraging for current efforts devoted to gathering metadata on ecological network structure at a global scale. We discuss several mechanisms potentially responsible for such patterns and draw attention to knowledge gaps in our understanding of networks for diverse interaction types. PMID- 26420601 TI - Association between HIV infection and bone mineral density in climacteric women. AB - A cross-sectional study was conducted with the purpose of evaluating bone mineral density in HIV seropositive and seronegative climacteric women. HIV infection was negatively associated with bone mineral density in the lumbar spine PURPOSE: To assess bone mineral density (BMD) and its associated factors in HIV seropositive and seronegative climacteric women METHODS: A cross-sectional study with 537 women (273 HIV seropositive and 264 HIV seronegative) aged between 40 and 60 years old receiving follow-up care at two hospitals in Brazil. A questionnaire on clinical and sociodemographic characteristics was completed. Laboratory tests were performed, and BMD was measured at the lumbar spine and hip. Statistical analysis was carried out by Yates and Pearson chi-squared tests, Mann-Whitney test, and multiple linear regression. RESULTS: The mean age was 47.7 years in HIV seropositive women, and 75 % had nadir CD4 above 200, and 77.8 % had viral load below the detection limit. The mean age in the HIV-seronegative women was 49.8 years. The prevalence of low spinal BMD was 14.6 % in the HIV-seropositive and 4.6 % in the HIV-seronegative women (p < 0.01). The prevalence of low BMD at the femoral neck was 5.6 % in HIV-seropositive and 3.3 % in the HIV-seronegative women (p = 0.38). Multiple analyses showed that the factors associated with lower BMD at the spine were being postmenopausal and being HIV-seropositive. Being overweight was associated with a higher BMD. At the femoral neck, factors associated with lower BMD were being postmenopausal and being white. Being overweight and having a greater number of pregnancies were associated with higher BMD CONCLUSIONS: HIV-seropositive women on long-term antiretroviral treatment and in good immunological conditions exhibited low BMD in the spine (L1-L4). However, BMD in the femoral neck was similar to non-infected women. PMID- 26420600 TI - [Kyphoplasty combined with intraoperative radiotherapy (Kypho-IORT). Alternative therapy for patients with oligometastatic spinal metastases]. AB - BACKGROUND: Due to a more effective systemic therapy the survival of patients suffering from malignant tumors has been significantly improved but a longer life span is often associated with a higher incidence of osseous metastases. The majority of these metastases are localized in the spine causing pain, instability and neurological impairments. The interdisciplinary management of spinal metastases previously consisted of stabilization followed by fractionated external body radiation therapy. A reduction in procedural severity and morbidity as well as consideration of self-sufficiency and hospitalization time are important target parameters for these palliative patients. METHOD AND RESULTS: Kyphoplasty combined with intraoperative radiotherapy (Kypho-IORT) is one of several modern treatment options, which involves a minimally invasive procedure with local high-dose transpedicular irradiation of the spine with low-energy (50 kV) X-rays. Immediately following irradiation, stabilization of the spine is carried out using kyphoplasty via the same access route so that a single stage procedure with excellent pain reduction and good local tumor control can be achieved. This article presents clinical data for this procedure and the different fields of indications are critically reviewed and compared to other therapy options. Methodological improvements and options for further individualization of therapy are demonstrated. CONCLUSION: The Kypho-IORT procedure is a safe, feasible and beneficial modern treatment option for instant stabilization and local tumor control in patients with spinal metastases. More than 100 operations have been successfully performed so that the method can be deemed suitable for inclusion in the clinical routine. A phase II dose escalation study has now been completed and submitted for publication and a 2-arm non inferiority trial (phase III study) for comparison with conventional irradiation is in progress. PMID- 26420602 TI - Assessment of susceptibility of mould isolates towards biocides. AB - OBJECTIVES: The aim of this study was to determine the susceptibility of 77 mould strains: Aspergillus fumigatus (20), Aspergillus flavus (8), Aspergillus niger (4), Aspergillus ochraceus (2), Penicillium citrinum (15), Penicillium crysogenum (14), Penicillium aurantiogriseum (1), Penicillium roquefortii (4), Penicillium paneum (2), Rhizopus spp. (3), Tricoderma spp. (1) and Mucor spp. (3) to biocides. METHODS: MIC determination was determined based on CLSI methodology. RESULTS: For hospital acquired strains, MIC50 was 0.5mg/L, MIC90 was 1mg/L for chlorhexidine (CHX); MIC50 was 0.5mg/L, and MIC90 was 1mg/L for benzalkonium chloride (BZC); MIC50 was 1mg/L, and MIC90 was 2mg/L for triclosan (TRC); MIC50 was 1024mg/L, and MIC90 was 2048mg/L for sodium hypochloride (SHC). For feed and food isolates MIC50 was 2mg/L, MIC90 was 8mg/L for CHX, MIC50 was 2mg/L, and MIC90 was 4mg/L for BZC, MIC50 was 2mg/L, and MIC90 was 4mg/L for TRC, MIC50 was 256mg/L, and MIC90 was 512mg/L for SHC. CONCLUSION: We can conclude that food isolates presented slightly higher MIC50 and MIC90 values for CHX, BNZ and TRC, but not for SHC. PMID- 26420603 TI - Targeted Gene Delivery to Macrophages by Biodegradable Star-Shaped Polymers. AB - In this report, two biodegradable star-shaped polyasparamide derivatives and four analogues modified with either mannose or folic acid moiety for preferential targeting of a difficult-to-transfect immune cell type, i.e., macrophage, have been synthesized. Each of the prepared star polymers complexes with plasmid DNA to form nanosized particles featuring a core-shell-like morphology. Mannose or folate functionalized star polymers can greatly improve the transfection performance on a macrophage cell line RAW 264.7. As a result, a combination of targeting ligand modification and topological structures of gene carriers is a promising strategy for immune cells-based gene therapy. PMID- 26420604 TI - Ochratoxin A in brewer's yeast used as food supplement. AB - Brewer's yeasts are rich in vitamins of the B-group and contain other nutritive factors; therefore, they are recommended as valuable food supplements for people with special dietary requirements like pregnant women, children, and adolescents, or for people with high physical activity. Additionally, certain strains of brewer's yeast are known to be capable of adsorbing xenobiotics such as mycotoxins. Because of that, these yeasts are regarded as having positive effects in food, beverage, and feed technology. Their potential to bind mycotoxins such as ochratoxin A (OTA), however, can subsequently lead to a contamination of such brewer's yeasts used as food supplements. In the present study, we analyzed 46 samples of brewer's yeasts for the occurrence of OTA by HPLC with fluorescence detector (HPLC-FLD) and for confirmatory measurements by liquid chromatography tandem mass spectrometry (LC-MS/MS). Nearly 90% of the samples were contaminated with OTA, the levels ranging from the limit of detection (LOD, 0.01 MUg/kg) to 4.2 MUg/kg. The mean and median levels of contamination were 0.49 and 0.27 MUg/kg, respectively. Based on these results, the additional weekly OTA exposure by regularly consuming such supplements was assessed. Depending on different subpopulations (adults, children) and levels of contamination used for calculation, the additional OTA intake via brewer's yeast products ranged from 9.3% (mean case) to 114% (worst case) of the published mean weekly OTA intake in Germany (adults 279.3 ng, children 195.3 ng). At present, maximum levels for OTA in nutritional supplements like brewer's yeast do not exist. Based on our results, however, it is recommended that producers of these dietary supplements should include mycotoxin analyses in ongoing and future self-monitoring programs and in product quality checks. PMID- 26420605 TI - Effects of deoxynivalenol in naturally contaminated wheat on feed intake and health status of horses. AB - The present study examined the short-term effects of deoxynivalenol (DON), administered at two different concentrations via a feed preparation using naturally contaminated wheat, on feed intake, liver and kidney metabolism and immunomodulatory properties in horses. Twelve geldings were randomly assigned to one of three dietary treatments for 21 days. DON was provided via naturally contaminated wheat (14.6 +/- 6.5 mg DON/kg dry matter). The daily feed intake was adjusted to 4 kg of wheat and 1.7 kg of silage per 100 kg of body weight (BW). Horses were fed one of the following diets: control wheat with 0% contaminated wheat (CON), wheat mixture containing 53 +/- 2% of DON-contaminated wheat [low DON intake (LDI)] or wheat mixture containing 78 +/- 4% of DON-contaminated wheat [high DON intake (HDI)]. CON, LDI and HDI corresponded to a targeted daily DON intake via the complete ration of <5, 50 and 75 MUg/kg BW, respectively. None of the horses demonstrated any clinical signs commonly associated with the intake of DON such as colic or depression. HDI was associated with lower daily wheat intake on day 21. Serum DON concentrations increased with higher DON intake. The non toxic DON metabolite, deepoxy-deoxynivalenol (DOM-1) was only detected on day 21 of the DON feeding period. No changes in haematological and serum parameters or serum globulins or in the ex vivo proliferation response of peripheral blood mononuclear cells were observed. These results suggest that horses are less sensitive to DON exposure than other domestic species, for example, swine. Therefore, the European Commission guidance value for critical DON concentrations in swine feed (complete diet) of 0.9 mg/kg could be safely applied for rations intended for feeding adult horses as well. PMID- 26420606 TI - A Toxoplasma gondii vaccine encoding multistage antigens in conjunction with ubiquitin confers protective immunity to BALB/c mice against parasite infection. AB - BACKGROUND: Toxoplasma gondii is a widely prevalent intracellular parasite which infects almost all warm-blooded animals including humans and causes serious zoonotic toxoplasmosis. DNA vaccines have proved effective in the protection against parasites. However, the problems of weak immunity and inefficient delivery of DNA vaccine remain major issues. Therefore, comprehensive antigens derived from all stages of the parasite, effective adjuvants and delivery systems should be considered in the vaccine construction. METHODS: SAG3101-144,ROP18347 396, MIC6288-347, GRA7182-224, MAG158-125, BAG1156-211 and SPA142-200, derived from antigens in tachyzoite, bradyzoite and sporozoite stages of T. gondii were screened based on CD8(+) T cell epitope binding affinity to HLA and H-2. We constructed a recombinant DNA vaccine and an adenovirus vaccine encoding multi stage antigen of T. gondii linked to ubiquitin molecules and vaccinated BALB/c mice with different strategies. Antibodies, cytokines, splenocytes proliferation, as well as the percentage of CD4(+) and CD8(+) T cells in immunized mouse were analyzed by the Enzyme-Linked Immunosorbent Assays (ELISA), Flow Cytometry (FCM). Protective efficacy was evaluated by challenging immunized mice with type I and type II parasite. RESULTS: Our results indicated that the DNA vaccine had the advantage of inducing a stronger humoral response, whereas the adenovirus vectored vaccine effectively improved the cellular immune response. Priming with DNA vaccine and boosting with adenovirus-vectored vaccine induced Th1-type immune responses with highest levels of IgG2a and secretion of cytokines IL-2 and IFN gamma. Effective protection against type I and type II parasite with an increase in survival rate and a decrease in brain cyst burden was achieved in immunized mice. CONCLUSIONS: Priming vaccination with DNA vaccine and boosting with the recombinant adenovirus vaccine encoding ubiquitin conjugated multi-stage antigens of T. gondii was proved to be a potential strategy against the infection of type I and type II parasite. PMID- 26420609 TI - Integration, Networking, and Global Biobanking in the Age of New Biology. AB - Scientific revolution is changing the world forever. Many new disciplines and fields have emerged with unlimited possibilities and opportunities. Biobanking is one of many that is benefiting from revolutionary milestones in human genome, post-genomic, and computer and bioinformatics discoveries. The storage, management, and analysis of massive clinical and biological data sets cannot be achieved without a global collaboration and networking. At the same time, biobanking is facing many significant challenges that need to be addressed and solved including dealing with an ever increasing complexity of sample storage and retrieval, data management and integration, and establishing common platforms in a global context. The overall picture of the biobanking of the future, however, is promising. Many population-based biobanks have been formed, and more are under development. It is certain that amazing discoveries will emerge from this large scale method of preserving and accessing human samples. Signs of a healthy collaboration between industry, academy, and government are encouraging. PMID- 26420607 TI - The association between temporal changes in the use of obstetrical intervention and small-for-gestational age live births. AB - BACKGROUND: The literature attributes secular declines in small-for-gestational age (SGA) live births to changes in maternal smoking and other maternal characteristics. However, there are reasons to believe that the observed reductions in SGA may be a consequence of early delivery following obstetric intervention. METHODS: We examined temporal trends in obstetrical intervention and SGA among singleton live births in the United States from 1990 to 2010. The modified Kitagawa decomposition, based on the fetuses-at-risk approach, was used to assess the relative contribution of changes in the gestational age distribution and gestational age-specific SGA to overall changes in SGA. Reductions in SGA rates due to a left shift in the gestational age distribution were assumed to primarily reflect increased obstetrical intervention, whereas decreases in overall SGA due to decreases in gestational-age-specific SGA rates were assumed to reflect declines in risk factors. RESULTS: Temporal trends in SGA followed a non-linear pattern, with substantial declines from 10.1% in 1990-92 to 8.9% in 2002-04, followed by a small increase to 9.1% in 2008-10. Rates of maternal smoking steadily decreased throughout the same time period and changes in SGA rates were more consistent with changes in the gestational age distribution. The modified Kitagawa decomposition analysis also attributed the initial decline in SGA rates to changes in the gestational age distribution. CONCLUSIONS: Complex temporal pattern in SGA rates cannot be explained by the linear pattern of changes in factors like maternal smoking. Changes in the gestational age distribution are more consistent with the observed secular trends in SGA rates. PMID- 26420608 TI - Granulosa cell apoptosis by impairing antioxidant defense system and cellular integrity in caprine antral follicles post malathion exposure. AB - Toxicological studies have demonstrated the exposure-risk relationship of several pesticides on reproduction of living organisms. To evaluate the role of malathion as a reproductive toxicant, this study aims at assessing the cytological and biochemical changes in the granulosa cells after malathion exposure in dose (1 nM, 10 nM, 100 nM) and time (4 h, 6 h, 8 h) dependent manner. Histomorphological analysis, fluorescence assay, apoptosis quantification, and terminal deoxynucleotidyl transferase d-UTP mediated nick end labeling (TUNEL) assay were done to determine cytological changes, whereas antioxidant enzyme assays were done to measure the oxidative stress in malathion treated ovarian antral follicles. Histological studies exhibited the occurrence of highly condensed or marginated chromatin with fragmented nucleus, pyknosis, loss of membrane integrity, increased empty spaces, and vacuolization in malathion treated granulosa cells. Ethidium bromide/acridine orange (EB/AO) fluorescence staining demonstrated a significant increase in incidence and percentage of apoptosis after malathion exposure (p < 0.001), both between and within the groups. Malathion exposure also resulted in increased DNA fragmentation and decline in both antioxidant enzymes activity namely catalase (CAT) and superoxide dismutase (SOD) in granulosa cells of antral follicles. Moreover, there was found a significant negative correlation between the apoptosis incidence and the level of antioxidant enzymes activity, SOD (r = -0.73 p < 0.01) and CAT (r = -0.80 p < 0.01), in malathion treated ovarian antral follicles. Thus, highlighting the role of DNA fragmentation and declining antioxidant level as a possible mechanism underlying malathion induced reproductive toxicity. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1944-1954, 2016. PMID- 26420610 TI - The Future of Biobanking: A Conceptual Look at How Biobanks Can Respond to the Growing Human Biospecimen Needs of Researchers. AB - Biobanking of human biological specimens has evolved from the simple private collection of often poorly annotated residual clinical specimens, to well annotated and organized collections setup by commercial and not-for-profit organizations. The activities of biobanks is now the focus of international and government agencies in recognition of the need to adopt best practices and provide scientific, ethical and legal guidelines for the industry. The demand for more, high quality and clinically annotated biospecimens will increase, primarily due to the unprecedented level of genomic, post genomic and personalized medicine research activities going on. Demand for more biospecimens provides new challenges and opportunities for developing strategies to build biobanking into a business that is better able to supply the biospecimen needs of the future. A paradigm shift is required particularly in organization and funding, as well as in how and where biospecimens are collected, stored and distributed. New collection sites, organized as Research Ready Hospitals (RRHs) and new public private partnership models are needed for sustainability and increased biospecimen availability. Biobanks will need to adopt industry-wide standard operating procedures, better and "non-destructive" methods for quality assessment, less expensive methods for sample storage/distribution, and objective methods to manage scarce biospecimens. Ultimately, the success of future biobanks will rely greatly on the success of public-private partnerships, number and diversity of available biospecimens, cost management and the realization that an effective biobank is one that provides high quality and affordable biospecimens to drive research that leads to better health and quality of life for all. PMID- 26420611 TI - Sustainability of Biobanks in the Future. AB - Human biorepositories are essential in providing high quality specimens that are well characterized. Biospecimens are used in basic, clinical, and translational research. However, as regulatory requirements and scientific demands increase the complexity of the daily operations of a biorepository, the cost of maintaining a biobank will increase. How can biobanks today maintain sustainability during the current economic climate and changing landscape of operating a biorepository? This is a brief review of how different biobanks have approached sustainability. PMID- 26420612 TI - Biobanking: The Future of Cell Preservation Strategies. AB - With established techniques cryopreservation is often viewed as an "old school" discipline yet modern cryopreservation is undergoing another scientific and technology development growth phase. In this regard, today's cryopreservation processes and cryopreserved products are found at the forefront of research in the areas of discovery science, stem cell research, diagnostic development and personalized medicine. As the utilization of cryopreserved cells continues to increase, the demands placed on the biobanking industry are increasing and evolving at an accelerated rate. No longer are samples providing for high immediate post-thaw viability adequate. Researchers are now requiring samples where not only is there high cell recovery but that the product recovered is physiologically and biochemically identical to its pre-freeze state at the genominic, proteomic, structural, functional and reproductive levels. Given this, biobanks are now facing the challenge of adapting strategies and protocols to address these needs moving forward. Recent studies have shown that the control and direction of the molecular response of cells to cryopreservation significantly impacts final outcome. This chapter provides an overview of the molecular stress responses of cells to cryopreservation, the impact of the apoptotic and necrotic cell death continuum and how studies focused on the targeted modulation of common and/or cell specific responses to freezing temperatures provide a path to improving sample quality and utility. This line of investigation has provided a new direction and molecular-based foundation guiding new research, technology development and procedures. As the use of and the knowledge base surrounding cryopreservation continues to expand, this path will continue to provide for improvements in overall efficacy and outcome. PMID- 26420613 TI - Biobanking for Personalized Medicine. AB - A biobank is an entity that collects, processes, stores, and distributes biospecimens and relevant data for use in basic, translational, and clinical research. Biobanking of high-quality human biospecimens such as tissue, blood and other bodily fluids along with associated patient clinical information provides a fundamental scientific infrastructure for personalized medicine. Identification of biomarkers that are specifically associated with particular medical conditions such as cancer, cardiovascular disease and neurological disorders are useful for early detection, prevention, and treatment of the diseases. The ability to determine individual tumor biomarkers and to use those biomarkers for disease diagnosis, prognosis and prediction of response to therapy is having a very significant impact on personalized medicine and is rapidly changing the way clinical care is conducted. As a critical requirement for personalized medicine is the availability of a large collection of patient samples with well annotated patient clinical and pathological data, biobanks thus play an important role in personalized medicine advancement. The goal of this chapter is to explore the role of biobanks in personalized medicine and discuss specific needs regarding biobank development for translational and clinical research, especially for personalized medicine advancement. PMID- 26420614 TI - A Global View of Breast Tissue Banking. AB - The importance of accessing high quality clinical samples for translational research is now firmly recognised. Traditionally these samples were collected and curated by individuals with an interest in a particular disease type. In recent years the idea of centralising and storing tissue collections in the form of tissue banks or biobanks has developed. As a result a number of biobanks have been established in many different countries. These can be either single centres or multi centre collaborations, often in the form of a federated network. This chapter outlines the development of breast tissue banking in a global context and discusses some of the challenges that lie ahead for the field, in particular how to meet the growing needs of researchers, how to make the best use of donated samples and how to increase the visibility of samples residing in biobanks to researchers. PMID- 26420615 TI - Biobanking of Cerebrospinal Fluid for Biomarker Analysis in Neurological Diseases. AB - Cerebrospinal fluid (CSF) reflects pathophysiological aspects of neurological diseases, where neuroprotective strategies and biomarkers are urgently needed. Therefore, biobanking is very relevant for biomarker discovery and evaluation for these neurological diseases.An important aspect of CSF biobanking is quality control, needed for e.g. consistent patient follow-up and the exchange of patient samples between research centers. Systematic studies to address effects of pre analytical and storage variation on a broad range of CSF proteins are needed and initiated.Important features of CSF biobanking are intensive collaboration in international networks and the tight application of standardized protocols. The current adoption of standardized protocols for CSF and blood collection and for biobanking of these samples, as presented in this chapter, enables biomarker studies in large cohorts of patients and controls.In conclusion, biomarker research in neurodegenerative diseases has entered a new era due to the collaborative and multicenter efforts of many groups. The streamlining of biobanking procedures, including sample collection, quality control, and the selection of optimal control groups for investigating biomarkers is an important improvement to perform high quality biomarker studies. PMID- 26420616 TI - Biobanking in the Twenty-First Century: Driving Population Metrics into Biobanking Quality. AB - Biospecimens are the essential substrates for human biomarker research. Across the globe, biobanks have developed the facilities and mechanisms to collect, process, store and distribute those substrates to researchers. However, despite some notable successes, less than one hundred of the tens of thousands of purported biomarkers have been independently validated. We propose the need for a new paradigm in biobanking; simply pursuing larger numbers of participants, larger networks of biobanks and higher sample integrity will not, in itself, transform the success rate or efficiency of biomarker research. We propose that biobanks must embrace the intrinsic observational nature of biospecimens and furnish the recipients of biospecimens with the population metrics (descriptive statistics) that can facilitate the scientific rigor that is mandated in other areas of observational research. In addition, we discuss the value of population based ascertainment and recruitment and the importance of the timing of biospecimen collections. Any assessment of biospecimen quality must go beyond the sample itself and consider both the patient/participant selection and the most appropriate and informative timing for specimen collection, particularly prior to any treatment intervention in diseased populations. The examples and rationales that we present are based largely on cancer-related collections because the feasibility of population metrics is greatly assisted by the comprehensive registries that are more common for cancer than other chronic diseases. Changing the biobanking paradigm from tacitly 'experimental' to explicitly 'observational' represents a profound but urgent methodological shift that will influence the establishment, management, reporting and impact of biobanks in the twenty-first century. PMID- 26420617 TI - Challenges in Developing a Cancer Oriented-Biobank: Experience from a 17 Year-Old Cancer Biobank in Sao Paulo, Brazil. AB - Brazil and Latin America will face a cancer epidemic in the coming years. Efforts towards cancer prevention, early detection and treatment must be associated with active research that helps understanding the geographical variations of this disease. The creation of cancer-oriented biobanks should be part of this strategy. This article outlines the challenges of establishing a cancer-oriented biobank at the A. C. Camargo Center, a private, non-profit institution located in Sao Paulo, Brazil. We analyze important issues related to the day-to-day operations of the biobank within an institutional and national context, as well as the lessons learned over the years. It is hoped that the information contained in this paper will be useful for the development of other biobanks in Brazil and other countries in Latin America. PMID- 26420618 TI - China Biobanking. AB - Biobanks are playing increasingly important roles in clinical and translational research nowadays. China, as a country with the largest population and abundant clinical resources, attaches great importance to the development of biobanks. In recent years, with the increasing support from the Chinese government, biobanks are blooming across the country. This paper provides a detailed overview of China biobanking, which is further divided in the following four parts: (i) general introduction of the number, category and distribution of current biobanks; (ii) summarization of the current development status, and issues that Chinese biobanks are faced with; (iii) international cooperation between China and the global biobanking community; (iv) prospect of the modern twenty-first century Chinese biobanks, which would achieve standardized operation, systematic specimen management, and extensive collaboration, and thus provide support for the robust research discoveries and personalized medicine etc. PMID- 26420619 TI - Establishing an Iso-Compliant Modern Cancer-Biobank in a Developing Country: A Model for International Cooperation. AB - King Hussein Cancer (KHCC) is a specialized cancer center that treats both adult and pediatric cancer patients from Jordan and the neighboring countries. KHCC is acknowledged as a leader in cancer treatment in the Middle East and its vision is to maintain its leading position in cancer therapy and research. Hence, KHCC embarked on establishing the first ISO compliant cancer biobank (KHCCBIO) in Jordan.Currently, there are very few biobanks in the Middle East, hence, KHCC wanted to change this situation by establishing an ISO-compliant cancer biobank which would incorporate all current international guidelines and best-in class practices under an approved quality management system for the benefit of researchers in Jordan, its neighboring countries, and throughout the world. The established biobank would follow the highest ethical standards in collecting, processing, storing and distributing high-quality, clinically annotated biospecimens.The strategy used in establishing KHCCBIO was based on taking advantage of international networking and collaboration. This in essence led to knowledge transfer between well established organizations, institutions and individuals from Europe and Jordan, in existing technological innovation and internationally recognized quality standards. KHCC efforts were facilitated by a grant from the European Union under the seventh frame work program.Future aims of KHCCBIO are to develop KHCC's research infrastructure, increase its scope and visibility and improve its competitiveness throughout the biomedical science arena. Moreover, KHCCBIO is aiming to establish a platform for future knowledge transfer and collaborative research; develop partnerships between European and Middle Eastern organizations. PMID- 26420620 TI - Nursing and Biobanking. AB - Nurses are a pivotal component of the translational research movement and apply scientific discoveries to the healthcare and clinical practice fields. Biobanking is also an important factor in furthering translational research by providing biospecimens and related clinical data to the research community. The effectiveness of any biobanking effort necessitates the enrollment of large numbers of diverse participants, which signifies a need for the nursing profession to secure the knowledge necessary to impact biobanking practices and to promote participant advocacy. In addition, biobanks provide the volume, variety, veracity, and velocity of data that can address the challenges of nursing research. Nurse scientists, research nurse coordinators and clinical research and practice nurses must be informed about the various benefits and risks associated with biobanking in addition to ethical issues surrounding informed consent, participant privacy, and the release of research results. Ultimately, nurses need to possess competencies to facilitate biobanking practices both at the research bench and at the point of care. PMID- 26420621 TI - A Data-Centric Strategy for Modern Biobanking. AB - Biobanking has been in existence for many decades and over that time has developed significantly. Biobanking originated from a need to collect, store and make available biological samples for a range of research purposes. It has changed as the understanding of biological processes has increased and new sample handling techniques have been developed to ensure samples were fit-for-purpose.As a result of these developments, modern biobanking is now facing two substantial new challenges. Firstly, new research methods such as next generation sequencing can generate datasets that are at an infinitely greater scale and resolution than previous methods. Secondly, as the understanding of diseases increases researchers require a far richer data set about the donors from which the sample originate.To retain a sample-centric strategy in a research environment that is increasingly dictated by data will place a biobank at a significant disadvantage and even result in the samples collected going unused. As a result biobanking is required to change strategic focus from a sample dominated perspective to a data centric strategy. PMID- 26420622 TI - The Importance of Quality Patient Advocacy to Biobanks: A Lay Perspective from Independent Cancer Patients Voice (ICPV), Based in the United Kingdom. AB - Biobanking in the twentieth century will become of increasing importance in health research. Regulation and governance of biobanks must be open and transparent to ensure public trust and confidence and increase donation. Effective Lay Involvement all levels in biobank organisations should be standard practice helping ensure patient benefit remains the central aim and assisting the Promotion of Biobanks and Recruitment of Donors. Properly selected, educated and supported, they become valued members of the Biobank Team. This chapter is based on the work of Independent Cancer Patients' Voice (ICPV) in the UK and recognises that the National Health Service provides a framework which is not universal and neither is the model of patient advocacy which has been developed particularly in cancer research. However, although it has not been easy to find potential members for ICPV, nor to attract funding, we have earned the respect of our professional colleagues by our commitment in giving time and developing the skills necessary to provide effective involvement. These colleagues have enthusiastically mentored and supported us and have provided venues and tutoring for Educational Events. We are sure that patient advocates in other countries would welcome the opportunity for similar involvement and hope our experiences will be of interest. PMID- 26420623 TI - Correction: Treatment Efficacy and Resistance Mechanisms Using the Second Generation ALK Inhibitor AP26113 in Human NPM-ALK-Positive Anaplastic Large Cell Lymphoma. PMID- 26420624 TI - Elevated Intact Proinsulin Levels During an Oral Glucose Challenge Indicate Progressive beta-Cell Dysfunction and May Be Predictive for Development of Type 2 Diabetes. AB - BACKGROUND: Elevated fasting intact proinsulin is a biomarker of late-stage beta cell-dysfunction associated with clinically relevant insulin resistance. In this pilot investigation, we explored the potential value of measuring intact proinsulin as a functional predictor of beta-cell exhaustion during an oral glucose tolerance test (OGTT). METHODS: The study was performed with 31 participants, 11 of whom were healthy subjects (7 female, age: 59 +/- 20 years), 10 had impaired glucose tolerance (IGT, 6 female, 62 +/- 10 years), and 10 had known type 2 diabetes (T2DM, 5 female, 53 +/- 11 years, HbA1c: 7.0 +/- 0.6%, disease duration: 8 +/- 5 years). During OGTT, blood was drawn after 0 hours, 1 hour, and 2 hours for determination of glucose and intact proinsulin. Five years later, patients were again contacted to assess their diabetes status and the association to the previous OGTT results was analyzed. RESULTS: The OGTT (0 hours/1 hour/2 hours) results were as follows: healthy subjects: glucose: 94 +/- 8 mg/dL/140 +/- 29 mg/dL/90 +/- 24 mg/dL, intact proinsulin: 3 +/- 2 pmol/L/10 +/ 7 pmol/L/10 +/- 5 pmol/L); IGT: glucose: 102 +/- 9 mg/dL/158 +/- 57 mg/dL/149 +/ 34 mg/dL, intact proinsulin: 7 +/- 4 pmol/L/23 +/- 8 pmol/L/28 +/- 6 pmol/L; T2DM: glucose: 121 +/- 20 mg/dL/230 +/- 51 mg/dL/213 +/- 34 mg/dL; intact proinsulin: 7 +/- 7 pmol/L/26 +/- 9 pmol/L/27 +/- 10 pmol/L). Five years later, all of the IGT and 2 of the healthy subjects had developed T2DM and one had devloped IGT. All of them had elevated 2-hour proinsulin values in the initial OGTT, while patients with normal intact proinsulin results did not develop diabetes. CONCLUSIONS: Elevated 2-hour intact proinsulin levels during OGTT were predictive for later type 2 diabetes development. Further studies need to confirm our findings in larger populations. PMID- 26420625 TI - Using Remote Communication Technology in Insulin Pump Training: A Feasibility Study. AB - PURPOSE: This feasibility study was designed to examine if remote communication technology can be used in the technical training of an insulin pump in adults with diabetes who were familiar with insulin pump therapy. METHODS: Surveys were emailed to 69 individuals who purchased an insulin pump and had been trained by the manufacturer's diabetes educators. In consultation with providers, participants were given the choice of receiving training in a face-to-face meeting or via remote communication technology. The survey consisted of 27 questions asking participants' characteristics, device proficiency, confidence, and their satisfaction with the insulin pump and the training method. Differences between the 2 groups were examined using bivariate analyses. RESULTS: There were 17 participants in the remote group and 20 participants in the face-to-face group. Participants had a mean age of 40.9 +/- 14.3 years, had diabetes for 24.3 +/- 13.8 years, and used an insulin pump for 9.8 +/- 4.9 years. The participants in both groups were not statistically different in age, diabetes history, years on insulin pump, device proficiency, confidence, or satisfaction with the training method. The remote group reported less graduate-level education (P < .05) and higher satisfaction scores with the insulin pump training (P < .05). CONCLUSION: Although this study has limitations associated with the small sample size and self-selection bias, the results suggest that remote communication technology may be an effective tool to provide technical training to adults who are familiar with insulin pump therapy. Additional research is required to determine the effectiveness of the remote insulin pump training. PMID- 26420626 TI - Are Systematic Reviews and Meta-Analyses Appropriate Tools for Assessing Evolving Medical Device Technologies? AB - Systematic reviews and meta-analyses (SRMAs) provide unique insights into comparative effectiveness of diabetes treatments. However, use of these analyses may be inappropriate for assessing the value and utility of technologies that involve significant behavioral interventions and encompass rapidly evolving technologies such as real-time continuous glucose monitoring (RT-CGM). The rapid evolution of RT-CGM, compared with the time required for publication of clinical studies used in SRMAs, may preclude differentiation between past and current generations of devices. In addition, the effect of performance and usability differences between the various commercial devices on possible clinical outcomes associated with the devices are often not clearly discussed, and many of the RT CGM studies assessed in SRMAs do not provide adequate information regarding whether and/or to what degree study subjects and clinicians were trained to use the RT-CGM and utilize the data to adjust therapy. Although numerous clinical studies have shown that the glycemic benefit of RT-CGM is related to the frequency and duration of use, a disproportionate number of RT-CGM studies included in recent SRMAs are based on the results of the intention-to-treat analyses and do not consider this fundamental behavioral component in their conclusions. Given these limitations, the generalizability of SRMA conclusions may be limited, and findings from these reports may significantly underestimate the potential glycemic benefit of current and future devices, posing challenges for coverage and reimbursement. We reviewed the potential limitations of the recent Cochrane Collaboration report on CGM, focusing on the 12 studies that assessed RT-CGM use in adults, children/adolescents or both. PMID- 26420627 TI - Effect of nickel titanium file design on the root surface strain and apical microcracks. AB - The aim of this study was to determine the effect of nickel titanium file design on the root surface strain generated and apical microcracks caused during canal shaping. Thirty-three mandibular incisors were distributed into LightSpeed X, FlexMaster and a control group. A strain gauge was fixed apically on the proximal root surface to determine the maximum strain during canal shaping. Except for the control group, all root canals were enlarged to size 50. Images were taken after removing the apical 1 and 2 mm of the root end. Mean maximum strain values and presence of microcracks were statistically compared using the t-test and chi square test, respectively. During canal shaping, the strain increased cumulatively with mean maximum strains of 808.2 +/- 228.8 and 525.1 +/- 168.9 microstrain in LightSpeed X and FlexMaster, respectively (P = 0.004). Both systems caused comparable microcracks. Although LightSpeed X produced higher maximum strain, no difference in microcrack development was found between both systems. PMID- 26420628 TI - Port type is a possible risk factor for implantable venous access port-related bloodstream infections and no sign of local infection predicts the growth of gram negative bacilli. AB - BACKGROUND: Implantable venous access port (IVAP)-related blood stream infections (BSIs) are one of the most common complications of implantable venous ports. The risk factors and pathogens for IVAP-related BSIs are still controversial. METHODS: We retrospectively reviewed all patients who received IVAPs at a Hospital in Taiwan from January 1, 2011 to June 31, 2014. Two types of venous port, BardPort(r) 6.6 fr (Bard port) and Autosuture Chemosite(r) 7.5 fr (TYCO port) were used. All patients with clinically proven venous port-related BSIs were enrolled. RESULTS: A total of 552 patients were enrolled. There were 34 episodes of IVAP-related BSIs during the study period for a total incidence of 0.177 events/1000 catheter days. Port type (TYCO vs. Bard, HR = 7.105 (95% confidence interval (CI), 1.688-29.904), p = 0.0075), age > 65 years (HR = 2.320 (95 % CI, 1.179-4.564), p = 0.0148), and lung cancer (HR = 5.807 (95% CI, 2.946 11.447), p < 0.001) were risk factors for port infections. We also found that no local sign of infection was significantly associated with the growth of gram negative bacilli (p = 0.031). CONCLUSIONS: TYCO venous ports, age > 65 years, and lung cancer were all significant risk factors for IVAP-related BSIs, and no sign of infection was significantly associated with the growth of gram-negative bacilli. PMID- 26420630 TI - Theoretical and experimental studies on the performances of barbital-imprinted systems. AB - By using density functional theory, we studied the interaction process between barbital and 2-vinyl-4,6-diamino-1,3,5-triazine in acetonitrile at 333 K. Barbital and 2-vinyl-4,6-diamino-1,3,5-triazine were used as the template and functional monomer, respectively. The molecularly imprinted polymer microspheres containing barbital and 2-vinyl-4,6-diamino-1,3,5-triazine were synthesized through precipitation polymerization. After removing the template molecule barbital, the average diameter of the obtained molecularly imprinted polymers was 1.45 MUm. By optimizing the molar ratio of barbital and the 2-vinyl-4,6-diamino 1,3,5-triazine, the resulting molecularly imprinted polymers showed the highest adsorption for the barbital. The analysis of the Scatchard plot revealed that the dissociation constant (Kd ) and apparent maximum adsorption quantity (Qmax ) of the molecularly imprinted polymers were 30.69 mg/L and 8.68 mg/g, respectively. The study of selective adsorption showed that molecularly imprinted polymers exhibited higher selectivity for barbtital than that for 1,3-dimethyl barbituric acid and pentobarbital. Herein, the studies can provide theoretical and experimental references for the barbital-imprinted system. PMID- 26420629 TI - Risk of low bone mineral density in patients with rheumatoid arthritis treated with biologics. AB - BACKGROUND: Osteoporosis is a complication of rheumatoid arthritis (RA). We identified risk factors for osteoporosis during treatment with biologics. METHODS: Femoral neck bone mineral density (BMD) was measured in 186 patients with biologics-treated RA. We compared the characteristics of those with BMD >=70% of young adult mean (YAM) and those with BMD <70% of YAM, and undertook multivariable logistic regression analysis to identify risk factors for bone loss. RESULTS: Mean age and disease duration, the proportion of females, scores in the Modified Health Assessment Questionnaire and history of vertebral fracture were significantly greater in the BMD <70% of YAM group, but body mass index (BMI) was significantly lower in the BMD <70% of YAM group. There was no significant difference between the groups in terms of other biomarkers of RA activity, the proportion treated with methylprednisolone, or the duration or choice of biologics. The proportions of patients treated with anti-osteoporosis drugs and parathyroid hormone were significantly higher in the BMD <70% of YAM group. In the multivariable analysis, advanced age, female, longer disease duration, history of past thoracic or lumbar vertebral fracture, higher Steinbrocker classification and lower BMI were significant factors for BMD <70% of YAM. DISCUSSION: We identified risk factors for bone loss in patients with RA treated with biologics. Before suppression of disease activity by biologics, bone loss might already be advanced. CONCLUSIONS: We recommend that patients with RA who possess these risk factors be considered for earlier and more intense treatment to prevent bone loss, as well as addressing RA disease progression. PMID- 26420631 TI - Corrigendum: Unravelling the origin of the giant Zn deficiency in wurtzite type ZnO nanoparticles. PMID- 26420632 TI - Cardiac autonomic dysfunction in chronic stroke women is attenuated after submaximal exercise test, as evaluated by linear and nonlinear analysis. AB - BACKGROUND: We evaluated cardiac autonomic modulation in women with chronic ischemic stroke (at least 4 years post-stroke) at rest and in response to submaximal exercise test. METHODS: Fourteen post-stroke women (S group) and 10 healthy women (C group) participated in this study. Autonomic modulation (using linear and nonlinear analysis), blood pressure and metabolic variables at rest were evaluated immediately after the exercise test and during the recovery period (20 min). All participants underwent submaximal exercise test on cycle ergometer with gas analysis. RESULTS: At rest, the S group displayed higher lactate concentration, systolic (SBP) and diastolic blood pressure (DBP) values when compared to C group. Furthermore, the S group had lower heart rate variability (HRV) in time domain (SDNN: S = 30 +/- 5 vs. 40 +/- 8 ms; rMSSD: S = 14 +/- 2 vs. C = 34 +/- 3 ms), decreased high frequency band of pulse interval (S = 8.4 +/- 2 vs. 33.1 +/- 9 %) and 2V pattern of symbolic analysis (S = 17.3 +/- 1 vs. 30 +/- 3 %) (both indicators of cardiac vagal modulation) when compared to C group. Immediately after exercise, S group presented higher values of lactate, SBP, DBP and double product when compared to C group, as well as decreased heart rate recovery (HRR) measured at the first, second and third minutes. At recovery time, all HRV parameters in time and frequency domains improved in the S group; however, HF band remained lower when compared to C group. CONCLUSIONS: After the exercise test, women with chronic stroke presented reduced heart rate variability, reduced cardiac vagal modulation, as well as reduced HRR, while displayed an improvement of heart rate variability and cardiac vagal modulation when compared to their baseline. These results reinforce the importance of a physically active lifestyle for cardiovascular autonomic disorders observed in chronic stroke women. PMID- 26420633 TI - Fluorescence Polarization Based Nucleic Acid Testing for Rapid and Cost-Effective Diagnosis of Infectious Disease. AB - A new nucleic acid detection method was developed for a rapid and cost-effective diagnosis of infectious disease. This approach relies on the three unique elements: 1) detection probes that regulate DNA polymerase activity in response to the complementary target DNA; 2) universal reporters conjugated with a single fluorophore; and 3) fluorescence polarization (FP) detection. As a proof-of concept, the assay was used to detect and sub-type Salmonella bacteria with sensitivities down to a single bacterium in less than three hours. PMID- 26420634 TI - Photoreduction of Hg(ii) and photodemethylation of methylmercury: the key role of thiol sites on dissolved organic matter. AB - This study examined the kinetics of photoreduction of Hg(ii) and photodemethylation of methylmercury (MeHg(+)) attached to, or in the presence of, dissolved organic matter (DOM). Both Hg(ii) and MeHg(+) are principally bound to reduced sulfur groups associated with DOM in many freshwater systems. We propose that a direct photolysis mechanism is plausible for reduction of Hg(ii) bound to reduced sulfur groups on DOM while an indirect mechanism is supported for photodemethylation of MeHg(+) bound to DOM. UV spectra of Hg(ii) and MeHg(+) bound to thiol containing molecules demonstrate that the Hg(ii)-S bond is capable of absorbing UV-light in the solar spectrum to a much greater extent than MeHg(+) S bonds. Experiments with chemically distinct DOM isolates suggest that concentration of DOM matters little in the photochemistry if there are enough reduced S sites present to strongly bind MeHg(+) and Hg(ii); DOM concentration does not play a prominent role in photodemethylation other than to screen light, which was demonstrated in a field experiment in the highly colored St. Louis River where photodemethylation was not observed at depths >= 10 cm. Experiments with thiol ligands yielded slower photodegradation rates for MeHg(+) than in experiments with DOM and thiols; rates in the presence of DOM alone were the fastest supporting an intra-DOM mechanism. Hg(ii) photoreduction rates, however, were similar in experiments with only DOM, thiols plus DOM, or only thiols suggesting a direct photolysis mechanism. Quenching experiments also support the existence of an intra-DOM photodemethylation mechanism for MeHg(+). Utilizing the difference in photodemethylation rates measured for MeHg(+) attached to DOM or thiol ligands, the binding constant for MeHg(+) attached to thiol groups on DOM was estimated to be 10(16.7). PMID- 26420636 TI - The effectiveness and safety of treatments used for polycystic ovarian syndrome management in adolescents: a systematic review and network meta-analysis protocol. AB - BACKGROUND: Polycystic ovarian syndrome (PCOS) is a common reproductive endocrine disease that is seen among adolescent women. Currently, there is limited evidence to support treatment options leading to considerable variation in practice among healthcare specialists. The objective of this study is to review and synthesize all the available evidence on treatment options for PCOS among adolescent women. METHODS/DESIGN: We will conduct a systematic review of all randomized controlled trials evaluating the use of metformin, oral contraceptive pills as monotherapy, or as combination with pioglitazone, spironolactone, flutamide, and lifestyle interventions in the treatment of PCOS in adolescent women ages 11 to 19 years. The primary outcome measures are menstrual regulation and change hirsutism scores. The secondary outcome measures include acne scores, prevalence of dysglycaemia, BMI, lipid profile, total testosterone level, and adverse events. We will perform literature searches through Ovid Medline, Ovid Embase, and Cochrane Central Register of Controlled Trials (CENTRAL), and gray literature resources. Two reviewers will independently screen titles and abstracts of identified citations, review the full texts of potentially eligible trials, extract information from eligible trials, and assess the risk of bias and quality of the evidence independently. Results of this review will be summarized narratively and quantitatively as appropriate. We will perform a multiple treatment comparison using network meta-analysis to estimate the pooled direct and indirect effects for all PCOS interventions on outcomes if adequate data is available. DISCUSSION: PCOS treatment poses a clinical challenge to the patients and physicians. This is the first systematic review and network meta-analysis for PCOS treatment in adolescents. We expect that our results will help improve patient care, unify the treatment approaches among specialists, and encourage research for other therapeutic options. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015016148. PMID- 26420637 TI - Drug-induced lupus erythematosus associated with donepezil: a case report. AB - The possibility that drug-induced lupus erythematosus (DILE) can be induced by donepezil is presented in this clinical case. Donepezil is an inhibitor of acetylcholinesterase used for the treatment of Alzheimer's disease. It is the first time that donepezil causes DILE. PMID- 26420638 TI - Dementia in older people admitted to hospital: a regional multi-hospital observational study of prevalence, associations and case recognition. AB - BACKGROUND: Previous studies have indicated a prevalence of dementia in older admissions of ~42% in a single London teaching hospital, and 21% in four Queensland hospitals. However, there is a lack of published data from any European country on the prevalence of dementia across hospitals and between patient groups. OBJECTIVE: To determine the prevalence and associations of dementia in older patients admitted to acute hospitals in Ireland. METHODS: Six hundred and six patients aged >=70 years were recruited on admission to six hospitals in Cork County. Screening consisted of Standardised Mini-Mental State Examination (SMMSE); patients with scores <27/30 had further assessment with the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Final expert diagnosis was based on SMMSE, IQCODE and relevant medical and demographic history. Patients were screened for delirium and depression, and assessed for co morbidity, functional ability and nutritional status. RESULTS: Of 598 older patients admitted to acute hospitals, 25% overall had dementia; with 29% in public hospitals. Prevalence varied between hospitals (P < 0.001); most common in rural hospitals and acute medical admissions. Only 35.6% of patients with dementia had a previous diagnosis. Patients with dementia were older and frailer, with higher co-morbidity, malnutrition and lower functional status (P < 0.001). Delirium was commonly superimposed on dementia (57%) on admission. CONCLUSION: Dementia is common in older people admitted to acute hospitals, particularly in acute medical admissions, and rural hospitals, where services may be less available. Most dementia is not previously diagnosed, emphasising the necessity for cognitive assessment in older people on presentation to hospital. PMID- 26420640 TI - Robotic surgery: It is a better mousetrap. PMID- 26420641 TI - How to do (or not to do) ... translation of national health accounts data to evidence for policy making in a low resourced setting. AB - For more than a decade, the Organization for Economic Co-operation and Development (OECD), the World Health Organization (WHO) and the World Bank have promoted the international standardization of National Health Accounts (NHA) for reporting global statistics on public, private and donor health expenditure and improve the quality of evidence-based decision-making at country level. A 2010 2012 World Bank review of NHA activity in 50 countries found structural and technical constraints (rather than cost) were key impediments to institutionalizing NHA in many low- and middle-income countries (LMICs). Pilot projects focused resources on data production, neglecting longer-term capacity building for analysing the data, developing ownership among local stakeholders and establishing routine production, utilization and dissemination of NHA data. Hence, genuine institutionalization of NHA in most LMICs has been slow to materialize. International manuals focus on the production of NHA data and do not include practical, incremental and low-cost strategies to guide countries in translating the data into evidence for policy-making. The main aim of this article is to recommend strategies for bridging this divide between production and utilization of NHA data in low-resource settings. The article begins by discussing the origins and purpose of NHA, including factors currently undermining their uptake. The focus then turns to the development and application of strategies to assist LMICs in 'unlocking' the hidden value of their NHA. The article draws on the example of Fiji, a country currently attempting to integrate their NHA data into policy formulation, despite minimal resources, training and familiarity with economic analysis of health systems. Simple, low cost recommendations such as embedding health finance indicators in planning documents, a user-friendly NHA guide for evaluating local health priorities, and sharing NHA data for collaborative research have helped translate NHA from raw data to evidence for policymaking. PMID- 26420639 TI - Large national series of patients with Xq28 duplication involving MECP2: Delineation of brain MRI abnormalities in 30 affected patients. AB - Xq28 duplications encompassing MECP2 have been described in male patients with a severe neurodevelopmental disorder associated with hypotonia and spasticity, severe learning disability, stereotyped movements, and recurrent pulmonary infections. We report on standardized brain magnetic resonance imaging (MRI) data of 30 affected patients carrying an Xq28 duplication involving MECP2 of various sizes (228 kb to 11.7 Mb). The aim of this study was to seek recurrent malformations and attempt to determine whether variations in imaging features could be explained by differences in the size of the duplications. We showed that 93% of patients had brain MRI abnormalities such as corpus callosum abnormalities (n = 20), reduced volume of the white matter (WM) (n = 12), ventricular dilatation (n = 9), abnormal increased hyperintensities on T2-weighted images involving posterior periventricular WM (n = 6), and vermis hypoplasia (n = 5). The occipitofrontal circumference varied considerably between >+2SD in five patients and <-2SD in four patients. Among the nine patients with dilatation of the lateral ventricles, six had a duplication involving L1CAM. The only patient harboring bilateral posterior subependymal nodular heterotopia also carried an FLNA gene duplication. We could not demonstrate a correlation between periventricular WM hyperintensities/delayed myelination and duplication of the IKBKG gene. We thus conclude that patients with an Xq28 duplication involving MECP2 share some similar but non-specific brain abnormalities. These imaging features, therefore, could not constitute a diagnostic clue. The genotype phenotype correlation failed to demonstrate a relationship between the presence of nodular heterotopia, ventricular dilatation, WM abnormalities, and the presence of FLNA, L1CAM, or IKBKG, respectively, in the duplicated segment. PMID- 26420642 TI - Quality at the centre of universal health coverage. AB - The last decade of the MDG era witnessed substantial focus on reaching the bottom economic quintiles in low and middle income countries. However, the inordinate focus on reducing financial risk burden and increasing coverage without sufficient focus on expanding quality of services may account for slow progress of the MDGs in many countries. Human Resources for Health underlie quality and service delivery improvements, yet remains under-addressed in many national strategies to achieve Universal Health Coverage. Without adequate investments in improving and expanding health professional education, making and sustaining gains will be unlikely. The transition from the Millennium Development Goals (MDG) to the Sustainable Development Goals (SDG), with exciting new financing initiatives such as the Global Financing Facility brings the potential to enact substantial gains in the quality of services delivered and upgrading human health resources. This focus should ensure effective methodologies to improve health worker competencies and change practice are employed and ineffective and harmful ones eliminated (including undue influence of commercial interests). PMID- 26420643 TI - Conformational Memory of a Protein Revealed by Single-Molecule Spectroscopy. AB - Proteins are supramolecular machines that carry out a wide range of different functions, many of which require flexibility. Up until now spontaneous conformational fluctuations of proteins have always been assumed to reflect a stochastic random process. However, if changing between different conformational states was random, then it would be difficult to understand how conformational control of protein function could have evolved. Here we demonstrate that a single protein can show conformational memory. This is exactly the process that can facilitate the evolution of control of switching between two conformational states that can then be used to regulate protein function. PMID- 26420644 TI - Professional translational research: a new hybrid paradigm in early drug discovery. AB - While industry makes cuts to early drug discovery research, the demand for innovation in the pursuit of novel medicines continues to grow. Who should fill this gap? Academia clearly is a rich source of innovation but how can new basic research concepts find their way into industrial application? A new paradigm for early drug discovery involves professional translational research centers, which function as facilitators and translators at the academia-industry interface, harnessing the strengths of both worlds and leveraging the high innovation potential of academia by using the robustness and efficiency of industry. In this article, the authors discuss the set-up and essential requirements for the successful translation of new drug concepts. PMID- 26420645 TI - Continuous activation of Nrf2 and its target antioxidant enzymes leads to arsenite-induced malignant transformation of human bronchial epithelial cells. AB - Long-term exposure to arsenite leads to human lung cancer, but the underlying mechanisms of carcinogenesis remain obscure. The transcription factor of nuclear factor-erythroid-2 p45-related factor (Nrf2)-mediated antioxidant response represents a critical cellular defense mechanism and protection against various diseases. Paradoxically, emerging data suggest that the constitutive activation of Nrf2 is associated with cancer development, progression and chemotherapy resistance. However, the role of Nrf2 in the occurrence of cancer induced by long term arsenite exposure remains to be fully understood. By establishing transformed human bronchial epithelial (HBE) cells via chronic low-dose arsenite treatment, we showed that, in acquiring this malignant phenotype, continuous low level of ROS and sustained enhancement of Nrf2 and its target antioxidant enzyme levels were observed in the later-stage of arsenite-induced cell transformation. The downregulation of Keap1 level may be responsible for the over-activation of Nrf2 and its target enzymes. To validate these observations, Nrf2 was knocked down in arsenite-transformed HBE cells by SiRNA transfection, and the levels of Nrf2 and its target antioxidant enzymes, ROS, cell proliferation, migration, and colony formation were determined following these treatments. Results showed that blocked Nrf2 expression significantly reduced Nrf2 and its target antioxidant enzyme levels, restored ROS levels, and eventually suppressed cell proliferation, migration, and colony formation of the transformed cells. In summary, the results of the study strongly suggested that the continuous activation of Nrf2 and its target antioxidant enzymes led to the over-depletion of intracellular ROS levels, which contributed to arsenite-induced HBE cell transformation. PMID- 26420646 TI - The cost-effectiveness of grip on challenging behaviour: an economic evaluation of a care programme for managing challenging behaviour. AB - OBJECTIVE: The objective of the study was to evaluate the cost-effectiveness of implementing the Grip on Challenging Behaviour care programme (GRIP) on dementia special care units in comparison with usual care. METHODS: A stepped wedge design was used. Challenging behaviour and quality of life were measured using the Cohen Mansfield Agitation Inventory (CMAI) and the QUALIDEM. Quality-adjusted life years (QALYs) were calculated using the EuroQol-5D. Psychoactive medication use (range 0-5 per measurement) and sick leave were registered. Costs included medication, time spent on challenging behaviour and education. Costs and effects were analysed using linear multilevel regression. Incremental cost-effectiveness ratios were calculated. Statistical uncertainty was estimated using bootstrapping. RESULTS: Seventeen dementia special care units participated. GRIP led to improvement on the QUALIDEM subscale social relations (1.6; 95% CI 0.18 to 3.4) and on the use of psychoactive medication (-0.73; 95% CI -1.1 to -0.46) and to a decrease in QALYs (-0.02; 95% CI -0.06 to -0.003). No significant effects on CMAI, sick leave and other QUALIDEM subscales were found. The intervention was not cost-effective in comparison with usual care with regard to CMAI score, QALYs and sick leave. The willingness to pay should be 320?/point improvement on the QUALIDEM subscale social relations and 370?/psychoactive medication less to reach a 0.95 probability of cost-effectiveness. CONCLUSION: It depends on how much society is willing to pay whether GRIP can be considered cost-effective. Because the appropriateness of the current methods for analysing cost-effectiveness in this specific population is uncertain, the positive effects on behaviour, medication and job satisfactions should also be taken in account in the decision making. PMID- 26420647 TI - Targeting danger-associated molecular patterns after myocardial infarction. AB - INTRODUCTION: Myocardial infarction (MI) provokes an intense inflammatory response that can lead to left ventricular adverse remodeling and heart failure (HF). The prognosis of HF patients is poor and related to a decreased quality of life and considerable health care costs. Hence, targeting the early inflammatory response after MI provides an interesting target to attenuate left ventricular remodeling and prevent HF. AREAS COVERED: In the current review, we discuss the theory that our immune system does not distinguish between self and non-self, but rather senses danger. So-called danger-associated molecular patterns (DAMPs) serve as ligands for pattern recognition receptors (PRRs), which act as signal transduction molecules to induce a pro-inflammatory state. Many different DAMPs and PRRs have been identified recently. Here, we provide a concise overview of their interactions as well as their role in the inflammatory response after MI. EXPERT OPINION: Interference with Toll-like receptor (TLR) 2, TLR4 and NLRP3 inflammasome signaling has consistently shown to reduce infarct size and preserve cardiac function post-MI in experimental animal models. Since clinically applicable inhibitors have been developed for these pathways, the path has been cleared to assess whether these promising results can be translated into the human situation. PMID- 26420648 TI - Comparative genomic analysis of human Chlamydia pneumoniae isolates from respiratory, brain and cardiac tissues. AB - Chlamydia pneumoniae is an obligate intracellular bacterium implicated in a wide range of human diseases including atherosclerosis and Alzheimer's disease. Efforts to understand the relationships between C. pneumoniae detected in these diseases have been hindered by the availability of sequence data for non respiratory strains. In this study, we sequenced the whole genomes for C. pneumoniae isolates from atherosclerosis and Alzheimer's disease, and compared these to previously published C. pneumoniae genomes. Phylogenetic analyses of these new C. pneumoniae strains indicate two sub-groups within human C. pneumoniae, and suggest that both recombination and mutation events have driven the evolution of human C. pneumoniae. Further fine-detailed analyses of these new C. pneumoniae sequences show several genetically variable loci. This suggests that similar strains of C. pneumoniae are found in the brain, lungs and cardiovascular system and that only minor genetic differences may contribute to the adaptation of particular strains in human disease. PMID- 26420649 TI - 'Watching an artist at work': aesthetic leadership in clinical nursing workplaces. AB - AIMS AND OBJECTIVES: To explore how clinical leaders enact aesthetic leadership in clinical nursing workplaces. BACKGROUND: Clinical leadership is heralded as vital for safe and effective nursing. Different leadership styles have been applied to the clinical nursing workplace over recent years. Many of these styles lack an explicit moral dimension, instead focusing on leader qualities and developing leader competence around team building, quality and safety. Aesthetic leadership, with its explicit moral dimension, could enhance clinical leadership effectiveness and improve nursing workplaces. How aesthetic leadership is enacted in clinical nursing settings requires exploration. DESIGN: A qualitative design, employing conversation-style interviews with experienced registered nurses and written responses gathered from an online descriptive survey. METHODS: Narrative data were gathered from interviews with 12 registered nurses and written accounts from 31 nurses who responded to an online survey. Together, transcribed interview data and the written accounts were subject to thematic analysis. RESULTS: Three main themes emerged: Leading by example: 'be seen in the clinical area'; Leading with composure: 'a sense of calm in a hideous shift'; and Leading through nursing values: 'create an environment just by your being'. CONCLUSIONS: Aesthetic leadership was shown to enhance clinical leadership activities in the nursing workplace. The capacity for clinical leaders to be self-reflective can positively influence the nursing workplace. It was apparent that clinical leader effectiveness can be enhanced with nursing values underpinning leadership activities and by being a visible, composed role model in the clinical workplace. RELEVANCE TO CLINICAL PRACTICE: Aesthetic leadership can enhance clinical nursing workplaces with its explicit moral purpose and strong link to nursing values. Clinical leaders who incorporate these attributes with being a visible, composed role model have the capacity to improve the working lives of nurses across a range of clinical settings. PMID- 26420655 TI - Shielding Upconversion by Surface Coating: A Study of the Emission Enhancement Factor. AB - Surface coating is a commonly used strategy to enhance upconversion emissions by shielding the luminescent core from surface quenching. In this work, we provide insights into the effect of surface coating on upconversion by investigating NaYF4 :Yb/Er nanoparticles and the corresponding NaYF4 :Yb/Er@NaYF4 core-shell nanoparticles, as a function of dopant concentration of Yb(3+) and excitation power. We observe declining emission enhancement factors with decreasing Yb(3+) concentration and increasing excitation power. Our mechanistic investigations suggest that the phenomenon originates from stepwise excitation in the upconversion process, as well as energy hopping among the Yb(3+) dopants. This increased understanding of the effect of surface coating on upconversion should be important towards the rational design of lanthanide-doped core-shell nanoparticles for various applications. PMID- 26420656 TI - Erratum: An assessment of the cost-effectiveness of magnetic resonance, including diffusion-weighted imaging, in patients with transient ischaemic attack and minor stroke: a systematic review, meta-analysis and economic evaluation. PMID- 26420657 TI - A covalent homodimer probing early oligomers along amyloid aggregation. AB - Early oligomers are crucial in amyloid aggregation; however, due to their transient nature they are among the least structurally characterized species. We focused on the amyloidogenic protein beta2-microglobulin (beta2m) whose early oligomers are still a matter of debate. An intermolecular interaction between D strands of facing beta2m molecules was repeatedly observed, suggesting that such interface may be relevant for beta2m dimerization. In this study, by mutating Ser33 to Cys, and assembling the disulphide-stabilized beta2m homodimer (DimC33), such DD strand interface was locked. Although the isolated DimC33 display a stability similar to wt beta2m under native conditions, it shows enhanced amyloid aggregation propensity. Three distinct crystal structures of DimC33 suggest that dimerization through the DD interface is instrumental for enhancing DimC33 aggregation propensity. Furthermore, the crystal structure of DimC33 in complex with the amyloid-specific dye Thioflavin-T pinpoints a second interface, which likely participates in the first steps of beta2m aggregation. The present data provide new insight into beta2m early steps of amyloid aggregation. PMID- 26420658 TI - Surgical excision of ovarian endometriomas: Does it truly impair ovarian reserve? Long term anti-Mullerian hormone (AMH) changes after surgery. AB - AIM: The long-term effects of laparoscopic cystectomy on ovarian reserve in patients with unilateral and bilateral ovarian endometriomas were evaluated. METHODS: A total of 22 patients undergoing laparoscopic cystectomy for unilateral endometrioma (n = 10) and bilateral endometriomas (n = 12) were included in the study. RESULT(S): Serum anti-Mullerian hormone (AMH) levels significantly decreased from the baseline value (3.98 +/- 3.27 ng/mL) one (1.67 +/- 1.56 ng/mL), three (2.01 +/- 1.70 ng/mL), and six months (2.43 +/- 2.39 ng/mL) postoperatively. There was no difference between preoperative and 12 month postoperative AMH levels (4.01 +/- 3.39 ng/mL) (P > 0.05). Patients with bilateral endometriomas had a significantly higher rate of decline in AMH levels 12 months after surgery than patients with monolateral endometriomas (P = 0.035), but in both groups there was no difference in AMH levels at one and 12 months postoperatively (P > 0.05). CONCLUSION(S): AMH levels temporarily decreased after laparoscopic cystectomy for ovarian endometriomas, with complete recovery of preoperative AMH values at 12 months postoperatively. This pattern was equal in patients with bilateral and unilateral ovarian involvement. Patients with bilateral cysts have higher rates of decline of AMH levels compared to patients with unilateral affection. PMID- 26420659 TI - Effect of intra-membrane C60 fullerenes on the modulus of elasticity and the mechanical resistance of gel and fluid lipid bilayers. AB - Penetration and partition of C60 to the lipid bilayer core are both relevant to C60 toxicity, and useful to realise C60 biomedical potential. A key aspect is the effect of C60 on bilayer mechanical properties. Here, we present an experimental study on the mechanical effect of the incorporation of C60 into the hydrophobic core of fluid and gel phase zwitterionic phosphatidylcholine (PC) lipid bilayers. We demonstrate its incorporation inside the hydrophobic lipid core and the effect on the packing of the lipids and the vesicle size using a combination of infrared (IR) spectroscopy, atomic force microscopy (AFM) and laser light scattering. Using AFM we measured the Young's modulus of elasticity (E) of 1,2-dipalmitoyl-sn glycero-3-phosphocholine (DPPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) in the absence (presence) of intra-membranous C60 at 24.5 degrees C. E of fluid phase supported bilayers is not altered by C60, but E increases with incorporation of C60 in gel phase bilayers. The increase is higher for longer hydrocarbon chains: 1.6 times for DPPC and 2 times for DSPC. However the mechanical resistance of gel phase bilayers of curved bilayered structures decreases with the incorporation of C60. Our combined results indicate that C60 causes a decrease in gel phase lipid mobility, i.e. an increase in membrane viscosity. PMID- 26420661 TI - Gene-gene interaction of ATG5, ATG7, BLK and BANK1 in systemic lupus erythematosus. AB - AIM: Autophagy-related gene 5 (ATG5), ATG7, B-lymphoid tyrosine kinase (BLK) and B-cell scaffold protein with ankyrin repeats 1 (BANK1) are involved in B-cell signaling; several genome-wide association studies detected these genes as candidates involved in systemic lupus erythematosus (SLE). We aimed to replicate the association of these genes with SLE in Chinese Han and to search for possible gene-gene interactions. METHODS: TaqMan single-nucleotide polymorphism (SNP) genotyping was used to detect rs548234, rs665791 in ATG5, rs11706903 in ATG7, rs2736340 in BLK and rs10516487 in BANK1 in 382 SLE patients and 660 healthy controls. The epistasis effect was analyzed by logistic regression, multifactor dimensionality reduction (MDR) and linear regression analysis. RESULTS: SLE was associated with frequency of rs548234 (P = 0.010; odds ratio [OR] = 1.298), rs2736340 (P = 2.47 * 10-5 ; OR = 1.574) and rs10516487 (P = 0.002; OR = 0.642). Although no epistasis effects were found among three autophagy-related gene loci or with rs2736340 and rs10516487, BLK and BANK1 had the closest interaction effect on logistic regression analysis (P = 0.013; OR = 1.205), MDR (P < 0.0001), and linear regression analysis (P = 0.0017; R2 = 0.1806). The risk genotype TT of rs2736340 was associated with decreased messenger RNA level of BLK; BLK transcript level was lower in SLE patients than healthy controls. CONCLUSION: We confirmed the association of rs548234, rs2736340 and rs10516487 with SLE in Chinese Han and reinforced our hypothesis of their epistasis effect in regulating B-cell signaling in SLE. PMID- 26420662 TI - A pilot before-and-after study of a brief teaching programme for psychiatry trainees in mentalizing skills. AB - BACKGROUND AND AIMS: Negative attitudes in clinicians towards people with personality disorder are common and associated with poor care. National guidelines recommend developing interventions to improve attitudes. Mentalization based treatment theory and techniques provide a plausible intervention. We therefore evaluated the effect of teaching mentalizing skills on clinicians' attitudes towards personality disorder. METHODS: Pilot before-and-after study of trainee psychiatrists receiving four teaching sessions in mentalizing skills. Self-report questionnaires were completed at baseline and post teaching programme. MAIN OUTCOME MEASURE: Attitudes to Personality Disorder Questionnaire. SECONDARY MEASURE: Knowledge and Application of Mentalization-based treatment Questionnaire. RESULTS: Sixteen doctors were recruited with no study drop-out. Mean Attitudes to Personality Disorder Questionnaire score was superior post teaching programme versus baseline (135.3 vs. 124.5, standardised mean difference = 0.72, 95% confidence interval = 0.01 to 1.44). Mean Knowledge and Application of Mentalization-based treatment Questionnaire score was superior post teaching programme versus baseline (112.5 vs. 97.1, standardised mean difference = 1.83, 95% confidence interval 0.98 to 2.67). CONCLUSIONS: As expected from a pilot study, the estimate of effect is imprecise. Within this limitation, our findings suggest that teaching in mentalizing skills improved attitudes and mentalization based treatment knowledge to a clinically relevant degree. This has important implications for patient outcomes and staff development. Our study paves the way for a full-scale study to provide more precise and robust evidence. PMID- 26420660 TI - Genetic diversity and evolutionary insights of respiratory syncytial virus A ON1 genotype: global and local transmission dynamics. AB - Human respiratory syncytial virus (RSV) A ON1 genotype, first detected in 2010 in Ontario, Canada, has been documented in 21 countries to date. This study investigated persistence and transmission dynamics of ON1 by grouping 406 randomly selected RSV-positive specimens submitted to Public Health Ontario from August 2011 to August 2012; RSV-A-positive specimens were genotyped. We identified 370 RSV-A (181 NA1, 135 NA2, 51 ON1 3 GA5) and 36 RSV-B positive specimens. We aligned time-stamped second hypervariable region (330 bp) of G-gene sequence data (global, n = 483; and Ontario, n = 60) to evaluate transmission dynamics. Global data suggests that the most recent common ancestor of ON1 emerged during the 2008-2009 season. Mean evolutionary rate of the global ON1 was 4.10 * 10(-3) substitutions/site/year (95% BCI 3.1-5.0 * 10(-3)), not significantly different to that of Ontario ON1. The estimated mean reproductive number (R0 = ~ 1.01) from global and Ontario sequences showed no significant difference and implies stability among global RSV-A ON1. This study suggests that local epidemics exhibit similar underlying evolutionary and epidemiological dynamics to that of the persistent global RSV-A ON1 population. These findings underscore the importance of continual molecular surveillance of RSV in order to gain a better understanding of epidemics. PMID- 26420664 TI - A Mechanochemically Triggered "Click" Catalyst. AB - "Click" chemistry represents one of the most powerful approaches for linking molecules in chemistry and materials science. Triggering this reaction by mechanical force would enable site- and stress-specific "click" reactions--a hitherto unreported observation. We introduce the design and realization of a homogeneous Cu catalyst able to activate through mechanical force when attached to suitable polymer chains, acting as a lever to transmit the force to the central catalytic system. Activation of the subsequent copper-catalyzed "click" reaction (CuAAC) is achieved either by ultrasonication or mechanical pressing of a polymeric material, using a fluorogenic dye to detect the activation of the catalyst. Based on an N-heterocyclic copper(I) carbene with attached polymeric chains of different flexibility, the force is transmitted to the central catalyst, thereby activating a CuAAC in solution and in the solid state. PMID- 26420663 TI - Triplet-triplet annihilation upconversion followed by FRET for the red light activation of a photodissociative ruthenium complex in liposomes. AB - Upconversion is a promising way to trigger high-energy photochemistry with low energy photons. However, combining upconversion schemes with non-radiative energy transfer is challenging because bringing several photochemically active components in close proximity results in complex multi-component systems where quenching processes may deactivate the whole assembly. In this work, PEGylated liposomes were prepared that contained three photoactive components: a porphyrin dye absorbing red light, a perylene moiety emitting in the blue, and a light activatable ruthenium prodrug sensitive to blue light. Time-dependent spectroscopic studies demonstrate that singlet perylene excited states are non radiatively transferred to the nearby ruthenium complex by Forster resonance energy transfer (FRET). Under red-light irradiation of the three-component membranes, triplet-triplet annihilation upconversion (TTA-UC) occurs followed by FRET, which results in a more efficient activation of the ruthenium prodrug compared to a physical mixture of two-component upconverting liposomes and liposomes containing only the ruthenium complex. This work represents a rare example where TTA-UC and Forster resonance energy transfer are combined to achieve prodrug activation in the phototherapeutic window. PMID- 26420665 TI - Frontal metabolic activity contributes to individual differences in vulnerability toward total sleep deprivation-induced changes in cognitive function. AB - Substantial individual differences characterize the changes induced by total sleep deprivation on cognitive functions. Despite some progress having been achieved, the mechanisms of individual differences in response to total sleep deprivation have not been clearly elucidated. Cerebral metabolism in the resting state is among the key physiological processes supporting the daily function of the brain, and may play an important role in these individual differences. Twenty two right-handed participants (nine females and 13 males) between 20 and 26 years old completed a mathematical processing task both in resting wakefulness and after 24 h of total sleep deprivation. Fluorine-18 fluorodeoxyglucose positron emission tomography-computed tomography was used to investigate brain metabolism changes. The mathematical task was performed after the positron emission tomography scans were completed. Correlation analysis was used to investigate the correlations between cognitive performance changes and brain metabolism changes. Large inter-individual differences were found in the throughput changes, but these inter-individual differences were not associated with baseline or post deprivation performance levels. Specifically, deterioration of throughput on the mathematical processing task was significantly correlated with metabolism changes in the superior frontal medial gyrus. These findings suggested that frontal metabolic activity contributes to individual differences in waking-induced impairment of cognitive performance. PMID- 26420666 TI - Neonatal Irradiation Leads to Persistent Proteome Alterations Involved in Synaptic Plasticity in the Mouse Hippocampus and Cortex. AB - Recent epidemiological data indicate that radiation doses as low as those used in computer tomography may result in long-term neurocognitive side effects. The aim of this study was to elucidate long-term molecular alterations related to memory formation in the brain after low and moderate doses of gamma radiation. Female C57BL/6J mice were irradiated on postnatal day 10 with total body doses of 0.1, 0.5, or 2.0 Gy; the control group was sham-irradiated. The proteome analysis of hippocampus, cortex, and synaptosomes isolated from these brain regions indicated changes in ephrin-related, RhoGDI, and axonal guidance signaling. Immunoblotting and miRNA-quantification demonstrated an imbalance in the synapse morphology related Rac1-Cofilin pathway and long-term potentiation-related cAMP response element-binding protein (CREB) signaling. Proteome profiling also showed impaired oxidative phosphorylation, especially in the synaptic mitochondria. This was accompanied by an early (4 weeks) reduction of mitochondrial respiration capacity in the hippocampus. Although the respiratory capacity was restored by 24 weeks, the number of deregulated mitochondrial complex proteins was increased at this time. All observed changes were significant at doses of 0.5 and 2.0 Gy but not at 0.1 Gy. This study strongly suggests that ionizing radiation at the neonatal state triggers persistent proteomic alterations associated with synaptic impairment. PMID- 26420667 TI - Evaluation of the POSSUM, p-POSSUM, o-POSSUM, and APACHE II scoring systems in predicting postoperative mortality and morbidity in gastric cancer patients. AB - BACKGROUND/OBJECTIVE: Gastric cancer is the fourth most prevalent cancer worldwide. The ability to accurately predict surgery-related morbidity and mortality is critical in deciding both the timing of surgery and choice of surgical procedure. The aim of this study is to compare the POSSUM, p-POSSUM, o POSSUM, and APACHE II scoring systems for predicting surgical morbidity and mortality in Chinese gastric cancer patients, as well as to create new scoring systems to achieve better prediction. METHODS: Data from 612 gastric cancer patients undergoing gastrectomy between January 2007 and December 2011 were included in this study. The predictive abilities of the four scoring systems were compared by examining observed-to-expected (O/E) ratios, the receiver operating characteristic curve, Student t test, and chi2 test results. RESULTS: The observed complication rate of 34% (n = 208) did not differ significantly from the rate of 36.6% (n = 208) predicted by the POSSUM scoring system (O/E ratio = 0.93). The observed mortality rate was 2.9% (n = 18). For predicting mortality, POSSUM had an O/E ratio of 0.34 as compared with p-POSSUM (O/E ratio = 0.91), o POSSUM (O/E ratio = 1.26), and APACHE II (O/E ratio = 0.28). CONCLUSION: The POSSUM scoring system performed well with respect to predicting morbidity risk following gastric cancer resection. For predicting postoperative mortality, p POSSUM and o-POSSUM exhibited superior performance relative to POSSUM and APACHE II. PMID- 26420668 TI - Spoof localized surface plasmons on ultrathin textured MIM ring resonator with enhanced resonances. AB - We numerically demonstrate that spoof localized surface plasmons (LSPs) resonant modes can be enhanced based on ultrathin corrugated metal-insulator-metal (MIM) ring resonator. Further enhancement of the LSPs modes has been achieved by incorporating an efficient and ease-of-integration exciting method. Quality factors of resonance peaks have become much larger and multipolar resonances modes can be easily observed on the textured MIM ring resonator excited by a microstrip line. Experimental results validate the high-efficiency excitation and resonance enhancements of spoof LSPs modes on the MIM ring resonator in the microwave frequencies. We have shown that the fabricated resonator is sensitive to the variation of both the dielectric constant and the thickness of surrounding materials under test. The spoof plasmonic resonator can be used as key elements to provide many important device functionalities such as optical communications, signal processing, and spectral engineering in the plasmonic integration platform. PMID- 26420669 TI - Is it worthwhile to screen patients with type 2 diabetes mellitus for subclinical Cushing's syndrome? AB - Variable prevalence of subclinical Cushing's syndrome (SCS) has been reported in patients with type 2 diabetes mellitus (T2DM), making the need for screening in this population uncertain. It is unknown if this variability is solely due to study-related methodological differences or a reflection of true differences in ethnic predisposition. The objective of this study is to explore the prevalence of SCS in Asian Indian patients with T2DM. In this prospective single center study conducted in a tertiary care referral center, 993 T2DM outpatients without any discriminatory clinical features (easy bruising, facial plethora, proximal muscle weakness, and/or striae) of hypercortisolism underwent an overnight 1 mg dexamethasone suppression test (ODST). ODST serum cortisol >=1.8 MUg/dl was considered positive, and those with positive results were subjected to 48 h, 2 mg/day low dose DST (LDDST). A stepwise evaluation for endogenous hypercortisolism was planned for patients with LDDST serum cortisol >=1.8 MUg/dl. Patients with positive ODST and negative LDDST were followed up clinically and re evaluated a year later for the development of clinically evident Cushing's syndrome (CS). In this largest single center study reported to date, we found 37 out of 993 (3.72%) patients had ODST serum cortisol >=1.8 MUg/dl. None of them had LDDST cortisol >=1.8 MUg/dl, nor did they develop clinically evident CS over a follow-up period of 1 year. Specificity of ODST for screening of CS was 96.3% in our cohort. None of the T2DM outpatients in our cohort had SCS, hence cautioning against routine biochemical screening for SCS in this cohort. We suggest screening be based on clinical suspicion only. PMID- 26420670 TI - Recombinant expression of a functional myo-inositol-1-phosphate synthase (MIPS) in Mycobacterium smegmatis. AB - Myo-inositol-1-phosphate synthase (MIPS, E.C. 5.5.1.4) catalyzes the first step in inositol production-the conversion of glucose-6-phosphate (Glc-6P) to myo inositol-1-phosphate. While the three dimensional structure of MIPS from Mycobacterium tuberculosis has been solved, biochemical studies examining the in vitro activity have not been reported to date. Herein we report the in vitro activity of mycobacterial MIPS expressed in E. coli and Mycobacterium smegmatis. Recombinant expression in E. coli yields a soluble protein capable of binding the NAD(+) cofactor; however, it has no significant activity with the Glc-6P substrate. In contrast, recombinant expression in M. smegmatis mc(2)4517 yields a functionally active protein. Examination of structural data suggests that MtMIPS expressed in E. coli adopts a fold that is missing a key helix containing two critical (conserved) Lys side chains, which likely explains the inability of the E. coli expressed protein to bind and turnover the Glc-6P substrate. Recombinant expression in M. smegmatis may yield a protein that adopts a fold in which this key helix is formed enabling proper positioning of important side chains, thereby allowing for Glc-6P substrate binding and turnover. Detailed mechanistic studies may be feasible following optimization of the recombinant MIPS expression protocol in M. smegmatis. PMID- 26420671 TI - See One, Do One, Order One: a study protocol for cluster randomized controlled trial testing three strategies for implementing motivational interviewing on medical inpatient units. AB - BACKGROUND: General medical hospitals provide care for a disproportionate share of patients who abuse or are dependent upon substances. This group is among the most costly to treat and has the poorest medical and addiction recovery outcomes. Hospitalization provides a unique opportunity to identify and motivate patients to address their substance use problems in that patients are accessible, have time for an intervention, and are often admitted for complications related to substance use that renders hospitalization a "teachable moment." METHODS/DESIGN: This randomized controlled trial will examine the effectiveness of three different strategies for integrating motivational interviewing (MI) into the practice of providers working within a general medical inpatient hospitalist service: (1) a continuing medical education workshop that provides background and "shows" providers how to conduct MI (See One); (2) an apprenticeship model involving workshop training plus live supervision of bedside practice (Do One); and (3) ordering MI from the psychiatry consultation-liaison (CL) service after learning about it in a workshop (Order One). Thirty providers (physicians, physician assistants, nurses) will be randomized to conditions and then assessed for their provision of MI to 40 study-eligible inpatients. The primary aims of the study are to assess (1) the utilization of MI in each condition; (2) the integrity of MI when providers use it on the medical units; and (3) the relative costs and cost-effectiveness of the three different implementation strategies. DISCUSSION: If implementation of Do One and Order One is successful, the field will have two alternative strategies for supporting medical providers' proficient use of brief behavioral interventions, such as MI, for medical inpatients who use substances problematically. TRIAL REGISTRATION: Clinical Trials.gov ( NCT01825057 ). PMID- 26420672 TI - Crisis Reliability Indicators Supporting Emergency Services (CRISES): A Framework for Developing Performance Measures for Behavioral Health Crisis and Psychiatric Emergency Programs. AB - Crisis and emergency psychiatric services are an integral part of the healthcare system, yet there are no standardized measures for programs providing these services. We developed the Crisis Reliability Indicators Supporting Emergency Services (CRISES) framework to create measures that inform internal performance improvement initiatives and allow comparison across programs. The framework consists of two components-the CRISES domains (timely, safe, accessible, least restrictive, effective, consumer/family centered, and partnership) and the measures supporting each domain. The CRISES framework provides a foundation for development of standardized measures for the crisis field. This will become increasingly important as pay-for-performance initiatives expand with healthcare reform. PMID- 26420674 TI - IMPAIRED FERTILITY AND PERCEIVED DIFFICULTIES CONCEIVING IN GHANA: MEASUREMENT PROBLEMS AND PROSPECTS. AB - What is the most appropriate measure of impaired fertility for understanding its social consequences in sub-Saharan Africa? The dearth of subjective measures in surveys in the region has prevented comparisons of subjective and objective measures. Perceived difficulties conceiving may have a greater impact than objective measures for social outcomes such as divorce, stigmatization and distress. This study compares 12- (clinical) and 24- (epidemiological) month measures from biomedicine and 5- and 7-year measures from demography with a subjective measure of impaired fertility using correlations, random effects models and test-retest models to assess relationships between measures, their association with sociodemographic characteristics and the stability of measures across time. Secondary panel data (1998-2004) from 1350 Ghanaian women aged 15-49 of all marital statuses are used. Longer waiting times to identification of impaired fertility required by demographic measures result in more stable measures, but perceived difficulties conceiving are most closely aligned with clinical infertility (r=0.61; p<0.05). Epidemiological infertility is also closely aligned with the subjective measure. A large proportion of those identified as having impaired fertility based purely on waiting times are successful contraceptors. Where subjective measures are not available, epidemiological (24-month) measures may be most appropriate for studies of the social consequences of impaired fertility. Accounting for contraceptive use is important in order to avoid false positives. Future research should consider a variety of measures of perceived difficulties conceiving and self-identified infertility to assess which is most valid; in order to accomplish this, it is imperative that subjective measures of infertility be included in social surveys in sub-Saharan Africa. PMID- 26420673 TI - Interplay between arginine methylation and ubiquitylation regulates KLF4-mediated genome stability and carcinogenesis. AB - KLF4 is an important regulator of cell-fate decision, including DNA damage response and apoptosis. We identify a novel interplay between protein modifications in regulating KLF4 function. Here we show that arginine methylation of KLF4 by PRMT5 inhibits KLF4 ubiquitylation by VHL and thereby reduces KLF4 turnover, resulting in the elevation of KLF4 protein levels concomitant with increased transcription of KLF4-dependent p21 and reduced expression of KLF4 repressed Bax. Structure-based modelling and simulations provide insight into the molecular mechanisms of KLF4 recognition and catalysis by PRMT5. Following genotoxic stress, disruption of PRMT5-mediated KLF4 methylation leads to abrogation of KLF4 accumulation, which, in turn, attenuates cell cycle arrest. Mutating KLF4 methylation sites suppresses breast tumour initiation and progression, and immunohistochemical stain shows increased levels of both KLF4 and PRMT5 in breast cancer tissues. Taken together, our results point to a critical role for aberrant KLF4 regulation by PRMT5 in genome stability and breast carcinogenesis. PMID- 26420675 TI - Target-Catalyzed DNA Four-Way Junctions for CRET Imaging of MicroRNA, Concatenated Logic Operations, and Self-Assembly of DNA Nanohydrogels for Targeted Drug Delivery. AB - Here we report a target-catalyzed DNA four-way junction (DNA-4WJ) on the basis of toehold-mediated DNA strand displacement reaction (TM-SDR), which is readily applied in enzyme-free amplified chemiluminescence resonance energy transfer (CRET) imaging of microRNA. In this system, the introduction of target microRNA let-7a (miR-let-7a) activates a cascade of assembly steps with four DNA hairpins, followed by a disassembly step in which the target microRNA is displaced and released from DNA-4WJ to catalyze the self-assembly of additional branched junctions. As a result, G-quadruplex subunit sequences and fluorophore fluorescein amidite (FAM) are encoded in DNA-4WJ in a close proximity, stimulating a CRET process in the presence of hemin/K(+) to form horseradish peroxidase (HRP)-mimicking DNAzyme that catalyzes the generation of luminol/H2O2 chemiluminescence (CL), which further transfers to FAM. The background signal is easily reduced using magnetic graphene oxide (MGO) to remove unreacted species through magnetic separation, which makes a great contribution to improve the detection sensitivity and achieves a detection limit as low as 6.9 fM microRNA let-7a (miR-let-7a). In addition, four-input concatenated logic circuits with an automatic reset function have been successfully constructed relying on the architecture of the proposed DNA-4WJ. More importantly, DNA nanohydrogels are self-assembled using DNA-4WJs as building units after centrifugation, which are driven by liquid crystallization and dense packaging of building units. Moreover, the DNA nanohydrogels are readily functionalized by incorporating with aptamers, bioimaging agents, and drug loading sites, which thus are served as efficient nanocarriers for targeted drug delivery and cancer therapy with high loading capacity and excellent biocompatibility. PMID- 26420676 TI - [Impact of learning curve in renal transplantation]. AB - OBJECTIVES: Renal transplantation is performed only in university hospital centres, in accredited transplanting centres. The aim of this study is to analyse the learning curve of this operation and its impact on the graft survival. PATIENTS-METHODS: Monocentric retrospective study in which 3 groups have been defined: Juniors 1, Juniors 2 and Seniors corresponding respectively to the first thirty transplantations and to the last thirty transplantations of 5 clinical leaders, and 30 transplantation graft of referent seniors. Data have been registered in a database. Operation times, lukewarm ischemic times and postoperative complications have been compared within the 3 groups. RESULTS: A clear difference of operation time has been noted within the 3 groups with an average time of 202 minutes for Juniors 1, 173 minutes for Juniors 2 and 140 minutes for Seniors (P<0.0001). Likewise, concerning lukewarm ischemic time and vascular anastomosis time respectively with an average time of 72, 59 and 40 min (P<0.0001). Vascular complications occurred in 20% of cases in Juniors 1, 44.3% of cases in Juniors 2 and 17% of cases in Seniors (P=0.65). There were no significant differences of survival without urinary complications: 20% of complications for Juniors 1, 10% for Juniors 2 and 17% for Seniors (P=0.63). Similarly results have been obtained with analysing complications following Clavien's order. CONCLUSION: This study reveals that renal transplantations operated by young surgeons require longer operation and lukeward ischemic time but without significant repercussions on the surgical complication rate and the global survival. This stresses on the importance of surgical training during medicine internship. PMID- 26420677 TI - [Neoadjuvant chemotherapy with MVAC in bladder carcinoma: Is the feasibility really established? Of: Benadiba et al.: Neoadjuvant chemotherapy in muscular invasive bladder cancer: Complications and consequences on cystectomy, Pr Urol 2015; 25: 549-554]. PMID- 26420678 TI - Efficacy and safety of nicotinamide in the management of hyperphosphatemia in pediatric patients on regular hemodialysis. AB - BACKGROUND: Hyperphosphatemia is a common problem in patients with end-stage renal disease (ESRD) who are on maintenance hemodialysis (HD) and contributes to the development of secondary hyperparathyroidism and cardiovascular complications. Nicotinamide (NAM) has been shown in some studies to inhibit intestinal and renal sodium/phosphorus co-transporters and reduce serum phosphorus levels. We have therefore evaluated the efficacy and safety of NAM as adjunctive therapy to calcium-based phosphate binders to control hyperphosphatemia in hemodialysis patients. METHODS: Sixty pediatric HD outpatients were randomly divided into two equally sized groups (30 children each). One group received calcium-based phosphate binder (control group), and the other received both the calcium-based phosphate binder + NAM at a dose of 100 mg twice or three times daily (nicotinamide group). Both groups were followed for a 6-month period. RESULTS: Over the 6-month treatment period, children in the NAM group showed a significant decline in the levels of serum phosphorus (p = 0.0001), serum calcium-phosphorus (Ca * P; p = 0.0001) product and parathyroid hormone (p = 0.02) versus baseline values and those of the control group. After 6 months of NAM treatment, the mean serum high-density lipoprotein cholesterol levels had increased significantly (p = 0.01), and the median serum triglyceride levels had decreased (p = 0.009). There was no significant change in any of these parameters among the children of the control group. The major adverse events associated with the NAM therapy were diarrhea, flushing and nausea. CONCLUSION: The addition of NAM to therapy with phosphate binders is effective in lowering phosphorus levels and has a beneficial effect on the lipid profile with only mild side effects. PMID- 26420680 TI - Effective use of the TSPY gene-specific copy number in determining fetal DNA in the maternal blood of cynomolgus monkeys. AB - Since the available concentration of single-copy fetal genes in maternal blood DNA is sometimes lower than detection limits by PCR methods, the development of specific and quantitative PCR detection methods for fetal DNA in maternal blood is anticipated, which may broaden the methods that can be used to monitor pregnancy. We used the TaqMan qPCR amplification for DYS14 multi-copy sequence and the SRY gene in maternal blood plasma (cell-free DNA) and fractional precipitated blood cells (cellular DNA) from individual cynomolgus monkeys at 22 weeks of pregnancy. The availability of cell-free fetal DNA was higher in maternal blood plasma than that of cellular DNA from fractional precipitated blood cells. There was a significantly higher (P < 0.001) mean copy number of fetal male DYS14 from maternal plasma (4.4 * 10(4) copies/mL) than that of detected fetal cellular DNA from fractional blood cell pellets. The sensitivity of the DYS14 PCR assay was found to be higher than that of the SRY assay for the detection of fetal DNA when its presence was at a minimum. The DYS14 assay is an improved method for quantifying male fetal DNA in circulating maternal blood in the primate model. PMID- 26420679 TI - Gender and obesity modify the impact of salt intake on blood pressure in children. AB - BACKGROUND: Most modifiable risk factors for high blood pressure (BP), such as obesity and salt intake, are imprinted in childhood and persist into adulthood. The aim of our study was to evaluate the intake of salt in children and to assess its impact on BP taking into account gender and nutritional status. METHODS: A total of 298 children aged 8-9 years were evaluated in a cross-sectional study. Anthropometric measurements and 24-h ambulatory monitoring were performed, and salt intake was determined by 24-h urinary sodium excretion. RESULTS: The average estimated salt intake among the entire cohort of children enrolled in the study was 6.5 +/- 2.2 g/day, and it was significantly higher in boys than in girls (6.8 +/- 2.4 vs. 6.1 +/- 1.9 g/day, respectively; p = 0.018) and in overweight/obese children than in normal weight children (6.8 +/- 2.4 vs. 6.1 +/- 2.0 g/day, respectively; p = 0.006). Salt intake exceeded the upper limit of the US Dietary Reference Intake in 72% of children. Daytime systolic BP increased by 1.00 mmHg (95% confidence interval 0.40-1.59) per gram of daily salt intake in overweight/obese boys, but not in normal weight boys or in girls. CONCLUSIONS: Our results demonstrate an extremely high salt intake among 8- to 9-year-old Portuguese children. Higher salt intake was associated with higher systolic BP in boys, specifically in those who were overweight/obese. Longitudinal studies are needed to further evaluate the causal relationship between obesity and high BP and the mechanism by which salt intake modulates this relationship. Nonetheless, based on our results, we urge that dietary salt reduction interventions, along with measures to fight the global epidemic of obesity, be implemented as early in life as possible. PMID- 26420681 TI - [Diabetic maculopathy]. AB - Diabetic maculopathy is the result of multifactorial and complex alterations of the retinal capillaries in association with diabetes mellitus and is divided into two forms, ischemic maculopathy and diabetic macular edema. Diabetic macular edema is the leading cause of blindness among people of working age. The functional and morphological results of intravitreal pharmacotherapy in cases of fovea-involving macular edema using vascular endothelial growth factor (VEGF) inhibitors such as ranibizumab and aflibercept obtained in large randomized clinical trials are excellent and are superior to results obtained with focal or grid laser coagulation alone. Steroids including dexamethasone and fluocinolone implants represent approved alternatives, although flucinolone is considered a second-line therapy in refractory and chronic cases. VEGF inhibitors can be used in different treatment strategies such as PRN and treat and extend strategies. Focal laser photocoagulation remains the gold standard for macular edema not involving the fovea (and therefore usually good visual acuity). Laser is also still indicated as a panretinal photocoagulation of peripheral retinal ischemic areas in order to prevent neovascular complications. It remains to be proven whether panretinal photocoagulation can have an effect on the treatment intervals of intravitreal pharmacotherapy, too. Surgical treatments such as vitrectomy are today limited to cases of macular edema with concomitant obvious tractional pathologies at the vitreoretinal interface. PMID- 26420683 TI - Different modes of synergistic toxicities between metam/copper (II) and metam/zinc (II) in HepG2 cells: apoptosis vs. necrosis. AB - Both metam sodium and copper/zinc-containing compounds are widely used as fungicides. They therefore may co-occur in the biosphere. Despite certain studies of individual toxicity for either metam or copper (II)/zinc (II), their synergistic toxicity has not been examined. In this paper, a remarkable synergistic toxicity was observed in HepG2 cells when metam and copper (II)/zinc (II) at non-toxic and sub-toxic levels were combined. Unexpectedly, cell death modes between metam/copper (II) and metam/zinc (II) were different: For metam/copper (II), apoptosis was evident from morphological characteristics including cytoplasm-chromatin condensation, phosphatidylserine (PS) exposure, SubG0 /G1 DNA fragmentation, mitochondrial membrane potential decrease, pro/anti apoptotic protein activation, and cytochrome c release; for metam/zinc (II), necrosis was evident from organelle swelling and uncontrolled collapse. To our knowledge, this work first not only demonstrates the synergistic toxicities of metam and both copper (II)/zinc (II), but also verifies the different modes of apoptosis/necrosis between metam/copper (II) and metam/zinc (II). (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1964-1973, 2016. PMID- 26420682 TI - The evolution of reduced antagonism--A role for host-parasite coevolution. AB - Why do some host-parasite interactions become less antagonistic over evolutionary time? Vertical transmission can select for reduced antagonism. Vertical transmission also promotes coevolution between hosts and parasites. Therefore, we hypothesized that coevolution itself may underlie transitions to reduced antagonism. To test the coevolution hypothesis, we selected for reduced antagonism between the host Caenorhabditis elegans and its parasite Serratia marcescens. This parasite is horizontally transmitted, which allowed us to study coevolution independently of vertical transmission. After 20 generations, we observed a response to selection when coevolution was possible: reduced antagonism evolved in the copassaged treatment. Reduced antagonism, however, did not evolve when hosts or parasites were independently selected without coevolution. In addition, we found strong local adaptation for reduced antagonism between replicate host/parasite lines in the copassaged treatment. Taken together, these results strongly suggest that coevolution was critical to the rapid evolution of reduced antagonism. PMID- 26420685 TI - Shaping ability of ProTaper NEXT, ProTaper Universal and iRace files in simulated S-shaped canals. AB - The aim of this study was to determine the shaping ability of three nickel titanium endodontic file systems by comparing three parameters: canal deviation, apical foramen position and instrumentation time. A glide path was established in 30 simulated S-shaped canal blocks that were randomly assigned into three groups (n = 10): ProTaper Universal, ProTaper NEXT and iRace. Each group was instrumented per its manufacturer's directions. Pre- and postoperative images were superimposed to determine any canal deviation or change in apical foramen position. The instrumentation times were recorded. The iRace system resulted in the least mean canal deviation. The apical foramen position was least shifted by the iRace system. The iRace system also required the least instrumentation time. The iRace system demonstrated the most favourable shaping ability in all three parameters. PMID- 26420684 TI - Serum survivin predicts responses to treatment in active rheumatoid arthritis: a post hoc analysis from the SWEFOT trial. AB - BACKGROUND: The identification of biomarkers that predict optimal and individual choices of treatment for patients with rheumatoid arthritis gains increasing attention. The purpose of this study was to investigate if the proto-oncogene survivin might aid in treatment decisions in early rheumatoid arthritis. METHODS: Serum survivin levels were measured in 302 patients who completed the Swedish pharmacotherapy (SWEFOT) trial at baseline, 3, 12, and 24 months. Survivin levels > 0.45 ng/mL were considered positive. Based on the survivin status, core set outcomes measuring disease activity, functional disability, as well as global health and pain were evaluated after methotrexate (MTX) monotherapy at 3 months, and at 12 and 24 months of follow-up. Treatment of non-responders was randomly intensified with either a combination of disease-modifying antirheumatic drugs (triple therapy: MTX, sulfasalazine, and hydroxychloroquine) or by adding antibodies against tumor necrosis factor (anti-TNF). RESULTS: Antirheumatic treatment resulted in an overall decrease of serum survivin levels. Survivin positive patients at baseline who initially responded to MTX had a higher risk of disease re-activation (OR 3.21 (95% CI 1.12-9.24), P = 0.032) and failed to improve in their functional disability (P = 0.018) if having continued on MTX monotherapy compared to survivin-negative patients. Ever-smokers who were survivin-positive were less likely to respond to MTX than those who were survivin negative (OR 1.91 (1.01-3.62), P = 0.045). In survivin-positive patients, triple therapy led to better improvements in disease activity than did MTX + anti-TNF. At 24 months, survivin-positive patients randomized to anti-TNF had a higher risk of active disease than those randomized to triple therapy (OR 3.15 (1.09-9.10), P = 0.037). DISCUSSION: We demonstrate for the first time that survivin is a valuable serologic marker that can distinguish drug-specific clinical responses in early rheumatoid arthritis through the pragmatic clinical setting of the care based SWEFOT trial. Although treatment response cannot solely be attributable to survivin status, per protocol sensitivity analyses confirmed the superior effect of triple therapy on survivin-positive patients. CONCLUSIONS: Survivin-positive patients have poor outcomes if treated with MTX monotherapy. A decrease of survivin levels during treatment is associated with better clinical responses. For survivin-positive patients who fail MTX, triple therapy is associated with better outcomes than anti-TNF therapy. TRIAL REGISTRATION: WHO database at the Karolinska University Hospital: CT20080004 ; ClinicalTrials.gov: NCT00764725, registered 1 October 2008. PMID- 26420686 TI - Supraclavicular skin temperature and BAT activity in lean healthy adults. AB - The 'gold standard' for measuring brown adipose tissue (BAT) in humans is [(18)F]FDG-PET/CT-imaging. With this technique subjects are exposed to ionizing radiation and are therefore limited in the number of scans that can be performed. We investigated the relation between supraclavicular skin temperatures and BAT activity values using a strictly temperature-controlled air-cooling protocol. Data of 36 male subjects was analyzed. BAT activity was evaluated by [(18)F]FDG PET/CT-imaging and skin temperature was measured by means of wireless temperature sensors. Supraclavicular skin temperature dropped less compared to skin temperatures at other sites (all P values <0.01). A significant positive correlation was found between the change in supraclavicular skin temperature with BAT activity (R (2) 0.23), and the change in supraclavicular skin temperature and non-shivering thermogenesis (R (2) 0.18, both P values <0.01). The correlations indicate that supraclavicular skin temperature (changes) can potentially be used as a qualitative measure of BAT activity and BAT thermogenesis. PMID- 26420689 TI - Mycobacterium angelicum sp. nov., a non-chromogenic, slow-growing species isolated from fish and related to Mycobacterium szulgai. AB - The name 'Mycobacterium angelicum' dates back to 2003 when it was suggested for a slowly growing mycobacterium isolated from freshwater angelfish. This name is revived here and the novel species is proposed on the basis of the polyphasic characterization of four strains including the original one. The four strains presented 100 % 16S rRNA gene sequence similarity with Mycobacterium szulgai but clearly differed from M. szulgai for the milky white aspect of the colonies. The sequence similarity with the type strain of M. szulgai ranged, in eight additionally investigated genetic targets, from 78.9 to 94.3 %, an evident contrast with the close relatedness that emerged at the level of 16S rRNA gene. The average nucleotide identity between the genomes of M. szulgai DSM 44166T and strain 126/5/03T (type strain of the novel species) was 92.92 %, and supported the status of independent species. The confirmation of the name Mycobacterium angelicum sp. nov. is proposed, with strain 126/5/03T ( = CIP 109313T = DSM 45057T) as the type strain. PMID- 26420688 TI - Dicalcin, a zona pellucida protein that regulates fertilization competence of the egg coat in Xenopus laevis. AB - Fertilization is a highly coordinated process whereby sperm interact with the egg coating envelope (called the zona pellucida, ZP) in a taxon-restricted manner, Fertilization triggers the resumption of the cell cycle of the egg, ultimately leading to generation of a new organism that contains hereditary information of the parents. The complete sperm-ZP interaction comprises sperm recognition of the ZP, the acrosome reaction, penetration of the ZP, and fusion with the egg. Recent evidence suggests that these processes involve oligosaccharides associated with a ZP constituent (termed ZP protein), the polypeptide backbone of a ZP protein, and/or the proper three-dimensional filamentous structure of the ZP. However, a detailed description of the molecular mechanisms involved in sperm-ZP interaction remains elusive. Recently, I found that dicalcin, a novel ZP protein-associated protein, suppresses fertilization through its association with gp41, the frog counterpart of the mammalian ZPC protein. This review focuses on molecular aspects of sperm-ZP interaction and describes the fertilization-suppressive function of dicalcin and associated molecular mechanisms. The amount of dicalcin in the ZP significantly correlates with alteration of the lectin-staining pattern within the ZP and the orientation pattern of ZP filaments, which may assist in elucidating the complex molecular mechanisms that underlie sperm-ZP interaction. PMID- 26420690 TI - Accuracy of optical coherence tomography (OCT) in pachymetry for glaucoma patients. AB - BACKGROUND: Central corneal thickness (CCT) measurement has become an important test in the diagnosis and management of glaucoma. Currently, ultrasound corneal thickness measurement (pachymetry) is the most frequently used clinical technique and the gold standard to assess CCT. Newer instruments are currently available including the optical coherence tomography (OCT) instrument. The aim of the present study was therefore to evaluate the accuracy of the CCT measurements performed by three different observers, both with the OCT and ultrasound pachymetry (USP), in patients suffering from glaucoma. METHODS: Patients who had been previously diagnosed with glaucoma participated in this cross-sectional study. Glaucoma was defined as patients who had at least two repeatable Humphrey visual fields showing glaucoma damage using the software 24-2, and with the optic nerve showing typical glaucoma damage. The patients CCTs were measured with OCT and USP by three different examiners. RESULTS: Seventy eyes of 35 patients were included. The average age was 74 +/- standard deviation (SD) 10.88, the average pachymetry value with OCT was 536 +/- 29 MUm, and the average pachymetry with USP was 532 +/- 32 MUm. The differences between OCT and USP were not significant (t test, p = 0.32). The intraclass correlation coefficients were, for OCT, 0.99 [confidence interval (CI): 0.98-0.996], and for USP, 0.97 (CI: 0.95-0.98). CONCLUSIONS: Agreement among the three observers using OCT or USP for pachymetry measurements was good. OCT might be used as an alternative method for pachymetry in glaucoma patients. PMID- 26420687 TI - Frontier studies on fatigue, autonomic nerve dysfunction, and sleep-rhythm disorder. AB - Fatigue is defined as a condition or phenomenon of decreased ability and efficiency of mental and/or physical activities, caused by excessive mental or physical activities, diseases, or syndromes. It is often accompanied by a peculiar sense of discomfort, a desire to rest, and reduced motivation, referred to as fatigue sensation. Acute fatigue is a normal condition or phenomenon that disappears after a period of rest; in contrast, chronic fatigue, lasting at least 6 months, does not disappear after ordinary rest. Chronic fatigue impairs activities and contributes to various medical conditions, such as cardiovascular disease, epileptic seizures, and death. In addition, many people complain of chronic fatigue. For example, in Japan, more than one third of the general adult population complains of chronic fatigue. It would thus be of great value to clarify the mechanisms underlying chronic fatigue and to develop efficient treatment methods to overcome it. Here, we review data primarily from behavioral, electrophysiological, and neuroimaging experiments related to neural dysfunction as well as autonomic nervous system, sleep, and circadian rhythm disorders in fatigue. These data provide new perspectives on the mechanisms underlying chronic fatigue and on overcoming it. PMID- 26420691 TI - Ingested cylindrical batteries in an incarcerated male: a caustic tale! AB - A 37-year-old incarcerated man presented to the accident and emergency department following the deliberate ingestion of eight cylindrical batteries. He also admitted to inserting a razor blade wrapped in cling-film into his rectum; in addition, he sustained a self-inflicted laceration to his left antecubital fossa, using the metal casing from a battery. His medical history included a borderline and emotionally unstable personality disorder. He had ingested several batteries 12 months previously and required an emergency laparotomy to retrieve them. On the present admission, as there was no clinical evidence of small bowel obstruction, he was treated conservatively with serial radiographs. Following conservative management, the batteries failed to progress through the gastrointestinal tract, hence a laparotomy was performed and all the batteries were extricated. This paper discusses the management and associated sequelae of patients presenting following the intentional ingestion of a battery. PMID- 26420692 TI - Intussusception in gestational choriocarcinoma (not histologically proven), resolving spontaneously with chemotherapy. AB - We present a rare case of advanced gestational choriocarcinoma with small bowel metastatic involvement and intussusception, which presented acutely as a lower gastrointestinal bleed with symptomatic anaemia and haemoglobin 3.8 g/dL in a young woman. A diagnosis of gestational choriocarcinoma was made without biopsy, using a combination of clinical history, isolated elevated human chorionic gonadotropin markers of 77,000 IU/mL and radiological findings. Surgical intervention was too high risk due to the presence of active bleeding and increased vascularity surrounding the intussusception. Owing to the highly responsive nature of gestational choriocarcinoma to chemotherapy, frontline chemotherapy alone was used to reduce the size of the metastatic small bowel deposits, with subsequent resolution of the bleeding and intussusception. This is the first time chemotherapy alone has been used to successfully resolve small bowel intussusception secondary to metastatic choriocarcinoma that has been documented according to PubMed searches. PMID- 26420693 TI - Lens coloboma treated with lens surgery. AB - A 5-year-old boy was referred to our clinic due to an abnormal visual acuity test at school. His corrected visual acuity was counting fingers in the left eye. A nasal side deficiency of the lens substituted by a membrane was found. Lens coloboma was diagnosed. After making a 3 mm limbal incision, the colobomatous lens was removed by anterior continuous curvilinear capsulorhexis and lens aspiration. Posterior capsulorhexis and anterior vitrectomy on the side of the lens was performed to prevent posterior capsular or anterior hyaloid opacity. As the defect in the lens was very large, intracapsular placement of an intraocular lens was not feasible. A three-piece acrylic soft intraocular lens was placed in the ciliary sulcus. Since amblyopia was diagnosed by poor corrected visual acuity as 20/800 1 month after the operation, occlusion therapy with correcting eyeglasses was started at 6 h a day on the contralateral eye. The patient's corrected visual acuity improved to 20/125 7 months after the operation. PMID- 26420694 TI - Pott's puffy tumour: a forgotten diagnosis. PMID- 26420695 TI - Endoscopic closure of a refractory gastrocutaneous fistula using a novel over-the scope Padlock clip following de-epithelialisation of the fistula tract. AB - Persistent gastrocutaneous fistula (GCF) is a difficult to manage complication following gastrostomy tube removal, with leakage resulting in distressing sequelae including cutaneous injury, infection and dehydration. Many such patients are high-risk for invasive surgery and, to date, endoscopic closure techniques, including clipping systems, have limitations. We present the case of a 62-year-old woman with persistently leaking GCF 6 months postgastrostomy tube removal, despite maximal antisecretory therapy and postpyloric feeding, and describe failed attempted endoscopic closure with conventional clips. Treatment options were discussed and informed consent was given for an attempt at endoscopic closure using a novel radial closure device ('Padlock clip') combined with surgical de-epithelialisation, with the understanding that this device has never previously been used in this setting. At follow-up 2 weeks postprocedure, the patient was asymptomatic with complete healing of the GCF. This approach has advantages over other endoscopic closure techniques and can be considered as an alternative approach to GCF closure. PMID- 26420696 TI - ST segment elevation myocardial infarction of a rare aetiology: an unexpected diagnosis. AB - A 43-year-old man presenting with acute coronary syndrome with ST segment elevation myocardial infarction underwent urgent coronary angiography. During the intervention, the patient was found to have several multiple filling defects with dynamic obstruction in the left coronary circulation. Thrombectomy was performed on distal left anterior descending artery and 2nd diagonal artery lesions with balloon angioplasty, which was unsuccessful. Considering the dynamic obstruction in the angiogram, immediate imaging was performed for structural evaluation of the heart. Cardiac CT revealed a circumferential groove on the heart, suggesting an external compression leading to dynamic obstruction of the coronary arteries on angiogram. Cardiac hernia, a very rare aetiology, was suspected to be the culprit for the ST segment elevation myocardial infarction. Thoracoscopy was performed, which revealed congenital cardiac hernia and a fibrous pericardial band encircling the apex. A left mini thoracotomy was performed to release the constriction imposed over the heart, with improvement in circulation. PMID- 26420697 TI - Combined laparoscopic-assisted nephrectomy and complete mesocolic excision for synchronous renal and colon cancers. AB - Cancers of the colon and kidney are common malignancies, however, the occurrence of primary synchronous neoplasms of these two organs is uncommon. To the best of our knowledge, this is the first case report of a laparoscopic radical left nephrectomy and extended right complete mesocolic excision (CME) for a patient with synchronous renal and colon cancers. While a radical nephrectomy has long been the standard of care for a renal malignancy, CME has only recently been used. Combined surgeries provide the patient with various benefits such as decreased hospital stay, less postoperative pain and morbidity, early return to work and better cosmoses. PMID- 26420698 TI - Upper gastrointestinal bleed associated with cholinesterase inhibitor use. AB - An 86-year-old man was admitted with a 3-day history of melaena and syncope. He was haemodynamically compromised and anaemic on presentation. His only medical history was mild Alzheimer's disease diagnosed 6 months prior. For this, he was on donepezil, a cholinesterase inhibitor (ChEI), with a recent dose increase 3 months earlier. After fluid resuscitation with packed red cells, an endoscopy was performed, which showed an acute duodenal ulcer. This was treated with a high dose proton pump inhibitor. The patient recovered well and was discharged on donepezil with the addition of a gastro-protective proton pump inhibitor. In view of other absent risk factors of upper gastrointestinal haemorrhage, donepezil was the likely causative agent. ChEIs are associated with frequent side effects and increased hospitalisation due to central and peripheral increase in acetylcholine. With this case report, we review the literature of side effects related to ChEIs, where the mechanisms of action, complications and appropriate management are discussed. PMID- 26420699 TI - Osteoblastoma of the coracoid process: an unusual location. AB - Bone tumours arising from the coracoid process of the scapula are very rare. We present a case of a 19-year-old man with left shoulder pain for 1 year, with associated infraclavicular swelling for 8 months. Examination revealed a tender, bony, hard swelling measuring 3*4 cm. Imaging revealed an expansile osteolytic lesion arising from the coracoid process with loss of corticomedullary differentiation. MRI showed altered signal in the adjacent soft tissues. The patient underwent en bloc resection of the lesion. Histology was suggestive of osteoblastoma. At the end of 2 years follow-up, the patient had no pain or recurrence of the lesion. We present this case for its rare location and have briefly discussed the difficulties in diagnosis of this condition. PMID- 26420700 TI - Thrombocytopenia and absent radius (TAR) syndrome in pregnancy. PMID- 26420701 TI - Unusual diagnosis of a solitary thyroid nodule in the paediatric population: cervical thymic cyst. AB - We present a case of an 8-year-old girl with a painless swelling in her neck. An ultrasonogram revealed a cystic nodule with internal echoes, lying posterior to right lobe of thyroid, and MRI confirmed it. Thyroid scintigraphy did not show any uptake in the swelling. Intraoperatively, the lesion was densely adherent to the thyroid gland, hence a hemithyroidectomy was performed. Histopathology showed it to be an ectopic cervical thymic cyst with parathyroid tissue. PMID- 26420702 TI - Landau-Kleffner syndrome: an uncommon dealt with case in Southeast Asia. AB - An 11-year-old boy was admitted with fever followed by convulsions. He had developed aphasia subsequent to this illness. His birth history was unremarkable, and he had normal growth and development including of language, hearing and vision. His neurological examination was normal except for aphasia. Investigations including cerebrospinal fluid study and MRI were normal. However, EEG was abnormal and the boy was diagnosed as a case of Landau-Kleffner syndrome (LKS) and treated with sodium valproate, levetiracetam and steroids. He responded well to treatment and has been on follow-up for the last 4 months. We present this case of LKS to increase awareness about early diagnosis and to highlight the importance of appropriate management for a better outcome. PMID- 26420703 TI - Amino acids, peptides, and proteins as chemically bonded stationary phases--A review. AB - The selectivity of chromatographic separation depends mostly on the stationary phase and mobile phase composition. Despite being a material with bonded simple organic molecule, a wide group of stationary phases contain immobilized compound that possesses biological activity. Stationary phases that contain amino acids and peptides as well as enzymes and proteins are alternative materials that may be used for liquid chromatographic separations and are reviewed in this work. In the case of peptide-bonded stationary phases, most of these types of materials were elaborated in the 1970s and 1980s; however, over the last few years a growing interest has been observed which is connected with hydrophilic interaction liquid chromatography. The most important application of amino acid and peptide-bonded stationary phases is connected with separation of amino acids, their derivatives, and peptides. The main advantage of such materials is the ability for chiral separations. PMID- 26420704 TI - Isolation of Lipid Rafts from Human Neutrophils by Density Gradient Centrifugation. AB - Neutrophils are present within minutes to the site of aggression in the body making them one of the first cells of the immune system to be in contact with incoming threats. The cell functions of neutrophils are elicited through the engagement of surface receptors, some of which are located in a specific region of the membrane called lipid rafts, a functionally segregated region of the membrane enriched with cholesterol and distinct species of sphingomyelin and glycerophospholipids. Lipid rafts are relatively resistant to detergent extraction and this can be taken advantage of to isolate them from the rest of the cell membrane. This chapter will describe a reliable method to obtain lipid rafts from detergent-resistant membrane fractions of human neutrophils. Cells are lysed in an HEPES solution containing 0.5% Triton X-100, supernatants are mixed with a 42% sucrose solution, which is then overlaid with a 35% and 5% sucrose solution. The gradient is centrifuged for 16 h and the resulting fractions can be further analyzed by immunoblotting or subjected to immunoprecipitation. PMID- 26420705 TI - Flow Cytometry Analysis of NK Cell Phenotype and Function in Aging. AB - Natural killer (NK) cells represent a subpopulation of lymphocytes involved in innate immunity, defined recently as group 1 of innate lymphoid cells (ILCs). NK cells are cytotoxic lymphocytes with a relevant role in the destruction of transformed cells as virus-infected or tumor cells, as well as the regulation of the immune response through cytokine and chemokine production that activates other cellular components of innate and adaptive immunity. In humans, NK cell subsets have been defined according to the level of expression of CD56. Aging differentially affects NK cell subsets and NK cell function. Here, we describe protocols for the delineation of NK cell subsets and the analysis of their functional capacity using multiparametric flow cytometry. PMID- 26420706 TI - Flow Cytometric Identification of Fibrocytes in the Human Circulation. AB - Because the incidence of organ fibrosis increases with age, various fibrosing disorders are projected to account for significant increases in morbidity, mortality, and healthcare costs in the years to come. Treatments for these diseases are scarce and better understanding of the immunopathogenesis of fibrosis and its relationship to aging are sorely needed. One area of interest in this field is the role that fibrocytes might play in the development of tissue remodeling and fibrosis. Fibrocytes are mesenchymal progenitor cells presumed to be of monocyte origin that possess the tissue remodeling properties of tissue resident fibroblasts such as extracellular matrix production and alpha-SMA related contractile properties, as well as the immunologic functions typically attributed to macrophages including production of cytokines and chemokines, antigen presentation, regulation of leukocyte trafficking, and modulation of angiogenesis. Fibrocytes could participate in the development of age-related fibrosing disorders through any or all of these functions. This chapter presents methods that have been developed for the study of circulating human fibrocytes. Protocols for the quantification of fibrocytes in the human circulation will be presented along with discussion of the technical challenges that are frequently encountered in this field. It is hoped that this information will facilitate further investigation of the relationship between fibrocytes, aging, and fibrosis, and perhaps uncover new areas of study in these difficult-to-treat and deadly diseases. PMID- 26420707 TI - Experimental Approaches to Tissue Injury and Repair in Advanced Age. AB - Cutaneous wound healing is a complex physiological process. This process can be altered by multiple physiological and pathological factors. Multiple pathophysiological disturbances act to impair resolution of cutaneous wound injury, including obesity, diabetes, peripheral vascular disease, and advanced age. As our longevity increases without a concomitant increase in healthy living years, it is plausible to assume that problematic wound closure will continue to consume a large portion of our health care resources. Furthermore, advanced age is associated with numerous alterations in the innate and adaptive immune responses that complicate outcomes following cutaneous injury, trauma, or infection. Thus, models that examine the impact of advanced age on cutaneous wound repair will be of great benefit to the development of potential therapeutics that target age-related aberrancies in tissue repair. Herein, we detail two animal models of tissue injury, excisional wound injury and burn injury, that can be used to evaluate wound healing in the context of advanced age. We also describe modifications of these methods to examine wound infection following either excisional or burn injury. Lastly, we discuss methods of subsequent tissue analysis following injury. Models described below can be further adapted to genetically engineered murine strains to study the effects of aging and other co-morbidities on wound healing. PMID- 26420708 TI - Multicolor Digital Flow Cytometry in Human Translational Immunology. AB - By facilitating the simultaneous analysis of parameters from diverse cell lineages and biological pathways, multicolor flow cytometry is integral to many studies in human immunology-particularly those in older individuals-where sample amounts may be limiting. Studies in human cohorts require particular attention to fluorochrome panel design and procedures to standardize instrument performance; reproducible instrument conditions (over time and between centers) are crucial to accurate comparisons and conclusions in the analysis of heterogeneous groups of human subjects. Here, we describe procedures for multicolor digital flow cytometry, our experience in flow cytometry panel design and our approach in standardizing instrument performance using BD Biosciences hardware and software (BD Biosciences, San Jose, CA). These techniques allow for the generation of accurate and precise data in a variety of settings. PMID- 26420709 TI - Flow Cytometry-Based Methods to Characterize Immune Senescence in Nonhuman Primates. AB - Flow cytometry is an invaluable technique that can be used to phenotypically and functionally characterize immune cell populations ex vivo. This technology has greatly advanced our ability to gain critical insight into age-related changes in immune function, commonly known as immune senescence. Rodents have been traditionally used to investigate the molecular mechanisms of immune senescence because they offer the distinct advantages of an extensive set of reagents, the presence of genetically modified strains, and a short lifespan that allows for longevity studies of short duration. More recently, nonhuman primates (NHPs), and specifically rhesus macaques, have emerged as a leading translational model to study various aspects of human aging. In contrast to rodents, they share significant genetic homology as well as physiological and behavioral characteristics with humans. Furthermore, rhesus macaques are a long-lived outbred species, which makes them an ideal translational model. Therefore, NHPs offer a unique opportunity to carry out mechanistic studies under controlled laboratory conditions (e.g., photoperiod, temperature, diet, and medications) in a species that closely mimics human biology. Moreover similar techniques (e.g., activity recording and MRI) can be used to measure physiological parameters in NHPs, making direct comparisons between NHP and human data sets possible. In addition, the outbred genetics of NHPs enables rigorous validation of research findings that goes beyond proof of principle. Finally, self-selection bias that is often unavoidable in human clinical trials can be completely eliminated with NHP studies. Here we describe flow cytometry-based methods to phenotypically and functionally characterize innate immune cells as well as T and B lymphocyte subsets from isolated peripheral blood mononuclear cells (PBMC) in rhesus macaques. PMID- 26420710 TI - Multiparameter Phenotyping of Human PBMCs Using Mass Cytometry. AB - The standard for single-cell analysis of phenotype and function in recent decades has been fluorescence flow cytometry. Mass cytometry is a newer technology that uses heavy metal ions, rather than fluorochromes, as labels for probes such as antibodies. The binding of these ion-labeled probes to cells is quantitated by mass spectrometry. This greatly increases the number of phenotypic and functional markers that can be probed simultaneously. Here, we review topics that must be considered when adapting existing flow cytometry panels to mass cytometry analysis. We present a protocol and representative panels for surface phenotyping and intracellular cytokine staining (ICS) assays. PMID- 26420711 TI - Imaging Immunosenescence. AB - To demonstrate effects of aging visually requires a robust technique that can reproducibly detect small differences in efficiency or kinetics between groups. Investigators of aging will greatly appreciate the benefits of Amnis ImageStream technology ( www.amnis.com/), which combines quantitative flow cytometry with simultaneous high-resolution digital imaging. Imagestream is quantitative, reproducible, feasible with limited samples, and it facilitates in-depth examination of cellular mechanisms between cohorts of samples. PMID- 26420712 TI - Activation-Induced Cytidine Deaminase and Switched Memory B Cells as Predictors of Effective In Vivo Responses to the Influenza Vaccine. AB - Aging impairs humoral immune responses, leading to increased frequency and severity of infectious diseases and reduced protective effects of vaccination. We have identified B-cell biomarkers that are reduced by aging and that can be used as predictive markers of the response of an individual to vaccination. The identification of these biomarkers will have an impact on the development of effective vaccines to protect the elderly from infections and other debilitating diseases. PMID- 26420713 TI - Analyzing the Effect of Aging on CD8+ T-Cell Phenotype Using Flow Cytometry. AB - One of the most noticeable changes in T-cell immunity with aging is the expansion of memory CD8+ T cells, with a decline in naive phenotype T cells that reflects both diminished thymopoiesis and the effects of chronic antigenic stimulation with age. Flow cytometry is a useful tool in evaluating immune cells including the phenotype characteristics of different T-cell subsets. Here, we show flow cytometric methods measuring the different subsets of human CD8+ T cells that change with aging. PMID- 26420714 TI - Cell-Mediated Immune Response to Influenza Using Ex Vivo Stimulation and Assays of Cytokine and Granzyme B Responses. AB - The antibody response to vaccination has been the industry and regulatory standard for evaluating influenza vaccine efficacy. Although antibodies are an important defense mechanism providing sterilizing immunity, in older adults, the cellular immune response is also needed for clinical protection against the serious complications of influenza. Thus, the demonstration of enhanced antibody responses as a strategy for advancing new influenza vaccines through the standard clinical development pipeline may fail to translate to enhanced protection in the older population. In peripheral blood mononuclear cells (PBMC) challenged with live influenza virus, an increase in the interferon-gamma:interleukin-10 (IFN gamma:IL-10) ratio and the level of the cytolytic mediator, granzyme B (GrzB), correlates with protection against influenza in vaccinated older adults. This chapter provides detailed methods for measuring these cell-mediated immune responses, which have been validated according to the International Conference on Harmonisation (ICH) guidelines. These immune correlates could be combined with antibody responses to improve the prediction of enhanced protection in vaccine trials in the older population. PMID- 26420715 TI - Assays for Monitoring Macroautophagy Activity in T cells. AB - Autophagy is an essential catabolic process that regulates a diverse array of functions by targeting cellular components for degradation by lysosomes. Studies in mammalian cells have shown that the regulation of autophagy is highly complex and optimization of experimental approaches to analyze this process needs to be developed for each model studied. This chapter provides an overview of two of the most commonly used ways to monitor autophagy activity in T cell. It involves description of common techniques, namely Western blot and cell immunostaining, giving specific recommendations for working with T cells and monitoring macroautophagy. We also discuss the analysis required for correct interpretation of the results and quantification of macroautophagy activity. PMID- 26420716 TI - Fluorescence-Based Approaches for Quantitative Assessment of Protein Carbonylation, Protein Disulfides, and Protein Conformation in Biological Tissues. AB - Protein oxidation and misfolding have been considered as key players for progression of aging and etiology of various pathological conditions. However, few attempts have been made to develop sensitive and reproducible assays to quantify the changes in protein oxidation and alteration in structure. Here we describe three distinct fluorescence-based assays to quantify changes in protein oxidation, namely carbonylation and disulfides and alteration in protein surface hydrophobicity as a reporter for protein conformation. These techniques will provide investigators the opportunity to address important biological questions in their experimental models. PMID- 26420717 TI - Monitoring the DNA Damage Response at Dysfunctional Telomeres. AB - Telomeres are repetitive DNA repeats that cap the ends of all eukaryotic chromosomes. Their proper maintenance is essential for genomic stability and cellular viability. Dysfunctional telomeres could arise through natural attrition of telomeric DNA or due to the removal of shelterin components. These uncapped chromosomal ends are recognized as DSBs by the DDR pathway, leading to the accumulation of DNA damage sensors at telomeres. The association of these DDR proteins with dysfunctional telomeres forms telomere dysfunction induced DNA damage foci (TIFs). Detection of TIFs at telomeres provides an opportunity to quantify the extent of telomere dysfunction and monitor downstream DNA damage signaling pathways. Here we describe a method for the detection of TIFs using a fluorescent in situ hybridization (FISH) approach. PMID- 26420718 TI - Single-Cell Analysis of T-Cell Receptor alphabeta Repertoire. AB - The unbiased, paired analysis of T-cell receptor (TCR) alpha- and beta-chain usage at the single-cell level provides a valuable window of understanding into the TCR repertoire and the nature of the immune response. Earlier technologies for TCR repertoire analysis were often limited to examining TCR complementarity determining region 3 (CDR3) beta expression or required in vitro cloning procedures that can artificially skew the TCR repertoire from its in vivo state. We describe here a direct ex vivo, single-cell-based strategy for the clonotypic analysis of TCRalphabeta repertoires that utilizes multiplexed panels of TCRalpha and TCRbeta-specific primers in a nested PCR to amplify expressed transcripts from individual, epitope-specific T cells. This strategy yields the paired TCRalphabeta sequences of any given population of alphabeta T cells of interest. PMID- 26420719 TI - Assessment of B Cell Repertoire in Humans. AB - The B cell receptor (BCR) repertoire is highly diverse. Repertoire diversity is achieved centrally by somatic recombination of immunoglobulin (Ig) genes and peripherally by somatic hypermutation and Ig heavy chain class-switching. Throughout these processes, there is selection for functional gene rearrangements, selection against gene combinations resulting in self-reactive BCRs, and selection for BCRs with high affinity for exogenous antigens after challenge. Hence, investigation of BCR repertoires from different groups of B cells can provide information on stages of B cell development and shed light on the etiology of B cell pathologies. In most instances, the third complementarity determining region of the Ig heavy chain (CDR-H3) contributes the majority of amino acids to the antibody/antigen binding interface. Although CDR-H3 spectratype analysis provides information on the overall diversity of BCR repertoires, this fairly simple technique analyzes the relative quantities of CDR H3 regions of each size, within a range of approximately 10-80 bp, without sequence detail and thus is limited in scope. High-throughput sequencing (HTS) techniques on the Roche 454 GS FLX Titanium system, however, can generate a wide coverage of Ig sequences to provide more qualitative data such as V, D, and J usage as well as detailed CDR3 sequence information. Here we present protocols in detail for CDR-H3 spectratype analysis and HTS of human BCR repertoires. PMID- 26420720 TI - Laboratory and Data Analysis Methods for Characterization of Human B Cell Repertoires by High-Throughput DNA Sequencing. AB - High-throughput DNA sequencing techniques have greatly accelerated the pace of research into the repertoires of antibody and T cell receptor gene rearrangements that confer antigen specificity to adaptive immune responses. Studies of aging related changes in human B cell repertoires have benefited from the ability to detect and quantify thousands to millions of B cell clones in human samples, and study the mutational lineages and isotype switching relationships within each clonal lineage. Correlation of repertoire analysis with antibody gene data from antigen-specific B cells is poised to give much greater insight into clinically relevant B cell responses and memory storage. Here, we describe strategies for preparing and analyzing human antibody gene libraries for studying B cell repertoires. PMID- 26420721 TI - Discovery of Novel microRNAs in Aging Caenorhabditis elegans. AB - The rapid development of deep sequencing technologies over the last few years and concomitant increases in sequencing depth and cost efficiencies have opened the door to a ever-widening range of applications in biology-from whole-genome sequencing, to ChIP-seq analysis, epigenomic and RNA transcriptome surveys. Here we describe the application of deep sequencing to the discovery of novel microRNAs and characterization of their differential expression during adulthood in Caenorhabditis elegans. PMID- 26420722 TI - Analysis of DNA Methylation by Pyrosequencing. AB - Pyrosequencing is a technique that uses a sequencing-by-synthesis system which is designed to quantify single-nucleotide polymorphisms (SNPs). Artificial C/T SNP creation via bisulfite modification permits measurement of DNA methylation locally and globally in real time. Alteration in DNA methylation has been implicated in aging, as well as aging-related conditions such as cancer, as well as cardiovascular, neurodegenerative, and autoimmune diseases. Considering its ubiquitous presence in divergent clinical pathologies, quantitative analysis of DNA CpG methylation both globally and at individual genes helps to elucidate the regulation of genes involved in pathophysiological conditions. The ability to detect and quantify the methylation pattern of DNA has the potential to serve as an early detection marker and potential drug target for several diseases. Here, we provide a detailed technical protocol for pyrosequencing supplemented by critical information about assay design and nuances of the system that provides a strong foundation for beginners in the field. PMID- 26420724 TI - Synthetic Curcumin Analogs as Inhibitors of beta -Amyloid Peptide Aggregation: Potential Therapeutic and Diagnostic Agents for Alzheimer's Disease. AB - There is a crucial need to develop new effective drugs for Alzheimer's disease (AD) as the currently available AD treatments provide only momentary and incomplete symptomatic relief. Amongst natural products, curcumin, a major constituent of turmeric, has been intensively investigated for its neuroprotective effect against beta-amyloid (Abeta)-induced toxicity in cultured neuronal cells. The ability of curcumin to attach to Abeta peptide and prevent its accumulation is attributed to its three structural characteristics such as the presence of two aromatic end groups and their co-planarity, the length and rigidity of the linker region and the substitution conformation of these aromatics. However, curcumin failed to reach adequate brain levels after oral absorption in AD clinical trials due to its low water solubility and poor oral bioavailability. A number of new curcumin analogs that mimic the active site of the compound along with analogs that mimic the curcumin anti-amyloid effect combined with anticholinesterase effect have been developed to enhance the bioavailability, pharmacokinetics, water solubility, stability at physiological conditions and delivery of curcumin. In this article, we have summarized all reported synthetic analogs of curcumin showing effects on beta-amyloid and discussed their potential as therapeutic and diagnostic agents for AD. PMID- 26420725 TI - Systematic review and network meta-analysis comparing clinical outcomes and effectiveness of surgical treatments for haemorrhoids. AB - BACKGROUND: The aim was to compare the clinical outcomes and effectiveness of surgical treatments for haemorrhoids. METHODS: Randomized clinical trials were identified by means of a systematic review. A Bayesian network meta-analysis was performed using the Markov chain Monte Carlo method in WinBUGS. RESULTS: Ninety eight trials were included with 7827 participants and 11 surgical treatments for grade III and IV haemorrhoids. Open, closed and radiofrequency haemorrhoidectomies resulted in significantly more postoperative complications than transanal haemorrhoidal dearterialization (THD), LigaSureTM and Harmonic(r) haemorrhoidectomies. THD had significantly less postoperative bleeding than open and stapled procedures, and resulted in significantly fewer emergency reoperations than open, closed, stapled and LigaSureTM haemorrhoidectomies. Open and closed haemorrhoidectomies resulted in more pain on postoperative day 1 than stapled, THD, LigaSureTM and Harmonic(r) procedures. After stapled, LigaSureTM and Harmonic(r) haemorrhoidectomies patients resumed normal daily activities earlier than after open and closed procedures. THD provided the earliest time to first bowel movement. The stapled and THD groups had significantly higher haemorrhoid recurrence rates than the open, closed and LigaSureTM groups. Recurrence of haemorrhoidal symptoms was more common after stapled haemorrhoidectomy than after open and LigaSureTM operations. No significant difference was identified between treatments for anal stenosis, incontinence and perianal skin tags. CONCLUSION: Open and closed haemorrhoidectomies resulted in more postoperative complications and slower recovery, but fewer haemorrhoid recurrences. THD and stapled haemorrhoidectomies were associated with decreased postoperative pain and faster recovery, but higher recurrence rates. The advantages and disadvantages of each surgical treatment should be discussed with the patient before surgery to allow an informed decision to be made. PMID- 26420726 TI - Adenosquamous carcinoma of the ampulla of Vater: a case report and literature review. AB - BACKGROUND: Adenosquamous carcinoma of the ampulla of Vater is extremely rare, and its clinicopathological features are limited and described in few previous case reports. Here, we report curative resection of adenosquamous carcinoma of the ampulla of Vater at an early stage. CASE PRESENTATION: An 81-year-old woman was referred to our hospital for investigation of the frequent elevation of hepatic and biliary enzymes and dilatation of the intrahepatic bile ducts. Preoperative examinations revealed an exposed reddish tumor in the ampulla of Vater, which was diagnosed on biopsy to be adenocarcinoma with squamous cell carcinoma component. Pylorus-preserving pancreaticoduodenectomy with regional lymph node dissection was performed. Pathological examinations revealed the presence of two malignant components in the lesion, including poorly differentiated tubular adenocarcinoma and squamous cell carcinoma, without invasion beyond the sphincter of Oddi or into the duodenal submucosa. These squamous cell carcinoma and adenocarcinoma components in the tumor comprised approximately 30 and 70% of the lesion, respectively. No metastasis into regional lymph nodes was observed, and the patient experienced no tumor recurrence or metastasis until 20 months after surgery. CONCLUSION: We identified only six reported cases of adenosquamous carcinoma of the ampulla of Vater in the English literature, and all of these patients died of recurrence within 14 months after surgery. To the best of our knowledge, this is the first report of adenosquamous carcinoma of the ampulla of Vater that was curatively resected at an early stage. Although more number of studies on clinicopathological findings are required to determine the appropriate surgical indication, we suggest that surgery remains the mainstay therapy for adenosquamous carcinoma of the ampulla of Vater detected at an early stage. PMID- 26420723 TI - Recent Advances in Discovering the Role of CCL5 in Metastatic Breast Cancer. AB - A variety of therapeutic strategies are currently under investigation to inhibit factors that promote tumor invasion, as metastasis is the most common cause of mortality for cancer patients. Notably, considerable emphasis has been placed on studying metastasis as a dynamic process that is highly dependent on the tumor microenvironment. In regards to breast cancer, chemokine C-C motif ligand 5 (CCL5), which is produced by tumor-associated stromal cells, has been established as an important contributor to metastatic disease. This review summarizes recent discoveries uncovering the role of this chemokine in breast cancer metastasis, including conditions that increase the generation of CCL5 and effects induced by this signaling pathway. In particular, CCL-5-mediated cancer cell migration and invasion are discussed in the context of intertwined feedback loops between breast cancer cells and stromal cells. Moreover, the potential use of CCL5 and its receptor chemokine C-C motif receptor 5 (CCR5) as targets for preventing breast cancer metastasis is also reviewed. PMID- 26420727 TI - Motor function benefits of visual restoration measured in age-related cataract and simulated patients: Case-control and clinical experimental studies. AB - The aim of the present study was to measure gait velocity in cataract and simulated patients. The study was performed on 239 cataract patients, 115 age matched subjects, and 11 simulated patients. We measured gait velocity and analyzed gait using a three-dimensional motion analysis system. Mean gait velocity before and 2 and 7 months after cataract surgery was 0.91 +/- 0.19, 1.04 +/- 0.21, and 1.06 +/- 0.21 m/s, respectively, for males and 0.84 +/- 0.22, 0.91 +/- 0.24, and 0.92 +/- 0.25 m/s, respectively, for females. The increase after surgery was significant in both groups at 7 months (P < 0.05). Gait velocity was significantly slower in cataract patients compared with controls before surgery, but no longer different after surgery. In simulated patients, mean velocity was 87.0 +/- 11.4% of normal vision with a 3 degrees visual field and 92.4 +/- 12.3% of normal when counting fingers. Initial velocity was 89.1 +/- 14.6% of normal vision with a 3 degrees visual field and 92.7 +/- 11.6% of normal when counting fingers. There was a significant difference between normal and impaired visual function (P < 0.05). The results demonstrate the close relationship between visual function and gait in cataract patients and simulated patients. PMID- 26420729 TI - Cobalt(III)-Catalyzed C-H/N-O Functionalizations: Isohypsic Access to Isoquinolines. AB - C-H/N-O functionalizations by cobalt(III) catalysis allowed the expedient synthesis of a broad range of isoquinolines. Thus, internal and challenging terminal alkynes proved to be viable substrates for an isohypsic annulation, which was shown to proceed by a facile C-H cobaltation. PMID- 26420728 TI - Impact of ABO blood group on the prognosis of patients undergoing surgery for esophageal cancer. AB - BACKGROUND: ABO blood type is an established prognostic factor in several malignancies, but its role in esophageal cancer (EC) is largely unknown. The aim of this study is to determine whether ABO blood group is associated with survival after esophagectomy for EC. METHODS: A total of 406 patients who underwent surgery for EC were enrolled. The associations of ABO blood group with clinical and pathological variables were assessed using chi-square test. Associations of ABO blood group with the survival were estimated using univariable and multivariable Cox proportional hazards regression models. RESULTS: The ABO blood group proportionally associated with the grade of EC tumor (P = 0.049). The ABO blood group status did not correlate with disease-free survival (DFS) in univariable analysis or multivariable analysis (P > 0.05). And there was no significant relationship between the ABO blood group and overall survival (OS) in univariable analysis or multivariable analysis (P > 0.05). CONCLUSIONS: Our results suggested that no association between ABO blood group and the survival was observed in patients undergoing surgery for EC. PMID- 26420730 TI - An integrated system for optical and electrical detection of single molecules/particles inside a solid-state nanopore. AB - Nanopore techniques have proven to be useful tools for single-molecule detection. The combination of optical detection and ionic current measurements enables a new possibility for the parallel readout of multiple nanopores without complex nanofluidics and embedded electrodes. In this study, we developed a new integrated system for the label-free optical and electrical detection of single molecules based on a metal-coated nanopore. The entire system, containing a dark field microscopy system and an ultralow current detection system with high temporal resolution, was designed and fabricated. An Au-coated nanopore was used to generate the optical signal. Light scattering from a single Au-coated nanopore was measured under a dark-field microscope. A lab-built ultralow current detection system was designed for the correlated optical and electrical readout. This integrated system might provide more direct and detailed information on single analytes inside the nanopore compared with classical ionic current measurements. PMID- 26420731 TI - Shortfalls in basic paediatric asthma education in healthcare professionals. PMID- 26420732 TI - Effectiveness of a 5-year school-based intervention programme to reduce adiposity and improve fitness and lifestyle in Indian children; the SYM-KEM study. AB - DESIGN: Non-randomised non-blinded school-based intervention study. SETTING: Two schools in the cities of Pune and Nasik, India. PARTICIPANTS: The intervention group comprised children attending a Pune school from 7-10 years until 12-15 years of age. Two control groups comprised children of the same age attending a similar school in Nasik, and children in the Pune intervention school but aged 12 15 years at the start of the study. INTERVENTION: A 5-year multi-intervention programme, covering three domains: physical activity, diet and general health, and including increased extracurricular and intracurricular physical activity sessions; daily yoga-based breathing exercises; making physical activity a 'scoring' subject; nutrition education; healthier school meals; removal of fast food hawkers from the school environs; and health and nutrition education for teachers, pupils and families. MAIN OUTCOME MEASURES: Body mass index (BMI), waist circumference, physical fitness according to simple tests of strength, flexibility and endurance; diet; and lifestyle indicators (time watching TV, studying and actively playing). RESULTS: After 5 years the intervention children were fitter than controls in running, long jump, sit-up and push-up tests (p<0.05 for all). They reported spending less time sedentary (watching TV and studying), more time actively playing and eating fruit more often (p<0.05). The intervention did not reduce BMI or the prevalence of overweight/obesity, but waist circumference was lower than in the Pune controls (p=0.004). CONCLUSIONS: It was possible to achieve multiple health-promoting changes in an academically competitive Indian school. These changes resulted in improved physical fitness, but had no impact on the children's BMI or on the prevalence of overweight/obesity. PMID- 26420733 TI - Indocyanine green (ICG) fluorescence-guided laparoscopic adrenalectomy. AB - OBJECTIVE: Laparoscopic adrenalectomy has become the standard of care for many adrenal tumors. However, the success of the operation hinges on identifying the adrenal vein and complete tumor resection. We demonstrate the use of a commercially available near infrared fluorescent imaging system to clearly delineate the vascular anatomy of adrenal neoplasms and enhance the border between tumor and normal tissue. We hypothesize that this will increase the safety of laparoscopic adrenalectomy. MATERIALS AND METHODS: We performed laparoscopic adrenalectomy utilizing indocyanine green (ICG) and a specialized laparoscopic fluorescence imaging system on four consecutive patients undergoing laparoscopic adrenalectomy over a 4-month period. RESULTS: The adrenal arteries and vein were vividly enhanced with ICG fluorescence guidance, and the border between tumor and adjacent tissue was clearly demarcated. The operations were performed safely with minimal blood loss and short operative times. There were no complications. CONCLUSIONS: Adrenal neoplasms can be resected laparoscopically under ICG fluorescence guidance and can be used to clearly identify vascular structures and enhance the borders of the tumor. This technique allows for clear identification of the adrenal vein and has the potential to improve the safety of laparoscopic adrenalectomy. PMID- 26420734 TI - Pathogenenic variant in the COL2A1 gene is associated with Spondyloepiphyseal dysplasia type Stanescu. PMID- 26420735 TI - Calcium supplements do not prevent fractures. PMID- 26420737 TI - Alphabet Soup. PMID- 26420736 TI - Diagnostic Accuracy of 2-Dimensional Computed Tomography for Articular Involvement and Fracture Pattern of Posterior Malleolar Fractures. AB - BACKGROUND: Up to 44% of ankle fractures have involvement of the posterior tibial margin. Fracture size and morphology are important factors to guide treatment of these fragments, but reliability of plain radiography in estimating size is low. The aim of the current study was to evaluate the accuracy of 2-dimensional computed tomography (2DCT) in the assessment of posterior malleolar fractures. Additionally, the diagnostic accuracy of 2DCT and its value in preoperative planning was evaluated. METHODS: Thirty-one patients with 31 ankle fractures including a posterior malleolar fragment were selected. Preoperative CT scans were analyzed by 50 observers from 23 countries. Quantitative 3-dimensional CT (Q3DCT) reconstructions were used as a reference standard. RESULTS: Articular involvement of the posterior fragment was overestimated on 2DCT by factors 1.6, 1.4, and 2.2 for Haraguchi types I, II, and III, respectively. Interobserver agreement on operative management ("to fix, or not to fix?") was substantial (kappa = 0.69) for Haraguchi type I fractures, fair (kappa = 0.23) for type II fractures, and poor (kappa = 0.09) for type III fractures. 2DCT images led to a change in treatment of the posterior malleolus in 23% of all fractures. Surgeons would operatively treat type I fractures in 63%, type II fractures in 67%, and type III fractures in 22%. CONCLUSION: Surgeons overestimated true articular involvement of posterior malleolar fractures on 2DCT scans. 2DCT showed some additional value in estimating the involved articular surface when compared to plain radiographs; however, this seemed not yet sufficient to accurately read the fractures. Analysis of the CT images showed a significant influence on choice of treatment in 23% with a shift toward operative treatment in 12% of cases compared to evaluating plain lateral radiographs alone. LEVEL OF EVIDENCE: Level III, comparative study. PMID- 26420738 TI - The effects of iodine blocking following nuclear accidents on thyroid cancer, hypothyroidism, and benign thyroid nodules: design of a systematic review. AB - BACKGROUND: One of the most efficient radiation protection methods to reduce the risk of adverse health outcomes in case of accidental radioactive iodine release is the administration of potassium iodine (KI). Although KI administration is recommended by WHO's guidelines for iodine prophylaxis following nuclear accidents and is also widely implemented in most national guidelines, the scientific evidence for the guidelines lacks as the guidelines are mostly based on expert opinions and recommendations. Therefore, this study will provide evidence by systematically reviewing the effects of KI administration in case of accidental radioactive iodine release on thyroid cancer, hypothyroidism, and benign nodules. METHODS: We will apply standard systematic review methodology for the identification of eligible studies, data extraction, assessment of risk of biases, heterogeneity, and data synthesis. The electronic database search will be conducted in MEDLINE (via PubMed) and EMBASE, and covers three search blocks with terms related to the health condition, intervention, and occurrence/location. We have no date or language restrictions, but restrictions to humans only. We will include studies comparing the effects of KI administration on thyroid cancer, hypothyroidism, and benign thyroid nodules in a population exposed to radioactive iodine release. The quality of the studies will be graded. If feasible, a meta analysis will be conducted. DISCUSSION: This proposed systematic review will update the existing WHO guideline from 1999. New evidence on the efficacy of KI administration to reduce thyroid cancer, hypothyroidism, and benign thyroid nodules in the event of an accidental release of radioactive iodine to the environment will provide the basis for an update of the WHO guideline for iodine prophylaxis following nuclear accidents. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015024340. PMID- 26420739 TI - Computational models of visual attention. PMID- 26420740 TI - Drainage of the Left Hepatic Vein into the Coronary Sinus, a Rare Intraoperative Finding. AB - In a 76-year-old female undergoing coronary artery bypass surgery, a persistent left hepatic vein was observed. Draining of this vein into the coronary sinus is an extremely rare embryological malformation and this is the first case to be reported as a solitary malformation in absence of other cardiac malformations. PMID- 26420742 TI - Construction and validation of a scale of assessment of self-care behaviours anticipatory to creation of arteriovenous fistula. AB - AIMS AND OBJECTIVES: We developed a scale to assess the self-care behaviours developed by patients with end-stage renal disease to preserve the vascular network prior to construction of arteriovenous fistula. BACKGROUND: The possibility of creation of an arteriovenous fistula depends on the existence of an arterial and venous network in good condition, namely the size and elasticity of the vessels. It is essential to teach the person to develop self-care behaviours for the preservation of the vascular network, regardless of the modality of dialysis selected. DESIGN: Methodological study. METHODS: The scale was developed based on clinical experience and research conducted by the researcher in the area of the vascular access for haemodialysis. The content of the scale was judged by two panels of experts for content validity. The revised version of the scale was administered to a convenience sample of 90 patients with end-stage renal disease. In the statistical analysis, we used the Cronbach's alpha, the Kaiser-Meyer-Olkin and scree plot and the principal component analysis with varimax rotation. RESULTS: A principal component analysis confirmed the univariate structure of the scale (KMO = 0.759, Bartlett's sphericity test approximate chi(2) 142.201, p < 0.000). Cronbach's alpha is 0.831, varying between 0.711-0.879. CONCLUSION: This scale revealed properties that allow its use to assess the patients self-care behaviours regarding the preservation of the vascular network. RELEVANCE TO CLINICAL PRACTICE: This scale can be used to evaluate educational programmes for the development of self-care behaviours in the preservation of vascular network. This scale can identify not only the patients that are able to take care of their vascular network but also the proportion of patients who are not able to do it, that need to be educated. PMID- 26420743 TI - Associations between allelic polymorphism of the BMP Binding Endothelial Regulator and phenotypic variation of cattle. AB - The BMP Binding Endothelial Regulator (BMPER) is an inhibitor of bone morphogenetic proteins (BMPs), which play fundamental roles in adipocyte differentiation, fat development and energy balance. The objectives of this study were to detect polymorphisms of BMPER gene in four indigenous Chinese cattle populations and to investigate their effects on body size traits. Initially, three SNPs, namely G100597A (SNP1), C105331A (SNP2), and G105521A (SNP3) and eight distinct haplotypes were identified. In a total of 12 SNP-SNP combinations, SNP2-SNP3 had a strong linkage in Qinchuan cattle. These four cattle populations belong to intermediate genetic diversity at three SNP loci except Shuxuan cattle population in SNP3. At SNP1, genotype AA was associated with an increased body size. For SNP2, the heterozygous genotype individuals had a greater rump length than those of two other homozygotic genotypes. At SNP3, individuals with GG genotype had smaller rump length and hip width. A total of seven haplotype combinations were detected in Qinchuan cattle population and association analysis results showed individuals with Haplotype combination 4/2 (AAA/CAA) had greater rump length than those with Hap3/1 and Hap3/3 (P < 0.05). These results strongly suggest that bovine BMPER gene may be used as a genetic marker for cattle breeding. PMID- 26420744 TI - Mechanochromic Fibers with Structural Color. AB - Responsive photonic crystals have been widely developed to realize tunable structural colors by manipulating the flow of light. Among them, mechanochromic photonic crystals attract increasing attention due to the easy operation, high safety and broad applications. Recently, mechanochromic photonic crystal fibers were proposed to satisfy the booming wearable smart textile market. In this Concept, the fundamental mechanism, fabrication, and recent progress on mechanochromic photonic crystals, especially in fiber shape, are summarized to represent a new direction in sensing and displaying. PMID- 26420745 TI - Engaging cultural resources to promote mental health in Dutch LSES neighborhoods: study of a community-based participatory media project. AB - Community-based participatory media projects form a promising new strategy for mental health promotion that can help address the mental health-gap identified by the World Health Organization. (2008b) mhGAP, Mental Health Gap Action Programme: Scaling Up Care for Mental, Neurological and Substance Use Disorders. World Health Organization, Geneva. In this article we present an ethnographic study about a participatory media project that was developed to promote mental health in selected Dutch low socio-economic status neighborhoods. Through narrowcastings (group film viewings), participant observation and interviews we mapped the ways in which the media project effected and facilitated the collective sense-making process of the audience with regard to sources of stress impacting mental health and opportunities for action. These determinants of mental health are shaped by cultural dimensions, since the cultural context shapes everyday experiences of stress as well as the resources and skills to manage them. Our analysis shows that the media project engaged cultural resources to challenge stressful social scripts. We conclude that more attention should be paid to cultural narratives in a community to understand how health promotion strategies can support social resilience. PMID- 26420746 TI - Annual report of the Committee on Gynecologic Oncology, the Japan Society of Obstetrics and Gynecology. AB - The Japan Society of Obstetrics and Gynecology collects and analyzes annual data on gynecologic cancers from member institutions. Here we present the Treatment Annual Report for 2007. Data on the prognosis of 3381 patients with cervical cancer, 3681 with endometrial cancer, and 2367 with ovarian cancer for whom treatment was initiated in 2007 were analyzed in the Treatment Annual Report. In the 2007 Treatment Annual Report, stage I accounted for 53.1%, stage II for 24.4%, stage III for 14.2%, and stage IV for 8.3% of all patients with cervical cancer. Stage I accounted for 64.8%, stage II for 8.2%, stage III for 20.2%, and stage IV for 6.9% of all patients with endometrial cancer. Stage I accounted for 41.4%, stage II for 9.9%, stage III for 30.6%, and stage IV for 8.6% of all patients with ovarian cancer. The 5-year overall survival rates for patients with cervical cancer were 91.8% for stage I, 71.5% for stage II, 53.0% for stage III, and 23.7% for stage IV; those for patients with endometrial cancer were 95.3%, 89.8%, 75.6%, and 29.1%, and those for patients with ovarian surface epithelial stromal tumors were 91.5%, 76.1%, 46.9%, and 31.3%, respectively. PMID- 26420747 TI - In situ associations between marine photosynthetic picoeukaryotes and potential parasites - a role for fungi? AB - Photosynthetic picoeukaryotes (PPEs) are important components of the marine picophytoplankton community playing a critical role in CO2 fixation but also as bacterivores, particularly in the oligotrophic gyres. Despite an increased interest in these organisms and an improved understanding of the genetic diversity of this group, we still know little of the environmental factors controlling the abundance of these organisms. Here, we investigated the quantitative importance of eukaryotic parasites in the free-living fraction as well as in associations with PPEs along a transect in the South Atlantic. Using tyramide signal amplification-fluorescence in situ hybridization (TSA-FISH), we provide quantitative evidence of the occurrence of free-living fungi in open ocean marine systems, while the Perkinsozoa and Syndiniales parasites were not abundant in these waters. Using flow cytometric cell sorting of different PPE populations followed by a dual-labelled TSA-FISH approach, we also demonstrate fungal associations, potentially parasitic, occurring with both pico Prymnesiophyceae and pico-Chrysophyceae. These data highlight the necessity for further work investigating the specific role of marine fungi as parasites of phytoplankton to improve understanding of carbon flow in marine ecosystems. PMID- 26420748 TI - Electrocatalytic Dihydrogen Production with a Robust Mesoionic Pyridylcarbene Cobalt Catalyst. AB - A Co(III) complex with a mesoionic pyridylcarbene ligand is presented. This complex is an efficient electrocatalyst for H2 production at very low overpotential and high turnovers when using a (glassy carbon) GC electrode. The corresponding triazole complexes display no catalytic activity whatsoever under identical conditions. The remarkable robustness of the Co-C(carbene) bond towards acids is likely responsible for the high efficiency of this catalyst. The present results thus open new avenues for carbene-based ligands for generating functional models for hydrogenases. PMID- 26420749 TI - Leaving school: a comparison of the worries held by adolescents with and without intellectual disabilities. AB - BACKGROUND: Leaving school is an important time for adolescents, with increasing autonomy and developing adult identities. The present study sought to shed light on the content and emotional impact of worries amongst adolescents with and without intellectual disabilities (IDs) at this time of change. METHODS: Twenty five adolescents with mild to moderate IDs and 27 adolescents without IDs, aged 15 to 18 years, took part in the study. Participants' worries were elicited using a structured interview. The levels of rumination and distress related to their most salient worries were also examined, along with their self-reported levels of anxiety. RESULTS: Content analysis of the interviews identified differences between the worries of the two groups of participants, with the adolescents with IDs expressing more general worries about failure and personal threat. Level of distress about worries was positively correlated with anxiety in both groups. The adolescents with IDs were significantly more anxious than their non-disabled peers. CONCLUSIONS: The differences between the groups' worries may be linked to differences in life experience and expectations. Consideration should be given to the specific worries of adolescents at the stage of leaving school. Doing so may allow solutions for their concerns to be identified, thus easing distress and leading to a less stressful transition. PMID- 26420750 TI - In Silico Modeling for the Prediction of Dose and Pathway-Related Adverse Effects in Humans From In Vitro Repeated-Dose Studies. AB - Long-term repeated-dose toxicity is mainly assessed in animals despite poor concordance of animal data with human toxicity. Nowadays advanced human in vitro systems, eg, metabolically competent HepaRG cells, are used for toxicity screening. Extrapolation of in vitro toxicity to in vivo effects is possible by reverse dosimetry using pharmacokinetic modeling. We assessed long-term repeated dose toxicity of bosentan and valproic acid (VPA) in HepaRG cells under serum free conditions. Upon 28-day exposure, the EC50 values for bosentan and VPA decreased by 21- and 33-fold, respectively. Using EC(10) as lowest threshold of toxicity in vitro, we estimated the oral equivalent doses for both test compounds using a simplified pharmacokinetic model for the extrapolation of in vitro toxicity to in vivo effect. The model predicts that bosentan is safe at the considered dose under the assumed conditions upon 4 weeks exposure. For VPA, hepatotoxicity is predicted for 4% and 47% of the virtual population at the maximum recommended daily dose after 3 and 4 weeks of exposure, respectively. We also investigated the changes in the central carbon metabolism of HepaRG cells exposed to orally bioavailable concentrations of both drugs. These concentrations are below the 28-day EC(10) and induce significant changes especially in glucose metabolism and urea production. These metabolic changes may have a pronounced impact in susceptible patients such as those with compromised liver function and urea cycle deficiency leading to idiosyncratic toxicity. We show that the combination of modeling based on in vitro repeated-dose data and metabolic changes allows the prediction of human relevant in vivo toxicity with mechanistic insights. PMID- 26420752 TI - What positive encounters with healthcare and social insurance staff promotes ability to return to work of long-term sickness absentees? AB - AIMS: Previous studies suggest that positive encounters with healthcare and social insurance staff may be important in promoting return to work among long term sickness absentees. This study aimed to identify more specifically what positive encounters are important for promoting ability to return to work. METHODS: A questionnaire about different types of encounters was sent to 10,042 people in Sweden on sick leave for 6-8 months (58% responded). For each positive encounter, we estimated the marginal probability difference (PD) of return to work, adjusting for age, sex, education, sick-leave diagnosis, and the sum score of all other encounters. Adjusting for the other encounters is important since of the observed variables these were the strongest confounders. RESULTS: The positive encounters with both healthcare and social insurance staff significantly associated with promoting ability to return to work after adjusting for the other positive encounters were "Believed in my work capacity" PD=16.9 (95% CI: 12.0, 21.9) and 12.0 (6.3, 17.7), respectively; "Supported my suggestions for solutions": 9.5 (3.1, 15.9) and 11.6 (5.7, 17.4); "Was supportive and encouraging": 10.1 (3.6, 16.7) and 7.3 (1.7, 12.8). Additionally, the encounter with healthcare staff most strongly associated with promoting return to work was "Let me take responsibility" 14.8 (7.2, 22.3); and with social security staff: "Showed that she/he liked me" 10.4 (5.4, 15.4). CONCLUSIONS: Healthcare and social security staff being supportive, encouraging, and believing in the sickness absentee's work capacity may be very important for increasing the probability for long-term sickness absentees' ability to return to work. PMID- 26420753 TI - Cochlear involvement in patients with ulcerative colitis. AB - OBJECTIVE: To investigate whether cochlear involvement is an extraintestinal manifestation in patients with ulcerative colitis. METHOD: Forty-four ulcerative colitis patients and 44 age-matched healthy subjects were included in the study. Pure tone and speech audiometry, and distortion product otoacoustic emission tests were performed on all participants. The audiometric test results were compared between groups and their relationship with disease activity was investigated. RESULTS: Pure tone threshold averages were significantly higher in ulcerative colitis patients compared to controls (p 0.05). CONCLUSION: Even though hearing thresholds may be within normal limits, decreased distortion product otoacoustic emission amplitude values indicate a cochlear involvement in ulcerative colitis patients. PMID- 26420754 TI - The Temporal Dynamics of Spoken Word Recognition in Adverse Listening Conditions. AB - This study examined the temporal dynamics of spoken word recognition in noise and background speech. In two visual-world experiments, English participants listened to target words while looking at four pictures on the screen: a target (e.g. candle), an onset competitor (e.g. candy), a rhyme competitor (e.g. sandal), and an unrelated distractor (e.g. lemon). Target words were presented in quiet, mixed with broadband noise, or mixed with background speech. Results showed that lexical competition changes throughout the observation window as a function of what is presented in the background. These findings suggest that, rather than being strictly sequential, stream segregation and lexical competition interact during spoken word recognition. PMID- 26420751 TI - Revealing Behavioral Learning Deficit Phenotypes Subsequent to In Utero Exposure to Benzo(a)pyrene. AB - To characterize behavioral deficits in pre-adolescent offspring exposed in utero to Benzo(a)pyrene [B(a)P], timed-pregnant Long Evans Hooded rats were treated with B(a)P (150, 300, 600, and 1200 ug/kg BW) or peanut oil (vehicle) on E14, 15, 16, and 17. Following birth, during the pre-weaning period, B(a)P metabolites were examined in plasma and whole brain or cerebral cortex from exposed and control offspring. Tissue concentrations of B(a)P metabolites were (1) dose dependent and (2) followed a time-dependence for elimination with ~60% reduction by PND5 in the 1200 ug/kg BW experimental group. Spatial discrimination-reversal learning was utilized to evaluate potential behavioral neurotoxicity in P40-P60 offspring. Late-adolescent offspring exposed in utero to 600 and 1200 ug/kg BW were indistinguishable from their control counterparts for ability to acquire an original discrimination (OD) and reach criterion. However, a dose-dependent effect of in utero B(a)P-exposure was evident upon a discrimination reversal as exposed offspring perseverated on the previously correct response. This newly characterized behavioral deficit phenotype for the first reversal was not apparent in either the (1) OD or (2) subsequent reversal sessions relative to the respective control offspring. Furthermore, the expression of activity related cytoskeletal-associated protein (Arc), an experience-dependent cortical protein marker known to be up-regulated in response to acquisition of a novel behavior, was greater in B(a)P-exposed offspring included in the spatial discrimination cohort versus home cage controls. Collectively, these findings support the hypothesis that in utero exposure to B(a)P during critical windows of development representing peak periods of neurogenesis results in behavioral deficits in later life. PMID- 26420755 TI - Effect of water-soluble carbohydrate content in orchardgrass pasture on grazing time and rumen fermentation in dairy cows. AB - Two experiments were conducted to clarify the effect of water-soluble carbohydrate (WSC) content in orchardgrass pasture on the diurnal distribution of grazing time. Six ruminally cannulated, non-lactating dairy cows were grazed on either of two pastures with different orchardgrass cultivars containing low WSC (LWSC; cultivar: 'Hokkai 28') or high WSC (HWSC; cultivar: 'Harunemidori'). The cows were grazed in morning and evening sessions in experiment 1, whereas the cows were grazed throughout the day in experiment 2. In experiment 1, grazing time of the cows on HWSC was longer than that of the cows on LWSC (P < 0.01). This difference was larger in the morning session than in the evening session (pasture * grazing session: P < 0.05). Effects on herbage intake were similar to those on grazing time. In experiment 2, daily total grazing time was longer for the cows on HWSC than for those on LWSC (P < 0.05). The cows on HWSC spent a longer time grazing than those on LWSC in the morning between 03.00 and 09.00 hours (P < 0.01). The results indicated that prolonged grazing time in the period between dawn and early morning could increase daily herbage intake in cows grazed on pastures of orchardgrass cultivars with high-WSC content. PMID- 26420756 TI - Suppression of the migration and invasion is mediated by triptolide in B16F10 mouse melanoma cells through the NF-kappaB-dependent pathway. AB - Melanoma cancer is one of the major causes of death in humans worldwide. Triptolide is one of the active components of Tripterygium wilfordii Hook F, and has biological activities including induced cell cycle arrest and induction of apoptosis but its antimetastatic effects on murine melanoma cells have not yet been elucidated. Herein, we investigated the effect of triptolide on the inhibition of migration and invasion and possible associated signal pathways in B16F10 murine melanoma cancer cells. Wound healing assay and Matrigel Cell Migration Assay and Invasion System demonstrated that triptolide marked inhibiting the migration and invasion of B16F10 cells. Gelatin zymography assay demonstrated that triptolide significantly inhibited the activities of matrix metalloproteinases-2 (MMP-2). Western blotting showed that triptolide markedly reduced CXCR4, SOS1, GRB2, p-ERK, FAK, p-AKT, Rho A, p-JNK, NF-kappaB, MMP-9, and MMP-2 but increased PI3K and p-p38 and COX2 after compared to the untreated (control) cells. Real time PCR indicated that triptolide inhibited the gene expression of MMP-2, FAK, ROCK-1, and NF-kappaB but did not significantly affect TIMP-1 and -2 gene expression in B16F10 cells in vitro. EMSA assay also showed that triptolide inhibited NF-kappaB DNA binding in a dose-dependent manner. Confocal laser microscopy examination also confirmed that triptolide inhibited the expression of NF-kappaB in B16F10 cells. Taken together, we suggest that triptolide inhibited B16F10 cell migration and invasion via the inhibition of NF kappaB expression then led to suppress MMP-2 and -9 expressions. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1974-1984, 2016. PMID- 26420757 TI - The effect of chloroform, orange oil and eucalyptol on root canal transportation in endodontic retreatment. AB - The purpose of the present study was to assess the effect of solvents on root canal transportation in endodontic retreatment. Sixty extracted human permanent mandibular first molars with curved root canals were selected. All of the root canals were prepared using Twisted File Adaptive instruments (SybronEndo, Orange, CA, USA) and filled with gutta-percha and AH Plus sealer (Dentsply DeTrey, Konstanz, Germany) using the cold lateral compaction technique. The teeth were assigned to four retreatment groups as follows (n = 15): eucalyptol, chloroform, orange oil and control. The canals were scanned using cone-beam computed tomography scanning before and after instrumentation. The chloroform group showed a significantly higher mean transportation value than the orange oil and control groups at the 3 and 5 mm levels (P = 0.011 and P = 0.003, respectively). There was no significant difference among the orange oil, eucalyptol and control groups in terms of canal transportation (P > 0.61). The chloroform led to more canal transportation than the eucalyptol and orange oil during endodontic retreatment. PMID- 26420758 TI - Sex differences in parental care: Gametic investment, sexual selection, and social environment. AB - Male and female parents often provide different type and amount of care to their offspring. Three major drivers have been proposed to explain parental sex roles: (1) differential gametic investment by males and females that precipitates into sex difference in care, (2) different intensity of sexual selection acting on males and females, and (3) biased social environment that facilitates the more common sex to provide more care. Here, we provide the most comprehensive assessment of these hypotheses using detailed parental care data from 792 bird species covering 126 families. We found no evidence for the gametic investment hypothesis: neither gamete sizes nor gamete production by males relative to females was related to sex difference in parental care. However, sexual selection correlated with parental sex roles, because the male share in care relative to female decreased with both extra-pair paternity and frequency of male polygamy. Parental sex roles were also related to social environment, because male parental care increased with male-biased adult sex ratios (ASRs). Taken together, our results are consistent with recent theories suggesting that gametic investment is not tied to parental sex roles, and highlight the importance of both sexual selection and ASR in influencing parental sex roles. PMID- 26420759 TI - Multiwavelength excitation of photosensitizers interacting with gold nanoparticles and its impact on optical properties of their hybrid mixtures. AB - In a hybrid mixture of organic (dye) and inorganic (metallic nanoparticles) components, the optical properties of a dye can be easily controlled by tailoring the shape or the concentration of the noble metal nanoparticles (NPs). The influences of multiexcitation (multiwavelength excitation) of photosensitizers (pheophorbide a and hematoporphyrin) on the interactions with pegylated Au-NPs and on the photophysical parameters of the dyes are studied. Detailed, systematic fluorescence quenching studies were performed in the mixtures of different contents of Au-NPs, and interpreted together with the results of quantum singlet oxygen yield examinations. According to the results, the fluorescence of the two dyes studied was effectively quenched in the presence of Au-NPs, mainly because of the resonance energy transfer between the donor (dye) and the acceptor (Au NPs). Stern-Volmer quenching constants were determined by a few orders of magnitude higher than those describing the photochemical quenching process. In hybrid mixtures analyzed, the mechanism of energy transfer between the donor and the acceptor was nanometal surface energy transfer. Furthermore, different behavior of the mixtures on excitation with the wavelengths from the Soret and Q bands of the dyes and with those corresponding to the surface plasmon resonance band of Au-NPs was analyzed. Moreover, for certain concentrations of Au-NPs and for certain excitation wavelengths, an increase in singlet oxygen generation was observed. The results obtained indicate the significance of further studies of photosensitizers in hybrid mixtures with NPs. PMID- 26420760 TI - Spatz 3 Adjustable Intragastric Balloon: Long-Term Safety Concerns. PMID- 26420761 TI - The Effect of Intraoperative N-Acetylcysteine on Hepatocellular Injury During Laparoscopic Bariatric Surgery. A Randomised Controlled Trial. AB - BACKGROUND: The combination of pneumoperitoneum and intraoperative retraction of the left lobe of the liver leads to hepatocellular injury during laparoscopic gastric surgery. Fatty livers are more susceptible to ischaemic insults. This trial investigated whether the antioxidant N-acetylcysteine (NAC) reduced liver injury during laparoscopic sleeve gastrectomy (LSG). METHODS: Patients undergoing LSG were randomised (single blinded) to receive intraoperative NAC infusion or standard anaesthetic treatment. Blood samples were taken before and after surgery (days 0 to 4). Primary endpoints included serum aminotransferases. Secondary measures were C-reactive protein, weight cell count (WCC), cytokines (interleukin 6 and 10) and cytokeratin-18 as markers of apoptosis. Intraoperative liver biopsy samples were assessed using a locally developed injury score. RESULTS: Twenty patients (14 females, mean age 44.5 (SEM +/- 2.9) years, mean BMI 60.8 (SEM +/- 2.4) kg/m(2)) were recruited (NAC n = 10, control n = 10). The trial was stopped early after a planned interim analysis. Baseline liver function was similar. The peak rise in liver enzymes was on day 1, but levels were not significantly different between the groups. Rates of complications and length of stay were not significantly different. Secondary outcome measures, including white cell count (WCC), cytokines and cytokeratin (CK)-18 fragments, were not different between groups. Liver injury scores did not differ significantly. CONCLUSIONS: NAC did not reduce intraoperative liver injury in this small number of patients. The heterogenous nature of the study population, with differences in co-morbidities, body mass index and intraabdominal anatomy, leads to a varied post-operative inflammatory response. Significant hepatocyte injury occurs through both necrosis and apoptosis. PMID- 26420762 TI - Letter to "Predictive Factors of Type 2 Diabetes Mellitus Remission Following Bariatric Surgery: a Meta-analysis". PMID- 26420763 TI - Chronic Non-specific Pain After Gastric Bypass. PMID- 26420764 TI - Metabolic Surgery Could Restore Hepatic Glucose Metabolism: Results from F-18 Fluorodeoxyglucose Positron Emission Tomography. PMID- 26420765 TI - Outcomes of Bariatric Surgery in Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Obesity has become prevalent in patients with inflammatory bowel disease (IBD). Bariatric surgery can be considered to be contraindicated in IBD patients. We aimed to evaluate feasibility, safety, and efficacy of bariatric surgery in IBD patients. METHODS: We retrospectively identified all morbidly obese patients with a known diagnosis of IBD, who underwent bariatric surgery between January 2005 and December 2012. Postoperative outcomes and status of IBD in patients on maintenance therapy for their disease were assessed. RESULTS: We identified 20 IBD patients including 13 ulcerative colitis (UC) and 7 Crohn's disease (CD) patients with a mean age of 54.0 +/- 10.5 years, BMI of 50.1 +/- 9.0 kg/m(2), and duration of IBD of 11.3 +/- 5.2 years. Eleven patients were on medication for IBD at baseline. Bariatric procedures included sleeve gastrectomy (N = 9), gastric bypass (N = 7), gastric banding (N = 3), and one conversion of band to gastric bypass. There were no intraoperative complications, but two conversions to laparotomy due to adhesions. Mean BMI change and excess weight loss at 1 year was 14.3 +/- 5.7 kg/m(2) and 58.9 +/- 21.1 %, respectively. Seven early postoperative complications occurred including dehydration (N = 5), pulmonary embolism (N = 1), and wound infection (N = 1). During a mean follow-up of 34.6 +/- 21.7 months, five patients developed complications including pancreatitis (N = 2), ventral hernia (N = 2), and marginal ulcer (N = 1). Nine out of ten eligible patients experienced improvement in their IBD status. CONCLUSIONS: Bariatric surgery is feasible and safe in morbidly obese patients suffering from IBD. In addition to being an effective weight loss procedure, bariatric surgery may help mitigate symptoms in this patient population. PMID- 26420766 TI - Pseudorhodoplanes sinuspersici gen. nov., sp. nov., isolated from oil contaminated soil. AB - Strain RIPI 110T was isolated from a soil sample collected from an oil contaminated site on Siri Island, Persian Gulf, Iran. Cells of the novel isolate were Gram-stain-negative, facultatively anaerobic, non-motile and rod-shaped. Cells divided asymmetrically by budding and formed rosette-like clusters. The optimum pH and temperature for growth were pH 7 and 30 degrees C, while the strain was able to grow at pH 5.5-8 and 15-35 degrees C. Strain RIPI 110T utilized only complex carbon sources and pyruvate as the sole carbon source and could not grow under photoautotrophic conditions. The highest 16S rRNA gene sequence similarities, 93.9, 93.9 and 93.5 %, were obtained with Variibacter gotjawalensis GJW-30T, Rhodoplanes roseus 941T and Rhodoplanes elegans AS130T, respectively. The major cellular fatty acids were summed feature 8 (C18 : 1omega7c/omega6c), C16 : 0 and C19 : 0 cyclo omega8c. Polar lipid analyses revealed that strain RIPI 110T contained phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, an unknown aminophospholipid and four unknown phospholipids. Ubiquinone-10 was the predominant quinone component. The DNA G+C content was 59.4 mol%. On the basis of the 16S rRNA gene sequence analysis, in combination with chemotaxonomic and physiological data, the novel isolate could not be classified in any recognized genera. Strain RIPI 110T is thus considered to represent a novel species of a new genus within the order Rhizobiales, for which the name Pseudorhodoplanes sinuspersici gen. nov., sp. nov. is proposed. The type strain of the type species is RIPI 110T ( = IBRC-M 10770T = CECT 8374T). PMID- 26420767 TI - The importance of tissue handling of surgically removed breast cancer for an accurate assessment of the Ki-67 index. AB - AIM: Insufficient attention for the Ki-67 immunohistochemistry has been given to the importance of tissue handling for surgical breast cancer specimens. We sought to investigate the effect of fixation status on the Ki-67. METHODS: We examined the effect of fixative, time to and duration of fixation using surgical specimens, and finally, compared the paired Ki-67 index in the tumour between core needle and surgical specimen. RESULTS: The Ki-67 was significantly higher when 10% neutral buffered formalin was used (p=0.0276). Insufficient fixation caused a drastic reduction in the Ki-67 index (p=0.0177), but not significant in oestrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). Sixteen hours delayed time to fixation also caused a reduction of the Ki-67 (p=0.0284), but not significant in ER. Prolonged fixation significantly led to a gradual reduction in the Ki-67 in a time-dependent manner, but not in both ER and HER2. Finally, cutting the tumour before fixation improved fixation status and consequently caused an increased level of the Ki-67 index (p=0.0181), which resulted in a strong correlation of the Ki-67 between core needle and surgical specimen (r=0.8595). CONCLUSIONS: Tissue handling of surgical specimen is critical for assessing the Ki-67 compared with ER and HER2. We should pay more attention to tissue fixation status for the standard assessment of the Ki-67 index. PMID- 26420769 TI - Preference pulses and the win-stay, fix-and-sample model of choice. AB - Two groups of six rats each were trained to respond to two levers for a food reinforcer. One group was trained on concurrent variable-ratio 20 extinction schedules of reinforcement. The second group was trained on a concurrent variable interval 27-s extinction schedule. In both groups, lever-schedule assignments changed randomly following reinforcement; a light cued the lever providing the next reinforcer. In the next condition, the light cue was removed and reinforcer assignment strictly alternated between levers. The next two conditions redetermined, in order, the first two conditions. Preference pulses, defined as a tendency for relative response rate to decline to the just-reinforced alternative with time since reinforcement, only appeared during the extinction schedule. Although the pulse's functional form was well described by a reinforcer-induction equation, there was a large residual between actual data and a pulse-as-artifact simulation (McLean, Grace, Pitts, & Hughes, 2014) used to discern reinforcer dependent contributions to pulsing. However, if that simulation was modified to include a win-stay tendency (a propensity to stay on the just-reinforced alternative), the residual was greatly reduced. Additional modifications of the parameter values of the pulse-as-artifact simulation enabled it to accommodate the present results as well as those it originally accommodated. In its revised form, this simulation was used to create a model that describes response runs to the preferred alternative as terminating probabilistically, and runs to the unpreferred alternative as punctate with occasional perseverative response runs. After reinforcement, choices are modeled as returning briefly to the lever location that had been just reinforced. This win-stay propensity is hypothesized as due to reinforcer induction. PMID- 26420768 TI - Impact of the AYA HOPE Comorbidity Index on Assessing Health Care Service Needs and Health Status among Adolescents and Young Adults with Cancer. AB - BACKGROUND: Existing comorbidity indices were not developed for adolescent and young adults (AYA) 15 to 39 years of age. The aim of this study was to assess impact of comorbidities on health care service needs and health status among AYA cancer survivors using the newly developed AYA HOPE comorbidity index in comparison with the existing indices. METHODS: Data on comorbid conditions were obtained from medical records and service needs and health status were from a survey of AYA cancer survivors. Prevalence of comorbidities was based on the AYA HOPE index. Charlson and NCI indices were compared. Multivariable logistic regression was used. RESULTS: Of the 485 patients, 14.6% had >=2 comorbidities based on the AYA HOPE Index. Prevalence of mental illness and obesity/overweight, which were not included in existing indices, were 8.2% and 5.8%, respectively. Prevalence of cardiovascular, endocrine, gastrointestinal, and neurologic conditions were higher with the AYA HOPE Index than the other two indices. Forty percent of AYA patients reported service needs, particularly for mental health services (25.2%) and support groups (17.7%). Having >=2 comorbidities on the AYA index was associated with higher mental health service needs [OR, 2.05; 95% confidence interval (CI), 1.10-3.82] adjusting for demographic and clinical factors. Comorbidities were associated with fair/poor self-reported health status. CONCLUSION: The AYA HOPE Index is a more comprehensive comorbidity index for AYA cancer patients than existing indices, and the number of comorbidities is associated with service needs and health status. IMPACT: The AYA HOPE index could identify patients' additional service needs early in therapy. PMID- 26420770 TI - Effectiveness of individualised intervention on older residents with constipation in nursing home: a randomised controlled trial. AB - AIMS AND OBJECTIVES: To develop and examine the effectiveness of individualised intervention to reduce constipation among older adults in nursing homes. BACKGROUND: In long-term care facilities, approximately 60-80% of the residents have symptoms of constipation. Constipation may lead to haemorrhoids, faecal impaction, ulcers, intestinal bleeding and can also lead to a decrease in quality of life. Although a high prevalence of constipation in older adults can be seen, there is a lack of empirical evidence for delivering interventions based on individual risk factors of constipation. Many factors cause constipation but the risk factors are different for each individual. DESIGN: A prospective, randomised control trial conducted in northern Taiwan. METHODS: Nursing home residents (n = 43) were randomly assigned to either the control group or the experimental group. The control group received no extra care from the researcher while the experimental group received an individualised intervention and an eight-week follow-up. Participants were assessed using the Bristol Stool Form Scale, the Patient Assessment of Constipation Symptoms, types and dosages of laxative, and bowel sound observations. Data were taken at baseline, four weeks as well as eight weeks after the intervention. RESULTS: The participants in the experimental group had a significantly higher increase in the frequency of defecation (group effect, p = 0.029) and in bowel sounds (interaction effect, p = 0.010) compared to those in the control group. However, the two groups did not differ significantly in symptoms and the severity of the constipation symptoms, Bristol Stool Form and use of laxatives. CONCLUSIONS: The results of this trial suggest that the individualised intervention may be appropriate for decreasing constipation among nursing home residents and encourage further study and confirmation. RELEVANCE TO CLINICAL PRACTICE: Using individualised intervention to enhance the self-care ability related to constipation among older adults is recommended. PMID- 26420771 TI - Recording casualties of war. PMID- 26420772 TI - Occurrence and severity of enamel decalcification adjacent to bracket bases and sub-bracket lesions during orthodontic treatment with two different lingual appliances. AB - BACKGROUND: Using lingual enamel surfaces for bracket placement not only has esthetic advantages, but may also be suitable in terms of reducing frequencies of enamel decalcifications. OBJECTIVE: To test the null-hypothesis that there is no significant difference in enamel decalcification or cavitation incidence adjacent to and beneath bracket bases between two lingual multi-bracket (MB) appliances that are different in terms of design, material composition, and manufacturing technology (group A: WIN, DW-LingualSystems; group B: Incognito, 3M-Unitek), taking into account patient- and treatment-related variables on white spot lesion (WSL) formation. METHODS: Standardized, digital, top-view photographs of 630 consecutive subjects (16214 teeth; n Incognito = 237/6076 teeth; n WIN = 393/10138 teeth; mean age: 17.47+/-7.8; m/f 43.2/56.8%) with completed lingual MB treatment of the upper and lower permanent teeth 1-7 were screened for decalcification or cavitation adjacent to and beneath the bracket bases before and after treatment, scored from 0 to 7. Non-parametric ANOVA was used for main effects 'appliance type', 'gender', 'treatment complexity', 'grouped age' (<=16/>16 years), and 'treatment duration' as covariable, at an alpha-level of 5%. RESULTS: About 2.57% [5.94%] of all teeth in group A [B] developed decalcifications. Subject-related incidence was 9.59% [16.17%] for upper incisors in group A [B], and 12.98% [25.74%] for all teeth 16-46. There were significant effects by gender, age, and treatment duration. CONCLUSION: The null-hypothesis was rejected: sub-bracket lesions were significantly less frequent in group A, while frequencies of WSL adjacent to brackets were not significantly affected by appliance type. In view of the overall low incidences of lingual post-orthodontic white-spot lesions, the use of lingual appliances is advocated as a valid strategy for a reduction of enamel decalcifications during orthodontic treatment. PMID- 26420773 TI - Brachioplasty: A Personal Approach. AB - Brachioplasty has become one of the most rapidly growing operations in plastic surgery. There are a variety of arm presentations, due to either weight loss or other reasons, and the extent of the defect can carry into the lateral chest wall and the back. In this featured operative technique article, the author describes indications, patient selection, and criteria for classifying brachioplasty, and illustrates the surgical techniques of this procedure. Markings, scar positioning, and the various operative steps are described along with the intricacies of postoperative care, including scar control. A personal experience, along with the limitations of brachioplasty, are discussed. PMID- 26420774 TI - Challenging Breast Augmentations: The Influence of Preoperative Anatomical Features on the Final Result. AB - BACKGROUND: Achieving satisfactory results may be difficult in augmentation mammaplasty patients in the presence of breast, chest wall, or vertebral deformities. These deformities have not been classified previously, and the impact of each deformity or combination of deformities has not been defined. OBJECTIVES: The aims of this study are to determine the complicating factors in augmentation mammaplasty, to classify these factors according to their influence on surgical outcome, and to develop an identification system for simplifying the recognition of challenging cases. METHODS: We retrospectively analyzed photographs and records of 100 consecutive patients who underwent augmentation mammaplasty. We observed suboptimal results in 18 cases. Preoperative deformities of the breast, chest wall, and vertebra were recorded in order to determine which factor or factors had complicated the surgeries. Eventually, the relationship between suboptimal surgical results and complicating factors was evaluated. RESULTS: We observed that some deformities alone caused suboptimal results, whereas others did not. Deformities that caused suboptimal results alone were called major complicating factors, and any others were called minor complicating factors. We observed that suboptimal results were also obtained in patients who had four minor complicating factors. Patients who had suboptimal results because of major or minor complicating factors were considered challenging cases. CONCLUSIONS: In this study, complicating factors for augmentation mammaplasty were defined and classified as major or minor depending on their effect on the surgical outcome. We suggest an identification system that simplifies the recognition of challenging cases in breast augmentation. PMID- 26420775 TI - A Personal Computer Freeware as a Tool for Surgeons to Plan Liver Resections. AB - BACKGROUND AND AIMS: The increase in liver surgery and the proportion of resections done on the margin to postoperative liver failure make preoperative calculations regarding liver volume important. Earlier studies have shown good correlation between calculations done with ImageJ and specimen weight as well as volume calculations done with more robust systems. The correlation to actual volumes of resected liver tissue has not been investigated, and this was the aim of this study. MATERIAL AND METHODS: A total of 30 patients undergoing well defined liver resections were included in this study. Volumes calculated with ImageJ were compared to volume measurements done after the retrieval of resected liver tissue. RESULTS AND CONCLUSIONS: A strong correlation between calculated and measured liver volume was found with sample concordance correlation coefficient (rhoc) = 0.9950. The knowledge on the nature of liver resections sets liver surgeons in a unique position to be able to accurately predict the volumes to be resected and, therefore, also the volume that will remain after surgery. This becomes increasingly important with the evolvement of methods to extend the boundaries of liver surgery. ImageJ is a reliable tool to preoperatively assess liver volume. PMID- 26420776 TI - Use of inhaled corticosteroids for the prevention and/or treatment of bronchopulmonary dysplasia in preterm infants: a systematic review protocol. AB - BACKGROUND: Inhaled steroids have been studied for both prevention and treatment of bronchopulmonary dysplasia (BPD). Results have been inconsistent. Recently, a large randomized controlled trial (RCT) has been reported. METHODS/DESIGN: We will perform a comprehensive systematic literature search for randomized and quasi-randomized controlled trials that studied the efficacy and safety of inhaled corticosteroids administered to preterm infants (22-36 weeks) for either the prevention or treatment of BPD diagnosed by both clinical and physiological outcome criteria. We will assess potential risk of bias for each RCT meeting our selection criteria using the Cochrane risk of bias tool for RCTs. The primary outcome of interest will be mortality or BPD or both at 28 days postnatal age or 36 weeks postmenstrual age. Pooled estimates will be calculated using RevMan software with a random effects model as primary analysis. We will assess the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. DISCUSSION: Meta-analytic estimates of eligible RCTs, potentially including a new large RCT, may significantly influence neonatal practice in the prevention and treatment of respiratory problems in preterm infants. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015019628. PMID- 26420777 TI - Current Usage of Traditional Chinese Medicine in the Management of Breast Cancer: A Practitioner's Perspective. AB - Introduction This qualitative study seeks to explore the role within the context of Australian breast cancer oncology treatments that traditional Chinese medicine (TCM) practitioners play in the treatment of breast cancer. Methods Semistructured interviews were used on 2 groups: the first group was TCM practitioners who were recognized experts in breast cancer, and the second group consisted of TCM practitioners who treated breast cancer as part of their practice but were not recognized experts. Data analysis was achieved through grounded theory with open coding. Results The main themes reported on here are the following: the role of TCM in the biomedical management of breast cancer, TCM strategies for the management of breast cancer, and the perceived holistic approach of the TCM practitioner and the importance of a TCM diagnosis in the role of breast cancer care. Discussion The role of TCM in biomedical breast cancer management is a supportive one; however, this role is difficult as there is a lack of understanding of TCM by biomedical practitioners. The viewpoints of practitioners differed on key strategies of TCM: diagnosis, and treatment protocols. Patients sought the holistic approach of TCM practitioners as they felt it addressed all aspects of their health and not just the symptoms relating to breast cancer. Conclusion The lack of an integrated medicine approach in relation to TCM makes it difficult to demonstrate the value of the contribution TCM can make to biomedicine in the field of breast care oncology. Effectiveness studies are needed that can accurately represent TCM in this field. PMID- 26420778 TI - The Effectiveness of Group Intervention on Enhancing Cognitive Emotion Regulation Strategies in Breast Cancer Patients: A 2-Year Follow-up. AB - Purpose To evaluate the long-term effect of group intervention on enhancing cognitive emotion regulation (CER) strategies in female patients with early-stage breast cancer. Methods The sample included 174 patients who were diagnosed with early-to-mid stage breast cancer, completed adjuvant therapy, and agreed to fill out demographic and cognitive emotion regulation questionnaires (CERQ). About half of the patients (86, 49.4%) chose to participate in an 8-session group intervention (intervention group) while the others (88, 50.6%) did not (comparison group). The structured intervention for enhancing coping strategies with special emphasis on emotion regulation was conducted at the oncology unit at Rabin Medical Center by 2 experienced therapists. Preliminary effects on CER evaluated 6, 12, and 24 months postintervention were compared to the CER of a group of patients that opted not to participate in the group intervention. Results In the intervention group, the long-term effect (from baseline to 24 months) was assessed using the mix models module. Significant interaction effects were found for both the Negative CER scales (F(3, 268 ,404) = 3.66, P = .01) and for the Positive CER scales (F(3, 271 ,660) = 5.12, P = .002). No statistically significant differences in socio-demographic characteristics and medical variables were observed between the intervention and comparison groups. Conclusion Our findings indicate that a group intervention aimed at empowerment of coping strategies had positive long-term outcomes that reinforce adaptive coping strategies and improve less effective strategies of cognitive emotion regulation. PMID- 26420779 TI - Bayesian multi-scale modeling for aggregated disease mapping data. AB - In disease mapping, a scale effect due to an aggregation of data from a finer resolution level to a coarser level is a common phenomenon. This article addresses this issue using a hierarchical Bayesian modeling framework. We propose four different multiscale models. The first two models use a shared random effect that the finer level inherits from the coarser level. The third model assumes two independent convolution models at the finer and coarser levels. The fourth model applies a convolution model at the finer level, but the relative risk at the coarser level is obtained by aggregating the estimates at the finer level. We compare the models using the deviance information criterion (DIC) and Watanabe Akaike information criterion (WAIC) that are applied to real and simulated data. The results indicate that the models with shared random effects outperform the other models on a range of criteria. PMID- 26420780 TI - The digital revolution in phenotyping. AB - Phenotypes have gained increased notoriety in the clinical and biological domain owing to their application in numerous areas such as the discovery of disease genes and drug targets, phylogenetics and pharmacogenomics. Phenotypes, defined as observable characteristics of organisms, can be seen as one of the bridges that lead to a translation of experimental findings into clinical applications and thereby support 'bench to bedside' efforts. However, to build this translational bridge, a common and universal understanding of phenotypes is required that goes beyond domain-specific definitions. To achieve this ambitious goal, a digital revolution is ongoing that enables the encoding of data in computer-readable formats and the data storage in specialized repositories, ready for integration, enabling translational research. While phenome research is an ongoing endeavor, the true potential hidden in the currently available data still needs to be unlocked, offering exciting opportunities for the forthcoming years. Here, we provide insights into the state-of-the-art in digital phenotyping, by means of representing, acquiring and analyzing phenotype data. In addition, we provide visions of this field for future research work that could enable better applications of phenotype data. PMID- 26420782 TI - Anisotropy of Human Horizontal and Vertical Navigation in Real Space: Behavioral and PET Correlates. AB - Spatial orientation was tested during a horizontal and vertical real navigation task in humans. Video tracking of eye movements was used to analyse the behavioral strategy and combined with simultaneous measurements of brain activation and metabolism ([18F]-FDG-PET). Spatial navigation performance was significantly better during horizontal navigation. Horizontal navigation was predominantly visually and landmark-guided. PET measurements indicated that glucose metabolism increased in the right hippocampus, bilateral retrosplenial cortex, and pontine tegmentum during horizontal navigation. In contrast, vertical navigation was less reliant on visual and landmark information. In PET, vertical navigation activated the bilateral hippocampus and insula. Direct comparison revealed a relative activation in the pontine tegmentum and visual cortical areas during horizontal navigation and in the flocculus, insula, and anterior cingulate cortex during vertical navigation. In conclusion, these data indicate a functional anisotropy of human 3D-navigation in favor of the horizontal plane. There are common brain areas for both forms of navigation (hippocampus) as well as unique areas such as the retrosplenial cortex, visual cortex (horizontal navigation), flocculus, and vestibular multisensory cortex (vertical navigation). Visually guided landmark recognition seems to be more important for horizontal navigation, while distance estimation based on vestibular input might be more relevant for vertical navigation. PMID- 26420781 TI - Recent Advances and Emerging Applications in Text and Data Mining for Biomedical Discovery. AB - Precision medicine will revolutionize the way we treat and prevent disease. A major barrier to the implementation of precision medicine that clinicians and translational scientists face is understanding the underlying mechanisms of disease. We are starting to address this challenge through automatic approaches for information extraction, representation and analysis. Recent advances in text and data mining have been applied to a broad spectrum of key biomedical questions in genomics, pharmacogenomics and other fields. We present an overview of the fundamental methods for text and data mining, as well as recent advances and emerging applications toward precision medicine. PMID- 26420783 TI - Basal Ganglia Activity Mirrors a Benefit of Action and Reward on Long-Lasting Event Memory. AB - The expectation of reward is known to enhance a consolidation of long-term memory for events. We tested whether this effect is driven by positive valence or action requirements tied to expected reward. Using a functional magnetic resonance imaging (fMRI) paradigm in young adults, novel images predicted gain or loss outcomes, which in turn were either obtained or avoided by action or inaction. After 24 h, memory for these images reflected a benefit of action as well as a congruence of action requirements and valence, namely, action for reward and inaction for avoidance. fMRI responses in the hippocampus, a region known to be critical for long-term memory function, reflected the anticipation of inaction. In contrast, activity in the putamen mirrored the congruence of action requirement and valence, whereas other basal ganglia regions mirrored overall action benefits on long-lasting memory. The findings indicate a novel type of functional division between the hippocampus and the basal ganglia in the motivational regulation of long-term memory consolidation, which favors remembering events that are worth acting for. PMID- 26420784 TI - Characterizing VIP Neurons in the Barrel Cortex of VIPcre/tdTomato Mice Reveals Layer-Specific Differences. AB - Neocortical GABAergic interneurons have a profound impact on cortical circuitry and its information processing capacity. Distinct subgroups of inhibitory interneurons can be distinguished by molecular markers, such as parvalbumin, somatostatin, and vasoactive intestinal polypeptide (VIP). Among these, VIP expressing interneurons sparked a substantial interest since these neurons seem to operate disinhibitory circuit motifs found in all major neocortical areas. Several of these recent studies used transgenic Vip-ires-cre mice to specifically target the population of VIP-expressing interneurons. This makes it necessary to elucidate in detail the sensitivity and specificity of Cre expression for VIP neurons in these animals. Thus, we quantitatively compared endogenous tdTomato with Vip fluorescence in situ hybridization and alphaVIP immunohistochemistry in the barrel cortex of VIPcre/tdTomato mice in a layer-specific manner. We show that VIPcre/tdTomato mice are highly sensitive and specific for the entire population of VIP-expressing neurons. In the barrel cortex, approximately 13% of all GABAergic neurons are VIP expressing. Most VIP neurons are found in layer II/III (~60%), whereas approximately 40% are found in the other layers of the barrel cortex. Layer II/III VIP neurons are significantly different from VIP neurons in layers IV-VI in several morphological and membrane properties, which suggest layer-dependent differences in functionality. PMID- 26420785 TI - Procedural Factors That Affect Psychophysical Measures of Spatial Selectivity in Cochlear Implant Users. AB - Behavioral measures of spatial selectivity in cochlear implants are important both for guiding the programing of individual users' implants and for the evaluation of different stimulation methods. However, the methods used are subject to a number of confounding factors that can contaminate estimates of spatial selectivity. These factors include off-site listening, charge interactions between masker and probe pulses in interleaved masking paradigms, and confusion effects in forward masking. We review the effects of these confounds and discuss methods for minimizing them. We describe one such method in which the level of a 125-pps masker is adjusted so as to mask a 125-pps probe, and where the masker and probe pulses are temporally interleaved. Five experiments describe the method and evaluate the potential roles of the different potential confounding factors. No evidence was obtained for off-site listening of the type observed in acoustic hearing. The choice of the masking paradigm was shown to alter the measured spatial selectivity. For short gaps between masker and probe pulses, both facilitation and refractory mechanisms had an effect on masking; this finding should inform the choice of stimulation rate in interleaved masking experiments. No evidence for confusion effects in forward masking was revealed. It is concluded that the proposed method avoids many potential confounds but that the choice of method should depend on the research question under investigation. PMID- 26420786 TI - Prevalence and compensation of academic leaders, professors, and trustees on publicly traded US healthcare company boards of directors: cross sectional study. AB - OBJECTIVE: To identify the prevalence, characteristics, and compensation of members of the boards of directors of healthcare industry companies who hold academic appointments as leaders, professors, or trustees. DESIGN: Cross sectional study. SETTING: US healthcare companies publicly traded on the NASDAQ or New York Stock Exchange in 2013. PARTICIPANTS: 3434 directors of pharmaceutical, biotechnology, medical equipment and supply, and healthcare provider companies. MAIN OUTCOME MEASURES: Prevalence, annual compensation, and beneficial stock ownership of directors with affiliations as leaders, professors, or trustees of academic medical and research institutions. RESULTS: 446 healthcare companies met the study search criteria, of which 442 (99%) had publicly accessible disclosures on boards of directors. 180 companies (41%) had one or more academically affiliated directors. Directors were affiliated with 85 geographically diverse non-profit academic institutions, including 19 of the top 20 National Institute of Health funded medical schools and all of the 17 US News honor roll hospitals. Overall, these 279 academically affiliated directors included 73 leaders, 121 professors, and 85 trustees. Leaders included 17 chief executive officers and 11 vice presidents or executive officers of health systems and hospitals; 15 university presidents, provosts, and chancellors; and eight medical school deans or presidents. The total annual compensation to academically affiliated directors for their services to companies was $54,995,786 (L35,836,000; ?49,185,900) (median individual compensation $193,000) and directors beneficially owned 59,831,477 shares of company stock (median 50,699 shares). CONCLUSIONS: A substantial number and diversity of academic leaders, professors, and trustees hold directorships at US healthcare companies, with compensation often approaching or surpassing common academic clinical salaries. Dual obligations to for profit company shareholders and non-profit clinical and educational institutions pose considerable personal, financial, and institutional conflicts of interest beyond that of simple consulting relationships. These conflicts have not been fully addressed by professional societies or academic institutions and deserve additional review, regulation, and, in some cases, prohibition when conflicts cannot be reconciled. PMID- 26420787 TI - Coupling Laser Diode Thermal Desorption with Acoustic Sample Deposition to Improve Throughput of Mass Spectrometry-Based Screening. AB - The move toward label-free screening in drug discovery has increased the demand for mass spectrometry (MS)-based analysis. Here we investigated the approach of coupling acoustic sample deposition (ASD) with laser diode thermal desorption (LDTD)-tandem mass spectrometry (MS/MS). We assessed its use in a cytochrome P450 (CYP) inhibition assay, where a decrease in metabolite formation signifies CYP inhibition. Metabolite levels for 3 CYP isoforms were measured as CYP3A4-1'-OH midazolam, CYP2D6-dextrorphan, and CYP2C9-4'-OH-diclofenac. After incubation, samples (100 nL) were acoustically deposited onto a stainless steel 384-LazWell plate, then desorbed by an infrared laser directly from the plate surface into the gas phase, ionized by atmospheric pressure chemical ionization (APCI), and analyzed by MS/MS. Using this method, we achieved a sample analysis speed of 2.14 s/well, with bioanalytical performance comparable to the current online solid phase extraction (SPE)-based MS method. An even faster readout speed was achieved when postreaction sample multiplexing was applied, where three reaction samples, one for each CYP, were transferred into the same well of the LazWell plate. In summary, LDTD coupled with acoustic sample deposition and multiplexing significantly decreased analysis time to 0.7 s/sample, making this MS-based approach feasible to support high-throughput screening (HTS) assays. PMID- 26420788 TI - Development of a Highly Sensitive Cell-Based Assay for Detecting Botulinum Neurotoxin Type A through Neural Culture Media Optimization. AB - Botulinum neurotoxin (BoNT) is the most lethal naturally produced neurotoxin. Due to the extreme toxicity, BoNTs are implicated in bioterrorism, while the specific mechanism of action and long-lasting effect was found to be medically applicable in treating various neurological disorders. Therefore, for both public and patient safety, a highly sensitive, physiologic, and specific assay is needed. In this paper, we show a method for achieving a highly sensitive cell-based assay for BoNT/A detection using the motor neuron-like continuous cell line NG108-15. To achieve high sensitivity, we performed a media optimization study evaluating three commercially available neural supplements in combination with retinoic acid, purmorphamine, transforming growth factor beta1 (TGFbeta1), and ganglioside GT1b. We found nonlinear combinatorial effects on BoNT/A detection sensitivity, achieving an EC50 of 7.4 U +/- 1.5 SD (or ~7.9 pM). The achieved detection sensitivity is comparable to that of assays that used primary and stem cell derived neurons as well as the mouse lethality assay. PMID- 26420789 TI - Global poplar root and leaf transcriptomes reveal links between growth and stress responses under nitrogen starvation and excess. AB - Nitrogen (N) starvation and excess have distinct effects on N uptake and metabolism in poplars, but the global transcriptomic changes underlying morphological and physiological acclimation to altered N availability are unknown. We found that N starvation stimulated the fine root length and surface area by 54 and 49%, respectively, decreased the net photosynthetic rate by 15% and reduced the concentrations of NH4+, NO3(-) and total free amino acids in the roots and leaves of Populus simonii Carr. in comparison with normal N supply, whereas N excess had the opposite effect in most cases. Global transcriptome analysis of roots and leaves elucidated the specific molecular responses to N starvation and excess. Under N starvation and excess, gene ontology (GO) terms related to ion transport and response to auxin stimulus were enriched in roots, whereas the GO term for response to abscisic acid stimulus was overrepresented in leaves. Common GO terms for all N treatments in roots and leaves were related to development, N metabolism, response to stress and hormone stimulus. Approximately 30-40% of the differentially expressed genes formed a transcriptomic regulatory network under each condition. These results suggest that global transcriptomic reprogramming plays a key role in the morphological and physiological acclimation of poplar roots and leaves to N starvation and excess. PMID- 26420790 TI - Waterlogging in late dormancy and the early growth phase affected root and leaf morphology in Betula pendula and Betula pubescens seedlings. AB - The warmer winters of the future will increase snow-melt frequency and rainfall, thereby increasing the risk of soil waterlogging and its effects on trees in winter and spring at northern latitudes. We studied the morphology of roots and leaves of 1-year-old silver birch (Betula pendula Roth) and pubescent birch (Betula pubescens Ehrh.) seedlings exposed to waterlogging during dormancy or at the beginning of the growing season in a growth-chamber experiment. The experiment included 4-week dormancy (Weeks 1-4), a 4-week early growing season (Weeks 5-8) and a 4-week late growing season (Weeks 9-12). The treatments were: (i) no waterlogging, throughout the experiment ('NW'); (ii) 4-week waterlogging during dormancy (dormancy waterlogging 'DW'); (iii) 4-week waterlogging during the early growing season (growth waterlogging 'GW'); and (iv) 4-week DW followed by 4-week GW during the early growing season ('DWGW'). Dormancy waterlogging affected the roots of silver birch and GW the roots and leaf characteristics of both species. Leaf area was reduced in both species by GW and DWGW. In pubescent birch, temporarily increased formation of thin roots was seen in root systems of GW seedlings, which suggests an adaptive mechanism with respect to excess soil water. Additionally, the high density of non-glandular trichomes and their increase in DWGW leaves were considered possible morphological adaptations to excess water in the soil, as was the constant density of stem lenticels during stem-diameter growth. The higher density in glandular trichomes of DWGW silver birch suggests morphological acclimation in that species. The naturally low density of non-glandular trichomes, low density of stem lenticels in waterlogged seedlings and decrease in root growth seen in DWGW and DW silver birch seedlings explain, at least partly, why silver birch grows more poorly relative to pubescent birch in wet soils. PMID- 26420791 TI - The influence of the soil on spring and autumn phenology in European beech. AB - Tree phenology is a key discipline in forest ecology linking seasonal fluctuations of photoperiod and temperature with the annual development of buds, leaves and flowers. Temperature and photoperiod are commonly considered as main determinants of tree phenology while little is known about interactions with soil chemical characteristics. Seedlings of 12 European beech (Fagus sylvatica L.) provenances were transplanted in 2011 to model ecosystems and grown for 4 years on acidic or calcareous forest soil. Spring bud burst and autumnal leaf senescence were assessed in the last 2 years, 2013 and 2014, which were characterized by contrasting annual temperatures with a very warm spring and autumn in 2014. In 2013, spring bud burst and autumnal leaf senescence were advanced on acidic soil with a greater effect on leaf senescence. Hence, the vegetation period 2013 was shorter on this soil type compared with that on calcareous soil. In 2014, a similar soil effect was observed for spring bud burst while autumnal leaf senescence and the length of the vegetation period were not affected, probably due to interferences with the overall extension of the vegetation period in this exceptionally warm year. A different soil responsiveness was observed among the provenances with early bursting or senescing provenances being more sensitive than late bursting or senescing provenances. The findings of this study highlight the soil as an ecologically relevant factor in tree phenology and might help explain existing uncertainties in current phenology models. PMID- 26420792 TI - Populus species from diverse habitats maintain high night-time conductance under drought. AB - We investigated the interspecific variability in nocturnal whole-plant stomatal conductance under well-watered and drought conditions in seedlings of four species of Populus from habitats characterized by abundant water supply (mesic and riparian) or from drier upland sites. The study was carried out to determine whether (i) nocturnal conductance varies across different species of Populus according to their natural habitat, (ii) nocturnal conductance is affected by water stress similarly to daytime conductance based on species habitat and (iii) differences in conductance among species could be explained partly by differences in stomatal traits. We measured whole-plant transpiration and conductance (G) of greenhouse-grown seedlings using an automated high-resolution gravimetric technique. No relationship was found between habitat preference and daytime G (GD), but night-time G (GN) was on average 1.5 times higher in riparian and mesic species (P. deltoides Bartr. ex Marsh. and P. trichocarpa Torr. & Gray) than in those from drier environments (P. tremuloides Michx. and P. * petrowskyana Schr.). GN was not significantly reduced under drought in riparian species. Upland species restricted GN significantly in response to drought, but it was still at least one order of magnitude greater that the cuticular conductance until leaf death was imminent. Under both well-watered and drought conditions, GN declined with increasing vapour pressure deficit (D). Also, a small increase in GN towards the end of the night period was observed in P. deltoides and P. * petrowskyana, suggesting the involvement of endogenous regulation. The anatomical analyses indicated a positive correlation between G and variable stomatal pore index among species and revealed that stomata are not likely to be leaky but instead seem capable of complete occlusion, which raises the question of the possible physiological role of the significant GN observed under drought. Further comparisons among closely related species that occupy ecologically diverse habitats may provide a better understanding of the genetic versus environmental regulations of nocturnal water loss. PMID- 26420793 TI - Phosphorus and nitrogen physiology of two contrasting poplar genotypes when exposed to phosphorus and/or nitrogen starvation. AB - Phosphorus (P) and nitrogen (N) are the two essential macronutrients for tree growth and development. To elucidate the P and N physiology of woody plants during acclimation to P and/or N starvation, we exposed saplings of the slow growing Populus simonii Carr (Ps) and the fast-growing Populus * euramericana Dode (Pe) to complete nutrients or starvation of P, N or both elements (NP). P. * euramericana had lower P and N concentrations and greater P and N amounts due to higher biomass production, thereby resulting in greater phosphorus use efficiency/N use efficiency (PUE/NUE) compared with Ps. Compared with the roots of Ps, the roots of Pe exhibited higher enzymatic activities in terms of acid phosphatases (APs) and malate dehydrogenase (MDH), which are involved in P mobilization, and nitrate reductase (NR), glutamate synthase (GOGAT) and glutamate dehydrogenase (GDH), which participate in N assimilation. The responsiveness of the transcriptional regulation of key genes encoding transporters for phosphate, ammonium and nitrate was stronger in Pe than in Ps. These results suggest that Pe possesses a higher capacity for P/N uptake and assimilation, which promote faster growth compared with Ps. In both poplars, P or NP starvation caused significant decreases in the P concentrations and increases in PUE. Phosphorus deprivation induced the activity levels of APs, phosphoenolpyruvate carboxylase and MDH in both genotypes. Nitrogen or NP deficiency resulted in lower N concentrations, amino acid levels, NR and GOGAT activities, and higher NUE in both poplars. Thus, in Ps and Pe, the mRNA levels of PHT1;5, PHT1;9, PHT2;1, AMT2;1 and NR increased in the roots, while PHT1;9, PHO1;H1, PHO2, AMT1;1 and NRT2;1 increased in the leaves during acclimation to P, N or NP deprivation. These results suggest that both poplars suppress P/N uptake, mobilization and assimilation during acclimation to P, N or NP starvation. PMID- 26420794 TI - Modification of the tree root electrical capacitance method under laboratory conditions. AB - For many years, scientists have been searching for nondestructive methods for the measurement of plant root system parameters. The measurement of electrical capacitance (EC) across the root has been proposed as one such nondestructive method. This article presents a study on the determination of relationships between EC measurement and the shape and size of the electrodes immersed in medium that are used for measurement. Measurement of EC and the parameters characterizing root systems of 1-year-old seedlings of the common beech Fagus sylvatica L. was conducted under laboratory conditions. The measurements of EC were performed between seedling root systems and two different electrodes in the form of a cylinder or a rectangular plate. Statistically significant correlations were found between the capacitance and root system parameters in both the variants; however, the correlations were higher in the case of the flat rectangular plate. Correlation coefficient (r) between EC and total root length was 0.688 for cylindrical electrode and 0.802 for rectangular plate, for total root area 0.641 and 0.818, and for dry weight of root system 0.502 and 0.747. The best-fitted linear regression relationships between the EC and the measured parameters were characterized by low determination coefficients in variants with cylindrical electrodes, and higher with flat rectangular plate electrodes. The results indicated that a two-dielectric media concept is a better model than Dalton's model when attempting to interpret the behavior of root and soil capacitance. The different electrodes probably allow root capacitance measurements to be interpreted from different aspects. However, this hypothesis requires further verification. PMID- 26420795 TI - Evolutionary Divergence of Aggregatibacter actinomycetemcomitans. AB - Gram-negative facultative Aggregatibacter actinomycetemcomitans is an oral pathogen associated with periodontitis. The genetic heterogeneity among A. actinomycetemcomitans strains has been long recognized. This study provides a comprehensive genomic analysis of A. actinomycetemcomitans and the closely related nonpathogenic Aggregatibacter aphrophilus. Whole genome sequencing by Illumina MiSeq platform was performed for 31 A. actinomycetemcomitans and 2 A. aphrophilus strains. Sequence similarity analysis shows a total of 3,220 unique genes across the 2 species, where 1,550 are core genes present in all genomes and 1,670 are variable genes (accessory genes) missing in at least 1 genome. Phylogenetic analysis based on 397 concatenated core genes distinguished A. aphrophilus and A. actinomycetemcomitans. The latter was in turn divided into 5 clades: clade b (serotype b), clade c (serotype c), clade e/f (serotypes e and f), clade a/d (serotypes a and d), and clade e' (serotype e strains). Accessory genes accounted for 14.1% to 23.2% of the A. actinomycetemcomitans genomes, with a majority belonging to the category of poorly characterized by Cluster of Orthologous Groups classification. These accessory genes were often organized into genomic islands (n = 387) with base composition biases, suggesting their acquisitions via horizontal gene transfer. There was a greater degree of similarity in gene content and genomic islands among strains within clades than between clades. Strains of clade e' isolated from human were found to be missing the genomic island that carries genes encoding cytolethal distending toxins. Taken together, the results suggest a pattern of sequential divergence, starting from the separation of A. aphrophilus and A. actinomycetemcomitans through gain and loss of genes and ending with the divergence of the latter species into distinct clades and serotypes. With differing constellations of genes, the A. actinomycetemcomitans clades may have evolved distinct adaptation strategies to the human oral cavity. PMID- 26420796 TI - Gene set differential analysis of time course expression profiles via sparse estimation in functional logistic model with application to time-dependent biomarker detection. AB - High-throughput time course expression profiles have been available in the last decade due to developments in measurement techniques and devices. Functional data analysis, which treats smoothed curves instead of originally observed discrete data, is effective for the time course expression profiles in terms of dimension reduction, robustness, and applicability to data measured at small and irregularly spaced time points. However, the statistical method of differential analysis for time course expression profiles has not been well established. We propose a functional logistic model based on elastic net regularization (F Logistic) in order to identify the genes with dynamic alterations in case/control study. We employ a mixed model as a smoothing method to obtain functional data; then F-Logistic is applied to time course profiles measured at small and irregularly spaced time points. We evaluate the performance of F-Logistic in comparison with another functional data approach, i.e. functional ANOVA test (F ANOVA), by applying the methods to real and synthetic time course data sets. The real data sets consist of the time course gene expression profiles for long-term effects of recombinant interferon beta on disease progression in multiple sclerosis. F-Logistic distinguishes dynamic alterations, which cannot be found by competitive approaches such as F-ANOVA, in case/control study based on time course expression profiles. F-Logistic is effective for time-dependent biomarker detection, diagnosis, and therapy. PMID- 26420798 TI - Acute Chagas Disease and Risk of Congenital Infection. PMID- 26420797 TI - Group association test using a hidden Markov model. AB - In the genomic era, group association tests are of great interest. Due to the overwhelming number of individual genomic features, the power of testing for association of a single genomic feature at a time is often very small, as are the effect sizes for most features. Many methods have been proposed to test association of a trait with a group of features within a functional unit as a whole, e.g. all SNPs in a gene, yet few of these methods account for the fact that generally a substantial proportion of the features are not associated with the trait. In this paper, we propose to model the association for each feature in the group as a mixture of features with no association and features with non-zero associations to explicitly account for the possibility that a fraction of features may not be associated with the trait while other features in the group are. The feature-level associations are first estimated by generalized linear models; the sequence of these estimated associations is then modeled by a hidden Markov chain. To test for global association, we develop a modified likelihood ratio test based on a log-likelihood function that ignores higher order dependency plus a penalty term. We derive the asymptotic distribution of the likelihood ratio test under the null hypothesis. Furthermore, we obtain the posterior probability of association for each feature, which provides evidence of feature-level association and is useful for potential follow-up studies. In simulations and data application, we show that our proposed method performs well when compared with existing group association tests especially when there are only few features associated with the outcome. PMID- 26420799 TI - Reply to Henao-Martinez, et al. PMID- 26420800 TI - Early, Real-Time Medical Diagnosis of Botulism by Endopeptidase-Mass Spectrometry. AB - Botulinum toxin was detected in patient serum using Endopeptidase-mass spectrometry assay, although all conventional tests provided negative results. Antitoxin was administered, resulting in patient improvement. Implementing this highly sensitive and rapid assay will improve preparedness for foodborne botulism and deliberate exposure. PMID- 26420801 TI - Influenza Vaccine Effectiveness in a Low-Income, Urban Community Cohort. AB - In this community-based cohort study of 275 primarily low-income, urban households in New York City, overall 2013-2014 influenza vaccine effectiveness (VE) was 62.5% (95% confidence interval, 21.7%-82.0%). VE point estimates were highest against 2009 H1N1 and for those who were vaccinated in 2013-2014 but not in 2012-2013. PMID- 26420803 TI - Contagious equine metritis cases reported in France since 2006. PMID- 26420802 TI - Combined Directional Atherectomy and Drug-Eluting Balloon Angioplasty for Isolated Popliteal Artery Lesions in Patients With Peripheral Artery Disease. AB - PURPOSE: To evaluate the midterm results of combined directional atherectomy (DA) and drug-eluting balloon (DEB) angioplasty for atherosclerotic lesions of the popliteal artery. METHODS: In a single-arm, prospective study, 21 patients (mean age 63+/-16 years; 16 men) with isolated popliteal artery lesions were enrolled and underwent treatment with combined DA and DEB angioplasty under filter protection between October 2009 and February 2014. The majority (18, 86%) presented with lifestyle-limiting intermittent claudication and 3 with critical limb ischemia. Fifteen (71%) target sites were de novo lesions; 4 were occlusions. The main outcome was primary patency; secondary outcomes were technical success, secondary patency, and early and midterm morbidity and mortality. RESULTS: The TurboHawk atherectomy device was used in 15 (71%) patients and the SilverHawk peripheral plaque excision system in the remaining 6 patients. The In.Pact Admiral/Pacific DEB was used in the majority of cases (15, 71%). The technical success rate was 90% (n=19). One flow-limiting dissection was treated with bailout stenting. Complications included a perforation of the popliteal artery and 2 puncture site hematomas; there was no distal embolic event. The mean follow-up was 18+/-12 months. Two restenoses were retreated successfully. Kaplan-Meier estimates of primary patency at 12 and 18 months were 95% and 90%, respectively; the secondary patency was 100%. One (5%) patient died in follow-up. None of the patients had an amputation. CONCLUSION: In this prospective single-arm study, the combined therapy of DA and DEB angioplasty for popliteal artery lesions showed promising midterm performance. The combination of DA and DEB may, in highly selected patients, overcome the challenges presented by the mobility of the knee joint. PMID- 26420804 TI - Reduction in daily milk yield associated with subclinical bovine herpesvirus 1 infection. AB - The aim of this observational cohort study was to investigate the potential economic impact of subclinical bovine herpesvirus 1 (BoHV-1) infection in a commercial UK dairy herd in terms of milk yield depression. Infection status of cows (infected or not infected) was assigned from serology on a single occasion. A multi-level linear model was used to evaluate the impact of infection status on milk production, using milk records that were routinely collected over two years. BoHV-1 seropositive cows produced 2.6 kg/day less milk over the study period compared with cows that were seronegative. This result highlights the importance of appropriate management of risks associated with subclinical infection with BoHV-1 as part of proactive herd health and production management. PMID- 26420805 TI - Foreword. PMID- 26420806 TI - Early childhood development and the social determinants of health inequities. AB - Children's health and development outcomes follow a social gradient: the further up the socioeconomic spectrum, the better the outcomes. Based upon a review of multiple forms of evidence, and with a specific focus upon Australia, this article investigates the causes of these socially produced inequities, their impact upon health and development during the early years and what works to reduce these inequities. Using VicHealth's Fair Foundations framework, we report upon child health inequity at three different levels: the socioeconomic, political and cultural level; daily living conditions; the individual health related behaviours. Although intensive interventions may improve the absolute conditions of significantly disadvantaged children and families, interventions that have been shown to effectively reduce the gap between the best and worst off families are rare. Numerous interventions have been shown to improve some aspect of prenatal, postnatal, family, physical and social environments for young children; however, sustainable or direct effects are difficult to achieve. Inequitable access to services has the potential to maintain or increase inequities during the early years, because those families most in need of services are typically least able to access them. Reducing inequities during early childhood requires a multi-level, multi-faceted response that incorporates: approaches to governance and decision-making; policies that improve access to quality services and facilitate secure, stable, flexible workplaces for parents; service systems that reflect the characteristics of proportionate universalism, function collaboratively, and deliver evidence-based programs in inclusive environments; strong, supportive communities; and information and timely assistance for parents so they feel supported and confident. PMID- 26420807 TI - Social innovation for the promotion of health equity. AB - The role of social innovations in transforming the lives of individuals and communities has been a source of popular attention in recent years. This article systematically reviews the available evidence of the relationship between social innovation and its promotion of health equity. Guided by Fair Foundations: The VicHealth framework for health equity and examining four types of social innovation--social movements, service-related social innovations, social enterprise and digital social innovations--we find a growing literature on social innovation activities, but inconsistent evaluative evidence of their impacts on health equities, particularly at the socio-economic, political and cultural level of the framework. Distinctive characteristics of social innovations related to the promotion of health equity include the mobilization of latent or unrealised value through new combinations of (social, cultural and material) resources; growing bridging social capital and purposeful approaches to linking individual knowledge and experience to institutional change. These have implications for health promotion practice and for research about social innovation and health equity. PMID- 26420808 TI - Addressing social determinants of health inequities through settings: a rapid review. AB - Changing settings to be more supportive of health and healthy choices is an optimum way to improve population health and health equity. This article uses the World Health Organisation's (1998) (WHO Health Promotion Glossary. WHO Collaborating Centre for Health Promotion, Department of Public Health and Community Medicine, University of Sydney, NSW) definition of settings approaches to health promotion as those focused on modifying settings' structure and nature. A rapid literature review was undertaken in the period June-August 2014, combining a systematically conducted search of two major databases with targeted searches. The review focused on identifying what works in settings approaches to address the social determinants of health inequities, using Fair Foundations: the VicHealth framework for health equity. This depicts the social determinants of health inequities as three layers of influence, and entry points for action to promote health equity. The evidence review identified work in 12 settings (cities; communities and neighbourhoods; educational; healthcare; online; faith based; sports; workplaces; prisons; and nightlife, green and temporary settings), and work at the socioeconomic, political and cultural context layer of the Fair Foundations framework (governance, legislation, regulation and policy). It located a relatively small amount of evidence that settings themselves are being changed in ways which address the social determinants of health inequities. Rather, many initiatives focus on individual behaviour change within settings. There is considerable potential for health promotion professionals to focus settings work more upstream and so replace or integrate individual approaches with those addressing daily living conditions and higher level structures, and a significant need for programmes to be evaluated for differential equity impacts and published to provide a more solid evidence base. PMID- 26420809 TI - Fair Foundations for health equity. PMID- 26420810 TI - Addressing inequities in alcohol consumption and related harms. AB - Social determinants, or the conditions in which individuals are born, grow, live, work and age, can result in inequities in health and well-being. However, to-date little research has examined alcohol use and alcohol-related problems from an inequities and social determinants perspective. This study reviewed the evidence base regarding inequities in alcohol consumption and alcohol-related health outcomes in Australia and identified promising approaches for promoting health equity. Fair Foundations: the VicHealth framework for health equity was used as an organizing schema. The review found that social determinants can strongly influence inequities in alcohol consumption and related harms. In general, lower socioeconomic groups experience more harm than wealthier groups with the same level of alcohol consumption. While Australia has implemented numerous alcohol related interventions and policies, most do not explicitly aim to reduce inequities, and some may inadvertently exacerbate existing inequities. Interventions with the greatest potential to decrease inequities in alcohol consumption and alcohol-related harms include town planning, zoning and licensing to prevent disproportionate clustering of outlets in disadvantaged areas; interventions targeting licensed venues; and interventions targeting vulnerable populations. Interventions that may worsen inequities include national guidelines, technological interventions and public drinking bans. There is a need for further research into the best methods for reducing inequities in alcohol consumption and related harms. PMID- 26420811 TI - Promoting equity in the mental wellbeing of children and young people: a scoping review. AB - There is increasing emphasis on wellbeing as a target for mental health promotion, especially during the formative period of childhood. Despite growing research on the importance of mental wellbeing, there is little information on how to effectively promote it or how to promote it equitably. This article presents a scoping review of interventions which seek to promote mental wellbeing and reduce inequities in children and young people living in high income countries. We used Fair Foundations: The VicHealth framework for health equity (VicHealth (2013) Melbourne, Australia: The Victorian Health Promotion Foundation) to identify points of entry at three layers of influence: (i) socioeconomic, cultural and political contexts, (ii) daily living conditions, and (iii) individual and family health-related factors. We identified more than 1000 interventions which aimed to prevent or treat childhood mental illness, but there were far fewer that aimed to promote children's or young people's mental wellbeing. The interventions we studied were either universal or specifically targeted children from disadvantaged families: none explicitly used an equity framework to guide their design or evaluation or addressed social gradients in wellbeing. Most interventions remained focused on proximate factors, although we also identified a handful of interventions that sought to address children's access to services and their educational and neighbourhood environments. However, we found encouraging evidence that interventions in family and educational settings were successful in building children's strengths and supporting positive parenting, universally and within disadvantaged groups. Such positive programme evaluations signal the potential for using a proportionate universalism approach that emphasizes equity in the promotion of mental wellbeing. PMID- 26420812 TI - Addressing inequities in healthy eating. AB - What, when, where and how much people eat is influenced by a complex mix of factors at societal, community and individual levels. These influences operate both directly through the food system and indirectly through political, economic, social and cultural pathways that cause social stratification and influence the quality of conditions in which people live their lives. These factors are the social determinants of inequities in healthy eating. This paper provides an overview of the current evidence base for addressing these determinants and for the promotion of equity in healthy eating. PMID- 26420813 TI - Tobacco control approaches and inequity--how far have we come and where are we going? AB - Despite Australia's success in reducing smoking rates, substantial inequities persist--with high smoking prevalence among disadvantaged groups. This article uses Fair Foundations: The VicHealth framework for health equity to identify promising strategies for promoting equity within tobacco control policies and programmes. A rapid review of the Australian and international literature was conducted in March 2014 using Pubmed, ISI web of Science and Scopus, Cochrane library and Google Scholar. A search of the grey literature was conducted to identify promising policy interventions. Population health surveys suggest that tobacco-related inequities in Victoria are beginning to decline. Data from the Victorian Smoking Survey shows that the inequity gap is narrowing, and in recent years, the prevalence of regular smoking declined fastest among disadvantaged smokers. Future approaches to accelerate reductions in tobacco-related inequities include: (i) continue proven population-based tobacco control policies- especially increasing the price of tobacco (while remaining cognisant of the increased economic burden for those smokers who do not quit), and continuing mass media campaigns; (ii) strengthening social policies to promote equity in early child development; educational experiences; quality of local environments; employment and working conditions; (iii) identifying and investing in targeted approaches to influence social norms and more effectively identify and support disadvantaged smokers to quit; (iv) within tobacco control programmes, give greatest priority to interventions focused on adult smokers (including pregnant women and their partners). PMID- 26420816 TI - Correction. AB - In the article by Quintavalle et al (Quintavalle C, Anselmi CV, De Micco F, Roscigno G, Visconti G, Golia B, Focaccio A, Ricciardelli B, Perna E, Papa L, Donnarumma E, Condorelli G, Briguori C. Neutrophil gelatinase-associated lipocalin and contrast-induced acute kidney injury. Circ Cardiovasc Interv. 2015;8:e002673. DOI: 10.1161/CIRCINTERVENTIONS.115.002673.), which published online September 2, 2015, and appears in the September 2015 issue of the journal, a correction was needed. On page 1, the institutional affiliation for Elvira Donnarumma, PhD, "SDN Foundation," has been changed to read, "IRCCS SDN, Naples, Italy." The institutional affiliation for Laura Papa, PhD, "Institute for Endocrinology and Experimental Oncology, National Research Council, Naples, Italy," has been changed to read, "Institute of Genetics and Biomedical Research, Milan Unit, Milan, Italy" and "Humanitas Research Hospital, Rozzano, Italy." The authors regret this error. PMID- 26420814 TI - Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial. AB - PURPOSE: To improve stratification of risk-adapted treatment for non-metastatic (M0), standard-risk medulloblastoma patients by prospective evaluation of biomarkers of reported biological or prognostic significance, alongside clinico pathological variables, within the multi-center HIT-SIOP-PNET4 trial. METHODS: Formalin-fixed paraffin-embedded tumor tissues were collected from 338 M0 patients (>4.0 years at diagnosis) for pathology review and assessment of the WNT subgroup (MBWNT) and genomic copy-number defects (chromosome 17, MYC/MYCN, 9q22 (PTCH1) and DNA ploidy). Clinical characteristics were reviewed centrally. RESULTS: The favorable prognosis of MBWNT was confirmed, however better outcomes were observed for non-MBWNT tumors in this clinical risk-defined cohort compared to previous disease-wide clinical trials. Chromosome 17p/q defects were heterogeneous when assessed at the cellular copy-number level, and predicted poor prognosis when they occurred against a diploid (ch17(im)/diploid(cen)), but not polyploid, genetic background. These factors, together with post-surgical tumor residuum (R+) and radiotherapy delay, were supported as independent prognostic markers in multivariate testing. Notably, MYC and MYCN amplification were not associated with adverse outcome. In cross-validated survival models derived for the clinical standard-risk (M0/R0) disease group, (ch17(im)/diploid(cen); 14% of patients) predicted high disease-risk, while the outcomes of patients without (ch17(im)/diploid(cen)) did not differ significantly from MBWNT, allowing re classification of 86% as favorable-risk. CONCLUSIONS: Biomarkers, established previously in disease-wide studies, behave differently in clinically-defined standard-risk disease. Distinct biomarkers are required to assess disease-risk in this group, and define improved risk-stratification models. Routine testing for specific patterns of chromosome 17 imbalance at the cellular level, and MBWNT, provides a strong basis for incorporation into future trials. PMID- 26420815 TI - Efficacy and safety of capecitabine-based first-line chemotherapy in advanced or metastatic breast cancer: a meta-analysis of randomised controlled trials. AB - We sought to evaluate the efficacy and safety of capecitabine-based therapy as first-line chemotherapy in advanced breast cancer. Randomised controlled trials of capecitabine monotherapy or combined treatment were included in the meta analysis. PubMed, EMBASE, the Cochrane Library database and important meeting summaries were searched systematically. Outcomes were progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and grades 3-4 drug related adverse events.Nine trials with 1798 patients were included. The results indicated a significant improvement with capecitabine-based chemotherapy compared with capecitabine-free chemotherapy in ORR (relative risk [RR] 1.14, 95% confidence interval [CI] 1.03 to 1.26, P = 0.013) and PFS (hazard ratio [HR] 0.77, 95% CI 0.69 to 0.87, P < 0.0001). Overall survival favoured capecitabine based chemotherapy, but this was not significant. There were more incidences of neutropenia and neutropenic fever in the capecitabine-free chemotherapy group and more vomiting, diarrhoea and hand-foot syndrome in the capecitabine-based chemotherapy group. There were no significant differences in nausea, fatigue, cardiotoxicity or mucositis/stomatitis between the two treatment regimens.Capecitabine-based chemotherapy significantly improves ORR and PFS in patients with advanced breast cancer, but has no demonstrable impact on OS. Capecitabine-based regimens are suitable as first-line treatment for patients with advanced breast cancer. PMID- 26420817 TI - Predictors of unstable distal radius fractures: a systematic review and meta analysis. AB - The aim of this study was to perform a systematic review in order to identify predictors of secondary displacement in distal radius fractures. We performed a systematic review and identified all studies that reported secondary displacement following distal radius fractures. Where possible, we pooled the odds ratios of predictors. The initial search yielded 3178 studies of which 27 were included. Multiple studies found that age, shortening, volar comminution, loss of radial inclination, the presence of a volar hook, AO type 3 fractures (A3, B3, C3) and the Older classification were significant predictors of secondary displacement. Pooling revealed a significantly increased risk of secondary displacement in fractures with dorsal comminution, in women and in patients aged >60 years. An associated ulna fracture or intra-articular involvement does not result in an increased risk of secondary displacement. The overview provided in this study can help surgeons to inform patients of the chances of success of closed treatment regarding the radiological outcome and facilitate shared decision making. LEVEL OF EVIDENCE: II. PMID- 26420818 TI - Safe use of MRI in people with cardiac implantable electronic devices. AB - MR scanning in patients with cardiac implantable electronic devices (CIEDs) was formerly felt to be contraindicated, but an increasing number of patients have an implanted MR conditional device, allowing them to safely undergo MR scanning, provided the manufacturer's guidance is adhered to. In addition, some patients with non-MR conditional devices may undergo MR scanning if no other imaging modality is deemed suitable and there is a clear clinical indication for scanning which outweighs the potential risk. The following guidance has been formulated by the British Heart Rhythm Society and endorsed by the British Cardiovascular Society and others. It describes protocols that should be followed for patients with CIEDs undergoing MR scanning. The recommendations, principles and conclusions are supported by the Royal College of Radiologists. PMID- 26420819 TI - Rac1 GTPase in pancreatic cancer. PMID- 26420820 TI - Improving Anticoagulation Measurement Novel Warfarin Composite Measure. AB - BACKGROUND: Percent time in therapeutic range (TTR) and international normalized ratio (INR) variability both measure warfarin control and are associated with outcomes independently. Here, we examine the advantages of a warfarin composite measure (WCM), which summarizes the 2 when measuring patient outcomes. We also examine how the measure chosen would affect anticoagulation clinic performance rankings. METHODS AND RESULTS: We constructed WCM using an equally weighted method, adding standardized TTR to standardized log-transformed INR variability using 103 897 warfarin-experienced patients from 100 anticoagulation clinics. We examined the association of WCM with ischemic stroke, major bleeding, and fatal bleeding, using a subset of patients with atrial fibrillation (n=40 404). We divided patients into quintiles based on their level of control for TTR, log INR variability, and WCM. We calculated the hazard ratios for ischemic stroke, major bleeding, and fatal bleeding stratified by these quintiles. WCM hazard ratios for stroke and fatal bleeding showed the largest difference between excellent control and poorest control quintile compared with TTR and log INR variability, but not for major bleeding. In addition, we compared site rankings obtained using each of our 3 performance measures. Kappa scores for identifying outlier and nonoutlier clinics between WCM and its components were moderate (kappa=0.56 for TTR and kappa=0.62 for log INR variability) but was weak between TTR and log INR variability (kappa=0.13). CONCLUSIONS: WCM produces the largest range of risk for warfarin complications, widening the floor ceiling effects that limit the use of TTR and INR variability as separate measures. Anticoagulation clinics ranking changed considerably according to the anticoagulation measure that was selected. PMID- 26420821 TI - Relaxation therapy and anxiety, self-esteem, and emotional regulation among adults with intellectual disabilities: A randomized controlled trial. AB - This pilot study is a randomized controlled trial on the effects of relaxation on anxiety, self-esteem, and emotional regulation in adults with intellectual disabilities (ID) working in a center of supported employment in France. We studied 30 adults with mild or moderate ID who were split at random into a relaxation group (RG, 15 subjects), who completed 10 sessions of relaxation therapy, and a control group (CG, 15 subjects), who were on a waiting list. The method used is the pretest and posttest. Variables were assessed by the State Trait Anxiety Inventory form Y scale, the Rosenberg Self-Esteem scale, and the Emotion Regulation Questionnaire. We found that in the RG, relaxation significantly reduced state anxiety, t(14, 15) = 17.8***, d = -0.72, and improved self-esteem, t(14, 15) = -7.7***, d = 1.03, and cognitive reappraisal, t(14, 15) = -6.3***, d = 1.3, while the CG showed no change for these variables. We conclude that relaxation seems to be an interesting therapeutic option for reducing anxiety in people with ID in a supported employment setting. PMID- 26420822 TI - AML treatment in older adults. PMID- 26420823 TI - Sonic Hedgehog in SCLC. PMID- 26420824 TI - Use of the Delphi process in paediatric cataract management. AB - PURPOSE: To identify areas of consensus and disagreement in the management of paediatric cataract using a modified Delphi approach among individuals recognised for publishing in this field. DESIGN: A modified Delphi method. PARTICIPANTS: International paediatric cataract experts with a publishing record in paediatric cataract management. METHODS: The process consisted of three rounds of anonymous electronic questionnaires followed by a face-to-face meeting, followed by a fourth anonymous electronic questionnaire. The executive committee created questions to be used for the electronic questionnaires. Questions were designed to have unit-based, multiple choice or true-false answers. The questionnaire included issues related to the preoperative, intraoperative and postoperative management of paediatric cataract. MAIN OUTCOME MEASURE: Consensus based on 85% of panellists being in agreement for electronic questionnaires or 80% for the face-to-face meeting, and near consensus based on 70%. RESULTS: Sixteen of 22 invited paediatric cataract surgeons agreed to participate. We arrived at consensus or near consensus for 85/108 (78.7%) questions and non-consensus for the remaining 23 (21.3%) questions. CONCLUSIONS: Those questions where consensus was not reached highlight areas of either poor evidence or contradicting evidence, and may help investigators identify possible research questions. PMID- 26420825 TI - Interobserver agreement using Goldmann applanation tonometry and dynamic contour tonometry: comparing ophthalmologists, nurses and technicians. AB - PURPOSE: To compare agreement between ophthalmologists and non-ophthalmologists (nurses and ophthalmic technicians) when measuring the intraocular pressure (IOP) using Goldmann applanation tonometry (GAT) and Pascal dynamic contour tonometry (DCT). METHODS: Patients attending for their routine glaucoma outpatient appointment were invited to participate. IOP was measured in one eye by either two ophthalmologists (observer group 1), two non-ophthalmologists (observer group 2) or one ophthalmologist and one non-ophthalmologist (observer group 3). All were experienced in using GAT and some experienced in using the DCT. The order of tonometer and staff was randomised. Agreement was calculated by Bland-Altman analysis, with the mean difference and 95% limits of agreement (LoA) of measurements calculated for each observer group. RESULTS: One hundred eyes were measured within each observer group. The mean difference (95% LoA) in IOP measurements were GAT: group 1=-0.20 (4.9) mm Hg, group 2=0.6 (5.4) mm Hg and group 3=0.0 (3.7) mm Hg; DCT: group 1=0.8 (7.7) mm Hg, group 2=0.3 (4.2) and group 3=0.0 (5.2) mm Hg. The DCT consistently over-read the GAT for all observer groups. DISCUSSION/CONCLUSIONS: Ophthalmologists show good levels of agreement with each other when using GAT, while technicians/nursing staff show better agreement when using the DCT. The DCT may be a better tonometer to use if permanently delegating IOP measurements to non-ophthalmologists, but measurements cannot be interchanged with the GAT. PMID- 26420826 TI - Mammalian splicing factor SF1 interacts with SURP domains of U2 snRNP-associated proteins. AB - Splicing factor 1 (SF1) recognizes the branch point sequence (BPS) at the 3' splice site during the formation of early complex E, thereby pre-bulging the BPS adenosine, thought to facilitate subsequent base-pairing of the U2 snRNA with the BPS. The 65-kDa subunit of U2 snRNP auxiliary factor (U2AF65) interacts with SF1 and was shown to recruit the U2 snRNP to the spliceosome. Co-immunoprecipitation experiments of SF1-interacting proteins from HeLa cell extracts shown here are consistent with the presence of SF1 in early splicing complexes. Surprisingly almost all U2 snRNP proteins were found associated with SF1. Yeast two-hybrid screens identified two SURP domain-containing U2 snRNP proteins as partners of SF1. A short, evolutionarily conserved region of SF1 interacts with the SURP domains, stressing their role in protein-protein interactions. A reduction of A complex formation in SF1-depleted extracts could be rescued with recombinant SF1 containing the SURP-interaction domain, but only partial rescue was observed with SF1 lacking this sequence. Thus, SF1 can initially recruit the U2 snRNP to the spliceosome during E complex formation, whereas U2AF65 may stabilize the association of the U2 snRNP with the spliceosome at later times. In addition, these findings may have implications for alternative splicing decisions. PMID- 26420827 TI - Direct-Coupling Analysis of nucleotide coevolution facilitates RNA secondary and tertiary structure prediction. AB - Despite the biological importance of non-coding RNA, their structural characterization remains challenging. Making use of the rapidly growing sequence databases, we analyze nucleotide coevolution across homologous sequences via Direct-Coupling Analysis to detect nucleotide-nucleotide contacts. For a representative set of riboswitches, we show that the results of Direct-Coupling Analysis in combination with a generalized Nussinov algorithm systematically improve the results of RNA secondary structure prediction beyond traditional covariance approaches based on mutual information. Even more importantly, we show that the results of Direct-Coupling Analysis are enriched in tertiary structure contacts. By integrating these predictions into molecular modeling tools, systematically improved tertiary structure predictions can be obtained, as compared to using secondary structure information alone. PMID- 26420829 TI - GeoPCA: a new tool for multivariate analysis of dihedral angles based on principal component geodesics. PMID- 26420828 TI - DNA double-strand breaks with 5' adducts are efficiently channeled to the DNA2 mediated resection pathway. AB - DNA double-strand breaks (DSBs) with 5' adducts are frequently formed from many nucleic acid processing enzymes, in particular DNA topoisomerase 2 (TOP2). The key intermediate of TOP2 catalysis is the covalent complex (TOP2cc), consisting of two TOP2 subunits covalently linked to the 5' ends of the nicked DNA. In cells, TOP2ccs can be trapped by cancer drugs such as etoposide and then converted into DNA double-strand breaks (DSBs) that carry adducts at the 5' end. The repair of such DSBs is critical to the survival of cells, but the underlying mechanism is still not well understood. We found that etoposide-induced DSBs are efficiently resected into 3' single-stranded DNA in cells and the major nuclease for resection is the DNA2 protein. DNA substrates carrying model 5' adducts were efficiently resected in Xenopus egg extracts and immunodepletion of Xenopus DNA2 also strongly inhibited resection. These results suggest that DNA2-mediated resection is a major mechanism for the repair of DSBs with 5' adducts. PMID- 26420830 TI - DnaC traps DnaB as an open ring and remodels the domain that binds primase. AB - Helicase loading at a DNA replication origin often requires the dynamic interactions between the DNA helicase and an accessory protein. In E. coli, the DNA helicase is DnaB and DnaC is its loading partner. We used the method of hydrogen/deuterium exchange mass spectrometry to address the importance of DnaB DnaC complex formation as a prerequisite for helicase loading. Our results show that the DnaB ring opens and closes, and that specific amino acids near the N terminus of DnaC interact with a site in DnaB's C-terminal domain to trap it as an open ring. This event correlates with conformational changes of the RecA fold of DnaB that is involved in nucleotide binding, and of the AAA+ domain of DnaC. DnaC also causes an alteration of the helical hairpins in the N-terminal domain of DnaB, presumably occluding this region from interacting with primase. Hence, DnaC controls the access of DnaB by primase. PMID- 26420831 TI - ATM and KAT5 safeguard replicating chromatin against formaldehyde damage. AB - Many carcinogens damage both DNA and protein constituents of chromatin, and it is unclear how cells respond to this compound injury. We examined activation of the main DNA damage-responsive kinase ATM and formation of DNA double-strand breaks (DSB) by formaldehyde (FA) that forms histone adducts and replication-blocking DNA-protein crosslinks (DPC). We found that low FA doses caused a strong and rapid activation of ATM signaling in human cells, which was ATR-independent and restricted to S-phase. High FA doses inactivated ATM via its covalent dimerization and formation of larger crosslinks. FA-induced ATM signaling showed higher CHK2 phosphorylation but much lower phospho-KAP1 relative to DSB inducers. Replication blockage by DPC did not produce damaged forks or detectable amounts of DSB during the main wave of ATM activation, which did not require MRE11. Chromatin-monitoring KAT5 (Tip60) acetyltransferase was responsible for acetylation and activation of ATM by FA. KAT5 and ATM were equally important for triggering of intra-S-phase checkpoint and ATM signaling promoted recovery of normal human cells after low-dose FA. Our results revealed a major role of the KAT5-ATM axis in protection of replicating chromatin against damage by the endogenous carcinogen FA. PMID- 26420832 TI - The players may change but the game remains: network analyses of ruminal microbiomes suggest taxonomic differences mask functional similarity. AB - By mapping translated metagenomic reads to a microbial metabolic network, we show that ruminal ecosystems that are rather dissimilar in their taxonomy can be considerably more similar at the metabolic network level. Using a new network bi partition approach for linking the microbial network to a bovine metabolic network, we observe that these ruminal metabolic networks exhibit properties consistent with distinct metabolic communities producing similar outputs from common inputs. For instance, the closer in network space that a microbial reaction is to a reaction found in the host, the lower will be the variability of its enzyme copy number across hosts. Similarly, these microbial enzymes that are nearby to host nodes are also higher in copy number than are more distant enzymes. Collectively, these results demonstrate a widely expected pattern that, to our knowledge, has not been explicitly demonstrated in microbial communities: namely that there can exist different community metabolic networks that have the same metabolic inputs and outputs but differ in their internal structure. PMID- 26420833 TI - Reduced cohesin destabilizes high-level gene amplification by disrupting pre replication complex bindings in human cancers with chromosomal instability. AB - Gene amplification is a hallmark of cancer with chromosomal instability although the underlying mechanism by which altered copy numbers are maintained is largely unclear. Cohesin, involved in sister chromatid cohesion, DNA repair, cell cycle progression and transcriptional regulation of key developmental genes, is frequently overexpressed in human cancer. Here we show that cohesin-dependent change in DNA replication controls the copy numbers of amplified genes in cancer cells with chromosomal instability. We found that the down-regulation of elevated cohesin leads to copy number-associated gene expression changes without disturbing chromosomal segregation. Highly amplified genes form typical long range chromatin interactions, which are stabilized by enriched cohesin. The spatial proximities among cohesin binding sites within amplified genes are decreased by RAD21-knockdown, resulting in the rapid decline of amplified gene expression. After several passages, cohesin depletion inhibits DNA replication initiation by reducing the recruitment of pre-replication complexes such as minichromosome maintenance subunits 7 (MCM7), DNA polymerase alpha, and CDC45 at replication origins near the amplified regions, and as a result, decreases the DNA copy numbers of highly amplified genes. Collectively, our data demonstrate that cohesin-mediated chromatin organization and DNA replication are important for stabilizing gene amplification in cancer cells with chromosomal instability. PMID- 26420835 TI - Ultra-fast local-haplotype variant calling using paired-end DNA-sequencing data reveals somatic mosaicism in tumor and normal blood samples. AB - Somatic mosaicism refers to the existence of somatic mutations in a fraction of somatic cells in a single biological sample. Its importance has mainly been discussed in theory although experimental work has started to emerge linking somatic mosaicism to disease diagnosis. Through novel statistical modeling of paired-end DNA-sequencing data using blood-derived DNA from healthy donors as well as DNA from tumor samples, we present an ultra-fast computational pipeline, LocHap that searches for multiple single nucleotide variants (SNVs) that are scaffolded by the same reads. We refer to scaffolded SNVs as local haplotypes (LH). When an LH exhibits more than two genotypes, we call it a local haplotype variant (LHV). The presence of LHVs is considered evidence of somatic mosaicism because a genetically homogeneous cell population will not harbor LHVs. Applying LocHap to whole-genome and whole-exome sequence data in DNA from normal blood and tumor samples, we find wide-spread LHVs across the genome. Importantly, we find more LHVs in tumor samples than in normal samples, and more in older adults than in younger ones. We confirm the existence of LHVs and somatic mosaicism by validation studies in normal blood samples. LocHap is publicly available at http://www.compgenome.org/lochap. PMID- 26420834 TI - ANISEED 2015: a digital framework for the comparative developmental biology of ascidians. AB - Ascidians belong to the tunicates, the sister group of vertebrates and are recognized model organisms in the field of embryonic development, regeneration and stem cells. ANISEED is the main information system in the field of ascidian developmental biology. This article reports the development of the system since its initial publication in 2010. Over the past five years, we refactored the system from an initial custom schema to an extended version of the Chado schema and redesigned all user and back end interfaces. This new architecture was used to improve and enrich the description of Ciona intestinalis embryonic development, based on an improved genome assembly and gene model set, refined functional gene annotation, and anatomical ontologies, and a new collection of full ORF cDNAs. The genomes of nine ascidian species have been sequenced since the release of the C. intestinalis genome. In ANISEED 2015, all nine new ascidian species can be explored via dedicated genome browsers, and searched by Blast. In addition, ANISEED provides full functional gene annotation, anatomical ontologies and some gene expression data for the six species with highest quality genomes. ANISEED is publicly available at: http://www.aniseed.cnrs.fr. PMID- 26420839 TI - Molecular and biochemical alterations in tubular epithelial cells of patients with isolated methylmalonic aciduria. AB - Methylmalonic acidurias (MMAurias) are a group of inherited disorders in the catabolism of branched-chain amino acids, odd-chain fatty acids and cholesterol caused by complete or partial deficiency of methylmalonyl-CoA mutase (mut(0) and mut(-) subtype respectively) and by defects in the metabolism of its cofactor 5' deoxyadenosylcobalamin (cblA, cblB or cblD variant 2 type). A long-term complication found in patients with mut(0) and cblB variant is chronic tubulointerstitial nephritis. The underlying pathomechanism has remained unknown. We established an in vitro model of tubular epithelial cells from patient urine (hTEC; 9 controls, 5 mut(0), 1 cblB). In all human tubular epithelial cell (hTEC) lines we found specific tubular markers (AQP1, UMOD, AQP2). Patient cells showed disturbance of energy metabolism in glycolysis, mitochondrial respiratory chain and Krebs cycle in concert with increased reactive oxygen species (ROS) formation. Electron micrographs indicated increased autophagosome production and endoplasmic reticulum stress, which was supported by positive acridine orange staining and elevated levels of LC3 II, P62 and pIRE1. Screening mTOR signaling revealed a release of inhibition of autophagy. Patient hTEC produced and secreted elevated amounts of the pro-inflammatory cytokine IL8, which was highly correlated with the acridine orange staining. Summarizing, hTEC of MMAuria patients are characterized by disturbed energy metabolism and ROS production that lead to increased autophagy and IL8 secretion. PMID- 26420838 TI - Neuronopathic Gaucher disease: dysregulated mRNAs and miRNAs in brain pathogenesis and effects of pharmacologic chaperone treatment in a mouse model. AB - Defective lysosomal acid beta-glucosidase (GCase) in Gaucher disease causes accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) that distress cellular functions. To study novel pathological mechanisms in neuronopathic Gaucher disease (nGD), a mouse model (4L;C*), an analogue to subacute human nGD, was investigated for global profiles of differentially expressed brain mRNAs (DEGs) and miRNAs (DEmiRs). 4L;C* mice displayed accumulation of GC and GS, activated microglial cells, reduced number of neurons and aberrant mitochondrial function in the brain followed by deterioration in motor function. DEGs and DEmiRs were characterized from sequencing of mRNA and miRNA from cerebral cortex, brain stem, midbrain and cerebellum of 4L;C* mice. Gene ontology enrichment and pathway analysis showed preferential mitochondrial dysfunction in midbrain and uniform inflammatory response and identified novel pathways, axonal guidance signaling, synaptic transmission, eIF2 and mammalian target of rapamycin (mTOR) signaling potentially involved in nGD. Similar analyses were performed with mice treated with isofagomine (IFG), a pharmacologic chaperone for GCase. IFG treatment did not alter the GS and GC accumulation significantly but attenuated the progression of the disease and altered numerous DEmiRs and target DEGs to their respective normal levels in inflammation, mitochondrial function and axonal guidance pathways, suggesting its regulation on miRNA and the associated mRNA that underlie the neurodegeneration in nGD. These analyses demonstrate that the neurodegenerative phenotype in 4L;C* mice was associated with dysregulation of brain mRNAs and miRNAs in axonal guidance, synaptic plasticity, mitochondria function, eIF2 and mTOR signaling and inflammation and provides new insights for the nGD pathological mechanism. PMID- 26420840 TI - A neural crest origin for cohesinopathy heart defects. AB - Mutations in subunits or regulators of cohesin cause a spectrum of disorders in humans known as the 'cohesinopathies'. Cohesinopathies, including the best known example Cornelia de Lange syndrome (CdLS), are characterized by broad spectrum, multifactorial developmental anomalies. Heart defects occur at high frequency and can reach up to 30% in CdLS. The mechanisms by which heart defects occur are enigmatic, but assumed to be developmental in origin. In this study, we depleted cohesin subunit Rad21 by 70-80% in a zebrafish cohesinopathy model. The hearts of Rad21-depleted animals were smaller, often failed to loop, and functioned less efficiently than size-matched controls. Functional deficiency was accompanied by valve defects and reduced ejection fraction. Interestingly, neural crest cells failed to populate the heart and instead exhibited a wandering behavior. Consequently, these cells also failed to condense correctly into pharyngeal arches. Transcriptome analysis revealed that Wnt pathway, chemokine and cadherin genes are dysregulated at the time of cardiac neural crest development. Our results give insight into the etiology of heart defects in the cohesinopathies, and raise the possibility that mild mutations in cohesin genes may be causative of a fraction of congenital heart disease in human populations. PMID- 26420841 TI - Mutsbeta generates both expansions and contractions in a mouse model of the Fragile X-associated disorders. AB - Fragile X-associated disorders are Repeat Expansion Diseases that result from expansion of a CGG/CCG-repeat in the FMR1 gene. Contractions of the repeat tract also occur, albeit at lower frequency. However, these contractions can potentially modulate disease symptoms or generate an allele with repeat numbers in the normal range. Little is known about the expansion mechanism and even less about contractions. We have previously demonstrated that the mismatch repair (MMR) protein MSH2 is required for expansions in a mouse model of these disorders. Here, we show that MSH3, the MSH2-binding partner in the MutSbeta complex, is required for 98% of germ line expansions and all somatic expansions in this model. In addition, we provide evidence for two different contraction mechanisms that operate in the mouse model, a MutSbeta-independent one that generates small contractions and a MutSbeta-dependent one that generates larger ones. We also show that MutSbeta complexes formed with the repeats have altered kinetics of ATP hydrolysis relative to complexes with bona fide MMR substrates and that MutSbeta increases the stability of the CCG-hairpins at physiological temperatures. These data may have important implications for our understanding of the mechanism(s) of repeat instability and for the role of MMR proteins in this process. PMID- 26420844 TI - Allee effects in tritrophic food chains: some insights in pest biological control. AB - Release of natural enemies to control pest populations is a common strategy in biological control. However, its effectiveness is supposed to be impaired, among other factors, by Allee effects in the biological control agent and by the fact that introduced pest natural enemies interact with some native species of the ecosystem. In this work, we devise a tritrophic food chain model where the assumptions previously raised are proved correct when a hyperpredator attacks the introduced pest natural enemy by a functional response type 2 or 3. Moreover, success of pest control is shown to be related to the release of large amounts (i.e., inundative releases) of natural enemies. PMID- 26420842 TI - Improved dual AAV vectors with reduced expression of truncated proteins are safe and effective in the retina of a mouse model of Stargardt disease. AB - Stargardt disease (STGD1) due to mutations in the large ABCA4 gene is the most common inherited macular degeneration in humans. We have shown that dual adeno associated viral (AAV) vectors effectively transfer ABCA4 to the retina of Abca4 /- mice. However, they express both lower levels of transgene compared with a single AAV and truncated proteins. To increase productive dual AAV concatemerization, which would overcome these limitations, we have explored the use of either various regions of homology or heterologous inverted terminal repeats (ITR). In addition, we tested the ability of various degradation signals to decrease the expression of truncated proteins. We found the highest levels of transgene expression using regions of homology based on either alkaline phosphatase or the F1 phage (AK). The use of heterologous ITR does not decrease the levels of truncated proteins relative to full-length ABCA4 and impairs AAV vector production. Conversely, the inclusion of the CL1 degradation signal results in the selective degradation of truncated proteins from the 5'-half without affecting full-length protein production. Therefore, we developed dual AAV hybrid ABCA4 vectors including homologous ITR2, the photoreceptor-specific G protein-coupled receptor kinase 1 promoter, the AK region of homology and the CL1 degradation signal. We show that upon subretinal administration these vectors are both safe in pigs and effective in Abca4-/- mice. Our data support the use of improved dual AAV vectors for gene therapy of STGD1. PMID- 26420843 TI - A study of whirlin isoforms in the mouse vestibular system suggests potential vestibular dysfunction in DFNB31-deficient patients. AB - The DFNB31 gene plays an indispensable role in the cochlea and retina. Mutations in this gene disrupt its various isoforms and lead to non-syndromic deafness, blindness and deaf-blindness. However, the known expression of Dfnb31, the mouse ortholog of DFNB31, in vestibular organs and the potential vestibular-deficient phenotype observed in one Dfnb31 mutant mouse (Dfnb31(wi/wi)) suggest that DFNB31 may also be important for vestibular function. In this study, we find that full length (FL-) and C-terminal (C-) whirlin isoforms are expressed in the vestibular organs, where their stereociliary localizations are similar to those of developing cochlear inner hair cells. No whirlin is detected in Dfnb31(wi/wi) vestibular organs, while only C-whirlin is expressed in Dfnb31(neo/neo) vestibular organs. Both FL- and C-whirlin isoforms are required for normal vestibular stereociliary growth, although they may play slightly different roles in the central and peripheral zones of the crista ampullaris. Vestibular sensory evoked potentials demonstrate severe to profound vestibular deficits in Dfnb31(neo/neo) and Dfnb31(wi/wi) mice. Swimming and rotarod tests demonstrate that the two Dfnb31 mutants have balance problems, with Dfnb31(wi/wi) mice being more affected than Dfnb31(neo/neo) mice. Because Dfnb31(wi/wi) and Dfnb31(neo/neo) mice faithfully recapitulate hearing and vision symptoms in patients, our findings of vestibular dysfunction in these Dfnb31 mutants raise the question of whether DFNB31-deficient patients may acquire vestibular as well as hearing and vision loss. PMID- 26420845 TI - Utilizing community and voluntary sector partnerships to survey and compare the health outcomes of hard-to- reach groups to the wider community-the EURO- URHIS 2 Hard-to-Reach Project. AB - Background: This article describes the Hard-to-Reach (HtR) Project that was developed to capture health and lifestyle data from groups who are HtR by postal surveys within the larger EURO-URHIS 2 project. By collaborating with partner organizations, data were collected using standard survey tools, allowing for comparison with the wider population. Following a scoping exercise to determine which groups were HtR in Greater Manchester, black and minority ethnic (BME) groups and students were selected. BME groups were surveyed through partnership with Community and Voluntary Sector Organizations (CVSOs). Language barriers were addressed through the recruitment of volunteer interpreters. Students were surveyed by accessing university premises. Fifteen survey visits took place at nine CVSOs and five visits to University facilities. In total, 144 eligible surveys were collected. There were significant differences for both HtR groups, compared with Greater Manchester and the EURO-URHIS 2 mean. Both HtR groups had worse outcomes than both Greater Manchester and EURO-URHIS 2 for psychological problems. In addition, students had worse outcomes for passive smoking, binge drinking, use of cannabis, lack of access to green spaces, less sense of belonging and social cohesion and damp or mildewed homes, and better outcomes for self-perceived health and overweight and obesity. BME had in addition worse outcomes than both Greater Manchester and EURO-URHIS 2 for long-standing restrictive illness. Despite the limitations of this study, the development of this methodology allowed for the collection of comparable data, showing up statistically significant differences between the HtR populations and the wider population which merits further investigation. PMID- 26420846 TI - Suicide mortality at time of armed conflict in Ukraine. AB - The purpose of this review is to explore the dynamics of suicide mortality rates in Ukraine during an ongoing armed conflict between 2014 and 2015. Suicide mortality data were obtained by reviewing annual analytical releases from the State Service for Emergent Situations of Ukraine and annual release of Russian Federal Service of State Statistics. Suicide mortality in mainland Ukraine and in the Crimea region demonstrated a mild decrease, whereas suicide mortality in the regions directly involved in the armed conflict demonstrated a prominent decrease. The results of this review support Durkheim theory. The limitation of this review includes general concern about quality of data at time of armed conflict in the country. PMID- 26420847 TI - A retrospective evaluation of the intrauterine device in a patient population in Buenos Aires, Argentina. AB - BACKGROUND: The intrauterine device (IUD) is a long-acting reversible contraceptive method that is safe for a wide range of women, including adolescents and nulliparous women. Globally, it is often underutilised due to misperceptions among patients. Examination of characteristics associated with IUD discontinuation including adverse effects and IUD expulsion can inform provider practices to improve contraception success and patient satisfaction with this method. We studied IUD performance at a public family planning clinic in Buenos Aires, Argentina, serving a predominantly immigrant, low-income population. METHODS: We conducted a retrospective evaluation of 1047 IUD insertions between 2002 and 2007 with 5 years of follow-up data. We performed bivariate and survival analysis to examine characteristics associated with IUD discontinuation: adverse outcomes including pain, bleeding, and IUD expulsion, and time to removal. FINDINGS: Of 1047 patients, only 188 (18%) had their IUD removed within 5 years. The main causes of IUD discontinuation were involuntary (38%) reasons such as an IUD expulsion and personal choice (34%) such as desiring pregnancy. CONCLUSIONS: Findings suggest overall good long-term performance with IUD insertion, with minimal complaints or adverse outcomes. These findings may help to support providers serving similar populations in promoting this method. PMID- 26420848 TI - Prioritization in Somali health system strengthening: a qualitative study. AB - BACKGROUND: After years of decline and disintegration, the Somalia Federal Government alongside international and domestic partners is beginning the process of rebuilding its national health system. In this study, we aim to shed light on the current approaches to health system strengthening, as viewed by stakeholders closely involved in its development. METHODS: Key informant interviews were undertaken with health and development professionals working within all three administrative regions of Somalia, as well as with Somali ministry of health officials, global health and policy specialists with interests in health system reconstruction in fragile states. A review of published and grey literature on Somalia, health systems, fragile and conflict-affected countries using PubMed and Reliefweb was also conducted. Technical documents designed for Somali health system building by external development partners were also reviewed. RESULTS: Key priorities identified by participants were, strengthening of local governance and management capacity, scaling-up efforts to structure a robust health financing mechanism, engagement with the burgeoning and dynamic private sector, as well as investing in the appropriate human resources for health. CONCLUSIONS: The study found that there was widespread agreement among participants that health system strengthening through a coordinated system would improve long-term capacity in Somalia's health sector. Future research should focus on the evaluation of the modalities by which health system strengthening interventions are implemented, on neglected topics such as mental health within the Somali health system, as well as on population-level barriers to accessing health systems. PMID- 26420849 TI - Multitargeting of selected prostanoid receptors provides agents with enhanced anti-inflammatory activity in macrophages. AB - A polypharmacologic approach to prostanoid based anti-inflammatory therapeutics was undertaken in order to exploit both the anti- and proinflammatory properties attributed to the various prostanoid receptors. Multitargeting of selected prostanoid receptors yielded a prototype compound, compound 1 (AGN 211377), that antagonizes prostaglandin D2 receptors (DPs) DP1 (49) and DP2 (558), prostaglandin E2 receptors (EPs) EP1 (266) and EP4 (117), prostaglandin F2alpha receptor (FP) (61), and thromboxane A2 receptor (TP) (11) while sparing EP2, EP3, and prostaglandin I2 receptors (IPs); Kb values (in nanomoles) are given in parentheses. Compound 1 evoked a pronounced inhibition of cytokine/chemokine secretion from lipopolysaccharide or TNF-alpha stimulated primary human macrophages. These cytokine/chemokines included cluster of designation 40 receptor (CD40), epithelial-derived neutrophil-activating protein 78 (ENA-78), granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), IL-8, IL-18, monocyte chemotactic protein-1 (CCL2) (MCP-1), tissue plasminogen activator inhibitor (PAI-1), and regulated on activation, normal T cell expressed and secreted (RANTES). In contrast, the inhibitory effects of most antagonists selective for a single receptor were modest or absent, and selective EP2 receptor blockade increased cytokine release in some instances. Compound 1 also showed clear superiority to the cyclooxygenase inhibitors diclofenac and rofecoxib. These findings reveal that blockade of multiple prostanoid receptors, with absent antagonism of EP2 and IP, may provide more effective anti-inflammatory activity than global suppression of prostanoid synthesis or highly selective prostanoid receptor blockade. These investigations demonstrate the first working example of prostanoid receptor polypharmacology for potentially safer and more effective anti-inflammatory therapeutics by blocking multiple proinflammatory receptors while sparing those with anti-inflammatory activity. PMID- 26420851 TI - Enhanced butyrate formation by cross-feeding between Faecalibacterium prausnitzii and Bifidobacterium adolescentis. AB - Cross-feeding is an important metabolic interaction mechanism of bacterial groups inhabiting the human colon and includes features such as the utilization of acetate by butyrate-producing bacteria as may occur between Bifidobacterium and Faecalibacterium genera. In this study, we assessed the utilization of different carbon sources (glucose, starch, inulin and fructooligosaccharides) by strains of both genera and selected the best suited combinations for evidencing this cross feeding phenomenon. Co-cultures of Bifidobacterium adolescentis L2-32 with Faecalibacterium prausnitzii S3/L3 with fructooligosaccharides as carbon source, as well as with F. prausnitzii A2-165 in starch, were carried out and the production of short-chain fatty acids was determined. In both co-cultures, acetate levels decreased between 8 and 24 h of incubation and were lower than in the corresponding B. adolescentis monocultures. In contrast, butyrate concentrations were higher in co-cultures as compared to the respective F. prausnitzii monocultures, indicating enhanced formation of butyrate by F. prausnitzii in the presence of the bifidobacteria. Variations in the levels of acetate and butyrate were more pronounced in the co-culture with fructooligosaccharides than with starch. Our results provide a clear demonstration of cross-feeding between B. adolescentis and F. prausnitzii. PMID- 26420852 TI - Inhibiting NAD+-dependent DNA ligase activity with 2-(cyclopentyloxy)-5' deoxyadenosine (CPOdA) offers a new tool for DNA replication and repair studies in the model archaeon Haloferax volcanii. AB - DNA ligases play an essential role in many aspects of DNA metabolism in all three domains of life. The haloarchaeal organism Haloferax volcanii encodes both ATP- and NAD(+)-dependent DNA ligase enzymes designated LigA and LigN, respectively. Neither LigA nor LigN alone is required for cell viability but they share an essential function, most likely the ligation of Okazaki fragments during chromosome replication. Here we show that 2-(cyclopentyloxy)-5'-deoxyadenosine (referred to as CPOdA), originally developed as a inhibitor of bacterial NAD(+) dependent DNA ligases, is a potent inhibitor of the growth of Hfx. volcanii cells expressing LigN alone, causing chromosome fragmentation and cell death, while cells expressing LigA are unaffected. Growth inhibition occurs at significantly lower CPOdA concentrations (MIC <= 50 ng ml(-1)) than those required for inhibition of bacterial growth (>=2 MUg ml(-1)). CPOdA has the potential to become a vital tool in DNA replication and repair studies in this important model organism. PMID- 26420853 TI - Spontaneous and on point: Do spontaneous mutations used for laboratory experiments cause pleiotropic effects that might confound bacterial infection and evolution assays? AB - Many selectable phenotypes in microbial systems, including antibiotic resistance, can be conferred by single point mutations. This is frequently exploited in research, where the selection and use of microbial mutants that are spontaneously resistant to antibiotics like rifampicin and streptomycin facilitate the recovery and/or quantification of a target microbe. Such mutations are commonly employed as genetic markers for in vitro and in vivo experiments, often with little consideration as to the ultimate system-level impact of these single nucleotide mutations on the physiology of the microbe. There is substantial literature on the pleiotropic effects of point mutations conferring antibiotic resistance; yet, it is unclear whether this work is considered by the research communities outside of the discipline. This review examines some of the known pleiotropic effects of point mutations that provide selectable resistance markers, and how these mutations may impact general physiology and growth in host and non-host environments. PMID- 26420855 TI - Extent and Location of Tumor-Infiltrating Lymphocytes in Microsatellite-Stable Colon Cancer Predict Outcome to Adjuvant Active Specific Immunotherapy. AB - PURPOSE: To determine the prognostic and predictive value of tumor-infiltrating lymphocytes (TIL) in colon cancer in a cohort of patients who previously took part in a trial on adjuvant active specific immunotherapy (ASI). EXPERIMENTAL DESIGN: We determined the number and location of CD3 and CD8 positive T cells in archival tumor samples of 106 colon cancers. We correlated stromal and epithelial TIL numbers with tumor stage and treatment and determined the effects on disease specific survival (DSS) and recurrence-free interval (RFI). RESULTS: On the basis of the data presented, we concluded that (i) high numbers of stromal CD3 T cells have positive prognostic value measured as DSS for patients with stage II microsatellite-stable tumors and (ii) high numbers of epithelial CD8-positive T cells have positive prognostic value measured as RFI for the group of patients with stage II microsatellite-stable tumors as well as for the whole group (so stage II plus stage III together). Furthermore, we concluded that high numbers of pre-existing stromal CD3-positive T cells are of positive predictive value in adjuvant ASI treatment measured as DSS as well as RFI. CONCLUSIONS: ASI therapy may contribute to an improved DSS and RFI in patients with microsatellite-stable colon tumors harboring high numbers of pre-existing stromal CD3(+) TIL. Validation in future clinical trials is awaited. PMID- 26420854 TI - Local HPV Recombinant Vaccinia Boost Following Priming with an HPV DNA Vaccine Enhances Local HPV-Specific CD8+ T-cell-Mediated Tumor Control in the Genital Tract. AB - PURPOSE: Two viral oncoproteins, E6 and E7, are expressed in all human papillomavirus (HPV)-infected cells, from initial infection in the genital tract to metastatic cervical cancer. Intramuscular vaccination of women with high-grade cervical intraepithelial neoplasia (CIN2/3) twice with a naked DNA vaccine, pNGVL4a-sig/E7(detox)/HSP70, and a single boost with HPVE6/E7 recombinant vaccinia vaccine (TA-HPV) elicited systemic HPV-specific CD8 T-cell responses that could traffic to the lesion and was associated with regression in some patients (NCT00788164). EXPERIMENTAL DESIGN: Here, we examine whether alteration of this vaccination regimen by administration of TA-HPV vaccination in the cervicovaginal tract, rather than intramuscular (IM) delivery, can more effectively recruit antigen-specific T cells in an orthotopic syngeneic mouse model of HPV16(+) cervical cancer (TC-1 luc). RESULTS: We found that pNGVL4a sig/E7(detox)/HSP70 vaccination followed by cervicovaginal vaccination with TA HPV increased accumulation of total and E7-specific CD8(+) T cells in the cervicovaginal tract and better controlled E7-expressing cervicovaginal TC-1 luc tumor than IM administration of TA-HPV. Furthermore, the E7-specific CD8(+) T cells in the cervicovaginal tract generated through the cervicovaginal route of vaccination expressed the alpha4beta7 integrin and CCR9, which are necessary for the homing of the E7-specific CD8(+) T cells to the cervicovaginal tract. Finally, we show that cervicovaginal vaccination with TA-HPV can induce potent local HPV-16 E7 antigen-specific CD8(+) T-cell immune responses regardless of whether an HPV DNA vaccine priming vaccination was administered IM or within the cervicovaginal tract. CONCLUSIONS: Our results support future clinical translation using cervicovaginal TA-HPV vaccination. PMID- 26420857 TI - Pan-HER Inhibitor Augments Radiation Response in Human Lung and Head and Neck Cancer Models. AB - PURPOSE: Aberrant regulation of the EGF receptor family (EGFR, HER2, HER3, HER4) contributes to tumorigenesis and metastasis in epithelial cancers. Pan-HER represents a novel molecular targeted therapeutic composed of a mixture of six monoclonal antibodies against EGFR, HER2, and HER3. EXPERIMENTAL DESIGN: In the current study, we examine the capacity of Pan-HER to augment radiation response across a series of human lung and head and neck cancers, including EGFR inhibitor resistant cell lines and xenografts. RESULTS: Pan-HER demonstrates superior antiproliferative and radiosensitizing impact when compared with cetuximab. The mechanisms underlying these effects appear to involve attenuation of DNA damage repair, enhancement of programmed cell death, cell-cycle redistribution, and induction of cellular senescence. Combined treatment of Pan-HER with single or fractionated radiation in human tumor xenografts reveals a potent antitumor and regrowth delay impact compared with Pan-HER or radiation treatment alone. CONCLUSIONS: These data highlight the capacity of Pan-HER to augment radiation response in lung and head and neck cancer models and support investigation of Pan HER combined with radiation as a promising clinical therapeutic strategy. PMID- 26420856 TI - Molecular Pathways: Targeting Diacylglycerol Kinase Alpha in Cancer. AB - Lipid kinases have largely been neglected as targets in cancer, and an increasing number of reports suggest diacylglycerol kinase alpha (DGKalpha) may be one with promising therapeutic potential. DGKalpha is one of 10 DGK family members that convert diacylglycerol (DAG) to phosphatidic acid (PA), and both DAG and PA are critical lipid second messengers in the plasma membrane. A host of important oncogenic proteins and pathways affect cancer cells in part through DGKalpha, including the c-Met and VEGF receptors. Others partially mediate the effects of DGKalpha inhibition in cancer, such as mTOR and HIF-1alpha. DGKalpha inhibition can directly impair cancer cell viability, inhibits angiogenesis, and notably may also boost T-cell activation and enhance cancer immunotherapies. Although two structurally similar inhibitors of DGKalpha were established decades ago, they have seen minimal in vivo usage, and it is unlikely that either of these older DGKalpha inhibitors will have utility for cancer. An abandoned compound that also inhibits serotonin receptors may have more translational potential as a DGKalpha inhibitor, but more potent and specific DGKalpha inhibitors are sorely needed. Other DGK family members may also provide therapeutic targets in cancer, but require further investigation. PMID- 26420858 TI - A Patient-Derived, Pan-Cancer EMT Signature Identifies Global Molecular Alterations and Immune Target Enrichment Following Epithelial-to-Mesenchymal Transition. AB - PURPOSE: We previously demonstrated the association between epithelial-to mesenchymal transition (EMT) and drug response in lung cancer using an EMT signature derived in cancer cell lines. Given the contribution of tumor microenvironments to EMT, we extended our investigation of EMT to patient tumors from 11 cancer types to develop a pan-cancer EMT signature. EXPERIMENTAL DESIGN: Using the pan-cancer EMT signature, we conducted an integrated, global analysis of genomic and proteomic profiles associated with EMT across 1,934 tumors including breast, lung, colon, ovarian, and bladder cancers. Differences in outcome and in vitro drug response corresponding to expression of the pan-cancer EMT signature were also investigated. RESULTS: Compared with the lung cancer EMT signature, the patient-derived, pan-cancer EMT signature encompasses a set of core EMT genes that correlate even more strongly with known EMT markers across diverse tumor types and identifies differences in drug sensitivity and global molecular alterations at the DNA, RNA, and protein levels. Among those changes associated with EMT, pathway analysis revealed a strong correlation between EMT and immune activation. Further supervised analysis demonstrated high expression of immune checkpoints and other druggable immune targets, such as PD1, PD-L1, CTLA4, OX40L, and PD-L2, in tumors with the most mesenchymal EMT scores. Elevated PD-L1 protein expression in mesenchymal tumors was confirmed by IHC in an independent lung cancer cohort. CONCLUSIONS: This new signature provides a novel, patient-based, histology-independent tool for the investigation of EMT and offers insights into potential novel therapeutic targets for mesenchymal tumors, independent of cancer type, including immune checkpoints. PMID- 26420860 TI - The Metabolic Regulator Histone Deacetylase 9 Contributes to Glucose Homeostasis Abnormality Induced by Hepatitis C Virus Infection. AB - Class IIa histone deacetylases (HDACs), such as HDAC4, HDAC5, and HDAC7, provide critical mechanisms for regulating glucose homeostasis. Here we report that HDAC9, another class IIa HDAC, regulates hepatic gluconeogenesis via deacetylation of a Forkhead box O (FoxO) family transcription factor, FoxO1, together with HDAC3. Specifically, HDAC9 expression can be strongly induced upon hepatitis C virus (HCV) infection. HCV-induced HDAC9 upregulation enhances gluconeogenesis by promoting the expression of gluconeogenic genes, including phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, indicating a major role for HDAC9 in the development of HCV-associated exaggerated gluconeogenic responses. Moreover, HDAC9 expression levels and gluconeogenic activities were elevated in livers from HCV-infected patients and persistent HCV-infected mice, emphasizing the clinical relevance of these results. Our results suggest HDAC9 is involved in glucose metabolism, HCV-induced abnormal glucose homeostasis, and type 2 diabetes. PMID- 26420861 TI - Protein Biomarkers for Insulin Resistance and Type 2 Diabetes Risk in Two Large Community Cohorts. AB - Insulin resistance (IR) is a precursor of type 2 diabetes (T2D), and improved risk prediction and understanding of the pathogenesis are needed. We used a novel high-throughput 92-protein assay to identify circulating biomarkers for HOMA of IR in two cohorts of community residents without diabetes (n = 1,367) (mean age 73 +/- 3.6 years). Adjusted linear regression identified cathepsin D and confirmed six proteins (leptin, renin, interleukin-1 receptor antagonist [IL 1ra], hepatocyte growth factor, fatty acid-binding protein 4, and tissue plasminogen activator [t-PA]) as IR biomarkers. Mendelian randomization analysis indicated a positive causal effect of IR on t-PA concentrations. Two biomarkers, IL-1ra (hazard ratio [HR] 1.28, 95% CI 1.03-1.59) and t-PA (HR 1.30, 1.02-1.65) were associated with incident T2D, and t-PA predicted 5-year transition to hyperglycemia (odds ratio 1.30, 95% CI 1.02-1.65). Additional adjustment for fasting glucose rendered both coefficients insignificant and revealed an association between renin and T2D (HR 0.79, 0.62-0.99). LASSO regression suggested a risk model including IL-1ra, t-PA, and the Framingham Offspring Study T2D score, but prediction improvement was nonsignificant (difference in C-index 0.02, 95% CI -0.08 to 0.12) over the T2D score only. In conclusion, proteomic blood profiling indicated cathepsin D as a new IR biomarker and suggested a causal effect of IR on t-PA. PMID- 26420862 TI - FGF1 Mediates Overnutrition-Induced Compensatory beta-Cell Differentiation. AB - Increased insulin demand resulting from insulin resistance and/or overnutrition induces a compensatory increase in beta-cell mass. The physiological factors responsible for the compensation have not been fully characterized. In zebrafish, overnutrition rapidly induces compensatory beta-cell differentiation through triggering the release of a paracrine signal from persistently activated beta cells. We identified Fgf1 signaling as a key component of the overnutrition induced beta-cell differentiation signal in a small molecule screen. Fgf1 was confirmed as the overnutrition-induced beta-cell differentiation signal, as inactivation of fgf1 abolished the compensatory beta-cell differentiation. Furthermore, expression of human FGF1 solely in beta-cells in fgf1(-/-) animals rescued the compensatory response, indicating that beta-cells can be the source of FGF1. Additionally, constitutive secretion of FGF1 with an exogenous signal peptide increased beta-cell number in the absence of overnutrition. These results demonstrate that fgf1 is necessary and FGF1 expression in beta-cells is sufficient for the compensatory beta-cell differentiation. We further show that FGF1 is secreted during prolonged activation of cultured mammalian beta-cells and that endoplasmic reticulum stress acts upstream of FGF1 release. Thus, the recently discovered antidiabetes function of FGF1 may act partially through increasing beta-cell differentiation. PMID- 26420863 TI - American Diabetes Association and JDRF Research Symposium: Diabetes and the Microbiome. AB - From 27-29 October 2014, more than 100 people gathered in Chicago, IL, to participate in a research symposium titled "Diabetes and the Microbiome," jointly sponsored by the American Diabetes Association and JDRF. The conference brought together international scholars and trainees from multiple disciplines, including microbiology, bioinformatics, endocrinology, metabolism, and immunology, to share the current understanding of host-microbe interactions and their influences on diabetes and metabolism. Notably, this gathering was the first to assemble specialists with distinct expertise in type 1 diabetes, type 2 diabetes, immunology, and microbiology with the goal of discussing and defining potential pathophysiologies linking the microbiome and diabetes. In addition to reviewing existing evidence in the field, speakers presented their own original research to provide a comprehensive view of the current understanding of the topics under discussion.Presentations and discussions throughout the conference reflected a number of important concepts. The microbiota in any host represent a complex ecosystem with a high degree of interindividual variability. Different microbial communities, comprising bacteria, archaea, viruses, and fungi, occupy separate niches in and on the human body. Individually and collectively, these microbes provide benefits to the host-including nutrient harvest from food and protection against pathogens. They are dynamically regulated by both host genes and the environment, and they critically influence both physiology and lifelong health. The objective of the symposium was to discuss the relationship between the host and the microbiome-the combination of microbiota and their biomolecular environment and ecology-specifically with regard to metabolic and immunological systems and to define the critical research needed to understand and potentially target the microbiome in the prevention and treatment of diabetes. In this report, we present meeting highlights in the following areas: 1) relationships between diabetes and the microbiome, 2) bioinformatic tools, resources, and study design considerations, 3) microbial programming of the immune system, 4) the microbiome and energy balance, 5) interventions, and 6) limitations, unanswered questions, and resource and policy needs. PMID- 26420865 TI - SPARC triggers a cell-autonomous program of synapse elimination. AB - Elimination of the excess synaptic contacts established in the early stages of neuronal development is required to refine the function of neuronal circuits. Here we investigate whether secreted protein acidic and rich in cysteine (SPARC), a molecule produced by glial cells, is involved in synapse removal. SPARC production peaks when innervation of the rat superior cervical ganglion and the tail of Xenopus tropicalis tadpoles are remodeled. The formation of new cholinergic synapses in autaptic single-cell microcultures is inhibited by SPARC. The effect resides in the C-terminal domain, which is also responsible for triggering a concentration- and time-dependent disassembly of stable cholinergic synapses. The loss of synaptic contacts is associated with the formation of retracted axon terminals containing multivesicular bodies and secondary lysosomes. The biological relevance of in vitro results was supported by injecting the tail of Xenopus tropicalis tadpoles with peptide 4.2, a 20-aa sequence derived from SPARC that mimics full-length protein effects. Swimming was severely impaired at ~5 h after peptide application, caused by the massive elimination of neuromuscular junctions and pruning of axonal branches. Effects revert by 6 d after injection, as motor innervation reforms. In conclusion, SPARC triggers a cell-autonomous program of synapse elimination in cholinergic neurons that likely occurs when protein production peaks during normal development. PMID- 26420864 TI - Discriminating direct and indirect connectivities in biological networks. AB - Reverse engineering of biological pathways involves an iterative process between experiments, data processing, and theoretical analysis. Despite concurrent advances in quality and quantity of data as well as computing resources and algorithms, difficulties in deciphering direct and indirect network connections are prevalent. Here, we adopt the notions of abstraction, emulation, benchmarking, and validation in the context of discovering features specific to this family of connectivities. After subjecting benchmark synthetic circuits to perturbations, we inferred the network connections using a combination of nonparametric single-cell data resampling and modular response analysis. Intriguingly, we discovered that recovered weights of specific network edges undergo divergent shifts under differential perturbations, and that the particular behavior is markedly different between topologies. Our results point to a conceptual advance for reverse engineering beyond weight inference. Investigating topological changes under differential perturbations may address the longstanding problem of discriminating direct and indirect connectivities in biological networks. PMID- 26420866 TI - Structural and evolutionary relationships of "AT-less" type I polyketide synthase ketosynthases. AB - Acyltransferase (AT)-less type I polyketide synthases (PKSs) break the type I PKS paradigm. They lack the integrated AT domains within their modules and instead use a discrete AT that acts in trans, whereas a type I PKS module minimally contains AT, acyl carrier protein (ACP), and ketosynthase (KS) domains. Structures of canonical type I PKS KS-AT didomains reveal structured linkers that connect the two domains. AT-less type I PKS KSs have remnants of these linkers, which have been hypothesized to be AT docking domains. Natural products produced by AT-less type I PKSs are very complex because of an increased representation of unique modifying domains. AT-less type I PKS KSs possess substrate specificity and fall into phylogenetic clades that correlate with their substrates, whereas canonical type I PKS KSs are monophyletic. We have solved crystal structures of seven AT-less type I PKS KS domains that represent various sequence clusters, revealing insight into the large structural and subtle amino acid residue differences that lead to unique active site topologies and substrate specificities. One set of structures represents a larger group of KS domains from both canonical and AT-less type I PKSs that accept amino acid-containing substrates. One structure has a partial AT-domain, revealing the structural consequences of a type I PKS KS evolving into an AT-less type I PKS KS. These structures highlight the structural diversity within the AT-less type I PKS KS family, and most important, provide a unique opportunity to study the molecular evolution of substrate specificity within the type I PKSs. PMID- 26420867 TI - Regulation of calreticulin-major histocompatibility complex (MHC) class I interactions by ATP. AB - The MHC class I peptide loading complex (PLC) facilitates the assembly of MHC class I molecules with peptides, but factors that regulate the stability and dynamics of the assembly complex are largely uncharacterized. Based on initial findings that ATP, in addition to MHC class I-specific peptide, is able to induce MHC class I dissociation from the PLC, we investigated the interaction of ATP with the chaperone calreticulin, an endoplasmic reticulum (ER) luminal, calcium binding component of the PLC that is known to bind ATP. We combined computational and experimental measurements to identify residues within the globular domain of calreticulin, in proximity to the high-affinity calcium-binding site, that are important for high-affinity ATP binding and for ATPase activity. High-affinity calcium binding by calreticulin is required for optimal nucleotide binding, but both ATP and ADP destabilize enthalpy-driven high-affinity calcium binding to calreticulin. ATP also selectively destabilizes the interaction of calreticulin with cellular substrates, including MHC class I molecules. Calreticulin mutants that affect ATP or high-affinity calcium binding display prolonged associations with monoglucosylated forms of cellular MHC class I, delaying MHC class I dissociation from the PLC and their transit through the secretory pathway. These studies reveal central roles for ATP and calcium binding as regulators of calreticulin-substrate interactions and as key determinants of PLC dynamics. PMID- 26420869 TI - Quantified abundance of magnetofossils at the Paleocene-Eocene boundary from synchrotron-based transmission X-ray microscopy. AB - The Paleocene-Eocene boundary (~55.8 million years ago) is marked by an abrupt negative carbon isotope excursion (CIE) that coincides with an oxygen isotope decrease interpreted as the Paleocene-Eocene thermal maximum. Biogenic magnetite (Fe3O4) in the form of giant (micron-sized) spearhead-like and spindle-like magnetofossils, as well as nano-sized magnetotactic bacteria magnetosome chains, have been reported in clay-rich sediments in the New Jersey Atlantic Coastal Plain and were thought to account for the distinctive single-domain magnetic properties of these sediments. Uncalibrated strong field magnet extraction techniques have been typically used to provide material for scanning and transmission electron microscopic imaging of these magnetic particles, whose concentration in the natural sediment is thus difficult to quantify. In this study, we use a recently developed ultrahigh-resolution, synchrotron-based, full field transmission X-ray microscope to study the iron-rich minerals within the clay sediment in their bulk state. We are able to estimate the total magnetization concentration of the giant biogenic magnetofossils to be only ~10% of whole sediment. Along with previous rock magnetic studies on the CIE clay, we suggest that most of the magnetite in the clay occurs as isolated, near equidimensional nanoparticles, a suggestion that points to a nonbiogenic origin, such as comet impact plume condensates in what may be very rapidly deposited CIE clays. PMID- 26420868 TI - Neurotransmission plays contrasting roles in the maturation of inhibitory synapses on axons and dendrites of retinal bipolar cells. AB - Neuronal output is modulated by inhibition onto both dendrites and axons. It is unknown whether inhibitory synapses at these two cellular compartments of an individual neuron are regulated coordinately or separately during in vivo development. Because neurotransmission influences synapse maturation and circuit development, we determined how loss of inhibition affects the expression of diverse types of inhibitory receptors on the axon and dendrites of mouse retinal bipolar cells. We found that axonal GABA but not glycine receptor expression depends on neurotransmission. Importantly, axonal and dendritic GABAA receptors comprise distinct subunit compositions that are regulated differentially by GABA release: Axonal GABAA receptors are down-regulated but dendritic receptors are up regulated in the absence of inhibition. The homeostatic increase in GABAA receptors on bipolar cell dendrites is pathway-specific: Cone but not rod bipolar cell dendrites maintain an up-regulation of receptors in the transmission deficient mutants. Furthermore, the bipolar cell GABAA receptor alterations are a consequence of impaired vesicular GABA release from amacrine but not horizontal interneurons. Thus, inhibitory neurotransmission regulates in vivo postsynaptic maturation of inhibitory synapses with contrasting modes of action specific to synapse type and location. PMID- 26420870 TI - Mutational analysis of Kaposica reveals that bridging of MG2 and CUB domains of target protein is crucial for the cofactor activity of RCA proteins. AB - The complement system has evolved to annul pathogens, but its improper regulation is linked with diseases. Efficient regulation of the system is primarily provided by a family of proteins termed regulators of complement activation (RCA). The knowledge of precise structural determinants of RCA proteins critical for imparting the regulatory activities and the molecular events underlying the regulatory processes, nonetheless, is still limited. Here, we have dissected the structural requirements of RCA proteins that are crucial for one of their two regulatory activities, the cofactor activity (CFA), by using the Kaposi's sarcoma associated herpesvirus RCA homolog Kaposica as a model protein. We have scanned the entire Kaposica molecule by sequential mutagenesis using swapping and site directed mutagenesis, which identified residues critical for its interaction with C3b and factor I. Mapping of these residues onto the modeled structure of C3b Kaposica-factor I complex supported the mutagenesis data. Furthermore, the model suggested that the C3b-interacting residues bridge the CUB (complement C1r-C1s, Uegf, Bmp1) and MG2 (macroglobulin-2) domains of C3b. Thus, it seems that stabilization of the CUB domain with respect to the core of the C3b molecule is central for its CFA. Identification of CFA-critical regions in Kaposica guided experiments in which the equivalent regions of membrane cofactor protein were swapped into decay-accelerating factor. This strategy allowed CFA to be introduced into decay-accelerating factor, suggesting that viral and human regulators use a common mechanism for CFA. PMID- 26420871 TI - Estimation of solid-liquid interfacial tension using curved surface of a soft solid. AB - Unlike liquids, for crystalline solids the surface tension is known to be different from the surface energy. However, the same cannot be said conclusively for amorphous materials like soft cross-linked elastomers. To resolve this issue we have introduced here a direct method for measuring solid-liquid interfacial tension by using the curved surface of a solid. In essence, we have used the inner surface of tiny cylindrical channels embedded inside a soft elastomeric film for sensing the effect of the interfacial tension. When a liquid is inserted into the channel, because of wetting-induced alteration in interfacial tension, its thin wall deflects considerably; the deflection is measured with an optical profilometer and analyzed using the Foppl-von Karman equation. We have used several liquids and cross-linked poly(dimethylsiloxane) as the solid to show that the estimated values of the solid-liquid interfacial tension matches with the corresponding solid-liquid interfacial energy reasonably well. PMID- 26420872 TI - Chemically tunable mucin chimeras assembled on living cells. AB - Mucins are a family of secreted and transmembrane glycoproteins characterized by a massive domain of dense O-glycosylation on serine and threonine residues. Mucins are intimately involved in immunity and cancer, yet elucidation of the biological roles of their glycodomains has been complicated by their massive size, domain polymorphisms, and variable glycosylation patterns. Here we developed a synthetic route to a library of compositionally defined, high molecular weight, dual end-functionalized mucin glycodomain constructs via N carboxyanhydride polymerization. These glycopolypeptides are the first synthetic analogs to our knowledge to feature the native alpha-GalNAc linkage to serine with molecular weights similar to native mucins, solving a nearly 50-year synthetic challenge. Physical characterization of the mimics revealed insights into the structure and properties of mucins. The synthetic glycodomains were end functionalized with an optical probe and a tetrazine moiety, which allowed site specific bioorthogonal conjugation to an engineered membrane protein on live mammalian cells. This strategy in protein engineering will open avenues to explore the biological roles of cell surface mucins. PMID- 26420873 TI - Wrinkles and splay conspire to give positive disclinations negative curvature. AB - Recently, there has been renewed interest in the coupling between geometry and topological defects in crystalline and striped systems. Standard lore dictates that positive disclinations are associated with positive Gaussian curvature, whereas negative disclinations give rise to negative curvature. Here, we present a diblock copolymer system exhibiting a striped columnar phase that preferentially forms wrinkles perpendicular to the underlying stripes. In free standing films this wrinkling behavior induces negative Gaussian curvature to form in the vicinity of positive disclinations. PMID- 26420874 TI - CD8 T-cell recognition of acquired alloantigen promotes acute allograft rejection. AB - Adaptive CD8 T-cell immunity is the principal arm of the cellular alloimmune response, but its development requires help. This can be provided by CD4 T cells that recognize alloantigen "indirectly," as self-restricted allopeptide, but this process remains unexplained, because the target epitopes for CD4 and CD8 T-cell recognition are "unlinked" on different cells (recipient and donor antigen presenting cells (APCs), respectively). Here, we test the hypothesis that the presentation of intact and processed MHC class I alloantigen by recipient dendritic cells (DCs) (the "semidirect" pathway) allows linked help to be delivered by indirect-pathway CD4 T cells for generating destructive cytotoxic CD8 T-cell alloresponses. We show that CD8 T-cell-mediated rejection of murine heart allografts that lack hematopoietic APCs requires host secondary lymphoid tissue (SLT). SLT is necessary because within it, recipient dendritic cells can acquire MHC from graft parenchymal cells and simultaneously present it as intact protein to alloreactive CD8 T cells and as processed peptide alloantigen for recognition by indirect-pathway CD4 T cells. This enables delivery of essential help for generating cytotoxic CD8 T-cell responses that cause rapid allograft rejection. In demonstrating the functional relevance of the semidirect pathway to transplant rejection, our findings provide a solution to a long-standing conundrum as to why SLT is required for CD8 T-cell allorecognition of graft parenchymal cells and suggest a mechanism by which indirect-pathway CD4 T cells provide help for generating effector cytotoxic CD8 T-cell alloresponses at late time points after transplantation. PMID- 26420875 TI - Extinction reverses olfactory fear-conditioned increases in neuron number and glomerular size. AB - Although much work has investigated the contribution of brain regions such as the amygdala, hippocampus, and prefrontal cortex to the processing of fear learning and memory, fewer studies have examined the role of sensory systems, in particular the olfactory system, in the detection and perception of cues involved in learning and memory. The primary sensory receptive field maps of the olfactory system are exquisitely organized and respond dynamically to cues in the environment, remaining plastic from development through adulthood. We have previously demonstrated that olfactory fear conditioning leads to increased odorant-specific receptor representation in the main olfactory epithelium and in glomeruli within the olfactory bulb. We now demonstrate that olfactory extinction training specific to the conditioned odor stimulus reverses the conditioning associated freezing behavior and odor learning-induced structural changes in the olfactory epithelium and olfactory bulb in an odorant ligand-specific manner. These data suggest that learning-induced freezing behavior, structural alterations, and enhanced neural sensory representation can be reversed in adult mice following extinction training. PMID- 26420876 TI - Requirement of full TCR repertoire for regulatory T cells to maintain intestinal homeostasis. AB - The regulation of intestinal homeostasis by the immune system involves the dynamic interplay between gut commensal microbiota and resident immune cells. It is well known that a large and diverse lymphocyte antigen receptor repertoire enables the immune system to recognize and respond to a wide range of invading pathogens. There is also an emerging appreciation for a critical role the T-cell receptor (TCR) repertoire serves in the maintenance of peripheral tolerance by regulatory T cells (Tregs). Nevertheless, how the diversity of the TCR repertoire in Tregs affects intestinal homeostasis remains unknown. To address this question, we studied mice whose T cells express a restricted TCR repertoire. We observed the development of spontaneous colitis, accompanied by the induction of T-helper type 17 cells in the colon that is driven by gut commensal microbiota. We provide further evidence that a restricted TCR repertoire causes a loss of tolerogenicity to microbiota, accompanied by a paucity of peripherally derived, Helios(-) Tregs and hyperactivation of migratory dendritic cells. These results thus reveal a new facet of the TCR repertoire in which Tregs require a diverse TCR repitoire for intestinal homeostasis, suggesting an additional driving force in the evolutional significance of the TCR repertoire. PMID- 26420877 TI - Connectivity Map-based discovery of parbendazole reveals targetable human osteogenic pathway. AB - Osteoporosis is a common skeletal disorder characterized by low bone mass leading to increased bone fragility and fracture susceptibility. In this study, we have identified pathways that stimulate differentiation of bone forming osteoblasts from human mesenchymal stromal cells (hMSCs). Gene expression profiling was performed in hMSCs differentiated toward osteoblasts (at 6 h). Significantly regulated genes were analyzed in silico, and the Connectivity Map (CMap) was used to identify candidate bone stimulatory compounds. The signature of parbendazole matches the expression changes observed for osteogenic hMSCs. Parbendazole stimulates osteoblast differentiation as indicated by increased alkaline phosphatase activity, mineralization, and up-regulation of bone marker genes (alkaline phosphatase/ALPL, osteopontin/SPP1, and bone sialoprotein II/IBSP) in a subset of the hMSC population resistant to the apoptotic effects of parbendazole. These osteogenic effects are independent of glucocorticoids because parbendazole does not up-regulate glucocorticoid receptor (GR) target genes and is not inhibited by the GR antagonist mifepristone. Parbendazole causes profound cytoskeletal changes including degradation of microtubules and increased focal adhesions. Stabilization of microtubules by pretreatment with Taxol inhibits osteoblast differentiation. Parbendazole up-regulates bone morphogenetic protein 2 (BMP-2) gene expression and activity. Cotreatment with the BMP-2 antagonist DMH1 limits, but does not block, parbendazole-induced mineralization. Using the CMap we have identified a previously unidentified lineage-specific, bone anabolic compound, parbendazole, which induces osteogenic differentiation through a combination of cytoskeletal changes and increased BMP-2 activity. PMID- 26420878 TI - ATP11C mutation is responsible for the defect in phosphatidylserine uptake in UPS 1 cells. AB - Type IV P-type ATPases (P4-ATPases) translocate phospholipids from the exoplasmic to the cytoplasmic leaflets of cellular membranes. We and others previously showed that ATP11C, a member of the P4-ATPases, translocates phosphatidylserine (PS) at the plasma membrane. Twenty years ago, the UPS-1 (uptake of fluorescent PS analogs) cell line was isolated from mutagenized Chinese hamster ovary (CHO) K1 cells with a defect in nonendocytic uptake of nitrobenzoxadiazole PS. Due to its defect in PS uptake, the UPS-1 cell line has been used in an assay for PS flipping activity; however, the gene(s) responsible for the defect have not been identified to date. Here, we found that the mRNA level of ATP11C was dramatically reduced in UPS-1 cells relative to parental CHO-K1 cells. By contrast, the level of ATP11A, another PS-flipping P4-ATPase at the plasma membrane, or CDC50A, which is essential for delivery of most P4-ATPases to the plasma membrane, was not affected in UPS-1 cells. Importantly, we identified a nonsense mutation in the ATP11C gene in UPS-1 cells, indicating that the intact ATP11C protein is not expressed. Moreover, exogenous expression of ATP11C can restore PS uptake in UPS 1 cells. These results indicate that lack of the functional ATP11C protein is responsible for the defect in PS uptake in UPS-1 cells and ATP11C is crucial for PS flipping in CHO-K1 cells. PMID- 26420879 TI - Quantitative GSL-glycome analysis of human whole serum based on an EGCase digestion and glycoblotting method. AB - Glycosphingolipids (GSLs) are lipid molecules linked to carbohydrate units that form the plasma membrane lipid raft, which is clustered with sphingolipids, sterols, and specific proteins, and thereby contributes to membrane physical properties and specific recognition sites for various biological events. These bioactive GSL molecules consequently affect the pathophysiology and pathogenesis of various diseases. Thus, altered expression of GSLs in various diseases may be of importance for disease-related biomarker discovery. However, analysis of GSLs in blood is particularly challenging because GSLs are present at extremely low concentrations in serum/plasma. In this study, we established absolute GSL-glycan analysis of human serum based on endoglycoceramidase digestion and glycoblotting purification. We established two sample preparation protocols, one with and the other without GSL extraction using chloroform/methanol. Similar amounts of GSL glycans were recovered with the two protocols. Both protocols permitted absolute quantitation of GSL-glycans using as little as 20 MUl of serum. Using 10 healthy human serum samples, up to 42 signals corresponding to GSL-glycan compositions could be quantitatively detected, and the total serum GSL-glycan concentration was calculated to be 12.1-21.4 MUM. We further applied this method to TLC prefractionated serum samples. These findings will assist the discovery of disease-related biomarkers by serum GSL-glycomics. PMID- 26420880 TI - Site specificity analysis of Piccolo NuA4-mediated acetylation for different histone complexes. AB - We have a limited understanding of the site specificity of multi-subunit lysine acetyltransferase (KAT) complexes for histone-based substrates, especially in regards to the different complexes formed during nucleosome assembly. Histone complexes could be a major factor in determining the acetylation specificity of KATs. In the present study, we utilized a label-free quantitative MS-based method to determine the site specificity of acetylation catalysed by Piccolo NuA4 on (H3/H4)2 tetramer, tetramer bound DNA (tetrasome) and nucleosome core particle (NCP). Our results show that Piccolo NuA4 can acetylate multiple lysine residues on these three histone complexes, of which NCP is the most favourable, (H3/H4)2 tetramer is the second and tetrasome is the least favourable substrate for Piccolo NuA4 acetylation. Although Piccolo NuA4 preferentially acetylates histone H4 (H4K12), the site specificity of the enzyme is altered with different histone complex substrates. Our results show that before nucleosome assembly is complete, H3K14 specificity is almost equal to that of H4K12 and DNA-histone interactions suppress the acetylation ability of Piccolo NuA4. These data suggest that the H2A/H2B dimer could play a critical role in the increase in acetylation specificity of Piccolo NuA4 for NCP. This demonstrates that histone complex formation can alter the acetylation preference of Piccolo NuA4. Such findings provide valuable insight into regulating Piccolo NuA4 specificity by modulating chromatin dynamics and in turn manipulating gene expression. PMID- 26420881 TI - Biological insights into the expression of translation initiation factors from recombinant CHOK1SV cell lines and their relationship to enhanced productivity. AB - Translation initiation is on the critical pathway for the production of monoclonal antibodies (mAbs) by mammalian cells. Formation of a closed loop structure comprised of mRNA, a number of eukaryotic initiation factors (eIFs) and ribosomal proteins has been proposed to aid re-initiation of translation and therefore increase global translational efficiency. We have determined mRNA and protein levels of the key components of the closed loop, eIFs (eIF3a, eIF3b, eIF3c, eIF3h, eIF3i and eIF4G1), poly(A)-binding protein (PABP) 1 and PABP interacting protein 1 (PAIP1), across a panel of 30 recombinant mAb-producing GS CHOK1SV cell lines with a broad range of growth characteristics and production levels of a model recombinant mAb. We have used a multi-level statistical approach to investigate the relationship between key performance indicators (cell growth and recombinant antibody productivity) and the intracellular amounts of target translation initiation factor proteins and the mRNAs encoding them. We show that high-producing cell lines maintain amounts of the translation initiation factors involved in the formation of the closed loop mRNA, maintaining these proteins at appropriate levels to deliver enhanced recombinant protein production. We then utilize knowledge of the amounts of these factors to build predictive models for and use cluster analysis to identify, high-producing cell lines. The present study therefore defines the translation initiation factor amounts that are associated with highly productive recombinant GS-CHOK1SV cell lines that may be targets for screening highly productive cell lines or to engineer new host cell lines with the potential for enhanced recombinant antibody productivity. PMID- 26420882 TI - Predictive Value Tools as an Aid in Chemopreventive Agent Development. AB - BACKGROUND: Over 25 years, the National Cancer Institute's Division of Cancer Prevention has entered some 800 agents into a chemopreventive agent testing program. Two critical steps involve: 1) in vitro/in vivo morphologic assays and 2) animal tumor assays (incidence/multiplicity reduction). We sought to determine how accurately the earlier-stage (morphologic) assays predict efficacy in the later-stage (animal tumor) assays. METHODS: Focusing on 210 agents tested in both morphologic and animal tumor assays, we carried out statistical modeling of how well the six most commonly used morphologic assays predicted drug efficacy in animal tumor assays. Using multimodel inference, three statistical models were generated to evaluate the ability of these six morphologic assays to predict tumor outcomes in three different sets of animal tumor assays: 1) all tumor types, 2) mammary cancer only, and 3) colon cancer only. Using this statistical modeling approach, each morphologic assay was assigned a value reflecting how strongly it predicted outcomes in each of the three different sets of animal tumor assays. RESULTS: We demonstrated differences in the predictive value of specific morphologic assays for positive animal tumor assay results. Some of the morphologic assays were strongly predictive of meaningful positive efficacy outcomes in animal tumor assays representing specific cancer types, particularly the aberrant crypt focus (ACF) assay for colon cancer. Moreover, less strongly predictive assays can be combined and sequenced, resulting in enhanced composite predictive ability. CONCLUSIONS: Predictive models such as these could be used to guide selection of preventive agents as well as morphologic and animal tumor assays, thereby improving the efficiency of our approach to chemopreventive agent development. PMID- 26420883 TI - How to Rationally Identify Promising Cancer Chemoprevention Agents? PMID- 26420884 TI - Strokes happen round the clock, but why is stroke care worse on weekends and overnight? PMID- 26420885 TI - Does age affect surgical outcomes in patients with degenerative cervical myelopathy? Results from the prospective multicenter AOSpine International study on 479 patients. AB - BACKGROUND: In general, older patients with degenerative cervical myelopathy (DCM) are felt to have lower recovery potential following surgery due to increased degenerative pathology, comorbidities, reduced physiological reserves and age-related changes to the spinal cord. This study aims to determine whether age truly is an independent predictor of surgical outcome and to provide evidence to guide practice and decision-making. METHODS: A total of 479 patients with DCM were prospectively enrolled in the CSM-International study at 16 centres. Our sample was divided into a younger group (<65 years) and an elderly (>=65 years) group. A mixed model analytic approach was used to evaluate differences in the modified Japanese Orthopaedic Association (mJOA), Nurick, Short Form-36 (SF-36) and Neck Disability Index (NDI) scores between groups. We first created an unadjusted model between age and surgical outcome and then developed two adjusted models that accounted for variations in (1) baseline characteristics and (2) both baseline and surgical factors. RESULTS: Of the 479 patients, 360 (75.16%) were <65 years and 119 (24.84%) were >=65 years. Elderly patients had a worse preoperative health status (p<0.0001) and were functionally more severe (p<0.0001). The majority of younger patients (64.96%) underwent anterior surgery, whereas the preferred approach in the elderly group was posterior (58.62%, p<0.0001). Elderly patients had a greater number of decompressed levels than younger patients (p<0.0001). At 24 months after surgery, younger patients achieved a higher postoperative mJOA (p<0.0001) and a lower Nurick score (p<0.0001) than elderly patients. After adjustments for patient and surgical characteristics, these differences in postoperative outcome scores decreased but remained significant. CONCLUSIONS: Older age is an independent predictor of functional status in patients with DCM. However, patients over 65 with DCM still achieve functionally significant improvement after surgical decompression. PMID- 26420886 TI - IVIG treatment of mild cognitive impairment due to Alzheimer's disease: a randomised double-blinded exploratory study of the effect on brain atrophy, cognition and conversion to dementia. AB - OBJECTIVE: To determine the effect of intravenous immunoglobulin (IVIG) on brain atrophy and cognitive function in mild cognitive impairment (MCI) due to Alzheimer's disease (AD). METHODS: 50 participant 50-84 years of age with amnestic MCI were administered 0.4 g/kg 10% IVIG or 0.9% saline every 2 weeks for a total of 5 infusions (2 g/kg total dose) in a randomised double-blinded design. MRI brain was completed at baseline, 12 and 24 months. Cognitive testing was completed at baseline and every 4 months. Participants were stratified into early and late (LMCI) MCI stages. Average annualised per cent change in ventricular volume was computed as a measure of brain atrophy. RESULTS: There was significantly less brain atrophy (p=0.037, adjusted for MCI status) in the IVIG group (5.87%) when compared with placebo (8.14%) at 12 months; at 24 months, the reduction in brain atrophy no longer reached statistical significance. The LMCI participants who received IVIG performed better on Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog; p=0.011) and Mini-Mental State Examination (MMSE; p=0.004) at 1 year; these differences were not present after 2 years. There was no difference in conversion to AD dementia between the treatment and control groups after 2 years; however, at 1 year, there were fewer conversions from LMCI to AD dementia in the IVIG group (33.3%) when compared with control group (58.3%). CONCLUSIONS: This exploratory study provides limited evidence that a short course of IVIG administered in the MCI stage of AD reduces brain atrophy, prevents cognitive decline in LMCI and delays conversion to AD dementia for at least 1 year; however, this effect of IVIG appears to wane by 2 years. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT01300728. PMID- 26420887 TI - FRONTIER Executive Screen: a brief executive battery to differentiate frontotemporal dementia and Alzheimer's disease. AB - BACKGROUND AND OBJECTIVE: Executive dysfunctions are a key clinical feature of behavioural-variant frontotemporal dementia (bvFTD). Such deficits are also found in Alzheimer's disease (AD), making the differentiation between these two diseases difficult at times, particularly in the absence of extensive cognitive assessments. To address this issue, we developed the FRONTIER Executive Screen (FES), which combines three abbreviated measures of verbal fluency, inhibitory control and working memory. METHODS: We administered the FES to 28 patients with dementia (14 bvFTD, 14 AD) matched for disease severity and 33 age-matched and education-matched healthy controls. We also administered traditional tests of executive function to establish the concurrent validity of the FES. RESULTS: Both patient groups obtained lower FES scores (total and subscores) compared to controls. Correct classification into patient or control groups was reached in over 90% of study participants based on the FES total score. Only two patients with bvFTD obtained FES scores within 2 SDs of the control group. Receiver operating characteristic analyses on the patient groups showed that a cut-off FES total score of 7/15 achieved 71% sensitivity and 73% specificity for a diagnosis of bvFTD. In addition, the FES showed high correlations with traditional measures of executive function. CONCLUSIONS: The FES is a brief (5-10 min) bedside screening measure which is simple to administer and score, and demonstrates good discriminative validity to differentiate bvFTD from AD. It is a useful addendum to general cognitive screening measures and can help with the differential diagnosis of dementia. PMID- 26420888 TI - ReCAP: Comparison of Independent Error Checks for Oral Versus Intravenous Chemotherapy. AB - PURPOSE: Intravenous (IV) chemotherapy is routinely delivered to patients in hospital settings, where safeguards such as independent checks and guidelines govern their administration. In contrast, oral chemotherapy, which is typically ordered in a cancer center but dispensed and administered in the community and home, respectively, is subject to fewer controls. Research in the United States has found that few safeguards in routine use for IV chemotherapy have been adopted for oral chemotherapy; however, less is known about the Canadian context. The objective of this study was to determine whether similar safeguards, in the form of independent checks, existed to identify potential errors related to both formulations. METHODS: Human factors specialists conducted observations and interviews in cancer center clinics, a cancer center pharmacy, and four community pharmacies across Nova Scotia. Processes were analyzed to determine if an independent check was performed, which qualified provider completed the check, and at what point of the process the check occurred. RESULTS: A total of 57 systematic checks were identified for IV chemotherapy, whereas only six systematic checks were identified for oral chemotherapy. Community pharmacists were the only qualified professionals involved in independent systematic checking of oral chemotherapy, which occurred during ordering and dispensing. CONCLUSION: There is an enormous opportunity for pharmacists and other qualified professionals to take on an expanded role in improving patient safety for oral chemotherapy. Greater involvement of pharmacists, in both the clinic environment and the community, would facilitate increased systematic checking, which could improve patient safety related to oral chemotherapy. PMID- 26420889 TI - Oncology Care Delivery Reform: Carpe Diem. PMID- 26420890 TI - ReCAP: Gaps in Insurance Coverage for Pediatric Patients With Acute Lymphoblastic Leukemia. AB - PURPOSE: Continuous insurance coverage is an important component of effective health care. Evaluation of insurance gaps in pediatric cancer care is an understudied area. METHODS: We conducted a retrospective analysis of payer data from outpatient oncology encounters at Primary Children's Hospital (Salt Lake City, UT) over the first 2 years of therapy for pediatric patients with acute lymphoblastic leukemia diagnosed from 1998 to 2010 (N = 380). Using logistic regression, we evaluated demographic and clinical predictors (age at diagnosis, sex, ethnicity, high/standard acute lymphoblastic leukemia risk, and rural/urban county of residence at diagnosis) of a gap in health insurance. RESULTS: The median age at diagnosis was 4 years (interquartile range, 3 to 8 years), and 172 patients (45%) were girls. In the first 2 years of treatment, 45 patients (12%) experienced a gap in health insurance. The odds of having a gap in insurance coverage decreased by 16% each year from 1998 to 2010 (odds ratio, 0.84; 95% CI, 0.76 to 0.93; test for trend, P = .001). Public insurance at diagnosis was associated with a four-fold increased likelihood of experiencing an insurance gap (odds ratio, 4.09; 95% CI, 1.98 to 8.44; P < .001) compared with patients with private insurance at diagnosis. CONCLUSION: Gaps in insurance coverage during pediatric cancer treatment are not uncommon, which highlights the importance of discussing insurance status at diagnosis and throughout a patient's treatment course to help patients and their families prepare for any changes and avoid unnecessary financial burden. Future research should focus on examining the effect of insurance gaps on patient outcomes and evaluating likelihood of gaps in insurance after health care reform. PMID- 26420892 TI - Delivering Patient Value by Using Process Improvement Tools to Decrease Patient Wait Time in an Outpatient Oncology Infusion Unit. AB - PURPOSE: This study aimed to streamline workflow from arrival to premedication by decreasing patient wait time to increase value in a high-volume academic outpatient oncology infusion unit. The streamlining process involved identifying and prioritizing patients for treatment by driving out waste in patient flow. METHODS: The plan-do-check-act (PDCA) method and Lean Methodology were used in completing a project to streamline a defined subset of patient experiences within an outpatient oncology infusion unit in an academic comprehensive cancer center. Wait time for patients whose labs were completed before treatment day and within normal limits and whose orders were signed the day before treatment was collected manually for a period of 5 months and tracked via value stream and control charts. RESULTS: Postimplementation, patients experienced a decrease of 17 minutes in mean patient arrival to premedication start time (preimplementation 77 minutes, postimplementation 60 minutes). Additionally, a value stream analysis demonstrated that in the new process, patient touch points were decreased by two, and value-added time was increased by 17%. CONCLUSION: By using the systematic PDCA tool, the team was able to identify opportunities to reduce waste in the system and streamline patient care. The results demonstrated a significant improvement in reducing patient wait time from arrival to premedication start time and increasing percentage of total value added during a patient's treatment cycle. PMID- 26420891 TI - Lessons From Early Implementation of a Patient-Centered Care Model in Oncology. AB - PURPOSE: Oncology practices may serve as the primary health provider for patients with cancer and the so-called neighbor during periods of transition and survivorship. New standards for patient-centered oncology practice articulate expectations for the primary health provider and neighbor roles. We report the implementation experiences of five oncology practices participating in a pilot of these standards. METHODS: For each practice, auditors reviewed workflows and documentation supporting the progress of the practice in meeting the oncology medical home standards. We also observed clinical encounters and practice workflow and interviewed clinicians, staff, and patients. RESULTS: Referral coordination and care management were the most demonstrated functions. The least commonly demonstrated functions related to tracking and coordination of tests and medications, as well as quality measurement and improvement. Some opportunities for structural and process improvement included improving the use of health information technology, care coordination, quality improvement, telephone triage, symptom management, patient education, financial counseling, and care team communication. Making patient-centered care a priority and motivation to change were cited as facilitators for transformation. CONCLUSION: The pilot oncology practices had many structures and processes in common, many of which were established during the early intervention period of this pilot. However, there was little standardization within and across practices in the way these processes were established and documented. Establishing structures for care coordination, quality improvement, and quality measurement should be priorities for practices considering transformation to a patient-centered model of care. PMID- 26420893 TI - Teenage suicide today--the facts and figures. PMID- 26420895 TI - Should chronic metabolic acidosis be treated in older people with chronic kidney disease? AB - Metabolic acidosis is common in advanced chronic kidney disease and has been associated with a range of physiological derangements of importance to the health of older people. These include associations with skeletal muscle weakness, cardiovascular risk factors, and bone and mineral disorders that may lead to fragility fractures. Although metabolic acidosis is associated with accelerated decline in kidney function, end-stage renal failure is a much less common outcome in older, frail patients than cardiovascular death. Correction of metabolic acidosis using bicarbonate therapy is commonly employed, but the existing evidence is insufficient to know whether such therapy is of net benefit to older people. Bicarbonate is bulky and awkward to take, may impose additional sodium load with effects on fluid retention and blood pressure, and may cause gastrointestinal side effects. Trial data to date suggest potential benefits of bicarbonate therapy on progression of renal disease and nutrition, but trials have not as yet been published examining the effect of bicarbonate therapy across a range of domains relevant to the health of older people. Fortunately, a number of trials are now underway that should allow us to ascertain whether bicarbonate therapy can improve physical function, quality of life, and vascular, bone and kidney health in older people, and hence decide whether any benefits seen outweigh adverse effects and additional treatment burden in this vulnerable group of patients. PMID- 26420894 TI - Genetic loci associated with renal function measures and chronic kidney disease in children: the Pediatric Investigation for Genetic Factors Linked with Renal Progression Consortium. AB - BACKGROUND: Chronic kidney disease (CKD) in children is characterized by rapid progression and a high incidence of end-stage renal disease and therefore constitutes an important health problem. While unbiased genetic screens have identified common risk variants influencing renal function and CKD in adults, the presence and identity of such variants in pediatric CKD are unknown. METHODS: The international Pediatric Investigation for Genetic Factors Linked with Renal Progression (PediGFR) Consortium comprises three pediatric CKD cohorts: Chronic Kidney Disease in Children (CKiD), Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) and Cardiovascular Comorbidity in Children with CKD (4C). Clean genotype data from > 10 million genotyped or imputed single-nucleotide polymorphisms (SNPs) were available for 1136 patients with measurements of serum creatinine at study enrollment. Genome-wide association studies were conducted to relate the SNPs to creatinine-based estimated glomerular filtration rate (eGFR crea) and proteinuria (urinary albumin- or protein-to-creatinine ratio >= 300 and >= 500 mg/g, respectively). In addition, European-ancestry PediGFR patients (cases) were compared with 1347 European-ancestry children without kidney disease (controls) to identify genetic variants associated with the presence of CKD. RESULTS: SNPs with suggestive association P-values < 1 * 10(-5) were identified in 10 regions for eGFR crea, four regions for proteinuria and six regions for CKD including some plausible biological candidates. No SNP was associated at genome-wide significance (P < 5 * 10(-8)). Investigation of the candidate genes for proteinuria in adults from the general population provided support for a region on chromosome 15 near RSL24D1/UNC13C/RAB27A. Conversely, targeted investigation of genes harboring GFR-associated variants in adults from the general population did not reveal significantly associated SNPs in children with CKD. CONCLUSIONS: Our findings suggest that larger collaborative efforts will be needed to draw reliable conclusions about the presence and identity of common variants associated with eGFR, proteinuria and CKD in pediatric populations. PMID- 26420896 TI - Prognostic relevance of epilepsy at presentation in glioblastoma patients. AB - BACKGROUND: Epileptogenic glioblastomas are thought to convey a favorable prognosis, either due to early diagnosis or potential antitumor effects of antiepileptic drugs. We investigated the relationship between survival and epilepsy at presentation, early diagnosis, and antiepileptic drug therapy in glioblastoma patients. METHODS: Multivariable Cox regression was applied to survival data of 647 consecutive patients diagnosed with de novo glioblastoma between 2005 and 2013 in order to investigate the association between epilepsy and survival in glioblastoma patients. In addition, we quantified the association between survival and valproic acid (VPA) treatment. RESULTS: Epilepsy correlated positively with survival (HR: 0.75 (95% CI: 0.61-0.92), P < .01). This effect is independent of age, sex, performance status, type of surgery, adjuvant therapy, tumor location, and tumor volume, suggesting that this positive correlation cannot be attributed solely to early diagnosis. For patients who presented with epilepsy, the use of the antiepileptic drug VPA did not associate with survival when compared with patients who did not receive VPA treatment. CONCLUSION: Epilepsy is an independent prognostic factor for longer survival in glioblastoma patients. This prognostic effect is not solely explained by early diagnosis, and survival is not associated with VPA treatment. PMID- 26420898 TI - CPAP Devices for Emergency Prehospital Use: A Bench Study. AB - BACKGROUND: CPAP is frequently used in prehospital and emergency settings. An air flow output minimum of 60 L/min and a constant positive pressure are 2 important features for a successful CPAP device. Unlike hospital CPAP devices, which require electricity, CPAP devices for ambulance use need only an oxygen source to function. The aim of the study was to evaluate and compare on a bench model the performance of 3 orofacial mask devices (Ventumask, EasyVent, and Boussignac CPAP system) and 2 helmets (Ventukit and EVE Coulisse) used to apply CPAP in the prehospital setting. METHODS: A static test evaluated air-flow output, positive pressure applied, and FIO2 delivered by each device. A dynamic test assessed airway pressure stability during simulated ventilation. Efficiency of devices was compared based on oxygen flow needed to generate a minimum air flow of 60 L/min at each CPAP setting. RESULTS: The EasyVent and EVE Coulisse devices delivered significantly higher mean air-flow outputs compared with the Ventumask and Ventukit under all CPAP conditions tested. The Boussignac CPAP system never reached an air-flow output of 60 L/min. The EasyVent had significantly lower pressure excursion than the Ventumask at all CPAP levels, and the EVE Coulisse had lower pressure excursion than the Ventukit at 5, 15, and 20 cm H2O, whereas at 10 cm H2O, no significant difference was observed between the 2 devices. Estimated oxygen consumption was lower for the EasyVent and EVE Coulisse compared with the Ventumask and Ventukit. CONCLUSIONS: Air-flow output, pressure applied, FIO2 delivered, device oxygen consumption, and ability to maintain air flow at 60 L/min differed significantly among the CPAP devices tested. Only the EasyVent and EVE Coulisse achieved the required minimum level of air-flow output needed to ensure an effective therapy under all CPAP conditions. PMID- 26420899 TI - Perception of Asthma Symptoms as Assessed on the Visual Analog Scale in Subjects With Asthma: A Real-Life Study. AB - BACKGROUND: The perception of symptoms is a cornerstone in asthma management, but studies concerning this aspect provide conflicting evidence. The visual analog scale has been proposed as a useful tool for assessing perception of respiratory symptoms. The present study investigated whether visual analog scale assessment of perception of asthma symptoms was correlated to lung function or clinical features. METHODS: This cross-sectional study enrolled 388 subjects with asthma (159 males; mean age 39.7 y). Perception of asthma symptoms was assessed by the visual analog scale; lung function was measured by spirometry. Asthma control was evaluated by the asthma control test. Anxiety and depression were evaluated on the Hospital Anxiety and Depression Scale questionnaire. RESULTS: Asthma was well controlled in 46.6% of subjects. Asthma symptoms in the prior month were reported by 59% of subjects; asthma signs were detected in 7.2%. The visual analog scale score was moderately correlated to FEV1 (r = 0.43). Subjects with bronchial obstruction had lower visual analog scale values than those without (P < .001). A visual analog scale score of 6 was a reliable cutoff point to discriminate subjects with bronchial obstruction (area under the curve = 0.71 at receiver operating characteristic curve; odds ratio [OR] = 7.58). Reported asthma symptoms (OR = 4.83), asthma signs (OR = 8.36), and anxiety (OR = 1.14) were predictive of a visual analog scale score of <6. CONCLUSIONS: This real-life study found that assessment of asthma symptoms by the visual analog scale might be a reliable tool in managing patients with asthma. PMID- 26420897 TI - Selective coexpression of VEGF receptor 2 in EGFRvIII-positive glioblastoma cells prevents cellular senescence and contributes to their aggressive nature. AB - BACKGROUND: In glioblastoma (GBM), the gene for epidermal growth factor receptor (EGFR) is frequently amplified. EGFR mutations also are common, including a truncation mutation that yields a constitutively active variant called EGFR variant (v)III. EGFRvIII-positive GBM progresses rapidly; however, the reason for this is not clear because the activity of EGFRvIII is attenuated compared with EGF-ligated wild-type EGFR. We hypothesized that EGFRvIII-expressing GBM cells selectively express other oncogenic receptors that support tumor progression. METHODS: Mining of The Cancer Genome Atlas prompted us to test whether GBM cells in culture, which express EGFRvIII, selectively express vascular endothelial growth factor receptor (VEGFR)2. We also studied human GBM propagated as xenografts. We then applied multiple approaches to test the effects of VEGFR2 on GBM cell growth, apoptosis, and cellular senescence. RESULTS: In human GBM, EGFR overexpression and EGFRvIII positivity were associated with increased VEGFR2 expression. In GBM cells in culture, EGFRvIII-initiated cell signaling increased expression of VEGFR2, which prevented cellular senescence and promoted cell cycle progression. The VEGFR-selective tyrosine kinase inhibitor cediranib decreased tumor DNA synthesis, increased staining for senescence-associated beta galactosidase, reduced retinoblastoma phosphorylation, and increased p27(Kip1), all markers of cellular senescence. Similar results were obtained when VEGFR2 was silenced. CONCLUSIONS: VEGFR2 expression by GBM cells supports cell cycle progression and prevents cellular senescence. Coexpression of VEGFR2 by GBM cells in which EGFR signaling is activated may contribute to the aggressive nature of these cells. PMID- 26420900 TI - Tolerance of Volume Control Noninvasive Ventilation in Subjects With Amyotrophic Lateral Sclerosis. AB - BACKGROUND: Noninvasive ventilation (NIV) tolerance has been identified as an independent predictor of survival in amyotrophic lateral sclerosis (ALS). Volume control continuous mandatory ventilation (VC-CMV) NIV has been associated with poor tolerance. The aim of this study was to determine the tolerance of subjects with ALS to VC-CMV NIV. METHODS: This was a prospective study involving subjects with ALS who were treated with VC-CMV NIV. Respiratory and functional parameters were recorded when the subjects began ventilatory support. NIV tolerance was evaluated after 3 months. RESULTS: Eighty-seven subjects with ALS were included. After 3 months, 80 subjects (92%) remained tolerant of NIV. Tolerant subjects presented greater survival (median 22.0 months, 95% CI 14.78-29.21) than intolerant subjects (median 6.0 months, 95% CI 0.86-11.13) (P = .03). The variables that best predicted NIV tolerance were mechanically assisted cough peak flow (P = .01) and percentage of time spent with SpO2 < 90% at night while on NIV (P = .03) CONCLUSIONS: VC-CMV NIV provides high rates of NIV tolerance in subjects with ALS. Mechanically assisted cough peak flow and percentage of time spent with SpO2 < 90% at night while using NIV are the 2 factors associated with tolerance of VC-CMV NIV in subjects with ALS. PMID- 26420901 TI - Hypoxemia During Extreme Hyperleukocytosis: How Spurious? AB - BACKGROUND: Spurious hypoxemia has been described in case reports during extreme hyperleukocytosis and has led to recommendations for immediate cooling and analysis of arterial blood gases (ABGs). We sought to determine, in samples processed as recommended, the magnitude of spurious hypoxemia in acute leukemia subjects with hyperleukocytosis. METHODS: A retrospective chart review was conducted of all subjects admitted between 2003 and July 2014 for acute leukemia, who presented with white blood cell (WBC) count > 50 * 10(9) cells/L and had ABGs performed. For each ABG, we collected PaO2 , SaO2 , simultaneous WBC count, and SpO2 when available. Bland and Altman analysis was used to assess the agreement between SpO2 and SaO2 . RESULTS: One-hundred forty-six samples (from 45 subjects) were included, of which 57 samples (from 18 subjects) had data available for Bland and Altman analysis. Mean (SpO2 - SaO2 ) was 2.5%, and 95% CI for limits of agreement between SpO2 and SaO2 was (-10.1,15.1)%. The mean (SpO2 - SaO2 ) was significantly higher for WBC count > 100 * 10(9)/L as compared with WBC count < 100 * 10(9)/L (3.8% vs 0.4%, P = .04), and the 95% CIs for limits of agreement were (-10.3,18)% versus (-7.9,8.6)%. SpO2 and SaO2 were poorly correlated (r(2) = 0.19), whereas the difference (SpO2 - SaO2 ) was fairly correlated with WBC count (r(2) = 0.44). Overall, 11 of 19 samples with WBC count > 150 * 10(9)/L had PaO2 < 55 mm Hg whereas SpO2 was > 94%, the proportion being 5 of 62 samples for WBC count < 150 * 10(9)/L (P < .001). Three subjects with WBC count > 150 * 10(9)/L exhibited large SpO2 to SaO2 differences (10-20%) before leukapheresis, which decreased to below 5% afterward. CONCLUSIONS: In subjects with acute leukemia and hyperleukocytosis, despite cooling and quickly analyzing the samples, we observed poor correlation and agreement between SpO2 and SaO2 , unacceptably low for WBC count > 100 * 10(9)/L. Our results suggest that current guidelines may not totally prevent the diagnosis of spurious hypoxemia. PMID- 26420902 TI - Face Masks for Noninvasive Ventilation: Fit, Excess Skin Hydration, and Pressure Ulcers. AB - BACKGROUND: Pressure ulcers (stages III and IV) are serious safety events (ie, never events). Healthcare institutions are no longer reimbursed for costs to care for affected patients. Medical devices are the leading cause of pediatric pressure ulcers. Face masks for noninvasive ventilation were associated with a high percentage of pressure ulcers at our institution. METHODS: A prospective cohort study investigated factors contributing to pressure ulcer development in 50 subjects using face masks for noninvasive ventilation. Color imaging, 3 dimensional surface imaging, and skin hydration measurements were used to identify early skin compromise and evaluate 3 interventions to reduce trauma: (1) a silicone foam dressing, (2) a water/polyethylene oxide hydrogel dressing, and (3) a flexible cloth mask. A novel mask fit technique was used to examine the impact of fit on the potential for skin compromise. RESULTS: Fifty subjects age 10.4 +/- 9.1 y participated with color images for 22, hydration for 34, and mask fit analysis for 16. Of these, 69% had diagnoses associated with craniofacial anomalies. Stage I pressure ulcers were the most common injury. Skin hydration difference was 317 +/- 29 for sites with erythema versus 75 +/- 28 for sites without erythema (P < .05) and smallest for the cloth mask (P < .05). Fit distance metrics differed for the nasal, oronasal, and face shield interfaces, with threshold distances being higher for the oronasal mask than the others (P < .05). Areas of high contact were associated with skin erythema and pressure ulcers. CONCLUSIONS: This fit method is currently being utilized to select best fit masks from available options, to identify the potential areas of increased tissue pressure, and to prevent skin injuries and their complications. Improvement of mask fit is an important priority for improving respiratory outcomes. Strategies to maintain normal skin hydration are important for protecting tissue integrity. PMID- 26420903 TI - EFFICIENCY STUDY OF A LEGe DETECTOR SYSTEM FOR THE ASSESSMENT OF 241Am IN SKULL AT CIEMAT WHOLE BODY COUNTER. AB - (241)Am incorporation due to an incident or chronic exposure causes an internal dose, which can be evaluated from the total activity of this isotope in the skeleton several months after the intake. For this purpose, it is necessary to perform in vivo measurements of this bone-seeker radionuclide in appropriate counting bone geometries with very low attenuation of surrounded tissue and to extrapolate to total activity in the skeleton (ICRP 89, Basic anatomical and physiological data for use in radiological protection: reference values. 2001. 265). The work here presented refers to direct measurements of americium in the Cohen skull phantom at the CIEMAT Whole Body Counter (WBC) using low-energy germanium (LEGe) detectors inside a shielding room. The main goal was to determinate the most adequate head counting geometry for the in vivo detection of americium in the bone. The calibration of the in vivo LEGe system was performed with four detectors with 2 cm of distance to Cohen phantom. Two geometries were measured, on junction of frontal to parietal bones and frontal bone. The efficiencies are very similar in both geometries, the preferred counting geometry is the most comfortable for the person, with the LEGe detectors in the highest part of the frontal bone, near the junction with the parietal bone, CIEMAT WBC participated in a skull intercomparison exercise organised by WG7 of EURADOS (European Radiation Dosimetry Group e.V.). Efficiencies using three different skull phantoms were obtained. Measurements were performed for different head counting positions, four of them in the plane of symmetry and others over the temporal bone. The detector was placed in parallel with the calibration phantom at a distance of 1 cm. The main gamma emission of (241)Am, 59.5 keV (36 %), was used for comparing efficiency values. The lower efficiency was obtained over the frontal and occipital bones. Measurement with one LEGe detector over the parietal bone is the most efficient. The activity of each skull phantom was calculated using CIEMAT head calibration. Results of the EURADOS intercomparison are presented here for discussion. PMID- 26420904 TI - DEVELOPMENT OF AGE-SPECIFIC JAPANESE PHYSICAL PHANTOMS FOR DOSE EVALUATION IN INFANT CT EXAMINATIONS. AB - Secondary to the previous development of age-specific Japanese head phantoms, the authors designed Japanese torso phantoms for dose assessment in infant computed tomography (CT) examinations and completed a Japanese 3-y-old head-torso phantom. For design of age-specific torso phantoms (0, 0.5, 1 and 3 y old), anatomical structures were measured from CT images of Japanese infant patients. From the CT morphometry, it was found that rib cages of Japanese infants were smaller than those in Europeans and Americans. Radiophotoluminescence glass dosemeters were used for dose measurement of a 3-y-old head-torso phantom. To examine the validity of the developed phantom, organ and effective doses by the in-phantom dosimetry system were compared with simulation values in a web-based CT dose calculation system (WAZA-ARI). The differences in doses between the two systems were <20 % at the doses of organs within scan regions and effective doses in head, chest and abdominopelvic CT examinations. PMID- 26420905 TI - Motivational Interviewing to Increase Cognitive Rehabilitation Adherence in Schizophrenia. AB - Adherence to treatment in psychiatric populations is notoriously low. In this randomized, controlled, proof-of-concept study, we sought to examine whether motivational interviewing (MI) could be used to enhance motivation for, adherence to, and benefit obtained from cognitive rehabilitation. Dual diagnosis MI, developed specifically for individuals with psychotic symptoms and disorganization, was further adapted to focus on cognitive impairments and their impact. Sixty-four outpatients diagnosed with schizophrenia spectrum disorders completed baseline assessments and were randomized to receive either the 2 session MI focused on cognitive functioning or a 2-session sham control interview focused on assessment and feedback about preferred learning styles. Next, all participants were given 4 weeks during which they could attend up to 10 sessions of a computer-based math training program, which served as a brief analog for a full course of cognitive rehabilitation. As hypothesized, MI condition was associated with greater increases in task-specific motivation along with greater training program session attendance. Moreover, postinterview motivation level predicted session attendance. There were no significant differences in improvement on a measure of cognitive training content, which may have been due to the abbreviated nature of the training. While the literature on the efficacy of MI for individuals with psychosis has been mixed, we speculate that our positive findings may have been influenced by the adaptations made to MI as well as the focus on a nonpharmacological intervention. PMID- 26420906 TI - Synapse and genome: An elusive tete-a-tete. AB - Two recent papers center on the emerging intersection of DNA methylation and homeostatic plasticity. To better appreciate the context of these studies, we first briefly review the mechanistic connections between DNA methylation and plasticity before delving into the ways in which these two papers fortify the connection between synapse and nucleus but also highlight the need for studies with a broader perspective. PMID- 26420907 TI - The insulin response integrates increased TGF-beta signaling through Akt-induced enhancement of cell surface delivery of TGF-beta receptors. AB - Increased activity of transforming growth factor-beta (TGF-beta), which binds to and stimulates cell surface receptors, contributes to cancer progression and fibrosis by driving epithelial cells toward a migratory mesenchymal phenotype and increasing the abundance of extracellular matrix proteins. The abundance of TGF beta receptors at the cell surface determines cellular responsiveness to TGF beta, which is often produced by the same cells that have the receptors, and thus serves as an autocrine signal. We found that Akt-mediated phosphorylation of AS160, a RabGAP [guanosine triphosphatase (GTPase)-activating protein], promoted the translocation of TGF-beta receptors from intracellular stores to the plasma membrane of mouse embryonic fibroblasts and NMuMG epithelial cells. Consequently, insulin, which is commonly used to treat hyperglycemia and activates Akt signaling, increased the amount of TGF-beta receptors at the cell surface, thereby enhancing TGF-beta responsiveness. This insulin-induced increase in autocrine TGF-beta signaling contributed to insulin-induced gene expression responses, attenuated the epithelial phenotype, and promoted the migration of NMuMG cells. Furthermore, the enhanced delivery of TGF-beta receptors at the cell surface enabled insulin to increase TGF-beta-induced gene responses. The enhancement of TGF-beta responsiveness in response to Akt activation may help to explain the biological effects of insulin, the progression of cancers in which Akt is activated, and the increased incidence of fibroses in diabetes. PMID- 26420909 TI - Malignant glomus tumor of trachea: a case report with literature review. AB - Glomus tumors of the trachea are extremely rare and generally benign, with very few cases of malignant transformation reported in literature. We present the case of a 74-year-old man explored for cough and dyspnea. Bronchoscopy showed a polypoid mass arising from the posterolateral tracheal wall. Computed tomography demonstrated a mid-tracheal tissular mass obliterating the tracheal lumen. Resection and anastomosis of the trachea were performed. The histological and immunohistochemical findings were consistent with malignant glomus tumor. PMID- 26420908 TI - Glutamine-dependent alpha-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. AB - T cell activation requires that the cell meet increased energetic and biosynthetic demands. We showed that exogenous nutrient availability regulated the differentiation of naive CD4(+) T cells into distinct subsets. Activation of naive CD4(+) T cells under conditions of glutamine deprivation resulted in their differentiation into Foxp3(+) (forkhead box P3-positive) regulatory T (Treg) cells, which had suppressor function in vivo. Moreover, glutamine-deprived CD4(+) T cells that were activated in the presence of cytokines that normally induce the generation of T helper 1 (TH1) cells instead differentiated into Foxp3(+) Treg cells. We found that alpha-ketoglutarate (alphaKG), the glutamine-derived metabolite that enters into the mitochondrial citric acid cycle, acted as a metabolic regulator of CD4(+) T cell differentiation. Activation of glutamine deprived naive CD4(+) T cells in the presence of a cell-permeable alphaKG analog increased the expression of the gene encoding the TH1 cell-associated transcription factor Tbet and resulted in their differentiation into TH1 cells, concomitant with stimulation of mammalian target of rapamycin complex 1 (mTORC1) signaling. Together, these data suggest that a decrease in the intracellular amount of alphaKG, caused by the limited availability of extracellular glutamine, shifts the balance between the generation of TH1 and Treg cells toward that of a Treg phenotype. PMID- 26420910 TI - Early-onset Streptomyces endocarditis in a prosthetic aortic valve. AB - A 66-year-old Australian man underwent elective replacement of a severely stenotic aortic valve with a 22-mm Medtronic-Hall valve. Six weeks later, he was readmitted with worsening dyspnea, fever, and mild anemia. Investigations confirmed pulmonary edema and moderate periprosthetic aortic regurgitation. The pulmonary edema was managed conservatively, and a second 22-mm Medtronic-Hall valve was implanted. Infective endocarditis was suspected in the aortic annulus below the orifice of the right coronary artery. A bacteriological study revealed a rare bacteria of Streptomyces species. The patient received intensive antibiotic therapy over a 6-week period of hospitalization, and the aortic regurgitation disappeared one week postoperatively. PMID- 26420911 TI - The Collapse and Expansion of Liquid-Filled Elastic Channels and Cracks. AB - The rate at which fluid drains from a collapsing channel or crack depends on the interaction between the elastic properties of the solid and the fluid flow. The same interaction controls the rate at which a pressurized fluid can flow into a crack. In this paper, we present an analysis for the interaction between the viscous flow and the elastic field associated with an expanding or collapsing fluid-filled channel. We first examine an axisymmetric problem for which a completely analytical solution can be developed. A thick-walled elastic cylinder is opened by external surface tractions, and its core is filled by a fluid. When the applied tractions are relaxed, a hydrostatic pressure gradient drives the fluid to the mouth of the cylinder. The relationship between the change in dimensions, time, and position along the cylinder is given by the diffusion equation, with the diffusion coefficient being dependent on the modulus of the substrate, the viscosity of the fluid, and the ratio of the core radius to the exterior radius of the cylinder. The second part of the paper examines the collapse of elliptical channels with arbitrary aspect ratios, so as to model the behavior of fluid-filled cracks. The channels are opened by a uniaxial tension parallel to their minor axes, filled with a fluid, and then allowed to collapse. The form of the analysis follows that of the axisymmetric calculations, but is complicated by the fact that the aspect ratio of the ellipse changes in response to the local pressure. Approximate analytical solutions in the form of the diffusion equation can be found for small aspect ratios. Numerical solutions are given for more extreme aspect ratios, such as those appropriate for cracks. Of particular note is that, for a given cross-sectional area, the rate of collapse is slower for larger aspect ratios. With minor modifications to the initial conditions and the boundary conditions, the analysis is also valid for cracks being opened by a pressurized fluid. PMID- 26420912 TI - Role of MALAT1 as a Prognostic Factor for Survival in Various Cancers: A Systematic Review of the Literature with Meta-Analysis. AB - OBJECTIVES: The expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a highly abundant and ubiquitously expressed long noncoding RNA (lncRNA), influences clinical parameters and may have prognostic value in cancer. This meta-analysis evaluated the prognostic role of MALAT1 in various cancers. MATERIALS AND METHODS: Systematic literature searches of PubMed and EMBASE databases were conducted for eligible studies of the prognostic role of MALAT1 in cancer. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were analyzed. Summary hazard ratios (HRs) and 95% confidence intervals (95% CIs) were assessed to evaluate the influence of MALAT1 expression on patient prognosis. RESULTS: Nine studies with a total of 932 patients were included in the analysis. Elevated MALAT1 expression was significantly correlated with poor OS (HR 2.02; 95% CI: 1.62-2.52; P < 0.001; I(2) = 0%). Subgroup analysis indicated that tumor type, histology type, ethnicity, and measurement technique did not affect the prognostic value of MALAT1 for OS. The HR of elevated MALAT1 for DFS was 2.78 (95% CI: 1.87-4.15; P < 0.001; I(2) = 0%). CONCLUSIONS: Elevated MALAT1 expression is correlated with poor OS in various types of cancer, suggesting that this gene is a prognostic factor for different types of cancer. PMID- 26420914 TI - Serum and Vitreous Concentrations of Omentin-1 in Diabetic Retinopathy. AB - OBJECTIVE: Omentin, a new discovered adipokine, is implicated to inhibit inflammation. Inflammation is one important mechanism of diabetic retinopathy (DR). The purpose of this work was to evaluate serum and vitreous concentrations of omentin-1 in patients with diabetic retinopathy (DR). METHODS: This study enrolled 204 diabetic patients (60 without DR, 49 with NPDR, and 95 with PDR) and 65 control subjects. RESULTS: Serum and vitreous omentin-1 levels in PDR patients were markedly decreased compared with those in the other three groups. NPDR patients showed reduced vitreous omentin-1 compared with patients without DR. In addition, control subjects had significantly higher levels of serum and vitreous omentin-1 compared with diabetic patients without DR, NPDR patients, and PDR patients. In addition, serum/vitreous omentin-1 ratio was positively correlated with the development and severity of DR. CONCLUSION: Serum and vitreous omentin-1 levels, as well as serum/vitreous omentin-1 ratio, are correlated with the presence and severity of DR. PMID- 26420913 TI - Activated Complement Factors as Disease Markers for Sepsis. AB - Sepsis is a leading cause of death in the United States and worldwide. Early recognition and effective management are essential for improved outcome. However, early recognition is impeded by lack of clinically utilized biomarkers. Complement factors play important roles in the mechanisms leading to sepsis and can potentially serve as early markers of sepsis and of sepsis severity and outcome. This review provides a synopsis of recent animal and clinical studies of the role of complement factors in sepsis development, together with their potential as disease markers. In addition, new results from our laboratory are presented regarding the involvement of the complement factor, mannose-binding lectin, in septic shock patients. Future clinical studies are needed to obtain the complete profiles of complement factors/their activated products during the course of sepsis development. We anticipate that the results of these studies will lead to a multipanel set of sepsis biomarkers which, along with currently used laboratory tests, will facilitate earlier diagnosis, timely treatment, and improved outcome. PMID- 26420916 TI - The Surgical Management of Concomitant Gallbladder and Common Bile Duct Stones. AB - Background. The management of choledocholithiasis has evolved from open common bile duct exploration (OCBDE) to therapeutic endoscopic retrograde cholangiopancreatography (ERCP) to laparoscopic common bile duct exploration (LCBDE). Each entails a degree of difficulty. Aim. To review 5-year results of bile duct exploration in an UGI unit. Methods. Common bile duct explorations (CBDEs) performed between January 2008 and January 2013 were identified from a prospectively collected clinical audit system and results reviewed retrospectively. Results. 216 CBDEs were performed, 119 (55%) as an emergency and 52 (24%) following failed ERCP. Open CBDE (OCBDE) was performed primarily in 34/216 (16%) patients and attempted laparoscopically in 182 (84%). Fifty nine (32%) Laparoscopic CBDEs (LCBDEs) were converted to OCBDE. Of the remaining 123 LCBDEs, 51 (41%) primary choledochotomies and 72 (59%) primary transcystic CBDEs (TC-CBDEs) were performed. Forty nine (68%) TC-CBDEs were considered successful and 23 (32%) failed. Fifteen failed TC-CBDEs were converted to a successful laparoscopic choledochotomy. Ductal clearance was achieved in 187/216 (87%) patients and retained stones were identified in 20/123 (16%) LCBDEs. Complications occurred in 52/216 (24%) patients. There were 8/216 (4%) bile leaks requiring further intervention. Postoperative ERCP was carried out in 32/216 (15%) patients and 9/216 (4%) required relaparoscopy/laparotomy. No patient died. Conclusions. Successful management of choledocholithiasis requires a breadth of laparoscopic and endoscopic expertise. PMID- 26420917 TI - A molecular modeling based screening for potential inhibitors to alpha hemolysin from Staphylococcus aureus. AB - Staphylococcus aureus, a Gram-positive bacterium is pathogenic in nature. It is known that secreted toxins remain active after antibiotic treatment. The alpha hemolysin or alpha toxin damages cell membrane and induces apoptosis and degradation of DNA. The titer of alphahemolysin increases and causes hemostasis disturbances, thrombocytopenia, and pulmonary lesions during staphylococcal infection. Therefore, it is of interest to inhibit alpha hemolysin using novel compounds. We used the structure of alpha hemolysin(PDB: 7AHL) to screen structures for 100,000 compounds from the ZINC database using molecular docking with AutoDock VINA. Nine (9) successive hits were then subjected for pharmacokinetic and toxicity properties by PROTOX (a webserver for the prediction of oral toxicities of small molecules) and FAFDrugs (a tool for prediction of ADME and Toxicity). This exercise further identified hit #1 ({[3a (Dihydroxymethyl)-6-hydroxy-2,2-dimethyl-1,3,4-trioxatetrahydro-2H-pentalen-5- yl]methyl}amino(9H-fluoren-9-yl)acetate with binding affinity: -10.3 kcal/mol) and hit #2 (6-(Dihydroxymethyl)-2-{2-[3- (methylamino)propyl]-2 azatricyclo[9.4.0.03,8]pentadeca-1(11),3,5,7,12,14-hexaen-6-yloxy}tetrahydro-2H pyran-3,4,5-triol with binding affinity: -9.6 kcal/mol) with acceptable toxicity and ADME properties for potential predicted hemolysin inhibition. These compounds should then be evaluated in vitro using inhibitory studies. PMID- 26420918 TI - Molecular Docking and Pharmacological Investigations of Rivastigmine-Fluoxetine and Coumarin-Tacrine hybrids against Acetyl Choline Esterase. AB - The present AChE inhibitors have been successful in the treatment of Alzheimer's Diseases however suffers serious side effects. Therefore in this view, the present study was sought to identify compounds with appreciable pharmacological profile targeting AChE. Analogue of Rivastigmine and Fluoxetine hybrid synthesized by Toda et al, 2003 (dataset1), and Coumarin-Tacrine hybrids synthesized by Qi Sun et al (dataset2) formed the test compounds for the present pharmacological evaluation. p-cholorophenyl substituted Rivastigmine and Fluoxetine hybrid compound (26d) from dataset 1 and -OCH3 substitute Coumarin Tacrine hybrids (1h) from dataset 2 demonstrated superior pharmacological profile. 26 d showed superior pharmacological profile comparison to the entire compounds in either dataset owing to its better electrostatic interactions and hydrogen bonding patterns. In order to identify still better compound with pharmacological profile than 26 d and 1h, virtual screening was performed. The best docked compound (PubCId: PubCid: 68874404) showed better affinity than its parent 26 d, however showed poor ADME profile and AMES toxicity. CHEMBL2391475 (PubCid: 71699632) similar to 1h had reduced affinity in comparison to its parent compound 1h. From, our extensive analysis involving binding affinity analysis, ADMET properties predictions and pharmacophoric mappings, we report p cholorophenyl substituted rivastigmine and fluoxetine hybrid (26d) to be a potential candidate for AcHE inhibition which in addition can overcome narrow therapeutic window of present AChE inhibitors in clinical treatment of Alzheimer's disease. ABBREVIATIONS: AD - Alzheimer's Disease, AChE - Acetyl Choline Estarase, OPLS - Optimized Potentials for Liquid Simulations, PDB - Protein Data Bank. PMID- 26420919 TI - Curcumin binds in silico to anti-cancer drug target enzyme MMP-3 (human stromelysin-1) with affinity comparable to two known inhibitors of the enzyme. AB - In silico interaction of curcumin with the enzyme MMP-3 (human stromelysin-1) was studied by molecular docking using AutoDock 4.2 as the docking software application. AutoDock 4.2 software serves as a valid and acceptable docking application to study the interactions of small compounds with proteins. Interactions of curcumin with MMP-3 were compared to those of two known inhibitors of the enzyme, PBSA and MPPT. The calculated free energy of binding (DeltaG binding) shows that curcumin binds with affinity comparable to or better than the two known inhibitors. Binding interactions of curcumin with active site residues of the enzyme are also predicted. Curcumin appears to bind in an extendended conformation making extensive VDW contacts in the active site of the enzyme. Hydrogen bonding and pi-pi interactions with key active site residues is also observed. Thus, curcumin can be considered as a good lead compound in the development of new inhibitors of MMP-3 which is a potential target of anticancer drugs. The results of these studies can serve as a starting point for further computational and experimental studies. PMID- 26420920 TI - Modelling and Characterization of Glial Fibrillary Acidic Protein. AB - Glial Fibrillary Acidic Protein (GFAP) is an intermediate-filament (IF) protein that maintains the astrocytes of the Central Nervous System in Human. This is differentially expressed during serological studies in inflamed condition such as Rheumatoid Arthritis (RA). Therefore, it is of interest to glean molecular insight using a model of GFAP (49.88 kDa) due to its crystallographic nonavailability. The present study has been taken into consideration to construct computational protein model using Modeller 9.11. The structural relevance of the protein was verified using Gromacs 4.5 followed by validation through PROCHECK, Verify 3D, WHAT-IF, ERRAT and PROVE for reliability. The constructed three dimensional (3D) model of GFAP protein had been scrutinized to reveal the associated functions by identifying ligand binding sites and active sites. Molecular level interaction study revealed five possible surface cavities as active sites. The model finds application in further computational analysis towards drug discovery in order to minimize the effect of inflammation. PMID- 26420915 TI - Syndecan-1 in Cancer: Implications for Cell Signaling, Differentiation, and Prognostication. AB - Syndecan-1, a cell surface heparan sulfate proteoglycan, is critically involved in the differentiation and prognosis of various tumors. In this review, we highlight the synthesis, cellular interactions, and the signalling pathways regulated by syndecan-1. The basal syndecan-1 level is also crucial for understanding the sequential changes involving malignant transformation, tumor progression, and advanced or disseminated cancer stages. Moreover, we focus on the cellular localization of this proteoglycan as cell membrane anchored and/or shed, soluble syndecan-1 with stromal or nuclear accumulation and how this may carry different, highly tissue specific prognostic information for individual tumor types. PMID- 26420921 TI - Pharmacophore Modeling and Molecular Docking Studies of potential inhibitors to E6 PBM-PDZ from Human Papilloma Virus (HPV). AB - High-risk human papillomaviruses (HPVs) are known to cause cervical cancer. Vaccines are now available to prevent HPV infection. However, a clinically approved drug is yet not available to treat HPV. The PDZ(PSD-95/Dlg/ZO-1)-binding motif (PBM) in the E6 protein of HPVs targets the PDZ domain (known to be associated with oncogenesis) for degradation. Therefore, it is of interest to study PBM-PDZ interaction towards its possible inhibition with a potential inhibitor. Thus, four pharmocophore models of PBM-PDZ complex were developed. In order to obtain potent small molecules for its inhibition, a commercial compound database was screened using both these pharmacophore models and molecule docking method. These efforts identified four potential compounds (1-4) towards its inhibition with the docking scores range -18.2 to -15.0. PMID- 26420922 TI - Codon bias and gene expression of mitochondrial ND2 gene in chordates. AB - BACKGROUND: Mitochondrial ND gene, which encodes NADH dehydrogenase, is the first enzyme of the mitochondrial electron transport chain. Leigh syndrome, a neurodegenerative disease caused by mutation in the ND2 gene (T4681C), is associated with bilateral symmetric lesions in basal ganglia and subcortical brain regions. Therefore, it is of interest to analyze mitochondrial DNA to glean information for evolutionary relationship. This study highlights on the analysis of compositional dynamics and selection pressure in shaping the codon usage patterns in the coding sequence of MT-ND2 gene across pisces, aves and mammals by using bioinformatics tools like effective number of codons (ENC), codon adaptation index (CAI), relative synonymous codon usage (RSCU) etc. RESULTS: We observed a low codon usage bias as reflected by high ENC values in MT-ND2 gene among pisces, aves and mammals. The most frequently used codons were ending with A/C at the 3(rd) position of codon and the gene was AT rich in all the three classes. The codons TCA, CTA, CGA and TGA were over represented in all three classes. The F1 correspondence showed significant positive correlation with G, T3 and CAI while the F2 axis showed significant negative correlation with A and T but significant positive correlation with G, C, G3, C3, ENC, GC, GC1, GC2 and GC3. CONCLUSIONS: The codon usage bias in MTND2 gene is not associated with expression level. Mutation pressure and natural selection affect the codon usage pattern in MT-ND 2 gene. PMID- 26420923 TI - ADSBET2: Automated Determination of Salt-Bridge Energy-Terms version 2. AB - Component (bridge: DeltaDeltaGbrd , background: DeltaDeltaGprot , desolvation: DeltaDeltaGdsolv ) and net (DeltaDeltaGnet ) energy-terms of salt-bridge structure (SBS) are auto-generated by the program ADSBET that makes use of general purpose Adaptive Poison Boltzmann Solver (APBS) method. While the procedure reports gross energy terms (Kcal Mol(-1) ), report on bond-multiplicity corrected normalized energyterms (Kcal Mol(-1) Bond(-1) ) along with their accessibility (ASA) in monomer, isolated-SBS (ISBS) and networked-SBS (NSBS) format would be very useful for statistical comparison among SBSs and understanding their location in protein structure. In this end, ADSBET2 potentially incorporates these features along with additional model for side chain. Gross and normalized energy-terms are redirected in monomer, ISBS and NSBS format along with their ASA informations. It works on any number of SBSs for any number of structure files present in a database. Taken together, ADSBET2 has been suitable for statistical analyses of SBSs energetics and finds applications in protein engineering and structural bioinformatics. AVAILABILITY: ADSBET2 is freely available at http://sourceforge.net/projects/ADSBET2/ for all users. PMID- 26420924 TI - NNvPDB: Neural Network based Protein Secondary Structure Prediction with PDB Validation. AB - The predicted secondary structural states are not cross validated by any of the existing servers. Hence, information on the level of accuracy for every sequence is not reported by the existing servers. This was overcome by NNvPDB, which not only reported greater Q3 but also validates every prediction with the homologous PDB entries. NNvPDB is based on the concept of Neural Network, with a new and different approach of training the network every time with five PDB structures that are similar to query sequence. The average accuracy for helix is 76%, beta sheet is 71% and overall (helix, sheet and coil) is 66%. AVAILABILITY: http://bit.srmuniv.ac.in/cgi-bin/bit/cfpdb/nnsecstruct.pl. PMID- 26420925 TI - Platelet-rich plasma therapy: A novel application in regenerative medicine. PMID- 26420926 TI - Hemolysis: A positive agglutination reaction while studying titration of anti A/B antibody for ABO-incompatible solid organ transplants. PMID- 26420928 TI - Comprehensive analysis of changes in clinically significant divalent serum cation levels during automated plateletpheresis in healthy donors in a tertiary care center in North India. AB - BACKGROUND: Adverse effects due to apheresis are unusual. The most common apheresis-specific reaction is hypocalcemia due to citrate anticoagulation and induces ionized hypocalcemia and hypomagnesemia by chelating effect during the plateletpheresis; generally transient and self-limiting but has the potential of severely injuring donor. We have investigated total calcium (tCa(++)) and magnesium (tMg(++)) levels in sixty healthy plateletpheresis donors at different intervals during the procedure and 30 min post-procedure. MATERIALS AND METHODS: A total of 60 procedures were performed on healthy donors. Blood samples were obtained from sterile diversion pouch placed on apheresis circuit. 5 ml sample in plain vials was obtained at different intervals during each procedure and 30 min after the end of the procedure. Samples were used for measurement of tCa(++) and tMg(++) levels. RESULTS: There is continuous decrease in mean tCa(++) from baseline levels (9.83 +/- 0.64 mg/dl) till end of procedure (8.33 +/- 0.78 mg/dl), but after 30 min, levels again reached near their respective baseline values (9.42 +/- 0.54 mg/dl). Similarly, mean tMg(++) fell from baseline levels (2.36 +/- 0.3 mg/dl) till the end of procedure (1.39 +/- 0.40 mg/dl). After 30 min, levels were again increased, their respective baseline values (2.25 +/- 0.25 mg/dl). CONCLUSION: There is continuous, gradual, and significant fall (P < 0.05) in mean tCa(++) and mean tMg(++) from baseline levels to till the end of procedure but after 30 min of completion of procedure, levels again reached near their respective baseline values. PMID- 26420927 TI - Current trends in platelet transfusions practice: The role of ABO-RhD and human leukocyte antigen incompatibility. AB - Platelet transfusions have contributed to the revolutionary modern treatment of hypoproliferative thrombocytopenia. Despite the long-term application of platelet transfusion in therapeutics, all aspects of their optimal use (i.e., in cases of ABO and/or Rh (D incompatibility) have not been definitively determined yet. We reviewed the available data on transfusion practices and outcome in ABO and RhD incompatibility and platelet refractoriness due to anti-human leukocyte antigen (HLA) antibodies. Transfusion of platelets with major ABO-incompatibility is related to reduced posttransfusion platelet (PLT) count increments, compared to ABO-identical and minor, but still are equally effective in preventing clinical bleeding. ABO-minor incompatible transfusions pose the risk of an acute hemolytic reaction of the recipient that is not always related to high anti-A, B donor titers. ABO-identical PLT transfusion seems to be the most effective and safest therapeutic strategy. Exclusive ABO-identical platelet transfusion policy could be feasible, but alternative approaches could facilitate platelet inventory management. Transfusion of platelets from RhD positive donors to RhD negative patients is considered to be effective and safe though is associated with low rate of anti-D alloimmunization due to contaminating red blood cells. The prevention of D alloimmunization is recommended only for women of childbearing age. HLA alloimmunization is a major cause of platelet refractoriness. Managing patients with refractoriness with cross-matched or HLA-matched platelets is the current practice although data are still lacking for the efficacy of this practice in terms of clinical outcome. Leukoreduction contributes to the reduction of both HLA and anti-D alloimmunization. PMID- 26420929 TI - Bombay blood group: Is prevalence decreasing with urbanization and the decreasing rate of consanguineous marriage. AB - CONTEXT: Bombay blood group although rare is found to be more prevalent in the Western and Southern states of India, believed to be associated with consanguineous marriage. AIMS: To estimate the prevalence of the Bombay blood group (Oh) in the urban population of Puducherry. To find the effect of urbanization on consanguineous marriage and to establish whether consanguinity plays a part in the prevalence of Oh group. To compare Oh group prevalence with that of other neighboring states, where population is not predominantly urban. SETTINGS AND DESIGN: This is a descriptive study in a tertiary care hospital in Puducherry, over a period of 6 years. MATERIALS AND METHODS: All blood samples showing 'O' group were tested with anti-H lectin. Specialized tests like Adsorption Elution Technique, inhibition assay for determination of secretor status were performed on Oh positive cases. Any history of consanguineous marriage was recorded. STATISTICAL ANALYSIS USED: All variables were categorical variable and percentage and proportions were calculated manually. RESULTS: Analysis of the results of 35,497 study subjects showed that the most common group was 'O' group constituting 14,164 (39.90%) of subjects. Only three "Oh" that is, Bombay phenotype (0.008%) were detected. Consanguinity was observed in two cases (66.66%). CONCLUSIONS: This study shows the prevalence of Bombay blood group representing the urban population of Puducherry, to be high (0.008%) and associated with consanguineous marriage (66.66%). Thus, consanguinity is still an important risk factor present, even in an urban population in Southern India. PMID- 26420930 TI - Frequencies of human neutrophil antigen-4 and human neutrophil antigen-5 among Thai blood donors. AB - CONTEXT: Antibodies against human neutrophil antigens (HNAs) are implicated in immune-mediated neutropenia, transfusion-related acute lung injury and febrile transfusion reactions. AIMS: This study aimed to determine HNA gene frequencies of the HNA-4 and HNA-5 systems among Thai populations and compare these frequencies with those previously reported for other populations. MATERIALS AND METHODS: 800 DNA samples obtained from 500 unrelated healthy blood donors from Bangkok and 300 samples from Chiang Mai, Thailand were included. Samples were typed for each HNA allele including HNA-4a, HNA-4b, HNA-5a, and HNA-5b using an in-house polymerase chain reaction with sequence-specific primer technique. RESULTS: The frequencies of HNA-4a and HNA-4b alleles in central Thais were 0.975 and 0.025, respectively and for Northern Thais, their frequencies were 0.965 and 0.035, respectively. For HNA-5a and HNA-5b alleles, their frequencies were 0.771 and 0.229; 0.748, and 0.252 in central and Northern Thais, respectively. The frequencies of HNA-4 and HNA-5 systems in central Thais are closely related to those in Northern Thais (P > 0.05). However, their frequencies were different from other populations (P < 0.001), except HNA-5a and HNA-5b gene frequencies in Thais were similar to Caucasians (P > 0.05). CONCLUSION: This study could contribute to predict the risk of alloimmunization to HNA-4 and HNA-5 systems, especially in feto-maternal incompatibility in Thais. PMID- 26420931 TI - Seroprevalence of hepatitis B virus infection and hepatitis B surface antibody status among laboratory health care workers in Isfahan, Iran. AB - BACKGROUND: Laboratory health care workers (HCWs) may become infected through their occupation with blood-borne pathogens. The aims of this study were determining the seroprevalence of hepatitis B virus (HBV) and the protection offered by HBV vaccine in medical laboratory HCWs. MATERIALS AND METHODS: A descriptive cross-sectional study was carried out on 203 employers of clinical laboratories. Participant data were obtained through a questionnaire, and the level of antigens and antibodies were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: All of the subjects were negative for HBV infection. Forty-seven (23.2%) were not immune, 126 (62.0%) were relatively immune, and 30 (14.8%) were highly immune. CONCLUSION: Hepatitis B infection is infrequent in laboratory HCWs in Isfahan. PMID- 26420932 TI - Unusual spontaneous cold auto-hemagglutination phenomenon in blood units stored under blood bank condition: A retrospective analysis. AB - BACKGROUND: Cold agglutinins (CA) are benign naturally occurring low titer autoantibodies present in most individuals. Those with moderate strength are found in infections, malignancies or autoimmune conditions with diagnostic importance. AIM: Present report deals with CA that brought spontaneous hemagglutination in blood units stored at 2-6 degrees C. STUDY DESIGN: Over 32 months period between July 1993 and December 1995, blood units were inspected for spontaneous cold auto-hemagglutination (SpCA) phenomenon. The plasma from these units was separated and investigated for serological specificity using in house red cell panel and standard serological methods. RESULTS: Among 51,671 blood units, 112 units showed SpCA phenomenon. A rising trend seen in first half of study period significantly fell in remaining half. Specificities of the antibodies detected include anti-I (27), anti-i (53), anti-Pr (21) with remaining few being undetermined specificity. Absorption of serum using enzyme-treated red cells revealed a presence of anti-Pr among the cases, the two of which with new specificities that reacted preferentially with red cells from either new-born or adults and were tentatively named as anti-Pr(Fetal) and anti-Pr(adult), respectively. While 9 cases showed optimum reaction at neutral pH of 7, 68 (62%) cases reacted at pH 5.8 through 8.0, 28 (26%) cases preferred an acidic pH 5.8 and 4 cases opted an alkaline pH 8. Of 28 cases with antibodies preferentially reacting in acidic medium, 17 (60%) cases were anti-i and 7 (25%) cases were anti Pr. CONCLUSION: Unique SpCA phenomenon observed in blood units stored under blood bank conditions seems to be due to CA developed in response to vector-borne infectious agents. Majority of the cases displayed their specificities, otherwise are rare to be encountered. PMID- 26420933 TI - Release of cytokines in stored whole blood and red cell concentrate: Effect of leukoreduction. AB - BACKGROUND: Storage time of blood components plays a major role in the accumulation of cytokines causing adverse transfusion reactions. AIMS: The aim was to study the trend in the levels of interleukin-6 (IL-6), IL-8, tumor necrosis factor-alpha (TNF-alpha) and regulated upon activation, normal T-cells expressed and secreted (RANTES) during storage of whole blood (WB) and red cell concentrate (RCC) and to study the effect of leukoreduction (LR). MATERIALS AND METHODS: WB sample was taken on 0, 7, 14, 21, and between 28 and 35 days and plasma aliquots were frozen. Samples from RCC and buffy-coat depleted RCC prepared using Optipress II were collected on 0, 7, 14, 21 and between 28 and 35 days. Cytokine estimation was done using ELISA development kits. Normal range of cytokines was established using 0 day samples of WB. Statistical analysis was done using nonparametric tests. RESULTS AND CONCLUSION: The normal range of IL-6 was 0-23 pg/ml, IL-8 0-12 pg/ml, TNF-alpha 0-3 pg/ml, and RANTES 1200-2000 pg/ml. IL-6 was in normal range and showed a decreasing trend during storage. IL-8 levels increased significantly from 0 to 35 days. In RCC, the highest level was 480 pg/ml on 28(th) day. It was in the normal range in buffy-coat depleted RCC up to 28 days. RANTES level was significantly low in buffy-coat depleted RCC compared to RCC. We conclude that WB has high levels of IL-8 and RANTES. The levels of cytokines are affected by storage period and LR. Comparison of WB and buffy-coat depleted RCC shows significantly low levels of IL-6, IL-8, and RANTES in buffy-coat depleted RCC. This study emphasizes the use of red cell components instead of WB and buffy-coat depleted RCC instead of RCC. PMID- 26420934 TI - Alloimmunization due to red cell antibodies in Rhesus positive Omani Pregnant Women: Maternal and Perinatal outcome. AB - OBJECTIVE: This study is aimed to determine the prevalence of alloimmunization due to antibodies to red blood cell (RBC) antigens (other than rhesus [Rh] antigen) and report the maternal, perinatal, and neonatal outcomes. MATERIALS AND METHODS: A retrospective review of medical records of all patients with minor RBCs antibodies alloimmunization who were followed and delivered at Sultan Qaboos University Hospital, Oman from June 2011 to June 2013. Maternal characteristics, antibody type, antibody titer in addition to perinatal and neonatal outcomes were reviewed. RESULTS: There were 1160 patients with Rh positive status in the study. The most common ABO blood group was O, followed by A, B, and AB. We found 33 out of 1160 Rh positive women alloimmunized with minor RBCs antibodies that gave a prevalence of minor RBCs alloimmunization of 2.7%. The most frequent antibody was anti-E 38%, followed by anti-c 17% and anti-kell 17%. 6 of these 33 patients were identified to have significant antibody titer, and two cases showed evidence of fetal anemia. Only one case required an intrauterine blood transfusion. The most common neonatal complication was jaundice in 53%, followed by respiratory distress syndrome in 28%. Two cases complicated by neonatal anemia required a postnatal blood transfusion. CONCLUSION: Alloimmunization with anti-E, anti-c, and anti-kell were the most common antibodies among the study group. Minor RBCs alloimmunization was an important cause of neonatal morbidity. PMID- 26420935 TI - Platelet growth factors from allogeneic platelet-rich plasma for clinical improvement in split-thickness skin graft. AB - BACKGROUND AND OBJECTIVES: Platelets are a source of numerous growth factors which facilitate repair and healing. Thus platelet rich plasma has been increasingly used as a treatment modality in the field of reconstructive surgeries for wound healing. This preliminary study was carried out to explore whether platelet growth factors from platelet rich plasma could be used for enhancement of split thickness skin graft survival. MATERIALS AND METHODS: Twenty patients (13 males and 7 females) requiring split thickness skin graft for various clinical reasons were enrolled in the study. Platelet rich plasma was collected by apheresis and frozen at -80 degrees C. It was thawed at room temperature immediately before its intended application. PRP was applied only on one half of the wound, while another half served as control. Patient was followed for 6 weeks. The effect was assessed at first dressing in terms of graft uptake and subsequently as time taken for complete healing. RESULTS: There was 100% uptake of the graft in the area where platelet rich plasma was applied. In the control area, there was complete graft loss in 4 cases, partial loss in 7 cases and complete uptake in 9 cases. CONCLUSION: This study demonstrated promising results on application of PRP to split thickness skin grafts. Further randomized studies with greater sample size may be undertaken to establish platelet rich plasma as a validated treatment modality. PMID- 26420936 TI - Efficacy of platelet-rich plasma in treatment of androgenic alopecia. AB - BACKGROUND: Platelet-rich plasma (PRP) has shown remarkable beneficial effects without any major adverse reactions in the treatment of androgenic alopecia. The growth factors in activated autologous PRP induce the proliferation of dermal papilla cells. OBJECTIVES: The objective was to investigate the clinical efficacy of PRP in treatment of androgenic alopecia. MATERIALS AND METHODS: Ten patients were given autologous PRP injections on the affected area of alopecia over a period of 3 months at interval of 2-3 weeks and results were assessed. RESULTS: Three months after the treatment, the patients presented clinical improvement in the hair counts, hair thickness, hair root strength, and overall alopecia. CONCLUSION: PRP appears to be a cheap, effective, and promising therapy for androgenic alopecia with no major adverse effects. PMID- 26420937 TI - Optimizing cord blood collections: Assessing the role of maternal and neonatal factors. AB - BACKGROUND: As processing and cryopreservation of cord blood is time consuming and costly, it is essential to select units with optimal CD34+ cells, total nucleated cell (TNC) number and colony forming units (CFUs). These are the most important factors affecting outcome of UCB transplantation and are influenced by various maternal and neonatal factors. AIM AND OBJECTIVES: To determine the maternal and neonatal factors affecting TNC and CD34+ cell counts in cord blood so as to aid in proper selection of cord blood units for cryopreservation. MATERIALS AND METHODS: A total of 100 UCB units were collected from normal vaginal deliveries, processed and assessed for volume, TNC, CD34+ cell count and CFU-GM. These parameters were then analyzed to find out whether they correlated with maternal and neonatal characteristics such as mother's age, parity, gestational age, baby's birth weight, and sex. RESULTS: The volume of CB collected significantly correlated with the TNC, CD34+ cell, and CFU-GM yields (P < 0.02). A heavier placenta (P < 0.05), and a heavier baby (P < 0.002) were associated with a significantly greater volume of CB whereas the age, parity of mother and the sex of the baby had no significant effect. CONCLUSION: The only factors found to affect the TNC and CD34+ cell counts significantly were weight of the baby and placenta and the volume of cord blood collected. Since these factors are of prognostic significance, their analysis will aid in deciding which UCB unit should be processed and cryopreserved for UCB banking and subsequent transplantation. PMID- 26420938 TI - Tranexamic acid reduces blood loss and need of blood transfusion in total knee arthroplasty: A prospective, randomized, double-blind study in Indian population. AB - INTRODUCTION: For quite a few years, tranexamic acid (TEA) has been used during total knee arthroplasty (TKA) to reduce blood loss. However, no consensus exits regarding its timing and doses. MATERIALS AND METHODS: We conducted a prospective, randomized double-blinded study of 56 patients in the Indian population undergoing TKA from 2011 to 2012. A dose of 10 mg/kg body weight of TEA (three doses) was given in one group and normal saline was administered in the other. RESULTS: The mean blood loss in the TEA unilateral group was 295 mL +/ 218 mL and in the placebo group was 482 mL +/- 186 mL (P < 0.005). In the bilateral TEA group, the mean blood loss was 596 mL +/- 235 mL and in the placebo group was 1349 mL +/- 41 mL (P < 0.005). CONCLUSION: The number of patients requiring blood transfusion reduced substantially. There was no increase in the risk of deep vein thrombosis (DVT) and pulmonary embolism. TEA reduces intraoperative and postoperative blood loss and thus reduces the need of allogenic blood transfusion. PMID- 26420939 TI - Clinical and serological characterization of cold agglutinin syndrome in a Tertiary Care Hospital in Eastern India. AB - BACKGROUND AND AIM: Cold agglutinin syndrome (CAS) primary or secondary represents approximately 16-32% of autoimmune hemolytic anemia cases. Most patients present with mild, chronic hemolytic anemia with exacerbation of the condition in the cold environment. Red cell transfusions are only indicated when there is a life-threatening anemia causing crisis. We studied the clinical and serological characterization of CAS with the aim that the information gained from this study would help in proper diagnosis and management of these patients. MATERIALS AND METHODS: The prospective study included nine patients who were admitted with severe anemia. Detailed work-up were conducted to establish the diagnosis, severity of in vivo hemolysis and transfusion management. RESULTS: All patients presented with pallor, weakness, fatigue and painful fingers and toes with exacerbation of symptoms in winter months. Secondary CAS was observed in three patients suffering from malignant lymphoma. Red cells of all patients were coated with complements (C3) more specifically C3d. In one patient suffering from malignant lymphoma, the cold autoagglutinin titer was as high as 4096. Autoantibody in seven patients was specific to "I" antigen and one to "i" antigen. CONCLUSIONS: We conclude that detailed clinical and serological characterization is needed to diagnose and manage CAS. Whereas avoidance of cold exposure is the primary therapy, but no critical patient should be denied blood transfusion due to serological complications. All transfusion services should follow the correct protocol to maximize blood safety in CAS. PMID- 26420940 TI - Dengue viremia in blood donors in Northern India: Challenges of emerging dengue outbreaks to blood transfusion safety. AB - BACKDROUND: Emerging infectious diseases pose threats to the general human population; including recipients of blood transfusions. Dengue is spreading rapidly to new areas and with increasing frequency of major outbreaks. Screening blood for dengue antigens in dengue-endemic countries would be costly and should, therefore, be recommended only after careful assessment of risk for infection and cost. AIM: A prospective study was conducted to establish the magnitude of the threat that dengue poses to blood safety where it is sporadic with seasonal variations, to quantify risk and to assess that whether screening is feasible and cost-effective. MATERIALS AND METHODS: Nonstructural protein 1 (NS1) antigen test was done on 1709 donations during dengue outbreak in the months August to November 2013 as an additional test using Bio-Rad Platelia Dengue NS1AG test kit which is one step sandwich format microplate enzyme immunoassay using murine monoclonal antibodies for capture and revelation. Chi-square test was used to find statistical significance. RESULTS AND CONCLUSIONS: Majority cases were whole blood, replacement, male donors with 76.10% donors in <35 years age group. About 17.85% were single donor platelet donations. NS1 antigen in all donors was negative. In the past, dengue affected mainly children who do not donate blood. With the changing trend, mean age of infection increased affecting the population that does donate blood, further reducing blood donation pool. Further studies need to be done in different geographic regions of the country during dengue transmission season to establish maximum incidence of viremic donations, rates of transfusion transmission and clinical consequences in recipients. If risk is found to be substantial, decision will be taken by the policymakers at what threshold screening should be instituted to ensure safe blood transfusion. PMID- 26420941 TI - Clinico-serologic co-relation in bi-directional ABO incompatible hemopoietic stem cell transplantation. AB - BACKGROUND: The ABO blood group system is of prime significance in red cell transfusion and organ transplantation. However, ABO compatibility is not critical in allogenic hemopoietic stem cell transplantation (HSCT) and approximately 40 50% of hemopoietic stem cell transplants are ABO incompatible. This incompatibility may be major, minor or bi-directional. Though there are descriptions of transfusion practice and protocols in ABO incompatible HSCT, there are considerable variations and transfusion support in these patients can be very challenging. AIMS: The immunohematologic observations in two cases of bi directional ABO incompatible HSCT have been described, and clinico-serologic correlation has been attempted. MATERIALS AND METHODS: In both cases, peripheral blood stem cell harvests were obtained using the Cobe spectra cell separator. Immunohematologic assessments in the donor and recipient were done as a part of pre HSCT evaluation. Both the standard tube technique and column agglutination method (Ortho Biovue Micro Bead System) was used. Antibody screen was done by column agglutination method using three cell panel (Surgiscreen cells). Isoagglutinin titration was done by the master dilution method and standard validated techniques were used. RESULTS: The pattern of laboratory findings in the two cases was different and so were the clinical outcomes. Although there was early engraftment in the first case, the second case developed pure red cell aplasia and this was well-reflected in the immunohematologic assessments. CONCLUSION: Immunohematologic assessment correlated well with the clinical picture and could be used to predict clinical outcome and onset of complications in ABO incompatible HSCT. PMID- 26420942 TI - Establishing a sample-to cut-off ratio for lab-diagnosis of hepatitis C virus in Indian context. AB - INTRODUCTION: Lab-diagnosis of hepatitis C virus (HCV) is based on detecting specific antibodies by enzyme immuno-assay (EIA) or chemiluminescence immuno assay (CIA). Center for Disease Control reported that signal-to-cut-off (s/co) ratios in anti-HCV antibody tests like EIA/CIA can be used to predict the probable result of supplemental test; above a certain s/co value it is most likely to be true-HCV positive result and below that certain s/co it is most likely to be false-positive result. A prospective study was undertaken in patients in tertiary care setting for establishing this "certain" s/co value. MATERIALS AND METHODS: The study was carried out in consecutive patients requiring HCV testing for screening/diagnosis and medical management. These samples were tested for anti-HCV on CIA (VITROS((r)) Anti-HCV assay, Ortho Clinical Diagnostics, New Jersey) for calculating s/co value. The supplemental nucleic acid test used was polymerase chain reaction (PCR) (Abbott). PCR test results were used to define true negatives, false negatives, true positives, and false positives. Performance of different putative s/co ratios versus PCR was measured using sensitivity, specificity, positive predictive value and negative predictive value and most appropriate s/co was considered on basis of highest specificity at sensitivity of at least 95%. RESULTS: An s/co ratio of >=6 worked out to be over 95% sensitive and almost 92% specific in 438 consecutive patient samples tested. CONCLUSION: The s/co ratio of six can be used for lab-diagnosis of HCV infection; those with s/co higher than six can be diagnosed to have HCV infection without any need for supplemental assays. PMID- 26420943 TI - A comprehensive serological and supplemental evaluation of hepatitis B "seroyield" blood donors: A cross-sectional study from a tertiary healthcare center in India. AB - BACKGROUND: The present study addressed the interesting findings of supplemental evaluation of hepatitis B "seroyield" donors. MATERIALS AND METHODS: Each blood donor sample was tested for anti-human immunodeficiency virus type I (HIV-I)/HIV type II (HIV-II), HBsAg, and anti-hepatitis C virus (HCV) antibody by enhanced chemiluminescence method and subjected to individual donor-nucleic acid testing (NAT) for HIV-I, hepatitis B virus (HBV), and HCV. NAT test was performed using the eSAS system, Procleix Ultrio Assay, Novartis Diagnostics, CA, US. Confirmation of HBsAg was done using HBsAg Confirmatory Kit (Ortho Clinical Diagnostics, Johnson & Johnson, USA) and viral load assessment was done using Cobas TaqMan real time-polymerase chain reaction (RT-PCR) assay (Roche Molecular Systems, Branchburg, NJ, USA). To provide information on the stage of infection, specimens were tested for anti-HBc total (IgG + IgM), anti-HBc IgM and HBeAg. HBeAg-negative samples were tested for anti-HBe antibody. RESULTS: A total of 60 hepatitis B seroyield donors which showed mean initial sample/cutoff of 1.6 with enhanced chemiluminescence assay were investigated further for confirmation of disease status. All 60 cases were confirmed positive with neutralization assay (VITROS HBsAg Confirmatory Kit) while no target was detected on viral load assessment with RT-PCR. Sixteen donors were HBeAg positive (4 IgM anti-HBc positive and 12 IgM anti-HBc negative) and 44 were IgM anti-HBc negative, anti HBc total positive, and anti-HBe positive. CONCLUSION: About 7.7% of HBsAg positive and NAT nonreactive donors (nondetectable HBV DNA) could be potentially infectious (HBeAg positive), whereas rest of the donors were consistent with chronic HBV infection. PMID- 26420944 TI - Evaluation of the pneumatic tube system for transportation of packed red cell units. AB - BACKGROUND: Pneumatic tube system (PTS) is commonly used in hospital settings to transport blood samples to diagnostic laboratories. At our blood center, we receive blood requisitions via the PTS, but units are carried to the ward by human courier. Recently we considered using the PTS for transporting blood units. Since, there are reports of hemolysis in blood samples sent through the PTS, we evaluated this system for transporting red cell units. AIMS: The aim was to assess the effect of PTS transport on the quality of packed red cell units. MATERIALS AND METHODS: A total of 50 red blood cells units (RBC), (25 non irradiated and 25 irradiated) were subjected to transportation through the PTS. The control arm in the study was age-matched RBC units not subjected to PTS transport. Each RBC unit was evaluated for hemoglobin (Hb), lactate dehydrogenase, potassium and plasma hemoglobin (Hb). The paired t-test was used to compare these parameters, and the P value was calculated. RESULTS AND CONCLUSION: The percentage of hemolysis after transportation through PTS was below the recommended guidelines. Delivery of the blood unit to the wrong station, bags lying unattended at the destination were few of the problems that had to be addressed. To conclude, though the PTS is a safe means of transporting blood products with reduction in the turn-around-time, it must be validated before use. PMID- 26420945 TI - Individual donor-nucleic acid testing for human immunodeficiency virus-1, hepatitis C virus and hepatitis B virus and its role in blood safety. AB - BACKGROUND: Transfusion-transmitted infections (TTIs) are one of the biggest threats to blood transfusion safety. Nucleic acid testing (NAT) in blood donor screening has been implemented in many countries to reduce the risk of TTIs. NAT shortens this window period, thereby offering blood centers a much higher sensitivity for detecting viral infections. AIMS: The objective was to assess the role of individual donor-NAT (ID-NAT) for human immunodeficiency virus-1 (HIV-1), hepatitis C virus (HCV) and hepatitis B virus (HBV) and its role in blood safety. MATERIALS AND METHODS: A total of 32978 donations were tested for all three viruses using enzyme-linked immuno-sorbent assay (Vironostika((r)) HIV Ag-Ab, Hepanostika((r)) HCV ultra and hepatitis B surface antigen ultra by Biomerieux) and ID-NAT using Procleix Ultrio plus((r)) Assay (Novartis Diagnostic, USA). All initial NAT reactive samples and serology nonreactive were retested in triplicate and NAT discriminatory assay for HIV-1, HCV and HBV were performed. RESULTS: Of the 32978 samples, 43 (0.13%) were found to be ID-NAT reactive but seronegative. Out of 43, one for HIV-1, 13 for HCV and 27 for HBV were reactive by discriminatory assays. There were two samples that were reactive for both HCV-HBV and counted as HCV-HBV co-infection NAT yield. The prevalence of these viruses in our sample, tested by ID-NAT is 0.06%, 0.71%, and 0.63% for HIV-1, HCV and HBV respectively. The combined NAT yield among blood donors was 1 in 753. CONCLUSION: ID-NAT testing for HIV-1, HCV and HBV can tremendously improve the efficacy of screening for protecting blood recipient from TTIs. It enables detection of these viruses that were undetected by serological test and thus helped in providing safe blood to the patients. PMID- 26420946 TI - Seroepidemiology of human T-cell lymphotropic virus type-I in blood donors of Northeastern Iran, Sabzevar. AB - BACKGROUND AND OBJECTIVES: Human T-cell lymphotropic virus type-I (HTLV-I) infection is considered as a public health challenge in endemic areas. The virus is associated with severe diseases, such as adult T-cell leukemia/lymphoma, and HTLV-I-associated myelopathy/tropical spastic paraparesis. One of the major routes of the HTLV-I transmission includes blood transfusion. Sabzevar is located in the endemic region of HTLV-I infection. The aim of the present study was to determine the seroprevalence of HTLV-I infection in the blood donors in Sabzevar. MATERIALS AND METHODS: A total of 35,067 blood donors in Sabzevar from March 2009 to April 2012 who were screened with HTLV-I on the enzyme-linked immunosorbent assay screening test were included in this survey. Reactive samples that confirmed by western blot were considered to be seropositive cases. The required data were obtained from blood donors' database of blood transfusion service. RESULTS: The overall prevalence of HTLV-1 based on the positive result of western blot test was 0.14%. The seropositive donors aged 17-59 years with a mean age of 38.10 +/- 11.82. The prevalence rates of HTLV-I infection in 3 years of study were 0.19%, 0.14%, and 0.09%, respectively. A significant relation between age, sex, educational level, and history of blood donation was observed with seropositivity of HTLV-I. CONCLUSION: The improvement of donor selection and laboratory screening caused a decline in the prevalence of infection in blood donors. Given the lower prevalence of infection in regular donors with lower age and higher educational level, more efforts should be done to attract blood donors from these populations. PMID- 26420947 TI - Successful use of the cell separator hemonetics multicomponent collection system+ for therapeutic thrombocytapheresis in a low body weight child of essential thrombocythemia. AB - In children, essential thrombocythemia (ET) is extremely rare with an incidence of 1/million. Since thromboembolic complications are more common than hemorrhagic manifestation, immediate thromboctyapheresis by an automated cell separator can prevent untoward consequences in the form of cerebrovascular, coronary or peripheral vascular occlusive events. Due to varied options of automated cell separators, selecting an appropriate cell separator in such acute emergency situation can be confusing for a treating physician, especially if the patient is a child of low body weight. We present here the successful use of hemonetics multicomponent collection system (MCS+) for therapeutic platelet reduction (TPR) in a 12-year-old male child of 28 kg with extreme thrombocytosis (TS) (3072 * 10(9)/l) due to ET. A total of three procedures were performed without priming of the machine with allogenic blood. We observed hemonetics MCS+, best suited for TPR even in children with low body weight. PMID- 26420948 TI - Anti-G antibody in alloimmunized pregnant women: Report of two cases. AB - Anti-G has been reported as a possible cause of hemolytic disease of the fetus and newborn (HDFN), either independently or in association with anti-D, anti-C or both. The antibody mimics the pattern of anti-C and anti-D reactivity in the identification panel and is often present along with either or both of these antibodies. The differentiation of anti-D, -C and-G in routine pretransfusion workup is particularly essential in antenatal cases. We report two antenatal cases where anti-G was identified on advanced immunohematological workup, in addition to other alloantibodies. PMID- 26420949 TI - An acute hemolytic transfusion reaction due to the "anti-c" rhesus antibody: A case report emphasizing the role of transfusion medicine. AB - Rhesus (Rh) mediated hemolytic transfusion reactions (HTR) are usually immunoglobulin G mediated and delayed onset. Rh antibodies being the cause of acute HTR (AHTR) and intravascular hemolysis are still under debate. We report here a case of a 53-year-old male who developed AHTR due to "anti-c" antibodies within 3 h of blood transfusion, precipitating fatal acute liver failure in a patient with hepatitis C related chronic liver disease. This case emphasizes the need of inclusion of antibody screening in routine pretransfusion testing as well as a critical role of transfusion medicine specialists for early diagnosis and minimizing transfusion-related morbidity and mortality. PMID- 26420950 TI - An incident of incorrect blood component transfusion: The need for constant hemovigilance. PMID- 26420951 TI - CAPA analysis of clotted red cell unit detected during leukodepletion process: Importance of quality check on blood collection monitors. PMID- 26420952 TI - Evidence for an influence of secretor status on levels of the ABO-isoantibodies in serum. PMID- 26420953 TI - Mesenchymal stem cell therapy for cirrhosis: Present and future perspectives. AB - Cirrhosis occurs as a result of various chronic liver injuries, which may be caused by viral infections, alcohol abuse and the administration of drugs and chemicals. Recently, bone marrow cells (BMCs), hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) have been used for developing treatments for cirrhosis. Clinical trials have investigated the therapeutic potential of BMCs, HSCs and MSCs for the treatment of cirrhosis based on their potential to differentiate into hepatocytes. Although the therapeutic mechanisms of BMC, HSC and MSC treatments are still not fully characterized, the evidence thus far has indicated that the potential therapeutic mechanisms of MSCs are clearer than those of BMCs or HSCs with respect to liver regenerative medicine. MSCs suppress inflammatory responses, reduce hepatocyte apoptosis, increase hepatocyte regeneration, reverse liver fibrosis and enhance liver functionality. This paper summarizes the clinical studies that have used BMCs, HSCs and MSCs in patients with liver failure or cirrhosis. We also present the potential therapeutic mechanisms of BMCs, HSCs and MSCs for the improvement of liver function. PMID- 26420954 TI - Molecular prognostic prediction in liver cirrhosis. AB - The natural history of cirrhosis varies and therefore prognostic prediction is critical given the sizable patient population. A variety of clinical prognostic indicators have been developed and enable patient risk stratification although their performance is somewhat limited especially within relatively earlier stage of disease. Molecular prognostic indicators are expected to refine the prediction, and potentially link a subset of patients with molecular targeted interventions that counteract poor prognosis. Here we overview clinical and molecular prognostic indicators in the literature, and discuss critical issues to successfully define, evaluate, and deploy prognostic indicators as clinical scores or tests. The use of liver biopsy has been diminishing due to sampling variability on fibrosis assessment and emergence of imaging- or lab test-based fibrosis assessment methods. However, recent rapid developments of genomics technologies and selective molecular targeted agents has highlighted the need for biopsy tissue specimen to explore and establish molecular information-guided personalized/stratified clinical care, and eventually achieve "precision medicine". PMID- 26420956 TI - Change of strategies and future perspectives against hepatitis B virus recurrence after liver transplantation. AB - A few decades ago, liver transplantation in patients with chronic hepatitis B virus (HBV) infection was considered a relative contraindication because of the high rate of graft infections and poor prognosis. Since then, remarkable progress was introduced by using nucleos(t)ide analogues and/or hepatitis B immunoglobulin (HBIg) and liver transplantation for HBV-related disease is now becoming one of the good indication. However, high cost burden is the main problem for this combination prophylaxis for a long time use, and this issue should be emerged to be resolved. In this review, we show the progress of post anti-HBV strategies showing the history from introduction of HBIg and nucleos(t)ide analogues to recent new strategies with hepatitis B vaccine or saving or stopping protocols of HBIg, and clarify and discuss how to do for further improvement of prevention strategies with better quality. PMID- 26420955 TI - Hepatitis B virus reactivation associated with antirheumatic therapy: Risk and prophylaxis recommendations. AB - Accompanying the increased use of biological and non-biological antirheumatic drugs, a greater number of cases of hepatitis B virus (HBV) reactivation have been reported in inactive hepatitis B surface antigen (HBsAg) carriers and also in HBsAg-negative patients who have resolved HBV infection. The prevalence of resolved infection varies in rheumatic disease patients, ranging from 7.3% to 66%. Through an electronic search of the PubMed database, we found that among 712 patients with resolved infection in 17 observational cohort studies, 12 experienced HBV reactivation (1.7%) during biological antirheumatic therapy. Reactivation rates were 2.4% for etanercept therapy, 0.6% for adalimumab, 0% for infliximab, 8.6% for tocilizumab, and 3.3% for rituximab. Regarding non biological antirheumatic drugs, HBV reactivation was observed in 10 out of 327 patients with resolved infection from five cohort studies (3.2%). Most of these patients received steroids concomitantly. Outcomes were favorable in rheumatic disease patients. A number of recommendations have been established, but most of the supporting evidence was derived from the oncology and transplantation fields. Compared with patients in these fields, rheumatic disease patients continue treatment with multiple immunosuppressants for longer periods. Optimal frequency and duration of HBV-DNA monitoring and reliable markers for discontinuation of nucleoside analogues should be clarified for rheumatic disease patients with resolved HBV infection. PMID- 26420957 TI - Chronic hepatitis C virus infection and lipoprotein metabolism. AB - Hepatitis C virus (HCV) is a hepatotrophic virus and a major cause of chronic liver disease, including hepatocellular carcinoma, worldwide. The life cycle of HCV is closely associated with the metabolism of lipids and lipoproteins. The main function of lipoproteins is transporting lipids throughout the body. Triglycerides, free cholesterol, cholesteryl esters, and phospholipids are the major components of the transported lipids. The pathway of HCV assembly and secretion is closely linked to lipoprotein production and secretion, and the infectivity of HCV particles largely depends on the interaction of lipoproteins. Moreover, HCV entry into hepatocytes is strongly influenced by lipoproteins. The key lipoprotein molecules mediating these interactions are apolipoproteins. Apolipoproteins are amphipathic proteins on the surface of a lipoprotein particle, which help stabilize lipoprotein structure. They perform a key role in lipoprotein metabolism by serving as receptor ligands, enzyme co-factors, and lipid transport carriers. Understanding the association between the life cycle of HCV and lipoprotein metabolism is important because each step of the life cycle of HCV that is associated with lipoprotein metabolism is a potential target for anti-HCV therapy. In this article, we first concisely review the nature of lipoprotein and its metabolism to better understand the complicated interaction of HCV with lipoprotein. Then, we review the outline of the processes of HCV assembly, secretion, and entry into hepatocytes, focusing on the association with lipoproteins. Finally, we discuss the clinical aspects of disturbed lipid/lipoprotein metabolism and the significance of dyslipoproteinemia in chronic HCV infection with regard to abnormal apolipoproteins. PMID- 26420958 TI - Potentiality of immunotherapy against hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the fifth most common cancer worldwide and the second leading cause of cancer related death. Despite the high incidence, treatment options remain limited for advanced HCC, and as a result prognosis continues to be poor. Current therapeutic options, surgery, chemotherapy and radiotherapy, have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising, novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here, we summarize the various types of HCC immunotherapy and argue that the new-found field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies, such as tumor-associated antigen therapy, immune checkpoint inhibitors and cell transfer immunotherapy, have demonstrated safety and feasibility in HCC patients. Unfortunately, immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this challenge will place immunotherapy at the forefront of HCC treatment, possibly in the near future. PMID- 26420959 TI - Transarterial chemoembolization in hepatocellular carcinoma treatment: Barcelona clinic liver cancer staging system. AB - Hepatocellular carcinoma (HCC), the fifth most common cancer that predominantly occurs in liver cirrhosis patients, requires staging systems to design treatments. The barcelona clinic liver cancer staging system (BCLC) is the most commonly used HCC management guideline. For BCLC stage B (intermediate HCC), transarterial chemoembolization (TACE) is the standard treatment. Many studies support the use of TACE in early and advanced HCC patients. For BCLC stage 0 (very early HCC), TACE could be an alternative for patients unsuitable for radiofrequency ablation (RFA) or hepatic resection. In patients with BCLC stage A, TACE plus RFA provides better local tumor control than RFA alone. TACE can serve as bridge therapy for patients awaiting liver transplantation. For patients with BCLC B, TACE provides survival benefits compared with supportive care options. However, because of the substantial heterogeneity in the patient population with this stage, a better patient stratification system is needed to select the best candidates for TACE. Sorafenib represents the first line treatment in patients with BCLC C stage HCC. Sorafenib plus TACE has shown a demonstrable effect in delaying tumor progression. Additionally, TACE plus radiotherapy has yielded better survival in patients with HCC and portal venous thrombosis. Considering these observations together, TACE clearly has a critical role in the treatment of HCC as a stand-alone or combination therapy in each stage of HCC. Diverse treatment modalities should be used for patients with HCC and a better patient stratification system should be developed to select the best candidates for TACE. PMID- 26420960 TI - Predictive biomarkers of sorafenib efficacy in advanced hepatocellular carcinoma: Are we getting there? AB - Sorafenib is the current standard treatment for advanced hepatocellular carcinoma (HCC), but its efficacy is modest with low response rates and short response duration. Predictive biomarkers for sorafenib efficacy are necessary. However, efforts to determine biomarkers for sorafenib have led only to potential candidates rather than clinically useful predictors. Studies based on patient cohorts identified the potential of blood levels of angiopoietin-2, hepatocyte growth factor, insulin-like growth factor-1, and transforming growth factor-beta1 for predicting sorafenib efficacy. Alpha-fetoprotein response, dynamic contrast enhanced magnetic resonance imaging, and treatment-related side effects may serve as early surrogate markers. Novel approaches based on super-responders or experimental mouse models may provide new directions in biomarker research. These studies identified tumor amplification of FGF3/FGF4 or VEGFA and tumor expression of phospho-Mapk14 and phospho-Atf2 as possible predictive markers that await validation. A group effort that considers various prognostic factors and proper collection of tumor tissues before treatment is imperative for the success of future biomarker research in advanced HCC. PMID- 26420961 TI - Laparoscopic sleeve gastrectomy and gastroesophageal reflux. AB - Bariatric surgery is the only effective procedure that provides long-term sustained weight loss. Sleeve gastrectomy (SG) has emerged over the last few years to be an ideal bariatric procedure because it has several advantages compared to more complex bariatric procedures, including avoiding an intestinal bypass. However, several published follow-up studies report an increased rate of gastroesophageal reflux (GERD) after a SG. GERD is described as either de novo or as being caused by aggravation of preexisting symptoms. However, the literature on this topic is ambivalent despite the potentially increased rate of GERDs that may occur after this common bariatric procedure. This article reviews the mechanisms responsible for GERD in obese subjects as well as the results after a SG with respect to GERD. Future directions for clinical research are discussed along with the current surgical options for morbidly obese patients with GERD and undergoing bariatric surgery. PMID- 26420962 TI - TP53 codon 72 Arg/Arg polymorphism is associated with a higher risk for inflammatory bowel disease development. AB - AIM: To investigate the association between tumor protein 53 (TP53) codon 72 polymorphisms and the risk for inflammatory bowel disease (IBD) development. METHODS: Numerous genetic and epigenetic drivers have been identified for IBD including the TP53 gene. Pathogenic mutations in TP53 gene have only been reported in 50% of colorectal cancer (CRC) patients. A single nucleotide polymorphism (SNP) in the TP53 gene resulting in the presence of either arginine (Arg) or proline (Pro) or both at codon 72 was shown to alter TP53 tumor suppressor properties. This SNP has been investigated as a risk factor for numerous cancers, including CRC. In this study we analyzed TP53 codon 72 polymorphism distribution in 461 IBD, 181 primary sclerosing cholangitis patients and 62 healthy controls. Genotyping of TP53 was performed by sequencing and restriction fragment length polymorphism analysis of genomic DNA extracted from peripheral blood. RESULTS: The most frequent TP53 genotype in IBD patients was Arg/Arg occurring in 54%-64% of cases (and in only 32% of controls). Arg/Pro was the most prevalent genotype in controls (53%) and less common in patients (31% 40%). Pro/Pro frequency was not significantly different between controls and IBD patients. CONCLUSION: The data suggests that the TP53 codon 72 Arg/Arg genotype is associated with increased risk for IBD development. PMID- 26420963 TI - Ursodeoxycholic acid induces apoptosis in hepatocellular carcinoma xenografts in mice. AB - AIM: To evaluate the efficacy of ursodeoxycholic acid (UDCA) as a chemotherapeutic agent for the treatment of hepatocellular carcinoma (HCC). METHODS: BALB/c nude mice were randomized into four groups 24 h before subcutaneous injection of hepatocarcinoma BEL7402 cells suspended in phosphate buffered saline (PBS) into the right flank. The control group (n = 10) was fed a standard diet while treatment groups (n = 10 each) were fed a standard daily diet supplemented with different concentrations of UDCA (30, 50 and 70 mg/kg per day) for 21 d. Tumor growth was measured once each week, and tumor volume (V) was calculated with the following equation: V = (L * W(2)) * 0.52, where L is the length and W is the width of the xenograft. After 21 d, mice were killed under ether anesthesia, and tumors were excised and weighed. Apoptosis was evaluated through detection of DNA fragmentation with gel electrophoresis and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Western blot analysis was performed to determine the expression of apoptosis-related proteins BAX, BCL2, APAF1, cleaved caspase-9, and cleaved caspase-3. RESULTS: UDCA suppressed tumor growth relative to controls. The mean tumor volumes were the following: control, 1090 +/- 89 mm(3); 30 mg/kg per day, 612 +/- 46 mm(3); 50 mg/kg per day, 563 +/- 38 mm(3); and 70 mg/kg per day, 221 +/- 26 mm(3). Decreased tumor volumes reached statistical significance relative to control xenografts (30 mg/kg per day, P < 0.05; 50 mg/kg per day, P < 0.05; 70 mg/kg per day, P < 0.01). Increasing concentrations of UDCA led to increased DNA fragmentation observed on gel electrophoresis and in the TUNEL assay (control, 1.6% +/- 0.3%; 30 mg/kg per day, 2.9% +/- 0.5%; 50 mg/kg per day, 3.15% +/- 0.7%, and 70 mg/kg per day, 4.86% +/- 0.9%). Western blot analysis revealed increased expression of BAX, APAF1, cleaved-caspase-9 and cleaved-caspase-3 proteins, which induce apoptosis, but decreased expression of BCL2 protein, which is an inhibitor of apoptosis, following administration of UDCA. CONCLUSION: UDCA suppresses growth of BEL7402 hepatocellular carcinoma cells in vivo, in part through apoptosis induction, and is thus a candidate for therapeutic treatment of HCC. PMID- 26420964 TI - Recql5 protects against lipopolysaccharide/D-galactosamine-induced liver injury in mice. AB - AIM: To investigate the effects of Recql5 deficiency on liver injury induced by lipopolysaccharide/D-galactosamine (LPS/D-Gal). METHODS: Liver injury was induced in wild type (WT) or Recql5-deficient mice using LPS/D-Gal, and assessed by histological, serum transaminases, and mortality analyses. Hepatocellular apoptosis was quantified by transferase dUTP nick end labeling assay and Western blot analysis of cleaved caspase-3. Liver inflammatory chemokine and cytochrome P450 expression was analyzed by quantitative reverse transcription-PCR. Neutrophil infiltration was evaluated by myeloperoxidase activity. Expression and phosphorylation of ERK, JNK, p65, and H2A.X was determined by Western blot. Oxidative stress was evaluated by measuring malondialdehyde production and nitric oxide synthase, superoxide dismutase, glutathione peroxidase, catalase, and glutathione reductase activity. RESULTS: Following LPS/D-Gal exposure, Recql5 deficient mice exhibited enhanced liver injury, as evidenced by more severe hepatic hemorrhage, higher serum aspartate transaminase and alanine transaminase levels, and lower survival rate. As compared to WT mice, Recql5-deficient mice showed an increased number of apoptotic hepatocytes and higher cleaved caspase-3 levels. Recql5-deficient mice exhibited increased DNA damage, as evidenced by increased gamma-H2A.X levels. Inflammatory cytokine levels, neutrophil infiltration, and ERK phosphorylation were also significantly increased in the knockout mice. Additionally, Recql5-deficient mice exhibited increased malondialdehyde production and elevated inducible nitric oxide synthase, superoxide dismutase, glutathione peroxidase, catalase, and glutathione reductase activity, indicative of enhanced oxidative stress. Moreover, CYP450 expression was significantly downregulated in Recql5-deficient mice after LPS/D-Gal treatment. CONCLUSION: Recql5 protects the liver against LPS/D-Gal-induced injury through suppression of hepatocyte apoptosis and oxidative stress and modulation of CYP450 expression. PMID- 26420966 TI - Liver resection for hepatocellular carcinoma using a microwave tissue coagulator: Experience of 1118 cases. AB - AIM: To present our extensive experience of hepatectomy for hepatocellular carcinoma using a microwave tissue coagulator to demonstrate the effectiveness of this device. METHODS: A total of 1118 cases (1990-2013) were reviewed, with an emphasis on intraoperative blood loss, postoperative bile leakage and fluid/abscess formation, and adaptability to anatomical resection and hepatectomy with hilar dissection. RESULTS: The median intraoperative blood loss was 250 mL; postoperative bile leakage and fluid/abscess formation were seen in 3.0% and 3.3% of cases, respectively. Anatomical resection was performed in 275 cases, including 103 cases of hilar dissection that required application of microwave coagulation near the hepatic hilum. There was no clinically relevant biliary tract stricture or any vascular problems due to heat injury. Regarding the influence of cirrhosis on intraoperative blood loss, no significant difference was seen between cirrhotic and non-cirrhotic patients (P = 0.38), although cirrhotic patients tended to have smaller tumors and underwent less invasive operations. CONCLUSION: This study demonstrated outcomes of an extensive experience of hepatectomy using heat coagulative necrosis by microwave tissue coagulator. PMID- 26420965 TI - Equol inhibits proliferation of human gastric carcinoma cells via modulating Akt pathway. AB - AIM: To investigate the anti-tumor effects of equol in gastric cancer cells and the underlying molecular mechanisms. METHODS: MGC-803 cells were employed for in vitro experiments in this study. Cells were treated with control (vehicle, 0.1% DMSO) or equol under specified dose titration or time courses. Cell viability was examined by MTS assay, and the levels of Ki67 were determined by qPCR and immunofluorescent assay. Changes in cell cycle distribution and apoptosis rate were detected by flow cytometry. The mRNA expression of cyclin E1 and P21(WAF1) was determined by qPCR. The protein levels of cell cycle regulators, PARP and Caspase-3 cleavage, and the phosphorylation of Akt were examined by Western blot. In addition, to characterize the role of elevated Akt activation in the anti tumor effect exerted by equol, Ly294002, a PI3K/AKT pathway inhibitor, was used to pretreat MGC-803 cells. RESULTS: Equol (5, 10, 20, 40, or 80 MUmol/L) inhibited viability of MGC-803 cells in a dose- and time-dependent manner after treatment for 24, 36, or 48 h (P < 0.05 for all). Equol also decreased the mRNA (P < 0.05 for 12 and 24 h treatment) and protein levels of Ki67. Equol treatment significantly induced G0/G1 cell cycle arrest (P < 0.05), with the percentages of G0/G1 cells of 32.23% +/- 3.62%, 36.31% +/- 0.24%, 45.58% +/- 2.29%, and 65.10% +/- 2.04% for equol (0, 10, 20, or 30 MUmol/L) treatment, respectively, accompanied by a significant decrease of CDK2/4 (P < 0.05 for 24 and 48 h treatment) and Cyclin D1/Cyclin E1 (P < 0.05), and an increased level of P21(WAF1) (P < 0.05). A marked increase of apoptosis was observed, with the percentages of apoptotic cells of 5.01% +/- 0.91%, 14.57% +/- 0.99%, 37.40% +/- 0.58%, and 38.46% +/- 2.01% for equol (0, 5, 10, or 20 MUmol/L) treatment, respectively, accompanied by increased levels of cleaved PARP and caspase-3. In addition, we found that equol treatment increased P-Akt (Ser473 and Thr308) at 12 and 24 h compared to vehicle-treated control; longer treatment for 48 h decreased P-Akt (Ser473 and Thr308). P-Akt at Thr450, however, was decreased by equol treatment at all time points examined (P < 0.05 for all). Moreover, Akt inhibition by Ly294002 could not prevent but led to enhanced G0/G1 arrest and apoptosis. CONCLUSION: Equol inhibits MGC-803 cells proliferation by induction of G0/G1 arrest and apoptosis. Its anti-cancer effects are likely mediated by dephosphorylation of Akt at Thr450. PMID- 26420967 TI - Pathogen profile and drug resistance analysis of spontaneous peritonitis in cirrhotic patients. AB - AIM: To investigate the microbiological characteristics and drug resistance in liver cirrhosis patients with spontaneous peritonitis. METHODS: We analyzed the data of patients with liver cirrhosis and abdominal infection at the First Affiliated Hospital of Zhejiang University between January 2011 and December 2013. Pathogens present in the ascites were identified, and their sensitivity to various antibiotics was determined. RESULTS: We isolated 306 pathogenic bacteria from 288 cases: In 178 cases, the infection was caused by gram-negative strains (58.2%); in 85 cases, gram-positive strains (27.8%); in 9 cases, fungi (2.9%); and in 16 cases, more than one pathogen. The main pathogens were Escherichia coli (E. coli) (24.2%), Klebsiella pneumoniae (18.9%), Enterococcus spp. (11.1%), and Staphylococcus aureus (7.5%). Of the 306 isolated pathogens, 99 caused nosocomial infections and 207 caused community-acquired and other infections. The E. coli and K. pneumoniae strains produced more extended-spectrum beta-lactamases in cases of nosocomial infections than non-nosocomial infections (62.5% vs 38%, P < 0.013; 36.8% vs 12.8%, P < 0.034, respectively). The sensitivity to individual antibiotics differed between nosocomial and non-nosocomial infections: Piperacillin/tazobactam was significantly more effective against non-nosocomial E. coli infections (4% vs 20.8%, P < 0.021). Nitrofurantoin had stronger antibacterial activity against Enterococcus species causing non-nosocomial infections (36.4% vs 86.3%, P < 0.009). CONCLUSION: The majority of pathogens that cause abdominal infection in patients with liver cirrhosis are gram negative, and drug resistance is significantly higher in nosocomial infections than in non-nosocomial infections. PMID- 26420968 TI - Predictive value of quantitative contrast-enhanced ultrasound in hepatocellular carcinoma recurrence after ablation. AB - AIM: To investigate the relationship between contrast-enhanced ultrasound (CEUS), basic fibroblast growth factor (bFGF), endothelin-1 (ET-1), and hepatocellular carcinoma (HCC) recurrence after ablation. METHODS: A total of 51 HCC patients (38 males and 13 females) who received radiofrequency ablation in our hospital from June 2012 to July 2014 were enrolled in this study. The patients were divided into two groups: recurrence group and non-recurrence group. Routine abdominal examination was first performed in the horizontal position. Then the patients underwent CEUS and immunohistochemical staining before receiving radiofrequency ablation. All patients were followed-up every three months for one year. The results of CEUS and serum tumor marker levels were evaluated and combined together to estimate HCC recurrence and metastasis. Patients were divided into two groups: recurrence group and non-recurrence group. Quantitative parameters of CEUS and tumor expression levels of bFGF and ET-1 were compared between the two groups, respectively. Binary logistic regression analysis was used to analyze the relationship between CEUS quantitative parameters, expression levels of ET-1 and bFGF, and HCC recurrence after ablation. RESULTS: Based on the quantitative parameters of CEUS before patients received radiofrequency ablation, the levels of tumor rise time (tRT), tumor time to peak (tTTP), tumor peak intensity (tPI) and tumor-parenchymal peak intensity (t-pPI) in the recurrence group were significantly lower than those in the non-recurrence group (16.6 +/- 6.1 vs 23.2 +/- 7.0, P = 0.000; 41.2 +/- 10.2 vs 59.6 +/- 14.2, P = 0.000; 23.8 +/- 6.7 vs 31.4 +/- 6.4, P = 0.000; 7.1 +/- 3.4 vs 14.6 +/- 7.4, P = 0.000; respectively). The expression levels of bFGF in the recurrence group were significantly higher than those in the non-recurrence group (P < 0.05). Levels of tTTP showed a significant inverse correlation with the level of bFGF in tumors (r = -0.312, P = 0.037). The Binary logistic regression analysis results revealed that the levels of tRT, tTTP, tPI and the level of bFGF were associated with HCC recurrence after radiofrequency ablation (P < 0.05). CONCLUSION: CEUS is a noninvasive and effective method for evaluating the angiogenesis of HCC, and predicting its recurrence and prognosis. PMID- 26420969 TI - Early endoscopic ultrasonography in acute biliary pancreatitis: A prospective pilot study. AB - AIM: To investigate the clinical usefulness of early endoscopic ultrasonography (EUS) in the management of acute biliary pancreatitis (ABP). METHODS: All consecutive patients entering the emergency department between January 2010 and December 2012 due to acute abdominal pain and showing biochemical and/or radiological findings consistent with possible ABP were prospectively enrolled. Patients were classified as having a low, moderate, or high probability of common bile duct (CBD) stones, according to the established risk stratification. Exclusion criteria were: gastrectomy or patient in whom the cause of biliary obstruction was already identified by ultrasonography. All enrolled patients underwent EUS within 48 h of their admission. Endoscopic retrograde cholangiopancreatography was performed immediately after EUS only in those cases with proven CBD stones or sludge. The following parameters were investigated: (1) clinical: age, sex, fever; (2) radiological: dilated CBD; and (3) biochemical: bilirubin, AST, ALT, gGT, ALP, amylase, lipasis, PCR. Association between presence of CBD stone at EUS and the individual predictors were assessed by univariate logistic regression. Predictors significantly associated with CBD stones (P < 0.05) were entered in a multivariate logistic regression model. RESULTS: A total of 181 patients with pancreatitis were admitted to the emergency department between January 2010 and December 2012. After exclusion criteria a total of 71 patients (38 females, 53.5%, mean age 58 +/- 20.12 years, range 27-89 years; 33 males, 46.5%, mean age 65 +/- 11.86 years, range 41-91 years) were included in the present study. The probability of CBD stones was considered low in 21 cases (29%), moderate in 26 (37%), and high in the remaining 24 (34%). The 71 patients included in the study underwent EUS, which allowed for a complete evaluation of the target sites in all the cases. The procedure was completed in a mean time of 14.7 min (range 9-34 min), without any notable complications.The overall CBD stone frequency was 44% (31 of 71), with a significant increase from the group at low pretest probability to that at moderate (OR = 5.79, P = 0.01) and high (OR = 4.25, P = 0.03) pretest probability. CONCLUSION: Early EUS in ABP allows, if appropriate, immediate endoscopic treatment and significant spare of unnecessary operative procedures thus reducing possible related complications. PMID- 26420970 TI - Hybrid vs sequential therapy for eradication of Helicobacter pylori in Taiwan: A prospective randomized trial. AB - AIM: To evaluate the efficacy of sequential vs hybrid therapy in patients with Helicobacter pylori (H. pylori) infection. METHODS: From March 2013 to May 2014, one hundred and seventy-five H. pylori infected patients who had not been treated for H. pylori before were randomized to receive either sequential therapy (rabeprazole 20 mg and amoxicillin 1 g twice daily for 5 d, followed by rabeprazole 20 mg, clarithromycin 500 mg and metronidazole 500 mg twice daily for 5 d) or hybrid therapy (rabeprazole 20 mg and amoxicillin 1 g for 7 d, followed by rabeprazole 20 mg, amoxicillin 1 g, clarithromycin 500 mg and metronidazole 500 mg twice daily for 7 d). H. pylori status was confirmed by positive results of both rapid urease test and histology examination or a positive result of culture. Eradication efficacy was assessed by follow-up endoscopy with rapid urease test and histological examination 8 wk after the end of anti-H. pylori therapy, or (13)C-urea breath test at least 4 wk after completion of treatment. The primary outcome was H. pylori eradication by intention-to-treat (ITT) and per protocol (PP) analyses. RESULTS: One hundred and sixty-seven patients (83 patients in the sequential group and 84 patients in the hybrid group) completed the study. The compliance rates were 97.6% and 97.7% for the two groups, respectively. The eradication rate was 78.2% for the sequential group and 92% for the hybrid group by ITT analysis (P = 0.01). The eradication rate was 81.9% for the sequential group and 96.4% for the hybrid group by PP analysis (P = 0.01). Univariate analysis for the clinical and bacterial factors did not identify any risk factors associated with treatment failure. Severe adverse events were observed in 2.3% of patients in the sequential group and 2.4% of those in the hybrid group. CONCLUSION: Due to a grade A (> 95%) success rate for H. pylori eradication by PP analysis, similar compliance and adverse events, hybrid therapy seems to be an appropriate eradication regimen in Taiwan. PMID- 26420972 TI - Prognostic value of Muc5AC in gastric cancer: A meta-analysis. AB - AIM: To assess the correlation between decreased Muc5AC expression and patients' survival and clinicopathological characteristics by conducting a meta-analysis. METHODS: Literature searches were performed in PubMed and EMBASE, and 11 studies met our criteria. Summary hazard ratios or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the effect. For the pooled analysis of the correlation between decreased Muc5AC expression and clinicopathological characteristics (tumour invasion depth, lymph node metastasis, tumour-node metastasis stage, tumour size, venous invasion and lymphatic invasion), ORs and their variance were combined to estimate the effect. RESULTS: Eleven retrospective cohort studies comprising 2135 patients were included to assess the association between Muc5AC expression and overall survival and/or clinicopathological characteristics. Decreased Muc5AC expression was significantly correlated with poor overall survival of gastric cancer patients (pooled HR = 1.35, 95%CI: 1.08-1.7). Moreover, decreased Muc5AC expression was also significantly associated with tumour invasion depth (pooled OR = 2.12, 95%CI: 1.56-2.87) and lymph node metastasis (pooled OR = 1.56, 95%CI: 1.00-2.44) in gastric cancer. CONCLUSION: Decreased Muc5AC expression might be a poor prognostic predictor for gastric cancer. PMID- 26420971 TI - Chemoembolization alone vs combined chemoembolization and hepatic arterial infusion chemotherapy in inoperable hepatocellular carcinoma patients. AB - AIM: To compare the efficacy and safety of chemoembolization alone or chemoembolization combined with hepatic arterial infusion chemotherapy (HAIC), including oxaliplatin (OXA), 5-fluorouracil (5-FU) and folinic acid (CF), in inoperable hepatocellular carcinoma (HCC) without distant metastasis. METHODS: Eighty-four inoperable HCC patients were enrolled. Thirty-nine patients underwent chemoembolization alone, and the other 45 patients underwent chemoembolization + HAIC (OXA/5-FU/CF) treatment non-randomly. The progression free survival (PFS), objective response rate (ORR), disease control rate (DCR) and adverse reactions were compared between the two groups. RESULTS: A significant difference in the ORR was observed between the chemoembolization alone and chemoembolization + HAIC groups. There was no statistically significant difference in DCR between the two groups. The median PFS (mPFS) showed a significant difference between the two groups. For patients with BCLC stage A/B disease, with or without vessel invasion, the chemoembolization + HAIC group showed better mPFS when compared to chemoembolization alone, but no significant difference was found in patients with BCLC stage C disease. The parameter of pain (grade III-IV) in the chemoembolization + HAIC group was increased statistically. CONCLUSION: Chemoembolization combined with HAIC with OXA/5-FU/CF may be safe and more effective than chemoembolization alone for inoperable HCC patients without distant metastasis. PMID- 26420973 TI - Jejunitis and brown bowel syndrome with multifocal carcinogenesis of the small bowel. AB - This is the first report describing a case where prolonged, severe malabsorption from brown bowel syndrome progressed to multifocally spread small bowel adenocarcinoma. This case involves a female patient who was initially diagnosed with chronic jejunitis associated with primary diffuse lymphangiectasia at the age of 26 years. The course of the disease was clinically, endoscopically, and histologically followed for 21 years until her death at the age 47 due to multifocal, metastasizing adenocarcinoma of the small bowel. Multiple lipofuscin deposits (so-called brown bowel syndrome) and severe jejunitis were observed microscopically, and sections of the small bowel showed dense lymphoplasmacytic infiltration of the lamina propria as well as blocked lymphatic vessels. After several decades, multifocal nests of adenocarcinoma cells and extensive, flat, neoplastic mucosal proliferations were found only in the small bowel, along with a loss of the mismatch repair protein MLH1 as a long-term consequence of chronic jejunitis with malabsorption. No evidence was found for hereditary nonpolyposis colon carcinoma syndrome. This article demonstrates for the first time multifocal carcinogenesis in the small bowel in a malabsorption syndrome in an enteritis dysplasia-carcinoma sequence. PMID- 26420974 TI - Lymphoepithelioma-like hepatocellular carcinoma: Case report and review of the literature. AB - Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is a rare form of undifferentiated carcinoma of the liver characterized by the presence of an abundant lymphoid infiltrate. Here, a case of LEL-HCC is described. An 81-year old woman with a chronic hepatitis C infection was referred to the general surgery department of our hospital in August 2013 with a diagnosis of HCC. A past ultrasound examination had revealed a 60 mm-diameter nodular lesion in the third segment of the liver. After a needle biopsy, the lesion was diagnosed as HCC. The patient underwent surgery with a liver segmentectomy. Two additional nodes on the gastric wall were detected during the surgical operation. The histology of the removed specimen showed a poorly differentiated HCC with significant lymphoid stroma. Immunohistochemical studies revealed that the epithelial component was reactive for CK CAM5.2, CK8, CK18, CEA (polyclonal) and was focally positive for hepar-1 and that the lymphoid infiltrate was positive for CD3, CD4 and CD8. The tumor cells were negative for Epstein-Barr virus. The gastric nodes were ultimately determined to be two small gastrointestinal stromal tumors (GISTs). The synchronous occurrence of HCC and GIST is another very uncommon finding rarely described in the literature. Here, we report the clinicopathological features of our case, along with a review of the few cases present in the literature. PMID- 26420975 TI - Autoimmune-like hepatitis during masitinib therapy in an amyotrophic lateral sclerosis patient. AB - We report a case of acute severe hepatitis resulting from masitinib in a young amyotrophic lateral sclerosis patient. Hepatotoxicity induced by masitinib, a tyrosine kinase inhibitor, is usually transient with mild elevation of transaminases, although acute hepatitis has been not reported to date. The hepatitis was resolved after masitinib was discontinued and a combination of prednisone and azathioprine was started. The transaminases returned to baseline normal values five months later. This is the first case in the hepatitis literature associated with masitinib. The autoimmune role of this drug-induced liver injury is discussed. Physicians should be aware of this potential complication. PMID- 26420976 TI - Small bowel volvulus with jejunal diverticulum: Primary or secondary? AB - Small bowel volvulus, which is torsion of the small bowel and its mesentery, is a medical emergency, and is categorized as primary or secondary type. Primary type often occurs without any apparent intrinsic anatomical anomalies, while the secondary type is common clinically and could be caused by numerous factors including postoperative adhesions, intestinal diverticulum, and/or tumors. Here, we report a rare case of a 60-year-old man diagnosed with small bowel volvulus using multidetector computed tomography (MDCT) angiography. Further discovery by laparotomy showed one jejunal diverticulum, longer corresponding mesentery with a narrower insertion, and a lack of mesenteric fat. This case report includes several etiological factors of small bowel volvulus, and we discuss the possible cause of small bowel volvulus in this patient. We also highlight the importance of MDCT angiography in the diagnosis of volvulus and share our experience in treating this disease. PMID- 26420977 TI - Corticosteroid and nucleoside analogue for hepatitis B virus-related acute liver failure. AB - The early introduction of combination therapy of high-dose corticosteroid and nucleoside analogue is beneficial for the rescue of severe acute exacerbation of chronic hepatitis B. PMID- 26420978 TI - Relationships Between Caregiver Violence Exposure, Caregiver Depression, and Youth Behavioral Health Among Homeless Families. AB - Homelessness affects a large and increasing number of families in the United States, and exposure to violence and other potentially traumatic events is common among homeless families. It is important to understand more about this population and, more specifically, about the relationship between youth mental health and caregiver mental health and trauma exposure among homeless families, in order to better serve the needs of this vulnerable population. The objective of this study is to explore the relationships between caregiver exposure to violence, caregiver depression, and youth depression and behavioral problems among homeless families. Preliminary findings indicate that among this sample of homeless families, caregiver violence exposure has statistically significant relationships with both youth behavioral problems and youth depression symptoms, as mediated by caregiver depression. These findings indicate that youth behavioral health is associated with caregiver mental health, which, in turn, is associated with caregiver trauma exposure. This highlights the importance of taking into account adult mental health while treating youth externalizing and internalizing behaviors and ensuring that caregivers, too, have access to adequate treatment and supports. Furthermore, this treatment should be trauma informed, given the link between trauma and mental health. PMID- 26420979 TI - Comparison of Capsule Endoscopy Findings to Subsequent Double Balloon Enteroscopy: A Dual Center Experience. AB - Background. There has been a growing use of both capsule endoscopy (CE) and double balloon enteroscopy (DBE) to diagnose and treat patients with obscure gastrointestinal blood loss and suspected small bowel pathology. Aim. To compare and correlate sequential CE and DBE findings in a large series of patients at two tertiary level hospitals in Wisconsin. Methods. An IRB approved retrospective study of patients who underwent sequential CE and DBE, at two separate tertiary care academic centers from May 2007 to December 2011, was performed. Results. 116 patients were included in the study. The mean age +/- SD was 66.6 +/- 13.2 years. There were 56% males and 43.9% females. Measure of agreement between prior capsule and DBE findings was performed using kappa statistics, which gave kappa value of 0.396 with P < 0.001. Also contingency coefficient was calculated and was found to be 0.732 (P < 0.001). Conclusions. Our study showed good overall agreement between DBE and CE. Findings of angioectasia had maximum agreement of 69%. PMID- 26420980 TI - Rhabdomyosarcoma: Advances in Molecular and Cellular Biology. AB - Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in childhood and adolescence. The two major histological subtypes of RMS are alveolar RMS, driven by the fusion protein PAX3-FKHR or PAX7-FKHR, and embryonic RMS, which is usually genetically heterogeneous. The prognosis of RMS has improved in the past several decades due to multidisciplinary care. However, in recent years, the treatment of patients with metastatic or refractory RMS has reached a plateau. Thus, to improve the survival rate of RMS patients and their overall well-being, further understanding of the molecular and cellular biology of RMS and identification of novel therapeutic targets are imperative. In this review, we describe the most recent discoveries in the molecular and cellular biology of RMS, including alterations in oncogenic pathways, miRNA (miR), in vivo models, stem cells, and important signal transduction cascades implicated in the development and progression of RMS. Furthermore, we discuss novel potential targeted therapies that may improve the current treatment of RMS. PMID- 26420982 TI - Not for the Last Time that I do Something for the First Time: A Time to Padhy! PMID- 26420981 TI - Toxicity of polymeric nanoparticles in vivo and in vitro. AB - Polybutylcyanoacrylate nanoparticles (PBCA NPs) are candidates for a drug delivery system, which can cross the blood-brain barrier (BBB). Because little is known about their toxicity, we exposed cells to PBCA NPs in vitro and in vivo and monitored their life and death assays. PBCA NPs were fabricated with different surfactants according to the mini-emulsion technique. Viabilities of HeLa and HEK293 cells after NP incubation were quantified by analysing cellular metabolic activity (MTT-test). We then repetitively injected i.v. rhodamine-labelled PBCA NP variations into rats and monitored the survival and morphology of retrogradely labelled neurons by in vivo confocal neuroimaging (ICON) for five weeks. To test for carrier-efficacy and safety, PBCA NPs loaded with Kyotorphin were injected in rats, and a hot plate test was used to quantify analgesic effects. In vitro, we found dose-dependent cell death which was, however, only detectable at very high doses and mainly seen in the cultures incubated with NPs fabricated with the tensids SDS and Tween. However, the in vivo experiments did not show any NP induced neuronal death, even with particles which were toxic at high dose in vitro, i.e. NPs with Tween and SDS. The increased pain threshold at the hot plate test demonstrated that PBCA NPs are able to cross the BBB and thus comprise a useful tool for drug delivery into the central nervous system (CNS). Our findings showing that different nanoparticle formulations are non-toxic have important implications for the value of NP engineering approaches in medicine. PMID- 26420984 TI - Development of Scintillators in Nuclear Medicine. AB - High-quality image is necessary for accurate diagnosis in nuclear medicine. There are many factors in creating a good image and detector is the most important one. In recent years, several detectors are studied to get a better picture. The aim of this paper is comparison of some type of these detectors such as thallium activated sodium iodide bismuth germinate cesium activated yttrium aluminum garnet (YAG: Ce) YAP: Ce "lutetium aluminum garnet activated by cerium" CRY018 "CRY019" lanthanum bromide and cadmium zinc telluride. We studied different properties of these crystals including density, energy resolution and decay times that are more important factors affecting the image quality. PMID- 26420983 TI - Radioiodine Remnant Ablation: A Critical Review. AB - Radioiodine remnant ablation (RRA) is considered a safe and effective method for eliminating residual thyroid tissue, as well as microscopic disease if at all present in thyroid bed following thyroidectomy. The rationale of RRA is that in the absence of thyroid tissue, serum thyroglobulin (Tg) measurement can be used as an excellent tumor marker. Other considerations are like the presence of significant remnant thyroid tissue makes detection and treatment of nodal or distant metastases difficult. Rarely, microscopic disease in the thyroid bed if not ablated, in the future, could be a source of anaplastic transformation. On the other hand, microscopic tumor emboli in distant sites could be the cause of distant metastasis too. The ablation of remnant tissue would in all probability eliminate these theoretical risks. It may be noted that all these are unproven contentious issues except postablation serum Tg estimation that could be a good tumor marker for detecting early biochemical recurrence in long-term follow-up strategy. Radioactive iodine is administered as a form of "adjuvant therapy" for remnant ablation. There have been several reports with regard to the administered dose for remnant ablation. The first report of a prospective randomized clinical trial was published from India by a prospective randomized study conducted at the All India Institute of Medical Sciences, New Delhi in the year 1996. The study reported that increasing the empirical (131)I initial dose to more than 50 mCi results in plateauing of the dose-response curve and thus, conventional high-dose remnant ablation needs critical evaluation. Recently, two important studies were published: One from French group and the other from UK on a similar line. Interestingly, all three studies conducted in three different geographical regions of the world showed exactly similar conclusion. The new era of low-dose remnant ablation has taken a firm scientific footing across the continents. PMID- 26420985 TI - The Effect of Parallel-hole Collimator Material on Image and Functional Parameters in SPECT Imaging: A SIMIND Monte Carlo Study. AB - The collimator in single-photon emission computed tomography (SPECT) is a critical component of the imaging system and plays an impressive role in the imaging quality. In this study, the effect of the collimator material on the radioisotopic image and its functional parameters was studied. The simulating medical imaging nuclear detectors (SIMIND) Monte Carlo program was used to simulate a Siemens E.CAM SPECT (Siemens Medical Solutions, Erlangen, Germany) system equipped with a low-energy high-resolution (LEHR) collimator. The simulation and experimental data from the SPECT imaging modality using (99m)Tc were obtained on a point source and Jaszczak phantom. Seventeen high atomic number materials were considered as LEHR collimator materials. In order to determine the effect of the collimator material on the image and functional parameters, the energy resolution, spatial resolution, contrast, and collimator characteristics parameters such as septal penetration and scatter-to-primary ratio were investigated. Energy spectra profiles, full width at half maximums (FWHMs) (mm) of the point spread function (PSF) curves, system sensitivity, and contrast of cold spheres of the Jaszczak phantom for the simulated and experiment systems have acceptability superimposed. The results of FWHM and energy resolution for the 17 collimators showed that the collimator made of 98% lead and 2% antimony could provide the best FWHM and energy resolution, 7.68 mm and 9.87%, respectively. The LEHR collimator with 98% lead and 2% antimony offers the best resolution and contrast when compared to other high atomic number metals and alloys. PMID- 26420986 TI - Dose Calibrator Linearity Testing: Radioisotope (99m)Tc or (18)F? An Alternative for Reducing Costs in Nuclear Medicine Quality Control. AB - Dose calibrator linearity testing is indispensable for evaluating the capacity of this equipment in measuring radioisotope activities at different magnitudes, a fundamental aspect of the daily routine of a nuclear medicine department, and with an impact on patient exposure. The main aims of this study were to evaluate the feasibility of substituting the radioisotope Fluorine-18 ((18)F) with Technetium-99m ((99m)Tc) in this test, and to indicate it with the lowest operational cost. The test was applied with sources of (99m)Tc (62 GBq) and (18)F (12 GBq), the activities of which were measured at different times, with the equipment preadjusted to measuring sources of (99m)Tc, (18)F, Gallium-67 ((67)Ga), and Iodine-131 ((131)I). Over time, the average deviation between measured and expected activities from (99m)Tc and (18)F were, respectively, 0.56 (+/-1.79)% and 0.92 (+/-1.19)%. The average ratios for 99(m)Tc source experimental activity, when measured with the equipment adjusted for measuring (18)F, (67)Ga, and (131)I sources, in real values, were, respectively, 3.42 (+/ 0.06), 1.45 (+/-0.03), and 1.13 (+/-0.02), and those for the (18)F source experimental activity, measured through adjustments of (99m)Tc, (67)Ga, and (131)I, were, respectively, 0.295 (+/-0.004), 0.335 (+/-0.007), and 0.426 (+/ 0.006). The adjustment of a simple exponential function for describing (99m)Tc and (18)F experimental activities facilitated the calculation of the physical half-lives of the radioisotopes, with a difference of about 1% in relation to the values described in the literature. Linearity test results, when using (99m)Tc, through being compatible with those acquired with (18)F, imply the possibility of using both radioisotopes during linearity testing. Nevertheless, this information, along with the high potential of exposure and the high cost of (18)F, implies that (99m)Tc should preferably be employed for linearity testing in clinics that normally use (18)F, without the risk of prejudicing either the procedure itself or the guarantee of a high-quality nuclear medicine service. PMID- 26420987 TI - Improving (18)F-Fluoro-D-Glucose-Positron Emission Tomography/Computed Tomography Imaging in Alzheimer's Disease Studies. AB - The goal was to improve Alzheimer's 2-deoxy-2-(18)F-fluoro-D-glucose ((18)F FDG) positron emission tomography (PET)/computed tomography (CT) imaging through application of a novel, hybrid Fourier-wavelet windowed Fourier transform (WFT) restoration technique, in order to provide earlier and more accurate clinical results. General Electric Medical Systems downward-looking sonar PET/CT 16 slice system was used to acquire studies. Patient data were acquired according the Alzheimer's disease Neuroimaging Initiative (ADNI) protocol. Here, we implemented Fourier-wavelet regularized restoration, with a Butterworth low-pass filter, order n = 6 and a cut-off frequency f = 0.35 cycles/pixel and wavelet (Daubechies, order 2) noise suppression. The original (PET-O) and restored (PET R) ADNI subject PET images were compared using the Alzheimer's discrimination analysis by dedicated software. Forty-two PET/CT scans were used in the study. They were performed on eleven ADNI subjects at intervals of approximately 6 months. The final clinical diagnosis was used as a gold standard. For three subjects, the final clinical diagnosis was mild cognitive impairment and those 13 PET/CT studies were not included in the final comparison, as the result was considered as inconclusive. Using the reminding 29 PET/CT studies (23 AD and 6 normal), the sensitivity and specificity of the PET-O and PET-R were calculated. The sensitivity was 0.65 and 0.96 for PET-O and PET-R, respectively, and the specificity was 0.67 and 0.50 for PET-O and PET-R. The accuracy was 0.66 and 0.86 for PET-O and PET-R, respectively. The results of the study demonstrated that the accuracy of three-dimensional brain F-18 FDG PET images was significantly improved by Fourier-wavelet restoration filtering. PMID- 26420988 TI - Modified PISAPED Criteria in Combination with Ventilation Scintigraphic Finding for Predicting Acute Pulmonary Embolism. AB - This prospective clinical study aimed at assessing three pulmonary scintigraphic algorithms to detect acute pulmonary embolism (PE): Lung ventilation/perfusion (V/Q) scintigraphy along with modified prospective investigation of pulmonary embolism diagnosis (PIOPED) criteria; lung perfusion scintigraphy along with prospective investigative study of acute pulmonary embolism diagnosis (PISAPED) criteria; and lung perfusion scan in combination with ventilation scan, along with modified PISAPED criteria, which were newly developed. Patients with suspicion of PE were eligible for this study if they had no abnormal chest x-ray. Their diagnostic workup included a clinical assessment, a pulmonary V/Q scintigraphy, and CT pulmonary angiography (CTPA), as well as a clinical outcome assessment over a period of 24 weeks. Referred to the final clinical diagnosis of patients, the sensitivity and specificity of each algorithm were evaluated. The diagnostic performance of each algorithm by the area under the maximum likelihood fitted receiver operating characteristic (ROC) curve was determined. With respect to the PISAPED criteria, the sensitivity was 60.8% and specificity was 87.3%. No patient was classified into nondiagnostic category. The PIOPED criteria showed that the sensitivity was 95.0% and specificity was 88.2%, while 57.4% of the patients were in nondiagnostic category. The areas under the ROC curve constructed from the PISAPED criteria results and the modified PIOPED criteria results were 0.734 and 0.859 (P < 0.01), respectively. The modified PISAPED criteria demonstrated that the sensitivity was 83.8% and specificity was 89.1%. No patient was classified into nondiagnostic category. The area under the ROC curve constructed from modified PISAPED criteria was 0.864 (P < 0.01). Perfusion scans used with ventilation scans and modified PISAPED criteria may increase the diagnostic accuracy of pulmonary scintigraphy for acute PE, compared with the two major algorithms. PMID- 26420989 TI - Is there a Role for Gallium-67 Citrate SPECT/CT, in Patients with Renal Impairment or Who are Renal Transplant Recipients, in Identifying and Localizing Suspected Infection? AB - To assess the added value of single-photon emission computed tomography/computed tomography (SPECT/CT) in patients with end-stage renal failure (ESRF) or renal transplant recipients in whom focal infection was suspected. Gallium-67 (Ga-67) citrate scintigrams of 18 patients (10 in ESRF and eight with renal transplants) were reviewed. Sites of abnormal uptake seen on the whole body and SPECT were noted. A SPECT/CT was also reviewed to see if additional information could be obtained. Imaging results were compared with the final diagnosis. Overall, 14 out of 18 (78%) patients had a proven cause to explain symptoms while four patients did not have a final cause identified. Infection was proven in the final diagnosis in 12 out of 14 (86%) patients. Of the 10 patients with ESRF, six had confirmed infection with the Ga-67 citrate study correctly identifying five out of six (83%) patients, and SPECT/CT providing additional information in four out of five (80%) patients. In the eight renal transplant recipients, six had a confirmed source of infection (all identified by the Ga-67 citrate study). SPECT/CT provided additional information in two out of six (33%) patients. Ga-67 citrate imaging had an overall sensitivity of 13/14 (93%), with one false negative. SPECT/CT provided an additional contribution in eight out of 18 (44%) patients by better defining the location/extent of infection and differentiating the physiological from the pathological uptake. PMID- 26420990 TI - Designing of High-Volume PET/CT Facility with Optimal Reduction of Radiation Exposure to the Staff: Implementation and Optimization in a Tertiary Health Care Facility in India. AB - Positron emission tomography (PET) has been in use for a few decades but with its fusion with computed tomography (CT) in 2001, the new PET/CT integrated system has become very popular and is now a key influential modality for patient management in oncology. However, along with its growing popularity, a growing concern of radiation safety among the radiation professionals has become evident. We have judiciously developed a PET/CT facility with optimal shielding, along with an efficient workflow to perform high volume procedures and minimize the radiation exposure to the staff and the general public by reducing unnecessary patient proximity to the staff and general public. PMID- 26420991 TI - The Relationship Between Some Complete Blood Count Parameters and Myocardial Perfusion: A Scintigraphic Approach. AB - Recent studies have shown that there is a relationship between some inflammatory and biochemical markers derived from complete blood count (CBC) such as neutrophil/lymphocyte (N/L) ratio, platelet/lymphocyte (P/L) ratio, platelet distribution width (PDW), red blood cell distribution width (RDW), and coronary artery disease (CAD). The aim of this study was to determine N/L ratio, P/L ratio, PDW values, and RDW values, which are associated with myocardial perfusion in patients diagnosed with CAD. This study included 262 patients (149 with myocardial ischemia/infarction and 113 with normal myocardial perfusion) undergoing myocardial perfusion scintigraphy (MPS) with CBC within 90 days of MPS. Myocardial perfusion parameters such as summed stress score and summed difference score (SDS) were compared with N/L ratio, P/L ratio, PDW values, and RDW values. Neutrophil counts and N/L ratios were significantly higher in patients diagnosed with myocardial ischemia and/or infarct. However, there was no statistically significant relationship between myocardial perfusion abnormalities and P/L ratio, PDW values, and RDW values. This study showed that N/L ratio is related to myocardial ischemia/infarction and correlated to left ventricular ejection fraction (LVEF). PMID- 26420992 TI - V/Q Matched Defect Larger than Hiatal Hernia Itself. AB - We present the case report of a patient 83 year old female who developed progressive shortness of breath and subsequently underwent scintigraphic evaluation of her symptoms with a ventilation/perfusion scintigraphic exam. A matched perfusion defect was seen involving the basal segments of the left lower lobe. Following this, the patient was examined with a contrast enhanced CT of the chest to further investigate the defect, which revealed compression of the bronchi and vasculature of the left lower lobe basal segments by the hernia larger than the actual hernia. To our knowledge there has not been a case report of a large hiatal hernia as a cause of matched lower lobe defect. PMID- 26420993 TI - Os Trigonum - Sheer Incidental or Quite Significant? Single Photon Emission Computed Tomography/Computed Tomography's Role in a Case of Ankle Impingement. AB - Accessory ossicles are widely prevalent in the ankle and foot. Although they are often asymptomatic, they can present clinically with symptoms at times. When they occur bilaterally in a patient who presents with unilateral complaints, it is clinically difficult to attribute the symptoms to the presence of these common anatomic variants. One needs specific imaging to assess the clinical relevance of the accessory ossicles, in order to tailor the treatment plan. The case presented in this article is one such example, where the patient presented with chronic unilateral ankle pain and initial radiographs revealed bilateral os trigonum and os subtibiale. He underwent a technetium-99m methyl diphosphonate (Tc-99m MDP) bone scan and single photon emission computed tomography/computed tomography (SPECT/CT). The Tc-99m MDP scan showed a focal uptake in the ankle of concern. SPECT/CT complemented the finding by exactly localizing the uptake to the posterior subtalar joint and around the os trigonum, thereby pointing to the diagnosis of os trigonum syndrome. PMID- 26420994 TI - Indium-111 Capromab Pendetide (ProstaScint((r))) Demonstrates Renal Cell Carcinoma and Aortocaval Nodal Metastases from Prostate Adenocarcinoma. AB - A 62-year-old male with a history of radical prostatectomy for a Gleason 9 (4 + 5) pT3N0Mx prostate cancer presented with rising prostate-specific antigen of 9.0 ng/dl. A contrast-enhanced computerized tomography (CT) revealed an enhancing left upper pole renal mass and aortocaval lymph nodes. Indium (In)-111 Capromab Pendetide (ProstaScint((r))) single-photon emission computerized tomography-CT showed abnormal increased uptake in left renal mass and aortocaval lymph nodes with no uptake in the prostate bed or pelvic lymph nodes. He underwent left radical nephrectomy and dissection of aortocaval lymph nodes. Pathology showed renal clear cell carcinoma and metastatic prostate adenocarcinoma involving aortocaval lymph nodes. Our case demonstrates a rare combination of two different malignancies, prostate cancer and clear cell renal cell cancer, showing In-111 ProstaScint((r)) uptake. Though ProstaScint((r)) uptake in renal cell carcinoma and in metastatic aortocaval lymph nodes from prostate cancer may be seen in clinical practice, this combination has not been reported previously. PMID- 26420995 TI - Nuclear Medicine to Evaluate Complications of Cerebral Shunts: Two Cases and Review of Literature. AB - We present two cases of cerebral shunts - a ventriculopleural shunt and a ventriculoperitoneal shunt, with their associated complications. We also hope to provide a comprehensive literature review on various imaging modalities, including nuclear medicine studies in evaluating cerebral shunt complications. PMID- 26420996 TI - Radiosynovectomy of Proximal Interphalangeal Joint Synovitis in Rheumatoid Arthritis Treated with Rhenium-188 Labeled Tin-colloid and Imaging with Single photon Emission Computerized Tomography/Computed Tomography: A First Case Report. AB - Rheumatoid arthritis (RA) is a chronic disease that is mainly characterized by the asymmetric erosive synovitis, particularly affecting peripheral joints. Radiation synovectomy or radiosynovectomy (RSV), also known as radiosynoviorthesis was first described in 1950's as an adjuvant treatment for RA. RSV is based on the irradiation of the joint synovium by the intra-articular administration of various beta-emitting radiopharmaceuticals. As a generator produced beta-emitting radionuclide, the importance of rhenium-188 (Re-188) for radionuclide therapy is increasing rapidly. There are previous reports which used Re-188 tin colloid in knee joint synovitis, but use of Re-188 tin colloid in small joint is not yet reported. We describe the use of Re-188 tin colloid in a 45-year-old female who presented with right 4(th) proximal interphalangeal joint synovitis due to rheumatoid arthritis. PMID- 26420997 TI - Colorectal Cancer with Uncommon Metastatic Spread. AB - The prevalence of bone metastases from colorectal cancer (CRC) is quite low and the presence of isolated osseous metastases at the time of diagnosis or the onset of bone metastases without other organ involvement during follow-up is even lower. Here, we present an interesting case of diffuse skeletal metastases from CRC in which both the atypical presentation of the metastatic spread and the presence of infective comorbidities created some troubles in getting the final diagnosis. PMID- 26420998 TI - Lynch Syndrome Associated Colon Adenocarcinoma Resembling Lymphoma on Fluoro Deoxyglucose-Positron Emission Tomography/Computed Tomography. AB - The patient was a 46-year-old Asian male diagnosed with lynch syndrome associated colon adenocarcinoma in the right ascending colon. A presurgical staging 18 fluoro-deoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) found increased metabolic activity in the cervical, axillary, mediastinal, supraclavicular, para-aortic and mesenteric lymph nodes. This pattern of metastasis was very unusual for lynch syndrome associated colon adenocarcinoma and the involvement of those lymph nodes resembles the pattern of spread of lymphoma. He underwent right hemicolectomy and he was subsequently treated with 12 cycles of folinic acid (leucovorin), fluorouracil (5-FU), irinotecan. A restaging FDG-PET/CT at the end of the chemotherapy showed interval decrease in size and metabolic activity in the affected lymph nodes. FDG-PET/CT is a useful imaging modality in following-up the treatment response in colon adenocarcinoma. PMID- 26420999 TI - Segmental Considerations in Colonoscopy Recommendations for Investigating Focal Colonic FDG Activity on PET/CT. PMID- 26421000 TI - Conversion of Saccharides into Formic Acid using Hydrogen Peroxide and a Recyclable Palladium(II) Catalyst in Aqueous Alkaline Media at Ambient Temperatures. AB - We have developed an effective method that converts a variety of mono- and disaccharides into formic acid predominantly. Our recyclable NHC-amidate palladium(II) catalyst facilitated oxidative degradation of carbohydrates without using excess oxidant. Stoichiometric amounts of hydrogen peroxide and sodium hydroxide were employed at ambient temperatures. PMID- 26421001 TI - Jacaric acid inhibits the growth of murine macrophage-like leukemia PU5-1.8 cells by inducing cell cycle arrest and apoptosis. AB - BACKGROUND: Conjugated linolenic acids (CLN) refer to the positional and geometric isomers of octadecatrienoic acids with three conjugated double bonds (C18:3). Previous researches have demonstrated that CLN can inhibit the growth of a wide variety of cancer cells, whereas the modulatory effect of CLN on various myeloid leukemia cells remains unclear. This study aims at demonstrating the in vitro anti-tumor effect and action mechanisms of jacaric acid, a CLN isomer which is present in jacaranda seed oil, on the murine macrophage-like leukemia PU5-1.8 cells. METHODS AND RESULTS: It was found that jacaric acid inhibited the proliferation of PU5-1.8 cells in a time- and concentration-dependent manner, as determined by the MTT reduction assay and by using CyQUANT((r)) NF Cell Proliferation Assay Kit, while it exerted minimal cytotoxicity on normal murine cells. Besides, the reactive oxygen species production in jacaric acid-treated PU5-1.8 cells was elevated in a concentration-dependent mannar. Flow cytometric analysis revealed the induction of G0/G1 cell cycle arrest, accompanied by a decrease in CDK2 and cyclin E proteins. Jacaric acid also triggered apoptosis as reflected by induction of DNA fragmentation, phosphatidylserine externalization, mitochondrial membrane depolarization, up-regulation of pro-apoptotic Bax protein and down-regulation of anti-apoptotic Bcl-2 and Bcl-xL proteins. CONCLUSIONS: Our results demonstrated the growth-inhibitory effect of jacaric acid on PU5-1.8 cells through inducing cell cycle arrest and apoptosis, while exhibiting minimal cytotoxicity to normal murine cells. Therefore, jacaric acid is a potential candidate for the treatment of some forms of myeloid leukemia with minimal toxicity and fewer side effects. PMID- 26421002 TI - PDK1-mTOR signaling pathway inhibitors reduce cell proliferation in MK2206 resistant neuroblastoma cells. AB - PURPOSE: AKT plays a pivotal role in the signal transduction of cancer cells. MK2206, an AKT inhibitor, has been shown to be an effective anti-cancer drug to a variety of cancer cell lines. However, some cancer cells acquire resistance to MK2206 and new strategies to suppress these cell lines remain to be developed. EXPERIMENTAL DESIGN: Acquired MK-2206-resistant neuroblastoma (NB) cell sublines were induced by stepwise escalation of MK-2206 exposure (4-12 weeks). MTT assay was used to validate cell proliferation. Flow cytometry was performed for cell cycle analysis. Western blot assay was used for cell signaling study. RESULTS: MK2206 (5-10 umol) significantly suppressed cell growth of MK2206 non-resistant NB cells (LAN-1, KP-N-SIFA, NB-19 and SK-N-DZ), but is less efficient in inhibiting that of resistant sublines, even after 2-week MK2206-free incubation. MK2206 acted in mTOR-S6K dependent and independent methods. MK-2206 resistant sublines (LAN-1-MK, KP-N-SIFA-MK, and SK-N-DZ-MK) showed lower IC50 of GSK2334470 (PDK1 inhibitor). The cell growth of all sublines was prohibited by AZD8805 (mTOR inhibitor), with IC50 of AZD8805 3-10 times lower than MK2206 non-resistant cells. The signaling profiles of these resistant sublines were characterized by elevated PDK1-mTOR-S6K activity, accompanying by low phosphorylation of AKT compared with non-resistant counterparts. GSK2334470 and AZD8055 effectively inhibited phosphorylation of PDK1 and mTOR, respectively, and induced higher G0 G1 ratio in LAN-1-MK than that in LAN-1 as well. PDK1 and mTOR inhibitors effected on phosphorylation of GSK3beta in some of resistant sublines. CONCLUSION: NB cells can acquire MK2206 resistance after exposure for 4-12 weeks. Resistant cells feature reliance on PDK1-mTOR-S6K pathway and are more sensitive to PDK1 and mTOR inhibitors than the non-resistant counterparts. Thus, suppression of PDK1-mTOR-S6K signaling pathway is an effective way to overcome the MK2206 resistance, and this may be a promising strategy for targeted therapy. PMID- 26421003 TI - Evaluation in medical education: A topical review of target parameters, data collection tools and confounding factors. AB - BACKGROUND AND OBJECTIVE: Evaluation is an integral part of education in German medical schools. According to the quality standards set by the German Society for Evaluation, evaluation tools must provide an accurate and fair appraisal of teaching quality. Thus, data collection tools must be highly reliable and valid. This review summarises the current literature on evaluation of medical education with regard to the possible dimensions of teaching quality, the psychometric properties of survey instruments and potential confounding factors. METHODS: We searched Pubmed, PsycINFO and PSYNDEX for literature on evaluation in medical education and included studies published up until June 30, 2011 as well as articles identified in the "grey literature". RESULTS are presented as a narrative review. RESULTS: We identified four dimensions of teaching quality: structure, process, teacher characteristics, and outcome. Student ratings are predominantly used to address the first three dimensions, and a number of reliable tools are available for this purpose. However, potential confounders of student ratings pose a threat to the validity of these instruments. Outcome is usually operationalised in terms of student performance on examinations, but methodological problems may limit the usability of these data for evaluation purposes. In addition, not all examinations at German medical schools meet current quality standards. CONCLUSION: The choice of tools for evaluating medical education should be guided by the dimension that is targeted by the evaluation. Likewise, evaluation results can only be interpreted within the context of the construct addressed by the data collection tool that was used as well as its specific confounding factors. PMID- 26421005 TI - Nonlinear Inertia Weighted Teaching-Learning-Based Optimization for Solving Global Optimization Problem. AB - Teaching-learning-based optimization (TLBO) algorithm is proposed in recent years that simulates the teaching-learning phenomenon of a classroom to effectively solve global optimization of multidimensional, linear, and nonlinear problems over continuous spaces. In this paper, an improved teaching-learning-based optimization algorithm is presented, which is called nonlinear inertia weighted teaching-learning-based optimization (NIWTLBO) algorithm. This algorithm introduces a nonlinear inertia weighted factor into the basic TLBO to control the memory rate of learners and uses a dynamic inertia weighted factor to replace the original random number in teacher phase and learner phase. The proposed algorithm is tested on a number of benchmark functions, and its performance comparisons are provided against the basic TLBO and some other well-known optimization algorithms. The experiment results show that the proposed algorithm has a faster convergence rate and better performance than the basic TLBO and some other algorithms as well. PMID- 26421006 TI - CDMBE: A Case Description Model Based on Evidence. AB - By combining the advantages of argument map and Bayesian network, a case description model based on evidence (CDMBE), which is suitable to continental law system, is proposed to describe the criminal cases. The logic of the model adopts the credibility logical reason and gets evidence-based reasoning quantitatively based on evidences. In order to consist with practical inference rules, five types of relationship and a set of rules are defined to calculate the credibility of assumptions based on the credibility and supportability of the related evidences. Experiments show that the model can get users' ideas into a figure and the results calculated from CDMBE are in line with those from Bayesian model. PMID- 26421004 TI - Guillain-Barre syndrome: clinical profile and management. AB - INTRODUCTION: Guillain-Barre syndrome (GBS) is a fulminant polyradiculoneuropathy that is acute, frequently severe and autoimmune in nature. Etiology of GBS is incompletely understood, prognosis is usually good with early detection and prompt treatment. This retrospective study was done to evaluate clinical profile, epidemiological, laboratory, and electrodiagnostic features of patients with GBS and mode of management, complications and prognostic factors. METHODS: Data of 1,166 patients admitted with GBS or presented to outpatient department (previous medical records) with GBS between January 2003 and January 2014 were analyzed. RESULTS: No difference in genders noted. Around 35% of patients are above 50 years of age. Poor control of diabetes with mean HbA1c of 8.1 +/- 2.11 is found on analysis. Seasonal occurrence in GBS is prominent in winter 484 (41.50%) and mechanically ventilated were 449 (38.50%) patients. 48 (4.11%) deaths were attributed to GBS. Neurological analysis revealed cranial nerve involvement in 407 (34.90%) patients, facial palsy in 401 (34.39%) and ataxia in 88 (7.54%) patients. Most patients in plasma exchange group belonged to the lower socio economic status. Mean cerebrospinal fluid (CSF) protein levels was (n=962) 113.8 +/- 11.8 mg/dl. Conduction block determined indirectly by absent H-reflex was noted in 891 (90.64%) patients. No difference in complications and outcome is found in treatment regimens of intravenous immunoglobulin (IVIG) and plasma exchange. CONCLUSION: Seasonal occurrence predominantly in winter is noted. Peak flow test may be a predictor of assessing requirement of mechanical ventilation and prognosis. Conduction block is the major abnormality noted in electrophysiological studies and proximal nerve segment assessing with Erb's point stimulation has high predictive value. IVIG treatment is more expensive but is associated with less duration of hospital stay. PMID- 26421007 TI - BF3.Et2O Catalysed 4-Aryl-3-phenyl-benzopyrones, Pro-SERMs, and Their Characterization. AB - We have synthesized the novel 4-(4-hydroxy-benzyl)-3-phenyl-chromen-2-one which is a precursor of SERMs with a smaller number of steps and good yield. Two methodologies for the synthesis have been worked out. Anhydrous BF3.Et2O catalyzed reaction was found to be selective for product formation while anhydrous AlCl3, FeCl3, and SnCl4 catalyzed ones were nonselective. PMID- 26421008 TI - Validated HPTLC Method for Quantification of Luteolin and Apigenin in Premna mucronata Roxb., Verbenaceae. AB - A simple, rapid, and precise high-performance thin-layer chromatographic method was developed for quantitative estimation of luteolin and apigenin in Premna mucronata Roxb., family Verbenaceae. Separation was performed on silica gel 60 F254 HPTLC plates using toluene : ethyl acetate : formic acid (6 : 4 : 0.3) as mobile phase for elution of markers from extract. The determination was carried out in fluorescence mode using densitometric absorbance-reflection mode at 366 nm for both luteolin and apigenin. The methanolic extract of Premna mucronata was found to contain 10.2 mg/g % luteolin and 0.165 mg/g % of apigenin. The method was validated in terms of linearity, LOD and LOQ, accuracy, precision, and specificity. The calibration curve was found to be linear between 200 and 1000 ng/band for luteolin and 50 and 250 ng/band for apigenin. For luteolin and apigenin, the limit of detection was found to be 42.6 ng/band and 7.97 ng/band while the limit of quantitation was found to be 129.08 ng/band and 24.155 ng/band, respectively. This developed validated method is capable of quantifying and resolving luteolin and apigenin and can be applicable for routine analysis of extract and plant as a whole. PMID- 26421009 TI - Role of Mas Receptor Antagonist A799 in Renal Blood Flow Response to Ang 1-7 after Bradykinin Administration in Ovariectomized Estradiol-Treated Rats. AB - Background. The accompanied role of Mas receptor (MasR), bradykinin (BK), and female sex hormone on renal blood flow (RBF) response to angiotensin 1-7 is not well defined. We investigated the role of MasR antagonist (A779) and BK on RBF response to Ang 1-7 infusion in ovariectomized estradiol-treated rats. Methods. Ovariectomized Wistar rats received estradiol (OVE) or vehicle (OV) for two weeks. Catheterized animals were subjected to BK and A799 infusion and mean arterial pressure (MAP), RBF, and renal vascular resistance (RVR) responses to Ang 1-7 (0, 100, and 300 ng kg(-1) min(-1)) were determined. Results. Percentage change of RBF (%RBF) in response to Ang1-7 infusion increased in a dose-dependent manner. In the presence of BK, when MasR was not blocked, %RBF response to Ang 1 7 in OVE group was greater than OV group significantly (P < 0.05). Infusion of 300 ng kg(-1) min(-1) Ang 1-7 increased RBF by 6.9 +/- 1.9% in OVE group versus 0.9 +/- 1.8% in OV group. However when MasR was blocked, %RBF response to Ang 1-7 in OV group was greater than OVE group insignificantly. Conclusion. Coadministration of BK and A779 compared to BK alone increased RBF response to Ang 1-7 in vehicle treated rats. Such observation was not seen in estradiol treated rats. PMID- 26421010 TI - Low Growth Hormone Levels in Short-Stature Children with Pituitary Hyperplasia Secondary to Primary Hypothyroidism. AB - Objective. The follow-up of GH levels in short-stature children with pituitary hyperplasia secondary to primary hypothyroidism (PPH) is reported in a few cases. We aimed to observe changes in GH secretion in short-stature children with PPH. Methods. A total of 11 short-stature children with PPH accompanied by low GH levels were included. They received levothyroxine therapy after diagnosis. Their thyroid hormones, IGF-1, PRL, and pituitary height were measured at baseline and 3 months after therapy. GH stimulation tests were performed at baseline and after regression of thyroid hormones and pituitary. Results. At baseline, they had decreased GH peak and FT3 and FT4 levels and elevated TSH levels. Decreased IGF-1 levels were found in seven children. Elevated PRL levels and positive thyroid antibodies were found in 10 children. The mean pituitary height was 14.3 +/- 3.8 mm. After 3 months, FT3, FT4, and IGF-1 levels were significantly increased (all p < 0.01), and values of TSH, PRL, and pituitary height were significantly decreased (all p < 0.001). After 6 months, pituitary hyperplasia completely regressed. GH levels returned to normal in nine children and were still low in two children. Conclusion. GH secretion can be resolved in most short-stature children with PPH. PMID- 26421011 TI - Influence of CAG Repeat Polymorphism on the Targets of Testosterone Action. AB - In the last decade, ample evidence has demonstrated the growing importance of androgen receptor (AR) CAG repeat polymorphism in andrology. This genetic parameter is able to condition the peripheral effects of testosterone and therefore to influence male sexual function and fertility, cardiovascular risk, body composition, bone metabolism, the risk of prostate and testicular cancer, the psychiatric status, and the onset of neurodegenerative disorders. In this review, we extensively discuss the literature data and identify a role for AR CAG repeat polymorphism in conditioning the systemic testosterone effects. In particular, our main purpose was to provide an updated text able to shed light on the many and often contradictory findings reporting an influence of CAG repeat polymorphism on the targets of testosterone action. PMID- 26421013 TI - Some Rare Earth Elements Analysis by Microwave Plasma Torch Coupled with the Linear Ion Trap Mass Spectrometry. AB - A sensitive mass spectrometric analysis method based on the microwave plasma technique is developed for the fast detection of trace rare earth elements (REEs) in aqueous solution. The plasma was produced from a microwave plasma torch (MPT) under atmospheric pressure and was used as ambient ion source of a linear ion trap mass spectrometer (LTQ). Water samples were directly pneumatically nebulized to flow into the plasma through the central tube of MPT. For some REEs, the generated composite ions were detected in both positive and negative ion modes and further characterized in tandem mass spectrometry. Under the optimized conditions, the limit of detection (LOD) was at the level 0.1 ng/mL using MS(2) procedure in negative mode. A single REE analysis can be completed within 2~3 minutes with the relative standard deviation ranging between 2.4% and 21.2% (six repeated measurements) for the 5 experimental runs. Moreover, the recovery rates of these REEs are between the range of 97.6%-122.1%. Two real samples have also been analyzed, including well and orange juice. These experimental data demonstrated that this method is a useful tool for the field analysis of REEs in water and can be used as an alternative supplement of ICP-MS. PMID- 26421014 TI - Modulation Effects of Curcumin on Erythrocyte Ion-Transporter Activity. AB - Curcumin ((1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), the yellow biphenolic pigment isolated from turmeric (Curcuma longa), has various medicinal benefits through antioxidation, anti-inflammation, cardiovascular protection, immunomodulation, enhancing of the apoptotic process, and antiangiogenic property. We explored the effects of curcumin in vitro (10(-5) M to 10(-8) M) and in vivo (340 and 170 mg/kg b.w., oral) on Na(+)/K(+) ATPase (NKA), Na(+)/H(+) exchanger (NHE) activity, and membrane lipid hydroperoxides (ROOH) in control and experimental oxidative stress erythrocytes of Wistar rats. As a result, we found that curcumin potently modulated the membrane transporters activity with protecting membrane lipids against hydro-peroxidation in control as well as oxidatively challenged erythrocytes evidenced by stimulation of NKA, downregulation of NHE, and reduction of ROOH in the membrane. The observed results corroborate membrane transporters activity with susceptibility of erythrocyte membrane towards oxidative damage. Results explain the protective mechanism of curcumin against oxidative stress mediated impairment in ions transporters activity and health beneficial effects. PMID- 26421015 TI - Predictors of Outcome and Severity in Adult Filipino Patients with Febrile Neutropenia. AB - Aim. The study aimed to describe the profile of Filipino febrile neutropenia patients and to determine parameters associated with severe outcomes. Methods. This is a retrospective study of Filipino febrile neutropenia patients admitted to the Philippine General Hospital. Patients were described in terms of clinical presentation and stratified according to the presence or absence of severe outcomes. Prognostic factors were then identified using regression analysis. Results. 115 febrile episodes in 102 patients were identified. Regression analysis yielded prolonged fever >7 days prior to admission (OR 2.43; 95% CI, 0.77-7.74), isolation of a pathogen on cultures (OR 2.69; 95% CI, 1.04-6.98), and nadir absolute neutrophil count (ANC) < 100 during admission (OR 1.96; 95% CI, 0.75-5.12) as significant predictors of poor outcome. Factors that significantly correlated with better outcome were granulocyte colony-stimulating factor (G-CSF) use (OR 0.31; 95% CI, 0.11-0.85) and completeness of antibiotic therapy (OR 0.26; 95% CI, 0.10-0.67). Conclusion. Prolonged fever >7 days prior to admission, positive pathogen on cultures, and nadir ANC < 100 during admission predicted severe outcomes, whereas G-CSF use and complete antibiotic therapy were associated with better outcomes. These prognostic variables might be useful in identifying patients that need more intensive treatment and monitoring. PMID- 26421012 TI - Gallbladder Cancer in the 21st Century. AB - Gallbladder cancer (GBC) is an uncommon disease in the majority of the world despite being the most common and aggressive malignancy of the biliary tree. Early diagnosis is essential for improved prognosis; however, indolent and nonspecific clinical presentations with a paucity of pathognomonic/predictive radiological features often preclude accurate identification of GBC at an early stage. As such, GBC remains a highly lethal disease, with only 10% of all patients presenting at a stage amenable to surgical resection. Among this select population, continued improvements in survival during the 21st century are attributable to aggressive radical surgery with improved surgical techniques. This paper reviews the current available literature of the 21st century on PubMed and Medline to provide a detailed summary of the epidemiology and risk factors, pathogenesis, clinical presentation, radiology, pathology, management, and prognosis of GBC. PMID- 26421016 TI - The Relationship of the Facial Nerve to the Condylar Process: A Cadaveric Study with Implications for Open Reduction Internal Fixation. AB - Introduction. The mandibular condyle is the most common site of mandibular fracture. Surgical treatment of condylar fractures by open reduction and internal fixation (ORIF) demands direct visualization of the fracture. This project aimed to investigate the anatomic relationship of the tragus to the facial nerve and condylar process. Materials and Methods. Twelve fresh hemicadavers heads were used. An extended retromandibular/preauricular approach was utilized, with the incision being based parallel to the posterior edge of the ramus. Measurements were obtained from the tragus to the facial nerve and condylar process. Results. The temporozygomatic division of the facial nerve was encountered during each approach, crossing the mandible at the condylar neck. The mean tissue depth separating the facial nerve from the condylar neck was 5.5 mm (range: 3.5 mm-7 mm, SD 1.2 mm). The upper division of the facial nerve crossed the posterior border of the condylar process on average 2.31 cm (SD 0.10 cm) anterior to the tragus. Conclusions. This study suggests that the temporozygomatic division of the facial nerve will be encountered in most approaches to the condylar process. As visualization of the relationship of the facial nerve to condyle is often limited, recognition that, on average, 5.5 mm of tissue separates condylar process from nerve should help reduce the incidence of facial nerve injury during this procedure. PMID- 26421017 TI - Bilateral Spontaneous Perirenal Hemorrhage due to Initial Presentation of Polyarteritis Nodosa. AB - Spontaneous perirenal hemorrhage (SPH) is uncommon but can be a life-threatening condition which is associated with flank or abdominal pain and hypovolemia. The etiologies of SPH include tumor, vascular disease, and infection. Among the vascular diseases, polyarteritis nodosa (PAN) is common cause of the SPH. However, patients with PAN usually complain of nonspecific symptoms and the incidence of PAN is relatively rare. So, diagnosis is difficult even though tissue biopsy and angiography help to confirm the PAN. Particularly bilateral perirenal hemorrhage is very rare complication in patients with PAN. We reported a case of bilateral perirenal hemorrhage in the patients with PAN who have continued to take exogenous sex hormone. PMID- 26421018 TI - New-Onset Myocarditis in an Immunocompetent Adult with Acute Metapneumovirus Infection. AB - Introduction. A number of viruses have been implicated in viral myocarditis; however, there has been no previous report of human metapneumovirus (hMPV) causing this condition. Discovered in 2001, hMPV is typically associated with upper respiratory illness, mainly affecting children. Case Presentation. We report the case of a 25-year-old man with acute systolic heart failure from viral myocarditis secondary to the hMPV. The patient was initially admitted to the general medical ward but developed increasing oxygen requirements resulting in transfer to the cardiac intensive care unit. Cardiac magnetic resonance imaging was used to help confirm the diagnosis. He was treated with intravenous diuretics, and afterload and preload agents, and he was subsequently discharged home after seven days of hospitalization. Discussion. hMPV is typically a respiratory pathogen; however, it was associated with in myocarditis in our patient. Due to the recent ability to detect this virus, we may see more cases of this, particularly during peak months of infection. Conclusion. This is the first case description of myocarditis associated with hMPV infection. PMID- 26421019 TI - Health-related quality of life in patients with primary immunodeficiency disease. AB - Primary immunodeficiency disease (PIDD) with hypogammaglobulinemia is characterized by recurrent and severe bacterial infections and IgG replacement is the standard of care in many of these patients. Health-related quality of life (HRQOL) is becoming increasingly recognized as a factor that affects patient well being and treatment preferences. In an effort to better understand what factors affect HRQOL in patients with PIDD, we reviewed the published literature that used standardized instruments for the measurement of HRQOL. We investigated HRQOL in PIDD patients compared with normal controls and patients with other chronic diseases; we also investigated the impact of treatment administration on patient satisfaction. The most commonly encountered health-related quality of life instruments were the child heath questionnaire parental form 50, short form 36, PedsQL 4.0, Lansky's play performance scale, and Life Quality Index. Patients with PIDD scored significantly lower on many of the instruments compared with normal controls. Also, while it appears that many patients appreciate home-based and subcutaneous IgG replacement therapy, patient satisfaction ultimately involves various clinical factors and individual patient preferences. By further analyzing what factors impact HRQOL, therapy adjustments can be made to maximize patient well-being and minimize disease impact on daily functioning. PMID- 26421021 TI - Liver Transplantation in Liver Cirrhosis Patients Accompanied by Portal Vein Thrombosis. AB - Benign portal vein thrombosis (PVT) is a challenging complication of an otherwise successful liver transplantation. PVT is caused by various conditions and results in pathologic hemodynamics of hepatofugal diversion of porto-mesenteric blood flow. Thus, adequate restoration of portal blood flow to the liver graft is a major concern when trying to achieve successful liver transplantation in patients with PVT. This letter describes the surgical view point of PVT in liver transplantation. PMID- 26421020 TI - Ideal Experimental Rat Models for Liver Diseases. AB - There are many limitations for conducting liver disease research in human beings due to the high cost and potential ethical issues. For this reason, conducting a study that is difficult to perform in humans using appropriate animal models, can be beneficial in ascertaining the pathological physiology, and in developing new treatment modalities. However, it is difficult to determine the appropriate animal model which is suitable for research purposes, since every patient has different and diverse clinical symptoms, adverse reactions, and complications due to the pathological physiology. Also, it is not easy to reproduce identically various clinical situations in animal models. Recently, the Guide for the Care and Use of Laboratory Animals has tightened up the regulations, and therefore it is advisable to select the appropriate animals and decide upon the appropriate quantities through scientific and systemic considerations before conducting animal testing. Therefore, in this review article the authors examined various white rat animal testing models and determined the appropriate usable rat model, and the pros and cons of its application in liver disease research. The authors believe that this review will be beneficial in selecting proper laboratory animals for research purposes. PMID- 26421022 TI - Risk Factors for Intrahepatic Recurrence after Resection of Hepatocellular Carcinomas in Patients with Hepatitis B Virus Infection. AB - PURPOSE: Although surgical resection offers patients with HCC the chance of a cure, the post-resection tumor recurrence rate is high, with reported cumulative 5-year tumor recurrence rates ranging from 40 to 70%. The objective of this study was to investigate risk factors for intrahepatic recurrence after resection of hepatocellular carcinoma, especially in patients with hepatitis B virus infection. METHODS: Between January 1999 and December 2003, 59 patients in our Hospital with hepatitis B virus infection underwent liver resection for hepatocellular carcinoma. Clinical, biological, and histopathological characteristics of these patients were collected and tested for their prognostic significance using a Chi-square test and a Student's t-test. Time to recurrence and survival rate were analyzed by the Kaplan-Meier method. RESULTS: Of the 59 patients who underwent liver resection, 24 (41%) experienced intrahepatic recurrence. The 1-, 3-, and 5-year overall survival rates of total enrolled patients were 83%, 63%, and 42%, respectively. The 1-, 3-, and 5-year overall survival rates after recurrence were 87%, 52%, and 20%, respectively. The risk factors for early recurrence were elevated serum aspartate aminotransferase (AST) level (p=0.044) and larger tumor size (p=0.049). For late recurrence, greater tumor size (p=0.039) was the only risk factor. CONCLUSION: Tumor size and serum aspartate aminotransferase are risk factors of intrahepatic recurrence after resection of HCC in patients with chronic hepatitis B virus infection. This finding indicates that patients who have these risk factors should be under more careful supervision and have more aggressive follow-up. PMID- 26421023 TI - Outcome of Hepatectomy for Huge Hepatocellular Carcinoma. AB - PURPOSE: In spite of the recent improved results of hepatectomy for huge hepatocellular carcinomas (HCC), the prognosis of patients with huge HCCs is still poor compared to that of patients with small HCCs. This study was performed to compare the results of hepatectomy between patients with huge HCCs and those with small HCCs, to identify the prognostic factors in patients with huge HCCs, and to determine the preoperative selection criteria. METHODS: We retrospectively analyzed 51 patients who underwent hepatectomy, between July 1994 and February 2009 at Dankook University Hospital. Patients with HCC>=10 cm were classified in large (L) group and others were classified in small (S) group. The clinicopathological features, operative procedures, and postoperative outcome were compared between both groups and various prognostic factors were investigated in group L. RESULTS: Eleven patients were classified in group L. Tumor size, vascular invasion, and tumor stage were higher in group L. Postoperative morbidity was higher in group L, but mortality was not different between the groups. Disease-free survivals were significantly lower in group L than in group S (36.4%, and 24.2% vs. 72.0%, and 44.0% for 1- and 3-year), but overall survival rates were similar in both groups (45.5%, and 15.2% in group L vs. 60.3%, and 41.3% in group S for 3- and 5-year). Presence of satellite nodules was the only prognostic factor in multivariate analysis after surgery for huge HCC. CONCLUSION: Regardless of tumor size, huge HCCs deserve consideration for surgery in patients with preserved liver function. Furthermore, the effect of surgery could be maximized with appropriate selection criteria, such as huge HCC without satellite nodules. PMID- 26421024 TI - Anatomical Variation of the Glissonean Pedicle of the Right Liver. AB - PURPOSE: Many studies have been conducted to date regarding whether the right hepatic vein is the accurate border that divides the anterior and posterior section of the right liver. It has been reported that the Glisson pedicle of the right liver may be an anatomical variation that does not have a consistent morphology. We analyzed the relationship between the true borders of the anterior and posterior sections, and the right hepatic vein, based on cadaver dissection and MD-CT image analysis of the anatomical variation of the Glisson pedicle of the right liver. METHODS: Sixteen cadaver livers were available for dissection from the Department of Anatomy, and pre-operative MD-CTs of 20 donor livers who underwent living donor liver transplantation prior to December 2009, were obtained. We analyzed the 3D-relationship between the branches of the Glisson pedicles and the right hepatic vein of the right liver. They were divided into 3 groups according to the sliding pattern of the branches of the Glisson pedicle origin. When all segmental branches of the anterior pedicle arise from the main trunk of the anterior pedicle and all branches of posterior pedicle arise from the main trunk of posterior pedicle, it was designated as Group A (Normal Group). When a portion of the segmental branches of the anterior pedicle arises from the main trunk of the posterior pedicle, it was designated as Group B (Posterior dominant group). When a portion of the branches of the posterior pedicle arises from the main trunk of the anterior pedicle, it was designated as Group C (Anterior dominant group). RESULTS: Among the 16 cadaver liver dissections, 6 cases were in Group A, 5 in Group B, and 3 in Group C. Two cases were excluded from the study because the inferior right hepatic vein was the main draining vein of the right liver. The analysis of preoperative MD-CT of the 20 donor livers showed that there were 13, 4, and 3 patients in Groups A, B, and C, respectively. CONCLUSION: According to Couinaud's theory of anatomy, the right hepatic vein serves as the border between the anterior and posterior sections of the right liver. But, due to the frequent anatomical variations, an adequate understanding of the anatomical variations of the right Glisson pedicle should be necessary for liver surgery. PMID- 26421025 TI - Effect of Liver Cell Transplantation on Acute Hepatic Failure Induced by Massive Liver Resection in the Rat. AB - PURPOSE: This study is designed to ascertain the most effective quantity and injection route of hepatocytes in an acute liver failure model induced by massive liver resection in rats. METHODS: Rats weighing 450 to 650 gm underwent partial hepatectomy that was 80% of their liver weight, resulting in acute liver failure. Hepatocytes were obtained by perfusing collagenase (Wako, Japan) solution through portal vein into liver of the allogenic rat. These hepatocytes were injected into different places with different dosage. The experimental groups were divided into the Control group, Splenic group I (2*10(6) cells into splenic capsule), Splenic group II (2*10(7) cells into splenic capsule), Portal vein group (2*10(7) cells into portal vein), Subperitoneal group (2*10(7) cells into subperitoneum). The experimental animals were observed carefully for 5 days for assessment of survival and regeneration of liver. Liver function tests including serum alanine aminotransferase (ALT), total bilirubin, gamma-glutamyl transferase (gamma-GTP) on postoperative 1, 2, 3, 5th days and histologic examinations of specimens obtained from each respective groups on postoperative 5th day were performed. RESULTS: Serum ALT level on postoperative day 1 peaked and then gradually normalized showing statistical significance (p=0.035). Study groups showing statistically significant difference under repeated anova analysis were between the Splenic group II and Control (p=0.035), and between the Splenic group II and Portal vein group (p=0.001) with respect to serum ALT levels. Also, progression of each study group showed statistical significance. (p=0.02). Serum total bilirubin and r-GTP did not show any significant difference. CONCLUSION: Hepatocyte transplantation of 2*10(7) cells into spleen showed the best results in the acute hepatic failure rat. PMID- 26421026 TI - Comparison of Bile Drainage Methods after Laparoscopic CBD Exploration. AB - PURPOSE: T-tube is a major procedure that prevents complication by biliary decompression, but which is accompanied by complications. Therefore, several procedures such as ENBD, PTBD, and antegrade biliary stent have been attempted, but with controversies as to which procedure is superior. Also, there are no standard procedures after laparoscopic CBD exploration. We performed this study to ascertain the most appropriate biliary drainage procedure after laparoscopic CBD exploration. METHODS: From March 2001 to December 2009, 121 patients who underwent Laparoscopic CBD exploration in Gunyang University were included for retrospective analysis. The patients were divided to 4 groups according to type of procedure, and we compared clinical parameters including age and gender, operation time, hospital stay, start of post-operative diet, and complications. RESULTS: There was no difference in age, gender, mean operation time, postoperative diet between the 4 groups. Hospital stay in the Stent group was shorter than T-tube group. There were 10 (7%) complications that occurred. Two 2 occurred in the T-tube, 3 in PTBD, and 5 in the Antegrade stent group. There were more complications in Stent group but no significant statistical difference. In 5 cases with remnant CBD stone, a total of 4 (3 PTBD, 1 Stent) was performed by endoscopic CBD stone removal. One T-tube case was removed easily by choledochoscopy through the T-tube. Three migrated and the impacted stents were removed by additional endoscopy. Perioperative biliary leakage (1) and peritonitis (1) post t-tube removal were resolved by conservative treatment. CONCLUSION: T-tube appears to be an appropriate method to patients who are suspected to have remnant CBD stones. Multiple procedures may be performed on a case by case basis such as performing PTBD first in a suspected cholangitis patient. PMID- 26421027 TI - Pancreatic Diabetes after Distal Pancreatectomy: Incidence Rate and Risk Factors. AB - PURPOSE: Pancreatectomy can impair production of endocrine and exocrine hormones. In this study, we evaluated: 1) the incidence rate of diabetes in patients undergoing distal pancreatectomy; 2) the correlation between the occurrence of pancreatic diabetes and the extent of the resected pancreas; and 3) factors associated with the development of pancreatic diabetes. METHODS: We retrospectively reviewed the cases of 26 patients who could be compared in abdominal computed tomography before and after distal pancreatectomy for benign or malignant lesions between January, 1999 to June, 2010. RESULTS: The incidence of pancreatic diabetes was 19.2%. Obese patients (BMI>25.0 kg/m(2)) had a higher incidence (p=0.029) of pancreatic diabetes after distal pancreatectomy than non obese patients. The diabetes group had larger volumes of resected pancreas, but the difference was not statistically significant (p=0.105). CONCLUSION: Several factors may be associated with the development of pancreatic diabetes after distal pancreatectomy. It is necessary to closely follow-up development of pancreatic diabetes regardless of the extent of resection. PMID- 26421028 TI - Fat Tissue Infiltration into the Pancreas Parenchyme and Its Effect on the Result of Surgery. AB - PURPOSE: In Korea, there are few reports regarding the infiltration of fat tissue in pancreatic parenchyma in surgically resected organs. It is necessary to ascertain the correlation between the presence of fat tissue in the resection margin of the pancreas and the surgery outcome. METHODS: Fifty four patients who underwent pancreatic resection from Jan. 2007 to Nov. 2008 were enrolled in this study. Pathologic examination was performed to determine the presence of fat tissue in resected pancreatic parenchyma. Statistical correlation between the presence of fat tissue with clinical parameters and postoperative complication rates was analyzed. RESULTS: Among the specimens of all fifty four patients, fat tissue was found in 32 specimens of patients (59.3%). Female gender and patients whose body mass index exceeded 24 kg/m(2) were statistically correlated with the presence of the fat tissue in pancreatic parenchyma. There was no statistical relationship between infiltration of fat tissue with postoperative complications. CONCLUSION: This study may serve as the base data for study in radiological imaging in detecting pancreatic tissue. A further larger scaled study is needed to validate the result of this study. PMID- 26421029 TI - Serous Cystic Neoplasm: Do We Have to Wait Till It Causes Trouble? AB - Serous cystic neoplasm (SCN) of the pancreas is considered a benign tumor with almost no malignant potential. Most surgeons agree that asymptomatic SCN requires only regular observation. However, several complexities and interference with organ preservation during the operation, may develop when a huge symptomatic tumor is treated with surgery. So, the purpose of this study is to develop a potential management plan based on a literature review and by describing three recent cases of SCN of the pancreas. We suggest that SCNs be responded to with a timely and appropriate surgical intervention - before they require clinical attention. PMID- 26421031 TI - Scoring of prognostic factors that influence long-term survival in patients with hepatic metastasis of colorectal cancer. AB - BACKGROUNDS/AIMS: To find independent predictors that affect the survival in patients with hepatic metastasis of colorectal cancer after surgery and to devise a risk scoring system. METHODS: Among 150 patients who underwent hepatic resection after diagnosis of colorectal cancer with hepatic metastasis between March 1994 and February 2009, we analyzed clinical, pathologic and outcome data retrospectively. RESULTS: The 1-year survival rate was 83%, and the 5-year survival rate was 35%. Nine factors were found to be independent predictors of adverse outcome by univariate analysis: stage of primary tumor, CA19-9 >36 U/ml, extrahepatic disease, distribution of the hepatic tumor, number of hepatic tumors >3, largest hepatic tumor >5 cm, total size >10 cm, CEA >10 ng/ml, and metachronous cancer. The last two of these criteria were also significant risk factors on multivariate analysis. When these criteria were used as a risk scoring system, assigning one point for each criterion and dividing the cases into A, B and C groups, the total score was highly predictive of outcomes (p<0.001). No patients in group C (6 to 9 points) were long-term survivors. CONCLUSIONS: Long term outcome can be predicted from nine criteria that are readily available for all patients. Patients meeting up to two criteria (group A) are more likely to have a favorable outcome compared to the three or over (groups B and C). This scoring system may offer an easy, rapid, and reliable prognostic indicator of survival outcome after hepatic resection in patients with hepatic metastasis from colorectal cancer. PMID- 26421030 TI - Selection of surgical treatment types for intrahepatic duct stones. AB - BACKGROUNDS/AIMS: Complete elimination of intrahepatic duct (IHD) stones is difficult and IHD stone disease is frequently associated with various complications, recurrence and sometimes cholangiocarcinoma. Therefore, we analyzed the long-term surgical results and evaluated the management currently considered appropriate. METHODS: Overall 110 patients who had been diagnosed with benign IHD stone disease and who underwent surgical treatment were enrolled in this study. The patients were categorized into three groups according to the type of surgery performed; liver resection (LR) group, intrahepatic duct exploration (IHDE) group and hepaticoenterostomy (HE) group. We compared and analyzed the results of these three groups. RESULTS: The number of cases in the LR group, IHDE group and HE group were 77, 25 and 8 respectively. The LR group required a longer operation time (p=0.000), more frequent transfusion (p=0.028) and had higher morbidity (p=0.049). However, the LR group had a higher clearance rate (90.9%) (p=0.000) than the other groups. In addition, there were a total of 22 cases of IHD stone recurrence during the follow-up, but there was no statistically significant difference among the three groups. The location of IHD stones was related to a risk factor for incomplete stone removal, but not for recurrence. CONCLUSIONS: The fundamental principle for the treatment of IHD stone disease should be liver resection. However, it can lead to a longer operative time and higher rate of complications than the other procedures. There is also no difference in the IHD stone recurrence rate among the procedures. Therefore, these alternative and minor procedures could also be taken into account for patients with poor preoperative condition. PMID- 26421032 TI - Treatment outcomes and prognostic factors of gallbladder cancer patients after postoperative radiation therapy. AB - BACKGROUNDS/AIMS: To investigate survival rates and prognostic factors of patients with gallbladder cancer who were treated with surgery and postoperative radiation therapy. METHODS: Seventeen gallbladder cancer patients who received surgery and postoperative radiotherapy from October 1989 to April 1998 were included in this retrospective study. Five patients had stage II, 8 patients had stage III, and 4 patients had stage IV disease according to the 1997 American Joint Committee on Cancer (AJCC) staging. All patients received >=40 Gy of postoperative radiotherapy with a daily dose of 2.0 Gy/fraction and 15 patients received concurrent chemotherapy. An analysis was performed for the end-points of overall and disease-free survival. RESULTS: Of the 17 patients, 13 had no residual disease (R0), 1 had microscopic residual disease (R1), and 3 had macroscopic residual disease (R2) after surgery. Among patients with no residual disease, 4 had locoregional recurrences during the follow-up period. One patient with microscopic residual disease had local recurrence. The 5-year overall survival rate was 38.2%. The median overall survival time was 21 months and the median disease-free survival time was 12 months. Old age (>=60 years old), female gender, a high pathological stage (>=IVA), and the presence of residual disease after surgery were significant prognostic factors for disease-free survival. CONCLUSIONS: Despite a high proportion of patients with advanced disease and macroscopic residual disease, the prognosis of gallbladder patients who had postoperative radiotherapy is encouraging. Additional investigation to improve the loco-regional control of gallbladder cancer patients with adverse prognostic factors is warranted. PMID- 26421033 TI - Clinical comparison of choledochal cysts between children and adults. AB - BACKGROUNDS/AIMS: Choledochal cyst of the bile duct is characterized by cystic dilatation of the intra- or extrahepatic bile ducts. It is a relatively uncommon disease and there is still much controversy regarding its etiology as being congenital or acquired. METHODS: The medical records of 60 patients who underwent surgical treatments for choledochal cyst between April 1995 and April 2009 at the Gachon University Gil Hospital were reviewed retrospectively. To compare the clinical characteristics, patients under 19 years of age were grouped into children and the others were grouped into adults. RESULTS: Of the overall 60 patients, 24 were grouped into children and 36 were grouped into adults. Female predominance was common in both groups (M : F=1 : 6.5). The most common clinical symptom was abdominal pain (73.3%) in both groups. Children had remarkable jaundice (33.3% vs. 0%) and gastrointestinal symptoms including nausea and vomiting. Fever and chills were more common in children because of the associated complications of cholangitis. According to the Todani classification, type I was the most common form of choledochal cyst in both groups, and type IVa was significantly more common in children than adults (45.3% vs. 16.7%). Thirty patients (50%) had anomalous pancreaticobiliary ductal union which was confirmed by preoperative imaging studies or intraoperative cholangiography. All patients except for one child underwent cyst excision with hepaticojejunostomy. CONCLUSION: There was no significant difference in the clinical characteristics of choledochal cysts between children and adults. However, combined diseases especially bile duct malignancy were common in aged patients, early detection and more aggressive surgery is necessary for patients with choledochal cysts. PMID- 26421034 TI - Risk factors for the clinical course of cholecystitis in patients who undergo cholecystectomy. AB - BACKGROUNDS/AIMS: The aims of this study were to evaluate risk factors for acute cholecystitis that have been previously acknowledged and to evaluate several co morbidities, such as hypertension, diabetes mellitus, cardiovascular disease, cerebrovascular accident and end-stage renal disease for which the prevalence rate has increased in the elderly. METHODS: We retrospectively reviewed 611 patients who underwent laparoscopic or open cholecystectomy for cholecystitis between January 2005 and January 2010. The relationships between the clinical outcomes and the clinico-demographic factors were analyzed by univariate and multivariate analyses. RESULTS: The diagnoses of the 611 patients who underwent laparoscopic cholecystectomy were acute cholecystitis (n=258; 42.2%) and chronic cholecystitis (n=353; 57.8%). Male gender (p<0.000), age >50 (p<0.000), fever (p<0.000), leukocytosis (p<0.000), AST elevation (p=0.009), alkaline phosphatase elevation (p<0.000) and an elevation of total bilirubin (p<0.000) were identified as risk factors for acute cholecystitis. The presence of diabetes mellitus (p=0.002) and hypertension (p=0.019) may be risk factors for acute cholecystitis. CONCLUSIONS: For patients with risk factors for acute cholecystitis, early management, that is, early checkup and diagnosis following early cholecystectomy, is recommended before the disease progresses to an acute form of cholecystitis. PMID- 26421035 TI - Adenocarcinoma of the ampulla of Vater: predictors of survival and recurrence after curative radical resection. AB - BACKGROUNDS/AIMS: Because of low incidence rates, there have been few reports on the patterns of and risk factors for recurrence after curative resection of the ampulla of Vater (AoV) cancer. The aim of this study was to characterize patterns of recurrence and to evaluate risk factors affecting survival rates and recurrence after curative resection. METHODS: Medical records of 181 patients who had undergone pancreaticoduodenectomy with curative intent for AoV adenocarcinoma between December 1994 and March 2010 at Samsung Medical Center were retrospectively reviewed. Factors influencing on overall survival rate, recurrence rates, and recurrence patterns were analyzed. RESULTS: Lymph node metastases and high preoperative serum carcinoembryonic antigen (CEA) level >5 ng/ml were identified as independent factors affecting overall survival (p=0.006, p<0.001, respectively). Among the 181 patients, 69 developed local or distant recurrence within 3 years after curative resection. Lymph node metastasis, preoperative serum CEA level >5 ng/ml, and total bilirubin level >1.5 mg/dl were identified as independent prognostic factors of recurrence after curative resection (p=0.008, p<0.001, p=0.003, respectively). CONCLUSIONS: AoV adenocarcinoma has a better prognosis than other periampullary carcinomas, but still has a high recurrence rate, especially during the first three years after curative radical resection. Therefore, careful follow-up is needed during the first 3 years, especially for the higher risk group. Further study of adjuvant therapy to decrease recurrence after curative resection is now warranted. PMID- 26421036 TI - Solitary percutaneous transhepatic biliary drainage tract metastasis after curative resection of perihilar cholangiocarcinoma: report of a case. AB - Percutaneous transhepatic biliary drainage (PTBD) has been widely used, but it has a potential risk of tumor spread along the catheter tract. We herein present a case of solitary PTBD tract metastasis after curative resection of perihilar cholangiocarcinoma. Initially, endoscopic nasobiliary drainage was done on a 65 year-old female patient, but the cholangitis did not resolve. Thus a PTBD catheter was inserted into the right posterior duct. Right portal vein embolization was also performed. Curative surgery including right hepatectomy and bile duct resection was performed 16 days after PTBD. After 12 months, serum CA19 9 had increased gradually without any symptoms. Finally, a small right pleural metastasis was found through strict tumor surveillance for 6 months. Chemoradiation therapy was performed, but there was no response to treatment. As the tumor progressed, she complained of severe dyspnea and finally died from tumor dissemination to the chest and bones 18 months after the first detection of PTBD tract recurrence and 36 months after surgery. No intra-abdominal recurrence was found until the terminal stage. This PTBD tract recurrence was attributed to the PTBD even though it was in place for only 16 days. Although such recurrence is rare, its risk should be taken into account during follow-up of patients who have received PTBD before. PMID- 26421037 TI - Cavo-caval intervention stent insertion after deceased-donor liver transplantation using side-to-side piggyback technique: report of a case. AB - Liver transplantation with preservation of the recipient vena cava (piggyback technique) has been performed as an alternative to the conventional method. Outflow disturbance or obstruction of the vena cava in the early period after liver transplantation is associated with high morbidity and mortality. We used side-to-side cavo-caval anastomosis (modified piggyback technique) in a deceased donor liver transplantation (DDLT) for venous outflow reconstruction. On postoperative day 9, the patient developed abdominal discomfort, and abnormal liver function showing serum total bilirubin of 6.2 mg/dl and serum AST/ALT of 297/597 IU/L. Doppler ultrasound showed mono-phasic wave forms of the hepatic vein. Computed tomography showed focal narrowing of 9.5 mm*12 mm in diameter at the cavo-caval anastomosis site. Liver biopsy was showed that there was no evidence of acute allograft rejection. Direct venogram showed stenosis of the cavo-caval anastomosis with a pressure gradient of 12 mmHg. An interventional stent was inserted in the stenotic site of the inferior vena cava, and the pressure gradient decreased to 2 mmHg. He was discharged from hospital on postoperative day 23 without any other complications. Herein we report a case of deceased-donor liver transplantation using the modified piggyback technique, who received an inferior vena cava stent due to stricture of the reconstructed orifice of the vena cava. PMID- 26421038 TI - Therapeutic induction of hepatic atrophy for isolated injury of the right posterior sectoral duct following laparoscopic cholecystectomy. AB - Laparoscopic cholecystectomy has resulted in various bile duct injuries. Treatment of these injuries is usually difficult and often leads to an intractable clinical course. We herein present a case of isolated right anterior sector (RAS) duct injury induced by laparoscopic cholecystectomy. The bile duct injury was successfully treated by hepatic atrophy induction. Imaging studies revealed that the RAS duct was severed, probably due to rare anatomical variations. Considering the difficulty in surgical reconstruction, atrophy induction of the involved hepatic parenchyma was attempted. This treatment consisted of embolization of the RAS portal branch to inhibit bile production, induction of heavy adhesion at the bile leak site to ensure percutaneous pigtail clamping, and sequential clamping and removal of pigtail catheters. This procedure took 3 months prior to pigtail catheter removal. She was free from other complications during the first 12 months and to date. She will be followed up for 5 years overall including surveillance for hepatobiliary complications. Although this therapeutic induction of atrophy approach is not universally applicable, it can be considered to be a feasible option in unique situations such as this one. PMID- 26421039 TI - Partial gastric outlet obstruction caused by a huge submucosal tumor originating in the heterotopic pancreas. AB - A 21-year-old woman presented gastrointestinal manifestation showing intermittent abdominal pain, nausea, and vomiting. An upper endoscopic examination showed round, elevated mucosa at the antrum of the stomach anterior wall. After CT scanning, a huge degenerated gastrointestinal stromal tumor was suspected. Subtotal gastrectomy with Billroth II anastomosis was performed. Histologically, pseudocystic degeneration of the heterotopic pancreas was confirmed. The patient showed eventful postoperative course except temporary dilated gastric emptying. The patient is doing well without any abnormal symptom at 8-month follow-up. This report is a rare case of gastric outlet obstruction caused by a pseudocyst originating from a heterotopic pancreas in the gastric antrum. PMID- 26421040 TI - Long-term outcome after liver resection and clinicopathological features in patients with small hepatocellular carcinoma. AB - BACKGROUNDS/AIMS: Surveillance programs and imaging modality developments have increased the detection rate of small hepatocellular carcinoma (HCC). In particular, liver transplantation produces good results and is now regarded an alternative to liver resection. However, optimal treatment for small HCC is still debated, and thus, the authors designed this study to document clinicopathological characteristics, to identify the prognostic factors of small HCC, and to determine the effectiveness of surgery. METHODS: A total of 507 patients underwent curative liver resection for HCC between January 1996 and August 2006 in our institution. One hundred and thirty four of these patients with a single HCC of less than 3 cm and no gross vascular invasion were enrolled. RESULTS: Major resection was performed in 32 (23.9%) patients; there was no postoperative mortality. Fifty-eight (43.3%) patients experienced recurrence, 53 developed intrahepatic recurrence alone, and 50 (94.3%) of 53 had tumors within the Milan criteria. Five-year disease-free and overall survival rates were 51.0% and 77.3%, respectively. Microscopic vascular invasion, positivity for hepatitis B surface antigen or antibody to hepatitis C, and an indocyanine green retention test at 15 minutes of more than 10% were found to be significantly correlated with disease-free overall survival. A platelet count of less than 100,000/mm(3) was the only independent prognostic factors of overall survival identified. CONCLUSIONS: This study showed favorable outcome comparable to the survival after liver transplantation, thus that liver resection appears to be the primary treatment option for small HCC, even in cases with poor prognostic factors. PMID- 26421041 TI - Is neoadjuvant chemotherapy necessary for patients with initially resectable colorectal liver metastases in the era of effective chemotherapy? AB - BACKGROUNDS/AIMS: Hepatic resection has only guaranteed long-term survival in patients with colorectal liver metastasis (CRLM) even in the era of effective chemotherapy. The definite role of neoadjuvant chemotherapy (NCT) is to improve outcomes of unresectable CRLMs, but it its role has not been defined for initially resectable CRLMs (IR-CRLMs). METHODS: We reviewed the medical records of 226 patients, who had been diagnosed and treated for IR-CRLM between 2003 and 2008; the patients had the following pathologies: 10% had more than 4 nodules, 11% had tumors larger than 5 cm, and 61% had synchronous CRMLs. Among these patients, 20 patients (Group Y) were treated with NCT, and 206 (Group N) did not receive NCT according to their physician's preference. The median follow-up time was 34.1 months. RESULTS: The initial surgical plans were changed after NCT to further resection in 20% and to limited resection in 10% of 20 patients. Complication rates of Groups Y (30%) were indifferent from Group N (23%) (p=0.233), but intraoperative transfusions were more frequent in Group N (15%) than in Group Y (5%) (p=0.006). There was one case of hospital mortality (0.44%). Disease-free survival rates in Groups Y and N were 23% and 39%, respectively, and patient survival rates were 42% and 66% (p>0.05). By multivariate analysis, old age (>=60 years), differentiation of primary tumor (poorly/mucinous), resection margin involvement, and no adjuvant chemotherapy were associated with poor patient survival; the number of CRLMs (>=4) was associated with poor disease-free survival. CONCLUSIONS: NCT had neither a positive impact nor a negative impact on survival, even with intraoperative transfusion, as observed on operative outcomes for patients with IR-CRLM. Further study is required to elucidate the role of NCT for treatment of patient with IR-CRLMs. PMID- 26421042 TI - What we learned from difficult hepatectomies in patients with advanced hepatic malignancy. AB - BACKGROUNDS/AIMS: By reviewing difficult resections for advanced hepatic malignancies, we discuss the effectiveness and extended indications for hepatectomy in such patients. METHODS: We reviewed 7 patients who underwent extensive surgery between July 2008 and March 2011 for advanced hepatic malignancies. They had stage IV disease, except for in one case that was a stage IIIC (T4N0M0) hepatocellular carcinoma (HCC). RESULTS: Patient 1 with intrahepatic cholangiocarcinoma (IHCC) underwent right hemihepatectomy and resection of the bile duct and left portal vein. At 39 months after surgery, she had no recurrence or metastasis. Patient 2 with HCC underwent palliative right trisectionectomy. At 38 months after surgery, he is alive despite residual pulmonary metastases. Patient 3 with HCC invading the hepatic vein and diaphragm underwent right trisectionectomy and caval venoplasty. At 12 months after surgery, he had no recurrence or metastasis. Patient 4, who had 2 large HCCs and pulmonary thromboembolism, underwent a right trisectionectomy. At 7 months after surgery, he had no evidence of recurred HCC. Patient 5, who had IHCC invading her inferior vena cava and main portal vein, underwent preoperative radiotherapy, left hemihepatectomy, and caval resection. At 20 months after surgery, she is well despite a caval thrombus. Patient 6 and 7 underwent repeated surgery due to a recurred IHCC and metastatic colon cancer, respectively. In addition, they are alive during each 20 and 17 months after surgery. CONCLUSIONS: Despite macroscopic extrahepatic metastases or major vessel involvement, extensive surgery for advanced hepatic malignancy may result in relatively favorable outcomes and be important modality for improving of survival in such patients. PMID- 26421043 TI - Efficacy and feasibility of laparoscopic subtotal cholecystectomy for acute cholecystitis. AB - BACKGROUNDS/AIMS: For patients with acute cholecystitis, conversion from laparoscopic cholecystectomy to open surgery is not uncommon due to possibilities of serious hemorrhage at the liver bed and bile duct injury. Recent studies reported successful laparoscopic subtotal cholecystectomy for acute cholecystitis. The purpose of this study was to determine the efficacy and feasibility of such an operation based on the experience of surgeons at our facility. METHODS: In this study, we enrolled 144 patients who had received either laparoscopic subtotal cholecystectomy (LSC), laparoscopic cholecystectomy (LC), or open cholecystectomy (OC) for acute cholecystitis from January 2004 to December 2009 at the Department of Surgery of our hospital. Their symptoms, signs, operative findings, pathologic results and postoperative results were compared and analyzed. RESULTS: There were 26 patients in the LSC group 80 in the LC group and 38 in the OC group. There were no differences in mean age, sex, and symptoms of acute cholecystitis. The LSC group showed higher CRP levels (p<0.001) and a higher grade according to the Tokyo criteria (p=0.001). The mean operative time was 115.6 minutes and mean blood loss was 158.9 ml without intra-operative or postoperative transfusion. There weren't any bile duct injuries during the operation. No group suffered bile leakage. Drains were removed 3.3 days after the operation in the LC group, the shortest time compared to the other groups (p<0.001). LC and LSC groups demonstrated shorter postoperative hospital days and time to diet resumption than the OC group (p<0.001). CONCLUSIONS: LSC appears to be a safe and effective treatment in cases of severe acute cholecystitis that require consideration of conversion to open surgery. PMID- 26421044 TI - Effectiveness of external drainage of the bile duct in pancreaticoduodenectomy: a single surgeon's experience. AB - BACKGROUNDS/AIMS: The rates of surgery-related complications during and after pancreaticoduodenectomy (PD) remain very high, reaching up to 41%. They were primarily caused by leakage of pancreatic juice. We evaluated the effectiveness of external drainage of the bile duct using a pigtail drain to prevent pancreatic leakage in patients undergoing PD. METHODS: We evaluated 79 patients who underwent PD using a single-layer continuous suture between the pancreatic parenchyma and jejunum after duct-to-mucosa anastomosis by a single surgeon from April 2005 to December 2008. Of the 79, 44 underwent external drainage (ED) of the bile duct using a pigtail drain, performed in the intraoperative field via a retrograde transhepatic approach, whereas 35 did not undergo ED. RESULTS: Age, sex distribution, number of total complications, pancreatic duct size, pancreatic texture and duration of hospital stay did not differ between patients who did and did not undergo ED. In groups with or without ED, 0 and 4 patients, respectively, showed leakage of pancreatic juice and the difference was statistically significant (p=0.02). CONCLUSIONS: The fact that none of the patients who underwent external drainage experienced pancreatic leakage, suggests that external drainage of the bile duct with a pigtail drain to decompress the jejunum and to drain pancreatic and bile juice is useful in preventing the complications of pancreatic leakage. PMID- 26421046 TI - Complication analysis of distal pancreatectomy based on early personal experience. AB - BACKGROUNDS/AIMS: The objective of this study was to evaluate the relationship between initial personal experiences with distal pancreatectomy and perioperative risk factors, outcomes, and management of pancreatic fistulas. METHODS: Between May, 2007 and May, 2010, a total of 28 patients who had undergone elective distal pancreatectomy were evaluated for this study. Perioperative factors and the occurrence of pancreatic fistula were analyzed on the basis of International Study Group of Pancreatic Fistula (ISGPF) criteria. RESULTS: There were sixteen cases of benign neoplasms and twelve cases of malignant tumors. The remnant pancreas was manually sutured with ligation of the pancreatic duct (n=14), auto suture stapling along with manual sutures (n=12), or stapling alone (n=2). According to the ISGPF classification, morbidity and mortality associated with pancreatic fistulas was 42.9% (n=12) and 0%, respectively. These pancreatic fistulae were classified as grade A in 8 cases (28.6%), grade B in 3 cases (10.7%), and grade C in one case (3.6%). All patients with pancreatic fistula were treated conservatively. CONCLUSIONS: Perioperative factors do not affect the risk of pancreatic fistula. Adequate drainage is the most effective method for management of a pancreatic fistula after distal pancreatectomy. PMID- 26421045 TI - Predictive factors for invasive intraductal papillary mucinous neoplasm of the pancreas. AB - BACKGROUNDS/AIMS: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas has malignant potential. Predicting invasive IPMN has proven difficult and controversial. We tried to identify predictive factors for invasive IPMN. METHODS: Thirty six patients underwent resection for IPMN from February 2001 to July 2011. Clinicopathological features including demographic, imaging, microscopic, and serological findings were retrospectively reviewed. Receiver operating characteristic (ROC) curve analysis was used to analyze sensitivity and specificity of all possible cut-off values for the diameter of the main pancreatic duct and mass size predicting invasive IPMN. Student t-test, chi square test, and logistic regression were used for univariate and multivariate analysis. RESULTS: The mean age was 63.5+/-8.4 years. Males were more commonly affected (58.3% vs 41.7%). Pancreaticoduodenectomy was performed in 55.6% of patients, distal pancreatectomy in 36.1%, and central pancreatic resection in 8.3%. Non-invasive IPMNs were present in 80.6% (n=29), whereas invasive IPMNs were present in 19.4% (n=7). In univariate analysis, tumor location (p=0.036), Kuroda classification (p=0.048), mural nodule (p=0.016), and main duct dilatation (>=8 mm) (p=0.006) were statistically significant variables. ROC curve analysis showed that a value of 8 mm for the main duct dilatation and a value of 35 mm for the size of the mass lesion have 80% sensitivity and 75% specificity and 100% sensitivity and 82.6% specificity, respectively. However, in multivariate analysis, main ductal dilatation (>=8 mm) was identified to be the only independent factor for invasive IPMN (p=0.049). CONCLUSIONS: Main duct dilatation appears to be a useful indicator for predicting invasive IPMN. PMID- 26421047 TI - The impact of old age on surgical outcomes after pancreaticoduodenectomy for distal bile duct cancer. AB - BACKGROUNDS/AIMS: To compare surgical results and survival of two groups of patients, age >=70 vs. age <70, who underwent pancreaticoduodenectomy and to identify the safety of this procedure for elderly patients for the treatment of distal common bile duct (CBD) cancer. METHODS: Between January 2003 and December 2009, 55 patients who underwent pancreaticoduodenectomy for the treatment of distal CBD cancer at Keimyung University Dong San Medical Center were enrolled in our study. RESULTS: Of 55 patients, 28 were male and 27 female. Nineteen were over 70 years old (older group) and 36 were below 70 years (younger group). The mean ages of the two groups of patients were 73.5 years and 60.5 years respectively. Although patients of the older group had significantly more comorbid diseases, perioperative results including operation time, amount of intraoperative bleeding, duration of postoperative hospital stay and postoperative complications were not significantly different. A higher level (more than 5 mg/dl) of preoperative initial bilirubin showed significant correlations with operative morbidity by univariate analysis, and age was not an independent risk factor of operative morbidity. Overall 5 year survival of older and younger groups were 45.9% and 39.5% respectively (p=0.671) and disease-free 5 year survival were 31.7% and 31.1%, respectively (p=0.942). CONCLUSIONS: Surgical outcomes of elderly patients were similar to those of younger patients, despite a higher incidence of comorbid disease. This results shows that pancreaticoduodenectomy can be applied safely to elderly patients. PMID- 26421048 TI - Self-Care Practices for Common Colds by Primary Care Patients: Study Protocol of a European Multicenter Survey-The COCO Study. AB - Background. Self-care for common colds is frequent, yet little is known about the spectrum, regional differences, and potential risks of self-care practices in patients from various European regions. Methods/Design. We describe the study protocol for a cross-sectional survey in 27 primary care centers from 14 European countries. At all sites, 120 consecutive adult patients, who visit their general practitioner for any reason, filled in a self-administered 27-item questionnaire. This addresses patients' self-care practices for common colds. Separately, the subjective level of discomfort when having a common cold, knowing about the diseases' self-limited nature, and medical and sociodemographic data are requested. Additionally, physicians are surveyed on their use of and recommendations for self-care practices. We are interested in investigating which self-care practices for common colds are used, whether the number of self-care practices used is influenced by knowledge about the self-limited nature of the disease, and the subjective level of discomfort when having a cold and to identify potential adverse interactions with chronic physician-prescribed medications. Further factors that will be considered are, for example, demographic characteristics, chronic conditions, and sources of information for self-care practices. All descriptive and analytical statistics will be performed on the pooled dataset and stratified by country and site. Discussion. To our knowledge, COCO is the first European survey on the use of self-care practices for common colds. The study will provide new insight into patients' and general practitioners' self-care measures for common colds across Europe. PMID- 26421049 TI - Effect of Lepidium meyenii Walp. on Semen Parameters and Serum Hormone Levels in Healthy Adult Men: A Double-Blind, Randomized, Placebo-Controlled Pilot Study. AB - Background/Aims. Products of Lepidium meyenii Walp. (maca) are touted worldwide as an alimentary supplement to enhance fertility and restore hormonal balance. Enhancing properties of maca on semen parameters in animals were previously reported by various authors, but we present to the best of our knowledge the first double-blind, randomized, placebo-controlled pilot trial in men. The aim of this study was to evaluate the effects of maca on semen parameters and serum hormone levels in healthy adult men. Methods. A group of 20 volunteers aged 20-40 years was supplied by milled hypocotyl of maca or placebo (1.75 g/day) for 12 weeks. Negative controls of semen were compared to the samples after 6 and 12 weeks of maca administration; negative blood controls were compared to the samples after 12 weeks of treatment. Results. Sperm concentration and motility showed rising trends compared to placebo even though levels of hormones did not change significantly after 12 weeks of trial. Conclusion. Our results indicate that maca possesses fertility enhancing properties in men. As long as men prefer to use alimentary supplement to enhance fertility rather than prescribed medication or any medical intervention, it is worth continuing to assess its possible benefits. PMID- 26421050 TI - A Novel Pharmacological Method to Study the Chinese Medicinal Formula Hua-Zheng Hui-Sheng-Dan. AB - Objectives. Hua-Zheng-Hui-Sheng-Dan (HZHSD) was used as an experimental model to explore research methods of large formulae in traditional Chinese medicine (TCM) using current molecular biology approaches. Materials and Methods. The trypan blue exclusion assay was used to determine cell viability and cell numbers. Flow cytometry was used to assess cell cycle distribution and apoptosis. The concentration of cyclin D1 was analyzed by enzyme-linked immunosorbent assay. The median effect principle was used in drug combination studies. An orthogonal experimental design was used to estimate the effects of each herb at different concentrations. The HeLa xenograft mouse model was used to compare the antitumor activity of drugs in vivo. Results. Among the 35 herbs that comprise HZHSD, Radix Rehmanniae Preparata (RRP), Caesalpinia sappan (CS), Evodia rutaecarpa (ER), Folium Artemisiae Argyi (FAA), Leonurus japonicus Houtt (LJH), Tumeric (Tu), Radix Paeoniae Alba (RPA), and Trogopterus Dung (TD) effectively inhibited the proliferation of HeLa and SKOV3 cells. Only RRR had an effect on HeLa and SKOV3 cell viability. According to the median effect principle, Angelica sinensis (Oliv.) (AS), Tabanus (Ta), and Pollen Typhae (PT), which were proven to have a significant synergistic inhibitory effect on the proliferation of HeLa cells, were added to the original eight positive herbs. The combination of RPA and AS had a synergistic effect on inducing cell cycle S phase arrest and decreasing intracellular cyclin D1 in HeLa cells. By orthogonal experimental design, LJH and Tu were considered unnecessary herbs. The small formula (SHZHSD) consisted of RPA, AS, RRR, Ta., TD, PT, ER, CS, and FAA and was able to inhibit cell proliferation and induce cell apoptosis. The antitumor effects of HZHSD and SHZHSD were also compared in vivo. Conclusions. Through molecular biology approaches both in vitro and in vivo, research into single drugs, and analysis using the median effect principle and orthogonal experimental design, the small formula (SHZHSD) was determined from the original formula (HZHSD). SHZHSD exhibited superior antitumor activity compared with the original formula both in vitro and in vivo. PMID- 26421051 TI - Sea Buckthorn Leaf Extract Protects Jejunum and Bone Marrow of (60)Cobalt-Gamma Irradiated Mice by Regulating Apoptosis and Tissue Regeneration. AB - A single dose (30 mg/kg body weight) of standardized sea buckthorn leaf extract (SBL-1), administered 30 min before whole body (60)Co-gamma-irradiation (lethal dose, 10 Gy), protected >90% of mice population. The purpose of this study was to investigate the mechanism of action of SBL-1 on jejunum and bone marrow, quantify key bioactive compounds, and analyze chemical composition of SBL-1. Study with 9 week-old inbred male Swiss albino Strain 'A' mice demonstrated that SBL-1 treatment before (60)Co-gamma-irradiation (10 Gy) significantly (p < 0.05) countered radiation induced decreases in jejunum crypts (1.27-fold), villi number (1.41-fold), villus height (1.25-fold), villus cellularity (2.27-fold), cryptal Paneth cells (1.89-fold), and Bcl2 level (1.54-fold). It countered radiation induced increases in cryptal apoptotic cells (1.64-fold) and Bax levels (1.88 fold). It also countered radiation (2 Gy and 3 Gy) induced bone marrow apoptosis (1.59-fold and 1.85-fold) and micronuclei frequency (1.72-fold and 2.6-fold). SBL 1 rendered radiation protection by promoting cryptal stem cells proliferation, by regulating apoptosis, and by countering radiation induced chromosomal damage. Quercetin, Ellagic acid, Gallic acid, high contents polyphenols, tannins, and thiols detected in SBL-1 may have contributed to radiation protection by neutralization of radiation induced oxidative species, supporting stem cell proliferation and tissue regeneration. PMID- 26421052 TI - Overcome Cancer Cell Drug Resistance Using Natural Products. AB - Chemotherapy is one of the major treatment methods for cancer. However, failure in chemotherapy is not uncommon, mainly due to dose-limiting toxicity associated with drug resistance. Management of drug resistance is important towards successful chemotherapy. There are many reports in the Chinese literature that natural products can overcome cancer cell drug resistance, which deserve sharing with scientific and industrial communities. We summarized the reports into four categories: (1) in vitro studies using cell line models; (2) serum pharmacology; (3) in vivo studies using animal models; and (4) clinical studies. Fourteen single compounds were reported to have antidrug resistance activity for the first time. In vitro, compounds were able to overcome drug resistance at nontoxic or subtoxic concentrations, in a dose-dependent manner, by inhibiting drug transporters, cell detoxification capacity, or cell apoptosis sensitivity. Studies in vivo showed that single compounds, herbal extract, and formulas had potent antidrug resistance activities. Importantly, many single compounds, herbal extracts, and formulas have been used clinically to treat various diseases including cancer. The review provides comprehensive data on use of natural compounds to overcome cancer cell drug resistance in China, which may facilitate the therapeutic development of natural products for clinical management of cancer drug resistance. PMID- 26421053 TI - Validation of a RP-HPLC-DAD Method for Chamomile (Matricaria recutita) Preparations and Assessment of the Marker, Apigenin-7-glucoside, Safety and Anti Inflammatory Effect. AB - Chamomile is a medicinal plant, which presents several biological effects, especially the anti-inflammatory effect. One of the compounds related to this effect is apigenin, a flavonoid that is mostly found in its glycosylated form, apigenin-7-glucoside (APG), in natural sources. However, the affectivity and safety of this glycoside have not been well explored for topical application. In this context, the aim of this work was to develop and validate a reversed-phase high-performance liquid chromatography (RP-HPLC-DAD) method to quantify APG in chamomile preparations. Additionally, the safety and the anti-inflammatory potential of this flavonoid were verified. The RP-HPLC-DAD method was developed and validated with linearity at 24.0-36.0 MUg/mL range (r = 0.9994). Intra- and interday precision (RSD) were 0.27-2.66% and accuracy was 98.27-101.21%. The validated method was applied in the analysis of chamomile flower heads, glycolic extract, and Kamillen cream, supporting the method application in the quality control of chamomile preparations. Furthermore, the APG safety was assessed by MTT cytotoxicity assay and mutagenic protocols and the anti-inflammatory activity was confirmed by a diminished TNF-alpha production showed by mice macrophages treated with APG following LPS treatment. PMID- 26421054 TI - A sustained high fat diet for two years decreases IgM and IL-1 beta in ageing Wistar rats. AB - BACKGROUND: The immune system undergoes several alterations of innate and adaptive immunity during ageing. The main features of the aged immune system are a reduced diversity of T cell receptors and a reduced activity of innate immune cells with subsequent changes in adaptive immunity resulting in a less effective, less specific, and dys-regulated immune response and in an increased susceptibility towards infection, malignancy, and autoimmunity. The process is referred to as immunosenescence and is also modulated by environmental modifiers, such as dietary factors. High fat diet (HFD), via direct modulation of immune cell function by fatty acids and/or increased body fat mass, influences immune function. However, it is not clear whether HFD is beneficial or detrimental for the functioning of the ageing immune system. METHODS: Male Wistar rats fed with either a high fat diet (HFD 43 en% of fat) or control diet (SD, 25 en% of fat) over up to 24 month and were analyzed for plasma IL-1beta, IL-6, TNF, IgM, IgG1, IgA, IgG2a, IgG2b, IgG2c, light chains lambda and kappa, testosterone, prolactin and percentage of splenic B cells and apoptosis rate, respectively. RESULTS: In general, all analyzed immunoglobuline isotypes increased with age, except for IgA. This increase was attenuated by HFD. In HFD and SD rats the percentage of B cells in the spleen and also their apoptotic rate was lower in aged as compared to young animals with no additional diet-induced effect. Testosterone and prolactin levels were lower in old animals, as expected. There was a statistical trend towards an increased prolactin/testosterone ratio in middle aged (6-12 monthsnth) HFD rats as compared to SD. IL-6 was neither affected by HFD nor age. On the other hand, HFD rats showed a decrease in IL-1beta as compared to SD, which correlated with the above-mentioned suppressive effect on immunoglobulin isotypes, especially IgM. CONCLUSION: In Wistar rats, HFD reveals an immunosuppressive effect in ageing animals by decreasing immunoglobulins, especially IgM, and IL-1beta when compared to SD. PMID- 26421055 TI - Reconstruction Method for Optical Tomography Based on the Linearized Bregman Iteration with Sparse Regularization. AB - Optical molecular imaging is a promising technique and has been widely used in physiology, and pathology at cellular and molecular levels, which includes different modalities such as bioluminescence tomography, fluorescence molecular tomography and Cerenkov luminescence tomography. The inverse problem is ill-posed for the above modalities, which cause a nonunique solution. In this paper, we propose an effective reconstruction method based on the linearized Bregman iterative algorithm with sparse regularization (LBSR) for reconstruction. Considering the sparsity characteristics of the reconstructed sources, the sparsity can be regarded as a kind of a priori information and sparse regularization is incorporated, which can accurately locate the position of the source. The linearized Bregman iteration method is exploited to minimize the sparse regularization problem so as to further achieve fast and accurate reconstruction results. Experimental results in a numerical simulation and in vivo mouse demonstrate the effectiveness and potential of the proposed method. PMID- 26421056 TI - Numerical Methods and Applications in Biomechanical Modeling 2014. PMID- 26421057 TI - Suicidality among adolescents engaging in nonsuicidal self-injury (NSSI) and firesetting: the role of psychosocial characteristics and reasons for living. AB - BACKGROUND: Co-occurrence of problem behaviors, particularly across internalizing and externalizing spectra, increases the risk of suicidality (i.e., suicidal ideation and attempt) among youth. METHODS: We examined differences in psychosocial risk factors across levels of suicidality in a sample of 77 school based adolescents engaging in both nonsuicidal self-injury (NSSI) and repeated firesetting. Participants completed questionnaires assessing engagement in problem behaviors, mental health difficulties, negative life events, poor coping, impulsivity, and suicidality. RESULTS: Adolescents endorsing suicidal ideation reported greater psychological distress, physical and sexual abuse, and less problem solving/goal pursuit than those with no history of suicidality; adolescents who had attempted suicide reported more severe NSSI, higher rates of victimization and exposure to suicide, relative to those with suicidal ideation but no history of attempt. Additional analyses suggested the importance of coping beliefs in protecting against suicidality. CONCLUSIONS: Clinical implications and suggestions for future research relating to suicide prevention are discussed. PMID- 26421059 TI - The functions of nonsuicidal self-injury: converging evidence for a two-factor structure. AB - Research has identified more than a dozen functions of non-suicidal self-injury (NSI), but the conceptual and empirical overlap among these functions remains unclear. The present study examined the structure of NSI functions in two large samples of patients receiving acute-care treatment for NSI. Two different measures of NSI functions were utilized to maximize generalizability of findings: one sample (n = 946) was administered the Inventory of Statements About Self injury (ISAS; Klonsky and Glenn in J Psychopathol Behav Assess 31:215-219, 2009), and a second sample (n = 211) was administered the Functional Assessment of Self Mutilation (FASM; Lloyd et al. in Self-mutilation in a community sample of adolescents: descriptive characteristics and provisional prevalence rates. Poster session at the annual meeting of the Society for Behavioral Medicine, New Orleans, LA, 1997). Exploratory factor analyses revealed that both measures exhibited a robust two-factor structure: one factor represented Intrapersonal functions, such as affect regulation and anti-dissociation, and a second factor represented Social functions, such as interpersonal influence and peer bonding. In support of the two-factor structure's construct validity, the factors exhibited a pattern of correlations with indicators of NSI severity that was consistent with past research and theory. Findings have important implications for theory, research, and treatment. In particular, the two-factor framework should guide clinical assessment, as well as future research on the implications of NSI functions for course, prognosis, treatment, and suicide risk. PMID- 26421058 TI - Parents of youth who self-injure: a review of the literature and implications for mental health professionals. AB - Non-suicidal self-injury (NSSI) is a common mental health concern among youth, and parents can be valuable supports for these youth. However, youth NSSI can have a significant impact on parents' wellbeing, which may in turn alter parents' ability to support the youth. To date, no single article has consolidated the research on parents of youth who self-injure. This review synthesizes the literature on parent factors implicated in youth NSSI risk, the role of parents in help-seeking and intervention for youth NSSI, and the impact of youth NSSI on parent wellbeing and parenting. Clinical implications for supporting parents as they support the youth are also discussed, and recommendations for future research are outlined. PMID- 26421060 TI - Microdeletions in 9q33.3-q34.11 in five patients with intellectual disability, microcephaly, and seizures of incomplete penetrance: is STXBP1 not the only causative gene? AB - BACKGROUND: Most microdeletions involving chromosome sub-bands 9q33.3-9q34.11 to this point have been detected by analyses focused on STXBP1, a gene known to cause early infantile epileptic encephalopathy 4 and other seizure phenotypes. Loss-of-function mutations of STXBP1 have also been identified in some patients with intellectual disability without epilepsy. Consequently, STXBP1 is widely assumed to be the gene causing both seizures and intellectual disability in patients with 9q33.3-q34.11 microdeletions. RESULTS: We report five patients with overlapping microdeletions of chromosome 9q33.3-q34.11, four of them previously unreported. Their common clinical features include intellectual disability, psychomotor developmental delay with delayed or absent speech, muscular hypotonia, and strabismus. Microcephaly and short stature are each present in four of the patients. Two of the patients had seizures. De novo deletions range from 1.23 to 4.13 Mb, whereas the smallest deletion of 432 kb in patient 3 was inherited from her mother who is reported to have mild intellectual disability. The smallest region of overlap (SRO) of these deletions in 9q33.3 does not encompass STXBP1, but includes two genes that have not been previously associated with disease, RALGPS1 and GARNL3. Sequencing of the two SRO genes RALGPS1 and GARNL3 in at least 156 unrelated patients with mild to severe idiopathic intellectual disability detected no causative mutations. Gene expression analyses in our patients demonstrated significantly reduced expression levels of GARNL3, RALGPS1 and STXBP1 only in patients with deletions of the corresponding genes. Thus, reduced expression of STXBP1 was ruled out as a cause for seizures in our patient whose deletion did not encompass STXBP1. CONCLUSIONS: We suggest that microdeletions of this region on chromosome 9q cause a clinical spectrum including intellectual disability, developmental delay especially concerning speech, microcephaly, short stature, mild dysmorphisms, strabismus, and seizures of incomplete penetrance, and may constitute a new contiguous gene deletion syndrome which cannot completely be explained by deletion of STXBP1. PMID- 26421061 TI - Dose-dependent alcohol-induced alterations in chromatin structure persist beyond the window of exposure and correlate with fetal alcohol syndrome birth defects. AB - BACKGROUND: In recent years, we have come to recognize that a multitude of in utero exposures have the capacity to induce the development of congenital and metabolic defects. As most of these encounters manifest their effects beyond the window of exposure, deciphering the mechanisms of teratogenesis is incredibly difficult. For many agents, altered epigenetic programming has become suspect in transmitting the lasting signature of exposure leading to dysgenesis. However, while several chemicals can perturb chromatin structure acutely, for many agents (particularly alcohol) it remains unclear if these modifications represent transient responses to exposure or heritable lesions leading to pathology. RESULTS: Here, we report that mice encountering an acute exposure to alcohol on gestational Day-7 exhibit significant alterations in chromatin structure (histone 3 lysine 9 dimethylation, lysine 9 acetylation, and lysine 27 trimethylation) at Day-17, and that these changes strongly correlate with the development of craniofacial and central nervous system defects. Using a neural cortical stem cell model, we find that the epigenetic changes arising as a consequence of alcohol exposure are heavily dependent on the gene under investigation, the dose of alcohol encountered, and that the signatures arising acutely differ significantly from those observed after a 4-day recovery period. Importantly, the changes observed post-recovery are consistent with those modeled in vivo, and associate with alterations in transcripts encoding multiple homeobox genes directing neurogenesis. Unexpectedly, we do not observe a correlation between alcohol-induced changes in chromatin structure and alterations in transcription. Interestingly, the majority of epigenetic changes observed occur in marks associated with repressive chromatin structure, and we identify correlative disruptions in transcripts encoding Dnmt1, Eed, Ehmt2 (G9a), EzH2, Kdm1a, Kdm4c, Setdb1, Sod3, Tet1 and Uhrf1. CONCLUSIONS: These observations suggest that the immediate and long-term impacts of alcohol exposure on chromatin structure are distinct, and hint at the existence of a possible coordinated epigenetic response to ethanol during development. Collectively, our results indicate that alcohol induced modifications to chromatin structure persist beyond the window of exposure, and likely contribute to the development of fetal alcohol syndrome associated congenital abnormalities. PMID- 26421062 TI - Prenatal ethanol exposure alters adult hippocampal VGLUT2 expression with concomitant changes in promoter DNA methylation, H3K4 trimethylation and miR-467b 5p levels. AB - BACKGROUND: Maternal consumption of alcohol during pregnancy is associated with a range of physical, cognitive and behavioural outcomes in the offspring which are collectively called foetal alcohol spectrum disorders. We and others have proposed that epigenetic modifications, such as DNA methylation and post translational histone modifications, mediate the effects of prenatal alcohol exposure on gene expression and, ultimately, phenotype. Here we use an inbred C57BL/6J mouse model of early gestational ethanol exposure equivalent, developmentally, to the first 3-4 weeks of pregnancy in humans to examine the long-term effects on gene expression and epigenetic state in the hippocampus. RESULTS: Gene expression analysis in the hippocampus revealed sex- and age specific up-regulation of solute carrier family 17 member 6 (Slc17a6), which encodes vesicular glutamate transporter 2 (VGLUT2). Transcriptional up-regulation correlated with decreased DNA methylation and enrichment of histone H3 lysine 4 trimethylation, an active chromatin mark, at the Slc17a6 promoter. In contrast to Slc17a6 mRNA levels, hippocampal VGLUT2 protein levels were significantly decreased in adult ethanol-exposed offspring, suggesting an additional level of post-transcriptional control. MicroRNA expression profiling in the hippocampus identified four ethanol-sensitive microRNAs, of which miR-467b-5p was predicted to target Slc17a6. In vitro reporter assays showed that miR-467b-5p specifically interacted with the 3'UTR of Slc17a6, suggesting that it contributes to the reduction of hippocampal VGLUT2 in vivo. A significant correlation between microRNA expression in the hippocampus and serum of ethanol-exposed offspring was also observed. CONCLUSIONS: Prenatal ethanol exposure has complex transcriptional and post-transcriptional effects on Slc17a6 (VGLUT2) expression in the mouse hippocampus. These effects are observed following a relatively moderate exposure that is restricted to early pregnancy, modelling human consumption of alcohol before pregnancy is confirmed, and are only apparent in male offspring in adulthood. Our findings are consistent with the idea that altered epigenetic and/or microRNA-mediated regulation of glutamate neurotransmission in the hippocampus contributes to the cognitive and behavioural phenotypes observed in foetal alcohol spectrum disorders. Although further work is needed in both mice and humans, the results also suggest that circulating microRNAs could be used as biomarkers of early gestational ethanol exposure and hippocampal dysfunction. PMID- 26421063 TI - Transgelin gene is frequently downregulated by promoter DNA hypermethylation in breast cancer. AB - BACKGROUND: CpG hypermethylation in gene promoters is a frequent mechanism of tumor suppressor gene silencing in various types of cancers. It usually occurs at early steps of cancer progression and can be detected easily, giving rise to development of promising biomarkers for both detection and progression of cancer, including breast cancer. 5-aza-2'-deoxycytidine (AZA) is a DNA demethylating and anti-cancer agent resulting in induction of genes suppressed via DNA hypermethylation. RESULTS: Using microarray expression profiling of AZA- or DMSO treated breast cancer and non-tumorigenic breast (NTB) cells, we identified for the first time TAGLN gene as a target of DNA hypermethylation in breast cancer. TAGLN expression was significantly and frequently downregulated via promoter DNA hypermethylation in breast cancer cells compared to NTB cells, and also in 13/21 (61.9 %) of breast tumors compared to matched normal tissues. Analyses of public microarray methylation data showed that TAGLN was also hypermethylated in 63.02 % of tumors compared to normal tissues; relapse-free survival of patients was worse with higher TAGLN methylation; and methylation levels could discriminate between tumors and healthy tissues with 83.14 % sensitivity and 100 % specificity. Additionally, qRT-PCR and immunohistochemistry experiments showed that TAGLN expression was significantly downregulated in two more independent sets of breast tumors compared to normal tissues and was lower in tumors with poor prognosis. Colony formation was increased in TAGLN silenced NTB cells, while decreased in overexpressing BC cells. CONCLUSIONS: TAGLN gene is frequently downregulated by DNA hypermethylation, and TAGLN promoter methylation profiles could serve as a future diagnostic biomarker, with possible clinical impact regarding the prognosis in breast cancer. PMID- 26421064 TI - Analysis of DNA methylation landscape reveals the roles of DNA methylation in the regulation of drug metabolizing enzymes. AB - BACKGROUND: Drug metabolizing enzymes (DMEs) exhibit dramatic inter- and intra individual variability in expression and activity. However, the mechanisms determining this variability have not been fully elucidated. The aim of this study was to evaluate the biological significance of DNA methylation in the regulation of DME genes by genome-wide integrative analysis. RESULTS: DNA methylation and mRNA expression profiles of human tissues and hepatoma cells were examined by microarrays. The data were combined with GEO datasets of liver tissues, and integrative analysis was performed on selected DME genes. Detailed DNA methylation statuses at individual CpG sites were evaluated by DNA methylation mapping. From analysis of 20 liver tissues, highly variable DNA methylation was observed in 37 DME genes, 7 of which showed significant inverse correlations between DNA methylation and mRNA expression. In hepatoma cells, treatment with a demethylating agent resulted in upregulation of 5 DME genes, which could be explained by DNA methylation status. Interestingly, some DMEs were suggested to act as tumor-suppressor or housekeeper based on their unique DNA methylation features. Moreover, tissue-specific and age-dependent expression of UDP-glucuronosyltransferase 1A splicing variants was associated with DNA methylation status of individual first exons. CONCLUSIONS: Some DME genes were regulated by DNA methylation, potentially resulting in inter- and intra individual differences in drug metabolism. Analysis of DNA methylation landscape facilitated elucidation of the role of DNA methylation in the regulation of DME genes, such as mediator of inter-individual variability, guide for correct alternative splicing, and potential tumor-suppressor or housekeeper. PMID- 26421065 TI - Is Endovascular Aneurysm Repair a Relative Contraindication for Patients with Preoperative Renal Dysfunction? AB - Whether endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA) is a relative contraindication in patients with preoperative renal dysfunction (Pre-RD), remains controversial because the contrast medium may induce nephrotoxicity. In this study 1658 patients were treated at ten Japanese medical centers between January 2005 and March 2011 (Open surgery (OS) vs. EVAR: n = 1270 vs. n = 388). They were retrospectively analyzed. Multiple logistic regression analysis (MLRA) with pre- and intra-operative variables was applied to all patients. The endpoints induced onset of new dialysis and postoperative renal dysfunction (Post-RD), were defined as a 50% decrease or more from the preoperative estimated glomerular filtration rate (eGFR) level. RESULTS: Early mortality, Post-RD, incidence of new dialysis in all patients were 1.6% (OS: EVAR = 1.9%:0.8%), 6% (OS: EVAR = 8%:2.3%) and 1.4% (OS: EVAR = 1.5%:1.0%) respectively. MLRA identified operation time, clamp of renal artery as risk factors for Post-RD, and operation time and Pre-eGFR level as risk factors for new dialysis. CONCLUSION: Although Post-RD was more frequently observed in the OS group, MLRA showed that the choice of OS or EVAR was not a risk factor for Post RD and new dialysis. It was strongly suggested that using contrast medium during EVAR is not a contraindication to AAA repair in patients with Pre-RD. (This article is a translation of J Jpn Coll Angiol 2014; 54: 13-18.). PMID- 26421066 TI - Long-Term Results of Treatment for Critical Limb Ischemia. AB - From 2001 to 2012, arterial reconstruction was performed in 306 out of 497 limbs (62%) with critical limb ischemia. The reasons for non-vascularization include high operative risk (36%), extended necrosis or infection (20%), and technical issues (15%). Cumulative patency and limb salvage in collagen disease were significantly worse compared to arteriosclerosis obliterans. Cumulative limb salvage, amputation free survival (AFS), and major adverse limb event and perioperative death (MALE + POD) in patients with end-stage renal disease (ESRD) were significantly worse compared to patients without ESRD, but not significant with regards to graft patency. Our finding suggests that aggressive arterial reconstruction provides satisfactory long-term results in critical limb ischemia so long as case selection for revascularization is properly made. (This article is a translation of J Jpn Coll Angiol 2014; 54: 5-11.). PMID- 26421067 TI - Efficacy of Ultrasonography at the Ankle Level for Estimation of Pedal Microcirculation. AB - Chronic wounds due to diabetes mellitus (DM) and/or peripheral arterial disease (PAD) often occur in the pedal region peripheral to the ankle. To predict wound healing potential of limb ulcers, skin perfusion pressure (SPP) and transcutaneous oxygen tension (TcPO2) have recently become popular as the parameters that reflect skin microcirculation. On the other hand, ultrasonography for the macrocirculatory vessels has already prevailed widely as the standard vascular investigation. The skin microcirculation peripheral to the ankle probably depends on the macrocirculatory blood flow at the ankle level. Thus, this study aims to estimate whether the blood flow of the anterior tibial artery (ATA) and the posterior tibial artery, at the ankle level, reflect the values of SPP and TcPO2 on the foot. The protocol enrolled 88 patients (122 limbs) with foot ulcers due to DM and/or PAD. The statistical analysis revealed that the sum of blood flow of the ATA and the PTA (posterior tibial artery), at the ankle level, significantly correlated with SPP on the foot. The findings support the availability of conventional ultrasonographic investigation to estimate microcirculation of the foot crucial for wound healing. (This article is a translation of J Jpn Coll Angiol 2014; 54: 45-50.). PMID- 26421068 TI - Occurrence of Deep Vein Thrombosis among Hospitalized Non-Surgical Japanese Patients. AB - OBJECTIVE: To estimate the frequency of deep vein thrombosis (DVT) among non surgical inpatients, and to evaluate the D-dimer assay as a screening tool for DVT. METHODS: Subjects were non-surgical inpatients aged 20 years or older who had been bedridden for at least 24 hours and had moderate-to-high risk factors for DVT. We assessed the presence of DVT by venous ultrasonography. Patients who received a diagnosis of venous thromboembolism (VTE) before admission, who had symptoms or findings of VTE at admission, or who had surgery or trauma within the past 3 months before admission were excluded. RESULTS: DVT was confirmed in 96 of 525 patients (18.3%). In a logistic regression analysis, longer duration of hospitalization, higher D-dimer value, and history of cancer surgery were significantly associated with the occurrence of DVT. The D-dimer assay showed high sensitivity (96.1%) and high negative predictive value (97.6%). CONCLUSION: Non-surgical inpatients with a long-term hospitalization or history of cancer surgery have a risk for DVT, and need to be considered for added DVT preventive measures as recommended in the prevention guidelines. In addition, the D-dimer assay is beneficial for the screening of DVT in medical practice. PMID- 26421069 TI - Open Surgical Repair Can Be One Option for the Treatment of Persistent Type II Endoleak after EVAR. AB - PURPOSES: Endovascular abdominal aortic aneurysm repair (EVAR) is an increasingly used method of repairing abdominal aortic aneurysm (AAA). However, the treatment of persistent type II endoleak is still a controversial issue. Five cases are reported here in which we performed open surgical repair of growing aneurysm due to persistent type II endoleak. METHOD: Totally 128 EVAR cases were retrospectively reviewed, which were operated in our hospital from April 2008 to October 2013. These cases were followed by periodical contrast-enhanced computed tomography (CT) after EVAR. When persistent type II endoleak caused aneurysm sac growth, we performed surgical repair method for the first line treatment. In the operation, we incised the aneurysm sac by abdominal small median incision approach and sutured lumber arteries from inside of aneurysm sac and tied inferior mesenteric artery (IMA) in addition to aneurysmorrhaphy. Contrast enhanced CT scanning was performed in a week after open repair for the confirmation of complete treatment. RESULTS: Five of 128 cases (3.9%) were needed to be surgically repaired because of aneurysm sac growth (>5 mm), including two ruptured AAA cases. All patients recovered uneventfully. Contrast-enhanced CT scanning performed a week after these operations showed no endoleak and intact stent grafts and reduction of the aneurysm size. CONCLUSION: We believe open surgical repair method of persistent type II endoleak with aneurysm expansion is secure method, and can be one of the preferable options for this life threatening complication after EVAR. PMID- 26421070 TI - Pre- and Intraoperative Predictors of Delirium after Open Abdominal Aortic Aneurysm Repair. AB - OBJECTIVES: We reviewed our series of patients who underwent open abdominal aortic aneurysm (AAA) repair and constructed a prediction model for postoperative delirium. METHODS: 397 patients who underwent open AAA repair at our institution between April 2005 and June 2013 were retrospectively reviewed. Postoperative delirium was diagnosed from the patients' medical records according to the Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV) criteria. Mental alterations resulting from postoperative cerebrovascular events or preexisting mental disorders were excluded. Parameters with significant differences on univariate analysis were subjected to a logistic regression analysis. RESULTS: There were 46 patients (11.5%) diagnosed with postoperative delirium. The following parameters were significant in the univariate analysis: age, history of stroke, hyperlipidemia, forced expiratory volume in 1 s (FEV1), percent vital capacity (%VC), and blood urea nitrogen (BUN) level. A logistic regression analysis revealed that an age >=70 years (odds ratio [95% confidence interval], 3.342 [1.437-7.774]), blood loss >=1517 mL (2.707 [1.359-5.391]), and the absence of hyperlipidemia (2.154 [1.060-4.374]) were significant risk factors. CONCLUSIONS: Older patients with substantial intraoperative blood loss require highly vigilant postoperative care. Further studies are necessary to elucidate the relationship between cholesterol and delirium. PMID- 26421071 TI - Popliteal Retrograde Approach is Effective and Safe for Superficial Femoral Artery Chronic Total Occlusion. AB - OBJECTIVE: Endovascular treatment (EVT) using a popliteal approach is effective for superficial femoral artery (SFA) chronic total occlusion (CTO); however, its effectiveness, safety, and consequent complications are unclear. MATERIALS AND METHODS: We studied 324 consecutive EVTs (in 187 patients) performed at three centers between April 2008 and March 2013, and selected all EVTs that included SFA CTO regions. A total of 91 EVTs (in 65 patients) were included and divided into two groups; "with popliteal approach" (WPA) and "without popliteal approach" (WOPA). RESULTS: Despite higher rates of hypertension (WPA, 88.9% vs. WOPA, 69.1%; p = 0.04) and CTO length >200 mm (55.6% vs. 28.3%, respectively; p <0.01), the primary success rate was better in the WPA group (97.2% vs. 78.2%, respectively; p <0.01); however, both total complication rate and major complication rate were not significantly different. We compared popliteal puncture using a sheath and using a microcatheter alone. There were no significant differences between sheath and microcatheter use in terms of primary success rates (95.5% vs. 100%, respectively; p = 0.61) and puncture site complications (22.7% vs. 14.2%, respectively; p = 0.53). CONCLUSION: A popliteal approach improved the primary success rate of EVT for SFA CTO. PMID- 26421072 TI - Ankle-Brachial Index, Toe-Brachial Index, and Pulse Volume Recording in Healthy Young Adults. AB - OBJECTIVE: To clarify the characteristics of ankle-brachial index (ABI), toe brachial index (TBI), and pulse volume recording (PVR) of the ankle with brachial ankle pulse wave velocity (baPWV) in healthy young adults. MATERIAL AND METHODS: We analyzed ABI, TBI, baPWV, and PVR in the ankle of healthy adults aged 20 to 25 years (median, 20 years) using an automatic oscillometric device between 2002 and 2013. The ABI, baPWV, and PVR in 1282 legs of 641 subjects (301 men and 340 women) and the TBI in 474 toes of 237 subjects (117 men and 120 women) were evaluated. RESULTS: The measured values showed no bilateral differences. ABI and baPWV were higher in men than in women, but TBI was similar in both sexes. ABI <1.0 was observed in 18.1% of the legs in men and in 25.6% in women. TBI <0.7 was observed in 16.2% of the toes in men and 19.1% in women. For ankle PVR, the % mean arterial pressure was higher in women than in men. The upstroke time was <180 ms in most subjects. CONCLUSIONS: For young people, ABI <1.0 or TBI <0.7 may not always indicate vascular abnormalities. When evaluating circulatory indexes, age and sex should be considered. PMID- 26421073 TI - Accuracy of Venous Filling Index on Standing (VFIst) and Pure Regurgitation Index (PRI), a Novel Index Obtained by Air Plethysmography, for Detecting Venous Reflux. AB - OBJECTIVE: To evaluate the accuracy of venous filling index on standing (VFIst) and a new index named pure regurgitation index (PRI), obtained by air plethysmography, for detecting venous reflux. MATERIALS AND METHODS: One hundred and sixty-one healthy subjects (161 limbs) and 180 varicose vein patients (180 limbs) were investigated. All subjects underwent duplex ultrasonography for verifying venous reflux and air plethysmography to obtain hemodynamic parameters such as VFIst, VFI in the supine position (VFIsu), and the maximum arterial inflow rate. To evaluate the accuracy of VFIst and PRI (= (VFIst - VFIsu)/body mass index), receiver operating characteristics curves were created. RESULTS: The optimal cut-off value, sensitivity, specificity, and area under the curve, obtained from analyzing the receiver operating characteristics curves, of VFIst vs. PRI were 2.058 mL/s vs. 0.059 mL . m(2)/s . kg, 93.3% vs. 90.3%, 88.8% vs. 91.3%, and 0.954 vs. 0.964, respectively. CONCLUSIONS: This study indicates that while both VFIst and PRI are highly accurate indicators of venous reflux, PRI, which is not affected by the arterial inflow rate and body mass index, is slightly superior to VFIst, especially in subjects with greater body mass index. PMID- 26421074 TI - Operative Management of Hilar Renal Artery Aneurysm in a Pregnant Patient. AB - Complications of renal artery aneurysms (RAAs) can be life threatening and include the spontaneous rupture which may lead to severe retroperitoneal hemorrhage, loss of the kidney, or death. As the incidence and diagnosis of RAAs is expected to rise, it is becoming increasingly important to enhance our awareness and knowledge of this rare clinical entity. Here, we present the case of a hilar right RAA and the surgical approach for primary repair during the postpartum period. Additionally, we discuss current pathophysiologic mechanisms, associated symptoms as well as current treatment modalities for RAAs. PMID- 26421075 TI - Extra-Anatomic Bypass Operation for an Infected Aortic Arch Aneurysm with Broad Mediastinal Abscess: A Case Report. AB - We encountered an informative case of infected aortic arch aneurysm. The proximal descending aorta, left common carotid artery, and left subclavian artery were severely involved in an abscess; thus, typical in situ reconstruction of the arch was considered impossible. Therefore, to secure more distal branches appropriate for anastomosis, a modified extra-anatomic arch repair was performed through additional incisions. The patient developed renal and respiratory failure and died of septicemia five and a half months after the operation. However, postoperative computed tomograms demonstrated that the abscess had disappeared. PMID- 26421076 TI - Effectiveness of the Use of Near-Infrared Spectroscopy to Treat Acute Type A Aortic Dissection Complicated with Limb Ischemia: Report of a Case. AB - We report an effectiveness of the use of near-infrared spectroscopy to evaluate the limb perfusion, which helps to continuously measure the tissue oxygen index of bilateral legs in treating acute type A aortic dissection complicated with limb ischemia. A 62-year-old man underwent total arch replacement for acute type A aortic dissection with limb ischemia. Intraoperative retrograde true lumen perfusion via bilateral femoral arteries during cardiopulmonary bypass improved ischemic condition of bilateral legs before the resection of primary intimal tear, and the use of near-infrared spectroscopy made it possible to assess additional revascularizations to the lower limbs were required or not. PMID- 26421077 TI - Repair of Acute Type B Aortic Dissection Complicated by Aortic Rupture with Debranching Thoracic Endovascular Aortic Repair and Left Subclavian Artery Occlusion Using Amplatzer Vascular Plug II. AB - An 88-year-old man with severe chest pain and syncope was admitted to our hospital. Contrast-enhanced computed tomography (CT) revealed acute type B aortic dissection with rupture. Considering age and operative risk, we performed emergency thoracic aortic endovascular repair with two-debranching of the left common carotid and left subclavian arteries. To prevent type II endoleak, we used Amplatzer Vascular Plug (AVP) II for left subclavian artery embolization. Postoperative contrast-enhanced CT showed no type II endoleak and rupture site exclusion. As postoperative persistent blood flow to the primary entry or rupture site causes re-rupture, AVP II was crucial in preventing type II endoleak. PMID- 26421078 TI - Delayed Intestinal Ischemia after Surgery for Type A Acute Aortic Dissection. AB - We report a rare case of delayed intestinal ischemia after total arch replacement for type A acute aortic dissection. At the onset of acute aortic dissection, computed tomography (CT) angiography revealed celiac trunk occlusion and progressive dissection into the superior mesenteric artery without stenosis. However, following total arch replacement, visceral malperfusion was not detected by exploratory laparotomy. On postoperative day 12, the patient developed paralytic ileus without an elevated lactate level. CT angiography revealed new superior mesenteric artery stenosis by a thrombosed false lumen with persistent celiac trunk occlusion. Endovascular treatment including stent implantation resolved intestinal ischemia. PMID- 26421079 TI - Open Surgical Bypass for Superficial Femoral Artery Occlusion Caused by Blunt Trauma. AB - Blunt vascular trauma of the lower extremities brings about a high amputation rate, because other organ injuries disturb revascularization. We experienced a case of a superficial femoral artery occlusion caused by blunt trauma. The patient also had a femoral bone fracture and a large skin defect with deep muscular injuries of the thigh. We performed a femoropopliteal (FP) bypass using a saphenous vein which was routed through the contaminated wound. Postoperative vacuum-assisted closure therapy was used to prevent graft infection. Surgical bypasses using saphenous veins are approved treatments for arterial occlusions from blunt trauma if the grafts go through contaminated wounds. PMID- 26421080 TI - Unusual Cases of Hypothenar Hammer Syndrome. AB - OBJECTIVE: Hypothenar hammer syndrome (HHS) is a rare occupational disease. The risk group of HHS is patient whose dominate hand used as a hammer. Our study report unusually cases in Chiang Mai University Hospital. RESULT: 19 year-old basketball player had right ulnar artery aneurysm for two months. After operation, his symptom was relieved and returned to play basketball again. 65 year-old housekeeper had non-dominated hand ulnar artery aneurysm for two years. After operation she still had hand claudication due to poor run-off vessel. CONCLUSION: HHS is previously state in risk group. But from our report there was a risk in different occupation. PMID- 26421081 TI - Open Surgery for Giant Bilateral Internal Iliac Artery Aneurysms with Compression of Neighboring Abdominal Structures: A Case Report. AB - We describe a patient with successfully treated giant bilateral internal iliac artery aneurysms that were associated with acute renal failure secondary to bilateral hydronephrosis, lumbosacral plexopathy, and ileus. After hemodialysis for 1 month, the patient underwent graft replacement of the abdominal aorta and iliac arteries, including complete obliteration of the internal iliac artery branches, reconstruction of the inferior mesenteric artery, and ureterolysis. Weaning from hemodialysis was achieved and postoperative renal function improved. Although the patient had serious preoperative co-morbidities, emergency traditional open surgery should be the gold standard for securely releasing compression of the neighboring organs instead of endovascular treatment. PMID- 26421082 TI - Early Stent Graft Perforation after Endovascular Repair for Pseudoaneurysm That Was Associated with Clavicle Nonunion. AB - We report the case of a 62-year-old man who experienced a left axillary artery pseudoaneurysm that was secondary to nonunion of a 30-year-old left midshaft clavicle fracture. He initially underwent endovascular repair using a self expanding nitinol stent graft, which was perforated at postoperative day 5. Therefore, we performed open repair with concomitant clavicle resection, and no complications were observed during an approximately 6-year follow-up. We recommend performing clavicle resection with vascular repair to prevent recurrence in similar cases. PMID- 26421083 TI - Surgical Treatment of a Giant Right Hepatic Artery Aneurysm with an Aberrant Left Hepatic Artery: Report of a Case. AB - Hepatic artery aneurysms are rare. We describe a case of a successful surgical treatment of a giant hepatic aneurysm without revascularization. A 63-year-old female was admitted to our department complaining of abdominal pain. Computed tomography showed a thrombosed hepatic artery aneurysm measuring 5.5 cm in diameter. A celiac angiography revealed an aberrant left hepatic artery and a right hepatic aneurysm. Liver blood flow and the right hepatic aneurysm were visualized via collateral pathway from the aberrant left hepatic artery. We performed an aneurysmorrhaphy without revascularization. Postoperative course was uneventful and the patient is doing well 3 months after surgery. PMID- 26421084 TI - Embodied Information in Cognitive Tasks: Haptic Weight Sensations Affect Task Performance and Processing Style. AB - Research in the field of embodied cognition showed that incidental weight sensations influence peoples' judgments about a variety of issues and objects. Most studies found that heaviness compared to lightness increases the perception of importance, seriousness, and potency. In two experiments, we broadened this scope by investigating the impact of weight sensations on cognitive performance. In Experiment 1, we found that the performance in an anagram task was reduced when participants held a heavy versus a light clipboard in their hands. Reduced performance was accompanied by an increase in the perceived effort. In Experiment 2, a heavy clipboard elicited a specific response heuristic in a two-alternative forced-choice task. Participants showed a significant right side bias when holding a heavy clipboard in their hands. After the task, participants in the heavy clipboard condition reported to be more frustrated than participants in the light clipboard condition. In both experiments, we did not find evidence for mediated effects that had been proposed by previous literature. Overall, the results indicate that weight effects go beyond judgment formation and highlight new avenues for future research. PMID- 26421085 TI - The Influence of Motor Imagery on Postural Sway: Differential Effects of Type of Body Movement and Person Perspective. AB - The present study examined the differential effects of kinesthetic imagery (first person perspective) and visual imagery (third person perspective) on postural sway during quiet standing. Based on an embodied cognition perspective, the authors predicted that kinesthetic imagery would lead to activations in movement relevant motor systems to a greater degree than visual imagery. This prediction was tested among 30 participants who imagined various motor activities from different visual perspectives while standing on a strain gauge plate. The results showed that kinesthetic imagery of lower body movements, but not of upper body movements, had clear effects on postural parameters (sway path length and frequency contents of sway). Visual imagery, in contrast, had no reliable effects on postural activity. We also found that postural effects were not affected by the vividness of imagery. The results suggest that during kinesthetic motor imagery participants partially simulated (re-activated) the imagined movements, leading to unintentional postural adjustments. These findings are consistent with an embodied cognition perspective on motor imagery. PMID- 26421086 TI - Preface to Special Topic: Microfluidics in Drug Delivery. AB - In this special topic of Biomicrofluidics, the importance of microfluidics in the field of drug delivery is highlighted. Different aspects from cell-drug carrier interactions, delivery vehicle assembly to novel drug delivery devices are considered. The contributing reviews and original articles illustrate the synergistic outcomes between these two areas of research with the aim to have a positive impact on biomedical applications. PMID- 26421087 TI - An off-the-shelf integrated microfluidic device comprising self-assembled monolayers for protein array experiments. AB - Microfluidic-based protein arrays are promising tools for life sciences, with increased sensitivity and specificity. One of the drawbacks of this technology is the need to create fresh surface chemistry for protein immobilization at the beginning of each experiment. In this work, we attempted to include the process of surface functionalization as part of the fabrication of the device, which would substitute the time consuming step of surface functionalization at the beginning of each protein array experiment. To this end, we employed a novel surface modification using self-assembled monolayers (SAMs) to immobilize biomolecules within the channels of a polydimethylsiloxane (PDMS) integrated microfluidic device. As a model, we present a general method for depositing siloxane-anchored SAMs, with 1-undecyl-thioacetate-trichlorosilane (C11TA) on the silica surfaces. The process involved developing PDMS-compatible conditions for both SAM deposition and functional group activation. We successfully demonstrated the ability to produce, within an integrated microfluidic channel, a C11TA monolayer with a covalently conjugated antibody. The antibody could then bind its antigen with a high signal to background ratio. We further demonstrated that the antibody was still active after storage of the device for a week. Integration of the surface chemistry into the device as part of its fabrication process has potential to significantly simplify and shorten many experimental procedures involving microfluidic-based protein arrays. In turn, this will allow for broader dissemination of this important technology. PMID- 26421088 TI - Microfluidic sampling system for tissue analytics. AB - We have developed a microfluidics based sampling system for tissue analytics. The proof-of-concept of the sampling system was demonstrated by extracting lipid samples from tissue biopsies. The sample collection system consists of a disposable silicon based multiport microneedle integrated with polymer microfluidics. The polymethyl methacrylate polymer microfluidic chip has a 10 MUl sample reservoir and actuation membranes for liquid pumping. A special automated robotic system was developed to control the positioning of the needle and the sampling procedure on preselected spots on the tissue. Real breast cancer tissue samples were used to test the feasibility of the sampling system. We successfully measured indicative cancer biomarkers from the tissue surface. Phosphatidylcholine and phosphoethanolamine were extracted from the tissue membrane with methyl tert-butyl ether solvent and detected by mass spectrometry. In the future, this tool could be used in characterization of preoperative biopsies and tumour tissues removed during surgery. PMID- 26421089 TI - An On-Site Thermoelectric Cooling Device for Cryotherapy and Control of Skin Blood Flow. AB - Cryotherapy involves the surface application of low temperatures to enhance the healing of soft tissue injuries. Typical devices embody a remote source of chilled water that is pumped through a circulation bladder placed on the treatment site. In contrast, the present device uses thermoelectric refrigeration modules to bring the cooling source directly to the tissue to be treated, thereby achieving significant improvements in control of therapeutic temperature while having a reduced size and weight. A prototype system was applied to test an oscillating cooling and heating protocol for efficacy in regulating skin blood perfusion in the treatment area. Data on 12 human subjects indicate that thermoelectric coolers (TECs) delivered significant and sustainable changes in perfusion for both heating (increase by (+/-SE) 173.0 +/- 66.0%, P < 0.005) and cooling (decrease by (+/-SE) 57.7 +/- 4.2%, P < 0.0005), thus supporting the feasibility of a TEC-based device for cryotherapy with local temperature regulation. PMID- 26421090 TI - Design of Novel Mixer and Applicator for Two-Component Surgical Adhesives. AB - Current mixer and applicator devices on the market are not able to properly and efficiently mix two-component surgical adhesives in small volumes necessary to achieve economic viability. Furthermore, in these devices a significant amount of adhesive is wasted during the application process, as material within the dead space of the mixing chamber must be discarded. We have designed and demonstrated a new active mixer and applicator system capable of rapidly and efficiently mixing two components of an adhesive and applying it to the surgical site. Recently, Messersmith et al. have developed a tissue adhesive inspired by the mussel byssus and have shown that it is effective as a surgical sealant, and is especially suited for wet environments such as in fetal surgery. Like some other tissue sealants, this one requires that two components of differing viscosities be thoroughly mixed within a specified and short time period. Through a combination of compression and shear testing, we demonstrated that our device could effectively mix the adhesive developed by Messersmith et al. and improve its shear strength to significantly higher values than what has been reported for vortex mixing. Overall, our mixer and applicator system not only has potential applications in mixing and applying various adhesives in multiple surgical fields but also makes this particular adhesive viable for clinical use. PMID- 26421091 TI - Atypical Spitz Nevi: A Case Report and Review of the Literature. AB - A case of atypical ("pagetoid") compound Spitz nevus on the face of a 2-year-old girl is reported with a review of the literature. The nevus was composed of broad but laterally demarcated compound proliferation of enlarged fusiform and epithelioid melanocytes, with florid pagetoid scatter above the junction. Immunohistochemical analyses revealed the Ki-67 proliferation index to be relatively low. Given the histomorphological overlap with melanoma, an array based comparative genomic hybridization approach revealed a subthreshold gain in chromosome 1q and gain in distal chromosome 17q, with no other associated chromosomal gains or losses. These molecular aberrations suggested a partially transformed tumor, without adequate evidence for a molecular diagnosis of melanoma. Because of the diagnostic dilemma posed by these lesions, recent research has focused on molecular alterations that may help differentiate Spitz tumors from malignant melanomas. PMID- 26421092 TI - Intraoperative Chemosis During Resection of Lower Eyelid Lesion. PMID- 26421093 TI - Unilateral Swollen Hand: A Rare Case of Primary Lymphedema Tarda. PMID- 26421094 TI - [Neurological complication in rheumatoid arthritis: tetraparesia by C1-C2 dislocation]. PMID- 26421095 TI - [Angiographic appearance of angioid streaks complicated by bilateral choroidal neovascularization]. PMID- 26421096 TI - Designing text-messaging (SMS) in HIV programs: ethics-framed recommendations from the field. AB - Text messages (SMS) are being increasingly integrated into HIV programs across Southern Africa to improve patient adherence, linkage to care and provide psycho social support. Careful attention needs to be paid to the design of SMS-based interventions for clients of HIV-care services to ensure that any potential harm, such as unwanted disclosure of HIV status, is minimized. In this article we propose a set of best practice recommendations to ensure that any SMS-based intervention considers ethical principles to safeguard safety, autonomy and confidentiality of its targeted HIV-positive beneficiaries. This analysis draws from our operational experience in Southern Africa in the design and conduct of mHealth interventions in the frame of HIV projects. The recommendations, framed in the context of the Belmont Report's three ethical pillars, may contribute to more safely operationalize any SMS service integrated into an HIV program if adopted by mHealth planners and implementers. We encourage actors to report on the ethical and methodological pathways followed when conducting SMS-based innovations to improve the wellbeing and quality provision of HIV-care for their targeted clients. PMID- 26421097 TI - Pneumothorax complicating isolated clavicle fracture. AB - Isolated clavicle fractures are among the commonest of traumatic fractures in the emergency department. Complications of isolated clavicle fractures are rare. Pneumothorax has been described as a complication of a fractured clavicle only rarely in English literature. In all the reported cases, the pneumothorax was treated by a thoracostomy and the clavicle fracture was treated conservatively. In our case, the pneumothorax required a chest drain insertion and the clavicle fracture was treated surgically with good result. PMID- 26421098 TI - [Sickle cell disease and biliary lithiasis - about two observations in Lubumbashi (DR Congo)]. PMID- 26421099 TI - [Secondary pathological fractures of benign tumors in children: about 20 cases]. PMID- 26421100 TI - The clinical pattern of renal diseases in the nephrology in-patient unit of the Yaounde General Hospital in Cameroon: a five-year audit. AB - INTRODUCTION: Kidney diseases are a growing worldwide problem and one of the major public health threats. We analyzed the spectrum of kidney diseases seen over a five-year period in the nephrology in-patient unit of the Yaounde general hospital. METHODS: This was a retrospective analysis of 225 medical records of patients admitted from January 2005 to December 2009 in the unit with a discharge diagnosis of kidney and urinary tract diseases. The first hospitalization was considered for patients admitted several times for the same disease. Socio demographic and clinical patient data were recorded. RESULTS: The patients mean age was 44.8+/-16 years with 135 (60%) males and 211 (93.8%) emergency admissions. All 139 (61.8%) patients with chronic kidney disease (CKD) had chronic renal failure. Acute kidney injury (AKI) (28%), nephrotic syndrome (7.6%), renal colic (1.3%) and acute pyelonephritis (1.3%) were other patterns observed. Chronic glomerulonephritis (25.9%), hypertension (22.3%) and diabetes (20.1%) were the main etiological factors of CKD. All AKI patients were in stage RIFLE-F. AKI was secondary to parenchymal (58.7%), functional (25.4%) and obstructive (15.9%) etiologies. Black water fever (36.4%), sepsis (22.7%), drugs (18.2%), eclampsia (13.6%) and herbal concoctions (9.1%) were the etiologies of acute tubular necrosis while enterocolitis (56.2%), heart failure (31.3%) and digestive hemorrhage (12.5%) were the etiologies of functional AKI. CONCLUSION: The clinical pattern of renal diseases is dominated by advanced CKD and AKI secondary to preventable causes. This study suggests a need for an array of actions including sensitization, continuous medical education and strengthening of the health system. PMID- 26421101 TI - Acute carpal tunnel syndrome of the hand following a cat bite. AB - Cat bites at the hand are common situation in emergency departments. Neglected or poorly supported, these lesions sometimes lead to serious injuries that may compromise the function of the hand. Pasteurellamultocida is the most offending germ in these lesions, despite their sensitivity to antibiotics; it can sometimes lead to deep infections involving the skin, bones and joints. Acute carpal tunnel syndrome is exceptional after cat bite. We report a case of a 56 Year old female presenting with an acute carpal tunnel syndrome associated with compartment syndrome of the right hand 6 days after a cat bite of her right thumb. The patient was treated by surgery to relieve the median nerve. Microbiology identified PasteurellaMultocida. PMID- 26421102 TI - Knee megaprosthesis: a salvage solution for severe open and complex distal femoral fracture associated with an ipsilateral brachial plexus injury (a case report with literature review). AB - Complex distal femoral fractures in the young patient often occur as a result of high velocity trauma. Timely recognition and treatment is everything in such a situation, and it needs a robust staged management pathway to optimize the chance of limb preservation. We report a case of a motorcyclist admitted to the department of orthopedics at Chambery hospital, France, with a complex comminuted and open distal femoral fracture of the left leg, associated with a brachial plexus injury to the ipsilateral upper limb. On arrival to the emergency department, damage control stabilization and surgery was commenced, debridement of contaminated non-viable tissue, abundant antiseptic lavage and application of external fixation coupled with the use of antibiotic spacer. Following normalization of inflammatory markers and ensuring no clinical signs of infection, subsequent management consisted of joint reconstruction to achieve a functional knee. The external fixator and femoral spacer was removed and a modular megaprosthesis was implanted with a lateral gastrocnemius flap to cover the exposed knee joint and reinforce the extensor apparatus. Nerve graft to the left brachial plexus injury was performed at University Hospital of Grenoble. Our patient entered an intensive rehabilitation program and at 1 year follow-up achieved good knee function and sensation to the left upper limb. PMID- 26421103 TI - Genome sequence of a native-feather degrading extremely thermophilic Eubacterium, Fervidobacterium islandicum AW-1. AB - Fervidobacterium islandicum AW-1 (KCTC 4680) is an extremely thermophilic anaerobe isolated from a hot spring in Indonesia. This bacterium could degrade native chicken feathers completely at 70 degrees C within 48 h, which is of potential importance on the basis of relevant environmental and agricultural issues in bioremediation and development of eco-friendly bioprocesses for the treatment of native feathers. However, its genomic and phylogenetic analysis remains unclear. Here, we report the high-quality draft genome sequence of an extremely thermophilic anaerobe, F. islandicum AW-1. The genome consists of 2,359,755 bp, which encodes 2,184 protein-coding genes and 64 RNA-encoding genes. This may reveal insights into anaerobic metabolism for keratin degradation and also provide a biological option for poultry waste treatments. PMID- 26421104 TI - High-resolution anoscopy: Unchartered territory for gastroenterologists? AB - High-resolution anoscopy (HRA) is a procedure where patients with an increased risk of anal cancer, like men who have sex with men, human immunodeficiency virus infected individuals, transplant patients and women with a history of lower genital tract neoplasia, with abnormal anal cytology results, are submitted to anal and perianal visualization under magnification. This will allow for a better detection of anal high-grade lesions that can be treated, in an effort to prevent anal cancer. Anal cancer screening follows the same principles that cervical cancer screening. During this procedure, an anoscope is inserted and a colposcope is used to examine systematically the squamocolumnar junction, the transformation zone and the perianal skin. Initially the observation is done with no staining and then with the application of acetic acid and Lugol's iodine solution, allowing for better lesion identification and characterization. Any suspicious lesion seen should be carefully evaluated and biopsied. Without HRA only a small percentage of suspicious lesions are identified. High-grade lesions that are detected can be ablated under HRA. This is a challenging exam to perform, with a long learning curve and the number of clinicians performing it is limited, although the growing number of patients that need to been screened. Specific equipment is required, with these patients ideally been followed by a multidisciplinary team, in a reference centre. HRA remains unfamiliar for many gastroenterologists. PMID- 26421105 TI - Upper non-variceal gastrointestinal bleeding - review the effectiveness of endoscopic hemostasis methods. AB - Upper non-variceal gastrointestinal bleeding is a condition that requires immediate medical intervention and has a high associated mortality rate (exceeding 10%). The vast majority of upper gastrointestinal bleeding cases are due to peptic ulcers. Helicobacter pylori infection, non-steroidal anti inflammatory drugs and aspirin are the main risk factors for peptic ulcer disease. Endoscopic therapy has generally been recommended as the first-line treatment for upper gastrointestinal bleeding as it has been shown to reduce recurrent bleeding, the need for surgery and mortality. Early endoscopy (within 24 h of hospital admission) has a greater impact than delayed endoscopy on the length of hospital stay and requirement for blood transfusion. This paper aims to review and compare the efficacy of the types of endoscopic hemostasis most commonly used to control non-variceal gastrointestinal bleeding by pooling data from the literature. PMID- 26421106 TI - Hospitalization for esophageal achalasia in the United States. AB - AIM: To assess the outcome of different treatments in patients admitted for esophageal achalasia in the United States. METHODS: This is a retrospective analysis using the Nationwide Inpatient Sample over an 8-year period (2003-2010). Patients admitted with a primary diagnosis of achalasia were divided into 3 groups based on their treatment: (1) Group 1: patients who underwent Heller myotomy during their hospital stay; (2) Group 2: patients who underwent esophagectomy; and (3) Group 3: patients not undergoing surgical treatment. Primary outcome was in-hospital mortality. Secondary outcomes included length of stay (LOS), discharge destination and total hospital charges. RESULTS: Among 27141 patients admitted with achalasia, nearly half (48.5%) underwent Heller myotomy, 2.5% underwent esophagectomy and 49.0% had endoscopic or other treatment. Patients in group 1 were younger, healthier, and had the lowest mortality when compared with the other two groups. Group 2 had the highest LOS and hospital charges among all groups. Group 3 had the highest mortality (1.2%, P < 0.001) and the lowest home discharge rate (78.8%) when compared to the other groups. The most frequently performed procedures among group 3 were esophageal dilatation (25.9%) and injection (13.3%). Among patients who died in this group the most common associated morbidities included acute respiratory failure, sepsis and aspiration pneumonia. CONCLUSION: Surgery for achalasia carries exceedingly low mortality in the modern era; however, in complicated patients, even less invasive treatments are burdened by significant mortality and morbidity. PMID- 26421107 TI - Triradiate caecal fold: Is it a useful landmark for caecal intubation in colonoscopy? AB - AIM: To determine the frequency of identification of the triradiate fold during colonoscopy and evaluate its reliability as a marker of caecal intubation. METHODS: One hundred consecutive patients undergoing colonoscopy in a tertiary hospital colorectal unit from May to September 2013 were studied. Video documentation of the caecum was recorded and shown to consultant colorectal surgeons on the unit. Each reviewer was asked through a series of questions to independently identify the triradiate fold. The main outcome was the frequency of visualisation of the triradiate fold in the caecum. RESULTS: The triradiate fold was seen on average in 18% of cases, but inter-observer agreement was poor. There were only four patients (4%) in which all reviewers agreed on the presence of a triradiate fold. In patients who had undergone previous appendicectomy, the appendiceal orifice was less frequently seen compared with patients who had not undergone appendicectomy. CONCLUSION: The triradiate fold is infrequently seen during colonoscopy and is therefore an unreliable landmark of caecal intubation. PMID- 26421108 TI - Endoscopic ultrasound guided thrombin injection of angiographically occult pancreatitis associated visceral artery pseudoaneurysms: Case series. AB - Pseudoaneurysm is a known complication of pancreatitis associated with significant mortality and morbidity. Imaging plays an important role in the diagnosis and management. Computed tomography (CT) helps localize the lesion and the severity of the background pancreatitis but digital subtraction angiography with coil embolization is recommended to avoid bleeding and inadvertent surgery. However, in cases where angiographic coil embolization is not feasible due to technical reasons, thrombin injection via CT or ultrasound guidance remains a viable option and often described in literature. In this series, effort has been made to highlight the role of endoscopic ultrasound guided thrombin instillation especially in patients with poorly visualized pseudoaneurysm on ultrasound thereby avoiding surgery and the associated mortality and morbidity. PMID- 26421109 TI - Medical Errors: Why Now and What's Next? PMID- 26421110 TI - Applicability of the Existing CVD Risk Assessment Tools to Type II Diabetics in Oman: A Review. AB - Patients with type II diabetes (T2DM) have an elevated risk for cardiovascular disease (CVD), and it is considered to be a leading cause of morbidity and premature mortality in these patients. Many traditional risk factors such as age, male sex, hypertension, dyslipidemia, glycemic control, diabetes duration, renal dysfunction, obesity, and smoking have been studied and identified as independent factors for CVD. Quantifying the risk of CVD among diabetics using the common risk factors in order to plan the treatment and preventive measures is important in the management of these patients as recommended by many clinical guidelines. Therefore, several risk assessment tools have been developed in different parts of the world for this purpose. These include the tools that have been developed for general populations and considered T2DM as a risk factor, and the tools that have been developed for T2DM populations specifically. However, due to the differences in sociodemographic factors and lifestyle patterns, as well as the differences in the distribution of various CVD risk factors in different diabetic populations, the external applicability of these tools on different populations is questionable. This review aims to address the applicability of the existing CVD risk models to the Omani diabetic population. PMID- 26421111 TI - Stopping Oxytocin in Active Labor Rather Than Continuing it until Delivery: A Viable Option for the Induction of Labor. AB - OBJECTIVE: Induction of labor (IOL), using intravenous oxytocin, is the artificial initiation of labor before its spontaneous onset for the purpose of delivery of the fetoplacental unit. Although there are various studies looking at dosages of oxytocin, only a few have addressed the issue of discontinuation of oxytocin in the active stage of labor. Thus, our study was conducted to evaluate the need for continuation versus discontinuation of oxytocin during active labor. METHODS: This prospective, randomized controlled trial included 106 women who needed IOL. Oxytocin infusion was initiated at a rate of 3mIU/min and was incremental until 4-6cm cervical dilation. At this point the patients were randomly assigned into one of two groups. In group one, oxytocin was discontinued, and infusion was continued with 0.9% sodium chloride solution. In group two, oxytocin was continued at the same dose until delivery. RESULTS: The duration of oxytocin infusion was 5.5 hours in the oxytocin discontinuation group and 11.0 hours in oxytocin continuation group (p<0.001). The total dose of oxytocin was significantly higher in group two (6.1 units vs. 16.5 units; p=<0.001). The induction-delivery interval was significantly less in group one (9.1 and 11.2 hours in group one and group two, respectively; p=0.023). CONCLUSION: Oxytocin discontinuation in the active stage of labor did not prolong the active stage. The total duration of labor and total oxytocin dose were significantly less in the oxytocin discontinuation group. Our results suggest that oxytocin discontinuation is an alternative and viable option particularly in resource poor and economically challenged settings. It not only reduces the need for intense monitoring and prolonged oxytocin use-associated dangers but reduces the total cost of labor management. PMID- 26421112 TI - Association of Hyperglycemia with In-Hospital Mortality and Morbidity in Libyan Patients with Diabetes and Acute Coronary Syndromes. AB - OBJECTIVE: Hyperglycemia on admission and during hospital stay is a well established predictor of short-term and long-term mortality in patients with acute myocardial infarction. Our study investigated the impact of blood glucose levels on admission and in-hospital hyperglycemia on the morbidity and mortality of Libyan patients admitted with acute coronary syndromes (acute myocardial infarction and unstable angina). METHODS: In this retrospective study, the records of patients admitted with acute coronary syndrome to The 7th Of October Hospital, Benghazi, Libya, between January 2011 and December 2011 were reviewed. The level of blood glucose on admission, and the average blood glucose during the hospital stay were recorded to determine their effects on in-hospital complications (e.g. cardiogenic shock, acute heart failure, arrhythmias, and/or heart block) and mortality. RESULTS: During the study period, 121 patients with diabetes were admitted with acute coronary syndrome. The mortality rate in patients with diabetes and acute coronary syndrome was 12.4%. Patients with a mean glucose level greater than 200mg/dL had a higher in-hospital mortality and a higher rate of complications than those with a mean glucose level <=200mg/dL (27.5% vs. 2.6%, p<0.001 and 19.7% vs. 45.5%, p=0.004, respectively). There was no difference in in-hospital mortality between patients with a glucose level at admission <=140mg/dL and those admitted with a glucose level >140mg/dL (6.9% vs. 14.3%; p=0.295), but the rate of complications was higher in the latter group (13.8% vs. 34.1%; p=0.036). Patients with admission glucose levels >140mg/dL also had a higher rate of complications at presentation (26.4% vs. 6.9%; p=0.027). CONCLUSION: In patients with diabetes and acute coronary syndrome, hyperglycemia during hospitalization predicted a worse outcome in terms of the rates of in hospital complications and in-hospital mortality. Hyperglycemia at the time of admission was also associated with higher rate of complications particularly at the time of presentation. PMID- 26421113 TI - Sociodemographic and Clinical Determinants of Time to Care-Seeking Among Febrile Children Under-Five in North-Central Nigeria. AB - OBJECTIVES: Our study sought to determine the time parents of febrile children under the age of five took to seek competent medical care. We also looked at the possible sociodemographic/ clinical factors that influenced this presentation. METHODS: Four hundred and nine under-fives presenting at the emergency unit with a history of fever in the last 48 hours along with their mothers were recruited over four months. Relevant sociodemographic information as well as symptoms and duration of illness were obtained. Multinomial regression analysis was performed to determine the predictors of early and late presentation. RESULTS: Over half (57%) of patients presented within 24 hours of onset of fever. The mean age of the children and mothers were 22+/-15 months and 30+/-5 years, respectively. High social class (odds ratio (OR) 6.5, 95% CI 1.6-26.4), Hausa ethnic group (OR 19.3, 95% CI 5.7-65.6), convulsions (OR 3.2, 95% CI 1.6-6.5) and appearance of other symptoms (OR 6.0, 95% CI 3.0-12.0) were significant predictors of early presentation. Secondary school education, belonging to another ethnic group, and non-resolution of fever were significant predictors of late presentation. CONCLUSION: The majority of febrile under-fives came to the hospital to seek competent medical care within the first 24 hours of illness. However, there is a need for more parental education on early hospital presentation for parents of low socioeconomic status and educational background. PMID- 26421114 TI - A Comparison of Continuous Subcutaneous Insulin Infusion vs. Multiple Daily Insulin Injection in Children with Type I Diabetes in Kuwait: Glycemic Control, Insulin Requirement, and BMI. AB - OBJECTIVE: Continuous subcutaneous insulin infusion (CSII) and multiple daily insulin injections (MDI) are two methods currently used to manage type I diabetes mellitus (T1DM). Here we compare our experiences with CSII and MDI in a large cohort of pediatric patients in Kuwait. METHODS: Data on 326 patients with T1DM who were started on CSII between 2007 and 2012 were retrospectively compared with those of 326 patients on MDI. They were matched for sex, age at diagnosis, T1DM duration, glycemic control, insulin requirement, and body mass index (BMI). Data were collected at baseline and every three months and included glycated hemoglobin (HbA1c), insulin dose, and adverse events (severe hypoglycemia, diabetic ketoacidosis, and skin problems). RESULTS: The main reason for switching to CSII was to achieve better glycemic control (37%), followed by reducing hypoglycemia, and improving the quality of life (13.3% each). Although HbA1c decrease was most significant in the first year, it continued to be significantly lower in the CSII group compared to the MDI throughout the study period. Total daily insulin requirements were significantly lower in the CSII group. BMI increased in both groups, but the difference was significant only at the end of the fifth year. There was no significant change in the rate of diabetic ketoacidosis in either group. The CSII patients had more severe hypoglycemic episodes at baseline; however, it significantly decreased throughout the study period. Only five patients discontinued CSII therapy and two of these restarted within three months. CONCLUSION: CSII is a safe intensive insulin therapy in youngsters with T1DM and achieved markedly fewer severe hypoglycemic episodes and lower daily insulin requirements. PMID- 26421115 TI - Survival Impact of Secondary Cytoreductive Surgery for Recurrent Ovarian Cancer in an Asian Population. AB - OBJECTIVE: The aim of this study was to evaluate the role of secondary cytoreductive surgery in Asian patients with recurrent ovarian cancer and to assess prognostic variables on overall post-recurrence survival time. METHODS: We conducted a retrospective review of patients with recurrent ovarian cancer who underwent secondary cytoreduction at the Gynaecological Cancer Center at the KK Women's and Children's Hospital, Singapore, between 1999 and 2009. Eligible patients included those who had been firstly treated by primary cytoreductive surgery and followed by adjuvant chemotherapy and had a period of clinical remission of at least six months and subsequently underwent secondary cytoreductive surgery for recurrence. Univariate analysis was performed to evaluate various variables influencing the overall survival. RESULTS: Twenty-five patients met our eligibility criteria. The median age was 52 years (range=31-78 years). The median time from completion of primary treatment to recurrence was 25.1 months (range=6.4-83.4). Secondary cytoreduction was optimal in 20 of 25 patients (80%). The median follow-up duration was 38.9 months (range=17.8-72.4) and median overall survival time was 33.1 months (95% confidence interval, 15.3 undefined.). Ten (40.0%) patients required bowel resection, but no end colostomy was performed. One (4.0%) patient had wedge resection of the liver, one (4.0%) had a distal pancreatectomy, one (4.0%) had a unilateral nephrectomy, and one (4.0%) had adrenalectomy. There were no operative deaths. The overall survival of patients who responded to secondary cytoreductive surgery and adjuvant chemotherapy was significantly longer than those patients who did not respond to the treatment. Of those patients who responded to the surgical management, patients with clear cell carcinoma fared well compared to those with the endometrioid, mucinous adenocarcinoma, and papillary serous type (p<0.001). Complete secondary cytoreductive surgery appeared to have some relationship to overall survival but was not statistically significant. CONCLUSION: In carefully selected patients with recurrent ovarian cancer, optimal cytoreductive surgery is possible and in a subgroup of patients who respond to surgery and chemotherapy survival is significantly longer. PMID- 26421116 TI - The Valuable Role of Measuring Serum Lipid Profile in Cancer Progression. AB - OBJECTIVE: Serum lipid levels are not only associated with etiology, but also with prognosis in cancer. To investigate this issue further, we aimed to evaluate the serum levels of lipids in association with the most important prognostic indicators in cancer patients at the start of chemotherapy. METHODS: In a retrospective cross-sectional study, using existing medical records obtained from 2009-2014, the data of all incident cancer cases in Iranian patients referred to the Semnan oncology clinic for chemotherapy were analyzed. Data on demographics, cancer type, prognostic indicators (e.g. lymph node involvement, metastasis, and stage of disease), as well as the patient's lipid profile were collected. We used multiple logistic regression models to show the relationship between prognosis indicators and lipid profile adjusting for age, gender, and type of cancer. RESULTS: The data of 205 patients was gathered. We found a significant difference in the lipid profile between different types of cancers (breast, colon, gastric, and ovarian). With the exception of high-density lipoprotein levels in women, which were higher than in men, the means of other lipid profiles were similar between the genders. There was a significant association between higher levels of low-density lipoprotein (LDL >110mg/dL) in the serum and metastasis (adjusted odds ratio=2.4, 95% CI 1.2-3.5). No significant association was reported between lipid profile and lymph nodes involvement and stage of the disease. CONCLUSION: Our study suggested a benefit of measuring serum levels of lipids for predicting cancer progression. Increased LDL levels can be considered a predictive factor for increasing the risk of metastasis. PMID- 26421117 TI - Prevalence of Chronic Suppurative Otitis Media (CSOM) and Associated Hearing Impairment Among School-aged Children in Yemen. AB - BACKGROUND: Chronic suppurative otitis media (CSOM) is one of the leading causes of preventable disabling hearing impairment (DHI) in developing countries. Early detection and management complements advances made in other survival programs, improves work capacity, and enhances learning opportunities for school children. We aimed to determine the prevalence of CSOM and associated DHI among school children aged six to 16 years in Socotra Island, Yemen. METHODS: We conducted a cross-sectional community-based survey, from 20 April 2011 to 20 June 2011. The study procedures involved completing a questionnaire, an otoscopic ear examination, an audiometric test of hearing, and tuning fork tests for the type of DHI. RESULTS: A total of 686 children were interviewed and examined for CSOM and associated DHI of CSOM cases. The prevalence of CSOM was 7.4%, (95% CI 5.5 9.4). CSOM status was significantly associated with DHI (p=0.001), but no significant associations were found between demographic characteristics and CSOM status. Logistic regression identified four significant independent contributing factors: history of ear discharge in the last 12 months (odds ratio (OR) 7.8, 95% CI 3.9-15.6); swimming in local pools (OR 6.0, 95% CI 1.4-25.4); recurrent respiratory tract infection more than three times per year (OR 5.3, 95% CI 2.5 11.0); and overcrowding with more than three families per house (OR 4.4, 95% CI 1.7-11.5). . CONCLUSION: The burden of CSOM in the children studied indicates a high level of DHI in these communities within Yemen. A history of ear discharge, swimming in local pools, recurrent respiratory infections, and overcrowded housing were the strongest predictors for CSOM. There is a need for better ear care and screening programs for early detection and management of this disease. PMID- 26421118 TI - Non-steroidal Anti-inflammatory Drugs (NSAIDs) Use in Primary Health Care Centers in A'Seeb, Muscat: A Clinical Audit. AB - OBJECTIVE: We sought to assess the trend of non-steroidal anti-inflammatory drug (NSAID) use in primary health care institutions located in A'Seeb, a province in the capital city of Oman, Muscat. Additionally, we evaluated the relationship between a physician's years of experience and the number of prescription issued, as well as the presence of risk factors and side effects in the patients who received these prescriptions. METHOD: A clinical audit was conducted in four primary health care centers in the Muscat region over a one-week period in April 2014. The target population included patients aged 18 years or over who attended one of the four health centers and were prescribed NSAIDs. Overall, 272 patients were recruited by systematic random sampling. The data were collected by two methods: direct face-to-face interviews and evaluations of the patient's electronic medical file. The prescribing doctors were blind to the audit. The collected information included patients demographics, past and current medical history of related comorbidities, NSAID type, dose, duration and indications for use, concomitant warfarin or/and aspirin prescriptions, and co-prescription of gastroprotective agents. RESULTS: In total, 15% of patients received an NSAID prescription: females were issued more prescriptions than males. The percentage of patients who received an NSAID prescription across the health centers ranged from 9% to 24%. The main reason for prescribing NSAIDs was musculoskeletal problems. The most frequently prescribed NSAID was ibuprofen. Sixteen percent of patients who received an NSAID prescription had a risk factor related to its use. The mean and median duration of the NSAID prescriptions of all types were 5.6 and 5.0 days, respectively. Physicians with a greater number of years experience prescribed more NSAIDs. CONCLUSION: Our study showed that the number of prescriptions of NSAIDs among various institutes varied, which could reflect the level of awareness concerning NSAID risks among the prescribing doctors. NSAIDs were prescribed for patients with comorbidities and patients with previously documented side effects without considering protective agents. Therefore, we suggest that the use of these medications is controlled, especially in high-risk populations. PMID- 26421119 TI - Unusual Cause of Swelling in the Upper Limb: Kimura Disease. AB - Kimura disease is a rare chronic inflammatory disease of unknown etiology. The disease typically presents in young Asian males with single or multiple slowly progressing painless subcutaneous lumps in the head and neck region; regional lymphadenopathy is commonly accompanied. The disease is associated with peripheral blood eosinophilia and elevated serum immunoglobulin E levels. This gives an important clinical clue to the diagnosis and implies a possible immune mediated pathophysiology. Although the disease commonly affects the head and neck region, it may also affect the extremities, axilla, groin, and abdomen. Upper limb involvement in Kimura's disease is rare and few cases have been reported in the literature. We describe the case of a man who presented with a history of progressive upper limb swelling. He was diagnosed with Kimura's disease based on concordant clinical, laboratory, radiological, and histopathological grounds. Although rare in the upper limb, the possibility of Kimura's disease has to be considered in young males presenting with painless swelling in the medial epitrochlear region with compatible imaging appearance, particularly if associated with lymph node enlargement and increased blood eosinophils. Characteristic imaging findings of Kimura's disease of the upper limb include specific location along the neuro-lymphovascular structures, the absence of necrosis or calcification, mutliple flow voids representing vascular structures, a varying amount of edema of subcutaneous fat plane overlying the lesion; displacement of adjacent muscles; and neurovascular structures without signs of direct invasion. Clinicians should be aware of this distinct entity in order to avoid misdiagnosis and to tailor appropriate management. PMID- 26421120 TI - Dermatofibrosarcoma Protuberans: A Rare Malignancy of the Breast. AB - Dermatofibrosarcoma protuberans (DFSP) of the breast is a rare skin cancer with only a few cases reported in the literature. It corresponds to approximately 1% of all soft tissue sarcomas and to less than 0.1% of all malignancies with annual incidence of 0.8-4.5 cases per million. DFSP usually affects young and middle aged adults and it can affect any site, but most commonly the trunk and extremities. This tumor arises from the deep dermis and subcutaneous tissues and is usually locally aggressive, but rarely metastasizes. Surgery including wide local excision with free margins remains the main modality of treatment. We report a case in a 28-year-old Omani woman who presented with a right breast lump to a local secondary hospital. She was offered excision biopsy of the lump and the histology came as DFSP with involved margins. The patient was then referred to the Breast Unit at the Royal Hospital where she was reviewed by multidisciplinary team including breast surgeons, oncologists, radiation oncologists, pathologists, and breast radiologists. Her laboratory and radiological investigations did not show any signs of distal metastasis and breast ultrasound did not reveal any residual breast lesions. We performed a wide re-excision of the previous surgical scar with the underlying breast tissues down to the level of the pectoral fascia followed by treatment with radiotherapy. The final histology report showed the presence of a 4*5mm residual tumor, and all resection margins were tumor-free. At six months follow-up, she had no signs of local recurrence. We publish this case report because of its rarity. PMID- 26421121 TI - A Rare Case of Adrenal Pheochromocytoma with Unusual Clinical and Biochemical Presentation: ?A Case Report and Literature Review. AB - A 50-year-old Omani woman presented to the Outpatient Clinic, Royal Hospital, Oman with right upper abdominal pain and backache that had lasted 10 days. She had no palpitation, sweating, or hypertension (blood pressure 122/78mmHg). The patient's history revealed that she had a similar incidence of abdominal pain two months prior, which was a "dull ache" in nature and somewhat associated with headache. The pain was relieved using a mild analgesic drug. Abdominal ultrasonography showed a right adrenal mass, and both computed tomography and magnetic resonance imaging of the adrenal glands confirmed a right adrenal mass consistent with adrenal pheochromocytoma. However, clinical biochemistry tests revealed normal levels of plasma catecholamines (dopamine, norepinephrine, and epinephrine) and metanephrine, which are unusual findings in adrenal pheochromocytoma. Meanwhile, the patient had markedly raised plasma normetanephrine (10-fold) which, together with the normal metanephrine, constitutes a metabolic profile that is compatible with extra-adrenal pheochromocytoma. The patient also had markedly raised chromogranin A (16-fold), consistent with the presence of a neuroendocrine tumor. Laparoscopic right adrenalectomy was done and the adrenal tumor was excised and retrieved in total. Histopathology and immunohistochemistry confirmed the diagnosis of adrenal pheochromocytoma; the tumor cells being positive for chromogranin, synaptophysin, and S-100 protein. Following surgery, the patient did well and showed full recovery at follow-up after three months. Molecular genetic testing showed no pathogenic mutation in pheochromocytoma genes: MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, VHL, and PRKAR1A. A review of the literature was conducted to identify the pathophysiology and any previous reports of such case. To our knowledge, this is the first report in Oman of the extremely rare entity of pheochromocytoma with an unusual clinical and biochemical scenario. PMID- 26421122 TI - Ensuring Clinical Competence in Oman. PMID- 26421123 TI - Right-sided Pleuritic Chest Pain in a 36-year-old Male. PMID- 26421124 TI - Nasopharyngeal Carcinoma in Oman and Malaysia: Is There Any Difference? PMID- 26421125 TI - Letter in Reply: Comparing Nasopharyngeal Carcinoma in Oman and Malaysia. PMID- 26421126 TI - Epidemiology of Cyclospora Species in Humans in Malatya Province in Turkey. AB - BACKGROUND: Cyclospora species are rare among other Coccidia parasites and can cause recurrent gastroenteritis. Cyclospora spp. can infect reptiles, insects, rodents, and mammals. OBJECTIVES: The present study aimed to determine the epidemiology of Cyclospora spp. in Malatya province and its neighboring provinces. PATIENTS AND METHODS: Totally, 2281 stool samples taken from patients with digestive system complaints who referred to the polyclinics affiliated with Inonu University, Faculty of Medicine in Malatya Province and its neighboring provinces, in 2006, and whose stool specimens were submitted to the parasitology department were examined. A questionnaire was developed to determine the epidemiology of Cyclospora spp. in the patients as the dependent variable of the study. All the participants signed an informed written consent. The samples were coated with EntellanTM after staining via acid-fast staining and were examined on an immersion microscope objective. The data are presented as mean, standard deviation, or number/percentage. The chi-square test was used for the statistical analyses. Statistically, a P value < 0.05 was accepted as meaningful. RESULTS: The stool samples were examined via direct microscopic examination and acid-fast staining. Positivity was determined in 129 (5.7%) cases. In the overall assessment of the patients with respect to general body itching, rectal itching, allergy, immunosuppression plus cancer, shortness of breath, ulcerative colitis, diarrhea, abdominal pain, salivation, constipation, nausea, vomiting, growth retardation, and anemia, there was no significant relationship. However, in the statistical evaluations among the positive cases, the difference was found to be significant. CONCLUSIONS: The study was conducted in Malatya Province, but patients from the neighboring provinces were also included in the evaluation during the study. Of all the positive cases, 5.6% were those from Malatya Province and its surrounding areas. Additionally, Cyclospora spp. were observed among the patients referring to the polyclinics with digestive system complaints in 8.1% of those from the Adiyaman province and in 6.9% of those from the Kahramanmaras region. The incidence of Cyclospora cayetanensis may be higher in these regions if an epidemiological study is performed. Consequently, we suggest that Cyclospora spp. be investigated in digestive system disorders, especially in immunosuppressed patients. PMID- 26421127 TI - Use of Padlock Probes and Rolling Circle Amplification (RCA) for Rapid Identification of Trichophyton Species, Related to Human and Animal Disorder. AB - BACKGROUND: The high degree of phenotypic similarity among Trichophyton species makes their identification difficult. OBJECTIVES: The current study aims to establish the use of rolling circle amplification (RCA) based on internal transcribed spacer ribosomal DNA (ITS rDNA) as a powerful, simple, and rapid procedure for distinguishing closely related organisms, and specifically to identify Trichophyton species, which cause human and animal disorders. MATERIALS AND METHODS: A total of sixty-one isolates belonging to three species of Trichophyton were identified to the species level based on microscopic and macroscopic examinations and their ITS rDNA regions were sequenced. Three specific circular oligonucleotide probes targeting the ITS1 and ITS2 regions were designed to differentiate Trichophyton rubrum, T. mentagrophytes, and T. tonsurans. RESULTS: Of the 61 putative Trichophyton clinical isolates, 52 were identified to the species level. The most common species was T. mentagrophytes var. interdigitale (31 isolates), followed by T. rubrum (11 isolates), T. tonsurans (9 isolates), and T. violaceum (1 isolates); moreover, 9 isolates were identified as non-Trichophyton species. The RCA method correctly identified four Trichophyton species and was 100% specific for each species. Neither cross reaction between the examined species of Trichophyton nor false positive or false negative results were observed. CONCLUSIONS: Species identification of Trichophyton is crucially important for epidemiological and phylogenetic purposes and for genotype delineation. RCA based on ITS polymorphisms can be used to generate identification barcodes and as an alternative to DNA sequencing; it is a very fast, specific, and economical tool for species identification. PMID- 26421128 TI - Dissemination of Extended-Spectrum beta-Lactamases and Quinolone Resistance Genes Among Clinical Isolates of Uropathogenic Escherichia coli in Children. AB - BACKGROUND: Urinary tract infection (UTI) is one of the most common childhood bacterial infections and Escherichia coli is the major pathogen. Producing beta lactamase enzymes are the most common mechanism of bacterial resistance. OBJECTIVES: This study aimed to determine the prevalence of Extended-Spectrum beta-Lactamases (ESBLs) and Quinolone Resistance (qnr) genes in E. coli strains isolated from UTIs. MATERIALS AND METHODS: In this study, a total of 120 isolates of E. coli from urinary tract infections of the children were collected at Besat Hospital in Hamadan, Iran, from October 2010 to October 2011. The bacterial isolates were identified by standard biochemical methods. Antimicrobial susceptibilities were determined by disk diffusion method, and ESBLs-producing was confirmed phenotypically using the double-disk synergy (DDS) test. The presence and identification of ESBLs and qnr genes were determined by Polymerase Chain Reaction (PCR). RESULTS: The highest sensitivity was seen to imipenem (96.7%), amikacin (92.5%), nitrofurantoin (93.3%), ofloxacin (81.7%), gentamicin norfloxacin (70.8%), and ciprofloxacin (79.2%). In contrast, the highest rate of resistance was seen to co-trimoxazole (77%) and nalidixic acid (40.9%). The results showed that 6 (2.18%) and 4 (1.12%) isolates of ESBL-producing E. coli were positive with respect to having qnrB and qnrS genes, respectively. No isolates was found to have qnrA. CONCLUSIONS: CTX-M was the most prevalent ESBL genotype in uropathogenic E. coli (UPEC) isolated from UTI. In addition, a high frequency of qnr genes among ESBL-producing E. coli was identified in this study. In order to avoid treatment failures, we recommend using phenotypic and molecular methods to diagnose these enzymes and qnr genes. PMID- 26421129 TI - Characteristics and Antibiotic Resistance of Urinary Tract Pathogens Isolated From Punjab, Pakistan. AB - BACKGROUND: Urinary tract infection (UTI) is deemed the most prevalent infectious disease in that it has now touched the overall incidence of 18/1000 persons per year in the general population. OBJECTIVES: This study sought to determine the characteristics of isolates from patients with UTI and their susceptibility to commonly used antibiotics in Punjab, Pakistan. PATIENTS AND METHODS: Totally, 1429 urine samples were analyzed from UTI patients for the isolation of uropathogens at Chughtai's Lahore Lab, Lahore, Pakistan, during a period of 14 months. The antimicrobial susceptibility test was performed via the disc diffusion method for the isolates obtained from 392 (26%) positive cultures. RESULTS: The highest percentage (67%) of isolates was from females in comparison to males (33%). The frequency of Escherichia coli was the highest (62%) in culture-positive urine samples, followed by E. faecalis (15%), Candida (14%), Pseudomonas (6%), Klebsiella spp. (1%), Proteus (1%), and Staphylococcus aureus (1%). E. coli was highly resistant to antimicrobial drugs, viz. cephalexin (95%), cephradine (95%), pipemidic acid (92%), amikacin (91%), and nalidixic acid (91%). Most of the routine beta-lactam antibiotics like amoxicillin/clavulanic acid, ampicillin, and aztreonam were also ineffective against E. coli, with resistance rates of 84%, 84%, and 72%, correspondingly. This pathogen showed maximum susceptibility (97%) against three drugs, namely imipenem, meropenem, and cefoperazone. Piperacillin and fosfomycin also provided significant results against E. coli with respective susceptibility rates of 96% and 90%. CONCLUSIONS: Our results showed that broad-spectrum antibiotics such as imipenem, meropenem, fosfomycin, cefoperazone/sulbactam, and vancomycin would be the first line and the most effective drugs for the empirical treatment of urinary tract pathogens due to their higher resistance rates against other drugs like cephalexin, cephradine, ciprofloxacin, levofloxacin, and norfloxacin. PMID- 26421130 TI - Seroprevalence of Hepatitis A and E Virus Infections Among Healthy Population in Shiraz, Southern Iran. AB - BACKGROUND: Enterically-transmitted acute viral hepatitis is caused predominantly by hepatitis A virus (HAV) and hepatitis E virus (HEV). The prevalence of HEV and HAV infections varies in different geographical regions. OBJECTIVES: This study was conducted to determine the prevalence of HEV and HAV infections among Iranian healthy individuals in southern Iran. PATIENTS AND METHODS: Totally, 1030 samples were collected from healthy subjects in schools, those referred to tertiary outpatient clinics and health centers in Shiraz between November 2011 and May 2012. Their ages ranged between six months and 95 years. The presence of total anti-HAV and anti-HEV immunoglobulin M (IgM) in plasma was assessed by ELISA. RESULTS: The results showed that 66.2% and 0.6% of the general population in this area were positive for total anti-HAV and IgM antibodies by ELISA, respectively. As seen, 13.4% and 0.9% were positive for total anti-HEV and IgM antibodies, respectively. The difference in total anti-HAV and anti-HEV antibodies was significant among the age groups (P < 0.001). CONCLUSIONS: This study showed that the prevalence rates of HAV and HEV antibodies were positively correlated with age. The results demonstrated that the infection with these two viruses in the region was high and some high-risk individuals including females at child-bearing age were more susceptible. HAV vaccination could be recommended for antibody negative adults. PMID- 26421131 TI - Biochemical Fingerprinting of Methicillin-Resistant Staphylococcus aureus Isolated From Sewage and Hospital in Iran. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is known as a common pathogen in nosocomial and community-acquired infections. Sewage acts as an environmental reservoir and may have a significant role in development and dissemination of antibiotic resistance. OBJECTIVES: This study was undertaken to determine the epidemiological relatedness between the MRSA isolated from sewage and human infections. MATERIALS AND METHODS: Samples were collected from a referral hospital and also a sewage treatment plant in Tehran, Iran, during 2010. All the MRSA isolates were identified at the species level and typed using Phene plate (PhP) system and SCCmec typing. Antibiotic susceptibility tests were also performed. RESULTS: Of the 1142 isolates, 200 MRSA strains from the sewage (n = 100) and the clinic (n = 100) were isolated. Distinct PhP types, consisting of 16 common types and 13 single types, and also 3 different staphylococcal cassette chromosome mec (SCCmec) types (III, IVa and IVc) were found amongst the MRSA isolated from the two different sources. The results of antibiotic susceptibility testing showed an increased resistance to penicillin, ciprofloxacin, erythromycin, clindamycin and tetracycline. In addition, none of the isolates showed resistance to vancomycin, quinupristin -dalfopristin and linezolid. CONCLUSIONS: The presence of common PhP types and also SCCmec type III, as an indicator for hospital strains, among the isolates, may indicate an epidemiological link between clinical and sewage MRSA isolates in Tehran. PMID- 26421132 TI - Sulfonamide Resistance Genes (sul) M in Extended Spectrum Beta Lactamase (ESBL) and Non-ESBL Producing Escherichia coli Isolated From Iranian Hospitals. AB - BACKGROUND: Extensive use of cotrimoxazole has been associated with increasing level of Escherichia coli resistance. OBJECTIVES: In the current study, we focused on assessing the prevalence of E. coli resistance to cotrimoxazole and frequency of its associated genes. MATERIALS AND METHODS: One-hundred and forty four E. coli isolates were identified during March 2007 to April 2012 at Ilam hospitals and Milad (Tehran) hospital. Antibiotic susceptibility for screening of resistance isolates was done by the Kirby-Bauer method. The sul1, sul2, sul3, dfrA1, dfrA5, int1, blaTEM, blaSHV and CTX-M genes were detected by polymerase chain reaction (PCR) amplification. Plasmid curing was done for identifying correlations between resistance genes and plasmids. RESULTS: Amongst the 144 E. coli isolates, seventy-two (50%) Extended Spectrum Beta Lactamase (ESBL) producing and seventy-two (50%) non-ESBL-producing E. coli isolates were identified; eighty-seven isolates (60.41%) were resistant to cotrimoxazole. Frequencies of sul1, sul2 and sul3, were 81% (116 isolates), 67% (96 isolates) and 2.29% (three isolates), respectively. Furthermore, 50.57% (72 isolates) had sul1 and sul2, 2.29% (3 isolates) contained sul2 and sul3, and 2.29% (three isolates) contained sul1, sul2 and sul3 genes, simultaneously. Thirty-four (39.1%) of the isolates had the dfrA1 gene. Five (5.7%) of the isolates had the dfrA5 gene. Sixty-eight (78.2%) strains contained the int1 gene. Furthermore, dfrA1 and dfrA5 were present in three (3.4%) of the isolates. The results showed that of the ESBL-producing isolates, 85.2% (n = 122), 53.2% (n = 76) and 26.1% (n = 37) were blaTEM, blaSHV and CTX-M harboring isolates, respectively. CONCLUSIONS: Our study indicated a high frequency of cotrimoxazole resistance gene in E. coli isolates from Ilam and Tehran (Milad) hospitals, and sul genes had a major role in cotrimoxazole resistance of these isolates. PMID- 26421133 TI - Antibiotic Susceptibility Pattern of Aerobic and Anaerobic Bacteria Isolated From Surgical Site Infection of Hospitalized Patients. AB - BACKGROUND: Surgical Site Infections (SSIs) are infections of incision or deep tissue at operation sites. These infections prolong hospitalization, delay wound healing, and increase the overall cost and morbidity. OBJECTIVES: This study aimed to investigate anaerobic and aerobic bacteria prevalence in surgical site infections and determinate antibiotic susceptibility pattern in these isolates. MATERIALS AND METHODS: One hundred SSIs specimens were obtained by needle aspiration from purulent material in depth of infected site. These specimens were cultured and incubated in both aerobic and anaerobic condition. For detection of antibiotic susceptibility pattern in aerobic and anaerobic bacteria, we used disk diffusion, agar dilution, and E-test methods. RESULTS: A total of 194 bacterial strains were isolated from 100 samples of surgical sites. Predominant aerobic and facultative anaerobic bacteria isolated from these specimens were the members of Enterobacteriaceae family (66, 34.03%) followed by Pseudomonas aeruginosa (26, 13.4%), Staphylococcus aureus (24, 12.37%), Acinetobacter spp. (18, 9.28%), Enterococcus spp. (16, 8.24%), coagulase negative Staphylococcus spp. (14, 7.22%) and nonhemolytic streptococci (2, 1.03%). Bacteroides fragilis (26, 13.4%), and Clostridium perfringens (2, 1.03%) were isolated as anaerobic bacteria. The most resistant bacteria among anaerobic isolates were B. fragilis. All Gram-positive isolates were susceptible to vancomycin and linezolid while most of Enterobacteriaceae showed sensitivity to imipenem. CONCLUSIONS: Most SSIs specimens were polymicrobial and predominant anaerobic isolate was B. fragilis. Isolated aerobic and anaerobic strains showed high level of resistance to antibiotics. PMID- 26421134 TI - The Dynamic of Staphylococcus aureus Nasal Carriage in Central Iran. AB - BACKGROUND: Nasal carriage of Staphylococcus aureus plays an important role in the pathogenesis of staphylococcal infections. Anterior nasal region is a primary origin of S. aureus. In longitudinal studies, three types of S. aureus nasal carriers can be distinguished: persistent carriers, intermittent or transient carriers, and noncarriers. OBJECTIVES: This study was designed to determine the dynamic of S. aureus nasal carriage in healthy carriers of central Iran. PATIENTS AND METHODS: A total of 813 healthy adults were subjected to this cross-sectional study from November 2011 to January 2012 in Arak University of Medical Sciences. Two anterior nasal swabs were taken with a week interval from each participant. All the isolates were identified as S. aureus phenotypically by standard laboratory methods. The isolates were reconfirmed by amplification of sa442 gene as the identification marker. All the isolates were screened for the presence of the PVL (Panton-Valentine leukocidin) virulence genes and arginine catabolic mobile element (ACME-arc). RESULTS: Among the 813 subjects screened, 83 (10.2%) were persistent carriers, 86 (10.6%) were transient carriers and 644 (79.2%) cases were found as noncarriers. A total of 169 (20.8%) participants had colonized S. aureus. The frequency of ACME-arc A and PVL genes in S. aureus strains were 17% and 20%, respectively. CONCLUSIONS: Carriage of PVL-positive S. aureus is common in this region, even in the low frequency of MRSA colonization. The detection of ACME-arcA gene in S. aureus isolates is a public-health concern and demands continued surveillance and close monitoring. PMID- 26421135 TI - Antibiotic Sensitivity of Clostridium perfringens Isolated From Faeces in Tabriz, Iran. AB - BACKGROUND: Clostridium perfringens, a Gram-positive, anaerobic bacterium that produces at least 16 virulence factors including 12 toxins (alpha-nu), enterotoxin, hemolysin and neuraminidase, can create variable pathogenic condition, ranging from a food poisoning to life-threatening myonecrosis. Among C. perfringens strains, resistance to the drug choices such as penicillin as well as to alternatives of penicillin like metronidazole and clindamycin has also been observed. OBJECTIVES: The aim of this study was to determine the resistance of isolated toxigenic and non-toxigenic C. perfringens strains against common antimicrobial agents. MATERIALS AND METHODS: In this descriptive study, a total of 136 stool specimens were collected. At first, cooked meat medium enrichment method was performed on samples at 45 degrees C. Thereafter, a loopful of the enriched culture was transferred to blood agar and incubated anaerobically at 37 degrees C for 24-72 hours. Colonies with double zone of hemolysis were identified by different biochemical tests such as phospholipase C (lecithinase) test, indole and urease production. The Minimum Inhibitory Concentration (MIC) for common antibiotics was determined by Etests (Epsilometer) and duplex Polymerase Chain Reaction (PCR) reaction was performed with specific primers for amplification of cpe (426 bp) and plc (283 bp) Genes. RESULTS: Of 136 stool samples including diarrhea [48] and non-diarrhea [88] ones, 83 (61.02%) C. perfringens were cultured. Of these 83, 79 C. perfringens isolates showed the alpha-toxin (phospholipase C) production gene by PCR. Respectively, 3 (9.09%) and 2 (4.34%) cpe genes were present in diarrhea and non-diarrhea samples. Of 79 isolates of C. perfringens, 34 (43.03%) cases showed no resistance, 18 (22.78%) had one resistance and 27 (34.17%) isolates had multiple resistance to imipenem, metronidazole, ceftriaxone, clindamycin, chloramphenicol, and penicillin. CONCLUSIONS: Periodic evaluation of antimicrobial susceptibility for C. perfringens should be performed. Harboring of enterotoxigenic C. perfringens in individuals not necessarily results in diarrhea. PMID- 26421136 TI - An Ultra-Violet Tolerant Wild-Type Strain of Melanin-Producing Bacillus thuringiensis. AB - BACKGROUND: Bacillus thuringiensis is the most successful biological control agent used in agriculture, forestry and mosquito control. However, the insecticidal activity of the B. thuringiensis formulation is not very stable and rapidly loses its biological activity under field conditions, due to the ultraviolet radiation in sunlight. Melanin is known to absorb radiation therefore photo protection of B. thuringiensis based on melanin has been extensively studied. OBJECTIVES: The aim of this study was to find a wild type strain of naturally melanin-producing B. thuringiensis to avoid any mutation or manipulation that can affect the Cry protein content. MATERIALS AND METHODS: Bacillus thuringiensis strains were isolated from soils of different States of Mexico and pigment extraction was followed by lowering the pH to 2 using 1N HCl. Pigment was characterized by some chemical tests based on its solubility, bleaching by H2O2 and flocculation with FeCl3, and using an Infrared (IR) spectrum. Ultraviolet (UV) irradiation experiment was performed to probe the melanin efficacy. RESULTS: ELI52 strain of B. thuringiensis was confirmed to naturally produce melanin. The Cry protein analysis suggested that ELI52 is probably a B. thuringiensis subsp. israelensis strain with toxic activity against the Diptera order of insects. Ultra Violet protection efficacy of melanin was probed counting total viable colonies after UV radiation and comparing the results with the non-producing melanin strain L-DOPA (L-3, 4 dihydroxyphenylalanine) was also detected in the culture. ELI52 strain showed an antagonistic effect over some common bacteria from the environment. CONCLUSIONS: ELI52 wild-type strain of B. thuringiensis is a good bio-insecticide that produces melanin with UV-resistance that is probably toxic against the Diptera order of insects and can inhibit the growth of other environmental bacteria. PMID- 26421137 TI - Prevalence and Clonal Dissemination of Metallo-Beta-Lactamase-Producing Pseudomonas aeruginosa in Kermanshah. AB - BACKGROUND: Pseudomonas aeruginosa is an opportunistic pathogen associated with nosocomial infections. The emergence and dissemination of metallo-beta-lactamases (MBLs) has contributed to the high rate of resistance among P. aeruginosa isolates. OBJECTIVES: The purpose of this study was to describe the prevalence and the clonal dissemination of MBL- producing P. aeruginosa isolates collected from major hospitals in Kermanshah. MATERIALS AND METHODS: Antibiotic susceptibility testing was performed using the minimal inhibitory concentrations. The MBLs were investigated using the Double-Disk Synergy Test (DDST) and Polymerase Chain Reaction. Molecular typing was performed by Pulsed-Field Gel Electrophoresis (PFGE). RESULTS: Of the 60 P. aeruginosa isolates included in this study, 30 (50%) were resistant to Gentamicin, 38 (63.3%) to Piperacillin, 42 (70%) to Ceftazidime, and 45 (75%) to Cefepime. Twenty-nine (48.3%) isolates were MBL producers in the DDST test. Five (8.3%) isolates were positive for the VIM gene. PFGE analysis among the MBL producers revealed 12 distinct clonal patterns. CONCLUSIONS: The inter- and intra-hospital dissemination of resistant clones is a matter of concern and is an indicator of the level of the improvement and surveillance of standard hygiene, particularly disinfection and hand washing before and after contact with patients. Given the emergence of MBL-producing strains, surveillance has become an important procedure to control the transmission of resistant strains. PMID- 26421138 TI - Analysis of Subcellular Prefoldin 1 Redistribution During Rabies Virus Infection. AB - BACKGROUND: Rabies virus (RABV) is one of the old deadly zoonotic viruses. It attacks the central nervous system and causes acute encephalitis in humans and animals. Host factors are known to be essential for virus infection and replication in cells. The identification of the key host factors required for RABV infection may provide important information on RABV replication and may provide new potential targets for RABV drug discovery. OBJECTIVES: This study aimed to investigate the change in the subcellular distribution and expression of the host protein Prefoldin subunit 1 (PFDN1) in RABV-infected cells and the viral expression of plasmids in the transfected cells. MATERIALS AND METHODS: Mouse Neuro-2a (N2a) cells were infected by RABV or transfected with the plasmids of the nucleoprotein (N) and/or phosphoprotein (P) gene of RABV. The subcellular distribution of PFDN1 was analyzed by confocal microscopy, and the transcription levels of PFDN1 in the N and/or P gene of the RABV-transfected or RABV-infected N2a cells were assessed via real-time quantitative polymerase chain reaction. RESULTS: Confocal microscopy showed that PFDN1 was colocalized with the N protein of RABV in the infected N2a cells and was mainly recruited to the characteristic Negri-Body-Like (NBL) structures in the cytoplasm, as well as the cotransfection of the N and P genes of RABV. The transcription of PFDN1 in the RABV-infected N2a cells was upregulated, whereas the transfection of the N and/or P genes did not result in the upregulation of PFDN1. CONCLUSIONS: The results of this work demonstrated that the subcellular distribution of PFDN1 was altered in the RABV infected N2a cells and colocalized with the N protein of RABV in the NBL structures. PMID- 26421139 TI - A Case of Recurrent Kikuchi-Fujimoto Disease. AB - INTRODUCTION: Kikuchi-Fujimoto Disease (KFD) is a benign, self-limited, inflammatory disorder, first reported in Japan. This condition is more prevalent among women and typically occurs in the third decade of life. It normally manifests as persistent, isolated cervical adenopathy with a recurrence rate of 3%. The identification of this condition is of high significance, given the risk of misdiagnosis with other disorders such as malignant lymphoma and extensive necrosis. CASE PRESENTATION: The patient was a 32-year-old female diagnosed with Kikuchi-Fujimoto disease via neck lymph node biopsy in August 2006 in the city of Mashhad, Iran. The disease regressed with proper follow-up, although after eight years the patient was readmitted to the hospital with severe weight loss, high fever, and uncommon symptoms of generalized adenopathy in cervical, axillary and inguinal regions. CONCLUSIONS: Although KFD is an uncommon condition, it should be featured in the list of differential diagnoses of tender lymphadenopathy, especially lymphadenopathy localized to the cervical region. We reported a case of KFD with a prolonged relapse of eight years. Full recovery with a good response to corticosteroid regimen was achieved after the recurrence. PMID- 26421140 TI - Molecular Identification of Resistance Determinants, Integrons and Genetic Relatedness of Extensively Drug Resistant Acinetobacter baumannii Isolated From Hospitals in Tehran, Iran. AB - BACKGROUND: Acinetobacter baumannii has emerged as an important nosocomial pathogen. Hospital outbreaks of extensively drug resistant (XDR) A. baumannii are a great concern. OBJECTIVES: Aims of this study were to characterize the resistance determinants and genetic relatedness of (XDR) A. baumannii isolates in hospitals in Tehran, Iran. MATERIALS AND METHODS: During a three-year study, clinical isolates of A. baumannii were collected from two hospitals in Tehran, Iran. Susceptibility testing to antibiotics was performed by disk diffusion method and XDR A. baumannii isolates were identified. Genes' encoding for carbapenemase production and integrons were identified by PCR. MICs of imipenem and meropenem were determined by agar dilution. Multiple locus variable-number tandem repeat analysis (MLVA) typing was used to determine genetic relationships of XDR isolates. RESULTS: Using PCR for amplification of bla OXA-51 , 93.9% (123.131) of isolates were identified as A. baumannii and 24.4% (30.123) were XDR. These isolates were resistant to gentamicin, ciprofloxacin, amikacin, cotrimoxazole, cefepime, cefotaxime, aztreonam and ceftazidime. Thirty percent of the isolates were resistant to tigecycline. All isolates were susceptible to colistin and polymyxin-B, while 93.3% (28.30) possessed bla OXA-23 -like and 6.7% (2.30) possessed bla OXA-24 -like. All isolates possessed insertion sequence (ISAba1) in the upstream region of the OXA-23-like gene. Almost 96.7% (29.30) of the isolates were positive for class I integron and 43.3% (13.30) for class II. These isolates were also positive for class I. Class III integron was not detected. MLVA typing of XDR isolates showed seven clonally complexes and 16 singletons. CONCLUSIONS: The population structure of the A. baumannii isolates in our hospitals was genetically diverse. A significant association between XDR pattern and presence of class 1 integron (P < 0.001) was found indicating that many antibiotic resistance determinants are involved in development of XDR strains. PMID- 26421141 TI - Determination of the Genetic Diversity of Different Bioluminescent Bacteria by Pulsed-Field Gel Electrophoresis (PFGE). AB - BACKGROUND: There are 4 different genera (i.e. Vibrio, Aliivibrio, Photobacterium, and Shewanella) in the new classification of bioluminescent bacteria. The mechanism of bioluminescence has yet to be fully elucidated. Therefore, the determination of physiological and genetic characteristics of bioluminescent bacteria isolated from different sources is very important. Pulsed Field Gel Electrophoresis (PFGE) has the highest discriminatory power among the different molecular typing methods for the investigation of the clonal relationships between bacteria. For the PFGE analysis of bioluminescent bacteria, the NotI-HFTM is the method of choice among the restriction enzymes. OBJECTIVES: The present study aimed to determine genetic relatedness via PFGE in 41 bioluminescent bacteria (belonging to 10 different species) isolated and identified from various marine sources. MATERIALS AND METHODS: Different bioluminescent bacteria (i.e. Vibrio gigantis, V. azureus, V. harveyi, V. lentus, V. crassostreae, V. orientalis, Aliivibrio logei, A. fischeri, Shewanella woodyi, and Photobacterium kishitanii) were analyzed by PFGE using the NotI-HFTM restriction enzyme. The whole DNA of the strains embedded into the agarose plugs was digested with enzyme at 37 degrees C for 30 minutes. CHEF-Mapper PFGE system was used for electrophoresis and band profile of the strains for the NotI-HFTM restriction enzyme were analyzed by Bio-Profil-1D++ software (Vilber Lourmat) at 10% homology coefficient. RESULTS: Although all experiments were performed three times, four of forty-one bioluminescent strains (V. gigantis E-16, H-16 and S3W46 strains and A. fischeri E-4 strain) could not be typed by PFGE technique with NotI-HFTM enzyme. While only two strains (V. crassostreae H-12 and H-19 strains) were exhibiting same band pattern profiles (100% genome homology), thirty-six different PFGE band patterns were obtained. Pattern homologies changed between 66% - 92%, 73% - 83% and 49% - 100% for V. gigantis, V. harveyi and other strains, respectively. CONCLUSIONS: The obtained results revealed that there has been a high rate of genetic diversity in bioluminescent strains isolated from Gulf of Izmir and V. lentus and V. crassostreae strains could be also bioluminescent for the first report. At the same time, PFGE analysis of bioluminescent bacteria including four different genera and ten different species were shown for the first time by this study. It is considered that data acquired by this study will contribute evolution and mechanism of bioluminescence to further works to be done. PMID- 26421142 TI - Metformin as an anticancer drug: A Commentary on the metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. PMID- 26421143 TI - Epidermal growth factor receptor signaling and the progression of diabetic nephropathy. PMID- 26421145 TI - Highly reliable behaviors. AB - A lack of respect between nursing and medical disciplines can lead to a lack of trust and disruptive behaviors that are a significant part of the culture of health care today. In order to ensure the best care for all patients, a systematic approach to defining desired and undesired behaviors is a place to begin. A systems view requires an appreciation of local culture and operations. Understanding the underlying root causes in different departments and specialties allows for the development and implementation of sustainable solutions which will ultimately change and transform an organization. Leadership action and commitment at the highest strategic level is essential for this to occur. PMID- 26421144 TI - Comparative expression of the four enamel matrix protein genes, amelogenin, ameloblastin, enamelin and amelotin during amelogenesis in the lizard Anolis carolinensis. AB - BACKGROUND: In a recent study, we have demonstrated that amelotin (AMTN) gene structure and its expression during amelogenesis have changed during tetrapod evolution. Indeed, this gene is expressed throughout enamel matrix deposition and maturation in non-mammalian tetrapods, while in mammals its expression is restricted to the transition and maturation stages of amelogenesis. Previous studies of amelogenin (AMEL) gene expression in a lizard and a salamander have shown similar expression pattern to that in mammals, but to our knowledge there are no data regarding ameloblastin (AMBN) and enamelin (ENAM) expression in non mammalian tetrapods. The present study aims to look at, and compare, the structure and expression of four enamel matrix protein genes, AMEL, AMBN, ENAM and AMTN during amelogenesis in the lizard Anolis carolinensis. RESULTS: We provide the full-length cDNA sequence of A. carolinensis AMEL and AMBN, and show for the first time the expression of ENAM and AMBN in a non-mammalian species. During amelogenesis in A. carolinensis, AMEL, AMBN and ENAM expression in ameloblasts is similar to that described in mammals. It is noteworthy that AMEL and AMBN expression is also found in odontoblasts. CONCLUSIONS: Our findings indicate that AMTN is the only enamel matrix protein gene that is differentially expressed in ameloblasts between mammals and sauropsids. Changes in AMTN structure and expression could be the key to explain the structural differences between mammalian and reptilian enamel, i.e. prismatic versus non-prismatic. PMID- 26421146 TI - High-coverage sequencing and annotated assembly of the genome of the Australian dragon lizard Pogona vitticeps. AB - BACKGROUND: The lizards of the family Agamidae are one of the most prominent elements of the Australian reptile fauna. Here, we present a genomic resource built on the basis of a wild-caught male ZZ central bearded dragon Pogona vitticeps. FINDINGS: The genomic sequence for P. vitticeps, generated on the Illumina HiSeq 2000 platform, comprised 317 Gbp (179X raw read depth) from 13 insert libraries ranging from 250 bp to 40 kbp. After filtering for low-quality and duplicated reads, 146 Gbp of data (83X) was available for assembly. Exceptionally high levels of heterozygosity (0.85 % of single nucleotide polymorphisms plus sequence insertions or deletions) complicated assembly; nevertheless, 96.4 % of reads mapped back to the assembled scaffolds, indicating that the assembly included most of the sequenced genome. Length of the assembly was 1.8 Gbp in 545,310 scaffolds (69,852 longer than 300 bp), the longest being 14.68 Mbp. N50 was 2.29 Mbp. Genes were annotated on the basis of de novo prediction, similarity to the green anole Anolis carolinensis, Gallus gallus and Homo sapiens proteins, and P. vitticeps transcriptome sequence assemblies, to yield 19,406 protein-coding genes in the assembly, 63 % of which had intact open reading frames. Our assembly captured 99 % (246 of 248) of core CEGMA genes, with 93 % (231) being complete. CONCLUSIONS: The quality of the P. vitticeps assembly is comparable or superior to that of other published squamate genomes, and the annotated P. vitticeps genome can be accessed through a genome browser available at https://genomics.canberra.edu.au. PMID- 26421147 TI - Tip of the iceberg: Extra-haematological consequences of early iron deficiency. PMID- 26421148 TI - Osteogenic programs during zebrafish fin regeneration. AB - Recent advances in genomic, screening and imaging technologies have provided new opportunities to examine the molecular and cellular landscape underlying human physiology and disease. In the context of skeletal research, technologies for systems genetics, high-throughput screening and high-content imaging can aid an unbiased approach when searching for new biological, pathological or therapeutic pathways. However, these approaches necessitate the use of specialized model systems that rapidly produce a phenotype, are easy to manipulate, and amenable to optical study, all while representing mammalian bone physiologies at the molecular and cellular levels. The emerging use of zebrafish (Danio rerio) for modeling human disease highlights its potential to accelerate therapeutic and pathway discovery in the mammalian skeleton. In this review, we consider the potential value of zebrafish fin ray regeneration (a rapid, genetically tractable and optically transparent model of intramembranous ossification) as a translational model for such studies. PMID- 26421149 TI - Preparation for teacher collaboration in inclusive classrooms - stress reduction for special education students via acceptance and commitment training: A controlled study. AB - BACKGROUND: The education system in Germany is beginning to witness a sea change, lately, owing to the country's ratification of the United Nation's Convention on the Rights of Persons with Disabilities. The enactment is aiming at making provision for special education teachers to share the same teaching platform and institution with other teachers for teaching children from all backgrounds, irrespective of their needs. While promoting the benefits of collaborative teaching, this provision would also effectively establish role demarcation among teachers. However, the level of participation and adaptiveness displayed by individual teachers would play a major role in determining the success or failure of the intended collaborative framework. Collaboration also becomes challenging due to the level of stress involved in the teaching profession. The fact that only 65 % of teachers in Germany reach retirement age while still in service, primarily due to psychiatric illness, has posed questions on adopting the collaborative framework for teachers from diverse backgrounds. In other words, it can be stated that the process of collaborating with teachers from different professional backgrounds and with varying levels of skills will potentially lead to further stress. The stress-related psychological states, developed through the collaborative processes, might affect the biological stress-response systems of the participating teachers. With stress-response contributing directly to the pathogenesis of stress-related diseases and disorders in the long term, it would be important to contain the ripple effect of collaborative framework that the enactment intends to establish between SEN (special educational needs) teachers and others. METHODS: In addition to impacting the long-term health of teachers, the collaborative framework is also suggestive of having similar effects on students studying special education (SEN students). A study was conducted to examine the stress levels associated with the collaborative framework. An expression in terms of two (group affiliation) * 2 (measurement time) between subjects design was implemented to examine the effects of an Acceptance and Commitment Training on the subjective tension of a sample (N = 68) of SEN students. The sample was split into an intervention and a control group (IG and CG). The effects of the training on collaborative competence were examined using the Chi-square test. Questionnaire and role plays were used to assess the collaborative competence and the subjective tension. RESULTS: The participants had significant stress levels and displayed an uncooperative attitude during the initial assessment. However, these results reversed after the Acceptance and Commitment Training. Significant decrease in stress levels and improved cooperation were evident among the participants in the intervention group, as opposed to the participants of the control group. CONCLUSIONS: The findings of this study show that the Acceptance and Commitment Training is an appropriate medium to establish and develop collaboration skills, and an effective technique to reduce high levels of subjective stress. Furthermore, the training evaluation and feedback indicate that it is well-accepted by all participants. The training is also endorsed as a practically relevant medium to help SEN students collaborate and combat stress. PMID- 26421150 TI - The metabolomics of asthma control: a promising link between genetics and disease. AB - Short-acting beta agonists (e.g., albuterol) are the most commonly used medications for asthma, a disease that affects over 300 million people in the world. Metabolomic profiling of asthmatics taking beta agonists presents a new and promising resource for identifying the molecular determinants of asthma control. The objective is to identify novel genetic and biochemical predictors of asthma control using an integrative "omics" approach. We generated lipidomic data by liquid chromatography tandem mass spectrometry (LC-MS), - using plasma samples from 20 individuals with asthma. The outcome of interest was a binary indicator of asthma control defined by the use of albuterol inhalers in the preceding week. We integrated metabolomic data with genome-wide genotype, gene expression, and methylation data of this cohort to identify genomic and molecular indicators of asthma control. A Conditional Gaussian Bayesian Network (CGBN) was generated using the strongest predictors from each of these analyses. Integrative and metabolic pathway over-representation analyses (ORA) identified enrichment of known biological pathways within the strongest molecular determinants. Of the 64 metabolites measured, 32 had known identities. The CGBN model based on four SNPs (rs9522789, rs7147228, rs2701423, rs759582) and two metabolites-monoHETE_0863 and sphingosine-1-phosphate (S1P) could predict asthma control with an AUC of 95%. Integrative ORA identified 17 significantly enriched pathways related to cellular immune response, interferon signaling, and cytokine-related signaling, for which arachidonic acid, PGE2 and S1P, in addition to six genes (CHN1, PRKCE, GNA12, OASL, OAS1, and IFIT3) appeared to drive the pathway results. Of these predictors, S1P, GNA12, and PRKCE were enriched in the results from integrative and metabolic ORAs. Through an integrative analysis of metabolomic, genomic, and methylation data from a small cohort of asthmatics, we implicate altered metabolic pathways, related to sphingolipid metabolism, in asthma control. These results provide insight into the pathophysiology of asthma control. PMID- 26421151 TI - Reproductive constraints influence habitat accessibility, segregation, and preference of sympatric albatross species. AB - BACKGROUND: The spatiotemporal distribution of animals is dependent on a suite of factors, including the distribution of resources, interactions within and between species, physiological limitations, and requirements for reproduction, dispersal, or migration. During breeding, reproductive constraints play a major role in the distribution and behavior of central place foragers, such as pelagic seabirds. We examined the foraging behavior and marine habitat selection of Laysan (Phoebastria immutabilis) and black-footed (P. nigripes) albatrosses throughout their eight month breeding cycle at Tern Island, Northwest Hawaiian Islands to evaluate how variable constraints of breeding influenced habitat availability and foraging decisions. We used satellite tracking and light-based geolocation to determine foraging locations of individuals, and applied a biologically realistic null usage model to generate control locations and model habitat preference under a case-control design. Remotely sensed oceanographic data were used to characterize albatross habitats in the North Pacific. RESULTS: Individuals of both species ranged significantly farther and for longer durations during incubation and chick-rearing compared to the brooding period. Interspecific segregation of core foraging areas was observed during incubation and chick rearing, but not during brooding. At-sea activity patterns were most similar between species during brooding; neither species altered foraging effort to compensate for presumed low prey availability and high energy demands during this stage. Habitat selection during long-ranging movements was most strongly associated with sea surface temperature for both species, with a preference for cooler ocean temperatures compared to overall availability. During brooding, lower explanatory power of habitat models was likely related to the narrow range of ocean temperatures available for selection. CONCLUSIONS: Laysan and black footed albatrosses differ from other albatross species in that they breed in an oligotrophic marine environment. During incubation and chick-rearing, they travel to cooler, more productive waters, but are restricted to the low-productivity environment near the colony during brooding, when energy requirements are greatest. Compared to other albatross species, Laysan and black-footed albatrosses spend a greater proportion of time in flight when foraging, especially during the brooding period; this strategy may be adaptive for locating dispersed prey in an oligotrophic environment. PMID- 26421152 TI - Investigation of potential genotoxic activity using the SOS Chromotest for real paracetamol wastewater and the wastewater treated by the Fenton process. AB - BACKGROUND: The potential genotoxic activity associated with high strength real paracetamol (PCT) wastewater (COD = 40,000 mg/L, TOC = 12,000 mg/L, BOD5 = 19,320 mg/L) from a large-scale drug-producing plant in the Marmara Region, was investigated in pre- and post- treated wastewater by the Fenton process (COD = 2,920 mg/L, TOC = 880 mg/L; BOD5 = 870 mg/L). METHODS: The SOS Chromotest, which is based on Escherichia coli PQ37 activities, was used for the assessment of genotoxicity. The corrected induction factors (CIF) values used as quantitative measurements of the genotoxic activity were obtained from a total of four different dilutions (100, 50, 6.25, and 0.078 % v/v.) for two samples, in triplicate, to detect potentially genotoxic activities with the SOS Chromotest. RESULTS: The results of the SOS Chromotest demonstrated CIFmax value of 1.24, indicating that the PCT effluent (non-treated) is genotoxic. The results of the SOS Chromotest showed an CIFmax value of 1.72, indicating that the wastewater treated by Fenton process is genotoxic. CONCLUSIONS: The findings of this study clearly reveal that the PCT wastewater (non-treated) samples have a potentially hazardous impact on the aquatic environment before treatment, and in the wastewater that was treated by the Fenton process, genotoxicity generally increased. PMID- 26421153 TI - A survey on parasite management by equine veterinarians highlights the need for a regulation change. AB - INTRODUCTION: In-depth knowledge of the use of anthelminthics in the field, especially by veterinarians, is required to design more sustainable parasite control strategies. MATERIALS AND METHODS: An online survey was sent by e-mail to 940 equine veterinary practitioners to describe their equine practice, their awareness about parasites and the management strategies they apply. RESULTS: Gastrointestinal parasites were generally considered (68%) as an issue of moderate importance. Drug efficacy failure was a minor or moderate issue for 47% and 48% of responders, respectively. Parasite management mostly relied on the use of systematic calendar treatments across a wide variety of horse owners (ie, riding schools, studs or hobby horse owners). Almost half of the practitioners (42%) never performed Faecal Egg Count (FEC) before drenching. Horse owners or their employees in charge of equines were reported to be the only person managing drenching in 59% of the collected answers. This was associated with the report of many off-label uses of anthelmintics and the frequent buying of drugs using the internet. CONCLUSIONS: Given the critical situation regarding anthelmintic resistance, it seems necessary for veterinarians to reclaim parasite management and prevention as a specific topic. Implementation of stricter regulations for use of anthelmintics, like the one applied in Denmark, may make parasitic management in equids more sustainable. PMID- 26421154 TI - Cardiac device-associated lead infection: a diagnosis not to be missed. AB - A 66-year-old gentleman was admitted to hospital with a history of general malaise for 5 months. His symptoms worsened 2 weeks prior to presentation. He experienced swinging pyrexia, night sweats and shortness of breath on exertion. Initial evaluation did not reveal any source of infection. Subsequent investigation revealed infection with vegetation affecting the intra-cardiac leads of cardiac resynchronization therapy device (CRT-D). The patient was treated with prolonged intravenous antibiotics and removal of the device and indwelling leads. The patient made a full recovery and a new device was implanted. PMID- 26421155 TI - Allergic angina following wasp sting: Kounis syndrome. AB - Kounis syndrome is defined as an acute coronary syndrome triggered by the release of inflammatory mediators following an allergic insult characterized by acute onset of breathlessness, palpitations, diaphoresis and chest tightness (Gazquez V, Dalmau G, Gaig P, Gomez C, Navarro S, Merce J. Kounis syndrome: report of 5 cases. J Investig Allergol Clin Immunol 2010;20:162-5). We report a 20-year-male patient who presented with acute myocardial infarction following a wasp sting at our institute. ECG showed non-ST-elevation myocardial infarction. Symptoms settled with hydrocortisone and adrenaline. Coronary angiogram revealed normal epicardial coronaries. PMID- 26421156 TI - Acute renal vein thrombosis and nephrotic syndrome in the setting of retroperitoneal fibrosis. AB - Idiopathic retroperitoneal fibrosis (RPF) is a rare disease that involves non specific inflammation and fibrosis surrounding the aorta. As a result, RPF is a challenging diagnosis to make; patients often seek medical attention after complications arise, such as nephrotic syndrome. The patient in our case report initially complained of flank pain. Laboratory evaluation revealed acute renal failure and nephrotic syndrome with substantial proteinuria. Multiple imaging modalities demonstrated a large, ill-defined, infiltrative retroperitoneal soft tissue mass that encased the great vessels. The patient was also noted to have acute left renal vein thrombosis. Although the patient was eventually diagnosed with RPF of unknown etiology, his clinical course is particularly unique given the rarity of the renal vein thrombosis. This case report adds a value to the medical community by helping to elucidate RPF and exposing its potentially life threatening complications. PMID- 26421157 TI - Neuro-Behcet's: a diagnostic challenge. AB - Behcet's disease (BD) is characterized by recurrent oral and genital ulcers and uveitis. It is also known to affect various organs; however, central nervous system involvement is rare and may cause parenchymal or vascular lesions with distinct clinical syndromes. Various viral encephalitides are important differential diagnoses. MRI may aid the correct diagnosis. This case report describes a patient with acute severe neurological involvement due to neuro-BD. PMID- 26421158 TI - Spontaneous oesophageal rupture: a diagnostic challenge in resource-limited setting. AB - Spontaneous oesophageal rupture after swallowing a bolus of food is a very rare condition. In resource-limited settings, it is very challenging to diagnose this condition especially when its presentation is atypical. Its prognosis is very poor when diagnosis is delayed due to risk of mediastinitis. We report a case of 37-year-old man who was admitted to our hospital complaining of sudden onset of chest tightness and pain after a meal 8 h prior to admission. Urgent chest radiograph revealed right hydropneumothorax with collapsed lung. Water-seal drainage was established gushing 1200 ml of food materials. Definitive diagnosis of oesophageal rupture was reached after post-mortem. PMID- 26421159 TI - Complete stent fracture 1 year after LIMA PCI due to LIMA and subclavian artery dissection. AB - Stent platforms are prone to fracture while incidental data are demonstrating a potential unfavorable outcome. Predisposing factors usually involve long lesions and tortuous vessels requiring more than one stent. This issue is magnified when it involves a periprocedural iatrogenic left internal mammary artery (LIMA) and subclavian artery dissection. In such complex clinical scenarios, the risk of potential complications including stent fractures is thought to be higher, though there is no data to determine the prognosis or to outline the outcomes of any management option. We present a case of complete stent fracture 1 year after LIMA percutaneous coronary intervention due to LIMA and subclavian artery dissection highlighting the circumstantial evidence in the literature that guided our management decisions. PMID- 26421160 TI - Corticosteroid induced hyperosmolar hyperglycaemic state and hemiballismus. AB - We present an 89-year-old man with new onset of left-sided hemiballismus affecting his face, arm and leg. He was found to have hyperglycaemia with a glucose level of 20.2 mmol/l and had started prednisolone 3 months earlier for polymyalgia rheumatica. A T 2-weighted magnetic resonance scan of the brain showed a hypointense lesion of the right lentiform nucleus. At follow-up, his symptoms had improved with treatment for diabetes mellitus. To our knowledge, this is the first patient to develop hemiballismus after starting corticosteroids. PMID- 26421161 TI - An unusual cause of suicidal ideations. AB - While the differential for suicidal ideations is broad, it is known that pathologic brain issues are a cause. Here, a case is presented of a gentleman who had an unusual growth into his frontal lobe leading to the suicidal ideations. The fact that he is chronically immunosuppressed likely led to this unique situation. PMID- 26421162 TI - Diseases Led to Refer Iranian Pilgrims From Hajj in 2012. AB - BACKGROUND: Some Iranian pilgrims are referred to Iran because of catching a new disease or exacerbation of their disease during the Hajj ceremony. These diseases need prolonged and specialized treatments. Investigation of the reasons led to their return to Iran is useful and effective in policy-making and planning of preventive health services. OBJECTIVES: This study aimed to investigate the causes of referring Iranian patients to Iran during Hajj in 2010. PATIENTS AND METHODS: In this cross-sectional study, all Iranian pilgrim cases in Hajj (2012) who referred to Iran were studied, and data analysis was performed. Demographic data and the causes of return to Iran during and after Hajj rituals were analyzed. RESULTS: A total of 106 cases were referred Iran during Hajj 2012. Psychiatric problems, with 26.4% allocated the highest rate of return to Iran during Hajj days, and significant difference was observed in the reasons before and after performing Hajj rituals (P = 0.001). CONCLUSIONS: Psychiatric, neurological, gastrointestinal, and respiratory diseases are the most frequent reasons of referring patients to Iran. More accuracy in screening and care of patients are recommended before Hajj in order to prevent references to Iran and its complications. PMID- 26421163 TI - Impact of Oral Sensory Motor Stimulation on Feeding Performance, Length of Hospital Stay, and Weight Gain of Preterm Infants in NICU. AB - BACKGROUND: One of the limiting factors for early hospital discharge in preterm infants is their inability to feed sufficiently to obtain consistent weight gain. Therefore, feeding difficulty is one of the most significant issues with which a preterm infant is faced. OBJECTIVES: The purpose of this study was to examine the effect of oral sensory motor stimulation on feeding performance, length of hospital stay, and weight gain in preterm infants at 30 - 32 weeks of gestational age. PATIENTS AND METHODS: Premature infants (n = 20) were randomly assigned to experimental and control groups. The experimental group received oral sensory motor stimulation of the oral structures (15 minutes / day) for 10 successive days, while these stimulations were not offered to the control group. Days elapsed to achieve oral feeding, length of hospital stay, and weight gain in the two groups were assessed. RESULTS: Transition to oral feeding was acquired significantly earlier in the infants in the experimental group than in the controls: 13 and 26 days, respectively (P < 0.001). Likewise, the length of hospitalization was significantly shorter in the experimental group than in the control group: 32 days and 38 days, correspondingly (P < 0.05). The two groups showed no significant difference in terms of weight gain in the first, second, third, and fourth weeks of birth: first week: 100 vs. 110; second week: 99 vs. 111; third week: 120 vs. 135; and fourth week: 129 vs. 140. CONCLUSIONS: The present research revealed that the number of days to reach oral feeding in our preterm babies was decreased by oral motor stimulation, which in turn conferred earlier hospital discharge. PMID- 26421164 TI - Epidemiology and Management Cost of Myocardial Infarction in North Punjab, Pakistan. AB - BACKGROUND: Coronary heart disease (CHD) is an important cause of morbidity and mortality in Pakistan. The temporal trends in the risk factors for myocardial infarction (MI) and the impact of socioeconomic status on these risk factors remain ambiguous. OBJECTIVES: The objectives of the present analysis were to investigate the potential association between various risk factors and MI in North Punjab, Pakistan, and to assess the status of the control of the risk factors associated with MI in this population. PATIENTS AND METHODS: The present study included 515 patients admitted to the coronary care units or equivalent cardiology wards of the participating hospitals between 2011 and 2012 in North Punjab, Pakistan. The analysis was focused on identifying the socioeconomic status, lifestyle, family history of MI, and risk factors (i.e. hypertension, diabetes, smoking, and hyperlipidemia). A structured questionnaire was designed to collect data. The lipid profile was recorded from the investigation chart of every patient. For statistical analysis, the Kruskal Wallis, Mann-Whitney U, Wilcoxon, and chi-square tests were used. RESULTS: MI was common in the males at the age of 41 - 60 years as compared to the females (P = 0.015). Patients with a positive parental history of CHD experienced MI at a younger age (P = 0.0001) at a body mass index (BMI) <= 25 kg/m(2). Sedentary lifestyle (70%) and smoking (60%) had a male predominance. Hypertension accounted for nearly 37%, hyperlipidemia 26%, and diabetes 19.4% of the rural and urban subjects (P < 0.01). High-density lipoprotein cholesterol decreased (up to 34 mg/dl), while low density lipoprotein cholesterol and hypertension increased with age. The mean monthly cost of medicines and physicians' fees per patient was 2381.132 Pakistani Rupees (24.24 USD). CONCLUSIONS: Higher BMI, positive family history, smoking, hypertension, hyperlipidemia, and diabetes were the strong predictors of MI in North Punjab, Pakistan. Preventive efforts are needed to start early in life and continue throughout the life course. PMID- 26421165 TI - Traumatic Lumbosacral Spondylolisthesis: A Case Report. AB - INTRODUCTION: Traumatic lumbar spondylolisthesis is rare disease and in the literature, different surgical approaches, including anterior, posterior, or combined approaches (posterior and anterior) are used to treat the lesion. CASE PRESENTATION: We treated a case of traumatic lumbosacral spondylolisthesis using posterior approach and the patient showed a satisfactory outcome. At the final follow-up, he was completely asymptomatic, and radiographic images revealed normal lumbar alignment and a solid interbody fusion. CONCLUSIONS: Traumatic lumbosacral spondylolisthesis can be treated using posterior approach alone to obtain reduction, decompression, and solid fusion. PMID- 26421166 TI - Desmopressin, Imipramine, and Oxybutynin in the Treatment of Primary Nocturnal Enuresis: A Randomized Clinical Trial. AB - BACKGROUND: Nocturnal enuresis is the most common pediatric urologic problem in outpatient clinics. OBJECTIVES: To assess the effect of various monotherapies, and comparing the effects of desmopressin, imipramine, and oxybutynin in children with enuresis, as well as the influence of socioeconomic and cultural factors of their families on the response and relapse rates. PATIENTS AND METHODS: The study was a randomized clinical trial conducted on 92 children aged 5 - 14 years, referred to the pediatric clinic of Semnan University Hospital in Semnan, Iran. Children with primary nocturnal enuresis were randomly allocated to three different treatment groups: desmopressin (n = 30), imipramine (n = 31), and oxybutynin (n = 31) all for 6 weeks. The socioeconomic and demographic characteristics of all participants were recorded. The number of wet nights per week was noted at the end of the 6-week-trial, and children were followed up to three months for relapse. RESULTS: Children in the oxybutynin group showed a slightly higher response rate (71.0% success) and a lower relapse rate (31.8%), while in the desmopressin group the response and relapse rates were 63.3% and 57.9%, respectively, and in the imipramine group 61.3% and 63.2%, respectively. However, the difference between the 3 groups in terms of response (P = 0.701) and relapse rates (P = 0.095) was not statistically significant. CONCLUSIONS: There is no significant difference between monotherapy with desmopressin, imipramine or oxybutynin in children with enuresis. However, oxybutynin showed a higher response rate and a lower relapse rate compared to other medications. More clinical trials with a larger sample size are needed to clarify these uncertainties. PMID- 26421167 TI - Clinical Assessment of Nursing Care Regarding Hemovigilance in Neonatal Wards and Neonatal Intensive Care Units in Selected Hospitals Affiliated to Shahid Beheshti University of Medical Sciences (2013 - 2014). AB - BACKGROUND: Hemovigilance is a series of surveillance procedures encompassing the entire transfusion chain from the collection of blood and its components to the follow-up of its recipients. It is intended to collect and access information on unanticipated or adverse effects stemming from the therapeutic use of labile blood products. Blood transfusion, particularly in neonates, requires meticulous clinical assessment to ensure safety before, during, and after the procedure. Therefore, it is essential to investigate how nurses and other health care providers implement hemovigilance with a view to elevating the standards of care. OBJECTIVES: The aim of this study, conducted between 2013 and 2014, was to assess nursing care regarding hemovigilance in the neonatal wards and neonatal intensive care units (NICUs) of selected hospitals affiliated to Shahid Beheshti University of Medical Sciences. MATERIALS AND METHODS: This descriptive study assessed nursing care concerning hemovigilance in 144 neonates. Data were collected using a checklist at the neonatal wards and NICUs of Mahdiyeh, Mofid, and Imam Hussain hospitals affiliated to Shahid Beheshti University of Medical Sciences. The checklist contained information on the standard of care in relation to neonatal hemovigilance in three components of request, transfusion, and documentation. Descriptive statistics with the Statistical Package for the Social Sciences (version 21) were used to analyze the collected data. RESULTS: The rates of compliance with the hemovigilance guidelines in terms of request, transfusion, and documentation were 47%, 63.2%, and 68%, correspondingly, with a total score of 59.6% in all areas of research. Accordingly, compliance with hemovigilance guidelines was highest in documentation (68%), followed by transfusion (63.2%) and request (47%). CONCLUSIONS: The overall score of nursing care as regards adherence to the neonatal hemovigilance guidelines was 59.6% in the present study, indicating a lack of care and failure in training in this regard. PMID- 26421168 TI - Prevalence of Hepatitis B Surface Antigen in Pregnant Women in Beheshti Hospital of Kashan, Isfahan. AB - BACKGROUND: The transmission of hepatitis B virus (HBV) is parenteral, sexual and prenatal. Prevention of vertical transmission of HBV is extremely important, because HBV infection in early life usually results in a chronic carrier state. There has been so much debate about hepatitis B surface antigen (HBsAg) screening in pregnant women. OBJECTIVES: The aim of this study was to determine the prevalence of HBsAg+ among pregnant women referred to Beheshti hospital in Kashan in 2012. PATIENTS AND METHODS: This descriptive study was carried out on 768 pregnant women, hospitalized in Beheshti Hospital of Kashan in 2012. After obtaining consent forms, the questionnaires including demographic and HBV infection-associated risk factors were filled through interview and then 5 mL blood was taken from each patient and HBsAg was examined by the enzyme-linked immunosorbent assay (ELISA) method. These data were analyzed by statistical package for the social science (SPSS) software. RESULTS: A total of 12 (1.56%) out of 768 pregnant women were HBsAg+. The mean age of HBsAg+ cases was 24.5 +/- 4 years. Most of the HBsAg+ cases (66.6%) were uneducated; 17.7% of the pregnant women were not Iranian, of which 7.4% were HBsAg+. There was no high-risk job, recent dentistry interruption or skin tattoo among the HBsAg+ cases. CONCLUSIONS: In this study, 1.56% of pregnant women were HBsAg+, which was higher than the previous studies. This increasing prevalence may be due to the increase of non Iranians' migrations to Iran. Control of migration and screening and vaccination of these groups should be considered by health policy makers. PMID- 26421169 TI - Study of Psycho-Social Factors Affecting Traffic Accidents Among Young Boys in Tehran. AB - BACKGROUND: Unprecedented growth of fatalities due to traffic accidents in the recent years has raised great concerns and efforts of authorities in order to identify and control the causes of these accidents. OBJECTIVES: In the present study, the contribution of psychological, social, demographic, environmental and behavioral factors on traffic accidents was studied for young boys in Tehran, emphasizing the importance of psychosocial factors. PATIENTS AND METHODS: The design of the present study was quantitative (correlational) in which a sample population including 253 boys from Tehran (Iran) with an age range of 18 to 24 who had been referred to insurance institutions, hospitals, correctional facilities as well as prisons, were selected using stratified cluster sampling during the year 2013.The subjects completed the following questionnaires: demographic, general health, lifestyle, Manchester Driving Behavior Questionnaire (MDBQ), young parenting, and NEO-Five Factor Inventory (NEO-FFI). For data analysis, descriptive statistics, correlation coefficient, and inferential statistics including simultaneous regression, stepwise regression, and structural equations modeling were used. RESULTS: The findings indicated that in the psychosocial model of driving behavior (including lapses, mistakes, and intentional violations) and accidents, psychological factors, depression (P < 0.02), personality trait of conscientiousness (P < 0.02), failure schema due to the parenting style of mother (P = 0.001), and perception of police commands (P < 0.002), played an important role in predicting driving behavior. Among social factors, perception of police regulations (P = 0.003), had an important effect on violations and mistakes. Among environmental and behavioral factors, major factors such as driving age (P = 0.001), drug and alcohol use (P = 0.001), having driver's license (P = 0.013), records of imprisonment or committing a crime (P = 0.012) were also able to predict occurrence of accidents. CONCLUSIONS: As the results of this study show, different factors contribute to different driving behaviors and accidents. The broad scope of these factors links accidents to other social issues and damages. PMID- 26421170 TI - Prognostic Significance of Nuclear beta-Catenin Expression in Patients with Colorectal Cancer from Iran. AB - BACKGROUND: Beta catenin plays a key role in cancer tumorigenesis. However, its prognostic significance in patients with colorectal cancer (CRC) remains controversial. It has been demonstrated that 90% of all tumors have a mutation in individual components of multiple oncogenes in Wnt/beta-catenin pathway. Accumulation of nuclear beta-catenin in cytoplasm leads to uncontrolled cell proliferation. Thus, nuclear beta-catenin accumulation may be a valuable biomarker associated with invasion, metastasis and poor prognosis of CRC. OBJECTIVES: In this study the prognostic value of beta catenin expression in 165 Iranian CRC patients was evaluated. PATIENTS AND METHODS: In this cross sectional retrospective study immunohistochemistry analyses of formalin-fixed paraffin embedded (FFPE) tumor tissues were performed to characterize the expression of nuclear beta-catenin in a series of 165 Iranian patients with colorectal carcinoma. Heat-induced antigen retrieval using the microwave method was applied for all staining procedures. Staining was scored independently by two observers, and a high level of concordance (90%) was achieved. Statistical analysis was done using the SPSS software for Windows, version 13.0.0 (SPSS Inc., Chicago, IL). Two tailed P < 0.05 was considered statistically significant. RESULTS: The patients consisted of 85 males and 80 females. Eighty-eight patients had primary tumor of the rectum and sigmoid, while 77 patients had primary tumor of the colon. The mean period of follow-up was 47.2 +/- 10 months and the median period of follow up was 38 months (range 6 - 58) for each patient. Of 165 tumors, 32 tumors (19.39 %) showed expression of beta-catenin and 133 (80.6 %) were negative for beta catenin expression. Based on our findings the distribution of Microsatellite Instability (MSI) status differed between patients with nuclear beta-catenin positive and negative tumors and this difference was significant (P = 0.001). Patients with nuclear beta-catenin positive expression profile were found to be younger than patients with negative nuclear beta-catenin expression (P = 0.010). Univariate and multivariate analysis showed that tumors with beta-catenin expression had a poorer prognosis compared to tumors without beta-catenin expression. CONCLUSIONS: According to our findings, the distribution of nuclear b catenin expression is a poor prognostic marker in patients with colon cancer. PMID- 26421171 TI - Factors Influencing the Successful Aging of Iranian Old Adult Women. AB - BACKGROUND: Aging is an irreversible natural process characterized by a decline in both the physical and mental status of individuals. Because of multiple factors, this process and its consequences vary greatly between individuals. A successful aging (SA) is the target of current health policies and well-being of individuals. Knowing the factors that contribute to SA and its barriers would translate in measurements that increase the quality of life of elderly and reduce health costs. OBJECTIVES: The aim of this study was to explore barriers and facilitators to Iranian elderly women's SA. PATIENTS AND METHODS: A purposive sample of 16 elderly women, aged 61 - 96 years, was recruited for this qualitative content analysis study. Study data were collected during 2012 -.2013 by conducting 16 face-to-face semi-structured in-depth interviews. We continued the data collection until reaching saturation. Study data were analyzed concurrently with data collection, by using the conventional qualitative content analysis approach. RESULTS: Barriers and facilitators to Iranian elderly women's SA fell into five main categories, including availability of support systems, state of health, personal capabilities, personality characteristics, and lifestyle. CONCLUSIONS: Availability of support systems, state of health, personal capabilities, personality characteristics, and lifestyle were the main interrelated factors affecting Iranian elderly women's SA. Accordingly, providing elderly women with strong educational, emotional, financial, cultural, and social supports can help facilitate their SA. PMID- 26421172 TI - Resiliency Improvements in Medical Emergency Staff in Burn Missions: A Qualitative Study in an Iranian Context. AB - BACKGROUND: Medical emergency staff complete understanding of the nature of resiliency in burn events is a prerequisite for improving the quality of clinical service delivery in pre-hospital burn events. OBJECTIVES: The present study aimed to describe resiliency in view of medical emergency staff in burn events. MATERIALS AND METHODS: The present qualitative study was performed using a content analysis method. In total, 18 Iranian emergency care personnel participated in the study. A purposeful sampling method was applied until reaching data saturation. Data was collected using semi-structured interviews and field observations. Afterwards, data was analyzed by face content analysis. RESULTS: By analyzing 456 primary codes, four main concepts including: 1) scene safety/security, 2) effective clinical decision making, 3) self-efficacy and 4) religious support were extracted through content analysis from experiences of pre hospital emergency personnel during burn care. CONCLUSIONS: Different factors affect resiliency improvements in medical emergency staff and consequently the quality of pre-hospital burn care. This study showed that various factors such as scene security/safety, effective decision making, self-efficacy and religious support are effective in the improvement of resiliency and the quality of pre hospital emergency care. PMID- 26421173 TI - Caloric Restriction and Formalin-Induced Inflammation: An Experimental Study in Rat Model. AB - BACKGROUND: Acute and chronic inflammations are difficult to control. Using chemical anti-inflammatory medications along with their complications considerably limit their use. According to Traditional Iranian Medicine (TIM), there is an important relation between inflammation and Imtila (food and blood accumulation in the body); food reduction or its more modern equivalent Caloric Restriction (CR) may act against both Imtila and inflammation. OBJECTIVES: This experimental study aimed to investigate the effect of 30% reduction in daily calorie intake on inflammation in rats. MATERIALS AND METHODS: A total of 18 male rats (Rattus rattus) weighing 220 to 270 g were obtained. Then, the inflammation was induced by injecting formalin in their paws. Next, the rats were randomized by generating random numbers into two equal groups (9 + 9) putting on either normal diet (controls) or a similar diet with 30% reduction of calorie (cases). Paw volume changes were recorded twice per day by one observer in both groups using a standard plethysmometer for 8 consecutive days. Serum C-reactive protein (CRP), Erythrocyte Sedimentation Rate (ESR), complete blood count (erythrocyte, platelet, and white blood cell) and hemoglobin were compared between the groups. RESULTS: Decline of both body weight and paw volume was significantly more prominent in the case than in the control rats within the study period (P < 0.001 and < 0.001, respectively). Paw volume decrease was more prominent after day 3. On day 8, serum CRP-positive (1 or 2 +) rats were more frequent in ad libitum fed group comparing with those received CR (33.3% vs. 11.1%). This difference, however, was insignificant (P = 0.58). At the same time, mean ESR was significantly higher in the control rats comparing with that in the case group (29.00 +/- 2.89 h vs. 14.00 +/- 1.55 h; P = 0.001). Other serum parameters were not significantly different between the two groups at endpoint. CONCLUSIONS: Rats fed with a 30% calorie-restricted diet in comparison with to ad libitum fed controls for 8 days had significantly more prominent regression of inflammation. PMID- 26421174 TI - A Semi-Experimental Study to Assess Whether the Current Recommended Protocol for Treating Vitamin D Deficiency is Enough? AB - BACKGROUND: Urbanization and diet change have increased the prevalence of Vitamin D deficiency. Unfortunately, none of the suggested treatments is widely accepted. OBJECTIVES: Therefore, we evaluated the most used and suggested protocol for treating Vitamin D deficiency in Percutaneous coronary intervention (PCI) candidate patients referred to our hospital in a short-term clinical trial. PATIENTS AND METHODS: All patients with coronary artery disease, referred to our hospital and candidates for PCI (drug eluted stents) were included. Deficient patients were randomly assigned to treatment (Vitamin D3 pearls of 50,000 IU; one per week for 10 weeks then one pearl every month for maintenance) and non treatment groups. Vitamin D was measured after nine months. RESULTS: After initial evaluation, 116 cases were found to be deficient, and were divided into two equal groups of 58. No significant difference was found between the normal, treated and non-treated groups regarding age and gender. Thirty-two out of 58 (55.1%) subjects were vitamin D deficient and reached normal levels by taking supplements and seven out of 58 (12%) were deficient and reached normal levels without taking supplements, with the difference being significant (P < 0.001). CONCLUSIONS: The used protocol is not enough for treating Vitamin D deficiency. Furthermore, the protocol should be revised according to baseline Vitamin D classification. PMID- 26421175 TI - No Evidence for Association Between Norepinephrine Transporter-3081 (A/T) Polymorphism and Attention Deficit Hyperactivity Disorder in Iranian Population. AB - BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) can lead to drastic problems for the patient and its worldwide prevalence is 5%-12%. It also has many comorbidities with other disorders, and the genetic contribution seems the most significant cause. OBJECTIVES: The current study was conducted to investigate the association between norepinephrine transporter-3081 (A/T) polymorphisms and ADHD in Iranian population. PATIENTS AND METHODS: Participants were chosen from children and adolescents diagnosed with ADHD referred to Imam Hoseyn Hospital. A child and adolescent psychiatrist confirmed the diagnosis using the Kiddie-Sads Present and Lifetime Version (K-SADS-PL) semi-structural interview. The control group was from pupils of schools in Tehran (capital city of Iran) who had no history or presence of psychiatric and medical complications. Also, a child and adolescent psychiatrist confirmed their health using the K-SADS-PL semi structural interview. Genetic examinations were DNA distraction, Polymerase Chain Reaction (PCR), and Restricted Fragment Length Polymorphism (RFLP), which were conducted according to standard protocols. The statistical analysis was performed using chi-square and Fisher's exact test in SPSS version 21. RESULTS: The percentages of ADHD subtypes for combined, inattentive, and hyperactive/impulsive were 72.2%, 17.2%, and 11.9%, respectively. There was no significant association between norepinephrine transporter polymorphism and ADHD (P = 0.81). Moreover, no significant relationship was found between gender [male (P = 0.92) and female (P = 0.63)] and polymorphism. No significant association was found between subtypes of ADHD [combined (P = 0.46), inattentive (P = 0.41), hyperactive/impulsive (P = 0.32)] and polymorphism SCL6A2. This lack of association can also be seen in gender in every subtype. CONCLUSIONS: The results of the study show no significant association between norepinephrine transporter polymorphism SCL6A2 and ADHD. PMID- 26421176 TI - Spontaneous Nontraumatic Pneumocephalus: A Case Report. AB - INTRODUCTION: Spontaneous pneumocephalus without any pathological condition is very rare. We described a patient with spontaneous pneumocephalus probably arising from the relatively enlarged air-filling sphenoid sinus. CASE PRESENTATION: A 51-year-old woman admitted Imam Reza Hospital, Mashhad, Iran with a sudden onset of severe headache and nausea without any neurological deficit. Brain computed tomography (CT) scan was performed to role out any pathology in the brain. Brain CT revealed large ethmoidal and sphenoid sinuses and disseminated intracranial pneumocephalus. A Cerebrospinal Fluid (CSF) examination was performed to rule out meningitis. Further evaluation confirmed a small defect in the sphenoid sinus. She has no recurrent headache or other symptoms after about six-month follow-up. CONCLUSIONS: An extremely rare condition, a spontaneous intracranial pneumocephalus with skull base defect origin could be considered as a possible diagnosis in patients with sudden and severe headache. We can safely conclude that medical treatment and close follow-up is an effective mode of therapy in this patient. PMID- 26421177 TI - A Meta-Analysis of Randomized Clinical Trials Comparing Shorter (Less or Equal Than 6 Months) and Longer (More or Equal Than 12 Months) Dual Anti-Platelet Therapy Following Drug-Eluting Coronary Stents. AB - CONTEXT: The optimal duration of dual anti-platelet therapy (DAPT) after the implantation of drug-eluting coronary stents (DES) is still the subject of ongoing debate. This meta-analysis was performed to investigate the optimal duration between <= 6 months and >= 12 months for DAPT after implantation of DES. EVIDENCE ACQUISITION: This study was conducted at the department of cardiology, the first college of clinical medical sciences, institute of cardiovascular diseases of Three Gorges university during December 2014. Pub-med, Cochrane, Scopus and clinicaltrials.gov databases were searched for papers published until December 2014. Searches of the above databases included terms "dual anti-platelet therapy" and "myocardial infarction (MI)" and "drug-eluting stents (DES)". All the searched literatures were limited to Randomized Controlled Trials (RCTs). Quality assessments were evaluated with the Jadad quality scale. Data were extracted by two independent observers (FZ and YC). For all analyses, the 95% confidence interval (CI) was calculated and heterogeneity of the studies was analyzed using I2 statistics. RESULTS: Five RCTs with 9979 participants satisfying the inclusion criteria were finally analyzed. Overall, there were 4993 patients with shorter duration of DAPT and 4986 patients with a longer treatment. Clopidogrel was the used P2Y12 receptor inhibitor in all five RCTs. On one hand compared to shorter duration (<= 12 months) DAPT, longer duration (>= 12 months) did not reduce risk of mortality, cardiac death, cerebrovascular accidents, myocardial infarction and stent thrombosis (pooled OR 1.03, 95% Confidence Interval (CI) 0.80 - 1.32, P = 0.85, I(2) = 0%; pooled OR 0.91, 95% CI 0.64 - 1.29, P = 0.60, I(2) = 0%; pooled OR 0.84, 95% CI 0.50 - 1.42, P = 0.51, I(2) = 0%; pooled OR 1.17, 95% CI 0.87 - 1.58, P = 0.29, I(2) = 0%; pooled OR 1.36, 95% CI 0.81 - 2.29, P = 0.24, I(2) = 0%). On the other hand, longer duration (>= 12 months) could also increase the risk of thrombolysis in myocardial infarction (TIMI) major bleeding (pooled OR 0.50, 95% CI 0.29 - 0.85, P = 0.01, I(2) = 0%). CONCLUSIONS: Regarding the efficacy outcomes of the patients after DES implantation, no differences were found between shorter (<= 6 months) and longer (>= 12 months) duration of DAPT. What is worse is that longer duration (>= 12 months) was associated with increased risk of bleeding complications. PMID- 26421178 TI - Thyroid Hormone Profile in Patients With Acute Coronary Syndrome. AB - BACKGROUND: Thyroid hormone has the a major role in the cardiovascular system function and cardiac a As well as to maintain the cardiovascular homeostasis A slightly change ind thyroid status actually affects cardiovascular mortality hemodynamic. The background of this study was to define the prevalence of thyroid dysfunction in acute coronary syndrome (ACS). OBJECTIVES: The primary objective was to define the prevalence of thyroid dysfunction in acute coronary syndrome, including Non-ST Segment Elevation Myocardial Infarction (NSTEMI), ST-segment Elevation Myocardial Infarction (STEMI), and unstable angina groups. The secondary objective was to determine any associations of thyroids function tests with cardiac catheterization and mortality. PATIENTS AND METHODS: In a prospective, observational, and cross section study, we enrolled 400 patients admitted at the coronary care unit of King Abdulaziz University Hospital in Jeddah, Saudi Arabia. Venous blood samples were collected from patients for the evaluation of thyroid function (thyroids stimulating hormones, free triiodothyronine, and free thyroxin). RESULTS: Excluding those taking thyroid hormone preparations, 76.7% of patients admitted with acute coronary heart disease (ST-segment elevation myocardial infarction and Non-ST segment elevation myocardial infarction), and unstable angina had euthyroidism. Thyroid dysfunction was reported in 23.3% of patients with coronary heart disease. Overall hypothyroidism prevalence was 7.8%, while subclinical hyperthyroidism in our study was 2.7%. Overt hyperthyroidism and subclinical hyperthyroidism was reported 2.0% and 0.5%, respectively. Euthyroid sick syndrome was noticed in 41 (10.2%) of critically ill patients. The mortality rate was 9.8%; all death patients had low triiodothyronine (T3) syndrome and were associated with statistically significant low free triiodothyronine (FT3) (P > 0.001). CONCLUSIONS: No significant variance was observed among patients underwent for cardiac catheterization, STEMI, NSTEMI, unstable angina, and atrial fibrillation with respect to FT4, FT3, and TSH levels during coronary care unit hospitalization based on their profile data. PMID- 26421179 TI - Relationship Between Serum Hepcidin and Ferritin Levels in Patients With Thalassemia Major and Intermedia in Southern Iran. AB - BACKGROUND: Hepcidin is a key regulator of iron absorption in humans. It is mainly affected by hypoxia and iron stores. OBJECTIVES: The current study aimed to determine the correlation between serum hepcidin and ferritin levels in patients with Thalassemia Major (TM) and Thalassemia Intermedia (TI). PATIENTS AND METHODS: The current cross-sectional study investigated 88 randomly selected patients with Thalassemia, 48 TM and 40 TI, registered at the Thalassemia Clinic of Shiraz University of Medical Sciences, a referral center for Thalassemia in Southern Iran in 2013. All patients with TI were receiving Hydroxyurea (HU) 10 - 15 mg/kg/day for at least 10 years. The serum hepcidin, ferritin levels, hemoglobin (Hb) and nucleated Red Blood Cell (RBC) of the two groups were measured. RESULTS: No statistically significant correlation was observed between serum hepcidin and ferritin levels in any of the two groups of patients with TM (rs = 0.02, P = 0.892) or TI (rs = 0.055, P = 0.734). The median Interquartile Range (IQR) for serum hepcidin and ferritin levels were significantly higher in TM compared to TI group, (hepcidin: 87.6 (43.9) vs. 51.8 (23.4), P < 0.001; ferritin: 2208 (3761) vs. 465 (632), P < 0.001). CONCLUSIONS: There was insignificant correlation between serum hepcidin and ferritin levels in the two groups of patients with TM and TI. It seems that regulation of hepcidin in patients with Thalassemia is more affected by erythropoeitic activity than iron stores. Also, hepcidin levels were significantly higher in patients with TM than TI, possibly due to higher erythropoeitic activity in TI. In TI, it seems that low dose HU increases Hb levels and leads to transfusion-independence, but it is not high enough to suppress bone marrow activity and ineffective erythropoiesis. Consequently, serum hepcidin level decreases. PMID- 26421180 TI - Effect of Nasal Calcitonin on the Health-Related Quality of Life in Postmenopause Women Affected With Low Bone Density. AB - BACKGROUND: Physical activity and mental health could be affected by osteoporosis and various therapeutic options such as calcitonin may influence Quality Of Life (QOL) of these patients with Low Bone Density (LBD). OBJECTIVES: This study aimed to evaluate the effect of nasal calcitonin on QOL in post menopause women with LBD. PATIENTS AND METHODS: This clinical trial study was performed on one hundred and fifteen menopause women with LBD less than 1 SD in Bone Mineral Densitometry (BMD) referred to Baqiyatallah Hospital in Tehran, Iran, during 2009 - 2010. They were assigned to receive 200 IU calcitonin nasal spray along with calcium (1000 mg) and vitamin D (400 IU) for 6 months. Quality of life was assessed by Short Form 36 (SF-36) questionnaire (Persian-validated version). RESULTS: The mean age (+/- SD) of the participants was 58.75 +/- 8.15 years. Intranasal spray of calcitonin increased QOL scores significantly (88.05 +/- 15.63 vs. 92.15 +/- 13.22, P value = 0.000). Bone mineral density of spine was increased from 0.834 +/- 0.11 to 0.12 +/- 0.852 and this difference in BMD of lumbar spine was statistically significant (P value: 0.003) but not significant in femur's BMD (P value = 0.061). In comparison with BMD indexes, The QOL scores especially Mental Health domain changes had only a significant correlation with the changes of total T score in BMD (P = 0.031, Coefficient Correlation = 0.248). CONCLUSIONS: It seems that nasal spray of calcitonin can effectively improve QOL of women with LBD and QOL changes were not influenced by clinical or para-clinical alteration. Mental health domain must be more considered in further studies as a predicting domain for Health-Related Quality of Life (HR-QOL) changes. PMID- 26421181 TI - Alternative Living Kidney Donation Programs Boost Genetically Unrelated Donation. AB - Donor-recipient ABO and/or HLA incompatibility used to lead to donor decline. Development of alternative transplantation programs enabled transplantation of incompatible couples. How did that influence couple characteristics? Between 2000 and 2014, 1232 living donor transplantations have been performed. In conventional and ABO-incompatible transplantation the willing donor becomes an actual donor for the intended recipient. In kidney-exchange and domino-donation the donor donates indirectly to the intended recipient. The relationship between the donor and intended recipient was studied. There were 935 conventional and 297 alternative program transplantations. There were 66 ABO-incompatible, 68 domino paired, 62 kidney-exchange, and 104 altruistic donor transplantations. Waiting list recipients (n = 101) were excluded as they did not bring a living donor. 1131 couples remained of whom 196 participated in alternative programs. Genetically unrelated donors (486) were primarily partners. Genetically related donors (645) were siblings, parents, children, and others. Compared to genetically related couples, almost three times as many genetically unrelated couples were incompatible and participated in alternative programs (P < 0.001). 62% of couples were genetically related in the conventional donation program versus 32% in alternative programs (P < 0.001). Patient and graft survival were not significantly different between recipient programs. Alternative donation programs increase the number of transplantations by enabling genetically unrelated donors to donate. PMID- 26421182 TI - Functional and Morphological Correlations before and after Video-Documented 23 Gauge Pars Plana Vitrectomy with Membrane and ILM Peeling in Patients with Macular Pucker. AB - Purpose. To assess functional and morphological alterations following video documented surgery for epiretinal membranes. Methods. Forty-two patients underwent video-documented 23-gauge vitrectomy with peeling of epiretinal (ERM) and inner limiting membrane (ILM). Patient assessment was performed before and 3 and 6 months including best corrected visual acuity (BCVA), slit lamp biomicroscopy, SD-OCT, and central 2 degrees and 18 degrees microperimetry. In addition, all video-documented areas of peeling on the retinal surface were evaluated postoperatively using an additional focal 2 degrees microperimetry. Retinal sensitivity and BCVA were correlated with morphological changes (EZ and ELM) in the foveal region and in regions of membrane peeling. Results. Overall, BCVA increased from 0.6 (+/-0.2) to 0.2 (+/-0.2) logMAR after 6 months with an increase in retinal sensitivity (17.9 +/- 2.7 dB to 26.8 +/- 3.1 dB, p < 0.01). We observed a significant correlation between the integrity of the EZ but not of the ELM and the retinal sensitivity, overall and in peeling areas (p < 0.05). However, no significant correlation between alterations in the area of peeling and overall retinal sensitivity regarding visual acuity gain could be observed after 6 months (p > 0.05). In contrast, overall postoperative retinal sensitivity was significantly decreased in patients with a visual acuity gain lower than 2 lines (p < 0.05) correlating with EZ defects seen in OCT. Conclusions. Mechanical trauma of epiretinal membrane and ILM peeling due to the use of intraocular forceps may affect the outer retinal structure. Nevertheless, these changes seem to have no significant impact on postoperative functional outcome. PMID- 26421184 TI - Hepatic but Not CNS-Expressed Human C-Reactive Protein Inhibits Experimental Autoimmune Encephalomyelitis in Transgenic Mice. AB - We recently demonstrated that human C-reactive protein (CRP), expressed hepatically in transgenic mice (CRPtg), improved the outcome of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). The liver is the primary site of CRP synthesis in humans and in CRPtg mice but is also expressed by both at low levels in the CNS. To determine if CNS expression of human CRP is sufficient to impact EAE, we generated neuronal CRP transgenic mice (nCRPtg) wherein human CRP expression is driven by the neuron-specific Ca(2+)/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha) gene promoter. We found that hepatically expressed/blood-borne CRP, but not CNS expressed CRP, lessened EAE severity. These outcomes indicate that the protective actions of human CRP in EAE are manifested in the periphery and not in the CNS and reveal a previously unappreciated site specificity for the beneficial actions of CRP in CNS disease. PMID- 26421183 TI - Retinal Changes Induced by Epiretinal Tangential Forces. AB - Two kinds of forces are active in vitreoretinal traction diseases: tangential and anterior-posterior forces. However, tangential forces are less characterized and classified in literature compared to the anterior-posterior ones. Tangential epiretinal forces are mainly due to anomalous posterior vitreous detachment (PVD), vitreoschisis, vitreopapillary adhesion (VPA), and epiretinal membranes (ERMs). Anomalous PVD plays a key role in the formation of the tangential vectorial forces on the retinal surface as consequence of gel liquefaction (synchysis) without sufficient and fast vitreous dehiscence at the vitreoretinal interface. The anomalous and persistent adherence of the posterior hyaloid to the retina can lead to vitreomacular/vitreopapillary adhesion or to a formation of avascular fibrocellular tissue (ERM) resulting from the proliferation and transdifferentiation of hyalocytes resident in the cortical vitreous remnants after vitreoschisis. The right interpretation of the forces involved in the epiretinal tangential tractions helps in a better definition of diagnosis, progression, prognosis, and surgical outcomes of vitreomacular interfaces. PMID- 26421185 TI - Green Space and Child Weight Status: Does Outcome Measurement Matter? Evidence from an Australian Longitudinal Study. AB - OBJECTIVE: To examine whether neighbourhood green space is beneficially associated with (i) waist circumference (WC) and (ii) waist-to-height ratio (WtHR) across childhood. METHODS: Gender-stratified multilevel linear regressions were used to examine associations between green space and objective measures of weight status in the Longitudinal Study of Australian Children, a nationally representative source of data on 4,423 children aged 6 y to 13 y. WC and WtHR were measured objectively. Percentage green space within the local area of residence was calculated. Effect modification by age was explored, adjusting for socioeconomic confounding. RESULTS: Compared to peers with 0-5% green space locally, boys and girls with >40% green space tended to have lower WC (beta boys -1.15, 95% CI -2.44, 0.14; beta girls -0.21, 95% CI -1.47, 1.05) and WtHR (beta boys -0.82, 95% CI -1.65, 0.01; beta girls -0.32, 95% CI -1.13, 0.49). Associations among boys were contingent upon age (p valuesage*green space < 0.001) and robust to adjustment for socioeconomic variables. The benefits of greener neighbourhoods appeared from age 7, with mean WC and WtHR for boys aged 13 y with >40% green space at 73.85 cm and 45.75% compared to those with 0-5% green space at 75.18 cm and 46.62%, respectively. CONCLUSIONS: Greener neighbourhoods appear beneficial to alternative child weight status measures, particularly among boys. PMID- 26421186 TI - Development of Delirium in the Intensive Care Unit in Patients after Endovascular Aortic Repair: A Retrospective Evaluation of the Prevalence and Risk Factors. AB - Delirium is an acute form of nervous system dysfunction often observed in patients in the intensive care unit. Endovascular aortic repair (EVAR) is considered a minimally invasive surgical treatment for abdominal aortic aneurysm. Although the operation method is widely used, there are few investigations of the rate and risk factors of delirium development after the operation. In this study, we retrospectively examined the rate of delirium development in the intensive care unit (ICU) after EVAR, as well as the associated preoperative risk factors and effects on the lengths of ICU and hospital stays. We examined the 81 consecutive patients who underwent elective EVAR between November 2013 and August 2014. The Intensive Care Delirium Screening Checklist was used to diagnose delirium. Twenty patients (24.7%) were diagnosed with delirium in this study. The ICU and hospital length of stays of patients with delirium were 3.3 +/- 2.4 days and 14.5 +/- 11.9 days, respectively, the latter of which was significantly longer than that of patients without delirium (p = 0.019). Additionally, renal dysfunction, preoperative benzodiazepine use, and intraoperative transfusion were found to be risk factors for the development of delirium after elective EVAR. PMID- 26421187 TI - Soft Tissue Masses of Hand: A Radio-Pathological Correlation. AB - Aim. To evaluate soft tissue masses of the hand with magnetic resonance imaging (MRI) and ultrasonography (USG) and to correlate imaging findings with pathological findings. Material and Methods. Thirty-five patients with soft tissue masses of the hand were evaluated with high resolution USG and contrast enhanced MRI of the hand, prospectively over a period of 2.5 years. The radiological diagnosis was then compared with cytology/histopathology. Results. There were a total of 19 (55%) females. The mean age was 27.45 +/- 14.7 years. Majority (45%) of cases were heteroechoic. Four cases were predominantly hyperechoic. These were later diagnosed as lipomas. Four cases were anechoic (diagnosed as ganglions). Only four lesions showed hyperintense signal on T1 weighted images. Out of these, 3 were lipomas and one was cavernous haemangioma. Three lesions were hypointense on T2-weighted images. All these lesions were diagnosed as giant cell tumor of the tendon sheath. A correct diagnosis was possible on MRI in 80% of cases (n = 28). Conclusion. MRI provides specific findings for diagnosis of certain soft tissue lesions of the hand. Ultrasonography allows accurate diagnosis of hemangioma/vascular malformations. However, in most conditions, imaging findings are nonspecific and diagnosis rests on pathologic evaluation. PMID- 26421188 TI - Hypoxia Strongly Affects Mitochondrial Ribosomal Proteins and Translocases, as Shown by Quantitative Proteomics of HeLa Cells. AB - Hypoxia is an important and common characteristic of many human tumors. It is a challenge clinically due to the correlation with poor prognosis and resistance to radiation and chemotherapy. Understanding the biochemical response to hypoxia would facilitate the development of novel therapeutics for cancer treatment. Here, we investigate alterations in gene expression in response to hypoxia by quantitative proteome analysis using stable isotope labeling with amino acids in cell culture (SILAC) in conjunction with LCMS/MS. Human HeLa cells were kept either in a hypoxic environment or under normoxic conditions. 125 proteins were found to be regulated, with maximum alteration of 18-fold. In particular, three clusters of differentially regulated proteins were identified, showing significant upregulation of glycolysis and downregulation of mitochondrial ribosomal proteins and translocases. This interaction is likely orchestrated by HIF-1. We also investigated the effect of hypoxia on the cell cycle, which shows accumulation in G1 and a prolonged S phase under these conditions. Implications. This work not only improves our understanding of the response to hypoxia, but also reveals proteins important for malignant progression, which may be targeted in future therapies. PMID- 26421189 TI - Favorable Outcomes after Implantation of Biodegradable Polymer Coated Sirolimus Eluting Stents in Diabetic Population: Results from INDOLIMUS-G Diabetic Registry. AB - Objective. The main aim is to evaluate safety, efficacy, and clinical performance of the Indolimus (Sahajanand Medical Technologies Pvt. Ltd., Surat, India) sirolimus-eluting stent in high-risk diabetic population with complex lesions. Methods. It was a multicentre, retrospective, non-randomized, single-arm study, which enrolled 372 diabetic patients treated with Indolimus. The primary endpoint of the study was major adverse cardiac events (MACE), which is a composite of cardiac death, target lesion revascularization (TLR), target vessel revascularization (TVR), myocardial infarction (MI), and stent thrombosis (ST). The clinical follow-ups were scheduled at 30 days, 6 months, and 9 months. Results. The mean age of the enrolled patients was 53.4 +/- 10.2 years. A total of 437 lesions were intervened successfully with 483 stents (1.1 +/- 0.3 per lesion). There were 256 (68.8%) male patients. Hypertension and totally occluded lesions were found in 202 (54.3%) and 45 (10.3%) patients, respectively. The incidence of MACE at 30 days, 6 months and 9 months was 0 (0%), 6 (1.6%), and 8 (2.2%), respectively. The event-free survival at 9-month follow-up by Kaplan Meier method was found to be 97.8%. Conclusion. The use of biodegradable polymer coated sirolimus-eluting stent is associated with favorable outcomes. The results demonstrated in our study depict its safety and efficacy in diabetic population. PMID- 26421190 TI - Medical History of Elderly Patients in the Emergency Setting: Not an Easy Point of-Care Diagnostic Marker. AB - Background. Medical histories are a crucially important diagnostic tool. Elderly patients represent a large and increasing group of emergency patients. Due to cognitive deficits, taking a reliable medical history in this patient group can be difficult. We sought to evaluate the medical history-taking in emergency patients above 75 years of age with respect to duration and completeness. Methods. Anonymous data of consecutive patients were recorded. Times for the defined basic medical history-taking were documented, as were the availability of other sources and times to assess these. Results. Data of 104 patients were included in the analysis. In a quarter of patients (25%, n = 26) no complete basic medical history could be obtained. In the group of patients where complete data could be gathered, only 16 patients were able to provide all necessary information on their own. Including other sources like relatives or GPs prolonged the time until complete medical history from 7.3 minutes (patient only) to 26.4 (+relatives) and 56.3 (+GP) minutes. Conclusions. Medical histories are important diagnostic tools in the emergency setting and are prolonged in the elderly, especially if additional documentation and third parties need to be involved. New technologies like emergency medical cards might help to improve the availability of important patient data but implementation of these technologies is costly and faces data protection issues. PMID- 26421191 TI - An Additive Effect of Oral N-Acetyl Cysteine on Eradication of Helicobacter pylori. AB - Background. Helicobacter pylori is highly adapted to the gastric environment where it lives within or beneath the gastric mucous layer. The aim of this study was to evaluate whether the addition of N-acetyl cysteine to the treatment regimen of H. pylori infection would affect eradication rates of the disease. Methods. A total of 79 H. pylori positive patients were randomized to two therapeutic groups. Both groups received a 14-day course of three-drug regimen including amoxicillin/clarithromycin/omeprazole. Experimental group (38 subjects) received NAC, and control group (41 subjects) received placebo, besides three drug regimen. H. pylori eradication was evaluated by urea breath test at least 4 weeks after the cessation of therapy. Results. The rate of H. pylori eradication was 72.9% and 60.9% in experimental and control groups, respectively (P = 0.005). By logistic regression modeling, female gender (OR 3.68, 95% CI: 1.06-5.79; P = 0.040) and treatment including NAC (OR 1.88, 95% CI: 0.68-3.15; P = 0.021) were independent factors associated with H. pylori eradication. Conclusion. The results of the present study show that NAC has an additive effect on the eradication rates of H. pylori obtained with three-drug regimen and appears to be a promising means of eradicating H. pylori infection. PMID- 26421192 TI - Effect of Perioperative beta-Blockers on Pulmonary Complications among Patients with Chronic Obstructive Pulmonary Disease Undergoing Lung Resection Surgery. AB - The aim of this study is to determine if COPD patients undergoing lung resection with perioperative beta-blocker use are more likely to suffer postoperative COPD exacerbations than those that did not receive perioperative beta-blockers. Methods. A historical cohort study of COPD patients, undergoing lung resection surgery at Memorial Sloan-Kettering Cancer Center between 2002 and 2006. Primary outcomes were the rate of postoperative COPD exacerbations, defined as any initiation or increase of glucocorticoids for documented bronchospasm. Results. 520 patients with COPD were identified who underwent lung resection. Of these, 205 (39%) received perioperative beta-blockers and 315 (61%) did not. COPD was mild among 361 patients (69% of all patients), moderate in 117 patients (23%), and severe in 42 patients (8%). COPD exacerbations occurred among 11 (5.4%) patients who received perioperative beta-blockers and among 20 (6.3%) patients who did not. Secondary outcomes, which included respiratory failure, 30-day mortality, and the presence or absence of any cardiovascular complication, ICU transfer, cardiovascular complication, or readmission within 30 days, did not differ in prevalence between the two groups. Conclusions. This study implies that perioperative beta-blockers use among COPD patients undergoing lung resection surgery does not impact the rate of exacerbations. PMID- 26421193 TI - Retrospective Clinical and Radiological Outcomes after Robotic Assisted Bicompartmental Knee Arthroplasty. AB - Purpose. Bicompartmental knee arthroplasty (BiKA) is a favorable alternative to total knee arthroplasty for degenerative disease limited to two knee compartments. Recently developed robotic-assisted systems improved the clinical efficacy of unicompartmental knee arthroplasty by providing enhanced component positioning with dynamic ligament balancing. The purpose of this study was to evaluate the short-term outcomes of patients, undergoing bicompartmental knee arthroplasty at a single institution by a single surgeon using a robotic-assisted system. It was hypothesized that robotic assisted BiKA is a prevailing choice for degenerative disease limited to two knee compartments with good functional results. Methods. A search of the institution's joint registry was conducted to identify patients that underwent robotic-assisted BiKA of the patellofemoral compartment and the medial or lateral compartment. Results. A total number of 29 patients (30 BiKA) with a mean age of 63.6 years were identified who received a patellofemoral resurfacing in combination with medial or lateral compartment resurfacing. Twenty-four out of 29 patients had good to excellent outcome. Conclusion. Robotic assisted bicompartmental arthroplasty using broad indications and only excluding patients with severe deformity and those that have less than 4 mm of joint space in the surviving compartment demonstrated 83% good to excellent results. PMID- 26421194 TI - Brain and Behavior Plasticity: From Fundamental Science to Health Outcomes. PMID- 26421195 TI - Isolated Right Ventricular Myocarditis: Rarely Reported Pathology. AB - Objective. Preventing the morbidity and mortality from isolated right ventricular myocarditis by its early recognition and treatment. Background. The clinical presentation of myocarditis ranges from nonspecific systemic symptoms (fever, myalgia, palpitations, or exertional dyspnea) to fulminant cardiac failure and sudden death. In our case, echocardiography raised the possibility of myocarditis at an early stage, although the signs and symptoms did not indicate right ventricular disease. Review of the literature showed only 4 previous reports, all diagnosed at autopsy, in which diagnosis was not suspected in vivo. Design/Methods. We are reporting case of a 23-year-old male with no past medical history who presented to emergency room with a nonexertional sharp left sided chest pain. Diagnostic tests were conducted, which revealed elevated troponins, decreased right ventricular ejection function but preserved left ventricular function, and no evidence of coronary artery disease. Results. A diagnosis of isolated right ventricular myocarditis was made on the basis of clinical, echocardiographic, and cardiac MRI findings. Conclusions. Isolated right ventricular myocarditis should be suspected in a patient with depressed right ventricular function without left ventricular involvement on echocardiography and cardiac MRI, elevated cardiac enzymes, and no evidence of coronary artery disease. PMID- 26421196 TI - Riga-Fede Disease Associated with Natal Teeth: Two Different Approaches in the Same Case. AB - Natal teeth are those present in the oral cavity at the child's birth. These teeth can cause ulcers on the ventral surface of the tongue, lip, and the mother's breast characterizing the Riga-Fede Disease. The treatment depends on the tooth's mobility and the risk of aspiration or swallowing; whether it is supernumerary or regular primary teeth; whether it is causing interference in breastfeeding; breast and oral soft tissue injuries; and the general state of child's health. A 1-month-old female infant was diagnosed with two natal teeth and an ulcerated lesion on the ventral surface of the tongue, leading to the clinical diagnosis of Riga-Fede Disease. The treatment performed consisted of the maintenance of the natal tooth that showed no increased mobility, adding a small increment of glass ionomer cement to its incisal edge, and orientation for hygiene with saline solution. Due to the increased mobility of the other natal tooth, surgical removal was performed. There was regular monitoring of the patient and complete wound healing was observed after 15 days. The proposed treatment was successful and the patient is still in follow-up without recurrence of the lesion after one year. PMID- 26421197 TI - Management of a Periodontal Pocket Using a Removable Orthodontic Appliance and Nonsurgical Periodontal Therapy. AB - Purpose. As documented in the literature, bony defects can be managed by an orthodontic approach. Methods. This case report describes the treatment of a bony defect caused by orthodontic malposition through phase I periodontal therapy and a simple removable orthodontic appliance used for the first time in a 20-year-old girl. Results. The periodontal pocket was reduced from 8 mm to 3 mm shortly after treatment. Conclusion. This case report concludes that orthodontic therapy can be used successfully in treatment of bony defects caused by mesially tilted molars. PMID- 26421198 TI - Solitary Peripheral Osteoma of the Angle of the Mandible. AB - Solitary peripheral osteoma is a benign, slow-growing osteogenic tumor arising from craniofacial bones such as the sinus, temporal, or jaw bones but rarely originating from the mandible. Osteoma consists of compact or cancellous bone that may be of peripheral, central, or extraskeletal type. Peripheral osteoma arises from the periosteum and is commonly a unilateral, pedunculated mushroom like mass. Solitary peripheral osteomas are characterized by well-defined, rounded, or oval radiopaque mass in the computed tomography. Although multiple osteomas of the jaws are a hallmark of Gardner's syndrome (familial adenomatous polyposis), nonsyndromic cases are typically solitary. Herein, we report a rare case of solitary peripheral osteoma of the angle of the mandible in a 27-year-old female with clinical, radiologic, and histopathologic findings. PMID- 26421199 TI - Recurrent Episodes of Thyrotoxicosis in a Man following Pregnancies of his Spouse with Hashimoto's Thyroiditis. AB - Over an 8-year period, a male patient presented three times to an endocrinologist with strikingly similar presentations, including palpitations, anxiety, and tremors. Each of his presentations occurred following either the birth of one of his two children or his wife's late termination of pregnancy. This patient's illness followed the typical time course of silent thyroiditis: hyperthyroidism, followed by euthyroidism, a late hypothyroid phase, and then a complete resolution of symptoms and normalization of thyroid function tests over a period of several months. We discuss the curious clinical presentation, diagnostic evaluation, and a literature review of alternate explanations for this patient's condition, including a discussion of the impact of seasonal shift, spousal's autoimmune disease, stress, and evolutionary changes in males postpartum. Although the differential diagnosis is broad in this case and the thyrotoxicosis could have coincidentally followed pregnancies of the patient's wife, documented hormonal changes in men during postpartum period in conjunction with the timeline of the patient's condition are suggestive of recurrent "sympathetic" postpartum thyroiditis. To our knowledge, this is the first case report of recurrent painless thyroiditis in a man following pregnancies of his wife with Hashimoto's thyroiditis. PMID- 26421200 TI - Bilateral Intracranial Vertebral Artery Stenosis Presenting as Recurrent Prolonged Presyncopal Episodes. AB - Amongst various mechanisms of presyncopal events, posterior circulation disease needs to be considered. This particular mechanism has been underrecognized. We describe a case of a 76-year-old patient with recurrent posterior circulation TIAs, presenting as recurrent prolonged presyncopal events. PMID- 26421201 TI - Modulation of the Left Prefrontal Cortex with High Frequency Repetitive Transcranial Magnetic Stimulation Facilitates Gait in Multiple Sclerosis. AB - Multiple Sclerosis (MS) is a chronic central nervous system (CNS) demyelinating disease. Gait abnormalities are common and disabling in patients with MS with limited treatment options available. Emerging evidence suggests a role of prefrontal attention networks in modulating gait. High-frequency repetitive transcranial magnetic stimulation (rTMS) is known to enhance cortical excitability in stimulated cortex and its correlates. We investigated the effect of high-frequency left prefrontal rTMS on gait parameters in a 51-year-old Caucasian male with chronic relapsing/remitting MS with residual disabling attention and gait symptoms. Patient received 6 Hz, rTMS at 90% motor threshold using figure of eight coil centered on F 3 location (using 10-20 electroencephalography (EEG) lead localization system). GAITRite gait analysis system was used to collect objective gait measures before and after one session and in another occasion three consecutive daily sessions of rTMS. Two-tailed within subject repeated measure t-test showed significant enhancement in ambulation time, gait velocity, and cadence after three consecutive daily sessions of rTMS. Modulating left prefrontal cortex excitability using rTMS resulted in significant change in gait parameters after three sessions. To our knowledge, this is the first report that demonstrates the effect of rTMS applied to the prefrontal cortex on gait in MS patients. PMID- 26421202 TI - Coincidence of Incomplete Pentalogy of Cantrell and Meningomyelocele in a Dizygotic Twin Pregnancy. AB - Pentalogy of Cantrell is an extremely rare and lethal syndrome. Ectopia cordis is frequently found in fetuses with POC but not required for incomplete forms. Likewise, meningomyelocele is a relatively uncommon neural tube defect affecting central nervous system and associated with neurological problems. Herein, we presented a woman with dizygotic twin pregnancy having coincidence of incomplete POC and MMC in each individual fetus, which has never been reported previously. PMID- 26421203 TI - Benign Lymphoid Hyperplasia Presenting as Bilateral Scleral Nodules. AB - Purpose. To report a case of transient lymphoid hyperplasia presenting as bilateral nodular scleral mass in a young male patient. Design. Observational case report. Methods. Chart review. Causes of scleritis were considered and excluded based on detailed history, physical examination, and laboratory investigations. Results. Excisional biopsy of scleral lesions indicated lymphoid tissue. Immunohistochemical studies revealed a polyclonal population of T and B cells consistent with a benign reactive process. Conclusions. Chronic exposure of the ocular adnexa to many allergens and irritants may lead to activation of the inflammatory cascade. In severely allergic patients activation may be exponential and elicit an immune-mediated response resulting in a transient lymphoid reactive process. PMID- 26421204 TI - Adie's Tonic Pupil in Systemic Sclerosis: A Rare Association. AB - We report a rare association of Adie's tonic pupil in a patient with systemic sclerosis who was otherwise systemically stable. This paper is an effort to unravel whether the tonic pupil and systemic sclerosis are an association by chance (which may be the case) or systemic sclerosis is the source of the tonic pupil. PMID- 26421205 TI - Iliac Crest Avulsion Fracture in a Young Sprinter. AB - Avulsion fracture of the iliac crest is an uncommon pathology. It usually occurs in teenagers during sport activities, more common in boys. We report a case of 16 year-old male competitive sprinter, who had an avulsion of a part of the iliac crest and the anterior-superior iliac spine during a competition. The traumatism occurred during the period of acceleration phase out of the blocks which corresponds to the maximum traction phase on the tendons. Then a total loss of function of the lower limb appears forcing him to stop the run. X-ray and CT scan confirmed the rare diagnosis of avulsion of the quasitotality of the iliac crest apophysis, corresponding to Salter 2 fracture. We performed an open reduction and internal fixation with two screws, allowing a return to sport after 3 months and his personal best record in the 100 meters at the 6th postoperative month. PMID- 26421206 TI - Mucinous Bladder Adenocarcinoma: Case Report and Literature Review. AB - Primary mucinous adenocarcinoma is an extremely rare type of bladder cancer, with aggressive behavior and poor response to chemotherapy and radiotherapy. The symptoms are similar to those of other bladder tumors. Surgery is the main treatment and remains the only curative option. There may be a progression from mucinous metaplasia to mucinous adenoma and then mucinous adenocarcinoma. We present the case of a 40-year-old woman with recurrent lower urinary tract infections, submitted to imaging tests, which showed a bladder tumor. After transurethral resection, pathology showed intestinal mucinous carcinoma. Metastatic work-up was negative. New surgical procedure showed metaplasia but no recurrence of the carcinoma. The patient is now using antibiotic prophylaxis and will undergo a cystoscopy every 3 months and computed tomography in one year. PMID- 26421207 TI - Successful Treatment of Acute on Chronic Mesenteric Ischaemia by Common Iliac to Inferior Mesenteric Artery Bypass. AB - Chronic mesenteric ischaemia is a rare and potentially fatal condition most commonly due to atherosclerotic stenosis or occlusion of two or more mesenteric arteries. Multivessel revascularisation of both primary mesenteric vessels, the celiac artery and superior mesenteric artery (SMA), is the current mainstay of treatment; however, in a certain cohort of patients, revascularisation one or both vessels may not be possible. Arteries may be technically unreconstructable or the patient may be surgically unfit for the prolonged aortic cross clamping times required. Here we present a case involving a 72-year-old woman with acute on chronic mesenteric ischaemia. She was a high risk surgical patient with severe unreconstructable stenotic disease of the SMA and celiac arteries. She was successfully treated with single vessel revascularisation of the inferior mesenteric artery (IMA) via a common iliac to IMA reversed vein bypass. At two year follow-up, the graft remains patent and the patient continues to be symptom free and is maintaining her weight. PMID- 26421209 TI - MRI Guided Focused Ultrasound Thalamotomy for Moderate-to-Severe Tremor in Parkinson's Disease. AB - Background. Thalamotomy is effective in alleviating tremor in Parkinson's disease (PD). Methods. Seven PD patients, mean age 59.4 +/- 9.8 years (range, 46-74) with a mean disease duration of 5.4 +/- 2.8 years (range, 2-10) suffering from severe refractory tremor, underwent ventral intermediate nucleus thalamotomy using MRI guided focused ultrasound (MRgFUS), an innovative technology that enables noninvasive surgery. Results. Tremor stopped in the contralateral upper extremity in all patients immediately following treatment. Total UPDRS decreased from 37.4 +/- 12.2 to 18.8 +/- 11.1 (p = 0.007) and PDQ-39 decreased from 42.3 +/- 16.4 to 21.6 +/- 10.8 (p = 0.008) following MRgFUS. These effects were sustained (mean follow-up 7.3 months). Adverse events during MRgFUS included headache (n = 3), dizziness (n = 2), vertigo (n = 4), and lip paresthesia (n = 1) and following MRgFUS were hypogeusia (n = 1), unsteady feeling when walking (n = 1, resolved), and disturbance when walking tandem (n = 1, resolved). Conclusions. Thalamotomy using MRgFUS is safe and effective in PD patients. Large randomized studies are needed to assess prolonged efficacy and safety. PMID- 26421210 TI - Effect of GBA Mutations on Phenotype of Parkinson's Disease: A Study on Chinese Population and a Meta-Analysis. AB - GBA has been identified as a genetic risk factor for PD. Whether the clinical manifestations of PD patients with or without GBA mutations are different has still not reached a consensus. We firstly detected the GBA mutation L444P in 1147 Chinese PD patients and simultaneously evaluated their corresponding clinical data. Then we compared the phenotypes between 646 PD patients with GBA mutations and 10344 PD patients without GBA mutations worldwide through meta-analysis. Through the method of meta-analysis, there was significant difference in age at onset (MD = -3.10 [95% CI: -4.88, -1.32]), bradykinesia as an initial symptom (OR = 1.49 [95% CI: 1.15, 1.94]), having family history (OR = 1.50 [95% CI: 1.18, 1.91]), and dementia (OR = 3.21 [95% CI: 1.97, 5.24]) during the comparison between PD patients with and without GBA mutations. While, in the aspect of tremor as an initial symptom (OR = 0.81 [95% CI: 0.64, 1.03]), the severity of motor symptoms such as H-Y (MD = 0.06 [95% CI: -0.06, 0.17]) and UPDRS-III (MD = 1.61 [95% CI: -0.65, 3.87]) and having dyskinesia (OR = 1.60 [95% CI: 0.90, 2.84]) during the comparison between the two groups revealed no statistical differences. Our results suggested that the phenotypes of PD patients with GBA mutations are different from GBA noncarriers. PMID- 26421208 TI - Evolutionary Consequences of Male Driven Sexual Selection and Sex-Biased Fitness Modifications in Drosophila melanogaster and Members of the simulans Clade. AB - Males have evolved a variety of behavioral, morphological, and physiological traits to manipulate their mates in order to maximize their chances of success. These traits are bound to influence how females respond to male behaviors and influence the nature of sexual selection/conflict. A common consequence of aggressive male mating strategies in Drosophila melanogaster is the reduction of female lifespan. Our study shows that this is common across members of the simulans clade. Reduced life expectancy of females implies that female contribution to a population is less than that of males per generation. Fitness differences between the sexes in every generation will invariably affect overall population fitness. How natural selection responds to the female deaths and thereby the unequal fitness of the sexes has rarely been addressed. We shed light on this issue and provide evidence, which suggests that additional gains of fitness by males due to their longevity and continued mating may provide one explanation as to why the loss of female fitness may be "invisible" (effectively neutral) to natural selection. Male driven sexual selection and additional, transgenerational gains of male fitness can be an important force of evolutionary change and need to be tested with other organisms. PMID- 26421211 TI - A Novel Analytical Method for Trace Ammonium in Freshwater and Seawater Using 4 Methoxyphthalaldehyde as Fluorescent Reagent. AB - A novel fluorescent reagent for determination of ammonium, 4 methoxyphthalaldehyde (MOPA), was successfully synthesized in this study. Under alkaline conditions, MOPA could reacted with ammonium rapidly at room temperature, producing fluorescent substance which had maximum excitation at 370 nm and emission wavelength at 454 nm. Based on this, a novel fluorescence analysis method was established for the determination of trace ammonium in natural water. Experimental parameters including reagent concentration, pH, reaction equilibrium time, and metal ions masking agent were optimized. The results showed that the optimized MOPA concentration was 0.12 g/L, pH was in the range of 11.2-12.0, and sulfite concentration was 0.051 g/L, respectively. Metal ions masking agent had no obvious effect on the fluorescence signal. With the reaction time of 15 minutes, linear range of this method was between 0.025 and 0.300 MUmol/L, and the method detecting limit was 0.0058 MUmol/L. The matrix recovery of the proposed method was in the range of 93.6-108.1%. Compared with the OPA method, this method was much more sensitive and rapid without the interference of background peak and would be more suitable for developing a portable fluorescence detection system. PMID- 26421212 TI - Ex vivo 3D osteocyte network construction with primary murine bone cells. AB - Osteocytes reside as three-dimensionally (3D) networked cells in the lacunocanalicular structure of bones and regulate bone and mineral homeostasis. Despite of their important regulatory roles, in vitro studies of osteocytes have been challenging because: (1) current cell lines do not sufficiently represent the phenotypic features of mature osteocytes and (2) primary cells rapidly differentiate to osteoblasts upon isolation. In this study, we used a 3D perfusion culture approach to: (1) construct the 3D cellular network of primary murine osteocytes by biomimetic assembly with microbeads and (2) reproduce ex vivo the phenotype of primary murine osteocytes, for the first time to our best knowledge. In order to enable 3D construction with a sufficient number of viable cells, we used a proliferated osteoblastic population of healthy cells outgrown from digested bone chips. The diameter of microbeads was controlled to: (1) distribute and entrap cells within the interstitial spaces between the microbeads and (2) maintain average cell-to-cell distance to be about 19 um. The entrapped cells formed a 3D cellular network by extending and connecting their processes through openings between the microbeads. Also, with increasing culture time, the entrapped cells exhibited the characteristic gene expressions (SOST and FGF23) and nonproliferative behavior of mature osteocytes. In contrast, 2D-cultured cells continued their osteoblastic differentiation and proliferation. This 3D biomimetic approach is expected to provide a new means of: (1) studying flow induced shear stress on the mechanotransduction function of primary osteocytes, (2) studying physiological functions of 3D-networked osteocytes with in vitro convenience, and (3) developing clinically relevant human bone disease models. PMID- 26421213 TI - Urine Club Cell 16-kDa Secretory Protein and Childhood Wheezing Illnesses After Lower Respiratory Tract Infections in Infancy. AB - Background: Infants with lower respiratory tract infections (LRTIs) are at an increased risk of developing childhood wheezing illnesses (including asthma), but it is not currently possible to predict those at risk for these long-term outcomes. The current objective was to examine whether urine levels of club cell 16-kDa secretory protein (CC16) at the time of an infant LRTI are associated with the development of childhood wheezing illnesses. Methods: Prospective study of 133 previously healthy infants enrolled during a healthcare visit for a LRTI and followed longitudinally for childhood wheezing illnesses. Urine levels of CC16 at the time of enrollment were measured after validating a commercially available enzyme-linked immunosorbent assay kit for serum. The outcome of interest was parental report of subsequent childhood wheeze (defined as >=1 episode of wheezing following the initial LRTI) at the 1-year follow-up visit. Logistic regression was used for the main analysis. Results: The median (interquartile range) urine levels of CC16 (ng/mg of creatinine) at the time of an infant LRTI were 11.1 (7.7-20.1) for infants with subsequent childhood wheeze and 13.4 (8.3 61.1) for those without (p = 0.11). In the main multivariate analysis using a logarithmic transformation of the urine levels of CC16, a twofold increase in urine levels of CC16 was associated with ~30% decreased odds (OR = 0.74 [95% confidence interval (CI) 0.56-0.98], p = 0.04) of subsequent childhood wheeze after adjustment for potential confounders. Conclusions: An inverse association was found between urine levels of CC16 at the time of an infant LRTI and the odds of subsequent childhood wheeze. Urine CC16 may be a useful biomarker of the development of childhood wheezing illnesses after LRTIs in infancy. PMID- 26421214 TI - Application of an Asthma Screening Questionnaire in Children with Sickle Cell Disease. AB - Objective: Asthma in sickle cell disease (SCD) patients is associated with elevated morbidity and mortality. Early detection and initiation of treatment may therefore lead to improved outcome. Utility of an asthma screening questionnaire to identify obstructive airway disease and physician diagnosed asthma in children with SCD at an outpatient setting as an effective, easy-to-administer screening tool has not previously been evaluated in this population. Methods: A previously validated asthma screening questionnaire and spirometry were prospectively administered to 41 SCD children at a routine clinic visit. Results: Prevalence of obstructive airway was 51.2% (n = 21) and physician diagnosis of asthma 33.3% (n = 13). Sensitivity (40%) and specificity (75%) of the questionnaire was poor in detecting obstructive airway disease, but sensitivity (77%), specificity (100%), positive predictive value (100%), and negative predictive value (90%) were high in detecting physician diagnosis of asthma. Conclusion: An asthma screening questionnaire could be a useful tool in identifying at-risk SCD children who may benefit from further management. PMID- 26421215 TI - Adolescent Asthma Pharmacotherapy in a State of Flux. AB - Recently, the United States Food and Drug Administration (FDA) elected not to approve a once-daily inhaled corticosteroid/long-acting beta2 agonist combination product in 12-17-year-old patients due to lack of sufficient data, despite approval of previous combination products with similar levels of supporting evidence. As the FDA's stance toward adolescent data is changing, the opportunity to learn about their response to asthma medication has now arisen. A review of the relevant issues pertinent to pharmacotherapy of asthma in the 12-17-year-old population is discussed in this review. PMID- 26421216 TI - A case of intravascular lymphoma presenting as myelopathy diagnosed with a skin biopsy. AB - BACKGROUND: Intravascular lymphoma (IVL) is a rare subtype of non-Hodgkin lymphoma with exclusively or predominantly intravascular proliferation. Without therapeutic intervention, the neurologic involvement is rapidly progressive and inevitably fatal. Most of the IVL patients have prominent or exclusive manifestations in the nervous system and there are several reports of patients presenting with spinal symptoms. CASE DESCRIPTION: A 68-year-old male patient admitted with the complaints of progressive paraparesis. T2-weighted magnetic resonance imaging (MRI) of the spinal cord showed hyperintense lesions in the thoracic cord. A diagnosis of myelitis of unknown etiology was assumed, and steroid pulse therapy was administered, which temporarily improved the patient's symptoms. However, the paraparesis recurred, and other symptoms, such as vertigo, psychosis, and seizures, developed 1-month after the initial treatment. Multiple high-intensity lesions were detected in the bilateral subcortical white matter on DW MRI. Based on the patient's clinical course, IVL was suspected; however, obtaining histological confirmation was not possible, as no Gd-enhanced brain or spinal lesions were identified and repeated cerebrospinal fluid examinations were negative for tumor cells. Therefore, a random skin biopsy was performed, and IVL was diagnosed. Obtaining a comparatively favorable outcome was possible owing to the subsequent administration of R-CHOP chemotherapy. CONCLUSION: IVL should be included in the differential diagnosis of atypical case of presumed myelitis. An early diagnosis and chemotherapy is crucial for improving the patient's outcome. When obtaining a diagnosis based on tissues other than skin is difficult, a random skin biopsy should be considered in patients with suspected IVL. PMID- 26421217 TI - Treatment of giant congenital cysts of the midline in adults: Report of two cases and review of the literature. AB - BACKGROUND: Giant cysts of the midline, not associated to a tumor, are exceptional finding in the brain of adults. Here we present two cases of symptomatic giant cerebral cysts of the midline occurred in an elderly and in a young adult patients both treated with mini-invasive unilateral neuroendoscopic procedure. In the recent literature (since 1999) similar cases have not been reported. Beside the clinical report, review of literature and major anatomical features of the region are described. CASE DESCRIPTION: These two adults (82 and 41 years old respectively) had a slow progressive development of headache, gait disturbances, memory impairment and urinary incontinence. Magnetic resonance imaging showed giant cyst of the midline and hydrocephalus. Surgery with the endoscopic procedure, through a right frontal burr hole, was followed by clinical and radiological improvement. CONCLUSION: Giant cerebral cysts of the midline in adults can be successfully treated through a neuroendoscopic monolateral approach that comprehends multiple openings, diffuse coagulation of the capsule, and careful releasing of capsule-ependyma adherences. Knowledge of major anatomical and developmental details of the septal region is necessary to avoid complication in a mini-invasive surgical procedure. PMID- 26421218 TI - Cavernous hemangioma of the dura mater mimicking meningioma. AB - BACKGROUND: Cavernomas are benign lesions that most commonly occur intra parenchymally, but occasionally they have been described as arising from the dura mater. Extra-axial cavernous angiomas (or hemangiomas) account for 0.4-2% of all intracranial vascular malformations, and they usually occur in the middle cranial fossa, associated with the cavernous sinus. Other possible localizations (e.g. tentorium, convexity, anterior cranial fossa, cerebellopontine angle, Meckel's cave, sella turcica and internal auditory meatus) are rare, and they account only for 0.2-0.5%. CASE DESCRIPTION: We report a case of a 30-year-old female presenting with a 2 years history of headache unresponsive to drug therapy. The magnetic resonance imaging showed a dural-based lesion in the left frontal region; the lesion size was: 1.5 cm * 3.5 cm. The appearance suggested a convexity meningioma. A left frontal craniotomy was performed, and the histopathological diagnosis deposed for a cavernous hemangioma of the dura mater. The follow-up at 1-year was good without any neurologic deficit. CONCLUSIONS: Dural-based cavernous hemangiomas of the convexity are uncommon lesions. Up to now, only 13 cases have been described in the literature. The authors have discussed clinical aspects, radiological features, surgical treatment, and operative findings. PMID- 26421219 TI - We Don't Know What We Don't Know About Adolescent and Young Adult Patients with Familial Adenomatous Polyposis-Related Colorectal Cancer. PMID- 26421221 TI - Exercise and Fatigue in Adolescent and Young Adult Survivors of Hodgkin Lymphoma: A Report from the Children's Oncology Group. AB - Fatigue is a significant problem for adolescent and young adult (AYA) Hodgkin lymphoma (HL) survivors. The relationship between exercise and fatigue is complex. This study explored the trajectory of and the relationship between exercise and fatigue over 36 months post-therapy in a cohort of 103 AYA-aged HL survivors treated on Children's Oncology Group (COG) study AHOD0031. Descriptive statistics and generalized estimating equations were used in this secondary data analysis. Exercise and fatigue improved over time but were unrelated; amount of exercise at end of therapy predicted amount of exercise at 12 (p = 0.02) and 36 (p = 0.0008) months post-therapy. PMID- 26421220 TI - Best Practices in Adolescent and Young Adult Patients with Acute Lymphoblastic Leukemia: A Focus on Asparaginase. AB - The inclusion of asparaginase in chemotherapy regimens to treat acute lymphoblastic leukemia (ALL) has had a positive impact on survival in pediatric patients. Historically, asparaginase has been excluded from most treatment protocols for adolescent and young adult (AYA) patients because of perceived toxicity in this population, and this is believed to have contributed to poorer outcomes in these patients. However, retrospective analyses over the past 12 years have shown that 2-, 5-, and 7-year overall survival of AYA patients is significantly improved with pediatric versus adult protocols. The addition of asparaginase to adult protocols yielded high rates of first remission and improved survival. However, long-term survival remains lower compared with what has been seen in pediatrics. The notion that asparaginase is poorly tolerated by AYA patients has been challenged in multiple studies. In some, but not all, studies, the incidences of hepatic and pancreatic toxicities were higher in AYA patients, whereas the rates of hypersensitivity reactions did not appear to differ with age. There is an increased risk of venous thromboembolic events, and management with anti-coagulation therapy is recommended. Overall, the risk of therapy-related mortality is low. Together, this suggests that high-intensity pediatric protocols offer an effective and tolerable approach to treating ALL in the AYA population. PMID- 26421223 TI - Novel Nut and Bolt Task Quantifies Motor Deficits in Premanifest and Manifest Huntington's Disease. AB - BACKGROUND: We investigated the use of a simple novel nut and bolt task in premanifest and manifest Huntington's disease (HD) patients to detect and quantify motor impairments at all stages of the disease. METHODS: Premanifest HD (n=24), manifest HD (n=27) and control (n=32) participants were asked to screw a nut onto a bolt in one direction, using three different sized bolts with their left and right hand in turn. RESULTS: We identified some impairments at all stages of HD and in the premanifest individuals, deficits in the non-dominant hand correlated with disease burden scores. CONCLUSION: This simple, cheap motor task was able to detect motor impairments in both premanifest and manifest HD and as such might be a useful quantifiable measure of motor function for use in clinical studies. PMID- 26421222 TI - Who Treats Adolescents and Young Adults with Cancer? A Report from the AYA HOPE Study. AB - PURPOSE: Physicians play a critical role in delivering effective treatment and enabling successful transition to survivorship among adolescent and young adult (AYA) cancer patients. However, with no AYA cancer medical specialty, information on where and by whom AYAs with cancer are treated is limited. METHODS: Using the National Cancer Institute's population-based AYA HOPE Study, 464 AYAs aged 15-39 at diagnosis treated by 903 physicians were identified. Differences in physician and hospital characteristics were examined by age at diagnosis and cancer type (germ cell cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, acute lymphocytic leukemia [ALL], and sarcoma) using chi-square tests. RESULTS: Treating physicians were predominately 51-64 years old, male, United States-trained in non-pediatric specialties, and in group practices within large metropolitan areas. Older patients were less often treated by pediatric physicians (p < 0.01) and more likely to be treated by United States-trained physicians without research/teaching responsibilities and in hospitals without residency programs (p < 0.05). The majority of the few pediatricians (n = 44) treated ALL patients. Physicians with research/teaching responsibilities and those based in medical schools were more likely to treat patients with ALL and sarcoma compared with other cancer types (p < 0.01). Of HL patients, 73% were treated at a cancer center compared with 56% of patients with germ cell cancer (p < 0.01), while ALL (85%) and sarcoma (87%) patients were more likely to be treated in hospitals with residency programs (p < 0.01). CONCLUSIONS: Most AYAs with cancer were treated by non-pediatric physicians in community settings, although physician characteristics varied significantly by patient cancer type and age at diagnosis. PMID- 26421224 TI - Acousto-plasmofluidics: Acoustic modulation of surface plasmon resonance in microfluidic systems. AB - We acoustically modulated the localized surface plasmon resonances (LSPRs) of metal nanostructures integrated within microfluidic systems. An acoustically driven micromixing device based on bubble microstreaming quickly and homogeneously mixes multiple laminar flows of different refractive indices. The altered refractive index of the mixed fluids enables rapid modulation of the LSPRs of gold nanodisk arrays embedded within the microfluidic channel. The device features fast response for dynamic operation, and the refractive index within the channel is tailorable. With these unique features, our "acousto plasmofluidic" device can be useful in applications such as optical switches, modulators, filters, biosensors, and lab-on-a-chip systems. PMID- 26421225 TI - The Wellbeing of the Workforce-In Healthcare and Beyond. PMID- 26421226 TI - Resilience, Empathy, and Wellbeing in the Health Professions: An Educational Imperative. PMID- 26421227 TI - In Name and Concept: The Global Uptake of the Movement for Integrative Medicine and Health. PMID- 26421228 TI - Caring for People Behind the Numbers: Measurement and Accountability for Health. PMID- 26421229 TI - Weaving Elders of the Andes. PMID- 26421230 TI - Prioritizing Clinician Wellbeing: The University of Virginia's Compassionate Care Initiative. AB - BACKGROUND: Working in healthcare is increasingly challenging for nurses, physicians, and other health professionals. Ongoing high stress takes a toll on clinicians and interferes with the quality of their patient care. Fostering clinician wellbeing needs to be a priority; if not, the human and financial consequences are significant. OBJECTIVE: To describe the University of Virginia (UVA) School of Nursing's Compassionate Care Initiative (CCI) as an example of an organizational case study that is engaged in multipronged efforts to cultivate a resilient healthcare workforce committed to high-quality, compassionate, relationship-based care. METHODS: This case report describes the development, implementation, and evaluation of the CCI at UVA. Various elements of the program are reviewed, which include harnessing talents and interests of the larger institution in the establishment of Compassionate Care Ambassadors, outreach to the community, innovative student-specific educational activities, and a national media program. CONCLUSION: The UVA CCI is a successful model of an organizational effort to promote clinician wellbeing and resilience. Aspects from this program can be adapted to other organizations that are committed to addressing this critical issue in US healthcare today. PMID- 26421231 TI - Preventing Chronic Pain: A Human Systems Approach-Results From a Massive Open Online Course. AB - Chronic pain conditions are the top reason patients seek care, the most common reason for disability and addiction, and the biggest driver of healthcare costs; their treatment costs more than cancer, heart disease, dementia, and diabetes care. The personal impact in terms of suffering, disability, depression, suicide, and other problems is incalculable. There has been much effort to prevent many medical and dental conditions, but little effort has been directed toward preventing chronic pain. To address this deficit, a massive open online course (MOOC) was developed for students and healthcare professionals. "Preventing Chronic Pain: A Human Systems Approach" was offered by the University of Minnesota through the online platform Coursera. The first offering of this free open course was in the spring of 2014 and had 23 650 participants; 53% were patients or consumers interested in pain. This article describes the course concepts in preventing chronic pain, the analytic data from course participants, and postcourse evaluation forms. PMID- 26421232 TI - Interprofessional Competencies in Integrative Primary Healthcare. AB - In October 2014, the National Center for Integrative Primary Healthcare (NCIPH) was launched as a collaboration between the University of Arizona Center for Integrative Medicine and the Academic Consortium for Integrative Health and Medicine and supported by a grant from the Health Resources and Services Administration. A primary goal of the NCIPH is to develop a core set of integrative healthcare (IH) competencies and educational programs that will span the interprofessional primary care training and practice spectra and ultimately become a required part of primary care education. This article reports on the first phase of the NCIPH effort, which focused on the development of a shared set of competencies in IH for primary care disciplines. The process of development, refinement, and adoption of 10 "meta-competencies" through a collaborative process involving a diverse interprofessional team is described. Team members represent nursing, the primary care medicine professions, pharmacy, public health, acupuncture, naturopathy, chiropractic, nutrition, and behavioral medicine. Examples of the discipline-specific sub-competencies being developed within each of the participating professions are provided, along with initial results of an assessment of potential barriers and facilitators of adoption within each discipline. The competencies presented here will form the basis of a 45-hour online curriculum produced by the NCIPH for use in primary care training programs that will be piloted in a wide range of programs in early 2016 and then revised for wider use over the following year. PMID- 26421233 TI - Aligning Theory and Design: The Development of an Online Learning Intervention to Teach Evidence-based Practice for Maximal Reach. AB - BACKGROUND: Online educational interventions to teach evidence-based practice (EBP) are a promising mechanism for overcoming some of the barriers to incorporating research into practice. However, attention must be paid to aligning strategies with adult learning theories to achieve optimal outcomes. METHODS: We describe the development of a series of short self-study modules, each covering a small set of learning objectives. Our approach, informed by design-based research (DBR), involved 6 phases: analysis, design, design evaluation, redesign, development/implementation, and evaluation. Participants were faculty and students in 3 health programs at a complementary and integrative educational institution. RESULTS: We chose a reusable learning object approach that allowed us to apply 4 main learning theories: events of instruction, cognitive load, dual processing, and ARCS (attention, relevance, confidence, satisfaction). A formative design evaluation suggested that the identified theories and instructional approaches were likely to facilitate learning and motivation. Summative evaluation was based on a student survey (N=116) that addressed how these theories supported learning. Results suggest that, overall, the selected theories helped students learn. CONCLUSION: The DBR approach allowed us to evaluate the specific intervention and theories for general applicability. This process also helped us define and document the intervention at a level of detail that covers almost all the proposed Guideline for Reporting Evidence-based practice Educational intervention and Teaching (GREET) items. This thorough description will facilitate the interpretation of future research and implementation of the intervention. Our approach can also serve as a model for others considering online EBP intervention development. PMID- 26421236 TI - Scanning the Global Literature. PMID- 26421234 TI - Advancing One Health Policy and Implementation Through the Concept of One Medicine One Science. AB - Numerous interspecies disease transmission events, Ebola virus being a recent and cogent example, highlight the complex interactions between human, animal, and environmental health and the importance of addressing medicine and health in a comprehensive scientific manner. The diversity of information gained from the natural, social, behavioral, and systems sciences is critical to developing and sustainably promoting integrated health approaches that can be implemented at the local, national, and international levels to meet grand challenges. The Concept of One Medicine One Science (COMOS) as outlined herein describes the interplay between scientific knowledge that underpins health and medicine and efforts toward stabilizing local systems using 2 linked case studies: the food system and emerging infectious disease. Forums such as the International Conference of One Medicine One Science (iCOMOS), where science and policy can be debated together, missing pieces identified, and science-based collaborations formed among industry, governmental, and nongovernmental policy makers and funders, is an essential step in addressing global health. The expertise of multiple disciplines and research foci to support policy development is critical to the implementation of one health and the successful achievement of global health security goals. PMID- 26421235 TI - Immediate Effect of Therapeutic Massage on Pain Sensation and Unpleasantness: A Consecutive Case Series. AB - BACKGROUND: Musculoskeletal pain is a common condition that poses a significant burden to its sufferers and costs the US economy billions of dollars each year in lost productivity. Individuals complaining of musculoskeletal pain make up a large proportion of clients treated by massage therapists in community practices, yet few studies have examined the immediate effect of therapeutic massage on this type of pain in the practice setting. PURPOSE: To assess the immediate effect of therapeutic massage on musculoskeletal pain sensation and unpleasantness in a community setting. SETTING: Solo private practice in central Virginia, United States. PARTICIPANTS: One hundred sixteen first-time clients who complained of musculoskeletal pain as a presenting symptom. RESEARCH DESIGN: Prospective, consecutive practice-based case series. INTERVENTION: A single 60-minute session of individualized therapeutic massage; techniques used included Swedish massage employing effleurage, petrissage, and friction,;deep tissue; myofascial; positional release; passive and resisted joint mobilization; and biofield modalities. MAIN OUTCOME MEASURES: Visual Analog Scales for pain sensation and unpleasantness. RESULTS: Both pain sensation and unpleasantness were significantly reduced by a single session of therapeutic massage. Mean pain sensation decreased from 3.76 (SD=1.87) prior to massage to .89 (SD=1.35) following massage, with t=18.87, P<.001. Mean pain unpleasantness decreased from 5.21 (SD=2.48) prior to massage to .64 (SD=1.23) following massage, with t =20.45, P<.001. Effect sizes were 1.76 and 1.90, respectively. CONCLUSIONS: In this case series, therapeutic massage appeared to be an effective intervention for common musculoskeletal pain that influenced both the physical and affective dimension of the pain experience. Although care was taken to reduce potential bias through limiting eligibility to first time clients and use of a standardized script, practice-based case series have inherent limitations. Issues in conducting practice-based research by massage therapists and recommendations for future research are discussed. PMID- 26421237 TI - Modeling historical tuberculosis epidemics among Canadian First Nations: effects of malnutrition and genetic variation. AB - Late 19th century epidemics of tuberculosis (TB) in Western Canadian First Nations resulted in peak TB mortality rates more than six times the highest rates recorded in Europe. Using a mathematical modeling approach and historical TB mortality time series, we investigate potential causes of high TB mortality and rapid epidemic decline in First Nations from 1885 to 1940. We explore two potential causes of dramatic epidemic dynamics observed in this setting: first, we explore effects of famine prior to 1900 on both TB and population dynamics. Malnutrition is recognized as an individual-level risk factor for TB progression and mortality; its population-level effects on TB epidemics have not been explored previously. Second, we explore effects of heterogeneity in susceptibility to TB in two ways: modeling heterogeneity in susceptibility to infection, and heterogeneity in risk of developing disease once infected. Our results indicate that models lacking famine-related changes in TB parameters or heterogeneity result in an implausibly poor fit to both the TB mortality time series and census data; the inclusion of these features allows for the characteristic decline and rise in population observed in First Nations during this time period and confers improved fits to TB mortality data. PMID- 26421238 TI - Prediction of junior faculty success in biomedical research: comparison of metrics and effects of mentoring programs. AB - Measuring and predicting the success of junior faculty is of considerable interest to faculty, academic institutions, funding agencies and faculty development and mentoring programs. Various metrics have been proposed to evaluate and predict research success and impact, such as the h-index, and modifications of this index, but they have not been evaluated and validated side by-side in a rigorous empirical study. Our study provides a retrospective analysis of how well bibliographic metrics and formulas (numbers of total, first- and co-authored papers in the PubMed database, numbers of papers in high-impact journals) would have predicted the success of biomedical investigators (n = 40) affiliated with the University of Nevada, Reno, prior to, and after completion of significant mentoring and research support (through funded Centers of Biomedical Research Excellence, COBREs), or lack thereof (unfunded COBREs), in 2000-2014. The h-index and similar indices had little prognostic value. Publishing as mid- or even first author in only one high-impact journal was poorly correlated with future success. Remarkably, junior investigators with >6 first-author papers within 10 years were significantly (p < 0.0001) more likely (93%) to succeed than those with <=6 first-author papers (4%), regardless of the journal's impact factor. The benefit of COBRE-support increased the success rate of junior faculty approximately 3-fold, from 15% to 47%. Our work defines a previously neglected set of metrics that predicted the success of junior faculty with high fidelity thus defining the pool of faculty that will benefit the most from faculty development programs such as COBREs. PMID- 26421239 TI - The influence of arbuscular mycorrhizal fungi inoculation on yam (Dioscorea spp.) tuber weights and secondary metabolite content. AB - Arbuscular mycorrhizal fungi (AMF) are widely distributed in nature. They live in the roots of higher plants, in a symbiotic relationship. In this study, five commercial species of yams (Dioscorea spp.) were inoculated with six species of AMF, Glomus clarum, G. etunicatum, G. fasciculatum, Gigaspora sp., G. mosseae, and Acaulospora sp., in field cultivation conditions to investigate the influence of AMF inoculation on tuber weights and secondary metabolite content in yam tubers. The results showed that mycorrhizae formation rates ranged from 63.33% to 90%. G. etunicatum inoculation treatment increased the tube weights of the five species of yam tubers by 39%, 35%, 20%, 56%, and 40% for Tainung 1, Tainung 2, Ercih, Zihyuxieshu, and Tainung 5, respectively. The content of secondary metabolites, such as polyphenols, flavonoids, and anthocyanin, was significantly increased by the AMF treatment in tuber flesh and peel of all the tested yam species. Specifically, the maximums exchange of secondary metabolite contents increased to 40%, 42%, and 106% for polyphenols, flavonoids, and anthocyanin, respectively, in the tuber fresh. This study revealed that different species of yam had varying degrees of affinity with various AMF species; selecting effective AMF species is necessary to facilitate yam growth and improve the quality and quantity of yam tubers. PMID- 26421240 TI - Looking for a generic inhibitor of amyloid-like fibril formation among flavone derivatives. AB - A range of diseases is associated with amyloid fibril formation. Despite different proteins being responsible for each disease, all of them share similar features including beta-sheet-rich secondary structure and fibril-like protein aggregates. A number of proteins can form amyloid-like fibrils in vitro, resembling structural features of disease-related amyloids. Given these generic structural properties of amyloid and amyloid-like fibrils, generic inhibitors of fibril formation would be of interest for treatment of amyloid diseases. Recently, we identified five outstanding inhibitors of insulin amyloid-like fibril formation among the pool of 265 commercially available flavone derivatives. Here we report testing of these five compounds and of epi gallocatechine-3-gallate (EGCG) on aggregation of alpha-synuclein and beta amyloid. We used a Thioflavin T (ThT) fluorescence assay, relying on halftimes of aggregation as the measure of inhibition. This method avoids large numbers of false positive results. Our data indicate that four of the five flavones and EGCG inhibit alpha-synuclein aggregation in a concentration-dependent manner. However none of these derivatives were able to increase halftimes of aggregation of beta amyloid. PMID- 26421241 TI - The impact of Docker containers on the performance of genomic pipelines. AB - Genomic pipelines consist of several pieces of third party software and, because of their experimental nature, frequent changes and updates are commonly necessary thus raising serious deployment and reproducibility issues. Docker containers are emerging as a possible solution for many of these problems, as they allow the packaging of pipelines in an isolated and self-contained manner. This makes it easy to distribute and execute pipelines in a portable manner across a wide range of computing platforms. Thus, the question that arises is to what extent the use of Docker containers might affect the performance of these pipelines. Here we address this question and conclude that Docker containers have only a minor impact on the performance of common genomic pipelines, which is negligible when the executed jobs are long in terms of computational time. PMID- 26421242 TI - Temporal stability of an endemic Mexican treefrog. AB - The demographic characteristics of an amphibian population fluctuate independently over time, mainly in response to the temporal variation of environmental factors, especially precipitation and temperature. These temporal fluctuations may contribute to the size of an amphibian population and could be used to determine the current conservation status of a species. During a five year (2004-2008) period, we studied the relative abundance, sex ratio, and age sex structure of a population of metamorphosed individuals of the endemic treefrog Hyla eximia in Central Mexico. We also studied the species' relationship with climatic variables such as temperature and precipitation. We found an interannual constant abundance during the study period. However, interannual differences were observed in the population structure by age-sex category (males, females, or juveniles), with decreased abundance of males and juveniles during the rainy months (August-November). The annual abundance of H. eximia was positively correlated with rainfall, but negatively with monthly temperature. We found the sex ratio was male-biased (2:1), except for year 2008. Also, differences in snout-vent length (SVL) were found between years, suggesting changes in recruitment of new individuals. We conclude that variations in abundance, and frequencies by age-sex category, of H. eximia are related to seasonal variations in temperature and precipitation characteristics of temperate zones. However, this temporal stability may suggest that anurans have an unusual capacity to persist even in the face of human-induced habitat change. PMID- 26421243 TI - Pair formation, home range, and spatial variation in density, size and social status in blotched foxface Siganus unimaculatus on an Okinawan coral reef. AB - The present study examined pair formation, spatial pattern of home range and spatial variation in density, size and social status of blotched foxface Siganus unimaculatus (family Siganidae) on an Okinawan coral reef. Of 32 pairs sampled for sexing, 31 (96.9%) were heterosexual and showed size-assortative pairing. Developed ovaries were found in April and July, whereas oocytes were immature in August, September and February. Heterosexual pairing was found in both reproductive and non-reproductive periods. Home range size tended to be positively related to fork length (FL). The degree of home range overlap for same size class pairs was smaller than that for different size class pairs. The intraspecific behavior when two pairs approached each other was categorized as 'attack,' 'agonistic display' and 'no interactions,' and the frequency of agonistic behaviors ("attack" or "agonistic display") was significantly greater than "no interactions." Underwater observations at a seagrass bed, a rocky reef flat and a sheltered reef slope revealed that the mean FL was significantly smaller at the sheltered reef slope (4-13 cm) than at the rocky reef flat (>13 cm). No individuals were found in the seagrass bed. Most individuals less than 6 cm FL were solitary, whereas most individuals over 7 cm FL were paired. Density was significantly greater on the sheltered reef slope than on the rocky reef flat. PMID- 26421244 TI - Acute effects of anterior thigh foam rolling on hip angle, knee angle, and rectus femoris length in the modified Thomas test. AB - Background. Foam rolling has been shown to acutely increase range of motion (ROM) during knee flexion and hip flexion with the experimenter applying an external force, yet no study to date has measured hip extensibility as a result of foam rolling with controlled knee flexion and hip extension moments. The purpose of this study was to investigate the acute effects of foam rolling on hip extension, knee flexion, and rectus femoris length during the modified Thomas test. Methods. Twenty-three healthy participants (male = 7; female = 16; age = 22 +/- 3.3 years; height = 170 +/- 9.18 cm; mass = 67.7 +/- 14.9 kg) performed two, one-minute bouts of foam rolling applied to the anterior thigh. Hip extension and knee flexion were measured via motion capture before and after the foam rolling intervention, from which rectus femoris length was calculated. Results. Although the increase in hip extension (change = +1.86 degrees (+0.11, +3.61); z(22) = 2.08; p = 0.0372; Pearson's r = 0.43 (0.02, 0.72)) was not due to chance alone, it cannot be said that the observed changes in knee flexion (change = -1.39 degrees (-5.53, +2.75); t(22) = -0.70; p = 0.4933; Cohen's d = - 0.15 (-0.58, 0.29)) or rectus femoris length (change = -0.005 (-0.013, +0.003); t(22) = -1.30; p = 0.2070; Cohen's d = - 0.27 (-0.70, 0.16)) were not due to chance alone. Conclusions. Although a small change in hip extension was observed, no changes in knee flexion or rectus femoris length were observed. From these data, it appears unlikely that foam rolling applied to the anterior thigh will improve passive hip extension and knee flexion ROM, especially if performed in combination with a dynamic stretching protocol. PMID- 26421245 TI - An examination of disparities in cancer incidence in Texas using Bayesian random coefficient models. AB - Disparities in cancer risk exist between ethnic groups in the United States. These disparities often result from differential access to healthcare, differences in socioeconomic status and differential exposure to carcinogens. This study uses cancer incidence data from the population based Texas Cancer Registry to investigate the disparities in digestive and respiratory cancers from 2000 to 2008. A Bayesian hierarchical regression approach is used. All models are fit using the INLA method of Bayesian model estimation. Specifically, a spatially varying coefficient model of the disparity between Hispanic and Non-Hispanic incidence is used. Results suggest that a spatio-temporal heterogeneity model best accounts for the observed Hispanic disparity in cancer risk. Overall, there is a significant disadvantage for the Hispanic population of Texas with respect to both of these cancers, and this disparity varies significantly over space. The greatest disparities between Hispanics and Non-Hispanics in digestive and respiratory cancers occur in eastern Texas, with patterns emerging as early as 2000 and continuing until 2008. PMID- 26421246 TI - Laparoscopic Gastric Plication: An Emerging Bariatric Procedure with High Surgical Revision Rate. AB - Introduction: Laparoscopic gastric plication (LGCP) reduces gastric volume without resecting or implanting a foreign body. Although still considered investigational, it could be appropriate for young patients with a low body mass index (BMI) and for those unwilling to undergo sleeve gastrectomy, gastric banding, or bypass. Objectives: The aim of this study was to assess the mid-term results (2 years) of LGCP in terms of safety and efficacy. Methods: A total of 56 obese patients (47 female; mean age=30.5+/-11.7 years; mean BMI=40.31+/-4.7 kg/m2) were candidates for LGCP from January 2011 to October 2013. Early and late complications, BMI, and excess BMI loss (EBL) were prospectively recorded at 3, 6, 9, 12, 18, and 24 months follow-up. Results: Mean operative time was 72.4+/ 15.6 minutes. No conversion was required. Mean hospital stay was 3 days. Mean %EBL was 34.3+/-18.40%, 40.1+/-24.5%, 47.4+/-30.2%, 46.5+/-34.6%, 47.8+/-43.2%, and 55.3+/-53.6% at 3, 6, 9, 12, 18, and 24 months, respectively. The overall complication rate was 32.14%. Perioperative mortality was zero. Surgical revision was needed in 30 patients: 12 for unsatisfactory weight loss and 18 for gastric prolapse (one acute within 30 days), respectively. Conclusion: LGCP showed high complication rates requiring surgical revision. PMID- 26421247 TI - Medication Use Among Patients Prior to Bariatric Surgery. AB - Purpose: The aims of this study were to describe the most common medications reported by candidates for weight loss surgery and to consider the potential implications for patient care. Methods: A secondary data analysis of data from bariatric surgery patients enrolled in a randomized, controlled trial. At study entry, participants recorded their use of prescription medications they had taken in the previous 90 days. The Anatomical Therapeutic Chemical (ATC)/Defined Daily Dose (DDD) Index 2014 was used to classify medications. Results: Participants (n=265) were 85.7% female and 83.0% white. Mean body mass index was 47.9+/-6.5 kg/m2, and age was 45.1+/-11 years. The average number of medications was 4.4+/ 4.1, and the median was 3. The top three anatomical main groups were the cardiovascular system, alimentary tract and metabolism, and nervous system (28.2%, 21.6%, and 21.3% of all medications, respectively). The top therapeutic subgroups were drugs used in diabetes, psychoanaleptics, and agents acting on the renin-angiotensin system (12%, 11.3%, and 8.2% of all medications, respectively). Conclusions: Candidates for weight loss surgery report taking medications associated with obesity-related comorbidities such as diabetes, depression, and hypertension. Although many may be able to eliminate these medications, others will require close monitoring and dosage adjustment after surgery. PMID- 26421248 TI - Does Preoperative Weight Change Predict Postoperative Weight Loss After Laparoscopic Sleeve Gastrectomy? AB - Background: Some institutions and insurance companies mandate a preoperative weight loss regimen prior to bariatric surgery. Previous studies suggest little to no correlation between preoperative and postoperative weight loss for laparoscopic Roux-en-Y gastric bypass (RNYGB). This study examined the impact of preoperative weight change for patients undergoing laparoscopic sleeve gastrectomy (LSG). Materials and Methods: A retrospective analysis was performed on patients undergoing LSG at the authors' institution from 2010 to 2012. Patients were grouped based on preoperative weight gain or loss. The correlation between preoperative BMI change and postoperative BMI change was studied, as well as length of surgery. Results: Of 141 patients with 1-year follow-up, 72 lost, six maintained, and 64 gained weight preoperatively. Percentage of excess BMI loss at 1 year was not statistically different between those who lost weight and those who gained weight. Percent change in BMI from initial visit to surgery does not correlate with change in BMI at 1 year postoperatively or with length of surgery. Conclusions: Preoperative weight loss is not a reliable predictor of postoperative weight loss or shorter operative time after LSG. Potential patients who otherwise meet indications for LSG should not be denied based on inability to lose weight. PMID- 26421249 TI - Characterization of 14 microsatellite markers for Silene acaulis (Caryophyllaceae)(1). AB - PREMISE OF THE STUDY: Fifty candidate microsatellite markers, generated using 454 shotgun sequencing, were tested for the widespread arctic/alpine herb Silene acaulis (Caryophyllaceae). METHODS AND RESULTS: Fourteen out of 50 markers resulted in polymorphic products with profiles that enabled interpretation. The numbers of alleles per locus ranged from two to six, and the expected heterozygosity per locus ranged from 0.06 to 0.68. Analysis of F0 and F1 samples proved that one allele was always inherited maternally. Four multiplex mixes have been developed. CONCLUSIONS: Microsatellite markers for this species will be a valuable tool to study detailed small-scale genetic patterns in an arctic/alpine herb and to relate them to demographic parameters. PMID- 26421250 TI - Development of 23 novel polymorphic EST-SSR markers for the endangered relict conifer Metasequoia glyptostroboides. AB - PREMISE OF THE STUDY: Metasequoia glyptostroboides is an endangered relict conifer species endemic to China. In this study, expressed sequence tag-simple sequence repeat (EST-SSR) markers were developed using transcriptome mining for future genetic and functional studies. METHODS AND RESULTS: We collected 97,565 unigene sequences generated by 454 pyrosequencing. A bioinformatics analysis identified 2087 unique and putative microsatellites, from which 96 novel microsatellite markers were developed. Fifty-three of the 96 primer sets successfully amplified clear fragments of the expected sizes; 23 of those loci were polymorphic. The number of alleles per locus ranged from two to eight, with an average of three, and the observed and expected heterozygosity values ranged from 0 to 1.0 and 0.117 to 0.813, respectively. CONCLUSIONS: These microsatellite loci will enrich the genetic resources to develop functional studies and conservation strategies for this endangered relict species. PMID- 26421251 TI - Bioinformatic identification and expression analysis of Nelumbo nucifera microRNA and their targets. AB - PREMISE OF THE STUDY: Sacred lotus (Nelumbo nucifera) is a perennial aquatic herbaceous plant of ecological, ornamental, and economic importance. MicroRNAs (miRNAs) play an important role in plant development. However, reports of miRNAs and their role in sacred lotus have been limited. METHODS: Using the homology search of known miRNAs with genome and transcriptome contig sequences, we employed a pipeline to identify miRNAs in N. nucifera. We also predicted the targets of these miRNAs. RESULTS: We found 106 conserved miRNAs in N. nucifera, and 456 of their miRNA targets were annotated. Quantitative real-time PCR (qRT PCR) analysis revealed the different expression levels of the 10 selected conserved miRNAs in tissues of young leaves, stems, and flowers of N. nucifera. Negative correlation of expression level between five miRNAs and their target genes was also revealed. DISCUSSION: Combining bioinformatics and experiment analysis, we identified the miRNAs in N. nucifera. The results can be used as a workbench for further investigation of the roles of miRNAs in N. nucifera. PMID- 26421252 TI - Development and characterization of microsatellite loci in the pantropical fern Hypolepis punctata (Dennstaedtiaceae). AB - PREMISE OF THE STUDY: Microsatellite loci were isolated in Hypolepis punctata (Dennstaedtiaceae) to further study the reproductive ecology of this species. METHODS AND RESULTS: We developed 16 microsatellite loci from one sample of H. punctata using an enriched genomic library. These loci were characterized in 28 individuals. The number of alleles per locus ranged from two to 10, and the expected heterozygosity ranged from 0.036 to 0.845. CONCLUSIONS: The results indicate that the microsatellite markers can facilitate further studies on inferring the phylogeography and population genetics of H. punctata and related species. PMID- 26421253 TI - Chloroplast microsatellite markers for Artocarpus (Moraceae) developed from transcriptome sequences. AB - PREMISE OF THE STUDY: Chloroplast microsatellite loci were characterized from transcriptomes of Artocarpus altilis (breadfruit) and A. camansi (breadnut). They were tested in A. odoratissimus (terap) and A. altilis and evaluated in silico for two congeners. METHODS AND RESULTS: Fifteen simple sequence repeats (SSRs) were identified in chloroplast sequences from four Artocarpus transcriptome assemblies. The markers were evaluated using capillary electrophoresis in A. odoratissimus (105 accessions) and A. altilis (73). They were also evaluated in silico in A. altilis (10), A. camansi (6), and A. altilis * A. mariannensis (7) transcriptomes. All loci were polymorphic in at least one species, with all 15 polymorphic in A. camansi. Per species, average alleles per locus ranged between 2.2 and 2.5. Three loci had evidence of fragment-length homoplasy. CONCLUSIONS: These markers will complement existing nuclear markers by enabling confident identification of maternal and clone lines, which are often important in vegetatively propagated crops such as breadfruit. PMID- 26421254 TI - Development and characterization of 11 microsatellite primers for the sedge Trichophorum planifolium (Cyperaceae). AB - PREMISE OF THE STUDY: Microsatellite loci were developed for Trichophorum planifolium (Cyperaceae), an endangered woodland sedge protected under federal and provincial legislation in Canada, to explore patterns of population genetic diversity and differentiation in the species. METHODS AND RESULTS: Sixty-three primer pairs were evaluated for amplification consistency and screened for polymorphisms in 96 samples collected from 12 populations of T. planifolium distributed through the range of the species. Of these, 11 loci were shown to be polymorphic, displaying two to six alleles. Mean observed heterozygosity across loci ranged from 0.00 to 0.06 among populations tested. CONCLUSIONS: The results suggest that the 11 primer pairs developed in this study will be useful for future studies of broad-scale genetic variation in T. planifolium and in guiding management protocols for the species in Canada. PMID- 26421255 TI - Development of microsatellite loci for the endangered seagrass Zostera japonica (Zosteraceae). AB - PREMISE OF THE STUDY: New microsatellite markers were developed for the Asian endangered seagrass Zostera japonica (Zosteraceae) to assess genetic diversity and population structure of this species. In China, Z. japonica populations have drastically decreased since the 1970s. METHODS AND RESULTS: A total of 12 polymorphic tetranucleotide microsatellite loci were isolated and characterized in Z. japonica. The number of alleles per locus ranged from one to 11. The expected and observed heterozygosity ranged from 0 to 0.772 and from 0 to 1.000, respectively. CONCLUSIONS: The new microsatellites will be useful in evaluating clonality and population structure of Z. japonica and aiding in conservation and management of the endangered seagrass in Asia. PMID- 26421257 TI - Correction: Hypersexuality Addiction and Withdrawal: Phenomenology, Neurogenetics and Epigenetics. AB - [This corrects the article DOI: 10.7759/cureus.290.]. PMID- 26421256 TI - Digitization workflows for flat sheets and packets of plants, algae, and fungi. AB - Effective workflows are essential components in the digitization of biodiversity specimen collections. To date, no comprehensive, community-vetted workflows have been published for digitizing flat sheets and packets of plants, algae, and fungi, even though latest estimates suggest that only 33% of herbarium specimens have been digitally transcribed, 54% of herbaria use a specimen database, and 24% are imaging specimens. In 2012, iDigBio, the U.S. National Science Foundation's (NSF) coordinating center and national resource for the digitization of public, nonfederal U.S. collections, launched several working groups to address this deficiency. Here, we report the development of 14 workflow modules with 7-36 tasks each. These workflows represent the combined work of approximately 35 curators, directors, and collections managers representing more than 30 herbaria, including 15 NSF-supported plant-related Thematic Collections Networks and collaboratives. The workflows are provided for download as Portable Document Format (PDF) and Microsoft Word files. Customization of these workflows for specific institutional implementation is encouraged. PMID- 26421258 TI - Limitations on the detection rate of high-risk HPV by hybrid capture 2 methodology in high grade intraepithelial (HSIL) or atypical squamous cells cannot exclude HSIL (ASC-H) cytological lesions with proved CIN2. AB - Recent literature data suggest that the high-risk human papillomaviruses (HR HPVs) testing with several molecular techniques could be an alternative to cytology in the detection of cervical intraepithelial neoplasias of grade 2 or worse (CIN2+). However, any molecular techniques have its own limits and may give false negative results which must be clearly known before undertaking a primary HPV screening. This study aims to evaluate the performance of the high-risk HPV hybrid capture II detection kit (HCII) which is considered as a "gold standard technique" in a series of 100 women having proved both cytological lesions of atypical squamous cells-cannot exclude an HSIL (ASC-H) or high-grade squamous intraepithelial lesion (HSIL) and histological lesions of CIN2+. The clinical sensitivity of HCII in women with a cytological diagnosis of ASC-H/HSIL and a diagnosis of CIN2+ is high but not absolute and estimated at 96% (95,6% and 100% of women with a diagnosis of CIN2/3 or invasive squamous cell carcinoma, resp.). These data although they are infrequent must be clearly referred before to start an HPV primary screening of CIN2+ especially with HCII methodology. PMID- 26421259 TI - Minimization vs tailoring: Where do we stand with personalized immunosuppression during renal transplantation in 2015? AB - The introduction of novel immunosuppressive agents over the last two decades and the improvement of our diagnostic tools for early detection of antibody-mediated injury offer us an opportunity, if not a mandate, to better match the immunosuppression needs of the individual patients with side effects of the therapy. However, immunosuppressive regimens in the majority of programs remain mostly protocol-driven, with relatively little inter-program heterogeneity in certain areas of the world. Emerging data showing different outcomes with a particular immunosuppressive strategy in populations with varying immunological risks underscore a real potential for "personalized medicine" in renal transplantation. Studies demonstrating marked differences in the adverse-effect profiles of individual drugs including the risk for viral infections, malignancy and renal toxicity call for a paradigm shift away from a "one size fits all" approach to an individually tailored immunosuppressive therapy for renal transplant recipients, assisted by both screening for predictors of graft loss and paying close attention to dose or class-related adverse effects. Our paper explores some of the opportunities during the care of these patients. Potential areas of improvements may include: (1) a thorough assessment of immunological and metabolic risk profile of each renal transplant recipient; (2) screening for predictors of graft loss and early signs of antibody-mediated rejection with donor-specific antibodies, protocol biopsies and proteinuria (including close follow up of adverse effects with dose adjustments or conversions as necessary); and (3) increased awareness of the possible link between poor tolerance of a given drug at a given dose and non-adherence with the prescribed regimen. Altogether, these considerations may enable the most effective use of the drugs we already have. PMID- 26421260 TI - Recent advances in post autologous transplantation maintenance therapies in B cell non-Hodgkin lymphomas. AB - Lymphomas constitute the second most common indication for high dose therapy (HDT) followed by autologous hematopoietic cell transplantation (auto-HCT). The intent of administering HDT in these heterogeneous disorders varies from cure (e.g., in relapsed aggressive lymphomas) to disease control (e.g., most indolent lymphomas). Regardless of the underlying histology or remission status at transplantation, disease relapse remains the number one cause of post auto-HCT therapy failure and mortality. The last decade has seen a proliferation of clinical studies looking at prevention of post auto-HCT therapy failure with various maintenance strategies. The benefit of such therapies is in turn dependent on disease histology and timing of transplantation. In relapsed, chemosensitive diffuse large B-cell lymphoma (DLBCL), although post auto-HCT maintenance rituximab seems to be safe and feasible, it does not provide improved survival outcomes and is not recommended. The preliminary results with anti- programmed death -1 (PD-1) antibody therapy as post auto-HCT maintenance in DLBCL is promising but requires randomized validation. Similarly in follicular lymphoma, maintenance therapies including rituximab following auto-HCT should be considered investigational and offered only on a clinical trial. Rituximab maintenance results in improved progression-free survival but has not yet shown to improve overall survival in mantle cell lymphoma (MCL), but given the poor prognosis with post auto-HCT failure in MCL, maintenance rituximab can be considered on a case-by-case basis. Ongoing trials evaluating the efficacy of post auto-HCT maintenance with novel compounds (e.g., immunomodulators, PD-1 inhibitors, proteasome inhibitors and bruton's tyrosine kinase inhibitors) will likely change the practice landscape in the near future for B cell non-Hodgkin lymphomas patients following HDT and auto-HCT. PMID- 26421261 TI - Split liver transplantation: What's unique? AB - The intraoperative management of split liver transplantation (SLT) has some unique features as compared to routine whole liver transplantations. Only the liver has this special ability to regenerate that confers benefits in survival and quality of life for two instead of one by splitting livers. Primary graft dysfunction may result from small for size syndrome. Graft weight to recipient body weight ratio is significant for both trisegmental and hemiliver grafts. Intraoperative surgical techniques aim to reduce portal hyperperfusion and decrease venous portal pressure. Ischemic preconditioning can be instituted to protect against ischemic reperfusion injury which impacts graft regeneration. Advancement of the technique of SLT is essential as use of split cadaveric grafts expands the donor pool and potentially has an excellent future. PMID- 26421262 TI - Obesity and liver transplantation. AB - The percentage of overweight and obese patients (OPs) waiting for a liver transplant continues to increase. Despite the significant advances occurred in bariatric medicine, obesity is still considered a relative contraindication to liver transplantation (LT). The main aim of this review is to appraise the literature on the outcomes of OPs undergoing LT, treatments that might reduce their weight before, during or after surgery, and discuss some of the controversies and limitations of the current knowledge with the intent of highlighting areas where future research is needed. PMID- 26421263 TI - Role of steroid maintenance in sensitized kidney transplant recipients. AB - AIM: To evaluate whether there is a threshold sensitization level beyond which benefits of chronic steroid maintenance (CSM) emerge. METHODS: Using Organ Procurement and Transplant Network/United Network of Organ Sharing database, we compared the adjusted graft and patient survivals for CSM vs early steroid withdrawal (ESW) among patients who underwent deceased-donor kidney (DDK) transplantation from 2000 to 2008 who were stratified by peak-panel reactive antibody (peak-PRA) titers (0%-30%, 31%-60% and > 60%). All patients received perioperative induction therapy and maintenance immunosuppression based on calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF). RESULTS: The study included 42851 patients. In the 0%-30% peak-PRA class, adjusted over-all graft failure (HR 1.11, 95%CI: 1.03-1.20, P = 0.009) and patient-death (HR 1.29, 95%CI: 1.16-1.43, P < 0.001) risks were higher and death-censored graft-failure risk (HR 1.06, 95%CI: 0.98-1.14, P = 0.16) similar for CSM (n = 25218) vs ESW (n = 7399). Over-all (HR 1.04, 95%CI: 0.85-1.28, P = 0.70) and death-censored (HR 0.97, 95%CI: 0.78-1.21, P = 0.81) graft-failure risks were similar and patient-death risk (HR 1.39, 95%CI: 1.03-1.87, P = 0.03) higher for CSM (n = 3495) vs ESW (n = 850) groups for 31%-60% peak-PRA class. In the > 60% peak-PRA class, adjusted overall graft-failure (HR 0.90, 95%CI: 0.76-1.08, P = 0.25) and patient-death (HR 0.92, 95%CI: 0.71-1.17, P = 0.47) risks were similar and death-censored graft failure risk lower (HR 0.84, 95%CI: 0.71-0.99, P = 0.04) for CSM (n = 4966) vs ESW (n = 923). CONCLUSION: In DDK transplant recipients who underwent perioperative induction and CNI/MMF maintenance, CSM appears to be associated with increased risk for death with functioning graft in minimally-sensitized patients and improved death-censored graft survival in highly-sensitized patients. PMID- 26421264 TI - Effectiveness of repeated transplantations of hematopoietic stem cells in spinal cord injury. AB - AIM: To evaluate the short and long-term effects of the complex cell therapy of 202 cases of spinal cord injury (SCI). METHODS: The main arm included 202 cases of SCI and the control arm included 20 SCI cases. For the therapy the hematopoietic stem cells (HSCs) and progenitor cells (PCs) were mobilized to peripheral blood by 8 subcutaneous injections of granulocyte colony-stimulating factor (G-CSF) for 4 d and are harvested at day 5. The cells were administered to the main arm intrathecally every 3 mo for a long term (3-5 years) according to the internal research protocol international medical institute of tissue engineering. Magnetic resonance imaging of the site of injury and urodynamic tests were performed every 6 mo. Motor evoked potentials (MEP), somatosensory evoked potentials (SSEP) were evaluated every 3 mo. The patients were evaluated with american spianl injury association (ASIA) index, functional independence measure index, the Medical Research Council Scale, the International Standards for Neurological Classification of Spinal Cord Injury (ISCSCI-92) and specifically developed scales. The function of bladder was evaluated by a specifically developed clinical scale. The long-term clinical outcomes were assessed for the SCI patients who received no less than 20 intrathecal transplantations of HSCs and hematopoietic precursors (HPs). RESULTS: The restoration of neurologic deficit after HSCs and HPs transplantations was proved stable and evident in 57.4% of the cases. In 42.6% cases no neurologic improvement has been observed. In 50% of the cases the motor restoration began after the first transplantation, which is confirmed in average by 9.9 points improvement in neurologic impairment as compared to the baseline (P < 0.05). Repair of the urinary system was observed in 47.7% of the cases. The sensitivity improved from baseline 124.3 points to 138.4 after the first and to 153.5 points after the second transplantations of HSCs and HPs (P < 0.05, between the stages of research). The evaluation with ASIA index demonstrated regress of neurologic symptoms in 23 cases. Motor progress was also assessed with the ISCISCI-92 motor and sensory scores, and the data coincided with those received with the specifically developed scale. The number of the patients with the signs of locomotive repair was 56.9%. No life threatening complications or adverse effects have been observed. CONCLUSION: The method is safe, effective and considerably improves the life quality of SCI patients. The therapy is approved for clinical use as the treatment of choice. PMID- 26421266 TI - Weight trends in United States living kidney donors: Analysis of the UNOS database. AB - AIM: To analyze the national trends associated with body mass index (BMI) and living kidney donation. METHODS: Forty-seven thousand seven hundred and five adult living kidney donors as reported to the Organ Procurement and Transplantation Network from 1999 to 2011 were analyzed using their pre-donation BMI. Predictor variables of interest included age, gender, ethnicity, relationship, education status, and transplant region. RESULTS: Sixteen thousand nine hundred and seventy-one of the living kidney donors were normal weight (35.6%); 19337 were overweight (40.5%); 9007 were mildly obese (18.9%); 1992 were moderate to morbidly obese (4.2%). Overweight and mildly obese kidney donors have increased through time by 12% and 20% every 5 years, respectively (P < 0.05). Donors 35-49 years of age, hispanic males or females and black females, those with high school diploma or general Education Degree, and biologically related or partner/spouses were more likely to be obese. CONCLUSION: Over the past 13 years, the majority of living kidney donors have spanned the overweight to obese categories. Paralleling the national rise is an increase in overweight and mildly obese kidney donors. A fair number of moderate to morbidly obese living kidney donors are still allowed to donate. PMID- 26421265 TI - Cytomegalovirus reactivation after autologous stem cell transplantation in myeloma and lymphoma patients: A single-center study. AB - AIM: To determine the incidence of and the risk factors for cytomegalovirus (CMV) symptomatic infection and end-organ disease after autologous stem cell transplantation (ASCT). METHODS: A total of 327 consecutive non CD34(+) selected autografts performed from the Hematology and Stem Cell Transplantation Unit of Regina Elena National Cancer Institute of Rome (Italy) in the period comprised between January 2003 to January 2015, were reviewed. Over the 327 autografts, 201 were performed in patients with multiple myeloma, whereas the remaining 126 in patients affected by non-Hodgkin's lymphoma and Hodgkin's lymphoma. The patients who underwent an ASCT for an acute leukemia (n = 20) in the same period were excluded from this analysis. CMV DNA load in the blood has been determined by polymerase-chain reaction in the case of a clinical suspicion of reactivation, therefore, no routine monitoring strategy was adopted. In the presence of signs and symptoms of CMV reactivation an antiviral treatment was performed. RESULTS: Overall, 36 patients (11%) required a specific antiviral treatment for a symptomatic CMV reactivation (n = 32) or an end-organ disease (n = 4). We observed 20 and 16 cases of CMV reactivation among lymphoma (16%) and myeloma patients (8%), respectively. Among cases of end-organ disease, 3 were diagnosed as interstitial pneumonia and one remaining case as hemorrhagic enteritis. All cases of CMV reactivation were observed in IgG seropositive patients, with no documented cases of primary CMV infection. All patients were treated with a specific antiviral therapy, with a global rate of hospitalization of 55%; four patients received intravenous immunoglobulins. Transplant-related mortality was significantly higher in patients who experienced a CMV reactivation (8.4% +/- 4.7% vs 1.7% +/- 0.8%; P = 0.047). In univariate analysis, a pre-transplant HBcIgG seropositivity, a diagnosis of T-cell non-Hodgkin's lymphoma and higher median age at transplant were significantly associated with the risk of developing a clinically relevant CMV infection requiring specific antiviral therapy (P < 0.001, P = 0.042 and P = 0.004, respectively). In multivariate analysis, only a pre-transplant HBcIgG seropositivity (OR = 8.928, 95%CI: 1.991 33.321; P = 0.023) and a diagnosis of T-cell non-Hodgkin's lymphoma (OR = 4.739, 95%CI: 1.511-11.112; P = 0.042) proved to be independent predictors of a post transplant clinically relevant CMV reactivation. CONCLUSION: A symptomatic CMV infection can occur in about 11% of adult patients with lymphoma or myeloma undergoing ASCT. A pre-transplant HBcIgG seropositivity and a diagnosis of T-cell non-Hodgkin's lymphoma should be considered as independent predictor factors of CMV reactivation. PMID- 26421267 TI - Serum levels of soluble vascular cell adhesion molecules may correlate with the severity of dengue virus-1 infection in adults. AB - The damage of vascular endothelial cells has been speculated to be involved in the pathogenesis of dengue virus (DENV) infection. However, little is known about the role of soluble vascular cell adhesion molecule-1 (sVCAM-1) in predicting the severity of dengue infection in adults. In this study, 51 adults with DENV-1 infection (21 with severe dengue and 30 with dengue fever (DF) were included, and their serum levels of sVCAM-1 and other parameters were determined. The results indicated that the levels of sVCAM-1 were elevated on days 1-3 to 16.75 (11.55 34.74) ng/mL in the severe dengue patients. These levels increased rapidly to peak values of 43.53 (37.15-47.02) ng/mL on days 10-12 and then declined; however, the values were maintained at a high level (38.07 (26.06-39.63) ng/mL). Other parameters, including reduced platelet (PLT) counts, neutrophil (NEU) counts and increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine kinase (CK), were also observed in the severe dengue group but not in the DF group. The levels of cytokines, such as interleukin (IL)-6, IL-10, interferon gamma (IFNgamma), and tumor necrosis factor alpha (TNF-alpha), were transiently increased in the severe dengue patients. Among the aforementioned parameters, only sVCAM-1 levels were significantly elevated earlier and more persistently in the severe dengue patients than in the DF patients. sVCAM-1 positively correlated with the levels of ALT, AST, LDH, TNF-alpha, and IL-6 and negatively correlated with the levels of PLT, NEU, and viremia. Notably, the high levels of sVCAM-1 were closely associated with the severe dengue patients. In conclusion, sVCAM-1 may be a superior indicator for monitoring the severity of dengue. PMID- 26421269 TI - Large Dengue virus type 1 outbreak in Taiwan. PMID- 26421268 TI - A sensitive and specific antigen detection assay for Middle East respiratory syndrome coronavirus. AB - Since its emergence in 2012, more than 900 laboratory-confirmed cases of Middle East respiratory syndrome (MERS) have been reported with a fatality rate of more than 30%. However, no antigen detection assay for commercial use is available for diagnosis. In this study, the full-length nucleocapsid protein (NP) gene of MERS coronavirus (MERS-CoV) was cloned and expressed in Escherichia coli. A MERS-CoV NP capture enzyme-linked immunosorbent assay (ELISA) using two MERS-CoV-NP specific monoclonal antibodies (MAbs) generated was developed. The ELISA was evaluated using 129 nasopharyngeal aspirates (NPAs) positive for various respiratory viruses and simulated positive NPAs by adding serial dilutions of MERS-CoV. Using a cutoff OD of 0.19, all 129 NPAs positive for respiratory viruses showed very low OD, with a specificity of 100%. For the two simulated MERS-CoV-positive NPAs with serial dilutions of live MERS-CoV, all samples with >=10 50% tissue culture infective dose (TCID50)/0.1 mL showed positive results. For the 10 additional NPAs with 20 and 200 TCID50/0.1 mL of live MERS-CoV added, all were positive. A highly sensitive and specific MAbs-based antigen capture ELISA has been developed for MERS. This sensitive and specific antigen capture ELISA should be useful for detection of MERS-CoV in human and dromedaries and in field studies. PMID- 26421270 TI - Outbreaks of enterovirus D68 in Malaysia: genetic relatedness to the recent US outbreak strains. PMID- 26421271 TI - Only a subset of C. canimorsus strains is dangerous for humans. AB - Capnocytophaga canimorsus are gram-negative bacteria living as commensals in the mouth of dogs and cats. C. canimorsus cause rare but life-threatening generalized infections in humans that have been in contact with a dog or a cat. Over the last years we collected 105 C. canimorsus strains from different geographical origins and from severe human infections or healthy dogs. All these strains were analyzed by 16S rDNA sequencing and a phylogenetic tree revealed two main groups of bacteria instead of one with no relation to the geographical origin. This branching was confirmed by the whole-genome sequencing of 10 strains, supporting the evidence of a new Capnocytophaga species in dogs. Interestingly, 19 out of 19 C. canimorsus strains isolated from human infections belonged to the same species. Furthermore, most strains from this species could grow in heat inactivated human serum (HIHS) (40/46 tested), deglycosylate IgM (48/66) and were cytochrome-oxidase positive (60/66) while most strains from the other species could not grow in HIHS (22/23 tested), could not deglycosylate IgM (33/34) and were cytochrome-oxidase negative (33/34). Here, we propose to call Capnocytophaga canis (Latin: dog) the novel, presumably less virulent dog-hosted Capnocytophaga species and to keep the name C. canimorsus for the species including human pathogens. PMID- 26421272 TI - Characterization of Listeria monocytogenes isolated from human Listeriosis cases in China. PMID- 26421273 TI - Persister mechanisms in Borrelia burgdorferi: implications for improved intervention. PMID- 26421276 TI - Advances in MRI Techniques and Applications. PMID- 26421275 TI - Genomic Copy Number Variation Affecting Genes Involved in the Cell Cycle Pathway: Implications for Somatic Mosaicism. AB - Somatic genome variations (mosaicism) seem to represent a common mechanism for human intercellular/interindividual diversity in health and disease. However, origins and mechanisms of somatic mosaicism remain a matter of conjecture. Recently, it has been hypothesized that zygotic genomic variation naturally occurring in humans is likely to predispose to nonheritable genetic changes (aneuploidy) acquired during the lifetime through affecting cell cycle regulation, genome stability maintenance, and related pathways. Here, we have evaluated genomic copy number variation (CNV) in genes implicated in the cell cycle pathway (according to Kyoto Encyclopedia of Genes and Genomes/KEGG) within a cohort of patients with intellectual disability, autism, and/or epilepsy, in which the phenotype was not associated with genomic rearrangements altering this pathway. Benign CNVs affecting 20 genes of the cell cycle pathway were detected in 161 out of 255 patients (71.6%). Among them, 62 individuals exhibited >2 CNVs affecting the cell cycle pathway. Taking into account the number of individuals demonstrating CNV of these genes, a support for this hypothesis appears to be presented. Accordingly, we speculate that further studies of CNV burden across the genes implicated in related pathways might clarify whether zygotic genomic variation generates somatic mosaicism in health and disease. PMID- 26421274 TI - An Omics Perspective on Molecular Biomarkers for Diagnosis, Prognosis, and Therapeutics of Cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy arising from the epithelial bile duct. The lack of early diagnostic biomarkers as well as therapeutic measures results in severe outcomes and poor prognosis. Thus, effective early diagnostic, prognostic, and therapeutic biomarkers are required to improve the prognosis and prolong survival rates in CCA patients. Recent advancement in omics technologies combined with the integrative experimental and clinical validations has provided an insight into the underlying mechanism of CCA initiation and progression as well as clues towards novel biomarkers. This work highlights the discovery and validation of molecular markers in CCA identified through omics approaches. The possible roles of these molecules in various cellular pathways, which render CCA carcinogenesis and progression, will also be discussed. This paper can serve as a reference point for further investigations to yield deeper understanding in the complex feature of this disease, potentially leading to better approaches for diagnosis, prognosis, and therapeutics. PMID- 26421278 TI - mmnet: An R Package for Metagenomics Systems Biology Analysis. AB - The human microbiome plays important roles in human health and disease. Previous microbiome studies focused mainly on single pure species function and overlooked the interactions in the complex communities on system-level. A metagenomic approach introduced recently integrates metagenomic data with community-level metabolic network modeling, but no comprehensive tool was available for such kind of approaches. To facilitate these kinds of studies, we developed an R package, mmnet, to implement community-level metabolic network reconstruction. The package also implements a set of functions for automatic analysis pipeline construction including functional annotation of metagenomic reads, abundance estimation of enzymatic genes, community-level metabolic network reconstruction, and integrated network analysis. The result can be represented in an intuitive way and sent to Cytoscape for further exploration. The package has substantial potentials in metagenomic studies that focus on identifying system-level variations of human microbiome associated with disease. PMID- 26421277 TI - Prognostic Outcomes and Risk Factors for Patients with Renal Cell Carcinoma and Venous Tumor Thrombus after Radical Nephrectomy and Thrombectomy: The Prognostic Significance of Venous Tumor Thrombus Level. AB - INTRODUCTION: To evaluate the prognostic outcomes and risk factors for renal cell carcinoma (RCC) patients with venous tumor thrombus in China. MATERIALS AND METHODS: We reviewed the clinical information of 169 patients who underwent radical nephrectomy and thrombectomy. Overall and cancer-specific survival rates were analyzed. Univariate and multivariate analyses were used to investigate the potential prognostic factors. RESULTS: The median survival time was 63 months. The five-year overall survival and cancer-specific survival rate were 53.6% and 54.4% for all patients. For all patients, significant survival difference was only observed between early (below hepatic vein) and advanced (above hepatic vein) tumor thrombus. However, significant differences existed between both RV/IVC and early/advanced tumor thrombus groups in N0M0 patients. Multivariate analysis demonstrated that higher tumor thrombus level (p = 0.016, RR = 1.58), N (p = 0.013, RR = 2.60), and M (p < 0.001, RR = 4.14) stages and adrenal gland invasion (p = 0.001, RR = 4.91) were the most significant negative prognostic predictors. CONCLUSIONS: In this study, we reported most cases of RCC patients with venous extension in China. We proved that patients with RCC and venous tumor thrombus may have relative promising long-term survival rate, especially those with early tumor thrombus. PMID- 26421279 TI - A Population-Based Model to Consider the Effect of Seasonal Variation on Serum 25(OH)D and Vitamin D Status. AB - BACKGROUND: We elaborated a model that predicts the centiles of the 25(OH)D distribution taking into account seasonal variation. METHODS: Data from two Swiss population-based studies were used to generate (CoLaus) and validate (Bus Sante) the model. Serum 25(OH)D was measured by ultra high pressure LC-MS/MS and immunoassay. Linear regression models on square-root transformed 25(OH)D values were used to predict centiles of the 25(OH)D distribution. Distribution functions of the observations from the replication set predicted with the model were inspected to assess replication. RESULTS: Overall, 4,912 and 2,537 Caucasians were included in original and replication sets, respectively. Mean (SD) 25(OH)D, age, BMI, and % of men were 47.5 (22.1) nmol/L, 49.8 (8.5) years, 25.6 (4.1) kg/m(2), and 49.3% in the original study. The best model included gender, BMI, and sin-cos functions of measurement day. Sex- and BMI-specific 25(OH)D centile curves as a function of measurement date were generated. The model estimates any centile of the 25(OH)D distribution for given values of sex, BMI, and date and the quantile corresponding to a 25(OH)D measurement. CONCLUSIONS: We generated and validated centile curves of 25(OH)D in the general adult Caucasian population. These curves can help rank vitamin D centile independently of when 25(OH)D is measured. PMID- 26421280 TI - Constructing a Genome-Wide LD Map of Wild A. gambiae Using Next-Generation Sequencing. AB - Anopheles gambiae is the major malaria vector in Africa. Examining the molecular basis of A. gambiae traits requires knowledge of both genetic variation and genome-wide linkage disequilibrium (LD) map of wild A. gambiae populations from malaria-endemic areas. We sequenced the genomes of nine wild A. gambiae mosquitoes individually using next-generation sequencing technologies and detected 2,219,815 common single nucleotide polymorphisms (SNPs), 88% of which are novel. SNPs are not evenly distributed across A. gambiae chromosomes. The low SNP-frequency regions overlay heterochromatin and chromosome inversion domains, consistent with the lower recombinant rates at these regions. Nearly one million SNPs that were genotyped correctly in all individual mosquitoes with 99.6% confidence were extracted from these high-throughput sequencing data. Based on these SNP genotypes, we constructed a genome-wide LD map for wild A. gambiae from malaria-endemic areas in Kenya and made it available through a public Website. The average size of LD blocks is less than 40 bp, and several large LD blocks were also discovered clustered around the para gene, which is consistent with the effect of insecticide selective sweeps. The SNPs and the LD map will be valuable resources for scientific communities to dissect the A. gambiae genome. PMID- 26421281 TI - Expression Signatures of Long Noncoding RNAs in Adolescent Idiopathic Scoliosis. AB - PURPOSE: Adolescent idiopathic scoliosis (AIS), the most common pediatric spinal deformity, is considered a complex genetic disease. Causing genes and pathogenesis of AIS are still unclear. This study was designed to identify differentially expressed long noncoding RNAs (lncRNAs) involving the pathogenesis of AIS. METHODS: We first performed comprehensive screening of lncRNA and mRNA in AIS patients and healthy children using Agilent human lncRNA + mRNA Array V3.0 microarray. LncRNAs expression in different AIS patients was further evaluated using quantitative PCR. RESULTS: A total of 139 lncRNAs and 546 mRNAs were differentially expressed between AIS patients and healthy control. GO and Pathway analysis showed that these mRNAs might be involved in bone mineralization, neuromuscular junction, skeletal system morphogenesis, nucleotide and nucleic acid metabolism, and regulation of signal pathway. Four lncRNAs (ENST00000440778.1, ENST00000602322.1, ENST00000414894.1, and TCONS_00028768) were differentially expressed between different patients when grouped according to age, height, classification, severity of scoliosis, and Risser grade. CONCLUSIONS: This study demonstrates the abnormal expression of lncRNAs and mRNAs in AIS, and the expression of some lncRNAs was related to clinical features. This study is helpful for further understanding of lncRNAs in pathogenesis, treatment, and prognosis of AIS. PMID- 26421282 TI - Functional Outcomes: One Year after a Cardiac Arrest. AB - OBJECTIVE: The study aim was to characterize the time-course of recovery in impairments, activity limitations, participation restrictions, disability, and quality of life during the first year after cardiac arrest. Secondarily, the study described the associations between the instruments used to measure each of these domains. METHODS: Measures of global disability (Cerebral Performance Category, CPC, Modified Rankin Scale, mRS), quality of life, activity limitations, participation restrictions, and affective and cognitive impairments were administered to 29 participants 1, 6, and 12 months after cardiac arrest. RESULTS: Global measures of disability indicated recovery between one month and one year after cardiac arrest (mean CPC: 2.1 versus 1.69, P < 0.05; mean mRS: 2.55 versus 1.83, P < 0.05). While global measures of disability were moderately associated with participation, they were poorly associated with other measures. The cohort endorsed depressive symptomatology throughout the year but did not have detectable cognitive impairment. CONCLUSIONS: Recovery from cardiac arrest is multifaceted and recovery continues for months depending upon the measures being used. Measures of global disability, reintegration into the community, and quality of life yield different information. Future clinical trials should include a combination of measures to yield the most complete representation of recovery after cardiac arrest. PMID- 26421283 TI - Prevention of Nausea and Vomiting in Patients Undergoing Oral Anticancer Therapies for Solid Tumors. AB - Chemotherapy-induced nausea and vomiting (CINV) is still a common and debilitating side effect despite recent advances in its prevention and treatment. The intrinsic emetogenicity of chemotherapy agents allowed grouping into four risk groups (high, moderate, low, and minimal risk of emetogenicity). The prevention of acute and delayed CINV for intravenous agents and one day regimens is well studied, although, there are few data about management of CINV induced by oral cytotoxic agents and targeted therapies, usually administered in extended regimens of daily oral use. Until now treatment of nausea and vomiting caused by oral antineoplastic agents remains largely empirical. The level of evidence of prophylactic antiemetics recommended for these agents is low. There are differences in the classification of emetogenic potential of oral antineoplastic agents between the international guidelines and different recommendations for prophylactic antiemetic regimens. Herein we review the evidence for antiemetic regimens for the most used oral antineoplastic agents for solid tumors and propose antiemetic regimens for high to moderate risk and low to minimal risk of emetogenicity. PMID- 26421285 TI - Effects of a Particular Heptapeptide on the IFN-alpha-Sensitive CML Cells. AB - Using the phage display biopanning technique, we have previously identified a heptapeptide KLWVIPQ which specifically binds to the surface of the IFN-alpha sensitive but not the IFN-alpha-resistant CML cells. The effects of this heptapeptide on the IFN-alpha-sensitive CML cells were investigated in the present study. IFN-alpha-sensitive KT-1/A3 and IFN-alpha-resistant KT-1/A3R CML cells were transfected by pEGFP-KLWVIPQ expression vector and/or induced by IFN alpha. WST-1 cell proliferation assay, flow cytometry, and western blotting were performed to determine the effects of this heptapeptide and/or IFN-alpha on CML cells. The viability of the KT-1/A3 cells was inhibited and apoptosis was induced by either expression of the heptapeptide KLWVIPQ or IFN-alpha treatment with concurrent upregulation of P53 and downregulation of P210(bcr/abl). However, these effects were not observed in the IFN-alpha-resistant KT-1/A3R cells. These results suggest that the heptapeptide KLWVIPQ shares a similar mechanism with IFN alpha in the regulation of CML cell growth and apoptosis, implying that the heptapeptide KLWVIPQ could be a novel target to go further into mechanisms of IFN alpha sensitivity and/or resistance in CML. PMID- 26421284 TI - Myocardial Dysfunction and Shock after Cardiac Arrest. AB - Postarrest myocardial dysfunction includes the development of low cardiac output or ventricular systolic or diastolic dysfunction after cardiac arrest. Impaired left ventricular systolic function is reported in nearly two-thirds of patients resuscitated after cardiac arrest. Hypotension and shock requiring vasopressor support are similarly common after cardiac arrest. Whereas shock requiring vasopressor support is consistently associated with an adverse outcome after cardiac arrest, the association between myocardial dysfunction and outcomes is less clear. Myocardial dysfunction and shock after cardiac arrest develop as the result of preexisting cardiac pathology with multiple superimposed insults from resuscitation. The pathophysiology involves cardiovascular ischemia/reperfusion injury and cardiovascular toxicity from excessive levels of inflammatory cytokine activation and catecholamines, among other contributing factors. Similar mechanisms occur in myocardial dysfunction after cardiopulmonary bypass, in sepsis, and in stress-induced cardiomyopathy. Hemodynamic stabilization after resuscitation from cardiac arrest involves restoration of preload, vasopressors to support arterial pressure, and inotropic support if needed to reverse the effects of myocardial dysfunction and improve systemic perfusion. Further research is needed to define the role of postarrest myocardial dysfunction on cardiac arrest outcomes and identify therapeutic strategies. PMID- 26421286 TI - Biomarkers of Brain Damage: S100B and NSE Concentrations in Cerebrospinal Fluid- A Normative Study. AB - NSE and S100B belong among the so-called structural proteins of the central nervous system (CNS). Lately, this group of structural proteins has been profusely used as specific biomarkers of CNS tissue damage. So far, the majority of the research papers have focused predominantly on the concentrations of these proteins in blood in relation to CNS damage of various origins. Considering the close anatomic and functional relationship between the brain or spinal cord and cerebrospinal fluid (CSF), in case of a CNS injury, a rapid and pronounced increase of the concentrations of structural proteins specifically in CSF takes place. This study inquires into the physiological concentrations of NSE and S100B proteins in CSF, carried out on a sufficiently large group of 601 patients. The detected values can be used for determination of a normal reference range in CSF in a clinical laboratory diagnostics. PMID- 26421288 TI - Biomarkers of Brain Function and Injury: Biological and Clinical Significance. PMID- 26421287 TI - Evaluation of Liver Fibrosis Using Texture Analysis on Combined-Contrast-Enhanced Magnetic Resonance Images at 3.0T. AB - PURPOSE: To noninvasively assess liver fibrosis using combined-contrast-enhanced (CCE) magnetic resonance imaging (MRI) and texture analysis. MATERIALS AND METHODS: In this IRB-approved, HIPAA-compliant prospective study, 46 adults with newly diagnosed HCV infection and recent liver biopsy underwent CCE liver MRI following intravenous administration of superparamagnetic iron oxides (ferumoxides) and gadolinium DTPA (gadopentetate dimeglumine). The image texture of the liver was quantified in regions-of-interest by calculating 165 texture features. Liver biopsy specimens were stained with Masson trichrome and assessed qualitatively (METAVIR fibrosis score) and quantitatively (% collagen stained area). Using L 1 regularization path algorithm, two texture-based multivariate linear models were constructed, one for quantitative and the other for quantitative histology prediction. The prediction performance of each model was assessed using receiver operating characteristics (ROC) and correlation analyses. RESULTS: The texture-based predicted fibrosis score significantly correlated with qualitative (r = 0.698, P < 0.001) and quantitative (r = 0.757, P < 0.001) histology. The prediction model for qualitative histology had 0.814-0.976 areas under the curve (AUC), 0.659-1.000 sensitivity, 0.778-0.930 specificity, and 0.674-0.935 accuracy, depending on the binary classification threshold. The prediction model for quantitative histology had 0.742-0.950 AUC, 0.688-1.000 sensitivity, 0.679-0.857 specificity, and 0.696-0.848 accuracy, depending on the binary classification threshold. CONCLUSION: CCE MRI and texture analysis may permit noninvasive assessment of liver fibrosis. PMID- 26421289 TI - Molecular Epidemiology of Human Norovirus in Korea in 2013. AB - Norovirus is a major cause of acute gastroenteritis. The molecular epidemiology of norovirus exhibits temporal and geographical fluctuations, and new variants of the GII.4 genotype emerge every 2-3 years to cause global epidemics of acute gastroenteritis. We investigated GI and GII genotypes of human norovirus strains isolated from patients with acute gastroenteritis in Korea in 2013. Norovirus antigen test was performed on 2,980 fecal specimens from January to December 2013. RNA was extracted from norovirus antigen-positive fecal suspensions, and the norovirus capsid (VP1) and polymerase (RdRp) genes were characterized by RT PCR and sequencing. Of the 230 genotyped strains, GII.4 (77.3%) was the most frequently observed capsid genotype, followed by GII.3 (6.1%) and GII.13 (3.9%). A norovirus GII.4 variant, GII.Pe/GII.4 Sydney 2012, was the most frequently found polymerase/capsid genotype (65.7%), followed by GII.P17/GII.17 (2.1%) and GII.P21/GII.3 (2.1%). Phylogenetic, similarity, and capsid epitope analyses of GII.Pe/GII.4 Sydney 2012 strains were performed. We concluded that the norovirus GII.4 variant, GII.Pe/GII.4 Sydney 2012, was the main cause of norovirus-related gastroenteritis in Korea in 2013. PMID- 26421290 TI - Cholesteryl Pullulan Encapsulated TNF-alpha Nanoparticles Are an Effective Mucosal Vaccine Adjuvant against Influenza Virus. AB - We encapsulated tumor necrosis factor-alpha (TNF-alpha), a major proinflammatory cytokine, into cholesteryl pullulan (CHP) to prepare TNF/CHP nanoparticles. In this report, we describe the immune-enhancing capability of the nanoparticles to act as a vaccine adjuvant. TNF/CHP nanoparticles showed excellent storage stability and enhanced host immune responses to external immunogens. The nanoparticles were effective via the nasal route of administration for inducing systemic IgG1 as well as mucosal IgA. We applied the nanoparticles in a model experimental influenza virus infection to investigate their adjuvant ability. TNF/CHP nanoparticles combined with a conventional split vaccine protected mice via nasal administration against a lethal challenge of A/PR/8/34 (H1N1) influenza virus. Mechanistic studies showed that the nanoparticles enhanced antigen uptake by dendritic cells (DCs) and moderately induced the expression of inflammation related genes in nasopharynx lymphoid tissue (NALT), leading to the activation of both B and T cells. Preliminary safety study revealed no severe toxicity to TNF/CHP nanoparticles. Slight-to-moderate influences in nasal mucosa were observed only in the repeated administration and they seemed to be reversible. Our data show that TNF/CHP nanoparticles effectively enhance both humoral and cellular immunity and could be a potential adjuvant for vaccines against infectious diseases, especially in the mucosa. PMID- 26421292 TI - A Randomized, Double-Blind Pilot Study of Dose Comparison of Ramosetron to Prevent Chemotherapy-Induced Nausea and Vomiting. AB - PURPOSE: This study was conducted to determine the optimal dose titration of ramosetron to prevent the Rhodes Index of Nausea, Vomiting, and Retching (RINVR). METHODS: Patients treated with folic acid, 5-fluorouracil, and oxaliplatin were randomized into three groups (0.3 mg, 0.45 mg, and 0.6 mg ramosetron before chemotherapy). The pharmacokinetics and pharmacodynamics using RINVR were evaluated. RESULTS: Seventeen, 15, and 18 patients received ramosetron at doses of 0.3 mg, 0.45 mg, and 0.6 mg, respectively. T max (h), C max (ng/mL), and AUClast (ng.h/mL) were associated with dose escalation significantly, showing a reverse correlation with the RINVR during chemotherapy. Acute CINV was observed in four patients (22.2%), two patients (14.3%), and one (5.6%) patient and a delayed CINV on day 7 was found in eight (47%), three (21.4%), and five (27.8%) patients in each group. The complete response rate was increased with dose escalation (35.3%, 50.0%, and 72.2% in each group) and also showed the tendency for decreasing moderate-to-severe CINV. CONCLUSIONS: This study shows a trend regarding the dose-response relationship for ramosetron to prevent CINV, including delayed emesis. It suggested that dose escalation should be considered in patients with CINV in a subsequent cycle of chemotherapy, and an individual approach using RINVR could be useful to monitor CINV. PMID- 26421291 TI - Biological and Pharmacological Aspects of the NK1-Receptor. AB - The neurokinin 1 receptor (NK-1R) is the main receptor for the tachykinin family of peptides. Substance P (SP) is the major mammalian ligand and the one with the highest affinity. SP is associated with multiple processes: hematopoiesis, wound healing, microvasculature permeability, neurogenic inflammation, leukocyte trafficking, and cell survival. It is also considered a mitogen, and it has been associated with tumorigenesis and metastasis. Tachykinins and their receptors are widely expressed in various human systems such as the nervous, cardiovascular, genitourinary, and immune system. Particularly, NK-1R is found in the nervous system and in peripheral tissues and are involved in cellular responses such as pain transmission, endocrine and paracrine secretion, vasodilation, and modulation of cell proliferation. It also acts as a neuromodulator contributing to brain homeostasis and to sensory neuronal transmission associated with depression, stress, anxiety, and emesis. NK-1R and SP are present in brain regions involved in the vomiting reflex (the nucleus tractus solitarius and the area postrema). This anatomical localization has led to the successful clinical development of antagonists against NK-1R in the treatment of chemotherapy-induced nausea and vomiting (CINV). The first of these antagonists, aprepitant (oral administration) and fosaprepitant (intravenous administration), are prescribed for high and moderate emesis. PMID- 26421293 TI - How to Isolate a Plant's Hypomethylome in One Shot. AB - Genome assembly remains a challenge for large and/or complex plant genomes due to their abundant repetitive regions resulting in studies focusing on gene space instead of the whole genome. Thus, DNA enrichment strategies facilitate the assembly by increasing the coverage and simultaneously reducing the complexity of the whole genome. In this paper we provide an easy, fast, and cost-effective variant of MRE-seq to obtain a plant's hypomethylome by an optimized methyl filtration protocol followed by next generation sequencing. The method is demonstrated on three plant species with knowingly large and/or complex (polyploid) genomes: Oryza sativa, Picea abies, and Crocus sativus. The identified hypomethylomes show clear enrichment for genes and their flanking regions and clear reduction of transposable elements. Additionally, genomic sequences around genes are captured including regulatory elements in introns and up- and downstream flanks. High similarity of the results obtained by a de novo assembly approach with a reference based mapping in rice supports the applicability for studying and understanding the genomes of nonmodel organisms. Hence we show the high potential of MRE-seq in a wide range of scenarios for the direct analysis of methylation differences, for example, between ecotypes, individuals, within or across species harbouring large, and complex genomes. PMID- 26421294 TI - Treatment of Breakthrough and Refractory Chemotherapy-Induced Nausea and Vomiting. AB - Despite significant progress in the prevention of chemotherapy-induced nausea and vomiting (CINV) with the introduction of new antiemetic agents, 30-50% of patients receiving moderately or highly emetogenic chemotherapy (MEC or HEC) and guideline directed prophylactic antiemetics develop breakthrough CINV. International guidelines recommend the treatment of breakthrough CINV with an agent from a drug class that was not used in the prophylactic antiemetic regimen and recommend using the breakthrough medication continuously rather than using it on an as needed basis. There have been very few studies on the treatment of breakthrough CINV. A recent double-blind, randomized, phase III study suggested that olanzapine may be an effective agent for the treatment of breakthrough CINV. Refractory CINV occurs when patients develop CINV during subsequent cycles of chemotherapy when antiemetic prophylaxis has not been successful in controlling CINV in earlier cycles. Patients who develop refractory CINV should be considered for a change in their prophylactic antiemetic regimen. If significant anxiety exists, a benzodiazepine may be added to the prophylactic regimen. If a refractory patient is receiving HEC, olanzapine may be added to the prophylactic regimen. If the patient is receiving MEC, olanzapine or an NK-1 receptor antagonist may be added to the prophylactic regimen. PMID- 26421295 TI - Growth Pattern of Clear Cell Renal Cell Carcinoma in Patients with Delayed Surgical Intervention: Fast Growth Rate Correlates with High Grade and May Result in Poor Prognosis. AB - OBJECTIVES: Previous studies revealed an unclear correlation between the growth rate of renal cell carcinoma (RCC) and tumor grade and did not focus on certain histological subtype. This report investigated the correlation between the growth rate and tumor grade in clear cell RCC (ccRCC). METHODS: We reviewed 60 patients with 61 ccRCC confirmed by delayed surgeries after at least 12 months of active surveillance. The linear growth rate (LGR), volumetric growth rate (VGR), and volume doubling time (VDT) were calculated, and their correlations with clinicopathologic characteristics were analyzed. RESULTS: The mean LGR, VGR, and VDT were 0.86 (range 0-4.74) cm/year, 20.96 (range 0.31-211.93) cm(3)/year, and 667 (range 33-3321) days, respectively. ccRCCs with high grade had greater LGR (P < 0.001) and VGR (P = 0.001) and lower VDT (P = 0.017) than ccRCCs with low grade. Grade (OR = 5.185, P = 0.004) was the only independent risk factor of LGR >0.5 cm/year, and grade (OR = 3.006, P = 0.046) and initial size (OR = 0.392, P = 0.004) were independent risk factors of VDT <1 year. Five patients developed metastasis after surgery with LGR >0.5 cm/yr altogether; of them, four had cancer related death by the last follow-up. CONCLUSIONS: Fast growth rate of ccRCC is significantly correlated with high tumor grade and may result in poor prognosis, especially for those with LGR >0.5 cm/yr. PMID- 26421296 TI - Initial Experience of Sorafenib Neoadjuvant Therapy Combined with Retroperitoneoscopy in Treating T2 Large Renal Carcinoma. AB - OBJECTIVES: To investigate the safety and feasibility of sorafenib neoadjuvant therapy combined with retroperitoneoscopic radical nephrectomy (RRN) in treating T2 large renal cell carcinoma (RCC). METHODS: Retrospectively analyzed 5 cases (2 males and 3 females, aged 52-73 years) of T2 stage large RCC who receive preoperative sorafenib targeted treatment (400 mg bid for 1-3 months) and RRN between March, 2013, and July, 2014. Patient information, therapeutic regimen, drug adverse effect, tumor changes before and after surgery, and perioperative parameters were recorded. RESULTS: During the sorafenib therapy adverse effects included 2 cases of hypertension (Grade I toxicity), 1 case of hand-foot syndrome (Grade I), and 1 case of diarrhea (Grade II), which were all tolerable for patients. CT scan and histopathological tests confirmed significant reduction in the longest dimension (LD) and medium density (MD) of the tumor after therapy as well as tumor hemorrhage, necrosis, and cystic degeneration. All 5 patients received RRN surgery successfully around 2 weeks after drug discontinuation with only 1 case of perioperative complication. CONCLUSIONS: Sorafenib neoadjuvant therapy could significantly reduce the size and aggressiveness of T2 large renal tumors, thus reducing the operative challenge and enabling patients who were previously disqualified for operation to receive surgical treatment. PMID- 26421297 TI - Age-Specific Gene Expression Profiles of Rhesus Monkey Ovaries Detected by Microarray Analysis. AB - The biological function of human ovaries declines with age. To identify the potential molecular changes in ovarian aging, we performed genome-wide gene expression analysis by microarray of ovaries from young, middle-aged, and old rhesus monkeys. Microarray data was validated by quantitative real-time PCR. Results showed that a total of 503 (60 upregulated, 443 downregulated) and 84 (downregulated) genes were differentially expressed in old ovaries compared to young and middle-aged groups, respectively. No difference in gene expression was found between middle-aged and young groups. Differentially expressed genes were mainly enriched in cell and organelle, cellular and physiological process, binding, and catalytic activity. These genes were primarily associated with KEGG pathways of cell cycle, DNA replication and repair, oocyte meiosis and maturation, MAPK, TGF-beta, and p53 signaling pathway. Genes upregulated were involved in aging, defense response, oxidation reduction, and negative regulation of cellular process; genes downregulated have functions in reproduction, cell cycle, DNA and RNA process, macromolecular complex assembly, and positive regulation of macromolecule metabolic process. These findings show that monkey ovary undergoes substantial change in global transcription with age. Gene expression profiles are useful in understanding the mechanisms underlying ovarian aging and age-associated infertility in primates. PMID- 26421298 TI - Heterogeneity of Breast Cancer Associations with Common Genetic Variants in FGFR2 according to the Intrinsic Subtypes in Southern Han Chinese Women. AB - GWAS have identified variation in the FGFR2 locus as risk factors for breast cancer. Validation studies, however, have shown inconsistent results by ethnics and pathological characteristics. To further explore this inconsistency and investigate the associations of FGFR2 variants with breast cancer according to intrinsic subtype (Luminal-A, Luminal-B, ER-&PR-&HER2+, and triple negative) among Southern Han Chinese women, we genotyped rs1078806, rs1219648, rs2420946, rs2981579, and rs2981582 polymorphisms in 609 patients and 882 controls. Significant associations with breast cancer risk were observed for rs2420946, rs2981579, and rs2981582 with OR (95% CI) per risk allele of 1.19 (1.03-1.39), 1.24 (1.07-1.43), and 1.17 (1.01-1.36), respectively. In subtype specific analysis, above three SNPs were significantly associated with increased Luminal-A risk in a dose-dependent manner (P trend < 0.01); however, only rs2981579 was associated with Luminal-B, and none were linked to ER-&PR- subtypes (ER-&PR &HER2+ and triple negative). Haplotype analyses also identified common haplotypes significantly associated with luminal-like subtypes (Luminal-A and Luminal-B), but not with ER-&PR- subtypes. Our results suggest that associations of FGFR2 SNPs with breast cancer were heterogeneous according to intrinsic subtype. Future studies stratifying patients by their intrinsic subtypes will provide new insights into the complex genetic mechanisms underlying breast cancer. PMID- 26421299 TI - Genetic Interactions Explain Variance in Cingulate Amyloid Burden: An AV-45 PET Genome-Wide Association and Interaction Study in the ADNI Cohort. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder. Using discrete disease status as the phenotype and computing statistics at the single marker level may not be able to address the underlying biological interactions that contribute to disease mechanism and may contribute to the issue of "missing heritability." We performed a genome-wide association study (GWAS) and a genome wide interaction study (GWIS) of an amyloid imaging phenotype, using the data from Alzheimer's Disease Neuroimaging Initiative. We investigated the genetic main effects and interaction effects on cingulate amyloid-beta (Abeta) load in an effort to better understand the genetic etiology of Abeta deposition that is a widely studied AD biomarker. PLINK was used in the single marker GWAS, and INTERSNP was used to perform the two-marker GWIS, focusing only on SNPs with p <= 0.01 for the GWAS analysis. Age, sex, and diagnosis were used as covariates in both analyses. Corrected p values using the Bonferroni method were reported. The GWAS analysis revealed significant hits within or proximal to APOE, APOC1, and TOMM40 genes, which were previously implicated in AD. The GWIS analysis yielded 8 novel SNP-SNP interaction findings that warrant replication and further investigation. PMID- 26421300 TI - A Review of NEPA, a Novel Fixed Antiemetic Combination with the Potential for Enhancing Guideline Adherence and Improving Control of Chemotherapy-Induced Nausea and Vomiting. AB - Combination antiemetic regimens targeting multiple molecular pathways associated with emesis have become the standard of care for prevention of chemotherapy induced nausea and vomiting (CINV) related to highly and moderately emetogenic chemotherapies. Antiemetic consensus guidelines from several professional societies are widely available and updated regularly as new data emerges. Unfortunately, despite substantial research supporting the notion that guideline conformity improves CINV control, adherence to antiemetic guidelines is unsatisfactory. While studies are needed to identify specific barriers to guideline use and explore measures to enhance adherence, a novel approach has been taken to improve clinician adherence and patient compliance, with the development of a new combination antiemetic. NEPA is an oral fixed combination of a new highly selective NK1 receptor antagonist (RA), netupitant, and the pharmacologically and clinically distinct 5-HT3 RA, palonosetron. This convenient antiemetic combination offers guideline-consistent prophylaxis by targeting two critical pathways associated with CINV in a single oral dose administered only once per cycle. This paper will review and discuss the NEPA data in the context of how this first combination antiemetic may overcome some of the barriers interfering with adherence to antiemetic guidelines, enhance patient compliance, and offer a possible advance in the prevention of CINV for patients. PMID- 26421302 TI - Sex Differences in Immunology: More Severe Development of Experimental Pulmonary Hypertension in Male Rats Exposed to Vascular Endothelial Growth Factor Receptor Blockade. AB - BACKGROUND: The epidemiology of pulmonary hypertension (PH) is characterized by a female preponderance, whereas males share higher severity of the disease. OBJECTIVE: To compare the severity of experimental PH between male and female athymic rats. METHODS: PH was induced in 11 male and 11 female athymic rats (resp., SU_M and SU_F groups) using an inhibitor of VEGF-receptors I and II, semaxanib (40 mg/kg). After 28 days, right ventricular (RV) remodeling, systolic function, and hemodynamics were measured using echocardiography and a pressure volume admittance catheter. Morphometric analyses of lung vasculature and RV myocardium were performed. RESULTS: Four weeks after semaxanib injection, RV end systolic pressure was higher in SU_M than in SU_F. Males developed marked RV enlargement and systolic dysfunction compared to females. Impairment of RV-PA coupling efficiency was observed only in SU_M. The smooth muscle cells of the pulmonary arteries switched from a contractile state to a dedifferentiated state only in males. CONCLUSIONS: Female athymic rats were protected against the development of severe PH. RV-PA coupling was preserved in females through limitation of pulmonary artery muscularization. Control of smooth muscle cells plasticity may be a promising therapeutic approach to reverse established vascular remodeling in PH patients. PMID- 26421301 TI - Molecular Biomarkers for Embryonic and Adult Neural Stem Cell and Neurogenesis. AB - The procedure of neurogenesis has made numerous achievements in the past decades, during which various molecular biomarkers have been emerging and have been broadly utilized for the investigation of embryonic and adult neural stem cell (NSC). Nevertheless, there is not a consistent and systematic illustration to depict the functional characteristics of the specific markers expressed in distinct cell types during the different stages of neurogenesis. Here we gathered and generalized a series of NSC biomarkers emerging during the procedures of embryonic and adult neural stem cell, which may be used to identify the subpopulation cells with distinguishing characters in different timeframes of neurogenesis. The identifications of cell patterns will provide applications to the detailed investigations of diverse developmental cell stages and the extents of cell differentiation, which will facilitate the tracing of cell time-course and fate determination of specific cell types and promote the further and literal discoveries of embryonic and adult neurogenesis. Meanwhile, via the utilization of comprehensive applications under the aiding of the systematic knowledge framework, researchers may broaden their insights into the derivation and establishment of novel technologies to analyze the more detailed process of embryogenesis and adult neurogenesis. PMID- 26421303 TI - Usefulness of Nonenhanced Computed Tomography for Diagnosing Urolithiasis without Pyuria in the Emergency Department. AB - We compared the clinical utility of nonenhanced computed tomography (NECT) and intravenous urography (IVU) in patients with classic symptoms of renal colic without evidence of a urine infection. This was a retrospective analysis of IVU and NECT performed in adult patients with suspected renal colic at an emergency department between January 2005 and December 2013. The records of all patients in NECT and IVU groups were reviewed, and the patients were categorized according to the cause of their symptoms. A total of 2218 patients were enrolled. Of these patients, 1525 (68.8%) underwent IVU and 693 (31.2%) underwent NECT. The patients in NECT group were older (45.48 +/- 14.96 versus 42.37 +/- 13.68 years, p < 0.001), had less gross hematuria (7.6 versus 2.9%, p < 0.001), and were admitted more often (18.6 versus 12.0%, p < 0.001) than the patients in IVU group. Urinary stones were detected in 1413 (63.7%) patients. NECT had a higher detection rate of urolithiasis than IVP (74.0 versus 59.0%, p < 0.001). No significant difference was observed in the incidence of urinary stones greater than 4mm between groups from the radiologic findings (p = 0.79) or the full medical record review (p = 0.87). PMID- 26421304 TI - Survey of Programs Used to Detect Alternative Splicing Isoforms from Deep Sequencing Data In Silico. AB - Next-generation sequencing techniques have been rapidly emerging. However, the massive sequencing reads hide a great deal of unknown important information. Advances have enabled researchers to discover alternative splicing (AS) sites and isoforms using computational approaches instead of molecular experiments. Given the importance of AS for gene expression and protein diversity in eukaryotes, detecting alternative splicing and isoforms represents a hot topic in systems biology and epigenetics research. The computational methods applied to AS prediction have improved since the emergence of next-generation sequencing. In this study, we introduce state-of-the-art research on AS and then compare the research methods and software tools available for AS based on next-generation sequencing reads. Finally, we discuss the prospects of computational methods related to AS. PMID- 26421305 TI - POD-1/TCF21 Reduces SHP Expression, Affecting LRH-1 Regulation and Cell Cycle Balance in Adrenocortical and Hepatocarcinoma Tumor Cells. AB - POD-1/TCF21 may play a crucial role in adrenal and gonadal homeostasis and represses Sf-1/SF-1 expression in adrenocortical tumor cells. SF-1 and LRH-1 are members of the Fzt-F1 subfamily of nuclear receptors. LRH-1 is involved in several biological processes, and both LRH-1 and its repressor SHP are involved in many types of cancer. In order to assess whether POD-1 can regulate LRH-1 via the same mechanism that regulates SF-1, we analyzed the endogenous mRNA levels of POD-1, SHP, and LRH-1 in hepatocarcinoma and adrenocortical tumor cells using qRT PCR. Hereafter, these tumor cells were transiently transfected with pCMVMycPod-1, and the effect of POD-1 overexpression on E-box elements in the LRH-1 and SHP promoter region were analyzed by ChIP assay. Also, Cyclin E1 protein expression was analyzed to detect cell cycle progression. We found that POD-1 overexpression significantly decreased SHP/SHP mRNA and protein levels through POD-1 binding to the E-box sequence in the SHP promoter. Decreased SHP expression affected LRH-1 regulation and increased Cyclin E1. These findings show that POD-1/TCF21 regulates SF-1 and LRH-1 by distinct mechanisms, contributing to the understanding of POD-1 involvement and its mechanisms of action in adrenal and liver tumorigenesis, which could lead to the discovery of relevant biomarkers. PMID- 26421306 TI - 454-Pyrosequencing Analysis of Bacterial Communities from Autotrophic Nitrogen Removal Bioreactors Utilizing Universal Primers: Effect of Annealing Temperature. AB - Identification of anaerobic ammonium oxidizing (anammox) bacteria by molecular tools aimed at the evaluation of bacterial diversity in autotrophic nitrogen removal systems is limited by the difficulty to design universal primers for the Bacteria domain able to amplify the anammox 16S rRNA genes. A metagenomic analysis (pyrosequencing) of total bacterial diversity including anammox population in five autotrophic nitrogen removal technologies, two bench-scale models (MBR and Low Temperature CANON) and three full-scale bioreactors (anammox, CANON, and DEMON), was successfully carried out by optimization of primer selection and PCR conditions (annealing temperature). The universal primer 530F was identified as the best candidate for total bacteria and anammox bacteria diversity coverage. Salt-adjusted optimum annealing temperature of primer 530F was calculated (47 degrees C) and hence a range of annealing temperatures of 44 49 degrees C was tested. Pyrosequencing data showed that annealing temperature of 45 degrees C yielded the best results in terms of species richness and diversity for all bioreactors analyzed. PMID- 26421307 TI - Molecular Detection of Equine Herpesvirus Types 1 and 4 Infection in Healthy Horses in Isfahan Central and Shahrekord Southwest Regions, Iran. AB - This study was undertaken to investigate molecularly the occurrence of EHV-1 and EHV-4 infection among equine population in regions, Iran. Blood samples from 53 and 37 randomly selected horses settled in Isfahan and Shahrekord, Iran, respectively, were collected. Detection of EHV-1 and EHV-4 genes in the blood samples was done using polymerase chain reaction (PCR). Out of 53 and 37 samples from Isfahan and Shahrekord, 4 (18.18%) and 3 (8.10%) were positive for PCR of EHV-1, respectively. Nine (16.98%) and 6 (16.21%) were positive for PCR of EHV-4, while 6 (11.32%) and 3 (8.10%) were positive for PCR of both EHV-1 and EHV-4, in Isfahan and Shahrekord, respectively. Of the 7 blood samples positive for EHV-1, 4 (16.66%) and 3 (8.10%) were from horses >3 years old while 2 (18.18%) and 1 (16.66%) were from 2-3 years old horses, in Isfahan and Shahrekord, respectively. Out of the 7 and 3 samples positive for PCR of EHV-1 in Isfahan and Shahrekord, 4 (22.2%) and 1 (7.69%) were Standardbred, while 3 (14.28%) and 2 (13.33%) were Thoroughbreds, respectively. EHV-4 was detected in blood of 4 (22.22%) and 2 (15.83%) Standardbreds and from 4 (19.04%) and 4 (26.66%) Thoroughbred horses in Isfahan and Shahrekord, respectively. This study has shown that horses settled in Isfahan central and Shahrekord southwest regions, Iran, are infected by EHV-1 and EHV-4 and thus serve as potential reservoirs and disseminators of the viruses. PMID- 26421308 TI - Nailfold Capillaroscopy in Rheumatic Diseases: Which Parameters Should Be Evaluated? AB - Video nailfold capillaroscopy (NFC), considered as an extension of the widefield technique, allows a more accurate measuring and storing of capillary data and a better defining, analyzing, and quantifying of capillary abnormalities. Capillaroscopic study is often performed on the patients suspected of having microcirculation problems such as Raynaud's phenomenon as the main indication for nailfold capillaroscopy. Capillaroscopic findings based on microcirculation studies can provide useful information in the fields of pathophysiology, differential diagnosis, and monitoring therapy. Nailfold capillaroscopy provides a vital assessment in clinical practices and research; for example, its reputation in the early diagnosis of systemic sclerosis is well established and it is also used as a classification criterion in this regard. This review focuses on the manner of performing video nailfold capillaroscopy and on a common approach for measuring capillary dimensions in fingers and toes. PMID- 26421310 TI - Phylogenetic Group Determination of Escherichia coli Isolated from Animals Samples. AB - This study analyzes the occurrence and distribution of phylogenetic groups of 391 strains of Escherichia coli isolated from poultry, cattle, and water buffalo. The frequency of the phylogroups was A = 19%, B1 = 57%, B2 = 2.3%, C = 4.6%, D = 2.8%, E = 11%, and F = 3.3%. Phylogroups A (P < 0.001) and F (P = 0.018) were associated with E. coli strains isolated from poultry, phylogroups B1 (P < 0.001) and E (P = 0.002) were associated with E. coli isolated from cattle, and phylogroups B2 (P = 0.003) and D (P = 0.017) were associated with E. coli isolated from water buffalo. This report demonstrated that some phylogroups are associated with the host analyzed and the results provide knowledge of the phylogenetic composition of E. coli from domestic animals. PMID- 26421311 TI - Computer Simulation and Field Experiment for Downlink Multiuser MIMO in Mobile WiMAX System. AB - The transmission performance for a downlink mobile WiMAX system with multiuser multiple-input multiple-output (MU-MIMO) systems in a computer simulation and field experiment is described. In computer simulation, a MU-MIMO transmission system can be realized by using the block diagonalization (BD) algorithm, and each user can receive signals without any signal interference from other users. The bit error rate (BER) performance and channel capacity in accordance with modulation schemes and the number of streams were simulated in a spatially correlated multipath fading environment. Furthermore, we propose a method for evaluating the transmission performance for this downlink mobile WiMAX system in this environment by using the computer simulation. In the field experiment, the received power and downlink throughput in the UDP layer were measured on an experimental mobile WiMAX system developed in Azumino City in Japan. In comparison with the simulated and experimented results, the measured maximum throughput performance in the downlink had almost the same performance as the simulated throughput. It was confirmed that the experimental mobile WiMAX system for MU-MIMO transmission successfully increased the total channel capacity of the system. PMID- 26421309 TI - Potential Renoprotective Agents through Inhibiting CTGF/CCN2 in Diabetic Nephropathy. AB - Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). The development and progression of DN might involve multiple factors. Connective tissue growth factor (CCN2, originally known as CTGF) is the one which plays a pivotal role. Therefore, increasing attention is being paid to CCN2 as a potential therapeutic target for DN. Up to date, there are also many drugs or agents which have been shown for their protective effects against DN via different mechanisms. In this review, we only focus on the potential renoprotective therapeutic agents which can specifically abolish CCN2 expression or nonspecifically inhibit CCN2 expression for retarding the development and progression of DN. PMID- 26421312 TI - Calibration of Smartphone-Based Weather Measurements Using Pairwise Gossip. AB - Accurate and reliable daily global weather reports are necessary for weather forecasting and climate analysis. However, the availability of these reports continues to decline due to the lack of economic support and policies in maintaining ground weather measurement systems from where these reports are obtained. Thus, to mitigate data scarcity, it is required to utilize weather information from existing sensors and built-in smartphone sensors. However, as smartphone usage often varies according to human activity, it is difficult to obtain accurate measurement data. In this paper, we present a heuristic-based pairwise gossip algorithm that will calibrate smartphone-based pressure sensors with respect to fixed weather stations as our referential ground truth. Based on actual measurements, we have verified that smartphone-based readings are unstable when observed during movement. Using our calibration algorithm on actual smartphone-based pressure readings, the updated values were significantly closer to the ground truth values. PMID- 26421313 TI - Investigations into Recycling Zinc from Used Metal Oxide Varistors via pH Selective Leaching: Characterization, Leaching, and Residue Analysis. AB - Metal oxide varistors (MOVs) are a type of resistor with significantly nonlinear current-voltage characteristics commonly used in power lines to protect against overvoltages. If a proper recycling plan is developed MOVs can be an excellent source of secondary zinc because they contain over 90 weight percent zinc oxide. The oxides of antimony, bismuth, and to a lesser degree cobalt, manganese, and nickel are also present in varistors. Characterization of the MOV showed that cobalt, nickel, and manganese were not present in the varistor material at concentrations greater than one weight percent. This investigation determined whether a pH selective dissolution (leaching) process can be utilized as a starting point for hydrometallurgical recycling of the zinc in MOVs. This investigation showed it was possible to selectively leach zinc from the MOV without coleaching of bismuth and antimony by selecting a suitable pH, mainly higher than 3 for acids investigated. It was not possible to leach zinc without coleaching of manganese, cobalt, and nickel. It can be concluded from results obtained with the acids used, acetic, hydrochloric, nitric, and sulfuric, that sulfate leaching produced the most desirable results with respect to zinc leaching and it is also used extensively in industrial zinc production. PMID- 26421315 TI - A Study on Suitability of EAF Oxidizing Slag in Concrete: An Eco-Friendly and Sustainable Replacement for Natural Coarse Aggregate. AB - Environmental and economic factors increasingly encourage higher utility of industrial by-products. The basic objective of this study was to identify alternative source for good quality aggregates which is depleting very fast due to fast pace of construction activities in India. EAF oxidizing slag as a by product obtained during the process in steel making industry provides great opportunity to utilize it as an alternative to normally available coarse aggregates. The primary aim of this research was to evaluate the physical, mechanical, and durability properties of concrete made with EAF oxidizing slag in addition to supplementary cementing material fly ash. This study presents the experimental investigations carried out on concrete grades of M20 and M30 with three mixes: (i) Mix A, conventional concrete mix with no material substitution, (ii) Mix B, 30% replacement of cement with fly ash, and (iii) Mix C, 30% replacement of cement with fly ash and 50% replacement of coarse aggregate with EAF oxidizing slag. Tests were conducted to determine mechanical and durability properties up to the age of 90 days. The test results concluded that concrete made with EAF oxidizing slag and fly ash (Mix C) had greater strength and durability characteristics when compared to Mix A and Mix B. Based on the overall observations, it could be recommended that EAF oxidizing slag and fly ash could be effectively utilized as coarse aggregate replacement and cement replacement in all concrete applications. PMID- 26421314 TI - Biological Events in Periodontal Ligament and Alveolar Bone Associated with Application of Orthodontic Forces. AB - Orthodontic force-induced stresses cause dynamic alterations within the extracellular matrix and within the cytoskeleton of cells in the periodontal ligament and alveolar bone, mediating bone remodelling, ultimately enabling orthodontic tooth movement. In the periodontal ligament and alveolar bone, the mechanically induced tensile strains upregulate the expression of osteogenic genes resulting in bone formation, while mechanically induced compressive strains mediate predominantly catabolic tissue changes and bone resorption. In this review article we summarize some of the currently known biological events occurring in the periodontal ligament and in the alveolar bone in response to application of orthodontic forces and how these facilitate tooth movement. PMID- 26421316 TI - Family Planning Knowledge, Attitudes, and Practices among Married Men and Women in Rural Areas of Pakistan: Findings from a Qualitative Need Assessment Study. AB - This paper presents the findings of a qualitative assessment aimed at exploring knowledge, attitudes, and practices regarding family planning and factors that influence the need for and use of modern contraceptives. A descriptive exploratory study was conducted with married women and men aged between 15 and 40. Overall, 24 focus group discussions were conducted with male and female participants in three provinces of Pakistan. The findings reveal that the majority knew about some modern contraceptive methods, but the overall contraceptive use was very low. Knowledge and use of any contraceptive method were particularly low. Reasons for not using family planning and modern contraception included incomplete family size, negative perceptions, in-laws' disapproval, religious concerns, side-effects, and lack of access to quality services. The majority preferred private facilities over the government health facilities as the later were cited as derided. The study concluded the need for qualified female healthcare providers, especially for long term family planning services at health facilities instead of camps arranged occasionally. Addressing issues around access, affordability, availability, and sociocultural barriers about modern contraception as well as involving men will help to meet the needs and ensure that the women and couples fulfill their childbearing and reproductive health goals. PMID- 26421318 TI - Evaluation of Factor VIII as a Risk Factor in Indian Patients with DVT. AB - Introduction. Elevated factor VIII population in the Indian population has not been studied as a possible risk factor for deep vein thrombosis (DVT). High factor VIII level is considered a predisposing factor for DVT and its recurrence. However it is known to vary between populations and its exact role in the etiopathogenesis of thrombophilia remains unknown. Material and Methods. Factor VIII levels of patients with DVT who had undergone a prothrombotic workup as a part of their workup was compared to normal age matched controls in a 1 : 3 ratio. Results. There were 75 patients with DVT who had undergone a prothrombotic workup in the course of their treatment for lower limb DVT. In these, 64% had levels of factor VIII more than 150 as compared to 63% of normal controls (p > 0.05, not significant). Conclusion. Elevated factor VIII in the Indians may not be associated with the same thrombotic risk as seen in the West. We find a variation in the levels of factor VIII with a different "normal" than what is reported in other populations. This needs further study to elucidate the role of factor VIII in the evaluation and treatment of thrombophilia. PMID- 26421317 TI - Normal Pregnancy Is Associated with Changes in Central Hemodynamics and Enhanced Recruitable, but Not Resting, Endothelial Function. AB - Introduction. Flow-mediated dilation (FMD), low flow-mediated constriction (L FMC), and reactive hyperemia-related changes in carotid-to-radial pulse wave velocity (DeltaPWVcr%) could offer complementary information about both "recruitability" and "resting" endothelial function (EF). Carotid-to-femoral pulse wave velocity (PWVcf) and pulse wave analysis-derived parameters (i.e., AIx@75) are the gold standard methods for noninvasive evaluation of aortic stiffness and central hemodynamics. If healthy pregnancy is associated with both changes in resting and recruitable EF, as well as in several arterial parameters, it remains unknown and/or controversial. Objectives. To simultaneously and noninvasively assess in healthy pregnant (HP) and nonpregnant (NP) women central parameters in conjunction with "basal and recruitable" EF, employing new complementary approaches. Methods. HP (n = 11, 34.2 +/- 3.3 weeks of gestation) and age- and cardiovascular risk factors-matched NP (n = 22) were included. Aortic blood pressure (BP), AIx@75, PWVcf, common carotid stiffness, and intima media thickness, as well as FMD, L-FMC, and DeltaPWVcr %, were measured. Results. Aortic BP, stiffness, and AIx@75 were reduced in HP. DeltaPWVcr% and FMD were enhanced in HP in comparison to NP. No differences were found in L-FMC between groups. Conclusion. HP is associated with reduced aortic stiffness, central BP, wave reflections, and enhanced recruitable, but not resting, EF. PMID- 26421319 TI - Recent progress in luminescence tuning of Ce(3+) and Eu(2+)-activated phosphors for pc-WLEDs. AB - Nowadays, phosphor converted white light-emitting diodes (pc-WLEDs) have been widely used in solid-state lighting and display areas due to their superior lifetime, efficiency, and reliability as well as significant reduction in power consumption. Phosphors are indispensable components of pc-WLED devices, and their luminescence properties determine the quality of WLED lighting and displays. In order to further achieve high luminous efficacy, chromatic stability, and color rending properties in pc-WLEDs, much effort has been focused on improving current pc-WLED phosphors and developing novel pc-WLED phosphors recently. This review article concerns commonly used rare earth ion (Eu(2+) and Ce(3+)) activated inorganic phosphors, highlighting the important effect of spectral tuning via local structural variations on improving the luminescence performance of phosphors. The main spectral tuning strategies are discussed in detail and summarized, including (1) doping level control; (2) cationic substitution; (3) anionic substitution; (4) cationic-anionic substitution; (5) the crystal-site engineering approach; (6) mixing of nanophases. PMID- 26421321 TI - Photoinduced electron transfer as a design concept for luminescent redox indicators. AB - The general design principle for developing luminescent redox indicators based on photoinduced electron transfer is described. The first part of the review introduces colorimetric and fluorimetric redox indicators. The second part of the review highlights recent developments regarding molecular luminescent redox switches and logic gates. Potential future applications in biology, environmental analysis, biomedical diagnostics, corrosion science and materials science are mentioned. PMID- 26421320 TI - Phage & phosphatase: a novel phage-based probe for rapid, multi-platform detection of bacteria. AB - Genetic engineering of bacteriophages allows for the development of rapid, highly specific, and easily manufactured probes for the detection of bacterial pathogens. A challenge for novel probes is the ease of their adoption in real world laboratories. We have engineered the bacteriophage T7, which targets Escherichia coli, to carry the alkaline phosphatase gene, phoA. This inclusion results in phoA overexpression following phage infection of E. coli. Alkaline phosphatase is commonly used in a wide range of diagnostics, and thus a signal produced by our phage-based probe could be detected using common laboratory equipment. Our work demonstrates the successful: (i) modification of T7 phage to carry phoA; (ii) overexpression of alkaline phosphatase in E. coli; and (iii) detection of this T7-induced alkaline phosphatase activity using commercially available colorimetric and chemilumiscent methods. Furthermore, we demonstrate the application of our phage-based probe to rapidly detect low levels of bacteria and discern the antibiotic resistance of E. coli isolates. Using our bioengineered phage-based probe we were able to detect 10(3) CFU per mL of E. coli in 6 hours using a chemiluminescent substrate and 10(4) CFU per mL within 7.5 hours using a colorimetric substrate. We also show the application of this phage-based probe for antibiotic resistance testing. We were able to determine whether an E. coli isolate was resistant to ampicillin within 4.5 hours using chemiluminescent substrate and within 6 hours using a colorimetric substrate. This phage-based scheme could be readily adopted in labs without significant capital investments and can be translated to other phage-bacteria pairs for further detection. PMID- 26421322 TI - Magnetic nanoparticles-cooperated fluorescence sensor for sensitive and accurate detection of DNA methyltransferase activity coupled with exonuclease III-assisted target recycling. AB - A fluorescence magnetic biosensor for the DNA methyltransferase activity was developed based on the cooperative amplification by combining the magnetic nanoparticles synergistic exonuclease III (Exo III)-assisted circular exponential amplification and a supramolecular structure ZnPPIX/G-quadruplex. First, a duplex DNA probe, which was constructed by the hybridization of a quadruplex-forming oligomer with a molecular beacon, was assembled on the magnetic nanoparticles (MNPs) as a reporter. A hairpin probe (HP)-containing sequence of GATC was used as the methylation substrate of DNA adenine methyltransferase (DAM). Once HP was methylated by DAM, it could be recognized and cleaved by Dpn I, which allows the release of a single-stranded DNA. The DNA (tDNA1) then hybridizes to the MNP probe, which then triggers the exonuclease III-mediated target exponential recycling reaction. Simultaneously, numerous quadruplex forming oligomers are liberated and folded into the G-quadruplex-ZnPPIX complexes with the help of zinc(ii)-protoporphyrin IX(ZnPPIX) on the MNP surface to give a remarkable fluorescence response. In the developed sensor, a small amount of target DAM can be converted to a large number of stable DNA triggers, leading to remarkable amplification of the target. Moreover, using MNPs as a vector of the sensor may reduce the interference from the real samples, which increases the anti interference of the sensing system. Based on this unique amplification strategy, a very low detection limit down to 2.0 * 10(-4) U mL(-1) was obtained. Furthermore, the sensor could be used to evaluate the DAM activity in different growth stages of E. coli cells and screen Dam MTase inhibitors. Therefore, the strategy proposed here provides a promising platform for monitoring the activity and inhibition of DNA MTases and has great potential to be applied further in early clinical diagnostics and medical research. PMID- 26421323 TI - An upconversion fluorescent resonant energy transfer biosensor for hepatitis B virus (HBV) DNA hybridization detection. AB - A novel fluorescent resonant energy transfer (FRET) biosensor was fabricated for the detection of hepatitis B virus (HBV) DNA using poly(ethylenimine) (PEI) modified upconversion nanoparticles (NH2-UCNPs) as energy donor and gold nanoparticles (Au NPs) as acceptor. The PEI modified upconversion nanoparticles were prepared directly with a simple one-pot hydrothermal method, which provides high quality amino-group functionalized UCNPs with uniform morphology and strong upconversion luminescence. Two single-stranded DNA strands, which were partially complementary to each other, were then conjugated with NH2-UCNPs and Au NPs. When DNA conjugated NH2-UCNPs and Au NPs are mixed together, the hybridization between complementary DNA sequences on UCNPs and Au NPs will lead to the quenching of the upconversion luminescence due to the FRET process. Meanwhile, upon the addition of target DNA, Au NPs will leave the surface of the UCNPs and the upconversion luminescence can be restored because of the formation of the more stable double stranded DNA on the UCNPs. The sensor we fabricated here for target DNA detection shows good sensitivity and high selectivity, which has the potential for clinical applications in the analysis of HBV and other DNA sequences. PMID- 26421325 TI - Photocatalytic CO2 reduction using visible light by metal-monocatecholato species in a metal-organic framework. AB - Metal-organic frameworks (MOFs) with isolated metal-monocatecholato groups have been synthesized via postsynthetic exchange (PSE) for CO2 reduction photocatalyst under visible light irradiation in the presence of 1-benzyl-1,4 dihydronicotinamide and triethanolamine. The Cr-monocatecholato species are more efficient than the Ga-monocatecholato species. PMID- 26421326 TI - A dinuclear Ru(II) complex capable of photoinduced ligand exchange at both metal centers. AB - {[Ru(CH3CN)3]2(tppz)}(4+) (tppz = tetra-2-pyridylpyrazine) undergoes photoinduced CH3CN exchange with lambdairr >= 610 nm in H2O. In contrast, cis {[Ru(tpy)(L)]2(bpm)}(4+) (tpy = 2,2':6',2''-terpyridine, bpm = 2,2'-bipyrimidine, L = CH3CN) is not reactive, but the complex with L = DMSO is photoactive. These complexes are potentially useful for the release of multiply caged drugs. PMID- 26421324 TI - New supercharging reagents produce highly charged protein ions in native mass spectrometry. AB - The effectiveness of two new supercharging reagents for producing highly charged ions by electrospray ionization (ESI) from aqueous solutions in which proteins have native structures and reactivities were investigated. In aqueous solution, 2 thiophenone and 4-hydroxymethyl-1,3-dioxolan-2-one (HD) at a concentration of 2% by volume can increase the average charge of cytochrome c and myoglobin by up to 163%, resulting in even higher charge states than those that are produced from water/methanol/acid solutions in which these proteins are denatured. The greatest extent of supercharging occurs in pure water, but these supercharging reagents are also highly effective in aqueous solutions containing 200 mM ammonium acetate buffer commonly used in native mass spectrometry (MS). These reagents are less effective supercharging reagents than m-nitrobenzyl alcohol (m-NBA) and propylene carbonate (PC) when ions are formed from water/methanol/acid. The extent to which loss of the heme group from myoglobin occurs is related to the extent of supercharging. Results from guanidine melts of cytochrome c monitored with tryptophan fluorescence show that the supercharging reagents PC, sulfolane and HD are effective chemical denaturants in solution. These results provide additional evidence for the role of protein structural changes in the electrospray droplet as the primary mechanism for supercharging with these reagents in native MS. These results also demonstrate that for at least some proteins, the formation of highly charged ions from native MS is no longer a significant barrier for obtaining structural information using conventional tandem MS methods. PMID- 26421327 TI - Lanthanide luminescent logic gate mimics in soft matter: [H(+)] and [F(-)] dual input device in a polymer gel with potential for selective component release. AB - The non-covalent incorporation of responsive luminescent lanthanide, Ln(III), complexes with orthogonal outputs from Eu(III) and Tb(III) in a gel matrix allows for in situ logic operation with colorimetric outputs. Herein, we report an exemplar system with two inputs ([H(+)] and [F(-)]) within a p(HEMA-co-MMA) polymer organogel acting as a dual-responsive device and identify future potential for such systems. PMID- 26421328 TI - Facile fabrication of cross-linked vesicle via "surface clicking" of calixarene based supra-amphiphiles. AB - A dynamic vesicle was constructed by the complexation of (dodecyloxybenzyl)tripropargylammonium and p-sulfonatocalix[4]arene, then the dynamic vesicle was cross-linked by a "click" reaction. The cross-linked vesicle presents improved stability over the dynamic one. Meanwhile, it can be disrupted with specific chemical stimuli to give the controlled release. PMID- 26421329 TI - Chemical labeling of intracellular proteins via affinity conjugation and strain promoted cycloadditions in live cells. AB - A versatile chemical labeling approach was developed, where intracellular proteins were first incorporated with a bioorthogonal group via affinity conjugation, and subsequently labeled via strain-promoted cycloaddition reactions in live cells. PMID- 26421330 TI - Disseminated blastic plasmacytoid dendritic cell neoplasm. PMID- 26421331 TI - Pseudoplatelets in acute myeloid leukemia. PMID- 26421332 TI - Current Management of Fetal and Neonatal Tumors. PMID- 26421333 TI - What Is the Optimal Duration of Advanced Physician Training? PMID- 26421335 TI - Abstracts of the 11th International Congress on Systemic Lupus Erythematosus, September 2-6, 2015, Vienna, Austria. PMID- 26421336 TI - Nuts to You!--Every Day. PMID- 26421337 TI - Animal Testing Ban Not for EU. PMID- 26421338 TI - A Cure for Color Blindness? Stand by Buck Rogers! PMID- 26421334 TI - Advances in the Science, Treatment, and Prevention of the Disease of Obesity: Reflections From a Diabetes Care Editors' Expert Forum. AB - As obesity rates increase, so too do the risks of type 2 diabetes, cardiovascular disease, and numerous other detrimental conditions. The prevalence of obesity in U.S. adults more than doubled between 1980 and 2010, from 15.0 to 36.1%. Although this trend may be leveling off, obesity and its individual, societal, and economic costs remain of grave concern. In June 2014, a Diabetes Care Editors' Expert Forum convened to review the state of obesity research and discuss the latest prevention initiatives and behavioral, medical, and surgical therapies. This article, an outgrowth of the forum, offers an expansive view of the obesity epidemic, beginning with a discussion of its root causes. Recent insights into the genetic and physiological factors that influence body weight are reviewed, as are the pathophysiology of obesity-related metabolic dysfunction and the concept of metabolically healthy obesity. The authors address the crucial question of how much weight loss is necessary to yield meaningful benefits. They describe the challenges of behavioral modification and predictors of its success. The effects of diabetes pharmacotherapies on body weight are reviewed, including potential weight-neutral combination therapies. The authors also summarize the evidence for safety and efficacy of pharmacotherapeutic and surgical obesity treatments. The article concludes with an impassioned call for researchers, clinicians, governmental agencies, health policymakers, and health-related industries to collectively embrace the urgent mandate to improve prevention and treatment and for society at large to acknowledge and manage obesity as a serious disease. PMID- 26421340 TI - Withdrawal: Asymmetric Dimethylarginine and Endothelial Progenitor Cells After Renal Transplantation: the Effect of Exercise Training. PMID- 26421339 TI - Moderate Market Growth Predicted for Glaucoma Treatments. PMID- 26421341 TI - The Social Origins of Networks and Diffusion. AB - Recent research on social contagion has demonstrated significant effects of network topology on the dynamics of diffusion. However, network topologies are not given a priori. Rather, they are patterns of relations that emerge from individual and structural features of society, such as population composition, group heterogeneity, homophily, and social consolidation. Following Blau and Schwartz, the author develops a model of social network formation that explores how social and structural constraints on tie formation generate emergent social topologies and then explores the effectiveness of these social networks for the dynamics of social diffusion. Results show that, at one extreme, high levels of consolidation can create highly balkanized communities with poor integration of shared norms and practices. As suggested by Blau and Schwartz, reducing consolidation creates more crosscutting circles and significantly improves the dynamics of social diffusion across the population. However, the author finds that further reducing consolidation creates highly intersecting social networks that fail to support the widespread diffusion of norms and practices, indicating that successful social diffusion can depend on moderate to high levels of structural consolidation. PMID- 26421342 TI - Go with Your Gut: Emotion and Evaluation in Job Interviews. AB - This article presents hiring as an emotional process rooted in interpersonal evaluation. Drawing from Randall Collins's theory of interaction ritual, the author offers a qualitative case study of elite professional service firms to unpack how employers' emotional reactions to applicants in job interviews affect hiring evaluations. She finds that employers use subjective feelings of excitement and enthusiasm toward candidates-akin to Collins's concept of emotional energy--to-evaluate applicants and make hiring decisions. With these data, she constructs an original theoretical framework of emotional energy development, which highlights the qualities that tend to produce or inhibit the subjective experience of emotional energy in job interviews. Additionally, she outlines the particular phases of an encounter where energy gains and losses are most consequential for influencing hiring outcomes and inequalities. She discusses the implications of these findings for research on hiring, labor market stratification, and interaction rituals. PMID- 26421343 TI - Do Reputation Systems Undermine Trust? Divergent Effects of Enforcement Type on Generalized Trust and Trustworthiness. AB - Research shows that enforcing cooperation using contracts or tangible sanctions can backfire, undermining people's intrinsic motivation to cooperate: when the enforcement is removed, people are less trusting or trustworthy than when there is no enforcement to begin with. The author examines whether reputation systems have similar consequences for generalized trust and trustworthiness. Using a web based experiment simulating online market transactions (studies 1 and 2), he shows that reputation systems can reinforce generalized trust and trustworthiness, unlike contractual enforcement or relational enforcement based on repeated interactions. In a survey experiment (study 3), he finds that recalling their eBay feedback scores made participants more trusting and trustworthy. These results are predicated on the diffuse nature of reputational enforcement to reinforce perceptions of trust and trustworthiness. These results have implications for understanding how different forms of governance affect generalized trust and trustworthiness. PMID- 26421344 TI - Why Do Liberals Drink Lattes? AB - Popular accounts of "lifestyle politics" and "culture wars" suggest that political and ideological divisions extend also to leisure activities, consumption, aesthetic taste, and personal morality. Drawing on a total of 22,572 pairwise correlations from the General Social Survey (1972-2010), the authors provide comprehensive empirical support for the anecdotal accounts. Moreover, most ideological differences in lifestyle cannot be explained by demographic covariates alone. The authors propose a surprisingly simplesolution to the puzzle of lifestyle politics. Computational experiments show how the self-reinforcing dynamics of homophily and influence dramatically amplify even very small elective affinities between lifestyle and ideology, producing a stereotypical world of "latte liberals" and "bird-hunting conservatives" much like the one in which we live. PMID- 26421345 TI - Stress and Hardship after Prison. AB - The historic increase in U.S. incarceration rates made the transition from prison to community common for poor, prime-age men and women. Leaving prison presents the challenge of social integration--of connecting with family and finding housing and a means of subsistence. The authors study variation in social integration in the first months after prison release with data from the Boston Reentry Study, a unique panel survey of 122 newly released prisoners. The data indicate severe material hardship immediately after incarceration. Over half of sample respondents were unemployed, two-thirds received public assistance, and many relied on female relatives for financial support and housing. Older respondents and those with histories of addiction and mental illness were the least socially integrated, with weak family ties, unstable housing, and low levels of employment. Qualitative interviews show that anxiety and feelings of isolation accompanied extreme material insecurity. Material insecurity combined with the adjustment to social life outside prison creates a stress of transition that burdens social relationships in high-incarceration communities. PMID- 26421346 TI - Decreased baseline variability on fetal heart rate pattern in a fetus with heterotaxy syndrome. AB - In a fetus with suspected heterotaxy syndrome, a decreased/absent baseline variability of fetal heart rate pattern developed at gestational week 36(+5) and continued for 5 days until birth at gestational week 37(+2), while repeat biophysical profile scorings with ultrasound were consistently unremarkable. This neonate weighing 2404 g with Apgar scores of 7 (1-min) and 8 (5-min) and umbilical arterial cord blood pH of 7.28 with base deficit of 3.9 mmol/L, showed a heart rate of 120 b.p.m. for 3 h after birth, but subsequently developed sinus bradycardia (84 b.p.m.) unresponsive to crying. Isoproterenol initiated 9 h after birth was effective in the increase of heart rate to 120 b.p.m. in this neonate. Brain magnetic resonance imaging at 16 days of age was unremarkable. The decreased/absent baseline variability of fetal heart rate pattern was speculated to have been caused by sinus node dysfunction, and not by reduced fetal oxygenation in this case. PMID- 26421347 TI - Editorial: Innovative practice. PMID- 26421349 TI - Exploring Elements of Fun to Motivate Youth to Do Cognitive Bias Modification. AB - OBJECTIVE: Heavy drinking among young adults poses severe health risks, including development of later addiction problems. Cognitive retraining of automatic appetitive processes related to alcohol (so-called cognitive bias modification [CBM]) may help to prevent escalation of use. Although effective as a treatment in clinical patients, the use of CBM in youth proves more difficult, as motivation in this group is typically low, and the paradigms used are often viewed as boring and tedious. This article presents two separate studies that focused on three approaches that may enhance user experience and motivation to train: a serious game, a serious game in a social networking context, and a mobile application. MATERIALS AND METHODS: In the Game Study, 77 participants performed a regular CBM training, aimed at response matching, a gamified version, or a placebo version of that training. The gamified version was presented as a stand-alone game or in the context of a social network. In the Mobile Study, 64 participants completed a different CBM training, aimed at approach bias, either on a computer or on their mobile device. RESULTS: Although no training effects were found in the Game Study, adding (social) game elements did increase aspects of the user experience and motivation to train. The mobile training appeared to increase motivation to train in terms how often participants trained, but this effect disappeared after controlling for baseline motivation to train. CONCLUSIONS: Adding (social) game elements can increase motivation to train, and mobile training did not underperform compared with the regular training in this sample, which warrants more research into motivational elements for CBM training in younger audiences. PMID- 26421350 TI - Stress and resolution in mothers of children with cerebral palsy. AB - Parental resolution of diagnosis represents coming to terms with and accepting the diagnosis of a serious condition in their child. As risk factors for achieving resolution, we investigated: a child's functional status, cumulative stress, and maternal depression. The current study tested the hypothesis that mothers who are unresolved to their child's diagnosis would have considerably higher levels of risk factors, compared to resolved mothers. We also examined whether the observed risk factors could predict the resolution status. Maternal resolution was assessed by means of the Reaction to Diagnosis Interview. The sample consisted of 100 mothers of children aged 2-7, diagnosed with cerebral palsy. The results showed that unresolved mothers had children with poorer functional status, experienced more stressful life events, and were more depressed compared to resolved ones. The functional status of a child and maternal depression were shown to be significant resolution predictors. Importantly, they were more successful in predicting the resolved than the unresolved status. Further research is needed in order to investigate more extensively the unresolved parental status. PMID- 26421351 TI - Dissatisfaction with maintenance of certification in academic pediatrics. PMID- 26421352 TI - Embodied Energy and GHG Emissions from Material Use in Conventional and Unconventional Oil and Gas Operations. AB - Environmental impacts embodied in oilfield capital equipment have not been thoroughly studied. In this paper, we present the first open-source model which computes the embodied energy and greenhouse gas (GHG) emissions associated with materials consumed in constructing oil and gas wells and associated infrastructure. The model includes well casing, wellbore cement, drilling mud, processing equipment, gas compression, and transport infrastructure. Default case results show that consumption of materials in constructing oilfield equipment consumes ~0.014 MJ of primary energy per MJ of oil produced, and results in ~1.3 gCO2-eq GHG emissions per MJ (lower heating value) of crude oil produced, an increase of 15% relative to upstream emissions assessed in earlier OPGEE model versions, and an increase of 1-1.5% of full life cycle emissions. A case study of a hydraulically fractured well in the Bakken formation of North Dakota suggests lower energy intensity (0.011 MJ/MJ) and emissions intensity (1.03 gCO2-eq/MJ) due to the high productivity of hydraulically fractured wells. Results are sensitive to per-well productivity, the complexity of wellbore casing design, and the energy and emissions intensity per kg of material consumed. PMID- 26421353 TI - Seroprevalence and Serointensity of Latent Toxoplasma gondii in a Sample of Elderly Adults With and Without Alzheimer Disease. AB - INTRODUCTION: Latent infection with Toxoplasma gondii has been associated with behavioral and cognitive changes in animal models and in humans. Early findings have suggested an association between latent toxoplasmosis and Alzheimer disease (AD). On the basis of these factors, we sought to determine whether there is an association between latent toxoplasmosis and AD using a large, well-characterized sample of subjects with AD and age-matched and sex-matched controls without dementia. METHODS: Using ELISA, we determined anti-T. gondii IgG antibody titers in 114 control subjects and in 105 subjects diagnosed with AD through an Alzheimer's Disease Research Center. RESULTS: There were no group differences between groups in age, ethnicity, or sex. Education and socioeconomic status was slightly higher in the control group. Neither the prevalence of anti-T. gondii IgG antibodies (33% in the nondemented control group compared with 41% in the AD group, P=0.25) nor log-transformed antibody concentration (106.6 IU/mL in the control group compared with 140.9 IU/mL in the AD group, P=0.85) differed between the control and AD groups. DISCUSSION: In this sample, we found neither a higher prevalence of latent toxoplasmosis in the AD group compared with the control group nor differences in serum anti-T. gondii IgG titers between groups. PMID- 26421354 TI - Heteronormativity and practitioner-patient interaction. AB - Heteronormativity is the presumption of heterosexuality as the default sexual orientation and can result in discrimination against the lesbian, gay, and bisexual (LGB) population. This study serves as one of the first experimental studies to examine heteronormative perceptions in communication and their effects on practitioner-patient relationships. LGB participants were randomly assigned to read either heteronormative or non-heteronormative vignettes of a doctor-patient interaction. They then indicated how much health-relevant information they would disclose to the doctor in the vignette and their level of trust in the doctor. In the heteronormative condition, participants were less likely to disclose health relevant information to the doctor in the vignette and were less trustful of the doctor as compared to those in the non-heteronormative condition. These results have important health implications, as lack of disclosure and trust may prevent people from getting needed care and prevent doctors from giving the best health advice possible. The results of this study provide further evidence that there is a need for more education for all health care professionals to feel comfortable while respectfully communicating with and treating patients who do not identify as heterosexual in order to ensure the best health care experience. PMID- 26421355 TI - Nonaqueous Dispersion Formed by an Emulsion Solvent Evaporation Method Using Block-Random Copolymer Surfactant Synthesized by RAFT Polymerization. AB - As surfactants for preparation of nonaqueous microcapsule dispersions by the emulsion solvent evaporation method, three copolymers composed of stearyl methacrylate (SMA) and glycidyl methacrylate (GMA) with different monomer sequences (i.e., random, block, and block-random) were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. Despite having the same comonomer composition, the copolymers exhibited different functionality as surfactants for creating emulsions with respective dispersed and continuous phases consisting of methanol and isoparaffin solvent. The optimal monomer sequence for the surfactant was determined based on the droplet sizes and the stabilities of the emulsions created using these copolymers. The block-random copolymer led to an emulsion with better stability than obtained using the random copolymer and a smaller droplet size than achieved with the block copolymer. Modification of the epoxy group of the GMA unit by diethanolamine (DEA) further decreased the droplet size, leading to higher stability of the emulsion. The DEA modified block-random copolymer gave rise to nonaqueous microcapsule dispersions after evaporation of methanol from the emulsions containing colored dyes in their dispersed phases. These dispersions exhibited high stability, and the particle sizes were small enough for application to the inkjet printing process. PMID- 26421356 TI - Social Welfare Expenditures and Infant Mortality. AB - This study examines the effects of social welfare expenditures on infant mortality (deaths younger than age 1 per 1,000 live births) across 19 Organisation for Economic Co-operation and Development (OECD) countries from 1980 to 2010. Data are obtained from various sources including the OECD, World Health Organization, and World Bank. The findings indicate that among three social welfare expenditure measures for families, the expenditures on family cash allowances are predicted to reduce infant mortality. However, the other two measures-the expenditures on parental and maternity leave and expenditures on family services-have no significant effects on infant mortality. PMID- 26421358 TI - Let's talk about society: A Critical Discourse Analysis of sociology courses in pre-registration nursing. AB - BACKGROUND: The discussion of teaching and learning in nursing has been prolific. Whereas most of the debate tends to focus on core contents of nursing programmes, little has been discussed about the teaching in 'supporting subjects' with relevance to both nursing education and nursing practice. This article offers a perspective on sociology scholarship for applied professions by using the case of nursing programmes. METHODOLOGY: Syllabus is a rich source of data, and in its representational capacity it becomes both a discursive construction and a vehicle of ideology. Accordingly, we present a Critical Discourse Analysis of syllabi of nursing schools in Chile as to identify core contents and ideologies, and implied challenges for nursing education. FINDINGS AND DISCUSSION: We argue that while the syllabus as a discourse discloses a significant cleavage, the biggest challenge is precisely to challenge the ideologies constructed by and embedded in the syllabi. Our reflection thus points to a better interdisciplinary dialogue as to enhance the actual contribution of sociology to nursing. PMID- 26421357 TI - Tris DBA palladium overcomes hypoxia-mediated drug resistance in multiple myeloma. AB - Despite recent progress in novel and targeted therapies, multiple myeloma (MM) remains a therapeutically challenging incurable disease. The regulation of important cellular processes and its link to cancer presented Src as an attractive target for MM. We suggest a novel strategy to improve the treatment of MM and overcome the drug resistance for the current therapeutic agents by specific inhibition of Src in MM cells by Tris (Dibenzylideneacetone) dipalladium (Tris DBA). Tris DBA reduces proliferation, induces G1 arrest and apoptosis in MM cells. Tris DBA showed additive effect with proteasome inhibitors reducing proliferation, cell cycle signaling, and increasing apoptosis more than each drug alone. Tris DBA overcame hypoxia-induced effects such as enhanced chemotaxis or drug resistance to proteasome inhibitors by inhibition of HIF1alpha expression. Moreover, we found that Tris DBA is an effective anti-myeloma agent alone or in combination with other targeted drugs and that it reverses hypoxia-induced drug resistance in myeloma. PMID- 26421359 TI - Protective effect of resveratrol against neuronal damage following transient global cerebral ischemia in mice. AB - Resveratrol (3,5,4'-trihydroxystilbene) is a natural polyphenol which is rich in grape seeds and skin. Several studies have revealed that resveratrol possesses neuroprotective effects. In the case of global brain ischemia, there are few reports regarding the protective effect of resveratrol. Therefore, the influence of resveratrol on neuronal damage after transient global brain ischemia remains to be clarified. In the current study, C57BL/6 black mice were subjected to 20 min of transient global brain ischemia and followed by 72 h of reperfusion. Resveratrol (20 or 40 mg/kg, once daily, dissolved in 0.5% carboxymethylcellulose) was administered orally for 7 days before ischemia and daily until the mice were euthanized. The effect of lower or higher dose of resveratrol on neuronal damage, matrix metalloproteinase (MMP) activity and in situ DNA fragmentation (TUNEL) assay in the hippocampus after global ischemia was examined. Neuronal damages were remarkable in CA1 and CA2 pyramidal cell layers after global ischemia. In resveratrol-treated mice (40 mg/kg), neuronal damage was significantly reduced compared with vehicle-treated mice. Mice treated with resveratrol showed reduced MMP-9 activity. Resveratrol also inhibited TUNEL staining. These data suggest that resveratrol, a natural polyphenol, reduces hippocampal neuronal cell damage following transient global ischemia by reducing MMP-9 activity. PMID- 26421360 TI - In situ synthesis of TiO2(B) nanotube/nanoparticle composite anode materials for lithium ion batteries. AB - Titania nanotubes were prepared by a simple hydrothermal route. Their electrochemical performance has been examined in detail and compared to TiO2(B) nanoparticles, TiO2 anatase and P25 titania nanoparticles. The cycling and rate performance of TiO2 nanotubes is superior to both types of nanoparticles, and it can be further improved by an in situ titanium precursor treatment, which results in the formation of TiO2 nanoparticles on/between the nanotubes. The obtained specific capacity after 200 cycles at 0.2 A g(-1) charge/discharge rate remained above 130 mAh g(-1). The enhanced lithium storage properties of these samples can be attributed to their unique morphology and crystal structure. PMID- 26421361 TI - Women's views and knowledge regarding healthcare seeking for gestational diabetes in the postpartum period: A systematic review of qualitative/survey studies. AB - AIM: To identify factors influencing postpartum healthcare seeking, from the perspective of women who have experienced gestational diabetes mellitus (GDM). METHODS: Systematic review that searched PubMed, Web of Science, EMBASE and CINAHL on 27th February 2013. Qualitative studies and surveys, with women as participants, which reported pre-specified outcomes, including barriers and facilitators to healthcare seeking for GDM after birth, were included. Two authors independently extracted data and assessed quality. Results were thematically synthesised. RESULTS: Forty-two studies were included, with data from 7949 women in several countries. The diagnosis of GDM was sometimes a concerning or upsetting experience. A need for more specific information about GDM to be available around the time of diagnosis was identified. Women had varied experiences of antenatal GDM care and management, ranging from very positive to difficult and confusing. Non-judgemental and positively focussed care was preferred. While women were often knowledgeable about type 2 diabetes risk and prevention, they faced multiple barriers to undertaking preventive behaviours. A need for lifestyle change support and more pro-active postpartum care was identified. CONCLUSIONS: Provision of improved GDM education, as well as positive and pro-active care from diagnosis until postpartum follow-up may increase healthcare seeking by women with recent GDM. PMID- 26421362 TI - mTOR inhibitors and diabetes. AB - The mammalian target of rapamycin (mTOR) inhibitors are drugs, primarily used as immunosuppressors that are now frequently used as antineoplastic therapies in various cancers (such as advanced renal cell carcinoma, advanced breast cancer, progressive pancreatic neuroendocrine tumors). They act on mTOR signaling pathway which plays a key role in regulating cell growth as well as lipid and glucose metabolism. Treatment with mTOR inhibitors is associated with a high incidence of hyperglycemia and new-onset diabetes, ranging from 13% to 50% in the clinical trials in which they have been used as anticancer therapies. The rate of severe hyperglycemia is also increased, ranging from 4 to 12% in the main phase III clinical trials. Due to limited human studies, the pathophysiology of mTOR inhibitor-induced hyperglycemia has not yet been totally clarified. However, data from animal studies suggest that the mechanisms responsible for hyperglycemia with mTOR inhibitors are likely due to the combination of impaired insulin secretion and insulin resistance. Due to the high rate of hyperglycemia associated with the use of mTOR inhibitors, a close and personalized follow-up of blood glucose is recommended in all patients. PMID- 26421363 TI - How does thiol/disulfide homeostasis change in prediabetic patients? AB - AIMS: Our aim was to examine thiol/disulfide homeostasis, which has a critical role in many cellular activities such as antioxidant protection, detoxification, cell growth and apoptosis, in prediabetic patients. METHODS: The study population was formed of a total of 250 participants; 125 (54 males, 71 females) of which were newly diagnosed with prediabetes, aged over 18 and who had not received any prior treatment and 125 (52 males, 73 females) healthy volunteers. Prediabetic patients were diagnosed using a glucose tolerance test. In both groups, native thiol-disulfide exchanges were examined using the automated measurement method newly developed by Erel and Neselioglu. RESULTS: When compared to the control group, the native thiol (p<0.001) and total thiol (p=0.008) levels, and the native thiol/total thiol (p=0.022) ratio was lower; while disulfide (p=0.001) level and, disulfide/native thiol (p=0.003) and disulfide/total thiol (p=0.022) ratios were higher in prediabetic patients. A positive correlation was determined between disulfide and the fasting blood glucose levels (r=0.394, p=0.017) and glycolysed hemoglobin (HbA1c) (r=0.307, p=0.011). On the other hand, a negative correlation was determined between native thiol and fasting blood glucose levels (r=-0.335, p=0.004). CONCLUSION: With this study, we have shown for the first time that thiol oxidation increases in prediabetic patients and that there is a positive correlation between the disulfide and blood glucose and HbA1c levels. PMID- 26421364 TI - Comparison between indexes of insulin resistance for risk prediction of cardiovascular diseases or development of diabetes. AB - AIM: The predictive effect of various insulin resistance indexes for risk of cardiovascular diseases (CVD) or type 2 diabetes (T2DM) is still unclear. METHODS: One thousand and forty-nine 71-years-old male subjects from the Swedish ULSAM study, mean follow-up 9 years. All subjects performed the euglycemic insulin clamp for M/I [glucose disposal/mean insulin], and 75-g oral glucose tolerance test for Ceder-IR: 1/glucose uptake rate/[mean glucose*log mean insulin]; Matsuda-IR: 1/10,000/square root [glucose0*insulin0*glucose120*insulin120]; Belfiore-IR: 1/([glucose0+glucose120]/normal mean glucose*[insulin0+insulin120]/normal mean insulin)+1); and HOMA-IR: [glucose0*insulin0]/22.5. RESULTS: Bland-Altman plots showed best agreement between M/I versus Belfiore-IR and Ceder-IR with mean difference near zero, -0.21 to -0.46, while -0.68 to -0.77 for the other indexes. ISI-Ceder was the strongest predictor for incident nonfatal/fatal ischemic heart disease (CHD) or CVD at Cox regression in all subjects, and for incident T2DM at logistic regression in 1024 subjects with no baseline T2DM, with significantly higher hazard ratios or odds ratios than with all other indexes, also with best model fit, after adjusting for clinical characteristics and the traditional cardiovascular risk factors, including metabolic syndrome for CVD risk. CONCLUSION: Ceder-IR performed strongest as independent predictor for incidences of CHD/CVD and T2DM. PMID- 26421365 TI - H7N9 Influenza Virus Is More Virulent in Ferrets than 2009 Pandemic H1N1 Influenza Virus. AB - The novel H7N9 influenza virus has been infecting humans in China since February 2013 and with a mortality rate of about 40%. This study compared the pathogenicity of the H7N9 and 2009 pandemic H1N1 influenza viruses in a ferret model, which shows similar symptoms to those of humans infected with influenza viruses. The H7N9 influenza virus caused a more severe disease than did the 2009 pandemic H1N1 influenza virus. All of the ferrets infected with the H7N9 influenza virus had died by 6 days after infection, while none of those infected with the 2009 pandemic H1N1 influenza virus died. Ferrets infected with the H7N9 influenza virus had higher viral titers in their lungs than did those infected with the 2009 pandemic H1N1 influenza virus. Histological findings indicated that hemorrhagic pneumonia was caused by infection with the H7N9 influenza virus, but not with the 2009 pandemic H1N1 influenza virus. In addition, the lung tissues of ferrets infected with the H7N9 influenza virus contained higher levels of chemokines than did those of ferrets infected with the 2009 pandemic H1N1 influenza virus. This study suggests that close monitoring is needed to prevent human infection by the lethal H7N9 influenza virus. PMID- 26421367 TI - A comparative study of APLI and APCI in IMS at atmospheric pressure to reveal and explain peak broadening effects by the use of APLI. AB - The details of the ionization mechanism in atmospheric pressure are still not completely known. In order to obtain further insight into the occurring processes in atmospheric pressure laser ionization (APLI) a comparative study of atmospheric pressure chemical ionization (APCI) and APLI is presented in this paper. This study is carried out using similar experimental condition at atmospheric pressure employing a commercial ion mobility spectrometer (IMS). Two different peak broadening mechanisms can then be assigned, one related to a range of different species generated and detected, and furthermore for the first time a power broadening effect on the signals can be identified. PMID- 26421368 TI - Doxycycline sclerotherapy in children with head and neck lymphatic malformations. AB - OBJECTIVE: This is a systematic review of the literature describing doxycycline sclerotherapy (DS) to treat pediatric head and neck lymphatic malformations and examine patient factors associated with treatment success. DATA SOURCES: PubMed, EMBASE, and Ovid. REVIEW METHODS: A query of PubMed, EMBASE, and Ovid search engines (1995-2014) for studies examining outcomes for doxycycline sclerotherapy (DS) as primary treatment strategy for children with head and neck lymphatic malformations was undertaken. Successful outcome was defined as clinical resolution of symptoms or greater than 50% reduction in radiographic involvement. RESULTS: Five studies met the inclusion criteria for review. All were retrospective case series reports with high risk of bias. The dose of doxycycline used in all but one of the studies was 10mg/mL, and the highest concentration administered was 20mg/mL. Thirty-eight children met the inclusion criteria for analysis. Thirty-two (84.2%) children were successfully treated with DS, with 23 (60.5%) utilizing only one treatment session. Average follow-up was 9.7months. Age, gender, de Serres stage 1, and type of lymphatic malformation were not related to successful treatment outcome (p=0.23, 1, 1, and 0.13, respectively). CONCLUSIONS: DS is very effective for treatment of macrocystic and mixed head and neck lymphatic malformations in children. Overall success with DS treatment in children with lymphatic malformation of the head and neck was 84.2%. DS has distinct advantages over other sclerotherapy agents including that it is inexpensive and widely available, and has minimal side effects. No associated patient characteristics were found to predict improved success. PMID- 26421366 TI - PGC-1alpha/ERRalpha-Sirt3 Pathway Regulates DAergic Neuronal Death by Directly Deacetylating SOD2 and ATP Synthase beta. AB - AIMS: Parkinson's disease (PD) heavily affects humans and little is known about its cause and pathogenesis. Sirtuin 3 (Sirt3) plays a key role in regulating mitochondrial dysfunction, which is the main cause of DAergic neuronal loss in PD. We investigated the mechanisms of neuroprotective role of Sirt3 in DAergic neuronal survival. RESULTS: Sirt3 was reduced in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated neurons with its overexpression being neuroprotective. We identified that Sirt3 interacted with manganese superoxide dismutase (SOD2) and adenosine triphosphate (ATP) synthase beta and modulated their activities by deacetylating SOD2 (K130) and ATP synthase beta (K485) to prevent reactive oxygen species accumulation and ATP depletion, and to alleviate DAergic neuronal death upon MPTP treatment. Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) interacted with estrogen-related receptor alpha (ERRalpha) that bound to the Sirt3 promoter as its transcription factor to regulate Sirt3 expression and DAergic neuronal death. In the mouse midbrain, MPTP administration led to the loss of PGC-1alpha and Sirt3, high acetylation level of SOD2 and ATP synthase beta, and the specific loss of DAergic neurons, while Sirt3 overexpression could protect against DAergic neuronal loss. Sirt3 knockout mice exhibited more sensitive and more DAergic neuronal loss to MPTP treatment. INNOVATION: The study provides new insights into a critical PGC 1alpha/ERRalpha-Sirt3 pathway, linking regulation of mitochondrial protein acetylation and DAergic neuronal death in PD pathogenesis, which provide a potential therapeutic strategy and target in PD treatment. CONCLUSION: These results provide a vital PGC-1alpha/ERRalpha-Sirt3 pathway that protects against DAergic neuronal death by directly deacetylating SOD2 (K130) and ATP synthase beta (K485) in PD. PMID- 26421369 TI - Crowdsourcing to Assess Surgical Skill. PMID- 26421371 TI - Psoriasis and the Risk of Depression in the US Population: National Health and Nutrition Examination Survey 2009-2012. AB - IMPORTANCE: Psoriasis is a risk factor for depression. Depression may also trigger or exacerbate psoriasis. The relationship between psoriasis and depression, however, remains to be fully explored. OBJECTIVE: To investigate the association between psoriasis and major depression in the US population. DESIGN, SETTING, AND PARTICIPANTS: Population-based study using participants in the National Health and Nutrition Examination Survey from 2009 through 2012. MAIN OUTCOMES AND MEASURES: Diagnosis of major depression based on the Patient Health Questionnaire-9. RESULTS: We identified 351 (2.8%) cases of psoriasis and 968 (7.8%) cases of major depression among 12,382 US citizens included in our study. Fifty-eight (16.5%) patients with psoriasis met criteria for a diagnosis of major depression. The mean (SD) Patient Health Questionnaire-9 score was significantly higher among patients with a history of psoriasis than those without psoriasis (4.54 [5.7] vs 3.22 [4.3], P < .001). Psoriasis was significantly associated with major depression, even after adjustment for sex, age, race, body mass index, physical activity, smoking history, alcohol use, history of myocardial infarction (MI), history of stroke, and history of diabetes mellitus (OR, 2.09 [95% CI, 1.41 3.11], P < .001). Interaction term analyses involving patients with a history of both psoriasis and a cardiovascular event, specifically MI or stroke, did not reveal a synergistically increased risk of major depression (psoriasis and MI: OR, 1.09 [95% CI, 0.28-3.60], P = .91; psoriasis and stroke: OR, 0.67 [95% CI, 0.12-3.66], P = .63). In adjusted multivariable models, the risk of major depression was not significantly different between patients with limited vs extensive psoriasis (OR, 0.66 [95% CI, 0.18-2.44], P = .53). CONCLUSIONS AND RELEVANCE: Self-reported history of psoriasis was independently associated with major depression as assessed by a validated screening tool, even when controlling for comorbidities. History of cardiovascular event did not modify the risk of major depression for patients with psoriasis. The severity of psoriasis was unrelated to the risk of major depression. Therefore, all patients with psoriasis, regardless of severity, may be at risk for major depression. PMID- 26421370 TI - Motility of liquid stored ram spermatozoa is altered by dilution rate independent of seminal plasma concentration. AB - The fertility after use of liquid stored ram semen following cervical AI rapidly decreases if semen is stored beyond 12h. The dilution of seminal plasma is often cited as a key contributor to the diminished motility and fertility of ram spermatozoa subjected to liquid preservation. Two experiments were conducted to assess the effect of spermatozoa concentration (i.e. dilution rate) and percentage of seminal plasma on the motility and viability of liquid stored ram spermatozoa. In Experiment 1, semen was diluted to one of seven concentrations ranging from 0.2 to 1.4*10(9)spermatozoa/ml with milk and assessed for motility after 3 or 24h of storage at 15 degrees C. In Experiment 2, semen was collected and washed to remove seminal plasma before re-dilution to 0.2 1.4*10(9)spermatozoa/ml with milk containing 0%, 20% or 40% (final v/v ratio) seminal plasma and assessed for viability and motility after 3 or 24h of storage at 15 degrees C. Whereas motility was not affected by spermatozoa concentration after 3h of storage, the proportion of progressive spermatozoa decreased after 24h of storage when spermatozoa concentration was greater than 1.0*10(9)spermatozoa/ml. The duration of preservation and the spermatozoa concentration affected spermatozoa motility but had no impact on spermatozoa viability. This negative effect of greater spermatozoa concentrations on motility was independent of the presence and the concentration of seminal plasma. The seminal plasma at both concentrations (20% and 40%) had a protective effect on spermatozoa motility after 24h of storage. These findings have the potential to improve the efficiency of cervical AI with liquid stored ram semen. PMID- 26421372 TI - Mortality Risk Prediction: Can Comorbidity Indices Be Improved With Psychosocial Data? AB - BACKGROUND: Predicting risk of premature death is one of the most basic tasks in medicine and public health, but has proven to be difficult over the long term even with the best prognostic models. One popular strategy has been to improve prognostic models with candidate genes and other novel biomarkers. However, the gains in predictive power have been modest and the costs have been high, leading to a demand for cost-effective alternatives. We conducted a proof-of-principle investigation to examine whether simple, cheap, and noninvasive paper-and-pencil measures of social class and personality phenotype could improve the performance of one of the most widely used prediction models for all-cause mortality, the Charlson Comorbidity Index (CCI). METHODS: We used data from baseline and 25-year mortality follow-up of the UK Health and Lifestyle Study cohort. In a subset of the cohort, we first identified 5 psychosocial factors highly predictive of mortality: income, education, type A personality, communalism (preference for the company of others), and "lie" scale (a measure of denial, putatively associated with ill health). We then examined the predictive performance of the CCI with and without these measures in a validation subsample. RESULTS: Across 5-, 10-, 15-, 20-, and 25-year time horizons, the psychosocially augmented CCI showed substantially better discrimination [area under the receiver-operating curves (95% confidence interval) from 0.83 (0.81-0.85) to 0.84 (0.83-0.86)] than the CCI [area under the receiver-operating curves from 0.74 (0.71-0.76) to 0.77 (0.76 0.79)]. These translated into net reclassification improvements from 27% (23% 31%) to 35% (32%-38%) of survivors and from 23% (17%-30%) to 34% (17%-30%) of decedents; and 23%-42% reductions in the Number Needed to Screen. Calibration improved at all time horizons except 25 years, where it was decreased. CONCLUSION: Widespread attempts to improve prognostic models might consider not only novel biomarkers, but also psychosocial questionnaire measures. PMID- 26421373 TI - Have Racial Disparities in Ambulatory Care Sensitive Admissions Abated Over Time? AB - BACKGROUND: Racial disparities in access to care and access to high-quality care have been persistent over many decades. They have been documented in all areas of health care, including ambulatory care. Policy initiatives have been implemented to address disparities and close the gaps in care that minorities face. Less is known about the effectiveness of these polices. OBJECTIVES: To evaluate whether disparities in quality of ambulatory care have abated during the decade of 2000 by answering 2 questions: (1) were there differences in ambulatory care sensitive hospital admissions rates by race?; (2) have these differences been declining over time? RESEARCH DESIGN: Multivariable linear regressions with fixed county effects and robust SEs of longitudinal panel data. SUBJECTS: A total of 4,032,322 discharges in 172 counties in 6 states during 2003-2009. MEASURES: Prevention Quality Indicators (PQIs) developed by the Agency for Healthcare Research and Quality, by county, and race calculated from the Healthcare Cost and Utilization Project dataset. RESULTS: In 2003 the overall PQI admission rates were higher for African Americans (around 16.5/1000) than for whites (around 15/1000). By 2009, the overall and the chronic PQI admission rates declined significantly (P<0.01) for whites. They either did not decline or increased for African Americans. Acute PQI rates declined significantly for whites and remained stable for African Americans. CONCLUSIONS: Policies addressing persisting racial disparities in quality of ambulatory care for African Americans should focus on the chronic PQIs. In addition, efforts should be made to improve data quality for race and ethnicity information on hospital discharge data to enable informed policy evaluation and planning. PMID- 26421374 TI - Experimental Realization of Two Decoupled Directional Couplers in a Subwavelength Packing by Adiabatic Elimination. AB - On-chip optical data processing and photonic quantum integrated circuits require the integration of densely packed directional couplers at the nanoscale. However, the inherent evanescent coupling at this length scale severely limits the compactness of such on-chip photonic circuits. Here, inspired by the adiabatic elimination in a N-level atomic system, we report an experimental realization of a pair of directional couplers that are effectively isolated from each other despite their subwavelength packing. This approach opens the way to ultradense arrays of waveguide couplers for integrated optical and quantum logic gates. PMID- 26421376 TI - Systemic sclerosis: a rare cause of heart failure? AB - Systemic sclerosis (SS) is a chronic disease in which there may be multisystem involvement. It is rare (estimated prevalence: 0.5-2/10000) with high morbidity and mortality, and there is as yet no curative treatment. We report the case of a young woman newly diagnosed with SS, in whom decompensated heart failure was the main manifestation. PMID- 26421377 TI - High-sensitivity C-reactive protein in obese children: too complex a marker to use? PMID- 26421378 TI - Iron metabolism in heart failure: mechanisms and therapeutic approaches. PMID- 26421379 TI - A 75-year-old woman with chest pain and transient severe left ventricular systolic dysfunction. AB - INTRODUCTION: Coronary spasm can cause myocardial ischemia and angina in both patients with and without obstructive coronary artery disease. However, provocation tests using intracoronary acetylcholine (ACh) have been rarely performed in the Western world. CASE REPORT: We report a case of a 75-year-old woman with a history of hypertension and a mechanical aortic prosthesis who presented in the emergency room with acute-onset chest pain, widespread ST segment depression and severe left ventricular systolic dysfunction, with no signs of prosthesis dysfunction. Emergent coronary angiography excluded obstructive coronary artery disease. Pain relief and normalization of ST segment and systolic function occurred within six hours. The patient was treated for a possible thromboembolic myocardial infarction and was discharged home asymptomatic. Two weeks later, cardiac magnetic resonance was performed showing inferoseptal transmural infarct scar, inferior and inferolateral subendocardial infarct and mid-basal ischemia in the anterior and anterolateral walls. She was readmitted with recurrence of chest pain and it was decided to perform a provocation test with ACh. After injection of ACh into the left anterior descending artery, chest pain, ST-segment depression, blood flow impairment (TIMI 1) and transient grade 3 atrioventricular (AV) block occurred. Intracoronary administration of nitrates reversed the coronary spasm and AV conduction disturbances. Twenty minutes later, chest pain and ischemic ST changes recurred; there was no response to vasodilators and the patient developed cardiac arrest with pulseless electrical activity. Advanced life support was maintained for 32 minutes without return of spontaneous circulation. CONCLUSIONS: Provocation tests have a high sensitivity and specificity for the diagnosis of vasospastic angina. Although it is rare, these tests have the potential risk of irreversible spasm leading to arrhythmia and death. PMID- 26421380 TI - Synthesis of beta-C-Glycopyranosyl Aldehydes and 2,6-Anhydro-heptitols. AB - A convenient route has been developed for the diastereoselective synthesis of beta-C-glycopyranosyl aldehydes from D-glucose, D-mannose, and D-galactose. The key step in the synthesis of C-glycosyl aldehydes is the aryl driven reductive dehydration on 1-phenyl-2-(2',3',4',6'-tetra-O-acetyl-beta-D glycopyranosyl)ethanone to afford alkenes, which on oxidation afford the desired compounds in good yield. beta-C-Glycopyranosyl aldehydes have been converted to 2,6-anhydro-heptitols in quantitative yields. The 2,6-anhydro-heptitols derived from D-mannose and D-galactose are enantiomeric and are useful linkers for the synthesis of macrocycles/amphiphiles of complementary chirality. PMID- 26421381 TI - Spectroscopic and MD simulation studies on unfolding processes of mitochondrial carbonic anhydrase VA induced by urea. AB - Carbonic anhydrase VA (CAVA) is primarily expressed in the mitochondria and involved in numerous physiological processes including lipogenesis, insulin secretion from pancreatic cells, ureagenesis, gluconeogenesis and neuronal transmission. To understand the biophysical properties of CAVA, we carried out a reversible urea-induced isothermal denaturation at pH 7.0 and 25 degrees C. Spectroscopic probes, [theta]222 (mean residue ellipticity at 222 nm), F344 (Trp fluorescence emission intensity at 344 nm) and Deltaepsilon280 (difference absorption at 280 nm) were used to monitor the effect of urea on the structure and stability of CAVA. The urea-induced reversible denaturation curves were used to estimate [Formula: see text], Gibbs free energy in the absence of urea; Cm, the mid-point of the denaturation curve, i.e. molar urea concentration ([urea]) at which DeltaGD = 0; and m, the slope (=?DeltaGD/?[urea]). Coincidence of normalized transition curves of all optical properties suggests that unfolding/refolding of CAVA is a two-state process. We further performed 40 ns molecular dynamics simulation of CAVA to see the dynamics at different urea concentrations. An excellent agreement was observed between in silico and in vitro studies. PMID- 26421382 TI - Sodium-Ion Storage in Pyroprotein-Based Carbon Nanoplates. AB - Pyroprotein-based carbon nanoplates are fabricated from self-assembled silk proteins as a versatile platform to examine sodium-ion storage characteristics in various carbon environments. It is found that, depending on the local carbon structure, sodium ions are stored via chemi-/physisorption, insertion, or nanoclustering of metallic sodium. PMID- 26421383 TI - Dynamics of pelvic floor muscle functional parameters and their correlations with urinary incontinence in men after radical prostatectomy. AB - AIMS: To evaluate the dynamics of pelvic floor muscle strength, endurance, and urinary incontinence in a 6-month period in men after radical prostatectomy and to determine correlations between pelvic floor muscle strength, endurance, and urinary incontinence. METHODS: Forty-two men with prostate cancer treated with radical prostatectomy participated in the study. Pelvic floor muscles parameters were evaluated using the anal perineometer. An 8-hour pad test was used with the catheter removed. RESULTS: The greatest change in strength occurred during the last 3 months, i.e., from the third to the sixth month following surgery (P <= 0.05). The average amount of urinary incontinence on the day of catheter removal was approximately 311 g per 8 hr. Urinary incontinence decreased by 93.6% from the day of catheter removal 6 months later. A strong correlation (P <= 0.001) of reverse dependence was determined between pelvic floor muscle strength before surgery and the amount of urinary incontinence 6 months following surgery. CONCLUSION: The greatest change of pelvic floor muscles strength and endurance occurred during the third to the sixth month following surgery. The greatest change in urinary incontinence occurred during the first month following surgery. Pelvic floor muscle strength causes a greater decrease in urinary incontinence than endurance. The greater the pelvic floor muscle strength before surgery, the lower the amount of urinary incontinence. Age also affects pelvic floor muscle strength and endurance; this relation gradually weakens and with age disappears. Neurourol. Urodynam. 36:126-131, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26421384 TI - Effect of breakfast omission on subjective appetite, metabolism, acylated ghrelin and GLP-17-36 during rest and exercise. AB - OBJECTIVES: Breakfast omission induces compensatory eating behaviour at lunch, but often reduces daily energy intake. This study investigated the effect of breakfast omission on within-day subjective appetite, energy expenditure, substrate utilisation, and appetite hormone profiles, in response to standardised feeding and exercise. METHODS: Eight male, habitual breakfast eaters completed two randomised trials. Subjects arrived overnight fasted (0 h), and either consumed (BC) or omitted (BO) a standardized breakfast (mean standard deviation [SD]) (3085 [217] kJ). Lunch (4162 [510] kJ) and dinner (4914 [345] kJ) were provided at 4.5 and 10 h, respectively and subjects performed 60 min fixed intensity cycling (50% VO2 peak) at 8 h. Blood samples were collected at 0, 4.5, 6, and 8 h, with expired air and subjective appetite sensations (hunger, fullness, desire to eat (DTE), and prospective food consumption [PFC]) collected throughout. Heart rate and perceived exertion were measured during exercise. RESULTS: Hunger, DTE and PFC were greater and fullness lower during BO (P < 0.05) between breakfast and lunch, with no differences after lunch (P > 0.193). Resting energy expenditure was greater at 2.5 h during BC (P < 0.05) with no other differences between trials (P > 0.156). Active glucogon-like peptide-1 (GLP-17 36) was greater (P < 0.05) and acylated ghrelin tended to be greater (P = 0.078) at 4.5 h during BC. Heart rate was greater on BO (P < 0.05) during exercise. CONCLUSIONS: The results of this laboratory-controlled study suggest that the effects of breakfast omission are transient and do not extend beyond lunch, even when the negative energy balance created by breakfast omission is sustained via standardised feeding and exercise. PMID- 26421386 TI - Predicted versus measured resting energy expenditure in patients requiring home parenteral nutrition. PMID- 26421385 TI - omega-3 fatty acids as an adjuvant therapy ameliorates methotrexate-induced hepatotoxicity in children and adolescents with acute lymphoblastic leukemia: A randomized placebo-controlled study. AB - OBJECTIVES: Methotrexate (MTX)-induced hepatotoxicity is a significant clinical problem that may affect overall prognosis and disease outcome. Oxidative stress is a key player in its pathogenesis. The aim of this study was to investigate the role of omega-3 fatty acids as an adjuvant therapy in children and adolescents with acute lymphoblastic leukemia (ALL) during the maintenance phase of chemotherapy and the effect of omega-3 on MTX-induced hepatotoxicity. METHODS: This randomized, double-blind, placebo-controlled trial included 70 patients with ALL who were in the maintenance phase. The participants were divided into two groups: group A received oral MTX and omega-3 fatty acids (1000 mg/d) and group B (received MTX and placebo). Both groups were followed-up for 6 mo with assessment of liver enzymes, total antioxidant capacity (TAC), uric acid, malondialdhyde, superoxide dismutase (SOD), and glutathione peroxidase. The trial was registered at ClinicalTrials.gov (NCT02373579). RESULTS: Baseline clinical and laboratory parameters were consistent between the two groups (P > 0.05). After 6 mo, liver enzymes and malondialdhyde increased, whereas TAC, uric acid, SOD, and glutathione peroxidase decreased in group B (MTX and placebo) compared with baseline levels or with group A ALL patients receiving omega-3 fatty acids (P < 0.001). The addition of omega-3 to MTX maintained normal liver function and oxidant-antioxidant levels among group A patients at the end of treatment compared with pretherapy levels (P > 0.05). No adverse reactions due to omega-3 supplementation were reported. ALT was inversely correlated to TAC and SOD in the MTX group. CONCLUSIONS: The study determined that omega-3 fatty acids ameliorated MTX-induced hepatotoxicity and could be safely used during the maintenance phase of ALL. PMID- 26421387 TI - Micronutrient deficiencies in early childhood can lower a country's GDP: The Myanmar example. AB - Myanmar (Burma) is a developing country in South East Asia. While Myanmar is among the 20 countries where 80% of the world's malnourished children live, its military consumes the majority of the national budget. Children who are malnourished between conception and age two are at high risk for impaired physical and mental development, which adversely affects the country's productivity and growth. Myanmar is facing three major micronutrient deficiencies which are iodine, iron and vitamin A deficiencies. The three micronutrient deficiencies can cost about 2.4% of the country's GDP. Children are the future of Myanmar and persistent micronutrient deficiencies will hamper its economic growth and lower its GDP. PMID- 26421389 TI - Interventional trials in atypical parkinsonism. AB - Atypical parkinson disorders (APD) are rapidly progressive neurodegenerative diseases with a variable clinical presentation that may even mimic Parkinson's disease. Multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are commonly summarized under this umbrella term. Significant developments in research have expanded knowledge and have broadened available symptomatic treatments, particularly for the treatment of neurogenic orthostatic hypotension. Nonetheless, symptomatic support still remains limited in all of these disorders. Currently, there exists no effective treatment to delay disease progression and disease-modifying trials have failed to provide coherent and convincing results. Recent trials of rasagiline (in MSA), rifampicin (in MSA), tideglusib (in PSP) and davunetide (in PSP) reported negative results. Nevertheless, large cohorts of patients were recruited for interventional studies in the last few years which improved our understanding of trial methodology in APDs immensely. In addition, remarkable progress in basic research has been reported recently and will provide a solid foundation for future therapeutic trials. In this review, we will summarize published randomized, placebo controlled clinical trials (RCTs) in APDs. Additionally, the design of ongoing and unpublished interventions will be presented. PMID- 26421388 TI - Expression of inflammation-related miRNAs in white blood cells from subjects with metabolic syndrome after 8 wk of following a Mediterranean diet-based weight loss program. AB - OBJECTIVES: The aim of this study was to evaluate the influence of a dietary strategy for weight loss (the RESMENA [reduction of metabolic syndrome in Navarra, Spain] diet) on the expression of inflammation-related microRNAS (miRNAs) and genes in white blood cells (WBC) from individuals with metabolic syndrome (MetS). METHODS: The clinical, anthropometric, and biochemical characteristics of 40 individuals with MetS (20 men and 20 women; age: 48.84 +/- 10.02 y; body mass index: 35.41 +/- 4.42 kg/m(2)) were evaluated before and after an 8-wk hypocaloric diet based on the Mediterranean dietary pattern. Nutrient intake was assessed with a food frequency questionnaire and 48-h weighed food records. Total RNA was isolated from WBC and the expression of some inflammation related miRNAs and mRNAs (IL-6, TNF-alpha, ICAM-1, IL-18, SERPINE1, VCAM-1, GAPDH) was assessed by quantitative polymerase chain reaction. RESULTS: The RESMENA nutritional intervention improved most anthropometric and biochemical features. The expression of miR-155-3p was decreased in WBC, whereas Let-7b was strongly upregulated as a consequence of the dietary treatment. However, they were not correlated with the expression of the proinflammatory genes in the same cells. The changes in the expression of let-7b, miR-125b, miR-130a, miR-132-3p, and miR-422b were significantly associated with changes in diet quality when assessed by the Healthy Eating Index. Moreover, low consumption of lipids and saturated fat (g/d) were associated with higher expression of let-7b after the nutritional intervention. CONCLUSIONS: The Mediterranean-based nutritional intervention was able to induce changes in the expression of let-7b and miR-155 3p in WBC from patients with MetS after 8 wk. Moreover, the quality of the diet has an important effect on the miRNAs expression changes. These results should be highlighted because these miRNAs have been associated with inflammatory gene regulation and important human diseases. PMID- 26421390 TI - Juvenile dystonia-parkinsonism syndrome caused by a novel p.S941Tfs1X ATP13A2 (PARK9) mutation. PMID- 26421392 TI - The phenotypic spectrum of progressive supranuclear palsy. AB - Traditionally, the clinical picture of progressive supranuclear palsy (PSP) was defined by early postural instability with falls, supranuclear vertical gaze palsy, symmetric akinesia and rigidity, frontal and subcortical dementia, and pseudobulbar palsy, leading to death after a mean disease duration of approximately six years. A definite diagnosis of PSP depends on neuropathological confirmation. In recent years, clinico-pathological studies have drawn attention to various "atypical" clinical manifestations of PSP. In these, a clinical diagnosis of PSP is delayed or never accomplished. Comprehensive understanding of the natural history of PSP is required to permit an early and accurate diagnosis. Based on current evidence, this review provides an update on the clinical spectrum of PSP. PMID- 26421391 TI - Speech discrimination is impaired in parkinsonian patients: Expanding the audiologic findings of Parkinson's disease. AB - BACKGROUND AND OBJECTIVES: Hearing impairment (HI) has been previously demonstrated in patients with Parkinson's disease (PD). Pure Tone Audiometry (PTA) gives no information about patients' ability to hear and understand speech. To find out hearing ability and speech discrimination of PD patients, we expanded audiological evaluation by means of speech audiometry (SA). PATIENTS AND METHODS: We screened a series of consecutive PD patients. Severity of motor symptoms and staging were measured by the UPDRS-III and the H&Y scales. Audiometric evaluation consisted of a standardized audiological examination, PTA and SA. Healthy age- and sex-matched subjects were selected as controls. RESULTS: 45 PD patients and 45 healthy controls were enrolled. PTA confirmed our previous finding of high frequency HI in PD patients. The mean values for the Speech Recognition Threshold were higher in PD patients as compared with controls. PD patients were more likely to have impaired speech discrimination profiles and higher disease stages. Neither the patients nor the controls showed a significant speech-tone dissociation and rollover phenomenon. CONCLUSION: Our results confirmed sensorineural HI in PD patients. Moreover, SA showed impaired speech discrimination abilities in PD patients as compared with control group thus expanding the audiologic findings of PD. PMID- 26421393 TI - Syndromic associations and RNF216 mutations. PMID- 26421395 TI - Promoting the science and art of veterinary medicine. PMID- 26421396 TI - A second glance at financial expectations of first-year veterinary students. PMID- 26421397 TI - Understanding companion animal practitioners' attitudes toward antimicrobial stewardship. PMID- 26421398 TI - What Is Your Diagnosis? Dilated cardiomyopathy. PMID- 26421399 TI - Theriogenology Question of the Month. Twins in an alpaca. PMID- 26421400 TI - Pathology in Practice. Cerebellar coenurosis in a sheep. PMID- 26421401 TI - Pathology in Practice. Dermatitis, cellulitis, and myositis caused by S marcescens infection in a cat. PMID- 26421402 TI - Injuries and illnesses among Federal Emergency Management Agency-certified search and-recovery and search-and-rescue dogs deployed to Oso, Washington, following the March 22, 2014, State Route 530 landslide. AB - OBJECTIVE: To establish types and rates of injuries and illnesses among search and-recovery and search-and-rescue dogs deployed to Oso, Wash, following the March 22, 2014, State Route 530 landslide. DESIGN: Medical records review and cross-sectional survey. ANIMALS: 25 Federal Emergency Management Agency-certified search dogs. PROCEDURES: On-site medical records and postdeployment laboratory test results were reviewed and an electronic survey was distributed to handlers within 8 days after demobilization. RESULTS: Dogs worked a total of 244 search shifts totaling 2,015 hours. Injuries and illnesses were reported in 21 (84%) dogs. Wounds (abrasions, pad wear, paw pad splits, and lacerations) were the most common injury, with an incidence rate of 28.3 wounds/1,000 hours worked. Dehydration was the most common illness, with an incidence rate of 10.4 cases of dehydration/1,000 hours worked. Total incidence rate for all health events was 66.5 events/1,000 hours worked. Two search dogs were removed from search operations for 2 days because of health issues. All others continued search operations while receiving treatment for their medical issues. All health issues were resolved during the deployment or within 2 weeks after demobilization. CONCLUSIONS AND CLINICAL RELEVANCE: Results revealed that search dogs deployed to the Oso, Wash, landslide incurred injuries and illnesses similar to those reported following other disasters (dehydration, wounding, vomiting, and diarrhea) but also incurred medical issues not previously documented (acute caudal myopathy, cutaneous mass ruptures, and fever). The reported medical issues were minor; however, prompt veterinary care helped prevent them from developing into more serious conditions. PMID- 26421403 TI - Association between methicillin-resistant Staphylococcus pseudintermedius carriage and the development of surgical site infections following tibial plateau leveling osteotomy in dogs. AB - OBJECTIVE: To evaluate the association between preoperative carriage of methicillin-resistant Staphylococcus pseudintermedius (MRSP) and the development of surgical site infections (SSIs) following tibial plateau leveling osteotomy (TPLO) in dogs. DESIGN: Prospective multicenter study. ANIMALS: 549 dogs. PROCEDURES: At 7 veterinary hospitals, swab specimens were obtained from the pharynx, nares, rectum, and skin of dogs admitted for TPLO. Specimens were submitted for culture of MRSP. For each dog, information regarding preoperative and postoperative antimicrobial administration, comorbidities, contact with other dogs, and whether the dog developed an SSI was obtained. Univariable and multivariable analyses were performed to identify variables associated with preoperative and postoperative MRSP colonization and the development of an SSI. RESULTS: Of the 549 study dogs, 24 (4.4%) were identified as MRSP carriers before TPLO and 37 (6.7%) developed an SSI after TPLO. Bacteriologic culture was performed on specimens obtained from 32 of the 37 SSIs, and MRSP was isolated from 11 (34%). Carriers of MRSP (OR, 6.72; 95% confidence interval [CI], 2.12 to 21.4) and Bulldogs (OR, 11.1; 95% CI, 2.07 to 59.3) were at risk for development of an SSI after TPLO, whereas postoperative administration of antimicrobials (OR, 0.36; 95% CI, 0.15 to 0.91) appeared to protect against development of an SSI. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that carriage of MRSP were a risk factor for development of an SSI after TPLO and measures to rapidly identify and treat MRSP carriers are warranted. Postoperative administration of antimicrobials protected against development of an SSI after TPLO. PMID- 26421404 TI - Factors associated with pathological fractures in dogs with appendicular primary bone neoplasia: 84 cases (2007-2013). AB - OBJECTIVE: To determine the incidence of pathological fractures associated with appendicular primary bone tumors in dogs managed medically and to identify potential risk factors at the time of radiographic diagnosis that may be associated with eventual pathological fracture. DESIGN: Retrospective case series. ANIMALS: 84 dogs with primary long bone neoplasia treated medically. PROCEDURES: Medical records for dogs with a diagnosis of primary long bone neoplasia based on results of radiography that was confirmed subsequently at necropsy were reviewed. Owners elected medical treatment at a pain clinic. Data regarding clinical signs, diagnostic testing, pathological findings, and outcome were evaluated. RESULTS: 84 dogs met study inclusion criteria with 85 limbs affected. Osteosarcoma was the most common tumor and was identified in 78 of 85 (91.8%) limbs. The median time from diagnosis to euthanasia was 111 days (range, 28 to 447 days). Pathological fractures were identified in 33 of 85 limbs (38%), with the femur most commonly affected, (8/14 [57.1%]), followed by the tibia (9/17 [52.9%]), humerus (10/27 [37%]), radius (5/25 [20%]), and ulna (1/2 [50%]). Logistic regression analysis indicated that tumors arising from long bones other than the radius had odds of eventual fracture 5.05 as great as the odds for tumors of the radius, and lytic tumors had odds of eventual fracture 3.22 as great as the odds for tumors that appeared blastic or mixed lytic-blastic. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that radial primary bone tumors were less likely and lytic tumors were more likely to fracture. The overall incidence of pathological fractures secondary to appendicular primary bone neoplasia in this study with patients treated by means of intensive management for bone pain was higher than previously reported. PMID- 26421405 TI - Subcutaneous ureteral bypass device for treatment of iatrogenic ureteral ligation in a kitten. AB - CASE DESCRIPTION: A 17-week-old spayed female Sphinx was evaluated after a 3-day history of inappetence, lethargy, and vomiting. Three weeks prior, the kitten had undergone routine elective ovariohysterectomy. CLINICAL FINDINGS: Abdominal ultrasonography revealed moderate hydronephrosis of the left kidney, and the left ureter was tortuous and dilated from the kidney to the level of the midureter, where it abruptly tapered. No discrete cause of obstruction could be identified. Clinicopathologic analyses revealed that the kitten was nonazotemic. TREATMENT AND OUTCOME: Exploratory laparotomy revealed that the distal portion of the left ureter was irregular with ill-defined margins and abundant scar tissue, likely secondary to iatrogenic ureteral ligation during the ovariohysterectomy (suture was not observed). Intraoperative antegrade pyelography confirmed complete left ureteral obstruction extending distally from the level of the midureter. A subcutaneous ureteral bypass device was placed to allow for renal decompression. No complications were encountered in the perioperative period, and the kitten recovered well after anesthesia. The kitten was discharged from the hospital 7 days after initial evaluation and continued to do well after surgery. At long term follow-up, abdominal ultrasonography confirmed resolution of hydronephrosis and ureteral dilation. CLINICAL RELEVANCE: A subcutaneous ureteral bypass device successfully allowed renal decompression in a kitten with iatrogenic ureteral ligation. A subcutaneous ureteral bypass device may be an alternative to historical surgical options in cases of unilateral ureteral obstruction and may result in a good long-term outcome. PMID- 26421406 TI - Prevalence of and risk factors associated with ovine progressive pneumonia in Wyoming sheep flocks. AB - OBJECTIVE: To determine the prevalence of antibodies against small ruminant lentivirus (SRLV), the causative agent of ovine progressive pneumonia (OPP), and to identify risk factors associated with OPP in Wyoming sheep flocks. DESIGN: Cross-sectional study. ANIMALS: 1,415 sheep from 54 flocks in Wyoming. PROCEDURES: Flocks were surveyed as part of the National Animal Health Monitoring System (NAHMS) 2011 sheep study. Serum samples obtained from sheep in Wyoming were analyzed for anti-SRLV antibodies by use of a competitive-inhibition ELISA. The prevalence of seropositive animals overall and within each flock was calculated. Respective associations between flock OPP status and various demographic and management variables were assessed. RESULTS: The estimated prevalence of sheep seropositive for anti-SRLV antibodies and OPP-infected flocks in Wyoming was 18.0% and 47.5%, respectively. Within OPP-infected flocks, the prevalence of seropositive sheep ranged from 3.9% to 96%. Flocks maintained on nonfenced range were more likely to be infected with OPP than were flocks maintained on fenced range (OR, 3.4; 95% confidence interval, 1.1 to 10.7). The estimated prevalence of OPP-infected flocks in Wyoming did not vary substantially from that at the regional or national level reported in the NAHMS 2001 sheep study. Compared with results of the NAHMS 2011 sheep study, Wyoming producers were more familiar with OPP than were other US sheep producers, but only 61% of Wyoming producers surveyed reported being very or somewhat familiar with the disease. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that OPP is prevalent in many Wyoming sheep flocks, which suggested that continued efforts are necessary to increase producer knowledge about the disease and investigate practices to minimize economic losses associated with OPP. PMID- 26421407 TI - Opinions of clinical veterinarians at a US veterinary teaching hospital regarding antimicrobial use and antimicrobial-resistant infections. AB - OBJECTIVE: To determine opinions of faculty members with clinical appointments, clinical veterinarians, residents, and interns at a US veterinary teaching hospital regarding antimicrobial use and antimicrobial-resistant infections. DESIGN: Cross-sectional survey. SAMPLE: 71 veterinarians. PROCEDURES: An online questionnaire was sent to all veterinarians with clinical service responsibilities at the North Carolina State University veterinary teaching hospital (n = 167). The survey included 23 questions regarding demographic information, educational experiences, current prescribing practices, and personal opinions related to antimicrobial selection, antimicrobial use, restrictions on antimicrobial use, and antimicrobial resistance. RESULTS: Of the 167 veterinarians eligible to participate, 71 (43%) responded. When respondents were asked to rate their level of concern (very concerned = 1; not concerned = 5) about antimicrobial-resistant infections, most (41/70 [59%]) assigned a score of 1, with mean score for all respondents being 1.5. Most survey participants rated their immediate colleagues (mean score, 1.9) as more concerned than other veterinary medical professionals (mean score, 2.3) and their clients (mean score, 3.4). Fifty-nine of 67 (88%) respondents felt that antimicrobials were overprescribed at the hospital, and 32 of 69 (46%) respondents felt uncomfortable prescribing at least one class of antimicrobials (eg, carbapenems or glycopeptides) because of public health concerns. CONCLUSIONS AND CLINICAL RELEVANCE: Findings indicated that veterinarians at this teaching hospital were concerned about antimicrobial resistance, thought antimicrobials were overprescribed, and supported restricting use of certain antimicrobial classes in companion animals. Findings may be useful in educating future veterinarians and altering prescribing habits and antimicrobial distribution systems in veterinary hospitals. PMID- 26421408 TI - Risk factors for suicide, attitudes toward mental illness, and practice-related stressors among US veterinarians. AB - OBJECTIVE: To evaluate the prevalence of suicide risk factors, attitudes toward mental illness, and practice-related stressors among US veterinarians. DESIGN: Cross-sectional survey. SAMPLE: 11,627 US veterinarians. PROCEDURES: Between July 1 and October 20, 2014, a Web-based questionnaire was made available through the Veterinary Information Network (VIN), VIN News Service, JAVMA News, and email messages to US veterinarians sent by a veterinary medical association, agriculture or livestock department, or health department of each state (except Maine) and Puerto Rico. RESULTS: Of 11,627 respondents, 3,628 (31%) were male. Modal age category was 30 to 39 years, and modal range for years practicing veterinary medicine was 10 to 19 years. There were 7,460 (64%) respondents who primarily practiced small animal medicine, and 4,224 (36%) who were practice owners. There were 1,077 (9%) respondents with current serious psychological distress. Since leaving veterinary school, 3,655 (31%) respondents experienced depressive episodes, 1,952 (17%) experienced suicidal ideation, and 157 (1%) attempted suicide. Currently, 2,228 (19%) respondents were receiving treatment for a mental health condition. Only 3,250 of 10,220 (32%) respondents somewhat or strongly agreed that people are sympathetic toward persons with mental illness. The most commonly reported practice-related stressor was demands of practice. CONCLUSIONS AND CLINICAL RELEVANCE: In this survey, approximately 1 in 11 veterinarians had serious psychological distress and 1 in 6 experienced suicidal ideation since leaving veterinary school. Implementing measures to help veterinarians cope with practice-related stressors and reducing barriers veterinarians face in seeking mental health treatment might reduce the risk for suicide among veterinarians. PMID- 26421409 TI - The efficacy of hydroxychloroquine in altering pregnancy outcome in women with antiphospholipid antibodies. Evidence and clinical judgment. AB - The use of low-dose aspirin and heparinoids has improved the pregnancy outcome in obstetric antiphospholipid syndrome (APS). However, current treatment fails in 20 30% of APS pregnancies, raising the need to explore other treatments to improve obstetrical outcome. Hydroxychloroquine (HCQ) is widely used in patients with autoimmune diseases, mainly systemic lupus erythematous (SLE), due to its anti inflammatory, anti-aggregant and immune-regulatory properties. Evidence from in vitro and animal models suggests a potential protective effect of HCQ in obstetric APS. Pending the availability of prospective trials, we aimed to systematically review the available evidence and to assess the clinical judgment of a panel of experts regarding the use of HCQ in improving pregnancy outcome in women with antiphospholipid antibodies (aPL). Clinical data on the ability of HCQ to improve pregnancy outcome in women with aPL are very limited in the available literature. Only one cohort study evaluating maternal and fetal outcome of pregnancy in patients with SLE who were exposed to HCQ was identified. Four of 14 (29%) treated with HCQ patients had pregnancy failure, compared with six of 24 (25%) of patients not treated with HCQ. However, the effect of HCQ was not adjusted for the use of other medications such as aspirin, heparins or steroids. Selected experts were contacted by e-mail and asked to review the summary of the evidence provided by the working group and to briefly answer each of the proposed questions. Overall, the panel of experts agreed that adding HCQ could be considered in selected cases or after failure of standard treatment with aspirin and a heparin agent. Specifically, the majority of experts considered adding HCQ in specific scenarios, such as women with previous thrombosis (either arterial and/or venous), and/or with previous ischaemic placenta-mediated complications. Prospective studies are necessary before the use of HCQ during pregnancy in women with aPL should be routinely recommended for clinical practice. PMID- 26421410 TI - Nonmotor disabilities in patients with facial palsy measured by patient-reported outcome measures. AB - OBJECTIVES/HYPOTHESIS: To describe changes of motor and nonmotor disabilities in patient with peripheral facial palsy (FP) during treatment using the patient reported outcome measures (PROMs) Facial Clinimetric Evaluation (FaCE), Facial Disability Index (FDI), and Short Form 36-Item Questionnaire (SF-36) and to analyze predictors for these changes STUDY DESIGN: Prospective, single-center longitudinal study. METHODS: One hundred twenty patients with FP underwent at least two PROMs between 2012 and 2015. Predictors for changes of the PROMs were analyzed univariately using Pearson's correlation and multivariately using linear regression models. RESULTS: The mean interval between onset of FP to first presentation was 29 +/- 64 months and between first and final assessment 8.7 +/- 7.2 months. Initial House-Brackmann grading was 4.0 +/- 1.3 and final House Brackmann grading was 2.8 +/- 1.6 (P < .001). All mean FaCE and FDI but only some SF-36 subscores improved over time (all P < .05). Adjuvant treatment was an independent predictor for improvement of the FaCE Facial Comfort subscore (P = .015) and a malignant tumor as primary disease for improvement of the FaCE Oral Function subscore (P = .044). Unemployment was a predictor for improvement of the FDI Social/Well-Being Function (P = .035). First assessment <90 days after onset was a predictor for improvement of the SF-36 Bodily Pain subscore (P = .025), a primary malignant disease for improvement of the SF-36 General Health perception (P = .004), and idiopathic FP for improvement of the SF-36 Social Functioning subscore (P = .017). CONCLUSIONS: Changes of motor function revealed by classical grading systems mostly do not correlate with changes of nonmotor disabilities during treatment of FP. Many other factors are associated with changes of PROMs during the FP treatment. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1516-1523, 2016. PMID- 26421411 TI - A Quasi-Solid-State Sodium-Ion Capacitor with High Energy Density. AB - A quasi-solid-state sodium-ion capacitor is demonstrated with nanoporous disordered carbon and macroporous graphene as the negative and positive electrodes, respectively, using a sodium-ion-conducting gel polymer electrolyte. It can operate at a cell voltage as high as 4.2 V with an energy density of record high 168 W h kg(-1). PMID- 26421412 TI - Postoperative prognostic nutritional index change is an independent predictor of survival in patients with small hepatocellular carcinoma. AB - BACKGROUND: There is limited information concerning the postoperative prognostic nutritional index change (DeltaPNI) in hepatocellular carcinoma (HCC). This study was designed to evaluate the prognostic value of DeltaPNI in patients with small HCC who underwent liver resection. METHODS: A retrospective cohort study was performed to analyze 243 patients with small HCC who underwent liver resection. Patients were divided into prognostic nutritional index (PNI)-increased group (n = 161) and PNI-decreased group (n = 82) according to postoperative PNI change. Clinical data, overall survival (OS), and recurrence-free survival (RFS) were statistically compared between the 2 groups, and a multivariate analysis was used to identify prognostic factors. RESULTS: Multivariable analysis revealed that DeltaPNI as independent predictors of OS and RFS in patients with small HCC after liver resection (P < .01 for both). CONCLUSIONS: Decreased PNI, but not low preoperative PNI was an independent risk factor for OS and RFS in patients with small HCC who underwent liver resection. PMID- 26421413 TI - Complicated breast cancer-related lymphedema: evaluating health care resource utilization and associated costs of management. AB - BACKGROUND: Lymphedema can become a disabling condition necessitating inpatient care. This study aimed to estimate complicated lymphedema incidence after breast cancer surgery and calculate associated hospital resource utilization. METHODS: We identified adult women undergoing lumpectomy and/or mastectomy with axillary lymph node surgery between 2006 and 2012 using 5-state inpatient databases. Patients were grouped according to the development of complicated lymphedema. The primary outcomes were all-cause hospitalizations and health care charges within 2 years of surgery. Multivariate regression models were used to compare outcomes. RESULTS: Of 56,075 women included, 2.3% had at least 1 hospital admission for complicated lymphedema within 2 years of surgery. Despite confounder adjustment, women with complicated lymphedema experienced 5 fold more all-cause (incidence rate ratio = 5.02, 95% confidence interval: 4.76 to 5.29) admissions compared with women without lymphedema. This resulted in substantially higher health care charges ($58,088 vs $31,819 per patient, P < .001). Although axillary dissection and certain comorbidities were associated with complicated lymphedema, breast reconstruction appeared unrelated. CONCLUSIONS: Complicated lymphedema develops in a quantifiable number of patients. The health care burden of lymphedema underscored here mandates further investigation into targeted, anticipatory management strategies for breast cancer-related lymphedema. PMID- 26421414 TI - Elucidation of the binding mechanism of renin using a wide array of computational techniques and biological assays. AB - We investigate the binding mechanism in renin complexes, involving three drugs (remikiren, zankiren and enalkiren) and one lead compound, which was selected after screening the ZINC database. For this purpose, we used ab initio methods (the effective fragment potential, the variational perturbation theory, the energy decomposition analysis, the atoms-in-molecules), docking, molecular dynamics, and the MM-PBSA method. A biological assay for the lead compound has been performed to validate the theoretical findings. Importantly, binding free energy calculations for the three drug complexes are within 3 kcal/mol of the experimental values, thus further justifying our computational protocol, which has been validated through previous studies on 11 drug-protein systems. The main elements of the discovered mechanism are: (i) minor changes are induced to renin upon drug binding, (ii) the three drugs form an extensive network of hydrogen bonds with renin, whilst the lead compound presented diminished interactions, (iii) ligand binding in all complexes is driven by favorable van der Waals interactions and the nonpolar contribution to solvation, while the lead compound is associated with diminished van der Waals interactions compared to the drug bound forms of renin, and (iv) the environment (H2O/Na(+)) has a small effect on the renin-remikiren interaction. PMID- 26421415 TI - Profile of interferon-gamma response to latency-associated and novel in vivo expressed antigens in a cohort of subjects recently exposed to Mycobacterium tuberculosis. AB - Recently some latency-associated antigens (LAA) of Mycobacterium tuberculosis were described, as Rv2029c, Rv2031c, Rv2034, Rv2628 and Rv3353c. Of which, the Rv2034 and Rv3353c also demonstrated in vivo expression. Therefore evaluating the immune response to these antigens may help to understand their role in latent TB infection. In a 1-year longitudinal study, IFN-gamma response by in vitro peripheral blood mononuclear cells stimulation with LAA was investigated in subjects recently exposed to TB, classified by IFN-gamma release assay (IGRA) using RD1 antigens (ESAT-6:CFP-10) and tuberculin skin test (TST) response. Except for Rv3353c, all the LAA triggered higher mean IFN-gamma response in IGRA RD1(+) groups (p < 0.05). Combining the IFN-gamma-responders to Rv2029c, Rv2031c plus Rv2034 detected 90.3% (28/31) of IGRA-RD1(+) and 66.7% (24/36) of TST(+) contacts, while 95% (19/20) and 11% (2/17) were identified by classifying them according to a TST and IGRA-RD1 double-positive or double-negative response, respectively. In the follow-up, the TST convertors (negative to positive) also demonstrated an IFN-gamma conversion to Rv2029c and Rv2031c, whereas the unique TB incident case was exclusively detected via IGRA-Rv2029c and TST before developing TB. A reversion rate to LAA (60%-100%) after prophylactic treatment was observed at TST(+)/IGRA-RD1(+) group. Further studies into the performance of these antigens are thus warranted. PMID- 26421416 TI - Just What the Doctor Ordered: Using Parks to Improve Children's Health. PMID- 26421417 TI - Spatiotemporally Controlled Reorganization of Signaling Complexes in the Plasma Membrane of Living Cells. AB - Triggered immobilization of proteins in the plasma membrane of living cells into functional micropatterns is established by using an adaptor protein, which is comprised of an antiGFP nanobody fused to the HaloTag protein. Efficient in situ reorganization of the type I interferon receptor subunits as well as intact, fully functional signaling complexes in living cells are achieved by this method. PMID- 26421418 TI - Flavored Tobacco Product Use Among Middle and High School Students--United States, 2014. AB - The 2009 Family Smoking Prevention and Tobacco Control Act prohibits "characterizing flavors" (e.g., candy, fruit, and chocolate) other than tobacco and menthol in cigarettes; however, characterizing flavors are not currently prohibited in other tobacco products. Analyses of retail sales data suggest that U.S. consumption of flavored noncigarette tobacco products, including flavored cigars and flavored e-cigarettes, has increased in recent years. There is growing concern that widely marketed varieties of new and existing flavored tobacco products might appeal to youths (2) and could be contributing to recent increases in the use of tobacco products, including e-cigarettes and hookah, among youths. CDC and the Food and Drug Administration (FDA) analyzed data from the 2014 National Youth Tobacco Survey (NYTS) to determine the prevalence of past 30 day use (current use) of flavored e-cigarette, hookah tobacco, cigar, pipe tobacco or smokeless tobacco products, and menthol cigarettes among middle and high school students, and the proportion of current tobacco product users who have used flavored products. An estimated 70.0% (3.26 million) of all current youth tobacco users had used at least one flavored tobacco product in the past 30 days. Among current users, 63.3%, (1.58 million) had used a flavored e-cigarette, 60.6%, (1.02 million) had used flavored hookah tobacco, and 63.5% (910,000) had used a flavored cigar in the past 30 days. Given the millions of current youth tobacco users, it is important for comprehensive tobacco prevention and control strategies to address all forms of tobacco use, including flavored tobacco products, among U.S. youths. PMID- 26421421 TI - Naringin Mitigates Cardiac Hypertrophy by Reducing Oxidative Stress and Inactivating c-Jun Nuclear Kinase-1 Protein in Type I Diabetes. AB - Cardiac hypertrophy (CH) in type 1 diabetes mellitus is attributed to increased oxidative stress-associated activation of c-Jun Nuclear Kinase (JNK). We investigated the effects of naringin on hyperglycemia-associated oxidative stress, activation of JNK-1, and CH. Male Sprague-Dawley rats (225-250 g) (n = 7) were divided into 6 groups. Groups I and II were orally treated with distilled water [3.0 mL/kg body weight/day (BW)] and naringin (50 mg/kg BW), respectively. Groups III-VI were rendered diabetic by a single intraperitoneal injection of 65 mg/kg BW of streptozotocin. Groups III, IV, and V were further treated with insulin (4.0 I.U, s.c, twice daily), naringin (50 mg/kg BW), and ramipril (3.0 mg/kg BW), respectively. After 56 days, the animals were sacrificed and then plasma and cardiac tissues obtained for further analysis. Naringin treatment of diabetic rats significantly reversed oxidative stress, lipid peroxidation, proteins oxidation, CH indices, and JNK protein activation compared with untreated diabetic animals. Our results do suggest that naringin mitigates CH by inhibiting oxidative stress leading to inactivation of JNK-1. Naringin supplements could therefore ameliorate CH in diabetic patients. PMID- 26421419 TI - Postoperative hepatitis B virus reactivation and surgery-induced immunosuppression in patients with hepatitis B-related hepatocellular carcinoma. AB - BACKGROUND: Hepatectomy in hepatocellular carcinoma (HCC) patients lead to postoperative hepatitis B virus (HBV) reactivation (PHR) as well as immunosuppression. METHODS: This prospective study involved 135 HBV-related HCC patients and 42 control hepatic hemangioma patients. RESULTS: Among HCC patients, 26 (19.3%) suffered PHR. Risk factors for PHR were HBV-cAg S1 positivity [hazard ratio (HR) = 404.82, P = 0.004], high preoperative total bilirubin level (HR = 186.38, P = 0.036), small preoperative proportions of CD3-CD16 + CD56 + cells (HR = 0.01, P = 0.014) and CD19 + B cells (HR = 0.02, P = 0.016), blood transfusion (HR = 157.03, P = 0.006) and high liver cirrhosis S score (HR = 270.45, P = 0.004). On postoperative day (POD) 3, PHR patients showed much greater immunosuppression than non-PHR patients based on proportions of T cells (CD3+, CD3 + CD4+, CD3 + CD8+), B cells (CD19+) and on levels of IgG, IgA antibodies, complement proteins C3, and C4. By POD 7, PHR patients had partially recovered but not as quickly as non-PHR patients: PHR patients still showed deficits in T cells (CD3+, CD3 + CD4+), CD3-CD16 + CD56+ cells and in levels of IgM, C3, C4, and C-reactive protein. CONCLUSION: PHR may be associated with resection-induced immunosuppression in patients with HBV-related HCC. PMID- 26421422 TI - Animal toxins and renal ion transport: Another dimension in tropical nephrology. AB - Renal vascular and tubular ion channels and transporters involved in toxin injury are reviewed. Vascular ion channels modulated by animal toxins, which result in haemodynamic alterations and changes in blood pressure, include ENaC/Degenerin/ASIC, ATP sensitive K channels (KATP ), Ca activated K channels (Kca) and voltage gated Ca channels, mostly L-type. Renal tubular Na channels and K channels are also targeted by animal toxins. NHE3 and ENaC are two important targets. NCC and NKCC may be involved indirectly by vasoactive mediators induced by inflammation. Most renal tubular K channels including voltage gated K channels (Kv1), KATP , ROMK1, BK and SK are blocked by scorpion toxins. Few are inhibited by bee, wasp and spider venoms. Due to small envenoming, incomplete block and several compensatory mechanisms in renal tubules, serum electrolyte charges are not apparent. Changes in serum electrolytes are observed in injury by large amount of venom when several channels or transporters are targeted. Envenomings by scorpions and bees are examples of toxins targeting multiple ion channels and transporters. PMID- 26421423 TI - WITHDRAWN: Metformin monotherapy for type 2 diabetes mellitus. PMID- 26421424 TI - Glycerin laxatives for prevention or treatment of feeding intolerance in very low birth weight infants. AB - BACKGROUND: Feeding intolerance is a common clinical problem among preterm infants. It may be an early sign of necrotising enterocolitis, sepsis or other serious gastrointestinal conditions, or it may result from gut immaturity with delayed passage of meconium. Glycerin laxatives stimulate passage of meconium by acting as an osmotic dehydrating agent and increasing osmotic pressure in the gut; they stimulate rectal contraction, potentially reducing the incidence of feeding intolerance. OBJECTIVES: To assess the effectiveness and safety of glycerin laxatives (enemas/suppositories) for prevention or treatment of feeding intolerance in very low birth weight (VLBW) infants. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 4), MEDLINE, EMBASE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We restricted our search to all randomised controlled trials and applied no language restrictions. We searched the references of identified studies and reviews on this topic and handsearched for additional articles. We searched the database maintained by the US National Institutes of Health (www.clinicaltrials.gov) and European trial registries to identify ongoing trials. SELECTION CRITERIA: We considered only randomised or quasi-randomised controlled trials that enrolled preterm infants < 32 weeks' gestational age (GA) and/or < 1500 g birth weight. We included trials if they administered glycerin laxatives and measured at least one prespecified clinical outcome. DATA COLLECTION AND ANALYSIS: We used standard methods of The Cochrane Collaboration and its Neonatal Group to assess methodological quality of trials, to collect data and to perform analyses. MAIN RESULTS: We identified three trials that evaluated use of prophylactic glycerin laxatives in preterm infants. We identified no trials that evaluated therapeutic use of glycerin laxatives for feeding intolerance. Our review showed that prophylactic administration of glycerin laxatives did not reduce the time required to achieve full enteral feeds and did not influence secondary outcomes, including duration of hospital stay, mortality and weight at discharge. Prophylactic administration of glycerin laxatives resulted in failure of fewer infants to pass stool over the first 48 hours. Included trials reported no adverse events. AUTHORS' CONCLUSIONS: Our review of available evidence for glycerin laxatives does not support the routine use of prophylactic glycerin laxatives in clinical practice. Additional studies are needed to confirm or refute the effectiveness and safety of glycerin laxatives for prevention or treatment of feeding intolerance in VLBW infants. PMID- 26421425 TI - Anticalins directed against the fibronectin extra domain B as diagnostic tracers for glioblastomas. AB - The standard of care for diagnosis and therapy monitoring of gliomas is magnetic resonance imaging (MRI), which however, provides only an indirect and incomplete representation of the tumor mass, offers limited information for patient stratification according to WHO-grades and may insufficiently indicate tumor relapse after antiangiogenic therapy. Anticalins are alternative binding proteins obtained via combinatorial protein design from the human lipocalin scaffold that offer novel diagnostic reagents for histology and imaging applications. Here, the Anticalins N7A, N7E and N9B, which possess exquisite specificity and affinity for oncofetal fibronectin carrying the extra domain B (ED-B), a well-known proangiogenic extracellular matrix protein, were applied for immunohistochemical studies. When investigating ED-B expression in biopsies from 41 patients with confirmed gliomas of WHO grades I to IV, or in non-neoplastic brain samples, we found that Anticalins specifically detect ED-B in primary glioblastoma multiforme (GBM; WHO IV) but not in tumors of lower histopathological grade or in tumor-free brain. In primary GBM samples, ED-B specific Anticalins locate to fibronectin rich perivascular areas that are associated with angiogenesis. Anticalins specifically detect ED-B both in fixed tumor specimen and on vital cells, as evidenced by cytofluorometry. Beyond that, we labeled an Anticalin with the gamma emitter (123) I and demonstrated specific binding to GBM-tissue samples using in vitro autoradiography. Overall, our data indicate that ED-B specific Anticalins are useful tools for the diagnosis of primary GBM and related angiogenic sites, presenting them as promising tracers for molecular tumor imaging. PMID- 26421426 TI - The Prognostic Significance of Metabolic Response Heterogeneity in Metastatic Colorectal Cancer. AB - BACKGROUND: Tumoral heterogeneity is a major determinant of resistance in solid tumors. FDG-PET/CT can identify early during chemotherapy non-responsive lesions within the whole body tumor load. This prospective multicentric proof-of-concept study explores intra-individual metabolic response (mR) heterogeneity as a treatment efficacy biomarker in chemorefractory metastatic colorectal cancer (mCRC). METHODS: Standardized FDG-PET/CT was performed at baseline and after the first cycle of combined sorafenib (600mg/day for 21 days, then 800mg/day) and capecitabine (1700 mg/m2/day administered D1-14 every 21 days). MR assessment was categorized according to the proportion of metabolically non-responding (non-mR) lesions (stable FDG uptake with SUVmax decrease <15%) among all measurable lesions. RESULTS: Ninety-two patients were included. The median overall survival (OS) and progression-free survival (PFS) were 8.2 months (95% CI: 6.8-10.5) and 4.2 months (95% CI: 3.4-4.8) respectively. In the 79 assessable patients, early PET-CT showed no metabolically refractory lesion in 47%, a heterogeneous mR with at least one non-mR lesion in 32%, and a consistent non-mR or early disease progression in 21%. On exploratory analysis, patients without any non-mR lesion showed a significantly longer PFS (HR 0.34; 95% CI: 0.21-0.56, P-value <0.001) and OS (HR 0.58; 95% CI: 0.36-0.92, P-value 0.02) compared to the other patients. The proportion of non-mR lesions within the tumor load did not impact PFS/OS. CONCLUSION: The presence of at least one metabolically refractory lesion is associated with a poorer outcome in advanced mCRC patients treated with combined sorafenib-capecitabine. Early detection of treatment-induced mR heterogeneity may represent an important predictive efficacy biomarker in mCRC. TRIAL REGISTRATION: ClinicalTrials.gov NCT01290926. PMID- 26421427 TI - Higher Lipoprotein (a) Levels Are Associated with Better Pulmonary Function in Community-Dwelling Older People - Data from the Berlin Aging Study II. AB - Reduced pulmonary function and elevated serum cholesterol levels are recognized risk factors for cardiovascular disease. Currently, there is some controversy concerning relationships between cholesterol, LDL-cholesterol, HDL-cholesterol, serum triglycerides and lung function. However, most previous studies compared patients suffering from chronic obstructive pulmonary disease (COPD) with healthy controls, and only a small number examined this relationship in population-based cohorts. Moreover, lipoprotein a [Lp(a)], another lipid parameter independently associated with cardiovascular diseases, appears not to have been addressed at all in studies of lung function at the population level. Here, we determined relationships between lung function and several lipid parameters including Lp(a) in 606 older community-dwelling participants (55.1% women, 68+/-4 years old) from the Berlin Aging Study II (BASE-II). We found a significantly lower forced expiration volume in 1 second (FEV1) in men with low Lp(a) concentrations (t test). This finding was further substantiated by linear regression models adjusting for known covariates, showing that these associations are statistically significant in both men and women. According to the highest adjusted model, men and women with Lp(a) levels below the 20th percentile had 217.3ml and 124.2ml less FEV1 and 239.0ml and 135.2ml less FVC, respectively, compared to participants with higher Lp(a) levels. The adjusted models also suggest that the known strong correlation between pro-inflammatory parameters and lung function has only a marginal impact on the Lp(a)-pulmonary function association. Our results do not support the hypothesis that higher Lp(a) levels are responsible for the increased CVD risk in people with reduced lung function, at least not in the group of community-dwelling older people studied here. PMID- 26421428 TI - Clinical Considerations of Preimplantation Genetic Diagnosis for Monogenic Diseases. AB - PURPOSE: The aim of this study was to explore factors contribute to the success of PGD cycles for monogenic diseases. METHODS: During a 3-year period (January 2009 to December 2012), 184 consecutive ICSI-PGD cycles for monogenic diseases reaching the ovum pick-up and fresh embryo-transfer stage performed at the Reproductive Medicine Center of The First Affiliated Hospital Of Sun Yat-sen University were evaluated. RESULTS: ICSI was performed on 2206 metaphase II oocytes, and normal fertilization and cleavage rates were 83.4% (1840/2206) and 96.2% (1770/1840), respectively. In the present study, 60.5% (181/299) of day 3 good-quality embryos developed into good-quality embryos on day 4 after biopsy. Collectively, 42.9% clinical pregnancy rate (79/184) and 28.5% implantation rate (111/389) were presented. In the adjusted linear regression model, the only two significant factors affecting the number of genetically unaffected embryos were the number of biopsied embryos (coefficient: 0.390, 95%CI 0.317-0.463, P = 0.000) and basal FSH level (coefficient: 0.198, 95%CI 0.031-0.365, P = 0.021). In the adjusted binary logistic regression model, the only two significant factors affecting pregnancy outcome were the number of genetically available transferable embryos after PGD (adjusted OR 1.345, 95% CI 1.148-1.575, P = 0.000) and number of oocyte retrieved (adjusted OR 0.934, 95% CI 0.877-0.994, P = 0.031). CONCLUSION: There should be at least four biopsied embryos to obtain at least one unaffected embryos in a PGD system for patients with single gene disorder and under the condition of basal FSH level smaller than 8.0mmol/L. Moreover, if only a low number (< 4) of biopsied embryos are available on day 3, the chance of unaffected embryos for transfer was small, with poor outcome. PMID- 26421429 TI - Non-Linear Characterisation of Cerebral Pressure-Flow Dynamics in Humans. AB - Cerebral metabolism is critically dependent on the regulation of cerebral blood flow (CBF), so it would be expected that vascular mechanisms that play a critical role in CBF regulation would be tightly conserved across individuals. However, the relationships between blood pressure (BP) and cerebral blood velocity fluctuations exhibit inter-individual variations consistent with heterogeneity in the integrity of CBF regulating systems. Here we sought to determine the nature and consistency of dynamic cerebral autoregulation (dCA) during the application of oscillatory lower body negative pressure (OLBNP). In 18 volunteers we recorded BP and middle cerebral artery blood flow velocity (MCAv) and examined the relationships between BP and MCAv fluctuations during 0.03, 0.05 and 0.07Hz OLBNP. dCA was characterised using project pursuit regression (PPR) and locally weighted scatterplot smoother (LOWESS) plots. Additionally, we proposed a piecewise regression method to statistically determine the presence of a dCA curve, which was defined as the presence of a restricted autoregulatory plateau shouldered by pressure-passive regions. Results show that LOWESS has similar explanatory power to that of PPR. However, we observed heterogeneous patterns of dynamic BP-MCAv relations with few individuals demonstrating clear evidence of a dCA central plateau. Thus, although BP explains a significant proportion of variance, dCA does not manifest as any single characteristic BP-MCAv function. PMID- 26421430 TI - Early Clinical Response after 2 Weeks of Sorafenib Therapy Predicts Outcomes and Anti-Tumor Response in Patients with Advanced Hepatocellular Carcinoma. AB - BACKGROUND & AIMS: We evaluated the relationship between the early clinical response after 2 weeks of sorafenib therapy and the outcomes and anti-tumor response in patients with advanced hepatocellular carcinoma. METHODS: Fifty-seven patients who had intrahepatic hypervascular hepatocellular carcinoma and Child Pugh (CP) class A disease at baseline were enrolled in this prospective, multicenter, observational, non-interventional study. As an early clinical response after 2 weeks of sorafenib therapy, changes in intra-tumor blood flow on contrast-enhanced computed tomography (CE-CT), alpha-fetoprotein (AFP) levels, and remnant liver function were investigated. RESULTS: After 2 weeks of sorafenib therapy, there were 26 patients (45.6%) without disappearance of arterial tumor enhancement on CE-CT, 15 patients (26.3%) with an AFP ratio of >1.2, and seven patients (12.3%) with two or more increments in the CP score. Multivariate analysis showed that the absence of disappearance of arterial tumor enhancement on CE-CT, AFP ratio of >1.2, and two or more increments in the CP score after 2 weeks of sorafenib therapy were significant and independent predictors of worse survival. Upon scoring these three variables as "poor prognostic factors", patients with poor prognostic score 4, 3 or 2 (n = 17) had significantly worse outcomes and a significantly higher progressive disease (PD) rate based on modified Response Evaluation Criteria in Solid Tumors at 6 weeks after sorafenib therapy than those with poor prognostic score 1 or 0 (n = 40) (median overall survival: 194 days vs. 378 days; p = 0.0010, PD rate: 70.6% vs. 20.0%; p = 0.0003, respectively). CONCLUSIONS: Changes in intra-tumor blood flow on CE-CT, AFP levels, and remnant liver function after 2 weeks of sorafenib therapy may be useful for predicting the outcomes and anti-tumor response to sorafenib in patients with advanced hepatocellular carcinoma. PMID- 26421431 TI - Angiogenic Factors and Doppler Evaluation in Normally Growing Fetuses at Routine Third-Trimester Scan: Prediction of Subsequent Low Birth Weight. AB - OBJECTIVE: To evaluate in normally growing fetuses at routine 32-36 weeks scan the performance of maternal angiogenic factors, Doppler and ultrasound indices in predicting smallness for gestational age (SGA) at birth. METHODS: A cohort of 1,000 singleton pregnancies with normal estimated fetal weight (EFW, >=10th centile) at 32-36 weeks scan was included. At inclusion, Doppler indices (mean uterine artery pulsatility index [mUtA-PI], cerebroplacental ratio and normalized umbilical vein blood flow by EFW (ml/min/kg) were evaluated, and blood samples were collected and frozen. Nested in this cohort, maternal circulating placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were assayed by enzyme-linked immunosorbent assay in all cases with a birth weight <10th centile by customized standards and in an equivalent number of controls (birth weight >=10th centile). RESULTS: 160 cases were included (80 SGA and 80 controls). EFW (2,128 vs. 2,279 g, p < 0.001), mUtA-PI z-values (-0.25 vs. -0.65, p = 0.034) and sFlt-1/PlGF ratio (11.10 vs. 6.74, p < 0.005) were lower in SGA. The combination of sFlt-1/PlGF ratio and EFW resulted in a 66.3% detection rate for subsequent SGA, with 20% of false-positives. Fetal Doppler indices were not predictive of SGA. CONCLUSIONS: In normally growing fetuses, maternal angiogenic factors add to ultrasound parameters in predicting subsequent SGA at birth. This supports further research to investigate composite scores in order to improve the definition and identification of fetal growth restriction. PMID- 26421432 TI - An Extremely Peramorphic Newt (Urodela: Salamandridae: Pleurodelini) from the Latest Oligocene of Germany, and a New Phylogenetic Analysis of Extant and Extinct Salamandrids. AB - We describe an Oligocene newt specimen from western Germany that has gone practically unnoticed in the literature despite having been housed in the Museum fur Naturkunde (Berlin) for a century. It is referable to the coeval Chelotriton, but is unusually peramorphic; for many characters it is more peramorphic than all other caudates or even all other lissamphibians. Most noticeable are the position of the jaw joints far caudal to the occiput, the honeycombed sculpture on the maxilla, and the possible presence of a septomaxilla (which would be unique among salamandrids). Referral to a species would require a revision of the genus, but the specimen likely does not belong to the type species. A phylogenetic analysis of nonmolecular characters of Salamandridae, far larger than all predecessors, confirms the referral to Chelotriton. It further loosely associates the Oligocene Archaeotriton and the Miocene Carpathotriton with the extant Lissotriton, though the former may alternatively lie outside Pleurodelinae altogether. The Miocene? I. randeckensis may not belong to the extant Ichthyosaura. The Miocene "Triturus" roehrsi is found neither with the extant Ommatotriton nor with Lissotriton, but inside an Asian/aquatic clade or, when geographic distribution is included as a character, as the sister-group to all other European molgins. The main cause for discrepancies between the results and the molecular consensus is not heterochrony, but adaptations to a life in mountain streams; this is the most likely reason why the Paleocene Koalliella from western Europe forms the sister group to some or all of the most aquatic extant newts in different analyses. We would like to urge neontologists working on salamandrids to pay renewed attention to the skeleton, not limited to the skull, as a source of diagnostic and phylogenetically informative characters. PMID- 26421433 TI - A Conservation-Based Approach to Compensation for Livestock Depredation: The Florida Panther Case Study. AB - Calf (Bos taurus) depredation by the federally endangered Florida panther (Puma concolor coryi) on ranches in southwest Florida is an important issue because ranches represent mixed landscapes that provide habitat critical to panther recovery. The objectives of this study were to (1) quantify calf depredation by panthers on two ranches in southwest Florida, and (2) develop a habitat suitability model to evaluate the quality of panther hunting habitat on ranchlands, assess whether the model could predict predation risk to calves, and discuss its potential to be incorporated into an incentive-based compensation program. We ear-tagged 409 calves with VHF transmitters on two ranches during 2011-2013 to document calf mortality. We developed a model to evaluate the quality of panther hunting habitat on private lands in southwest Florida using environmental variables obtained from the Florida Natural Areas Inventory (FNAI) Cooperative Landcover Database and nocturnal GPS locations of panthers provided by the Florida Fish and Wildlife Conservation Commission (FWC). We then tested whether the model could predict the location of calf depredation sites. Tagged calf loss to panthers varied between the two ranches (0.5%/yr to 5.3%/yr) and may have been influenced by the amount of panther hunting habitat on each ranch as the ranch that experienced higher depredation rates contained a significantly higher probability of panther presence. Depredation sites of tagged calves had a significantly greater probability of panther presence than depredation sites of untagged calves that were found by ranchers in open pastures. This suggests that there may be more calves killed in high risk environments than are being found and reported by ranchers and that panthers can hunt effectively in open environments. It also suggests that the model may provide a means for evaluating the quality of panther hunting habitat and the corresponding risk of depredation to livestock across the landscape. We suggest that our approach could be applied to prioritize and categorize private lands for participation in a Payment for Ecosystem Services program that compensates landowners for livestock loss and incentivizes conserving high quality habitat for large carnivores where livestock depredation is a concern. PMID- 26421434 TI - Hormetic Effect of Berberine Attenuates the Anticancer Activity of Chemotherapeutic Agents. AB - Hormesis is a phenomenon of biphasic dose response characterized by exhibiting stimulatory or beneficial effects at low doses and inhibitory or toxic effects at high doses. Increasing numbers of chemicals of various types have been shown to induce apparent hormetic effect on cancer cells. However, the underlying significance and mechanisms remain to be elucidated. Berberine, one of the major active components of Rhizoma coptidis, has been manifested with notable anticancer activities. This study aims to investigate the hormetic effect of berberine and its influence on the anticancer activities of chemotherapeutic agents. Our results demonstrated that berberine at low dose range (1.25 ~ 5 MUM) promoted cell proliferation to 112% ~170% of the untreated control in various cancer cells, while berberine at high dose rage (10 ~ 80 MUM) inhibited cell proliferation. Further, we observed that co-treatment with low dose berberine could significantly attenuate the anticancer activity of chemotherapeutic agents, including fluorouracil (5-FU), camptothecin (CPT), and paclitaxel (TAX). The hormetic effect and thereby the attenuated anticancer activity of chemotherapeutic drugs by berberine may attributable to the activated protective stress response in cancer cells triggered by berberine, as evidenced by up regulated MAPK/ERK1/2 and PI3K/AKT signaling pathways. These results provided important information to understand the potential side effects of hormesis, and suggested cautious application of natural compounds and relevant herbs in adjuvant treatment of cancer. PMID- 26421435 TI - The Influence of Infective Dose on the Virulence of a Generalist Pathogen in Rainbow Trout (Oncorhynchus mykiss) and Zebra Fish (Danio rerio). AB - Pathogen density and genetic diversity fluctuate in the outside-host environment during and between epidemics, affecting disease emergence and the severity and probability of infections. Although the importance of these factors for pathogen virulence and infection probability has been acknowledged, their interactive effects are not well understood. We studied how an infective dose in an environmentally transmitted opportunistic fish pathogen, Flavobacterium columnare, affects its virulence both in rainbow trout, which are frequently infected at fish farms, and in zebra fish, a host that is not naturally infected by F. columnare. We used previously isolated strains of confirmed high and low virulence in a single infection and in a co-infection. Infection success (measured as host morbidity) correlated positively with dose when the hosts were exposed to the high-virulence strain, but no response for the dose increase was found when the hosts were exposed to the low-virulence strain. Interestingly, the co-infection resulted in poorer infection success than the single infection with the high-virulence strain. The rainbow trout were more susceptible to the infection than the zebra fish but, in both species, the effects of the doses and the strains were qualitatively similar. We suggest that as an increase in dose can lead to increased host morbidity, both the interstrain interactions and differences in infectivity in different hosts may influence the severity and consequently the evolution of disease. Our results also confirm that the zebra fish is a good laboratory model to study F. columnare infection. PMID- 26421436 TI - Local Pain Dynamics during Constant Exhaustive Exercise. AB - The purpose of this study was to delineate the topological dynamics of pain and discomfort during constant exercise performed until volitional exhaustion. Eleven physical education students were tested while cycling and running at a "hard" intensity level (e.g., corresponding to Borg's RPE (6-20) = 15). During the tests, participants reported their discomfort and pain on a body map every 15s. "Time on task" for each participant was divided into five equal non-overlapping temporal windows within which their ratings were considered for analysis. The analyses revealed that the number of body locations with perceived pain and discomfort increased throughout the five temporal windows until reaching the mean (+/- SE) values of 4.2 +/- 0.7 and 4.1 +/- 0.6 in cycling and running, respectively. The dominant locations included the quadriceps and hamstrings during cycling and quadriceps and chest during running. In conclusion, pain seemed to spread throughout the body during constant cycling and running performed up to volitional exhaustion with differences between cycling and running in the upper body but not in the lower body dynamics. PMID- 26421437 TI - Sputtering Yields for Mixtures of Organic Materials Using Argon Gas Cluster Ions. AB - The sputtering yield volumes of binary mixtures of Irganox 1010 with either Irganox 1098 or Fmoc-pentafluoro-L-phenylalanine (FMOC) have been measured for 5 keV Ar2000(+) ions incident at 45 degrees to the surface normal. The sputtering yields are determined from the doses to sputter through various compositions of 100 nm thick, intimately mixed, layers. Because of matrix effects, the profiles for secondary ions are distorted, and profile shifts in depth of 15 nm are observed leading to errors above 20% in the deduced sputtering yield. Secondary ions are selected to avoid this. The sputtering yield volumes for the mixtures are shown to be lower than those deduced from a linear interpolation from the pure materials. This is shown to be consistent with a simple model involving the changing energy absorbed for the sputtering of intimate mixtures. Evidence to support this comes from the secondary ion data for pairs of the different molecules. Both binary mixtures behave similarly, but matrix effects are stronger for the Irganox 1010/FMOC system. PMID- 26421438 TI - EPR Distance Measurements in Native Proteins with Genetically Encoded Spin Labels. AB - The genetic encoding of nitroxide amino acids in combination with electron paramagnetic resonance (EPR) distance measurements enables precise structural studies of native proteins, i.e. without the need for mutations to create unique reactive sites for chemical labeling and thus with minimal structural perturbation. We here report on in vitro DEER measurements in native E. coli thioredoxin (TRX) that establish the nitroxide amino acid SLK-1 as a spectroscopic probe that reports distances and conformational flexibilities in the enzyme with nonmutated catalytic centers that are not accessible by the use of the traditional methanethiosulfonate spin label (MTSSL). We generated a rotamer library for SLK-1 that in combination with molecular dynamics (MD) simulation enables predictions of distance distributions between two SLK-1 labels incorporated into a target protein. Toward a routine use of SLK-1 for EPR distance measurements in proteins and the advancement of the approach to intracellular environments, we study the stability of SLK-1 in E. coli cultures and lysates and establish guidelines for protein expression and purification that offer maximal nitroxide stability. These advancements and insights provide new perspectives for facile structural studies of native, endogenous proteins by EPR distance measurements. PMID- 26421439 TI - A Journey toward Sulfolane Microemulsions Suggested as Inert, Nonaqueous Reaction Media. AB - Recently, it turned out that nanostructured reaction media containing highly inert solvents as tetrahydrothiophen-1,1-dioxide (sulfolane) are beneficial for strongly oxidizing or reductive reactions. Because of their ability of solubilizing polar and nonpolar solvents with a large nanostructured interface in particular microemulsions provide such interesting reaction media. Starting from the pseudoternary microemulsion H2O-n-octane-C12E4/C12E5 (polyoxyethylene n-alkyl ether), water was successively replaced by the highly inert tetrahydrothiophen 1,1-dioxide (sulfolane). We found that an increasing sulfolane content drives the system beyond the tricritical point. Replacing the already long chain surfactants C12E4 and C12E5 by a mixture of the even longer chain surfactants C18E6 and C18E8, we were able to prepare nonaqueous sulfolane microemulsions for the first time. We also teach how in a second step the phase behavior of the hydrophilic sulfolane-n-octane-C18E8 system can be tuned at constant temperature (as required by the reaction conditions) by addition of the hydrophobic cosurfactant 1-octanol (C8E0). The change in curvature that occurs by adding 1-octanol is demonstrated measuring the size of reverse micelles by DLS. We found that the radius varies from at least 8 to 16 nm, a suitable sizes for inverse nanoreaction vessels. PMID- 26421440 TI - The combination of gold nanorods and nanoparticles with DNA nanodevices for logic gates construction. AB - In this work, two DNA nanodevices were constructed utilizing a DNA strand displacement reaction. With the assistance of gold nanoparticles (AuNPs) and gold nanorods (AuNRs), the autonomous reactions can be reflected from the aggregation states of nanoparticles. By sequence design and the two non-overlapping double hump-like UV-vis spectral peaks of AuNPs and AuNRs, two logic gates with multiple inputs and outputs were successfully run with expected outcomes. This method not only shows how to achieve computing with multiple logic calculations but also has great potential for multiple targets detection. PMID- 26421441 TI - Crystallographic Characterization of II-VI Semiconducting Nanostructures via Optical Second Harmonic Generation. AB - We demonstrate the utility of optical second harmonic generation (SHG) polarimetry to perform structural characterization of noncentrosymmetric, single crystalline II-VI semiconducting nanowires, nanobelts, and nanoflakes. By analyzing anisotropic SHG polarimetric patterns, we distinguish between wurtzite and zincblende II-VI semiconducting crystal structures and determine their growth orientation. The crystallography of these nanostructures was then confirmed via transmission electron microscopy measurements performed on the same system. In addition, we show that some intrinsic material properties such as nonlinear coefficients and geometry-dependent optical in-coupling coefficients can also be determined from the SHG experiments in WZ nanobelts. The ability to perform SHG based structural characterization and crystallographic study of II-VI semiconducting single-crystalline nanomaterials will be useful to correlate structure-property relationships of nanodevices on which transmission electron microscopy measurements cannot be typically performed. PMID- 26421442 TI - Coordinate Activation of Redox-Dependent ASK1/TGF-beta Signaling by a Multiprotein Complex (MPK38, ASK1, SMADs, ZPR9, and TRX) Improves Glucose and Lipid Metabolism in Mice. AB - AIMS: To explore the molecular connections between redox-dependent apoptosis signal-regulating kinase 1 (ASK1) and transforming growth factor-beta (TGF-beta) signaling pathways and to examine the physiological processes in which coordinated regulation of these two signaling pathways plays a critical role. RESULTS: We provide evidence that the ASK1 and TGF-beta signaling pathways are interconnected by a multiprotein complex harboring murine protein serine threonine kinase 38 (MPK38), ASK1, Sma- and Mad-related proteins (SMADs), zinc finger-like protein 9 (ZPR9), and thioredoxin (TRX) and demonstrate that the activation of either ASK1 or TGF-beta activity is sufficient to activate both the redox-dependent ASK1 and TGF-beta signaling pathways. Physiologically, the restoration of the downregulated activation levels of ASK1 and TGF-beta signaling in genetically and diet-induced obese mice by adenoviral delivery of SMAD3 or ZPR9 results in the amelioration of adiposity, hyperglycemia, hyperlipidemia, and impaired ketogenesis. INNOVATION AND CONCLUSION: Our data suggest that the multiprotein complex linking ASK1 and TGF-beta signaling pathways may be a potential target for redox-mediated metabolic complications. PMID- 26421443 TI - alpha-Quaternary Proline Derivatives by Intramolecular Diastereoselective Arylation of N-Carboxamido Proline Ester Enolates. AB - Pyrrolidine-2-carboxylate esters substituted in the 3-, 4- or 5-positions were converted to their N'-aryl urea derivatives. Deprotonation at the 2-position to form a potassium enolate led to migration of the N'-aryl substituent to the 2 position of the pyrrolidine ring, followed by cyclization of the resulting urea to give bicyclic alpha-aryl hydantoin derivatives of substituted prolines. Depending on the substitution pattern of the starting material, high diastereoselectivity was observed in the aryl migration, allowing formation of the products in enantiomerically enriched form, despite the intermediacy of a planar enolate. The hydrolysis of the bicyclic hydantoins under basic conditions gave a range of enantiopure and enantioenriched quaternary alpha-aryl proline derivatives. PMID- 26421444 TI - Examining the Process of Responding to Circumplex Scales of Interpersonal Values Items: Should Ideal Point Scoring Methods Be Considered? AB - The Circumplex Scales of Interpersonal Values (CSIV) is a 64-item self-report measure of goals from each octant of the interpersonal circumplex. We used item response theory methods to compare whether dominance models or ideal point models best described how people respond to CSIV items. Specifically, we fit a polytomous dominance model called the generalized partial credit model and an ideal point model of similar complexity called the generalized graded unfolding model to the responses of 1,893 college students. The results of both graphical comparisons of item characteristic curves and statistical comparisons of model fit suggested that an ideal point model best describes the process of responding to CSIV items. The different models produced different rank orderings of high scoring respondents, but overall the models did not differ in their prediction of criterion variables (agentic and communal interpersonal traits and implicit motives). PMID- 26421445 TI - The impact of intrauterine infection on fetal brain damage assessed by S100B protein concentrations in umbilical cord arteries. AB - OBJECTIVE: To assess the impact of intrauterine infection on fetal brain damage by measuring S100B protein concentration in umbilical cord arteries. METHODS: In the intrauterine infection cases determined by pathology of 25 deliveries (Group I) and non-infection cases of 35 deliveries as control (Group C), we compared gestational age at delivery, birth weight, fetal heart rate monitoring during labor, Apgar score, umbilical cord artery pH and S100B protein concentrations in umbilical arteries measured by two-site immunoradiometric assay kit. RESULTS: (1) There was no significant correlation between pH and concentration of S100B protein. (2) Gestational age at delivery was found to be earlier in Group I, resulting in lower birth weights, when compared with Group C. (3) There was no significant difference between two groups concerning Apgar scores, pH. (4) S100B protein concentrations in Group I was significantly higher than those of Group C (3.9 7 +/- 0.66 versus 1.8 9 +/- 0.56 MUg/L, p < 0.05). (5) The concentration of S100B protein in severe chorioamnionitis (CAM) cases were significantly higher than those of mild CAM and control cases. CONCLUSION: Higher concentration of S100B protein in Group I suggests that intrauterine infection itself has a serious risk factor on fetal brain damage. PMID- 26421446 TI - The use and safety of medications known to affect driving in Jordan: A cross sectional study. AB - OBJECTIVES: The aim of this study was to estimate the main driving-impairing medications used by drivers in Jordan, the reported frequency of medication side effects, the frequency of motor vehicle crashes (MVCs) while using driving impairing medicines, as well as factors associated with MVCs. METHODS: A cross sectional study involving 1,049 individuals (age 18-75 years) who are actively driving vehicles and taking at least one medication known to affect driving (anxiolytics, antidepressants, hypnotics, antiepileptics, opioids, sedating antihistamines, hypoglycemic agents, antihypertensives, central nervous system [CNS] stimulants, and herbals with CNS-related effects) was conducted in Amman, Jordan, over a period of 8 months (September 2013-May 2014) using a structured validated questionnaire. RESULTS: Sixty-three percent of participants noticed a link between a medicine taken and feeling sleepy and 57% stated that they experience at least one adverse effect other than sleepiness from their medication. About 22% of the participants reported having a MVC while on medication. Multiple logistic regression analysis showed that among the participants who reported having a crash while taking a driving-impairing medication, the odds ratios were significantly higher for the use of inhalant substance (odds ratio [OR] = 2.787, P = .014), having chronic conditions (OR = 1.869, P = .001), and use of antiepileptic medications (OR = 2.348, P = .008) and significantly lower for the use of antihypertensives (OR = 0.533, P = .008). CONCLUSION: The study results show high prevalence of adverse effects of medications with potential for driving impairment, including involvement in MVCs. Our findings highlight the types of patient-related and medication-related factors associated with MVCs in Jordan, such as inhalant use, presence of chronic conditions, and use of antiepileptics. PMID- 26421447 TI - The Stimulatory Effect of Notochordal Cell-Conditioned Medium in a Nucleus Pulposus Explant Culture. AB - OBJECTIVES: Notochordal cell-conditioned medium (NCCM) has previously shown to have a stimulatory effect on nucleus pulposus cells (NPCs) and bone marrow stromal cells (BMSCs) in alginate and pellet cultures. These culture methods provide a different environment than the nucleus pulposus (NP) tissue, in which the NCCM ultimately should exert its effect. The objective of this study is to test whether NCCM stimulates NPCs within their native environment, and whether combined stimulation with NCCM and addition of BMSCs has a synergistic effect on extracellular matrix production. METHODS: Bovine NP tissue was cultured in an artificial annulus in base medium (BM), porcine NCCM, or BM supplemented with 1 MUg/mL Link N. Furthermore, BM and NCCM samples were injected with 10(6) BMSCs per NP sample. Samples were cultured for 4 weeks, and analyzed for biochemical contents (water, glycosaminoglycan [GAG], hydroxyproline, and DNA), gene expression (COL1A1, COL2A1, ACAN, and SOX9), and histology by Safranin O/Fast Green staining. RESULTS: Culture in NCCM resulted in increased proteoglycan content compared to day 0 and BM, similar to Link N. However, only minor differences in gene expression compared to day 0 were observed. Addition of BMSCs did not result in increased GAG content, and surprisingly, DNA content in BMSC injected groups was not higher than in the other groups after 4 weeks of culture. DISCUSSION: This study shows that, indeed, NCCM is capable of stimulating NPC matrix production within the NP environment. The lack of increased DNA content in the BMSC-injected groups indicates that BMSCs have died over time. Identification of the bioactive factors in NCCM is crucial for further development of an NCCM based treatment for intervertebral disc regeneration. PMID- 26421448 TI - The Influence of Social and Nonsocial Variables on the Simon Effect. AB - Recently, the Simon effect (SE) has been observed in social contexts when two individuals share a two-choice task. This joint SE (JSE) has been interpreted as evidence that people co-represent their actions. However, it is still not clear if the JSE is driven by social factors or low-level mechanisms. To address this question, we applied a common paradigm to a joint Simon task (Experiments 1 and 4), a standard Simon task (Experiment 2), and a go/no-go task (Experiment 3). The results showed that both the JSE and the SE were modulated by the repetition/non repetition of task features. Moreover, the JSE was differently modulated by the gender composition of the two individuals involved in the shared task and by their interpersonal relationship. Taken together, our results do not support a pure social explanation of the JSE, nevertheless, they show the independent role of different social factors in modulating the effect. PMID- 26421449 TI - Change Detection in Visual Short-Term Memory: The Relative Impact of Pairwise Switches and Identity Substitutions. AB - Numerous kinds of visual event challenge our ability to keep track of the objects that populate our visual environment from moment to moment. These include blinks, occlusion, shifting visual attention, and changes to object's visual and spatial properties over time. These visual events may lead to objects falling out of our visual awareness, but can also lead to unnoticed changes, such as undetected object replacements and positional exchanges. Current visual memory models do not predict which visual changes are likely to be the most difficult to detect. We examine the accuracy with which switches (where two objects exchange locations) and substitutions (where one or two objects are replaced) are detected. Inferior performance for one-object substitutions versus two-objects switches, along with superior performance for two-object substitutions versus two-object switches was found. Our results are interpreted in terms of object file theory, trade-offs between diffused and localized attention, and net visual change. PMID- 26421450 TI - Tactile Stimuli Increase Effects of Modality Compatibility in Task Switching. AB - Modality compatibility refers to the similarity of stimulus modality and modality of response-related sensory consequences. Previous dual-task studies found increased switch costs for modality incompatible tasks (auditory-manual/visual vocal) compared to modality compatible tasks (auditory-vocal/visual-manual). The present task-switching study further examined modality compatibility and investigated vibrotactile stimulation as a novel alternative to visual stimulation. Interestingly, a stronger modality compatibility effect on switch costs was revealed for the group with tactile-auditory stimulation compared to the visual-auditory stimulation group. We suggest that the modality compatibility effect is based on crosstalk of central processing codes due to ideomotor "backward" linkages between the anticipated response effects and the stimuli indicating this response. This crosstalk is increased in the tactile-auditory stimulus group compared to the visual-auditory stimulus group due to a higher degree of ideomotor-compatibility in the tactile-manual tasks. Since crosstalk arises between tasks, performance is only affected in task switching and not in single tasks. PMID- 26421452 TI - Additional Post-Concussion Impact Exposure May Affect Recovery in Adolescent Athletes. AB - Repeat concussion has been associated with risk for prolonged and pronounced clinical recovery in athletes. In this study of adolescent athletes, we examined whether an additional head impact within 24 h of a sports-related concussion (SRC) is associated with higher symptom burden and prolonged clinical recovery compared with a single-injury group. Forty-two student-athletes (52% male, mean age = 14.9 years) diagnosed with an SRC in a concussion clinic were selected for this study: (1) 21 athletes who sustained an additional significant head impact within 24 h of the initial injury (additional-impact group); (2) 21 single-injury athletes, age and gender matched, who sustained only one discrete concussive blow to the head (single-injury group). Groups did not differ on initial injury characteristics or pre-injury risk factors. The effect of injury status (single- vs. additional-impact) was examined on athlete- and parent-reported symptom burden (at first clinic visit) and length of recovery (LOR). Higher symptom burden was reported by the athletes and parents in the additional-impact group at the time of first visit. The additional-impact group also had a significantly longer LOR compared with the single-injury group. These findings provide preliminary, hypothesis-generating evidence for the importance of immediate removal from play following an SRC to protect athletes from re-injury, which may worsen symptoms and prolong recovery. The retrospective study design from a specialized clinical sample points to the need for future prospective studies of the relationship between single- and additional-impact injuries on symptom burden and LOR. PMID- 26421454 TI - Protein extraction methods of tomato, environmental changes of the Amazon Forest in Roraima (northernmost part of Brazil) for the last 1000 years, and histological characteristics of a dolphin species. PMID- 26421453 TI - Clinicopathologic features and outcomes of lymphoplasmacytic lymphoma patients with monoclonal IgG or IgA paraprotein expression. AB - Lymphoplasmacytic lymphoma secreting IgG or IgA (non-IgM LPL) is rarely seen. Systematic studies of the clinical features and treatment outcomes are lacking in these patients. This study evaluated 17 patients with non-IgM LPL. The paraprotein secreted by these tumors was IgA (n=8; 47%) and IgG (n=9; 53%). The median serum level of paraprotein was 2,475 mg/dl (range=747-5260) for IgA and 2580 mg/dl (range=1900-7100) for IgG. The IgA-LPL group was more likely to present with B symptoms, a high beta2-microglobulin level and extramedullary involvement. Compared with patients with Waldenstrom macroglobulinemia (WM), patients with non-IgM LPL showed similar clinical and pathologic features, but a higher mortality within the first year after diagnosis (p<0.001) and worse overall survival (p=0.024), with no difference in progression-free survival and disease-specific survival. Rituximab alone or rituximab-based therapy was used frequently and was effective as either first-line or salvage therapy. PMID- 26421455 TI - Infinitesimal Hartman-Grobman Theorem in Dimension Three. AB - In this paper we give the main ideas to show that a real analytic vector field in R3 with a singular point at the origin is locally topologically equivalent to its principal part defined through Newton polyhedra under non-degeneracy conditions. PMID- 26421456 TI - An Analysis of Total Phosphorus Dispersion in Lake Used As a Municipal Water Supply. AB - In Belem city is located the potable water supply system of its metropolitan area, which includes, in addition to this city, four more municipalities. In this water supply complex is the Agua Preta lake, which serves as a reservoir for the water pumped from the Guama river. Due to the great importance of this lake for this system, several works have been devoted to its study, from the monitoring of the quality of its waters to its hydrodynamic modeling. This paper presents the results obtained by computer simulation of the phosphorus dispersion within this reservoir by the numerical solution of two-dimensional equation of advection diffusion-reaction by the method theta/SUPG. Comparing these results with data concentration of total phosphorus collected from November 2008 to October 2009 and from satellite photos show that the biggest polluters of the water of this lake are the domestic sewage dumps from the population living in its vicinity. The results obtained indicate the need for more information for more precise quantitative analysis. However, they show that the phosphorus brought by the Guama river water is consumed in an area adjacent to the canal that carries this water into the lake. Phosphorus deposits in the lake bottom should be monitored to verify their behavior, thus preventing the quality of water maintained therein. PMID- 26421457 TI - Linking environmental drivers with amphibian species diversity in ponds from subtropical grasslands. AB - Amphibian distribution patterns are known to be influenced by habitat diversity at breeding sites. Thus, breeding sites variability and how such variability influences anuran diversity is important. Here, we examine which characteristics at breeding sites are most influential on anuran diversity in grasslands associated with Araucaria forest, southern Brazil, especially in places at risk due to anthropic activities. We evaluate the associations between habitat heterogeneity and anuran species diversity in nine body of water from September 2008 to March 2010, in 12 field campaigns in which 16 species of anurans were found. Of the seven habitat descriptors we examined, water depth, pond surface area and distance to the nearest forest fragment explained 81% of total species diversity. Water depth, margin vegetation type, surface area and distance to the next body of water explained between 31-74% of the variance in abundance of nine of the 16 species. Thus, maintenance of body of water, of the vegetation along the water edge and natural forest fragments in the grasslands, along with fire control (used to renovation of pasture), are fundamentally important for the maintenance of anuran species diversity through the conservation of their breeding sites. PMID- 26421458 TI - Antioxidant status in women with uterine leiomyoma: relation with sex hormones. AB - Uterine leiomyomas are benign soft-tissues tumors that arise from uterine smooth muscle tissue. Etiopathogenesis of leiomyomas is not well understood. We aimed to examine whether antioxidant enzyme activities and lipid hydroperoxides level in patients with leiomyoma are influenced by changes in sex hormones and gonadotropins (estradiol (E2), progesterone, FSH, and LH) during menstrual cycle and in postmenopause. The material consisted of blood and uterine tissue specimens. Hormone concentrations were determined and assays for superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities and lipid hydroperoxides concentration were performed. In blood of examined women, a significant difference in catalase, glutathione peroxidase and glutathione reductase activity was recorded among the phases. There was also a positive correlation between the estradiol/progesterone concentration and the catalase activity. Progesterone negatively correlated with lipid hydroperoxides level. In myoma tissue, we recorded a phase-related difference in lipid hydroperoxides level and activities of superoxide dismutase, glutathione peroxidase activities, and glutathione reductase. Negative correlation was observed between FSH and glutathione peroxidase. The results suggest that antioxidant status in patients with uterine leiomyoma is influenced by the changes in sex hormones during the menstrual cycle and in postmenopause, indicating a role of the observed relationship in the leiomyoma etiology. PMID- 26421459 TI - Growing a New Study: Environmental Influences on Child Health Outcomes. PMID- 26421460 TI - Q Fever Outbreak Among Travelers to Germany Who Received Live Cell Therapy- United States and Canada, 2014. AB - During September-November 2014, the New York State Department of Health (NYSDOH) was notified of five New York state residents who had tested seropositive for Coxiella burnetii, the causative agent of Q fever. All five patients had symptoms compatible with Q fever (e.g., fever, fatigue, chills, and headache) and a history of travel to Germany to receive a medical treatment called "live cell therapy" (sometimes called "fresh cell therapy") in May 2014. Live cell therapy is the practice of injecting processed cells from organs or fetuses of nonhuman animals (e.g., sheep) into human recipients. It is advertised to treat a variety of health conditions. This practice is unavailable in the United States; however, persons can travel to foreign locations to receive injections. Local health departments interviewed the patients, and NYSDOH notified CDC and posted a report on CDC's Epidemic Information Exchange to solicit additional cases. Clinical and exposure information for each patient was reported to the Robert Koch Institute in Germany, which forwarded the information to local health authorities. A Canada resident who also received live cell therapy in May 2014 was diagnosed with Q fever in July 2014. Clinicians should be aware of health risks, such as Q fever and other zoonotic diseases, among patients with a history of receiving treatment with live cell therapy products. PMID- 26421461 TI - Effectiveness, Good Tolerability, and High Compliance of Doses of Risperidone Long-Acting Injectable Higher Than 75 mg in People With Severe Schizophrenia: A 3 Year Follow-Up. AB - Tolerability and effectiveness of antipsychotics are important to increase treatment compliance in people with schizophrenia. The aim of this study was to evaluate effectiveness, tolerability, and adherence to treatment with high doses of risperidone long-acting injectable (RLAI) in patients with severe schizophrenia.It is a 3-year prospective, observational study of patients with severe (Clinical Global Impression Severity scale [CGI-S] score of >=5) schizophrenia according to International Classification of Diseases (ICD-10) criteria. Subjects were the consecutive 60 who first underwent treatment with RLAI with doses of 75 mg or higher every 14 days to get clinical stabilization.Assessment included the following: CGI-S, World Health Organization Disability Assessment Schedule, Camberwell Assessment of Need (CAN), Medication Adherence Rating Scale, laboratory tests, weight, and hospital admissions.The mean (SD) dose of RLAI was 111.2 (9.1) mg per 14 days. Tolerability was good and there were almost no interruptions due to adverse effects or to relevant biological parameters alterations. Also, weight gain was not significant.Retention rate in treatment after 3 years was 95%. Clinical Global Impression Severity (P < 0.01) and Camberwell Assessment of Need (P < 0.01) decreased and also Disability Assessment Schedule in the 4 areas (P < 0.01). Medication Adherence Rating Scale score increased from 3.6 (0.7) to 8.9 (0.9) (P < 0.001). There were significantly few hospital admissions than during the previous 36 months (1.9 [1.3] vs 0.31 [0.2], P < 0.001).As a conclusion, we highlight that the effectiveness and tolerability of 75 mg or higher every 14 days of RLAI were high, being useful in improving treatment adherence in patients with severe schizophrenia, getting good clinical and functional outcomes. PMID- 26421462 TI - Treatment of relapsed urothelial bladder cancer with vinflunine: real-world evidence by the Hellenic Genitourinary Cancer Group. AB - Relapsed urothelial cancer represents an unmet medical need. Vinflunine is a third-generation antimicrotubuline inhibitor and is currently the only approved drug for second-line treatment across the European Union. We conducted a retrospective analysis assessing the efficacy and safety of vinflunine in 71 Greek patients with relapsed urothelial cancer who were treated between 2005 and 2014. An overall 84% of our patients received vinflunine as second-line treatment, 77% had a performance status of Eastern Cooperative Oncology Group scale 0 or 1, and 30% had liver metastasis at the time of vinflunine administration. A median of four cycles of vinflunine were administered (range 1 16). The most common reported adverse events were constipation, fatigue, and anemia. Median progression-free survival was 6.2 months (95% confidence interval: 4.4-8.8) and overall survival was 11.9 months (95% confidence interval: 7.4-21). Two patients (3%) achieved a complete remission, seven a partial remission (10%), and 22 (31%) had stable disease according to an intention-to-treat analysis. Hemoglobin level less than 10 g/dl and Eastern Cooperative Oncology Group performance status greater than 1 were independent adverse prognostic factors. Stratification according to the Bellmunt risk model was also associated with progression-free survival and overall survival in our population. Vinflunine appears to be a safe and effective treatment modality for relapsed urothelial cancer. More effective therapies and more accurate prognostic algorithms should be sought. PMID- 26421463 TI - Glycodendrimersomes from Sequence-Defined Janus Glycodendrimers Reveal High Activity and Sensor Capacity for the Agglutination by Natural Variants of Human Lectins. AB - A library of eight amphiphilic Janus glycodendrimers (Janus-GDs) presenting D lactose (Lac) and a combination of Lac with up to eight methoxytriethoxy (3EO) units in a sequence-defined arrangement was synthesized via an iterative modular methodology. The length of the linker between Lac and the hydrophobic part of the Janus-GDs was also varied. Self-assembly by injection from THF solution into phosphate-buffered saline led to unilamellar, monodisperse glycodendrimersomes (GDSs) with dimensions predicted by Janus-GD concentration. These GDSs provided a toolbox to measure bioactivity profiles in agglutination assays with sugar binding proteins (lectins). Three naturally occurring forms of the human adhesion/growth-regulatory lectin galectin-8, Gal-8S and Gal-8L, which differ by the length of linker connecting their two active domains, and a single amino acid mutant (F19Y), were used as probes to study activity and sensor capacity. Unpredictably, the sequence of Lac on the Janus-GDs was demonstrated to determine bioactivity, with the highest level revealed for a Janus-GD with six 3EO groups and one Lac. A further increase in Lac density was invariably accompanied by a substantial decrease in agglutination, whereas a decrease in Lac density resulted in similar or lower bioactivity and sensor capacity. Both changes in topology of Lac presentation of the GDSs and seemingly subtle alterations in protein structure resulted in different levels of bioactivity, demonstrating the presence of regulation on both GDS surface and lectin. These results illustrate the applicability of Janus-GDs to dissect structure-activity relationships between programmable cell surface models and human lectins in a highly sensitive and physiologically relevant manner. PMID- 26421464 TI - Isolated sphenoid sinus disease: An overlooked cause of headache. AB - OBJECTIVES: The aim of this study was to evaluate patients who underwent endoscopic sphenoid sinus surgery for isolated sphenoid sinus disease. We also investigated the impact of sphenoid sinus surgery on headache intensity. MATERIAL AND METHODS: Twenty-one consecutive patients who underwent endoscopic sphenoidotomy for isolated sphenoid sinus disease were included in the study. Diagnosis of isolated sphenoid sinus pathology was based on history, physical examination, and radiologic evaluation. All patients had headache with various localizations. Pre- and postoperative headache intensity of patients was scored using a visual analogue scale (VAS). RESULTS: The most common location of headache was the vertex (24%). The preoperative and postoperative mean VAS scores for headache were 8.24 +/- 0.94 and 2.67 +/- 1.49, respectively. Statistical comparison revealed a significant improvement in headache intensity (p < 0.01). Polyps (33.3%) were the most common pathology, followed by inflammation (23.8%). CONCLUSIONS: The most common presenting symptom of isolated sphenoid sinus disease is headache. In this study, we demonstrated that headache induced by isolated sphenoid disease can be relieved by endoscopic sphenoidotomy. Sphenoid sinus disease should be considered in the differential diagnosis of patients presenting with subacute or chronic headache. PMID- 26421465 TI - Ibandronate treatment of diffuse sclerosing osteomyelitis of the mandible: Pain relief and insight into pathogenesis. AB - PURPOSE: Diffuse sclerosing osteomyelitis of the mandible (DSO) is a rare and poorly understood disease. Current treatment protocols, including steroid or analgesic medication and corticotomies, show poor or frustrating outcome results and are accompanied by potentially severe side effects. The aim of this study was to determine whether there is a beneficial role of infusions with nitrogen containing bisphosphonates (ibandronate) in acute conditions of DSO. MATERIAL AND METHODS: Eleven patients were enrolled in the study. In acute conditions of treatment-resistant DSO, single-shot infusions of ibandronate (6 mg) were administered. Pain levels were documented 10 days before and after the infusion on a visual analogue scale (VAS). Patients were monitored regularly. RESULTS: Of the 11 patients, 10 showed a distinct improvement in pain (based on VAS scores) within 48-72 h after infusion. The pain levels of the patients were significantly lower after ibandronate infusions (p < 0.01). The majority of patients were free or almost free of complaints over the following months. Four of the 11 patients returned for repeated infusions. At the time of writing, no severe side effects have been observed, and in particular there has been no case of medication related jaw osteonecrosis. CONCLUSION: We conclude that single-shot bisphosphonate infusions on demand are promising treatment alternatives in acute DSO. Single-shot bisphosphonate infusions of ibandronate were well tolerated and resulted in distinct, long lasting improvement in subjective pain levels based on VAS scores. PMID- 26421466 TI - The association of cleft severity and cleft palate repair technique on hearing outcomes in children in northern Finland. AB - BACKGROUND: The consequences of cleft lip and palate include scaring, dental malformations, tooth misalignment, speech problems, and hearing loss. Otitis media with effusion causing hearing loss is a problem for many cleft palate patients. METHODS: This study examines the association among cleft severity, palate repair technique, and hearing outcomes in children from northern Finland with clefts, aged 3-9 years. The study included 90 cleft patients who were treated at the Oulu University Hospital Cleft Lip and Palate Center between 1998 and 2011. The severity of the cleft, the surgical technique used to repair the palate, audiogram configuration data, and the need for ventilation tube placement were determined retrospectively from patient records. RESULTS: Only 3.3% of cleft patients had an abnormal pure tone average hearing threshold representing abnormal hearing. Neither the surgical technique used to repair the cleft palate nor the severity of the cleft was a significant factor related to hearing loss or to the number of ventilation tubes required. Hearing improved significantly with increasing age over a span of 6 years. CONCLUSIONS: Continuous follow-up with proactive placement of ventilation tubes before or at the time of palatoplasty results in hearing outcomes in cleft children that are similar to those reported in non-cleft children. PMID- 26421467 TI - Surgical learning curve in performing palatoplasty: A retrospective study in 200 patients. AB - OBJECTIVES: The aim of the study was to assess the influence of the experience of the surgeon on the occurrence of fistulas following palatoplasty. MATERIALS AND METHODS: A retrospective review was performed of consecutive children treated between 2006 and 2013 for cleft palate by a single surgeon. Cleft palate repair was performed using the von Langenbeck technique, Furlow palatoplasty, buccal flap or Vomer flap. Data was collected for age, sex, date of birth, syndrome, adoption, cleft palate type, type of repair, cleft width, fistula occurrence and location of fistula. RESULTS: A total of 276 operations were performed in 200 children (Veau I, II, III, IV). Mean age at surgery was 21.9 months (range: 6.2 months to 26 years 8.3 months). Postoperatively, palatal fistulas occurred in eight patients (4.0%), however, the incidence was 3.0% in the non-adoption group and 9.7% in the adoption population. In this study there was no statistically significant evidence of a surgical learning curve, and no significant associations between fistula rate and sex, adoption, syndrome, cleft type, cleft width, or type of repair. CONCLUSION AND CLINICAL RELEVANCE: This study demonstrates a fistula formation rate of 3.0% for the non-adoption population and 9.7% for the adoption population. There was no statistically significant evidence of a learning curve during the first few years of performing cleft palate repair. No other independent risk factors for postoperative fistula formation were identified; however, the benefit of a vomer flap and subsequent reduction in fistula incidence was demonstrated. PMID- 26421468 TI - Three-dimensional quantitative evaluation of midfacial skeletal changes after trans-sutural distraction osteogenesis for midfacial hypoplasia in growing patients with cleft lip and palate. AB - PURPOSE: Trans-sutural distraction osteogenesis (TSDO) is an alternative method for the early treatment of midfacial hypoplasia in growing patients with cleft lip and palate (CLP). The purpose of this study was to analyze three-dimensional (3D) midfacial skeletal changes after TSDO and to explore the mechanism in this process. MATERIAL AND METHODS: All patients with nonsyndromic CLP who underwent bone-borne TSDO for midfacial hypoplasia from 2005 to 2014 were reviewed in this retrospective study. 3D morphological and quantitative measurement analyses were performed to evaluate midfacial skeletal changes by superimposition of preoperative and postoperative computed tomographic images. RESULTS: Twenty-six patients with mean age of 11.5 years met the inclusion criteria. The 3D morphological findings exhibited the most significant suture stress changes at the pterygomaxillary suture area, with obvious bone generation in all patients. The whole midfacial skeleton had progressively increased advancement in a craniocaudal direction along the midface segment, associated with morphological changes in skeleton itself. The 3D quantitative measurement findings showed differential advancement of each landmark at the maxillary alveolar, zygomatic bone, orbital rim, and nasal bone, which was consistent with morphological findings. CONCLUSIONS: TSDO allows rotation advancement of the midfacial skeleton to achieve occlusal correction and facial harmony through the mechanism of both suture remodeling and bone remodeling. PMID- 26421469 TI - Quality of life after different oncologic interventions in head and neck cancer patients. AB - Patient reported outcomes following head and neck cancer are of great importance, given the functional, psychological, and social impacts of the disease and its treatment. In addition, not only is the number of publications on health-related quality of life (HRQOL) increasing in a variety of specialties, but there is also a growing awareness of the potential role of HRQOL in practice. Therefore, we aimed to investigate the HRQOL of head and neck cancer patients following different oncologic interventions, using an internationally established test. In this cross-sectional study, we included three different groups of 32 patients each. Participants had histologically confirmed invasive oral squamous cell carcinoma (OSCC) in the anterior floor of the mouth. Group allocation was based on treatment modality, as follows: only surgery (group 1), operation and adjuvant radiotherapy (XRT) (group 2), and the additional presence of osteoradionecrosis (ORN) (group 3). All patients were questioned about their HRQOL, using the standardized University of Washington Quality of Life Questionnaire (UW-QOL). Surveys for groups 1 and 2 were conducted at least 24 months after the end of tumor-related treatment, in cases of ORN (group 3) 12 months after completion of disease-related treatment. A total of 96 patients were included into this study. The mean age was 62.79 +/- 8.93 years. The patients in groups 1 and 2 revealed a reduced quality of life, of a greater magnitude after radiation therapy. Patients felt that radiotherapy was much worse than surgery; however, half of the patients stated that they would repeat radiation therapy if necessary. The subjective evaluation of the HRQOL after surgery and radiotherapy was a valuable instrument for assessing the rehabilitation of patients in the context of their function and quality of life. Radiation therapy can be considered a trigger of functional limitations and emotional distress that contributes to decreased HRQOL in patients with head and neck cancer. PMID- 26421470 TI - The 3dMD photogrammetric photo system in cranio-maxillofacial surgery: Validation of interexaminer variations and perceptions. AB - BACKGROUND: Three-dimensional photography of the face is increasingly used to overcome the downsides of conventional photography or anthropometry regarding reliable evaluation. However, the precision of such a system has to be validated before it can be implemented for clinical use. MATERIAL AND METHODS: Eight people were photographed with the 3dMDface system using lighting from sets of 2 * 4 compact fluorescent lights in a clinical photography room without natural light sources. Two different operators then individually, and without interaction, marked 27 different anatomical landmarks using the 3dMD Patient software. During this process, the operators were fully blinded against each other. The purpose of the study was to determine the repeatability and accuracy of the system when used by different operators and at different times. The 3D differentiation was analyzed using mixed ANOVA with person as the random factor, and operator, repetition, and landmark as the fixed factors. The ANOVA was followed by a Ryan Einot-Gabriel-Welsch F post-hoc test for landmarks. RESULTS: Statistical analysis grouped the landmarks into three subgroups: high precision, medium precision and low precision. CONCLUSIONS: Virtual 3D models derived from the 3dMDface system not only provide a high level of technical precision but also of intra- and interobserver reliability regarding landmark identification. However, some of the classical landmarks are not reliable when it comes to virtual models; these are generally landmarks that examiners of real patients would tend to identify using palpation of underlying bony structures, such as the soft gonion. PMID- 26421471 TI - The relationship between changes in the expression of growth associated protein 43 and functional recovery of the injured inferior alveolar nerve following transection without repair in adult rats. AB - OBJECTIVE: The objective of this study was to analyze the changes in the expression of growth associated protein-43 (GAP-43) in trigeminal ganglions (TGs) and in the distal stumps of transected inferior alveolar nerves (IANs), and to clarify the relationship between these changes and functional recovery of the transected IAN without repair using a rat IAN axotomy model. MATERIAL AND METHODS: Following transection, GAP-43 expression was measured at multiple time points. The functional recovery of the transected IAN was evaluated based on the compound muscle action potentials recorded from the digastric muscle. RESULTS: GAP-43 expression in TGs was significantly higher at 2, 7, 14, 28, and 56 days following IAN transection compared to that in samples from sham-operated rats (p < 0.0005, p < 0.0005, p < 0.0005, p = 0.007, and p = 0.023, respectively). GAP-43 expression in the distal stumps of transected IANs was significantly higher at 2, 7, 14, and 28 days following IAN transection compared to that in samples taken from sham rats (p < 0.0005, p < 0.0005, p < 0.0005, and p = 0.009, respectively). GAP-43 expression in the distal stumps of transected IANs returned nearly to sham levels by day 56 following IAN transection. On days 7, 14, 28, and 56 following transection, the amplitude of the compound muscle action potential gradually increased, the latency gradually decreased, and the duration gradually increased. The amplitude, latency, and duration of the compound muscle action potentials nearly returned to sham levels on post-transection day 56. CONCLUSIONS: Time dependent changes in the expression of GAP-43 in both TGs and distal stumps of transected IANs without repair are synchronously consistent with the regeneration and functional recovery of the transected IAN. The recovery of the amplitude, latency, and duration of the compound muscle action potentials indicates increased myelination and increased axon density of the regenerated nerve fibers. PMID- 26421472 TI - Approach to intraoperative electromagnetic navigation in orthognathic surgery: A phantom skull based trial. AB - INTRODUCTION: Intraoperative guidance using electromagnetic navigation is an upcoming method in maxillofacial surgery. However, due to their unwieldy structures, especially the line-of-sight problem, optical navigation devices are not used for daily orthognathic surgery. Therefore, orthognathic surgery was simulated on study phantom skulls, evaluating the accuracy and handling of a new electromagnetic tracking system. MATERIAL AND METHODS: Le-Fort I osteotomies were performed on 10 plastic skulls. Orthognathic surgical planning was done in the conventional way using plaster models. Accuracy of the gold standard, splint based model surgery versus an electromagnetic tracking system was evaluated by measuring the actual maxillary deviation using bimaxillary splints and preoperative and postoperative cone beam computer tomography imaging. The distance of five anatomical marker points were compared pre- and postoperatively. RESULTS: The electromagnetic tracking system was significantly more accurate in all measured parameters compared with the gold standard using bimaxillary splints (p < 0.01). The data shows a discrepancy between the model surgical plans and the actual correction of the upper jaw of 0.8 mm. Using the electromagnetic tracking, we could reduce the discrepancy of the maxillary transposition between the planned and actual orthognathic surgery to 0.3 mm on average. DISCUSSION: The data of this preliminary study shows a high level of accuracy in surgical orthognathic performance using electromagnetic navigation, and may offer greater precision than the conventional plaster model surgery with bimaxillary splints. CONCLUSION: This preliminary work shows great potential for the establishment of an intraoperative electromagnetic navigation system for maxillofacial surgery. PMID- 26421473 TI - Predictive Significance of Tumor Grade Using 256-Slice CT Whole-Tumor Perfusion Imaging in Colorectal Adenocarcinoma. AB - RATIONALE AND OBJECTIVES: The preoperative assessment of tumor grade has important clinical implications for the treatment and prognosis of patients with colorectal adenocarcinomas. The purpose of this study is to investigate the predictive significance of colorectal adenocarcinoma grade using 256-slice whole tumor computed tomography (CT) perfusion. MATERIALS AND METHODS: Fifty-three patients with proven colorectal adenocarcinomas were enrolled. All of them underwent 256-slice whole-tumor CT perfusion. They were divided into two different subgroups according to postoperative pathological results: low grade and high grade. The Kruskal-Wallis test or one-way analysis of variance was used for comparison of CT perfusion parameters between different tumor grades. Multivariant correlation between pathologic tumor stage, histologic tumor differentiation, and whole-tumor CT perfusion parameters was evaluated by Spearman rank correlation coefficient. According to receiver operating characteristic (ROC) curves, perfusion parameters including blood flow (BF), peak enhancement index (PEI), blood volume (BV), and time to peak (TTP) of 53 patients were analyzed, and the sensitivity, specificity, and accuracy of these parameters in predicting tumor grade were calculated. RESULTS: There were significant differences in BF and TTP between low-grade and high-grade tumors. According to the ROC curve, BF and TTP were of diagnostic significance, with the area under the curve values of 0.828 and 0.736, respectively. The diagnostic threshold of BF was 32.12 mL/min/100 g and that of TTP was 18.10 seconds. CONCLUSIONS: The CT perfusion parameters (BF, TTP) of first-pass 256-slice whole-tumor CT perfusion imaging can reflect tumor grade in colorectal adenocarcinoma. PMID- 26421475 TI - The basis, ethics and provision of palliative care for dementia: A review. AB - Interest in palliative care for people with dementia has been around for over two decades. There are clinical and ethical challenges and practical problems around the implementation of good quality palliative care in dementia. This narrative review of the literature focuses on the rationale or basis for services, some of the ethical issues that arise (particularly to do with artificial nutrition and hydration) and on the provision and implementation of services. We focus on the most recent literature. The rationale for palliative care for people with dementia is based on research and on an identified need for better clinical care. But the research largely demonstrates a paucity of good quality evidence, albeit particular interventions (and non-interventions) can be justified in certain circumstances. Numerous specific clinical challenges in end-of-life care for people with dementia are ethical in nature. We focus on literature around artificial nutrition and hydration and conclude that good communication, attention to the evidence and keeping the well-being of the person with dementia firmly in mind will guide ethical decision-making. Numerous challenges surround the provision of palliative care for people with dementia. Palliative care in dementia has been given definition, but can still be contested. Different professionals provide services in different locations. More research and education are required. No single service can provide palliative care for people with dementia. PMID- 26421474 TI - Vaginal atrophy of women in postmenopause. Results from a multicentric observational study: The AGATA study. AB - OBJECTIVES: Prevalence of vulvar-vaginal atrophy (VVA) has been always investigated by phone or web interview without any objective evaluation. Objective signs associated with symptoms of VVA are now termed genitourinary syndrome of menopause (GSM). This multi-centric study was performed in order to provide nation-wide data on the prevalence and management of GSM. METHODS: Nine hundred thirteen females, 59.3 +/- 7.4 years old asking for a routine gynecological examination were recruited. Diagnosis of GSM was based on patient sensation of vaginal dryness, any objective sign of VVA and a pH > 5. RESULTS: A 722/913 (79.1%) women were diagnosed with GSM with a prevalence ranging from 64.7% to 84.2%, starting from 1 to 6 years after menopause. Sedentary women were at higher risk of GSM (OR 1.8, 95% CI: 1.3-2.5; p = 0.0005). Recent vaginal infection was more likely in women with GSM (OR 2.48, 95% CI: 1.33-4.62; p = 0.0041). Symptoms reported by women with GSM were vaginal dryness (100%), dyspareunia (77.6%), burning (56.9%), itching (56.6%) and dysuria (36.1%). Signs detected by gynecologists were mucosal dryness (99%), thinning of vaginal rugae (92.1%), pallor of the mucosa (90.7%), mucosal fragility (71.9%) and petechiae (46.7%). Only 274 (30%) of women had had a previous diagnosis of VVA/GSM. These were treated either with no therapy (9.8%), systemic hormone (9.2%), local hormone (44.5%) or local non-hormonal (36.5%) therapy. At the time of our investigation 266 of them (97.1%) still had the disorder. CONCLUSIONS: GSM is a common, under-diagnosed and under-treated disorder. Measures to improve its early detection and its appropriate management are needed. PMID- 26421476 TI - Does repeated palpation-digitization of pelvic landmarks for measurement of innominate motion introduce a systematic error?--A psychometric investigation. AB - BACKGROUND: Palpation-digitization technique for measurement of innominate motion involves repeated manual palpation-digitization of pelvic landmarks, which could introduce a systematic variation between subsequent trials and thereby influence final innominate angular measurement. OBJECTIVES: The aim of this study is to quantify the effect of repeated palpation-digitization errors on overall variability of innominate vector length measurements; and to determine if there is a systematic variation between subsequent repeated trials. METHOD: A single group repeated measures study, using four testers and fourteen healthy participants, was conducted. Four pelvic landmarks, left and right posterior superior iliac spine and anterior superior iliac spine, were palpated and digitized using 3D digitizing stylus of Polhemus electromagnetic tracking device, for ten consecutive trials by each tester in their random order. The ten individual trials of innominate vector lengths measured by each tester for each participant were used for the analysis. RESULTS AND CONCLUSIONS: Repeated measures ANOVA demonstrated a very small effect of repeated trial factor (<=0.66%) as well as error component (<=0.32%) on innominate vector length variability. Further, residual versus order plots demonstrated a random pattern of errors across zero; thus indicating no systematic variation between subsequent trials of innominate vector length measurements. PMID- 26421477 TI - Complications after intraoral vertical ramus osteotomy: relationship to the shape of the osteotomy line. AB - Intraoral vertical ramus osteotomy (IVRO) is used widely to correct mandibular prognathism. However, several disadvantages of this procedure have been reported, such as condylar luxation and bony interference at the osteotomy site. The aim of this study was to survey the incidence of complications (condylar luxation and bony interference) based on the shape of the osteotomy line. One hundred and eighty-five rami in 118 patients with jaw deformities, which were treated with IVRO, were examined retrospectively. The shape of the osteotomy line and the postoperative complications were examined on panoramic radiographs. Osteotomy lines were classified into three types: vertical, C-shaped, and oblique. Of the 185 osteotomy sites, 98 were vertical, 37 C-shaped, and 50 oblique. Condylar luxation was found in six rami (3.2%); four had undergone vertical osteotomy and two had undergone C-shaped osteotomy. Bony interference occurred in seven rami (3.8%), all with vertical type osteotomy lines. Most complications occurred in the vertical type cases and no complications were found in oblique type cases. Condylar luxation was found mainly in unilateral IVRO cases and bony interference was found in bilateral IVRO cases. These results suggest that the oblique type of osteotomy line has the advantage of avoiding complications. PMID- 26421478 TI - The use of free flaps in skull base reconstruction. AB - Skull base tumours are rare, comprising less than 1% of all tumours of the head and neck. Surgical treatment of these tumours involves the approach, the resection, and the reconstruction of the defect, which present a challenge due to the technical difficulty and anatomical complexity. A retrospective study of 17 patients with tumours involving the skull base, treated by resection and immediate reconstruction using microsurgical free flaps, is presented; 11 were men and six were women. The following types of flap were used: osteocutaneous fibula flaps, fasciocutaneous anterolateral thigh flaps, and myocutaneous latissimus dorsi flaps. The most common histology of the tumours was squamous cell carcinoma. The most frequent point of origin was the paranasal sinuses (58.8%). All of the free flaps used for reconstruction were viable. A cerebrospinal fluid fistula occurred in two patients, and in one of these cases, meningoencephalitis led to death. In conclusion, the reconstruction of large defects of the skull base after ablation requires a viable tissue that in many cases can be obtained only through the use of microvascular free flaps. The type of flap to be selected depends on the anatomical structures and size of the defect to be restored. PMID- 26421479 TI - Correction to Molecular Umbrella-Amphotericin B Conjugates. PMID- 26421480 TI - Municipal solid waste characterization and quantification as a measure towards effective waste management in Ghana. AB - Reliable national data on waste generation and composition that will inform effective planning on waste management in Ghana is absent. To help obtain this data on a regional basis, selected households in each region were recruited to obtain data on rate of waste generation, physical composition of waste, sorting and separation efficiency and per capita of waste. Results show that rate of waste generation in Ghana was 0.47 kg/person/day, which translates into about 12,710 tons of waste per day per the current population of 27,043,093. Nationally, biodegradable waste (organics and papers) was 0.318 kg/person/day and non-biodegradable or recyclables (metals, glass, textiles, leather and rubbers) was 0.096 kg/person/day. Inert and miscellaneous waste was 0.055 kg/person/day. The average household waste generation rate among the metropolitan cities, except Tamale, was high, 0.72 kg/person/day. Metropolises generated higher waste (average 0.63 kg/person/day) than the municipalities (0.40 kg/person/day) and the least in the districts (0.28 kg/person/day) which are less developed. The waste generation rate also varied across geographical locations, the coastal and forest zones generated higher waste than the northern savanna zone. Waste composition was 61% organics, 14% plastics, 6% inert, 5% miscellaneous, 5% paper, 3% metals, 3% glass, 1% leather and rubber, and 1% textiles. However, organics and plastics, the two major fractions of the household waste varied considerably across the geographical areas. In the coastal zone, the organic waste fraction was highest but decreased through the forest zone towards the northern savanna. However, through the same zones towards the north, plastic waste rather increased in percentage fraction. Households did separate their waste effectively averaging 80%. However, in terms of separating into the bin marked biodegradables, 84% effectiveness was obtained whiles 76% effectiveness for sorting into the bin labeled other waste was achieved. PMID- 26421481 TI - Anaerobic digestion of pre-fermented potato peel wastes for methane production. AB - This study investigated the feasibility of anaerobic digestion (AD) of potato peel waste (PPW) and its lactic acid fermentation residue (PPW-FR) for methane (CH4) production. The experimental results showed that about 60-70% CH4 content was obtained. The digester using PPW-FR as feedstock exhibited better performance and produced a highest cumulative CH4 production of 273 L/kg VS fed, followed by 239 L/kg VS fed using PPW under the same conditions. However, with increasing solid loadings of PPW-FR feedstock from 6.4% to 9.1%, the CH4 production was inhibited. The generation, accumulation, and degradation of volatile fatty acids (VFAs) in digesters were also investigated in this research. PMID- 26421482 TI - Estimating travel and service times for automated route planning and service certification in municipal waste management. AB - Nowadays, route planning algorithms are commonly used to generate detailed work schedules for solid waste collection vehicles. However, the reliability of such schedules relies heavily on the accuracy of a number of parameters, such as the actual service time at each collection location and the traversal times of the streets (which depend on the specific day of the week and the time of day). In this paper, we propose an automated classification and estimation algorithm that, based on Global Positioning System data collected by the fleet, estimates such parameters in a timely and accurate fashion. In particular, our approach is able to classify automatically events like stops due to traffic jams, stops at traffic lights and stops at collection sites. The system can also be used for automated fleet supervision and in order to notify on a web site whether certain services have been actually provided on a certain day, thus making waste management more accountable to citizens. An experimentation carried out in an Italian municipality shows the advantages of our approach. PMID- 26421483 TI - MR imaging of cavernous sinus lesions: Pictorial review. AB - The main purpose of this pictorial review is to highlight the important MR imaging findings of various conditions involving the cavernous sinus in addition to brief description of normal anatomy. The pathological conditions that can involve the cavernous sinus can be categorized into infective, inflammatory, granulomatous, vascular and neoplastic causes. Imaging, especially with MRI, plays an important role not only in detection but also in definition of disease extent and in characterization of the pathology. Currently, high-resolution MR images clearly show various components of cavernous sinus which help in making a proper diagnosis and thus appropriate further management. PMID- 26421484 TI - Controlled release of cytokines using silk-biomaterials for macrophage polarization. AB - Polarization of macrophages into an inflammatory (M1) or anti-inflammatory (M2) phenotype is important for clearing pathogens and wound repair, however chronic activation of either type of macrophage has been implicated in several diseases. Methods to locally control the polarization of macrophages is of great interest for biomedical implants and tissue engineering. To that end, silk protein was used to form biopolymer films that release either IFN-gamma or IL-4 to control the polarization of macrophages. Modulation of the solubility of the silk films through regulation of beta-sheet (crystalline) content enabled a short-term release (4-8 h) of either cytokine, with smaller amounts released out to 24 h. Altering the solubility of the films was accomplished by varying the time that the films were exposed to water vapor. The released IFN-gamma or IL-4 induced polarization of THP-1 derived macrophages into the M1 or M2 phenotypes, respectively. The silk biomaterials were able to release enough IFN-gamma or IL-4 to repolarize the macrophage from M1 to M2 and vice versa, demonstrating the well established plasticity of macrophages. High beta-sheet content films that are not soluble and do not release the trapped cytokines were also able to polarize macrophages that adhered to the surface through degradation of the silk protein. Chemically conjugating IFN-gamma to silk films through disulfide bonds allowed for longer-term release to 10 days. The release of covalently attached IFN-gamma from the films was also able to polarize M1 macrophages in vitro. Thus, the strategy described here offers new approaches to utilizing biomaterials for directing the polarization of macrophages. PMID- 26421485 TI - Secular Trends of Overweight and Obesity in Young Southern Californians 2008 2013. AB - OBJECTIVE: To investigate secular trends in pediatric obesity in Southern California between 2008 and 2013. STUDY DESIGN: In a population-based cohort study, measured weight and height were extracted from electronic health records of 1,331,931 patients aged 2-19 years who were enrolled in an integrated prepaid health plan between 2008 and 2013. Outcomes were the prevalence of overweight and obesity (body mass index-for-age >=85th percentile). RESULTS: The prevalence of obesity was 19.1% in 2008 and decreased by 1.6% (95% CI, 1.7%-1.5%) by 2013, corresponding to a relative decline of 8.4%. A significant decline was observed across all ages, sexes, races, and socioeconomic groups, but the magnitude of the decrease varied. The relative decline in obesity was stronger in boys (-9.3%) than in girls (-7.2%), in children aged 2-5 years (-15.4%) and 6-11 years ( 11.8%) than in adolescents aged 12-19 years (-4.5%), and in whites (-12.6%) and Asians (-12.2%) than in Hispanics (-6.9%) and African Americans (-7.5%). CONCLUSION: Secular trends from this large population-based cohort suggest that overweight and obesity in boys and girls are declining across age and racial/ethnic groups. However, the declines are less pronounced in adolescents compared with children, in girls, and in some minority groups. Programs addressing childhood obesity may need to be targeted. PMID- 26421487 TI - Histologic Evidence of Intrapulmonary Bronchopulmonary Anastomotic Pathways in Neonates with Meconium Aspiration Syndrome. AB - We examined lung histology from 8 infants who died with meconium aspiration syndrome in order to determine the presence of intrapulmonary bronchopulmonary anastomotic pathways. Each infant required mechanical ventilation to treat hypoxemic respiratory distress. Lung histology from each infant shows evidence of prominent bronchopulmonary vascular connections. PMID- 26421486 TI - Pollution, Poverty, and Potentially Preventable Childhood Morbidity in Central California. AB - OBJECTIVE: To measure ecological relationships between neighborhood pollution burden, poverty, race/ethnicity, and pediatric preventable disease hospitalization rates. STUDY DESIGN: Preventable disease hospitalization rates were obtained from the 2012 California Office of Statewide Health Planning and Development database, for 8 Central Valley counties. US Census Data was used to incorporate zip code level factors including racial diversity and poverty rates. The pollution burden score was calculated by the California Office of Environmental Health Hazard Assessment using 11 indicators. Poisson-based negative binomial regression was used for final analysis. Stratification of sample by age, race/ethnicity, and insurance coverage was also incorporated. RESULTS: Children experiencing potentially preventable hospitalizations are disproportionately low income and under the age of 4 years. With every unit increase in pollution burden, preventable disease hospitalizations rates increase between 21% and 32%, depending on racial and age subgroups. Although living in a poor neighborhood was not associated with potentially avoidable hospitalizations, children enrolled in Medi-Cal who live in neighborhoods with lower pollution burden and lower levels of poverty, face 32% lower risk for ambulatory care sensitive condition hospitalization. Children living in primary care shortage areas are at increased risk of preventable hospitalizations. Preventable disease hospitalizations increase for all subgroups, except white/non-Hispanic children, as neighborhoods became more racially diverse. CONCLUSIONS: Understanding the geographic distribution of disease and impact of individual and community level factors is essential to expanding access to care and preventive resources to improve the health of children in California's most polluted and underserved region. PMID- 26421488 TI - Preparing Pediatric Patients for Adult Care: Are We Ready? PMID- 26421489 TI - The Challenges of Adolescence, Mood Disorders, and Chronic Illness. PMID- 26421490 TI - Recent advances in genomics and transcriptomics of cnidarians. AB - The advent of the genomic era has provided important and surprising insights into the deducted genetic composition of the common ancestor of cnidarians and bilaterians. This has changed our view of how genomes of metazoans evolve and when crucial gene families arose and diverged in animal evolution. Sequencing of several cnidarian genomes showed that cnidarians share a great part of their gene repertoire as well as genome synteny with vertebrates, with less gene losses in the anthozoan cnidarian lineage than for example in ecdysozoans like Drosophila melanogaster or Caenorhabditis elegans. The Hydra genome on the other hand has evolved more rapidly indicated by more divergent sequences, more cases of gene losses and many taxonomically restricted genes. Cnidarian genomes also contain a rich repertoire of transcription factors, including those that in bilaterian model organisms regulate the development of key bilaterian traits such as mesoderm, nervous system development and bilaterality. The sea anemone Nematostella vectensis, and possibly cnidarians in general, does not only share its complex gene repertoire with bilaterians, but also the regulation of crucial developmental regulatory genes via distal enhancer elements. In addition, epigenetic modifications on DNA and chromatin are shared among eumetazoans. This suggests that most conserved genes present in our genomes today, as well as the mechanisms guiding their expression, evolved before the divergence of cnidarians and bilaterians about 600 Myr ago. PMID- 26421491 TI - Effects of CYP3A4/5 and ABCB1 genetic polymorphisms on carbamazepine metabolism and transport in Chinese patients with epilepsy treated with carbamazepine in monotherapy and bitherapy. AB - OBJECTIVE: To examine the effects of cytochrome P450 3A4 (CYP3A4), cytochrome P450 3A5 (CYP3A5) and ATP-binding cassette sub-family B member 1 (ABCB1) genetic polymorphisms on carbamazepine (CBZ) plasma concentrations in Chinese patients with epilepsy using CBZ as monotherapy and bitherapy with phenytoin (PHT), phenobarbital (PB), or valproic acid (VPA). METHODS: Eighty-eight Chinese patients with epilepsy were recruited from Xiangya Hospital Central South University, of whom 66 patients were placed in the CBZ monotherapy group, 10 patients were placed in the CBZ bitherapy group combined with one enzyme-inducing anti-seizure medications (PHT or PB), and 12 patients were placed in the CBZ bitherapy group combined with VPA. Carbamazepine and carbamazepine-10,11-epoxide (CBZ-E) plasma concentration of these patients were measured. In addition, the genetic polymorphisms of rs4646440 and rs2242480 in the CYP3A4 gene, rs15524 and rs776746 in the CYP3A5 gene, and rs1045642, rs2032582, rs10234411 and rs1128503 in the ABCB1 gene of the cohort were genotyped. Subsequently, the associations between CBZ plasma concentrations and target single-nucleotide polymorphisms (SNPs), as well as haplotypes, were analysed. RESULTS: In the CBZ monotherapy group, dose-adjusted CBZ concentrations were not associated with the eight SNPs and haplotypes. In the CBZ+PHT/PB group, rs776746, rs15524 and rs15524-rs776746 GT, AC haplotype were significantly associated with dose-adjusted CBZ plasma concentration (P=0.006, 0.006, 0.003, 0.003, respectively) and CBZ plus CBZ-E concentrations (P=0.006, 0.006, 0.006, 0.006, respectively); rs2032582, rs10234411 and rs2032582-rs10234411 AT, and CA haplotype were associated with the CBZ-E/CBZ ratio (P=0.007, 0.004, 0.004, 0.007, respectively). CONCLUSIONS: rs776746 and rs15524 in the CYP3A5 gene tend to affect CBZ metabolism, and rs2032582, rs10234411 in the ABCB1 gene may contribute to inter-individual variation in CBZ and in CBZ-E transport among patients with epilepsy using CBZ in combination with PHT or PB. PMID- 26421492 TI - Machine learning classification of mesial temporal sclerosis in epilepsy patients. AB - BACKGROUND AND PURPOSE: Novel approaches applying machine-learning methods to neuroimaging data seek to develop individualized measures that will aid in the diagnosis and treatment of brain-based disorders such as temporal lobe epilepsy (TLE). Using a large cohort of epilepsy patients with and without mesial temporal sclerosis (MTS), we sought to automatically classify MTS using measures of cortical morphology, and to further relate classification probabilities to measures of disease burden. MATERIALS AND METHODS: Our sample consisted of high resolution T1 structural scans of 169 adults with epilepsy collected across five different 1.5T and four different 3T scanners at UCLA. We applied a multiple support vector machine recursive feature elimination algorithm to morphological measures generated from FreeSurfer's automated segmentation and parcellation in order to classify Epilepsy patients with MTS (n=85) from those without MTS (N=84). RESULTS: In addition to hippocampal volume, we found that alterations in cortical thickness, surface area, volume and curvature in inferior frontal and anterior and inferior temporal regions contributed to a classification accuracy of up to 81% (p=1.3*10(-17)) in identifying MTS. We also found that MTS classification probabilities were associated with a longer duration of disease for epilepsy patients both with and without MTS. CONCLUSIONS: In addition to implicating extra-hippocampal involvement of MTS, these findings shed further light on the pathogenesis of TLE and may ultimately assist in the development of automated tools that incorporate multiple neuroimaging measures to assist clinicians in detecting more subtle cases of TLE and MTS. PMID- 26421493 TI - Evaluation of multiple putative risk alleles within the 15q13.3 region for genetic generalized epilepsy. AB - The chromosome 15q13.3 region has been implicated in epilepsy, intellectual disability and neuropsychiatric disorders, especially schizophrenia. Deficiency of the acetylcholine receptor gene CHRNA7 and the partial duplication, CHRFAM7A, may contribute to these phenotypes and we sought to comprehensively analyze these genes in genetic generalized epilepsy. We analyzed using DHPLC, Sanger sequencing and long range PCR, 174 probands with genetic generalized epilepsy with or without intellectual disability or psychosis, including 8 with the recurrent 15q13.3 microdeletion. We searched CHRNA7 and CHRFAM7A for single sequence variants, small copy number variants, and the common 2-bp deletion in CHRFAM7A. We identified two novel and one reported missense variants. The common 2-bp deletion was not enriched in patients compared to controls. Our data suggest that missense mutations in CHRNA7 contribute to complex inheritance in genetic generalized epilepsy in a similar fashion to the 15q13.3 microdeletion. They do not support a pathogenic role for the common 2-bp CHRFAM7A deletion. PMID- 26421494 TI - A "turn-on" fluorescent chemosensor for aluminum ion and cell imaging application. AB - A simple and efficient fluorescent chemosensor for Al(3+) is reported in the paper. The chemosensor is obtained by dehydration reaction of 2-hydroxy-1 naphthaldehyde and 2-aminophenol. The chemosensor has high selectivity and sensitivity for Al(3+) and displays fluorescence "off-on" switch signal. The detection limit of the chemosensor for Al(3+) can reach 1.0*10(-7) M in DMSO/H2O (1:9, v/v) solution. The mass spectra and Job's plot analysis confirm the 1:1 stoichiometry between chemosensor and Al(3+). Potential utilization of the probe as an intracellular sensor of Al(3+) in human cancer (HiSa) cells is also examined by confocal fluorescence microscopy. PMID- 26421495 TI - Tyrosyl-DNA-phosphodiesterase I (TDP1) participates in the removal and repair of stabilized-Top2alpha cleavage complexes in human cells. AB - Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a DNA repair enzyme that removes irreversible protein-linked 3' DNA complexes, 3' phosphoglycolates, alkylation damage-induced DNA breaks, and 3' deoxyribose nucleosides. In addition to its extended spectrum of substrates, TDP1 interacts with several DNA damage response factors. To determine whether TDP1 participates in the repair of topoisomerase II (Top2) induced DNA lesions, we generated TDP1 depleted (TDP1kd) human tumoral cells. We found that TDP1kd cells are hypersensitive to etoposide (ETO). Moreover, we established in a chromatin context that following treatment with ETO, TDP1kd cells accumulate increased amounts of Top2alpha cleavage complexes, removing them with an altered kinetics. We also showed that TDP1 depleted cells accumulate increased gammaH2AX and pS296Chk1 signals following treatment with ETO. Similarly, cytogenetics analyses following Top2 poisoning revealed increased amounts of chromatid and chromosome breaks and exchanges on TDP1kd cells in the presence or not of the DNA-PKcs inhibitor NU7026. However, the levels of sister chromatid exchanges were similar in both TDP1kd and control non-silenced cell lines. This suggests a role of TDP1 in both canonical non-homologous end joining and alternative end joining, but not in the homologous recombination repair pathway. Finally, micronucleus analyses following ETO treatment revealed a higher frequency of micronucleus containing gammaH2AX signals on TDP1kd cells. Together, our results highlight an active role of TDP1 in the repair of Top2-induced DNA damage and its relevance on the genome stability maintenance in human cells. PMID- 26421496 TI - Twenty-Seven-Year Experience With the St. Jude Medical Biocor Bioprosthesis in the Aortic Position. AB - BACKGROUND: The aim of this study was to evaluate the long-term performance of the St. Jude Medical Biocor porcine stented bioprosthesis in the aortic position. METHODS: From January 1985 to December 1996, 455 patients underwent aortic valve replacement with the St. Jude Medical Biocor prosthesis at the German Heart Center Munich. Mean age at time of operation was 72.5 +/- 9 years. In all, 172 patients (37.8%) underwent concomitant coronary artery bypass grafting and 20 patients (4.4%) had had previous cardiac surgery. Event-free rates are given as mean +/- SD. Adverse events were recorded according to the guidelines for reporting morbidity and mortality after cardiac valvular operations. RESULTS: Follow-up was complete in 93.4%. Mean follow-up time was 8.4 +/- 5.6 years, with a total of 3,834 patient-years and a maximum of 27.4 years. Thirty patients were lost to follow-up after a mean of 9.2 +/- 4.1 years. Overall survival rate at 10 and 15 years was 43.3% +/- 2.4% and 19.2% +/- 2.0%, respectively. Freedom from structural valve deterioration at 10 and 15 years was 92.1% +/- 1.7% and 84.8% +/ 3.0%, respectively. Freedom from valve-related reoperation at 10 and 15 years was 90.6 +/- 1.7% and 86.3 +/- 2.5%, respectively. Twenty-four patients needed reoperation for structural valve deterioration, 9 patients for endocarditis, 3 patients for paravalvular leakage, and 2 patients for aortic root aneurysm. At 15 years, freedom from major bleeding was 91.0% +/- 2.0% and freedom from thromboembolism was 72.2% +/- 2.8%. CONCLUSIONS: This study represents the longest follow-up for the St. Jude Medical Biocor prosthesis and shows an excellent durability with a low incidence of valve-related complications. PMID- 26421497 TI - Energetic and topological determinants of a phosphorylation-induced disorder-to order protein conformational switch. AB - We show that the phosphorylation of 4E-BP2 acts as a triggering event to shape its folding-function landscape that is delicately balanced between conflicting favorable energetics and intrinsically unfavorable topological connectivity. We further provide first evidence that the fitness landscapes of proteins at the threshold of disorder can differ considerably from ordered domains. PMID- 26421498 TI - Efficacy of laparoscopically assisted high ligation of patent processus vaginalis in children. AB - INTRODUCTION: Laparoscopic hernia repairs have been proven to be efficient and safe for children, despite the slightly higher recurrence rate compared with the classic surgical repair. They have the advantage of easy and precise identification of the type of defect and its correction, both in ipsilateral and contralateral sides. OBJECTIVES: The objectives of this study were to evaluate the efficacy, safety and outcome of the laparoscopically assisted piecemeal high ligation of a patent processus vaginalis (PPV) in children. METHODS: A total of 40 children were enrolled into this prospective study; they were aged >= 6 months and had an inguinal hernia. The peritoneal cavity, including the contralateral side, was inspected for the possibility of bilateral hernias using a 3-mm 30 degrees telescope. Another 3-mm port was introduced through the same infra umbilical incision. The hernia was manually reduced or with the aid of a working infra-umbilical grasper. A prolene or vicryl 2/0 or 3/0 suture on a curved semicircle round-bodied taper-ended 25-30 mm needle was introduced through a very small inguinal skin-crease incision. It was passed through the abdominal wall layers to the peritoneum and was manipulated by the laparoscopic grasper to pick up the peritoneum in piecemeal all around the internal ring. The needle was then pushed to the outside near to the entrance site, thus forming a semicircle around the internal ring. The suture was then tied and the knot was subcutaneously buried. The primary outcome of the procedure was the incidence of intraoperative diagnosis and surgical repair of contralateral hernias in pre-operatively diagnosed unilateral cases. The secondary outcomes were defined as the incidence of complications and hernia recurrence. RESULTS: DISCUSSION: The exploratory laparoscopy found contralateral patent processus vaginalis (CPPV) with a detection rate of 28.1%. Chan et al., Esposito et al., Toufique et al. and Niyogi et al. reported similar figures for laparoscopic contralateral hernia detection rates of 28%, 39%, 39.7% and 29.2%, respectively. The limitations of this study were the small sample size, plus the risk factors and clinical significance for CPPV. CONCLUSION: Laparascopically assisted piecemeal closure of the internal inguinal ring in children is a safe and effective procedure. It helps in detecting a contralateral hernia without prolonging the operative time. PMID- 26421499 TI - Implications of a Biosignature Study of the Placebo Response in Major Depressive Disorder. PMID- 26421500 TI - Distinct Packings of Supramolecular Building Blocks in Metal-Organic Frameworks Based on Imidazoledicarboxylic Acid. AB - When the supramolecular building block packings (face-centered, body-centered, and primitive cubic) with different interactions (hydrogen and coordination bonding) were controlled, four new structures based on octahedral M(II) (M = Zn, Ni, Mn) and imidazoledicarboxylate were constructed. The interaction modes between the supramolecular building blocks affect the water stability of the structures. Furthermore, with uncoordinated carboxylate O atoms in the structures, these compounds demonstrate a strong capability of capturing metal ions in the solution. PMID- 26421502 TI - Detection of thiocyanate through limiting growth of AuNPs with C-dots acting as reductant. AB - We have found that hydroxyl-rich carbon dots (C-dots) have the ability to reduce Au(3+) to form gold nanoparticles (AuNPs). Thiocyanate (SCN(-)) can be absorbed on the surface of the AuNPs due to its high affinity toward the AuNPs, which inhibits the growth of the AuNPs. Meanwhile, SCN(-) has the ability to etch the as-synthesized big AuNPs to small AuNPs, which can also cause the absorption peak of the AuNPs to decrease. Therefore, an optical sensor is developed for the detection of SCN(-) based on measuring the plasmon resonance absorption peak change of the AuNPs. Under optimal conditions, this method yields excellent sensitivity (the limit of detection is 0.16 MUM) and selectivity toward SCN(-). This method can detect SCN(-) in raw milk with satisfactory results. This work gives new insight into monitoring the quality of milk. PMID- 26421501 TI - The Recognition of Identical Ligands by Unrelated Proteins. AB - The binding of drugs and reagents to off-targets is well-known. Whereas many off targets are related to the primary target by sequence and fold, many ligands bind to unrelated pairs of proteins, and these are harder to anticipate. If the binding site in the off-target can be related to that of the primary target, this challenge resolves into aligning the two pockets. However, other cases are possible: the ligand might interact with entirely different residues and environments in the off-target, or wholly different ligand atoms may be implicated in the two complexes. To investigate these scenarios at atomic resolution, the structures of 59 ligands in 116 complexes (62 pairs in total), where the protein pairs were unrelated by fold but bound an identical ligand, were examined. In almost half of the pairs, the ligand interacted with unrelated residues in the two proteins (29 pairs), and in 14 of the pairs wholly different ligand moieties were implicated in each complex. Even in those 19 pairs of complexes that presented similar environments to the ligand, ligand superposition rarely resulted in the overlap of related residues. There appears to be no single pattern-matching "code" for identifying binding sites in unrelated proteins that bind identical ligands, though modeling suggests that there might be a limited number of different patterns that suffice to recognize different ligand functional groups. PMID- 26421503 TI - Evidence-Based Clinical Prevention in the Era of the Patient Protection and Affordable Care Act: The Role of the US Preventive Services Task Force. PMID- 26421504 TI - Performance Enhancement of Dye-Sensitized Solar Cells Based on TiO2 Thick Mesoporous Photoanodes by Morphological Manipulation. AB - This study is an attempt to give an account of the preparation of mesoporous TiO2 thick templated films of nonsimilar pore architecture and their use in dye sensitized solar cells (DSSCs). Highly crystallized mesoporous titania thick templated films with four different morphologies including hexagonal, wormlike, cubic, and gridlike mesostructure, have been successfully synthesized through an evaporation-induced self-assembly (EISA) route followed by layer-by-layer deposition. Stabilization, followed by each coating, and calcinations, carried out after every five layers, were used to produce crack-free thick films. These mesoporous templated titanium dioxide samples were characterized by TEM, XRD, SEM, BET, and UV-vis measurements and used as a photoelectrode material in DSSCs. The mesostructured films with a thickness of about 7 MUm demonstrated better performance in comparison to nanocrystalline TiO2 films (NC-TiO2) at a film thickness of 13 MUm as the most typical films utilized in DSSCs. The findings reveal that a surfactant/Ti ratio change undergone for developing cubic mesostructures can enhance the crystallinity and roughness factor and therefore increase the energy conversion efficiency of DSSC. The cell performances derived from these mesofilms were enhanced compared to the efficiencies reported thus far. The best photovoltaic performance of 8.73% came from DSSC using the cubic mesoporous TiO2 photoelectrode with the following properties: open circuit voltage of 743 mV, short circuit photocurrent density of 16.35 mA/cm(2), and fill factor of 0.72. PMID- 26421505 TI - Carrier Recombination Dynamics in Sulfur-Doped InP Nanowires. AB - Measuring lifetime of photogenerated charges in semiconductor nanowires (NW) is important for understanding light-induced processes in these materials and is relevant for their photovoltaic and photodetector applications. In this paper, we investigate the dynamics of photogenerated charge carriers in a series of as grown InP NW with different levels of sulfur (S) doping. We observe that photoluminescence (PL) decay time as well as integrated PL intensity decreases with increasing S doping. We attribute these observations to hole trapping with the trap density increased due to S-doping level followed by nonradiative recombination of trapped charges. This assignment is proven by observation of the trap saturation in three independent experiments: via excitation power and repetition rate PL lifetime dependencies and by PL pump-probe experiment. PMID- 26421506 TI - Changes in fetal myocardial performance index following intravascular transfusion: preliminary report. AB - OBJECTIVE: To investigate the changes in fetal left ventricle myocardial performance index (MPI) following intrauterine intravascular transfusion (IUT). METHODS: Prospective study, including 25 IUT performed in 13 singleton pregnancies with maternal Rh D alloimmune disease. Left ventricle MPI was evaluated prior to transfusion and repeated 24 h after each procedure. Delta MPI was calculated as the difference between post- and pre-transfusion MPI z-scores. Multilevel regression analysis was used to examine the association between delta MPI and gestational age at procedure, fetal middle cerebral artery peak velocity MoM, pre- and post-MPI and hemoglobin z-score values, the volume of blood transfused and feto-placental volume percentage expansion. Adjustments were made for repeated measurements within the same fetus, and across different time points. The significance level was set as 0.05. RESULTS: MPI z-score values increased significantly following transfusion (delta MPI = 1.10 +/- 2.47, p=0.036). Delta MPI showed a significant correlation with gestational age at transfusion (r= -0.47, p=0.018), pre-transfusion MPI z-score (r= -0.50, p=0.012) and feto-placental volume percentage expansion (r= -0.41, p=0.044). CONCLUSION: Left ventricle MPI increases significantly after intrauterine blood transfusion and greater changes are associated with procedures at an earlier gestational age, lower pre-transfusion MPI z-scores and smaller feto-placental volume expansion. PMID- 26421507 TI - Detecting lateral composition modulation in dilute Ga(As,Bi) epilayers. AB - The ability to characterize a structure into the finest details in a quantitative manner is a key issue to understanding and controlling nanoscale phase separation in novel nanomaterials. In this work, we consider the detectability of lateral composition modulation (LCM), a type of nanoscale phase separation in GaAs(1 x)Bix epilayers, by x-ray diffraction (XRD). We show that the satellite peaks due to LCM are hardly detectable in reasonable time with a lab x-ray diffractometer for GaAs(1-x)Bix samples with an average x up to 25% and relative modulation up to 50%. This is in contrast to LCM reported in other III-V combinations, where the intensity of the satellite peak is relatively high and can be easily detected. Our theoretical considerations are complemented experimentally using highly brilliant synchrotron radiation. The results are in good agreement with the predictions. This work provides a guideline for the systematic characterization of LCM in zincblende III-V semiconductor epilayers and points to the critical role of quantitative characterization of nanoscale phase separation. PMID- 26421508 TI - Adult Daughters' Descriptions of Their Mother-Daughter Relationship in the Context of Chronic Conflict. AB - The purpose of this article is to describe, from the perspective of the adult daughter, the mother-daughter relationship in the context of chronic conflict. Grounded theory methodology was used. An online recruitment strategy was used to identify a sample of adult daughters (N = 13) who self-identified as having an abusive relationship with their aging mother. Data collection was completed through semi-structured telephone interviews. Daughters framed their relationship around their perceptions of past childhood injustices. These injustices invoked strong negative emotions. Daughters had equally strong motivations for sustaining the relationship, driven by desire to reconcile their negative experience through seeking validation and futile-hoping as well as a sense of obligation to do due diligence. Together these factors created an environment of inevitable confrontation and a relationship defined by chronic conflict. Findings from the study provide theoretical insights to the conceptualization of aggression, power relationships, and the development of elder abuse and neglect. PMID- 26421509 TI - The Genetics of Nitrogen Use Efficiency in Crop Plants. AB - In the past 50 years, the application of synthetic nitrogen (N) fertilizer to farmland resulted in a dramatic increase in crop yields but with considerable negative impacts on the environment. New solutions are therefore needed to simultaneously increase yields while maintaining, or preferably decreasing, applied N to maximize the nitrogen use efficiency (NUE) of crops. In this review, we outline the definition of NUE, the selection and development of NUE crops, and the factors that interact with NUE. In particular, we emphasize the challenges of developing crop plants with enhanced NUE, using more classical genetic approaches based on utilizing existing allelic variation for NUE traits. The challenges of phenotyping, mapping quantitative trait loci (QTLs), and selecting candidate genes for NUE improvement are described. In addition, we highlight the importance of different factors that lead to changes in the NUE components of nitrogen uptake efficiency (NUpE) and nitrogen utilization efficiency (NUtE). PMID- 26421510 TI - Centromere Associations in Meiotic Chromosome Pairing. AB - Production of gametes of halved ploidy for sexual reproduction requires a specialized cell division called meiosis. The fusion of two gametes restores the original ploidy in the new generation, and meiosis thus stabilizes ploidy across generations. To ensure balanced distribution of chromosomes, pairs of homologous chromosomes (homologs) must recognize each other and pair in the first meiotic division. Recombination plays a key role in this in most studied species, but it is not the only actor and particular chromosomal regions are known to facilitate the meiotic pairing of homologs. In this review, we focus on the roles of centromeres and in particular on the clustering and pairwise associations of nonhomologous centromeres that precede stable pairing between homologs. Although details vary from species to species, it is becoming increasingly clear that these associations play active roles in the meiotic chromosome pairing process, analogous to those of the telomere bouquet. PMID- 26421513 TI - Scaffolded Active Learning: Nine Pedagogical Principles for Building a Modern Veterinary Curriculum. AB - Veterinary discipline experts unfamiliar with the broader educational literature can find the adoption of an evidence-based approach to curriculum development challenging. However, greater societal and professional demands for achieving and verifying Day One knowledge and skills, together with continued progress in information generation and technology, make it all the more important that the defined period for initial professional training be well used. This article presents and discusses nine pedagogical principles that have been used in modern curricular development in Australia, the United Kingdom, and the United States: (1) outcomes-based curriculum design; (2) valid and reliable assessments; (3) active learning; (4) integrated knowledge for action; (5) tightly controlled core curriculum; (6) "just-in-time" rather than "just-in-case" knowledge; (7) vertical integration, the spiral curriculum, and sequential skills development; (8) learning skills support; and (9) bridges from classroom to workplace. Crucial to effective educational progress is active learning that embraces the skills required by the modern professional, made possible by tight control of curricular content. In this information age, professionals' ability to source information on a "just-in-time" basis to support high quality reasoning and decision making is far more important than the memorization of large bodies of increasingly redundant information on a "just-in-case" basis. It is important that those with responsibility for veterinary curriculum design ensure that their programs fully equip the modern veterinary professional for confident entry into the variety of roles in which society needs their skills. PMID- 26421511 TI - The Behavioral Definitions of "Having Sex With a Man" and "Having Sex With a Woman" Identified by Women Who Have Engaged in Sexual Activity With Both Men and Women. AB - A sizable minority of women report lifetime sexual behavior with both men and women. In the present study, a multinational sample of women who reported genital contact with at least one man and one woman in their lifetime (N = 2,751) were asked to provide their behavioral definitions of "having sex with a woman" and "having sex with a man." Replicating previous research, participants were asked "Would you say you 'had sex' with a woman/man if the most intimate behavior you engaged in with her/him was ..." followed by a list of behaviors that differed based on the hypothetical partner gender. While most participants indicated that they would consider "having had sex" if they engaged in a variety of behaviors, behaviors involving genital contact were most often included within the participants' definitions of having sex, regardless of partner gender. The percentage of behaviors included in the participants' definitions of having sex with a woman (M = 59.40%, SD = 20.77%) was higher than the percentage of behaviors included in their definition of having sex with a man (M = 37.26%, SD = 28.97%). Broadening our understanding of "having sex" for individuals with diverse sexual experiences may have important implications for clinicians and researchers. PMID- 26421514 TI - Final-Year Students' and Clinical instructors' Experience of Workplace-Based Assessments Used in a Small-Animal Primary-Veterinary-Care Clinical Rotation. AB - Final-year veterinary students must meet baseline clinical competency upon completion of their training for entry to practice. Workplace-based assessments (WBAs), widely used in human medical training to assess post-graduate students' professionalism and clinical performance, have recently been adopted in undergraduate veterinary clinical teaching environments. WBAs should support veterinary trainees' learning in a clinical teaching environment, though utility of WBAs within veterinary education may differ from that in medical training due to differences in context and in learners' stage of clinical development. We conducted focus groups with final-year veterinary students and clinical instructors following the implementation of three WBAs (Direct Observation of Procedural Skills [DOPS], the Mini-Clinical evaluation exercise [Mini-CEX], and the In-Training Evaluation Report [ITER]) during a small-animal primary veterinary-care rotation. Students and clinical instructors viewed the DOPS and Mini-CEX as feasible and valuable learning and assessment tools that offered an overall opportunity for timely in-the-moment feedback. Instructors viewed the ITER as less feasible in the context of a service-oriented veterinary clinical teaching environment. Students believed the ITER had potential to be informative, although in its existing application the ITER had limited utility due to time constraints on instructors that prevented them from providing students with individualized and specific feedback. In service-oriented veterinary clinical teaching environments, successful implementation of WBAs requires balancing provision of feedback to students, time demands on clinical instructors, and flexibility of assessment tools. PMID- 26421515 TI - Clients and Veterinarians as Partners in Problem Solving during Cancer Management: Implications for Veterinary Education. AB - This research explores client satisfaction with veterinarian interactions and support during cancer management. Ninety-four members of the online Pet Cancer Support group completed the electronic communication and support questionnaire. Results show that 77% of respondents (n=72) are satisfied with their veterinarian; 71% (n=67) are satisfied with the information their veterinarian provides about treatment options; and 70% percent (n=66) are satisfied with the support they receive from their veterinarian. Strong, positive correlations exist between level of satisfaction and information about treatment options (rs=.795, n=91, p<.001) and between level of satisfaction and support received from the veterinarian (rs=.759, n=90, p<.001). Problem-focused informational support and tangible support dominated clients' descriptions of support and affected their support satisfaction. Emotion-focused support was not as important, and in some cases was not expected of the veterinarian. Results suggested that clients' overall satisfaction with their veterinarian is related to their satisfaction with information about treatment options and satisfaction with the support the veterinarian provides. By providing problem-focused support, veterinarians can empower clients and enhance their sense of control, thus positively affecting satisfaction and the likelihood of a long-lasting relationship. Taken together, these findings have implications for our understanding of veterinarian-client communication related to relationship-centered care and client empowerment, as well as implications for veterinary medical education and communication curricula. PMID- 26421516 TI - Closing the Loop: Using Evidence to Inform Refinements to an Admissions Process. AB - Substantive changes in our evaluation of applicants have been implemented in response to the findings of the various phases of outcomes assessment. This article will describe the changes that have been implemented as a result of analyzing the association of pre-veterinary academic, subjective, and behavioral event interview scores with veterinary students' performance in the DVM program, including clinical competencies, and their performance on the North American Veterinary Licensing Examination. Pre-veterinary academic performance predicted academic performance in veterinary school. Subjective measures did not, and we have reduced the faculty workload associated with that part of the evaluation of applicants. Interview scores provide additional but small value in predicting performance on clinical competencies. PMID- 26421517 TI - Monitoring the Veterinary Medical Student Experience: An Institutional Pilot Study. AB - Veterinary medical school challenges students academically and personally, and some students report depression and anxiety at rates higher than the general population and other medical students. This study describes changes in veterinary medical student self-esteem (SE) over four years of professional education, attending to differences between high and low SE students and the characteristics specific to low SE veterinary medical students. The study population was students enrolled at the Michigan State University College of Veterinary Medicine from 2006 to 2012. We used data from the annual anonymous survey administered college wide that is used to monitor the curriculum and learning environment. The survey asked respondents to rate their knowledge and skill development, learning environment, perceptions of stress, skill development, and SE. Participants also provided information on their academic performance and demographics. A contrasting groups design was used: high and low SE students were compared using logistic regression to identify factors associated with low SE. A total of 1,653 respondents met inclusion criteria: 789 low SE and 864 high SE students. The proportion of high and low SE students varied over time, with the greatest proportion of low SE students during the second-year of the program. Perceived stress was associated with low SE, whereas perceived supportive learning environment and skill development were associated with high SE. These data have provided impetus for curricular and learning environment changes to enhance student support. They also provide guidance for additional research to better understand various student academic trajectories and their implications for success. PMID- 26421518 TI - Zebrafish Database: Customizable, Free, and Open-Source Solution for Facility Management. AB - Zebrafish Database is a web-based customizable database solution, which can be easily adapted to serve both single laboratories and facilities housing thousands of zebrafish lines. The database allows the users to keep track of details regarding the various genomic features, zebrafish lines, zebrafish batches, and their respective locations. Advanced search and reporting options are available. Unique features are the ability to upload files and images that are associated with the respective records and an integrated calendar component that supports multiple calendars and categories. Built on the basis of the Joomla content management system, the Zebrafish Database is easily extendable without the need for advanced programming skills. PMID- 26421519 TI - S-Nitrosylation of Sarcomeric Proteins Depresses Myofilament Ca2+)Sensitivity in Intact Cardiomyocytes. AB - AIMS: The heart responds to physiological and pathophysiological stress factors by increasing its production of nitric oxide (NO), which reacts with intracellular glutathione to form S-nitrosoglutathione (GSNO), a protein S nitrosylating agent. Although S-nitrosylation protects some cardiac proteins against oxidative stress, direct effects on myofilament performance are unknown. We hypothesize that S-nitrosylation of sarcomeric proteins will modulate the performance of cardiac myofilaments. RESULTS: Incubation of intact mouse cardiomyocytes with S-nitrosocysteine (CysNO, a cell-permeable low-molecular weight nitrosothiol) significantly decreased myofilament Ca(2+) sensitivity. In demembranated (skinned) fibers, S-nitrosylation with 1 MUM GSNO also decreased Ca(2+) sensitivity of contraction and 10 MUM reduced maximal isometric force, while inhibition of relaxation and myofibrillar ATPase required higher concentrations (>= 100 MUM). Reducing S-nitrosylation with ascorbate partially reversed the effects on Ca(2+) sensitivity and ATPase activity. In live cardiomyocytes treated with CysNO, resin-assisted capture of S-nitrosylated protein thiols was combined with label-free liquid chromatography-tandem mass spectrometry to quantify S-nitrosylation and determine the susceptible cysteine sites on myosin, actin, myosin-binding protein C, troponin C and I, tropomyosin, and titin. The ability of sarcomere proteins to form S-NO from 10-500 MUM CysNO in intact cardiomyocytes was further determined by immunoblot, with actin, myosin, myosin-binding protein C, and troponin C being the more susceptible sarcomeric proteins. INNOVATION AND CONCLUSIONS: Thus, specific physiological effects are associated with S-nitrosylation of a limited number of cysteine residues in sarcomeric proteins, which also offer potential targets for interventions in pathophysiological situations. PMID- 26421520 TI - Dual expression of MYC and BCL2 proteins predicts worse outcomes in diffuse large B-cell lymphoma. AB - Recent studies suggested that MYC and BCL2 protein co-expression is an independent indicator of poor prognosis in diffuse large B-cell lymphoma. However, the immunohistochemistry protocols for dual-expression staining and the scoring cut-offs vary by study. Sixty-nine cases of diffuse large B-cell lymphoma were evaluated for MYC and BCL2 protein expression using various cut-offs that have been recommended in prior studies. Independent of the International Prognostic Index risk group, cases with dual protein expression of BCL2 and MYC using >=50%/40% cut-offs and >=70%/40% had significantly shorter overall survival than cases without. It was verified in this patient population that the use of BCL2 and MYC immunohistochemistry, performed with available in vitro diagnostic cleared antibodies, provides rapid prognostic information in patients with de novo diffuse large B-cell lymphoma. This study has practical implications for diagnostic laboratories and serves as a guide for implementation in the setting of future clinical trials. PMID- 26421521 TI - Improvement of Neuroenergetics by Hypertonic Lactate Therapy in Patients with Traumatic Brain Injury Is Dependent on Baseline Cerebral Lactate/Pyruvate Ratio. AB - Energy dysfunction is associated with worse prognosis after traumatic brain injury (TBI). Recent data suggest that hypertonic sodium lactate infusion (HL) improves energy metabolism after TBI. Here, we specifically examined whether the efficacy of HL (3h infusion, 30-40 MUmol/kg/min) in improving brain energetics (using cerebral microdialysis [CMD] glucose as a main therapeutic end-point) was dependent on baseline cerebral metabolic state (assessed by CMD lactate/pyruvate ratio [LPR]) and cerebral blood flow (CBF, measured with perfusion computed tomography [PCT]). Using a prospective cohort of 24 severe TBI patients, we found CMD glucose increase during HL was significant only in the subgroup of patients with elevated CMD LPR >25 (n = 13; +0.13 [95% confidence interval (CI) 0.08-0.19] mmol/L, p < 0.001; vs. +0.04 [-0.05-0.13] in those with normal LPR, p = 0.33, mixed-effects model). In contrast, CMD glucose increase was independent from baseline CBF (coefficient +0.13 [0.04-0.21] mmol/L when global CBF was <32.5 mL/100 g/min vs. +0.09 [0.04-0.14] mmol/L at normal CBF, both p < 0.005) and systemic glucose. Our data suggest that improvement of brain energetics upon HL seems predominantly dependent on baseline cerebral metabolic state and support the concept that CMD LPR - rather than CBF - could be used as a diagnostic indication for systemic lactate supplementation following TBI. PMID- 26421523 TI - A One-Two Punch to Bone: Assessing the Combined Impact of Lead and a High-Fat Diet. PMID- 26421522 TI - Low-Intensity Pulsed Ultrasound Stimulation Enhances Heat-Shock Protein 90 and Mineralized Nodule Formation in Mouse Calvaria-Derived Osteoblasts. AB - Low-intensity pulsed ultrasound (LIPUS) has demonstrated its positive effects on osteogenic differentiation of mesenchymal stem cells and the proliferation and differentiation of osteoblasts, negative effects on osteoclast growth, and promotion of angiogenesis, leading to improvement of the tissue perfusion. Heat shock proteins (HSPs) are initially identified as molecules encouraged and expressed by heat stress or chemical stress to cells and involved in the balance between differentiation and apoptosis of osteoblasts. However, it remains unclear if the effect of LIPUS on osteoblast differentiation could involve HSP expression and contribution. In this study, mouse calvarial osteoblasts were exposed to LIPUS at a frequency of 3.0 MHz by 30 mW/cm(2) for 15 min or to 42 degrees C heat shock for 20 min at day 3 of cell culture and examined for osteogenesis with pursuing induction of HSP27, HSP70, and HSP90. LIPUS as well as heat shock initially upregulated HSP90 and phosphorylation of Smad1 and Smad5, encouraging cell viability and proliferation at 24 h, enhancing mineralized nodule formation stronger by LIPUS after 10 days. However, HSP27, associated with BMP2-stimulated p38 mitogen-activated protein kinase during osteoblast differentiation, was downregulated by both stimulations at this early time point. Notably, these two stimuli maintained Smad1 phosphorylation with mineralized nodule formation even under BMP2 signal blockage. Therefore, LIPUS might be a novel inducer of osteoblastic differentiation through a noncanonical signal pathway. In conclusion, LIPUS stimulation enhanced cell viability and proliferation as early as 24 h after treatment, and HSP90 was upregulated, leading to dense mineralization in the osteoblast cell culture after 10 days. PMID- 26421524 TI - Interface Promoted Reversible Mg Insertion in Nanostructured Tin-Antimony Alloys. AB - An interface promoted approach is developed for guiding the design of stable and high capacity materials for Mg batteries using SnSb alloys as model materials. Experimental and theoretical studies reveal that the SnSb alloy has exceptionally high reversible capacity (420 mA h g(-1)), excellent rate capability, and good cyclic stability for hosting Mg ions due to the stabilization/promotion effects of the interfaces between the multicomponent phases generated during repeated magnesiation-demagnesiation. PMID- 26421526 TI - Retrieval of the equivalent acoustic constitutive parameters of an inhomogeneous fluid-like object by nonlinear full waveform inversion. AB - This study addresses the problem of the acoustic characterization of an inhomogeneous object such as a soft-tissue organ containing a cyst or tumor whose size and/or composition evolve either negatively due to increased disease or positively due to increased response to treatment. The so-called 'corrupted' binary object, probed by a transient, acoustic plane wave, is a tube composed of a homogenous fluid-like (or assumed as such) mantle (medium 1: three acoustic constitutive parameters, one geometric parameter) surrounding a homogeneous fluid like (or assumed as such) core (medium 2: three acoustic constitutive parameters, one geometric parameter), immersed in a spatially-infinite, homogeneous fluid (host medium 0: two acoustic parameters). The complete inversion of the diffracted acoustic field response of this object involves the retrieval of seven (six acoustic and one geometric) parameters, assuming we know beforehand the outer radius of the tube and acoustic parameters of the host. An alternative to this time-consuming, hazardous (due to the ill-posed nature of the) procedure, is to minimize the discrepancy, between the full waveform response of the binary object to a transient plane wave and the response of a homogeneous cylinder (medium characterized by three acoustic parameters, one geometric parameter) to the same transient plane wave, so as to retrieve the (three so-called equivalent) acoustic parameters of the homogeneous object. Thus, the first inverse problem is replaced by a second one (same assumptions concerning the outer radius of the objects, the host medium, the probe radiation and the sensing configuration as the first one) involving the retrieval of only three (instead of six) acoustic parameters. This procedure is potentially useful if the variation of at least one of the three equivalent parameters is sensitive to the variation of a key parameter of the inhomogeneous body (usually the characteristic dimension or the wavespeed of the core) and this variation can be expressed in a simple algebraic form (such as by a mixing formula). It is shown that this situation can arise if the average frequency of the acoustic probe radiation is sufficiently low. A sidelight of this investigation is the discovery that the equivalent constitutive parameters of the homogeneous cylinder are dispersive even when the component materials of the tube are not dispersive. PMID- 26421525 TI - Effect of low-intensity laser treatment on pain after extraction of impacted mandibular third molars: a randomised, controlled, clinical trial. AB - Extraction of impacted third molars is painful, so we have evaluated whether low intensity laser could reduce the pain. Sixty patients were randomly allocated to five groups that were treated with laser immediately after extraction. Postoperative pain was evaluated after two and seven days. The Shapiro-Wilk test was used to assess whether the distribution was normal, and as it was skewed, the Kruskal-Wallis test, ANOVA and the Student-Newman-Keuls test for multiple comparisons were used to compare the groups. The Wilcoxon test was used for comparisons of pain (measured by visual analogue scale (VAS) and numerical rating scale (NRS) 101 between the second and seventh postoperative days). Probabilities of less than 0.05 were accepted as significant. We conclude that a single session of low intensity laser had no significant effect on the amount of pain under the conditions investigated. PMID- 26421527 TI - Spatiotemporal Changes of Built-Up Land Expansion and Carbon Emissions Caused by the Chinese Construction Industry. AB - China is undergoing rapid urbanization, enlarging the construction industry, greatly expanding built-up land, and generating substantial carbon emissions. We calculated both the direct and indirect carbon emissions from energy consumption (anthropogenic emissions) in the construction sector and analyzed built-up land expansion and carbon storage losses from the terrestrial ecosystem. According to our study, the total anthropogenic carbon emissions from the construction sector increased from 3,905*10(4) to 103,721.17*10(4) t from 1995 to 2010, representing 27.87%-34.31% of the total carbon emissions from energy consumption in China. Indirect carbon emissions from other industrial sectors induced by the construction sector represented approximately 97% of the total anthropogenic carbon emissions of the sector. These emissions were mainly concentrated in seven upstream industry sectors. Based on our assumptions, built-up land expansion caused 3704.84*10(4) t of carbon storage loss from vegetation between 1995 and 2010. Cropland was the main built-up land expansion type across all regions. The study shows great regional differences. Coastal regions showed dramatic built-up land expansion, greater carbon storage losses from vegetation, and greater anthropogenic carbon emissions. These regional differences were the most obvious in East China followed by Midsouth China. These regions are under pressure for strong carbon emissions reduction. PMID- 26421528 TI - Prediction of susceptible biomarkers for end stage renal disease among North Indians. AB - AIM: Involvement of pro-inflammatory genes has been correlated with basic kidney diseases and end stage renal disease (ESRD). However, results at odds were often noted from such independent association studies. This study proposes a genome wide analysis approach to predict ESRD risk associated genes. METHODS: We included 42 single nucleotide polymorphisms (SNPs) showing association among north Indian ESRD cases and controls. ESRD cases comprised chronic glomerulonephritis (CGN), chronic interstitial nephritis (CIN), hypertension (HTN) and autosomal dominant polycystic kidney disease (ADPKD). Genotyping data obtained from our prior published reports were compared with Genome-Wide Association Studies (GWAS) SNPs retrieved from HapMap and GWASCentral databases using R-statistical package SNPAssoc. Linkage disequilibrium (LD), gene-gene interaction, classification and regression tree (CART) and pathway analysis were carried out in the present study supplemented with IL-6 and TNF-alpha levels estimation using enzyme linked immunosorbent assay (ELISA). RESULTS: Comparison of genotyping data with GWAS SNPs revealed significant associations for interleukin (IL)1-RN, IL-6, MTHFR, tumour necrosis factor-alpha (TNF-alpha) and CCR3 genes with ESRD. Nine SNPs were commonly associated with CGN, CIN, HTN, ADPKD and ESRD. LD (D = 0.9) and gene-gene interaction (P = 0.0002) analyses revealed significant associations for IL-6 and TNF-alpha genes. In a consistent manner, CART analysis and functional analysis servers predict predisposing effects for TNF-alpha and IL-6 with ESRD. Finally, higher body circulating levels were observed for mutant TNF-alpha and IL-6 alleles among ESRD. CONCLUSION: The study indicates significance for IL-6 and TNF-alpha gene with basic kidney diseases and ESRD. Extensive statistical tests, pathway analysis and functional assays also reflect attenuated level of significance for these SNPs. In future these may be brought from bench side to clinical practice as diagnostic biomarkers upon external and prospective replication and confirmation among other cohorts. PMID- 26421529 TI - A Solution-Processed Resonance Host for Highly Efficient Electrophosphorescent Devices with Extremely Low Efficiency Roll-off. AB - Solution-processible N-P=O resonance-host molecules are applied successfully in spin-coated phosphorescent light-emitting diodes (PHOLEDs) to selectively and self-adaptively tune the electrical properties for balanced charge transportation. The resonance-molecule-hosted PHOLEDs exhibit a high maximum quantum efficiency of 16.5% and a low efficiency roll-off down to 0.7%, highlighting the significant progress of these solution-processed PHOLEDs with high efficiency and flat efficiency roll-off achieved simultaneously. PMID- 26421530 TI - Estimated Lifetime Medical and Work-Loss Costs of Fatal Injuries--United States, 2013. AB - Injury-associated deaths have substantial economic consequences. In 2013, unintentional injury was the fourth leading cause of death, suicide was the tenth, and homicide was the sixteenth; these three causes accounted for approximately 187,000 deaths in the United States. To assess the economic impact of fatal injuries, CDC analyzed death data from the National Vital Statistics System for 2013, along with cost of injury data using the Web-Based Injury Statistics Query and Reporting System. This report updates a previous study that analyzed death data from the year 2000, and employs recently revised methodology for determining the costs of injury outcomes, which uses the most current economic data and incorporates improvements for estimating medical costs associated with injury. Number of deaths, crude and age-specific death rates, and total lifetime work-loss costs and medical costs were calculated for fatal injuries by sex, age group, intent (intentional versus unintentional), and mechanism of injury. During 2013, the rate of fatal injury was 61.0 per 100,000 population, with combined medical and work-loss costs exceeding $214 billion. Costs from fatal injuries represent approximately one third of the total $671 billion medical and work-loss costs associated with all injuries in 2013. The magnitude of the economic burden associated with injury-associated deaths underscores the need for effective prevention. PMID- 26421531 TI - Babies, Bathwater, and Screening for Autism Spectrum Disorder: Comments on the USPSTF Recommendations for Autism Spectrum Disorder Screening. AB - Current guidelines for developmental screening and screening for autism spectrum disorders (ASDs) recommend screening of all children for ASD at ages 18 and 24 months. In a draft recommendation, the United States Preventive Services Task Force finds insufficient evidence to support this practice. Some of the assumptions behind these recommendations fail to consider other benefits of developmental surveillance and screening that ensue from periodic formal screening of all children. Primary care clinicians should err on the side of discovery and advocate for continued formal screening at designated intervals. PMID- 26421532 TI - Dipyridamole stress myocardial perfusion by computed tomography in patients with left bundle branch block. AB - BACKGROUND: Functional tests have limited accuracy for identifying myocardial ischemia in patients with left bundle branch block (LBBB). OBJECTIVE: To assess the diagnostic accuracy of dipyridamole-stress myocardial computed tomography perfusion (CTP) by 320-detector CT in patients with LBBB using invasive quantitative coronary angiography (QCA) (stenosis >= 70%) as reference; to investigate the advantage of adding CTP to coronary computed tomography angiography (CTA) and compare the results with those of single photon emission computed tomography (SPECT) myocardial perfusion scintigraphy. METHODS: Thirty patients with LBBB who had undergone SPECT for the investigation of coronary artery disease were referred for stress tomography. Independent examiners performed per-patient and per-coronary territory assessments. All patients gave written informed consent to participate in the study that was approved by the institution's ethics committee. RESULTS: The patients' mean age was 62 +/- 10 years. The mean dose of radiation for the tomography protocol was 9.3 +/- 4.6 mSv. With regard to CTP, the per-patient values for sensitivity, specificity, positive and negative predictive values, and accuracy were 86%, 81%, 80%, 87%, and 83%, respectively (p = 0.001). The per-territory values were 63%, 86%, 65%, 84%, and 79%, respectively (p < 0.001). In both analyses, the addition of CTP to CTA achieved higher diagnostic accuracy for detecting myocardial ischemia than SPECT (p < 0.001). CONCLUSION: The use of the stress tomography protocol is feasible and has good diagnostic accuracy for assessing myocardial ischemia in patients with LBBB. PMID- 26421536 TI - 750 nm 1.5 W frequency-doubled semiconductor disk laser with a 44 nm tuning range. AB - We demonstrate 1.5 W of output power at the wavelength of 750 nm by intracavity frequency doubling a wafer-fused semiconductor disk laser diode-pumped at 980 nm. An optical-to-optical efficiency of 8.3% was achieved using a bismuth borate crystal. The wavelength of the doubled emission could be tuned from 720 to 764 nm with an intracavity birefringent plate. The beam quality parameter M2 of the laser output was measured to be below 1.5 at all pump powers. The laser is a promising tool for biomedical applications that can take advantage of the large penetration depth of light in tissue in the 700-800 nm spectral range. PMID- 26421535 TI - Incidence and Predictors of Cardiovascular Complications and Death after Vascular Surgery. AB - BACKGROUND: Patients undergoing arterial vascular surgery are considered at increased risk for post-operative complications. OBJECTIVE: To assess the incidence and predictors of complications and death, as well as the performance of two models of risk stratification, in vascular surgery. METHODS: This study determined the incidence of cardiovascular complications and deaths within 30 days from surgery in adults. Univariate comparison and logistic regression assessed the risk factors associated with the outcomes, and the receiver operating characteristic (ROC) curve assessed the discriminatory capacity of the revised cardiac risk index (RCRI) and vascular study group of New England cardiac risk index (VSG-CRI). RESULTS: 141 patients (mean age, 66 years; 65% men) underwent the following surgeries: carotid (15); lower limbs (65); abdominal aorta (56); and others (5). Cardiovascular complications and death occurred within 30 days in 28 (19.9%) and 20 (14.2%) patients, respectively. The risk predictors were: age, obesity, stroke, poor functional capacity, altered scintigraphy, surgery of the aorta, and troponin change. The scores RCRI and VSG CRI had area under the curve of 0.635 and 0.639 for early cardiovascular complications, and 0.562 and 0.610 for death in 30 days. CONCLUSION: In this small and selected group of patients undergoing arterial vascular surgery, the incidence of adverse events was elevated. The risk assessment indices RCRI and VSG-CRI did not perform well for complications within 30 days. PMID- 26421537 TI - High-resolution chalcogenide fiber bundles for infrared imaging. AB - An ordered chalcogenide fiber bundle with a high resolution for infrared imaging was fabricated using a stack-and-draw approach. The fiber bundle consisted of about 810,000 single fibers with an As2S3 glass core of 9 MUm in diameter and a polyetherimide (PEI) polymer cladding of 10 MUm in diameter. The As2S3/PEI fibers showed good transparency in the 1.5-6.5 MUm spectral region. It presented a resolution of ~45 lp/mm and a crosstalk of ~2.5%. Fine thermal images of a hot soldering iron tip were delivered through the fiber bundle. PMID- 26421538 TI - Critical-angle-based sensor with improved figure of merit using dip detection. AB - It is demonstrated theoretically and experimentally that a one-dimensional photonic crystal (1D-PC) made of quarter waves stacked on top of a prism exhibits both TE and TM resonances that coincide with the critical angle theta(c) when the 1D-PC is semi-infinite and with very little deviation from theta(c) for a finite 1D-PC. As a refractive index (RI) sensor, it behaves as a total internal reflection sensor at theta(c) with the advantage of detecting a narrow dip rather than an edge and enhanced figure of merit by increasing the number of periods in the 1D-PC. Using the diverging beam approach on an optical bench, a two channel sensor is demonstrated with a sensitivity of 120.9 deg/RIU and a detection limit of 1.9*10(-5) RIU. PMID- 26421539 TI - Photoswitchable and dye-doped bubble domain texture of cholesteric liquid crystals. AB - We demonstrate control of the transmittance of the naturally formed bubble domain (BD) texture of cholesteric liquid crystals (CLC) with negative dielectric anisotropy confined into a cell with homeotropic surface anchoring. By using a photosensitive chiral dopant with variable helical twisting power under light irradiation, control of packing density of bubbles, spatial patterning, and all optical switching between bistable states with different optical densities is achieved. By introducing dichroic dye into the CLC mixture, a bistable and switchable by applied electric field guest-host system is obtained. The light dimming properties of dye-doped BD CLC systems may lead to development of a wide range of applications. PMID- 26421540 TI - SU-8 nanoimprint fabrication of wire-grid polarizers using deep-UV interference lithography. AB - We describe a new fabrication method for making wire-grid polarizers for the visible and near-IR based on deep-UV interference lithography, nanoimprint, and glancing angle deposition. We fabricated aluminum wire grids with periods ranging from 375 to 230 nm with heights from 145 to 110 nm, respectively. The measured extinction ratio was as high as 220:1 at 1064 nm. The performance of the polarizer is limited by the roughness and porosity of the Al film and the underlying SU-8 structure. This method allows patterning of wire grids on any substrate material, which makes this an attractive method for fabricating wire grid micropolarizers in a timely and cost-effective manner. PMID- 26421541 TI - Speed optimized linear-mode high-voltage CMOS avalanche photodiodes with high responsivity. AB - Two different speed optimized avalanche photodiodes (APDs) fabricated in a 0.35 MUm standard high-voltage (HV) complementary metal-oxide-semiconductor (CMOS) process with a high unamplified responsivity (avalanche gain M=1) of 0.41 A/W at 670 nm are presented. These APDs differ regarding the effective doping of the deep p well (90% and 75%), using lateral well modulation doping. Compared to the 3 dB bandwidth of the unmodulated APD with 100% doping (850 MHz), this optimization leads to an improved bandwidth of 1.02 and 1.25 GHz for the 75% APD and 90% APD, respectively, both at a gain of M=50. PMID- 26421542 TI - Superluminal propagation through 500 m optical fiber via stimulated Brillouin scattering. AB - We have experimentally demonstrated superluminal propagation through a 500 m optical fiber using stimulated Brillouin scattering (SBS), which is the longest superluminal propagating distance reported so far, to the best of our knowledge. Brillouin-induced loss resonance for fast light generation of pump signals is achieved in a single frequency Brillouin lasing oscillator with a highly nonlinear fiber as the SBS medium. The single frequency operation is realized by embedding the saturable absorber fiber loop with an unpumped erbium-doped fiber. Consequently, signals with a pulse width of 710 ns experience a maximum advancement of 1330 ns. Furthermore, the effects of pulse width and the duty cycle of pump signals are also investigated. PMID- 26421543 TI - Electrically controllable extraordinary optical transmission in gold gratings on vanadium dioxide. AB - Highly tunable optical transmission through one-dimensional gold gratings patterned on top of a film of the phase transition material, vanadium dioxide (VO2), is demonstrated. Dense electrical integration is enabled by grating features that also function as electrical contacts to the VO2. Extraordinary optical transmission is observed in the VO2 insulator phase, and the optical transmission is extinguished by up to about 6 dB in a 170 nm thick VO2 film. Measurements of gratings with varying duty cycles demonstrate the dependence of the optical transmission and tuning on the device geometry. PMID- 26421544 TI - Phase measurement of soft x-ray multilayer mirrors. AB - We propose a new model enabling the extraction of the phase of a multilayer mirror from photocurrent measurements in the soft x rays. In this range, the effects of the mean free path of the electrons inside the stack can no longer be neglected, which prevents the phase reconstruction by conventional photocurrent measurements. The new model takes into account this phenomenon and thus extends up to the x rays the applicability range of the technique. This approach has been validated through a numerical and experimental study of chromium/scandium multilayers used near 360 eV. To our knowledge, this work constitutes the first measurement of the phase of a multilayer mirror in the soft x-ray range. PMID- 26421545 TI - Time-delay concealment and complexity enhancement of an external-cavity laser through optical injection. AB - The concealment of the time-delay signature (TDS) of chaotic external-cavity lasers is necessary to ensure the security of optical chaos-based cryptosystems. We show that this signature can be removed simply by optically injecting an external-cavity laser with a large linewidth-enhancement factor into a second, noninjection-locked, semiconductor laser. Concealment is ensured both in the amplitude and in the phase of the optical field, satisfying a sought-after property of optical chaos-based communications. Meanwhile, enhancement of the dynamical complexity, characterized by permutation entropy, coincides with strong TDS suppression over a wide range of parameters, the area for which depends sensitively on the linewidth-enhancement factor. PMID- 26421546 TI - Wide-field optical coherence microscopy of the mouse brain slice. AB - The imaging capability of optical coherence microscopy (OCM) has great potential to be used in neuroscience research because it is able to visualize anatomic features of brain tissue without labeling or external contrast agents. However, the field of view of OCM is still narrow, which dilutes the strength of OCM and limits its application. In this study, we present fully automated wide-field OCM for mosaic imaging of sliced mouse brains. A total of 308 segmented OCM images were acquired, stitched, and reconstructed as an en-face brain image after intensive imaging processing. The overall imaging area was 11.2*7.0 mm (horizontal*vertical), and the corresponding pixel resolution was 1.2*1.2 MUm. OCM images were compared to traditional histology stained with Nissl and Luxol fast blue (LFB). In particular, the orientation of the fibers was analyzed and quantified in wide-field OCM. PMID- 26421548 TI - Widely tunable telecom MEMS-VCSEL for terahertz photomixing. AB - We report frequency-tunable terahertz (THz) generation with a photomixer driven by an ultra-broadband tunable micro-electro-mechanical system vertical-cavity surface-emitting laser (MEMS-VCSEL) and a fixed-wavelength VCSEL, as well as a tunable MEMS-VCSEL mixed with a distributed feedback (DFB) diode. A total frequency span of 3.4 THz is covered in direct detection mode and 3.23 THz in the homodyne mode. The tuning range is solely limited by the dynamic range of the photomixers and the Schottky diode/photoconductor used in the experiment. PMID- 26421547 TI - Cryogenic-temperature profiling of high-power superconducting lines using local and distributed optical-fiber sensors. AB - This contribution presents distributed and multipoint fiber-optic monitoring of cryogenic temperatures along a superconducting power transmission line down to 30 K and over 20 m distance. Multipoint measurements were conducted using fiber Bragg gratings sensors coated with two different functional overlays (epoxy and poly methyl methacrylate (PMMA)) demonstrating cryogenic operation in the range 300-4.2 K. Distributed measurements exploited optical frequency-domain reflectometry to analyze the Rayleigh scattering along two concatenated fibers with different coatings (acrylate and polyimide). The integrated system has been placed along the 20 m long cryostat of a superconducting power transmission line, which is currently being tested at the European Organization for Nuclear Research (CERN). Cool-down events from 300-30 K have been successfully measured in space and time, confirming the viability of these approaches to the monitoring of cryogenic temperatures along a superconducting transmission line. PMID- 26421549 TI - Prediction of multiple resonance characteristics by an extended resistor-inductor capacitor circuit model for plasmonic metamaterials absorbers in infrared. AB - The resonance characteristics of plasmonic metamaterials absorbers (PMAs) are strongly dependent on geometric parameters. A resistor-inductor-capacitor (RLC) circuit model has been extended to predict the resonance wavelengths and the bandwidths of multiple magnetic polaritons modes in PMAs. For a typical metallic dielectric-metallic structure absorber working in the infrared region, the developed model describes the correlation between the resonance characteristics and the dimensional sizes. In particular, the RLC model is suitable for not only the fundamental resonance mode, but also for the second- and third-order resonance modes. The prediction of the resonance characteristics agrees fairly well with those calculated by the finite-difference time-domain simulation and the experimental results. The developed RLC model enables the facilitation of designing multi-band PMAs for infrared radiation detectors and thermal emitters. PMID- 26421550 TI - High-finesse sub-GHz-resolution spectrometer employing VIPA etalons of different dispersion. AB - We report a novel configuration of a two-stage virtually imaged phased array spectrometer that enables high-throughput sub-GHz spectroscopy at a high finesse (>750). Two etalons with different free spectral range and different dispersion are arranged in an orthogonal direction and spread the spectrum across two dimensions, with a greatly improved rejection ratio of white-light background noise. A proof-of-concept application for Brillouin spectroscopy is demonstrated. PMID- 26421551 TI - Complementary metal-oxide-semiconductor compatible 1060 nm photodetector with ultrahigh gain under low bias. AB - Falling on the tail of the absorption spectrum of silicon, 1060 nm Si detectors often suffer from low responsivity unless an exceedingly thick absorption layer is used, a design that requires high operation voltage and high purity epitaxial or substrate material. We report an all-silicon 1060 nm detector with ultrahigh gain to allow for low operation voltage (<4 V) and thin (200 nm) effective absorption layer, using the recently discovered cycling excitation process. With 1% external quantum efficiency, a responsivity of 93 A/W was demonstrated in a p/n junction device compatible with the complementary metal-oxide-semiconductor process. PMID- 26421552 TI - Unveiling the photonic spin Hall effect of freely propagating fan-shaped cylindrical vector vortex beams. AB - An intriguing photonic spin Hall effect (SHE) for a freely propagating fan-shaped cylindrical vector (CV) vortex beam in a paraxial situation is theoretically and experimentally studied. A developed model to describe this kind of photonic SHE is proposed based on angular spectrum diffraction theory. With this model, the close dependences of spin-dependent splitting on the azimuthal order of polarization, the topological charge of the spiral phase, and the propagation distance are accurately revealed. Furthermore, it is demonstrated that the asymmetric spin-dependent splitting of a fan-shaped CV beam can be consciously managed, even with a constant azimuthal order of polarization. Such a controllable photonic SHE is experimentally verified by measuring the Stokes parameters. PMID- 26421553 TI - Fast subcellular optical coherence photoacoustic microscopy for pigment cell imaging. AB - We developed a fast ultrahigh resolution optical coherence photoacoustic microscopy (FU-OCPAM) system by combining two complementary imaging modes of optical coherence microscopy (OCM) and photoacoustic microscopy (PAM) for cellular/subcellular imaging. The system used optical scanning to realize fast imaging speed and provided ultrahigh resolution of 1.24 and 0.59 MUm for OCM and PAM, respectively. We imaged the retinal pigment epithelium (RPE) to demonstrate the subcellular imaging capability of the FU-OCPAM system. The OCM and PAM images clearly showed the RPE cell morphology and reflected the complementary optical properties of scattering and absorption. A quantitative analysis of the RPE cells was made based on photoacoustic (PA) signals. The cell area mainly ranged from 80 to 300 MUm2, and had a linear relationship with the sum intensity of PA signals which mainly reflected the melanin content of the cells. The morphology and the PA signal could be used to identify qualitatively and quantitatively the aging and healthy states of the RPE cells. The results show the potential applications in studying the real-time cellular response to external stimulations and the progress of aging and diseases at the cellular level with FU-OCPAM. PMID- 26421554 TI - Distributed fiber surface plasmon resonance sensor based on the incident angle adjusting method. AB - We propose and demonstrate a distributed surface plasmon resonance (SPR) fiber sensor based on a novel, simple, and effective incident angle adjusting method. For normal fiber SPR sensors, it is hard to realize distributed sensing because it is hard to produce two dynamic ranges (resonance wavebands) with a great difference. The dynamic range depends on the incident angle, and therefore, we propose an incident angle adjusting method that is implemented by grinding an eccentric-core fiber to different angles, which helps to produce different SPR wavebands with great difference, thus realizing distributed sensing. In our two cascaded distributed configuration, with the refractive index range of 1.333 1.385, the fiber grind angles are 9 degrees and 17 degrees , the testing wavelength ranges are 613-760 nm and 745-944 nm, and the average testing sensitivities are 2826 nm/RIU and 4738 nm/RIU, respectively. Larger resonance wavelengths are associated with larger testing sensitivities. This distributed fiber sensor has important significance in the fields of multichannel liquid refractive indices and temperature self-reference measurements. PMID- 26421555 TI - Measurement of beam profiles by terahertz sensor card with cholesteric liquid crystals. AB - We demonstrate a sensor card with cholesteric liquid crystals (CLCs) for terahertz (THz) waves generated from a nonlinear crystal pumped by a table-top laser. A beam profile of the THz waves is successfully visualized as color change by the sensor card without additional electronic devices, power supplies, and connecting cables. Above the power density of 4.3 mW/cm2, the approximate beam diameter of the THz waves is measured using the hue image that is digitalized from the picture of the sensor card. The sensor card is low in cost, portable, and suitable for various situations such as THz imaging and alignment of THz systems. PMID- 26421556 TI - Shaping of light beams by 3D direct laser writing on facets of nonlinear crystals. AB - We demonstrate experimentally spatial-mode conversions of light beams generated in a quadratic nonlinear process by micron-scale structures placed on the facets of nonlinear crystals. These structures were printed on the crystal facets using a three-dimensional (3D) direct laser writing system. The functional structures were designed to modify the phase of the beam at specific wavelengths, thereby enabling conversion of a fundamental Gaussian laser beam into different high order Hermite-Gaussian modes, Laguerre-Gaussian modes, and zeroth-order Bessel beams of the second harmonic. This facet functionalization opens exciting new opportunities for robust and compact beam shaping in a nonlinear interaction without compromising the conversion efficiency. PMID- 26421557 TI - Compressive correlation imaging with random illumination. AB - Achieving high rates and high resolution in noisy conditions is a main desiderate for computational imaging. Here, we demonstrate both numerically and experimentally that binary illumination based on spatially random distributions provides superior imaging capabilities at high compression ratios while operating in noisy environments. The proposed method permits decreasing the time for image formation without adding complexity to the imaging system or compromising the resolution. PMID- 26421558 TI - Mechanoluminescence of ZnS:Mn phosphors and its correlation to impact energy and contact geometry. AB - The influence of the impulsive mechanical energy and the contact geometrical parameters on stress-induced light emission of ZnS-based phosphors dispersed in polymeric matrix is investigated using modified impact test equipment. At a low to moderate energy region, luminescent pulses consist of two distinguishable peaks that can be assigned to a loading and unloading sequence, respectively. Transient characteristics are found to be independent of the external excitation. An increment of peak emission intensity with higher impact energy and smaller tip diameter indicates a significant relationship of mechanoluminescence to the geometry of contact. Intense emission deviating from the linearity and an absence of the secondary peak are suggested to be the consequence of fractoluminescence. PMID- 26421559 TI - Stabilized phase detection of heterodyne sum frequency generation for interfacial studies. AB - We present a collinear-geometry heterodyne sum frequency generation (HD-SFG) method for interfacial studies. The HD detection is based on a collinear SFG configuration, in which picosecond visible and femtosecond IR beams are used to first produce a strong local oscillator and then to generate weak SFG signals from an interface. A time-delay compensator, consisting of an MgF2 window, is placed before the sample to introduce the time delay between the local oscillator and the interfacial SFG signals for spectral interferometry. Our HD-SFG method exhibits advantages of long-time phase stability. It is not sensitive to sample heights, does not require reflection correction, and is easy to implement. PMID- 26421560 TI - Robust postfabrication trimming of ultracompact resonators on silicon on insulator with relaxed requirements on resolution and alignment. AB - One of the main drawbacks of the high-index-contrast silicon-on-insulator platform in integrated photonics is the high sensitivity of the resonance wavelength of resonators to dimensional variations caused by fabrication imperfection. In this work, we experimentally demonstrate an accurate postfabrication trimming technique for compensating the fabrication-induced variations in the resonance properties of nanophotonic devices. Using this technique, we reduce the variation of the resonance wavelength of 4 MUm diameter microdonut resonators by more than 1 order of magnitude to about 25 pm, which is adequate for most interconnect, optical signal processing, and sensing applications. In addition, our proposed technique has improved misalignment toleration and throughput compared to previous reports. PMID- 26421561 TI - Proposed high-speed micron-scale spatial light valve based on a silicon-graphene hybrid structure. AB - We propose a new ultracompact CMOS-compatible variable-transmission spatial light valve based on a silicon-graphene hybrid structure. Normally incident ~1560 nm light can be coupled to a silicon-graphene-based 1D photonic crystal cavity through a perturbation-based diffractive coupling scheme. The lightwave modulation is achieved by tuning the Fermi level of the graphene, which can change both the loss and the resonant wavelength of the cavity. Based on finite difference time-domain simulation, the modulation depth is larger than 10 dB with driving voltage of about 4.8 V(pp) while the modulation speed is estimated to be higher than 45 GHz. PMID- 26421562 TI - Noncollinear third-harmonic generation with large angular acceptance by noncritical phase matching in KDP crystal. AB - The scheme of prefocusing to focus sum frequency generation (SFG) without a lens is proposed and experimentally verified in this study. Noncollinear type-I noncritical phase-matching SFG to generate a third-harmonic wave with large angular acceptance is presented. The principle of broad angular acceptance and the advantages of this PM configuration are also described in detail. External angular bandwidth of 7.33 degrees for noncollinear SFG was measured in a 2 mm long KH2PO4 (KDP) crystal, which is in reasonably good agreement with the theoretical calculation. The mechanism of broadband SFG and the prefocusing scheme make it possible for the realization of convergent third-harmonic generation without involving a lens, which provides a promising way to avoid damage to optical components during the focusing of high-energy UV light in high power laser facilities. PMID- 26421563 TI - Dispersion of coupled mode-gap cavities. AB - The dispersion of a coupled resonator optical waveguide made of photonic crystal mode-gap cavities is pronouncedly asymmetric. This asymmetry cannot be explained by the standard tight binding model. We show that the fundamental cause of the asymmetric dispersion is the inherent dispersive cavity mode profile; i.e., the mode wave function depends on the driving frequency, not the eigenfrequency. This occurs because the photonic crystal cavity resonances do not form a complete set. We formulate a dispersive mode coupling model that accurately describes the asymmetric dispersion without introducing any new free parameters. PMID- 26421564 TI - Self temperature regulation of photothermal therapy by laser-shared photoacoustic feedback. AB - This article describes a laser-shared photothermal system that achieves tight temperature regulation by frequency-domain photoacoustic (FD-PA) feedback. To this end, a continuous-wave laser system was designed with arbitrarily modulatable laser intensity. And, by fast alternating in the time domain between a constant laser intensity for photothermal heating and a modulated laser intensity for FD-PA temperature measurement, photothermal temperature variations are captured by FD-PA in real time. A proportional-integral-derivative (PID) controller monitors the feedback from FD-PA measurements and controls photothermal heating dose accordingly, thus stabilizing the temperature at preset values. The proposed system is demonstrated to achieve ultrafast temperature measurement at a 4 kHz rate, and with proper averaging, the measurement and regulation accuracy are 0.75 deg and 0.9 deg respectively. PMID- 26421565 TI - Two-frequency pulsed YLiF4:Nd lasing out of the principal axes and THz generation. AB - Thanks to a propagation direction at 50.3 degrees from the c axis in a LiYF4:Nd crystal, we have equalized the emission cross-sections at 1047 and 1053 nm, respectively, for extraordinary and ordinary waves. The double refraction is used to balance the "o" and "e" pumping. Actively Q-switching the laser cavity leads to simultaneous pulses with duration less than 10 ns. Frequency conversion to THz radiation was performed through difference frequency mixing in two nonlinear crystals: GaSe and OH1. In the first case, we obtained 132 nW and in the second case we obtained 51 nW THz power at 6.67 kHz repetition rate. PMID- 26421566 TI - Coherence enhancement of a chirped DFB laser for frequency-modulated continuous wave reflectometry using a composite feedback loop. AB - We demonstrate efficient coherence enhancement of a chirped distributed feedback (DFB) laser for frequency-modulated continuous-wave (FMCW) reflectometry. Both sweep nonlinearity and broadband stochastic frequency noises during the laser chirp are efficiently suppressed by a composite feedback loop. The residual frequency error relative to a perfect linear chirp is shown to be about 89 kHz for a laser chirp of 50 GHz in 100 ms, compared with 44 MHz with the loop open. The broadband frequency noise suppression of the frequency-swept laser greatly improves its coherence, leading to a higher signal-to-noise ratio and a significantly extended measurement range in FMCW reflectometry ranging. We demonstrate a 2 mm transform-limited spatial resolution at a range window of 50 m and a 17.5 cm spatial resolution at an extended measurement range of 750 m, which is about 15 times the intrinsic laser round-trip coherence length. PMID- 26421567 TI - Twisted Schell-model beams with axial symmetry. AB - The problem of when a twist can be impressed on a partially coherent beam is solved for Schell-model fields endowed with axial symmetry. A modal analysis can be performed for any such beam, thus permitting evaluation of whether it will withstand the twisting process. Beyond exemplifying some twistable beams, it is shown that, for certain correlation functions, the beam cannot be twisted, no matter how the numerical parameters are chosen. PMID- 26421568 TI - Generation of hyper-parametric oscillations in silica microbubbles. AB - Cavity resonant enhanced stimulated Raman scattering (SRS), four-wave mixing, and broadband hyper-parametric oscillation in silica microbubble whispering gallery mode resonators (WGMR) in forward and backward directions are reported in this Letter. We show that microbubbles can operate not only in a highly ideal two photon emission regime, but also generate combs, both natively and multi-mode spaced. The nonlinear process is phase matched because of the interaction of different mode families of the resonator. PMID- 26421569 TI - Tuning nanosecond transient absorption in a-Ge25As10Se65 thin films via background illumination. AB - In this Letter, we report for the first time, to the best of our knowledge, continuous-wave laser background illumination (BGI) as a simple and yet useful tool to tune nanosecond transient absorption (TA) in a-Ge25As10Se65 thin films. In our experiments, we observed remarkable blueshift in TA as a function of the BGI intensity. Strikingly, relaxations of TA in background-illuminated samples are much faster than the as-prepared samples. This observation provides new insights into the bond-breaking mechanism. Further, decay time constants of TA are wavelength dependent, which signifies that excited carriers have a longer lifetime in deep traps than in shallow traps. PMID- 26421570 TI - Polarization properties of the Airy beam. AB - Polarization of paraxial Airy beam solutions of Maxwell's equations and its evolution with propagation have been studied. We experimentally demonstrate the existence of the cross-polarization component of the Airy beam, typical of nonplanar phase fronts, and study its evolution with propagation. PMID- 26421571 TI - Dual-period tunable phase grating using polymer stabilized blue phase liquid crystal. AB - Dual-period tunable phase grating using polymer stabilized blue phase liquid crystal is demonstrated by controlling its driving scheme. High efficiencies of 35.3% for the small-period phase grating and 28.7% for the large-period phase grating have been achieved because of the rectangular-like phase profile which shows good agreement with the simulation results. The diffraction angle can be alternatively tuned, as well as the diffraction efficiency. Moreover, this device also possesses polarization independency and fast response with a rise time of 826 MUs and a decay time of 1.143 ms which shows great potential for diffractive optics. PMID- 26421572 TI - Coupling of plasmon and photon modes in a graphene-based multilayer structure. AB - We propose a graphene-based plasmonic heterostructure in which a new class of plasmon polariton modes can be realized via fundamental coupling of conventional graphene plasmons (GPs) and spoof surface plasmons or radiation modes. We name these electromagnetic modes coupled graphene plasmon polaritons (CGPPs). It is found that the properties of the CGPPs can be tuned by the geometry of the heterostructure, the material used to fill the holes, and the electron density in graphene. Most interestingly, we show that it is possible to achieve CGPPs with about 10 times enhancement of wave localization or about 300 times enhancement of propagation length, compared to usual GPs through varying device parameters. These features can be applied to tunable terahertz and infrared plasmonic devices. PMID- 26421573 TI - Four-wave-mixing in the loss low submicrometer Ta2O5 channel waveguide. AB - A degenerate four-wave-mixing (FWM) operation in the Ta2O5 submicrometer channel waveguide has been successfully demonstrated. The propagation loss of 1.5 dB/cm and total insertion loss of 5.1 dB are realized in a 12.6 mm long waveguide with inverse taper structure. The wavelength and quadratic pumping power-dependent measurements on optical transmission confirm FWM performance and characterize the nonlinearity of waveguide. The conversion efficiency of -50 dB at coupled pump power of 40 mW is observed, suggesting that the nonlinear refractive index of Ta2O5 waveguide at 1550 nm is estimated to be 1*10(-14) cm2/W. Our primary results indicate that the Ta2O5 submicrometer channel waveguide has great potential in developing nonlinear waveguide applications. PMID- 26421574 TI - Near-field radiative transfer between magneto-dielectric uniaxial anisotropic media. AB - We investigate the near-field radiative heat transfer between two semi-infinite magneto-dielectric uniaxial anisotropic media (MDUAM). SiC nanowires embedded in metamaterials are used to implement electric and magnetic anisotropy, which leads to the hyperbolic dispersion relation for both TE and TM waves. The results show that the TM and TE waves can support both hyperbolic modes and surface modes and that there exist additional modes contributing to the heat transfer for TE waves. Moreover, the MDUAM exhibit super-Planckian thermal emission at ultra-broad bandwidths. This work paves the way for applying the near-field radiative heat transfer in the area of thermal management and energy harvesting. PMID- 26421575 TI - Spectral modification of whispering-gallery-mode resonances in spheroidal resonators due to interaction with ultra-small particles. AB - The recently developed general ab initio theory of nanoparticle-induced modifications of the spectrum of whispering gallery modes of optical spheroidal resonators is applied to the case in which distinct particle-induced resonances overlap and cannot be resolved. This situation occurs in the case of resonances with low Q-factors and/or ultra-small particles. The position of the single resonance observed in these situations depends on the strengths and widths of the overlapping resonances. We determine this position by considering the spectral characteristics of the total power scattered by the resonator. The obtained theoretical results are compared against the available experimental data and heuristic theories. PMID- 26421576 TI - Continuous wave terahertz radiation from antennas fabricated on C12-irradiated semi-insulating GaAs. AB - We demonstrate continuous wave (CW) terahertz generation from antennas fabricated on C12-irradiated semi-insulating (SI) GaAs substrates. The dark current drawn by the antennas fabricated on irradiated substrates is ~3 to 4 orders of magnitude lower compared to antennas fabricated on un-irradiated substrates, while the photocurrents decrease by only ~1.5 orders of magnitude. This can be attributed to the strong reduction of the carrier lifetime that is 2.5 orders of magnitude, with values around tau(rec)=0.2 ps. Reduced thermal heating allows for higher bias voltages to the irradiated antenna devices resulting in higher CW terahertz power, just slightly lower than that of low-temperature grown GaAs (LT GaAs)at similar excitation conditions. PMID- 26421577 TI - Fluorescence intensity ratio method for temperature sensing. AB - A thermometry method based on the ratio between the valley intensity formed by fluorescence peak overlap and the peak fluorescence intensity has been developed. Excited by a 405 nm laser, the valley to peak ratio (VPR) of the emissions originating from 5D0 to 7F2 Stark sublevels in Eu3+-doped CaWO4 shows a monotonic change with temperature. Spectrum analysis indicates that this monotonic increase is caused by the homogeneous broadening of the spectral lines as the temperature increases. The relative sensitivity S(r) is in the magnitude of 10(-4) K(-1) in the experimental temperature range of 303-573 K. PMID- 26421578 TI - Angular dependence of filament-induced plasma emission from a GaAs surface. AB - Quantitative measurements of the angular distribution of the plasma line emission from a gallium arsenide (GaAs) target irradiated by a single laser-air filament are reported. These enable reliable estimates of the stand-off ranges possible with single-filament-induced laser-induced breakdown spectroscopy materials detection. PMID- 26421579 TI - Linear response, multi-order grating interferometry using a reversal shearing imaging system. AB - Linear response, multi-order grating interferometry is proposed to measure grating displacement. The system, a combination of a reversal shearing interferometer and an imaging system, enables calculating multi-order, integrated intensity signals with a linear waveform response. A theoretical multi-order model for the linear response signal analysis is presented with a Fourier series expansion. The results of the experiment, which prove the validity of the theoretical model, indicate a linear response to displacement with a linearity of 98.7% and a resolution of 10 nm. We conclude that the proposed method enables the development of a new class of potent linear response grating interferometry for displacement metrology. PMID- 26421580 TI - Error probability performance of a short-reach multicore fiber optical interconnect transmission system. AB - A standalone module for rectangular array multicore fiber (MCF)-based optical interconnect (OI) is realized that includes inherent intercore crosstalk and provides space division multiplexed coupling/decoupling of optical power. The module is integrated in a short-reach communication system to provide bit error probability (BEP). Next, a closed-form equation for BEP applicable to MCF OI with intercore crosstalk is derived. For characteristic parameters of the module, results obtained by two approaches agree within 1% for 40 Gbps per channel and predict an error-free transmission of aggregated data rate of 2.5 Tbps through the MCF OI under consideration. PMID- 26421581 TI - Real-time multiplexed digital cavity-enhanced spectroscopy. AB - Cavity-enhanced spectroscopy is a sensitive optical absorption technique but one where the practical applications have been limited to studying small wavelength ranges. This Letter shows that wideband operation can be achieved by combining techniques usually reserved for the communications community with that of cavity enhanced spectroscopy, producing a multiplexed real-time cavity-enhanced spectrometer. We use multiple collinear laser sources operating asynchronously and simultaneously while being detected on a single photodetector. This is synonymous with radio frequency (RF) cellular systems in which signals are detected on a single antenna but decoded uniquely. Here, we demonstrate results with spectra of methyl salicylate and show parts-per-billion per root hertz sensitivity measured in real-time. PMID- 26421582 TI - 10 m/25 Gbps LiFi transmission system based on a two-stage injection-locked 680 nm VCSEL transmitter. AB - A 10 m/25 Gbps light-based WiFi (LiFi) transmission system based on a two-stage injection-locked 680 nm vertical-cavity surface-emitting laser (VCSEL) transmitter is proposed. A LiFi transmission system with a data rate of 25 Gbps is experimentally demonstrated over a 10 m free-space link. To the best of our knowledge, it is the first time a two-stage injection-locked 680 nm VCSEL transmitter in a 10 m/25 Gbps LiFi transmission system has been employed. Impressive bit error rate performance and a clear eye diagram are achieved in the proposed systems. Such a 10 m/25 Gbps LiFi transmission system provides the advantage of a communication link for higher data rates that could accelerate the deployment of visible laser light communication. PMID- 26421583 TI - Polarization sensitive phase-shifting Mirau interferometry using a liquid crystal variable retarder. AB - We present all-optical motionless arrangement for polarization sensitive phase shifting (P-S) interferometry, where the phase shifts are accurately implemented by a liquid crystal variable retarder (LCVR). The LCVR is used as a polarization selective device capable of introducing a computer-controlled phase retardance between signal and reference waves with orthogonal linear polarizations. The proposed optical P-S is deployed in a polarization adapted common-path Mirau interferometer. Application of the method to a setup using the Michelson interference objective or Linnik interference module is also outlined. The accuracy of the quantitative phase reconstruction is examined theoretically, and a possibility to reduce the optical path difference error below 1/200 wavelength is demonstrated experimentally. Benefits and application potential of the polarization P-S interferometry supported by versatile liquid crystal devices are also discussed. PMID- 26421584 TI - Conscientious Objection or Dishonorable Disobedience? PMID- 26421585 TI - Cyclophosphamide versus ifosfamide for paediatric and young adult bone and soft tissue sarcoma patients. AB - BACKGROUND: Alkylating agents, such as cyclophosphamide and ifosfamide, play a major role in the improved survival of children and young adults with bone and soft tissue sarcoma. However, there is still controversy as to their comparative anti-tumour efficacy and possible adverse effects. This is the second update of the first systematic review evaluating the state of evidence on the effectiveness of cyclophosphamide as compared to ifosfamide for paediatric and young adult patients with sarcoma. OBJECTIVES: The primary obective was to compare the effectiveness, that is response rate, event-free survival and overall survival, of cyclophosphamide with that of ifosfamide for paediatric and young adult patients with sarcoma. Secondary objectives were to determine effects of these agents on toxicities (including late effects) and quality of life. SEARCH METHODS: We searched CENTRAL (The Cochrane Library 2015, issue 2), MEDLINE/PubMed (from 1966 to March 2015) and EMBASE/Ovid (from 1980 to March 2015) with prespecified terms. In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases (www.controlled trials.com; searched June 2015). SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing cyclophosphamide and ifosfamide for the treatment of different types of sarcoma in paediatric and young adult patients (aged less than 30 years at diagnosis). Chemotherapy other than either cyclophosphamide or ifosfamide should have been the same in both treatment groups. DATA COLLECTION AND ANALYSIS: Two authors independently performed the study selection. MAIN RESULTS: No studies meeting the inclusion criteria of the review were identified. AUTHORS' CONCLUSIONS: No RCTs or CCTs comparing the effectiveness of cyclophosphamide and ifosfamide in the treatment of bone and soft tissue sarcoma in children and young adults were identified. Therefore no definitive conclusions can be made about the effects of cyclophosphamide and ifosfamide in these patients. Based on the currently available evidence, we are not able to give recommendations for clinical practice. More high-quality research is needed. PMID- 26421586 TI - Outcome of patients with clinically node-positive bladder cancer undergoing consolidative surgery after preoperative chemotherapy: The M.D. Anderson Cancer Center Experience. AB - PURPOSE: Patients with urothelial cancer with nodal metastasis have a poor prognosis, with many deemed incurable. We report outcomes of a prospective clinical protocol of patients with clinically node-positive disease treated via a multimodality treatment approach. PATIENTS AND METHODS: A total of 55 patients with bladder urothelial carcinoma with concurrent node-positive disease including pelvic nodal and retroperitoneal lymph node (RPLN) involvement underwent preoperative chemotherapy followed by consolidative surgery between 1995 and 2010. Associations between clinicopathologic factors and outcomes were analyzed using log-rank test and Cox regression analysis. RESULTS: Median cancer-specific survival (CSS) was 26 months (95% CI: 12.9-not applicable) for all patients. A total of 30 (55%) patients had pN0 category disease at the time of surgical extirpation. Despite radiologic complete response after chemotherapy, 6 of 21 patients (29%) had pN+category disease. The 5-year CSS rate was 66% for pN0 category disease vs. 12% for pN+category disease (P<0.001). Radiologic complete response to chemotherapy was associated with a 5-year CSS rate of 60% vs. 33% for a partial response (P = 0.038). Although no recurrences occurred within the lymphadenectomy template, 2 (14%) patients with cM1 RPLN disease who did not undergo RPLN dissection had recurrences in the RPLN basin and died within 6 months. CONCLUSION: Multimodality treatment approach with upfront chemotherapy followed by surgery can result in a 66% 5-year CSS rate for patients rendered as having pN0 category disease despite initially presenting with node-positive disease. However, as those with residual disease do so poorly, further efforts in refining selection of patients for surgical consolidation are needed. PMID- 26421587 TI - Targeted p21(WAF1/CIP1) activation by miR-1236 inhibits cell proliferation and correlates with favorable survival in renal cell carcinoma. AB - BACKGROUND: microRNA's function to silence gene expression by targeting 3'UTR regions has been widely studied. And microRNAs, similar to small double-stranded RNAs, have also been implicated to gene activation triggered by promoter targeted, which is known as RNA activation (RNAa). p21(WAF1/CIP1) (p21), as a key negative regulator of cell proliferation, is frequently down-regulated in various cancers, making it an ideal target for RNAa-based activation to restore its tumor suppressor function in renal cell carcinoma (RCC). METHODS: Real-time polymerase chain reaction was used to identify the expression of miR-1236 and p21 in RCC cell lines and clinical specimens. Protein expression and signaling pathway modulation were validated through Western blot analysis, whereas p21, direct target of miR-1236, was validated by using chromatin immunoprecipitation assay. The Kaplan-Meier method and the log-rank test were used to calculate overall survival. The CellTiter 96((r)) AQueous One Solution Cell Proliferation Assay, colony formation assay, and 5-ethynyl-2'-deoxyuridine assays were used to evaluate the effect of miR-1236 on RCC cell proliferation. RESULTS: In this study, we found that miR-1236 and p21 were both significantly down-regulated in RCC tissues and cell lines. Combined low expression of both miR-1236 and p21 emerged as an independent prognostic factor for poor clinical survival in 45 patients with RCC. Chromatin immunoprecipitation assay in the human RCC cell lines 786-O and ACHN showed that miR-1236 directly targeted the p21 promoter and that its activation may provide a plausible link between the positive correlation of miR-1236 and p21 in RCC specimens. Functional experiments showed that increased miR-1236 expression inhibited cell proliferation, and decreased CDK4/6 and cyclin D1 expression. Furthermore, knockdown of p21 using small interfering RNA reversed the antiproliferation function of miR-1236, whereas silencing the p21 expression attenuated the function of miR-1236 in RCC cells. CONCLUSION: Our findings provide insight into the specific RNAa of miR-1236-targeted p21 promoter activation in suppressing RCC cell proliferation. Considering the poor prognostic outcomes associated with reduced miR-1236 and p21 expression, our data imply that these factors likely play important antitumor effects in RCC progression. PMID- 26421588 TI - Variation in Patient Characteristics and Outcomes Between Early and Delayed Surgery in Poor-Grade Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: There is no consensus regarding the optimal timing for surgery for poor-grade aneurysmal subarachnoid hemorrhage. OBJECTIVE: To retrospectively evaluate variation in patient characteristics and outcomes between early and delayed surgery groups. METHODS: Poor-grade aneurysmal subarachnoid hemorrhage was defined as a World Federation of Neurosurgical Societies grade of IV or V after resuscitation. Early surgery was defined as surgery performed within 72 hours of ictus, and delayed surgery was defined as surgery after 72 hours. Outcomes were assessed by modified Rankin score. The mean time of follow-up was 12.5 +/- 3.4 months. RESULTS: Of the 118 patients included in the study, 80 (68%) underwent early surgery and 38 (32%) underwent delayed surgery. Patients with brain herniation (P < .001) and a lower Fisher grade (P = .02) more often underwent early surgery. Patients in the early group more often underwent decompressive craniectomy (P < .001). Postoperative complications and length of hospital stay did not differ, and outcomes were similar between the 2 groups. Forty (34%) patients had an excellent outcome (modified Rankin score 0-1). Multivariate analysis showed a slight trend toward an excellent outcome in the early surgery group. Younger age, World Federation of Neurosurgical Societies grade IV after resuscitation, and middle cerebral artery aneurysms were independent predictors of an excellent outcome. CONCLUSION: Although patients with brain herniation and a lower Fisher grade were more likely to undergo early surgery, there was a slight trend toward an excellent outcome in the early surgery group. Patients with a younger age, World Federation of Neurosurgical Societies grade IV after resuscitation, and middle cerebral artery aneurysms were more likely to experience an excellent outcome. PMID- 26421589 TI - Detection of Cerebral Vasospasm Following Aneurysmal Subarachnoid Hemorrhage Using Motor Evoked Potentials. AB - BACKGROUND: Early detection of vasospasm (VS) following aneurysmal subarachnoid hemorrhage (aSAH) is vital to trigger therapy and to prevent infarction and subsequent permanent neurological deficit. Although motor evoked potentials (MEPs) are a well-established method for intraoperative detection of cerebral VS and cerebral ischemia during aneurysm surgery, there are no studies investigating the diagnostic value of MEPs for detecting delayed VS following aSAH in an intensive care unit. OBJECTIVE: A prospective study was conceived to assess the diagnostic accuracy of MEPs in comparison with digital subtraction angiography. METHODS: MEP threshold changes were determined in patients both with and without angiographic VS following high-grade aSAHs. Sensitivity, specificity, and the positive and negative predictive values of significant MEP threshold increases, which indicate angiographic VS, were calculated. RESULTS: In all patients experiencing VS of the arteries supplying cerebral motor areas, a minimal MEP threshold increase of 50 mA (mean 66.25 mA) was observed, whereas a maximum MEP threshold increase of 30 mA was observed in patients without VS. Therefore, an increase from a baseline of >=50 mA was considered significant and resulted in a sensitivity of 0.83, a specificity of 0.92, a positive predictive value of 0.83, and a negative predictive value of 0.92. CONCLUSION: VS following aSAH can be detected accurately by using MEPs. MEPs are a feasible bedside tool for online VS detection in an intensive care unit and, therefore, may complement existing diagnostic tools. PMID- 26421590 TI - Predictors of Poor Quality of Life 1 Year After Subarachnoid Hemorrhage. AB - BACKGROUND: Risk factors for poor quality of life (QOL) after subarachnoid hemorrhage (SAH) remain poorly described. OBJECTIVE: To identify the frequency and predictors of poor QOL 1 year after SAH. METHODS: We studied 1-year QOL in a prospectively collected cohort of 1181 consecutively admitted SAH survivors between July 1996 and May 2013. Patient clinical, radiographic, surgical, and acute clinical course information was recorded. Reduced QOL (overall, physical, and psychosocial) at 1 year was assessed with the Sickness Impact Profile and defined as 2 SD below population-based normative Sickness Impact Profile values. Logistic regression leveraging multiple imputation to handle missing data was used to evaluate reduced QOL. RESULTS: Poor overall QOL was observed in 35% of patients. Multivariable analysis revealed that nonwhite ethnicity, high school education or less, history of depression, poor clinical grade (Hunt-Hess Grade >=3), and delayed infarction were predictors of poor overall and psychosocial QOL. Poor physical QOL was additionally associated with older age, hydrocephalus, pneumonia, and sepsis. At 1 year, patients with poor QOL had increased difficulty concentrating, cognitive dysfunction, depression, and reduced activities of daily living. More than 91% of patients with poor QOL failed to fully return to work. These patients frequently received physical rehabilitation, but few received cognitive rehabilitation or emotional-behavioral support. CONCLUSION: Reduced QOL affects as many as one-third of SAH survivors 1 year after SAH. Delayed infarction is the most important in-hospital modifiable factor that affects QOL. Increased attention to cognitive and emotional difficulties after hospital discharge may help patients achieve greater QOL. PMID- 26421592 TI - Long-Term Results of Stereotactic Radiosurgery for Skull Base Meningiomas. AB - BACKGROUND: Gamma knife radiosurgery (GKRS) is well established in the management of inaccessible, recurrent, or residual benign skull base meningiomas. Most series report clinical outcome parameters and complications in the short intermediate period after radiosurgery. Reports of long-term tumor control and neurological status are still lacking. OBJECTIVE: To report the presentation, treatment, and long-term outcome of skull base meningiomas after GKRS. METHODS: From a prospectively collected institutional review board-approved database, we selected patients with a World Health Organization grade I skull base meningioma treated with a single-session GKRS and a minimum of 60 months follow-up. One hundred thirty-five patients, 54.1% males (n = 73), form the cohort. Median age was 54 years (19-80). Median tumor volume was 4.7 cm (0.5-23). Median margin dose was 15 Gy (7.5-36). Median follow-up was 102.5 months (60.1-235.4). Patient and tumor characteristics were assessed to determine the predictors of neurological function and tumor progression. RESULTS: At last follow-up, tumor volume control was achieved in 88.1% (n = 119). Post-GKRS clinical improvement or stability was reported in 61.5%. The 5-, 10-, and 15-year actuarial progression-free survival rates were 100%, 95.4%, and 68.8%, respectively. Favorable outcome (both tumor control and clinical preservation/improvement) was attained in 60.8% (n = 79). Pre-GKRS performance status (Karnofsky Performance Scale) was shown to influence tumor progression (P = .001) and post-GKRS clinical improvement/preservation (P = .003). CONCLUSION: GKRS offers a highly durable rate of tumor control for World Health Organization grade I skull base meningiomas, with an acceptably low incidence of neurological deficits. The Karnofsky Performance Scale at the time of radiosurgery serves as a reliable long-term predictor of overall outcome. ABBREVIATIONS: ARE, adverse radiation effectGKRS, Gamma knife radiosurgeryKPS, Karnofsky Performance ScaleWHO, World Health Organization. PMID- 26421593 TI - Lung cancer treatment is influenced by income, education, age and place of residence in a country with universal health coverage. AB - Selection of lung cancer treatment should be based on tumour characteristics, physiological reserves and preferences of the patient. Our aims were to identify and quantify other factors associated with treatment received. Lung cancer patient data from 2002 to 2011 were obtained from the national population-based Cancer Registry of Norway, Statistics Norway and the Norwegian Patient Register. Multivariable logistic regression examined whether year of diagnosis, age, sex, education, income, health trust, smoking status, extent of disease, histology and comorbidities were associated with choice of treatment; surgery or radical or palliative radiotherapy, within 1 year of diagnosis. Among the 24,324 lung cancer patients identified, the resection rate remained constant while the proportion of radical radiotherapy administered increased from 8.6 to 14.1%. Older patients, those with lower household incomes and certain health trusts were less likely to receive any treatment. Lower education and the male gender were identified as negative predictors for receiving surgery. Smoking history was positively associated with both radical and palliative radiotherapy, while comorbidity and symptoms were independently associated with receiving surgery and palliative radiotherapy. Although Norway is a highly egalitarian country with a free, universal healthcare system, this study indicates that surgery and radical and palliative radiotherapy were under-used among the elderly, those with a lower socioeconomic status and those living in certain health trusts. PMID- 26421594 TI - Correlation of minimal extrathyroidal extension with pathologic features of lymph node metastasis in patients with papillary thyroid carcinoma. AB - BACKGROUND: The impact of minimal extrathyroidal extension (mETE) to the prognosis of patients with papillary thyroid carcinoma (PTC) is controversial. In this study, we investigated whether mETE is related to the aggressive biology of metastatic lymph node (LN) in patients with PTC. METHODS: A retrospective review of 369 patients who had biopsy-confirmed cervical LN metastasis after initial surgery for PTC was conducted. The correlations of mETE with the specific features of metastatic LNs such as the LN size, number, LN ratio, and presence of extranodal extension (ENE) were statistically analyzed. RESULTS: Size of the primary tumor (>=1 cm) had independent correlations to mETE (HR = 5.750). While mETE was related to number of metastatic LNs (>=5), LN ratio (>=0.31) and ENE in univariate analysis, only ENE (HR = 2.322) was independently correlated to mETE in our series. Along with mETE, size of primary tumor (>=1 cm) had significant impact on ENE (HR = 2.107). CONCLUSION: Minimal ETE particularly those with larger primary tumor (>=1 cm) may be still considered as a significant factor regarding the management of cervical LNs in patients with PTC. PMID- 26421595 TI - Trauma-induced schwannoma of the recurrent laryngeal nerve after thyroidectomy. AB - Laryngeal schwannomas are rare, benign tumors, most often arising from the superior laryngeal nerve. We describe a case of a 68-year-old female with a laryngeal schwannoma of the recurrent laryngeal nerve after traumatic injury. We postulate that trauma to the recurrent laryngeal nerve during thyroidectomy or thyroplasty incited growth of a nerve sheath tumor. This is the first reported case of a trauma-induced schwannoma of the recurrent laryngeal nerve and second case of a recurrent laryngeal nerve schwannoma. Although rare, this case demonstrates that these tumors should be considered during workup of vocal cord paresis after surgery or failed thyroplasty. Laryngoscope, 126:1408-1410, 2016. PMID- 26421596 TI - Protective immunity against acute toxoplasmosis in BALB/c mice induced by a DNA vaccine encoding Toxoplasma gondii 10 kDa excretory-secretory antigen (TgESA10). AB - Toxoplasma gondii 10 kDa excretory-secretory antigen (TgESA10) is involved in the early stages of host invasion. The aim of this study was to evaluate the immune protective efficacy of a DNA vaccine encoding TgESA10 gene against acute T. gondii infection in mice. The gene sequence encoding TgESA10 was inserted into the eukaryotic expression vector pVAX I, and the efficacy of intramuscular vaccination of BALB/c mice with pVAX-ESA10 was analyzed. Mice immunized with pVAX ESA10 elicited high titers of total IgG, IgG1, IgG2a, IgA and IgM antibodies, while IgE showed no changes. Analysis of cytokine profiles revealed significant increases of IFN-gamma, IL-4 and IL-17, while no significant changes were detected in TGF-beta1. Additionally, we found that pVAX-ESA10 enhanced the activation of CD4(+) and CD8(+) T cells and the expression of MHC-I and MHC-II molecules in spleen in mice. Immunization with pVAX-ESA10 significantly prolonged survival time (14.3 +/- 1.7 days) after challenge infection with the virulent T. gondii RH strain, compared with the control groups which died within 8 days. These results suggested that TgESA10 DNA vaccine could trigger strong humoral and cellular responses and induce partial protection against acute toxoplasmosis. PMID- 26421597 TI - Preferences for end-of-life care among community-dwelling older adults and patients with advanced cancer: A discrete choice experiment. AB - Singapore is in the midst of several healthcare reforms in efforts to finance and deliver health services for a rapidly aging population. The primary focus of these reforms is to make healthcare services, including those at the end of life (EOL), affordable. Given the increasingly high health care costs at the EOL, policy makers need to consider how best to allocate resources. One strategy is to allocate resources based on the preferences of sub-populations most likely to be affected. This paper thus aims to quantify preferences for EOL care both among community dwelling older adults (CDOAs) and among patients with a life-limiting illness. A discrete choice experiment was administered to CDOAs and advanced cancer patients in Singapore and willingness to pay (WTP) for specific EOL improvements was estimated. We find that patients have a higher WTP for nearly all EOL attributes compared with CDOAs. We also show that, for both groups, moderate life extension is not the most important consideration; WTP for one additional life year is lower than common thresholds for cost-effectiveness. Irrespective of whose preference are considered, the results highlight the importance of pain management and supporting home deaths at the EOL, perhaps at the expense of public funding for costly but only marginally effective treatments. PMID- 26421598 TI - Health workforce planning and service expansion during an economic crisis: A case study of the national breast screening programme in Ireland. AB - This article aims to estimate the workforce and resource implications of the proposed age extension of the national breast screening programme, under the economic constraints of reduced health budgets and staffing levels in the Irish health system. Using a mixed method design, a purposive sample of 20 participants were interviewed and data were analysed thematically (June-September 2012). Quantitative data (programme-level activity data, screening activity, staffing levels and screening plans) were used to model potential workload and resource requirements. The analysis indicates that over 90% operational efficiency was achieved throughout the first six months of 2012. Accounting for maternity leave (10%) and sick leave (3.5%), 16.1 additional radiographers (whole time equivalent) would be required for the workload created by the age extension of the screening programme, at 90% operational efficiency. The results suggest that service expansion is possible with relatively minimal additional radiography resources if the efficiency of the skill mix and the use of equipment are improved. Investing in the appropriate skill mix should not be limited to clinical groups but should also include administrative staff to manage and support the service. Workload modelling may contribute to improved health workforce planning and service efficiency. PMID- 26421599 TI - First-Trimester Placental Growth Factor in Screening for Gestational Diabetes. AB - OBJECTIVE: The aim of this study was first to assess whether first-trimester serum concentrations of placental growth factor (PlGF) differ between patients with and without gestational diabetes (GDM) and second to test whether there is a correlation between glycosylated hemoglobin (HbA1c), a factor recently shown to be useful in predicting GDM, and PlGF. METHODS: PlGF was measured at 8-14 weeks with the Kryptor Immunoassay Analyzer (Brahms, Berlin, Germany). Absolute values were converted to multiples of the median using the software provided by the Fetal Medicine Foundation London. GDM was diagnosed using internationally accepted criteria. HbA1c levels were quantified using the TOSOH G7 automated hemoglobin analyzer. RESULTS: From January to December 2014, 328 women were included in the study, 51 (15.5%) of whom developed GDM. First-trimester PlGF quantification does not discriminate between women at risk to develop GDM and controls, while HbA1c is able to do so. No correlation was found between PlGF and HbA1c. CONCLUSION: Our findings do not lend support to the hypothesis that early PlGF values are different in women who later develop GDM. PMID- 26421600 TI - Irrigation and Debridement Before a 2-Stage Revision Total Knee Arthroplasty Does Not Increase Risk of Failure. AB - BACKGROUND: Studies have suggested that the success of 2-stage revision total knee arthroplasty (rTKA) may be compromised by a prior failed irrigation and debridement (I&D). The purpose of this study was to use 2 large state inpatient databases to compare the 2-stage rTKA failure rates for those patients with and without a prior I&D. METHODS: This retrospective, longitudinal study used inpatient discharge data from the State Inpatient Database of 2 states (California and New York) from 2005 to 2011. A combination of International Classification of Diseases, Ninth Revision, diagnosis and procedure codes was used to identify rTKA patients and compare failure rates for rTKA patients with and without prior I&D. The primary outcome was failure of the staged revision, which was defined as subsequent surgery due to infection within 4 years of the 2 stage rTKA. RESULTS: Of the 750 patients who underwent 2-stage rTKA, 57 had undergone a prior I&D. In all, 126 patients failed rTKA. After 4 years, the estimated failure rate was 8.7% (95% confidence interval [CI], 1.9%-16.9%) in the group with prior I&D and 17.5% (95% CI, 14.7%-20.4%) in the group without prior I&D. After adjusting for sex, race, insurance, median household income, and comorbidities, the hazard ratio for the group with a failed I&D was 0.49 (P = .122; 95% CI, 0.20-1.20), which indicated a lower risk of failure compared to the group without prior I&D. CONCLUSION: These findings indicate that the failure rate of 2-stage rTKA is not increased by prior failed I&D. PMID- 26421601 TI - The Use of Hyaluronic Acid and Corticosteroid Injections Among Medicare Patients With Knee Osteoarthritis. AB - INTRODUCTION: Hyaluronic acid (HA) and corticosteroid (CS) injections are frequently used in the management of osteoarthritis (OA) of the knee, despite a lack of strong evidence supporting their efficacy in the literature. The purpose of this study is to evaluate trends in HA and CS usage in Medicare patients over the past 15 years. METHODS: The Medicare 5% national sample database was used to identify 581,022 patients (representing an estimated 11.6 million) with a diagnosis of knee OA between 1999 and 2013. RESULTS: The percentage of newly diagnosed knee OA patients who received any injection trended from 39% in 1999 to 47% in 2006 and then declined to 37.5% in 2013. However, the mean number of injections per newly diagnosed OA patient nearly doubled from 0.27 to 0.45 for CS and from 0.18 to 0.36 for HA. Among those having both HA and CS injections, 69% had CS as first-line treatment, whereas 31% had HA first. CONCLUSION: The percentage of newly diagnosed knee OA patients receiving injections peaked in 2007 and then decreased steadily through 2013, as did the proportion of patients receiving HA injections as first-line therapy. However, the number of injections per patient has increased significantly over the past 15 years in both groups. PMID- 26421602 TI - Editorial overview: Pharmaceutical biotechnology: Expanding horizons for pharmaceutical biotechnology in industry and academia. PMID- 26421603 TI - Social casino gaming and adolescents: Should we be concerned and is regulation in sight? AB - While gambling has traditionally been viewed as an adult activity, there is a growing body of research that a significant number of adolescents are not only gambling but are experiencing gambling related problems. As ease of access via Internet wagering has increased, so too have some of the concomitant problems. Social casino gambling, often thought of gambling without risking one's money through the use of virtual currency, has become increasingly popular. The current review examines whether we should be concerned over its widespread use and whether such social games should be regulated. PMID- 26421604 TI - Biomechanical investigations of the expanded platform-switching concept in immediately loaded small diameter implants. AB - STATEMENT OF PROBLEM: Use of a small diameter implant may increase the stress on bone around the implant neck; however, an expanded platform design may mitigate these stress concentrations. To date, no study has compared the biomechanical effect of regular platform and extended platform designs on an implant. PURPOSE: The purpose of this in vitro study was to evaluate the biomechanical effects of an expanded platform-switching design for immediately loaded small diameter implants on bone strains. MATERIAL AND METHODS: Three groups of artificial jawbone models were prepared for small diameter (3.25-mm) and standard diameter (4.0-mm) implants with expanded or regular platform designs. Platform-switching implant design was implemented by assembling implants with a smaller connected abutment. Specimens were tested under both vertical and lateral static loads at 190 N. Peak values of the principal microstrain of bone were recorded and analyzed statistically with Kruskal-Wallis test and multiple comparisons Bonferroni test (alpha=.05). The initial stability of each implant was also measured for 3 types of implant. RESULTS: Under vertical loading, the bone strain was lowest for the regular type of immediately loaded small diameter implant. Under lateral loading, peak bone strain around the expanded platform small diameter implant with platform switched abutment was up to 74.9% lower than that of the regular type of small diameter implant. Increasing the implant diameter from 3.25 mm to 4.0 mm on the expanded platform implants reduced the bone strain by approximately 10% and 30% under lateral and vertical loading, respectively. The initial implant stability did not vary significantly among the implants tested. CONCLUSIONS: Using the expanded platform small diameter implant with a platform-switched abutment may decrease the marginal bone strains around immediately loaded small-diameter implants under lateral loading. PMID- 26421606 TI - Study of lip print types among Nigerians. AB - Lip prints in a narrow sense are normal lines and fissures in the form of wrinkles and grooves present in the zone of transition of lips. The aims of this study were to determine the types and association of lip prints as well as the role of the lip print as genetic marker in ethnic differentiation in multi-ethnic population of Nigeria. A total of 820 individuals (414 males and 406 females) participated. The study sample was drawn from different ethnic groups of Nigeria. The three major ethnic groups were identified and the minor groups were lumped together. This was to provide clear evidence on the ethnic differentiation based on lip print types among Nigerians. The lip prints were collected on microscopic glass slides and developed using carbon black powder. Each print was then divided into 10 compartments and analyzed using a magnifying lens. Chi-squared test was used for association between ethnicity and lip print types; p<0.05 was set as a level of significance. The result of the study showed the following lip print pattern in Nigerian population where Type V (31.39%) was predominant, followed by Type III (24.18%), Type IV (18.70%), Type I (14.87%), Type II (10.29%) and least frequent was Type I' (0.57%). Statistically significant association (p<0.05) of lip print types with ethnicity was found in upper left lateral compartments (ULL). It was concluded that lip prints show ethnic differences. Hence, they may hold potential promise as a supplementary tool in ethnic differentiation and in personal identification. PMID- 26421605 TI - Characterization of Vertical Accelerations Experienced by Older People Attending an Aerobics Class Designed to Produce High Impacts. AB - The purpose of this study was to establish the feasibility of using an aerobics class to produce potentially bone protective vertical impacts of >= 4g in older adults and to determine whether impacts can be predicted by physical function. Participants recruited from older adult exercise classes completed an SF-12 questionnaire, short physical performance battery, and an aerobics class with seven different components, performed at low and high intensity. Maximum g and jerk values were identified for each activity. Forty-one participants (mean 69 years) were included. Mean maximal values approached or exceeded the 4g threshold for four of the seven exercises. In multivariate analyses, age (-0.53; -0.77, 0.28) (standardized beta coefficient; 95% CI) and 4-m walk time (-0.39; -0.63, 0.16) were inversely related to maximum g. Aerobics classes can be used to produce relatively high vertical accelerations in older individuals, although the outcome is strongly dependent on age and physical function. PMID- 26421607 TI - A case of semi-combusted pregnant female in the Phoenician-Punic necropolis of Monte Sirai (Carbonia, Sardinia, Italy). AB - We present a case of a pregnant woman with the fetus skeletal remains in situ, belonging to the Phoenician-Punic necropolis of Monte Sirai (Sardinia, Italy). The burial dates back to the late 6th to early 5th century BCE. Of the unborn fetal cases documented in the literature this is amongst the oldest four and it represents the first documented case of a pregnant woman in the Phoenician and Punic necropolis literature. A physico-chemical investigation of bones combining X-ray diffraction and Fourier transform-infrared spectroscopy suggests that the female skeleton and fetus were subjected to an incomplete heat treatment according to a funerary practice, perhaps limited to the period of early 5th century BCE, that appears to be peculiar to this site. PMID- 26421609 TI - Copper-Catalyzed Electrophilic Amination of Heteroarenes via C-H Alumination. AB - A highly efficient Cu-catalyzed electrophilic amination reaction of readily available heteroarenes with O-benzoyl hydroxylamines via a one-pot C-H alumination is reported. The reactions were catalyzed using 1 mol % of CuCl to afford various heteroaryl amines in good to excellent yields. The direct C-H lithiation/transalumination of heteroarenes and catalytic amination sequence can be performed in a single vessel on gram scales. PMID- 26421608 TI - Arthroscopic treatment of septic arthritis of the knee in children. AB - INTRODUCTION: Childhood septic arthritis of the knee is a serious disease that can impair growth and cause serious functional sequelae. There are few data on arthroscopic treatment in children, and series were always less than 20 cases. HYPOTHESIS: The objective of this study was to assess clinical and radiographic results of arthroscopic drainage combined with antibiotic therapy for the treatment of childhood septic arthritis of the knee. The hypothesis was that arthroscopic treatment is also effective in children. MATERIALS AND METHODS: A retrospective study, conducted between January 2003 and December 2012, included patients under 15 years of age with septic arthritis of the knee treated by arthroscopic drainage with a minimum of 2 years' follow-up. RESULTS: Fifty-six patients, with a mean age at surgery of 3.4 years (range, 3 months to 12 years), were included. Staphylococcus aureus was the most common causative organism. Two patients (3.6%) had recurrence, successfully treated by repeat arthroscopic drainage. Mean Lysholm score was 96.9 (range, 70-100) and mean KOOS-Child pain, symptoms, daily life, sports and quality of life scores were respectively 97 (81 100), 95 (75-100), 98 (89-100), 93 (71-100) and 95 (70-100) at a mean 65 months' follow-up. Ranges of motion were normal. Radiology found no joint damage. DISCUSSION AND CONCLUSION: Arthroscopic drainage combined with antibiotic treatment is a simple and effective treatment for childhood septic arthritis of the knee and is for our reference attitude. It can also be indicated in case of recurrence. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 26421610 TI - Optimization of the steam explosion and enzymatic hydrolysis for sugars production from oak woods. AB - Fermentable sugars production from three kind of steam-exploded oak wood was optimized by Response Surface Methodology (RSM), using the severity factor (R0), the pretreated total solids (TS%) and the enzyme loading (EL%) as variables of a central composite design. A total of 17 experiments for each biomass were carried out. The optimal conditions established with RSM were: severity, 4.46 for holm, 4.03 for turkey oak and 3.92 for downey oak; total solids, 5.4% for holm, 5.0% for turkey oak and 12.7% for downey oak; and enzyme concentration, 9.6% for holm, 15.0% for turkey oak and 15.0% for downey oak. Under these conditions, the model predicted an overall sugar yield of 67.1% for holm, 79.9% for turkey oak and 68.4% for downey oak. The results of the confirmation experiments under optimal conditions agreed well with model predictions. Oak wood species may be a good feedstock for the production of reducing sugars. PMID- 26421611 TI - The Origin and Diversity of Cpt1 Genes in Vertebrate Species. AB - The Carnitine palmitoyltransferase I (Cpt1) gene family plays a crucial role in energy homeostasis since it is required for the occurrence of fatty acid beta oxidation in the mitochondria. The exact gene repertoire in different vertebrate lineages is variable. Presently, four genes are documented: Cpt1a, also known as Cpt1a1, Cpt1a2; Cpt1b and Cpt1c. The later is considered a mammalian innovation resulting from a gene duplication event in the ancestor of mammals, after the divergence of sauropsids. In contrast, Cpt1a2 has been found exclusively in teleosts. Here, we reassess the overall evolutionary relationships of Cpt1 genes using a combination of approaches, including the survey of the gene repertoire in basal gnathostome lineages. Through molecular phylogenetics and synteny studies, we find that Cpt1c is most likely a rapidly evolving orthologue of Cpt1a2. Thus, Cpt1c is present in other lineages such as cartilaginous fish, reptiles, amphibians and the coelacanth. We show that genome duplications (2R) and variable rates of sequence evolution contribute to the history of Cpt1 genes in vertebrates. Finally, we propose that loss of Cpt1b is the likely cause for the unusual energy metabolism of elasmobranch. PMID- 26421612 TI - Characterization of Bacterial, Archaeal and Eukaryote Symbionts from Antarctic Sponges Reveals a High Diversity at a Three-Domain Level and a Particular Signature for This Ecosystem. AB - Sponge-associated microbial communities include members from the three domains of life. In the case of bacteria, they are diverse, host specific and different from the surrounding seawater. However, little is known about the diversity and specificity of Eukarya and Archaea living in association with marine sponges. This knowledge gap is even greater regarding sponges from regions other than temperate and tropical environments. In Antarctica, marine sponges are abundant and important members of the benthos, structuring the Antarctic marine ecosystem. In this study, we used high throughput ribosomal gene sequencing to investigate the three-domain diversity and community composition from eight different Antarctic sponges. Taxonomic identification reveals that they belong to families Acarnidae, Chalinidae, Hymedesmiidae, Hymeniacidonidae, Leucettidae, Microcionidae, and Myxillidae. Our study indicates that there are different diversity and similarity patterns between bacterial/archaeal and eukaryote microbial symbionts from these Antarctic marine sponges, indicating inherent differences in how organisms from different domains establish symbiotic relationships. In general, when considering diversity indices and number of phyla detected, sponge-associated communities are more diverse than the planktonic communities. We conclude that three-domain microbial communities from Antarctic sponges are different from surrounding planktonic communities, expanding previous observations for Bacteria and including the Antarctic environment. Furthermore, we reveal differences in the composition of the sponge associated bacterial assemblages between Antarctic and tropical-temperate environments and the presence of a highly complex microbial eukaryote community, suggesting a particular signature for Antarctic sponges, different to that reported from other ecosystems. PMID- 26421613 TI - Temporal Structure of Human Gaze Dynamics Is Invariant During Free Viewing. AB - We investigate the dynamic structure of human gaze and present an experimental study of the frequency components of the change in gaze position over time during free viewing of computer-generated fractal images. We show that changes in gaze position are scale-invariant in time with statistical properties that are characteristic of a random walk process. We quantify and track changes in the temporal structure using a well-defined scaling parameter called the Hurst exponent, H. We find H is robust regardless of the spatial complexity generated by the fractal images. In addition, we find the Hurst exponent is invariant across all participants, including those with distinct changes to higher order visual processes due to neural degeneration. The value we find for H of 0.57 shows that the gaze dynamics during free viewing of fractal images are consistent with a random walk process with persistent movements. Our research suggests the human visual system may have a common strategy that drives the dynamics of human gaze during exploration. PMID- 26421614 TI - Expression of the Stem Cell Factor Nestin in Malignant Pleural Mesothelioma Is Associated with Poor Prognosis. AB - BACKGROUND: The epithelioid and sarcomatoid histologic variants of malignant pleural mesothelioma (MPM) can be considered as E- and M-parts of the epithelial mesenchymal transition (EMT) axis; the biphasic being an intermediate. EMT is associated with an increase of stem cell (SC) traits. We correlated the neural crest SC marker nestin and the EMT marker periostin with histology, type of neo adjuvant chemotherapy (CT) and overall survival (OS) of MPM patients. PATIENTS AND METHODS: Tumor tissues of a historic cohort 1 (320 patients) and an intended induction chemotherapy followed by extrapleural pneumonectomy (EPP) cohort 2 (145 patients) were immunohistochemically H-scored (intensity of immunoreactivity multiplied by frequency of stained cells). Paired chemo-naive biopsies and treated surgical specimens were available for 105/145 patients. CT included platinum/gemcitabine (Pla/Gem) or platinum/pemetrexed (Pla/Pem). RESULTS: Expression of any cytosolic nestin progressively increased from epithelioid to biphasic to sarcomatoid MPM in cohort 1, whereas the diagnostic markers calretinin and podoplanin decreased. In cohort 2, Pla/Pem CT increased the expression level of nestin in comparison to Pla/Gem, whereas the opposite was found for periostin. In Pla/Pem treated patients, nestin was higher in biphasic MPM compared to epithelioid. In addition to non-epithelioid histology, any expression of nestin in chemo-naive biopsies (median overall survival: 22 vs. 17 months) and chemo-treated surgical specimens (18 vs. 12 months) as well as high periostin in biopsies (23 vs. 15 months) were associated with poor prognosis. In the multivariate survival analysis, any nestin expression in chemo-naive biopsies proved to be an independent prognosticator against histology. In both pre- and post-CT situations, the combination of nestin or periostin expression with non epithelioid histology was particularly/ dismal (all p-values <0.05). CONCLUSIONS: The SC marker nestin and the EMT marker periostin allow for further prognostic stratification among histologic variants of MPM. Their expression level is influenced by neo-adjuvant chemotherapy. PMID- 26421616 TI - Probabilistic Analysis of Pattern Formation in Monotonic Self-Assembly. AB - Inspired by biological systems, self-assembly aims to construct complex structures. It functions through piece-wise, local interactions among component parts and has the potential to produce novel materials and devices at the nanoscale. Algorithmic self-assembly models the product of self-assembly as the output of some computational process, and attempts to control the process of assembly algorithmically. Though providing fundamental insights, these computational models have yet to fully account for the randomness that is inherent in experimental realizations, which tend to be based on trial and error methods. In order to develop a method of analysis that addresses experimental parameters, such as error and yield, this work focuses on the capability of assembly systems to produce a pre-determined set of target patterns, either accurately or perhaps only approximately. Self-assembly systems that assemble patterns that are similar to the targets in a significant percentage are "strong" assemblers. In addition, assemblers should predominantly produce target patterns, with a small percentage of errors or junk. These definitions approximate notions of yield and purity in chemistry and manufacturing. By combining these definitions, a criterion for efficient assembly is developed that can be used to compare the ability of different assembly systems to produce a given target set. Efficiency is a composite measure of the accuracy and purity of an assembler. Typical examples in algorithmic assembly are assessed in the context of these metrics. In addition to validating the method, they also provide some insight that might be used to guide experimentation. Finally, some general results are established that, for efficient assembly, imply that every target pattern is guaranteed to be assembled with a minimum common positive probability, regardless of its size, and that a trichotomy exists to characterize the global behavior of typical efficient, monotonic self-assembly systems in the literature. PMID- 26421617 TI - Fourier Spot Volatility Estimator: Asymptotic Normality and Efficiency with Liquid and Illiquid High-Frequency Data. AB - The recent availability of high frequency data has permitted more efficient ways of computing volatility. However, estimation of volatility from asset price observations is challenging because observed high frequency data are generally affected by noise-microstructure effects. We address this issue by using the Fourier estimator of instantaneous volatility introduced in Malliavin and Mancino 2002. We prove a central limit theorem for this estimator with optimal rate and asymptotic variance. An extensive simulation study shows the accuracy of the spot volatility estimates obtained using the Fourier estimator and its robustness even in the presence of different microstructure noise specifications. An empirical analysis on high frequency data (U.S. S&P500 and FIB 30 indices) illustrates how the Fourier spot volatility estimates can be successfully used to study intraday variations of volatility and to predict intraday Value at Risk. PMID- 26421615 TI - Ammonia Affects Astroglial Proliferation in Culture. AB - Primary cultures of rat astroglial cells were exposed to 1, 3 and 5 mM NH4Cl for up to 10 days. Dose- and time-dependent reductions in cell numbers were seen, plus an increase in the proportion of cells in the S phase. The DNA content was reduced in the treated cells, and BrdU incorporation diminished. However, neither ammonia nor ammonia plus glutamine had any effect on DNA polymerase activity. iTRAQ analysis showed that exposure to ammonia induced a significant reduction in histone and heterochromatin protein 1 expression. A reduction in cell viability was also noted. The ammonia-induced reduction of proliferative activity in these cultured astroglial cells seems to be due to a delay in the completion of the S phase provoked by the inhibition of chromatin protein synthesis. PMID- 26421618 TI - The Role of Electrostatic Interactions in Binding of Histone H3K4me2/3 to the Sgf29 Tandem Tudor Domain. AB - Several reader domain proteins that specifically recognize methyllysine containing histones contain the negatively-charged aspartate or glutamate residues as part of the aromatic cage. Herein, we report thermodynamic analyses for the recognition of histone H3K4me3 and H3K4me2 by the tandem tudor domain of Sgf29 and its recognition site variants. Small uncharged and large aromatic substitutions on the Asp266 site resulted in a significant decrease in binding affinities for both H3K4me3 and H3K4me2, demonstrating the role of the negative charge of Asp266 in the readout process by Sgf29. This study emphasizes the essential contribution of electrostatic interactions to the overall binding affinity, and reveals that the underlying mechanisms for the recognition of Kme2/3 depend on the composition and arrangement of the aromatic cage. PMID- 26421619 TI - Evolutionary Changes of Hepatitis B Virus Pre-S Mutations Prior to Development of Hepatocellular Carcinoma. AB - BACKGROUND AND AIMS: Deletions/mutations in the hepatitis B virus (HBV) pre-S region have been associated with hepatocellular carcinoma (HCC). We aimed to study the evolutionary changes of pre-S mutations prior to HCC development. METHODS: We studied the HBV pre-S sequences at 1 to 10 years preceding diagnosis of HCC in 74 patients with HBV-related HCC (HCC group). 148 chronic hepatitis B patients matched for sex and age in 2:1 ratio, who had been followed up for at least 3 years without HCC (HCC-free group) were recruited as controls. 56 and 47 patients of HCC and HCC-free groups respectively had serially stored sera for longitudinally examination at 1-3 years, 4-6 years, 7-9 years and >=10 years prior to the recruitment of the study. RESULTS: Compared to the HCC-free group, higher frequencies of pre-S deletions and point mutations (at 11 codons) were observed in the HCC group (p<0.05). Multiple logistic regression analysis showed that pre-S deletions, point mutations at codon 51 and 167 were independent factors associated with HCC. Longitudinal observation showed that pre-S deletions and most of the 11 HCC-associated pre-S point mutations existed at least 10 years before HCC development, and were more prevalent preceding HCC development in patients from HCC groups than HCC-free group. The number of HCC-associated pre-S point mutations increased over time preceding HCC development, and correlated positively with the time to HCC diagnosis (r = 0.220, p = 0.005). CONCLUSIONS: High prevalence and cumulative evolution of pre-S mutations preceding HCC development suggested a possible carcinogenic role of pre-S mutations and their potential application in HCC risk prediction. PMID- 26421620 TI - Risk of Major Cardiovascular Events in People with Down Syndrome. AB - BACKGROUND: Improved medical care over more than five decades has markedly increased life expectancy, from 12 years to approximately 60 years, in people with Down syndrome (DS). With increased survival into late adulthood, there is now a greater need for the medical care of people with DS to prevent and treat aging-related disorders. In the wider population, acquired cardiovascular diseases such as stroke and coronary heart disease are common with increasing age, but the risks of these diseases in people with DS are unknown. There are no population-level data on the incidence of acquired major cerebrovascular and coronary diseases in DS, and no data examining how cardiovascular comorbidities or risk factors in DS might impact on cardiovascular event incidence. Such data would be also valuable to inform health care planning for people with DS. Our objective was therefore to conduct a population-level matched cohort study to quantify the risk of incident major cardiovascular events in DS. METHODS AND FINDINGS: A population-level matched cohort study compared the risk of incident cardiovascular events between hospitalized patients with and without DS, adjusting for sex, and vascular risk factors. The sample was derived from hospitalization data within the Australian state of Victoria from 1993-2010. For each DS admission, 4 exact age-matched non-DS admissions were randomly selected from all hospitalizations within a week of the relevant DS admission to form the comparison cohort. There were 4,081 people with DS and 16,324 without DS, with a total of 212,539 person-years of observation. Compared to the group without DS, there was a higher prevalence in the DS group of congenital heart disease, cardiac arrhythmia, dementia, pulmonary hypertension, diabetes and sleep apnea, and a lower prevalence of ever-smoking. DS was associated with a greater risk of incident cerebrovascular events (Risk Ratio, RR 2.70, 95% CI 2.08, 3.53) especially among females (RR 3.31, 95% CI 2.21, 4.94) and patients aged <= 50 years old. The association of DS with ischemic strokes was substantially attenuated on adjustment for cardioembolic risk (RR 1.93, 95% CI 1.04, 3.20), but unaffected by adjustment for atherosclerotic risk. DS was associated with a 40 70% reduced risk of any coronary event in males (RR 0.58, 95% CI 0.40, 0.84) but not in females (RR 1.14, 95% CI 0.73, 1.77). CONCLUSIONS: DS is associated with a high risk of stroke, expressed across all ages. Ischemic stroke risk in DS appears mostly driven by cardioembolic risk. The greater risk of hemorrhagic stroke and lower risk of coronary events (in males) in DS remain unexplained. PMID- 26421621 TI - Organophosphate pesticide method development and presence of chlorpyrifos in the feet of nearctic-neotropical migratory songbirds from Canada that over-winter in Central America agricultural areas. AB - Recent modeling analysis suggests that numerous birds may be at risk of acute poisoning in insecticide-treated fields. Although the majority of avian field studies on pesticides have focused on treated seed, granule, insect or vegetation (oral exposure) ingestion, dermal exposure is an important exposure route when birds come into contact with deposited pesticides on foliage and other surfaces. Some nearctic-neotropical migratory songbirds are likely exposed to pesticides on their non-breeding habitats and include treated crops, plantations or farmlands. In the present study, we developed a method for four environmentally-relevant organophosphate (OP) pesticides (fenthion, fenamiphos, chlorpyrifos and diazinon) in the feet of migratory songbirds (i.e. Common yellowthroat, Gray catbird, Indigo bunting, America redstart, Northern waterthrush, Northern parula, and an additional 12 species of warblers). A total of 190 specimens of the 18 species of songbirds were sampled from available window-killed birds (spring of 2007 and 2011) in downtown Toronto, Canada. The species that were available most likely over-wintered in Mexican/Central American crops such as citrus, coffee and cacao. The feet of the dead birds were sampled and where OP foot exposure likely occurred during over-wintering foraging on pesticide-treated crops. Chlorpyrifos was the only measurable OP (pg mg feet weight(-1)) and in the 2011-collected feet of Black throated blue warbler (0.5), Tennessee warbler (1.0), Northern parula (1.2), Northern waterthrush (0.6), Common yellowthroat (1.0) and the Blue winged warbler (0.9). Dermal contact with OP pesticides during over-wintering in agricultural areas resulted in low levels of chlorpyrifos and long time retention on the feet of a subset of songbirds. PMID- 26421622 TI - Degradation of organic dyes by Si/SiOx core-shell nanowires: Spontaneous generation of superoxides without light irradiation. AB - Recently, silicon nanowires (SiNWs) have been proven to be highly active in the photocatalysis of dye degradation. However, the unstable hydrogen-terminated surface and the need for constant light irradiation hinder their extensive use. In this work, a stable silica shell was intentionally formed on the surface of SiNWs to produce Si/SiOx core-shell silicon nanowires (S-SiNWs). Light illuminated or not, S-SiNWs showed almost identical degradation ability for the degradation of indigo carmine (IC) in both conditions, which meant neither hydrogen termination nor light irradiation was a prerequisite for the degradation activity of S-SiNWs. UV/Vis spectroscopy and liquid chromatography/mass spectrometry showed that IC was converted into isatin sulfonic acid in this process. Quenching studies and electron paramagnetic resonance spectroscopy revealed that this bleaching ability was highly dependent on superoxides. A possible mechanism was accordingly suggested. In addition, the recently discovered reductase-like activity of SiNWs can be explained by the superoxides generation. PMID- 26421624 TI - Low dietary levels of Al, Pb and Cd may affect the non-enzymatic antioxidant capacity in caged honey bees (Apis mellifera). AB - Several hypotheses have been proposed to explain the abnormally high mortality rate observed in bee populations in Europe and North America. While studies based on the effects of pesticides are paramount, the metals present in agroecosystems are often overlooked. Sources of metals are linked to the nature of soils and to agricultural practices, namely the use of natural or chemical nutrients as well as residual materials from waste-water treatment sludge. The aim of this study was to investigate the effects of metals on honey bees exposed for 10 days to environmentally realistic concentrations of Al, Pb and Cd (dissolved in syrup). The monitoring of syrup consumption combined with the quantification of metals in bees revealed the following order for metal bioconcentration ratios: Cd > Pb > Al. Alpha-tocopherol, metallothionein-like proteins (MTLPs) and lipid peroxidation were quantified. When bees were exposed to increasing amounts of Cd, a marked augmentation of MTLPs levels was found. Lead (Pb) and Cd caused an increase in alpha-tocopherol content, while alteration of lipid peroxidation was observed only with Al exposure. These findings raise concerns about the bioavailability and the additional threat posed by metals for pollinators in agricultural areas while providing new insights for potential use of the honey bee as a sentinel species for metal exposure. PMID- 26421623 TI - Potential application of a bioemulsifier-producing actinobacterium for treatment of vinasse. AB - Vinasse is a complex effluent created during production of ethyl alcohol, which can present serious pollution hazard in areas where it is discharged. A variety of technologies, many based upon recovery of the effluent via microbial pathways, are continually being evaluated in order to mitigate the pollution potential of vinasse. The present work reports on initial advances related to the effectiveness of the actinobacterium Streptomyces sp. MC1 for vinasse treatment. Alternative use of raw vinasse as a substrate for producing metabolites of biotechnological interest such as bioemulsifiers, was also evaluated. The strain was able to grow at very high vinasse concentrations (until 50% v/v) and remove over 50% of the biodegradable organic matter in a time period as short as 4 d. Potentially toxic metals such as Mn, Fe, Zn, As, and Pb were also effectively removed during bacterial growth. Decrease in the pollution potential of treated vinasse compared to raw effluent, was reflected in a significant increase in the vigour index of Lactuca sativa (letucce) used as bioremediation indicator. Finally, significant bioemulsifier production was detected when this strain was incubated in a vinasse-based culture medium. These results represent the first advances on the recovery and re-valuation of an actual effluent, by using an actinobacterium from our collection of cultures. PMID- 26421625 TI - Degradation of triclosan in aqueous solution by dielectric barrier discharge plasma combined with activated carbon fibers. AB - The degradation of triclosan (TCS) in aqueous solution by dielectric barrier discharge (DBD) plasma with activated carbon fibers (ACFs) was investigated. In this study, ACFs and DBD plasma coexisted in a planar DBD plasma reactor, which could synchronously achieve degradation of TCS, modification and in situ regeneration of ACFs, enhancing the effect of recycling of ACFs. The properties of ACFs before and after modification by DBD plasma were characterized by BET and XPS. Various processing parameters affecting the synergetic degradation of TCS were also investigated. The results exhibited excellent synergetic effects in DBD plasma-ACFs system on TCS degradation. The degradation efficiency of 120 mL TCS with initial concentration of 10 mg L(-1) could reach 93% with 1 mm thick ACFs in 18 min at input power of 80 W, compared with 85% by single DBD plasma. Meanwhile, the removal rate of total organic carbon increased from 12% at pH 6.26-24% at pH 3.50. ACFs could ameliorate the degradation efficiency for planar DBD plasma when treating TCS solution at high flow rates or at low initial concentrations. A possible degradation pathway of TCS was investigated according to the detected intermediates, which were identified by liquid chromatography-hybrid quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) combined with theoretical calculation of Gaussian 09 program. PMID- 26421626 TI - Ecotoxicological analysis during the removal of carbofuran in fungal bioaugmented matrices. AB - Biomixtures are used for the removal of pesticides from agricultural wastewater. As biomixtures employ high content of lignocellulosic substrates, their bioaugmentation with ligninolytic fungi represents a novel approach for their enhancement. Nonetheless, the decrease in the concentration of the pesticide may result in sublethal concentrations that still affect ecosystems. Two matrices, a microcosm of rice husk (lignocellulosic substrate) bioaugmented with the fungus Trametes versicolor and a biomixture that contained fungally colonized rice husk were used in the degradation of the insecticide/nematicide carbofuran (CFN). Elutriates simulating lixiviates from these matrices were used to assay the ecotoxicological effects at sublethal level over Daphnia magna (Straus) and the fish Oreochromis aureus (Steindachner) and Oncorhynchus mykiss (Walbaum). Elutriates obtained after 30 d of treatment in the rice husk microcosms at dilutions over 2.5% increased the offspring of D. magna as a trade-off stress response, and produced mortality of neonates at dilutions over 5%. Elutriates (dilution 1:200) obtained during a 30 d period did not produce alterations on the oxygen consumption and ammonium excretion of O. mykiss, however these physiological parameters were affected in O. aureus at every time point of treatment, irrespective of the decrease in CFN concentration. When the fungally colonized rice husk was used to prepare a biomixture, where more accelerated degradation is expected, similar alterations on the responses by O. aureus were achieved. Results suggest that despite the good removal of the pesticide, it is necessary to optimize biomixtures to minimize their residual toxicity and potential chronic effects on aquatic life. PMID- 26421627 TI - Copper toxicity and the influence of water quality of Dongnai River and Mekong River waters on copper bioavailability and toxicity to three tropical species. AB - The present study investigated copper (Cu) toxicity and the influence of water quality characteristics of Dongnai River and Mekong River (Vietnam) surface waters to three tropical species; Daphnia lumholtzi, Ceriodaphnia cornuta, and Danio rerio. The river waters had a range of water quality parameters that modify Cu bioavailability and toxicity. The range of total hardness, alkalinity, pH and dissolved organic carbon were 15-64 mg/L as CaCO3, 18-58 mg/L as CaCO3, 6.62 7.88, and 6.9-14.7 mg/l, respectively. The US EPA acute toxicity test method with a modification to the light photoperiod and temperature for tropical organisms was used to investigate Cu toxicity. Result of the present study found that Cu produced toxic effect to the studied organisms at low concentrations. The 48-h LC50 ranged from 3.92 to 8.61 ug/l, 2.92-9.56 ug/l, and 15.71-68.69 ug/l dissolved Cu for D. lumholtzi, C. cornuta, and D. rerio, respectively. In general, water quality had an influence on Cu bioavailability and toxicity to the studied organisms. The toxicity of Cu was higher in water with lower hardness, DOC, and/or pH. The present study indicates a contribution of Cu hydroxide and carbonate to Cu bioavailability to Mekong organisms. Results of the present study will be used for calibrating the US Cu Biotic Ligand Model (BLM) to Mekong River water and organisms in support of application of the BLM for setting site specific Cu water quality guidelines in the ecosystem of the Lower Mekong River Basin. PMID- 26421628 TI - Sorption of hydrophobic organic compounds to a diverse suite of carbonaceous materials with emphasis on biochar. AB - Carbonaceous materials like biochars are increasingly recognized as effective sorbent materials for sequestering organic pollutants. Here, we study sorption behavior of two common hydrophobic organic contaminants 2,2',5,5' tetrachlorobiphenyl (CB52) and phenanthrene (PHE), on biochars and other carbonaceous materials (CM) produced at a wide range of conditions and temperatures from various feedstocks. The primary aim was to establish structure reactivity relationships responsible for the observed variation in CM and biochar sorption characteristics. CM were characterized for their elemental composition, surface area, pore size distribution, aromaticity and thermal stability. Freundlich sorption coefficients for CB52 and PHE (i.e. LogK(F,CB52) and K(F,PHE), respectively) to CM showed a variation of two to three orders of magnitude, with LogK(F,CB52) ranging from 5.12 +/- 0.38 to 8.01 +/- 0.18 and LogK(F,PHE) from 5.18 +/- 0.09 to 7.42 +/- 1.09. The highest LogK(F) values were observed for the activated CM, however, non-activated biochars produced at high temperatures (>700 degrees C) sorbed almost as strongly (within 0.2-0.5 Log units) as the activated ones. Sorption coefficients significantly increased with pyrolysis temperature, CM surface area and pore volume, aromaticity, and thermal stability, and decreased with H/C, O/C, (O + N)/C content. The results of our study contribute to the understanding of processes underlying HOC sorption to CM and explore the potential of CM as engineered sorbents for environmental applications. PMID- 26421629 TI - A facile and novel strategy to synthesize reduced TiO2 nanotubes photoelectrode for photoelectrocatalytic degradation of diclofenac. AB - TiO2 nano-materials have been considered as a versatile candidate for the photoelectrochemical (PECH) applications. In this study, we reported a facile and novel strategy to synthesize reduced TiO2 nanotubes (TiO2 NTs) photoelectrode. The microwave reduction could introduce oxygen vacancy in the lattice of TiO2, while the rapid-production of oxygen vacancy facilitated the generation of impurity level between the forbidden band and greatly enhancement of visible light absorption, thereby resulting in an improved separation efficiency of photogenerated charge carriers and photocatalytic (PC) performance. Additionally, the derived valence band X-ray photoelectron spectroscopy (VBXPS) and photoluminescence (PL) spectra confirmed the existence of oxygen vacancy in the lattice of TiO2 NTs photoelectrode, in which the valence bond maximum (VBM) and charge carriers concentration of reduced TiO2 NTs photoelectrode was determined to be 1.75 eV and 5.36 * 10(19) cm(-3), respectively. Furthermore, the scavenging experiments revealed that .OH radical was the dominated species for the degradation of diclofenac. The enhanced-visible-light PC mechanism could mainly be attributed to the generation of oxygen vacancy, which can provide not only the visible light absorption capacity but also charge separation efficiency. PMID- 26421630 TI - Characteristics and influencing factors of tetrachloroethylene sorption desorption on soil and its components. AB - To investigate the effects of soil structure, soil organic carbon (SOC), minerals, initial tetrachloroethylene (PCE) concentration (C0), and ionic strength (Ci) on PCE sorption-desorption, six types of soil were adopted as adsorbents, including two types of natural soil and four types of soil with most of the "soft carbon" pre-treated by H2O2 or with all SOC removed from the original soil by 600 degrees C ignition. The results showed that all of the sorption-desorption isotherms of PCE were non-linear within the experimental range, and the H2O2-treated samples exhibited higher non-linear sorption isotherms than those of the original soils. The hysteresis index of PCE sorption to original soil is less pronounced than that of the H2O2-treated and 600 degrees C-heated samples due to the entrapment of sorbate molecules in the "hard carbon" domain, together with the meso- and microporous structures within the 600 degrees C-heated samples. Both SOC and minerals have impacts on the sorption desorption of PCE, and the sorption-desorption contribution rate of minerals increased with decreasing SOC content. C0 has almost no influence on the sorption to minerals of the soils, but the contribution rate of minerals decreased with increasing C0 in the desorption stage. As a result of the salting-out effect, PCE sorption capacity was increased by increasing Ci, especially when Ci >= 0.1 M. Moreover, desorption increased and hysteresis weakened with increasing Ci, except for the 600 degrees C-heated samples. In addition, no significant effect of Ci on desorption of PCE and no hysteresis was observed in this experimental range for the 600 degrees C-heated samples. PMID- 26421631 TI - Surface doping of La ions into ZnO nanocrystals to lower the optimal working temperature for HCHO sensing properties. AB - Lowering the working temperature without sacrificing other good gas-sensing properties is of particular interest to gas sensors for an excellent performance. In this work, La surface doped ZnO nanocrystals were successfully prepared by a facile thermal treatment with lanthanum nitrate (La(NO3)3) solution injected into ZnO thick films, which exhibited a remarkable decrease in the optimal working temperature for formaldehyde (HCHO) sensing properties. This was probably attributed to the formation of surface LaZn defects in the ZnO nanocrystals which was evidenced by XRD, XPS results and DFT calculations. The surface LaZn defects can introduce a shallower donor level than oxygen vacancies, and probably facilitate the charge transfer from oxygen species to ZnO for producing chemisorbed oxygen species more easily. This was in good agreement with the DFT results that the absorption energy of oxygen molecules on the surface of La doped ZnO was only -10.61 eV, much lower than that of pure ZnO. Moreover, the optimal working temperature of the La doped ZnO based sensor was significantly decreased from 350 to 250 degrees C without sacrificing the high and quick response to HCHO gas as the content of surface LaZn defects was increased gradually. Therefore, the behavior of the surface LaZn defects in the optimal working temperature revealed a HCHO response mechanism in ZnO, which can provide new insights into the enhanced HCHO sensing performance of gas sensors. PMID- 26421632 TI - Human fetal cardiac progenitors: The role of stem cells and progenitors in the fetal and adult heart. AB - The human fetal heart is formed early during embryogenesis as a result of cell migrations, differentiation, and formative blood flow. It begins to beat around gestation day 22. Progenitor cells are derived from mesoderm (endocardium and myocardium), proepicardium (epicardium and coronary vessels), and neural crest (heart valves, outflow tract septation, and parasympathetic innervation). A variety of molecular disturbances in the factors regulating the specification and differentiation of these cells can cause congenital heart disease. This review explores the contribution of different cardiac progenitors to the embryonic heart development; the pathways and transcription factors guiding their expansion, migration, and functional differentiation; and the endogenous regenerative capacity of the adult heart including the plasticity of cardiomyocytes. Unfolding these mechanisms will become the basis for understanding the dynamics of specific congenital heart disease as well as a means to develop therapy for fetal as well as postnatal cardiac defects and heart failure. PMID- 26421633 TI - Relativistic and Solvation Effects on the Stability of Gold(III) Halides in Aqueous Solution. AB - The redox stability of gold halide complexes in aqueous solution has been examined quantum-chemically by a systematic comparison of scalar- and nonrelativistic pseudopotential calculations, using both COSMO and D-COSMO-RS solvent models for water. After a computational benchmarking of density functional methods against CCSD(T) results for the gas phase decomposition AuX4( ) -> AuX2(-) + X2, B3LYP calculations have been used to establish solvent contributions. While relativity clearly enhances the stability of AuX4(-) (X = F, Cl, Br, I) complexes against X2 elimination, solvation favors the lower oxidation state. Solvation and relativity are nonadditive, due to the relativistic reduction of bond polarity. At scalar relativistic D-COSMO-RS level, the reaction AuX4(-) ? AuX2(-) + X2 is computed to be endergonic, except for X = I, where it is slightly exergonic. Under the chosen conditions, partial hydrolysis of AuCl4( ) to AuCl3OH(-) is exergonic. The latter complex in turn is stable against Cl2 elimination. The disproportionation 3 AuCl2(-) ? AuCl4(-) + 2 Au(s) + 2 Cl(-) is clearly exergonic. All of the computed reaction energies at scalar relativistic D COSMO-RS level agree well with the observed speciation in dilute pH-neutral solutions at ambient temperatures. PMID- 26421635 TI - Correlative Synchrotron Fourier Transform Infrared Spectroscopy and Single Molecule Super Resolution Microscopy for the Detection of Composition and Ultrastructure Alterations in Single Cells. AB - Single molecule localization microscopy (SMLM) and synchrotron Fourier transform infrared (S-FTIR) spectroscopy are two techniques capable of elucidating unique and valuable biological detail. SMLM provides images of the structures and distributions of targeted biomolecules at spatial resolutions up to an order of magnitude better than the diffraction limit, whereas IR spectroscopy objectively measures the holistic biochemistry of an entire sample, thereby revealing any variations in overall composition. Both tools are currently applied extensively to detect cellular response to disease, chemical treatment, and environmental change. Here, these two techniques have been applied correlatively at the single cell level to probe the biochemistry of common fixation methods and have detected various fixation-induced losses of biomolecular composition and cellular ultrastructure. Furthermore, by extensive honing and optimizing of fixation protocols, many fixation artifacts previously considered pervasive and regularly identified using IR spectroscopy and fluorescence techniques have been avoided. Both paraformaldehyde and two-step glutaraldehyde fixation were identified as best preserving biochemistry for both SMLM and IR studies while other glutaraldehyde and methanol fixation protocols were demonstrated to cause significant biochemical changes and higher variability between samples. Moreover, the potential complementarity of the two techniques was strikingly demonstrated in the correlated detection of biochemical changes as well as in the detection of fixation-induced damage that was only revealed by one of the two techniques. PMID- 26421636 TI - Cancer screening via infrared spectral cytopathology (SCP): results for the upper respiratory and digestive tracts. AB - Instrumental advances in infrared micro-spectroscopy have made possible the observation of individual human cells and even subcellular structures. The observed spectra represent a snapshot of the biochemical composition of a cell; this composition varies subtly but reproducibly with cellular effects such as progression through the cell cycle, cell maturation and differentiation, and disease. The aim of this summary is to provide a synopsis of the progress achieved in infrared spectral cytopathology (SCP) - the combination of infrared micro-spectroscopy and multivariate methods of analysis - for the detection of abnormalities in exfoliated human cells of the upper respiratory and digestive tract, namely the oral and nasopharyngeal cavities, and the esophagus. PMID- 26421642 TI - Optimizing Pin-Printed and Hydrosilylated Microarray Spot Density on Porous Silicon Platforms. AB - Microarrays of spatially isolated chemistries on planar surfaces are powerful tools. An important factor in microarray technology is the density of chemically unique spots that can be formed per unit area. In this paper, we use contact pin printing and evaluate how to decrease contact pin-printed spot diameters on porous silicon (pSi) platforms. Using hydrosilylation chemistry to covalently attach chemistries to the pSi surface, the variables studied included pSi porosity and surface polarity, active agent viscosity, and pin diameter. The spot characteristics were assessed by Fourier transform infrared spectroscopy (FT-IR) microscopy and X-ray photoelectron spectroscopy (XPS). Spot size decreased as pSi porosity increased in accordance with molecular kinetic theory and Darcy's law of imbibition. Increasing active agent viscosity and pin diameter (volume of printed agent) led to larger spot diameters in accordance with molecular kinetic theory and Darcy's law. Oxidizing the pSi with H2O2 increased the surface polarity but had no detectable impact on the spot size. This is consistent with formation of an oxide layer atop an unoxidized pSi sublayer. PMID- 26421634 TI - Association Between Placebo-Activated Neural Systems and Antidepressant Responses: Neurochemistry of Placebo Effects in Major Depression. AB - IMPORTANCE: High placebo responses have been observed across a wide range of pathologies, severely impacting drug development. OBJECTIVE: To examine neurochemical mechanisms underlying the formation of placebo effects in patients with major depressive disorder (MDD). DESIGN, SETTING, AND PARTICIPANTS: In this study involving 2 placebo lead-in phases followed by an open antidepressant administration, we performed a single-blinded 2-week crossover randomized clinical trial of 2 identical oral placebos (described as having either active or inactive fast-acting antidepressant-like effects) followed by a 10-week open label treatment with a selective serotonin reuptake inhibitor or, in some cases, another agent as clinically indicated. The volunteers (35 medication-free patients with MDD at a university health system) were studied with positron emission tomography and the u-opioid receptor-selective radiotracer [11C]carfentanil after each 1-week inactive and active oral placebo treatment. In addition, 1 mL of isotonic saline was administered intravenously within sight of the volunteer during positron emission tomographic scanning every 4 minutes over 20 minutes only after the 1-week active placebo treatment, with instructions that the compound may be associated with the activation of brain systems involved in mood improvement. This challenge stimulus was used to test the individual capacity to acutely activate endogenous opioid neurotransmision under expectations of antidepressant effect. MAIN OUTCOMES AND MEASURES: Changes in depressive symptoms in response to active placebo and antidepressant. Baseline and activation measures of u-opioid receptor binding. RESULTS: Higher baseline u opioid receptor binding in the nucleus accumbens was associated with better response to antidepressant treatment (r = 0.48; P = .02). Reductions in depressive symptoms after 1 week of active placebo treatment, compared with the inactive, were associated with increased placebo-induced u-opioid neurotransmission in a network of regions implicated in emotion, stress regulation, and the pathophysiology of MDD, namely, the subgenual anterior cingulate cortex, nucleus accumbens, midline thalamus, and amygdala (nucleus accumbens: r = 0.6; P < .001). Placebo-induced endogenous opioid release in these regions was associated with better antidepressant treatment response, predicting 43% of the variance in symptom improvement at the end of the antidepressant trial. CONCLUSIONS AND RELEVANCE: These data demonstrate that placebo-induced activation of the u-opioid system is implicated in the formation of placebo antidepressant effects in patients with MDD and also participate in antidepressant responses, conferring illness resiliency, during open administration. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT02178696. PMID- 26421643 TI - Catalytic Asymmetric Synthesis of Tertiary Alcohols and Oxetenes Bearing a Difluoromethyl Group. AB - The catalytic asymmetric ene reaction with difluoropyruvate as an electrophile in the presence of a dicationic palladium complex is shown. This is the reliable and practical catalytic asymmetric synthesis for various alpha-CF2H tertiary alcohols in high yields and enantioselectivities. The reaction with isobutene can be catalyzed efficiently under solvent-free conditions with low catalyst loading (up to S/C 2000). Furthermore, difluoropyruvate is applicable to the [2 + 2] cycloaddition reaction in high yields and enantioselectivities. PMID- 26421644 TI - Does metoclopramide exposure alter endometrial receptivity and decrease pregnancy rates? AB - OBJECTIVE: The aim of this study was to investigate the effect of metoclopramide on endometrial receptivity with an immunohistochemical investigation of integrin beta3 expression in pregnant rats. MATERIALS AND METHODS: In the present study, the pregnant mice administrated by different doses of metoclopramide were used to explore the effect of metoclopramide on embryo implantation, especially on the endometrial receptivity. RESULTS: The statistical results showed that the number of implanted embryos was gradually declining along the increasing dose of metoclopramide. When the administrated dose of metoclopramide was 3 mg/kg per day, great changes were observed in the exposed uterine morphology and down regulated integrin beta3 were also found in high dose metoclopramide-exposed mice. CONCLUSION: Metoclopramide exposure, especially in high doses may alter endometrial receptivity by effecting integrin expression on decidual tissue which can decrease pregnancy rates. This drug should only be recommended for use during pregnancy when benefit outweighs the risk. PMID- 26421645 TI - Electronic levels in silicon MaWCE nanowires: evidence of a limited diffusion of Ag. AB - Deep level transient spectroscopy (DLTS) was performed on lowly n-doped silicon nanowires grown by metal-assisted wet chemical etching (MaWCE) with silver as the catalyst in order to investigate the energetic scheme inside the bandgap. To observe the possible diffusion of atoms into the bulk, DLTS investigation was also performed on the samples after removing the nanowires. Two of the four energy levels observed in the nanowires were also detected inside the substrate. Based on these results and on literature data about deep levels in bulk silicon, some hypotheses are advanced regarding the identification of the defects responsible for the energy levels revealed. PMID- 26421646 TI - Financial Exploitation of Older Women: A Case Analysis Using the Struggle for Recognition Theory. AB - This article aims to make a theoretical contribution to the field of mistreatment of older adults by introducing Honneth's Struggle for Recognition theory in order to document financial mistreatment of older women. Through a case analysis of an older woman financially exploited by her son, considering self-agency and structure, it shows how financial mistreatment disrespects the three components of Honneth's theory, primary relationships, legal relations, and community of value. Personal integrity, social integrity, and honor and dignity are threatened by mistreatment. This case analysis opens for further theoretical exploration of the Struggle for Recognition theory in the understanding of mistreatment of older adults. PMID- 26421647 TI - Partner Type, Sexual Double Standard Endorsement, and Ambivalence Predict Abdication and Unprotected Sex Intentions in a Community Sample of Young Women. AB - In-the-moment ambivalence about having sex may influence sexual decisions but has rarely been examined. We investigated how ambivalence about sex might be related to intentions to abdicate sexual decisions to a male partner and to engage in unprotected sex in a community sample of young women. Predictors of abdication and unprotected sex intentions included partner type (new casual versus previous relationship), sexual double standard (SDS) endorsement, and two types of ambivalence. After completing a SDS endorsement measure, women (N = 360) projected themselves into a hypothetical sexual situation and completed dependent measures. In the new casual partner condition, SDS endorsement indirectly negatively predicted unprotected sex intentions through its associations with ambivalence and abdication. In both partner conditions SDS endorsement positively predicted abdication, which then positively predicted unprotected sex intentions. Ambivalence indirectly predicted unprotected sex intentions through its negative association with abdication intentions. Results suggest the importance of ambivalence for sexual decisions and the complexity of understanding the sexual decision making processes for women who endorse the SDS. PMID- 26421648 TI - Comment on "Using Satellite-Based Spatiotemporal Resolved Air Temperature Exposure to Study the Association between Ambient Air Temperature and Birth Outcomes in Massachusetts". PMID- 26421651 TI - Distant peer-tutoring for developing countries. PMID- 26421650 TI - The hydatidiform mole. AB - The hydatidiform mole (HM) is a placental pathology of androgenetic origin. Placental villi have an abnormal hyperproliferation event and hydropic degeneration. Three situations can be envisaged at its origin: 1. The destruction/expulsion of the female pronucleus at the time of fertilization by 1 or 2 spermatozoa with the former being followed by an endoreplication of the male pronucleus leading to a complete hydatidiform mole (CHM) 2. A triploid zygote (fertilization by 2 spermatozoa) leading to a partial hydatidiform mole (PHM) but can also lead to haploid and diploid clones. The diploid clone may produce a normal fetus while the haploid clone after endoreplication generates a CHM 3. A nutritional defect during the differentiation of the oocytes or the deterioration of the limited oxygen pressure during the first trimester of gestation may lead to the formation of a HM. In countries with poor medical health care system, moles (mainly the CHM) can become invasive or, in rare cases, lead to gestational choriocarcinomas. PMID- 26421652 TI - Obesogen Holdover: Prenatal Exposure Predicts Cardiometabolic Risk Factors in Childhood. PMID- 26421654 TI - Biomechanical assessment of the stabilization capacity of monolithic spinal rods with different flexural stiffness and anchoring arrangement. AB - BACKGROUND: Spinal disorders can be treated by several means including fusion surgery. Rigid posterior instrumentations are used to obtain the stability needed for fusion. However, the abrupt stiffness variation between the stabilized and intact segments leads to proximal junctional kyphosis. The concept of spinal rods with variable flexural stiffness is proposed to create a more gradual transition at the end of the instrumentation. METHOD: Biomechanical tests were conducted on porcine spine segments (L1-L6) to assess the stabilization capacity of spinal rods with different flexural stiffness. Dual-rod fusion constructs containing three kinds of rods (Ti, Ti-Ni superelastic, and Ti-Ni half stiff-half superelastic) were implanted using two anchor arrangements: pedicle screws at all levels or pedicle screws at all levels except for upper instrumented vertebra in which case pedicle screws were replaced with transverse process hooks. Specimens were loaded in forward flexion, extension, and lateral bending before and after implantation of the fusion constructs. The effects of different rods on specimen stiffness, vertebra mobility, intradiscal pressures, and anchor forces were evaluated. FINDING: The differences in rod properties had a moderate impact on the biomechanics of the instrumented spine when only pedicle screws were used. However, this effect was amplified when transverse process hooks were used as proximal anchors. INTERPRETATION: Combining transverse hooks and softer (Ti-Ni superelastic and Ti-Ni half stiff-half superelastic) rods provided more motion at the upper instrumented level and applied less force on the anchors, potentially improving the load sharing capacity of the instrumentation. PMID- 26421653 TI - Self-Propelled Micro-/Nanomotors Based on Controlled Assembled Architectures. AB - Synthetic micro-/nanomotors (MNMs) are capable of performing self-propelled motion in fluids through harvesting different types of energies into mechanical movement, with potential applications in biomedicine and other fields. To address the challenges in these applications, a promising strategy that combines controlled assembly (bottom-up approaches) with top-down approaches for engineering autonomous, multifunctionalized MNMs is under investigation, beginning in 2012. These MNMs, derived from layer-by-layer assembly or molecular self-assembly, display the advantages of: i) mass production, ii) response to the external stimuli, and iii) access to multifunctionality, biocompatibility, and biodegradability. The advance on how to integrate diverse functional components into different architectures based on controlled assemblies, to realize controlled fabrication, motion control (including the movement speed, direction, and state), and biomedical applications of MNMs, directed by the concept of nanoarchitectonics, are highlighted here. The remaining challenges and future research directions are also discussed. PMID- 26421657 TI - Study of Reciprocal Effects between Mandatory Pollutant Emissions Reduction Policy and Structural Change within the Manufacturing Sector in a Chinese Coastal Area. AB - We develop a multicriteria decision-making model coupled with scenario analysis to quantitatively elucidate the reciprocal effect between a mandatory pollutant emissions reduction policy and industrial structure change within the manufacturing sector on the basis of an in-depth study of a well-developed coastal area in East China, Ningbo City, toward 2020. First, 18 two-digit level industries (TDLIs) in the manufacturing sector are screened out due to intensive emissions of the four pollutants (COD, NH3-N, SO2, and NOx). Second, a model is established to identify the optimal solution for the industrial structure adjustment of the 18 TDLIs under two scenarios, the "business-as-usual" scenario and the "industrial structure adjustment" scenario. Both scenarios are expanded into three subscenarios. Quantitative constraint conditions and two criteria are formulated to screen out the optimal solutions. We propose a coefficient of industrial structure adjustment, Ki, which could clearly reflect the policy preference in terms of industrial development and reallocate the quota of the four-pollutant emission among the 18 TDLIs with regards to the different expectations of economy development in 2020. The model will help local authorities make tailored policies to reduce pollution emissions effectively through industrial structure change by delicately allocating the pollutant emission quota and setting reasonable targets of emission intensity reduction among TDLIs. PMID- 26421658 TI - Temporal and Regional Expression of Glucose-Dependent Insulinotropic Peptide and Its Receptor in Spinal Cord Injured Rats. AB - Spinal cord injury (SCI) results in loss of movement, sensibility, and autonomic control at the level of the lesion and at lower parts of the body. Several experimental strategies have been used in attempts to increase endogenous mechanisms of neuroprotection, neuroplasticity, and repair, but with limited success. It is known that glucose-dependent insulinotropic peptide (GIP) and its receptor (GIPR) can enhance synaptic plasticity, neurogenesis, and axonal outgrowth. However, their role in the injury has never been studied. The aim of this study was to evaluate the changes in expression levels of both GIP and GIPR in acute and chronic phases of SCI in rats. Following SCI (2 to 24 h after damage), the rat spinal cord showed a lesion in which the epicenter had a cavity with hemorrhage and necrosis. Furthermore, the lesion cavity also showed ballooned cells 14 and 28 days after injury. We found that SCI induced increases in GIPR expression in areas neighboring the site of injury at 6 h and 28 days after the injury. Moreover, higher GIP expression was observed in these regions on day 28. Neuronal projections from the injury epicenter showed an increase in GIP immunoreactivity 24 h and 14 and 28 days after SCI. Interestingly, GIP was also found in progenitor cells at the spinal cord canal 24 h after injury, whereas both GIP and GIPR were present in progenitor cells at the injury epicenter 14 days after in SCI animals. These results suggest that GIP and its receptor might be implicated with neurogenesis and the repair process after SCI. PMID- 26421659 TI - Estimation of surface-level PM concentration from satellite observation taking into account the aerosol vertical profiles and hygroscopicity. AB - Surface-level PM10 distribution was estimated from the satellite aerosol optical depth (AOD) products, taking the account of vertical profiles and hygroscopicity of aerosols over Jeju, Korea during March 2008 and October 2009. In this study, MODIS AOD data from the Terra and Aqua satellites were corrected with aerosol extinction profiles and relative humidity data. PBLH (Planetary Boundary Layer Height) was determined from MPLNET lidar-derived aerosol extinction coefficient profiles. Through statistical analysis, better agreement in correlation (R = 0.82) between the hourly PM10 concentration and hourly average Sunphotometer AOD was the obtained when vertical fraction method (VFM) considering Haze Layer Height (HLH) and hygroscopic growth factor f(RH) was used. The validity of the derived relationship between satellite AOD and surface PM10 concentration clearly demonstrates that satellite AOD data can be utilized for remote sensing of spatial distribution of regional PM10 concentration. PMID- 26421660 TI - Regenerative Electrode Interfaces for Neural Prostheses. AB - Neural prostheses are electrode arrays implanted in the nervous system that record or stimulate electrical activity in neurons. Rapid growth in the use of neural prostheses in research and clinical applications has occurred in recent years, but instability and poor patency in the tissue-electrode interface undermines the longevity and performance of these devices. The application of tissue engineering strategies to the device interface is a promising approach to improve connectivity and communication between implanted electrodes and local neurons, and several research groups have developed new and innovative modifications to neural prostheses with the goal of seamless device-tissue integration. These approaches can be broadly categorized based on the strategy used to maintain and regenerate neurons at the device interface: (1) redesign of the prosthesis architecture to include finer-scale geometries and/or provide topographical cues to guide regenerating neural outgrowth, (2) incorporation of material coatings and bioactive molecules on the prosthesis to improve neuronal growth, viability, and adhesion, and (3) inclusion of cellular grafts to replenish the local neuron population or provide a target site for reinnervation (biohybrid devices). In addition to stabilizing the contact between neurons and electrodes, the potential to selectively interface specific subpopulations of neurons with individual electrode sites is a key advantage of regenerative interfaces. In this study, we review the development of regenerative interfaces for applications in both the peripheral and central nervous system. Current and future development of regenerative interfaces has the potential to improve the stability and selectivity of neural prostheses, improving the patency and resolution of information transfer between neurons and implanted electrodes. PMID- 26421661 TI - "Mind the Gap": Raman Evidence for Rapid Inactivation of CTX-M-9 beta-Lactamase Using Mechanism-Based Inhibitors that Bridge the Active Site. AB - CTX-M beta-lactamases are one of the fastest growing extended-spectrum beta lactamase (ESBL) families found in Escherichia coli rendering this organism extremely difficult to treat with beta-lactam antibiotics. Although they are grouped in class A beta-lactamases, the CTX-M family possesses low sequence identity with other enzymes. In addition, they have high hydrolytic activity against oxyimino-cephalosporins, despite having smaller active sites compared to other ESBLs in class A. Similar to most class A enzymes, most of the CTX-M beta lactamases can be inhibited by the clinical inhibitors (clavulanic acid, sulbactam, and tazobactam), but the prevalence of inhibitor resistance is an emerging clinical threat. Thus, the mechanistic details of inhibition pathways are needed for new inhibitor development. Here, we use Raman microscopy to study the CTX-M-9 inactivation reaction with the three commercially available inhibitors and compare these findings to the analysis of the S130G variant. Characterization of the reactions in CTX-M-9 single crystals and solution show the formation of a unique cross-linked species, probably involving Ser70 and Ser130, with subsequent hydrolysis leading to an acrylate species linked to Ser130. In solution, a major population of this species is seen at 25 ms after mixing. Support for this finding comes from the CTX-M-9 S130G variant that reacts with clavulanic acid, sulbactam, and tazobactam in solution, but lacks the characteristic spectroscopic signature for the Ser130-linked species. Understanding the mechanism of inactivation of this clinically important ESBL type class A lactamase permits us to approach the challenge of inhibitor resistance using knowledge of the bridging species in the inactivation pathway. PMID- 26421662 TI - Dipstick albuminuria and acute kidney injury recovery in critically ill septic patients. AB - AIM: Acute kidney injury (AKI) is a frequent complication of sepsis, a pro inflammatory state that alters tubular handling of filtered albumin. We hypothesized that dipstick albuminuria (DA) is associated with a lower rate of AKI recovery in septic patients. METHODS: This was a single-centre, retrospective cohort study of adults with sepsis-associated AKI in an urban academic intensive care unit (ICU). Patients with unknown baseline serum creatinine (SCr), absent urinalysis, and those with estimated glomerular filtration rate (eGFR) <15 mL/min per 1.73m(2) or receiving chronic renal replacement therapy (RRT) were excluded. The independent variable was DA (negative or trace, 30 mg/dL, and >=100 mg/dL) within the first 72 h of ICU stay. The outcome variable was AKI recovery at 30 days following hospital discharge, defined as the last SCr returning to a level less than 1.5 times the baseline SCr level and independence of RRT. RESULTS: A total of 988 patients were included in the study. The median length of hospitalization was 11 days. The patients with higher degree of DA had worse critical illness scores. After adjustment for several confounders, DA >=30 mg/dL was independently associated with "no AKI recovery" at 30 days post-discharge (adjusted OR 1.40, 95% CI, 1.01-1.95 for DA =30 mg/dL and 1.67, 1.15-2.42 for DA >=100 mg/dL, P = 0.02). Other independent predictors of "no AKI recovery" were cumulative fluid balance, Sequential Organ Failure Assessment (SOFA) score, exposure to diuretics, and the need for mechanical ventilation. CONCLUSION: Dipstick albuminuria >=30 mg/dL is independently associated with lower rate of AKI recovery at 30 days post-discharge. Our findings emphasize the potential utility of a simple routine test of DA in the risk-stratification of AKI recovery in ICU septic patients. PMID- 26421663 TI - Estimated Lifetime Medical and Work-Loss Costs of Emergency Department-Treated Nonfatal Injuries--United States, 2013. AB - A large number of nonfatal injuries are treated in U.S. emergency departments (EDs) every year. CDC's National Center for Health Statistics estimates that approximately 29% of all ED visits in 2010 were for injuries. To assess the economic impact of ED-treated injuries, CDC examined injury data from the National Electronic Injury Surveillance System--All Injury Program (NEISS-AIP) for 2013, as well as injury-related lifetime medical and work-loss costs from the Web-Based Injury Statistics Query and Reporting System (WISQARS). NEISS-AIP collects data from a nationally representative sample of EDs, using specific guidelines for recording the primary diagnosis and mechanism of injury. Number of injuries, crude- and age-specific injury rates, and total lifetime work-loss costs and medical costs were calculated for ED-treated injuries, stratified by sex, age groups, and intent and mechanism of injury. ED-treated injuries were further classified as those that were subsequently hospitalized or treated and released. The rate of hospitalized injuries was 950.8 per 100,000, and the rate of treated and released injuries was 8,549.8 per 100,000. Combined medical and work-loss costs for all ED-treated injuries (both hospitalized and treated and released) were $456.9 billion, or approximately 68% of the total costs of $671 billion associated with all fatal and ED-treated injuries. The substantial economic burden associated with nonfatal injuries underscores the need for effective prevention strategies. PMID- 26421664 TI - The c.63A>G polymorphism in the NKX2.5 gene is associated with thyroid hypoplasia in children with thyroid dysgenesis. AB - OBJECTIVE: To search for genetic alteration in NKX2.5 gene in patients presenting both congenital heart disease (CHD) and TD. SUBJECTS AND METHODS: Individual phenotypes were carefully analyzed in 86 children with thyroid dysgenesis (TD) using thyroid function tests, scintigraphy, ultrasound and echocardiography. DNA was extracted and NKX2.5 gene coding region was amplified by polymerase chain reaction (PCR) and sequenced. RESULTS: CHD were found in 8.1% of patients with TD. The mutation screening revealed two known polymorphisms in patients with isolated TD or TD associated with CHD. None of them are predicted to result in codon change in conserved domain. The c.63A>G polymorphism was detected in 54/86 patients (49 with isolated TD and 5 with TD combined with CHD). There was a significant association of c.63A>G polymorphism with hypoplasia (p < 0.036). The c.541G>A polymorphism was observed in only one patient with isolated thyroid hypoplasia. CONCLUSION: NKX2.5 mutations were not found. The c.63A>G polymorphism might be associated with thyroid hypoplasia. PMID- 26421665 TI - Low iodine diet does not improve the efficacy of radioiodine for the treatment of Graves' disease. AB - OBJECTIVE: Consuming a low-iodine diet (LID) is a widely accepted practice before administering radioiodine (131I) to evaluate and to treat thyroid disease. Although this procedure is well established for the management of patients with differentiated thyroid cancer, its use in patients with benign disease is unclear. So, we aimed to evaluate the influence of a LID on the outcome in patients with Graves' disease (GD) treated with 131I. SUBJECTS AND METHODS: We evaluated 67 patients with GD who were divided into 2 groups: one group (n = 31) consumed a LID for 1-2 weeks, and the second group (n = 36) was instructed to maintain a regular diet (RD). RESULTS: The LID group experienced a 23% decrease in urinary iodine after 1 week on the diet and a significant 42% decrease after 2 weeks on the diet. The majority (53%) of the patients in the LID group had urinary iodine levels that were consistent with deficient iodine intake. However, there was no difference in the rate of hyperthyroidism's cure between the LID and the RD groups 6 months after 131I therapy. Furthermore, the therapeutic efficacy did not differ in patients with varying degrees of sufficient iodine intake (corresponding urinary iodine levels: < 10 MUg/dL is deficient; 10-29.9 MUg/dL is sufficient; and > 30 MUg/dL is excessive). CONCLUSION: In the present study, we demonstrated that although a LID decreased urinary iodine levels, those levels corresponding with sufficient or a mild excess in iodine intake did not compromise the therapeutic efficacy of 131I for the treatment of GD. PMID- 26421666 TI - Effects of thyroid hormone replacement on glycated hemoglobin levels in non diabetic subjects with overt hypothyroidism. AB - OBJECTIVE: Glycated hemoglobin (HbA1c) may not accurately reflect the level of glycemia in conditions of altered erythrocyte turnover. Hypothyroidism is one condition associated with sluggish erythropoesis. To assess changes in HbA1c, independent of changes in plasma glucose after initiation of thyroxine replacement in patients with overt hypothyroidism. MATERIALS AND METHODS: In this prospective longitudinal study carried out in a tertiary care centre, adult non diabetic patients with overt hypothyroidism recruited between March 2012 to August 2013 were rendered euthyroid on thyroxine. They underwent testing for hemoglobin, HbA1c, reticulocyte count, thyroxine, thyrotropin and a standard oral glucose tolerance test, both before and at 3 months after restoration to the euthyroid state. Main outcome assessed was the change in HbA1c independent of the change in glucose parameters. RESULTS: Thirty eight patients (35 female and 3 male) aged 37.8 +/- 10.2 years with overt hypothyroidism (thyroxine 12.6 +/- 13.4 ng/mL and thyrotropin -98.1 +/- 63.7 uIU/mL respectively) were recruited. While HbA1c fell from 5.8 +/- 0.7% to 5.6 +/- 0.5% (p = 0.009) at 3 months following the correction of hypothyroidism, there were no changes in the fasting and the 2 hr post oral glucose tolerance test glucose (p = 0.67 and 0.56 respectively). The number of patients with dysglycemia diagnosed by HbA1c (i.e HbA1c >= 5.7%) fell from 25 (65.78%) to 17 (44.7%) after treatment (p = 0.008). There were 7 (18.4%) patients with HbA1c >= 6.5% at baseline, but this fell to just 4 (10.5%) (p < 0.001) after 3 months of euthyroidism. CONCLUSION: HbA1c is not a reliable diagnostic test for diabetes in the presence of hypothyroidism. PMID- 26421667 TI - Atkins diet program rapidly decreases atherogenic index of plasma in trained adapted overweight men. AB - BACKGROUND: The Atkins diet program is a great example of the application of low carbohydrate diets for obesity, with the intention of weight loss and improvement in cardiovascular risk (CV risk). A good CV risk predictor is the atherogenic index of plasma (AIP) calculated as log (TG/HDL [mmol]), which is strongly affected by serum triglycerides, which in turn is associated with the carbohydrate intake. This study determined the effect of the initial phase of Atkins diet program, consisting in 20 g/day of carbohydrate intake with positive urinary ketones measure, in AIP of 12 adult overweight trained adapted men. The AIP was calculated before and after intervention. RESULTS: After 14 days, BMI and triglycerides decreased significantly, while HDL-C increased. No alterations were described in LDL plasmatic concentration. Prior to the diet, 58.3% of subjects presented high CV risk and after 14 days of the diet program only 33.3% of subjects were classified as high CV risk, while more than 66% were low CV risk. The intervention was effective in 11 of 12 participants. However, in one person the dietary intervention increased AIP index. CONCLUSION: The initial phase of Atkins diet program could significantly decrease the AIP in 11 of 12 adult overweight trained adapted men. Dietary individual responses need to be more studied. PMID- 26421669 TI - Anti-thyroid drug-induced lupus: a case report and review of the literature. AB - We report a case of drug-induced lupus (DIL) on a Chinese woman caused by methimazole (MMI). This report discusses DIL associated with MMI and briefly reviewed the literature concerning to anti-thyroid DIL. PMID- 26421668 TI - Evaluation of central precocious puberty treatment with GnRH analogue at the Triangulo Mineiro Federal University (UFTM). AB - OBJECTIVE: To report our experience of treating central precocious puberty (CPP) with a GnRH analogue with respect to the final heights (FH) attained in patients who completed treatment. SUBJECTS AND METHODS: Among 105 records of children diagnosed with precocious puberty, 62 cases (54 girls and 8 boys), who were treated with leuprolide acetate/3.75 mg/monthly, were selected, and divided into 4 groups: group 1 (G1), 25 girls who attained FH; group 2 (G2), 18 girls who completed treatment but did not reach FH; group 3 (G3), 11 girls still under treatment; and group 4 (G4), 8 boys, 5 of which attained FH. Treatment was concluded at a bone age of 12 years, and follow-up continued until FH was achieved. RESULTS: In both G1 and G2 groups, height standard deviation score (SDS), weight-SDS and percentile of body mass index (PBMI) did not show intra/intergroup differences at the beginning and at interruption of treatment, but when added, G1+G2, height-SDS and weight-SDS differed significantly (p = 0.002 and 0.0001, respectively). In G1, 19 of 25 cases attained TH, and average height gain was 16.7 cm (7.7- 27.1); there was significant difference between FH and prediction of FH at the start (PFH at start) (p = 0.0001), as well as between PFH at interruption vs TH and vs FH (p = 0.007) with FH higher than TH (p = 0.004). Significant correlation was identified between FH and height gain after treatment. CONCLUSION: As shown by some studies, GnRH analogue treatment was effective in children with CPP reaching FH near the genetic target. PMID- 26421670 TI - Effect of the consumption on buriti oil on the metabolism of rats induced by iron overload. AB - OBJECTIVES: To compare the effect of the consumption of buriti oil and soybean oil on the metabolism of rats under stress induced by iron overload. MATERIALS AND METHODS: A total of 28 rats were randomized into control groups who consumed diet added of soybean (CS) or buriti oil (CB) and gavage with saline and two experimental groups who consumed diet added of soybean (ES) or buriti oil (EB) and daily gavage with iron II sulfate as stress inducer. The fatty acid profile of diets was analyzed. Body weight and diet consumption were evaluated every two days. The lipid profile and liver weight of animals were evaluated at the end of the experiment. RESULTS: Diet added of soybean oil showed higher percentage of polyunsaturated fatty acids (45.6%) and diet with buriti oil was rich in monounsaturated fatty acids (66.9%). There were no differences in food intake, total cholesterol, HDL-cholesterol and LDL-cholesterol among groups (p > 0.05). However, animals fed with diet supplemented with buriti oil showed intermediate triglyceride levels (CB: 65 mg/dL; EB: 68.7 mg/dL) compared to ES group (102.5 mg/dL). The liver of rats from the CS group had higher weight (2.06 +/- 0.2 g) compared to the CB group (1.56 +/- 0.1 g). CONCLUSION: Buriti oil consumption was able to minimize some changes related to iron overload. PMID- 26421671 TI - Painless thyroiditis associated to thyroid carcinoma: role of initial ultrasonography evaluation. AB - Even though it is a rare event, most associations of thyroid carcinoma with subacute thyroiditis described in the literature are related to its granulomatous form (Quervain's thyroiditis). We present a patient with subacute lymphocytic thyroiditis (painless thyroiditis) and papillary thyroid cancer that was first suspected in an initial ultrasound evaluation. A 30-year old female patient who was referred to the emergency room due to hyperthyroidism symptoms was diagnosed with painless thyroiditis established by physical examination and laboratory findings. With the presence of a palpable painless thyroid nodule an ultrasound was prescribed and the images revealed a suspicious thyroid nodule, microcalcification focus in the heterogeneous thyroid parenquima and cervical lymphadenopathy. Fine needle aspiration biopsy was taken from this nodule; cytology was assessed for compatibility with papillary thyroid carcinoma. Postsurgical pathology evaluation showed a multicentric papillary carcinoma and lymphocytic infiltration. Subacute thyroiditis, regardless of type, may produce transitory ultrasound changes that obscure the coexistence of papillary carcinoma. Due to this, initial thyroid ultrasound evaluation should be delayed until clinical recovery. We recommended a thyroid ultrasound exam for initial evaluation of painless thyroiditis, particularly in patients with palpable thyroid nodule. Further cytological examination is recommended in cases presenting with suspect thyroid nodule and/or non-nodular hypoechoic (> 1 cm) or heterogeneous areas with microcalcification focus. PMID- 26421672 TI - Six-week anaerobic training improves proteolytic profile of diabetic rats. AB - OBJECTIVE: To evaluate the effect of six-week anaerobic training on the mRNA expression of genes related to proteolysis Ubb (Ubiquitin), E2-14kDa, Trim63 (MuRF1 protein) and Nfkb1 in the skeletal muscle of diabetic rats. MATERIALS AND METHODS: Four groups were established: DE (DiabetesExercised), DS (Diabetes Sedentary), CE (Control Exercised) and CS (Control Sedentary). The training consisted of 3 sets of 12 jumps in the liquid mean with load equivalent to 50% of BW for 6 weeks. Euthanasia occurred under ip anesthesia, and blood, adipose tissue and skeletal muscles were collected. Gene expression was quantified by RT PCR in the gastrocnemius muscle. ANOVA one-way was used for comparison among groups, with post-hoc (Tukey) when necessary, considering p < 0.05. RESULTS: We observed reduction in the body weight and adipose tissue in the diabetic groups. The muscle mass was reduced in DS, which could be reversed by training (DE). Although DS and DE have presented similar body weight, the training protocol in DE promoted reduction in the adipose tissue, and increase of muscle mass. Anaerobic training was efficient to reduce glycaemia only in the diabetic animals until 6 hours after the end of training. The Trim63 gene expression was increased in DS; decreased Ubb gene level was observed in trained rats (CE and DE) compared to sedentary (CS and DS), and DE presented the lowest level of E2-14kDa gene expression. CONCLUSION: Six-week anaerobic training promoted muscle mass gain, improved glycemic control, and exerted inhibitory effect on the proteolysis of gastrocnemius muscle of diabetic rats. PMID- 26421673 TI - Genetic and environmental influence on thyroid gland volume and thickness of thyroid isthmus: a twin study. AB - OBJECTIVES: Decreased thyroid volume has been related to increased prevalence of thyroid cancer. SUBJECTS AND METHODS: One hundred and fourteen Hungarian adult twin pairs (69 monozygotic, 45 dizygotic) with or without known thyroid disorders underwent thyroid ultrasound. Thickness of the thyroid isthmus was measured at the thickest portion of the gland in the midline using electronic calipers at the time of scanning. Volume of the thyroid lobe was computed according to the following formula: thyroid height*width*depth*correction factor (0.63). RESULTS: Age-, sex-, body mass index- and smoking-adjusted heritability of the thickness of thyroid isthmus was 50% (95% confidence interval [CI], 35 to 66%). Neither left nor right thyroid volume showed additive genetic effects, but shared environments were 68% (95% CI, 48 to 80%) and 79% (95% CI, 72 to 87%), respectively. Magnitudes of monozygotic and dizygotic co-twin correlations were not substantially impacted by the correction of covariates of body mass index and smoking. Unshared environmental effects showed a moderate influence on dependent parameters (24-50%). CONCLUSIONS: Our analysis support that familial factors are important for thyroid measures in a general twin population. A larger sample size is needed to show whether this is because of common environmental (e.g. intrauterine effects, regional nutrition habits, iodine supply) or genetic effects. PMID- 26421674 TI - Association between atypical parathyroid adenoma and neurofibromatosis. AB - Primary hyperparathyroidism is a disease characterized by excessive production of parathyroid hormone (PTH), which is due to a parathyroid adenoma in 85% of cases. An atypical parathyroid adenoma, with some histopathological features of parathyroid carcinoma, may be found in some of the cases, although it may not fulfill all the criteria for this diagnosis. Neurofibromatosis type 1 (NF1) is an autosomal dominant systemic disease that may be associated with hyperparathyroidism. We report here the rare combination of a patient with NF1 and clinical manifestations of hyperparathyroidism due to an atypical parathyroid adenoma. PMID- 26421675 TI - The Clinical Practice of Assessing Cognitive Function in Adults Receiving Electroconvulsive Therapy: Whom Are We Missing? AB - BACKGROUND: Cognition can be affected by electroconvulsive therapy (ECT). Good clinical practice includes neuropsychological assessment, although this is seldom a part of routine clinical practice. It looks like a substantial part of patients fail to complete cognitive assessments. This constitutes a problem in the generalizability of published clinical research on cognitive side effects. Most studies of ECT-related cognitive adverse effects do not discuss this important issue of so-called cognitive test nonparticipants. Recent findings suggest that cognitive test nonparticipants are more severely ill, and probably more vulnerable to cognitive side effects. OBJECTIVES: To examine the feasibility of a neuropsychological test battery in daily clinical practice, in an adult population referred for ECT. METHODS: We reviewed the clinical records of 84 patients referred for ECT. Demographic and clinical characteristics of those patients who were able to complete our routine cognitive testing at baseline are compared with those who could not complete the assessment. RESULTS: From 84 ECT patients, 60 (71%) completed a pre-ECT cognitive assessment, whereas 24 (29%) did not. Patients with a unipolar depression, with psychotic symptoms, who started their treatment with a bitemporal electrode placement were more likely to be test noncompleters than test completers. CONCLUSIONS: Patients with a unipolar depression, with psychotic features, who are treated with a bitemporal electrode placement, have a higher likelihood of not completing a pre-ECT cognitive assessment. These patients probably represent a subgroup more vulnerable to cognitive side effects. PMID- 26421676 TI - Current Resources for Evidence-Based Practice, September/October 2015. PMID- 26421677 TI - Buprenorphine for neuropathic pain in adults. AB - BACKGROUND: Opioid drugs, including buprenorphine, are commonly used to treat neuropathic pain, and are considered effective by some professionals. Most reviews have examined all opioids together. This review sought evidence specifically for buprenorphine, at any dose, and by any route of administration. Other opioids are considered in separate reviews. OBJECTIVES: To assess the analgesic efficacy of buprenorphine for chronic neuropathic pain in adults, and the adverse events associated with its use in clinical trials. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE from inception to 11 June 2015, together with reference lists of retrieved papers and reviews, and two online study registries. SELECTION CRITERIA: We included randomised, double-blind studies of two weeks' duration or longer, comparing any oral dose or formulation of buprenorphine with placebo or another active treatment in chronic neuropathic pain. DATA COLLECTION AND ANALYSIS: Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality. We did not carry out any pooled analyses. MAIN RESULTS: Searches identified 10 published studies, and one study with results in ClinicalTrials.gov. None of these 11 studies satisfied our inclusion criteria, and so we included no studies in the review. AUTHORS' CONCLUSIONS: There was insufficient evidence to support or refute the suggestion that buprenorphine has any efficacy in any neuropathic pain condition. PMID- 26421678 TI - Food Ingredients as Anti-Obesity Agents. AB - Brown adipose tissue (BAT) is a site of adaptive non-shivering thermogenesis after cold exposure, and is involved in the regulation of energy expenditure and body fatness. BAT can be activated and recruited by not only cold exposure but also by various food ingredients including capsaicin in chili pepper and catechins in green tea, which would be easily and safely applicable to our daily life for preventing obesity. PMID- 26421681 TI - The clinical presentation of acute bacterial meningitis varies with age, sex and duration of illness. AB - AIM: This Swedish study reviewed differences in clinical presentation and laboratory findings of acute bacterial meningitis in children aged one month to 17 years in Vasterbotten County, Sweden. METHODS: A register-based study was performed for the period 1986 to 2013 using the Vasterbotten County Council's patient registration and laboratory records at the Department of Laboratory Medicine at Umea University Hospital. The medical records were reviewed to extract data and confirm the diagnosis. RESULTS: We found 103 cases of acute bacterial meningitis, and Haemophilus influenzae was the most common pathogen, causing 40.8% of all cases, followed by Streptococcus pneumoniae at 30.1% and Neisseria meningitidis at 9.7%. Significant differences in clinical presentation and laboratory findings were found. Younger children were more unwell than older ones and had more diffuse symptoms on admission. In addition, important sex related differences were found that might explain the higher case fatality rates for boys than girls. For example, boys tended to have a higher disturbance in the blood-brain barrier, which is known to be a negative prognostic factor. CONCLUSION: This study showed that clinical presentation for acute bacterial meningitis varied with age and sex and, to a lesser extent, on the duration of the illness. PMID- 26421679 TI - Ty3 Retrotransposon Hijacks Mating Yeast RNA Processing Bodies to Infect New Genomes. AB - Retrotransposition of the budding yeast long terminal repeat retrotransposon Ty3 is activated during mating. In this study, proteins that associate with Ty3 Gag3 capsid protein during virus-like particle (VLP) assembly were identified by mass spectrometry and screened for roles in mating-stimulated retrotransposition. Components of RNA processing bodies including DEAD box helicases Dhh1/DDX6 and Ded1/DDX3, Sm-like protein Lsm1, decapping protein Dcp2, and 5' to 3' exonuclease Xrn1 were among the proteins identified. These proteins associated with Ty3 proteins and RNA, and were required for formation of Ty3 VLP retrosome assembly factories and for retrotransposition. Specifically, Dhh1/DDX6 was required for normal levels of Ty3 genomic RNA, and Lsm1 and Xrn1 were required for association of Ty3 protein and RNA into retrosomes. This role for components of RNA processing bodies in promoting VLP assembly and retrotransposition during mating in a yeast that lacks RNA interference, contrasts with roles proposed for orthologous components in animal germ cell ribonucleoprotein granules in turnover and epigenetic suppression of retrotransposon RNAs. PMID- 26421680 TI - A study of stromal riboflavin absorption in ex vivo porcine corneas using new and existing delivery protocols for corneal cross-linking. AB - PURPOSE: To indirectly measure stromal riboflavin penetration using commercially available riboflavin solutions and new and existing epithelium-off, trans epithelial and iontophoresis-assisted delivery protocols. METHODS: Forty porcine eyes were divided into eight groups. Group 1: Ricrolin applied to the de epithelialised cornea for 30 min; Group 2: epithelium-intact, no treatment; Groups 3-5: epithelium-intact, 30-min application of Ricrolin TE, Mediocross TE or ParaCel/Vibex, respectively. Group 6: epithelium-intact, Ricrolin(+) iontophoresis-assisted delivery for 5 min; Group 7: epithelium-intact, Ricrolin(+) iontophoresis-assisted delivery for 5 min with a 20-min riboflavin soak; and Group 8: epithelium-intact, Ricrolin(+) iontophoresis-assisted delivery for 5 min, 15-min soak and another 5 min of iontophoresis. After a saline wash, light transmission spectra were obtained from each cornea, before and after epithelial removal. RESULTS: Corneas in groups 1 and 8 showed a distinct riboflavin absorption peak between 400 and 520 nm. The optical density of the corneas in groups 3-7 did not differ significantly from that of the untreated corneas (group 2). CONCLUSIONS: A modification to the standard iontophoresis trans-epithelial technique resulted in successful penetration of riboflavin into the stroma and appears to offer the most promise for epithelium-on cross-linking. PMID- 26421682 TI - Diagnostic Dilemma in Sequential Branch Retinal Vein and Artery Occlusion. AB - PURPOSE: To report on an unusual case of a branch retinal vein occlusion followed by occlusion of the respective branch retinal artery of the same eye 7 years later, in a young, otherwise healthy man with marginal elevation of antiphospholipid antibodies. CASE REPORT: On first presentation, a 30-year-old male patient was diagnosed as having a branch retinal vein occlusion with the sole risk factor of slightly increased diastolic pressure. On second presentation, 7 years later, a transient occlusion of the respective branch retinal artery was diagnosed on the same patient. Extensive ophthalmologic and general medical evaluations were performed including cardiovascular, coagulation, and immunology testing. Coagulopathy screening revealed slightly elevated titers of anticardiolipin IgM and anti-beta 2 glycoprotein-I IgM antibodies, and aspirin prophylaxis was initiated. CONCLUSIONS: Retinal vascular occlusions are typically associated with well-defined, classical risk factors in older people. In younger, otherwise healthy patients, further autoimmune hypercoagulable disorders are often causal. Our case suggests the contribution of slightly elevated antiphospholipid IgM antibodies, although this remains to be proven. PMID- 26421683 TI - Head-Eye Coordination Increases with Age and Varies across Countries. AB - PURPOSE: Head movements in older people may contribute to their dizziness and equilibrium problems. Head gain is the ratio of head movement to total movement (head + eye) when executing a saccade to an eccentric target. Two studies have investigated the relationship between head gain and age but have provided conflicting results. METHODS: We report head gain data collected from research laboratories and optician stores. Our sample sizes are much larger (n = 657 for laboratory, n = 64,458 for optician stores), permitting more detailed analyses. RESULTS: The head-eye coefficient, expressed as 100 times the square root of head gain, was bimodal with one mode of primarily eye movers and one mode of eye-and head movers. Head-eye coefficient increased with age and was invariant with eye correction and gender. We also found an effect of nation that seemed associated with gross domestic product or by latitude (in the northern hemisphere) and log population density. DISCUSSION: Assuming that head movements and visual distortions contribute to dizziness and equilibrium problems, our study suggests that customizing eyewear based on age and country may help in reducing the prevalence of problems associated with head and/or eye movements. PMID- 26421685 TI - A Pragmatic Approach to Dry Eye Diagnosis: Evidence into Practice. AB - Dry eye disease (DED) is a common, multifactorial disease of the tears and anterior ocular surface. The clinical diagnosis of DED is complex, requiring the consideration of both patient symptoms and signs, which can be apparently contradictory. Misdiagnosis can lead to suboptimal clinical management. Studies of the practice behaviors of optometrists suggest that there is the potential to improve the translation of research evidence relating to the diagnosis of DED into primary ophthalmic care. This review describes an evidence-based, pragmatic approach to the contemporary clinical diagnosis of DED, as a means for guiding best practice for the care of dry eye patients. PMID- 26421684 TI - Accommodative Gain in Relation to Perceived Target Clarity. AB - PURPOSE: The purpose of this study is to determine the relationship between target clarity and the magnitude of accommodative lag using the metric accommodative gain (AG). METHODS: Monocular accommodative responses were measured with Grand Seiko autorefraction using both proximal and minus lens techniques in 139 subjects aged 5 to 35 years. Subjects viewed a 1.5-mm letter at 13 discrete distances (range, 40 to 3.33 cm) for the proximal technique and fixed at 33 cm through minus lenses of increasing power for the lens technique. Subjects were instructed to keep the target clear and report when it blurred. The AG was calculated (accommodative response/accommodative demand) for the four greatest consecutive demands perceived clear (termed conditions 1 to 4) and the first demand perceived blurry (termed condition 5). RESULTS: Multivariate planned contrast, including age as a predictor, revealed that mean AG was significantly larger when the target was clear (range, 0.71 to 0.77 for conditions 1 to 4 across techniques) versus blurry (0.59 and 0.68 for condition 5 across techniques) (p < 0.001 for proximal and p < 0.036 for lens). Age was only a contributing factor for the proximal technique, with the youngest subjects having the largest decrease in AG when the target changed from clear to blurry (p = 0.017). CONCLUSIONS: These data suggest that across age and technique, the AG is relatively constant when the target is perceived clear but drops below approximately 70%, on average, once the target is perceived as blurry for subjects aged 5 to 35 years. The AG may be a useful metric to compare accommodative responses across a range of demands and to identify accommodative responses that may not be sufficient to perceive a clear target. PMID- 26421686 TI - Association of IOP with Systemic Factors in a Korean Cohort. AB - PURPOSE: To assess the relationship of intraocular pressure (IOP) to age, sex, and other demographic and health characteristics in a Korean cohort. METHODS: This retrospective cross-sectional study included subjects (n = 155,198) without glaucoma. All participants underwent health screening at the Kangbuk Samsung Hospital from August 2012 to July 2013. Anthropometric measurements, systemic health characteristics, and ocular examination including noncontact tonometry were performed on all participants. Additionally, sociodemographic and behavioral questionnaires were obtained. The systemic variables were analyzed by multiple regression analysis to identify their relationship with IOP. RESULTS: The mean IOP tended to be highest in subjects in their 50s and lowest in subjects in their 20s and 60s for both Korean men and women. This pattern remained the same after adjusting for several demographic and health characteristics. The mean IOP for men was significantly higher than that for women (p < 0.001), but the difference between sexes decreased with increasing age. In the univariate analysis, almost all systemic factors showed a positive association with IOP except for high density lipoprotein cholesterol. By multiple regression analysis, IOP was positively associated with sex (male), current smoking status, systolic blood pressure, fasting plasma glucose, body mass index, total cholesterol, and high density lipoprotein (p <= 0.001). CONCLUSIONS: In a Korean cohort, the mean IOP was highest in subjects in their 50s. The mean IOP for men was significantly higher than that for women. Several systemic factors were significantly correlated with IOP. PMID- 26421687 TI - The APC I1307K allele conveys a significant increased risk for cancer. AB - This study is the first attempt to evaluate the association between the APC I1307K variant and overall cancer risk. It is unique in both its large sample size and in the reliability of data in the control group. The findings described in this article have major implications in terms of identifying asymptomatic individuals who are at increased risk to harbor cancer and therefore targeted to be enrolled in specific early detection and prevention programs. The prevalence of the APC I1307K missense mutation among Ashkenazi Jews is ~ 6%. Carriers are at an increased risk for colorectal neoplasia. In this study, we examined the association of this variant with non-colorectal cancers. Consecutive 13,013 healthy subjects who underwent screening at the Integrated Cancer Prevention Center between 2006 and 2014 were enrolled. This population was supplemented with 1,611 cancer patients from the same institution. Demographics, medical history, and pathological data were recorded. Mortality data were obtained from the Ministry of Health's registry. The prevalence of APC I1307K in cancer patients and healthy subjects was compared. The APC I1307K variant was detected in 189 (11.8%) cancer patients compared to 614 (4.7%) healthy subjects, reflecting an adjusted age and sex odds ratio (OR) of 2.53 (p < 0.0001). History of two or more cancer types was associated with a positive carrier prevalence (OR = 4.38 p < 0.0001). Males had significantly increased carrier prevalence in lung, urologic, pancreatic, and skin cancers. The carrier prevalence among females was significantly higher only in breast and skin cancers. Female carriers developed cancer at a significantly older age compared to non-carriers (average 62.7 years vs. 57.8, respectively, p = 0.027), had better survival rates (HR = 0.58, p = 0.022) and overall increased longevity (average age of death 78.8 vs. 70.4 years, respectively, p = 0.003). In conclusion, the APC I1307K variant is a reliable marker for overall cancer risk (OR 2.53). Further studies are needed to evaluate its use for specific cancer types-particularly in males. Female carriers have better prognosis and increased lifespan. PMID- 26421688 TI - Missed Opportunity: Laparoscopic Colorectal Resection Is Associated With Lower Incidence of Small Bowel Obstruction Compared to an Open Approach. AB - OBJECTIVE: To investigate the effect of a laparoscopic approach on the rate of adhesion-related small bowel obstruction (SBO) following colorectal resection. BACKGROUND: Currently, there is little compelling evidence with regard to rates of SBO after laparoscopic versus open abdominal surgery. Few studies have compared risk-adjusted rates of SBO following laparoscopic and open colorectal resection. METHODS: The Statewide Planning and Research Cooperative System was queried for elective colorectal resections in New York State from 2003 to 2010. A propensity score was calculated to account for selection bias between choice of laparoscopic versus open resection. Bivariate and multivariable competing-risks models were constructed to assess patient, hospital, surgeon, and operative characteristics associated with SBO and operation for SBO within 3 years of resection. RESULTS: Among 69,303 patients who underwent elective colorectal resection (26% laparoscopic, 74% open), 5.3% of patients developed SBO and 2% of patients underwent an operation for SBO. After controlling for other risk factors and conducting an intention-to-treat analysis, open resection was associated with a higher risk of both SBO [hazard ratio (HR) 1.14, 95% confidence interval (CI) 1.03-1.26] and operation for SBO (HR 1.12, 95% CI 0.94-1.32). This effect was even greater when characterizing laparoscopic-to-open conversions as an open approach (SBO: HR 1.34, 95% CI 1.20-1.49; SBO operation: HR 1.35, 95% CI 1.12 1.63). Most other independent risk factors were nonmodifiable and included age <60, female sex, black race, higher comorbidity burden, previous surgery, inflammatory bowel disease, and procedure type. CONCLUSIONS: Open colorectal resection increases the risk of SBO compared with laparoscopy. Increased utilization of a laparoscopic approach has the potential to achieve a significant reduction in the incidence of SBO following colorectal resection. PMID- 26421689 TI - In response to A new theory on the pathogenesis of acquired cholesteatoma: Mucosal traction. PMID- 26421690 TI - Paternal and maternal ages have contrasting associations with self-reported schizophrenia liability. AB - BACKGROUND: Older paternal age predicts schizophrenia diagnosis in offspring. If this relationship reflects a pathogenic process, paternal age should predict the expression of subclinical schizophrenia liability (schizotypy). We hypothesized that paternal and maternal ages predict positive, negative, and disorganized features of schizotypy, that family history of psychosis moderates the relationship of paternal age with schizotypy, and that stress sensitivity mediates the relationship of maternal age with schizotypy. METHOD: Two studies are reported, each of undergraduates (n=500 and n=211) who completed the Schizotypal Personality Questionnaire. The second was designed to replicate and extend the first and included assessment of stress sensitivity. RESULTS: In Study 1, older paternal age and younger maternal age predicted greater positive schizotypy (beta=.13 and beta=-.19, respectively). Parental ages did not predict negative or disorganized features and family history did not moderate the paternal age association. In Study 2, the same pattern of associations between parental ages and schizotypy components was observed. Additionally, stress sensitivity partially mediated the association of maternal age with positive schizotypy whereas it did not contribute to the paternal age association. CONCLUSION: The association between older paternal age and schizophrenia extends to self-reported positive features of schizophrenia liability, consistent with the notion that this relationship arises from a pathogenic process, such as de novo mutations. Importantly, younger maternal age was an equally potent predictor of positive schizotypy, with its association partially mediated by stress sensitivity. PMID- 26421691 TI - Linkage and whole genome sequencing identify a locus on 6q25-26 for formal thought disorder and implicate MEF2A regulation. AB - Formal thought disorder is a major feature of schizophrenia and other psychotic disorders. It is heritable, found in healthy relatives of patients with schizophrenia and other mental disorders but knowledge of specific genetic factors is lacking. The aim of this study was to search for biologically relevant high-risk variants. Formal thought disorder was assessed in participants in the Copenhagen Schizophrenia Linkage Study (N=236), a unique high-risk family study comprised of six large pedigrees. Microsatellite linkage analysis of formal thought disorder was performed and subsequent haplotype analysis of the implicated region using phased microsatellite and SNP genotypes. Whole genome sequencing (N=3) was used in the attempt to identify causative variants in the linkage region. Linkage analysis of formal thought disorder resulted in a single peak at chromosome 6(q26-q27) centred on marker D6S1277, with a maximum LOD score of 4.0. Phasing and fine mapping of the linkage peak identified a 5.5Mb haplotype (chr6:162242322-167753547, hg18) in 31 individuals, all belonging to the same pedigree sharing the haplotype from a common ancestor. The haplotype segregated with increased total thought disorder index score (P=4.9 * 10(-5)) and qualitatively severe forms of thought disturbances. Whole genome sequencing identified a novel nucleotide deletion (chr6:164377205 AG>A, hg18) predicted to disrupt the potential binding of the transcription factor MEF2A. The MEF2A binding site is located between two genes previously reported to associate with schizophrenia, QKI (HGNC:21100) and PDE10A (HGNC:8772). The findings are consistent with MEF2A deregulation conferring risk of formal thought disorder. PMID- 26421692 TI - Computerised working-memory focused cognitive remediation therapy for psychosis- A preliminary study. AB - BACKGROUND: Cognitive deficits are a core feature of schizophrenia and related psychotic disorders and are associated with decreased levels of functioning. Behavioural interventions have shown success in remediating these deficits; determining how best to maximise this benefit while minimising the cost is an important next step in optimising this intervention for clinical use. AIMS: To examine the effects of a novel working-memory focused cognitive remediation (CR) training on cognitive difficulties based on internet delivery of training and weekly telephone support. METHOD: Participants with a diagnosis of psychosis (n=56) underwent either 8 weeks of CR (approximately 20 h) or 8 weeks of treatment as usual (TAU). General cognitive ability, working memory and episodic memory were measured both pre and post intervention for all participants. RESULTS: In addition to improvements on trained working memory tasks, CR training was associated with significant improvements in two tests of verbal episodic memory. No association between CR and changes in general cognitive ability was observed. Effect sizes for statistically significant changes in memory were comparable to those reported in the literature based primarily on 1:1 training. CONCLUSIONS: The cognitive benefits observed in this non-randomised preliminary study indicate that internet-based working memory training can be an effective cognitive remediation therapy. The successes and challenges of an internet-based treatment are discussed. PMID- 26421693 TI - Measuring the impact of burn scarring on health-related quality of life: Development and preliminary content validation of the Brisbane Burn Scar Impact Profile (BBSIP) for children and adults. AB - INTRODUCTION: No burn-scar specific, health-related quality of life (HRQOL) measure exists. This study aimed to develop a patient-reported, evaluative HRQOL measure to assess the impact of burn scarring in children and adults. METHOD: Semi-structured interviews, content validation surveys, and cognitive interviews were used to develop and test content validity of a new measure - the Brisbane Burn Scar Impact Profile (BBSIP). RESULTS: Participants comprised Australian adults (n=23) and children (n=19) with burn scarring; caregivers of children with burn scarring (n=28); and international scar management experts (n=14). Items distinct from other burn scar measures emerged. Four versions of the BBSIP were developed; one for children aged 8-18 years, one for adults, one for caregivers (as proxies for children aged less than 8-years), and one for caregivers of children aged 8-18 years. Preliminary content validity of the BBSIP was supported. Final items covered physical and sensory symptoms; emotional reactions; impact on social functioning and daily activities; impact of treatment; and environmental factors. CONCLUSION: The BBSIP was developed to assess burn-scar specific HRQOL and will be available at http://www.coolburns.com.au under a creative commons license. Further testing is underway. PMID- 26421694 TI - A comparison of non-invasive imaging modalities: Infrared thermography, spectrophotometric intracutaneous analysis and laser Doppler imaging for the assessment of adult burns. AB - BACKGROUND: Currently, the only evidence-based adjunct to clinical evaluation of burn depth is laser Doppler imaging (LDI), although preliminary studies of alternative imaging modalities with instant image acquisition are promising. This is a study to investigate the accuracy of infrared thermography (IRT) and spectrophotometric intracutaneous analysis (SIA) for burn depth assessment, and compare this to the current gold standard: LDI. We include a comparison of the three modalities in terms of cost, reliability and usability. METHODS: We recruited 20 patients with burns presenting to the Chelsea and Westminster Adult Burns Service. Between 48h and 5 days afterburn we recorded imaging using moorLDI2-BI-VR (LDI), FLIR E60 (IRT) and ScanoskinTM (SIA). Subsequent clinical management and outcome was as normal, and not affected by the extra images taken. RESULTS: 24 burn regions were grouped according to burn wound healing: group A healed within 14 days, group B within 14-21 days, and group C took more than 21 days or underwent grafting. Both LDI and IRT accurately determined healing potential in groups A and C, but failed to distinguish between groups B and C (p>0.05). ScanoskinTM interpretation of SIA was 100% consistent with clinical outcome. CONCLUSION: FLIR E60 and ScanoskinTM both present advantages to moorLDI2 BI-VR in terms of cost, ease-of-use and acceptability to patients. IRT is unlikely to challenge LDI as the gold standard as it is subject to the systematic bias of evaporative cooling. At present, the LDI colour-coded palette is the easiest method for image interpretation, whereas ScanoskinTM monochrome colour palettes are more difficult to interpret. However the additional analyses of pigment available using SIA may help more accurately indicate the depth of burn compared with perfusion alone. We suggest development of ScanoskinTM software to include a simplified colour-palette similar to LDI and additional work to further investigate the potential of SIA as an alternative to the current gold standard. PMID- 26421695 TI - The effect of lower body burns on physical function. AB - OBJECTIVE: To attenuate burn-induced catabolism, patients are often enrolled in a resistance exercise program as part of their physical rehabilitation. This study assessed how lower body burn locations affected strength and cardiopulmonary function. METHODS: Children enrolled in an exercise study between 2003 and 2013, were 7-18 years of age, and burned >=30% of their total body surface area were included. Analysis of variance was used to model the relationship of lower body strength (PTW) and cardiopulmonary function (VO2peak) due to burns which traverse the subject's lower body joints. RESULTS: There was a significant relationship between PTW and burns at the hip and toe joints, showing a 26 N m/kg (p=0.010) and 33 N m/kg (p=0.013) decrease in peak torque, respectively. Burns at the hip joint corresponded to a significant decrease in VO2peak by 4.9 ml kg(-1) min(-1) (p=0.010) in peak cardiopulmonary function. CONCLUSION: Physical function and performance are detrimentally affected by burns that traverse specific lower body joints. The most significant relationship on exercise performance was that of hip joint burns as it affected both strength and cardiopulmonary measurements. Ultimately, burns at hip and toe joints need to be considered when interpreting exercise test results involving the lower body. PMID- 26421696 TI - Quantitative breast lesion classification based on multichannel distributions in shear-wave imaging. AB - BACKGROUND AND OBJECTIVES: A computer-aided diagnosis (CAD) system based on the quantified color distributions in shear-wave elastography (SWE) was developed to evaluate the malignancies of breast tumors. METHODS: For 57 benign and 31 malignant tumors, 18 SWE features were extracted from regions of interest (ROI), including the tumor and peritumoral areas. In the ROI, a histogram in each color channel was described using moments such as the mean, variance, skewness, and kurtosis. Moreover, three color channels were combined as a vector to evaluate tissue elasticity. The SWE features were then combined in a logistic regression classifier for breast tumor classification. RESULTS: The performance of the CAD system achieved an accuracy of 81%. Combining the CAD system with a BI-RADS assessment obtained an Az improvement from 0.77 to 0.89 (p-value <0.05). CONCLUSIONS: The combination of the proposed CAD system based on SWE features and the BI-RADS assessment would provide a promising diagnostic suggestion. PMID- 26421697 TI - Whole-blood neutrophil gelatinase-associated lipocalin to predict adverse events in acute kidney injury: A prospective observational cohort study. AB - PURPOSE: Acute kidney injury is common in intensive care units and is associated with increased morbidity and mortality. We evaluated the ability of whole-blood neutrophil gelatinase-associated lipocalin (wbNGAL) to predict mortality and need for renal replacement therapy (RRT) in critically ill patients with kidney dysfunction. METHODS: We prospectively enrolled adult patients in 5 Canadian intensive care units. We measured wbNGAL at the time of enrollment to determine whether NGAL concentration could predict the primary composite outcome of death or need for RRT by day 30 in addition to other secondary outcomes. RESULTS: We recruited 234 patients; 227 were included in the analysis. In a multivariable model, wbNGAL did not predict 30-day mortality or need for RRT (odds ratio, 1.05; 95% confidence interval, 0.99-1.12). Neutrophil gelatinase-associated lipocalin was similar in patients who died (654 [303-1180] ng/mL) vs those who survived (541.5 [255.5-1080] ng/mL, P=.26) by 90 days. Whole-blood NGAL poorly predicted the primary outcome (area under receiver operator curve, 0.65; 95% confidence interval, 0.58-0.73). CONCLUSIONS: In a cohort of critically ill patients with abnormal kidney function, wbNGAL was not effective in the prediction of death or RRT within 30 days. These data do not support the use of this biomarker for the detection of clinical outcomes in this population. PMID- 26421698 TI - Complications of 761 short-term intrathecal macrocatheters in obstetric patients: a retrospective review of cases over a 12-year period. AB - BACKGROUND: A continuous spinal catheter is a reliable alternative to standard neuraxial techniques in obstetric anesthesia. Despite the potential advantages of intrathecal catheters, they remain underutilized due to fear of infection, nerve damage or post-dural puncture headache. In our tertiary care center, intrathecal catheters are either placed intentionally in high-risk obstetric patients or following inadvertent dural puncture using a 19-gauge macrocatheter passed through a 17-gauge epidural needle. METHODS: A retrospective review of 761 intrathecal catheters placed from 2001 to 2012 was conducted. An institutional obstetric anesthesia database was used to identify patients with intrathecal catheters. Medical records were reviewed for procedural details and complications. RESULTS: There were no serious complications, including meningitis, epidural or spinal abscess, hematoma, arachnoiditis, or cauda equina syndrome, associated with intrathecal catheters. The failure rates were 2.8% (3/108) for intentional placements and 6.1% (40/653) for placements following accidental dural puncture. The incidence of post-dural puncture headache was 41% (312/761) and the epidural blood patch rate was 31% (97/312). CONCLUSIONS: This review demonstrates that intrathecal catheters are dependable and an option for labor analgesia and surgical anesthesia for cesarean delivery. Serious long lasting complications are rare. PMID- 26421699 TI - Management of the obstetric airway - time for a paradigm shift (or two)? PMID- 26421700 TI - A randomised controlled trial of the effect of a head-elevation pillow on intrathecal local anaesthetic spread in caesarean section. AB - BACKGROUND: A head-elevation pillow places a patient in a ramped posture, which maximises the view of the larynx during laryngoscopy, particularly in obese parturients. In our institution an elevation pillow is used pre-emptively for neuraxial anaesthesia. We hypothesised that head-elevation may impair cephalad spread of local anaesthetic before caesarean section resulting in a lower block or longer time to achieve a T6 level. We aimed to investigate the effect of head elevation on spread of intrathecal local anaesthetics during anaesthesia for caesarean section. METHODS: One-hundred parturients presenting for caesarean section under combined spinal-epidural anaesthesia were randomised to either the standard supine position with lateral displacement or in the supine position with lateral displacement on an head-elevation pillow. Each patient received intrathecal hyperbaric bupivacaine 11 mg, morphine 100 MUg and fentanyl 15 MUg. Patients were assessed for adequacy of sensory block (T6 or higher) at 10 min. RESULTS: Sensory block to T6 was achieved within 10 min in 65.9% of parturients in the Elevation Pillow Group compared to 95.7% in the Control Group (P<0.05). Compared to the Control Group, patients in the Elevation Pillow Group had greater requirements for epidural supplementation (43.5% vs 2.1%, P<0.001) or conversion to general anaesthesia (9.3% vs 0%, P<0.04). CONCLUSIONS: Use of a ramped position with an head-elevation pillow following injection of the intrathecal component of a combined spinal-epidural anaesthetic for scheduled caesarean section was associated with a significantly lower block height at 10min. PMID- 26421701 TI - Effects of prophylactic ondansetron on spinal anesthesia-induced hypotension: a meta-analysis. AB - BACKGROUND: A range of strategies including physical interventions, intravenous fluids and vasopressor drugs have been used to minimize or prevent spinal anesthesia-induced hypotension. Recent studies suggest that ondansetron, a commonly used antiemetic, also affects hypotension. This systematic review investigated the effects of prophylactic ondansetron on hemodynamic changes following spinal anesthesia. METHODS: Medline, Embase, Cochrane Library databases and www.clinicaltrials.gov were searched for randomized controlled trials studying the effects of ondansetron on hemodynamic changes induced by spinal anesthesia. The primary outcome was hypotension. Relative risk (RR) or mean difference, with 95% confidence intervals (CI), were used to analyze outcomes. RESULTS: Ten randomized controlled trials with 863 patients were included in the analysis. Prophylactic ondansetron reduced the incidence of spinal anesthesia induced hypotension in both obstetric and non-obstetric patients. The RR of spinal anesthesia-induced hypotension after ondansetron administration was 0.53 (95% CI 0.32 to 0.86) in obstetric patients and 0.16 (95% CI 0.05 to 0.51) in non obstetric patients. There was significant heterogeneity among obstetric studies (I(2) = 71%). Ondansetron also reduced the incidence of bradycardia, nausea and vomiting after spinal anesthesia with RRs of 0.27 (95% CI 0.16 to 0.47), 0.24 (95% CI 0.14 to 0.42) and 0.48 (95% CI 0.08 to 3.08), respectively. The doses of ephedrine and phenylephrine required to treat hypotension were reduced by ondansetron with mean differences of -2.35 mg (95% CI -4.14 to -0.55 mg) and 31.16 MUg (95% CI -57.46 to -4.87 MUg), respectively. CONCLUSION: This review suggests that prophylactic ondansetron reduces the incidence of spinal anesthesia induced hypotension and vasopressor consumption in both obstetric and non obstetric patients. In addition, ondansetron can also reduce related adverse outcomes such as bradycardia, nausea and vomiting. However, given the relatively large heterogeneity and small sample sizes in current studies, further large and strict randomized clinical trials investigating the effects of ondansetron on spinal anesthesia-induced hemodynamic changes and side effects are still needed, especially among obstetric patients. PMID- 26421702 TI - The use of phenylephrine to obtund oxytocin-induced hypotension and tachycardia during caesarean section. AB - BACKGROUND: Oxytocin causes clinically significant hypotension and tachycardia. This study examined whether prior administration of phenylephrine obtunds these unwanted haemodynamic effects. METHODS: Forty pregnant women undergoing elective caesarean section under spinal anaesthesia were randomised to receive either an intravenous 50 MUg bolus of phenylephrine (Group P) or saline (Group S) immediately before oxytocin (3U over 15s). Systolic blood pressure, diastolic blood pressure, mean arterial pressure and heart rate were recorded using a continuous non-invasive arterial pressure device. Baseline values were averaged for 20s post-delivery. Between-group comparisons were made of the mean peak changes in blood pressure and heart rate, and the mean percentage changes from baseline, during the 150s after oxytocin administration. RESULTS: The mean +/- SD peak percentage change in systolic blood pressure was -16.9 +/- 2% in Group P, and -19.0 +/- 1.9% in Group S and the estimated mean difference was 2.1% (95% CI 3.5% to 7.8%; P=0.44); corresponding changes in heart rate were 13.5 +/- 2.3% and 14.0+/-1.5% and the mean estimated difference was 0.5% (95% CI -6.0% to 5%; P=0.87). The mean percentage change from the baseline measurements during the 150s period of measurement was greater for Group S than Group P: systolic blood pressure -5.9% vs -3.4% (P=0.149); diastolic blood pressure -7.2% vs -1.5% (P=0.014); mean arterial pressure -6.8% vs -1.5% (P=0.007); heart rate 2.1% vs 2.4% (P=0.033). CONCLUSION: Intravenous phenylephrine 50 MUg immediately before 3U oxytocin during elective caesarean section does not prevent maternal hypotension and tachycardia. PMID- 26421703 TI - The extension of epidural blockade for emergency caesarean section: a survey of Scandinavian practice. AB - BACKGROUND: Little is known about drugs and safety precautions used during epidural top-ups for emergency caesarean section in Scandinavia. We surveyed Scandinavian practice of epidural top-up regimens for emergency caesarean sections. METHODS: Anaesthetic departments in Denmark, Norway and Sweden were identified via National Boards of Health. An electronic questionnaire was sent to Scandinavian specialist anaesthesiologists performing obstetric anaesthesia asking for information on anaesthetic practice for emergency caesarean section. RESULTS: The response rate was 80% (n=145). One hundred and twenty (83%) specialists reported the existence of local guidelines for epidural top-ups. Fourteen (9.7%) specialists gave a full-dose top-up in the delivery room, 34 (23.4%) initiated the top-up with a test-dose, and 87 (60%) only administered local anaesthetics in the operating theatre. Twenty-five different drug combinations for epidural top-ups were reported. Lidocaine was used by 67 (47.9%) and ropivacaine was used by 53 (37.9%). Seventy (50%) specialists added opioid to the top-up, 15 (10.7%) added bicarbonate and 53 (37.9%) supplemented with adrenaline. Median top-up volume ranged from 16 to 19mL for lidocaine, ropivacaine and chloroprocaine. One-hundred-and-eighteen (81%) specialists recommended trainees use the same regimen. Forty (83%) of 48 specialists topping up in the labour unit had ephedrine readily available. During transport, pulse oximetry was used by nine (19%) and non-invasive blood pressure monitoring by eight (17%). CONCLUSIONS: Epidural top-ups for emergency caesarean section in Scandinavia are used frequently but normally performed in the operating theatre. Drugs used differ greatly between countries and departments although top-up volumes appear similar. During transport, available equipment and drugs were limited. Best practice guidelines and national guidelines present little information on epidural top-ups that could explain the variation found. PMID- 26421704 TI - Phenylephrine infusion test to evaluate alpha blockade in a pregnant patient with pheochromocytoma. PMID- 26421705 TI - Checklists and multidisciplinary team performance during simulated obstetric hemorrhage. AB - BACKGROUND: Checklists can optimize team performance during medical crises. However, there has been limited examination of checklist use during obstetric crises. In this simulation study we exposed multidisciplinary teams to checklist training to evaluate checklist use and team performance during a severe postpartum hemorrhage. METHODS: Fourteen multidisciplinary teams participated in a postpartum hemorrhage simulation occurring after vaginal delivery. Before participating, each team received checklist training. The primary study outcome was whether each team used the checklist during the simulation. Secondary outcomes were the times taken to activate our institution-specific massive transfusion protocol and commence red blood cell transfusion, and whether a designated checklist reader was used. RESULTS: The majority of teams (12/14 (86%)) used the checklist. Red blood cell transfusion was administered by all teams. The median [IQR] times taken to activate the massive transfusion protocol and transfuse red blood cells were 5min 14s [3:23-6:43] and 14min 40s [12:56 17:28], respectively. A designated checklist reader was used by 7/12 (58%) teams that used the checklist. Among teams that used a checklist with versus without a designated reader, we observed no differences in the times to activate the massive transfusion protocol or to commence red blood cell transfusion (P>0.05). CONCLUSIONS: Although checklist training was effective in promoting checklist use, multidisciplinary teams varied in their scope of checklist use during a postpartum hemorrhage simulation. Future studies are required to determine whether structured checklist training can result in more standardized checklist use during a postpartum hemorrhage. PMID- 26421706 TI - The Psychosocial and Clinical Outcomes of Orbital Decompression Surgery for Thyroid Eye Disease and Predictors of Change in Quality of Life. AB - PURPOSE: Thyroid eye disease (TED) has been found to reduce quality of life for many patients because of changes in their appearance and vision, although some seem to adjust better than others. This study was designed to investigate whether a patient's quality of life changes after having orbital decompression for improvement of appearance, vision, or both, and whether any demographic, clinical, or psychosocial factors can predict which patients might benefit from this surgery. DESIGN: This study used a within-subjects repeated-measures design, in which patients were assessed before and at 6 weeks and 6 months after surgery. PARTICIPANTS: A total of 123 adults (aged >18 years) with TED and undergoing orbital decompression surgery were recruited at Moorfields Eye Hospital. METHODS: Participants received lateral wall, medial wall, 2.5 wall, or 3 wall decompression and were followed up after surgery with a range of psychosocial and clinical assessments. MAIN OUTCOME MEASURES: The Graves' Ophthalmopathy Quality of Life (GO-QOL) scale was completed at each time point, and this was used as the dependent variable in each hierarchical multiple regression model. RESULTS: Significant improvements were found in all clinical characteristics after orbital decompression and in most psychosocial variables. The GO-QOL visual function scores did not change significantly until 6 months after surgery. In contrast, GO QOL appearance scores changed significantly by 6 weeks after surgery and continued to increase to 6 months, reaching a minimal clinically important difference for this scale. None of the changes in clinical or psychosocial outcomes significantly predicted change in GO-QOL visual function. However, the hierarchical regression model explained 79% of the variance in change in GO-QOL appearance, with change in subjective evaluation of appearance being the only unique predictor of change in appearance-related quality of life. CONCLUSIONS: This study highlights the importance of appearance-related cognitions in predicting quality of life outcomes after surgery. Implications for clinical practice need to be considered in light of the limitations of this study, but it is suggested that psychosocial interventions targeting appearance-related cognitive processes, in particular personal evaluation of appearance, could enhance the quality of life outcomes for patients with TED undergoing orbital decompression surgery. PMID- 26421707 TI - Importance of Normal Aging in Estimating the Rate of Glaucomatous Neuroretinal Rim and Retinal Nerve Fiber Layer Loss. AB - PURPOSE: To describe longitudinal rates of change of neuroretinal parameters in patients with glaucoma and healthy controls, and to evaluate the influence of covariates. DESIGN: Prospective longitudinal study. PARTICIPANTS: Treated patients with glaucoma (n = 192) and healthy controls (n = 37). METHODS: Global disc margin-based neuroretinal rim area (DMRA) was measured with confocal scanning laser tomography, while Bruch's membrane opening-minimum rim width (BMO MRW), BMO area (BMOA), and peripapillary retinal nerve fiber layer thickness (RNFLT) were measured with optical coherence tomography at 6-month intervals. Individual rates of change were estimated with ordinary least-squares regression, and linear mixed effects modeling was used to estimate the average rate of change and differences between the groups, and to evaluate the effects of baseline measurement and baseline age on rates of change. MAIN OUTCOME MEASURES: Rates of change for each parameter. RESULTS: Subjects were followed for a median (range) of 4 (2-6) years. The proportion of controls who had significant reduction of neuroretinal parameters was 35% for BMO-MRW, 31% for RNFLT, and 11% for DMRA. The corresponding figures for patients with glaucoma were not statistically different (42%, P = 0.45; 31%, P = 0.99; 14%, P = 0.99, respectively). Controls had a significant reduction of BMO-MRW (mean: -1.92 MUm/year, P < 0.01) and RNFLT (mean: -0.44 MUm/year, P = 0.01), but not DMRA (mean: -0.22*10(-2) mm(2)/year, P = 0.41). After adjusting for covariates, patients with glaucoma had faster, but not statistically different, rates of deterioration compared with controls, by 1.26 MUm/year (P = 0.07) for BMO-MRW, -0.40 MUm/year (P = 0.11) for RNFLT, and 0.38*10(-2) mm(2)/year (P = 0.23) for DMRA. Baseline BMO-MRW and RNFLT significantly influenced the respective rates of change, with higher baseline values relating to faster reductions. Older age at baseline was associated with a slower reduction in rates of BMO-MRW. Reductions in intraocular pressure were related to increases in BMO-MRW and DMRA. There was a tendency for BMOA to decrease over time (-0.38*10(-2) mm(2)/year; P = 0.04). CONCLUSIONS: Age-related loss of neuroretinal parameters may explain a large proportion of the deterioration observed in treated patients with glaucoma and should be carefully considered in estimating rates of change. PMID- 26421708 TI - Short-term outcomes of intracorporeal esophagojejunostomy using the transorally inserted anvil versus extracorporeal circular anastomosis during laparoscopic total gastrectomy for gastric cancer: a propensity score matching analysis. AB - BACKGROUND: To assess the short-term outcomes of intracorporeal Roux-en-Y esophagojejunostomy using the transorally inserted anvil (OrVil) compared with extracorporeal circular Roux-en-Y anastomosis during laparoscopic total gastrectomy (LTG) for gastric cancer. METHODS: From January 2011-April 2014, a total of 165 consecutive patients with gastric cancer underwent either intracorporeal Roux-en-Y esophagojejunostomy (n = 25) using the Orvil or extracorporeal circular anastomosis (n = 140) during LTG. After generating propensity scores with six covariates, including gender, age, body mass index (BMI), Eastern Cooperative Oncology Group performance status, tumor location, and tumor size, 25 patients undergoing the OrVil method (intracorporeal group) were one-to-one matched with 25 patients undergoing the extracorporeal method (extracorporeal group). The short-term outcomes were compared between the two groups. RESULTS: Both groups were balanced regarding baseline variables. The total operative time was not significantly different between the two groups (216.5 +/- 24.9 min versus 224.0 +/- 30.5 min, P = 0.344), whereas either the duration of anvil insertion (9.9 +/- 2.4 min versus 12.9 +/- 2.0 min, P < 0.001) or reconstruction completion (44.4 +/- 9.4 min versus 50.1 +/- 5.4 min, P = 0.012) in the intracorporeal group was less. The mean length of minilaparotomy in the intracorporeal group was shorter (5.6 +/- 0.4 cm versus 7.2 +/- 1.7 cm, P < 0.001). No significant differences were observed in intraoperative complication rate, estimated blood loss, length of proximal margin, or postoperative recovery course (including the time to first flatus, liquid resumption, liquid, and soft diet) between the two groups. No patients suffered from anastomosis-related complications. The overall morbidity rates of 28.0% in the intracorporeal group and 32.0% in the extracorporeal group were comparable (P = 0.758). CONCLUSIONS: Intracorporeal Roux-en-Y esophagojejunostomy using the transorally inserted anvil system may be a safe procedure during LTG for gastric cancer. However, a longer follow-up in a well-designed randomized controlled trial is necessary to more thoroughly evaluate this technique. PMID- 26421709 TI - Decellularized amniotic membrane attenuates postinfarct left ventricular remodeling. AB - BACKGROUND: Placenta and amnion have been suggested as sources of juvenile cells and tissues for use in surgical regenerative medicine. We previously determined the impact of amniotic epithelial cells induced to undergo epithelial-to mesenchymal transition (EMT) on myocardial remodeling processes and now evaluated the effects of naive and processed amniotic membrane (AM) on postischemic left ventricular (LV) geometry and function. METHODS: Human AM was used in unmodified form (AM), after EMT induction by transforming growth factor beta (EMT-AM), and after decellularization (Decell-AM). After characterization by histology, electron microscopy, splenocyte proliferation assay, and cytokine release, myocardial infarction was induced in 6-8-week old male BALB/c mice by permanent left anterior descending coronary occlusion, and AM patches were sutured to the anterior LV surface (n = 10 per group). Infarcted hearts without AM or sham operated mice were used as controls (n = 10 each). After 4 weeks, LV pressure volume curves were recorded using a conductance catheter before the animals were sacrificed and the hearts analyzed by histology. RESULTS: TGF-beta treatment induced EMT-like changes in amniotic epithelial cells but increased AM xenoreactivity in vitro (splenocyte proliferation) and in vivo (CD4+ cell invasion). Moreover, in vitro interleukin-6 release from AM and from cardiac fibroblasts co-incubated with AM was 300- or 100-fold higher than that of interleukin-10, whereas Decell-AM did not release any cytokines. AM- and Decell AM-treated hearts had smaller infarct size and greater infarct scar thickness than infarct control hearts, but there was no difference in myocardial capillary density or the number of TUNEL positive apoptotic cells. LV contractile function was better in the AM and EMT-AM groups than in infarcted control hearts, but dP/dt max, dP/dt min, stroke work, and cardiac output were best preserved in mice treated with Decell-AM. Volume-based parameters (LV end-systolic and end diastolic volume as well as LV ejection fraction) did not differ between AM and Decell-AM. CONCLUSIONS: Decellularized AM supports postinfarct ventricular dynamics independent of the actual regeneration processes. As a cell-free approach to support the infarcted heart, this concept warrants further investigation. PMID- 26421710 TI - High mitochondrial mass identifies a sub-population of stem-like cancer cells that are chemo-resistant. AB - Chemo-resistance is a clinical barrier to more effective anti-cancer therapy. In this context, cancer stem-like cells (CSCs) are thought to be chemo-resistant, resulting in tumor recurrence and distant metastasis. Our hypothesis is that chemo-resistance in CSCs is driven, in part, by enhanced mitochondrial function. Here, we used breast cell lines and metastatic breast cancer patient samples to begin to dissect the role of mitochondrial metabolism in conferring the CSC phenotype. More specifically, we employed fluorescent staining with MitoTracker (MT) to metabolically fractionate these cell lines into mito-high and mito-low sub-populations, by flow-cytometry. Interestingly, cells with high mitochondrial mass (mito-high) were specifically enriched in a number of known CSC markers, such as aldehyde dehydrogenase (ALDH) activity, and they were ESA+/CD24-/low and formed mammospheres with higher efficiency. Large cell size is another independent characteristic of the stem cell phenotype; here, we observed a >2 fold increase in mitochondrial mass in large cells (>12-MUm), relative to the smaller cell population (4-8-MUm). Moreover, the mito-high cell population showed a 2.4-fold enrichment in tumor-initiating cell activity, based on limiting dilution assays in murine xenografts. Importantly, primary human breast CSCs isolated from patients with metastatic breast cancer or a patient derived xenograft (PDX) also showed the co-enrichment of ALDH activity and mitochondrial mass. Most significantly, our investigations demonstrated that mito-high cells were resistant to paclitaxel, resulting in little or no DNA damage, as measured using the comet assay. In summary, increased mitochondrial mass in a sub population of breast cancer cells confers a stem-like phenotype and chemo resistance. As such, our current findings have important clinical implications for over-coming drug resistance, by therapeutically targeting the mito-high CSC population. PMID- 26421713 TI - The design and implementation of an accelerometer-assisted velocity observer. AB - This paper presents a dynamically compensated velocity observer (DCVO), in which acceleration measurement is employed to estimate velocity. Its sensitivity to the noise that is associated with the acceleration measurement is formulated and compared with that of a conventional state-space velocity observer (SSVO). Unlike the SSVO, the DCVO is completely insensitive to an accelerometer offset. The DCVO, the SSVO and a common ITM-based estimator are all realized in a linear motion stage, to determine their effectiveness. A sliding-mode controller is also implemented with different velocity observers, and it is shown that the DCVO enables high-frequency switching of the sliding-mode controller and also practically improves the positioning accuracy. PMID- 26421712 TI - The MTHFR C677T Polymorphism Is Related to Plasma Concentration of Oxidized Low Density Lipoprotein in Adolescents with Cardiovascular Risk Factors. AB - AIM: The aim of this study was to investigate possible relationships among the A1298C (rs1801131) and C677T (rs1801133) polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and levels of homocysteine, vitamins B6, B12, folic acid and lipid profile, including oxidized low-density lipoprotein (ox-LDL), of adolescents at cardiovascular risk. METHODS: We recruited 115 adolescents (10-19 years old), 58.3% (n = 67) female, from a public school in Brazil who underwent anthropometric, biochemical and genetic tests as well as food consumption evaluation. RESULTS: An important prevalence of hyperhomocysteinemia (19.1%) and alterations in triacylglycerol (17.4%), total cholesterol (26.9%) and high-density lipoprotein (HDL) cholesterol (48.0%) concentrations were observed, as well as low vitamin B6 concentrations (23.5%). The categorization of homocysteine concentrations into tertiles revealed significant differences in serum concentrations of folate, vitamin B12 and HDL, waist circumference and intake of total and saturated fat among the tertiles. The presence of variant alleles regarding the MTHFR C677T polymorphism interfered with vitamin B6 and ox-LDL cholesterol concentrations. There was a trend for higher waist circumference values in T carriers (C677T), but not in C carriers (A1298C). CONCLUSIONS: The MTHFR C677T allele was associated with higher plasma vitamin B6 and ox-LDL compared to the CC genotype. PMID- 26421714 TI - Coarctate and Pseudocoarctate Reactions: Stereochemical Rules. AB - Coarctate reactions are a distinct class of concerted reactions. They differ from other concerted reactions, such as S(N)2, E2, or pericyclic reactions, in such a way that atoms are involved in the transition state at which two bonds are made and two bonds are broken simultaneously. Similar to pericyclic reactions, an electron count can be used to predict reactivity and stereochemistry. The "coarctate rules" are derived from a topological variant of the aromaticity of the transition state principle. Pseudocoarctate transition states exhibit disconnections in the topology of orbital overlap and do not necessarily follow the coarctate rules. PMID- 26421711 TI - Mitochondrial mass, a new metabolic biomarker for stem-like cancer cells: Understanding WNT/FGF-driven anabolic signaling. AB - Here, we developed an isogenic cell model of "stemness" to facilitate protein biomarker discovery in breast cancer. For this purpose, we used knowledge gained previously from the study of the mouse mammary tumor virus (MMTV). MMTV initiates mammary tumorigenesis in mice by promoter insertion adjacent to two main integration sites, namely Int-1 (Wnt1) and Int-2 (Fgf3), which ultimately activates Wnt/beta-catenin signaling, driving the propagation of mammary cancer stem cells (CSCs). Thus, to develop a humanized model of MMTV signaling, we over expressed WNT1 and FGF3 in MCF7 cells, an ER(+) human breast cancer cell line. We then validated that MCF7 cells over-expressing both WNT1 and FGF3 show a 3.5-fold increase in mammosphere formation, and that conditioned media from these cells is also sufficient to promote stem cell activity in untransfected parental MCF7 and T47D cells, as WNT1 and FGF3 are secreted factors. Proteomic analysis of this model system revealed the induction of i) EMT markers, ii) mitochondrial proteins, iii) glycolytic enzymes and iv) protein synthesis machinery, consistent with an anabolic CSC phenotype. MitoTracker staining validated the expected WNT1/FGF3-induced increase in mitochondrial mass and activity, which presumably reflects increased mitochondrial biogenesis. Importantly, many of the proteins that were up-regulated by WNT/FGF-signaling in MCF7 cells, were also transcriptionally over-expressed in human breast cancer cells in vivo, based on the bioinformatic analysis of public gene expression datasets of laser-captured patient samples. As such, this isogenic cell model should accelerate the discovery of new biomarkers to predict clinical outcome in breast cancer, facilitating the development of personalized medicine.Finally, we used mitochondrial mass as a surrogate marker for increased mitochondrial biogenesis in untransfected MCF7 cells. As predicted, metabolic fractionation of parental MCF7 cells, via MitoTracker staining, indicated that high mitochondrial mass is a new metabolic biomarker for the enrichment of anabolic CSCs, as functionally assessed by mammosphere-forming activity. This observation has broad implications for understanding the role of mitochondrial biogenesis in the propagation of stem like cancer cells. Technically, this general metabolic approach could be applied to any cancer type, to identify and target the mitochondrial-rich CSC population.The implications of our work for understanding the role of mitochondrial metabolism in viral oncogenesis driven by random promoter insertions are also discussed, in the context of MMTV and ALV infections. PMID- 26421715 TI - Histological and morphological observations on tongue of Scincella tsinlingensis (Reptilia, Squamata, Scincidae). AB - The histology and morphology characteristics of the tongue in Scincella tsinlingensis were studied by light and electronic microscopy. Under light microscopy, the tongue consists of tip, lingual body and radix in sequence. Numerous lingual papillae widely distribute on the surface of the dorsal and ventral flanks in the tongue, in addition to some regions of the tip. The papillae's surface is covered with the epithelial layer. The lamina propria and dense connective tissue are distinct existing under the epithelial layer. There are many lingual glands spread over the lamina propria. Tongue muscle is developed and composed of distinct intrinsic muscle, hyoglossus and genioglossus. By scanning electron microscopy, at higher magnification, the epithelial cells of the dorsal surface in the divaricate tongue tips show numerous microvilli, micro ridges and micro-pores. The surface of dorsal side of the papillae in lingual body is covered with abundant of micro-ridges and taste bud lacuna. On the surface of the papillae in radix, micro-facets and micro-ridges are compactly distributed, as well as scattered mucilage-pores. The lingual epithelium is divided into four layers observed by the transmission electron microscope. Cells of basal layer are irregularly elliptical in shape, with sparse organelles in the cytoplasm. The deep intermediate layer is not always distinct. Small numbers of organelles are scattered into the cytoplasm. The cells of the superficial intermediate layer gradually flatten, as do their nuclei. The cytoplasm contains many keratohyalin granules. Cell membranes are formed processes around cells and joined by abundant desmosomes to the cell membranes of adjacent cells. The cells located on the extreme free-surface side of the keratinized layer have fallen off. The basal lamina is intercalated between the basal layer and the lamina propria. The lamina propria of lingual body contains lingual gland. A large part of the cytoplasm is occupied by mucus granules which located in the distal part of the cell. The connective tissue contains myelinated nerve fibers, vessel and muscle cells. PMID- 26421716 TI - Microbiological Evaluation of Household Drinking Water Treatment in Rural China Shows Benefits of Electric Kettles: A Cross-Sectional Study. AB - BACKGROUND: In rural China ~607 million people drink boiled water, yet little is known about prevailing household water treatment (HWT) methods or their effectiveness. Boiling, the most common HWT method globally, is microbiologically effective, but household air pollution (HAP) from burning solid fuels causes cardiovascular and respiratory disease, and black carbon emissions exacerbate climate change. Boiled water is also easily re-contaminated. Our study was designed to identify the HWT methods used in rural China and to evaluate their effectiveness. METHODS: We used a geographically stratified cross-sectional design in rural Guangxi Province to collect survey data from 450 households in the summer of 2013. Household drinking water samples were collected and assayed for Thermotolerant Coliforms (TTC), and physicochemical analyses were conducted for village drinking water sources. In the winter of 2013-2104, we surveyed 120 additional households and used remote sensors to corroborate self-reported boiling data. FINDINGS: Our HWT prevalence estimates were: 27.1% boiling with electric kettles, 20.3% boiling with pots, 34.4% purchasing bottled water, and 18.2% drinking untreated water (for these analyses we treated bottled water as a HWT method). Households using electric kettles had the lowest concentrations of TTC (73% lower than households drinking untreated water). Multilevel mixed effects regression analyses showed that electric kettles were associated with the largest Log10TTC reduction (-0.60, p<0.001), followed by bottled water (-0.45, p<0.001) and pots (-0.44, p<0.01). Compared to households drinking untreated water, electric kettle users also had the lowest risk of having TTC detected in their drinking water (risk ratio, RR = 0.49, 0.34-0.70, p<0.001), followed by bottled water users (RR = 0.70, 0.53-0.93, p<0.05) and households boiling with pots (RR = 0.74, 0.54-1.02, p = 0.06). CONCLUSION: As far as we are aware, this is the first HWT-focused study in China, and the first to quantify the comparative advantage of boiling with electric kettles over pots. Our results suggest that electric kettles could be used to rapidly expand safe drinking water access and reduce HAP exposure in rural China. PMID- 26421717 TI - Calmodulin Interacts with the Sodium/Calcium Exchanger NCX1 to Regulate Activity. AB - Changes in intracellular Ca2+ concentrations ([Ca2+]i) are an important signal for various physiological activities. The Na+/Ca2+ exchangers (NCX) at the plasma membrane transport Ca2+ into or out of the cell according to the electrochemical gradients of Na+ and Ca2+ to modulate [Ca2+]i homeostasis. Calmodulin (CaM) senses [Ca2+]i changes and relays Ca2+ signals by binding to target proteins such as channels and transporters. However, it is not clear how calmodulin modulates NCX activity. Using CaM as a bait, we pulled down the intracellular loops subcloned from the NCX1 splice variants NCX1.1 and NCX1.3. This interaction requires both Ca2+ and a putative CaM-binding segment (CaMS). To determine whether CaM modulates NCX activity, we co-expressed NCX1 splice variants with CaM or CaM1234 (a Ca2+-binding deficient mutant) in HEK293T cells and measured the increase in [Ca2+]i contributed by the influx of Ca2+ through NCX. Deleting the CaMS from NCX1.1 and NCX1.3 attenuated exchange activity and decreased membrane localization. Without the mutually exclusive exon, the exchange activity was decreased and could be partially rescued by CaM1234. Point-mutations at any of the 4 conserved a.a. residues in the CaMS had differential effects in NCX1.1 and NCX1.3. Mutating the first two conserved a.a. in NCX1.1 decreased exchange activity; mutating the 3rd or 4th conserved a.a. residues did not alter exchange activity, but CaM co-expression suppressed activity. Mutating the 2nd and 3rd conserved a.a. residues in NCX1.3 decreased exchange activity. Taken together, our results demonstrate that CaM senses changes in [Ca2+]i and binds to the cytoplasmic loop of NCX1 to regulate exchange activity. PMID- 26421718 TI - Whole Genomic Analysis of an Unusual Human G6P[14] Rotavirus Strain Isolated from a Child with Diarrhea in Thailand: Evidence for Bovine-To-Human Interspecies Transmission and Reassortment Events. AB - An unusual rotavirus strain, SKT-27, with the G6P[14] genotypes (RVA/Human wt/THA/SKT-27/2012/G6P[14]), was identified in a stool specimen from a hospitalized child aged eight months with severe diarrhea. In this study, we sequenced and characterized the complete genome of strain SKT-27. On whole genomic analysis, strain SKT-27 was found to have a unique genotype constellation: G6-P[14]-I2-R2-C2-M2-A3-N2-T6-E2-H3. The non-G/P genotype constellation of this strain (I2-R2-C2-M2-A3-N2-T6-E2-H3) is commonly shared with rotavirus strains from artiodactyls such as cattle. Phylogenetic analysis indicated that nine of the 11 genes of strain SKT-27 (VP7, VP4, VP6, VP2-3, NSP1, NSP3-5) appeared to be of artiodactyl (likely bovine) origin, while the remaining VP1 and NSP2 genes were assumed to be of human origin. Thus, strain SKT-27 was found to have a bovine rotavirus genetic backbone, and thus is likely to be of bovine origin. Furthermore, strain SKT-27 appeared to be derived through interspecies transmission and reassortment events involving bovine and human rotavirus strains. Of note is that the VP7 gene of strain SKT-27 was located in G6 lineage-5 together with those of bovine rotavirus strains, away from the clusters comprising other G6P[14] strains in G6 lineages-2/6, suggesting the occurrence of independent bovine-to-human interspecies transmission events. To our knowledge, this is the first report on full genome-based characterization of human G6P[14] strains that have emerged in Southeast Asia. Our observations will provide important insights into the origin of G6P[14] strains, and into dynamic interactions between human and bovine rotavirus strains. PMID- 26421720 TI - Utilization of bone impedance for age estimation in postmortem cases. AB - In the field of Forensic Medicine the number of unidentified cadavers has increased due to natural disasters and international terrorism. The age estimation is very important for identification of the victims. The degree of sagittal closure is one of such age estimation methods. However it is not widely accepted as a reliable method for age estimation. In this study, we have examined whether measuring impedance value (z-values) of the sagittal suture of the skull is related to the age in men and women and discussed the possibility to use bone impedance for age estimation. Bone impedance values increased with aging and decreased after the age of 64.5. Then we compared age estimation through the conventional visual method and the proposed bone impedance measurement technique. It is suggested that the bone impedance measuring technique may be of value to forensic science as a method of age estimation. PMID- 26421719 TI - Patterns of Brain Activation and Meal Reduction Induced by Abdominal Surgery in Mice and Modulation by Rikkunshito. AB - Abdominal surgery inhibits food intake and induces c-Fos expression in the hypothalamic and medullary nuclei in rats. Rikkunshito (RKT), a Kampo medicine improves anorexia. We assessed the alterations in meal microstructure and c-Fos expression in brain nuclei induced by abdominal surgery and the modulation by RKT in mice. RKT or vehicle was gavaged daily for 1 week. On day 8 mice had no access to food for 6-7 h and were treated twice with RKT or vehicle. Abdominal surgery (laparotomy-cecum palpation) was performed 1-2 h before the dark phase. The food intake and meal structures were monitored using an automated monitoring system for mice. Brain sections were processed for c-Fos immunoreactivity (ir) 2-h after abdominal surgery. Abdominal surgery significantly reduced bouts, meal frequency, size and duration, and time spent on meals, and increased inter-meal interval and satiety ratio resulting in 92-86% suppression of food intake at 2-24 h post surgery compared with control group (no surgery). RKT significantly increased bouts, meal duration and the cumulative 12-h food intake by 11%. Abdominal surgery increased c-Fos in the prelimbic, cingulate and insular cortexes, and autonomic nuclei, such as the bed nucleus of the stria terminalis, central amygdala, hypothalamic supraoptic (SON), paraventricular and arcuate nuclei, Edinger-Westphal nucleus (E-W), lateral periaqueduct gray (PAG), lateral parabrachial nucleus, locus coeruleus, ventrolateral medulla and nucleus tractus solitarius (NTS). RKT induced a small increase in c-Fos-ir neurons in the SON and E-W of control mice, and in mice with surgery there was an increase in the lateral PAG and a decrease in the NTS. These findings indicate that abdominal surgery inhibits food intake by increasing both satiation (meal duration) and satiety (meal interval) and activates brain circuits involved in pain, feeding behavior and stress that may underlie the alterations of meal pattern and food intake inhibition. RKT improves food consumption post-surgically that may involve modulation of pain pathway. PMID- 26421721 TI - Geographic Distribution of Radiologists and Utilization of Teleradiology in Japan: A Longitudinal Analysis Based on National Census Data. AB - BACKGROUND: Japan has the most CT and MRI scanners per unit population in the world, and as these technologies spread, their geographic distribution is becoming equalized. In contrast, the number of radiologists per unit population in Japan is the lowest among OECD countries and their geographic distribution is unknown. Likewise, little is known about the use of teleradiology, which can compensate for the uneven distribution of radiologists. METHODS: Based on the Survey of Physicians, Dentists and Pharmacists and the Static Survey of Medical Institutions by the Ministry of Health, Labour and Welfare, a dataset of radiologists and CT and MRI utilizations in each of Japan's 1811 municipalities was created. The inter-municipality equity of the number of radiologists was evaluated using Gini coefficient. Logistic regression analysis, based on Static Survey data, was performed to evaluate the association between hospital location and teleradiology use. RESULTS: Between 2006 and 2012 the number of radiologists increased by 21.7%, but the Gini coefficient remained unchanged. The number of radiologists per 1,000 CT (MRI) utilizations decreased by 17.9% (1.0%); the number was highest in metropolis and lowest in town/village and the disparity has widened from 1.9 to 2.2 (1.6 to 2.0) times. The number of hospitals and clinics using teleradiology has increased (by 69.6% and 18.1%, respectively). Hospitals located in towns/villages (odds ratio 1.61; 95% confidence interval 1.26-2.07) were more likely to use teleradiology than those in metropolises. CONCLUSIONS: Contrary to the CT and MRI distributions, radiologist distribution has not been evened out by the increase in their number; in other words, the distribution of radiologists was not affected by market-derived spatial competition force. As a consequence, the gap of the radiologist shortage between urban and rural areas is increasing. Teleradiology, which is one way to ameliorate this gap, should be encouraged. PMID- 26421723 TI - Probing Microenvironment in Ionic Liquids by Time-Resolved EPR of Photoexcited Triplets. AB - Unusual physicochemical properties of ionic liquids (ILs) open vistas for a variety of new applications. Herewith, we investigate the influence of microviscosity and nanostructuring of ILs on spin dynamics of the dissolved photoexcited molecules. We use two most common ILs [Bmim]PF6 and [Bmim]BF4 (with its close analogue [C10mim]BF4) as solvents and photoexcited Zn tetraphenylporphyrin (ZnTPP) as a probe. Time-resolved electron paramagnetic resonance (TR EPR) is employed to investigate spectra and kinetics of spin polarized triplet ZnTPP in the temperature range 100-270 K. TR EPR data clearly indicate the presence of two microenvironments of ZnTPP in frozen ILs at 100-200 K, being manifested in different spectral shapes and different spin relaxation rates. For one of these microenvironments TR EPR data is quite similar to those obtained in common frozen organic solvents (toluene, glycerol, N-methyl-2 pyrrolidone). However, the second one favors the remarkably slow relaxation of spin polarization, being much longer than in the case of common solvents. Additional experiments using continuous wave EPR and stable nitroxide as a probe confirmed the formation of heterogeneities upon freezing of ILs and complemented TR EPR results. Thus, TR EPR of photoexcited triplets can be effectively used for probing heterogeneities and nanostructuring in frozen ILs. In addition, the increase of polarization lifetime in frozen ILs is an interesting finding that might allow investigation of short-lived intermediates inaccessible otherwise. PMID- 26421722 TI - Agent-Based Model Forecasts Aging of the Population of People Who Inject Drugs in Metropolitan Chicago and Changing Prevalence of Hepatitis C Infections. AB - People who inject drugs (PWID) are at high risk for blood-borne pathogens transmitted during the sharing of contaminated injection equipment, particularly hepatitis C virus (HCV). HCV prevalence is influenced by a complex interplay of drug-use behaviors, social networks, and geography, as well as the availability of interventions, such as needle exchange programs. To adequately address this complexity in HCV epidemic forecasting, we have developed a computational model, the Agent-based Pathogen Kinetics model (APK). APK simulates the PWID population in metropolitan Chicago, including the social interactions that result in HCV infection. We used multiple empirical data sources on Chicago PWID to build a spatial distribution of an in silico PWID population and modeled networks among the PWID by considering the geography of the city and its suburbs. APK was validated against 2012 empirical data (the latest available) and shown to agree with network and epidemiological surveys to within 1%. For the period 2010-2020, APK forecasts a decline in HCV prevalence of 0.8% per year from 44(+/- 2)% to 36(+/- 5)%, although some sub-populations would continue to have relatively high prevalence, including Non-Hispanic Blacks, 48(+/- 5)%. The rate of decline will be lowest in Non-Hispanic Whites and we find, in a reversal of historical trends, that incidence among non-Hispanic Whites would exceed incidence among Non Hispanic Blacks (0.66 per 100 per years vs 0.17 per 100 person years). APK also forecasts an increase in PWID mean age from 35(+/- 1) to 40(+/- 2) with a corresponding increase from 59(+/- 2)% to 80(+/- 6)% in the proportion of the population >30 years old. Our studies highlight the importance of analyzing subpopulations in disease predictions, the utility of computer simulation for analyzing demographic and health trends among PWID and serve as a tool for guiding intervention and prevention strategies in Chicago, and other major cities. PMID- 26421725 TI - A Magnetic Bead-Based Sensor for the Quantification of Multiple Prostate Cancer Biomarkers. AB - Novel biomarker assays and upgraded analytical tools are urgently needed to accurately discriminate benign prostatic hypertrophy (BPH) from prostate cancer (CaP). To address this unmet clinical need, we report a piezeoelectric/magnetic bead-based assay to quantitate prostate specific antigen (PSA; free and total), prostatic acid phosphatase, carbonic anhydrase 1 (CA1), osteonectin, IL-6 soluble receptor (IL-6sr), and spondin-2. We used the sensor to measure these seven proteins in serum samples from 120 benign prostate hypertrophy patients and 100 Gleason score 6 and 7 CaP using serum samples previously collected and banked. The results were analyzed with receiver operator characteristic curve analysis. There were significant differences between BPH and CaP patients in the PSA, CA1, and spondin-2 assays. The highest AUC discrimination was achieved with a spondin 2 OR free/total PSA operation--the area under the curve was 0.84 with a p value below 10(-6). Some of these data seem to contradict previous reports and highlight the importance of sample selection and proper assay building in the development of biomarker measurement schemes. This bead-based system offers important advantages in assay building including low cost, high throughput, and rapid identification of an optimal matched antibody pair. PMID- 26421724 TI - Interactions of L-3,5,3'-Triiodothyronine [corrected], Allopregnanolone, and Ivermectin with the GABAA Receptor: Evidence for Overlapping Intersubunit Binding Modes. AB - Structural mechanisms of modulation of gamma-aminobutyric acid (GABA) type A receptors by neurosteroids and hormones remain unclear. The thyroid hormone L 3,5,3'-triiodothyronine (T3) inhibits GABAA receptors at micromolar concentrations and has common features with neurosteroids such as allopregnanolone (ALLOP). Here we use functional experiments on alpha2beta1gamma2 GABAA receptors expressed in Xenopus oocytes to detect competitive interactions between T3 and an agonist (ivermectin, IVM) with a crystallographically determined binding site at subunit interfaces in the transmembrane domain of a homologous receptor (glutamate-gated chloride channel, GluCl). T3 and ALLOP also show competitive effects, supporting the presence of both a T3 and ALLOP binding site at one or more subunit interfaces. Molecular dynamics (MD) simulations over 200 ns are used to investigate the dynamics and energetics of T3 in the identified intersubunit sites. In these simulations, T3 molecules occupying all intersubunit sites (with the exception of the alpha-beta interface) display numerous energetically favorable conformations with multiple hydrogen bonding partners, including previously implicated polar/acidic sidechains and a structurally conserved deformation in the M1 backbone. PMID- 26421726 TI - Legacy of Pre-Disturbance Spatial Pattern Determines Early Structural Diversity following Severe Disturbance in Montane Spruce Forests. AB - BACKGROUND: Severe canopy-removing disturbances are native to many temperate forests and radically alter stand structure, but biotic legacies (surviving elements or patterns) can lend continuity to ecosystem function after such events. Poorly understood is the degree to which the structural complexity of an old-growth forest carries over to the next stand. We asked how pre-disturbance spatial pattern acts as a legacy to influence post-disturbance stand structure, and how this legacy influences the structural diversity within the early-seral stand. METHODS: Two stem-mapped one-hectare forest plots in the Czech Republic experienced a severe bark beetle outbreak, thus providing before-and-after data on spatial patterns in live and dead trees, crown projections, down logs, and herb cover. RESULTS: Post-disturbance stands were dominated by an advanced regeneration layer present before the disturbance. Both major species, Norway spruce (Picea abies) and rowan (Sorbus aucuparia), were strongly self-aggregated and also clustered to former canopy trees, pre-disturbance snags, stumps and logs, suggesting positive overstory to understory neighbourhood effects. Thus, although the disturbance dramatically reduced the stand's height profile with ~100% mortality of the canopy layer, the spatial structure of post-disturbance stands still closely reflected the pre-disturbance structure. The former upper tree layer influenced advanced regeneration through microsite and light limitation. Under formerly dense canopies, regeneration density was high but relatively homogeneous in height; while in former small gaps with greater herb cover, regeneration density was lower but with greater heterogeneity in heights. CONCLUSION: These findings suggest that pre-disturbance spatial patterns of forests can persist through severe canopy-removing disturbance, and determine the spatial structure of the succeeding stand. Such patterns constitute a subtle but key legacy effect, promoting structural complexity in early-seral forests as well as variable successional pathways and rates. This influence suggests a continuity in spatial ecosystem structure that may well persist through multiple forest generations. PMID- 26421728 TI - Maintenance Therapy in Colorectal Cancer: Moving the Artillery Down While Keeping an Eye on the Enemy. AB - The survival improvement in metastatic colorectal cancer, achieved with more intensive chemotherapy regimens, has recently led clinicians to question the optimal duration of therapies and to consider the role of maintenance. Indeed, patients whose disease is controlled after induction chemotherapy may benefit from continuing a less intensive regimen in order to reinforce the results achieved with up-front treatment. In addition, the more favorable toxicity profile of maintenance approaches would ensure a better quality of life. After discussing the rationale and the difference of pursuing a maintenance strategy with chemotherapeutic and/or biologic agents, we present significant available data from the literature and comment on the current implications and future directions of maintenance therapy. The current roles of depotentiated treatment schedules, antiangiogenic compounds, epidermal growth factor receptor inhibitors, and novel targeted therapies are also reviewed. Finally, we address elements that may foster clinical and social debate on this topic, suggesting potential aspects that need to be further investigated. PMID- 26421727 TI - Acute Biphasic Effects of Ayahuasca. AB - Ritual use of ayahuasca, an amazonian Amerindian medicine turned sacrament in syncretic religions in Brazil, is rapidly growing around the world. Because of this internationalization, a comprehensive understanding of the pharmacological mechanisms of action of the brew and the neural correlates of the modified states of consciousness it induces is important. Employing a combination of electroencephalogram (EEG) recordings and quantification of ayahuasca's compounds and their metabolites in the systemic circulation we found ayahuasca to induce a biphasic effect in the brain. This effect was composed of reduced power in the alpha band (8-13 Hz) after 50 minutes from ingestion of the brew and increased slow- and fast-gamma power (30-50 and 50-100 Hz, respectively) between 75 and 125 minutes. Alpha power reductions were mostly located at left parieto-occipital cortex, slow-gamma power increase was observed at left centro-parieto-occipital, left fronto-temporal and right frontal cortices while fast-gamma increases were significant at left centro-parieto-occipital, left fronto-temporal, right frontal and right parieto-occipital cortices. These effects were significantly associated with circulating levels of ayahuasca's chemical compounds, mostly N,N dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine and some of their metabolites. An interpretation based on a cognitive and emotional framework relevant to the ritual use of ayahuasca, as well as it's potential therapeutic effects is offered. PMID- 26421729 TI - Models of the Ni-L and Ni-SIa States of the [NiFe]-Hydrogenase Active Site. AB - A new class of synthetic models for the active site of [NiFe]-hydrogenases are described. The Ni(I/II)(SCys)2 and Fe(II)(CN)2CO sites are represented with (RC5H4)Ni(I/II) and Fe(II)(diphos)(CO) modules, where diphos = 1,2 C2H4(PPh2)2(dppe) or cis-1,2-C2H2(PPh2)2(dppv). The two bridging thiolate ligands are represented by CH2(CH2S)2(2-) (pdt(2-)), Me2C(CH2S)2(2-) (Me2pdt(2-)), and (C6H5S)2(2-). The reaction of Fe(pdt)(CO)2(dppe) and [(C5H5)3Ni2]BF4 affords [(C5H5)Ni(pdt)Fe(dppe)(CO)]BF4 ([1a]BF4). Monocarbonyl [1a]BF4 features an S = 0 Ni(II)Fe(II) center with five-coordinated iron, as proposed for the Ni-SIa state of the enzyme. One-electron reduction of [1a](+) affords the S = 1/2 derivative [1a](0), which, according to density functional theory (DFT) calculations and electron paramagnetic resonance and Mossbauer spectroscopies, is best described as a Ni(I)Fe(II) compound. The Ni(I)Fe(II) assignment matches that for the Ni-L state in [NiFe]-hydrogenase, unlike recently reported Ni(II)Fe(I)-based models. Compound [1a](0) reacts with strong acids to liberate 0.5 equiv of H2 and regenerate [1a](+), indicating that H2 evolution is catalyzed by [1a](0). DFT calculations were used to investigate the pathway for H2 evolution and revealed that the mechanism can proceed through two isomers of [1a](0) that differ in the stereochemistry of the Fe(dppe)CO center. Calculations suggest that protonation of [1a](0) (both isomers) affords Ni(III)-H-Fe(II) intermediates, which represent mimics of the Ni-C state of the enzyme. PMID- 26421730 TI - Determination of cytotoxicity of traditional Chinese medicine herbs, Rhizoma coptidis, Radix scutellariae, and Cortex phellodendri, by three methods. AB - BACKGROUND: Many herbs are used in traditional Chinese medicine TCM) for treatment of infections but their properties, in particular, their effects on normal cells have received little attention. This study investigated the cytotoxic properties of three TCM herbs with potential use in prevention and treatment of ocular infections, including Acanthamoeba keratitis. METHOD: The study investigated cytotoxic effects of the herbal extracts of Rhizoma coptidis, Radix scutellariae, and Cortex phellodendri on human corneal epithelial cells using trypan blue staining, MTT production, and flow cytometry. Differences between herbs were determined using repeated measures one-way analysis of variance, followed by paired t-tests where appropriate. RESULTS: These three herbs appeared to lack cytotoxicity when tested with trypan blue and MTT, but flow cytometry revealed that R. coptidis led to cell membrane damage. CONCLUSION: Lack of cytotoxicity of R. scutellariae and C. phellodendri extracts suggest that these are potentially suitable for use in ocular preparations. Only flow cytometry was able to accurately predict cytotoxic effects of extracts of TCM herbs on HCEC, demonstrating the importance of using a sensitive method of detection of cytotoxicity. PMID- 26421731 TI - Opportunities for New Drug Development in Psychiatry: A Glass Half-Full. PMID- 26421732 TI - Harnessing the Synergistic and Complementary Properties of Fullerene and Transition-Metal Compounds for Nanomaterial Applications. PMID- 26421733 TI - Feroxyhyte nanoflakes coupled to up-converting carbon nanodots: a highly active, magnetically recoverable, Fenton-like photocatalyst in the visible-NIR range. AB - We demonstrate the enhanced photocatalytic response of a novel Fenton-like heterogeneous catalyst obtained through the assembly of superparamagnetic feroxyhyte nanoflakes synthesized by continuous gas-slug microfluidics and carbon nanodots obtained by pyrolysis from a natural organic source. The novel nanohybrids enable the utilization of the visible and near-infrared ranges due to the active role of the carbon nanodots as up-converting photo-sensitizers. This novel photocatalyst is magnetically recoverable and maintains an excellent response after multiple reutilization cycles. In addition, its synthesis is based on inexpensive and abundant raw materials and its photocatalytic response is evaluated in the presence of energy efficient, affordable light-emitting diodes (LEDs), thereby providing a promising and feasible alternative to the homogeneous Fenton process. PMID- 26421734 TI - Biofilm formation on polystyrene in detached vs. planktonic cells of polyhydroxyalkanoate-accumulating Halomonas venusta. AB - Biofilm development is characterized by distinct stages of initial attachment, microcolony formation and maturation (sessile cells), and final detachment (dispersal of new, planktonic cells). In this work we examined the influence of polyhydroxyalkanoate (PHA) accumulation on bacterial surface properties and biofilm formation on polystyrene in detached vs. planktonic cells of an environmental strain isolated from microbial mats, Halomonas venusta MAT28. This strain was cultured either in an artificial biofilm in which the cells were immobilized on alginate beads (sessile) or as free-swimming (planktonic) cells. For the two modes of growth, conditions allowing or preventing PHA accumulation were established. Cells detached from alginate beads and their planktonic counterparts were used to study cell surface properties and cellular adhesion on polystyrene. Detached cells showed a slightly higher affinity than planktonic cells for chloroform (Lewis-acid) and a greater hydrophobicity (affinity for hexadecane and hexane). Those surface characteristics of the detached cells may explain their better adhesion on polystyrene compared to planktonic cells. Adhesion to polystyrene was not significantly different between H. venusta cells that had accumulated PHA vs. those that did not. These observations suggest that the surface properties of detached cells clearly differ from those of planktonic cells and that for at least the first 48 h after detachment from alginate beads H. venusta retained the capacity of sessile cells to adhere to polystyrene and to form a biofilm. PMID- 26421735 TI - Transforming activities of Chlamydia pneumoniae in human mesothelial cells. AB - Knowledge in viral oncology has made considerable progress in the field of cancer fight. However, the role of bacteria as mediators of oncogenesis has not yet been elucidated. As cancer still is the leading cause of death in developed countries, understanding the long-term effects of bacteria has become of great importance as a possible means of cancer prevention. This study reports that Chlamydia pneumoniae infection induces transformation of human mesothelial cells. Mes1 cells infected with C. pneumoniae at a multiplicity of infection of 4 inclusion forming units/cell showed many intracellular inclusion bodies. After a 7-day infection an increased proliferative activity was also observed. Real-time PCR analysis revealed a strong induction of calretinin, Wilms' tumour gene 1, osteopontin, matrix metalloproteinases-2, and membrane-type 1 metalloproteinases gene expression in Mes1 cell, infected for a longer period (14 days). The results were confirmed by western blot analysis. Zymography analysis showed that C. pneumoniae modulated the in-vitro secretion of MMP-2 in Mes1 cells both at 7 and 14 days. Cell invasion, as measured by matrigel-coated filter, increased after 7 and 14 days infection with C. pneumoniae, compared with uninfected Mes1 cells. The results of this study suggest that C. pneumoniae infection might support cellular transformation, thus increasing lung cancer risk. PMID- 26421736 TI - Impact of formate on the growth and productivity of Clostridium ljungdahlii PETC and Clostridium carboxidivorans P7 grown on syngas. AB - The current energy model based on fossil fuels is coming to an end due to the increase in global energy demand. Biofuels such as ethanol and butanol can be produced through the syngas fermentation by acetogenic bacteria. The present work hypothesizes that formate addition would positively impact kinetic parameters for growth and alcohol production in Clostridium ljungdahlii PETC and Clostridium carboxidivorans P7 by diminishing the need for reducing equivalents. Fermentation experiments were conducted using completely anaerobic batch cultures at different pH values and formate concentrations. PETC cultures were more tolerant to formate concentrations than P7, specially at pH 5.0 and 6.0. Complete growth inhibition of PETC occurred at sodium formate concentrations of 30.0 mM; however, no differences in growth rates were observed at pH 7.0 for the two strains. Incubation at formate concentrations lower than 2.0 mM resulted in increased growth rates for both strains. The most recognizable effects of formate addition on the fermentation products were the increase in the total carbon fixed into acids and alcohols at pH 5.0 and pH 6.0, as well as, a higher ethanol to total products ratio at pH 7.0. Taken all together, these results show the ability of acetogens to use formate diminishing the energy demand for growth, and enhancing strain productivity. PMID- 26421737 TI - Stabilization process in Saccharomyces intra and interspecific hybrids in fermentative conditions. AB - We evaluated the genetic stabilization of artificial intra- (Saccharomyces cerevisiae) and interspecific (S. cerevisiae * S. kudriavzevii) hybrids under wine fermentative conditions. Large-scale transitions in genome size and genome reorganizations were observed during this process. Interspecific hybrids seem to need fewer generations to reach genetic stability than intraspecific hybrids. The largest number of molecular patterns recovered among the derived clones was observed for intraspecific hybrids, particularly for those obtained by rare mating. Molecular marker analyses revealed that unstable clones could change during the industrial process to obtain active dry yeast. When no changes in molecular markers and ploidy were observed after this process, no changes in genetic composition were confirmed by comparative genome hybridization, considering the clone as a stable hybrid. According to our results, under these conditions, fermentation steps 3 and 5 (30-50 generations) would suffice to obtain genetically stable interspecific and intraspecific hybrids, respectively. PMID- 26421738 TI - Comparative microbial ecology of the water column of an extreme acidic pit lake, Nuestra Senora del Carmen, and the Rio Tinto basin (Iberian Pyrite Belt). AB - The Iberian Pyrite Belt, located in Southwestern Spain, represents one of the world's largest accumulations of mine wastes and acid mine drainages. This study reports the comparative microbial ecology of the water column of Nuestra Senora del Carmen acid pit lake with the extreme acidic Rio Tinto basin. The canonical correspondence analysis identified members of the Leptospirillum, Acidiphilium, Metallibacterium, Acidithiobacillus, Ferrimicrobium and Acidisphaera genera as the most representative microorganisms of both ecosystems. The presence of archaeal members is scarce in both systems. Only sequences clustering with the Thermoplasmata have been retrieved in the bottom layer of Nuestra Senora del Carmen and one station of Rio Tinto. Although the photosynthetically active radiation values measured in this lake upper layer were low, they were sufficient to activate photosynthesis in acidophilic microorganisms. All identified photosynthetic microorganisms in Nuestra Senora del Carmen (members of the Chlamydomonas, Zygnemopsis and Klebsormidium genera) are major members of the photosynthetic eukaryotic community characterized in Rio Tinto basin. This study demonstrates a close relationship between the microbial diversity of Nuestra Senora del Carmen pit lake and the diversity detected in the Rio Tinto basin, which underlain the influence of the shared mineral substrates in the microbial ecology of these ecosystems. PMID- 26421739 TI - Ignimbrite textural properties as determinants of endolithic colonization patterns from hyper-arid Atacama Desert. AB - This study explores the photosynthetic microbial colonization of rhyolitic ignimbrites in Lomas de Tilocalar, a hyper-arid region of the Atacama Desert, Chile. Colonization appeared in the form of a green layer a few millimeters beneath the ignimbrite surface. Some ignimbrite rocks revealed two distinct micromorphological areas of identical mineralogical and chemical composition but different textural properties. According to texture, colonization patterns varied in terms of the extension and depth of colonization. The diversity of photosynthetic microorganisms was assessed by denaturing gradient gel electrophoresis (DGGE) of the 23S rRNA gene and by generating clone libraries of the 16S rRNA gene. We observed a low diversity of photosynthetic microorganisms colonizing the ignimbrite microhabitat. Most rRNA gene sequences recovered greatly resembled those of Chroococcidiopsis hypolith clones from arid deserts. These results point to highly restrictive conditions of the hyper-arid Atacama Desert conditioning the diversity of cyanobacteria, and suggest that microbial colonization and composition patterns might be determined by the microscale physico-chemical properties of the ignimbrite rocks. PMID- 26421740 TI - ALLEA Statement on Enhancement of Open Access to Scientific Publications in Europe. PMID- 26421741 TI - Small Molecules in the Cone Snail Arsenal. AB - Cone snails are renowned for producing peptide-based venom, containing conopeptides and conotoxins, to capture their prey. A novel small-molecule guanine derivative with unprecedented features, genuanine, was isolated from the venom of two cone snail species. Genuanine causes paralysis in mice, indicating that small molecules and not just polypeptides may contribute to the activity of cone snail venom. PMID- 26421743 TI - Postpartum duodenal perforation after acute fatty liver of pregnancy. PMID- 26421742 TI - Submicrometric Films of Surface-Attached Polymer Network with Temperature Responsive Properties. AB - Temperature-responsive properties of surface-attached poly(N-isopropylacrylamide) (PNIPAM) network films with well-controlled chemistry are investigated. The synthesis consists of cross-linking and grafting preformed ene-reactive polymer chains through thiol-ene click chemistry. The formation of surface-attached and cross-linked polymer films has the advantage of being well-controlled without any caution of no-oxygen atmosphere or addition of initiators. PNIPAM hydrogel films with same cross-link density are synthesized on a wide range of thickness, from nanometers to micrometers. The swelling-collapse transition with temperature is studied by using ellipsometry, neutron reflectivity, and atomic force microscopy as complementary surface-probing techniques. Sharp and high amplitude temperature induced phase transition is observed for all submicrometric PNIPAM hydrogel films. For temperature above LCST, surface-attached PNIPAM hydrogels collapse similarly but without complete expulsion of water. For temperature below LCST, the swelling of PNIPAM hydrogels depends on the film thickness. It is shown that the swelling is strongly affected by the surface attachment for ultrathin films below ~150 nm. For thicker films above 150 nm (to micrometers), surface-attached polymer networks with the same cross-link density swell equally. The density profile of the hydrogel films in the direction normal to the substrate is confronted with in-plane topography of the free surface. It results that the free interface width is much larger than the roughness of the hydrogel film, suggesting pendant chains at the free surface. PMID- 26421744 TI - Manipulating the kinetics and mechanism of phase separation in dynamically asymmetric LCST blends by nanoparticles. AB - The addition of nanoparticles in dynamically asymmetric LCST blends is used to induce preferred phase-separating morphology by tuning the dynamic asymmetry, and to control the kinetics of phase separation by slowing down (or even arresting) the domain growth. For this purpose, we used hydrophobic and hydrophilic fumed silica, which self-assemble during phase separation into the bulk of the slow (PS rich) and fast (PVME-rich) dynamic phases, respectively. Both types of nanoparticles slow down considerably nucleation and growth (NG), spinodal decomposition (SD), and viscoelastic phase separation (VPS) at volume fractions as low as 0.5%. Remarkably, beyond a critical volume fraction of hydrophobic nanosilica thermodynamically controlled phase separation mechanisms (NG and SD) change to the VPS mechanism due to enhanced dynamic asymmetry. However, in the presence of hydrophilic nanosilica dynamic asymmetry decreases and beyond a critical particle volume fraction a transition from the VPS to the SD mechanism is observed. Phase separation is arrested at 2% nanoparticle loading, and VPS percolating networks as well as co-continuous SD structures are completely stabilized by hydrophobic silica or hydrophilic silica, respectively. Electron microscopy images confirm that double percolated structures are induced in the presence of 2 vol% of either hydrophobic or hydrophilic nanoparticles. PMID- 26421745 TI - Analysis of the stability of InGaN/GaN multiquantum wells against ion beam intermixing. AB - Ion-induced damage and intermixing was evaluated in InGaN/GaN multi-quantum wells (MQWs) using 35 keV N(+) implantation at room temperature. In situ ion channeling measurements show that damage builds up with a similar trend for In and Ga atoms, with a high threshold for amorphization. The extended defects induced during the implantation, basal and prismatic stacking faults, are uniformly distributed across the quantum well structure. Despite the extremely high fluences used (up to 4 * 10(16) cm(-2)), the InGaN MQWs exhibit a high stability against ion beam mixing. PMID- 26421746 TI - Silent Victims: A Brief Report on Abused Older Women in Taiwan. AB - Around the world, previous research on elder abuse has consistently neglected abused older women; in many countries, older women often "fall through the cracks" in elder protection practice as well. This is true in Taiwan, where traditional cultural concepts cause many older women to suffer as silent victims of abuse. PMID- 26421747 TI - A Database of Formation Enthalpies of Nitrogen Species by Compound Methods (CBS QB3, CBS-APNO, G3, G4). AB - Accurate thermochemical data for compounds containing C/H/N/O are required to underpin kinetics simulation and modeling of the reactions of these species in different environments. There is a dearth of experimental data so computational quantum chemistry has stepped in to fill this breach and to verify whether particular experiments are in need of revision. A number of composite model chemistries (CBS-QB3, CBS-APNO, G3, and G4) are used to compute theoretical atomization energies and hence enthalpies of formation at 0 and 298.15 K, and these are benchmarked against the best available compendium of values, the Active Thermochemical Tables or ATcT. In general the agreement is very good for some 28 species with the only discrepancy being for hydrazine. It is shown that, although individually the methods do not perform that well, collectively the mean unsigned error is <1.7 kJ mol(-1); hence, this approach provides a useful tool to screen published values and validate new experimental results. Using multiple model chemistries does have some drawbacks but can produce good results even for challenging molecules like HOON and CN2O2. The results for these smaller validated molecules are then used as anchors for determining the formation enthalpies of larger species such as methylated hydrazines and diazenes, five- and six-membered heterocyclics via carefully chosen isodesmic working reactions with the aim of resolving some discrepancies in the literature and establishing a properly validated database. This expanded database could be useful in testing the performance of computationally less-demanding density function methods with newer functionals that have the capacity to treat much larger systems than those tested here. PMID- 26421748 TI - In Memoriam: Louis J. Guillette, Jr. PMID- 26421749 TI - Extradyadic Sexual Involvement and Sexual Compulsivity in Male and Female Sexual Abuse Survivors. AB - We tested a mediation model in which the relationship between child sexual abuse (CSA) severity and extradyadic sexual involvement (ESI) is explained through sexual compulsivity. Participants were 669 adults currently involved in an intimate relationship who completed self-report questionnaires. Prevalence of ESI was 32% in women and 57% in men survivors, more than twice the rates among participants with no CSA history. Sexual compulsivity was significantly higher in participants with multiple extradyadic partners as compared to participants reporting only one extradyadic relationship, who nevertheless scored higher than participants reporting no extradyadic partner. The hypothesized structural equation model (SEM) was invariant across men and women and indicated CSA severity was positively and significantly associated with sexual compulsivity, which, in turn, predicted ESI. However, there was also a direct association between CSA and ESI. High CSA severity, directly and through high sexual compulsivity, led to the highest probability of ESI. PMID- 26421751 TI - OSCE circuit performance effects: Does circuit order influence scores? AB - It is not uncommon for medical students to raise concerns over the difficulty of a single station within an Objective Structured Clinical Examination (OSCE), particularly when they feel they were subject to an unfair situation. Indeed, test developers also share these concerns about the possibility that a single extremely difficult station may impact student performance on the station that follows. As a reaction to the concerns of both students and examiners, we conducted a study, analyzing the scores of multiple OSCEs. Although our analyses did not support the complaints of unfairness targeted at the OSCE, we feel it is a rather enlightening story nevertheless, and one worth sharing. PMID- 26421752 TI - Antibody Engineering & Therapeutics 2015: The Antibody Society's annual meeting December 7-10, 2015, San Diego, CA. AB - Antibody Engineering & Therapeutics, the annual meeting of The Antibody Society, will be held in San Diego, CA in early December 2015. In this meeting preview, the chairs provide their thoughts on the importance of their session topics, which include antibody effector functions, reproducibility of research and diagnostic antibodies, new developments in antibody-drug conjugates (ADCs), preclinical and clinical ADC data, new technologies and applications for bispecific antibodies, antibody therapeutics for non-cancer and orphan indications, antibodies to harness the cellular immune system, overcoming resistance to clinical immunotherapy, and building comprehensive IGVH-gene repertoires through discovering, confirming and cataloging new germline IGVH genes. The Antibody Society's special session will focus on "Antibodies to watch" in 2016, which are a subset of the nearly 50 antibodies currently in Phase 3 clinical studies. Featuring over 100 speakers in total, the meeting will commence with keynote presentations by Erica Ollmann Saphire (The Scripps Research Institute), Wayne A. Marasco (Dana-Farber Cancer Institute/Harvard Medical School), Joe W. Gray (Oregon Health & Science University), and Anna M. Wu (University of California Los Angeles), and it will conclude with workshops on the promise and challenges of using next-generation sequencing for antibody discovery and engineering from synthetic and in vivo libraries and on computational antibody design. PMID- 26421753 TI - POPs and Pubertal Timing: Evidence of Delayed Development. PMID- 26421754 TI - Ultra-thin Solid-State Li-Ion Electrolyte Membrane Facilitated by a Self-Healing Polymer Matrix. AB - Thin solid membranes are formed by a new strategy, whereby an in situ derived self-healing polymer matrix that penetrates the void space of an inorganic solid is created. The concept is applied as a separator in an all-solid-state battery with an FeS2 -based cathode and achieves tremendous performance for over 200 cycles. Processing in dry conditions represents a paradigm shift for incorporating high active-material mass loadings into mixed-matrix membranes. PMID- 26421755 TI - Opioid Use in Hemodialysis Patients. PMID- 26421756 TI - Phosphorus flows and balances of the European Union Member States. AB - Global society faces serious "phosphorus challenges" given the scarcity, essentiality, unequal global distribution and, at the same time, regional excess of phosphorus (P). Phosphorus flow studies can be used to analyze these challenges, providing insight into how society (re)uses and loses phosphorus, identifying potential solutions. Phosphorus flows were analyzed in detail for EU 27 and its Member States. To quantify food system and non-food flows, country specific data and historical context were considered. The sectors covered were crop production (CP), animal production (AP), food processing (FP), non-food production (NF) and consumption (HC). The results show that the EU-27 imported 2392 Gg P in 2005, half of which accumulated in agricultural soils (924 Gg) and half was lost as waste (1217 Gg). Net accumulation was 4.9 kg P/ha/year ranging between +23.2 (Belgium) and -2.8 (Slovakia). From the system losses, 54% was lost from HC in diverse waste flows and 28% from FP, mainly through incinerated slaughter residues. The largest HC losses (655 Gg) were wastewater (55%), food waste (27%), and pet excreta (11%). Phosphorus recycling rates were 73% in AP, 29% in FP, 21% in HC and ~0% in NF. The phosphorus use efficiencies showed that, relative to sector input, about 70% was taken up by crops (CP), 24% was retained in animals (AP), 52% was contained in food products (FP), 76% was stored in non food materials (NF), and 21% was recycled (HC). Although wide-ranging variation between countries, generally phosphorus use in EU-27 was characterized by relatively (1) large dependency on (primary) imports, (2) long-term accumulation in agricultural soils, especially in west European countries, (3) leaky losses throughout entire society, especially emissions to the environment and sequestered waste, (4) little recycling with the exception of manure, and (5) low use efficiencies, because of aforementioned issues, providing ample opportunities for improvement. PMID- 26421757 TI - Manufacture of Clinical-Grade Human Clonal Mesenchymal Stem Cell Products from Single Colony Forming Unit-Derived Colonies Based on the Subfractionation Culturing Method. AB - Stem cell products derived from mesenchymal stem cells (MSCs) have been widely used in clinical trials, and a few products have been already commercialized. However, the therapeutic effects of clinical-grade MSCs are still controversial owing to mixed results from recent clinical trials. A potential solution to overcome this hurdle may be to use clonal stem cells as the starting cell material to increase the homogeneity of the final stem cell products. We have previously developed an alternative isolation and culture protocol for establishing a population of clonal MSCs (cMSCs) from single colony forming unit (CFU)-derived colonies. In this study, we established a good manufacturing practice (GMP)-compatible procedure for the clinical-grade production of human bone marrow-derived cMSCs based on the subfractionation culturing method. We optimized the culture procedures to expand and obtain a clonal population of final MSC products from single CFU-derived colonies in a GMP facility. The characterization results of the final cMSC products met our preset criteria. Animal toxicity tests were performed in a good laboratory practice facility, and showed no toxicity or tumor formation in vivo. These tests include single injection toxicity, multiple injection toxicity, biodistribution analysis, and tumorigenicity tests in vivo. No chromosomal abnormalities were detected by in situ karyotyping using oligo-fluorescence in situ hydridization (oligo-FISH), providing evidence of genetic stability of the clinical-grade cMSC products. The manufacture and quality control results indicated that our GMP methodology could produce sufficient clonal population of MSC products from a small amount of bone marrow aspirate to treat a number of patients. PMID- 26421758 TI - Comparison of Over-the-Rail and Rail Yard Measurements of Diesel Locomotives. AB - Locomotive prime mover engine emission rates are typically measured at steady state for discrete throttle notches using an engine dynamometer weighted by a standard duty cycle. However, this method may not represent real-world locomotive emissions. A method for in-use measurement of passenger locomotives, using a portable emissions measurement system (PEMS), was developed to estimate duty cycle average emission rates. We conducted 48 measurements of one-way trips between Raleigh and Charlotte, NC, on 7 locomotives and 18 sets of measurements in the rail yard (RY). Real-world duty cycles differed from those used for regulatory analyses, leading to statistically significant lower cycle average NOx and HC emission rates. Compared to RY measurements, notch average NOx emission rates measured over-the-rail (OTR) at the highest two notch settings were, on average, 19% lower for four locomotives. At the highest notch, OTR CO2 emission rates were, on average, 12% lower than RY rates for five locomotives. For a more accurate representation of real-world emission rates, OTR measurements are preferred. However, using steady-state notch average RY emission rates and standard duty cycles may be tolerable for some applications. OTR versus RY cycle average emission rates typically differed by less than 10%. PMID- 26421760 TI - Potatoes - A crop resistant against input of heavy metals from the metallicaly contaminated soil. AB - The objective of our study was to assess the extent of accumulation of cadmium, lead and zinc in potato tubers depending on the concentration of these heavy metals in soil and to evaluate the resistance of 11 cultivars of potato cultivated in 5 localities of the Slovakia against input of these heavy metals into the consumption part of potato. Contents of Cd (Pb, Zn) in soil were 0.94 2.54 (18.03-24.90, 35.71-72.40) mg/kg in soil extract by aqua regia and 0.030 0.188 (0.149-0.356, 0.052-0.238) mg/kg in soil extract by NH4NO3. The contents of Cd, Pb, and Zn were determined in potatoes in extracts of freeze-dried samples and expressed in mg/kg of fresh matter (FM). Determined contents of heavy metals were in the range of ND-0.058 mg Cd/kg FM, 0.020-0.630 mg Pb/kg FM, 1.836-3.457 mg Zn/kg FM, resp. The statistically significant correlation between heavy metal content in soil and its content in potato tubers were confirmed only: cv. Laura - Spissky Stvrtok (Cd), cv. Red Anna - Odorin (Pb) and Marabel, Red Anna - Odorin, cv. Marabel - Belusa, cv. Volumia - Imel (Zn). PMID- 26421759 TI - Combinatorial Motor Training Results in Functional Reorganization of Remaining Motor Cortex after Controlled Cortical Impact in Rats. AB - Cortical reorganization subsequent to post-stroke motor rehabilitative training (RT) has been extensively examined in animal models and humans. However, similar studies focused on the effects of motor training after traumatic brain injury (TBI) are lacking. We previously reported that after a moderate/severe TBI in adult male rats, functional improvements in forelimb use were accomplished only with a combination of skilled forelimb reach training and aerobic exercise, with or without nonimpaired forelimb constraint. Thus, the current study was designed to examine the relationship between functional motor cortical map reorganization after experimental TBI and the behavioral improvements resulting from this combinatorial rehabilitative regime. Adult male rats were trained to proficiency on a skilled reaching task, received a unilateral controlled cortical impact (CCI) over the forelimb area of the caudal motor cortex (CMC). Three days post CCI, animals began RT (n = 13) or no rehabilitative training (NoRT) control procedures (n = 13). The RT group participated in daily skilled reach training, voluntary aerobic exercise, and nonimpaired forelimb constraint. This RT regimen significantly improved impaired forelimb reaching success and normalized reaching strategies, consistent with previous findings. RT also enlarged the area of motor cortical wrist representation, derived by intracortical microstimulation, compared to NoRT. These findings indicate that sufficient RT can greatly improve motor function and improve the functional integrity of remaining motor cortex after a moderate/severe CCI. When compared with findings from stroke models, these findings also suggest that more intense RT may be needed to improve motor function and remodel the injured cortex after TBI. PMID- 26421761 TI - Ebola Virus Disease in Health Care Workers--Guinea, 2014. AB - An outbreak of Ebola virus disease (Ebola) began in Guinea in December 2013 and has continued through September 2015. Health care workers (HCWs) in West Africa are at high risk for Ebola infection owing to lack of appropriate triage procedures, insufficient equipment, and inadequate infection control practices. To characterize recent epidemiology of Ebola infections among HCWs in Guinea, national Viral Hemorrhagic Fever (VHF) surveillance data were analyzed for HCW cases reported during January 1-December 31, 2014. During 2014, a total of 162 (7.9%) of 2,210 laboratory-confirmed or probable Ebola cases among Guinean adults aged >=15 years occurred among HCWs, resulting in an incidence of Ebola infection among HCWs 42.2 times higher than among non-HCWs. The disproportionate burden of Ebola infection among HCWs taxes an already stressed health infrastructure, underscoring the need for increased understanding of transmission among HCWs and improved infection prevention and control measures to prevent Ebola infection among HCWs. PMID- 26421762 TI - Contents of constituents and antioxidant activity of seed and pulp extracts of Annona coriacea and Annona sylvatica. AB - The antioxidant potential of fruit pulp and seeds of extracts of the Annona coriacea, and A. sylvatica (Annonaceae) were investigated, as well contents total phenolics, flavonoids, condensed tannins and ascorbic acid. Was used to determine the antioxidant activity the 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH), beta-carotene bleaching and ABTS radical cation method. The total phenol, total flavonoid, condensed tannin, and ascorbic acid contents were measured spectrophotometrically. In this study, the pulp and seeds of the fruits were extracted using methanol/water (8:2) for maceration. The seed extracts of A. coriacea demonstrated a moderate antioxidant effect with free radical scavenging activity of 31.53%, by the DPPH test, 51.59% by the beta-carotene bleaching test and 159.50 uM trolx/g of extract in the ABTS assay. We found that the hydromethanolic seed extract of A. coriacea had high total phenol (147.08 +/- 4.20 mg of GAE/g of extract) and flavonoid (131.18 +/- 2.31 mg of QE/g of extract) content. This indicated that the antioxidant activity of the extracts was related to the contents of these constituents. PMID- 26421763 TI - Gastrointestinal parasites of maned wolf (Chrysocyon brachyurus, Illiger 1815) in a suburban area in southeastern Brazil. AB - We examined 42 maned wolf scats in an unprotected and disturbed area of Cerrado in southeastern Brazil. We identified six helminth endoparasite taxa, being Phylum Acantocephala and Family Trichuridae the most prevalent. The high prevalence of the Family Ancylostomatidae indicates a possible transmission via domestic dogs, which are abundant in the study area. Nevertheless, our results indicate that the endoparasite species found are not different from those observed in protected or least disturbed areas, suggesting a high resilience of maned wolf and their parasites to human impacts, or a common scenario of disease transmission from domestic dogs to wild canid whether in protected or unprotected areas of southeastern Brazil. PMID- 26421764 TI - Vertical stratification and effect of petiole and dry leaf size on arthropod feeding guilds in Cecropia pachystachya (Urticaceae). AB - This study aimed to test for vertical stratification and the effects of dry leaf size on herbivore and predator arthropods and petiole length on insect borers in Cecropia pachystachya. The leaves were sampled in three strata: attached to the plant, suspended on the vegetation and on the ground. We detected vertical stratification only in the guild of predator arthropods associated with dry leaves, with lower richness and abundance in the attached stratum. In addition, larger leaves positively affected the insect herbivore fauna, whereas the richness and abundance of insect borers increased with petiole length. The greater isolation of leaves attached to trees relative to the surrounding vegetation likely creates greater difficulty for dispersal and colonization by non-winged predators such as spiders. Larger dry leaves provide more shelter against predators and climate variations for insect herbivores. Moreover, larger petioles increase the availability of resources and nesting sites for insect borers. These results are consistent with other studies that found a similarity in the structure of feeding guilds across vertical strata and with studies that showed an increase in species richness and abundance of free-feeding insect herbivores with increasing structural complexity of their host. PMID- 26421765 TI - Jaguar (Panthera onca Linnaeus, 1758) roadkill in Brazilian Atlantic Forest and implications for species conservation. AB - We report the roadkill of a jaguar in one of the longest highways in Brazil (BR 101), in the stretch where this road crosses one of the most important Atlantic Forest remnants in the country: the Linhares-Sooretama block. The jaguar population present in this area represents the very last in entire Espirito Santo state. There is an approved project to the lines duplication of the entire BR-101 Highway and the company responsible by the work has already started the first activities in the state. However, there is no environmental impact assessment already done neither planning for the implementation of measures to avoid or reduce the roadkill risk in the region. Thus, to minimize the impacts associated with the BR-101, we do not recommend its lines duplication along the 15 km stretch traversing the Linhares-Sooretama block. In addition, alternatively, we suggest the deviation of the current route of the BR-101 Highway or the construction of overpasses to fauna in the most critical points, interspersing these overpasses with electronic speed monitoring devices and warning and educational plates. PMID- 26421766 TI - Jaw musculature of Cyclarhis gujanensis (Aves: Vireonidae). AB - Cyclarhis gujanensis is a little bird which feeds on high number of large preys, such frogs, lizards, snakes, bats and birds. As there are few studies on the cranial anatomy of this species, we aimed to describe the cranial myology to contribute to the anatomical knowledge of this species and to make some assumptions about functional anatomy. Thus, we described the muscles from the jaw apparatus (external and internal adductor muscles, the muscles of the pterygoid system and the depressor muscles of the mandible). The adductor system is the greatest and multipinulated, particularly in its origin in the caudal portion of the temporal fossa. The depressor jaw muscles systems are enlarged with many components in complexity. The most of jaw apparatus muscles are short, but the strength (biting or crushing forces) from short feeding apparatus fibers probably is increased by high number of components and pinnulation. These anatomical aspects of the muscles indicate a considerable force in the jaws, without which C. gujanensis probably could not cut their prey into smaller pieces. However, functional approaches to analysis of forces of the muscle fibers are needed to corroborate / refute the hypotheses mentioned above. PMID- 26421767 TI - Feather mites (Acari, Astigmata) associated with birds in an Atlantic Forest fragment in Northeastern Brazil. AB - The present study reports associations between feather mites (Astigmata) and birds in an Atlantic Forest fragment in Rio Grande do Norte state, in Brazil. In the laboratory, mites were collected through visual examination of freshly killed birds. Overall, 172 individuals from 38 bird species were examined, between October 2011 and July 2012. The prevalence of feather mites was 80.8%, corresponding to 139 infested individuals distributed into 30 species and 15 families of hosts. Fifteen feather mite taxa could be identified to the species level, sixteen to the genus level and three to the subfamily level, distributed into the families Analgidae, Proctophyllodidae, Psoroptoididae, Pteronyssidae, Xolalgidae, Trouessartiidae, Falculiferidae and Gabuciniidae. Hitherto unknown associations between feather mites and birds were recorded for eleven taxa identified to the species level, and nine taxa were recorded for the first time in Brazil. The number of new geographic records, as well as the hitherto unknown mite-host associations, supports the high estimates of diversity for feather mites of Brazil and show the need for research to increase knowledge of plumicole mites in the Neotropical region. PMID- 26421768 TI - Growth of Paecilomyces variotii in B0 (diesel), B100 (biodiesel) and B7 (blend), degradation and molecular detection. AB - The introduction of biodiesel to diesel may allow the fuel to be more susceptible to microorganism growth, especially during incorrect storage. To evaluate the effect of adding biodiesel in pure diesel on the growth of Paecilomyces variotii, microcosms containing pure diesel (B0), blend diesel/biodiesel (B7) and pure biodiesel (B100) were used. In microcosm with minimal mineral medium and B0, B7 or B100, after 60 days, the biomass (dry weight) formed at interface oil-water in B7 and B100 was significantly higher when compared to that of B0. Infrared analysis showed reduction of the carbonile fraction in B7 and B100 suggesting formation of intermediate compounds in B7. To monitor possible contamination of fuel storage tank by P. variotii samples were collected and analysed by specific PCR assay for detection of P. variotii spores in the aqueous phase. This method was able to detect a minimum of 103 spores ml-1, corresponding to 0.0144 ng ul-1 of DNA. Specificity was tested against Aspergillus fumigatus and Pseudallescheria boydii. PMID- 26421770 TI - Variations of Salminus hilarii diet (Ostariophysi, Characidae): seasonal and ontogenetic effects. AB - This study described the variations seasonal and ontogenetic of Salminus hilarii diet. Samples were collected in the Sorocaba River, Sao Paulo, Brazil, one of the few rivers where individuals of the species still occur in a higher frequency. The preys consumed were analyzed by Importance Alimentary Index (AIi). To determine similarities between year seasons, the AIi data were analyzed by the Morisita-Horn index and reduced in cluster analysis, along with a statistical comparison made by one-way ANOSIM test (5%). The feeding activity was analyzed according to the stomach repletion index and compared among the year seasons using non parametric variance analysis Kruskal-Wallis test (5%). Comparison of prey consumed between immature and adult individuals was made by Spearman correlation (5%). A Pearson correlation (5%) was applied between the standard length of the fish and prey consumed, as well as between the mouth and prey heights. The analyzes of stomach contents showed that the diet of this species was exclusively piscivorous, with significant difference of prey consumption during the period, the same happening among adult and immature individuals. It was observed that these fishes use to swallow their prey whole and that significant correlations between size of predator and prey size can be observed. There is also correlation between the mouth height and the maximum prey depth. Salminus hilarii feeds on the available prey, and the species food composition and feeding activity depends on prey's abundance, their size and morphology, as do the water temperatures. PMID- 26421769 TI - The hyporheic zone and its functions: revision and research status in Neotropical regions. AB - The hyporheic zone (HZ), as the connecting ecotone between surface- and groundwater, is functionally part of both fluvial and groundwater ecosystems. Its hydrological, chemical, biological and metabolic features are specific of this zone, not belonging truly neither to surface- nor to groundwater. Exchanges of water, nutrients, and organic matter occur in response to variations in discharge and bed topography and porosity. Dynamic gradients exist at all scales and vary temporally. Across all scales, the functional significance of the HZ relates to its activity and connection with the surface stream. The HZ is a relatively rich environment and almost all invertebrate groups have colonized this habitat. This fauna, so-called hyporheos, is composed of species typical from interstitial environment, and also of benthic epigean and phreatic species. The hyporheic microbiocenose consists in bacteria, archaea, protozoa and fungi. The HZ provides several ecosystem services, playing a pivotal role in mediating exchange processes, including both matter and energy, between surface and subterranean ecosystems, functioning as regulator of water flow, benthic invertebrates refuge and place of storage, source and transformation of organic matter. The hyporheic zone is one of the most threatened aquatic environments, being strongly influenced by human activities, and the least protected by legislation worldwide. Its maintenance and conservation is compelling in order to preserve the ecological interconnectivity among the three spatial dimensions of the aquatic environment. Although several researchers addressed the importance of the hyporheic zone early, and most contemporary stream ecosystem models explicitly include it, very little is known about the HZ of Neotropical regions. From a biological standpoint, hyporheos fauna in Neotropical regions are still largely underestimated. This review focuses on a brief presentation of the hyporheic zone and its functions and significance as an ecotone. We also highlighted the key aspects considering also the current status of research in Neotropical regions. PMID- 26421771 TI - Impacts of artificial reservoirs on floristic diversity and plant functional traits in dry forests after 15 years. AB - Dams are of paramount importance to a wide variety of human services and many of their environmental problems are known; however, there are few studies in the world addressing the impacts on the native vegetation previously distant from water bodies which became close to the lakeshore created by a dam. Thus, this paper aims to analyze the responses of a dry forest to a dam after 15 years. For this, 20 random samples of 40 trees were made, 10 close to the lakeshore and 10 distant from it, by applying the central square point method. Close to the dam, we found higher values regarding basal area, number of trees, number of evergreen trees, and zoochoric syndrome, but there were lower values of Shannon's diversity index. Therefore, the impacts of the dam after 15 years caused several changes to the tree community. The greater basal area close to the dam suggests that water deficit during the dry season was decreased and plants have thicker trunks. On the other hand, this sector had much more zoochoric syndrome and a larger number of evergreen trees than plots which are distant from water, suggesting changes with regard to the community's ecological functions. Furthermore, structural floristic data shows that the sector close to the dam is less similar to other deciduous forests within the same geographical region than the sector distant from water, thus providing evidence of the impacts of dams on the tree community. PMID- 26421772 TI - Does the habitat structure control the distribution and diversity of the Odonatofauna? AB - The statement that the habitat complexity and structure govern the abundance and diversity of biological communities has been widely investigated. In this context, we assumed the hypothesis of habitat heterogeneity, that is, the higher habitat complexity leads to greater diversity of Odonata. In addition, we analyzed the influence of habitat structure on the distribution of this community, and evaluated the effects of abiotic variables. Odonata larvae were collected with sieves and by electrofishing in ten neotropical streams belonging to the Pirapo River basin. Forty species of Odonata were registered, which were distributed in eight families, Libellulidae stood out with the highest richness. The high gamma diversity and distribution of Odonata were associated with habitat heterogeneity in these streams. However, the abiotic variables also seem to affect the distribution of Odonata species, in view of the impact of the land use in the vicinity of streams. PMID- 26421773 TI - First record of Hysterothylacium sp. Moravec, Kohn et Fernandes, 1993 larvae (Nematoda: Anisakidae) infecting the ornamental fish Hyphessobrycon eques Steindachner, 1882 (Characiformes, Characidae). AB - This study reports for the first time infection with Hysterothylacium sp. larvae in the ornamental fish Hyphessobrycon eques from the Paranapanema River, Jurumirim Reservoir, Sao Paulo State, Brazil. A sample of 33 specimens of H. eques was collected in October, 2011. Four specimens of H. eques were parasitized by Hysterothylacium sp. larvae in the intestine and coelomic cavity, with prevalence of 12.1%, mean intensity of infection of 1, and mean abundance of 0.121 +/- 0.05. A total of 40 unidentified free-living nematodes were found in the stomach content of 17 fish. This fish species is introduced in the Paranapanema River. Invasive species may affect the native fauna given the introduction of pathogens and parasites. This study also complements data on the diet of H. eques due to the records of free-living nematode as part of the stomach content. Infections with Hysterothylacium sp. larvae may affect the biology of this fish and bring about profit losses to aquarists. PMID- 26421774 TI - The effects of rainfall and vegetation on litterfall production in the semiarid region of northeastern Brazil. AB - Litterfall has a strong influence on biodiversity and on the chemical and physical characteristics of the soil. Its production can be quite variable over time and space, and can be influenced by both natural and anthropogenic factors. We evaluated litterfall production and its relationship with rainfall, species richness, and the densities of the arboreal vegetation. Thirty litter traps were constructed with 1.0 m2 nylon mesh (1.0 mm) and randomly installed within a 2000 m * 500 m area of arboreal/shrub Caatinga (dryland) vegetation. Litter samples were collected monthly from November/2010 to June/2012, and the collected material was classified, dried, and weighted. Species richness and tree densities were determined by conducting phytosociological surveys in 20 m * 20 m plots surrounding each of the litter traps. The litterfall accumulation rate was 3.673 Mgha-1yr-1, similar to values from other seasonally dry tropical forests. Litterfall production was continuous, and principally accompanied the rainfall rate, but with a time interval of 2 to 3 months, with the greatest accumulation at the beginning of the dry season and the least during the rainy season. The different fractions of materials demonstrated distinct accumulation rates, with leaves being the principal category. Litterfall production was found to be related to tree density, but no link was found to species richness. The observed temporal heterogeneity of litterfall production demonstrated a strong link between rainfall and the dynamics of nutrient cycling in the semiarid region of Brazil. PMID- 26421775 TI - Nursing Home Registered Nurses' and Licensed Practical Nurses' Knowledge of Causes of Falls. AB - Reducing falls in nursing homes requires a knowledgeable nursing workforce. To test knowledge, 8 validated vignettes representing multifactorial fall causes were administered to 47 nurses from 3 nursing homes. Although licensed practical nurses scored higher than registered nurses in individual categories of falls, when we computed the average score of all 8 categories between groups of registered nurses and licensed practical nurses, registered nurses scored higher (F = 4.106; P < .05) in identifying 8 causal reasons for older adults to fall. PMID- 26421776 TI - Global Mental Health: What is Your Role in This Movement? PMID- 26421777 TI - The Future of the Portuguese Health System. PMID- 26421778 TI - [Regulation of Parental Leave Among Parents of Very Preterm Infants]. PMID- 26421780 TI - Clinical and Radiological Characterization of Progressive Multifocal Leukoencephalopathy in HIV-Infected Patients: A Retrospective Analysis and Review of the Literature. AB - INTRODUCTION: Progressive multifocal leukoencephalopathy is a demyelinating disease of the central nervous system caused by John Cunningham virus, mostly associated with immunodeficiency conditions, such as the human immunodeficiency virus infection. Progressive multifocal leukoencephalopathy can have multiple clinical features and usually presents a typical lesion pattern on brain magnetic resonance imaging. Its course may be rapidly progressive, although immunological responsiveness can be associated with an improved prognosis. MATERIAL AND METHODS: We performed a retrospective analysis of the clinical and radiological data from patients admitted in our institution between January 2005 and April 2014 with the diagnosis of definitive progressive multifocal leukoencephalopathy (ICD10:A81.2) in the setting of human immunodeficiency virus infection. RESULTS: Twenty-one patients were included in our study, mostly men (n = 20, 95.2%). Mean age at diagnosis was 39 years. Motor deficits were the most common clinical finding. John Cunningham virus-DNA was detected in the cerebral spinal fluid in 20 patients (95.2%). Brain imaging studies most commonly disclosed bilateral supratentorial, asymmetric lesions. Four (19%) patients developed immune reconstitution inflammatory syndrome in the follow-up. Therapeutic approach included initiation and continuation/optimization of antiretroviral therapy, with adjunctive therapy with corticosteroids in four patients. Seventeen (81%) patients died during the study period; median survival time following progressive multifocal leukoencephalopathy diagnosis was 3 months (range 1 - 13). DISCUSSION: The results of our study are in accordance with the data previously published on progressive multifocal leukoencephalopathy in human immunodeficiency virus patients. Progressive multifocal leukoencephalopathy is predominantly associated with severe immunosuppression, particularly in patients who are not under anti retroviral therapy, and usually presents with motor and cognitive symptoms and signs. A typical bilateral asymmetric pattern in conventional magnetic resonance imaging is present in the majority of the patients. There is no specific therapy for progressive multifocal leukoencephalopathy and it is usually fatal, although outcomes can improve with highly active anti-retroviral therapy. Immune reconstitution inflammatory syndrome is also an important complication related with progressive multifocal leukoencephalopathy, usually associated with anti retroviral therapy. Progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome presents with different imaging characteristics from progressive multifocal leukoencephalopathy and treatment with steroids can improve survival. CONCLUSION: The mortality rate and long-term neurological morbidity associated with progressive multifocal leukoencephalopathy are quite high. These data should increase clinician awareness to the occurrence of progressive multifocal leukoencephalopathy among human immunodeficiency virus patients and highlight the important role of magnetic resonance imaging, as early diagnosis may beassociated with better outcome. PMID- 26421779 TI - [Analysis of the Cochrane Review: Angiotensin Converging Enzyme Inhibitors Versus Angiotensin Receptor Blockers for Primary Hypertension. Cochrane Database Syst Rev. 2014,8: CD009096]. AB - Angiotensin converting enzyme inhibitors and angiotensin receptor blockers are first line drugs in the treatment of hypertension. The aim of this review was to assess if there are differences between these drug classes regarding the prevention of total mortality, occurrence of cardiovascular events and of adverse effects. A systematic review and metanalysis was performed, searching for studies that compare angiotensin converting enzyme inhibitors and angiotensin receptor blockers face-to-face, in several databases until July 2014. The study selection and data extraction were performed by 2 independent researchers. Nine studies were included, with a total of 10 963 participants, 9 398 of which participated in the same study and had high cardiovascular risk. No differences were observed regarding total mortality, cardiovascular mortality or total cardiovascular events. A slightly smaller risk was observed with angiotensin receptor blockers regarding withdrawal due to adverse effects (55 people were needed to be treated with angiotensin receptor blockers for 4.1 years to avoid one withdrawal due to adverse effect), mainly due to the occurrence of dry cough with angiotensin converting enzyme inhibitors. Thus, no differences were observed between angiotensin converting enzyme inhibitors and angiotensin receptor blockers in the prevention of total mortality and cardiovascular events, and angiotensin receptor blockers were better tolerated. Given the large proportion of participants with a high cardiovascular risk, the generalization of these results to other populations is limited. PMID- 26421781 TI - Off-Label and Unlicensed Drug Use in Neonatology: Reality in a Portuguese University Hospital. AB - INTRODUCTION: This study aims to characterize the drugs used in a Portuguese Neonatal Intensive Unit Care, assess the rate of off-label or unlicensed drugs use according to the information available in the Summary of Product Characteristics and compare results between preterm and full-term neonates. MATERIAL AND METHODS: A 6-month period retrospective cross-sectional study was conducted in our Neonatal Intensive Unit Care in 2013. Prescribed drugs data were recorded and compared with the paediatric information contained in drugs Summary of Product Characteristics. RESULTS: We analyzed 1011 prescriptions of 84 active substances, made in 218 admissions. In 42.9% of the cases, medicines were used according to Summary of Product Characteristics information; 27.9% of drugs were approved for neonatal period but used in an off-label manner; off-label drugs for neonates were used in 10.1%, whereas those with undetermined approval state and contraindicated were used 6.0% and 8.7% of the cases, respectively. Unlicensed prescriptions accounted for 4.4% of total. Preterm received a higher rate of drugs used according to Summary of Product Characteristics (p < 0.0001), whereas full-term received more off-label drugs for dose/frequency (p < 0.0001) and contra-indicated for neonates (p < 0.012). DISCUSSION: Preterm neonates received a higher median number of drugs, since they stayed longer in the unit. The main reason for off-label prescribing was the use of doses/frequencies of administration different from those stated in the Summary of Product Characteristics, suggesting that updating these documents is necessary. Manipulation of medicines is one of the causes for unlicensed drugs use, emphasizing the lack of appropriate formulations for neonatal age. CONCLUSION: Progresses have been made to reduce the risks of off-label/unlicensed prescriptions, but competent authorities must continue their efforts to develop safer and more effective drugs for neonatal period. PMID- 26421782 TI - The Role of Haemoglobin A1c in Screening Obese Children and Adolescents for Glucose Intolerance and Type 2 Diabetes. AB - INTRODUCTION: In 2012, an international expert committee in diabetes wrote in favor of screening adult and paediatric patients for glucose intolerance and type 2 diabetes using glycated haemoglobin. The aim of this study was to evaluate glycated haemoglobin utility as a screening tool in a young obese mainly Caucasian population. MATERIAL AND METHODS: Children [(n = 266), body mass index z-score 3.35 +/- 0.59, 90% Caucasian 90%, 55% female, median age 12.3 (range: 8.9 - 17.6) years old] recently referred to a tertiary hospital-based obesity clinic underwent a routine oral glicose tolerance test and glycated haemoglobin measurement. EXCLUSION CRITERIA: abnormal forms of haemoglobin and conditions linked to increased erythrocyte turnover. RESULTS: The oral glicose tolerance test diagnosed 13 (4.9%) subjects as prediabetic but none as diabetic. According to glycated haemoglobin, 32 would be prediabetic (29 false positives) and one would be diabetic (when he was only glucose intolerant). On the other hand, 10 prediabetic patients would not have been identified (false negatives). Glycated haemoglobin receiver operator characteristic analysis area under the curve was 0.59 (CI 95% 0.40 - 0.78), confirming its reduced capacity to identify prediabetes. Better results were achieved when calculating receiver operator characteristic analysis area under the curve for fasting glucose (0.76;CI 95% 0.66 - 0.87), homeostasis model assessment for insulin resistance (0.77; CI 95% 0.64 - 0.90) and triglycerides:HDL cholesterol ratio (0.81; CI 95% 0.66 - 0.96). DISCUSSION: In Paediatric populations, especially when mainly Caucasian, glycated haemoglobin does not seem to be a useful screening tool for prediabetes. CONCLUSION: For this reason, it would appear premature to advise it as a diagnostic tool until significantly more data is available. Homeostasis model assessment for insulin resistance and triglycerides: HDL cholesterol have higher precision and can be calculated using a fasting blood sample. PMID- 26421783 TI - Cephalometric Evaluation of Children with Allergic Rhinitis and Mouth Breathing. AB - INTRODUCTION: Orthodontists frequently treat children with mouth breathing. The purpose of the present study was to examine dental positions, skeletal effects and the pharyngeal airway space of children with chronic allergic rhinitis, when compared with a control group exhibiting a normal breathing pattern. MATERIAL AND METHODS: Seventy Caucasian children from Santa Maria University Hospital - North Lisbon Hospital Center were evaluated, between September 2009 and February 2013. The study group comprised of 35 children with chronic allergic rhinitis, both genders, aged 5 - 14, with positive reaction to allergens, mouth breathing and malocclusion. The control group was composed of 35 children, both genders, displaying normal nasal breathing and malocclusion, who resorted to the orthodontic department. Measures of Ricketts, Steiner and McNamara's analysis were used and the t- Student test was applied to the data obtained. RESULTS: Statistically significant differences were observed between the oral and nasal breathers, respectively: lower facial height (49.1/45.9 mm), Frankfurt a mandibular plane angle (30.1/26.9o) and Sela-Nasion - oclusal plane angle (17.3/15o), maxillary length (78.4/82.4 mm), mandibular length (102.4/107 mm), overbite (0.8/3.1mm) and overjet (4/4.7 mm). DISCUSSION: Comparison between the allergic rhinitis and control group showed that there is an increased lower facial height, larger Frankfurt a mandibular plane angle and Sela-Nasion oclusal plane angle in children with chronic allergic rhinitis. This group also had a shorter maxillary and mandibular length, less overbite and decreased upper airway space. CONCLUSIONS: Children with allergic rhinitis and mouth breathing have longer faces, shorter maxillas and mandibles and a narrowed pharyngeal airway space. No statistical differences between the groups in sagital relationships or in dental inclinations were found. PMID- 26421784 TI - Parathyroid Hormone as a Predictor of Post-Thyroidectomy Hipocalcemia: A Prospective Evaluation of 100 Patients. AB - INTRODUCTION: Hypocalcemia is a frequent complication after total thyroidectomy and the main reason for prolonged hospitalization of these patients. MATERIAL AND METHODS: We studied prospectively 112 patients who underwent total or completation thyroidectomy between June 2012 and November 2013. Twelve patients with preoperative changes in parathyroid function were excluded. Parathyroid hormone and calcium levels were determined pre-operatively, immediately after surgery, on 1st day and on 14th day after surgery. RESULTS: Of the 100 patients enrolled, 60 have developed hypocalcaemia (60%) but only 14 patients had symptomatic hypocalcaemia. It mostly occurs 24 hours after surgery (76.7%). It was permanent in 3 patients and temporary in the others. In the 60 patients with hypocalcaemia, it has been found hypoparathyroidism in 19 patients immediately after surgery, in 14 patients on 1st day but only 3 had hypoparathyroidism (patients with permanent hypocalcaemia). Comparing the group of patients with and without hypocalcaemia we found a decrease of parathyroid hormone in both (immediately after surgery and on 1st day) but was more important in the hypocalcaemia group (p = 0.004 and p < 0.001). The decrease of PTH levels was more pronounced in the hypocalcaemia group, with significance on the first day (22.29% vs 50.29%, p < 0.001). The best predictor of hypocalcaemia identified was the decrease of parathyroid hormone levels > 19.4% determined on the 1st day (sensitivity = 82%; specificity = 63%). DISCUSSION: In our study there was a high incidence of hypocalcemia (60%), expressed predominantly 24 hours after surgery and conditioned, in these patients, a longer hospital stay. However, only 3 patients (3%) had permanent hypocalcemia. We still found a match in the oscillation of serum calcium levels and parathyroid hormone which identified the decrease in parathyroid hormone on the first day after surgery as a reliable predictor of hypocalcemia. CONCLUSION: Decrease of parathyroid hormone levels > 19.4% determined on 1st day is a good predictor of hypocalcemia after total / completation thyroidectomy, allowing to identify patients at higher risk of hypocalcemia, medicate them prophylactically and get early and safe discharges. PMID- 26421785 TI - Hansen Neuropathy: Still a Possible Diagnosis in the Investigation of a Peripheral Neuropathy. AB - INTRODUCTION: Leprosy is still one of the most frequent causes of peripheral neuropathy. Although regarded as eradicated in Portugal, is still documented in neuropathological study of patients with clinical peripheral neuropathy without proper diagnosis. MATERIAL AND METHODS: Review of the cases of Hansen disease neuropathy diagnosed in Neuropathology Unit of Centro Hospitalar do Porto between 1978 and 2013, atending to gender, age, clinical manifestations and neuropathological findings. RESULTS: Twenty one patients were identified with neuropathological diagnosis of Hansenas disease neuropathy, predominantly male. The mean age at diagnosis was 52 years, and sensory symptoms predominate as neurological manifestation of disease. Interval between symptoms and diagnosis was 1-38 years. In most nerve samples tuberculoid type of disease was identified. Bacilli were detected in skin and nerve in 44% of cases. DISCUSSION: Mononeuritis is the most common presentation of leprosy but other clinical manifestations are possible, including skin lesions. Infection with M. leprae injures myelinated and unmyelinated fibres, with replacement of nerve tissue by collagen fibrosis. The diagnosis of leprosy is only achieved by neuropathological study of skin lesions and / or peripheral nerve, supported by the identification of the bacillus. CONCLUSION: Hansen disease remains a public health problem in tropical areas and, although rare, still described in Western countries reason why should still be considered as a diagnostic possibility in the investigation of peripheral neuropathy. PMID- 26421787 TI - Invasive Meningococcal Disease: Application of Base Excess and Platelets Score in a Portuguese Paediatric Intensive Care Unit. AB - INTRODUCTION: Meningococcal infection has a high mortality and morbidity. Recently a new prognostic scoring system was developed for paediatric invasive meningococcal disease, based on platelet count and base excess a base excess and platelets score. The main objective of this study was to evaluate the accuracy of base excess and platelets score to predict mortality in children admitted to intensive care due to invasive meningococcal disease. MATERIAL AND METHODS: Observational study, with retrospective data collection, during a 13.5 years period (01/2000 to 06/2013). Mortality by invasive meningococcal disease and related factors (organ dysfunction and multi-organ failure) were analysed. The base excess and platelets score was calculated retrospectively, to evaluate its accuracy in predicting mortality and compared with Paediatric Risk of Mortality and Paediatric Index of Mortality2. RESULTS: Were admitted 76 children with invasive meningococcal disease. The most frequent type of dysfunction was cardiovascular (92%), followed by hematologic (55%). Of the total, 47 patients (62%) had criteria for multi-organ failure. The global mortality was 16%. Neurologic and renal dysfunction showed the strongest association with mortality, adjusted odds ratio 315 (26 - 3 804) and 155 (20 - 1 299). After application of receiver operating characteristic curves, Base Excess and Platelets score had an area under curve of 0.81, Paediatric Index of Mortality2 of 0.91 and Paediatric Risk of Mortality of 0.96. DISCUSSION: The Base Excess and Platelets score showed good accuracy, although not as high as Paediatric Risk of Mortality or Paediatric Index of Mortality2. CONCLUSIONS: The Base Excess and Platelets score may be useful tool in invasive meningococcal disease because is highly sensitive and specific and is objectively measurable and readily available at presentation. PMID- 26421786 TI - Cystatin C: A Promising Marker of Renal Function in Patients with Systemic Lupus Erythematosus? AB - PURPOSE: Cystatin C has a higher correlation with glomerular filtration rate and a more significant clinical prognosis than creatinine. We sought to determine whether it is a marker of renal function different from creatinine (cystatin C potentially superior to creatinine), in patients with systemic lupus erythematosus. MATERIAL AND METHODS: 37 patients with systemic lupus erythematosus were evaluated. Serum cystatin C was determined by nephelometry and creatinine by modified Jaffe method. We compared five formulas: Chronic Kidney Disease a Epidemiology Collaboration cystiatin; Chronic Kidney Disease a Epidemiology Collaboration creatinine-cystatin; Cockcroft-Gault; Modification of Diet in Renal Disease and Chronic Kidney Disease a Epidemiology Collaboration creatinine, using the latter as a reference. We analyzed the influence of clinical and laboratory factors in cystatin C variation, using multivariate linear regression. RESULTS: Cystatin C was singly elevated in ten participants, versus none isolated creatinine elevation, and this difference was significant (p = 0.002). There was a difference between the estimated glomerular filtration rate by Chronic Kidney Disease a Epidemiology Collaboration cystatin and by Chronic Kidney Disease a Epidemiology Collaboration creatinine (-6.0541 mL/min/1.73 m2, p = 0.07), more pronounced for lower glomerular filtration rate. Consequently, Chronic Kidney Disease a Epidemiology Collaboration cystatin reclassified 4 patients as having chronic kidney disease de novo and 1 patient as not having chronic kidney disease (p = 0.375). Cystatin C was only significantly influenced by age (p < 0.001). DISCUSSION: Several reports showed cystatin C as a better marker to define chronic kidney disease, allowing more accurate classification and risk stratification, compared with creatinine. In this study, Cystatin C revealed as a promisor marker of renal function in patient with lupus, mainly in patients with lower glomerular filtration rates. The correlation between age and cystatin C seems to be a confounding factor, as glomerular filtration rate physiologically declines with ageing. CONCLUSION: Cystatin C was potentially superior to creatinine and in this study and cystatin C seems to detect changes in glomerular filtration rate earlier than creatinine and may be a better screening method for chronic kidney disease in systemic lupus erythematosus. PMID- 26421788 TI - Validation of the Portuguese Version of EHP-30 (The Endometriosis Health Profile 30). AB - INTRODUCTION: Endometriosis Health Profile Questionnaire-30 is currently the most used questionnaire for quality of life measurement in women with endometriosis. The aim of this study is to evaluate the psychometric properties and to validate the Portuguese Endometriosis Health Profile Questionnaire-30 version. MATERIAL AND METHODS: A sequential sample of 152 patients with endometriosis, followed in a Portugal reference center, were asked to complete a questionnaire on social and demographic features, the Portuguese version of the Endometriosis Health Profile Questionnaire-30 and of the Short Form Health Survey 36 Item a version 2. Appropriate statistical analysis was performed using descriptive statistics, factor analysis, internal consistency, item-total correlation and convergent validity. RESULTS: Factorial analysis confirmed the validity of the five dimension structure of the Endometriosis Health Profile Questionnaire-30 core questionnaire, which explained 83.2% of the total variance. All item-total correlations presented acceptable results and high internal consistency, with Cronbach's alpha ranging between 0.876 and 0.981 for the core questionnaire and between 0.863 and 0.951 for the modular questionnaire. Significant negative associations between similar scales of Endometriosis Health Profile Questionnaire 30 and Short Form Health Survey 36 Item a version 2 were demonstrated. Data completeness achieved was high for all dimensions. The emotional well-being scale in the core questionnaire and the infertility scale in the modular section had the highest median scores, and therefore the most negative impact on the quality of life of participating women. DISCUSSION: The test-retest reliability and responsiveness of the questionnaire should be evaluated in future studies. CONCLUSION: The present study demonstrates that the Portuguese version of the Endometriosis Health Profile Questionnaire-30 is a valid, reliable and acceptable tool for evaluating the health-related quality of life of Portuguese women with endometriosis. PMID- 26421790 TI - Genetic Heterogeneity in Colorectal Cancer and its Clinical Implications. AB - Despite the recent advances in the development of complementary diagnostic exams and modern targeted therapies, colorectal cancer remains a major cause of morbidity and mortality worldwide. In this context, a lot of research has been conducted in the last years to find new markers of poor prognosis. The existence of a complex tumour architecture formed by multiple subclones genetically heterogeneous has been increasingly considered in recent studies as an element of particular importance. This feature seems to influence factors as relevant as the representativeness of tumour biopsies for genetic diagnosis and the efficacy of targeted therapies.There is growing evidence suggesting a relation between genetic heterogeneity and the patientsa prognosis. The widespread use of next generation sequencing techniques will allow a better understanding of the true degree of genetic heterogeneity in colorectal tumours, its causes and impact on the course of the disease. In this review we intend to analyse the recent findings related to the genetic heterogeneity of colorectal cancer, as well as its major clinical implications. PMID- 26421789 TI - Prognostic Factors after Liver Resection for Colorectal Liver Metastasis. AB - INTRODUCTION: Surgery is the only potentially curative treatment for patients with colorectal liver metastases, resulting in 5-year survival rates of 36 -?? 58. Although many studies have been performed to determine prognostic factors for tumor recurrence and survival after resection of colorectal liver metastases, there are few prognostic scoring systems stratifying patients undergoing surgery for colorectal liver metastases into risk group models. OBJECTIVES: To identify, evaluate and compare the existing prognostic scores for survival after surgery for resection of colorectal liver metastases. MATERIAL AND METHODS: Electronic search in PubMed, Cochrane and Embase from 1990 to 2013 using the terms '??hepatic resection', '??colorectal cancer'??, 'liver metastasis', '??hepatectomy', '??prognostic'??, and '??score'??. Only studies proposing a prognostic model or risk stratification based on clinical and/or pathological variables were included. RESULTS: From 1996 to June 2013, 19 scoring systems were identified, including one nomogram. Thirty prognostic factors were identified although none of the factors was common to all prognostic models. The 4 factors most often included were: number of liver metastases, regional lymph node metastization of primary tumor, preoperative CEA level and maximum size of metastases. The median study sample size was 305 patients (81-1 568 patients) and median follow-up was 33 months (16-54 months). All studies were retrospective and used the Cox proportional hazards model for multi-variable analysis. CONCLUSION: Several factors have been constantly reported as having prognostic value after liver resection of colorectal livermetastases, although there is no consensus on the ideal scoring system. PMID- 26421791 TI - Cancer-Related Pain Management and the Optimal Use of Opioids. AB - Pain relief is vital to the treatment of cancer. Despite the widespread use and recognition of clinical recommendations for the management of cancer-related pain, avoidable suffering is still prevalent in patients with malignant disease. A gap exists between what is known about pain medical management and actual practices of patients, caregivers, healthcare professionals and institutions. Opioids are the pillar of the medical management of moderate to severe pain. The prescription of opioid analgesics - by a registered medical practitioner for absolute pain control - is a legitimate practice. In this article we look at patients' fears and physicians' general hesitations towards morphine and alike. We examine misconceptions that yield fallacies on the therapeutically use of opioids and, therefore, sustain inadequate pain management. PMID- 26421792 TI - [Urinary Tuberculosis: Serious Complications May Occur when Diagnosis is Delayed]. AB - Genitourinary tuberculosis is the third most common form of extrapulmonary tuberculosis, comprising 4 - 17% of extrapulmonary forms. The authors describe the case of a patient with recurrent urinary tract infections, without isolation of an infectious agent and without symptomatic resolution, despite antibiotic treatment. Imaging exams showed left ureteral stenosis with moderate hydronephrosis. The attempt of retrograde catheterization was impossible so we opted for percutaneous nephrostomy to renal relief. Microbiological urine analysis colleted by that way was positive for Mycobacterium tuberculosis complex. The patient started therapy with classical quadruple therapy and underwent nephrostomy for catheter placement. Despite therapeutic measures the patient required nephrectomy due to nonfunctioning kidney. Genitourinary tuberculosis is a diagnosis that should be considered in the presence of a persistent sterile pyuria. PMID- 26421794 TI - [Superwarfarine Poisoning]. AB - The superwarfarin-type anticoagulant rodenticides are used throughout the world and distinguish themselves from warfarin for its high potency and long acting anticoagulant activity. Easy access to these products enables the accidental or deliberate human poisoning. A case of voluntary rodenticide poisoning (RATIBRONA) by a woman who ingested an estimated 27.5 mg of bromadiolone total quantity for two weeks, with minor bleeding episodes, whose reversal of the anticoagulant effect with the correction of the abnormal values of the clotting tests took about one month to reverse is reported here. The correction of the haemostasis defects takes usually a long time and there are no treatment guidelines, but a gradually vitamin K dosage reduction, as out patients, along with the monitoring of the International Normalized Ratio levels, allows a safe evaluation of the therapeutic response. PMID- 26421793 TI - [Metallosis: A Rare Cause of Autoimmune Hemolytic Anemia]. AB - INTRODUCTION: Hemolytic anemia may be associated with multiple etiologies, including toxic substances, such as metals, which is a rare cause. CASE STUDY: 55 year-old male, who underwent a total arthroplasty of the right hip (uncemented prostheses with ceramic-ceramic articulation with an acetabular component consisting of a dome composed of an alloy of titanium, aluminum and vanadium into which fitted a ceramic 'insert'). Approximately 4 years after surgery the patient complained of noise originating from the prosthesis which occurred on movement. A surgical revision was performed and showed the presence of dark thick intracapsular fluid, fracture of the ceramic acetabular 'insert' and signs of wear of the acetabular metal dome. Extensive washing was carried out and the fractured ceramic 'insert' was replaced for a polyethylene 'insert'. Two months later he was referred to the Emergency Room due to worsening of his general health, floating in the right hip and mucocutaneous jaundice. Laboratory tests suggested autoimmune hemolytic anemia. Arthrocentesis was performed and a large volume of metal fluid was drained off. The CT scan showed a large heterogeneous pelvic cystic collection seeded with prosthesis fragments, suggestive of metallosis. Hemolytic anemia was explained as toxicity of the particles and metal ions caused by the wear of the prosthesis. The patient was started on a high-dose steroid treatment. Afterwards, when he was stable, prosthesis components replacement and drainage of pelvic debris fluid were carried out. DISCUSSION: After the fracture of the ceramic 'insert' the ceramic head began to articulate directly with the metallic acetabular component, causing noise and wear with release of particles and ions. This caused a cystic pelvic abscess, which went unnoticed on the first surgical revision. Surgical debridement lead to the cystic collection extending into the adjacent tissues and the systemic circulation, triggering serious systemic effects, such as autoimmune hemolytic anemia. The potential toxicity of each of the metal elements of this prosthesis is unknown, and there are still no available laboratory tests for its detection. CONCLUSION: Metallosis is a rare cause of autoimmune hemolytic anemia. PMID- 26421795 TI - Lingua Villosa Nigra Associated with the Use of Electronic Cigarette. PMID- 26421796 TI - "Apple Jelly" Sign: Diascopy in Cutaneous Sarcoidosis. PMID- 26421797 TI - [Clinical Guidelines 2.0: Translation of Tables 2 and 3 and Apendix 1 of Schunemann HJ et al. CMAJ. 2014; 186:E123-42]. AB - Clinical Practice Guidelines are instruments to support decision to improve the quality of clinical care. An expert group from McMaster University (Canada) has developed - from high-quality literature sources - a guidance on the practical steps for their development, dissemination, implementation and evaluation. This is the 1st time anyone seeks to bring together in one document all information regarding the Clinical Practice Guidelines. Due to the interest of this paper, the Centre for Evidence Based Medicine at the University of Lisbon School of Medicine contacted the authors of the article and the journal where it was published (the Canadian Medical Association Journal) in order to translate the most relevant parts of the article (including the practice tables), which was agreed. This guide should be useful to those who, being interested in the development, dissemination and implementation of Clinical Practice Guidelines, want to ensure their intrinsic quality based on relevant and updated evidence. PMID- 26421798 TI - [On Tentacoes de Santo Antao: The Way Things Mean]. PMID- 26421800 TI - Defining the role of radiofrequency ablation and stereotactic ablative radiotherapy in patients with high-risk, early-stage non-small cell lung cancer. PMID- 26421799 TI - Dopamine impairs functional integrity of rat hepatocytes through nuclear factor kappa B activity modulation: An in vivo, ex vivo, and in vitro study. AB - Dopamine (DA) is commonly used to maintain the hemodynamic stability of brain dead donors despite its controversial effects on organ functions. This study aimed at examining the hemodynamic effect of DA in a rat brain-dead model in vivo, alteration of hepatocyte integrity in liver grafts after ex vivo preservation, and changes in cultured clone-9 hepatocytes including cellular viability, cell cycle, apoptotic regulators, and lipopolysaccharide (LPS) stimulated nuclear factor kappa B (NF-kappaB) signaling machinery. Although in vivo findings demonstrated enhanced portal venous blood flow and hepatic microcirculatory perfusion after DA infusion, no apparent advantage was noted in preserving hepatocyte integrity ex vivo. In vitro, prolonged exposure to high dose DA reduced proliferation and induced G1 growth arrest of clone-9 hepatocytes with concomitant decreases in B cell lymphoma 2 (BCL2)/B cell lymphoma 2 associated X protein (BAX) and heat shock protein 70/BAX protein ratios and intracellular NF-kappaB p65. Moreover, DA pretreatment suppressed LPS-elicited inhibitor of kappaBalpha phosphorylation and subsequent NF-kappaB nuclear translocation, suggesting that DA may down-regulate NF-kappaB signaling, thereby reducing expression of antiapoptotic regulators, such as BCL2. In conclusion, despite augmentation of hepatic perfusion, DA infusion failed to preserve hepatocyte integrity both in vivo and ex vivo. In vitro findings demonstrated that high-dose DA may hamper the function of NF-kappaB signaling machinery and eventually undermine functional integrity of hepatocytes in liver grafts. PMID- 26421801 TI - Carbon dioxide insufflation during colonoscopy can significantly decrease post interventional abdominal discomfort in deeply sedated patients: A prospective, randomized, double-blinded, controlled trial. AB - BACKGROUND AND AIM: CO2 has been reported to be absorbed from the bowel more rapidly than air, resulting in a discomfort reduction after colonoscopy. Its role in deeply sedated patients is limited. This study was designed to investigate the efficacy and safety of CO2 insufflation during colonoscopy in patients deeply sedated with propofol. METHODS: A total of 125 continuous patients were randomly assigned to receive either CO2 (n = 63) or air (n = 62) insufflation during propofol-sedated colonoscopy. Postcolonoscopy abdominal pain, distention, and satisfaction were assessed at 1, 3, and 24 h after the procedure, and the proportions of pain-free and distention-free patients were compared. Residual bowel gas in the colon and small bowel was evaluated at 1 h after colonoscopy. End-tidal CO2 and O2 saturation was measured for safety analysis. RESULTS: There was a significant difference between the two groups regarding the postcolonoscopy abdominal pain, distention, and subjective satisfaction at 1 h (P < 0.001) and 3 h (P < 0.01) after the procedure. Patients' pain and distention at 1 and 3 h after the procedure were significantly lower in the CO2 group (P < 0.01). Residual bowel gas in the colon and small bowel was significantly less in the CO2 group (P < 0.001). There was no significant difference in end-tidal CO2 levels between two groups before, during, and after the procedure. CONCLUSIONS: Compared with air, CO2 insufflation during colonoscopy reduced postcolonoscopy abdominal discomfort and improved patients' satisfaction. It was safe to use CO2 insufflation in deeply sedated colonoscopy. PMID- 26421802 TI - Novel RAB3GAP1 compound heterozygous mutations in Japanese siblings with Warburg Micro syndrome. AB - BACKGROUND: Warburg Micro syndrome (WARBM) is a rare autosomal recessive disease characterized by postnatal growth retardation, microcephaly, severely delayed motor and intellectual development, microcornea, congenital cataracts, optic atrophy, and hypogonadism. While WARBM is a genetically heterogeneous condition, RAB3GAP1 mutations account for ~40% of WARBM patients, and 69 different mutations of various types (nonsense, missense, frameshift, and splice site mutations) have been identified to date. PATIENTS: Japanese siblings (a 7 years 3 months old male and a 2 years 1month old female) were found to have WARBM-compatible phenotypes. Direct sequencing of RAB3GAP1 revealed novel compound heterozygous mutations in the siblings: a paternally inherited missense mutation (c.560G>C; p.Arg187Pro) in exon 7 and a maternally derived nonsense mutation (c.1009C>T; p.Arg337Ter) in exon 12. CONCLUSION: The siblings had WARBM caused by novel mutations in RAB3GAP1. Since molecular diagnosis permits adequate genetic counseling and appropriate management for predicted complications such as adequate sex steroid supplementation therapy for hypogonadism, in addition to standard supportive therapies for developmental delay and visual dysfunction, we recommend molecular studies for this rare condition. PMID- 26421803 TI - Lack of Impact of Body Mass Index at Young Age on Otitis Media Occurrence During Preschool Years: Wheezing Illnesses Study Leidsche Rijn Cohort Study. AB - Using data on weight and height at 6 and 11 months of age and primary care electronic health records data from 1960 children participating in the Wheezing Illnesses Study Leidsche Rijn birth cohort study, we found that body mass index at 6 and 11 months of age was not associated with otitis media occurrence during the first 4 years of life. PMID- 26421804 TI - High Prevalence of Dyslipidemia and Insulin Resistance in HIV-infected Prepubertal African Children on Antiretroviral Therapy. AB - BACKGROUND: Data describing the true extent of antiretroviral therapy (ART) induced dyslipidemia and insulin resistance in perinatally infected children on ART in Africa are sparse. METHODS: Fasting total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, insulin and glucose were performed on the first 100 of 190 pediatric ART clinic attendees. Diet assessment was performed by a trained dietician. Lipoatrophy was formally graded by consensus between 2 expert HIV pediatricians. Durations of previous ART exposures, clinical stage, pre-ART viral load, nadir and current CD4 were recorded. Dual-energy X-ray absorptiometry was performed on a subset of 42 patients selected semi-randomly. RESULTS: Prevalences of insulin resistance, abnormal total cholesterol, LDL, HDL and triglyceride were 10%, 13%, 12%, 13% and 9%, respectively. Overall, 40% had at least 1 lipid abnormality or insulin resistance. Adjusted mean LDL cholesterol increased by 0.24 mmol/L for each additional year of cumulative lopinavir/r exposure (P = 0.03) after correcting for age, gender, body mass index, previous stavudine exposure, age at ART initiation, dietary fat and refined carbohydrate, whereas adjusted mean LDL cholesterol was 0.9 mmol/L higher in children exposed to efavirenz within the previous 6 months (P = 0.02). Adjusting for age, gender and ethnicity, dual energy X-ray absorptiometry revealed that greater trunk fat and lower peripheral subcutaneous fat were associated with elevated triglycerides but not with total cholesterol, LDL, HDL or homeostatic model assessment. Similarly, the presence of visually obvious lipoatrophy was associated with elevated triglycerides but not with total cholesterol, LDL, HDL, homeostatic model assessment or lactate. CONCLUSIONS: Prevalences of insulin resistance and dyslipidemia were high. Cumulative lopinavir is an independent risk factor for dyslipidemia, with efavirenz exposure having only transitory effect. PMID- 26421805 TI - Burden of Influenza and Influenza-associated Pneumonia in the First Year of Life in a Prospective Cohort Study in Managua, Nicaragua. AB - BACKGROUND: Influenza is a major public health problem worldwide; however, relatively little is known about influenza in tropical regions, especially for infants. Additional information is required to inform public health policy making, in particular vaccination guidelines. METHODS: Between September 2011 and July 2013, we enrolled newborns into the Nicaraguan Birth Cohort Study. Infants were provided primary medical care and actively followed for reverse transcription polymerase chain reaction-confirmed influenza virus infection when presenting with influenza-like illness or undifferentiated fever. This report presents data pertaining to the first year of life. RESULTS: Of the 518 children enrolled in the study, 441 participated throughout their first year of life, 71 were withdrawn, and 6 died. Overall, 13% of the participants experienced at least 1 laboratory-confirmed influenza virus infection. The overall incidence of influenza was 15.5 cases per 100 person-years [95% confidence interval (CI): 12.2 19.5]. Infants aged 6-11 months experienced significantly higher rates of laboratory-confirmed influenza than infants aged 0-5 months (incidence rate ratio: 2.1; 95% CI: 1.3-3.4). The overall incidence of pneumonia was 52.6 cases per 100 person-years (95% CI: 46.3-59.6). Three percent of the pneumonia cases were influenza associated, and the incidence of influenza-associated pneumonia and hospitalization was 1.7 (95% CI: 0.9-3.5) and 0.22 (95% CI: 0.03-1.55) cases per 100 person-years, respectively. CONCLUSIONS: We found a significant burden of influenza and influenza-associated severe respiratory outcomes in infants. Our results support the need to explore the potential value of vaccinating pregnant women and infants aged >6 months, as recommended by the World Health Organization in 2012. PMID- 26421806 TI - Disease Burden of Rotavirus Gastroenteritis in Children Residing in Germany: A Retrospective, Hospital-based Surveillance. AB - BACKGROUND: Representative, population-based epidemiologic data for gastroenteritis caused by rotavirus (RV) are rare. RV vaccines were first licensed in Europe in 2006 and recommended in 5 western federal states in 2008 or thereafter. This study establishes a baseline for assessing the impact of vaccination and delineates the RV disease burden in Germany today. METHODS: Nationwide data obtained from hospitals for children 0 to 10 years of age and transferred to the Federal Statistical Office were analyzed retrospectively. Acute gastroenteritis cases because of RV were identified by the International Classification of Diseases code (ICD-10) combined with the referring diagnosis related group code. Coding quality was validated by random sampling the patient records (n=1003). Crude and age-standardized rates per 100,000 person-years were calculated. The rate ratios of seasonal effects and recommended immunization adjusted for year, federal state and age were estimated using Poisson regression. RESULTS: Between 2005 and 2010, 5,843,730 children were hospitalized; 520,606 cases were hospitalized because of acute gastroenteritis. RV caused 152,636 of these cases or an age-standardized rate of 302 hospitalizations per 100,000 person-years. Rates were slightly higher in boys than girls, decreased with age, and differed by federal state, year and season. Rate ratios decreased in those western federal states that recommended immunization and were inversely associated with vaccine doses sold. CONCLUSIONS: With an average of 25,440 children hospitalized yearly, RV infection has a great impact on the German healthcare system. Our findings indicate that RV immunization will lead to a decline in in-patient treatment and associated costs. PMID- 26421807 TI - Effectiveness of novel, lower cost molecular human papillomavirus-based tests for cervical cancer screening in rural china. AB - This study examined the efficacy of the OncoE6TM Cervical Test, careHPVTM and visual inspection with acetic acid (VIA) in identifying women at risk for cervical cancer and their capability to detect incident cervical precancer and cancer at 1-year follow-up. In a population of 7,543 women living in rural China, women provided a self-collected and two clinician-collected specimens and underwent VIA. All screen positive women for any of the tests, a ~ 10% random sample of test-negative women that underwent colposcopy at baseline, and an additional ~ 10% random sample of test-negative women who did not undergo colposcopy at baseline (n = 3,290) were recruited. 2,904 women were rescreened 1 year later using the same tests, colposcopic referral criteria, and procedures. Sensitivities of baseline tests to detect 1-year cumulative cervical intraepithelial neoplasia Grade 3 or cancer (CIN3+) were 96.5% and 81.6% for careHPVTM on clinician-collected and self-collected specimens, respectively, and 54.4% for OncoE6TM test. The OncoE6TM test was very specific (99.1%) and had the greatest positive predictive value (PPV; 47.7%) for CIN3+. Baseline and 1-year follow-up cervical specimens testing HPV DNA positive was sensitive (88.0%) but poorly predictive (5.5-6.0%) of incident CIN2+, whereas testing repeat HPV16, 18 and 45 E6 positive identified only 24.0% of incident CIN2+ but had a predictive value of 33.3%. This study highlights the different utility of HPV DNA and E6 tests, the former as a screening and the latter as a diagnostic test, for detection of cervical precancer and cancer. PMID- 26421808 TI - Understanding Heterogeneity in the Impact of National Neglected Tropical Disease Control Programmes: Evidence from School-Based Deworming in Kenya. AB - BACKGROUND: The implementation of soil-transmitted helminth (STH) treatment programmes occurs in varied environmental, social and economic contexts. Programme impact will be influenced by factors that affect the reduction in the prevalence and intensity of infections following treatment, as well as the subsequent rate of reinfection. To better understand the heterogeneity of programme impact and its underlying reasons, we investigated the influence of contextual factors on reduction in STH infection as part of the national school based deworming (SBD) programme in Kenya. MATERIALS AND METHODS: Data on the prevalence and intensity of infection were collected within the monitoring and evaluation component of the SBD programme at baseline and after delivery of two annual treatment rounds in 153 schools in western Kenya. Using a framework that considers STH epidemiology and transmission dynamics, capacity to deliver treatment, operational feasibility and financial capacity, data were assembled at both school and district (county) levels. Geographic heterogeneity of programme impact was assessed by descriptive and spatial analyses. Factors associated with absolute reductions of Ascaris lumbricoides and hookworm infection prevalence and intensity were identified using mixed effects linear regression modelling adjusting for baseline infection levels. PRINCIPAL FINDINGS: The reduction in prevalence and intensity of A. lumbricoides and hookworms varied significantly by county and within counties by school. Multivariable analysis of factors associated with programme impact showed that absolute A. lumbricoides reductions varied by environmental conditions and access to improved sanitation at schools or within the community. Larger reduction in prevalence and intensity of hookworms were found in schools located within areas with higher community level access to improved sanitation and within counties with higher economic and health service delivery indicator scores. CONCLUSIONS: The study identifies factors associated with the impact of school-based deworming and in particular highlights how access to water, sanitation and hygiene and environmental conditions influence the impact of deworming programmes. PMID- 26421809 TI - Modification of Bupivacaine-Induced Myotoxicity with Dantrolene and Caffeine In Vitro. AB - BACKGROUND: Local anesthetics, especially bupivacaine, have myotoxic effects in clinically used concentrations and context. Detailed mechanisms of these effects are unknown, but an increase in intracellular calcium levels is suspected to be the most important trigger. Dantrolene and caffeine modify cellular calcium release from the sarcoplasmic reticulum. The aim of our study was to investigate the effect of dantrolene and caffeine on bupivacaine-induced myotoxicity in vitro. METHODS: A cell culture model of primary muscle cells of BALB/c AnNCrl mice was established. Cells were incubated simultaneously with increasing concentrations of bupivacaine, dantrolene, and caffeine. The fraction of dead cells was calculated after staining with propidium iodide and analysis by flow cytometry. The half-maximal inhibitory concentration of bupivacaine was calculated for each concentration. Group differences were determined by using 1 way analysis of variances with subsequent post hoc 1-way Dunnett t test. RESULTS: Both dantrolene and caffeine alone had no effect on muscle cell survival. Increasing concentrations of bupivacaine caused increasing cell death. Dantrolene dose-dependently reduced the fraction of necrotic cells, whereas caffeine dose dependently increased the fraction of dead cells. CONCLUSIONS: Dantrolene attenuated, and caffeine enhanced, bupivacaine-induced myotoxicity, presumably by modifying sarcoplasmic calcium release. This indicates that intracellular calcium release is an important factor for local anesthetic-induced cell death. PMID- 26421810 TI - Perioperative Duloxetine to Improve Postoperative Recovery After Abdominal Hysterectomy: A Prospective, Randomized, Double-Blinded, Placebo-Controlled Study. AB - BACKGROUND: Postsurgical quality of recovery is worse in female than that in male patients. Duloxetine has been used successfully for the treatment of chronic pain conditions, but its use for preventing acute postoperative pain has been limited to a single previous study. More importantly, the effect of preoperative duloxetine on global postoperative quality of recovery has yet to be evaluated. The main objective of the current investigation was to evaluate the effect of perioperative duloxetine on postoperative quality of recovery in women undergoing abdominal hysterectomy. METHODS: The study was a prospective, randomized, placebo controlled, double-blinded trial. Female patients undergoing abdominal hysterectomy were randomized to receive duloxetine (60 mg orally 2 hours before surgery and 24 hours after surgery) or an identical placebo pill. The primary outcome was the quality of recovery-40 score at 24 hours. Secondary outcomes included opioid consumption and postoperative pain scores. A P value <0.05 was used to reject type I error. RESULTS: Seventy patients were recruited, and 63 completed the study. The median difference (95% confidence interval) in global recovery scores (quality of recovery-40) at 24 hours after surgery between the duloxetine and the placebo group was 9 (4-20) (P < 0.001). Total opioid consumption was reduced at 24 hours in the duloxetine group compared with the placebo group, median (interquartile range) of 1 (0-5) mg IV morphine compared with 5.5 (0.5-9) mg IV morphine (P = 0.004). Nausea, vomiting, and time to postanesthesia care unit discharge were not significantly reduced in the duloxetine group compared with placebo. CONCLUSIONS: Duloxetine improves postoperative quality of recovery after abdominal hysterectomy. In addition, duloxetine reduces postoperative opioid consumption, even in the presence of a robust multimodal analgesic strategy. Duloxetine seems to be a viable pharmacologic strategy to improve postoperative quality of recovery in female patients undergoing abdominal hysterectomy. PMID- 26421811 TI - In reference to endoscope-assisted transoral removal of a thyroglossal duct cyst using a frenotomy incision: A prospective clinical trial. PMID- 26421812 TI - X-linked ichthyosis in a patient with a novel nonsense mutation in the STS gene. PMID- 26421814 TI - Cancer survival in Europe, 1999-2007: Doing better, feeling worse? PMID- 26421813 TI - Intermediate and long-term adverse effects of radioiodine therapy for differentiated thyroid carcinoma--a systematic review. AB - BACKGROUND: Treatment of differentiated thyroid carcinoma (DTC) often involves administration of radioactive iodine (I-131) for remnant ablation or adjuvant therapy. As DTC has favorable outcome and the incidence is increasing, concerns have been raised about the possible adverse effects of I-131 therapy. We systematically reviewed the literature to examine the risk of intermediate and long-term adverse effects of I-131 therapy in DTC patients. METHODS: Multiple electronic databases were searched up to November 2014 for English-language, controlled studies that reported on the risk of salivary gland dysfunction, lacrimal gland dysfunction, gonadal dysfunction, female reproductive outcomes or second primary malignancies (SPM) after I-131 exposure. The certainty of the evidence found was assessed using GRADE. RESULTS: In total, 37 articles met all inclusion criteria, no studies reporting on adverse effects after I-131 treatment focused solely on children. After exposure to I-131 for DTC, patients experienced significantly more frequently salivary gland dysfunction (prevalence range: 16 54%, moderate-level evidence), lacrimal gland dysfunction (prevalence: 11%, low level evidence), transient male gonadal dysfunction (prevalence: 35-100%, high level evidence), transient female gonadal dysfunction (prevalence: 28%, low-level evidence) and SPM (prevalence: 2.7-8.7%, moderate-level evidence) compared to unexposed patients. I-131 therapy seems to have no deleterious effects on female reproductive outcomes (very-low level evidence). The prevalence and severity of adverse effects were correlated to increasing cumulative I-131 activity. CONCLUSION: Treatment with I-131 for DTC may have significant adverse effects, which seem to be dose dependent. These adverse effects of treatment must be balanced when choosing for I-131 therapy in patients with DTC. PMID- 26421815 TI - The EUROCARE-5 study on cancer survival in Europe 1999-2007: Database, quality checks and statistical analysis methods. AB - BACKGROUND: Since 25years the EUROCARE study monitors the survival of cancer patients in Europe through centralised collection, quality check and statistical analysis of population-based cancer registries (CRs) data. The European population covered by the study increased remarkably in the latest round. The study design and statistical methods were also changed to improve timeliness and comparability of survival estimates. To interpret the EUROCARE-5 results on adult cancer patients better here we assess the impact of these changes on data quality and on survival comparisons. METHODS: In EUROCARE-5 the survival differences by area were studied applying the complete cohort approach to data on nearly nine million cancer patients diagnosed in 2000-2007 and followed up to 2008. Survival time trends were analysed applying the period approach to data on about 10 million cancer cases diagnosed from 1995 to 2007 and followed up to 2008. Differently from EUROCARE-4, multiple primary cancers were included and relative survival was estimated with the Ederer II method. RESULTS: EUROCARE-5 covered a population of 232 million resident persons, corresponding to 50% of the 29 participating countries. The population coverage increased particularly in Eastern Europe. Cases identified from death certificate only (DCO) were on average 2.9%, range 0-12%. Microscopically confirmed cases amounted to over 85% in most CRs. Compared to previous methods, including multiple cancers and using the Ederer II estimator reduced survival estimates by 0.4 and 0.3 absolute percentage points, on average. CONCLUSIONS: The increased population size and registration coverage of the EUROCARE-5 study ensures more robust and comparable estimates across European countries. This enlargement did not impact on data quality, which was generally satisfactory. Estimates may be slightly inflated in countries with high or null DCO proportions, especially for poor prognosis cancers. The updated methods improved the comparability of survival estimates between recently and long-term established registries and reduced biases due to informative censoring. PMID- 26421816 TI - Age and case mix-standardised survival for all cancer patients in Europe 1999 2007: Results of EUROCARE-5, a population-based study. AB - BACKGROUND: Overall survival after cancer is frequently used when assessing a health care service's performance as a whole. It is mainly used by the public, politicians and the media, and is often dismissed by clinicians because of the heterogeneous mix of different cancers, risk factors and treatment modalities. Here we give survival details for all cancers combined in Europe, correlating it with economic variables to suggest reasons for differences. METHODS: We computed age and cancer site case-mix standardised relative survival for all cancers combined (ACRS) for 29 countries participating in the EUROCARE-5 project with data on more than 7.5million cancer cases from 87 population-based cancer registries, using complete and period approach. RESULTS: Denmark, United Kingdom (UK) and Eastern European countries had lower survival than neighbouring countries. Five-year ACRS has been increasing throughout Europe, and substantial increases, between 1999-2001 and 2005-2007, have been achieved in countries where survival was lower in the past. Five-year ACRS for men and women are positively correlated with macro-economic variables like the Gross Domestic Product (GDP) and Total National Expenditure on Health (TNEH) (R2 about 70%). Countries with recent larger increases in GDP and TNEH had greater increases in cancer survival. CONCLUSIONS: ACRS serves to compare all cancer survival in Europe taking account of the geographical variability in case-mixes. The EUROCARE-5 data on ACRS confirm previous EUROCARE findings. Survival appears to correlate with macro economic determinants, particularly with investments in the health care system. PMID- 26421817 TI - Prognoses and improvement for head and neck cancers diagnosed in Europe in early 2000s: The EUROCARE-5 population-based study. AB - BACKGROUND: Head and neck (H&N) cancers are a heterogeneous group of malignancies, affecting various sites, with different prognoses. The aims of this study are to analyse survival for patients with H&N cancers in relation to tumour location, to assess the change in survival between European countries, and to investigate whether survival improved over time. METHODS: We analysed about 250,000 H&N cancer cases from 86 cancer registries (CRs). Relative survival (RS) was estimated by sex, age, country and stage. We described survival time trends over 1999-2007, using the period approach. Model based survival estimates of relative excess risks (RERs) of death were also provided by country, after adjusting for sex, age and sub-site. RESULTS: Five-year RS was the poorest for hypopharynx (25%) and the highest for larynx (59%). Outcome was significantly better in female than in male patients. In Europe, age-standardised 5-year survival remained stable from 1999-2001 to 2005-2007 for laryngeal cancer, while it increased for all the other H&N cancers. Five-year age-standardised RS was low in Eastern countries, 47% for larynx and 28% for all the other H&N cancers combined, and high in Ireland and the United Kingdom (UK), and Northern Europe (62% and 46%). Adjustment for sub-site narrowed the difference between countries. Fifty-four percent of patients was diagnosed at advanced stage (regional or metastatic). Five-year RS for localised cases ranged between 42% (hypopharynx) and 74% (larynx). CONCLUSIONS: This study shows survival progresses during the study period. However, slightly more than half of patients were diagnosed with regional or metastatic disease at diagnosis. Early diagnosis and timely start of treatment are crucial to reduce the European gap to further improve H&N cancers outcome. PMID- 26421819 TI - On-going improvement and persistent differences in the survival for patients with colon and rectum cancer across Europe 1999-2007 - Results from the EUROCARE-5 study. AB - BACKGROUND: Previous population-based studies revealed major variation in survival for patients with colorectal cancer (CRC) in Europe by age and between different countries and regions, but also a sustained improvement in survival for patients with CRC in recent years. This EUROCARE-5 paper aims to update available knowledge from previous studies and to provide the latest survival estimates for CRC patients from Europe. METHODS: The study analysed data of patients diagnosed with CRC from population-based cancer registries diagnosed in 29 European countries. Estimates of 1-year and 5-year relative survival (RS) were derived for patients diagnosed in 2000-2007 by European region, country and age at diagnosis. Additionally to these cohort estimates, time trends in 5-year RS were obtained for the calendar periods 1999-2001 and 2005-2007, using the period analysis methodology. RESULTS: European average 5-year RS for patients diagnosed with colon and rectum cancer was 57% and 56%, respectively. The analyses showed persistent differences in cancer survival across Europe with lowest survival for CRC patients observed in Eastern Europe. The analyses further showed a strong gradient in age-specific survival. Even though the study revealed sustained improvement in patient survival between 1999-2001 and 2005-2007 (absolute increase of 4 and 6 percentage points for colon and rectum, respectively), the differences in the survival for CRC patients observed at the beginning of the millennium persisted over time. CONCLUSION: Although survival for CRC patients in Europe improved markedly in the study period, significant geographic variations and a strong age gradient still persisted. Enhanced access to effective diagnostic procedures and treatment options might be the keys to reducing the existing disparities in the survival of CRC patients across Europe. PMID- 26421820 TI - Survival in patients with primary liver cancer, gallbladder and extrahepatic biliary tract cancer and pancreatic cancer in Europe 1999-2007: Results of EUROCARE-5. AB - BACKGROUND: The EUROCARE study collects and analyses survival data from population-based cancer registries (CRs) in Europe in order to provide data on between-country differences in survival and time trends in survival. METHODS: This study analyses data on liver cancer, gallbladder and extrahepatic biliary tract cancers ("biliary tract cancers"), and pancreatic cancer diagnosed in 2000 2007 from 88 CRs in 29 countries. Relative survival (RS) was estimated overall, by region, sex, age and period of diagnosis using the complete approach. Time trends in 5-year RS over 1999-2007 were also analysed using the period approach. RESULTS: The prognosis of the studied cancers was poor. Age-standardised 5-year RS was 12% for liver cancer, 17% for biliary tract cancers and 7% for pancreatic cancer. There were some between-country differences in survival. In general, RS was low in Eastern Europe and high in Central and Southern Europe. For all sites, 5-year RS was similar in men and women and decreased with advancing age. No substantial changes in survival were reported for pancreatic cancer over the period 1999-2007. On average, there was a crude increase in 5-year RS of 3 percentage points between the periods 1999-2001 and 2005-2007 for liver cancer and biliary tract cancers. CONCLUSIONS: The major changes in imaging techniques over the study period for the diagnosis of the three studied cancers did not result in an improvement in the prognosis of these cancers. In the near future, new innovative treatments might be the best way to improve the prognosis in these cancers. PMID- 26421821 TI - Survival of patients with skin melanoma in Europe increases further: Results of the EUROCARE-5 study. AB - BACKGROUND: In Europe skin melanoma (SM) survival has increased over time. The aims were to evaluate recent trends and differences between countries and regions of Europe. METHODS: Relative survival (RS) estimates and geographical comparisons were based on 241,485 patients aged 15years and over with a diagnosis of invasive SM in Europe (2000-2007). Survival time trends during 1999-2007 were estimated using the period approach, for 213,101 patients. Age, gender, sub-sites and morphology subgroups were considered. RESULTS: In European patients, estimated 5 year RS was 83% (95% confidence interval, CI 83-84%). The highest values were found for patients resident in Northern (88%; 87-88%) and Central (88%; 87-88%) Europe, followed by Ireland and United Kingdom (UK) (86%; 85-86%) and Southern Europe (83%; 82-83%). The lowest survival was in Eastern Europe (74%; 74-75%). Within regions the intercountry absolute difference in percentage points of RS varied from 4% (North) to 34% (East). RS decreased markedly with patients' age and was higher in women than men. Differences according to SM morphology and skin sub-sites also emerged. Survival has slightly increased from 1999 to 2007, with a small improvement in Northern and the most pronounced improvement in Eastern Europe. DISCUSSION: SM survival is high and still increasing in European patients. The gap between Northern and Southern and especially Eastern European countries, although still present, diminished over time. Differences in stage distribution at diagnosis may explain most of the geographical differences. However, part of the improvement in survival may be attributed to overdiagnosis from early diagnosis practices. PMID- 26421818 TI - Survival for oesophageal, stomach and small intestine cancers in Europe 1999 2007: Results from EUROCARE-5. AB - BACKGROUND: European regional variation in cancer survival was reported in the EUROCARE-4 study for patients diagnosed in 1995-1999. Relative survival (RS) estimates are here updated for patients diagnosed with cancer of the oesophagus, stomach and small intestine from 2000 to 2007. Trends in RS from 1999-2001 to 2005-2007 are presented to monitor and discuss improvements in patient survival in Europe. MATERIALS AND METHODS: EUROCARE-5 data from 29 countries (87 cancer registries) were used to investigate 1- and 5-year RS. Using registry-specific life-tables stratified by age, gender and calendar year, age-standardised 'complete analysis' RS estimates by country and region were calculated for Northern, Southern, Eastern and Central Europe, and for Ireland and United Kingdom (UK). Survival trends of patients in periods 1999-2001, 2002-2004 and 2005-2007 were investigated using the 'period' RS approach. We computed the 5 year RS conditional on surviving the first year (5-year conditional survival), as the ratio of age-standardised 5-year RS to 1-year RS. RESULTS: Oesophageal cancer 1- and 5-year RS (40% and 12%, respectively) remained poor in Europe. Patient survival was worst in Eastern (8%), Northern (11%) and Southern Europe (10%). Europe-wide, there was a 3% improvement in oesophageal cancer 5-year survival by 2005-2007, with Ireland and the UK (3%), and Central Europe (4%) showing large improvements. Europe-wide, stomach cancer 5-year RS was 25%. Ireland and UK (17%) and Eastern Europe (19%) had the poorest 5-year patient survival. Southern Europe had the best 5-year survival (30%), though only showing an improvement of 2% by 2005-2007. Small intestine cancer 5-year RS for Europe was 48%, with Central Europe having the best (54%), and Ireland and UK the poorest (37%). Five-year patient survival improvement for Europe was 8% by 2005-2007, with Central, Southern and Eastern Europe showing the greatest increases (?9%). CONCLUSIONS: Survival for these cancer sites, particularly oesophageal cancer, remains poor in Europe with wide variation. Further investigation into the wide variation, including analysis by histology and anatomical sub-site, will yield insights to better monitor and explain the improvements in survival observed over time. PMID- 26421822 TI - Survival of women with cancers of breast and genital organs in Europe 1999-2007: Results of the EUROCARE-5 study. AB - BACKGROUND: Survival differences across Europe for patients with cancers of breast, uterus, cervix, ovary, vagina and vulva have been documented by previous EUROCARE studies. In the present EUROCARE-5 study we update survival estimates and investigate changes in country-specific and over time survival, discussing their relationship with incidence and mortality dynamics for cancers for which organised screening programs are ongoing. METHODS: We analysed cases archived in over 80 population-based cancer registries in 29 countries grouped into five European regions. We used the cohort approach to estimate 5-year relative survival (RS) for adult (?15years) women diagnosed 2000-2007, by age, country and region; and the period approach to estimate time trends (1999-2007) in RS for breast and cervical cancers. RESULTS: In 2000-2007, 5-year RS was 57% overall, 82% for women diagnosed with breast, 76% with corpus uteri, 62% with cervical, 38% with ovarian, 40% with vaginal and 62% with vulvar cancer. Survival was low for patients resident in Eastern Europe (34% ovary-74% breast) and Ireland and the United Kingdom [Ireland/UK] (31-79%) and high for those resident in Northern Europe (41-85%) except Denmark. Survival decreased with advancing age: markedly for women with ovarian (71% 15-44years; 20% ?75years) and breast (86%; 72%) cancers. Survival for patients with breast and cervical cancers increased from 1999-2001 to 2005-2007, remarkably for those resident in countries with initially low survival. CONCLUSIONS: Despite increases over time, survival for women's cancers remained poor in Eastern Europe, likely due to advanced stage at diagnosis and/or suboptimum access to adequate care. Low survival for women living in Ireland/UK and Denmark could indicate late detection, possibly related also to referral delay. Poor survival for ovarian cancer across the continent and over time suggests the need for a major research effort to improve prognosis for this common cancer. PMID- 26421823 TI - Survival of male genital cancers (prostate, testis and penis) in Europe 1999 2007: Results from the EUROCARE-5 study. AB - BACKGROUND: We provide updated estimates of survival and survival trends of male genital tumours (prostate, testicular and penis cancers), in Europe and across European areas. METHODS: The complete approach was used to obtain relative survival estimates for patients diagnosed in 2000-2007, and followed up through 2008 in 29 countries. Data came from 87 cancer registries (CRs) for prostate tumours and from 86 CRs for testis and penis tumours. Relative survival time trends in 1999-2007 were estimated by the period approach. Data came from 49 CRs in 25 countries. RESULTS: We analysed 1,021,275 male genital cancer cases. Five year relative survival was high and decreased with increasing age for all tumours considered. We found limited variation in survival between European regions with Eastern Europe countries having lower survival than the others. Survival for penile cancer patients did not improve from 1999 to 2007. Survival for testicular cancer patients remained stable at high levels since 1999. Survival for prostate cancer patients increased over time. CONCLUSIONS: Treatment standardisation and centralisation for very rare diseases such as penile cancers or advanced testicular tumours should be supported. The high survival of testicular cancer makes long-term monitoring of testicular cancer survivors necessary and CRs can be an important resource. Prostate cancer patients' survival must be interpreted considering incidence and mortality data. The follow-up of the European Randomised Study of Screening for Prostate Cancer should continue to clarify the impact of screening on prostate cancer mortality together with population based studies including information on stage and treatments. PMID- 26421824 TI - Urinary tract cancer survival in Europe 1999-2007: Results of the population based study EUROCARE-5. AB - BACKGROUND: This work presents relative survival estimates regarding urinary tract tumours among adult patients (age?15years) diagnosed in Europe. It reports on survival estimates of cases diagnosed in 2000-2007, and on survival time trends from 1999-2001 to 2005-2007. METHODS: Data on 677,340 adult urinary tract tumour patients, (429,154 cases of invasive and non-invasive bladder and 248,186 cases of invasive kidney cancers) diagnosed between 2000 and 2007 were provided by 86 population-based cancer registries from 29 European countries. The complete approach was used to estimate survival in 2000-2007; the period approach was used to estimate survival over time. RESULTS: The age-standardised 5-year relative survival for patients with kidney tumours diagnosed in Europe during 2000-2007 was 60%. The best prognosis was observed in Southern and Central Europe and prognosis improved in all regions along the time period. For invasive and non invasive patients with bladder tumours combined the age-standardised 5-year relative survival in Europe was 68%. The best prognosis was observed in Southern and Northern Europe. However, in Scotland and The Netherlands the relative survival was significantly lower, although the survival estimates for these two countries were based on invasive tumours only. CONCLUSIONS: Differences in registration practices affect comparisons of survival values between European countries, especially in patients with urinary bladder cancers. The between country variation in survival is influenced by the varying use of diagnostic investigation in urinary tract tumours. Further data on stage at diagnosis can help to elucidate the influence of diagnostic intensity or early diagnosis on the survival patterns. PMID- 26421825 TI - Survival of adults with primary malignant brain tumours in Europe; Results of the EUROCARE-5 study. AB - BACKGROUND: Primary malignant brain tumours are rare but represent a serious health burden due to their poor survival. This manuscript describes the survival of malignant brain tumours in adults diagnosed 2000-2007 in Europe. METHODS: For this study we analysed patients archived in 86 European population-based cancer registries, followed up to 31st December 2008. Only primary malignant neuroepithelial brain tumours (with pathological confirmation) and primary malignant unspecified brain tumours without pathological confirmation were included. We estimated 1-year and 5-year relative survival (RS) weighted by age group and country. We also estimated country-specific and age-specific survival, together with survival differences between time periods (for 1999-2001, 2002-2004 and 2005-2007). RESULTS: Glioblastoma represents 49% of all brain tumours, followed by other/unspecified astrocytoma (18%), oligodendroglioma/oligoastrocytoma (9%), ependymoma (1.5%) and embryonal tumours (1%). Five-year RS was 20% for all tumours combined, but ranged from 58% for ependymoma to only 6% for glioblastoma and sharply decreased with increasing age. Differences between countries were relatively small, but generally RS in Ireland/United Kingdom (UK) and Eastern Europe was below the average. An increase in 1-year RS (up to 10-12%) was noted over time, being largest in Central and Northern Europe in patients between 45 and 74years of age. CONCLUSIONS: Despite an increase in 1-year RS in most European regions, the survival of primary malignant brain tumours is still poor. Disparities between countries were evident, being even larger at the end of the study period than at the beginning, suggesting differences in availability of the latest treatment modalities. PMID- 26421828 TI - Aluminum induces inflammatory and proteolytic alterations in human monocytic cell line. AB - The increasing exposure to aluminum has been linked with the development of different human pathologies (e.g., breast cancer, myofasciitis, neurodegenerative diseases), probably due to the consistent presence of aluminum salts in widely diffused cosmetic products and vaccines. However, the mechanisms underlying immunologic and proliferative alterations still remain unknown. In the present study we investigated the ability of different aluminum compounds (i.e., aluminum chloride vs Imject(r) Alum, a mixture of aluminum and magnesium hydroxide) to trigger both inflammatory and proteolytic responses in U-937 human monocytic cell line. We demonstrated, by multiplex immunoassay analyses, that monocytic cells treated with both Imject Alum and aluminum chloride showed different and peculiar expression profiles of 27 inflammatory mediators and 5 matrix metalloproteinases, with respect to untreated control cells. In particular, we found dose-dependent significantly increased levels of pro-inflammatory cytokines, growth factors, and chemoattractant chemokines; whereas among metalloproteinases, only collagenolytic protease showed a significant dose-dependent increase in Imject-treated cells with respect to controls and Al-chloride treated cells. Noteworthy, we found only in Imject Alum-treated cells the significant positive correlations among collagenolytic metalloproteinase and increased expression of pro-inflammatory chemokines, suggesting a possible involvement of aluminum in regulating the acute inflammatory responses. In agreement to emerging evidences, for the first time we demonstrated that the treatment of monocyte cells with aluminum-based adjuvant is able to induce an inflammatory status and a proteolytic cascade activation. In fact, the cell treatment with Imject Alum induced increased levels of several cytokines and proteinases, suggesting these monocyte mediators as possible biomarkers for aluminum-linked diseases. The identification of the biochemical pathways involved in Al-induced cell injury pave the way for improving the knowledge on the potential impact of aluminum in human physio-pathology. PMID- 26421829 TI - Tremor in multiple sclerosis: The intriguing role of the cerebellum. AB - Tremor is frequently encountered in multiple sclerosis (MS) patients. However, its underlying pathophysiological mechanisms remain poorly understood. Our aim was to assess the potential role of the cerebellum and brain stem structures in the generation of MS tremor.We performed accelerometric (ACC) and electromyographic(EMG) assessment of tremor in 32MS patients with manual clumsiness. In addition to clinical examination, patients underwent a neurophysiological exploration of the brainstem and cerebellar functions,which consisted of blink and masseter inhibitory reflexes, cerebello-thalamo-cortical inhibition (CTCi), and somatosensory evoked potentials. Tremor was clinically visible in 18 patients and absent in 14. Patients with visible tremor had more severe score of ataxia and clinical signs of cerebellar dysfunction, as well as a more reduced CTCi on neurophysiological investigation. However, ACC and EMG recordings confirmed the presence of a real rhythmic activity in only one patient. In most MS patients, the clinically visible tremor corresponded to a pseudorhythmic activity without coupling between ACC and EMG recordings. Cerebellar dysfunction may contribute to the occurrence of this pseudorhythmic activity mimicking tremor during posture and movement execution. PMID- 26421830 TI - Effects of long-term whole-body vibration training on mobility in patients with multiple sclerosis: A meta-analysis of randomized controlled trials. AB - BACKGROUND: This meta-analysis evaluated feasibility and efficacy of long-term whole-body vibration (WBV) training in improving mobility of multiple sclerosis (MS) patients. METHODS: The primary search of this meta-analysis was conducted from four electronic databases (PubMed, Sport, CINAHL and Cochrane) in order to find all relevant randomized, controlled WBV intervention trials of MS patients published between January 2000 and October 2013. The primary search was complemented by a recent (Aug 2015) PubMed search. Data on patients' characteristics and type of WBV intervention were extracted from the published reports and supplementary material. Two researchers independently assessed the methodological quality of these studies and outcomes. Standardized mean differences based on the baseline-adjusted follow-up results were calculated as indicators of the effect size (ES) of WBV training. RESULTS: Seven randomized controlled trials (RCTs) involving 250 MS patients were found. Relevant group based data for analysis were available from 109 patients in WBV groups and from 100 control patients; 41 patients withdrew from the studies. Quality assessment revealed that the WBV training protocols were heterogeneous and the methodological quality of the studies was generally poor. We found borderline indication for improved 2-6 min walking endurance [ES=0.25 (95% CI=-0.06-0.0.55)] favoring WBV training whereas no benefits were indicated for short-distance (20m or less) walking speed or balance. CONCLUSION: This meta-analysis suggests that WBV training has potential in improving walking endurance in MS patients with low disability status. However, evidence for more severely disabled MS patients is lacking, and further well-designed, long-term RCTs with adequate sample sizes are needed. PMID- 26421826 TI - Survival patterns in lung and pleural cancer in Europe 1999-2007: Results from the EUROCARE-5 study. AB - BACKGROUND: Survival of patients diagnosed with lung and pleura cancer is a relevant health care indicator which is related to the availability and access to early diagnosis and treatment facilities. Aim of this paper is to update lung and pleural cancer survival patterns and time trends in Europe using the EUROCARE-5 database. METHODS: Data on adults diagnosed with lung and pleural cancer from 87 European cancer registries in 28 countries were analysed. Relative survival (RS) in 2000-2007 by country/region, age and gender, and over time trends in 1999-2007 were estimated. RESULTS: Lung cancer survival is poor everywhere in Europe, with a RS of 39% and 13% at 1 and 5years since diagnosis, respectively. A geographical variability is present across European areas with a maximum regional difference of 12 and 5 percentage points in 1-year and 5-year RS respectively. Pleural cancer represents 4% of cases included in the present study with 7% 5-year RS overall in Europe. Most pleural cancers (83%) are microscopically verified mesotheliomas. Survival for both cancers decreases with advancing age at diagnosis for both cancers. Slight increasing trends are described for lung cancer. Survival over time is higher for squamous cell carcinoma and adenocarcinomas than for small and large cell carcinoma; and better among women than men. CONCLUSIONS: Despite the generalised although slight increase, survival of lung and pleural cancer patients still remains poor in European countries. Priority should be given to prevention, with tobacco control policies across Europe for lung cancer and banning asbestos exposure for pleural cancer, and in early diagnosis and better treatment. The management of mesothelioma needs a multidisciplinary team and standardised health care strategies. PMID- 26421827 TI - Survival variations by country and age for lymphoid and myeloid malignancies in Europe 2000-2007: Results of EUROCARE-5 population-based study. AB - BACKGROUND: Significant advances in the management of patients with lymphoid and myeloid malignancies entered clinical practice in the early 2000's. The EUROCARE 5 study database provides an opportunity to assess the impact of these changes at the population level by country in Europe. We provide survival estimates for clinically relevant haematological malignancies (HM), using the International Classification of Diseases for Oncology 3, by country, gender and age in Europe. METHODS: We estimated age-standardised relative survival using the complete cohort approach for 625,000 adult patients diagnosed in 2000-2007 and followed up to 2008. Survival information was provided by 89 participating cancer registries from 29 European countries. Mean survival in Europe was calculated as the population weighted average of country-specific estimates. RESULTS: On average in Europe, 5-year relative survival was highest for Hodgkin lymphoma (81%; 40,625 cases), poorest for acute myeloid leukaemia (17%; 57,026 cases), and intermediate for non-Hodgkin lymphoma (59%; 329,204 cases), chronic myeloid leukaemia (53%; 17,713 cases) and plasma cell neoplasms (39%; 94,024 cases). Survival was generally lower in Eastern Europe and highest in Central and Northern Europe. Wider between country differences (>10%) were observed for malignancies that benefited from therapeutic advances, such as chronic myeloid leukaemia, chronic lymphocytic leukaemia, follicular lymphoma, diffuse large B-cell lymphoma and multiple myeloma. Lower differences (<10%) were observed for Hodgkin lymphoma. CONCLUSIONS: Delayed or reduced access to innovative and appropriate therapies could plausibly have contributed to the observed geographical disparities between European regions and countries. Population based survival by morphological sub type is important for measuring outcomes of HM management. To better inform quality of care research, the collection of detailed clinical information at the population level should be prioritised. PMID- 26421831 TI - Decreased regional cerebral blood flow in the bilateral thalami and medulla oblongata determined by an easy Z-score (eZIS) analysis of (99m)Tc-ECD-SPECT images in a case of MM2-thalamic-type sporadic Creutzfeldt-Jakob disease. AB - We report a case of autopsy-verified MM2-thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD) in a 46-year-old patient with a 16-month history of abnormal behavior, progressive dementia, insomnia, and speech disturbances without family history. Neurological examination revealed progressive dementia, frontal signs, insomnia, speech disturbance, gait disturbance and bilaterally exaggerated tendon reflexes. Both brain MRI and cerebrospinal fluid examinations, including 14-3-3 protein, yielded normal results. An easy Z-score (eZIS) analysis for (99m)Tc ethyl cysteinate dimer-single photon emission computed tomography ((99m)Tc-ECD SPECT) revealed decreased regional cerebral blood flow in the bilateral thalami and medulla oblongata. PRNP gene analysis revealed methionine homozygosity at codon 129 without mutation. Neuropathological examinations revealed severe neuronal loss, gliosis, and hypertrophic astrocytosis in the medial thalamus and inferior olivary nucleus. A slight depletion of Purkinje cells was observed. PrP immunostaining showed no obvious PrP deposits in the basal ganglia, thalamus, cerebellum, or brainstem; however, mild synaptic-type PrP deposits with some smaller plaque-like structures were only partially observed in the localized region of the frontal lobe with the spongiform change. Western blot analyses of protease-resistant PrP showed a type 2 pattern. In conclusion, eZIS analysis of (99m)Tc-ECD-SPECT images is useful for detecting both thalamic and medullary lesions. This is the first case of medullary lesions detected in a live patient with MM2-thalamic-type sCJD using SPECT. PMID- 26421832 TI - Detection of viable Mycobacterium avium subspecies paratuberculosis in powdered infant formula by phage-PCR and confirmed by culture. AB - Surveys from different parts of the world have reported that viable Mycobacterium avium subsp. paratuberculosis (MAP) can be cultured from approximately 2% of samples of retail pasteurised milk samples. Pasteurised milk is used for the production of powdered infant formula (PIF) and therefore there is a concern that MAP may also be present in these products. Several studies have previously reported the detection of MAP in PIF using PCR-based assays. However, culture based surveys of PIF have not detected viable MAP. Here we describe a phage amplification assay coupled with PCR (page-PCR) that can rapidly detect viable MAP in PIF. The results of a small survey showed that the phage-PCR assay detected viable MAP in 13% (4/32) of PIF samples. Culture detected viable MAP in 9% (3/32) PIF samples, all of which were also phage-PCR positive. Direct IS900 PCR detected MAP DNA in 22% (7/32) of PIF samples. The presence of viable MAP in PIF indicates that MAP either survived PIF manufacturing or that post-production contamination occurred. Irrespective of the route of MAP contamination, the presence of viable MAP in PIF is a potential public health concern. PMID- 26421833 TI - A meta-analysis of dehydroepiandrosterone supplementation among women with diminished ovarian reserve undergoing in vitro fertilization or intracytoplasmic sperm injection. AB - BACKGROUND: Evidence for the efficacy of dehydroepiandrosterone (DHEA) in improving ovarian responsiveness among poor responders, especially women with diminished ovarian reserve (DOR), remains inconsistent. OBJECTIVES: To evaluate the effectiveness of DHEA in women with DOR undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). SEARCH STRATEGY: PubMed and Embase were searched for reports published in any language before October 31, 2014, using keywords such as "DHEA," "poor ovarian response," "diminished ovarian reserve," and "premature ovarian aging." SELECTION CRITERIA: Studies that explored the effects of DHEA in women with DOR undergoing IVF/ICSI were included if they evaluated the number of oocytes retrieved and/or the rates of clinical pregnancy, implantation, and spontaneous abortion. DATA COLLECTION AND ANALYSIS: Risk ratios (RRs) and standardized mean differences with 95% confidence intervals (CIs) were calculated, combined with subgroup and sensitivity analyses. MAIN RESULTS: Eight studies were included. The use of DHEA increased the clinical pregnancy rate (RR 2.13; 95% CI 1.12-4.08). Similar results were obtained in subgroup analyses including randomized controlled trials and case-control studies (RR 2.57; 95% CI 1.43-4.63) and self-controlled studies (RR 3.95; 95% CI 1.28 12.19). However, the effects of DHEA on oocyte retrieval, implantation, and abortion were not significant. CONCLUSIONS: Supplementation with DHEA has a positive effect in women undergoing IVF/ICSI treatment for DOR. PMID- 26421834 TI - Overview of 3-year experience with large-scale electronic portal imaging device based 3-dimensional transit dosimetry. AB - PURPOSE: To assess the usefulness of electronic portal imaging device (EPID) based 3-dimensional (3D) transit dosimetry in a radiation therapy department by analyzing a large set of dose verification results. METHODS AND MATERIALS: In our institution, routine in vivo dose verification of all treatments is performed by means of 3D transit dosimetry using amorphous silicon EPIDs. The total 3D dose distribution is reconstructed using a back-projection algorithm and compared with the planned dose distribution using 3D gamma evaluation. Dose reconstruction and gamma evaluation software runs automatically in our clinic, and analysis results are (almost) immediately available. If a deviation exceeds our alert criteria, manual inspection is required. If necessary, additional phantom measurements are performed to separate patient-related errors from planning or delivery errors. Three-dimensional transit dosimetry results were analyzed per treatment site between 2012 and 2014 and the origin of the deviations was assessed. RESULTS: In total, 4689 of 15,076 plans (31%) exceeded the alert criteria between 2012 and 2014. These alerts were patient-related and attributable to limitations of our back-projection and dose calculation algorithm or to external sources. Clinically relevant deviations were detected for approximately 1 of 430 patient treatments. Most of these errors were because of anatomical changes or deviations from the routine clinical procedure and would not have been detected by pretreatment verification. Although cone beam computed tomography scans yielded information about anatomical changes, their effect on the dose delivery was assessed quantitatively by means of 3D in vivo dosimetry. CONCLUSIONS: EPID-based transit dosimetry is a fast and efficient dose verification technique. It provides more useful information and is less time-consuming than pretreatment verification measurements of intensity modulated radiation therapy and volumetric modulated arc therapy. Large-scale implementation of 3D transit dosimetry is therefore a powerful method to guarantee safe dose delivery during radiation therapy. PMID- 26421835 TI - Patient-reported outcomes after electron radiation treatment for early-stage palmar and plantar fibromatosis. AB - PURPOSE: Palmar and plantar fibromatosis (PPF) is a progressive connective tissue disorder of the hand/foot that often leads to debilitating functional impairment. In Europe, orthovoltage radiation therapy (RT) has been demonstrated to prevent local disease progression for up to 80% of patients with early-stage PPF. There are limited data reporting outcomes for populations outside of Europe or using electron RT. METHODS AND MATERIALS: Between 2008 and 2013, 44 early-stage PPF cases received RT. RT fields involved clinically defined targets encompassing involved areas (skin changes, cords, nodules) with at least 1.5-cm margins. En face electrons (6-12 MeV) and bolus (0.5-1 cm) were selected individually. Outcomes are reported for patients who participated in an institutional review board-approved standardized questionnaire and chart review. RESULTS: Thirty-three patients received 66 treatments (45 hands/15 feet and 6 reirradiations). Most frequent dose schemes were 21 Gy (3 Gy in 7 fractions) and 30 Gy (3 Gy in 10 fractions with 6- to 8-week breaks after 15 Gy). Median time to follow-up survey was 31 months. Disease progression at any location within or outside the RT treatment field occurred in 20 of 33 patients (61%). Fourteen of 60 sites (23%) developed in-field progression, but 4 sites were successfully reirradiated with final local control in 50 of 60 sites (83%). RT improved pretreatment symptoms of pain with strain at 30 of 37 sites (81%) and itch/burn sensations at 17 of 21 sites (81%). There were no reported grade >=2 late toxicities even with reirradiation. Patient reported overall success with treatment was 31 of 33 patients (94%). CONCLUSION: PPF is a progressive disease. En face electron RT is an effective therapy that stabilizes or improves symptoms in the majority of patients. Reirradiation can be considered as a treatment option for in-field progression. Patients report minimal toxicity and a high rate of satisfaction with treatment. PMID- 26421836 TI - Stereoselective Chlorination and Bromination of Enamides and Enamines via an Electrostatic Attraction Effect Using (1,1-Diacetoxyiodo)benzene and a Halide Source. AB - The direct chlorination and bromination of (E)-enamines and (Z)-enamides to the corresponding (Z)-configurated alpha-chloroenamines, alpha-bromoenamines, and alpha-chloroenamides have been realized using NiCl2.6H2O or tetrabutyl ammonium bromide as a halide source and (1,1-diacetoxyiodo)benzene as an oxidant. The high stereoselective reactions which produce products with only (Z)-configurations can be attributed to the structure of the intermediates, the conformations of which are controlled by the electrostatic attractions between the positively charged nitrogen atoms and the oxygen atoms of the carbonyl group. This type of electrostatic effect has never been reported in olefin halogenations. For this reason, the three-membered bromonium ion is only a minor intermediate in the enamine bromination pathway. These methods open pathways to prepare alpha chloroenamines and alpha-chloroenamides, which are not accessible via the currently used methods. PMID- 26421838 TI - Seasonal Differences in Relative Gene Expression of Putative Central Appetite Regulators in Arctic Charr (Salvelinus alpinus) Do Not Reflect Its Annual Feeding Cycle. AB - The highly seasonal anadromous Arctic charr (Salvelinus alpinus) was used to investigate the possible involvement of altered gene expression of brain neuropeptides in seasonal appetite regulation. Pro-opiomelanocortin (POMCA1, POMCA2), Cocaine and amphetamine regulated transcript (CART), Agouti related Peptide (AgRP), Neuropeptide Y (NPY) and Melanocortin Receptor 4 (MC4-R) genes were examined. The function of centrally expressed Leptin (Lep) in fish remains unclear, so Lep (LepA1, LepA2) and Leptin Receptor (LepR) genes were included in the investigation. In a ten months study gene expression was analysed in hypothalamus, mesencephalon and telencephalon of immature charr held under natural photoperiod (69 degrees 38'N) and ambient temperature and given excess feed. From April to the beginning of June the charr did not feed and lost weight, during July and August they were feeding and had a marked increase in weight and condition factor, and from November until the end of the study the charr lost appetite and decreased in weight and condition factor. Brain compartments were sampled from non-feeding charr (May), feeding charr (July), and non-feeding charr (January). Reverse transcription real-time quantitative PCR revealed temporal patterns of gene expression that differed across brain compartments. The non feeding charr (May, January) had a lower expression of the anorexigenic LepA1, MC4-R and LepR in hypothalamus and a higher expression of the orexigenic NPY and AgRP in mesencephalon, than the feeding charr (July). In the telencephalon, LepR was more highly expressed in January and May than in July. These results do not indicate that changes in central gene expression of the neuropeptides investigated here directly induce seasonal changes in feeding in Arctic charr. PMID- 26421837 TI - Hair and Scalp Disorders in a Tuscan Pediatric Dermatological Outpatient Clinic: A Clinical and Epidemiological Evaluation. AB - OBJECTIVES: The aim of this study was to evaluate the clinical and epidemiological profile of hair and scalp disorders in children referred to the Pediatric Dermatology Outpatient Clinic. MATERIALS AND METHODS: We performed a retrospective study of children with hair loss problems or scalp diseases who turned to the Pediatric Dermatology Service, Anna Meyer Pediatric Hospital, Florence, Italy, from January 1, 2009, to December 31, 2009. Demographics, personal and familial medical history, laboratory tests, clinical examination, final diagnosis and therapeutic interventions were obtained from the manual chart review. RESULTS: Of the 2,640 children who had access to the Pediatric Dermatology Service, 190 (7.19%) had a hair or scalp disorder. Among the 190 children, 60 (31.57%) presented with nonscarring alopecia, 56 (29.47%) had benign neoplasias, hamartomas or vascular malformations of the scalp, 51 (26.84%) had scalp inflammatory diseases, 14 (7.36%) had scarring alopecia, 5 (2.63%) had infections and 2 (1.05%) had infestation of the scalp. A case of constitutional hypertrichosis (0.52%) and also a case (0.52%) of lamellar ichthyosis were diagnosed. CONCLUSIONS: Our results underline that hair and scalp diseases represent an important percentage of admittances to a dermatological pediatric outpatient clinic. The variety and complexity of the diseases observed in this study included diseases commonly found also in adulthood. PMID- 26421839 TI - Incidence, Characteristics and Risk Factors of Acute Kidney Injury among Dengue Patients: A Retrospective Analysis. AB - BACKGROUND: Dengue induced acute kidney injury (AKI) imposes heavy burden of illness in terms of morbidity and mortality. A retrospective study was conducted to investigate incidence, characteristics, risk factors and clinical outcomes of AKI among dengue patients. METHODOLOGY: A total 667 dengue patients (2008-2013) were retrospectively evaluated and were stratified into AKI and non-AKI groups by using AKIN criteria. Two groups were compared by using appropriate statistical methods. RESULTS: There were 95 patients (14.2%) who had AKI, with AKIN-I, AKIN II and AKIN-III in 76.8%, 16.8% and 6.4% patients, respectively. Significant differences (P<0.05) in demographics and clinico-laboratory characteristics were observed between patients with and without AKI. Presence of dengue hemorrhagic fever [OR (95% CI): 8.0 (3.64-17.59), P<0.001],rhabdomyolysis [OR (95% CI): 7.9 (3.04-20.49)], multiple organ dysfunction OR (95% CI):17.9 (9.14-35.12), P<0.001], diabetes mellitus [OR (95% CI): 4.7 (1.12-19.86), P = 0.034], late hospitalization [OR (95% CI): 2.1 (1.12-19.86), P = 0.033] and use of nephrotoxic drugs [OR(95% CI): 2.9 (1.12-19.86), P = 0.006] were associated with AKI. Longer hospital stay (>3days) was also observed among AKI patients (OR = 1.3, P = 0.044) [corrected].Additionally, 48.4% AKI patients had renal insufficiencies at discharge that were signicantly associated with severe dengue, secondary infection and diabetes mellitus. Overall mortality was 1.2% and all fatal cases had AKI. CONCLUSIONS: The incidence of AKI is high at 14.2% among dengue patients, and those with AKI portended significant morbidity, mortality, longer hospital stay and poor renal outcomes. Our findings suggest that AKI in dengue is likely to increase healthcare burden that underscores the need of clinicians' alertness to this highly morbid and potentially fatal complication for optimal prevention and management. PMID- 26421840 TI - Thyroid metastasis from renal cell carcinoma-A case report after 9 years. AB - INTRODUCTION: The thyroid gland is a rare site of clinically detectable tumor metastasis. As thyroid tumors are usually assumed to be primary in origin, its recognition as a secondary is difficult. PRESENTATION OF CASE: We report a case of an 80-year old female who was referred to the Department of Surgery for a symptomatic thyroid nodule. Her medical history included a radical nephrectomy for renal cell carcinoma (RCC) nine years ago. During follow-up a pancreatic nodule was noted suggestive of a neuroendocrine tumor and the von Hippel-Lindau syndrome had to be ruled out. The fine-needle aspiration biopsy (FNAB) guided by ultrasound (US) of the thyroid nodule was inconclusive and a hemithyroidectomy and isthmectomy were performed. Histological examination revealed metastasis of a clear cell carcinoma. DISCUSSION: RCC disseminates in an unpredictable manner and can show late recurrences. Although secondary involvement of the thyroid gland by RCC is rare, it is still one of the more common neoplasms to metastasize to this site. There are no specific clinical features and few characteristic findings of metastatic thyroid carcinoma on imaging studies. FNAB is a useful procedure to diagnose metastatic thyroid cancer, but one should remain suspicious when the result for malignant cells is negative or indeterminate. After thyroidectomy the diagnosis of RCC is confirmed immunohistochemically. There is a clear survival benefit if a surgical approach to the thyroid metastasis is chosen. CONCLUSION: Thyroid metastasis should be considered in patients with a thyroid nodule and positive history for RCC. PMID- 26421841 TI - The Association between Maternal Reproductive Age and Progression of Refractive Error in Urban Students in Beijing. AB - PURPOSE: To investigate the association between maternal reproductive age and their children' refractive error progression in Chinese urban students. METHODS: The Beijing Myopia Progression Study was a three-year cohort investigation. Cycloplegic refraction of these students at both baseline and follow-up vision examinations, as well as non-cycloplegic refraction of their parents at baseline, were performed. Student's refractive change was defined as the cycloplegic spherical equivalent (SE) of the right eye at the final follow-up minus the cycloplegic SE of the right eye at baseline. RESULTS: At the final follow-up, 241 students (62.4%) were reexamined. 226 students (58.5%) with completed refractive data, as well as completed parental reproductive age data, were enrolled. The average paternal and maternal age increased from 29.4 years and 27.5 years in 1993-1994 to 32.6 years and 29.2 years in 2003-2004, respectively. In the multivariate analysis, students who were younger (beta = 0.08 diopter/year/year, P<0.001), with more myopic refraction at baseline (beta = 0.02 diopter/year/diopter, P = 0.01), and with older maternal reproductive age (beta = -0.18 diopter/year/decade, P = 0.01), had more myopic refractive change. After stratifying the parental reproductive age into quartile groups, children with older maternal reproductive age (trend test: P = 0.04) had more myopic refractive change, after adjusting for the children's age, baseline refraction, maternal refraction, and near work time. However, no significant association between myopic refractive change and paternal reproductive age was found. CONCLUSIONS: In this cohort, children with older maternal reproductive age had more myopic refractive change. This new risk factor for myopia progression may partially explain the faster myopic progression found in the Chinese population in recent decades. PMID- 26421842 TI - Hydration of Caffeine at High Temperature by Neutron Scattering and Simulation Studies. AB - The solvation of caffeine in water is examined with neutron diffraction experiments at 353 K. The experimental data, obtained by taking advantage of isotopic H/D substitution in water, were analyzed by empirical potential structure refinement (EPSR) in order to extract partial structure factors and site-site radial distribution functions. In parallel, molecular dynamics (MD) simulations were carried out to interpret the data and gain insight into the intermolecular interactions in the solutions and the solvation process. The results obtained with the two approaches evidence differences in the individual radial distribution functions, although both confirm the presence of caffeine stacks at this temperature. The two approaches point to different accessibility of water to the caffeine sites due to different stacking configurations. PMID- 26421843 TI - Using Trust to Establish a Secure Routing Model in Cognitive Radio Network. AB - Specific to the selective forwarding attack on routing in cognitive radio network, this paper proposes a trust-based secure routing model. Through monitoring nodes' forwarding behaviors, trusts of nodes are constructed to identify malicious nodes. In consideration of that routing selection-based model must be closely collaborative with spectrum allocation, a route request piggybacking available spectrum opportunities is sent to non-malicious nodes. In the routing decision phase, nodes' trusts are used to construct available path trusts and delay measurement is combined for making routing decisions. At the same time, according to the trust classification, different responses are made specific to their service requests. By adopting stricter punishment on malicious behaviors from non-trusted nodes, the cooperation of nodes in routing can be stimulated. Simulation results and analysis indicate that this model has good performance in network throughput and end-to-end delay under the selective forwarding attack. PMID- 26421844 TI - WormGender - Open-Source Software for Automatic Caenorhabditis elegans Sex Ratio Measurement. AB - Fast and quantitative analysis of animal phenotypes is one of the major challenges of current biology. Here we report the WormGender open-source software, which is designed for accurate quantification of sex ratio in Caenorhabditis elegans. The software functions include, i) automatic recognition and counting of adult hermaphrodites and males, ii) a manual inspection feature that enables manual correction of errors, and iii) flexibility to use new training images to optimize the software for different imaging conditions. We evaluated the performance of our software by comparing manual and automated assessment of sex ratio. Our data showed that the WormGender software provided overall accurate sex ratio measurements. We further demonstrated the usage of WormGender by quantifying the high incidence of male (him) phenotype in 27 mutant strains. Mutants of nine genes (brc-1, C30G12.6, cep-1, coh-3, him-3, him-5, him 8, skr-1, unc-86) showed significant him phenotype. The WormGender is written in Java and can be installed and run on both Windows and Mac platforms. The source code is freely available together with a user manual and sample data at http://www.QuantWorm.org/. The source code and sample data are also available at http://dx.doi.org/10.6084/m9.figshare.1541248. PMID- 26421845 TI - Electrostatic Charge on Flying Hummingbirds and Its Potential Role in Pollination. AB - Electrostatic phenomena are known to enhance both wind- and insect-mediated pollination, but have not yet been described for nectar-feeding vertebrates. Here we demonstrate that wild Anna's Hummingbirds (Calypte anna) can carry positive charges up to 800 pC while in flight (mean +/- s.d.: 66 +/- 129 pC). Triboelectric charging obtained by rubbing an isolated hummingbird wing against various plant structures generated charges up to 700 pC. A metal hummingbird model charged to 400 pC induced bending of floral stamens in four plants (Nicotiana, Hemerocallis, Penstemon, and Aloe spp.), and also attracted falling Lycopodium spores at distances of < 2 mm. Electrostatic forces may therefore influence pollen transfer onto nectar-feeding birds. PMID- 26421846 TI - The Prediction and Validation of Small CDSs Expand the Gene Repertoire of the Smallest Known Eukaryotic Genomes. AB - The proper prediction of the gene catalogue of an organism is essential to obtain a representative snapshot of its overall lifestyle, especially when it is not amenable to culturing. Microsporidia are obligate intracellular, sometimes hard to culture, eukaryotic parasites known to infect members of every animal phylum. To date, sequencing and annotation of microsporidian genomes have revealed a poor gene complement with highly reduced gene sizes. In the present paper, we investigated whether such gene sizes may have induced biases for the methodologies used for genome annotation, with an emphasis on small coding sequence (CDS) gene prediction. Using better delineated intergenic regions from four Encephalitozoon genomes, we predicted de novo new small CDSs with sizes ranging from 78 to 255 bp (median 168) and corroborated these predictions by RACE PCR experiments in Encephalitozoon cuniculi. Most of the newly found genes are present in other distantly related microsporidian species, suggesting their biological relevance. The present study provides a better framework for annotating microsporidian genomes and to train and evaluate new computational methods dedicated at detecting ultra-small genes in various organisms. PMID- 26421848 TI - Relationship between Cerebral Microbleeds and Liver Stiffness Determined by Transient Elastography. AB - BACKGROUND & AIMS: Liver fibrosis is a multifactorial disease that can affect the development of cerebral small vessel diseases (SVDs) including cerebral microbleeds (CMBs), leukoaraiosis, and silent infarctions. Transient elastography can accurately assess the degree of liver fibrosis by measuring liver stiffness (LS). In the present study, we investigated the association between SVDs and LS values. METHODS: We recruited 300 participants (mean age 56 years, 170 men) who underwent a comprehensive medical health check-up between January 2011 and December 2012. Transient elastography was taken on the right lobe of the liver through intercostal space with patients lying in the dorsal decubitus position with the right arm in maximal abduction. Mild and significant fibrosis were defined as LS values >5.6 and >8.0 kPa, respectively. The presence of each SVD was determined using the FLAIR, GRE MR imaging as well as T1-, T2-weighted MR images. We tested whether the presence and burden of each type of SVD were different by LS values. RESULTS: Of the different types of SVDs, only the presence (p = 0.001) and number of CMBs (p<0.001) were positively associated with LS values. Multivariate analysis revealed that significant fibrosis (>8.0 kPa) was an independent predictor of CMBs (odds ratio 6.079, 95% confidence interval 1.489-24.819, p = 0.012). However, leukoaraiosis and silent infarctions were not associated with LS values (all p>0.05). CONCLUSIONS: The degree of liver fibrosis, as assessed using transient elastography, was independently associated with the presence and burden of CMBs in healthy, asymptomatic participants. Understanding the link between the brain and liver may advance future research on the pathomechanisms of CMBs. PMID- 26421847 TI - High-Resolution Analyses of Human Leukocyte Antigens Allele and Haplotype Frequencies Based on 169,995 Volunteers from the China Bone Marrow Donor Registry Program. AB - Allogeneic hematopoietic stem cell transplantation is a widely used and effective therapy for hematopoietic malignant diseases and numerous other disorders. High resolution human leukocyte antigen (HLA) haplotype frequency distributions not only facilitate individual donor searches but also determine the probability with which a particular patient can find HLA-matched donors in a registry. The frequencies of the HLA-A, -B, -C, -DRB1, and -DQB1 alleles and haplotypes were estimated among 169,995 Chinese volunteers using the sequencing-based typing (SBT) method. Totals of 191 HLA-A, 244 HLA-B, 146 HLA-C, 143 HLA-DRB1 and 47 HLA DQB1 alleles were observed, which accounted for 6.98%, 7.06%, 6.46%, 9.11% and 7.91%, respectively, of the alleles in each locus in the world (IMGT 3.16 Release, Apr. 2014). Among the 100 most common haplotypes from the 169,995 individuals, nine distinct haplotypes displayed significant regionally specific distributions. Among these, three were predominant in the South China region (i.e., the 20th, 31st, and 81sthaplotypes), another three were predominant in the Southwest China region (i.e., the 68th, 79th, and 95th haplotypes), one was predominant in the South and Southwest China regions (the 18th haplotype), one was relatively common in the Northeast and North China regions (the 94th haplotype), and one was common in the Northeast, North and Northwest China (the 40th haplotype). In conclusion, this is the first to analyze high-resolution HLA diversities across the entire country of China, based on a detailed and complete data set that covered 31 provinces, autonomous regions, and municipalities. Specifically, we also evaluated the HLA matching probabilities within and between geographic regions and analyzed the regional differences in the HLA diversities in China. We believe that the data presented in this study might be useful for unrelated HLA-matched donor searches, donor registry planning, population genetic studies, and anthropogenesis studies. PMID- 26421849 TI - Quality of Animal Experiments in Anti-Angiogenic Cancer Drug Development--A Systematic Review. AB - Translation from preclinical animal research to clinical bedside has proven to be difficult to impossible in many fields of research (e.g. acute stroke, ALS and HIV vaccination development) with oncology showing particularly low translation rates (5% vs. 20% for cardiovascular diseases). Several investigations on published preclinical animal research have revealed that apart from plain species differences, translational problems can arise from low study quality (e.g. study design) or non-representative experimental conditions (e.g. treatment schedule). This review assessed the published experimental circumstances and quality of anti angiogenic cancer drug development in 232 in vivo studies. The quality of study design was often insufficient; at least the information published about the experiments was not satisfactory in most cases. There was no quality improvement over time, with the exception of conflict of interest statements. This increase presumably arose mainly because journal guidelines request such statements more often recently. Visual inspection of data and a cluster analysis confirmed a trend described in literature that low study quality tends to overestimate study outcome. It was also found that experimental outcome was more favorable when a potential drug was investigated as the main focus of a study, compared to drugs that were used as comparison interventions. We assume that this effect arises from the frequent neglect of blinding investigators towards treatment arms and refer to it as hypothesis bias. In conclusion, the reporting and presumably also the experimental performance of animal studies in drug development for oncology suffer from similar shortcomings as other fields of research (such as stroke or ALS). We consider it necessary to enforce experimental quality and reporting that corresponds to the level of clinical studies. It seems that only clear journal guidelines or guidelines from licensing authorities, where failure to fulfill prevents publication or experimental license, can help to improve this situation. PMID- 26421850 TI - Targeted gamma-Secretase Inhibition To Control the Notch Pathway in Renal Diseases. AB - Notch is a membrane inserted protein activated by the membrane-inserted gamma secretase proteolytic complex. The Notch pathway is a potential therapeutic target for the treatment of renal diseases but also controls the function of other cells, requiring cell-targeting of Notch antagonists. Toward selective targeting, we have developed the gamma-secretase inhibitor-based prodrugs 13a and 15a as substrates for gamma-glutamyltranspeptidase (gamma-GT) and/or gamma glutamylcyclotransferase (gamma-GCT) as well as aminopeptidase A (APA), which are overexpressed in renal diseases, and have evaluated them in experimental in vitro and in vivo models. In nondiseased mice, the cleavage product from Ac-gamma-Glu gamma-secretase inhibitor prodrug 13a (gamma-GT-targeting and gamma-GCT targeting) but not from Ac-alpha-Glu-gamma-secretase inhibitor prodrug 15a (APA targeting) accumulated in kidneys when compared to blood and liver. Potential nephroprotective effects of the gamma-secretase inhibitor targeted prodrugs were investigated in vivo in a mouse model of acute kidney injury, demonstrating that the expression of Notch1 and cleaved Notch1 could be selectively down-regulated upon treatment with the Ac-gamma-Glu-gamma-secretase-inhibitor 13a. PMID- 26421851 TI - Structured Reporting and Communication. PMID- 26421852 TI - Impact of Interactive e-Learning Modules on Appropriateness of Imaging Referrals: A Multicenter, Randomized, Crossover Study. AB - PURPOSE: Health care expenditure on diagnostic imaging investigations is increasing, and many tests are ordered inappropriately. Validated clinical decision rules (CDRs) for certain conditions are available to aid in assessing the need for imaging. However, awareness and utilization of CDRs are lacking. This study compared the efficacy and perceived impact of interactive e-learning modules versus static versions of CDRs, for learning about appropriate imaging referrals. METHODS: A multicenter, randomized, crossover trial was performed; participants were volunteer medical students and recent graduates. In week 1, group 1 received an e-learning module on appropriate imaging referrals for pulmonary embolism; group 2 received PDF versions of relevant CDRs, and an online quiz with feedback. In week 2, the groups crossed over, focusing on imaging referrals for cervical spine trauma in adults. Online assessments were administered to both groups at the end of each week, and participants completed an online questionnaire at the end of the trial. RESULTS: Group 1 (e-learning module) performed significantly better on the pulmonary embolism knowledge assessment. After the crossover, participants in group 2 (e-learning module) were significantly more likely to improve their scores in the assessment of cervical spine trauma knowledge. Both groups gave positive evaluations of the e-learning modules. CONCLUSIONS: Interactive e-learning was significantly more effective for learning in this cohort, compared with static CDRs. We believe that the authentic clinical scenarios, feedback, and integration provided by the e-learning modules contributed to their impact. This study has implications for implementation of e learning tools to facilitate appropriate referrals for imaging investigations in clinical practice. PMID- 26421853 TI - Insignificant Findings: Don't Leave Them Questioning the Significance. PMID- 26421854 TI - Simulation for Teaching and Assessment of Nodule Perception on Chest Radiography in Nonradiology Health Care Trainees. AB - PURPOSE: Simulation has been used as an educational and assessment tool in several fields, generally involving training of physical skills. To date, simulation has found limited application in teaching and assessment of skills related to image perception and interpretation. The goal of this pilot study was to evaluate the feasibility of simulation as a tool for teaching and assessment of skills related to perception of nodules on chest radiography. METHODS: This study received an exemption from the institutional review board. Subjects consisted of nonradiology health care trainees. Subjects underwent training and assessment of pulmonary nodule identification skills on chest radiographs at simulated radiology workstations. Subject performance was quantified by changes in area under the localization receiver operating characteristic curve. At the conclusion of the study, all subjects were given a questionnaire with five questions comparing learning at a simulated workstation with training using conventional materials. Statistical significance for questionnaire responses was tested using the Wilcoxon signed rank test. RESULTS: Subjects demonstrated statistically significant improvement in nodule identification after training at a simulated radiology workstation (change in area under the curve, 0.1079; P = .015). Subjects indicated that training on simulated radiology workstations was preferable to conventional training methods for all questions; P values for all questions were less than .01. CONCLUSIONS: Simulation may be a useful tool for teaching and assessment of skills related to medical image perception and interpretation. Further study is needed to determine which skills and trainee populations may be most amenable to training and assessment using simulation. PMID- 26421855 TI - [New Developments in Pharmacotherapy of Vertigo and Balance Disorders]. PMID- 26421856 TI - [Pharmacotherapy of Vestibular Disorders, Nystagmus and Cerebellar Disorders]. AB - There are currently different groups of drugs for the pharmacotherapy of vertigo, nystagmus and cerebellar disorders: antiemetics; anti-inflammatories, antimenieres, and antimigraineous medications and antidepressants, anticonvulsants, aminopyridines as well as acetyl-DL-leucine. In acute unilateral vestibulopathy, corticosteroids improve the recovery of peripheral vestibular function, but currently there is not sufficient evidence for a general recommendation. There is insufficient evidence to support the view that 16 mg t. i. d. or 48 mg t. i. d. betahistine has an effect in Meniere's disease. Therefore, higher dosages are recommended. In animal studies, it was shown that betahistine increases cochlear blood flow. In vestibular paroxysmia, oxcarbazepine was effective (one randomized controlled trial (RCT)). Aminopyridines are recommended for the treatment of downbeat nystagmus (two RCTs) and episodic ataxia type 2 (EA2, one RCT). There has been no RCT on the efficacy of beta-blockers or topiramate but one RCT on flunarizine in vestibular migraine. Based on clinical experience, a treatment analogous to that for migraine without aura can be recommended. Acetyl-DL-leucine improved cerebellar ataxia (two observational studies); it also accelerated central compensation in an animal model of acute unilateral lesion, but RCTs were negative. There are ongoing RCTs on treatment of vestibular paroxysmia with carbamazepine (VESPA), acute unilateral vestibulopathy with betahistine (BETAVEST), vestibular migraine with metoprolol (PROVEMIG), benign paroxysmal positional vertigo with vitamin D (VitD@BPPV), EA2 with 4-aminopyridine versus acetazolamide (EAT-2-TREAT), and cerebellar ataxias with acetyl-DL-leucine (ALCAT). PMID- 26421857 TI - [Evaluation of Psychiatric Disorders on the Basis of a SCID Screening]. AB - BACKGROUND: Psychiatric symptoms/syndromes such as depression, apathy, anxiety or psychotic episodes are present in a range of neurological disorders including Parkinson's disease. The Structured Clinical Interview for DSM-IV (SCID) represents the gold standard for the assessment of psychiatric disorders but is often too time-consuming for application in clinical practice. METHODS: 66 participants were examined using the screening items and the first two questions of section A of the SCID as well as the complete version of the SCID, part I. The accuracy of the screening and the complete SCID was evaluated, and logistic regression was conducted to analyze factors associated with measure disagreement between the two procedures. RESULTS: Overall, psychiatric disorders were identified by screening in 40/66 (60.6%), as against 31/66 (47.0%) using the complete SCID. Compared to the complete SCID, the sensitivity and specificity of the screening items were 88% and 59%, respectively. CONCLUSION: Based on its good sensitivity, the SCID screening may be used in clinical practice to yield an overview of psychiatric disorders that may require treatment. Due to its moderate specificity, however, the complete version of the SCID should be subsequently used in cases whenever the SCID screening is positive. In any case, the SCID screening must be regarded as inadequate for the detection of psychotic symptoms. PMID- 26421858 TI - [Hallucinogen Persisting Perception Disorder (HPPD) and Flashback Phenomena - Differential Diagnosis and Explanation Models]. AB - OBJECTIVE: The purpose of this article is to provide an overview of the current research on "Hallucinogen Persisting Perception Disorder" (HPPD) and "Flashback" phenomena. The definition and diagnostic features of "Flashback" and HPPD remained often unclear and since the 1960 s interchangeable. METHODS: Relevant literature was identified by means of a computerized MEDLINE search including the years 1994-2014. Finally 75 journal articles out were included in the review. RESULTS: Consistent with the ICD-10 (F16.70) definition "Flashback" is often used to describe brief visual perceptual, mood, and altered states of consciousness effects reminiscent of acute hallucinogen intoxication effects. Many users regard flashback phenomena as benign and even pleasant. HPPD is described in DSM-5 as a visual perceptual disorder, sometimes persisting for months or years causing severe individual distress. The prevalence of flashback and HPPD is unknown. It is considered to be remarkable in view of the relatively few case reports published out of millions of hallucinogen users since the 1960 s and 1970 s. Despite a multitude of etiological and therapeutic approaches the exact pathophysiological mechanisms underlying HPPD remain elusive. At present HPPD appears to be further a DSM-5-genuine but still puzzling disorder. The different consequences including new therapeutic approaches are discussed in clinical context. PMID- 26421859 TI - [Willingness of Psychotherapists in Private Practice to Treat Patients With Complex Post-Traumatic Stress and Dissociative Disorders]. AB - OBJECTIVE: Analyses of patient care with severe mental disorders. METHODS: Psychotherapists in private praxis were interviewed about their willingness to treat patients with a range of diagnoses in the context of post-traumatic disorders. RESULTS: Therapists were found more willing to treat "less severe" disorders, independent of years in practice, school of psychotherapy, a rural or urban practice setting. Therapists criticized the quality of their training and the health insurance review process. CONCLUSIONS: Therapists are generally willing to treat patients with severe mental disorders, but experience limits of competency attributed to training deficits. They further experience the bureaucratic procedures of the health insurance review process as barriers to accepting these patients into treatment.These results indicate that recently developed concepts of psychotherapy for these patient groups should be more intensively integrated into the existing training curricula. Furthermore, a simplified health insurance review process ought to be considered. PMID- 26421860 TI - [Relevance of Magnet Resonance Tomography in the Diagnosis and Assessment of Course of Disease in Patients with Multiple Sclerosis]. AB - Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with a substantial destructive axonal component that is responsible for the permanent disability accumulating during the course of the disease. Magnetic resonance imaging (MRI) has become the most important method in the diagnosis of MS. The high sensitivity of the MRI permits to detect focal and diffuse inflammatory disease involvement in vivo. In clinical routine the detection and quantification of focal pathology contributes substantially to an early diagnosis of MS. The detection of a substantial lesion load at the beginning of the disease increases the probability of an early conversion to clinically definite MS and the risk of accumulating disability in the first years of the disease. In 2001 this diagnostic and prognostic gain of information at an early stage of the disease resulted in a conceptual shift regarding diagnostic criteria. This concept comprises clinical and MRI criteria. The current 2010 revised criteria follow the concept of substituting a clinical relapse by subclinical MRI activity and allow the diagnosis of MS from one single MRI after the first relapse. This diagnostic approach using MRI allows an early treatment within an appropriate window of treatment opportunity. PMID- 26421862 TI - Studies on human papillomavirus (HPV) 16 E2, E5 and E7 mRNA in HPV-positive tonsillar and base of tongue cancer in relation to clinical outcome and immunological parameters. AB - OBJECTIVES: Three-year survival is 80% for human papillomavirus (HPV) positive tonsillar and base of tongue squamous cell carcinoma (TSCC and BOTSCC) and higher (95-100%) in patients with tumors without HLA class I expression, or with high CD8(+) tumor-infiltrating lymphocyte (TIL) counts. The former paradoxical, the latter expected, but it is known that E5 and E7 can downregulate HLA class I expression. Furthermore, upon HPV integration, E2, sometimes in combination with E5 is lost. Here, HPV16 E2, E5 and E7 mRNA was therefore examined in relation to HLA class I expression, TIL counts and survival. PATIENTS AND METHODS: HPV16 DNA positive TSCC and BOTSCC biopsies, analyzed for HLA class I and CD8(+) TILs, of 133 patients, treated curatively between 2000 and 2011, were tested for HPV16 E2, E5 and E7 mRNA expression. Totally 127 samples could be evaluated and of these 117 patients, all with HPV16/E7-mRNA-positive tumors, were included in the final analysis. RESULTS: Most tumors (92%) expressed E7 mRNA, and of these 64% also expressed E2 and E5 mRNA. Patients with tumors lacking E2 mRNA had worse 3-year relapse and progression free survival (p<0.01 and p<0.05), while presence of E5 had no impact on clinical outcome. Furthermore, HLA class I expression and TILs were not correlated to E5 or to E2 mRNA expression. CONCLUSION: Lack of E2 but not E5 mRNA in HPV16 positive TSCC and BOTSCC was a negative prognostic marker. Presence of HPV16 E2, E5 and E7 mRNA expression was not correlated to HLA class I expression or CD8(+) TILs. PMID- 26421861 TI - Effect of a Cognitive-Behavioral Prevention Program on Depression 6 Years After Implementation Among At-Risk Adolescents: A Randomized Clinical Trial. AB - IMPORTANCE: Adolescents whose parents have a history of depression are at risk for developing depression and functional impairment. The long-term effects of prevention programs on adolescent depression and functioning are not known. OBJECTIVE: To determine whether a cognitive-behavioral prevention (CBP) program reduced the incidence of depressive episodes, increased depression-free days, and improved developmental competence 6 years after implementation. DESIGN, SETTING, AND PARTICIPANTS: A 4-site randomized clinical trial compared the effect of CBP plus usual care vs usual care, through follow-up 75 months after the intervention (88% retention), with recruitment from August 2003 through February 2006 at a health maintenance organization, university medical centers, and a community mental health center. A total of 316 participants were 13 to 17 years of age at enrollment and had at least 1 parent with current or prior depressive episodes. Participants could not be in a current depressive episode but had to have subsyndromal depressive symptoms or a prior depressive episode currently in remission. Analysis was conducted between August 2014 and June 2015. INTERVENTIONS: The CBP program consisted of 8 weekly 90-minute group sessions followed by 6 monthly continuation sessions. Usual care consisted of any family initiated mental health treatment. MAIN OUTCOMES AND MEASURES: The Depression Symptoms Rating scale was used to assess the primary outcome, new onsets of depressive episodes, and to calculate depression-free days. A modified Status Questionnaire assessed developmental competence (eg, academic or interpersonal) in young adulthood. RESULTS: Over the 75-month follow-up, youths assigned to CBP had a lower incidence of depression, adjusting for current parental depression at enrollment, site, and all interactions (hazard ratio, 0.71 [95% CI, 0.53-0.96]). The CBP program's overall significant effect was driven by a lower incidence of depressive episodes during the first 9 months after enrollment. The CBP program's benefit was seen in youths whose index parent was not depressed at enrollment, on depression incidence (hazard ratio, 0.54 [95% CI, 0.36-0.81]), depression-free days (d = 0.34, P = .01), and developmental competence (d = 0.36, P = .04); these effects on developmental competence were mediated via the CBP program's effect on depression-free days. CONCLUSIONS AND RELEVANCE: The effect of CBP on new onsets of depression was strongest early and was maintained throughout the follow-up period; developmental competence was positively affected 6 years later. The effectiveness of CBP may be enhanced by additional booster sessions and concomitant treatment of parental depression. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT00073671. PMID- 26421863 TI - Clinical implications of epigenetic regulation in oral cancer. AB - Oral cancer is a high incidence cancer which is of major public health concern in India being the most common cancer in males and fifth most common cancer in females in India, contributing to 26% of the global oral cancer burden. The major risk factors of oral cancer are tobacco, alcohol and high risk Human Papilloma Virus type 16/18. However, only 3-12% of the high risk individuals with dysplasia develop oral cancer. Thus, individual genomic variants representing the genomic constitution and epigenetic alterations play a critical role in the development of oral cancer. Extensive epigenetic studies on the molecular lesions including oncogenes, tumor suppressor genes, genes associated with apoptosis, DNA damage repair have been reported. The current review highlights epigenetic regulation with a focus on molecular biomarkers and epidrug therapy in oral cancer. Epigenetic regulation by hypermethylation, histone modifications and specific microRNAs are often associated with early events and advanced stages in oral cancer, and thus indicate epidrug therapy for intervention. The presence of epigenetic marks in oral lesions, cancers and tumor associated mucosa emphasizes indications as biomarkers and epidrugs with therapeutic potential for better patient management. PMID- 26421864 TI - Osteonecrosis of the jaw a new complication related to Ipilimumab. PMID- 26421865 TI - Effect of Poor Access to Water and Sanitation As Risk Factors for Soil Transmitted Helminth Infection: Selectiveness by the Infective Route. AB - BACKGROUND: Soil-transmitted helminth (STH) infections are a public health problem in resource-limited settings worldwide. Chronic STH infection impairs optimum learning and productivity, contributing to the perpetuation of the poverty-disease cycle. Regular massive drug administration (MDA) is the cardinal recommendation for its control; along with water, sanitation and hygiene (WASH) interventions. The impact of joint WASH interventions on STH infections has been reported; studies on the independent effect of WASH components are needed to contribute with the improvement of current recommendations for the control of STH. The aim of this study is to assess the association of lacking access to water and sanitation with STH infections, taking into account the differences in route of infection among species and the availability of adequate water and sanitation at home. METHODS AND FINDINGS: Cross-sectional study, conducted in Salta province, Argentina. During a deworming program that enrolled 6957 individuals; 771 were randomly selected for stool/serum sampling for parasitological and serological diagnosis of STH. Bivariate stratified analysis was performed to explore significant correlations between risk factors and STH infections grouped by mechanism of entry as skin-penetrators (hookworms and Strongyloides stercoralis) vs. orally-ingested (Ascaris lumbricoides and Trichuris trichiura). After controlling for potential confounders, unimproved sanitation was significantly associated with increased odds of infection of skin penetrators (adjusted odds ratio [aOR] = 3.9; 95% CI: 2.6-5.9). Unimproved drinking water was significantly associated with increased odds of infection of orally-ingested (aOR = 2.2; 95% CI: 1.3-3.7). CONCLUSIONS: Lack of safe water and proper sanitation pose a risk of STH infections that is distinct according to the route of entry to the human host used by each of the STH species. Interventions aimed to improve water and sanitation access should be highlighted in the recommendations for the control of STH. PMID- 26421866 TI - Association between NOx exposure and deaths caused by respiratory diseases in a medium-sized Brazilian city. AB - Exposure to nitrogen oxides (NOx) emitted by burning fossil fuels has been associated with respiratory diseases. We aimed to estimate the effects of NOx exposure on mortality owing to respiratory diseases in residents of Taubate, Sao Paulo, Brazil, of all ages and both sexes. This time-series ecological study from August 1, 2011 to July 31, 2012 used information on deaths caused by respiratory diseases obtained from the Health Department of Taubate. Estimated daily levels of pollutants (NOx, particulate matter, ozone, carbon monoxide) were obtained from the Centro de Previsao de Tempo e Estudos Climaticos Coupled Aerosol and Tracer Transport model to the Brazilian developments on the Regional Atmospheric Modeling System. These environmental variables were used to adjust the multipollutant model for apparent temperature. To estimate association between hospitalizations owing to asthma and air pollutants, generalized additive Poisson regression models were developed, with lags as much as 5 days. There were 385 deaths with a daily mean (+/-SD) of 1.05+/-1.03 (range: 0-5). Exposure to NOx was significantly associated with mortality owing to respiratory diseases: relative risk (RR)=1.035 (95% confidence interval [CI]: 1.008-1.063) for lag 2, RR=1.064 (95%CI: 1.017-1.112) lag 3, RR=1.055 (95%CI: 1.025-1.085) lag 4, and RR=1.042 (95%CI: 1.010-1.076) lag 5. A 3 ug/m3 reduction in NOx concentration resulted in a decrease of 10-18 percentage points in risk of death caused by respiratory diseases. Even at NOx concentrations below the acceptable standard, there is association with deaths caused by respiratory diseases. PMID- 26421867 TI - POD-1/Tcf21 overexpression reduces endogenous SF-1 and StAR expression in rat adrenal cells. AB - During gonad and adrenal development, the POD-1/capsulin/TCF21transcription factor negatively regulates SF-1/NR5A1expression, with higher SF-1 levels being associated with increased adrenal cell proliferation and tumorigenesis. In adrenocortical tumor cells, POD-1 binds to the SF-1 E-box promoter region, decreasing SF-1 expression. However, the modulation of SF-1 expression by POD-1 has not previously been described in normal adrenal cells. Here, we analyzed the basal expression of Pod-1 and Sf-1 in primary cultures of glomerulosa (G) and fasciculata/reticularis (F/R) cells isolated from male Sprague-Dawley rats, and investigated whether POD-1 overexpression modulates the expression of endogenous Sf-1 and its target genes in these cells. POD-1 overexpression, following the transfection of pCMVMycPod-1, significantly decreased the endogenous levels of Sf 1 mRNA and protein in F/R cells, but not in G cells, and also decreased the expression of the SF-1 target StAR in F/R cells. In G cells overexpressing POD-1, no modulation of the expression of SF-1 targets, StAR and CYP11B2, was observed. Our data showing that G and F/R cells respond differently to ectopic POD-1 expression emphasize the functional differences between the outer and inner zones of the adrenal cortex, and support the hypothesis that SF-1 is regulated by POD 1/Tcf21 in normal adrenocortical cells lacking the alterations in cellular physiology found in tumor cells. PMID- 26421868 TI - Optical coherence tomography imaging of the basal ganglia: feasibility and brief review. AB - Optical coherence tomography (OCT) is a promising medical imaging technique that uses light to capture real-time cross-sectional images from biological tissues in micrometer resolution. Commercially available optical coherence tomography systems are employed in diverse applications, including art conservation and diagnostic medicine, notably in cardiology and ophthalmology. Application of this technology in the brain may enable distinction between white matter and gray matter, and obtainment of detailed images from within the encephalon. We present, herein, the in vivo implementation of OCT imaging in the rat brain striatum. For this, two male 60-day-old rats (Rattus norvegicus, Albinus variation, Wistar) were stereotactically implanted with guide cannulas into the striatum to guide a 2.7-French diameter high-definition OCT imaging catheter (DragonflyTM, St. Jude Medical, USA). Obtained images were compared with corresponding histologically stained sections to collect imaging samples. A brief analysis of OCT technology and its current applications is also reported, as well as intra-cerebral OCT feasibility on brain mapping during neurosurgical procedures. PMID- 26421869 TI - Effects of exercise and metformin on the prevention of glucose intolerance: a comparative study. AB - We aimed to evaluate the effects of aerobic exercise training (4 days) and metformin exposure on acute glucose intolerance after dexamethasone treatment in rats. Forty-two adult male Wistar rats (8 weeks old) were divided randomly into four groups: sedentary control (SCT), sedentary dexamethasone-treated (SDX), training dexamethasone-treated (DPE), and dexamethasone and metformin treated group (DMT). Glucose tolerance tests and in situ liver perfusion were undertaken on fasting rats to obtain glucose profiles. The DPE group displayed a significant decrease in glucose values compared with the SDX group. Average glucose levels in the DPE group did not differ from those of the DMT group, so we suggest that exercise training corrects dexamethasone-induced glucose intolerance and improves glucose profiles in a similar manner to that observed with metformin. These data suggest that exercise may prevent the development of glucose intolerance induced by dexamethasone in rats to a similar magnitude to that observed after metformin treatment. PMID- 26421870 TI - Correlation of cadherin-17 protein expression with clinicopathological features and prognosis of patients with sporadic gastric cancer. AB - This study aimed to explore the correlations between cadherin-17 (CDH17) protein expression and the clinicopathological features and prognosis of patients with sporadic gastric cancer (GC). Nine relevant studies of 1,960 patients were identified using electronic database searches supplemented with a manual search in strict accordance with inclusion and exclusion criteria. Statistical analyses were conducted using STATA 12.0 statistical software. Relative risks and 95% confidence intervals were determined, and Z test was used to measure the significance of the overall effect size. A total of nine eligible cohort studies were included in this meta-analysis. The expression of CDH17 in patients with diffuse GC was significantly higher than in those with intestinal-type GC. Moreover, the tumor depth of invasion differed significantly between patients with positive CDH17 (CDH17+) and negative CDH17 (CDH17-) GC. However, there were no significant differences between CDH17+ and CDH17- GC patients with respect to tumor node metastasis clinical stages, histological grades, or lymph node metastasis. Despite the differences in invasive depth, there was no significant difference in 5-year survival rates between CDH17+ and CDH17- GC patients. Our meta-analysis provides evidence that CDH17 protein expression may be associated with the development of GC, suggesting that CDH17 is an important biomarker that could be useful for the early diagnosis of GC. However, CDH17 levels do not appear to impact overall survival. PMID- 26421872 TI - Glycan-based diagnostic devices: current progress, challenges and perspectives. AB - Diagnosis is an essential launching point for accurate medical treatment, and rapid and accurate diagnostic approaches have become the increasingly vital goal inspiring developments in a variety of analytical methods. With increasing attention in the area of glycosciences, the roles that carbohydrates play in many diseases have been elucidated, and the use of carbohydrates as disease biomarkers has become an emerging diagnostics strategy. This review article does not intend to comprehensively include all carbohydrate-related diagnostics studies. We do, however, wish to describe carbohydrate recognition and the design of sensitive detecting devices, especially those developed recently, so that readers might better grasp the principles behind such devices and relevant detection strategies, particularly those favoring inexpensive, rapid, and point-of-care (POC) approaches. PMID- 26421871 TI - Activation of endogenous angiotensin converting enzyme 2 prevents early injuries induced by hyperglycemia in rat retina. AB - Diabetic retinopathy (DR) is a serious complication of diabetes mellitus that may result in blindness. We evaluated the effects of activation of endogenous angiotensin converting enzyme (ACE) 2 on the early stages of DR. Rats were administered an intravenous injection of streptozotocin to induce hyperglycemia. The ACE2 activator 1-[[2-(dimethylamino) ethyl] amino]-4-(hydroxymethyl)-7-[[(4 methylphenyl) sulfonyl] oxy]-9H-xanthone 9 (XNT) was administered by daily gavage. The death of retinal ganglion cells (RGC) was evaluated in histological sections, and retinal ACE2, caspase-3, and vascular endothelial growth factor (VEGF) expressions were analyzed by immunohistochemistry. XNT treatment increased ACE2 expression in retinas of hyperglycemic (HG) rats (control: 13.81+/-2.71 area%; HG: 14.29+/-4.30 area%; HG+XNT: 26.87+/-1.86 area%; P<0.05). Importantly, ACE2 activation significantly increased the RCG number in comparison with HG animals (control: 553.5+/-14.29; HG: 530.8+/-10.3 cells; HG+XNT: 575.3+/-16.5 cells; P<0.05). This effect was accompanied by a reduction in the expression of caspase-3 in RGC of the HG+XNT group when compared with untreated HG rats (control: 18.74+/-1.59; HG: 38.39+/-3.39 area%; HG+XNT: 27.83+/-2.80 area%; P<0.05). Treatment with XNT did not alter the VEGF expression in HG animals (P>0.05). Altogether, these findings indicate that activation of ACE2 reduced the death of retinal ganglion cells by apoptosis in HG rats. PMID- 26421874 TI - Sc2O@C(2v)(5)-C80: Dimetallic Oxide Cluster Inside a C80 Fullerene Cage. AB - A new oxide cluster fullerene, Sc2O@C(2v)(5)-C80, has been isolated and characterized by mass spectrometry, UV-vis-NIR absorption spectroscopy, cyclic voltammetry, (45)Sc NMR, DFT calculations, and single crystal X-ray diffraction. The crystallographic analysis unambiguously elucidated that the cage symmetry was assigned to C(2v)(5)-C80 and suggests that the Sc2O cluster is ordered inside the cage. The crystallographic data further reveals that the Sc1-O-Sc2 angle is much larger than that found in Sc2O@T(d)(19151)-C76 but almost comparable to that in Sc2O@Cs(6)-C82, suggesting that the endohedral Sc2O unit is flexible and can display large variation in the Sc-O-Sc angle, which depends on the size and shape of the cage. Computational studies show that there is a formal transfer of four electrons from the Sc2O unit to the C80 cage, i.e., (Sc2O)(4+)@(C80)(4-), and the HOMO and LUMO are mainly localized on the C80 framework. Moreover, thermal and entropic effects are seen to be relevant in the isomer selection. Comparative studies between the recently reported Sc2C2@C(2v)(5)-C80 and Sc2O@C(2v)(5)-C80 reveal that, despite their close structural resemblance, subtle differences exist on the crystal structures, and the clusters exert notable impact on their spectroscopic properties as well as interactions between the clusters and corresponding cages. PMID- 26421873 TI - pH Responsiveness of Multilayered Films and Membranes Made of Polysaccharides. AB - We investigated the pH-dependent properties of multilayered films made of chitosan (CHI) and alginate (ALG) and focused on their postassembly response to different pH environments using a quartz crystal microbalance with dissipation monitoring (QCM-D), swelling studies, zeta potential measurements, and dynamic mechanical analysis (DMA). In an acidic environment, the multilayers presented lower dissipation values and, consequently, higher moduli when compared with the values obtained for the pH used during the assembly (5.5). When the multilayers were exposed to alkaline environments, the opposite behavior occurred. These results were further corroborated by the ability of this multilayered system to exhibit a reversible swelling-deswelling behavior within the pH range from 3 to 9. The changes in the physicochemical properties of the multilayer system were gradual and different from those of individual solubilized polyelectrolytes. This behavior is related to electrostatic interactions between the ionizable groups combined with hydrogen bonding and hydrophobic interactions. Beyond the pH range of 3-9, the multilayers were stabilized by genipin cross-linking. The multilayered films also became more rigid while the pH responsiveness conferred by the ionizable moieties of the polyelectrolytes was preserved. This work demonstrates the versatility and feasibility of LbL methodology to generate inherently pH stimulus-responsive nanostructured films. Surface functionalization using pH responsiveness endows several biomedical applications with abilities such as drug delivery, diagnostics, microfluidics, biosensing, and biomimetic implantable membranes. PMID- 26421875 TI - Multicomponent Coculture System of Cancer Cells and Two Types of Stromal Cells for In Vitro Evaluation of Anticancer Drugs. AB - In vitro evaluation of anticancer drugs using cancer cells has long been performed for the development of novel drugs and the selection of effective drugs for different patients. Recent studies have suggested that tumor stromal cells affect the drug sensitivity of cancer cells; however, most conventional culture systems for drug evaluation lack stromal cells. In this study, we fabricated a multicomponent coculture system that takes account of cancer-stroma interactions for drug evaluation. In this system, small-cell and nonsmall-cell lung cancer cells embedded in collagen gel were cocultured with two types of stromal cells, including stromal fibroblasts and proinflammatory cytokine-secreting monocytes, thus recreating the in vivo cancer microenvironment. Cancer drug sensitivity was significantly altered by the presence of stromal cells. Fibroblasts induced resistance of cancer cells to anticancer drugs. Monocytes induced the upregulation of thymidine phosphorylase in cancer cells, promoting the conversion of an anticancer prodrug to a cytotoxic drug, and consequently enhanced the sensitivity of cancer cells to the anticancer prodrug. These results clearly show the importance of incorporating stromal cells into culture systems for drug evaluation. Our system will help to improve the accuracy of in vitro drug evaluation and provide useful information for the in vitro recreation of cancer microenvironments. PMID- 26421876 TI - Thermal and magnetic properties of iron oxide colloids: influence of surfactants. AB - Iron oxide nanoparticles (NPs) have been extensively studied in the last few decades for several biomedical applications such as magnetic resonance imaging, magnetic drug delivery and hyperthermia. Hyperthermia is a technique used for cancer treatment which consists in inducing a temperature of about 41-45 degrees C in cancerous cells through magnetic NPs and an external magnetic field. Chemical precipitation was used to produce iron oxide NPs 9 nm in size coated with oleic acid and trisodium citrate. The influence of both stabilizers on the heating ability and in vitro cytotoxicity of the produced iron oxide NPs was assessed. Physicochemical characterization of the samples confirmed that the used surfactants do not change the particles' average size and that the presence of the surfactants has a strong effect on both the magnetic properties and the heating ability. The heating ability of Fe3O4 NPs shows a proportional increase with the increase of iron concentration, although when coated with trisodium citrate or oleic acid the heating ability decreases. Cytotoxicity assays demonstrated that both pristine and trisodium citrate Fe3O4 samples do not reduce cell viability. However, oleic acid Fe3O4 strongly reduces cell viability, more drastically in the SaOs-2 cell line. The produced iron oxide NPs are suitable for cancer hyperthermia treatment and the use of a surfactant brings great advantages concerning the dispersion of NPs, also allowing better control of the hyperthermia temperature. PMID- 26421879 TI - Activation of Manganese Oxidants with Bisulfite for Enhanced Oxidation of Organic Contaminants: The Involvement of Mn(III). AB - MnO4(-) was activated by HSO3(-), resulting in a process that oxidizes organic contaminants at extraordinarily high rates. The permanganate/bisulfite (PM/BS) process oxidized phenol, ciprofloxacin, and methyl blue at pHini 5.0 with rates (kobs ~ 60-150 s(-1)) that were 5-6 orders of magnitude faster than those measured for permanganate alone, and ~5 to 7 orders of magnitude faster than conventional advanced oxidation processes for water treatment. Oxidation of phenol was fastest at pH 4.0, but still effective at pH 7.0, and only slightly slower when performed in tap water. A smaller, but still considerable (~3 orders of magnitude) increase in oxidation rates of methyl blue was observed with MnO2 activated by HSO3(-) (MO/BS). The above results, time-resolved spectroscopy of manganese species under various conditions, stoichiometric analysis of pH changes, and the effect of pyrophosphate on UV absorbance spectra suggest that the reactive intermediate(s) responsible for the extremely rapid oxidation of organic contaminants in the PM/BS process involve manganese(III) species with minimal stabilization by complexation. The PM/BS process may lead to a new category of advanced oxidation technologies based on contaminant oxidation by reactive manganese(III) species, rather than hydroxyl and sulfate radicals. PMID- 26421880 TI - Presentation, Endoscopic Management, and Significance of Hemostatic Clip Migration into the Lower Urinary Tract Following Radical Prostatectomy. AB - OBJECTIVES: Hemostatic clip migration into the lower urinary tract is a potential complication of radical prostatectomy that may cause symptoms, anxiety, and functional concern. Our objective was to evaluate initial presentation, endoscopic management, and outcomes of patients with hemostatic clip migration following radical prostatectomy. PATIENTS AND METHODS: We retrospectively identified all patients with hemostatic clip migration at our institution from 1977 to 2012. Patient records were then reviewed to identify causative factors, presentation, and long-term functional outcomes. RESULTS: Seventeen patients were identified with clip migration following radical prostatectomy. Eight (47%) patients had undergone open retropubic radical prostatectomy, and 9 (53%) had received robot-assisted radical prostatectomy. Hemostatic clip migration was diagnosed at a median of 8 (range, 1-252) months after prostatectomy. The majority of patients (n = 16, 94%) were symptomatic upon the diagnosis of clip migration. Symptoms included irritative urinary symptoms (n = 14, 82%), perineal pain (n = 3, 18%), hematuria (n = 2, 12%), and infection (n = 2, 12%). Five (29%) had concomitant bladder neck contracture. Fifteen (88%) underwent successful endoscopic clip removal, whereas 2 (13%) patients required a repeat operation for recurrent clip erosion. With a median follow-up of 1.6 years, the majority (n = 13, 87%) had complete symptom resolution after clip removal, although 2 patients had recurrent bladder neck contracture. CONCLUSIONS: Hemostatic clip migration after prostatectomy is often symptomatic with irritative voiding complaints, perineal pain, hematuria, infection, or bladder neck contracture. Fortunately, clips can be removed endoscopically with expected symptom resolution in the vast majority of patients. PMID- 26421877 TI - Role of Species-Specific Primary Structure Differences in Abeta42 Assembly and Neurotoxicity. AB - A variety of species express the amyloid beta-protein (Abeta (the term "Abeta" refers both to Abeta40 and Abeta42, whereas "Abeta40" and "Abeta42" refer to each isoform specifically). Those species expressing Abeta with primary structure identical to that expressed in humans have been found to develop amyloid deposits and Alzheimer's disease-like neuropathology. In contrast, the Abeta sequence in mice and rats contains three amino acid substitutions, Arg5Gly, His13Arg, and Tyr10Phe, which apparently prevent the development of AD-like neuropathology. Interestingly, the brush-tailed rat, Octodon degus, expresses Abeta containing only one of these substitutions, His13Arg, and does develop AD-like pathology. We investigate here the biophysical and biological properties of Abeta peptides from humans, mice (Mus musculus), and rats (Octodon degus). We find that each peptide displays statistical coil -> beta-sheet secondary structure transitions, transitory formation of hydrophobic surfaces, oligomerization, formation of annuli, protofibrils, and fibrils, and an inverse correlation between rate of aggregation and aggregate size (faster aggregation produced smaller aggregates). The rank order of assembly rate was mouse > rat > Abeta42. The rank order of neurotoxicity of assemblies formed by each peptide immediately after preparation was Abeta42 > mouse ~ rat. These data do not support long-standing hypotheses that the primary factor controlling development of AD-like neuropathology in rodents is Abeta sequence. Instead, the data support a hypothesis that assembly quaternary structure and organismal responses to toxic peptide assemblies mediate neuropathogenetic effects. The implication of this hypothesis is that a valid understanding of disease causation within a given system (organism, tissue, etc.) requires the coevaluation of both biophysical and cell biological properties of that system. PMID- 26421881 TI - An Anomalous Formation Pathway for Dislocation-Sulfur Vacancy Complexes in Polycrystalline Monolayer MoS2. AB - Two-dimensional (2D) molybdenum disulfide (MoS2) has attracted significant attention recently due to its direct bandgap semiconducting characteristics. Experimental studies on monolayer MoS2 show that S vacancy concentration varies greatly; while recent theoretical studies show that the formation energy of S vacancy is high and thus its concentration should be low. We perform density functional theory calculations to study the structures and energetics of vacancy and interstitial in both grain boundary (GB) and grain interior (GI) in monolayer MoS2 and uncover an anomalous formation pathway for dislocation-double S vacancy (V2S) complexes in MoS2. In this pathway, a (5|7) defect in an S-polar GB energetically favorably converts to a (4|6) defect, which possesses a duality: dislocation and double S vacancy. Its dislocation character allows it to glide into GI through thermal activation at high temperatures, bringing the double vacancy with it. Our findings here not only explain why VS is predominant in exfoliated 2D MoS2 and V2S is predominant in chemical vapor deposition (CVD) grown 2D MoS2 but also reproduce GB patterns in CVD-grown MoS2. The new pathway for sulfur vacancy formation revealed here provides important insights and guidelines for controlling the quality of monolayer MoS2. PMID- 26421882 TI - Exploring a Little-Known Pathway: Dermal Exposure to Phthalates in Indoor Air. PMID- 26421883 TI - Electrochemical Imprinted Polycrystalline Nickel-Nickel Oxide Half-Nanotube Modified Boron-Doped Diamond Electrode for the Detection of L-Serine. AB - This paper presents a novel and versatile method for the fabrication of half nanotubes (HNTs) using a flexible template-based nanofabrication method denoted as electrochemical imprinting. With use of this method, polycrystalline nickel and nickel(II) oxide (Ni-NiO) HNTs were synthesized using pulsed electrodeposition to transfer Ni, deposited by radio frequency magnetron sputtering on a porous polytetrafluoroethylene template, onto a boron-doped diamond (BDD) film. The Ni-NiO HNTs exhibited semicircular profiles along their entire lengths, with outer diameters of 50-120 nm and inner diameters of 20-50 nm. The HNT walls were formed of Ni and NiO nanoparticles. A biosensor for the detection of L-serine was fabricated using a BDD electrode modified with Ni-NiO HNTs, and the device demonstrated satisfactory analytical performance with high sensitivity (0.33 MUA MUM(-1)) and a low limit of detection (0.1 MUM). The biosensor also exhibited very good reproducibility and stability, as well as a high anti-interference ability against amino acids such as L-leucine, L tryptophan, L-cysteine, L-phenylalanine, L-arginine, and L-lysine. PMID- 26421884 TI - Synthesis of 6- and 7-Membered N-Heterocycles Using alpha-Phenylvinylsulfonium Salts. AB - A concise synthesis of stereodefined C-substituted morpholines, piperazines, azepines, and oxazepines in moderate to excellent yields (27% to 75%) is reported by reaction of 1,2- or 1,3-amino alcohol/1,2- or 1,3-diamine with an alpha phenylvinylsulfonium salt. High levels of regio- and diastereoselectivity (from 2:1 to >20:1) are observed through judicious choice of base (Cs2CO3) and solvent (CH2Cl2). Reactions are performed at ambient temperature and open to air and do not require anhydrous solvent. The deprotection of the N-sulfonamide protecting groups (N-Ts and N-Ns) is also demonstrated. Factors affecting regio- and diastereocontrol are discussed. PMID- 26421886 TI - Community Professionals' Response to Intimate Partner Violence Against Rural Older Women. AB - The purpose of this study was to examine rural community professionals' awareness, perceptions, and experience with intimate partner violence (IPV) in late life. Using standard focus group methodology, 87 community professionals were engaged in discussions about IPV in late life and their experience in providing support to victims. Responses were analyzed using an open coding process. Most professionals were not aware that IPV against older women was a problem in their communities, although were willing to offer support if asked. Support for older victims was provided within the purview of each profession. Referrals to other support services were made, although collaboration did not occur unless a health-related emergency arose in which professionals were mandated to work together. Findings provide the groundwork for further research on the education and training of community professionals on IPV in late life and the development of more integrated community-based service protocols to address this hidden, but widespread concern. PMID- 26421887 TI - Rheumatoid arthritis in elderly and young patients. PMID- 26421888 TI - Successful management of mad honey intoxication in a pregnant woman. PMID- 26421890 TI - OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY AND WIDEFIELD FUNDUS AUTOFLUORESCENCE IN PUNCTATE INNER CHOROIDOPATHY. AB - PURPOSE: To present the optical coherence tomography angiography and widefield fundus autofluorescence (FAF) imaging findings of a 34-year-old woman with punctate inner choroidopathy and Type 2 neovascularization. METHODS: In the retrospective case report, optical coherence tomography angiography imaging was performed with the RTVue XR Avanti (Optovue Inc, Fremont, CA) platform, which uses split spectrum amplitude decorrelation angiography to detect flow. PATIENTS: Single patient with the diagnosis of punctate inner choroidopathy. RESULTS: Spectral domain optical coherence tomography of the macula showed an inactive submacular scar but optical coherence tomography angiography demonstrated the fine detailed structure of a Type 2 neovascular membrane. Peripheral FAF abnormalities were detected despite the notable absence of these lesions with clinical examination and color fundus photography. These FAF findings were important in guiding clinical follow-up and response to therapy. The FAF lesions resolved with normal follow-up and treatment with oral naproxen. DISCUSSION: This is the first case report of optical coherence tomography angiography imaging of choroidal neovascularization associated with punctate inner choroidopathy and the first report of widefield FAF abnormalities in punctate inner choroidopathy. Optical coherence tomography angiography may provide a more noninvasive and sensitive imaging system for the evaluation of choroidal neovascularization than traditional fluorescein angiography and may provide a direct gauge of response to therapy. Widefield FAF may improve detection of inflammatory activity of retinal disease and monitoring of disease activity. PMID- 26421891 TI - MULTIMODAL IMAGING OF THE RETINA AND CHOROID IN SYSTEMIC AMYLOIDOSIS. AB - PURPOSE: To present the multimodal imaging findings of four patients with systemic amyloidosis, renal failure, and chorioretinopathy. METHODS: Retrospective analysis of four patients presenting to four institutions with evidence of amyloid induced chorioretinopathy. Fundus photography, autofluorescence, and spectral domain optical coherence tomography findings were studied and are presented. RESULTS: Four patients with biopsy-proven systemic amyloidosis demonstrated progressive chorioretinal degeneration with color fundus photography and autofluorescent imaging. With spectral domain optical coherence tomography analysis, amyloidosis-induced chorioretinopathy was characterized by a widened choriocapillaris band, choroidal infiltration, diffuse photoreceptor dysfunction, and thinning of the outer nuclear layer. CONCLUSION: Multimodal imaging including spectral domain optical coherence tomography analysis in eyes of patients with systemic amyloidosis shows deposition in the choroid. The deposition may cause a secondary toxic and or barrier effect resulting in diffuse retinal pigment epithelium and photoreceptor dysfunction. PMID- 26421889 TI - Determinants of outcome among patients with acute liver failure listed for liver transplantation in the United States. AB - Analyses of outcomes after acute liver failure (ALF) have typically included all ALF patients regardless of whether they were listed for liver transplantation (LT). We hypothesized that limiting analysis to listed patients might provide novel insights into factors associated with outcome, focusing attention on disease evolution after listing. Listed adult ALF patients enrolled in the US Acute Liver Failure Study Group registry between 2000 and 2013 were analyzed to determine baseline factors associated with 21-day outcomes after listing. We classified 617 patients (36% of overall ALF group) by 3-week outcome after study admission: 117 were spontaneous survivors (SSs; survival without LT), 108 died without LT, and 392 underwent LT. Only 22% of N-acetyl-p-aminophenol (APAP) ALF patients were listed; however, this group of 173 patients demonstrated greater illness severity: higher coma grades and more patients requiring ventilator, vasopressor, or renal replacement therapy support. Only 62/173 (36%) of APAP patients received a graft versus 66% for drug-induced liver injury patients, 86% for autoimmune-related ALF, and 71% for hepatitis B-related ALF. APAP patients were more likely to die than non-APAP patients (24% versus 17%), and the median time to death was sooner (2 versus 4.5 days). Despite greater severity of illness, the listed APAP group still had a SS rate of 40% versus 11% for non-APAP causes (P < 0.001). APAP outcomes evolve rapidly, mainly to SS or death. Patients with APAP ALF listed for LT had the highest death rate of any etiology, whereas more slowly evolving etiologies yielded higher LT rates and, consequently, fewer deaths. Decisions to list and transplant must be made early in all ALF patients, particularly in those with APAP ALF. PMID- 26421892 TI - MULTIMODAL IMAGING OF GEOGRAPHIC AREAS OF RETINAL DARKENING. AB - PURPOSE: To describe the clinical and multimodal imaging characteristics of a patient with unilateral asymptomatic dark retinal lesions corresponding to ellipsoid zone hyporeflectivity on optical coherence tomography (OCT). METHODS: The authors report a case of a 35-year-old man with HIV who presents with asymptomatic dark geographic retinal lesions corresponding to ellipsoid zone hyporeflectivity on OCT. Multimodal imaging techniques, including fundus color and widefield photographs, autofluorescence, spectral domain OCT (Spectralis, Heidelberg, Germany), prototype spectral domain OCT (Carl Zeiss Meditec, Dublin, CA) with OCT angiography, and en face images, were performed to evaluate and characterize the morphology of these lesions. RESULTS: Clinical examination and multimodal imaging reveal geographic darkening of the retina. Optical coherence tomography conveys hyporeflectivity of the ellipsoid zone band, which occurs abruptly and is present only in the areas of geographic retinal darkening. Optical coherence tomographic angiography shows a qualitatively similar appearance of the vasculature from the superficial retina through the avascular retina and the choriocapillaris, on both sides of the demarcation of retinal darkening, and also as compared to the unaffected eye. En face images from spectral domain OCT reveal an abrupt darkening of the tissue that localizes and is limited to the ellipsoid zone, with similar topographic appearance across the demarcation line. CONCLUSION: Geographic areas of darkening with photoreceptor hyporeflectivity have been described previously as "dark without pressure." In this case, the authors demonstrate photoreceptor hyporeflectivity that localizes to the clinically darkened areas, without topographic qualitative differences on en face spectral domain OCT images. The authors term these dark areas as geographic areas of retinal darkening because of ellipsoid nonreflectivity (GARDEN) spots. PMID- 26421893 TI - CHIKUNGUNYA-ASSOCIATED UVEITIS AND EXUDATIVE RETINAL DETACHMENT: A CASE REPORT. AB - PURPOSE: To report the first known case of bilateral granulomatous panuveitis secondary to chikungunya fever in the United States, acquired by a U.S. citizen traveling from an endemic region. METHODS: Case report. RESULTS: A 47-year-old woman presented with 10 days of bilateral decreased vision and photophobia concurrent with a febrile illness contracted while visiting the Dominican Republic. She presented with bilateral granulomatous panuveitis and exudative retinal detachments. Extensive workup was negative with the exception of positive chikungunya virus immunoglobulin G and immunoglobulin M titers. Initially, she responded to corticosteroid treatment but developed recurrent inflammation 3 months after completing the initial treatment. Immunomodulatory therapy was initiated at the time of recurrence, and with immunomodulatory therapy alone her inflammation has been controlled for 6 months. CONCLUSION: The prevalence of chikungunya fever-related uveitis is increasing with the recent epidemics throughout the Americas. Inflammation can occur during the febrile illness or months later and can manifest in a variety of ways. Posterior segment inflammation is more commonly a delayed presentation. Previous reports suggest that chikungunya fever-related uveitis responds well to corticosteroid therapy. This is the first reported case of recurrent inflammation. Given the wide variety of presentations, chikungunya fever-related uveitis should be included in the differential diagnosis of all at-risk patients presenting with acute ocular inflammation, particularly those traveling from endemic regions. PMID- 26421894 TI - CONGENITAL MACROVESSEL ASSOCIATED WITH CYSTOID MACULAR EDEMA AND AN IPSILATERAL INTRACRANIAL VENOUS MALFORMATION. AB - BACKGROUND/PURPOSE: To report a case of congenital retinal macrovessel associated with cystoid macular edema and an ipsilateral intracranial venous malformation. METHODS: Case report. RESULTS: A 58-year-old woman with decreased vision was found to have a congenital retinal venous macrovessel associated with cystoid macular edema because of tributary venous occlusion. The patient underwent neuroimaging and an ipsilateral venous malformation of the frontal lobe was discovered. CONCLUSION: Congenital retinal macrovessel can occasionally be complicated by vascular occlusion and macular edema. The authors report a case of congenital retinal macrovessel associated with an intracranial venous malformation. Clinicians should be aware of this potential association, and further studies are warranted. PMID- 26421895 TI - Molecular-Scale Tools for Studying Mechanotransduction. AB - Mechanical stimuli are known to be potent regulators of the form and function of cells and organisms. Although biological regulation has classically been understood in terms of principles from solution biochemistry, advancements in many fields have led to the development of a suite of techniques that are able to reveal the interplay between mechanical loading and changes in the biochemical properties of proteins in systems ranging from single molecules to living organisms. Here, we review these techniques and highlight the emergence of a new molecular-scale understanding of the mechanisms mediating the detection and response of cells to mechanical stimuli, a process termed mechanotransduction. Specifically, we focus on the role of subcellular adhesion structures in sensing the stiffness of the surrounding environment because this process is pertinent to applications in tissue engineering as well the onset of several mechanosensitive disease states, including cancer. PMID- 26421897 TI - Acute Epidural Hematoma Following Acute Subdural Hematoma Evacuation in a Child With Glanzmann Thrombasthenia. PMID- 26421898 TI - Smoking and reverse causation create an obesity paradox in cardiovascular disease. AB - OBJECTIVE: Many studies find that excess weight is associated with better survival among individuals with cardiovascular disease (CVD). Investigations were carried out to see whether this "obesity paradox" can be explained by biases. METHODS: The association between weight status and mortality in the US population ages 35 and above with CVD was investigated. Data were obtained from the National Health and Nutrition Examination Survey, 1988-2010, linked to mortality records through 2011. To minimize biases resulting from illness-induced weight loss, a reference category consisting of individuals who have always maintained normal weight was used. Age-standardized mortality rates and Cox models were estimated, comparing overweight/obesity (body mass index (BMI) >=25.0 kg m(-2) ) to normal weight (BMI 18.5-24.9 kg m(-2) ). RESULTS: The paradox was present among those with overweight/obesity at the time of survey (hazard ratio (HR) = 0.89; 95% confidence interval (CI) 0.78-1.01). However, when the reference category was limited to the always-normal-weight, the paradox disappeared (HR = 1.16; 95% CI 0.95-1.41). When analysis was additionally confined to never-smokers, mortality risks were significantly higher in the overweight/obesity group (HR = 1.51; 95% CI 1.07-2.15; P = 0.021). CONCLUSIONS: The findings provide support for the hypothesis that lower mortality among individuals with CVD and overweight/obesity is a product of biases involving reverse causation and confounding by smoking. PMID- 26421899 TI - Reply to defining the role of radiofrequency ablation and stereotactic ablative radiotherapy in patients with high-risk, early-stage non-small cell lung cancer. PMID- 26421896 TI - Biomaterial Strategies for Immunomodulation. AB - Strategies to enhance, suppress, or qualitatively shape the immune response are of importance for diverse biomedical applications, such as the development of new vaccines, treatments for autoimmune diseases and allergies, strategies for regenerative medicine, and immunotherapies for cancer. However, the intricate cellular and molecular signals regulating the immune system are major hurdles to predictably manipulating the immune response and developing safe and effective therapies. To meet this challenge, biomaterials are being developed that control how, where, and when immune cells are stimulated in vivo, and that can finely control their differentiation in vitro. We review recent advances in the field of biomaterials for immunomodulation, focusing particularly on designing biomaterials to provide controlled immunostimulation, targeting drugs and vaccines to lymphoid organs, and serving as scaffolds to organize immune cells and emulate lymphoid tissues. These ongoing efforts highlight the many ways in which biomaterials can be brought to bear to engineer the immune system. PMID- 26421900 TI - A decrease in protein level and a missense polymorphism of KIF17 are associated with schizophrenia. AB - It has been shown that the dysfunction of N-methyl-d-asparate (NMDA) receptors mediated neurotransmission plays a role in the pathophysiology of schizophrenia. Especially, GluN2B, a subunit of NMDA receptors, associated trafficking complex is altered in the prefrontal cortex of schizophrenia. The kinesin superfamily motor protein 17 (KIF17) is known as a transporter of NR2B.Previous studies showed that a structural variant of KIF17 gene is associated with a schizophrenic phenotype. Therefore, here we investigated KIF17 levels in postmortem prefrontal cortex in schizophrenia and the association of a missense polymorphism (Ile341Val) in KIF17 with schizophrenia. The protein expression of KIF17 in schizophrenic postmortem brains was significantly lower than that in controls. Next, the association of missense polymorphisms (rs631375, rs13375609, rs522496 and rs2296225) of KIF17 gene in 567 schizophrenia and 710 healthy subjects was examined. Both genotypic distribution and allelic frequency of rs2296225 polymorphism were significantly different between the chronic schizophrenia subjects and controls. However, our findings described above were not replicated with the independent subjects (555 schizophrenia and 814 healthy controls). Furthermore, the two alleles of rs2296225 polymorphism did not affect the mRNA expression of KIF17. These results suggest that the dysfunction of KIF17 might be involved in the pathophysiology of schizophrenia. PMID- 26421901 TI - Relationship between personality traits and perceived internalized stigma in bipolar patients and their treatment partners. AB - Internalized stigma of mental disorders has significant negative outcomes for patients with bipolar disorder and their families. The aim of this study is to evaluate the association between personality traits and internalized stigma of mental disorders in bipolar patients and their treatment partners. Five different questionnaires were utilized in this study: (1) Demographic data questionnaire, (2) Millon Clinical Multiaxial Inventory-III (MCMI-III) for personality traits, (3) Internalized Stigma of Mental Illness (ISMI) for stigma, (4) Self Report Manic Inventory (SRMI) for mania and (5) Center for Epidemiological Studies Depression Scale (CES-D) for depression. The scores of personality traits were combined to create externalizing and internalizing personality trait scores. Results showed that patients with bipolar disorder and their treatment partners both experienced internalized stigma of mental health disorders. There was a significant positive correlation between internalized stigma and internalizing personality traits, but not externalizing traits. In a multi-variate regression analysis, internalizing personality trait score was found to be a significant predictor of internalized stigma. In conclusion, patients with bipolar disorder and their treatment partners perceive higher level of internalized stigma of mental disorders if they have internalizing personality traits. PMID- 26421902 TI - A Tunable Dispersion-Free Terahertz Metadevice with Pancharatnam-Berry-Phase Enabled Modulation and Polarization Control. AB - It is extremely challenging to control the phase of light at will in free space. Here, Pancharatnam-Berry-phase-enabled, tunable phase control of free-space light is experimentally demonstrated in an ultrathin flexible dispersion-free metadevice. This metadevice enables the broadband conversion of linearly polarized light into any desired output polarization. PMID- 26421903 TI - Measles Outbreak Associated with Vaccine Failure in Adults--Federated States of Micronesia, February-August 2014. AB - On May 15, 2014, CDC was notified of two laboratory-confirmed measles cases in the Federated States of Micronesia (FSM), after 20 years with no reported measles. FSM was assisted by the World Health Organization (WHO), the United Nations Children's Fund (UNICEF), and CDC in investigating suspected cases, identify contacts, conduct analyses to guide outbreak vaccination response, and review vaccine cold chain practices. During February-August, three of FSM's four states reported measles cases: Kosrae (139 cases), Pohnpei (251), and Chuuk (3). Two thirds of cases occurred among adults aged >=20 years; of these, 49% had received >=2 doses of measles-containing vaccine (MCV). Apart from infants aged <12 months who were too young for routine vaccination, measles incidence was lower among children than adults. A review of current cold chain practices in Kosrae revealed minor weaknesses; however, an absence of historical cold chain maintenance records precluded an evaluation of earlier problems. Each state implemented vaccination campaigns targeting children as young as age 6 months through adults up to age 57 years. The preponderance of cases in this outbreak associated with vaccine failure in adults highlights the need for both thorough case investigation and epidemiologic analysis to guide outbreak response vaccination. Routine childhood vaccination coverage achieved in recent years limited the transmission of measles among children. Even in areas where transmission has not occurred for years, maintaining high 2-dose MCV coverage through routine and supplemental immunization is needed to prevent outbreaks resulting from increased measles susceptibility in the population. PMID- 26421904 TI - Creation of a head and neck Keloid quality of life questionnaire. AB - OBJECTIVES: Create a head-and-neck keloid quality of life (QOL) questionnaire. Demonstrate the reliability of the keloid-specific QOL scale according to test retest and internal consistency standards. STUDY DESIGN: Prospective cohort study. METHODS: Patients presenting to a keloid clinic in a tertiary referral institution between April 2012 and February 2013 were enrolled on their first visit. They were administered a questionnaire assessing demographics and a 21 item Likert keloid-specific survey assessing symptomatology, self-esteem, social functioning, and therapeutic motivation during their first three visits. Reliability of the keloid questionnaire was assessed for internal consistency (Cronbach's alpha) and test-retest correlations. Patients were treated with Kenalog steroid injections at each visit. The 126-point total score from the questionnaire was then compared to each subscale (physical symptoms, self-esteem, social function, and medical motivation) using a Pearson coefficient. RESULTS: The keloid QOL questionnaire showed a Cronbach's alpha of 0.87 for the overall questionnaire and ranged from 0.66 to 0.86 for individual questions. The test retest Pearson's R was 0.70 between visits 1 and 2 and 0.77 between visits 2 and 3. The Pearson correlation between symptoms, self-esteem, social functioning, and medical motivation subscales and the overall scale were 0.77, 0.73, 0.72, and 0.57, respectively. CONCLUSION: This head and neck keloid-specific QOL questionnaire proved to be a reproducible method of reliably assessing QOL burden on patients with head and neck keloids. LEVEL OF EVIDENCE: N/A. PMID- 26421905 TI - Psychometric properties of the Turkish version of the Internet Addiction Test (IAT). AB - OBJECTIVE: Of many instruments developed to assess Internet addiction, the Internet Addiction Test (IAT), an expanded version of the Internet Addiction Diagnostic Questionnaire (IADQ), has been the most widely used scale in English and non-English speaking populations. In this study, our aim was to investigate the psychometric properties of short and expanded versions of the IAT in a Turkish undergraduate sample. METHOD: Overall, 455 undergraduate students from Turkey aged between 18 and 30 participated in the study (63.53% were females). Explanatory and confirmatory factor analytic procedures investigated factor structures of the IADQ and IAT. The Internet Addiction Scale (IAS), Coping Inventory for Stressful Situations (CISS), Obsessive Compulsive Inventory-Revised (OCI-R) and Dissociative Experiences Scale (DES) were administered to assess convergent and divergent validities of the IADQ and IAT. Internal consistency and 15-day test-retest reliability were computed. RESULTS: In the factorial analytic investigation, we found a unidimensional factor structure for each measure fit the current data best. Significant but weak to moderate correlations of the IADQ and the IAT with the CISS, OCI-R and DES provided empirical evidence for divergent validity, whereas strong associations with the subscales of the IAS pointed to the convergent validity of Young's Internet addiction construct. Internal consistency of the IADQ was weak (alpha=0.67) and of the IAT was high (alpha=0.93). Temporal reliability of both instruments was very high (alpha=0.81 and alpha=0.87; respectively). CONCLUSION: The IAT revealed promising and sound psychometric properties in a Turkish sample. PMID- 26421906 TI - Reactions to Participating in Intimate Partner Violence and Minority Stress Research: A Mixed Methodological Study of Self-Identified Lesbian and Gay Emerging Adults. AB - The purpose of this study was to examine lesbian and gay (LG) young adults' reactions to participating in intimate partner violence (IPV) and minority stress research using a mixed methodological design. Participants were 277 U.S. college students currently involved in same-sex relationships and self-identified cisgender LG who completed an online questionnaire that included closed- and open ended questions. Results suggested that IPV research was well tolerated by the vast majority of participants; close to one in 10 participants reported being upset by the study questions, yet 75% of upset individuals reported some level of personal benefit. Reasons for upset as identified in the open-ended responses included thinking about personal experiences with IPV, as the perpetrator or friend of a victim, as well as thinking about the uncertainty of their future with their current partner. The correlates of emotional reactions and personal benefits to research participation were also examined, and these varied among gay men and lesbian women. Implications of these findings underscore the importance of accurate reflection of risk and benefits in informed consent documents as well as systematic evaluation of sexual minority participants' reactions to research participation in an effort to conduct ethically sound sexual science research. PMID- 26421907 TI - Single-Molecule Force Spectroscopy of an Artificial DNA Duplex Comprising a Silver(I)-Mediated Base Pair. AB - Single-molecule force spectroscopy measurements of a DNA duplex comprising an artificial metal-mediated base pair are reported. The measurements reveal that DNA duplexes comprising one central imidazole:imidazole mispair rupture at lower forces than a related duplex with canonical base pairs only. In contrast, DNA duplexes with one central imidazole-Ag(+)-imidazole base pair (formed by the addition of Ag(+) to the aforementioned duplex with the mispair) rupture at higher forces. These measurements indicate for the first time that the increase in thermal stability of a nucleic acid duplex that is observed upon the formation of a metal-mediated base pair is accompanied by a concomitant mechanical stabilization. In fact, the mechanical stabilization even exceeds the thermal one. This result indicates that nucleic acids with metal-mediated base pairs should be ideal building blocks for rigid functionalized DNA nano-objects. PMID- 26421908 TI - In reference to A new theory on the pathogenesis of acquired cholesteatoma: mucosal traction. PMID- 26421909 TI - A clinical score to rule out the concomitant presence of deep vein thrombosis in patients presenting with superficial vein thrombosis: The ICARO study. AB - BACKGROUND: Superficial vein thrombosis (SVT) is commonly encountered in clinical practice. Recent studies have suggested that the concomitant presence of deep vein thrombosis (DVT) or pulmonary embolism (PE) at the time of SVT diagnosis is not uncommon, thus increasing the interest on this disease. Whether this coexistence is predicted by specific risk factors remains unknown. AIM OF THE STUDY: To evaluate potential risk factors for DVT coexistence in patients presenting with acute objectively diagnosed SVT of the lower limbs and to develop a simple score entirely based on clinical variables to define the pre-test probability of DVT in these patients. METHODS: A multicenter, retrospective cohort study on SVT patients was conducted. Information was collected on clinical signs and on risk factors for venous thrombosis. RESULTS: 494 patients (mean age 56.3 +/- 17.9 years, 64.2% women) were included. Concomitant DVT was found in 16.0% of patients. After multivariate analysis, we identified 5 independent variables that were used to develop the ICARO score: active malignancy (1.5 points), limb edema (1.5 points), rope-like sign (-1 point), age >= 50 years (1 point), unprovoked SVT (-1 point). The prevalence of concomitant DVT was 1.1% in the low-probability category (< 0 points), 12.0% in the intermediate-probability category (0 to 1 points), and 32.3% in the high probability category (>= 1.5 points). CONCLUSIONS: The concomitant presence of major DVT is not negligible in patients with SVT. Our prediction score entirely based on simple clinical variables may be useful in assessing the risk of concomitant DVT in these patients. PMID- 26421911 TI - The role of high-involvement work practices and professional self-image in nursing recruits' turnover: A three-year prospective study. AB - BACKGROUND: The retention of young graduate nurses has become a major management challenge among hospitals in Western countries, which is amplified in a context of aging of populations and an increasing demand for services from patients. Moreover, as it has been reported that 50% of experienced nurses do not recommend a career in nursing, it is likely that retention problems occur not only at the level of the organization, but also at the level of the nursing profession. Although research has identified some predictors of nurse turnover, it is unclear which factors influence nurses' turnover from the organization and from the profession and how these factors interrelate with one another over time. OBJECTIVE: The present study extends previous research on nurse turnover by looking at the combined effects of nurses' pre-entry expectations, perceived high involvement work practices, and professional self-image, on intended and actual turnover from the organization and the profession. DESIGN AND METHODS: A prospective, longitudinal study of a sample of 160 graduated nurses affiliated with the Quebec Nurses' Association, Canada, was conducted. Participants were surveyed at three points in time, spread over a 3-year period. Graduated nurses' pre-entry expectations and professional self-image were surveyed at graduation (Time 1), while perceived high-involvement work practices, professional self image, and intention to leave the organization and the profession were captured six months following nurses' entry into the labor market (Time 2). Finally, participants were surveyed with respect to organizational and professional turnover three years after the Time 2 survey (Time 3). Structural equations modeling was used to examine the structure of the measures and the relationships among the constructs. RESULTS: Although pre-entry expectations had no effect, perceived high-involvement work practices were positively related to Time 2, professional self-image (controlling for pre-entry professional self-image). Moreover, high-involvement work practices exerted an indirect, negative effect on organizational and professional turnover through intention to leave the organization, and an indirect negative effect on intention to leave the profession through professional self-image. Nonetheless, professional self-image did not affect turnover. CONCLUSIONS: The current study indicates that hospitals and nurse directors can take advantage of developing high-involvement work practices as these practices foster a stronger professional self-image among nurses, thereby contributing to their sense of value as care providers, and indirectly reduce intended and actual turnover from the organization and the profession. PMID- 26421910 TI - Impact of a person-centred dementia care training programme on hospital staff attitudes, role efficacy and perceptions of caring for people with dementia: A repeated measures study. AB - BACKGROUND: People with dementia occupy up to one quarter of acute hospital beds. However, the quality of care delivered to this patient group is of national concern. Staff working in acute hospitals report lack of knowledge, skills and confidence in caring for people with dementia. There is limited evidence about the most effective approaches to supporting acute hospital staff to deliver more person-centred care. OBJECTIVES: This study aimed to evaluate the efficacy of a specialist training programme for acute hospital staff regarding improving attitudes, satisfaction and feelings of caring efficacy, in provision of care to people with dementia. DESIGN: A repeated measures design, with measures completed immediately prior to commencing training (T1), after completion of Foundation level training (T2: 4-6 weeks post-baseline), and following Intermediate level training (T3: 3-4 months post-baseline). SETTING: One NHS Trust in the North of England, UK. PARTICIPANTS: 40 acute hospital staff working in clinical roles, the majority of whom (90%) were nurses. METHODS: All participants received the 3.5 day Person-centred Care Training for Acute Hospitals (PCTAH) programme, comprised of two levels, Foundation (0.5 day) and Intermediate (3 days), delivered over a 3 4 months period. Staff demographics and previous exposure to dementia training were collected via a questionnaire. Staff attitudes were measured using the Approaches to Dementia Questionnaire (ADQ), satisfaction in caring for people with dementia was captured using the Staff Experiences of Working with Demented Residents questionnaire (SEWDR) and perceived caring efficacy was measured using the Caring Efficacy Scale (CES). RESULTS: The training programme was effective in producing a significant positive change on all three outcome measures following intermediate training compared to baseline. A significant positive effect was found on the ADQ between baseline and after completion of Foundation level training, but not for either of the other measures. CONCLUSIONS: Training acute hospital staff in Intermediate level person-centred dementia care is effective in producing significant improvements in attitudes towards and satisfaction in caring for people with dementia and feelings of caring efficacy. Foundation level training is effective in changing attitudes but does not seem to be sufficient to bring about change in satisfaction or caring efficacy. PMID- 26421912 TI - The influence of hormone therapies on type I and II endometrial cancer: A nationwide cohort study. AB - The influence of hormone therapy (HT) on risk for endometrial cancer is still casting which type of HT the clinicians recommend. It is unrevealed if HT has a differential influence on Type I versus Type II endometrial tumors, and little is known about the influence of, e.g., different routes of administration and about the influence of tibolone. We followed all Danish women aged 50-79 years without previous cancer or hysterectomy (n = 914,595) during 1995-2009. From the National Prescription Register, we computed HT exposures as time-dependent covariates. Incident endometrial cancers (n = 6,202) were identified from the National Cancer Registry: 4,972 Type I tumors and 500 Type II tumors. Incidence rate ratios (RRs) and 95% confidence intervals (Cls) were estimated by Poisson regression. Compared with women never on HT, the RR of endometrial cancer was increased with conjugated estrogen: 4.27 (1.92-9.52), nonconjugated estrogen: 2.00 (1.87-2.13), long cycle combined therapy: 2.89 (2.27-3.67), cyclic combined therapy: 2.06 (1.88-2.27), tibolone 3.56 (2.94-4.32), transdermal estrogen: 2.77 (2.12-3.62) and vaginal estrogen: 1.96 (1.77-2.17), but not with continuous combined therapy: 1.02 (0.87-1.20). In contrast, the risk of Type II tumors appeared decreased with continuous combined therapy: 0.45 (0.20-1.01), and estrogen therapy implied a nonsignificantly altered risk of 1.43 (0.85-2.41). Our findings support that continuous combined therapy is risk free for Type I tumors, while all other hormone therapies increase risk. In contrast, Type II endometrial cancer was less convincingly associated with hormone use, and continuous combined therapy appeared to decrease the risk. PMID- 26421913 TI - A (210)Pb-based chronological model for recent sediments with random entries of mass and activities: Model development. AB - Unsupported (210)Pb ((210)Pbexc) vs. mass depth profiles do not contain enough information as to extract a unique chronology when both, (210)Pbexc fluxes and mass sediment accumulation rates (SAR) independently vary with time. Restrictive assumptions are needed to develop a suitable dating tool. A statistical correlation between fluxes and SAR seems to be a quite general rule. This paper builds up a new (210)Pb-based dating tool by using such a statistical correlation. It operates with SAR and initial activities that closely follow normal distributions, what leads to the expected correlation between fluxes and SAR. An intelligent algorithm solves their best arrangement downcore to fit the experimental (210)Pbexc vs. mass depth profile, generating then solutions for the chronological line, and for the histories of SAR and fluxes. Parametric maps of a chi-function serve to find out the solution and to support error estimates. Optionally, the model's answers can be better constrained through the use of time markers. The performance of the model is illustrated with a synthetic core, and with real cases using published data for varved sediment cores. PMID- 26421914 TI - Children With ADHD Show Impairments in Multiple Stages of Information Processing in a Stroop Task: An ERP Study. AB - This study investigated the role of impaired inhibitory control as a factor underlying attention deficit hyperactivity disorder (ADHD). Children with ADHD and typically developing children completed an animal Stroop task while electroencephalogram (EEG) was recorded. The lateralized readiness potential and event-related brain potentials associated with perceptual and conflict processing were analyzed. Children with ADHD were slower to give correct responses irrespective of congruency, and slower to prepare correct responses in the incongruent condition. This delay could result from enhanced effort allocation at earlier processing stages, indicated by differences in P1, N1, and conflict sustained potential. Results suggest multiple deficits in information processing rather than a specific response inhibition impairment. PMID- 26421915 TI - Photochemical Oxidation of Thioketones by Singlet Molecular Oxygen Revisited: Insights into Photoproducts, Kinetics, and Reaction Mechanism. AB - Photosensitized oxidation of trimethyl[2.2.1]bicycloheptane thioketones by (1)O2 can yield more photoproducts than exclusively ketones and sulfines. Moreover, the ketone/sulfine ratio can be reversed when protic conditions and high thioketone concentrations are used, conversely to earlier results reporting ketones as the main photoproducts. A new mechanistic proposal for sulfine formation is suggested following intermolecular oxygen transfer from a peroxythiocarbonyl intermediate to a second thioketone molecule. Reaction quantum yields (10(-5)-10(-2)) depend on the reaction conditions and time. Sulfine production reaches a maximum at short irradiation times, whereas decomposition to the corresponding ketone is observed at long reaction times. When the thioketone substrate has a hydrogen atom at the alpha position a peroxyvinylsulfenic acid intermediate can be formed by proton transfer. Reaction of this intermediate with another thioketone molecule can yield more sulfine and its tautomeric vinylsulfenic acid, which dimerizes in situ to the thiosulfinate. The hydroperoxyl group of the peroxyvinylsulfenic acid can also rearrange to the alpha position, and by reaction with the starting thioketone, alpha-hydroxy thioketone and additional sulfine can be formed, while dehydration yields the alpha-oxo thioketone. In situ [2 + 2] and [4 + 2] self-cycloaddition of the alpha-oxo thioketone yields significant amounts of the corresponding adducts at prolonged irradiation times. PMID- 26421916 TI - Layer-by-layer assembly for biomedical applications in the last decade. AB - In the past two decades, the design and manufacture of nanostructured materials has been of tremendous interest to the scientific community for their application in the biomedical field. Among the available techniques, layer-by-layer (LBL) assembly has attracted considerable attention as a convenient method to fabricate functional coatings. Nowadays, more than 1000 scientific papers are published every year, tens of patents have been deposited and some commercial products based on LBL technology have become commercially available. LBL presents several advantages, such as (1): a precise control of the coating properties; (2) environmentally friendly, mild conditions and low-cost manufacturing; (3) versatility for coating all available surfaces; (4) obtainment of homogeneous film with controlled thickness; and (5) incorporation and controlled release of biomolecules/drugs. This paper critically reviews the scientific challenge of the last 10 years--functionalizing biomaterials by LBL to obtain appropriate properties for biomedical applications, in particular in tissue engineering (TE). The analysis of the state-of-the-art highlights the current techniques and the innovative materials for scaffold and medical device preparation that are opening the way for the preparation of LBL-functionalized substrates capable of modifying their surface properties for modulating cell interaction to improve substitution, repair or enhancement of tissue function. PMID- 26421917 TI - Mechanism of One-to-Many Molecular Recognition Accompanying Target-Dependent Structure Formation: For the Tumor Suppressor p53 Protein as an Example. AB - The new type of molecular recognition, in which an intrinsically disordered region (IDR) of a protein binds to many different target proteins with target dependent structure formation, is indispensable to the expression of life phenomena and also implicated in a number of diseases. According to the prevailing view, the physicochemical factors responsible for the binding are also target dependent. Here we consider an IDR of the tumor suppressor p53 protein, p53CTD, as an important example related to carcinogenesis and analyze its binding to four targets accompanying the formation of target-dependent structures (i.e., helix, sheet, and two different coils) using our statistical-mechanical method combined with molecular models for water. We find that all of the seemingly different binding processes are driven by a large gain of the translational, configurational entropy of water in the system. The gain originates from sufficiently high shape complementarity on the atomic level within the p53CTD target interface. It is also required that the electrostatic complementarity be ensured as much as possible to compensate for the dehydration. Such complementarities are achieved in harmony with the portion of the target to which p53CTD binds, leading to a large diversity of structures of p53CTD formed upon binding: If they are not achievable, the binding does not occur. This finding is made possible only by calculating the changes in thermodynamic quantities upon binding and decomposing them into physically insightful components. PMID- 26421918 TI - Genome-Wide Analysis and Expression Profiling of the Phospholipase C Gene Family in Soybean (Glycine max). AB - Phosphatidylinositol-specific phospholipase C (PI-PLC) hydrolyses phosphatidylinositol-4,5-bisphosphate to produce diacylglycerol and inositol 1,4,5-trisphosphate. It plays an important role in plant development and abiotic stress responses. However, systematic analysis and expression profiling of the phospholipase C (PLC) gene family in soybean have not been reported. In this study, 12 putative PLC genes were identified in the soybean genome. Soybean PLCs were found on chromosomes 2, 11, 14 and 18 and encoded 58.8-70.06 kD proteins. Expression pattern analysis by RT-PCR demonstrated that expression of the GmPLCs was induced by PEG, NaCl and saline-alkali treatments in roots and leaves. GmPLC transcripts accumulated specifically in roots after ABA treatment. Furthermore, GmPLC transcripts were analyzed in various tissues. The results showed that GmPLC7 was highly expressed in most tissues, whereas GmPLC12 was expressed in early pods specifically. In addition, subcellular localization analysis was carried out and confirmed that GmPLC10 was localized in the plasma membrane in Nicotiana benthamiana. Our genomic analysis of the soybean PLC family provides an insight into the regulation of abiotic stress responses and development. It also provides a solid foundation for the functional characterization of the soybean PLC gene family. PMID- 26421919 TI - Association of High-Resolution Manometry Metrics with the Symptoms of Achalasia and the Symptomatic Outcomes of Peroral Esophageal Myotomy. AB - BACKGROUND: High-resolution manometry (HRM) has improved the accuracy of manometry in detecting achalasia and has helped distinguish between clinically relevant subtypes. This study investigated whether HRM metrics correlate with the achalasia symptoms and symptomatic outcomes of peroral esophageal myotomy (POEM). METHODS: Of the 30 patients who were enrolled, 25 were treated with POEM, 12 of who underwent HRM after 3 months. All the patients completed the Eckardt score questionnaires, and those who underwent POEM were followed up for about 6 months. Pearson correlation was used to assess the relationship between the HRM metrics and symptoms and outcomes. KEY RESULTS: The integrated relaxation pressure (IRP) score positively correlated with the total Eckardt score, regurgitation score and weight loss score in all the patients, and with the weight loss score in type I achalasia. In 25 patients (10 patients, type I; 15 patients, type II) who underwent POEM, the total Eckardt scores and individual symptom scores significantly decreased after surgery. Changes in the Eckardt scores were similar between type I and type II. Further, the Eckardt scores and weight loss score changes were positively correlated with baseline IRP. Twelve patients (4 patients, type I; 8 patients, type II) underwent HRM again after POEM. IRP changed significantly after POEM, as did the DEP in type II. The IRP changes after POEM were positively correlated with the Eckardt score changes. CONCLUSIONS & INFERENCES: IRP is correlated with the symptoms and outcomes of achalasia patients. Thus, HRM is effective for assessing the severity of achalasia and can predict the efficacy of POEM. PMID- 26421920 TI - A Simple "Blood-Saving Bundle" Reduces Diagnostic Blood Loss and the Transfusion Rate in Mechanically Ventilated Patients. AB - INTRODUCTION: Aim of this study was to reduce blood loss caused by diagnostic blood sampling and to minimize the development of anemia in a high-risk group of mechanically ventilated medical intensive care patients. We therefore implemented a "blood-saving bundle" (BSB) combining a closed-loop arterial blood sampling system, smaller sampling tubes, reduced frequency of blood drawings, and reduced sample numbers. METHODS: The study included all patients from our medical ICU who were ventilated for more than 72 hours. Exclusion criteria were: acute or chronic anemia on admission, bleeding episode(s) during the ICU stay, or end-of-life therapy. The BSB was introduced in 2009 with training and educational support. Patients treated in 2008, before the introduction of the BSB, served as a control group (n = 41, 617 observation days), and were compared with patients treated in 2010 after the introduction of the BSB (BSB group, n = 50, 559 observation days). Primary endpoints were blood loss per day, and development of anemia. Secondary endpoints were numbers of blood transfusions, number of days on mechanical ventilation, and length of the ICU stay. RESULTS: Mean blood loss per ICU day was decreased from 43.3 ml (95% CI: 41.2 to 45.3 ml) in the controls to 15.0 ml (14.3 to 15.7 ml) in the BSB group (P < 0.001). The introduction of a closed-loop arterial blood sampling system was the major contributor to this effect. Mean hemoglobin concentrations showed no significant differences in both groups during the ICU stay. Hemoglobin values <9 g/dl, however, were recorded in 21.2% of observation days in the controls versus 15.4% in the BSB group (P = 0.01). Units of transfused red blood cells per 100 observation days decreased from 7 to 2.3 (P < 0.001). The mean number of ventilation days was 7.1 days (6.1 to 8.3 days) in the controls and 7.5 days (6.6 to 8.5 days) in the BSB group (P = NS). In total, patients in the BSB group stayed in ICU for a mean of 9.9 days (8.6 to 11.3 days), compared to a mean ICU stay of 13.0 days (10.9 to 15.4 days) in the control group (P = 0.014). Due to the longitudinal study design, however, we cannot exclude uncontrolled confounders affecting the transfusion frequency and mean ICU stay. CONCLUSION: Our BSB could be easily implemented and was able to reduce diagnostic blood loss. PMID- 26421921 TI - Design, Synthesis, and Pharmacological Evaluation of 5,6-Disubstituted Pyridin 2(1H)-one Derivatives as Phosphodiesterase 10A (PDE10A) Antagonists. AB - We report the design and synthesis of novel 5,6-diarylated pyridin-2(1H)-one derivatives as pharmacophoric PDE10A inhibitors. This highly potent molecular scaffold was developed from an inactive diarylpyridine-2-amine derivative 3b by extensive and systematic analogue synthesis and SAR analysis. Further optimization of the scaffold resulted in identification of pyridin-2(1H)-one 18b as a lead compound with good potency (IC50 = 1.6 nM) and selectivity (>6000-fold) over other related PDEs but with a poor pharmacokinetic profile. Careful metabolite profiling of 18b revealed that poor systemic exposure in rats (Cmax = 44 ng/mL; AUC0-t = 359 ng . h/mL) at 10 mg/kg was due to the formation of O glucuronide conjugate by phase 2 metabolism. The structure of the glucuronide metabolite was confirmed by retention time and LC-MS/MS fragmentation matching with the synthetic glucuronide 26. The problem of low exposure of 18b was effectively addressed by its conversion to an acetate prodrug 25b, which upon oral dosing resulted in an improved pharmacokinetic profile (Cmax = 359 ng.h/mL; AUC0-t = 2436 ng.h/mL) and a desirable brain to plasma ratio of 1.2. The prodrug 25b showed good efficacy in selected rodent models of psychosis. PMID- 26421922 TI - Endocytosed 2-Microglobulin Amyloid Fibrils Induce Necrosis and Apoptosis of Rabbit Synovial Fibroblasts by Disrupting Endosomal/Lysosomal Membranes: A Novel Mechanism on the Cytotoxicity of Amyloid Fibrils. AB - Dialysis-related amyloidosis is a major complication in long-term hemodialysis patients. In dialysis-related amyloidosis, beta2-microglobulin (beta2-m) amyloid fibrils deposit in the osteoarticular tissue, leading to carpal tunnel syndrome and destructive arthropathy with cystic bone lesions, but the mechanism by which these amyloid fibrils destruct bone and joint tissue is not fully understood. In this study, we assessed the cytotoxic effect of beta2-m amyloid fibrils on the cultured rabbit synovial fibroblasts. Under light microscopy, the cells treated with amyloid fibrils exhibited both necrotic and apoptotic changes, while the cells treated with beta2-m monomers and vehicle buffer exhibited no morphological changes. As compared to beta2-m monomers and vehicle buffer, beta2-m amyloid fibrils significantly reduced cellular viability as measured by the lactate dehydrogenase release assay and the 3-(4,5-di-methylthiazol-2-yl)-2,5 diphenyltetrazolium bromide reduction assay and significantly increased the percentage of apoptotic cells as measured by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method. beta2-m amyloid fibrils added to the medium adhered to cell surfaces, but did not disrupt artificial plasma membranes as measured by the liposome dye release assay. Interestingly, when the cells were incubated with amyloid fibrils for several hours, many endosomes/lysosomes filled with amyloid fibrils were observed under confocal laser microscopy and electron microscopy, Moreover, some endosomal/lysosomal membranes were disrupted by intravesicular fibrils, leading to the leakage of the fibrils into the cytosol and adjacent to mitochondria. Inhibition of actin dependent endocytosis by cytochalasin D attenuated the toxicity of amyloid fibrils. These results suggest that endocytosed beta2-m amyloid fibrils induce necrosis and apoptosis by disrupting endosomal/lysosomal membranes, and this novel mechanism on the cytotoxicity of amyloid fibrils is described. PMID- 26421923 TI - Extensive Hair-Shaft Elongation by Isolated Mouse Whisker Follicles in Very Long Term Gelfoam(r) Histoculture. AB - We have previously studied mouse whisker follicles in Gelfoam(r) histoculture to determine the role of nestin-expressing plutipotent stem cells, located within the follicle, in the growth of the follicular sensory nerve. Long-term Gelfoam(r) whisker histoculture enabled hair follicle nestin-expressing stem cells to promote the extensive elongation of the whisker sensory nerve, which contained axon fibers. Transgenic mice in which the nestin promoter drives green fluorescent protein (ND-GFP) were used as the source of the whiskers allowing imaging of the nestin-expressing stem cells as they formed the follicular sensory nerve. In the present report, we show that Gelfoam(r)-histocultured whisker follicles produced growing pigmented and unpigmented hair shafts. Hair-shaft length increased rapidly by day-4 and continued growing until at least day-12 after which the hair-shaft length was constant. By day-63 in histoculture, the number of ND-GFP hair follicle stem cells increased significantly and the follicles were intact. The present study shows that Gelfoam(r) histoculture can support extensive hair-shaft growth as well as hair follicle sensory-nerve growth from isolated hair follicles which were maintained over very long periods of time. Gelfoam(r) histoculture of hair follicles can provide a very long-term period for evaluating novel agents to promote hair growth. PMID- 26421924 TI - Conserved Motifs within Hepatitis C Virus Envelope (E2) RNA and Protein Independently Inhibit T Cell Activation. AB - T cell receptor (TCR) signaling is required for T-cell activation, proliferation, differentiation, and effector function. Hepatitis C virus (HCV) infection is associated with impaired T-cell function leading to persistent viremia, delayed and inconsistent antibody responses, and mild immune dysfunction. Although multiple factors appear to contribute to T-cell dysfunction, a role for HCV particles in this process has not been identified. Here, we show that incubation of primary human CD4+ and CD8+ T-cells with HCV RNA-containing serum, HCV-RNA containing extracellular vesicles (EVs), cell culture derived HCV particles (HCVcc) and HCV envelope pseudotyped retrovirus particles (HCVpp) inhibited TCR mediated signaling. Since HCVpp's contain only E1 and E2, we examined the effect of HCV E2 on TCR signaling pathways. HCV E2 expression recapitulated HCV particle induced TCR inhibition. A highly conserved, 51 nucleotide (nt) RNA sequence was sufficient to inhibit TCR signaling. Cells expressing the HCV E2 coding RNA contained a short, virus-derived RNA predicted to be a Dicer substrate, which targeted a phosphatase involved in Src-kinase signaling (PTPRE). T-cells and hepatocytes containing HCV E2 RNA had reduced PTPRE protein levels. Mutation of 6 nts abolished the predicted Dicer interactions and restored PTPRE expression and proximal TCR signaling. HCV RNA did not inhibit distal TCR signaling induced by PMA and Ionomycin; however, HCV E2 protein inhibited distal TCR signaling. This inhibition required lymphocyte-specific tyrosine kinase (Lck). Lck phosphorylated HCV E2 at a conserved tyrosine (Y613), and phospho-E2 inhibited nuclear translocation of NFAT. Mutation of Y613 restored distal TCR signaling, even in the context of HCVpps. Thus, HCV particles delivered viral RNA and E2 protein to T-cells, and these inhibited proximal and distal TCR signaling respectively. These effects of HCV particles likely aid in establishing infection and contribute to viral persistence. PMID- 26421925 TI - Dynamic FDG-PET Imaging to Differentiate Malignancies from Inflammation in Subcutaneous and In Situ Mouse Model for Non-Small Cell Lung Carcinoma (NSCLC). AB - BACKGROUND: [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) has been widely used in oncologic procedures such as tumor diagnosis and staging. However, false-positive rates have been high, unacceptable and mainly caused by inflammatory lesions. Misinterpretations take place especially when non subcutaneous inflammations appear at the tumor site, for instance in the lung. The aim of the current study is to evaluate the use of dynamic PET imaging procedure to differentiate in situ and subcutaneous non-small cell lung carcinoma (NSCLC) from inflammation, and estimate the kinetics of inflammations in various locations. METHODS: Dynamic FDG-PET was performed on 33 female mice inoculated with tumor and/or inflammation subcutaneously or inside the lung. Standardized Uptake Values (SUVs) from static imaging (SUVmax) as well as values of influx rate constant (Ki) of compartmental modeling from dynamic imaging were obtained. Static and kinetic data from different lesions (tumor and inflammations) or different locations (subcutaneous, in situ and spontaneous group) were compared. RESULTS: Values of SUVmax showed significant difference in subcutaneous tumor and inflammation (p<0.01), and in inflammations from different locations (p<0.005). However, SUVmax showed no statistical difference between in situ tumor and inflammation (p = 1.0) and among tumors from different locations (subcutaneous and in situ, p = 0.91). Values of Ki calculated from compartmental modeling showed significant difference between tumor and inflammation both subcutaneously (p<0.005) and orthotopically (p<0.01). Ki showed also location specific values for inflammations (subcutaneous, in situ and spontaneous, p<0.015). However, Ki of tumors from different locations (subcutaneous and in situ) showed no significant difference (p = 0.46). CONCLUSION: In contrast to static PET based SUVmax, both subcutaneous and in situ inflammations and malignancies can be differentiated via dynamic FDG-PET based Ki. Moreover, Values of influx rate constant Ki from compartmental modeling can offer an assessment for inflammations at different locations of the body, which also implies further validation is necessary before the replacement of in situ inflammation with its subcutaneous counterpart in animal experiments. PMID- 26421926 TI - Exploiting Human Resource Requirements to Infer Human Movement Patterns for Use in Modelling Disease Transmission Systems: An Example from Eastern Province, Zambia. AB - In this research, an agent-based model (ABM) was developed to generate human movement routes between homes and water resources in a rural setting, given commonly available geospatial datasets on population distribution, land cover and landscape resources. ABMs are an object-oriented computational approach to modelling a system, focusing on the interactions of autonomous agents, and aiming to assess the impact of these agents and their interactions on the system as a whole. An A* pathfinding algorithm was implemented to produce walking routes, given data on the terrain in the area. A* is an extension of Dijkstra's algorithm with an enhanced time performance through the use of heuristics. In this example, it was possible to impute daily activity movement patterns to the water resource for all villages in a 75 km long study transect across the Luangwa Valley, Zambia, and the simulated human movements were statistically similar to empirical observations on travel times to the water resource (Chi-squared, 95% confidence interval). This indicates that it is possible to produce realistic data regarding human movements without costly measurement as is commonly achieved, for example, through GPS, or retrospective or real-time diaries. The approach is transferable between different geographical locations, and the product can be useful in providing an insight into human movement patterns, and therefore has use in many human exposure-related applications, specifically epidemiological research in rural areas, where spatial heterogeneity in the disease landscape, and space-time proximity of individuals, can play a crucial role in disease spread. PMID- 26421927 TI - Methicillin Resistant Staphylococcus aureus among HIV Infected Pediatric Patients in Northwest Ethiopia: Carriage Rates and Antibiotic Co-Resistance Profiles. AB - BACKGROUND: MRSA infections are becoming more prevalent throughout the HIV community. MRSA infections are a challenge to both physicians and patients due to limited choice of therapeutic options and increased cost of care. OBJECTIVES: This study was aimed to determine the prevalence of colonization and co resistance patterns of MRSA species among HIV positive pediatric patients in the Amhara National Regional State, Northwest Ethiopia. METHODS: Culture swabs were collected from the anterior nares, the skin and the perineum of 400 participants. In vitro antimicrobial susceptibility testing was done on Muller Hinton Agar by the Kirby-Bauer disk diffusion method, using 30 MUg cefoxitin (OXOID, ENGLAND) according to the recommendations of the Clinical and Laboratory Standards Institute. Methicillin sensitivity/resistance was tested using cefoxitin. Data was analyzed by descriptive statistics and logistic regression model using Epi Info 7. RESULTS: S. aureus was detected in 206 participants (51.5%). The prevalence of MRSA colonization in this study was 16.8%. Colonization by S. aureus was associated with male gender (OR = 0.5869; 95% CI: 0.3812-0.9036; p value = 0.0155), history of antibiotic use over the previous 3 months (OR = 2.3126; 95% CI: 1.0707-4.9948; p-value = 0.0329) and having CD4 T-cell counts of more than 350 x 10(6) cells / L (OR = 0.5739; 95% CI = 0.3343-0.9851; p-value = 0.0440). Colonization by MRSA was not associated with any one of the variables. Concomitant resistance of the MRSA to clindamycin, chloramphenicol, co trimoxazole, ceftriaxone, erythromycin and tetracycline was 7.6%, 6%, 5.25%, 20.9%, 23.9% and 72.1%, respectively. CONCLUSION: High rates of colonization by pathogenic MRSA strains is observed among HIV positive pediatric patients in the Amhara National Regional state. PMID- 26421928 TI - Survival Tactics and Strategies of Methamphetamine-Using HIV-Positive Men Who Have Sex with Men in San Diego. AB - In this article, two ways that HIV-positive drug users survive under the supervision of law enforcement agencies, community health organizations, and social welfare offices are differentiated. First, strategies are long-ranging and often carefully planned, and they involve conscious utilization and manipulation of bureaucratic processes. Second, tactics are short-ranging and often haphazard, and they are used to survive on daily or weekly bases, with entrenched problems and structural solutions avoided or ignored. Data from three years of ethnographic fieldwork with 14 methamphetamine-using HIV-positive men who have sex with men in San Diego, California is used to expand upon these two categories, explaining the different, often ineffectual, ways these men accessed care, services, shelter, drugs, and companionship. This article also examines the policy implications of taking in consideration these different kinds of survival methods, arguing for intensive client-specific interventions when working with long-term addicts with multiple health problems. PMID- 26421929 TI - A 1-year videoconferencing-based psychoeducational group intervention following bariatric surgery: results of a randomized controlled study. AB - BACKGROUND: For severely obese patients, bariatric surgery has been recommended as an effective therapy. OBJECTIVES: The Bariataric Surgery and Education (BaSE) study aimed to assess the efficacy of a videoconferencing-based psychoeducational group intervention in patients after bariatric surgery. SETTING: The BaSE study is a randomized, controlled multicenter clinical trial involving 117 patients undergoing bariatric surgery (mean preoperative body mass index [BMI] 49.9 kg/m(2), SD 6.4). Patients were enrolled between May 2009 and November 2012 and were randomly assigned to receive either conventional postsurgical visits or, in addition, a videoconferencing-based 1-year group program. METHODS: Primary outcome measures were weight in kilograms, health-related quality of life (HRQOL), and general self-efficacy (GSE). Secondary outcome measures were depression symptoms and eating behavior. RESULTS: 94% of the patients completed the study. Mean weight loss for all patients was 45.9 kg (SD 16.4) 1 year after surgery (mean excess weight loss [EWL] 63%). Intention-to-treat analyses revealed no differences in weight loss, EWL, HRQOL, or self-efficacy between study groups at 1 year after surgery. However, patients with clinically significant depression symptoms (CSD) at baseline assigned to the intervention group (n = 29) had a significantly better HRQOL (P = .03), lower depression scores (P = .02), and a trend for a better EWL (.06) 1 year after surgery compared with the control group (n = 20). CONCLUSION: We could not prove the efficacy of the group program for the whole study sample. However, results indicate that the intervention is effective for the important subgroup of patients with CSD. PMID- 26421931 TI - How to deal with the "Gordian knot" of evidence base? PMID- 26421930 TI - Trends of Mycobacterium bovis Isolation and First-Line Anti-tuberculosis Drug Susceptibility Profile: A Fifteen-Year Laboratory-Based Surveillance. AB - BACKGROUND: Mycobacterium tuberculosis causes the majority of tuberculosis (TB) cases in humans; however, in developing countries, human TB caused by M. bovis may be frequent but undetected. Human TB caused by M. bovis is considered a zoonosis; transmission is mainly through consumption of unpasteurized dairy products, and it is less frequently attributed to animal-to-human or human-to human contact. We describe the trends of M. bovis isolation from human samples and first-line drug susceptibility during a 15-year period in a referral laboratory located in a tertiary care hospital in Mexico City. METHODOLOGY/PRINCIPAL FINDINGS: Data on mycobacterial isolates from human clinical samples were retrieved from the laboratory's database for the 2000-2014 period. Susceptibility to first-line drugs: rifampin, isoniazid, streptomycin (STR) and ethambutol was determined. We identified 1,165 isolates, 73.7% were M. tuberculosis and 26.2%, M. bovis. Among pulmonary samples, 16.6% were M. bovis. The proportion of M. bovis isolates significantly increased from 7.8% in 2000 to 28.4% in 2014 (X(2)trend, p<0.001). Primary STR resistance was higher among M. bovis compared with M. tuberculosis isolates (10.9% vs.3.4%, p<0.001). Secondary multidrug resistance (MDR) rates were 38.5% and 34.4% for M. bovis and M. tuberculosis, respectively (p = 0.637). A rising trend of primary STR monoresistance was observed for both species (3.4% in 2000-2004 vs. 7.6% in 2010 2014; p = 0.02). CONCLUSIONS/SIGNIFICANCE: There is a high prevalence and a rising trend of M. bovis isolates in our region. The proportion of pulmonary M. bovis isolates is higher than in previous reports. Additionally, we report high rates of primary anti-tuberculosis resistance and secondary MDR in both M. tuberculosis and M. bovis. This is one of the largest reports on drug susceptibility of M. bovis from human samples and shows a significant proportion of first-line anti-tuberculosis drug resistance. PMID- 26421932 TI - A lack of evidence for neurophysiological intraoperative monitoring? PMID- 26421933 TI - Glycan-Dependent Mutual and Reversible Sequestration of Two Thyroid Cancer Biomarkers. AB - BACKGROUND: Thyroglobulin (Tg), the major thyroidal protein, plays important roles in thyroid hormone biosynthesis and in autoimmune thyroid diseases (AITD). Tg also serves as a pre- and postoperative biomarker of differentiated thyroid cancer (DTC). The endogenous beta-galactoside binding lectin galectin-3 (Gal-3), secreted by transformed thyroid cells, has been shown to be another useful biomarker of DTC. Tg contains covalently linked complex-type glycans that can serve as binding epitopes of Gal-3. The objective of the study is to investigate the interaction between Tg and Gal-3 and discuss its potential consequences. METHODS: Binding interaction between Tg and Gal-3 was first studied by hemagglutination inhibition assays. Subsequently, a detailed analysis of binding thermodynamics was carried out by isothermal titration calorimetry. Quantitative precipitation was performed to study the complex formation between Tg and Gal-3 and to determine the binding stoichiometry. The concentration-dependent rate and amount of complex formation between Tg and Gal-3 was examined spectrophotometrically. A similar approach was taken to study the effect of free Tg and Gal-3 on preformed Tg-Gal-3 complex. RESULTS: Quantitative biochemical and biophysical data show that these two biomarkers produced by thyroid cancer cells interact with each other with submicromolar affinity and form an insoluble complex at their stoichiometric concentration. One Tg molecule could bind up to 14 molecules of Gal-3. Such complex formation mutually sequestered both Tg and Gal-3, decreasing the concentration of their freely available forms. Formation of the Tg-Gal-3 complex was reversible as the preformed complex was dissolved by free Tg as well as free Gal-3. While free Tg rapidly dissolved preformed Tg-Gal-3 complex in a concentration-dependent manner, Gal-3 was found to be much less efficient and slowly dissolved only a fraction of the preformed complex at a relatively higher Gal-3 concentration. CONCLUSIONS: Complex formation between Tg and Gal-3 through high affinity binding and the sensitivity of the complex to free Tg and Gal-3 can potentially influence their biological functions. Interactions between Tg and Gal-3 might also interfere with their clinical detection, the same way Tg autoantibody (TgAb) is reported to interfere with Tg assays. The data support a model of Gal-3-mediated homeostatic process of Tg. PMID- 26421934 TI - Association of interleukin-10 levels with age of onset and duration of illness in patients with major depressive disorder. AB - OBJECTIVE: To investigate peripheral levels of interleukin-10 (IL-10) in patients with major depressive disorder (MDD) and bipolar disorder (BD) and evaluate the relationship between IL-10, age of disease onset, and duration of illness. METHODS: Case-control study nested in a population-based cohort of 231 individuals (age 18-24 years) living in Pelotas, state of Rio Grande do Sul, Brazil. Participants were screened for psychopathology using the Mini International Neuropsychiatric Interview (MINI) and the Structured Clinical Interview for DSM-IV (SCID-I). Serum IL-10 was measured using commercially available immunoassay kits. RESULTS: Peripheral levels of IL-10 were not significantly different in individuals with MDD or BD as compared to controls. However, higher IL-10 levels were found in MDD patients with a later disease onset as compared with controls or early-onset patients. In addition, IL-10 levels correlated negatively with illness duration in the MDD group. In the BD group, age of onset and duration of illness did not correlate with IL-10 levels. CONCLUSION: Higher levels of IL-10 are correlated with late onset of MDD symptoms. Moreover, levels of this cytokine might decrease with disease progression, suggesting that an anti-inflammatory balance may be involved in the onset of depressive symptoms and disease progression in susceptible individuals. PMID- 26421935 TI - Serpentine diffusion trajectories and the Ouzo effect in partially miscible ternary liquid mixtures. AB - This work investigates the transient equilibration process when partially miscible ternary liquid mixtures of two different compositions are brought into contact with each other. Diffusional coupling effects are shown to become increasingly significant as the mixture compositions approach the meta-stable regions of the phase equilibrium diagrams. The proper modelling of coupled diffusion phenomena requires the use of a Fick diffusivity matrix [D], with inclusion of non-zero off-diagonal elements. The primary objective of this article is to develop a simple, robust, procedure for the estimation of the matrix [D], using the Maxwell-Stefan (M-S) formulation as a convenient starting point. In the developed simplified approach, the Fick diffusivity matrix [D] is expressed as the product of a scalar diffusivity and the matrix of thermodynamic correction factors [Gamma]. By detailed examination of experimental data for the matrix [D] in a wide variety of ternary mixtures, it is deduced that the major contribution of diffusional coupling arises from the contributions of non-ideal solution thermodynamics, quantified by the matrix of thermodynamic correction factors [Gamma]. An important consequence of strong thermodynamic coupling is that equilibration trajectories are serpentine in shape and may exhibit incursions into meta-stable zones opening up the possibility of spontaneous emulsification and the Ouzo effect. If diffusional coupling effects are ignored, the equilibration trajectory is linear in composition space. For a wide variety of partially miscible ternary mixtures, it is demonstrated that the corresponding linear equilibration trajectories do not anticipate the possibility of emulsification. PMID- 26421936 TI - A Study of the Monohydrate and Dihydrate Complexes of Perfluoropropionic Acid Using Chirped-Pulse Fourier Transform Microwave (CP-FTMW) Spectroscopy. AB - This work reports the first known spectroscopic observation of the monohydrate and dihydrate complexes of perfluoropropionic acid (PFPA). The spectra have been observed using a chirped-pulse Fourier transform microwave (CP-FTMW) spectrometer in the 7750 to 14,250 MHz region. The structures of the species have been confirmed with the aid of ab initio quantum chemical calculations. Rotational constants A, B, and C have been determined and reported for both species along with centrifugal distortion constants DeltaJ, DeltaJK, DeltaK, deltaJ, deltaK for H2O-PFPA and DeltaJ, DeltaJK, and deltaJ for (H2O)2-PFPA. Effects due to large amplitude motions were not observable in these experiments. Structures of the complexes have been determined using a combination of experimental second moment values and ab initio results. The complexation of the -OH of one or two water molecules has been found to occur in the plane of the carboxylic acid group forming a six- or eight-member ring. PMID- 26421937 TI - A rapid and efficient one-pot method for the reduction of N-protected alpha-amino acids to chiral alpha-amino aldehydes using CDI/DIBAL-H. AB - N-Protected amino acids can be easily converted into chiral alpha-amino aldehydes in a one-pot reaction by activation with CDI followed by reduction with DIBAL-H. This method delivers Boc-, Cbz- and Fmoc-protected amino aldehydes from proteinogenic amino acids in very good isolated yields and complete stereointegrity. PMID- 26421938 TI - In Situ ATR FTIR Spectroscopic Study of the Formation and Hydration of a Fucoidan/Chitosan Polyelectrolyte Multilayer. AB - The formation of fucoidan/chitosan-based polyelectrolyte multilayers (PEMs) has been studied with in situ Fourier transform infrared (FTIR) spectroscopy. Attenuated total reflectance (ATR) FTIR spectroscopy has been used to follow the sequential build-up of the multilayer, with peaks characteristic of each polymer being seen to increase in intensity with each respective adsorption stage. In addition, spectral processing has allowed for the extraction of spectra from individual adsorbed layers, which have been used to provide unambiguous determination of the adsorbed mass of the PEM at each stage of formation. The PEM was seen to undergo a transition in growth regimes during build-up: from supra linear to linear. In addition, the wettability of the PEM has been probed at each stage of the build-up, using the captive bubble contact angle technique. The contact angles were uniformly low, but showed variation in value depending on the nature of the outer polymer layer, and this variation correlated with the overall percentage hydration of the PEM (determined from FTIR and quartz crystal microbalance data). The nature of the hydration water within the polyelectrolyte multilayer has also been studied with FTIR spectroscopy, specifically in situ synchrotron ATR FTIR microscopy of the multilayer confined between two solid surfaces. The acquired spectra have enabled the hydrogen bonding environment of the PEM hydration water to be determined. The PEM hydration water is seen to have an environment in which it is subject to fewer hydrogen bonding interactions than in bulk electrolyte solution. PMID- 26421939 TI - Poly(ionic liquid)s as phase splitting promoters in aqueous biphasic systems. AB - Aqueous biphasic systems (ABSs) provide a sustainable and efficient alternative to conventional liquid-liquid extraction techniques with volatile organic solvents, and can be used for the extraction, recovery, and purification of diverse solutes. In this work, and for the first time, ABSs composed of poly(ionic liquid)s (PILs) and inorganic salts were measured at 25 degrees C and atmospheric pressure. New PILs having pyrrolidinium polycations combined with different counter-anions, namely acetate [Ac](-), trifluoroacetate [TFAc](-), hexanoate [Hex](-), adipate [Adi](-), and citrate [Cit](-) were synthesized, by a simple and environmentally-friendly procedure, and characterized. The effect of the PIL features, namely molecular weight and anionic character, and other experimental variables, such as temperature, on the phase splitting ability was researched. The aptitude of the studied ABS to be implemented as separation technologies was also evaluated through the use of a model biomolecule, tryptophan. PMID- 26421940 TI - Pediatric Venous Thromboembolism--Like Adult Clots, Only Smaller. PMID- 26421942 TI - Balanced Ambipolar Poly(diketopyrrolopyrrole-alt-tetrafluorobenzene) Semiconducting Polymers Synthesized via Direct Arylation Polymerization. AB - The synthesis of an ambipolar pi-conjugated copolymer consisting of alternating diketopyrrolopyrrole and tetrafluorobenzene via direct arylation polymerization (DAP) is reported. Two different combinations of monomers are investigated under various catalytic conditions for DAP. The target polymer obtained under an optimized catalytic condition shows minimal structural defects, a number-average molecular weight of 33.2 kDa, and balanced electron and hole mobility of 1 * 10( 2) cm(2) V(-1) S(-1) in the organic field-effect transistors fabricated and tested under ambient conditions. PMID- 26421941 TI - Known-component 3D-2D registration for quality assurance of spine surgery pedicle screw placement. AB - A 3D-2D image registration method is presented that exploits knowledge of interventional devices (e.g. K-wires or spine screws-referred to as 'known components') to extend the functionality of intraoperative radiography/fluoroscopy by providing quantitative measurement and quality assurance (QA) of the surgical product. The known-component registration (KC-Reg) algorithm uses robust 3D-2D registration combined with 3D component models of surgical devices known to be present in intraoperative 2D radiographs. Component models were investigated that vary in fidelity from simple parametric models (e.g. approximation of a screw as a simple cylinder, referred to as 'parametrically-known' component [pKC] registration) to precise models based on device-specific CAD drawings (referred to as 'exactly-known' component [eKC] registration). 3D-2D registration from three intraoperative radiographs was solved using the covariance matrix adaptation evolution strategy (CMA-ES) to maximize image-gradient similarity, relating device placement relative to 3D preoperative CT of the patient. Spine phantom and cadaver studies were conducted to evaluate registration accuracy and demonstrate QA of the surgical product by verification of the type of devices delivered and conformance within the 'acceptance window' of the spinal pedicle. Pedicle screws were successfully registered to radiographs acquired from a mobile C-arm, providing TRE 1-4 mm and <5 degrees using simple parametric (pKC) models, further improved to <1 mm and <1 degrees using eKC registration. Using advanced pKC models, screws that did not match the device models specified in the surgical plan were detected with an accuracy of >99%. Visualization of registered devices relative to surgical planning and the pedicle acceptance window provided potentially valuable QA of the surgical product and reliable detection of pedicle screw breach. 3D-2D registration combined with 3D models of known surgical devices offers a novel method for intraoperative QA. The method provides a near-real-time independent check against pedicle breach, facilitating revision within the same procedure if necessary and providing more rigorous verification of the surgical product. PMID- 26421943 TI - Design Strategies for CeO2-MoO3 Catalysts for DeNOx and Hg(0) Oxidation in the Presence of HCl: The Significance of the Surface Acid-Base Properties. AB - A series of CeMoOx catalysts with different surface Ce/Mo ratios was synthesized by a coprecipitation method via changing precipitation pH value. The surface basicity on selective catalytic reduction (SCR) catalysts (CeMoOx and VMo/Ti) was characterized and correlated to the durability and activity of catalyst for simultaneous elimination of NOx and Hg(0). The pH value in the preparation process affected the surface concentrations of Ce and Mo, the Brunauer-Emmett Teller (BET) specific surface area, and the acid-base properties over the CeMoOx catalysts. The O 1s X-ray photoelectron spectroscopy (XPS) spectra and CO2 temperature programmed desorption (TPD) suggested that the surface basicity increased as the pH value increased. The existence of strong basic sites contributed to the deactivation effect of HCl over the VMo/Ti and CeMoOx catalysts prepared at pH = 12. For the CeMoOx catalysts prepared at pH = 9 and 6, the appearance of surface molybdena species replaced the surface -OH, and the existence of appropriate medium-strength basic sites contributed to their resistance to HCl poisoning in the SCR reaction. Moreover, these sites facilitated the adsorption and activation of HCl and enhanced Hg(0) oxidation. On the other hand, the inhibitory effect of NH3 on Hg(0) oxidation was correlated with the competitive adsorption of NH3 and Hg(0) on acidic surface sites. Therefore, acidic surface sites may play an important role in Hg(0) adsorption. The characterization and balance of basicity and acidity of an SCR catalyst is believed to be helpful in preventing deactivation by acid gas in the SCR reaction and simultaneous Hg(0) oxidation. PMID- 26421944 TI - Health impacts due to particulate air pollution in Volos City, Greece. AB - There is great consensus among the scientific community that suspended particulate matter is considered as one of the most harmful pollutants, particularly the inhalable particulate matter with aerodynamic diameter less than 10 MUm (PM10) causing respiratory health problems and heart disorders. Average daily concentrations exceeding established standard values appear, among other cases, to be the main cause of such episodes, especially during Saharan dust episodes, a natural phenomenon that degrades air quality in the urban area of Volos. In this study the AirQ2.2.3 model, developed by the World Health Organization (WHO) European Center for Environment and Health, was used to evaluate adverse health effects by PM10 pollution in the city of Volos during a 5 year period (2007-2011). Volos is a coastal medium size city in the Thessaly region. The city is located on the northern side of the Gulf of Pagassitikos, on the east coast of Central Greece. Air pollution data were obtained by a fully automated monitoring station, which was established by the Municipal Water Supply and Sewage Department in the Greater Area of Volos, located in the centre of the city. The results of the current study indicate that when the mean annual PM10 concentration exceeds the corresponding European Union (EU) threshold value, the number of hospital admissions for respiratory disease (HARD) is increased by 25% on average. There is also an estimated increase of about 2.5% in HARD compared to the expected annual HARD cases for Volos. Finally, a strong correlation was found between the number of days exceeding the EU daily threshold concentration ([PM10] >= 50 MUg m(-3)) and the annual HARD cases. PMID- 26421945 TI - Optimizing 1-MUs-Resolution Single-Molecule Force Spectroscopy on a Commercial Atomic Force Microscope. AB - Atomic force microscopy (AFM)-based single-molecule force spectroscopy (SMFS) is widely used to mechanically measure the folding and unfolding of proteins. However, the temporal resolution of a standard commercial cantilever is 50-1000 MUs, masking rapid transitions and short-lived intermediates. Recently, SMFS with 0.7-MUs temporal resolution was achieved using an ultrashort (L = 9 MUm) cantilever on a custom-built, high-speed AFM. By micromachining such cantilevers with a focused ion beam, we optimized them for SMFS rather than tapping-mode imaging. To enhance usability and throughput, we detected the modified cantilevers on a commercial AFM retrofitted with a detection laser system featuring a 3-MUm circular spot size. Moreover, individual cantilevers were reused over multiple days. The improved capabilities of the modified cantilevers for SMFS were showcased by unfolding a polyprotein, a popular biophysical assay. Specifically, these cantilevers maintained a 1-MUs response time while eliminating cantilever ringing (Q ? 0.5). We therefore expect such cantilevers, along with the instrumentational improvements to detect them on a commercial AFM, to accelerate high-precision AFM-based SMFS studies. PMID- 26421946 TI - A comparison of the effectiveness of an adult nutrition education program for Aboriginal and non-Aboriginal Australians. AB - BACKGROUND: Adult nutrition education is an important component of broader societal efforts to address the high prevalence of nutrition-related diseases. In Australia, Aboriginal people are a critical target group for such programs because of their substantially higher rates of these diseases. OBJECTIVE: The aim of this study was to assess the relative effectiveness of an adult nutrition education program for Aboriginal and non-Aboriginal participants. METHODS: Pre and post-course evaluation data were used to assess changes in confidence in ability to buy healthy foods on a budget, nutrition knowledge, and dietary behaviours among individuals attending FOODcents nutrition education courses. The total sample of 875 Western Australians included 169 who self-identified as Aboriginal or Torres Strait Islander. RESULTS: Perceptions of course usefulness were very high and comparable between Aboriginal and non-Aboriginal participants. Significantly larger improvements in confidence, nutrition knowledge, and reported consumption behaviours were evident among Aboriginal participants. CONCLUSION: The findings suggest that adult nutrition education programs that address specific knowledge and skill deficits that are common among disadvantaged groups can be effective for multiple target groups, and may also assist in reducing nutrition-related inequalities. PMID- 26421947 TI - Happiness and longevity in the United States. AB - This is the first study to our knowledge to examine the relationship between happiness and longevity among a nationally representative sample of adults. We use the recently-released General Social Survey-National Death Index dataset and Cox proportional hazards models to reveal that overall happiness is related to longer lives among U.S. adults. Indeed, compared to very happy people, the risk of death over the follow-up period is 6% (95% CI 1.01-1.11) higher among individuals who are pretty happy and 14% (95% CI 1.06-1.22) higher among those who are not happy, net of marital status, socioeconomic status, census division, and religious attendance. This study provides support for happiness as a stand alone indicator of well-being that should be used more widely in social science and health research. PMID- 26421948 TI - Trauma and Chinese heroin users. AB - This qualitative study explores the traumas of Chinese heroin users. The results showed that the Chinese experience traumas during (childhood, later in life but prior to heroin-use onset, and throughout their heroin-use career. Themes related to the traumas include the historical economic transition, the value of family orientation, an emphasis on scholarly pursuits, the shame orientation, and a scarcity of resources conducive to recovery. This article provides a framework to understand the traumas experienced by Chinese people and offers insights on how macrofactors may impact the trauma and its treatment in different societies. PMID- 26421949 TI - Photo Lewis acid generators: photorelease of B(C6F5)3 and applications to catalysis. AB - A series of molecules capable of releasing of the strong organometallic Lewis acid B(C6F5)3 upon exposure to 254 nm light have been developed. These photo Lewis acid generators (PhLAGs) can now serve as photoinitiators for several important B(C6F5)3-catalyzed reactions. Herein is described the synthesis of the triphenylsulfonium and diphenyliodonium salts of carbamato- and hydridoborates, their establishment as PhLAGs, and studies aimed at defining the mechanism of borane release. Factors affecting these photolytic reactions and the application of this concept to photoinduced hydrosilylation reactions and construction of siloxane scaffolds are also discussed. PMID- 26421950 TI - [Tubulointerstitial rejection of renal allografts]. AB - Tubulo-intersticial rejection represents T-cell mediated rejection of kidney allografts with the morphology of immune-mediated interstitial nephritis. Diagnosis is dependent on the histopathological evaluation of a graft biopsy sample. The key morphological features are interstitial inflammatory infiltrate and damage to tubular epithelial cell which in severe cases can result in the ruptures of the tubular basement membranes. The differential diagnosis of tubulo interstitial rejection includes acute interstitial nephritis and viral inflammatory kidney diseases, mainly polyomavirus nephropathy. PMID- 26421952 TI - [Infections after kidney transplantation]. AB - Immunosuppressed kidney transplant recipients are at risk for a variety of infectious complications and more than half of them suffered from this complication in the early post-transplant period. Despite the fact that the long term risk of serious infectious complications in the early postoperative period decreased, remain the infection the most frequent cause of morbidity in the first 6 months after transplant. It is important to realize that the clinical manifestations of infection in the compromised host are variable and often atypical. In the later period, infections that affect the kidney graft become clinically important, and some of them occur only in immunosuppressed patients. Here we will discuss polyomavirus nephropathy which represents the most important and most frequent viral disease of renal allografts. PMID- 26421951 TI - [Antibody-mediated rejection of renal allograft and the update Banff classification 2013]. AB - The view on the role of donor-specific antibodies in organ transplantation has been changed during the last several decades. Today, it is considered that the majority of cases of the late renal allograft dysfunction and loss are caused by the presence of donor-specific antibodies to HLA antigens. The real breakthrough in the diagnosis of antibody-mediated rejection was represented by the discovery of C4d, which enabled the determination of the diagnostic criteria of acute and later chronic antibody-mediated rejection. Although detection of C4d has been the cornerstone in the diagnosis of antibody-mediated rejection for over 10 years, it has become clear that some cases with similar morphological and clinical features do not have detectable C4d. Outcomes of key studies concerning presence of donor specific antibodies and morphological features in the graft biopsy samples resulted in the modification of Banff classification of 2013, which includes integrating C4d negative antibody-mediated rejection and also that acute vascular rejection (v1, v2) can be a part of the antibody-mediated rejection. PMID- 26421953 TI - Shadow cell differentiation in endometrioid carcinomas of the uterus. Its frequent occurrence and beta-catenin expression. AB - Shadow cell differentiation (SCD) is typical for pilomatrixoma and related follicular tumors of the skin. However, it has been described rarely in some extra-cutaneous lesions such as gonadal teratoma, craniopharyngioma, odontogenic cyst, and in rare visceral carcinomas (lung, bladder, gallbladder, uterus, ovary, and colon). In our practice, we have noticed that the occurrence of shadow cells is not very rare in endometrioid carcinoma (EC) of the uterus. For exact determination of SCD in these tumors, we reviewed 59 consecutive cases of uterine EC. The series included curettage and hysteroscopic specimens. We have found SCD in 9 (15.3 %) of the tumors. In these cases, the age of the patients and FIGO grade did not differ significantly from other ECs. Immunohistochemically, all ECs with SCD showed nuclear expression of beta-catenin in areas of SCD, indicating a possible role of the Wnt signaling pathway in tumorigenesis as well as a role of nuclear accumulation of beta-catenin by trans-differentiation from glandular toward squamous and shadow cell phenotypes. We have found that the relatively frequent presence of SCD in ECs can assists in the diagnosis of these tumors. PMID- 26421954 TI - [Neuroendocrine tumor of the breast--metastasis or primary breast carcinoma? Case report]. AB - A 74-year-old women with a history of neuroendocrine tumor in the terminal ileum presented on screening mammography with an irregular hypoechogenic mass in the upper outer quadrant of the left breast. A core biopsy showed a neuroendocrine tumor, interpreted as a probable metastasis from the intestinal primary. Other masses were found in the right lobe of the liver. Resection of the masses in the breast and liver was performed at the same time. Morphological and immunohistochemical findings (positive neuroendocrine markers, estrogene receptors and negative cytokeratine 7, mammaglobin, GCDFP-15, cytokeratine 20 and progesterone receptors) were consistent with a diagnosis of a metastatic well differentiated neuroendocrine tumor, despite some estrogen receptor positivity. Issues of primary and metastatic breast neuroendocrine tumors are discussed in detail. PMID- 26421955 TI - [Melanocytic matricoma--a case report]. AB - A rare skin tumor (melanocytic matricoma), 6 mm in diameter, was diagnosed on the skin of the back in a 66-year-old man. It was composed of two cellular types: 1. epithelial cells with hair follicle differentiation and 2. dendritic melanocytes. After two years of follow-up there are no signs of a relapse or generalisation of the tumor. PMID- 26421956 TI - Pyloric gland adenoma: a histologic, immunohistochemical and molecular genetic study of 23 cases. AB - Pyloric gland adenoma is a rare neoplasm with a gastric epithelial differentiation. We report 23 cases of pyloric gland adenoma in older persons, with a mean age of 74 years (range 52 - 87 years). They occurred in the esophagus (3 cases), corporal gastric mucosa (7 cases), duodenum (10 cases), gallbladder (2 cases), and choledochus (one case). Histologically, they were characterized by closely packed pyloric gland-type tubules with a monolayer of cuboidal to low columnar epithelial cells containing basally located round nuclei, and a superficial layer of tall, columnar, foveolar-type epithelium. Immunohistochemically, most tumor glands expressed pyloric gland mucin MUC6, whereas MUC5AC was positive in superficial gastric foveolar epithelium, and in a minority of glands. In addition, scattered neuroendocrine cells positive for chromogranin A and/or synaptophysin were seen in all cases. In 3 cases (two cases in the gallbladder and one case in the esophagus), areas of intestinal metaplasia with CK20, CDX2, and MUC2 positivity were found. Focal low-grade dysplasia was found in five cases (21.7%), and diffuse high-grade dysplasia was seen in one adenoma (4.4%), i.e., 6 of 23 PGAs (26.1%) showed dysplastic features. In one esophageal case, an invasive adenocarcinoma was diagnosed. Scattered p53 positive cells were found in all cases. Their number was higher in lesions with low-grade dysplasia and it was substantially increased in adenoma with high-grade dysplasia and in adenocarcinoma. Our molecular genetic results indicate that pyloric gland adenomas neoplastic nature is associated with p53 accumulation, mutations in oncogenes GNAS, KRAS, CTTNB1 and tumor suppressor genes SMAD4, and TP53. Pyloric gland adenoma can evolve into dysplasia and adenocarcinoma. PMID- 26421957 TI - A two-centre, open-label, randomised study of ovulation inhibition with three transdermal contraceptive patches, each containing different amounts of ethinyl estradiol and gestodene in healthy, young women. AB - Here we report the findings of a two-centre, open-label, randomised, Phase IIa study designed to investigate whether an ethinyl estradiol (EE)/gestodene (GSD) patch that has been developed (referred to herein as the 'EE/GSD patch') reliably inhibits ovulation in comparison with patches delivering lower doses of these hormones. The study rationale was to provide justification of the doses of EE and GSD selected for the EE/GSD patch. Healthy women, aged 18-35 years, were randomised to receive treatment with either the EE/GSD patch, a 'reduced-GSD patch' (delivering similar amounts of EE and approximately half the amount of GSD) or a 'reduced-EE/GSD patch' (delivering half the amount of EE and GSD). Treatment was administered for three 28-day cycles (three * 7 patch-wearing days, plus a 7-day patch-free interval). The primary pharmacodynamic variable was the percentage of women with ovulation in at least one of Cycles 2 and/or 3, as indicated by Hoogland score. Pharmacokinetic parameters for EE and GSD were also measured. Results indicated that the EE/GSD patch effectively suppressed ovulation, while patches delivering lower doses of EE and GSD were less effective for this purpose. All three patches showed comparable tolerability. PMID- 26421958 TI - A preliminary investigation into the psychometric properties of the Dublin Extrapersonal Neglect Assessment (DENA): A novel screening tool for extrapersonal neglect. AB - Extrapersonal neglect is one clinical manifestation that can occur following stroke. Existing neglect assessment procedures have been criticised for lengthy administration and do not assess how extrapersonal space is affected. This study investigated the psychometric properties of a new, time-efficient screening tool for extrapersonal neglect. Full ethical approval was granted and consent obtained from 50 participants with first-time stroke. Participants were screened for extrapersonal neglect on two consecutive days by two raters using the Dublin Extrapersonal Neglect Assessment (DENA) to test inter-rater reliability. Construct validity of the DENA was investigated by comparing the DENA to the Catherine Bergego Scale (CBS). Additional analyses were calculated between the DENA and the extrapersonal items of the CBS (CBS-E). The kappa statistic, intraclass correlation coefficients (ICCs) and Bland Altman analyses were calculated to determine excellent inter-rater reliability (ICC 0.971, kappa = .876) and significant correlation between the DENA and the CBS and CBS-E (ICC 0.870, 0.934, kappa = .793, .833, respectively). Bland Altman analyses demonstrated acceptable levels of agreement between the DENA raters, and the DENA and CBS, with no systematic differences evident. The DENA provides clinicians with a quick and psychometrically sound screening tool for extrapersonal neglect to ensure this impairment is addressed in stroke rehabilitation. PMID- 26421959 TI - Mast cells phagocyte Candida albicans and produce nitric oxide by mechanisms involving TLR2 and Dectin-1. AB - Candida albicans (C. albicans) is a fungus commonly found in the human mucosa, which may cause superficial and systemic infections, especially in immunosuppression. Until now, the main actors in the defense against this fungus are the epithelial cells, neutrophils, macrophages/monocytes and dendritic cells. However, mast cells are strategically located to play a first line of anti Candida defense and it has appropriate mechanisms to do it. As with other cells, the recognition of C. albicans occurs meanly via TLR2 and Dectin-1. We assess the TLR2/Dectin-1 involvement in phagocytosis and production of nitric oxide (NO) and reactive oxygen species (ROS) by mast cells challenged with C. albicans. Bone marrow-derived mast cells (MC) from wild type (Wt) or knockout (TLR2-/-) mice C57BL/6 were subjected to in vitro Dectin-1 blockade. After challenged with FITC labeled C. albicans or zymosan, phagocytosis was analyzed by microscopy. The intracellular production of NO and ROS was measured by DAF-FM diacetate and CellROX Deep/Red Reagent kits. The nitrite formation and hydrogen peroxide release were analyzed by Griess reaction and Amplex Red Hydrogen Peroxide/Peroxidase Assay Kit. Wt/MC phagocytose C. albicans with production of intracellular NO, but not ROS. Moreover, increased levels of nitrite were also observed. The absence and/or blockade of TLR2/Dectin-1 caused significant decreased in C. albicans phagocytosis and NO production. Our results showed that mast cells are able to phagocytose and produce NO against C. albicans via TLR2/Dectin-1. Therefore, mast cells could be important during the course of Candida infection and as a therapeutic target. PMID- 26421961 TI - Simultaneous Phase Transfer and Surface Modification of TiO2 Nanoparticles Using Alkylphosphonic Acids: Optimization and Structure of the Organosols. AB - An original protocol of simultaneous surface modification and transfer from aqueous to organic phases of anatase TiO2 nanoparticles (NPs) using alkylphosphonic acids (PAs) is studied. The influence of the solvent, the nature and concentration of the PA, and the size, concentration, and aggregation state of the TiO2 NPs was investigated. Complete transfer was observed for linear alkyl chains (5, 8, 12, and 18 C atoms), even at very high sol concentrations. After transfer, the grafted NPs were characterized by (31)P solid-state MAS NMR. The dispersion state of NPs before and after phase transfer was monitored by dynamic light scattering (DLS). Small-angle neutron scattering (SANS) was used to characterize the structure of PA-grafted NPs in the organic solvent. Using a quantitative core-shell model cross-checked under different contrast conditions, it is found that the primary particles making up the NPs are homogeneously grafted with a solvated PA-layer. The nanometric thickness of the latter is shown to increase with the length of the linear carbon chain of the PA, independent of the size of the primary TiO2 NP. Interestingly, a reversible temperature dependent aggregation was evidenced visually for C18PA, and confirmed by DLS and SANS: heating the sample induces the breakup of aggregates, which reassemble upon cooling. Finally, in the case of NPs agglomerated by playing with the pH or the salt concentration of the sols, the phase transfer with PA is capable of redispersing the agglomerates. This new and highly versatile method of NP surface modification with PAs and simultaneous transfer is thus well suited for obtaining well-dispersed grafted NPs. PMID- 26421960 TI - Expression of surfactant proteins SP-A and SP-D in murine decidua and immunomodulatory effects on decidual macrophages. AB - Surfactant proteins SP-A and SP-D are pattern recognition innate immune molecules that belong to the C-type lectin family. In lungs, they play an important role in the clearance of pathogens and control of inflammation. SP-A and SP-D are also expressed in the female reproductive tract where they play an important role in pregnancy and parturition. However, the role of SP-A and SP-D expressed at the feto-maternal interface (decidua) remains unclear. Here, we have examined the expression of SP-A and SP-D in the murine decidua at 17.5 (pre-parturition) and 19.5dpc (near parturition) and their effect on lipopolysaccharide (LPS)-treated decidual macrophages. SP-A and SP-D were localized to stromal cells in the murine decidua at 17.5 and 19.5dpc in addition to cells lining the maternal spiral artery. Purified pre-parturition decidual cells were challenged with LPS with and without SP-A or SP-D, and expression of F4/80 and TNF-alpha were measured by flow cytometry. On their own, SP-A or SP-D did not affect the percentage of F4/80 positive cells while they suppressed the percentage of TNF-alpha positive cells. However, simultaneous addition of SP-A or SP-D, together with LPS, reduced TNF alpha secreting F4/80 positive cells. It is likely that exogenous administration of SP-A and SP-D in decidua can potentially control infection and inflammation mediators during spontaneous term labor and infection-induced preterm labor. Thus, the presence of SP-A and SP-D in the murine decidua is likely to play a protective role against intrauterine infection during pregnancy. PMID- 26421962 TI - Quantification of 4'-geranyloxyferulic acid (GOFA) in honey samples of different origin by validated RP-HPLC-UV method. AB - Natural honey has been employed as a nutraceutical agent with benefits and therapeutic promises for humans for many centuries. It has been largely used as food and medicine by all generations, traditions, and civilizations, both ancient and modern. Several chemicals having beneficial effects for human health have been reported as components of natural honey and these include sugars, organic acids, aminoacids, minerals, and vitamins. Also some important phytochemicals have been described and these comprise tannins, flavonoids, terpenes, saponins, and alkaloids. In this note it is described the successful application of a RP HPLC-UV-vis method for the separation and quantification of 4'-geranyloxyferulic acid (GOFA) in four honey samples of different origin. Concentration values showed a great variation between the four samples tested, being chestnut honey the one richest in GOFA (7.87 mg/g). The findings described herein represent the first example reported in the literature of the characterization of an oxyprenylated phenylpropanoid in honey. PMID- 26421963 TI - PARACENTRAL ACUTE MIDDLE MACULOPATHY IN BIRDSHOT CHORIORETINOPATHY: A NOVEL ASSOCIATION. AB - BACKGROUND/PURPOSE: To present a novel case of paracentral acute middle maculopathy in association with birdshot chorioretinopathy. METHODS: Case report. RESULTS: A patient presented with decreased vision and findings of uveitis, vasculitis and a paracentral scotoma. Multimodal imaging was consistent with paracentral acute middle maculopathy in the setting of a multifocal chorioretinopathy and a laboratory workup was consistent with birdshot chorioretinopathy. CONCLUSION: Paracentral acute middle maculopathy is a newly described entity that may be associated with birdshot chorioretinopathy, and clinicians should be aware of it when patients present with new paracentral scotoma and signs of intraocular inflammation. PMID- 26421964 TI - SPONTANEOUS RESOLUTION OF MACULAR EPIRETINAL MEMBRANES AFTER FLUORESCEIN POTENTIATED ARGON LASER TREATMENT OF VON HIPPEL-LINDAU ASSOCIATED RETINAL HEMANGIOMAS: CASE REPORT AND REVIEW OF LITERATURE. AB - PURPOSE: To illustrate spontaneous resolution of macular epiretinal membranes and inactivation of retinal hemangioma exudation after fluorescein potentiated argon laser treatment of bilateral capillary hemangiomas in a patient with a de novo heterozygous deletion in Exon 2 of the von Hippel-Lindau gene. METHODS: Interventional case report. RESULTS: A 23-year-old man with subjective complaints of blurry vision, photophobia, and glare. On presentation, visual acuity was 20/20 in the right eye and 20/25 in the left eye with metamorphopsia. On the basis of bilateral retinal hemangiomas on clinical examination and characterization with multimodal imaging, a diagnosis of von Hippel-Lindau disease was made. Genetic testing identified a de novo, disease-causing heterozygous deletion in Exon 2 of the von Hippel-Lindau gene. The patient underwent 4 sessions of fluorescein potentiated 532 nm argon green laser treatment directed at retinal hemangiomas. No adverse sequelae of laser treatment were noted. Seven months after the initial presentation, the patient's vision was 20/20 in both eyes with interval resolution of metamorphopsia. There was spontaneous resolution of a macular epiretinal membrane with normalization of the macular retinal microstructure. The retinal hemangiomas in both eyes appeared inactive, and no new lesions were noted. CONCLUSION: Fluorescein potentiated argon laser successfully treated bilateral retinal hemangiomas in our patient with von Hippel-Lindau disease. Additional studies to characterize the full clinical potential of fluorescein potentiated argon laser therapy may be warranted. PMID- 26421965 TI - Resolution of fibrinogen deficiency in a patient with congenital afibrinogenemia after liver transplantation. PMID- 26421969 TI - Are There Differences in Central Coherence and Set Shifting Across the Subtypes of Anorexia Nervosa?: A Systematic Review. AB - Anorexia nervosa (AN) has been associated with weaknesses in central coherence and set shifting. In this line, it has been proposed to directly address these neuropsychological features in treatment (e.g., cognitive remediation therapy). It is not clear, however, whether the 2 subtypes of AN, the restricting (AN-R) and bingeing/purging (AN-BP) type, have the same amount of problems in these domains. A systematic search of the literature was conducted, using the databases Web of Science and PubMed, looking for studies on the comparison of AN-R and AN BP in performing central coherence/set-shifting tasks. Notably, very few authors describe the results of a direct comparison of the performance of patients with AN-R and AN-BP. In summary, the available indications for possible group differences are not strong enough to draw definitive conclusions. PMID- 26421970 TI - Sex Bias in Classifying Borderline and Narcissistic Personality Disorder. AB - This study investigated sex bias in the classification of borderline and narcissistic personality disorders. A sample of psychologists in training for a post-master degree (N = 180) read brief case histories (male or female version) and made DSM classification. To differentiate sex bias due to sex stereotyping or to base rate variation, we used different case histories, respectively: (1) non ambiguous case histories with enough criteria of either borderline or narcissistic personality disorder to meet the threshold for classification, and (2) an ambiguous case with subthreshold features of both borderline and narcissistic personality disorder. Results showed significant differences due to sex of the patient in the ambiguous condition. Thus, when the diagnosis is not straightforward, as in the case of mixed subthreshold features, sex bias is present and is influenced by base-rate variation. These findings emphasize the need for caution in classifying personality disorders, especially borderline or narcissistic traits. PMID- 26421971 TI - The Need for Vigilance in the Marketing of Genomic Tests in Psychiatry. PMID- 26421972 TI - The efficacy of sugar labeling formats: Implications for labeling policy. AB - OBJECTIVE: To examine knowledge of sugar recommendations and test the efficacy of formats for labeling total and added sugar on pre-packaged foods. METHODS: Online surveys were conducted among 2008 Canadians aged 16-24. Participants were asked to identify recommended limits for total and added sugar consumption. In Experiment 1, participants were randomized to one of six labeling conditions with varying information for total sugar for a high- or low-sugar product and were asked to identify the relative amount of total sugar in the product. In Experiment 2, participants were randomized to one of three labels with different added sugar formats and were asked if the product contained added sugar and the relative amount of added sugar. RESULTS: Few young people correctly identified recommendations for total sugar (5%) or added sugar (7%). In Experiment 1, those who were shown percent daily value information were more likely to correctly identify the relative amount of total sugar (P < 0.05). In Experiment 2, those shown added sugar information were more likely to correctly identify that the product contained added sugar and the relative amount of added sugar in the product (P < 0.05). CONCLUSIONS: Improved labeling may improve consumer understanding of the amount of sugars in food products. PMID- 26421974 TI - Speech processing in children with cochlear implant. AB - Cochlear implants (CIs) can be used effectively in the profoundly impaired children individuals. OBJECTIVES: This work was designed to assess speech processing at brainstem and cortical level in children fitted with CIs to investigate the possible influence of brainstem processing of speech on the cortical processing in those children. METHOD: Twenty children fitted with CIs underwent aided sound-field audiologic evaluation, speech evoked cortical auditory evoked potentials (S-CAEPs) and according to the results, children were classified into two groups: group I with good cortical response and group II with poor cortical response. This was followed by speech evoked ABR (S-ABR) recoding. RESULTS: P1 component of CAEPs was recorded in all children while other component showed variable results. S-ABR was recorded in all children even those with poor S-CAEPs response who showed delayed D, E, F and O latencies. However, S-ABR amplitudes did not show any significant difference between both groups. CONCLUSIONS: Children fitted with CI showed immediate cortical activation following device programming and this activity depends on the age of implantation as well as the child's age. S-ABR provides a new clinical tool that showed an important role of brainstem in complex sound processing that contribute to cortical processing. PMID- 26421973 TI - Concept-elicitation phase for the development of the pediatric patient-reported outcome version of the Common Terminology Criteria for Adverse Events. AB - BACKGROUND: Symptoms arising from disease or treatment are subjective experiences. Insight into pediatric oncology treatment side effects or symptoms is ideally obtained from direct inquiry to the ill child. A concept-elicitation phase in a patient-reported outcome (PRO) instrument design provides an opportunity to elicit children's voices to shape cancer symptom selection and terminology. METHODS: Through semistructured, one-on-one, voice-recorded interviews, symptom data were collected from 96 children with cancer between the ages of 7 and 20 years who were undergoing oncologic treatment at 7 pediatric oncology sites in the United States and Canada. RESULTS: The mean number of symptoms reported per child over the prior 7 days was 1.49 (range, 0-7; median, 1; standard deviation, 1.56). The most common symptoms across all age groups were tiredness or fatigue, nausea or vomiting, aches or pains, and weakness. There was not a statistically significant correlation between self-reported wellness and the number of reported symptoms (r = -0.156, n = 65, P = .215) or the number of symptoms reported by age group or diagnosis type. Forty participants reported experiencing a change in their body in the past week, with one-third of these changes unanticipated. Only through direct questions about feelings were emotional symptoms revealed because 90.6% of interviewees who discussed feelings (48 of 53) did so only in the context of direct questioning on feelings. Adolescents were more likely than younger children to discuss feelings as part of the interview. CONCLUSIONS: Concept elicitation from children and adolescents has the potential to enable researchers to develop age-appropriate, accurately representative PRO measures. PMID- 26421975 TI - Polarization-Mediated Thermal Stability of Metal/Oxide Heterointerface. AB - A polarization-mediated heterointerface is designed to research the thermal stability of magnetic metal/oxide interfaces. Using polarization engineering, the thermal stability of the interface between BiFeO3 and CoFeB can be improved by about 100 degrees C. This finding provides new insight into the chemistry of the metal/oxide heterointerface. PMID- 26421977 TI - Ossicular calisthenics: Pneumomassage of the tympanic membrane. AB - OBJECTIVES/HYPOTHESIS: Throughout the latter portion of the 19th and early 20th centuries, pneumomassage devices were widely used by otologists to treat a variety of ear diseases. The so-called eardrum massagers produced a regular, repetitive, oscillatory movement through modifying the air pressure in the ear canal. The goal of this study was to trace the invention, clinical use, technological diversification, abandonment, and ultimate resurrection of tympanic pneumomassage. METHOD: Review of the 19th- and early 20th-century medical journals, texts, and trade catalogs concerning the tympanic pneumomassage. RESULTS: In 1884, the Belgian otologist Charles Delstanche introduced what he called a rarefacteur, and 5 years later he introduced the masseur du tympan. This lead to a frenzied development of imaginative mechanical and electrical pneumassagers with a goal to exercise the tympanic membrane and ossicles to overcome contraction and rigidity. Tympanic pneumomassage rose to prominence in mainstream otology as a treatment for otitis media, chronic deafness, and tinnitus. After gradually fading out of the otological practice by the 1930s, pneumomassage was reintroduced in the 1980s after a half century of obscurity, this time as a novel invention notably for the treatment of Meniere's disease. CONCLUSION: The golden era of pneumomassage illustrates the ingenuity of otologists and medical instrument makers in creating a proliferation of clever devices, as well as how highly touted treatment methods may become widely adopted by practitioners despite the lack of efficacy. It also noteworthy that historic therapeutic methods are sometimes reintroduced for purposes not envisioned by their original makers. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:1180-1186, 2016. PMID- 26421978 TI - Vascular restoration: Is there a window of opportunity? AB - The usage of drug eluting stents (DES) has markedly reduced the rates of coronary revascularization procedures compared with bare metal stents (BMS). However, this technology still faces challenges in terms of the prevention of late stent thrombosis, major adverse cardiac events (MACE) progression, and the catch-up phenomenon of restenosis. Restoration of endothelial function upon after stenting, therefore, is the key to mitigating the risk of these toxicities and determining the level of the efficacy and safety of an implant. Review of the clinical studies of multiple DES, has suggested that there exists a window of opportunity, within the first two to three months after stent implantation, for restoring vascular function. If re-endothelialization reaches sufficient level within this period, vascular restoration can occur; however, if this opportunity is missed, re-endothelialization is unlikely to reach the level of endothelial maturation necessary to prevent the late stent thrombosis, MACE progression and the catch-up on restenosis. This hypothesis could aid in explaining variable clinical responses for revascularization treatments such as plain old balloon angioplasty (POBA), BMS, or DES. Patients could be grouped according to responses to the different treatment modalities: for Type 1 patients, POBA is sufficient and safe because they possess the capacity with effective endothelial response; for Type 2 patients, re-endothelialization occurs within the window but BMS are needed to maintain the arterial lumen open; for Type 3 individuals, overly accelerated vascular smooth muscle proliferation render sufficient re endothelialization impossible. Designing based on this principle predicts that the next technology advancement for the interventional cardiology will not be biodegradable DES by default, but rather a DES that can spur early restoration of the endothelial function within the window period. PMID- 26421979 TI - Growth hormone signaling pathways. AB - Over 20years ago, our laboratory showed that growth hormone (GH) signals through the GH receptor-associated tyrosine kinase JAK2. We showed that GH binding to its membrane-bound receptor enhances binding of JAK2 to the GHR, activates JAK2, and stimulates tyrosyl phosphorylation of both JAK2 and GHR. The activated JAK2/GHR complex recruits a variety of signaling proteins, thereby initiating multiple signaling pathways and cellular responses. These proteins and pathways include: 1) Stat transcription factors implicated in the expression of multiple genes, including the gene encoding insulin-like growth factor 1; 2) Shc adapter proteins that lead to activation of the grb2-SOS-Ras-Raf-MEK-ERK1,2 pathway; 3) insulin receptor substrate proteins implicated in the phosphatidylinositol-3-kinase and Akt pathway; 4) signal regulatory protein alpha, a transmembrane scaffold protein that recruits proteins including the tyrosine phosphatase SHP2; and 5) SH2B1, a scaffold protein that can activate JAK2 and enhance GH regulation of the actin cytoskeleton. Our recent work has focused on the function of SH2B1. We have shown that SH2B1beta is recruited to and phosphorylated by JAK2 in response to GH. SH2B1 localizes to the plasma membrane, cytoplasm and focal adhesions; it also cycles through the nucleus. SH2B1 regulates the actin cytoskeleton and promotes GH-dependent motility of RAW264.7 macrophages. Mutations in SH2B1 have been found in humans exhibiting severe early-onset childhood obesity and insulin resistance. These mutations impair SH2B1 enhancement of GH-induced macrophage motility. As SH2B1 is expressed ubiquitously and is also recruited to a variety of receptor tyrosine kinases, our results raise the possibility that effects of SH2B1 on the actin cytoskeleton in various cell types, including neurons, may play a role in regulating body weight. PMID- 26421980 TI - Sexual Behavior Among Young Carers in the Context of a Kenyan Empowerment Program Combining Cash-Transfer, Psychosocial Support, and Entrepreneurship. AB - This study examined associations between sexual initiation, unprotected sex, and having multiple sex partners in the past year with participation in a three-year empowerment program targeting orphan and vulnerable children (OVC). The Kenya based program combines community-conditioned cash transfer, psychosocial empowerment, health education, and microenterprise development. Program participants (n = 1,060) were interviewed in a cross-sectional design. Analyses used gender-stratified hierarchical logit models to assess program participation and other potential predictors. Significant predictors of increased female sexual activity included less program exposure, higher age, younger age at most recent parental death, fewer years of schooling, higher food consumption, higher psychological resilience, and lower general self-efficacy. Significant predictors of increased male sexual activity included more program exposure, higher age, better food consumption, not having a living father, and literacy. Findings support a nuanced view of current cash transfer programs, where female sexual activity may be reduced through improved financial status but male sexual activity may increase. Targeting of OVC sexual risk behaviors would likely benefit from being tailored according to associations found in this study. Data suggest involving fathers in sexual education, targeting women who lost a parent at a younger age, and providing social support for female OVC may decrease risk of human immunodeficiency virus (HIV) transmission. PMID- 26421981 TI - In vitro activity against Mycobacterium tuberculosis of levofloxacin, moxifloxacin and UB-8902 in combination with clofazimine and pretomanid. AB - Multidrug resistance has become a problem in the management of tuberculosis, with an urgent need for research into new drugs as well as the development of efficacious drug combinations and regimens. The main objective of this study was to assess and compare the efficacy of three antituberculous combinations (clofazimine/pretomanid/levofloxacin, clofazimine/pretomanid/moxifloxacin and clofazimine/pretomanid/UB-8902) against multidrug-resistant (MDR) and drug susceptible clinical isolates of Mycobacterium tuberculosis using an in vitro adaptation of the chequerboard assay. A total of 7 MDR and 11 drug-susceptible clinical isolates were studied. The fractional inhibitory concentration index (FICI) was interpreted as synergism when the value was <0.75, antagonism when it was >4 and additive activity between these two values. The FICI of all of the combinations ranged from 1.2 to 2.3, showing additive activity against all of the isolates. No differences were found between MDR and drug-susceptible isolates. In conclusion, the three combinations are effective against M. tuberculosis with equal effects. Moreover, in vitro testing of drug combinations could be useful to predict their clinical use. PMID- 26421982 TI - Plenary presentations and public citations from The American Association for Thoracic Surgery. AB - OBJECTIVE: We examined the impact of work presented in the plenary sessions at the meeting of The American Association for Thoracic Surgery (AATS), by determining how frequently the published papers corresponding to the session presentations during the past 20 years, were cited; those that were most cited were identified. METHODS: We reviewed the AATS meeting programs from the 20-year period from 1994 to 2014 and identified the corresponding publications in the Journal of Thoracic and Cardiovascular Surgery (JTCVS) from all abstracts presented at the plenary sessions. Papers were categorized as cardiac, thoracic, or congenital. References were evaluated for subsequent citation in the Web of Science (WoS), and Google Scholar (GS). We determined both the median number of citations overall, and per year. For comparison, we evaluated numbers of citations in WoS from current JTCVS papers in issues containing the 3 most-cited plenary session papers. RESULTS: Among 195 published plenary papers, the median number of citations in WoS and GS was 49 and 76, respectively. The median total number of citations in WoS was as follows: 51 for cardiac-category papers (n = 105); 61 for thoracic (n = 55), and 41 for congenital (n = 35). These values were higher than the median total number of citations for contemporary nonplenary JTCVS papers: cardiac (22, n = 55; P < .001); thoracic (31.5, n = 8; P = .183); and congenital (15.5, n = 24; P = .002) papers published in JTCVS. The median number of citations per year since publication for plenary publications was 5.9 (cardiac), 6 (thoracic), and 3.7 (congenital), respectively. CONCLUSIONS: Publications corresponding to the plenary sessions of the AATS are highly cited and include some of the seminal studies in our field in the past 20 years. PMID- 26421983 TI - Periportal fibrosis without cirrhosis does not affect outcomes after continuous flow ventricular assist device implantation. AB - OBJECTIVE: This study investigates the relationship of periportal fibrosis on postoperative outcomes after ventricular assist device (VAD) implantation. METHODS: Between July 2005 and August 2014, a total of 233 patients were implanted with continuous flow VADs. Liver biopsy was performed on 16 patients with concern for liver disease. Survival was evaluated using the Kaplan-Meier method. The effect of fibrosis on length of stay (LOS) in the intensive care unit was modeled using Poisson regression. Adjustments were made for age, profile from the Interagency Registry for Mechanically Assisted Circulatory Support, biopsy, and model for end-stage liver disease score. RESULTS: Fourteen of the 16 patients who underwent biopsy had periportal fibrosis without cirrhosis. One-year survival for the groups with and without biopsy-proven fibrosis was 93% +/- 7% and 86% +/- 2% (P = .97), respectively. The intensive care unit LOS was not different for those with (median, 7 days; interquartile range: 3-14 days) versus without fibrosis (median, 6 days; interquartile range 4-10 days; P = .65). Fibrosis (P = .42), age (0.95), model for end-stage liver disease excluding internal normalized ratio-XI score (P = .64), performance of a biopsy (P = .28), and Interagency Registry for Mechanically Assisted Circulatory Support class (P = .70) were not associated with intensive care unit LOS. Risk was increased of gastrointestinal bleeding (14% vs 4%; P = .026) in the first year among patients with fibrosis. CONCLUSIONS: The presence of periportal fibrosis did not affect survival or outcomes in patients undergoing VAD implantation. These findings suggest that carefully selected patients with advanced heart failure and hepatic fibrosis without cirrhosis may achieve acceptable outcomes with VAD implantation. PMID- 26421984 TI - Will transcatheter valve-in-valve become the standard for replacing the degenerative aortic valve bioprosthesis? Hold your horses, the jury is still out. PMID- 26421985 TI - One-year clinical and angiographic results of hybrid myocardial revascularization: Still a long way to go. PMID- 26421986 TI - Discussion. PMID- 26421987 TI - The Incidence of Postconcussion Syndrome Remains Stable Following Mild Traumatic Brain Injury in Children. AB - BACKGROUND: Improving our knowledge about the natural history and persistence of symptoms following mild traumatic brain injury is a vital step in improving the provision of health care to children with postconcussion syndrome. The purposes of this study were to (1) determine the incidence and persistence of symptoms after mild traumatic brain injury and (2) ascertain whether Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), symptom criteria for postconcussion syndrome in adults are appropriate for use in children. METHODS: A tertiary care pediatric emergency department was the setting for this study. This was a prospective observational follow-up cohort study of children (ages 2 to 18 years) with mild traumatic brain injury. Data were collected in person during the acute presentation, and subsequent follow-up was performed by telephone at 7-10 days and 1, 2, and 3 months postinjury. Postconcussion Symptom Inventory for parents and children was used. The DSM-IV diagnostic criteria for postconcussion syndrome were explored using receiver operating characteristic curve analysis. RESULTS: A total of 467 children (62.5% boys, median age 12.04, range 2.34-18.0) with mild traumatic brain injury participated. The median time until symptom resolution was 29.0 days (95% confidence intervals: 26.09-31.91). Three months after injury, 11.8% of children with mild traumatic brain injury remained symptomatic. Receiver operating curve characteristic analysis of the postconcussion syndrome criteria successfully classified symptomatic participants at three months postinjury; the adolescent receiver operating characteristic curve was excellent with the area under the curve being 0.928 (P < 0.001, standard error 0.019). CONCLUSIONS: Consistent with our previous study, 11.8% of children presenting to the emergency room with a mild traumatic brain injury remain symptomatic at 3 months postinjury. This is the first study to demonstrate stable incidence rates of postconcussion syndrome in children and that modified DSM-IV criteria can be used to successfully classify postconcussion syndrome in children. Although most children report a decay in symptoms over time, 10% of children develop symptoms even though they initially had a good outcome. Caution should be used when using only parent report as a surrogate for childhood outcomes following a concussion. PMID- 26421988 TI - Recurrent Stroke-Like Episodes in FBXL4-Associated Early-Onset Mitochondrial Encephalomyopathy. PMID- 26421990 TI - Spinal Subdural Hematoma in Nonaccidental Trauma. PMID- 26421989 TI - Successful Treatment of Electrographic Status Epilepticus of Sleep With Felbamate in a Patient With SLC9A6 Mutation. AB - BACKGROUND: Mutations of SLC9A6 may cause an X-linked clinical syndrome first described by Christianson in 1999 in which affected males exhibited profound intellectual disability, autism, drug-resistant epilepsy, ophthalmoplegia, mild craniofacial dysmorphism, microcephaly, and ataxia. METHODS: We describe a child with an SLC9A6 mutation and an electroencephalographic pattern consistent with electrographic status epilepticus of sleep. RESULTS: Our patient's electrographic status epilepticus of sleep resolved after treatment with felbamate. Following treatment, he remained seizure-free but did not make significant or lasting gains in language. CONCLUSION: Our report extends the clinical epilepsy phenotype in children with SLC9A6 mutations to include electrographic status epilepticus of sleep. In addition, felbamate was an effective treatment for electrographic status epilepticus of sleep in our patient. PMID- 26421991 TI - Highly efficient and fast pre-activation cyclization of the long peptide: Succinimidyl ester-amine reaction revisited. AB - A new method for the pre-activation cyclization of a long peptide is described. The approach involves the formation of a pre-activated succinimidyl ester species in advance of amidation, which completely eliminates the potentially troublesome amine end-capping side reaction. The cyclization reactions proceed with high efficiency and fast reaction kinetics for the long peptide with 25 residues. The exploration and large-scale preparation of synthetic cyclic peptides should become more accessible and feasible with this approach. This method has a potential to be further applied for the synthesis of much longer and more complex cyclic peptides. PMID- 26421992 TI - Synthesis and preliminary biological evaluation of a small library of hybrid compounds based on Ugi isocyanide multicomponent reactions with a marine natural product scaffold. AB - A mixture-based combinatorial library of five Ugi adducts (4-8) incorporating known antitubercular and antimalarial pharmacophores was successfully synthesized, starting from the naturally occurring diisocyanide 3, via parallel Ugi four-center three-component reactions (U-4C-3CR). The novel alpha-acylamino amides obtained were evaluated for their antiinfective potential against laboratory strains of Mycobacterium tuberculosis H37Rv and chloroquine susceptible 3D7 Plasmodium falciparum. Interestingly, compounds 4-8 displayed potent in vitro antiparasitic activity with higher cytotoxicity in comparison to their diisocyanide precursor 3, with the best compound exhibiting an IC50 value of 3.6 nM. Additionally, these natural product inspired hybrids potently inhibited in vitro thromboxane B2 (TXB2) and superoxide anion (O2(-)) generation from Escherichia coli lipopolysaccharide (LPS)-activated rat neonatal microglia, with concomitant low short-term toxicity. PMID- 26421994 TI - Site-specific incorporation of a fluorescent terphenyl unnatural amino acid. AB - The site-specific incorporation of unnatural amino acids into proteins has a wide range of biological implications. Of particular interest is the incorporation of fluorescent probes as a mechanism to track protein function, transport, and folding. Thus, the development of a novel system for the incorporation of new fluorescent unnatural amino acids has significant utility. Specifically, we have elucidated an aminoacyl-tRNA synthetase capable of recognizing a terphenyl UAA derivative, and charging a cognate tRNA with this amino acid for protein incorporation. Moreover, we have successfully incorporated this fluorescent UAA into GFP at several key residues, demonstrating a novel means to modulate fluorescence within the protein. PMID- 26421993 TI - Structure-guided discovery of 2-aryl/pyridin-2-yl-1H-indole derivatives as potent and selective hepsin inhibitors. AB - Hepsin, a type II transmembrane serine protease, is upregulated in prostate cancer and known to be involved in the progression of metastasis. Here we report a structure-guided approach, which resulted in the discovery of 2-aryl/pyridin-2 yl-1H-indole derivatives as potent and selective inhibitors of hepsin. Potent and selective inhibition of hepsin by compound 8 is likely due to interactions of the amidine group at the S1 site with the cyclohexyl ring from the 2-aryl group projecting towards the S1' site and the tert-hydroxyl group interacting with His57 side-chain as revealed by X-ray crystallography. Compounds 8 and 10, showed Ki of 0.1 MUM for hepsin, and exhibited inhibition of invasion and migration of hepsin-overexpressing cell line. Compounds described here could serve as useful tool reagents to investigate the role of hepsin as a potential therapeutic target in cancer. PMID- 26421995 TI - Design, synthesis and biological evaluation of 3-aryl-rhodanine benzoic acids as anti-apoptotic protein Bcl-2 inhibitors. AB - A new class of 3-aryl-rhodanine benzoic acid derivatives were designed, synthesized, and evaluated for their inhibition activities against anti-apoptotic Bcl-2 proteins. The potent compounds 33 and 41 bound to Bcl-2 with submicromolar Ki values and had selectivities to Bcl-2/Mcl-1 over Bcl-xL. In addition, they exhibited obvious antiproliferative activities in three human tumor cell lines (MDA-MB-231, K562 and PC-3). PMID- 26421997 TI - Unpaid work in health economic evaluations. AB - Given its societal importance, unpaid work should be included in economic evaluations of health care technology aiming to take a societal perspective. However, in practice this does not often appear to be the case. This paper provides an overview of the current place of unpaid work in economic evaluations in theory and in practice. It does so first by summarizing recommendations regarding the inclusion of unpaid labor reported in health economic textbooks and national guidelines for economic evaluations. In total, three prominent health economic text-books were studied and 28 national health economic guidelines. The paper, moreover, provides an overview of the instruments available to measure lost unpaid labor and reports on a review of the place of unpaid labor in applied economic evaluations in the area of rheumatoid arthritis. The review was conducted by examining methodology of evaluations published between 1 March 2008 and 1 March 2013. The results of this study show that little guidance is offered regarding the inclusion of unpaid labor in economic evaluations in textbooks and guidelines. The review identified five productivity costs instruments including questions about unpaid work and 33 economic evaluations of treatments for rheumatoid arthritis of which only one included unpaid work. The results indicate that unpaid work is rarely included in applied economic evaluations of treatments for rheumatoid arthritis, despite this disease expecting to be associated with lost unpaid work. Given the strong effects of certain diseases and treatments on the ability to perform unpaid work, unpaid work currently receives less attention in economic evaluations than it deserves. PMID- 26421996 TI - Panaxydol, a component of Panax ginseng, induces apoptosis in cancer cells through EGFR activation and ER stress and inhibits tumor growth in mouse models. AB - We reported previously that panaxydol, a component of Panax ginseng roots, induced mitochondria-mediated apoptosis preferentially in transformed cells. This study demonstrates that EGFR activation and the resulting ER stress mediate panaxydol-induced apoptosis, and that panaxydol suppresses in vivo tumor growth in syngeneic and xenogeneic mouse tumor models. In addition, we elucidated that CaMKII and TGF-beta-activated kinase (TAK1) participate in p38/JNK activation by elevated cytoplasmic Ca(2+) concentration ([Ca(2+)]c). In MCF-7 cells, EGFR was activated immediately after exposure to panaxydol, and this activation was necessary for induction of apoptosis, suggesting that panaxydol might be a promising anticancer candidate, especially for EGFR-addicted cancer. Activation of PLCgamma followed EGFR activation, resulting in Ca(2+) release from the endoplasmic reticulum (ER) via inositol triphosphate and ryanodine receptors. ER Ca(2+) release triggered mitochondrial Ca(2+) uptake indirectly through oxidative stress and ensuing ER stress. Elevated [Ca(2+)]c triggered sequential activation of calmodulin/CaMKII, TAK1 and p38/JNK. As shown previously, p38 and JNK activate NADPH oxidase. Here, it was shown that the resulting oxidative stress triggered ER stress. Among the three signaling branches of the unfolded protein response, protein kinase R-like ER kinase (PERK), but not inositol-requiring enzyme 1 or activating transcription factor 6, played a role in transmitting the apoptosis signal. PERK induced C/EBP homologous protein (CHOP), and CHOP elevated Bim expression, initiating mitochondrial Ca(2+) uptake and apoptosis. In summary, we identified roles of EGFR, the CAMKII-TAK1-p38/JNK pathway, and ER stress in panaxydol-induced apoptosis and demonstrated the in vivo anticancer effect of panaxydol. PMID- 26421999 TI - Sustained Increased Entry of Medical Students into Surgical Careers: A Student Led Approach. AB - OBJECTIVE: To determine whether a surgical interest group run entirely by preclinical students can influence medical students to enter general surgery residency programs. DESIGN: Matriculation rates into general surgery and affiliated subspecialties from Columbia University College of Physicians and Surgeons residency match lists were compared to National Residency Match Program data for all U.S. senior students from 2006 to 2014. SETTING: The Columbia University College of Physicians and Surgeons. RESULTS: After establishing the interest group, entrance rates into general surgery programs tripled from the early 2000s to more than 12% of 2006 Columbia University College of Physicians and Surgeons graduates. After 8 years, our data illustrate sustained results, with more than 8% of students entering surgical residencies, significantly higher than the National Residency Match Program's average (p < 0.025). CONCLUSIONS: Surgical interest groups spark early and lasting interest in surgery that may influence residency decisions. Moreover, these programs can be successfully run entirely by preclinical students and implemented in other institutions. PMID- 26422000 TI - Attending Surgeons' Leadership Style in the Operating Room: Comparing Junior Residents' Experiences and Preferences. AB - PURPOSE: Recent studies have focused on surgeons' nontechnical skills in the operating room (OR), especially leadership. In an attempt to identify trainee preferences, we explored junior residents' opinions about the OR leadership style of teaching faculty. METHODS: Overall, 20 interns and 20 mid-level residents completed a previously validated survey on the style of leadership they encountered, the style they preferred to receive, and the style they personally employed in the OR. In all, 4 styles were explored; authoritative: leader makes decisions and communicates them firmly; explanatory: leader makes decisions promptly, but explains them fully; consultative: leader consults with trainees when important decisions are made, and delegative: leader puts the problem before the group and makes decisions by majority opinion. Comparisons were completed using chi-square analysis. RESULTS: Junior resident preference for leadership style of attending surgeons in the OR differed from what they encountered. Overall, 62% of residents encountered an authoritative leadership style; however, only 9% preferred this (p < 0.001). Instead, residents preferred explanatory (53%) or consultative styles (41%). Preferences differed by postgraduate year. Although 40% of interns preferred a consultative style, 50% of mid-level residents preferred explanatory leadership. CONCLUSIONS: Junior resident preference of leadership style in the OR differs from what they actually encounter. This has the potential to create unwanted tension and may erode team performance. Awareness of this difference provides an opportunity for an educational intervention directed at both attendings and trainees. PMID- 26422001 TI - The Effect of Instrumentation on Suture Tensile Strength and Knot Pullout Strength of Common Suture Materials. AB - OBJECTIVE: To determine the effect of instrumentation of suture material on knot security and tensile strength. STUDY DESIGN: In all, 5 types of suture material were used; 10 knots were tied without any instrumentation and 10 knots were tied with a hemostat holding tension on the first throw while the second throw was made for each suture type. Each group was tested to failure with the maximum load and mode of failure recorded. The maximum load between groups of each suture type was compared; frequency of failure through knot slippage vs material fracture was also compared between groups. RESULTS: There was no significant difference observed in the maximum load to failure for any suture type between instrumented and noninstrumented groups. Additionally, there was no difference between any instrumented and noninstrumented groups for material failure vs failure due to knot slippage. CONCLUSIONS: Instrumentation of suture material during two-hand tying does not affect the strength of suture material or knot security. PMID- 26421998 TI - Site-Directed Mutagenesis of Surface-Exposed Lysine Residues Leads to Improved Transduction by AAV2, But Not AAV8, Vectors in Murine Hepatocytes In Vivo. AB - The ubiquitin-proteasome pathway plays a critical role in the intracellular trafficking of recombinant adeno-associated virus 2 (AAV2) vectors, which negatively impacts the transduction efficiency of these vectors. Because ubiquitination occurs on lysine (K) residues, we performed site-directed mutagenesis where we replaced each of 10 surface-exposed K residues (K258, K490, K507, K527, K532, K544, K549, K556, K665, and K706) with glutamic acid (E) because of similarity of size and lack of recognition by modifying enzymes. The transduction efficiency of K490E, K544E, K549E, and K556E scAAV2 vectors increased in HeLa cells in vitro up to 5-fold compared with wild-type (WT) AAV2 vectors, with the K556E mutant being the most efficient. Intravenous delivery of WT and K-mutant ssAAV2 vectors further corroborated these results in murine hepatocytes in vivo. Because AAV8 vectors transduce murine hepatocytes exceedingly well, and because some of the surface-exposed K residues are conserved between these serotypes, we generated and tested two single mutants (K547E and K569E), and one double-mutant (K547 + 569E) AAV8 vector. However, no significant increase in the transduction efficiency of any of these mutant AAV8 vectors was observed in murine hepatocytes in vivo. These studies suggest that although targeting the surface-exposed K residues is yet another strategy to improve the transduction efficiency of AAV vectors, phenotypic outcome is serotype specific. PMID- 26422002 TI - Reducing involuntary memory by interfering consolidation of stressful auditory information: A pilot study. AB - BACKGROUND AND OBJECTIVES: Intrusive emotional memories were induced by aversive auditory stimuli and modulated with cognitive tasks performed post-encoding (i.e., during consolidation). METHOD: A between-subjects design was used with four conditions; three consolidation-interference tasks (a visuospatial and two verbal interference tasks) and a no-task control condition. Forty-one participants listened to a soundtrack depicting traumatic scenes (e.g., police brutality, torture and rape). Immediately after listening to the soundtrack, the subjects completed a randomly assigned task for 10 min. Intrusions from the soundtrack were reported in a diary during the following seven-day period. RESULTS: In line with a modality-specific approach to intrusion modulation, auditory intrusions were reduced by verbal tasks compared to both a no-task and a visuospatial interference task.. LIMITATIONS: The study did not control for individual differences in imagery ability which may be a feature in intrusion development. CONCLUSIONS: The results provide an increased understanding of how intrusive mental images can be modulated which may have implications for preventive treatment.. PMID- 26422003 TI - Multifunctional Fe2O3@PPy-PEG nanocomposite for combination cancer therapy with MR imaging. AB - In recent years, magnetic hyperthermia nanoparticles have drawn great attention for cancer therapy because they have no limitation of tissue penetration during the therapy process. In this study, cubic nanoporous Fe2O3 nanoparticles derived from cubic Prussian blue nanoparticles were used as magnetic cores to generate heat by alternating the current magnetic field (AMF) for killing cancer cells. In addition, polypyrrole (PPy) was coated on the surfaces of the cubic Fe2O3 nanoparticles to load doxorubicin hydrochloride (DOX). The PEG component was then physically adsorbed onto the surfaces of the nanoparticles, resulting in a Fe2O3@PPy-DOX-PEG nanocomposite. The nanocomposite was triggered by acid stimulus and AMF to release DOX, resulting in a remarkable combination therapeutic effect via chemotherapy and magnetic hyperthermia. Furthermore, the nanocomposite could realize magnetic resonance imaging (MRI) due to the magnetic core structure. The study provides an alternative for the development of new nanocomposites for combination cancer therapy with MR imaging in vivo. PMID- 26422004 TI - Prenatal Cannabis and Tobacco Exposure in Relation to Brain Morphology: A Prospective Neuroimaging Study in Young Children. AB - BACKGROUND: Cannabis use during pregnancy has been associated with negative behavioral outcomes and psychopathology in offspring. However, there has been little research evaluating alterations in brain structure as a result of maternal cannabis use. In this prospective study, we investigated the association between prenatal cannabis exposure and brain morphology in young children. METHODS: We matched 96 children prenatally exposed to tobacco only (without cannabis) with 113 unexposed control subjects on the basis of age and gender and subsequently selected 54 children exposed to prenatal cannabis (mostly combined with tobacco exposure). These children (aged 6 to 8 years) were part of a population-based study in the Netherlands, the Generation R Study, and were followed from pregnancy onward. We assessed brain volumetric measures and cortical thickness in magnetic resonance imaging scans using FreeSurfer. We performed vertexwise analyses in FreeSurfer and linear regression analyses adjusting for relevant covariates using Statistical Package for the Social Sciences. RESULTS: Prenatal cannabis exposure was not associated with global brain volumes, such as total brain volume, gray matter volume, or white matter volume. However, prenatal cannabis exposure was associated with differences in cortical thickness: compared with nonexposed control subjects, cannabis-exposed children had thicker frontal cortices. Prenatal tobacco exposure compared with nonexposed control subjects was associated with cortical thinning, primarily in the superior frontal and superior parietal cortices. CONCLUSIONS: Our findings suggest an association between prenatal cannabis exposure and cortical thickness in children. Further research is needed to explore the causal nature of this association. PMID- 26422006 TI - Inhibiting the Inflammasome: A Chemical Perspective. AB - Inflammasomes are high molecular weight complexes that sense and react to injury and infection. Their activation induces caspase-1 activation and release of interleukin-1beta, a pro-inflammatory cytokine involved in both acute and chronic inflammatory responses. There is increasing evidence that inflammasomes, particularly the NLRP3 inflammasome, act as guardians against noninfectious material. Inappropriate activation of the NLRP3 inflammasome contributes to the progression of many noncommunicable diseases such as gout, type II diabetes, and Alzheimer's disease. Inhibiting the inflammasome may significantly reduce damaging inflammation and is therefore regarded as a therapeutic target. Currently approved inhibitors of interleukin-1beta are rilonacept, canakinumab, and anakinra. However, these proteins do not possess ideal pharmacokinetic properties and are unlikely to easily cross the blood-brain barrier. Because inflammation can contribute to neurological disorders, this review focuses on the development of small-molecule inhibitors of the NLRP3 inflammasome. PMID- 26422007 TI - The 4th Bi-annual international African-Caribbean Cancer Consortium conference: building capacity to address cancer health disparities in populations of African descent. AB - This is a brief summary of the 4(th) International Meeting of the African Caribbean Cancer Consortium (AC3), organized and sponsored by Fox Chase Cancer Center (FCCC), and held on July 21-22, 2012 at the Lincoln University Graduate Center, Lincoln Plaza, Philadelphia, Pennsylvania. AC3 investigators gathered in Philadelphia, PA to present the results of our ongoing collaborative research efforts throughout the African Diaspora. The general theme addressed cancer health disparities and presentations represented all cancer types. However, there was particular emphasis on women's cancers, related to human papillomavirus (HPV) and human immunodeficiency virus (HIV) infections. PMID- 26422005 TI - Neuroanatomic Differences Associated With Stress Susceptibility and Resilience. AB - BACKGROUND: We examined the neurobiological mechanisms underlying stress susceptibility using structural magnetic resonance imaging and diffusion tensor imaging to determine neuroanatomic differences between stress-susceptible and resilient mice. We also examined synchronized anatomic differences between brain regions to gain insight into the plasticity of neural networks underlying stress susceptibility. METHODS: C57BL/6 mice underwent 10 days of social defeat stress and were subsequently tested for social avoidance. For magnetic resonance imaging, brains of stressed (susceptible, n = 11; resilient, n = 8) and control (n = 12) mice were imaged ex vivo at 56 um resolution using a T2-weighted sequence. We tested for behavior-structure correlations by regressing social avoidance z-scores against local brain volume. For diffusion tensor imaging, brains were scanned with a diffusion-weighted fast spin echo sequence at 78 MUm isotropic voxels. Structural covariance was assessed by correlating local volume between brain regions. RESULTS: Social avoidance correlated negatively with local volume of the cingulate cortex, nucleus accumbens, thalamus, raphe nuclei, and bed nucleus of the stria terminals. Social avoidance correlated positively with volume of the ventral tegmental area (VTA), habenula, periaqueductal gray, cerebellum, hypothalamus, and hippocampal CA3. Fractional anisotropy was increased in the hypothalamus and hippocampal CA3. We observed synchronized anatomic differences between the VTA and cingulate cortex, hippocampus and VTA, hippocampus and cingulate cortex, and hippocampus and hypothalamus. These correlations revealed different structural covariance between brain regions in susceptible and resilient mice. CONCLUSIONS: Stress-integrative brain regions shape the neural architecture underlying individual differences in susceptibility and resilience to chronic stress. PMID- 26422008 TI - Molecular Binding Mechanism of TtgR Repressor to Antibiotics and Antimicrobials. AB - A disturbing phenomenon in contemporary medicine is the prevalence of multidrug resistant pathogenic bacteria. Efflux pumps contribute strongly to this antimicrobial drug resistance, which leads to the subsequent failure of clinical treatments. The TtgR protein of Pseudomonas putida is a HTH-type transcriptional repressor that controls expression of the TtgABC efflux pump, which is the main contributor to resistance against several antimicrobials and toxic compounds in this microbe. One of the main strategies to modulate the bacterial resistance is the rational modification of the ligand binding target site. We report the design and characterization of four mutants-TtgRS77A, TtgRE78A, TtgRN110A and TtgRH114A at the active ligand binding site. The biophysical characterization of the mutants, in the presence and in the absence of different antimicrobials, revealed that TtgRN110A is the variant with highest thermal stability, under any of the experimental conditions tested. EMSA experiments also showed a different dissociation pattern from the operator for TtgRN110A, in the presence of several antimicrobials, making it a key residue in the TtgR protein repression mechanism of the TtgABC efflux pump. We found that TtgRE78A stability is the most affected upon effector binding. We also probe that one mutation at the C-terminal half of helix-alpha4, TtgRS77A, provokes a severe protein structure distortion, demonstrating the important role of this residue in the overall protein structure and on the ligand binding site. The data provide new information and deepen the understanding of the TtgR-effector binding mechanism and consequently the TtgABC efflux pump regulation mechanism in Pseudomonas putida. PMID- 26422009 TI - Effects of Dietary Crude Protein Levels and Cysteamine Supplementation on Protein Synthetic and Degradative Signaling in Skeletal Muscle of Finishing Pigs. AB - Dietary protein levels and cysteamine (CS) supplementation can affect growth performance and protein metabolism of pigs. However, the influence of dietary protein intake on the growth response of CS-treated pigs is unclear, and the mechanisms involved in protein metabolism remain unknown. Hence, we investigated the interactions between dietary protein levels and CS supplementation and the effects of dietary crude protein levels and CS supplementation on protein synthetic and degradative signaling in skeletal muscle of finishing pigs. One hundred twenty barrows (65.84 +/- 0.61 kg) were allocated to a 2 * 2 factorial arrangement with five replicates of six pigs each. The primary variations were dietary crude protein (CP) levels (14% or 10%) and CS supplemental levels (0 or 700 mg/kg). The low-protein (LP) diets (10% CP) were supplemented with enough essential amino acids (EAA) to meet the NRC AA requirements of pigs and maintain the balanced supply of eight EAA including lysine, methionine, threonine, tryptophan, valine, phenylalanine, isoleucine, and leucine. After 41 days, 10 pigs per treatment were slaughtered. We found that LP diets supplemented with EAA resulted in decreased concentrations of plasma somatostatin (SS) (P<0.01) and plasma urea nitrogen (PUN) (P<0.001), while dietary protein levels did not affect other traits. However, CS supplementation increased the average daily gain (P<0.001) and lean percentage (P<0.05), and decreased the feed conversion ratio (P<0.05) and back fat (P<0.05). CS supplementation also increased the concentrations of plasma insulin-like growth factor 1 (IGF-1) (P<0.001), and reduced the concentrations of leptin, SS, and PUN (P<0.001). Increased mRNA abundance of Akt1 and IGF-1 signaling (P<0.001) and decreased mRNA abundance of Forkhead Box O (FOXO) 4 (P<0.01) and muscle atrophy F-box (P<0.001) were observed in pigs receiving CS. Additionally, CS supplementation increased the protein levels for the phosphorylated mammalian target of rapamycin (mTOR), eIF-4E binding protein 1, and ribosomal protein S6 kinase 1 (P<0.001). There were no interactions between dietary protein levels and CS supplementation for all traits. In conclusion, dietary protein levels and CS supplementation influenced growth and protein metabolism through independent mechanisms in pigs. In addition, LP diets supplemented with EAA did not affect growth performance and other traits except the concentrations of SS and PUN probably through maintenance of protein synthesis and degradation signaling. Moreover, CS supplementation improved growth performance by increasing plasma IGF-1 concentrations possibly through alterations of mTOR and Akt/FOXO signaling pathways in skeletal muscle of finishing pigs. PMID- 26422010 TI - Evaluation of the Anti-Inflammatory, Antioxidant and Immunomodulatory Effects of the Organic Extract of the Red Sea Marine Sponge Xestospongia testudinaria against Carrageenan Induced Rat Paw Inflammation. AB - Marine sponges are found to be a rich source of bioactive compounds which show a wide range of biological activities including antiviral, antibacterial, and anti inflammatory activities. This study aimed to investigate the possible anti inflammatory, antioxidant and immunomodulator effects of the methanolic extract of the Red Sea marine sponge Xestospongia testudinaria. The chemical composition of the Xestospongia testudinaria methanolic extract was determined using Gas chromatography-mass spectroscopy (GC-MS) analysis. DPPH (2, 2-diphenyl-1-picryl hydrazyl) was measured to assess the antioxidant activity of the sponge extract. Carrageenan-induced rat hind paw edema was adopted in this study. Six groups of rats were used: group1: Control, group 2: Carrageenan, group 3: indomethacin (10 mg/kg), group 4-6: Xestospongia testudinaria methanolic extract (25, 50, and 100 mg/kg). Evaluation of the anti-inflammatory activity was performed by both calculating the percentage increase in paw weight and hisopathologically. Assessment of the antioxidant and immunomodulatory activity was performed. GC-MS analysis revealed that there were 41 different compounds present in the methanolic extract. Sponge extract exhibited antioxidant activity against DPPH free radicals. Xestospongia testudinaria methanolic extract (100 mg/kg) significantly decreased % increase in paw weight measured at 1, 2, 3 and 4 h after carrageenan injection. Histopathologically, the extract caused a marked decrease in the capillary congestion and inflammatory cells infiltrate. The extract decreased paw malondialdehyde (MDA) and nitric oxide (NO) and increased the reduced glutathione (GSH), glutathione peroxidase (GPx), and catalase (CAT) activity. It also decreased the inflammatory cytokines, tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta(IL-1beta) and IL-6. The results of this study demonstrated the anti-inflammatory, antioxidant, and immunomodulatory effects of the methanolic extract of the Red Sea sponge Xestospongia testudinaria (100 mg/kg). PMID- 26422013 TI - Nonfamilial Chronic Serum Alpha-Fetoprotein Increase in a Patient With Clinical Stage I Seminoma. PMID- 26422012 TI - Modelling Future Coronary Heart Disease Mortality to 2030 in the British Isles. AB - OBJECTIVE: Despite rapid declines over the last two decades, coronary heart disease (CHD) mortality rates in the British Isles are still amongst the highest in Europe. This study uses a modelling approach to compare the potential impact of future risk factor scenarios relating to smoking and physical activity levels, dietary salt and saturated fat intakes on future CHD mortality in three countries: Northern Ireland (NI), Republic of Ireland (RoI) and Scotland. METHODS: CHD mortality models previously developed and validated in each country were extended to predict potential reductions in CHD mortality from 2010 (baseline year) to 2030. Risk factor trends data from recent surveys at baseline were used to model alternative future risk factor scenarios: Absolute decreases in (i) smoking prevalence and (ii) physical inactivity rates of up to 15% by 2030; relative decreases in (iii) dietary salt intake of up to 30% by 2030 and (iv) dietary saturated fat of up to 6% by 2030. Probabilistic sensitivity analyses were then conducted. RESULTS: Projected populations in 2030 were 1.3, 3.4 and 3.9 million in NI, RoI and Scotland respectively (adults aged 25-84). In 2030: assuming recent declining mortality trends continue: 15% absolute reductions in smoking could decrease CHD deaths by 5.8-7.2%. 15% absolute reductions in physical inactivity levels could decrease CHD deaths by 3.1-3.6%. Relative reductions in salt intake of 30% could decrease CHD deaths by 5.2-5.6% and a 6% reduction in saturated fat intake might decrease CHD deaths by some 7.8 9.0%. These projections remained stable under a wide range of sensitivity analyses. CONCLUSIONS: Feasible reductions in four cardiovascular risk factors (already achieved elsewhere) could substantially reduce future coronary deaths. More aggressive polices are therefore needed in the British Isles to control tobacco, promote healthy food and increase physical activity. PMID- 26422011 TI - Placental Cadmium Levels Are Associated with Increased Preeclampsia Risk. AB - Environmental exposure to heavy metals is a potentially modifiable risk factor for preeclampsia (PE). Toxicologically, there are known interactions between the toxic metal cadmium (Cd) and essential metals such as selenium (Se) and zinc (Zn), as these metals can protect against the toxicity of Cd. As they relate to preeclampsia, the interaction between Cd and these essential metals is unknown. The aims of the present study were to measure placental levels of Cd, Se, and Zn in a cohort of 172 pregnant women from across the southeast US and to examine associations of metals levels with the odds of PE in a nested case-control design. Logistic regressions were performed to assess odds ratios (OR) for PE with exposure to Cd controlling for confounders, as well as interactive models with Se or Zn. The mean placental Cd level was 3.6 ng/g, ranging from 0.52 to 14.5 ng/g. There was an increased odds ratio for PE in relationship to placental levels of Cd (OR = 1.5; 95% CI: 1.1-2.2). The Cd-associated OR for PE increased when analyzed in relationship to lower placental Se levels (OR = 2.0; 95% CI: 1.1 3.5) and decreased with higher placental Se levels (OR = 0.98; 95% CI: 0.5-1.9). Similarly, under conditions of lower placental Zn, the Cd-associated OR for PE was elevated (OR = 1.8; 95% CI: 0.8-3.9), whereas with higher placental Zn it was reduced (OR = 1.3; 95% CI: 0.8-2.0). Data from this pilot study suggest that essential metals may play an important role in reducing the odds of Cd-associated preeclampsia and that replication in a larger cohort is warranted. PMID- 26422014 TI - Tumor Vascularity in Renal Masses: Correlation of Arterial Spin-Labeled and Dynamic Contrast-Enhanced Magnetic Resonance Imaging Assessments. AB - Arterial spin-labeled (ASL) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) have been proposed to quantitatively assess vascularity in renal cell carcinoma (RCC). However, there are intrinsic differences between these 2 imaging methods, such as the relative contribution of vascular permeability and blood flow to signal intensity for DCE MRI. We found a correlation between ASL perfusion and the DCE-derived volume transfer constant and rate constant parameters in renal masses > 2 cm in size and these measures correlated with microvessel density in clear cell RCC. BACKGROUND: The objective of this study was to investigate potential correlations between perfusion using arterial spin-labeled (ASL) magnetic resonance imaging (MRI) and dynamic contrast enhanced (DCE) MRI-derived quantitative measures of vascularity in renal masses > 2 cm and to correlate these with microvessel density (MVD) in clear cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: Informed written consent was obtained from all patients before imaging in this Health Insurance Portability and Accountability Act-compliant, institutional review board-approved, prospective study. Thirty-six consecutive patients scheduled for surgery of a known renal mass > 2 cm underwent 3T ASL and DCE MRI. ASL perfusion measures (PASL) of mean, peak, and low perfusion areas within the mass were correlated to DCE-derived volume transfer constant (K(trans)), rate constant (Kep), and fractional volume of the extravascular extracellular space (Ve) in the same locations using a region of interest analysis. MRI data were correlated to MVD measures in the same tumor regions in ccRCC. Spearman correlation was used to evaluate the correlation between PASL and DCE-derived measurements, and MVD. P < .05 was considered statistically significant. RESULTS: Histopathologic diagnosis was obtained in 36 patients (25 men; mean age 58 +/- 12 years). PASL correlated with K(trans) (rho = 0.48 and P = .0091 for the entire tumor and rho = 0.43 and P = .03 for the high flow area, respectively) and Kep (rho = 0.46 and P = .01 for the entire tumor and rho = 0.52 and P = .008 for the high flow area, respectively). PASL (rho = 0.66; P = .0002), K(trans) (rho = 0.61; P = .001), and Kep (rho = 0.64; P = .0006) also correlated with MVD in high and low perfusion areas in ccRCC. CONCLUSION: PASL correlated with the DCE-derived measures of vascular permeability and flow, K(trans) and Kep, in renal masses > 2 cm in size. Both measures correlated to MVD in clear cell histology. PMID- 26422015 TI - Epidemiological Characteristics and Spatial-Temporal Clusters of Hand, Foot, and Mouth Disease in Zhejiang Province, China, 2008-2012. AB - Hand, foot and mouth disease (HFMD) is one of the major public health concerns in China. Being the province with high incidence rates of HFMD, the epidemiological features and the spatial-temporal patterns of Zhejiang Province were still unknown. The objective of this study was to investigate the epidemiological characteristics and the high-incidence clusters, as well as explore some potential risk factors. The surveillance data of HFMD during 2008-2012 were collected from the communicable disease surveillance network system of Zhejiang Provincial Center for Disease Control and Prevention. The distributions of age, gender, occupation, season, region, pathogen's serotype and disease severity were analyzed to describe the epidemiological features of HFMD in Zhejiang Province. Seroprevalence survey for human enterovirus 71 (EV71) in 549 healthy children of Zhejiang Province was also performed, as well as 27 seroprevalence publications between 1997 and 2015 were summarized. The spatial-temporal methods were performed to explore the clusters at county level. Furthermore, pathogens' serotypes such as EV71 and coxsackievirus A16 (Cox A16) and meteorological factors were analyzed to explore the potential factors associated with the clusters. A total of 454,339 HFMD cases were reported in Zhejiang Province during 2008-2012, including 1688 (0.37%) severe cases. The annual average incidence rate was 172.98 per 100,000 (ranged from 72.61 to 270.04). The male-to-female ratio for mild cases was around 1.64:1, and up to 1.87:1 for severe cases. Of the total cases, children aged under three years old and under five years old accounted for almost 60% and 90%, respectively. Among all enteroviruses, the predominant serotype was EV71 (49.70%), followed by Cox A16 (26.05%) and other enteroviruses (24.24%) for mild cases. In severe cases, EV71 (82.85%) was the major causative agent. EV71 seroprevalence survey in healthy children confirmed that occult infection was common in children. Furthermore, literature summary for 26 seroprevalence studies during 1997-2015 confirmed that 0-5 years group showed lowest level of EV71 seroprevalence (29.1% on average) compared to the elder children (6-10 years group: 54.6%; 11-20 years group: 61.8%). Global positive spatial autocorrelation patterns (Moran's Is>0.25, P<0.05) were discovered not only for mild cases but also for severe cases, and local positive spatial autocorrelation patterns were revealed for counties from the eastern coastal and southern regions. The retrospective space-time cluster analysis also confirmed these patterns. Risk factors analyses implied that more EV71 and less sunshine were associated with the clusters of HFMD in Zhejiang Province. Our study confirmed that Zhejiang Province was one of the highly epidemic provinces in China and that the epidemiological characteristics of HFMD were similar to other provinces. Occult infection in elder children and adults was one of the important reasons why most HFMD cases were children aged under-five. Combining the results of spatial autocorrelation analysis and the space-time cluster analysis, the major spatial-temporal clusters were from the eastern coastal and southern regions. The distribution of pathogens' serotypes and the level of sunshine could be risk factors for, and serve as an early warning of, the outbreak of HFMD in Zhejiang Province. PMID- 26422016 TI - Detecting Lung Diseases from Exhaled Aerosols: Non-Invasive Lung Diagnosis Using Fractal Analysis and SVM Classification. AB - BACKGROUND: Each lung structure exhales a unique pattern of aerosols, which can be used to detect and monitor lung diseases non-invasively. The challenges are accurately interpreting the exhaled aerosol fingerprints and quantitatively correlating them to the lung diseases. OBJECTIVE AND METHODS: In this study, we presented a paradigm of an exhaled aerosol test that addresses the above two challenges and is promising to detect the site and severity of lung diseases. This paradigm consists of two steps: image feature extraction using sub-regional fractal analysis and data classification using a support vector machine (SVM). Numerical experiments were conducted to evaluate the feasibility of the breath test in four asthmatic lung models. A high-fidelity image-CFD approach was employed to compute the exhaled aerosol patterns under different disease conditions. FINDINGS: By employing the 10-fold cross-validation method, we achieved 100% classification accuracy among four asthmatic models using an ideal 108-sample dataset and 99.1% accuracy using a more realistic 324-sample dataset. The fractal-SVM classifier has been shown to be robust, highly sensitive to structural variations, and inherently suitable for investigating aerosol-disease correlations. CONCLUSION: For the first time, this study quantitatively linked the exhaled aerosol patterns with their underlying diseases and set the stage for the development of a computer-aided diagnostic system for non-invasive detection of obstructive respiratory diseases. PMID- 26422017 TI - Marital Quality and Stress in Pregnancy Predict the Risk of Infectious Disease in the Offspring: The Norwegian Mother and Child Cohort Study. AB - OBJECTIVES: The aim of this study was to explore the degree to which couples' relationship dissatisfaction and stressful life events during pregnancy predict the risk of infectious disease in the offspring during their first year of life. METHODS: Data were obtained from the Norwegian Mother and Child Cohort Study, conducted by the Norwegian Institute of Public Health. Pregnant women completed questionnaires in week 30 of pregnancy concerning the couples' relationship satisfaction and stressful life events. In follow-up questionnaires, the women reported whether their children (n = 74,801) had been subject to various categories of infectious disease: the common cold, throat infection, bronchitis, RS virus, pneumonia, pseudocroup, gastric flu, ear infection, conjunctivitis and urinary tract infection. Reports from two age groups of infants were used. Associations between the predictor and outcome variables were assessed via logistic regression and linear regression analyses. RESULTS: Separate logistic regression analyses for each disease and age group showed that prenatal relationship dissatisfaction and stressful life events were significantly associated with all reported categories of infectious disease. After controlling for socioeconomic factors, social support, smoking, breastfeeding, maternal depression, the sex of the offspring, and use of child care, 29 out of 32 tested associations were statistically significant. Finally, multivariate linear regression analyses showed that prenatal relationship dissatisfaction and stressful life events were significantly associated with the frequency, as well as the variety, of infectious disease in the offspring. PMID- 26422018 TI - Cloud-Based Service Information System for Evaluating Quality of Life after Breast Cancer Surgery. AB - OBJECTIVE: Although recent studies have improved understanding of quality of life (QOL) outcomes of breast conserving surgery, few have used longitudinal data for more than two time points, and few have examined predictors of QOL over two years. Additionally, the longitudinal data analyses in such studies rarely apply the appropriate statistical methodology to control for censoring and inter correlations arising from repeated measures obtained from the same patient pool. This study evaluated an internet-based system for measuring longitudinal changes in QOL and developed a cloud-based system for managing patients after breast conserving surgery. METHODS: This prospective study analyzed 657 breast cancer patients treated at three tertiary academic hospitals. Related hospital personnel such as surgeons and other healthcare professionals were also interviewed to determine the requirements for an effective cloud-based system for surveying QOL in breast cancer patients. All patients completed the SF-36, Quality of Life Questionnaire (QLQ-C30) and its supplementary breast cancer measure (QLQ-BR23) at baseline, 6 months, 1 year, and 2 years postoperatively. The 95% confidence intervals for differences in responsiveness estimates were derived by bootstrap estimation. Scores derived by these instruments were interpreted by generalized estimating equation before and after surgery. RESULTS: All breast cancer surgery patients had significantly improved QLQ-C30 and QLQ-BR23 subscale scores throughout the 2-year follow-up period (p<0.05). During the study period, QOL generally had a negative association with advanced age, high Charlson comorbidity index score, tumor stage III or IV, previous chemotherapy, and long post operative LOS. Conversely, QOL was positively associated with previous radiotherapy and hormone therapy. Additionally, patients with high scores for preoperative QOL tended to have high scores for QLQ-C30, QLQ-BR23 and SF-36 subscales. Based on the results of usability testing, the five constructs were rated on a Likert scale from 1-7 as follows: system usefulness (5.6+/-1.8), ease of use (5.6+/-1.5), information quality (5.4+/-1.4), interface quality (5.5+/ 1.4), and overall satisfaction (5.5+/-1.6). CONCLUSIONS: The current trend in clinical medicine is applying therapies and interventions that improve QOL. Therefore, a potentially vast amount of internet-based QOL data is available for use in defining patient populations that may benefit from therapeutic intervention. Additionally, before undergoing breast conserving surgery, patients should be advised that their postoperative QOL depends not only on the success of the surgery, but also on their preoperative functional status. PMID- 26422019 TI - Ictal bruxism treated with temporal lobectomy. PMID- 26422021 TI - Renal sympathetic denervation in uncontrolled arterial hypertension after successful repair for aortic coarctation. AB - BACKGROUND: Uncontrolled arterial hypertension is a frequent problem after successful repair of CoA and has been attributed to increased central sympathetic drive as well as a blunted baroreceptor reflex. RSD is a promising therapy to reduce central sympathetic drive and improve baroreflex sensitivity. METHODS: 8 patients (age: 27+/-6 years) with previous surgical and/or percutaneous repair of CoA, absence of any relevant restenosis (invasive gradient across the site of previous treatment 3+/-4 mmHg) and resistant arterial hypertension (daytime SBP>=140 mmHg on 24 hour ambulatory blood pressure measurements [ABPM] in spite of the concurrent use of 3 antihypertensive agents of different classes or intolerance to BP medications) were included. Bilateral RSD was performed using the Symplicity FlexTM catheter (Medtronic, MN, USA). RESULTS: RSD was successful in all patients with no procedural complications and no evidence for renal artery stenosis 6 months post procedure. From baseline to 6 month follow-up, RSD was followed by a significant reduction in average daytime systolic BP (150.4+/-7.8 to 143.1+/-8.0 mmHg; p=0.0117) as well as systolic BP throughout 24 h (146.8+/ 7.3 vs. 140.5+/-7.8, p=0.04). CONCLUSION: The BP reductions observed in these patients justify engaging in a larger clinical trial on the efficacy of RSD in this specific type of secondary hypertension and bares the hope that RSD might extend the currently very limited armory against arterial hypertension in young adults with previous repair of CoA. PMID- 26422022 TI - Physical activity and diet on quality of life and mortality: The importance of meeting one specific or both behaviors. PMID- 26422020 TI - Localization of CD8 T cell epitope within cardiac myosin heavy chain-alpha334-352 that induces autoimmune myocarditis in A/J mice. AB - BACKGROUND: Cardiac myosin heavy chain-alpha (Myhc), an intracellular protein expressed in the cardiomyocytes, has been identified as a major autoantigen in cardiac autoimmunity. In our studies with Myhc334-352-induced experimental autoimmune myocarditis in A/J mice (H-2a), we discovered that Myhc334-352, supposedly a CD4 T cell epitope, also induced antigen-specific CD8 T cells that transfer disease to naive animals. METHODS AND RESULTS: In our efforts to identify the CD8 T cell determinants, we localized Myhc338-348 within the full length-Myhc334-352, leading to four key findings. (1) By acting as a dual epitope, Myhc338-348 induces both CD4 and CD8 T cell responses. (2) In a major histocompatibility complex (MHC) class I-stabilization assay, Myhc338-348 was found to bind H-2Dd-but not H-2Kk or H-2Ld-alleles. (3) The CD8 T cell response induced by Myhc338-348 was antigen-specific, as evaluated by MHC class I/H-2Dd dextramer staining. The antigen-sensitized T cells predominantly produced interferon-gamma, the critical cytokine of effector cytotoxic T lymphocytes. (4) Myhc338-348 was found to induce myocarditis in immunized animals as determined by histology and magnetic resonance microscopy imaging. CONCLUSIONS: Our data provide new insights as to how different immune cells can recognize the same antigen and inflict damage through different mechanisms. PMID- 26422023 TI - Histopathologic and Clinical Characterization of Thyroid Tumors Carrying the BRAF(K601E) Mutation. AB - BACKGROUND: While the association of the BRAF(V600E) mutation with aggressive histopathological tumor features and clinical behavior has been extensively studied in papillary thyroid carcinoma (PTC), the BRAF(K601E) mutation has not been well characterized. This study reports what is currently the largest series of BRAF(K601E) mutated thyroid nodules. METHODS: Histopathologic, cytologic, and molecular reports over a period of seven years (June 2007 to June 2014) were reviewed to identify thyroid cases with various types of BRAF mutations. All cases positive for the BRAF(K601E) mutation were reviewed to confirm histopathologic diagnosis and establish tumor variant, and clinical charts were reviewed to obtain clinical characteristics and follow-up information. RESULTS: The BRAF(K601E) mutation was identified in 39 patients and comprised 5.3% of all BRAF mutations noted in thyroidectomy specimens. Twenty-seven out of 29 nodules (93%) with BRAF(K601E) mutated tumors with surgical pathology results available for review were PTC, one (3.4%) was a follicular thyroid carcinoma, and one (3.4%) was a follicular adenoma. The majority of K601E-mutant PTCs (20 cases) were follicular variant PTC. Encapsulation was present in all but one case, and one case showed capsular invasion. Coexisting mutations overall were not identified in BRAF(K601E) mutated thyroid nodules except in a case that exhibited a complex K601E + T599I mutation and had a classic PTC phenotype. The majority of K601E mutant nodules were T1 lesions (69%) and T2 lesions (28%) by TNM staging. With a median follow-up of 19.6 months, no structural or biochemical recurrence or metastases were found in patients with an isolated BRAF(K601E) mutation. CONCLUSIONS: The BRAF(K601E) mutation is the second most common BRAF mutation found in thyroid nodules. Unlike BRAF(V600E), the most common mutation, K601E is strongly associated with follicular-patterned cancer, particularly with the encapsulated follicular variant of PTC, and may also be found in follicular thyroid carcinomas. Overall, BRAF(K601E) mutant tumors show better clinical outcomes than BRAF(V600E) positive tumors, and preoperative BRAF(K601E) analysis may provide important prognostic information for use in clinical management. PMID- 26422024 TI - Research in nursing and new pathways based on SENPE. PMID- 26422025 TI - Considerations about the manuscript published. Re: Chinese auriculotherapy to improve quality of life of nursing team. PMID- 26422026 TI - AUTHORS'S ANSWER. PMID- 26422027 TI - Beliefs of older adults about their vulnerability to HIV/Aids, for the construction of nursing diagnoses. AB - OBJECTIVE: to know the beliefs of older adults about their vulnerability to HIV/Aids, and to identify nursing diagnoses. METHOD: a field research implemented in Family Health Units, in Joao Pessoa, Brazil. The sample included 250 older adults of both genders with data collected from April to July of 2011. A Test of Free Word Association was applied using the term HIV/Aids. A content analysis and cross-mapping of the most frequent terms with the International Classification for Nursing Practice, 2011 were performed. RESULTS: 202 terms were identified in terms, with an overall frequency of 1156. Of the 202 terms, 16 were more frequent and were used to construct the nursing diagnoses. The diagnoses identified were knowledge about appropriate sexual behavior, ability for partial protection, fear of death and hopelessness. CONCLUSION: understanding these beliefs drew from knowledge about factors related to, vulnerability to HIV/Aids aimed at planning health care actions for this population segment. PMID- 26422028 TI - Multiprofessional residency in health: a document analysis of political pedagogical projects. AB - The object of the present study was collaborative education in multiprofessional residency in health (MPRH) through interprofessional education (IPE). OBJECTIVE: To analyze MPRH political pedagogical projects (PPP) developed in the state of Sao Paulo and identify scenarios that are highly favorable to IPE. METHOD: This was a descriptive exploratory study conducted through document analysis. RESULTS: The analysis revealed a heterogeneous scenario regarding the curricula, didactic and pedagogical organization, educational objectives, pedagogical matrices and evaluation systems employed. One of the programs was identified as providing a highly favorable setting for IPE. CONCLUSION: The analysis adequately evaluated IPE in educational settings and found a highly favorable scenario for it, identifying didactic, pedagogical, political and organizational MPRH elements. PMID- 26422029 TI - The family living the child recovery process after hospital discharge. AB - OBJECTIVE: to understand the meaning attributed by the family to its experience in the recovery process of a child affected by an acute disease after discharge, and to develop a theoretical model of this experience. Symbolic interactionism was adopted as a theoretical reference, and grounded theory was adopted as a methodological reference. METHOD: data were collected through interviews and participant observation with 11 families, totaling 15 interviews. A theoretical model consisting of two interactive phenomena was formulated from the analysis: Mobilizing to restore functional balance and Suffering from the possibility of a child's readmission. RESULTS: the family remains alert to identify early changes in the child's health, in an attempt to avoid rehospitalization. CONCLUSION: the effects of the disease and hospitalization continue to manifest in family functioning, causing suffering even after the child's discharge and recovery. PMID- 26422030 TI - Prevalence and factors associated with smoking among tobacco growers in southern Brazil. AB - OBJECTIVE: identify the prevalence and factors associated with smoking in tobacco growers. METHOD: descriptive, cross-sectional research. Data collection occurred in 2012 through household survey and interviews, including application of a structured instrument and scale Fargestrom. RESULTS: there were 100 growers included, average age of 46,9 +/- 10,8 years; 90(90%) married; 72(72%) white, average family composition 3,7+/-1,1 people; median number of children 3(1-3), and the average study time 6+/-2,5. The prevalence of smoking among tobacco growers was 17%, which had less education (p=0.010) and fewer people in the household (p=0.049). CONCLUSION: the prevalence of smoking among tobacco growers was higher than the national average, but the nicotine dependence was low, which can facilitate the smoking cessation process. Highlights the need to implement a program to control smoking among tobacco growers. PMID- 26422031 TI - Social representations about religion and spirituality. AB - OBJECTIVE: to identify the social representations about the concepts of spirituality and religion of of health teachers. METHOD: exploratory and descriptive study, based on a qualitative approach. 25 subjects participated in it. The following instruments were used to collect data: questionnaire to identify the profile; questionnaire of free association, whose inducing words were religion and spirituality, and an interview based on the scale FICA (Puchalski, 2006). RESULTS: the representations about religion and spirituality, for professors, are forged around the faith in God and it gives them meaning and purpose to deal with the challenges of personal and professional living. CONCLUSION: there are still barriers that need to be overcome with a view to a comprehensive care. For this, it is essential to incorporate spirituality in the process in the curricula of health courses. PMID- 26422032 TI - Violence in the eye of adolescents: education intervention with Culture Circles. AB - OBJECTIVE: to apply the methodology of Culture Circles on adolescents as a strategy for health education of nurses in the construction of the collective knowledge of the thematic violence. METHOD: action research type and qualitative study. Participants were 11 adolescents from a public school in Recife, PE, Brazil. Data production in Culture Circles included the participant observation with field diary, photographic recording and filming, as well as the photovoice technique. The analysis was performed by triangulating data in dialogue with the literature. RESULTS: it was shown that the problematizing action provided by the Culture Circle made possible to create situations in which adolescents felt invited to critically refl ect on the phenomenon of violence in all its complexity. CONCLUSION: the health education intervention, performed by Culture Circles, added learning and mutual growth subsidizing nursing care actions that excel at leadership and autonomy of adolescents. PMID- 26422033 TI - Hypertension and Diabetes Mellitus Program evaluation on user's view. AB - OBJECTIVES: to evaluate the program proposed by the Reorganization Care Plan for Hypertension and Diabetes Mellitus on user's view, and describe aspects of the trajectory of the participants correlating with the program's evaluation. METHOD: evaluative study with a qualitative approach conducted in health units with the Family Health Strategy, in a city of the metropolitan region of Curitiba, in the period from September to March, 2012. A total of 30 adults with hypertension and/or Diabetes mellitus were interviewed. Data were analyzed through content analysis. RESULTS: Four categories were identified: Disease diagnosis; Reasons for the program need; Knowledge of the program, and program evaluation. CONCLUSION: there was the recognition of the orientations, and the monitoring of activities developed, with emphasis in cost reduction for users. PMID- 26422034 TI - Functional disability and socioeconomic and demographic factors in elderly. AB - OBJECTIVE: to verify the prevalence of functional disability and associated socioeconomic and demographic factors in elderly patients of Campina Grande/PB. METHOD: cross-sectional study with elderly patients of both genders. The variables associated with functional disability were assessed using Poisson regression. RESULTS: A total of 420 elderly patients were included (68.1% women). The highest prevalence of functional disability were found among females aged 80 or older, white, widowed, of economic classes D/E , who lived alone, with frequency of contacts of up to 224 people and diversity of contacts of up to 14 people. After multivariate analysis, statistically significant association was observed between functional disability, gender and age group. CONCLUSION: the association between functional disability gender and age group is shown to be an important guidance for health interventions since it will allow health services to plan actions aiming to improve, maintain or restore the functional capacity of the elderly population. PMID- 26422035 TI - Nursing care management for children hospitalized with chronic conditions. AB - OBJECTIVE: to understand the interactions of nurses managing nursing care for the hospitalized child with a chronic condition. METHOD: Theoretical and methodological references were used, Complex Thought and grounded theory, respectively. In the study 18 subjects have participated arranged in three groups: nurses, nursing technicians and family members. A semi-structured interview was used as technique for data collection. The data analysis followed three stages of coding: open, axial and selective. RESULTS: the category "Needing to manage nursing care to the hospitalized child with chronic condition in Pediatric Inpatient Unit" and their subcategories show the complex inter subjective bindings established by nurses that support the practice of nursing care management. CONCLUSION: There are difficulties for nursing professionals to interact with the child's family and the dialogical order/disorder/interaction/organization in the implementation of the management process of care is. PMID- 26422036 TI - Social support towards the necessity of caring after myocardial infarction. AB - OBJECTIVE: to know the received or assisted social support by the family towards the necessity of care after acute myocardial infarction. METHOD: qualitative and exploratory research. Data collection was carried out through observation and interviews with six families, from February to May, 2012. Data were also analyzed based on the thematic analysis. RESULTS: three categories emerged: Immediate social support; Mediate social support; Late social support. CONCLUSION: social support follows the infarction trajectory, which attains the family members and favors the support according to the needs of care in each lived moments by the patient. PMID- 26422037 TI - Post-accident work behavior in caring for people with HIV/Aids. AB - OBJECTIVE: To identify post-accident conduct in the workplace by health professionals in caring for people with HIV/Aids. METHOD: A qualitative and descriptive research study with a socio-historical perspective (1986-2006), performed in a reference hospital for infectious diseases in the State of Santa Catarina. To collect data, interviews were conducted with oral history among 23 health workers and, for the treatment of data, Bardin's content analysis was used. RESULTS: Post-accident behaviors emerged that included assessment, accident records, chemoprophylaxis when necessary, support, monitoring of the injured worker, and mainly psychological support. CONCLUSION: In situations in which the accident could not be avoided, post-exposure behaviors were important biosecurity strategies mentioned by health workers caring for patients with HIV/Aids, in the sense of minimizing the possible transmission of the HIV virus. PMID- 26422038 TI - Social representations of sexuality for the elderly. AB - OBJECTIVE: to know the social representations of sexuality for the elderly, based on the Social Representation Theory. METHOD: study performed in a Basic Family Health Unit in Maracanau-CE, Brazil, with 30 elderly adults. Data were collected from March through April of 2013, using the free word evocation technique. Data were organized and processed using the EVOC 2000.software RESULTS: the subjects evoked 150 words associated with the evocator word "sexuality". Out of these, 43 were different. At the possible core of the representation of sexuality for the elderly, the following words were found: love, affection and respect. Sex, companionship, understanding and coexistence composed the intermediate elements of representation. CONCLUSION: the performed analyses pointed to love, respect and affection as central elements that structured and organized the social representation of sexuality in the elder years for the group studied. PMID- 26422039 TI - Analysis of the decision-making process of nurse managers: a collective reflection. AB - OBJECTIVE: to analyze the decision-making model adopted by nurses from the perspective of some decision-making process theories. METHOD: qualitative approach, based on action research. Semi-structured questionnaires and seminars were conducted from April to June 2012 in order to understand the nature of decisions and the decision-making process of nine nurses in position of managers at a public hospital in Southern Brazil. Data were subjected to content analysis. RESULTS: data were classified in two categories: the current situation of decision-making, which showed a lack of systematization; the construction and collective decision-making, which emphasizes the need to develop a decision making model. CONCLUSION: the decision-making model used by nurses is limited because it does not consider two important factors: the limits of human rationality, and the external and internal organizational environments that influence and determine right decisions. PMID- 26422040 TI - Health status and mental health in patients after percutaneous coronary intervention. AB - OBJECTIVE: to assess the association between perceived health status and the mental health of patients submitted to percutaneous coronary intervention after hospital discharge. METHOD: a quantitative and cross-sectional study involving 101 participants. The following instruments were used: a sociodemographic and clinical characterization instrument, the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), and the Hospital Anxiety and Depression Scale (HADS). Participants were divided into three groups: no anxiety and no depression (G1); anxiety or depression (G2); and both (G3). The ANOVA test was used for the intergroup comparison of means on the SF-36 domains. RESULTS: There was an association between perceived health status and mental health. The participants in G1 presented higher scores in all SF-36 domains in comparison with participants in G2 and G3. CONCLUSION: Participants with no anxiety and depression presented better-perceived health status in comparison with those with anxiety or depression, or both. PMID- 26422041 TI - Direct cost of development and documentation of the nursing process. AB - OBJECTIVE: identify the average direct cost (ADC) of the activities performed by nursing professionals in the nursing process development and documentation at the medical clinic of a teaching hospital. METHOD: 1040 activities were observed and the ADC was calculated by multiplying the time spent by professionals by the unit cost of direct labor. RESULTS: the ADC of patient admission was R$ 55.57 (SD=19.44); among the activities of patient follow-up, the assessment phase documentation had the most significant ADC (R$ 17.70 - SD=14.60); the ADC of descriptive records corresponded to R$ 1.21 (SD=1.21) and the ADC of the nursing team for shift change was R$ 54.23 (SD=28.95). CONCLUSION: the study promotes visibility of the work performed by nursing professionals in the development of the nursing process, providing financial data to ensure consistent arguments for proper resources to its feasibility. PMID- 26422042 TI - Accuracy in inference of nursing diagnoses in heart failure patients. AB - Heart failure (HF) is a common cause of hospitalization and requires accuracy in clinical judgment and appropriate nursing diagnoses. OBJECTIVE: to determine the accuracy of nursing diagnoses of fatigue, intolerance to activity and decreased cardiac output in hospitalized HF patients. METHOD: descriptive study applied to nurses with experience in NANDA-I and/or HF nursing diagnoses. Evaluation and accuracy were determined by calculating efficacy (E), false negative (FN), false positive (FP) and trend (T) measures. Nurses who showed acceptable inspection for two diagnoses were selected. RESULTS: the nursing diagnosis of fatigue was the most commonly mistaken diagnosis identified by the nursing evaluators. DISCUSSION: the search for improving diagnostic accuracy reaffirms the need for continuous and specific training to improve the diagnosis capability of nurses. CONCLUSION: the training allowed the exercise of clinical judgment and better accuracy of nurses. PMID- 26422043 TI - Longevity according to life histories of the oldest-old. AB - OBJECTIVE: to interpret life histories of the oldest-old in a community, grounded on the perspective of the Active Aging and Life Course. METHOD: this is a qualitative research. Participants included twenty seniors 80 years and older, users of a Basic Health Unit. Life histories were collected and analyzed according to the proposition of the Autobiographical Narrative Interview. RESULTS: during the analytic process, elements found in the elders' present and past arose, contributing to the development of a theoretical model: "Building longevity along the life course." CONCLUSION: longevity is rooted in the past, strongly influenced by the family culture and life course; assumptions of the Active Aging are more meaningful in the informants' present trajectory. The content of the narratives pointed to new possibilities of Gerontology Nursing intervention in Primary Care, aiming at health promotion and intervention, specially grounded on the respect to the oldest-elders' culture. PMID- 26422044 TI - Nursing scientific production on health promotion, chronic condition, and aging. AB - OBJECTIVE: to characterize the scientific production of Postgraduate Programs Nursing in Brazil on health promotion with a focus on elderly people with chronic conditions in the period from 2006 to 2010. METHOD: integrative research developed by searching for dissertations and theses in the database of the Center for Nursing Studies and Research of the Brazilian Nursing Association published in the period from 2006 to 2010 and which focused on health promotion for elderly people with chronic conditions. RESULTS: five themes emerged: "Living with the disease"; "Technologies of care", "Potential for self-care" "Psycho-spiritual dimension", and "Family caregiver". CONCLUSION: it was possible to identify nursing care as a key element to promote the health of elderly people and make them more independent in their care so as to live with their limitations or disabilities, even when affected by chronic diseases. PMID- 26422045 TI - Using the theory of meaningful learning in nursing education. AB - OBJECTIVE: to synthesize the scientific literature about the Theory of Meaningful Learning in the process of teaching and learning in nursing. METHOD: this is an integrative review conducted in the databases MEDLINE, LILACS, SciELO, BDENF and CINAHL with studies addressing the subject or aspects of the theory of meaningful learning of David Ausubel. Ten studies were included, from which six were written in Portuguese and four in English, published from 1998 to 2013. RESULTS: five studies used the theory of meaningful learning, four studies cited Ausubel as the author of this theory and only two studies followed the framework for the application of the theory completely. There are only a few studies on this subject and those which explore it are not correlated with Ausubel's theory. CONCLUSION: it is necessary to break with the dichotomy between theory and practice and promote the articulation of content with action, introducing the student as the author of their own knowledge. PMID- 26422046 TI - [Research lines in nursing: phylosophical and epistemological highlights]. AB - In this paper scientific investigation is explained as related to the Nursing Research Lines and Priorities based on the theory of knowledge application and as tangible to Subjectivity and Objectivity on what relates to the integrated categorical terms in the literature as professional, caring and organizational. OBJECTIVE: to elucidate philosophical and epistemological highlights in the face of meaningful, essential considerations, in favor of question causalities of interest to Nursing. METHOD: the reality approach is founded on the theoretical propositions of Johannes Hessen, with held attention to conceptions of other recognized authors. RESULTS: one can state the exposition value to clarify substantive aspects and adjective implications, not only of interest to investigation, but just to pinpoint the essential meanings on the subject related to elaborated thesis and dissertations (Marters' and Doctoral). CONCLUSION: represents a valuable contribution to better clarify details on knowledge construction and on the subject theme under discussion. PMID- 26422048 TI - Full-Dimensional Potential Energy Surface and Ro-vibrational Levels of Dioxirane. AB - A full-dimensional potential energy surface is developed for dioxirane based on a high-fidelity fit of ~46,000 ab initio points at the CCSD(T)-F12a/AVTZ level. The ro-vibrational levels of dioxirane were computed using the MULTIMODE method on this potential energy surface, and the agreement with the available experimental microwave spectrum is quite satisfactory. In addition, dipole moment surfaces have been constructed from ab initio data, and they allow the prediction of the infrared (IR) spectrum. PMID- 26422050 TI - Effect of Modified Phospholipid Bilayers on the Electrochemical Activity of a Membrane-Spanning Conjugated Oligoelectrolyte. AB - The incorporation and electrochemical activity of a conjugated oligoelectrolyte (COE) in model phospholipid bilayers have been characterized using cyclic voltammetry and UV-vis absorption measurements. Several other modifiers were also incorporated into the phospholipid membranes to alter properties such as charge and alkyl chain disorder. Using potassium ferricyanide to measure charge transport, it was observed that bilayers that contained cholic acid, a negatively charged additive that also promotes alkyl chain disorder, had higher COE uptake and charge permeability than unmodified bilayers. In contrast, when the positively charged choline was incorporated, charge permeability decreased and COE uptake was similar to that of unmodified bilayers. The incorporation of cholesterol at low concentrations within the phospholipid membranes was shown to enhance the COE's effectiveness at increasing membrane charge permeability without increasing the COE concentration in the bilayer. Higher concentrations of cholesterol reduce membrane fluidity and membrane charge permeability. Collectively, these results demonstrate that changes in phospholipid membrane charge permeability upon COE incorporation depend not only on the concentration in the membrane but also on interactions with the phospholipid bilayer and other additives present in the membranes. This approach of manipulating the properties of phospholipid membranes to understand COE interactions is applicable to understanding the behavior of a wide range of molecules that impart useful properties to phospholipid membranes. PMID- 26422051 TI - Effects of Exercise Intervention on Habitual Physical Activity Above Lactate Threshold Under Free-living Conditions: A Randomized Controlled Trial. AB - The purpose of the present investigation was to examine the effects of an exercise-based intervention on the daily physical activity (PA) above the lactate threshold under free-living conditions. A total of 81 middle-aged to older males (51+/-7 years) were randomly assigned into one of 2 groups. The subjects' body weight, visceral fat area, lactate threshold (LT), and PA levels were measured before and after the 8-week lifestyle intervention. The PA levels were assessed using a pedometer with a uni-axial accelerometer (Lifecorder, Kenz, Nagoya). During the intervention, 300 min/week of exercise at LT was targeted in the exercise group. The LT was determined by the log-log transformation method. The subjects in the control group were instructed to maintain their usual lifestyles. In the exercise group, the body weight, visceral fat area and LT significantly improved after the intervention. In contrast, the duration of PA at an intensity of LT, >3 METs and >6 METs did not differ significantly. The present investigation did not find significant changes in the PA at LT under free-living conditions as a result of an 8-week exercise-based intervention, although the participants successfully improved their aerobic capacity and body composition. PMID- 26422049 TI - A Social-Ecological View of Barriers and Facilitators for HIV Treatment Adherence: Interviews with Puerto Rican HIV Patients. AB - PURPOSE: To identify perceived barriers and facilitators for HAART adherence among people living with HIV/AIDS in Southern Puerto Rico using a Social Ecological framework. PATIENTS AND METHODS: Individual in-depths interviews were conducted with 12 HIV patients with a history of HAART non-adherence. Interviews were audio-taped and transcribed. Content analysis was performed for each transcribed interview by three independent coders using a codebook. Using Atlas TI, super-codes and families were generated to facilitate the categorization tree as well as grounded analyses and density estimates. RESULTS: Most participants reported a monthly income of $500 or less (n = 7), a high school education level (n = 7), being unemployed (n = 9) and being recipients of government health insurance (n = 11). Three out of six women reported living alone with their children and most men informed living with their parents or other relatives (n = 4). For the grounded analyses, the top four sub-categories linked to high number of quotations were mental health barriers (G = 32) followed by treatment regimen (G = 28), health system (G = 24) and interpersonal relations (G = 16). The top four sub-categories linked to high number of codes are treatment regimen (D = 4), health status perception (D = 3), interpersonal relations (D = 3) and health system (D = 3). CONCLUSION: The results of this study suggest the interconnection of HIV treatment adherence barriers at various system levels. Future studies on HIV treatment barriers should explore these interactions and investigate the possible synergistic effect on non-adherent behavior. PMID- 26422052 TI - Strength and Pain Threshold Handheld Dynamometry Test Reliability in Patellofemoral Pain. AB - Patellofemoral pain syndrome (PFPS), characterized by peri- and retropatellar pain, is a common disorder in young, active people. The etiology is unclear; however, quadriceps strength seems to be a contributing factor, and sensitization might play a role. The study purpose is determining the inter-rater reliability of handheld dynamometry to test both quadriceps strength and pressure pain threshold (PPT), a measure for sensitization, in patients with PFPS. This cross sectional case-control study comprises 3 quadriceps strength and one PPT measurements performed by 2 independent investigators in 22 PFPS patients and 16 matched controls. Inter-rater reliability was analyzed using intraclass correlation coefficients (ICC) and Bland-Altman plots. Inter-rater reliability of quadriceps strength testing was fair to good in PFPS patients (ICC=0.72) and controls (ICC=0.63). Bland-Altman plots showed an increased difference between assessors when average quadriceps strength values exceeded 250 N. Inter-rater reliability of PPT was excellent in patients (ICC=0.79) and fair to good in controls (ICC=0.52). Handheld dynamometry seems to be a reliable method to test both quadriceps strength and PPT in PFPS patients. Inter-rater reliability was higher in PFPS patients compared to control subjects. With regard to quadriceps testing, a higher variance between assessors occurs when quadriceps strength increases. PMID- 26422053 TI - Functional Fatigue Alters Lower-extremity Neuromechanics during a Forward-side Jump. AB - Neuromuscular fatigue impairs neuromuscular control of the lower extremity. The purpose of the study was to investigate the effect of functional fatiguing exercises on sagittal-plane lower-extremity neuromechanics during a forward-side jump. 21 participants performed 5 forward-side jump tasks before and after functional fatiguing exercises. A functional analysis of variance (FANOVA) evaluated differences between 2 different conditions (pre- vs. post-fatigue) for joint angle, moment, and EMG amplitude during stance of a forward-side jump. FANOVA compared variables as polynomial functions, and differences between functions with 95% confidence interval bands were plotted to determine significant differences. Plantar, knee, and hip flexion decreased during the initial stages of landing following fatigue. Plantarflexion moment decreased during 10-20% of stance in post-fatigue. Knee extension moment initially increased while decreased during 20-30% of stance following fatigue. Hip extension moment initially decreased while increased at 20% of stance. Tibialis anterior EMG decreased during 30-40% of stance, vastus lateralis EMG increased at 15% of stance, hamstring EMG decreased at foot contact and during 25-60% of stance, and gluteus maximus EMG decreased at foot contact and 35% of stance. The functional fatiguing exercises resulted in a more upright landing position, potentially indicating a greater reliance upon skeletal structures for support. PMID- 26422054 TI - Alterations in Body Fluid Balance During Fin Swimming in 29 degrees C Water in a Population of Special Forces Divers. AB - Highly trained "combat swimmers" encounter physiological difficulties when performing missions in warm water. The aim of this study was to assess the respective roles of immersion and physical activity in perturbing fluid balance of military divers on duty in warm water. 12 trained divers performed 2 dives each (2 h, 3 m depth) in fresh water at 29 degrees C. Divers either remained Static or swam continuously (Fin) during the dive. In the Fin condition, oxygen consumption and heart rate were 2-fold greater than during the Static dive. Core and skin temperatures were also higher (Fin: 38.5+/-0.4 degrees C and 36.2+/-0.3 degrees C and Static: 37.2+/-0.3 degrees C and 34.3+/-0.3 degrees C; respectively p=0.0002 and p=0.0003). During the Fin dive, the average mass loss was 989 g (39% urine loss, 41% sweating and 20% insensible water loss and blood sampling); Static divers lost 720 g (84% urine loss, 2% sweating and 14% insensible water loss and blood sampling) (p=0.003). In the Fin condition, a greater decrease in total body mass and greater sweating occurred, without effects on circulating renin and aldosterone concentrations; diuresis was reduced, and plasma volume decreased more than in the Static condition. PMID- 26422055 TI - Running-based Anaerobic Sprint Test as a Procedure to Evaluate Anaerobic Power. AB - The aim of this study was to evaluate the use of the running anaerobic sprint test (RAST) as a predictor of anaerobic capacity, compare it to the maximal accumulated oxygen deficit (MAOD) and to compare the RAST's parameters with the parameters of 30-s all-out tethered running on a treadmill. 39 (17.0+/-1.4 years) soccer players participated in this study. The participants underwent an incremental test, 10 submaximal efforts [50-95% of velocity correspondent to VO(2MAX) (vVO(2MAX))] and one supramaximal effort at 110% of vVO(2MAX) for the determination of MAOD. Furthermore, the athletes performed the RAST. In the second stage the 30-s all-out tethered running was performed on a treadmill (30-s all-out), and compared with RAST. No significant correlation was observed between MAOD and RAST parameters. However, significant correlations were found between the power of the fifth effort (P5) of RAST with peak and mean power of 30-s all out (r=0.73 and 0.50; p<0.05, respectively). In conclusion, the parameters from RAST do not have an association with MAOD, suggesting that this method should not be used to evaluate anaerobic capacity. Although the correlations between RAST parameters with 30-s all-out do reinforce the RAST as an evaluation method of anaerobic metabolism, such as anaerobic power. PMID- 26422056 TI - The Power of Advanced Capability and Informed Policy. PMID- 26422057 TI - Excited Biexcitons in Transition Metal Dichalcogenides. AB - The Stochastic Variational Method (SVM) is used to show that the effective mass model correctly estimates the binding energies of excitons and trions but fails to predict the experimental binding energy of the biexciton. Using high-accuracy variational calculations, it is demonstrated that the biexciton binding energy in transition metal dichalcogenides is smaller than the trion binding energy, contradicting experimental findings. It is also shown that the biexciton has bound excited states and that the binding energy of the L = 0 excited state is in very good agreement with experimental data. This excited state corresponds to a hole attached to a negative trion and may be a possible resolution of the discrepancy between theory and experiment. PMID- 26422058 TI - Pain grade and sleep disturbance in older adults: evaluation the role of pain, and stress for depressed and non-depressed individuals. AB - OBJECTIVE: The aim of this paper was to assess the relationship between pain and sleep in older adults taking depression, stress, and medical comorbidities into account. METHODS: A cross-sectional analysis was performed using Einstein Aging Study, a community-based cohort study of adults aged 70 years and older. Ratings of pain intensity and interference from the Medical Outcomes Study (MOS) Short Form 36 were used to assign individuals to low-pain versus high-pain severity. Sleep disturbance was assessed using the nine-item sleep problems index from the Medical Outcomes Study Sleep Scale. Other measures included the Geriatric Depression Scale and Perceived Stress Scale (PSS). Linear regression models were used to assess the association between pain grade and sleep disturbance adjusted for demographics, PSS, Geriatric Depression Scale, and other comorbidities. RESULTS: Five hundred sixty-two eligible participants with a mean age of 78.22 years (standard deviation = 5.43) were included; 64% were women. Pain grade [beta = 5.40, 95% confidence interval (CI) 2.56-8.21, p < 0.001] was associated with sleep disturbance after adjusting for demographic variables. In models including pain grade (beta = 3.08, 95% CI 0.32-5.85, p = 0.03) and PSS (beta = 0.57, 95% CI 0.39-0.75, p < 0.001), both were associated with sleep disturbance, although the PSS attenuated the relationship between pain and sleep by 34%. Depression, when added to previous model, was also associated with sleep (beta = 2.17, 95% CI 1.48 2.85, p < 0.001) and attenuated the relationship between pain (beta = 2.41, 95% CI -0.25 to 5.08, p = 0.07) and sleep by 22%. Stratified for depression, we found that pain, stress, and other medical comorbidities were significantly associated with sleep disturbance in non-depressed individuals but not individuals with depression. CONCLUSIONS: Pain, stress, and medical comorbidities are associated with sleep disturbance, especially in non-depressed older adults. PMID- 26422059 TI - Material identification in x-ray microscopy and micro CT using multi-layer, multi color scintillation detectors. AB - We demonstrate that a dual-layer, dual-color scintillator construct for microscopic CT, originally proposed to increase sensitivity in synchrotron imaging, can also be used to perform material quantification and classification when coupled with polychromatic illumination. We consider two different approaches to data handling: (1) a data-domain material decomposition whose estimation performance can be characterized by the Cramer-Rao lower bound formalism but which requires careful calibration and (2) an image-domain material classification approach that is more robust to calibration errors. The data domain analysis indicates that useful levels of SNR (>5) could be achieved in one second or less at typical bending magnet fluxes for relatively large amounts of contrast (several mm path length, such as in a fluid flow experiment) and at typical undulator fluxes for small amount of contrast (tens of microns path length, such as an angiography experiment). The tools introduced could of course be used to study and optimize parameters for a wider range of potential applications. The image domain approach was analyzed in terms of its ability to distinguish different elemental stains by characterizing the angle between the lines traced out in a two-dimensional space of effective attenuation coefficient in the front and back layer images. This approach was implemented at a synchrotron and the results were consistent with simulation predictions. PMID- 26422060 TI - Distribution of trace elements in sediment and soil from river Vardar Basin, Macedonia/Greece. AB - A systematic study was carried out to investigate the distribution of 59 elements in the sediment and soil samples collected from the river Vardar (Republic of Macedonia and Greece) and its major tributaries. The samples were collected from 28 sampling sites. Analyses were performed by inductively coupled plasma-mass spectrometry. R-mode factor analysis (FA) was used to identify and characterise element associations. Seven associations of elements were determined by the method of multivariate statistics. Every factor (Factors 1-3 and 6 and 7 as geogenic and Factors 4 and 5 as anthropogenic associations of elements) are examined and explained separately. The distribution of various elements showed that there is a presence of anthropogenic elements (Ag, Cd, Cu, Ge, Pb, Sn and Zn) introduced in the river sediments and soils from the mining, metallurgical, industrial and agricultural activities in Vardar River Basin, which covers most of the Republic of Macedonia and Central-northern part of Greece. PMID- 26422061 TI - Zinc Isotope Variability in Three Coal-Fired Power Plants: A Predictive Model for Determining Isotopic Fractionation during Combustion. AB - The zinc (Zn) isotope compositions of feed materials and combustion byproducts were investigated in three different coal-fired power plants, and the results were used to develop a generalized model that can account for Zn isotopic fractionation during coal combustion. The isotope signatures in the coal (delta(66)ZnIRMM) ranged between +0.73 and +1.180/00, values that fall well within those previously determined for peat (+0.6 +/-2.00/00). We therefore propose that the speciation of Zn in peat determines the isotope fingerprint in coal. All of the bottom ashes collected in these power plants were isotopically depleted in the heavy isotopes relative to the coals, with delta(66)ZnIRMM values ranging between +0.260/00 and +0.640/00. This suggests that the heavy isotopes, possibly associated with the organic matter of the coal, may be preferentially released into the vapor phase. The fly ash in all of these power plants was, in contrast, enriched in the heavy isotopes relative to coal. The signatures in the fly ash can be accounted for using a simple unidirectional fractionation model with isotope fractionation factors (alphasolid-vapor) ranging between 1.0003 and 1.0007, and we suggest that condensation is the controlling process. The model proposed allows, once the isotope composition of the feed coal is known, the constraining of the Zn signatures in the byproducts. This will now enable the integration of Zn isotopes as a quantitative tool for the source apportionment of this metal from coal combustion in the atmosphere. PMID- 26422062 TI - Growth of Cu2ZnSnS4 Nanocrystallites on TiO2 Nanorod Arrays as Novel Extremely Thin Absorber Solar Cell Structure via the Successive-Ion-Layer-Adsorption Reaction Method. AB - Cu2ZnSnS4 (CZTS) is an environmentally benign semiconductor with excellent optoelectronic properties that attracts a lot of interest in thin film photovoltaics. In departure from that conventional configuration, we fabricate and test a novel absorber-conductor structure featuring in situ successive-ion layer-adsorption-reaction (SILAR)-deposited CZTS nanocrystallites as a light absorber on one-dimensional TiO2 (rutile) nanorods as an electron conductor. The effectiveness of the nanoscale heterostructure in visible light harvesting and photoelectron generation is demonstrated with an initial short circuit current density of 3.22 mA/cm(2) and an internal quantum efficiency of ~60% at the blue light region, revealing great potential in developing CZTS extremely thin absorber (ETA) solar cells. PMID- 26422063 TI - [Lengthening temporalis myoplasty: Technical refinements]. AB - First described by Labbe in 1997, the lengthening temporalis myoplasty (LTM) ensures the transfer of the entire temporal muscle from the coronoid process to the upper half of the lip without interposition of aponeurotic tissue. Thanks to brain plasticity, the temporal muscle is able to change its function because it is entirely mobilized towards another effector: the labial commissure. After 6 months of speech rehabilitation, the muscle loses its chewing function and it acquires its new smiling function. We describe as far as possible all the technical points to guide surgeons who would like to perform this powerful surgical procedure. We show the coronoid process approaches both through an upper temporal fossa approach and a lower nasolabial fold approach. Rehabilitation starts 3 weeks after the surgery following a standardized protocol to move from a mandibular smile to a voluntary smile, and then a spontaneous smile in 3 steps. The LTM is the main part of a one-stage global treatment of the paralyzed face. It constitutes a dynamic palliative treatment usually started at the sequelae stage, 18 months after the outcome of a peripheral facial paralysis. This one stage procedure is a reproducible and relevant surgical technique in the difficult treatment of peripheral facial paralysis. An active muscle is transferred to reanimate the labial commissure and to recreate a mobile nasolabial fold. PMID- 26422065 TI - Synthesis of tin oxide nanospheres under ambient conditions and their strong adsorption of As(III) from water. AB - The development of highly efficient As(iii) adsorbents is critical to largely simplify the arsenic treatment process and lower its cost. For the first time, SnO2 nanospheres were demonstrated to possess a highly efficient As(iii) adsorption capability from water in a near neutral pH environment as predicted by the material criterion we recently developed for the selection of highly efficient arsenic adsorbents. These SnO2 nanospheres were synthesized by a simple and cost-effective hydrolysis process with the assistance of ethyl acetate under ambient conditions, which had a good dispersity, a narrow size distribution, a relatively large specific surface area, and a porous structure. A fast As(iii) adsorption was observed in the kinetics study on these SnO2 nanospheres, and their Langmuir adsorption capacity was determined to be ~112.7 mg g(-1) at pH ~7. The As(iii) adsorption mechanism on SnO2 nanospheres was examined by both macroscopic and microscopic techniques, which demonstrated that it followed the inner-sphere complex model. These SnO2 nanospheres demonstrated effective As(iii) adsorption even with exceptionally high concentrations of co-existing ions, and a good regeneration capability by washing with NaOH solution. PMID- 26422064 TI - Cultural differences and shame in an expressive writing alcohol intervention. AB - The present study evaluates the relationships between shame, culture, and drinking behavior in predicting drinking intentions in the context of an expressive writing intervention. Theory and empirical findings have generally found that shame is maladaptive and can lead to anxiety, depression, and problematic alcohol use. However, research on cultural differences suggests that shame may be differentially damaging to individuals of collectivist, Asian cultures. Previous research evaluating expressive writing as a brief alcohol intervention has shown promising results such as reduced drinking intentions and increased readiness to change drinking behavior. The present study tested the hypothesis that feelings of shame after writing about a negative heavy drinking event would be associated with greater alcohol use generally and that this effect would differ for Caucasian compared to Asian individuals. We also explored whether this differed for light and heavy drinkers. Two hundred sixty-four undergraduates (74% female) who drank at least one alcoholic beverage in the past month completed measures of demographics, baseline drinking, event-related shame and guilt, pre- and postwriting affect, and drinking intentions. Results revealed that, independent of affect, social desirability, and event-related guilt, shame was generally negatively associated with drinking intentions for Caucasians and light drinking Asians. However, for heavy drinking Asians, shame was associated with increased drinking intentions. Results suggest that interventions that elicit shame are differentially effective and should be targeted accordingly. PMID- 26422066 TI - A Versatile Cell Death Screening Assay Using Dye-Stained Cells and Multivariate Image Analysis. AB - A novel dye-based method for measuring cell death in image-based screens is presented. Unlike conventional high- and medium-throughput cell death assays that measure only one form of cell death accurately, using multivariate analysis of micrographs of cells stained with the inexpensive mix, red dye nonyl acridine orange, and a nuclear stain, it was possible to quantify cell death induced by a variety of different agonists even without a positive control. Surprisingly, using a single known cytotoxic agent as a positive control for training a multivariate classifier allowed accurate quantification of cytotoxicity for mechanistically unrelated compounds enabling generation of dose-response curves. Comparison with low throughput biochemical methods suggested that cell death was accurately distinguished from cell stress induced by low concentrations of the bioactive compounds Tunicamycin and Brefeldin A. High-throughput image-based format analyses of more than 300 kinase inhibitors correctly identified 11 as cytotoxic with only 1 false positive. The simplicity and robustness of this dye based assay makes it particularly suited to live cell screening for toxic compounds. PMID- 26422067 TI - [General practitioners are the first to observe psychoses]. PMID- 26422068 TI - [Psychotherapy: sitting or reclining?]. PMID- 26422069 TI - [CME. Patient advance directives in family medicine]. PMID- 26422071 TI - [Endocrine causes of delirium]. AB - Delirium is common in hospitalized patients and apart from well known vascular, infectious and toxic causes there are many endocrine diseases which may also present as an acute confusional state. The review provides an overview of the different endocrine etiologies of delirium and the prompt diagnosis and treatment. PMID- 26422072 TI - [Psychotic disorders: special aspects in general practice]. AB - In emergency situations the general practitioner is often the first professional contact psychotic patients have. The following article conveys basic knowledge about psychotic disorders and their clinical features typically seen in general practice. PMID- 26422074 TI - Pyogenic Hepatic Abscess--Less is More. A Review for General Internists. AB - Pyogenic hepatic abscesses are rare, and fatal if untreated. Recent progresses in diagnostic and interventional radiology facilitated their management. However, abscesses located in the caudate lobe are still a diagnostic and therapeutic challenge, especially to general internists, who tend to overtreatment. Literature of this specific form of hepatic abscess is scarce. The aim of this article was to review the existing literature on caudate lobe abscesses, as well as to provide a brief overview over pyogenic liver abscesses in order to draw attention of general internists to this important differential diagnosis and facilitate the decision-making on therapy. We underline that current evidence suggests a less is more position, so as to warrant a quality approach. PMID- 26422073 TI - [How healthy are and behave men? Differences in health status and health behavior between the two sexes in the Canton of Zurich]. AB - Men have not been the focus of health monitoring and reporting in German-speaking Switzerland so far and are a largely neglected target group of governmental preventive efforts. Without good reason. Men have a substantial preventive potential regarding health, health behavior and use of health and medical services, as can be seen in the recently published global health report of the Canton Zurich. Men have a shorter life expectancy compared to women and a significantly higher mortality with regard to strongly behavior-related chronic diseases as well as fatal traffic accidents and suicides. Men also show comparably unfavourable health behavior and a reduced utilization of health services. The stronger, but also less healthy and less healthy behaving sex should increasingly be the focus of health reporting and health monitoring in the future. PMID- 26422075 TI - [Mass on the neck]. AB - Malignant peripheral nerve sheath tumors (MPNST) are rare. But especially in patients with known neurofibromatosis type 1 (von Recklinghausen), this entity of tumors should not be forgotten. The indication for open biopsy or excision should be made generously. In the following, we report a rare case of MPNST, which highlights the importance of rapid diagnosis and treatment. PMID- 26422076 TI - [Liraglutide for weight loss in overweight and obese adults]. PMID- 26422077 TI - [Cannabinoids in medical procedures - Review and Meta-analysis]. PMID- 26422082 TI - Primary autoimmune myelofibrosis as etiology of pancytopenia mimicking myelodysplastic syndrome. PMID- 26422081 TI - Living in biological soil crust communities of African deserts-Physiological traits of green algal Klebsormidium species (Streptophyta) to cope with desiccation, light and temperature gradients. AB - Green algae of the genus Klebsormidium (Klebsormidiales, Streptophyta) are typical members of biological soil crusts (BSCs) worldwide. The phylogeny and ecophysiology of Klebsormidium has been intensively studied in recent years, and a new lineage called superclade G, which was isolated from BSCs in arid southern Africa and comprising undescribed species, was reported. Three different African strains, that have previously been isolated from hot-desert BSCs and molecular taxonomically characterized, were comparatively investigated. In addition, Klebsormidium subtilissimum from a cold-desert habitat (Alaska, USA, superclade E) was included in the study as well. Photosynthetic performance was measured under different controlled abiotic conditions, including dehydration and rehydration, as well as under a light and temperature gradient. All Klebsormidium strains exhibited optimum photosynthetic oxygen production at low photon fluence rates, but with no indication of photoinhibition under high light conditions pointing to flexible acclimation mechanisms of the photosynthetic apparatus. Respiration under lower temperatures was generally much less effective than photosynthesis, while the opposite was true for higher temperatures. The Klebsormidium strains tested showed a decrease and inhibition of the effective quantum yield during desiccation, however with different kinetics. While the single celled and small filamentous strains exhibited relatively fast inhibition, the uniserate filament forming isolates desiccated slower. Except one, all other strains fully recovered effective quantum yield after rehydration. The presented data provide an explanation for the regular occurrence of Klebsormidium strains or species in hot and cold deserts, which are characterized by low water availability and other stressful conditions. PMID- 26422083 TI - Donor-specific HLA alloantibodies: Impact on cardiac allograft vasculopathy, rejection, and survival after pediatric heart transplantation. AB - BACKGROUND: There is increasing evidence that donor-specific anti-HLA antibodies (DSA) are associated with poor outcomes after cardiac transplantation in adults, but data are limited in children. The objective of this study was to examine the development and consequences of de novo DSA in pediatric recipients of heart transplants. METHODS: We analyzed 105 pediatric patients who received heart transplants at our center from January 2002 to December 2012. All patients had negative T-cell and B-cell post-transplant crossmatches. Patients underwent HLA antibody screening at 1, 2, 3, 6, and 12 months post-transplant and annually thereafter unless there was suspicion for rejection. HLA class I and II antibodies were identified using Luminex assay. Coronary angiography was performed at 1 year and annually thereafter. Acute cellular rejection, antibody mediated rejection, and treated clinical rejections were included together as rejection events. RESULTS: Of 105 patients, 45 (43%) developed de novo DSA. DSA positive patients had significantly higher rates of coronary artery vasculopathy (CAV) compared with DSA-negative patients (36% vs 13%). CAV-free survival at 1 year and 5 years post-transplant for DSA-negative patients was 90% and 25%, respectively, compared with 70% and 0%, respectively, for DSA-positive patients (p < 0.01). DSA-positive patients had 2.5 times more rejection events per year than DSA-negative patients. The 5-year graft survival rate was 72.4% for DSA negative patients and 21% for DSA-positive patients (p < 0.001). CONCLUSIONS: De novo DSA has a strong negative impact on CAV, rejection, and graft survival in pediatric recipients of heart transplants. PMID- 26422084 TI - The Effectiveness of Interventions for Improving the Research Literacy of Nurses: A Systematic Review. AB - BACKGROUND: Internationally, a considerable body of research exists examining why nurses do not use evidence in practice. Consistently, the research finds that lack of knowledge about research or discomfort with understanding research terminology are among the chief reasons given. Research education is commonly included in undergraduate nursing degree programs, but this does not seem to translate into a strong understanding of research following graduation, or an ability to use it in practice. AIM: The objective of this review was to identify the effectiveness of workplace, tertiary-level educational, or other interventions designed to improve or increase postregistration nurses' understanding of research literature and ability to critically interact with research literature with the aim of promoting the use of research evidence in practice in comparison to no intervention, other intervention, or usual practice. METHODS: A wide range of databases were searched for quantitative studies of registered nurses receiving educational interventions designed to increase or improve their understanding of research literature in tertiary or workplace settings. Two reviewers working independently critically appraised the relevant papers and extracted the data using Joanna Briggs Institute instruments. Data are presented as a narrative summary as no meta-analysis was possible. RESULTS: Searching identified 4,545 potentially relevant papers, and after the sifting of titles and abstracts, 96 papers were selected for retrieval. On examination of full-text versions, 10 of the 96 retrieved papers were found to meet the inclusion criteria. Included studies were low to moderate quality. Interactive or activity-based learning seems to be effective in terms of improving research knowledge, critical appraisal ability, and research self-efficacy. Utilizing a program with a strong base in an appropriate theory also seems to be associated with greater effectiveness, particularly for workplace interventions. LINKING EVIDENCE TO ACTION: The included studies strongly favored interactive interventions, and those utilizing theory in their construction. Therefore, these types of interventions should be implemented to improve the effectiveness of research education for nurses as well as their research literacy. PMID- 26422085 TI - Diagnosis of pulmonary and extrapulmonary tuberculosis based on detection of mycobacterial antigen 85B by immuno-PCR. AB - We developed a novel indirect sandwich immuno-polymerase chain reaction (I-PCR) assay for the detection of mycobacterial antigen 85B (Ag85B, 30kDa, Rv1886c) in pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) patients. The amino-modified reporter DNA was covalently attached with the antidetection antibody through a heterobifunctional cross-linking agent succinimidyl 4-[N maleimidomethyl]-cyclohexane-1-carboxylate. The detection limit of Ag85B by I-PCR was found to be 1 femtogram (fg)/mL, which was 10(6)-fold lower than an analogous enzyme-linked immunosorbent assay (ELISA). The sensitivities of 85% and 77% with I-PCR and 77.6% and 62.5% with ELISA were observed in smear-positive and smear negative PTB patients, respectively, with high specificity. On the other hand, sensitivities of 84% and 63.7% with I-PCR and 68% and 47.5% with ELISA were observed in confirmed and clinically suspected EPTB cases, respectively, with high specificity. PMID- 26422086 TI - Bacteremia caused by a mecA-positive oxacillin-susceptible Staphylococcus aureus strain with inducible resistance. PMID- 26422087 TI - Outcomes of Prolonged Laparoscopic Bariatric Operations Compared With Shorter Open Procedures. AB - PURPOSE: Prolonged operative time (ORT) is a drawback of laparoscopic bariatric surgery due to concerns for increased morbidity. This study aims to identify the ORT when open procedures are superior to laparoscopic procedures. METHODS: Thirty day outcomes for bariatric procedures in the NSQIP database were analyzed comparing laparoscopic ORT to equal or shorter open ORT. Multivariate regression was utilized to control for patient demographics and comorbidities. RESULTS: Among 48,274 cases, laparoscopic procedures reduced morbidity and mortality compared with open procedures of similar ORT. Laparoscopic procedures <=3 hours were equal or superior to shorter open procedures. Laparoscopic procedures >6 hours had worse outcomes than open operations <3 hours. Open operations >3 hours had no benefit regardless of ORT. CONCLUSIONS: Laparoscopic bariatric operations have less mortality and morbidity compared with open procedures of similar ORT. The advantages of laparoscopic procedures are eliminated when ORT exceeds 6 hours compared with shorter open procedures. PMID- 26422088 TI - Postoperative Pain After Robotic Thyroidectomy by a Gasless Unilateral Axillo Breast or Axillary Approach. AB - The aim of this study was to compare postoperative pain after robotic thyroidectomy with that after conventional open thyroidectomy. We analyzed 123 patients who underwent robotic thyroidectomy and 170 patients who underwent conventional open thyroidectomy. Postoperative pain was evaluated on a visual analogue scale rating of 0 to 10, 1 day to 1 month after surgery. Mean pain visual analogue scale scores for the robotic and open groups were 3.33 and 3.57 (P=0.476) on day 1, 2.29 and 2.58 (P=0.285) on day 3, 2.19 and 1.74 (P=0.057) after 1 week, and 0.98 and 1.01 (P=0.843) after 1 month, respectively. There was no difference between the 2 groups in the doses of parenteral analgesic medication administered (robotic vs. open, mean 174 vs. 194 mg, P=0.189). In conclusion, postoperative pain and the dose of analgesic medication in both groups are similar. PMID- 26422089 TI - Laparoscopic Splenectomy in Patients With Spleen Injuries. AB - INTRODUCTION: Spleen injury appears in 10% to 30% of abdominal trauma patients. Mortality among the patients in the last 20 years remains high (6% to 7%) and shows no tendency to decline. Nowadays nonoperative management is widely accepted management of patients with low-grade spleen injury, whereas management of patients with high-grade spleen injury (III and higher) is not so obvious. There are 3 methods exist in treatment of such patients: conservative (with or without angioembolization), spleen-preserving operations, and splenectomy. Today laparoscopic splenectomy is not a widely used operation and only few studies reported about successful use of laparoscopic splenectomy in patients with spleen injury.The aim of the study was to determine indications and contraindications for laparoscopic splenectomy in abdominal trauma patients and to analyze results of the operations. PATIENTS AND METHODS: The study involved 42 patients with spleen injury grade III who were admitted in our institute in the years of 2010 to 2014. The patients were divided in 2 groups. Laparoscopic splenectomy was performed in 23 patients (group I) and "traditional" splenectomy was carried out in 19 patients (group II). There was no difference in the demographic data and trauma severity between the 2 groups. Noninvasive investigations, such as laboratory investigations, serial abdominal ultrasound examinations, x-ray in multiple views, and computed tomography had been performed before the decision about necessity of an operation was made. RESULTS: Patients after laparoscopic operations had better recovering conditions compared with patients with the same injury after "traditional" splenectomy. Neither surgery-related complications nor mortalities were registered in both groups. Laparoscopic splenectomy was more time-consuming operation than "traditional" splenectomy. We suggest that as experience of laparoscopic splenectomy is gained the operation time will be reduced. CONCLUSIONS: Laparoscopic splenectomy is a safe feasible operation in patients with spleen injury. The operation is indicated in patients with spleen laceration >3 cm of parenchymal depth with moderate continuing bleeding or expanding hematoma and contraindicated in patients with hemodynamic instability and high bleeding rate (>500 mL/h on serial ultrasound examinations). PMID- 26422090 TI - Infectious disease, injection practices, and risky sexual behavior among anabolic steroid users. AB - Anabolic-androgenic steroids (AAS) and other performance-enhancing drugs (PEDs) are commonly misused to increase muscle size and strength, as well as improve physical appearance. Many AAS and certain PEDs are administered via injection and therefore pose a risk for transmission of infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and skin and soft tissue infections (SSTIs). Further, AAS users may be more likely to take part in high-risk sexual behaviors than non-AAS users. This review explores the prevalence of infectious diseases as well as risky injection practices and sexual behaviors of AAS users in the current literature. A comprehensive MEDLINE search (1984-17 April 2015) for English language reports was performed on AAS users. Ten studies analyzed the prevalence of HIV infection, 6 studies analyzed HBV infection, and 6 studies analyzed HCV infection; 20 studies analyzed injection practices and 7 studies analyzed high-risk sexual behaviors of AAS users. HIV, HBV, HCV, and SSTIs have been associated with AAS users. In particular, HIV infection seems much higher among homosexual male AAS users. AAS users also take part in high-risk injection practices but to a much lower extent than intravenous drug users. AAS users are also more likely to engage in high-risk sexual behaviors than the general population. Clinicians and health-policy leaders may utilize these findings to implement strategies to decrease the spread of infectious diseases. PMID- 26422091 TI - X-linked moyamoya syndrome associated with severe haemophilia A. PMID- 26422092 TI - Introduction. PMID- 26422093 TI - Safety and Tolerability of Esomeprazole in Children With Gastroesophageal Reflux Disease. AB - OBJECTIVES: To evaluate safety, tolerability, and symptom improvement with once daily esomeprazole in children with endoscopically proven gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: In this 8-week, multicenter, randomized, uncontrolled, double-blind study, children ages 1 to 11 years were stratified by weight to receive esomeprazole 5 or 10 mg (children < 20 kg) or 10 or 20 mg (children >= 20 kg) once daily. Safety and tolerability was assessed by evaluating adverse events (AEs; both treatment- and non-treatment-related AEs) and changes from baseline in medical history, physical examinations, and clinical laboratory tests. Investigators scored symptom severity every 2 weeks using the Physician's Global Assessment (PGA). Patients' parents rated GERD symptoms of heartburn, acid regurgitation, and epigastric pain (none to severe, 0-3) at baseline (based on past 72 hours) and daily (from past 24 hours). RESULTS: Of 109 patients randomized, 108 had safety data. AEs were experienced by 68.0% and 65.2% of children <20 kg receiving esomeprazole 5 and 10 mg, respectively, and 83.9% and 82.8% of children >= 20 kg receiving esomeprazole 10 and 20 mg, respectively, regardless of causality. Overall, only 9.3% of patients reported 13 treatment related AEs; the most common were diarrhea (2.8% [3/108]), headache (1.9% [2/108]), and somnolence (1.9% [2/108]). Vomiting, a serious AE in 2 patients, was not judged by the investigator to be related to treatment. At the final visit, PGA scores improved significantly from baseline (P < 0.001). Of 58 patients with moderate to severe baseline PGA symptom scores, 91.4% had lower scores by the final visit. GERD symptom scores were significantly improved from baseline to the final week of the study in all of the treatment groups (P < 0.01) CONCLUSIONS:: In children ages 1 to 11 years with endoscopically proven GERD, esomeprazole (at daily doses of 5, 10, or 20 mg) was generally well tolerated. The frequency and severity of GERD-related symptoms were significantly reduced during the active treatment period. PMID- 26422094 TI - Pharmacokinetics and Acid-suppressive Effects of Esomeprazole in Infants 1-24 Months Old With Symptoms of Gastroesophageal Reflux Disease. AB - OBJECTIVES: To evaluate the pharmacokinetics and acid-suppressive effects of esomeprazole in infants with gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: In this single-blind, randomized, parallel-group study, 50 infants 1 to 24 months old with symptoms of GERD, and >= 5% of time with intraesophageal pH <4 during 24-hour dual pH monitoring, received oral esomeprazole 0.25 mg/kg (n = 26) or 1 mg/kg (n = 24) once daily for 1 week. Intraesophageal and intragastric pH were recorded at 1 week, and blood samples were taken for pharmacokinetic analysis. RESULTS: At baseline, mean percentages of time with intragastric pH >4 and intraesophageal pH <4 were 30.5% and 11.6%, respectively, in the esomeprazole 0.25 mg/kg group and 28.6% and 12.5% in the esomeprazole 1 mg/kg group. After 1 week of treatment, times with intragastric pH >4 were 47.9% and 69.3% in the esomeprazole 0.25 mg/kg and 1 mg/kg groups, respectively (P < 0.001 vs baseline), and times with intraesophageal pH <4 were 8.4% (P < 0.05 vs baseline) and 5.5% (P < 0.001 vs. baseline), respectively. The mean number of acid reflux episodes of >5 minutes duration decreased from 6 at baseline to 3 and 2 with esomeprazole 0.25 mg/kg and 1 mg/kg, respectively. The geometric mean AUC0-t of esomeprazole were 0.24 and 1.79 MUmol . h/L for the 0.25 mg/kg and 1 mg/kg dosages of esomeprazole, respectively. Both esomeprazole dosages were well tolerated. CONCLUSIONS: Oral treatment with esomeprazole 0.25 mg/kg and 1 mg/kg was well tolerated and provided dose-related acid suppression, dose-related exposure to esomeprazole, and decreased esophageal acid exposure in infants 1-24 months old with GERD. PMID- 26422095 TI - Esomeprazole for the Treatment of Erosive Esophagitis in Children: An International, Multicenter, Randomized, Parallel-Group, Double-Blind (for Dose) Study. AB - BACKGROUND: Acid suppression with a proton pump inhibitor is standard treatment for gastroesophageal reflux disease and erosive esophagitis in adults and increasingly is becoming first-line therapy for children aged 1-17 years. We evaluated endoscopic healing of erosive esophagitis with esomeprazole in young children with gastroesophageal reflux disease and described esophageal histology. METHODS: Children aged 1-11 years with endoscopically or histologically confirmed gastroesophageal reflux disease were randomized to esomeprazole 5 or 10 mg daily (<20 kg) or 10 or 20 mg daily (>= 20 kg) for 8 weeks. Patients with erosive esophagitis underwent an endoscopy after 8 weeks to assess healing of erosions. RESULTS: Of 109 patients, 49% had erosive esophagitis and 51% had histologic evidence of reflux esophagitis without erosive esophagitis. Of the 45 patients who had erosive esophagitis and underwent follow-up endoscopy, 89% experienced erosion resolution. Dilation of intercellular space was reported in 24% of patients with histologic examination. CONCLUSIONS: Esomeprazole (0.2-1.0 mg/kg) effectively heals macroscopic and microscopic erosive esophagitis in this pediatric population with gastroesophageal reflux disease. Dilation of intercellular space may be an important histologic marker of erosive esophagitis in children. PMID- 26422096 TI - Healing of Erosive Esophagitis and Improvement of Symptoms of Gastroesophageal Reflux Disease After Esomeprazole Treatment in Children 12 to 36 Months Old. AB - OBJECTIVES: The aim of the study was to evaluate erosive esophagitis healing and symptom improvement with once-daily esomeprazole in children ages 12 to 36 months with endoscopically or histologically proven gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: Data from children ages 12 to 36 months were included in a post-hoc analysis of an 8-week, multicenter, randomized, and double blind by dose strata study of patients ages 1 to 11 years with endoscopically or histologically confirmed GERD. Children were randomized to receive esomeprazole 5 or 10 mg once daily. Patients underwent endoscopy and, if required, mucosal biopsy at baseline. Patients who had erosive esophagitis (graded using the Los Angeles classification system) at baseline underwent a follow-up endoscopy at final study visit to assess healing of erosive esophagitis. Investigators scored severity of GERD symptoms at baseline and every 2 weeks using the Physician Global Assessment. RESULTS: Thirty-one of 109 primary study patients ages 12 to 36 months were included in the post hoc analysis. At baseline, 15 patients (48.4%) had erosive esophagitis, underwent follow-up endoscopy, and were healed after 8 weeks of esomeprazole treatment. Of the 19 patients with moderate-to severe baseline Physician Global Assessment symptom scores, 84.2% had lower scores by the final visit. Following esomeprazole treatment, GERD symptoms were significantly improved from baseline to final visit (P <= 0.0018). CONCLUSIONS: Esomeprazole 5 or 10 mg may be used to successfully treat erosive esophagitis and symptoms of GERD in children as young as 1 year.Moreover, although not yet validated in pediatric patients, the Los Angeles classification system was useful in grading erosive esophagitis in children ages 12 to 36 months. PMID- 26422097 TI - Esomeprazole for the Treatment of GERD in Infants Ages 1-11 Months. AB - OBJECTIVES: Gastroesophageal reflux disease (GERD) is present in pediatric patients when reflux of gastric contents causes troublesome symptoms and/ or complications. The present study evaluates the efficacy and safety of esomeprazole in infants ages 1 to 11 months with GERD. METHODS: In this multicenter randomized, double-blind, placebo-controlled, parallel-group, treatment-withdrawal study, infants received open-label, weight-adjusted doses of esomeprazole (2.5-10 mg) once daily for 2 weeks. Infants with symptom improvement were randomized to esomeprazole (weight-adjusted doses [2.5-10 mg]) or placebo for 4 weeks. The primary endpoint was time to discontinuation owing to symptom worsening based on global assessments by the parent/guardian and physician. Adverse events were recorded. RESULTS: Of the 98 patients enrolled, 81 (82.7%) experienced symptom improvement determined by physician global assessment (PGA) during open-label esomeprazole treatment; 80 entered the double-blind phase. During this phase, discontinuation rates owing to symptom worsening were 48.8% (20/41) for placebo-treated versus 38.5% (15/39) for esomeprazole-treated patients (hazard ratio 0.69; P = 0.28). Posthoc analysis of infants with symptomatic GERD (ie, no diagnostic procedure performed) revealed that time to discontinuation was significantly longer with esomeprazole than placebo (hazard ratio 0.24; P = 0.01); the complementary subgroup difference was not significant (hazard ratio 1.39; P = 0.48). Esomeprazole was well tolerated. CONCLUSIONS: The discontinuation rate owing to symptom worsening did not differ significantly between infants receiving esomeprazole versus those receiving placebo. Improved diagnostic criteria in this age group are needed to identify infants with GERD who may benefit from acid suppression therapy. PMID- 26422098 TI - Has Afirma gene expression classifier testing refined the indeterminate thyroid category in cytology? AB - BACKGROUND: Thyroid fine-needle aspiration (FNA) plays a pivotal role in the evaluation of thyroid nodules. Up to 30% of cases are diagnosed as indeterminate by FNA, including atypia of undetermined significance, follicular lesion of undetermined significance, suspicious for a follicular neoplasm, and follicular neoplasm, with approximately two-thirds having a benign outcome. The gene expression classifier (GEC) test is a molecular test for cases with indeterminate cytology. The purpose of the current study was to examine the refining role of the GEC test within a single institution. METHODS: Retrospective analysis of all thyroid FNAs during a 20-month period after implementation of GEC was performed. Cases of indeterminate cytology with concomitant GEC testing were selected and divided further in 4 subgroups. Correlation with surgical follow-up, when available, was performed. The results were compared with previously published data from the study institution before the implementation of GEC testing. RESULTS: Among the 217 cases, there were 189 with indeterminate cytology, 42% of which were benign and 50% of which were suspicious by GEC. The excisional rate of atypia of undetermined significance-follicular lesion of undetermined significance in the pre-GEC category was 63%, which decreased to 35% in the post GEC category, whereas the malignancy rate in the excised thyroids increased from 35% in the pre-GEC category to 47% in the post-GEC category. Similar findings also were obtained for suspicious for a follicular neoplasm-follicular neoplasm lesions. CONCLUSIONS: The strength of the GEC test appears to lie in its ability to reclassify 42% of indeterminate cytology cases as benign, thereby decreasing the number of unnecessary surgical procedures. PMID- 26422099 TI - Hormonal impact on tumor growth and progression. AB - In this review, current knowledge of hormones impact on prostate, breast and endometrium cancer growth and transition to hormone therapy resistant phenotype is summarized. A special consideration is given to genetic alterations and hormone responsive signa-ling pathways. Estrogen, androgen and progesterone are the key drivers in these cancer variants. Hormone receptors and their interplay with plenty of growth factors generated by the tumor microenvironment contribute greatly to carcinogenesis and cancer cell proliferation. The tumor cell plasticity that could explain a loss of responsiveness to hormone deprivation therapy and aggressive course of the diseases has been addressed. PMID- 26422100 TI - Application of serex-analysis for identification of human colon cancer antigens. AB - BACKGROUND: Colorectal, lung and breast tumors are the most devastating and frequent malignances in clinical oncology. SEREX-analysis of colon cancer leads to identification of more than hundred antigens which are potential tumor markers. With idea that immunoscreening with pool of allogeneic sera is more productive for antigen isolation, SEREX-analysis was applied to four cases of stages II-IV primary colon tumor and 22 new antigens were isolated. OBJECTIVE: To characterize 22 primary colon cancer antigens isolated by SEREX-technique. MATERIALS AND METHODS: Allogenic screening, real-time PCR analysis. RESULTS: After allogeneic immunoscreening, for 5 of 22 (22%) isolated antigens were confirmed colon cancer restricted serological profile solely positive for 14% of tested colon cancer sera. Through these five antigens, KY-CC-17/beta-actin has cytoskeleton function; KY-CC-14/ACTR1A and KY-CC-19/TSGA2 participate in chromosome segregation; KY-CC-12/FKBP4 regulates steroid receptor function and KY CC-15/PLRG1 is a component of spliceosome complex. For the last four antigens tested were found aberrant mRNA expression in some cases of colon tumor. CONCLUSION: The exploration of identified antigens may define suitable targets for immunotherapy or diagnostic of colon cancer. PMID- 26422101 TI - Modifying effects of lactoferrin in vitro on molecular phenotype of human breast cancer cells. AB - AIM: To assess the role of endogenous lactoferrin (LF) in the formation of the molecular phenotype of human breast cancer (BC) cell lines with varying degrees of malignancy, including cisplatin/doxorubicin resistant cell lines, and identify possible impact of exogenous LF. MATERIALS AND METHODS: 5 breast cell lines of different origin - MCF-10 A, MCF-7, including doxorubicin/cisplatin resistant ones, T47D, MDA-MB-231, and MDA-MB-468. Immunocytochemistry: expression of LF, Ki 67, adhesion molecules E- and N-cadherin, CD44, CD24 rating the invasive potential of cells. RESULTS: Expression of LF in human BC cell lines varies. It is associated with the heterogeneity of molecular profiles of cell lines in terms of adhesion. A link has been established between the level of LF expression in the resistant cell line MCF-7/CP and MCF-7/Dox, features of their molecular profile and invasive properties. Exogenous LF was shown to be capable of modifying the molecular profile and invasive properties of all the studied cell lines including resistant ones (MCF-7/CP and MCF-7/Dox). CONCLUSIONS: The sensitivity of cytostatic-resistant cell lines (MCF-7/CP and MCF-7/Dox) tends to increase under the influence of exogenous LF. It is likely that this effect is due to LF-mediated inhibition of the expression of proteins associated with drug resistance. PMID- 26422102 TI - Enhanced cytotoxicity of photoexcited fullerene C60 and cisplatin combination against drug-resistant leukemic cells. AB - AIM: To evaluate the viability of leukemic cells sensitive (L1210S) and resistant (L1210R) to cisplatin, ROS production and free cytosolic Ca(2+) concentration under treatment with cisplatin or its combination with photoexcited fullerene C60. METHODS: Cell viability was assessed by the MTT reduction assay. Light emitting diode lamp (2.45 J/cm(2)) was used for photoexcitation of intracellular accumulated fullerene C60. Free cytosolic calcium concentration ([Ca(2+)]i) and ROS production in cells were estimated with the use of fluorescent probes Indo-1 and 2',7'-dichlorodihydrofluorescein diacetate (DCF-DA), respectively. RESULTS: It is shown that viability of L1210R cells wasn't changed under treatment with cisplatin in concentration range 0.1-10 MUg/ml. 50% and 30% decrease of L1210S cells were observed after 24 h of incubation with cisplatin at concentrations 5 and 1 MUg/ml, respectively. Intensification of extranuclear cytotoxic effects (ROS production and [Ca(2+)]i increase) after treatment with 1 MUg/ml was detected in L1210S, but not in L1210R cells. The most strongly pronounced increase of ROS production and [Ca(2+)]i in both L1210 cell lines was revealed in dynamics after combined treatment with cisplatin (1 MUg/ml) and photoexcited fullerene C60 (10(-5) M) and was followed by decreased viability of not only L1210S, but of L1210R cells as well.. CONCLUSION: Combined treatment with photoexcited C60 and cisplatin allowed to decrease effective concentration of cisplatin against parental L1210 cells and to increase sensibility of resistant cells to the drug. PMID- 26422103 TI - Aconitine-containing agent enhances antitumor activity of dichloroacetate against Ehrlich carcinoma. AB - Significant variability of anticancer efficacy of dichloroacetate (DCA) stimulated an active search for the agents capable to enhance it antitumor action. Therefore, the aim of this work is the study of capability of aconitine containing antiangiogenic agent BC1 to enhance anticancer activity of DCA against Ehrlich carcinoma. MATERIALS AND METHODS: DCA (total dose was 1.3 g/kg of b.w.) and BC1 (total dose was 0.9 mg/kg of b.w.) were administered per os starting from the 2(nd) and 3(rd) days, respectively (8 admini-strations for each agent). Antitumor efficacy of agents was estimated. Lactate level, LDH activity and the state of mitochondrial electron transport chain in tumor cells as well as phagocytic activity and reactive oxygen species (ROS) production of tumor associated macrophages (TAM) were studied. RESULTS: Combined administration of DCA and VS1 resulted in 89.8% tumor growth inhibition (p < 0.001), what is by 22.5% (p < 0.05) higher that that of DCA alone. This combined treatment was accompanied with a decrease of lactate level in tumor tissue by 30% (p < 0.05) and significant elevation of LDH activity by 70% (p < 0.01). Increased level of NO-Fe-S clusters and 2-fold reduction of Fe-S cluster content were revealed in tumor tissue of mice after DCA and BC1 administration. It was shown that combined therapy did not effect TAM quantity and their phagocytic activity but stimulated ROS production by TAMs by 78% (p < 0.05) compared to this index in control animals. CONCLUSION: Antiangiogenic agent VS1 in combination with DCA considerably enhances antitumor activity of DCA via significant decrease of Fe-S containing protein level resulted from substantial elevation of nitrosylation of these proteins. PMID- 26422104 TI - Anticancer effectiveness of vaccination based on xenogeneic embryo proteins applied in different schedules. AB - THE AIM: To evaluate anticancer activity of vaccination with chicken embryo proteins (CEP) applied in different schedules. MATERIALS AND METHODS: C57Bl mice were vaccinated with CEP before (prophylactic schedule) or after (different therapeutic schedules with or without preliminary tumor removal) the Lewis lung carcinoma cells transplantation. The latent period of tumor development, tumor volume and metastasis rate were evaluated. RESULTS: Potent antimetastatic effect of CEP-based vaccination was seen in case of therapeutic regimen after primary tumor removal. The metastasis inhibition index (MII) reached 96.9 and 97.8% on 18(th) and 34(th) day after tumor removal, respectively. When CEP vaccination was performed in the settings of therapeutic regimen without primary tumor removal the anticancer effect was evident only if vaccinations started as early as 24 h after the cancer cells injections. The highest MII achieved in such condition was 77.6%, tumor volume in the group of vaccinated animals was by 53.1-42.1% lower than in the control tumor-bearing mice. CEP vaccination before tumor challenge (prophylactic immunization) led to a statistically significant prolongation of the latent period of tumor development, a reduction of tumor volume (35.8-48.8% compared to control unvaccinated mice) and a marked inhibition of metastasis (MII was 71.1%). CONCLUSION: Vaccination based on CEP exhibited both prophylactic and therapeutic anticancer effects. The last one is more pronounced when the vaccination starts shortly after the primary tumor resection. PMID- 26422105 TI - Anticancer efficacy of allogeneic vaccine modified with progenitor neural cells supernatant in rats with glioma 101.8. AB - The aim of the work was to investigate the antitumor efficacy of allogeneic tumor vaccine (ATV) modified with rat progenitor neural cell supernatant (RPNS) in rats with glioma 101.8. MATERIALS AND METHODS: The study was performed on 74 white random-bred rats. ATV was developed on the basis of glioma 101.8 cell suspension modified with RPNS (0.02 or 0.10 mg/ml). RPNS was prepared from suspension made from whole rat brain tissue on 14(th) (E14) day of gestation. Model of brain glioma 101.8 was reproduced by intracerebral injection of glioma 101.8 cell suspension. ATV was injected intraperitoneally in a volume of 0.2 ml per animal once on the 10(th) day after tumor transplantation. For survival analysis Kaplan Mayer multiple assessments method was used. Cytotoxic activity of rat lymphocytes (effector cells) was evaluated in MTT-colorimetric test by determining the state of mitochondrial dehydrogenase enzymes in target cells (allogeneic glioma 101.8 cells). RESULTS: Intraperitoneal administration of ATV modified with 0.10 mg/ml RPNS significantly increased mean survival time and median survival of glioma-bearing rats compared with unvaccinated group (MST (19.9 +/- 2.4), 21.4 days; versus MST (14.6 +/- 2.8); 14 days; p = 0.0002, Gehan's - Wilcoxon test). Intraperitoneal administration of ATV modified with 0.10 mg/ml RPNS resulted in increased cytotoxic activity of immune cells of rats with glioma in vitro compared with this index in unvaccinated group (p = 0.026, U Mann - Whitney test). CONCLUSION: Antitumor effect of vaccination with RPNS modified ATV is realized via increased cytotoxic activity of immune cells, what could be used for further optimization of whole tumor cell vaccine. PMID- 26422106 TI - TRP genes family expression in colorectal cancer. AB - Colorectal cancer (CRC) is the most common cancer of the gastrointestinal tract. Different factors are responsible for the development of CRC. Transient Receptor Potential (TRP) which is an important component of calcium channel is associated with several pathological conditions like cancer, neurodegenerative and cardiovascular diseases. Thirty members of the family of TRP ion channel in mammals have been determined till now. The aim of this study is to investigate TRPM, TRPV and TRPC gene expression levels in tumor tissues of CRC patients and to analyze the relationship of expression in tumor tissue of CRC with other known prognostic factors. MATERIAL AND METHODS: In this study, 93 CRC patients were included. The level of TRP gene expression in paraffin blocks of normal and cancerous colorectal tissue samples were studied at the level of mRNA with Real time PCR. RESULTS: The mRNA expression level of TRPV3, TRPV4, TRPV5, TRPM4 and TRPC6 genes in 37 female and 56 male patients diagnosed with CRC was revealed lower in tumor tissue as compared to normal tissue (p < 0.05). No statistically significant differences of mRNA expression levels of other TRP genes were found. CONCLUSIONS: TRP gene family like TRPV3, TRPV4, TRPV5, TRPM4 and TRPC6 may be thought as potential genes contributing to tumorigenesis as their expression decreases in CRC as compared to normal tissues. PMID- 26422107 TI - Role of vascular endothelial growth factor in non-small cell lung cancer pathogenesis. AB - The angiogenesis is an important process in the pathogenesis of malignancies. It is regulated by various growth factors, with the vascular endothelial growth factor (VEGF) playing the central role. The aim of the present study was to evaluate possible associations of functional VEGF -2578C>A, -634G>C, and +936C>T polymorphisms with the risk for occurrence and progression of non-small cell lung cancer (NSCLC) in patients living in Republic of Belarus. MATERIALS AND METHODS: A total of 202 patients (147 males and 55 females) diagnosed as having the NSCLC. The control group consisted of 336 individuals (245 males and 91 females) without an oncopathology. The total DNA was isolated from peripheral blood. We investigated the single nucleotide polymorphisms of VEGF (rs 2010963), (rs 699947), (rs 3025039). The genotyping was performed by PCR-RFLP analysis. RESULTS: Our results revealed a marginally significant association of the -2578CC genotype (p=0.002) with a greater degree of tumor spread (T2-T4). Heterozygous genotypes -2578SA and +936ST carriers were included into the follow-up group significantly more often (r=0.021 and r=0.012, respectively). Our study demonstrate that VEGF -2578A/C and +936C/T polymorphisms are among the factors determining the individual peculiarities of NSCLC course in this population and can be used for clarifying the prognosis of the disease. PMID- 26422108 TI - Plasma homocysteine, folate and vitamin B12 levels in patients with lung cancer. AB - AIM: Disorders in the metabolism of homocysteine and B vitamins, which are involved in a one-carbon transfer reaction and important for DNA synthesis and methylation, have been hypothesized to be associated with carcinogenesis. The purpose of this study is to evalu-ate the levels of homocysteine, vitamin B12 and folic acid in patients with newly diagnosed lung cancer and determines whether they might be used as an accurate tumor marker for monitoring the patients if they are found to be elevated in lung cancer. MATERIALS AND METHODS: Forty male patients with lung cancer were included in this study. Age-matched forty healthy males who had not malignant disease or had not received any drug affecting plasma homocysteine levels were selected as control group. Homocysteine, vitamin B12 and folate levels were measured in the samples obtained from the patients and controls. RESULTS: Mean age of the patients with lung cancer was 58.7 +/- 9.9 years. All the patients were cigarettes smokers. Mean daily consumption of cigarettes was 2.0+/-0.7 packs and mean duration of smoking was 30 +/- 11 years. Histologic type of carcinoma was found to be squamous cell carcinoma in 55%, adenocarcinoma - in 35%, and small cell carcinoma - in 10% of the cases. Clinical stage was stage IA in 20%, stage IB - in 20%, stage IIA - in 2.5%, stage IIB - in 10%, stage IIIA - in 12.5%, stage IIIB - in 20%, and stage IV - in 15% of the cases. Mean homocysteine level was 15.3 +/- 7.3 umol/l in the patients with lung cancer while 9.8 +/- 2.6 umol/l in controls. Homocysteine level was significantly higher in the patients with lung cancer compared to control group (p < 0.001). Mean folate level was 4.3 +/- 1.8 pg/ml in cancer cases while 6.1 +/- 2.3 pg/ml in controls. That is to say, plasma folate levels were significantly lower in cases of lung cancer compared to controls (p < 0.001). There was no significantly difference between groups with regard to B12 levels (mean B12 level was 234 +/- 99 and 240 +/- 104 ng/ml in the patients with lung cancer and controls, respectively, p = 0.78). Plasma homocysteine, vitamin B12 and folate levels did not show significant difference with respect to histologic type of carcinoma. No significant correlation was found between plasma homocysteine, vitamin B12, folate levels and number of cigarettes smoked per day, duration of smoking, age of the patient, and clinical stage of carcinoma. There was also no correlation between number of cigarettes smoked per day, duration of smoking, age of the patient and clinical stage of carcinoma. A possible inverse correlation between plasma homocysteine, vitamin B12 and folate levels was not observed. CONCLUSION: In conclusion, high plasma homocysteine and low folate levels could be associated with lung cancer. However, further studies performed on large patient population are needed. PMID- 26422109 TI - Primary testicular lymphoma: a single centre experience. AB - AIM: Primary testicular lymphoma (PTL) is an uncommon and aggressive form of extranodal non-Hodgkin's lymphoma (NHL). We aimed to analyse the clinicopathological characteristics and outcomes of our PTL cases. MATERIALS AND METHODS: A review was made of the medical records of 339 NHL patients who were treated in the Medical Oncology Department between January 2005 and December 2013. RESULTS: 8 PTL patients were identified from the 339 NHL patients. The average age of the patients was 67.7 +/- 7.9 years (range 53-79 years). The mean follow-up time was 24.8 months (range 7-98 months). Inguinal orchiectomy was performed as a diagnostic and initial therapy and all the patients underwent 4-6 cycles of chemoimmunotherapy consisting of cyclophosphamide, doxorubicin, vincristine and prednisone plus rituximab. 4 of 8 patients received intrathecal prophylactic chemotherapy and 6 of 8 patients continued contralateral testis irradiation. Relapse occured in only 1 patient in central nervous system after 6 months who had not received intrathecal prophylaxis. No contralateral testis relapse was observed. CONCLUSIONS: Primary testicular NHL is an uncommon entity and we evaluated 8 patients; with one relapse in central nervous system and no relapse in the contralateral testis. PMID- 26422110 TI - Rare case of intraintestinal stromal tumors in the patient with familial adenomatous polyposis. AB - AIM: To describe the case of metachronous gastrointestinal stromal tumors in a proband with familial adenomatous polyposis (FAP), carrier of APC gene mutation in codon 1309. MATERIAL AND METHODS: The physical examination, genealogical analysis and molecular genetic analysis of peripheral blood in 15-years-old girl with FAP and her sister, were carried out. Macroscopic, standard histological and immunohistochemical study of surgical specimens - intraintestinal tumors of the small intestine in proband was performed. RESULTS: Extraintestinal manifestations, including congenital abnormalities of facial skeleton, typical for Gardner's syndrome, were observed in the sisters with FAP as the addition symptoms of the disease. Frameshift mutation in codon 1309 in the APC gene was detected in these patients. A rare neoplasia - metachronous gastrointestinal stromal tumor was found in proband 15 months after total colectomy for FAP. This is the third case described in the accessible medical literature. CONCLUSION: The possible role of APC gene mutation in the development of mesenchymal neoplasms is discussed. The study of stromal tumors is important for understanding of their pathogenesis that will enable to develop effective targeted therapy. PMID- 26422111 TI - Intercorrelated Superhybrid of AgBr Supported on Graphitic-C3N4-Decorated Nitrogen-Doped Graphene: High Engineering Photocatalytic Activities for Water Purification and CO2 Reduction. AB - AgBr nanoparticles supported on graphitic-C3N4-decorated nitrogen-doped graphene intercorrelated ternary superhybrid composites (ACNNG-x) acting as a novel visible-light driven photocatalyst are reported. Because of the fast interfacial charge separation and photoelectrochemical performance, the representative of ACNNG-50 superhybrid structure achieves high efficiency and stable photocatalytic capability for organic contaminant degradation and CO2 reduction. PMID- 26422113 TI - The role of surgery in the management of phantosmia. PMID- 26422114 TI - Gastrointestinal Stromal Tumors: Imaging Features Before and After Treatment. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, with most occurring in the stomach. GISTs may present with clinical symptoms (eg, gastrointestinal bleeding) or may be found incidentally at surgery, endoscopy, or imaging. At initial staging, GISTs often appear as well-circumscribed, round, solid masses. Small tumors may appear solid, whereas larger tumors may demonstrate central areas of necrosis. At follow-up imaging, decreasing tumor attenuation at computed tomographic indicates treatment response even in the setting of stable tumor size. Localized tumors are treated with resection. Imatinib mesylate, a tyrosine kinase inhibitor, is typically prescribed for metastatic disease and increasingly in a neoadjuvant role before resection. Imaging plays a key role in the identification of GISTs, evaluation of tumor extent and presence or absence of metastatic disease, and in assessing response to therapy. PMID- 26422112 TI - The impact of HLA class I and EBV latency-II antigen-specific CD8(+) T cells on the pathogenesis of EBV(+) Hodgkin lymphoma. AB - In 40% of cases of classical Hodgkin lymphoma (cHL), Epstein-Barr virus (EBV) latency-II antigens [EBV nuclear antigen 1 (EBNA1)/latent membrane protein (LMP)1/LMP2A] are present (EBV(+) cHL) in the malignant cells and antigen presentation is intact. Previous studies have shown consistently that HLA-A*02 is protective in EBV(+) cHL, yet its role in disease pathogenesis is unknown. To explore the basis for this observation, gene expression was assessed in 33 cHL nodes. Interestingly, CD8 and LMP2A expression were correlated strongly and, for a given LMP2A level, CD8 was elevated markedly in HLA-A*02(-) versus HLA-A*02(+) EBV(+) cHL patients, suggesting that LMP2A-specific CD8(+) T cell anti-tumoral immunity may be relatively ineffective in HLA-A*02(-) EBV(+) cHL. To ascertain the impact of HLA class I on EBV latency antigen-specific immunodominance, we used a stepwise functional T cell approach. In newly diagnosed EBV(+) cHL, the magnitude of ex-vivo LMP1/2A-specific CD8(+) T cell responses was elevated in HLA A*02(+) patients. Furthermore, in a controlled in-vitro assay, LMP2A-specific CD8(+) T cells from healthy HLA-A*02 heterozygotes expanded to a greater extent with HLA-A*02-restricted compared to non-HLA-A*02-restricted cell lines. In an extensive analysis of HLA class I-restricted immunity, immunodominant EBNA3A/3B/3C-specific CD8(+) T cell responses were stimulated by numerous HLA class I molecules, whereas the subdominant LMP1/2A-specific responses were confined largely to HLA-A*02. Our results demonstrate that HLA-A*02 mediates a modest, but none the less stronger, EBV-specific CD8(+) T cell response than non HLA-A*02 alleles, an effect confined to EBV latency-II antigens. Thus, the protective effect of HLA-A*02 against EBV(+) cHL is not a surrogate association, but reflects the impact of HLA class I on EBV latency-II antigen-specific CD8(+) T cell hierarchies. PMID- 26422115 TI - From rare to common and back again: 60years of lysosomal dysfunction. AB - Sixty years after its discovery, the lysosome is no longer considered as cell's waste bin but as an organelle playing a central role in cell metabolism. Besides its well known association with lysosomal storage disorders (mostly rare and life threatening diseases), recent data have shown that the lysosome is also a player in some of the most common conditions of our time; and, perhaps even most important, it is not only a target for orphan drugs (rare disease therapeutic approaches) but also a putative target to treat patients suffering from common complex diseases worldwide. Here we review the striking associations linking rare lysosomal storage disorders such as the well-known Gaucher disease, or even the recently discovered, extremely rare Neuronal Ceroid Lipofuscinosis-11 and some of the most frequent, multifaceted and complex disorders of modern society such as cancer, Parkinson's disease and frontotemporal lobar degeneration. PMID- 26422117 TI - Characterising intra- and inter-intrinsic network synchrony in combat-related post-traumatic stress disorder. AB - Soldiers with post-traumatic stress disorder (PTSD) exhibit elevated gamma-band synchrony in left fronto-temporal cortex, and connectivity measures in these regions correlate with comorbidities and PTSD severity, which suggests increased gamma synchrony is related to symptomology. However, little is known about the role of intrinsic, phase-synchronised networks in the disorder. Using magnetoencephalography (MEG), we characterised spectral connectivity in the default-mode, salience, visual, and attention networks during resting-state in a PTSD population and a trauma-exposed control group. Intrinsic network connectivity was examined in canonical frequency bands. We observed increased inter-network synchronisation in the PTSD group compared with controls in the gamma (30-80 Hz) and high-gamma range (80-150 Hz). Analyses of connectivity and symptomology revealed that PTSD severity was positively associated with beta synchrony in the ventral-attention-to-salience networks, and gamma synchrony within the salience network, but also negatively correlated with beta synchrony within the visual network. These novel results show that frequency-specific, network-level atypicalities may reflect trauma-related alterations of ongoing functional connectivity, and correlations of beta synchrony in attentional-to salience and visual networks with PTSD severity suggest complicated network interactions mediate symptoms. These results contribute to accumulating evidence that PTSD is a complicated network-based disorder expressed as altered neural interactions. PMID- 26422116 TI - Delayed hypertrophic differentiation of epiphyseal chondrocytes contributes to failed secondary ossification in mucopolysaccharidosis VII dogs. AB - Mucopolysaccharidosis (MPS) VII is a lysosomal storage disorder characterized by deficient beta-glucuronidase activity, which leads to the accumulation of incompletely degraded glycosaminoglycans (GAGs). MPS VII patients present with severe skeletal abnormalities, which are particularly prevalent in the spine. Incomplete cartilage-to-bone conversion in MPS VII vertebrae during postnatal development is associated with progressive spinal deformity and spinal cord compression. The objectives of this study were to determine the earliest postnatal developmental stage at which vertebral bone disease manifests in MPS VII and to identify the underlying cellular basis of impaired cartilage-to-bone conversion, using the naturally-occurring canine model. Control and MPS VII dogs were euthanized at 9 and 14 days-of-age, and vertebral secondary ossification centers analyzed using micro-computed tomography, histology, qPCR, and protein immunoblotting. Imaging studies and mRNA analysis of bone formation markers established that secondary ossification commences between 9 and 14 days in control animals, but not in MPS VII animals. mRNA analysis of differentiation markers revealed that MPS VII epiphyseal chondrocytes are unable to successfully transition from proliferation to hypertrophy during this critical developmental window. Immunoblotting demonstrated abnormal persistence of Sox9 protein in MPS VII cells between 9 and 14 days-of-age, and biochemical assays revealed abnormally high intra and extracellular GAG content in MPS VII epiphyseal cartilage at as early as 9 days-of-age. In contrast, assessment of vertebral growth plates and primary ossification centers revealed no significant abnormalities at either age. The results of this study establish that failed vertebral bone formation in MPS VII can be traced to the failure of epiphyseal chondrocytes to undergo hypertrophic differentiation at the appropriate developmental stage, and suggest that aberrant processing of Sox9 protein may contribute to this cellular dysfunction. These results also highlight the importance of early diagnosis and therapeutic intervention to prevent the progression of debilitating skeletal disease in MPS patients. PMID- 26422118 TI - The Short French Internet Addiction Test Adapted to Online Sexual Activities: Validation and Links With Online Sexual Preferences and Addiction Symptoms. AB - The goal of this study was to investigate the psychometric properties of a French version of the short Internet Addiction Test adapted to online sexual activities (s-IAT-sex). The French version of the s-IAT-sex was administered to a sample of 401 men. The participants also completed a questionnaire that screened for sexual addiction (PATHOS). The relationships of s-IAT-sex scores with time spent online for online sexual activities (OSAs) and the types of OSAs favored were also considered. Confirmatory analyses supported a two-factor model of s-IAT-sex, corresponding to the factorial structure found in earlier studies that used the short IAT. The first factor regroups loss of control and time management, whereas the second factor regroups craving and social problems. Internal consistency for each factor was evaluated with Cronbach's alpha coefficient, resulting in .87 for Factor 1, .76 for Factor 2, and .88 for the global scale. Concurrent validity was supported by relationships with symptoms of sexual addiction, types of OSAs practiced, and time spent online for OSAs. The prevalence of sexual addiction (measured by PATHOS) was 28.1% in the current sample of self-selected male OSA users. The French version of the s-IAT-sex presents good psychometric properties and constitutes a useful tool for researchers and practitioners. PMID- 26422119 TI - Progressive cranial nerve involvement and grading of facial paralysis in gelsolin amyloidosis. AB - INTRODUCTION: Hereditary gelsolin amyloidosis (GA) is a rare condition caused by the gelsolin gene mutation. The diagnostic triad includes corneal lattice dystrophy (type 2), progressive bilateral facial paralysis, and cutis laxa. Detailed information on facial paralysis in GA and the extent of cranial nerve injury is lacking. METHODS: 29 GA patients undergoing facial corrective surgery were interviewed, examined, and studied electroneurophysiologically. RESULTS: All showed dysfunction of facial (VII) and trigeminal (V) nerves, two-thirds of oculomotor (III) and hypoglossal (XII) nerves, and half of vestibulocochlear (acoustic) (VIII) nerve. Clinical involvement of frontal, zygomatic, and buccal facial nerve branches was seen in 97%, 83%, and 52% of patients, respectively. Electromyography showed marked motor unit potential loss in facial musculature. CONCLUSIONS: Cranial nerve involvement in GA is more widespread than previously described, and correlates with age, severity of facial paralysis, and electromyographic findings. We describe a grading method for bilateral facial paralysis in GA, which is essential for evaluation of disease progression and the need for treatment. PMID- 26422120 TI - Sagittal range of motion of the thoracic spine using inertial tracking device and effect of measurement errors on model predictions. AB - Range of motion (ROM) of the thoracic spine has implications in patient discrimination for diagnostic purposes and in biomechanical models for predictions of spinal loads. Few previous studies have reported quite different thoracic ROMs. Total (T1-T12), lower (T5-T12) and upper (T1-T5) thoracic, lumbar (T12-S1), pelvis, and entire trunk (T1) ROMs were measured using an inertial tracking device as asymptomatic subjects flexed forward from their neutral upright position to full forward flexion. Correlations between body height and the ROMs were conducted. An effect of measurement errors of the trunk flexion (T1) on the model-predicted spinal loads was investigated. Mean of peak voluntary total flexion of trunk (T1) was 118.4 +/- 13.9 degrees , of which 20.5 +/- 6.5 degrees was generated by flexion of the T1 to T12 (thoracic ROM), and the remaining by flexion of the T12 to S1 (lumbar ROM) (50.2 +/- 7.0 degrees ) and pelvis (47.8 +/- 6.9 degrees ). Lower thoracic ROM was significantly larger than upper thoracic ROM (14.8 +/- 5.4 degrees versus 5.8 +/- 3.1 degrees ). There were non-significant weak correlations between body height and the ROMs. Contribution of the pelvis to generate the total trunk flexion increased from ~20% to 40% and that of the lumbar decreased from ~60% to 42% as subjects flexed forward from upright to maximal flexion while that of the thoracic spine remained almost constant (~16% to 20%) during the entire movement. Small uncertainties (+/ 5 degrees ) in the measurement of trunk flexion angle resulted in considerable errors (~27%) in the model-predicted spinal loads only in activities involving small trunk flexion. PMID- 26422121 TI - Metabarcoding approach for nonindigenous species surveillance in marine coastal waters. AB - In this study, high-throughput sequencing (HTS) metabarcoding was applied for the surveillance of plankton communities within the southeastern (SE) Baltic Sea coastal zone. These results were compared with those from routine monitoring survey and morphological analyses. Four of five nonindigenous species found in the samples were identified exclusively by metabarcoding. All of them are considered as invasive in the Baltic Sea with reported impact on the ecosystem and biodiversity. This study indicates that, despite some current limitations, HTS metabarcoding can provide information on the presence of exotic species and advantageously complement conventional approaches, only requiring the same monitoring effort as before. Even in the currently immature status of HTS, this combination of HTS metabarcoding and observational records is recommended in the early detection of marine pests and delivery of the environmental status metrics of nonindigenous species. PMID- 26422122 TI - Bioassessment of marine sediment quality using meiofaunal assemblages in a semi enclosed bay. AB - In order to assess marine sediment quality of a semi-enclosed bay, sediment and meiofaunal samples were analyzed at 35 stations in coastal waters of Bohai Bay, China. Concentrations of heavy metals (Cd, Cr, Cu, Ni, Pb, Zn, Co and Mn) in sediment were measured and the Hakanson potential ecological risk index coupled with the ratio of nematodes to copepods (N/C ratio) was used. Results showed that the concentration of Mn was the highest while Cd was the main risk contributor. The Hakanson potential ecological risk index indicated that all pollutants posed low risks in the study area. However, the N/C ratio exhibited different results compared with Hakanson potential ecological risk index. BIOENV analysis identified the concentration of Ni and sediment grain size as the most important environmental variables influencing meiofaunal assemblages. The present study indicated that, in marine sediment quality assessments, meiofaunal assemblages should be involved besides pollutant concentrations. PMID- 26422123 TI - Application of baited remote underwater video stations to assess benthic coverage in the Persian Gulf. AB - A baited remote underwater video station (BRUVS) is generally considered an appropriate sampling tool for fish. The applicability of BRUVS to determine the substrate coverage was assessed by comparing stills from BRUVS videos to traditional point intercept transect (PIT) data to estimate percentage cover (PC) of different benthic substrate categories. Mean PCs of hard corals, rock, sand, and coral growth forms yielded statistically identical values with the two survey methods, while PCs of motile epibenthic invertebrates were underestimated by BRUVS in areas of both high and moderate relief. Yet, multivariate analyses revealed that the two methods yield similar substrate assemblage in an area of moderate relief. Results of our study suggest that the BRUVS can be effectively used to quantify both the presence/absence of a basic set of benthic habitat characteristics and diversity of coral growth forms on coral reefs in the Persian Gulf. PMID- 26422124 TI - Dry eyes and AIs: If you don't ask you won't find out. AB - OBJECTIVES: Our objective was to investigate the hypothesis that women on adjuvant aromatase inhibitors (AIs) for treatment of breast cancer have a higher prevalence of dry eye syndrome (DES) compared with controls. MATERIALS AND METHODS: Exposure and control groups were recruited. A cross sectional questionnaire-based study was performed. Demographic data and medical histories were collected. The presence of dry eye syndrome was determined by the ocular surface disease index (OSDI). The Functional Assessment of Cancer Treatment - Endocrine Subscale (FACT-ES) was performed to investigate correlations with other side effects of AIs. RESULTS: 93 exposure group and 100 control group questionnaires were included. The groups were similar in all demographic variables. The prevalence of dry eye syndrome was 35% (exposure) and 18% (control) (p < 0.01, OR 2.5). AIs were the only factor associated with dry eyes. The OSDI score was negatively correlated with the total FACT-ES score and positively correlated with duration of treatment. CONCLUSION: Our study is the first to use a validated questionnaire to assess for DES in this population. DES is significantly more prevalent in women on AIs compared with controls. This is a newly emerging, and easily treated side effect of AIs. Self-reporting of dry eye symptoms underestimates the prevalence of DES with AIs. We recommend routine screening of patients on AIs with the OSDI with the aim of improving patient quality of life and possibly adherence. PMID- 26422125 TI - Exploring information provision in reconstructive breast surgery: A qualitative study. AB - OBJECTIVE: Women considering reconstructive breast surgery (RBS) require adequate information to make informed treatment decisions. This study explored patients' and health professionals' (HPs) perceptions of the adequacy of information provided for decision-making in RBS. METHODS: Semi-structured interviews with a purposive sample of patients who had undergone RBS and HPs providing specialist care explored participants' experiences of information provision prior to RBS. RESULTS: Professionals reported providing standardised verbal, written and photographic information about the process and outcomes of surgery. Women, by contrast, reported varying levels of information provision. Some felt fully informed but others perceived they had received insufficient information about available treatment options or possible outcomes of surgery to make an informed decision. CONCLUSIONS: Women need adequate information to make informed decisions about RBS and current practice may not meet women's needs. Minimum agreed standards of information provision, especially about alternative types of reconstruction, are recommended to improve decision-making in RBS. PMID- 26422127 TI - Othering the Chronically Ill: A Discourse Analysis of New Zealand Health Policy Documents. AB - It is widely recognized that chronic illnesses pose significant challenges for health care systems around the world. In response, most governments have set health policies in order to manage (or better, reduce) demand and improve the health of their populations. A discourse analysis of four policy documents that shape these strategies in New Zealand reveals that the policies construct the chronically ill as "others," that is, as deviant or different from the "normal" population. The discourse further serves to blame the chronically ill both for being sick, and for placing a serious financial burden on society. We identify problems that arise from this discourse. They relate to (a) the fact that chronic illnesses are so prevalent, (b) the fallacy of categorizing all chronic illnesses as the same, PMID- 26422126 TI - Development of hyperdynamic circulation and response to beta-blockers in compensated cirrhosis with portal hypertension. AB - Nonselective beta-blockers are useful to prevent bleeding in patients with cirrhosis and large varices but not to prevent the development of varices in those with compensated cirrhosis and portal hypertension (PHT). This suggests that the evolutionary stage of PHT may influence the response to beta-blockers. To characterize the hemodynamic profile of each stage of PHT in compensated cirrhosis and the response to beta-blockers according to stage, we performed a prospective, multicenter (tertiary care setting), cross-sectional study. Hepatic venous pressure gradient (HVPG) and systemic hemodynamic were measured in 273 patients with compensated cirrhosis before and after intravenous propranolol (0.15 mg/kg): 194 patients had an HVPG >=10 mm Hg (clinically significant PHT [CSPH]), with either no varices (n = 80) or small varices (n = 114), and 79 had an HVPG >5 and <10 mm Hg (subclinical PHT). Patients with CSPH had higher liver stiffness (P < 0.001), worse Model for End-Stage Liver Disease score (P < 0.001), more portosystemic collaterals (P = 0.01) and splenomegaly (P = 0.01) on ultrasound, and lower platelet count (P < 0.001) than those with subclinical PHT. Patients with CSPH had lower systemic vascular resistance (1336 +/- 423 versus 1469 +/- 335 dyne . s . cm(-5) , P < 0.05) and higher cardiac index (3.3 +/- 0.9 versus 2.8 +/- 0.4 L/min/m(2) , P < 0.01). After propranolol, the HVPG decreased significantly in both groups, although the reduction was greater in those with CSPH (-16 +/- 12% versus -8 +/- 9%, P < 0.01). The HVPG decreased >=10% from baseline in 69% of patients with CSPH versus 35% with subclinical PHT (P < 0.001) and decreased >=20% in 40% versus 13%, respectively (P = 0.001). CONCLUSION: Patients with subclinical PHT have less hyperdynamic circulation and significantly lower portal pressure reduction after acute beta-blockade than those with CSPH, suggesting that beta-blockers are more suitable to prevent decompensation of cirrhosis in patients with CSPH than in earlier stages. PMID- 26422128 TI - Prorating WAIS - IV summary scores for patients with relapsing-remitting multiple sclerosis. AB - We evaluated the utility of prorating appropriate combinations of two, six and eight Wechsler Adult Intelligence Scale - Fourth Edition (WAIS - IV) subtests for estimating the Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Full Scale IQ (FSIQ) and General Ability Index (GAI) in a sample of individuals diagnosed with multiple sclerosis (MS). Forty-eight outpatients completed the WAIS - IV and Wechsler Memory Scale - Fourth Edition (WMS - IV) as part of a comprehensive neuropsychological battery. Means for age, education and duration of diagnosis were 42.35, 14.21 and 8.30 years, respectively. Paired t tests showed no significant differences between prorated and standard means for VCI (93.46 vs. 93.73), PRI (90.19 vs. 89.44), FSIQ (88.53 vs. 88.47) or GAI (90.56 vs. 90.65). Correlations between prorated and standard composites were >=0.89 in every instance. Correlations between the standard and prorated composites and education, disability status and WMS - IV indexes did not reveal a single contrast, where the correlations were significantly different. The present findings support the use of the two-subtest VCI and PRI composites and the eight subtest FSIQ and four-subtest GAI in the assessment of patients with MS. PMID- 26422130 TI - A NIR-remote controlled upconverting nanoparticle: an improved tool for living cell dye-labeling. AB - In living cells, due to the selective permeability and complicated cellular environment, the uptake efficiency and fluorescence decay of organic dyes during dye-labeling may be influenced, which may eventually result in poor fluorescent imaging. In this work, a protocol of UCNs@mSiO2-(FA and Azo) core-shell nanocarriers was designed and prepared successfully. The core-shell nanocarriers were assembled from two parts, including a mesoporous silica shell surface modified by folate (FA) and azobenzene (Azo), and an upconverting nanocrystal (UCN) core. The mesoporous silica shell is used for loading organic dyes and conjugating folate which helps to enhance the cellular uptake of nanocarriers. The UCN core works as a transducer to convert near infrared (NIR) light to local UV and visible light to activate a back-and-forth wagging motion of azobenzene molecules on the surface, while the azobenzene acts as a molecular impeller for propelling the release of organic dyes. The nanocarriers of loading organic dyes can maintain the stability of the fluorescent imaging effect better than free organic dyes. The experimental results show that with the help of the nanoparticle, cell uptake efficiency of the model dyes of rhodamine and 4', 6 diamidino-2-phenylindole (DAPI) was significantly improved. The release of dyes can only be triggered by NIR light exposure and their quantity is highly dependent on the duration of NIR light exposure, thus realizing NIR-regulated dye release spatiotemporally. Our work may open a novel avenue for precisely controlling UCN-based living cell imaging in biotechnology and diagnostics, as well as studying cell dynamics, cell-cell interactions, and tissue morphogenesis. PMID- 26422129 TI - Noise-Enhanced Vestibular Input Improves Dynamic Walking Stability in Healthy Subjects. AB - BACKGROUND: White noise galvanic vestibular stimulation (GVS) is thought to enhance the sensitivity of vestibular organs. OBJECTIVE: To examine the effects of noise-enhanced vestibular input on the walking performance in healthy subjects walking with eyes closed. METHODS: Walking performance of 17 healthy subjects (mean age 28.8 +/- 1.7 years) at slow, preferred, and fast speeds was examined during three different conditions: (1) walking with eyes open (EO) as baseline condition, (2) walking with eyes closed and sham noisy GVS (EC), and (3) walking with eyes closed and non-zero amplitude noisy GVS set to 80% of the individual sensory threshold for GVS (EC-GVS). Ten gait parameters were examined: stride time, stride length, base of support, swing time percentage, double support time percentage as well as gait asymmetry, bilateral phase coordination and the coefficient of variation (CV) of stride time, stride length and base of support. RESULTS: Noisy GVS improved stride time CV by 36% (p < 0.034), stride length CV by 31% (p < 0.037), base of support CV by 14% (p < 0.009), and bilateral phase coordination by 23% (p < 0.034). The ameliorating effects of noisy GVS on locomotion function were primarily observable during slow walking speeds. CONCLUSION: Noise-enhanced vestibular input is effective in improving locomotion function and is accompanied by a subjectively felt improvement of walking balance. It predominantly targets the variability and bilateral coordination characteristics of the walking pattern, which are critically linked to dynamic walking stability. Noisy GVS might present an effective treatment option to improve walking performance in patients with bilateral vestibular dysfunction. PMID- 26422131 TI - Cytotoxic Barrigenol-like Triterpenoids from an Extract of Cyrilla racemiflora Housed in a Repository. AB - Two new [(+)-cyrillins A (1) and B (2)] and four known barrigenol-like triterpenoids (3-6), along with betulinic acid and (+)-3beta-O-trans feruloylbetulinic acid, were isolated from a sample-restricted CH2Cl2-soluble extract of the bark of Cyrilla racemiflora, collected in Dominica. The structures of the new compounds were elucidated by interpretation of their spectroscopic data, and the absolute configuration of the cyclic 1,2-diol unit of (+)-cyrillin A (1) was ascertained by analysis of the electronic circular dichroism (ECD) spectrum induced with [Mo2(OAc)4]. In the case of (+)-cyrillin B (2), which was found to contain a diangeloylated glucose residue, the structure proposed was supported by analysis of its MS(2) and MS(3) spectra. All compounds isolated were evaluated for their cytotoxicity against HT-29 human colon cancer cells, and the known compound, (+)-barringtogenol B (3), was found to be the most potent, exhibiting an IC50 value of 1.7 MUM. This compound also showed inhibitory activity toward the CCD-112CoN human normal colon cell line, with an IC50 value of 5.9 MUM, indicating a lack of cytotoxic selectivity. PMID- 26422133 TI - Histone modification and chromatin remodeling during NER. AB - Here we review our developments of and results with high resolution studies on global genome nucleotide excision repair (GG-NER) in Saccharomyces cerevisiae. Technologies were developed to examine NER at nucleotide resolution in yeast sequences of choice and to determine how these related to local changes in chromatin. We focused on how GG-NER relates to histone acetylation for its functioning and we identified the histone acetyltransferase Gcn5 and acetylation at lysines 9/14 of histone H3 as a major factor in enabling efficient repair. Factors influencing this Gcn5-mediated event are considered which include Rad16, a GG-NER specific SWI/SNF factor and the yeast histone variant of H2AZ (Htz1). We describe results employing primarily MFA2 as a model gene, but also those with URA3 located at subtelomeric sequences. In the latter case we also see a role for acetylation at histone H4. We then consider the development of a high resolution genome-wide approach that enables one to examine correlations between histone modifications and the NER of UV-induced cyclobutane pyrimidine dimers throughout entire yeast genome. This is an approach that will enable rapid advances in understanding the complexities of how compacted chromatin in chromosomes is processed to access DNA damage before it is returned to its pre-damaged status to maintain epigenetic codes. PMID- 26422132 TI - DNA excision repair at telomeres. AB - DNA damage is caused by either endogenous cellular metabolic processes such as hydrolysis, oxidation, alkylation, and DNA base mismatches, or exogenous sources including ultraviolet (UV) light, ionizing radiation, and chemical agents. Damaged DNA that is not properly repaired can lead to genomic instability, driving tumorigenesis. To protect genomic stability, mammalian cells have evolved highly conserved DNA repair mechanisms to remove and repair DNA lesions. Telomeres are composed of long tandem TTAGGG repeats located at the ends of chromosomes. Maintenance of functional telomeres is critical for preventing genome instability. The telomeric sequence possesses unique features that predispose telomeres to a variety of DNA damage induced by environmental genotoxins. This review briefly describes the relevance of excision repair pathways in telomere maintenance, with the focus on base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR). By summarizing current knowledge on excision repair of telomere damage and outlining many unanswered questions, it is our hope to stimulate further interest in a better understanding of excision repair processes at telomeres and in how these processes contribute to telomere maintenance. PMID- 26422136 TI - DNA damage mediated transcription arrest: Step back to go forward. AB - The disturbance of DNA helix conformation by bulky DNA damage poses hindrance to transcription elongating due to stalling of RNA polymerase at transcription blocking lesions. Stalling of RNA polymerase provokes the formation of R-loops, i.e. the formation of a DNA-RNA hybrid and a displaced single stranded DNA strand as well as displacement of spliceosomes. R-loops are processed into DNA single and double strand breaks by NER factors depending on TC-NER factors leading to genome instability. Moreover, stalling of RNA polymerase induces a strong signal for cell cycle arrest and apoptosis. These toxic and mutagenic effects are counteracted by a rapid recruitment of DNA repair proteins to perform transcription coupled nucleotide excision repair (TC-NER) to remove the blocking DNA lesions and to restore transcription. Recent studies have highlighted the role of backtracking of RNA polymerase to facilitate TC-NER and identified novel factors that play key roles in TC-NER and in restoration of transcription. On the molecular level these factors facilitate stability of the repair complex by promotion and regulation of various post-translational modifications of NER factors and chromatin substrate. In addition, the continuous flow of new factors that emerge from screening assays hints to several regulatory levels to safeguard the integrity of transcription elongation after disturbance by DNA damage that have yet to be explored. PMID- 26422135 TI - XPC: Going where no DNA damage sensor has gone before. AB - XPC has long been considered instrumental in DNA damage recognition during global genome nucleotide excision repair (GG-NER). While this recognition is crucial for organismal health and survival, as XPC's recognition of lesions stimulates global genomic repair, more recent lines of research have uncovered many new non canonical pathways in which XPC plays a role, such as base excision repair (BER), chromatin remodeling, cell signaling, proteolytic degradation, and cellular viability. Since the first discovery of its yeast homolog, Rad4, the involvement of XPC in cellular regulation has expanded considerably. Indeed, our understanding appears to barely scratch the surface of the incredible potential influence of XPC on maintaining proper cellular function. Here, we first review the canonical role of XPC in lesion recognition and then explore the new world of XPC function. PMID- 26422134 TI - Facilitation of base excision repair by chromatin remodeling. AB - Base Excision Repair (BER) is a conserved, intracellular DNA repair system that recognizes and removes chemically modified bases to insure genomic integrity and prevent mutagenesis. Aberrant BER has been tightly linked with a broad spectrum of human pathologies, such as several types of cancer, neurological degeneration, developmental abnormalities, immune dysfunction and aging. In the cell, BER must recognize and remove DNA lesions from the tightly condensed, protein-coated chromatin. Because chromatin is necessarily refractory to DNA metabolic processes, like transcription and replication, the compaction of the genomic material is also inhibitory to the repair systems necessary for its upkeep. Multiple ATP-dependent chromatin remodelling (ACR) complexes play essential roles in modulating the protein-DNA interactions within chromatin, regulating transcription and promoting activities of some DNA repair systems, including double-strand break repair and nucleotide excision repair. However, it remains unclear how BER operates in the context of chromatin, and if the chromatin remodelling processes that govern transcription and replication also actively regulate the efficiency of BER. In this review we highlight the emerging role of ACR in regulation of BER. PMID- 26422137 TI - Histone ubiquitylation and its roles in transcription and DNA damage response. AB - DNA in human cells is constantly assaulted by endogenous and exogenous DNA damaging agents. It is vital for the cell to respond rapidly and precisely to DNA damage to maintain genome integrity and reduce the risk of mutagenesis. Sophisticated reactions occur in chromatin surrounding the damaged site leading to the activation of DNA damage response (DDR), including transcription reprogramming, cell cycle checkpoint, and DNA repair. Histone proteins around the DNA damage play essential roles in DDR, through extensive post-translational modifications (PTMs) by a variety of modifying enzymes. One PTM on histones, mono ubiquitylation, has emerged as a key player in cellular response to DNA damage. In this review, we will (1) briefly summarize the history of histone H2A and H2B ubiquitylation (H2Aub and H2Bub, respectively), (2) discuss their roles in transcription, and (3) their functions in DDR. PMID- 26422138 TI - In vitro Autoradiographic Analysis of Regional Changes in Estrogen Receptor Alpha in the Brains of Cycling Female Rats. AB - BACKGROUND/AIMS: The contributions of the three principal ovarian steroid hormones (estradiol, progesterone and testosterone) to the regulation of estrogen receptor alpha (ERalpha) levels in the rat brain were examined during the estrous cycle. METHODS: Receptor concentrations were measured using an in vitro autoradiographic technique designed to separately quantify free, unoccupied receptors and receptors 'occupied' by (bound to) endogenous hormone. RESULTS: ERalpha occupation increased at proestrus and declined at estrus, reflecting changes in circulating estradiol and testosterone levels. Total ERalpha content followed a pattern that was the inverse of the occupation data, falling over the night of proestrus. Between 2.00 and 10.00 a.m. on the day of estrus, total ERalpha concentrations recovered in all brain regions except the ventromedial nucleus (VMN), in which ERalpha binding remained depressed at estrus. Administration of the progesterone antagonist mifepristone on the afternoon of proestrus resulted in recovery of ERalpha levels in the VMN by the morning of estrus, consistent with the hypothesis that the preovulatory progesterone surge selectively inhibits VMN ERalpha expression. Residual ERalpha occupation observed at estrus, when estradiol is not detectable in the serum, likely reflects intracranial aromatization of circulating androgens, since the pattern of receptor occupation observed at this stage of the cycle could be reproduced in ovariectomized rats by replacement with testosterone. CONCLUSION: These findings indicate that ERalpha binding in the brain fluctuates during the rat estrous cycle in a region-specific manner and suggest that local aromatization of testosterone may contribute significantly to ERalpha occupation when circulating estradiol levels are low. PMID- 26422140 TI - Analysis of Chaotic Resonance in Izhikevich Neuron Model. AB - In stochastic resonance (SR), the presence of noise helps a nonlinear system amplify a weak (sub-threshold) signal. Chaotic resonance (CR) is a phenomenon similar to SR but without stochastic noise, which has been observed in neural systems. However, no study to date has investigated and compared the characteristics and performance of the signal responses of a spiking neural system in some chaotic states in CR. In this paper, we focus on the Izhikevich neuron model, which can reproduce major spike patterns that have been experimentally observed. We examine and classify the chaotic characteristics of this model by using Lyapunov exponents with a saltation matrix and Poincare section methods in order to address the measurement challenge posed by the state dependent jump in the resetting process. We found the existence of two distinctive states, a chaotic state involving primarily turbulent movement and an intermittent chaotic state. In order to assess the signal responses of CR in these classified states, we introduced an extended Izhikevich neuron model by considering weak periodic signals, and defined the cycle histogram of neuron spikes as well as the corresponding mutual correlation and information. Through computer simulations, we confirmed that both chaotic states in CR can sensitively respond to weak signals. Moreover, we found that the intermittent chaotic state exhibited a prompter response than the chaotic state with primarily turbulent movement. PMID- 26422139 TI - DJ-1 Protects Pancreatic Beta Cells from Cytokine- and Streptozotocin-Mediated Cell Death. AB - A hallmark feature of type 1 and type 2 diabetes mellitus is the progressive dysfunction and loss of insulin-producing pancreatic beta cells, and inflammatory cytokines are known to trigger beta cell death. Here we asked whether the anti oxidant protein DJ-1 encoded by the Parkinson's disease gene PARK7 protects islet cells from cytokine- and streptozotocin-mediated cell death. Wild type and DJ-1 knockout mice (KO) were treated with multiple low doses of streptozotocin (MLDS) to induce inflammatory beta cell stress and cell death. Subsequently, glucose tolerance tests were performed, and plasma insulin as well as fasting and random blood glucose concentrations were monitored. Mitochondrial morphology and number of insulin granules were quantified in beta cells. Moreover, islet cell damage was determined in vitro after streptozotocin and cytokine treatment of isolated wild type and DJ-1 KO islets using calcein AM/ethidium homodimer-1 staining and TUNEL staining. Compared to wild type mice, DJ-1 KO mice became diabetic following MLDS treatment. Insulin concentrations were substantially reduced, and fasting blood glucose concentrations were significantly higher in MLDS-treated DJ 1 KO mice compared to equally treated wild type mice. Rates of beta cell apoptosis upon MLDS treatment were twofold higher in DJ-1 KO mice compared to wild type mice, and in vitro inflammatory cytokines led to twice as much beta cell death in pancreatic islets from DJ-1 KO mice versus those of wild type mice. In conclusion, this study identified the anti-oxidant protein DJ-1 as being capable of protecting pancreatic islet cells from cell death induced by an inflammatory and cytotoxic setting. PMID- 26422141 TI - An Alternative Method to Facilitate cDNA Cloning for Expression Studies in Mammalian Cells by Introducing Positive Blue White Selection in Vaccinia Topoisomerase I-Mediated Recombination. AB - One of the most basic techniques in biomedical research is cDNA cloning for expression studies in mammalian cells. Vaccinia topoisomerase I-mediated cloning (TOPO cloning by Invitrogen) allows fast and efficient recombination of PCR amplified DNAs. Among TOPO vectors, a pcDNA3.1 directional cloning vector is particularly convenient, since it can be used for expression analysis immediately after cloning. However, I found that the cloning efficiency was reduced when RT PCR products were used as inserts (about one-quarter). Since TOPO vectors accept any PCR products, contaminating fragments in the insert DNA create negative clones. Therefore, I designed a new mammalian expression vector enabling positive blue white selection in Vaccinia topoisomerase I-mediated cloning. The method utilized a short nontoxic LacZalpha peptide as a linker for GFP fusion. When cDNAs were properly inserted into the vector, minimal expression of the fusion proteins in E. coli (harboring lacZDeltaM15) resulted in formation of blue colonies on X-gal plates. This method improved both cloning efficiency (75%) and directional cloning (99%) by distinguishing some of the negative clones having non-cording sequences, since these inserts often disturbed translation of lacZalpha. Recombinant plasmids were directly applied to expression studies using GFP as a reporter. Utilization of the P2A peptide allowed for separate expression of GFP. In addition, the preparation of Vaccinia topoisomerase I-linked vectors was streamlined, which consisted of successive enzymatic reactions with a single precipitation step, completing in 3 hr. The arrangement of unique restriction sites enabled further modification of vector components for specific applications. This system provides an alternative method for cDNA cloning and expression in mammalian cells. PMID- 26422143 TI - Why Robots Should Be Social: Enhancing Machine Learning through Social Human Robot Interaction. AB - Social learning is a powerful method for cultural propagation of knowledge and skills relying on a complex interplay of learning strategies, social ecology and the human propensity for both learning and tutoring. Social learning has the potential to be an equally potent learning strategy for artificial systems and robots in specific. However, given the complexity and unstructured nature of social learning, implementing social machine learning proves to be a challenging problem. We study one particular aspect of social machine learning: that of offering social cues during the learning interaction. Specifically, we study whether people are sensitive to social cues offered by a learning robot, in a similar way to children's social bids for tutoring. We use a child-like social robot and a task in which the robot has to learn the meaning of words. For this a simple turn-based interaction is used, based on language games. Two conditions are tested: one in which the robot uses social means to invite a human teacher to provide information based on what the robot requires to fill gaps in its knowledge (i.e. expression of a learning preference); the other in which the robot does not provide social cues to communicate a learning preference. We observe that conveying a learning preference through the use of social cues results in better and faster learning by the robot. People also seem to form a "mental model" of the robot, tailoring the tutoring to the robot's performance as opposed to using simply random teaching. In addition, the social learning shows a clear gender effect with female participants being responsive to the robot's bids, while male teachers appear to be less receptive. This work shows how additional social cues in social machine learning can result in people offering better quality learning input to artificial systems, resulting in improved learning performance. PMID- 26422142 TI - Entamoeba histolytica Dmc1 Catalyzes Homologous DNA Pairing and Strand Exchange That Is Stimulated by Calcium and Hop2-Mnd1. AB - Meiosis depends on homologous recombination (HR) in most sexually reproducing organisms. Efficient meiotic HR requires the activity of the meiosis-specific recombinase, Dmc1. Previous work shows Dmc1 is expressed in Entamoeba histolytica, a eukaryotic parasite responsible for amoebiasis throughout the world, suggesting this organism undergoes meiosis. Here, we demonstrate Dmc1 protein is expressed in E. histolytica. We show that purified ehDmc1 forms presynaptic filaments and catalyzes ATP-dependent homologous DNA pairing and DNA strand exchange over at least several thousand base pairs. The DNA pairing and strand exchange activities are enhanced by the presence of calcium and the meiosis-specific recombination accessory factor, Hop2-Mnd1. In combination, calcium and Hop2-Mnd1 dramatically increase the rate of DNA strand exchange activity of ehDmc1. The biochemical system described herein provides a basis on which to better understand the role of ehDmc1 and other HR proteins in E. histolytica. PMID- 26422145 TI - Development and implementation of a remote-sensing and in situ data-assimilating version of CMAQ for operational PM2.5 forecasting. Part 1: MODIS aerosol optical depth (AOD) data-assimilation design and testing. AB - This two-part paper reports on the development, implementation, and improvement of a version of the Community Multi-Scale Air Quality (CMAQ) model that assimilates real-time remotely-sensed aerosol optical depth (AOD) information and ground-based PM2.5 monitor data in routine prognostic application. The model is being used by operational air quality forecasters to help guide their daily issuance of state or local-agency-based air quality alerts (e.g. action days, health advisories). Part 1 describes the development and testing of the initial assimilation capability, which was implemented offline in partnership with NASA and the Visibility Improvement State and Tribal Association of the Southeast (VISTAS) Regional Planning Organization (RPO). In the initial effort, MODIS derived aerosol optical depth (AOD) data are input into a variational data assimilation scheme using both the traditional Dark Target and relatively new "Deep Blue" retrieval methods. Evaluation of the developmental offline version, reported in Part 1 here, showed sufficient promise to implement the capability within the online, prognostic operational model described in Part 2. In Part 2, the addition of real-time surface PM2.5 monitoring data to improve the assimilation and an initial evaluation of the prognostic modeling system across the continental United States (CONUS) is presented. IMPLICATIONS: Air quality forecasts are now routinely used to understand when air pollution may reach unhealthy levels. For the first time, an operational air quality forecast model that includes the assimilation of remotely-sensed aerosol optical depth and ground based PM2.5 observations is being used. The assimilation enables quantifiable improvements in model forecast skill, which improves confidence in the accuracy of the officially-issued forecasts. This helps air quality stakeholders be more effective in taking mitigating actions (reducing power consumption, ride-sharing, etc.) and avoiding exposures that could otherwise result in more serious air quality episodes or more deleterious health effects. PMID- 26422144 TI - Sternal Wound Infection after Cardiac Surgery: Management and Outcome. AB - BACKGROUND: Sternal Wound Infection (SWI) is a severe complication after cardiac surgery. Debridement associated with primary closure using Redon drains (RD) is an effective treatment, but data on RD management and antibiotic treatment are scarce. METHODS: We performed a single-center analysis of consecutive patients who were re-operated for SWI between 01/2009 and 12/2012. All patients underwent a closed drainage with RD (CDRD). Patients with endocarditis or those who died within the first 45 days were excluded from management analysis. RD fluid was cultured twice weekly. Variables recorded were clinical and biological data at SWI diagnosis, severity of SWI based on criteria for mediastinitis as defined by the Centers for Disease Control (CDC), antibiotic therapy, RD management and patient's outcome. RESULTS: 160 patients developed SWI, 102 (64%) fulfilled CDC criteria (CDC+) and 58 (36%) did not (CDC- SWI). Initial antibiotic treatment and surgical management were similar in CDC+ and CDC- SWI. Patients with CDC+ SWI had a longer duration of antibiotic therapy and a mortality rate of 17% as compared to 3% in patients with CDC- SWI (p = 0.025). Rates of superinfection (10% and 9%) and need for second reoperation (12% and 17%) were similar. Failure (death or need for another reoperation) was associated with female gender, higher EuroScore for prediction of operative mortality, and stay in the ICU. CONCLUSION: In patients with SWI, initial one-stage surgical debridement with CDRD is associated with favorable outcomes. CDC+ and CDC- SWI received essentially the same management, but CDC+ SWI has a more severe outcome. PMID- 26422146 TI - Attenuated Tonic and Enhanced Phasic Release of Dopamine in Attention Deficit Hyperactivity Disorder. AB - It is unclear whether attention deficit hyperactive disorder (ADHD) is a hypodopaminergic or hyperdopaminergic condition. Different sets of data suggest either hyperactive or hypoactive dopamine system. Since indirect methods used in earlier studies have arrived at contradictory conclusions, we directly measured the tonic and phasic release of dopamine in ADHD volunteers. The tonic release in ADHD and healthy control volunteers was measured and compared using dynamic molecular imaging technique. The phasic release during performance of Eriksen's flanker task was measured in the two groups using single scan dynamic molecular imaging technique. In these experiments volunteers were positioned in a positron emission tomography (PET) camera and administered a dopamine receptor ligand (11)C-raclopride intravenously. After the injection PET data were acquired dynamically while volunteers either stayed still (tonic release experiments) or performed the flanker task (phasic release experiments). PET data were analyzed to measure dynamic changes in ligand binding potential (BP) and other receptor kinetic parameters. The analysis revealed that at rest the ligand BP was significantly higher in the right caudate of ADHD volunteers suggesting reduced tonic release. During task performance significantly lower ligand BP was observed in the same area, indicating increased phasic release. In ADHD tonic release of dopamine is attenuated and the phasic release is enhanced in the right caudate. By characterizing the nature of dysregulated dopamine neurotransmission in ADHD, the results explain earlier findings of reduced or increased dopaminergic activity. PMID- 26422148 TI - Distribution and Feeding Behavior of Omorgus suberosus (Coleoptera: Trogidae) in Lepidochelys olivacea Turtle Nests. AB - Omorgus suberosus (Fabricius, 1775) has been identified as a potential predator of the eggs of the turtle Lepidochelys olivacea (Eschscholtz, 1829) on one of the main turtle nesting beaches in the world, La Escobilla in Oaxaca, Mexico. This study presents an analysis of the spatio-temporal distribution of the beetle on this beach (in areas of high and low density of L. olivacea nests over two arrival seasons) and an evaluation, under laboratory conditions, of the probability of damage to the turtle eggs by this beetle. O. suberosus adults and larvae exhibited an aggregated pattern at both turtle nest densities; however, aggregation was greater in areas of low nest density, where we found the highest proportion of damaged eggs. Also, there were fluctuations in the temporal distribution of the adult beetles following the arrival of the turtles on the beach. Under laboratory conditions, the beetles quickly damaged both dead eggs and a mixture of live and dead eggs, but were found to consume live eggs more slowly. This suggests that O. suberosus may be recycling organic material; however, its consumption of live eggs may be sufficient in some cases to interrupt the incubation period of the turtle. We intend to apply these results when making decisions regarding the L. olivacea nests on La Escobilla Beach, one of the most important sites for the conservation of this species. PMID- 26422147 TI - Rice-Infecting Pseudomonas Genomes Are Highly Accessorized and Harbor Multiple Putative Virulence Mechanisms to Cause Sheath Brown Rot. AB - Sheath rot complex and seed discoloration in rice involve a number of pathogenic bacteria that cannot be associated with distinctive symptoms. These pathogens can easily travel on asymptomatic seeds and therefore represent a threat to rice cropping systems. Among the rice-infecting Pseudomonas, P. fuscovaginae has been associated with sheath brown rot disease in several rice growing areas around the world. The appearance of a similar Pseudomonas population, which here we named P. fuscovaginae-like, represents a perfect opportunity to understand common genomic features that can explain the infection mechanism in rice. We showed that the novel population is indeed closely related to P. fuscovaginae. A comparative genomics approach on eight rice-infecting Pseudomonas revealed heterogeneous genomes and a high number of strain-specific genes. The genomes of P. fuscovaginae-like harbor four secretion systems (Type I, II, III, and VI) and other important pathogenicity machinery that could probably facilitate rice colonization. We identified 123 core secreted proteins, most of which have strong signatures of positive selection suggesting functional adaptation. Transcript accumulation of putative pathogenicity-related genes during rice colonization revealed a concerted virulence mechanism. The study suggests that rice-infecting Pseudomonas causing sheath brown rot are intrinsically diverse and maintain a variable set of metabolic capabilities as a potential strategy to occupy a range of environments. PMID- 26422149 TI - SIXTEEN YEARS OF PITYRIASIS VERSICOLOR IN METROPOLITAN AREA OF PORTO ALEGRE, SOUTHERN BRAZIL. AB - Pityriasis versicolor is the most common of the diseases caused by Malassezia yeasts. The aim of this study is to determine the prevalence of pityriasis versicolor and its etiological aspects in the metropolitan area of Porto Alegre, Brazil. A retrospective cross-sectional study with data from patients of a reference hospital from 1996 to 2011 was performed. Collected data included: date, age, gender, ethnicity, anatomical region of lesion and the direct mycological examination results. Among the positive results in the direct mycological examination, 5.8% (2,239) were positive for pityriasis versicolor. The angular coefficient (B) was -0.3%/year, showing a decrease over the years. The disease was more prevalent in men (7.1% of men versus 5.1% of women that underwent the direct mycological examination); younger age (median 31 years old); "pardo" and black people (3.7% more than expected in the sample); trunk (73.44% of the affected anatomic sites). Lesions in rare sites (groin, genitals, legs, feet and hands) were also observed in this study. In conclusion, due to the decrease in the prevalence of pityriasis versicolor, long-term epidemiological studies in the metropolitan area of Porto Alegre, Brazil, are needed to continue the monitoring of this disease. PMID- 26422150 TI - COMPARISON BETWEEN FOUR USUAL METHODS OF IDENTIFICATION OF Candida SPECIES. AB - Infection by Candida spp. is associated with high mortality rates, especially when treatment is not appropriate and/or not immediate. Therefore, it is necessary to correctly identify the genus and species of Candida. The aim of this study was to compare the identification of 89 samples of Candida spp. by the manual methods germ tube test, auxanogram and chromogenic medium in relation to the ID 32C automated method. The concordances between the methods in ascending order, measured by the Kappa index were: ID 32C with CHROMagar Candida(kappa = 0.38), ID 32C with auxanogram (kappa = 0.59) and ID 32C with germ tube (kappa = 0.9). One of the species identified in this study was C. tropicalis,which demonstrated a sensitivity of 46.2%, a specificity of 95.2%, PPV of 80%, NPV of 81.1%, and an accuracy of 80.9% in tests performed with CHROMagar Candida;and a sensitivity of 76.9%, a specificity of 96.8%, PPV of 90.9%, NPV of 91%, and an accuracy of 91% in the auxanogram tests. Therefore, it is necessary to know the advantages and limitations of methods to choose the best combination between them for a fast and correct identification of Candida species. PMID- 26422151 TI - Sporothrix schenckii COMPLEX:SUSCEPTIBILITIES TO COMBINED ANTIFUNGAL AGENTS AND CHARACTERIZATION OF ENZYMATIC PROFILES. AB - Sporothrix schenckii was reclassified as a complex encompassing six cryptic species, which calls for the reassessment of clinical and epidemiological data of these new species. We evaluated the susceptibility of Sporothrix albicans(n = 1) , S. brasiliensis(n = 6) , S. globosa(n = 1), S. mexicana(n = 1) and S. schenckii(n = 36) to terbinafine (TRB) alone and in combination with itraconazole (ITZ), ketoconazole (KTZ), and voriconazole (VRZ) by a checkerboard microdilution method and determined the enzymatic profile of these species with the API-ZYM kit. Most interactions were additive (27.5%, 32.5% and 5%) or indifferent (70%, 50% and 52.5%) for TRB+KTZ, TRB+ITZ and TRB+VRZ, respectively. Antagonisms were observed in 42.5% of isolates for the TRB+VRZ combination. Based on enzymatic profiling, the Sporothrix schenckii strains were categorized into 14 biotypes. Leucine arylamidase (LA) activity was observed only for S. albicans and S. mexicana. The species S. globosa and S. Mexicana were the only species without beta-glucosidase (GS) activity. Our results may contribute to a better understanding of virulence and resistance among species of the genus Sporothrix in further studies. PMID- 26422152 TI - ISOLATION OF Cryptococcus neoformans FROM ENVIRONMENTAL SAMPLES COLLECTED IN SOUTHEASTERN NIGERIA. AB - Cryptococcosis caused by Cryptococcus neoformans is the second most common fungal opportunistic pathogen and a life-threatening infection with serious clinical manifestations especially in HIV/AIDS and other immunocompromised patients. In Nigeria, HIV/AIDS infection has reached an alarming level. Despite this, information on the presence of this fungus in clinical and environmental samples is very scanty in Nigeria and many other parts of Africa. We set out to evaluate the presence of Cryptococcus neoformans or C. gattiiin pigeon droppings obtained from Southeastern Nigeria. One hundred and seventy-seven samples of pigeon droppings from six sample types were collected. The area covered comprised of ten cities and other locations spanning across five States in Nigeria. Using established techniques, Cryptococcus neoformans was isolated from 39 of the 177 (22.0%) samples overall. No C. gattiiwas isolated. Most of the isolates (32.4%) were recovered from dovecotes (11 of 34) followed closely by samples taken from markets (31.8%; seven of 22) and least from the church (4.0%; one of 25). The highest isolation rate (38.9%) was found in samples from Enugu-Ezike(seven of 23) while the least came from Afikpo and the other locations each with 9.1% isolation rate. This is the first large-scale screening of Cryptococcus neoformans from pigeon droppings in Nigeria. The ecological and epidemiological significance of these findings are discussed. PMID- 26422153 TI - QUANTITATIVE VS. CONVENTIONAL PCR FOR DETECTION OF HUMAN ADENOVIRUSES IN WATER AND SEDIMENT SAMPLES. AB - Human Adenoviruses (HAdV) are notably resistant in the environment. These agents may serve as effective indicators of fecal contamination, and may act as causative agents of a number of different diseases in human beings. Conventional polymerase chain reaction (PCR) and, more recently, quantitative PCR (qPCR) are widely used for detection of viral agents in environmental matrices. In the present study PCR and SYBR(r)Green qPCR assays were compared for detection of HAdV in water (55) and sediments (20) samples of spring and artesian wells, ponds and streams, collected from dairy farms. By the quantitative methodology HAdV were detected in 87.3% of the water samples and 80% of the sediments, while by the conventional PCR 47.3% and 35% were detected in water samples and sediments, respectively. PMID- 26422154 TI - ROTAVIRUS GENOTYPES CIRCULATING IN BRAZIL, 2007-2012: IMPLICATIONS FOR THE VACCINE PROGRAM. AB - Regarding public health in Brazil, a new scenario emerged with the establishment of universal rotavirus (RV) vaccination programs. Herein, the data from the five years of surveillance (2007-2012) of G- and P-type RV strains isolated from individuals with acute gastroenteritis in Brazil are reported. A total of 6,196 fecal specimens were investigated by ELISA and RT-PCR. RVs were detected in 19.1% (1,181/6,196). The peak of RV incidence moved from June-August to September. RV was detected less frequently (19.5%) among children <= 5 years than in older children and adolescents (6-18 years) (40.6%). Genotype distribution showed a different profile for each year: G2P[4] strains were most prevalent during 2007 2010, G9P[8] in 2011, and G12P[8] in 2012. Mixed infections (G1+G2P[4], G2+G3P[4]+P[8], G2+G12P[8]), unusual combinations (G1P[4], G2P[6]), and rare strains (G3P[3]) were also identified throughout the study period. Widespread vaccination may alter the RV seasonal pattern. The finding of RV disease affecting older children and adolescents after vaccine implementation has been reported worldwide. G2P[4] emergence most likely follows a global trend seemingly unrelated to vaccination, and G12, apparently, is emerging in the Brazilian population. The rapidly changing RV genotype patterns detected during this study illustrate a dynamic population of co-circulating wildtype RVs in Brazil. PMID- 26422155 TI - SERUM LEVELS OF COPPER AND IRON IN DENGUE FEVER. AB - The role of trace elements in dengue virulence is not yet known. The present study assessed the serum levels of two micronutrients, copper and iron, in cases of dengue fever. The study involved 96 patients of whom 48 had either severe or non-severe forms of dengue (with and without warning signs), and the remaining 48 were patients with other febrile illnesses (OFI), used as controls. Serum levels of copper and iron were evaluated at admission and by the time of defervescence using commercially available kits. At admission, no difference in the level of serum copper was observed between cases and controls. In the group of dengue cases, the copper level was found to be significantly decreased in severe and non severe cases with warning signs, compared to non-severe cases without warning signs. In contrast, by the time of defervescence the copper level was found to be increased in all dengue cases compared to OFI controls, but no difference was observed among dengue cases. Unlike OFI controls, dengue cases showed an increasing pattern of copper levels from admission until defervescence. On the other hand, no such significant differences were observed in the serum level of iron in the clinical groups, except for a decreased iron level found in severe cases, compared to non-severe dengue without warning signs. The results show that copper is associated with dengue severity and this finding emphasizes the need to investigate the involvement of trace elements in disease severity so as to improve the prognosis of dengue. PMID- 26422156 TI - IDENTIFICATION OF SANDFLIES (Diptera: Psychodidae: Phlebotominae) BLOOD MEALS IN AN ENDEMIC LEISHMANIASIS AREA IN BRAZIL. AB - The aim of this study was to identify blood meals of female sandflies captured in the municipality of Governador Valadares, an endemic area of visceral and cutaneous leishmaniasis, in the State of Minas Gerais, Brazil. From May 2011 to January 2012, captures were performed using HP light traps in four districts. There were 2,614 specimens (2,090 males and 524 females) captured; 97 engorged females were identified belonging to the species Lutzomyia longipalpis(82.1%) and Lutzomyia cortelezzii(17.9%). Considering simple and mixed feeding, the enzyme linked immunosorbent assay revealed a predominance of chicken blood (43.6%) in Lutzomyia longipalpis, showing the important role that chickens exert around the residential areas of Governador Valadares. This finding increases the chances of sandflies contact with other vertebrates and consequently the risk of leishmaniasis transmission. PMID- 26422158 TI - WATER FROM DIFFERENT SOURCES USED FOR THE IRRIGATION OF VEGETABLES TO BE MARKETED: RESEARCH ON Cryptosporidium spp., Giardia spp., AND COLIFORMS IN PARANA, BRAZIL. AB - The aim of this work was to compare, from a parasitological ( Cryptosporidium spp. and Giardia duodenalis), bacteriological (total and thermotolerants coliforms) and physicochemical perspective, water sources used for drinking and irrigation of vegetables intended to be sold for human consumption. From January 2010 to May 2011, samples of different water sources from vegetable producing properties were collected; 100 liters for parasitological analysis, 200 mL for bacteriological analysis, and five liters for physicochemical analysis. Water samples were filtered under vacuum with a kit containing a cellulose acetate membrane filter, 1.2 um (Millipore(r), Barueri, SP, Brazil). The material retained on the membrane was mechanically extracted and analyzed by direct immunofluorescence (Merifluor(r)kit). From 20 rural properties investigated, 10 had artesian wells (40 samples), 10 had common wells (40 samples), and one had a mine (four samples), the latter contaminated by Cryptosporidium spp. In samples from artesian wells, 90 to 130 meters depth, 42.5% were positive for total coliforms and 5.0% were identified to have abnormal coloration. From the samples of common wells, 14 to 37 meters depth, 87.5% were contaminated with total coliforms, 82.5% were positive for thermotolerant coliforms, and 12.5% had color abnormalities. We did not detect the presence of Giardia spp. or Cryptosporidium spp. in artesian and common wells. The use of artesian or common wells is an important step in the control of the spreading of zoonoses, particularly Cryptosporidium spp. and Giardia spp., as well as artesian wells for coliform control in local production of vegetables to be marketed. PMID- 26422157 TI - CANINE VISCERAL LEISHMANIASIS CASE INVESTIGATION IN THE JACARE REGION OF NITEROI, RIO DE JANEIRO, BRAZIL. AB - American visceral leishmaniasis is a vector-borne zoonosis in expansion in Brazil. Dogs are the main urban reservoir. Departing from a case of canine visceral leishmaniasis (CVL) in Jacare, Niteroi, Rio de Janeiro State, an epidemiological canine and entomological study was performed to assess the extension of the disease at the location. Sample was collected around the case and the dogs identified by serological tests (rapid double platform immunochromatographic exams, immunoenzymatic assay/ELISA, indirect immunofluorescence/IFAT). The parasitological diagnosis was performed in animals positive in at least one of these tests. The entomological study was carried out by using light traps and manual collection. The associations between canine variables and outcome (ELISA and IFAT reagents) were assessed by the chi-square test and adjusted by multivariate logistic regression for those associations with p < 0.1 in the bivariate analysis. Seventeen cases of CVL were detected among 110 evaluated dogs (prevalence of 15.5%). Presence of ectoparasites (OR 6.5; 95% CI 1.1-37.4), animals with clinical signs (OR 9.5; 95% CI 1.2-76.6), and previous cases of CVL in the same house (OR 17.9; 95% CI 2.2-147.1) were associated with the outcome. Lutzomyia longipalpis was not detected. Our results are indicative of an ongoing transmission in the area. PMID- 26422159 TI - EFFICACY OF NITAZOXANIDE AGAINST Toxocara canis: LARVAL RECOVERY AND HUMORAL IMMUNE RESPONSE IN EXPERIMENTALLY INFECTED MICE. AB - The efficacy of nitazoxanide (NTZ) against toxocariasis was investigated in an experimental murine model and results were compared to those obtained using mebendazole. Sixty male BALB/c mice, aged six to eight weeks-old, were divided into groups of 10 each; fifty were orally infected with 300 larvaed eggs of T. canis and grouped as follows, G I: infected untreated mice; G II: infected mice treated with MBZ (15 mg/kg/day) 10 days postinfection (dpi); G III: infected mice treated with NTZ (20 mg/kg/day) 10 dpi; G IV: infected mice treated with MBZ 60 dpi; G V: infected mice treated with NTZ 60 dpi; GVI: control group comprising uninfected mice. Mice were bled via retro-orbital plexus on four occasions between 30 and 120 dpi. Sera were processed using the ELISA technique to detect IgG anti- Toxocara antibodies. At 120 dpi, mice were sacrificed for larval recovery in the CNS, liver, lungs, kidneys, eyes and carcass. Results showed similar levels of anti- Toxocara IgG antibodies among mice infected but not submitted to treatment and groups treated with MBZ or NTZ, 10 and 60 dpi. Larval recovery showed similar values in groups treated with NTZ and MBZ 10 dpi. MBZ showed better efficacy 60 dpi, with a 72.6% reduction in the parasite load compared with NTZ, which showed only 46.5% reduction. We conclude that administration of these anthelmintics did not modify the humoral response in experimental infection by T. canis. No parasitological cure was observed with either drug; however, a greater reduction in parasite load was achieved following treatment with MBZ. PMID- 26422160 TI - MOLECULAR CHARACTERIZATION OF AMERICAN CUTANEOUS LEISHMANIASIS IN THE TRI-BORDER AREA OF ASSIS BRASIL, ACRE STATE, BRAZIL. AB - In this study, Leishmania species were identified by Polymerase Chain Reaction (PCR). The epidemiology of patients suspected of having American Cutaneous Leishmaniasis in the municipality of Assis Brasil, Acre State, located in the Brazil/Peru/Bolivia tri-border was also investigated. By PCR, the DNA of Leishmania was detected in 100% of the cases (37 samples) and a PCR-Restriction Fragment Length Polymorphism (RFLP) of the hsp 70 gene identified the species in 32 samples: Leishmania (Viannia) braziliensis (65.6%) , L. (V.) shawi (28.1%) , L. (V.) guyanensis (3.1%) and mixed infection L. (V.) guyanensis and L. (Leishmania) amazonensis(3.1%)This is the first report of L. (V.) shawi and L. (L.) amazonensis in Acre. The two predominant species were found in patients living in urban and rural areas. Most cases were found in males living in rural areas for at least three years and involved in rural work. This suggests, in most cases, a possible transmission of the disease from a rural/forest source, although some patients had not engaged in activities associated with permanence in forestall areas, which indicate a possible sandflies adaptation to the periurban setting. PMID- 26422161 TI - DIARRHEA OUTBREAK IN PERNAMBUCO, BRAZIL, ASSOCIATED WITH A HEAT-STABLE CYTOTOXIC ENTEROTOXIN PRODUCED BY Aeromonas caviae. AB - In the present study enterotoxic and cytotoxic activities of twenty Aeromonas caviae strains were examined. They originated from fecal specimens of patients with acute diarrhea during an outbreak in Brazil in 2004. Culture supernatants of fourteen strains (70%) caused fluid accumulation in rabbit ileal intestinal loops and in suckling mice assays, and also showed a cytotoxic activity in Vero and Caco-2 cells. The enterotoxic and cytotoxic factors were heat-stable after culture supernatants treatment at 100 oC. The results revealed that A. caviae strains produce a putative diarrheagenic virulence factor, a heat-stable cytotoxic enterotoxin that could be linked to the diarrhea outbreak that took place in Brazil. PMID- 26422163 TI - PROBABLE RECOGNITION OF HUMAN ANISAKIASIS IN BRAZIL? PMID- 26422164 TI - KPC-PRODUCING Serratia marcescens IN A HOME-CARE PATIENT FROM RECIFE, BRAZIL. AB - In this brief communication we describe the occurrence of a KPC-producing Serratia marcescens isolate in a home-care patient from Recife, Brazil. The blaKPC, blaSPM, blaIMP, blaVIM, blaOXA, blaCTX-M, blaSHV, blaTEM and blaGES genes were investigated by Polymerase Chain Reaction (PCR) and DNA sequencing. The isolate was positive for blaKPC-2 and blaTEM-1 and was resistant to aztreonam, cefepime, cefotaxime, imipenem, meropenem, gentamicin, ciprofloxacin and cefazidime, and susceptible only to amikacin, tigecycline and gatifloxacin. This is the first report in Brazil of KPC-producing S. marcescens clinical isolate outside of a hospital environment. Caregivers should be alert for the presence of this isolate in the community setting. PMID- 26422162 TI - MOLECULAR INVESTIGATION OF HEMOTROPIC MYCOPLASMAS IN HUMAN BEINGS, DOGS AND HORSES IN A RURAL SETTLEMENT IN SOUTHERN BRAZIL. AB - The aims of this study were to determine the prevalence of hemoplasmas in a rural Brazilian settlement's population of human beings, their dogs and horses, highly exposed to tick bites; to identify the tick species parasitizing dogs and horses, and analyze factors associated with their infection. Blood samples from 132 dogs, 16 horses and 100 humans were screened using a pan-hemoplasma SYBR green real time PCR assay followed by a species-specific TaqMan real-time PCR. A total of 59/132 (44.7%) dog samples were positive for hemoplasmas (21 Mycoplasma haemocanis alone, 12 ' Candidatus Mycoplasma haematoparvum' alone and 21 both). Only 1/100 (1.0%) human sample was positive by qPCR SYBR green, with no successful amplification of 16S rRNA or 23 rRNA genes despite multiple attempts. All horse samples were negative. Dogs >1 year of age were more likely to be positive for hemoplasmas ( p= 0.0014). In conclusion, although canine hemoplasma infection was highly prevalent, cross-species hemoplasma transmission was not observed, and therefore may not frequently occur despite overexposure of agents and vectors. PMID- 26422165 TI - FIRST REPORT OF ACUTE CHAGAS DISEASE BY VECTOR TRANSMISSION IN RIO DE JANEIRO STATE, BRAZIL. AB - Chagas disease (CD) is an endemic anthropozoonosis from Latin America of which the main means of transmission is the contact of skin lesions or mucosa with the feces of triatomine bugs infected by Trypanosoma cruzi. In this article, we describe the first acute CD case acquired by vector transmission in the Rio de Janeiro State and confirmed by parasitological, serological and PCR tests. The patient presented acute cardiomyopathy and pericardial effusion without cardiac tamponade. Together with fever and malaise, a 3 cm wide erythematous, non pruritic, papule compatible with a "chagoma" was found on his left wrist. This case report draws attention to the possible transmission of CD by non-domiciled native vectors in non-endemic areas. Therefore, acute CD should be included in the diagnostic workout of febrile diseases and acute myopericarditis in Rio de Janeiro. PMID- 26422166 TI - FATAL DISSEMINATED CRYPTOCOCCOSIS WITH RENAL INVOLVEMENT IN AN HIV-INFECTED PATIENT. AB - INTRODUCTION: We present a fatal case of disseminated cryptococcosis in a young man whose diagnosis of HIV infection was made at the time of admission to the emergency room. CASE REPORT: The patient was a twenty-three-year-old man, with a history of daily fever during one month associated with diarrhea, weight loss, headache, vomiting and generalized seizures. He also had a history of diabetes mellitus, alcoholism and drug addiction. Upon physical examination the patient was pale, disoriented and had periods of agitation. White blood cells count was 3,440/mm3 (5% lymphocytes), hemoglobin was 10 g/dL, platelets were 83,000/ mm3. Creatinine was 0.7 mg/dL; urea 19 mg/dL; Na, K, and liver enzymes were within normal limits. Lactic dehydrogenase was 494 IU/L. Cerebrospinal fluid (CSF) analysis revealed 10 white blood cells/mm3 (58% neutrophils, 31% lymphocytes, 11% monocytes) and 2 red blood cells/mm3. India ink test revealed six Cryptococcus yeasts/mm3. CSF glucose was 122 mg/dL and protein was 36 mg/ dL. VDRL test was negative and anti-HIV test was positive. Intravenous hydration, insulin, phenytoin, fluconazole, pyrimethamine, sulfadiazine, folinic acid, and amphotericin B were started. The patient did not improve and became obtunded and hypotensive. He was intubated and put on mechanical respiration. He received vasoactive drugs and died less than 24 hours after admission. A postmortem examination was performed and revealed disseminated cryptococcosis, with severe involvement of the kidneys. CONCLUSION: Cryptococcosis, as a rule, is a systemic disease that affects mostly immunocompromised individuals, especially patients with AIDS. When diagnosed late in its course it has a very high mortality. PMID- 26422167 TI - EMPHYSEMATOUS PYELONEPHRITIS. PMID- 26422169 TI - A Practical Diabatisation Scheme for Use with the Direct-Dynamics Variational Multi-Configuration Gaussian Method. AB - A method for diabatising multiple electronic states on-the-fly within the direct dynamics variational multi-configuration Gaussian method for calculating quantum nuclear dynamics is presented. The method is based upon the propagation of the adiabatic-diabatic transformation matrix along the paths followed by the Gaussian basis functions that constitute the nuclear wave function, by use of a well-known differential equation relating the matrix and the nonadiabatic vector coupling terms between the electronic states. The implementation of the method is described, and test calculations are presented using the ground and first-excited states of the butatriene cation as an example, allowing comparison to the earlier regularisation diabatisation scheme as well as to full nuclear dynamics on a precomputed potential energy surface. The new scheme is termed propagation diabatisation. PMID- 26422168 TI - Linkage-specific conformational ensembles of non-canonical polyubiquitin chains. AB - Polyubiquitination is a critical protein post-translational modification involved in a variety of processes in eukaryotic cells. The molecular basis for selective recognition of the polyubiquitin signals by cellular receptors is determined by the conformations polyubiquitin chains adopt; this has been demonstrated for K48- and K63-linked chains. Recent studies of the so-called non-canonical chains (linked via K6, K11, K27, K29, or K33) suggest they play important regulatory roles in growth, development, and immune system pathways, but biophysical studies are needed to elucidate the physical/structural basis of their interactions with receptors. A first step towards this goal is characterization of the conformations these chains adopt in solution. We assembled diubiquitins (Ub2) comprised of every lysine linkage. Using solution NMR measurements, small-angle neutron scattering (SANS), and in silico ensemble generation, we determined population-weighted conformational ensembles that shed light on the structure and dynamics of the non-canonical polyubiquitin chains. We found that polyubiquitin is conformationally heterogeneous, and each chain type exhibits unique conformational ensembles. For example, K6-Ub2 and K11-Ub2 (at physiological salt concentration) are in dynamic equilibrium between at least two conformers, where one exhibits a unique Ub/Ub interface, distinct from that observed in K48-Ub2 but similar to crystal structures of these chains. Conformers for K29-Ub2 and K33-Ub2 resemble recent crystal structures in the ligand-bound state. Remarkably, a number of diubiquitins adopt conformers similar to K48-Ub2 or K63-Ub2, suggesting potential overlap of biological function among different lysine linkages. These studies highlight the potential power of determining function from elucidation of conformational states. PMID- 26422170 TI - Dynamics of Electrically Modulated Colloidal Droplet Transport. AB - Electrically actuated transport dynamics of colloidal droplets, on a hydrophobic dielectric film covering an array of electrodes, is studied here. Specifically, the effects of the size and electrical properties (zeta-potential) of the colloidal particles on such transport characteristics are investigated. For the colloidal droplets, the application of an electrical voltage leads to additional attenuation of the local dielectric-droplet interfacial tension. This is due to the electrically triggered enhanced colloidal particle adsorption at the dielectric-droplet interface, in the immediate vicinity of the droplet three phase contact line (TPCL). The extent of such interfacial particle adsorption, and hence, the extent of the consequential reduction in the interfacial tension, is dictated by the combined effects of the three-phase contact line spreading, particle size, the interfacial electrostatic interaction between the colloidal particles (if charged) and the charged dielectric surface above the activated electrode, and the interparticle electrostatic repulsion. The electrical driving force of varying magnitude, stemming from this altered solid-liquid interfacial tension gradient in the presence of the colloidal particles, culminates in different droplet transport velocity and droplet transfer frequency for different colloidal droplets. We substantiate the inferences from our experimental results by a quasi-steady state force balance model for colloidal droplet transport. We believe that the present work will provide an accurate framework for determining the optimal design and operational parameters for digital microfluidic chips handling colloidal droplets, as encountered in a plethora of applications. PMID- 26422171 TI - Effect of Media Usage Selection on Social Mobilization Speed: Facebook vs E-Mail. AB - Social mobilization is a process that enlists a large number of people to achieve a goal within a limited time, especially through the use of social media. There is increasing interest in understanding the factors that affect the speed of social mobilization. Based on the Langley Knights competition data set, we analyzed the differences in mobilization speed between users of Facebook and e mail. We include other factors that may influence mobilization speed (gender, age, timing, and homophily of information source) in our model as control variables in order to isolate the effect of such factors. We show that, in this experiment, although more people used e-mail to recruit, the mobilization speed of Facebook users was faster than that of those that used e-mail. We were also able to measure and show that the mobilization speed for Facebook users was on average seven times faster compared to e-mail before controlling for other factors. After controlling for other factors, we show that Facebook users were 1.84 times more likely to register compared to e-mail users in the next period if they have not done so at any point in time. This finding could provide useful insights for future social mobilization efforts. PMID- 26422172 TI - Indocyanine Green Lymphography Findings in Limb Lymphedema. AB - BACKGROUND AND METHODS: Indocyanine green (ICG) lymphography is one of several methods of lymphography to detect lymphatic channels and evaluate patients clinically with limb lymphedema. ICG imaging is made possible by the use of a near-infrared camera device. The fluorescence images were digitalized for real time display. RESULTS: ICG lymphography findings are largely classifiable into two patterns: normal linear pattern and abnormal dermal backflow (DB) pattern. ICG lymphography pattern changes from the normal linear pattern to abnormal DB patterns in obstructive peripheral lymphedema; with progression of lymphedema, DB patterns change from splash pattern, to stardust pattern, and finally to diffuse pattern. We classify ICG lymphography progression into 0 to V stages for the upper extremity, the lower extremity and into 0 to IV stages for the genital area. CONCLUSION: In DB stage II, most patients are symptomatic; thus, aggressive treatments, such as lymphaticovenular anastomosis, are indicated. In DB stages III to V, lymphaticovenular anastomosis is recommended because most patients are refractory to conservative therapies. PMID- 26422173 TI - The V-Plasty: A Novel Microsurgical Technique for Anastomosis of Vessels with Marked Size Discrepancy. AB - BACKGROUND: The art of reconstructive microsurgery is still progressing after Carrel's original description of "vascular repair" in 1902. Reports of the successful repair of vessels smaller than 1 mm in diameter are currently commonplace. However, the technique of microvascular anastomosis to connect vessels with large diameter discrepancy, greater than 1 mm, has not yet been perfected. This article reports a novel option to anastomose two vessels of different sizes by adapting the diameters of the two stumps and creating a gentle slope that dramatically reduces turbulences in the blood stream. METHODS: The "V plasty" consists in designing a v-shaped flap on the wall of the large vessel and a longitudinal incision on the small one. The V-flap is then introduced into the V-defect of the small vessel, creating a smooth transition of the diameters between the two vessels. Mathematical calculation of the dimensions of the V-flap was conducted with different ratios' discrepancies of the two vessels ranging from 1.5 to 4. Clinically, 14 microvascular V-plasty were performed in 8 patients. RESULTS: The theoretical simulation and our clinical experience of 14 cases allowed us to propose the different dimensions (length and width) of the V plasty according to the ratio of vessels discrepancies. CONCLUSION: The V-plasty microanastomosis is an alternative method to attach vessels with size discrepancy. It simply equalizes the donor and recipient vessels' diameters. Its main advantage is to maintain a linear axis between the two vessels whatever the discrepancy ratio is. PMID- 26422174 TI - Effect of Vascular Endothelial Growth Factor Administration on Nerve Regeneration after Autologous Nerve Grafting. AB - BACKGROUND: The aim of this study was to evaluate the effect of vascular endothelial growth factor (VEGF) administration around the autologous nerve graft on nerve recovery in a rat model. METHODS: A total of 69 rats were randomly divided into three experimental groups. A 10-mm sciatic nerve defect was made and reconstructed with the reversed nerve segment. Group I received an osmotic pump with saline, group II received an osmotic pump with VEGF, and group III added a silicone tube around the nerve graft to decrease the surrounding blood supply. Nine animals in each group were sacrificed on day 3 to evaluate improvement in new vessel formation. In each group 14 animals were sacrificed at 16 weeks after the initial procedure to evaluate the functional motor nerve regeneration using compound muscle action potential, isometric tetanic force, wet muscle weight, and nerve histomorphometry. RESULTS: The average vascular density on day 3 was 10.7% in group I, 21.4% in group II, and 0.9% in group III. These differences were significant. However, the average maximum isometric tetanic force at 16 weeks was 54.4% in group I, 57.5% in group II, and 47.6% in group III. No difference was found with or without VEGF administration. Histomorphometric analysis was also not significantly different between the groups. CONCLUSIONS: New vessel formation on autologous nerve graft was enhanced by VEGF administration. However, the neovascularization effect of VEGF administration did not translate into better motor nerve recovery. PMID- 26422175 TI - Use of Model for End-Stage Liver Disease Scoring Dynamics in Critically Ill Cirrhotic Trauma Patients. PMID- 26422176 TI - Analysis of heavy metals from water, sediment, and tissues of Labeo angra (Hamilton, 1822), from an Ox-box lake- an wetland site from Assam, India. AB - The aim of this study was to assess the regional impacts of heavy metals (Mn, Fe, Mg, Ca, Cu, Zn, Cd, Cr, Pb and Ni) on water, sediment and a native, teleost fish species, Labeo angra, inhabiting a flood plain wetland of Barak River in Assam, India. Heavy metal concentrations in the water, sediments and fish were measured; bioaccumulation factor, metal pollution index as well as condition indices were calculated, to assess the pollution load and health status of the fish. Multivariate statistical analysis was used on wetland water and sediment heavy metals to ascertain the possible sources and seasonal variations of the pollutants. Results showed that most heavy metals in the wetland water and sediments exceeded the water (drinking and irrigation) and sediment quality guidelines, respectively. Seasonal variations were observed for geogenic heavy metals, Mn, Fe, Mg and Ca while no seasonal variations were observed for anthropogenic heavy metals, Cu, Cd, Cr, Pb and Ni. Multivariate statistical analysis showed that there was strong correlation between geogenic and anthropogenic heavy metals in water and sediment, both originating from the common anthropogenic sources. Accumulation of most of the metals in all the tissues was above the safe limits as recommended by the Food and Agriculture Organization. High bioaccumulation factors and metal pollution index for these metals in the different tissues revealed that metals were extensively bio accumulated and bioconcentrated. Condition indices in fish from the wetland suggested metabolic abnormalities. PMID- 26422177 TI - Region specific optimization of continuous linear attenuation coefficients based on UTE (RESOLUTE): application to PET/MR brain imaging. AB - The reconstruction of PET brain data in a PET/MR hybrid scanner is challenging in the absence of transmission sources, where MR images are used for MR-based attenuation correction (MR-AC). The main challenge of MR-AC is to separate bone and air, as neither have a signal in traditional MR images, and to assign the correct linear attenuation coefficient to bone. The ultra-short echo time (UTE) MR sequence was proposed as a basis for MR-AC as this sequence shows a small signal in bone. The purpose of this study was to develop a new clinically feasible MR-AC method with patient specific continuous-valued linear attenuation coefficients in bone that provides accurate reconstructed PET image data. A total of 164 [(18)F]FDG PET/MR patients were included in this study, of which 10 were used for training. MR-AC was based on either standard CT (reference), UTE or our method (RESOLUTE). The reconstructed PET images were evaluated in the whole brain, as well as regionally in the brain using a ROI-based analysis. Our method segments air, brain, cerebral spinal fluid, and soft tissue voxels on the unprocessed UTE TE images, and uses a mapping of R(*)2 values to CT Hounsfield Units (HU) to measure the density in bone voxels. The average error of our method in the brain was 0.1% and less than 1.2% in any region of the brain. On average 95% of the brain was within +/-10% of PETCT, compared to 72% when using UTE. The proposed method is clinically feasible, reducing both the global and local errors on the reconstructed PET images, as well as limiting the number and extent of the outliers. PMID- 26422178 TI - High Trap Formation and Low Metabolite Production by Disruption of the Polyketide Synthase Gene Involved in the Biosynthesis of Arthrosporols from Nematode Trapping Fungus Arthrobotrys oligospora. AB - A group of morphology regulatory arthrosporol metabolites have been recently characterized from carnivorous fungus Arthrobotrys oligospora that can develop trapping networks to capture their prey. A combination of genetic manipulation and chemical analyses was applied to characterize the function of one polyketide synthase (PKS) gene AOL_s00215g283 in A. oligospora, which was putatively involved in the production of 6-methylsalicylic acid. High-performance liquid chromatography analysis showed that the disruption of the PKS gene not only led to the total loss of the arthrosporol A but also resulted in significant reduction in the production of secondary metabolites in the cultural broth of the mutant DeltaAOL_s00215g283 strain. Interestingly, the mutant strain displayed significant increases in the trap formation and the nematicidal activity by 10 and 2 times, respectively, higher than the wild-type strain. These findings revealed a pathogenicity-related biosynthetic gene of this agriculturally important biological agent and have implications for establishment of efficient fungal biocontrol agents. PMID- 26422179 TI - Mechanism and Mitigation of the Decomposition of an Oxorhenium Complex-Based Heterogeneous Catalyst for Perchlorate Reduction in Water. AB - A biomimetic heterogeneous catalyst combining palladium nanoparticles and an organic ligand-coordinated oxorhenium complex on activated carbon, Re(hoz)2-Pd/C, was previously developed and shown to reduce aqueous perchlorate (ClO4-) with H2 at a rate ~100 times faster than the first generation ReOx-Pd/C catalyst prepared from perrhenate (ReO4-). However, the immobilized Re(hoz)2 complex was shown to partially decompose and leach into water as ReO4-, leading to an irreversible loss of catalytic activity. In this work, the stability of the immobilized Re(hoz)2 complex is shown to depend on kinetic competition between three processes: (1) ReV(hoz)2 oxidation by ClO4- and its reduction intermediates ClOx , (2) ReVII(hoz)2 reduction by Pd-activated hydrogen, and (3) hydrolytic ReVII(hoz)2 decomposition. When ReV(hoz)2 oxidation is faster than ReVII(hoz)2 reduction, the ReVII(hoz)2 concentration builds up and leads to hydrolytic decomposition to ReO4- and free hoz ligand. Rapid ReV(hoz)2 oxidation is mainly promoted by highly reactive ClOx- formed from the reduction of ClO4-. To mitigate Re(hoz)2 decomposition and preserve catalytic activity, ruthenium (Ru) and rhodium (Rh) were evaluated as alternative H2 activators to Pd. Rh showed superior activity for reducing the ClO3- intermediate to Cl-, thereby preventing ClOx- buildup and lowering Re complex decomposition in the Re(hoz)2-Rh/C catalyst. In contrast, Ru showed the lowest ClO3- reduction activity and resulted in the most Re(hoz)2 decomposition among the Re(hoz)2-M/C catalysts. This work highlights the importance of using mechanistic insights from kinetic and spectroscopic tests to rationally design water treatment catalysts for enhanced performance and stability. PMID- 26422180 TI - Dissemination of antibiotic resistance in methicillin-resistant Staphylococcus aureus and vancomycin-resistant S aureus strains isolated from hospital effluents. AB - Vancomycin-resistant Staphylococcus aureus (VRSA) and methicillin-resistant S aureus (MRSA) strains were examined in hospital effluents. Most S aureus strains are resistant to methicillin (MRSA), followed by tetracycline. Approximately 15% of MRSA strains are also resistant to vancomycin (VRSA). All VRSA strains developed a VanR/VanS-regulated 2-component system of VanA-type resistance in their genome. Results indicate that there is a possibility of developing resistance to aminoglycosides by VRSA strains in the near future. PMID- 26422181 TI - Sociocognitive determinants of self-reported compliance with standard precautions: Development and preliminary testing of a questionnaire with French health care workers. AB - BACKGROUND: Inconsistent compliance of health care workers with standard precautions has already been documented. The objective of this study was to develop a questionnaire to investigate the sociocognitive determinants of compliance with standard precautions based on the theory of planned behavior. METHODS: To construct the Standard Precautions Questionnaire (SPQ), items were selected using a systematic review of literature and semistructured interviews with 54 health care workers. Thirty-five items were selected for a draft questionnaire. These questionnaires were sent to 649 health care workers in 3 medical specialties (pediatrics, geriatrics, and intensive care) in a French University hospital. A total of 331 valid questionnaires were analyzed. RESULTS: Factor analysis yielded a final 7-factor solution with an explained variance of 66.51%, with 24 items. The 7 dimensions were the following: attitude toward standard precautions, social influence facilitating organization, exemplary behavior of colleagues, organizational constraints, individual constraints, and intention to perform standard precautions. Some differences were observed between medical specialties on attitude toward standard precautions, social influence, and individual constraints. CONCLUSION: The SPQ met the conditions of reliability and validity in accordance with psychometric demands and could be used to evaluate attitudes and intention to perform standard precautions among medical and nursing staff. PMID- 26422182 TI - Effects of a catheter-associated urinary tract infection prevention campaign on infection rate, catheter utilization, and health care workers' perspective at a community safety net hospital. AB - Preventing catheter-associated urinary tract infections is in the forefront of health care quality. However, nurse and physician engagement is a common barrier in infection prevention efforts. After implementation of a multidisciplinary catheter-associated urinary tract infection (CAUTI) prevention campaign, we studied the impact of our campaign and showed its association with reducing the CAUTI rate and catheter utilization and the positive effect on health care workers' engagement and perspectives. CAUTI prevention campaigns can lead to lower infection rates and change health care workers' perspective. PMID- 26422183 TI - Non-invasive ventilation: Has it been forgotten in the diagnosis-related groups? PMID- 26422184 TI - Pleural empyema in a pneumonectomized patient as a complication of colonoscopy. PMID- 26422185 TI - Pulmonary Embolism Detection with Three-dimensional Ultrashort Echo Time MR Imaging: Experimental Study in Canines. AB - PURPOSE: To demonstrate the feasibility of free-breathing three-dimensional (3D) radial ultrashort echo time (UTE) magnetic resonance (MR) imaging in the simultaneous detection of pulmonary embolism (PE) and high-quality evaluation of lung parenchyma. MATERIALS AND METHODS: The institutional animal care committee approved this study. A total of 12 beagles underwent MR imaging and computed tomography (CT) before and after induction of PE with autologous clots. Breath hold 3D MR angiography and free-breathing 3D radial UTE (1.0-mm isotropic spatial resolution; echo time, 0.08 msec) were performed at 3 T. Two blinded radiologists independently marked and graded all PEs on a four-point scale (1 = low confidence, 4 = absolutely certain) on MR angiographic and UTE images. Image quality of pulmonary arteries and lung parenchyma was scored on a four-point scale (1 = poor, 4 = excellent). Locations and ratings of emboli were compared with reference standard CT images by using an alternative free-response receiver operating characteristic curve (AFROC) method. Areas under the curve and image quality ratings were compared by using the F test and the Wilcoxon signed-rank test. RESULTS: A total of 48 emboli were detected with CT. Both readers showed higher sensitivity for PE detection with UTE (83% and 79%) than with MR angiography (75% and 71%). The AFROC area under the curve was higher for UTE than for MR angiography (0.95 vs 0.89), with a significant difference in area under the curve of 0.06 (95% confidence interval: 0.01, 0.11; P = .018). UTE image quality exceeded that of MR angiography for subsegmental arteries (3.5 +/- 0.7 vs 2.9 +/- 0.5, P = .002) and lung parenchyma (3.8 +/- 0.5 vs 2.2 +/- 0.2, P < .001). The apparent signal-to-noise ratio in pulmonary arteries and lung parenchyma was significantly higher for UTE than for MR angiography (41.0 +/- 5.2 vs 24.5 +/- 6.2 [P < .001] and 10.2 +/- 1.8 vs 3.5 +/- 0.8 [P < .001], respectively). The apparent contrast-to-noise ratio between arteries and PEs was higher for UTE than for MR angiography (20.3 +/- 5.2 vs 15.4 +/- 6.7, P = .055). CONCLUSION: In a canine model, free-breathing 3D radial UTE performs better than breath-hold 3D MR angiography in the detection of PE and yields better image quality for visualization of small vessels and lung parenchyma. Free-breathing 3D radial UTE for detection of PE is feasible and warrants evaluation in human subjects. PMID- 26422186 TI - A pilot study of what African American maternal caregivers and their adolescent daughters talk about when asked to discuss tobacco together. AB - Parents play a critical role in shaping their children's substance use behaviors, yet few studies have examined the messages that caregivers give their adolescents about tobacco. In this study, we identify tobacco-related messages discussed by African American maternal caregivers and their adolescent daughters. Twenty-five African American maternal caregivers and their adolescent daughters participated in a video-taped discussion about tobacco. Discussions were transcribed and coded thematically. Seven themes emerged, which were grouped into tobacco-messages and communication strategies. Messages included health risks, non-health-related reasons to stop smoking, reasons people smoke, and tobacco products and marijuana. Strategies caregivers used to communicate their tobacco-related messages included sharing personal or their families' experience with smoking, using humor, and role-playing. Finally, embedded within all of the themes, participants expressed their disapproval of tobacco use, whether it was directed at their own use, their adolescents' use, a family members' use, or peers' use. African American maternal caregivers and their daughters openly talk about a variety of tobacco-related topics, and caregivers are open to sharing their own and their families' experience with substance use. Findings also suggest that having caregivers and their adolescents participate in discussions tasks could be potentially beneficial in facilitating discussions and could identify areas in which caregivers could use help in discussing sensitive topics. PMID- 26422187 TI - The Association of Human Cytomegalovirus with Biomarkers of Inflammation and Immune Activation in HIV-1-Infected Women. AB - Three groups of cytomegalovirus (CMV)-seropositive women (total n = 164) were selected from the Chicago Women's Interagency HIV-1 Study to investigate the association between CMV coinfection and immune activation: (1) HIV-1 viremic, (2) HIV-1 aviremic, and (3) HIV-1 uninfected. Quantitative measures of CMV serum IgG, CMV DNA, and serum biomarkers interleukin (IL)-6, soluble CD163 (sCD163), soluble CD14 (sCD14), and interferon gamma-induced protein (IP10) were obtained. Levels of CMV IgG and the serum biomarkers were significantly higher in the HIV-1 viremic group compared to the aviremic and uninfected groups (p < 0.001). No significant associations with CMV IgG levels were found for HIV-uninfected women. When each of the HIV-infected groups was analyzed, sCD14 levels in the viremic women were significantly associated with CMV IgG levels with p < 0.02 when adjusted for age, CD4 count, and HIV viral load. There was also a modest association (p = 0.036) with IL-6 from plasma and cervical vaginal lavage specimens both unadjusted and adjusted for CD4 count and HIV viral load. The association of CMV IgG level with sCD14 implicates the monocyte as a potential site for interaction of the two viruses, which eventually may lead to non-AIDS defining pathological conditions. PMID- 26422188 TI - EBV-associated Burkitt lymphoma in Taiwan is not age-related. AB - This study retrospectively investigated 54 cases of sporadic Burkitt lymphoma in Taiwan with histopathology review, immunohistochemistry, Epstein-Barr virus (EBV) in situ hybridization (EBER) and fluorescence in situ hybridization (FISH). The great majority revealed typical immunophenotype and 89% (47/53) cases expressed myc protein. EBER was positive in 20% (11/54) of cases, more frequently with nodal presentation, but not significantly associated with age (pediatric vs. adult), abdominal vs. extra-abdominal presentation or overall survival (OS). MYC and IGH were rearranged in 94% (46/49) and 85% (41/48) of cases, respectively. The concordance rate between myc expression and MYC translocation was 83% (40/48). By univariate analysis, OS was statistically associated with age, with or without chemotherapy, central nervous system (CNS) involvement, CNS prophylaxis and leukemic transformation, but not gender, nodal vs. extranodal involvement, stage, immunohistochemistry, EBER, myc expression, MYC translocation or radiotherapy. By multivariate analysis, CNS involvement at presentation and administration of chemotherapy were statistically associated with OS. PMID- 26422189 TI - Using the Program Logic Model to Evaluate !Cuidate!: A Sexual Health Program for Latino Adolescents in a School-Based Health Center. AB - BACKGROUND: Addressing the disparities in pregnancy and sexually transmitted infection (STI) rates for Latino youth in the United States requires an evidence based approach. Although randomized controlled trials for sexual risk reduction interventions have shown promise in improving short-term outcomes, program sustainability has not been extensively examined in school settings where teens spend time. Latina teen pregnancy rates are nearly twice the national average. Adolescents comprise only 17% of the U.S. population, yet they account for 50% of STIs. !Cuidate! is a high-impact sexual health group program endorsed by the Centers for Disease Control and Prevention that has not been replicated in a real world setting. AIMS: The program logic model (PLM) was used as the systematic approach to plan, implement, and evaluate a sustainable model of sexual health group programing (!Cuidate!) in a U.S. high school with a large Latino student population. METHODS: The PLM provided the framework for the evaluation of outputs, outcome, and impact. A multivariate repeated measures analysis of variance was used as the means to evaluate the participant outcomes immediately postprogram and at 8-12 weeks. RESULTS: !Cuidate! was executed within an existing school structure and time constraints, below cost projections, and with high participant retention (95.8%). Three cohorts (N = 24) of female teens demonstrated significant increases in STI or HIV knowledge, self-efficacy, and intention to use condoms (p < .01). Condom use increased postprogram. No participants initiated sexual behavior, nor were there any reported pregnancies or STIs. CONCLUSIONS: An evidence-based intervention previously tested in randomized controlled trials can be sustained in a school-based health center with similar results of efficacy. LINKING EVIDENCE TO ACTION: Our success served as a platform for a sustainable program. We continue to extend the impact of the program by delivering !Cuidate! in the school setting using a community health worker. PMID- 26422190 TI - The options of reversal of a dabigatran effect. PMID- 26422191 TI - Synthetic cannabinoid hyperemesis resulting in rhabdomyolysis and acute renal failure. AB - Synthetic cannabinoid usage has increased in the past decade. Concurrently, emergency management of associated adverse effects due to synthetic cannabinoid usage has also risen. Reported toxicities include psychosis, seizures, cardiotoxicity, acute kidney injury, and death. While cannabis was first described as a cause of acute hyperemesis in 2004, a more recent case series also describes the association between cannabinoid hyperemesis and risk of acute renal failure. Synthetic cannabinoids have also been reported to cause acute hyperemesis and acute renal failure; however, the risk of rhabdomyolysis-induced renal failure has yet to be elucidated. In this article, we report the first known case of synthetic cannabinoid hyperemesis leading to rhabdomyolysis and acute renal failure. PMID- 26422192 TI - Are physicians overlooking the clinical assessment of hypovolemia? PMID- 26422193 TI - Basal Joint Arthroplasty and Radial-sided Carpal Tunnel Release Using a Single Incision. AB - PURPOSE: The purpose of our study was to determine in vivo outcomes and consistency of relief of symptoms attributable to carpal tunnel syndrome in patients who underwent radial-sided carpal tunnel release in conjunction with basal joint arthroplasty through a single incision. MATERIALS AND METHODS: A retrospective chart review identified all patients who had undergone radial-sided carpal tunnel release in combination with basal joint arthroplasty at 1 institution from February 2011 through April 2014. Both preoperative and postoperative symptoms attributable to carpal tunnel syndrome were documented. Patient outcomes were assessed using the QuickDASH (Disabilities of the Arm, Shoulder, and Hand) questionnaire. The mean length of follow-up was 16 months (range, 2 to 37 mo). RESULTS: Eight patients (7 women; 10 extremities) were available for follow-up. There was complete resolution of all symptoms attributable to carpal tunnel syndrome in 9 of 10 extremities. There was complete relief of paresthesias in the remaining extremity (and the patient reported complete relief of night waking), as well as improvement but not resolution of hypoesthesia and pain. CONCLUSIONS: Radial-sided carpal tunnel release performed with basal joint arthroplasty through a single incision provided reliable improvement or resolution of carpal tunnel syndrome symptoms. PMID- 26422194 TI - Duration of dual antiplatelet therapy following drug-eluting coronary stents: Longer or shorter? PMID- 26422195 TI - Suicide attempts and completions in Veterans Affairs nursing home care units and long-term care facilities: a review of root-cause analysis reports. AB - OBJECTIVE: Suicide was the 10th leading cause of death for Americans in 2010. The suicide rate is highest among men who are aged 75 and older. The prevalence of suicidal behavior in nursing homes and long-term care (LTC) facilities was estimated to be 1%. This study describes the systemic vulnerabilities found after suicidal behavior in LTC facilities as well as steps to decrease or mitigate the risk. METHOD: This is a retrospective review of root-cause analysis (RCA) reports of suicide attempts and completions between 1 January 2000 and 31 December 2013 in the Veterans Health Administration LTC and nursing home care units. The RCA reports of suicide attempts and completions were coded for patient demographics, method of attempt or completion, root causes, and actions developed to address the root cause. RESULTS: Thirty-five RCA reports were identified. The average age was 65 years, 11 had a previous suicide attempt, and the primary mental health diagnoses were depression, posttraumatic stress disorder, and schizophrenia. The primary methods of self-harm were cutting with a sharp object, overdose, and strangulation. CONCLUSIONS: It is recommended that all staff members are aware of the signs and risk factors for depression and suicide in this population and should systematically assess and treat mental disorders. In addition, LTC facilities should have a standard protocol for evaluating the environment for suicide hazards and use interdisciplinary teams to promote good communication about risk factors identified among patients. Finally, staff should go beyond staff education and policy to make clinical changes at the bedside. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. PMID- 26422196 TI - Saying 'No' to PrEP research in Malawi: what constitutes 'failure' in offshored HIV prevention research? AB - Between 2004 and 2005, the first multi-sited clinical trial tested whether an existing, marketed antiretroviral drug, Tenofovir (TDF), could prevent HIV transmission. Referred to as pre-exposure prophylaxis (PrEP), most of these trial sites prematurely closed down. Two sites located in Cambodia and Cameroon received international media attention. But little attention was drawn to sites in Malawi and Nigeria, where university ethicists and research scientists extensively debated PrEP. This article focuses on events that took place in Malawi where there was a prolonged dispute over the scientific rationales of PrEP and not trial specific ethics referred to as 'bioethics'. Specifically, the article discusses debates pertaining to three PrEP trial protocols that were refused ethics approval in Malawi between 2004 and 2009. It is argued that HIV science debates in Malawi are embedded in postcolonial politics--geopolitical histories and state and household economic dispossessions that have created the structural possibilities for Malawi to become an offshore destination for HIV clinical research. As such, ethics in this case does not pertain to trial or bioethical 'failures'. Rather, ethics is located at the scale of imperial relations that give rise to multiple, often invisible, research concerns and constraints. PMID- 26422198 TI - Toward Highly Efficient Large-Area ITO-Free Organic Solar Cells with a Conductance-Gradient Transparent Electrode. AB - Highly efficient large-area organic solar cells (OSCs) with power conversion efficiency up to 7.09%, and device area of 4 cm(2) are demonstrated on flexible substrates. A conductance- or thickness-gradient ultra-thin Ag-based transparent electrode is developed to better balance the light trapping and energy loss, owing to the inhomogeneous energy-loss density on the large OSC sheet. PMID- 26422197 TI - A Phase II Randomized Trial of Lycopene-Rich Tomato Extract Among Men with High Grade Prostatic Intraepithelial Neoplasia. AB - A diverse body of evidence suggests that lycopene might inhibit prostate cancer development. We conducted a 6-mo repeat biopsy randomized trial among men with high-grade prostatic intraepithelial neoplasia (HGPIN). Here we report results for serum lycopene, prostate specific antigen (PSA) and insulin-like growth factor (IGF) proteins, histopathological review, and tissue markers for proliferation [minichromosome maintenance protein 2 (MCM-2)] and cell cycle inhibition (p27). Participants consumed placebo or tomato extract capsules containing 30 mg/day lycopene. Pre- and posttreatment biopsies were immunostained and digitally scored. Serum lycopene was determined by LC-MS-MS. In secondary analyses, pathologists blindly reviewed each biopsy to score histological features. Fifty-eight men completed the trial. Serum lycopene increased 0.55 MUmol/L with treatment and declined 0.29 MUmol/L with placebo. We observed no meaningful differences in PSA, IGF-1, or IGF binding protein 3 concentrations between groups, nor any differences in expression of MCM-2 or p27 in epithelial nuclei. Prevalences of cancer, HGPIN, atrophy, or inflammation posttreatment were similar; however, more extensive atrophy and less extensive HGPIN was more common in the lycopene group. Despite large differences in serum lycopene following intervention, no treatment effects were apparent on either the serum or benign tissue endpoints. Larger studies are warranted to determine whether changes observed in extent of HGPIN and focal atrophy can be replicated. PMID- 26422199 TI - Gamma-index method sensitivity for gauging plan delivery accuracy of volumetric modulated arc therapy. AB - PURPOSE: The aim of this study was to investigate the sensitivity of the gamma index method according to various gamma criteria for volumetric modulated arc therapy (VMAT). METHODS: Twenty head and neck (HN) and twenty prostate VMAT plans were retrospectively selected for this study. Both global and local 2D gamma evaluations were performed with criteria of 3%/3 mm, 2%/2 mm, 1%/2 mm and 2%/1 mm. In this study, the global and local gamma-index calculated the differences in doses relative to the maximum dose and the dose at the current measurement point, respectively. Using log files acquired during delivery, the differences in parameters at every control point between the VMAT plans and the log files were acquired. The differences in dose-volumetric parameters between reconstructed VMAT plans using the log files and the original VMAT plans were calculated. The Spearman's rank correlation coefficients (rs) were calculated between the passing rates and those differences. RESULTS: Considerable correlations with statistical significances were observed between global 1%/2 mm, local 1%/2 mm and local 2%/1 mm and the MLC position differences (rs = -0.712, -0.628 and -0.581). The numbers of rs values with statistical significance between the passing rates and the changes in dose-volumetric parameters were largest in global 2%/2 mm (n = 16), global 2%/1 mm (n = 15) and local 2%/1 mm (n = 13) criteria. CONCLUSION: Local gamma-index method with 2%/1 mm generally showed higher sensitivity to detect deviations between a VMAT plan and the delivery of the VMAT plan. PMID- 26422200 TI - Ultrasound versus Cone-beam CT image-guided radiotherapy for prostate and post prostatectomy pretreatment localization. AB - PURPOSE: To evaluate the accuracy of an intra-modality trans-abdominal ultrasound (TA-US) device against soft-tissue based Cone-Beam Computed tomography (CBCT) registration for prostate and post-prostatectomy pre-treatment positioning. METHODS: The differences between CBCT and US shifts were calculated on 25 prostate cancer patients (cohort A) and 11 post-prostatectomy patients (cohort B), resulting in 284 and 106 paired shifts for cohorts A and B, respectively. As a second step, a corrective method was applied to the US registration results to decrease the systematic shifts observed between TA-US and CBCT results. This method consisted of subtracting the mean difference obtained between US and CBCT registration results during the first 3 sessions from the US registration results of the subsequent sessions. Inter-operator registration variability (IOV) was also investigated for both modalities. RESULTS: After initial review, about 20% of the US images were excluded because of insufficient quality. The average differences between US and CBCT were: 2.8 +/- 4.1 mm, -0.9 +/- 4.2 mm, 0.4 +/- 3.4 mm for cohort A and 1.3 +/- 5.0 mm, -2.3 +/- 4.6 mm, 0.5 +/- 2.9 mm for cohort B, in the anterior-posterior (AP), superior-inferior (SI) and lateral (LR) directions, respectively. After applying the corrective method, only the differences in the AP direction remained significant (p < 0.05). The IOV values were between 0.6-2.0 mm and 2.1-3.5 mm for the CBCT and TA-US modalities, respectively. CONCLUSIONS: Based on the obtained results and on the image quality, the TA-US imaging modality is not safely interchangeable with CBCT for pre-treatment repositioning. Treatment margins adaptation based on the correction of the systematic shifts should be considered. PMID- 26422202 TI - Equivalent Porous Media (EPM) Simulation of Groundwater Hydraulics and Contaminant Transport in Karst Aquifers. AB - Karst aquifers have a high degree of heterogeneity and anisotropy in their geologic and hydrogeologic properties which makes predicting their behavior difficult. This paper evaluates the application of the Equivalent Porous Media (EPM) approach to simulate groundwater hydraulics and contaminant transport in karst aquifers using an example from the North Coast limestone aquifer system in Puerto Rico. The goal is to evaluate if the EPM approach, which approximates the karst features with a conceptualized, equivalent continuous medium, is feasible for an actual project, based on available data and the study scale and purpose. Existing National Oceanic Atmospheric Administration (NOAA) data and previous hydrogeological U. S. Geological Survey (USGS) studies were used to define the model input parameters. Hydraulic conductivity and specific yield were estimated using measured groundwater heads over the study area and further calibrated against continuous water level data of three USGS observation wells. The water table fluctuation results indicate that the model can practically reflect the steady-state groundwater hydraulics (normalized RMSE of 12.4%) and long-term variability (normalized RMSE of 3.0%) at regional and intermediate scales and can be applied to predict future water table behavior under different hydrogeological conditions. The application of the EPM approach to simulate transport is limited because it does not directly consider possible irregular conduit flow pathways. However, the results from the present study suggest that the EPM approach is capable to reproduce the spreading of a TCE plume at intermediate scales with sufficient accuracy (normalized RMSE of 8.45%) for groundwater resources management and the planning of contamination mitigation strategies. PMID- 26422201 TI - Improved Estimation of Human Lipoprotein Kinetics with Mixed Effects Models. AB - CONTEXT: Mathematical models may help the analysis of biological systems by providing estimates of otherwise un-measurable quantities such as concentrations and fluxes. The variability in such systems makes it difficult to translate individual characteristics to group behavior. Mixed effects models offer a tool to simultaneously assess individual and population behavior from experimental data. Lipoproteins and plasma lipids are key mediators for cardiovascular disease in metabolic disorders such as diabetes mellitus type 2. By the use of mathematical models and tracer experiments fluxes and production rates of lipoproteins may be estimated. RESULTS: We developed a mixed effects model to study lipoprotein kinetics in a data set of 15 healthy individuals and 15 patients with type 2 diabetes. We compare the traditional and the mixed effects approach in terms of group estimates at various sample and data set sizes. CONCLUSION: We conclude that the mixed effects approach provided better estimates using the full data set as well as with both sparse and truncated data sets. Sample size estimates showed that to compare lipoprotein secretion the mixed effects approach needed almost half the sample size as the traditional method. PMID- 26422203 TI - Salicylic Acid Induces Changes in Mango Fruit that Affect Oviposition Behavior and Development of the Oriental Fruit Fly, Bactrocera dorsalis. AB - The Oriental fruit fly, Bactrocera dorsalis (Hendel) is an important quarantine pest around the globe. Although measures for its control are implemented worldwide through IPM and male annihilation, there is little effect on their population. Hence, there is a need for new strategies to control this minacious pest. A strategy that has received negligible attention is the induction of 'natural plant defenses' by phytohormones. In this study, we investigated the effect of salicylic acid (SA) treatment of mango fruit (cv. Totapuri) on oviposition and larval development of B. dorsalis. In oviposition choice assays, gravid females laid significantly less eggs in SA treated compared to untreated fruit. Headspace volatiles collected from SA treated fruit were less attractive to gravid females compared to volatiles from untreated fruit. GC-MS analysis of the headspace volatiles from SA treated and untreated fruit showed noticeable changes in their chemical compositions. Cis-ocimene and 3-carene (attractants to B. dorsalis) were reduced in the headspace volatiles of treated fruit. Further, reduced pupae formation and adult emergence was observed in treated fruit compared to control. Increased phenol and flavonoid content was recorded in treated fruit. We also observed differential expression of anti-oxidative enzymes namely catalase (CAT), polyphenoloxidase (PPO) and peroxidase (POD). In summary, the results indicate that SA treatment reduced oviposition, larval development and adult emergence of B. dorsalis and suggest a role of SA in enhancing mango tolerance to B. dorsalis. PMID- 26422204 TI - Strategies for Primary Prevention of Coronary Heart Disease Based on Risk Stratification by the ACC/AHA Lipid Guidelines, ATP III Guidelines, Coronary Calcium Scoring, and C-Reactive Protein, and a Global Treat-All Strategy: A Comparative--Effectiveness Modeling Study. AB - BACKGROUND: Several approaches have been proposed for risk-stratification and primary prevention of coronary heart disease (CHD), but their comparative and cost-effectiveness is unknown. METHODS: We constructed a state-transition microsimulation model to compare multiple approaches to the primary prevention of CHD in a simulated cohort of men aged 45-75 and women 55-75. Risk-stratification strategies included the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the treatment of blood cholesterol, the Adult Treatment Panel (ATP) III guidelines, and approaches based on coronary artery calcium (CAC) scoring and C-reactive protein (CRP). Additionally we assessed a treat-all strategy in which all individuals were prescribed either moderate-dose or high-dose statins and all males received low-dose aspirin. Outcome measures included CHD events, costs, medication-related side effects, radiation attributable cancers, and quality-adjusted-life-years (QALYs) over a 30-year timeframe. RESULTS: Treat-all with high-dose statins dominated all other strategies for both men and women, gaining 15.7 million QALYs, preventing 7.3 million myocardial infarctions, and saving over $238 billion, compared to the status quo, far outweighing its associated adverse events including bleeding, hepatitis, myopathy, and new-onset diabetes. ACC/AHA guidelines were more cost effective than ATP III guidelines for both men and women despite placing 8.7 million more people on statins. For women at low CHD risk, treat-all with high dose statins was more likely to cause a statin-related adverse event than to prevent a CHD event. CONCLUSIONS: Despite leading to a greater proportion of the population placed on statin therapy, the ACC/AHA guidelines are more cost effective than ATP III. Even so, at generic prices, treating all men and women with statins and all men with low-dose aspirin appears to be more cost-effective than all risk-stratification approaches for the primary prevention of CHD. Especially for low-CHD risk women, decisions on the appropriate primary prevention strategy should be based on shared decision making between patients and healthcare providers. PMID- 26422205 TI - Statistical Mechanics and Thermodynamics of Viral Evolution. AB - This paper uses methods drawn from physics to study the life cycle of viruses. The paper analyzes a model of viral infection and evolution using the "grand canonical ensemble" and formalisms from statistical mechanics and thermodynamics. Using this approach we enumerate all possible genetic states of a model virus and host as a function of two independent pressures-immune response and system temperature. We prove the system has a real thermodynamic temperature, and discover a new phase transition between a positive temperature regime of normal replication and a negative temperature "disordered" phase of the virus. We distinguish this from previous observations of a phase transition that arises as a function of mutation rate. From an evolutionary biology point of view, at steady state the viruses naturally evolve to distinct quasispecies. This paper also reveals a universal relationship that relates the order parameter (as a measure of mutational robustness) to evolvability in agreement with recent experimental and theoretical work. Given that real viruses have finite length RNA segments that encode proteins which determine virus fitness, the approach used here could be refined to apply to real biological systems, perhaps providing insight into immune escape, the emergence of novel pathogens and other results of viral evolution. PMID- 26422206 TI - Efferent Vestibular Neurons Show Homogenous Discharge Output But Heterogeneous Synaptic Input Profile In Vitro. AB - Despite the importance of our sense of balance we still know remarkably little about the central control of the peripheral balance system. While previous work has shown that activation of the efferent vestibular system results in modulation of afferent vestibular neuron discharge, the intrinsic and synaptic properties of efferent neurons themselves are largely unknown. Here we substantiate the location of the efferent vestibular nucleus (EVN) in the mouse, before characterizing the input and output properties of EVN neurons in vitro. We made transverse serial sections through the brainstem of 4-week-old mice, and performed immunohistochemistry for calcitonin gene-related peptide (CGRP) and choline acetyltransferase (ChAT), both expressed in the EVN of other species. We also injected fluorogold into the posterior canal and retrogradely labelled neurons in the EVN of ChAT:: tdTomato mice expressing tdTomato in all cholinergic neurons. As expected the EVN lies dorsolateral to the genu of the facial nerve (CNVII). We then made whole-cell current-, and voltage-clamp recordings from visually identified EVN neurons. In current-clamp, EVN neurons display a homogeneous discharge pattern. This is characterized by a high frequency burst of action potentials at the onset of a depolarizing stimulus and the offset of a hyperpolarizing stimulus that is mediated by T-type calcium channels. In voltage clamp, EVN neurons receive either exclusively excitatory or inhibitory inputs, or a combination of both. Despite this heterogeneous mixture of inputs, we show that synaptic inputs onto EVN neurons are predominantly excitatory. Together these findings suggest that the inputs onto EVN neurons, and more specifically the origin of these inputs may underlie EVN neuron function. PMID- 26422207 TI - VEP Responses to Op-Art Stimuli. AB - Several types of striped patterns have been reported to cause adverse sensations described as visual discomfort. Previous research using op-art-based stimuli has demonstrated that spurious eye movement signals can cause the experience of illusory motion, or shimmering effects, which might be perceived as uncomfortable. Whilst the shimmering effects are one cause of discomfort, another possible contributor to discomfort is excessive neural responses: As striped patterns do not have the statistical redundancy typical of natural images, they are perhaps unable to be encoded efficiently. If this is the case, then this should be seen in the amplitude of the EEG response. This study found that stimuli that were judged to be most comfortable were also those with the lowest EEG amplitude. This provides some support for the idea that excessive neural responses might also contribute to discomfort judgements in normal populations, in stimuli controlled for perceived contrast. PMID- 26422209 TI - The hydrochloride and hydrobromide salt forms of (S)-amphetamine. AB - Despite the high profile of amphetamine, there have been relatively few structural studies of its salt forms. The lack of any halide salt forms is surprising as the typical synthetic route for amphetamine initially produces the chloride salt. (S)-Amphetamine hydrochloride [systematic name: (2S)-1 phenylpropan-2-aminium chloride], C9H14N(+).Cl(-), has a Z' = 6 structure with six independent cation-anion pairs. That these are indeed crystallographically independent is supported by different packing orientations of the cations and by the observation of a wide range of cation conformations generated by rotation about the phenyl-CH2 bond. The supramolecular contacts about the anions also differ, such that both a wide variation in the geometry of the three N-H...Cl hydrogen bonds formed by each chloride anion and differences in C-H...Cl contacts are apparent. (S)-Amphetamine hydrobromide [systematic name: (2S)-1-phenylpropan 2-aminium bromide], C9H14N(+).Br(-), is broadly similar to the hydrochloride in terms of cation conformation, the existence of three N-H...X hydrogen-bond contacts per anion and the overall two-dimensional hydrogen-bonded sheet motif. However, only the chloride structure features organic bilayers and Z' > 1. PMID- 26422208 TI - Magnitude of Treatment Abandonment in Childhood Cancer. AB - BACKGROUND: Treatment abandonment (TxA) is recognized as a leading cause of treatment failure for children with cancer in low-and-middle-income countries (LMC). However, its global frequency and burden have remained elusive due to lack of global data. This study aimed to obtain an estimate using survey and population data. METHODS: Childhood cancer clinicians (medical oncologists, surgeons, and radiation therapists), nurses, social workers, and psychologists involved in care of children with cancer were approached through an online survey February-May 2012. Incidence and population data were obtained from public sources. Descriptive, univariable, and multivariable analyses were conducted. RESULTS: 602 responses from 101 countries were obtained from physicians (84%), practicing pediatric hematology/oncology (83%) in general or children's hospitals (79%). Results suggested, 23,854 (15%) of 155,088 children <15 years old newly diagnosed with cancer annually in the countries analyzed, abandon therapy. Importantly, 83% of new childhood cancer cases and 99% of TxA were attributable to LMC. The annual number of cases of TxA expected in LMC worldwide (26,166) was nearly equivalent to the annual number of cancer cases in children <15 years expected in HIC (26,368). Approximately two thirds of LMC had median TxA >= 6%, but TxA >= 6% was reported in high- (9%), upper-middle- (41%), lower-middle- (80%), and low-income countries (90%, p<0.001). Most LMC centers reporting TxA > 6% were outside the capital. Lower national income category, higher reliance on out-of-pocket payments, and high prevalence of economic hardship at the center were independent contextual predictors for TxA >= 6% (p<0.001). Global survival data available for more developed and less developed regions suggests TxA may account for at least a third of the survival gap between HIC and LMC. CONCLUSION: Results show TxA is prevalent (compromising cancer survival for 1 in 7 children globally), confirm the suspected high burden of TxA in LMC, and illustrate the negative impact of poverty on its occurrence. The present estimates may appear small compared to the global burden of child death from malnutrition and infection (measured in millions). However, absolute numbers suggest the burden of TxA in LMC is nearly equivalent to annually losing all kids diagnosed with cancer in HIC just to TxA, without even considering deaths from disease progression, relapse or toxicity-the main causes of childhood cancer mortality in HIC. Results document the importance of monitoring and addressing TxA as part of childhood cancer outcomes in at-risk settings. PMID- 26422210 TI - Two different anionic manganese(II) coordination polymers constructed through dicyanamide coordination bridges. AB - In order to explore new metal coordination polymers and to search for new types of ferroelectrics among hybrid coordination polymers, two manganese dicyanamide complexes, poly[tetramethylammonium [di-MU3-dicyanamido-kappa(6)N(1):N(3):N(5) tri-MU2-dicyanamido-kappa(6)N(1):N(5)-dimanganese(II)]], {[(CH3)4N][Mn2(NCNCN)5]}n, (I), and catena-poly[bis(butyltriphenylphosphonium) [[(dicyanamido-kappaN(1))manganese(II)]-di-MU2-dicyanamido-kappa(4)N(1):N(5)]], {[(C4H9)(C6H5)3P]2[Mn(NCNCN)4]}n, (II), were synthesized in aqueous solution. In (I), one Mn(II) cation is octahedrally coordinated by six nitrile N atoms from six anionic dicyanamide (dca) ligands, while the second Mn(II) cation is coordinated by four nitrile N atoms and two amide N atoms from six anionic dca ligands. Neighbouring Mn(II) cations are linked together by MU-1,5- and MU-1,3,5 bridging dca anions to form a three-dimensional polymeric structure. The anionic framework exhibits a solvent-accessible void of 289.8 A(3), amounting to 28.0% of the total unit-cell volume. Each of the cavities in the network is occupied by only one tetramethylammonium cation. In (II), each Mn(II) cation is octahedrally coordinated by six nitrile N atoms from six dca ligands. Neighbouring Mn(II) cations are linked together by double dca bridges to form a one-dimensional polymeric chain, and C-H...N hydrogen-bonding interactions are involved in the formation of the one-dimensional layer structure. PMID- 26422211 TI - A moderate distortion of the 'picket-fence' porphyrin (cryptand-222)potassium chlorido[meso-alpha,alpha,alpha,alpha-tetrakis(o pivalamidophenyl)porphyrinato]ferrate(II) n-hexane monosolvate. AB - As representative porphyrin model compounds, the structures of 'picket-fence' porphyrins have been studied intensively. The title solvated complex salt {systematic name: (4,7,13,16,21,24-hexaoxa-1,10 diazabicyclo[8.8.8]hexacosane)potassium(I) [5,10,15,20-tetrakis(2-tert butanamidophenyl)porphyrinato]iron(II) n-hexane monosolvate}, [K(C18H36N2O6)][Fe(C64H64N8O4)Cl].C6H14 or [K(222)][Fe(TpivPP)Cl].C6H14 [222 is cryptand-222 or 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane, and TpivPP is meso-alpha,alpha,alpha,alpha-tetrakis(o-pivalamidophenyl)porphyrinate(2 )], [K(222)][Fe(TpivPP)Cl].C6H14, is a five-coordinate high-spin iron(II) picket fence porphyrin complex. It crystallizes with a potassium cation chelated inside a cryptand-222 molecule; the average K-O and K-N distances are 2.81 (2) and 3.05 (2) A, respectively. One of the protecting tert-butyl pickets is disordered. The porphyrin plane presents a moderately ruffled distortion, as suggested by the atomic displacements. The axial chloride ligand is located inside the molecular cavity on the hindered porphyrin side and the Fe-Cl bond is tilted slightly off the normal to the porphyrin plane by 4.1 degrees . The out-of-plane displacement of the metal centre relative to the 24-atom mean plane (Delta24) is 0.62 A, indicating a noticeable doming of the porphyrin core. PMID- 26422212 TI - Structure and packing of aminoxyl and piperidinyl acrylamide monomers. AB - The closely related title compounds, 4-acrylamido-2,2,6,6-tetramethylpiperidine-1 oxyl, C12H21N2O2, (I), and N-(2,2,6,6-tetramethylpiperidin-4-yl)acrylamide monohydrate, C12H22N2O.H2O, (II), are important monomers in the preparation of redox-active polymers. They comprise an acrylamide group of the usual s-cis configuration appended to a 2,2,6,6-tetramethyl-substituted piperidine-1-oxyl radical or a piperidinyl chair, respectively. The adjacent amide and piperidinyl H atoms are approximately trans across the C-N bond. The packing in (I) is dominated by N-H...O hydrogen bonds; these are supported by C-H...O contacts to form an R2(1)(6) ring repeat, a motif which has been observed in other acrylamide structures. In (II), hydrogen bonds are again key to the packing arrangements. In this case, the incorporated solvent water molecule acts as an acceptor through its O atom and as a donor through both H atoms, binding three adjacent piperidinylacrylamide molecules into layers. In both structures, weak C-H...O contacts involving the piperidinyl methyl H atoms and a proximal acrylamide carbonyl O atom extend the structure in the third dimension. PMID- 26422213 TI - Unusual centrosymmetric structure of [M(18-crown-6)](+) (M = Rb, Cs and NH4) complexes stabilized in an environment of hexachloridoantimonate(V) anions. AB - In (1,4,7,10,13,16-hexaoxacyclooctadecane)rubidium hexachloridoantimonate(V), [Rb(C12H24O6)][SbCl6], (1), and its isomorphous caesium {(1,4,7,10,13,16 hexaoxacyclooctadecane)caesium hexachloridoantimonate(V), [Cs(C12H24O6)][SbCl6]}, (2), and ammonium {ammonium hexachloridoantimonate(V)-1,4,7,10,13,16 hexaoxacyclooctadecane (1/1), (NH4)[SbCl6].C12H24O6}, (3), analogues, the hexachloridoantimonate(V) anions and 18-crown-6 molecules reside across -3 axes passing through the Sb atoms and the centroids of the 18-crown-6 groups, both of which coincide with centres of inversion. The Rb(+) [in (1)], Cs(+) [in (2)] and NH4(+) [in (3)] cations are situated inside the cavity of the 18-crown-6 ring; they are situated on -3 axes and are equally disordered about centres of inversion, deviating from the centroid of the 18-crown-6 molecule by 0.4808 (13), 0.9344 (7) and 0.515 (8) A, respectively. Interaction of the ammonium cation and the 18-crown-6 group is supported by three equivalent hydrogen bonds [N...O = 2.928 (3) A and N-H...O = 162 degrees ]. The centrosymmetric structure of [Cs(18 crown-6)](+), with the large Cs(+) cation approaching the centre of the ligand cavity, is unprecedented and accompanied by unusually short Cs-O bonds [2.939 (2) and 3.091 (2) A]. For all three compounds, the [M(18-crown-6)](+) cations and [SbCl6](-) anions afford linear stacks along the c axis, with the cationic complexes embedded between pairs of inversion-related anions. PMID- 26422214 TI - Polymorphism in 3-acetyl-4-hydroxy-2H-chromen-2-one. AB - A new polymorph (denoted polymorph II) of 3-acetyl-4-hydroxy-2H-chromen-2-one, C11H8O4, was obtained unexpectedly during an attempt to recrystallize the compound from salt-melted ice, and the structure is compared with that of the original polymorph (denoted polymorph I) [Lyssenko & Antipin (2001). Russ. Chem. Bull. 50, 418-431]. Strong intramolecular O-H...O hydrogen bonds are observed equally in the two polymorphs [O...O = 2.4263 (13) A in polymorph II and 2.442 (1) A in polymorph I], with a slight delocalization of the hydroxy H atom towards the ketonic O atom in polymorph II [H...O = 1.32 (2) A in polymorph II and 1.45 (3) A in polymorph I]. In both crystal structures, the packing of the molecules is dominated and stabilized by weak intermolecular C-H...O hydrogen bonds. Additional pi-pi stacking interactions between the keto-enol hydrogen-bonded rings stabilize polymorph I [the centres are separated by 3.28 (1) A], while polymorph II is stabilized by interactions between alpha-pyrone rings, which are parallel to one another and separated by 3.670 (5) A. PMID- 26422215 TI - Two new cadmium(II) coordination polymers based on bis(1,2,4-triazol-1-yl)alkane ligands and pyrazine-2,3-dicarboxylic acid. AB - Assemblies of pyrazine-2,3-dicarboxylic acid and Cd(II) in the presence of bis(1,2,4-triazol-1-yl)butane or bis(1,2,4-triazol-1-yl)ethane under ambient conditions yielded two new coordination polymers, namely poly[[tetraaqua[MU2-1,4 bis(1,2,4-triazol-1-yl)butane-kappa(2)N(4):N(4')]bis(MU2-pyrazine-2,3 dicarboxylato-kappa(3)N(1),O(2):O(3))dicadmium(II)] dihydrate], {[Cd2(C6H2N2O4)2(C8H12N6)(H2O)4].2H2O}n, (I), and poly[[diaqua[MU2-1,2-bis(1,2,4 triazol-1-yl)ethane-kappa(2)N(4):N(4')]bis(MU3-pyrazine-2,3-dicarboxylato kappa(4)N(1),O(2):O(3):O(3'))dicadmium(II)] dihydrate], {[Cd2(C6H2N2O4)2(C6H8N6)(H2O)2].2H2O}n, (II). Complex (I) displays an interesting two-dimensional wave-like structure and forms a distinct extended three dimensional supramolecular structure with the help of O-H...N and O-H...O hydrogen bonds. Complex (II) has a three-dimensional framework structure in which hydrogen bonds of the O-H...N and O-H...O types are found. PMID- 26422216 TI - A structural study of Si6-ring-containing [Si6Cl14](2-) chlorosilicates. AB - The crystal structures of four substituted-ammonium dichloride dodecachlorohexasilanes are presented. Each is crystallized with a different cation and one of the structures contains a benzene solvent molecule: bis(tetraethylammonium) dichloride dodecachlorohexasilane, 2C8H20N(+).2Cl( ).Cl12Si6, (I), tetrabutylammonium tributylmethylammonium dichloride dodecachlorohexasilane, C16H36N(+).C13H30N(+).2Cl(-).Cl12Si6, (II), bis(tetrabutylammonium) dichloride dodecachlorohexasilane benzene disolvate, 2C16H36N(+).2Cl(-).Cl12Si6.2C6H6, (III), and bis(benzyltriphenylphosphonium) dichloride dodecachlorohexasilane, 2C25H22P(+).2Cl(-).Cl12Si6, (IV). In all four structures, the dodecachlorohexasilane ring is located on a crystallographic centre of inversion. The geometry of the dichloride dodecachlorohexasilanes in the different structures is almost the same, irrespective of the cocrystallized cation and solvent. However, the crystal structure of the parent dodecachlorohexasilane molecule shows that this molecule adopts a chair conformation. In (IV), the P atom and the benzyl group of the cation are disordered over two sites, with a site-occupation factor of 0.560 (5) for the major-occupied site. PMID- 26422217 TI - A new Co(II) complex of diniconazole: synthesis, crystal structure and antifungal activity. AB - A new Co(II) complex of diniconazole, namely diaqua[(E)-(RS)-1-(2,4 dichlorophenyl)-4,4-dimethyl-2-(1H-1,2,4-triazol-1-yl-kappaN(4))pent-1-en-3 ol]cobalt(II) dinitrate dihydrate, [Co(C15H17Cl2N3O)3(H2O)2](NO3)2.2H2O, was synthesized and characterized by elemental analysis, IR spectroscopy and single crystal X-ray diffraction. Crystal structural analysis shows that the centrosymmetric Co(II) cation is coordinated by four diniconazole ligands and two water molecules, forming a six-coordinated octahedral structure. There are also two free nitrate counter-anions and two additional solvent water molecules in the structure. Intermolecular O-H...O hydrogen bonds link the complex cations into a one-dimensional chain. In addition, the antifungal activity of the complex against Botryosphaeria ribis, Gibberella nicotiancola, Botryosphaeria berengriana and Alternariasolani was studied. The results indicate that the complex shows a higher antifungal activity for Botryosphaeria ribis and Botryosphaeria berengriana than diniconazole, but a lower antifungal activity for Gibberella nicotiancola and Alternariasolani. PMID- 26422218 TI - Synthesis and structure determination of seven ternary bismuthides: crystal chemistry of the RELi3Bi2 family (RE = La-Nd, Sm, Gd, and Tb). AB - Zintl phases are renowned for their diverse crystal structures with rich structural chemistry and have recently exhibited some remarkable heat- and charge transport properties. The ternary bismuthides RELi3Bi2 (RE = La-Nd, Sm, Gd, and Tb) (namely, lanthanum trilithium dibismuthide, LaLi3Bi2, cerium trilithium dibismuthide, CeLi3Bi2, praseodymium trilithium dibismuthide, PrLi3Bi2, neodymium trilithium dibismuthide, NdLi3Bi2, samarium trilithium dibismuthide, SmLi3Bi2, gadolinium trilithium dibismuthide, GdLi3Bi2, and terbium trilithium dibismuthide, TbLi3Bi2) were synthesized by high-temperature reactions of the elements in sealed Nb ampoules. Single-crystal X-ray diffraction analysis shows that all seven compounds are isostructural and crystallize in the LaLi3Sb2 type structure in the trigonal space group P-3m1 (Pearson symbol hP6). The unit-cell volumes decrease monotonically on moving from the La to the Tb compound, owing to the lanthanide contraction. The structure features a rare-earth metal atom and one Li atom in a nearly perfect octahedral coordination by six Bi atoms. The second crystallographically unique Li atom is surrounded by four Bi atoms in a slightly distorted tetrahedral geometry. The atomic arrangements are best described as layered structures consisting of two-dimensional layers of fused LiBi4 tetrahedra and LiBi6 octahedra, separated by rare-earth metal cations. As such, these compounds are expected to be valance-precise semiconductors, whose formulae can be represented as (RE(3+))(Li(1+))3(Bi(3-))2. PMID- 26422219 TI - Halogen-bonded adduct of 1,2-dibromo-1,1,2,2-tetrafluoroethane and 1,4 diazabicyclo[2.2.2]octane. AB - Halogen bonding is an intermolecular interaction capable of being used to direct extended structures. Typical halogen-bonding systems involve a noncovalent interaction between a Lewis base, such as an amine, as an acceptor and a halogen atom of a halofluorocarbon as a donor. Vapour-phase diffusion of 1,4 diazabicyclo[2.2.2]octane (DABCO) with 1,2-dibromotetrafluoroethane results in crystals of the 1:1 adduct, C2Br2F4.C6H12N2, which crystallizes as an infinite one-dimensional polymeric structure linked by intermolecular N...Br halogen bonds [2.829 (3) A], which are 0.57 A shorter than the sum of the van der Waals radii. PMID- 26422220 TI - The first three-dimensional Fe(III)-Sr(II) heterometallic coordination polymer: poly[[diaquatetrakis(MU3-pyridine-2,3-dicarboxylato)diiron(III)strontium(II)] dihydrate]. AB - The title compound, poly[[diaqua-1kappa(2)O-tetrakis(MU3-pyridine-2,3 dicarboxylato) 2:1:2'kappa(10)N,O(2):O(2'),O(3):O(3');2:1:2'kappa(8)O(3):O(3'):N,O(2) diiron(III)strontium(II)] dihydrate], {[Fe2Sr(C7H3O4)4(H2O)2].2H2O}n, which has triclinic (P-1) symmetry, was prepared by the reaction of pyridine-2,3 dicarboxylic acid, SrCl2.6H2O and Fe(OAc)2(OH) (OAc is acetate) in the presence of imidazole in water at 363 K. In the crystal structure, the pyridine-2,3 dicarboxylate (pydc(2-)) ligand exhibits MU3-eta(1),eta(1):eta(1):eta(1) and MU3 eta(1),eta(1):eta(1),eta(1):eta(1) coordination modes, bridging two Fe(III) cations and one Sr(II) cation. The Sr(II) cation, which is located on an inversion centre, is eight-coordinated by six O atoms of four pydc(2-) ligands and two water molecules. The coordination geometry of the Sr(II) cation can be best described as distorted dodecahedral. The Fe(III) cation is six-coordinated by O and N atoms of four pydc(2-) ligands in a slightly distorted octahedral geometry. Each Fe(III) cation bridges two neighbouring Fe(III) cations to form a one-dimensional [Fe2(pydc)4]n chain. The chains are connected by Sr(II) cations to form a three-dimensional framework. The topology type of this framework is tfj. The structure displays O-H...O and C-H...O hydrogen bonding. PMID- 26422221 TI - Photoluminescence properties of a cationic trinuclear zinc(II) complex with the tetradentate Schiff base ligand 6-methyl-2-({[(pyridin-2 yl)methyl]imino}methyl)phenolate. AB - Metal complexes with Schiff base ligands have been suggested as potential phosphors in electroluminescent devices. In the title complex, tetrakis[6-methyl 2-({[(pyridin-2-yl)methyl]imino}methyl)phenolato 1:2kappa(8)N,N',O:O;3:2kappa(8)N,N',O:O]trizinc(II) hexafluoridophosphate methanol monosolvate, [Zn3(C14H13N2O)4](PF6)2.CH3OH, the Zn(II) cations adopt both six- and four-coordinate geometries involving the N and O atoms of tetradentate 6-methyl-2-({[(pyridin-2-yl)methyl]imino}methyl)phenolate ligands. Two terminal Zn(II) cations adopt distorted octahedral geometries and the central Zn(II) cation adopts a distorted tetrahedral geometry. The O atoms of the phenolate ligands bridge three Zn(II) cations, forming a dicationic trinuclear metal cluster. The title complex exhibits a strong emission at 469 nm with a quantum yield of 15.5%. PMID- 26422222 TI - 5-Iodouracil: structure of a reflection twin. AB - The crystal structure of 5-iodouracil, C4H3IN2O2, has been determined in the noncentrosymmetric space group P21 on a nonmerohedrally twinned crystal. Both twin components are enantiomorphically pure, but the twin element is a mirror plane perpendicular to c*. The molecular structure is discussed and stacking faults in the two-dimensional packing are proposed as a reason for the twinning. PMID- 26422223 TI - Methods of space-group determination - a supplement dealing with twinned crystals and metric specialization. AB - Tables for the determination of space group for single crystals, twinned crystals and crystals with a specialized metric are presented in the form of a spreadsheet for use on a computer. There are 14 tables, one for each of the Bravais-lattice types. The content of the tables is arranged so that at the intersection of rows, displaying the conditions for reflection, and of columns, displaying the Laue and crystal classes, one finds those space groups compatible with the observed Bravais-lattice type, the conditions for reflection and the Laue and crystal classes. The tables are intended to be of direct use to an experimentalist working with an unknown structure. PMID- 26422224 TI - Crystal structures of four delta-keto esters and a Cambridge Structural Database analysis of cyano-halogen interactions. AB - The revived interest in halogen bonding as a tool in pharmaceutical cocrystals and drug design has indicated that cyano-halogen interactions could play an important role. The crystal structures of four closely related delta-keto esters, which differ only in the substitution at a single C atom (by H, OMe, Cl and Br), are compared, namely ethyl 2-cyano-5-oxo-5-phenyl-3-(piperidin-1-yl)pent-2 enoate, C19H22N2O3, (1), ethyl 2-cyano-5-(4-methoxyphenyl)-5-oxo-3-(piperidin-1 yl)pent-2-enoate, C20H24N2O4, (2), ethyl 5-(4-chlorophenyl)-2-cyano-5-oxo-3 (piperidin-1-yl)pent-2-enoate, C19H21ClN2O3, (3), and the previously published ethyl 5-(4-bromophenyl)-2-cyano-5-oxo-3-(piperidin-1-yl)pent-2-enoate, C19H21BrN2O3, (4) [Maurya, Vasudev & Gupta (2013). RSC Adv. 3, 12955-12962]. The molecular conformations are very similar, while there are differences in the molecular assemblies. Intermolecular C-H...O hydrogen bonds are found to be the primary interactions in the crystal packing and are present in all four structures. The halogenated derivatives have additional aromatic-aromatic interactions and cyano-halogen interactions, further stabilizing the molecular packing. A database analysis of cyano-halogen interactions using the Cambridge Structural Database [CSD; Groom & Allen (2014). Angew. Chem. Int. Ed. 53, 662 671] revealed that about 13% of the organic molecular crystals containing both cyano and halogen groups have cyano-halogen interactions in their packing. Three geometric parameters for the C-X...N[triple-bond]C interaction (X = F, Cl, Br or I), viz. the N...X distance and the C-X...N and C-N...X angles, were analysed. The results indicate that all the short cyano-halogen contacts in the CSD can be classified as halogen bonds, which are directional noncovalent interactions. PMID- 26422225 TI - One-dimensional Cu(II) coordination polymers containing C2h-symmetric 1,1':4',1'' terphenyl-3,3'-dicarboxylate linkers. AB - Two new one-dimensional Cu(II) coordination polymers (CPs) containing the C2h symmetric terphenyl-based dicarboxylate linker 1,1':4',1''-terphenyl-3,3' dicarboxylate (3,3'-TPDC), namely catena-poly[[bis(dimethylamine kappaN)copper(II)]-MU-1,1':4',1''-terphenyl-3,3'-dicarboxylato kappa(4)O,O':O'':O'''] monohydrate], {[Cu(C20H12O4)(C2H7N)2].H2O}n, (I), and catena-poly[[aquabis(dimethylamine-kappaN)copper(II)]-MU-1,1':4',1''-terphenyl 3,3'-dicarboxylato-kappa(2)O(3):O(3')] monohydrate], {[Cu(C20H12O4)(C2H7N)2(H2O)].H2O}n, (II), were both obtained from two different methods of preparation: one reaction was performed in the presence of 1,4 diazabicyclo[2.2.2]octane (DABCO) as a potential pillar ligand and the other was carried out in the absence of the DABCO pillar. Both reactions afforded crystals of different colours, i.e. violet plates for (I) and blue needles for (II), both of which were analysed by X-ray crystallography. The 3,3'-TPDC bridging ligands coordinate the Cu(II) ions in asymmetric chelating modes in (I) and in monodenate binding modes in (II), forming one-dimensional chains in each case. Both coordination polymers contain two coordinated dimethylamine ligands in mutually trans positions, and there is an additional aqua ligand in (II). The solvent water molecules are involved in hydrogen bonds between the one-dimensional coordination polymer chains, forming a two-dimensional network in (I) and a three dimensional network in (II). PMID- 26422226 TI - Self-Compassion as a Resource in the Self-Stigma Process of Overweight and Obese Individuals. AB - OBJECTIVE: Self-stigma in overweight and obese individuals has strong associations with impairment in mental and global health. This study sought to explore self-compassion as a psychological resource in the self-stigma process. METHODS: In a 2012 representative German population survey of N = 1,158 overweight and obese individuals, self-compassion was examined as a mediator between self-stigma and mental and physical health outcomes, including BMI (kg/m2), using structural equation modeling and controlling for sociodemographic factors. RESULTS: Psychological variables were assessed using validated self report questionnaires. Self-compassion partially mediated the relationships between self-stigma and depression, somatic symptoms, and health status/quality of life, lowering the predictive effect of self-stigma on the outcomes by approximately one-third. In contrast, self-compassion, because it was unrelated to BMI, did not mediate the association between self-stigma and BMI. CONCLUSION: Self-compassion has the potential to act as a buffer against the mental and global health detriments of self-stigma in overweight and obesity and could thus represent a target for interventions to reduce self-stigma and prevent these health impairments. In order to influence the association between self-stigma and BMI, self-compassion should conceptually be linked to weight management. PMID- 26422227 TI - Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR-Cas system. AB - The microbial adaptive immune system CRISPR mediates defense against foreign genetic elements through two classes of RNA-guided nuclease effectors. Class 1 effectors utilize multi-protein complexes, whereas class 2 effectors rely on single-component effector proteins such as the well-characterized Cas9. Here, we report characterization of Cpf1, a putative class 2 CRISPR effector. We demonstrate that Cpf1 mediates robust DNA interference with features distinct from Cas9. Cpf1 is a single RNA-guided endonuclease lacking tracrRNA, and it utilizes a T-rich protospacer-adjacent motif. Moreover, Cpf1 cleaves DNA via a staggered DNA double-stranded break. Out of 16 Cpf1-family proteins, we identified two candidate enzymes from Acidaminococcus and Lachnospiraceae, with efficient genome-editing activity in human cells. Identifying this mechanism of interference broadens our understanding of CRISPR-Cas systems and advances their genome editing applications. PMID- 26422228 TI - Lung function comparison between two decades in cystic fibrosis children: A single centre study. AB - OBJECTIVES: The purpose of this study was to compare two cohorts of cystic fibrosis (CF) patients born and treated in two different decades, diagnosed through a CF neonatal screening program. METHODOLOGY: We compared pulmonary function decline from 10 to 15 years of age in patients with cystic fibrosis born between 1979 and 1984 (Cohort 1) and between 1991 and 1996 (Cohort 2). Forced expiratory volume in 1 sec (FEV1%) and forced expiratory flow from 25% to 75% (FEF 25-75%) were analyzed by a linear mixed model approach. The differences between the two cohorts were estimated and the overall cohort effect was tested. RESULTS: Ninety-two patients (51 males, 41 females) fulfilled the selection criteria. Pancreatic insufficiency and CF related diabetes were present in 91% and 20% of patients, respectively. The mean absolute decrement of FEV1% was 9.2 (standard deviation [SD] 11.2) in Cohort 1 and 0.6 (SD 10.4) in Cohort 2 (P < 0.001). The mean decrement of FEF 25-75% was 16.3 (SD 19.5) in Cohort 1 and 1.3 (SD 16.8) in Cohort 2 (P < 0.001) and the Pseudomonas aeruginosa (Pa) colonization was 28% and 15% respectively (P = 0.1). CONCLUSIONS: Our results show that pulmonary function has clearly ameliorated over a decade in young CF patients, in a period during which several significant therapeutic changes have been introduced, such as dornase alfa, tobramycin and hypertonic saline. To our knowledge this is the first study showing a cohort effect in patients diagnosed after neonatal screening. PMID- 26422229 TI - Tissue-Specific Enrichment of Lymphoma Risk Loci in Regulatory Elements. AB - Though numerous polymorphisms have been associated with risk of developing lymphoma, how these variants function to promote tumorigenesis is poorly understood. Here, we report that lymphoma risk SNPs, especially in the non Hodgkin's lymphoma subtype chronic lymphocytic leukemia, are significantly enriched for co-localization with epigenetic marks of active gene regulation. These enrichments were seen in a lymphoid-specific manner for numerous ENCODE datasets, including DNase-hypersensitivity as well as multiple segmentation defined enhancer regions. Furthermore, we identify putatively functional SNPs that are both in regulatory elements in lymphocytes and are associated with gene expression changes in blood. We developed an algorithm, UES, that uses a Monte Carlo simulation approach to calculate the enrichment of previously identified risk SNPs in various functional elements. This multiscale approach integrating multiple datasets helps disentangle the underlying biology of lymphoma, and more broadly, is generally applicable to GWAS results from other diseases as well. PMID- 26422230 TI - Intratumor Heterogeneity of ALK-Rearrangements and Homogeneity of EGFR-Mutations in Mixed Lung Adenocarcinoma. AB - BACKGROUND: Non Small Cell Lung Cancer is a highly heterogeneous tumor. Histologic intratumor heterogeneity could be 'major', characterized by a single tumor showing two different histologic types, and 'minor', due to at least 2 different growth patterns in the same tumor. Therefore, a morphological heterogeneity could reflect an intratumor molecular heterogeneity. To date, few data are reported in literature about molecular features of the mixed adenocarcinoma. The aim of our study was to assess EGFR-mutations and ALK rearrangements in different intratumor subtypes and/or growth patterns in a series of mixed adenocarcinomas and adenosquamous carcinomas. METHODS: 590 Non Small Cell Lung Carcinomas tumor samples were revised in order to select mixed adenocarcinomas with available tumor components. Finally, only 105 mixed adenocarcinomas and 17 adenosquamous carcinomas were included in the study for further analyses. Two TMAs were built selecting the different intratumor histotypes. ALK-rearrangements were detected through FISH and IHC, and EGFR mutations were detected through IHC and confirmed by RT-PCR. RESULTS: 10/122 cases were ALK-rearranged and 7 from those 10 showing an intratumor heterogeneity of the rearrangements. 12/122 cases were EGFR-mutated, uniformly expressing the EGFR-mutated protein in all histologic components. CONCLUSION: Our data suggests that EGFR-mutations is generally homogeneously expressed. On the contrary, ALK rearrangement showed an intratumor heterogeneity in both mixed adenocarcinomas and adenosquamous carcinomas. The intratumor heterogeneity of ALK-rearrangements could lead to a possible impact on the therapeutic responses and the disease outcomes. PMID- 26422231 TI - Narrative Exposure Therapy: A Proposed Model to Address Intimate Partner Violence Related PTSD in Parenting and Pregnant Adolescents. AB - Pregnant and parenting adolescents experience high rates of intimate partner violence (IPV) and its sequelae posttraumatic stress disorder (PTSD) and depression. Narrative exposure therapy (NET) is an innovative intervention that has demonstrated strong preliminary evidence in improving mental health. The specific aims of this article are 3-fold: (1) provide a brief background about IPV-related PTSD and depression among pregnant and parenting adolescents; (2) describe NET's theoretical principles, its therapeutic process, and provide a review of existing evidence; and (3) discuss NET as a potential treatment to address the mental health burden among adolescents experiencing IPV-related PTSD and depression. PMID- 26422232 TI - Particulate Matter Contributions from Agricultural Tilling Operations in an Irrigated Desert Region. AB - Sources of regional particulate matter (PM), particularly agricultural operations, must be understood in order to manage the air quality in irrigated dry climates. Direct monitoring measurements alone are useful, but not sufficient, to estimate regional PM source concentrations. This paper combines modeling with ground (point) and airplane (spatial) measurement methods to estimate regional PM10 (PM diameter<=10 MUm) contributions from agricultural operations. Hourly data from three air quality monitoring stations positioned at a 2-m height located on the west and east mesas of New Mexico's Mesilla Valley and in the valley at Anthony, NM were acquired from the New Mexico Air Quality Bureau. The study spanned the agricultural tilling season, March 1 to April 30, for the years 2008 to 2012. One- second spatial PM10 concentrations at 200 m above the valley floor were measured during a two-hour controlled field tilling operation on April 1, 2008. The HYSPLIT 4.0 (Hybrid Single-Particle Lagrangian Integrated Trajectory version 4) model was run at the corresponding times and heights, outputting PM10 concentrations from all potential agricultural tilling operations. The calculated percentage contribution (modeled PM10 concentration/measured PM10 concentration) indicated that the near-surface (2-m height) proportion from the agricultural operations for five seasonal averages ranged from 0.7% to 1.5% on the west and east mesas and 1.3% for the valley site at Anthony. There were 71 hourly high values of contribution ratios ranging from 30 to 100% at the three sites, depending on the wind speed and direction. PMID- 26422234 TI - PATBox: A Toolbox for Classification and Analysis of P-Type ATPases. AB - P-Type ATPases are part of the regulatory system of the cell where they are responsible for transporting ions and lipids through the cell membrane. These pumps are found in all eukaryotes and their malfunction has been found to cause several severe diseases. Knowing which substrate is pumped by a certain P-Type ATPase is therefore vital. The P-Type ATPases can be divided into 11 subtypes based on their specificity, that is, the substrate that they pump. Determining the subtype experimentally is time-consuming. Thus it is of great interest to be able to accurately predict the subtype based on the amino acid sequence only. We present an approach to P-Type ATPase sequence classification based on the k nearest neighbors, similar to a homology search, and show that this method provides performs very well and, to the best of our knowledge, better than any existing method despite its simplicity. The classifier is made available as a web service at http://services.birc.au.dk/patbox/ which also provides access to a database of potential P-Type ATPases and their predicted subtypes. PMID- 26422233 TI - Vitamin A Deficiency Impairs Mucin Expression and Suppresses the Mucosal Immune Function of the Respiratory Tract in Chicks. AB - The chicken immune system is immature at the time of hatching. The development of the respiratory immune system after hatching is vital to young chicks. The aim of this study was to investigate the effect of dietary vitamin A supplement levels on respiratory mucin and IgA production in chicks. In this study, 120 one-day-old broiler chicks were randomly divided into 4 groups consisting of three replicates of 10 broilers and subjected to dietary vitamin A supplement levels of 0, 1,500, 6,000, or 12,000 IU/kg for seven days. Compared with control birds, vitamin A supplementation significantly increased the mucin and IgA levels in the bronchoalveolar lavage fluid (BALF) as well as the IgA level in serum. In the lungs, vitamin A supplementation downregulated TNF-alpha and EGFR mRNA expression. The TGF-beta and MUC5AC mRNA expression levels were upregulated by vitamin A supplementation at a dose of 6,000 IU/kg, and the IL-13 mRNA expression level was increased at the 12,000 IU/kg supplement level. Vitamin A deficiency (control) significantly decreased the mRNA expression levels of MUC2, IgA, EGFR, IL-13 and TGF-beta in trachea tissue. Histological section analysis revealed that the number of goblet cells in the tracheal epithelium was less in the 0 and 12,000 IU/kg vitamin A supplement groups than in the other groups. In conclusion, vitamin A deficiency suppressed the immunity of the airway by decreasing the IgA and mucin concentrations in neonatal chicks. This study suggested that a suitable level of vitamin A is essential for the secretion of IgA and mucin in the respiratory tract by regulating the gene expression of cytokines and epithelial growth factors. PMID- 26422235 TI - Responding to Young People's Health Risks in Primary Care: A Cluster Randomised Trial of Training Clinicians in Screening and Motivational Interviewing. AB - OBJECTIVE: To evaluate the effectiveness of a complex intervention implementing best practice guidelines recommending clinicians screen and counsel young people across multiple psychosocial risk factors, on clinicians' detection of health risks and patients' risk taking behaviour, compared to a didactic seminar on young people's health. DESIGN: Pragmatic cluster randomised trial where volunteer general practices were stratified by postcode advantage or disadvantage score and billing type (private, free national health, community health centre), then randomised into either intervention or comparison arms using a computer generated random sequence. Three months post-intervention, patients were recruited from all practices post-consultation for a Computer Assisted Telephone Interview and followed up three and 12 months later. Researchers recruiting, consenting and interviewing patients and patients themselves were masked to allocation status; clinicians were not. SETTING: General practices in metropolitan and rural Victoria, Australia. PARTICIPANTS: General practices with at least one interested clinician (general practitioner or nurse) and their 14-24 year old patients. INTERVENTION: This complex intervention was designed using evidence based practice in learning and change in clinician behaviour and general practice systems, and included best practice approaches to motivating change in adolescent risk taking behaviours. The intervention involved training clinicians (nine hours) in health risk screening, use of a screening tool and motivational interviewing; training all practice staff (receptionists and clinicians) in engaging youth; provision of feedback to clinicians of patients' risk data; and two practice visits to support new screening and referral resources. Comparison clinicians received one didactic educational seminar (three hours) on engaging youth and health risk screening. OUTCOME MEASURES: Primary outcomes were patient report of (1) clinician detection of at least one of six health risk behaviours (tobacco, alcohol and illicit drug use, risks for sexually transmitted infection, STI, unplanned pregnancy, and road risks); and (2) change in one or more of the six health risk behaviours, at three months or at 12 months. Secondary outcomes were likelihood of future visits, trust in the clinician after exit interview, clinician detection of emotional distress and fear and abuse in relationships, and emotional distress at three and 12 months. Patient acceptability of the screening tool was also described for the intervention arm. Analyses were adjusted for practice location and billing type, patients' sex, age, and recruitment method, and past health risks, where appropriate. An intention to treat analysis approach was used, which included multilevel multiple imputation for missing outcome data. RESULTS: 42 practices were randomly allocated to intervention or comparison arms. Two intervention practices withdrew post allocation, prior to training, leaving 19 intervention (53 clinicians, 377 patients) and 21 comparison (79 clinicians, 524 patients) practices. 69% of patients in both intervention (260) and comparison (360) arms completed the 12 month follow-up. Intervention clinicians discussed more health risks per patient (59.7%) than comparison clinicians (52.7%) and thus were more likely to detect a higher proportion of young people with at least one of the six health risk behaviours (38.4% vs 26.7%, risk difference [RD] 11.6%, Confidence Interval [CI] 2.93% to 20.3%; adjusted odds ratio [OR] 1.7, CI 1.1 to 2.5). Patients reported less illicit drug use (RD -6.0, CI -11 to -1.2; OR 0.52, CI 0.28 to 0.96), and less risk for STI (RD -5.4, CI -11 to 0.2; OR 0.66, CI 0.46 to 0.96) at three months in the intervention relative to the comparison arm, and for unplanned pregnancy at 12 months (RD -4.4; CI -8.7 to -0.1; OR 0.40, CI 0.20 to 0.80). No differences were detected between arms on other health risks. There were no differences on secondary outcomes, apart from a greater detection of abuse (OR 13.8, CI 1.71 to 111). There were no reports of harmful events and intervention arm youth had high acceptance of the screening tool. CONCLUSIONS: A complex intervention, compared to a simple educational seminar for practices, improved detection of health risk behaviours in young people. Impact on health outcomes was inconclusive. Technology enabling more efficient, systematic health-risk screening may allow providers to target counselling toward higher risk individuals. Further trials require more power to confirm health benefits. TRIAL REGISTRATION: ISRCTN.com ISRCTN16059206. PMID- 26422236 TI - Cytologic and Immunophenotypic Features of Malignant Cells in Pediatric Body Fluids. AB - OBJECTIVE: Cytospin preparations and immunocytochemistry are common methods in hospitals to evaluate malignancies in body fluids. Characteristics of malignant cells in pediatric body fluids have not been adequately evaluated. STUDY DESIGN: 183 pleural, peritoneal and pericardial pediatric fluid specimens were examined by cytospin preparations and immunocytochemistry from two hospitals using similar procedural techniques. Cytologic diagnoses were correlated with the results of clinical history, histology and ancillary studies. RESULTS: Forty cases with malignancy were identified (21.9%); the most common diagnoses were rhabdomyosarcoma and acute lymphoblastic lymphoma (9 and 8 cases, respectively). Small round cell tumors revealed similar morphology as clusters of small round cells with central nuclei and scant cytoplasm with frequent small vacuoles. Twenty-one cases were evaluated by immunocytochemistry, 12 by flow cytometry and 5 by cytogenetic analysis. CD3, CD20, TdT, CD10, desmin and myogenin were the most common markers. Staining artifacts causing interpretation difficulties were noted in 5 cases that were resolved by molecular studies and deferral for surgical specimens. CONCLUSIONS: Small round cell tumors are the most common malignancies encountered in pediatric body fluids and share a nonspecific morphology. Although immunocytochemistry is helpful to arrive at the correct diagnosis, other ancillary studies may be necessary, particularly in hematologic malignancies and other difficult cases. PMID- 26422237 TI - Seasonal Preservation Success of the Marine Dinoflagellate Coral Symbiont, Symbiodinium sp. AB - Coral reefs are some of the most diverse and productive ecosystems on the planet, but are threatened by global and local stressors, mandating the need for incorporating ex situ conservation practices. One approach that is highly protective is the development of genome resource banks that preserve the species and its genetic diversity. A critical component of the reef are the endosymbiotic algae, Symbiodinium sp., living within most coral that transfer energy-rich sugars to their hosts. Although Symbiodinium are maintained alive in culture collections around the world, the cryopreservation of these algae to prevent loss and genetic drift is not well-defined. This study examined the quantum yield physiology and freezing protocols that resulted in survival of Symbiodinium at 24 h post-thawing. Only the ultra-rapid procedure called vitrification resulted in success whereas conventional slow freezing protocols did not. We determined that success also depended on using a thin film of agar with embedded Symbiodinium on Cryotops, a process that yielded a post-thaw viability of >50% in extracted and vitrified Symbiodinium from Fungia scutaria, Pocillopora damicornis and Porites compressa. Additionally, there also was a seasonal influence on vitrification success as the best post-thaw survival of F. scutaria occurred in winter and spring compared to summer and fall (P < 0.05). These findings lay the foundation for developing a viable genome resource bank for the world's Symbiodinium that, in turn, will not only protect this critical element of coral functionality but serve as a resource for understanding the complexities of symbiosis, support selective breeding experiments to develop more thermally resilient strains of coral, and provide a 'gold-standard' genomics collection, allowing for full genomic sequencing of unique Symbiodinium strains. PMID- 26422238 TI - The effect of noninvasive brain stimulation on neural connectivity in Tinnitus: A randomized trial. AB - OBJECTIVES/HYPOTHESIS: To explore neural connectivity changes associated with repetitive transcranial magnetic stimulation (rTMS) to the temporoparietal junction for patients with bothersome tinnitus. STUDY DESIGN: Randomized, double blind, controlled clinical trial. METHODS: Thirty patients with subjective, nonpulsatile tinnitus for 6 months duration or longer and a score of 36 or greater on the Tinnitus Handicap Inventory completed the study. Participants were randomized to receive either sham or active treatment with rTMS to the temporoparietal junction for either 2 or 4 weeks of therapy. Participants underwent resting state functional connectivity magnetic resonance imaging before therapy and immediately following treatment. Functional connectivity changes between active and sham treatment groups were compared using regions of interest in auditory, default mode, ventral attention, and executive attention networks. RESULTS: Sixteen patients received active rTMS treatment; 14 patients received sham treatment. There were no differences between the active and sham groups in baseline functional connectivity. Neither treatment with rTMS nor sham therapy resulted in statistically significant functional connectivity changes in the examined brain networks. CONCLUSIONS: The analysis did not identify any changes in neural connectivity following treatment in patients with bothersome tinnitus. These results are consistent with our findings of lack of symptom changes previously reported in the same group of patients. Measures of neural connectivity may inform future work using rTMS to better understand the possible benefits of neural stimulation for tinnitus. LEVEL OF EVIDENCE: 1b. Laryngoscope, 126:1201-1206, 2016. PMID- 26422239 TI - Physical Functional Limitations among Aboriginal and Non-Aboriginal Older Adults: Associations with Socio-Demographic Factors and Health. AB - BACKGROUND: Australian Aboriginal people are disproportionately affected by physical disability; the reasons for this are unclear. This study aimed to quantify associations between severe physical functional limitations and socio demographic and health-related factors among older Aboriginal and non-Aboriginal adults. METHODS: Questionnaire data from 1,563 Aboriginal and 226,802 non Aboriginal participants aged >=45 years from the Sax Institute's 45 and Up Study (New South Wales, Australia) were used to calculate age- and sex-adjusted prevalence ratios (aPRs) for severe limitation [MOS-PF score <60] according to socio-demographic and health-related factors. RESULTS: Overall, 26% (410/1563) of Aboriginal participants and 13% (29,569/226,802) of non-Aboriginal participants had severe limitations (aPR 2.8, 95%CI 2.5-3.0). In both Aboriginal and non Aboriginal participants, severe limitation was significantly associated with: being >=70 vs <70 years old (aPRs 1.8, 1.3-2.4 and 5.3, 5.0-5.5, within Aboriginal and non-Aboriginal participants, respectively), none vs tertiary educational qualifications (aPRs 2.4, 1.7-3.3 and 3.1, 3.0-3.2), lower vs higher income (aPRs 6.6, 4.2-10.5 and 5.5, 5.2-5.8), current vs never-smoking (aPRs 2.0, 1.6-2.5 and 2.2, 2.1-2.3), obese vs normal weight (aPRs 1.7, 1.3-2.2 and 2.7, 2.7 2.8) and sitting for >=7 vs <7 hours/day (aPRs 1.6, 1.2-2.0 and 1.6, 1.6-1.7). Severe limitations increased with increasing ill-health, with aPRs rising to 5-6 for >=5 versus no chronic conditions. It was significantly higher in those with few vs many social contacts (aPRs 1.7, 1.4-2.0 and 1.4, 1.4-1.4) and with very high vs low psychological distress (aPRs 4.4, 3.6-5.4 and 5.7, 5.5-5.9). CONCLUSIONS: Although the prevalence of severe physical limitation among Aboriginal people in this study is around three-fold that of non-Aboriginal people, the factors related to it are similar, indicating that Aboriginal people have higher levels of risk factors for and consequences of severe limitations. Effective management of chronic disease and reducing the prevalence of obesity and smoking are important areas for attention. PMID- 26422240 TI - Pyrocarbon Proximal Interphalangeal Joint Arthroplasty: Minimum Five-Year Follow Up. AB - PURPOSE: To report the outcomes, complications, and survivorship of pyrocarbon proximal interphalangeal joint arthroplasty at a minimum of 5-year follow-up. METHODS: A review of 97 implants in 72 consecutive patients from our joint arthroplasty database was undertaken. Patient demographics, complications, further surgery, and implant revision were recorded. Objective outcome was assessed by grip strength, range of motion, and radiological assessment of alignment, loosening, and subsidence. Subjective outcome was assessed by Patient Evaluation Measure; Quick Disabilities of the Arm, Shoulder, and Hand score; and visual analog scores (0, best; 10, worst) for appearance, satisfaction, and pain. RESULTS: Diagnosis was osteoarthritis in 60 joints, rheumatoid arthritis in 12 joints, psoriatic arthritis in 11 joints, and trauma in 14 joints. The average follow-up was 118 months (range, 60-164 months). The mean arc of motion was 35 degrees (range, 0 degrees to 90 degrees ). There was no difference in grip strength between operated and nonoperated side. Of the 97 implants, 36 required additional surgery, of which 14 were revised and 22 required reconstruction around a retained implant. The average Patient Evaluation Measure and Quick Disabilities of the Arm, Shoulder and Hand scores were 33 (range, 10-69) and 35 (range, 0-93), respectively. Mean visual analog scores for pain, satisfaction, and appearance were 2 (range, 0-8), 7 (0-10), and 8 (0-10), respectively. All implants had a lucent line with nearly all classified as either Herren grade 2 or 3. Progressive loosening was seen in 48% of implants. Implant survival as assessed by Kaplan-Meier was 85% at both 5 and 10 years. CONCLUSIONS: Good pain relief and maintenance of preoperative arc of motion was achieved with no major deterioration over time. Most implant revisions were performed within 24 months of the index procedure. Currently progressive loosening was not translated into revision surgery. Implant revision rate was higher than with other prostheses. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 26422242 TI - Chronic Disease Prevalence and Healthy Lifestyle Behaviors Among US Health Care Professionals. AB - Although health care professionals may be assumed to make healthier lifestyle choices and have better health outcomes than others because of their greater health literacy, little is known about how actual health outcomes of health care professionals compare with those of the overall population. We analyzed how trends in obesity, diabetes, hypertension, and coronary artery disease prevalence as well as several health behaviors (smoking, alcohol use, and exercise) varied between health care professionals and the general US population from 2002 to 2013, using nationally representative data collected by the National Health Interview Survey. We estimated multivariate logistic regressions of each disease and behavior adjusted for age, race, sex, geographic region, and year. Although rates of obesity, diabetes, and hypertension were lower among health care professionals compared with the overall population, disease was still common among health care professionals and increased over time at a rate similar to that of the overall population. For example, obesity prevalence was lower among health care professionals but increased similarly from 2002 to 2013 (health care professionals, 20.5% in 2002 to 22.1% in 2013; other occupations, 28.4% to 31.7%; P=.64 for difference in trend). Diabetes prevalence was modestly lower among health care professionals but increased at a similar rate (health care professionals, 7.4% in 2005 to 8.6% in 2013; other occupations, 8.7% to 9.9%; P=.67 for difference in trend). Similar patterns were noted in hypertension. Coronary artery disease prevalence declined over time among health care professionals but increased for others. Health care professionals reported better health behaviors than others in smoking and physical activity but not in moderate to heavy alcohol use. PMID- 26422243 TI - Standing, Obesity, and Metabolic Syndrome: Findings From the Cooper Center Longitudinal Study. AB - OBJECTIVE: To examine the cross-sectional relationships between standing time, obesity, and metabolic syndrome alongside and independent of leisure-time physical activity (LTPA). PARTICIPANTS AND METHODS: The primary study sample consisted of 7075 adult patients (aged 20-79 years) from Cooper Clinic (Dallas, Texas). In this cross-sectional study we assessed the associations between reported standing time and directly measured obesity (body mass index >= 30), elevated waist circumference (men: >= 102 cm; women: >= 88 cm), body fat percentage (men: >= 25%; women >= 30%), and metabolic syndrome (yes/no). In addition, the joint associations of standing and LTPA on each outcome were examined. Multivariable logistic regression adjusting for confounders was used for statistical analyses. RESULTS: Standing a quarter of the time or more was significantly associated with reduced odds of an elevated body fat percentage in men (P < .001) and a reduced likelihood of obesity (P < .009) and abdominal obesity (P=.04) in women. In addition, joint association analyses indicated that compared with the reference group (ie, not meeting the physical activity guidelines/standing almost none of the time), men and women who met the physical activity guidelines had lower odds of all obesity outcomes and metabolic syndrome with incremental additions of standing time (ie, a dose-response relationship). CONCLUSION: Standing a quarter of the time per day or more is associated with reduced odds of obesity. The inverse relationship of standing to obesity and metabolic syndrome is more robust when combined with health-promoting LTPA. Prospective studies are warranted to confirm these findings and establish a causal relationship. PMID- 26422241 TI - Loss of Hif-2alpha Rescues the Hif-1alpha Deletion Phenotype of Neonatal Respiratory Distress In Mice. AB - Hypoxia is a state of decreased oxygen reaching the tissues of the body. During prenatal development, the fetus experiences localized occurrences of hypoxia that are essential for proper organogenesis and survival. The response to decreased oxygen availability is primarily regulated by hypoxia-inducible factors (HIFs), a family of transcription factors that modulate the expression of key genes involved in glycolysis, angiogenesis, and erythropoiesis. HIF-1alpha and HIF 2alpha, two key isoforms, are important in embryonic development, and likely are involved in lung morphogenesis. We have recently shown that the inducible loss of Hif-1alpha in lung epithelium starting at E4.5 leads to death within an hour of parturition, with symptoms similar to neonatal respiratory distress syndrome (RDS). In addition to Hif-1alpha, Hif-2alpha is also expressed in the developing lung, although the overlapping roles of Hif-1alpha and Hif-2alpha in this context are not fully understood. To further investigate the independent role of Hif 2alpha in lung epithelium and its ability to alter Hif-1alpha-mediated lung maturation, we generated two additional lung-specific inducible Hif-alpha knockout models (Hif-2alpha and Hif-1alpha+Hif-2alpha). The intrauterine loss of Hif-2alpha in the lungs does not lead to decreased viability or observable phenotypic changes in the lung. More interestingly, survivability observed after the loss of both Hif-1alpha and Hif-2alpha suggests that the loss of Hif-2alpha is capable of rescuing the neonatal RDS phenotype seen in Hif-1alpha-deficient pups. Microarray analyses of lung tissue from these three genotypes identified several factors, such as Scd1, Retlngamma, and Il-1r2, which are differentially regulated by the two HIF-alpha isoforms. Moreover, network analysis suggests that modulation of hormone-mediated, NF-kappaB, C/EBPalpha, and c-MYC signaling are central to HIF-mediated changes in lung development. PMID- 26422244 TI - Less Sitting, More Physical Activity, or Higher Fitness? AB - Epidemiological studies have found that time spent in sedentary behaviors, levels of physical activity, and cardiorespiratory fitness are all associated with mortality rates. They are also related to the risks of obesity, type 2 diabetes mellitus, hypertension, cardiovascular disease, aging-associated frailty, and cancer. The evidence is such that the National Institutes of Health recently launched a new Common Fund initiative aimed at identifying the molecular transducers of adaptation to physical activity in various tissues and organs. It has been estimated that 9.4% of all 57 million deaths in the world in 2008 could be attributed to physical inactivity, which translates into more than 5 million deaths worldwide. Physical inactivity has a deleterious effect that is comparable to smoking and obesity. Importantly, this global estimate relates to levels of physical activity and does not take into account sedentary behavior and cardiorespiratory fitness. Currently, there are national and international guidelines for physical activity level that are highly concordant. The weekly recommendations include 150 minutes of moderate-intensity activity, 75 minutes of vigorous-intensity activity, or some combination of moderate and vigorous activity with 2 days of resistance exercise. However, these guidelines offer no recommendations regarding sedentary time or goals for cardiorespiratory fitness levels. It will be increasingly important for disease prevention, successful aging, and reduction of premature mortality to broaden the focus of the public health message to include not only more physical activity but also less sitting and higher cardiorespiratory fitness. We briefly review the evidence and discuss key issues to be addressed to make this approach a reality. PMID- 26422245 TI - Synthesis of Triazole Schiff's Base Derivatives and Their Inhibitory Kinetics on Tyrosinase Activity. AB - In the present study, new Schiff's base derivatives: (Z)-4-amino-5-(2-(3- fluorobenzylidene)hydrazinyl)-4H-1,2,4-triazole-3-thiol (Y1), (Z)-3-((2-(4-amino 5- mercapto-4H-1,2,4-triazol-3-yl)hydrazono)methyl)phenol (Y2), (Z)-2-((2-(4 amino-5- mercapto-4H-1,2,4-triazol-3-yl)hydrazono)methyl)phenol (Y3) and 3-((Z) (2-(4- (((E)-3-hydroxybenzylidene)amino)-5-mercapto-4H-1,2,4-triazol-3 yl)hydrazono)methyl)phenol (Y4) were synthesized and their structures were characterized by LC-MS, IR and 1H NMR. The inhibitory effects of these compounds on tyrosinase activites were evaluated. Compounds Y1, Y2 and Y3 showed potent inhibitory effects with respective IC50 value of 12.5, 7.0 and 1.5 MUM on the diphenolase activities. Moreover, the inhibition mechanisms were determined to be reversible and mixed types. Interactions of the compounds with tyrosinase were further analyzed by fluorescence quenching, copper interaction, and molecular simulation assays. The results together with the anti-tyrosinase activities data indicated that substitution on the second position of benzene ring showed superior ant-ityrosinase activities than that on third position, and that hydroxyl substitutes were better than fluorine substitutes. In addition, two benzene rings connecting to the triazole ring would produce larger steric hindrance, and affect the bonding between tyrosinase and inhibitors to decrease the inhibitory effects. The anti-tyrosinase effects of these compounds were in contrast to their antioxidant activities. In summary, this research will contribute to the development and design of antityrosinase agents. PMID- 26422246 TI - Pneumocystis Pneumonia in Patients with Autoimmune Diseases: A Retrospective Study Focused on Clinical Characteristics and Prognostic Factors Related to Death. AB - BACKGROUND: With the increasing use of immunosuppressive agents, the number of opportunistic infections has risen in patients with autoimmune diseases. Pneumocystis pneumonia (PCP) is one of these opportunistic infections that have a high mortality rate. However, only a few studies have described PCP in these patients, and these studies are limited in scope. We conducted this retrospective study to describe the clinical characteristics and factors associated with outcomes of PCP in patients with autoimmune diseases. METHODS: A retrospective study was performed in laboratory diagnosed PCP patients with autoimmune diseases in an academic hospital over a 10-year period. Patients with human immunodeficiency virus (HIV) infection were not included. Clinical characteristics were collected and the factors related to death were analysed. RESULTS: A total of 69 patients with PCP during the study period were included. Common clinical features included fever (81%), cough (56%), and dyspnea (35%). Ground glass opacity (81%) and reticulation (52%) were the most common radiological findings. Concurrent pulmonary infections including bacterium, aspergillus and cytomegalovirus were found in 34% of the patients. The overall in hospital mortality rate was 32%. High mortality was associated with lower PaO2/FiO2 ratios and albumin levels. The lymphocyte count, CD4+ T cell count, previous usage of immunosuppressive agents, the duration and dose of glucocorticoids did not affect the outcome. CONCLUSIONS: The mortality rate in PCP patients with autoimmune diseases is high. Low PaO2/FiO2 ratios and albumin levels are independent prognostic factors of mortality. PMID- 26422248 TI - Determinants of False-Negative Fine-Needle Aspirates of Axillary Lymph Nodes in Women with Breast Cancer: Lymph Node Size, Cortical Thickness and Hilar Fat Retention. AB - OBJECTIVE: Ultrasound-guided fine-needle aspiration (UG-FNA) is utilized to sample axillary lymph nodes in breast cancer patients. Diagnostic sensitivity is good but few data exist regarding the causes of false-negative results. STUDY DESIGN: Fifty-four UG-FNAs of sentinel lymph nodes with histologic follow-up were identified. Gross and radiographic lymph node size, the percentage replaced by carcinoma and the cortical thickness were correlated with false-negative rates. RESULTS: Thirty-seven aspirates were negative, 5 of these being false-negative (9%). True-positive lymph nodes averaged 1.3 cm in dimension while false negatives averaged 0.92 cm. Percentage involvement by carcinoma for true-positive FNAs averaged 69% while false-negatives averaged 25%. Cortical thickness averaged 5.6 mm in true-positive FNAs but 2.9 mm in false-negatives. CONCLUSION: A relationship exists between lymph node size and the likelihood of a false negative FNA. Lymph nodes <1.2 cm have a higher incidence of false-negative results. Lymph nodes with <30% involvement demonstrated a higher percentage of false-negatives than those with >30% replacement. Sentinel lymph nodes <1 cm appear to be relatively poor candidates for UG-FNA. Lymph nodes with a cortical thickness <3.5 mm are more often associated with a false-negative result than nodes with a thicker cortex. PMID- 26422247 TI - Human Polyclonal Antibodies Produced through DNA Vaccination of Transchromosomal Cattle Provide Mice with Post-Exposure Protection against Lethal Zaire and Sudan Ebolaviruses. AB - DNA vaccination of transchromosomal bovines (TcBs) with DNA vaccines expressing the codon-optimized (co) glycoprotein (GP) genes of Ebola virus (EBOV) and Sudan virus (SUDV) produce fully human polyclonal antibodies (pAbs) that recognize both viruses and demonstrate robust neutralizing activity. Each TcB was vaccinated by intramuscular electroporation (IM-EP) a total of four times and at each administration received 10 mg of the EBOV-GPco DNA vaccine and 10 mg of the SUDV GPco DNA vaccine at two sites on the left and right sides, respectively. After two vaccinations, robust antibody responses (titers > 1000) were detected by ELISA against whole irradiated EBOV or SUDV and recombinant EBOV-GP or SUDV-GP (rGP) antigens, with higher titers observed for the rGP antigens. Strong, virus neutralizing antibody responses (titers >1000) were detected after three vaccinations when measured by vesicular stomatitis virus-based pseudovirion neutralization assay (PsVNA). Maximal neutralizing antibody responses were identified by traditional plaque reduction neutralization tests (PRNT) after four vaccinations. Neutralizing activity of human immunoglobulins (IgG) purified from TcB plasma collected after three vaccinations and injected intraperitoneally (IP) into mice at a 100 mg/kg dose was detected in the serum by PsVNA up to 14 days after administration. Passive transfer by IP injection of the purified IgG (100 mg/kg) to groups of BALB/c mice one day after IP challenge with mouse adapted (ma) EBOV resulted in 80% protection while all mice treated with non-specific pAbs succumbed. Similarly, interferon receptor 1 knockout (IFNAR(-/-)) mice receiving the purified IgG (100 mg/kg) by IP injection one day after IP challenge with wild type SUDV resulted in 89% survival. These results are the first to demonstrate that filovirus GP DNA vaccines administered to TcBs by IM-EP can elicit neutralizing antibodies that provide post-exposure protection. Additionally, these data describe production of fully human IgG in a large animal system, a system which is capable of producing large quantities of a clinical grade therapeutic product. PMID- 26422249 TI - Design and Development of Micro-Power Generating Device for Biomedical Applications of Lab-on-a-Disc. AB - The development of micro-power generators for centrifugal microfluidic discs enhances the platform as a green point-of-care diagnostic system and eliminates the need for attaching external peripherals to the disc. In this work, we present micro-power generators that harvest energy from the disc's rotational movement to power biomedical applications on the disc. To implement these ideas, we developed two types of micro-power generators using piezoelectric films and an electromagnetic induction system. The piezoelectric-based generator takes advantage of the film's vibration during the disc's rotational motion, whereas the electromagnetic induction-based generator operates on the principle of current generation in stacks of coil exposed to varying magnetic flux. We have successfully demonstrated that at the spinning speed of 800 revolutions per minute (RPM) the piezoelectric film-based generator is able to produce up to 24 microwatts using 6 sets of films and the magnetic induction-based generator is capable of producing up to 125 milliwatts using 6 stacks of coil. As a proof of concept, a custom made localized heating system was constructed to test the capability of the magnetic induction-based generator. The heating system was able to achieve a temperature of 58.62 degrees C at 2200 RPM. This development of lab on-a-disc micro power generators preserves the portability standards and enhances the future biomedical applications of centrifugal microfluidic platforms. PMID- 26422250 TI - The Role of beta-Catenin in Bcr/Abl Negative Myeloproliferative Neoplasms: An Immunohistochemical Study. AB - INTRODUCTION: beta-Catenin is a multifunctional protein that acts as a central effector molecule in the Wnt signaling pathway. Aberrant activation of the Wnt/beta-catenin signaling pathway causes various diseases including cancer. In this study we evaluated beta-catenin expression in bcr/abl-negative myeloproliferative neoplasms (MPNs). MATERIALS AND METHODS: The expression of beta-catenin was evaluated in bone marrow using immunohistochemical methods in 66 patients with bcr/abl-negative myeloproliferative neoplasms (MPNs) and in 30 healthy control subjects. Immunreactive score (IRS; staining intensity * percentage of positive stained cells) was used for the evaluation of the cell staining reaction. RESULTS: IRS of megakaryocytes (IRSmega) was higher in essential thrombocytemia (ET) compared with the control group (P = .022) and primary myelofibrosis (PMF; P = .001). IRS of vascular endothelial cells (IRSvas) was higher in the bcr/abl negative MPN compared with the control group (P = .024). Also, IRSvas was higher in the PMF compared with the control group (P = .001), policythemia vera (PV; P = .005), and ET (P = .006). A positive correlation was detected between IRSmega and platelet counts (P = .019). CONCLUSION: Results of this study suggest that the Wnt/beta-catenin signaling pathway has a role in the angiogenesis of PMF and in the thrombopoiesis of PV and ET. Hence, targeting the Wnt/beta-catenin signaling pathway could open new avenues for novel therapeutic approaches in bcr/abl-negative MPNs. PMID- 26422251 TI - Impact of Alemtuzumab Therapy and Route of Administration in T-Prolymphocytic Leukemia: A Single-Center Experience. AB - OBJECTIVE: We conducted a single-center retrospective analysis to determine the impact of the anti-CD52 monoclonal antibody alemtuzumab including route of administration compared to non-alemtuzumab-containing regimens in T prolymphocytic leukemia (T-PLL). PATIENTS AND METHODS: The study was a retrospective analysis of a consecutive cohort of adult patients diagnosed with T PLL at Mayo Clinic Rochester from January 1, 1997, through September 30, 2014. RESULTS: A total of 41 patients were diagnosed with T-PLL per the World Health Organization 2008 classification. The median age was 66 years, and 23 (56%) were male. After a median follow-up of 18 months (range, 0.4-66.1 months), 32 patients (78%) had died, with a median overall survival of 16.9 months. Approximately half the cohort was treated with alemtuzumab, almost exclusively after 2004. Median survival for patients receiving intravenous alemtuzumab-based therapy was 40.5 versus 10.3 months for all other therapies (P = .0004). A significant survival difference between intravenous versus subcutaneous alemtuzumab administration of 40.5 versus 13.7 months was noted (P = .0014). Only 4 (14%) of 28 patients aged < 70 years underwent hematopoietic stem cell transplantation, with a median survival after transplantation of 4 months. CONCLUSION: In this large series of T PLL patients treated at a single tertiary-care center, we confirmed the prior observation of the superiority of intravenous alemtuzumab over other therapies. Hematopoietic stem cell transplantation was feasible in a minority of potentially eligible patients. Early transplant referral should be considered for all eligible patients. PMID- 26422253 TI - Unclassified bleeding disorders: outcome of haemostatic challenges following tranexamic acid and/or desmopressin. AB - INTRODUCTION: In a minority of patients with a significant bleeding history no cause is found despite extensive testing and we diagnose such cases as unclassified bleeding disorders (UBD). UBDs may have diverse underlying causes and currently no standard management strategy exists in the event of a haemorrhage or to cover surgery. AIM: To document the clinical characteristics and response to treatment of UBDs. METHODS: We performed a retrospective chart review of all patients with UBDs who had an invasive procedure at our centre between 1998 and 2014. RESULTS: The commonest symptoms were menorrhagia (89%) and bleeding at the time of surgery (88%) or dental extraction (85%). A total of 33 patients underwent 78 minor and major haemostatic challenges. Haemostatic cover was provided in 28 procedures with tranexamic acid alone, two with desmopressin and 45 with both agents in combination. A successful haemostatic outcome was observed in 70/78 (90%) cases. No patient required additional surgical intervention to achieve haemostasis, but one patient required a platelet transfusion to control postoperative bleeding. CONCLUSIONS: This is the first study to report on the investigation and treatment of UBD. Future studies are needed to further our understanding of the bleeding phenotype and identify any underlying causes. PMID- 26422252 TI - Treatment of Patients With Myelodysplastic Syndrome With Lenalidomide in Clinical Routine in Austria. AB - BACKGROUND: Lenalidomide has demonstrated remarkable efficacy for therapy of lower-risk myelodysplastic syndromes (MDS) associated with 5q(-). The present evaluation aimed to describe the characteristics and outcomes of low-risk MDS patients treated with lenalidomide in Austria. PATIENTS AND METHODS: For this retrospective, multicenter, observational analysis of MDS patients who received lenalidomide, data were collected at various hospitals in Austria over a period of 3 years. MDS classification, previous and current MDS therapies, and outcome and safety of lenalidomide were evaluated. RESULTS: Forty-six percent of the patients (n = 23) had a 5q(-) syndrome, while 12% (n = 6) exhibited 5q(-) plus additional aberrations or isolated 5q(-) but >= 5% blasts in the bone marrow (10%, n = 5). The remaining 32% of patients (n = 16) had MDS with other World Health Organization classifications. Seventy percent belonged to lower International Prognostic Scoring System risk classes. Sixteen centers participated, involving a total of 50 patients. Most frequently used lenalidomide doses were 10 mg and 5 mg on days 1 to 21 of a 28-day cycle. Seventy-five percent of the patients received 11 months of treatment, with a median therapy period of 3.5 months; median follow-up was 3.9 months (range, 0-26 months). Response rate, defined as transfusion independence during the 2 months after lenalidomide therapy, was 64%. Median overall survival was not reached. CONCLUSION: Lenalidomide was well tolerated and is an effective and well-tolerated option for therapy of patients with 5q(-) syndrome but also lower-risk MDS patients with other World Health Organization classifications in clinical practice. PMID- 26422255 TI - Dependency of Phytoprostane Fingerprints of Must and Wine on Viticulture and Enological Processes. AB - Wine is one of the most consumed alcoholic beverages around the world. Red wine has demonstrated several benefits for health maintenance. One group of potential anti-inflammatory compounds is the phytoprostanes, oxidative degradation products of linolenic acid. The aim of the present study was to measure, for the first time, the phytoprostane content in wine and must by an UHPLC-QqQ-MS/MS method after solid-phase extraction. The data showed two predominant classes of phytoprostanes: F1- and D1-phytoprostane series. In wines, the total phytoprostane concentration ranged from 134.1 +/- 2.3 to 216.2 +/- 3.06 ng/mL. Musts showed concentrations between 21.4 +/- 0.8 and 447.1 +/- 15.8 ng/mL. The vinification and aging procedures for the production of wine seem to influence the final phytoprostane levels in red wine and to modify the phytoprostane profile. The high concentrations observed and previous reports on anti inflammatory effects of phytoprostanes make further research on the benefits of phytoprostanes more important. PMID- 26422254 TI - Hemorrhage Exacerbates Radiation Effects on Survival, Leukocytopenia, Thrombopenia, Erythropenia, Bone Marrow Cell Depletion and Hematopoiesis, and Inflammation-Associated microRNAs Expression in Kidney. AB - Exposure to high-dose radiation results in detrimental effects on survival. The effects of combined trauma, such as radiation in combination with hemorrhage, the typical injury of victims exposed to a radiation blast, on survival and hematopoietic effects have yet to be understood. The purpose of this study was to evaluate the effects of radiation injury (RI) combined with hemorrhage (i.e., combined injury, CI) on survival and hematopoietic effects, and to investigate whether hemorrhage (Hemo) enhanced RI-induced mortality and hematopoietic syndrome. Male CD2F1 mice (10 weeks old) were given one single exposure of gamma- radiation (60Co) at various doses (0.6 Gy/min). Within 2 hr after RI, animals under anesthesia were bled 0% (Sham) or 20% (Hemo) of total blood volume via the submandibular vein. In these mice, Hemo reduced the LD50/30 for 30-day survival from 9.1 Gy (RI) to 8.75 Gy (CI) with a DMF of 1.046. RI resulted in leukocytopenia, thrombopenia, erythropenia, and bone marrow cell depletion, but decreased the caspase-3 activation response. RI increased IL-1beta, IL-6, IL-17A, and TNF-alpha concentrations in serum, bone marrow, ileum, spleen, and kidney. Some of these adverse alterations were magnified by CI. Erythropoietin production was increased in kidney and blood more after CI than RI. Furthermore, CI altered the global miRNAs expression in kidney and the ingenuity pathway analysis showed that miRNAs viz., let-7e, miR-30e and miR-29b that were associated with hematopoiesis and inflammation. This study provides preliminary evidence that non lethal Hemo exacerbates RI-induced mortality and cell losses associated with high dose gamma-radiation. We identified some of the initial changes occurring due to CI which may have facilitated in worsening the injury and hampering the recovery of animals ultimately resulting in higher mortality. PMID- 26422256 TI - RF inhomogeneity and how it controls CPMAS. AB - In this report we discuss the effect of radiofrequency field (RF) inhomogeneity on cross-polarization (CP) under magic-angle spinning (MAS) by reviewing the dependence of the CP-detected signal intensity as a function of the position in the sample space. We introduce a power-function model to quantify the position dependent RF-amplitude profile. The applicability of this model is experimentally verified by nutation spectra obtained by direct signal detection, as well as by CPMAS signal detection, in two commercial MAS probes with different degrees of RF inhomogeneity. A conclusion is that substantial sections of a totally filled rotor, even in a probe with rather good homogeneity, do not contribute at all to the detected spectra. The consequence is that in CPMAS-based recoupling experiments, such as the CP-with-variable-contact-time (CPVC), spatial selectivity of the Hartmann-Hahn matching condition overcomes complications that could be caused by RF inhomogeneity permitting determination of accurate spectral parameters even in cases with high inhomogeneity. PMID- 26422257 TI - Methionine bound to Pd/gamma-Al2O3 catalysts studied by solid-state (13)C NMR. AB - The chemisorption and breakdown of methionine (Met) adsorbed on Pd/gamma-Al2O3 catalysts were investigated by solid-state NMR. (13)C-enriched Met (ca. 0.4mg) impregnated onto gamma-Al2O3 or Pd/gamma-Al2O3 gives NMR spectra with characteristic features of binding to gamma-Al2O3, to Pd nanoparticles, and oxidative or reductive breakdown of Met. The SCH3 groups of Met showed characteristic changes in chemical shift on gamma-Al2O3 (13ppm) vs. Pd (19ppm), providing strong evidence for preferential binding to Pd, while the NC carbon generates a small resonance at 96ppm assigned to a distinct nonprotonated species bound to O or Pd. Additionally, NMR shows that the SCH3 groups of Met are mobile on gamma-Al2O3 but immobilized by binding to Pd particles; on small Pd particles (ca. 4nm), the NCH groups undergo large-amplitude motions. In a reducing environment, Met breaks down by C-S bond cleavage followed by formation of C2-C4 organic acids. The SCH3 signal shifts to 22ppm, which is likely the signature of the principal species responsible for strong catalyst inhibition. These experiments demonstrate that solid-state magic-angle spinning NMR of (13)C enriched Met can be a sensitive probe to investigate catalyst surfaces and characterize catalyst inhibition both before reaction and postmortem. PMID- 26422258 TI - Oseltamivir Resistance in Influenza A(H6N2) Caused by an R292K Substitution in Neuraminidase Is Not Maintained in Mallards without Drug Pressure. AB - BACKGROUND: Wild waterfowl is the natural reservoir of influenza A virus (IAV); hosted viruses are very variable and provide a source for genetic segments which can reassort with poultry or mammalian adapted IAVs to generate novel species crossing viruses. Additionally, wild waterfowl act as a reservoir for highly pathogenic IAVs. Exposure of wild birds to the antiviral drug oseltamivir may occur in the environment as its active metabolite can be released from sewage treatment plants to river water. Resistance to oseltamivir, or to other neuraminidase inhibitors (NAIs), in IAVs of wild waterfowl has not been extensively studied. AIM AND METHODS: In a previous in vivo Mallard experiment, an influenza A(H6N2) virus developed oseltamivir resistance by the R292K substitution in the neuraminidase (NA), when the birds were exposed to oseltamivir. In this study we tested if the resistance could be maintained in Mallards without drug exposure. Three variants of resistant H6N2/R292K virus were each propagated during 17 days in five successive pairs of naive Mallards, while oseltamivir exposure was decreased and removed. Daily fecal samples were analyzed for viral presence, genotype and phenotype. RESULTS AND CONCLUSION: Within three days without drug exposure no resistant viruses could be detected by NA sequencing, which was confirmed by functional NAI sensitivity testing. We conclude that this resistant N2 virus could not compete in fitness with wild type subpopulations without oseltamivir drug pressure, and thus has no potential to circulate among wild birds. The results of this study contrast to previous observations of drug induced resistance in an avian H1N1 virus, which was maintained also without drug exposure in Mallards. Experimental observations on persistence of NAI resistance in avian IAVs resemble NAI resistance seen in human IAVs, in which resistant N2 subtypes do not circulate, while N1 subtypes with permissive mutations can circulate without drug pressure. We speculate that the phylogenetic group N1 NAs may easier compensate for NAI resistance than group N2 NAs, though further studies are needed to confirm such conclusions. PMID- 26422259 TI - The Cost-Effectiveness of Emergency Hormonal Contraception with Ulipristal Acetate versus Levonorgestrel for Minors in France. AB - OBJECTIVE: To evaluate the cost-effectiveness of ulipristal acetate and levonorgestrel in minors in France, and analyze whether it is worthwhile to provide ulipristal acetate to minors free of charge. METHODS: The cost effectiveness of two emergency contraceptive methods was compared based on a decision-analytical model. Pregnancy rates, outcomes of unintended pregnancies, and resource utilization were derived from the literature. Resources and their costs were considered until termination or a few days after delivery. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: The cost of an unintended pregnancy in a French minor is estimated to be 1,630 ? (range 1,330 ? - 1,803 ?). Almost 4 million ? (3.1 ? - 13.7 ? million) in unintended pregnancy spending in 2010 could have been saved by the use of ulipristal acetate instead of levonorgestrel. The incremental cost of ulipristal acetate compared to levonorgestrel is 3.30 ? per intake, or 418 ? per pregnancy avoided (intake within 72 hours). In the intake within 24 hours subgroup, ulipristal acetate was found to be more efficacious at a lower cost compared to levonorgestrel. CONCLUSIONS: Ulipristal acetate dominates levonorgestrel when taken within 24 hours after unprotected intercourse, i.e., it is more effective at a lower cost. When taken within 72 hours, ulipristal acetate is a cost- effective alternative to levonorgestrel, given that the cost of avoiding an additional pregnancy with ulipristal acetate is less than the average cost of these pregnancies. In the light of these findings, it is worthwhile to provide free access to minors. PMID- 26422261 TI - Modeling conformational redox-switch modulation of human succinic semialdehyde dehydrogenase. AB - Succinic semialdehyde dehydrogenase (SSADH) converts succinic semialdehyde (SSA) to succinic acid in the mitochondrial matrix and is involved in the metabolism of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The molecular structure of human SSADH revealed the intrinsic regulatory mechanism--redox switch modulation--by which large conformational changes are brought about in the catalytic loop through disulfide bonding. The crystal structures revealed two SSADH conformations, and computational modeling of transformation between them can provide substantial insights into detailed dynamic redox modulation. On the basis of these two clear crystal structures, we modeled the conformational motion between these structures in silico. For that purpose, we proposed and used a geometry-based coarse-grained mathematical model of long-range protein motion and the related modeling algorithm. The algorithm is based on solving the special optimization problem, which is similar to the classical Monge-Kantorovich mass transportation problem. The modeled transformation was supported by another morphing method based on a completely different framework. The result of the modeling facilitates better interpretation and understanding of the SSADH biological role. PMID- 26422260 TI - Bird Richness and Abundance in Response to Urban Form in a Latin American City: Valdivia, Chile as a Case Study. AB - There is mounting evidence that urban areas influence biodiversity. Generalizations however require that multiple urban areas on multiple continents be examined. Here we evaluated the role of urban areas on avian diversity for a South American city, allowing us to examine the effects of urban features common worldwide, using the city of Valdivia, Chile as case study. We assessed the number of birds and their relative abundance in 152 grid cells of equal size (250 m2) distributed across the city. We estimated nine independent variables: land cover diversity (DC), building density (BD), impervious surface (IS),municipal green space (MG),non-municipal green space (NG), domestic garden space (DG), distance to the periphery (DP), social welfare index (SW), and vegetation diversity (RV). Impervious surface represent 41.8% of the study area, while municipal green, non-municipal green and domestic garden represent 11.6%, 23.6% and 16% of the non- man made surface. Exotic vegetation species represent 74.6% of the total species identified across the city. We found 32 bird species, all native with the exception of House Sparrow and Rock Pigeon. The most common species were House Sparrow and Chilean Swallow. Total bird richness responds negatively to IS and MG, while native bird richness responds positively to NG and negatively to BD, IS DG and, RV. Total abundance increase in areas with higher values of DC and BD, and decrease in areas of higher values of IS, SW and VR. Native bird abundance responds positively to NG and negatively to BD, IS MG, DG and RV. Our results suggest that not all the general patterns described in previous studies, conducted mainly in the USA, Europe, and Australia, can be applied to Latin American cities, having important implications for urban planning. Conservation efforts should focus on non-municipal areas, which harbor higher bird diversity, while municipal green areas need to be improved to include elements that can enhance habitat quality for birds and other species. These findings are relevant for urban planning in where both types of green space need to be considered, especially non-municipal green areas, which includes wetlands, today critically threatened by urban development. PMID- 26422262 TI - Using Multitouch Collaboration Technology to Enhance Social Interaction of Children with High-Functioning Autism. AB - AIMS: Children with high-functioning Autism Spectrum Disorder (HFASD) have major difficulties in social communication skills, which may impact their performance and participation in everyday life. The goal of this study was to examine whether the StoryTable, an intervention paradigm based on a collaborative narrative, multitouch tabletop interface, enhanced social interaction for children with HFASD, and to determine whether the acquired abilities were transferred to behaviors during other tasks. METHODS: Fourteen boys with HFASD, aged 7-12 years, participated in a 3-week, 11-session intervention. Social interactions during two nonintervention tasks were videotaped at three points in time, one prior to the intervention (pre), a second immediately following the intervention (post) and a third three weeks after the intervention (follow-up). The video-recorded files were coded using the Friendship Observation Scale to ascertain the frequencies of positive and negative social interactions and collaborative play. Differences in these behaviors were tested for significance using nonparametric statistical tests. RESULTS: There were significantly higher rates of positive social interactions and collaborative play, and lower rates of negative social interactions following the intervention suggesting generalization of the social skills learned during the intervention. Improvement was maintained when tested three weeks later. CONCLUSION: These findings provide support for the use of collaborative technology-based interventions within educational settings to enhance social interaction of children with HFASD. PMID- 26422263 TI - A Content Analysis of Organ Donation Stories Printed in U.S. Newspapers: Application of Newsworthiness. AB - The current study applied a theory of newsworthiness to the topic of organ donation. Specifically, content analysis of newspaper stories published in the United States (N = 1,988) was performed to identify whether deviance and significance of a story predicted story prominence, measured as story length and placement in the newspaper. Results indicated support for study hypotheses: Longer stories and front-page stories pertaining to organ donation were more deviant and more significant in content. Analyses also indicated stories more negative in nature were more likely given front-page coverage, represented international events, and were high on deviance and significance. Higher circulating newspapers were more likely to publish stories recounting negative events in organ donation. Results indicated organ donation coverage represents a valid application of newsworthiness theory, and implications of study findings are discussed in relation to the agenda-setting function of news stories. PMID- 26422264 TI - Aqueous Emulsion Droplets Stabilized by Lipid Vesicles as Microcompartments for Biomimetic Mineralization. AB - Mineral deposition within living cells relies on control over the distribution and availability of precursors as well as the location and rates of nucleation and growth. This control is provided in large part by biomolecular chelators, which bind precursors and regulate their availability, and compartmentalization within specialized mineralizing vesicles. Biomimetic mineralization in self assembled lipid vesicles is an attractive means of studying the mineralization process, but has proven challenging due to vesicle heterogeneity in lamellarity, contents, and size across a population, difficulties encapsulating high and uniform precursor concentrations, and the need to transport reagents across an intact lipid bilayer membrane. Here, we report the use of liposome-stabilized all aqueous emulsion droplets as simple artificial mineralizing vesicles (AMVs). These biomimetic microreactors allow the entry of precursors while retaining a protein catalyst by equilibrium partitioning between internal and external polymer-rich phases. Small molecule chelators with intermediate binding affinity were employed to control Ca(2+) availability during CaCO3 mineralization, providing protection against liposome aggregation while allowing CaCO3 formation. Mineral deposition was limited to the AMV interior, due to localized production of CO3(2-) by compartmentalized urease. Particle formation was uniform across the entire population of AMVs, with multiple submicrometer amorphous CaCO3 particles produced in each one. The all-aqueous emulsion-based approach to biomimetic giant mineral deposition vesicles introduced here should be adaptable for enzyme catalyzed synthesis of a wide variety of materials, by varying the metal ion, enzyme, and/or chelator. PMID- 26422265 TI - Kinetics and Thermodynamics of Reserpine Adsorption onto Strong Acidic Cationic Exchange Fiber. AB - The kinetics and thermodynamics of the adsorption process of reserpine adsorbed onto the strong acidic cationic exchange fiber (SACEF) were studied by batch adsorption experiments. The adsorption capacity strongly depended on pH values, and the optimum reserpine adsorption onto the SACEF occurred at pH = 5 of reserpine solution. With the increase of temperature and initial concentration, the adsorption capacity increased. The equilibrium was attained within 20 mins. The adsorption process could be better described by the pseudo-second-order model and the Freundlich isotherm model. The calculated activation energy Ea was 4.35 kJ/mol. And the thermodynamic parameters were: 4.97=1000 ng/mL). The prevalence of iron overload in subjects with a history of allogeneic HSCT was 25.9% (95% CI, 9.4%-42.5%) compared with only 3.7% (95% CI, 0%-10.8%) in subjects treated without HSCT and 0% in subjects treated with autologous HSCT. No association was found between serum ferritin levels and the presence of cardiac, liver, or endocrine dysfunction. The prevalence of iron overload in subjects who received no HSCT or autologous HSCT is low in our study. A higher prevalence was found in patients receiving allogeneic HSCT, reiterating the importance of screening these patients for iron overload in accordance with the current Children's Oncology Group Long Term Follow-Up Guidelines. PMID- 26422287 TI - Hypothalamic Glioma in a Patient With Sturge-Weber Syndrome. AB - Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by vascular malformations involving brain, skin, and occasionally eyes. There is no recognized tumor predisposition in patients with SWS as there is with some other phakomatoses. We present a patient with SWS who developed a low-grade glioma (LGG). We hypothesize that there could be an association between SWS and LGG formation, noting that GNAQ mutations have been implicated in the underlying biology of both SWS and a subset of pediatric LGG. It is suggested that SWS may be a cancer predisposition syndrome. PMID- 26422288 TI - Pulmonary Functions in Children With Thalassemia Major. AB - BACKGROUND: Thalassemia major (TM) is a chronic disease requiring regular transfusions that may result in generalized iron loading, such as in the heart, the liver, endocrine organs, and the lungs. We aimed to determine pulmonary function abnormalities in children with TM in our center. PATIENTS AND METHODS: In this study, pulmonary function tests (PFTs) of 49 patients with TM who received regular blood transfusion and had no history of chronic respiratory disease were evaluated. The relationship between PFTs and the age, the body surface area, pretransfusional hemoglobin, and serum ferritin was evaluated. RESULTS: Among the beta-TM patients included in this study, 61% were male and 39% were female, with a mean age of 10.8+/-3 years (range, 5 to 17 y). The patients' mean level of ferritin was 3873+/-2011 ng/dL (range, 676 to 9476 ng/dL). A reduced forced vital capacity (FVC) was found in 33 patients (67%). A reduced forced expiratory volume in 1 second (FEV1) was found in 15 patients (30%). A forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) ratio of >80% was found in all patients. The peak expiratory flow (PEF) was decreased in 23 patients (46.9%). The forced mid-expiratory flow between 25% and 75% of the exhaled vital capacity (MEF25%-75%) was decreased in 5 patients (10%). FVC and FEV1 values in patients with a high ferritin level (>2500 ng/dL) were decreased compared with patients with a low ferritin level (<2500 ng/dL) (P=0.04, 0.03). FVC, FEV1, and PEF parameters were negatively correlated with the age and the body surface area. Age was a predictor of FVC (beta=-0.450, P<0.001), FEV1 (beta= 0.419, P<0.001), and PEF (beta=-0.505, P<0.001), and hemoglobin was a predictor of FEV1/FVC (beta=0.366, P=0.01) and MEF25%-75% (beta=0.323, P=0.003). CONCLUSIONS: Our results concluded that the respiratory system should be evaluated by PFTs even in asymptomatic patients with high serum ferritin levels during the adolescent period annually to prevent the squeal of pulmonary disease in TM. Patients who have abnormal PFTs should be reevaluated for compliance with chelation therapy and the transfusion program. PMID- 26422289 TI - A Practitioner's Guide to Electronic Cigarettes in the Adolescent Population. AB - We present guidance on electronic nicotine delivery systems (ENDS) for health care professionals who care for adolescents. ENDS provide users with inhaled nicotine in an aerosolized mist. Popular forms of ENDS include e-cigarettes and vape-pens. ENDS range in disposability, customization, and price. Growth of ENDS usage has been particularly rapid in the adolescent population, surpassing that of conventional cigarettes in 2014. Despite surging use throughout the United States, little is known about the health risks posed by ENDS, especially in the vulnerable adolescent population. These products may potentiate nicotine addiction in adolescents and have been found to contain potentially harmful chemicals. The growth in these products may be driven by relaxed purchasing restrictions for minors, lack of advertising regulations, and youth friendly flavors. Taken together, ENDS represent a new and growing health risk to the adolescent population, one that health care professionals should address with their patients. We suggest a patient centered strategy to incorporate ENDS use into routine substance counseling. PMID- 26422290 TI - Avoidant/Restrictive Food Intake Disorder: Illness and Hospital Course in Patients Hospitalized for Nutritional Insufficiency. AB - PURPOSE: Avoidant/restrictive food intake disorder (ARFID), a recently defined Diagnostic and Statistical Manual of Mental Disorders-5 eating disorder diagnosis, has not been extensively studied in the inpatient population. This study compares hospitalized ARFID and anorexia nervosa (AN) patients, including differences in presentation, treatment response, and 1-year outcomes. METHODS: We conducted a retrospective chart review of ARFID and AN patients hospitalized between 2008 and 2014 for acute medical stabilization at an academic medical center. Data, including characteristics on admission, during hospitalization, and 1 year after discharge, were recorded for each patient and compared between ARFID and AN patients. RESULTS: On presentation, ARFID patients (n = 41) were younger with fewer traditional eating disorder behaviors and less weight loss, comorbidity, and bradycardia than AN patients (n = 203). During hospitalization, although ARFID and AN patients had similar caloric intake, ARFID patients relied on more enteral nutrition and required longer hospitalizations than AN patients (8 vs. 5 days; p = .0006). One year after discharge, around half of ARFID and AN patients met criteria for remission (62% vs. 46%; p = .18), and less than one quarter required readmission (21% vs. 24%; p = .65). CONCLUSIONS: The findings from this study reveal several differences in hospitalized eating disorder patients and emphasize the need for further research on ARFID patients, including research on markers of illness severity and optimal approaches to refeeding. Similar remission and readmission rates among ARFID and AN patients highlight both the success and the continued need for improvement in eating disorder treatment regardless of diagnosis. PMID- 26422292 TI - Magnetic resonance imaging of the small bowel in Crohn disease: A systematic review and meta-analysis. PMID- 26422291 TI - Somatic p.T771R KDR (VEGFR2) Mutation Arising in a Sporadic Angioma During Ramucirumab Therapy. AB - IMPORTANCE: Inhibition of angiogenesis is an effective anticancer strategy because neoplasms require a rich blood supply. Ramucirumab, approved by the US Food and Drug Administration in 2014 to treat gastric adenocarcinomas and non small cell lung carcinomas, targets vascular endothelial growth factor 2 (VEGFR2). We identified a patient prescribed a regimen of irinotecan hydrochloride, cetuximab, and ramucirumab for metastatic rectal cancer (diagnosed in November 2013 and treated through early January 2015) who developed a new onset, expanding vascular lesion on his right leg. Via exome sequencing, we found that the lesion contained a single somatic mutation in KDR (encodes VEGFR2), possibly in response to ramucirumab. Vascular tumors are not a known complication of antiangiogenic therapeutics. OBSERVATIONS: Exome sequencing of the well demarcated, blanching vascular lesion on the lateral right shin revealed a somatic p.T771R mutation in KDR, without evidence of other somatic mutations or loss of heterozygosity. Histological features included lobules of small vessels within the dermis, resembling a tufted angioma. CONCLUSIONS AND RELEVANCE: A potential adverse effect of ramucirumab in combination therapy is the development of sporadic angiomas. The p.T771R mutation was previously implicated in autophosphorylation of VEGFR2 and reported in angiosarcomas alongside other driver mutations. Our observations suggest that this mutation confers a proliferative advantage in the setting of ramucirumab therapy. Patients receiving ramucirumab should be monitored for the development of new vascular lesions. PMID- 26422293 TI - Celiac disease and gluten-free oats: A Canadian position based on a literature review. PMID- 26422294 TI - Development Trends in Porous Adsorbents for Carbon Capture. AB - Accumulation of greenhouse gases especially CO2 in the atmosphere leading to global warming with undesirable climate changes has been a serious global concern. Major power generation in the world is from coal based power plants. Carbon capture through pre- and post- combustion technologies with various technical options like adsorption, absorption, membrane separations, and chemical looping combustion with and without oxygen uncoupling have received considerable attention of researchers, environmentalists and the stake holders. Carbon capture from flue gases can be achieved with micro and meso porous adsorbents. This review covers carbonaceous (organic and metal organic frameworks) and noncarbonaceous (inorganic) porous adsorbents for CO2 adsorption at different process conditions and pore sizes. Focus is also given to noncarbonaceous micro and meso porous adsorbents in chemical looping combustion involving insitu CO2 capture at high temperature (>400 degrees C). Adsorption mechanisms, material characteristics, and synthesis methods are discussed. Attention is given to isosteric heats and characterization techniques. The options to enhance the techno-economic viability of carbon capture techniques by integrating with CO2 utilization to produce industrially important chemicals like ammonia and urea are analyzed. From the reader's perspective, for different classes of materials, each section has been summarized in the form of tables or figures to get a quick glance of the developments. PMID- 26422295 TI - The Effect of Tissue Entrapment on Screw Loosening at the Implant/Abutment Interface of External- and Internal-Connection Implants: An In Vitro Study. AB - PURPOSE: To compare the removal of torque values of machined implant abutment connections (internal and external) with and without soft tissue entrapment using an in vitro model. MATERIALS AND METHODS: Thirty external- and 30 internal connection implants were embedded in urethane dimethacrylate. Porcine tissue was prepared and measured to thicknesses of 0.5 and 1.0 mm. Six groups (n = 10) were studied: External- and internal-connection implants with no tissue (control), 0.5, and 1.0 mm of tissue were entrapped at the implant/abutment interface. Abutments were inserted to 20 Ncm for all six groups. Insertion torque values were recorded using a digital torque gauge. All groups were then immersed in 1 M NaOH for 48 hours to dissolve tissue. Subsequent reverse torque measurements were recorded. Mean and standard deviation were determined for each group, and one-way ANOVA and Bonferroni test were used for statistical analysis. RESULTS: All 60 specimens achieved a 20-Ncm insertion torque, despite tissue entrapment. Reverse torque measurements for external connection displayed a statistically significant difference (p < 0.05) between all groups with mean reverse torque values for the control (13.71 +/- 1.4 Ncm), 0.5 mm (7.83 +/- 2.4 Ncm), and 1.0 mm tissue entrapment (2.29 +/- 1.4 Ncm) groups. Some statistically significant differences (p < 0.05) were found between internal-connection groups. In all specimens, tissue did not completely dissolve after 48 hours. CONCLUSIONS: External connection implants were significantly affected by tissue entrapment; the thicker the tissue, the lower the reverse torque values noted. Internal-connection implants were less affected by tissue entrapment. PMID- 26422296 TI - Highly Improved Efficiency of Deep-Blue Fluorescent Polymer Light-Emitting Device Based on a Novel Hole Interface Modifier with 1,3,5-Triazine Core. AB - We present an investigation of deep-blue fluorescent polymer light-emitting diodes (PLEDs) with a novel functional 1,3,5-triazine core material (HQTZ) sandwiched between poly(3,4-ethylene dioxythiophene):poly(styrene sulfonic acid) layer and poly(vinylcarbazole) layer as a hole injection layer (HIL) without interface intermixing. Ultraviolet photoemission spectroscopy and Kelvin probe measurements were carried out to determine the change of anode work function influenced by the HQTZ modifier. The thin HQTZ layer can efficiently maximize the charge injection from anode to blue emitter and simultaneously enhance the hole mobility of HILs. The deep-blue device performance is remarkably improved with the maximum luminous efficiency of 4.50 cd/A enhanced by 80% and the maximum quantum efficiency of 4.93%, which is 1.8-fold higher than that of the conventional device without HQTZ layer, including a lower turn-on voltage of 3.7 V and comparable Commission Internationale de L'Eclairage coordinates of (0.16, 0.09). It is the highest efficiency ever reported to date for solution-processed deep-blue PLEDs based on the device structure of ITO/HILs/poly(9,9-dialkoxyphenyl 2,7-silafluorene)/CsF/AL. The results indicate that HQTZ based on 1,3,5-triazine core can be a promising candidate of interfacial materials for deep-blue fluorescent PLEDs. PMID- 26422297 TI - Postsynthetic conjugation of RNA to carboxylate and dicarboxylate molecules. AB - Carboxylates and dicarboxylates are important phosphate mimics. Herein, we present a simple synthetic route for the preparation of RNA carboxylate/dicarboxylate conjugates, starting from suitably protected NH2- and COOH-containing molecules that are coupled to the RNA on the solid support. The key point in our method was the use of trimethylsilylethanol (TMSE-OH) protecting group, which is removed simultaneously with the silyl protecting group on the 2' OH of the RNA ribose (e.g. t-Butyldimethylsilyl) during the final RNA cleavage/deprotection steps. The usefulness of this method was demonstrated by preparing different RNA-phosphate mimics oligos. PMID- 26422299 TI - Paroxysmal nocturnal hemoglobinuria and hematopoietic stem cell transplantation: Better results in 2015? PMID- 26422298 TI - A quantitative benefit-risk assessment approach to improve decision making in drug development: Application of a multicriteria decision analysis model in the development of combination therapy for overactive bladder. AB - A multicriteria decision analysis (MCDA) approach was developed and used to estimate the benefit-risk of solifenacin and mirabegron and their combination in the treatment of overactive bladder (OAB). The objectives were 1) to develop an MCDA tool to compare drug effects in OAB quantitatively, 2) to establish transparency in the evaluation of the benefit-risk profile of various dose combinations, and 3) to quantify the added value of combination use compared to monotherapies. The MCDA model was developed using efficacy, safety, and tolerability attributes and the results of a phase II factorial design combination study were evaluated. Combinations of solifenacin 5 mg and mirabegron 25 mg and mirabegron 50 (5+25 and 5+50) scored the highest clinical utility and supported combination therapy development of solifenacin and mirabegron for phase III clinical development at these dose regimens. This case study underlines the benefit of using a quantitative approach in clinical drug development programs. PMID- 26422300 TI - Usefulness of scheduled follow-up CT in discharged patients with acute pancreatitis. AB - BACKGROUND AND AIM: Follow-up computed tomography (CT) in patients with acute pancreatitis has been advocated but rarely studied. The aim of this study was to determine whether follow-up CT for acute pancreatitis might be helpful in establishing the prognosis or complications, and in determining a selected subgroup of patients for whom computed tomography could be beneficial. METHODS: Between January 2010 and December 2012, patients with acute pancreatitis who underwent follow-up CT in the outpatient department between one and three months after discharge were retrospectively enrolled. Events discovered on follow-up CT were defined as newly developed or increased pancreatic collection such as pseudocyst or walled off necrosis, and diagnosis of pancreatic cancer. RESULTS: Ultimately, 106 asymptomatic patients were enrolled (mean age 50.24 +/- 16, 74.5% male, 31.1% moderately severe and severe acute pancreatitis). The median duration of follow-up CT was 69 (31-90) days. On follow-up CT, 23 patients showed events (2 pancreatic cancer, 21 increasing or developed pancreatic collections). In multivariate analysis, the predictive factors for events on follow-up CT were CTSI >=3 (OR 4.46, CI 1.08-18.43, p = 0.039) and BISAP >= 2 (OR 4.83, CI 1.08 21.55, p = 0.039). CONCLUSIONS: Follow-up CT within three months after discharge may be helpful for acute pancreatitis patients with CTSI >= 3 points or BISAP score >= 2 points. PMID- 26422302 TI - Direct electrokinetic injection of inorganic cations from whole fruits and vegetables for capillary electrophoresis analysis. AB - A novel approach for the direct injection from plant tissues without any sample pre-treatment has been developed by simply placing a small piece of the tissue into a capillary electrophoresis vial followed by application of a voltage for electrokinetic injection. Separations of sodium, potassium, calcium and magnesium were achieved using a BGE comprising 10mM imidazole and 2.5mM 18-crown-6-ether at pH 4.5. The addition of 2% (m/v) hydroxypropylmethyl cellulose to the separation buffer allowed for precise and accurate electrokinetic injection of ions from the plant material by halting the movement of tissue fluid into the capillary. This method provides both qualitative and quantitative data of inorganic cations, with quantitation in zucchini, mushroom and apple samples in agreement with Sector Field Inductively Coupled Plasma Mass Spectrometric analysis (r(2)=0.98, n=9). This method provides a new way for rapid, quantitative analysis by eliminating sample preparation procedures, and has great potential for a range of applications in plant science and food chemistry. PMID- 26422303 TI - Use of MiniColumns for linear isotherm parameter estimation and prediction of benchtop column performance. AB - In this paper, a comparison between experimental chromatography data and column simulations is carried out to determine the efficacy of using miniaturized chromatography columns (MiniColumns) for both column modeling parameter estimation and process development. Normalization of the data with respect to column volumes along with appropriate translations to account for system differences is shown to result in comparability of the experimental data for the MiniColumn and benchtop systems. A parameter estimation protocol is then employed to determine the linear steric mass-action (SMA) isotherm and lumped mass transport parameters for two cation exchange resins. The models are then validated and simulations using different parameter sets from the MiniColumn and benchtop systems are shown to result in similar predicted chromatography profiles and calculated retention volumes. The parameters generated from the MiniColumn system are demonstrated to be well suited for predicting experimental data from the benchtop system. These simulation results, the ability to operate MiniColumns in parallel, and the significantly lower material requirements per experiment support an industry trend toward increased usage of miniaturized chromatography columns as a scale-down model for process development. PMID- 26422305 TI - Feasibility of correlating separation of ternary mixtures of neutral analytes via thin layer chromatography with supercritical fluid chromatography in support of green flash separations. AB - Method development for normal phase flash liquid chromatography traditionally employs preliminary screening using thin layer chromatography (TLC) with conventional solvents on bare silica. Extension to green flash chromatography via correlation of TLC migration results, with conventional polar/nonpolar liquid mixtures, and packed column supercritical fluid chromatography (SFC) retention times, via gradient elution on bare silica with a suite of carbon dioxide mobile phase modifiers, is reported. Feasibility of TLC/SFC correlation is individually described for eight ternary mixtures for a total of 24 neutral analytes. The experimental criteria for TLC/SFC correlation was assumed to be as follows: SFC/UV/MS retention (tR) increases among each of the three resolved mixture components; while, TLC migration (Rf) decreases among the same resolved mixture components. Successful correlation of TLC to SFC was observed for most of the polar organic solvents tested, with the best results observed via SFC on bare silica with methanol as the CO2 modifier and TLC on bare silica with a methanol/dichloromethane mixture. PMID- 26422304 TI - Comparison of sodium dodecyl sulfate depletion techniques for proteome analysis by mass spectrometry. AB - In proteomics, sodium dodecyl sulfate (SDS) is favored for protein solubilization and mass-based separation (e.g. GELFrEE or SDS PAGE). Numerous SDS depletion techniques are available to purify proteins ahead of mass spectrometry. The effectiveness of the purification has a controlling influence on the success of the analysis. Here we quantitatively assess eight approaches to SDS depletion: in gel digestion; protein precipitation in acetone or with TCA; detergent precipitation with KCl; strong cation exchange; protein level and peptide level purification with Pierce detergent removal cartridges; and FASP II. Considering protein purity, FASP II showed the highest degree of SDS removal, matching that of in-gel digestion (over 99.99% depleted). Other methods (acetone, strong cation exchange, Pierce cartridges) also deplete SDS to levels amenable to LC-MS (>99%). Accounting for protein recovery, FASP II revealed significant sample loss (<40% yield); other approaches show even greater protein loss. We further assessed acetone precipitation, having the highest protein recovery relative to FASP II, to process GELFrEE fractionated Escherichia coli ahead of bottom-up mass spectrometry. Acetone precipitation yielded a 17% average increase in identified proteins, and 40% increase in peptides, indicating this approach as a favored strategy for SDS depletion in a proteomics workflow. PMID- 26422306 TI - Mild and cost-effective green fluorescent protein purification employing small synthetic ligands. AB - The green fluorescent protein (GFP) is a useful indicator in a broad range of applications including cell biology, gene expression and biosensing. However, its full potential is hampered by the lack of a selective, mild and low-cost purification scheme. In order to address this demand, a novel adsorbent was developed as a generic platform for the purification of GFP or GFP fusion proteins, giving GFP a dual function as reporter and purification tag. After screening a solid-phase combinatorial library of small synthetic ligands based on the Ugi-reaction, the lead ligand (A4C7) selectively recovered GFP with 94% yield and 94% purity under mild conditions and directly from Escherichia coli extracts. Adsorbents containing the ligand A4C7 maintained the selectivity to recover other proteins fused to GFP. The performance of A4C7 adsorbents was compared with two commercially available methods (immunoprecipitation and hydrophobic interaction chromatography), confirming the new adsorbent as a low-cost viable alternative for GFP purification. PMID- 26422307 TI - Online post-column solvent assisted and direct solvent-assisted electrospray ionization for chiral analysis of propranolol enantiomers in plasma samples. AB - An Online post-column solvent-assisted ionization (OPSAI) method was developed for enhancing the ionization of the beta-blocker propranolol utilizing normal phase LC-MS/MS. Solvent-assisted electrospray ionization (SAESI) was studied by the introduction of the assistant solvents A: 0.5% Formic acid in Isopropanolol, B: 0.5% Formic acid in Isopropanolol-Water (1:1), and C: 0.5% Formic acid in water into the electrospray ionization chamber using a spray needle. Analyte molecules can be directly ionized by the aid of the assistant solvent spray. Both methods were applied to the chiral separation of propranolol enantiomers using normal phase analysis on cellulose-based chiral column. Interestingly, both methods are easy to handle and offer a wide range of assistant solvents that can be used in order to gain the optimum ionization of the analyte molecules. The both methods considerably improved the analyte signal and the peak area greatly increased. The propranolol average signal-to-noise (S/N) ratio was enhanced from 26+/-1 and 42+/-1 to 2341+/-61 and 1725+/-29 for R-propranolol and S-propranolol, respectively, when the post-column solvent method (OPSAI) was used with isopropanol-assistant solvent (A). While in case of solvent-assisted electrospray ionization method (SAESI) signal was enhanced from 26+/-1 and 42+/-1 to 2223+/-72 and 2155+/-58 for R-propranolol and S-propranolol, respectively, with water as an assistant solvent. The limit of detection was 10ng/mL and the method was linear in the range 50-2000ng/mL. The NPLC-MS method was applied for the determination of propranolol enantiomers in human plasma after microextraction by packed C18 sorbent. PMID- 26422308 TI - Electronic cigarette solutions and resultant aerosol profiles. AB - Electronic cigarettes (e-cigarettes) are growing in popularity exponentially. Despite their ever-growing acceptance, their aerosol has not been fully characterized. The current study focused on evaluating e-cigarette solutions and their resultant aerosol for potential differences. A simple sampling device was developed to draw e-cigarette aerosol into a multi-sorbent thermal desorption (TD) tube, which was then thermally extracted and analyzed via a gas chromatography (GC) mass spectrometry (GC-MS) method. This novel application provided detectable levels of over one hundred fifteen volatile organic compounds (VOCs) and semivolatile organic compounds (SVOCs) from a single 40mL puff. The aerosol profiles from four commercially available e-cigarettes were compared to their respective solution profiles with the same GC-MS method. Solution profiles produced upwards of sixty four unidentified and identified (some only tentatively) constituents and aerosol profiles produced upwards of eighty two compounds. Results demonstrated distinct analyte profiles between liquid and aerosol samples. Most notably, formaldehyde, acetaldehyde, acrolein, and siloxanes were found in the aerosol profiles; however, these compounds were never present in the solutions. These results implicate the aerosolization process in the formation of compounds not found in solutions; have potential implications for human health; and stress the need for an emphasis on electronic cigarette aerosol testing. PMID- 26422309 TI - A resolution approach of racemic phenylalanine with aqueous two-phase systems of chiral tropine ionic liquids. AB - Aqueous two-phase systems (ATPS) based on tropine type chiral ionic liquids and inorganic salt solution were designed and prepared for the enantiomeric separation of racemic phenylalanine. The phase behavior of IL-based ATPS was comprehensive investigated, and phase equilibrium data were correlated by Merchuk equation. Various factors were also systematically investigated for their influence on separation efficiency. Under the appropriate conditions (0.13g/g [C8Tropine]pro, 35mg/g Cu(Ac)2, 20mg/g d,l-phenylalanine, 0.51g/g H2O and 0.30g/g K2HPO4), the enantiomeric excess value of phenylalanine in solid phase (mainly containing l-enantiomer) was 65%. Finally, the interaction mechanism was studied via 1D and 2D NMR. The results indicate that d-enantiomer of phenylalanine interacts more strongly with chiral ILs and Cu(2+) based on the chiral ion-pairs space coordination mechanism, which makes it tend to remain in the top IL-rich phase. By contrast, l-enantiomer is transferred into the solid phase. Above chiral ionic liquids aqueous two-phase systems have demonstrated obvious resolution to racemic phenylalanine and could be promising alterative resolution approach for racemic amino acids in aqueous circumstance. PMID- 26422310 TI - [Which Articles are Favored by Readers of the PPmP?]. PMID- 26422311 TI - [Work Life Participation of Mentally Ill Individuals--Implications for Research and Best Practice]. AB - Participation in working life improves the health outcome of mentally ill individuals. The paper reviews the current situation of mentally ill individuals and barriers to enter the open labour market. Barriers are discussed and the contribution of mental health professionals is outlined. Implications for research and best practice are considered. PMID- 26422312 TI - [Psychotherapy in Palliative Care]. PMID- 26422313 TI - [In Process Citation]. PMID- 26422314 TI - Racial matching and adolescent self-disclosure of substance use and mental health symptoms. AB - Obtaining accurate assessment data from adolescents in treatment aids clinical decision making and facilitates more accurate outcome evaluations. However, findings could be biased due to underreported substance use and mental health symptoms. This article compares self-reports of youth in non-White matched client assessor dyads and those in nonmatched dyads. There were no differences on self reported substance use, but matched youth reported significantly fewer attention deficit/hyperactivity disorder symptoms versus the comparison group. One possible reason for these findings is the effect of in-group stereotype threat. Future studies should examine the potential effect that in-group stereotyping and perceived racism have on the therapeutic relationship. PMID- 26422315 TI - Isolation and identification of a novel peptide from zein with antioxidant and antihypertensive activities. AB - The aim of this study is to isolate and identify a novel corn peptide (CP) from zein with antioxidant and antihypertensive activities based on bioactive-guided isolation procedures. Zein was hydrolyzed by using double enzymes immobilized with calcium alginate-chitosan beads and then fractionated and purified. The antioxidant and antihypertensive activities of the CP fractions were screened by in vitro and in vivo assays. The in vivo animal studies using spontaneously hypertensive rats (SHRs) confirmed the antihypertensive effects of the CP, and its angiotensin I-converting enzyme (ACE) inhibitory activity was retained after thermal treatment and simulated gastrointestinal digestion. The primary structure of CP-2-1 was identified by RP-HPLC-MS/MS and the amino acid sequence was determined as M-I/L-P-P with the molecular weight of 452.3 Da. CP-2-1 showed effective antioxidant and ACE inhibitory activities (IC50 values of 220 MUg mL( 1) and 70.32 MUg mL(-1), respectively) and it might be a potential candidate for antioxidant functional food or pharmaceuticals for hypertension. PMID- 26422316 TI - Irisin: A true, circulating hormone. PMID- 26422317 TI - Cyclic Deformation in Metallic Glasses. AB - Despite the utmost importance and decades of experimental studies on fatigue in metallic glasses (MGs), there has been so far little or no atomic-level understanding of the mechanisms involved. Here we perform molecular dynamics simulations of tension-compression fatigue in Cu50Zr50 MGs under strain controlled cyclic loading. It is shown that the shear band (SB) initiation under cyclic loading is distinctly different from that under monotonic loading. Under cyclic loading, SB initiation takes place when aggregates of shear transformation zones (STZs) accumulating at the MG surface reach a critical size comparable to the SB width, and the accumulation of STZs follows a power law with rate depending on the applied strain. It is further shown that almost the entire fatigue life of nanoscale MGs under low cycle fatigue is spent in the SB initiation stage, similar to that of crystalline materials. Furthermore, a qualitative investigation of the effect of cycling frequency on the fatigue behavior of MGs suggests that higher cycling frequency leads to more cycles to failure. The present study sheds light on the fundamental fatigue mechanisms of MGs that could be useful in developing strategies for their engineering applications. PMID- 26422318 TI - Forsythoneosides A-D, Neuroprotective Phenethanoid and Flavone Glycoside Heterodimers from the Fruits of Forsythia suspensa. AB - Forsythoneosides A-D (1-4), four unusual adducts of a flavonoid unit fused to a phenylethanoid glycoside through a pyran ring or carbon-carbon bond, and four new phenylethanoid glycosides (5-8) were isolated from the fruits of Forsythia suspensa, together with nine known compounds. The structures of 1-8, including their absolute configurations, were elucidated by spectroscopic data as well as experimental and calculated electronic circular dichroism analysis. Compounds 2 and 4 inhibited PC12 cell damage induced by rotenone, and increased cell viability from 53.9 +/- 7.1% to 70.1 +/- 4.0% and 67.9 +/- 5.2% at 0.1 MUM, respectively. PMID- 26422319 TI - Association of P-Wave Dispersion with Overall and Cardiovascular Mortality in Hemodialysis Patients. AB - BACKGROUND/AIMS: The P-wave parameters that are measured using a 12-lead electrocardiogram are commonly used as noninvasive tools for assessing left atrial enlargement. This study was designed to assess whether P-wave dispersion is associated with overall and cardiovascular mortality in hemodialysis patients. METHODS: This study enrolled 209 hemodialysis patients. We measured the P-wave dispersion corrected by heart rate, that is, the corrected P-wave dispersion (PWdisperC), and assessed its correlation with overall and cardiovascular mortalities. RESULTS: The mean PWdisperC of all the patients was 93.3 +/- 21.1 ms. During the follow-up period (mean 5.4 years), 58 deaths and 37 cardiovascular deaths were recorded. The adjusted value of PWdisperC was also associated with overall (hazards ratio (HR) 1.018, 95% CI 1.004-1.033, p = 0.014) and cardiovascular (HR 1.032, 95% CI 1.012-1.053, p = 0.002) mortalities. Multivariate Cox regression analysis identified tertile 3 of PWdisperC (vs. tertile 1) to be associated with overall (HR 2.472, 95% CI 1.181-5.174, p = 0.016) and cardiovascular (HR 3.896, 95% CI 1.463-10.376, p = 0.007) mortalities, after adjustment for demographic, clinical and biochemical parameters. Adding PWdisperC to a model of clinical features could significantly improve the predictive value for overall (p = 0.044) and cardiovascular (p = 0.002) mortalities. CONCLUSIONS: We concluded that PWdisperC was positively associated with overall and cardiovascular mortalities in hemodialysis patients and could provide additional prognostic values. Screening hemodialysis patients by using PWdisperC may facilitate identifying a group of patients with poor prognosis. PMID- 26422320 TI - [Clinical problems in medical mycology: Problem number 49]. AB - The case of a 59-year-old female born in Buenos Aires (Argentina) is presented. She had been diagnosed with HIV in 2007 and received highly active antiretroviral therapy until 2011; she also suffered from diabetes type 2. She had received empirical treatment (pyrimethamine-clindamycin) for cerebral toxoplasmosis. Fifteen days later she suffered a drug-induced skin disorder and was treated in the Dermatology Service of the Hospital Muniz with corticosteroids. After five weeks she was readmitted to the Infectious Disease Unit due to asthenia, weight loss, left hip pain and weakness in all four limbs. Septic arthritis and aseptic hip necrosis were ruled out. Blood cultures were positive for Staphylococcus aureus and Escherichia coli. The patient received intravenous antibiotics, but before being discharged Acinetobacter baumannii was isolated from blood, catheter and urine cultures, and a new series of antibiotics were prescribed. On the 3rd day she presented encephalic facies, changes of behaviour and disorientation, without nuchal rigidity, Kernig and Brudzinski signs or focal signs. An X-ray computed tomography did not show parenchymal lesions. A yeast identified as Candida albicans was isolated in a cerebrospinal fluid culture. The same yeast was recovered in a new cerebrospinal fluid sample. The isolate was susceptible to amphotericin B and susceptible dose dependent to fluconazole. The patient was treated with amphotericin B (0.7mg/kg plus 800mg fluconazole daily). Three weeks later, new cerebrospinal fluid cultures were negative. Unfortunately, the patient died soon afterwards. PMID- 26422321 TI - Antifungal stewardship in a tertiary hospital. AB - BACKGROUND: The inappropriate use of antifungals is an important health problem related to increasing adverse effects, unnecessary cost and promotion of resistant and emerging fungal infections. Despite its relevance, many health institutions assign few resources to improve prescribing practices. AIMS: To evaluate the efficiency of an antifungal stewardship programme (ASP) centered on restricted antifungal agents. METHODS: The main activity during the eight-month study was to perform a programmed review of restricted antifungals (lipid formulations of amphotericin B, echinocandins and voriconazole) prescribed in hospitalized patients. In the case of amendable antifungal treatment, a recommendation was included in the electronic medical record. RESULTS: A total of 280 antifungal prescriptions for 262 patients were revised during the study period. The indications were prophylactic in 85 cases (30.4%), pre-emptive in 10 cases (3.5%), empiric in 122 cases (43.6%), and directed in 63 cases (22.5%). A total of 70 prescriptions (25%) in 61 patients were considered to be amendable. In most of these cases, treatment could have been reduced considering the patient's clinical improvement and microbiological results. The most common advice was antifungals change (70%), antifungal withdrawal (21%), removal of one antifungal drug in cases of combined therapy (7%), and switching to oral route (1%). Proposed recommendations were addressed in 28 cases (40%). There was no significant difference in adherence with respect to the type of recommendation (p=0.554). There was a 42% lower use of antifungals during the period of the study compared to that observed during a similar previous period. Mortality among patients who were treated according to the recommendations of the ASP was 17% and in whom treatment was not modified it was 30% (p=0.393). CONCLUSIONS: ASPs centered on hospitalized patients may be an efficient strategy to ameliorate antifungal use in hospitals. PMID- 26422322 TI - Cutaneous blastomycosis. An imported case with good response to itraconazole. AB - BACKGROUND: Blastomycosis is a subacute or chronic deep mycosis caused by a dimorphic fungus called Blastomyces dermatitidis, which generally produces a pulmonary form of the disease and, to a lesser extent, extra-pulmonary forms such as cutaneous, osteoarticular and genitourinary, among others. Cutaneous blastomycosis is the second clinical presentation in frequency. It is considered as primary when it begins by inoculation of the fungus due to traumas, and secondary when the lung fails to contain the infection. CASE-REPORT: We present the case of a 57 year-old male who had a 5 year-history of an irregularly shaped verrucous infiltrative plaque related to and insect bite and posterior trauma due to the manipulation of the lesion. B. dermatitidis was identified using direct examination, stains, isolation in culture media, histopathology, and molecular studies. An antifungal susceptibility test was performed using method M38-A2 (CLSI). Clinical and mycological cure was achieved with itraconazole. CONCLUSIONS: This cutaneous blastomycosis case acquired in the United States (Indianapolis) is rather interesting and looks quite similar to other mycoses such as coccidioidomycosis or sporotrichosis. The presented case shows one of the multiple issues concerning migration between neighboring countries. PMID- 26422323 TI - Vacuolar proteases from Candida glabrata: Acid aspartic protease PrA, neutral serine protease PrB and serine carboxypeptidase CpY. The nitrogen source influences their level of expression. AB - BACKGROUND: The Saccharomyces cerevisiae vacuole is actively involved in the mechanism of autophagy and is important in homeostasis, degradation, turnover, detoxification and protection under stressful conditions. In contrast, vacuolar proteases have not been fully studied in phylogenetically related Candida glabrata. AIMS: The present paper is the first report on proteolytic activity in the C. glabrata vacuole. METHODS: Biochemical studies in C. glabrata have highlighted the presence of different kinds of intracellular proteolytic activity: acid aspartyl proteinase (PrA) acts on substrates such as albumin and denatured acid hemoglobin, neutral serine protease (PrB) on collagen-type hide powder azure, and serine carboxypeptidase (CpY) on N-benzoyl-tyr-pNA. RESULTS: Our results showed a subcellular fraction with highly specific enzymatic activity for these three proteases, which allowed to confirm its vacuolar location. Expression analyses were performed in the genes CgPEP4 (CgAPR1), CgPRB1 and CgCPY1 (CgPRC), coding for vacuolar aspartic protease A, neutral protease B and carboxypeptidase Y, respectively. The results show a differential regulation of protease expression depending on the nitrogen source. CONCLUSIONS: The proteases encoded by genes CgPEP4, CgPRB1 and CgCPY1 from C. glabrata could participate in the process of autophagy and survival of this opportunistic pathogen. PMID- 26422324 TI - [Effects of pesticides and plant bio-stimulants on the germination of chlamydospores and in vitro development of the nematophagous fungus Pochonia chlamydosporia]. AB - BACKGROUND: The effects of pesticides and plant bio-stimulants used in protected vegetable production systems on the fungus Pochonia chlamydosporia are unknown. AIMS: The effectiveness of P. chlamydosporia against Meloidogyne spp. could be affected by products used in protected vegetable production systems. Two in vitro assays were carried out to evaluate any potential effect that pesticides and bio stimulants often used in these systems could have on the fungus. METHODS: The effect on chlamydospore germination was evaluated in a first assay, and mycelia growth and sporulation in a second. With these results, the compatibility of each product with the fungus was determined. RESULTS: Chlamydospores germination was over 50% with the control, FitoMas E, Biobras-16 and Amidor. Lower results were observed with other products, with some of them even inhibiting germination completely. Fungal growth was potentiated by Biobras-16 to 106.23%, promoted up to 50-100% by the control, FitoMas E and Cuproflow, and was below 50% with the rest of the products.Cipermetrina, Benomilo, Zineb, Mitigan, Karate, FitoMas E and Amidor promoted fungal sporulation, which was below 50% with Cuproflow and completely inhibited by the other products. Fifty-four percent of the products evaluated were compatible with P. chlamydosporia, while 8% were toxic and 38%, very toxic. CONCLUSIONS: Cipermetrina, Karate, Amidor, Benomilo, Zineb, Mitigan and FitoMas E were compatible with P. chlamydosporia. If it is necessary to use any of the other products for integrated pest management in protected vegetable production systems, it is recommended to avoid direct contact with P. chlamydosporia. PMID- 26422325 TI - [Clinical problems in medical mycology: Problem number 48]. AB - We present the case of a 42-year-old man, HIV-positive, with low CD4(+) T cell count (31 cells/MUl), who was admitted to Hospital de Infecciosas F. J. Muniz in Buenos Aires (Argentina) due to a severe lower back pain. He had a history of several highly active antiretroviral therapy treatments and he also had diabetes and chronic B and C viral hepatitis. A spinal cord CT scan showed two lytic bone lesions in L2 and L3. A bone biopsy was carried out and its microbiological study allowed the isolation of a methicillin-resistant Staphylococcus aureus. Intravenous vancomycin was prescribed, together with a corset and physical rest. A few days later the patient presented with acute dermatitis with papules, vesicles, scales and erythema, which spread over the whole lumbar region. The mycological study of the scales led to the isolation in culture of Candida albicans and Candida parapsilosis. With the diagnosis of decubitus candidiasis he was initially treated with a topical ointment containing 3% salicylic acid and 6% benzoic acid, but only slow, partial improvement was observed. The treatment was changed to oral fluconazole at a daily dose of 200mg. With the latter the patient showed a rapid, complete clinical response. PMID- 26422326 TI - Intravenous Morphine Sulfate versus Intravenous Tramadol for Acute Pain in the Afghan National Security Forces. PMID- 26422327 TI - Family Presence During Resuscitation Benefits-Risks Scale (FPDR-BRS): Instrument Development and Psychometric Validation. AB - Family presence during resuscitation (FPDR) is a growing health care practice; nevertheless, countless controversies surround this medical principle. Several studies have investigated the perceptions of health care professionals toward FPDR, yet psychometrically sound instruments assessing family members' perceptions of FPDR are scarce. Hence we aimed to develop and psychometrically validate the Family Presence During Resuscitation Benefits-Risks Scale (FPDR BRS). METHODS: Using a methodological design, an initial 27-item questionnaire was developed after extensive literature and theoretical review. Psychometric validation assessed content validity through a 2-step process involving expert nurses and doctors, basic item analysis, internal consistency using Cronbach's alpha, and construct validity via exploratory factor analysis. After acquiring Ethics Review Board approval, the FPDR-BRS was tested on 130 randomly selected eligible family members from a tertiary government hospital in the Philippines. RESULTS: The initial 27-item questionnaire was reduced to 23 items after content validation, yielding an item content validity index and scale content validity index/Ave rage of 1.00. Basic item analysis revealed acceptable inter-item and item-scale correlations. Exploratory factor analysis extracted 4 factors, namely, personnel risks, personal risks, insight-building benefits, and connection forming benefits. Cronbach's alpha for the entire scale was 0.90, with high subscale reliability coefficients. DISCUSSION: The 23-item FPDR-BRS exhibited satisfactory psychometric properties and may be used to quantitatively measure a family member's perception towards witnessing the resuscitation of his or her significant other. Further comprehensive psychometric evaluations are warranted to ensure robust cross-cultural comparisons. PMID- 26422328 TI - A cost and time analysis of laryngology procedures in the endoscopy suite versus the operating room. AB - OBJECTIVES/HYPOTHESIS: To assess the costs, charges, reimbursement, and efficiency of performing awake laryngology procedures in an endoscopy suite (ES) compared with like procedures performed in the operating room (OR). STUDY DESIGN: Retrospective review of billing records. METHODS: Cost, charges, and reimbursements for the hospital, surgeon, and anesthesiologist were compared between ES injection laryngoplasty and laser excision procedures and matched case controls in the OR. Time spent in 1) the preoperative unit, 2) the operating or endoscopy suite, and 3) recovery unit were compared between OR and ES procedures. RESULTS: Hospital expenses were significantly less for ES procedures when compared to OR procedures. Reimbursement was similar for ES and OR injection laryngoplasty, though greater for OR laser excisions. Net balance (reimbursement expenses) was greater for ES procedures. A predictive model of payer costs over a 3-year period showed similar costs for ES and OR laser procedures and reduced costs for ES compared to OR injection laryngoplasty. Times spent preoperatively and the procedure were significantly less for ES procedures. CONCLUSIONS: For individual laryngology procedures, the ES reduces time and costs compared to the OR, increasing otolaryngologist and hospital efficiency. This reveals cost and time savings of ES injection laryngoplasty, which occurs at a similar frequency as OR injection laryngoplasty. Given the increased frequency for ES laser procedures, total costs are similar for ES and OR laser excision of papilloma, which usually require repeated procedures. When regulated office space is unavailable, endoscopy rooms represent an alternative setting for unsedated laryngology procedures. LEVEL OF EVIDENCE: NA Laryngoscope, 126:1385-1389, 2016. PMID- 26422329 TI - Rate and duration of hospitalization for deep vein thrombosis and pulmonary embolism in real-world clinical practice. AB - BACKGROUND: Current guidelines recommend initial treatment with anticoagulants at home in patients with acute deep vein thrombosis (DVT) and in patients with low risk pulmonary embolism (PE) with adequate home circumstances. However, most of the patients with acute venous thromboembolism (VTE) are currently hospitalized regardless of their risk of short-term complications. AIM OF THE STUDY: To assess the proportion of outpatients with acute VTE initially treated in hospitals, to assess the mean duration of hospitalization, and to identify predictors for in hospital or home treatment. METHODS: Data of Italian patients enrolled in the RIETE registry from January 2006 to December 2013 were included. RESULTS: Altogether 766 PE and 1,452 isolated DVT were included. Among PE patients, mean PESI score was 84 points (SD 35), and 56% of patients had a low-risk PESI score (<85). In all, 53.7% of DVT and 17.0% of PE were entirely treated at home, and 38.2% of DVT patients and 19.9% of PE patients were hospitalized for <=5 days. On multivariate analysis, low PESI score was not independently associated with the hospitalization of PE patients. CONCLUSIONS: One in every two patients with DVT and five in every six with PE are still hospitalized. PMID- 26422330 TI - Validation of the Brazilian version of the childhood asthma control test (c-ACT). AB - BACKGROUND: Children's perception of their symptoms has proved reliable and relevant to disease management and should be considered when assessing their asthma control. The aim of the study is to validate the Brazilian Portuguese version of the Childhood Asthma Control Test (c-ACT) in children aged 4-11 years. METHODS: This is a cross-sectional study in children diagnosed with asthma undergoing treatment in a pediatric pulmonology outpatient clinic in Porto Alegre, Brazil. The translation and linguistic adaptation of the instrument were performed in accordance with international recommendations for questionnaire validation. RESULTS: A total of 105 participants were included, aged 4-11 years. VALIDITY: all correlations between the total score and items on the questionnaire were significant and obtained values of r >= 0.3, and c-ACT means showed statistically significant differences between the GINA categories (P < 0.01). The controlled asthma group showed significantly higher c-ACT scores than those of uncontrolled asthma group (controlled 22.0 +/- 2.9 vs. uncontrolled 16.3 +/- 5.3 P < 0.01); and partially controlled asthma group showed significantly higher c ACT scores than those of uncontrolled asthma group (partially controlled 20.0 +/- 4.0 vs. uncontrolled 16.3 +/- 5.3 P = 0.03). Correlations between the c-ACT total score and spirometry and nitric oxide were poor (r = 0.020; P = 0.866 and r = 0.035; P = 0.753, respectively). Reliability: the alpha-C coefficient for the c ACT total score was 0.677 (95%CI 0.573-0763). Sensitivity to change had an effect size of 0.8 and an intraclass correlation coefficient of 0.598. No floor or ceiling effects were observed. CONCLUSION: The Brazilian version of the Childhood Asthma Control Test proved to be valid and reliable in children aged 4-11 years. PMID- 26422332 TI - The pathway of collagen secretion. AB - COPII vesicles mediate export of secretory cargo from the endoplasmic reticulum (ER). However, a standard COPII vesicle with a diameter of 60-90 nm is too small to export collagens that are composed of rigid triple helices of up to 400 nm in length. How do cells pack and secrete such bulky molecules? This issue is fundamentally important, as collagens constitute approximately 25% of our dry body weight and are essential for almost all cell-cell interactions. Recently, a potential mechanism for the biogenesis of mega-transport carriers was identified, involving packing collagens and increasing the size of COPII coats. Packing is mediated by TANGO1, which binds procollagen VII in the lumen and interacts with the COPII proteins Sec23/Sec24 on the cytoplasmic side of the ER. Cullin3, an E3 ligase, and its specific adaptor protein, KLHL12, ubiquitinate Sec31, which could increase the size of COPII coats. Recruitment of these proteins and their specific interactors into COPII-mediated vesicle biogenesis may be all that is needed for the export of bulky collagens from the ER. Nonetheless, we present an alternative pathway in which TANGO1 and COPII cooperate to export collagens without generating a mega-transport carrier. PMID- 26422331 TI - The marriage of surgical simulation and telementoring for damage-control surgical training of operational first responders: A pilot study. AB - BACKGROUND: Hemorrhage is the leading cause of preventable posttraumatic death. Many such deaths may be potentially salvageable with remote damage-control surgical interventions. As recent innovations in information technology enable remote specialist support to point-of-care providers, advanced interventions, such as remote damage-control surgery, may be possible in remote settings. METHODS: An anatomically realistic perfused surgical training mannequin with intrinsic fluid loss measurements (the "Cut Suit") was used to study perihepatic packing with massive liver hemorrhage. The primary outcome was loss of simulated blood (water) during six stages, namely, incision, retraction, direction, identification, packing, and postpacking. Six fully credentialed surgeons performed the same task as 12 military medical technicians who were randomized to remotely telementored (RTM) (n = 7) or unmentored (UTM) (n=5) real-time guidance by a trauma surgeon. RESULTS: There were no significant differences in fluid loss between the surgeons and the UTM group or between the UTM and RTM groups. However, when comparing the RTM group with the surgeons, there was significantly more total fluid loss (p = 0.001) and greater loss during the identification (p = 0.002), retraction (p = 0.035), direction (p = 0.014), and packing(p = 0.022) stages. There were no significant differences in fluid loss after packing between the groups despite differences in the number of sponges used; RTM group used more sponges than the surgeons and significantly more than the UTM group (p = 0.048). However, mentoring significantly increased self-assessed nonsurgeon procedural confidence (p = 0.004). CONCLUSION: Perihepatic packing of an exsanguinating liver hemorrhage model was readily performed by military medical technicians after a focused briefing. While real-time telementoring did not improve fluid loss, it significantly increased nonsurgeon procedural confidence, which may augment the feasibility of the concept by allowing them to undertake psychologically daunting procedures. PMID- 26422333 TI - Development of dendritic form and function. AB - The nervous system is populated by numerous types of neurons, each bearing a dendritic arbor with a characteristic morphology. These type-specific features influence many aspects of a neuron's function, including the number and identity of presynaptic inputs and how inputs are integrated to determine firing properties. Here, we review the mechanisms that regulate the construction of cell type-specific dendrite patterns during development. We focus on four aspects of dendrite patterning that are particularly important in determining the function of the mature neuron: (a) dendrite shape, including branching pattern and geometry of the arbor; (b) dendritic arbor size; PMID- 26422334 TI - Optical Biopsy of Bladder Cancer Using Crowd-Sourced Assessment. PMID- 26422335 TI - Older type 2 diabetic patients are more likely to achieve glycaemic and cardiovascular risk factors targets than younger patients: analysis of a primary care database. AB - BACKGROUND: Older subjects with type 2 diabetes mellitus (T2DM) have differential characteristics compared with middle-aged or younger populations, and require tailored management of the disease. AIMS: To evaluate how clinical characteristics, degree of control of glycaemia and cardiovascular risk factors, presence of chronic complications and treatments differ between older T2DM patients and younger adults. METHODS: Cross-sectional study using data from a population-based electronic database. We retrieved data from 318,020 patients >= 30 years diagnosed with T2DM, attended during 2011 in primary care centres in Catalonia, Spain. We performed descriptive and comparative analyses stratified by gender and age subgroups: <= 65, 66-75, 76-85 and >85 years. RESULTS: Both men and women across older age subgroups (> 65 years) had longer diabetes duration than younger adults (8.0 vs. 5.6 in men and 8.4 vs. 6.9 years in women; p < 0.001), but better glycaemic control (mean glycated haemoglobin 7.1 vs. 7.7 in men and 7.1 vs. 7.4 in women; p < 0.001), and better combined control of different cardiovascular risk factors (p < 0.001). Moreover, older patients were more likely to achieve glycaemic targets irrespective of having cardiovascular disease. The use of oral antidiabetics decreased with increasing age, and insulin in monotherapy was more frequently prescribed among patients in the older age subgroups. Diabetes-related complications were more frequent in men of all group ages. In the older age subgroups, patients of both sexes had a longer duration of T2DM but better glycaemic control. In this context, the prevalence of diabetic retinopathy decreased unexpectedly with increasing age. CONCLUSION: Control of glycaemia and cardiovascular risk factors was better among older T2DM patients. There is a need for prospective studies to quantify the weight of risk factors in each complication to adapt the therapeutic and care approaches in elderly people. PMID- 26422336 TI - Improved child behavioural and emotional functioning after Circle of Security 20 week intervention. AB - This study examined the efficacy of the attachment-based Circle of Security 20 week intervention in improving child behavioural and emotional functioning. Participants were 83 parents of children (1-7 years) referred to a clinical service with concerns about their young children's behaviour. Parents (and teachers, when available) completed questionnaires assessing child protective factors, behavioural concerns, internalizing and externalizing problems, prior to and immediately after the intervention. The following were considered as potential moderators: child gender and age, parent representations, reflective functioning, child attachment indices and severity of presenting problems, prior to treatment. Results showed significant improvement for parent ratings of child protective factors, behavioural concerns, internalizing and externalizing symptoms, all ps < .05, and children with more severe problems showed most improvement. Teachers also reported improvements, but change was significant only for externalizing problems (p = .030). Findings suggest Circle of Security is effective in improving child behavioural and emotional functioning in clinically referred children aged 1-7 years. PMID- 26422337 TI - Transforming Quality Improvement Into Evidence-Based Quality Improvement: A Key Solution to Improve Healthcare Outcomes. PMID- 26422338 TI - Pulmonary sarcoidosis in the context of a telaprevir-based triple therapy for hepatitis C. PMID- 26422340 TI - Functional outcomes of arthroscopic treatment of lateral epicondylitis. AB - OBJECTIVE: The aim of this study is to evaluate the functional results of arthroscopic lateral epicondylitis (LE) treatment in patients in whom conservative treatment proved insufficient. METHODS: Between 2011-2014, 29 patients with LE (15 women, 14 men; mean age: 46 years; range: 33-79) who received at least 6 months of conservative treatment methods and did not achieve full recovery and thus underwent arthroscopic surgery were included in this study. RESULTS: One patient was excluded from the functional assessment. Mean follow-up was 20.5 months (range: 7-42). Mean preoperative and postoperative Disabilities of the Arm, Shoulder and Hand (DASH) scores were 81.1+/-17.5 and 34.7+/-26.8 (p<0.0001), respectively, and Mayo Elbow Performance Scores (MEPS) were 48.5+/-11.5 and 101.2+/-22.9 (p<0.0001), respectively. Twenty-one patients (75%) were satisfied with the functional outcome. CONCLUSION: As a result, LE treated with the arthroscopic method, with its low complication rate, successful degenerated tendon debridement, and decortication of the lateral epicondyle, is a useful method for intervention in pathologies such as annular plica, loose body, synovial hypertrophy, and radiocapitellar chondropathy. PMID- 26422339 TI - Comparison of extracorporeal shock wave therapy in acute and chronic lateral epicondylitis. AB - OBJECTIVE: The aim of this study is to evaluate and compare the results of extracorporeal shock wave therapy (ESWT) in the treatment of acute (<3 months) lateral epicondylitis (LE) and chronic (>6 months) LE groups. METHODS: Fifty-four patients who were diagnosed with LE and treated with BTL-5000 SWT Power (BTL Turkiye Medikal Cihazlar, Ankara, Turkey) ESWT were included in the study. Twenty four patients who had symptoms for <3 months were defined as the acute LE group (Group A), and 30 patients who had symptoms for >6 months were defined as the chronic LE group (Group B). All cases were evaluated pretherapy and at Weeks 2, 12, and 24 posttherapy according to pain while resting, pain while stretching, pain when pressed, pain while lifting chair, pain while working, nighttime pain on LE zone. RESULTS: Almost all values in both Group A and Group B were significantly improved at Weeks 2, 12, and 24 compared to the baseline values. CONCLUSION: ESWT is equally effective in the treatment of acute LE and chronic LE. In addition, the current data suggest the progression of LE cases from acute phase to chronic phase may be prevented by treatment with ESWT. PMID- 26422341 TI - The triangle between the anterior and posterior cruciate ligaments: an arthroscopic anatomy study. AB - OBJECTIVE: The goal of anterior cruciate ligament (ACL) reconstruction is to place the graft in closest proximity to the native ACL anatomy. This study aims to examine the angular relation between intact anterior and posterior cruciate ligaments (PCL) from an arthroscopic perspective. METHODS: Forty patients (20 male, 20 female) with a mean age of 35.12 (range: 18-40) years that underwent knee arthroscopy for reasons other than ACL rupture were included in the study. Following diagnostic examination and repair of the primary pathology, the triangle between ACL and PCL was seen at different flexion degrees of the knee joint (120, 90, 60, and 30 degrees ) through standard anterolateral (AL) and anteromedial (AM) portals. The narrow top angle of the triangle between the long intersecting axes of ACL and PCL was measured using recorded images by 3 blind observers. RESULTS: The average ACL-PCL angle was 61 degrees , (standard deviation+/-2 degrees ) at 90 degrees of knee flexion. The angles were narrower when viewed through the AM portal. The degree of the angles was not affected by age, sex, body mass index (BMI), or the side (right or left) on which the procedure was performed. There was good-to-excellent intra- and interobserver reliability. CONCLUSION: The angular relation between intact ACL and PCL has the potential to provide a better view of the anatomy during arthroscopic ACL surgery. To perform better anatomic reconstructions, it is important to create a 60 degrees angle between the ACL graft and PCL (as viewed through AL portal) at 90 degrees of knee flexion. PMID- 26422342 TI - Does the anteromedial portal provide clinical superiority compared to the transtibial portal in anterior cruciate ligament reconstruction in nonprofessional athletes in short-term follow-up? AB - OBJECTIVE: Two drilling techniques of the femoral tunnel are commonly used in anterior cruciate ligament (ACL) reconstruction: through the transtibial (TT) portal or through the anteromedial (AM) portal. The aim of the present study is to investigate the radiological and clinical outcomes of arthroscopic single bundle ACL reconstruction using AM and TT portal techniques for drilling the femoral tunnel in nonprofessional athletes. METHODS: A retrospective review was made of 44 nonprofessional athletes undergoing ACL reconstruction using AM and TT techniques between 2011-2013. The femoral tunnel clock position on axial magnetic resonance imaging (MRI) and the anterior-posterior position of the tibial tunnel on sagittal-cut MRI scan were measured. Radiological femoral tunnel and tibial tunnel anterior-posterior inclination angles were assessed. At final follow-up, the Lachman test and pivot-shift test were used in the evaluation of the anterior posterior stability of the knee and the rotational stability of the knee. For clinical and functional evaluation, the modified Cincinnati knee grading system, Lysholm knee scoring scale, and International Knee Documentation Committee (IKDC) form were used. RESULTS: No statistically significant difference was determined between the groups in terms of patient age, follow-up period, gender, and affected side distribution. There were 6 outliers in the TT group due to the clock face position. The mean femoral tunnel inclination angle was 31.07 degrees +/-8.44 degrees in the AM group and 19.02 degrees +/-8.93 degrees in the TT group. The tibial tunnel inclination angle was 21.08 degrees +/-5.42 degrees in the TT group and 16.58 degrees +/-7.02 degrees in the AM group. A statistically significant difference was determined between the 2 groups. No statistically significant difference was observed between the 2 groups in terms of Lachman test, pivot-shift test, Lysholm score, IKDC score, and modified Cincinnati score results. CONCLUSION: The AM technique has no clinical superiority compared to the TT technique in ACL reconstruction in nonprofessional athletes. PMID- 26422343 TI - Psychiatric and functional evaluation of professional athletes following anterior cruciate ligament reconstruction. AB - OBJECTIVE: The aim of this study is to evaluate early phase depression and anxiety in the proffessional athletes who underwent anterior cruciate ligament (ACL) reconstruction and compare them with the functional improvement of knee. METHODS: Thirty-eight patients (35 males, 3 females; mean age+/-SD: 26.84+/-8.03) were included in this study. Measurements were obtained immediately following the operation and at Week 6 of postoperative rehabilitation. Depression and anxiety symptoms were evaluated by the Hospital Anxiety and Depression Scale (HADS), and knee function was evaluated by Lysholm Knee Scoring Scale (LKSS). RESULTS: Change in total LKSS scores from the time of admission (56.4+/-20.2) to the end of the sixth week (78.7+/-13.8) was significant (t=-8.21, p<0.001). Neither the HADS depression nor the HADS anxiety scores were above the cutoff values in the 2 assessments. Significant difference was noted in HADS anxiety scores between the time of admission (6.21+/-3.50) and at the sixth week (5.33+/-3.33) (t=2.02, p=0.05). However, HADS depression scores were not statistically different between the 2 evaluations (5.95+/-3.68 and 5.35+/-3.50 at admission and Week 6 week, respectively) (t=1.07, p=0.29). Changes between the 2 LKSS and HADS anxiety assessments were negatively correlated (r=-0.49, p=0.002), but there no correlation was detected between the total LKSS and HADS score changes. CONCLUSION: The decline of the signs of anxiety and depression at the sixth week of rehabilitation indicate that proper rehabilitation positively affects the emotional status of ACL reconstruction patients. PMID- 26422344 TI - Effects of two different continuous passive motion protocols on the functional activities of total knee arthroplasty inpatients. AB - OBJECTIVE: The aim of this study was to compare the effects of two different continuous passive motion (CPM) application protocols (low- and high-angle) on the early phase functional activities of total knee arthroplasty inpatients. METHODS: The study included 170 patients who underwent primary TKA. While 84 of the TKA patients underwent low-angle CPM application, 86 of the patients underwent high-angle CPM application. The patients' functional activities were compared using the Iowa Level of Assistance Scale (ILAS), gait speeds using the Iowa Ambulation Velocity Scale (IAVS), knee scores using the Hospital for Special Surgery (HSS) Knee Score, and the duration of hospital stays with the Visual Analog Scale (VAS) preoperatively and on postoperative Day 2, Day 6, and at discharge. RESULTS: It was found that patients in the high-angle group had lower pain levels than did the patients in the low-angle group postsurgery (p<0.05). Patients in the high-angle group achieved their functional activities more independently on postoperative Day 2, Day 6, and at discharge than did the patients in the low-angle group (p<0.05). However, gait speed of patients in the former group was lower than that of the patients in the latter group (p<0.05). CONCLUSION: Although low-angle CPM application produced better results in terms of gait speed following TKA, the high-angle CPM application was superior in terms of independence levels of functional activities in the early postsurgery period. This result suggests that the appropriate use of rehabilitation methods such as CPM applications may guide clinicians to increase patients' level of independence. PMID- 26422345 TI - Total knee arthroplasty after osseous ankylosis of the knee joint. AB - OBJECTIVE: A knee fusion is associated with considerable restrictions, including the inability to sit properly, use public transportation, and climb stairs. The purpose of this study is to report and discuss our cases of spontaneous ankylosed knees which were taken down and underwent total knee arthroplasty (TKA). METHODS: Six patients who experienced spontaneous ankylosis of the knee undergoing conversion to TKA between 2003-2012 were enrolled retrospectively in this study. The etiology was childhood pyogenic arthritis in 2 patients, intraarticular fractures in 2, gunshot in 1, and juvenile rheumatoid arthritis in 1. The clinical data were recorded with the use of the Hospital for Special Surgery (HSS) knee rating system, Western Ontario and McMaster Questionnaire (WOMAC), and Visual Analog Scale (VAS), preoperatively and postoperatively at final follow-up. RESULTS: The average follow-up time was 86 months (range: 22-126 months). At the final follow-up, the average range of active flexion was 85 degrees (range: 75 95 degrees ). Postoperative average HSS knee rating system was improved from 19.5 (range: 18-22) to 57.49 (range: 46-80), WOMAC was improved from 39.75 (range: 36.4-43) to 62.41 (range: 50.8-74.5). VAS was improved from 9.5 (range: 7-9) to 2.8 (range: 2-4). A pyogenic infection developed in 2 patients; 1 was managed by debridement, and 1 was managed by arthrodesis 2 years later. CONCLUSION: The ability to walk and sit in a normal fashion is of great importance for patients. With good preoperative planning and careful handling, gratifying results are possible with TKA. PMID- 26422346 TI - Analysis of the reliability and validity of the Turkish version of the intermittent and constant osteoarthritis pain questionnaire. AB - OBJECTIVE: The aim of this study was to analyze the validity and reliability of the Turkish version (ICOAP-TR) of the intermittent and constant osteoarthritis pain (ICOAP) questionnaire in patients with knee osteoarthritis (OA). METHODS: Thirty-eight volunteer patients diagnosed with knee OA answered the questionnaire twice with an interval of 2-4 days. The reliability of the measurement was assessed using Cronbach's alpha coefficient and intraclass correlation (ICC) for test-retest reliability. Criterion validity was tested against the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score and visual analog scale (VAS) designed to assess the perceived discomfort rated by the patient. RESULTS: Test-retest reliability was found to be ICC=0.942 for total score, 0.902 for constant pain subscale, and 0.945 for intermittent pain subscale. Internal consistency was tested using Cronbach's alpha and was found to be 0.970 for total score, 0.948 for constant pain subscale, and 0.972 for intermittent pain subscale. For criterion validity, the correlation between the total score of ICOAP-TR and WOMAC pain subscale was r=0.779 (p<0.05), and correlation between total score of ICOAP-TR and VAS was r=0.570 (p<0.05). CONCLUSION: The ICOAP-TR is a reliable and valid instrument to be used with patients with knee OA. PMID- 26422347 TI - Single-stage posterior transforaminal lumbar interbody fusion, debridement, limited decompression, 3-column reconstruction, and posterior instrumentation in surgical treatment for single-segment lumbar spinal tuberculosis. AB - OBJECTIVE: The aim of this study is to determine the feasibility and efficacy of surgical management of single-segment lumbar spinal tuberculosis (TB) by using single-stage posterior transforaminal lumbar interbody fusion, debridement, limited decompression, 3-column reconstruction, and posterior instrumentation. METHODS: Seventeen cases of single-segment lumbar TB were treated with single stage posterior transforaminal lumbar interbody fusion, debridement, limited decompression, 3-column reconstruction, and posterior instrumentation. The mean follow-up was 36.9 months (range: 24-62 months). The kyphotic angle ranged from 15.2-35.1 degrees preoperatively, with an average measurement of 27.8 degrees . The American Spinal Injury Association (ASIA) score system was used to evaluate the neurological deficits and erythrocyte sedimentation rate (ESR) used to judge the activity of TB. RESULTS: Spinal TB was completely cured in all 17 patients. There was no recurrent TB infection. The postoperative kyphotic angle was 6.6 10.2 degrees , 8.1 degrees in average, and there was no significant loss of the correction at final follow-up. Solid fusion was achieved in all cases. Neurological condition in all patients was improved after surgery. CONCLUSION: Single-stage posterior transforaminal lumbar interbody fusion, debridement, limited decompression, 3-column reconstruction, and posterior instrumentation can be a feasible and effective method the in treatment of single-segment lumbar spinal TB. PMID- 26422348 TI - Safety and feasibility of lumbar spine for intralaminar screw fixation: a computed tomography-based morphometric study. AB - OBJECTIVE: The use of intralaminar screws (ILS) in spinal surgery has experienced a recent increase in popularity. The aim of this study is to define the morphological parameters of the lumbar laminas so that guidance may be defined for ILS placement. METHODS: The study involved the evaluation of lumbar computed tomography (CT) images of patients. Two hundred thirty-five patients (127 male, 108 female) were included in the study. The mean patient age was 44.2 years (19 78 years). The measured parameters of the lamina were the transverse inner diameter, transverse outer diameter (lamina width), lamina length, subdural space (safe zone), and spinolaminar angle for each lumbar level (L1-L5). RESULTS: The mean transverse outer diameter (L1-L5) ranged from 7.2-7.8 mm, and mean transverse inner diameter ranged from 2.5-3.0 mm. The lamina of L3 had the largest width and the lamina of L1 and L5 the smallest. The mean lamina length was 26.6 mm, ranging from 21.0-34.0 mm, and the mean spinolaminar angle was 124.7 degrees , ranging from 111-135 degrees . The L1 level had the shortest mean lamina length and L4 the lowest spinolaminar angle. Mean subdural space (safe zone), which was narrowest at the L5 level, was 2.4 mm, ranging from 1.3-3.6 mm. CONCLUSION: ILS of the appropriate size (3.5-4.5 mm) and length (20 and 25 mm) can be used safely in the lumbar spine. However, further biomechanical studies should be performed to measure strength of the fixation. PMID- 26422349 TI - A combined procedure for irreducible dislocation of patella in children with ligamentous laxity: a preliminary report. AB - OBJECTIVE: Irreducible patellar dislocation accompanying ligamentous laxity is rarely seen in pediatric patients. The most common complaints due to this condition are inability to walk, delayed walking, and difficulties with orthotics. The purpose of this retrospective study is to describe a novel surgical technique to treat dislocated patella in patients with symptomatic ligamentous laxity. METHODS: Fourteen knees of 9 patients operated on by a single surgeon between 2009-2012 were included in the study. The tensor fascia was divided into 2 strips, and these strips were passed via the joint and sutured to themselves. The combined procedure additionally includes lateral capsular release, vastus lateralis (VL) resection, medial capsular plication, and Z-plasty of the rectus femoris (RF) tendon. RESULTS: Mean age at the time of surgery was 6.9+/-3.3 years (range: 4-13 years). The mean follow-up was 37.6+/-0.9 months (range: 26-49 months). Patellofemoral instability was restored for all patients by using combined surgical technique. Patellar lateralization developed in 2 patients, in whom stability was obtained via secondary medial plication. CONCLUSION: Our results show that this combined surgical procedure stabilizes the knee and treats patellar dislocation accompanying ligamentous laxity in pediatric patients. PMID- 26422350 TI - Comparison between knot and Winograd techniques on ingrown nail treatment. AB - OBJECTIVE: The aim of this study was to compare the Winograd and knot techniques based on efficiency, complication rate, surgery time, and amount of local anesthetic required. This study also aimed to determine the etiology of ingrown nails, whether due to involvement of the nail or soft tissue. METHODS: Seventy five patients with a total of 90 ingrown nails (stages 2 and 3) who presented at our clinic between 2012-2014 were included in this study. Patients were divided into 2 groups: those treated with the knot technique and those treated with the Winograd technique. Patients in both groups were evaluated for the amount of local anesthetic required, intraoperative pain, effectiveness of preventing/stopping hemorrhage, surgery time, complications, postoperative nail size, recurrence, nail deformities, and secondary surgery rates. RESULTS: The mean surgical time, relapse rate, number of additional surgeries required, and amount of local anesthetic were significantly greater in the Winograd group than in the knot group. The mean nail diameter was significantly decreased, with a mean of 3 mm in the Winograd group. No statistically significant differences were found between the groups in the incidence of infection, intraoperative pain, hematoma, or nail deformity. CONCLUSION: This study demonstrated that the knot technique, consisting of wedge excision of soft tissue without affecting the nail itself, is a simple technique to treat ingrown nails with a lower complication rate and shorter surgical time. We believe that successful treatment of ingrown nails depends only on excision of soft tissue, with no need to operate on the nail bed. PMID- 26422351 TI - Effect of platelet-rich plasma for treatment of Achilles tendons in free-moving rats after surgical incision and treatment. AB - OBJECTIVE: The purpose of this study is to investigate, both histopathologically and biomechanically, the effect of platelet-rich plasma (PRP) on surgically repaired Achilles tendon rupture recovery in rats. METHODS: The study included 25 17-month-old male Sprague-Dawley rats with an average weight of 500-550 g. Five rats were used as donors, while 20 rats were separated as PRP group (n=10) and control group (n=10). The Achilles tendons of the rats were cut transversely, and PRP was administered to the PRP group, while the control group received serum physiologically to create the same surgical effect. In previous studies, it was shown that this serum does not affect tendon recovery. Fifteen and 30 days post treatment, the rats were sacrificed, and their Achilles tendons were extracted and examined histopathologically and biomechanically. RESULTS: Based on the obtained findings, it was observed that the histopathologic Movin and Bonar scores of PRP group on the 15th and 30th day post-treatment were significantly lower than those of the control group (p=0.019, p=0.017, respectively), while no significant difference was found in maximum force (Fmax) values in biomechanical measures on the 15th and 30th day post-treatment. CONCLUSION: It is thought that PRP use in Achilles tendon ruptures positively affects histopathological recovery in the early period, but that it does not produce the same biomechanical effect. We believe that PRP use for qualified tendon recovery is histopathologically beneficial. PMID- 26422352 TI - Reliability of threaded locking screws. AB - OBJECTIVE: A frequent problem for interlocking nailing that affects the treatment of the fracture is locking screw deformation. The aim of this study is to determine whether bending resistance is different between high, low, and unthreaded locking screws of interlocking femoral nails. METHODS: Ninety screws were used in this experimental study, with 10 screws used in each of 9 groups. Three-point bending tests were performed on 6 groups of 5 mm screws (titanium, stainless steel, crossed with unthreaded, low threaded, and high threaded) and the same 3 thread types of 5.5 mm stainless steel screws in a 30-mm inner diameter steel tube, imitating the level of the lesser trochanter. An axial compressor was used to determine the yield points for permanent deformation in the locking screws by way of 3-point bending tests. RESULTS: The mean yield point value of the 3-point bending tests of 5-mm low threaded stainless steel locking screws was 2071 N, 53% less than that of unthreaded screws (3169 N). The mean yield point value of 5-mm high threaded stainless steel locking screws was 556 N, 272% less than that of low threaded screws (2071 N). CONCLUSION: To avoid locking screw deformation, high threaded screws must not be used as locking screws. In cases of unreliable patients, 5-mm low threaded screws should not be used in the nailing of comminuted or oblique femur shaft fractures. All 5-mm unthreaded screws and 5.5-mm low threaded stainless steel screws can be used safely in full weight-bearing conditions of unreliable patients. PMID- 26422353 TI - Effects of intraperitoneal hydrogen injection on nitric oxide synthase mRNA and malondialdehyde following limb ischemia-reperfusion in rabbits. AB - OBJECTIVE: The purpose of this study was to investigate the effects of intraperitoneal hydrogen (H2) injection on the mRNA expression levels of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) as well as the serum malondialdehyde (MDA) level in a rabbit model of limb ischemia-reperfusion (I/R)-induced skeletal muscle injury. METHODS: To establish the hind limb I/R animal model, 30 rabbits were randomly assigned to one of 3 groups: sham, I/R, and ischemia-reperfusion + H2 (IRH). An intraperitoneal injection of H2 was given to the IRH group, while an equivalent amount of air was given to the sham and I/R groups. At 3, 6, 12, and 24 h after reperfusion, serum MDA level as well as skeletal muscle iNOS and eNOS mRNA expression levels were determined. RESULTS: Both iNOS mRNA expression and serum MDA levels were higher in the I/R group than the sham group (p<0.01) and lower in the IRH group than the I/R group (p<0.01, p<0.05, respectively) at various time points after reperfusion. The eNOS mRNA expression level exhibited no significant difference between the I/R and sham groups after reperfusion but was significantly higher in the IRH group than in the sham group (p<0.01, p<0.05, respectively). CONCLUSION: During the I/R process, the expression of iNOS mRNA was up-regulated along with an increase in MDA. Intraperitoneal injection of H2 can down-regulate iNOS mRNA expression and up-regulate eNOS mRNA expression in the I/R process, suggesting a protective effect of H2 in I/R-induced skeletal muscle injury. PMID- 26422354 TI - A mechanically locked knee joint due to free-floating flake-shaped rice bodies: a case report. AB - Originating from the synovium, multiple free-floating intra-articular particles, called rice bodies, typically resemble cartilage and have a fibrin structure. While the etiology of rice body formation is unclear, they often occur in rheumatoid arthritis and other seronegative arthropathies; they also occur in tuberculosis, though the incidence is much lower. They are often encountered by rheumatologists or clinical orthopedists. A 33-year-old female who suffered from occasional swelling and pain of her left knee for 3 months was admitted with a mechanically locked knee. Free-floating rice bodies were identified on magnetic resonance imaging (MRI), and arthroscopic intervention was performed for diagnostic and therapeutic purposes. After the removal of all bodies and effusion with mechanical irrigation, an arthroscopic subtotal synovectomy was performed. PMID- 26422355 TI - Parvovirus B19-induced acute bilateral carpal tunnel syndrome in twin girls. AB - We describe 2 cases of 6-year-old twin girls presenting with acute carpal tunnel syndrome (CTS) associated with human parvovirus B19 (HPV-B19) infection, as evidenced by serological data and detection of HPV-B19 DNA in blood with use of polymerase chain reaction (PCR). To our knowledge, this is the first time that HPV-B19 infection has been suggested as the causal agent of simultaneous acute bilateral CTS in twins, thus presenting the possibility that similar immunologic responses can be observed in twins during viral infections. PMID- 26422356 TI - Omentum and reverse turnover latissimus dorsi musculocutaneous flap for the treatment of cerebrospinal fluid fistula. AB - Conventional procedures can usually prevent cerebrospinal fluid (CSF) leakages, but they may not work for complicated cases. In this case presentation, we demonstrated the effectiveness of combined omental and latissimus dorsi musculocutaneous flaps for management of difficult CSF fistula. A reverse turnover latissimus dorsi musculocutaneous flap and omental flap were transferred for reconstruction of the posterior wound and CSF leakage. The omental flap component was used for CSF absorption, and the latissimus dorsi muscle component was used for obliteration of the dead space, covering of the exposed bone, and tension-free closure of the wound. The wound healed dramatically, with no observed severe donor site morbidity. The patient has been followed for 30 months with no evidence of CSF leakage and no pseudomeningocele formation, which was confirmed by magnetic resonance imaging (MRI). Although this is a case presentation, we can say that the combination of the omental and musculocutaneous flaps allow effective treatment and prevention of CSF fistulas in selected high risk patients and provide durable coverage of complex spinal wounds. PMID- 26422357 TI - Comment on: Functional outcomes of minimal invasive percutaneous plate osteosynthesis (MIPPO) in humerus shaft fractures: a clinical study. PMID- 26422358 TI - Authors' reply. PMID- 26422360 TI - Impact of glucocerebrosidase mutations on motor and nonmotor complications in Parkinson's disease. AB - Homozygous mutations of the glucocerebrosidase gene (GBA) cause Gaucher disease (GD), and heterozygous mutations of GBA are a major risk factor for Parkinson's disease (PD). This study examined the impact of GBA mutations on the longitudinal clinical course of PD patients by retrospective cohort design. GBA-coding regions were fully sequenced in 215 PD patients and GD-associated GBA mutations were identified in 19 (8.8%) PD patients. In a retrospective cohort study, time to develop dementia, psychosis, wearing-off, and dyskinesia were examined. Survival time analysis followed a maximum 12-year observation (median 6.0 years), revealing that PD patients with GD-associated mutations developed dementia and psychosis significantly earlier than those without mutations (p < 0.001 and p = 0.017, respectively). Adjusted hazard ratios of GBA mutations were 8.3 for dementia (p < 0.001) and 3.1 for psychosis (p = 0.002). No statistically significant differences were observed for wearing-off and dyskinesia between the groups. N-isopropyl-p[(123)I] iodoamphetamine single-photon emission tomography pixel-by-pixel analysis revealed that regional cerebral blood flow was reduced in the bilateral parietal cortex, including the precuneus of GD-associated mutant PD patients, compared with matched PD controls without mutations. PMID- 26422359 TI - Suspected non-AD pathology in mild cognitive impairment. AB - We aim to better characterize mild cognitive impairment (MCI) patients with suspected non-Alzheimer's disease (AD) pathology (SNAP) based on their longitudinal outcome, cognition, biofluid, and neuroimaging profile. MCI participants (n = 361) from ADNI-GO/2 were designated "amyloid positive" with abnormal amyloid-beta 42 levels (AMY+) and "neurodegeneration positive" (NEU+) with abnormal hippocampal volume or hypometabolism using fluorodeoxyglucose positron emission tomography. SNAP was compared with the other MCI groups and with AMY- controls. AMY-NEU+/SNAP, 16.6%, were older than the NEU- groups but not AMY- controls. They had a lower conversion rate to AD after 24 months than AMY+NEU+ MCI participants. SNAP-MCI participants had similar amyloid-beta 42 levels, florbetapir and tau levels, but larger white matter hyperintensity volumes than AMY- controls and AMY-NEU- MCI participants. SNAP participants performed worse on all memory domains and on other cognitive domains, than AMY NEU- participants but less so than AMY+NEU+ participants. Subthreshold levels of cerebral amyloidosis are unlikely to play a role in SNAP-MCI, but pathologies involving the hippocampus and cerebrovascular disease may underlie the neurodegeneration and cognitive impairment in this group. PMID- 26422361 TI - DNA methylation levels of alpha-synuclein intron 1 in the aging brain. AB - DNA methylation patterns change with age, and aging itself is a major confounding risk factor for Parkinson's disease (PD). Duplication and triplication, that is, increased expression of the alpha-synuclein (SNCA) gene, cause familial PD, and demethylation of SNCA intron 1 has been shown to result in increased expression of SNCA. We thus hypothesized that age-related alterations of SNCA methylation might underly the increased susceptibility toward PD in later life. The present study sought to determine (1) whether alterations of SNCA intron 1 methylation occurred during aging, (2) whether the methylation pattern differed between men and women, and (3) whether purified neurons compared with non-neuronal cells exhibited different methylation patterns. The analysis of DNA from brain tissue and fluorescence activated cell sorting-sorted purified neurons of 41 individuals revealed only a minor increase of SNCA intron 1 DNA methylation levels in presumably healthy individuals during aging but no significant difference between men and women. Interestingly enough, methylation of SNCA intron 1 was higher in neurons compared with non-neuronal cells, although non-neuronal cells express lower levels of SNCA. Therefore, the normal pattern of SNCA methylation during aging should not result in increased expression of alpha-synuclein protein. It is thus likely that additional, yet not identified, mechanisms contribute to the tissue specificity of SNCA expression and the presumed dysregulation in PD. PMID- 26422362 TI - Probable novel PSEN2 Pro123Leu mutation in a Chinese Han family of Alzheimer's disease. AB - We describe a probably novel mutation in exon 5 of the presenilin 2 gene (Pro123Leu) in a Chinese familial early-onset Alzheimer's disease, which clinically manifests as progressive memory loss, cognitive impairment, parkinsonism, and myoclonic jerks. Clinical and neuroimaging examination, target region capture, and high-throughput sequencing were performed in a family of 4 generations. Cerebral perfusion and glucose metabolism were evaluated using arterial spin labeling perfusion magnetic resonance imaging and (18)F fludeoxyglucose positron emission tomography, respectively. Target region capture sequencing yielded a novel missense mutation at codon 123 (P123L) which is a heterozygous C to T point mutation at position 368 (c.368C>T) in exon 5 of the presenilin 2 leading to a proline-to-leucine substitution. The results were also identified by Sanger sequencing in 7 family members but not in the other 9 unaffected family members and 100 control subjects. This mutation is probably pathogenic and is the first of its kind reported in an early-onset familial AD associated with atypical symptom presentation. PMID- 26422363 TI - Rapid and Versatile Photonic Annealing of Graphene Inks for Flexible Printed Electronics. AB - Intense pulsed light (IPL) annealing of graphene inks is demonstrated for rapid post-processing of inkjet-printed patterns on various substrates. A conductivity of ~25,000 S m(-1) is achieved following a single printing pass using a concentrated ink containing 20 mg mL(-1) graphene, establishing this strategy as a practical and effective approach for the versatile and high-performance integration of graphene in printed and flexible electronics. PMID- 26422364 TI - The effect of animal health compensation on 'positive' behaviours towards exotic disease reporting and implementing biosecurity: A review, a synthesis and a research agenda. AB - With an increasing burden on public sector budgets, increased responsibility and cost sharing mechanisms for animal diseases are being considered. To achieve this, fiscal and non-fiscal intervention policies need to be designed such that they consistently promote positive disease risk management practices by animal keepers. This paper presents a review of the available evidence towards whether and how the level and type of funding mechanism affects change within biosecurity behaviours and the frequency of disease reporting. A Nuffield Health Ladder of Interventions approach is proposed as a way to frame the debate surrounding both current compensation mechanisms and how it is expected to change behaviour. Results of the review reveal a division between economic modelling approaches, which implicitly assume a causal link between payments and positive behaviours, and socio-geographic approaches which tend to ignore the influence of compensation mechanisms on influencing behaviours. Generally, economic studies suggest less than full compensation rates will encourage positive behaviours, but the non-economic literature indicate significant variation in response to compensation reflecting heterogeneity of livestock keepers in terms of their values, goals, risk attitudes, size of operation, animal species and production chain characteristics. This may be of encouragement to Western Governments seeking to shift cost burdens as it may induce greater targeting of non-fiscal mechanisms, or suggest more novel ways to augment current compensation mechanisms to both increase responsibility sharing and reduce this cost burden. This review suggests that a range of regulatory, fiscal and nudging policies are required to achieve socially optimal results with respect to positive behaviour change. However, the lack of directly available evidence which proves these causal links may hinder progress towards this optimal mixture of choice and non-choice based interventions. PMID- 26422365 TI - [Customized and non-customized French intrauterine growth curves. I - Methodology]. AB - OBJECTIVES: We developed intrauterine growth references, called EPOPe curves, in line with recommendations for screening of intra-uterine growth restriction issued in 2013 by the French College of Obstetricians and Gynecologists. POPULATION AND METHODS: Using the French Perinatal Survey (FPS) 2010, we adapted the methodology developed by Gardosi (1) to model intrauterine growth and its distribution and (2) to adjust for physiological fetal and maternal factors influencing fetal weight. Based on this model, 3 reference curves (unadjusted, adjusted for fetal sex, and adjusted for fetal sex, and maternal height, weight and parity) were proposed. We applied these models to births in the 2010 FPS and the French hospital discharge database (PMSI) in 2011-2012. RESULTS: Among singleton live births in the FPS and the PMSI, the model adjusted for fetal sex identified 3.2 and 3.3% of births below the 3rd centile respectively, and 10.0 and 10.2% below the 10th. In model adjusted for maternal factors, 4.0% of births from the FPS 2010 were reclassified, but population rates remained at 3.0 and 10.0%. CONCLUSION: This growth model is appropriate for French births, and allows for the implementation of a homogeneous definition of small for gestational age infants during pregnancy and at birth. PMID- 26422366 TI - A light fingertip touch reduces postural sway in children with autism spectrum disorders. AB - This study examined the effects of a light fingertip touch on postural control in children with autism spectrum disorders (ASD) and typically developing children (TDC). METHODS: We recruited 16 children with ASD (age=11.041+/-1.275), and 16 TDC (age=10.966+/-1.166 years). A force platform measured postural sway in the anteroposterior (AP) and mediolateral (ML) directions under light fingertip touch (LT) and no touch (NT) conditions, with both eyes open (EO) and both eyes closed (EC). As a summary of the experimental conditions, ML sway was significantly greater in the ASD group than in the TDC group. Also, results showed a significant reduction in postural sway in the ML direction in the LT condition compared with the NT condition. These effects applied to both the EO and EC conditions. Lastly, the reduction in ML sway between the NT and LT conditions was significantly greater in the ASD than the TDC group. CONCLUSION: The effects of a light fingertip touch on reducing postural sway appear more efficient in children with ASD compared with TDC. These findings suggest that a light fingertip touch may be of clinical and practical importance, and provides a useful means of enhancing postural stability in children with ASD. PMID- 26422367 TI - Gradual Reduction in Sodium Content in Cooked Ham, with Corresponding Change in Sensorial Properties Measured by Sensory Evaluation and a Multimodal Machine Vision System. AB - The European diet today generally contains too much sodium (Na(+)). A partial substitution of NaCl by KCl has shown to be a promising method for reducing sodium content. The aim of this work was to investigate the sensorial changes of cooked ham with reduced sodium content. Traditional sensorial evaluation and objective multimodal machine vision were used. The salt content in the hams was decreased from 3.4% to 1.4%, and 25% of the Na(+) was replaced by K(+). The salt reduction had highest influence on the sensory attributes salty taste, after taste, tenderness, hardness and color hue. The multimodal machine vision system showed changes in lightness, as a function of reduced salt content. Compared to the reference ham (3.4% salt), a replacement of Na(+)-ions by K(+)-ions of 25% gave no significant changes in WHC, moisture, pH, expressed moisture, the sensory profile attributes or the surface lightness and shininess. A further reduction of salt down to 1.7-1.4% salt, led to a decrease in WHC and an increase in expressible moisture. PMID- 26422368 TI - Harmony Search Algorithm for Word Sense Disambiguation. AB - Word Sense Disambiguation (WSD) is the task of determining which sense of an ambiguous word (word with multiple meanings) is chosen in a particular use of that word, by considering its context. A sentence is considered ambiguous if it contains ambiguous word(s). Practically, any sentence that has been classified as ambiguous usually has multiple interpretations, but just one of them presents the correct interpretation. We propose an unsupervised method that exploits knowledge based approaches for word sense disambiguation using Harmony Search Algorithm (HSA) based on a Stanford dependencies generator (HSDG). The role of the dependency generator is to parse sentences to obtain their dependency relations. Whereas, the goal of using the HSA is to maximize the overall semantic similarity of the set of parsed words. HSA invokes a combination of semantic similarity and relatedness measurements, i.e., Jiang and Conrath (jcn) and an adapted Lesk algorithm, to perform the HSA fitness function. Our proposed method was experimented on benchmark datasets, which yielded results comparable to the state of-the-art WSD methods. In order to evaluate the effectiveness of the dependency generator, we perform the same methodology without the parser, but with a window of words. The empirical results demonstrate that the proposed method is able to produce effective solutions for most instances of the datasets used. PMID- 26422369 TI - The Jebsen Taylor Test of Hand Function: A Pilot Test-Retest Reliability Study in Typically Developing Children. AB - AIMS: The aim of this pilot study was to evaluate reproducibility of the Jebsen Taylor Test of Hand Function (JTTHF) in children. METHODS: Eighty-seven typically developing children 5 to 10 years old were included from five Outside School Hours Care centers in the Greater Brisbane Region, Australia. Hand function was assessed on two occasions with a modified JTTHF, then reproducibility was assessed using Intraclass Correlation Coefficient (ICC [3,1]) and the Standard Error of Measurement (SEM). RESULTS: Total scores for male and female children were not significantly different. Five-year-old children were significantly different to all other age groups and were excluded from further analysis. Results for 71 children, 6 to 10 years old were analyzed (mean age 8.31 years (SD 1.32); 33 males). Test-retest reliability for total scores on the dominant and nondominant hands were ICC 0.74 (95% CI 0.61, 0.83) and ICC 0.72 (95% CI 0.59, 0.82), respectively. 'Writing' and 'Simulated Feeding' subtests demonstrated poor reproducibility. The Smallest Real Difference was 5.09 seconds for total score on the dominant hand. CONCLUSIONS: Findings indicate good test-retest reliability for the JTTHF total score to measure hand function in typically developing children aged 6 to 10 years. PMID- 26422370 TI - Crystal structures of halohydrin hydrogen-halide-lyases from Corynebacterium sp. N-1074. AB - Halohydrin hydrogen-halide-lyase (H-Lyase) is a bacterial enzyme that is involved in the degradation of halohydrins. This enzyme catalyzes the intramolecular nucleophilic displacement of a halogen by a vicinal hydroxyl group in halohydrins to produce the corresponding epoxides. The epoxide products are subsequently hydrolyzed by an epoxide hydrolase, yielding the corresponding 1, 2-diol. Until now, six different H-Lyases have been studied. These H-Lyases are grouped into three subtypes (A, B, and C) based on amino acid sequence similarities and exhibit different enantioselectivity. Corynebacterium sp. strain N-1074 has two different isozymes of H-Lyase, HheA (A-type) and HheB (B-type). We have determined their crystal structures to elucidate the differences in enantioselectivity among them. All three groups share a similar structure, including catalytic sites. The lack of enantioselectivity of HheA seems to be due to the relatively wide size of the substrate tunnel compared to that of other H Lyases. Among the B-type H-Lyases, HheB shows relatively high enantioselectivity compared to that of HheBGP1 . This difference seems to be due to amino acid replacements at the active site tunnel. The binding mode of 1, 3-dicyano-2 propanol at the catalytic site in the crystal structure of the HheB-DiCN complex suggests that the product should be (R)-epichlorohydrin, which agrees with the enantioselectivity of HheB. Comparison with the structure of HheC provides a clue for the difference in their enantioselectivity. PMID- 26422371 TI - Effects of Dexamethasone and Insulin Alone or in Combination on Energy and Protein Metabolism Indicators and Milk Production in Dairy Cows in Early Lactation - A Randomized Controlled Trial. AB - OBJECTIVES: This study investigated the effects of dexamethasone and insulin, when administered at 3rd or 10th day of lactation on energy and protein metabolism in dairy cows. MATERIALS AND METHODS: Two hundred Holstein cows were enrolled in a randomized controlled clinical trial. The cows were randomly assigned to receive 1 of 4 treatments at 3 or 10 days in milk: control group, 10 mL i.m. injection of sterile water, group insulin, s.c. injection of 100 units of insulin, group dexamethasone, i.m. injection of 20 mg of dexamethasone, group insulin plus dexamethasone, i.m. injection of 20 mg of dexamethasone and 100 units of insulin. The cows randomly assigned to receive the treatments on 3 or 10 days of lactation. Serum samples obtained at the time of enrollment, time of treatment and at 2, 4, 7 and 14 days after intervention. The sera were analyzed for beta-hydroxybutyrate (BHBA), nonesterified fatty acids (NEFA), glucose, cholesterol, albumin, urea, and aspartate amino transferase (AST). Data were analyzed using a repeated measures mixed model that accounted for the effects of parity, body condition score, dystocia, retained placenta, metritis and the random effect of cow. RESULTS: There was no significant interaction of group of treatment and time of intervention (day 3 or 10 post-partum) on serum components. Cows that received insulin or dexamethasone alone or in combination, had lower BHBA 2 days after treatment compared with control cows, whereas concentrations of NEFA, were unaffected suggesting that glucocorticoids lipolytic effects do not appear to be important in healthy cows. AST activities significantly reduced in cows that received dexamethasone with or without insulin at 2 and 4 days after treatment. Albumin and urea concentrations 2 days after treatment were higher for cows that received dexamethasone only or dexamethasone plus insulin compared with control and Ins received cows. There were no treatment effects on test-day milk production, milk fat and protein percentages. CONCLUSIONS: The results suggested that administration of glucocorticoids in early lactation resulted in short-term improvement of metabolism in postpartum dairy cows in biochemical terms. PMID- 26422372 TI - Social Support for First-Time Chinese Mothers in Contexts of Provider-Recipient Relationships. AB - This study examined the influence of social support on perceived stress and online support activities in two relationship contexts. In 2013, we surveyed 366 first-time mothers between the ages of 26 and 30 years from mainland China about their social support experiences with their mothers and mothers-in-law in regard to child rearing. Women who received higher levels of support from their mothers reported lower levels of perceived stress and higher levels of online support activities. Receiving support from mothers-in-law was not associated with either perceived stress or online support activities. The findings demonstrate the importance of considering relationship contexts when examining social support outcomes. Implications for future research on social support and interpersonal relationships are discussed. PMID- 26422373 TI - Co-delivery of Pirarubicin and Paclitaxel by Human Serum Albumin Nanoparticles to Enhance Antitumor Effect and Reduce Systemic Toxicity in Breast Cancers. AB - In our study, we aimed to develop a codelivery nanoparticulate system of pirarubicin (THP) and paclitaxel (PTX) (Co-AN) using human serum albumin to improve the therapeutic effect and reduce systemic toxicities. The prepared Co-AN demonstrated a narrow size distribution around 156.9 +/- 3.2 nm (PDI = 0.16 +/- 0.02) and high loading efficiency (87.91 +/- 2.85% for THP and 80.20 +/- 2.21% for PTX) with sustained release profiles. Significantly higher drug accumulation in tumors and decreased distribution in normal tissues were observed for Co-AN in xenograft 4T1 murine breast cancer bearing BALB/c mice. Cytotoxicity test against 4T1 cells in vitro and antitumor assay on 4T1 breast cancer in vivo demonstrated that the antitumor effect of Co-AN was superior to that of the single drug or free combination. Also, Co-AN induced increased apoptosis and G2/M cell cycle arrest against 4T1 cells compared to that of the single drug formulation. Remarkably, Co-AN exhibited significantly lower side effects regarding bone marrow suppression and organ and gastrointestinal toxicities. This human serum albumin-based codelivery system represents a promising platform for combination chemotherapy in breast cancers. PMID- 26422374 TI - Sequence Factorization with Multiple References. AB - The success of high-throughput sequencing has lead to an increasing number of projects which sequence large populations of a species. Storage and analysis of sequence data is a key challenge in these projects, because of the sheer size of the datasets. Compression is one simple technology to deal with this challenge. Referential factorization and compression schemes, which store only the differences between input sequence and a reference sequence, gained lots of interest in this field. Highly-similar sequences, e.g., Human genomes, can be compressed with a compression ratio of 1,000:1 and more, up to two orders of magnitude better than with standard compression techniques. Recently, it was shown that the compression against multiple references from the same species can boost the compression ratio up to 4,000:1. However, a detailed analysis of using multiple references is lacking, e.g., for main memory consumption and optimality. In this paper, we describe one key technique for the referential compression against multiple references: The factorization of sequences. Based on the notion of an optimal factorization, we propose optimization heuristics and identify parameter settings which greatly influence 1) the size of the factorization, 2) the time for factorization, and 3) the required amount of main memory. We evaluate a total of 30 setups with a varying number of references on data from three different species. Our results show a wide range of factorization sizes (optimal to an overhead of up to 300%), factorization speed (0.01 MB/s to more than 600 MB/s), and main memory usage (few dozen MB to dozens of GB). Based on our evaluation, we identify the best configurations for common use cases. Our evaluation shows that multi-reference factorization is much better than single reference factorization. PMID- 26422375 TI - Assessment of Bacterial Community Assembly Patterns and Processes in Pig Manure Slurry. AB - The bacterial community assembly patterns and processes are poorly understood in pig manure slurry. We collected pig manure slurry samples during the winter and summer seasons from eight commercial pig farms in South Korea. The V3 region of 16S rRNA genes was PCR amplified and sequenced using paired-end Illumina technology for in-depth characterization of bacterial community. Firmicutes, Bacteroidetes, Proteobacteria, Spirochaetes, and Tenericutes were the predominant bacterial phyla present in slurry samples. Bacterial taxonomic community composition was not influenced by the season; however, phylogenetic community composition was affected by seasonal variations. The community composition and diversity patterns were strongly influenced by pH. The bacterial diversity indices showed a unimodal relationship with pH. Phylogenetic signals were detected over only short phylogenetic distances, revealing that closely related bacterial operational taxonomic units (OTUs) tend to co-occur in the same environment; hence, they are ecologically similar. Across all samples, a niche based process, through strong environmental filtering imposed by pH, primarily governed bacterial community assembly; however, in samples close to the neutral pH range, the role of environmental filtering was decreased due to neutral community assembly. In summary, pH emerged as the major physico-chemical variable in pig manure slurry that regulates the relative importance of niche-based and neutral processes in shaping the community assembly of bacteria. PMID- 26422377 TI - Enhanced recovery: Minimally aggressive perioperative practice. PMID- 26422376 TI - Gut Microbiome of an 11th Century A.D. Pre-Columbian Andean Mummy. AB - The process of natural mummification is a rare and unique process from which little is known about the resulting microbial community structure. In the present study, we characterized the microbiome of paleofeces, and ascending, transverse and descending colon of an 11th century A.D. pre-Columbian Andean mummy by 16S rRNA gene high-throughput sequencing and metagenomics. Firmicutes were the most abundant bacterial group, with Clostridium spp. comprising up to 96.2% of the mummified gut, while Turicibacter spp. represented 89.2% of the bacteria identified in the paleofeces. Microbiome profile of the paleofeces was unique when compared to previously characterized coprolites that did not undergo natural mummification. We identified DNA sequences homologous to Clostridium botulinum, Trypanosoma cruzi and human papillomaviruses (HPVs). Unexpectedly, putative antibiotic-resistance genes including beta-lactamases, penicillin-binding proteins, resistance to fosfomycin, chloramphenicol, aminoglycosides, macrolides, sulfa, quinolones, tetracycline and vancomycin, and multi-drug transporters, were also identified. The presence of putative antibiotic-resistance genes suggests that resistance may not necessarily be associated with a selective pressure of antibiotics or contact with European cultures. Identification of pathogens and antibiotic-resistance genes in ancient human specimens will aid in the understanding of the evolution of pathogens as a way to treat and prevent diseases caused by bacteria, microbial eukaryotes and viruses. PMID- 26422379 TI - Validity of Self-Reported Psoriasis in a General Population: The HUNT Study, Norway. PMID- 26422380 TI - Desmoglein 3-Dependent Signaling Regulates Keratinocyte Migration and Wound Healing. AB - The desmosomal transmembrane adhesion molecules desmoglein 3 (Dsg3) and desmocollin 3 (Dsc3) are required for strong keratinocyte cohesion. Recently, we have shown that Dsg3 associates with p38MAPK and suppresses its activity. Here, we further investigated the role of Dsg3-dependent control of p38MAPK function. Dsg3-deficient mice display recurrent spontaneously healing skin erosions. In lesional and perilesional biopsies, p38MAPK activation was detectable compared to control animals. This led us to speculate that Dsg3 regulates wound repair in a p38MAPK-dependent manner. Indeed, scratch wounded keratinocyte monolayers exhibited p38MAPK activation and loss of Dsg3 in cells lining the wound edge. Human keratinocytes after silencing of Dsg3 as well as primary cells isolated from Dsg3 knockout animals exhibited accelerated migration, which was further corroborated in an ex vivo skin outgrowth assay. Importantly, migration was efficiently blocked by inhibition of p38MAPK, indicating that p38MAPK mediates the effects observed upon loss of Dsg3. In line with this, we show that levels of active p38MAPK associated with Dsc3 are increased in Dsg3-deficient cells. These data indicate that Dsg3 controls a switch from an adhesive to a migratory keratinocyte phenotype via p38MAPK inhibition. Thus, loss of Dsg3 adhesion may foster wound closure by allowing p38MAPK-dependent migration.Journal of Investigative Dermatology accepted article preview online, 30 September 2015. doi:10.1038/jid.2015.380. PMID- 26422378 TI - The GADD45A (1506T>C) Polymorphism Is Associated with Ovarian Cancer Susceptibility and Prognosis. AB - GADD45A (growth arrest and DNA damage 45 A) is the first stress-inducible gene identified to be a target of p53. However, no studies to date have assessed variants of the GADD45 gene and their potential relationship to tumor susceptibility. We investigated the association of the GADD45A (1506T>C) polymorphism with ovarian cancer development in 258 ovarian cancer patients and 332 age-matched healthy women as controls using sequence analysis. We found a statistically significant difference in the GADD45A (1506T>C) genotype distributions between the case and control groups (TT vs. TC vs. CC, P = 0.0021) and found that variant 1506T>C was significantly associated with an increased risk of ovarian cancer (P<0.001, OR = 1.71, 95% CI [1.28-2.29]). We observed a statistically significant effect between tumor histology (P = 0.032) and CA125 status (P = 0.021). Carrying the C allele (TC+CC) was associated with an increased risk of positive CA125 (OR = 3.20, 95% CI [1.15-8.71). Carrying the T allele (TT+TC) showed a significant correlation with both higher GADD45A mRNA expression and longer ovarian cancer RFS (relapse-free survival) and OS (overall survival). We are the first group to demonstrate that the GADD45A (1506T>C) polymorphism is associated with ovarian cancer susceptibility and prognosis. These data suggest that GADD45A (1506T>C) is a new tumor susceptibility gene and could be a useful molecular marker for assessing ovarian cancer risk and for predicting ovarian cancer patient prognosis. PMID- 26422381 TI - Immunomodulatory Activities of the Benzoxathiole Derivative BOT-4-One Ameliorate Pathogenic Skin Inflammation in Mice. AB - T cell-mediated immune responses play an important role in body protection. However, aberrantly activated immune responses are responsible for inflammatory and autoimmune diseases. The regulation of pathological immune responses may be a potential therapeutic strategy for the treatment of these diseases. Despite multiple pharmacological properties of benzoxathiole derivatives have been defined, the molecular mechanisms underlying these properties remain to be clarified. Here, we demonstrated the benzoxathiole derivative 2-cyclohexylimino-6 methyl-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one (BOT-4-one) regulated immune responses and ameliorated experimentally induced inflammatory skin diseases both in vitro and in vivo. BOT-4-one inhibited the differentiation of CD4+ T-cell subsets by regulating the expression and production of T cell lineage-specific master transcription factors and cytokines and activating the signal transducer and activator of transcription (STAT) proteins. In addition, BOT-4-one inhibited T-cell receptor (TCR)-mediated Akt and nuclear factor-kappaB (NF-kappaB) signaling. Topical application of BOT-4-one ameliorated experimentally induced inflammatory skin diseases in mice models such as TNCB-induced contact and atopic dermatitis and IL-23-induced psoriasis-like skin inflammation. Our study demonstrated that BOT-4-one ameliorates inflammatory skin diseases by suppressing the pathogenic CD4+ T cell differentiation and the overall immune responses.Journal of Investigative Dermatology accepted article preview online, 30 September 2015. doi:10.1038/jid.2015.384. PMID- 26422382 TI - Increased Bacterial Load and Expression of Antimicrobial Peptides in Skin of Barrier-Deficient Mice with Reduced Cancer Susceptibility. AB - Mice lacking three epidermal barrier proteins-envoplakin, periplakin and involucrin-(EPI-/- mice) have a defective cornified layer, reduced epidermal gammadelta T cells, increased dermal CD4+ T cells and are resistant to developing skin tumours. The tumour-protective mechanism involves signalling between Rae-1 expressing keratinocytes and the Natural Killer Group 2D (NKG2D) receptor on immune cells, which also plays a role in host defences against infection. Given the emerging link between bacteria and cancer, we investigated whether EPI-/- mice have an altered skin microbiota. The bacterial phyla were similar in wild type and EPI-/- skin. However, bacteria were 3-fold more abundant in EPI-/- skin and penetrated deeper into the epidermis. The major epithelial defense mechanism against bacteria is production of antimicrobial proteins (AMPs). EPI-/- skin exhibited enhanced expression of antimicrobial peptides. However, reducing the bacterial load by antibiotic treatment or breeding mice under specific pathogen free conditions did not reduce AMP expression or alleviate the abnormalities in T cell populations. We conclude that the atopic characteristics of EPI-/- skin are a consequence of the defective barrier rather than a response to the increased bacterial load. It is therefore unlikely that the increase in skin microbiota contributes directly to the observed cancer resistance.Journal of Investigative Dermatology accepted article preview online, 30 September 2015. doi:10.1038/jid.2015.383. PMID- 26422383 TI - Spleen Tyrosine Kinase Mediates EGFR Signaling to Regulate Keratinocyte Terminal Differentiation. AB - Spleen tyrosine kinase (Syk), a non-receptor tyrosine kinase, was initially identified as a crucial regulator in proximal immunoreceptor signaling. Additional studies have revealed its pleiotropic roles, and drugs targeting Syk are under development for inflammatory diseases. Syk expression in the skin has been detected, but its functions in the skin are still unknown. Here, we found that Syk phosphorylation and expression in primary human keratinocytes decrease gradually along with terminal differentiation. Human skin specimens showed similar in vivo patterns. Syk inhibitors or knockdown of Syk increased the expression of differentiation markers under in vitro differentiation models. Furthermore, EGFR activation prominently induced Syk phosphorylation, which could be inhibited by the EGFR inhibitor gefitinib or knockdown of EGFR. The Src inhibitor also partially attenuated EGF-induced phosphorylation of Syk. However, Syk inhibition suppressed EGF-induced phosphorylation of EGFR. Immunoprecipitation and confocal microscopy further revealed the increased molecular interaction between EGFR and Syk after EGF stimulation. This study unravels the role of Syk in EGFR-mediated signaling and reveals regulatory roles of Syk in keratinocyte differentiation, suggesting the clinical potential of topical or systemic Syk inhibitors in the treatment of skin diseases with aberrant differentiation.Journal of Investigative Dermatology accepted article preview online, 30 September 2015. doi:10.1038/jid.2015.381. PMID- 26422386 TI - In vitro Characterization of the Rapid Cytotoxicity of Anticancer Peptide HPRP-A2 through Membrane Destruction and Intracellular Mechanism against Gastric Cancer Cell Lines. AB - In this study, HPRP-A2, a synthetic 15-mer cationic peptides with all D-amino acids, effectively inhibited the survival of gastric cell lines in a dose dependent manner. Gastric tumor cells killing by HPRP-A2 involves a rapid collapse of the membrane integrity and intracellular pathways. Propidium iodide (PI) and lactate dehydrogenase (LDH) assays demonstrated that one-hour treatment with HPRP-A2 led to membrane permeability changes of BGC-823 cells in a dose dependent manner. Moreover, HPRP-A2 induced apoptosis in BGC-823 cells involves a marked increase in generation of reactive oxygen species (ROS),caspase-3, -8 and 9 activation, a reduction of mitochondrial membrane potential (MMP), and cell cycle arrest in G1 phase. In addition to its inherent cytotoxicity, HPRP-A2 synergized strongly with doxorubicin (DOX) to enhance the efficacy of killing gastric tumor cells in vitro. We believe that HPRP-A2 with all D-amino acids could be a potent candidate of anticancer therapeutics, especially in combination therapy. PMID- 26422387 TI - Spotting 2D atomic layers on aluminum nitride thin films. AB - Substrates for 2D materials are important for tailoring their fundamental properties and realizing device applications. Aluminum nitride (AIN) films on silicon are promising large-area substrates for such devices in view of their high surface phonon energies and reasonably large dielectric constants. In this paper epitaxial layers of AlN on 2" Si wafers have been investigated as a necessary first step to realize devices from exfoliated or transferred atomic layers. Significant thickness dependent contrast enhancements are both predicted and observed for monolayers of graphene and MoS2 on AlN films as compared to the conventional SiO2 films on silicon, with calculated contrast values approaching 100% for graphene on AlN as compared to 8% for SiO2 at normal incidences. Quantitative estimates of experimentally measured contrast using reflectance spectroscopy show very good agreement with calculated values. Transistors of monolayer graphene on AlN films are demonstrated, indicating the feasibility of complete device fabrication on the identified layers. PMID- 26422388 TI - Intragroup genetic relatedness in two howler monkey species (Alouatta pigra and A. palliata): Implications for understanding social systems and dispersal. AB - The degree of genetic relatedness among group members is influenced by dispersal, group formation and composition, mating systems, and other socioecological factors. Making inferences about differences between species in their socio genetic structure is difficult because studies rarely compare multiple species. In this study, we use multilocus microsatellite genotype data to analyze intragroup genetic relatedness in two howler monkey species (Alouatta palliata and A. pigra). We test the prediction that their patterns of intragroup genetic relatedness will be distinct based on expectations derived from their distinct social systems. Alouatta palliata is expected to have low levels of intragroup relatedness, given that both males and females are reported to disperse from their natal groups, and to join groups with no close kin. Levels of relatedness among A. pigra group members are expected to be variable according to the history of group formation, with new groups formed by unrelated individuals and well established groups having close kin due to female nepotism and sometimes by takeovers by coalitions of related males. Our results indicate that in both species, most groups contain closely related same-sex and/or inter-sex dyads. This suggests that philopatry in A. palliata may be more common than reported or that individuals are using alternative strategies to reside with close kin. We found greater variation among groups in female-female relatedness in A. palliata than in A. pigra, implying that these species have distinct socio-genetic structures. Further studies including both long-term observational and genetic data are necessary to understand the mechanisms that determine the degree of variation in intragroup genetic relatedness within and among populations for both species. Ecological and demographic data are also necessary to determine the importance of other factors, especially habitat loss and fragmentation, in determining the degree of relatedness in howler monkey groups. PMID- 26422390 TI - The Impact of Conservation Management on the Community Composition of Multiple Organism Groups in Eutrophic Interconnected Man-Made Ponds. AB - Ponds throughout the world are subjected to a variety of management measures for purposes of biodiversity conservation. Current conservation efforts typically comprise a combination of multiple measures that directly and indirectly impact a wide range of organism groups. Knowledge of the relative impact of individual measures on different taxonomic groups is important for the development of effective conservation programs. We conducted a field study of 28 man-made ponds, representing four management types differing in the frequency of periodic pond drainage and the intensity of fish stock management. We disentangled the relative importance of direct and indirect effects of pond management measures on the community composition of phytoplankton, zooplankton, aquatic macro-invertebrates, submerged and emergent vascular plants. With the exception of phytoplankton, pond management had strong effects on the community composition of all investigated biota. Whether management affected communities directly or indirectly through its impact on fish communities or local environmental conditions in the pond varied between organism groups. Overall, the impact of pond drainage regime and fish community characteristics on the community composition of target organism groups were more important than local environmental conditions. The majority of taxa were negatively associated with fish density, whereas multiple emergent plant species and several taxa of aquatic macro-invertebrates were positively affected by increased drainage frequency. The effects of fish community and drainage tended to be largely independent. The present study indicates that pond drainage is an important element for biodiversity conservation in eutrophicated shallow and interconnected man-made ponds. PMID- 26422389 TI - High HER2 protein levels correlate with increased survival in breast cancer patients treated with anti-HER2 therapy. AB - INTRODUCTION: Current methods to determine HER2 (human epidermal growth factor receptor 2) status are affected by reproducibility issues and do not reliably predict benefit from anti-HER2 therapy. Quantitative measurement of HER2 may more accurately identify breast cancer (BC) patients who will respond to anti-HER2 treatments. METHODS: Using selected reaction monitoring mass spectrometry (SRM MS), we quantified HER2 protein levels in formalin-fixed, paraffin-embedded (FFPE) tissue samples that had been classified as HER2 0, 1+, 2+ or 3+ by immunohistochemistry (IHC). Receiver operator curve (ROC) analysis was conducted to obtain optimal HER2 protein expression thresholds predictive of HER2 status (by standard IHC or in situ hybridization [ISH]) and of survival benefit after anti-HER2 therapy. RESULTS: Absolute HER2 amol/MUg levels were significantly correlated with both HER2 IHC and amplification status by ISH (p < 0.0001). A HER2 threshold of 740 amol/MUg showed an agreement rate of 94% with IHC and ISH standard HER2 testing (p < 0.0001). Discordant cases (SRM-MS-negative/ISH positive) showed a characteristic amplification pattern known as double minutes. HER2 levels >2200 amol/MUg were significantly associated with longer disease-free survival (DFS) and overall survival (OS) in an adjuvant setting and with longer OS in a metastatic setting. CONCLUSION: Quantitative HER2 measurement by SRM-MS is superior to IHC and ISH in predicting outcome after treatment with anti-HER2 therapy. PMID- 26422391 TI - Candidate Loci are Revealed by an Initial Genome-wide Association Study of Juvenile Osteochondritis Dissecans. AB - BACKGROUND: Osteochondritis dissecans (OCD) is a condition that oftentimes causes significant knee pain in pediatric patient populations. If left untreated, OCD significantly increases the risk of developing degenerative osteoarthritis along with its associated consequences and costs. Although a genetic component has been suggested to play a role in this disorder, few studies have been carried out in order to determine the underlying genetic etiology of this relatively common complex trait. The goal of our study was to perform an initial genome-wide association study (GWAS) to uncover candidate loci associated with the pathogenesis of OCD. METHODS: Blood samples were acquired from 2 cohorts, aged 0 to 18 years old, consisting of 209 OCD cases and 1855 population-matched controls. Agencourt Genfind DNA isolation technology was used to isolate high quality DNA from each sample. Genotype data was then generated utilizing the Illumina Infinium BeadChip array to examine single-nucleotide polymorphisms (SNPs). RESULTS: In an initial GWAS analysis of our cohort, where a SNP was excluded if the Hardy-Weinberg Equilibrium test P<0.0001, the minor allele frequency<5%, and the genotyping call rate<90%, we obtained our first results for OCD. Although there was no SNP strictly reaching the threshold for genome-wide significance at this early stage, multiple SNPs (35) at several loci revealed evidence of suggestive association with OCD (P<5.0*10). CONCLUSIONS: The results from our preliminary study are encouraging. Herein we not only discuss the relevance and applicability of GWAS in studying a genetic basis for OCD, but have also identified top signals that may suggest loci involved in coordinated expression as well as a transcription factor involved in development that may be highly relevant to this trait. CLINICAL RELEVANCE: If genetic predispositions for OCD are detected early enough in life, attempts at activity modification, counseling, and orthopaedic monitoring may successfully reduce progression of this condition, which may lead to progressive osteoarthritis in the third to fourth decade in at-risk patients. PMID- 26422392 TI - Successful Pavlik Harness Treatment for Developmental Dysplasia of the Hip and Normal X-Ray at the Age of 2 Years: Is a Longer Follow-up Necessary? AB - BACKGROUND: Management of developmental dysplasia of the hip (DDH) with a Pavlik harness is a well-known treatment.Follow-up until skeletal maturity is recommended as long-term studies mention late sequelae.The purpose of this study was to determine whether such a follow-up is necessary in patients treated successfully under a strict protocol. METHODS: A retrospective review of a consecutive series of normal infants treated for DDH between January 1995 and July 2004 was undertaken.Only normal infants with frankly pathologic hips treated successfully with a Pavlik harness were included, and with a normal anteroposterior (AP) pelvis x-ray at the age of 2 years.All infants with any type of neurological disease, syndrome, other form of treatment for DDH, and failure of the Pavlik harness were excluded.At the last follow-up, a clinical examination and a standing AP pelvis x-ray were performed. RESULTS: A total of 109 hips in 83 children were available for review. The mean follow-up was of 10 years and 2 months. All 109 hips had a normal clinical examination and a normal AP pelvis x ray: a mean center-edge angle (CEA) of 29.5 degrees, SD+/-4.1 degrees, a mean acetabular index (AI) of 1457+/-3.74 degrees, a mean Sharp's angle of 41.92+/ 3.42 degrees, a Seringe-Severin score of IA, a normal teardrop figure, no signs of avascular necrosis, and Moses circles <2. CONCLUSION: This study strongly suggests that in a selected group of patients treated for DDH with a Pavlik harness, under a strict protocol, and a normal x-ray at 2 years of age, a long term follow-up is not necessary. LEVEL OF EVIDENCE: Level III-therapeutic. PMID- 26422393 TI - Spontaneous Fatal Intraoperative Rupture of Great Vessel During Growing Rod Lengthening: Do Children With Ehlers-Danlos Syndrome Require the Availability of Vascular Expertise? A Case Report and Review of the Literature. AB - BACKGROUND: Ehlers-Danlos syndrome (EDS) is a family of inherited connective tissue diseases. Kyphoscoliotic EDS (kEDS) is associated with severe and early spinal deformity. Very little has been reported regarding the orthopaedic surgical care of kEDS likely due to its rare incidence. A more common subtype is the vascular-type EDS (vEDS, previously labeled type IV), which is associated with reports of vascular complications in the literature. METHODS: The case report of a single, fatal complication of spontaneous rupture of the superior vena cava, after extubation, subsequent to revision minimal growing rod lengthening in a child with kEDS. We additionally review prior reported cases of kEDS for pediatric spine surgery and the sentinel event of spontaneous vascular rupture in all EDS patients. RESULTS: The anterior thoracoabdominal approach in children with kEDS has been associated with severe intravascular complications, with no deaths reported to date. Posterior spinal procedures were associated with frequent overall complications, but no events of perioperative or spontaneous vascular injury were identified before our case.Reports of spontaneous vessel rupture (n=39) appear more frequently in vEDS, but have been documented in patients with EDS type I (classic EDS or cEDS) and kEDS disease. The 30-day mortality in these patients was 59%. The majority of the deaths occurred on the day of the vascular event. Surviving patients overwhelmingly received intraoperative consultation and treatment from either general or vascular surgeons at their respective institutions for assistance. CONCLUSIONS: Providers should consider their proximity to available emergent consultation before operating on patients with EDS of any subtype. LEVEL OF EVIDENCE: Level V-expert opinion. PMID- 26422394 TI - Bivalved Versus Circumferential Cast Immobilization for Displaced Forearm Fractures: A Randomized Clinical Trial to Assess Efficacy and Safety. AB - BACKGROUND: The purpose of this study was to determine the effects of bivalved versus circumferential cast immobilization on maintenance of reduction and associated complications after closed reduction (CR) of radius and/or ulna fractures in children. METHODS: Two hundred two children with displaced radius and/or ulna fractures were randomized to either circumferential (n=101) or bivalved (n=101) long-arm casts after CR. The mean age was 10+/-3 years. There were no significant differences between groups in terms of age, sex, or initial fracture displacement or angulation. Clinical and radiographic evaluations were performed at 1, 2, 4, and 6 weeks postreduction. Radiographic loss of reduction (LOR), need for remanipulation or surgery, and associated complications of compartment syndrome, cast saw injury, and neurovascular compromise were recorded. RESULTS: Overall, the median angulation of the radius and ulna fractures improved from 20 and 18 degrees to 3 and 2 degrees after CR, respectively. The median cast index after reduction was 0.78 in the bivalved group and 0.80 in the circumferential group. The median angulation of the radius and ulna was 8 and 1 degrees at 4 weeks, with no significant difference between groups. By the fourth week of follow-up, 70 patients (34%)-35 bivalved and 35 circumferential-had radiographic LOR. Forty-seven patients (23%)-23 bivalved and 24 circumferential-underwent remanipulation or surgical reduction and fixation. There were no significant differences between groups with respect to LOR rate or need for surgical treatment. One bivalved patient sustained a cast saw injury, and 3 bivalved patients had transient neurological abnormalities. No patients developed compartment syndrome. CONCLUSIONS: Cast immobilization is effective in the majority of patients after CR of displaced forearm fractures. There were no significant differences in maintenance of reduction, need for surgery, or complications between bivalved or circumferential long-arm casts. LEVEL OF EVIDENCE: Level I-therapeutic. PMID- 26422395 TI - SIRT1 and insulin resistance. AB - Sirtuin 1 (SIRT1) is a prototype mammalian NAD(+)-dependent protein deacetylase that has emerged as a key metabolic sensor in various metabolic tissues. Growing evidence suggests that SIRT1 regulates glucose and lipid metabolism through its deacetylase activity. In this review, we have summarized the recent progress in SIRT1 research with a particular focus on the role of SIRT1 in insulin resistance at different metabolic tissues. Recent data indicate that activated SIRT1 improves the insulin sensitivity of liver, skeletal muscle and adipose tissues and protects the function and cell mass of pancreatic beta-cells. These findings suggest that SIRT1 might be a new therapeutic target for the prevention of disease related to insulin resistance, such as metabolic syndrome and type 2 diabetes mellitus. PMID- 26422396 TI - The relationship between carbohydrate and the mealtime insulin dose in type 1 diabetes. AB - A primary focus of the nutritional management of type 1 diabetes has been on matching prandial insulin therapy with carbohydrate amount consumed. Different methods exist to quantify carbohydrate including counting in one gram increments, 10g portions or 15g exchanges. Clinicians have assumed that counting in one gram increments is necessary to precisely dose insulin and optimize postprandial control. Carbohydrate estimations in portions or exchanges have been thought of as inadequate because they may result in less precise matching of insulin dose to carbohydrate amount. However, studies examining the impact of errors in carbohydrate quantification on postprandial glycemia challenge this commonly held view. In addition it has been found that a single mealtime bolus of insulin can cover a range of carbohydrate intake without deterioration in postprandial control. Furthermore, limitations exist in the accuracy of the nutrition information panel on a food label. This article reviews the relationship between carbohydrate quantity and insulin dose, highlighting limitations in the evidence for a linear association. These insights have significant implications for patient education and mealtime insulin dose calculations. PMID- 26422398 TI - A Case Report of Unresectable Cutaneous Squamous Cell Carcinoma Responsive to Pembrolizumab, a Programmed Cell Death Protein 1 Inhibitor. PMID- 26422397 TI - SATB1 Mediates Long-Range Chromatin Interactions: A Dual Regulator of Anti Apoptotic BCL2 and Pro-Apoptotic NOXA Genes. AB - Aberrant expression of special AT-rich binding protein 1 (SATB1), a global genomic organizer, has been associated with various cancers, which raises the question of how higher-order chromatin structure contributes to carcinogenesis. Disruption of apoptosis is one of the hallmarks of cancer. We previously demonstrated that SATB1 mediated specific long-range chromosomal interactions between the mbr enhancer located within 3'-UTR of the BCL2 gene and the promoter to regulate BCL2 expression during early apoptosis. In the present study, we used chromosome conformation capture (3C) assays and molecular analyses to further investigate the function of the SATB1-mediated higher-order chromatin structure in co-regulation of the anti-apoptotic BCL2 gene and the pro-apoptotic NOXA gene located 3.4Mb downstream on Chromosome 18. We demonstrated that the mbr enhancer spatially juxtaposed the promoters of BCL2 and NOXA genes through SATB1-mediated chromatin-loop in Jurkat cells. Decreased SATB1 levels switched the mbr-BCL2 loop to mbr-NOXA loop, and thus changed expression of these two genes. The SATB1 mediated dynamic switch of the chromatin loop structures was essential for the cooperative expression of the BCL2 and NOXA genes in apoptosis. Notably, the role of SATB1 was specific, since inhibition of SATB1 degradation by caspase-6 inhibitor or caspase-6-resistant SATB1 mutant reversed expression of BCL-2 and NOXA in response to apoptotic stimulation. This study reveals the critical role of SATB1-organized higher-order chromatin structure in regulating the dynamic equilibrium of apoptosis-controlling genes with antagonistic functions and suggests that aberrant SATB1 expression might contribute to cancer development by disrupting the co-regulated genes in apoptosis pathways. PMID- 26422399 TI - Facile Preparation of Graphene/SnO2 Xerogel Hybrids as the Anode Material in Li Ion Batteries. AB - SnO2 has been considered as one of the most promising anode materials for Li-ion batteries due to its theoretical ability to store up to 8.4 Li(+). However, it suffers from poor rate performance and short cycle life due to the low intrinsic electrical conductivity and particle pulverization caused by the large volume change upon lithiation/delithiation. Here, we report a facile synthesis of graphene/SnO2 xerogel hybrids as anode materials using epoxide-initiated gelation method. The synthesized hybrid materials (19% graphene/SnO2 xerogel) exhibit excellent electrochemical performance: high specific capacity, stable cyclability, and good rate capability. Even cycled at a high current density of 1 A/g for 300 cycles, the hybrid electrode can still deliver a specific capacity of about 380 mAh/g, corresponding to more than 60% capacity retention. The incorporation of graphene sheets provides fast electron transfer between the interfaces of the graphene nanosheets and the SnO2 and a short lithium ion diffusion path. The porous structure of graphene/xerogel and the strong interaction between SnO2 and graphene can effectively accommodate the volume change and tightly confine the formed Li2O and Sn nanoparticles, thus preventing the irreversible capacity degradation. PMID- 26422400 TI - Update on nonsurgical lung volume reduction procedures. PMID- 26422402 TI - Clinical outcomes associated with home mechanical ventilation: A systematic review. PMID- 26422401 TI - Investigation of occupational asthma: Do clinicians fail to identify relevant occupational exposures? AB - BACKGROUND: Specific inhalation challenges (SIC) enable the identification of the agent responsible of occupational asthma (OA). A clinician may fail to identify a specific agent in the workplace, which may potentially lead to a misdiagnosis. The expert assessment method performed by an occupational hygienist has been used to evaluate occupational exposures in epidemiological studies. OBJECTIVE: The broad aim of the present study was to evaluate the contribution of an expert assessment performed by an occupational hygienist to the diagnosis of OA. The specific aim was to compare workplace exposures identified by an occupational hygienist and by chest physicians in subjects with positive SICs and subjects with asthma, but with a negative SIC. METHODS: SICs were performed in 120 cases: 67 were positive and 53 were negative. A clinician assessed occupational exposures to sensitizers during a routine clinical evaluation preceding the performance of the SIC. An expert assessment of occupational exposures was performed by an occupational hygienist blind to the result of the SIC. RESULTS: The occupational hygienist identified the causal agent in 96.7% of the 61 cases of positive SIC. In 33 (62.3%) cases of negative SICs, the occupational hygienist identified >=1 sensitizing agent(s) that had not been identified by the clinician. CONCLUSION: The hygienist identified the causal agent in almost all subjects with OA. In contrast, the clinician failed to identify potential exposures to sensitizers in >60% of the negative SIC subjects, which may have resulted in some subjects being misdiagnosed as not having OA. PMID- 26422403 TI - MgtE From Rhizobium leguminosarum Is a Mg2+ Channel Essential for Growth at Low pH and N2 Fixation on Specific Plants. AB - MgtE is predicted to be a Rhizobium leguminosarum channel and is essential for growth when both Mg2+ is limiting and the pH is low. N2was only fixed at 8% of the rate of wild type when the crop legume Pisum sativum was inoculated with an mgtE mutant of R. leguminosarum and, although bacteroids were present, they were few in number and not fully developed. R. leguminosarum MgtE was also essential for N2fixation on the native legume Vicia hirsuta but not when in symbiosis with Vicia faba. The importance of MgtE and the relevance of the contrasting phenotypes is discussed. PMID- 26422404 TI - Sinorhizobium meliloti Controls Nitric Oxide-Mediated Post-Translational Modification of a Medicago truncatula Nodule Protein. AB - Nitric oxide (NO) is involved in various plant-microbe interactions. In the symbiosis between soil bacterium Sinorhizobium meliloti and model legume Medicago truncatula, NO is required for an optimal establishment of the interaction but is also a signal for nodule senescence. Little is known about the molecular mechanisms responsible for NO effects in the legume-rhizobium interaction. Here, we investigate the contribution of the bacterial NO response to the modulation of a plant protein post-translational modification in nitrogen-fixing nodules. We made use of different bacterial mutants to finely modulate NO levels inside M. truncatula root nodules and to examine the consequence on tyrosine nitration of the plant glutamine synthetase, a protein responsible for assimilation of the ammonia released by nitrogen fixation. Our results reveal that S. meliloti possesses several proteins that limit inactivation of plant enzyme activity via NO-mediated post-translational modifications. This is the first demonstration that rhizobia can impact the course of nitrogen fixation by modulating the activity of a plant protein. PMID- 26422405 TI - Effects of Elevated CO2and Temperature on Pathogenicity Determinants and Virulence of Potato virus X/Potyvirus-Associated Synergism. AB - Infections of plants by multiple viruses are common in nature and may result in synergisms in pathologies. Several environmental factors influence plant-virus interactions and act on virulence and host defense responses. Mixed viral infections may be more frequent under environmental conditions associated with global warming. Here, we address how changes in the two main parameters behind global warming, carbon dioxide concentrations ([CO2]) and temperature, may affect virulence of Potato virus X (PVX)/potyvirus-associated synergism compared with single infections in Nicotiana benthamiana. Elevated [CO2] resulted in attenuated virulence of single infection by PVX, which correlated with a lower accumulation of virus. In contrast, virulence of PVX/potyvirus-associated synergism was maintained at elevated [CO2]. On the other hand, elevated temperature decreased markedly both virulence and virus titers in the synergistic infection. We also show that the HR-like response elicited by transient coexpression of PVX P25 together with the potyviral helper component-proteinase protein was significantly enhanced by elevated temperature, whereas it was reduced by elevated [CO2]. Both proteins are main pathogenicity determinants in PVX-associated synergisms. These findings indicate that, under environmental conditions associated with global warming, virulence of PVX/potyvirus-associated synergisms is expected to vary relative to single infections and, thus, may have pathological consequences in the future. PMID- 26422406 TI - Changes in Upper Airway Volume in Edentulous Obstructive Sleep Apnea Patients Treated with Modified Mandibular Advancement Device. AB - PURPOSE: This study was an attempt to verify the utility of complete dentures modified as a mandibular advancement device (MAD) in effecting expansion in pharyngeal volume to treat obstructive sleep apnea (OSA) in edentulous patients. MATERIALS AND METHODS: The sample consisted of 17 patients (12 male, 5 female, average age 61 +/- 4 years; BMI, 22 +/- 5; apnea hypopnea index [AHI] 15 to 30). All patients had worn complete dentures for at least 1 year; all patients had the dentures modified to a MAD. Five variables were assessed preoperatively and 6 months after wearing the modified MADs. These variables were: sleep efficiency, AHI, oxygen desaturation events/hr., mean oxygen saturation, snoring index, and airway volume. This assessment was done by subjecting the patients to all-night polysomnography. RESULTS: Without any prosthesis or device in the edentulous patients, the mean velopharyngeal volume was 8.05 +/- 0.58 cm(3) , oropharyngeal volume was 2.14 +/- 0.38 cm(3) , and hypopharyngeal volume was 3.26 +/- 0.78 cm(3) . With complete dentures (unaltered) in the edentulous patients, the mean velopharyngeal, oropharyngeal, and hypopharyngeal volumes were 10.73 +/- 0.98 cm(3) , 2.60 +/- 0.48 cm(3) , and 4.31 +/- 0.89 cm(3) , respectively. There was a statistically significant change in the airway volume following insertion of the complete dentures modified as MADs with velopharyngeal, oropharyngeal, and hypopharyngeal volume recorded as 11.76 +/- 1.07 cm(3) , 3.33 +/- 0.51 cm(3) , and 4.94 +/- 0.83 cm(3) , respectively. CONCLUSION: From the results obtained in this limited small sample study, it was inferred that the pharyngeal expansion induced by complete dentures modified as MADs effectively reduced symptoms of OSA. Increased volume was most pronounced in the velopharynx region followed by hypopharynx and oropharynx. PMID- 26422407 TI - Serological survey of Bartonella spp., Borrelia burgdorferi, Brucella spp., Coxiella burnetii, Francisella tularensis, Leptospira spp., Echinococcus, Hanta-, TBE- and XMR-virus infection in employees of two forestry enterprises in North Rhine-Westphalia, Germany, 2011-2013. AB - We initiated a survey to collect basic data on the frequency and regional distribution of various zoonoses in 722 employees of forestry enterprises in the German state of North Rhine-Westphalia (NRW) from 2011 to 2013. Exposures associated with seropositivity were identified to give insight into the possible risk factors for infection with each pathogen. 41.2% of participants were found to be seropositive for anti-Bartonella IgG, 30.6% for anti-Borrelia burgdorferi IgG, 14.2% for anti-Leptospira IgG, 6.5% for anti-Coxiella burnetii IgG, 6.0% for anti-Hantavirus IgG, 4.0% for anti-Francisella tularensis IgG, 3.4% for anti-TBE virus IgG, 1.7% for anti-Echinococcus IgG, 0.0% for anti-Brucella IgG and anti XMRV IgG. Participants seropositive for B. burgdorferi were 3.96 times more likely to be professional forestry workers (univariable analysis: OR 3.96; 95% CI 2.60-6.04; p<0.001); and participants seropositive for Hantavirus 3.72 times more likely (univariable analysis: OR 3.72; 95% CI 1.44-9.57; p=0.007). This study found a surprisingly high percentage of participants seropositive for anti-B. henselae IgG and for anti-F. tularensis IgG. The relatively high seroprevalence for anti-Leptospira IgG seen in this study could be related to living conditions rather than to exposure at work. No specific risk for exposure to C. burnetii and Echinococcus was identified, indicating that neither forestry workers nor office workers represent a risk population and that NRW is not a typical endemic area. Forestry workers appear to have higher risk for contact with B. burgdorferi infected ticks and a regionally diverse risk for acquiring Hantavirus-infection. The regional epidemiology of zoonoses is without question of great importance for public health. Knowledge of the regional risk factors facilitates the development of efficient prevention strategies and the implementation of such prevention measures in a sustainable manner. PMID- 26422408 TI - Lymph nodes can accurately be measured on PET-CT for lymphoma staging/restaging without a concomitant contrast enhanced CT scan. AB - Dual imaging with both contrast enhanced CT scan and PET-CT is recommended for evaluation of lymphoma. We compared the performance in identification and size measurements of involved lymph nodes in FDG-avid lymphomas on the low dose non contrast enhanced CT of a PET-CT scan with those on a diagnostic contrast enhanced CT scan. The size of FDG-avid lymph nodes was measured in both the short and long axis on both the low dose non-contrast CT of the PET-CT and the contrast enhanced CT by two independent readers. A total of 307 FGD avid lymph nodes were identified in 52 patients. There was no statistically significant differences in the measured size of the nodes on the non-contrast and contrast enhanced scans (p=0.21). Baseline staging and restaging of FDG-avid lymphomas can be performed with one test, PET-CT, without an accompanying contrast enhanced CT scan, with no effect on the measured nodal size. PMID- 26422409 TI - Reassessing the Efficiency Penalty from Carbon Capture in Coal-Fired Power Plants. AB - This paper examines thermal efficiency penalties and greenhouse gas as well as other pollutant emissions associated with pulverized coal (PC) power plants equipped with postcombustion CO2 capture for carbon sequestration. We find that, depending on the source of heat used to meet the steam requirements in the capture unit, retrofitting a PC power plant that maintains its gross power output (compared to a PC power plant without a capture unit) can cause a drop in plant thermal efficiency of 11.3-22.9%-points. This estimate for efficiency penalty is significantly higher than literature values and corresponds to an increase of about 5.3-7.7 USc/kWh in the levelized cost of electricity (COE) over the 8.4 USc/kWh COE value for PC plants without CO2 capture. The results follow from the inclusion of mass and energy feedbacks in PC power plants with CO2 capture into previous analyses, as well as including potential quality considerations for safe and reliable transportation and sequestration of CO2. We conclude that PC power plants with CO2 capture are likely to remain less competitive than natural gas combined cycle (without CO2 capture) and on-shore wind power plants, both from a levelized and marginal COE point of view. PMID- 26422411 TI - NMR-based investigation of the Drosophila melanogaster metabolome under the influence of daily cycles of light and temperature. AB - We utilized an NMR-based metabolomic approach to profile the metabolites in Drosophila melanogaster that cycle with a daily rhythm. 1H 1D and 2D NMR experiments were performed on whole-body extracts sampled from flies that experienced strong time cues in the form of both light and temperature cycles. Multivariate and univariate statistical analysis was used to identify those metabolites whose concentrations oscillate diurnally. We compared metabolite levels at two time points twelve hours apart, one close to the end of the day and the other close to the end of the night, and identified metabolites that differed significantly in their relative concentrations. We were able to identify 14 such metabolites whose concentrations differed significantly between the two time points. The concentrations of metabolites such as sterols, fatty acids, amino acids such as leucine, valine, isoleucine, alanine and lysine as well as other metabolites such as creatine, glucose, AMP and NAD were higher close to the end of the night, whereas the levels of lactic acid, and a few amino acids such as histidine and tryptophan were higher close to the end of the day. We compared signal intensities across 12 equally spaced time points for these 14 metabolites, in order to profile the changes in their levels across the day, since the NMR metabolite peak intensity is directly proportional to its molar concentration. Through this report we establish NMR-based metabolomics combined with multivariate statistical analysis as a useful method for future studies on the interactions between circadian clocks and metabolic processes. PMID- 26422412 TI - Simultaneous Occurrence of Pancreatic Adenocarcinoma and Brunner's Gland Adenoma in a Siberian Tiger (Panthera tigris altaica). AB - We describe a case of pancreatic adenocarcinoma and Brunner's gland adenoma in an 18-year-old male Siberian tiger (Panthera tigris altaica) from the Ljubljana Zoo. The tiger was humanely destroyed due to weakness and progressive weight loss. Necropsy examination revealed a large, grey, predominantly necrotic mass replacing the major part of the pancreatic body. Microscopically, the mass was unencapsulated, poorly demarcated, highly cellular and composed of highly pleomorphic, cuboidal to tall columnar cells with basal, round or oval, moderately anisokaryotic nuclei with prominent nucleoli and moderate to large amounts of eosinophilic cytoplasm. The tumour was diagnosed as pancreatic tubular adenocarcinoma with infiltration into the duodenum and mesentery. There were tumour emboli in mesenteric blood vessels and hepatic metastases. The non affected part of the pancreas exhibited severe chronic pancreatitis. In addition, one firm white neoplastic nodule was observed in the duodenal wall. The nodule was set in the tunica muscularis and was unencapsulated, well demarcated and highly cellular, and consisted of a closely packed layer of normal Brunner's glands and a centrally positioned group of irregularly branched tubules with small amounts of debris in the lumen. The neoplastic nodule was diagnosed as Brunner's gland adenoma. The present case is, to the best of our knowledge, the first report of concurrent pancreatic adenocarcinoma and Brunner's gland adenoma, most probably induced by chronic pancreatitis, either in man or animals. PMID- 26422413 TI - Disease Risk Assessments Involving Companion Animals: an Overview for 15 Selected Pathogens Taking a European Perspective. AB - Prioritization of companion animal transmissible diseases was performed by the Companion Animals multisectoriaL interprofessionaL Interdisciplinary Strategic Think tank On zoonoses (CALLISTO) project. The project considered diseases occurring in domesticated species commonly kept as pets, such as dogs and cats, but also included diseases occurring in captive wild animals and production animal species. The prioritization process led to the selection of 15 diseases of prime public health relevance, agricultural economic importance, or both. An analysis was made of the current knowledge on the risk of occurrence and transmission of these diseases among companion animals, and from companion animals to man (zoonoses) or to livestock. The literature was scanned for risk assessments for these diseases. Studies were classified as import risk assessments (IRAs) or risk factor analyses (RFAs) in endemic areas. For those pathogens that are absent from Europe, only IRAs were considered; for pathogens present throughout Europe, only RFAs were considered. IRAs were identified for seven of the eight diseases totally or partially absent from Europe. IRAs for classical rabies and alveolar echinococcosis found an increased risk for introduction of the pathogen into officially disease-free areas as a consequence of abandoning national rules and adopting the harmonized EU rules for pet travel. IRAs for leishmaniosis focused on risk associated with the presence of persistently infected dogs in new geographical areas, taking into consideration the risk of disease establishment should a competent vector arise. IRAs for Crimean-Congo haemorrhagic fever and West Nile fever indicated that the likelihood of introduction via companion animals was low. IRAs for bluetongue paid no attention to the risk of introduction via companion animals, which was also the case for IRAs for foot-and-mouth disease, the only disease considered to be absent from Europe. RFAs dealing with the risk factors for companion animals to become infected were identified for eight of the 14 diseases found in Europe or parts of it. RFAs for leptospirosis were most numerous (four studies). The host related risk factor 'age' was identified as significant for dogs in at least two RFAs for cystic echinococcosis and giardiasis. Among husbandry and healthcare related factors, 'eating (uncooked) offal', 'being free roaming' and 'poor deworming practice' were associated with risk for dogs in at least two RFAs for cystic echinococcosis, while 'having received recent veterinary treatment' was identified as a risk factor in at least two studies on infection with extended spectrum beta lactamase-producing bacteria, one in horses and the other in dogs and cats. Finally, although the environmental factors 'season' and 'hydrological density' were identified as significant risk factors for dogs in at least two RFAs for leptospirosis, the inconsistent case definitions used in those studies made comparison of study results problematic. RFAs considering the risk of people becoming infected from companion animals were identified for eight of the 14 diseases found in Europe or parts of it. RFAs for human campylobacteriosis were the most numerous (n = 6). Most studies made an assessment as to whether keeping a pet per se, or keeping a pet with supposed or known risk factors, was a risk factor for people relative to other risks. This allowed some studies to report the population attributable risk or population attributable fraction of the incidence of human disease due to companion animals (for campylobacteriosis, salmonellosis and toxoplasmosis), which is a measure that is easy to perceive for laymen and policy makers. No RFAs were found that dealt with the risk to food animals from companion animals for any of the 15 pathogens investigated. Few risk method-based studies were identified that provided information on risk factors for companion animals and on their role as a source of these 15 selected diseases, indicating a clear knowledge gap. There were not enough assessments for any of the 15 diseases to allow meta-analyses, whether these assessments dealt with companion animal disease risk or companion animal-associated human disease risk. Important method and technology gaps were the lack of harmonization in the case definitions used for a given disease and the lack of good diagnostics allowing pathogen identification to taxonomic levels that are meaningful for risk analysis. Molecular epidemiology studies on zoonotic pathogens, which included companion animals among the potential human risk factors, were not found, although such studies would provide good preliminary insights without requiring any tracing of people or any interviews. In addition to performing further risk studies that take into account these issues, there is a need for responsible pet ownership and continued education of professionals in companion animal zoonoses. Additional risk assessment studies should allow more targeted actions to reduce the risk of zoonotic diseases transferred via companion animals and provide information that will promote risk-awareness in healthy human-animal relationships. PMID- 26422414 TI - Swiss Feline Cancer Registry: A Retrospective Study of the Occurrence of Tumours in Cats in Switzerland from 1965 to 2008. AB - Cancer is one of the leading causes of death in companion animals. Information on the epidemiology of cancer is instrumental for veterinary practitioners in patient management; however, spontaneously arising tumours in companion animals also resemble those in man and can provide useful data in combating cancer. Veterinary cancer registries for cats are few in number and have often remained short-lived. This paper presents a retrospective study of tumours in cats in Switzerland from 1965 to 2008. Tumour diagnoses were coded according to topographical and morphological keys of the International Classification of Oncology for Humans (ICD-O-3). Correlations between breed, sex and age were then examined using a multiple logistic regression model. A total of 18,375 tumours were diagnosed in 51,322 cats. Of these, 14,759 (80.3%) tumours were malignant. Several breeds had significantly lower odds ratios for developing a tumour compared with European shorthair cats. The odds of a cat developing a tumour increased with age, up to the age of 16 years, and female cats had higher risk of developing a tumour compared with male cats. Skin (4,970; 27.05%) was the most frequent location for tumours, followed by connective tissue (3,498; 19.04%), unknown location (2,532; 13.78%) and female sexual organs (1,564; 8.51%). The most common tumour types were epithelial tumours (7,913; 43.06%), mesenchymal tumours (5,142; 27.98%) and lymphoid tumours (3,911; 21.28%). PMID- 26422416 TI - Can Contrast-Enhanced Multi-Detector Computed Tomography Replace Transesophageal Echocardiography for the Detection of Thrombogenic Milieu and Thrombi in the Left Atrial Appendage: A Prospective Study with 124 Patients. AB - PURPOSE: To assess the diagnostic value of contrast-enhanced multi-detector computed tomography (MD-CT) for identifying patients with left atrial appendage (LAA) thrombus or circulatory stasis. MATERIALS AND METHODS: 124 patients with a history of atrial fibrillation and/or cerebral ischemia (83 men, mean age 58.6 +/ 12.4 years) and with a clinical indication for MD-CT of the heart and for transesophageal echocardiography (TEE) were included in the study. LAA thrombus or thrombogenic milieu was visually identified in TEE and MD-CT. In addition, MD CT was analyzed quantitatively measuring the Hounsfield units (HU) of the left atrium (LA), the LAA and the ascending aorta (AA), and calculating the HU ratios LAA/AA (HU [LAA/AA]) und LAA/LA (HU [LAA/LA]). Sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) were calculated. RESULTS: The prevalence of a thrombus or thrombogenic milieu as assessed by TEE was 21.8 %. The HU ratio was lower in patients with thrombus or thrombogenic milieu (HU [LAA/AA]: 0.590 +/- 0.248 vs. 0.909 +/- 0.141; p < 0.001 und HU [LAA/LA] 0.689 +/- 0.366 vs. 1.082 +/- 0.228; p < 0.001). For the diagnosis of thrombus or a thrombogenic milieu, visual analysis yielded a sensitivity of 81.5 %, a specificity of 96.9 %, a PPV of 87.5 % and a NPV of 95.2 %. By combining visual and quantitative analysis with one criterion being positive, the specificity decreased to 91.8 %, the sensitivity to 77.8 %, the PPV to 72.4 %, and the NPV to 94.9 %. CONCLUSION: Visual analysis of the LAA in the evaluation of thrombus or thrombogenic milieu yields a high NPV of 95.1 % and may especially be useful to rule out LAA thrombi in patients with contraindications for TEE. Additional calculation of HU ratios did not improve the diagnostic performance of MD-CT. KEY POINTS: * MD-CT can reliably exclude atrial appendage thrombi/thrombogenic milieu. * MD-CT is an alternative method in patients with contraindications to TEE. * Calculation of relative HU ratios does not improve the diagnostic value of MD-CT. PMID- 26422415 TI - Racial differences in adherence and response to combined treatment for full and subthreshold post-traumatic stress disorder and alcohol use disorders: A secondary analysis. AB - We conducted a secondary data analysis to examine whether there were racial differences in adherence and treatment outcomes for participants with co occurring full and subthreshold post-traumatic stress disorder (PTSD) and alcohol/substance use disorders (A/SUD) who were treated with Seeking Safety (a cognitive-behavioral therapy) and sertraline or Seeking Safety and placebo as part of a clinical trial. Bivarate analyses examined the association between race and adherence, and generalized estimating equations assessed whether race moderated the effect of combination treatment on PTSD and alcohol use outcomes. Except for education, there were no statistically significant racial differences in baseline demographic and psychiatric characteristics. African Americans and Caucasians were equally adherent in number of psychotherapy and medication sessions attended and medication compliance. After controlling for baseline demographics and psychiatric symptoms, however, a race by treatment condition interaction emerged suggesting that African Americans who received the Seeking Safety and sertraline treatment had significantly lower PTSD symptom severity posttreatment and at six months follow-up compared to their counterparts who received Seeking Safety and placebo. No differential effect of treatment condition was found for Caucasians. Moreover, results indicated that a diagnosis of major depressive disorder negatively impacted PTSD symptom recovery for African American participants but not for Caucasians. In conclusion, no differences emerged between African Americans and Caucasians in adherence to combination treatments for PTSD and A/SUD. Findings also suggest assessment and treatment of MDD among African Americans may improve treatment outcomes. More research is needed to determine whether the differential response to Seeking Safety and sertraline among African Americans compared to Caucasians can be replicated. PMID- 26422417 TI - Implementation of Dose Monitoring Software in the Clinical Routine: First Experiences. AB - PURPOSE: Radiation exposure of the public as a result of medical imaging has significantly increased during the last decades. To have a tool to register and control patient dose exposure, we implemented dose monitoring software at our institution and first connected our computed tomography (CT) scanners. MATERIALS AND METHODS: CT dose data from July 2014 to February 2015 was retrospectively analyzed using dose monitoring software. We evaluated a number of scans above predefined dose thresholds ("alerts"), assessed reasons for alerts and compared data of two CT scanners, one located close to the emergency room ("emergency CT scanner") and one mainly used on an outpatient basis ("clinical routine CT scanner"). To check for statistically significant differences between scanners, chi-square-tests were performed. RESULTS: A total of 8883 scans were acquired (clinical routine CT scanner, n = 3415; emergency CT scanner, n = 5468) during which 316 alerts were encountered (alert quota, 4 %). The overall alert quota ranged from 2 - 5 % with significantly higher values for the clinical routine CT scanner. Reasons for alerts were high BMI (51 %), patient off-centering (24 %), scan repetition (11 %), orthopedic hardware (9 %), or other (5 %). Scan repetition was necessary significantly more often with the emergency CT scanner (p = 0.019), while high BMI, off-centering and orthopedic hardware were more frequently seen with the clinical routine CT scanner (for all, p < 0.05). There was a good correlation between high body weight and dose above threshold (r = 0.585). CONCLUSION: Implementation of dose monitoring software in the clinical routine was successfully accomplished and provides important information regarding patient radiation protection. KEY POINTS: ? Implementation of dose monitoring software in the clinical routine can be successfully accomplished. . Dose notifications are due to human error or patient-specific factors. . Dose monitoring software provides important information regarding radiation protection of patients. PMID- 26422418 TI - Texture-Based Analysis of 100 MR Examinations of Head and Neck Tumors - Is It Possible to Discriminate Between Benign and Malignant Masses in a Multicenter Trial? AB - AIM: To evaluate whether texture-based analysis of standard MRI sequences can help in the discrimination between benign and malignant head and neck tumors. MATERIALS AND METHODS: The MR images of 100 patients with a histologically clarified head or neck mass, from two different institutions, were analyzed. Texture-based analysis was performed using texture analysis software, with region of interest measurements for 2 D and 3 D evaluation independently for all axial sequences. COC, RUN, GRA, ARM, and WAV features were calculated for all ROIs. 10 texture feature subsets were used for a linear discriminant analysis, in combination with k-nearest-neighbor classification. Benign and malignant tumors were compared with regard to texture-based values. RESULTS: There were differences in the images from different field-strength scanners, as well as from different vendors. For the differentiation of benign and malignant tumors, we found differences on STIR and T2-weighted images for 2 D, and on contrast enhanced T1-TSE with fat saturation for 3 D evaluation. In a separate analysis of the subgroups 1.5 and 3 Tesla, more discriminating features were found. CONCLUSION: Texture-based analysis is a useful tool in the discrimination of benign and malignant tumors when performed on one scanner with the same protocol. We cannot recommend this technique for the use of multicenter studies with clinical data. KEY POINTS: 2 D/3 D texture-based analysis can be performed in head and neck tumors. Texture-based analysis can differentiate between benign and malignant masses. Analyzed MR images should originate from one scanner with an identical protocol. PMID- 26422419 TI - [Not Available]. PMID- 26422420 TI - [Ectopic ductus Bellini carcinoma of the adrenal gland: a rare differential malignant adrenal gland tumors diagnosis]. PMID- 26422421 TI - Learning to decode human emotions with Echo State Networks. AB - The aim of this paper is to identify the common neural signatures based on which the positive and negative valence of human emotions across multiple subjects can be reliably discriminated. The brain activity is observed via Event Related Potentials (ERPs). ERPs are transient components in the Electroencephalography (EEG) generated in response to a stimulus. ERPs were collected while subjects were viewing images with positive or negative emotional content. Building inter subject discrimination models is a challenging problem due to the high ERPs variability between individuals. We propose to solve this problem with the aid of the Echo State Networks (ESN) as a general framework for extracting the most relevant discriminative features between multiple subjects. The original feature vector is mapped into the reservoir feature space defined by the number of the reservoir equilibrium states. The dominant features are extracted iteratively from low dimensional combinations of reservoir states. The relevance of the new feature space was validated by experiments with standard supervised and unsupervised machine learning techniques. From one side this proof of concept application enhances the usability context of the reservoir computing for high dimensional static data representations by low-dimensional feature transformation as functions of the reservoir states. From other side, the proposed solution for emotion valence detection across subjects is suitable for brain studies as a complement to statistical methods. This problem is important because such decision making systems constitute "virtual sensors" of hidden emotional states, which are useful in psychology science research and clinical applications. PMID- 26422422 TI - Neuromorphic implementations of neurobiological learning algorithms for spiking neural networks. AB - The application of biologically inspired methods in design and control has a long tradition in robotics. Unlike previous approaches in this direction, the emerging field of neurorobotics not only mimics biological mechanisms at a relatively high level of abstraction but employs highly realistic simulations of actual biological nervous systems. Even today, carrying out these simulations efficiently at appropriate timescales is challenging. Neuromorphic chip designs specially tailored to this task therefore offer an interesting perspective for neurorobotics. Unlike Von Neumann CPUs, these chips cannot be simply programmed with a standard programming language. Like real brains, their functionality is determined by the structure of neural connectivity and synaptic efficacies. Enabling higher cognitive functions for neurorobotics consequently requires the application of neurobiological learning algorithms to adjust synaptic weights in a biologically plausible way. In this paper, we therefore investigate how to program neuromorphic chips by means of learning. First, we provide an overview over selected neuromorphic chip designs and analyze them in terms of neural computation, communication systems and software infrastructure. On the theoretical side, we review neurobiological learning techniques. Based on this overview, we then examine on-die implementations of these learning algorithms on the considered neuromorphic chips. A final discussion puts the findings of this work into context and highlights how neuromorphic hardware can potentially advance the field of autonomous robot systems. The paper thus gives an in-depth overview of neuromorphic implementations of basic mechanisms of synaptic plasticity which are required to realize advanced cognitive capabilities with spiking neural networks. PMID- 26422423 TI - Circadian Kisspeptin expression in human term placenta. AB - Kisspeptin is an essential gatekeeper of reproductive function. During pregnancy high circulating levels of kisspeptin have been described, however the clear role of this neuropeptide in pregnancy remains unknown. We tested the existence of rhythmic kisspeptin expression in human full-term placenta from healthy pregnant women at six different time points during the day. The data obtained by Western blotting were fitted to a mathematical model (Fourier series), demonstrating, for the first time, the existence of a circadian rhythm in placental kisspeptin expression. PMID- 26422424 TI - Chemotherapy-Related Reticulate Hyperpigmentation: A Case Series and Review of the Literature. AB - BACKGROUND: Inherited or acquired reticulate hyperpigmentation represents a heterogeneous group of infrequent dermatological conditions. The development of reticulate hyperpigmentation has so far been rarely reported to be associated with chemotherapeutic agents, including fluorouracil, bleomycin or a combination of cytarabine and idarubicin. CASE REPORTS: We describe 5 cases of chemotherapy related reticulate hyperpigmentation in patients treated with different chemotherapeutic regimens, in particular paclitaxel or cytarabine. The lesions were similar in all cases, with reticulate and/or linear hyperpigmented streaks, which were mainly located to the back and buttocks. Histology showed increased melanogenesis, which suggests a direct toxic effect of chemotherapy on melanocytes. Reflectance confocal microscopy was performed in 2 patients showing a similar pattern, with an increased amount of melanin in basal keratinocytes. These features have been compared with the available data through a literature review. CONCLUSION: Reticulate hyperpigmentation is an underestimated but characteristic complication of chemotherapy. Neither specific management nor discontinuation of the chemotherapeutic regimen is required. PMID- 26422425 TI - Obesity: a key component of psoriasis. AB - Psoriasis has been associated with several cardiometabolic comorbidities as well as clinically significant increased risk of cardiovascular disease and mortality. Obesity seems to have a key role in linking psoriasis and cardiovascular disease. There are a growing number of epidemiological studies associating psoriasis and obesity. The mechanism responsible for this association is not certain, but it is probably multifactorial, involving genetic, environmental and immune-mediated factors. Nonetheless, the chronic inflammatory state associated with obesity appears to be a key component of this relationship. Obesity is, therefore, a major factor in the management of psoriatic patients, with implications in treatment efficacy and safety. Moreover, weight loss has been shown to have a positive effect on psoriasis severity and response to treatment. The aim of this review is to synthesize the current evidence on the association between psoriasis and obesity, exploring the physiopathological mechanisms that link both diseases and highlighting the importance of obesity control in the efficacy and safety of systemic treatment of psoriasis. All clinicians must be aware of this association, so they can recognize it and provide the patients a proper follow-up and multidisciplinary approach when needed. PMID- 26422426 TI - Systematic review on safety and drug interaction of herbal therapy in hyperlipidemia: a guide for internist. AB - Because of reporting high side effects related to biosynthetic drugs, recent attention has been paid to the use of herbs instead of chemical drugs to balance serum lipids. The present systematic review aimed to evaluate the safety of herbal medicines and also to assess drug interaction in herbal therapy in treating hyperlipidemia. The international research databases including MEDLINE; Google scholar, Web of Science SciVerse Scopus (SCOPUS); EBSCO Academic Search; Cochrane Central Register of Controlled Trials (CENTRAL); and a Chinese database (China Network Knowledge Infrastructure [CNKI]) were searched from their respective inceptions up to September 2014 with the search terms of "hyperlipidemia", "herbal medicine", "medicine traditional", "extract plant", "Traditional Medicine" and "Chinese Herbal Medicine" without narrowing or limiting search elements. A total of 85 randomized clinical trials (RCTs) studies were finally assessed on human subjects. A notable number of herbal drugs that are commonly used as an anti-hyperlipidemia agent may be interacted with a variety of biosynthetic drugs. In this regard, the most common reported herb-drug reactions were related to anticoagulants, antidepressants, anti-epileptic, anti inflammatory, and/or even antihypertension and anti-lipidemic drugs. Also, a considerable number of anti-lipidemic drugs of plants origin may be accompanied with metabolic disturbances and serious complications within pregnancy and breast feeding. The main fundamental principles for administration of these drugs include physicians' complete awareness of the effects and interactions of these drugs, educating people not taking these drugs arbitrarily, and closely monitoring the verification and distribution of the drugs in the society. PMID- 26422427 TI - In children with Hashimoto's thyroiditis the evolution over time of thyroid status may differ according to the different presentation patterns. AB - AIM: to report the salient literature news concerning the relationships between thyroid function presenting patterns and subsequent biochemical evolution of Hashimoto's thyroiditis (HT) in pediatric age. DESIGN: the most recent reports from pediatric literature concerning biochemical thyroid function patterns at HT presentation and their spontaneous changes over time were analyzed and shortly commented. RESULTS: from the analysis of pediatric literature on this theme, it emerges that HT in children may present with a very heterogeneous biochemical picture ranging from overt hypothyroidism to overt hyperthyroidism. The presenting biochemical pattern may also condition its subsequent evolution over time. CONCLUSIONS: a) the most common biochemical pattern at HT diagnosis in children is euthyroidism, followed by overt hypothyroidism, subclinical hypothyroidism (SH) and hyperthyroidism; b) the association with HT negatively affects the evolution over time of SH; c) in the cases with either Turner syndrome or Down syndrome the evolution over time of SH is more severe than in those without these chromosomopathies. PMID- 26422428 TI - Quality of life and functional disability in patients with interstitial lung disease related to Systemic Sclerosis. AB - BACKGROUND: Systemic Sclerosis (SSc) is a connective disease impairing respiratory function. SSc worsens patients' Health Assessment Questionnaire (HAQ DI), Short Form 36 Physical and Mental Component Summary (SF36-PCS and SF36-MCS). The aim of this work is to verify whether there is correlation between quality of life and lung interstitiopathy in SSc patients. METHODS: SF36 and HAQ-DI were given to each patient (48 in all). Lung involvement was evaluated with Baseline Dyspnea Index (BDI), spirometry and pulmonary fibrosis radiological assessment (PFRA). Correlations between SF36, HAQ-DI and lung involvement severity were investigated with Spearman's rank test. A p-value<0.05 was considered statistically significant. RESULTS: SF36-PCS and SF36-MCS correlate with BDI (respectively rho=0.553 p=0.0001; rho=0.357 p=0.0150). The best correlating SF36 subsets are Physical Role (rho =0.566 p<0.0001) and Bodily Pain (rho=0.444 p=0.0020). BDI correlates with HAQ-DI (rho=-0.655 p<0.0001). No statistically significant correlation was found between SF36, HAQ-DI and spirometrical values nor PFRA. CONCLUSIONS: The SSc patients enrolled have an impaired quality of life as widely demonstrated in literature. Quality of life reduction and functional ability decrease are only related to respiratory subjective impairment (assessed by BDI). Actually no correlation with objective lung damage (assessed by spirometry and PFRA) was detected. PMID- 26422429 TI - Chronic pain treatment and scrambler therapy: a multicenter retrospective analysis. AB - BACKGROUND AND AIM: Scrambler Therapy is a novel neuromodulation that works by electrocutaneous stimulation in a non-invasive manner through C fibers surface receptors. It substitutes pain information with synthetic "non pain" information. The primary aim of this study was to analyze the efficacy and safety of Scrambler Therapy after ten sessions related to different usage conditions and different learning curves that occur in a multi-center study. METHODS: 201 patients have been treated with Scrambler Therapy. All the patients were suffering from chronic pain with a mean pain NRS of 7.41 (SD 2.06) before treatment. Main causes of chronic pain: post herpetic neuralgia 18.40 %, chronic low back pain (LBP) 37.31%, polyneuropathy 10.94%, and peripheral neuropathy 14.42 %. The remaining 18.93 % included chronic pain due to other causes. RESULTS: The difference between pre-treatment NRS 7.41 (SD 2.06) and post-treatment 1.60 (SD 2.22) was statistically significant (P< 0.0001). The mean number of sessions per patient was 10, but 39 had complete absence of pain sooner and used fewer sessions. Only 7 patients stopped treatment due to lack of results, and 2 for personal reasons not ascribable to the treatment. Stimulation pain score of 0 during treatment, and not just pain reduction, predicts long term effectiveness, so this must be pursued by optimizing electrode positioning and correct fine-tuning of stimulation intensity. CONCLUSION: Scrambler Therapy is an efficient and safe alternative for several different types of refractory chronic neuropathic pain, with a very rare possibility of adverse events. PMID- 26422430 TI - Metabolic syndrome and its association with left ventricular dysfunction in patients with left bundle branch block. AB - BACKGROUND: The present study and for the first time hypothesizes that the patients with left bundle branch block (LBBB) suffer considerably from metabolic syndrome (MetS) and this metabolic phenomenon can be associated with cardiac dysfunction status such as ventricular dilation and reduced left ventricular ejection fraction (LVEF) in these patients. METHODS: A retrospective study was conducted on 220 consecutive patients with diagnosed LBBB. MetS status was diagnosed using the Adult Treatment Panel III of the National Cholesterol Education Program criteria. Systolic function state was assessed using two dimensional echocardiography. RESULTS: The overall prevalence of MetS among studied LBBB patients was 16.8%. Regarding left ventricular functional status in the two groups, the mean LVEF in the groups with and without MetS was 37.03 +/- 9.09% and 43.43 +/- 15.62% with a significant difference (p = 0.017). However, left ventricular dilation was similarly detected in both groups with and without MetS (21.6% versus 30.6%, p = 0.273). Multivariable linear regression model showed subjects with MetS had lower LVEF in the presence of confounders (Beta = 6.915, p = 0.039). CONCLUSION: A notable number of LBBB patients suffered from MetS and this metabolic phenomenon is significantly associated with lowering left ventricular function in LBBB patients. PMID- 26422431 TI - Prevalence, main determinants, and early outcome of patients with atrial fibrillation hospitalized with ischemic stroke: evaluation of the value of risk assessment scores for predicting risk of stroke or major bleeding following anticoagulation therapy. AB - BACKGROUND: Despite controllable nature of atrial fibrillation in most patients, it increases the risk of atrial thrombosis leading to ischemic stroke. The researchers assessed the underlying risk factors for brain stroke and also major bleeding in patients with ischemic stroke and atrial fibrillation. METHODS: Among 900 patients hospitalized with the diagnosis of ischemic brain stroke between 2013 and 2014, 100 patients had atrial fibrillation that included into this cross sectional study. The risk of stroke and major bleeding was assessed using CHA2DS2 VASc and HAS-BLED risk scores, respectively; but new stroke was not considered. RESULTS: Of 900 patients with evidences of ischemic stroke, 100 had atrial fibrillation with an overall prevalence of 11.1%. Mean CHA2DS2-VASc score was 4.35 +/- 1.76 that the total score was >= 2 points in 93% of subjects showing necessity to anticoagulation therapy in 93% of the patients before recent stroke. Mean HAS-BLED score was 2.83 +/- 1.30 that was >= 3 in 61% indicating risk of bleeding in 61% of all patients. 31% of the patients had previous history of atrial fibrillation, but only less than half of them (51%) were under treatment with warfarin, and also the measured INR was lower than the therapeutic range in 95.5% of individuals on warfarin therapy. In-hospital mortality was reported in 9% of all study subjects. The main determinants of early mortality included history of stroke, renal failure, presence of coronary artery disease, acetylsalicylic acid use, and Clopidogrel use. The analysis using the ROC curve showed that both CHA2DS2-VASc score (AUC = 0.788) and HAS-BLED score (AUC = 0.960) could strongly predict in-hospital mortality. CONCLUSION: The patients with atrial fibrillation hospitalized with ischemic stroke showed an important absolute risk of further stroke and early mortality. Despite substantiated advantages of warfarin prophylaxis, its limited application is still very common. PMID- 26422432 TI - Overcrowding and clinical risk in Emergency Departments. A model for the reduction in NEDOCS: preliminary results. AB - Overcrowding in Emergency Departments represents one of the main concerns in effective hospital management today. In order to reduce this phenomenon, this study experimented with a new organizational model that exploited available resources, without incurring additional costs. Through the redistribution of hospital beds, it was possible to reduce access blocks in the Emergency Department of the test hospital. The observational period of this study was of 120 days, and daily surveys of crowding were performed at predetermined intervals. The measurement of overcrowding was calculated utilizing the National Emergency Department Overcrowding Score. The findings reveal a significant reduction in overcrowding due to an increase of only 6 beds in the Emergency Department. Currently, it is known that the principle cause of overcrowding is attributed to a lack of hospital beds for inpatients. Numerous studies have shown that through the lengthening of inpatient hospitalizations it is possible to improve crowding levels in Emergency Department. This findings of this study robustly demonstrate that a small increase in the number of available beds available in emergency department leads to a decrease in all variables of the NEDOCS, and in particular, that of the severely and dangerous overcrowding score. PMID- 26422433 TI - Tubal ectopic pregnancy: our experience from 2000 to 2013. AB - In this paper we summarize our experience in diagnosis and treatment of 402 retrospectively collected tubal EP and review the most recent topics from the literature. Systemic Methotrexate (MTX) was effective in 56 out of 65 patients (failure rate 13.8%), in whom hCG level was significantly lower when compared to the failure group (p<0,05); we performed 299 salpingectomies, 297 of whom through laparoscopic approach. MTX single-dose is safe and effective in eligible patients; surgery represents the treatment of most of the EPs, mainly through laparoscopic approach. PMID- 26422434 TI - Immunization practices in athletes. AB - INTRODUCTION: Immunization practices of athletes is a topic of growing interest in preventive medicine. Several reasons contribute to support such statement including: the demonstrated decrease of the immune response of athletes, the recent increase in vaccine-preventable diseases, the increasing mobility of professional athletes and coaches and sports doctors' frequent lack of awareness of on the issue of athletes' immune prophylaxis. RESULTS: This review offers a concise and schematic framework to the immunization practices in athletes, based on the most recent scientific evidences and the vaccine schedules proposed by international organizations and scientific societies including the recent "Life Vaccination Schedule" proposed by four Italian Scientific Societies and Professional Associations. CONCLUSION: vaccination in athletes, if correctly managed, represents a powerful, costly and long lasting tool for athletes sport teams. PMID- 26422435 TI - Hypoglicemia related to big Haemangiopericitoma: a difficult diagnostic definition. AB - We describe the case of a 91 years old woman admitted to our department for dyspnea associated with drowsiness. At the admission to the Emergency Room the patient stay in a comatose state and blood tests performed showing severe hypoglycemia (38 mg/dl at admission in non diabetic patient). Anamnestic history: multifactorial anemia; frequent hospitalizations for heart failure; AMI treated with stenting; in 1986 Haemangiopericytoma resection in the right iliac region; in 2006 palliative surgery for recurrence with residual mass. Blood tests showed lower levels of insulin and normal C- peptide serum concentration in correspondence of low glucose concentration (in relation to continuous and adequate parenteral nutrition), IGF 1 and GH level was respectively suppressed (IGF1=47 ng/ml whit normal range 97-331 ng/ml) and normal/low (GH 0.43 uUI/mL whit normal range 0.06-14.00 uUI/mL).Therefore hypoglycemia appeared related to paraneoplastic production of IGF -2. PMID- 26422436 TI - Occult nasolacrimal duct ectasia in a child with acute sinusitis: clinicopathological considerations and literature review. AB - BACKGROUND: Enlargement of the nasolacrimal duct (NLD) in the absence of neoplasm is rare. As there are few reports on this condition in the literature, its pathologic significance and proper management remain unclear. We report a case of asymptomatic NLD enlargement incidentally discovered on high resolution computed tomography scan performed for a complicated acute sinusitis. METHODOLOGY: Case report and literature review. RESULTS AND CONCLUSIONS: NLD enlargement, defined as a truly isolated asymptomatic dilatation of the NLD, is rarely encountered. Etiology and clinical significance are unclear although the absence of nasolacrimal pathway or sinonasal disease and radiological findings of bone remodelling suggest that it may be congenital. In such cases, diagnosis may be incidental and based on imaging studies, and the term NLD ectasia seems to be more appropriate to describe this distinct entity. NLD enlargement may favour osteomeatal complex obstruction, thus leading to severe acute sinusitis. PMID- 26422437 TI - Fall from height: a case report. AB - The manuscript reports the case of a 16-year-old boy who fell from a height of 15 meters while having a cellphone conversation. Surprisingly, only minor injuries were reported. Prognostic factors related to falls from height are still debated; the present case is a further contribution to the discussion. PMID- 26422438 TI - Integrated treatment of the severely injured patient with coexistent comorbidities. A case report and literature review. AB - Major trauma represents a paradigmatic clinical condition, needing multidisciplinary and structured approach. When a patient is affected by significant comorbidities such as diabetes mellitus and other conditions that compromise the immune competence the risk of infections in the presence of exposed fractures is remarkably high. Although usually managed by multidisciplinary teams, these patients often have unfavorable functional outcomes. We describe here the case of a young diabetic and immunosuppressed man, treated for a destroying injury of the left lower limb, with more than 60 centimeters of multiple fractures exposition. The prompt and fast integration of several different competences led to favorable functional outcome, without any severe local or systemic complication. Therefore, in severely injured patients, especially when affected by significant comorbidities, a quick and highly integrated treatment, provided by a polyspecialistic team, is crucial for reducing unfavorable outcomes and improving the recovery rate. PMID- 26422439 TI - The "atrial dancing": echocardiographic diagnosis of electrocardiographic query. AB - The direct observation of the cardiac structure through the echocardiographic exam offers, in some cases, the advantage to resolve difficult diagnostic definition. In this paradigmatic case we emphasize as an accurate observation of the echocardiographic figures and movies can resolve also an electrocardiographic query. PMID- 26422440 TI - The Italian Code of Medical Deontology: characterizing features of its 2014 edition. AB - The latest edition of the Italian Code of Medical Deontology has been released by the Italian Federation of the Registers of Physicians and Dentists in May 2014 (1). The previous edition of the Italian Code dated back to 2006 (2), and it has been integrated and updated by a multi-professional and inter-disciplinary panel involving, besides physicians, representatives of scientific societies and trade unions, jurisconsults and experts in bioethics.... PMID- 26422441 TI - Informed consent: Do not be afraid. AB - Informed consent is the cornerstone of the doctor-patient relationship. At least this is how it is presented in theory. In practice, doctors struggle with their obligation to inform their patient before obtaining their approval prior to a medical intervention. In Taiwan, the culture is often mentioned to justify the doctor's reluctance to speak openly with their patient. Invoking the importance of the family in the society, doctors tend to rely less on their patients and more on their relatives to make important decisions. Yet, the cultural argument for not seeking the patients' informed consent sounds more like a mere excuse than the real cause of the difficulties doctors face today in obtaining their patients' consent. This paper argues that today the doctors in Taiwan are mostly governed by the same fear that was the rule in the USA and Europe until the 1980s. It may be time for changing the paradigm, admitting that patients are able to handle even the most dramatic diagnosis. It seems also important to get away from the sterile opposition of doctor's paternalism versus patient's autonomy and to introduce a true partnership between doctors and patients. PMID- 26422443 TI - Geriatric polypharmacy in Taiwan. PMID- 26422442 TI - Quality of life and its determinants for heroin addicts receiving a methadone maintenance program: Comparison with matched referents from the general population. AB - BACKGROUND/PURPOSE: Quality of life (QoL) is found to be lower in heroin addicts; however, few studies examine detailed QoL performance and related factors in heroin patients attending a methadone maintenance treatment program (MMTP). The study thus aimed to explore QoL and its determinants for publicly-funded and self paid patients attending an MMTP. METHODS: Participants were recruited in Jianan Psychiatric Center, Tainan, Taiwan, during their first clinic visit for the MMTP. Age-, sex-, education-, and municipality-matched referents were collected from the 2001 Taiwan National Health Interview Survey database. The participants had a mean age of 38.29 years [standard deviation (SD) = 7.65 years] for publicly funded (n = 129) and 37.97 years (SD = 7.16 years) for self-paid (n = 105) MMTP patients. Matched referents (n = 217) were 37.74 years (SD = 7.44 years). All participants were measured with the brief version of the World Health Organization's Quality of Life (WHOQOL-BREF) assessment. MMTP patients additionally went through tests for the hepatitis B virus, hepatitis C virus, and human immunodeficiency virus (HIV). RESULTS: Both publicly-funded and self-paid MMTP patients had lower QoL scores than their matched counterparts in the physical and psychological domains (p < 0.05) after control for confounding by age, sex, education, and municipality. Detailed individual item analyses showed that publicly-funded MMTP patients had lower scores for almost all items related to the physical, psychological, and social domains as compared to the referents because of HIV infection (p < 0.05). CONCLUSION: To improve the QoL of heroin users coming for MMTP, we recommend that clinicians pay attention to the comorbidity of HIV infection and individual items/facets. PMID- 26422445 TI - Emotional Aspects of Never Events. PMID- 26422444 TI - The role of Smad3 in the fibrotic phenotype in human vocal fold fibroblasts. AB - OBJECTIVES/HYPOTHESIS: To investigate the role of Smad3 as a regulator of transforming growth factor (TGF)-beta1-mediated cell activities associated with fibrosis in normal human vocal fold fibroblasts. We also sought to confirm the temporal stability of Smad3 knockdown via small inhibitor ribonucleic acid (siRNA). Vocal fold fibroblasts were employed to determine the effects of Smad3 knockdown on TGF-beta1-mediated migration and contraction, as well as regulation of connective tissue growth factor (CTGF). We hypothesized that Smad3 is an ideal candidate for therapeutic manipulation in vivo based on its role in fibrosis. STUDY DESIGN: In vitro. METHODS: Knockdown of Smad3 via siRNA was performed in our normal human vocal fold cell line. Three-dimensional collagen gel contraction and scratch assays were employed to determine the role of Smad3 on TGF-beta1 mediated contraction and migration, respectively. The role Smad3 in the induction of CTGF was characterized via sodium dodecyl sulfate polyacrylamide gel electrophoresis. The effects of Smad3 signaling on Smad7 messenger (m)RNA and protein were also quantified. RESULTS: Smad3 knockdown was temporally-stable up to 72 hours (P < 0.001), diminished TGF-beta1-mediated collagen gel contraction and migration, and blunted induction of CTGF, but it had no effect on TGF-beta1 mediated Smad7 mRNA or protein induction. CONCLUSION: Transforming growth factor beta1 stimulated profibrotic cell activities in our cell line and these actions were largely reduced with Smad3 knockdown. These data provide continued support for therapeutic targeting of Smad3 for vocal fold fibrosis because it appears to regulate the fibrotic phenotype. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:1151 1156, 2016. PMID- 26422446 TI - Offering statins to a population attending health checks with a 10-year cardiovascular disease risk between 10% and 20. AB - BACKGROUND: In 2014 the UK National Institute for Health and Care Excellence recommended reducing the threshold for offering statin therapy to patients from a 10-year modelled risk of cardiovascular disease (CVD) of 20% to 10%. AIM: To describe the response of patients in UK primary care with a CVD risk between 10% and 20% to an invitation to attend a consultation to discuss statins. DESIGN AND SETTING: Review of electronic medical records at one GP practice in the East of England. METHOD: We invited all patients who had attended an NHS Health Check at the practice, had a QRisk((r)) score between 10% and 20%, and were not prescribed statins to attend designated clinics in the practice to discuss starting statins. We reviewed the medical records to identify those who had attended the clinics and those who had chosen to start a statin. RESULTS: Of 410 patients invited, 100 (24.4%) patients attended the designated clinics and 45 (11%) chose to start a statin. Those who chose to start a statin were older and with a higher QRisk((r)) than those who did not. Among those who attended, individuals who started a statin had a higher QRisk((r)) than those who did not and were more likely to be current or ex-smokers. CONCLUSIONS: The proportion choosing to start a statin was substantially lower than previously estimated. Large population-based studies with long-term follow-up are needed to assess the impact on health and workload of this change in guidance. PMID- 26422447 TI - Development and evaluation of alginate-chitosan gastric floating beads loading with oxymatrine solid dispersion. AB - Oxymatrine (OM) can be metabolized to matrine in gastrointestinal ileocecal valve after oral administration, which affects pharmacological activity and reduce bioavailability of OM. A type of multiple-unit alginate-chitosan (Alg-Cs) floating beads was prepared by the ionotropic gelation method for gastroretention delivery of OM. A solid dispersion technique was applied and incorporated into beads to enhance the OM encapsulation efficiency (EE) and sustain the drug release. The surface morphology and internal hollow structure of beads were evaluated using optical microscopy and scanning electron microscopy (SEM). The developed Alg-Cs beads were spherical in shape with hollow internal structure and had particle size of 3.49 +/- 0.09 mm and 1.33 +/- 0.09 mm for wet and dried beads. Over 84% of the optimized OM solid dispersion-loaded Alg-Cs beads were able to continuously float over the simulated gastric fluid for 12 h in vitro. The OM solid dispersion-loaded Alg-Cs beads showed drug EE of 67.07%, which was much higher than that of beads loading with pure OM. Compared with the immediate release of OM capsules and pure OM-loaded beads, the release of OM from solid dispersion-loaded Alg-Cs beads was in a sustained-release manner for 12 h. Prolonged gastric retention time of over 8.5 h was achieved for OM solid dispersion-loaded Alg-Cs floating beads in healthy rabbit in in vivo floating ability evaluated by X-ray imaging. The developed Alg-Cs beads loading with OM solid dispersion displayed excellent performance features characterized by excellent gastric floating ability, high drug EE and sustained-release pattern. The study illustrated the potential use of Alg-Cs floating beads combined with the solid dispersion technique for prolonging gastric retention and sustaining release of OM, which could provide a promising drug delivery system for gastric specific delivery of OM for bioavailability enhancement. PMID- 26422448 TI - Campylobacter species in animal, food, and environmental sources, and relevant testing programs in Canada. AB - Campylobacter species, particularly thermophilic campylobacters, have emerged as a leading cause of human foodborne gastroenteritis worldwide, with Campylobacter jejuni, Campylobacter coli, and Campylobacter lari responsible for the majority of human infections. Although most cases of campylobacteriosis are self-limiting, campylobacteriosis represents a significant public health burden. Human illness caused by infection with campylobacters has been reported across Canada since the early 1970s. Many studies have shown that dietary sources, including food, particularly raw poultry and other meat products, raw milk, and contaminated water, have contributed to outbreaks of campylobacteriosis in Canada. Campylobacter spp. have also been detected in a wide range of animal and environmental sources, including water, in Canada. The purpose of this article is to review (i) the prevalence of Campylobacter spp. in animals, food, and the environment, and (ii) the relevant testing programs in Canada with a focus on the potential links between campylobacters and human health in Canada. PMID- 26422449 TI - Diagnostic accuracy of capnography during high-frequency ventilation in neonatal intensive care units. AB - BACKGROUND AND OBJECTIVE: High-frequency ventilation (HFV) is a powerful tool for CO2 elimination, and thus requires careful monitoring of CO2 . Our aim was to assess the diagnostic accuracy (correlation, agreement, and trending) of continuous distal capnography (dCap) with PaCO2 in infants ventilated with HFV. DESIGN: This was a prospective, observational, multicenter study. dCap was compared with simultaneous PaCO2 ("gold standard") drawn from indwelling arterial line for patient care in term and preterm infants ventilated with HFV. dCap was obtained via the side-port of a double-lumen endotracheal-tube by a Microstream capnograph with specially designed software for HFV. RESULTS: Twenty-four infants participated in the study (median [range] gestational age [GA]: 26.8 [23.6-38.6] weeks). Analysis included 332 measurements. dCap was in correlation (r = 0.70, P < 0.001) but with less than adequate agreement (mean difference +/- SD of the differences: -11.7 +/- 10.3 mmHg) with PaCO2 . Comparable findings were found in the subgroup of infants <1,000 g (n = 240 measurements). Correlations were maintained in severe lung disease. Changes in dCap and in PaCO2 for consecutive measurements within each patient were correlated (r = 0.63, P < 0.001). Area under the receiver operating curves (ROC) for dCap to detect high (>60 mmHg) or low (<30 mmHg) PaCO2 was 0.83 (CI: 0.76-0.90) and 0.88 (CI: 0.79-0.97), respectively; P < 0.001. CONCLUSIONS: Our prospective study suggests that continuous dCap in infants ventilated with HFV may be helpful for trends and alarm for unsafe levels of PaCO2 . dCap is only a complimentary tool and cannot replace PaCO2 sampling because the agreement between these measurements was less than adequate. PMID- 26422450 TI - A Technical Assistance Framework to Facilitate the Delivery of Integrated Behavioral Health Services in Federally Qualified Health Centers (FQHCs). AB - An implementation approach, featuring direct, onsite technical assistance is described, and findings from a pilot study assessing the capability of Federally Qualified Health Centers to provide integrated behavioral health services are presented. Investigators used the Behavioral Health Integration in Medical Care (BHIMC) index to measure integration at baseline and follow-up at four FQHCs in New Jersey. Results indicate that the average baseline capability score of 1.95 increased to 2.44 at follow-up, almost one-half point on the five-point BHIMC index. This pilot project demonstrates that co-occurring capability can be assessed, and system-wide technical assistance can be delivered to assist FQHCs in integrating behavioral health services. Future research should test technical assistance as an implementation strategy to promote the integration of medical care and behavioral health treatment on a wider scale. PMID- 26422451 TI - Heterogeneity of biomaterial-induced multinucleated giant cells: Possible importance for the regeneration process? AB - Biomaterial-associated multinucleated giant cells (BMGCs) have been found within the implantation beds of many different biomaterials. However, their exact differentiation and their involvement in the inflammatory and healing events of the foreign body response still remain mostly unclear. Silk fibroin (SF) scaffolds, which induces a tissue reaction involving both macrophages and BMGCs, was implanted in the subcutaneous connective tissue of four CD-1 mice for 15 days using an established subcutaneous implantation model. Analysis of macrophage polarization and BMGCs was performed by immunohistochemcial detection of pro- (cyclooxygenase-2 (COX-2), C-C chemokine receptor type 7 (CCR7), nuclear factor "kappa-light-chain-enhancer" (NF-kappaB)) and anti-(heme oxygenase-1 (HO-1) and mannose receptor (MR, also known as CD206)). Furthermore, histochemical detection of tartrate-resistant acid phosphatase (TRAP) was conducted to test its predictive efficiency for the pro-inflammatory differentiation of cells. An established system for histomorphometrical analysis was used for counting of BMGCs expressing these molecules. The results show that BMGCs express both pro- and anti-inflammatory molecules within the implantation beds of SF scaffolds in comparable numbers, while only statistically significantly lower numbers of TRAP positive BMGCs were measured in comparison to the BMGCs expressing the above mentioned molecules. As these data substantiate the heterogeneity of BMGCs, the question arises to what extent BMGCs can "support" the process of tissue regeneration. Furthermore, the data prompt the question to what extent TRAP expression within a biomaterial implantation bed can be seen as a predictive marker for an inflammatory condition, as in this study no obvious correlation between TRAP-expression and other pro-inflammatory markers could be observed. PMID- 26422452 TI - The National Cancer Institute's Dietary Assessment Primer: A Resource for Diet Research. AB - This monograph describes the National Cancer Institute's Dietary Assessment Primer, a web resource developed to help researchers choose the best available dietary assessment approach to achieve their research objective. All self-report instruments have error, but understanding the nature of that error can lead to better assessment, analysis, and interpretation of results. The Primer includes profiles of the major self-report dietary assessment instruments, including guidance on the best uses of each instrument; discussion of validation and measurement error generally and with respect to each instrument; guidance for choosing a dietary assessment approach for different research questions; and additional resources, such as a glossary, references, and overviews of specific/important issues in the field. This monograph also describes some future research needs in the field of dietary assessment. PMID- 26422453 TI - Variant Neurogenic Stunned Myocardium in a Young Female After Subarachnoid Hemorrhage. AB - Neurogenic stunned myocardium is a significant complication of subarachnoid hemorrhage. Diagnosis of neurogenic stunned myocardium is complicated by variable presentation. We present a case of a 23-year-old woman admitted with a subarachnoid hemorrhage from an arteriovenous malformation and associated aneurysm. Postoperatively, she developed pulmonary edema and mildly elevated cardiac biomarkers. Echocardiography showed hypokinesis of the basal left ventricular segments and normal contraction of the apical left ventricular segments consistent with a variant form of neurogenic stunned myocardium. We describe characteristics and outcomes of neurogenic stunned myocardium in this young patient with arteriovenous malformation-associated aneurysmal subarachnoid hemorrhage. PMID- 26422454 TI - Anesthesia in an Aging Infant: Neonatal Progeroid Syndrome. AB - Neonatal progeroid syndrome is a unique condition wherein features of aging are apparent in a newborn at birth. It is a very rare genetic disorder. The first case in India was reported in December 2011. The anesthetic management of any infant with this condition could not be found in the medical literature. Independently described by Rautenstrauch and Wiedemann, neonatal progeroid syndrome poses significant challenges to the anesthesiologist for a variety of anatomic and physiologic reasons. Coronary and cerebrovascular atherosclerosis pose significant concerns in such children. Here, we present the successful anesthetic management of a 6-month-old male infant with neonatal progeroid syndrome operated on for bilateral inguinoscrotal swellings. PMID- 26422455 TI - Liver Transplantation Using Dexmedetomidine in a Patient with a History of Takotsubo Cardiomyopathy. AB - Takotsubo cardiomyopathy has been described in patients undergoing liver transplantation. However, the ideal anesthetic management of patients with a history of takotsubo cardiomyopathy remains unclear, especially in patients undergoing liver transplantation. We describe the use of dexmedetomidine in a patient with a history of takotsubo cardiomyopathy undergoing living-donor liver transplantation. PMID- 26422456 TI - First Job Search of Residents in the United States: A Survey of Anesthesiology Trainees' Interest in Academic Positions in Cities Distant from Previous Residences. AB - We surveyed anesthesiology residents to evaluate the predictive effect of prior residence on desired location for future practice opportunities. One thousand five hundred United States anesthesiology residents were invited to participate. One question asked whether they intend to enter academic practice when they graduate from their residency/fellowship training. The analysis categorized the responses into "surely yes" and "probably" versus "even," "probably not," and "surely no." "After finishing your residency/fellowship training, are you planning to look seriously (e.g., interview) at jobs located more than a 2-hour drive from a location where you or your family (e.g., spouse or partner/significant other) have lived previously?" Responses were categorized into "very probably" and "somewhat probably" versus "somewhat improbably" and "not probable." Other questions explored predictors of the relationships quantified using the area under the receiver operating characteristic curve (area under the curve) +/- its standard error. Among the 696 respondents, 36.9% (N = 256) would "probably" consider an academic practice. Fewer than half of those (P < 0.0001) would "very probably" consider a distant location (31.6%, 99% CI 24.4% 39.6%). Respondents with prior formal research training (e.g., PhD or Master's) had greater interest in academic practice at a distant location (AUC 0.63 +/- 0.03, P = 0.0002). Except among respondents with formal research training, a good question to ask a job applicant is whether the applicant or the applicant's family has previously lived in the area. PMID- 26422457 TI - Carbon/Silicon Heterojunction Solar Cells: State of the Art and Prospects. AB - In the last few decades, advances and breakthroughs of carbon materials have been witnessed in both scientific fundamentals and potential applications. The combination of carbon materials with traditional silicon semiconductors to fabricate solar cells has been a promising field of carbon science. The power conversion efficiency has reached 15-17% with an astonishing speed, and the diversity of systems stimulates interest in further research. Here, the historical development and state-of-the-art carbon/silicon heterojunction solar cells are covered. Firstly, the basic concept and mechanism of carbon/silicon solar cells are introduced with a specific focus on solar cells assembled with carbon nanotubes and graphene due to their unique structures and properties. Then, several key technologies with special electrical and optical designs are introduced to improve the cell performance, such as chemical doping, interface passivation, anti-reflection coatings, and textured surfaces. Finally, potential pathways and opportunities based on the carbon/silicon heterojunction are envisaged. The aspects discussed here may enable researchers to better understand the photovoltaic effect of carbon/silicon heterojunctions and to optimize the design of graphene-based photodevices for a wide range of applications. PMID- 26422458 TI - Asp1 from Schizosaccharomyces pombe binds a [2Fe-2S](2+) cluster which inhibits inositol pyrophosphate 1-phosphatase activity. AB - Iron-sulfur (Fe-S) clusters are widely distributed protein cofactors that are vital to cellular biochemistry and the maintenance of bioenergetic homeostasis, but to our knowledge, they have never been identified in any phosphatase. Here, we describe an iron-sulfur cluster in Asp1, a dual-function kinase/phosphatase that regulates cell morphogenesis in Schizosaccharomyces pombe. Full-length Asp1, and its phosphatase domain (Asp1(371-920)), were each heterologously expressed in Escherichia coli. The phosphatase activity is exquisitely specific: it hydrolyzes the 1-diphosphate from just two members of the inositol pyrophosphate (PP-InsP) signaling family, namely, 1-InsP7 and 1,5-InsP8. We demonstrate that Asp1 does not hydrolyze either InsP6, 2-InsP7, 3-InsP7, 4-InsP7, 5-InsP7, 6-InsP7, or 3,5 InsP8. We also recorded 1-phosphatase activity in a human homologue of Asp1, hPPIP5K1, which was heterologously expressed in Drosophila S3 cells with a biotinylated N-terminal tag, and then isolated from cell lysates with avidin beads. Purified, recombinant Asp1(371-920) contained iron and acid-labile sulfide, but the stoichiometry (0.8 atoms of each per protein molecule) indicates incomplete iron-sulfur cluster assembly. We reconstituted the Fe-S cluster in vitro under anaerobic conditions, which increased the stoichiometry to approximately 2 atoms of iron and acid-labile sulfide per Asp1 molecule. The presence of a [2Fe-2S](2+) cluster in Asp1(371-920) was demonstrated by UV visible absorption, resonance Raman spectroscopy, and electron paramagnetic resonance spectroscopy. We determined that this [2Fe-2S](2+) cluster is unlikely to participate in redox chemistry, since it rapidly degraded upon reduction by dithionite. Biochemical and mutagenic studies demonstrated that the [2Fe-2S](2+) cluster substantially inhibits the phosphatase activity of Asp1, thereby increasing its net kinase activity. PMID- 26422460 TI - Mechanism of dynamic reorientation of cortical microtubules due to mechanical stress. AB - Directional growth caused by gravitropism and corresponding bending of plant cells has been explored since 19th century, however, many aspects of mechanisms underlying the perception of gravity at the molecular level are still not well known. Perception of gravity in root and shoot gravitropisms is usually attributed to gravisensitive cells, called statocytes, which exploit sedimentation of macroscopic and heavy organelles, amyloplasts, to sense the direction of gravity. Gravity stimulus is then transduced into distal elongation zone, which is several mm far from statocytes, where it causes stretching. It is suggested that gravity stimulus is conveyed by gradients in auxin flux. We propose a theoretical model that may explain how concentration gradients and/or stretching may indirectly affect the global orientation of cortical microtubules, attached to the cell membrane and induce their dynamic reorientation perpendicular to the gradients. In turn, oriented microtubule arrays direct the growth and orientation of cellulose microfibrils, forming part of the cell external skeleton and determine the shape of the cell. Reorientation of microtubules is also observed in reaction to light in phototropism and mechanical bending, thus suggesting universality of the proposed mechanism. PMID- 26422459 TI - Quantitative proteomics unveiled: Regulation of DNA double strand break repair by EGFR involves PARP1. AB - BACKGROUND: EGFR inhibition blocks DNA double strand break (DSB) repair but the detailed mechanisms are still unclear. We asked whether EGFR inhibition blocks DSB repair by reducing the X-ray-induced phosphorylation of repair proteins using a phosphoproteomic approach. MATERIALS AND METHODS: Using UT-SCC5 and SAS head and neck cancer cells we established a differential phosphoproteomic approach for quantitative analysis of DNA repair proteins by stable isotope labeling with amino acids. Nuclear phosphoproteins were isolated and analyzed by liquid chromatography/tandem mass spectrometry. Erlotinib, PD98059 and olaparib were used to inhibit EGFR, MEK1/2 and PARP1, respectively. PARP1 was knocked down by siRNA. DSB repair was measured by quantifying residual 53BP1 foci. RESULTS: Over 150 nuclear phosphoproteins were quantified after irradiation, including 24 DNA repair proteins. Two of these, including PARP1, were consistently reduced in both cell lines upon erlotinib treatment. PARP1 inhibition or knock-down and EGFR inhibition resulted in an analog number of residual foci which was not further increased by combination of both strategies. MEK1/2 inhibition with or without blockage of EGFR or PARP1 caused similar effects. CONCLUSION: We have established a powerful, quantitative phosphoproteomic approach to investigate regulatory mechanisms in DSB repair, dependent on protein phosphorylation after irradiation. Using this approach we have identified PARP1 as a mediator of EGFR/MEK-dependent regulation of DSB repair. PMID- 26422461 TI - Establishing Australian Norms for the Jebsen Taylor Test of Hand Function in Typically Developing Children Aged Five to 10 Years: A Pilot Study. AB - AIMS: The aim of this study was to present preliminary normative data for the Jebsen Taylor Test of Hand Function test (JTTHF) in Australian children. Normative data provide reference values for comparison of upper limb capacity when evaluating and planning treatment. METHODS: The JTTHF administration procedures and materials were standardized. One hundred and two typically developing children aged 5 to 10 years in Brisbane, Australia, were then assessed using the JTTHF. RESULTS: Five-year-old children were significantly different to all other groups (one year age bands), and 6-year-old children were significantly different from 9-year-old children in the dominant hand. Regression modeling showed improvements of 0.9 and 0.89 s in JTTHF total time for the dominant and nondominant hands, respectively, for every 12 months of maturation in 6- to 10 year-old children. CONCLUSIONS: This paper presents preliminary JTTHF norms for Australian typically developing children 5 years, 6 to 7 years, 8 to 9 years, and 10 years of age. PMID- 26422462 TI - Patterns of cannabis use in patients with Inflammatory Bowel Disease: A population based analysis. AB - BACKGROUND: Tobacco use patterns and effects in patients with Inflammatory Bowel Disease have been extensively studied, however the role and patterns of cannabis use remains poorly defined. Our aim was to evaluate patterns of marijuana use in a large population based survey. METHODS: Cases were identified from the NHANES database from the National Center for Health Statistics for the time period from January, 2009 through December, 2010 as having ulcerative colitis or Crohn's disease, and exact matched with controls using the Propensity Score Module of SPSS, based on age, gender, and sample weighted using the nearest neighbor method. RESULTS: After weighting, 2084,895 subjects with IBD and 2013,901 control subjects were identified with no significant differences in demographic characteristics. Subjects with IBD had a higher incidence of ever having used marijuana/hashish (M/H) (67.3% vs. 60.0%) and an earlier age of onset of M/H use (15.7 years vs. 19.6 years). Patients with IBD were less likely to have used M/H every month for a year, but more likely to use a heavier amount per day (64.9% subjects with IBD used three or more joints per day vs. 80.5% of subjects without IBD used two or fewer joints per day). In multivariable logistic regression, presence of IBD, male gender, and age over 40 years predicted M/H use. CONCLUSION: Our study is the first to evaluate marijuana patterns in a large scale population based survey. Older, male IBD patients have the highest odds of marijuana use. PMID- 26422463 TI - Engineering Microbiomes to Improve Plant and Animal Health. AB - Animal and plant microbiomes encompass diverse microbial communities that colonize every accessible host tissue. These microbiomes enhance host functions, contributing to host health and fitness. A novel approach to improve animal and plant fitness is to artificially select upon microbiomes, thus engineering evolved microbiomes with specific effects on host fitness. We call this engineering approach host-mediated microbiome selection, because this method selects upon microbial communities indirectly through the host and leverages host traits that evolved to influence microbiomes. In essence, host phenotypes are used as probes to gauge and manipulate those microbiome functions that impact host fitness. To facilitate research on host-mediated microbiome engineering, we explain and compare the principal methods to impose artificial selection on microbiomes; discuss advantages and potential challenges of each method; offer a skeptical appraisal of each method in light of these potential challenges; and outline experimental strategies to optimize microbiome engineering. Finally, we develop a predictive framework for microbiome engineering that organizes research around principles of artificial selection, quantitative genetics, and microbial community-ecology. PMID- 26422465 TI - Dated Plant Phylogenies Resolve Neogene Climate and Landscape Evolution in the Cape Floristic Region. AB - In the context of molecularly-dated phylogenies, inferences informed by ancestral habitat reconstruction can yield valuable insights into the origins of biomes, palaeoenvironments and landforms. In this paper, we use dated phylogenies of 12 plant clades from the Cape Floristic Region (CFR) in southern Africa to test hypotheses of Neogene climatic and geomorphic evolution. Our combined dataset for the CFR strengthens and refines previous palaeoenvironmental reconstructions based on a sparse, mostly offshore fossil record. Our reconstructions show remarkable consistency across all 12 clades with regard to both the types of environments identified as ancestral, and the timing of shifts to alternative conditions. They reveal that Early Miocene land surfaces of the CFR were wetter than at present and were dominated by quartzitic substrata. These conditions continue to characterize the higher-elevation settings of the Cape Fold Belt, where they have fostered the persistence of ancient fynbos lineages. The Middle Miocene (13-17 Ma) saw the development of perennial to weakly-seasonal arid conditions, with the strongly seasonal rainfall regime of the west coast arising ~6.5-8 Ma. Although the Late Miocene may have seen some exposure of the underlying shale substrata, the present-day substrate diversity of the CFR lowlands was shaped by Pliocene-Pleistocene events. Particularly important was renewed erosion, following the post-African II uplift episode, and the reworking of sediments on the coastal platform as a consequence of marine transgressions and tectonic uplift. These changes facilitated adaptive radiations in some, but not all, lineages studied. PMID- 26422467 TI - Cultural Beliefs Underlying Medication Adherence in People of Chinese Descent in the United States. AB - This article examines the meanings, practices, and cultural beliefs underlying medication adherence in people of Chinese descent living in the United States. The narratives were analyzed using interpretive phenomenology, resulting in the following themes that influenced the communication and behaviors around medication adherence of the participants: (a) cultural concepts of yin yang balance and "qi," (b) understandings of Western and Chinese medicine's efficacy profiles, (c) importance of family and social support, and (d) level of acculturation. This article discusses the influence of these themes on medication adherence and proposes that health communication campaigns, interventions, and doctor-patient communication about increasing medication adherence with people of Chinese descent should engage these understandings. PMID- 26422464 TI - Dopamine D3 receptor binding of (18)F-fallypride: Evaluation using in vitro and in vivo PET imaging studies. AB - Identification of dopamine D3 receptors (D3R) in vivo is important to understand several brain functions related to addiction. The goal of this work was to identify D3R binding of the dopamine D2 receptor (D2R)/D3R imaging agent, (18)F fallypride. Brain slices from male Sprague-Dawley rats (n = 6) and New Zealand White rabbits (n = 6) were incubated with (18)F-fallypride and D3R selective agonist (R)-7-OH-DPAT (98-fold D3R selective). Rat slices were also treated with BP 897 (68-fold D3R selective partial agonist) and NGB 2904 (56-fold D3R selective antagonist). In vivo rat studies (n = 6) were done on Inveon PET using 18-37 MBq (18)F-fallypride and drug-induced displacement by (R)-7-OH-DPAT, BP 897 and NGB 2904. PET/CT imaging of wild type (WT, n = 2) and D2R knock-out (KO, n = 2) mice were carried out with (18)F-fallypride. (R)-7-OH-DPAT displaced binding of (18)F-fallypride, both in vitro and in vivo. In vitro, at 10 nM (R)-7-OH-DPAT, (18)F-fallypride binding in the rat ventral striatum (VST) and dorsal striatum (DST) and rabbit nucleus accumbens were reduced by ~10-15%. At 10 MUM (R)-7-OH DPAT all regions in rat and rabbit were reduced by >=85%. In vivo reductions for DST and VST before and after (R)-7-OH-DPAT were: low-dose (0.015 mg kg(-1)) DST 22%, VST -29%; high-dose (1.88 mg kg(-1)) DST -58%, VST -77%, suggesting D3R/D2R displacement. BP 897 and NGB 2904 competed with (18)F-fallypride in vitro, but unlike BP 897, NGB 2904 did not displace (18)F-fallypride in vivo. The D2R KO mice lacked (18)F-fallypride binding in the DST. In summary, our findings suggest that up to 20% of (18)F-fallypride may be bound to D3R sites in vivo. PMID- 26422466 TI - Patient-Provider Interactions Affect Symptoms in Gastroesophageal Reflux Disease: A Pilot Randomized, Double-Blind, Placebo-Controlled Trial. AB - BACKGROUND: It is unclear whether the benefits that some patients derive from complementary and integrative medicine (CIM) are related to the therapies recommended or to the consultation process as some CIM provider visits are more involved than conventional medical visits. Many patients with gastrointestinal conditions seek out CIM therapies, and prior work has demonstrated that the quality of the patient-provider interaction can improve health outcomes in irritable bowel syndrome, however, the impact of this interaction on gastroesophageal reflux disease (GERD) is unknown. We aimed to assess the safety and feasibility of conducting a 2 x 2 factorial design study preliminarily exploring the impact of the patient-provider interaction, and the effect of an over-the-counter homeopathic product, Acidil, on symptoms and health-related quality of life in subjects with GERD. METHODS: 24 subjects with GERD-related symptoms were randomized in a 2 x 2 factorial design to receive 1) either a standard visit based on an empathic conventional primary care evaluation or an expanded visit with questions modeled after a CIM consultation and 2) either Acidil or placebo for two weeks. Subjects completed a daily GERD symptom diary and additional measures of symptom severity and health-related quality of life. RESULTS: There was no significant difference in GERD symptom severity between the Acidil and placebo groups from baseline to follow-up (p = 0.41), however, subjects who received the expanded visit were significantly more likely to report a 50% or greater improvement in symptom severity compared to subjects who received the standard visit (p = 0.01). Total consultation length, perceived empathy, and baseline beliefs in CIM were not associated with treatment outcomes. CONCLUSION: An expanded patient-provider visit resulted in greater GERD symptom improvement than a standard empathic medical visit. CIM consultations may have enhanced placebo effects, and further studies to assess the active components of this visit-based intervention are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01915173. PMID- 26422468 TI - Identify Beta-Hairpin Motifs with Quadratic Discriminant Algorithm Based on the Chemical Shifts. AB - Successful prediction of the beta-hairpin motif will be helpful for understanding the of the fold recognition. Some algorithms have been proposed for the prediction of beta-hairpin motifs. However, the parameters used by these methods were primarily based on the amino acid sequences. Here, we proposed a novel model for predicting beta-hairpin structure based on the chemical shift. Firstly, we analyzed the statistical distribution of chemical shifts of six nuclei in not beta-hairpin and beta-hairpin motifs. Secondly, we used these chemical shifts as features combined with three algorithms to predict beta-hairpin structure. Finally, we achieved the best prediction, namely sensitivity of 92%, the specificity of 94% with 0.85 of Mathew's correlation coefficient using quadratic discriminant analysis algorithm, which is clearly superior to the same method for the prediction of beta-hairpin structure from 20 amino acid compositions in the three-fold cross-validation. Our finding showed that the chemical shift is an effective parameter for beta-hairpin prediction, suggesting the quadratic discriminant analysis is a powerful algorithm for the prediction of beta-hairpin. PMID- 26422471 TI - High-throughput determination of octanol/water partition coefficients using a shake-flask method and novel two-phase solvent system. AB - A high-throughput method for determining the octanol/water partition coefficient (P(o/w)) of a large variety of compounds exhibiting a wide range in hydrophobicity was established. The method combines a simple shake-flask method with a novel two-phase solvent system comprising an acetonitrile-phosphate buffer (0.1 M, pH 7.4)-1-octanol (25:25:4, v/v/v; AN system). The AN system partition coefficients (K(AN)) of 51 standard compounds for which log P(o/w) (at pH 7.4; log D) values had been reported were determined by single two-phase partitioning in test tubes, followed by measurement of the solute concentration in both phases using an automatic flow injection-ultraviolet detection system. The log K(AN) values were closely related to reported log D values, and the relationship could be expressed by the following linear regression equation: log D=2.8630 log K(AN) 0.1497(n=51). The relationship reveals that log D values (+8 to -8) for a large variety of highly hydrophobic and/or hydrophilic compounds can be estimated indirectly from the narrow range of log K(AN) values (+3 to -3) determined using the present method. Furthermore, log K(AN) values for highly polar compounds for which no log D values have been reported, such as amino acids, peptides, proteins, nucleosides, and nucleotides, can be estimated using the present method. The wide-ranging log D values (+5.9 to -7.5) of these molecules were estimated for the first time from their log K(AN) values and the above regression equation. PMID- 26422470 TI - Novel Vitamin D Receptor Mutations in Hereditary Vitamin D Resistant Rickets in Chinese. AB - Hereditary 1, 25-dihydroxyvitamin D-resistant rickets (HVDRR), a rare recessive disease, is caused by mutation in the VDR gene encoding the vitamin D receptor leading to the resistance to vitamin D. We described a female toddler with initial presentation of leg tenderness and clinical features of HVDRR including severe rickets, hypocalcemia and hypophosphatemia without alopecia. Genetic analysis revealed novel compound heterozygous mutations of p.M4I and p.H229Q in patient's VDR gene. In cis p.M4I with FOKI-F eliminated both translation start sites of the VDR protein. The p.H229Q VDR exhibited significantly reduced VDR transactivation activity with intact dimerization with RXR. Our report expanded the mutation spectrum of HVDRR, and provided the first case of a benign variant p.M4I plus a common p.M1T polymorphism leading to a pathogenic allele. PMID- 26422472 TI - Using Fish Population Metrics to Compare the Effects of Artificial Reef Density. AB - Artificial reefs continue to be added as habitat throughout the world, yet questions remain about how reef design affects fish diversity and abundance. In the present study, the effects of reef density were assessed for fish communities and sizes of economically valuable Lutjanus campechanus 13 km off Port Mansfield, Texas, at a reef composed of more than 4000 concrete culverts. The study spanned from May to June in 2013 and 2014, and sites sampled included natural reefs, bare areas, and varying culvert patch density categories, ranging from 1-190 culverts. Abundances of adults and species evenness of juvenile populations differed between the years. Fish communities did not significantly differ among density categories; however, highest species richness and total abundances were observed at intermediate culvert densities and at natural reefs. Whereas the abundance of L. campechanus did not differ among density categories, mean total lengths of L. campechanus were greatest at the lower density. Our findings suggest that reefs should be deployed with intermediate patch density of 71-120 culverts in a 30-m radius to yield the highest fish abundances. PMID- 26422469 TI - Adaptation in Toxic Environments: Arsenic Genomic Islands in the Bacterial Genus Thiomonas. AB - Acid mine drainage (AMD) is a highly toxic environment for most living organisms due to the presence of many lethal elements including arsenic (As). Thiomonas (Tm.) bacteria are found ubiquitously in AMD and can withstand these extreme conditions, in part because they are able to oxidize arsenite. In order to further improve our knowledge concerning the adaptive capacities of these bacteria, we sequenced and assembled the genome of six isolates derived from the Carnoules AMD, and compared them to the genomes of Tm. arsenitoxydans 3As (isolated from the same site) and Tm. intermedia K12 (isolated from a sewage pipe). A detailed analysis of the Tm. sp. CB2 genome revealed various rearrangements had occurred in comparison to what was observed in 3As and K12 and over 20 genomic islands (GEIs) were found in each of these three genomes. We performed a detailed comparison of the two arsenic-related islands found in CB2, carrying the genes required for arsenite oxidation and As resistance, with those found in K12, 3As, and five other Thiomonas strains also isolated from Carnoules (CB1, CB3, CB6, ACO3 and ACO7). Our results suggest that these arsenic-related islands have evolved differentially in these closely related Thiomonas strains, leading to divergent capacities to survive in As rich environments. PMID- 26422473 TI - Emotional Dynamics in the Age of Misinformation. AB - According to the World Economic Forum, the diffusion of unsubstantiated rumors on online social media is one of the main threats for our society. The disintermediated paradigm of content production and consumption on online social media might foster the formation of homogeneous communities (echo-chambers) around specific worldviews. Such a scenario has been shown to be a vivid environment for the diffusion of false claim. Not rarely, viral phenomena trigger naive (and funny) social responses-e.g., the recent case of Jade Helm 15 where a simple military exercise turned out to be perceived as the beginning of the civil war in the US. In this work, we address the emotional dynamics of collective debates around distinct kinds of information-i.e., science and conspiracy news and inside and across their respective polarized communities. We find that for both kinds of content the longer the discussion the more the negativity of the sentiment. We show that comments on conspiracy posts tend to be more negative than on science posts. However, the more the engagement of users, the more they tend to negative commenting (both on science and conspiracy). Finally, zooming in at the interaction among polarized communities, we find a general negative pattern. As the number of comments increases-i.e., the discussion becomes longer the sentiment of the post is more and more negative. PMID- 26422476 TI - A measurement of the maximal forces in plasmonic tweezers. AB - Plasmonic tweezers that are designed to trap nanoscale objects create many new possibilities for single-molecule targeted studies. Numerous novel designs of plasmonic nanostructures are proposed in order to attain stronger forces and weaker laser intensity. Most experiments have consisted only of immobilization observations--that is, particles stick when the laser is turned on and fall away when the laser is turned off. Studies of the exertable forces were only theoretical. A few studies have experimentally measured trap stiffness. However, as far as we know, no studies have addressed maximal forces. In this paper, we present a new experimental design in which the motion of the trapped particle can be monitored in either parallel or orthogonal directions to the plasmonic structure's symmetric axis. We measured maximal trapping force through such monitoring. Although stiffness would be useful for force-calibration or immobilization purposes, for which most plasmonic tweezers are used, we believe that the maximal endurable force is significant and thus, this paper presents this aspect. PMID- 26422475 TI - Multiresidue Method for Analysis of beta Agonists in Swine Urine by Enzyme Linked Receptor Assay Based on beta2 Adrenergic Receptor Expressed in HEK293 Cells. AB - A novel enzyme-linked receptor assay (ELRA) based on beta2-adrenergic receptor (beta2-AR) has been developed for rapid and high-throughput detection of beta adrenergic agonists (beta-agonists) in urine. Human embryonic kidney cells (HEK293) were introduced as the expression system to enhance the functionality of the recombinant beta2-AR, and the attempt to detect beta-agonists in swine urine using such approaches was accomplished unprecedentedly. In this article, a recombinant porcine beta2-AR was produced in the inner membrane of HEK293 cells and purified from crude membrane protein by nickel-nitrilotriacetic acid affinity chromatography. After activity identification, the recombinant receptor was used in the development of direct competitive ELRA. Several parameters such as blocking buffer and blocking process were optimized and the performance of the system was determined. The IC50 concentrations of clenbuterol, salbutamol, and ractopamine were 34, 53 and 63 MUg/L, and the average recovery rates were 68.2%, 60.3% and 65.5%, respectively. ELRA based on beta2-AR shows a series of advantages such as safety, easy operation, and high efficiency, making it promising for the rapid screening of beta-agonists in animal urine. PMID- 26422477 TI - Rebooting Our Boots on the Ground. PMID- 26422474 TI - High Treatment Retention Rate in HIV-Infected Patients Receiving Antiretroviral Therapy at Two Large HIV Clinics in Hanoi, Vietnam. AB - BACKGROUND: Loss to follow-up (LTFU) is viewed as a major challenge in improving retention in HIV treatment. In Vietnam, the reasons for disengagement from clinics and the effect of injection drug use (IDU) on LTFU with unknown outcome (true LTFU) are not well known. METHODS: Patients receiving antiretroviral therapy (ART) from two HIV clinics in Hanoi were included in this observational study between 2007 and 2012, and followed up every 6 months until the end of 2013. The reasons for disengagement from the clinic, and ART status during imprisonment were investigated in patients with a history of IDU to identify true LTFU. The retention rate at 6-54 months and true LTFU rate were calculated. Cox proportional hazards regression models were performed to identify factors associated with true LTFU. RESULTS: There were 1,431 patients, with a follow-up time of 4,371 person-years (median 2.49 years). At the end of the follow-up period, 71 (5.0%) patients died, 79 (5.5%) transferred to other clinics, 16 (1.1%) disengaged from the clinics, and the calculated true LTFU was 45 (3.1%), with 12-month ART retention rate of 95.3% for the entire study population. Imprisonment was the most frequent reason for disengagement from the clinics. True LTFU correlated significantly with low CD4 count and high plasma viral load, but not history of IDU. CONCLUSION: Imprisonment is a major cause of disengagement from HIV care among patients with a history of IDU. PMID- 26422478 TI - Knowing Where Public Health Is Going: Levels and Determinants of Workforce Awareness of National Public Health Trends. AB - CONTEXT: Several recent developments are trending in public health, providing an important window into the future of policy and practice in the field. The extent to which public health workforce is aware of these trends has not been assessed. OBJECTIVE: This research examined the extent to which the public health workforce is familiar with 8 important developments and trends in public health and explored factors associated with variation in awareness levels. DESIGN: This study characterizes an observational cross-sectional design, based on analysis of secondary data collected by the Association of State and Territorial Health Officials through the Public Health Workforce Interests and Needs Survey (PH WINS). SETTING: Our study used data from those states for which representative samples for the local health department (LHD) employees were also available. PARTICIPANTS: We included survey responses from employees of state health agencies' central offices and LHDs. MAIN OUTCOME MEASURE: The primary outcome variable for the analysis was the level of awareness about emerging public health trends in the public health workforce. RESULTS: Awareness of emerging trends was lowest for Public Health Systems and Services Research; roughly 1 in 4 employees were aware of this trend. The second least heard of trends were Health in All Policies, and cross-jurisdictional sharing. The public health trends about which the highest proportion of public health employees had heard were implementation of the Patient Protection and Affordable Care Act and evidence-based public health practice. Awareness about public health trends was generally higher among state health agency employees than among LHD employees. Work environment, supervisory status, employee education, and female gender were significantly associated with higher awareness levels for both state health agency and LHD employees. CONCLUSIONS: Public health trends that are important for health agencies should be brought to the spotlight in national dialogue in order to increase practitioner involvement in those initiatives. PMID- 26422479 TI - Not So Strange Bedfellows: How Practice and Academia Together Will Ensure the Future of the Public Health Workforce. PMID- 26422480 TI - The Work Experiences of Community Health Professionals: Implications for the Continued Rollout of the Affordable Care Act. AB - OBJECTIVE: State health reform (Patient Protection and Affordable Care Act [ACA]) policies may impact the work experiences of community health professionals. We examine the extent to which community health professional work experiences differ depending on state Medicaid expansion and health insurance exchange policies. DESIGN: Public Health Workforce Interests and Needs Survey (PH WINS) (2014) responses from public health nurses, community health workers, health educators, and other public health professionals were merged with state ACA Medicaid expansion and health insurance exchange operations data. We used multivariate regression to examine the extent to which community health professionals in states without Medicaid expansion, or expansion states without a state-run health insurance exchange, reported lower-quality work experiences and less leadership support than did community health professionals working in Medicaid expansion states with state-run health insurance exchanges, controlling for worker characteristics. SETTING: Local and state health departments (SHD) in 37 states. PARTICIPANTS: 10,246 state health department and 6450 local health department (LHD) workers. MAIN OUTCOMES: Work satisfaction (job, organization, pay, and job security), quality of work experiences, leadership support, and impact of the ACA on work. RESULTS: In adjusted analyses, LHD community health professionals in states without Medicaid expansion reported worse experiences of leadership support (beta = -9.83; P < .05). LHD community health professionals in Medicaid expansion states without state-run health insurance exchange operations reported lower-quality work experiences (beta = -13.06; P < .01), less leadership support (beta = -11.52; P < .001), and perceived greater impacts of the ACA on their work (beta = 9.18; P < .001) than did LHD community health professionals in expansion states with state-run health insurance exchanges. CONCLUSIONS: Less state control over health insurance exchange operations or state inaction with respect to Medicaid expansion may negatively impact LHD community health professional work experiences and perceptions of leadership support. PMID- 26422481 TI - Successful Academic-Public Health Practice Collaboration: What Works From the Public Health Workforce's Perspective. AB - CONTEXT: Public health departments and academic institutions engage in a range of cooperative activities that can greatly benefit a public health department and can often be mutually beneficial. Yet, little is known regarding practitioners' views of successful academic collaborations. OBJECTIVE: The purpose of this study was to explore predictors and correlates of beneficial academic collaboration from the perspective of those on the front lines--the practitioners constituting the public health workforce. DESIGN: Analysis of the Public Health Workforce Interests and Needs Survey (PH WINS), a cross-sectional survey of state health department practitioners, conducted in 2014. PARTICIPANTS: PH WINS is a nationally representative survey of state health department practitioners. Data were available for a total of 8718 respondents in 37 states. MAIN OUTCOME MEASURES: Two main outcome measures were used--(a) whether a respondent reported collaborating with an academic entity (including faculty/staff/students) in the past year, and (b) when collaboration did occur, the success of the collaboration insofar as the respondent perceived the engagement as very helpful. RESULTS: Health department practitioners (27.2%) reported participating in an academic practice collaboration. Factors associated with partnering included respondents' supervisory status, positional duties, and public health background. Of these respondents, 46.6% reported a successful collaboration. Factors associated with a successful collaboration included respondents' self-reported job skills and public health background. CONCLUSION: While characteristics related to a public health practitioner's position are most significant in predicting whether a collaboration will occur, characteristics of the individual him- or herself are more relevant in predicting whether a collaboration will be successful. Public health managers interested in fostering an environment that promotes a successful academic-practice collaboration may benefit from ensuring that the public health practitioners involved in such collaborations are themselves trained in public health. PMID- 26422482 TI - The Public Health Workforce Interests and Needs Survey: The First National Survey of State Health Agency Employees. AB - CONTEXT: Public health practitioners, policy makers, and researchers alike have called for more data on individual worker's perceptions about workplace environment, job satisfaction, and training needs for a quarter of a century. The Public Health Workforce Interests and Needs Survey (PH WINS) was created to answer that call. OBJECTIVE: Characterize key components of the public health workforce, including demographics, workplace environment, perceptions about national trends, and perceived training needs. DESIGN: A nationally representative survey of central office employees at state health agencies (SHAs) was conducted in 2014. Approximately 25,000 e-mail invitations to a Web-based survey were sent out to public health staff in 37 states, based on a stratified sampling approach. Balanced repeated replication weights were used to account for the complex sampling design. SETTING AND PARTICIPANTS: A total of 10,246 permanently employed SHA central office employees participated in PH WINS (46% response rate). MAIN OUTCOME MEASURES: Perceptions about training needs; workplace environment and job satisfaction; national initiatives and trends; and demographics. RESULTS: Although the majority of staff said they were somewhat or very satisfied with their job (79%; 95% confidence interval [CI], 78-80), as well as their organization (65%; 95% CI, 64-66), more than 42% (95% CI, 41-43) were considering leaving their organization in the next year or retiring before 2020; 4% of those were considering leaving for another job elsewhere in governmental public health. The majority of public health staff at SHA central offices are female (72%; 95% CI, 71-73), non-Hispanic white (70%; 95% CI, 69-71), and older than 40 years (73%; 95% CI, 72-74). The greatest training needs include influencing policy development, preparing a budget, and training related to the social determinants of health. CONCLUSIONS: PH WINS represents the first nationally representative survey of SHA employees. It holds significant potential to help answer previously unaddressed questions in public health workforce research and provides actionable findings for SHA leaders. PMID- 26422483 TI - Characterizing Informatics Roles and Needs of Public Health Workers: Results From the Public Health Workforce Interests and Needs Survey. AB - OBJECTIVE: To characterize public health workers who specialize in informatics and to assess informatics-related aspects of the work performed by the public health workforce. METHODS (DESIGN, SETTING, PARTICIPANTS): Using the nationally representative Public Health Workforce Interests and Needs Survey (PH WINS), we characterized and compared responses from informatics, information technology (IT), clinical and laboratory, and other public health science specialists working in state health agencies. MAIN OUTCOME MEASURES: Demographics, income, education, and agency size were analyzed using descriptive statistics. Weighted medians and interquartile ranges were calculated for responses pertaining to job satisfaction, workplace environment, training needs, and informatics-related competencies. RESULTS: Of 10,246 state health workers, we identified 137 (1.3%) informatics specialists and 419 (4.1%) IT specialists. Overall, informatics specialists are younger, but share many common traits with other public health science roles, including positive attitudes toward their contributions to the mission of public health as well as job satisfaction. Informatics specialists differ demographically from IT specialists, and the 2 groups also differ with respect to salary as well as their distribution across agencies of varying size. All groups identified unmet public health and informatics competency needs, particularly limited training necessary to fully utilize technology for their work. Moreover, all groups indicated a need for greater future emphasis on leveraging electronic health information for public health functions. CONCLUSIONS: Findings from the PH WINS establish a framework and baseline measurements that can be leveraged to routinely monitor and evaluate the ineludible expansion and maturation of the public health informatics workforce and can also support assessment of the growth and evolution of informatics training needs for the broader field. Ultimately, such routine evaluations have the potential to guide local and national informatics workforce development policy. PMID- 26422484 TI - Perceptions Regarding Importance and Skill at Policy Development Among Public Health Staff. AB - CONTEXT: Policy development is recognized as a core function of public health and a core competency in formal public health education. However, relatively little is known nationally about worker perceptions and competencies related to policy development in the governmental public health workforce. OBJECTIVE: To characterize perceived importance and presence or absence of competency gaps related to policy development. DESIGN: As part of the Public Health Workforce Interests and Needs Survey (PH WINS), a nationally representative stratified sample of permanently employed state health agency (SHA) central office staff was created. Descriptive and inferential analyses examined correlates of perceived importance and competency gaps related to policy development. SETTING AND PARTICIPANTS: Permanently employed central office employees of SHAs. MAIN OUTCOME MEASURE: Analyses focus on 2 self-reported measures of perceived importance and ability related to policy development skills, as well as awareness and perceptions regarding Health in All Policies (HiAP). RESULTS: Seventy-two percent of SHA central office staff (95% confidence interval, 71-73) indicated "influencing policy development" was somewhat or very important to their day-to day work. Among that group, 35% (95% confidence interval, 34-36) reported that they were unable to perform this or they considered themselves to be a beginner at this skill. Approximately three-fourths of staff indicated "understanding the relationship between a new policy and many types of public health problems" was somewhat or very important, and 30% of those who did said they were unable to perform this skill or were a beginner at it. Nationally, one-half of staff have not heard of HiAP. Among those who have, 86% indicated it was somewhat or very important to public health, and 41% reported they would like to see more emphasis on HiAP. CONCLUSIONS: Workforce development, both formal education and on-the-job training, may benefit from placing a greater emphasis on the development of policy skills. HiAP is an important approach to policy development. PMID- 26422485 TI - Perception of Workforce Skills Needed Among Public Health Professionals in Local Health Departments: Staff Versus Top Executives. AB - OBJECTIVES: To examine how top executives and staff from local health departments (LHDs) perceive the importance of various types of workforce skills, and to assess the differences in the perception of the importance of these workforce skills between these 2 groups and among LHDs serving different-sized jurisdictions. DESIGN: Data for this study were drawn from the 2014 Public Health Workforce Interests and Needs Survey (PH WINS) and the 2015 Forces of Change survey. While PH WINS collected data from LHD staff, the Forces of Change survey was administered to LHD top executives. Ratings of perceived importance of workforce skills from LHD staff and top executives were compared. RESULTS: Overall, LHD workers at all levels believe that core competencies are important for their jobs. The perceived importance of these skills differed somewhat across supervisory level (nonsupervisory staff vs supervisory staff vs top executives). Communication was rated as one of the most important skills by all groups. For top executives, ensuring that programs are managed within budget constraints was the most important skill for their employees. However, this skill was rated much lower among staff. Policy development skills were rated to be of lowest importance by LHD leaders and staff. CONCLUSIONS: LHD leaders and staff agree on the relative importance of some competencies, although they also show some clear differences in the relative importance that they place on other competencies. It is essential to strengthen the communication between public health leaders and staff regarding the importance of workforce skills. More investigation is needed to assess whether and how gaps in staff competencies are addressed in the workforce development strategies. PMID- 26422486 TI - Characterizing the Business Skills of the Public Health Workforce: Practical Implications From the Public Health Workforce Interests and Needs Survey (PH WINS). AB - CONTEXT: Public health financial competencies are often overlooked or underrepresented in public health training programs. These skills are important for public health workforce members who are involved in managing resources and strategic planning and have been defined as key competencies by several national entities. OBJECTIVE: To characterize business skills among state health agency employees and examine self-reported skill levels and their association with job satisfaction, worksite training and development opportunities, and annual salary. DESIGN: A cross-sectional survey, the Public Health Workforce Interests and Needs Survey (PH WINS), of state health agency central office employees was conducted in 2014. Multivariable logistic regression analyses, controlling for job classification, supervisory status, years of public health practice, annual compensation, educational attainment, geographic region, and sociodemographic status, were used to assess the relationship between business skills and training environment and job satisfaction. Linear regression was used to correlate business skills and annual compensation. SETTING AND PARTICIPANTS: A total of 10,246 state health agency staff completed a Web-based survey. MAIN OUTCOME MEASURE: Self-reported proficiency in business skills, job satisfaction, opportunities for training, and annual salary. RESULTS: The workforce reported high levels of proficiency in applying quality improvement concepts and managing change (67.5% and 69.2%, respectively). Half of the respondents reported proficiency in budget skills (49.3%). Participants who were proficient in applying quality improvement concepts were significantly more likely to report job satisfaction (OR = 1.27). A supportive training environment was significantly associated with business competencies (range of OR = 1.08-1.11). Managing change (beta = .15) and budget skill proficiency (beta = .37) were significantly associated with increased yearly compensation. CONCLUSIONS: Public health workers who self-report proficiency with business skills report increased job satisfaction, higher annual salary, and a supportive training environment. These findings support the need for the development of appropriately designed business skill training opportunities to increase competencies in this critical domain. PMID- 26422487 TI - ASTHO Affiliates Find Value in PH WINS. PMID- 26422488 TI - Public Health Wins When We Use Data to Drive Decision Making. PMID- 26422489 TI - When We Have Data We Can Count on, Everyone WINS. PMID- 26422490 TI - The Methods Behind PH WINS. AB - The Public Health Workforce Interests and Needs Survey (PH WINS) has yielded the first-ever nationally representative sample of state health agency central office employees. The survey represents a step forward in rigorous, systematic data collection to inform the public health workforce development agenda in the United States. PH WINS is a Web-based survey and was developed with guidance from a panel of public health workforce experts including practitioners and researchers. It draws heavily from existing and validated items and focuses on 4 main areas: workforce perceptions about training needs, workplace environment and job satisfaction, perceptions about national trends, and demographics. This article outlines the conceptualization, development, and implementation of PH WINS, as well as considerations and limitations. It also describes the creation of 2 new data sets that will be available in public use for public health officials and researchers--a nationally representative data set for permanently employed state health agency central office employees comprising over 10,000 responses, and a pilot data set with approximately 12,000 local and regional health department staff responses. PMID- 26422491 TI - A Strong Public Health Workforce for Today and Tomorrow. PMID- 26422492 TI - Application of a Taxonomy to Characterize the Public Health Workforce. AB - OBJECTIVE: A public health workforce taxonomy was published in 2014 to provide a standardized mechanism for describing public health worker characteristics. The Public Health Workforce Interests and Needs Survey (PH WINS) used 7 of the taxonomy's 12 axes as a basis for its survey response choices, 3 of which are the focus of this analysis. The purpose of this study was to determine the relative utility, reliability, and accuracy of the public health workforce taxonomy in categorizing local and state public health workers using a survey tool. This specifically included the goal of reducing the number of responses classified as "other" occupation, certification, or program area by recoding responses into taxonomy categories and determining potential missing categories for recommendation to the advisory committee that developed the taxonomy. DESIGN: Survey questions associated with the occupation, certification, and program area taxonomy axes yielded qualitative data from respondents who selected "other." The "other" responses were coded by 2 separate research teams at the University of Michigan Center of Excellence in Public Health Workforce Studies and NORC at the University of Chicago. MAIN OUTCOME MEASURES: Researchers assigned taxonomy categories to all analyzable qualitative responses and assessed the percentage of PH WINS responses that could be successfully mapped to taxonomy categories. RESULTS: Between respondent self-selection and research team recoding, the public health workforce taxonomy successfully categorized 95% of occupation responses, 75% of credential responses, and 83% of program area responses. Occupational categories that may be considered for inclusion in the taxonomy in the future include disease intervention specialists and occupations associated with regulation, certification, and licensing. CONCLUSIONS: The public health workforce taxonomy performed remarkably well in categorizing worker characteristics in its first use in a national survey. The analysis provides some recommendations for future taxonomy refinement. PMID- 26422493 TI - Job Satisfaction: A Critical, Understudied Facet of Workforce Development in Public Health. AB - CONTEXT: The field of public health faces multiple challenges in its efforts to recruit and retain a robust workforce. Public health departments offer salaries that are lower than the private sector, and government bureaucracy can be a deterrent for those seeking to make a difference. OBJECTIVE: The objective of this research was to explore the relationship between general employee satisfaction and specific characteristics of the job and the health agency and to make recommendations regarding what health agencies can do to support recruitment and retention. DESIGN: This is a cross-sectional study using data collected from the 2014 Public Health Workforce Interests and Needs Survey (PH WINS). A nationally representative sample was constructed from 5 geographic (paired adjacent HHS [US Department of Health and Human Services]) regions and stratified by population and state governance type. Descriptive and inferential statistics were analyzed using the balanced repeated replication method to account for the complex sampling design. A multivariate linear regression was used to examine job satisfaction and factors related to supervisory and organizational support adjusting for relevant covariates. SETTING AND PARTICIPANTS: PH WINS data were collected from state health agency central office employees using an online survey. MAIN OUTCOME MEASURE: Level of job satisfaction using the Job in General Scale (abridged). RESULTS: State health agency central office staff (n = 10,246) participated in the survey (response rate 46%). Characteristics related to supervisory and organizational support were highly associated with increased job satisfaction. Supervisory status, race, organization size, and agency tenure were also associated with job satisfaction. CONCLUSIONS: Public health leaders aiming to improve levels of job satisfaction should focus on workforce development and training efforts as well as adequate supervisory support, especially for new hires and nonsupervisors. PMID- 26422494 TI - Addressing Urgent Public Health Workforce Needs: Building Informatics Competency and Strengthening Management and Leadership Skills. PMID- 26422495 TI - Educational Attainment of the Public Health Workforce and Its Implications for Workforce Development. AB - CONTEXT: Educational attainment is a critical issue in public health workforce development. However, relatively little is known about the actual attainment of staff in state health agencies (SHAs). OBJECTIVE: Ascertain the levels of educational attainment among SHA employees, as well as the correlates of attainment. DESIGN: Using a stratified sampling approaching, staff from SHAs were surveyed using the Public Health Workforce Interests and Needs Survey (PH WINS) instrument in late 2014. A nationally representative sample was drawn across 5 geographic (paired adjacent HHS) regions. Descriptive and inferential statistics were analyzed using balanced repeated replication weights to account for complex sampling. A logistic regression was conducted with attainment of a bachelor's degree as the dependent variable and age, region, supervisory status, race/ethnicity, gender, and staff type as independent variables. SETTING AND PARTICIPANTS: Web-based survey of SHA central office employees. MAIN OUTCOME MEASURE: Educational attainment overall, as well as receipt of a degree with a major in public health. RESULTS: A total of 10,246 permanently-employed SHA central office staff participated in the survey (response rate 46%). Seventy-five percent (95% confidence interval [CI], 74-77) had a bachelor's degree, 38% (95% CI, 37-40) had a master's degree, and 9% (95% CI, 8%-10%) had a doctoral degree. A logistic regression showed Asian staff had the highest odds of having a bachelor's degree (odds ratio [OR] = 2.8; 95% CI, 2.2-3.7) compared with non Hispanic whites, and Hispanic/Latino staff had lower odds (OR = 0.6; 95% CI, 0.4 0.8). Women had lower odds of having a bachelor's degree than men (OR = 0.5; 95% CI, 0.4-0.6). About 17% of the workforce (95% CI, 16-18) had a degree in public health at any level. CONCLUSIONS: Educational attainment among SHA central office staff is high, but relatively few have formal training of any sort in public health. This makes efforts to increase availability of on-the-job training and distance learning all the more critical. PMID- 26422497 TI - Data, Workforce, Action! PMID- 26422496 TI - Does Money Matter: Earnings Patterns Among a National Sample of the US State Governmental Public Health Agency Workforce. AB - CONTEXT: Earnings have been shown to be a critical point in workforce recruitment and retention. However, little is known about how much governmental public health staff are paid across the United States. OBJECTIVE: To characterize earnings among state health agency central office employees. DESIGN: A cross-sectional survey was conducted of state health agency central office employees in late 2014. The sampling approach was stratified by 5 (paired HHS) regions. Balanced repeated replication weights were used to correctly calculate variance estimates, given the complex sampling design. Descriptive and bivariate statistical comparisons were conducted. A linear regression model was used to examine correlates of earnings among full-time employees. SETTING AND PARTICIPANTS: A total of 9300 permanently employed, full-time state health agency central office staff who reported earnings information. MAIN OUTCOME MEASURE: Earnings are the main outcomes examined in this article. RESULTS: Central office staff earn between $55,000 and $65,000 on average annually. Ascending supervisory status, educational attainment, and tenure are all associated with greater earnings. Those employed in clinical and laboratory positions and public health science positions earn more than their colleagues in administrative positions. Disparities exist between men and women, with men earning more, all else being equal (P < .001). Racial/ethnic disparities also exist, after accounting for other factors. CONCLUSIONS: This study provides baseline information to characterize the workforce and key challenges that result from earnings levels, including disparities in earnings that persist after accounting for education and experience. Data from the survey can inform strategies to address earnings issues and help reduce disparities. PMID- 26422498 TI - Building and Sustaining Strong Public Health Agencies: Determinants of Workforce Turnover. AB - CONTEXT: Workforce shortages have been identified as a priority for US public health agencies. Voluntary turnover results in loss of expertise and institutional knowledge as well as high costs to recruit and train replacement workers. OBJECTIVE: To analyze patterns and predictors of voluntary turnover among public health workers. DESIGN: Descriptive analysis and linear probability regression models. PARTICIPANTS: Employees of state health agencies in the United States who participated in the Public Health Workforce Interests and Needs Survey (PH WINS). MAIN OUTCOME MEASURES: Intended retirement and voluntary departure; pay satisfaction; job satisfaction. RESULTS: Nearly 25% of workers reported plans to retire before 2020, and an additional 18% reported the intention to leave their current organization within 1 year. Four percent of staff are considering leaving their organization in the next year for a job at a different health department. There was significant heterogeneity by demographic, socioeconomic, and job characteristics. Areas such as administration/management, health education, health services, social services, and epidemiology may be particularly vulnerable to turnover. The strongest predictors of voluntary departure were pay and job satisfaction, which were associated with 9 (P < .001) and 24 (P < .001) percentage-point decreases, respectively, in the probability to report the intention to leave. Our findings suggest that if all workers were satisfied with their job and pay, intended departure would be 7.4%, or less than half the current 18% rate. Controlling for salary levels, higher levels of education and longer work experience were associated with lower pay satisfaction, except for physicians, who were 11 percentage points (P = .02) more likely to be satisfied with their pay than employees with doctoral degrees. Several workplace characteristics related to relationships with supervisors, workplace environment, and employee motivation/morale were significantly associated with job satisfaction. CONCLUSIONS: Our findings suggest that public health agencies may face significant pressure from worker retirement and voluntary departures in coming years. Although retirement can be addressed through recruitment efforts, addressing other voluntary departures will require focusing on improving pay and job satisfaction. PMID- 26422499 TI - Health Resources and Services Administration Perspective on the Public Health Workforce Interests and Needs Survey. PMID- 26422500 TI - Loving and Leaving Public Health: Predictors of Intentions to Quit Among State Health Agency Workers. AB - CONTEXT: State health agencies play a critical role in protecting and promoting the health and well-being of the people they serve. To be effective, they must maintain a highly skilled, diverse workforce of sufficient size and with proper training. OBJECTIVE: The goal of this study was to examine demographics, job and workplace environment characteristics, job satisfaction, and reasons for initially joining the public health workforce as predictors of an employee's intentions to leave an organization within the next year. DESIGN: This study used a cross-sectional design. Respondents were selected on the basis of a stratified sampling approach, with 5 geographic (paired Health and Human Services [HHS] regions) as the primary strata. Balanced repeated replication was used as a resampling method for variance estimation. A logistic regression model was used to examine the correlates of intentions to leave one's organization within the next year. The independent variables included several measures of satisfaction, perceptions about the workplace environment, initial reasons for joining public health, gender, age, education, salary, supervisory status, program area, and paired HHS region. SETTING AND PARTICIPANTS: The sample for this study consisted of 10,246 permanently employed state health agency central office employees who responded to the Public Health Workforce Interests and Needs Survey (PH WINS). MAIN OUTCOME MEASURE: Considering leaving one's organization within the next year. RESULTS: Being a person of color, living in the West (HHS regions 9 and 10), and shorter tenure in one's current position were all associated with higher odds of intentions to leave an organization within the next year. Conversely, greater employee engagement, organizational support, job satisfaction, organization satisfaction, and pay satisfaction were all significant predictors of lower intentions to leave one's organization within the next year. CONCLUSIONS: Results from this study suggest several variables related to demographics, job characteristics, workplace environment, and job satisfaction that are predictive of intentions to leave. Future researchers and state health agencies should explore how these findings can be used to help with retention of employees in the state health agency workforce. PMID- 26422501 TI - Deletion of mineralocorticoid receptors in smooth muscle cells blunts renal vascular resistance following acute cyclosporine administration. AB - Calcineurin inhibitors such as cyclosporine A (CsA) are still commonly used after renal transplantation, despite CsA--induced nephrotoxicity (CIN), which is partly related to vasoactive mechanisms. The mineralocorticoid receptor (MR) is now recognized as a key player in the control of vascular tone, and both endothelial cell- and vascular smooth muscle cell (SMC)-MR modulate the vasoactive responses to vasodilators and vasoconstrictors. Here we tested whether vascular MR is involved in renal hemodynamic changes induced by CsA. The relative contribution of vascular MR in acute CsA treatment was evaluated using mouse models with targeted deletion of MR in endothelial cell or SMC. Results indicate that MR expressed in SMC, but not in endothelium, contributes to the increase of plasma urea and creatinine, the appearance of isometric tubular vacuolization, and overexpression of a kidney injury biomarker (neutrophil gelatinase--associated lipocalin) after CsA treatment. Inactivation of MR in SMC blunted CsA--induced phosphorylation of contractile proteins. Finally, the in vivo increase of renal vascular resistance induced by CsA was blunted when MR was deleted from SMC cells, and this was associated with decreased L-type Ca2D channel activity. Thus, our study provides new insights into the role of vascular MR in renal hemodynamics during acute CIN, and provides rationale for clinical studies of MR antagonism to manage the side effects of calcineurin inhibitors. PMID- 26422502 TI - Relationship of dietary phosphate intake with risk of end-stage renal disease and mortality in chronic kidney disease stages 3-5: The Modification of Diet in Renal Disease Study. AB - KDIGO guidelines recommend dietary phosphate restriction to lower serum phosphate levels in CKD stages 3-5. Recent studies suggest that dietary phosphate intake is only weakly linked to its serum concentration, and the relationship of phosphate intake with adverse outcomes is uncertain. To evaluate this, we used Cox proportional hazards models to assess associations of baseline 24-h urine phosphate excretion with risk of end-stage renal disease (ESRD), all-cause mortality, and mortality subtypes (cardiovascular disease [CVD] and non-CVD) using the Modification of Diet in Renal Disease data. Models were adjusted for demographics, CVD risk factors, iothalamate GFR, and urine protein and nitrogen excretion. Phosphate excretion was modestly inversely correlated with serum phosphate concentrations. There was no association of 24-h urinary phosphate excretion with risk of ESRD, CVD, non-CVD, or all-cause mortality. For comparison, higher serum phosphate concentrations were associated with all-cause mortality (hazard ratio per 0.7 mg/dl higher, 1.15 [95% CI 1.01, 1.30]). Thus, phosphate intake is not tightly linked with serum phosphate concentrations in CKD stages 3-5, and there was no evidence that greater phosphate intake, assessed by 24-h phosphate excretion, is associated with ESRD, CVD, non-CVD, or all-cause mortality in CKD stages 3-5. Hence, factors other than dietary intake may be key determinants of serum phosphate concentrations and require additional investigation. PMID- 26422503 TI - Proximal tubule-derived colony stimulating factor-1 mediates polarization of renal macrophages and dendritic cells, and recovery in acute kidney injury. AB - Infiltrating cells play an important role in both the development of and recovery from acute kidney injury (AKI). Macrophages and renal dendritic cells are of particular interest because they can exhibit distinctly different functional phenotypes, broadly characterized as proinflammatory (M1) or tissue reparative (M2). Resident renal macrophages and dendritic cells participate in recovery from AKI in response to either ischemia/reperfusion or a model of selective proximal tubule injury induced by diphtheria-toxin-induced apoptosis in transgenic mice expressing the human diphtheria toxin receptor on proximal tubule cells. Colony stimulating factor-1 (CSF-1) is an important factor mediating the recovery from AKI, and CSF-1 can stimulate macrophage and dendritic cell proliferation and polarization during the recovery phase of AKI. The kidney, and specifically the proximal tubule, is a major source of intrarenal CSF-1 production in response to AKI. We induced selective deletion of proximal tubule CSF-1 to determine its role in expansion and proliferation of renal macrophages and dendritic cells and in recovery from AKI. In both models of AKI, there was decreased M2 polarization, delayed functional and structural recovery, and increased tubulointerstitial fibrosis. Thus, intrarenal CSF-1 is an important mediator of macrophage/dendritic cell polarization and recovery from AKI. PMID- 26422504 TI - Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis. AB - Dietary potassium deficiency activates thiazide-sensitive sodium chloride cotransport along the distal nephron. This may explain, in part, the hypertension and cardiovascular mortality observed in individuals who consume a low-potassium diet. Recent data suggest that plasma potassium affects the distal nephron directly by influencing intracellular chloride, an inhibitor of the with-no lysine kinase (WNK)-Ste20p-related proline- and alanine-rich kinase (SPAK) pathway. As previous studies used extreme dietary manipulations, we sought to determine whether the relationship between potassium and NaCl cotransporter (NCC) is physiologically relevant and clarify the mechanisms involved. We report that modest changes in both dietary and plasma potassium affect NCC in vivo. Kinase assay studies showed that chloride inhibits WNK4 kinase activity at lower concentrations than it inhibits activity of WNK1 or WNK3. Also, chloride inhibited WNK4 within the range of distal cell chloride concentration. Mutation of a previously identified WNK chloride-binding motif converted WNK4 effects on SPAK from inhibitory to stimulatory in mammalian cells. Disruption of this motif in WNKs 1, 3, and 4 had different effects on NCC, consistent with the three WNKs having different chloride sensitivities. Thus, potassium effects on NCC are graded within the physiological range, which explains how unique chloride-sensing properties of WNK4 enable it to mediate effects of potassium on NCC in vivo. PMID- 26422505 TI - Development and validation of a prognostic index for allograft outcome in kidney recipients with transplant glomerulopathy. AB - We studied 92 patients with transplant glomerulopathy to develop a prognostic index based on the risk factors for allograft failure within five years of diagnosis (Development cohort). During 60 months (median) follow-up, 64 patients developed allograft failure. A chronic-inflammation score generated by combining Banff ci, ct and ti scores, serum creatinine and proteinuria at biopsy, were independent risk factors for allograft failure. Based on the Cox model, we developed a prognostic index and classified patients into risk groups. Compared to the low-risk group (median allograft survival over 60 months from diagnosis), patients in the medium risk group had a hazard ratio of 2.83 (median survival 25 months), while those in the high-risk group had a hazard ratio of 5.96 (median survival 3.7 months). We next evaluated the performance of the prognostic index in an independent external cohort of 47 patients with transplant glomerulopathy (Validation cohort). The hazard ratios were 2.18 (median survival 19 months) and 16.27 (median survival 1.6 months), respectively, for patients in the medium and high-risk groups, compared to the low-risk group (median survival 47 months). Our prognostic index model did well in measures of discrimination and calibration. Thus, risk stratification of transplant glomerulopathy based on our prognostic index may provide informative insight for both the patient and physician regarding prognosis and treatment. PMID- 26422506 TI - Clinical and molecular significance of microvascular inflammation in transplant kidney biopsies. AB - The diagnostic criteria for antibody-mediated rejection (AMR) are continuously evolving. Here we investigated the clinical and molecular significance of different Banff microvascular inflammation (MVI) scores in transplant kidney biopsies. A total of 356 patients with clinically indicated kidney transplant biopsies were classified into three groups based on MVI scores of 0, 1, 2, or more for Groups 1-3, respectively. Gene expression profiles were assessed using arrays on a representative subset of 93 patients. The incidence of donor-specific anti-HLA antibodies was increased from 25% in Group 1 to 36% in Group 2 and to 54% in Group 3. Acute and chronic AMR were significantly more frequent in Group 3 (15% and 35%) compared with the Group 2 (3% and 15%) and Group 1 (0% and 5%), respectively. Gene expression profiles showed increased interferon-gamma and rejection-induced, cytotoxic and regulatory T-cell, natural killer cell associated and donor-specific antibody (DSA)-selective transcripts in Group 3 compared with Groups 1 and 2. There was no significant difference in gene expression profiles between the Groups 1 and 2. Increased intragraft expression of DSA-selective transcripts was found in the biopsies of C4d- Group 3 patients. Thus, an MVI score of 2 or more was significantly associated with a histological diagnosis of acute and chronic antibody-mediated rejection. Hence, increased intragraft DSA-selective gene transcripts may be used as molecular markers for AMR, especially in C4d- biopsies. PMID- 26422508 TI - Compensatory Growth in Juveniles of Freshwater Redclaw Crayfish Cherax quadricarinatus Reared at Three Different Temperatures: Hyperphagia and Food Efficiency as Primary Mechanisms. AB - Feeding restriction, as a trigger for compensatory growth, might be considered an alternative viable strategy for minimizing waste as well as production costs. The study assessed whether juvenile redclaw crayfish Cherax quadricarinatus (initial weight 0.99 +/- 0.03 g) was able to compensate for feeding restriction at different temperatures (23 +/- 1, 27 +/- 1 and 31 +/- 1 degrees C). Hyperphagia, food utilization efficiency, energetic reserves, and hepatopancreas structure were analyzed. Three temperatures and two feeding regimes (DF-daily fed throughout the experiment and CF- 4 days food deprivation followed by 4 days of feeding, intermittently) were tested. The restriction period was from day 1 to 45, and the recovery period was from day 45 to 90. The previously restricted crayfish held at 23, 27, and 31 +/- 1 degrees C displayed complete body weight catch-up through compensatory growth following the restriction period with depressed growth. The mechanisms that might explain this response were higher feed intake (hyperphagia), and increased food utilization efficiency. Hepatopancreatic lipids were used as a metabolic fuel and hepatosomatic index was reduced in the previously restricted crayfish, but recovery at the same level of unrestricted crayfish occurred after the shift to daily feeding. The highest temperature affected adversely growth, feed intake, food efficiency, and metabolism of crayfish, whereas the lowest temperature and feeding restriction induced a more efficient growth of the crayfish. PMID- 26422507 TI - Integrated transcriptomic and proteomic analyses uncover regulatory roles of Nrf2 in the kidney. AB - The transcription factor Nrf2 exerts protective effects in numerous experimental models of acute kidney injury, and is a promising therapeutic target in chronic kidney disease. To provide a detailed insight into the regulatory roles of Nrf2 in the kidney, we performed integrated transcriptomic and proteomic analyses of kidney tissue from wild-type and Nrf2 knockout mice treated with the Nrf2 inducer methyl-2-cyano-3,12-dioxooleano-1,9-dien-28-oate (CDDO-Me, also known as bardoxolone methyl). After 24 h, analyses identified 2561 transcripts and 240 proteins that were differentially expressed in the kidneys of Nrf2 knockout mice, compared with those of wild-type counterparts, and 3122 transcripts and 68 proteins that were differentially expressed in wild-type mice treated with CDDO Me, compared with those of vehicle control. In the light of their sensitivity to genetic and pharmacological modulation of renal Nrf2 activity, genes/proteins that regulate xenobiotic disposition, redox balance, the intra/extracellular transport of small molecules, and the supply of NADPH and other cellular fuels were found to be positively regulated by Nrf2 in the kidney. This was verified by qPCR, immunoblotting, pathway analysis, and immunohistochemistry. In addition, the levels of NADPH and glutathione were found to be significantly decreased in the kidneys of Nrf2 knockout mice. Thus, Nrf2 regulates genes that coordinate homeostatic processes in the kidney, highlighting its potential as a novel therapeutic target. PMID- 26422509 TI - [French-Mexican Strategic Partnership for Liver Transplantation]. PMID- 26422511 TI - Distinct mechanisms define murine B cell lineage immunoglobulin heavy chain (IgH) repertoires. AB - Processes that define immunoglobulin repertoires are commonly presumed to be the same for all murine B cells. However, studies here that couple high-dimensional FACS sorting with large-scale quantitative IgH deep-sequencing demonstrate that B 1a IgH repertoire differs dramatically from the follicular and marginal zone B cells repertoires and is defined by distinct mechanisms. We track B-1a cells from their early appearance in neonatal spleen to their long-term residence in adult peritoneum and spleen. We show that de novo B-1a IgH rearrangement mainly occurs during the first few weeks of life, after which their repertoire continues to evolve profoundly, including convergent selection of certain V(D)J rearrangements encoding specific CDR3 peptides in all adults and progressive introduction of hypermutation and class-switching as animals age. This V(D)J selection and AID mediated diversification operate comparably in germ-free and conventional mice, indicating these unique B-1a repertoire-defining mechanisms are driven by antigens that are not derived from microbiota. PMID- 26422512 TI - Food odors trigger Drosophila males to deposit a pheromone that guides aggregation and female oviposition decisions. AB - Animals use olfactory cues for navigating complex environments. Food odors in particular provide crucial information regarding potential foraging sites. Many behaviors occur at food sites, yet how food odors regulate such behaviors at these sites is unclear. Using Drosophila melanogaster as an animal model, we found that males deposit the pheromone 9-tricosene upon stimulation with the food odor apple cider vinegar. This pheromone acts as a potent aggregation pheromone and as an oviposition guidance cue for females. We use genetic, molecular, electrophysiological, and behavioral approaches to show that 9-tricosene activates antennal basiconic Or7a receptors, a receptor activated by many alcohols and aldehydes such as the green leaf volatile E2-hexenal. We demonstrate that loss of Or7a positive neurons or the Or7a receptor abolishes aggregation behavior and oviposition site-selection towards 9-tricosene and E2-hexenal. 9 Tricosene thus functions via Or7a to link food-odor perception with aggregation and egg-laying decisions. PMID- 26422513 TI - Mapping the conformational landscape of a dynamic enzyme by multitemperature and XFEL crystallography. AB - Determining the interconverting conformations of dynamic proteins in atomic detail is a major challenge for structural biology. Conformational heterogeneity in the active site of the dynamic enzyme cyclophilin A (CypA) has been previously linked to its catalytic function, but the extent to which the different conformations of these residues are correlated is unclear. Here we compare the conformational ensembles of CypA by multitemperature synchrotron crystallography and fixed-target X-ray free-electron laser (XFEL) crystallography. The diffraction-before-destruction nature of XFEL experiments provides a radiation damage-free view of the functionally important alternative conformations of CypA, confirming earlier synchrotron-based results. We monitored the temperature dependences of these alternative conformations with eight synchrotron datasets spanning 100-310 K. Multiconformer models show that many alternative conformations in CypA are populated only at 240 K and above, yet others remain populated or become populated at 180 K and below. These results point to a complex evolution of conformational heterogeneity between 180--240 K that involves both thermal deactivation and solvent-driven arrest of protein motions in the crystal. The lack of a single shared conformational response to temperature within the dynamic active-site network provides evidence for a conformation shuffling model, in which exchange between rotamer states of a large aromatic ring in the middle of the network shifts the conformational ensemble for the other residues in the network. Together, our multitemperature analyses and XFEL data motivate a new generation of temperature- and time-resolved experiments to structurally characterize the dynamic underpinnings of protein function. PMID- 26422515 TI - Identification of Clinical and Genetic Parameters Associated with Hidradenitis Suppurativa in Inflammatory Bowel Disease. AB - BACKGROUND: Hidradenitis suppurativa (HS) has recently been associated with inflammatory bowel disease (IBD). The objective of this study is to investigate the prevalence of HS in IBD and to identify clinical and genetic parameters associated with HS in IBD. METHODS: A questionnaire, validated for HS, was sent to 1969 patients suffering from IBD. RESULTS: The prevalence of HS in our IBD cohort (1260 participating patients) was significantly higher than in the general population (6.8%-10.6% versus 1%-2%). IBD patients with HS were affected by IBD significantly earlier and more often treated with anti-TNF-alpha therapy and surgical resection compared to IBD without HS. Female gender, smoking, a higher body mass index, and younger age were independent associated parameters for HS. Within cases allelic association analysis was performed for 59 cases (IBD with HS) and 293 controls (IBD without HS). We observed 2 promising new associations in genomic regions harboring ELOVL7 (rsnumber 10057395 P = 7.15 * 10, odds ratio = 0.4), and in the intergenic region between SULT1B1 and SULT1E1 (rsnumber 2014777 P = 7.48 * 10, odds ratio = 2.3). CONCLUSIONS: HS is present in 6.8% to 10.6% of IBD patients. Co-morbid HS is associated with an early onset of IBD in which anti-tumor necrosis factor-alpha therapy and surgical resections are often needed. We identified a suggestive protective association with ELOVL7 and suggestive risk association with the genes SULT1B1 and SULT1E1 for HS, in the context of IBD. These genetic associations need further exploration and replication in additional independent cohorts. PMID- 26422514 TI - Protein biogenesis machinery is a driver of replicative aging in yeast. AB - An integrated account of the molecular changes occurring during the process of cellular aging is crucial towards understanding the underlying mechanisms. Here, using novel culturing and computational methods as well as latest analytical techniques, we mapped the proteome and transcriptome during the replicative lifespan of budding yeast. With age, we found primarily proteins involved in protein biogenesis to increase relative to their transcript levels. Exploiting the dynamic nature of our data, we reconstructed high-level directional networks, where we found the same protein biogenesis-related genes to have the strongest ability to predict the behavior of other genes in the system. We identified metabolic shifts and the loss of stoichiometry in protein complexes as being consequences of aging. We propose a model whereby the uncoupling of protein levels of biogenesis-related genes from their transcript levels is causal for the changes occurring in aging yeast. Our model explains why targeting protein synthesis, or repairing the downstream consequences, can serve as interventions in aging. PMID- 26422517 TI - Increasing Patient Activation Could Improve Outcomes for Patients with Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD) is a complex disease process that often requires the integration of skills from various health care providers to adequately meet the needs of patients with IBD. The medical and surgical treatment options for IBD have become more complicated and are frequently a source of angst for both the patient and provider. However, it has become more important than ever to engage patients in navigating the treatment algorithm. Although novel in the IBD world, the concept of patients' becoming more active and effective managers of their care has been well studied in other disease processes such as diabetes mellitus and mental illness. This idea of patient activation refers to a patient understanding his or her role in the care process and having the skill sets and self-reliance necessary to manage his or her own health care. Over the past decade, evidence supporting the role of patient activation in chronic illness has grown, revealing improved health outcomes, enhanced patient experiences, and lower overall costs. Patient activation can be measured, and interventions have been shown to improve levels of activation over time and influence outcomes. A focus on patient activation is very appropriate for patients with IBD because this may potentially serve as a tool for IBD providers to not only improve patient outcomes and experience but also reduce health care costs. PMID- 26422516 TI - Anti-Tumor Necrosis Factor-alpha Antibody Therapy Management Before and After Intestinal Surgery for Inflammatory Bowel Disease: A CCFA Position Paper. AB - Biologic therapy with anti-tumor necrosis factor (TNF)-alpha antibody medications has become part of the standard of care for medical therapy for patients with inflammatory bowel disease and may help to avoid surgery in some. However, many of these patients will still require surgical intervention in the form of bowel resection and anastomosis or ostomy formation for the treatment of their disease. Postsurgical studies suggest up to 30% of patients with inflammatory bowel disease may be on or have used anti-TNF-alpha antibody medications for disease management preoperatively. Significant controversy exists regarding the potential deleterious impact of these medications on the outcomes of surgery, specifically overall and/or infectious complications. In this position statement, we systematically reviewed the literature regarding the potential risk of anti-TNF alpha antibody use in the perioperative period, offer recommendations based both on the best-available evidence and expert opinion on the use and timing of anti TNF-alpha antibody therapy in the perioperative period, and discuss whether or not the presence of these medications should lead to an alteration in surgical technique such as temporary stoma formation. PMID- 26422518 TI - Pustular Skin Reaction to Tumor Necrosis Factor Alpha Antagonists in Patients with Inflammatory Bowel Diseases. PMID- 26422519 TI - Surgery for Crohn's Disease: An Emerging Surgical Specialty. PMID- 26422520 TI - "Blindly" ADA Dose Escalation to 80 mg Weekly in Crohn's Disease Patients with LOR: Is It Cost Effective or Not? PMID- 26422521 TI - Mechanical and Electrical Anisotropy of Few-Layer Black Phosphorus. AB - We combined reflection difference microscopy, electron transport measurements, and atomic force microscopy to characterize the mechanical and electrical anisotropy of few-layer black phosphorus. We were able to identify the lattice orientations of the two-dimensional material and construct suspended structures aligned with specific crystal axes. The approach allowed us to probe the anisotropic mechanical and electrical properties along each lattice axis in separate measurements. We measured the Young's modulus of few-layer black phosphorus to be 58.6 +/- 11.7 and 27.2 +/- 4.1 GPa in zigzag and armchair directions. The breaking stress scaled almost linearly with the Young's modulus and was measured to be 4.79 +/- 1.43 and 2.31 +/- 0.71 GPa in the two directions. We have also observed highly anisotropic transport behavior in black phosphorus and derived the conductance anisotropy to be 63.7%. The test results agreed well with theoretical predictions. Our work provided very valuable experimental data and suggested an effective characterization means for future studies on black phosphorus and anisotropic two-dimensional nanomaterials in general. PMID- 26422523 TI - Mandibular Overdentures Retained by Two Mini-Implants: A Seven-Year Retention and Satisfaction Study. AB - PURPOSE: Patients with atrophic edentulous ridges generally have problems with retention, therapeutic satisfaction, and comfort with their complete dentures. An alternative treatment to assist in improving retention and stability involves the use of mini-implants. The aim of this study was to evaluate the retention of mandibular overdentures connected to two mini-implants and overall patient satisfaction with them. MATERIALS AND METHODS: Seven patients with atrophic mandibular ridges (Type 4D Misch classification), aged 62 to 74 years old were rehabilitated with complete dentures. In each patient, two mini-implants measuring 15 or 13 mm in length and 1.8 mm in diameter were placed. After 15 days, overdentures were connected to the mini-implants with O-ring attachments. In each patient, retention of the overdentures was measured, and a survey of therapeutic satisfaction before and after connection to the mini-implants was administered. Prosthesis retention was measured with a digital dynamometer at 1 month, 6 months, and 2, 3, 5, and 7 years after mini-implant placement. Patient satisfaction was assessed with a survey. Data were analyzed with Student's t-test (satisfaction survey) and the Friedman test (retention measurements and satisfaction survey). RESULTS: The initial retention values (0.34 to 0.63 N without mini-implants) varied significantly (p <= 0.050). These values were less than the subsequent measurements of 3.92 to 9.64 N, taken after placement of the mini-implants and connecting them to the dentures. Satisfaction was good to very good over the 7-year observation period. Mucosa and peri-implant bone showed no pathological changes. CONCLUSIONS: In this limited sample size clinical study the results indicated that after connecting mandibular overdentures to two mini implants, patient satisfaction significantly increased and retention significantly improved during the 7-year observation period. PMID- 26422522 TI - Compensatory processing during rule-based category learning in older adults. AB - Healthy older adults typically perform worse than younger adults at rule-based category learning, but better than patients with Alzheimer's or Parkinson's disease. To further investigate aging's effect on rule-based category learning, we monitored event-related potentials (ERPs) while younger and neuropsychologically typical older adults performed a visual category-learning task with a rule-based category structure and trial-by-trial feedback. Using these procedures, we previously identified ERPs sensitive to categorization strategy and accuracy in young participants. In addition, previous studies have demonstrated the importance of neural processing in the prefrontal cortex and the medial temporal lobe for this task. In this study, older adults showed lower accuracy and longer response times than younger adults, but there were two distinct subgroups of older adults. One subgroup showed near-chance performance throughout the procedure, never categorizing accurately. The other subgroup reached asymptotic accuracy that was equivalent to that in younger adults, although they categorized more slowly. These two subgroups were further distinguished via ERPs. Consistent with the compensation theory of cognitive aging, older adults who successfully learned showed larger frontal ERPs when compared with younger adults. Recruitment of prefrontal resources may have improved performance while slowing response times. Additionally, correlations of feedback-locked P300 amplitudes with category-learning accuracy differentiated successful younger and older adults. Overall, the results suggest that the ability to adapt one's behavior in response to feedback during learning varies across older individuals, and that the failure of some to adapt their behavior may reflect inadequate engagement of prefrontal cortex. PMID- 26422524 TI - Mechanism of Decarboxylation of Pyruvic Acid in the Presence of Hydrogen Peroxide. AB - The purpose of this work was to probe the rate and mechanism of rapid decarboxylation of pyruvic acid in the presence of hydrogen peroxide (H2O2) to acetic acid and carbon dioxide over the pH range 2-9 at 25 degrees C, utilizing UV spectrophotometry, high performance liquid chromatography (HPLC), and proton and carbon nuclear magnetic resonance spectrometry ((1)H, (13)C-NMR). Changes in UV absorbance at 220 nm were used to determine the kinetics as the reaction was too fast to follow by HPLC or NMR in much of the pH range. The rate constants for the reaction were determined in the presence of molar excess of H2O2 resulting in pseudo first-order kinetics. No buffer catalysis was observed. The calculated second-order rate constants for the reaction followed a sigmoidal shape with pH independent regions below pH 3 and above pH 7 but increased between pH 4 and 6. Between pH 4 and 9, the results were in agreement with a change from rate determining nucleophilic attack of the deprotonated peroxide species, HOO(-), on the alpha-carbonyl group followed by rapid decarboxylation at pH values below 6 to rate-determining decarboxylation above pH 7. The addition of H2O2 to ethyl pyruvate was also characterized. PMID- 26422525 TI - The minimal clinically important difference for function and strength in patients undergoing reverse shoulder arthroplasty. AB - HYPOTHESIS: Despite a statistically significant improvement in functional scores after receiving a reverse shoulder arthroplasty (RSA) in a cuff-deficient shoulder, not all patients perceive a minimal clinically important difference (MCID) in every functional domain of the score. METHODS: This was a prospective longitudinal study including 60 consecutive patients with a cuff-deficient shoulder treated with a RSA. The Constant score was recorded before surgery and at a 1-year follow-up assessment. At the 1-year follow-up, all patients also filled out a 15-item anchor questionnaire to assess their perception of change in their overall function, forward elevation, lateral rotation, internal rotation, and strength to determine the MCID. RESULTS: The mean Constant score was 30.1 (standard deviation, 10.7) before surgery and was 58.4 (standard deviation, 16.2) at the 1-year follow-up, with statistically significant improvement (P < .001). A statistically significant improvement was found in the domains of forward elevation (P < .001), lateral rotation (P < .001), and strength (P < .001) except for internal rotation (P = .15). The MCID for overall function, forward elevation, lateral rotation, internal rotation, and strength in the Constant score increased by 8, 6, 2, 2, and 11.5 points, respectively; only 46.7%, 20%, 50%, 45.8%, and 33.3% of the patients, respectively, exceeded the MCID on each domain after surgery. CONCLUSIONS: A statistically significant improvement in the Constant score is expected after receiving an RSA in a cuff-deficient shoulder, but a considerable number of patients do not reach the MCID in the function and strength domains. A small improvement in rotation is perceived to be beneficial by patients, whereas large improvements in forward elevation are required for the improvement to be perceived to be beneficial. PMID- 26422526 TI - Radiographic and clinical outcomes of total shoulder arthroplasty with an all polyethylene pegged bone ingrowth glenoid component: prospective short- to medium term follow-up. AB - BACKGROUND: Glenoid components often cause total shoulder arthroplasty failure. This study examines short-term to midterm radiographic and clinical results of a hybrid glenoid component with 3 cemented peripheral pegs and a central peg, which allows biologic fixation with use of native humeral head autograft. METHODS: In 4 years, 80 glenoid components were implanted during primary total shoulder arthroplasty with at least 2-year follow-up data. Within 12 months, 4 shoulders were revised and excluded from final analyses. Seven patients did not complete their questionnaires. Outcomes data included the American Shoulder and Elbow Surgeons (ASES) questionnaire, Constant score, and satisfaction score. A shoulder and elbow fellowship-trained surgeon, not involved in the care of these patients, analyzed radiographs for radiolucent lines, glenoid seating, and radiodensity in between the flanges of the central peg. RESULTS: Only 1 of 80 shoulders was revised for aseptic glenoid loosening. At final follow-up, 81.6% had a radiolucency grade of 0 or 1. Nearly 90% had a glenoid seating grade of A or B. Grade 2 or 3 bone around the central peg was seen in 88.2%. No statistical association existed between Walch glenoid types and radiolucency grades, bone grades around the central peg, perfect radiolucency grade, seating grade, and grade 3 bone around the central peg. There was significant improvement in mean ASES score, adjusted ASES pain score, Constant score, and satisfaction score as well as in forward flexion, abduction, and external rotation. CONCLUSIONS: The hybrid glenoid can produce stable radiographic and clinical outcomes at short- to medium-term follow-up. PMID- 26422527 TI - In vivo three-dimensional elbow biomechanics during forearm rotation. AB - BACKGROUND: It is unclear how elbow kinematics changes during forearm rotation. This study investigated in vivo 3-dimensional elbow kinematics during forearm rotation. METHODS: We studied 12 normal elbows using in vivo 3-dimensional computed tomography data in maximum forearm supination, neutral, and maximum pronation with the elbows in extension. We measured the motion of the radius and ulna relative to the humerus using a markerless bone registration technique and the contact area of the radiocapitellar joint, proximal radioulnar joint, and ulnohumeral joint using a proximity mapping method. RESULTS: When the forearm rotated from the supinated position to the pronated position, the radius showed significant varus rotation, internal rotation, and extension relative to the humerus. The center of the radial head significantly translated anteriorly, proximally, and laterally. The ulna significantly rotated in valgus, and the deepest point on the sagittal ridge of the trochlear notch translated medially with forearm pronation. The contact area of the radiocapitellar joint was largest in pronation. The contact area of the proximal radioulnar joint was largest in supination. The contact area of the ulnohumeral joint showed no significant change during forearm rotation. CONCLUSIONS: In pronation, because of the proximal migration of the radial head, the radiocapitellar joint was most congruent compared with other positions. The proximal radioulnar joint was most congruent in supination. The ulnohumeral joint congruency was not affected by forearm rotation. This study provides useful information for understanding 3 dimensional elbow motion and joint osseous stability related to forearm rotation. PMID- 26422528 TI - Abrasiveness of high-strength sutures used in rotator cuff surgery: are they all the same? AB - BACKGROUND: The suture-tendon interface remains the most common point of failure in rotator cuff repairs via suture pullout. Several high-strength braided sutures are available for rotator cuff surgery and are more abrasive than monofilaments. However, a comparison of these sutures has not been performed in a tissue model. METHODS: Ninety infraspinatus sheep tendons were randomized among 9 groups of sutures (n = 10), including FiberWire (Arthrex, Naples, FL, USA), Collagen Coated FiberWire (Arthrex), Orthocord (DePuy Mitek, Raynham, MA, USA), MaxBraid (Biomet, Warsaw, IN, USA), Force Fiber (Teleflex, Research Triangle Park, NC, USA), ULTRABRAID (Smith & Nephew, Memphis, TN, USA), Phantom Fiber BioFiber (Tornier, Bloomington, MN, USA), and Ti-Cron (Syneture, Mansfield, MA), with Surgipro (Syneture) monofilament as a control. Each suture was cycled 50 times through the tendon, which was fixed to a mechanical testing system under a constant load in saline solution. The distance cut through the tendon was measured and divided by the distance of suture sliding to determine displacement (mm/cm). Twist angle and picks per inch of each suture were measured using digital photography. One-way analysis of variance was used to compare the displacement and twist angle between sutures. RESULTS: Collagen Coated FiberWire was the most abrasive of the high strength sutures. Four of the sutures (Collagen Coated FiberWire, Phantom Fiber BioFiber, FiberWire, Ti-Cron) had a mean displacement rate greater than 0.150 mm/cm. The remainder of the sutures had a mean displacement rate less than 0.050 mm/cm (Orthocord, Force Fiber, MaxBraid, ULTRABRAID). The difference in the displacement rates between these 2 groups was significant (P < .0001) and was related to both the twist angle and the picks per inch. CONCLUSION: Significant differences in suture abrasiveness were identified among high-strength braided sutures and correlated with lower twist angle and lower picks per inch. PMID- 26422530 TI - Selective, Spontaneous One-Way Oil-Transport Fabrics and Their Novel Use for Gauging Liquid Surface Tension. AB - Thin porous materials that can spontaneously transport oil fluids just in a single direction have great potential for making energy-saving functional membranes. However, there is little data for the preparation and functionalities of this smart material. Here, we report a novel method to prepare one-way oil transport fabrics and their application in detecting liquid surface tension. This functional fabric was prepared by a two-step coating process to apply flowerlike ZnO nanorods, fluorinated decyl polyhedral oligomeric silsesquioxanes, and hydrolyzed fluorinated alkylsilane on a fabric substrate. Upon one-sided UV irradiation, the coated fabric shows a one-way transport feature that allows oil fluid transport automatically from the unirradiated side to the UV-irradiated surface, but it stops fluid transport in the opposite direction. The fabric still maintains high superhydrophobicity after UV treatment. The one-way fluid transport takes place only for the oil fluids with a specific surface tension value, and the fluid selectivity is dependent on the UV treatment time. Changing the UV irradiation time from 6 to 30 h broadened the one-way transport for fluids with surface tension from around 22.3 mN/m to a range of 22.3-56.7 mN/m. We further proved that this selective one-way oil transport can be used to estimate the surface tension of a liquid simply by observing its transport feature on a series of fabrics with different one-way oil-transport selectivities. To our knowledge, this is the first example to use one-way fluid-transport materials for testing the liquid surface tension. It may open up further theoretical studies and the development of novel fluid sensors. PMID- 26422529 TI - Compensatory hypertrophy of the teres minor muscle after large rotator cuff tear model in adult male rat. AB - BACKGROUND: Rotator cuff tear (RCT) is a common musculoskeletal disorder in the elderly. The large RCT is often irreparable due to the retraction and degeneration of the rotator cuff muscle. The integrity of the teres minor (TM) muscle is thought to affect postoperative functional recovery in some surgical treatments. Hypertrophy of the TM is found in some patients with large RCTs; however, the process underlying this hypertrophy is still unclear. The objective of this study was to determine if compensatory hypertrophy of the TM muscle occurs in a large RCT rat model. METHODS: Twelve Wistar rats underwent transection of the suprascapular nerve and the supraspinatus and infraspinatus tendons in the left shoulder. The rats were euthanized 4 weeks after the surgery, and the cuff muscles were collected and weighed. The cross-sectional area and the involvement of Akt/mammalian target of rapamycin (mTOR) signaling were examined in the remaining TM muscle. RESULTS: The weight and cross-sectional area of the TM muscle was higher in the operated-on side than in the control side. The phosphorylated Akt/Akt protein ratio was not significantly different between these sides. The phosphorylated-mTOR/mTOR protein ratio was significantly higher on the operated-on side. CONCLUSION: Transection of the suprascapular nerve and the supraspinatus and infraspinatus tendons activates mTOR signaling in the TM muscle, which results in muscle hypertrophy. The Akt-signaling pathway may not be involved in this process. Nevertheless, activation of mTOR signaling in the TM muscle after RCT may be an effective therapeutic target of a large RCT. PMID- 26422531 TI - Global Quantitative Techniques for Positron Emission Tomographic Assessment of Disease Activity in Cutaneous T-Cell Lymphoma and Response to Treatment. PMID- 26422532 TI - Risk of multiple myeloma in a case-spouse study. AB - This study examined lifestyle, occupation, medical history and medication use with multiple myeloma risk in a case-spouse study (481 patients, 351 spouses). Odds ratios (ORs) and 95% confidence intervals (CI) were calculated using logistic regression. Compared to spouse controls, cases were more likely to have a family history of multiple myeloma (OR = 2.8, 95% CI = 1.2-6.4) and smoked cigarettes (OR = 1.7, 95% CI = 1.2-2.5), but less likely to have consumed alcohol (OR = 0.6, 95% CI = 0.4-0.9). Nurse/health practitioners (OR = 2.8, 95% CI = 1.3 6.2) and production workers (OR = 3.7, 95% CI = 1.0-13.7) had significantly increased risks; and some occupations linked to diesel exhaust had elevated, but non-significant, risks. History of herpes simplex (OR = 1.7, 95% CI = 1.2-2.4), shingles (OR = 1.7, 95% CI = 1.1-2.7), sexually transmitted diseases (OR = 2.0, 95% CI = 1.0-3.7) and medication allergies (OR = 1.7, 95% CI = 1.2-2.4) were associated with higher risks. Use of angiotensin-converting enzyme inhibitors, anti-convulsants, antidepressants, statins and diuretics were associated with reduced risks. The results are consistent with previous population-based studies and support the utility of patient databanks and spouse controls as a resource in epidemiologic research. PMID- 26422533 TI - Characteristics and Clinical Course of STEMI Patients who Received no Reperfusion in the Australia and New Zealand SNAPSHOT ACS Registry. AB - BACKGROUND: Cohort studies of STEMI patients have reported that over 30% receive no reperfusion. Barriers to greater use of reperfusion in STEMI patients require further elucidation. METHODS: We collected data on STEMI patients with no reperfusion as part of the SNAPSHOT ACS Registry, which recruited consecutive ACS patients in 478 hospitals throughout Australia and New Zealand during 14-27 May 2012. RESULTS: Of 4387 patients enrolled, 419 were diagnosed with STEMI. Primary PCI (PPCI) was performed in 160 (38.2%), fibrinolysis was used in 105 (25.1%), and 154 (36.7%) had no reperfusion. Patients with no reperfusion had a mean age of 70.3+/-15.0 years compared with 63.1+/-13.5 in the reperfusion group (p<0.0001). There were more females in the no reperfusion group (37.1% v 23.0% p=0.002) and they were significantly more likely to have prior PCI or CABG, heart failure, atrial fibrillation, chronic kidney disease and other vascular disease, and to be nursing home residents (all p<0.05). Patients without reperfusion had a significantly higher mortality in hospital (11.7% v 4.9%, p=0.011). In 370 patients who presented within 12hours, 28 had early angiography without PCI, which was considered an attempt at reperfusion. Therefore reperfusion was attempted in 293 of 370 eligible patients (79.2%). CONCLUSION: Of consecutive STEMI patients, 36.7% did not receive any reperfusion and they had a higher risk of death in hospital. In eligible patients, reperfusion was attempted in 79.2%. National strategies to encourage earlier medical contact and greater use of reperfusion in eligible patients may lead to better outcomes. PMID- 26422534 TI - Retrograde Type A Aortic Dissection Treated with Continuous Perfusion "Branch First" Aortic Arch Replacement Technique. AB - The development of thoracic endovascular aortic repair in recent years has revolutionised the way aortic disease is treated. However, there are potential complications associated with this which can be life threatening and pose a difficult challenge to manage. We present a case of retrograde ascending aortic dissection complicating thoracic endovascular aortic repair, and its repair using a technique of continuous perfusion "branch-first" aortic arch replacement. We discuss the complication of retrograde ascending aortic dissection and the issues that affect its surgical management. PMID- 26422535 TI - Association of Sleep Duration with the Morbidity and Mortality of Coronary Artery Disease: A Meta-analysis of Prospective Studies. AB - PURPOSE: Insufficient and excessive sleep duration have become increasingly common in modern society. Published literatures report controversial results about the association of sleep duration with coronary artery disease (CAD). METHODS: A comprehensive search was performed to identify related prospective studies providing quantitative estimates between sleep duration and CAD. Meta analysis was applied to calculate the combined relative risks (RRs) with 95% confidence intervals (CI) for sleep with morbidity and mortality of CAD. The risk of bias was assessed by the Egger regression asymmetry test. RESULTS: Fifteen studies conformed to the criteria. Compared with normal sleep duration, the pooled RRs (95%CI) of short sleep duration were 1.10(1.04-1.17) and 1.25(1.06 1.47) for the morbidity and mortality of CAD, and the pooled RRs (95%CI) of long sleep duration were 1.03(0.92-1.16) and 1.26(1.11-1.42) for the morbidity and mortality of CAD, respectively. The effect of short and long sleep duration on mortality of CAD were always significantly greater than the morbidity of CAD. CONCLUSIONS: Short sleep duration was associated with higher morbidity of CAD, and short sleepers and long sleepers had higher risk for CAD mortality. Keeping normal sleep duration is an appropriate recommendation to prevent and control CAD. PMID- 26422536 TI - Particle- and Gaseous Emissions from an LNG Powered Ship. AB - Measurements of particle number and mass concentrations and number size distribution of particles from a ship running on liquefied natural gas (LNG) were made on-board a ship with dual-fuel engines installed. Today there is a large interest in LNG as a marine fuel, as a means to comply with sulfur and NOX regulations. Particles were studied in a wide size range together with measurements of other exhaust gases under different engine loads and different mixtures of LNG and marine gas oil. Results from these measurements show that emissions of particles, NOX, and CO2 are considerably lower for LNG compared to present marine fuel oils. Emitted particles were mainly of volatile character and mainly had diameters below 50 nm. Number size distribution for LNG showed a distinct peak at 9-10 nm and a part of a peak at diameter 6 nm and below. Emissions of total hydrocarbons and carbon monoxide are higher for LNG compared to present marine fuel oils, which points to the importance of considering the methane slip from combustion of LNG. PMID- 26422538 TI - Ageism in Health Care? PMID- 26422539 TI - Advances in the Molecular Profiling of Tumor Tissue. PMID- 26422540 TI - Mutation Profiling of Clinically Advanced Cancers Using Next-Generation Sequencing for Targeted Therapy: A Lifespan Experience. AB - The application of modern molecular tests such as next-generation sequencing (NGS) to human malignancies has led to better understanding of tumor biology and the design of targeted molecular therapies. In the research setting, important genomic alterations in tumors have been discovered with potential therapeutic implications but data regarding the impact of this technology in a real world oncology practice is limited. As a result, we decided to review the results of NGS in 144 advanced-stage cancer patients referred to the oncology practices of Lifespan-affiliated centers in Rhode Island. Most cancers revealed genomic alterations in genes commonly mutated in cancer. However, several unexpected genomic alterations were discovered in certain cancers with potential therapeutic intervention. Most cancers contained "actionable" genomic alterations despite being of advanced stage. Our experience demonstrates that application of NGS in the clinical setting contributes both to increasing the therapeutic armamentarium as well as our understanding of tumor biology. PMID- 26422541 TI - Updates in Tumor Profiling in Gastrointestinal Cancers. AB - In the last decade there has been a focus on biomarkers that play a critical role in understanding molecular and cellular mechanisms which drive tumor initiation, maintenance and progression of cancers. Characterization of genomes by next generation sequencing (NGS) has permitted significant advances in gastrointestinal cancer care. These discoveries have fueled the development of novel therapeutics and have laid the groundwork for the development of new treatment strategies. Work in colorectal cancer (CRC) has been in the forefront of these advances. With the continued development of NGS technology and the positive clinical experience in CRC, genome work has begun in esophagogastric, pancreatic, and hepatocellular carcinomas as well. PMID- 26422542 TI - NSCLC: An Update of Driver Mutations, Their Role in Pathogenesis and Clinical Significance. AB - Lung cancer is the most common malignancy in the US and causes the most cancer related deaths. Non-small-cell lung carcinoma (NSCLC) accounts for the majority of cases. NSCLC historically was considered one entity, reflected by platinum based therapy as the standard of care; however, with the discovery of EGFR mutations and ALK rearrangements, the landscape of treatment has become more personalized reflecting genomic heterogeneity. The molecular basis for tumor genesis was recognized and became a new method of classification. The availability of tumor sequencing and testing for these mutations is also becoming more accessible outside of major academic institutions. Targeted therapies offer alternatives to dangerous cytotoxic chemotherapy with equal or better efficacy. With these changes, driver mutations will play an increasing role in the diagnosis and treatment of NSCLC. In this review we will examine the characteristics of several NSCLC driver mutations and gene rearrangements and emerging data on therapies directed against them. PMID- 26422543 TI - Primary Care Physicians' Use of Electronic Health Records in Rhode Island: 2009 2014. AB - We used data from the mandatory statewide Rhode Island (RI) Health Information Technology (HIT) Survey to characterize office-based PCPs' adoption and use of EHRs from 2009-2014. We found accelerated adoption of EHRs in the five years since state and federal incentive programs began targeting PCPs' adoption of HIT. There was room for improvement, however; for example, when asked to indicate the proportion of patients with whom they used various functionalities, only 13.4% of office-based PCPs said they "almost always" communicated with patients using secure messaging and 22.3% "almost always" used secure clinical messaging with outside providers. Results suggest uneven use of EHR functionalities, with low rates and slower uptake in some areas. These findings highlight opportunities to increase use of functionalities related to improved patient care and quality based payment models. PMID- 26422544 TI - Recurrent Mixed Cryoglobulinemia (MCS): A Case Report and Literature Review. AB - We report a case of recurrent mixed type II cryoglobulinemia with difficult diagnosis and treatment dilemma and uncertain prognosis in view of limited studies. A 60-year-old male with history of essential mixed cryoglobulinemia 12 years ago treated successfully with six months of cyclophosphamide and prednisone presented with bilateral lower extremity pupuric rash and swelling. He was found to have proteinuria, hematuria, RBC casts, low serum complement levels, and acute kidney injury (AKI). Initial therapy with methylprednisone and oral cyclophosphamide was ineffective (patient developed respiratory failure due to alveolar hemorrhage). Additional labs revealed positive type II cryoglobulins, high free Kappa/Lambda, UPEP with minimal urine protein, SPEP with marked hypogammaglobulinemia, and negative tests for HIV, HCV, ANA, and ANCA. More aggressive therapy with daily plasmapheresis and rituximab was instituted with very good clinical response. He achieved clinical remission but developed another flare 8 months later. Kidney biopsy showed membranoproliferatve glomerulonephritis with cryoglobulin deposits. Flow cytometry and biopsy of bone marrow was consistent with lymphoplasmacytic lymphoma. His diagnosis was eventually confirmed and responded clinically to another course of rituximab and plasmapheresis, but prognosis is yet to be seen. PMID- 26422545 TI - Understanding the Disparities of Citizen Health Preparedness - Can Providers Help Close the Gaps? PMID- 26422546 TI - van der Waals force-induced loading of proangiogenic nanoparticles on microbubbles for enhanced neovascularization. AB - Nanoparticles emerged as carriers of promising diagnostic and therapeutic molecules due to their unique size, injectability, and potential to sustainably release molecular cargos. However, with local injection of particles into target tissue, the significant particle loss caused by external biomechanical forces is a great challenge yet to be resolved to date. We hypothesized that nanoparticles associated with tissue-adherent microbubbles in the form of core-shell particles due to van der Waals attractive forces would stably remain on an implanted site and significantly increase therapeutic efficacy of drug cargos. To examine this hypothesis, we used 100 nm diameter nanoparticles made of poly(lactide-co glycolic acid) (PLGA) as a model nanoparticle and 50 MUm diameter microbubbles made of poly(2-hydroxyethyl aspartamide) (PHEA) grafted with octadecyl chains, PHEA-g-C18, as a model microbubble. Simple mixing of PLGA nanoparticles and PHEA g-C18 microbubbles resulted in the core-shell particles. Following implantation, the PHEA-g-C18 microbubbles acted as glue to minimize the displacement of PLGA nanoparticles, because of the association between the octadecyl chains on PHEA-g C18 and the epithelium of the tissue. As a consequence, the core-shell particles prepared with Angiopoietin-1 (Ang1)-encapsulated PLGA nanoparticles significantly promoted vascularization in the implanted tissue. Overall, the results of this study provide a simple but advanced strategy for improving therapeutic efficacy of drug-carrying nanoparticles without altering their surface chemistry and potential. PMID- 26422547 TI - In memoriam: A tribute to the work and lives of Ron Selvester and Rory Childers. AB - At the April, 2015 International Society for Computerized Electrocardiology (ISCE) Annual Conference in San Jose, CA, a special session entitled Remembering Ron & Rory was held to pay tribute to the extraordinary work and lives of two experts in electrocardiology. The session was well attended by conference attendees, Childers' family members and friends, and additional colleagues who traveled to San Jose solely to participate in this session. The purpose of the present paper is to document the spirit of this special session as faithfully as possible using the words of the session speakers. PMID- 26422548 TI - Correlates of health-related quality of life in Thai patients with alcohol dependence. AB - This study aimed to examine the correlates of health related quality of life in Thai patients with alcohol dependence. The amount of alcohol intake was calculated by timeline followback chart and the health related quality of life was determined by Short Form-36 Health Survey. The means of the Short Form-36 Physical Component and Mental Component Summary were 67.43 (18.74) and 64.45 (20.90), respectively. Stepwise linear regression models showed the number of heavy drinking days was significantly correlated with the Physical Component Summary and Mental Component Summary. Such moderate correlations suggest that drinking and health related quality of life measures might tap different aspects of alcohol outcomes and should be concurrently administered. PMID- 26422549 TI - Can electrodynamic interaction between a molecule and metal dominate a continuum background in surface-enhanced Raman scattering? AB - A continuum background is always coincident with the Raman spectrum enhanced by metallic nanostructures and still remains elusive. Not only does it constitute a stymied mystery in the origin per se, but also it reduces the useful quantifiable range of detection based on surface-enhanced Raman scattering (SERS). We examined theoretically near-field molecule-metal interaction to reveal its contribution to the SERS background. The results show that the spectral broadening of fluorescence and Raman scattering due to a nearby metal object is insignificant compared with experimental findings. This study abnegates the role of near-field interaction in the SERS continuum background and elucidates the microscopic molecule-metal electromagnetic interaction, despite being unable to pinpoint the primary source of the SERS background. PMID- 26422550 TI - Effect of kinesiotaping, non-elastic taping and bracing on segmental foot kinematics during drop landing in healthy subjects and subjects with chronic ankle instability. AB - OBJECTIVE: To evaluate the effects of kinesiotape, non-elastic tape, and soft brace on segmental foot kinematics during drop landing in subjects with chronic ankle instability and healthy subjects. DESIGN: Controlled study with repeated measurements. SETTING: Three-dimensional motion analysis laboratory. PARTICIPANTS: Twenty participants with chronic ankle instability and 20 healthy subjects. INTERVENTIONS: The subjects performed drop landings with 17 retroreflective markers on the foot and lower leg in four conditions: barefoot, with kinesiotape, with non-elastic tape and with a soft brace. MAIN OUTCOME MEASURES: Ranges of motion of foot segments using a foot measurement method. RESULTS: In participants with chronic ankle instability, midfoot movement in the frontal plane (inclination of the medial arch) was reduced significantly by non elastic taping, but kinesiotaping and bracing had no effect. In healthy subjects, both non-elastic taping and bracing reduced that movement. In both groups, non elastic taping and bracing reduced rearfoot excursion in inversion/eversion significantly, which indicates a stabilisation effect. No such effect was found with kinesiotaping. All three methods reduced maximum plantar flexion significantly. CONCLUSIONS: Non-elastic taping stabilised the midfoot best in patients with chronic ankle instability, while kinesiotaping did not influence foot kinematics other than to stabilise the rearfoot in the sagittal plane. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01810471. PMID- 26422552 TI - How Can Relation Between Pericardial Effusion and Acute Kidney Injury Be Explained? PMID- 26422551 TI - Musculoskeletal pain, depression, and stress among Latino manual laborers in North Carolina. AB - The jobs of Latino manual laborers place their mental and physical health at risk. This study evaluates the associations among musculoskeletal pain, mental health, and work organization in Latino manual laborers. Farmworkers and nonfarmworkers (n = 189) in North Carolina were interviewed for self-reported musculoskeletal pain, depressive symptoms, stress, work safety climate, and precarious job status. More nonfarmworkers than farmworkers had neck and shoulder pain, but they did not differ in other areas of musculoskeletal pain. Depressive symptoms had a significant association with neck and shoulder pain (p < .05). Precariousness had a significant association with back pain (p < .05). Farmworker participants had H-2A visas and were afforded some protection compared to nonfarmworker manual workers. Research is needed to improve policy that relieves pain and improves mental health for all Latino manual workers. PMID- 26422553 TI - Previously Complicated Nuss Procedure Does Not Preclude Blind Removal of the Bar. AB - BACKGROUND: Nuss procedure has become the procedure of choice for well-selected patients with pectus excavatum. Perioperative complications may pose difficulty during the subsequent bar removal due to adhesions and tissue plane disruptions during the initial surgery and repair. This report describes bar removal experience in patients whose Nuss procedures were complicated by cardiac injury, pericardial breach, and lung parenchyma/diaphragm injury during the initial procedure. METHODS: A total of 529 patients who underwent Nuss procedure between 2007 and 2014 were recorded in a prospective database. Twenty patients with complications (cardiac injury [n = 1], pericardial breach [n = 3], and lung parenchyma/diaphragm injury [n = 16]) were identified. All bars were removed via subcutaneous tissue dissection, without intrathoracic visualization. RESULTS: Average duration of bars was 36 months (+/-16 months). All bar removal procedures were completed without any need for extra interventions with negligible blood loss. Eighteen patients were able to be discharged within 2 postoperative days. CONCLUSION: Blind bar removal in patients with previously complicated Nuss procedure seems safe and no other interventions (videothoracoscopy, subxiphoid incision, etc.) during bar removal seem to be necessary. PMID- 26422554 TI - Reply by the Authors of the Original Article. PMID- 26422555 TI - Doppler Systolic Signal Void in Hypertrophic Cardiomyopathy: Apical Aneurysm and Severe Obstruction without Elevated Intraventricular Velocities. AB - BACKGROUND: In patients with hypertrophic cardiomyopathy (HCM), akinetic apical aneurysms are associated with ventricular tachycardia, heart failure, apical thrombus, and mortality. The cause of apical aneurysms remains unresolved, and there is controversy about prevalence and significance of mid-left ventricular (LV) obstruction, often present in these patients. The aim of this study was to test the hypothesis that low velocities in patients with aneurysms are due to near complete cessation of mid-LV flow, characteristically marked by a Doppler signal void. METHODS: This was a retrospective analysis of 39 patients with HCM with segmental hypertrophy of the mid left ventricle and complete systolic emptying at the mid-LV level. The severity of dynamic obstruction was evaluated by measuring the time during which cross-sectional mid-LV cavity area was <1 cm(2). Presence or absence of an LV Doppler midsystolic signal void was determined. RESULTS: Akinetic apical aneurysms were present in 21 patients. The duration of two-dimensional mid-LV short-axis complete emptying was longer in patients with akinetic apical aneurysms (194 +/- 45 vs 148 +/- 63 msec, P = .013), nearly 50% of systole. Midsystolic signal voids were seen only in patients with akinetic apical aneurysms (P < .001), present in 86%. In patients with akinetic aneurysms, there was a strong correlation between the duration of the systolic signal void and the proportion of systole with complete emptying < 1 cm(2) (r = 0.704; P = .001). Complete emptying < 1 cm(2) for >= 38% of systole was associated with akinetic aneurysm (odds ratio, 9.35; P < .004). CONCLUSION: Patients with akinetic apical aneurysm HCM have near complete cessation of flow across severe dynamic mid-LV obstruction for nearly 50% of systole. This explains how the adverse effects of obstruction may occur without high velocities on echocardiography. PMID- 26422557 TI - The presence of low-count chronic lymphocytic leukemia-like monoclonal B lymphocytosis in patients with Ph-myeloproliferative neoplasms: A random event or a shared causal pathobiology? PMID- 26422556 TI - Reconstitution of lymphocyte subpopulations after hematopoietic stem cell transplantation: comparison of hematologic malignancies and donor types in event free patients. AB - The reconstitution of different immunocyte subsets after hematopoietic stem cell transplantation (HSCT), follows different timelines. We prospectively investigated changes in lymphocyte subsets after HSCT and their associations with primary diagnosis, conditioning regimen, and HSCT type in event-free patients. A total of 95 patients (48 with acute myeloid leukemia, 22 with acute lymphoid leukemia, and 25 with myelodysplastic syndrome) who underwent allogeneic HSCT (34 sibling matched, 37 unrelated matched, and 24 haploidentical HSCT) but did not experience any events such as relapse or death were enrolled in this study. Lymphocyte subpopulations (T cells, helper/inducer T cells, cytotoxic/suppressor T cells, memory T cells, regulatory T cells, natural killer (NK) cells, NK-T cells, and B cells) were quantified by flow cytometry of peripheral blood from recipients 7 days before and 1, 2, 3, 6, and 12 months after HSCT. Leukocyte counts recovered within 1 month after HSCT. However, the number of T and B lymphocytes recovered at 2 months after HSCT. NK cell counts recovered shortly after haploidentical HSCT. However, T lymphocytes and their subpopulations showed delayed recovery after haploidentical HSCT. Lymphocyte subsets showed different sequential patterns according to HSCT type but no differences were seen according to primary diagnosis or conditioning regimen. PMID- 26422558 TI - Flow cytometry in immunoglobulin light chain amyloidosis: Short review. AB - Flow cytometry (FCM) has found its application in clinical diagnosis and evaluation of monoclonal gammopathies (MG). Although, research has been mainly focused on multiple myeloma (MM), nowadays FCM becomes to be potential tool in the field of AL amyloidosis. Clonal plasma cells identification and specific phenotype profile detection is important for diagnosis, monitoring and prognosis of AL amyloidosis. Therefore, FCM could be a perspective method for study not only MM but also AL amyloidosis. This review provides an overview and possibilities of FCM application in AL amyloidosis. PMID- 26422559 TI - High-Quality InAsSb Nanowires Grown by Catalyst-Free Selective-Area Metal-Organic Chemical Vapor Deposition. AB - We report on the first demonstration of InAs1-xSbx nanowires grown by catalyst free selective-area metal-organic chemical vapor deposition (SA-MOCVD). Antimony composition as high as 15 % is achieved, with strong photoluminescence at all compositions. The quality of the material is assessed by comparing the photoluminescence (PL) peak full-width at half-max (fwhm) of the nanowires to that of epitaxially grown InAsSb thin films on InAs. We find that the fwhm of the nanowires is only a few meV broader than epitaxial films, and a similar trend of relatively constant fwhm for increasing antimony composition is observed. Furthermore, the PL peak energy shows a strong dependence on temperature, suggesting wave-vector conserving transitions are responsible for the observed PL in spite of lattice mismatched growth on InAs substrate. This study shows that high-quality InAsSb nanowires can be grown by SA-MOCVD on lattice mismatched substrate, resulting in material suitable for infrared detectors and high performance nanoelectronic devices. PMID- 26422560 TI - Unveiling the Atomic-Level Determinants of Acylase-Ligand Complexes: An Experimental and Computational Study. AB - The industrial production of higher-generation semisynthetic cephalosporins starts from 7-aminocephalosporanic acid (7-ACA), which is obtained by deacylation of the naturally occurring antibiotic cephalosporin C (CephC). The enzymatic process in which CephC is directly converted into 7-ACA by a cephalosporin C acylase has attracted industrial interest because of the prospects of simplifying the process and reducing costs. We recently enhanced the catalytic efficiency on CephC of a glutaryl acylase from Pseudomonas N176 (named VAC) by a protein engineering approach and solved the crystal structures of wild-type VAC and the H57betaS-H70betaS VAC double variant. In the present work, experimental measurements on several CephC derivatives and six VAC variants were carried out, and the binding of ligands into the VAC active site was investigated at an atomistic level by means of molecular docking and molecular dynamics simulations and analyzed on the basis of the molecular geometry of encounter complex formation and protein-ligand potential of mean force profiles. The observed significant correlation between the experimental data and estimated binding energies highlights the predictive power of our computational method to identify the ligand binding mode. The present experimental-computational study is well suited both to provide deep insight into the reaction mechanism of cephalosporin C acylase and to improve the efficiency of the corresponding industrial process. PMID- 26422561 TI - Sarcoidosis and risk of venous thromboembolism: A systematic review and meta analysis. AB - BACKGROUND: Several chronic inflammatory disorders, such as rheumatoid arthritis, inflammatory myositis and systemic lupus erythematosus, have been linked to an increased risk of venous thromboembolism (VTE). However, the data on sarcoidosis is unclear. OBJECTIVES: To evaluate the risk of VTE among patients with sarcoidosis. METHODS: We conducted a systematic review and meta-analysis of observational studies that reported odds ratio, relative risk, hazard ratio or standardized incidence ratio comparing risk of VTE in patients with sarcoidosis versus non-sarcoidosis participants. Estimated effects were extracted from each study and were pooled together using the random-effect, generic inverse variance method of DerSimonian and Laird. RESULT: Out of 772 potentially relevant articles, three eligible studies were identified and included in the data analysis. The pooled risk ratio of VTE in patients with sarcoidosis was 1.42 (95% CI, 1.12-1.79). The statistical heterogeneity of this study was moderate with an I2 of 72%. CONCLUSION: Our study demonstrated a statistically significant increased VTE risk among patients with sarcoidosis. PMID- 26422562 TI - Diagnostic efficacy of ultrasound-guided core-needle biopsy of peripheral lymph nodes in sarcoidosis. AB - BACKGROUND: Core-needle biopsy guided by ultrasound can be performed for investigating peripheral lymph node (PLN). The aim of this study was to determine the efficacy of this technique in sarcoidosis. METHODS: Retrospective review of files of all patients in the database of the radiology department of Avicenne university hospital who underwent PLN biopsies guided by ultrasound from January 2008 to June 2011 (n=292). Cases with either granulomas at histology with the procedure or with a final diagnosis of sarcoidosis were included in the study. RESULTS: The histological specimens were adequate in 282 out of 292 cases (96%) showing non-caseating granulomas in 22 cases (n=20 patients with a final diagnosis of sarcoidosis and n=2 patients with tuberculosis). After reviewing clinical files of the 282 patient, 22 were confirmed to have sarcoidosis, at initial presentation (n=19) or later during flare-up or relapse (n=3) with only 2 patients having no granuloma on PLN biopsy. PLN were palpable in 18 cases and only detected by (18F)FDG-PET/CT showing increased PLN uptake in 4 cases. The sensitivity and specificity of adequate biopsy were 91 and 99% and the positive and negative predictive values were 91 and 99%, respectively. CONCLUSION: Core needle biopsy guided by ultrasound has a high efficacy for evidencing granulomas in sarcoidosis patients with PLN involvement either clinically palpable or in the presence of (18F)FDG-PET/CT uptake. PMID- 26422563 TI - Common chitotriosidase duplication gene polymorphism and clinical outcome status in sarcoidosis. AB - BACKGROUND: Chitotriosidase has been found to be useful as a sarcoidosis biomarker. In patients with better outcome lower values were observed. Some subjects have 24-base pair duplication in the chitotriosidase gene (CHIT1) that results in the production of inactive enzyme. This might influence the outcome of sarcoidosis and account for described observations. OBJECTIVES: The aim of this study was to correlate common CHIT1 duplication polymorphism and clinical outcome status in sarcoidosis (COS). METHODS: This retrospective study comprised 180 patients with sarcoidosis. COS at 3, 5 and 10 years was determined and correlated with CHIT1 24-base pair duplication polymorphism. CHIT1 genotyping was done by the PCR method. RESULTS: There was no significant correlation between CHIT1 24 base pair duplication polymorphism and COS at 3, 5 or 10 years but a subgroup analysis showed higher frequency of patients with Loefgren's syndrome (50% vs. 17.1%) and better COS in CHIT1 24-base pair duplication homozygotes vs. all other subjects in major COS groups (no, minimal and persistent disease) at 3 years (p=0.025) and borderline significant at 5 years (p = 0.090). CONCLUSIONS: In this study no correlation between CHIT1 24-base pair duplication polymorphism and COS was shown, but possible protective role of homozygous condition for CHIT1 24-base pair duplication polymorphism is suggested. PMID- 26422564 TI - Sarcoid in cancer patients: clinical characteristics and associated disease status. AB - BACKGROUND: The increased risk of cancer in patients with sarcoidosis is well established, but there is little information regarding sarcoid diagnosed during or following cancer. The purpose of this study is to describe and analyze the disease status and events associated with the diagnosis of sarcoid in cancer patients. METHODS: At a large cancer center, we identified 64 patients with a pathologic diagnosis of sarcoid-like granuloma during or following a diagnosis of malignancy. Pathology specimens were re-examined by experts, and clinical and imaging information were reviewed. Disease-related events including recurrence, progression, death, and second malignancy were analyzed. RESULTS: The most common primary malignancies were breast (17%), lymphoma (16%), lung (13%), and testicular cancer (11%). Thirty-six out of 64 patients (56%) were diagnosed with sarcoid within 10 months of their primary malignancy, whereas 28 (44%) were diagnosed with sarcoid in follow-up, including 15/28 without evidence of disease, 6 with associated diagnosis of recurrence, 5 with associated diagnosis of second malignancy, 1 with stable disease, and 1 with progressive disease. Sarcoid biopsy sites included mediastinal nodes (59%), hilar nodes (13%), lung (30%), and other nodes (17%), and the reason for biopsy was usually abnormal imaging (66%). Sarcoid and tumor were co-localized in 34%. Including long-term follow-up events, sarcoid was present in association with 10 of 19 recurrences (53%) and 8 of 12 second malignancies (67%). CONCLUSION: While sarcoid often presents at initial diagnosis or staging of cancer, in a significant number of patients, it appears in association with recurrence or second malignancy. PMID- 26422565 TI - Heart transplantation for advanced heart failure due to cardiac sarcoidosis. AB - BACKGROUND: Selected patients with cardiac sarcoidosis undergo heart transplantation, but outcomes may be adversely affected by recurrent cardiac sarcoidosis or progressive extra-cardiac sarcoidosis. OBJECTIVES: We present our single-center experience of patients with cardiac sarcoidosis who underwent heart transplantation. METHODS: Consecutive patients that underwent heart transplantation between 1990 and 2012 were assessed. Cardiac sarcoidosis was defined by the presence of multiple non-caseating epithelioid cell granulomata in the explanted heart. Baseline characteristics and clinical outcomes were compared with a control group without cardiac sarcoidosis that underwent heart transplantation during this period. RESULTS: 901 patients underwent heart transplantation during the study period, of whom 4 patients had a pre-transplant diagnosis of cardiac sarcoidosis and 8 patients had sarcoidosis identified in the explanted heart. Patients with cardiac sarcoidosis had excellent post-transplant outcomes with survival of 92% at one year and 83% at five years. Survival was similar to patients that underwent heart transplantation for an alternate diagnosis. We did not encounter recurrent cardiac sarcoidosis or progressive extra-cardiac sarcoidosis during 1001 months of follow-up. CONCLUSIONS: Carefully selected patients with advanced heart failure due to cardiac sarcoidosis have an acceptable outcome after transplantation. Cardiologists should be aware that reported experience of transplantation for cardiac sarcoidosis mostly represents isolated cardiac sarcoidosis that was only diagnosed at pathological examination of the explanted heart. PMID- 26422566 TI - Efficacy and Safety of Rituximab in Connective Tissue Disease related Interstitial Lung Disease. AB - BACKGROUND: Pulmonary complications of connective tissue disease are being identified more frequently with the advent of more sophisticated radiological investigations. Limited previous studies have suggested Rituximab (RTX), a chimeric monoclonal antibody with activity against CD-20, may benefit connective tissue disease patients with pulmonary complications. We performed a retrospective analysis of the efficacy and safety of RTX in patients attending a tertiary referral centre. METHODS: Ten patients treated with RTX for pulmonary complications of CTD in our institution were identified. Baseline demographics, pre- and post-treatment investigations and adverse events were documented with an average follow up time-frame of 12.3 months (range: 3 - 27). Statistical analysis was performed using the Wilcoxan Signed-Rank test in SPSS. RESULTS: There was a statistically significant improvement in pulmonary function, with a mean increase of 19% in DLCO (median DLCO (ml/min/mmHg) pre-treatment vs. post-treatment: 13.94 vs. 19.34, p=0.028) and a mean increase of 13% in FVC (median FVC (L) pre treatment vs. post-treatment: 3.47 vs.3.6, p=0.28). For patients with pulmonary fibrosis (n=7), CT severity was improved on post-treatment scan, though this did not reach statistical significance. There was a reduction in the number of nodules seen on the follow-up scans of two patients without fibrosis. No patient had a severe adverse reaction to RTX. CONCLUSIONS: Treatment with RTX resulted in an objective, measurable improvement in pulmonary function and/or radiological severity for the majority of patients included in the series. This was statistically significant despite the small numbers included. These results indicate a positive response to RTX with few complications of treatment. PMID- 26422567 TI - Cathelicidin as a link between sarcoidosis and tuberculosis. AB - SETTING: Sarcoidosis and tuberculosis share notable clinical, radiological, histological, and immunological similarities. The importance of vitamin D has long been investigated in these two granulomatous lung diseases. Cathelicidin is an antimicrobial peptide of the innate immune system, directly induced by vitD3. OBJECTIVE: To evaluate the role of cathelicidin in sarcoidosis and tuberculosis development. DESIGN: The study included 30 consecutive patients with active lung tuberculosis, 30 patients with sarcoidosis, and 20 healthy controls. 25 hydroxyvitamin D [25(OH)D] and cathelicidin levels were measured in blood samples. RESULTS: Vitamin D levels were significantly higher (p<0.001) in tuberculosis patients (22.5 +/- 9.96 ng/ml) than in sarcoidosis patients (11.75 +/- 8.92 ng/ml). Severe vitamin D deficiency was as frequent as 47% in sarcoidosis patients compared to only 3% in tuberculosis patients. Cathelicidin levels were significantly higher in the control group (120.37 +/- 41.03 pg/ml) than in sarcoidosis (67.68 +/- 38.03 pg/ml) and tuberculosis (68.74 +/- 39.44 pg/ml) patients (p<0.001). However, no significant difference in cathelicidin levels was observed between tuberculosis and sarcoidosis patients (p=0.966). The optimum cathelicidin cut-off value to distinguish sarcoidosis patients from healthy controls was 107.14 pg/ml (sensitivity 81.5%, specificity 71.2%). CONCLUSION: Cathelicidin appears to play different roles in the development of granulomatous lung disease. PMID- 26422568 TI - Biomarkers to identify ILD and predict lung function decline in scleroderma lung disease or idiopathic pulmonary fibrosis. AB - BACKGROUND: SSc-ILD and IPF demonstrate significant morbidity and mortality. Predicting disease progression is challenging in both diseases. OBJECTIVES: We sought a serum biomarker that could identify patients with SSc-ILD or IPF and prospectively predict short-term decline in lung function in these patients. METHODS: 10 healthy controls, 5 SSc w/o ILD, 6 SSc-ILD and 13 IPF patients underwent venesection. An array of cytokines including KL-6, SP-D and MMP7 were measured. PFTs were obtained at baseline and six months. Cytokine measurements were correlated with PFTs. RESULTS: KL-6 in IPF patients (633 ng/ml, IQR 492 1675) was significantly elevated compared to controls (198 ng/ml, IQR 52-360, p<0.01) and SSc w/o ILD patients (192 ng/ml, IQR 0-524, p<0.05); KL-6 in SSc-ILD patients (836 ng/ml, IQR 431-1303) was significantly higher than in controls (p<0.05). SP-D was significantly higher in IPF patients (542 ng/ml, IQR 305-577) compared to controls (137 ng/ml, IQR 97-284, p<0.01) or to SSc w/o ILD patients (169 ng/ml, IQR 137-219, p<0.05). In comparison with controls (0.0 ng/ml, IQR 0.0 0.6), MMP7 was significantly higher in both IPF patients (2.85 ng/ml, IQR 1.5 3.6, p<0.05) and SSc-ILD patients (5.41 ng/ml, IQR 2.6-7.2, p<0.001). Using a cut off level of 459ng/ml for KL-6 and of 1.28 ng/ml for MMP7, 18 out of 19 patients with ILD had a serum value of either KL-6 or MMP7 above these thresholds. For all ILD patients, baseline serum SP-D correlated with DeltaFVC %pred over six months (r=-0.63, p=0.005, 95% CI -0.85 to -0.24). CONCLUSIONS: Combining KL-6 with MMP7 may be a useful screening tool for patients at risk of ILD. SP-D may predict short-term decline in lung function. PMID- 26422569 TI - Ocular and systemic features of sarcoidosis and correlation with the International Workshop for Ocular Sarcoidosis diagnostic criteria. AB - PURPOSE: To describe the ocular and systemic features in biopsy proven (definite) and non-biopsy proven (clinical) ocular sarcoidosis and to compare the ocular features with those proposed by the International Workshop for Ocular Sarcoidosis (IWOS). METHODS: Retrospective chart review of 83 patients who attended a tertiary referral uveitis clinic and were diagnosed with sarcoidosis. Patients were divided into two groups based on the type of diagnosis: those who had tissue biopsy confirmed diagnosis 'definite sarcoidosis' (n= 42; 50.60 %) and those who had 'clinical sarcoidosis' (n= 41; 49.40%). Ocular and systemic manifestations, including lung function tests and bronchoalveolar lavage findings were compared in the two groups. The ocular features were also compared with the categories laid down by the International Workshop on Ocular Sarcoidosis (IWOS). RESULTS: The mean age at presentation was 38.75 years (SD=12.33), 55.42% patients were female and mean follow-up was 24.35 months (SD=18.35). Trabecular meshwork nodules and/or tent-shaped PAS (category II of IWOS) were observed more frequently in patients with biopsy proven sarcoidosis (26.19 % v/s 9.76%; p=0.08). After logistic regression analysis, the predictor coefficient curve showed area under curve of 0.7262. Lymphocytosis (38.61% and 28.02%, p=0.93) and monocytosis (55.11% and 53.83%, p=0.56) on bronchoalveolar lavage analysis was present in both the groups, highlighting presence of granulomatous disease. CONCLUSION: This study suggests high reliability for the clinical diagnosis of ocular sarcoidosis in patients with signs recommended by IWOS and that our diagnostic criteria are consistent with that of the IWOS. PMID- 26422570 TI - Fibrosing interstitial lung diseases involve different pathogenic pathways with similar outcomes. AB - Fibrosing interstitial lung diseases (ILDs) are a large group of diseases triggered by external or internal stimuli that can have similar outcomes, i.e. lung fibrosis. Some ILDs are primarily fibro-proliferative disorders in which alveolar loss and epithelial/fibroblastic proliferation and dysplasia lead to lung fibrosis and architectural derangement, while other ILDs are considered inflammatory disorders in which specific underlying conditions (with either an external or an internal origin) can shift the pathogenic process to the fibro proliferative pathway. The treatment of primarily inflammatory ILDs, regardless of their tendency to switch to lung fibrosis usually consists of anti inflammatory drugs (e.g. corticosteroids, cytostatic + immunosuppressive agents), targeted 'biologic treatment' (e.g. anti TNF-alpha, anti CD20) and combinations thereof. However, we have entered an era in which new drugs that specifically target fibrosing ILDs, namely IPF, have emerged. Continuing laboratory research and clinical studies will hopefully provide us with a more complete understanding of the pathogenesis of fibrosing ILDs. Additionally, we are optimistic about the discovery of new pharmacological targets for the treatment of these serious diseases.The complex issues concerning fibrosing ILDs were addressed and passionately discussed during the Prague postgraduate course and conference devoted to these diseases (June 19th - 21th, 2014). PMID- 26422571 TI - Efficacy and safety of surgical lung biopsy for interstitial disease. Experience of 161 consecutive patients from a single institution in Italy. AB - BACKGROUND: The role of surgical biopsy for interstitial lung disease (ILD) is controversial, because of possible postoperative morbidity and mortality. We aimed to assess the efficacy and safety of surgical biopsy for ILD. METHODS: We retrospectively analysed the diagnostic performance and the postoperative complications of 161 consecutive surgical lung biopsy procedures carried out in suspected ILD cases that were undefined after multidisciplinary clinico radiological evaluation. In 151 cases (93.8%) the biopsy was performed by video assisted thoracoscopic surgery (VATS), in 6.2% by limited thoracotomy. RESULTS: A specific histological diagnosis was obtained in 154 (95.7%) of the surgically biopsied patients, while 4.3% remained histologically unclassified. The predominant histological patterns were sarcoidosis (29.8 %), usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) (24.2%), cryptogenic organizing pneumonia (18.6%) and nonspecific interstitial pneumonia (8.1%). The postoperative course was uneventful in 142 cases. In 19 patients (11.8%) we observed postoperative complications, predominantly prolonged air leakage (5.0% of all cases). Thirty-day postoperative mortality was 3.1%, mostly due to acute exacerbation of respiratory insufficiency. Postoperative mortality independently correlated with preoperative need of oxygen therapy (OR, 5.21; 95% CI, 1.19 22.95) and with UIP/IPF histology (OR, 5.67; 95% CI, 1.27-25.25). CONCLUSIONS: Lung biopsy was performed mostly by VATS, with limited morbidity, and was effective in yielding a specific histologic diagnosis in the vast majority of undefined ILD cases. To optimize the outcome of surgical biopsy for specific diagnosis of ILD, this procedure should be performed only exceptionally in patients with critical respiratory illness as postoperative mortality risk in these subjects is exceedingly high. PMID- 26422572 TI - Long-term stable lung function and second uncomplicated pregnancy on sirolimus in lymphangioleiomyomatosis (LAM). AB - We present a patient with lymphangioleiomyomatosis (LAM) on long-term sirolimus (now 79 months) who has had a second successful pregnancy. The second pregnancy on uninterrupted low-dose sirolimus (plasma levels 3-5 mg/L) was uncomplicated both with respect to mother and child suggesting that low-dose sirolimus might be safe in selected pregnant patients with stable LAM. The long-term time course in this patient is in agreement with recent reports of a long-term beneficial effect of sirolimus in LAM. In this patient, the pregnancies did not seem to impair the long-term improvement of lung-function on sirolimus. PMID- 26422573 TI - Early detection of colon cancer by increased serum level of Krebs von den Lungen 6 in a patient with dermatomyositis-associated interstitial pneumonia. AB - Krebs von den Lungen-6 (KL-6) is a high-molecular-weight glycoprotein which is elevated in serum of patients with interstitial pneumonia (IP). Serum KL-6 level is clinically used for the diagnosis of IP as well as the evaluation of its disease activity. KL-6 is originally identified when exploring novel soluble antigens in patients with lung cancer, and is known to be elevated in patients with several malignant tumors. The risk of malignant tumors is high in IP patients with polymyositis and dermatomyositis (PM/DM), and follow-up of KL-6 levels may allow earlier detection of such tumors. However, to date, there are only a few reports showing the usefulness of following-up serum KL-6 levels for finding malignant tumors in IP patients with PM/DM. Here, we described the first patient in whom increased serum KL-6 led to the diagnosis of colon cancer during follow-up of DM-associated IP. PMID- 26422574 TI - Propionibacterium acnes isolated from lymph nodes of patients with sarcoidosis. AB - Propionibacterium acnes has been repeatedly suggested as a candidate causative agent of sarcoidosis. It is the only microorganism that has been isolated from sarcoid lesions by bacterial culture so far and this has been described in Japanese patients only. We report two non-Japanese patients in whom mediastinoscopy was performed in order to obtain lymph node tissue for histopathology, which was suggestive for sarcoidosis. Bacterial culture of these uncontaminated mediastinal lymph nodes revealed P. acnes in both patients. As shown in these two cases, P. acnes can be isolated from sterile biopsied sarcoid lymph nodes of non-Japanese patients and supports the belief that there is an etiologic link between P. acnes sarcoidosis. Further elucidation could provide an opening to novel strategies using antibiotics for treating sarcoidosis. PMID- 26422575 TI - Pulmonary manifestations revealing Rosai-Dorfman disease. AB - Rosai-Dorfman disease is a rare non-Langerhans cell histiocytosis, mainly involving cervical nodes. We present the case of a patient with a pulmonary form of Rosai-Dorfman disease without peripheral or intra-thoracic lymph nodes, characterized by the presence of pulmonary nodules and cysts associated with bilateral pleural effusions. PMID- 26422576 TI - Improved dose calculation accuracy for low energy brachytherapy by optimizing dual energy CT imaging protocols for noise reduction using sinogram affirmed iterative reconstruction. AB - The goal of this study was to evaluate the noise reduction achievable from dual energy computed tomography (CT) imaging (DECT) using filtered backprojection (FBP) and iterative image reconstruction algorithms combined with increased imaging exposure. We evaluated the data in the context of imaging for brachytherapy dose calculation, where accurate quantification of electron density rhoe and effective atomic number Zeff is beneficial. A dual source CT scanner was used to scan a phantom containing tissue mimicking inserts. DECT scans were acquired at 80 kVp/140Sn kVp (where Sn stands for tin filtration) and 100 kVp/140Sn kVp, using the same values of the CT dose index CTDIvol for both settings as a measure for the radiation imaging exposure. Four CTDIvol levels were investigated. Images were reconstructed using FBP and sinogram affirmed iterative reconstruction (SAFIRE) with strength 1,3 and 5. From DECT scans two material quantities were derived, Zeff and rhoe. DECT images were used to assign material types and the amount of improperly assigned voxels was quantified for each protocol. The dosimetric impact of improperly assigned voxels was evaluated with Geant4 Monte Carlo (MC) dose calculations for an (125)I source in numerical phantoms. Standard deviations for Zeff and rhoe were reduced up to a factor ~2 when using SAFIRE with strength 5 compared to FBP. Standard deviations on Zeff and rhoe as low as 0.15 and 0.006 were achieved for the muscle insert representing typical soft tissue using a CTDIvol of 40 mGy and 3mm slice thickness. Dose calculation accuracy was generally improved when using SAFIRE. Mean (maximum absolute) dose errors of up to 1.3% (21%) with FBP were reduced to less than 1% (6%) with SAFIRE at a CTDIvol of 10 mGy. Using a CTDIvol of 40mGy and SAFIRE yielded mean dose calculation errors of the order of 0.6% which was the MC dose calculation precision in this study and no error was larger than +/ 2.5% as opposed to errors of up to -4% with FPB. This phantom study showed that the SAFIRE image reconstruction algorithm provided reduced standard deviations of Zeff and rhoe in uniform regions of interest while preserving mean Zeff and rhoe values. This resulted in improved material type assignment. The use of SAFIRE improved brachytherapy dose calculations for the materials from the phantom investigated in this study using (125)I. PMID- 26422577 TI - [Benchmark experiment to verify radiation transport calculations for dosimetry in radiation therapy]. AB - Monte Carlo simulations are regarded as the most accurate method of solving complex problems in the field of dosimetry and radiation transport. In (external) radiation therapy they are increasingly used for the calculation of dose distributions during treatment planning. In comparison to other algorithms for the calculation of dose distributions, Monte Carlo methods have the capability of improving the accuracy of dose calculations - especially under complex circumstances (e.g. consideration of inhomogeneities). However, there is a lack of knowledge of how accurate the results of Monte Carlo calculations are on an absolute basis. A practical verification of the calculations can be performed by direct comparison with the results of a benchmark experiment. This work presents such a benchmark experiment and compares its results (with detailed consideration of measurement uncertainty) with the results of Monte Carlo calculations using the well-established Monte Carlo code EGSnrc. The experiment was designed to have parallels to external beam radiation therapy with respect to the type and energy of the radiation, the materials used and the kind of dose measurement. Because the properties of the beam have to be well known in order to compare the results of the experiment and the simulation on an absolute basis, the benchmark experiment was performed using the research electron accelerator of the Physikalisch-Technische Bundesanstalt (PTB), whose beam was accurately characterized in advance. The benchmark experiment and the corresponding Monte Carlo simulations were carried out for two different types of ionization chambers and the results were compared. Considering the uncertainty, which is about 0.7 % for the experimental values and about 1.0 % for the Monte Carlo simulation, the results of the simulation and the experiment coincide. PMID- 26422578 TI - Incorporation of local dependent reliability information into the Prior Image Constrained Compressed Sensing (PICCS) reconstruction algorithm. AB - PURPOSE: The reduction of dose in cone beam computer tomography (CBCT) arises from the decrease of the tube current for each projection as well as from the reduction of the number of projections. In order to maintain good image quality, sophisticated image reconstruction techniques are required. The Prior Image Constrained Compressed Sensing (PICCS) incorporates prior images into the reconstruction algorithm and outperforms the widespread used Feldkamp-Davis-Kress algorithm (FDK) when the number of projections is reduced. However, prior images that contain major variations are not appropriately considered so far in PICCS. We therefore propose the partial-PICCS (pPICCS) algorithm. This framework is a problem-specific extension of PICCS and enables the incorporation of the reliability of the prior images additionally. MATERIAL AND METHODS: We assumed that the prior images are composed of areas with large and small deviations. Accordingly, a weighting matrix considered the assigned areas in the objective function. We applied our algorithm to the problem of image reconstruction from few views by simulations with a computer phantom as well as on clinical CBCT projections from a head-and-neck case. All prior images contained large local variations. The reconstructed images were compared to the reconstruction results by the FDK-algorithm, by Compressed Sensing (CS) and by PICCS. To show the gain of image quality we compared image details with the reference image and used quantitative metrics (root-mean-square error (RMSE), contrast-to-noise-ratio (CNR)). RESULTS: The pPICCS reconstruction framework yield images with substantially improved quality even when the number of projections was very small. The images contained less streaking, blurring and inaccurately reconstructed structures compared to the images reconstructed by FDK, CS and conventional PICCS. The increased image quality is also reflected in large RMSE differences. CONCLUSIONS: We proposed a modification of the original PICCS algorithm. The pPICCS algorithm incorporates prior images as well as information about location dependent uncertainties of the prior images into the algorithm. The computer phantom and experimental data studies indicate the potential to lowering the radiation dose to the patient due to imaging while maintaining good image quality. PMID- 26422579 TI - Effects of chemotherapy on gene expression of lingual taste receptors in patients with head and neck cancer. AB - OBJECTIVES/HYPOTHESIS: We aimed to test the hypothesis that chemotherapy changes the gene expression of taste receptors in the tongue to induce dysgeusia in patients with head and neck cancer. STUDY DESIGN: Prospective observation study. METHODS: We enrolled 21 patients who received chemoradiotherapy and five patients who underwent radiotherapy for head and neck cancer. The messenger RNA (mRNA) levels of the taste receptor subunits T1R1, T1R2, T1R3, and T2R5 were measured in lingual mucosa scrapings obtained with a small spatula. The perception thresholds of umami, sweet, and bitter tastes were assessed by the whole mouth gustatory test. RESULTS: In four patients with severe stomatitis induced by chemoradiotherapy, the mRNA levels of T1R1, T1R2, T1R3, and T2R5 in the lingual mucosa were significantly decreased. However, in 17 patients with mild/moderate stomatitis, the mRNA levels of T1R3 were significantly and transiently decreased, whereas those of T1R1 and T1R2 remained unchanged and those of T2R5 mRNA were significantly and transiently increased after chemotherapy. There was a significant negative correlation between the perception thresholds of umami or sweet tastes and lingual mRNA levels of T1R3 in patients with mild/moderate stomatitis after chemotherapy. Although the perception threshold of bitter taste remained unchanged, lingual mRNA levels of T2R5 were significantly increased in patients who complained of phantogeusia after chemotherapy. CONCLUSION: Chemotherapy specifically changed the gene expression of T1R3 and T2R5 in head and neck cancer patients with mild/moderate stomatitis, resulting in both dysgeusia of umami and sweet tastes as well as phantogeusia. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:E103-E109, 2016. PMID- 26422580 TI - Remission of Type 2 Diabetes Mellitus in Patients After Different Types of Bariatric Surgery: A Population-Based Cohort Study in the United Kingdom. AB - IMPORTANCE: To our knowledge, an observational study on the remission of type 2 diabetes mellitus (T2DM) after different types of bariatric surgery based on data from general practice has not been carried out. OBJECTIVE: To assess the effect of different types of bariatric surgery in patients with T2DM on diabetes remission compared with matched control patients, and the effect of the type of bariatric surgery on improvement of glycemic control and related clinical parameters. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study conducted from May 2013 to May 2014 within the Clinical Practice Research Datalink involving 2978 patients with a record of bariatric surgery (2005-2012) and a body mass index (calculated as weight in kilograms divided by height in meters squared) of 35 or greater. We identified 569 patients with T2DM and matched them to 1881 patients with diabetes without bariatric surgery. Data on the use of medication and laboratory results were evaluated. EXPOSURES: Bariatric surgery, stratified by type of surgery (gastric banding, Roux-en-Y gastric bypass, sleeve gastrectomy, or other/unknown). MAIN OUTCOMES AND MEASURES: Remission of T2DM (complete discontinuation of glycemic therapy, accompanied with a subsequently recorded hemoglobin A1c level<6.0%). RESULTS: Among patients undergoing bariatric surgery, we found a prevalence of 19.1% for T2DM. Per 1000 person-years, 94.5 diabetes mellitus remissions were found in patients who underwent bariatric surgery compared with 4.9 diabetes mellitus remissions in matched control patients. Patients with diabetes who underwent bariatric surgery had an 18-fold increased chance for T2DM remission (adjusted relative rate [RR], 17.8; 95% CI, 11.2-28.4) compared with matched control patients. The greatest effect size was observed for gastric bypass (adjusted RR, 43.1; 95% CI, 19.7 94.5), followed by sleeve gastrectomy (adjusted RR, 16.6; 95% CI, 4.7-58.4) and gastric banding (adjusted RR, 6.9; 95% CI, 3.1-15.2). Body mass index and triglyceride, blood glucose, and hemoglobin A1c levels sharply decreased during the first 2 years after bariatric surgery. CONCLUSIONS AND RELEVANCE: Population based data show that bariatric surgery strongly increases the chance for remission of T2DM. Gastric bypass and sleeve gastrectomy have a greater effect than gastric banding. Although the risks and possible adverse effects of surgery should be weighed against its benefits, bariatric surgery and, in particular, gastric bypass or sleeve gastrectomy may be considered as new treatment options for T2DM. PMID- 26422581 TI - Variable asialoglycoprotein receptor 1 expression in liver disease: Implications for therapeutic intervention. AB - AIM: One of the most promising strategies for the treatment of liver diseases is targeted drug delivery via the asialoglycoprotein receptor (ASGPR). The success of this approach heavily depends on the ASGPR expression level on parenchymal liver cells. In this study, we assessed the mRNA and protein expression levels of the major receptor subunit, ASGR1, in hepatocytes both in vitro and in vivo. METHODS: In vitro, various liver cancer-derived cell lines were evaluated. In vivo, we screened the ASGR1 mRNA on 59 hepatocellular carcinoma and matched non neoplastic tissue using RNA microarray. In addition, 350 human liver specimens of patients with hepatocellular carcinoma or non-neoplastic liver diseases were screened for ASGR1 protein level using tissue microarray analysis. RESULTS: Our data reveal that the ASGR1 mRNA expression directly correlates with the protein level. We demonstrate that the ASGR1 expression is upregulated in cirrhotic specimens and is significantly decreased with increasing hepatocellular carcinoma grade. CONCLUSION: Because the ASGR1 expression levels are variable between patients, our findings suggest that ASGPR-based targeting strategies should be combined with ASGPR-companion diagnostics to maximize clinical benefit. PMID- 26422582 TI - Intracellular delivery of 10-hydroxycamptothecin with targeted nanostructured lipid carriers against multidrug resistance. AB - 10-Hydroxycamptothecin (HCPT) is a clinical therapy agent against hepatoma. The chemotherapy of HCPT is strongly obstructed by the emergence of multidrug resistance (MDR), serious systemic toxicity, malfunction of rapid phagocytic and renal clearance disorder which are undesirable for its chemotherapy. In this paper, a drug delivery system (DDS) for HCPT has been developed in order to overcome MDR. Nanostructured lipid carriers (NLC) coated with xyloglucan (XG) was prepared by soya oil and XG consisting of side chains with galactose residues, a terminal moiety that can be used to target HCPT to hepatoma. The therapeutic potential of XG-NLC/HCPT was investigated on HepG2/HCPT cells and on human tumor xenograft nude mouse model (implanted with HepG2/HCPT cells). XG-NLC/HCPT not only indicated superior cytotoxicity against the drug resistant HepG2 cells but also in vivo, generated a higher therapeutic effect. Systemic toxicity study demonstrated that the carrier reduced systemic toxicity. XG-NLC/HCPT proved a great potential to serve as DDS to overcome MDR of HepG2/HCPT cells. These results suggested that XG NLC/HCPT represent a promising carrier for drug delivery to the hepatoma and reverse the drug resistant of HepG2 cells and XG could be exploited as a potential targeting device for liver tissue. PMID- 26422583 TI - Persuasive appeals in road safety communication campaigns: Theoretical frameworks and practical implications from the analysis of a decade of road safety campaign materials. AB - Communication campaigns are employed as an important tool to promote road safety practices. Researchers maintain road safety communication campaigns are more effective when their persuasive appeals, which are central to their communicative strategy, are based on explicit theoretical frameworks. This study's main objectives were to develop a detailed categorization of persuasive appeals used in road safety communication campaigns that differentiate between appeals that appear to be similar but differ conceptually, and to indicate the advantages, limitations and ethical issues associated with each type, drawing on behavior change theories. Materials from over 300 campaigns were obtained from 41 countries, mainly using road safety organizations' websites. Drawing on the literature, five types of main approaches were identified, and the analysis yielded a more detailed categorizations of appeals within these general categories. The analysis points to advantages, limitations, ethical issues and challenges in using different types of appeals. The discussion summarizes challenges in designing persuasive-appeals for road safety communication campaigns. PMID- 26422584 TI - Multidisciplinary care of children with repaired esophageal atresia and tracheoesophageal fistula. AB - OBJECTIVES: Children with congenital esophageal atresia with tracheoesophageal fistula (TEF) require complex medical and surgical care, but few guidelines exist to guide the long term care of this population. The purpose of this study is to describe the findings and initial management of a comprehensive aerodigestive team in order to understand the ongoing needs of children with repaired TEF. METHODS: A retrospective chart review was performed on children with TEF who were seen in the multidisciplinary Aerodigestive Clinic at Children's Hospital Colorado. Diagnostic studies were ordered based on physician discretion. RESULTS: Twenty-nine children with TEF were evaluated (mean age 3.8 years) between 2010 and 2014. All children had symptoms attributed to breathing, swallowing, and digestive difficulties. Less than half of the children had seen a pulmonary or gastrointestinal specialist in the past year. Tracheomalacia was diagnosed in all children who had a bronchoscopy (23/23), and the presence of dysphagia was correlated with severe tracheomalacia. 7/25 children who had a swallow study had aspiration. 7/25 children had a diagnosis of active reflux despite current management. Four patients were diagnosed with bronchiectasis as a result of the multidisciplinary evaluation. CONCLUSION: Although all children had persistent aerodigestive symptoms, over 50% had not been seen by an appropriate subspecialist in the year prior to the clinic visit. The multidisciplinary evaluation resulted in new diagnoses of bronchiectasis and active reflux, which can both lead to long-term morbidity and mortality. Children with TEF require evaluation by multiple subspecialists to manage not only current symptoms but also long term risks. Ongoing care should be guided by protocols based on known risks. Pediatr Pulmonol. 2016;51:576-581. (c) 2015 Wiley Periodicals, Inc. PMID- 26422586 TI - Understanding the surgical pitfalls in total mesorectal excision: Investigating the histology of the perirectal fascia and the pelvic autonomic nerves. AB - AIM: Excellent understanding of fasciae and nerves surrounding the rectum is necessary for total mesorectal excision (TME). However, fasciae anterolateral to the rectum and surrounding the low rectum are still poorly understood. We studied the perirectal fascia enfolding the extraperitoneally located part of the rectum in en-bloc cadaveric specimens and the University Medical Center Utrecht (UMCU) pelvic dataset, and describe implications for TME. METHODS: Four donated human adult cadaveric specimens (two males, two females) were obtained through the Leeds GIFT Research Tissue Programme. Paraffin-embedded blocks were produced and serially sectioned at 50 and 250 MUm intervals. Whole mount sections were stained with haematoxylin & eosin, Masson's trichrome and Millers' elastin. Additionally, the UMCU pelvic dataset including digitalised cryosections of a female pelvis in three axes was studied. RESULTS: The mid and lower rectum were surrounded by a multi-layered perirectal fascia, of which the mesorectal fascia (MRF) and parietal fascia bordered the 'holy plane'. There was no extra constant fascia forming a potential surgical plane. Nerves ran laterally to the MRF. More caudally, the mesorectal fat strongly reduced and the MRF approached the rectal muscularis propria. The MRF had a variable appearance in terms of thickness and completeness, most prominently at the anterolateral lower rectum. CONCLUSION: Dissection onto the MRF allows nerve preservation in TME. Rectal surgeons are challenged in doing so as the MRF varies in thickness and shows gaps, most prominently at the anterolateral lower rectum. At this site, the risk of entering the mesorectum is great and may result in an incomplete specimen. PMID- 26422587 TI - HER2 expression in oesophageal carcinoma and Barrett's oesophagus associated adenocarcinoma: An Australian study. AB - BACKGROUND: Several studies have evaluated the prognostic value of HER2 in oesophageal cancer, but the prognostic influence of HER2 overexpression in oesophageal cancer remains uncertain. The aim of this study was to assess the incidence of HER2 positivity and relationship with clinicopathological features in patients with oesophageal cancer. DESIGN: The study cohort consisted of 269 patients diagnosed with oesophageal carcinoma in a single institution. HER2 expression was analysed by immunohistochemistry (IHC) and silver in situ hybridization (SISH) in 152 archival oesophageal cancer specimens. Survival analysis was assessed using Hazard models. RESULTS: HER2 expression was IHC3+ in 14 (9.2%), IHC2+ in 14 (9.2%), IHC1+ in 57 (37.5%), and IHC0 in 67 (44.1%) cases. SISH results confirmed that 15 specimens (9.9%) were HER2 gene amplified. Among 27 squamous cell carcinomas (SCCs) only 3.7% were HER2 positive whereas 11.2% of 125 adenocarcinomas were HER2 positive. The HER2 positive tumours were more likely to occur in men (OR: 5.00, 95% CI: 1.69-14.29), smokers (OR: 10.00, 95% CI: 4.17-25) and in patients with Barrett's oesophagus (OR: 8.33, 95% CI: 3.71 20.00). There was no significant difference in survival between the (HER2 +ve, 14.3 months vs HER2 -ve, 24.6 months, p = 0.42) CONCLUSION: A HER2 prevalence rate of 9.9% was found among patients with oesophageal cancer and no correlation with survival was detected overall. PMID- 26422589 TI - Asymptomatic gingival nodule in the anterior maxilla. PMID- 26422588 TI - Injectable hydrogel provides growth-permissive environment for human nucleus pulposus cells. AB - Degeneration of intervertebral discs (IVDs) results in an overall alteration of the biomechanics of the spinal column and becomes a major cause of low back pain. In this study, an injectable hydrogel composite is fabricated and characterized as a potential scaffold for the treatment of degenerated IVDs. Crosslinking of type II collagen-hyaluronic acid (HA) hydrogel with 1-ethyl-3(3-dimethyl aminopropyl) carbodiimide (EDC) increases the gel stability against collagenase digestion and reduces water uptake in comparison with non-crosslinked gel. Cell viability assay exhibits the proliferation of human nucleus pulposus (HNP) cells in hydrogels. The cells in non-crosslinked gel and the gel crosslinked with a low concentration of EDC (0.1 mM) show superior cell viability and morphology compared with cells in gels crosslinked with higher concentration of EDC. Quantitative PCR assay demonstrates the gene expression of extracellular matrix (ECM) by cells cultured in the gels. The expression of ECM genes by HNP cells in the gels demonstrated the phenotypic change of the cells. This study suggests that the type II collagen-HA hydrogel and crosslinked hydrogel (0.1 mM EDC) are permissive matrix for the growth of HNP cells and can be potentially applied in NP repair. PMID- 26422590 TI - Human SAS-6 C-Terminus Nucleates and Promotes Microtubule Assembly in Vitro by Binding to Microtubules. AB - Centrioles are essential components of the animal centrosome and play crucial roles in the formation of cilia and flagella. They are cylindrical structures composed of nine triplet microtubules organized around a central cartwheel. Recent studies have identified spindle assembly abnormal protein SAS-6 as a critical component necessary for formation of the cartwheel. However, the molecular details of how the cartwheel participates in centriolar microtubule assembly have not been clearly understood. In this report, we show that the C terminal tail (residues 470-657) of human SAS-6, HsSAS-6 C, the region that has been shown to extend toward the centriolar wall where the microtubule triplets are organized, nucleated and induced microtubule polymerization in vitro. The N terminus (residues 1-166) of HsSAS-6, the domain known to be involved in formation of the central hub of the cartwheel, did not, however, exert any effect on microtubule polymerization. HsSAS-6 C bound to the microtubules and localized along the lengths of the microtubules in vitro. Microtubule pull-down and coimmunoprecipitation (Co-IP) experiments with S-phase synchronized HeLa cell lysates showed that the endogenous HsSAS-6 coprecipitated with the microtubules, and it mediated interaction with tubulin. Isothermal calorimetry titration and size exclusion chromatography showed that HsSAS-6 C bound to the alphabeta tubulin dimer in vitro. The results demonstrate that HsSAS-6 possesses an intrinsic microtubule assembly promoting activity and further implicate that its outer exposed C-terminal tail may play critical roles in microtubule assembly and stabilizing microtubule attachment with the centriolar cartwheel. PMID- 26422591 TI - The Association Between Premedical Curricular and Admission Requirements and Medical School Performance and Residency Placement: A Study of Two Admission Routes. AB - PURPOSE: The curricular elements of undergraduate premedical education are the subject of an ongoing debate. The Warren Alpert Medical School of Brown University (AMS) matriculates students via the traditional premedical route (TPM) and an eight-year baccalaureate/MD program-the Program in Liberal Medical Education (PLME)-which provides students with a broad and liberal education. Using the juxtaposition of these two admission routes, the authors aimed to determine whether there is an association between highly distinct premedical curricular and admission requirements and medical school performance and residency placement. METHOD: The cohorts studied included all of the PLME (n = 295) and TPM (n = 215) students who graduated from the AMS between 2010 and 2015. Outcome variables consisted of multiple measures of medical school performance, including standardized multiple-choice examination scores and honors grades, and residency placement. The authors employed unadjusted tests of averages and proportions (independent t tests and chi-square tests) to compare variables. RESULTS: The TPM students attained marginally, but statistically significantly, higher average scores on standardized multiple-choice examinations than their PLME counterparts. The number of undergraduate premedical science courses completed by PLME students accounted for less than 4% of the variance in key metrics of medical school performance. The residency placement record of the PLME and TPM cohorts proved comparable. CONCLUSIONS: These findings suggest that the association between medical school performance and residency placement and undergraduate premedical curricular and admission requirements is weak. Further study is needed to determine the optimal premedical preparation of students. PMID- 26422592 TI - Health Reform and Academic Health Centers: Commentary on an Evolving Paradigm. AB - The Patient Protection and Affordable Care Act (ACA), both directly and indirectly, has had a demonstrable impact on academic health centers. Given the highly cross-subsidized nature of institutional funds flows, the impact of health reform is not limited to the clinical care mission but also extends to the research and education missions of these institutions. This Commentary discusses how public policy and market-based health reforms have played out relative to expectations. The authors identify six formidable challenges facing academic health centers in the post-ACA environment: finding the best mission balance; preparing for the era of no open-ended funding; developing an integrated, interprofessional vision; broadening the institutional perspective; addressing health beyond clinical care; and finding the right leadership for the times. Academic health centers will be well positioned for success if they can focus on 21st-century realities, reengineer their business models, and find transformational leaders to change institutional culture and behavior. PMID- 26422593 TI - From Impairment to Empowerment: A Longitudinal Medical School Curriculum on Disabilities. AB - PROBLEM: All physicians will care for individuals with disabilities; however, education about disabilities is lacking at most medical schools. Most of the schools that do include such education exclusively teach the medical model, in which disability is viewed as an impairment to be overcome. Disability advocates contest this approach because it overlooks the social and societal contexts of disability. A collaboration between individuals with disabilities, educators, and physicians to design a medical school curriculum on disabilities could overcome these differences. APPROACH: A curriculum on disabilities for first- and second year medical students was developed during the 2013-2014 academic year and involved a major collaboration between a medical student, medical educators, disability advocates, and academic disability specialists. The guiding principle of the project was the Disability Rights Movement motto, "Nothing about us without us." Two small-group sessions were created, one for each medical school class. They included discussions about different models of disability, video and in-person narratives of individuals with disabilities, and explorations of concepts central to social perceptions of disability, such as power relationships, naming and stigmatization, and disability as identity. OUTCOMES: According to evaluations conducted after each session, students reported positive feedback about both sessions. NEXT STEPS: Through this curriculum, first- and second-year medical students learned about the obstacles faced by individuals with disabilities and became better equipped to understand and address the concerns, hopes, and societal challenges of their future patients. This inclusive approach may be used to design additional curricula about disabilities for the clinical and postgraduate years. PMID- 26422594 TI - A Diversity 3.0 Update: Are We Moving the Needle Enough? AB - Five years ago, in a previous Academic Medicine Commentary, the author asserted that the move toward health reform and a more equitable health system required a transformation of more than how we finance, deliver, and evaluate health care. It also required a new role for diversity and inclusion as a solution to our problems, rather than continuing to see it as just another problem to be fixed. In this update, the author assesses the collective progress made by the nation's medical schools and teaching hospitals in integrating diversity into their core strategic activities, as well as highlighting areas for continued improvement.The author identifies five new trends in diversity and inclusion within academic medicine: broader definitions of diversity to include lesbian, gay, bisexual, and transgender people and those who have disabilities; elevated roles for diversity leaders in medical school administration; growing use of a holistic approach to evaluating medical school applicants; recognition of diversity and inclusion as a core marker of excellence; and appreciation of the significance of subpopulations within minority and underrepresented groups.More work remains to be done, but institutional initiatives to foster and prioritize diversity and inclusion coupled with national efforts by organizations such as the Association of American Medical Colleges are working to build the capacity of U.S. medical schools and teaching hospitals to move diversity from a peripheral initiative to a core strategy for improving the education of medical students and, ultimately, the care delivered to all of our nation's people. PMID- 26422595 TI - [Effects of a physical restraint removal program on older people with dementia in residential care]. AB - OBJECTIVE: To analyse the results of removing physical restraints from elderly patients with dementia living in nursing homes. This objective is part of a wider process of change in residential care. METHODS: Quasi-experimental study conducted in two residences from May 2010 to May 2012. Information was collected at 7 time points and longitudinal analyses were performed. After training staff, the physical restraints in El Puig centre were phased out, while in the Conarda centre, restraints were still applied to elderly people. The main variables studied were: falls, psychotropic medication prescriptions, different indicators of mental impairment, and degree of dependence (Norton, NPI, Mini-mental, Tinetti, Barthel). RESULTS: In the El Puig centre all the physical restraints were removed. A slight improvement was seen in the number of falls, and their consequences. The ANOVA showed significant improvements in the centre that removed restraints in prescribing psychotropic medications, cognitive impairment, and behavioural changes. DISCUSSION: It is shown that removing physical restraints do not cause negative effects as regards the number of falls, and also positively affects the welfare and independence of elderly people (through changes in behaviour and mental impairment). Furthermore, it is demonstrated that this program must be accompanied by the reduction and control of medicines (withdrawal of the number of psychotropic prescriptions). PMID- 26422597 TI - Conductive Inorganic-Organic Hybrid Distributed Bragg Reflectors. AB - A conductive hybrid distributed Bragg reflector (DBR) is demonstrated, consisting of inorganic and organic semiconductor films and assembled by a thermal deposition technique. A maximum reflectance of 92.2% and a wide spectral width of more than 70 nm are achieved. The hybrid DBR shows good electrical conductivity, which provides the possibility of practical applications in novel optoelectronic devices, such as electrically pumped organic vertical-cavity surface-emitting lasers. PMID- 26422596 TI - Nitroxide malonate methanofullerene as biomimetic model of interaction of nitroxide species with antioxidants. AB - Bis-nitroxide malonate methanofullerene (NO)2-MF was studied as a biomimetic model of reduction-oxidation activity with natural compounds-cytochrome c (cyt c), dihydroquercetin (DHQ), ascorbic acid (AA) and synthetic drug-1-(beta oxyethyl)-4,6-dimethyl-1,2-dihydro-2-oxopyrimidine (xymedon((r))). (NO)2-MF may be used as the component of Langmuir monolayers on an aqueous subphase and as the adsorbate on silica gel. The activity of (NO)2-MF in the reaction with cyt c was compared with the effect of nitroxide species such as gaseous nitric oxide, 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO) by using UV-vis and EPR spectra. It has been shown, that iron(III) in cyt c(3+) under action (NO)2-MF was reduced up to iron(II), similar effect was observed under the influence of gaseous NO in aqueous solution, but reduction of iron(III) in heme cyt c was reversible in the presence of TEMPO. Therefore, the state of Fe-heme in cyt c can be used as the indicator of the interaction of cyt c with nitroxide species in vitro. The interaction of cyt c, DHQ, xymedon((r)) with (NO)2-MF monolayers was confirmed by the increasing of limiting area A0 from 0.88 nm(2) up to 1.70 nm(2) of (NO)2-MF on the aqueous subphase, by the paramagnetism and UV-vis spectral data changes. These results can be explained by appearance of oxoammonium ion (NO(+))2-MF adlayers and monolayers. The antioxidant and regenerating effects were shown when treating wounds by xymedon((r)) in the presence of additives (0.001%) of (NO)2-MF in the experiments on the rats. PMID- 26422598 TI - Sensory Processing and Its Relationship with Children's Daily Life Participation. AB - AIMS: To investigate whether children with probable or definite differences in sensory processing (SP) had participation restrictions, and the relationship between Short Sensory Profile (SSP) scores and children's participation. METHODS: The participants were parents of 64 children (mean age 8 years 1 month); 36 with potential impairments in regulating sensory input and filtering out unnecessary stimuli (29 boys, 7 girls) and 28 with typical SP abilities (25 boys, 3 girls). Parents' completed the SSP and Participation in Childhood Occupations Questionnaire (PICO-Q). The SSP score was used to categorize children as potential SP impairment group and typical SP ability group. RESULTS: Children categorized as having probable or definite differences in SP exhibited significantly lower participation levels and enjoyment than children categorized as having typical SP abilities. However, participation frequency between both groups was similar. Six out of the seven SP impairment types had small to moderate correlations with children's participation (r = 0.25-0.48, p < 0.05). Multiple regression analyses indicated that only three impairment types (Underresponsive/Seeks Sensation, Low Energy/Weak, and Visual/Auditory Sensitivity) were significant predictors of PICO-Q participation domains. CONCLUSIONS: The results suggest that children with potential SP impairments have restrictions in the degree of participation and enjoyment. Three SP types were related to specific participation domains, but they explained a small amount of variance or none in some participation domains. Other variables should be considered to identify determinants of children's participation. PMID- 26422599 TI - Studies on the ultrastructure in Anacardium occidentale L. leaves from Amazon in northern Brazil by scanning microscopy. AB - Leaves surfaces have various structures with specific functions and contribute to the relationship with the environment. On morphological studies are analyzed various parameters, ranging from macro scale through the micro scale to the nanometer scale, which contribute to the study of taxonomy, pharmacognosy, and ecology, among others. Functional structures found in leaves are responsible for the wide variety of surfaces and some behaviors are given in terms of cellular adaptation and the presence or absence of wax. This study reports the characterization of Anacardium occidentale L. leaf surface and the techniques used therein. A set of scanning electron microscope (SEM) and atomic force microscope (AFM) images performed on fresh leaf allowed observation of textured and heterogeneous profiles on both sides. SCANNING 38:329-335, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26422600 TI - Outcomes of percutaneous pedicle screw fixation for spinal trauma and tumours. AB - We investigated the clinical and radiological results of percutaneous pedicle screw fixation in the management of spinal trauma and metastatic tumours. A retrospective analysis was performed on a series of 14 patients who were operated on from March 2009 to November 2011 by a single surgeon (RJM). Following a radiological review (CT scan/MRI), six patients underwent short segment fixation, while the remaining underwent long segment fixation. All patients had routine follow-ups at 4, 6, 12months, and annually thereafter. Clinical examinations were conducted preoperatively and postoperatively, and the length of operation, blood loss, and postoperative pain relief were recorded. There was a single patient with an incision site complication. The mean blood loss was 269mL. All of the parameters demonstrated no significant differences between the trauma and the tumour groups (p=0.10). The neurological power scores improved for all patients, with the largest increase being from a score of 2 to 4. At follow-up, the majority of patients had returned to their previous activities and had reduced pain scores. One patient suffered high pain levels from other medical conditions that were not related to the operation. Minimally invasive pedicle screw fixation is a suitable option for patients with spinal tumours and fractures, with acceptable safety and efficacy in this small retrospective patient series. We have seen favourable results in our patients, who have experienced an increased quality of life following their surgery. PMID- 26422601 TI - Synthesis, Structural Characterization, and Chiroptical Studies of Bidentate Salen-Type Lanthanide (III) Complexes. AB - The salen-type ligand prepared with (R,R) diphenylethan-1,2-diamine and salicylaldehyde provides stable and inert complexes KLnL2 upon simple reaction with lanthanide halides or pseudohalides LnX3 (Ln = Tb(3+) -Lu(3+) ; X = Cl(-) or TfO(-) ) of its potassium salt. All the complexes were completely characterized through nuclear magnetic resonance (NMR), electronic circular dichroism (ECD) in the UV and some (Er(3+) , Tm(3+) , Yb(3+) ) also with Near-IR ECD (NIR-ECD) and luminescence (Tb(3+) , Tm(3+) ). Careful analysis of the NMR shifts demonstrated that the complexes are isostructural in solution and afforded an accurate geometry. This was further confirmed by means of Density Functional Theory (DFT) optimization of the Lu(3+) complex, and by comparing the ligand-centered experimental and time-dependent TD-DFT computed UV-ECD spectra. As final validation, we used the NIR-ECD spectrum of the Yb(3+) derivative calculated by means of Richardson's equations. The excellent match between calculated and experimental ECD spectra confirm the quality of the NMR structure. PMID- 26422602 TI - What do high school students say when they talk to their friends about substance use? Exploring the content of substance-use-specific communication with friends. AB - In this study, we examined the content of adolescents' conversations with their friends about substance use, adolescents' reactions to such conversations, and reasons why some adolescents did not engage in such conversations. Based on 25 semistructured interviews with high school students, we identified three themes: informational, persuasive, and relational messages. Informational messages included discussing how many peers use substances and clarifying rumors about a friend's substance use. Persuasive messages involved direct anti-substance-use messages (e.g., warning), direct pro-substance-use messages (e.g., legalizing marijuana), indirect anti-substance-use messages (e.g., disliking their substance use experience), and indirect pro-substance-use messages (e.g., intentions to use substances). Relational messages included joking about substance use and establishing code words for use. Adolescents reacted to their conversations in several ways, such as shock and increased relational closeness. When adolescents did not talk about substance use with their friend, they offered several reasons, including low response efficacy and fear of ruining the friendship. PMID- 26422603 TI - Bioinformatics Analyses of the Role of Vascular Endothelial Growth Factor in Patients with Non-Small Cell Lung Cancer. AB - PURPOSE: This study was aimed to identify the expression pattern of vascular endothelial growth factor (VEGF) in non-small cell lung cancer (NSCLC) and to explore its potential correlation with the progression of NSCLC. METHODS: Gene expression profile GSE39345 was downloaded from the Gene Expression Omnibus database. Twenty healthy controls and 32 NSCLC samples before chemotherapy were analyzed to identify the differentially expressed genes (DEGs). Then pathway enrichment analysis of the DEGs was performed and protein-protein interaction networks were constructed. Particularly, VEGF genes and the VEGF signaling pathway were analyzed. The sub-network was constructed followed by functional enrichment analysis. RESULTS: Total 1666 up-regulated and 1542 down-regulated DEGs were identified. The down-regulated DEGs were mainly enriched in the pathways associated with cancer. VEGFA and VEGFB were found to be the initiating factor of VEGF signaling pathway. In addition, in the epidermal growth factor receptor (EGFR), VEGFA and VEGFB associated sub-network, kinase insert domain receptor (KDR), fibronectin 1 (FN1), transforming growth factor beta induced (TGFBI) and proliferating cell nuclear antigen (PCNA) were found to interact with at least two of the three hub genes. The DEGs in this sub-network were mainly enriched in Gene Ontology terms related to cell proliferation. CONCLUSION: EGFR, KDR, FN1, TGFBI and PCNA may interact with VEGFA to play important roles in NSCLC tumorigenesis. These genes and corresponding proteins may have the potential to be used as the targets for either diagnosis or treatment of patients with NSCLC. PMID- 26422604 TI - Does Publication Bias Inflate the Apparent Efficacy of Psychological Treatment for Major Depressive Disorder? A Systematic Review and Meta-Analysis of US National Institutes of Health-Funded Trials. AB - BACKGROUND: The efficacy of antidepressant medication has been shown empirically to be overestimated due to publication bias, but this has only been inferred statistically with regard to psychological treatment for depression. We assessed directly the extent of study publication bias in trials examining the efficacy of psychological treatment for depression. METHODS AND FINDINGS: We identified US National Institutes of Health grants awarded to fund randomized clinical trials comparing psychological treatment to control conditions or other treatments in patients diagnosed with major depressive disorder for the period 1972-2008, and we determined whether those grants led to publications. For studies that were not published, data were requested from investigators and included in the meta analyses. Thirteen (23.6%) of the 55 funded grants that began trials did not result in publications, and two others never started. Among comparisons to control conditions, adding unpublished studies (Hedges' g = 0.20; CI95% 0.11~0.51; k = 6) to published studies (g = 0.52; 0.37~0.68; k = 20) reduced the psychotherapy effect size point estimate (g = 0.39; 0.08~0.70) by 25%. Moreover, these findings may overestimate the "true" effect of psychological treatment for depression as outcome reporting bias could not be examined quantitatively. CONCLUSION: The efficacy of psychological interventions for depression has been overestimated in the published literature, just as it has been for pharmacotherapy. Both are efficacious but not to the extent that the published literature would suggest. Funding agencies and journals should archive both original protocols and raw data from treatment trials to allow the detection and correction of outcome reporting bias. Clinicians, guidelines developers, and decision makers should be aware that the published literature overestimates the effects of the predominant treatments for depression. PMID- 26422605 TI - Defining treatment response in trichotillomania: a signal detection analysis. AB - The Massachusetts General Hospital Hairpulling Scale (MGH-HPS) and the NIMH Trichotillomania Severity Scale (NIMH-TSS) are two widely used measures of trichotillomania severity. Despite their popular use, currently no empirically supported guidelines exist to determine the degrees of change on these scales that best indicate treatment response. Determination of such criteria could aid in clinical decision-making by defining clinically significant treatment response/recovery and producing accurate power analyses for use in clinical trials research. Adults with trichotillomania (N=69) participated in a randomized controlled trial of psychotherapy and were assessed before and after treatment. Response status was measured via the Clinical Global Impressions-Improvement Scale, and remission status was measured via the Clinical Global Impressions Severity Scale. For treatment response, a 45% reduction or 7-point raw score change on the MGH-HPS was the best indicator of clinically significant treatment response, and on the NIMH-TSS, a 30-40% reduction or 6-point raw score difference was most effective cutoff. For disorder remission, a 55-60% reduction or 7-point raw score change on the MGH-HPS was the best predictor, and on the NIMH-TSS, a 65% reduction or 6-point raw score change was the best indicator of disorder remission. Implications of these findings are discussed. PMID- 26422608 TI - Ordered FePdCu nanoisland arrays made by templated solid-state dewetting. AB - Ordered FePdCu nanoisland arrays were formed by annealing at 600 degrees C, which caused solid state dewetting of [Cu/Fe/Pd] multilayers deposited on self assembled SiO2 nanospheres with a size of 100 nm. A single FePdCu island was formed on the top of each SiO2 nanosphere. The structure of the obtained system was studied by x-ray diffraction (XRD), while its magnetic properties were studied by SQUID magnetometry. A partially ordered L10 alloy appeared in the annealed films, leading to magnetic hardening of the material. The paper presents the influence of the patterning on the system properties. It is shown that templated dewetting is a method providing nanoislands with well-controlled sizes and positions. The role of copper admixture in controlling the structural and magnetic properties is also discussed. PMID- 26422607 TI - Replication Inhibition of Hepatitis B Virus and Hepatitis C Virus in Co-Infected Patients in Chinese Population. AB - BACKGROUND: Hepatitis B virus (HBV) and hepatitis C virus (HCV) co-infections contributes to a substantial proportion of liver disease worldwide. The aim of this study was to assess the clinical and virological features of HBV-HCV co infection. METHODS: Demographic data were collected for 3238 high-risk people from an HCV-endemic region in China. Laboratory tests included HCV antibody and HBV serological markers, liver function tests, and routine blood analysis. Anti HCV positive samples were analyzed for HCV RNA levels and subgenotypes. HBsAg positive samples were tested for HBV DNA. RESULTS: A total of 1468 patients had chronic HCV and/or HBV infections. Among them, 1200 individuals were classified as HCV mono-infected, 161 were classified as HBV mono-infected, and 107 were classified as co-infected. The HBV-HCV co-infected patients not only had a lower HBV DNA positive rate compared to HBV mono-infected patients (84.1% versus 94.4%, respectively; P < 0.001). The median HCV RNA levels in HBV-HCV co-infected patients were significantly lower than those in the HCV mono-infected patients (1.18[Interquartile range (IQR) 0-5.57] versus 5.87[IQR, 3.54-6.71] Log10 IU/mL, respectively; P < 0.001). Furthermore, co-infected patients were less likely to have detectable HCV RNA levels than HCV mono-infected patients (23.4% versus 56.5%, respectively; P < 0.001). Those HBV-HCV co-infected patients had significantly lower median HBV DNA levels than those mono-infected with HBV (1.97[IQR, 1.3-3.43] versus 3.06[IQR, 2-4.28] Log10 IU/mL, respectively; P < 0.001). The HBV-HCV co-infection group had higher ALT, AST, ALP, GGT, APRI and FIB-4 levels, but lower ALB and total platelet compared to the HBV mono-infection group, and similar to that of the HCV mono-infected group. CONCLUSION: These results suggest that co-infection with HCV and HBV inhibits the replication of both viruses. The serologic results of HBV-HCV co-infection in patients suggests more liver injury compared to HBV mono-infected patients, but is similar to HCV mono-infection. PMID- 26422606 TI - Analysis of Transmission of MRSA and ESBL-E among Pigs and Farm Personnel. AB - Livestock-associated bacteria with resistance to two or more antibiotic drug classes have heightened our awareness for the consequences of antibiotic consumption and spread of resistant bacterial strains in the veterinary field. In this study we assessed the prevalence of concomitant colonization with livestock associated methicillin-resistant Staphylococcus aureus (LA-MRSA) and enterobacteriaceae expressing extended-spectrum betalactamases (ESBL-E) in farms at the German-Dutch border region. Nasal colonization of pigs with MRSA (113/547 (20.7%)) was less frequent than rectal colonization with ESBL-E (163/540 (30.2%)). On the individual farm level MRSA correlated with ESBL-E recovery. The data further provide information on prevalence at different stages of pig production, including abattoirs, as well as in air samples and humans living and working on the farms. Notably, MRSA was detected in stable air samples of 34 out of 35 pig farms, highlighting air as an important MRSA transmission reservoir. The majority of MRSA isolates, including those from humans, displayed tetracycline resistance and spa types t011 and t034 characteristic for LA-MRSA, demonstrating transmission from pigs to humans. ESBL-E positive air samples were detected on 6 out of 35 farms but no pig-to-human transmission was found. Detection of ESBL-E, e.g. mostly Escherichia coli with CTX-M-type ESBL, was limited to these six farms. Molecular typing revealed transmission of ESBL-E within the pig compartments; however, related strains were also found on unrelated farms. Although our data suggest that acquisition of MRSA and ESBL-E might occur among pigs in the abattoirs, MRSA and ESBL-E were not detected on the carcasses. Altogether, our data define stable air (MRSA), pig compartments (ESBL E) and abattoir waiting areas (MRSA and ESBL-E) as major hot spots for transmission of MRSA and/or ESBL-E along the pig production chain. PMID- 26422609 TI - The Association of Maternal Lifestyle with Birth Defects in Shaanxi Province, Northwest China. AB - BACKGROUND: The main objective was to investigate the burden of birth defects among alive infants and explore the impact of maternal lifestyle during pregnancy on the burden of birth defects in Northwest China. METHODS: A stratified multi stage sampling method was used to study infants born during 2010-2013 (and their mothers) in Shaanxi province of Northwest China. Socio-demographic information was collected using a structured questionnaire, and medical records from the local hospitals were used to determine the final diagnosis of birth defects. Poisson regression analysis was performed to assess the association between maternal lifestyles during pregnancy and the burden of birth defects, while adjusting for potential confounders. RESULTS: We sampled 29098 infants, of whom 629 (i.e. 216.17 per 10000) were observed to have congenital defects. Cardiovascular system defects (77.32 per 10000) were found to be the most common. Mothers who had ever consumed alcohol during pregnancy were found to have infants with a higher prevalence of some categories of birth defects, including nervous system (Prevalence Rate Ratio, PRR:14.67, 95% CI: 1.94, 110.92), cardiovascular system (PRR:3.22, 95% CI: 1.02, 10.16) and oral clefts (PRR:9.02, 95% CI: 2.08, 39.10) in contrast to infants of mothers without any alcohol consumption. Maternal passive smoking during pregnancy lead to the increased burden of malformations of eye, ear, face and neck (PRR:1.95, 95% CI: 1.15, 3.33), cardiovascular system (PRR:1.70, 95% CI: 1.25, 2.31) and respiratory system (PRR:9.94, 95% CI: 2.37, 41.76) in their newborns. Further, tea or coffee consumption during pregnancy was positively correlated with the burden of specific birth defects, such as cardiovascular system (PRR: 2.44, 95% CI: 1.33, 4.46) and genital organs (PRR:14.72, 95% CI: 1.87, 116.11) among infants. CONCLUSIONS: The prevalence of birth defects was high in Shaanxi province of Northwest China. The unhealthy lifestyles of mothers during pregnancy may increase the prevalence of congenital malformations. These findings in future may have some important implications for prevention of birth defects in Northwest China. PMID- 26422610 TI - Activation of Spinal Stabilizers and Shoulder Complex Muscles During an Inverted Row Using a Portable Pull-up Device and Body Weight Resistance. AB - Youdas, JW, Keith, JM, Nonn, DE, Squires, AC, and Hollman, JH. Activation of spinal stabilizers and shoulder complex muscles during an inverted row using a portable pull-up device and body weight resistance. J Strength Cond Res 30(7): 1933-1941, 2016-We recorded muscle activation normalized to a maximum voluntary isometric contraction (% MVIC) during an inverted body weight row using a commercially available portable pull-up device. Surface electromyographic (EMG) analysis was conducted on 13 male and 13 female subjects performing 4 inverted row exercises: (a) pronated grip both feet weight-bearing (WB); (b) supinated grip both feet WB; (c) pronated grip one leg WB; and (d) supinated grip single leg WB. Nine muscles were analyzed: (a) posterior deltoid (PD), (b) latissimus dorsi (LD), (c) biceps brachii (BB), (d) lower trapezius (LT), (e) upper trapezius (UT), (f) lumbar multifidus (LM), (g) middle trapezius (MT), (h) lumbar thoracis (LTh), and (i) rectus abdominis (RA). Normalized peak EMG activity was examined separately for each muscle with 9 repeated measures analysis of variance (ANOVA) at alpha = 0.05. Post hoc comparisons of EMG activation across exercises for statistically significant ANOVAs were conducted with Bonferroni corrections for multiple comparisons. We observed statistically significant differences in EMG activation of the LD between supinated and pronated double-leg WB (p = 0.001) condition. Additionally, we found statistical significance in the UT between pronated and supinated single-leg WB (p = 0.007). No statistically significant differences in muscle activation existed between single- and double-leg WB in any muscles. Four muscles (BB, LD, LT, and PD) demonstrated very high (>61% MVIC) EMG activation during all 4 exercise conditions. Three muscles (UT, MT, and LM) demonstrated high (41-60% MVIC) activation, whereas 2 muscles (LTh and RA) demonstrated moderate (21-40% MVIC) activation. Four inverted row exercises activated the LD, UT, MT, LT, and BB at levels conducive to strengthening. PMID- 26422611 TI - The 400- and 800-m Track Running Induces Inspiratory Muscle Fatigue in Trained Female Middle-Distance Runners. AB - Inspiratory muscle fatigue (IMF) may limit exercise performance. A few studies have reported that IMF occurs after short-duration swimming exercise, but whether short-duration running can induce IMF remains unclear. Intra-abdominal pressure is increased during running through diaphragmatic activation to stabilize the spine during movements of the upper limbs. This occurs along with the increased inspiratory muscle effort associated with increased respirations during exercise; thus, we hypothesized that short-duration running exercise would induce IMF. To test this hypothesis, we measured maximal inspiratory pressure (MIP) before and after 400- and 800-m track running sessions. Eight female middle-distance (400, 800 m) runners performed a 400- and 800-m running test. Maximal inspiratory pressure was measured before and after each test using a portable autospirometer. The mean MIPs were significantly lower after running than before running; values obtained were 107 +/- 25 vs. 97 +/- 27 cmH2O (p = 0.01, effect size [ES] = 0.65) and 108 +/- 26 vs. 92 +/- 27 cmH2O (p = 0.01, ES = 0.74) before vs. after the 400 and 800-m tests, respectively. The mean MIP after the 800-m test was significantly lower than after the 400-m test (p = 0.04, ES = 0.48). There was no correlation between IMF value and running time (r = 0.53 and r = -0.28 for either the 400- and 800-m tests, respectively; p > 0.05). In conclusion, IMF occurs after short-duration running exercise. Coaches could consider prescribing inspiratory muscle training or warm-up in an effort to reduce the inevitable IMF associated with maximal effort running. PMID- 26422612 TI - Changes in Sprint and Jump Performances After Traditional, Plyometric, and Combined Resistance Training in Male Youth Pre- and Post-Peak Height Velocity. AB - The purpose of this study was to compare the effectiveness of 6-week training interventions using different modes of resistance (traditional strength, plyometric, and combined training) on sprinting and jumping performances in boys before and after peak height velocity (PHV). Eighty school-aged boys were categorized into 2 maturity groups (pre- or post-PHV) and then randomly assigned to (a) plyometric training, (b) traditional strength training, (c) combined training, or (d) a control group. Experimental groups participated in twice weekly training programs for 6 weeks. Acceleration, maximal running velocity, squat jump height, and reactive strength index data were collected pre- and postintervention. All training groups made significant gains in measures of sprinting and jumping irrespective of the mode of resistance training and maturity. Plyometric training elicited the greatest gains across all performance variables in pre-PHV children, whereas combined training was the most effective in eliciting change in all performance variables for the post-PHV cohort. Statistical analysis indicated that plyometric training produced greater changes in squat jump and acceleration performances in the pre-PHV group compared with the post-PHV cohort. All other training responses between pre- and post-PHV cohorts were not significant and not clinically meaningful. The study indicates that plyometric training might be more effective in eliciting short-term gains in jumping and sprinting in boys who are pre-PHV, whereas those who are post-PHV may benefit from the additive stimulus of combined training. PMID- 26422613 TI - Influence of Load Carriage on High-Intensity Running Performance Estimation. AB - Load carriage is a necessary burden for tactical athletes. A combination of training modes, including aerobic conditioning and progressive load carriage, may lead to improved performance. The critical speed (CS) concept enables the practitioner to prescribe high-intensity interval training (HIIT) time limits (TLIMs) from a single 3-minute all-out exercise test (3 MT). We sought to examine the effect of a standard load carriage (18.86 kg) on CS and the finite running capacity > CS (D'). A group of trained subjects (age: 26 +/- 5 years, height: 181 +/- 4 cm, body mass [BM]: 90 +/- 14 kg) completed a loaded and unloaded (UL) 3 MT. The CS was reduced by 0.66 +/- 0.24 m.s (p < 0.01) in the loaded condition. There was a small nonsignificant increase in D' (21.25 +/- 39.53 m, p = 0.07). The higher the % load carriage relative to BM is, the greater decline in CS (r = 0.83, p < 0.01). A revised CS with load carriage from the UL 3 MT may be calculated using: adjusted CS = original CS + ([-0.0638 * %load]) + 0.6982. Our results indicate that revised CS and TLIMs for fixed distance, fixed time, or fixed speed HIIT prescriptions may be derived from a UL 3 MT. Such calculations would enable more expeditious training for tactical athletes. We recommend further research involving implementation of HIIT using this new method. PMID- 26422614 TI - Modeling and Analyzing the Transmission Dynamics of HBV Epidemic in Xinjiang, China. AB - Hepatitis B is an infectious disease caused by the hepatitis B virus (HBV) which affects livers. In this paper, we formulate a hepatitis B model to study the transmission dynamics of hepatitis B in Xinjiang, China. The epidemic model involves an exponential birth rate and vertical transmission. For a better understanding of HBV transmission dynamics, we analyze the dynamic behavior of the model. The modified reproductive number sigma is obtained. When sigma < 1, the disease-free equilibrium is locally asymptotically stable, when sigma > 1, the disease-free equilibrium is unstable and the disease is uniformly persistent. In the simulation, parameters are chosen to fit public data in Xinjiang. The simulation indicates that the cumulated HBV infection number in Xinjiang will attain about 600,000 cases unless there are stronger or more effective control measures by the end of 2017. Sensitive analysis results show that enhancing the vaccination rate for newborns in Xinjiang is very effective to stop the transmission of HBV. Hence, we recommend that all infants in Xinjiang receive the hepatitis B vaccine as soon as possible after birth. PMID- 26422616 TI - Clarification of the Identity of the Tea Green Leafhopper Based on Morphological Comparison between Chinese and Japanese Specimens. AB - Tea green leafhopper is one of the most dominant pests in major tea production regions of East Asia. This species has been variously identified as Empoasca vitis (Goethe), Jacobiasca formosana (Paoli) and Empoasca onukii Matsuda in Mainland China, Taiwan and Japan, respectively. Recent study of DNA sequence data suggested that treatment of this pest as different species in these three adjacent regions is incorrect and that they were a single species; but the correct scientific name for the species has remained unclear. Consistent with the prior molecular evidence, morphological study shows that the male genital characters of Chinese specimens are the same as those of specimens from Japan, so the correct scientific name of tea green leafhopper in China is Empoasca (Matsumurasca) onukii Matsuda. PMID- 26422615 TI - The Influence of Second-Hand Cigarette Smoke Exposure during Childhood and Active Cigarette Smoking on Crohn's Disease Phenotype Defined by the Montreal Classification Scheme in a Western Cape Population, South Africa. AB - BACKGROUND: Smoking may worsen the disease outcomes in patients with Crohn's disease (CD), however the effect of exposure to second-hand cigarette smoke during childhood is unclear. In South Africa, no such literature exists. The aim of this study was to investigate whether disease phenotype, at time of diagnosis of CD, was associated with exposure to second-hand cigarette during childhood and active cigarette smoking habits. METHODS: A cross sectional examination of all consecutive CD patients seen during the period September 2011-January 2013 at 2 large inflammatory bowel disease centers in the Western Cape, South Africa was performed. Data were collected via review of patient case notes, interviewer administered questionnaire and clinical examination by the attending gastroenterologist. Disease phenotype (behavior and location) was evaluated at time of diagnosis, according to the Montreal Classification scheme. In addition, disease behavior was stratified as 'complicated' or 'uncomplicated', using predefined definitions. Passive cigarette smoke exposure was evaluated during 3 age intervals: 0-5, 6-10, and 11-18 years. RESULTS: One hundred and ninety four CD patients were identified. Cigarette smoking during the 6 months prior to, or at time of diagnosis was significantly associated with ileo-colonic (L3) disease (RRR = 3.63; 95% CI, 1.32-9.98, p = 0.012) and ileal (L1) disease (RRR = 3.54; 95% CI, 1.06-11.83, p = 0.040) compared with colonic disease. In smokers, childhood passive cigarette smoke exposure during the 0-5 years age interval was significantly associated with ileo-colonic CD location (RRR = 21.3; 95% CI, 1.16 391.55, p = 0.040). No significant association between smoking habits and disease behavior at diagnosis, whether defined by the Montreal scheme, or stratified as 'complicated' vs 'uncomplicated', was observed. CONCLUSION: Smoking habits were associated with ileo-colonic (L3) and ileal (L1) disease at time of diagnosis in a South African cohort. PMID- 26422618 TI - Reusing and recycling dialysis reverse osmosis system reject water. PMID- 26422620 TI - Klotho upregulation by rapamycin protects against vascular disease in CKD. AB - Medial arterial calcification involves chondrogenic/osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Zhao et al. report that phosphate activates the mammalian target of rapamycin (mTOR) cascade in VSMCs, leading to downregulation of Klotho. Furthermore, rapamycin was shown to halt medial calcification. This effect was blunted in the absence of Klotho. Given the concomitant anti-atherosclerotic effects of the mTOR inhibitor, this agent has clinical potential as an inhibitor of intimal atherosclerosis and medial calcification. PMID- 26422621 TI - Relevance of TNF-alpha in the context of other inflammatory cytokines in the progression of diabetic nephropathy. AB - An ancillary paradigm that has evolved recently in the pathogenesis of diabetic nephropathy includes subclinical microinflammation with influx of macrophages and consequent generation of myriad proinflammatory cytokines and ensuing kidney damage. Among various proinflammatory cytokines, tumor necrosis factor-alpha (TNF alpha) has attracted the most attention, since it amplifies the inflammatory network of cytokines, leading to worsening of the progression of diabetic nephropathy. The article by Awad et al. examines the role of TNF-alpha in the pathogenesis of experimental diabetic nephropathy. PMID- 26422622 TI - Epigenetic regulation in acute kidney injury: new light in a dark area. AB - Epigenetic mechanisms have been implicated in the pathogenesis of renal diseases, including acute kidney injury (AKI). Mar et al. now unravel the acetylation and methylation at histones that are associated with the transcription of key genes in AKI. Notably, histone modifications display a remarkable heterogeneity in ischemic and endotoxic AKI. Targeting epigenetic programs may offer novel strategies to protect kidneys from AKI and enhance kidney repair and recovery. PMID- 26422623 TI - Epigenetic control of podocyte differentiation: a new target of the renin angiotensin system in kidney disease. AB - Glomerular podocyte integrity is essential to limit protein filtration in the urine. Hayashi et al. report that epigenetic mechanisms control podocyte differentiation and that activation of the renin-angiotensin system in kidney disease affects podocyte differentiation and proteinuria by resetting the podocyte epigenome. These findings suggest that modulation of DNA methylation could be a promising target for the control of proteinuric kidney disease. PMID- 26422624 TI - Does early-start renal replacement therapy improve outcomes for patients with acute kidney injury? AB - There is a paucity of high-quality evidence to guide clinicians on thresholds for commencement of renal replacement therapy (RRT) in critically ill patients with acute kidney injury (AKI), and wide international practice variation. Wald et al. report a pilot randomized trial examining accelerated use of RRT for moderate AKI in the intensive care unit, providing a workable design for a definitive trial examining the timing of RRT in critical illness. PMID- 26422625 TI - Oral or intravenous iron for anemia correction in chronic kidney disease? AB - Iron deficiency in patients with chronic kidney disease (CKD) can be corrected by the oral or intravenous route. The natural intestinal barrier against iron overload is circumvented by intravenous iron. The balance between benefit and risk of high iron doses remains unclear. In a randomized controlled trial in CKD patients, Agarwal et al. find similar effects of oral and intravenous iron on hemoglobin levels and kidney function decline but more serious cardiovascular events and infections with intravenous iron. PMID- 26422626 TI - Re: Microparticles: markers and mediators of sepsis-induced microvascular dysfunction, immunosuppression, and AKI. PMID- 26422627 TI - The Authors Reply. PMID- 26422628 TI - The bumpy lumpy kidney that dumped protein: granulomatous glomerular and tubulointerstitial nephritis. PMID- 26422629 TI - Pincer nails following arteriovenous fistula creation. PMID- 26422630 TI - Oxalate nephropathy: a three-dimensional view. PMID- 26422631 TI - Hyponatremia in a patient with obstructive jaundice. PMID- 26422632 TI - Acute kidney injury after Chernobyl. PMID- 26422633 TI - APACHE III Outcome Prediction in Patients Admitted to the Intensive Care Unit with Sepsis Associated Acute Lung Injury. AB - BACKGROUND AND OBJECTIVE: Acute Physiology and Chronic Health Evaluation (APACHE) III score has been widely used for prediction of clinical outcomes in mixed critically ill patients. However, it has not been validated in patients with sepsis-associated acute lung injury (ALI). The aim of the study was to explore the calibration and predictive value of APACHE III in patients with sepsis associated ALI. METHOD: The study was a secondary analysis of a prospective randomized controlled trial investigating the efficacy of rosuvastatin in sepsis associated ALI (Statins for Acutely Injured Lungs from Sepsis, SAILS). The study population was sepsis-related ALI patients. The primary outcome of the current study was the same as in the original trial, 60-day in-hospital mortality, defined as death before hospital discharge, censored 60 days after enrollment. Discrimination of APACHE III was assessed by calculating the area under the receiver operating characteristic (ROC) curve (AUC) with its 95% CI. Hosmer Lemeshow goodness-of-fit statistic was used to assess the calibration of APACHE III. The Brier score was reported to represent the overall performance of APACHE III in predicting outcome. MAIN RESULTS: A total of 745 patients were included in the study, including 540 survivors and 205 non-survivors. Non-survivors were significantly older than survivors (59.71 +/- 16.17 vs 52.00 +/- 15.92 years, p < 0.001). The primary causes of ALI were also different between survivors and non survivors (p = 0.017). Survivors were more likely to have the cause of sepsis than non-survivors (21.2% vs. 15.1%). APACHE III score was higher in non survivors than in survivors (106.72 +/- 27.30 vs. 88.42 +/- 26.86; p < 0.001). Discrimination of APACHE III to predict mortality in ALI patients was moderate with an AUC of 0.68 (95% confidence interval: 0.64-0.73). CONCLUSION: this study for the first time validated the discrimination of APACHE III in sepsis associated ALI patients. The result shows that APACHE III score has moderate predictive value for in-hospital mortality among adults with sepsis-associated acute lung injury. PMID- 26422634 TI - Profile and Determinants of Neurocognitive Dysfunction in a Sample of Adult Nigerians With Heart Failure. AB - BACKGROUND: Heart failure (HF) in Africans is peculiar because subjects are younger than whites and have lower socioeconomic and educational level in addition to the high prevalence of hypertension-related etiology and increased mortality. Whereas cognitive dysfunction have been demonstrated among whites with HF, the prevalence and pattern of cognitive dysfunction among sub-Saharan African patients with HF have not been evaluated against this background. OBJECTIVES: The aim of this study is to determine the 1-year prevalence and the factors contributing to cognitive dysfunction in a cohort of Nigerian patients with HF. MATERIALS AND METHODS: In this cross-sectional case-control study, cognitive performance was evaluated in 111 consecutive individuals (60 HF patients and 51 controls matched for age, gender, and level of education) using the Community Screening Interview for Dementia, Word List Learning Delayed Recall, Boston Naming Test, and Modified Token Test. Other clinical and disease-specific variables were collated and correlated with cognitive performance. RESULTS: The mean total Community Screening Interview for Dementia, Word List Learning Delayed Recall, Boston Naming Test, and Modified Token Test scores were significantly lower among HF patients (P = < .001). The prevalence of global cognitive dysfunction was 90.0% in HF and 5.9% among controls (odds ratio, 15.3; 95% confidence interval, 5.08-46.01). Elevated systolic blood pressure, increased comorbidity index, and wide pulse pressure were significantly associated with poorer performance on at least 1 neuropsychological test. Using a multivariate linear regression analysis, pulse pressure retained its significance (P = .029; 95% confidence interval, -0.117 to -0.007) as the most important predictor of cognitive dysfunction in the cohort of HF patients. CONCLUSION: Cognitive dysfunction is prevalent among this sample of Nigerians with HF. Regular cognitive screening is therefore advocated among this high-risk group. Controlling comorbidities as well as blood pressure may improve cognitive performance among patients with HF. PMID- 26422635 TI - Is Knowledge Level of Coronary Heart Disease and Risk Factors Among Post Percutaneous Coronary Intervention Patients Adequate? AB - BACKGROUND: Percutaneous coronary intervention (PCI) is now commonly used in the treatment of coronary heart disease. However, shorter hospital stays after intervention may affect patients' knowledge and subsequent required lifestyle changes. OBJECTIVE: The aim of this study is to investigate participants' risk factor profile, knowledge of coronary heart disease, and the influence of demographic and risk factors on this knowledge. METHODS: This prospective, cross sectional 1-site study recruited both elective and emergency PCI patients postdischarge. The questionnaire collected data on demographics, risk factor profile, and coronary heart disease knowledge as measured on the Bergman Heart Disease Knowledge Questionnaire. Bivariate and multivariate analyses were used to analyze the influence of 11 risk and sociodemographic factors on knowledge. RESULTS: The response rate was 67% (n = 84). The sample was mostly male and aged 65.79 +/- 9.9 years, and 59% had an elective PCI. Risk factor burden was high; 2 or more risk factors were seen in 66% of participants. Mean knowledge score overall was 51%, with the highest score achieved in the risk factor domain (61%). Lowest scores were in the medical and symptoms domains (both 46%). Neither the bivariate nor the multivariate analyses were significant. A large proportion of patients believed that coronary heart disease was no longer a concern for them after PCI. CONCLUSIONS: As expected, the risk factor profile of post-PCI patients was high. However, their knowledge levels and awareness were unrelated to risk factor profile and poor in comparison with studies in other cardiac patients. This, in addition to the short stay in hospital and the low attendance of this cohort at cardiac rehabilitation, identifies this group of patients as a priority for further targeted education. Innovations are needed to increase knowledge and begin behavioral change predischarge after PCI. This should include target and goal setting for lifestyle change to avail of this critical education opportunity. PMID- 26422636 TI - Falls in Patients With Heart Failure: A Systematic Review. AB - BACKGROUND: Many heart failure patients show fall-related signs/symptoms including postural hypotension, cerebellar injury, and cognitive impairments. Falls contribute to injuries, increased healthcare use, and death, but falls have been understudied in this population. OBJECTIVE: The purpose of this review is to identify fall rates, fall injuries, and risk factors for falls in heart failure patients. METHODS: A systematic literature review was conducted using MEDLINE, CINAHL, PubMed, PsycINFO, and Cochrane Library to identify publications from August 1973 to June 2013. Keywords were accidental falls, heart failure, fall rates, fall injuries, and fall risk. Inclusion criteria were publications that were primary data based, included heart failure sample, had falls/fall risk as study variables, and were written in English language. Exclusion criteria were quality improvement/evaluation, case reports/studies, news, opinions, narrative reviews, meeting reports, reflections, and letters to editors. Data were abstracted using a standardized data collection form. RESULTS: Four publications met the inclusion criteria. In the first study, fall rate was 43%, which is higher than the fall rates among community-dwelling older adults. Fall-related injuries were not examined in any of studies. Benzodiazepines and digoxin were identified as medications that increased risk of falls in 1 case-control study. Loop diuretics were not significantly associated with falls in 1 cohort study. In the fourth study, patients who had poor gait and balance were at greater risk of falling. CONCLUSIONS: Future studies are needed to determine factors associated with falls, characterize injuries resulting from falls, and most importantly design testable interventions to prevent falls in heart failure patients. PMID- 26422637 TI - A Ventricular Assist Device Recipient and Suicidality: Multidisciplinary Collaboration With a Psychiatrically Distressed Patient. AB - BACKGROUND: Ventricular assist device (VAD) recipients are at high risk of depression and anxiety, and poor psychosocial functioning is associated with worse medical outcomes. PURPOSE: We present a case of a 31-year-old depressed patient who demonstrated passive suicidal behavior through multiple episodes of noncompliance, including temporarily discontinuing warfarin (Coumadin) several months after VAD implantation. The patient's psychosocial and medical histories and outcomes are presented. CONCLUSIONS: This case underscores the importance of pre-VAD as well and ongoing psychosocial evaluation and management for this unique patient population. CLINICAL IMPLICATIONS: Medical teams who are treating patients with cardiovascular disease who are under consideration for VAD or heart transplantation need to be aware of the multitude of ways in which patients can express depressed and suicidal mood and work with a multidisciplinary team to treat such symptoms to optimize patients' success with VAD/heart transplantation. PMID- 26422638 TI - Cardiac Rehabilitation Online Pilot: Extending Reach of Cardiac Rehabilitation. AB - BACKGROUND: While cardiac rehabilitation (CR) is recommended for all patients after an acute cardiac event, limitations exist in reach. OBJECTIVE: The purpose of the current study was to develop and pilot a flexible online CR program based on self-management principles "Help Yourself Online." METHODS: The program was designed as an alternative to group-based CR as well as to complement traditional CR. The program was based on existing self-management resources developed previously by the Heart Research Centre. Twenty-one patients admitted to Cabrini Health for an acute cardiac event were recruited to test the program. The program was evaluated using qualitative and quantitative methods. RESULTS: Quantitative results demonstrated that patients believed the program would assist them in their self-management. Qualitative evaluation, using focus group and interview methods with 15 patients, showed that patients perceived the online CR approach to be a useful instrument for self-management. CONCLUSIONS: Broader implications of the data include the acceptability of the intervention, timing of intervention delivery, and patients' desire for additional online community support. PMID- 26422639 TI - Comorbidities and Psychosocial Characteristics as Determinants of Dropout in Outpatient Cardiac Rehabilitation. AB - BACKGROUND: Despite the clear benefits of cardiac rehabilitation (CR), a considerable number of patients drop out early. OBJECTIVE: Therefore, we wanted to evaluate dropout in CR with a special focus on comorbidities and psychosocial background. METHODS: Patients who attended CR after acute coronary syndrome, cardiac surgery, or heart failure (N = 489) were prospectively included. Dropout was defined as attending 50% of the training sessions or less (n = 96 [20%]). Demographic and clinical characteristics, exercise parameters, and psychosocial factors were analyzed according to dropout, and those with a trend toward a significant difference (P < .10) were entered in a multivariate logistic model. RESULTS: The presence of a cerebrovascular accident (4.18 [1.39-12.52]) involved a higher risk of dropout, and a comparable trend was seen for the presence of chronic obstructive pulmonary disease (2.55 [0.99-6.54]). Attending the training program only twice per week also implicated a higher risk of an early withdrawal (3.76 [2.23-6.35]). In contrast, patients on beta-blockers were less likely to withdraw prematurely (0.47 [0.22-0.98]). Singles were more likely to drop out (2.89 [1.56-5.35]), as well as those patients who were dependent on others to get to CR (2.01 [1.16-3.47]). Finally, the reporting of severe problems on the anxiety/depression subscale of the EuroQOL-5D questionnaire involved a higher odds for dropout (7.17 [1.46-35.29]). CONCLUSIONS: Neither demographic characteristics nor clinical status or exercise capacity could independently identify patients who were at risk of dropout. The presence of comorbidities and a vulnerable psychosocial background rather seem to play a key role in dropout. PMID- 26422641 TI - Synthesis of alpha,beta-Unsaturated N-Sulfonyl Imides through Zinc-Catalyzed Intermolecular Oxidation of N-Sulfonyl Ynamides. AB - A novel zinc-catalyzed intermolecular oxidation of N-sulfonyl ynamides has been developed. A variety of functionalized alpha,beta-unsaturated N-sulfonyl imides are readily accessed by utilizing this approach, thus providing a viable alternative to synthetically useful alpha,beta-unsaturated imides. Importantly, the reaction is proposed to proceed by a vinyligous E2-type elimination pathway, but not metal carbene pathway. PMID- 26422640 TI - A Randomized Feasibility Trial of a New Lifestyle Referral Assessment Versus Usual Assessment in an Acute Cardiology Setting. AB - BACKGROUND: A healthy diet, taking exercise, and not smoking or consuming alcohol in excess are important to reduce the risk of cardiovascular disease either alone or in combination with statin medication. Health education, including providing information to patients on healthy living and guidance on how to achieve it, is a key nursing function. OBJECTIVES: This study aims first to assess the feasibility of conducting a full-scale trial of lifestyle referral assessment as shown by recruitment rate, data collection, and follow-up and second to assess proof of concept and explore possible mechanisms of change. METHODS: This was a single center, randomized, 2-arm, parallel-group, unblinded feasibility trial conducted in an acute teaching hospital trust. Participants were followed up at 3 and 6 months after randomization. RESULTS: Eight hundred eighty-seven patients were screened for eligibility, of whom 132 (15%) were randomized into the trial. Of the patients allocated to the individualized assessment, 27% accepted referral or self-referred by 3 months in comparison to 5% allocated to the usual assessment. CONCLUSIONS: We demonstrated that a full-scale trial is feasible and that an individualized approach increased the number of patients accepting referral to a formal program and initiating lifestyle change. However, we should consider the aim of the assessment and ways in which the process of change can be optimized in order to produce long-term benefit for patients. TRIAL REGISTRATION: current controlled trials ISRCTN41781196. PMID- 26422642 TI - Dynamic Cross-Linking of Polymeric Binders Based on Host-Guest Interactions for Silicon Anodes in Lithium Ion Batteries. AB - We report supramolecular cross-linking of polymer binders via dynamic host-guest interactions between hyperbranched beta-cyclodextrin polymer and a dendritic gallic acid cross-linker incorporating six adamantane units for high-capacity silicon anodes. Calorimetric analysis in the solution phase indicates that the given host-guest complexation is a highly spontaneous and enthalpically driven process. These findings are further verified by carrying out gelation experiments in both aqueous and organic media. The dynamic cross-linking process enables intimate silicon-binder interaction, structural stability of electrode film, and controlled electrode-electrolyte interface, yielding enhanced cycling performance. Control experiments using both alpha, gamma-CDp with different cavity sizes and a guest molecule incorporating a single adamantane unit verified that the enhanced cycle life originates from the host-guest interaction between beta-cyclodextrin and adamantane. The impact of the dynamic cross-linking is maximized at an optimal stoichiometry between the two components. Importantly, the present investigation proves that the molecular-level tuning of the host guest interactions can be translated directly to the cycling performance of silicon anodes. PMID- 26422643 TI - Interaction at the silicon/transition metal oxide heterojunction interface and its effect on the photovoltaic performance. AB - The interfacial reaction and energy level alignment at the Si/transition metal oxide (TMO, including MoO3-x, V2O5-x, WO3-x) heterojunction are systematically investigated. We confirm that the interfacial reaction appears during the thermal deposition of TMO, with the reaction extent increasing from MoO3-x, to V2O5-x, and to WO3-x. The reaction causes the surface oxidation of silicon for faster electron/hole recombination, and the reduction of TMO for effective hole collection. The photovoltaic performance of the Si/TMO heterojunction devices is affected by the interface reaction. MoO3-x are the best hole selecting materials that induce least surface oxidation but strongest reduction. Compared with H passivation, methyl group passivation is an effective way to reduce the interface reaction and improve the interfacial energy level alignment for better electron and hole collection. PMID- 26422644 TI - Reforming the Veterans Health Administration--Beyond Palliation of Symptoms. PMID- 26422645 TI - Challenges for Medicare at 50. PMID- 26422646 TI - Hypoxia Differentially Modulates the Genomic Stability of Clinical-Grade ADSCs and BM-MSCs in Long-Term Culture. AB - Long-term cultures under hypoxic conditions have been demonstrated to maintain the phenotype of mesenchymal stromal/stem cells (MSCs) and to prevent the emergence of senescence. According to several studies, hypoxia has frequently been reported to drive genomic instability in cancer cells and in MSCs by hindering the DNA damage response and DNA repair. Thus, we evaluated the occurrence of DNA damage and repair events during the ex vivo expansion of clinical-grade adipose-derived stromal cells (ADSCs) and bone marrow (BM)-derived MSCs cultured with platelet lysate under 21% (normoxia) or 1% (hypoxia) O2 conditions. Hypoxia did not impair cell survival after DNA damage, regardless of MSC origin. However, ADSCs, unlike BM-MSCs, displayed altered gammaH2AX signaling and increased ubiquitylated gammaH2AX levels under hypoxic conditions, indicating an impaired resolution of DNA damage-induced foci. Moreover, hypoxia specifically promoted BM-MSC DNA integrity, with increased Ku80, TP53BP1, BRCA1, and RAD51 expression levels and more efficient nonhomologous end joining and homologous recombination repair. We further observed that hypoxia favored mtDNA stability and maintenance of differentiation potential after genotoxic stress. We conclude that long-term cultures under 1% O2 were more suitable for BM-MSCs as suggested by improved genomic stability compared with ADSCs. PMID- 26422647 TI - Freeze-Drying of L-Arginine/Sucrose-Based Protein Formulations, Part 2: Optimization of Formulation Design and Freeze-Drying Process Conditions for an L Arginine Chloride-Based Protein Formulation System. AB - We recently reported that the presence of chloride counter ions in freeze-dried l arginine/sucrose formulations provided the greatest protein stability, but led to low collapse temperatures and glass transition temperatures of the freeze concentrates. The objectives of this study were to identify l-arginine chloride based formulations and optimize freeze-drying process conditions to deliver a freeze-dried product with good physical quality attributes (including cake appearance, residual moisture, and reconstitution time). Additional properties were tested such as thermal properties, cake microstructure, and protein physical stability. Excipient concentrations were varied with and without a model protein (bovine serum albumin, BSA). Formulations were frozen with and without annealing or with and without controlled nucleation. Primary drying was conducted at high and low shelf temperature. Cakes with least defects and optimum physical attributes were achieved when protein to excipient ratios were high. Controlled nucleation led to elegant cakes for most systems at a low shelf temperature. Replacing BSA by a monoclonal antibody showed that protein (physical) stability was slightly improved under stress storage temperature (i.e., 40 degrees C) in the presence of a low concentration of l-arginine in a sucrose-based formulation. At higher l-arginine concentrations, cake defects increased. Using optimized formulation design, addition of l-arginine chloride to a sucrose-based formulation provided elegant cakes and benefits for protein stability. PMID- 26422648 TI - Clinic and Emergency Room Evaluation and Testing of Headache. AB - BACKGROUND: Evaluation of the headache patient in the outpatient clinic and emergency department (ED) has different focuses and goals. The focus of this paper is to review the evaluation of patients in both settings with mention of evaluation in the pediatric and pregnant patient population. The patient's history should drive the practitioner's decision and evaluation choices. We review recommendations made by the American Board of Internal Medicine and American Headache Society through the Choosing Wisely Campaign, which has an emphasis on choosing the right imaging modality for the clinical situation and elimination/prevention of medication overuse headache, as well as the US Headache Consortium guidelines for migraine headache. We will also review focusing on ED evaluation of the pediatric patient and pregnant patient presenting with headache. CONCLUSION: At the end of the review we hope to have provided you with a framework to think about the headache patient and what is the appropriate test in the given clinical setting in order to ensure that the patient gets the right diagnosis and is set on a path to the appropriate management plan. PMID- 26422649 TI - Fentanyl Patches to Supplement Ultrasound-Guided Nerve Blocks for Improving Pain Control After Foot and Ankle Surgery: A Prospective Study. AB - The analgesic effects of preoperative ultrasound-guided nerve blocks wear off after about 12 hours, leaving some patients in substantial pain. Transdermal fentanyl concentrations peak at 12 to 24 hours after application and maintain this concentration for approximately 72 hours. We sought to determine whether combining the use of a transdermal fentanyl patch with either a sciatic or femoral-sciatic nerve block would improve pain control in patients undergoing foot and/or ankle surgery. Consecutive patients in the no-patch control group (n = 104) were enrolled from July 2011 to October 2011, and those in the treatment group (n = 232) were enrolled from November 2011 to May 2012 and received a transdermal patch (4.125 mg/7.5 cm(2) releasing 25 MUg of fentanyl per hour) applied to their chest postoperatively. Pain was assessed using a visual analog scale at 6, 12, 24, and 48 hours after surgery. The primary outcome measure was the number of requests for additional postoperative pain medication. Additional postoperative analgesia was requested by 49 of the 104 control patients (47.1%) and 63 of the 232 treated patients (27.1%; p = .002). The mean pain scores were also lower in the treatment group, with a statistically significant difference (p < .05) at 12, 24, and 48 hours. Thus, patients receiving a fentanyl patch combined with an ultrasound-guided nerve block required less supplemental analgesia to maintain adequate pain control than did those receiving a nerve block alone. In conclusion, a fentanyl patch is a useful adjunct to an ultrasound guided nerve block in foot and ankle surgery. PMID- 26422650 TI - The Gift Box Open Achilles Tendon Repair Method: A Retrospective Clinical Series. AB - Previous biomechanical studies have shown that the gift box technique for open Achilles tendon repair is twice as strong as a Krackow repair. The technique incorporates a paramedian skin incision with a midline paratenon incision, and a modification of the Krackow stitch is used to reinforce the repair. The wound is closed in layers such that the paratenon repair is offset from paramedian skin incision, further protecting the repair. The present study retrospectively reviews the clinical results for a series of patients who underwent the gift box technique for treatment of acute Achilles tendon ruptures from March 2002 to April 2007. The patients completed the Foot Function Index and the American Orthopaedic Foot and Ankle Society ankle-hindfoot scale. The tendon width and calf circumference were measured bilaterally and compared using paired t tests with a 5% alpha level. A total of 44 subjects, mean age 37.5 +/- 8.6 years, underwent surgery approximately 10.8 +/- 6.5 days after injury. The response rate was 35 (79.54%) patients for the questionnaire and 20 (45.45%) for the examination. The mean follow-up period was 35.7 +/- 20.1 months. The complications included one stitch abscess, persistent pain, and keloid formation. One (2.86%) respondent reported significant weakness. Five (14.29%) respondents indicated persistent peri-incisional numbness. The range of motion was full or adequate. The mean American Orthopaedic Foot and Ankle Society ankle-hindfoot scale score was 93.2 +/- 6.8) and the mean Foot Function Index score was 7.0 +/- 10.5. The calf girth and tendon width differences were statistically significantly between the limbs. The patients reported no repeat ruptures, sural nerve injuries, dehiscence, or infections. We present the outcomes data from patients who had undergone this alternative technique for Achilles tendon repair. The technique is reproducible, with good patient satisfaction and return to activity. The results compared well with the historical repeat rupture rates and incidence of nerve injury and dehiscence for open and percutaneous Achilles tendon repairs. PMID- 26422651 TI - MAP4K4 Is a Threonine Kinase That Phosphorylates FARP1. AB - Mitogen-activated protein kinase 4 (MAP4K4) regulates the MEK kinase cascade and is implicated in cytoskeletal rearrangement and migration; however, identifying MAP4K4 substrates has remained a challenge. To ascertain MAP4K4-dependent phosphorylation events, we combined phosphoproteomic studies of MAP4K4 inhibition with in vitro assessment of its kinase specificity. We identified 235 phosphosites affected by MAP4K4 inhibition in cells and found that pTP and pSP motifs were predominant among them. In contrast, in vitro assessment of kinase specificity showed that MAP4K4 favors a pTL motif. We showed that MAP4K4 directly phosphorylates and coimmunoprecipitates with FERM, RhoGEF, and pleckstrin domain containing protein 1 (FARP1). MAP4K4 inhibition in SH-SY5Y cells increases neurite outgrowth, a process known to involve FARP1. As FARP1 and MAP4K4 both contribute to cytoskeletal rearrangement, the results suggest that MAP4K4 exerts some of its effects on the cytoskeleton via phosphorylation of FARP1. PMID- 26422653 TI - The effect of late infection and antibiotic treatment on capsular contracture in silicone breast implants: A rat model. AB - BACKGROUND: The effect of late infection on capsular contracture has yet to be established, leaving a gap in clinical guidelines for the treatment patients with breast implants. This trial is the first to assess if the treatment of these infections can reverse this effect in an in vivo rat model and whether late distant infections increase the incidence of capsular contracture. MATERIALS AND METHODS: Three groups of female Wistar rats (n = 42) received two silicone implants in separate dorsal, subcutaneous pockets. All groups except control underwent injection of a human strain of methicillin-sensitive Staphylococcus aureus (MSSA) at least 30 days after implantation, allowing for physiologic capsule formation. The infection group received a peritoneal injection, inducing a transient bacteremia, the treated group received a course of antibiotics following bacterial inoculation, and a final group received no intervention and served as control. RESULTS: Implants were removed 4 months after insertion, and capsules measured for thickness and sent for bacterial quantification. Compared to both the control and treated groups, capsule thickness in the infection group was statistically greater (p < 0.05), a difference not observed between treated and control groups. In addition, a statistically significant positive correlation was found between capsule thickness and bacterial count (R = 0.614, p < 0.01). CONCLUSIONS: The difference in thickness between the control capsules and those from the infection group is an indication that bacterial contamination of a capsule from a remote late infection may increase the incidence of capsular contracture suggesting that treating late infections could in fact prevent capsular contracture. PMID- 26422652 TI - Nanotechnology and regenerative therapeutics in plastic surgery: The next frontier. AB - The rapid ascent of nanotechnology and regenerative therapeutics as applied to medicine and surgery has seen an exponential rise in the scale of research generated in this field. This is evidenced not only by the sheer volume of papers dedicated to nanotechnology but also in a large number of new journals dedicated to nanotechnology and regenerative therapeutics specifically to medicine and surgery. Aspects of nanotechnology that have already brought benefits to these areas include advanced drug delivery platforms, molecular imaging and materials engineering for surgical implants. Particular areas of interest include nerve regeneration, burns and wound care, artificial skin with nanoelectronic sensors and head and neck surgery. This study presents a review of nanotechnology and regenerative therapeutics, with focus on its applications and implications in plastic surgery. PMID- 26422654 TI - Analysis of the vertical mammaplasty design in skin-sparing mastectomy and immediate autologous reconstruction. AB - BACKGROUND: Skin-sparing mastectomy designs for immediate autologous breast reconstruction include racquet, Wise, and vertical mammaplasty incisions. The vertical design addresses ptosis while maintaining viable skin flaps. This study compares the racquet to the vertical incision. METHODS: Immediate skin-sparing autologous breast reconstructions by a single surgeon using either vertical or racquet incisions from August 2006 to September 2011 were analyzed. Aesthetic scoring was based on a Likert-scale assessment of scar appearance, shape, preoperative versus postoperative aesthetic comparison, and overall aesthetic outcome. Responses were analyzed using the Mann-Whitney test. RESULTS: Seventy seven patients (48 racquets and 29 vertical) were included. Patient demographics and complications did not differ. Vertical design reconstructions were used for patients with higher-grade ptosis (p < 0.001). Significantly better-appearing scars (3.8 vs. 3.5; p = 0.04) were observed in the vertical group. Vertical reconstructions showed a trend toward significance in cosmetic improvement compared with preoperative appearance (3.2 vs. 3.0; p = 0.06). There was no difference in shape (vertical 3.6, racquet 3.6; p = 0.86) or in postoperative aesthetic result (vertical 3.6, racquet 3.4; p = 0.41). CONCLUSIONS: Shape and overall postoperative aesthetic appearance did not significantly differ despite greater ptosis preoperatively in the vertical group, demonstrating the efficacy of the vertical design in reconstruction. Vertical design reconstructions were rated aesthetically superior to their pre-mastectomy appearance. Significantly better scar scores in the vertical group reflect the camouflaged nature of vertical incisions. These results demonstrate that the aesthetic outcome of the vertical design reconstruction in ptotic breasts is as good as and potentially superior to the racquet design reconstruction in non-ptotic breasts. PMID- 26422655 TI - Sorafenib-Induced Eruption Mimicking Erythema Multiforme. PMID- 26422656 TI - Protein profiles distinguish stable and progressive chronic lymphocytic leukemia. AB - Patients with a stable chronic lymphocytic leukemia (CLL) double their blood lymphocyte count in >5 years, but may develop progressive disease with lymphocytes doubling in <12 months. To identify a protein signature for progressive CLL, whole cell extracts of peripheral blood mononuclear cells from patients with CLL (n=27) were screened using iTRAQ (isobaric tags for relative and absolute quantification) analysis. A total of 84 differentially abundant proteins were identified from patients with stable and progressive CLL. Subsequently, 32 of these proteins were quantified by SRM (selected reaction monitoring) using extracts of purified CD19+ CLL cells from patients (n=50). Hierarchical clustering of these protein profiles showed two clusters of patients that correlated with progressive and stable CLL, providing signatures that should be useful for triaging patients. Some of the proteins in the progressive cluster have not been linked with CLL, for example, glutamate dehydrogenase 1 and transcription intermediary factor 1-beta. PMID- 26422657 TI - Quantitative activation suppression assay to evaluate human bone marrow-derived mesenchymal stromal cell potency. AB - BACKGROUND AIMS: With the increasing use of cell therapies involving immune modulatory cells, there is a need for a simple standardized method to evaluate and compare the suppressive potency of different cell products. We used the Karpas 299 (K299) cell line as the reference suppressor cell to develop a standardized suppression assay to quantify the immune-modulatory capacity of bone marrow-derived mesenchymal stromal cells (BM-MSCs). METHODS: Healthy donor CD4 T cells were co-cultured with the K299 cell line or with third-party BM-MSCs. After stimulation with anti-CD3/CD28 beads, CD154 activation and proliferation of CD4 T cells were measured to calculate suppression. RESULTS: The K299 cell line reproducibly suppressed both the activation and proliferation of healthy donor CD4 T cells in a dose-dependent manner. A rapid (16-h) assay that was based on activation-suppression was selected for development. In replicate testing, there was an inherent variability of suppression of 11% coefficient of variation between different responder T cells. Suppression by BM-MSCs on different responders correlated with suppression by K299. We therefore used K299 suppression as the reference to define suppression potency of BM-MSCs in K299 Suppression Units. We found that inter-donor variability, passage number, method of manufacture and exposure of BM-MSCs to steroids or interferon-gamma all affected BM-MSC potency of suppression. CONCLUSIONS: This method provides a platform for standardizing suppressor function to facilitate comparisons between laboratories and for use as a cell product release assay. PMID- 26422658 TI - Proteolytically active ADAM10 and ADAM17 carried on membrane microvesicles in human abdominal aortic aneurysms. AB - The intraluminal thrombus (ILT) of human abdominal aortic aneurysm (AAA) has been suggested to damage the underlying aortic wall, but previous work found scant activity of soluble proteases in the abluminal layer of the ILT, adjacent to the aneurysm. We hypothesised that transmembrane proteases carried by membrane microvesicles (MV) from dying cells remain active in the abluminal ILT. ILTs and AAA segments collected from 21 patients during surgical repair were assayed for two major transmembrane proteases, ADAM10 (a disintegrin and metalloprotease-10) and ADAM17. We also exposed cultured cells to tobacco smoke and assessed ADAM10 and ADAM17 expression and release on MVs. Immunohistochemistry showed abundant ADAM10 and ADAM17 protein in the ILT and underlying aneurysmal aorta. Domain specific antibodies indicated both transmembrane and shed ADAM17. Importantly, ADAM10 and ADAM 17 in the abluminal ILT were enzymatically active. Electron microscopy of abluminal ILT and aortic wall showed MVs with ADAM10 and ADAM17. By flow cytometry, ADAM-positive microvesicles from abluminal ILT carried the neutrophil marker CD66, but not the platelet marker CD61. Cultured HL60 neutrophils exposed to tobacco smoke extract showed increased ADAM10 and ADAM17 content, cleavage of these molecules into active forms, and release of MVs carrying mature ADAM10 and detectable ADAM17. In conclusion, our results implicate persistent, enzymatically active ADAMs on MVs in the abluminal ILT, adjacent to the aneurysmal wall. The production of ADAM10- and ADAM17-positive MVs from smoke-exposed neutrophils provides a novel molecular mechanism for the vastly accelerated risk of AAA in smokers. PMID- 26422660 TI - Preparation, optical and electrical properties of PTCDA nanostructures. AB - Film, nanorods (NRs), nanowires (NWs), and nanoparticles (NPs) of perylene 3,4,9,10-tetracarboxylic dianhydride (PTCDA) were prepared by organic molecular beam deposition (OMBD) on porous anodic alumina oxide (AAO) at different substrate temperatures (Ts). Scanning electron microscopy (SEM) study showed that the morphologies of the nanostructures (NS) formed on AAO strongly depend on the Ts. The absorption spectra of different PTCDA NS present strong absorbance in the wavelength range of 400-600 nm, and the photoluminescence (PL) spectra show a blue shift as Ts increases. The current versus voltage (I-V) characteristic illustrates that the electrical conductivity of the single-crystal NW is about 3 +/- 0.1 S m(-1), which is much higher than the conductivity of PTCDA film reported previously. PMID- 26422659 TI - Mitochondrial Dysfunction Due to Lack of Manganese Superoxide Dismutase Promotes Hepatocarcinogenesis. AB - AIMS: One of the cancer hallmarks is mitochondrial dysfunction associated with oxidative stress. Among the first line of defense against oxidative stress is the dismutation of superoxide radicals, which in the mitochondria is carried out by manganese superoxide dismutase (MnSOD). Accordingly, carcinogenesis would be associated with a dysregulation in MnSOD expression. However, the association studies available so far are conflicting, and no direct proof concerning the role of MnSOD as a tumor promoter or suppressor has been provided. Therefore, we investigated the role of MnSOD in carcinogenesis by studying the effect of MnSOD deficiency in cells and in the livers of mice. RESULTS: We found that loss of MnSOD in hepatoma cells contributed to their conversion toward a more malignant phenotype, affecting all cellular properties generally associated with metabolic transformation and tumorigenesis. In vivo, hepatocyte-specific MnSOD-deficient mice showed changed organ architecture, increased expression of tumor markers, and a faster response to carcinogenesis. Moreover, deficiency of MnSOD in both the in vitro and in vivo model reduced beta-catenin and hypoxia-inducible factor 1alpha levels. INNOVATION: The present study shows for the first time the important correlation between MnSOD presence and the regulation of two major pathways involved in carcinogenesis, the Wnt/beta-catenin and hypoxia signaling pathway. CONCLUSION: Our study points toward a tumor suppressive role of MnSOD in liver, where the Wnt/beta-catenin and hypoxia pathway may be crucial elements. PMID- 26422662 TI - Distinguishing shyness and sociability in children: An event-related potential study. AB - Shyness and sociability are independent personality dimensions, each with distinct behavioral and psychophysiological correlates that are conserved across development, culture, and phylogeny. However, relatively little is known regarding how shyness and sociability are instantiated in the brain, particularly during childhood and during the processing of nonsocial stimuli. Using a three stimulus auditory oddball task, we examined whether variations in shyness and sociability were related to the N200 and P300 event-related potential (ERP) brain responses to processing task-relevant, novel, and standard auditory tones in 53 typically developing 10-year-old children. ERP amplitudes were measured at four midline scalp sites: Fz, FCz, Cz, and Pz. We found that increases in shyness were correlated with increases in target P300 amplitudes across all four head sites, increases in standard P300 amplitudes, and decreases in target P300 latencies in anterior sites. No relations were found for sociability and P300 responses. We also found that P300 amplitude in the frontal region to standard tones mediated the relation between conflicted shyness (i.e., high shyness and high sociability) and emotional instability. These results suggest that shyness and sociability are distinguishable on neurocognitive measures and that these neurocognitive measures may be putative mechanisms in understanding risk for emotional instability and a broad range of dysregulated behavioral problems observed in individuals characterized by conflicted shyness. PMID- 26422661 TI - Maternal negative affect during infancy is linked to disrupted patterns of diurnal cortisol and alpha asymmetry across contexts during childhood. AB - Maternal negative affect in the early environment is believed to sensitize long term coping capacities in children. Yet, little work has identified physiological systems associated with coping responses, which may serve as mechanisms for links between early maternal negativity and child outcomes. Using a longitudinal twin sample (N=89), we found that high levels of maternal negative affect during infancy were associated with dysregulation of diurnal cortisol and electroencephalograph (EEG) asymmetry, two physiological systems that may support active approach-oriented coping when children are 7years old. Flattened slopes of diurnal cortisol were also associated with greater numbers of concurrent overanxious behaviors in children. A mediation analysis supported the role of dysregulated diurnal cortisol as a mediator of the link between maternal negative affect in the early environment and childhood risk for anxiety problems. PMID- 26422663 TI - Understanding differences in alcohol consumption and depressed mood between U.S.- and foreign-born Asian and Caucasian college students. AB - The number and proportion of foreign-born individuals in the U.S. population has increased in recent decades. From 1970 to 2007, the foreign-born population more than tripled to approximately 37 million (U.S. Census Bureau, 1997 , 2008 ). Foreign-born students are a key subpopulation of college students. About 23% of U.S. undergraduate college students in 2007-2008 were either born outside of the United States (10%) or were children of at least one first-generation immigrant parent (13%; National Center for Education Statistics, U.S. Department of Education [NCES], 2012 ). Asian students constitute the majority (30%) of foreign born undergraduates. Although foreign-born Asian students compose nearly one quarter of the college population, limited research has examined how rates of alcohol use and depression differ between foreign-born and U.S.-born Asian college students (Gonzalez, Reynolds, & Skewes, 2011 ; Ralston & Palfai, 2012 ). The limited research is worrisome given their increasing rates of college enrollment (U.S. Census Bureau, 2011 ), alcohol consumption (Aud, Fox, & KewalRamani, 2010 ), alcohol abuse and dependence (Grant et al., 2004 ), and underutilization of mental health services (U.S. Department of Health and Human Services, 2001 ). Collectively, these factors point to the need for further research tailored to Asian college drinkers. PMID- 26422664 TI - Chemistry of Urban Grime: Inorganic Ion Composition of Grime vs Particles in Leipzig, Germany. AB - Deposition of atmospheric constituents--either gas phase or particulate--onto urban impervious surfaces gives rise to a thin "urban grime" film. The area exposed by these impervious surfaces in a typical urban environment is comparable to, or greater than, that of particles present in the urban boundary layer; however, it is largely overlooked as a site for heterogeneous reactions. Here we present the results of a field campaign to determine and compare the chemical composition of urban grime and of particles collected simultaneously during the autumn of 2014 at an urban site in central Leipzig, Germany. We see dramatically reduced ammonium and nitrate levels in the film as compared to particles, suggesting a significant loss of ammonium nitrate, thus enhancing the mobility of these species in the environment. Nitrate levels are 10% lower for films exposed to sunlight compared to those that were shielded from direct sun, indicating a possible mechanism for recycling nitrate anion to reactive nitrogen species. Finally, chloride levels in the film suggest that urban grime could represent an unrecognized source of continental chloride available for ClNO2 production even in times of low particulate chloride. Such source and recycling processes could prove to be important to local and regional air quality. PMID- 26422666 TI - [Dissection of the wired endotracheal tube's lumen during general anesthesia: a case report]. AB - OBJECTIVE: The aim of this study is to report a case of a clinically significant obstruction during mechanical ventilation caused by the dissection of the wired endotracheal tube's lumen during general anesthesia in a pediatric patient. CASE REPORT: A12-years old patient undergoing general anesthesia for open appendectomy was intubated with a wired endotracheal tube and difficult removal of the guide. After starting the mechanical ventilation, there was increased expiratory fraction of CO2 and need for increased inspiratory pressure. Chance of complications with higher incidences were raised and treated unsuccessfully. Finally, during patient reintubation, the dissection of the endotracheal tube lumen was observed, and ventilation was restored to normal. CONCLUSION: Anesthesia involves numerous possible complications. Suspicion and constant vigilance are essential for early diagnosis and treatment of any threat to the individual integrity. This case is relevant for emphasizing a possible very rare complication related to airway, which can quickly cause hypoxia and irreversible damage. Thus, this case contributes to the detection of this complication more frequently. PMID- 26422667 TI - The Effect of the Pressure Exerted on the Maternal Abdominal Wall by the US Probe on Fetal MCA Peak Systolic Velocity. AB - Purpose To quantify the pressure exerted on the maternal abdominal wall during ultrasound examination and evaluate its effect on the fetal middle cerebral artery (MCA) peak systolic velocity (PSV). Materials and Method Gravid women with singleton pregnancies in their 2nd-3 rd trimester undergoing fetal sonographic evaluation for various indications were recruited. Each subject underwent transabdominal US measuring fetal distance from the probe, abdominal thickness, amniotic fluid index and biophysical profile. The applied pressure was measured simultaneously using an electronic pressure sensor attached directly to the US probe. For each subject baseline values of the pressure required for proper visualization were obtained. Fetal MCA was then demonstrated using color Doppler US. The PSV was measured at different pressure ranges with each subject used as her own control. Care was taken not to exceed the baseline pressure for each subject. Results 29 women were recruited. 24 subjects (82.7 %) demonstrated a statistically significant positive correlation between the pressure exerted and MCA-PSV (R-0.37, p < 0.0001). Of these, 4 subjects (13.8 % of study population) demonstrated elevation of PSV values above 1.29 MOM and 5 subjects (17.2 %) demonstrated elevation of PSV values above 1.5 MOM for gestational age with increasing pressure. In total, 9 subjects (31 %) demonstrated significant changes in the MCA-PSV measurements (owing to increase in pressure applied) that could potentially falsely influence clinical obstetric diagnosis and management. Conclusion The pressure exerted on the maternal abdominal wall during US examination is an important parameter, producing clinically significant measurable changes in fetal MCA hemodynamics. Further study is needed in order to demonstrate the potential effect of pressure as a parameter influencing the diagnostic accuracy of the MCA-PSV in the setting of fetal anemia. PMID- 26422668 TI - Optimized Sonographic Weight Estimation of Fetuses over 3500 g Using Biometry Guided Formula Selection. AB - Purpose The Hadlock et al. formula tends to underestimate fetal weight, in particular > 3500 g. At the high end of the range, the Merz et al. formula is more accurate, but becomes less so in smaller fetuses. This study was designed to improve fetal weight estimation in fetuses > 3500 g by identifying the fetal biometric parameter providing the most reliable guidance to optimal formula selection. Materials and Methods Regression analysis of 12 032 pregnancies showed that multiplication of abdominal circumference by femur length (AC * FL) gave the best choice of appropriate formula: Hadlock for AC * FL < 24 600, Merz for those >= 24 600. We then tested this rule, ('Zurich method'), prospectively in 4073 pregnancies, comparing it with the Hadlock, Merz and the Kehl formulas. Birth weights were merged into 7 categories (< 1500 to >= 4000 g, interval of 500 g). The percentage error (PE) and absolute percentage error (APE) were calculated. Results The PE using the Zurich method was lower in both > 3500 g groups than with the Hadlock formula alone (3500 - 3999 g: 0.9 % vs. - 5.3 %, > 4000 g: - 3.2 % vs. - 8.6 %), similar to that with the Merz formula alone, and lower than with the Kehl formulas (3500 - 3999 g: - 9.0 % vs. - 3.2 %, > 4000g: - 5.1 % vs. 0.9 %). The Zurich method and Hadlock formula also shared the lowest PE in the < 1500 g group: 0.2 % vs. 6.8 % (Kehl) vs. 9.6 % (Merz). In terms of APE the Zurich method performed almost as well as the Merz formula in the > 4000 g group, while sharing the lowest value with the Hadlock formula in the < 1500 g group (8.2 % vs. 10.5 % [Kehl], 23.6 % [Merz]). Conclusion The Zurich method uses a pivotal value of the biometry parameter AC * FL to switch between formulas and corrects for the errors of the Hadlock formula in fetuses >= 3500 g and those of the Merz formula in fetuses < 3500 g. PMID- 26422665 TI - Miniature and Fieldable Mass Spectrometers: Recent Advances. PMID- 26422669 TI - Doppler Audio Signal Analysis as an Additional Tool in Evaluation of Umbilical Artery Circulation. AB - Purpose To investigate the predictive capacity of a new method for sound spectrum analysis of Doppler signals recorded from the umbilical artery in high-risk pregnancies. Material and Methods The retrospective study comprised 127 pregnant women with various pregnancy complications between 23 and 39 gestational weeks. Umbilical artery blood flow velocity waveforms were recorded with Doppler ultrasound and characterized by pulsatility index (PI) and blood flow class (BFC). Doppler audio signals were stored on a digital video recorder and the sound frequency at the energy level 15 dB below its peak (MAXpeak-15 dB) was estimated off-line. The prediction of probability for composite adverse pregnancy outcome (operative delivery for fetal distress, admission to neonatal intensive care unit, perinatal death) was evaluated using the area under the curve (AUC) of the receiver operating characteristics (ROC) curve. Results With increasing umbilical artery BFC, the MAXpeak-15 dB frequencies decreased (p < 0.0001) and the PI increased (p < 0.0001). The ROC AUCs for adverse outcome for MAXpeak-15 dB and for PI were 0.842 and 0.836 (p = 0.88), respectively. For the combination of MAXpeak-15 dB and PI, the corresponding AUC was 0.894, significantly higher than that of PI (p < 0.03) and of MAXpeak-15 dB (p < 0.05). Conclusion Umbilical artery Doppler sound spectrum analysis might be a useful supplement to PI in the clinical evaluation of fetoplacental circulation. PMID- 26422670 TI - A Cu25 Nanocluster with Partial Cu(0) Character. AB - Atomically precise copper nanoclusters (NCs) are of immense interest for a variety of applications, but have remained elusive. Herein, we report the isolation of a copper NC, [Cu25H22(PPh3)12]Cl (1), from the reaction of Cu(OAc) and CuCl with Ph2SiH2, in the presence of PPh3. Complex 1 has been fully characterized, including analysis by X-ray crystallography, XANES, and XPS. In the solid state, complex 1 is constructed around a Cu13 centered-icosahedron and formally features partial Cu(0) character. XANES of 1 reveals a Cu K-edge at 8979.6 eV, intermediate between the edge energies of Cu(0) and Cu(I), confirming our oxidation state assignment. This assignment is further corroborated by determination of the Auger parameter for 1, which also falls between those recorded for Cu(0) and Cu(I). PMID- 26422671 TI - Mg(2+)-dependent facilitation and inactivation of L-type Ca(2+) channels in guinea pig ventricular myocytes. AB - This study aimed to investigate the intracellular Mg(2+) regulation of the L-type Ca(2+) channels in guinea pig ventricular myocytes. By adopting the inside-out configuration of the patch clamp technique, single channel currents of the L-type Ca(2+) channels were recorded at different intracellular Mg(2+) concentrations ([Mg(2+)]i). At free [Mg(2+)]i of 0, 10(-9), 10(-7), 10(-5), 10(-3), and 10(-1) M, 1.4 MUM CaM + 3 mM ATP induced channel activities of 44%, 117%, 202%, 181%, 147%, and 20% of the control activity in cell-attached mode, respectively, showing a bell-shaped concentration-response relationship. Moreover, the intracellular Mg(2+) modulated the Ca(2+) channel gating properties, accounting for alterations in channel activities. These results imply that Mg(2+) has a dual effect on the L-type Ca(2+) channels: facilitation and inhibition. Lower [Mg(2+)]i maintains and enhances the basal activity of Ca(2+) channels, whereas higher [Mg(2+)]i inhibits channel activity. Taken together, our data from the application of an [Mg(2+)]i series suggest that the dual effect of Mg(2+) upon the L-type Ca(2+) channels exhibits long open-time dependence. PMID- 26422672 TI - Mitogen-activated protein kinases regulate expression of neuronal nitric oxide synthase and neurite outgrowth via non-classical retinoic acid receptor signaling in human neuroblastoma SH-SY5Y cells. AB - We have previously shown that retinoic acid receptor (RAR) stimulation by an agonist Am80 recruits nitric oxide-dependent signaling via increased expression of neuronal nitric oxide synthase (nNOS) in rat midbrain slice cultures. Using neuroblastoma SH-SY5Y cells, here we investigated the mechanisms of RAR-induced nNOS expression, together with relationship between nNOS expression and neurite outgrowth. Am80 promoted neurite outgrowth, which was attenuated by inhibitors of phosphoinositide 3-kinase (PI3K; LY294002), c-Jun N-terminal kinase (JNK; SP600125) and p38 mitogen-activated protein kinase (p38 MAPK; SB203580). A selective nNOS inhibitor 3-bromo-nitroindazole also suppressed Am80-induced neurite outgrowth. Am80-induced increase in nNOS protein expression was attenuated by LY294002, SP600125 and SB203580, whereas increase in nNOS mRNA expression was attenuated only by LY294002. Am80-induced activation of JNK and p38 MAPK was blocked by LY294002, suggesting that these kinases acted downstream of PI3K. We also confirmed that DAX1, a nuclear receptor reported to regulate nNOS expression, was up-regulated in response to Am80. siRNA-mediated knockdown of DAX1 abrogated Am80-induced nNOS expression and neurite outgrowth. These results reveal for the first time that nNOS expression is crucial for RAR mediated neurite outgrowth, and that non-genomic signaling such as JNK and p38 MAPK is involved in RAR-mediated nNOS expression. PMID- 26422673 TI - Labor induction in the patient with preterm premature rupture of membranes. AB - Preterm premature rupture of membranes (PPROM) affects up to one-third of all preterm births and confers serious maternal risks, including intra-amniotic infection, and an increased risk of neonatal complications, including respiratory distress and intraventricular hemorrhage. Management of PPROM is a highly individualized process that requires an accurate determination of gestational age and causal factors, as well as the balancing of maternal and fetal risks. In this review of the existing literature on induction of labor in PPROM, we examine the differences in appropriate management of patients with early (32 weeks 0 days to 33 weeks 6 days) and near term (34 weeks 0 days to 36 weeks 6 days) PPROM, and compare the safety and efficacy of available treatment options. This review of previous research findings provides general guidelines for clinical decision making and highlights the need for future research on management of PPROM. PMID- 26422674 TI - Magnetic Field-Controlled Lithium Polysulfide Semiliquid Battery with Ferrofluidic Properties. AB - Large-scale energy storage systems are of critical importance for electric grids, especially with the rapid increasing deployment of intermittent renewable energy sources such as wind and solar. New cost-effective systems that can deliver high energy density and efficiency for such storage often involve the flow of redox molecules and particles. Enhancing the mass and electron transport is critical for efficient battery operation in these systems. Herein, we report the design and characterization of a novel proof-of-concept magnetic field-controlled flow battery using lithium metal-polysulfide semiliquid battery as an example. A biphasic magnetic solution containing lithium polysulfide and magnetic nanoparticles is used as catholyte, and lithium metal is used as anode. The catholyte is composed of two phases of polysulfide with different concentrations, in which most of the polysulfide molecules and the superparamagnetic iron oxide nanoparticles can be extracted together to form a high-concentration polysulfide phase, in close contact with the current collector under the influence of applied magnetic field. This unique feature can help to maximize the utilization of the polysulfide and minimize the polysulfide shuttle effect, contributing to enhanced energy density and Coulombic efficiency. Additionally, owing to the effect of the superparamagnetic nanoparticles, the concentrated polysulfide phase shows the behavior of a ferrofluid that is flowable with the control of magnetic field, which can be used for a hybrid flow battery without the employment of any pumps. Our innovative design provides new insight for a broad range of flow battery chemistries and systems. PMID- 26422675 TI - Cardiovascular Safety of beta3-adrenoceptor Agonists for the Treatment of Patients with Overactive Bladder Syndrome. AB - CONTEXT: Mirabegron, the first beta3-adrenoceptor agonist in clinical practice, is approved for treatment of overactive bladder (OAB) syndrome symptoms. Because beta3-adrenoceptors are expressed in cardiovascular (CV) tissues, there are concerns that OAB treatment with beta3-adrenoceptor agonists may affect the heart and vasculature. OBJECTIVE: To provide a summary of CV effects of beta3 adrenoceptor agonists in clinical studies. EVIDENCE ACQUISITION: A systematic literature search from inception until November 2014 was performed on studies in PubMed and Medline. EVIDENCE SYNTHESIS: Twenty papers, published between 1994 and 2014, were identified: mirabegron (16), solabegron (2), AK-677 (1), and BRL35135 (1). More detailed CV data from mirabegron studies were available in online regulatory documents filed with the US Food and Drug Administration and the UK National Institute for Health and Care Excellence. CONCLUSIONS: The CV safety of mirabegron appears to be acceptable at therapeutic doses and comparable with that of antimuscarinic agents, currently first-line therapy for OAB. PATIENT SUMMARY: In this review we looked at the cardiovascular (CV) effects of beta3-adrenoceptor agonists used for the treatment of overactive bladder (OAB). The CV safety of mirabegron (the only clinically approved beta3-adrenoceptor agonist) appears to be acceptable at therapeutic doses and comparable with that of antimuscarinic agents, the current first-line therapy for OAB. PMID- 26422676 TI - Addition of Docetaxel to Androgen Deprivation Therapy for Patients with Hormone sensitive Metastatic Prostate Cancer: A Systematic Review and Meta-analysis. AB - CONTEXT: Several randomized clinical trials (RCTs) have recently tested the early addition of docetaxel to androgen deprivation therapy (ADT) in hormone-sensitive metastatic prostate cancer (PCa). OBJECTIVE: To perform a systematic review and meta-analysis of RCTs evaluating the combination of docetaxel and ADT in hormone sensitive metastatic PCa. The primary end point was overall survival (OS). Secondary end point was progression-free survival. Exploratory subgroup analysis according to high-volume versus low-volume disease was performed. EVIDENCE ACQUISITION: A systematic review of PubMed/Medline, Embase, and the proceedings of major international meetings was performed in June 2015 and updated in August 2015. Three trials were selected for inclusion. EVIDENCE SYNTHESIS: Overall, 2951 patients were included in the three trials. Two trials enrolled only metastatic patients; in the third trial, 61% were metastatic. A total of 2262 patients (951 docetaxel and ADT; 1311 ADT alone) were metastatic. Most patients had a good performance status. In metastatic patients, the addition of docetaxel was associated with improved OS (hazard ratio [HR]: 0.73; 95% confidence interval [CI], 0.60-0.90; p=0.002), with nonsignificant heterogeneity among the three trials. Considering the whole study population (2951 patients), the addition of docetaxel was associated with a similar OS improvement (HR: 0.74; 95% CI, 0.61 0.91; p=0.003). Although with limited statistical power, no significant interaction was demonstrated between the addition of docetaxel and the high or low volume of disease (p=0.5). The addition of docetaxel was associated with improvement in progression-free survival (metastatic patients: HR: 0.63; 95% CI, 0.57-0.70; p<0.001). CONCLUSIONS: This meta-analysis shows a significant OS benefit from concomitant administration of docetaxel and ADT in patients with metastatic hormone-sensitive PCa. PATIENT SUMMARY: We synthesized the evidence available about the early administration of docetaxel in patients starting hormonal treatment for metastatic prostate cancer. Based on the results of this meta-analysis, we believe the combination of chemotherapy and hormonal treatment should be considered in fit patients. PMID- 26422677 TI - Chronic lead poisoning magnifies bone detrimental effects in an ovariectomized rat model of postmenopausal osteoporosis. AB - Lead (Pb) is a persistent environmental contaminant that is mainly stored in bones being an important source of endogenous lead exposure during periods of increased bone resorption as occurs in menopause. As no evidence exists of which bone biomechanical properties are impaired in those elderly women who had been exposed to Pb during their lifetime, the aim of the present study is to discern whether chronic lead poisoning magnifies the deterioration of bone biology that occurs in later stages of life. We investigated the effect of Pb in the femora of ovariectomized (OVX) female Wistar rats who had been intoxicated with 1000 ppm of Pb acetate in drinking water for 8 months. Structural properties were determined using a three-point bending mechanical test, and geometrical and material properties were evaluated after obtaining the load/deformation curve. Areal Bone Mineral Density (BMD) was estimated using a bone densitometer. Femoral histomorphometry was carried out on slices dyed with H&E (Hematoxylin and Eosin). Pb and OVX decreased all structural properties with a higher effect when both treatments were applied together. Medullar and cortical area of femurs under OVX increased, allowing the bone to accommodate its architecture, which was not observed under Pb intoxication. Pb and OVX significantly decreased BMD, showing lead treated ovariectomized rats (PbOVX) animals the lowest BMD levels. Trabecular bone volume per total volume (BV/TV%) was decreased in OVX and PbOVX animals in 54% compared to the control animals (p<0.001). Pb femurs also showed 28% less trabeculae than the control (p<0.05). We demonstrated that Pb intoxication magnifies the impairment in bone biomechanics of OVX rats with a consequent enhancement of the risk of fracture. These results enable the discussion of the detrimental effects of lead intoxication in bone biology in elderly women. PMID- 26422678 TI - A Clinical Tool for the Prediction of Venous Thromboembolism in Pediatric Trauma Patients. AB - IMPORTANCE: Although rare, the incidence of venous thromboembolism (VTE) in pediatric trauma patients is increasing, and the consequences of VTE in children are significant. Studies have demonstrated increasing VTE risk in older pediatric trauma patients and improved VTE rates with institutional interventions. While national evidence-based guidelines for VTE screening and prevention are in place for adults, none exist for pediatric patients, to our knowledge. OBJECTIVES: To develop a risk prediction calculator for VTE in children admitted to the hospital after traumatic injury to assist efforts in developing screening and prophylaxis guidelines for this population. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of 536,423 pediatric patients 0 to 17 years old using the National Trauma Data Bank from January 1, 2007, to December 31, 2012. Five mixed-effects logistic regression models of varying complexity were fit on a training data set. Model validity was determined by comparison of the area under the receiver operating characteristic curve (AUROC) for the training and validation data sets from the original model fit. A clinical tool to predict the risk of VTE based on individual patient clinical characteristics was developed from the optimal model. MAIN OUTCOME AND MEASURE: Diagnosis of VTE during hospital admission. RESULTS: Venous thromboembolism was diagnosed in 1141 of 536,423 children (overall rate, 0.2%). The AUROCs in the training data set were high (range, 0.873-0.946) for each model, with minimal AUROC attenuation in the validation data set. A prediction tool was developed from a model that achieved a balance of high performance (AUROCs, 0.945 and 0.932 in the training and validation data sets, respectively; P = .048) and parsimony. Points are assigned to each variable considered (Glasgow Coma Scale score, age, sex, intensive care unit admission, intubation, transfusion of blood products, central venous catheter placement, presence of pelvic or lower extremity fractures, and major surgery), and the points total is converted to a VTE risk score. The predicted risk of VTE ranged from 0.0% to 14.4%. CONCLUSIONS AND RELEVANCE: We developed a simple clinical tool to predict the risk of developing VTE in pediatric trauma patients. It is based on a model created using a large national database and was internally validated. The clinical tool requires external validation but provides an initial step toward the development of the specific VTE protocols for pediatric trauma patients. PMID- 26422679 TI - Proximal bronchial balloon dilation for embedded distal airway foreign bodies. PMID- 26422680 TI - Efficacy of entecavir therapy for hepatitis B e-antigen positive chronic hepatitis B patients with prior exposure to interferon or nucleoside/nucleotide analogues. PMID- 26422681 TI - Life-Threatening Contraceptive-Related Pulmonary Embolism in a 14-Year-Old Girl with Hereditary Thrombophilia. AB - BACKGROUND: The prothrombotic effect of combined oral contraceptives (COCs) is well-established, with a 3-6-fold increased risk of VTE compared to non-users. When initiation of COCs is considered, it is therefore of paramount importance to carefully evaluate all other potential risk factors for VTE. Based on a case of life-threatening COC-associated pulmonary embolism in a girl heterozygous for the prothrombin G20210A mutation and with a family history of thrombotic disease, we discuss the importance of assessing not just the genotype but also the phenotype when considering initiation of COCs in patients with thrombophilia. CASE REPORT: A 14-year-old girl presented with acute onset of chest pain and dyspnea followed by syncope. She was hypoxic and hemodynamically compromised at admission. Computed tomography pulmonary angiography revealed a large central "saddle" pulmonary embolism causing nearly total occlusion of the right pulmonary artery, and several minor peripheral embolisms bilaterally. She was successfully treated with thrombolysis (alteplase) followed by aPTT-adjusted heparin infusion until adequate anticoagulation with warfarin was achieved. Two years earlier, the patient had been found heterozygote for the prothrombin G20210A mutation, and 9 months before admission she had initiated use of second-generation COCs. CONCLUSIONS: Hereditary thrombophilia and a family history of early-onset venous thromboembolism (VTE) each pose an increased risk of VTE and should be considered as separate, irreversible risk factors. Other contraceptive methods should be used when treatment with COCs is expected to result in an unacceptable high risk of VTE. PMID- 26422682 TI - Sex Steroid Hormone Levels May Not Explain Gender Differences in Development of Nephrolithiasis. AB - OBJECTIVES: To determine whether serum sex steroid hormone levels, or the subsequent change in those levels over time, represent a risk factor for the development of nephrolithiasis in men. METHODS: We retrospectively identified patients participating in a long-term cohort study (Rochester Epidemiology Project) in Olmsted County, Minnesota. Patients had previously undergone baseline detailed clinical examination and sex steroid hormone studies, including estradiol, testosterone, and bioavailable testosterone. Patients were followed on a biennial basis. Records were then reviewed to assess for formation of nephrolithiasis. RESULTS: We identified 684 patients, with a median follow-up for stone formation of 12.8 years. All 684 patients had measurement of testosterone, of which 78.9% were in normal range. Five hundred eighteen men had baseline-free testosterone, of whom 88.6% were normal. Three hundred seventy-one patients had baseline estradiol, of whom 88.7% were normal. One hundred two men (14.9%) were found to have stones, with 61 of those (59.8%) occurring before first hormone measurement and 41 (40.2%) occurring after. On multivariate analysis, there was no significant association of serum hormones with nephrolithiasis, although a trend toward higher baseline testosterone and stones was seen (odds ratio [OR] 1.29; 95% confidence intervals [CI] 0.71, 2.33). Using a time-to-event for incident stone formation, we found no significant association of baseline hormones or percentage change in hormone levels over time with risk of stones. CONCLUSION: We found no significant association of sex steroid hormone levels with the risk of nephrolithiasis formation in men, although a weak trend toward an increased risk with elevated testosterone was seen. PMID- 26422683 TI - High-visfatin levels in women with polycystic ovary syndrome: evidence from a meta-analysis. AB - OBJECTIVE: Previous studies regarding visfatin levels in women with polycystic ovary syndrome (PCOS) showed conflicting results. To evaluate the visfatin levels in PCOS, a meta-analysis was performed. METHODS: A comprehensive literature search of eligible studies in Embase, Pubmed and the Cochrane Library was undertaken through November 2014. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association. RESULTS: A total of 1341 subjects (695 cases and 646 controls) were included in this meta-analysis. The pooled analysis results indicated that the visfatin levels were significantly higher in PCOS patients than that of controls (SMD = 1.19, 95% CI 0.77-1.60, p = 0.000). The results from stratified analysis and univariate analysis suggested that high-visfatin levels were not related to body mass index (BMI), insulin resistance (IR) and total testosterone ratio. Significant heterogeneity was observed in all analysis. CONCLUSION: Our results indicate that high-circulating visfatin level is an intrinsic characteristic of PCOS, which suggests visfatin could be a potential biomarker for PCOS. PMID- 26422684 TI - Habitat Effects on the Breeding Performance of Three Forest-Dwelling Hawks. AB - Habitat loss causes population declines, but the mechanisms are rarely known. In the European Boreal Zone, loss of old forest due to intensive forestry is suspected to cause declines in forest-dwelling raptors by reducing their breeding performance. We studied the boreal breeding habitat and habitat-associated breeding performance of the northern goshawk (Accipiter gentilis), common buzzard (Buteo buteo) and European honey buzzard (Pernis apivorus). We combined long-term Finnish bird-of-prey data with multi-source national forest inventory data at various distances (100-4000 m) around the hawk nests. We found that breeding success of the goshawk was best explained by the habitat within a 2000-m radius around the nests; breeding was more successful with increasing proportions of old spruce forest and water, and decreasing proportions of young thinning forest. None of the habitat variables affected significantly the breeding success of the common buzzard or the honey buzzard, or the brood size of any of the species. The amount of old spruce forest decreased both around goshawk and common buzzard nests and throughout southern Finland in 1992-2010. In contrast, the area of young forest increased in southern Finland but not around hawk nests. We emphasize the importance of studying habitats at several spatial and temporal scales to determine the relevant species-specific scale and to detect environmental changes. Further effort is needed to reconcile the socioeconomic and ecological functions of forests and habitat requirements of old forest specialists. PMID- 26422685 TI - Effective Linkages of Continuum of Care for Improving Neonatal, Perinatal, and Maternal Mortality: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Continuum of care has the potential to improve maternal, newborn, and child health (MNCH) by ensuring care for mothers and children. Continuum of care in MNCH is widely accepted as comprising sequential time (from pre-pregnancy to motherhood and childhood) and space dimensions (from community-family care to clinical care). However, it is unclear which linkages of care could have a greater effect on MNCH outcomes. The objective of the present study is to assess the effectiveness of different continuum of care linkages for reducing neonatal, perinatal, and maternal mortality in low- and middle-income countries. METHODS: We searched for randomized and quasi-randomized controlled trials that addressed two or more linkages of continuum of care and attempted to increase mothers' uptake of antenatal care, skilled birth attendance, and postnatal care. The outcome variables were neonatal, perinatal, and maternal mortality. RESULTS: Out of the 7,142 retrieved articles, we selected 19 as eligible for the final analysis. Of these studies, 13 used packages of intervention that linked antenatal care, skilled birth attendance, and postnatal care. One study each used packages that linked antenatal care and skilled birth attendance or skilled birth attendance and postnatal care. Four studies used an intervention package that linked antenatal care and postnatal care. Among the packages that linked antenatal care, skilled birth attendance, and postnatal care, a significant reduction was observed in combined neonatal, perinatal, and maternal mortality risks (RR 0.83; 95% CI 0.77 to 0.89, I2 79%). Furthermore, this linkage reduced combined neonatal, perinatal, and maternal mortality when integrating the continuum of care space dimension (RR 0.85; 95% CI 0.77 to 0.93, I2 81%). CONCLUSIONS: Our review suggests that continuous uptake of antenatal care, skilled birth attendance, and postnatal care is necessary to improve MNCH outcomes in low- and middle-income countries. The review was conclusive for the reduction of neonatal and perinatal deaths. Although maternal deaths were not significantly reduced, composite measures of all mortality were. Thus, the evidence is sufficient to scale up this intervention package for the improvement of MNCH outcomes. PMID- 26422686 TI - Thermodynamics of Rev-RNA interactions in HIV-1 Rev-RRE assembly. AB - The HIV-1 protein Rev facilitates the nuclear export of intron-containing viral mRNAs by recognizing a structured RNA site, the Rev-response-element (RRE), contained in an intron. Rev assembles as a homo-oligomer on the RRE using its alpha-helical arginine-rich-motif (ARM) for RNA recognition. One unique feature of this assembly is the repeated use of the ARM from individual Rev subunits to contact distinct parts of the RRE in different binding modes. How the individual interactions differ and how they contribute toward forming a functional complex is poorly understood. Here we examine the thermodynamics of Rev-ARM peptide binding to two sites, RRE stem IIB, the high-affinity site that nucleates Rev assembly, and stem IA, a potential intermediate site during assembly, using NMR spectroscopy and isothermal titration calorimetry (ITC). NMR data indicate that the Rev-IIB complex forms a stable interface, whereas the Rev-IA interface is highly dynamic. ITC studies show that both interactions are enthalpy-driven, with binding to IIB being 20-30 fold tighter than to IA. Salt-dependent decreases in affinity were similar at both sites and predominantly enthalpic in nature, reflecting the roles of electrostatic interactions with arginines. However, the two interactions display strikingly different partitioning between enthalpy and entropy components, correlating well with the NMR observations. Our results illustrate how the variation in binding modes to different RRE target sites may influence the stability or order of Rev-RRE assembly and disassembly, and consequently its function. PMID- 26422687 TI - How Can Childbirth Care for the Rural Poor Be Improved? A Contribution from Spatial Modelling in Rural Tanzania. AB - INTRODUCTION: Maternal and perinatal mortality remain a challenge in resource limited countries, particularly among the rural poor. To save lives at birth health facility delivery is recommended. However, increasing coverage of institutional deliveries may not translate into mortality reduction if shortage of qualified staff and lack of enabling working conditions affect quality of services. In Tanzania childbirth care is available in all facilities; yet maternal and newborn mortality are high. The study aimed to assess in a high facility density rural context whether a health system organization with fewer delivery sites is feasible in terms of population access. METHODS: Data on health facilities' location, staffing and delivery caseload were examined in Ludewa and Iringa Districts, Southern Tanzania. Geospatial raster and network analysis were performed to estimate access to obstetric services in walking time. The present geographical accessibility was compared to a theoretical scenario with a 40% reduction of delivery sites. RESULTS: About half of first-line health facilities had insufficient staff to offer full-time obstetric services (45.7% in Iringa and 78.8% in Ludewa District). Yearly delivery caseload at first-line health facilities was low, with less than 100 deliveries in 48/70 and 43/52 facilities in Iringa and Ludewa District respectively. Wide geographical overlaps of facility catchment areas were observed. In Iringa 54% of the population was within 1-hour walking distance from the nearest facility and 87.8% within 2 hours, in Ludewa, the percentages were 39.9% and 82.3%. With a 40% reduction of delivery sites, approximately 80% of population will still be within 2 hours' walking time. CONCLUSIONS: Our findings from spatial modelling in a high facility density context indicate that reducing delivery sites by 40% will decrease population access within 2 hours by 7%. Focused efforts on fewer delivery sites might assist strengthening delivery services in resource-limited settings. PMID- 26422689 TI - The GroEL-GroES Chaperonin Machine: A Nano-Cage for Protein Folding. AB - The bacterial chaperonin GroEL and its cofactor GroES constitute the paradigmatic molecular machine of protein folding. GroEL is a large double-ring cylinder with ATPase activity that binds non-native substrate protein (SP) via hydrophobic residues exposed towards the ring center. Binding of the lid-shaped GroES to GroEL displaces the bound protein into an enlarged chamber, allowing folding to occur unimpaired by aggregation. GroES and SP undergo cycles of binding and release, regulated allosterically by the GroEL ATPase. Recent structural and functional studies are providing insights into how the physical environment of the chaperonin cage actively promotes protein folding, in addition to preventing aggregation. Here, we review different models of chaperonin action and discuss issues of current debate. PMID- 26422688 TI - [Smoking prevalence in hospital workers: meta-analysis in 45 Catalan hospitals]. AB - OBJECTIVE: To estimate the prevalence of smoking in workers from hospitals within the Catalan Network for Smoke-free hospitals from 2009 to 2012 according to workers' sociodemographic characteristics and the type of hospital. METHOD: A meta-analysis was performed of prevalence surveys from representative samples of workers from 45 hospitals. The combined prevalence for all hospitals was calculated using a regression model with a random effects model weighted by sample size. RESULTS: The overall prevalence of smoking was 28.1% (95%CI: 26.1 to 30.0%) with a maximum and minimum of 40.3% and 19.1%, respectively. The health professionals with the lowest prevalence of smoking were physicians (16.4%; 95%CI: 12.9 to 19.9) and nurses (25.4%; 95%CI 21.6 to 29.2). CONCLUSION: The prevalence of smoking in hospital health workers was lower than in the general population of working age. Physicians were the group with the lowest smoking prevalence. Smoking cessation should be promoted among other professional groups. PMID- 26422690 TI - Demethylation of Circulating Estrogen Receptor Alpha Gene in Cerebral Ischemic Stroke. AB - BACKGROUND: Estrogen is involved in neuron plasticity and can promote neuronal survival in stroke. Its actions are mostly exerted via estrogen receptor alpha (ERalpha). Previous animal studies have shown that ERalpha is upregulated by DNA demethylation following ischemic injury. This study investigated the methylation levels in the ERalpha promoter in the peripheral blood of ischemic stroke patients. METHODS: The study included 201 ischemic stroke patients, and 217 age- and sex-comparable healthy controls. The quantitative methylation level in the 14 CpG sites of the ERalpha promoter was measured by pyrosequencing in each participant. Multivariate regression model was used to adjust for stroke traditional risk factors. Stroke subtypes and sex-specific analysis were also conducted. RESULTS: The results demonstrated that the stroke cases had a lower ERalpha methylation level than controls in all 14 CpG sites, and site 13 and site 14 had significant adjusted p-values of 0.035 and 0.026, respectively. Stroke subtypes analysis showed that large-artery atherosclerosis and cardio-embolic subtypes had significantly lower methylation levels than the healthy controls at CpG site 5, site 9, site 12, site 13 and site 14 with adjusted p = 0.039, 0.009, 0.025, 0.046 and 0.027 respectively. However, the methylation level for the patients with small vessel subtype was not significant. We combined the methylation data from the above five sites for further sex-specific analysis. The results showed that the significant association only existed in women (adjusted p = 0.011), but not in men (adjusted p = 0.300). CONCLUSIONS: Female stroke cases have lower ERalpha methylation levels than those in the controls, especially in large-artery and cardio-embolic stroke subtypes. The study implies that women suffering from ischemic stroke of specific subtype may undergo different protective mechanisms to reduce the brain injury. PMID- 26422692 TI - Wingspan Stenting for Severe Symptomatic Intracranial Atherosclerotic Stenosis in 433 Patients Treated at a Single Medical Center. AB - PURPOSE: To investigate the safety and outcome of intracranial stenting for intracranial atherosclerotic stenosis (IAS). MATERIALS AND METHODS: Between July 2007 and April 2013, 433 consecutive patients with IAS > 70% underwent intracranial Wingspan stenting, and the data were prospectively analyzed. RESULTS: Intracranial stenting was successful in 429 patients (99.1%), and the mean stenosis rate was improved from prestenting (82.3 +/- 7.6)% to poststenting (16.6 +/- 6.6)%. During the 30-day perioperative period, 29 patients (6.7%) developed stroke. The total perioperative stroke rate was significantly (P < 0.01) higher in the basilar artery area than in others, whereas the hemorrhagic stroke rate was significantly (P < 0.05) greater in the middle cerebral artery area than in others. The experience accumulation stage (13%) had a significantly (P < 0.05) higher stroke rate than the technical maturation stage (4.8%). Clinical follow-up 6-69 months poststenting revealed ipsilateral stroke in 20 patients (5.5%). The one- and two-year cumulative stroke rates were 9.5% and 11.5%, respectively; the two-year cumulative stroke rate was significantly (P < 0.05) greater in the experience accumulation stage (18.8%) than in the technical maturation stage (9.1%). CONCLUSION: Wingspan stenting for intracranial atherosclerotic stenosis is safe and the long-term stroke rate after stenting is low in a Chinese subpopulation. PMID- 26422693 TI - Double-Door or "French-Door" Cervical Laminoplasty. AB - PURPOSE: Cervical spondylotic myelopathy (CSM) is a condition resulting from cervical stenosis. Manifestations of CSM include paresthesia in the extremities, loss of fine motor skills, balance problems, and bowel and bladder dysfunction in advanced disease. Laminoplasty is one surgical treatment option. The goal of laminoplasty is to reposition the laminae to expand the spinal canal, allowing the spinal cord to migrate posteriorly. There are various laminoplasty techniques; the main ones being open-door laminoplasty and double-door laminoplasty. This manuscript demonstrates a double-door laminoplasty otherwise known as a "French-door" laminoplasty discusses the indications and outcomes of this procedure. METHODS: The double-door laminoplasty creates an opening in the midline of the spinous processes and a symmetrical expansion with hinges on both laminae. Bilateral troughs are drilled on each laminae using a bur, and opened liked a French-door, allowing the spinal cord to move posteriorly in the enlarged spinal canal. The space between the gapped laminae are then stabilized by allograft. RESULTS: This manuscript presents the case of a 56-year-old man with CSM caused by multilevel cervical stenosis. The patient had classic signs and symptoms of CSM including problems with fine motor skills and walking difficulty. The video demonstrates the spinal cord decompression achieved with the French door technique from C4 to C6 with a dome laminectomy at C3. CONCLUSIONS: There are many surgical treatments for cervical stenosis including anterior cervical discectomy and fusions and posterior procedures such as laminoplasty or laminectomy and fusion. The indications and technical pearls for French-door laminoplasty are presented as an effective option for the treatment of multilevel cervical stenosis. PMID- 26422691 TI - Evidence that beta7 Integrin Regulates Hematopoietic Stem Cell Homing and Engraftment Through Interaction with MAdCAM-1. AB - alpha4beta7 integrin is a cell adhesion receptor that is crucial for the migration of hematopoietic progenitors and mature effector cells in the periphery, but its role in adult hematopoiesis is controversial. We identified a subset of hematopoietic stem cells (HSCs) in the bone marrow (BM) that expressed beta7 integrin. These beta7(+) HSCs were capable of multilineage, long-term reconstitution and had an inherent competitive advantage over beta7(-) HSCs. On the other hand, HSCs that lacked beta7 integrin (beta7KO) had reduced engraftment potential. Interestingly, quantitative RT-PCR and flow cytometry revealed that beta7KO HSCs expressed lower levels of the chemokine receptor CXCR4. Accordingly, beta7KO HSCs exhibited impaired migration abilities in vitro and BM homing capabilities in vivo. Lethal irradiation induced expression of the alpha4beta7 integrin ligand-mucosal addressin cell adhesion molecule-1 (MAdCAM-1) on BM endothelial cells. Moreover, blocking MAdCAM-1 reduced the homing of HSCs and impaired the survival of recipient mice. Altogether, these data indicate that beta7 integrin, when expressed by HSCs, interacted with its endothelial ligand MAdCAM-1 in the BM microenvironment, thereby promoting HSC homing and engraftment. PMID- 26422694 TI - Tracking Public Beliefs About Anthropogenic Climate Change. AB - A simple question about climate change, with one choice designed to match consensus statements by scientists, was asked on 35 US nationwide, single-state or regional surveys from 2010 to 2015. Analysis of these data (over 28,000 interviews) yields robust and exceptionally well replicated findings on public beliefs about anthropogenic climate change, including regional variations, change over time, demographic bases, and the interacting effects of respondent education and political views. We find that more than half of the US public accepts the scientific consensus that climate change is happening now, caused mainly by human activities. A sizable, politically opposite minority (about 30 to 40%) concede the fact of climate change, but believe it has mainly natural causes. Few (about 10 to 15%) say they believe climate is not changing, or express no opinion. The overall proportions appear relatively stable nationwide, but exhibit place-to place variations. Detailed analysis of 21 consecutive surveys within one fairly representative state (New Hampshire) finds a mild but statistically significant rise in agreement with the scientific consensus over 2010-2015. Effects from daily temperature are detectable but minor. Hurricane Sandy, which brushed New Hampshire but caused no disaster there, shows no lasting impact on that state's time series-suggesting that non-immediate weather disasters have limited effects. In all datasets political orientation dominates among individual-level predictors of climate beliefs, moderating the otherwise positive effects from education. Acceptance of anthropogenic climate change rises with education among Democrats and Independents, but not so among Republicans. The continuing series of surveys provides a baseline for tracking how future scientific, political, socioeconomic or climate developments impact public acceptance of the scientific consensus. PMID- 26422696 TI - Tin Nanodots Encapsulated in Porous Nitrogen-Doped Carbon Nanofibers as a Free Standing Anode for Advanced Sodium-Ion Batteries. AB - Ultrasmall Sn nanodots (1-2 nm) are homogeneously encapsulated in porous N-doped carbon nanofibers using a simple and scalable electrospinning method. The composite nanofibers weave into flexible free-standing membrane and can be directly used as binder- and current collector-free anode for Na-ion batteries, exhibiting excellent electrochemical performance with high reversible capacity, exceptional rate capability, and ultralong cycle life. PMID- 26422697 TI - Thin-dielectric-layer engineering for 3D nanostructure integration using an innovative planarization approach. AB - Three-dimensional (3D) nanostructures are emerging as promising building blocks for a large spectrum of applications. One critical issue in integration regards mastering the thin, flat, and chemically stable insulating layer that must be implemented on the nanostructure network in order to build striking nano architectures. In this letter, we report an innovative method for nanoscale planarization on 3D nanostructures by using hydrogen silesquioxane as a spin-on glass (SOG) dielectric material. To decouple the thickness of the final layer from the height of the nanostructure, we propose to embed the nanowire network in the insulator layer by exploiting the planarizing properties of the SOG approach. To achieve the desired dielectric thickness, the structure is chemically etched back with a highly diluted solution to control the etch rate precisely. The roughness of the top surface was less than 2 nm. There were no surface defects and the planarity was excellent, even in the vicinity of the nanowires. This newly developed process was used to realize a multilevel stack architecture with sub-deca-nanometer-range layer thickness. PMID- 26422695 TI - MicroRNA expression profiling in children with different asthma phenotypes. AB - An improved understanding of the molecular mechanisms in asthma through exploring the role of microRNAs may offer promise to reveal new approaches for primary prevention and identification of new therapeutic targets in childhood asthma. The primary goal of this study is to identify the microRNAs that play a role in the pathogenesis of asthma in pediatric age group. The secondary goal is to analyze these microRNAs according to the asthma phenotype, atopic status, and severity of the disease exacerbation. To our knowledge, this is the first research project in the literature which studies the relationship between microRNA expression and the severity of childhood asthma. One hundred children between 6 and 18 years old with a diagnosis of asthma, and 100 age-matched healthy children were enrolled in this study, and the analyses of microRNA expression profiles were performed in the Medical Genetics Laboratories of Ege University between November 2009 and June 2010. The expression of 10 microRNAs were shown to be higher in patients with more severe asthma, and the expression of these microRNAs were also found to be higher in patients who present with more severe acute asthma exacerbation symptoms (P < 0.001). Also, five microRNAs were found to be expressed more than twofold in allergic patients when compared to non-allergic participants (P <0.001). Asthma is one of the best examples of complex genetic diseases, and further studies, which will investigate the relationship between these microRNA's and their target genes, are needed to learn more about the specific roles of microRNAs in respiratory diseases. Pediatr Pulmonol. 2016;51:582-587. (c) 2015 Wiley Periodicals, Inc. PMID- 26422698 TI - Effect of Risk of Bias on the Effect Size of Meta-Analytic Estimates in Randomized Controlled Trials in Periodontology and Implant Dentistry. AB - BACKGROUND: Risk of bias (ROB) may threaten the internal validity of a clinical trial by distorting the magnitude of treatment effect estimates, although some conflicting information on this assumption exists. OBJECTIVE: The objective of this study was evaluate the effect of ROB on the magnitude of treatment effect estimates in randomized controlled trials (RCTs) in periodontology and implant dentistry. METHODS: A search for Cochrane systematic reviews (SRs), including meta-analyses of RCTs published in periodontology and implant dentistry fields, was performed in the Cochrane Library in September 2014. Random-effect meta analyses were performed by grouping RCTs with different levels of ROBs in three domains (sequence generation, allocation concealment, and blinding of outcome assessment). To increase power and precision, only SRs with meta-analyses including at least 10 RCTs were included. Meta-regression was performed to investigate the association between ROB characteristics and the magnitudes of intervention effects in the meta-analyses. RESULTS: Of the 24 initially screened SRs, 21 SRs were excluded because they did not include at least 10 RCTs in the meta-analyses. Three SRs (two from periodontology field) generated information for conducting 27 meta-analyses. Meta-regression did not reveal significant differences in the relationship of the ROB level with the size of treatment effect estimates, although a trend for inflated estimates was observed in domains with unclear ROBs. CONCLUSION: In this sample of RCTs, high and (mainly) unclear risks of selection and detection biases did not seem to influence the size of treatment effect estimates, although several confounders might have influenced the strength of the association. PMID- 26422699 TI - Low-energy structures of benzene clusters with a novel accurate potential surface. AB - The benzene-benzene (Bz-Bz) interaction is present in several chemical systems and it is known to be crucial in understanding the specificity of important biological phenomena. In this work, we propose a novel Bz-Bz analytical potential energy surface which is fine-tuned on accurate ab initio calculations in order to improve its reliability. Once the Bz-Bz interaction is modeled, an analytical function for the energy of the Bzn clusters may be obtained by summing up over all pair potentials. We apply an evolutionary algorithm (EA) to discover the lowest-energy structures of Bzn clusters (for n=2-25), and the results are compared with previous global optimization studies where different potential functions were employed. Besides the global minimum, the EA also gives the structures of other low-lying isomers ranked by the corresponding energy. Additional ab initio calculations are carried out for the low-lying isomers of Bz3 and Bz4 clusters, and the global minimum is confirmed as the most stable structure for both sizes. Finally, a detailed analysis of the low-energy isomers of the n = 13 and 19 magic-number clusters is performed. The two lowest-energy Bz13 isomers show S6 and C3 symmetry, respectively, which is compatible with the experimental results available in the literature. The Bz19 structures reported here are all non-symmetric, showing two central Bz molecules surrounded by 12 nearest-neighbor monomers in the case of the five lowest-energy structures. PMID- 26422700 TI - High incidence of metachronous advanced adenoma and cancer after endoscopic resection of colon polyps >=20 mm in size. AB - BACKGROUND AND AIM: There are limited studies on incidence rates of metachronous neoplastic lesions after resecting large colorectal polyps. In the present study, we analyzed metachronous lesions after endoscopic resection of colorectal polyps >=20 mm in size. METHODS: We retrospectively analyzed consecutive patients who underwent endoscopic resection of polyps from 2006 to 2013 at two affiliated hospitals. All patients underwent at least two total colonoscopies before follow up to ensure minimal missed polyps. Only patients who had follow-up colonoscopy annually after resection were recruited. We separated patients according to size of polyp resected; there were 239 patients in the >=20-mm group and 330 patients in the <20-mm group. Clinical characteristics and cumulative rates of metachronous advanced adenoma and cancer in both groups were analyzed. Advanced adenoma was defined as a neoplastic lesion >=10 mm in size and adenoma with a villous component. RESULTS: Cumulative rate of development of metachronous advanced adenoma and cancer in the >=20-mm group was significantly higher than in the <20-mm group (22.9% vs. 9.5%, P < 0.001) at 36 months. There was also more development of small polyps 5-9 mm in the >=20-mm group than in the <20-mm group (45.2% vs. 28.8%, P < 0.001). With respect to metachronous lesions, there were more right-sided colonic lesions in the >=20-mm group than in the <20-mm group (78.8% vs. 50.0%, P = 0.015). CONCLUSION: High incidence rates of development of metachronous neoplastic lesions were detected after resection of colorectal polyps >=20 mm in size. PMID- 26422702 TI - Motivating contributions to online forums: can locus of control moderate the effects of interface cues? AB - In an effort to encourage users to participate rather than lurk, online health forums provide authority badges (e.g., guru) to frequent contributors and popularity indicators (e.g., number of views) to their postings. Studies have shown the latter to be more effective, implying that bulletin-board users are motivated by external validation of their contributions. However, no consideration has yet been given to individual differences in the influence of such popularity indicators. Personality psychology suggests that individuals with external, rather than internal, locus of control are more likely to be other directed and therefore more likely to be motivated by interface cues showing the bandwagon effect of their online posts. We investigate this hypothesis by analyzing data from a 2 (high vs. low authority cue) * 2 (strong vs. weak bandwagon cue) experiment with an online health community. Results show that strong bandwagon cues promote sense of community among users with internal, rather than external, locus of control. When bandwagon cues are weak, bestowal of high authority serves to heighten their sense of agency. Contrary to prediction, weak bandwagon cues appear to promote sense of community and sense of agency among those with external locus of control. Theoretical and practical implications are discussed. PMID- 26422701 TI - ANXIOUS AND AGGRESSIVE: THE CO-OCCURRENCE OF IED WITH ANXIETY DISORDERS. AB - BACKGROUND: Evidence suggests that impulsive aggression and explosive anger are common among individuals with anxiety disorders; yet, the influence of intermittent explosive disorder (IED) on the onset, course, consequences, and patterns of comorbidity among those with anxiety disorders is unknown. METHODS: Data were drawn from the National Comorbidity Survey Replication (N = 9,282) and Adolescent Supplement (N = 9,632), nationally representative surveys conducted between 2001 and 2004. Diagnoses were based on structured lay-administered interviews. Lifetime diagnoses were assessed with structured instruments. Outcomes included comorbidity, functional and role impairment, and treatment utilization. RESULTS: Adolescents with a lifetime anxiety disorder had a higher prevalence of a lifetime anger attacks (68.5%) and IED (22.9%) than adolescents without a lifetime anxiety disorder (48.6 and 7.8%, respectively), especially social phobia and panic disorders. Similar elevation was found for adults. Age of onset and course of anxiety disorders did not differ by IED. Severe functional impairment associated with anxiety was higher among adolescents (39.3%) and adults (45.7%) with IED than those without IED (29.2 and 28.2%, respectively). Comorbidity for all other disorders was elevated. However, individuals with anxiety disorders and IED were no more likely to use treatment services than those with anxiety disorders without IED. CONCLUSIONS: Individuals with IED concomitant to anxiety disorder, especially social phobia and panic, are at marked risk for worse functional impairment and a higher burden of comorbidity, but onset and course of anxiety disorder do not differ, and those with anxiety and IED are no more likely to utilize treatment services. Assessment, identification, and specialized treatment of anger in the context of anxiety disorders are critical to reducing burden. PMID- 26422703 TI - High-affinity selective inhibitor against phospholipase A2 (PLA2): a computational study. AB - Phospholipase A2 (PLA2) is the most abundant protein found in snake venom. PLA2 induces a variety of pharmacological effects such as neurotoxicity, myotoxicity and cardiotoxicity as well as anticoagulant, hemolytic, anti-platelet, hypertensive, hemorrhagic and edema inducing effects. In this study, the three dimensional structure of PLA2 of Naja sputatrix (Malayan spitting cobra) was modeled by I-TASSER, SWISS-MODEL, PRIME and MODELLER programs. The best model was selected based on overall stereo-chemical quality. Further, molecular dynamics simulation was performed to know the stability of the modeled protein using Gromacs software. Average structure was generated during the simulation period of 10 ns. High throughput virtual screening was employed through different databases (Asinex, Hit finder, Maybridge, TOSLab and ZINC databases) against PLA2. The top seven compounds were selected based on the docking score and free energy binding calculations. These compounds were analyzed by quantum polarized ligand docking, induced fit docking and density functional theory calculation. Furthermore, the stability of lead molecules in the active site of PLA2 was employed by MD simulation. The results show that selected lead molecules were highly stable in the active site of PLA2. PMID- 26422704 TI - A Morphologic and Quantitative Study of Mechanoreceptors in the Remnant Stump of the Human Anterior Cruciate Ligament. AB - PURPOSE: To investigate the morphology and quantity of mechanoreceptors in the remnant stumps of injured anterior cruciate ligaments (ACLs) and the association of the number of mechanoreceptors with the time from injury to surgery. METHODS: Complete ACL stump specimens were collected from 40 volunteer patients who underwent arthroscopic ACL reconstruction surgery. Serial sections, 20 MUm in thickness, were prepared from each specimen. After H&E staining and immunohistochemical labeling, the morphology, type, size, and quantity of the mechanoreceptors were observed under an optical microscope. RESULTS: A total of 176 Ruffini corpuscles, 61 pacinian corpuscles, 15 Golgi-like tendon organs, and 66 atypical mechanoreceptors were observed. Free nerve endings were commonly present in the specimens. The time from injury to surgery (log10 days) was negatively correlated with the number of total mechanoreceptors (r = -0.43, P < .006), Ruffini corpuscles (r = -0.45, P < .003), and the volume of the ACL stump (r = -0.52, P < .01), and these correlations were independent of age, gender, injury side, and career. CONCLUSIONS: The number of mechanoreceptors in an ACL stump and the volume of the stump decreased with the time from injury to surgery. CLINICAL RELEVANCE: This study provides a further theoretical basis for ACL reconstruction with remnant preservation. PMID- 26422705 TI - Comparison of Femoral Tunnel Length and Obliquity Between Transtibial, Anteromedial Portal, and Outside-In Surgical Techniques in Single-Bundle Anterior Cruciate Ligament Reconstruction: A Meta-analysis. AB - PURPOSE: It is unclear whether femoral tunnel length and obliquity differ after transtibial and independent femoral drilling techniques of anterior cruciate ligament (ACL) reconstruction. This meta-analysis therefore compared femoral tunnel length and obliquity in patients who underwent ACL reconstruction by the transtibial, anteromedial (AM) portal, and outside-in (OI) techniques. METHODS: In accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, all studies comparing femoral tunnel length and obliquity with various measurement tools-from direct measurement to imaging methods such as plain radiography, computed tomography, or magnetic resonance imaging-in patients who underwent reconstruction by the transtibial or independent femoral drilling (AM portal or OI) techniques were included. RESULTS: Fourteen studies were included in the meta-analysis. The femoral tunnel length was 7.8 to 11.0 mm longer (P < .05) and coronal obliquity was 7.5 degrees to 29.1 degrees more vertical (P < .05) with the transtibial technique than with the AM portal or OI technique. Femoral tunnel and graft obliquity in the sagittal plane, however, did not differ significantly (P > .05). CONCLUSIONS: ACL reconstruction using the AM portal and OI femoral drilling techniques resulted in a shorter length and greater coronal obliquity of the femoral tunnel than did the transtibial technique. However, these 3 femoral drilling techniques resulted in similar obliquities of the femoral tunnel and graft in the sagittal plane. LEVEL OF EVIDENCE: Level III, meta-analysis. PMID- 26422706 TI - Risk of Infection After Intra-articular Steroid Injection at the Time of Ankle Arthroscopy in a Medicare Population. AB - PURPOSE: To employ a national database to evaluate the association between intraoperative corticosteroid injection at the time of ankle arthroscopy and postoperative infection rates in Medicare patients. METHODS: A national insurance database was queried for Medicare patients who underwent ankle arthroscopy, including arthroscopic removal of loose body, synovectomy, and limited or extensive debridement. Two groups were created: ankle arthroscopy with concomitant local steroid injection (n = 459) and a control group of patients who underwent ankle arthroscopy without intraoperative local steroid injection (n = 9,327). The demographics and Charlson Comorbidity Index of each group were compared. Infection rates within 6 months postoperatively were assessed using International Classification of Diseases, 9th revision, and Current Procedural Terminology codes and compared between groups using chi(2)-tests. RESULTS: A total of 9,786 unique patients who underwent ankle arthroscopy were included in the study. There were no statistically significant differences between the steroid injection study group and controls for the assessed infection-related variables, including gender, age group, obesity, smoking, and average Charlson Comorbidity Index. The infection rate for patients who had a local steroid injection at the time of surgery was 3.9% (18/459 patients), compared with 1.8% (168/9,327 patients) in the control group (odds ratio, 2.2; 95% confidence interval, 1.4 to 3.7; P = .002.) The majority of this difference was noted between the 65 and 79 years age groups. CONCLUSIONS: The use of intraoperative intraarticular corticosteroid injection at the time of ankle arthroscopy in Medicare patients is associated with significantly increased rates of postoperative infection compared with controls without intraoperative steroid injections. PMID- 26422707 TI - Repair of the Posterior Third of the Meniscus During Meniscus Allograft Transplantation: Conventional Inside-Out Repair Versus FasT-Fix All-Inside Repair. AB - PURPOSE: To compare conventional inside-out (IO) repair and all-inside (AI) repair for the posterior third of the meniscus during meniscus allograft transplantation (MAT). METHODS: Among the 64 enrolled patients, 31 patients underwent MAT with conventional IO repair, and 33 patients underwent MAT with AI repair using the FasT-Fix instrument for the posterior third of the meniscus allograft. All of the patients were retrospectively evaluated through clinical assessment at the last follow-up (54.3 months in the IO group and 55.4 months in the AI group) and through magnetic resonance imaging assessment for meniscal extrusion at 1 year postoperatively. Thirty patients (15 in each group) were evaluated through second-look arthroscopy at 1 year postoperatively. RESULTS: There was no significant difference in the mean Lysholm score (91.3 in the IO group and 92.3 in the AI group; P = .358) or the mean Tegner activity scale (7.1 in each group; P = .885) between the 2 groups. There was no significant difference in the mean meniscal extrusion (2.6 mm in the IO group and 2.8 mm in the AI group; P = .454), relative percentage of extrusion value (25.6% in the IO group and 24.7% in the AI group; P = .721), or meniscal healing on second-look arthroscopy (P = .796) between the 2 groups. The difference in operative time between the 2 groups was found to be statistically significant (169.9 minutes in the IO group and 123.3 minutes in the AI group; P < .001). CONCLUSIONS: Our comparative study on the different techniques for posterior repair of meniscus allograft suggested that AI posterior repair using FasT-Fix could be an alternative method to conventional IO repair as it gives a similar postoperative result and requires a shorter operative time. PMID- 26422708 TI - Allograft Use in Arthroscopic Labral Reconstruction of the Hip With Front-to-Back Fixation Technique: Minimum 2-Year Follow-up. AB - PURPOSE: To present minimum 2-year outcomes in patients who underwent a modified technique for arthroscopic labral reconstruction using iliotibial band allograft tissue and a front-to-back fixation. METHODS: From April 2011 to July 2012, all consecutive arthroscopic labral reconstruction patients were included in this Institutional Review Board-approved, prospective case series study. Inclusion criteria were arthroscopic iliotibial band allograft labral reconstruction performed by a single surgeon, age >=16 years at the time of arthroscopy, and a minimum of 2 years of follow-up. Patients completed subjective questionnaires both preoperatively and postoperatively, including Modified Harris Hip Score (MHHS), the Lower Extremity Function Score (LEFS), Visual Analogue Scale (VAS) pain scores, and patient satisfaction. A modified front-to-back fixation technique for labral reconstruction was used. RESULTS: One hundred fifty-two hips (142 patients) met the inclusion criteria for this study; 131 hips (86.2%) had complete follow-up at a minimum of 2 years, and 21 hips (13.8%) were lost to follow-up or had incomplete data during the study period. Seventy hips had concomitant procedures performed; 27 microfracture, 30 chondroplasty, 26 psoas release, 5 os acetabuli resection, and 3 Ganz osteotomy. Overall, 18 hips (13.7%) required revision procedures at a mean of 17 months (range, 1 to 37 months) after the labral reconstruction. In the remaining 113 hips, there was significant improvement in all outcome measures from preoperative to most recent follow-up (P < .0001). The mean MHHS improved by 34 points (P < .0001), and the mean LEFS improved by 27 points (P < .0001). The mean VAS pain score improved by 3 points at rest (P < .0001), 4 points with average pain with daily activities (P < .0001), and 5 points with sport (P < .0001). Patients reported an overall satisfaction of 9 (range, 1 to 10). CONCLUSIONS: Arthroscopic iliotibial band allograft labral reconstruction of the hip shows promising outcomes at minimum 2 year follow-up. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 26422709 TI - Medial Meniscal Root Avulsion: A Biomechanical Comparison of 4 Different Repair Constructs. AB - PURPOSE: To evaluate the time-zero load-to-failure strength of 4 different constructs used to repair medial meniscal root avulsions. METHODS: Sixty fresh frozen cadaveric knees with a mean age of 74 years were used for this study. Each knee was dissected to isolate the attachment of the posterior root of the medial meniscus to the tibial plateau. An Instron machine (Instron, Norwood, MA) with a custom-designed clamp was used to avulse the intact posterior meniscal root in 12 control specimens. An additional 48 specimens were tested after transection of the native meniscal root to evaluate the pullout strength of 4 different repair constructs using No. 0 FiberWire suture (Arthrex, Naples, FL): a single suture (n = 12), a double suture (n = 12), a loop stitch (n = 12), and a locking loop stitch (n = 12). Analysis of variance was used to compare load to failure and stiffness of all 4 groups; pair-wise, between-group differences were also assessed. RESULTS: Repair failure occurred most commonly by suture pullout in 94% of the specimens in the repair groups. For the controls, failure occurred most commonly at the meniscus-clamp interface. Failure load was highest for the control group (mean, 359.5 +/- 168 N), followed in descending order by the locking loop stitch (191.4 +/- 45.1 N), loop stitch (119.6 +/- 55.0 N), double suture (96.2 +/- 51.4 N), and single suture (58.2 +/- 29.6 N). The control group was significantly stronger than 3 of the experimental groups (single suture [95% CI, 3.8 to 11.3], double suture [95% CI, 2.1 to 6.4], and loop stitch [95% CI, 2.0 to 4.5]; P < .0001) but not the locking loop stitch (P = .003; 95% CI, 1.2 to 3.2). The locking loop stitch was significantly stronger than the single suture (P < .0001; 95% CI, 2.0 to 5.4) and double suture (P = .003; 95% CI, 1.2 to 2.9). The locking loop stitch was significantly stiffer than the single suture (P < .0001; 95% CI, 3.8 to 20.3), double suture (P < .0001; 95% CI, 2.0 to 9.8), and loop stitch (P = .03; 95% CI, 1.1 to 5.5) but not significantly different from the control group (P = .93; 95% CI, 0.3 to 1.9). Age and gender had no effect on pullout strength. CONCLUSIONS: The results of this study show that the locking loop stitch provided time-zero load-to-failure strength that most closely approximated the strength of the native meniscal root in addition to being significantly stronger and stiffer than 3 other commonly used repair methods. The true strength of the native meniscal root is unknown based on limitations with our testing methodology. CLINICAL RELEVANCE: The locking loop stitch exhibited the highest load to failure and stiffness of the 4 fixation methods tested, despite the fact that none of the fixation methods replicated the strength of the intact meniscal root. It is currently unknown what strength of fixation is required for healing of meniscal root repairs. PMID- 26422710 TI - Failures and Reoperations After Matrix-Assisted Cartilage Repair of the Knee: A Systematic Review. AB - PURPOSE: To quantify the reported failures and reoperations for the emerging technique of matrix-assisted cartilage repair at short-term and midterm follow up. METHODS: We conducted a systematic review of 3 databases from March 2004 to February 2014 using keywords important for articular cartilage repair. Two authors reviewed the articles, the study exclusion criteria were applied, and articles were determined to be relevant (or not) to the research question. All studies with a minimum of 2 years' clinical follow-up were reviewed for all reported reoperations. The reasons for reoperations were recorded. RESULTS: We reviewed 66 articles from the 301 articles identified in the original systematic search. There were 60 articles on matrix-assisted cartilage transplantation and 6 articles on matrix-induced chondrogenesis. The matrix-assisted cartilage transplantation studies reported on a total of 1,380 patients at 2 to 5 years' follow-up. Among these, there were 72 reoperations (5%) including 46 treatment failures (3%). These numbers increased to an 11% reoperation rate and 9% treatment failure rate at minimum 5-year follow-up of 961 patients. The most common procedures performed other than revision cartilage surgery or arthroplasty were manipulation under anesthesia for arthrofibrosis (0.7%) and debridement for graft hypertrophy (1.2%). The matrix-induced chondrogenesis studies reported on 163 patients. Among these, there were 15 reoperations (9%) that included 4 treatment failures (2%), 9 manipulations under anesthesia (6%), and 2 debridements for graft hypertrophy (1%). CONCLUSIONS: Treatment failure rates for matrix-assisted cartilage repair increase from short-term to midterm follow-up, with 11% of patients having undergone further surgery at a minimum of 5 years' follow-up. These data can be used to counsel patients on the potential need for further operative intervention after this emerging cartilage repair technique. PMID- 26422711 TI - Panel manipulation in social stress testing: The Bath Experimental Stress Test for Children (BEST-C). AB - BACKGROUND: Whilst acute stress paradigms in adults make use of adult panel members, similar paradigms modified for child participants have not manipulated the panel. Most work has utilised an audience of adult confederates, regardless of the age of the population being tested. The aim of this study was to trial a social stress test for children that provided a meaningful environment using age matched child peers as panel actors. METHODS: Thirty-three participants (7-11 years) underwent the Bath Experimental Stress Test for Children (BEST-C). Based on the Trier Social Stress Test (TSST), it comprises a shortened six-minute public speaking task and four-minute maths challenge. It differs from previous stress tests by using age-matched children on the panel, pre-recorded and presented as a live feed, and includes an expanded manipulation check of subjective experience. Salivary cortisol was assessed at four time points, pre post stress testing; life events, daily hassles and coping strategies were measured through questionnaires. A simple numerical coding scheme was applied to post-test interview data. RESULTS: The BEST-C generated a typical stress and adaptation response in salivary cortisol (p=.032). Age and gender differences were observed during recovery. Cortisol responses mapped directly onto three distinct subjective response patterns: (i) expected response and recovery; (ii) expected response, no recovery; (iii) no response. CONCLUSIONS: The BEST-C, utilising child confederates of participant target age is a meaningful social stress test for children. This is the first social stress test developed specifically for children that manipulates panel characteristics by using child confederates and a pre-recorded sham panel. Greater cortisol responses to the test were also found to match subjective verbal accounts of the experience. It offers a meaningful acute stress paradigm with potential applications to other child and adolescent age groups. Furthermore, it leads the way in the use of panel manipulation in social stress testing. PMID- 26422712 TI - Efficacy of combined vaccination against Mycoplasma hyopneumoniae and porcine reproductive and respiratory syndrome virus in dually infected pigs. AB - Porcine respiratory disease complex (PRDC) is one of the main causes of economic losses for swine producers. This complex is due to a combination of different pathogens and their interactions. Two major pathogens involved in PRDC are Mycoplasma hyopneumoniae (Mhp) and porcine reproductive and respiratory syndrome virus (PRRSV). The objectives of this study were (i) to develop an experimental model of dual Mhp/PRRSV infection in SPF pigs with European strains of Mhp and PRRSV and (ii) to assess and compare the effects of single Mhp, single PRRSV or combined Mhp/PRRSV vaccination against this dual infection. Pigs dually infected with Mhp and PRRSV showed a combination of symptoms characteristic of each pathogen but no significant exacerbation of pathogenicity. Thus, the co-infected pigs displayed coughing and pneumonia typical of Mhp infection in addition to PRRSV-related hyperthermia and decrease in average daily gain (ADG). Hyperthermia was reduced in PRRSV vaccinated animals (single or combined vaccination), whereas ADG was restored in Mhp/PRRSV vaccinated pigs only. Regarding respiratory symptoms and lung lesions, no vaccine decreased coughing. However, all vaccines reduced the pneumonia score but more so in animals receiving the Mhp vaccine, whether single or combined. This vaccine also decreased the Mhp load in the respiratory tract. In conclusion, combined vaccination against both Mhp and PRRSV efficiently pooled the efficacy of each single PRRSV and Mhp vaccination and could be an interesting tool to control PRDC in European swine production. PMID- 26422713 TI - CD25 expression on residual leukemic blasts at the time of allogeneic hematopoietic stem cell transplant predicts relapse in patients with acute myeloid leukemia without complete remission. AB - Recent studies have shown that CD25 expression at the time of diagnosis of acute myeloid leukemia (AML) may be associated with an unfavorable outcome. We focus on patients with AML without complete remission (CR) and examine the clinical correlation between surface CD25 expression at the time of transplant and subsequent transplant outcomes. We observed a significant difference in overall survival (OS), disease-free survival (DFS) and cumulative incidence of relapse (CIR) between CD25 positive (+) (n = 22) and negative (-) groups (n = 44) (2-year OS; CD25 (+) group: 5% vs. CD25 (-) group: 40%, p < 0.0001, 2-year DFS; 5% vs. 29%, p < 0.0001, 2-year CIR; 77% vs. 52%, p = 0.03). Multivariate analysis showed that CD25 expression was an independent adverse factor for OS (p = 0.002) and relapse (p = 0.001). Patients with AML with residual CD25 positive blasts at the time of transplant may require additional therapy before or after transplant to improve survival. PMID- 26422714 TI - [Adipocytic tumors of the salivary glands: A retrospective study]. AB - INTRODUCTION: Adipocytic tumors are the most common soft tissue mesenchymal tumors. Their occurrence in salivary glands is rare. We studied the epidemiology, the diagnostic and the therapeutic features of the salivary adipocytic tumors followed in our department. PATIENTS AND METHODS: A retrospective study was conducted in our department between January 1997 and December 2011. Nine cases of adipocytic tumors of the salivary glands were found. Data were collected from medical records and processed by Excel. RESULTS: Mean age was 44 with a clear predominance of males (sex ratio: 3.5). In 8 cases the tumors were benign (7 lipomas and 1 lipofibroma). The only malignant tumor was a metastatic myxoid liposarcoma. Parotid was the main location (8 cases/9). Ultrasonography and MRI were prescribed. The treatment was tumor and parotid gland removal with conservation of the facial nerve excepted in the malignant case. One transient facial palsy, two earlobe dysesthesia and one retromandibular depression were observed. No recurrence was noted. DISCUSSION: Our study confirmed the epidemiological profile of these adipocytic salivary gland tumors, which are rarely observed, but mainly in the parotid gland. They are often benign and lipoma is the main histological type. PMID- 26422715 TI - Characteristics of Consecutive Esophageal Motility Diagnoses After a Decade of Change. AB - BACKGROUND AND AIMS: Combined multichannel intraluminal impedance and esophageal manometry (MII-EM) measures concomitantly bolus transit and pressure changes allowing determination of the functional impact of esophageal motility abnormalities. Ten years ago our laboratory reported MII-EM results in 350 consecutive patients. Since then high-resolution impedance manometry (HRIM) became available and the definitions of ineffective esophageal motility (IEM) and nutcracker esophagus were revised. The aim of this study was to assess the impact of these developments on esophageal function testing. METHODS: From August 2012 through May 2013, HRIM was performed in 350 patients referred for esophageal function testing. Each patient received 10 liquid and 10 viscous swallows. While taking advantage of the new technology and revised criteria, HRIM findings were classified according to the conventional criteria to allow more appropriate comparison with our earlier analysis. RESULTS: Compared with the study performed 10 years ago, the prevalence of normal manometry (36% vs. 35%), achalasia (7% vs. 8%), scleroderma (1% vs. 1%), hypertensive lower esophageal sphincter (LES) (7% vs. 7%), and hypotensive LES (1% vs. 2%) remained the same, whereas the prevalence of distal esophageal spasm (9% vs. 3%), nutcracker esophagus (9% vs. 3%), and poorly relaxing LES (10% vs. 3%) decreased and the prevalence of IEM increased (20% vs. 31%) significantly. Compared with the early study, normal liquid bolus transit was significantly different in patients with hypertensive LES (96% vs. 57%) and poorly relaxing LES (55% vs. 100%). CONCLUSIONS: This study brings to light the increase in prevalence of IEM. In addition, it suggests that the hypertensive LES and poorly relaxing LES may each affect bolus transit in about half of these patients. PMID- 26422716 TI - Zinc Triflate Catalyzed C-Benzylation: Chemo- and Regioselective Route to Amido Substituted Diaryl and Arylheteroarylmethanes. AB - An unprecedented zinc triflate catalyzed selective C-benzylation of anilides and heteroaryl amides with benzyl chlorides having electron-donating group at para position is reported. The protocol offers moderate to high yield of para-amido substituted diaryl and arylheteroarylmethanes, uses cheap and easily available benzyl chlorides as the benzylating agent, catalytic amount of zinc triflate, and takes place under ambient conditions. Aminodiarylmethane derivatives can be obtained by hydrolysis of the corresponding amides. The methodology has also been applied for preparing dimethoxydiarylmethanes in good yields, which are the key precursors for synthesis of phenolic natural products. PMID- 26422717 TI - Allergic Contact Dermatitis Due to Dittrichia viscosa. PMID- 26422718 TI - Risk Analysis of Pneumonitis in Taxane Therapy After Chemoradiotherapy for Patients With Metastatic or Recurrent Esophageal Cancer. AB - OBJECTIVES: Taxane chemotherapy for esophageal cancer causes pneumonitis, not only by itself but also by radiation recall. This study aimed to clarify the risk of pneumonitis in patients with esophageal cancer who receive taxane therapy after chemoradiotherapy. METHODS: The data of 129 patients with metastatic or recurrent esophageal cancer who initiated taxane therapy between September 2002 and June 2013 were retrospectively analyzed. Patient selection criteria were as follows: performance status <=2, preserved organ functions, previous chemoradiotherapy with a radiation dose of >=50 Gy, grade 0 or 1 pneumonitis at taxane initiation, and no concomitant malignancy. Logistic regression analysis was performed to identify risk factors for pneumonitis. RESULTS: Patient characteristics were as follows: males/females, 116/13; median age, 63 years (range, 44 to 80 y); performance status of 0/1/2, 61/60/8; smoking history, 112 (88%); location of the primary tumor Ce/Ut/Mt/Lt/Ae 12/30/66/20/1; median radiation dose, 60 Gy; history of radiation pneumonitis, 39 (30%); history of other pulmonary disease, 4 (3%); and median duration between the last radiation therapy (RT) exposure and taxane initiation, 6.1 months (range, 1.0 to 71 mo). During the median observation period of 7.8 months from taxane initiation, the incidence of grade 2 and 3 pneumonitis was observed in 7 (5.4%) and 3 (2.3%) patients, respectively. No patient died of pneumonitis. The only independent risk factor for pneumonitis was a <=4-month period between the last RT exposure and taxane initiation (P=0.03). CONCLUSIONS: A short period between the last RT exposure and taxane initiation is an independent risk factor for pneumonitis development. PMID- 26422719 TI - Transforming Turkey's Health System--Lessons for Universal Coverage. PMID- 26422720 TI - Reduced-Nicotine Cigarettes--A Promising Regulatory Pathway. PMID- 26422721 TI - Cardiometabolic Risks and Severity of Obesity in Children and Young Adults. AB - BACKGROUND: The prevalence of severe obesity among children and young adults has increased over the past decade. Although the prevalence of cardiometabolic risk factors is relatively low among children and young adults who are overweight or obese, those with more severe forms of obesity may be at greater risk. METHODS: We performed a cross-sectional analysis of data from overweight or obese children and young adults 3 to 19 years of age who were included in the National Health and Nutrition Examination Survey from 1999 through 2012 to assess the prevalence of multiple cardiometabolic risk factors according to the severity of obesity. Weight status was classified on the basis of measured height and weight. We used standard definitions of abnormal values for total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, triglycerides, blood pressure, glycated hemoglobin, and fasting glucose and report the prevalence of abnormal values in children and young adults according to weight status. RESULTS: Among 8579 children and young adults with a body-mass index at the 85th percentile or higher (according to the Centers for Disease Control and Prevention growth charts), 46.9% were overweight, 36.4% had class I obesity, 11.9% had class II obesity, and 4.8% had class III obesity. Mean values for some, but not all, cardiometabolic variables were higher with greater severity of obesity in both male and female participants, and the values were higher in male participants than in female participants; for HDL cholesterol, the mean values were lower with greater severity of obesity. Multivariable models that controlled for age, race or ethnic group, and sex showed that the greater the severity of obesity, the higher the risks of a low HDL cholesterol level, high systolic and diastolic blood pressures, and high triglyceride and glycated hemoglobin levels. CONCLUSIONS: Severe obesity in children and young adults was associated with an increased prevalence of cardiometabolic risk factors, particularly among boys and young men. PMID- 26422722 TI - Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis. AB - BACKGROUND: Early clinical studies suggested that the anti-interleukin-17 receptor A monoclonal antibody brodalumab has efficacy in the treatment of psoriasis. METHODS: In two phase 3 studies (AMAGINE-2 and AMAGINE-3), patients with moderate-to-severe psoriasis were randomly assigned to receive brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for patients with a body weight <=100 kg and 90 mg for patients >100 kg), or placebo. At week 12, patients receiving brodalumab were randomly assigned again to receive a brodalumab maintenance dose of 210 mg every 2 weeks or 140 mg every 2 weeks, every 4 weeks, or every 8 weeks; patients receiving ustekinumab continued to receive ustekinumab every 12 weeks, and patients receiving placebo received 210 mg of brodalumab every 2 weeks. The primary aims were to evaluate the superiority of brodalumab over placebo at week 12 with respect to at least a 75% reduction in the psoriasis area-and-severity index score (PASI 75) and a static physician's global assessment (sPGA) score of 0 or 1 (clear or almost clear skin), as well as the superiority of brodalumab over ustekinumab at week 12 with respect to a 100% reduction in PASI score (PASI 100). RESULTS: At week 12, the PASI 75 response rates were higher with brodalumab at the 210-mg and 140-mg doses than with placebo (86% and 67%, respectively, vs. 8% [AMAGINE-2] and 85% and 69%, respectively, vs. 6% [AMAGINE-3]; P<0.001); the rates of sPGA scores of 0 or 1 were also higher with brodalumab (P<0.001). The week 12 PASI 100 response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (44% vs. 22% [AMAGINE-2] and 37% vs. 19% [AMAGINE-3], P<0.001). The PASI 100 response rates with 140 mg of brodalumab were 26% in AMAGINE-2 (P=0.08 for the comparison with ustekinumab) and 27% in AMAGINE-3 (P=0.007). Rates of neutropenia were higher with brodalumab and with ustekinumab than with placebo. Mild or moderate candida infections were more frequent with brodalumab than with ustekinumab or placebo. Through week 52, the rates of serious infectious episodes were 1.0 (AMAGINE-2) and 1.3 (AMAGINE-3) per 100 patient-years of exposure to brodalumab. CONCLUSIONS: Brodalumab treatment resulted in significant clinical improvements in patients with moderate-to-severe psoriasis. (Funded by Amgen; AMAGINE-2 and AMAGINE-3 ClinicalTrials.gov numbers, NCT01708603 and NCT01708629.). PMID- 26422725 TI - Maintenance Intravenous Fluids in Acutely Ill Patients. PMID- 26422726 TI - IMAGES IN CLINICAL MEDICINE. Pseudoaneurysm after Transradial Coronary Angiography. PMID- 26422723 TI - Secukinumab Inhibition of Interleukin-17A in Patients with Psoriatic Arthritis. AB - BACKGROUND: In a phase 2 study, the inhibition of the interleukin-17A receptor improved signs and symptoms of psoriatic arthritis. We sought to evaluate the efficacy and safety of secukinumab, an anti-interleukin-17A monoclonal antibody, in such patients. METHODS: In this double-blind, phase 3 study, 606 patients with psoriatic arthritis were randomly assigned in a 1:1:1 ratio to receive intravenous secukinumab (at a dose of 10 mg per kilogram) at weeks 0, 2, and 4, followed by subcutaneous secukinumab at a dose of either 150 mg or 75 mg every 4 weeks, or placebo. Patients in the placebo group were switched to subcutaneous secukinumab at a dose of 150 mg or 75 mg at week 16 or 24, depending on clinical response. The primary end point was the proportion of patients with an American College of Rheumatology 20 (ACR20) response at week 24, defined as a 20% improvement from baseline in the number of tender and swollen joints and at least three other important domains. RESULTS: ACR20 response rates at week 24 were significantly higher in the group receiving secukinumab at doses of 150 mg (50.0%) and 75 mg (50.5%) than in those receiving placebo (17.3%) (P<0.001 for both comparisons with placebo). Secondary end points, including the ACR50 response and joint structural damage, were significantly better in the secukinumab groups than in the placebo group. Improvements were sustained through 52 weeks. Infections, including candida, were more common in the secukinumab groups. Throughout the study (mean secukinumab exposure, 438.5 days; mean placebo exposure, 128.5 days), four patients in the secukinumab groups had a stroke (0.6 per 100 patient-years; 95% confidence interval [CI], 0.2 to 1.5), and two had a myocardial infarction (0.3 per 100 patient-years; 95% CI, 0.0 to 1.0), as compared with no patients in the placebo group. CONCLUSIONS: Secukinumab was more effective than placebo in patients with psoriatic arthritis, which validates interleukin-17A as a therapeutic target. Infections were more common in the secukinumab groups than in the placebo group. The study was neither large enough nor long enough to evaluate uncommon serious adverse events or the risks associated with long-term use. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT01392326.). PMID- 26422724 TI - Randomized Trial of Reduced-Nicotine Standards for Cigarettes. AB - BACKGROUND: The Food and Drug Administration can set standards that reduce the nicotine content of cigarettes. METHODS: We conducted a double-blind, parallel, randomized clinical trial between June 2013 and July 2014 at 10 sites. Eligibility criteria included an age of 18 years or older, smoking of five or more cigarettes per day, and no current interest in quitting smoking. Participants were randomly assigned to smoke for 6 weeks either their usual brand of cigarettes or one of six types of investigational cigarettes, provided free. The investigational cigarettes had nicotine content ranging from 15.8 mg per gram of tobacco (typical of commercial brands) to 0.4 mg per gram. The primary outcome was the number of cigarettes smoked per day during week 6. RESULTS: A total of 840 participants underwent randomization, and 780 completed the 6-week study. During week 6, the average number of cigarettes smoked per day was lower for participants randomly assigned to cigarettes containing 2.4, 1.3, or 0.4 mg of nicotine per gram of tobacco (16.5, 16.3, and 14.9 cigarettes, respectively) than for participants randomly assigned to their usual brand or to cigarettes containing 15.8 mg per gram (22.2 and 21.3 cigarettes, respectively; P<0.001). Participants assigned to cigarettes with 5.2 mg per gram smoked an average of 20.8 cigarettes per day, which did not differ significantly from the average number among those who smoked control cigarettes. Cigarettes with lower nicotine content, as compared with control cigarettes, reduced exposure to and dependence on nicotine, as well as craving during abstinence from smoking, without significantly increasing the expired carbon monoxide level or total puff volume, suggesting minimal compensation. Adverse events were generally mild and similar among groups. CONCLUSIONS: In this 6-week study, reduced-nicotine cigarettes versus standard-nicotine cigarettes reduced nicotine exposure and dependence and the number of cigarettes smoked. (Funded by the National Institute on Drug Abuse and the Food and Drug Administration Center for Tobacco Products; ClinicalTrials.gov number, NCT01681875.). PMID- 26422727 TI - CLINICAL PROBLEM-SOLVING. Springing a Leak. PMID- 26422728 TI - Hardly Tendentious--Repairing Like with Like. PMID- 26422730 TI - High-Flow Nasal Cannula Oxygen in Respiratory Failure. PMID- 26422729 TI - High-Flow Nasal Cannula Oxygen in Respiratory Failure. PMID- 26422731 TI - High-Flow Nasal Cannula Oxygen in Respiratory Failure. PMID- 26422732 TI - High-Flow Nasal Cannula Oxygen in Respiratory Failure. PMID- 26422733 TI - High-Flow Nasal Cannula Oxygen in Respiratory Failure. PMID- 26422734 TI - Efficacy of a Sexual Assault Resistance Program for University Women. PMID- 26422735 TI - Efficacy of a Sexual Assault Resistance Program for University Women. PMID- 26422736 TI - ClinGen and Genetic Testing. PMID- 26422737 TI - ClinGen and Genetic Testing. PMID- 26422738 TI - ClinGen and Genetic Testing. PMID- 26422739 TI - ClinGen and Genetic Testing. PMID- 26422740 TI - ClinGen and Genetic Testing. PMID- 26422741 TI - HIV Outbreak in Indiana. PMID- 26422742 TI - HIV Outbreak in Indiana. PMID- 26422744 TI - IMAGES IN CLINICAL MEDICINE. An Acute Dystonic Reaction after Treatment with Metoclopramide. PMID- 26422743 TI - Ibrutinib in Refractory Classic Hodgkin's Lymphoma. PMID- 26422745 TI - Influence of Quality of Relationship Between Patient With Melanoma and Partner on Partner-Assisted Skin Examination Education: A Randomized Clinical Trial. AB - IMPORTANCE: Melanoma has a high survival rate if it is detected early. Training patients with early-stage melanoma who are at risk of developing new melanomas to perform skin self-examination (SSE) may improve survival. OBJECTIVE: To examine for whom the intervention works best in a sample composed of dyads of patients with melanoma and skin-check partners who received an SSE intervention vs customary care. DESIGN, SETTING, AND PARTICIPANTS: For 494 patients with stage 0 to IIB melanoma (mean age, 55 years; 253 [51.2%] females) and their skin-check partners (mean age, 55 years; 280 [56.7%] females), a randomized clinical trial was conducted in ambulatory care dermatologic offices from June 6, 2011, to April 14, 2014. Follow-up assessments were performed at 12 months. Analysis was performed between March 23 and June 25, 2015. METHODS: Dyads of 494 patients and their partners were randomly assigned to receive the intervention (395 patients) or customary care (control) (99 patients). The main outcome was patient SSE self efficacy. Partner motivation to assist with SSE and relationship quality (eg, agreeability, activities with partner, and happiness) were assessed for moderation of the influence of the intervention's effect on SSE self-efficacy. RESULTS: Relationship quality, defined by activities with the partner (beta = 0.892, SE = 0.432, t = -2.066; P = .001) and happiness (beta = -4.586, SE = 2.044, t = -2.24; P = .001), significantly moderated the intervention effects on patients' SSE self-efficacy. In contrast, patient-partner agreeability (beta = 0.262, SE = 0.148, t = -1.773; P = .09) and partner motivation (beta = -0.328, SE = 1.024, t = -0.320; P = .10) did not significantly moderate the intervention effects on patients' SSE self-efficacy. Differences between the conditions were highest when activities performed with the partner were below average (mean difference, 6.652; P = .001) and when happiness was below average (mean difference, 7.000; P = .001). Although everyone receiving the intervention experienced some benefit, the findings indicate the greatest increases in self efficacy were observed for those with below-average activities performed with the partner and happiness. CONCLUSIONS AND RELEVANCE: The training of patients with melanoma and their partners in early-detection SSE benefited some more than others. Pairs who have low relationship quality, as determined by activities performed with the partner and happiness, may have received the greatest benefits from the training intervention because they were given an activity to perform together. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01432860. PMID- 26422747 TI - Firearm Injury in the United States: An Overview of an Evolving Public Health Problem. PMID- 26422746 TI - Frailty for Surgeons: Review of a National Institute on Aging Conference on Frailty for Specialists. PMID- 26422748 TI - Coupling Underwater Superoleophobic Membranes with Magnetic Pickering Emulsions for Fouling-Free Separation of Crude Oil/Water Mixtures: An Experimental and Theoretical Study. AB - Oil/water separations have become an area of great interest, as growing oil extraction activities are increasing the generation of oily wastewaters as well as increasing the risk of oil spills. Here, we demonstrate a membrane-based and fouling-free oil/water separation method that couples carbon nanotube-poly(vinyl alcohol) underwater superoleophobic ultrafiltration membranes with magnetic Pickering emulsions. We demonstrate that this process is insensitive to low water temperatures, high ionic strength, or crude oil loading, while allowing operation at high permeate fluxes and producing high quality permeate. Furthermore, we develop a theoretical framework that analyzes the stability of Pickering emulsions under filtration mechanics, relating membrane surface properties and hydrodynamic conditions in the Pickering emulsion cake layer to membrane performance. Finally, we demonstrate the recovery and recyclability of the nanomagnetite used to form the Pickering emulsions through a magnetic separation step, resulting in an environmentally friendly, continuous process for oil/water separation. PMID- 26422749 TI - A combined binding mechanism of nonionic ethoxylated surfactants to bovine serum albumin revealed by fluorescence and circular dichroism. AB - The study systematically investigates aqueous mixtures of fixed bovine serum albumin (BSA) and various ethoxylated nonionic surfactants belonging to a homologous series or not. Mono-disperse tetra-(C12E4), hexa-(C12E6) and octa ethyleneglycol mono-n-dodecyl ether (C12E8), and poly-disperse eicosa ethyleneglycol mono-n-tetradecyl ether (C14EO20) are respectively employed. Fluorescence and circular dichroism measurements are performed at surfactant/protein molar ratios (rm)s lower and higher than one. We aim to get new insights into the binding mechanism of these species and to differentiate among the interaction abilities of these surfactants. The relative magnitude of the binding thermodynamic parameters by fluorescence, and the increase of alpha helix prove that hydrogen bonding drives the interaction next to the hydrophobic attraction. C12En (n=4,6,8) develop more H bonds with the albumin than C14EO20 owing to a zigzag conformation of their short ethyleneoxide chains. Among the homologous surfactants, C12E6 has a slightly stronger interaction with BSA due to a maximal number of H bonds at a minimal hindering. Static fluorescence and dynamic fluorescence indicate an inter-conversion between the tryptophan (Trp) rotamers which happens around the surfactants critical micellar concentration. For C14EO20, the meander conformation of the polar group determines a less evident conversion of the Trp rotamers and smaller alpha-helix rise. Binding isotherms of the homologous surfactants and the fluorescence quenching mechanism by C12E6 are also provided. PMID- 26422750 TI - Remarkable Role of C-I...N Halogen Bonding in Thixotropic 'Halo'gel Formation. AB - Halogen-bonding-induced self-assembly in the solution of equimolar mixtures of certain pyridyl-ended oligo p-phenylenevinylene (OPV)-derivatives with 1,4 diiodotetrafluorobenzene is reported. The mode of self-assembly, that is, cocrystallization, thixotropic gelation, or precipitation, depends strongly on the nature of chains (n-alkyl chains as a function of length or short oxyethylene chain) appended to the OPV-backbone as well as on the cooling rate of the corresponding hot solution. Single-crystal X-ray diffraction studies of the cocrystals reveal the "infinite" chain formation via C-I...N halogen-bonding interactions between the two components. In addition, multiple noncovalent interactions induce cross-links among these halogen-bonded "infinite" chains. Interestingly, the molecular packing in the "Cogel" bearing OPV-derivative with oxyethylene chains is found to be very similar to that of the cocrystal of the same. PMID- 26422751 TI - Phoniatry: otorhinolaryngology expands its limits. PMID- 26422752 TI - Effects of Tris(1,3-dichloro-2-propyl) Phosphate on Growth, Reproduction, and Gene Transcription of Daphnia magna at Environmentally Relevant Concentrations. AB - The synthetic flame retardant tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) has been frequently detected in natural waters, and its maximum concentration ever reported is 377 ng/L. However, information on the adverse effects of environmentally relevant concentrations of TDCIPP on aquatic organisms are totally unknown. In this study, <12-h old water fleas, D. magna, were exposed to concentrations of 0, 65+/-7.1, 550+/-33, or 6500+/-1400 ng/L TDCIPP, and dose- and time-dependent effects on reproduction and development were evaluated. Sequences of genes of D. magna were obtained from the National Center for Biotechnology Information and were used to develop PCR arrays for D. magna. Arrays were then used to study transcriptional responses of D. magna to TDCIPP. Exposure to environmentally relevant concentrations of TDCIPP significantly decreased fecundity as well as length of F0 and F1 generations. Transcriptional responses showed that, of the 155 genes tested, expressions of 57 genes were significantly changed, and some changes occurred following exposure to environmentally relevant concentrations (i.e., 65+/-7.1 and 550+/-23 ng/L). Furthermore, pathways related to protein synthesis and metabolism and endocytosis were considered to be significantly affected in a dose- and time-dependent manner and might be responsible for TDCIPP-induced reproductive and developmental toxicities. PMID- 26422755 TI - Alice in Wonderland Syndrome, Burning Mouth Syndrome, Cold Stimulus Headache, and HaNDL: Narrative Review. AB - BACKGROUND: Unusual headache syndromes are not as infrequent in clinical practice as was generally believed. About three fourths of the classified headache disorders found in the ICHD-II can be considered rare. OBJECTIVE: The aim of this narrative review was to perform a literature review of the pathophysiology, clinical presentation, diagnostic criteria, and treatment of the following unusual headache disorders: Alice in Wonderland syndrome, burning mouth syndrome, cold stimulus headache, and the syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis. METHOD: A literature review was performed using PubMed for each of the abovementioned headache disorders. CONCLUSION: The unusual headache syndromes as a distinct group of disorders are not as infrequent in clinical practice as was generally believed. Some of them, albeit considered as unusual, may occur with relative frequency, such as cold stimulus headache and burning mouth syndrome. PMID- 26422753 TI - CD11b immunophenotyping identifies inflammatory profiles in the mouse and human lungs. AB - The development of easily accessible tools for human immunophenotyping to classify patients into discrete disease endotypes is advancing personalized therapy. However, no systematic approach has been developed for the study of inflammatory lung diseases with often complex and highly heterogeneous disease etiologies. We have devised an internally standardized flow cytometry approach that can identify parallel inflammatory alveolar macrophage phenotypes in both the mouse and human lungs. In mice, lung innate immune cell alterations during endotoxin challenge, influenza virus infection, and in two genetic models of chronic obstructive lung disease could be segregated based on the presence or absence of CD11b alveolar macrophage upregulation and lung eosinophilia. Additionally, heightened alveolar macrophage CD11b expression was a novel feature of acute lung exacerbations in the SHIP-1(-/-) model of chronic obstructive lung disease, and anti-CD11b antibody administration selectively blocked inflammatory CD11b(pos) but not homeostatic CD11b(neg) alveolar macrophages in vivo. The identification of analogous profiles in respiratory disease patients highlights this approach as a translational avenue for lung disease endotyping and suggests that heterogeneous innate immune cell phenotypes are an underappreciated component of the human lung disease microenvironment. PMID- 26422754 TI - Social stress-enhanced severity of Citrobacter rodentium-induced colitis is CCL2 dependent and attenuated by probiotic Lactobacillus reuteri. AB - Psychological stressors are known to affect colonic diseases but the mechanisms by which this occurs, and whether probiotics can prevent stressor effects, are not understood. Because inflammatory monocytes that traffic into the colon can exacerbate colitis, we tested whether CCL2, a chemokine involved in monocyte recruitment, was necessary for stressor-induced exacerbation of infectious colitis. Mice were exposed to a social disruption stressor that entails repeated social defeat. During stressor exposure, mice were orally challenged with Citrobacter rodentium to induce a colonic inflammatory response. Exposure to the stressor during challenge resulted in significantly higher colonic pathogen levels, translocation to the spleen, increases in colonic macrophages, and increases in inflammatory cytokines and chemokines. The stressor-enhanced severity of C. rodentium-induced colitis was not evident in CCL2(-/-) mice, indicating the effects of the stressor are CCL2-dependent. In addition, we tested whether probiotic intervention could attenuate stressor-enhanced infectious colitis by reducing monocyte/macrophage accumulation. Treating mice with probiotic Lactobacillus reuteri reduced CCL2 mRNA levels in the colon and attenuated stressor-enhanced infectious colitis. These data demonstrate that probiotic L. reuteri can prevent the exacerbating effects of stressor exposure on pathogen-induced colitis, and suggest that one mechanism by which this occurs is through downregulation of the chemokine CCL2. PMID- 26422757 TI - Neuron-like differentiation of mesenchymal stem cells on silicon nanowires. AB - The behavior of mammalian cells on vertical nanowire (NW) arrays, including cell spreading and the dynamic distribution of focal adhesions and cytoskeletal proteins, has been intensively studied to extend the implications for cellular manipulations in vitro. Prompted by the result that cells on silicon (Si) NWs showed morphological changes and reduced migration rates, we have explored the transition of mesenchymal stem cells into a neuronal lineage by using SiNWs with varying lengths. When human mesenchymal stem cells (hMSCs) were cultured on the longest SiNWs for 3 days, most of the cells exhibited elongated shapes with neurite-like extensions and dot-like focal adhesions that were prominently observed along with actin filaments. Under these circumstances, the cell motility analyzed by live cell imaging was found to decrease due to the presence of SiNWs. In addition, the slowed growth rate, as well as the reduced population of S phase cells, suggested that the cell cycle was likely arrested in response to the differentiation process. Furthermore, we measured the mRNA levels of several lineage-specific markers to confirm that the SiNWs actually induced neuron-like differentiation of the hMSCs while hampering their osteogenic differentiation. Taken together, our results implied that SiNWs were capable of inducing active reorganization of cellular behaviors, collectively guiding the fate of hMSCs into the neural lineage even in the absence of any inducing reagent. PMID- 26422756 TI - SIRT3 Mediates the Antioxidant Effect of Hydrogen Sulfide in Endothelial Cells. AB - AIM: Oxidative stress is a key contributor to endothelial dysfunction and associated cardiovascular pathogenesis. Hydrogen sulfide (H2S) is an antioxidant gasotransmitter that protects endothelial cells against oxidative stress. Sirtuin3 (SIRT3), which belongs to the silent information regulator 2 (SIR2) family, is an important deacetylase under oxidative stress. H2S is able to regulate the activity of several sirtuins. The present study aims to investigate the role of SIRT3 in the antioxidant effect of H2S in endothelial cells. RESULTS: Cultured EA.hy926 endothelial cells were exposed to hydrogen peroxide (H2O2) as a model of oxidative stress-induced cell injury. GYY4137, a slow-releasing H2S donor, improved cell viability, reduced oxidative stress and apoptosis, and improved mitochondrial function following H2O2 treatment. H2S reversed the stimulation of MAPK phosphorylation, downregulation of SIRT3 mRNA and reduction of the superoxide dismutase 2 and isocitrate dehydrogenase 2 expression which were induced by H2O2. H2S also increased activator protein 1 (AP-1) binding activity with SIRT3 promoter and this effect was absent in the presence of the specific AP-1 inhibitor, SR11302 or curcumin. Paraquat administration to mice induced a defected endothelium-dependent aortic vasodilatation and increased oxidative stress in both mouse aorta and small mesenteric artery, which were alleviated by GYY4137 treatment. This vasoprotective effect of H2S was absent in SIRT3 knockout mice. INNOVATION: The present results highlight a novel role for SIRT3 in the protective effect of H2S against oxidant damage in the endothelium both in vitro and in vivo. CONCLUSION: H2S enhances AP-1 binding activity with the SIRT3 promoter, thereby upregulating SIRT3 expression and ultimately reducing oxidant-provoked vascular endothelial dysfunction. Antioxid. Redox Signal. 24, 329-343. PMID- 26422758 TI - Biophysical Characterization of the Type III Secretion System Translocator Proteins and the Translocator Proteins Attached to Bacterium-Like Particles. AB - Diarrhea caused by Shigella, Salmonella, and Yersinia is an important public health problem, but development of safe and effective vaccines against such diseases is challenging. A new antigen delivery platform called bacterium-like particles (BLPs) was explored as a means for delivering protective antigens from the type III secretion systems (T3SS) of these pathogens. BLPs are peptidoglycan skeletons derived from Lactococcus lactis that are safe for newborns and can carry multiple antigens. Hydrophobic T3SS translocator proteins were fused to a peptidoglycan anchor (PA) for BLP attachment. The proteins and protein-BLP complexes associated with BLPs were characterized and the resulting data used to create three-index empirical phase diagrams (EPDs). On the basis of these EPDs, IpaB (Shigella) and SipB (Salmonella) behave distinctly from YopB (Yersinia) under different environmental stresses. Adding the PA domain appears to enhance the stability of both the PA and translocator proteins, which was confirmed using differential scanning calorimetry, and although the particles dominated the spectroscopic signals in the protein-loaded BLPs, structural changes in the proteins were still detected. The protein-BLPs were most stable near neutral pH, but these proteins' hydrophobicity made them sensitive to environmental stresses. PMID- 26422759 TI - Music as a mediator between ethnicity and substance use among college students. AB - The current study examined the relationship between substance use references contained in music lyrics and videos and the attitudes and behaviors regarding substance use of White non-Hispanic, African American, and Hispanic emerging adults from a cultivation and social norms framework by assessing 425 male and female college students. It was hypothesized that there would be ethnic variations in perceived harm from substance use and reported recent substance use and that exposure to substance use references contained in music could mediate this relationship. Results confirmed ethnic differences in perceived risk associated with substance use as well as reported substance use with White non Hispanic college students reporting the least perceived risk and the most substance use. African American college students reported the most perceived risk associated with substance use and the least amount of reported substance use. Results of the Test of Joint Significance confirmed the mediational model in that participant ethnicity was associated with exposure to substance use references in music lyrics and music videos. Substance use references in music lyrics, then, was able to predict actual reported substance use of participants but not perceived risk associated with substance use. PMID- 26422760 TI - Controlled Lateral Positioning of Microparticles Inside Droplets Using Acoustophoresis. AB - In this paper, we utilize bulk acoustic waves to control the position of microparticles inside droplets in two-phase microfluidic systems and demonstrate a method to enrich the microparticles. In droplet microfluidics, different unit operations are combined and integrated on-chip to miniaturize complex biochemical assays. We present a droplet unit operation capable of controlling the position of microparticles during a trident shaped droplet split. An acoustic standing wave field is generated in the microchannel, and the acoustic forces direct the encapsulated microparticles to the center of the droplets. The method is generic, requires no labeling of the microparticles, and is operated in a noncontact fashion. It was possible to achieve 2+-fold enrichment of polystyrene beads (5 MUm in diameter) in the center daughter droplet with an average recovery of 89% of the beads. Red blood cells were also successfully manipulated inside droplets. These results show the possibility to use acoustophoresis in two-phase systems to enrich microparticles and open up the possibility for new droplet-based assays that are not performed today. PMID- 26422761 TI - The Morphology of TiO2 (B) Nanoparticles. AB - The morphology of a nanomaterial (geometric shape and dimension) has a significant impact on its physical and chemical properties. It is, therefore, essential to determine the morphology of nanomaterials so as to link shape with performance in specific applications. In practice, structural features with different length scales are encoded in a specific angular range of the X-ray or neutron total scattering pattern of the material. By combining small- and wide angle scattering (typically X-ray) experiments, the full angular range can be covered, allowing structure to be determined accurately at both the meso- and the nanoscale. In this Article, a comprehensive morphology analysis of lithium-ion battery anode material, TiO2 (B) nanoparticles (described in Ren, Y.; Liu, Z.; Pourpoint, F.; Armstrong, A. R.; Grey, C. P.; Bruce, P. G. Angew. Chem. Int. Ed. 2012, 51, 2164), incorporating structure modeling with small-angle X-ray scattering (SAXS), pair distribution function (PDF), and X-ray powder diffraction (XRPD) techniques, is presented. The particles are oblate-shaped, contracted along the [010] direction, this particular morphology providing a plausible rationale for the excellent electrochemical behavior of these TiO2(B) nanoparticles, while also provides a structural foundation to model the strain driven distortion induced by lithiation. The work demonstrates the importance of analyzing various structure features at multiple length scales to determine the morphologies of nanomaterials. PMID- 26422762 TI - Discussion. PMID- 26422763 TI - Discussion. PMID- 26422764 TI - Early outcome of thoracoscopic and hybrid esophagectomy: Propensity-matched comparative analysis. AB - BACKGROUND: Transthoracic esophagectomy remains the current therapeutic standard for localized esophageal carcinoma. Minimally invasive surgery has proven at least equivalent to open surgery regarding the early outcomes, but only 1 randomized study has compared the thoracoscopic with the thoracotomy approach. The primary objective of this study was to assess the early outcome of the thoracoscopic prone esophagectomy (TPE) and the hybrid Ivor Lewis (HIL) esophagectomy in 2 concurrent patient cohorts. METHODS: We compared the 1-year outcome of 3-stage TPE and 2-stage HIL done over the same time period in a single center. The propensity score matching method was used to reduce selection bias by creating 2 groups of patients similarly likely to receive a treatment on the basis of measured baseline characteristics. After generating propensity scores using the covariates of age, sex, body mass index, forced expiration volume at 1 second, Charlson comorbidity index, American Society of Anesthesiologists score, histologic tumor type, tumor site, pTNM stage, and neoadjuvant therapy, 93 TPE patients were matched with 197 HIL patients using a 1:1 ratio and the nearest neighbor score matching. Main outcome measure was the incidence of postoperative complications. RESULTS: Operative time was longer in TPE patients (P < .01). All postoperative outcomes, including morbidity, mortality, nodal harvest, R0 resection rate, and 1-year survival rates were similar in the 2 matched groups. CONCLUSION: Both operative approaches are safe and effective; using 1 or the other depends on the tumor site, surgeon experience and preference, and patient expectations. PMID- 26422765 TI - A novel lateral-approach laryngeal ultrasonography for vocal cord evaluation. AB - BACKGROUND: Laryngeal ultrasonography (LUS) is a new method of vocal cord (VC) evaluation in patients with risk of vocal cord palsy (VCP). The previously described anterior-approach LUS reportedly, however, has high failure rate of VC visualization in male patients. We devised a novel lateral-approach LUS to overcome this limitation. METHODS: A total of 382 (82 male, 300 female) consecutive LUS and direct laryngoscopy (DL) examinations were performed on perioperative thyroidectomy and parathyroidectomy patients. The anterior-approach LUS was used for female patients whereas the lateral-approach LUS was used for male patients. Findings were cross-validated independently with DL examinations. RESULTS: Both anterior and lateral LUS methods had 100% visualization rate (no failed visualization) with an overall sensitivity of 100% (23/23) and specificity of 99.2% (356/359) for VCP. Among the 300 female patients, 18 patients had VCP. Sensitivity and specificity of anterior-approach LUS were 100% (18/18) and 99.3% (280/282), respectively. Among the 80 male patients, 5 patients had VCP. Sensitivity and specificity of lateral-approach LU were 100% (5/5) and 98.7% (76/77), respectively. CONCLUSION: The new LUS approach significantly enhances the visualization of vocal cords and, therefore, overall diagnostic efficacy of LUS in male patients. PMID- 26422766 TI - Cosyntropin stimulation testing on postoperative day 1 allows for selective glucocorticoid replacement therapy after adrenalectomy for hypercortisolism: Results of a novel, multidisciplinary institutional protocol. AB - BACKGROUND: Secondary adrenal insufficiency (AI) can occur after unilateral adrenalectomy for adrenal-dependent hypercortisolism. Postoperative glucocorticoid replacement (GR), although given routinely, may not be necessary. We sought to identify factors that, in combination with postoperative day 1 cosyntropin stimulation testing (POD1-CST), would predict the need for GR. METHODS: We reviewed 31 consecutive patients who underwent unilateral adrenalectomy for hypercortisolism (study patients) or hyperaldosteronism (control patients). A standard POD1-CST protocol was used. Hydrocortisone was started for clinical evidence of AI, basal plasma cortisol <= 5 (MUg/dL), or a stimulated plasma cortisol <18. RESULTS: A normal POD1-CST was found in all nine control patients and 11 of 22 patients (50%) with Cushing's syndrome; the other 11 study patients (50%) received GR based on the POD1-CST. These patients were younger (51 vs 62 years; P = .017), had a higher body mass index (BMI; 31 vs 29 kg/m(2)), and smaller adrenal neoplasms (16.9 vs 33.0 g; P = .009) than non-GR study patients. CONCLUSION: After unilateral adrenalectomy for hypercortisolism, only 50% of patients received GR. No preoperative biochemical characteristics were associated with postoperative AI, although patients who received GR were younger, and tended to have a higher BMI and smaller adrenal nodules. Use of this novel protocol for postoperative dynamic adrenal function testing prevented unnecessary GR in 50% of patients and allowed for individualized patient care. PMID- 26422768 TI - A case of epidermoid cyst in an intrapancreatic accessory spleen mimicking pancreas neoplasms: MRI with DWI. AB - We report on a rare case of an epidermoid cyst in an intrapancreatic accessory spleen (ECIAS) that presented as a cystic lesion in the tail of the pancreas, in a 21-year-old woman. ECIAS is very rare; thus, accurate diagnosis before surgery is difficult. When a wall within the lesion presents with similar imaging features to accessory splenic tissues on magnetic resonance imaging with diffusion-weighted imaging, ECIAS should be considered in the differential diagnosis of cystic lesions in the tail of the pancreas. PMID- 26422769 TI - MRI safety: a report of current practice and advancements in patient preparation and screening. AB - MRI offers detailed diagnostic images without ionizing radiation; however, there are considerable safety concerns associated with high electromagnetic field strength. With increasing use of high and ultra high (7T) magnetic field strength, adequate patient preparation and screening for ferrous material is increasingly important. We review current safety standards for patient screening and preparation and how they are implemented at our institution. In addition, we describe a novel supplemental screening technique wherein the lights are dimmed in response to detected ferrous metal at the threshold of Zone IV. PMID- 26422770 TI - Influence of sonication conditions on the efficiency of ultrasonic cleaning with flowing micrometer-sized air bubbles. AB - This paper describes the sizes of cleaned areas under different sonication conditions with the addition of flowing micrometer-sized air bubbles. The differences in the cleaned area of a glass plate pasted with silicon grease as a dirty material under different sonication conditions were investigated after tiny bubbles were blown on the dirty plate placed in an underwater sound field. The ultrasound was applied perpendicular to the bubble flow direction. The shape of the cleaned areas was nearly elliptical, so the lengths of the minor and major axes were measured. The length of the minor axis under sweep conditions (amplitude modulation), for which the average power was lower than that for continuous wave (CW) irradiation, was comparable to that for CW irradiation and was slightly larger than under bubble flow only. Not only the relatively high power for CW irradiation, but also the larger angular change of the bubble flow direction under sweep conditions contributed to the enlargement of the cleaned area in the direction of the minor axis. The combination of bubble flow and sonication under sweep or CW conditions produced a larger cleaned area compared with bubble flow only, although the increase was not higher than 20%. A rapid change from an air to water interface caused by the bubble flow and water jets caused by the collapse of bubbles due to violent pulsation is the main cleaning mechanism under a combination of ultrasound and bubble flow. PMID- 26422771 TI - Is Caenorhabditis elegans the Magic Bullet for Anthelminthic Drug Discovery? AB - Recent advances in handling and readout have facilitated high-throughput screens with Caenorhabditis elegans. A new study demonstrates that C. elegans is a useful tool in high-throughput anthelminthic drug discovery. Despite challenges, drug discovery using C. elegans offers opportunities that might lead the way to novel anthelminthic drugs. PMID- 26422767 TI - A therapeutic-only versus prophylactic platelet transfusion strategy for preventing bleeding in patients with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation. AB - BACKGROUND: Platelet transfusions are used in modern clinical practice to prevent and treat bleeding in thrombocytopenic patients with bone marrow failure. Although considerable advances have been made in platelet transfusion therapy in the last 40 years, some areas continue to provoke debate, especially concerning the use of prophylactic platelet transfusions for the prevention of thrombocytopenic bleeding.This is an update of a Cochrane review first published in 2004 and updated in 2012 that addressed four separate questions: therapeutic only versus prophylactic platelet transfusion policy; prophylactic platelet transfusion threshold; prophylactic platelet transfusion dose; and platelet transfusions compared to alternative treatments. We have now split this review into four smaller reviews looking at these questions individually; this review is the first part of the original review. OBJECTIVES: To determine whether a therapeutic-only platelet transfusion policy (platelet transfusions given when patient bleeds) is as effective and safe as a prophylactic platelet transfusion policy (platelet transfusions given to prevent bleeding, usually when the platelet count falls below a given trigger level) in patients with haematological disorders undergoing myelosuppressive chemotherapy or stem cell transplantation. SEARCH METHODS: We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (Cochrane Library 2015, Issue 6), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1950) and ongoing trial databases to 23 July 2015. SELECTION CRITERIA: RCTs involving transfusions of platelet concentrates prepared either from individual units of whole blood or by apheresis, and given to prevent or treat bleeding in patients with malignant haematological disorders receiving myelosuppressive chemotherapy or undergoing HSCT. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We identified seven RCTs that compared therapeutic platelet transfusions to prophylactic platelet transfusions in haematology patients undergoing myelosuppressive chemotherapy or HSCT. One trial is still ongoing, leaving six trials eligible with a total of 1195 participants. These trials were conducted between 1978 and 2013 and enrolled participants from fairly comparable patient populations. We were able to critically appraise five of these studies, which contained separate data for each arm, and were unable to perform quantitative analysis on one study that did not report the numbers of participants in each treatment arm.Overall the quality of evidence per outcome was low to moderate according to the GRADE approach. None of the included studies were at low risk of bias in every domain, and all the studies identified had some threats to validity. We deemed only one study to be at low risk of bias in all domains other than blinding.Two RCTs (801 participants) reported at least one bleeding episode within 30 days of the start of the study. We were unable to perform a meta-analysis due to considerable statistical heterogeneity between studies. The statistical heterogeneity seen may relate to the different methods used in studies for the assessment and grading of bleeding. The underlying patient diagnostic and treatment categories also appeared to have some effect on bleeding risk. Individually these studies showed a similar effect, that a therapeutic-only platelet transfusion strategy was associated with an increased risk of clinically significant bleeding compared with a prophylactic platelet transfusion policy. Number of days with a clinically significant bleeding event per participant was higher in the therapeutic-only group than in the prophylactic group (one RCT; 600 participants; mean difference 0.50, 95% confidence interval (CI) 0.10 to 0.90; moderate-quality evidence). There was insufficient evidence to determine whether there was any difference in the number of participants with severe or life-threatening bleeding between a therapeutic-only transfusion policy and a prophylactic platelet transfusion policy (two RCTs; 801 participants; risk ratio (RR) 4.91, 95% CI 0.86 to 28.12; low-quality evidence). Two RCTs (801 participants) reported time to first bleeding episode. As there was considerable heterogeneity between the studies, we were unable to perform a meta-analysis. Both studies individually found that time to first bleeding episode was shorter in the therapeutic-only group compared with the prophylactic platelet transfusion group.There was insufficient evidence to determine any difference in all-cause mortality within 30 days of the start of the study using a therapeutic-only platelet transfusion policy compared with a prophylactic platelet transfusion policy (two RCTs; 629 participants). Mortality was a rare event, and therefore larger studies would be needed to establish the effect of these alternative strategies. There was a clear reduction in the number of platelet transfusions per participant in the therapeutic-only arm (two RCTs, 991 participants; standardised mean reduction of 0.50 platelet transfusions per participant, 95% CI -0.63 to -0.37; moderate-quality evidence). None of the studies reported quality of life. There was no evidence of any difference in the frequency of adverse events, such as transfusion reactions, between a therapeutic-only and prophylactic platelet transfusion policy (two RCTs; 991 participants; RR 1.02, 95% CI 0.62 to 1.68), although the confidence intervals were wide. AUTHORS' CONCLUSIONS: We found low- to moderate-grade evidence that a therapeutic-only platelet transfusion policy is associated with increased risk of bleeding when compared with a prophylactic platelet transfusion policy in haematology patients who are thrombocytopenic due to myelosuppressive chemotherapy or HSCT. There is insufficient evidence to determine any difference in mortality rates and no evidence of any difference in adverse events between a therapeutic-only platelet transfusion policy and a prophylactic platelet transfusion policy. A therapeutic only platelet transfusion policy is associated with a clear reduction in the number of platelet components administered. PMID- 26422772 TI - Releasing the Brake on IFN-gamma Signaling on Infection. AB - Toxoplasma gondii effectively inhibits the responsiveness of its host cell to interferon gamma (IFN-gamma). Using a genome-wide genetic screen, Beiting and colleagues have recently identified coactivators of the transcription factor STAT1 that can diminish this inhibitory effect. One of these coactivators, TLX, enhances type 1 helper (Th1) immune responses and restricts parasite replication during chronic toxoplasmosis. PMID- 26422773 TI - Climate and Population Immunity in Malaria Dynamics: Harnessing Information from Endemicity Gradients. AB - It is clear that climate variability and climate change influence malaria in low transmission regions. Much less understood is how climate forcing interacts with population immunity as one moves towards higher transmission intensity. The same transmission model confronted to time series data from two contrasting intensities helps unravel this interaction. PMID- 26422774 TI - Time trends and case fatality rate of in-hospital treated pulmonary embolism during 11 years of observation in Northwestern Italy. AB - Pulmonary embolism (PE) is a common disorder with high mortality and morbidity rates. However, population-based information on its incidence and prognosis remains limited. We conducted a large epidemiology study collecting data on hospitalisation for PE (from 2002 to 2012) in a population of about 13 million people in Northwestern Italy. Patients were identified using the ICD-9-CM codes: 415.11, 415.19; gender and age specific incidence rate of PE during the study period were estimated using the resident population for each year of the study. Furthermore, time trends in the in-hospital PE-related mortality and case fatality rate were calculated. Results were adjusted for possible confounders. A total of 60,853 patients (mean age 72.8 years, +/- 14.1, 59.6% females) with PE were included; the overall crude incidence rate for the entire study period was 55.4 and 40.6 events per year per 100,000 inhabitants for women and men, respectively (p <0.001). However, this difference was completely lost after standardisation for age. The incidence of PE significantly increased in both genders during the study period. In-hospital case fatality rate significantly decreased throughout the study period (p < 0.001) in women (from 15.6% to 10.2%) and in men (from 17.6% to 10.1%). The observed decrease of the in-hospital case fatality throughout the study period remained significant also after adjustment for possible confounders. In conclusion, time trends over an 11-year period show an increasing incidence of PE, but a significant reduction in mortality during hospitalisation. Reduction in the case fatality rate remained significant after adjustment for these possible confounders. PMID- 26422775 TI - Nano-sized polystyrene affects feeding, behavior and physiology of brine shrimp Artemia franciscana larvae. AB - Nano-sized polymers as polystyrene (PS) constitute one of the main challenges for marine ecosystems, since they can distribute along the whole water column affecting planktonic species and consequently disrupting the energy flow of marine ecosystems. Nowadays very little knowledge is available on the impact of nano-sized plastics on marine organisms. Therefore, the present study aims to evaluate the effects of 40nm anionic carboxylated (PS-COOH) and 50nm cationic amino (PS-NH2) polystyrene nanoparticles (PS NPs) on brine shrimp Artemia franciscana larvae. No signs of mortality were observed at 48h of exposure for both PS NPs at naplius stage but several sub-lethal effects were evident. PS-COOH (5-100MUg/ml) resulted massively sequestered inside the gut lumen of larvae (48h) probably limiting food intake. Some of them were lately excreted as fecal pellets but not a full release was observed. Likewise, PS-NH2 (5-100ug/ml) accumulated in larvae (48h) but also adsorbed at the surface of sensorial antennules and appendages probably hampering larvae motility. In addition, larvae exposed to PS NH2 undergo multiple molting events during 48h of exposure compared to controls. The activation of a defense mechanism based on a physiological process able to release toxic cationic NPs (PS-NH2) from the body can be hypothesized. The general observed accumulation of PS NPs within the gut during the 48h of exposure indicates a continuous bioavailability of nano-sized PS for planktonic species as well as a potential transfer along the trophic web. Therefore, nano-sized PS might be able to impair food uptake (feeding), behavior (motility) and physiology (multiple molting) of brine shrimp larvae with consequences not only at organism and population level but on the overall ecosystem based on the key role of zooplankton on marine food webs. PMID- 26422776 TI - Distinguishing the Photothermal and Photoinjection Effects in Vanadium Dioxide Nanowires. AB - Vanadium dioxide (VO2) has drawn significant attention for its unique metal-to insulator transition near the room temperature. The high electrical resistivity below the transition temperature (~68 degrees C) is a result of the strong electron correlation with the assistance of lattice (Peierls) distortion. Theoretical calculations indicated that the strong interelectron interactions might induce intriguing optoelectronic phenomena, such as the multiple exciton generation (MEG), a process desirable for efficient optoelectronics and photovoltaics. However, the resistivity of VO2 is quite temperature sensitive, and therefore, the light-induced conductivity in VO2 has often been attributed to the photothermal effects. In this work, we distinguished the photothermal and photoinjection effects in VO2 nanowires by varying the chopping frequency of the optical illumination. We found that, in our VO2 nanowires, the relatively slow photothermal processes can be well suppressed when the chopping frequency is >2 kHz, whereas the fast photoinjection component (direct photoexcitation of charge carriers) remains constant at all chopping frequencies. By separating the photothermal and photoinjection processes, our work set the basis for further studies of carrier dynamics under optical excitations in strongly correlated materials. PMID- 26422777 TI - Anesthetic management of patients undergoing resection of carcinoid metastasis to the brain. AB - BACKGROUND: Carcinoid tumors are derived from enterochromaffin cells and may release physiologically active compounds into the systemic circulation, leading to the development of carcinoid syndrome. Occasionally, these tumors metastasize to the brain, warranting biopsy or resection. In these surgical patients, the perioperative implications for anesthetic management are not heretofore defined in the indexed literature. METHODS: Patients who had craniotomy for biopsy or resection of intracranial carcinoid tumors were retrospectively identified at a single medical center. Patient demographics, perioperative anesthetic management, adverse events, and outcome were summarized in this case series. RESULTS: Eleven patients were identified; median age was 60 years (range = 42-78 years), and 45% were male. Immediately before surgery, 4 patients (36%) were receiving a somatostatin analog drug, and no patient had unchecked carcinoid syndrome. All patients received general anesthesia that included inhaled isoflurane and nitrous oxide, and all had invasive arterial blood pressure monitoring. One patient developed sustained hypotension after induction of anesthesia, likely related to hypovolemia and anesthetic drugs, but the possibility of carcinoid mediator release cannot be excluded. There were no other signs or symptoms of carcinoid syndrome in this or any other patient. Of all 11 patients, 10 (91%) experienced either significant disease progression (n = 2; 18%) or death (n = 8; 73%) from carcinoid disease, its sequelae, or an undetermined cause within 3 years after surgery. Of note, 3 of the deaths occurred shortly after surgery, on postoperative days 3, 7, and 8. CONCLUSIONS: In our experience, carcinoid tumor metastasis to the brain-whether because of tumor makeup or prior treatment-is unlikely to produce symptoms of new-onset carcinoid syndrome intraoperatively; however, the risk cannot be completely excluded. Postsurgical prognosis was poor, both within the hospital and after hospital discharge. PMID- 26422778 TI - The Effect of a Golden Hour Policy on the Morbidity and Mortality of Combat Casualties. AB - IMPORTANCE: The term golden hour was coined to encourage urgency of trauma care. In 2009, Secretary of Defense Robert M. Gates mandated prehospital helicopter transport of critically injured combat casualties in 60 minutes or less. OBJECTIVES: To compare morbidity and mortality outcomes for casualties before vs after the mandate and for those who underwent prehospital helicopter transport in 60 minutes or less vs more than 60 minutes. DESIGN, SETTING, AND PARTICIPANTS: A retrospective descriptive analysis of battlefield data examined 21,089 US military casualties that occurred during the Afghanistan conflict from September 11, 2001, to March 31, 2014. Analysis was conducted from September 1, 2014, to January 21, 2015. MAIN OUTCOMES AND MEASURES: Data for all casualties were analyzed according to whether they occurred before or after the mandate. Detailed data for those who underwent prehospital helicopter transport were analyzed according to whether they occurred before or after the mandate and whether they occurred in 60 minutes or less vs more than 60 minutes. Casualties with minor wounds were excluded. Mortality and morbidity outcomes and treatment capability related variables were compared. RESULTS: For the total casualty population, the percentage killed in action (16.0% [386 of 2411] vs 9.9% [964 of 9755]; P < .001) and the case fatality rate ([CFR] 13.7 [469 of 3429] vs 7.6 [1344 of 17,660]; P < .001) were higher before vs after the mandate, while the percentage died of wounds (4.1% [83 of 2025] vs 4.3% [380 of 8791]; P = .71) remained unchanged. Decline in CFR after the mandate was associated with an increasing percentage of casualties transported in 60 minutes or less (regression coefficient, -0.141; P < .001), with projected vs actual CFR equating to 359 lives saved. Among 4542 casualties (mean injury severity score, 17.3; mortality, 10.1% [457 of 4542]) with detailed data, there was a decrease in median transport time after the mandate (90 min vs 43 min; P < .001) and an increase in missions achieving prehospital helicopter transport in 60 minutes or less (24.8% [181 of 731] vs 75.2% [2867 of 3811]; P < .001). When adjusted for injury severity score and time period, the percentage killed in action was lower for those critically injured who received a blood transfusion (6.8% [40 of 589] vs 51.0% [249 of 488]; P < .001) and were transported in 60 minutes or less (25.7% [205 of 799] vs 30.2% [84 of 278]; P < .01), while the percentage died of wounds was lower among those critically injured initially treated by combat support hospitals (9.1% [48 of 530] vs 15.7% [86 of 547]; P < .01). Acute morbidity was higher among those critically injured who were transported in 60 minutes or less (36.9% [295 of 799] vs 27.3% [76 of 278]; P < .01), those severely and critically injured initially treated at combat support hospitals (severely injured, 51.1% [161 of 315] vs 33.1% [104 of 314]; P < .001; and critically injured, 39.8% [211 of 530] vs 29.3% [160 of 547]; P < .001), and casualties who received a blood transfusion (50.2% [618 of 1231] vs 3.7% [121 of 3311]; P < .001), emphasizing the need for timely advanced treatment. CONCLUSIONS AND RELEVANCE: A mandate made in 2009 by Secretary of Defense Gates reduced the time between combat injury and receiving definitive care. Prehospital transport time and treatment capability are important factors for casualty survival on the battlefield. PMID- 26422779 TI - Age: An effect modifier of the association between allergic rhinitis and Otitis media with effusion. AB - OBJECTIVES/HYPOTHESIS: 1) To determine whether there is a significant relationship between allergic rhinitis and otitis media with effusion (OME), Eustachian tube dysfunction (ETD), or tympanic membrane retraction (TMR) in children in a nationally representative population; and 2) to determine whether age is an effect modifier of any such association because this hypothesis has yet to be tested. STUDY DESIGN: Retrospective analysis of cross-sectional national databases with limited potential for referral bias. SETTING AND SUBJECTS: National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, 2005-2010. METHODS: Univariate, multivariate, stratified, and subgroup analyses were performed as defined a priori. The primary outcomes were OME, ETD, or TMR; the primary predictor variable was allergic rhinitis, with age evaluated as an effect modifier. RESULTS: Data representing 1,491,045,375 pediatric visits were examined and demonstrated that age was an effect modifier of the assessed association. More specifically, in children 6 years of age or older, the presence of allergic rhinitis significantly increased the odds of OME, ETD, or TMR (odds ratio [OR] 4.20; 95% confidence interval [CI] 2.17, 8.09; P < 0.001), whereas in children less than 6 years of age there was no significant association (OR 1.13; 95% CI 0.53, 2.46; P = 0.745). CONCLUSION: Age is an effect modifier of the association between allergic rhinitis and OME; a significant relationship is observed in children 6 years of age and older, whereas there is no significant association in younger children. LEVEL OF EVIDENCE: 2c. Laryngoscope, 126:1687-1692, 2016. PMID- 26422780 TI - A Concise and Highly Enantioselective Total Synthesis of (+)-anti- and (-)-syn Mefloquine Hydrochloride: Definitive Absolute Stereochemical Assignment of the Mefloquines. AB - A concise asymmetric (>99:1 e.r.) total synthesis of (+)-anti- and (-)-syn mefloquine hydrochloride from a common intermediate is described. The key asymmetric transformation is a Sharpless dihydroxylation of an olefin that is accessed in three steps from commercially available materials. The Sharpless derived diol is converted into either a trans or cis epoxide, and these are subsequently converted into (+)-anti- and (-)-syn-mefloquine, respectively. The synthetic (+)-anti- and (-)-syn-mefloquine samples were derivatized with (S)-(+) mandelic acid tert-butyldimethylsilyl ether, and a crystal structure of each derivative was obtained. These are the first X-ray structures for mefloquine derivatives that were obtained by coupling to a known chiral, nonracemic compound, and provide definitive confirmation of the absolute stereochemistry of (+)-anti- as well as (-)-syn-mefloquine. PMID- 26422781 TI - Frequency of Tobacco Use Among Middle and High School Students--United States, 2014. AB - The use of tobacco products during adolescence increases the risk for adverse health effects and lifelong nicotine addiction. In 2014, an estimated 4.6 million middle and high school students were current users of any tobacco product, of whom an estimated 2.2 million were current users of two or more types of tobacco products. Symptoms of nicotine dependence are increased for multiple tobacco product users compared with single-product users. CDC and the Food and Drug Administration (FDA) analyzed data from the 2014 National Youth Tobacco Survey (NYTS) to determine how frequently (the number of days in the preceding 30 days) U.S. middle school (grades 6-8) and high school (grades 9-12) students used cigarettes, e-cigarettes, cigars, and smokeless tobacco products. Among current users (>=1 day during the preceding 30 days) in high school, frequent use (>=20 days during the preceding 30 days) was most prevalent among smokeless tobacco users (42.0%), followed by cigarette smokers (31.6%), e-cigarette users (15.5%), and cigar smokers (13.1%); a similar pattern was observed for those who used during all 30 days. Among current users in middle school, frequent use was greatest among smokeless tobacco users (29.2%), followed by cigarette smokers (20.0%), cigar smokers (13.2%) and e-cigarette users (11.8%). Current use of two or more types of tobacco products was common, even among students who used tobacco products 1-5 days during the preceding 30 days: 77.3% for cigar smokers, 76.9% for cigarette smokers, 63.4% for smokeless tobacco users, and 54.8% for e cigarettes users. Preventing youths from initiating the use of any tobacco product is important to tobacco use prevention and control strategies in the United States. Monitoring the frequency and patterns of tobacco use among youths, including the use of two or more tobacco products, is important to inform evidence-based interventions to prevent and reduce all forms of tobacco use among youths. PMID- 26422782 TI - Risk of hematological toxicities in patients with solid tumors treated with ramucirumab: a meta-analysis. AB - BACKGROUND: We performed a meta-analysis of the risk of hematological adverse events associated with ramucirumab. METHODS: Eligible studies included randomized Phase II and III trials of patients with solid tumors on ramucirumab, describing events of anemia, leucopenia, neutropenia, febrile neutropenia and thrombocytopenia. RESULTS: A total of 11 clinical trials were considered eligible for the meta-analysis. The relative risks of all-grade anemia, leucopenia, neutropenia, febrile neutropenia and thrombocytopenia were 0.88 (95% CI: 0.80 0.96; p = 0.007), 1.13 (95% CI: 0.85-1.49; p = 0.41), 1.25 (95% CI: 1.08-1.44; p = 0.002), 1.63 (95% CI: 1.30-2.06; p < 0.0001), 1.91 (95% CI: 1.52-2.42; p < 0.00001), respectively. CONCLUSION: Our meta-analysis has demonstrated an increased risk of febrile neutropenia, all-grade and high-grade neutropenia and thrombocytopenia with ramucirumab-based treatment compared with control. PMID- 26422783 TI - Classic PCOS phenotype is not associated with deficiency of endogenous vitamin D and VDR gene polymorphisms rs731236 (TaqI), rs7975232 (ApaI), rs1544410 (BsmI), rs10735810 (FokI): a case-control study of lower Silesian women. AB - CONTEXT: The role of endogenous vitamin D and vitamin D receptor (VDR) gene polymorphism in polycystic ovary syndrome (PCOS) is still controversial. OBJECTIVE: The objective of this study was to investigate for the first time in women with "classic" PCOS phenotype and healthy controls the role of the serum endogenous vitamin D level and VDR gene polymorphisms in PCOS etiology. DESIGN: Ninety-two women with "classic" PCOS phenotype and 85 controls from lower Silesia with comparable body mass index (BMI) were studied. In all women the waist circumference, android/gynoid fat deposit, parameters of lipid and glucose metabolism, testosterone, free androgen index, sex hormone binding globulin (SHBG) and vitamin D were evaluated. Also, VDR gene polymorphisms rs731236, rs7975232, rs1544410 and rs10735810 were assessed. RESULTS: Serum vitamin D levels in both groups were comparable. Also high, comparable frequencies of hypovitaminosis and vitamin D deficiency in both groups were observed. Women with "classic" PCOS phenotype had statistically significantly higher values of all measured parameters, except serum SHBG and high-density lipoprotein (HDL) cholesterol, which were lower. The frequency of VDR genotype polymorphism was also comparable in both groups. CONCLUSIONS: For the first time, we show that endogenous vitamin D deficiency and VDR polymorphisms are not associated with homogeneous "classic" PCOS phenotype. PMID- 26422784 TI - [Normal pressure hydrocephalus: A review and practical aspects]. AB - Idiopathic normal pressure hydrocephalus is a chronic disorder affecting the elderly. It is defined by Adams and Hakim's triad in addition to ventricular dilation visible by brain imaging and normal cerebrospinal fluid pressure during lumbar puncture. The objective of this review was to propose a standard of care for idiopathic normal pressure hydrocephalus based on an extensive literature review conducted on 459 articles published over the last 10 years. Those articles were obtained by searching for the keywords "normal pressure hydrocephalus" in the PubMed database and selecting all the articles published in English or in French. The diagnosis of idiopathic normal pressure hydrocephalus is difficult because of commonly associated diseases, such as Alzheimer's disease and microangiopathy. Brain MRI is one of the key procedures to assist in the diagnosis of idiopathic normal pressure hydrocephalus. Indeed, the presence of certain MRI features is highly predictive of a positive tap test and shunt responsiveness. Nevertheless, tap test remains the standard of care for diagnosis. Continuous cerebrospinal fluid drainage test is an alternative because it improves the sensitivity of diagnosis (but is a more complicated test to perform). Alzheimer's biomarkers dosing in the cerebrospinal fluid seems interesting when diagnosis remains uncertain: the presence of Alzheimer's profile of the biological markers is predictive of a lower response to the tap test. PMID- 26422785 TI - Is there still a place for "old therapies" in the management of immune thrombocytopenia? AB - New molecules such as rituximab or thrombopoietin receptor agonists (romiplostim and eltrombopag) have changed the management of immune thrombocytopenia. Therefore, old drugs which are less expensive and with a well-known benefit/risk ratio are being underused. We aim to define the place of dapsone, danazol, hydroxychloroquine and vinca-alkaloids at the era of targeted therapy in immune thrombocytopenia. With a response rate around 30% to 50%, dapsone is an interesting second-line therapy to be used just after corticosteroids. Patients with positive antinuclear antibodies can benefit from hydroxychloroquine with a 50% response rate. Because of its side effects, mostly virilization, danazol will be preferentially used in the elderly. Vinca-alkaloids could be temporarily used in patients that do not respond to intravenous immunoglobulins or to limit their use to avoid shortage periods. PMID- 26422786 TI - Discovery and SAR study of 2-(1-propylpiperidin-4-yl)-3H-imidazo[4,5-c]pyridine-7 carboxamide: A potent inhibitor of poly(ADP-ribose) polymerase-1 (PARP-1) for the treatment of cancer. AB - A series of imidazo[4,5-c]pyridine-7-carboxamide derivatives as poly(ADP-ribose) polymerase (PARP) inhibitors have been developed. All target compounds were evaluated for their PARP-1 inhibitory activity and some were further assessed for cellular potency. These efforts led to identification of a novel PARP-1 inhibitor 2-(1-propylpiperidin-4-yl)-3H-imidazo[4,5-c]pyridine-7-carboxamide 11a (XZ 120312). 11a displayed strong inhibition against the PARP-1 enzyme with an IC50 of 8.6+/-0.6 nM and excellent potentiation of temozolomide cytotoxicity in cancer cell lines SW-620, MDA-MB-468 and A549 by 4.0, 3.0 and 7.7 times, respectively. PMID- 26422787 TI - Synthesis of novel acridine bis-sulfonamides with effective inhibitory activity against the carbonic anhydrase isoforms I, II, IX and XII. AB - By using a multi component reaction system (MCR), nitro acridine sulfonamides were obtained from cyclic-1,3-diketones, 4-aminobenzene sulfonamide and aromatic aldehydes. Some novel acridine bis-sulfonamides 6a-l were then synthesized by the reaction between sulfonyl chlorides and the novel amino-acridine sulfonamides 5a and 5b, obtained by reduction of nitro-acridine sulfonamide derivatives 4a and 4b. The newly synthesized compounds were investigated as inhibitors of 4 human carbonic anhydrase isoforms (hCA, EC 4.2.1.1). Several of the compounds showed low micromolar inhibition against the medically relevant isoforms hCA I, II, IX, and XII. PMID- 26422788 TI - Mucin-drugs interaction: The case of theophylline, prednisolone and cephalexin. AB - The binding of mucin with three commercially available drugs (theophylline, cephalexin and prednisolone) belonging to different pharmaceutical classes was investigated. The studied drugs are normally used to treat the symptomatology of cystic fibrosis. The interaction between drugs and mucin has been investigated using fluorescence and UV-Vis absorption spectroscopy; quenching mechanism, binding constants, binding sites, thermodynamic parameters and binding distance of the interaction were obtained. PMID- 26422789 TI - In Vitro and In Vivo Plant Growth Promoting Activities and DNA Fingerprinting of Antagonistic Endophytic Actinomycetes Associates with Medicinal Plants. AB - Endophytic actinomycetes have shown unique plant growth promoting as well as antagonistic activity against fungal phytopathogens. In the present study forty two endophytic actinomycetes recovered from medicinal plants were evaluated for their antagonistic potential and plant growth-promoting abilities. Twenty-two isolates which showed the inhibitory activity against at least one pathogen were subsequently tested for their plant-growth promoting activities and were compared genotypically using DNA based fingerprinting, including enterobacterial repetitive intergenic consensus (ERIC) and BOX repetitive elements. Genetic relatedness based on both ERIC and BOX-PCR generates specific patterns corresponding to particular genotypes. Exponentially grown antagonistic isolates were used to evaluate phosphate solubilization, siderophores, HCN, ammonia, chitinase, indole-3-acetic acid production, as well as antifungal activities. Out of 22 isolates, the amount of indole-3-acetic acid (IAA) ranging between 10-32 MUg/ml was produced by 20 isolates and all isolates were positive for ammonia production ranging between 5.2 to 54 mg/ml. Among 22 isolates tested, the amount of hydroxamate-type siderophores were produced by 16 isolates ranging between 5.2 to 36.4 MUg/ml, while catechols-type siderophores produced by 5 isolates ranging from 3.2 to 5.4 MUg/ml. Fourteen isolates showed the solubilisation of inorganic phosphorous ranging from 3.2 to 32.6 mg/100ml. Chitinase and HCN production was shown by 19 and 15 different isolates, respectively. In addition, genes of indole acetic acid (iaaM) and chitinase (chiC) were successively amplified from 20 and 19 isolates respectively. The two potential strains Streptomyces sp. (BPSAC34) and Leifsonia xyli (BPSAC24) were tested in vivo and improved a range of growth parameters in chilli (Capsicum annuum L.) under greenhouse conditions. This study is the first published report that actinomycetes can be isolated as endophytes from within these plants and were shown to have antagonistic and plant growth promoting abilities. These results clearly suggest the possibility of using endophytic actinomycetes as bioinoculant for plant growth promotion, nutrient mobilization or as biocontrol agent against fungal phytopathogens for sustainable agriculture. PMID- 26422790 TI - Action in Perception: Prominent Visuo-Motor Functional Symmetry in Musicians during Music Listening. AB - Musical training leads to sensory and motor neuroplastic changes in the human brain. Motivated by findings on enlarged corpus callosum in musicians and asymmetric somatomotor representation in string players, we investigated the relationship between musical training, callosal anatomy, and interhemispheric functional symmetry during music listening. Functional symmetry was increased in musicians compared to nonmusicians, and in keyboardists compared to string players. This increased functional symmetry was prominent in visual and motor brain networks. Callosal size did not significantly differ between groups except for the posterior callosum in musicians compared to nonmusicians. We conclude that the distinctive postural and kinematic symmetry in instrument playing cross modally shapes information processing in sensory-motor cortical areas during music listening. This cross-modal plasticity suggests that motor training affects music perception. PMID- 26422791 TI - Organic Solar Cells Based on a 2D Benzo[1,2-b:4,5-b']difuran-Conjugated Polymer with High-Power Conversion Efficiency. AB - A novel 2D benzodifuran (BDF)-based copolymer (PBDF-T1) is synthesized. Polymer solar cells fabricated with PBDF-T1 show high power conversion efficiency of 9.43% and fill factor of 77.4%, which is higher than the performance of its benzothiophene (BDT) counterpart (PBDT-T1). These results provide important progress for BDF-based copolymers and demonstrate that BDF-based copolymers can be competitive with the well-studied BDT counterparts via molecular structure design and device optimization. PMID- 26422792 TI - On the mechanism and optimization of triboelectric nanogenerators. AB - The mechanism for a triboelectric nanogenerator (TENG) with contacting materials being different conductors is essentially the same as that of a Kelvin probe. The difference between the two is that the former is designed for harvesting mechanical energy while the latter is used for measuring contact potential differences. The formalism developed for the conductor-conductor TENG can be equivalently applied to conductor-dielectric and dielectric-dielectric TENGs under appropriate approximations. The phenomenological parameter of tribo-charge surface density used in the previous model can also be accounted for in the current formalism. The dependence of average output power on load resistance and motion speed is analyzed, and the optimal output power and corresponding resistance are calculated for different motions. The formula that relates output power to charge and displacement is given, and based on this formula different ways to improve output power and load resistance matching have been conceived. PMID- 26422793 TI - N-acteyl-beta-D-glucosaminidase and kidney injury molecule-1: New predictors for long-term progression of chronic kidney disease in patients with heart failure. AB - AIM: Patients with chronic heart failure (CHF) are often characterized by the cardiorenal syndrome (CRS). The aim of the present study was to assess whether novel markers of kidney injury are able to predict progression of chronic kidney disease (CKD) in patients with CHF. METHODS: New renal biomarkers, N-acteyl-beta D-glucosaminidase (NAG), kidney injury molecule-1 (KIM-1) and Neutrophil Gelatinase-Associated Lipocalin (NGAL), were assessed from urine samples of 149 patients with chronic heart failure. During a 5-year-follow-up, renal function was assessed by creatinine and estimated glomerular filtration rate (eGFR CKD EPI) and was available for 138 patients. Further, data regarding all-cause mortality was obtained. RESULTS: Twenty-six patients (18.8%) developed a progression of CKD during the follow-up period, as defined by decline in eGFR category accompanied by a >=25% drop in eGFR form baseline. No difference regarding age, sex, body mass index, hypertension, diabetes or EF was present between patients with and without CKD progression (each P = n.s.). At baseline, creatinine concentrations and eGFR were significantly different between both groups (sCr: 1.50 +/- 0.67 vs 1.04 +/- 0.37, P = < 0.001; eGFR: 47.8 +/- 12.3 vs. 77.3 +/- 23.5 mL/min per 1.73m(2) , each P < 0.001). In a Kaplan-Meier-analysis, KIM-1 and NAG were significant predictors for CKD progression (both P < 0.05). In Cox regression analysis, NAG > median (OR 3.25,P = 0.013), initial eGFR (OR 0.94, P < 0.001) and diuretic use (OR 3.92, P = 0.001) were independent predictors of CKD progression. Further, KIM-1 and NAG were also independent predictors of a combined endpoint of CKD progression and all-cause mortality by Cox regression analysis (each P < 0.05). The combination of both markers showed additive value regarding both endpoints. NGAL showed no association with CKD progression. CONCLUSIONS: During long-term follow-up chronic heart failure patients with CKD show a relevant disease progression. The current study emphasizes a strong association of the tubular biomarkers NAG and KIM-1 with CKD progression in chronic heart failure and suggests their usefulness as cardiorenal markers. PMID- 26422794 TI - Cloning, expression and biochemical characterization of recombinant superoxide dismutase from Antarctic psychrophilic bacterium Pseudoalteromonas sp. ANT506. AB - In this study, a superoxide dismutase gene (PsSOD) from Pseudoalteromonas sp. ANT506 was cloned and over expressed in Escherichia coli. The PsSOD has an open reading frame of 582 bp with a putative product of 193 amino acid residue and an estimated molecular size of 21.4 kDa. His-tagged PsSOD was subsequently purified 12.6-fold by Ni-affinity chromatography and the yield of 22.9%. The characterization of the purified rPsSOD exhibited maximum activity at 30 degrees C and pH 8.0. The enzyme exhibited 13.9% activity at 0 degrees C and had high thermo lability at higher than 50 degrees C. rPsSOD exhibited well capability to 2.5 M NaCl (62.4%). These results indicated that rPsSOD exhibited special catalytic properties. PMID- 26422795 TI - Palladium-Based Nanomaterials: A Platform to Produce Reactive Oxygen Species for Catalyzing Oxidation Reactions. AB - Oxidation reactions by molecular oxygen (O2 ) over palladium (Pd)-based nanomaterials are a series of processes crucial to the synthesis of fine chemicals. In the past decades, investigations of related catalytic materials have mainly been focused on the synthesis of Pd-based nanomaterials from the angle of tailoring their surface structures, compositions and supporting materials, in efforts to improve their activities in organic reactions. From the perspective of rational materials design, it is imperative to address the fundamental issues associated with catalyst performance, one of which should be oxygen activation by Pd-based nanomaterials. Here, the fundamentals that account for the transformation from O2 to reactive oxygen species over Pd, with a focus on singlet O2 and its analogue, are introduced. Methods for detecting and differentiating species are also presented to facilitate future fundamental research. Key factors for tuning the oxygen activation efficiencies of catalytic materials are then outlined, and recent developments in Pd-catalyzed oxygen related organic reactions are summarized in alignment with each key factor. To close, we discuss the challenges and opportunities for photocatalysis research at this unique intersection as well as the potential impact on other research fields. PMID- 26422796 TI - Serum microRNA-221 functions as a potential diagnostic and prognostic marker for patients with osteosarcoma. AB - BACKGROUND: Upregulation of microRNA-221 (miR-221) has been reported to induce the malignant phenotype of human osteosarcoma, suggesting its potential as a therapeutic target for this malignancy. However, the role of miR-221 in diagnosis and prognosis of osteosarcoma has been well less elaborated. Our aim was to investigate the clinicopathological, diagnostic, and prognostic value of miR-221 in human osteosarcoma. METHODS: Expression levels of miR-221 in tumor tissues and patients' sera obtained from 108 cases of primary osteosarcomas were detected by quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR). RESULTS: Compared with normal controls, the expression levels of miR-221 in osteosarcoma tissues and patients' sera were both dramatically upregulated (both P=0.001). Then, receiver operating characteristics (ROC) analysis showed that serum miR-221 level could efficiently distinguish osteosarcoma patients from healthy controls (Area Under ROC Curve, AUC=0.844). Additionally, the serum level of miR-221 in osteosarcoma patients with positive distance metastasis (P=0.01) and advanced clinical stage (P=0.006) was significantly higher than those without distance metastasis and with early clinical stage. Moreover, we found that high serum miR-221 level was correlated with shorter recurrence-free survival (RFS) and overall survival (OS) than low level (both P=0.001). Multivariate survival analysis confirmed that serum miR-221 level was an independent prognostic factor influencing the survival of patients with osteosarcoma. CONCLUSION: These findings reveal that miR-221 may play a crucial role in the occurrence and the progression of human osteosarcoma. More importantly, miR-221 may function as a promising marker for screening individuals with osteosarcoma and for identifying individuals with poor prognostic potentials. PMID- 26422797 TI - Challenging integration: clinicians' perspectives of communicating collaboration in a center for integrative medicine. AB - A shift has occurred in the provision of health care to include a focus not just on biology and disease but also on the whole person, preventative care, and an array of healing modalities based on systems of beliefs and values not typically included within biomedical practice. This approach to health care, termed integrative medicine (IM), blends biomedicine with a broader understanding of patients and their illnesses, including elements of mind, body, and spirit that may be contributing to an ailment. While the use of integrative medicine has increased and centers for integrative medicine have proliferated within conventional health care organizations, distinct tensions arise from this amalgamation. The tensions between IM and biomedical clinicians often center on their differing training and philosophies, as well as on a larger system of health care that privileges biomedicine. As a result, this research is designed to explore the challenges IM clinicians face in collaborating with conventional practitioners to provide patient care. Analysis of interviews with 14 clinicians at one center for integrative medicine revealed four specific challenges they face in their attempt to co-practice IM with conventional medicine. The four challenges include (a) challenges to collaboration, (b) challenges to legitimacy, (c) challenges to consistency, and (d) challenges to unification. Future research should investigate the ways in which these challenges can be addressed so that collaboration throughout the system is facilitated. The professional training of clinicians, the structuring and institutionalization of integrative medicine, and enhanced systems for communicating patient information all play a significant role in this transformation. PMID- 26422798 TI - The influence of thermal processing on the fatty acid profile of pork and lamb meat fed diet with increased levels of unsaturated fatty acids. AB - The research was carried out on 32 crossbred pigs of Polish Large White * Danish Landrace with Duroc and 80 rams, crossbreds of the Prolific-Dairy Koludzka Sheep with the Ile de France, a meat sheep. The fodder for the animals was enriched with the unsaturated fatty acids originated mainly from linseed and rapeseed oils. The fatty acid profile was determined in cooked longissimus lumborum, roasted triceps brachii and raw ripened rump from pigs as well as in grilled lambs' legs and their corresponding raw materials. Roasting caused the most pronounced increase of the saturated fatty acids and decrease in the polyunsaturated fatty acids of heated pork muscles. The smallest changes were observed in grilled lamb legs. The heating processes applied in this study, in most cases, did not cause essential changes in the indices of pro-health properties of fatty acid, therefore meat in the majority fulfil the latest recommendations of EFSA and FAO/WHO according to human health. PMID- 26422799 TI - Neural circuits underlying motor facilitation during observation of implied motion. AB - In the present study we used single and paired-pulse Transcranial Magnetic Stimulation (TMS) to evaluate the effect of implied motion on primary motor cortex microcircuits. We found that observation of the implied motion of a static image increases MEP amplitude and reduces short-interval intracortical inhibition (SICI), without significant modulation of intracortical facilitation and sensory motor integration. Our results add to the existing literature on the activation of the observation-execution matching system and describe a selective modulation of GABAergic cortical microcircuits during observation of implied motion. PMID- 26422800 TI - Effect of Time after Anterior Cruciate Ligament Tears on Proprioception and Postural Stability. AB - This study was designed to compare proprioception and postural stability in patients with acute (time from injury <= 3 months) and chronic (time from injury > 3 months) ACL tears, and to evaluate the correlation between time interval after ACL injury and proprioception. Thigh muscle strength, postural stability, and joint position sense were compared in 48 patients with acute ACL tears and in 28 with chronic ACL tears. Maximal torque (60 degrees /sec) of the quadriceps and hamstring was evaluated using an isokinetic testing device. Postural stability was determined from the anterior-posterior (APSI), medial-lateral (MLSI), and overall (OSI) stability indices using stabilometry. Joint position sense was also tested by reproduction of passive positioning (RPP). Muscle strengths and stability indices on both the involved and uninvolved sides were similar in the acute and chronic ACL tear groups. RPP on the involved side was significantly greater in the chronic than in the acute ACL tear group (7.8 degrees vs. 5.6 degrees , P = 0.041). Two of three stability indices (APSI, OSI) and RPP were significantly greater on the involved than the uninvolved side in the chronic ACL tear group. PMID- 26422801 TI - Neurobehavioral development prior to term-age of preterm infants and acute stressful events during neonatal hospitalization. AB - BACKGROUND: Neonatal Intensive Care Units (NICUs) protect preterm infants; otherwise, this is a stressful environment including painful stimuli. AIMS: To compare early neurobehavioral development prior to term-age in preterm infants at 34-36weeks of post-conceptional age in different gestational ages, and to examine the effects of prematurity level and acute stressful events during NICU hospitalization on neurobehavioral development. STUDY DESIGN: Cross-sectional design. SUBJECTS: Forth-five preterm infants, 34-36weeks of post-conceptional age, were distributed into groups: extreme preterm (EPT; 23-28weeks of gestational age; n=10), moderate preterm (MPT; 29-32weeks of gestational age; n=10), late preterm (LPT; 34-36weeks of gestational age; n=25). OUTCOME MEASURES: All of the neonates were evaluated using the Neurobehavioral Assessment of Preterm Infant (NAPI) prior to 37weeks of post-conceptional age. The Neonatal Infant Stressor Scale (NISS) was applied for EPT and MPT infants during NICU hospitalization, and medical charts were analyzed. RESULTS: The EPT group experienced significantly more acute stressful events during NICU hospitalization than the MPT group. The MPT group had lower scores in motor development and vigor than the EPT and LPT group, and they exhibited poorer quality crying than the LPT group. Motor development and vigor and alertness and orientation in preterm infants were predicted by prematurity level and acute stressful events. CONCLUSION: The extreme preterm was exposed to higher stressful experiences than moderate and late preterm infants. However, the moderate preterm infants presented more vulnerable than the other counterparts in motor and vigor outcomes. PMID- 26422802 TI - Bacterial membrane vesicles, an overlooked environmental colloid: Biology, environmental perspectives and applications. AB - Phospholipid vesicles play important roles in biological systems. Bacteria are one of the most abundant organisms on Earth, and bacterial membrane vesicles (MVs) were first observed 50 years ago. Many bacteria release MVs to the environment that mainly consist of the cell membrane and typically range from 20 to 400 nm in size. Bacterial MVs are involved in several biological functions, such as delivery of cargo, virulence and gene transfer. MVs can be isolated from laboratory culture and directly from the environment, indicating their high abundance in and impact on ecosystems. Many colloidal particles in the environment ranging in size from 1 nm to 1 MUm have been reported but not characterized at the molecular level, and MVs remain to be explored. Hence, MVs can be considered terra incognita in environmental colloid research. Although MV biogenesis and biological roles are yet to be fully understood, the accumulation of knowledge has opened new avenues for their applications. Via genetic engineering, the MV yield can be greatly increased, and the components of MVs can be tailored. Recent studies have demonstrated that MVs have promising potential for applications such as drug delivery systems and nanobiocatalysts. For instance, MV vaccines have been extensively studied and have already been approved in Europe. Recent MV studies have evoked great interest in the fields of biology and biotechnology, but fundamental questions, such as their transport in the environment or physicochemical features of MVs, remain to be addressed. In this review, we present the current understanding of bacterial MVs and environmental perspectives and further introduce their applications. PMID- 26422803 TI - Airway Covered Metallic Stent Based on Different Fistula Location and Size in Malignant Tracheoesophageal Fistula. AB - BACKGROUND: Malignant tracheoesophageal fistula (MTEF) is a devastating complication of esophageal cancer, lung cancer or other carcinoma with a shorter life-span and poor life quality. The aim of this study was to assess the effect of airway stent insertion on MTEF patients. METHODS: A total of 63 MTEF patients were included, 12 patients with lung cancer and 46 patients with esophageal cancers. Eight zones were proposed to classify various fistula locations. Airway stents were selected based on the various zones and fistula size. RESULTS: Airway stents were successfully inserted in all patients, and both airway and esophageal stents in 8 patients. Most fistula were located in locations II (18/63, 28.6%), III (22/63, 34.9%), then VII (9/63, 14.3%). The stents included 10 (15.9%) I shaped, 8 (12.7%) L shaped and 45 (71.4%) Y shaped. Different stents were placed based on different locations and sizes of fistulas. Overall, mean survival time was 163 days (2-270 days). Most symptoms relieved after stent insertion. Mean Karnofsky score jumped from 43.0 +/- 10.7 before stent placement to 66.7 +/- 10.8 after stent insertion (P = 0.000). Complete closure was achieved in 45 patients (71.4%), and incomplete closure and leakage were found in 18 patients. CONCLUSIONS: Airway stent insertion provides an effective approach to improve symptoms and quality of life. The choice of stent based on different fistula location and size may be a reasonable way in clinical practice. PMID- 26422804 TI - Severe Azotemia and Hyperchloremic Metabolic Acidosis Associated With Reverse Flow Enterovesical Fistula. PMID- 26422805 TI - Future directions in human-environment research. AB - Human-environment research in the 21st century will need to change in major ways. It will need to integrate the natural and the social sciences; it will need to engage stakeholders and citizens in the design of research and in the delivery of science for the benefit of society; it will need to address ethical and democratic goals; and it will need to address a myriad of important theoretical and methodological challenges that continue to impede progress in the advance of sustainability science. PMID- 26422806 TI - Erratum: "Pollinator Power: Nutrition Security Benefits of an Ecosystem Service". PMID- 26422808 TI - Properties of noncovalent tetraphenylporphine...C60 dyads as studied by different long-range and dispersion-corrected DFT functionals. AB - The noncovalent dyad of tetraphenylporphine and C60 fullerene (H2TPP...C60) and the tetraphenylporphine dimer (H2TPP...H2TPP) were studied by density functional theory (DFT), using functionals that incorporate empirical dispersion correction (DFT-D), functionals that use a long-range correction (LC) scheme, a hybrid functional (B3LYP) and a highly parametrized empirical exchange-correlation functional (M05-2X). The results were compared to X-ray structures and interaction energies reported in previous experimental and theoretical studies. It was found that B3LYP and CAM-B3LYP functionals fail to reproduce the X-ray structures and binding energies of the TPP...C60 system. DFT-D functionals overestimated the pi...pi energy interactions for both systems, however, the optimized structures agree well with those observed experimentally. The LC-BLYP functional predicts geometries similar to X-ray structures; nevertheless, due to the lack of correction in the dispersion energy, the predicted energies for both model systems are low. On the other hand, the M05-2X functional exhibited the best performance. Both the structures and binding energies calculated with M05-2X are consistent with experimental and theoretical evidence reported by other authors, as well as with our experimental results obtained by means of atomic force microscopy on H2TPP thin films grown on the HOPG/C60 substrate by physical vapor deposition. PMID- 26422807 TI - Weight gain and changes in plasma adiponectin and leptin concentrations after 12 month insulin intensive therapy for Chinese male patients with newly diagnosed type 2 diabetes. AB - AIM: To examine the effects of intensive insulin therapy (IIT) in Chinese male patients with newly diagnosed type 2 diabetes in 12 months on plasma adiponectin and leptin levels and to assess whether changes in plasma adiponectin and leptin could be associated with subsequent weight gain or not. METHODS: Overall 84 patients were taken IIT. Total, and high-, and low-molecular-weight (HMW, LMW) adiponectin and leptin concentrations were measured at the time of study inclusion, days 7, and 1, 3, 6 and 12 months after IIT, respectively. Patients' body weight was recorded every time when adiponectin and leptin were measured. RESULTS: With improvement of diabetes control, plasma total and HMW adiponectin and leptin concentrations increased from inclusion to 3 months significantly and progressively, but remained steady after 6 months. Weight increased relatively modestly with a mean gain of 2kg for 12 months. Moreover, higher increments of total and HMW adiponectin from inclusion to 12 months were associated with significantly less subsequent weight gain after adjustment for confounding factors: the patients in the lowest tertile of total adiponectin increased by 2.47kg compared to patients in the highest tertile who increased by 0.56kg (P value=0.006). Whereas, the higher increments of leptin levels under the same condition were linked with more subsequent weight gain significantly (P value=0.003). CONCLUSIONS: Our researches suggest that glycaemic control with IIT increases total and HMW adiponectin and leptin in newly diagnosed type 2 diabetes male patients, the elevation of total and HMW adiponectin and leptin levels may predict weight gain after IIT. PMID- 26422810 TI - Late-Breaking Abstracts: 57th Annual Scientific Meeting of the American Headache Society. PMID- 26422809 TI - Role of Lipid Blooming and Crystallite Size in the Performance of Highly Soluble Drug-Loaded Microcapsules. AB - Hot-melt coating is of growing interest, because it does not require solvents, resulting in reduced process times and costs. However, excipients for this technology are mainly triacylglycerides (TAGs) or their derivatives, which exhibit polymorphism, surface disruption, and complex crystallite networks, affecting the release profile of produced microcapsules. In this work, anhydrous citric acid crystals were coated with molten tristearin using conventional inlet air temperatures (microcapsules A) and temperatures above the melting point of alpha-form (microcapsules B). Additionally, microcapsules A were tempered to achieve polymorphic stability (microcapsules AB). The product yield and coating efficacy were above 90% and 97%, respectively, demonstrating the feasibility and efficacy of the process. Small angle X-ray scattering analysis confirmed that the tristearin shell of microcapsules B is in the beta-form with a larger average crystallite size than microcapsules A and AB. Scanning electron microscopy images revealed a nonbloomed surface of microcapsules B. We showed that blooming does not play a critical role in the drug release, but the apparent diffusion coefficient of drug is dramatically reduced by increasing TAGs crystallite size and resulting tortuosity. This work brings new insights on the micrometric properties of solid lipid dosage forms, being an important step to prevent the overuse of excipients with unknown toxicity. PMID- 26422811 TI - Interventions for preventing and treating low-back and pelvic pain during pregnancy. AB - BACKGROUND: More than two-thirds of pregnant women experience low-back pain and almost one-fifth experience pelvic pain. The two conditions may occur separately or together (low-back and pelvic pain) and typically increase with advancing pregnancy, interfering with work, daily activities and sleep. OBJECTIVES: To update the evidence assessing the effects of any intervention used to prevent and treat low-back pain, pelvic pain or both during pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth (to 19 January 2015), and the Cochrane Back Review Groups' (to 19 January 2015) Trials Registers, identified relevant studies and reviews and checked their reference lists. SELECTION CRITERIA: Randomised controlled trials (RCTs) of any treatment, or combination of treatments, to prevent or reduce the incidence or severity of low-back pain, pelvic pain or both, related functional disability, sick leave and adverse effects during pregnancy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: We included 34 RCTs examining 5121 pregnant women, aged 16 to 45 years and, when reported, from 12 to 38 weeks' gestation. Fifteen RCTs examined women with low-back pain (participants = 1847); six examined pelvic pain (participants = 889); and 13 examined women with both low-back and pelvic pain (participants = 2385). Two studies also investigated low back pain prevention and four, low-back and pelvic pain prevention. Diagnoses ranged from self-reported symptoms to clinicians' interpretation of specific tests. All interventions were added to usual prenatal care and, unless noted, were compared with usual prenatal care. The quality of the evidence ranged from moderate to low, raising concerns about the confidence we could put in the estimates of effect. For low-back painResults from meta-analyses provided low quality evidence (study design limitations, inconsistency) that any land-based exercise significantly reduced pain (standardised mean difference (SMD) -0.64; 95% confidence interval (CI) -1.03 to -0.25; participants = 645; studies = seven) and functional disability (SMD -0.56; 95% CI -0.89 to -0.23; participants = 146; studies = two). Low-quality evidence (study design limitations, imprecision) also suggested no significant differences in the number of women reporting low-back pain between group exercise, added to information about managing pain, versus usual prenatal care (risk ratio (RR) 0.97; 95% CI 0.80 to 1.17; participants = 374; studies = two). For pelvic painResults from a meta-analysis provided low quality evidence (study design limitations, imprecision) of no significant difference in the number of women reporting pelvic pain between group exercise, added to information about managing pain, and usual prenatal care (RR 0.97; 95% CI 0.77 to 1.23; participants = 374; studies = two). For low-back and pelvic painResults from meta-analyses provided moderate-quality evidence (study design limitations) that: an eight- to 12-week exercise program reduced the number of women who reported low-back and pelvic pain (RR 0.66; 95% CI 0.45 to 0.97; participants = 1176; studies = four); land-based exercise, in a variety of formats, significantly reduced low-back and pelvic pain-related sick leave (RR 0.76; 95% CI 0.62 to 0.94; participants = 1062; studies = two).The results from a number of individual studies, incorporating various other interventions, could not be pooled due to clinical heterogeneity. There was moderate-quality evidence (study design limitations or imprecision) from individual studies suggesting that osteomanipulative therapy significantly reduced low-back pain and functional disability, and acupuncture or craniosacral therapy improved pelvic pain more than usual prenatal care. Evidence from individual studies was largely of low quality (study design limitations, imprecision), and suggested that pain and functional disability, but not sick leave, were significantly reduced following a multi-modal intervention (manual therapy, exercise and education) for low-back and pelvic pain.When reported, adverse effects were minor and transient. AUTHORS' CONCLUSIONS: There is low-quality evidence that exercise (any exercise on land or in water), may reduce pregnancy-related low-back pain and moderate- to low quality evidence suggesting that any exercise improves functional disability and reduces sick leave more than usual prenatal care. Evidence from single studies suggests that acupuncture or craniosacral therapy improves pregnancy-related pelvic pain, and osteomanipulative therapy or a multi-modal intervention (manual therapy, exercise and education) may also be of benefit.Clinical heterogeneity precluded pooling of results in many cases. Statistical heterogeneity was substantial in all but three meta-analyses, which did not improve following sensitivity analyses. Publication bias and selective reporting cannot be ruled out.Further evidence is very likely to have an important impact on our confidence in the estimates of effect and change the estimates. Studies would benefit from the introduction of an agreed classification system that can be used to categorise women according to their presenting symptoms, so that treatment can be tailored accordingly. PMID- 26422812 TI - A molecular simulation study on the adhesion behavior of a functionalized polyethylene-functionalized graphene interface. AB - Molecular dynamics simulations were applied to investigate interfacial adhesion between functionalized polyethylene (fPE) and functionalized graphene (fG) surfaces. In order to functionalize the PE and graphene surfaces, various types of functional groups were covalently bonded on the surfaces in a random manner. Adhesion between fPE and fG surfaces was evaluated by the calculation of work of separation (Wsep), while the interfaces were not allowed to relax. According to the simulation results, the combination of the atomic roughness effect and the electronic properties of the functional groups had influence on the adhesion between PE and graphene. The effect of surface reorganization was also investigated by devoting sufficient time for relaxation of the interface. The adhesion in the relaxed interfaces was evaluated via the work of adhesion (Wadh). Relaxation of the interface caused to decrease the atomic roughness of the PE surface, which enhanced adhesion in all of the systems compared to their unrelaxed models. In addition to surface flattening, relaxation also brought about an increase in the atomic density at the interface, which led to enhance the van der Waals interaction and increase interfacial adhesion. PMID- 26422813 TI - We're all in this together: Midwifery student peer mentoring. AB - Many higher education institutions have adopted mentoring programs for students as a means of providing support, improve learning and enhance the student experience. The aim of this project was to improve midwifery students experience by offering a peer mentoring program to commencing students to assist with the transition to university life and the rigours of the midwifery program. This paper reports the evaluation of this specific mentoring program and the ongoing development and implementation of a sustainable program within an Australian University. A survey design was adopted to gather feedback from both mentees to evaluate if the peer mentoring program enhanced the first year midwifery student experience and ascertain how the program could be further developed. Fifty-five students engaged with the peer mentors and completed the questionnaire regarding the mentoring program. Specifically valuable was the positive impact that mentoring had on midwifery student confidence, managing the demands of the program and being motivated to keep going when the program requirements were challenging. The success of this program rested largely with mentoring students sharing their own experiences and providing reassurance that other students could also succeed. PMID- 26422814 TI - Development and validation of a tool for patient reporting of symptoms and signs of the post-thrombotic syndrome. AB - Post-thrombotic syndrome (PTS) is a long-term complication of deep-vein thrombosis (DVT). The Villalta scale is the recommended tool for diagnosing PTS, but requires a clinician's assessment in addition to patient self-assessment. In the present study, we validated a self-administered tool for patient reporting of leg symptoms and signs as a mean to assess PTS. We first validated a form for patient self-reported Villalta (PRV1), then developed and validated a visually assisted form (PRV2). The validity of PRV1 and PRV2 was assessed in patients diagnosed with DVT between 2004 and 2012. Median time from DVT to inclusion was 5.1 and 3.5 years for PRV1 (n=162) and PRV2 (n=94), respectively. Patients were requested to complete the PRV form before a scheduled visit. PTS diagnosed by the original Villalta scale during the visit served as the reference method. PRV1 showed only moderate agreement for diagnosing PTS compared with the original Villalta scale (kappa agreement 0.60, 95% CI 0.48-0.72), whereas PRV2 showed very good agreement (0.82, 95% CI 0.71-0.94). In the validation of PRV2, PTS was diagnosed in 54 (57%) patients according to the original Villalta scale and in 60 (64%) by PRV2. The sensitivity of PRV2 to detect PTS was 98% and the specificity was 83%. We conclude that the visually assisted form for PRV is a valid and sensitive tool for diagnosing PTS. Such a tool could be applied in further clinical studies of PTS, making studies less resource demanding by reducing the need for in-person clinic visits. PMID- 26422815 TI - Flow dynamics in pediatric rigid bronchoscopes using computer-aided design modeling software. AB - OBJECTIVES/HYPOTHESIS: Observed complications during rigid bronchoscopy, including hypercarbia and hypoxemia, prompted us to assess how well rigid bronchoscopes serve as an airway device. We performed computer-aided design flow analysis of pediatric rigid bronchoscopes to gain insight into flow dynamics. STUDY DESIGN: We made accurate three-dimensional computer models of pediatric rigid bronchoscopes and endotracheal tubes. SOLIDWORKS (Dassault Systemes, Velizy Villacoublay, France) flow analysis software was used to analyze fluid dynamics during pressure-controlled and volume-controlled ventilation. METHODS: Flow analysis was performed on rigid bronchoscopes and similar outer diameter endotracheal tubes comparing resistance, flow, and turbulence during two ventilation modalities and in common surgical scenarios. RESULTS: Increased turbulent flow was observed in bronchoscopes compared to more laminar flow in endotracheal tubes of similar outer diameter. Flow analysis displayed higher resistances in all pediatric bronchoscope sizes except one (3.0 bronchoscope) compared to similar-sized endotracheal tubes. Loss of adequate ventilation was observed if the bronchoscope was not assembled correctly or if increased peak inspiratory pressures were needed. Anesthesia flow to the patient was reduced by 63% during telescope insertion. CONCLUSIONS: Flow analysis illustrates increased turbulent flow and increased airflow resistance in all but one size of pediatric bronchoscopes compared to endotracheal tubes. This increased turbulence and resistance, along with the unanticipated gas distal exit pattern, may contribute to the documented hypercarbia and hypoxemia during procedures. These findings may explain why hypoxemia and hypercarbia are commonly observed during rigid bronchoscopy, especially when positive pressure ventilation is needed. LEVEL OF EVIDENCE: NA Laryngoscope, 126:1940-1945, 2016. PMID- 26422816 TI - Copper-transporting ATPases: The evolutionarily conserved machineries for balancing copper in living systems. AB - Copper ATPases (Cu-ATPases) are ubiquitous transmembrane proteins using energy from ATP to transport copper across different biological membranes of prokaryotic and eukaryotic cells. As they belong to the P-ATPase family, Cu-ATPases contain a characteristic catalytic domain with an evolutionarily conserved aspartate residue phosphorylated by ATP to form a phosphoenzyme intermediate, as well as transmembrane helices containing a cation-binding cysteine-proline cysteine/histidine/serine (CPx) motif for catalytic activation and cation translocation. In addition, most Cu-ATPases possess the N-terminal Cu-binding CxxC motif required for regulation of enzyme activity. In cells, the Cu-ATPases receive copper from soluble chaperones and maintain intracellular copper homeostasis by efflux of copper from the cell or transport of the metal into the intracellular compartments. In addition, copper pumps play an essential role in cuproprotein biosynthesis by the uptake of copper into the cell or delivery of the metal into the chloroplasts and thylakoid lumen or into the lumen of the secretory pathway, where the metal ion is incorporated into copper-dependent enzymes. In the recent years, significant progress has been made toward understanding the function and regulation of Cu-transporting ATPases in archaea, bacteria, yeast, humans, and plants, providing new insights into the specific physiological roles of these essential proteins in various organisms and revealing some conservative regulatory mechanisms of Cu-ATPase activity. In this review, the structural, biochemical, and functional properties of Cu-ATPases from phylogenetically different organisms are summarized and discussed, with particular attention given to the recent insights into the molecular biology of copper pumps in plants. PMID- 26422817 TI - Association of Model for End-Stage Liver Disease Score and Mortality in Trauma Patients With Chronic Liver Disease. AB - IMPORTANCE: The Model for End-Stage Liver Disease (MELD) score is predictive of trauma outcomes. OBJECTIVE: To determine whether a decrease in MELD score is associated with improved mortality in critically ill trauma patients. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective registry study of critically ill trauma patients 18 years or older with chronic liver disease treated between August 3, 1998, and January 5, 2012, at 2 level I trauma centers in Boston, Massachusetts. The consecutive sample included 525 patients (male, 373 [71.0%]; white, 399 [76.0%]; mean [SD] age, 55.0 [12.4] years). EXPOSURES: Change in MELD score from intensive care unit (ICU) admission to 48 to 72 hours later. MAIN OUTCOMES AND MEASURES: Thirty-day all-cause mortality. RESULTS: The mean (SD) MELD score at ICU admission was 19.3 (9.7). The 30-day mortality was 21.9%. The odds of 30-day mortality with a change in MELD score of less than -2, -2 to 1, +1 to +4, and greater than +4 were 0.23 (95% CI, 0.10-0.51), 0.30 (95% CI, 0.10-0.85), 0.57 (95% CI, 0.27-1.20), and 1.31 (95% CI, 0.58-2.96), respectively, relative to a change in MELD score of 0 and adjusted for age, sex, race, Charlson/Deyo Index, sepsis, number of acute organ failures, International Classification of Diseases, Ninth Revision-based injury severity score, and ICU admission MELD score. CONCLUSIONS AND RELEVANCE: A decrease in MELD score within 72 hours of ICU admission is associated with improved mortality. PMID- 26422819 TI - On-chip supercapacitors with ultrahigh volumetric performance based on electrochemically co-deposited CuO/polypyrrole nanosheet arrays. AB - We introduce a new method for fabricating unique on-chip supercapacitors based on CuO/polypyrrole core/shell nanosheet arrays by means of direct electrochemical co deposition on interdigital-like electrodes. The prepared all-solid-state device demonstrates exceptionally high specific capacitance of 1275.5 F cm(-3) (~40 times larger than that of CuO-only supercapacitors) and high-energy-density of 28.35 mWh cm(-3), which are both significantly greater than other solid-state supercapacitors. More importantly, the device maintains approximately 100% capacity retention at 2.5 A cm(-3) after 3000 cycles. The in situ co-deposition of CuO/polypyrrole nanosheets on interdigital substrate enables effective charge transport, electrode fabrication integrity, and device integration. Because of their high energy, power density, and stable cycling stability, these newly developed on-chip supercapacitors permit fast, reliable applications in portable and miniaturized electronic devices. PMID- 26422818 TI - Multifunctional Pristine Chemically Modified Graphene Films as Strong as Stainless Steel. AB - Pristine chemically modified graphene films with light weights and excellent mechanical properties can be prepared by chemically engineering the structure of the graphene oxide sheets and the microstructures of the films. Particularly, these reduced graphene oxide films are as strong as stainless steel, ultra-tough, and have high electrical and thermal conductivities. PMID- 26422820 TI - Recombinational DNA repair is regulated by compartmentalization of DNA lesions at the nuclear pore complex. AB - The nuclear pore complex (NPC) is emerging as a center for recruitment of a class of "difficult to repair" lesions such as double-strand breaks without a repair template and eroded telomeres in telomerase-deficient cells. In addition to such pathological situations, a recent study by Su and colleagues shows that also physiological threats to genome integrity such as DNA secondary structure-forming triplet repeat sequences relocalize to the NPC during DNA replication. Mutants that fail to reposition the triplet repeat locus to the NPC cause repeat instability. Here, we review the types of DNA lesions that relocalize to the NPC, the putative mechanisms of relocalization, and the types of recombinational repair that are stimulated by the NPC, and present a model for NPC-facilitated repair. PMID- 26422821 TI - A S-Layer Protein of Bacillus anthracis as a Building Block for Functional Protein Arrays by In Vitro Self-Assembly. AB - S-layer proteins create a cell-surface layer architecture in both bacteria and archaea. Because S-layer proteins self-assemble into a native-like S-layer crystalline structure in vitro, they are attractive building blocks in nanotechnology. Here, the potential use of the S-layer protein EA1 from Bacillus anthracis in constructing a functional nanostructure is investigated, and apply this nanostructure in a proof-of-principle study for serological diagnosis of anthrax. EA1 is genetically fused with methyl parathion hydrolase (MPH), to degrade methyl parathion and provide a label for signal amplification. EA1 not only serves as a nanocarrier, but also as a specific antigen to capture anthrax specific antibodies. As results, purified EA1-MPH forms a single layer of crystalline nanostructure through self-assembly. Our chimeric nanocatalyst greatly improves enzymatic stability of MPH. When applied to the detection of anthrax-specific antibodies in serum samples, the detection of our EA1-MPH nanostructure is nearly 300 times more sensitive than that of the unassembled complex. Together, it is shown that it is possible to build a functional and highly sensitive nanosensor based on S-layer protein. In conclusion, our present study should serve as a model for the development of other multifunctional nanomaterials using S-layer proteins. PMID- 26422822 TI - Disorder-specific versus transdiagnostic and clinician-guided versus self-guided treatment for major depressive disorder and comorbid anxiety disorders: A randomized controlled trial. AB - Disorder-specific cognitive behavior therapy (DS-CBT) is effective at treating major depressive disorder (MDD) while transdiagnostic CBT (TD-CBT) addresses both principal and comorbid disorders by targeting underlying and common symptoms. The relative benefits of these two models of therapy have not been determined. Participants with MDD (n=290) were randomly allocated to receive an internet delivered TD-CBT or DS-CBT intervention delivered in either clinician-guided (CG CBT) or self-guided (SG-CBT) formats. Large reductions in symptoms of MDD (Cohen's d>=1.44; avg. reduction>=45%) and moderate-to-large reductions in symptoms of comorbid generalised anxiety disorder (Cohen's d>=1.08; avg. reduction>=43%), social anxiety disorder (Cohen's d>=0.65; avg. reduction>=29%) and panic disorder (Cohen's d>=0.45; avg. reduction>=31%) were found. No marked or consistent differences were observed across the four conditions, highlighting the efficacy of different forms of CBT at treating MDD and comorbid disorders. PMID- 26422823 TI - Treatment of Hypercholesterolemia in 2015. AB - Randomized, double-blind, placebo-controlled secondary prevention and primary prevention studies and observational studies have documented that statins reduce cardiovascular events in high-risk patients with hypercholesterolemia. The 2013 American College of Cardiology/American Heart Association guidelines on treatment of hypercholesterolemia support the use of statins in 4 major groups that will be discussed. The Expert Panel of these guidelines could find no data supporting the routine use of nonstatin drugs combined with statins to further reduce cardiovascular events. Since these guidelines were published, a double-blind randomized trial of 18,144 patients with an acute coronary syndrome demonstrated at a 7-year follow-up that the incidence of cardiovascular events was 34.7% in patients randomized to simvastatin plus placebo versus 32.7% in patients randomized to simvastatin plus ezetimibe (hazard ratio = 0.936; P = 0.016). Proprotein convertase subtilisin/kexin type 9 inhibitors further lower serum low density lipoprotein cholesterol by 50%-70% in patients treated with statins and 4 phase 3 trials including more than 70,000 patients are investigating whether these monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 will lower cardiovascular events. PMID- 26422824 TI - Challenges of LADA Diagnosis and Treatment: Lessons From 2 Case Reports. AB - Latent autoimmune diabetes in adults (LADA) is a subtype of autoimmune diabetes, which shares characteristics of both Type 1 and 2 diabetes (T1D and T2D), and for this reason, it is often confused with other types of diabetes, misdiagnosed, and inappropriately treated. Two cases were presented (41-year-old and 50-year-old females), one occasionally diagnosed during routine health checkup, the other one identified as having T2D, and as far as misclassified and not optimally treated. Now, after approximately 9 months of LADA diagnosis, the first patient has an optimal metabolic control while maintaining the values of glycated hemoglobin to around 7% with small doses of analogue insulin (lispro 4-6 UI) before meals and long acting insulin (glargine 4-6 UI) at bedtime. The second patient, after approximately 2 years from the LADA diagnosis, has an optimal metabolic control, with maintenance of glycated hemoglobin to around 6.5%, and stable C-peptide level (around 1.5 ng/mL), only with dietary and exercise habits. To avoid misclassification, any patient who does not fit the typical T2D profile, or with poor glycemic control, and who does not follow the expected clinical course, as become insulin dependent sooner than expected, should be investigated to exclude LADA. To define the best therapeutic approach, each patient must be evaluated and therapy tailored on his/her specific profile, considering as very low insulin doses may be effective to maintain a successful metabolic control and the only dietary approach may be sufficient until the insulin-secretory capacity remains good. PMID- 26422825 TI - Economic analyses of stress urinary incontinence surgical procedures in women. AB - INTRODUCTION: To evaluate the quality of economic analysis (EA) of surgical procedures for stress urinary incontinence (SUI) in women. METHODS: A MEDLINE search on EA for SUI surgical procedures for the years 2000-2014 included the MeSH terms "tension-free vaginal tape," "TVT," "trans-obturator tape," "TOT," "Burch colposuspension" (BC), "stress urinary incontinence," "economic analysis," and "cost-effectiveness analysis." Important criteria for evaluating articles were selected from panels that set out criteria to evaluate EA [Scales CD, Jr., Christopher SS, American Urological Association 32:121-128, 2013], [Hsieh MH, Maxwell MV, J Urol 178 1867-1874, 2007], [Wu JM, Catherine CM, Conover MM, et al., Obstet Gynecol 123 1201-1206, 2014]. RESULTS: Thirteen articles were identified: TVT compared to BC (6), to other surgical procedures for SUI (1), to TOT (3) and to the mini-sling (1); open BC compared to laparoscopic BC (1), and analysis of various slings and meshes for various types of incontinence (1). Articles originated from: United States (3), Europe (4), United Kingdom (4), and Canada (2). Eight described cost-effectiveness analysis (CEA), two cost-utility analysis, and three cost comparison. Follow-up time for patients ranged from 6 to 24 months in eight articles, with four having a minimum of 24 months follow-up. Studies mostly adhered to the criteria, however indirect costs, sensitivity analysis, and efficacy parameters varied. Long-term synthetic sling-related complications were not included. CONCLUSION: Although CEA for SUI surgery is a burgeoning field, study comparisons remain difficult due to some variability, including health care delivery systems. As women live longer, long-term data will become critical as complications and reoperations can affect the real cost of SUI corrective procedures. Neurourol. Urodynam. 35:1040-1045, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26422826 TI - Activation of Prodrug Treosulfan at pH 7.4 and 37 degrees C Accompanied by Hydrolysis of Its Active Epoxides: Kinetic Studies with Clinical Relevance. AB - Treosulfan (TREO), originally registered for treatment of ovarian cancer, is currently being investigated for conditioning prior to hematopoietic stem cell transplantation. TREO is a prodrug, which undergoes a pH- and temperature dependent two-step conversion to active monoepoxide [S,S-EBDM, (2S,3S)-1,2 epoxybutane-3,4-diol-4-methanesulfonate] and diepoxide [S,S-DEB, (2S,3S)-1,2:3,4 diepoxybutane]. In this paper, the kinetics of the nonenzymatic transformation of TREO at pH 7.4 and 37 degrees C were studied for the first time including the effects of the TREO concentration, buffer concentration, ionic strength, and the presence of NaCl. Transformation of TREO was well described by a kinetic model, which included first-order reactions for TREO activation, that is, TREO -> S,S EBDM -> S,S-DEB, and pseudo-first-order reactions for the hydrolytic decomposition of S,S-EBDM and S,S-DEB. In contrast to the two-step activation of TREO, the hydrolysis of epoxides was influenced by electrolytes. In phosphate buffered saline, decomposition of S,S-EBDM and S,S-DEB (mean half-lives 25.7 and 15.4 h) proceeded much slower than their formation (mean half-lives 1.5 and 3.5 h). In conclusion, the kinetics of the nonenzymatic transformation of TREO in the presence of plasma electrolytes cannot contribute to the very low levels of S,S EBDM and S,S-DEB observed in patient plasma. The results also indicate that elimination of TREO proceeds primarily via conversion to S,S-EBDM. PMID- 26422827 TI - Alterations in cellular metabolome after pharmacological inhibition of Notch in glioblastoma cells. AB - Notch signaling can promote tumorigenesis in the nervous system and plays important roles in stem-like cancer cells. However, little is known about how Notch inhibition might alter tumor metabolism, particularly in lesions arising in the brain. The gamma-secretase inhibitor MRK003 was used to treat glioblastoma neurospheres, and they were subdivided into sensitive and insensitive groups in terms of canonical Notch target response. Global metabolomes were then examined using proton magnetic resonance spectroscopy, and changes in intracellular concentration of various metabolites identified which correlate with Notch inhibition. Reductions in glutamate were verified by oxidation-based colorimetric assays. Interestingly, the alkylating chemotherapeutic agent temozolomide, the mTOR-inhibitor MLN0128, and the WNT inhibitor LGK974 did not reduce glutamate levels, suggesting that changes to this metabolite might reflect specific downstream effects of Notch blockade in gliomas rather than general sequelae of tumor growth inhibition. Global and targeted expression analyses revealed that multiple genes important in glutamate homeostasis, including glutaminase, are dysregulated after Notch inhibition. Treatment with an allosteric inhibitor of glutaminase, compound 968, could slow glioblastoma growth, and Notch inhibition may act at least in part by regulating glutaminase and glutamate. PMID- 26422828 TI - Reply: To PMID 25747677. PMID- 26422829 TI - The Effects of Cataract Surgery on Patients With Wet Macular Degeneration. PMID- 26422830 TI - Spectral-Domain Optical Coherence Tomography of Subretinal Hyperreflective Exudation in Myopic Choroidal Neovascularization. PMID- 26422832 TI - Epidural Cortical Stimulation as a Treatment for Poststroke Aphasia: A Systematic Review of the Literature and Underlying Neurophysiological Mechanisms. AB - BACKGROUND: Nearly 15 million people suffer from stroke every year worldwide, with about 20% of the survivors retaining chronic aphasic symptoms. Spontaneous recovery is limited to 3 to 6 months. Cortical stimulation techniques have been proposed to enhance the recovery process. OBJECTIVE: The goal of this study was to evaluate the benefit of epidural cortical stimulation for the treatment of poststroke aphasia, based on a systematic review of the literature. METHODS: An extensive PubMed search was performed for English language articles published from 1990 to 2014 with the keywords (cortical OR epidural) AND stimulation AND stroke AND (aphasia OR language OR speech). The criteria analyzed included the type of study, epidemiology of patients, stroke, aphasia, stimulation protocol, concurrent rehabilitation therapies, language evaluations, results observed, and follow-up. RESULTS: Seven cases were reported to date (3 case reports, 1 randomized controlled trial). All patients experienced nonfluent aphasia following an ischemic stroke. All four studies reported encouraging effects of the stimulation with improved lexical access and fluency for all patients. The effects were specific, independent of the motor recovery or of the pain reported by the patients, and they were linked to the stimulation parameters. CONCLUSIONS: Due to the small number of existing cases in the literature, the strength of the evidence is still low. Two main hypotheses of neurobiological mechanisms have been explored: either using continuous stimulation to modify cortical perilesional inhibition or using intermittent stimulation during the speech and language therapy sessions to explore synaptic plasticity and long-term potentiation or depression. To establish the role of epidural stimulation and the relevant stimulation protocols and parameters, large randomized controlled trials are mandatory. We suggest avenues of investigation. PMID- 26422831 TI - Reply: To PMID 26314663. PMID- 26422834 TI - Distance education: Not for PAs, yet. PMID- 26422833 TI - The role of MAGT1 in genetic syndromes. AB - Disturbances in magnesium homeostasis, often linked to altered expression and/or function of magnesium channels, have been implicated in a plethora of diseases. This review focuses on magnesium transporter 1 (MAGT1), as recently described changes in this gene have further extended our understanding of the role of magnesium in human health and disease. The identification of genetic changes and their functional consequences in patients with immunodeficiency revealed that magnesium and MAGT1 are key molecular players for T cell-mediated immune responses. This led to the description of XMEN (X-linked immunodeficiency with magnesium defect, Epstein Barr Virus infection, and neoplasia) syndrome, for which Mg2+ supplementation has been shown to be beneficial. Similarly, the identification of a copy-number variation (CNV) leading to dysfunctional MAGT1 in a family with atypical ATRX syndrome and skin abnormalities, suggested that the MAGT1 defect could be responsible for the cutaneous problems. On the other hand, recent genetic investigations question the previously proposed role for MAGT1 in intellectual disability. Understanding the molecular basis of the involvement of magnesium and its channels in human pathogenesis will improve opportunities for Mg2+ therapies in the clinic. PMID- 26422835 TI - Patient-derived orthotopic xenografts: better mimic of metastasis than subcutaneous xenografts. AB - The majority of human solid tumours do not metastasize when grown subcutaneously in immunocompromised mice; this includes patient-derived xenograft (PDX) models. However, orthotopic implantation of intact tumour tissue can lead to metastasis that mimics that seen in patients. These patient-derived orthotopic xenograft (PDOX) models have a long history and might better recapitulate human tumours than PDX models. PMID- 26422836 TI - Medical Devices; Cardiovascular Devices; Classification of the Steerable Cardiac Ablation Catheter Remote Control System. Final order. AB - The Food and Drug Administration (FDA) is classifying the steerable cardiac ablation catheter remote control system into class II (special controls). The special controls that will apply to the device are identified in this order and will be part of the codified language for the steerable cardiac ablation catheter remote control system's classification. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 26422837 TI - Preventing falls and fall-related injuries in health care facilities. PMID- 26422839 TI - Equitable and inequitable healthcare. PMID- 26422840 TI - The evaluation of transient hypothyroidism in patients diagnosed with congenital hypothyroidism. AB - BACKGROUND/AIM: Congenital hypothyroidism (CH) is divided into two groups as 'permanent' and 'transient' We aimed to determine the rate of transient and permanent congenital hypothyroidism of the newborns referred to our clinic. MATERIALS AND METHODS: Of the newborns who were referred to our clinic from the neonatal screening program, those who were diagnosed with CH and started treatment were included in the study. The treatments of the patients whose required daily treatment dose was reduced to under 1 ug/kg were terminated and those who were followed monthly and whose fT4 and thyroid-stimulating hormone (TSH) levels were normal at least 3 times without treatment were considered to have transient hypothyroidism. RESULTS: Of the 256 newborns referred to our clinic from the neonatal screening program, 114 (44.5%) were diagnosed with CH. Of the CH patients, 70% (n = 58) were evaluated to have permanent and 30% (n = 25) transient hypothyroidism. Neonatal and serum TSH levels and treatment doses were found to be significantly lower in the transient hypothyroidism patients. CONCLUSION: Initial measurements of the serum TSH level and the required doses of L-thyroxine therapy for maintaining normal thyroid hormone levels, growth, and development may have a predictive role for differentiating permanent forms of CH from transient forms. PMID- 26422838 TI - Italian guidelines for the use of antiretroviral agents and the diagnostic clinical management of HIV-1 infected persons. Update December 2014. PMID- 26422841 TI - Cardiac factors affecting the success of vardenafil in erectile dysfunction. AB - BACKGROUND/AIM: To evaluate the predictability of vardenafil success in patients with erectile dysfunction (ED) by using cardiological tests. MATERIALS AND METHODS: Patients diagnosed with ED who did not benefit from lifestyle changes (n = 68) were evaluated with an abridged 5-item version of the International Index of Erectile Function (IIEF-5). The pretreatment and posttreatment IIEF-5 scores were compared with pretreatment data obtained from cardiological examinations. RESULTS: When pretreatment scores were compared with test parameters, mitral flow E/A ratio and tissue Doppler imaging (TDI) E'/ A', exercise test duration, exercise capacity in MET, and percentage of maximum heart rate were found to be statistically significant. Furthermore, there was a significant negative correlation between mitral flow E/A ratio, TDI E'/A', exercise test duration, exercise capacity in MET, and the difference in post- and pretreatment IIEF-5 scores. CONCLUSION: As a diastolic function indicator, TDI E'/A' positively correlates with pretreatment IIEF-5 scores and negatively correlates with the beneficial effect of vardenafil treatment. As a result, the cardiological status of the patient correlates with individual IIEF-5 scores, and it seems to be useful in predicting vardenafil success. PMID- 26422842 TI - Sexuality and sexual dysfunction in spinal cord-injured men in Turkey. AB - BACKGROUND/AIM: To provide a comprehensive evaluation of sexual function and dysfunction in spinal cord-injured men based on self-reports of patients. MATERIALS AND METHODS: Forty-seven spinal cord-injured men who completed the spinal shock and rehabilitation period were included. Patients were asked to complete a questionnaire developed to assess social status, sexual activities, abilities, and sexuality education after injury. Neurologic levels of patients were classified according to American Spinal Cord Injury Association protocol. Erectile function was evaluated by International Index of Erectile Function-5 (IIEF-5) questionnaire. RESULTS: Patients were aged between 20 and 62 years (mean: 35.2). Twenty-eight patients had T10 and above, 15 between T11 and L2, and 4 cauda conus injury. While 61.7% of the patients declared sexual activity, 93.6% declared some degree of erection. Mean IIEF-5 score was 5.3 and 87.3% of the patients had moderate to severe erectile dysfunction. CONCLUSION: Continuation of sexual activity after injury is very important and has a great impact on quality of life and interpersonal relationships for spinal cord-injured men. More attention must be given to sexuality after spinal cord injury. A very high rate of sexual dysfunction in spinal cord-injured patients was found and the importance of sexual education was emphasized in this study. PMID- 26422843 TI - Esophageal replacement by hydroxylated bacterial cellulose patch in a rabbit model. AB - BACKGROUND/AIM: To repair esophageal defects by hydroxylated and kombucha synthesized bacterial cellulose (HKBC) patch in a rabbit model. MATERIALS AND METHODS: Semicircular esophageal defects 1 cm in length of the cervical esophagus were initially created in 18 Japanese big-ear rabbits and then repaired with HKBC patch grafts. The clinical outcomes including survival rate, weight change, food intake, and hematological and radiologic evaluation were observed. After X-ray evaluation, the rabbits were sacrificed sequentially at 1, 3, and 6 months for histopathologic analysis with light microscopy and scanning electron microscopy. RESULTS: Survival rate during the first month was 88.9% (n = 16). Two rabbits died from anastomotic leakage during the entire follow-up. Postoperatively, feeding function and body weight were gradually restored in the surviving animals. No hematological abnormalities were found, and no obvious anastomotic leakage, stenosis, or obstruction was observed under X-ray examination. The histopathologic results showed a progressive regeneration of the esophagus in the graft area, where the neo-esophagus tissue had characteristics similar to native esophageal tissue after 3 months of surgery. CONCLUSION: HKBC is beneficial for esophageal tissue regeneration and may be a promising material for esophageal reconstruction. PMID- 26422844 TI - Bilateral sympathicotomy for hyperhidrosis without using single-lung ventilation. AB - BACKGROUND/AIM: The goal of this retrospective study was to evaluate the outcomes and complications of bilateral videothoracoscopic sympathicotomy without using single-lung ventilation in the treatment of primary hyperhidrosis and facial blushing. MATERIALS AND METHODS: We retrospectively reviewed 154 consecutive patients (70 females and 84 males) who underwent bilateral sympathicotomy for palmar, axillary, and facial/scalp hyperhidrosis or facial blushing from February 2005 to June 2013. The patients were intubated with single-lumen endotracheal tube, and then sympathicotomies were performed via videothoracoscopy during controlled apnea periods. RESULTS: Sympathicotomies were performed at costal levels 2, 3, and 4. No perioperative mortality or conversion to open surgery was recorded. Mean operation time was 31.2 +/- 2.4 min and mean hospital stay was 1.1 +/- 0.6 days. One patient experienced a unilateral pneumothorax that required treatment. There were no abnormal hemodynamic parameters measured during the perioperative apnea periods. The long term follow-up period was 21.4 +/- 5 months. Twenty-nine cases (18.8%) were complicated by compensatory sweating. No recurrence was observed during the follow-up period. CONCLUSION: Video-assisted thoracoscopic sympathicotomy without lung isolation provides effective cure of primary hyperhidrosis and facial blushing. This procedure can shorten the operative time without any aberrant hemodynamic shifts. PMID- 26422845 TI - Determining the health beliefs and breast cancer fear levels of women regarding mammography. AB - BACKGROUND/AIM: Women's fears and health beliefs impact their participation in early breast cancer diagnosis approaches. This study was conducted to determine the health beliefs and fear levels of women older than 50 regarding mammography. MATERIALS AND METHODS: A cross-sectional study was conducted in Turkey. The study cohort consisted of 300 women selected by cluster sampling who agreed to participate in the study. A health belief model scale and breast cancer fear scale were used in data collection. Descriptive statistics, t-test, chi-square test, and correlation analysis were used in the data analysis. RESULTS: Participants had an age average of 59.88 +/- 6.49 years, and 86.3% were illiterate. Only 34.7% of women stated that they had had a mammogram in the past. The women's average scores on the lower dimensions of the health belief model scale were determined as follows: 6.52 +/- 2.81 for sensitivity perception, 18.49 +/- 5.22 for seriousness perception, 16.80 +/- 4.31 for health motivation perception, 15.83 +/- 3.89 for mammography benefit perception, and 28.74 +/- 8.35 for mammography barrier perception. The score average of the breast cancer fear scale was determined as 23.81 +/- 9.71. CONCLUSION: We observed that women's health beliefs and breast cancer fear levels impacted their participation in mammography. PMID- 26422846 TI - Self-perception of quality of life in patients treated with antipsychotics. AB - BACKGROUND/AIM: Despite extensive research, normal functionality remains problematic in patients with schizophrenia. Issues such as quality of life, subjective well-being, or psychosocial performance are currently objectives of interest. There are limited data collected prospectively on patients' perception of quality of life as compared between treatment groups, especially in developing countries. The aim of the present study was to analyze the evolution of patients' reported quality of life in patients with schizophrenia or related disorders treated with antipsychotics, in naturalistic settings. MATERIALS AND METHODS: The study was designed as a 12-month prospective observational study of 131 subjects with schizophrenia or related disorders treated with haloperidol, olanzapine, risperidone, quetiapine, or aripiprazole, recruited from consecutive hospitalized patients in a psychiatry department. RESULTS: The mean scores for patients' reported quality of life and its components and for satisfaction with treatment had a favorable evolution, but increases were of reduced magnitude. The differences among treatment groups were not statistically significant, with few exceptions. A great variability of data was found. CONCLUSION: Studies with a stratified analysis by factors influencing quality of life perceptions in this category of patients might allow the identification of differences, if any, between antipsychotics in this domain. PMID- 26422847 TI - Multidrug resistance and integron carriage in clinical isolates of Pseudomonas aeruginosa in Tehran, Iran. AB - BACKGROUND/AIM: Pseudomonas aeruginosa is the cause of 10% of hospital-acquired infections. The organisms are often multidrug- resistant, mediated mostly by antibiotic-resistant integrons. The aim of this research was to study integron carriage and its association with multidrug resistance in burn and nonburn clinical isolates of P. aeruginosa. MATERIALS AND METHODS: A total of 112 P. aeruginosa clinical isolates were collected from the Motahari and Shohadaye Tajrish hospitals in Tehran between July and December 2011. Antibiotic susceptibility to 13 antibiotics was determined by disk diffusion. Detection of integron classes 1 and 2 and amplifications of internal variable regions (IVRs) of class 1 integrons were carried out by PCR and specific primers. RESULTS: Among the 112 isolates, 77 were from burn patients and 35 were nonburn isolates. Multidrug resistance and class 1 integron carriage were both significantly higher in the burn isolates compared to the nonburn strains (97.4% vs. 22.8% and 82.3% vs. 17.7%, respectively). Class 2 integron (2.7%) was only present in the burn isolates. Amplification of IVRs of class 1 integrons revealed 3 different fragment arrays. CONCLUSION: The significant association between multidrug resistance and integron carriage among P. aeruginosa burn isolates suggests a dissemination of resistance determinants by horizontal gene transfer. PMID- 26422848 TI - A study of the effect of Bacillus thuringiensis serotype H14 (subspecies israelensis) delta endotoxin on Musca larva. AB - BACKGROUND/AIM: House flies (Musca domestica) are of major public health concern in areas with poor sanitation and hygiene conditions. Biological control through the use of parasitoids and pathogens is one of the alternatives to the use of chemical pesticides for control of insects of public health importance. MATERIALS AND METHODS: The effects of the delta endotoxin of Bacillus thuringiensis on house fly larval mortality were studied. Gel filtration and SDS-PAGE methods were used for separation and purification of proteins. Delta endotoxin was incubated with larvae in concentrations of 0.43 mg/mL and 0.27 mg/mL in bioassay tests. RESULTS: The results of this study indicated protein crystal toxicity against larvae of the house fly. A concentration of 0.43 mg/mL of this toxin caused 100% mortality in house fly larvae. The LD50 amount of these toxins was calculated as 125 ug/g. CONCLUSION: The results of this study suggest that the use of the protein crystal including delta endotoxin of Bacillus thuringiensis serotype H14 is an effective weapon in the biological fight against the house fly. PMID- 26422850 TI - Effects of Turkish propolis on expression of hOGG-1 and NEIL-1. AB - BACKGROUND/AIM: Propolis is a bee product with antioxidative, antimutagenic, and other beneficial properties, and it is used as a natural drug. It is rich in polyphenolic compounds. Its composition varies depending on the particular geographical region. Oxidative stress is caused by an imbalanced free radical production and antioxidant system. The effects of flavonoids on the expression of DNA repair enzymes have been examined previously; however, no study has investigated the effects of propolis. This study investigated the effects of ethanolic extracts of Turkish propolis (EEP) on the expression of DNA repair enzymes. MATERIALS AND METHODS: The effects of EEP and tertiary-butyl hydroperoxide (t-BHP) on cell viability were determined using MTT DNA damage was determined using comet assay. mRNA expression of target enzymes was detected using RT-PCR. RESULTS: According to the cytotoxicity analysis, after a recovery time of 4 h, appropriate damage agent t-BHP and optimum EEP concentrations were 300 uM and 200 ug/mL, respectively. 8-Oxoguanine-glycosylase (hOGG-1) and endonuclease-VIII-like-1 (NEIL-1) expressions increased in the positive control group (t-BHP alone) and the study group (t-BHP+EEP). Maximum increase in NEIL-I expression was at hour 12 in the positive control group and at hour 8 in the study group. CONCLUSION: EEP can be considered as a potential source of functional food and pharmaceutical agents. PMID- 26422849 TI - Is there a role of interstitial cells of Cajal and mast cells and eosinophils in appendicitis in children? AB - BACKGROUND/AIM: The aim of this study was to compare the distribution of interstitial Cajal cells, eosinophils, and mast cells in normal and inflamed appendices, and to evaluate the correlation of presence of these cells with severity of inflammation in appendicitis. MATERIALS AND METHODS: The appendicitis group (n = 30) was divided further into three groups according to the macroscopic description and the histological findings. Ten normal appendices served as controls. Tissue samples were processed for routine histological examination. Additionally, all sections were immunohistochemically stained with CD117 and mast cell tryptase antibodies. RESULTS: When specimens were compared in terms of Cajal cells, the observed mean number for the appendicitis group was 4.9 and for the control group it was 8.3. In contrast, eosinophils and mast cells were significantly increased in the appendicitis group when compared with the control group. CONCLUSION: We detected that eosinophils and mast cells are increased in appendicitis, and correlate with the degree of inflammation of the appendix. The density of interstitial Cajal cells was significantly lower in patients with severe appendix inflammation compared to controls. The histopathological differences observed in this study may help elucidate the pathophysiology of appendicitis. PMID- 26422851 TI - The effects of aspirin, flurbiprofen, and NO-donating acetylsalicylic acid (NCX 4016) on mice models of endotoxic and septic shock. AB - BACKGROUND/AIM: Nitric oxide-donating nonsteroidal antiinflammatory drugs (NO NSAIDs) are a promising new class of antiinflammatory agents, which are obtained by adding NO-donating moieties to the existing conventional NSAID molecules. The aim of this study was to investigate the effects of aspirin, flurbiprofen, and NO donating acetylsalicylic acid (NCX 4016) on cecal ligation and puncture (CLP) and endotoxin-induced septic shock (LPS) models in mice. MATERIALS AND METHODS: Overall survival and spleen and liver weights were monitored in LPS and CLP models. Histopathological examinations of liver and spleen were performed at the end of the experimental protocols. RESULTS: NCX 4016 was able to reverse the increased spleen weight in CLP-operated animals, whereas aspirin or flurbiprofen did not. Similar to the results of the CLP model, none of the drugs modified the survival rates in the LPS model. Flurbiprofen in particular produced significant histopathological damage in spleens and livers, which was less significant with aspirin. NCX 4016 did not cause any liver damage. CONCLUSION: NCX 4016 has the potential to be used in septic states, while special attention has to be paid to the effects of aspirin and flurbiprofen on the liver and spleen. PMID- 26422852 TI - Epidemiology, causative agents, and risk factors affecting human otomycosis infections. AB - BACKGROUND/AIM: Otomycosis, or fungal otitis externa, has typically been described as fungal infection of the external auditory canal, with infrequent complications involving the middle ear. This study assessed a mycological analysis of fungal debris from externalauditory canals of patients at Tanta University Hospital, Gharbia Governorate, Egypt. MATERIALS AND METHODS: The samples were collected over a year from the 110 patients that were clinically diagnosed to have otomycosis. The samples were then inoculated and culture plates were examined for the presence of fungal growth. RESULTS: The results showed that Aspergillus niger was the most common fungus causing otomycosis. It was more common among males aged 21-40 years. The incidence was higher in the summer and spring seasons. Manual workers and students had the highest frequency based on occupational incidence. The most common presenting complaint was itching. Trauma to the external auditory canal was the most common predisposing factor. CONCLUSION: The epidemiological profile of otomycosis infection varied according to different factors in the study population. PMID- 26422853 TI - The effect of swimming and type of stroke on bone metabolism in competitive adolescent swimmers: a pilot study. AB - BACKGROUND/AIM: Physical activity plays a key role in increasing and preserving bone mineral density (BMD). Effects on bone development associated with various nonweight-bearing sporting activities, such as swimming, are controversial. Different strokes used in swimming may also present as another factor. The aim of this study was to evaluate the effect of swimming and type of stroke on BMD in competitive adolescent athletes. MATERIALS AND METHODS: Seventy-nine swimmers between the ages of 10 and 21 years participated in this study. BMD was measured with dual-energy X-ray absorptiometry at the lumbar vertebrae and left proximal femur. Daily calorie intake and calcium consumption, and measurements of calcium, phosphorus, alkaline phosphates, 25-hydroxyvitamin D (25(OH) D), and osteocalcin were evaluated. RESULTS: Preliminary results revealed that the type of stroke had no effect on BMD (P = 0.79). Additionally competitive swimmers did not have augmented bone mineral accretion, and in 13.9% of athletes low BMD was confirmed. Sixty percent of swimmers had either deficient or insufficient 25(OH) D levels and a low mean calorie (P = 0.542) and calcium (P = 0.038) intake was observed. CONCLUSION: This was the first study to evaluate the effect of swimming stroke on BMD. Although no effect was statistically shown, further studies with a larger series may determine this effect. PMID- 26422854 TI - Vitamin and mineral deficiency in children newly diagnosed with celiac disease. AB - BACKGROUND/AIM: To establish the frequency of vitamin and mineral deficiency in children newly diagnosed with celiac disease. MATERIALS AND METHODS: The files of patients diagnosed with celiac disease in our Pediatric Gastroenterology Clinic from June 2008 to June 2013 were reviewed retrospectively. RESULTS: A total of 52 pediatric patients diagnosed with celiac disease via serology and duodenal biopsy and who fulfilled the study criteria were enrolled in the study. The mean diagnosis age of the patients was 8.5 +/- 3.9 years and 33 (63.5%) of the patients were female. Vitamin D, vitamin A, vitamin E, zinc, and iron deficiencies were determined in 27 (51.9%), 4 (7.7%), 7 (13.5%), 35 (67.3%), and 18 (34.6%) patients, respectively, at the time of diagnosis. Vitamin D deficiency was observed more frequently in patients with growth retardation at the time of application (P = 0.02). CONCLUSION: Vitamin D, zinc, and iron deficiency are frequently observed in pediatric patients with celiac disease at the time of diagnosis. Therefore, serum vitamin D, zinc, and iron levels should be checked in all children diagnosed with celiac disease. PMID- 26422855 TI - A case-control study: evaluation of vitamin D metabolism in patients with vitiligo. AB - BACKGROUND/AIM: Reduced vitamin D is considered as one of the environmental factors that can increase the prevalence of certain autoimmune diseases. This study aimed to assess vitamin D metabolism in patients with vitiligo. MATERIALS AND METHODS: A prospective case-control study was conducted on 44 consecutive patients with vitiligo vulgaris and 43 healthy controls. Their plasma 25 hydroxyvitamin D (25(OH)D), parathormone (PTH), calcium, magnesium, and phosphate levels were measured. RESULTS: There was no significant difference in the mean age, sex and Fitzpatrick skin phototype between the patient and control groups (P > 0.05). The plasma levels of 25(OH)D and calcium were significantly decreased (P = 0.002, P < 0.0001, respectively) and PTH and magnesium levels were significantly increased in patients with vitiligo (P < 0.0001, P < 0.0001, respectively). The advancement of age (P = 0.03, R = -0.18) and comorbid autoimmune illnesses (P = 0.04) were found to be significantly associated with lower 25(OH)D levels. CONCLUSION: There is a universal lack of 25(OH)D in the Turkish population. Screening for vitamin D may be a tool for the presence of comorbid autoimmune diseases. Further studies are needed to understand the role of vitamin D metabolism in the pathogenesis of vitiligo. PMID- 26422856 TI - Effects of melatonin and theanine administration on pentylenetetrazole-induced seizures and brain tissue oxidative damage in ovariectomized rats. AB - BACKGROUND/AIM: The effects of coadministration of melatonin and theanine (Mel/Thea) on pentylenetetrazole (PTZ)-induced seizures and brain tissue oxidative damage were investigated in ovariectomized (OVX) and sham-operated rats. MATERIALS AND METHODS: The rats were divided into the following groups: 1) sham, 2) ovariectomized (OVX), 3) sham-PTZ, 4) OVX- PTZ, 5) sham-Mel/Thea-PTZ, and 6) OVX-Mel/Thea-PTZ. Groups 1-4 received saline, while groups 5 and 6 received a combination of Mel/Thea for 6 weeks. All animals except for those in groups 1 and 2 received a single injection of PTZ. RESULTS: The OVX-PTZ group had higher generalized tonic-clonic seizure (GTCS) latency compared to the sham-PTZ group. Administration of Mel/Thea increased minimal clonic seizure and GTCS latencies in both the sham-Mel/Thea-PTZ and OVX-Mel/Thea-PTZ groups compared to the controls. Additionally, PTZ exposure increased malondialdehyde levels and reduced thiol concentrations in brain tissues of both the sham-PTZ and OVX-PTZ groups. Mel/Thea pretreatment resulted in MDA reduction and thiol increase in brain tissues. CONCLUSION: The results of this study demonstrated the antioxidant and anticonvulsant activities of Mel/Thea despite the presence or absence of ovarian hormones. PMID- 26422857 TI - Evaluation of GCF MMP-1, MMP-8, TGF-beta1, PDGF-AB, and VEGF levels in periodontally healthy smokers. AB - BACKGROUND/AIM: The effect of smoking on inflammatory biomarkers in gingival crevicular fluid (GCF) is well established in the presence of periodontal inflammation. However, it is not clear if smoking has an influence on matrix metalloproteinase (MMP) and growth factor levels in the GCF of periodontally healthy subjects. The aim of this study was to investigate GCF levels of MMP-1, MMP-8, transforming growth factor (TGF)-beta1, platelet-derived growth factor (PDGF)-AB, and vascular endothelial growth factor (VEGF) in smoking versus nonsmoking periodontally healthy subjects. MATERIALS AND METHODS: Thirty-two periodontally healthy subjects were included in this study. Probing depths, bleeding on probing, and plaque index was assessed. GCF levels of MMP-1, MMP-8, TGF-beta1, PDGF-AB, and VEGF were analyzed by enzyme-linked immunosorbent assay. RESULTS: No significant differences were observed in the distribution of demographic data between study groups. GCF total amount of PDGF-AB was significantly lower in smokers compared to nonsmokers (P = 0.014). Total amount of GCF MMP-1, MMP-8, TGF-beta1, and VEGF levels were similar in both study groups (P = 0.022). CONCLUSION: Smoking has the effect of decreasing GCF PDGF-AB while it does not affect GCF MMP-1, MMP-8, TGF-beta1, and VEGF in periodontally healthy subjects. Since increased levels of these molecules are involved in periodontal breakdown, our findings may emphasize the importance for maintenance of periodontal health in smokers. PMID- 26422858 TI - Hepatoprotective and antioxidant effects of lycopene in acute cholestasis. AB - BACKGROUND/AIM: Lycopene, which is suggested to be a potent antioxidant, may play a protective role in diseases related to oxidative stress. In order to understand the effects of lycopene in the pathogenesis of cholestasis, we investigated the effects of lycopene on oxidative stress parameters and DNA damage induced by experimental biliary obstruction in the liver tissues and the lymphocytes of Wistar albino rats. MATERIALS AND METHODS: The animals were randomized into 3 groups. The sham group was subjected to a sham operation, the BDL group was subjected to bile duct ligation (BDL), and the BDL+L group was subjected to BDL and treated with 10 mg/kg body weight of lycopene. After 7 days of treatment, the liver functions, oxidative stress parameters, and DNA damage were evaluated. RESULTS: The lycopene treatment significantly ameliorated the liver function parameters in BDL rats. It significantly reduced malondialdehyde and nitric oxide levels and enhanced reduced glutathione levels and catalase, superoxide dismutase, and glutathione S transferase activities in the BDL rats. The lycopene treatment also decreased DNA damage as assessed by comet assay in the lymphocytes and hepatocytes of the BDL rats. CONCLUSION: These results suggest that lycopene might have protective effects on acute cholestasis. PMID- 26422859 TI - Determination-of apoptosis and cell cycle modulators (p16, p21, p27, p53, BCL-2, Bax, BCL-xL, and cyclin D1) in thyroid follicular carcinoma, follicular adenoma, and adenomatous nodules via a tissue microarray method. AB - BACKGROUND/AIM: To identify the role of gene products associated with apoptosis and cell cycle in the pathogenesis of thyroid follicular neoplasm. MATERIALS AND METHODS: Thirty follicular adenomas (FAs), 16 follicular carcinomas (FCs), and 20 adenomatous nodules (ANs) were investigated with immunohistochemical staining of p16, p21, p27, p53, Bcl-2, Bax, Bcl-xL, and cyclin D1 via a tissue microarray method. RESULTS: Bcl-2 showed a significant difference between the benign groups (AN and FA) and the malignant group (FC). Bax was significantly higher in the FC group. p53 was lowest in the AN group and highest in the FC group with significant differences between the groups. p16 was significantly higher in the FC group than in the other groups. There was a significant difference between the AN group and neoplastic lesions in terms of p21 staining. The number of cases with positive p27 was lower in the AN group than the neoplastic groups. There was no significant difference in terms of Bcl-xL and cyclin D1. CONCLUSION: Cell cycle modulators, led by the Bcl-2 family, played an important role in the pathogenesis of thyroid follicular neoplasm, and p53, p16, and p21 in particular played a role in the carcinogenesis of FC. PMID- 26422860 TI - The risk of tumor cell dissemination in mediastinoscopy: a cytological study. AB - BACKGROUND/AIM: Mediastinoscopy is an invasive procedure that is used in the diagnosis of mediastinal diseases and in staging lung cancer. Tumor cell seeding during mediastinoscopy along the mediastinum and the incision line is a very rare complication. This study aimed to test the safety of mediastinoscopy in terms of tumor seeding by cytological evaluation of mediastinal lavage samples taken before and after biopsy. MATERIALS AND METHODS: The patients who underwent mediastinoscopy in our hospital between 2011 and 2014 were studied prospectively. Seventy-three patients with a diagnosis of lung or mediastinal malignancy were included in the study. All patients underwent classical cervical mediastinoscopy and mediastinal lavages were taken before and after the biopsy. Both lavage samples were sent to the pathology department in syringes for malignant cell cytology screening. RESULTS: The results of the histopathological examinations of lymph node biopsies were reactive in 25 patients and positive for malignancy in 48 patients. In 2 of 48 patients whose lymph nodes were reported to be positive for malignancy, the mediastinal lavage sample was reported to be positive for malignancy after biopsy, although it was negative preoperatively. In two patients, both the pre- and postbiopsy lavage samples were reported to be positive for malignancy. CONCLUSION: While performing dissection and biopsy during mediastinoscopy, tumor seeding into the mediastinum may occur. Long follow up periods and large patient series are needed to determine how cytopathological examination of both fluids would affect the prognosis. PMID- 26422861 TI - Does Atraucan cause more postdural puncture backache? AB - BACKGROUND/AIM: Postdural puncture backache (PDPB) is the most frequent complaint after spinal anesthesia. In the literature its importance is generally overshadowed by postdural puncture headache. We studied two different kinds of spinal anesthesia needles to compare their technical handling capacities and incidences of PDPB. MATERIALS AND METHODS: Data of 256 pregnant female patients undergoing cesarean delivery under spinal anesthesia were collected for the study. Patients were divided into two groups as Group A (n = 109) and Group Q (n = 147) according to the spinal needle used for spinal anesthesia (i.e. 26-gauge atraumatic and 26-gauge Quincke needles, respectively). Backache incidences during a 1-week period postoperatively and handling characteristics of the needles were noted. RESULTS: Spinal anesthesia was successfully performed at one attempt in 92.7% and 86.4% of patients in Groups A and Q, respectively. PDPB was encountered in 62.4% and 44.2% of patients in Groups A and Q, respectively, and the difference was statistically significant (P = 0.037). CONCLUSION: Both 26 gauge Atraucan and Quincke needles have excellent handling characteristics. PDPB seems to be less common with the 26-gauge Quincke needle than with the Atraucan needle. PMID- 26422862 TI - Acute tuberculosis in the intensive care unit. AB - BACKGROUND/AIM: The aim of this study was to determine mortality rates and to evaluate clinical features of patients with active tuberculosis (TB) requiring intensive care unit (ICU) admission. MATERIALS AND METHODS: The medical records of active TB patients requiring ICU admission were retrospectively reviewed over a 5-year period. RESULTS: Sixteen patients with active TB admitted to the ICU were included in the study. Seven (43.8%) patients died in the ICU The cause of mortality was septic shock in 5 patients and respiratory failure in 2 patients. The Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores were higher in patients who died (P = 0.012 and 0.048, respectively). Six of the 8 immunosuppressed patients and 1 of the 8 nonimmunosuppressed patients died (P = 0.041). The median mechanical ventilation (MV) duration was longer in patients who died (11 (5-45) days) than in patients who survived (4.5 (3-7) days) (P = 0.036). Seven of the 8 patients with nosocomial infection and/or coinfection died, while all of the patients without additional infection survived (P = 0.01). CONCLUSION: Active TB patients admitted to the ICU had higher mortality rates, especially patients with immunosuppression, nosocomial infection, high APACHE II and SOFA scores, and patients receiving MV. PMID- 26422863 TI - Healthy subjects' knowledge of surgical complications: a hospital-based survey. AB - BACKGROUND/AIM: There is an ongoing debate about how much a patient should know about serious or frequently occurring risks of their surgery. In this study, we evaluated healthy subjects' perspectives on knowledge of serious surgical complications. MATERIALS AND METHODS: Three hundred and thirty healthy subjects (151 women, 179 men; mean age: 43.6 +/- 17.3 years) were surveyed with the study questionnaire. Social profile, surgical history of the healthy subjects, and presence of a relative while giving preoperative consent were assessed. RESULTS: Only 23.5% (39/166) of the subjects were informed about all the potential complications of their previous surgical operation and 44.9% (73/166) did not get any preoperative consent on surgical complications. A statistically significant percentage of subjects who did not get proper information about the serious complications involved in their surgery indicated a desire for preoperative informed consent (97.0%, 128/132, P = 0.0001). CONCLUSION: The results indicated that a significant percentage of the subjects wanted to be informed of the potential complications of a surgery in the presence of a relative (73.9%, 192/260, P = 0.009). Involving a relative in preoperative consent may have a positive effect on the patient and can increase the level of postoperative recall of the risks. PMID- 26422864 TI - Smoking cessation and the effect of nicotine dependence on relapse rate in Izmir, Turkey. AB - BACKGROUND/AIM: Smoking is the leading preventable cause of death in the world. There is growing evidence of the need for community- based programs on smoking cessation. The main purpose of this study is to establish the rate of smoking cessation and restarting in 1 year at the Balcova Smoking Cessation Center. MATERIALS AND METHODS: This is a prospective study with a study group of 359 individuals who quit smoking at the Balcova Smoking Cessation Center for at least 4 weeks between October 2009 and April 2010. The outcomes of the study were 1 year cessation rate and relapse rate. Individuals who reported restarting and/or had CO measurements above 6 ppm were accepted as quitters who had relapsed. RESULTS: The 1-year rate of smoking cessation was 30.1% for the study group. Of the subjects who quit smoking, 50.1% started smoking again during the 1-year follow-up. Relapse rate was also higher in nicotine addicts. Pharmacological treatment was associated with increased success rates in smoking cessation. CONCLUSION: Nicotine dependency was shown to be associated with lower rates of smoking cessation and higher rates of relapse. Therefore, it is important to begin smoking cessation attempts before individuals become serious addicts. PMID- 26422865 TI - Epidemiological and clinical characteristics and management of oropharyngeal tularemia outbreak. AB - BACKGROUND/AIM: The purpose of this study was to determine the epidemiological and clinical characteristics of patients diagnosed with tularemia and the effectiveness of the administered treatments. MATERIALS AND METHODS: Patients treated in our hospital between January 2009 and March 2011 and diagnosed with tularemia were evaluated retrospectively. Patients' epidemiological and clinical characteristics, administered treatments, and posttreatment findings were recorded on patient monitoring forms. RESULTS: At anamnesis, 29% of patients used water from wells and 71% used water from the network supply; moreover, 48.4% had a history of contact with animals and 87.1% a history of lethargy. At physical examination, 96.8% had a mass in the neck and 90.3% had fever. Gentamycin + doxycycline therapy was administered to 45.2% of patients, while levofloxacin, gentamycin, and streptomycin were used for the other patients. After treatment, neck masses persisted in 48.4% of patients and complaints of lethargy and fever in 6.5%. Treatment of these patients was initiated once tularemia had been diagnosed, as test results were announced about 3 weeks later. Lymphadenopathy excision was performed on 19.4% of patients in whom neck mass persisted. CONCLUSION: Appropriate empiric antibiotherapy should be commenced in patients presenting with neck mass, fever, and lethargy in regions with tularemia epidemics. PMID- 26422866 TI - Prevalence of hypertension and its association with obesity among school children aged 6-15 living in Sakarya Province in Turkey. AB - BACKGROUND/AIM: Childhood hypertension and its association with obesity are becoming important issues worldwide. The prevalence of hypertension and obesity are growing in both developed and developing countries. This paper aimed to determine the prevalence of hypertension among school-aged children in Sakarya (western part of Turkey) and to determine whether or not obesity is associated with hypertension. MATERIALS AND METHODS: Twelve schools were randomly selected from an area in the center of the Sakarya. A total of 2166 students participated in the study. The students were visited at school, and their weights, heights, and blood pressures were measured. The World Health Organization references were used to determine the prevalence of overweightness, obesity, and hypertension. RESULTS: The prevalences of hypertension and obesity were 15.1% (n = 326) and 18.0% (n = 390), respectively. Overweightness, obesity included, was found to be present in 26.3% of the children. Sex and obesity were found to be associated with hypertension; nevertheless, a positive family history of hypertension was not associated with hypertension in children. CONCLUSION: The prevalence of obesity and hypertension are high among school children of 6-15 years of age in Sakarya. Obesity is associated with hypertension. Blood pressure measurements should be part of routine clinical examination, especially in obese children. PMID- 26422867 TI - VKORC1 and CYP2C9 genotypic data-based dose prediction alone does not accurately predict warfarin dose requirements in some Malaysian patients. AB - BACKGROUND/AIM: VKORC1 and CYP2C9 genetic polymorphisms may not accurately predict warfarin dose requirements. We evaluated an existing warfarin dosing algorithm developed for Malaysian patients that was based only on VKORC1 and CYP2C9 genes. MATERIALS AND METHODS: Five Malay patients receiving warfarin maintenance therapy were investigated for their CYP2C9*2, CYP2C9*3, and VKORC1 1639G>A genotypes and their vitamin K-dependent (VKD) clotting factor activities. The records of their daily warfarin doses and international normalized ratio (INR) 2 years prior to and after the measurement of VKD clotting factors activities were acquired. The mean warfarin doses were compared with predicted warfarin doses calculated from a genotypic-based dosing model developed for Asians. RESULTS: A patient with the VKORC1-1639 GA genotype, who was supposed to have higher dose requirements, had a lower mean warfarin dose similar to those having the VKORC1-1639 AA genotype. This discrepancy may be due to the coadministration of celecoxib, which has the potential to decrease warfarins metabolism. Not all patients' predicted mean warfarin doses based on a previously developed dosing algorithm for Asians were similar to the actual mean warfarin dose, with the worst predicted dose being 54.34% higher than the required warfarin dose. CONCLUSION: Multiple clinical factors can significantly change the actual required dose from the predicted dose from time to time. The additions of other dynamic variables, especially INR, VKD clotting factors, and concomitant drug use, into the dosing model are important in order to improve its accuracy. PMID- 26422868 TI - Antibiofilm activity of trans-cinnamaldehyde, p-coumaric, and ferulic acids on uropathogenic Escherichia coli. AB - BACKGROUND/AIM: Biofilm on urinary catheters results in persistent infections that are resistant to antibiotics. In this study, phytochemicals were assessed as alternative antimicrobials in preventing and inactivating E. coli biofilm on urinary catheters. MATERIALS AND METHODS: Biofilm prevention was tested using catheter fragments inoculated with E. coli and treated with trans- cinnamaldehyde, p-coumaric, and ferulic acids (0%, 0.1%, 0.25%, and 0.5%) for 0, 1, 3, and 5 days. Inactivation of E. coli biofilm with the same agents at concentrations of 0%, 1%, 1.25%, or 1.5% used for 0, 1, 3, or 5 days was also evaluated. RESULTS: All used concentrations of trans-cinnamaldehyde prevented and effectively inactivated E. coli biofilm formed on urinary catheter fragments. p Coumaric (0.25% and 0.5%) and ferulic acids (0.5%) had preventive action on E. coli biofilm formation in urinary catheter fragments. The number of uropathogenic E. coli cells in biofilm formed in the lumen of a urinary catheter was significantly reduced in the presence of p-coumaric and ferulic acids, but complete inactivation of the biofilm formed was not observed, as opposed to the use of trans-cinnamaldehyde. CONCLUSION: The obtained results indicate that phytochemicals maybe an important source of antibiofilm agents that have preventive action on E. coli biofilm formation on urinary catheters. PMID- 26422869 TI - Periocular changes in topical bimatoprost and latanoprost use. AB - BACKGROUND/AIM: To evaluate the periocular changes due to topical bimatoprost and latanoprost use and to investigate their effects on the lacrimal drainage system. MATERIALS AND METHODS: All participants (69 eyes of 43 patients, 52 eyes of 26 controls) were classified into three groups: bimatoprost (0.03%) users, latanoprost (0.005%) users, and healthy controls. Each patient was examined before prostaglandin therapy, and then at the first, third, sixth, and twelfth month of therapy. Palpebral fissure height, upper eyelid crease, and levator function were measured, and lacrimal system drainage irrigation was performed. Periocular hyperpigmentation and upper eyelid sulcus were also examined. RESULTS: No significant change was identified in palpebral fissure height or levator function in any group. However, in upper eyelid crease, among bimatoprost users, a statistically significant increase was observed when compared to the control group (P < 0.001). Patients with skin type II and III, in bimatoprost users, and patients with skin type III, in latanoprost users, had statistically significant hyperpigmentation (P < 0.001) after the third month of therapy. During follow-up, no lacrimal drainage system obstruction was seen. CONCLUSION: Topical bimatoprost therapy causes more periocular changes than latanoprost therapy. Thus, in unilateral cases, patients should be well informed about these probable changes before therapy. PMID- 26422870 TI - Urinary incontinence among women registered with a family health center in the Southeastern Anatolia Region and the factors affecting its prevalence. AB - BACKGROUND/AIM: In regions such as Sanliurfa, Turkey, where the fertility rate is high, suitable health policies to easily and successfully treat urinary incontinence (UI) are needed. This study was conducted to determine the prevalence and risk factors for UI among women in the region. MATERIALS AND METHODS: The participants in this cross-sectional study were selected by using 30 cluster sampling methods. A total of 300 women in the age group of 15-49 years were contacted to participate. RESULTS: The prevalence of UI was 39.3% among women in this sample but only 8.0% actually received treatment. The logistic regression analysis showed that UI risk is increased 1.8 times by chronic diseases, 2.7 times by menopause, 3.4 times by uterine prolapse, and 9.12 times by cystocele. CONCLUSION: UI is a common health problem among the women in the study region; however, these women do not actively seek treatment for this problem. PMID- 26422871 TI - Prevalence of Helicobacter pylori cagA, babA2, and dupA genotypes and correlation with clinical outcome in Malaysian patients with dyspepsia. AB - BACKGROUND/AIM: The severity of disease outcome in dyspepsia has been attributed to Helicobacter pylori virulence genes. The aim of this study was to determine the distribution of H. pylori virulence genes (cagA, babA2, and dupA) and to determine whether or not there arises a significant correlation with clinical dyspepsia outcomes. MATERIALS AND METHODS: H. pylori genotypes cagA, babA2, and dupA were identified by polymerase chain reactions from gastric biopsy samples in 105 H. pylori-positive patients. RESULTS: The positive rates for cagA, babA2, and dupA genes in H. pylori dyspeptic patients were 69.5%, 41.0%, and 22.9%, respectivel cagA was more prevalent in Indians (39.7%), babA2 was more prevalent in Malays (39.5%), and dupA detection occurred more frequently in both Indians and Malays and at the same rate (37.5%). The Chinese inhabitants had the lowest prevalence of the three genes. Nonulcer disease patients had a significantly higher distribution of cagA (76.7%), babA2 (74.4%), and dupA (75.0%). There was no apparent association between these virulence genes and the clinical outcomes. CONCLUSION: The lower prevalence of these genes and variations among different ethnicities implies that the strains are geographically and ethnically dependent. None of the virulence genes were knowingly beneficial in predicting the clinical outcome of H. pylori infection in our subjects. PMID- 26422872 TI - The relation between oxidative stress parameters, ischemic stroke, and hemorrhagic stroke. AB - BACKGROUND/AIM: The aims of this study were to investigate the significance of oxidative stress parameters in the pathogenesis of ischemic stroke and hemorrhagic stroke and to investigate their effects on stroke severity using the National Institutes of Health Stroke Scale (NIHSS). MATERIALS AND METHODS: A total of 92 patients, including 74 with ischemic stroke and 18 with hemorrhagic stroke, and 75 volunteers were enrolled in the study. Total oxidant status (TOS), total antioxidant status (TAS), paraoxonase, stimulating paraoxonase, arylesterase, and thiol levels were measured in both the patient and volunteer groups. NIHSS and oxidative stress index (OSI) scores were calculated. RESULTS: TOS and OSI levels were significantly higher in the ischemia and hemorrhagic stroke groups than in the control group (P < 0.05). Arylesterase and thiol levels were significantly lower in the ischemia group than the control group (P < 0.05). No significant correlation was found between NIHSS score and TAS, TOS, OSI, paraoxonase, arylesterase, stimulated paraoxonase, and thiol levels (P > 0.05). CONCLUSION: Oxidative stress may play a role in the pathogenesis of both ischemic stroke and hemorrhagic stroke in terms of oxidants. We do not think that oxidative stress has any effect in determining stroke severity in either type of stroke. PMID- 26422873 TI - Asymmetric dimethylarginine is not a good predictor of ischemia using myocardial perfusion scintigraphy. AB - BACKGROUND/AIM: Asymmetric dimethylarginine (ADMA) plays role in the pathogenesis of coronary artery disease and related mortality and morbidity through a number of mechanisms. We hypothesized that plasma ADMA levels would be increased in the presence of reversible ischemia as measured by GATED single photon emission computed tomography (SPECT) myocardial perfusion scintigraphy (MPS). MATERIALS AND METHODS: Fasting i.v. blood samples were drawn before testing. All patients underwent 99mTc-sestamibi GATED SPECT MPS with a one-day stress-rest protocol; the images were visually analyzed. Post-stress GATED parameters, including ejection fraction, end systolic and end diastolic volumes, and automatic stress defect scores, were recorded. RESULTS: The plasma ADMA levels were higher in the ischemic group than in the non-ischemic group (0.46 +/- 0.19 vs. 0.40 +/- 0.15; P = 0.016). Plasma ADMA levels (odds ratio [OR] = 13.5; 95% confidence interval [CI] = 1.7-109.01; P = 0.015) and sex (OR = 2.49, 95% CI = 1.18-5.26; P = 0.017) were independent predictors of ischemia. There was no linear correlation between plasma ADMA levels and both the GATED SPECT and stress test parameters. CONCLUSION: Our data support the hypothesis that increased baseline ADMA levels are independently related with the presence of reversible ischemia. PMID- 26422874 TI - Effects of pretreatment with esmolol and lidocaine on injection pain and rocuronium-induced withdrawal response. AB - BACKGROUND/AIM: We aimed to compare the effectiveness of esmolol 1 mg/kg and lidocaine 1 mg/kg for injection pain and for the prevention of rocuronium-induced withdrawal response. MATERIALS AND METHODS: We enrolled a total of 81 patients in the study. Patients were randomly assigned to receive either 10 mL of 0.9% NaCl (Group P), esmolol 1 mg/kg (Group E), or lidocaine 1.0 mg/kg (Group L). A subparalyzing dose of rocuronium 0.05 mg/ kg was administered to all patients and its effects were recorded. Anesthesia was induced with intravenous propofol and intravenous rocuronium 0.5 mg/kg in all groups. The withdrawal movements of the patient groups were subsequently graded. RESULTS: There was a statistically significant difference in overall incidence of pain in group E and L compared to the placebo group after administrating the subparalyzed dose (no pain response: Group E = 81.5%, Group L = 77.8%, Group P = 14.8%) (P < 0.001). After intravenous administration of an intubating dose of rocuronium, the esmolol group had a significantly lower incidence of withdrawal movement than the other groups (no response: Group E = 81.5%, Group L = 63%, Group P = 22.2%) (P < 0.001). CONCLUSION: We found that esmolol significantly attenuates rocuronium-induced withdrawal movement and also reduces pain when used at subparalyzing doses. PMID- 26422875 TI - Herbal self-medication use in patients with diabetes mellitus type 2. AB - BACKGROUND/AIM: A considerable number of patients suffering from diabetes mellitus (DM) turn to self-medication using medicinal plants, preparations, and medicine. The aim of this study was to investigate self-medication using medicinal plants and the potential influence of health care professionals' advice or media information regarding the use of herbal dietary supplements with hypoglycemic effect in a population of patients with type 2 DM. MATERIALS AND METHODS: This research, in the form of an analytic cross-sectional study, was conducted in 6 pharmacies in the territory of Nis, Serbia, during October 2013. The criterion set for the study was to include patients diagnosed with type 2 diabetes who used pharmacotherapy in addition to herbal supplements. RESULTS: Surveyed women showed a statistically significant difference in the frequency of using herbal supplements compared to men (P < 0.001). More frequent symptoms of hypoglycemia were reported in the group of diabetic respondents who used herbal dietary supplements (P < 0.05). The media was most responsible for influencing decisions about self-medication that included the use of herbal dietary supplements. CONCLUSION: The role of health professionals is indispensable and very important, especially when the media is a potential cause of seeking self medication. PMID- 26422876 TI - Evaluation of patency following revision technique of high-velocity arteriovenous fistula. AB - BACKGROUND/AIM: The objective of this study is to report our experience with surgical revision of dialysis access-induced ischemia syndrome. MATERIALS AND METHODS: Between January 2005 and July 2013, 1254 patients underwent arteriovenous fistula operation, and 86 of them [53 males, mean age: 55 +/- 25 (range: 25 to 75) years; 33 females, mean age: 50 +/- 20 (range: 30 to 70) years] subsequently developed steal syndrome. These patients were treated with arterial pressure-controlled polytetrafluoroethylene banding or constriction with polypropylene suturing technique. Patients were followed in the outpatient clinic at regular intervals. RESULTS: Symptoms were not relieved during the first 15 days in 4 patients; therefore, reintervention was performed. Thrombosis occurred in one patient after reintervention. No early or late complications were detected in other patients, and fistulae were suitable for hemodialysis. Patency rates at 6 and 12 months were 96% and 92%, respectively, and thrombosis rates were 7% and 9%. There was no hospital mortality in our study, but one patient died from unrelated causes and two other patients quit follow-up after 6 months. CONCLUSION: We think that arterial pressure-controlled surgical revision is an effective and safe technique in patients with fistula-related hand ischemia. PMID- 26422877 TI - Investigation of the effect of changes in muscle strength in gestational age upon fear of falling and quality of life. AB - BACKGROUND/AIM: The aim of this study is the investigation of the effect of changes in muscle strength in gestational age upon fear of falling and quality of life. MATERIALS AND METHODS: This longitudinal, descriptive study included a sample of 37 pregnant women who volunteered to participate. The research data were collected at 20 and 32 weeks of gestation. Data collection instruments included a newly developed questionnaire form, the Tinetti Falls Efficacy Scale, a visual analog scale, and the Turkish language version of the WHO Quality of Life Scale. Upper body flexibility was measured by the back scratch test, while muscle strength was measured by a handgrip dynamometer and balance by the unipedal stance test. RESULTS: It was found that, as pregnancy advanced, pregnant women had an increased fear of falling, as well as elevated systolic and diastolic blood pressure levels. Participants suffered significant impairments in their balance, handgrip strength, and quality of life within the physical, psychological, and environmental domains. CONCLUSION: As pregnancy advances, muscle strength decreases and the fear of falling experienced by pregnant women increases, which significantly impairs the quality of life in the domains of environment, physical, and mental health. PMID- 26422878 TI - Risk factors and maximum standardized uptake values within lymph nodes of anthracosis diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration. AB - BACKGROUND/AIM: Enlarged mediastinal lymph nodes can result from serious etiologies including granulomatous disease, neoplasia, etc., and a rare condition called anthracosis . The aim of this study was to determine the incidence of risk factors and the uptake values within the anthracotic lymph nodes. MATERIALS AND METHODS: 106 patients who underwent endobronchial ultrasound transbronchial needle aspiration and were diagnosed as having anthracosis were analyzed retrospectively. Patients with positive confirmation by surgical biopsies or a 1 year follow-up period were enrolled. RESULTS: 201 lymph nodes were sampled from 106 patients. Subcarinal and interlobar lymph nodes were the most commonly affected stations (36.8% and 34.3%, respectively). The mean durations of exposure to biomass and cigarette smoke were 35.5 and 33 years, respectively. The mean maximum standardized uptake value (SUVmax) within the lymph nodes was 4.76. The SUVmax of the patients with associated malignancy was 4.19 and the SUVmax of nonmalignant patients was 5.28. This difference was statistically significant (P = 0.009). CONCLUSION: These findings suggest that anthracosis also affects the mediastinal and hilar stations; it should be considered in differential diagnosis in patients with mediastinal and hilar lymphadenopathies with intense uptake on positron emission tomography scans, especially when there is a history of exposure to known risk factors. PMID- 26422879 TI - Value of prealbumin in assessment of nutrition for critically ill patients. PMID- 26422880 TI - Reply to Letter to the Editor. PMID- 26422881 TI - [THE INCENTIVE FOR SURGEONS TO IMPROVE THEIR MOTIVATION]. PMID- 26422882 TI - [NEW BOARD CERTIFICATION SYSTEM FOR SURGICAL SPECIALISTS]. PMID- 26422883 TI - [FRONTIER IN PERIOPERATIVE MANAGEMENT--ENHANCED RECOVERY AFTER SURGERY]. PMID- 26422884 TI - [IS EARLY ENTERAL FEEDING POSSIBLE?]. AB - In conventional postoperative management, early oral feeding after preoperative oral supplementary water and gastrointestinal tract anastomosis was contraindicated for two main reasons. Primarily, it was believed that it would be dangerous because the gastrointestinal tract was in a physiological state of paralytic ileus for 3-5 days after open surgery. The second reason for concern was the risk of causing anastomotic suture rupture if patients did not rest quietly until sufficient secondary wound healing of the gastrointestinal anastomosis had occurred. However, this was counter to common sense, and the current Enhanced Recovery after Surgery (ERAS) protocols recommend early oral intake after preoperative oral supplementary water. This stimulates intestinal tract motility and decreases complications. The ERAS protocols appear safe for patient management after surgery involving the large intestine and are now being assessed for patients undergoing upper gastrointestinal tract procedures. PMID- 26422885 TI - [IMPACT OF PREOPERATIVE BOWEL PREPARATION ON PREVENTION OF SURGICAL SITE INFECTION]. AB - Preoperative preparation of the bowel includes two methods, mechanical bowel preparation (MBP) to remove gross feces and oral antibiotic bowel preparation (OABP) to reduce the colonic bacterial load. MBP and OABP have been performed since the 1940s to 1950s. MBP is routinely performed to reduce the morbidity and mortality of elective colorectal surgery and has been a surgical dogma since the early 1970s. However, numerous prospective, randomized, controlled trials and meta-analyses have questioned the need for MBP in elective colorectal surgery, and a meta-analysis showed that significantly more anastomotic leaks were found after MBP. OABP decreases postoperative infectious complications considerably, although the results differ with the type of antibiotic used. Recently, several large retrospective studies have demonstrated that MBP plus OABP is associated with reduced postoperative infectious complications including surgical site infection rates after elective colorectal surgery. Further prospective, randomized trials of MBP and OABP alone and in combination should be conducted. PMID- 26422886 TI - [ANESTHESIA MANAGEMENT FOR ENHANCED RECOVERY AFTER SURGERY]. AB - In programs to enhance patient recovery after surgery, anesthesiologists play an important role. In conventional management, patients managed with the "starvation, stress, and drowning" regimen experience delays in the recovery process. In contrast, anesthesiologists in the current perioperative management scenario reduce the fasting period, maintain sufficient depth of anesthesia, and administer appropriate infusion levels. In particular, three major factors inhibiting postoperative recovery are known to be pain, gastrointestinal dysfunction, and immobility. To prevent these, anesthesiologists should emphasize pain control and manage patient care with the goals of early oral intake and early mobility. It is important for surgeons and anesthesiologists to share information and techniques to promote postoperative recovery. Multidisciplinary cooperation can be expected to have synergistic effects leading to improved safety, better treatment outcomes, and smooth perioperative management. PMID- 26422887 TI - [OBJECTIVE ASSESSMENT OF POSTOPERATIVE PAIN AFTER DIGESTIVE TRACT SURGERY]. AB - Pain is a sensation associated with subjective factors, making it difficult to measure and assess. Currently, there is no widely accepted method of objectively assessing pain, and therefore subjective assessments such as the Visual Analogue Scale (VAS) are generally used. The PainVision system has been developed for the quantitative analysis of pain and comparison of postoperative pain intensity. In this study, we investigated whether postoperative pain could be objectively assessed using this system in digestive tract surgery patients. Pain scores were measured with the VAS, the PainVision system, and the short-form McGill Pain Questionnaire in patients undergoing open or laparoscopic hepatectomy, open or laparoscopic gastrectomy, and laparoscopic cholecystectomy. As measured using the PainVision system, postoperative pain intensity was lower in patients who underwent laparoscopic surgery compared with open hepatectomy. In open hepatectomy patients, pain intensity measured by the PainVision system was significantly lower on postoperative days (POD) 7 and 10 than on POD 1. Preemptive use of nonsteroidal antiinflammatory drugs significantly reduced postoperative pain in open hepatectomy patients. The results showed that PainVision effectively quantifies pain intensity after digestive tract surgery. Objective assessment of postoperative pain may lead to earlier mobility and improved quality of life. PMID- 26422888 TI - [EFFECTS AND LIMITATIONS OF PREOPERATIVE CARBOHYDRATE LOADING: A REVIEW FROM THE VIEWPOINT OF ITS MECHANISM OF ACTION]. AB - Preoperative carbohydrate loading has been adopted as an integral part of many enhanced-recovery or fast-track surgery programs. The main aim is to reduce postoperative insulin resistance (IR), thereby allowing for effective postoperative nutrition with more anabolic properties and less risk of hyperglycemia, which may improve postoperative outcomes. Based on the mechanism underlying postoperative IR, preoperative carbohydrate loading can inhibit only the exacerbating peripheral IR caused by excessive circulating concentrations of free fatty acids secondary to starvation but not the peripheral and central IR induced by stress hormones and inflammatory cytokines released as part of the surgical stress response, suggesting that preoperative carbohydrate loading may have only limited benefit. The Cochrane review of the effects of preoperative carbohydrate treatment (published in 2014) provided results that were completely consistent with the legitimate expectation described above, i.e., a small reduction of uncertain clinical significance in the length of hospital stay and little or no effect on postoperative complications or other important clinical outcomes, despite increased postoperative peripheral insulin sensitivity. Because preoperative carbohydrate loading has only limited benefit both theoretically and clinically, we should complement its effect through the introduction of a less invasive approach capable of attenuating surgical stress-mediated IR. PMID- 26422889 TI - [EARLY AMBULATION AFTER SURGERY AND PERIOPERATIVE REHABILITATION]. AB - Early ambulation following a surgical procedure is a central concept in fast track surgery according to Enhanced Recovery after Surgery protocols. Although a shorter hospital stay is reported to be a benefit of perioperative rehabilitation, its effect on patient metabolism has not been fully explored. Thirty-eight patients who had undergone esophagectomy, a highly stressful surgery, received intensive rehabilitation (group R) with regular evaluation of their metabolic parameters compared with 41 control group patients (group C) who received conventional care without such rehabilitation. Nitrogen balances calculated daily were significantly higher in group R on the third postoperative day. Fluid retention after surgery improved earlier in group R than in group C. Liver dysfunction occurred 1 week after surgery in group C but was avoided in group R. Total lymphocyte counts decreased after surgery in both groups, but their recovery was observed earlier in group R. Early mobility after esophagectomy is thought to avoid disuse atrophy of skeletal muscles in postsurgical patients. Fluid retention and immune dysfunction are also improved through perioperative rehabilitation. The biological mechanisms underlying the benefits of rehabilitation should be further elucidated for its clinical application in all surgical care pathways. PMID- 26422890 TI - [PRESENT MAJOR ISSUES OF CLINICAL TRIALS IN JAPAN]. PMID- 26422891 TI - [WHAT WE CAN LEARN FROM A CASE OF MEDICAL MALPRACTICE--PATIENT AWARDED DAMAGES FOR A CLAIM THAT A NON-STROKE SPECIALIST RULED OUT A DIAGNOSIS OF TRANSIENT ISCHEMIC ATTACK (TIA) DESPITE HIS CLINICAL PRESENTATION OF TIA OR A STRONG SUSPICION THEREOF]. PMID- 26422892 TI - [PERIANAL PROCEDURE FOR THE TREATMENT OF RECTAL PROLAPSE]. PMID- 26422893 TI - [THE ROLE OF NURSE PRACTIONER AND PHYSICIAN ASSISTANT IN CARDIOTHORACIC SURGERY AT NYU MEDICAL CENTER--COMPARED WITH JAPANESE INSTITUTION]. PMID- 26422894 TI - [COMMUNITY HOSPITAL OF THE MONTEREY PENINSULA DIABETES AND NUTRITION PROGRAM FAMILY NURSE PRACTITIONER]. PMID- 26422895 TI - [OPERATIONAL EXPERIENCE OF AUTOMATIC POSTING SYSTEM TO THE NATIONAL CLINICAL DATABASE USING FILEMAKER PRO]. AB - We would like to introduce a semi-automated registration system for the National Clinical Database. Japan Surgery Society runs the National Clinical Database since January 2011. And automated registration system is long-awaited due to the number of cases and diverse items to register. Well-known database management system, FileMakerPro enabled collecting and registering the items to the web-site automatically. Still some items need to copy one by one, but after filling the data, all data would be input to the web page for registration. Merit for this automated system is increasing not only the efficiency of administration work but the quality and the usefulness of this database. This paper is to report the outline of the registration system to the NCD database. PMID- 26422897 TI - PPP. PMID- 26422896 TI - [A REPORT FROM THE 132ND CONGRESS OF THE GERMAN SURGICAL SOCIETY]. PMID- 26422898 TI - Visual directional anisotropy does not mirror the directional anisotropy apparent in postural sway. AB - Presenting a large optic flow pattern to observers is likely to cause postural sway. However, directional anisotropies have been reported, in that contracting optic flow induces more postural sway than expanding optic flow. Recently, we showed that the biomechanics of the lower leg cannot account for this anisotropy (Holten, Donker, Verstraten, & van der Smagt, 2013, Experimental Brain Research, 228, 117-129). The question we address in the current study is whether differences in visual processing of optic flow directions, in particular the perceptual strength of these directions, mirrors the anisotropy apparent in postural sway. That is, can contracting optic flow be considered to be a perceptually stronger visual stimulus than expanding optic flow? In the current study we use a breaking continuous flash suppression paradigm where we assume that perceptually stronger visual stimuli will break the flash suppression earlier, making the suppressed optic flow stimulus visible sooner. Surprisingly, our results show the opposite, in that expanding optic flow is detected earlier than contracting optic flow. PMID- 26422899 TI - Dimensional interaction in distance judgment. AB - Participants decided under speed stress whether or not the horizontal distances between pairs of frontal locations exceeded a criterion distance. The error rate reflected parallel effects of the horizontal and vertical distance between the locations. Whereas dimensional interaction in perceptual judgment has previously been attributed either to the perception of the stimulus or to the response decision concerning the stimulus, here dimensional interaction was attributed to the process of distance assessment regarding the test locations. Under the proposed account, the horizontal distance between the locations could not be assessed independently of the vertical distance. Only the overall distance between the locations could be assessed. However, because the horizontal and vertical positions of the locations could be independently assessed, the horizontal distance between the locations was available to the extent that the vertical positions of the locations were weighted so as to minimize vertical distance prior to the assessment of overall distance. In support of this account, parallel effects of horizontal and vertical distance were not observed when participants decided whether or not pairs of locations had the same horizontal position. PMID- 26422900 TI - Global shape information increases but color information decreases the composite face effect. AB - The separation of visual shape and surface information may be useful for understanding holistic face perception--that is, the perception of a face as a single unit (Jiang, Blanz, & Rossion, 2011, Visual Cognition, 19, 1003-1034). A widely used measure of holistic face perception is the composite face effect (CFE), in which identical top face halves appear different when aligned with bottom face halves from different identities. In the present study the influences of global face shape (ie contour of the face) and color information on the CFE are investigated, with the hypothesis that global face shape supports but color impairs holistic face perception as measured in this paradigm. In experiment 1 the CFE is significantly increased when face stimuli possess natural global shape information than when cropped to a generic (ie oval) global shape; this effect is not found when the stimuli are presented inverted. In experiment 2 the CFE is significantly decreased when face stimuli are presented with color information than when presented in grayscale. These findings indicate that grayscale stimuli maintaining natural global face shape information provide the most adept measure of holistic face perception in the behavioral composite face paradigm. More generally, they show that reducing different types of information diagnostic for individual face perception can have opposite effects on the CFE, illustrating the functional dissociation between shape and surface information in face perception. PMID- 26422901 TI - Eye shape illusions induced by eyebrow positions. AB - We investigated whether the position of the eyebrows influences the perceived shape of the eyes by employing psychophysical measurements. Experiment 1 used arched and straight eyebrows at five different inclinations as stimuli and measured the perceived inclination of the eyes. The results demonstrated that the eyes are perceived to be somewhat inclined in the same direction as the eyebrows. Experiment 2 measured the perceived eye size by manipulating the distance between the eyes and the eyebrows and the curvature of the eyebrows across three levels. The results showed that the lower eyebrows (ie closer to eyes) made the eyes appear larger and the higher eyebrows made the eyes appear smaller, while eyebrow curvature had no effect on perceived eye size. Experiment 3 examined the role of the eye-eyebrow distance in the eye inclination illusion shown in experiment 1. The eye inclination illusion was unaffected by the eye-eyebrow distance, suggesting that the eye inclination illusion and the eye size illusion may involve different kinds of assimilation. These illusions are discussed in terms of face perception and possible practical applications. PMID- 26422902 TI - Unbiased measures of interocular transfer of motion adaptation. AB - Numerous studies have measured the extent to which motion aftereffects transfer interocularly. However, many have done so using bias-prone methods, and studies rarely compare different types of motion directly. Here, we use a technique designed to reduce bias (Morgan, 2013, Journal of Vision, 13(8):26, 1-11) to estimate interocular transfer (IOT) for five types of motion: simple translational motion, expansion/contraction, rotation, spiral, and complex translational motion. We used both static and dynamic targets with subjects making binary judgments of perceived speed. Overall, the average IOT was 65%, consistent with previous studies (mean over 17 studies of 67% transfer). There was a main effect of motion type, with translational motion producing stronger IOT (mean: 86%) overall than any of the more complex varieties of motion (mean: 51%). This is inconsistent with the notion that IOT should be strongest for motion processed in extrastriate regions that are fully binocular. We conclude that adaptation is a complex phenomenon too poorly understood to make firm inferences about the binocular structure of motion systems. PMID- 26422903 TI - Aesthetic preference in the spatial composition of traditional Chinese paintings. AB - Aesthetic psychology has discussed many aspects of aesthetic preferences for spatial composition. However, there have been few empirical explorations of the spatial composition of traditional Chinese paintings. The results of this experiment showed that the shape of the frame had a significant effect on aesthetic preferences. Participants preferred to put two figures at certain relative horizontal distances from each other according to the horizontal shape of the frame but may have difficulty in adapting the relative vertical distance according to the vertical shape of the frame. Furthermore, the unique aesthetic interest of traditional Chinese long-vertical scroll paintings was discussed. This discussion revealed that, in a creative way, ancient Chinese artists followed the same aesthetic principles we observed, and they developed the artistic conception and romantic charm of traditional Chinese paintings. PMID- 26422904 TI - The sensory experiences of adults with autism spectrum disorder: A qualitative analysis. AB - It has been well established that individuals with autism spectrum disorder report unusual experiences with sensory stimuli compared with typically developing individuals. However, there is a paucity of research exploring the nature of such experiences. A focus group was conducted with six adults with a diagnosis of autism or Asperger syndrome. Data were coded and analysed using an inductive, qualitative thematic analysis. Four main themes encompassing both positive and negative sensory experiences emerged from these data: (a) the importance of particular aspects of stimuli in their perception, (b) the importance of having control over stimuli, (c) how emotions/mental states could impact/be impacted by sensory stimuli, and (d) physical responses to stimuli. These data are discussed alongside extant literature. Limitations, possible implications, and potential directions of future research are also discussed. PMID- 26422906 TI - The reference point for monocular visual direction can, sometimes, be one of the eyes rather than the cyclopean eye. AB - We found that the imaginary line passing through two stimuli that points to an eye appears to do so when seen monocularly, which is consistent with Porterfield's axiom but inconsistent with Wells's proposition regarding visual direction. We also found that the imaginary line appears to point to the bridge of the nose when the near stimulus is seen binocularly and the far one is seen monocularly, which is consistent with Wells's proposition but inconsistent with Porterfield's axiom. We argue that these findings themselves do not necessarily vitiate the axiom or the proposition and that one should explore the different experimental conditions and hypothesize about the processes that might be involved. PMID- 26422905 TI - The effect of age and gender on pressure pain thresholds and suprathreshold stimuli. AB - OBJECTIVES: The study investigates the impact of age and gender on (1) experimental pressure pain detection thresholds (PPDT) and pressure pain tolerance thresholds (PPTolT) and (2) participants' self-reports of pain intensity and unpleasantness at suprathreshold and subthreshold levels. METHODS: twenty young (20-34, mean age = 24.6 +/- 3.6 years, ten female) and twenty elderly (65-88, mean age = 73.6 +/- 6.6 years, ten female) healthy volunteers were compared. Mini-Mental State Examination (MMSE 28-30) assessed intact cognitive functioning. Pain thresholds were assessed together with the sensory intensity ratings to 1.3 x PPDT (pain) and 0.2 x PPDT (no pain). RESULTS: PPDT and PPTolT significantly decreased with age and were lower in young females as compared with young males. No gender differences were observed in the elderly group. PPDT decreased significantly with age in males but not in females. Conversely, the intensity and unpleasantness of the pain stimulus were significantly rated lower in the elderly as compared with the young. No gender differences were observed in the report of intensity and unpleasantness of the stimulations. DISCUSSION: A mismatch in pain sensitivity, tolerance, and pain self-reports was observed. Findings suggest that pain experiences in the elderly differ from the experiences in the young on multiple dimensions: sensory, affective, and cognitive. Findings may also indicate that the elderly appraise pain experiences using different psychological strategies. PMID- 26422908 TI - [[The most frequent vices of authors of medical publications]]. PMID- 26422909 TI - [Contraception in women with chronic diseases]. AB - BACKGROUND: Almost 10% of women in reproductive age had a chronic disease, and contraception is frequently ignored by these patients. The lack of use of contraceptives methods has a higher repercussion in these patients; if pregnant, the risk is increased in morbidity and feto-maternal mortality. OBJECTIVES: to know the contraceptive coverage in women with chronic degenerative diseases, the kind of contraceptive methods and the unsatisfied demand. MATERIAL AND METHODS: A descriptive study was made with the application of a survey from the one elaborated by the IMSS. It explores contraception socio-demographic data, causes of non-protection and also explores Medical Doctor (MD) participation. Sample size was calculated in 385 women in reproductive age with a chronic disease. RESULTS: 428 women about 30-49 years old were interviewed, 53% of them were married, they had various diseases, the contraceptive coverage was 84%. The definitive methods were the most used with 47%, followed by the condom with 20%, intrauterine device with 13% and others in minor proportion. 38.5% of patients with sexual life have risk of pregnancy for lack of use of method or for using one of low effectiveness and continuity. Of 45 (16%) patients with sexual life that did not use methods, 29% because they wish pregnancy, 18% by collateral effects and the rest for other causes. From this same patients 21 wished getting pregnant and 24 did not, this is an unsatisfied demand of 53%. The MD's informed about risks in case of pregnancy of 83.4% of the patients. CONCLUSIONS: The contraceptive coverage is low and the unsatisfied demand is higher than in the general population. It requires the effective participation of health personal in this group of high reproductive risk. PMID- 26422910 TI - [Neddle-guided biopsy in the diagnosis of non-palpable breast cancer]. AB - OBJECTIVE: To estimate the diagnostic accuracy of the spearfishing or neddle guided biopsy to breast cancer and no palpable mammography and ultrasound findings suspicious for malignancy. MATERIAL AND METHODS: Observational, transversal, prolective, and descriptive study was made. A histopathological diagnosis were conducted from August 2004 to December 2011 in the Radiology and Image Departmen of Centro Medico La Raza to patients sent by the service of Surgical Oncology-with non-palpable breast findings identified by mammography and/or ultrasound with any suspicion of malignancy. Radiographic and ultrasonographic images of the specimen were obtained after the surgical procedure. RESULTS: Harpoon 532 placements with histopathological report. Malignancies were 4.0% of the biopsies were performed in negative mammograms (ACR BI-RADS(r) 3) and 34.3% (p <= 0.05) of which were performed in positive mammography: 19.5% of mammograms ACR BI-4 and RADS(r) 89.7% (p < 0.0001) of mammograms ACR BI-RADS(r) 5. The negative mammography (ACR BI-RADS(r) 3) which resulted in cancer occurred in a patient with a personal history of breast cancer who had a solid nodule in one breast. In the evaluation of mammography studies and placing seven harpoons participated certified radiologists and additional qualification in breast imaging, and five radiology technicians trained in mammography. CONCLUSIONS: The positive cases in the evaluation of mammography studies and placing seven harpoons participated certified radiologists and additional qualification in breast imaging, and five radiology technicians trained in mammography. (sum of the ACR BI-RADS(r) cases 4 and ACR BI-RADS(r) 5) and individual cases ACR BI-RADS(r) 4 had a PPV within recommended ranges ACR BI RADS(r); PPV ACR BI-RADS(r) may was lower than recommended by the literature, although most recommended by other series, which forces us to emphasize adherence to the semiotics suggested by ACR BI-RADS(r) and avoid unnecessary surgery. Patients with a personal history of breast cancer and finding a new ACR BI RADS(r) 3 should have an individual assessment and consider biopsy before the short-term monitoring. PMID- 26422911 TI - [Perinatal complications and serotonin level (5-HT) associated with low birth weight]. AB - BACKGROUND: Studies in human and in experimental models suggest that interaction among the adverse prenatal and postnatal environment increases susceptibility for chronic diseases. This environment could induce changes in the metabolism balance. OBJECTIVE: To analyze how the low birth weight (LBW) influences on the perinatal complications and serotonin serum concentration associated with the possible changes in the alimentary behavior. MATERIAL AND METHODS: A prospective, longitudinal and descriptive study was made during 6 months of the obstetric events to know the frequency and complications of LBW. To evaluate if these complications could have some relationship with the serotonin concentration we measured through their metabolite 5-hidroxitriptamina (5-HT) and the possible chronic illnesses of the adult life. RESULTS: From 1,418 obstetric events attended during the study period, 506 patients with viable pregnancies and met the inclusion criteria were included, 26.8% had LBW and the immediate clinical complications were presented in 52.2% of them and serum concentration 5-HT of 362.2 +/- 21.8 vs 82.1 +/- 13.6 ng/mL. CONCLUSION: Low birth weight, besides causing perinatal complica- tions, also conditions permanent changes in the expression of satiety neurotransmitters and some tissues, that alter the regulation mechanisms to maintain the energy balance leading to metabolic stability, which is needed to the proper endocrine functioning in the adult life of these individuals. PMID- 26422912 TI - [Interobserver diagnostic agreement on digital images of hysteroscopic studies]. AB - BACKGROUND: Hysteroscopic studies are of the most used methods to examine the uterine cavity in patients that present abnormal uterine hemorrhage as well as those patients with infertility. The use of hysteroscopic studies during reproductive cycles has increased the successful of pregnancy rates. Up to date, there are not many studies evaluating the inter-observer agreement in the diagnosis of different uterine pathology when using a hysteroscopic study. OBJECTIVE: To evaluate the inter-observer agreement in the diagnosis of uterine pathology when using digitalized images in hysteroscopic studies made by residents of gynecological endoscopy. MATERIALS AND METHODS: A cross-sectional, descriptive and observational study was made including 28 images of hysteroscopic studies selected by at least two of three experts in hysteroscopy, who determined that they were adequate to do a diagnostic impresion. From a total of four residents, two were selected using a randomized sampling. The images were shown to each resident in a randomized presentation and the diagnosis agreement was evaluated. Kappa test was used to evaluate the interobserver agreement with 95% confidence interval. RESULTS: The interobserver agreement obtained by Kappa test for different images for diagnosis of uterine pathology were: normal uterine cavity (kappa = 0.81 with CI 95%, 0.56-1.00), endometrial polypus (kappa = 0.71 with CI 95%, 0.33-1.00), submucous myoma (kappa = 0.71 with Cl 95%, 0.33- 1.00), intrauterine adherences (kappa = 0.84 with Cl 95%, 0.52-1.00), uterine septum (kappa = 0.76 with CI 95%, 0.43-1.00) and endometrial hyperplasia or potential endometrial cancer (kappa = 0.87 with Cl 95%, 0.61-1.00). CONCLUSIONS: The interobserver agreement using digitalized images in the diagnosis of different uterine pathology from hysteroscopic studies made by residents of endoscopic surgery was high and very high in all cases. PMID- 26422913 TI - [Hysteroscopic polypectomy, treatment of abnormal uterine bleeding]. AB - OBJECTIVES: To evaluate the effectiveness of the hysteroscopic polypectomy in terms of the decrease of the abnormal uterine bleeding. METHODS: A cross sectional and analytical study was done with patients to whom a hysteroscopic polypectomy was done for treating the abnormal uterine bleeding, between January 2009 and December 2013. The response to the treatment was evaluated via a survey given to the patients about the behavior of the abnormal uterine bleeding after the procedure and about overall satisfaction. RESULTS: The results were obtained after a hysteroscopic polypectomy done to 128 patients and were as follows. The average time from the polypectomy applied until the survey was 30.5 months, with a standard deviation of 18 months. 67.2% of the patients reported decreased abnormal uterine bleeding and the 32.8% reported a persistence of symptoms. On average 82.8% of the. patients were satisfied with the treatment. Bivariate and multivariate analysis showed no association between the variables studied and no improvement of abnormal uterine bleeding after surgery (polypectomy). There were no complications. CONCLUSION: Hysteroscopic polypectomy is a safe surgical treatment, which decreases on two of three patients the abnormal uterine bleeding in the presence of endometrial polyps, with an acceptable level of satisfaction. PMID- 26422914 TI - [Rate of human papillomavirus infection in rural areas diagnosed by direct visualization with acetic acid and lugol]. AB - BACKGROUND: Infection by HPV is a major global health problem and the main risk factor for cervical cancer with high morbidity and mortality. Simple diagnostic methods, such as visual inspection with the naked eye of the cervix with acetic acid application 5% (VAT) or solution of iodine (tincture of iodine) are simple to detect early lesions, sensitivity varies from 87 to 99% and specificity varies from 23 to 87%. OBJECTIVE: To find the proportion of infection by human papillomavirus in a population of extreme poverty. MATERIAL AND METHOD: Linear, observational and descriptive pilot study was done in patients of marginalized communities in extreme poverty in Chiapas (Mexico), from 1 to 30 November 2013. The existence of acetowhite lesions suggestive of virus was verified human papillomavirus, and medical history of all patients was formed for the incidence of risk factors. RESULTS: 214 women with age limits of 19 and 78 years, median age of 37 years were studied. Of the total, 66 (31%) had acetowhite lesions consistent with human papillomavirus at the time of the study. CONCLUSIONS: Marginalized populations have a higher risk of infection with human papillomavirus, consequently high rate of progression to cervical cancer due to sociodemographic characteristics, risk factors and lack of resources in health. Diagnostic tests like the simple display with acetic acid are ideal for people such as this. PMID- 26422915 TI - [Risk factors of evolution of postpartum hemorrhage towards severe postpartum hemorrhage: A case-control study]. AB - OBJECTIVE: To describe the incidence and risk factors for evolution of postpartum haemorrhage towards severe. MATERIAL AND METHODS: Epidemiologic, observational, analytical, case-control study was done from total data of deliveries in Complexo Hospitalario de Ourense between January 1st 2004 and June 30th 2014. Mann-Whitney U test was used to determine the differences between cases and controls. The statistical analyses were made with the informatic programs Spss 15.0 y Epidat 3.0. We considered statistical significance for p < 0.05. RESULTS: The initial size of the sample was 17,116 deliveries from which we selected 150 patients with the diagnosis of postpartum haemorrhage. The incidence for HPSe form all deliveries was 3.3% reaching 36% of the total of postpartum haemorrhages. 79.63% of HPSe showed symptoms withing the first 24h postpartum, but we found that 20.37% debuted as secondary postpartum haemorrhages. BMI >= 35, hypertensive gestational manifestations, labor's second phase >= 120 minutes and weight at birth > 4000 g presented statistical significance as risk factor for evolution to severe postpartum haemhorrage. The relative risk for evolution towards HPSe was 2.81 for instrumental delivery and 3.55 for cesarean section. The most prevalent etiology was uterine atony. CONCLUSION: The incidence of HPSe in our hospital is low, as well as secondary maternal mortality. The major risk factor for the appearance of the clinical symptoms is cesarean section, followed, in less proportion by instrumental delivery. It is possible for the HPSe to make its appearance delayed after delivery, usually secondary to infrequent and non well known clinical presentations. PMID- 26422916 TI - [Influence of age on laparoscopic colposacropexy]. AB - OBJECTIVES: To evaluate the influence of age on laparoscopic colposacropexy (LCS) outcome and complications for pelvic organ prolapse. MATERIAL AND METHODS: A retrospective and comparative study of 105 patients who underwent standard LCS for Baden-Walker graded pelvic organ prolapse from February 2002 to March 2015. They were categorized into two groups according to age. Group 1 consisted in <= 50 years old patients and included 55 women. Group 2 included 50 women who were >= 60 years old. Outcomes and complications were compared in both groups. RESULTS: Previous history of abdominal surgery or surgery for pelvic floor disorders was significantly greater in group 2 (43.6 vs 70%). There was no significant difference regarding urinary stress incontinence, urge incontinence or severe organ prolapse between groups (47.2 vs 36%; 1.8 vs 8% and 90.9 vs 92% for Groups 1 and 2 respectively). Although a statistically significant greater proportion of vaginal vault prolapse was present in the elderly group (16.3 vs 38%), the same LCS surgical technique was used in both groups of patients. Despite operating time was significantly greater in the younger group (205.8 +/- 53.4 minutes in Group 1 vs 182 +/- 42.3 minutes in Group 2), hospital stay was similar in both groups (2.9 +/- 1.1 days vs 3.0 +/- 1.9 days in group 1 and group 2 respectively). Postoperative complications were not severe and there were no clinically significant differences between groups (20 vs 14%). We found no statistically differences between groups when comparing cure rates (87 vs 92%) in groups 1 and 2 respectively, patient satisfaction and postoperative anatomical findings. CONCLUSIONS: LCS has shown excellent cure rates in both young and elder female patients with pelvic organ prolapse. PMID- 26422917 TI - [Abdominal ectopic pregnancy. A case report and literature review]. AB - Abdominal ectopic pregnancy is an extremely rare entity, which represents 1% of all ectopic pregnancies and is associated with high maternal and fetal morbidity and mortality. The maternal mortality risk of an abdominal ectopic pregnancy is seven to eight times greater than the risk of a tubal ectopic pregnancy and is 90 times greater than the risk of intrauterine pregnancy. This is a disease of difficult diagnosis that often takes place late. We report the case of a patient with an abdominal ectopic pregnancy, which was diagnosed by abdominal ultrasound in the second trimester; the patient was suc- cessfully treated with exploratory laparotomy with complete removal of the fetus and placenta. We provide a review of the literature on the risk factors for abdominal ectopic pregnancy, diagnostic tests and therapeutic options. PMID- 26422918 TI - [SCREENING AND SELECTION OF THE SOIL MICROORGANISMS ON THE ABILITY OF "NITROGEN FIXING ACTIVITY"]. AB - The isolates of microorganisms from the rhizosphere of spring barley plants and soil at the use of analytical selection method was isolated. Its isolates on the ability of "nitrogen-fixing activity" was tested. It was shown that isolates of microorganisms had different of the colonies formed and cultural growth on the Eshbi's selective medium as well as the ability to fixing of molecular nitrogen. The different levels of intensity and dynamics of isolates nitrogenase activity in vitro were identified. New isolates of the soil microorganisms complement of the gene pool diazotrophic bacteria. Its isolates are perspectivity for the study as the basis or components of the bacterial fertilizers for the crops. PMID- 26422919 TI - [INFLUENCE OF FUNGICIDES COMPLEX INOCULUM EKOVITAL ON RHIZOSPHERE MICROBIOCENOSIS, DISEASES RESISTANCE AND SOYBEEN PRODUCTIVITY]. AB - It has been investigated the effect of fungicide with systemic action of Vitavaks 200 FF, Maxim Star 025 FS, Kinto duo and the complex inoculum Ekovital on rhizospheric microbial communities, diseases resistance and soybean productivity of Annushka biovar. The combined use of fungicides and inoculation has contributed to better formation of nodulation apparatus (the number of nodules on the roots was increased in 1.3-2.8 times), resistance increase to soybean pathogens septoriosis and ascochitosis, plant productivity increase on 17.4-32.1% relatively to the variant with Ekovital. The efficiency of the combined treatment of seeds against septoriosis and ascochitosis has become 45.8-64.1% and 82.0 95.1% respectively, in the flowering-early fruiting stage and 38.1-60.6% and 70.3 82.1% respectively, in the loading beans phase. PMID- 26422920 TI - [THE EFFECT OF METAL IONES AND SPECIFIC CHEMICAL REAGENTS ON THE ACTIVITY OF ASPERGILLUS FLAVUS VAR. ORYZAE AND BACILLUS SUBTILIS alpha-AMYLASES]. AB - The effect of cations and anions on the activity of Aspergillus flavus var. oryzae and Bacillus subtilis alpha-amylases showed that the tested enzymes are sensitive to most of cations and resistant to anions. The most significant inhibitory effects on the activity of A. flavus var. oryzae alpha-amylase have been demonstrated by Al3+ and Fe3+ ions, while on the activity of B. subtilis alpha-amylase - Hg2+, Cu2+ and Fe3+ ions. Inactivation of A. flavus var. oryzae and B. subtilis alpha-amylases in the presence of EGTA is indicated on the presence within their structure of metal ions. An important role in the enzymatic catalysis of both enzymes play carboxyl groups as evidenced by their inhibition of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide. Inhibition of B. subtilis alpha-amylase by p-chloromercuribenzoate, N-ethylmaleimide and sodium sulfite is indicated on the probable involvement of the sulfhydryl groups in the functioning of the enzyme. Unlike most studied glycosidases the tested enzymes do not contain histidine imidazole group in the active center. PMID- 26422921 TI - [OPTIMIZATION OF CULTIVATION CONDITIONS OF PENICILLIUM TARDUM--THE alpha-L- RHAMNOSIDASE PRODUCER]. AB - The influence of some technological cultivation parameters of Penicillium tardum to synthesize of the extracellular alpha.-L-rhamnosidase were studied. It was shown that rhamnose (0.8%), yeasts autolysate (0.2%), temperature of the cultivation 25 degrees C, pH 5.0 are necessary for maximal alpha-L-rhamnosidase production. The enzyme reaches the maximal activity level in 96 hours with sulphitic number equal 0.44. At cultivation of P. tardum in the picked up conditions the alpha-L-rhamnosidase synthesis has raised in 4 times. PMID- 26422922 TI - [EFFECT OF MICROSCOPIC FUNGI ON COMPONENT COMPOSITION OF RUBBER SCN-18]. AB - Resistance to the action of microscopic fungi of the material SCN-18, which had been characterized by high resistance to microscopic fungi was idefenited. It has been noted that in the case of using of test cultures of fungi isolated from the rubber substrates, the intensity of damage of the SCN-18 was higher than in the case of using of species proposed by GOST 9.049-91. During 1-year trial of resistance to the action of microscopic fungi of SCN-18 it had been set decreasing of the amount of ester groups in the studied material, which indicated about gradual degradation of the plasticizer dibutylphthalate, which was included to the component composition of SCN-18. PMID- 26422923 TI - THE EFFECT OF P-NITROCHLOROBENZENE ON HOMEOSTASIS QUANTITATIVE PARAMETERS OF KARST CAVE CLAYS AND ECUADOR SOILS MICROBIAL COMMUNITIES. AB - In this paper it was given the effect of p-nitrochlorobenzene (NCB) on the homeostasis quantitative parameters of cave clays microbial communities from Western Ukraine and Abkhazia (Mushkarova Yama, Kuybushevskaya) and soils of Ecuador tropical ecosystems. For these microbial communities were determined maximum permissible concentrations and types of responses on xenobiotic. Microbial communities of Mushkarova Yama cave clays and rainforest soils of Ecuador were characterized by the first type of response. Microbial communities of Kuybushevskaya clays and mountain jungles of Ecuador were characterized by the second type of response. Maximum permissible concentration of NCB for Mushkarova Yama was 200 mg/l, for the other studied microbial communities--300 mg/l. It was shown, that microbial communities were not only highly resistant to NCB but also interacted with it by destroying this xenobiotic and decreasing its concentration in 4 times. PMID- 26422924 TI - RESISTANCE OF MICROBIAL COMMUNITIES FROM ECUADOR ECOSYSTEMS TO REPRESENTATIVE TOXIC METALS - CrO4(2-), Co2+, Ni2+, Cu2+, Hg2+. AB - Microbial communities of the Ecuadorian Andes and volcano Tungurahua were shown to be super resistant to representative toxic metals. Maximum permissible concentrations of toxic metals were 100 ppm of Hg2+, 500 ppm of Co2+ and Ni2+, 1000 and 1500 ppm of Cr(VI), 10000 and 20000 ppm of Cu2+. The effect of metal concentration increasing on the biomass growth, CO2 and H2 synthesis was investigated. Two types of response of microbial communities on the increasing of toxic metals concentrations were discovered. The first type of response is the catastrophic inhibition of microbial growth. The second type of response is the absence of microbial growth inhibition at certain metal concentration gradient. The succession of qualitative structure of Ecuadorian microbial communities was shown for the first time. Bacteria, yeasts and finally fungi consistently dominate in the microbial community at the Cu2+ concentration raising. Microorganisms resistant to ultra-high concentrations of toxic metals (e.g., 3000 ... 20000 ppm of Cu2+) were isolated from Ecuadorian ecosystems. These microorganisms are able to accumulate toxic metals. PMID- 26422925 TI - THE WIDESPREAD OF Fe(III)-REDUCING BACTERIA IN NATURAL ECOSYSTEMS OF ECUADOR. AB - The widespread of Fe(III)-reducing microorganisms in natural ecosystems of Ecuador of La Favorita, Tungurahua volcano and Papallacta areas was experimentally proved. High efficiency of microbial precipitation of soluble iron compounds was also demonstrated. Obtained results indicate the potential ability of Fe(III)-reducing microorganisms to influence the formation of carbon and iron vector fluxes in ecosystems, as well as development of effective biotechnologies of water purification from iron compounds. PMID- 26422926 TI - [INFLUENCE OF DOXORUBICIN AND ETOPOSIDE ON THE CD 95 MEDIATED APOPTOSIS IN EBV INFECTED LYMPHOMA CELLS BL-41 AND DG-75]. AB - The aim of work was to study the effect of anticancer drugs on the process of CD 95 mediated apoptosis in BL-41 and DG-75 infected with Epstein-Barr virus. Studies of the effect of anticancer drugs "Doxorubicin" "Ebewe" and "Vepesid" (Etoposide) on the apoptosis in EBV infected cells using cytomorphological methods, spectrophotometry and PCR carried out. The influence of the tested drugs in cell culture was assessed by calculating the CC50. It was shown that it was 20 MUg ml both for Etoposide and for Doxorubicin in the case of cell line DG-75. BL 41 cells were more sensitive to the tested drugs. CC50 was 5 MUg/mI. PCR method showed that in the studied cell lines active accumulation of EBV DNA took place. In 24 hours after infection in the DG 75 + EBV system 20 MUg/ml Doxorubicin provoked apoptosis in 89% of cells, and Etoposide-induced apoptosis was 35%. Cell culture BL-41 was equally sensitive to both drugs. At the same time, in the EBV super infected cells + Doxorubicin only 10% of apoptotic cells were detected. The obtained data prove the impact of viral infection on the sensitivity of lymphoma cells BL-41 and DG-75 to tested anticancer drugs. PMID- 26422927 TI - Retirement Savings Shortfalls: Evidence from EBRI's Retirement Security Projection Model. PMID- 26422928 TI - Utilization Patterns and Out-of-Pocket Expenses for Different Health Care Services Among American Retirees. PMID- 26422929 TI - Financial Incentives and Workplace Wellness-Program Participation. PMID- 26422930 TI - The 2015 Retirement Confidence Survey: Having a Retirement Savings Plan a Key Factor in Americans' Retirement Confidence. PMID- 26422931 TI - Individual Retirement Account Balances, Contributions, and Rollovers, 2013; With Longitudinal Results 2010-2013: The EBRI IRA Database. PMID- 26422932 TI - Health Savings Accounts and Health Reimbursement Arrangements: Assets, Account Balances, and Rollovers, 2006-2014. PMID- 26422934 TI - [Can We Avoid the War?]. PMID- 26422933 TI - Intra-Family Cash Transfers in Older American Households. PMID- 26422935 TI - [Rehabilitation for Pain Relief: Preface and Comments]. AB - Chronic intractable pain is difficult to manage as the mechanisms of chronic pain are complicated. Recently rehabilitation is used in patients with chronic pain not responding to NSAIDs, non-opioids, anti-depressants and so on. Rehabilitation includes acute, recovery and maintained modes of rehabilitation. This review is focused on the concept of rehabilitation, rehabilitation therapy, rehabilitation during recovery period, nerve rehabilitation, music-trampoline therapy and so on. PMID- 26422936 TI - [Basic Strategy for Pain Control in Rehabilitation]. AB - Rehabilitation medicine regards pain as one disorder of whole human character and handles pain through multilateral approaches. When only the pain is treated it will not be relieved easily. Chronic pain can be more effectively handled if pain is considered as one obstacle of the whole human character and handled using many skills of rehabilitation medicine. We should apply physiotherapy including functional treatment, physical treatment and exercise from early stages of acute pain and approach chronic pain. This could improve the effectiveness of treatment for many kinds of acute pain and chronic pain disorders. PMID- 26422937 TI - [The Rehabilitation in Pain Clinic]. AB - Rehabilitation is becoming an important field of care at pain clinics designed to alleviate pain. Exercise and physical therapies are widely used in rehabilitation, and exercise therapy in particular is considered a treatment that should be actively incorporated. Intervention must continue to be provided after ascertaining whether exercise therapy is within the scope of pain clinicians themselves, or whether it should be offered in collaboration with physical therapists. This can be achieved by deepening knowledge of exercise therapy and investigating how it should be offered depending on the disease. Focus should be placed on abnormal posture and exercise, as well as secondary pain. Visualizing movement and building up associated sensorimotor experiences are also considered important. To achieve this, cooperation between physiatrists and physical therapists, they must deepen and exchange understanding and knowledge with each other. PMID- 26422938 TI - [Concept of the Pain Rehabilitation]. AB - Pain causes physical disability and psychosocial issues and consequently reduces quality of life. Pain rehabilitation with exercise, cognitive-behavioral therapy, interdisciplinary rehabilitation and patient education improves not only subjective pain perception but also pain-associated dysfunction. The pain rehabilitation is characterized by enabling self-management based on patient centered perspective and decision-making by the patient. PMID- 26422939 TI - [Rehabilitative Intervention for Low Back Pain]. AB - In the evolution process to a bipedalism animal, human's spinal structure has been formed by responding to the contradicting functions (firm and flexibility). Thus, low back pain easily occurs even by a break of extremely slight balance. As for the cause of the pain, a consistency theory is not established, and we need to depend on conservative treatment for the treatment And the leading role of the conservative therapy is rehabilitation. In this report, we introduce scientific evidence for the effect of the rehabilitative intervention for low back pain. PMID- 26422940 TI - [Concept of the Pain Management in the Convalescent Rehabilitation]. AB - Convalescent rehabilitation is a treatment designed to facilitate the process of recovery from disease or injury to as normal a condition as possible. The effective rehabilitation is required to improve functions to bring about the highest possible level of independence, physically, psychologically, socially and economically within a limited hospitalization period. Pain often inhibits the effective rehabilitation, and the pain management in the convalescent rehabilitation ward is important. In particular, it is important to evaluate the pain promptly and accurately, and to treat it by a multidisciplinary team approach, preventing a shift to chronic pain. In this article, we describe the role of each member in the convalescent rehabilitation team and the characteristic pains caused by representative diseases. PMID- 26422941 TI - [Neurorehabilitation for Neuropathic Pain]. AB - Deafferentation, like as in limb amputation, brachial plexus avulsion injury and spinal cord injury, is usually followed by neuropathic pain. Neuropathic pain is a debilitating condition and it impairs the quality of life profoundly. Based on recent advances in the cognitive neuroscience, we explain intimate relationships among neuropathic pain, reorganization of primary sensory and motor cortices and the sensorimotor integration of the deafferentated limb. From the standpoint of the sensorimotor integration theory for emerging phantom limb pain, we further discuss the analgesic mechanism of neurorehabilitation techniques such as mirror visual feedback treatment and its related neurorobotics advancement for neuropathic pain. PMID- 26422942 TI - [HRV-Spectral analysis of Pain, by 3D Evaluation and by Balance Index in the Pain Rehabilitation Field]. AB - Pain signaling is achieved by electrical impulses in the body; however, some electrical abnormalities can cause pain in the body without generating any visible symptoms. This phenomenon is sensed by the brain and a signal that may affect cardiac rhythms is immediately transmitted to the heart. To evaluate heart rate variability (HRV), the balance correction between an increase and decrease of heart rate was recorded in real time. Using a special method for spectral analysis of the HRV, techniques for analyzing the essence of pain were developed, namely, the 'Balance index' and the '3D spectrum evaluation method'. Using these techniques, an alpha wave-like factor or a beta wave-like reaction can be obtained, and the nature and strength of pain can be displayed as spectral zones, as in a rainbow. The balance reaction can be shown by analyzing data in the frequency band using a 1/f-like spectral-analysis method. Additionally, emotional reactions can be detected using a 'Balance index' that can demonstrate imbalance responding to the pain. The mental state of the subject can also be inferred because this technique is adapted from the 1/f fluctuation theory related to the best balanced 1/f-sound wave in nature that comforts the human mind, similar to music (artificial sound wave). In this study, the variety and intensity of pain were determined from the frequency band resulting from the 1/f-spectral analysis of HRV fluctuation. These techniques could explain several situations related to medication or anesthesia and can be helpful in preventative treatment and/or explaining the differences in the effectiveness of various techniques for the rehabilitation of chronic pain. PMID- 26422943 TI - [Does the Residual Regurgitation on Intraoperative Transesophageal Echocardiography after Valve Surgery Deteriorate in Early Postoperative Period?]. AB - BACKGROUND: Residual regurgitation after valve surgery affects patients' long term prognosis. Whether post-repair regurgitation deteriorates postoperatively or not remains unclear, but this issue is a primary concern of the anesthesiologists responsible for intraoperative evaluation by transesophageal echocardiography (TEE). This study was conducted to assess changes in the severity of residual regurgitation during the early postoperative period. METHODS: Among 160 consecutive patients who underwent valve repair or valve replacement surgery during April 2010-June 2013 at our institution, 38 (24%) were found to have residual regurgitation by intraoperative TEE. We retrospectively evaluated these patients by reviewing follow-up transthoracic echocardiographic examination records. RESULTS: Residual regurgitation improved in 14 (37%), remained unchanged in 21 (55%), and worse in 3 (8%). All three patients showing worse regurgitation had undergone valve repair. Of them, one had reoperation one year later. No worsening of regurgitation, including perivalvular leakage, was found in patients who had undergone valve replacement. CONCLUSIONS: In valve repair, even mild residual regurgitation deteriorates postoperatively. Therefore, it should be observed cautiously. In valve replacement mild residual regurgitation did not deteriorate, irrespective of the regurgitation mechanism. PMID- 26422944 TI - [Levobupivacaine for Ultrasound-guided Interscalene Block: Block with 6 ml Leads to Less Occurrence of Respiratory Depression and Hemidiaphragmatic Paralysis]. AB - BACKGROUND: Interscalene brachial plexus block (ISBPB) complications depend usually on the dose administered. METHODS: The object of this study was to determine whether ultrasound-guided ISBPB with 6 ml of 0.5% levobupivacaine would reduce occurrence of respiratory depression and hemidiaphragmatic paralysis. RESULTS: Patients undergoing arthroscopic shoulder surgery under nerve block with general anesthesia (n = 20) were recruited. There were no differences between pre and post operative respiratory function (forced expiratory volume 1.0 (sec) % and vital capacity). Hemidiaphragmatic paralysis on postoperative ultrasonography was found in two patients. CONCLUSIONS: The use of low-volume ultrasound-guided ISBPB is associated with less respiratory depression and hemidiaphragmatic paralysis. PMID- 26422945 TI - [A Case of Mitral Valvular Re-repair in a Patient with Hemolytic Anemia after Mitral Valvular Repair]. AB - A 54-year-old woman was admitted for mitral valvular repair. After folding plasty to A3, a 30 mm Cosgrove-Edwards ring was placed. There was no mitral regurgitation jet observed by transesophageal echocardiography (TEE) during the operation. However, high blood pressure was monitored and treated in the intensive care unit, hemolytic anemia developed, and the serum lactate dehydrogenase level was elevated. Two weeks after the operation, serum lactate dehydrogenase was again elevated. TEE showed mild mitral regurgitation and the regurgitation jet colliding with the annuloplasty ring. Multiple transfusions of red blood cells were required. Repeat surgery was therefore undertaken. Lam and associates previously studying patients on hemolysis after mitral valvular repair noted high grade mitral regurgitation jets fragmented or accelerated. In the present case, mitral regurgitation was mild, but the high velocity and manner of regurgitation (collision with the annuloplasty ring) could cause hemolytic anemia. In the present case, high blood pressure might have caused chordae rupture. Furthermore, a flexible ring, such as the Cosgrove-Edwards ring, is likely to cause hemolytic anemia. As contributing factors to hemolysis after mitral valvular repair, perioperative blood pressure management and type of ring are significant. PMID- 26422946 TI - [Anesthetic Management of a Patient with Quasi-moyamoya Disease Undergoing Total Thyroidectomy for Graves' Disease]. AB - Quasi-moyamoya disease defined as moyamoya disease combined with autoimmune diseases such as Graves' disease is rare. We report anesthetic management of a patient with quasi-moyamoya disease undergoing total thyroidectomy for Graves' disease resistant to medical therapy. This disease is characterized by the aggravation of cerebral ischemic symptoms with hyperthyroidism. We, therefore, applied steroid pulse therapy before the operation to induce temporal normalization of the thyroid function, and could perform safe anesthetic management of this patient with quasi-moyamoya disease. PMID- 26422948 TI - [The SorbaView SHIELD is a Useful Product for Use in Perioperative Management]. AB - BACKGROUND: We studied the stability of the continuous arterial pressure line (A line) achieved by using a catheter securement device. METHODS: A total of 100 patients requiring an arterial catheter were divided into 2 groups of fixation: (1) fixation achieved by using the SorbaView SHIELD (Centurion Medical Products Corporation, USA) and (2) fixation by using Tegaderm 3 M (TEGADERM 3 M, Japan). We analyzed the stability of the fixation, presence or absence of skin disorders, and the preference by nurses. RESULTS: The SorbaView SHIELD was superior judged by nurses and was found to render more stability to the fixation of the A line as compared to Tegaderm 3 M, especially when transferring a patient into the intensive care unit after surgery. CONCLUSIONS: We conclude that stability of the A line maintained by the use of the SorbaView SHIELD is more effective in maintaining the stability of the A line. PMID- 26422947 TI - [Simulation-based Perioperative Team Training in the Operating Room]. AB - Here, we report the development of a simulation-based perioperative training course. Participants were anesthesiologists and operating room nurses. Three different courses were held with different themes, such as airway management, circulation management and central venous management. The courses included a lecture and simulation training with scenario-based discussions or a simulator. At the end of each course, participants discussed problems associated with medical safety in the context of each theme. Participants commented not only on changes in their views regarding individual technical or non-technical improvements, but also on general medical safety in the operating room. Our findings suggest that simulation-based perioperative team training may serve as a vehicle to promote operating room safety. PMID- 26422949 TI - [Did Seikyo Sugita Perform Two Surgical Operations under Ether Anesthesia in 1855?]. AB - Although Seikyou Sugita is said to have provided ether anesthesia for two surgical oprations in 1855 including the scur resection of burned fingers of a man and the resection of a breast cancer of a woman. The details of his administration of the drug were not known because he did not describe these cases at all. According to Treatise on Inhalation of Ether written in 1863 by Shinryo Tsuboi, Sugita failed to provide successful general anesthesia using ether for these patients. The ether he used was prepared by Ryuho Shima, and the failures were likely to be due to impure nature of the agent. PMID- 26422950 TI - [Several Issues before and after the Recognition of "Anesthesiology" as "Specially Approved Specialty"]. AB - A movement occurred at the end of 1940's among members of the Japan Medical Association (JMA) to recognize "specially approved specialty" in the practice of medicine, but their petition was rejected by the Medical Ethics Committee. Thus, the JMA expanded an energetic campaign for the recognition, by the support from four diet members. Consequently, six specialties including neurology and venereology were eventually accredited as "generally approved specialty" in 1950. About 1960, several years after anesthesiology having been recognized as a "specially approved medical specialty", some elder members of the Japan Society of Anesthesiology (JSA) discussed to change the term "specially approved specialty" to "generally approved medical specialty"in the Medical Service Law, but their motion could not gain majority support at the Councils of Elders of the JSA. The council also presented to the Ministry of Health and Welfare (MHW), a written request to alter the eligibility criteria of a registered anesthesiologist; however, the request was declined because of a strong opposition of the MHW which was under the strong influence of the JMA. The JSA did never show interest to these issues since then, and the situation remains unchanged to the present. PMID- 26422951 TI - [My Personal Opinion Facing the Gender Equality Society]. PMID- 26422952 TI - [Intraoperative Neurological Monitoring from the Anesthesiologist's Point of View Preface and Comments]. AB - Intraoperative neurophysiological monitoring has been increasingly utilized for many neurosurgical procedures as well as for spine and aortic surgery. The recent advances in monitoring devices and anesthesia techniques have improved the reliability and accuracy of intraoperative neurological monitoring. In this issue, we review the basic principle, methods, and clinical application of several modalities of neurological monitoring to detect neural tissue ischemia and the direct physical injury to the specific neural pathway during surgical procedures. These modalities include near-infrared spectroscopy, motor evoked potentials, somatosensory evoked potentials, auditory brainstem responses, and visual evoked potentials. Pitfalls and limitations of each modality are also discussed. Evidence for the efficacy of the monitoring varied with surgical procedures, but has been well validated in some procedures. Anesthesiologists can contribute to the reliability and efficacy of neurophysiological monitoring by maintaining good physiological homeostasis and stable levels of anesthesia during the surgical procedure. With appropriate knowledge and experience, the anesthesiologist should work together with the neuromonitoring staff and surgeon to ensure neurological safety for the patient during and after surgery. PMID- 26422953 TI - [Validity of Near-infrared Spectroscopy]. AB - Regional cerebral oxygen saturation measured by near-infrared spectroscopy has been used clinically. Its usefulness in cardiac surgery and neurosurgery was also reported. On the other hand, accuracy of rSO2 values has been supposed to be doubtful due to extra-cerebral contamination and unstable mean optical path length. Therefore, we tried to review issues for accuracy of rSO2 values and clinical usefulness. Our aim is to clarify the issue and clinical usefulness of measuring regional cerebral oxygen saturation. PMID- 26422954 TI - [Somatosensory Evoked Potential during Cardiac Surgery]. AB - Neurologic complications are common in cardiac surgery. The rate of complication can range from 1.6% to 23% for permanent neurologic deficits and from 7% to 61% for transient neurologic deficits. Although several studies have suggested the effectiveness of brain monitoring in reducing postoperative adverse neurologic outcomes, brain monitoring during cardiac surgery has not yet been adopted for routine use. Somatosensory evoked potential (SEP) can provide direct information on the integrity of somatosensory pathway such as SEP elicited by median nerve stimulation in cardiac surgery. An electrode is placed over primary sensory cortex, C3' C4', so called Shagss point. The N20/P25 waveform can be recorded. N20/P25 evoked potentials reflect the perfusion of medial brain circulation. When cerebral blood flow decreases or when brachial plexus is obstructed, N20/P25 amplitude decreases with latency delay. SEP can quickly detect brain ischemia and brachial plexus dysfunction, and it is useful for nervous system monitoring in cardiac surgery. PMID- 26422955 TI - [Motor Evoked Potentials and Aortic Surgery]. AB - Motor dysfunction following descending and thoracoabdominal aortic surgery including thoracic endovascular aortic repair remains as one of their devastating complications, although several interventions have tried to preserve spinal cord blood flow during and after aortic aneurysm surgery for the purpose of reducing the incidence of postoperative paraplegia. One of the main limitations of protective strategies is the inability to assess the adequacy of spinal cord perfusion and spinal cord function intraoperatively. Advances in stimulation technique using short train pulses could make intraoperative monitoring of functional integrity of motor pathways possible by recording myogenic motor evoked potentials (MEP), which is a highly sensitive technique to assess spinal cord integrity, identifying insufficient blood flow. To reduce the risk of neurologic injury, anesthesiologists are required to properly understand monitoring of MEP and to manage anesthesia and hemodynamics appropriately. Here, we summarize the strategies for spinal cord protection, including the functional monitoring of spinal cord and anesthetic techniques. PMID- 26422956 TI - [Intraoperative Electrophysiological Monitoring for Neurosurgery]. AB - Both motor evoked potential (MEP) and somatosensory evoked potential (SEP) have been used for the purpose of preventing postoperative neurological complications in patients undergoing neurosurgery. Although not completely, they can detect insufficient cerebral blood flow during aneurysm surgery and carotid surgery and prevent functional deterioration during tumor resection. Regarding MEP, there are several points to be considered for maximizing the potential of MEP. First, suprathreshold stimulus should be used because supramaximal stimulus may be too strong, resulting in false negative responses. Second, direct cortical stimulation in addition to transcranial stimulation may be useful for stimulating the target area precisely. Third, subcortical stimulation can provide decisive information during tumor resection. Although there is no such thing as 100% accuracy in electrophysiological monitoring, a multimodal electrophysiological monitoring system may contribute to decrease neurological deficits. Irreversible neurological deficits could be prevented by early detection of the changes in the amplitude and by prompt intervention to correct deteriorating condition. Therefore, it is important for anesthesiologists to select suitable anesthetics for the monitoring, maintain the depth of anesthesia, and discuss the patient management with surgeons. PMID- 26422957 TI - [Intraoperative ABR Monitoring in Neurosurgery]. AB - Monitoring of the intraoperative auditory brainstem response (ABR) is a less invasive, easy, and useful method for hearing preservation in patient undergoing cerebellopontine angle surgery such as microvascular decompression (MVD) and excision of an acoustic neurinoma. The ABR is tolerant of both inhalation and intravenous anesthesia. However, ABR recordings are highly susceptible to electrical noise from surgical devices. Therefore, for ABR recordings to be reliable, noise must be minimized and appropriate evaluation of waveform changes is critical. Electrode setting with low contact impedance and bilateral derivation effectively address these issues. Prolongation of the wave V latency alerts to surgical stress on the cochlear nerve due to nerve stretching from cerebellar retraction. According to Sekiya, the surgeon performing MVD or acoustic neurinoma excision should be warned as soon as latency prolongation exceeds 1.5 msec or characteristics of ABR must be understood. even less than 0.5 msec, respectively. However, hearing was preserved in some patients with false positive results with respect to intraoperative wave V diminution. To use it as a useful intraoperative modality, the Characteristics of ABR must be understood. PMID- 26422958 TI - [Intraoperative Visual Evoked Potential Monitoring]. AB - Visual evoked potential (VEP) is recorded from the back of the head, which is elicited by retinal stimulation transmitted through optic nerve, optic chiasm, optic tract lateral geniculate body, optic radiation and finally cortical visual area. VEP monitoring did not prevail since 1990s because marked intra-individual difference and instability of VEP recording limited the clinical usefulness under inhalation anesthetic management and techniques of VEP monitoring at the time. However, recent advances in techniques including a new light-stimulating device consisting of high-luminosity LEDs and induction of electroretinography to ascertain the arrival of the stimulus at the retina provided better conditions for stable VEP recording under general anesthesia. In addition, the introduction of total intravenous anesthesia using propofol is important for the successful VEP recordings because inhaled anesthetics have suppressive effect on VEP waveform. Intraoperative VEP has been considered to monitor the functional integrity of visual function during neurosurgical procedures, in which the optic pathway is at a risk of injury. Intraoperative VEP monitoring may allow us to detect reversible damage to the visual pathway intraoperatively and enable us to prevent permanent impairment. PMID- 26422959 TI - [Motor Evoked Potential and Somatosensory Evoked Potential during Spine and Spinal Surgery]. AB - Spine and spinal cord surgery carries a significant risk of neurological impairment Intraoperative neurological monitoring should now include not only somatosensory evoked potential (SEP), but also motor evoked potential (MEP). While SEP monitors the posterior cord, MEP provides better information regarding the status of the anterior/anterolateral cord. The multimodality SEP and MEP monitoring essentially covers physiological changes of the entire cord, and thereby reduces the risk of development of irreversible neural injury. A 50% drop in SEP amplitude is the universally accepted warning criteria. Conversely, different warning criteria for MEP have been proposed because of MEP especially sensitive to the effects of anesthetic agents. Although evidence lacks that intraoperative evoked potential reduces the rate of neurologic deficits, it is recommended to monitor MEP for spine and spinal surgery, when the spinal cord is considered to be at risk. The anesthesiologist must be familiar with SEP and MEP monitoring to increase the preciseness of the monitoring. PMID- 26422960 TI - [Spontaneous Respiration Technique for Pediatric Microlaryngeal Surgery without Endotracheal Intubation]. AB - We report the anesthetic management of microlaryngeal surgery in children using tubeless total intravenous anesthesia (TIVA) without endotracheal intubation under spontaneous breathing. In 9 patients (median age : 4.9 yr. range 1 months 14 years, body weight : 17 kg, range 3-61 kg), 19 procedures were performed with TIVA using propofol and remifentanil. The median time from the start of TIVA to rigid laryngoscope insertion was 11 minutes. Propofol 15.7 mg x kg(-1) x hr(-1) and remifentanil 0.05 MUg x kg(-1) x min(-1) was infused in this interval. Laryngospasm was observed in two cases, but it responded to a bolus of propofol (0.5-1.0 mg x kg(-1)) and additional topical anesthesia with 1% lidocaine. Three children were found apneic after a bolus administration of remifentanil or after increasing the rate of remifentanil infusion accompanied with desaturation and their tracheae were intubated. The spontaneous respiration technique using TIVA without intubation provides an excellent view of the operative field while allowing stable anesthesia. Further studies are required to establish the optimal dose of propofol and remifentanil and the timing of rigid laryngoscope insertion. PMID- 26422961 TI - [Anesthetic Management of Right Lower Lobectomy in a Patient with Marfan Syndrome]. AB - We report a case of partial lobectomy in a patient with Marfan syndrome. A 56 year-old woman with Marfan syndrome was scheduled for partial lobectomy for suspected lung cancer under general anesthesia. She underwent a Bentall operation and mitral valve replacement 10 months before and strict blood pressure management was required. After induction of general anesthesia with propofol and fentanyl, topical intratracheal lidocaine anesthesia was performed using the Pentax-AWS Airwayscope (AWS) for visualization, allowing for the Soft-tipped Tube Exchanger (TE-Soft) to be inserted into the trachea. Next, a double-lumen tracheal tube was uneventfully intubated via the TE-Soft with minimal change in vital signs. During the operation, pressure-controlled ventilation was performed to minimize the risk of pneumothorax. After the operation, under continuous administration of landiorol and dexmedetomidine, the double-lumen tracheal tube was extubated uneventfully. Strict airway and circulation management is needed for lung or vessel preservation in patients whose conditions are complicated by Marfan syndrome. PMID- 26422962 TI - [Tracheal Intubation via the i-gel and the Aintree Intubation Catheter in a Patient with Unexpected Difficult Intubation]. AB - A 64-year-old man was scheduled for radical sinus operation. Preoperatively, we did not expect difficult airway. We induced general anesthesia, and ventilation via facemask was adequate, but tracheal intubation using a Macintosh laryngoscope was difficult (Cormack-Lehane classification III). We inserted the i-gel, and a fiberoptic bronchoscope covered with the Aintree Intubation Catheter (AIC), was passed through the i-gel to the trachea. We removed i-gel and fiberscope, leaving the AIC in place, and could easily advance a reinforced tube over the AIC into the trachea. Fiberoptic tracheal intubation via the i-gel and AIC is useful in a patient with difficult intubation. PMID- 26422963 TI - [Lateral Approach Tracheal Intubation in a Semi-sitting Position Utilizing a Videolaryngoscope in a Patient with Respiratory Failure due to Septic Shock]. AB - Here we report our success in performing lateral approach tracheal intubation in a patient with severe respiratory failure due to septic shock caused by shoulder joint abscess. A 71-year-old woman presented with severe respiratory difficulty due to sepsis from a shoulder joint abscess and was scheduled for emergent drainage and irrigation. She could not breathe sufficiently in the supine position and thus maintained a semi-sitting position. She was also unable to move from the ward bed to the operating table due to severe shoulder pain. We induced anesthesia in a semi-sitting position in the ward bed. Mask ventilation was performed using the two-hand technique from the lateral approach. Tracheal intubation was also performed with a left lateral approach utilizing the Pentax AWS Airwayscope (AWS). Lateral approach for tracheal intubation utilizing AWS may be useful in patients who present with severe respiratory difficulty. PMID- 26422964 TI - [Ossification of the Posterior Longitudinal Ligament Found in a Case of Sudden Head-tilt Difficulty following Induction of General Anesthesia]. AB - We report a case of sudden head-tilt difficulty after induction of general anesthesia which was postoperatively diagnosed as ossification of the posterior longitudinal ligament. A 42-year-old man weighing 115 kg was scheduled for emergent laparoscopic appendectomy for acute appendicitis. Prior to induction of anesthesia, the patient could tilt his head, but was unable to do so afterwards. Following mask ventilation with jaw-thrust maneuver, we successfully performed tracheal intubation using the Pentax-AWS Airwayscope. After surgery, he was diagnosed with ossification of the posterior longitudinal ligament by an orthopedist. PMID- 26422965 TI - [Successful Airway Management Using the air-Q Intubating Laryngeal Airway under Dexmedetomidine and Laryngeus Superior Nerve Block for Severe Tracheal Stenosis due to Thyroid Cancer Invasion]. AB - A 75-year-old woman suffering from respiratory difficulty was diagnosed with severe tracheal stenosis due o malignant thyroid cancer. She was scheduled for an mergent tracheotomy, but preoperative computed omography revealed severe tracheal stenosis below he glottis due to thyroid cancer invasion. Anticipating lifficult tracheal intubation and risk of obstruction from hemorrhage, intubation preserving spontaneous ventiation was performed to avoid a 'can't ventilate, can't intubate' situation. A size 3.5 air-Q intubating laryngeal airway was inserted using a bronchofiberscope to perform tracheal intubation in a semi sitting position. Successful tracheal intubation which avoided damage to the tumor was achieved while maintaining spontaneous ventilation. The air-Q intubating laryngeal airway was useful in this setting of severe tracheal stenosis due to thyroid cancer just under the glottis. PMID- 26422966 TI - [Anesthetic Management of a Patient for Total Gastrectomy after Coronary Artery Bypass Grafting Using the Right Gastroepiploic Artery]. AB - We report anesthetic management of total gastrectomy for gastric cancer under general anesthesia supplemented with a transversus abdominis plane (TAP) block. The patient was a 78-year-old man who had received coronary artery bypass grafting (CABG) with the right gastroepiploic artery (RGEA) 12 years before. Preoperative coronary angiography (CAG) showed that RCA was obstructed completely and RGEA was patent and the surgeons carried out gastrectomy with the utmost attention not to injure the RGEA. There were no signs of myocardial ischemia under monitoring by transesophageal echocardiography (TEE). The ultrasound-guided TAP block was effective. This case demonstrates that the ultrasound-guided TAP block is an alternative approach for providing analgesia and intraoperative TEE monitoring is useful in a patient with gastrectomy after CABG using the RGEA with coagulation abnormality. PMID- 26422967 TI - [Anesthetic Management Using Frontal Nerve, Greater Occipital Nerve, and Superficial Cervical Plexus Block for Posterior Cervical Spinal Fusion in a Patient with Athetoid Cerebral Palsy]. AB - Here, we report successful anesthetic management of posterior cervical spinal fusion utilizing block of the frontal nerve, the greater occipital nerve, and the superficial cervical plexus in a patient with athetoid cerebral palsy. A 69-year old woman (height 157 cm; weight 33 kg) with athetoid cerebral palsy was scheduled to undergo posterior cervical spinal fusion for cervical spondylotic myelopathy. After induction of general anesthesia, we performed tracheal intubation using the Pentax-AWS Airwayscope with a thin Intlock. After tracheal intubation, we used ropivacaine for the frontal nerve, greater occipital nerve, and superficial cervical plexus block. Anesthetic maintenance was performed with total intravenous anesthesia utilizing propofol and remifentanil. Continuous administration of dexmedetomidine was started during operation. Following surgery, smooth spontaneous ventilation was observed following uneventful extubation. No significant pain and no athetoid movement were observed under continuous administration of dexmedetomidine. PMID- 26422968 TI - [A Case of Severe Bradycardia Associated with Bladder Perforation during Spinal Anesthesia]. AB - Here we report a case of severe bradycardia associated with bladder perforation during transurethral resection of the bladder. The patient was diagnosed with bladder cancer eight months ago and underwent transurethral resection of the bladder tumor. After balloon-occluded arterial infusion chemotherapy, she was scheduled for a bladder biopsy under spinal anesthesia. Spinal anesthesia was induced with 2.5 ml of 0.5% bupivacaine hydrochloride at L3-4, and sensory loss (T9) was confirmed. The operation started uneventfully 20 minutes after bupivacaine administration. However, ten minutes into the operation, bladder perforation occurred and was followed by severe bradycardia (20-30 beats x min( 1)). While preparing for transcutaneous pacing, bradycardia improved with intravenous atropine and ephedrine. The level of spinal anesthesia remained unchanged. General anesthesia was induced with propofol, rocuronium and fentanyl. The patient was extubated uneventfully after the operation and was discharged 14 days later. PMID- 26422969 TI - [A Problem with Flow Indicators of Anesthesia Machine]. AB - Some anesthesia machines indicate both analog and digital flow volumes of oxygen, air and nitrous oxide. We have noticed that there are discrepancies in the flows between analog and digital flow indicators of two anesthesia machine models (Drager ; Fabius GS premium and Fabius Tiro). When oxygen or air flow is low, the analog indicator shows higher flows than the digital indicator. In contrast, when oxygen or air flow is high, the analog indicator shows lower flows than the digital indicator. This discrepancy is comparatively small when total gas flow is within the range of 2-5 l x min(-1). We contacted the manufacturer, which replied that the digital indicator is correct and the analog indicator should be regarded as an adjunctive, in case of a power failure when the digital indicator does not function. But this discrepancy may cause practical problems. When we cannot use a digital indicator and have to perform ventilation using a supporting gas cylinder, we may misjudge the available time for oxygen. In addition, when we use only analog indicator, insufficient volume of oxygen may be delivered, leading to the grave hypoxia. PMID- 26422970 TI - [Video Laryngoscopy Reduces the Incidence of Erroneous Esophageal Intubation: A Meta-analysis]. AB - BACKGROUND: The aim of this meta-analysis is to compare the incidence of erroneous esophageal intubations by video laryngoscopy to that by direct laryngoscopy. METHODS: The systematic search, data extraction, critical appraisal, and pooled analysis were performed according the PRISMA statement. The odds ratio(OR) and 95% confidence interval (CI) were calculated by the Review Manager 5.2 software for dichotomous outcome. RESULTS: Eleven trials included 1425 tracheal intubations by video laryngoscopy and 1632 tracheal intubations by Macintosh laryngoscopy. Video laryngoscopy reduced the risk of erroneous esophageal intubations (OR 0.10, 95% CI 0.04-0.24, P < 0.00001, I2 : 0%) compared with Macintosh laryngoscopy. CONCLUSIONS: Our meta-analysis showed that video laryngoscopy would reduce the incidence of erroneous esophageal intubations. PMID- 26422971 TI - [Development and Hosting of a Perioperative Advanced Life Support Training Course for Anesthesiologists]. AB - Participation in the American Heart Association advanced cardiac life support provider course is a prerequisite for taking the anesthesiology specialist examination in Japan. The course teaches fundamental resuscitation methods for different types of cardiac arrest. However, crisis in the perioperative period can result from airway trouble, central venous catheter displacement, or massive hemorrhage. We report our experience of holding a problem- and learning-based perioperative advanced life support training course, Advanced Life Support for Operation (ALS-OP). Main contents of the course included circulation management, airway management central venous catheters, and pain clinic-related complications. ALS-OP simulation training may be beneficial for educating anesthesiologist and promoting perioperative patient safety. PMID- 26422972 TI - [Laryngeal Tube Position Shift after Chest Compression: Comparison of Fixation Methods Using Durapore Tape, Multipore Tape, or a Neck Tape]. AB - BACKGROUND: The laryngeal tube (LT ; Smiths Medical, Minnesota, U. S. A) is an inflatable supraglottic device for emergency airway management such as during chest compression, the instability after insertion remains a problem. METHODS: We investigated the effectiveness of three fixation methods of LT using a manikin and automated chest compressor. RESULTS: After 10-minute chest compression, LT without fixation was shifted by 0.4 +/- 0.1 cm, which was greater than with Durapore tape (0.2 +/- 0.1 cm), Multipore tape (0.2 +/- 0.1 cm), or a neck tape (0.1 +/- 0.1 cm). The shift of the position was smaller with neck tape fixation compared to Durapore or Multipore tape fixation. CONCLUSIONS: A fixation neck tape may be useful in stabilizing the inserted position of LT during cardiopulmonary resuscitation. PMID- 26422973 TI - Primary pancreatic Hodgkin's lymphoma diagnosed on EUS-guided FNA. PMID- 26422974 TI - A knotty problem. PMID- 26422975 TI - Mirizzi's syndrome presenting after laparoscopic cholecystectomy. PMID- 26422976 TI - Rendezvous procedure at 6 weeks of age. PMID- 26422977 TI - Sodium polystyrene sulfonate-induced esophageal ulcer. PMID- 26422978 TI - A case of extramedullary involvement of acute monocytic leukemia that presented as obstructive jaundice. PMID- 26422979 TI - Diagnostic yield of EUS-guided FNA for malignant biliary stricture: a systematic review and meta-analysis. AB - BACKGROUND AND AIMS: EUS-guided FNA (EUS-FNA) is increasingly being used for tissue diagnosis of extrahepatic biliary strictures. The aim of this study was to determine the diagnostic yield of EUS-FNA in malignant biliary strictures. METHODS: A comprehensive literature review was carried out by 2 reviewers for studies evaluating the accuracy of EUS-FNA in biliary stricture. A meta-analysis was performed to determine the pooled estimates of sensitivity, specificity, likelihood ratios, and diagnostic odds ratio for EUS-FNA of extrahepatic biliary stricture. A Quality Assessment of Diagnostic Accuracy Studies questionnaire was used to assess the quality of the selected studies. Several sensitivity analyses were performed to assess the effect of the quality of the studies on the accuracy of the final results of the meta-analysis. RESULTS: Twenty studies involving 957 patients met inclusion criteria and were included in the meta-analysis. The pooled sensitivity and specificity of EUS-FNA for diagnosis of malignant biliary stricture were 80% (95% confidence interval [CI], 74%-86%), and 97% (95% CI, 94% 99%), respectively. The pooled positive likelihood ratio was 12.35 (95% CI, 7.37 20.72), and the negative likelihood ratio was 0.26 (95% CI, 0.18-0.38). The pooled diagnostic odds ratio for diagnosing a malignant biliary stricture was 70.53 (95% CI, 38.62-128.82). The area under the receiver-operating characteristic curve was 0.97. Sensitivity analyses showed that the quality of the included studies did not affect the accuracy of the final results of the meta analysis. CONCLUSION: This meta-analysis demonstrates that EUS-FNA is sensitive and highly specific for diagnosing malignancy in biliary strictures. Further studies are needed to compare EUS--FNA with emerging methods including cholangioscopy-guided biopsy and laser endomicroscopy. PMID- 26422981 TI - Unifying Mechanism of Controlling Kir3 Channel Activity by G Proteins and Phosphoinositides. AB - The question that started with the pioneering work of Otto Loewi in the 1920s, to identify how stimulation of the vagus nerve decreased heart rate, is approaching its 100th year anniversary. In the meantime, we have learned that the neurotransmitter acetylcholine acting through muscarinic M2 receptors activates cardiac potassium (Kir3) channels via the betagamma subunits of G proteins, an important effect that contributes to slowing atrial pacemaker activity. Concurrent stimulation of M1 or M3 receptors hydrolyzes PIP2, a signaling phospholipid essential to maintaining Kir3 channel activity, thus causing desensitization of channel activity and protecting the heart from overinhibition of pacemaker activity. Four mammalian members of the Kir3 subfamily, expressed in heart, brain, endocrine organs, etc., are modulated by a plethora of stimuli to regulate cellular excitability. With the recent great advances in ion channel structural biology, three-dimensional structures of Kir3 channels with PIP2 and the Gbetagamma subunits are now available. Mechanistic insights have emerged that explain how modulatory control of activity feeds into a core mechanism of channel PIP2 interactions to regulate the conformation of channel gates. This complex but beautiful system continues to surprise us for almost 100 years with an apparent wisdom in its intricate design. PMID- 26422980 TI - Double-blind randomised controlled trial of percutaneous tibial nerve stimulation versus sham electrical stimulation in the treatment of faecal incontinence: CONtrol of Faecal Incontinence using Distal NeuromodulaTion (the CONFIDeNT trial). AB - BACKGROUND: Faecal incontinence (FI) is a common condition which is often under reported. It is distressing for those suffering from it, impacting heavily on their quality of life. When conservative strategies fail, treatment options are limited. Percutaneous tibial nerve stimulation (PTNS) is a minimally invasive outpatient treatment, shown in preliminary case series to have significant effectiveness; however, no randomised controlled trial has been conducted. OBJECTIVES: To assess the effectiveness of PTNS compared with sham electrical stimulation in the treatment of patients with FI in whom initial conservative strategies have failed. DESIGN: Multicentre, parallel-arm, double-blind randomised (1 : 1) controlled trial. SETTING: Eighteen UK centres providing specialist nurse-led (or equivalent) treatment for pelvic floor disorders. PARTICIPANTS: Participants aged > 18 years with FI who have failed conservative treatments and whose symptoms are sufficiently severe to merit further intervention. INTERVENTIONS: PTNS was delivered via the Urgent((r)) PC device (Uroplasty Limited, Manchester, UK), a hand-held pulse generator unit, with single-use leads and fine-needle electrodes. The needle was inserted near the tibial nerve on the right leg adhering to the manufacturer's protocol (and specialist training). Treatment was for 30 minutes weekly for a duration of 12 treatments. Validated sham stimulation involved insertion of the Urgent PC needle subcutaneously at the same site with electrical stimulation delivered to the distal foot using transcutaneous electrical nerve stimulation. MAIN OUTCOME MEASURES: Outcome measures were assessed at baseline and 2 weeks following treatment. Clinical outcomes were derived from bowel diaries and validated, investigator-administered questionnaires. The primary outcome classified patients as responders or non-responders, with a responder defined as someone having achieved >= 50% reduction in weekly faecal incontinence episodes (FIEs). RESULTS: In total, 227 patients were randomised from 373 screened: 115 received PTNS and 112 received sham stimulation. There were 12 trial withdrawals: seven from the PTNS arm and five from the sham arm. Missing data were multiply imputed. For the primary outcome, the proportion of patients achieving a >= 50% reduction in weekly FIEs was similar in both arms: 39 in the PTNS arm (38%) compared with 32 in the sham arm (31%) [odds ratio 1.28, 95% confidence interval (CI) 0.72 to 2.28; p = 0.396]. For the secondary outcomes, significantly greater decreases in weekly FIEs were observed in the PTNS arm than in the sham arm (beta -2.3, 95% CI -4.2 to -0.3; p = 0.02), comprising a reduction in urge FIEs (p = 0.02) rather than passive FIEs (p = 0.23). No significant differences were found in the St Mark's Continence Score or any quality-of-life measures. No serious adverse events related to treatment were reported. CONCLUSIONS: PTNS did not show significant clinical benefit over sham electrical stimulation in the treatment of FI based on number of patients who received at least a 50% reduction in weekly FIE. It would be difficult to recommend this therapy for the patient population studied. Further research will concentrate on particular subgroups of patients, for example those with pure urge FI. TRIAL REGISTRATION: Current Controlled Trials ISRCTN88559475. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 77. See the NIHR Journals Library website for further project information. PMID- 26422982 TI - The Roles of Gbetagamma and Galpha in Gating and Regulation of GIRK Channels. AB - G protein-gated K(+) (GIRK, or Kir3) channels mediate inhibitory neurotransmission via G protein-coupled receptors (GPCRs) in heart and brain. The signaling cascade involves activation of GPCR by an agonist, activation of a G protein followed by rearrangement or dissociation of activated Galpha(GTP) from Gbetagamma, and activation of GIRK by Gbetagamma. Gbetagamma is the main transducer of GPCR activating signal to the GIRK channel. It promotes channel opening by direct binding to GIRK's cytosolic domain formed by the N- and C terminal segments of the GIRK's four subunits. Gbetagamma's interaction with, and activation of, the GIRK channels are well understood and reviewed elsewhere; however, several important details involving distal parts of the cytosolic domain remain incompletely understood. Galpha(i/o) also binds to GIRKs and has been implicated in regulating channel's gating, in concert with Gbetagamma. Among known functions of Galpha, best-described (though not well understood) are selectivity of signaling (only G(i/o) proteins normally couple to GIRKs) and regulation of the basal activity of GIRKs (I(basal)). A role for a direct effect of the activated Galpha(i/o)(GTP) in GIRK gating has also been proposed but remains elusive. This chapter discusses the mechanisms of signaling within the essential cascade, from GPCR to the heterotrimeric G protein and to the channel. The focus is on the role of Galpha and on the relationships between Galpha and Gbetagamma in channel regulation, their role in specific signaling from GPCRs to GIRKs, and the role of stoichiometry and cooperativity of G protein-GIRK interactions in channel's function. PMID- 26422983 TI - RGS Redundancy and Implications in GPCR-GIRK Signaling. AB - Regulators of G protein signaling (RGS proteins) are key components of GPCR complexes, interacting directly with G protein alpha-subunits to enhance their intrinsic GTPase activity. The functional consequence is an accelerated termination of G protein effectors including certain ion channels. RGS proteins have a profound impact on the membrane-delimited gating behavior of G-protein activated inwardly rectifying K(+) (GIRK) channels as demonstrated in reconstitution assays and recent RGS knockout mice studies. Akin to GPCRs and G protein alphabetagamma subunits, multiple RGS isoforms are expressed within single GIRK-expressing neurons, suggesting functional redundancy and/or specificity in GPCR-GIRK channel signaling. The extent and impact of RGS redundancy in neuronal GPCR-GIRK channel signaling is currently not fully appreciated; however, recent studies from RGS knockout mice are providing important new clues on the impact of individual endogenous RGS proteins and the extent of RGS functional redundancy. Incorporating "tools" such as engineered RGS resistant Galphai/o subunits provide an important assessment method for determining the impact of all endogenous RGS proteins on a given GPCR response and an accounting benchmark to assess the impact of individual RGS knockouts on overall RGS redundancy within a given neuron. Elucidating the degree of regulation attributable to specific RGS proteins in GIRK channel function will aid in the assessment of individual RGS proteins as viable therapeutic targets in epilepsy, ataxia's, memory disorders, and a growing list of neurological disorders. PMID- 26422984 TI - Structural Insights into GIRK Channel Function. AB - G protein-gated inwardly rectifying potassium (GIRK; Kir3) channels, which are members of the large family of inwardly rectifying potassium channels (Kir1 Kir7), regulate excitability in the heart and brain. GIRK channels are activated following stimulation of G protein-coupled receptors that couple to the G(i/o) (pertussis toxin-sensitive) G proteins. GIRK channels, like all other Kir channels, possess an extrinsic mechanism of inward rectification involving intracellular Mg(2+) and polyamines that occlude the conduction pathway at membrane potentials positive to E(K). In the past 17 years, more than 20 high resolution atomic structures containing GIRK channel cytoplasmic domains and transmembrane domains have been solved. These structures have provided valuable insights into the structural determinants of many of the properties common to all inward rectifiers, such as permeation and rectification, as well as revealing the structural bases for GIRK channel gating. In this chapter, we describe advances in our understanding of GIRK channel function based on recent high-resolution atomic structures of inwardly rectifying K(+) channels discussed in the context of classical structure-function experiments. PMID- 26422985 TI - Localization and Targeting of GIRK Channels in Mammalian Central Neurons. AB - G protein-gated inwardly rectifying K(+) (GIRK/K(ir)3) channels are critical to brain function. They hyperpolarize neurons in response to activation of different G protein-coupled receptors, reducing cell excitability. Molecular cloning has revealed four distinct mammalian genes (GIRK1-4), which, with the exception of GIRK4, are broadly expressed in the central nervous system (CNS) and have been implicated in a variety of neurological disorders. Although the molecular structure and composition of GIRK channels are key determinants of their biophysical properties, their cellular and subcellular localization patterns and densities on the neuronal surface are just as important to nerve function. Current data obtained with high-resolution quantitative localization techniques reveal complex, subcellular compartment-specific distribution patterns of GIRK channel subunits. Recent efforts have focused on determining the associated proteins that form macromolecular complexes with GIRK channels. Demonstration of the precise subcellular compartmentalization of GIRK channels and their associated proteins represents a crucial step in understanding the contribution of these channels to specific aspects of neuronal function under both physiological and pathological conditions. Here, we present an overview of studies aimed at determining the cellular and subcellular localization of GIRK channel subunits in mammalian brain neurons and discuss implications for neuronal physiology. PMID- 26422986 TI - GIRK Channel Plasticity and Implications for Drug Addiction. AB - Drugs of abuse can "hijack" synaptic plasticity, a physiological basis of learning and memory, establishing maladaptations that can promote drug addiction. A wealth of data supports the existence and importance of neuroadaptations in excitatory neurotransmission upon drug exposure. Recent discoveries, however, have shown that inhibitory neurotransmission mediated by G protein-gated inwardly rectifying potassium (K(+)) (GIRK/Kir3) channels is also subject to adaptation triggered by exposure to drugs of abuse. GIRK channels are expressed in neuronal populations relevant to reward and reward-related behaviors, where their activation by neurotransmitters such as GABA, dopamine, and adenosine reduces neuronal excitability. Studies in animal models have implicated GIRK channels in a number of behaviors including reward. Drugs of abuse also affect the inhibitory neurotransmission mediated by GIRK channels. These changes might be important for the development, maintenance, or relapse of addiction, making GIRK channels promising targets for novel addiction therapies. PMID- 26422987 TI - GIRK Channels: A Potential Link Between Learning and Addiction. AB - The ability of drug-associated cues to reinitiate drug craving and seeking, even after long periods of abstinence, has led to the hypothesis that addiction represents a form of pathological learning, in which drugs of abuse hijack normal learning and memory processes to support long-term addictive behaviors. In this chapter, we review evidence suggesting that G protein-gated inwardly rectifying potassium (GIRK/Kir3) channels are one mechanism through which numerous drugs of abuse can modulate learning and memory processes. We will examine the role of GIRK channels in two forms of experience-dependent long-term changes in neuronal function: homeostatic plasticity and synaptic plasticity. We will also discuss how drug-induced changes in GIRK-mediated signaling can lead to changes that support the development and maintenance of addiction. PMID- 26422989 TI - Preface. PMID- 26422991 TI - Vitis vinifera L. Single-Nucleotide Polymorphism Detection with High-Resolution Melting Analysis Based on the UDP-Glucose:Flavonoid 3-O-Glucosyltransferase Gene. AB - Vitis vinifera L. is a species with a large number of varieties, which differ in terms of anthocyanin content. The genes involved in the anthocyanin biosynthesis pathway have a direct effect in the anthocyanin profile of each variety, being potentially interesting for varietal identification. The current study aimed at the design of an assay suitable for the discrimination of the largest number of grapevine varieties. Two genes of the anthocyanin pathway, chalcone isomerase (CHI) and UDP-glucose:flavonoid 3-O-glucosyltransferase (UFGT), were sequenced in 22 grapevine varieties. The CHI gene presented 5 SNPs within the sequence. A total of 58 SNPs and 1 INDEL were found among the UFGT gene, allowing the discrimination of 18 different genotypes within the 22 grapevine varieties. A HRM assay designed for UFGT, containing 704 bp, produced differentiated melting curves for each of the 18 haplotypes. The developed HRM assay is efficient in grapevine varietal discrimination. PMID- 26422990 TI - Palmitate-induced endothelial dysfunction is attenuated by cyanidin-3-O-glucoside through modulation of Nrf2/Bach1 and NF-kappaB pathways. AB - Free fatty acids (FFA), commonly elevated in diabetes and obesity, have been shown to impair endothelial functions and cause oxidative stress, inflammation, and insulin resistance. Anthocyanins represent one of the most important and interesting classes of flavonoids and seem to play a role in preventing cardiovascular diseases. Herein, we investigated the in vitro protective effects of cyanidin-3-O-glucoside (C3G) on cell signaling pathways in human umbilical vein endothelial cells (HUVECs) exposed to palmitic acid (PA), the most prevalent saturated FFA in circulation. Our data reported a significant augmentation of free radicals and oxidative stress in HUVECs exposed to PA for 3h, while C3G pretreatment improved intracellular redox status altered by FFA. Moreover, C3G significantly inhibited NF-kappaB proinflammatory pathway and adhesion molecules induced by PA, and these effects were attributed to the activation of Nrf2/EpRE pathway. In fact, C3G induced Nrf2 nuclear localization and activation of cellular antioxidant and cytoprotective genes at baseline and after PA exposure in endothelial cells. Our data confirm the hypothesis that natural Nrf2 inducers, such as C3G, might be a potential therapeutic strategy to protect vascular system against various stressors preventing several pathological conditions. PMID- 26422988 TI - Behavioral and Genetic Evidence for GIRK Channels in the CNS: Role in Physiology, Pathophysiology, and Drug Addiction. AB - G protein-coupled inwardly rectifying potassium (GIRK) channels are widely expressed throughout the brain and mediate the inhibitory effects of many neurotransmitters. As a result, these channels are important for normal CNS function and have also been implicated in Down syndrome, Parkinson's disease, psychiatric disorders, epilepsy, and drug addiction. Knockout mouse models have provided extensive insight into the significance of GIRK channels under these conditions. This review examines the behavioral and genetic evidence from animal models and genetic association studies in humans linking GIRK channels with CNS disorders. We further explore the possibility that subunit-selective modulators and other advanced research tools will be instrumental in establishing the role of individual GIRK subunits in drug addiction and other relevant CNS diseases and in potentially advancing treatment options for these disorders. PMID- 26422992 TI - Differential phenotypic and functional properties of liver-resident NK cells and mucosal ILC1s. AB - Group 1 innate lymphoid cells (ILCs) consist of conventional natural killer (cNK) cells, tissue-resident NK cells and mucosal ILC1s. Recently identified liver resident NK cells, which can mount contact hypersensitivity responses, and mucosal ILC1s that are involved in pathogenesis of colitis are distinct from cNK cells in several aspects, but the issue of how they are related to each other has not been clearly clarified. Here, we show that liver-resident NK cells and mucosal ILC1s have different phenotypes, as evidenced by distinct expression patterns of homing-associated molecules. Moreover, mucosal ILC1s exhibit tissue residency akin to liver-resident NK cells. Importantly, liver-resident NK cells express relative high levels of cytotoxic effector molecules, which are poorly expressed by mucosal ILC1s, and exhibit stronger cytotoxic activity compared with mucosal ILC1s. These results demonstrate differential phenotypic and functional characteristics of liver-resident NK cells and mucosal ILC1s, shedding new light on the diversity of ILC family. PMID- 26422993 TI - Mucosal signaling in the bladder. AB - The bladder mucosa is comprised of the multilayered urothelium, lamina propria (LP), microvasculature, and smooth muscle fibers (muscularis mucosae). The muscularis mucosae is not always present in the mucosa, and its presence is related to the thickness of the LP. Since there are no mucus secreting cells, "mucosa" is an imprecise term. Nerve fibers are present in the LP of the mucosa. Efferent nerves mediate mucosal contractions which can be elicited by electrical field stimulation (EFS) and various agonists. The source of mucosal contractility is unknown, but may arise from the muscularis mucosae or myofibroblasts. EFS also increases frequency of mucosal venule contractions. Thus, efferent neural activity has multiple effects on the mucosa. Afferent activity has been measured when the mucosa is stimulated by mechanical and stretch stimuli from the luminal side. Nerve fibers have been shown to penetrate into the urothelium, allowing urothelial cells to interact with nerves. Myofibroblasts are specialized cells within the LP that generate spontaneous electrical activity which then can modulate both afferent and efferent neural activities. Thus mucosal signaling is defined as interactions between bladder autonomic nerves with non-neuronal cells within the mucosa. Mucosal signaling is likely to be involved in clinical functional hypersensory bladder disorders (e.g. overactive bladder, urgency, urgency incontinence, bladder pain syndrome) in which mechanisms are poorly understood despite high prevalence of these conditions. Targeting aberrant mucosal signaling could represent a new approach in treating these disorders. PMID- 26422994 TI - Indiana HIV outbreak should inspire long-term changes. PMID- 26422996 TI - How to motivate hard-to-reach men to accept circumcision. PMID- 26422997 TI - Psychological therapy to improve HIV care and reduce stigma. PMID- 26422998 TI - The link between modelling and doing. PMID- 26422999 TI - ART coverage in Rwanda: successes and remaining challenges. PMID- 26423000 TI - Definitions of implementation science in HIV/AIDS. PMID- 26423001 TI - Group support psychotherapy for depression treatment in people with HIV/AIDS in northern Uganda: a single-centre randomised controlled trial. AB - BACKGROUND: Group support psychotherapy (GSP) is a culturally sensitive intervention that aims to treat depression by enhancing social support, teaching coping skills, and income-generating skills. We compared GSP with group HIV education (GHE) for treatment of depression in people with HIV in Uganda. METHODS: In this open-label randomised controlled trial, we included men and women with HIV, aged 19 years or older, who met the Mini International Neuropsychiatric Interview criteria for major depression from an urban HIV care centre in Kitgum district, northern Uganda. Participants were randomly assigned to receive eight weekly sessions of either GSP or GHE. Randomisation was achieved by urn (men and women separately picked a paper containing the intervention allocation from a basket; ratio 1:1), and the intervention sessions were given to gender-specific groups. Participants were followed up immediately after the intervention and 6 months after the end of treatment. The primary outcomes were change in depressive symptom scores (measured with the Self-Reporting Questionnaire) and in function scores (measured with a locally developed method), analysed by intention to treat using cluster-adjusted t tests and permutation tests. This trial is registered with The Pan African Clinical Trials Registry, number PACTR201402000742370. FINDINGS: Between Jan 6, and Jan 20, 2014, we assessed 150 individuals, of whom 109 were randomly assigned to receive eight weekly sessions of either GSP (n=57) or GHE (n=52). Change in mean depression scores immediately after intervention did not differ between groups (mean difference -0.19, 95% CI -1.77 to 1.39, p=0.78). Mean function scores did not differ between groups either (0.24, -0.41 to 0.88; p=0.41). At 6 months after end of treatment, participants in the GSP group had lower mean depression scores than did those in the GHE group (-2.50, -3.98 to 1.02, p value=0.005), and higher function scores (0.74, -0.17 to 1.65, p=0.09) than did participants in the GHE group. No adverse events were reported. INTERPRETATION: The benefits of existing HIV educational interventions in HIV care services could be improved by the addition of GSP content. Potential benefits of the integration of GSP into existing HIV interventions, such as adherence counselling or group HIV educational programmes, should be addressed in future studies. FUNDING: Grand Challenges Canada. PMID- 26423002 TI - Scaling up of HIV treatment for men who have sex with men in Bangkok: a modelling and costing study. AB - BACKGROUND: Despite the high prevalence of HIV in men who have sex with men (MSM) in Bangkok, little investment in HIV prevention for MSM has been made. HIV testing and treatment coverage remains low. Through a pragmatic programme planning approach, we assess possible service linkage and provision of HIV testing and antiretroviral treatment (ART) to MSM in Bangkok, and the most cost effective scale-up strategy. METHODS: We obtained epidemiological and service capacity data from the Thai National Health Security Office database for 2011. We surveyed 13 representative medical facilities for detailed operational costs of HIV-related services for sexually active MSM (defined as having sex with men in the past 12 months) in metropolitan Bangkok. We estimated the costs of various ART scale-up scenarios, accounting for geographical accessibility across Bangkok. We used an HIV transmission population-based model to assess the cost effectiveness of the scenarios. FINDINGS: For present HIV testing (23% [95% CI 17 36] of MSM at high risk in 2011) and ART provision (20% of treatment-eligible MSM at high risk on ART in 2011) to be sustained, a US$73.8 million ($51.0 million to $97.0 million) investment during the next decade would be needed, which would link an extra 43,000 (27,900-58,000) MSM at high risk to HIV testing and 5100 (3500-6700) to ART, achieving an ART coverage of 44% for MSM at high risk in 2022. An additional $55.3 million investment would link an extra 46,700 (30,300 63,200) MSM to HIV testing and 12,600 (8800-16,600) to ART, achieving universal ART coverage of this population by 2022. This increased investment is achievable within present infrastructure capacity. Consequently, an estimated 5100 (3600 6700) HIV-related deaths and 3700 (2600-4900) new infections could be averted in MSM by 2022, corresponding to a 53% reduction in deaths and a 35% reduction in infections from 2012 levels. The expansion would cost an estimated $10,809 (9071 13,274) for each HIV-related death, $14,783 (12,389-17,960) per new infection averted, and $351 (290-424) per disability-adjusted life-year averted. INTERPRETATION: Spare capacity in Bangkok's medical facilities can be used to expand ART access for MSM with large epidemiological benefits. The expansion needs increased funding directed to MSM services, but given the epidemiological trends, is probably cost effective. Our modelling approach and outcomes are likely to be applicable to other settings. FUNDING: World Bank Group and Australian National Health and Medical Research Council. PMID- 26423003 TI - HIV care continuum in Rwanda: a cross-sectional analysis of the national programme. AB - BACKGROUND: Rwanda has made remarkable progress towards HIV care programme with strong national monitoring and surveillance. Knowledge about the HIV care continuum model can help to improve outcomes in patients. We aimed to quantify engagement, mortality, and loss to follow-up of patients along the HIV care continuum in Rwanda in 2013. METHODS: We collated data for individuals with HIV who participated in the national HIV care programme in Rwanda and calculated the numbers of individuals or proportions of the population at each stage and the transition probabilities between stages of the continuum. We calculated factors associated with mortality and loss to follow-up by fitting Cox proportional hazards regression models, one for the stage of care before antiretroviral therapy (ART) initiation and another for stage of care during ART. FINDINGS: An estimated 204,899 individuals were HIV-positive in Rwanda in 2013. Among these individuals, 176,174 (86%) were in pre-ART or in ART stages and 129,405 (63%) had initiated ART by the end of 2013. 82.1% (95% CI 80.7-83.4) of patients with viral load measurements (n=3066) were virally suppressed (translating to 106,371 individuals or 52% of HIV-positive individuals). Mortality was 0.6% (304 patients) in the pre-ART stage and 1.0% (1255 patients) in the ART stage; 2247 (3.9%) patients were lost to follow-up in pre-ART stage and 2847 (2.2%) lost in ART stage. Risk factors for mortality among patients in both pre-ART and ART stages included older age, CD4 cell count at initiation, and male sex. Risk factors for loss to follow-up among patients at both pre-ART and ART stages included younger age (age 10-29 year) and male sex. INTERPRETATION: The HIV care continuum is a multitrajectory pathway in which patients have many opportunities to leave and re-engage in care. Knowledge about the points at which individuals are most likely to leave care could improve large-scale delivery of HIV programmes. FUNDING: The Bill & Melinda Gates Foundation. PMID- 26423005 TI - Protein Transfer Free Energy Obeys Entropy-Enthalpy Compensation. AB - We have found significant entropy-enthalpy compensation for the transfer of a diverse set of two-state folding proteins from water into water containing a diverse set of cosolutes, including osmolytes, denaturants, and crowders. In extracting thermodynamic parameters from experimental data, we show the potential importance of accounting for the cosolute concentration-dependence of the heat capacity change upon unfolding, as well as the potential importance of the temperature-dependence of the heat capacity change upon unfolding. We introduce a new Monte Carlo method to estimate the experimental uncertainty in the thermodynamic data and use this to show by bootstrapping methods that entropy enthalpy compensation is statistically significant, in spite of large, correlated scatter in the data. We show that plotting the data at the transition midpoint provides the most accurate experimental values by avoiding extrapolation errors due to uncertainty in the heat capacity, and that this representation exhibits the strongest evidence of compensation. Entropy-enthalpy compensation is still significant at lab temperature however. We also find that compensation is still significant when considering variations due to heat capacity models, as well as typical measurement discrepancies lab-to-lab when such data is available. Extracting transfer entropy and enthalpy along with their uncertainties can provide a valuable consistency check between experimental data and simulation models, which may involve tests of simulated unfolded ensembles and/or models of the transfer free energy; we include specific applications to cold shock protein and protein L. PMID- 26423006 TI - Comparison of proteome typing and serotyping of Streptococcus parauberis isolates from olive flounder (Paralichthys olivaceus). AB - The olive flounder (Paralichthys olivaceus) is a cultivated marine species that is economically important in Korea and Japan. Several bacterial pathogens have caused severe mortalities in farmed olive flounder, especially Streptococcus parauberis. We collected 145 S. parauberis isolates from diseased olive flounders from 2003 to 2008 in Jeju Island, South Korea and characterized them by Matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI TOF MS) and by serology. The serological analysis divided the isolates into serotype I (62.1%) and serotype II (36.6%) and the proteome analysis divided the isolates into cluster 1 (43.4%) and cluster 2 (56.6%). All cluster 1 isolates had serotype I, but cluster 2 consisted of serotype I (32.9%), serotype II (64.6%), and others (2.5%). Further detailed analysis of the mass spectra led to identification of several specific m/z peaks that enabled discrimination between cluster 1 and 2 and between serotype I and II within cluster 2. Our results suggest that MALDI TOF MS analysis has potential as an alternative method for the rapid and reliable identification of the fish pathogen S. parauberis. PMID- 26423004 TI - The structural basis of Miranda-mediated Staufen localization during Drosophila neuroblast asymmetric division. AB - During the asymmetric division of Drosophila neuroblasts (NBs), the scaffold Miranda (Mira) coordinates the subcellular distribution of cell-fate determinants including Staufen (Stau) and segregates them into the ganglion mother cells (GMCs). Here we show the fifth double-stranded RNA (dsRNA)-binding domain (dsRBD5) of Stau is necessary and sufficient for binding to a coiled-coil region of Mira cargo-binding domain (CBD). The crystal structure of Mira514-595/Stau dsRBD5 complex illustrates that Mira forms an elongated parallel coiled-coil dimer, and two dsRBD5 symmetrically bind to the Mira dimer through their exposed beta-sheet faces, revealing a previously unrecognized protein interaction mode for dsRBDs. We further demonstrate that the Mira-Stau dsRBD5 interaction is responsible for the asymmetric localization of Stau during Drosophila NB asymmetric divisions. Finally, we find the CBD-mediated dimer assembly is likely a common requirement for Mira to recognize and translocate other cargos including brain tumour (Brat). PMID- 26423009 TI - Animal Obesity - causes, consequences and comparative aspects: meeting abstracts. PMID- 26423007 TI - Design and characterization of calcium phosphate ceramic scaffolds for bone tissue engineering. AB - OBJECTIVES: Our goal is to review design strategies for the fabrication of calcium phosphate ceramic scaffolds (CPS), in light of their transient role in bone tissue engineering and associated requirements for effective bone regeneration. METHODS: We examine the various design options available to meet mechanical and biological requirements of CPS and later focus on the importance of proper characterization of CPS in terms of architecture, mechanical properties and time-sensitive properties such as biodegradability. Finally, relationships between in vitro versus in vivo testing are addressed, with an attempt to highlight reliable performance predictors. RESULTS: A combinatory design strategy should be used with CPS, taking into consideration 3D architecture, adequate surface chemistry and topography, all of which are needed to promote bone formation. CPS represent the media of choice for delivery of osteogenic factors and anti-infectives. Non-osteoblast mediated mineral deposition can confound in vitro osteogenesis testing of CPS and therefore the expression of a variety of proteins or genes including collagen type I, bone sialoprotein and osteocalcin should be confirmed in addition to increased mineral content. CONCLUSIONS: CPS are a superior scaffold material for bone regeneration because they actively promote osteogenesis. Biodegradability of CPS via calcium and phosphate release represents a unique asset. Structural control of CPS at the macro, micro and nanoscale and their combination with cells and polymeric materials is likely to lead to significant developments in bone tissue engineering. PMID- 26423008 TI - Secondary caries and microleakage. AB - OBJECTIVES: To critically appraise experimental ex vivo research that has focused on secondary caries, and to offer possible explanations for the seemingly poor correlation to clinical observations. METHODS: The literature relating to the etiopathogenesis or prevention of secondary caries gained from experimental ex vivo research was reviewed, with particular emphasis on microleakage and artificial caries-like lesions. RESULTS: It is doubtful whether a caries wall lesion can exist independently of an outer enamel caries lesion. Microleakage experiments apparently continue to emerge regardless of multiple reviews questioning the reliability and validity of the method. Several of the approaches used to generate artificial caries-like lesions are very aggressive. Remarkably little discussion has evolved about how these aggressive approaches create microenvironments that do not occur in reality. Corrosion- and biodegradation products may influence the biofilm qualitatively and quantitatively and it is difficult to replicate these variables in any ex vivo environment. Clinical data sampling method, patient demography as well as study methodology influences the incidence and prevalence estimates of secondary caries. Clinical results based on clinical work in settings where cost per unit time is of nominal concern do not provide any indications on how the restorative material will perform when placed by the average dentists in the mouths of their spectrum of patients during a busy workday. SIGNIFICANCE AND RECOMMENDATIONS: The term "wall lesion" including its variants is ill defined, has been, and is still being used indiscriminately. Stakeholders should avoid using this ambiguous label due to its connotation to an entity that does not exist per se. PMID- 26423010 TI - Ionic Driven Embedment of Hyaluronic Acid Coated Liposomes in Polyelectrolyte Multilayer Films for Local Therapeutic Delivery. AB - The ability to control the spatial distribution and temporal release of a therapeutic remains a central challenge for biomedical research. Here, we report the development and optimization of a novel substrate mediated therapeutic delivery system comprising of hyaluronic acid covalently functionalized liposomes (HALNPs) embedded into polyelectrolyte multilayer (PEM) platform via ionic stabilization. The PEM platform was constructed from sequential deposition of Poly-L-Lysine (PLL) and Poly(Sodium styrene sulfonate) (SPS) "(PLL/SPS)4.5" followed by adsorption of anionic HALNPs. An adsorption affinity assay and saturation curve illustrated the preferential HALNP deposition density for precise therapeutic loading. (PLL/SPS)2.5 capping layer on top of the deposited HALNP monolayer further facilitated complete nanoparticle immobilization, cell adhesion, and provided nanoparticle confinement for controlled linear release profiles of the nanocarrier and encapsulated cargo. To our knowledge, this is the first study to demonstrate the successful embedment of a translatable lipid based nanocarrier into a substrate that allows for temporal and spatial release of both hydrophobic and hydrophilic drugs. Specifically, we have utilized our platform to deliver chemotherapeutic drug Doxorubicin from PEM confined HALNPs. Overall, we believe the development of our HALNP embedded PEM system is significant and will catalyze the usage of substrate mediated delivery platforms in biomedical applications. PMID- 26423012 TI - Elucidating COPD pathogenesis by large-scale genetic analyses. PMID- 26423013 TI - Monitoring the health of the work environment with a daily assessment tool: the REAL - Relative Environment Assessment Lens - indicator. AB - BACKGROUND: Evidence shows that the health of the work environment impacts staff satisfaction, interdisciplinary communication, and patient outcomes. Utilising the American Association of Critical-Care Nurses' Healthy Work Environment standards, we developed a daily assessment tool. METHODS: The Relative Environment Assessment Lens (REAL) Indicator was developed using a consensus based method to evaluate the health of the work environment and to identify opportunities for improvement from the front-line staff. A visual scale using images that resemble emoticons was linked with a written description of feelings about their work environment that day, with the highest number corresponding to the most positive experience. Face validity was established by seeking staff feedback and goals were set. RESULTS: Over 10 months, results from the REAL Indicator in the cardiac catheterisation laboratory indicated an overall good work environment. The goal of 80% of the respondents reporting their work environment to be "Great", "Good", or "Satisfactory" was met each month. During the same time frame, this goal was met four times in the cardiovascular operating room. On average, 72.7% of cardiovascular operating room respondents reported their work environment to be "Satisfactory" or better. CONCLUSION: The REAL Indicator has become a valuable tool in assessing the specific issues of the clinical area and identifying opportunities for improvement. Given the feasibility of and positive response to this tool in the cardiac catheterisation laboratory, it has been adopted in other patient-care areas where staff and leaders believe that they need to understand the health of the environment in a more specific and frequent time frame. PMID- 26423016 TI - Corrigendum: Lattice Distortion in In3SbTe2 Phase Change Material with Substitutional Bi. PMID- 26423015 TI - Optimizing plasmonic nanoantennas via coordinated multiple coupling. AB - Plasmonic nanoantennas, which can efficiently convert light from free space into sub-wavelength scale with the local field enhancement, are fundamental building blocks for nanophotonic systems. Predominant design methods, which exploit a single type of near- or far-field coupling in pairs or arrays of plasmonic nanostructures, have limited the tunability of spectral response and the local field enhancement. To overcome this limit, we are developing a general strategy towards exploiting the coordinated effects of multiple coupling. Using Au bowtie nanoantenna arrays with metal-insulator-metal configuration as examples, we numerically demonstrate that coordinated design and implementation of various optical coupling effects leads to both the increased tunability in the spectral response and the significantly enhanced electromagnetic field. Furthermore, we design and analyze a refractive index sensor with an ultra-high figure-of-merit (254), a high signal-to-noise ratio and a wide working range of refractive indices, and a narrow-band near-infrared plasmonic absorber with 100% absorption efficiency, high quality factor of up to 114 and a wide range of tunable wavelength from 800 nm to 1,500 nm. The plasmonic nanoantennas that exploit coordinated multiple coupling will benefit a broad range of applications, including label-free bio-chemical detection, reflective filter, optical trapping, hot-electron generation, and heat-assisted magnetic recording. PMID- 26423014 TI - High-dose esomeprazole and amoxicillin dual therapy for first-line Helicobacter pylori eradication: a proof of concept study. AB - BACKGROUND: The prevalence of resistance to clarithromycin and metronidazole has considerably increased, with a corresponding decrease in the eradication rate for Helicobacter pylori (H. pylori) infection. Primary resistance to amoxicillin is extremely low, and esomeprazole was found to exert a noteworthy antimicrobial activity in vitro against H. pylori. A dual therapy with high-dose of esomeprazole coupled with high-dose amoxicillin might be therefore an ideal first line treatment for H. pylori eradication. We aimed to assess the efficacy of a first-line 10-day, high-dose dual therapy consisting of amoxicillin and esomeprazole to eradicate H. pylori infection. METHODS: Consecutive naive H. pylori-infected patients, who underwent an upper endoscopy in 4 Italian hospitals due to dyspeptic symptoms and found to be infected at routine histological assessment, were invited to participate. Patients enrolled received a 10-day, high-dose dual therapy comprising esomeprazole (40 mg t.i.d) and amoxicillin (1 g t.i.d.). At least 4 weeks after the end of the treatment a (13)C-urea breath test was performed to evaluate the eradication. RESULTS: A total of 56 patients agreed to participate in the study and were all followed-up. The overall eradication was 87.5% (95% CI=78.8*96.2), without a statistically significant difference among centres. Overall, 5 (8.9%; 1.5*16.4%) patients complained of side-effects. CONCLUSIONS: The 10-day, high-dose dual therapy with esomeprazole and amoxicillin might be an effective and safe first-line regimen. The efficacy of a longer 14 day regimen should be tested. PMID- 26423017 TI - Fractional flow reserve-guided paclitaxel-coated balloon treatment for de novo coronary lesions. AB - OBJECTIVES: To assess the safety and efficacy of fractional flow reserve (FFR) guided paclitaxel-coated balloon (PCB) treatment for de novo coronary artery lesions. BACKGROUND: There is limited data on PCB treatment for de novo lesions especially of major epicardial coronary arteries. METHODS: Sixty-six patients with 67 de novo lesions who underwent successful plain old balloon angioplasty (POBA) were included. If POBA-FFR was favorable (>= 0.85), PCB was applied and if POBA-FFR was <0.85, stent implantation was preferred over PCB. RESULTS: Forty five lesions were treated with PCB (67.2%) and 22 lesions with stents (32.8%). Dual antiplatelet therapy duration was 6 weeks. Late luminal loss with PCB was significantly less than stent (0.05 +/- 0.27 mm vs. 0.40 +/- 0.54 mm, P = 0.022). The baseline FFR of target lesions was 0.69 +/- 0.16 in PCB and 0.60 +/- 0.11 in stent group (P = 0.015), however, the FFR at 9 months was not different between groups (0.85 +/- 0.08 in PCB vs. 0.85 +/- 0.05 in stent group, P = 0.973). At 1 year, one myocardial infarction and one target lesion revascularization related to in-stent restenosis were detected, both in the stent group. CONCLUSION: POBA FFR-guided PCB treatment is safe and effective for de novo coronary lesions with good anatomical and physiological patency at mid-term follow-up. (c) 2015 Wiley Periodicals, Inc. PMID- 26423011 TI - Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank. AB - BACKGROUND: Understanding the genetic basis of airflow obstruction and smoking behaviour is key to determining the pathophysiology of chronic obstructive pulmonary disease (COPD). We used UK Biobank data to study the genetic causes of smoking behaviour and lung health. METHODS: We sampled individuals of European ancestry from UK Biobank, from the middle and extremes of the forced expiratory volume in 1 s (FEV1) distribution among heavy smokers (mean 35 pack-years) and never smokers. We developed a custom array for UK Biobank to provide optimum genome-wide coverage of common and low-frequency variants, dense coverage of genomic regions already implicated in lung health and disease, and to assay rare coding variants relevant to the UK population. We investigated whether there were shared genetic causes between different phenotypes defined by extremes of FEV1. We also looked for novel variants associated with extremes of FEV1 and smoking behaviour and assessed regions of the genome that had already shown evidence for a role in lung health and disease. We set genome-wide significance at p<5 * 10( 8). FINDINGS: UK Biobank participants were recruited from March 15, 2006, to July 7, 2010. Sample selection for the UK BiLEVE study started on Nov 22, 2012, and was completed on Dec 20, 2012. We selected 50,008 unique samples: 10,002 individuals with low FEV1, 10,000 with average FEV1, and 5002 with high FEV1 from each of the heavy smoker and never smoker groups. We noted a substantial sharing of genetic causes of low FEV1 between heavy smokers and never smokers (p=2.29 * 10(-16)) and between individuals with and without doctor-diagnosed asthma (p=6.06 * 10(-11)). We discovered six novel genome-wide significant signals of association with extremes of FEV1, including signals at four novel loci (KANSL1, TSEN54, TET2, and RBM19/TBX5) and independent signals at two previously reported loci (NPNT and HLA-DQB1/HLA-DQA2). These variants also showed association with COPD, including in individuals with no history of smoking. The number of copies of a 150 kb region containing the 5' end of KANSL1, a gene that is important for epigenetic gene regulation, was associated with extremes of FEV1. We also discovered five new genome-wide significant signals for smoking behaviour, including a variant in NCAM1 (chromosome 11) and a variant on chromosome 2 (between TEX41 and PABPC1P2) that has a trans effect on expression of NCAM1 in brain tissue. INTERPRETATION: By sampling from the extremes of the lung function distribution in UK Biobank, we identified novel genetic causes of lung function and smoking behaviour. These results provide new insight into the specific mechanisms underlying airflow obstruction, COPD, and tobacco addiction, and show substantial shared genetic architecture underlying airflow obstruction across individuals, irrespective of smoking behaviour and other airway disease. FUNDING: Medical Research Council. PMID- 26423018 TI - Chronic Phase Intracranial Hemorrhage Caused by Ruptured Pseudoaneurysm Induced by Carmustine Wafer Implantation for Insulo-opercular Anaplastic Astrocytoma: A Case Report. AB - Carmustine wafers improve the survival of patients with high-grade gliomas, but several adverse events have been reported. A 42-year-old man with left Insulo opercular anaplastic astrocytoma developed a massive intra-cavital hematoma with subarachnoid hemorrhage caused by ruptured pseudoaneurysm of the left middle cerebral artery (MCA) adjacent to the site of carmustine wafers implanted 6 months previously. Intraoperative finding demonstrated a dissection of the insular portion of the MCA, and pathological examination identified the resected pseudoaneurysm. This case demonstrates that carmustine wafers can cause changes in local vessels. Therefore, implantation of carmustine wafers near to important vessels passing close to the resection cavity should be considered with great caution. PMID- 26423019 TI - Platelet density per monocyte predicts adverse events in patients after percutaneous coronary intervention. AB - Monocyte recruitment to damaged endothelium is enhanced by platelet binding to monocytes and contributes to vascular repair. Therefore, we studied whether the number of platelets per monocyte affects the recurrence of adverse events in patients after percutaneous coronary intervention (PCI). Platelet-monocytes complexes with high and low median fluorescence intensities (MFI) of the platelet marker CD42b were isolated using cell sorting. Microscopic analysis revealed that a high platelet marker MFI on monocytes corresponded with a high platelet density per monocyte while a low platelet marker MFI corresponded with a low platelet density per monocyte (3.4 +/- 0.7 vs 1.4 +/- 0.1 platelets per monocyte, P=0.01). Using real-time video microscopy, we observed increased recruitment of high platelet density monocytes to endothelial cells as compared with low platelet density monocytes (P=0.01). Next, we classified PCI scheduled patients (N=263) into groups with high, medium and low platelet densities per monocyte and assessed the recurrence of adverse events. After multivariate adjustment for potential confounders, we observed a 2.5-fold reduction in the recurrence of adverse events in patients with a high platelet density per monocyte as compared with a low platelet density per monocyte [hazard ratio=0.4 (95% confidence interval, 0.2-0.8), P=0.01]. We show that a high platelet density per monocyte increases monocyte recruitment to endothelial cells and predicts a reduction in the recurrence of adverse events in patients after PCI. These findings may imply that a high platelet density per monocyte protects against recurrence of adverse events. PMID- 26423020 TI - Approach for classification and taxonomy within family Rickettsiaceae based on the Formal Order Analysis. AB - Genome sequences of 36 Rickettsia and Orientia were analyzed using Formal Order Analysis (FOA). This approach takes into account arrangement of nucleotides in each sequence. A numerical characteristic, the average distance (remoteness) - "g" was used to compare of genomes. Our results corroborated previous separation of three groups within the genus Rickettsia, including typhus group, classic spotted fever group, and the ancestral group and Orientia as a separate genus. Rickettsia felis URRWXCal2 and R. akari Hartford were not in the same group based on FOA, therefore designation of a so-called transitional Rickettsia group could not be confirmed with this approach. PMID- 26423021 TI - Permissivity of insect cells to Waddlia chondrophila, Estrella lausannensis and Parachlamydia acanthamoebae. AB - Recent large scale studies questioning the presence of intracellular bacteria of the Chlamydiales order in ticks and fleas revealed that arthropods, similarly to mammals, reptiles, birds or fishes, can be colonized by Chlamydia-related bacteria with a predominant representation of the Rhabdochlamydiaceae and Parachlamydiaceae families. We thus investigated the permissivity of two insect cell lines towards Waddlia chondrophila, Estrella lausannensis and Parachlamydia acanthamoebae, three bacteria representative of three distinct families within the Chlamydiales order, all documented in ticks and/or in other arthropods. We demonstrated that W. chondrophila and E. lausannensis are able to very efficiently multiply in these insect cell lines. E. lausannensis however induced a rapid cytopathic effect, which somehow restricted its replication. P. acanthamoebae was not able to grow in these cell lines even if inclusions containing a few replicating bacteria could occasionally be observed. PMID- 26423022 TI - Rates of inbreeding and genetic adaptation for populations managed as herds in zoos with a rotational mating system or with optimized contribution of parents. AB - This study compares two genetic management scenarios for species kept in herds, such as deer. The simulations were designed so that their results can be extended to a wide range of zoo populations. In the first scenario, the simulated populations of size 3 * 20, 6 * 40 or 20 * 60 (herds * animals in herd) were managed with a rotational mating (RM) scheme in which 10%, 20% or 50% of males were selected for breeding and moved between herds in a circular fashion. The second scenario was based on optimal contribution theory (OC). OC requires an accurate pedigree to calculate kinship; males were selected and assigned numbers of offspring to minimize kinship in the next generation. RM was efficient in restriction of inbreeding and produced results comparable with OC. However, RM can result in genetic adaptation of the population to the zoo environment, in particular when 20% or less males are selected for rotation and selection of animals is not random. Lowest rates of inbreeding were obtained by combining OC with rotation of males as in the RM scheme. RM is easy to implement in practice and does not require pedigree data. When full pedigree is available, OC management is preferable. PMID- 26423023 TI - The effect of sagittal rotation of the glenoid on axial glenoid width and glenoid version in computed tomography scan imaging. AB - BACKGROUND: Computed tomography (CT) scans of the shoulder are often not well aligned to the axis of the scapula and glenoid. The purpose of this paper was to determine the effect of sagittal rotation of the glenoid on axial measurements of anterior-posterior (AP) glenoid width and glenoid version attained by standard CT scan. In addition, we sought to define the angle of rotation required to correct the CT scan to optimal positioning. METHODS: A total of 30 CT scans of the shoulder were reformatted using OsiriX software multiplanar reconstruction. The uncorrected (UNCORR) and corrected (CORR) CT scans were compared for measurements of both (1) axial AP glenoid width and (2) glenoid version at 5 standardized axial cuts. RESULTS: The mean difference in glenoid version was 2.6% (2 degrees +/- 0.1 degrees ; P = .0222) and the mean difference in AP glenoid width was 5.2% (1.2 +/- 0.42 mm; P = .0026) in comparing the CORR and UNCORR scans. The mean angle of correction required to align the sagittal plane was 20.1 degrees of rotation (range, 9 degrees -39 degrees ; standard error of mean, 1.2 degrees ). CONCLUSION: These findings demonstrate that UNCORR CT scans of the glenohumeral joint do not correct for the sagittal rotation of the glenoid, and this affects the characteristics of the axial images. Failure to align the sagittal image to the 12-o'clock to 6-o'clock axis results in measurement error in both glenoid version and AP glenoid width. Use of UNCORR CT images may have notable implications for decision-making and surgical treatment. PMID- 26423024 TI - Multiple effect of social influence on cooperation in interdependent network games. AB - The social influence exists widely in the human society, where individual decision-making process (from congressional election to electronic commerce) may be affected by the attitude and behavior of others belonging to different social networks. Here, we couple the snowdrift (SD) game and the prisoner's dilemma (PD) game on two interdependent networks, where strategies in both games are associated by social influence to mimick the majority rule. More accurately, individuals' strategies updating refers to social learning (based on payoff difference) and above-mentioned social influence (related with environment of interdependent group), which is controlled by social influence strength s. Setting s = 0 decouples the networks and returns the traditional network game; while its increase involves the interactions between networks. By means of numerous Monte Carlo simulations, we find that such a mechanism brings multiple influence to the evolution of cooperation. Small s leads to unequal cooperation level in both games, because social learning is still the main updating rule for most players. Though intermediate and large s guarantees the synchronized evolution of strategy pairs, cooperation finally dies out and reaches a completely dominance in both cases. Interestingly, these observations are attributed to the expansion of cooperation clusters. Our work may provide a new understanding to the emergence of cooperation in intercorrelated social systems. PMID- 26423025 TI - Management of gag reflex for patients undergoing dental treatment. AB - BACKGROUND: Gag reflex is an involuntary defence mechanism to protect the pharynx and throat from foreign objects. Gagging is a common problem encountered during dental treatment, which makes therapeutic procedures distressing and often difficult or even impossible to perform. Various interventions can be used to control the gag reflex; for example, anti-nausea medicines, sedatives, local and general anaesthetics, herbal remedies, behavioural therapies, acupressure, acupuncture, and prosthetic devices. OBJECTIVES: To assess the effects of pharmacological and non-pharmacological interventions for the management of gagging in people undergoing dental treatment. SEARCH METHODS: We searched the Cochrane Oral Health Group's Trials Register (to 7 April 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, Issue 4, 2014), MEDLINE via OVID (1946 to 7 April 2015), EMBASE via OVID (1980 to 7 April 2015), CINAHL via EBSCO (1980 to 7 April 2015), AMED via OVID (1985 to 7 April 2015), IADR Conference Proceedings (online, 2001 to 7 April 2015), clinical trial registries and Google search engine. SELECTION CRITERIA: We included randomised controlled trials (RCTs), involving people who were given a pharmacological or non-pharmacological intervention to manage gagging that interfered with dental treatment. We excluded quasi-RCTs and cross-over trials. We excluded trials with participants who had central or peripheral nervous system disorders; who had oral lesions or were on systemic medications that might affect the gag sensation; or had undergone surgery which might alter anatomy permanently. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials. Three review authors independently extracted data and assessed risk of bias in the included trials. We estimated risk ratios (RRs) for dichotomous data, and mean differences (MDs) for continuous data, with 95% confidence intervals (CIs). We assessed the overall quality of the evidence using the GRADE approach. MAIN RESULTS: One RCT, a trial on acupuncture at P6 (Pericardium 6 - situated on the anterior surface of wrist), met the inclusion criteria. It included 33 adults who reported previous nausea during dental procedures that hindered or prevented dental treatment from being carried out properly. The trial was at unclear risk of bias. The outcome reported in this trial was reduction in gagging. We obtained data for our primary outcome (successful completion of dental procedure) by contacting the trial author.Successful completion of dental procedure reported by the assessor showed no difference in acupuncture at P6 group compared to sham acupuncture (RR 1.65, 95% CI 0.59 to 4.57). Reduction in gagging as reported by the assessor showed no difference between acupuncture at P6 and sham acupuncture at any stage (stage 1: MD 0.40, 95% CI -0.12 to 0.93; stage 2: MD 0.49, 95 % CI -0.26 to 1.24; stage 3: MD 0.67, 95% CI -0.18 to 1.53). Reduction in gagging as reported by the participant also showed no difference between acupuncture at P6 and sham acupuncture (MD 0.86, 95% CI -1.13 to 2.85). The quality of the evidence for all outcomes was very low.No noteworthy adverse effects were reported.We did not find trials evaluating any other interventions used to manage gagging in people undergoing dental treatment. AUTHORS' CONCLUSIONS: We found very low quality evidence from a single trial that was insufficient to conclude if there is any benefit of acupuncture in reducing gagging and allowing successful completion of dental procedures. We did not find any evidence on any other interventions for managing the gag reflex during dental treatment. More well-designed and well reported trials evaluating different interventions are needed. PMID- 26423026 TI - Natural small molecule FMHM inhibits lipopolysaccharide-induced inflammatory response by promoting TRAF6 degradation via K48-linked polyubiquitination. AB - TNF receptor-associated factor 6 (TRAF6) is a key hub protein involved in Toll like receptor-dependent inflammatory signaling pathway, and it recruits additional proteins to form multiprotein complexes capable of activating downstream NF-kappaB inflammatory signaling pathway. Ubiquitin-proteasome system (UPS) plays a crucial role in various protein degradations, such as TRAF6, leading to inhibitory effects on inflammatory response and immunologic function. However, whether ubiquitination-dependent TRAF6 degradation can be used as a novel anti-inflammatory drug target still remains to be explored. FMHM, a bioactive natural small molecule compound extracted from Chinese herbal medicine Radix Polygalae, suppressed acute inflammatory response by targeting ubiquitin protein and inducing UPS-dependent TRAF6 degradation mechanism. It was found that FMHM targeted ubiquitin protein via Lys48 site directly induced Lys48 residue linked polyubiquitination. This promoted Lys48 residue-linked polyubiquitin chain formation on TRAF6, resulting in increased TRAF6 degradation via UPS and inactivation of downstream NF-kappaB inflammatory pathway. Consequently, FMHM down-regulated inflammatory mediator levels in circulation, protected multiple organs against inflammatory injury in vivo, and prolong the survival of endotoxemia mouse models. Therefore, FMHM can serve as a novel lead compound for the development of TRAF6 scavenging agent via ubiquitination-dependent mode, which represents a promising strategy for treating inflammatory diseases. PMID- 26423027 TI - Unusual cause of lower extremity wounds: Cobb syndrome. AB - Cobb syndrome (Cutaneomeningospinal Angiomatosis) is a rare segmental neurocutaneous syndrome associated with metameric cutaneous and spinal cord arteriovenous malformations (AVMs). In this syndrome, capillary malformation or angiokeratoma-like lesions are formed in a dermatomal distribution, with an AVM in the corresponding segment of the spinal cord. The spinal cord lesions can cause neurological disorder and paraplegia, which typically develop during young adulthood. We report a 32-year-old male with the Cobb syndrome associated with lower extremity painful wounds and acute-onset paraplegia due to metameric vascular malformations. PMID- 26423028 TI - The Diarylprolinol Silyl Ethers: Ten Years After. AB - Asymmetric organocatalysis has experienced an incredible development since the beginning of this century. The expansion of the field has led to a large number of efficient types of catalysts. One group, the diarylprolinol silyl ethers, was introduced in 2005 and has been established as one of the most frequently used in aminocatalysis. In this Minireview, we will take a look in the rear-view mirror, ten years after the introduction of the diarylprolinol silyl ethers. We will focus on the perspectives of the different activation modes made available by this catalytic system. Starting with a short introduction to aminocatalysis, we will outline the properties that have made the diarylprolinol silyl ethers a common choice of catalyst. Furthermore, we will describe the major tendencies in the activation and reaction concepts developed with regard to reactivity patterns and combinations with other activation concepts. PMID- 26423030 TI - Self-Running Liquid Metal Drops that Delaminate Metal Films at Record Velocities. AB - This paper describes a new method to spontaneously accelerate droplets of liquid metal (eutectic gallium indium, EGaIn) to extremely fast velocities through a liquid medium and along predefined metallic paths. The droplet wets a thin metal trace (a film ~100 nm thick, ~ 1 mm wide) and generates a force that simultaneously delaminates the trace from the substrate (enhanced by spontaneous electrochemical reactions) while accelerating the droplet along the trace. The formation of a surface oxide on EGaIn prevents it from moving, but the use of an acidic medium or application of a reducing bias to the trace continuously removes the oxide skin to enable motion. The trace ultimately provides a sacrificial pathway for the metal and provides a mm-scale mimic to the templates used to guide molecular motors found in biology (e.g., actin filaments). The liquid metal can accelerate along linear, curved and U-shaped traces as well as uphill on surfaces inclined by 30 degrees. The droplets can accelerate through a viscous medium up to 180 mm/sec which is almost double the highest reported speed for self-running liquid metal droplets. The actuation of microscale objects found in nature (e.g., cells, microorganisms) inspires new mechanisms, such as these, to manipulate small objects. Droplets that are metallic may find additional applications in reconfigurable circuits, optics, heat transfer elements, and transient electronic circuits; the paper demonstrates the latter. PMID- 26423029 TI - Glial activation in the periaqueductal gray promotes descending facilitation of neuropathic pain through the p38 MAPK signaling pathway. AB - The midbrain ventrolateral periaqueductal gray (VL-PAG) is a key component that mediates pain modulation. Although spinal cord glial cells appear to play an important role in chronic pain development, the precise mechanisms involving descending facilitation pathways from the PAG following nerve injury are poorly understood. This study shows that cellular events that occur during glial activation in the VL-PAG may promote descending facilitation from the PAG during neuropathic pain. Chronic constriction nerve injury (CCI) was induced by ligature construction of the sciatic nerve in male Sprague-Dawley rats. Behavioral responses to noxious mechanical (paw withdrawal threshold; PWT) and thermal (paw withdrawal latency; PWL) stimuli were evaluated. After CCI, immunohistochemical and Western blot analysis of microglia and astrocytes in the VL-PAG showed morphological and quantitative changes indicative of activation in microglia and astrocytes. Intra-VL-PAG injection of microglial or astrocytic inhibitors attenuated PWT and PWL at days 7 and 14, respectively, following CCI. We also evaluated the effects of intra-VL-PAG administration of the phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) inhibitor SB 203580 at day 7 after CCI. This treatment abolished microglial activation and produced a significant time-dependent attenuation of PWT and PWL. Western blot analysis showed localized expression of p-p38 in the VL-PAG after CCI. P-p38 was expressed in labeled microglia of the VL-PAG but was not present in astrocytes and neurons on day 7 after CCI. These results demonstrate that CCI-induced neuropathic pain is associated with glial activation in the VL-PAG, which likely participates in descending pain facilitation through the p38 MAPK signaling pathway. PMID- 26423031 TI - Gold-Catalyzed Benzylic Azidation of Phthalans and Isochromans and Subsequent FeCl3-Catalyzed Nucleophilic Substitutions. AB - The benzylic positions of the phthalan and isochroman derivatives (1) as benzene fused cyclic ethers effectively underwent gold-catalyzed direct azidation using trimethylsilylazide (TMSN3) to give the corresponding 1-azidated products (2) possessing the N,O-acetal partial structure. The azido group of the N,O-acetal behaved as a leaving group in the presence of catalytic iron(III) chloride, and 1 aryl or allyl phthalan and isochroman derivatives were obtained by nucleophilic arylation or allylation, respectively. Meanwhile, a double nucleophilic substitution toward the 1-azidated products (2) occurred at the 1-position using indole derivatives as a nucleophile accompanied by elimination of the azido group and subsequent ring opening of the cyclic ether nucleus produced the bisindolylarylmethane derivatives. PMID- 26423032 TI - A Reliable Method for the Separation and Detection of Synthetic Cannabinoids by Supercritical Fluid Chromatography with Mass Spectrometry, and Its Application to Plant Products. AB - A reliable method using supercritical fluid chromatography with mass spectrometry (SFC-MS) was developed for cannabinoids using compressed carbon dioxide (CO2) and methanol as the mobile-phase. The cannabinoids, i.e., cannabicyclohexanol (CCH: cis-isomer), trans-CCH, 5-(1,1-dimethylheptyl)-2-[(1R,3S)-3-hydroxycyclohexyl] phenol (CP-47497), 5-(1,1-dimethylheptyl)-2-[(1R,2R,5R)-5-hydroxy-2-(3 hydroxypropyl)cyclohexyl]-phenol (CP-55940), 3-(1,1'-dimethylheptyl) 6aR,7,10,10aR-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol (HU-210), 2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3 benzenediol (CBD), (1-pentyl-1H-indol-3-yl)-1-naphthalenyl-methanone (JWH-018), (1-butyl-1H-indol-3-yl)-1-naphthalenyl-methanone (JWH-073) and 1-(1-pentyl-1H indol-3-yl)-2-(2-methoxyphenyl)-ethanone (JWH-250), were determined within 12 min using a conventional column (2-EP) for SFC. Furthermore, two optical isomers of CCH and trans-CCH were completely and rapidly separated by a chiral stationary phase column (AMY1). A highly sensitive detection (0.002-3.75 ppb) was also obtained by these methods using 2-EP and AMY1 columns. These methods were applied to the qualitative and quantitative determination of cannabinoids in dried plant products. Although the concentration and species were different in the products, JWH-018, JWH-073 and CCH, including the cis-isomer, trans-isomer and the optical isomers, were detected in the products. Therefore, the proposed SFC-MS method seems to be useful as an alternative method to GC-MS and LC-MS for illegal drugs, such as cannabinoids. PMID- 26423033 TI - Reconstitution of L-Asparaginase in Siliconized Syringes with Shaking and Headspace Air Induces Protein Aggregation. AB - The aim of this study was to characterize protein aggregation during reconstitution of a highly concentrated solution of lyophilized L-asparaginase (L ASP). The effect of the preparation method on L-ASP aggregation using siliconized or non-siliconized syringes and the effect of storage after preparation were evaluated by far-UV circular dichroism spectroscopy, Raman microscopy, flow cytometry, and flow particle image analysis. To investigate the effect of syringe type in combination with shaking and headspace air on L-ASP aggregation, four kinds of L-ASP in 5% glucose solutions were prepared (in the presence or absence of silicon oil and headspace air). Slight differences in L-ASP secondary structure were observed between the siliconized and non-siliconized syringe systems before shaking. Large numbers of sub-visible (0.1-100 um) and submicron (0.1-1 um) particles were formed by preparation with siliconized syringes and the combination of shaking and headspace air. The number of aggregated particles was not decreased with increased storage time. The Raman microscopy, flow cytometry and flow particle image results suggested that L-ASP interacted with silicone oil, which induced aggregation. Nevertheless, sub-visible and submicron particles were also formed with non-siliconized syringes. However, using non-siliconized syringes, the number of aggregated particles decreased with storage. No changes in particle character were observed before or after shaking with headspace air in non-siliconized syringes, indicating that soluble aggregates formed and dissolved with storage. Silicone oil in syringes, in combination with shaking and headspace air, strongly affected the aggregation of lyophilized L-ASP formulations during preparation. PMID- 26423035 TI - Effect of Process Parameters on Formation and Aggregation of Nanoparticles Prepared with a Shirasu Porous Glass Membrane. AB - The objectives of this study were to prepare itraconazole (ITZ) nanoparticles using a Shirasu porous glass (SPG) membrane and to characterize the effects of diverse preparation parameters on the physical stability of nanoparticles. SPG membrane technology was used for the antisolvent precipitation method. The preparation of nanoparticles was carried out over a wide range of continuous phase factors (type of surfactant, surfactant concentration), dispersed-phase factors (solvent type, solvent volume used to dissolve ITZ), and technical factors (pressure, membrane pore size, stirring speed in the continuous phase, temperature). Improved physical stability of nanoparticles was observed when surfactant with a lower molecular weight and higher hydrophilic segment ratio was used. The water miscibility of the solvent also had an effect on the physical stability. N,N-Dimethylacetamide contributed to creating a well-rounded shape and narrow size distribution due to high miscibility. Concentration of the surfactant and solvent volume used for dissolving ITZ were related to instability of nanoparticles, resulting from depletion attraction and Ostwald ripening. In addition to these factors, technical factors changed the environment surrounding ITZ nanoparticles, such as the physicochemical equilibrium between surfactant and ITZ nanoparticles. Therefore, the appropriate continuous-phase factors, dispersed phase factors, and technical factors should be maintained for stabilizing ITZ nanoparticles. PMID- 26423034 TI - Discovery of Novel Selective ERalpha/ERbeta Ligands by Multi-pharmacophore Modeling and Virtual Screening. AB - Estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) regulate different sets of gene expression, and have different ligand responses, which make the estrogen tissue-specific. Thus, the estrogen receptor (ER) subtype selective ligands can improve the target-site selectivity and decrease the off target effect. In order to discover the selective ER subtype ligands with novel scaffolds, in this work three-dimensional (3D) pharmacophore models of the ERalpha ligands (Hypo 1) and the ERbeta ligands (Hypo 2) were established (correlation coefficients were 0.959 and 0.966) and validated (R=0.936 and 0.879; enrichment factors (EFs) at 2% were 16.2 and 8.4; areas under the concentration time curve (AUC) of the receiver operating curve (ROC) were 0.88 and 0.91) using the Discovery Studio 4.0 software package. Hypo 1 and Hypo 2 were then employed for virtual screening and ten hits were found as potential candidate leads. Based on their ERalpha/ERbeta binding affinity results by fluorescence polarization technology, two of these leads, AH-262/34334025 (AH) and AG-670/08803023 (AG) with novel scaffolds were identified as selective ERalpha ligands. A molecular docking study was also performed, which provided the explanation for the ER subtype preferences for AH and AG. PMID- 26423036 TI - Preparation and Evaluation of Newly Developed Chitosan Salt Coating Dispersions for Colon Delivery without Requiring Overcoating. AB - Although chitosan (CS) has been recognized as a good material for colon-specific drug delivery systems, an overcoating with an enteric coating polymer on the surface of CS is absolutely necessary because CS is soluble in acidic conditions before reaching the colon. In the present study, to improve its stability in the presence of acid, a newly developed CS-laurate (CS-LA) material was evaluated as a coating dispersion for the development of colon-specific drug delivery systems. Two types of CS with different molecular weights, CS250 and CS600, were used to prepare CS-LA films by the casting method. The CS250-LA films had smooth surfaces, whereas the surfaces of the CS600-LA films were rough, indicating that the CS250-LA dispersion could form a denser film than CS600-LA. Both of these CS LA films maintained a constant shape over 22 h in a pH 1.2 HCl/NaCl buffer, where the corresponding CS films rapidly disintegrated. In addition, the CS250-LA film showed specific colon degradability in a pH 6.0 phosphate buffered solution containing 1.0% (w/v) beta-glucosidase. As a result of tensile strength and elongation at the break, both CS-LA films were found to have flexible film properties. Finally, the release of acetaminophen from disks coated with CS250-LA dispersions was significantly suppressed in fluids at pH 1.2 and 6.8, whereas disks coated with CS solution rapidly released the drug in pH 1.2 fluids. Taken together, this study shows that LA modification could be a useful approach in preparing CS films with acid stability and colonic degradability properties without requiring overcoating. PMID- 26423037 TI - Virtual Screening with Docking Simulations and Biochemical Evaluation of VHY Phosphatase Inhibitors. AB - Although VH1-related member Y (VHY) phosphatase is responsible for the pathogenesis of neuroinflammatory diseases, no small-molecule inhibitor of VHY has been reported so far. Here we first report eight VHY inhibitors identified from molecular docking-based virtual screening and subsequent enzyme inhibition assays. These inhibitors exhibit good biochemical potencies against VHY, with associated IC50 values ranging from 1 to 9 uM. Because all these inhibitors were also screened in silico for having desirable physicochemical properties as a drug candidate, they deserve further investigation by structure-activity relationship studies to develop new medicines for the treatment of neuroinflammatory diseases. The structural features of VHY-inhibitor interactions relevant to the micromolar level inhibitory activity are addressed in detail. PMID- 26423038 TI - Synthesis and Antimicrobial Evaluation of Thieno[2,3-d]-pyrimidine, Thieno[2',3':4,5]pyrimido[1,2-a][1,3,5]triazine, Thieno[2,3-d]-1,3-thiazine and 1,2,4-Triazole Systems. AB - The reaction of lauroyl isothiocyanate with ethyl 2-amino-4,5,6,7 tetrahydrobenzo[b]thiophene-3-carboxylate gave ethyl 2-(3-dodecanoylthioureido) 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate 3. Compound 3 could serve as a main building block in synthesis of the target heterocyclic systems like thieno[2,3-d]-pyrimidine, thieno[2',3':4,5]pyrimido[1,2-a][1,3,5]triazine, thieno[2,3-d]-1,3-thiazine and 1,2,4-triazole systems attached to the lauryl group. The structures of the synthesized target heterocyclic compounds were confirmed by microanalytical and spectral data. The antimicrobial activity of some of the synthesized compounds was tested. PMID- 26423039 TI - Clean Synthesis of N-Pyrrolyl Azoles by Metal-Free Oxidative Cross-Coupling Using Recyclable Hypervalent Iodine Reagent. AB - The facile and clean oxidative coupling reaction of pyrroles with azoles has been achieved using the recyclable hypervalent iodine(III) reagents having adamantane structures. These iodine(III) reagents could be recovered from the reaction mixtures by a simple solid-liquid separation, i.e., filtration, for reuse. PMID- 26423040 TI - Structural Optimization of Ghrelin Receptor Inverse Agonists to Improve Lipophilicity and Avoid Mechanism-Based CYP3A4 Inactivation. AB - Structural optimization of 2-aminonicotinamide derivatives as ghrelin receptor inverse agonists is reported. So as to avoid mechanism-based inactivation (MBI) of CYP3A4, 1,3-benzodioxol ring of the lead compound was modified. Improvement of the main activity and lipophilicity was achieved simultaneously, leading to compound 18a, which showed high lipophilic ligand efficiency (LLE) and low MBI activity. PMID- 26423041 TI - Novel Monoterpene Lactones from Cinnamomum inunctum. AB - Four new monoterpene lactones, 5-(2,3-dihydroxy-3-methylbutyl)-4-hydroxy-4 methyldihydrofuran-2(3H)-one (1), 5-(2,3-dihydroxy-3-methylbutyl)-4-methylfuran 2(5H)-one (2), 8-hydroxy-4,7,7-trimethyl-1,6-dioxaspiro[4.4]non-3-en-2-one (3) and 8-hydroxy-4,7,7-trimethyl-1,6-dioxaspiro[4.4]non-3-en-2-one (4), were isolated from the methanolic extract of the fruit of Cinnamomum inunctum, a folk medicine in Myanmar, together with a known compound, 3-hydroxy-4,4-dimethyl-4 butyrolactone (5). Their chemical structures were determined by spectral methods. Among these, 3 and 4 possessed unique spirolactone moieties. PMID- 26423042 TI - Antineuroinflammatory and Antiproliferative Activities of Constituents from Tilia amurensis. AB - As part of our ongoing search for bioactive constituents of natural Korean medicinal resources, we found in a preliminary study that the methanol (MeOH) extract from the trunks of Tilia amurensis RUPR. showed an inhibitory effect on nitric oxide (NO) production in an activated murine microglial cell line. A bioassay-guided fractionation and chemical investigation of the MeOH extract resulted in the isolation and identification of a new isoflavonoid glycoside, orobol 4'-O-beta-D-apiofuranosyl-(1->6)-beta-D-glucopyranoside (1) and 16 known compounds (2-17). The structure of the new compound was determined by spectroscopic methods, i.e., one-dimensional (1D) and two-dimensional (2D)-NMR techniques and high resolution (HR)-MS, and chemical methods. The antineuroinflammatory activities of the isolated compounds were determined by measuring NO levels in the medium using murine microglial BV-2 cells. Among them, 12 compounds, including compound 1 (most active with an IC50 value of 23.42 uM), inhibited NO production in lipopolysaccharide-stimulated BV-2 cells. Moreover, compounds 1-4 showed moderate antiproliferative activities against the SK-MEL-2 cell line, with IC50 values ranging from 12.31 to 19.67 uM. PMID- 26423043 TI - Saponins, Esculeosides B-1 and B-2, in Tomato Juice and Sapogenol, Esculeogenin B1. AB - It has been shown that commercial tomato juice packaged in 900 g plastic bottles contains rare, naturally occurring steroidal solanocapsine-type tomato glycosides in which the saponins consist of esculeosides B-1 (2) and B-2 (3) in 0.041% as major components lacking esculeoside A. We suggest that these saponins are derived from esculeoside A (1) when the juice in plastic bottles is prepared by treatment with boiling water, similar to the process used in preparing canned tomatoes. Herein, the obtained tomato saponins (2) and (3) provided sapogenols esculeogenin B1 (4) and B2 (5), respectively, by acid hydrolysis. The former was identical to esculeogenin B previously reported, and the latter was a new sapogenol characterized to be (5alpha,22S,23S,25S)-22,26-epimino-16beta,23-epoxy 3beta,23,27-trihydroxycholestane. PMID- 26423044 TI - A log-linear multidimensional Rasch model for capture-recapture. AB - In this paper, a log-linear multidimensional Rasch model is proposed for capture recapture analysis of registration data. In the model, heterogeneity of capture probabilities is taken into account, and registrations are viewed as dichotomously scored indicators of one or more latent variables that can account for correlations among registrations. It is shown how the probability of a generic capture profile is expressed under the log-linear multidimensional Rasch model and how the parameters of the traditional log-linear model are derived from those of the log-linear multidimensional Rasch model. Finally, an application of the model to neural tube defects data is presented. PMID- 26423045 TI - Efficient Light-Driven Water Oxidation Catalysis by Dinuclear Ruthenium Complexes. AB - Mastering the light-induced four-electron oxidation of water to molecular oxygen is a key step towards the achievement of overall water splitting to produce alternative solar fuels. In this work, we report two rugged molecular pyrazolate based diruthenium complexes that efficiently catalyze visible-light-driven water oxidation. These complexes were fully characterized both in the solid state (by X ray diffraction analysis) and in solution (spectroscopically and electrochemically). Benchmark performances for homogeneous oxygen production have been obtained for both catalysts in the presence of a photosensitizer and a sacrificial electron acceptor at pH 7, and a turnover frequency of up to 11.1 s( 1) and a turnover number of 5300 were obtained after three successive catalytic runs. Under the same experimental conditions with the same setup, the pyrazolate based diruthenium complexes outperform other well-known water oxidation catalysts owing to both electrochemical and mechanistic aspects. PMID- 26423046 TI - Botulinum toxin therapy for chronic anal fissures: where are we at currently? AB - BACKGROUND: Botulinum toxin (Botox) injection for chronic anal fissure (CAF) is commonly performed, yet there remains no consensus on optimal dosage or frequency of injections required to achieve complete resolution of anal fissure. The aim of this study was to determine the effectiveness of Botox and side-effect profile in the management of CAF. METHODS: A retrospective clinical study of patients between 2010 and 2014 who underwent a Botox injection for CAF at a tertiary centre was performed. The effectiveness of Botox was measured using standardized outcomes including overall healing rate, presence of anal pain, recurrence and need for repeat botulinum injection. Binary outcomes were assessed using logistic regression model. The analysis was performed using Stata version 13 (StataCorp, College Station, TX, USA). RESULTS: One hundred and one patients underwent 126 Botox injections within the study period. The mean first post-operative visit was at 1 month. The overall recurrence rate was 32%. The majority of patients were given 33 U. No statistically significant relationship between dose and recurrence was identified. The presence of pain at the first post-operative visit was a predictor of future recurrence (odds ratio 3.92, confidence interval 1.58-9.74, P = 0.003). CONCLUSION: Botox is an effective strategy for CAF. Low doses can be given with good efficacy as highlighted by our audit and has the potential for great cost saving. The best predictor of recurrence is the presence of pain at the first post-procedure visit. PMID- 26423047 TI - Detrimental effects of duplicate reads and low complexity regions on RNA- and ChIP-seq data. AB - BACKGROUND: Adapter trimming and removal of duplicate reads are common practices in next-generation sequencing pipelines. Sequencing reads ambiguously mapped to repetitive and low complexity regions can also be problematic for accurate assessment of the biological signal, yet their impact on sequencing data has not received much attention. We investigate how trimming the adapters, removing duplicates, and filtering out reads overlapping low complexity regions influence the significance of biological signal in RNA- and ChIP-seq experiments. METHODS: We assessed the effect of data processing steps on the alignment statistics and the functional enrichment analysis results of RNA- and ChIP-seq data. We compared differentially processed RNA-seq data with matching microarray data on the same patient samples to determine whether changes in pre-processing improved correlation between the two. We have developed a simple tool to remove low complexity regions, RepeatSoaker, available at https://github.com/mdozmorov/RepeatSoaker, and tested its effect on the alignment statistics and the results of the enrichment analyses. RESULTS: Both adapter trimming and duplicate removal moderately improved the strength of biological signals in RNA-seq and ChIP-seq data. Aggressive filtering of reads overlapping with low complexity regions, as defined by RepeatMasker, further improved the strength of biological signals, and the correlation between RNA-seq and microarray gene expression data. CONCLUSIONS: Adapter trimming and duplicates removal, coupled with filtering out reads overlapping low complexity regions, is shown to increase the quality and reliability of detecting biological signals in RNA-seq and ChIP-seq data. PMID- 26423048 TI - Biofeedback therapy for chronic constipation in a patient with Prader-Willi syndrome. AB - Constipation is a common feature of Prader-Willi syndrome. Research exploring the prevalence, cause and treatment options for constipation is limited and lacks objective measurements such as anorectal manometry. We report a case of a 16-year old lady with Prader-Willi syndrome presenting with rectal pain and constipation for 2 years despite multiple medications and weekly enemas. She also noted passive fecal incontinence that required frequent manual disimpactions. Anorectal manometry revealed an abnormal relaxation of the puborectalis and external sphincter muscles on push maneuvers suggesting dyssynergic defecation and rectal hypersensitivity. Contraction and relaxation of her pelvic muscles were recorded with electromyography. Relaxation of the puborectalis muscle improved significantly after three biofeedback sessions. Patient was successfully tapered off laxatives and has been maintained on linaclotide only. Dyssynergic defecation may be a common finding in Prader-Willi syndrome. In selected cases we recommend anorectal manometry to identify neuromuscular dysfunction and subsequent biofeedback therapy depending on the degree of mental retardation to minimize overuse of laxatives. PMID- 26423049 TI - A qualitative assessment of health extension workers' relationships with the community and health sector in Ethiopia: opportunities for enhancing maternal health performance. AB - BACKGROUND: Health extension workers (HEWs) in Ethiopia have a unique position, connecting communities to the health sector. This intermediary position requires strong interpersonal relationships with actors in both the community and health sector, in order to enhance HEW performance. This study aimed to understand how relationships between HEWs, the community and health sector were shaped, in order to inform policy on optimizing HEW performance in providing maternal health services. METHODS: We conducted a qualitative study in six districts in the Sidama zone, which included focus group discussions (FGDs) with HEWs, women and men from the community and semi-structured interviews with HEWs; key informants working in programme management, health service delivery and supervision of HEWs; mothers; and traditional birth attendants. Respondents were asked about facilitators and barriers regarding HEWs' relationships with the community and health sector. Interviews and FGDs were recorded, transcribed, translated, coded and thematically analysed. RESULTS: HEWs were selected by their communities, which enhanced trust and engagement between them. Relationships were facilitated by programme design elements related to support, referral, supervision, training, monitoring and accountability. Trust, communication and dialogue and expectations influenced the strength of relationships. From the community side, the health development army supported HEWs in liaising with community members. From the health sector side, top-down supervision and inadequate training possibilities hampered relationships and demotivated HEWs. Health professionals, administrators, HEWs and communities occasionally met to monitor HEW and programme performance. Expectations from the community and health sector regarding HEWs' tasks sometimes differed, negatively affecting motivation and satisfaction of HEWs. CONCLUSION: HEWs' relationships with the community and health sector can be constrained as a result of inadequate support systems, lack of trust, communication and dialogue and differing expectations. Clearly defined roles at all levels and standardized support, monitoring and accountability, referral, supervision and training, which are executed regularly with clear communication lines, could improve dialogue and trust between HEWs and actors from the community and health sector. This is important to increase HEW performance and maximize the value of HEWs' unique position. PMID- 26423050 TI - Effect of local anesthetic concentration, dose and volume on the duration of single-injection ultrasound-guided axillary brachial plexus block with mepivacaine: a randomized controlled trial. AB - BACKGROUND: In what way volume, concentration and dose affect block duration is controversial. The purpose of the present study is to investigate the effect of dose, volume and concentration of mepivacaine on the duration of sensory and motor blockade in ultrasound-guided single shot axillary brachial plexus blockade. METHODS: In this parallel group randomized trial conducted in the Sint Maartenskliniek Nijmegen, 45 adult patients undergoing minor orthopaedic forearm, wrist or hand surgery were randomized to 3 groups. Group A: 20 mL mepivacaine 1.5 %, Group B: 30 mL mepivacaine 1 % and Group C: 30 mL mepivacaine 1.5 %. Randomization was computer-generated, with allocation concealment by opaque sequentially numbered sealed envelopes. Patients and observers were blinded to group allocation. PRIMARY OUTCOME MEASURE: duration of sensory block. RESULTS: Forty-five patients were randomized, four patients were excluded and replaced, and 15 patients in each group were included in the analysis. Mean (95 % CI) sensory and motor block duration was 256 (230-282) and 254 (226-282) minutes in Group A, 226 (209-243) and 220 (200-240) minutes in Group B and 270 (249-291) and 264 (244-284) minutes in Group C. Duration of sensory and motor block duration differed significantly between groups (p = 0.012 and p = 0.016 respectively). Post-hoc analysis showed a significantly reduced sensory and motor block duration in Group B when compared to Group C of 44 min. No local anesthetic systemic toxicity was reported. CONCLUSIONS: When using mepivacaine for axillary brachial plexus block, a higher dose and concentration was associated with a longer duration of sensory and motor blockade, but not a higher volume. TRIAL REGISTRATION: The Netherlands National Trial Register NTR3648 . Registered October 3, 2012. PMID- 26423051 TI - The role of social networks in the development of overweight and obesity among adults: a scoping review. AB - BACKGROUND: Although it is increasingly acknowledged that social networks are important to our understanding ofoverweight and obesity, there is limited understanding about the processes by which such networks shapetheir progression. This paper reports the findings of a scoping review of the literature that sought to identify the key processes through which social networks are understood to influence the development of overweight and obesity. METHODS: A scoping review was conducted. Forty five papers were included in the final review, the findings of which were synthesised to provide an overview of the main processes through which networks have been understood to influence the development of overweight and obesity. RESULTS: Included papers addressed a wide range of research questions framed around six types of networks: a paired network (one's spouse or intimate partner); friends and family (including work colleagues and people within social clubs); ephemeral networks in shared public spaces (such as fellow shoppers in a supermarket or diners in a restaurant); people living within the same geographical region; peers (including co-workers, fellow students, fellow participants in a weight loss programme); and cultural groups (often related toethnicity). As individuals are embedded in many of these different types of social networks at any one time, the pathways of influence from social networks to the development of patterns of overweight and obesity are likely to be complex and interrelated. Included papers addressed a diverse set of issues: body weight trends over time; body size norms or preferences; weight loss and management; physical activity patterns; and dietary patterns. DISCUSSION: Three inter-related processes were identified: social contagion (whereby the network in which people are embedded influences their weight or weight influencing behaviours), social capital (whereby sense of belonging and social support influence weight or weight influencing behaviours), and social selection (whereby a person's network might develop according to his or her weight). CONCLUSIONS: The findings have important implications for understanding about methods to target the spread of obesity, indicating that much greater attention needs to be paid to the social context in which people make decisions about their weight and weight influencing behaviours. PMID- 26423052 TI - Molecular analysis of clinical isolates previously diagnosed as Mycobacterium intracellulare reveals incidental findings of "Mycobacterium indicus pranii" genotypes in human lung infection. AB - BACKGROUND: Mycobacterium intracellulare is a major cause of Mycobacterium avium complex lung disease in many countries. Molecular studies have revealed several new Mycobacteria species that are closely related to M. intracellulare. The aim of this study was to re-identify and characterize clinical isolates from patients previously diagnosed with M. intracellulare lung disease at the molecular level. METHODS: Mycobacterial isolates from 77 patients, initially diagnosed with M. intracellulare lung disease were re-analyzed by multi-locus sequencing and pattern of insertion sequences. RESULTS: Among the 77 isolates, 74 (96 %) isolates were designated as M. intracellulare based on multigene sequence-based analysis. Interestingly, the three remaining strains (4 %) were re-identified as "Mycobacterium indicus pranii" according to distinct molecular phylogenetic positions in rpoB and hsp65 sequence-based typing. In hsp65 sequevar analysis, code 13 was found in the majority of cases and three unreported codes were identified. In 16S-23S rRNA internal transcribed spacer (ITS) sequevar analysis, all isolates of both species were classified within the Min-A ITS sequevar. Interestingly, four of the M. intracellulare isolates harbored IS1311, a M. avium specific element. Two of three patients infected with "M. indicus pranii" had persistent positive sputum cultures after antibiotic therapy, indicating the clinical relevance of this study. CONCLUSIONS: This analysis highlights the importance of precise identification of clinical isolates genetically close to Mycobacterium species, and suggests that greater attention should be paid to nontuberculous mycobacteria lung disease caused by "M. indicus pranii". PMID- 26423054 TI - Is patellar denervation necessary in total knee arthroplasty without patellar resurfacing? AB - PURPOSE: To conduct a meta-analysis with randomized controlled trials (RCTs) published in full text to determine the effectiveness of patellar denervation (PD) in primary total knee arthroplasty (TKA). METHODS: Literature search was performed in PubMed, Embase, Web of Science and Cochrane Library for information from the earliest date of data collection to February 2015. RCTs comparing the benefits and risks of PD with those of no patellar denervation (NPD) in primary TKAs were included. Statistical heterogeneity was quantitatively evaluated by X(2) test with the significance set P < 0.10 or I (2) > 50 %. RESULTS: Six RCTs consisting of 751 patients were included. The incidences of AKP in PD group and NPD group were 38.3 % (90/235) and 46.3 % (107/231), respectively. Meta-analysis showed significant prevention effect of PD on the incidence of AKP (OR 0.65; 95 % CI 0.42, 1.00; P = 0.05) without significant heterogeneity (I (2) = 44 %, P = 0.15). Our results also indicated that PD was significantly associated with better American Knee Society knee (WMD = 2.50; 95 % CI 0.34, 4.67; P = 0.02) and functional scores (WMD = 4.07; 95 % CI 1.34, 6.80; P = 0.0003) and range of motion (ROM) (WMD = 4.27; 95 % CI 1.95, 6.60; P = 0.0003) compared with NPD. However, there was no significant difference between the two groups no matter in Oxford knee score, patellar score or visual analogue scale at any other time. Complications and revisions did not differ significantly between the two groups. CONCLUSION: This meta-analysis showed that PD in TKAs without patellar resurfacing, compared with NPD, could prevent the incidence of post-operative AKP and improve clinical outcome in KSS and post-operative ROM. Based on the above results, PD was a safe procedure with no significant complications and revision or re-operations. LEVEL OF EVIDENCE: Therapeutic study, Level II. PMID- 26423056 TI - Editorial: Colorectal Cancer Screening Education in Medically Vulnerable Populations: the Role of the Journal of Cancer Education. PMID- 26423055 TI - Total knee arthroplasty after failed high tibial osteotomy: a systematic review of open versus closed wedge osteotomy. AB - PURPOSE: Medial opening wedge high tibial osteotomy (HTO) has become increasingly popular as an alternative to lateral closing wedge osteotomy for the treatment of medial compartment knee osteoarthritis with varus deformity. The present systematic review was conducted to provide an objective analysis of total knee arthroplasty (TKA) outcomes following previous knee osteotomy (medial opening wedge vs. lateral closing wedge). METHODS: A literature search of online databases (MEDLINE, EMBASE, Cochrane Library database) was made, in addition to manual search of major orthopaedic journals. The methodological quality of each of the studies was assessed on the Newcastle-Ottawa Scale and Effective Practice and Organization of Care. A total of ten studies were included in the review. There were eight studies with Level IV and two studies with Level III evidence. RESULTS: Eight studies reported clinical and radiologic scores. Comparative studies between TKA following medial opening and lateral closing wedge HTO did not demonstrate statistically significant clinical and radiologic differences. The revision rates were similar. However, more technical issues during TKA surgery after lateral closing wedge HTO were mentioned than the medial open wedge group. The quadriceps snip, tibial tubercle osteotomy, and lateral soft tissue release were more frequently needed in the lateral closing wedge HTO group. In addition, because of loss of proximal tibia bone geometry in the lateral closing wedge HTO group, concerns such as tibia stem impingement in the lateral tibial cortex was noted. CONCLUSION: The present systematic review suggests that TKA after medial opening and lateral closing wedge HTO showed similar performance. Clinical and radiologic outcome including revision rates did not statistically differ from included studies. However, there are more surgical technical concerns in TKA conversion from lateral closing wedge HTO than from the medial opening wedge HTO group. LEVEL OF EVIDENCE: IV. PMID- 26423053 TI - Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies. AB - BACKGROUND: In addition to HLA genetic incompatibility, non-HLA difference between donor and recipients of transplantation leading to allograft rejection are now becoming evident. We aimed to create a unique genome-wide platform to facilitate genomic research studies in transplant-related studies. We designed a genome-wide genotyping tool based on the most recent human genomic reference datasets, and included customization for known and potentially relevant metabolic and pharmacological loci relevant to transplantation. METHODS: We describe here the design and implementation of a customized genome-wide genotyping array, the 'TxArray', comprising approximately 782,000 markers with tailored content for deeper capture of variants across HLA, KIR, pharmacogenomic, and metabolic loci important in transplantation. To test concordance and genotyping quality, we genotyped 85 HapMap samples on the array, including eight trios. RESULTS: We show low Mendelian error rates and high concordance rates for HapMap samples (average parent-parent-child heritability of 0.997, and concordance of 0.996). We performed genotype imputation across autosomal regions, masking directly genotyped SNPs to assess imputation accuracy and report an accuracy of >0.962 for directly genotyped SNPs. We demonstrate much higher capture of the natural killer cell immunoglobulin-like receptor (KIR) region versus comparable platforms. Overall, we show that the genotyping quality and coverage of the TxArray is very high when compared to reference samples and to other genome-wide genotyping platforms. CONCLUSIONS: We have designed a comprehensive genome-wide genotyping tool which enables accurate association testing and imputation of ungenotyped SNPs, facilitating powerful and cost-effective large-scale genotyping of transplant-related studies. PMID- 26423057 TI - The Evolution of Undergraduate Medical Student Research Activities: Personal Experience of a Developing Nation's Uprise. PMID- 26423058 TI - Web-Based Study for Improving Mammography Among Korean American Women. AB - Web-based culture-specific interventions for Korean American (KA) women to improve mammography utilization are not available. An established intervention developed to improve mammography utilizations for Korean American (KA) women was tested via the Web for its efficacy, feasibility, and acceptability. A randomized controlled trial, with a pretest-posttest control group design, was conducted with 136 KA women and their spouses. Intention to have a mammogram within the next 12 months increased significantly in the intervention group compare to controls. Among women whose mammograms had not been updated, 22 % of women in the intervention and 13 % of women in the control group obtained a mammogram at 2 month post-baseline, even though the difference was not statistically significant. The Web-based study educating couples was feasible and could improve KA women's breast cancer screening intention and behaviors. Combining off-line contact for recruitment/data collection with online intervention material could decrease the attrition rate in the future study because the attrition rate in this study was higher than the original study. PMID- 26423059 TI - Oral Cancer: Awareness and Knowledge Among Dental Patients in Riyadh. AB - More than 50 % of oral cancer cases are diagnosed at advanced stages. Public knowledge about oral cancer can help in prevention and early detection of the disease. The aim of the present study was to assess the levels of awareness and knowledge about signs and risk factors of oral cancer among dental patients in Saudi Arabia. A self-administered questionnaire was used to collect information from 1410 randomly selected patients attending dental departments within public hospitals in Riyadh, Saudi Arabia. The collected data were analyzed using SPSS software. The significance level was set at P < 0.05. The study revealed that only 62.4 % were aware of oral cancer. Some 68.2 and 56.5 %, respectively, were able to correctly identify tobacco and alcohol as risk factors. More than two thirds of subjects had no knowledge about any signs of oral cancer. Participants with lower than university education were significantly less aware, and had much less knowledge, of the signs and risk factors of oral cancer. The knowledge regarding oral cancer among Saudi dental patients is alarmingly low. Interventions to improve public knowledge about oral cancer and attitudes towards early diagnosis and treatment are urgently indicated. PMID- 26423060 TI - Laparoscopic surgery of benign entero-vesical or entero-vaginal fistulae. AB - PURPOSE: Entero-vesical or entero-vaginal fistulae (EVF) are an uncommon septic complication mainly of diverticular disease. The fistulae are usually situated within extensive and dense inflammatory masses occluding the entrance of the pelvis. There are still some controversies regarding laparoscopic feasibility and treatment modalities of this disorder. METHODS: A retrospective chart review of all patients with EVF operated at our department since 2008. Patients were identified by use of the computerized hospital information system. RESULTS: In nineteen patients (ten males), median age 68 years, 13 patients had entero vesical fistulae, and 6 patients had entero-vaginal fistulae. The fistulae were caused by complicated diverticular disease in 16 patients (84 %), Crohn's disease (two patients), and ulcerative colitis (one patient). All cases were attempted laparoscopically. Operative treatment involved separation of the inflammatory mass and resection of the affected colorectal segment. There were three conversions (16 %), all three requiring bladder repair considered too extensive for laparoscopic means. In two further patients small bladder defects were sutured laparoscopically, the remaining patients required no bladder repair. The inferior mesentric artery (IMA) was preserved in all cases. Median operative time was 180 min. Two patients received a protective ileostomy: one converted patient and one cachectic patient with Crohn's disease under immune-modulating therapy. Both ileostomies were closed. Altogether, there were five complications in five patients (26 %), four of them were minor (Clavien grade I and II). The cachectic patient with Crohn's disease suffered a major (grade IIIb) complication (stoma prolapse, treated by early closure of the ileostomy). There was no anastomotic leakage and no mortality. Median hospital stay was 12 days. CONCLUSIONS: The laparoscopic approach is a safe option for the treatment of EVF of benign inflammatory origin. In most cases it offers all the advantages pertaining to minimally invasive surgery. For a definite and causal approach, the disorder belongs primarily within the therapeutic domain of the visceral surgeon. Following the separation of the inflammatory colon, most of the bladder lesions caused by EVF will heal without further surgical measures. PMID- 26423061 TI - Dulaglutide: A Review in Type 2 Diabetes. AB - Dulaglutide (TrulicityTM) is a once-weekly subcutaneously administered glucagon like peptide-1 (GLP-1) receptor agonist produced by recombinant DNA technology and approved in numerous countries as an adjunct to diet and exercise for the treatment of adults with type 2 diabetes (T2DM). In randomized controlled trials in patients with T2DM, dulaglutide monotherapy was noninferior to once-daily subcutaneous liraglutide monotherapy and significantly more effective than oral metformin monotherapy in improving glycemic control at 26 weeks. When used in combination with other agents (including metformin, metformin and a sulfonylurea, metformin and oral pioglitazone, and prandial insulin +/- metformin), dulaglutide was noninferior to once-daily liraglutide and significantly more effective than once-daily oral sitagliptin, twice-daily subcutaneous exenatide, and once-daily subcutaneous insulin glargine in terms of improvements in glycated hemoglobin from baseline at 26 or 52 weeks, in trials of 26-104 weeks' duration. Moreover, dulaglutide 1.5 mg once weekly, but not 0.75 mg once weekly, was associated with consistent reductions form baseline in bodyweight. Improvements in glycemic control and bodyweight were maintained during long-term treatment (up to 2 years). Dulaglutide was generally well tolerated, with a low inherent risk of hypoglycemia. The most frequently reported adverse events in clinical trials were gastrointestinal-related (e.g., nausea, vomiting, and diarrhea). Thus, dulaglutide is a useful option for the treatment of adult patients with T2DM. PMID- 26423063 TI - 'Predatory' open access: a longitudinal study of article volumes and market characteristics. AB - BACKGROUND: A negative consequence of the rapid growth of scholarly open access publishing funded by article processing charges is the emergence of publishers and journals with highly questionable marketing and peer review practices. These so-called predatory publishers are causing unfounded negative publicity for open access publishing in general. Reports about this branch of e-business have so far mainly concentrated on exposing lacking peer review and scandals involving publishers and journals. There is a lack of comprehensive studies about several aspects of this phenomenon, including extent and regional distribution. METHODS: After an initial scan of all predatory publishers and journals included in the so called Beall's list, a sample of 613 journals was constructed using a stratified sampling method from the total of over 11,000 journals identified. Information about the subject field, country of publisher, article processing charge and article volumes published between 2010 and 2014 were manually collected from the journal websites. For a subset of journals, individual articles were sampled in order to study the country affiliation of authors and the publication delays. RESULTS: Over the studied period, predatory journals have rapidly increased their publication volumes from 53,000 in 2010 to an estimated 420,000 articles in 2014, published by around 8,000 active journals. Early on, publishers with more than 100 journals dominated the market, but since 2012 publishers in the 10-99 journal size category have captured the largest market share. The regional distribution of both the publisher's country and authorship is highly skewed, in particular Asia and Africa contributed three quarters of authors. Authors paid an average article processing charge of 178 USD per article for articles typically published within 2 to 3 months of submission. CONCLUSIONS: Despite a total number of journals and publishing volumes comparable to respectable (indexed by the Directory of Open Access Journals) open access journals, the problem of predatory open access seems highly contained to just a few countries, where the academic evaluation practices strongly favor international publication, but without further quality checks. PMID- 26423064 TI - Ramakrishna and the Clinic of Paradox. AB - This study presents a clinical conception of the human being as the paradox between immanence and transcendence. Through an exposition of the clinical conceptions of Brazilian author Gilberto Safra, we search for an integral manner in which to understand mystical experience as a way to rethink the ontological conceptions inherent to clinical practice. In such perspective, we elaborate a critique of both the psychological-only approach to mystical experience as well as the spiritual-only approach. We present it through the life of Indian mystic Ramakrishna, by comparing the interpretation different authors make of his experiences and placing our own perspective. PMID- 26423065 TI - Assessing Age Differences in the Relationship Between Emotional Support and Health Among Older Mexican Americans. AB - Research reveals that people tend to place greater value on emotional support as they move through the life course. Older people are likely to do so because emotional support benefits them in some way. The purpose of this study was to see whether there are age differences in the relationship between emotional support and the number of chronic health conditions. In the process, an effort is made to contribute to the literature in three ways. First, an emphasis placed on assessing the relationship between emotional support and health within late life. Second, variations in the source of support are taken into account by contrasting support within religious institutions with support that is received outside church. Third, these issues are examined with data provided by a nationally representative sample of older Mexican Americans (N = 663). The findings suggest that age differences in the relationship between emotional support and health are present within late life. Moreover, the data indicate that this relationship holds for church-based social support but not support that is received outside the church. PMID- 26423066 TI - Sex differences in the shoulder joint position sense acuity: a cross-sectional study. AB - BACKGROUND: Work-related musculoskeletal disorders (WMSD) is the most expensive form of work disability. Female sex has been considered as an individual risk factor for the development of WMSD, specifically in the neck and shoulder region. One of the factors that might contribute to the higher injury rate in women is possible differences in neuromuscular control. Accordingly the purpose of this study was to estimate the effect of sex on shoulder joint position sense acuity (as a part of shoulder neuromuscular control) in healthy individuals. METHODS: Twenty-eight healthy participants, 14 females and 14 males were recruited for this study. To test position sense acuity, subjects were asked to flex their dominant shoulder to one of the three pre-defined angle ranges (low, mid and high ranges) with eyes closed, hold their arm in that position for three seconds, go back to the starting position and then immediately replicate the same joint flexion angle, while the difference between the reproduced and original angle was taken as the measure of position sense error. The errors were measured using Vicon motion capture system. Subjects reproduced nine positions in total (3 ranges * 3 trials each). RESULTS: Calculation of absolute repositioning error (magnitude of error) showed no significant difference between men and women (p value >= 0.05). However, the analysis of the direction of error (constant error) showed a significant difference between the sexes, as women tended to mostly overestimate the target, whereas men tended to both overestimate and underestimate the target (p-value <= 0.01, observed power = 0.79). The results also showed that men had a significantly more variable error, indicating more variability in their position sense, compared to women (p-value <= 0.05, observed power = 0.78). DISCUSSION: Differences observed in the constant JPS error suggest that men and women might use different neuromuscular control strategies in the upper limb. In addition, higher JPS variability observed in men might be one of the factors that could contribute to their lower rate of musculoskeletal disorders, compared to women. CONCLUSIONS: The result of this study showed that shoulder position sense, as part of the neuromuscular control system, differs between men and women. This finding can help us better understand the reasons behind the higher rate of musculoskeletal disorders in women, especially in the working environments. PMID- 26423067 TI - Structural features of conopeptide genes inferred from partial sequences of the Conus tribblei genome. AB - The evolvability of venom components (in particular, the gene-encoded peptide toxins) in venomous species serves as an adaptive strategy allowing them to target new prey types or respond to changes in the prey field. The structure, organization, and expression of the venom peptide genes may provide insights into the molecular mechanisms that drive the evolution of such genes. Conus is a particularly interesting group given the high chemical diversity of their venom peptides, and the rapid evolution of the conopeptide-encoding genes. Conus genomes, however, are large and characterized by a high proportion of repetitive sequences. As a result, the structure and organization of conopeptide genes have remained poorly known. In this study, a survey of the genome of Conus tribblei was undertaken to address this gap. A partial assembly of C. tribblei genome was generated; the assembly, though consisting of a large number of fragments, accounted for 2160.5 Mb of sequence. A large number of repetitive genomic elements consisting of 642.6 Mb of retrotransposable elements, simple repeats, and novel interspersed repeats were observed. We characterized the structural organization and distribution of conotoxin genes in the genome. A significant number of conopeptide genes (estimated to be between 148 and 193) belonging to different superfamilies with complete or nearly complete exon regions were observed, ~60 % of which were expressed. The unexpressed conopeptide genes represent hidden but significant conotoxin diversity. The conotoxin genes also differed in the frequency and length of the introns. The interruption of exons by long introns in the conopeptide genes and the presence of repeats in the introns may indicate the importance of introns in facilitating recombination, evolution and diversification of conotoxins. These findings advance our understanding of the structural framework that promotes the gene-level molecular evolution of venom peptides. PMID- 26423068 TI - High reactive oxygen species levels are detected at the end of the chronological life span of translocant yeast cells. AB - Chromosome translocation is a major genomic event for a cell, affecting almost every of its life aspects ranging from metabolism, organelle maintenance and homeostasis to gene maintenance and expression. By using the bridge-induced translocation system, we defined the effects of induced chromosome translocation on the chronological life span (CLS) of yeast with particular interest to the oxidative stress condition. The results demonstrate that every translocant strain has a different CLS, but all have a high increase in reactive oxygen species and in lipid peroxides levels at the end of the life span. This could be due to the very unique and strong deregulation of the oxidative stress network. Furthermore, the loss of the translocated chromosome occurs at the end of the life span and is locus dependent. Additionally, the RDH54 gene may play a role in the correct segregation of the translocant chromosome, since in its absence there is an increase in loss of the bridge-induced translocated chromosome. PMID- 26423069 TI - GDSL esterase/lipase genes in Brassica rapa L.: genome-wide identification and expression analysis. AB - GDSL esterase/lipase proteins (GELPs), a very large subfamily of lipolytic enzymes, have been identified in microbes and many plants, but only a few have been characterized with respect to their roles in growth, development, and stress responses. In Brassica crops, as in many other species, genome-wide systematic analysis and functional studies of these genes are still lacking. As a first step to study their function in B. rapa ssp. pekinensis (Chinese cabbage), we comprehensively identified all GELP genes in the genome. We found a total of 121 Brassica rapa GDSL esterase/lipase protein genes (BrGELPs), forming three clades in the phylogenetic analysis (two major and one minor), with an asymmetrical chromosomal distribution. Most BrGELPs possess four strictly conserved residues (Ser-Gly-Asn-His) in four separate conserved regions, along with short conserved and clade-specific blocks, suggesting functional diversification of these proteins. Detailed expression profiling revealed that BrGELPs were expressed in various tissues, including floral organs, implying that BrGELPs play diverse roles in various tissues and during development. Ten percent of BrGELPs were specifically expressed in fertile buds, rather than male-sterile buds, implying their involvement in pollen development. Analyses of EXL6 (extracellular lipase 6) expression and its co-expressed genes in both B. rapa and Arabidopsis, as well as knockdown of this gene in Arabidopsis, revealed that this gene plays an important role in pollen development in both species. The data described in this study will facilitate future investigations of other BrGELP functions. PMID- 26423070 TI - Colour learning when foraging for nectar and pollen: bees learn two colours at once. AB - Bees are model organisms for the study of learning and memory, yet nearly all such research to date has used a single reward, nectar. Many bees collect both nectar (carbohydrates) and pollen (protein) on a single foraging bout, sometimes from different plant species. We tested whether individual bumblebees could learn colour associations with nectar and pollen rewards simultaneously in a foraging scenario where one floral type offered only nectar and the other only pollen. We found that bees readily learned multiple reward-colour associations, and when presented with novel floral targets generalized to colours similar to those trained for each reward type. These results expand the ecological significance of work on bee learning and raise new questions regarding the cognitive ecology of pollination. PMID- 26423071 TI - Low BIK outside-inside-out interactive inflammation immune-induced transcription dependent apoptosis through FUT3-PMM2-SQSTM1-SFN-ZNF384. AB - Eighteen different Pearson mutual-positive-correlation BIK-activatory molecular feedback upstream and downstream networks were constructed from 79 overlapping of 376 GRNInfer and 98 Pearson under BIK CC >= 0.25 in low normal adjacent tissues of Taiwan compared with high lung adenocarcinoma. Our identified BIK interactive total feedback molecular network showed FUT3 [fucosyltransferase 3 (galactoside 3(4)-L-fucosyltransferase Lewis blood group)], PMM2 (phosphomannomutase 2), SQSTM1 (sequestosome 1), SFN_2 [REX2 RNA exonuclease 2 homolog (S. cerevisiae)] and ZNF384 (zinc finger protein 384) in low normal adjacent tissues of lung adenocarcinoma. BIK interactive total feedback terms included mitochondrial envelope, endomembrane system, integral to membrane, Golgi apparatus, cytoplasm, nucleus, cytosol, intracellular signaling cascade, mitochondrion, extracellular space, inflammation, immune response, apoptosis, cell differentiation, cell cycle, regulation of cell cycle, cell proliferation, estrogen-responsive protein Efp controls cell cycle and breast tumors growth, induction or regulation of apoptosis based on integrative GO, KEGG, GenMAPP, BioCarta and disease databases in low normal adjacent tissues of lung adenocarcinoma. Therefore, we propose low BIK outside-inside-out interactive inflammation immune-induced transcription dependent apoptosis through FUT3-PMM2-SQSTM1-SFN-ZNF384 in normal adjacent tissues of lung adenocarcinoma. PMID- 26423073 TI - In-Situ Remediation Approaches for the Management of Contaminated Sites: A Comprehensive Overview. AB - Though several in-situ treatment methods exist to remediate polluted sites, selecting an appropriate site-specific remediation technology is challenging and is critical for successful clean up of polluted sites. Hence, a comprehensive overview of all the available remediation technologies to date is necessary to choose the right technology for an anticipated pollutant. This review has critically evaluated the (i) technological profile of existing in-situ remediation approaches for priority and emerging pollutants, (ii) recent innovative technologies for on-site pollutant remediation, and (iii) current challenges as well as future prospects for developing innovative approaches to enhance the efficacy of remediation at contaminated sites. PMID- 26423072 TI - Prognostic implications of heart failure with preserved ejection fraction in patients with an exacerbation of chronic obstructive pulmonary disease. AB - Diagnosing heart failure with preserved ejection fraction (HFpEF) in patients with chronic obstructive pulmonary disease (COPD) is difficult due to overlapping pathophysiological pathways, risk factors and clinical presentations. We investigated the prevalence and prognostic implications of coexisting HFpEF in patients hospitalized for acute exacerbation of COPD. A total of 116 consecutive patients with an acute exacerbation of COPD were evaluated for HFpEF and followed for an average period of 22 +/- 9 months for the occurrence of death from any cause. HFpEF was diagnosed in 22 (19 %) patients with COPD, who were older, and also had higher LV mass, left atrial size, and mitral E/Ea ratio than those without HFpEF (p < 0.05 for all comparisons). HFpEF was not independently associated with all-cause mortality [hazard ratio (HR) 1.07, 95 % confidence interval (CI) 0.44-2.62]. Global initiative for chronic Obstructive Lung Disease (GOLD) stage (IV vs. I-III, HR 2.37, CI 1.23-4.59) and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels (HR 2.79, CI 1.12-6.98) were independent predictors of long-term survival. HFpEF is present in one-fifth of patients with exacerbated COPD. Non-invasively diagnosed HFpEF may not be an independent predictor of all-cause mortality. Elevated NT-proBNP levels and very severe COPD were independently associated with unfavorable overall survival. PMID- 26423074 TI - Ex-Situ Remediation Technologies for Environmental Pollutants: A Critical Perspective. AB - Pollution and the global health impacts from toxic environmental pollutants are presently of great concern. At present, more than 100 million people are at risk from exposure to a plethora of toxic organic and inorganic pollutants. This review is an exploration of the ex-situ technologies for cleaning-up the contaminated soil, groundwater and air emissions, highlighting their principles, advantages, deficiencies and the knowledge gaps. Challenges and strategies for removing different types of contaminants, mainly heavy metals and priority organic pollutants, are also described. PMID- 26423075 TI - Lead Exposure and Oxidative Stress: A Systematic Review. AB - Lead is an environmental toxicant that can induce oxidative stress (OS) via reactive oxygen species (ROS) generation, which has been reported as an important mechanism underlying lead toxicity (Gurer and Ercal 2000; Pande and Flora 2002; Kasperczyk et al. 2004a; Farmand et al. 2005; Verstraeten et al. 2008; Wang et al. 2009; Martinez-Haro et al. 2011). OS occurs when the generation of ROS exceeds the antioxidant system's ability to defend cells against oxidized molecules. ROS is a term generally used to refer to free radicals derived from O2 (e.g., superoxide anions [O2-] and hydroxyl radicals [OH-]) or to non-radical species (e.g. hydrogen peroxide [H2O2]) (Halliwell and Cross 1994). PMID- 26423076 TI - Nanostructured Metal Oxides for Stoichiometric Degradation of Chemical Warfare Agents. AB - Metal oxides have very important applications in many areas of chemistry, physics and materials science; their properties are dependent on the method of preparation, the morphology and texture. Nanostructured metal oxides can exhibit unique characteristics unlike those of the bulk form depending on their morphology, with a high density of edges, corners and defect surfaces. In recent years, methods have been developed for the preparation of metal oxide powders with tunable control of the primary particle size as well as of a secondary particle size: the size of agglomerates of crystallites. One of the many ways to take advantage of unique properties of nanostructured oxide materials is stoichiometric degradation of chemical warfare agents (CWAs) and volatile organic compounds (VOC) pollutants on their surfaces. PMID- 26423077 TI - Ecological Recovery Potential of Freshwater Organisms: Consequences for Environmental Risk Assessment of Chemicals. AB - Chemical contaminants released into the in the environment may have adverse effects on (non-target) species, populations and communities. The return of a stressed system to its pre-disturbance or other reference state, i.e. the ecological recovery, may depend on various factors related to the affected taxon, the ecosystem of concern and the type of stressor with consequences for the assessment and management of risks associated with chemical contaminants. Whereas the effects caused by short-term exposure might be acceptable to some extent, the conditions under which ecological recovery can serve as a decision criterion in the environmental risk assessment of chemical stressors remains to be evaluated. For a generic consideration of recovery in the risk assessment of chemicals, we reviewed case studies of natural and artificial aquatic systems and evaluate five aspects that might cause variability in population recovery time: (1) taxonomic differences and life-history variability, (2) factors related to ecosystem type and community processes, (3) type of disturbance, (4) comparison of field and semi-field studies, and (5) effect magnitude, i.e., the decline in population size following disturbance. We discuss our findings with regard to both retrospective assessments and prospective risk assessment. PMID- 26423078 TI - Soluble Dietary Fibers Can Protect the Small Intestinal Mucosa Without Affecting the Anti-inflammatory Effect of Indomethacin in Adjuvant-Induced Arthritis Rats. AB - BACKGROUND/AIM: How to prevent the small intestinal damage induced by NSAIDs is an urgent issue to be resolved. In the present study, we examined the effects of soluble dietary fibers on both anti-inflammatory and ulcerogenic effects of indomethacin in arthritic rats. METHODS: Male Wistar rats weighing 180-220 g were used. Arthritis was induced by injecting Freund's complete adjuvant (killed M. tuberculosis) into the plantar region of the right hindpaw. The animals were fed a regular powder diet for rats or a diet supplemented with soluble dietary fibers such as pectin or guar gum. Indomethacin was administered once a day for 3 days starting 14 days after the adjuvant injection, when marked arthritis was observed. The volumes of the hindpaw were measured before and after indomethacin treatment to evaluate the effect of indomethacin on edema. The lesions in the small intestine were examined 24 h after the final dosing of indomethacin. RESULTS: Hindpaw volume was increased about 3 times 14 days after injection of the adjuvant. Indomethacin (3-10 mg/kg, p.o.) decreased hindpaw volume dose dependently, but caused severe lesions in the small intestine at doses of 6 and 10 mg/kg. The addition of pectin (1-10 %) or guar gum (10 %) to the diet markedly decreased the lesion formation without affecting the anti-edema action of indomethacin. The same effects of pectin were observed when indomethacin was administered subcutaneously. CONCLUSIONS: It is suggested that soluble dietary fibers can prevent intestinal damage induced by NSAIDs without affecting the anti inflammatory effect of these agents. PMID- 26423079 TI - Diagnostic Utility of Endoscopic Retrograde Cholangiography/Intraductal Ultrasound (ERC/IDUS) in Distinguishing Malignant from Benign Bile Duct Obstruction. AB - BACKGROUND AND AIM: Accurately differentiating malignant diseases from benign ones in patients having bile duct obstruction is of significant importance and remains a major clinical problem. This study investigated the diagnostic yield of endoscopic retrograde cholangiography/intraductal ultrasound (ERC/IDUS) in distinguishing malignant from benign bile duct obstruction and assessed some image findings from ERC/IDUS which might be useful in differentiation. METHODS: From January 2008 to January 2015, patients who underwent ERC/IDUS for bile duct obstruction were enrolled. Patient's ERC/IDUS diagnosis was compared with the final diagnosis determined by pathologic findings and/or clinical outcome of follow-up. RESULTS: One hundred and ninety-three patients with bile duct obstruction were included. IDUS correctly identified 94 of 97 malignant diseases and 76 of 96 benign diseases with sensitivity, specificity, and accuracy rate of 96.91, 79.17, and 88.08 %, respectively. Additionally, the accuracy rate of IDUS for diagnosis of proximal bile duct obstruction was higher than that of distal bile duct obstruction (98.08 vs. 82.73 %, p = 0.006). Besides, there was a significant difference in the length at the obstruction site between benign and malignant diseases (13.76 +/- 7.37 vs. 19.97 +/- 11.37 mm, p < 0.001) as well as thickness of bile duct wall at the site of obstruction (3.06 +/- 0.92 vs. 7.03 +/ 3.70 mm, p = 0.008). Biliary wall thickness >7 mm without extrinsic compression had a positive predictive value (PPV) of 100 % for including malignancy, while length ?20 mm demonstrated a PPV of 93.44 %. CONCLUSIONS: ERC/IDUS is effective in distinguishing malignant from benign bile duct obstruction, thus helping in further clinical management. PMID- 26423080 TI - Analysis of Hospital-Based Emergency Department Visits for Inflammatory Bowel Disease in the USA. AB - BACKGROUND: Inflammatory bowel disease (IBD) is a chronic, debilitating condition with high emergency department (ED) utilization. We aimed to investigate the utilization patterns of ED by IBD patients and measure hospitalization and surgical rates following ED visits. METHODS: We conducted a cross-sectional study of adults with IBD listed as the primary ED diagnosis from the 2009 to 2011 Nationwide Emergency Department Sample. The characteristics of the IBD-related ED visits in relation to following hospitalizations and surgeries were analyzed. RESULTS: Adult IBD patients constitute 0.09 % of the total ED visits. Crohn's disease (CD) contributed to 69 % of the IBD-ED visits. The hospitalization rate from ED was 59.9 % nationally, ranging from 56 % in west to 69 % in northeast. The most significant factors associated with hospitalization were intra-abdominal abscess [odds ratio (OR) 24.22], bowel obstruction (OR 17.77), anemia (OR 7.54), malnutrition (OR 6.29), hypovolemia/electrolyte abnormalities (OR 5.57), and fever/abnormal white cell count (OR 3.18). Patients with CD (OR 0.66), low-income group (OR 0.90), and female gender (OR 0.87) have a lower odds of getting hospitalized. Age above 65 years (OR 1.63), CD (OR 1.89), bowel obstruction (OR 9.24), and intra-abdominal abscess (OR 18.41) were significantly associated with surgical intervention. CONCLUSION: The IBD-related ED visits have remained relatively stable from 2009 to 2011. The presence of anemia, malnutrition, hypovolemia, electrolyte abnormalities, fever, abnormal white cell count, bowel obstruction, or intra-abdominal abscess during the ED visit was associated with hospitalization. The presence of bowel obstruction and intra-abdominal abscess was strongly associated with surgical intervention. PMID- 26423081 TI - Morphological Characteristics of Early Gastric Neoplasms Detected After Helicobacter pylori Eradication. AB - BACKGROUND: Previous morphological studies indicated that the eradication of Helicobacter pylori (H. pylori) made gastric neoplasms endoscopically indistinct through the flattening and covering of tumors with a non-neoplastic epithelium (NE). AIM: To validate these alterations. METHODS: We reviewed and compared the endoscopic and histological findings of early gastric carcinomas and high-grade dysplasias resected endoscopically from H. pylori-infected and H. pylori eradicated patients. The extent of NE covering a tumor was expressed as the histological length ratio of NE to the tumor. Tumor morphology was compared before and after therapies in patients who received H. pylori eradication treatments during the period from tumor discovery to endoscopic resection. RESULTS: NE-covered ratios were higher in the 59 tumors detected after the eradication of H. pylori than in the 152 tumors detected during the infection (median 8 vs. 0 %, respectively), whereas the frequency at which an elevated morphology and whitish discoloration of a tumor were observed was less (14 vs. 56 %, and 14 vs. 43 %, respectively). These were also independent characteristics for tumors detected after the eradication of H. pylori. Two elevated tumors showing whitish discoloration out of 16 tumors became endoscopically indistinct following H. pylori eradication treatments through the flattening of tumors and muting of the discoloration. CONCLUSION: The eradication of H. pylori promoted covering with NE, the flattening of tumors, and muting of the whitish discoloration, which may make a subset of tumors, potentially including whitish elevated neoplasms, indistinct. PMID- 26423082 TI - Enteractinococcus lamae sp. nov. and Enteractinococcus viverrae sp. nov., isolated from animal faeces. AB - Two novel actinobacteria, designated strains YIM 101617(T) and YIM 101632(T), were isolated from Lama pacos (alpaca) and Viverra zibetha (civet) faeces in Yunnan Wild Animal Park in Yunnan province, southwestern China. Both strains should be placed in genus Enteractinococcus based on phylogenetic analysis. Based on 16S rRNA gene sequence analysis, strain YIM 101617(T) exhibits high similarity to Enteractinococcus fodinae DSM 22966(T) (97.70 %) and Enteractinococcus coprophilus YIM 100590(T) (97.45 %), whilst YIM 101632(T) exhibits high similarity to Enteractinococcus coprophilus YIM 100590(T) (97.25 %), and the similarity between YIM 101617(T) and YIM 101632(T) is 95.90 %. However, DNA-DNA hybridization values of the two strains with the type strains in the genus Enteractinococcus were low (<70 %). Most morphological and chemotaxonomic characteristics of the two strains were found to be similar to those of species in the genus Enteractinococcus but also some differences were observed. The DNA G+C contents of strains YIM 101617(T) and YIM 101632(T) were determined to be 55.9 and 56.4 mol%, respectively. Based on these data, the two strains are concluded to represent two different novel species in the genus Enteractinococcus. The names Enteractinococcus lamae sp. nov. (type strain YIM 101617(T)=DSM 27612(T)=CCTCC AB 2013230(T)) and Enteractinococcus viverrae sp. nov. (type strain YIM 101632(T)=KCTC 39552(T)=CCTCC AB 2013280(T)) are proposed, respectively. PMID- 26423083 TI - Treatment of Cardiovascular Risk Factors in Women. AB - Cardiovascular disease (CVD) is a leading cause of death for both women and men. Common traditional risk factors for CVD, such as hypercholesterolemia, hypertension and smoking have a high prevalence in women and in some cases a greater health impact compared with men. Nevertheless, risk factors are treated less often and less aggressively in women than in men, partly due to decreased awareness on the part of public health opinion makers, patients and physicians. About seventy five percent of all coronary heart disease deaths among women could be avoided if CVD risk factors like hypercholesterolemia, hypertension and smoking are adequately treated. This narrative review discusses the treatment of the 4 CVD risk factors, namely hypercholesterolemia, hypertension, smoking and diabetes. These risk factors were examined in the Framingham Heart study and years later they were found in the INTERHEART study to be the 4 most important risk factors for the development of CVD. PMID- 26423084 TI - Unique Coronary Artery Disease Differences in Women as Related to Revascularization. AB - There are significant differences in coronary heart disease (CHD) in women whenever a comparison is made to men and these carry over to revascularization procedures including percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) surgery. The coronary arteries of women are smaller, which presents additional challenges for PCI and CABG procedures. Unique atypical symptomatology in response to acute coronary syndrome (ACS) in women can confound diagnosis, women notoriously delay seeking medical help for ACS, and physicians and other caregivers have had a tendency to minimize the significance of these symptoms, contributing further to a delay in necessary care. There also appears to be an increased association of inflammation and CHD in women. The younger the female patient with CHD, the higher the mortality and that mortality clearly exceeds that of comparable male patients. For cardiovascular (CV) risk prevention in women, statins have had controversy associated with their use but overall, the proof of beneficial outcomes results from statins is also valid in women. An increased rate of adverse outcomes has been reported in women after PCI and CABG surgery. These worse clinical outcomes have persisted in contemporary years but lessened due to advancement in invasive techniques. Nevertheless, PCI that could improve clinical outcomes in women who have high-risk ACS is, unfortunately, performed on a less frequent basis and, in addition, there are greater delays involving women as compared to men. With increased clinical comorbidity associated with complex CHD in women, a lower anatomical SYNTAX score (from: SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery [SYNTAX] trial) appears necessary in order for women to achieve a similar long term mortality benefit from CABG surgery as compared to PCI. PMID- 26423085 TI - On the evolutionary advantage of coagulation factor V Leiden (FVL). AB - Carriership of coagulation factor V Leiden (FVL) is by far the most common thrombophilia in Western populations. FVL is caused by a single point mutation in the gene coding for coagulation factor V (FV) causing a lifelong procoagulatory state with an increased risk of venous thromboembolism (VTE) which might be fatal. It is believed that the mutation occurred in one person 21,000 years ago and today 3% to 15% of the Western populations are carriers. A potentially dangerous mutation such as FVL ought to be rare and should have been reduced, if not eradicated, by selection during the course of human evolution. Thus, FVL must confer the carriers with an evolutionary advantage in order to be so prevalent. Lower risk of profuse bleeding and increased fecundity might give carriers an advantage. In this paper we give an updated short background and discuss possible evolutionary advantages and disadvantages. PMID- 26423086 TI - Non-viral Delivery Systems for the Application in p53 Cancer Gene Therapy. AB - A key barrier to the development of gene therapy remains the lack of safe, efficient and easily controllable vehicles for gene delivery. The fundamental problems associated with the viral vehicles, e.g. lack of specificity and immunogenic potential, have driven the development of non-viral systems of gene delivery. In the last decade, studies on p53 gene replacement therapy have dominated the literature. Although clinical trials of p53 gene therapy have achieved limited success, it remains the only tumor suppressor gene to be evaluated formally in clinical trials for cancer treatment, with increasing focus on delivery using non-viral systems. In this article, we particularly review current investigations on p53 gene delivery using non-viral methods, including both physical and chemical approaches, with an emphasis on the latter. The existing opportunities and challenges for successful p53 cancer gene therapy are also discussed. PMID- 26423087 TI - Silver and other metals in the treatment of gastrointestinal diseases. AB - Disturbance in the functioning of the gastrointestinal (GI) tract can critically affect the health and even the life of the whole organism. Several factors, both exo- and endogenous may contribute to the dysregulation of homeostasis in the digestive system, including genetic background, ingestion of highly processed food, exposition to environmental pollution or chronic stress, and changes in gut microflora, to name just a few. An important number of these factors rely on metals, which often play a dual, stimulatory and inhibitory role in crucial physiological processes. In this paper, we focus on the structures incorporating silver, copper and other metals as future drugs against GI diseases. We critically review available literature for their effectiveness and potential application, and discuss clinical relevance of these findings. PMID- 26423088 TI - Calcium-related neurotoxicity of oxaliplatin: understanding the mechanisms to drive therapy. AB - Oxaliplatin is one of the most widely used anticancer drugs representing the cornerstone of the treatment of colorectal cancer. Yet a number of side effects, including oxaliplatin- induced peripheral neurotoxicity (OIPN) which represents a dose-limiting side effect in the clinical use of oxaliplatin, limit its use and a better understanding of its pathogenesis would offer a great opportunity to improve the "quality of survival" of cancer patients. So far, no treatment able to prevent or limit OIPN has been approved, and one of the reasons for this unmet clinical need is the incomplete knowledge of its pathogenesis preventing the development of rationalebased pharmacological interventions. Preclinical and clinical evidence raised the hypothesis that intracellular calcium-related events might play an important role in the onset of OIPN. Yet, the results of mechanistic pre-clinical studies appear inconsistent and, therefore, their relevance in neuroprotective drugs design is still uncertain. Indeed, it is at present unclear whether aberrant calcium signalling is the key pathogenetic moment or whether it just constitutes the mediator of the clinical phenotype. This review will summarize the preclinical results involving calcium-related events and OIPN with the aim to provide an updated overview of the available evidence and highlight the most promising strategies to design effective neuroprotective drugs. In particular, we will focus on the pre-clinical evidence suggesting that TRPV1, TRPM8 or TRPA1 might be involved, as these appear particularly amenable to pharmacological modulation. PMID- 26423089 TI - Authors' reply to Gupta. PMID- 26423090 TI - Middle East respiratory syndrome coronavirus (MERS-CoV) in pilgrims returning from the Hajj. PMID- 26423091 TI - Elastofibroma With Amyloid Deposition. PMID- 26423092 TI - End-of-life care in patients with primary malignant brain tumors: early is better. PMID- 26423093 TI - Hue Selectivity in Human Visual Cortex Revealed by Functional Magnetic Resonance Imaging. AB - The variability of color-selective neurons in human visual cortex is considered more diverse than cone-opponent mechanisms. We addressed this issue by deriving histograms of hue-selective voxels measured using fMRI with a novel stimulation paradigm, where the stimulus hue changed continuously. Despite the large between subject difference in hue-selective histograms, individual voxels exhibited selectivity for intermediate hues, such as purple, cyan, and orange, in addition to those along cone-opponent axes. In order to rule the possibility out that the selectivity for intermediate hues emerged through spatial summation of activities of neurons selectively responding to cone-opponent signals, we further tested hue selective adaptations in intermediate directions of cone-opponent axes, by measuring responses to 4 diagonal hues during concurrent adaptation to 1 of the 4 hues. The selective and unidirectional reduction in response to the adapted hue lends supports to our argument that cortical neurons respond selectively to intermediate hues. PMID- 26423094 TI - Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis. AB - Metabolic syndrome and type 2 diabetes mellitus constitute a major problem to global health, and their incidence is increasing at an alarming rate. Non alcoholic fatty liver disease, which affects up to 90% of obese people and nearly 70% of the overweight, is commonly associated with MetS characteristics such as obesity, insulin resistance, hypertension and dyslipidemia. In the present study, we demonstrate that hepatic lipase (HL)-inactivation in mice fed with a high-fat, high-cholesterol diet produced dyslipidemia including hypercholesterolemia, hypertriglyceridemia and increased non-esterified fatty acid levels. These changes were accompanied by glucose intolerance, pancreatic and hepatic inflammation and steatosis. In addition, compared with WT mice, HL(-/-) mice exhibited enhanced circulating MCP1 levels, monocytosis and higher percentage of CD4+Th17+ cells. Consistent with increased inflammation, livers from HL(-/-) mice had augmented activation of the stress SAPK/JNK- and p38-pathways compared with the activation levels of the kinases in livers from WT mice. Analysis of HL(-/-) and WT mice fed regular chow diet showed dyslipidemia and glucose intolerance in HL(-/-) mice without any other changes in inflammation or hepatic steatosis. Altogether, these results indicate that dyslipidemia induced by HL-deficiency in combination with a high-fat, high-cholesterol diet promotes hepatic steatosis and inflammation in mice which are, at least in part, mediated by the activation of the stress SAPK/JNK- and p38-pathways. Future studies are warranted to asses the viability of therapeutic strategies based on the modulation of these kinases to reduce hepatic steatosis associated to lipase dysfunction. PMID- 26423095 TI - Recombinant human thyrotropin preparation for adjuvant radioiodine treatment in children and adolescents with differentiated thyroid cancer. AB - AIM: Although recombinant human thyrotropin (rhTSH) is widely used in treating differentiated thyroid cancer (DTC), almost all clinical investigation has been in adults. The aim of our retrospective study was to evaluate outcomes of adjuvant, rhTSH-aided radioiodine treatment in children/adolescents with DTC and to compare them to (131)I therapy during l-thyroxin withdrawal (THW). METHODS: Patients with the diagnosis of DTC who were <=18 years of age and had no signs of persistent disease at the time of (131)I treatment were included; 48 patients were treated after rhTSH (rhTSH group) and 82 after THW group. The median time of follow-up after therapy was 67 months and was longer in the THW group (99 vs 43 months, P<0.05). RESULTS: On the day of (131)I administration, all but one patient had TSH levels above 25 MUIU/ml. Peak TSH concentration was significantly higher in the rhTSH group (152 MUIU/ml vs 91 MUIU/ml). Similarly, the thyroglobulin concentration was higher in the rhTSH group (9.7 ng/ml vs 1.8 ng/ml). No side effects requiring medical intervention were recorded after rhTSH administration. The evaluation of disease outcomes during TSH stimulation (6-18 months after (131)I treatment) revealed equal rates of thyroid ablation (71%) in both groups. During subsequent follow-up, five patients showed recurrence (P>0.05). CONCLUSIONS: In children/adolescents, rhTSH-aided adjuvant radioiodine treatment is associated with rates of remnant ablation and short-term recurrence similar to THW. As this preparation has several advantages over THW, rhTSH may become the preferred method of TSH stimulation once studies of long-term outcomes show non-inferiority to THW in this age group. PMID- 26423096 TI - Evaluation of a culturally adapted training course in Indigenous e-mental health. AB - OBJECTIVE: To report the impact of the Indigenous e-mental health training course 'Yarning about Indigenous Mental Health using the AIMhi Stay Strong App'. METHOD: Participants were trained in e-mental health and the use of one of the first culturally adapted e-mental health interventions - The AIMhi Stay Strong App. Between October 2013 and December 2014, 138 participants completed the 'Yarning about Indigenous Mental Health using the AIMhi Stay Strong App' training course and 130 completed pre- and post-training questionnaires to explore knowledge and confidence in a number of areas trained. RESULTS: Paired t-tests showed significant improvements across all measures of skill and knowledge except for confidence in using computers. CONCLUSIONS: E-mental health is a relatively new development that may contribute to improved access to mental health services for rural and remote Indigenous Australians, particularly where such tools are culturally adapted. Whilst current knowledge and use of e-mental health tools in this group of Northern Territory service providers was limited, perceived knowledge and confidence in use was significantly improved following training. PMID- 26423097 TI - Prevalence and Diagnosis Rates of Childhood ADHD Among Racial-Ethnic Groups in a Public Mental Health System. AB - OBJECTIVE: This study estimated the proportions of Hispanic and non-Hispanic white and black children ages three to 17 with a diagnosis of attention-deficit hyperactivity disorder (ADHD) receiving services from the New York State public mental health system (NYS PMHS) and their annual treated ADHD prevalence rates. Findings were compared with those of recent national studies of general population samples. METHODS: Data were from a 2011 survey of users of NYS PMHS nonresidential services. Adjusted odds ratios compared the probability of an ADHD diagnosis among the groups by age, gender, and insurance type. Prevalence rates were compared among groups by age and gender. RESULTS: An estimated 133,091 children used the NYS PMHS, of whom 31% had an ADHD diagnosis. The prevalence rate of ADHD among whites was significantly lower than that among Hispanics or blacks in all gender and age groups except Hispanic females ages 13 to 17. White children were significantly less likely than black children to receive an ADHD diagnosis. CONCLUSIONS: National studies have reported higher ADHD rates among white children. Compared with children in the NYS PMHS, those in national studies had multiple access points to care, including private psychiatrists and clinicians and primary care practitioners. The higher reported ADHD rates in national studies may reflect higher rates of private insurance among white children, which would increase the likelihood of their using private practitioners. Cultural factors that influence whether and where care is sought and whether practitioners appropriately diagnosis ADHD may also explain the difference in findings. PMID- 26423098 TI - Practices of Depression Care in Home Health Care: Home Health Clinician Perspectives. AB - OBJECTIVE: The study assessed gaps between published best practices and real world practices of treating depression in home health care (HHC) and barriers to closing gaps. METHODS: The qualitative study used semistructured interviews with nurses and administrators (N=20) from five HHC agencies in five states. Audio recorded interviews were transcribed and analyzed by a multidisciplinary team using grounded theory method to identify themes. RESULTS: Routine HHC nursing overlapped with all functional areas of depression care. However, gaps were noted between best and real-world practices. Gaps were associated with perceived scope of practice by HHC nurses, knowledge gaps and low self-efficacy in depression treatment, stigma attached to depression, poor quality of antidepressant management in primary care, and poor communication between HHC and primary care clinicians. CONCLUSIONS: Strategies to close gaps between typical and best practices include enhancing HHC clinicians' knowledge and self-efficacy with depression treatment and improving the quality of antidepressant management and communication with primary care. PMID- 26423099 TI - Provider and Nonprovider Sources of Mental Health Help in the Military and the Effects of Stigma, Negative Attitudes, and Organizational Barriers to Care. AB - OBJECTIVE: This study examined sources of help (providers or nonproviders) used by soldiers for mental health problems. Differences in perceived barriers to care by type of help used were also assessed. METHODS: Active-duty soldiers from four brigade combat teams (N=3,380) were surveyed in 2008-2009. Items assessed posttraumatic stress disorder; depression; anxiety; help needed because of a stress, emotional, alcohol, or family problem; stigma; negative attitudes toward care; and organizational barriers. Participants reported receipt of help in the past three months from providers (mental health or medical professionals or an Army resource hotline) or nonproviders (fellow soldier, medic, chaplain, or chain of command). RESULTS: Nearly a third (31%) were identified as being in need of mental health care. Of those, 5% reported using nonprovider help exclusively, 14% used provider help exclusively, and 7% used both types. Stigma was rated significantly lower as a barrier among those who used help exclusively from providers than among those who did not use help from any source; however, no significant differences in stigma scores were found between those who used help from nonproviders and those who did not use help from any source. Soldiers who used help from nonproviders were more likely than those who used help from providers to perceive organizational barriers. CONCLUSIONS: Results show that soldiers may view nonproviders as alternative sources of mental health help, suggesting that the Army should ensure that such resources are adequately trained and integrated into the mental health community so that soldiers can receive the help they need. PMID- 26423100 TI - Use of Active-Play Video Games to Enhance Aerobic Fitness in Schizophrenia: Feasibility, Safety, and Adherence. AB - OBJECTIVE: Active-play video games have been used to enhance aerobic fitness in various clinical populations, but their use among individuals with schizophrenia has been limited. METHODS: Feasibility, acceptability, safety, and adherence data were obtained for use of aerobic exercise (AE) equipment by 16 individuals with schizophrenia during a 12-week AE program consisting of three one-hour exercise sessions per week. Equipment included exercise video games for Xbox 360 with Kinect motion sensing devices and traditional exercise equipment. RESULTS: Most participants (81%) completed the training, attending an average of 79% of sessions. The proportion of time spent playing Xbox (39%) exceeded time spent on any other type of equipment. When using Xbox, participants played 2.24+/-1.59 games per session and reported high acceptability and enjoyment ratings, with no adverse events. CONCLUSIONS: Measures of feasibility, acceptability, adherence, and safety support the integration of active-play video games into AE training for people with schizophrenia. PMID- 26423101 TI - Perception of Coercion Among Patients With a Psychiatric Community Treatment Order: A Literature Review. AB - OBJECTIVE: Various forms of compulsory psychiatric community treatment orders (CTOs) are commonly utilized internationally. CTOs remain contentious because of the ethical implications of coercing patients to receive treatment. Understanding patients' experience of CTOs can assist in the development of more patient centered and recovery-focused community care. This review examined the relationship between CTOs and patients' perceptions of coercion in the literature. METHODS: A search of key terms relating to CTOs and patients' perceptions of coercion was conducted of relevant databases from their inception to March 31, 2014. Publications were included if they were peer reviewed, reported on original research, surveyed or interviewed patients who were or had been subject to a CTO, and were written in English. Factors influencing patients' perceptions of coercion, including the regional context of the studies, were identified. RESULTS: Twenty-three primary research articles, reporting on 14 studies from seven countries, were included. Evidence indicated that CTOs may contribute to a patient's sense of coercion, with marked variations among studies in the levels of coercion. Contextual factors, including perceptions of alternatives to CTOs, the presence of additional forms of leverage in patients' lives, and the process of CTO initiation and enforcement, may mitigate or enhance perceptions of coercion. CONCLUSIONS: Coercive elements of CTOs may be reduced through increased patient access to information, better working relationships with service providers, and accessible, fair processes. The coercive aspects of CTOs should be seen as part of a broader understanding of the daily pressures and leverage applied in outpatient psychiatric treatment. PMID- 26423102 TI - The Impact of Psychiatric Practice Guidelines on Medication Costs and Youth Aggression in a Juvenile Justice Residential Treatment Program. AB - OBJECTIVE: Stakeholders have expressed concern over the appropriate use of psychiatric medications and adequacy of mental health services for youths involved with the juvenile justice system. This study assessed the impact of implementing psychiatric practice guidelines on medication costs and youth aggression in a juvenile justice facility. The study examined whether implementing psychiatric practice guidelines in a facility with an organized psychosocial treatment program would reduce psychiatric medication costs, compared with two other facilities, and whether lower psychotropic medication costs would be associated with increases in youth aggression. METHODS: Administrative data from three state-run juvenile justice facilities were analyzed to determine psychiatric medication costs and rates of youth aggression. Psychiatric practice guidelines that involved screening, shared decision making, psychosocial treatments, medication prescribing, and monitoring of side effects were implemented in only one of the three facilities, with a goal of applying evidence-based psychopharmacology and benefit-risk considerations. RESULTS: Over the ten-year study period (2003-2012), psychiatric medication costs decreased 26% at the facility implementing the psychiatric practice guidelines, whereas costs at the two comparison facilities increased by 104% and 152%. As psychiatric medication costs decreased at the facility implementing the guidelines, youth aggression there did not increase. CONCLUSIONS: Implementing psychiatric practice guidelines in juvenile justice facilities can reduce psychotropic medication costs without an increase in youth aggression. Implementation of the guidelines requires an organized psychosocial treatment program to help deter an inappropriate focus on psychotropic treatments. PMID- 26423103 TI - Same-Day Integrated Mental Health Care and PTSD Diagnosis and Treatment Among VHA Primary Care Patients With Positive PTSD Screens. AB - OBJECTIVE: The study examined whether same-day integrated mental health services are associated with increased diagnosis and treatment initiation among primary care patients with positive posttraumatic stress disorder (PTSD) screens. METHODS: Data were from a national sample of Veterans Health Administration (VHA) primary care patients with a positive PTSD screen (N=21,427). Patients were assessed for PTSD diagnosis and treatment initiation on the screening day and <= 7 days, <= 12 weeks, <= 6 months, and <= 1 year after screening positive. The service setting on screening day was categorized as primary care only, same-day primary care-mental health integration (PC-MHI), or same-day specialty mental health care. Multivariable generalized estimating equations logistic regression was used to estimate associations between category of screening day services and diagnosis and treatment initiation, with adjustment for demographic characteristics, prior psychiatric diagnoses, prior VHA service utilization, and PTSD screen score. RESULTS: Of the 21,427 patients with positive PTSD screens, 10,809 (50.4%) received a diagnosis within one year of screening positive. Same day PC-MHI services were associated with greater odds of PTSD diagnosis, both on the same day as (odds ratio [OR]=2.23) and one year (OR=1.67) after screening positive compared with primary care-only services (p<.001). Among those who received a diagnosis on the same day as their positive screen, same-day PC-MHI services were associated with increased odds of initiating PTSD treatment (OR=3.39) within 12 weeks of diagnosis, compared with primary care only (p<.001). CONCLUSIONS: Same-day integrated mental health services may help facilitate PTSD diagnosis and treatment initiation after a positive screen. PMID- 26423105 TI - XXI Congress of the Italian Society of Neonatology. PMID- 26423104 TI - Homeless Veterans Eligible for Medicaid Under the Affordable Care Act. AB - OBJECTIVE: Among homeless veterans and those at risk of homelessness currently enrolled in Veterans Affairs (VA) health care, this study examined the proportion likely to become eligible for Medicaid in 2014 and their health needs. METHODS: A total of 114,497 homeless and at-risk veterans were categorized into three groups: currently covered by Medicaid, likely to become eligible for Medicaid, and not likely. RESULTS: Seventy-eight percent of the sample was determined to be likely to become eligible for Medicaid in states that expand Medicaid. Compared with veterans not likely to become eligible for Medicaid, those likely to become eligible were less likely to have general medical and psychiatric conditions and to have a VA service-connected disability but more likely to have substance use disorders. CONCLUSIONS: Programs serving homeless and at-risk veterans should anticipate the potential interplay between VA health care and the expansion of Medicaid in states that implement the expansion. PMID- 26423106 TI - Application of real-time machine learning to myoelectric prosthesis control: A case series in adaptive switching. AB - BACKGROUND: Myoelectric prostheses currently used by amputees can be difficult to control. Machine learning, and in particular learned predictions about user intent, could help to reduce the time and cognitive load required by amputees while operating their prosthetic device. OBJECTIVES: The goal of this study was to compare two switching-based methods of controlling a myoelectric arm: non adaptive (or conventional) control and adaptive control (involving real-time prediction learning). STUDY DESIGN: Case series study. METHODS: We compared non adaptive and adaptive control in two different experiments. In the first, one amputee and one non-amputee subject controlled a robotic arm to perform a simple task; in the second, three able-bodied subjects controlled a robotic arm to perform a more complex task. For both tasks, we calculated the mean time and total number of switches between robotic arm functions over three trials. RESULTS: Adaptive control significantly decreased the number of switches and total switching time for both tasks compared with the conventional control method. CONCLUSION: Real-time prediction learning was successfully used to improve the control interface of a myoelectric robotic arm during uninterrupted use by an amputee subject and able-bodied subjects. CLINICAL RELEVANCE: Adaptive control using real-time prediction learning has the potential to help decrease both the time and the cognitive load required by amputees in real-world functional situations when using myoelectric prostheses. PMID- 26423107 TI - Axial bone-socket displacement for persons with a traumatic transtibial amputation: The effect of elevated vacuum suspension at progressive body-weight loads. AB - BACKGROUND: Elevated vacuum suspension systems use a pump to draw air from the socket with the intent of reducing bone-socket motion as compared to passive suction systems. However, it remains unknown if elevated vacuum suspension systems decrease limb displacement uniformly during transitions from unloaded to full-body-weight support. OBJECTIVES: To compare limb-socket motion between elevated vacuum and passive suction suspension sockets using a controlled loading paradigm. STUDY DESIGN: Comparative analysis. METHODS: Persons with transtibial amputation were assessed while wearing either an elevated vacuum or passive suction suspension socket. Digital video fluoroscopy was used to measure axial bone-socket motion while the limb was loaded in 20% body-weight increments. An analysis of variance model was used to compare between suspension types. RESULTS: Total axial displacement (0%-100% body weight) was significantly lower using the elevated vacuum (vacuum: 1.3 cm, passive suction: 1.8 cm; p < 0.0001). Total displacement decreased primarily due to decreased motion during initial loading (0%-20%; p < 0.0001). Other body-weight intervals were not significantly different between systems. CONCLUSION: Elevated vacuum suspension reduced axial limb-socket motion by maintaining position of the limb within the socket during unloaded conditions. Elevated vacuum provided no meaningful improvement in limb socket motion past initial loading. CLINICAL RELEVANCE: Excessive bone-socket motion contributes to poor residual limb health. Our results suggest elevated vacuum suspensions can reduce this axial displacement. Visual assessment of the images suggests that this occurs through the reduction or elimination of the air pocket between the liner and socket wall while the limb is unloaded. PMID- 26423108 TI - Left Atrial Appendage Closure Reduces the Incidence of Postoperative Cerebrovascular Accident in Patients Undergoing Cardiac Surgery. AB - BACKGROUND: Cerebrovascular accidents (CVA) are a major adverse event following cardiac surgery, for which atrial fibrillation (AF) is considered as a risk factor. We have recently performed left atrial appendage (LAA) surgical closure or amputation (LAAC/A), which is the main source of emboli, during open-heart surgery. METHODS AND RESULTS: A prospective observational study of 1,831 consecutive patients (69.2% male, aged 66.8+/-12.2 years) undergoing cardiac surgery between 2009 and 2013 was performed. The incidence of postoperative CVA within 6 months in patients with and without LAAC/A was compared. We further stratified patients according to their risk of CVA using CHA2DS2-VASc score; dichotomizing low-risk (score <2) and high-risk groups (>=2). A total of 369 patients (20.2%) underwent LAAC/A. Although these patients had larger left atrial diameter preoperatively and developed postoperative AF more frequently than those without LAAC/A (45.4 vs. 41.1 mm, 49.3 vs. 39.1%, respectively, both P<0.001), the CVA incidence was not different between the groups (3.5 vs. 3.0%, P=0.612). Multivariate analysis revealed no association between LAAC/A and CVA in patients with CHA2DS2-VASc score >=2, whereas in patients with CHA2DS2-VASc score <2, LAAC/A was the only and independent factor negatively associated with CVA development (odds ratio <10(-6); P=0.021). CONCLUSIONS: Additional LAA procedure at the time of cardiac surgery reduces the incidence of early postoperative CVA in patients with low CHA2DS2-VASc score. PMID- 26423109 TI - Serum levels of ghrelin and obestatin in children with symptoms suggestive of delayed gastric emptying of unclear etiology. AB - BACKGROUND: Ghrelin and obestatin are peptides of the gut-brain axis affecting appetite and gastrointestinal motility. METHODS: We conducted a cross-sectional, case-control study to determine pre- and postprandial serum levels of total ghrelin and obestatin along with gastric emptying scintigraphy in children with symptoms suggestive of delayed gastric emptying time (GET), not attributable to any identifiable cause. RESULTS: Twenty children with symptoms suggestive of delayed GET, of whom 9 had delayed GET, and 20 age-matched healthy children were enrolled. Preprandial ghrelin and obestatin were higher compared to controls (GHR mean level in patients and controls: 1162 pg/mL and 401 pg/mL respectively; P<0.05; OB mean level in patients and controls: 417 pg/mL and 325 pg/mL respectively; not statistically significant). Postprandial ghrelin was significantly decreased in the subgroup of patients with delayed GET (GHR mean level in children with normal and prolonged GET: 1237 pg/mL and 584 pg/mL respectively; P<0.05). CONCLUSION: Obestatin and ghrelin were deranged in children with symptoms indicative of delayed GET of unexplained etiology. Gastric emptying was prolonged in almost half of the patients thus gastric emptying scintigraphy should be considered in the investigation of children with such symptomatology. PMID- 26423110 TI - Point-of-care genetic profiling and/or platelet function testing in acute coronary syndrome. AB - Our aim was to demonstrate that the sequential use of the Verigene(r) rapid CYP2C19 test for genetic profiling and the VerifyNowTM bedside test for platelet function measurement in ACS patients may optimise P2Y12 inhibition. "Rapid" (CYP2C19*1/*1 or CYP2C19*17 carriers, n=211) and "slow" metabolisers (CYP2C19*2 carriers, n=58) were first put on clopidogrel and prasugrel for >= 2 weeks, respectively. Patients with low platelet reactivity (PRU<30) on prasugrel or high platelet reactivity (>208 PRU) on clopidogrel were then switched to clopidogrel and prasugrel, respectively. Our objectives were (i) to demonstrate that the proportion of "rapid" metabolisers on 75 mg of clopidogrel within 30-208 (PRU) of P2Y12 inhibition is non-inferior to "slow" metabolisers on prasugrel 10 mg and (ii) to evaluate the same end-point after switching drugs. The proportion of "rapid" and "slow" metabolisers within 30-208 PRU of P2Y12 inhibition was 71% and 56.9%, respectively, an absolute difference of +14.1% (95% CI, -0.05% to 28.28%) with a non-inferiority margin greater than the predefined margin of -10%. Among patients out of target, all but one "slow" metabolisers displayed low-on prasugrel platelet reactivity while the majority of "rapid" metabolisers (68%) displayed high-on clopidogrel platelet reactivity. After switching, the proportion of patients within 30-208 PRU of P2Y12 inhibition was 83.6% and 79.3% in "rapid" and "slow" metabolisers, respectively (+4.3%, 95% CI -7.3% to 15.9%). In conclusion, this study demonstrates a loose relationship between genotype and platelet function phenotype approaches but that they are complementary to select prasugrel or clopidogrel MD in stented ACS patients. PMID- 26423111 TI - An unusual cause of odynophagia. PMID- 26423112 TI - Prolonged suppression of HBV in mice by a novel antibody that targets a unique epitope on hepatitis B surface antigen. AB - OBJECTIVE: This study aimed to investigate the therapeutic potential of monoclonal antibody (mAb) against HBV as a novel treatment approach to chronic hepatitis B (CHB) in mouse models. METHODS: Therapeutic effects of mAbs against various epitopes on viral surface protein were evaluated in mice mimicking persistent HBV infection. The immunological mechanisms of mAb-mediated viral clearance were systematically investigated. RESULTS: Among 11 tested mAbs, a novel mAb E6F6 exhibited the most striking therapeutic effects in several HBV persistent mice. Single-dose administration of E6F6 could profoundly suppress the levels of hepatitis B surface antigen (HBsAg) and HBV DNA for several weeks in HBV-transgenic mice. E6F6 regimen efficiently prevented initial HBV infection, and reduced viral dissemination from infected hepatocytes in human-liver-chimeric mice. E6F6-based immunotherapy facilitated the restoration of anti-HBV T-cell response in hydrodynamic injection (HDI)-based HBV carrier mice. Immunological analyses suggested that the Fcgamma receptor-dependent phagocytosis plays a predominant role in E6F6-mediated viral suppression. Molecular analyses suggested that E6F6 recognises an evolutionarily conserved epitope (GPCK(R)TCT) and only forms a smaller antibody-viral particle immune complex with limited interparticle crosslinking when it binds to viral particles. This unique binding characteristic of E6F6 to HBV was possibly associated with its effective in vivo opsonophagocytosis for viral clearance. CONCLUSIONS: These results provided new insight into understanding the therapeutic role and mechanism of antibody against persistent viral infection. The E6F6-like mAbs may provide a novel immunotherapeutic agent against human chronic HBV infection. PMID- 26423113 TI - Specific members of the predominant gut microbiota predict pouchitis following colectomy and IPAA in UC. AB - OBJECTIVE: Pouchitis is the most common complication after colectomy with ileal pouch-anal anastomosis (IPAA) for UC and the risk is the highest within the 1st year after surgery. The pathogenesis is not completely understood but clinical response to antibiotics suggests a role for gut microbiota. We hypothesised that the risk for pouchitis can be predicted based on the faecal microbial composition before colectomy. DESIGN: Faecal samples from 21 patients with UC undergoing IPAA were prospectively collected before colectomy and at predefined clinical visits at 1 month, 3 months, 6 months and 12 months after IPAA. The predominant microbiota was analysed using community profiling with denaturing gradient gel electrophoresis followed by quantitative real-time PCR validation. RESULTS: Cluster analysis before colectomy distinguished patients with pouchitis from those with normal pouch during the 1st year of follow-up. In patients developing pouchitis, an increase of Ruminococcus gnavus (p<0.001), Bacteroides vulgatus (p=0.043), Clostridium perfringens (p=0.011) and a reduction of two Lachnospiraceae genera (Blautia (p=0.04), Roseburia (p=0.008)) was observed. A score combining these five bacterial risk factors was calculated and presence of at least two risk factors showed a sensitivity and specificity of 100% and 63.6%, respectively. CONCLUSIONS: Presence of R. gnavus, B. vulgatus and C. perfringens and absence of Blautia and Roseburia in faecal samples of patients with UC before surgery is associated with a higher risk of pouchitis after IPAA. Our findings suggest new predictive and therapeutic strategies in patients undergoing colectomy with IPAA. PMID- 26423114 TI - Changes of intracellular Ca2+ in quercetin-induced autophagy progression. AB - Quercetin was previously reported to exhibit significant anti-proliferative activities, and its major effect on tumors was to induce cell apoptosis or autophagy. However, the specific mechanism remains controversial. In this study, autophagy induced by quercetin was determined with various methods. Intracellular Ca2+ ([Ca2+]i) was measured after being incubated with Fluo-3 acetoxymethyl (AM). At the same time, the relationship between the intracellular Ca2+ and autophagy induced by quercetin was further analyzed. These results showed that autophagy induced by quercetin (0-50 ug/ml) in HepG2 cells was in a dose-dependent manner. Meanwhile, when autophagy was induced by quercetin, [Ca2+]i was significantly increased. And after being incubated with calcium chelator 1,2-bis(2 aminophenoxy)ethane-N,N,N',N-tetraacetic acid-AM, autophagy was suppressed, which implied that [Ca2+]i elevation appeared to be the cause for autophagy induction. These results suggested that calcium from intracellular calcium storage may play an important role in quercetin-induced autophagy. PMID- 26423115 TI - H2S protects PC12 cells against toxicity of corticosterone by modulation of BDNF TrkB pathway. AB - Corticosterone, one of the glucocorticoids, is toxic to neurons and plays an important role in depressive-like behavior and depression. We previously showed that hydrogen sulfide (H2S), a novel physiological mediator, plays an inhibitory role in depression. However, the mechanism underlying H2S-triggered antidepressant-like role is not clearly known. Brain-derived neurotrophic factor (BDNF), a neurotrophic factor, plays a neuroprotective role that is mediated by its high-affinity tropomysin-related kinase B (TrkB) receptor. In this study, to investigate the underlying mechanism of H2S-induced antidepressant-like role, we explored whether H2S could protect neurons against corticosterone-mediated cyctotoxicity and whether this protective role of H2S was involved in the regulation of BDNF-TrkB pathway. Our data demonstrated that sodium hydrosulfide (NaHS), the donor of H2S, could prevent corticosterone-induced cytotoxicity, apoptosis, accumulation of intracellular reactive oxygen species (ROS) and loss of mitochondrial membrane potential (MMP) in PC12 cells. NaHS not only induced the up-regulation of BDNF but also prevented the down-regulation of BDNF by corticosterone. It was also found that blocking BDNF-TrkB pathway by K252a, an inhibitor of TrkB, abolished the protection of H2S against corticosterone-induced cytotoxicity, apoptosis, accumulation of ROS, and loss of MMP. These results suggest that H2S protects against the neurotoxicity of corticosterone by modulation of the BDNF-TrkB pathway. PMID- 26423116 TI - C-terminal extension of calmodulin-like 3 protein from Oryza sativa L.: interaction with a high mobility group target protein. AB - A large number of calmodulin-like (CML) proteins are present in plants, but there is little detailed information on the functions of these proteins in rice (Oryza sativa L.). Here, the CML3 protein from rice (OsCML3) and its truncated form lacking the C-terminal extension (OsCML3m) were found to exhibit a Ca2+-binding property and subsequent conformational change, but the ability to bind the CaM kinase II peptide was only observed for OsCML3m. Changes in their secondary structure upon Ca2+-binding measured by circular dichroism revealed that OsCML3m had a higher helical content than OsCML3. Moreover, OsCML3 was mainly localized in the plasma membrane, whereas OsCML3m was found in the nucleus. The rice high mobility group B1 (OsHMGB1) protein was identified as one of the putative OsCML3 target proteins. Bimolecular fluorescence complementation analysis revealed that OsHMGB1 bound OsCML3, OsCML3m or OsCML3s (cysteine to serine mutation at the prenylation site) in the nucleus presumably through the methionine and phenylalanine-rich hydrophobic patches, confirming that OsHMGB1 is a target protein in planta. The effect of OsCML3 or OsCML3m on the DNA-binding ability of OsHMGB1 was measured using an electrophoretic mobility shift assay. OsCML3m decreased the level of OsHMGB1 binding to pUC19 double-stranded DNA whereas OsCML3 did not. Taken together, OsCML3 probably provides a mechanism for manipulating the DNA-binding ability of OsHMGB1 in the nucleus and its C-terminal extension provides an intracellular Ca2+ regulatory switch. PMID- 26423117 TI - Development of Novel Polymeric Prodrugs Synthesized by Mechanochemical Solid State Copolymerization of Hydroxyethylcellulose and Vinyl Monomers. AB - Novel polymeric prodrugs were synthesized by mechanochemical solid-state copolymerization of hydroxyethylcellulose and the methacryloyloxy derivative of 5 fluorouracil (5-FU). Copolymerization was about 94% complete after 4 h, and the polymeric prodrug was quantitatively obtained after 14 h of reaction. The number average molecular weight (Mn) and polydispersity (H) of the polymeric prodrug were 39000 g/mol and 6.20, respectively. Mechanical fracturing of the polymer in a stainless steel twin-shell blender improved these properties (Mn=16000 g/mol and H=1.94). 5-FU was sustainably released from the polymeric prodrugs, and the rate was not affected by the molecular weight or molecular weight distribution of the prodrug under the experimental conditions used. These results suggest that novel polymeric prodrugs composed of a polysaccharide and a synthetic polymer can be fabricated by mechanochemical solid-state copolymerization under anaerobic conditions. PMID- 26423118 TI - Copper N-Heterocyclic Carbene Complexes As Active Catalysts for the Synthesis of 2-Substituted Oxazolines from Nitriles and Aminoalcohols. AB - The reaction between nitriles and aminoalcohols to access 2-substituted oxazolines was investigated. Using copper-NHC complexes, various nitriles were successfully converted into the corresponding oxazolines, under milder and less wasteful conditions than those of previously reported methods. PMID- 26423120 TI - Diamond-Based Supercapacitors: Realization and Properties. AB - In this Spotlight on Applications, we describe our recent progress on the fabrication of surface-enlarged boron-doped polycrystalline diamond electrodes, and evaluate their performance in supercapacitor applications. We begin with a discussion of the fabrication methods of porous diamond materials. The diamond surface enlargement starts with a top-down plasma etching method. Although the extra surface area provided by surface roughening or nanostructuring provides good outcome for sensing applications, a capacitance value <1 mF cm-2 or a surface-enlargement factor <100 fail to meet the requirement of a practical supercapacitor. Driven by the need for large surface areas, we recently focused on the tempated-growth method. We worked on both supported and free-standing porous diamond materials to enhance the areal capacitance to the "mF cm-2" range. With our newly developed free-standing diamond paper, areal capacitance can be multiplied by stacking multilayers of the electrode material. Finally, considering the fact that there is no real diamond-based supercapacitor device up to now, we fabricated the first prototype pouch-cell device based on the free standing diamond paper to evaluate its performance. The results reveal that the diamond paper is suitable for operation in high potential windows (up to 2.5 V) in aqueous electrolyte with a capacitance of 0.688 mF cm-2 per layer of paper (or 0.645 F g-1). Impedance spectroscopy revealed that the operation frequency of the device exceeds 30 Hz. Because of the large potential window and the ability to work at high frequency, the specific power of the device reached 1 * 105 W kg-1. In the end, we made estimations on the future target performance of diamond supercapacitors based on the existing information. PMID- 26423119 TI - Advancing Urinary Protein Biomarker Discovery by Data-Independent Acquisition on a Quadrupole-Orbitrap Mass Spectrometer. AB - The promises of data-independent acquisition (DIA) strategies are a comprehensive and reproducible digital qualitative and quantitative record of the proteins present in a sample. We developed a fast and robust DIA method for comprehensive mapping of the urinary proteome that enables large scale urine proteomics studies. Compared to a data-dependent acquisition (DDA) experiments, our DIA assay doubled the number of identified peptides and proteins per sample at half the coefficients of variation observed for DDA data (DIA = ~8%; DDA = ~16%). We also tested different spectral libraries and their effects on overall protein and peptide identifications and their reproducibilities, which provided clear evidence that sample type-specific spectral libraries are preferred for reliable data analysis. To show applicability for biomarker discovery experiments, we analyzed a sample set of 87 urine samples from children seen in the emergency department with abdominal pain. The whole set was analyzed with high proteome coverage (~1300 proteins/sample) in less than 4 days. The data set revealed excellent biomarker candidates for ovarian cyst and urinary tract infection. The improved throughput and quantitative performance of our optimized DIA workflow allow for the efficient simultaneous discovery and verification of biomarker candidates without the requirement for an early bias toward selected proteins. PMID- 26423122 TI - Evaluation of a focussed protocol for hand-held echocardiography and computer assisted auscultation in detecting latent rheumatic heart disease in scholars. AB - Introduction Echocardiography is the diagnostic test of choice for latent rheumatic heart disease. The utility of echocardiography for large-scale screening is limited by high cost, complex diagnostic protocols, and time to acquire multiple images. We evaluated the performance of a brief hand-held echocardiography protocol and computer-assisted auscultation in detecting latent rheumatic heart disease with or without pathological murmur. METHODS: A total of 27 asymptomatic patients with latent rheumatic heart disease based on the World Heart Federation criteria and 66 healthy controls were examined by standard cardiac auscultation to detect pathological murmur. Hand-held echocardiography using a focussed protocol that utilises one view - that is, the parasternal long axis view - and one measurement - that is, mitral regurgitant jet - and a computer-assisted auscultation utilising an automated decision tool were performed on all patients. RESULTS: The sensitivity and specificity of computer assisted auscultation in latent rheumatic heart disease were 4% (95% CI 1.0 20.4%) and 93.7% (95% CI 84.5-98.3%), respectively. The sensitivity and specificity of the focussed hand-held echocardiography protocol for definite rheumatic heart disease were 92.3% (95% CI 63.9-99.8%) and 100%, respectively. The test reliability of hand-held echocardiography was 98.7% for definite and 94.7% for borderline disease, and the adjusted diagnostic odds ratios were 1041 and 263.9 for definite and borderline disease, respectively. CONCLUSION: Computer assisted auscultation has extremely low sensitivity but high specificity for pathological murmur in latent rheumatic heart disease. Focussed hand-held echocardiography has fair sensitivity but high specificity and diagnostic utility for definite or borderline rheumatic heart disease in asymptomatic patients. PMID- 26423121 TI - Corticocortical connection patterns reveal two distinct visual cortical areas bordering dorsal V2 in marmoset monkey. AB - The organization of the cortex located immediately anterior to the second visual area (V2), i.e., the third tier visual cortex, remains controversial, especially in New World primates. In particular, there is lack of consensus regarding the exact location and extent of the lower visual quadrant representation of the third visual area V3 (or ventrolateral posterior -VLP - of a different nomenclature). Microelectrode and connectional mapping studies have revealed the existence of an upper visual quadrant representation abutting dorsal V2 anteriorly, and bordered medially and laterally by representations of the lower visual quadrant. It remains unclear whether these lower field regions are both part of a single area V3, which is split into two patches by an interposed region of upper field representation, or whether they are the lower field representations of two different areas, the dorsomedial area (DM) and area V3/VLP, respectively. To address this question, we quantitatively analyzed the patterns of corticocortical afferent connections labeled by tracer injections targeted to these two lower field regions in the dorsal aspect of the third tier cortex. We found different inter-areal connectivity patterns arising from these two regions, strongly suggesting that they belong to two different visual areas. In particular, our results indicate that the dorsal aspect of the third tier cortex consists of two distinct areas: a full area DM, representing the lower quadrant medially, and the upper quadrant laterally, and the lower quadrant representation of V3/VLP, located laterally to upper field DM. DM is predominantly connected with areas of the dorsal visual stream, and V3/VLP with areas of the ventral stream. These results prompt further functional investigations of the third tier cortex, as previous studies of this cortical territory may have pooled response properties of two very different areas into a single area V3. PMID- 26423123 TI - Extracellular Vesicles from Bovine Follicular Fluid Support Cumulus Expansion. AB - Expansion of the cumulus complex surrounding the oocyte is critical for ovulation of a fertilizable egg. The ovulation-inducing surge of luteinizing hormone leads to an increased expression of genes such as prostaglandin-endoperoxide synthase 2 (Ptgs2), pentraxin-related protein 3 (Ptx3), and tumor necrosis factor alpha induced protein 6 (Tnfaip6) that support cumulus expansion. Factors released by mural granulosa and cumulus granulosa cells into the follicular fluid induce paracrine signaling within the follicular compartment. The follicular fluid that separates these distinct granulosa cell types is an enriched fluid containing numerous proteins, nucleic acids, and other macromolecules. Extracellular vesicles (EVs) are also present; however, no physiologically relevant functions of follicular EVs have yet been demonstrated. In our study, the effect of follicular EVs on cumulus-oocyte complex (COC) expansion and relevant gene expression was assayed. Follicular EVs were isolated using ultracentrifugation from follicular fluid of small (3-5 mm) and large (>9 mm) antral bovine follicles, then characterized by nanoparticle tracking analysis, electron microscopy, and Western blot analysis. To test for bioactivity, mouse and bovine COCs were cultured with follicular EVs. Cumulus expansion and Ptgs2, Ptx3, and Tnfaip6 gene expression were measured following COC maturation culture. The results demonstrated that follicular EVs can support both measurable cumulus expansion and increased gene expression. PMID- 26423124 TI - How Is the Number of Primordial Follicles in the Ovarian Reserve Established? AB - The number of primordial follicles in the ovarian reserve is an important determinant of the length of the ovarian lifespan, and therefore the fertility of an individual. This reserve contains all of the oocytes potentially available for fertilization throughout the fertile lifespan. The maximum number is set during pregnancy or just after birth in most mammalian species; current evidence does not support neofolliculogenesis after the ovarian reserve is established, although this is increasingly being reexamined. Under physiological circumstances, this number will be influenced by the number of primordial germ cells initially specified in the epiblast of the developing embryo, their proliferation during and after migration to the developing gonads, and their death during oogenesis and formation of primordial follicles at nest breakdown. Death of germ cells during the establishment of the ovarian reserve occurs principally by autophagy or apoptosis, although the triggers that initiate these remain elusive. This review outlines the regulatory steps that determine the number of primordial follicles and thus the number of oocytes in the ovarian reserve at birth, using the mouse as the model, interspersed with human data where available. This information has application for understanding the variability in duration of fertility that occurs between normal individuals and with age, in premature ovarian insufficiency, and after chemotherapy or radiotherapy. PMID- 26423125 TI - Involvement of Mitochondrial Activity and OXPHOS in ATP Synthesis During the Motility Phase of Spermatozoa in the Pacific Oyster, Crassostrea gigas. AB - In the Pacific oyster, spermatozoa are characterized by a remarkably long movement phase (i.e., over 24 h) sustained by a capacity to maintain intracellular ATP level. To gain information on oxidative phosphorylation (OXPHOS) functionality during the motility phase of Pacific oyster spermatozoa, we studied 1) changes in spermatozoal mitochondrial activity, that is, mitochondrial membrane potential (MMP), and intracellular ATP content in relation to motion parameters and 2) the involvement of OXPHOS for spermatozoal movement using carbonyl cyanide m-chlorophenyl hydrazone (CCCP). The percentage of motile spermatozoa decreased over a 24 h movement period. MMP increased steadily during the first 9 h of the movement phase and was subsequently maintained at a constant level. Conversely, spermatozoal ATP content decreased steadily during the first 9 h postactivation and was maintained at this level during the following hours of the movement phase. When OXPHOS was decoupled by CCCP, the movement of spermatozoa was maintained 2 h and totally stopped after 4 h of incubation, whereas spermatozoa were still motile in the control after 4 h. Our results suggest that the ATP sustaining flagellar movement of spermatozoa may partially originate from glycolysis or from mobilization of stored ATP or from potential phosphagens during the first 2 h of movement as deduced by the decoupling by CCCP of OXPHOS. However, OXPHOS is required to sustain the long motility phase of Pacific oyster spermatozoa. In addition, spermatozoa may hydrolyze intracellular ATP content during the early part of the movement phase, stimulating mitochondrial activity. This stimulation seems to be involved in sustaining a high ATP level until the end of the motility phase. PMID- 26423126 TI - A Whole-Mount Approach for Accurate Quantitative and Spatial Assessment of Fetal Oocyte Dynamics in Mice. AB - Depletion of oocytes from the embryonic ovary is a key feature of mammalian oogenesis; however, the rational and molecular bases for this phenomenon remain poorly understood. Presently in the field, the most systematic analysis used to understand the effect of a given molecular pathway on fetal oocyte attrition is to count the number of oocytes in ovaries at different stages of development. This analysis is commonly done using a sampling method based on sectioning of the ovary, a technique that includes many laborious steps culminating in an inaccurate estimate of oocyte number contained within that ovary. This inability to generate data that are directly comparable between labs hinders the field and raises questions about the timing and rate of oocyte depletion. Therefore, we set out to implement a robust method that can be easily used by most research laboratories to study the dynamics of oogenesis during fetal mouse ovary development in both normal and experimental conditions. Here we describe an approach to accurately count the total number of oocytes in embryonic ovaries. This method is based on whole-mount immunofluorescence, tissue clearing with sucrose and ScaleA2 reagent, and automatic detection and counting of germ cells in intact ovaries using confocal microscopy and three-dimensional software analyses. We demonstrate the power of the method by assessing variation of fetal oocyte numbers between left and right ovaries and between litters of mice. Finally, we anticipate that the method could be adopted to the analysis of substages of meiotic prophase I and ovarian somatic cells. PMID- 26423127 TI - Involvement of Receptor Activity-Modifying Protein 3 (RAMP3) in the Vascular Actions of Adrenomedullin in Rat Mesenteric Artery Smooth Muscle Cells. AB - CALCB, ADM, and ADM2 are potent vasodilators that share a seven-transmembrane GPCR, calcitonin receptor-like receptor (CALCRL), whose ligand specificity is dictated by the presence of one of the three receptor activity-modifying proteins (RAMPs). We assessed the relative pharmacologic potency of these peptides in mesenteric artery smooth muscle cells (VSMCs) and the specific RAMP that mediates the effect of ADM in VSMCs. VSMCs, with or without RAMP knockdown, were treated with CALCB, ADM, or ADM2 in the presence or absence of their antagonists, CALCB8 37, ADM22-52, and ADM217-47, respectively, to assess the relative effect of peptides on cAMP production and their pharmacologic potency. Proximity ligation assay was used to assess the specific RAMP that associates with CALCRL to mediate the actions of ADM in VSMCs. All three peptides induced cAMP generation in VSMCs and the order of their potency is CALCB > ADM > ADM2. Effects of CALCB were blocked by CALCB8-37, ADM effects were blocked by CALCB8-37 and ADM217-47 but not ADM22-52, and ADM2 effects were blocked by all three antagonists. Knockdown of RAMP2 was ineffective, whereas knockdown of RAMP3 inhibited ADM-induced cAMP production in VSMCs, suggesting involvement of RAMP3 with CALCRL to mediate ADM effects. Absence of both RAMP2 and RAMP3 further increased CALCB-induced cAMP synthesis compared to control (P < 0.05). ADM increased CALCRL and RAMP3 association and RAMP3 knockdown inhibited the interaction of ADM with CALCRL. PMID- 26423128 TI - Global multiple protein-protein interaction network alignment by combining pairwise network alignments. AB - BACKGROUND: A wealth of protein interaction data has become available in recent years, creating an urgent need for powerful analysis techniques. In this context, the problem of finding biologically meaningful correspondences between different protein-protein interaction networks (PPIN) is of particular interest. The PPIN of a species can be compared with that of other species through the process of PPIN alignment. Such an alignment can provide insight into basic problems like species evolution and network component function determination, as well as translational problems such as target identification and elucidation of mechanisms of disease spread. Furthermore, multiple PPINs can be aligned simultaneously, expanding the analytical implications of the result. While there are several pairwise network alignment algorithms, few methods are capable of multiple network alignment. RESULTS: We propose SMAL, a MNA algorithm based on the philosophy of scaffold-based alignment. SMAL is capable of converting results from any global pairwise alignment algorithms into a MNA in linear time. Using this method, we have built multiple network alignments based on combining pairwise alignments from a number of publicly available (pairwise) network aligners. We tested SMAL using PPINs of eight species derived from the IntAct repository and employed a number of measures to evaluate performance. Additionally, as part of our experimental investigations, we compared the effectiveness of SMAL while aligning up to eight input PPINs, and examined the effect of scaffold network choice on the alignments. CONCLUSIONS: A key advantage of SMAL lies in its ability to create MNAs through the use of pairwise network aligners for which native MNA implementations do not exist. Experiments indicate that the performance of SMAL was comparable to that of the native MNA implementation of established methods such as IsoRankN and SMETANA. However, in terms of computational time, SMAL was significantly faster. SMAL was also able to retain many important characteristics of the native pairwise alignments, such as the number of aligned nodes and edges, as well as the functional and homologene similarity of aligned nodes. The speed, flexibility and the ability to retain prior correspondences as new networks are aligned, makes SMAL a compelling choice for alignment of multiple large networks. PMID- 26423130 TI - The gut-brain axis: interactions between Helicobacter pylori and enteric and central nervous systems. PMID- 26423129 TI - Role of Diffusion Tensor MR Imaging in Degenerative Cervical Spine Disease: a Review of the Literature. AB - In the article we review the current role of diffusion tensor imaging (DTI), a modern magnetic resonance (MR) technique, in the diagnosis and the management of cervical spondylotic myelopathy (CSM), the most serious complication of degenerative cervical spine disease (DCSD). The pathogenesis of DCSD is presented first with an emphasis placed on the pathological processes leading to myelopathy development. An understanding of the pathophysiological background of DCSD is necessary for appropriate interpretation of MR images, both plain and DTI. Conventional MRI is currently the imaging modality of choice in DCSD and provides useful information concerning the extent of spondylotic changes and degree of central spinal canal stenosis; however its capability in myelopathy detection is limited. DTI is a state of the art imaging method which recently has emerged in spinal cord investigations and has the potential to detect microscopic alterations which are beyond the capability of plain MRI. In the article we present the physical principles underlying DTI which determine its sensitivity, followed by an overview of technical aspects of DTI acquisition with a special consideration of spinal cord imaging. Finally, the scientific reports concerning DTI utility in DSCD are also reviewed. DTI detects spinal cord injury in the course of DCSD earlier than any other method and could be useful in predicting surgical outcomes in CMS patients, however technical and methodology improvement as well as standardization of acquisition protocols and postprocessing methods among the imaging centers are needed before its implementation in clinical practice. PMID- 26423131 TI - Allocation of freshly assimilated carbon into primary and secondary metabolites after in situ 13C pulse labelling of Norway spruce (Picea abies). AB - Plants allocate carbon (C) to sink tissues depending on phenological, physiological or environmental factors. We still have little knowledge on C partitioning into various cellular compounds and metabolic pathways at various ecophysiological stages. We used compound-specific stable isotope analysis to investigate C partitioning of freshly assimilated C into tree compartments (needles, branches and stem) as well as into needle water-soluble organic C (WSOC), non-hydrolysable structural organic C (stOC) and individual chemical compound classes (amino acids, hemicellulose sugars, fatty acids and alkanes) of Norway spruce (Picea abies) following in situ (13)C pulse labelling 15 days after bud break. The (13)C allocation within the above-ground tree biomass demonstrated needles as a major C sink, accounting for 86% of the freshly assimilated C 6 h after labelling. In needles, the highest allocation occurred not only into the WSOC pool (44.1% of recovered needle (13)C) but also into stOC (33.9%). Needle growth, however, also caused high (13)C allocation into pathways not involved in the formation of structural compounds: (i) pathways in secondary metabolism, (ii) C-1 metabolism and (iii) amino acid synthesis from photorespiration. These pathways could be identified by a high (13)C enrichment of their key amino acids. In addition, (13)C was strongly allocated into the n-alkyl lipid fraction (0.3% of recovered (13)C), whereby (13)C allocation into cellular and cuticular exceeded that of epicuticular fatty acids. (13)C allocation decreased along the lipid transformation and translocation pathways: the allocation was highest for precursor fatty acids, lower for elongated fatty acids and lowest for the decarbonylated n-alkanes. The combination of (13)C pulse labelling with compound specific (13)C analysis of key metabolites enabled tracing relevant C allocation pathways under field conditions. Besides the primary metabolism synthesizing structural cell compounds, a complex network of pathways consumed the assimilated (13)C and kept most of the assimilated C in the growing needles. PMID- 26423133 TI - Isolation and characterization of a subgroup IIa WRKY transcription factor PtrWRKY40 from Populus trichocarpa. AB - Salicylic acid (SA) is a defense-related key signaling molecule involved in plant immunity. In this study, a subgroup IIa WRKY gene PtrWRKY40 was isolated from Populus trichocarpa, which displayed amino acid sequence similar to Arabidopsis AtWRKY40, AtWRKY18 and AtWRKY60. PtrWRKY40 transcripts accumulated significantly in response to SA, methyl jasmonate and hemibiotrophic fungus Dothiorella gregaria Sacc. Overexpression of PtrWRKY40 in transgenic poplar conferred higher susceptibility to D. gregaria infection. This susceptibility was coupled with reduced expression of SA-associated genes (PR1.1, PR2.1, PR5.9, CPR5 and SID2) and jasmonic acid (JA)-related gene JAZ8. Decreased accumulation of endogenous SA was observed in transgenic lines overexpressing PtrWRKY40 when compared with wild type plants. However, constitutive expression of PtrWRKY40 in Arabidopsis thaliana displayed resistance to necrotrophic fungus Botrytis cinerea, and the expression of JA-defense-related genes such as PDF1.2, VSP2 and PR3 was remarkably increased in transgenic plants upon infection with fugal pathogens. Together, our findings indicate that PtrWRKY40 plays a negative role in resistance to hemibiotrophic fungi in poplar but functions as a positive regulator of resistance toward the necrotrophic fungi in Arabidopsis. PMID- 26423132 TI - Non-structural carbohydrates in woody plants compared among laboratories. AB - Non-structural carbohydrates (NSC) in plant tissue are frequently quantified to make inferences about plant responses to environmental conditions. Laboratories publishing estimates of NSC of woody plants use many different methods to evaluate NSC. We asked whether NSC estimates in the recent literature could be quantitatively compared among studies. We also asked whether any differences among laboratories were related to the extraction and quantification methods used to determine starch and sugar concentrations. These questions were addressed by sending sub-samples collected from five woody plant tissues, which varied in NSC content and chemical composition, to 29 laboratories. Each laboratory analyzed the samples with their laboratory-specific protocols, based on recent publications, to determine concentrations of soluble sugars, starch and their sum, total NSC. Laboratory estimates differed substantially for all samples. For example, estimates for Eucalyptus globulus leaves (EGL) varied from 23 to 116 (mean = 56) mg g(-1) for soluble sugars, 6-533 (mean = 94) mg g(-1) for starch and 53-649 (mean = 153) mg g(-1) for total NSC. Mixed model analysis of variance showed that much of the variability among laboratories was unrelated to the categories we used for extraction and quantification methods (method category R(2) = 0.05-0.12 for soluble sugars, 0.10-0.33 for starch and 0.01-0.09 for total NSC). For EGL, the difference between the highest and lowest least squares means for categories in the mixed model analysis was 33 mg g(-1) for total NSC, compared with the range of laboratory estimates of 596 mg g(-1). Laboratories were reasonably consistent in their ranks of estimates among tissues for starch (r = 0.41-0.91), but less so for total NSC (r = 0.45-0.84) and soluble sugars (r = 0.11-0.83). Our results show that NSC estimates for woody plant tissues cannot be compared among laboratories. The relative changes in NSC between treatments measured within a laboratory may be comparable within and between laboratories, especially for starch. To obtain comparable NSC estimates, we suggest that users can either adopt the reference method given in this publication, or report estimates for a portion of samples using the reference method, and report estimates for a standard reference material. Researchers interested in NSC estimates should work to identify and adopt standard methods. PMID- 26423134 TI - Defective sister chromatid cohesion is synthetically lethal with impaired APC/C function. AB - Warsaw breakage syndrome (WABS) is caused by defective DDX11, a DNA helicase that is essential for chromatid cohesion. Here, a paired genome-wide siRNA screen in patient-derived cell lines reveals that WABS cells do not tolerate partial depletion of individual APC/C subunits or the spindle checkpoint inhibitor p31(comet). A combination of reduced cohesion and impaired APC/C function also leads to fatal mitotic arrest in diploid RPE1 cells. Moreover, WABS cell lines, and several cancer cell lines with cohesion defects, display a highly increased response to a new cell-permeable APC/C inhibitor, apcin, but not to the spindle poison paclitaxel. Synthetic lethality of APC/C inhibition and cohesion defects strictly depends on a functional mitotic spindle checkpoint as well as on intact microtubule pulling forces. This indicates that the underlying mechanism involves cohesion fatigue in response to mitotic delay, leading to spindle checkpoint re activation and lethal mitotic arrest. Our results point to APC/C inhibitors as promising therapeutic agents targeting cohesion-defective cancers. PMID- 26423136 TI - Demonstration of self-truncated ionization injection for GeV electron beams. AB - Ionization-induced injection mechanism was introduced in 2010 to reduce the laser intensity threshold for controllable electron trapping in laser wakefield accelerators (LWFA). However, usually it generates electron beams with continuous energy spectra. Subsequently, a dual-stage target separating the injection and acceleration processes was regarded as essential to achieve narrow energy-spread electron beams by ionization injection. Recently, we numerically proposed a self truncation scenario of the ionization injection process based upon overshooting of the laser-focusing in plasma which can reduce the electron injection length down to a few hundred micrometers, leading to accelerated beams with extremely low energy-spread in a single-stage. Here, using 100 TW-class laser pulses we report experimental observations of this injection scenario in centimeter-long plasma leading to the generation of narrow energy-spread GeV electron beams, demonstrating its robustness and scalability. Compared with the self-injection and dual-stage schemes, the self-truncated ionization injection generates higher quality electron beams at lower intensities and densities, and is therefore promising for practical applications. PMID- 26423135 TI - The lethal response to Cdk1 inhibition depends on sister chromatid alignment errors generated by KIF4 and isoform 1 of PRC1. AB - Cyclin-dependent kinase 1 (Cdk1) is absolutely essential for cell division. Complete ablation of Cdk1 precludes the entry of G2 phase cells into mitosis, and is early embryonic lethal in mice. Dampening Cdk1 activation, by reducing gene expression or upon treatment with cell-permeable Cdk1 inhibitors, is also detrimental for proliferating cells, but has been associated with defects in mitotic progression, and the formation of aneuploid daughter cells. Here, we used a large-scale RNAi screen to identify the human genes that critically determine the cellular toxicity of Cdk1 inhibition. We show that Cdk1 inhibition leads to fatal sister chromatid alignment errors and mitotic arrest in the spindle checkpoint. These problems start early in mitosis and are alleviated by depletion of isoform 1 of PRC1 (PRC1-1), by gene ablation of its binding partner KIF4, or by abrogation of KIF4 motor activity. Our results show that, normally, Cdk1 activity must rise above the level required for mitotic entry. This prevents KIF4 dependent PRC1-1 translocation to astral microtubule tips and safeguards proper chromosome congression. We conclude that cell death in response to Cdk1 inhibitors directly relates to chromosome alignment defects generated by insufficient repression of PRC1-1 and KIF4 during prometaphase. PMID- 26423137 TI - The recombinant expression and activity detection of MAF-1 fusion protein. AB - This study establishes the recombinant expression system of MAF-1 (Musca domestica antifungal peptide-1) and demonstrates the antifungal activity of the expression product and shows the relationship between biological activity and structure. The gene segments on mature peptide part of MAF-1 were cloned, based on the primers designed according to the cDNA sequence of MAF-1. We constructed the recombinant prokaryotic expression plasmid using prokaryotic expression vector (pET-28a(+)) and converted it to the competent cell of BL21(DE3) to gain recombinant MAF-1 fusion protein with His tag sequence through purifying affinity chromatographic column of Ni-NTA. To conduct the Western Blotting test, recombinant MAF-1 fusion protein was used to produce the polyclonal antibody of rat. The antifungal activity of the expression product was detected using Candida albicans (ATCC10231) as the indicator. The MAF-1 recombinant fusion protein was purified to exhibit obvious antifungal activity, which lays the foundation for the further study of MAF-1 biological activity, the relationship between structure and function, as well as control of gene expression. PMID- 26423138 TI - Comparative proteomics reveals human pluripotent stem cell-derived limbal epithelial stem cells are similar to native ocular surface epithelial cells. AB - Limbal epithelial stem cells (LESCs) are tissue-specific stem cells responsible for renewing the corneal epithelium. Acute trauma or chronic disease affecting LESCs may disrupt corneal epithelial renewal, causing vision threatening and painful ocular surface disorders, collectively referred to as LESC deficiency (LESCD). These disorders cannot be treated with traditional corneal transplantation and therefore alternative cell sources for successful cell-based therapy are needed. LESCs derived from human pluripotent stem cells (hPSCs) are a prospective source for ocular surface reconstruction, yet critical evaluation of these cells is crucial before considering clinical applications. In order to quantitatively evaluate hPSC-derived LESCs, we compared protein expression in native human corneal cells to that in hPSC-derived LESCs using isobaric tag for relative and absolute quantitation (iTRAQ) technology. We identified 860 unique proteins present in all samples, including proteins involved in cell cycling, proliferation, differentiation and apoptosis, various LESC niche components, and limbal and corneal epithelial markers. Protein expression profiles were nearly identical in LESCs derived from two different hPSC lines, indicating that the differentiation protocol is reproducible, yielding homogeneous cell populations. Their protein expression profile suggests that hPSC-derived LESCs are similar to the human ocular surface epithelial cells, and possess LESC-like characteristics. PMID- 26423140 TI - Detailed classification of swimming paths in the Morris Water Maze: multiple strategies within one trial. AB - The Morris Water Maze is a widely used task in studies of spatial learning with rodents. Classical performance measures of animals in the Morris Water Maze include the escape latency, and the cumulative distance to the platform. Other methods focus on classifying trajectory patterns to stereotypical classes representing different animal strategies. However, these approaches typically consider trajectories as a whole, and as a consequence they assign one full trajectory to one class, whereas animals often switch between these strategies, and their corresponding classes, within a single trial. To this end, we take a different approach: we look for segments of diverse animal behaviour within one trial and employ a semi-automated classification method for identifying the various strategies exhibited by the animals within a trial. Our method allows us to reveal significant and systematic differences in the exploration strategies of two animal groups (stressed, non-stressed), that would be unobserved by earlier methods. PMID- 26423139 TI - NFkappaB signaling drives pro-granulocytic astroglial responses to neuromyelitis optica patient IgG. AB - BACKGROUND: Astrocytes expressing the aquaporin-4 water channel are a primary target of pathogenic, disease-specific immunoglobulins (IgG) found in patients with neuromyelitis optica (NMO). Immunopathological analyses of active NMO lesions highlight a unique inflammatory phenotype marked by infiltration of granulocytes. Previous studies characterized this granulocytic infiltrate as a response to vasculocentric complement activation and localized tissue destruction. In contrast, we observe that granulocytic infiltration in NMO lesions occurs independently of complement-mediated tissue destruction or active demyelination. These immunopathological findings led to the hypothesis that NMO IgG stimulates astrocyte signaling that is responsible for granulocytic recruitment in NMO. METHODS: Histopathology was performed on archival formalin fixed paraffin-embedded autopsy-derived CNS tissue from 23 patients clinically and pathologically diagnosed with NMO or NMO spectrum disorder. Primary murine astroglial cultures were stimulated with IgG isolated from NMO patients or control IgG from healthy donors. Transcriptional responses were assessed by microarray, and translational responses were measured by ELISA. Signaling through the NFkappaB pathway was measured by western blotting and immunostaining. RESULTS: Stimulation of primary murine astroglial cultures with NMO IgG elicited a reactive and inflammatory transcriptional response that involved signaling through the canonical NFkappaB pathway. This signaling resulted in the release of pro-granulocytic chemokines and was inhibited by the clinically relevant proteasome inhibitors bortezomib and PR-957. CONCLUSIONS: We propose that the astrocytic NFkappaB-dependent inflammatory response to stimulation by NMO IgG represents one of the earliest events in NMO pathogenesis, providing a target for therapeutic intervention upstream of irreversible cell death and tissue damage. PMID- 26423141 TI - Prevalence and association of asthma and allergic sensitization with dietary factors in schoolchildren: data from the french six cities study. AB - BACKGROUND: The prevalence of asthma and allergy has recently risen among children. This increase in prevalence might be related to various factors, particularly diet. The aim of this study is to assess the prevalence and association of asthma and allergic sensitization with dietary factors in the French Six Cities Study. METHODS: Cross-sectional studies were performed among 7432 schoolchildren aged 9-11 years in Bordeaux, Clermont-Ferrand, Creteil, Marseille, Reims, and Strasbourg. Parental questionnaires, based on the International Study on Asthma and Allergies in Childhood (ISAAC), were used to collect information on allergic diseases and potential exposure factors including a food frequency questionnaire to evaluate dietary habits. Skin prick testing to common allergens for allergic sensitization and bronchial hyper-responsiveness (BHR) testing to exercise were performed. Confounders control was performed with multiple logistic regressions. RESULTS: Asthma symptoms, asthma and allergic sensitization were more prevalent in boys than in girls and were more prevalent in the South than in the North of France. After adjustment for confounders, fruit juice intake was associated with a low prevalence of lifetime asthma (ORa [95 % CI]; 0.73 [0.56-0.97]), butter intake was positively associated with atopic wheeze (1.48 [1.07-2.05]) and having lunch at the canteen 1-2 times/week compared to never or occasionally was associated with a lower prevalence of past year wheeze (0.71 [0.52-0.96]), lifetime asthma (0.76 [0.60-0.96]) and allergic sensitization (0.80 [0.67-0.95]). Meat intake was inversely related to past year wheeze among atopic children (0.68 [0.50-0.98]) while fast food consumption and butter intake were associated with an increase prevalence of asthma (2.39 [1.47 3.93] and 1.51 [1.17-2.00] respectively). Fish intake was associated with a lower prevalence of asthma among non-atopic children (0.61 [0.43-0.87]. None of the dietary factors was associated with BHR. CONCLUSIONS: Diet is associated with wheeze, asthma and allergic sensitization but not with BHR in children. These results provide further evidence that adherence to a healthy diet including fruits, meat and fish seems to have a protective effect on asthma and allergy in childhood. However, prospective and experimental studies are needed to provide causal evidence concerning the effect of diet on asthma and atopy. PMID- 26423143 TI - [Use in France of Baclofen for Alcohol Dependence from 2007 to 2013: Cohort Study Based on the Databases SNIIRAM and PMSI]. AB - AIM: To quantify and describe the population starting treatment with baclofen for alcohol dependence during the period 2007-2013 in France. METHODS: The French national health insurance (systeme national d'information inter-regimes de l'Assurance maladie [SNIIRAM]) and French hospital discharge (programme de medicalisation des systemes d'information [PMSI]) databases were used to identify the population starting treatment with baclofen, determine the algorithm of baclofen use, define patient characteristics and their treatment. RESULTS: About 200,000 subjects initiated baclofen therapy between 2007 and 2013, for alcohol dependence in 52.0% of cases. In 2013, this population was predominantly male (62.3%), with a mean age of 50.1 years, the first prescriber was a general practitioner in 58.9% of cases, they continued their treatment 6 months after their initiation in 48.8% of cases and one half of these subjects consumed at least 57.0 mg of baclofen daily. CONCLUSIONS: The use of baclofen for alcohol dependence increased considerably since 2008, with more than 34,000 new users and more than 9,000 general practitioners as first prescribers in 2013. PMID- 26423142 TI - Acute cardiac injury events <=30 days after laboratory-confirmed influenza virus infection among U.S. veterans, 2010-2012. AB - BACKGROUND: Cardiac injury is a known potential complication of influenza infection. Because U.S. veterans cared for at the U.S. Department of Veterans Affairs are older and have more cardiovascular disease (CVD) risk factors than the general U.S. population, veterans are at risk for cardiac complications of influenza infection. We investigated biomarkers of cardiac injury characteristics and associated cardiac events among veterans who received cardiac biomarker testing <=30 days after laboratory-confirmed influenza virus infection. METHODS: Laboratory-confirmed influenza cases among veterans cared for at U.S. Department of Veterans Affairs' facilities for October 2010-December 2012 were identified using electronic medical records (EMRs). Influenza confirmation was based on respiratory specimen viral culture or antigen or nucleic acid detection. Acute cardiac injury (ACI) was defined as an elevated cardiac biomarker (troponin I or creatinine kinase isoenzyme MB) >99 % of the upper reference limit occurring <=30 days after influenza specimen collection. EMRs were reviewed for demographics, CVD history and risk factors, and ACI-associated cardiac events. RESULTS: Among 38,197 patients with influenza testing results, 4,469 (12 %) had a positive result; 600 of those patients had cardiac biomarker testing performed <=30 days after influenza testing, and 143 (24 %) had one or more elevated cardiac biomarkers. Among these 143, median age was 73 years (range 44-98 years), and 98 (69 %) were non-Hispanic white. All patients had one or more CVD risk factors, and 98 (69 %) had a history of CVD. Eighty-six percent of ACI-associated events occurred within 3 days of influenza specimen collection date. Seventy patients (49 %) had documented or probable acute myocardial infarction, 8 (6 %) acute congestive heart failure, 6 (4 %) myocarditis, and 4 (3 %) atrial fibrillation. Eleven (8 %) had non-cardiac explanations for elevated cardiac biomarkers, and 44 (31 %) had no documented explanation. Sixty-eight (48 %) patients had received influenza vaccination during the related influenza season. CONCLUSION: Among veterans with laboratory-confirmed influenza infection and cardiac biomarker testing <=30 days after influenza testing, approximately 25 % had evidence of ACI, the majority within 3 days. Approximately half were myocardial infarctions. Our findings emphasize the importance of considering ACI associated with influenza infection among patients at high risk, including this older population with prevalent CVD risk factors. PMID- 26423144 TI - Validation and Reproducibility of the Updated French Causality Assessment Method: an Evaluation by Pharmacovigilance Centres & Pharmaceutical Companies. AB - OBJECTIVE: Assess the validity and reproducibility of the updated version of the French causality assessment method in conditions approaching real-life use. METHODS: A random sample of 31 drug-event pairs from the French pharmacovigilance database was assessed by the consensual judgement of three experts (gold standard). Separately, a team from a pharmacovigilance centre (PhVC) and another from a pharmaceutical company assessed these pairs using the current method, then with the updated method. To test the inter- and intra-rater reproducibility, two seniors and two juniors from a PhVC and a pharmaceutical company assessed the pairs twice with the updated method. A weighted kappa coefficient was used to measure the agreement of the two causality assessment methods with the consensual expert judgement (validity) as well as the agreement of the updated causality assessment over time (intra-rater reproducibility) and between evaluators (inter rater reproducibility). RESULTS: Agreement between the current method and consensual expert judgement was fair for the PhVC team (weighted kappa [Kw] 0.33) and moderate for the pharmaceutical company team (Kw 0.41). For the updated method, agreement was better for both the PhVC (Kw 0.58) and the pharmaceutical company (Kw 0.52) teams. The inter- and intra-rater reproducibility of the updated method based on the intrinsic imputability was satisfactory overall (Kw 0.30-0.91). Discrepancies between evaluations from PhVC and pharmaceutical companies were observed with the updated method. CONCLUSION: The updated method performed better than the current one for drug causality assessment, suggesting that it should be used in routine pharmacovigilance. PMID- 26423145 TI - Clinico-laboratory spectrum of dengue viral infection and risk factors associated with dengue hemorrhagic fever: a retrospective study. AB - BACKGROUND: The incidence of dengue is rising steadily in Malaysia since the first major outbreak in 1973. Despite aggressive measures taken by the relevant authorities, Malaysia is still facing worsening dengue crisis over the past few years. There is an urgent need to evaluate dengue cases for better understanding of clinic-laboratory spectrum in order to combat this disease. METHODS: A retrospective analysis of dengue patients admitted to a tertiary care teaching hospital during the period of six years (2008 - 2013) was performed. Patient's demographics, clinical and laboratory findings were recorded via structured data collection form. Patients were categorized into dengue fever (DF) and dengue hemorrhagic fever (DHF). Appropriate statistical methods were used to compare these two groups in order to determine difference in clinico-laboratory characteristics and to identify independent risk factors of DHF. RESULTS: A total 667 dengue patients (30.69 +/- 16.13 years; Male: 56.7 %) were reviewed. Typical manifestations of dengue like fever, myalgia, arthralgia, headache, vomiting, abdominal pain and skin rash were observed in more than 40 % patients. DHF was observed in 79 (11.8 %) cases. Skin rash, dehydration, shortness of breath, pleural effusion and thick gall bladder were more significantly (P < 0.05) associated with DHF than DF. Multivariate regression analysis demonstrated presence of age > 40 years (OR: 4.1, P < 0.001), secondary infection (OR: 2.7, P = 0.042), diabetes mellitus (OR: 2.8, P = 0.041), lethargy (OR: 3.1, P = 0.005), thick gallbladder (OR: 1.7, P = 0.029) and delayed hospitalization (OR: 2.3, P = 0.037) as independent predictors of DHF. Overall mortality was 1.2 % in our study. CONCLUSIONS: Current study demonstrated that DF and DHF present significantly different clinico-laboratory profile. Older age, secondary infection, diabetes mellitus, lethargy, thick gallbladder and delayed hospitalization significantly predict DHF. Prior knowledge of expected clinical profile and predictors of DHF/DSS development would provide information to identify individuals at higher risk and on the other hand, give sufficient time to clinicians for reducing dengue related morbidity and mortality. PMID- 26423146 TI - Genome expansion in bacteria: the curios case of Chlamydia trachomatis. AB - BACKGROUND: Recent findings indicated that a correlation between genomic % AT and genome size within strains of microbial species was predominantly associated with the uptake of foreign DNA. One species however, Chlamydia trachomatis, defied any explanation. In the present study 79 fully sequenced C. trachomatis genomes, representing ocular- (nine strains), urogenital- (36 strains) and lymphogranuloma venereum strains (LGV, 22 strains), in three pathogroups, in addition to 12 laboratory isolates, were scrutinized with the intent of elucidating the positive correlation between genomic AT content and genome size. RESULTS: The average size difference between the strains of each pathogroup was largely explained by the incorporation of genetic fragments. These fragments were slightly more AT rich than their corresponding host genomes, but not enough to justify the difference in AT content between the strains of the smaller genomes lacking the fragments. In addition, a genetic region predominantly found in the ocular strains, which had the largest genomes, was on average more GC rich than the host genomes of the urogenital strains (58.64% AT vs. 58.69% AT), which had the second largest genomes, implying that the foreign genetic regions cannot alone explain the association between genome size and AT content in C. trachomatis. 23,492 SNPs were identified for all 79 genomes, and although the SNPs were on average slightly GC rich (~47% AT), a significant association was found between genome wide SNP AT content, for each pathogroup, and genome size (p < 0.001, R (2) = 0.86) in the C. trachomatis strains. CONCLUSIONS: The correlation between genome size and AT content, with respect to the C. trachomatis pathogroups, was explained by the incorporation of genetic fragments unique to the ocular and/or urogenital strains into the LGV- and urogential strains in addition to the genome wide SNP AT content differences between the three pathogroups. PMID- 26423147 TI - Integrating vector control across diseases. AB - BACKGROUND: Vector-borne diseases cause a significant proportion of the overall burden of disease across the globe, accounting for over 10 % of the burden of infectious diseases. Despite the availability of effective interventions for many of these diseases, a lack of resources prevents their effective control. Many existing vector control interventions are known to be effective against multiple diseases, so combining vector control programmes to simultaneously tackle several diseases could offer more cost-effective and therefore sustainable disease reductions. DISCUSSION: The highly successful cross-disease integration of vaccine and mass drug administration programmes in low-resource settings acts a precedent for cross-disease vector control. Whilst deliberate implementation of vector control programmes across multiple diseases has yet to be trialled on a large scale, a number of examples of 'accidental' cross-disease vector control suggest the potential of such an approach. Combining contemporary high-resolution global maps of the major vector-borne pathogens enables us to quantify overlap in their distributions and to estimate the populations jointly at risk of multiple diseases. Such an analysis shows that over 80 % of the global population live in regions of the world at risk from one vector-borne disease, and more than half the world's population live in areas where at least two different vector-borne diseases pose a threat to health. Combining information on co-endemicity with an assessment of the overlap of vector control methods effective against these diseases allows us to highlight opportunities for such integration. Malaria, leishmaniasis, lymphatic filariasis, and dengue are prime candidates for combined vector control. All four of these diseases overlap considerably in their distributions and there is a growing body of evidence for the effectiveness of insecticide-treated nets, screens, and curtains for controlling all of their vectors. The real-world effectiveness of cross-disease vector control programmes can only be evaluated by large-scale trials, but there is clear evidence of the potential of such an approach to enable greater overall health benefit using the limited funds available. PMID- 26423148 TI - Antigen Specificity of Type I NKT Cells Is Governed by TCR beta-Chain Diversity. AB - NKT cells recognize lipid-based Ags presented by CD1d. Type I NKT cells are often referred to as invariant owing to their mostly invariant TCR alpha-chain usage (Valpha14-Jalpha18 in mice, Valpha24-Jalpha18 in humans). However, these cells have diverse TCR beta-chains, including Vbeta8, Vbeta7, and Vbeta2 in mice and Vbeta11 in humans, joined to a range of TCR Dbeta and Jbeta genes. In this study, we demonstrate that TCR beta-chain composition can dramatically influence lipid Ag recognition in an Ag-dependent manner. Namely, the glycolipids alpha glucosylceramide and isoglobotrihexosylceramide were preferentially recognized by Vbeta7(+) NKT cells from mice, whereas the alpha-galactosylceramide analog OCH, with a truncated sphingosine chain, was preferentially recognized by Vbeta8(+) NKT cells from mice. We show that the influence of the TCR beta-chain is due to a combination of Vbeta-, Jbeta-, and CDR3beta-encoded residues and that these TCRs can recapitulate the selective Ag reactivity in TCR-transduced cell lines. Similar observations were made with human NKT cells where different CDR3beta encoded residues determined Ag preference. These findings indicate that NKT TCR beta-chain diversity results in differential and nonhierarchical Ag recognition by these cells, which implies that some Ags can preferentially activate type I NKT cell subsets. PMID- 26423150 TI - Immunosuppression and Aberrant T Cell Development in the Absence of N Myristoylation. AB - N-myristoylation refers to the attachment of myristic acid to the N-terminal glycine of proteins and substantially affects their intracellular targeting and functions. The thymus represents an organ with a prominent N-myristoylation activity. To elucidate the role of protein N-myristoylation for thymocyte development, we generated mice with a T cell lineage-specific deficiency in N myristoyl transferase (Nmt)1 and 2. Depletion of Nmt activity in T cells led to a defective transmission of TCR signals, a developmental blockage of thymocytes at the transition from double-negative 3 to 4 stages, and a reduction of all the following stages. We could demonstrate that Lck and myristoylated alanine-rich C kinase substrate, two main myristoylated kinases in T cells, were mislocalized in the absence of Nmt activity. N-myristoylation was also indispensable for early and distal TCR signaling events such as CD3zeta, Zap70, and Erk activation and for release of cytokines such as IFN-gamma and IL-2. As a consequence, the initiation and propagation of the TCR signaling cascade was severely impaired. Furthermore, we showed that the absence of myristoylation had an immunosuppressive effect on T cells in vivo after treatment with CpG and stimulation of the TCR with the staphylococcal enterotoxin B superantigen. Therefore, protein myristoylation is indispensable in T cell development and activation and its inhibition might offer a novel strategy to achieve immunosuppression. PMID- 26423149 TI - SARM1, Not MyD88, Mediates TLR7/TLR9-Induced Apoptosis in Neurons. AB - Neuronal apoptosis is a key aspect of many different neurologic diseases, but the mechanisms remain unresolved. Recent studies have suggested a mechanism of innate immune-induced neuronal apoptosis through the stimulation of endosomal TLRs in neurons. TLRs are stimulated both by pathogen-associated molecular patterns as well as by damage-associated molecular patterns, including microRNAs released by damaged neurons. In the present study, we identified the mechanism responsible for TLR7/TLR9-mediated neuronal apoptosis. TLR-induced apoptosis required endosomal localization of TLRs but was independent of MyD88 signaling. Instead, apoptosis required the TLR adaptor molecule SARM1, which localized to the mitochondria following TLR activation and was associated with mitochondrial accumulation in neurites. Deficiency in SARM1 inhibited both mitochondrial accumulation in neurites and TLR-induced apoptosis. These studies identify a non MyD88 pathway of TLR7/ TLR9 signaling in neurons and provide a mechanism for how innate immune responses in the CNS directly induce neuronal damage. PMID- 26423152 TI - Authentic GITR Signaling Fails To Induce Tumor Regression unless Foxp3+ Regulatory T Cells Are Depleted. AB - The glucocorticoid-induced TNFR family-related protein (GITR, TNFRSF18, CD357) is expressed on effector and regulatory T (Treg) cells. Previous studies demonstrated that GITR triggering by anti-GITR mAb enhanced T and B cell-mediated immune responses. GITR-deficient T cells, however, also proliferate more than normal T cells, and this effect is unexplained. Because the activities of mAbs are controlled by their Fc regions, the true effect of GITR signaling needs to be determined by examining its interaction with authentic ligand. Therefore, we generated a pentamerized form of the GITRL extracellular domain (pGITRL) for ligation to GITR and compared its effect on T cells with that of anti-GITR mAb. The pGITRL was more effective than anti-GITR mAb in enhancing the proliferation of effector and regulatory cells in vitro and in vivo. Nonetheless, the growth of MC38 adenocarcinoma cells in vivo was only suppressed for initial 15 d by pGITRL, whereas it was suppressed indefinitely by anti-GITR mAb. Detailed analysis revealed that pGITRL induced extensive proliferation of Foxp3(+)CD4(+) Treg cells and led to the accumulation of activated Treg cells in tumor tissue and draining lymph nodes. Because GITR signaling could not neutralize the suppressive activity of activated Treg cells, pGITRL seems to lose its adjuvant effect when sufficient activated Treg cells have accumulated in the lymph nodes and tumor tissue. Indeed, the antitumor effects of pGITRL were markedly enhanced by depleting CD4(+) cells. These results suggest that GITR signaling has stimulatory effects on effector T cells and inhibitory effects through Treg cells. PMID- 26423151 TI - IL-25 or IL-17E Protects against High-Fat Diet-Induced Hepatic Steatosis in Mice Dependent upon IL-13 Activation of STAT6. AB - IL-25 or IL-17E is a member of IL-17 cytokine family and has immune-modulating activities. The role of IL-25 in maintaining lipid metabolic homeostasis remains unknown. We investigated the effects of exogenous IL-25 or deficiency of IL-25 on hepatic lipid accumulation. IL-25 expression was examined in paraffin-embedded tissue sections of liver from patients or in the livers from mice. Mouse model of steatosis was induced by feeding a high-fat diet (HFD). Extent of steatosis as well as expression of cytokines, key enzymes for lipid metabolic pathways, markers for Kupffer cells/macrophages, and lipid droplet (LD) proteins, were analyzed. Our results show that hepatic steatosis in mice was accompanied by increased LD proteins, but decreased IL-25 in the liver. Decreased hepatic IL-25 was also observed in patients with fatty liver. Administration of IL-25 to HFD fed wild-type mice led to a significant improvement in hepatic steatosis. This effect was associated with increased expression of IL-13, development of alternatively activated Kupffer cells/macrophages, and decreased expression of LD proteins in the liver. In contrast, administration of IL-25 to HFD-fed mice deficient in STAT6 or IL-13 had no effects. In addition, stimulation of primary hepatocytes with IL-13, but not IL-25, resulted in downregulation of LD proteins. Finally, mice deficient in IL-25 had exacerbated hepatic lipid accumulation when fed the HFD. These data demonstrate that dysregulated IL-25 expression contributes to lipid accumulation, whereas exogenous IL-25 protects against hepatic steatosis through IL-13 activation of STAT6. IL-25 and IL-13 are potential therapeutic agents for hepatic steatosis and associated pathologies. PMID- 26423153 TI - Adaptor Protein-3-Mediated Trafficking of TLR2 Ligands Controls Specificity of Inflammatory Responses but Not Adaptor Complex Assembly. AB - Innate immune engagement results in the activation of host defenses that produce microbe-specific inflammatory responses. A long-standing interest in the field of innate immunity is to understand how varied host responses are generated through the signaling of just a limited number of receptors. Recently, intracellular trafficking and compartmental partitioning have been identified as mechanisms that provide signaling specificity for receptors by regulating signaling platform assembly. We show that cytokine activation as a result of TLR2 stimulation occurs at different intracellular locations and is mediated by the phagosomal trafficking molecule adaptor protein-3 (AP-3). AP-3 is required for trafficking TLR2 purified ligands or the Lyme disease causing bacterium, Borrelia burgdorferi, to LAMP-1 lysosomal compartments. The presence of AP-3 is necessary for the activation of cytokines such as IL-6 but not TNF-alpha or type I IFNs, suggesting induction of these cytokines occurs from a different compartment. Lack of AP-3 does not interfere with the recruitment of TLR signaling adaptors TRAM and MyD88 to the phagosome, indicating that the TLR-MyD88 signaling complex is assembled at a prelysosomal stage and that IL-6 activation depends on proper localization of signaling molecules downstream of MyD88. Finally, infection of AP 3-deficient mice with B. burgdorferi resulted in altered joint inflammation during murine Lyme arthritis. Our studies further elucidate the effects of phagosomal trafficking on tailoring immune responses in vitro and in vivo. PMID- 26423155 TI - Editorial: Engineered Magnetic Core@Shell Structures. PMID- 26423154 TI - Effect of sex and fatigue on single leg squat kinematics in healthy young adults. AB - BACKGROUND: The single-leg squat (SLS) test is widely used in screening for musculoskeletal injury risk. Little is known, however, of lower limb, pelvis, and trunk kinematics of SLS performance or the effect of sex and fatigue. Our aim was to determine sex differences and the influence of fatigue on SLS kinematics in healthy young adults. METHODS: We recruited 60 healthy men and women between the ages of 20 and 40 years. Three-dimensional kinematic data was collected for SLSs with a ten-camera VICON motion analysis system (Oxford Metrics, UK) before and after a lower limb fatiguing exercise regime. One-way ANCOVA was used to make sex comparisons of kinematic parameters and repeated measures ANOVA was used to determine the effect of fatigue and the interaction with sex. RESULTS: 30 men (25.6 +/- 4.8 years) and 30 women (25.1 +/- 3.8 years) volunteered to participate. Peak pelvic rotation (3.9 +/- 4.1 vs. 7.7 +/- 6.2 deg, P = 0.03), peak hip internal rotation (-1.8 +/- 5.7 vs. 3.0 +/- 7.3 deg, P = 0.02), hip adduction range (11.7 +/- 4.8 vs. 18.3 +/- 6.7 deg, P = 0.004), and hip rotation range (10.7 +/- 3.9 vs. 13.0 +/- 4.2 deg, P = 0.04) were smaller for men than for women. Likewise, distance of mediolateral knee motion (180 +/- 51 vs. 227 +/- 50 mm, P = 0.001) was shorter for men than for women. The kinematic response to fatigue was an increase in trunk flexion, lateral flexion and rotation, an increase in pelvic tilt, obliquity and rotation, and an increase in hip flexion and adduction range (P <=0.05). CONCLUSIONS: Sex differences in SLS kinematics appear to apply only at the hip, knee, and pelvis and not at the trunk. Fatiguing exercise, however, produces changes at the trunk and pelvis with little effect on the knee. PMID- 26423157 TI - 71st Congress of the Italian Society of Pediatrics. PMID- 26423156 TI - CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis. AB - Long noncoding RNAs (lncRNAs) are emerging as important regulators of developmental pathways. However, their roles in human cardiac precursor cell (CPC) remain unexplored. To characterize the long noncoding transcriptome during human CPC cardiac differentiation, we profiled the lncRNA transcriptome in CPCs isolated from the human fetal heart and identified 570 lncRNAs that were modulated during cardiac differentiation. Many of these were associated with active cardiac enhancer and super enhancers (SE) with their expression being correlated with proximal cardiac genes. One of the most upregulated lncRNAs was a SE-associated lncRNA that was named CARMEN, (CAR)diac (M)esoderm (E)nhancer associated (N)oncoding RNA. CARMEN exhibits RNA-dependent enhancing activity and is upstream of the cardiac mesoderm-specifying gene regulatory network. Interestingly, CARMEN interacts with SUZ12 and EZH2, two components of the polycomb repressive complex 2 (PRC2). We demonstrate that CARMEN knockdown inhibits cardiac specification and differentiation in cardiac precursor cells independently of MIR-143 and -145 expression, two microRNAs located proximal to the enhancer sequences. Importantly, CARMEN expression was activated during pathological remodeling in the mouse and human hearts, and was necessary for maintaining cardiac identity in differentiated cardiomyocytes. This study demonstrates therefore that CARMEN is a crucial regulator of cardiac cell differentiation and homeostasis. PMID- 26423159 TI - What Can We Do About Stigma? PMID- 26423158 TI - Can preoperative 3-T MRI predict nipple-areolar complex involvement in patients with breast cancer? AB - PURPOSE: To evaluate the diagnostic performances of preoperative 3-T breast MRI for predicting nipple-areolar complex (NAC) involvement. MATERIALS AND METHODS: We analyzed the predictors of NAC involvement in breast cancer, with diagnostic performances. RESULTS: Among the 403 patients, 43 cases were surgically confirmed for NAC involvement. For predicting NAC involvement, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 60.5%, 87.5%, 36.6%, 94.9%, and 84.6%, respectively. Continuity to NAC, unilateral enhancement of NAC and thickening of NAC were significant magnetic resonance findings predictive of NAC involvement. CONCLUSIONS: Preoperative 3-T breast MRI is a useful method to predict NAC involvement in breast cancer patients. PMID- 26423161 TI - Can the Americans With Disabilities Act Reduce the Death Toll From Police Encounters With Persons With Mental Illness? AB - A substantial proportion of people shot by police have mental disorders, and many of these killings appear to have been avoidable. One tool to encourage better police training and more cautious behavior is the Americans with Disabilities Act (ADA). However, police groups oppose application of the ADA to arrests, fearing limits on their discretion, and the U.S. Supreme Court appears to favor that view. When the Court declined a recent opportunity to decide the question, it left open a window of opportunity during which the ADA can be leveraged to improve how police officers deal with persons with mental illness. PMID- 26423162 TI - Back From the Blue and the Black. PMID- 26423163 TI - Preventing First Hospitalization for Psychosis: In Reply. PMID- 26423164 TI - Preventing First Hospitalization for Psychosis. PMID- 26423165 TI - Suicide Prevention in Patient and Nonpatient Populations. PMID- 26423166 TI - Suicide Prevention in Patient and Nonpatient Populations: In Reply. PMID- 26423167 TI - Were Concerns With Misidentification in Special Education Overlooked? In Reply. PMID- 26423168 TI - Were Concerns With Misidentification in Special Education Overlooked? PMID- 26423171 TI - Gold Award: Improving Community Safety by Providing Treatment to a Highly Marginalized Clinical Population. Sexual Behaviours Clinic, Integrated Forensic Program, Royal Ottawa Mental Health Centre, Ottawa, Ontario, Canada. PMID- 26423172 TI - Bronze Award: A Private-Public Partnership to Deliver Population-Level Integrated Care to Low-Income Seniors in Pennsylvania. SUSTAIN (SUpporting Seniors receiving Treatment And INtervention), Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and the Department of Aging, Commonwealth of Pennsylvania, Harrisburg. PMID- 26423173 TI - Gold Award: Community-Based Program: A Health Care Home for the "Whole Person" in Missouri's Community Mental Health Centers. Missouri Community Mental Health Center Health Home Program, Jefferson City, Missouri. PMID- 26423174 TI - Silver Award: Student Outreach and Teacher Training to Ensure Prevention, Early Recognition, and Treatment of Mental Health Problems. Mental Health 101 and Typical or Troubled?, Mental Health Association of East Tennessee, Knoxville. PMID- 26423175 TI - Tadalafil-loaded nanostructured lipid carriers using permeation enhancers. AB - Tadalafil is a phosphodiesterase-5 inhibitor indicated for the treatment of erectile dysfunction. In this study, we prepared and evaluated transdermal nanostructured lipid carriers (NLC) to improve the skin permeability of tadalafil. Tadalafil-loaded NLC dispersions were prepared using glyceryl monostearate as a solid lipid, oleic acid as a liquid lipid, and Tween 80 as a surfactant. We characterized the dispersions according to particle size, polydispersity index, zeta potential, encapsulation efficiency, and transmission electron microscopy. In vitro skin permeation studies were carried out using Franz diffusion cells, and cytotoxicity was examined using HaCaT keratinocyte cell lines. Tadalafil skin permeability increased for all tadalafil-loaded NLC formulations. The tadalafil-loaded NLC dispersion with ethanol and limonene as skin permeation enhancers exhibited the highest flux (~4.8-fold) compared to that observed with tadalafil solution alone. Furthermore, a tadalafil-loaded NLC gel with selected permeation enhancers showed tolerance against toxicity in HaCaT cells. These results suggest that the NLC formulations with ethanol and limonene as skin permeation enhancers could be a promising dermal delivery carrier for tadalafil. PMID- 26423176 TI - Use of similarity scoring in the development of oral solid dosage forms. AB - In the oral solid dosage form space, material physical properties have a strong impact on the behaviour of the formulation during processing. The ability to identify materials with similar characteristics (and thus expected to exhibit similar behaviour) within the company's portfolio can help accelerate drug development by enabling early assessment and prediction of potential challenges associated with the powder properties of a new active pharmaceutical ingredient. Such developments will aid the production of robust dosage forms, in an efficient manner. Similarity scoring metrics are widely used in a number of scientific fields. This study proposes a practical implementation of this methodology within pharmaceutical development. The developed similarity metrics is based on the Mahalanobis distance. Scanning electron microscopy was used to confirm morphological similarity between the reference material and the closest matches identified by the metrics proposed. The results show that the metrics proposed are able to successfully identify material with similar physical properties. PMID- 26423177 TI - Ocular safety comparison of non-steroidal anti-inflammatory eye drops used in pseudophakic cystoid macular edema prevention. AB - Non-steroidal anti-inflammatory drug (NSAID) eye drops are widely used to treat ocular inflammatory conditions related to ophthalmic surgical procedures, such as pseudophakic cystoid macular edema, and they have been used for off-label treatments. The most commonly used NSAIDs are diclofenac and ketorolac and the new molecules bromfenac and nepafenac have also been used. We used primary human keratocytes in cell culture in combination with a novel technology that evaluates dynamic real-time cytotoxicity through impedance analysis. This study also included classic cell viability tests (WST-1((r)) and AlamarBlue((r))), wound healing assay, Hen's Egg Test and an ex vivo histopathological assay. NSAIDs were shown to have important cytotoxicities and to retard the healing response. Furthermore, the new eye drops containing bromfenac and nepafenac were more cytotoxic than the more classical eye drops. Nevertheless, no immuno histochemical changes or acute irritation processes were observed after the administration of any eye drops tested. Due to cytotoxicity and the total absence of discomfort and observable injuries after the administration of these drugs, significant corneal alterations, such as corneal melts, can develop without any previous warning signs of toxicity. PMID- 26423178 TI - Interferon-stimulated gene (ISG) 60, as well as ISG56 and ISG54, positively regulates TLR3/IFN-beta/STAT1 axis in U373MG human astrocytoma cells. AB - Treatment of cells with interferons (IFNs) induces the phosphorylation of signal transducer and activator of transcription 1 (STAT1), leading to the expression of hundreds of IFN-stimulated genes (ISGs). ISGs exert various antiviral and pro inflammatory reactions. We have previously reported that ISG56 and ISG54 are induced by polyinosinic-polycytidylic acid (poly IC), an authentic agonist for Toll-like receptor 3 (TLR3), in U373MG human astrocytoma cells. ISG56 and ISG54 are also named as IFN-induced proteins with tetratricopeptide repeats (IFIT) 1 and IFIT2, respectively. In the present study, we demonstrated that poly IC induces the expression of ISG60, also named as IFIT3, in U373MG cells. RNA interference experiments showed that the induction of ISG60 by poly IC was mediated by TLR3, IFN-beta, ISG56 and ISG54, whereas ISG60 is involved in poly IC induced expression of ISG56, ISG54 and a chemokine CXCL10. The level of phosphorylated STAT1 was enhanced by poly IC, and it was inhibited by knockdown of ISG56, ISG54 or ISG60. These results suggest that there is a positive feedback loop between phosphorylated STAT1 and these ISGs. PMID- 26423179 TI - Management of late-life depression: a major leap forward. PMID- 26423180 TI - Increasing value and reducing waste in biomedical research: who's listening? AB - The biomedical research complex has been estimated to consume almost a quarter of a trillion US dollars every year. Unfortunately, evidence suggests that a high proportion of this sum is avoidably wasted. In 2014, The Lancet published a series of five reviews showing how dividends from the investment in research might be increased from the relevance and priorities of the questions being asked, to how the research is designed, conducted, and reported. 17 recommendations were addressed to five main stakeholders-funders, regulators, journals, academic institutions, and researchers. This Review provides some initial observations on the possible effects of the Series, which seems to have provoked several important discussions and is on the agendas of several key players. Some examples of individual initiatives show ways to reduce waste and increase value in biomedical research. This momentum will probably move strongly across stakeholder groups, if collaborative relationships evolve between key players; further important work is needed to increase research value. A forthcoming meeting in Edinburgh, UK, will provide an initial forum within which to foster the collaboration needed. PMID- 26423181 TI - Acute-on-chronic liver failure. AB - Acute-on-chronic liver failure combines an acute deterioration in liver function in an individual with pre-existing chronic liver disease and hepatic and extrahepatic organ failures, and is associated with substantial short-term mortality. Common precipitants include bacterial and viral infections, alcoholic hepatitis, and surgery, but in more than 40% of patients, no precipitating event is identified. Systemic inflammation and susceptibility to infection are characteristic pathophysiological features. A new diagnostic score, the Chronic Liver Failure Consortium (CLIF-C) organ failure score, has been developed for classification and prognostic assessment of patients with acute-on-chronic liver failure. Disease can be reversed in many patients, and thus clinical management focuses upon the identification and treatment of the precipitant while providing multiorgan-supportive care that addresses the complex pattern of physiological disturbance in critically ill patients with liver disease. Liver transplantation is a highly effective intervention in some specific cases, but recipient identification, organ availability, timing of transplantation, and high resource use are barriers to more widespread application. Recognition of acute-on-chronic liver failure as a clinically and pathophysiologically distinct syndrome with defined diagnostic and prognostic criteria will help to encourage the development of new management pathways and interventions to address the unacceptably high mortality. PMID- 26423183 TI - Logistic Regression Analysis of Contrast-Enhanced Ultrasound and Conventional Ultrasound Characteristics of Sub-centimeter Thyroid Nodules. AB - The purpose of the study described here was to determine specific characteristics of thyroid microcarcinoma (TMC) and explore the value of contrast-enhanced ultrasound (CEUS) combined with conventional ultrasound (US) in the diagnosis of TMC. Characteristics of 63 patients with TMC and 39 with benign sub-centimeter thyroid nodules were retrospectively analyzed. Multivariate logistic regression analysis was performed to determine independent risk factors. Four variables were included in the logistic regression models: age, shape, blood flow distribution and enhancement pattern. The area under the receiver operating characteristic curve was 0.919. With 0.113 selected as the cutoff value, sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 90.5%, 82.1%, 89.1%, 84.2% and 87.3%, respectively. Independent risk factors for TMC determined with the combination of CEUS and conventional US were age, shape, blood flow distribution and enhancement pattern. Age was negatively correlated with malignancy, whereas shape, blood flow distribution and enhancement pattern were positively correlated. The logistic regression model involving CEUS and conventional US was found to be effective in the diagnosis of sub-centimeter thyroid nodules. PMID- 26423182 TI - Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Treatment-resistant major depression is common and potentially life threatening in elderly people, in whom little is known about the benefits and risks of augmentation pharmacotherapy. We aimed to assess whether aripiprazole is associated with a higher probability of remission than is placebo. METHODS: We did a randomised, double-blind, placebo-controlled trial at three centres in the USA and Canada to test the efficacy and safety of aripiprazole augmentation for adults aged older than 60 years with treatment-resistant depression (Montgomery Asberg Depression Rating Scale [MADRS] score of >=15). Patients who did not achieve remission during a pre-trial with venlafaxine extended-release (150-300 mg/day) were randomly assigned (1:1) to the addition of aripiprazole (target dose 10 mg [maximum 15 mg] daily) daily or placebo for 12 weeks. The computer generated randomisation was done in blocks and stratified by site. Only the database administrator and research pharmacists had knowledge of treatment assignment. The primary endpoint was remission, defined as an MADRS score of 10 or less (and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00892047. FINDINGS: From July 20, 2009, to Dec 30, 2013, we recruited 468 eligible participants, 181 (39%) of whom did not remit and were randomly assigned to aripiprazole (n=91) or placebo (n=90). A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 [44%] vs 26 [29%] participants; odds ratio [OR] 2.0 [95% CI 1.1-3.7], p=0.03; number needed to treat [NNT] 6.6 [95% CI 3.5-81.8]). Akathisia was the most common adverse effect of aripiprazole (reported in 24 [26%] of 91 participants on aripiprazole vs 11 [12%] of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 [17%] of 86 vs two [2%] of 81 participants), but not with treatment-emergent suicidal ideation (13 [21%] of 61 vs 19 [29%] of 65 participants) or other measured safety variables. INTERPRETATION: In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism. FUNDING: National Institute of Mental Health, UPMC Endowment in Geriatric Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, National Center for Advancing Translational Sciences, and the Campbell Family Mental Health Research Institute. PMID- 26423184 TI - Lixisenatide clinical experience on patients with type 2 diabetes and obesity in endocrinology offices in Malaga. PMID- 26423185 TI - Transcatheter pulmonary valve replacement: State of the art. AB - BACKGROUND: The number of patients undergoing transcatheter pulmonary valve replacement has been steadily increasing, resulting in many research projects focusing on this patient population. This has highlighted the need to summarize the currently available data. METHODS: A review of the literature was conducted and the results summarized. RESULTS: At present, the two commercially available valves approved for transcatheter pulmonary valve replacement include the Edwards Sapien valve and the Medtronic Melody valve. More data has been published relating to the Melody valve; this included the incidence of coronary anatomy prohibiting valve implantation of 5%, an incidence of conduit disruption of 6%, and freedom from stent fracture of the Melody valve stent of 60% at 30 months. Short and medium term outcomes seem to be comparable if not superior to surgical valve replacement, but long-term data is still lacking. There may also be a cost benefit with transcatheter valve implantation when compared to surgical pulmonary valve replacement. CONCLUSIONS: Transcatheter pulmonary valve replacement is here to stay. The main challenge of treating patients with a native right ventricular outflow tract still needs to be addressed and device development efforts centered in this area. (c) 2015 Wiley Periodicals, Inc. PMID- 26423186 TI - Making the most of a new HIV self-test. PMID- 26423187 TI - HIV testing in primary care. PMID- 26423188 TI - HIV eradication: is cord blood the answer? PMID- 26423189 TI - ART and prevention of HIV-associated tuberculosis. PMID- 26423190 TI - Behaviour, not mobility, is a risk factor for HIV. PMID- 26423191 TI - The need for standardisation of the HIV continuum of care. PMID- 26423192 TI - Co-trimoxazole in people on antiretroviral therapy for HIV. PMID- 26423193 TI - Co-trimoxazole in people on antiretroviral therapy for HIV--authors' reply. PMID- 26423194 TI - The FACTS about women and pre-exposure prophylaxis. PMID- 26423195 TI - Promotion of rapid testing for HIV in primary care (RHIVA2): a cluster-randomised controlled trial. AB - BACKGROUND: Many people with HIV are undiagnosed. Early diagnosis saves lives and reduces onward transmission. We assessed whether an education programme promoting rapid HIV testing in general practice would lead to increased and earlier HIV diagnosis. METHODS: In this cluster randomised controlled trial in Hackney (London, UK), general practices were randomly assigned (1:1) to offer either opt out rapid HIV testing to newly registering adults or continue usual care. All practices were invited to take part. Practices were randomised by an independent clinical trials unit statistician with a minimisation program, maintaining allocation concealment. Neither patients nor investigators were masked to treatment allocation. The primary outcome was CD4 count at diagnosis. Secondary outcomes were rate of diagnosis, proportion with CD4 count less than 350 cells per MUL, and proportion with CD4 count less than 200 cells per MUL. This study is registered with ClinicalTrials.gov, number ISRCTN63473710. FINDINGS: 40 of 45 (89%) general practices agreed to participate: 20 were assigned to the intervention group (44 971 newly registered adult patients) and 20 to the control group (38 464 newly registered adult patients), between April 19, 2010, and Aug 31, 2012. Intervention practices diagnosed 32 people with HIV versus 14 in control practices. Mean CD4 count at diagnosis was 356 cells per MUL (SD 254) intervention practices versus 270 (SD 257) in control practices (adjusted difference of square root CD4 count 3.1, 95% CI -1.2 to 7.4; p=0.16);); in a pre planned sensitivity analysis excluding patients diagnosed via antenatal care, the difference was 6.4 (95% CI, 1.2 to 11.6; p=0.017). Rate of HIV diagnosis was 0.30 (95% CI 0.11 to 0.85) per 10 000 patients per year in intervention practices versus 0.07 (0.02 to 0.20) in control practices (adjusted ratio of geometric means 4.51, 95% CI 1.27 to 16.05; p=0.021). 55% of patients in intervention practices versus 73% in control practices had CD4 count less than 350 cells per MUL (risk ratio 0.75, 95% CI 0.53 to 1.07). 28% versus 46% had CD4 count less than 200 cells per MUL (0.60, 0.32 to 1.13). All patients diagnosed by rapid testing were successfully transferred into specialist care. No adverse events occurred. INTERPRETATION: Promotion of opt-out rapid testing in general practice led to increased rate of diagnosis, and might increase early detection, of HIV. We therefore recommend implementation of HIV screening in general practices in areas with high HIV prevalence. FUNDING: UK Department of Health, NHS City and Hackney. PMID- 26423196 TI - CCR5 Delta32 homozygous cord blood allogeneic transplantation in a patient with HIV: a case report. AB - BACKGROUND: Allogeneic donor CCR5 Delta32 homozygous haemopoietic cell transplantation (HCT) provides the only evidence to date of long-term control of HIV infection. However, availability of conventional CCR5 Delta32 homozygous donors is insufficient to develop this as a therapeutic strategy further. METHODS: We present a 37-year-old patient with HIV-1 infection and aggressive lymphoma who had disease progression after five lines of radiochemotherapy including an autologous HCT, and in the absence of matched sibling donors, received an allogeneic HCT with four of six HLA-matched CCR5 Delta32 homozygous cord blood cells (StemCyte, Covina, CA), supported with purified CD34+ cells from a haploidentical sibling. Blood or tissue samples were obtained before and weekly after HCT to monitor transplant and HIV infection, including chimerism analysis, CCR5 genotyping and viral tropism, viral isolation and sequence, viral reservoir analysis, immune activation and proliferation, and ex-vivo cell infectivity assays. Combined antiretroviral therapy continued during the procedure. FINDINGS: The patient's HIV was CCR5-tropic by genotypic and phenotypic analyses. Baseline latent reservoir tests showed HIV DNA copies in bulk and resting CD4 T cells and in gut-associated lymphoid tissue, CD4 T-cell-associated HIV RNA, replication competent viral size of 2.1 copies per 10(7) CD4 T cells, and single copy assay of 303 copies per mL. After HCT, plasma HIV DNA load was undetectable by ultrasensitive analyses. Upon cord blood full chimerism, the patient's CCR5 Delta32 homozygous CD4 T cells responded to proliferation and activation stimuli and became resistant to infection by the patient's viral isolate and by laboratory-adapted HIV-1 strains. Death related to lymphoma progression regretfully prevented long-term monitoring of the patient's viral reservoir. INTERPRETATION: CCR5 Delta32 homozygous cord blood reconstitution can successfully eliminate HIV-1 and render the allogeneic graft recipient's T lymphocytes resistant to HIV infection. Thus, they build on the evidence available to strongly support the use of cord blood as a strategic platform for a broader application of non-functional CCR5 transplantation to other infected individuals. FUNDING: Spanish Secretariat of Research, the American Foundation for AIDS Research (amfAR). PMID- 26423197 TI - Does antiretroviral therapy reduce HIV-associated tuberculosis incidence to background rates? A national observational cohort study from England, Wales, and Northern Ireland. AB - BACKGROUND: Whether the incidence of tuberculosis in HIV-positive people receiving long-term antiretroviral therapy (ART) remains above background population rates is unclear. We compared tuberculosis incidence in people receiving ART with background rates in England, Wales, and Northern Ireland. METHODS: We analysed a national cohort of HIV-positive individuals linked to the national tuberculosis register. Tuberculosis incidence in the HIV-positive cohort (2007-11) was stratified by ethnic origin and time on ART and compared with background rates (2009). Ethnic groups were defined as follows: the black African group included all individuals of black African origin, including those born in the UK and overseas; the white ethnic group included all white individuals born in the UK and overseas; the south Asian group included those of Indian, Pakistani, and Bangladeshi origin, born in the UK and overseas; and the other ethnic group included all other ethnic origins, including black Afro-Caribbeans. FINDINGS: The HIV-positive cohort comprised 79 919 individuals, in whom there were 1550 incident cases in 231 664 person-years of observation (incidence 6.7 cases per 1000 person-years). Incidence of tuberculosis in the HIV-positive cohort was 13.6 per 1000 person-years in black Africans and 1.7 per 1000 person years in white individuals. Incidence of tuberculosis during long-term ART (>=5 years) in black Africans with HIV was 2.4 per 1000 person-years, similar to background rates of 1.9 per 1000 person-years in this group (rate ratio 1.2, 95% CI 0.96-1.6; p=0.083); but in white individuals with HIV on long-term ART the incidence of 0.5 per 1000 person-years was higher than the background rate of 0.04 per 1000 person-years (rate ratio 14.5, 9.4-21.3; p<0.0001). The increased incidence relative to background in white HIV-positive individuals persisted when analysis was restricted to person-time accrued on ART with CD4 counts of at least 500 cells per MUL and when white HIV-positive individuals born abroad were excluded. INTERPRETATION: Tuberculosis incidence is unacceptably high irrespective of HIV status in black Africans. In white individuals with HIV, tuberculosis incidence is significantly higher than background rates in white people despite long-term ART. Expanded testing and treatment for latent tuberculosis infection to all HIV-infected adults, irrespective of ART status and CD4 cell count, might be warranted. FUNDING: Public Health England. PMID- 26423198 TI - Evaluation of paper gradient concentration strips for antifungal combination testing of Candida spp. AB - In vitro combination testing with broth microdilution chequerboard (CHEQ) method is widely used although it is time-consuming, cumbersome and difficult to apply in routine setting of clinical microbiology laboratory. A new gradient concentration paper strip method, the Liofilchem((r)) MIC test strips (MTS), provides an alternative easy and fast method enabling the simultaneous diffusion of both drugs in combination. We therefore tested a polyene+azole and an azole+echinocandin combination against 18 Candida isolates with the CHEQ method based on EUCAST guidelines and the MTS method in research and routine settings. Fractional inhibitory concentration (FIC) indices were calculated after 24 and 48 h of incubation based on complete and prominent (FIC-2) growth inhibition endpoints. Reproducibility and agreement within 1 twofold dilution was assessed. The FICs of the two methods were correlated quantitatively with t-test and Pearson analysis and qualitatively with Chi-squared test. The reproducibility of the CHEQ and MTS method was 88-100% and their agreement was 80% with 62-77% of MTS FICs being higher than the corresponding CHEQ FICs. A statistically significant Pearson correlation (r = 0.86, P = 0.0003) and association (chi(2) = 17.05, df = 4, P = 0.002) was found between MTS FIC and CHEQ FIC-2 after 24 h. Categorical agreement was 63% with no very major or major errors. All MTS synergistic interactions were also synergistic with the CHEQ method. PMID- 26423199 TI - Redescription and life cycle of the monorchiid Postmonorcheides maclovini Szidat, 1950 (Digenea) from the Southwestern Atlantic Ocean: Morphological and molecular data. AB - The adult monorchiid, Postmonorcheides maclovini Szidat, 1950, digenean parasite of the Patagonian blennie Eleginops maclovinus (Cuvier) (Eleginopidae) from Puerto Deseado (47 degrees 45' S, 65 degrees 55' W), Argentina, was characterized and its life cycle elucidated. P. maclovinus is the only species of the genus Postmonorcheides, proposed by Szidat (1950) from Tierra del Fuego province (~54 degrees S), Argentina. This digenean uses the Patagonian blennie as definitive host, and the intertidal bivalve Lasaea adansoni (Gmelin) (Lasaeidae) as both first and second intermediate hosts (metacercariae encyst inside sporocysts), being the first record of this clam as intermediate host of trematode parasites. The cercaria may, in addition to encysting in the sporocyst, emerge and presumably infect other intermediate hosts. This is the second report of a monorchiid species with metacercariae encysting inside the sporocyst. Adults were found parasitizing the fish stomach, pyloric caeca and intestine with a prevalence of 100%; sporocysts with cercariae and/or metacercariae were found parasitizing the gonad of the bivalve with a prevalence of 2.78%. The cercariae possess a well-developed tail and eye-spots are absent. The ITS1 sequence from the adult digeneans found in the Patagonian blennie, identified as P. maclovini, was found to be identical to the ITS1 sequences obtained both from sporocysts containing cercariae and encysted metacercariae found in L. adansoni. PMID- 26423200 TI - Transition-Metal-Catalyzed Cleavage of C-N Single Bonds. PMID- 26423201 TI - Persistent Left Ventricular Apical Ballooning Induced by Right Ventricular Apical Pacing. PMID- 26423202 TI - A Neutral Silicon/Phosphorus Frustrated Lewis Pair. AB - Frustrated Lewis pairs (FLPs) have a great potential for activation of small molecules. Most known FLP systems are based on boron or aluminum atoms as acid functions, few on zinc, and only two on boron-isoelectronic silicenium cation systems. The first FLP system based on a neutral silane, (C2F5)3SiCH2P(tBu)2 (1), was prepared from (C2F5)3SiCl with C2F5 groups of very high electronegativity and LiCH2P(tBu)2. 1 is capable of cleaving hydrogen, and adds CO2 and SO2. Hydrogen splitting was confirmed by H/D scrambling reactions. The structures of 1, its CO2 and SO2 adducts, and a decomposition product with CO2 were elucidated by X-ray diffraction. PMID- 26423203 TI - A consensus review on the development of palliative care for patients with chronic and progressive neurological disease. AB - BACKGROUND AND PURPOSE: The European Association of Palliative Care Taskforce, in collaboration with the Scientific Panel on Palliative Care in Neurology of the European Federation of Neurological Societies (now the European Academy of Neurology), aimed to undertake a review of the literature to establish an evidence-based consensus for palliative and end of life care for patients with progressive neurological disease, and their families. METHODS: A search of the literature yielded 942 articles on this area. These were reviewed by two investigators to determine the main areas and the subsections. A draft list of papers supporting the evidence for each area was circulated to the other authors in an iterative process leading to the agreed recommendations. RESULTS: Overall there is limited evidence to support the recommendations but there is increasing evidence that palliative care and a multidisciplinary approach to care do lead to improved symptoms (Level B) and quality of life of patients and their families (Level C). The main areas in which consensus was found and recommendations could be made are in the early integration of palliative care (Level C), involvement of the wider multidisciplinary team (Level B), communication with patients and families including advance care planning (Level C), symptom management (Level B), end of life care (Level C), carer support and training (Level C), and education for all professionals involved in the care of these patients and families (Good Practice Point). CONCLUSIONS: The care of patients with progressive neurological disease and their families continues to improve and develop. There is a pressing need for increased collaboration between neurology and palliative care. PMID- 26423204 TI - Prenatal ultrasonographic features of mature cystic teratoma in undescended testicle. PMID- 26423205 TI - Improving Procedure Start Times and Decreasing Delays in Interventional Radiology: A Department's Quality Improvement Initiative. AB - RATIONALE AND OBJECTIVES: To identify and reduce reasons for delays in procedure start times, particularly the first cases of the day, within the interventional radiology (IR) divisions of the Department of Radiology using principles of continuous quality improvement. MATERIALS AND METHODS: An interdisciplinary team representative of the IR and preprocedure/postprocedure care area (PPCA) health care personnel, managers, and data analysts was formed. A standardized form was used to document both inpatient and outpatient progress through the PPCA and IR workflow in six rooms and to document reasons for delays. Data generated were used to identify key problems areas, implement improvement interventions, and monitor their effects. Project duration was 6 months. RESULTS: The average number of on-time starts for the first case of the day increased from 23% to 56% (P value < .01). The average number of on-time, scheduled outpatients increased from 30% to 45% (P value < .01). Patient wait time to arrive at treatment room once they were ready for their procedure was reduced on average by 10 minutes (P value < .01). Patient care delay duration per 100 patients was reduced from 30.3 to 21.6 hours (29% reduction). Number of patient care delays per 100 patients was reduced from 46.6 to 40.1 (17% reduction). Top reasons for delay included waiting for consent (26% of delays duration) and laboratory tests (12%). CONCLUSIONS: Many complex factors contribute to procedure start time delays within an IR practice. A data-driven and patient-centered, interdisciplinary team approach was effective in reducing delays in IR. PMID- 26423206 TI - Placental inflammation is not increased in inflammatory bowel disease. AB - BACKGROUND: Women with inflammatory bowel disease (IBD) are at increased risk for adverse birth outcomes such as preterm delivery and small for gestational age (SGA) infants. Most recognized cases of fetal growth restriction in singleton pregnancies have underlying placental causes. However, studies in IBD examining poor birth outcomes have focused on maternal factors. We examined whether women with IBD have a higher rate of placental inflammation than non-IBD controls. METHODS: Between 2008 and 2011, the placental tissue of 7 ulcerative colitis, 5 Crohn's disease, and 2 IBD-unclassified subjects enrolled in the Pregnancy in Inflammatory Bowel Disease and Neonatal Outcome (PIANO) registry were evaluated for villitis, deciduitis, and chorioamnionitis with/without a fetal inflammatory response. The history and birth outcomes of all IBD subjects were reviewed and matched to 26 non-IBD controls by gestational age at delivery. RESULTS: Of women with IBD, 29% delivered preterm infants and 21% delivered SGA infants. Half of the IBD patients had mild-moderate disease flares during pregnancy. Five (36%) patients required corticosteroids, 2 (14%) were maintained on an immunomodulator, and 3 (21%) others received tumor necrosis factor-alpha inhibitors during their pregnancy. Chorioamnionitis was the only identified placental pathology present in the placentas reviewed, occurring less frequently in cases compared to controls (7% vs. 27%, P=0.32). CONCLUSIONS: Placental inflammatory activation does not appear to be responsible for the increase in adverse birth outcome in women with IBD. Further studies are necessary to validate these findings in IBD to explain poor birth outcomes. PMID- 26423207 TI - Effects of Cyanidin-3-O-glucoside on Synthetic and Metabolic Activity of Ethanol Stimulated Human Pancreatic Stellate Cells. AB - Activated pancreatic stellate cells (PSC) play a major role in the development of chronic pancreatitis. Flavonoids (C-3-O-G) theoretically may have potential to suppress activated PSC. The aim of our study was to determine the ability of C-3 O-G to invert synthetic and metabolic activity of alcohol stimulated human pancreatic stellate cells (hPSC). In the present study we demonstrate that treatment with C-3-O-G decreased proliferation rate of ethanol activated hPSC by 51%. Synthesis of extracellular matrix proteins in activated hPSC was markedly inhibited, as shown by reduced levels of collagen I and fibronectin expression. The decrease of secretion of fibronectin by 33% and in collagen I-25% in ethanol activated and C-3-O-G treated hPSC was observed. Moreover, treatment of ethanol activated hPSC with C-3-O-G resulted in the decrease of oxygen consumption rate by 44% and reduced levels of ATP synthesis (i.e. energy production) by 41%. Hence, the effects of C-3-O-G on ethanol activated hPSC may provide new insights for the use of anthocyanins as anti-fibrogenic agents in treatment and/or prevention of pancreatic fibrosis. PMID- 26423208 TI - Newborn screening for homocystinuria. AB - BACKGROUND: Homocystinuria is a rare inherited disorder due to a deficiency in cystathionine beta synthase. Individuals with this condition appear normal at birth but develop serious complications in childhood. Diagnosis and treatment started sufficiently early in life can effectively prevent or reduce the severity of these complications. This is an update of a previously published review. OBJECTIVES: To determine if newborn population screening for the diagnosis of homocystinuria due to cystathionine beta synthase deficiency leads to clinical benefit compared to later clinical diagnosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register.Date of the most recent search of the Inborn Errors of Metabolism Register: 08 June 2015. SELECTION CRITERIA: Randomised controlled trials and controlled clinical trials assessing the use of any neonatal screening test to diagnose infants with homocystinuria before the condition becomes clinically evident. Eligible studies compare a screened population versus a non screened population. DATA COLLECTION AND ANALYSIS: No studies were identified for inclusion in the review. MAIN RESULTS: No studies were identified for inclusion in the review. AUTHORS' CONCLUSIONS: We were unable to identify eligible studies for inclusion in this review and hence it is not possible to draw any conclusions based on controlled studies; however, we are aware of uncontrolled case-series which support the efficacy of newborn screening for homocystinuria and its early treatment. Any future randomised controlled trial would need to be both multicentre and long term in order to provide robust evidence for or against screening and to allow a cost effectiveness analysis to be undertaken. PMID- 26423210 TI - Adolescent presentations with alcohol intoxication to the emergency department at Joondalup Health Campus in 2013. AB - OBJECTIVE: To document the number of adolescents aged 16 years and under presenting to the ED at Joondalup Health Campus (JHC) with problems related primarily to alcohol intoxication, and document information about these presentations. METHOD: Presentations of adolescents were sourced from the Emergency Department Information System database at JHC. The patient's notes were interrogated for data on presentation and discharge times, means of arrival to the ED, age, gender, arrival Glasgow Coma Score (GCS), location from where the adolescent was brought and blood alcohol levels (BALs), if done. These were analysed, and descriptive statistics was reported. RESULTS: Fifty-six adolescents (61% girls) were brought in to JHC ED with alcohol intoxication in 2013. The majority (76.8%) arrived between 21.00 hours and 05.00 hours, most often by ambulance or police (58.9%). Most adolescents had BALs performed (80.4%) and of those, nearly seven in eight (86.7%) had a BAL >0.1 g/L, with a mean of 0.161 g/L (SD 0.066). Girls had a lower mean BAL, but 26.5% presented with a GCS <14. Most 16 year olds were brought from organised parties, whereas other age groups were more likely drinking at a friend's house or with friends. Few (12.5%) were drinking at home. CONCLUSION: Adolescents requiring review in an ED for alcohol intoxication are most often brought in by ambulance or police in the late evening or early morning. They are most likely to have high BALs and a significant proportion will have a GCS <14. PMID- 26423209 TI - Extending DerSimonian and Laird's methodology to perform network meta-analyses with random inconsistency effects. AB - Network meta-analysis is becoming more popular as a way to compare multiple treatments simultaneously. Here, we develop a new estimation method for fitting models for network meta-analysis with random inconsistency effects. This method is an extension of the procedure originally proposed by DerSimonian and Laird. Our methodology allows for inconsistency within the network. The proposed procedure is semi-parametric, non-iterative, fast and highly accessible to applied researchers. The methodology is found to perform satisfactorily in a simulation study provided that the sample size is large enough and the extent of the inconsistency is not very severe. We apply our approach to two real examples. PMID- 26423211 TI - Choosing sides: making decisions in an escape response. PMID- 26423212 TI - Convenient and Simple Esterification in Continuous-Flow Systems using g-DMAP. AB - The utility and applicability of polyethylene-g-polyacrylic acid-immobilized dimethylaminopyridine (g-DMAP) as a catalyst in a continuous-flow system were investigated for decarboxylative esterification. High catalytic activity toward acylation was provided by g-DMAP containing a flexible grafted-polymer structure. During decarboxylation, carboxylic acids and alcohols were converted cleanly using di-tert-butyl dicarbonate (Boc2O) as a coupling reagent, which reduced by products. In addition, the use of Boc2O resulted in the formation of tert-butyl esters. These esterifications dramatically reduced the reaction time under continuous-flow conditions, with a residence time of approximately 2 min. This highly efficient esterification procedure will provide more practical industrial applications. PMID- 26423214 TI - Synthesis of 2-Nickela(II)oxetanes from Nickel(0) and Epoxides: Structure, Reactivity, and a New Mechanism of Formation. AB - 2-Nickelaoxetanes have been frequently invoked as reactive intermediates in catalytic reactions of epoxides using nickel, but have never been isolated or experimentally observed in these transformations. Herein, we report the preparation of a series of well-defined nickelaoxetanes formed via the oxidative addition of nickel(0) with epoxides featuring ketones. The stereochemistry of the products is retained, which has not yet been reported for nickelaoxetanes. Theoretical calculations support a bimetallic ring-opening/closing pathway over a concerted oxidative addition. Initial reactivity studies of a nickelaoxetane demonstrated protonolysis, oxidatively induced reductive elimination, deoxygenation, and elimination reactions when treated with the appropriate reagents. PMID- 26423213 TI - Anomalous Evidence, Confidence Change, and Theory Change. AB - A novel experimental paradigm that measured theory change and confidence in participants' theories was used in three experiments to test the effects of anomalous evidence. Experiment 1 varied the amount of anomalous evidence to see if "dose size" made incremental changes in confidence toward theory change. Experiment 2 varied whether anomalous evidence was convergent (of multiple types) or replicating (similar finding repeated). Experiment 3 varied whether participants were provided with an alternative theory that explained the anomalous evidence. All experiments showed that participants' confidence changes were commensurate with the amount of anomalous evidence presented, and that larger decreases in confidence predicted theory changes. Convergent evidence and the presentation of an alternative theory led to larger confidence change. Convergent evidence also caused more theory changes. Even when people do not change theories, factors pertinent to the evidence and alternative theories decrease their confidence in their current theory and move them incrementally closer to theory change. PMID- 26423215 TI - Recurrent myocardial infarctions and premature coronary atherosclerosis in a 23 year-old man with antiphospholipid syndrome. PMID- 26423216 TI - Laparoscopic and robotic hepatectomy: experience from a single centre. AB - BACKGROUND: Both laparoscopic and robotic hepatectomy have been adopted in our centre for selected patients with benign or malignant liver diseases. This article reports the perioperative outcomes of these two approaches and tries to determine any difference between them. METHODS: A retrospective review of prospectively collected data was performed for all patients who underwent laparoscopic hepatectomy (LH) and robotic hepatectomy (RH) in our institute. The perioperative results were reported and compared. In order to standardise the type of liver resection performed, a subgroup analysis was made for laparoscopic left lateral sectionectomy (LS) and robotic left lateral sectionectomy (RS). RESULTS: Sixty-six LH and 70 RH were performed between November 2003 and January 2015. The two groups were comparable in demographic data and disease characteristics except more patient with recurrent pyogenic cholangitis (RPC) occurred in RH group. More major hepatectomies were performed in RH (20.0% versus 3.0%, P = 0.002). There was no mortality. No difference was noted in morbidity (LH 4.5%, RH 11.4%), conversion rate (LH 12.1%, RH 5.7%), median blood loss (both 100 mL) and median length of post-operative hospital stay (both 5 days) but operative time was longer in RH (251.5 min versus 215 min, P = 0.008). There were 29 LS and 38 RS, no difference was noted in all perioperative outcomes between the two groups. CONCLUSION: Both laparoscopic and robotic hepatectomy are safe and their perioperative outcomes are comparable and favourable. PMID- 26423217 TI - Profiling of EBV-Encoded microRNAs in EBV-Associated Hemophagocytic Lymphohistiocytosis. AB - Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a life-threatening complication of EBV infection. MicroRNAs (miRNAs) were small non coding RNA, and EBV could encode miRNAs that are involved in the progression of infection. However, the profiles of EBV-miRNAs in EBV-HLH were unknown. Here, we aimed to profile the expression of EBV-miRNAs in children with EBV-HLH by analyzing 44 known EBV-miRNAs, encoded within the BamHI fragment H rightward open reading frame 1 (BHRF1) and the BamHI-A region rightward transcript (BART), in plasma and cellular targets by real-time quantitative PCR. The study included 15 children with EBV-HLH, 15 children with infectious mononucleosis (IM), and 15 healthy controls. CD8(+) T cells were found to be the cellular target of EBV infection in EBV-HLH, while CD19(+) B cells were infected with EBV in IM. We also found the greater levels of several miRNAs encoded by BART in EBV-HLH, compared to those in IM and healthy controls, whereas the levels of BHRF1 miRNAs were lower than those in IM. The profile and pattern of EBV-miRNAs in EBV-HLH indicated that EBV could display type II latency in EBV-HLH. Importantly, the level of plasma miR-BART16-1 continued decreasing during the whole chemotherapy, suggesting that plasma miR-BART16-1 could be a potential biomarker for monitoring EBV-HLH progression. The pathogenesis of EBV-HLH might be attributed to the abundance of EBV-miRNAs in EBV-HLH. These findings help elucidate the roles of EBV miRNAs in EBV-HLH, enabling the understanding of the basis of this disease and providing clues for its treatment. PMID- 26423218 TI - Structured Biodegradable Polymeric Microparticles for Drug Delivery Produced Using Flow Focusing Glass Microfluidic Devices. AB - Biodegradable poly(DL-lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) microparticles with tunable size, shape, internal structure and surface morphology were produced by counter-current flow focusing in axisymmetric (3D) glass capillary devices. The dispersed phase was composed of 0.5-2 wt % polymer solution in a volatile organic solvent (ethyl acetate or dichloromethane) and the continuous phase was 5 wt % aqueous poly(vinyl alcohol) solution. The droplets with a coefficient of variation in dripping regime below 2.5% were evaporated to form polymeric particles with uniform sizes ranging between 4 and 30 MUm. The particle microstructure and surface roughness were modified by adding nanofiller (montmorillonite nanoclay) or porogen (2-methylpentane) in the dispersed phase to form less porous polymer matrix or porous particles with golf-ball-like dimpled surface, respectively. The presence of 2-4 wt % nanoclay in the host polymer significantly reduced the release rate of paracetamol and prevented the early burst release, as a result of reduced polymer porosity and tortuous path for the diffusing drug molecules. Numerical modeling results using the volume of fluid continuum surface force model agreed well with experimental behavior and revealed trapping of nanoclay particles in the dispersed phase upstream of the orifice at low dispersed phase flow rates and for 4 wt % nanoclay content, due to vortex formation. Janus PLA/PCL (polycaprolactone) particles were produced by solvent evaporation-induced phase separation within organic phase droplets containing 3% (v/v) PLA/PCL (30/70 or 70/30) mixture in dichloromethane. A strong preferential adsorption of Rhodamine 6G dye onto PLA was utilized to identify PLA portions of the Janus particles by confocal laser scanning microscopy (CLSM). Uniform hemispherical PCL particles were produced by dissolution of PLA domes with acetone. PMID- 26423219 TI - Nonretinotopic visual processing in the brain. AB - A basic principle in visual neuroscience is the retinotopic organization of neural receptive fields. Here, we review behavioral, neurophysiological, and neuroimaging evidence for nonretinotopic processing of visual stimuli. A number of behavioral studies have shown perception depending on object or external-space coordinate systems, in addition to retinal coordinates. Both single-cell neurophysiology and neuroimaging have provided evidence for the modulation of neural firing by gaze position and processing of visual information based on craniotopic or spatiotopic coordinates. Transient remapping of the spatial and temporal properties of neurons contingent on saccadic eye movements has been demonstrated in visual cortex, as well as frontal and parietal areas involved in saliency/priority maps, and is a good candidate to mediate some of the spatial invariance demonstrated by perception. Recent studies suggest that spatiotopic selectivity depends on a low spatial resolution system of maps that operates over a longer time frame than retinotopic processing and is strongly modulated by high level cognitive factors such as attention. The interaction of an initial and rapid retinotopic processing stage, tied to new fixations, and a longer lasting but less precise nonretinotopic level of visual representation could underlie the perception of both a detailed and a stable visual world across saccadic eye movements. PMID- 26423220 TI - Systematic psychosocial screening in a paediatric cardiology clinic: clinical utility of the Pediatric Symptom Checklist 17. AB - OBJECTIVE: To examine the clinical utility of the Pediatric Symptom Checklist 17 for identifying psychosocial concerns and improving access to psychology services within a paediatric cardiology clinic. METHOD: Parents of 561 children (aged 4-17 years) presenting for follow-up of CHD, acquired heart disease, or arrhythmia completed the Pediatric Symptom Checklist 17 as part of routine care; three items assessing parental (1) concern for learning/development, (2) questions about adjustment to cardiac diagnosis, and (3) interest in discussing concerns with a behavioural healthcare specialist were added to the questionnaire. A psychologist contacted the parents by phone if they indicated interest in speaking with a behavioural healthcare specialist. RESULTS: Percentages of children scoring above clinical cut-offs for externalising (10.5%), attention (8.7%), and total (9.3%) problems were similar to a "normative" primary-care sample, whereas fewer children in this study scored above the cut-off for internalising problems (7.8%; p<0.01). Sociodemographic, but not clinical, characteristics were associated with Pediatric Symptom Checklist 17 scores. 17% of the parents endorsed concerns about learning/development, and 20% endorsed questions about adjustment to diagnosis. History of cardiac surgery was associated with increased concern about learning/development (p<0.01). Only 37% of the parents expressing psychosocial concerns reported interest in speaking with a psychologist. CONCLUSIONS: The Pediatric Symptom Checklist 17 may not be sensitive to specific difficulties experienced by this patient population. A questionnaire with greater focus on learning/development and adjustment to diagnosis may yield improved utility. Psychology integration in clinics serving high-risk cardiac patients may decrease barriers to behavioural healthcare services. PMID- 26423221 TI - Computational identification of genetic subnetwork modules associated with maize defense response to Fusarium verticillioides. AB - BACKGROUND: Maize, a crop of global significance, is vulnerable to a variety of biotic stresses resulting in economic losses. Fusarium verticillioides (teleomorph Gibberella moniliformis) is one of the key fungal pathogens of maize, causing ear rots and stalk rots. To better understand the genetic mechanisms involved in maize defense as well as F. verticillioides virulence, a systematic investigation of the host-pathogen interaction is needed. The aim of this study was to computationally identify potential maize subnetwork modules associated with its defense response against F. verticillioides. RESULTS: We obtained time course RNA-seq data from B73 maize inoculated with wild type F. verticillioides and a loss-of-virulence mutant, and subsequently established a computational pipeline for network-based comparative analysis. Specifically, we first analyzed the RNA-seq data by a cointegration-correlation-expression approach, where maize genes were jointly analyzed with known F. verticillioides virulence genes to find candidate maize genes likely associated with the defense mechanism. We predicted maize co-expression networks around the selected maize candidate genes based on partial correlation, and subsequently searched for subnetwork modules that were differentially activated when inoculated with two different fungal strains. Based on our analysis pipeline, we identified four potential maize defense subnetwork modules. Two were directly associated with maize defense response and were associated with significant GO terms such as GO:0009817 (defense response to fungus) and GO:0009620 (response to fungus). The other two predicted modules were indirectly involved in the defense response, where the most significant GO terms associated with these modules were GO:0046914 (transition metal ion binding) and GO:0046686 (response to cadmium ion). CONCLUSION: Through our RNA-seq data analysis, we have shown that a network-based approach can enhance our understanding of the complicated host-pathogen interactions between maize and F. verticillioides by interpreting the transcriptome data in a system-oriented manner. We expect that the proposed analytic pipeline can also be adapted for investigating potential functional modules associated with host defense response in diverse plant-pathogen interactions. PMID- 26423222 TI - Controllability of structural brain networks. AB - Cognitive function is driven by dynamic interactions between large-scale neural circuits or networks, enabling behaviour. However, fundamental principles constraining these dynamic network processes have remained elusive. Here we use tools from control and network theories to offer a mechanistic explanation for how the brain moves between cognitive states drawn from the network organization of white matter microstructure. Our results suggest that densely connected areas, particularly in the default mode system, facilitate the movement of the brain to many easily reachable states. Weakly connected areas, particularly in cognitive control systems, facilitate the movement of the brain to difficult-to-reach states. Areas located on the boundary between network communities, particularly in attentional control systems, facilitate the integration or segregation of diverse cognitive systems. Our results suggest that structural network differences between cognitive circuits dictate their distinct roles in controlling trajectories of brain network function. PMID- 26423223 TI - Seroepidemiology of mumps in the general population of Jiangsu province, China after introduction of a one-dose measles-mumps-rubella vaccine. AB - The mumps surveillance data from 2004 to 2011 showed that the incidence of mumps remained high after the one-dose measles-mumps-rubella (MMR) vaccine was introduced in China in 2008. A cross-sectional survey of mumps IgG in the general population of Jiangsu province was conducted in 2012 to gain comprehensive information on the immunity profile of the general population. The mean incidence was 15.2 per 100 000 individuals in Jiangsu province from 2004-2013. Two mumps incidence peaks were observed each year after introduction of the one-dose MMR vaccine. The seroprevalence did not significantly differ by region or sex, while the GMC significantly differed by region and sex. The overall GMC in Jiangsu province was 99.1 IU/ml (95% CI: 90.1-108.2), while the seroprevalence was only 59.1% (95% CI: 56.5-61.6). The seroprevalences for the 2 age groups that received the one-dose MMR vaccine, with reported coverage exceeding 95%, were 42.6% and 70.0%, respectively. The data on the incidence, MMR coverage, and seroprevalence in children younger than 6 years of age indicate that a two-dose MMR strategy should be considered. Mumps surveillance should be strengthened in children aged 6-11 and in those aged 12-17 because of their high contact rates and relatively low seroprevalences. PMID- 26423224 TI - Volatile fragrances associated with flowers mediate host plant alternation of a polyphagous mirid bug. AB - Apolygus lucorum (Hemiptera: Miridae) is an important insect pest of cotton and fruit trees in China. The adults prefer host plants at the flowering stage, and their populations track flowering plants both spatially and temporally. In this study, we examine whether flower preference of its adults is mediated by plant volatiles, and which volatile compositions play an important role in attracting them. In olfactometer tests with 18 key host species, the adults preferred flowering plants over non-flowering plants of each species. Coupled gas chromatography-electroantennography revealed the presence of seven electrophysiologically active compounds from flowering plants. Although the adults responded to all seven synthetic plant volatiles in electroantennography tests, only four (m-xylene, butyl acrylate, butyl propionate and butyl butyrate) elicited positive behavioral responses in Y-tube olfactometer bioassays. The adults were strongly attracted to these four active volatiles in multi-year laboratory and field trials. Our results suggest that these four fragrant volatiles, which are emitted in greater amounts once plants begin to flower, mediate A. lucorum's preference to flowering host plants. We proved that the use of commonly occurring plant volatiles to recognize a large range of plant species can facilitate host selection and preference of polyphagous insect herbivore. PMID- 26423225 TI - Antiviral therapy leads to histological improvement in HBeAg-negative chronic hepatitis B patients. PMID- 26423226 TI - Navigating through digital folders uses the same brain structures as real world navigation. AB - Efficient storage and retrieval of digital data is the focus of much commercial and academic attention. With personal computers, there are two main ways to retrieve files: hierarchical navigation and query-based search. In navigation, users move down their virtual folder hierarchy until they reach the folder in which the target item is stored. When searching, users first generate a query specifying some property of the target file (e.g., a word it contains), and then select the relevant file when the search engine returns a set of results. Despite advances in search technology, users prefer retrieving files using virtual folder navigation, rather than the more flexible query-based search. Using fMRI we provide an explanation for this phenomenon by demonstrating that folder navigation results in activation of the posterior limbic (including the retrosplenial cortex) and parahippocampal regions similar to that previously observed during real-world navigation in both animals and humans. In contrast, search activates the left inferior frontal gyrus, commonly observed in linguistic processing. We suggest that the preference for navigation may be due to the triggering of automatic object finding routines and lower dependence on linguistic processing. We conclude with suggestions for future computer systems design. PMID- 26423227 TI - Three-dimensional matrix fiber alignment modulates cell migration and MT1-MMP utility by spatially and temporally directing protrusions. AB - Multiple attributes of the three-dimensional (3D) extracellular matrix (ECM) have been independently implicated as regulators of cell motility, including pore size, crosslink density, structural organization, and stiffness. However, these parameters cannot be independently varied within a complex 3D ECM protein network. We present an integrated, quantitative study of these parameters across a broad range of complex matrix configurations using self-assembling 3D collagen and show how each parameter relates to the others and to cell motility. Increasing collagen density resulted in a decrease and then an increase in both pore size and fiber alignment, which both correlated significantly with cell motility but not bulk matrix stiffness within the range tested. However, using the crosslinking enzyme Transglutaminase II to alter microstructure independently of density revealed that motility is most significantly predicted by fiber alignment. Cellular protrusion rate, protrusion orientation, speed of migration, and invasion distance showed coupled biphasic responses to increasing collagen density not predicted by 2D models or by stiffness, but instead by fiber alignment. The requirement of matrix metalloproteinase (MMP) activity was also observed to depend on microstructure, and a threshold of MMP utility was identified. Our results suggest that fiber topography guides protrusions and thereby MMP activity and motility. PMID- 26423230 TI - INEBRIA 12th Congress. PMID- 26423228 TI - Anti-interleukin-6 therapy through application of a monogenic protein inhibitor via gene delivery. AB - Anti-cytokine therapies have substantially improved the treatment of inflammatory and autoimmune diseases. Cytokine-targeting drugs are usually biologics such as antibodies or other engineered proteins. Production of biologics, however, is complex and intricate and therefore expensive which might limit therapeutic application. To overcome this limitation we developed a strategy that involves the design of an optimized, monogenic cytokine inhibitor and the protein producing capacity of the host. Here, we engineered and characterized a receptor fusion protein, mIL-6-RFP-Fc, for the inhibition of interleukin-6 (IL-6), a well established target in anti-cytokine therapy. Upon application in mice mIL-6-RFP Fc inhibited IL-6-induced activation of the transcription factor STAT3 and ERK1/2 kinases in liver and kidney. mIL-6-RFP-Fc is encoded by a single gene and therefore most relevant for gene transfer approaches. Gene transfer through hydrodynamic plasmid delivery in mice resulted in hepatic production and secretion of mIL-6-RFP-Fc into the blood in considerable amounts, blocked hepatic acute phase protein synthesis and improved kidney function in an ischemia and reperfusion injury model. Our study establishes receptor fusion proteins as promising agents in anti-cytokine therapies through gene therapeutic approaches for future targeted and cost-effective treatments. The strategy described here is applicable for many cytokines involved in inflammatory and other diseases. PMID- 26423229 TI - Eastern equine encephalitis virus in mice II: pathogenesis is dependent on route of exposure. AB - BACKGROUND: Eastern equine encephalitis virus (EEEV) is an alphavirus with a case fatality rate estimated to be as high as 75 % in humans and 90 % in horses. Surviving patients often have long-lasting and severe neurological sequelae. At present, there is no licensed vaccine or therapeutic for EEEV infection. This study completes the clinical and pathological analysis of mice infected with a North American strain of EEEV by three different routes: aerosol, intranasal, and subcutaneous. Such an understanding is imperative for use of the mouse model in vaccine and antiviral drug development. METHODS: Twelve-week-old female BALB/c mice were infected with EEEV strain FL93-939 by the intranasal, aerosol, or subcutaneous route. Mice were euthanized 6 hpi through 8 dpi and tissues were harvested for histopathological and immunohistochemical analysis. RESULTS: Viral antigen was detected in the olfactory bulb as early as 1-2 dpi in aerosol and intranasal infected mice. However, histologic lesions in the brain were evident about 24 hours earlier (3 dpi vs 4 dpi), and were more pronounced following aerosol infection relative to intranasal infection. Following subcutaneous infection, viral antigen was also detected in the olfactory bulb, though not as routinely or as early. Significant histologic lesions were not observed until 6 dpi. CONCLUSION: These pathologic studies suggest EEEV enters the brain through the olfactory system when mice are exposed via the intranasal and aerosol routes. In contrast, the histopathologic lesions were delayed in the subcutaneous group and it appears the virus may utilize both the vascular and olfactory routes to enter the brain when mice are exposed to EEEV subcutaneously. PMID- 26423231 TI - Can dietary selenium intake increase the risk of toxicity in healthy children? PMID- 26423233 TI - Omics Approaches Deciphering Molecular Function in Large Biological Systems. PMID- 26423232 TI - Herbal supplement Kamishimotsuto augments resistance exercise-induced mTORC1 signaling in rat skeletal muscle. AB - OBJECTIVES: Kamishimotsuto (KST) is a supplement containing 13 different herbs including Phellodendron bark, Anemarrhena rhizome and ginseng that have been shown to activate mammalian target of rapamycin complex 1 (mTORC1) and thereby increase muscle protein synthesis in vitro. However, the combined effect of KST and resistance exercise on muscle protein anabolism has not been investigated in vivo. Therefore, the purpose of this study was to investigate the effect of KST supplementation, resistance exercise on (mTORC1) signaling and subsequent muscle protein synthesis. METHODS: Male Sprague-Dawley rats were divided into two groups: one group received KST (500 mg/kg/d in water) and the other group received placebo (PLA) for 7 d. After 12 h of fasting, the right gastrocnemius muscle was isometrically exercised via percutaneous electrical stimulation. Muscle samples were analyzed for muscle protein synthesis (MPS) and by western blotting analysis to assess the phosphorylation of p70S6K (Thr389), rpS6 (Ser240/244), and Akt (Ser473 and Thr308). RESULTS: KST supplementation for 7 d significantly increased basal p-Akt (Ser473) levels compared with PLA, phosphorylation of the signaling proteins and MPS at baseline were otherwise unaffected. p-p70S6K and p-rpS6 levels significantly increased 1 h and 3 h after exercise in the PLA group, and these elevations were augmented in the KST group (P < 0.05). Furthermore, MPS at 6 h after resistance exercise was greater in the KST group than in the PLA group (P < 0.05). CONCLUSIONS: While resistance exercise alone was able to increase p70S6K and rpS6 phosphorylation, Kamishimotsuto supplementation further augmented resistance exercise-induced muscle protein synthesis through mTORC1 signaling. PMID- 26423234 TI - Nuclear Reformation at the End of Mitosis. AB - Cells have developed highly sophisticated ways to accurately pass on their genetic information to the daughter cells. In animal cells, which undergo open mitosis, the nuclear envelope breaks down at the beginning of mitosis and the chromatin massively condenses to be captured and segregated by the mitotic spindle. These events have to be reverted in order to allow the reformation of a nucleus competent for DNA transcription and replication, as well as all other nuclear processes occurring in interphase. Here, we summarize our current knowledge of how, in animal cells, the highly compacted mitotic chromosomes are decondensed at the end of mitosis and how a nuclear envelope, including functional nuclear pore complexes, reassembles around these decondensing chromosomes. PMID- 26423235 TI - A new classification of interphase nuclei based on spatial organizations of chromosome 8 and 21 for t(8;21) (q22;q22) acute myeloid leukemia by three dimensional fluorescence in situ hybridization. AB - Interphase heterogenous chromosomes spatially close to each other are predominantly located near the center of nuclei and are prone to incur translocations. We screened a t(8;21) (q22;q22) acute myeloid leukemia-M2 patient during three phases (post-chemotherapy, remittent stage, and relapse) and a donor of normal karyotype as control by two-(2D) and three-dimensional (3D) fluorescence in situ hybridization (FISH). Our classification of nuclei (normal, transitional, and malignant nuclei) by 3D-FISH analyses may provide a more precise prognosis than 2D-FISH results, especially for remittent stage sample in our study, in which 2D-FISH findings showed normal results, whereas 3D-FISH results showed extreme abnormalities (normal nuclei 27%, transitional nuclei 36%, malignant nuclei 37%). The relative radial positions (d/R) of chromosomes 8 were similar to d/R of chromosomes 21 for the relapse sample. We classified heterogenous chromosome pairs into close pairs and normal pairs based on their relative distances (d'/(2R)). The centers of close pairs were more internal than normal pairs in nuclei in all samples, and the d/R values of a given-type pairwise heterogenous chromosomes were similar among four samples. Our data demonstrate that the classification of nuclei based on spatial organization of chromosomes by 3D-FISH is reasonable and essential for evaluating acute myeloid leukemia prognosis. PMID- 26423236 TI - In vitro-in vivo correlation of parenteral risperidone polymeric microspheres. AB - The objective of the present study was to determine whether an in vitro-in vivo correlation (IVIVC) can be established for polymeric microspheres that are equivalent in formulation composition but prepared with different manufacturing processes. Risperidone was chosen as a model therapeutic and poly(lactic-co glycolic acid) (PLGA) with similar molecular weight as that used in the commercial product Risperdal(r) Consta(r) was used to prepare risperidone microspheres. Various manufacturing processes were investigated to produce the risperidone microspheres with similar drug loading (approx. 37%) but distinctly different physicochemical properties (e.g. porosity, particle size and particle size distribution). In vitro release of the risperidone microspheres was investigated using different release testing methods (such as sample-and-separate and USP apparatus 4). In vivo pharmacokinetic profiles of the risperidone microsphere formulations following intramuscular administration were determined using a rabbit model. Furthermore, the obtained pharmacokinetic profiles were deconvoluted using the Loo-Riegelman method and the calculated in vivo release was compared with the in vitro release of these microspheres. Level A IVIVCs were established and validated for the compositionally equivalent risperidone microspheres based on the in vitro release data obtained using USP apparatus 4. The developed IVIVCs demonstrated good predictability and were robust. These results showed that the developed USP apparatus 4 method was capable of discriminating PLGA microspheres that are equivalent in formulation composition but with manufacturing differences and predicting their in vivo performance in the investigated animal model. PMID- 26423237 TI - One-component nanomedicine. AB - One-component nanomedicine (OCN) represents an emerging class of therapeutic nanostructures that contain only one type of chemical substance. This one component feature allows for fine-tuning and optimization of the drug loading and physicochemical properties of nanomedicine in a precise manner through molecular engineering of the underlying building blocks. Using a precipitation procedure or effective molecular assembly strategies, molecularly crafted therapeutic agents (e.g. polymer-drug conjugates, small molecule prodrugs, or drug amphiphiles) could involuntarily aggregate, or self-assemble into nanoscale objects of well defined sizes and shapes. Unlike traditional carrier-based nanomedicines that are inherently multicomponent systems, an OCN does not require the use of additional carriers and could itself possess desired physicochemical features for preferential accumulation at target sites. We review here recent progress in the molecular design, conjugation methods, and fabrication strategies of OCN, and analyze the opportunities that this emerging platform could open for the new and improved treatment of devastating diseases such as cancer. PMID- 26423238 TI - Improving cell-based therapies by nanomodification. AB - Cell-based therapies are emerging as a promising approach for various diseases. Their therapeutic efficacy depends on rational control and regulation of the functions and behaviors of cells during their treatments. Different from conventional regulatory strategy by chemical adjuvants or genetic engineering, which is restricted by limited synergistic regulatory efficiency or uncertain safety problems, a novel approach based on nanoscale artificial materials can be applied to modify living cells to endow them with novel functions and unique properties. Inspired by natural "nano shell" and "nano compass" structures, cell nanomodification can be developed through both external and internal pathways. In this review, some novel cell surface engineering and intracellular nanoconjugation strategies are summarized. Their potential applications are also discussed, including cell protection, cell labeling, targeted delivery and in situ regulation. It is believed that these novel cell-material complexes can have great potentials for biomedical applications. PMID- 26423241 TI - Low-Density Lipoprotein Uptake Demonstrates a Hepatocyte Phenotype in the Dog, but Is Nonspecific. AB - Low-density lipoprotein (LDL) uptake is one of a number of tests used to demonstrate hepatocyte-like function after stem cell differentiation. Use of two compounds, LDL and acetylated LDL (AcLDL), has been described despite each having different mechanisms of uptake. Three primary hepatocyte cultures and three sets of mesenchymal stromal cell (MSC) cultures, derived from both adipose tissue and bone marrow, were harvested from dogs. Those cells were compared to commercially available human and mouse bone marrow-derived MSCs. LDL receptor expression was demonstrated by gene expression and immunofluorescence in all primary hepatocyte cultures, undifferentiated canine bone marrow MSCs and canine adipose MSCs. Undifferentiated human and mouse bone marrow MSCs also expressed the LDL receptor. In vitro, canine hepatocytes took up labeled LDL, but not AcLDL. All undifferentiated MSCs took up LDL, but not AcLDL. In conclusion, LDL and not AcLDL is a test of canine hepatocyte-like phenotype, but this is not tissue or species specific and, therefore, is not informative assay when testing proof of MSC to hepatocyte differentiation. PMID- 26423239 TI - Designing polymers with sugar-based advantages for bioactive delivery applications. AB - Sugar-based polymers have been extensively explored as a means to increase drug delivery systems' biocompatibility and biodegradation. Here,we review he use of sugar-based polymers for drug delivery applications, with a particular focus on the utility of the sugar component(s) to provide benefits for drug targeting and stimuli responsive systems. Specifically, numerous synthetic methods have been developed to reliably modify naturally-occurring polysaccharides, conjugate sugar moieties to synthetic polymer scaffolds to generate glycopolymers, and utilize sugars as a multifunctional building block to develop sugar-linked polymers. The design of sugar-based polymer systems has tremendous implications on both the physiological and biological properties imparted by the saccharide units and are unique from synthetic polymers. These features include the ability of glycopolymers to preferentially target various cell types and tissues through receptor interactions, exhibit bioadhesion for prolonged residence time, and be rapidly recognized and internalized by cancer cells. Also discussed are the distinct stimuli-sensitive properties of saccharide-modified polymers to mediate drug release under desired conditions. Saccharide-based systems with inherent pH- and temperature-sensitive properties, as well as enzyme-cleavable polysaccharides for targeted bioactive delivery, are covered. Overall, this work emphasizes inherent benefits of sugar-containing polymer systems for bioactive delivery. PMID- 26423240 TI - Do telomeres have a higher plasticity than thought? Results from the German Chronic Kidney Disease (GCKD) study as a high-risk population. AB - Telomere length is considered as a biological marker for aging. It is expected that telomeres shorten with age and with conditions associated with oxidative stress and inflammation. Both are present in patients with chronic kidney disease (CKD) who have a very high cardiovascular risk. We investigated whether CKD duration is associated with relative telomere length (RTL) in 4802 patients from the German Chronic Kidney Disease (GCKD) study. We measured RTL in each sample in quadruplicates using a quantitative polymerase chain reaction (qPCR). We observed a U-shaped association of RTL with CKD duration: the longest RTL was found in those 339 patients who reported the shortest disease duration (<6 months) and shorter RTL in 2108 patients with duration between 6 months and less than 5 years. Most importantly, those 2331 patients who reported a CKD duration of 5 years and more had significantly longer RTL compared to those with intermediate CKD duration (6 months to less than 5 years): mean 0.954, 95%CI 0.946-0.961 versus 0.937, 95%CI 0.929-0.944, p=0.002). Due to the cross-sectional nature of the study these surprising results have to be considered with caution and as hypothesis-generating. Whether the longer RTL in patients with long-lasting disease is caused by an activation of telomerase to counteract the shortening of RTL due to oxidative stress and inflammation or whether they are caused by a survival bias needs to be investigated in longitudinal studies. Our data are in support of a higher plasticity of shortening and elongations of RTL as until recently anticipated. PMID- 26423242 TI - Elevated resting heart rate predisposes metabolic syndrome in women rather than in men: a 15-year prospective study. AB - BACKGROUND: Increasing evidences have indicated that there are gender differences in the prevalence of metabolic syndrome(MS), but the mechanism is uncertain. METHODS: A total of 711 subjects aged 35-65 years accepted health examinations both in 1992 and 2007. Since 114 subjects had MS and 7 had heart disease at baseline, they were excluded from the analysis. Therefore, 590 subjects with complete data (male: 61.5 %) were available and analysed. After the relationship between gender and incident MS at follow-up was tested, these subjects were categorized into four groups according to the baseline resting heart rate(RHR) classified by genders. Trend tests of MS incidences across the four groups of resting heart rate were conducted by Cochran-Armitage tend tests in both men and women. Additionally, three logistic regression models were used to estimate the effects of RHR on the new onset of MS by taking RHR as a continuous variable(per 4 beats/min elevation). RESULTS: Gender(women) itself was an independent risk factor for incident MS at follow-up(OR = 2.64, 1.33-5.23, P = 0.005). The incidences of MS according to the RHR categories showed a statistical linear trend in women(P for trend = 0.018) rather than in men(P for trend = 0.194). The ORs[95 % confidence intervals(CIs)] of MS for each 4 bpm elevation in RHR was 1.18(1.03-1.36)(P = 0.020) in a univariate model, 1.20 (1.04-1.38) (P = 0.011) adjusted for age and health related behaviors only and 1.23(1.06-1.43)(P = 0.007) adjusted for age, health related behaviors and pre-existing components of MS in the baseline in women. Otherwise, RHR did not have any significant associations with incident MS in men neither in a univariate model nor in multivariate models. CONCLUSIONS: In this study, elevated RHR is correlated with the development of MS in women rather than in men. PMID- 26423243 TI - No effect of unemployment on intimate partner-related femicide during the financial crisis: a longitudinal ecological study in Spain. AB - BACKGROUND: Spain's financial crisis has been characterized by an increase in unemployment. This increase could have produced an increase in deaths of women due to intimate partner-related femicides (IPF). This study aims to determine whether the increase in unemployment among both sexes in different regions in Spain is related to an increase in the rates of IPF during the current financial crisis period. METHODS: An ecological longitudinal study was carried out in Spain's 17 regions. Two study periods were defined: pre-crisis period (2005-2007) and crisis period (2008-2013). IPF rates adjusted by age and unemployment rates for men and women were calculated. We fitted multilevel linear regression models in which observations at level 1 were nested within regions according to a repeated measurements design. RESULTS: Rates of unemployment have progressively increased in Spain, rising above 20 % from 2008 to 2013 in some regions. IPF rates decreased in some regions during crisis period with respect to pre-crisis period. The multilevel analysis does not support the existence of a significant relationship between the increase in unemployment in men and women and the decrease in IPF since 2008. DISCUSSION: The increase in unemployment in men and women in Spain does not appear to have an effect on IPF. The results of the multilevel analysis discard the hypothesis that the increase in the rates of unemployment in women and men are related to an increase in IPF rates. CONCLUSIONS: The decline in IPF since 2008 might be interpreted as the result of exposure to other factors such as the lower frequency of divorces in recent years or the medium term effects of the integral protection measures of the law on gender violence that began in 2005. PMID- 26423244 TI - Fluoroquinolone therapy for bloodstream infections caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae. AB - BACKGROUND/PURPOSE: For extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae infections, carbapenems are recommended as first line therapy, and clinical data on the therapeutic efficacy of fluoroquinolones (FQs) is limited. This study compares the efficacy of FQs and carbapenems for bloodstream infections caused by ESBL-producing Escherichia coli or Klebsiella pneumoniae. METHODS: Between 2008 and 2010, adults with ESBL-producing E. coli or K. pneumoniae bacteremia at two medical centers were reviewed. Adults receiving definitive FQ or carbapenem therapy were compared in a propensity score-matched analysis, and 30-day mortality was the primary endpoint. RESULTS: A total of 299 patients were eligible. Patients receiving a FQ (n = 24), either ciprofloxacin or levofloxacin, had a lower 30-day mortality rate than those with carbapenem therapy (8.3%, 2/24 vs. 23.3%, 64/275; p = 0.12). Multivariate regression analysis revealed that a critical illness [Pitt bacteremia score >= 4 points; odds ratio (OR), 7.09; p < 0.001], rapidly fatal underlying disease (OR, 5.73; p < 0.001), and hospital-associated infection (OR, 2.57; p = 0.01) were independently associated with 30-day mortality. By contrast, FQ definitive therapy was a protective factor compared with carbapenems (OR, 0.18; p = 0.04). There were 72 matched cases with carbapenem therapy in a propensity score-matched analysis, and a difference in the 30-day mortality rate of two groups was noted (8.3% vs. 29.2%; p = 0.05). CONSLUSION: For ESBL-producing E. coli or K. pneumoniae bacteremia, ciprofloxacin or levofloxacin, if active in vitro, can be considered as a carbapenem-sparing alternative. PMID- 26423246 TI - New paediatric formulation is a milestone in treatment. PMID- 26423245 TI - Histone deacetylase inhibitors and epigenetic regulation in lymphoid malignancies. AB - A vast majority of lymphomas and leukaemias are results of translocations. These translocations produce various genetic and epigenetic changes that lead to oncogenesis. This opens an opportunity to use a relatively new class of anti cancer agents, inhibitors of histone deacetylases (HDACi) to target lymphoid malignancies. Surprisingly, the rational basis for treatment of lymphomas with HDACi is far from clear, although some positive results have been obtained. Here we analyze the effect of histone deacetylase (HDAC) inhibitors on lymphoid malignancies. PMID- 26423247 TI - ART in sub-Saharan Africa: the value of viral load monitoring. PMID- 26423248 TI - DMPA use and HIV acquisition: time to switch to NET-EN? PMID- 26423249 TI - HIV-infection and comorbidities: a complex mix. PMID- 26423250 TI - Nigeria, MSM, and the law: from evidence to strategy. PMID- 26423251 TI - Overlap of HIV and low health literacy in the southern USA. PMID- 26423253 TI - Time trends for risk of severe age-related diseases in individuals with and without HIV infection in Denmark: a nationwide population-based cohort study. AB - BACKGROUND: Whether the reported high risk of age-related diseases in HIV infected people is caused by biological ageing or HIV-associated risk factors such as chronic immune activation and low-grade inflammation is unknown. We assessed time trends in age-standardised and relative risks of nine serious age related diseases in a nationwide cohort study of HIV-infected individuals and population controls. METHODS: We identified all HIV-infected individuals in the Danish HIV Cohort Study who had received HIV care in Denmark between Jan 1, 1995, and June 1, 2014. Population controls were identified from the Danish Civil Registration System and individually matched in a ratio of nine to one to the HIV infected individuals for year of birth, sex, and date of study inclusion. Individuals were included in the study if they had a Danish personal identification number, were aged 16 years or older, and were living in Denmark at the time of study inclusion. Data for study outcomes were obtained from the Danish National Hospital Registry and the Danish National Registry of Causes of Death and were cardiovascular diseases (myocardial infarction and stroke), cancers (virus associated, smoking related, and other), severe neurocognitive disease, chronic kidney disease, chronic liver disease, and osteoporotic fractures. We calculated excess and age-standardised incidence rates and adjusted incidence rate ratios of outcomes for time after HIV diagnosis, highly active antiretroviral therapy (ART) initiation, and calendar time. The regression analyses were adjusted for age, sex, calendar time, and origin. FINDINGS: We identified 5897 HIV-infected individuals and 53,073 population controls; median age was 36.8 years (IQR 30.6-44.4), and 76% were men in both cohorts. Dependent on disease, the HIV cohort had 55,050-57,631 person-years of follow-up and the population controls had 638,204-659,237 person-years of follow-up. Compared with the population controls, people with HIV had high excess and relative risk of all age-related diseases except other cancers. Overall, the age-standardised and relative risks of cardiovascular diseases, cancers, and severe neurocognitive disease did not increase substantially with time after HIV diagnosis or ART initiation. Except for chronic kidney diseases, the age-standardised and relative risks of age-related diseases did not increase with calendar time. INTERPRETATIONS: Severe age-related diseases are highly prevalent in people with HIV, and continued attention and strategies for risk reduction are needed. The findings from our study do not suggest that accelerated ageing is a major problem in the HIV-infected population. FUNDING: Preben og Anna Simonsens Fond, Novo Nordisk Foundation, Danish AIDS Foundation, Augustinus Foundation, and Odense University Hospitals Frie Fonds Midler. PMID- 26423255 TI - The journey of nisin development in China, a natural-green food preservative. PMID- 26423252 TI - Monitoring and switching of first-line antiretroviral therapy in adult treatment cohorts in sub-Saharan Africa: collaborative analysis. AB - BACKGROUND: HIV-1 viral load testing is recommended to monitor antiretroviral therapy (ART) but is not universally available. The aim of our study was to assess monitoring of first-line ART and switching to second-line ART in sub Saharan Africa. METHODS: We did a collaborative analysis of cohort studies from 16 countries in east Africa, southern Africa, and west Africa that participate in the international epidemiological database to evaluate AIDS (IeDEA). We included adults infected with HIV-1 who started combination ART between January, 2004, and January, 2013. We defined switching of ART as a change from a non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based regimen to one including a protease inhibitor, with adjustment of one or more nucleoside reverse-transcriptase inhibitors (NRTIs). Virological and immunological failures were defined according to WHO criteria. We calculated cumulative probabilities of switching and hazard ratios with 95% CIs comparing routine viral load monitoring, targeted viral load monitoring, CD4 monitoring, and clinical monitoring, adjusting for programme and individual characteristics. FINDINGS: Of 297,825 eligible patients, 10,352 (3%) switched to second-line ART during 782 ,412 person-years of follow-up. Compared with CD4 monitoring, hazard ratios for switching were 3.15 (95% CI 2.92-3.40) for routine viral load monitoring, 1.21 (1.13-1.30) for targeted viral load monitoring, and 0.49 (0.43-0.56) for clinical monitoring. Of 6450 patients with confirmed virological failure, 58.0% (95% CI 56.5-59.6) switched by 2 years, and of 15,892 patients with confirmed immunological failure, 19.3% (18.5-20.0) switched by 2 years. Of 10,352 patients who switched, evidence of treatment failure based on one CD4 count or viral load measurement ranged from 86 (32%) of 268 patients with clinical monitoring to 3754 (84%) of 4452 with targeted viral load monitoring. Median CD4 counts at switching were 215 cells per MUL (IQR 117 335) with routine viral load monitoring, but were lower with other types of monitoring (range 114-133 cells per MUL). INTERPRETATION: Overall, few patients switched to second-line ART and switching happened late in the absence of routine viral load monitoring. Switching was more common and happened earlier after initiation of ART with targeted or routine viral load testing. FUNDING: National Institute of Allergy and Infectious Diseases, Swiss National Science Foundation. PMID- 26423257 TI - [Not Available]. PMID- 26423256 TI - Macroscopic and microscopic assessments of the glenohumeral and subacromial synovitis in rotator cuff disease. AB - BACKGROUND: Whereas synovitis is one of most common findings during arthroscopic surgery in patients with rotator cuff diseases, no study has investigated its characteristics. We propose a macroscopic assessment system for investigating the characteristics of synovitis. METHODS: Fifty-four patients with a full-thickness rotator cuff tear undergoing arthroscopic rotator cuff repair with an average age of 62.5 +/- 7.0 years were included. For the macroscopic assessment, 3 parameters, villous hypertrophy, hyperemia, and density, were measured and translated into grades in 3 regions-of-interest (ROI) in the glenohumeral joint and 4 ROIs in the subacromial space. For the microscopic assessments, 4 commonly used microscopic assessment systems were used. The reliability and association between the macroscopic and microscopic assessments were investigated. RESULTS: The inter- and intra-observer reliability of all of the macroscopic and microscopic assessments were excellent. The severity of synovitis was significantly greater in the glenohumeral joint than that in the subacromial space, 1.54 +/- 0.61 versus 0.94 +/- 0.56 (p < 0.001). Synovitis varied with respect to location, and was generally more severe near the tear with the macroscopic assessment system. Meanwhile, none of the microscopic assessment systems demonstrated differences between different ROIs in both the glenohumeral joint and the subacromial space. CONCLUSIONS: The macroscopic assessment system for synovitis in rotator cuff disease in this study showed excellent reliability. It critically described characteristics of synovitis that microscopic assessment systems could not. Therefore, this system could be a useful tool for investigating synovitis in rotator cuff disease. PMID- 26423258 TI - [Drowning versus cardiac ischemia: Cardiac arrest of an 11-year-old boy at a swimming lake]. AB - This report describes a case of sudden cardiac arrest and subsequent attempted cardiopulmonary resuscitation of an 11-year-old child on the shores of a swimming lake. Reports of eyewitnesses excluded the obviously suspected diagnosis of a drowning accident. The result of the autopsy was sudden cardiac death due to a congenital coronary anomaly (abnormal left coronary artery, ALCA). Favored by vigorous physical activity, this anomaly can lead to malignant arrhythmias because the ectopic coronary artery with its intramural course through the aortic wall is compressed during every systole. This pathology was not known to the boy or his family; in fact he liked sports but had suffered of a syncope once which was not followed up. Without a strong suspicion it is difficult to diagnose a coronary artery anomaly and it is often missed even in college athletes. Tragically, sudden cardiac arrest may be the first symptom of an undiagnosed abnormal coronary artery. Following syncope or chest pain during exercise with a normal electrocardiogram (ECG) cardiac imaging, such as computed tomography (CT) or angiography should be initiated in order to enable surgical repair of an abnormal coronary artery. PMID- 26423259 TI - Risk factors for obstetric anal sphincter injuries in twin deliveries: a retrospective review. AB - INTRODUCTION AND HYPOTHESIS: Risk factors for obstetric anal sphincter injuries (OASIS) have been well-established in singleton pregnancies. Considering the unique characteristics of twin deliveries, our aim was to identify risk factors for OASIS that are specific to twins. METHODS: A retrospective study of all vaginal twin deliveries in a tertiary center between 2000 and 2014. Women who experienced OASIS (the OASIS group) were compared with those whose anal sphincter was intact (controls). RESULTS: Overall 717 women were eligible for the study, of whom 20 (2.8 %) experienced OASIS. Women in the OASIS group were more likely to be nulliparous (95.0 % vs 53.7 %, p < 0.001) and were characterized by a higher gestational age at delivery (36.1 +/- 2.5 vs 34.6 +/- 3.3, p = 0.04), a higher birth weight for both twin A and twin B (2,507 +/- 540 g vs 2,254 +/- 525 g, p = 0.03, and 25,49 +/- 420 g vs 2,232 +/- 606 g, p = 0.004 respectively), and a higher rate of episiotomy (40.0 % vs 14.2 %, p = 0.001), instrumental delivery for twin A (80.0 % vs 13.5 %, p < 0.001) or twin B (80.0 % vs 18.7 %, p < 0.001), and inter-twin delivery interval of over 30 min (20.0 % vs 7.5 %, p = 0.04). The only factor that remained significant on multivariate analysis was instrumental delivery: forceps delivery of twin A (OR = 8.8, 95 % CI 2.6-30.1), vacuum extraction of twin A (OR = 9.2, 95 % CI 2.6-34.6), and forceps delivery of twin B (OR = 15.4, 95 % CI 4.9-48.6). In women with certain combinations of risk factors the risk of OASIS was as high as 30 %. CONCLUSION: The overall rate of OASIS in twins is low and instrumental delivery, especially by forceps, is a risk factor. PMID- 26423261 TI - Post-void residual urine under 150 ml does not exclude voiding dysfunction in women. AB - INTRODUCTION AND HYPOTHESIS: It has been claimed that post-void residual urine (PVR) below 150 ml rules out voiding dysfunction in women with stress urinary incontinence (SUI) and provides license to perform sling surgery. The cut-off of 150 ml seems arbitrary, not evidence-based, and so we sought to investigate the ability of PVR < 150 ml to exclude voiding dysfunction. METHODS: We retrospectively reviewed the charts of all patients who underwent invasive urodynamics from 1 January 2013 to 31 December 2013. Voiding dysfunction was diagnosed if both the invasive urodynamic and the free flow showed abnormal results. We registered the PVR in patients with voiding dysfunction and divided them into groups with PVR < 150 ml and PVR >= 150 ml. Patients were then analyzed for bladder outlet obstruction and detrusor underactivity. RESULTS: Of the 205 patients undergoing invasive urodynamics in 2013, a total of 20 had voiding dysfunction, 2 with PVR >= 150 ml. Eighteen patients had PVR < 150 ml (range 0-50 ml); 9 had bladder outlet obstruction while 7 had detrusor underactivity. Two patients were uncategorized. Out of the 20 patients, 7 had no symptoms or complaints indicating voiding dysfunction. CONCLUSIONS: Patients with voiding dysfunction often have normal PVR and so PVR < 150 ml cannot exclude voiding dysfunction. All patients should be evaluated using free flow measurements along with PVR to obtain a reliable, objective measurement of their voiding pattern, before anti-incontinence surgery. PMID- 26423260 TI - Incontinence medication response relates to the female urinary microbiota. AB - INTRODUCTION AND HYPOTHESIS: Many adult women have resident urinary bacteria (urinary microbiome/microbiota). In adult women affected by urinary urgency incontinence (UUI), the etiologic and/or therapeutic role of the urinary microbiome/microbiota remains unknown. We hypothesized that microbiome/microbiota characteristics would relate to clinically relevant treatment response to UUI medication per os. METHODS: Adult women initiating medication treatment orally for UUI and a comparator group of unaffected women were recruited in a tertiary care health-care system. All participants provided baseline clinical data and urine samples. Women with UUI were given 5 mg solifenacin, with potential dose escalation to 10 mg for inadequate UUI symptom control at 4 weeks. Additional data and urine samples were collected from women with UUI at 4 and 12 weeks. The samples were assessed using 16S ribosomal RNA (rRNA) gene sequencing and enhanced quantitative urine culturing. The primary outcome was treatment response as measured by the validated Patient Global Symptom Control (PGSC) questionnaire. Clinically relevant UUI symptom control was defined as a 4 or 5 score on the PGSC. RESULTS: Diversity and composition of the urinary microbiome/microbiota of women with and without UUI differed at baseline. Women with UUI had more bacteria and a more diverse microbiome/microbiota. The clinical response to solifenacin in UUI participants was related to baseline microbiome/microbiota, with responders more likely to have fewer bacteria and a less diverse community at baseline. Nonresponders had a more diverse community that often included bacteria not typically found in responders. CONCLUSIONS: Knowledge of an individual's urinary microbiome/microbiota may help refine UUI treatment. Complementary tools, DNA sequencing, and expanded urine culture provide information about bacteria that appear to be related to UUI incontinence status and treatment response in this population of adult women. PMID- 26423264 TI - Effects of a new community-based reproductive health intervention on knowledge of and attitudes and behaviors toward stress urinary incontinence among young women in Shanghai: a cluster-randomized controlled trial. AB - INTRODUCTION AND HYPOTHESIS: This study aimed to evaluate the prevalence of stress urinary incontinence (SUI) and to introduce a new community-based reproductive health intervention. We then evaluated the effectiveness of this intervention. METHODS: In this cluster-randomized trial, 2100 participants aged 18-40 years were divided randomly into an intervention group (IG, 1400 women) and a control group (CG, 700 women). The CG received traditional community intervention, cmprising limited reproductive information and education; the IG received the new community-based reproductive health intervention model, comprising self-designed handbooks, health lectures, and free medical consultations, in addition to the traditional community intervention. All participants were surveyed face to face using a self-designed questionnaire before and after the 6-month intervention. RESULTS: In Shanghai, the prevalence rate of SUI was 14.3 %. No difference was observed between groups regarding mean knowledge, attitudes, and practices (KAPs) about SUI and the total score at baseline (P > 0.05). The IG scored significantly higher than the CG on the KAP questions at follow-up, and a significant improvement was observed in the IG after the intervention. Total scores increased with age, educational level, income, and time spent working in Shanghai per year but decreased with gravidity and the number of abortions. Native respondents scored higher than did migrants. CONCLUSIONS: The prevalence of SUI is high in Shanghai, and the new community based reproductive health intervention model is both effective and easily implemented. This intervention should focus on women with a low income, women with low education levels, young women, migrant women, and women who have had multiple abortions or pregnancies. PMID- 26423265 TI - Digital assessment and quantification of pelvic organ prolapse (DPOP-Q): a randomised cross-over diagnostic agreement trial. AB - INTRODUCTION: Pelvic Organ Prolapse Quantification (POP-Q) system, measured in centimetres using a ruler (e.g. POPstix(r)), is recommended to quantify prolapse severity. POPstix(r) are costly (US $1/ruler). Home-made devices are used instead, but these have not been shown to be reproducible. HYPOTHESIS: Digitally assessed POP-Q (DPOP-Q) is as reliable, reproducible and acceptable as POP-Q assessed using POPstix(r). METHODS: In this randomised crossover diagnostic agreement trial, each assessor measured the index finger of their dominant hand using a ruler. At visit one, patients were randomised to either POPstix(r) POP-Q assessment in a modified lithotomy position or DPOP-Q in both modified a lithotomy and a standing position. After the first clinician conducted this assessment, a second blinded clinician then carried out the remaining assessment on the same patient. For each examination, duration was recorded, along with a patient-completed discomfort score. Twenty-five women were invited for visit two, at which DPOP-Q was recorded by the same clinician who undertook DPOP-Q at the first visit. This allowed evaluation of inter- and intraobserver agreement together with examination acceptability. RESULTS: One hundred and nine women were recruited [median age 55 years, parity 2, body mass index (BMI) 27.1]. Of the 25 patients invited, 23 returned for visit two. DPOP-Q had high interobserver reliability [kappa = 0.94, 95 % confidence interval (CI) 0.878-0.996] and intraobserver reliability (alpha = 0.96) with POPstix(r). DPOP-Q was significantly quicker (p = 0.02) and less uncomfortable (p < 0.01) than POPstix(r) POP-Q. CONCLUSION: DPOP-Q is reliable, acceptable and cost effective. PMID- 26423266 TI - Design and engineering of a man-made diffusive electron-transport protein. AB - Maquettes are man-made cofactor-binding oxidoreductases designed from first principles with minimal reference to natural protein sequences. Here we focus on water-soluble maquettes designed and engineered to perform diffusive electron transport of the kind typically carried out by cytochromes, ferredoxins and flavodoxins and other small proteins in photosynthetic and respiratory energy conversion and oxido-reductive metabolism. Our designs were tested by analysis of electron transfer between heme maquettes and the well-known natural electron transporter, cytochrome c. Electron-transfer kinetics were measured from seconds to milliseconds by stopped-flow, while sub-millisecond resolution was achieved through laser photolysis of the carbon monoxide maquette heme complex. These measurements demonstrate electron transfer from the maquette to cytochrome c, reproducing the timescales and charge complementarity modulation observed in natural systems. The ionic strength dependence of inter-protein electron transfer from 9.7*10(6) M(-1) s(-1) to 1.2*10(9) M(-1) s(-1) follows a simple Debye-Huckel model for attraction between +8 net charged oxidized cytochrome c and -19 net charged heme maquette, with no indication of significant protein dipole moment steering. Successfully recreating essential components of energy conversion and downstream metabolism in man-made proteins holds promise for in vivo clinical intervention and for the production of fuel or other industrial products. This article is part of a Special Issue entitled Biodesign for Bioenergetics--the design and engineering of electronic transfer cofactors, proteins and protein networks, edited by Ronald L. Koder and J.L. Ross Anderson. PMID- 26423268 TI - Simultaneous progression patterns of scoliosis, pelvic obliquity, and hip subluxation/dislocation in non-ambulatory neuromuscular patients: an approach to deformity documentation. AB - BACKGROUND: A triad of deformities-thoracolumbar scoliosis, pelvic obliquity, and femoral head (hip) subluxation/dislocation-occurs frequently in non-ambulatory neuromuscular patients, but their close inter-relationship is infrequently appreciated or quantified. We propose a deformity documentation approach to assess each component simultaneously. METHODS: The documentation assesses each component for maximal functional level, deformity, and flexibility/rigidity: deformity from antero-posterior radiographs (scoliosis-maximal functional position, pelvic obliquity-sitting, hip position-supine) and flexibility/rigidity from extent of repositioning on supine (spine, pelvis) and frog lateral (hip) radiographs. The approach was applied in 211 patients: Duchenne muscular dystrophy (110), spinal muscular atrophy (49), cerebral palsy (26), and other neuromuscular disorders (26). RESULTS: Measurement of 2124 radiological data points allowed for deformity (mild to moderate to severe) and flexibility/rigidity (fully reducible to partially to non-reducible) gradations for scoliosis, pelvic obliquity, and hip subluxation/dislocation. The charting documented: (1) numerical deformity and flexibility/rigidity changes [x-axis: age; y-axis: angulation (scoliosis and pelvic obliquity) and percent coverage (hip subluxation or dislocation) from 0-120]; and (2) grade deformity and flexibility/rigidity changes [x-axis: age; y-axis: deformity and flexibility/rigidity, following conversion of numerical measurements to a 1-5 grade scale]. In subgroups with the most extensive documentation, thoracolumbar and lumbar scoliosis extended into the sacrum with 98 % (114/116) accompanied by pelvic obliquity; and scoliosis developed more rapidly than hip deformity in 44 % (28/63), scoliosis and hip deformity developed at the same time in 40 % (25/63), and hip deformity developed more rapidly than scoliosis in 16 % (10/63) (Pearson's chi-squared test p = 0.0501, almost significant). CONCLUSION AND SIGNIFICANCE: Documentation of the triad of neuromuscular deformities is applicable to all diagnoses; it outlines maximal functional level, deformity, and flexibility/rigidity at each site; and it shows the relationship between spine, pelvic, and hip deformation. Prospective charting will enhance both clinical management and clinical research into neuromuscular deformity. PMID- 26423267 TI - Breeding on the leading edge of a northward range expansion: differences in morphology and the stress response in the arctic Gambel's white-crowned sparrow. AB - Individuals at the forefront of a range shift are likely to exhibit phenotypic traits that distinguish them from the population breeding within the historic range. Recent studies have examined morphological, physiological and behavioral phenotypes of individuals at the edge of their range. Several studies have found differences in the hypothalamic-pituitary-adrenal (HPA) axis activity in response to acute restraint stress in individuals at the range limits. HPA axis activation leads to elevations in glucocorticoids that regulate physiology and behavior. Here we compare the hormonal profiles and morphometrics from Gambel's white crowned sparrows (Zonotrichia leucophrys gambelii) breeding at the northern limit of the population's range to those birds breeding within the historic population range. Birds breeding at the northern limit experienced a harsher environment with colder temperatures; however, we found no differences in arthropod prey biomass between the northern limit and more southern (historic) sites. Males at the northern limit had higher body condition scores (mass corrected for body size) compared to individuals within the historic range, but no differences were found in beak and tarsus lengths, wing chord, muscle profile or fat stores. In males during the pre-parental stage, before breeding commenced, HPA axis activity was elevated in birds at the northern limit of the range, but no differences were found during the parental or molt stages. Females showed no differences in HPA axis activity during the parental stage. This study suggests that "pioneering" individuals at the limits of their breeding range exhibit physiology and morphology that are distinct from individuals within the historic range. PMID- 26423269 TI - Proximal subscapularis release for the treatment of adduction-internal rotation shoulder contracture in obstetric brachial plexus palsy. AB - INTRODUCTION: The purpose of this paper was to evaluate the results on shoulder function following isolated proximal subscapularis release in children with Erb's palsy. METHODS: A retrospective study was conducted on 64 consecutive children with Erb's palsy who underwent a Carlioz proximal subscapularis release between 2001 and 2012. Fifty children with complete records and a minimum follow-up of 2 years were included for evaluation. Age at surgery ranged from 1.3 to 4.5 years (average 2.6 years). Preoperative active shoulder abduction/anterior elevation, active external and internal rotations as well as the Mallet score were compared with those found at 6 and 24 months postoperatively using the Student paired t test, with a confidence interval of 95 %. The results were compared between children <3 years of age at surgery and those older, and between children who had an isolated C5-C6 and those with greater involvement. p < 0.05 was considered statistically significant. RESULTS: Active abduction improved 21 degrees at 6 months and 31 degrees (total) at 2 years (p < 0.01) with an overall Mallet abduction score improvement of 0.58 at 6 months and 0.6 (overall) at 2 years (p < 0.01). Active external rotation improved 52 degrees at 6 months and 35 degrees (total) at 2 years (p < 0.01) with an overall Mallet external rotation score improvement of 1.3 at 6 months (p < 0.01) and 0.52 (overall) at 2 years (p = 0.013). There was no statistically significant change in internal rotation (p = 0.37). We found no correlation between the child's age or the severity of involvement at surgery and the end result. CONCLUSION: Proximal subscapularis release according to Carlioz is simple and effective in improving overall shoulder function in children with obstetric brachial plexus palsy, mainly abduction and external rotation. Improvement tends to reach a plateau around 6-12 months postoperatively. PMID- 26423270 TI - Percutaneous epiphysiodesis using transphyseal screws for limb-length discrepancies: high variability among growth predictor models. AB - PURPOSE: Percutaneous epiphysiodesis using transphyseal screws (PETS) was developed as a minimally invasive outpatient procedure to address limb-length discrepancy (LLD) that allowed immediate postoperative weight bearing and was potentially reversible by removing the screws. The aims of our study were to report our results using PETS for LLD and evaluate the accuracy of three growth predictor models. METHODS: Sixteen patients with an average age of 14 years were treated for LLD using PETS. Thirteen patients had screws inserted in a parallel fashion and 3 had crossed screws. We compared the predicted LLD at skeletal maturity using the three growth predictor methods with the actual LLD at skeletal maturity and preoperative LLD with the final LLD at skeletal maturity. RESULTS: The mean LLD at skeletal maturity between the predicted and final measurements was 0.2 cm using the Green-Anderson method, 1.4 cm using the Moseley method, and 0.1 cm using the Paley method. The mean preoperative LLD of 3.1 cm was corrected to 1.7 cm at skeletal maturity (p < 0.001). Six patients complained of pain over the screw heads; however, no patient developed an infection or angular deformity. CONCLUSIONS: The three growth predictor methods predicted the final LLD within an average of 1.4 cm, but there was high variability. Although PETS improved the LLD by a mean of 1.4 cm, we believe the results would have been better if PETS was performed at an earlier skeletal age. PMID- 26423271 TI - Effects of training on LV strain in competitive athletes. AB - OBJECTIVE: LV longitudinal strain, a recognised marker of LV function, has been recently applied to the evaluation of the athlete's heart. At present, little is known about the influence of training on LV global longitudinal strain (GLS) in athletes. The aim of this study was to prospectively investigate the impact of training on LV longitudinal strain and twist mechanics in a cohort of competitive athletes. METHODS: Ninety-one competitive athletes, practising team sports and competing at national or international level, were analysed. Echocardiographic evaluation was performed at the beginning of the season (low training) and after 18+/-2 weeks of a supervised, intensive training programme (peak training). RESULTS: A significant increase in LV mass (p<0.0001), LV end-diastolic and end systolic volume (p=0.0001 and <0.0001, respectively) was found at peak training. LV basal and apical torsion (p=0.59 and 0.43, respectively) and LV twisting (p=0.78) did not change, and only a mild increase in LV GLS was evident after training (p=0.044). Resting heart rate was identified as the only independent predictor of LV GLS after training (beta=0.30, p=0.005). CONCLUSIONS: A 18-week, intensive training programme induced only a slight increase in LV GLS despite marked changes in cardiac morphology, suggesting a physiological adaptation of the LV to exercise conditioning. PMID- 26423272 TI - Pharmacotherapy to Enhance Cognitive and Motor Recovery Following Stroke. AB - Stroke is a leading cause of disability among older adults and more than half of stroke survivors have some residual neurological impairment. Traditionally, managing the aftermath of stroke has been by the implementation of several physical and language therapy modalities. The limitations of these rehabilitation efforts have sparked an interest in finding other ways to enhance neurological recovery. Some of these novel approaches have included pharmacological interventions, cell-derived treatments, and cortical magnetic stimulation. Mounting evidence over the last 2 decades suggests that pharmacological manipulations may have the potential to modulate practice-dependent neuroplasticity and potentially improve neurological recovery after stroke. Multiple pharmacological agents with different mechanisms of action have been evaluated, showing conflicting results. Some studies suggest some promise, yet the quality of the available studies is suboptimal overall, with most of the studies being underpowered. So far, the most promising agents include the antidepressants for motor recovery and acetylcholinesterase inhibitors and memantine for aphasia. However, large, well-designed clinical trials are needed to address the shortcomings of the available data and before any pharmacological agent can be recommended for routine use as part of the standard algorithm of stroke management. PMID- 26423273 TI - Inadvertent ligation of the left pulmonary artery during intended ductal ligation. AB - BACKGROUND: Inadvertent ligation of the left pulmonary artery during attempted surgical closure of a Patent Ductus Arteriosus has long been recognized as one of the less common complications of this procedure. Surgical reconstruction of the left pulmonary artery was then often attempted but was difficult or impossible in some of the patients with hypoplasia of the left pulmonary artery and the left lung. CASE PRESENTATION: A 10-year-old girl presented with marked exercise intolerance and palpitations and was diagnosed to have large PDA. She had feeding difficulty, diaphoresis, failure to gain weight, recurrent chest infections during infancy and early childhood. Physical examination revealed an underweight child with wide pulse pressure and bounding peripheral pulses. She had active precordium with accentuated P2 and machinery murmur in the left 2nd intercostal space and mid diastolic rumble at the mitral area. Echocardiography showed a 12 mm patent arterial duct. She was taken for an intended surgical ligation of the duct but a control echocardiogram on the 3rd postoperative day revealed that the left pulmonary artery, instead of the duct, was ligated. Surgical reconstruction of the left pulmonary artery was undertaken 3 years later, however, this was complicated by post reconstruction left pulmonary artery stenosis. Successful percutaneous stenting of the left pulmonary artery was performed 18 months after the surgical reconstruction. CONCLUSION: The incidence of inadvertent LPA ligation may be underestimated where PDA ligation is done by less experienced surgeons and postoperative echocardiography is not routinely performed. Late correction of inadvertent LPA ligation is an important surgical challenge, especially if the duct is still patent. Percutaneous stenting as a primary option may carry significant risk, as the ligated pulmonary artery is fragile. In our case, a good result was achieved with surgical repair followed by percutaneous stenting. PMID- 26423275 TI - Recognising the role of primary care in cancer control. PMID- 26423274 TI - AMBRA1 and SQSTM1 expression pattern in prostate cancer. AB - Prostate cancer is among the most commonly diagnosed male diseases and a leading cause of cancer mortality in men. There is emerging evidence that autophagy plays an important role in malignant cell survival and offers protection from the anti cancer drugs in prostate cancer cells. AMBRA1 and the autophagic protein sequestosome-1 (SQSTM1; p62) expression were evaluated by immunohistochemistry and western blot on tissue samples from both benign and malignant prostatic lesions. The data reported in this pilot study demonstrated an increased expression of AMBRA1 and SQSTM1, which were also associated with an accumulation of LC3II in prostate cancer but not in benign lesion. In the present study we found that: (i) at variance with benign lesion, prostate cancer cells underwent SQSTM1 accumulation, i.e., clearly displayed a defective autophagic process but, also, (ii) prostate cancer accumulated AMBRA1 and (iii) this increase positively correlated with the Gleason score. These results underscore a possible implication of autophagy in prostate cancer phenotype and of AMBRA1 as possible cancer progression biomarker in this malignancy. PMID- 26423276 TI - T1-hyperintense renal lesions: can high signal predict lack of enhancement? AB - OBJECTIVE: To establish highly specific criteria for predicting non-enhancement in T1-hyperintense non-fat-containing (T1-high) renal lesions using unenhanced fat-suppressed T1-weighted (T1-FS) images. MATERIALS AND METHODS: This IRB approved, HIPAA-compliant, retrospective study included T1-high renal lesions found between 7/1/2012 and 7/1/2014. The largest lesion diameter and heterogeneity, mean signal intensity of lesion, and adjacent renal cortex were recorded from T1-FS images. The presence/absence of lesion enhancement was determined from subtraction images. T1 signal ratio (T1-SR) was calculated as (mean SI of lesion)/(mean SI of cortex). Logistic regression with binary outcome of the presence or absence of lesion enhancement was performed. Cut-off T1-SR to maximize specificity was established from receiver operator curve analysis. RESULTS: There were 101 patients (58 [57.4%] male) with non-enhancing lesions and 80 patients (51 [63.8%] male) with enhancing lesions, mean ages 64.0 +/- 13.3 and 62.1 +/- 13.8 years, respectively. Median sizes were 11 mm (IQR 8-16) and 20.5 mm (IQR 15-29) for non-enhancing and enhancing lesions, respectively (p < 0.0001). 19/101 (18.8%) of non-enhancing and 56/80 (70.0%) of enhancing lesions were heterogeneous (p < 0.0001). T1-SR was 1.77 +/- 0.6 and 1.25 +/- 0.42 for non enhancing and enhancing lesions, respectively (p < 0.0001). For each increase of 0.5 in T1-SR, odds ratio for non-enhancement was 3.3 (95% CI 1.85-5.79), adjusted for lesion size and heterogeneity. T1-SR alone had area under the curve of 0.88 (95% CI 0.78-10.89) for non-enhancement. T1-SR >= 2.15 had positive likelihood ratio of 9.5 for non-enhancement. CONCLUSION: Signal ratio of lesion to cortex >= 2.15 on unenhanced T1-weighted images is a highly specific predictor for non enhancement. PMID- 26423277 TI - Assessment of Directly Observed Therapy (DOT) following tuberculosis regimen change in Addis Ababa, Ethiopia: a qualitative study. AB - BACKGROUND: Tuberculosis remains a major public health problem in Ethiopia. In 2010 the TB treatment regimen was shortened from 8 to 6-months treatment. With this new regimen, the full course of treatment should be taken under Directly Observed Therapy (DOT) unlike the 8-month regimen where TB patients were only observed during the intensive phase, this has not been tried before and may be difficult to implement. Therefore this study aimed to investigate the experiences from both TB patients and health care providers' perspective of implementing DOT for the full course of TB treatment. METHODS: Qualitative study consisted of 11 in-depth interviews and 4 Focus Group Discussions (FDGs) were conducted between March and April, 2014. Overall, 18 TB patients and 16 HCPs were involved from three selected public health facilities (2 Health Centers and 1 Hospital) in Addis Ababa, Ethiopia. Qualitative data analysis software (Open Code Version 3.5) was employed to identify the key issues from these interviews through coding, categorization and grouping into emergent themes. RESULTS: Participants reported that making a daily visit to health facilities for DOT was difficult due to the distance of the facilities from their residences, lack of or high transportation cost and had undesired implications on their work and social lives. TB patients had to overcome many challenges to comply with TB treatment on a daily basis. HCPs also indicated the difficulties of implementing facility based daily DOT mainly due the implication it had on their TB patients and stated DOT had not always been implemented for the full course as recommended. HCPs also shared deep concern regarding the risk of acquiring multiple drug resistant TB. CONCLUSION: This study indicated there are several challenges associated with facility based daily DOT as a method of TB treatment supervision in public health facilities in Addis Ababa. This may be indicative of the situation in other health facilities in Addis Ababa as well as elsewhere in the country. Hence the TB control program has to explore how best to improve TB treatment delivery options to ensure adequate treatment. A more patient-centered approach could be strengthened by further decentralizing the DOT to the community level in order to ensure adherence of patients to their TB treatment. PMID- 26423278 TI - Evaluating the ameliorative efficacy of Spirulina platensis on spermatogenesis and steroidogenesis in cadmium-intoxicated rats. AB - The present study was conducted to evaluate the ameliorative efficacy of Spirulina platensis (SP) on reproductive dysfunctions induced by cadmium chloride (CdCl2) in male rats. Rats (n = 40) were divided into five groups (eight rats/each). Group 1: served as control without any treatment. Group 2: Rats were administered SP (150 mg/kg body weight (BW)) in drinking water for 10 days. Group 3: Rats were subcutaneously injected with CdCl2 (2 mg/kg BW) daily for 10 days. Group 4: Rats were co-treated with both CdCl2 (2 mg/kg BW) and SP (150 mg/kg BW) daily for 10 days (SP prophylactic group). Group 5: Rats received CdCl2 for 10 days followed by administration of SP alone in drinking water daily for another 30 days with the same mentioned routes and doses (SP treatment group). From our findings, the administration of SP alone or co-administration with Cd significantly attenuated the harmful effects of Cd, suggesting its beneficial role in improving spermatogenesis and steroidogenesis after Cd exposure. PMID- 26423279 TI - Thiosulphate conversion in a methane and acetate fed membrane bioreactor. AB - The use of methane and acetate as electron donors for biological reduction of thiosulphate in a 5-L laboratory membrane bioreactor was studied and compared to disproportionation of thiosulphate as competing biological reaction. The reactor was operated for 454 days in semi-batch mode; 30 % of its liquid phase was removed and periodically replenished (days 77, 119, 166, 258, 312 and 385). Although the reactor was operated under conditions favourable to promote thiosulphate reduction coupled to methane oxidation, thiosulphate disproportionation was the dominant microbial process. Pyrosequencing analysis showed that the most abundant microorganisms in the bioreactor were phototrophic green sulphur bacteria (GSB) belonging to the family Chlorobiaceae and thiosulphate-disproportionating bacteria belonging to the genus Desulfocapsa. Even though the reactor system was surrounded with opaque plastic capable of filtering most of the light, the GSB used it to oxidize the hydrogen sulphide produced from thiosulphate disproportionation to elemental sulphur. Interrupting methane and acetate supply did not have any effect on the microbial processes taking place. The ultimate goal of our research was to develop a process that could be applied for thiosulphate and sulphate removal and biogenic sulphide formation for metal precipitation. Even though the system achieved in this study did not accomplish the targeted conversion using methane as electron donor, it does perform microbial conversions which allow to directly obtain elemental sulphur from thiosulphate. PMID- 26423280 TI - Proteomic changes in Corbicula fluminea exposed to wastewater from a psychiatric hospital. AB - The increase use of pharmaceutical compounds in veterinary practice and human population results in the ubiquitous presence of these compounds in aquatic ecosystems. Because pharmaceuticals are highly bioactive, there is concern about their toxicological effects in aquatic organisms. Therefore, the aim of this study was to assess the effects of an effluent from a psychiatric hospital (containing a complex mixture of 25 pharmaceutical compounds from eleven therapeutic classes) on the freshwater clam Corbicula fluminea using a proteomic approach. The exposure of C. fluminea to this complex effluent containing anxiolytics, analgesics, lipid regulators, beta blockers, antidepressants, antiepileptics, antihistamines, antihypertensives, antiplatelets and antiarrhythmics induced protein changes after 1 day of exposure in clam gills and digestive gland more evident in the digestive gland. These changes included increase in the abundance of proteins associated with structural (actin and tubulin), cellular functions (calreticulin, proliferating cell nuclear antigen (PCNA), T complex protein 1 (TCP1)) and metabolism (aldehyde dehydrogenase (ALDH), alcohol dehydrogenase, 6 phosphogluconate dehydrogenase). Results from this study indicate that calreticulin, PCNA, ALDH and alcohol dehydrogenase in the digestive gland and T complex protein 1 (TCP1)) and 6 phosphogluconate dehydrogenase in the gills represent useful biomarkers for the ecotoxicological characterization of psychiatric hospital effluents in this species. PMID- 26423281 TI - Environmental risks of HBCDD from construction and demolition waste: a contemporary and future issue. AB - Hexabromocyclododecane (HBCDD), as one of the most widely used brominated flame retardants (BFRs), is of great concern globally because of its persistence in the environment and negative impacts on humans and animals. HBCDD has been mainly used in flame-retarded expanded (EPS) and extruded (XPS) polystyrene foams for insulation in the construction industry. Most of these products will become a part of the construction and demolition (C&D) waste at the end of their life cycle (30-50 years) which is typically disposed of into landfills or incineration. However, the recycling of this material takes quite a low share compared with landfill and incineration. Consequently, high environmental risks will exist in these disposal approaches due to the HBCDD in C&D waste. Currently, XPS or EPS products containing HBCDD in the construction industry have not reached the end of their life cycle in most countries. Relatively little attention has been paid to this emergency issue by either the government or public. Furthermore, C&D waste is most likely disposed of by direct dumping, simple stacking, or open burning in developing countries. Therefore, this paper highlights the global environmental risks of HBCDD from C&D waste. Areas of research for key problems of HBCDD contained in C&D waste are suggested to help control and finally eliminate the impact. PMID- 26423282 TI - Cadmium exposure and risk of pancreatic cancer: a meta-analysis of prospective cohort studies and case-control studies among individuals without occupational exposure history. AB - Pancreatic cancer is one of the most deadly types of cancer for both genders. Classified as a human carcinogen, cadmium has been related to diverse cancers. However, the association between cadmium exposure and the risk of pancreatic cancer is still unclear. We quantitatively reviewed the observational studies on the association of cadmium exposure with pancreatic cancer risk among individuals without occupational exposure history published through July 2014 in PubMed by using a fixed-effect model. Four prospective cohort studies (112,934 participants with 335 events) and two case-control studies (177 cases and 539 controls) were identified. The summarized relative risk (RR) with a 95% confidence interval (CI) was 2.05 (95% CI = 1.58-2.66), comparing the highest to the lowest category of cadmium exposure. This positive association persisted in men (RR = 1.78, 95% CI = 1.04-3.05) but not in women (RR = 1.02, 95% CI = 0.63-1.65). Further research is needed to provide more solid evidence on the association of cadmium exposure with pancreatic cancer risk and to elucidate the underlying biological mechanism of the potential gender difference. PMID- 26423283 TI - Improving the efficiency of phytoremediation using electrically charged plant and chelating agents. AB - The low efficiency of phytoremediation is a considerable problem that limits the application of this environmentally friendly method on heavy metal-polluted soils. The combination of chelate-assisted phytoextraction and electrokinetic remediation could offer new opportunities to improve the effectiveness of phytoextraction. The current experiment aims to investigate the effects of electrical fields and chelating agents on phytoremediation efficiency. In a pot experiment using mine soil, poultry manure extract (PME), cow manure extract (CME), and ethylenediaminetetraacetic acid (EDTA) were applied to soil as chelating agents (2 g kg(-1)) at the beginning of the flowering stage. A week later, Helianthus annuus (sunflower) was negatively charged by inserting a stainless steel needle with 10 and 30 V DC electricity in the lowest part of the stems for 1 h each day for a 14-day period. At the end of the experiment, the shoot and root dry weight, lead (Pb) concentration in plant organs, translocation factor (TF), metal uptake index (UI), and soil available Pb (diethylene triamine pentaacetic acid (DTPA) extractable) were detected. Results indicated that the application of electrical fields had no significant impact on the shoot and root dry weights, while Pb concentration and UI increased in the 10-V EDTA treatment by 500 % compared to control. There was no significant difference between UI in 30- and 10-V EDTA treatments. Soil available Pb significantly increased in the 30 V treated soil. A positive correlation was observed between the available Pb in soil near the root and Pb concentration in shoot, its TF, and UI. In conclusion, a negatively charged plant along with the application of EDTA significantly increased the phytoremediation efficiency. PMID- 26423284 TI - Influence of environmental factors on the phosphorus adsorption of lanthanum modified bentonite in eutrophic water and sediment. AB - Lanthanum-modified bentonite has potential for wide application in eutrophication control. We investigated P adsorption on a lanthanum-modified bentonite by analysis of adsorption kinetics, equilibrium, and the effect of environmental factors. P adsorption closely followed the pseudo-second-order kinetic model, and the isotherm was well described by the Langmuir model. This adsorbent could effectively immobilize P into the sediment, but the adsorption process was strongly dependent on pH, anions, and low molecular weight organic acids (LMWOAs). P adsorption increased with increasing pH from 0.52 mg P/g at pH 3.0 to 0.93 mg P/g at pH 7.0 with no adsorption at pH 11. P adsorption was strongly inhibited in the presence of anions and three LMWOAs, with P even re-released at high concentrations. These environmental factors should be given significant attention when considering the application of lanthanum-modified bentonite in eutrophication control. PMID- 26423285 TI - Effects of electromagnetic fields on serum lipids in workers of a power plant. AB - This study aimed to evaluate the effects of electromagnetic fields (EMF) exposure on levels of serum lipids in workers of an electric power plant. A cross sectional study was carried out in an electric power plant in Zhejiang province, China, from August to September 2011. All participants were divided into two groups with high occupational EMF exposure and low occupational EMF exposure. The occupational EMF exposure included radiofrequency EMF and extremely low-frequency EMF. Occupational EMF exposure was associated with an increased level of low density lipoprotein cholesterol (LDL-c; beta = 0.17 mmol/L, P = 0.022). High EMF exposure group with longer employment duration, longer daily EMF exposure duration, and more mobile phone or electric fee per month had significantly higher levels of total cholesterol, LDL-c, or triglyceride than the corresponding reference group. However, significantly decreased level of high-density lipoprotein cholesterol was only observed in high EMF exposure group with more mobile phone fee per month. Similar results were also found in 544 participants with available data of serum lipids in 2010. The findings showed that chronic EMF exposure was associated with the change of serum lipid levels. EMF exposure might modulate the process of lipid metabolism. PMID- 26423286 TI - Endogenous mitigation of H2S inside of the landfills. AB - Vast quantities of hydrogen sulfide (H2S) emitted from landfill sites require urgent disposal. The current study focused on source control and examined the migration and conversion behavior of sulfur compounds in two lab-scale simulated landfills with different operation modes. It aimed to explore the possible strategies and mechanisms for H2S endogenous mitigation inside of landfills during decomposition. It was found that the strength of H2S emissions from the landfill sites was dependent on the municipal solid waste (MSW) degradation speed and vertical distribution of sulfide. Leachate recirculation can shorten both the H2S influence period and pollution risk to the surrounding environment. H2S endogenous mitigation may be achieved by chemical oxidation, biological oxidation, adsorption, and/or precipitation in different stages. Migration and conversion mainly affected H2S release behavior during the initial stabilization phase in the landfill. Microbial activities related to sulfur, nitrogen, and iron can further promote H2S endogenous mitigation during the high reducing phase. Thus, H2S endogenous mitigation can be effectively enhanced via control of the aforementioned processes. PMID- 26423287 TI - Retention and efficacy of ultra-low volume pesticide applications on Culex quinquefasciatus (Diptera: Culicidae). AB - To combat mosquitoes and the public health hazards they present, spraying chemical adulticides is an efficient and timely control method for immediate reduction of adult populations. With the growing consciousness of environmental and public health concerns, effective mosquito control means not only maximizing the effectiveness (in terms of mosquito mortality rates) of the pesticide application, but also minimizing the unintended effects (health hazard and environmental pollution). A series of experiments was carried out to assess the efficacy and deposition of ultra-low volume (ULV) sprays on adult mosquitoes which included the influence of chemical type, spray volume, spray concentration, droplet size, and deposit location (where the droplets land on the mosquito). A modified Potter Tower was used to apply an extremely fine spray (volume median diameter ~20 MUm) on caged adult mosquitoes (Culex quinquefasciatus). Reslin (50 g/L bioresmethrin) was diluted in either water or D-C-Tron plus spray oil (782 g/L paraffinic petroleum oil), Twilight (89 g/L phenothrin) was diluted in D-C Tron, and the mosquito mortality was assessed 24 h after spraying. A fluorescent tracer was added to the spray mixture to determine the amount of spray on mosquitoes. A fluorescent microscope was also used to view the deposit of droplets on mosquitoes. It was found that droplet retention and mortality were reduced with the larger droplet sizes. Large water-based droplets tend to bounce off adult mosquitoes. There is a tendency for droplets approximately 20 MUm in size to be retained on the fine hairs on the mosquito. The largest spray deposit was found on the adult mosquito wings and the lowest deposit on the head. Mortality was higher for formulations diluted with oil compared to those diluted with water. ULV applications with ultra-fine sprays (VMD 20 MUm) and oil-based products resulted in maximum target efficacy under laboratory conditions, at minimum cost, and with the minimum amount of chemical adulticides. PMID- 26423288 TI - Biomonitoring of agricultural workers exposed to pesticide mixtures in Guerrero state, Mexico, with comet assay and micronucleus test. AB - The aim of this study was to evaluate the genotoxic effect of pesticides in exfoliated buccal cells of workers occupationally exposed in Guerrero, Mexico, using the comet assay and the micronucleus test. The study compared 111 agricultural workers in three rural communities (Arcelia 62, Ajuchitlan 13, and Tlapehuala 36), with 60 non-exposed individuals. All the participants were males. The presence of DNA damage was investigated in the exfoliated buccal cells of study participants with the comet assay and the micronucleus (MN) test; comet tail length was evaluated in 100 nuclei and 3000 epithelial cells of each individual, respectively; other nuclear anomalies such as nuclear buds, karyolysis, karyorrhexis, and binucleate cells were also evaluated. Study results revealed that the tail migration of DNA and the frequency of MN increased significantly in the exposed group, which also showed nuclear anomalies associated with cytotoxic or genotoxic effect. No positive correlation was noted between exposure time and tail length and micronuclei frequencies. No significant effect on genetic damage was observed as a result of age, smoking, and alcohol consumption. The MN and comet assay in exfoliated buccal cells are useful and minimally invasive methods for monitoring genetic damage in individuals exposed to pesticides. This study provided valuable data for establishing the possible risk to human health associated with pesticide exposure. PMID- 26423289 TI - Ecotoxicological effects of sediments from Mar Piccolo, South Italy: toxicity testing with organisms from different trophic levels. AB - The Mar Piccolo of Taranto (Ionian Sea, Southern Italy) is a semi-enclosed and strongly polluted basin. For decades, it has been subjected to different anthropogenic impacts. These stressors caused severe sediments contamination with high concentration of different pollutants (PAHs, PCB, heavy metals). In order to assess the current status of sediments contamination, an ecotoxicological investigation combined with chemical analysis (heavy metals, PAH, and PCB) has been performed. In order to derive ecologically relevant conclusions, a multiorganisms and multiend-points approach has been applied, exposing organisms from different trophic levels to elutriate and whole sediment. The battery of bioassays consists of a microalgal growth inhibition test (Dunaliella tertiolecta), acute and sublethal assays (end-points: mortality, immobilization and swimming speed alteration) on crustaceans larvae and juveniles, and rotifers (Amphibalanus amphitrite, Artemia salina, Corophium insidiosum and Brachionus plicatilis), and embryotoxicity test on echinoderms (Paracentrotus lividus). Considering the high levels of sediment contamination highlighted from chemical analysis, an unexpected very low toxic effect was observed, even considering the sublethal end-point (larval swimming speed alteration). The results of this study suggest a very complex contaminants dynamic in the Mar Piccolo sediments that, despite a strong level of contamination, seems to not affect in a proportional manner the biological compartment. PMID- 26423290 TI - Effect of arbuscular mycorrhizal and bacterial inocula on nitrate concentration in mesocosms simulating a wastewater treatment system relying on phytodepuration. AB - High nitrogen concentration in wastewaters requires treatments to prevent the risks of eutrophication in rivers, lakes and coastal waters. The use of constructed wetlands is one of the possible approaches to lower nitrate concentration in wastewaters. Beyond supporting the growth of the bacteria operating denitrification, plants can directly take up nitrogen. Since plant roots interact with a number of soil microorganisms, in the present work we report the monitoring of nitrate concentration in macrocosms with four different levels of added nitrate (0, 30, 60 and 90 mg l(-1)), using Phragmites australis, inoculated with bacteria or arbuscular mycorrhizal fungi, to assess whether the use of such inocula could improve wastewater denitrification. Higher potassium nitrate concentration increased plant growth and inoculation with arbuscular mycorrhizal fungi or bacteria resulted in larger plants with more developed root systems. In the case of plants inoculated with arbuscular mycorrhizal fungi, a faster decrease of nitrate concentration was observed, while the N%/C% ratio of the plants of the different treatments remained similar. At 90 mg l(-1) of added nitrate, only mycorrhizal plants were able to decrease nitrate concentration to the limits prescribed by the Italian law. These data suggest that mycorrhizal and microbial inoculation can be an additional tool to improve the efficiency of denitrification in the treatment of wastewaters via constructed wetlands. PMID- 26423291 TI - Aqueous chlorination of acebutolol: kinetics, transformation by-products, and mechanism. AB - This study investigated the reaction kinetics and the transformation by-products of acebutolol during aqueous chlorination. Acebutolol is one of the commonly used beta-blockers for the treatment of cardiovascular diseases. It has been frequently detected in the aquatic environment. In the kinetics study, the second order rate constant for the reaction between acebutolol and chlorine (k app) was determined at 25 +/- 0.1 degrees C. The degradation of acebutolol by free available chlorine was highly pH dependence. When the pH increased from 6 to 8, it was found that the k app for the reaction between acebutolol and free available chlorine was increased from 1.68 to 11.2 M(-1) min(-1). By comparing with the reported k app values, the reactivity of acebutolol toward free available chlorine was found to be higher than atenolol and metoprolol but lower than nadolol and propranolol. Characterization of the transformation by-products formed during the chlorination of acebutolol was carried out using liquid chromatography-quadrupole time-of-flight high-resolution mass spectrometry. Seven major transformation by-products were identified. These transformation by products were mainly formed through dealkylation, hydroxylation, chlorination, and oxidation reactions. PMID- 26423292 TI - Study of CO2 cyclic absorption stability of CaO-based sorbents derived from lime mud purified by sucrose method. AB - Using lime mud (LM) purified by sucrose method, derived from paper-making industry, as calcium precursor, and using mineral rejects-bauxite-tailings (BTs) from aluminum production as dopant, the CaO-based sorbents for high-temperature CO2 capture were prepared. Effects of BTs content, precalcining time, and temperature on CO2 cyclic absorption stability were illustrated. The cyclic carbonation behavior was investigated in a thermogravimetric analyzer (TGA). Phase composition and morphologies were analyzed by XRD and SEM. The results reflected that the as-synthesized CaO-based sorbent doped with 10 wt% BTs showed a superior CO2 cyclic absorption-desorption conversion during multiple cycles, with conversion being >38 % after 50 cycles. Occurrence of Ca12Al14O33 phase during precalcination was probably responsible for the excellent CO2 cyclic stability. PMID- 26423293 TI - Comparing systematic reviews and meta-analyses of randomized clinical trials with cohort studies: a paradigm of single-incision laparoscopic surgery. PMID- 26423294 TI - Traumatic lumbar hernia repair: experience at the Royal Brisbane and Women's Hospital. AB - BACKGROUND: Traumatic lumbar hernias (TLH) are a rare clinical entity with fewer than 100 cases reported in the English literature worldwide. Due to the surrounding anatomy, surgical repair is often difficult. There is currently no consensus on the timing of operative repair of TLH. The aim of this study is to present a case series on the management of TLH performed at the Royal Brisbane and Women's Hospital (RBWH) utilizing both open and laparoscopic techniques with both early and delayed repairs being undertaken. METHODS: Cases were identified retrospectively from the Trauma Database at the RBWH, a tertiary-level hospital in Brisbane, Australia. RESULTS: Four cases of TLH were identified from 2009 to 2014. The diagnosis was confirmed pre-operatively on CT imaging. Early repair was undertaken when the patient was stable from other associated injuries. Herniation was managed in three cases by open repair (2x open lumbar approaches, 1 via midline laparotomy) with sublay extraperitoneal mesh placement. The remaining case was managed by laparoscopic extra-peritoneal mesh repair. At a minimal 4 months follow-up, no evidence of recurrence or complications was detected in three cases. One patient was lost to follow-up. CONCLUSIONS: TLH are a rare clinical entity. Operative management can be achieved via open or laparoscopic techniques, with placement of mesh in the extraperitoneal plane. Both early, when the patients clinical status allows, and delayed repair appear to have good short term results. Long-term data are not available at this stage. PMID- 26423295 TI - The Use of Mathematical Modelling for Improving the Tissue Engineering of Organs and Stem Cell Therapy. AB - Regenerative medicine is a multidisciplinary field where continued progress relies on the incorporation of a diverse set of technologies from a wide range of disciplines within medicine, science and engineering. This review describes how one such technique, mathematical modelling, can be utilised to improve the tissue engineering of organs and stem cell therapy. Several case studies, taken from research carried out by our group, ACTREM, demonstrate the utility of mechanistic mathematical models to help aid the design and optimisation of protocols in regenerative medicine. PMID- 26423297 TI - Telocytes as a Source of Progenitor Cells in Regeneration and Repair Through Granulation Tissue. AB - This review outlines the role of CD34+ stromal cells/telocytes (CD34+ SC/TCs) in repair and considers the following issues. Firstly, the conceptual aspects of repair, including regeneration and repair through granulation tissue (RTGT) as two types of repair, RTGT stages (inflammatory, proliferative, and remodeling), and tissue in repair as a substrate to assess the in vivo behavior of activated CD34+ SC/TCs. Subsequently, current knowledge of CD34+ SC/TCs, such as identification, characteristics, and functions, as well as possible stages (quiescent and activated) are taken into account. We then consider the role in regeneration of quiescent CD34+ SC/TCs (in unperturbed physiological conditions) as a nurse of stem cells (e.g., in the heart, skin, respiratory tree, gastrointestinal tract, liver, eye, and choroid plexus). Special attention is paid to the characteristics of activated CD34+ SC/TCs and the overlapping steps of activation with and without loss of CD34 expression and with and without gain of alphaSMA expression. With this contribution, we establish the role of CD34+ SC/TCs as progenitor cells and as a source of fibroblasts and myofibroblasts in repair through granulation tissue, fibrosis, and tumor stroma. Activated CD34+ SC/TCs in encapsulation and other processes (e.g., Reinke's edema, cutaneous myxoid cyst, mixomatous mitral valve degeneration, and fibrous papula of the face) are also outlined. Finally, similarities between modifications of CD34+ SC/TCs during in vivo activation and of multipotent mesenchymal stromal/stem cells in culture are examined in order to correlate the growing literature on CD34+ SC/TCs and the exponential research in cultured mesenchymal stromal/stem cells. PMID- 26423298 TI - Filling the Gaps between the In Vivo and In Vitro Microenvironment: Engineering of Spheroids for Stem Cell Technology. AB - Engineering of in vitro three-dimensional cultures of stem cells and their progenies has offered promising alternatives to recapitulate the in vivo microenvironment, or stem cell niche, and has provided more specific cues for proper stem cell differentiation, maintenance and culture. In particular, tissue spheroids are cellular aggregates with defined cellular and extracellular features and have provided optimal conditions for stem cell technology, both in culture and for potential engraftment. Recent studies have focused on spheroid formation and the developmental roles played by cellular and extracellular signals necessary for cellular aggegation into spheroids. This review will provide insights into the factors that regulate in vitro spheroid formation by comparing them with their developmental counterparts in vivo. At the same time, we will identify cellular and extracellular signals that could be used to bioengineer spheroids with improved features according to their application. Finally, this review will provide an overview of the applications to date of spheroid cultures of stem cells and their progenies, providing insights for future studies. PMID- 26423299 TI - Nano-Engineered Environment for Nerve Regeneration: Scaffolds, Functional Molecules and Stem Cells. AB - One of the most complex systems in the human body is the nervous system, which is divided into the central and peripheral nervous systems. The regeneration of the CNS is a complex and challenging biological phenomenon hindered by the low regenerative capacity of neurons and the prohibition factors in response to nerve injuries. To date, no effective approach can achieve complete recovery and fully restore the functions of the nervous system once it has been damaged. Developments in neuroscience have identified properties of the local environment with a critical role in nerve regeneration. Advances in biomaterials and biomedical engineering have explored new approaches of constructing permissive environments for nerve regeneration, thereby enabling optimism with regard to nerve-injury treatment. This article reviews recent progress in nanoengineered environments for aiding nerveinjury repair and regeneration, including nanofibrous scaffolds, functional molecules, and stem cells. PMID- 26423300 TI - The Influence of Diabetes Mellitus on Proliferation and Osteoblastic Differentiation of MSCs. AB - BACKGROUND: Diabetes mellitus (DM) is a widespread chronic metabolic disease which has high mortality due to its complications. In addition to traditional medication, stem cell transplantation therapeutics has become a brand-new and prospective remedy for DM. With strong self-renewal and multi-potential ability, mesenchymal stem cells (MSCs) are considered as ideal cell sources of cell therapy for DM and many other diseases. However, not only do endogenous MSCs fail to replace the impaired islet cells, but also transplanted MSCs fail to cure many patients complicated with DM. Besides, quite a few DM patients suffer from high risk of fracture and low efficiency of bone regeneration, which are often associated with the osteoblastic differentiation of MSCs. Recently, a number of researches have investigated that the changes in micro-environment by DM can affect biological characteristics of MSCs through many factors. SUMMARY: In this review, we summarize the developments in the influence of DM on proliferation and osteoblastic differentiation of MSCs, and moreover, osteoporosis, obesity and metabolism syndrome, as they are closely related to DM. PMID- 26423301 TI - Induced pluripotent stem cell-derived mesenchymal stem cells: A leap toward personalized therapies. AB - Mesenchymal Stem/stromal cell (MSCs) transplantation procedures have been used since the 1960's to treat leukemia and other diseases, but due to the risks involved only patients with life threatening illnesses were typically subjected to the transplantation procedure until the last decade. Recent advancements in transplantation techniques have made it more feasible to use it for non-life threatening diseases. However, the potential uses for stem cells are still limited by their rarity, and, in the case of allogeneic transplants, graft-vs. host complications. An evolving alternative to conventional stem cell therapies is induced pluripotent stem-cell derived mesenchymal stem/stromal cells (iPSC- MSCs), which have a multi-lineage potential comparable to conventionally acquired MSCs with the added benefit of being less immunoreactive. However there are still many hurdles left to be overcome before they can be used regularly for personalized therapies. This review will focus on recent advancements that have been made regarding the role MSCs play in tumor development and the potential uses iPSC-MSCs may have in future cancer treatment. PMID- 26423302 TI - Nonparametric inference for the joint distribution of recurrent marked variables and recurrent survival time. AB - Time between recurrent medical events may be correlated with the cost incurred at each event. As a result, it may be of interest to describe the relationship between recurrent events and recurrent medical costs by estimating a joint distribution. In this paper, we propose a nonparametric estimator for the joint distribution of recurrent events and recurrent medical costs in right-censored data. We also derive the asymptotic variance of our estimator, a test for equality of recurrent marker distributions, and present simulation studies to demonstrate the performance of our point and variance estimators. Our estimator is shown to perform well for a wide range of levels of correlation, demonstrating that our estimators can be employed in a variety of situations when the correlation structure may be unknown in advance. We apply our methods to hospitalization events and their corresponding costs in the second Multicenter Automatic Defibrillator Implantation Trial (MADIT-II), which was a randomized clinical trial studying the effect of implantable cardioverter-defibrillators in preventing ventricular arrhythmia. PMID- 26423296 TI - Stem Cells in Skeletal Tissue Engineering: Technologies and Models. AB - This review surveys the use of pluripotent and multipotent stem cells in skeletal tissue engineering. Specific emphasis is focused on evaluating the function and activities of these cells in the context of development in vivo, and how technologies and methods of stem cell-based tissue engineering for stem cells must draw inspiration from developmental biology. Information on the embryonic origin and in vivo differentiation of skeletal tissues is first reviewed, to shed light on the persistence and activities of adult stem cells that remain in skeletal tissues after embryogenesis. Next, the development and differentiation of pluripotent stem cells is discussed, and some of their advantages and disadvantages in the context of tissue engineering are presented. The final section highlights current use of multipotent adult mesenchymal stem cells, reviewing their origin, differentiation capacity, and potential applications to tissue engineering. PMID- 26423303 TI - Beneficial effect of zinc chloride and zinc ionophore pyrithione on attenuated cardioprotective potential of preconditioning phenomenon in STZ-induced diabetic rat heart. AB - Ischemic preconditioning (IPC) is well demonstrated to produce cardioprotection by phosphorylation and subsequent inactivation of glycogen synthase kinase-3beta (GSk-3beta) in the normal rat heart, but its effect is attenuated in the diabetic rat heart. This study was designed to investigate the effect of zinc chloride and zinc ionophore pyrithione (ZIP) on the attenuated cardioprotective potential of IPC in the diabetic rat heart. Diabetes mellitus (DM) was induced by a single intraperitoneal administration of streptozotocin (STZ) (50 mg/kg; i.p). The isolated perfused rat heart was subjected to 30 minutes of ischemia followed by 120 minutes of reperfusion. Myocardial infarct size was estimated by triphenyltetrazolium chloride (TTC) staining and cardiac injury was measured by estimating lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) in the coronary effluent. Also, GSK-3beta was measured and neutrophil accumulation was measured by estimating myeloperoxidase (MPO) levels. IPC significantly decreased the myocardial infarct size, the release of LDH and CK-MB, the GSK-3beta levels and the MPO levels in the normal rat heart. Pre- and post-ischemic treatment with zinc chloride and zinc ionophore pyrithione (ZIP) in the normal and diabetic rat hearts significantly decreased the myocardial infarct size, the level of CK-MB and LDH in the coronary effluent and GSK-3beta and MPO levels. Our results suggest that pharmacological preconditioning with zinc chloride and ZIP significantly restored the attenuated cardioprotective potential of IPC in the diabetic rat heart. PMID- 26423304 TI - [Hospital safety in paediatrics]. PMID- 26423305 TI - Benefit-harm analysis and charts for individualized and preference-sensitive prevention: example of low dose aspirin for primary prevention of cardiovascular disease and cancer. AB - BACKGROUND: Clinical practice guidelines provide separate recommendations for different diseases that may be prevented or treated by the same intervention. Also, they commonly provide recommendations for entire populations but not for individuals. To address these two limitations, our aim was to conduct benefit harm analyses for a wide range of individuals using the example of low dose aspirin for primary prevention of cardiovascular disease and cancer and to develop Benefit-Harm Charts that show the overall benefit-harm balance for individuals. METHODS: We used quantitative benefit-harm modeling that included 16 outcomes to estimate the probability that low dose aspirin provides more benefits than harms for a wide range of men and women between 45 and 84 years of age and without a previous myocardial infarction, severe ischemic stroke, or cancer. We repeated the quantitative benefit-harm modeling for different combinations of age, sex, and outcome risks for severe ischemic and hemorrhagic stroke, myocardial infarction, cancers, and severe gastrointestinal bleeds. The analyses considered weights for the outcomes, statistical uncertainty of the effects of aspirin, and death as a competing risk. We constructed Benefit-Harm Charts that show the benefit-harm balance for different combinations of outcome risks. RESULTS: The Benefit-Harm Charts ( http://www.benefit-harm-balance.com ) we have created show that the benefit-harm balance differs largely across a primary prevention population. Low dose aspirin is likely to provide more benefits than harms in men, elderly people, and in those at low risk for severe gastrointestinal bleeds. Individual preferences have a major impact on the benefit-harm balance. If, for example, it is a high priority for individuals to prevent stroke and severe cancers while severe gastrointestinal bleeds are deemed to be of little importance, the benefit-harm balance is likely to favor low dose aspirin for most individuals. Instead, if severe gastrointestinal bleeds are judged to be similarly important compared to the benefit outcomes, low dose aspirin is unlikely to provide more benefits than harms. CONCLUSIONS: Benefit Harm Charts support individualized benefit-harm assessments and decision making. Similarly, individualized benefit-harm assessments may allow guideline developers to issue more finely granulated recommendations that reduce the risk of over- and underuse of interventions. The example of low dose aspirin for primary prevention of cardiovascular disease and cancer shows that it may be time for guideline developers to provide combined recommendations for different diseases that may be prevented or treated by the same intervention. PMID- 26423307 TI - Cor Triatriatum Sinister - Source of Unusual Thrombogenesis in Mitral Stenosis. PMID- 26423306 TI - Serum Phenylalanine, Tyrosine, and their Ratio in Acute Ischemic Stroke: on the Trail of a Biomarker? AB - Fast diagnosis and appropriate treatment are of utmost importance to improving the outcome in patients with acute ischemic stroke (AIS). A rapid and sensitive blood test for ischemic stroke is required. The aim of this study was to examine the usefulness of phenylalanine (PHE) and tyrosine (TYR) as diagnostic biomarkers in AIS. Serum levels of PHE and TYR, measured using HPLC, and their ratio (PHE/TYR) were compared between 45 patients with AIS and 40 healthy control subjects. The relationship between PHE/TYR and the serum levels of several cytokines were also examined. PHE/TYR was significantly higher in AIS patients than in healthy controls (1.75 vs 1.24, p < 0.001). A receiver operating characteristic (ROC) curve analysis of PHE/TYR in AIS patients relative to healthy controls revealed promising sensitivity and specificity, which at an optimal cutoff of 1.45 were 76 and 85 %, respectively. PHE/TYR was positively correlated with interleukin (IL)-1beta (r = 0.37, p = 0.011) and IL-6 (r = 0.33, p = 0.025). This study shows that PHE/TYR is highly elevated in the acute phase of AIS, and that this elevation is coupled to the inflammatory response. The ROC analysis documents the possible value of PHE/TYR as a biomarker for AIS and demonstrates its clinical potential as a blood-based test for AIS. PMID- 26423308 TI - Low-dose warfarin with prothrombin time-international normalized ratio between 1.6 and 2.6 for very old Japanese patients. PMID- 26423310 TI - Hospitals are wrong to ban e-cigarette use. PMID- 26423309 TI - IL-17-producing gammadeltaT cells are regulated by estrogen during development of experimental arthritis. AB - Interleukin-17 (IL-17) drives inflammation and destruction of joints in rheumatoid arthritis (RA). The female sex hormone 17beta-estradiol (E2) inhibits experimental arthritis. gammadeltaT cells are significant producers of IL-17, thus the aim of this study was to investigate if E2 influenced IL-17(+) gammadeltaT cells during arthritis development using a variety of experimental RA models: collagen-induced arthritis (CIA); antigen-induced arthritis (AIA); and collagen antibody-induced arthritis (CAIA). We demonstrate that E2 treatment decreases IL-17(+) gammadeltaT cell number in joints, but increases IL-17(+) gammadeltaT cells in draining lymph nodes, suggesting an E2-mediated prevention of IL-17(+) gammadeltaT cell migration from lymph nodes to joints, in concert with our recently reported effects of E2 on Th17 cells (Andersson et al., 2015). E2 did neither influence the general gammadeltaT cell population nor IFNgamma(+) gammadeltaT cells, implying a selective regulation of IL-17-producing cells. In conclusion, this study contributes to the understanding of estrogen's role in autoimmune disease. PMID- 26423311 TI - Minimum unit pricing: better late than never. PMID- 26423312 TI - Mesoporous Fluorinated Metal-Organic Frameworks with Exceptional Adsorption of Fluorocarbons and CFCs. AB - Two mesoporous fluorinated metal-organic frameworks (MOFs) were synthesized from extensively fluorinated tritopic carboxylate- and tetrazolate-based ligands. The tetrazolate-based framework MOFF-5 has an accessible surface area of 2445 m(2) g( 1), the highest among fluorinated MOFs. Crystals of MOFF-5 adsorb hydrocarbons, fluorocarbons, and chlorofluorocarbons (CFCs)-the latter two being ozone depleting substances and potent greenhouse species-with weight capacities of up to 225%. The material exhibits an apparent preference for the adsorption of non spherical molecules, binding unusually low amounts of both tetrafluoromethane and sulfur hexafluoride. PMID- 26423313 TI - Immunopathogenesis of olmesartan-associated enteropathy. AB - BACKGROUND: Olmesartan-associated enteropathy (OAE) is characterised by diarrhoea, nausea, vomiting, abdominal pain, weight loss and severe sprue-like enteropathy, all of which are resolved after discontinuation of olmesartan medoximil. AIM: To determine the mechanistic similarities of OAE with coeliac sprue. METHODS: Duodenal biopsies were extracted from OAE patients before (n = 11) or after (n = 17) discontinuation of olmesartan medoxomil (on or off olmesartan medoxomil). There were seven 'on/off' paired samples. Formalin-fixed biopsies were stained for CD8, CD4, FoxP3, IL-15R and psmad 2/3. Caco2 cells (human colonic epithelial line) were treated with olmesartan medoxomil and stained for IL-15, IL-15R and ZO-1. RESULTS: In the 'on olmesartan medoxomil' duodenal biopsies, a significant increase in the numbers of CD8+ cells and the number of cells that are FoxP3+ (a regulatory T-cell marker) are present in the duodenum as compared to the duodenal biopsies from patients who discontinued olmesartan medoxomil. IL15R expression is also increased with olmesartan medoxomil use. Evaluation of the effect of olmesartan medoxomil upon Caco-2 cells demonstrated that IL15 expression is increased in response to olmesartan medoxomil treatment. Further, ZO-1, a tight junction protein, is disrupted in olmesartan medoxomil-treated Caco-2 cells. CONCLUSIONS: Olmesartan-associated enteropathy shares many features with coeliac disease, including symptoms and immunopathogenic pathways, such as increased numbers of CD8+ cells and corresponding overexpression of IL15 by epithelial cells. Taken together, the treatment of epithelial cells with olmesartan medoxomil induces a response by intestinal epithelial cells that is similar to the innate effects of gluten upon the epithelium of coeliac patients. PMID- 26423314 TI - Evaluation of an automated fetal myocardial performance index. AB - OBJECTIVE: To compare automated measurements of the fetal left myocardial performance index (MPI) with manual measurements for absolute value, repeatability and waveform acceptability. METHODS: This was a multicenter international online study using images from uncomplicated, morphologically normal singleton pregnancies (16-38 weeks' gestation). Single Doppler ultrasound cardiac cycle images of 25 cases were selected, triplicated and randomized (n = 75). Six senior observers, unaware of the repetition of images, manually calculated MPI for each waveform and the results were compared with automation. Intraobserver repeatability and interobserver reproducibility were assessed using intraclass correlation coefficients (ICCs) and 95% CI. The agreement between each observer's manual MPI measurements and corresponding automated measurements was evaluated using Bland-Altman plots and ICCs with 95% CI. The degree of variation between experts in the classification of fetal MPI waveform quality was assessed using individual cardiac cycle left MPI images previously classified by two authors as 'optimal', 'suboptimal' or 'unacceptable', with 30 images selected for each quality group. Ten images in each category were duplicated and the resulting 120 images were randomized and then classified online by five observers. The kappa statistic (kappa) was used to demonstrate interobserver and intraobserver agreement and agreement of classifications by the five observers. RESULTS: The automated measurement software returned the same value for any given image, resulting in an ICC of 1.00. Manual measurements had intraobserver repeatability ICC values ranging from 0.69 to 0.97, and the interobserver reproducibility ICC was 0.78. Comparison of automated vs manual MPI absolute measurements for each observer gave ICCs ranging from 0.77 to 0.96. Interobserver image quality classification agreement gave k = 0.69 (P < 0.001), and the intraobserver agreement was variable (kappa ranging from 0.40 to 0.81). CONCLUSIONS: Automated fetal MPI provides superior repeatability and reproducibility to manual methodology. Additionally, experts vary significantly when classifying suitability of fetal MPI waveforms. Automated MPI may facilitate clinical translation by removing human subjectivity. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26423315 TI - Long-term Symptomatic Endoleak type 1a as a Result of Aortic Endograft Material Fatigue. PMID- 26423316 TI - Peritumoral tissue compression is predictive of exudate flux in a rat model of cerebral tumor: an MRI study in an embedded tumor. AB - MRI estimates of extracellular volume and tumor exudate flux in peritumoral tissue are demonstrated in an experimental model of cerebral tumor. Peritumoral extracellular volume predicted the tumor exudate flux. Eighteen RNU athymic rats were inoculated intracerebrally with U251MG tumor cells and studied with dynamic contrast enhanced MRI (DCE-MRI) approximately 18 days post implantation. Using a model selection paradigm and a novel application of Patlak and Logan plots to DCE MRI data, the distribution volume (i.e. tissue porosity) in the leaky rim of the tumor and that in the tissue external to the rim (the outer rim) were estimated, as was the tumor exudate flow from the inner rim of the tumor through the outer rim. Distribution volume in the outer rim was approximately half that of the inner adjacent region (p < 1 * 10(-4)). The distribution volume of the outer ring was significantly correlated (R(2) = 0.9) with tumor exudate flow from the inner rim. Thus, peritumoral extracellular volume predicted the rate of tumor exudate flux. One explanation for these data is that perfusion, i.e. the delivery of blood to the tumor, was regulated by the compression of the mostly normal tissue of the tumor rim, and that the tumor exudate flow was limited by tumor perfusion. PMID- 26423317 TI - Simethicone adjunct to polyethylene glycol improves small bowel capsule endoscopy imaging in non-Crohn's disease patients. AB - BACKGROUND: Currently, there is no standardized protocol for bowel preparation before small bowel capsule endoscopy (SBCE). This study aimed to investigate the effect of simethicone combined with polyethylene glycol (PEG) on the visualization quality (VQ) of the SBCE in patients with or without known or suspected Crohn's disease (CD). METHODS: This observational, prospective, single center study included consecutive patients undergoing a SBCE between 2007 and 2008. Patients received either a standard bowel cleansing preparation of 2 L PEG and 80 mg simethicone orally 12 and 1 h before SBCE respectively (Group A) or only PEG (Group B). VQ, based on scores for luminal bubbles in frames taken from the small intestine, examination completeness, SBCE diagnostic yield, gastric and small bowel transit times were recorded. RESULTS: Of the 115 patients finally included (Group A, n=56 and Group B, n=59) the cecum was visualized in 103 (89.6%). Simethicone overall improved the VQ in the proximal [OR: 2.43 (95%CI: 1.08-5.45), P=0.032] but not in the distal bowel segment (P=0.064). Nevertheless, this effect was not observed in patients undergoing SBCE for either known or suspected CD. CONCLUSION: Simethicone as an adjunct to PEG for bowel preparation in patients undergoing SBCE significantly improved the VQ in non-CD patients. PMID- 26423318 TI - Surgery for scoliosis in Duchenne muscular dystrophy. AB - BACKGROUND: Scoliosis in patients with Duchenne muscular dystrophy (DMD) is usually progressive and is treated with surgery. However, it is unclear whether the existing evidence is sufficiently scientifically rigorous to support a recommendation for spinal surgery for most patients with DMD and scoliosis. This is an updated review, and an updated search was undertaken in which no new studies were found for inclusion. OBJECTIVES: To determine the effectiveness and safety of spinal surgery in patients with DMD with scoliosis. We intended to test whether spinal surgery is effective in increasing survival and improving respiratory function, quality of life, and overall functioning, and whether spinal surgery is associated with severe adverse effects. SEARCH METHODS: On 16 June 2015 we searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL Plus. We also searched ProQuest Dissertation and Thesis database (January 1980 to June 2015), the National Institutes of Health Clinical Trials Database (6 January 2015), and the WHO International Clinical Trials Registry Platform (17 June 2015), and checked references. We imposed no language restrictions. SELECTION CRITERIA: We planned to include controlled clinical trials using random or quasi-random allocation of treatment evaluating all forms of spinal surgery for scoliosis in patients with DMD in the review. The control interventions would have been no treatment, non-operative treatment, or a different form of spinal surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. Two review authors independently examined the search results and evaluated the study characteristics against inclusion criteria in order to decide which studies to include in the review. MAIN RESULTS: Of the 49 relevant studies we found, none met the inclusion criteria for the review because they were not clinical trials, but prospective or retrospective reviews of case series. AUTHORS' CONCLUSIONS: Since no randomized controlled clinical trials were available to evaluate the effectiveness of scoliosis surgery in patients with DMD, we can make no good evidence-based conclusion to guide clinical practice. Patients with scoliosis should be informed as to the uncertainty of benefits and potential risks of surgery for scoliosis. Randomized controlled trials are needed to investigate the effectiveness of scoliosis surgery, in terms of quality of life, functional status, respiratory function, and life expectancy. PMID- 26423319 TI - Misspecified poisson regression models for large-scale registry data: inference for 'large n and small p'. AB - Poisson regression is an important tool in register-based epidemiology where it is used to study the association between exposure variables and event rates. In this paper, we will discuss the situation with 'large n and small p', where n is the sample size and p is the number of available covariates. Specifically, we are concerned with modeling options when there are time-varying covariates that can have time-varying effects. One problem is that tests of the proportional hazards assumption, of no interactions between exposure and other observed variables, or of other modeling assumptions have large power due to the large sample size and will often indicate statistical significance even for numerically small deviations that are unimportant for the subject matter. Another problem is that information on important confounders may be unavailable. In practice, this situation may lead to simple working models that are then likely misspecified. To support and improve conclusions drawn from such models, we discuss methods for sensitivity analysis, for estimation of average exposure effects using aggregated data, and a semi-parametric bootstrap method to obtain robust standard errors. The methods are illustrated using data from the Danish national registries investigating the diabetes incidence for individuals treated with antipsychotics compared with the general unexposed population. PMID- 26423320 TI - Effects of alternating hands during in-hospital one-handed chest compression: A randomised cross-over manikin trial. AB - OBJECTIVE: We evaluated the decrease in chest compression depth during continuous one-handed chest compression (OHCC) in an in-hospital paediatric arrest setting, and whether switching hands could delay the decrease in chest compression depth. METHODS: In total, 30 healthcare providers were randomised into groups A and B. Group A performed test 1 (chest compressors alternated hands every 30 s in 2 min of OHCC), followed by test 2 (chest compressors used one hand for 2 min without switching to the other hand) and group B, vice versa. Participants performed 2 min continuous OHCC on a paediatric manikin on a bed. Mean compression depth (MCD) and mean compression rate (MCR) were analysed at 30 s intervals. RESULTS: The MCDs in 30 s intervals changed significantly with time passed in tests 1 and 2 (0-30 s: 43.4 +/- 7.4 vs 42.8 +/- 7.6 mm, 30-60 s: 42.8 +/- 8.7 vs 40.3 +/- 8.8 mm, 60-90 s: 40.5 +/- 8.9 vs 38.2 +/- 9.6 mm, 90-120 s: 40.2 +/- 10.2 vs 36.9 +/- 9.7 mm; P < 0.01). However, with the exception of the first 30 s interval, MCD in test 1 showed significantly higher values than in test 2 (P < 0.05). The MCRs in 30 s intervals did not change significantly with time passed in all tests and were not different between the two tests. All hand-off times measured during switching hands in test 1 were less than 1 s. CONCLUSIONS: Chest compression depth decreased significantly when continuous OHCC was performed without switching hands. Alternating hands every 30 s can delay the decrease in MCD and maintain deeper MCD for longer. PMID- 26423321 TI - Profiles of Resilience and Growth in Youth With Cancer and Healthy Comparisons. AB - OBJECTIVE: Inconsistent links between posttraumatic stress symptoms (PTS) and posttraumatic growth (PTG) in youth following a stressful life event have been observed in previous literature. Latent profile analysis (LPA) provides a novel approach to examine the heterogeneity of relations between these constructs. METHOD: Participants were 435 youth (cancer group=253; healthy comparisons = 182) and one parent. Children completed measures of PTS, PTG, and a life-events checklist. Parents reported on their own PTS and PTG. LPA was conducted to identify distinct adjustment classes. RESULTS: LPA revealed three profiles. The majority of youth (83%) fell into two resilient groups differing by levels of PTG. Several factors predicted youth's profile membership. CONCLUSIONS: PTS and PTG appear to be relatively independent constructs, and their relation is dependent on contextual factors. The majority of youth appear to be resilient, and even those who experience significant distress were able to find benefit. PMID- 26423322 TI - Illness Uncertainty, Global Psychological Distress, and Posttraumatic Stress in Pediatric Cancer: A Preliminary Examination Using a Path Analysis Approach. AB - OBJECTIVE: To investigate the relationship of illness uncertainty (IU) to global psychological distress (GPD) and posttraumatic stress symptomatology (PTSS) using a path analysis approach. METHODS: Participants were 105 caregivers (MAge = 36.9 years, standard deviation [SD] = 8.7) of children (MAge = 8.6 years, SD = 5.0) with newly diagnosed cancer. A path analysis model examined the indirect and direct effects of each IU subscale on PTSS through GPD. RESULTS: The final model accounted for 47.30% of the variance in PTSS, and the ambiguity facet of IU had a significant indirect effect on PTSS through GPD. Lack of clarity and unpredictability were not significant predictors. CONCLUSIONS: Ambiguity experienced by parents may be salient in the development of PTSS. Future research should examine these relationships longitudinally in larger samples to better understand adjustment in parents of children with cancer. PMID- 26423323 TI - Epidemiological Profile of Wild Rabies in Brazil (2002-2012). AB - Rabies is one of the most important zoonosis in the world with high impact on public health. Studies report the presence of Lyssavirus in reservoirs of the wild cycle, highlighting the role of wild canines, marmosets, and vampire and non vampire bats as potential vectors of the disease to domestic animals and human beings. Therefore, the reintroduction of rabies in urban environments from reservoirs of the wild cycle is a matter of concern. This study describes the profile of rabies cases documented in Brazil from 2002 to 2012, with emphasis on the wild transmission cycle of the disease. We carried out a descriptive study using records with information on the time of infection, persons with infection and location of confirmed cases of rabies in humans and animals, as well as data on anti-rabies treatments obtained from the Information System of Notifiable Diseases (Sinan) database. Within the study period, 82 cases of rabies transmitted by wild animals to humans were reported, predominantly in rural areas of the northern and north-eastern regions. Of the cases in humans, 72% did not receive post-exposure prophylaxis. Among wild mammals, vampire bats were the most frequent vectors of the disease. In the north-east region, 460 terrestrial wild mammals were reported with confirmed rabies. Over the study period, 1703 bats were reported to carry the rabies virus. In the south-east region, the most frequently reported carriers of the virus were non-vampire bats. The midwest and northern regions presented a lower number of records of rabies cases among terrestrial wild mammals. However, the high number of rabies cases among bovines reflects the role of the vampire bat as a maintainer of the rabies virus in the rural cycle. The present results are key to adjust the planning of rabies control in Brazil to the current epidemiological trends. PMID- 26423324 TI - Putting Everything in Context. AB - In response to Casasanto, Brookshire, and Ivry (2015), we address four points: First, we engaged in conceptual replications of Brookshire, Casasanto, and Ivry (2010), not direct replications. Second, we did not question the validity of Brookshire et al.'s (2010) results, nor the similar findings of other researchers, but instead explained divergent findings within an integrated theoretical framework. Third, challenges to the construct of automaticity, including ours, were widespread, long before Brookshire et al.'s (2010) article. Fourth, the planned comparisons that we reported tested our theoretical claims and offered strong evidence for them. PMID- 26423325 TI - F11 is associated with recurrent VTE in women. A prospective cohort study. AB - Genetic associations for the reoccurrence of venous thromboembolism (VTE) are not well described. Our aim was to investigate if common genetic variants, previously found to contribute to the prediction of first time thrombosis in women, were associated with risk of recurrence. The Thromboembolism Hormone Study (TEHS) is a Swedish nationwide case-control study (2002-2009). A cohort of 1,010 women with first time VTE was followed up until a recurrent event, death or November 2011. The genetic variants in F5 rs6025, F2 rs1799963, ABO rs514659, FGG rs2066865, F11 rs2289252, PROC rs1799810 and KNG1 rs710446 were assessed together with clinical variables. Recurrence rate was calculated as the number of events over the accumulated patient-time. Cumulative recurrence was calculated by Kaplan-Meier curve. Cox proportional-hazard model was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) between groups. A total of 101 recurrent events occurred during a mean follow-up time of five years. The overall recurrence rate was 20 per 1,000 person-years (95% CI; 16-24). The recurrence rate was highest in women with unprovoked first event and obesity. Carriers of the risk alleles of F5 rs6025 (HR=1.7 (95% CI; 1.1-2.6)) and F11 rs2289252 (HR=1.8 (95% CI; 1.1-3.0)) had significantly higher rates of recurrence compared to non-carriers. The cumulative recurrence was 2.5-fold larger in carriers of both F5 rs6025 and F11 rs2289252 than in non-carriers at five years follow-up. In conclusion, F5 rs6025 and F11 rs2289252 contributed to the risk of recurrent VTE and the combination is of potential clinical relevance for risk prediction. PMID- 26423326 TI - Marine reserves can enhance ecological resilience. AB - The goals of ecosystem-based management (EBM) include protecting ecological resilience, the magnitude of a perturbation that a community can withstand and remain in a given state. As a tool to achieve this goal, no-take marine reserves may enhance resilience by protecting source populations or reduce it by concentrating fishing in harvested areas. Here, we test whether spatial management with marine reserves can increase ecological resilience compared to non-spatial (conventional) management using a dynamic model of a simplified fish community with structured predation and competition that causes alternative stable states. Relative to non-spatial management, reserves increase the resilience of the desired (predator-dominated) equilibrium state in both stochastic and deterministic environments, especially under intensive fishing. As a result, spatial management also increases the feasibility of restoring degraded (competitor-dominated) systems, particularly if combined with culling of competitors or stock enhancement of adult predators. PMID- 26423327 TI - A pilot study examining if satisfaction of basic needs can ameliorate negative effects of shift work. AB - The objective of the present study was to investigate if satisfaction of the basic needs of autonomy, competence, and relatedness is related to shift work tolerance, specifically physical and mental fatigue, insomnia, and digestive troubles in a sample of shift workers. This is a cross-sectional pilot questionnaire study, including 252 shift workers employed in a municipality in Norway. Autonomy was negatively related to physical fatigue and digestive troubles, while competence was negatively related to mental fatigue. Relatedness showed significant correlations with insomnia and mental fatigue, but did not reach significance in the regression model controlling for the two other basic needs as well as work scheduling, night work exposure, and sleep medication. Sleep medication was significant in the final regression model for insomnia, but unrelated to fatigue and digestive troubles. The demographic variables, work hours per week, work schedule, and night work exposure were unrelated to all four measures of shift work tolerance. Autonomy and competence may be more important for fatigue and digestive troubles among shift workers than work arrangement variables, night work exposure, and sleep medication use. PMID- 26423328 TI - Effects of mop handle height on shoulder muscle activity and perceived exertion during floor mopping using a figure eight method. AB - The aim of this study was to investigate effects of mop handle height on electromyographic (EMG) activities of the shoulder muscles and perceived exertion for the shoulder area during floor mopping using a figure eight method. An experimental study with 13 cleaners was conducted using surface EMG and category ratio (CR-10) scale. EMG activity was recorded unilaterally from the upper trapezius, infraspinatus, anterior and middle deltoid muscles. Each subject performed four trials of mopping and each trial consisted of using a different mop handle height (mop adjustment at the level of shoulder, chin, nose and eye) in randomized order. EMG data were normalized to a percentage of maximal voluntary contraction (%MVC). The muscle activities were assessed by estimating the 10th, 50th and 90th percentiles of the amplitude probability distribution function (APDF) of the EMG signals and analysed by linear mixed model analysis. Results showed that shoulder muscle activity was significantly lower when the mop handle height was adjusted to shoulder level or chin level as compared to eye level. These findings were supported by subjective ratings of exertion. It seems that mop handle height adjustment between shoulder and chin level may be recommended as a basis for figure eight mopping. PMID- 26423329 TI - Silicosis and renal disease: insights from a case of IgA nephropathy. AB - A 68-yr-old male, smoker, is admitted for proteinuria (2,800 mg/24 h) and reduced renal function (serum creatinine 2 mg/dl, GFR 35 ml/min). Renter, he started working 20-yr-old as a sandstone cave miner. Despite the high levels of silica dusts, he reported no mandatory use of airways protection devices during the first 25 yr of activity. No clinical or radiological signs of silicosis or pneumoconiosis where reported until the year of retirement (1997). Erythrocyte sedimentation rate (91 mm/h) and C reactive protein (35 mg/l) suggested a pro inflammatory status. High serum IgA was found (465 mg/dl). A renal biopsy identified glomerular sclerosis with IgA deposition, signs of diffuse vasculitis and tubular atrophia suggesting a diagnosis of IgA nephropathy. Chest X-Rays showed emphysema and diffuse nodularity suggesting diagnosis of silicosis. Chest tomography was also positive for mild signs of silicosis with silicotic nodules and without honeycombing. IgA nephropathy is the most common type of glomerulonephritis worldwide. Several clues suggest a genetic or acquired abnormality of immune system as a trigger of the increased production of IgA. In our case report, simultaneous kidney and pulmonary disease could suggest same triggers (e.g. exposure to virus, bacteria or environmental agents) inducing IgA synthesis and pulmonary immune system activation. PMID- 26423330 TI - Relations of biomarkers of manganese exposure and neuropsychological effects among welders and ferroalloy smelters. AB - The objective of present study was to assess relationship between biomarkers of Manganese (Mn) and neuropsychological effects. The study was carried out on 27 welders and 31 ferroalloy smelters as Mn-exposed groups and 30 office workers as unexposed controls. Air Mn concentrations were determined according to NIOSH method 7300. The biological samples were prepared using microwave assisted acid digestion and all samples were analyzed by graphite furnace- atomic absorption spectroscopy (GF-AAS) in order to determine manganese. Questionnaire 16 (Q16) and Cambridge Neuropsychological Test Automated Battery (CANTAB) were used to evaluate the neuropsychological effects. The mean concentrations of air Mn for the welder and ferroalloy smelter groups were 0.023 +/- 0.012 mg/m(3) and 0.008 +/- 0.005 mg/m(3), respectively. Manganese concentrations in blood, urine, and toenail samples of exposed workers ranged between 1.80-32.60 (ug/l), 1.00-42.50 (ug/l), and 0.10-6.08 (ug/g), respectively. Mean Mn concentrations in all biological samples of cases were significantly higher than unexposed controls (p<0.05). A moderate relationship was observed between biomarkers of Mn exposure, air Mn, Q16 as well as some neurocognitive outcome measures. The present study shows that blood Mn, urine Mn and toenail Mn could be used to distinguish Mn exposed workers from unexposed population at the group level. PMID- 26423331 TI - Evaluation of ergonomic physical risk factors in a truck manufacturing plant: case study in SCANIA Production Angers. AB - The aims of this study were 1) to assess the ergonomic physical risk factors from practitioner's viewpoint in a truck assembly plant with an in-house observational method and the NIOSH lifting equation, and 2) to compare the results of both methods and their differences. The in-house ergonomic observational method for truck assembly i.e. the SCANIA Ergonomics Standard (SES) and the NIOSH lifting equation were applied to evaluate physical risk factors and lifting of loads by operators. Both risk assessment approaches revealed various levels of risk, ranging from low to high. Two workstations were identified by the SES method as high risk. The NIOSH lifting index (LI) was greater than two for four lifting tasks. The results of the SES method disagreed with the NIOSH lifting equation for lifting tasks. Moreover, meaningful variations in ergonomic risk patterns were found for various truck models at each workstation. These results provide a better understanding of the physical ergonomic exposure from practitioner's point of view in the automotive assembly plant. PMID- 26423332 TI - Work-family conflict and sleep disturbance: the Malaysian working women study. AB - This study aimed at assessing effect of the four dimensions of work-family conflicts (strain and time-based work interference into family and family interference into work) on sleep disturbance in Malaysian working women. This cross-sectional study was conducted among 325 Malaysian married working women. Multiple-stage simple random sampling method was used to recruit women from public service departments of Malaysia. Self-administrated questionnaires were used to measure the study variables and data were analyzed using SPSS version 21. We found that high level of the four dimensions of work-family conflicts significantly increase sleep disturbance. Our analyses also revealed an age dependent effect of the work-family conflict on sleep disturbance. Women in their 20 to 30 yr old suffer from sleep disturbance due to high level of time-based and strain-based work-interference into family. However, the quality of sleep among women aged 30-39 were affected by strain-based family-interference into work. Finally, women older than 40 yr had significantly disturbed sleep due to strain based work-interference into family as well as time-based family interference into work. Our findings showed that sleep quality of working women might be disturbed by experiencing high level of work-family conflict. However, the effects of inter-role conflicts on sleep varied among different age groups. PMID- 26423333 TI - HIV testing and attitudes among the working-age population of Japan: annual health checkups may offer an effective way forwards. AB - In Japan, Voluntary Counselling and Testing (VCT) for HIV has been recommended for people concerned about their infection risk, especially those in high-risk groups. Although HIV awareness has declined in this country somewhat during recent years, the number of newly-infected cases has been increasing. The purpose of the current study therefore, was to determine the prevalence of HIV testing, individuals' reasons for being tested, and the overall acceptance of HIV testing among working-age Japanese. We utilized an anonymous, nationwide survey which was administered to a total of 3,055 participants aged 20-69 yr. The lifetime prevalence of HIV testing was 14% (2% within the past year). A gap was observed between a prior history of HIV testing and willingness to be tested in future (32%) or willingness to be tested during health checkups in the workplace (41%). HIV testing appears to have only been conducted among a limited number of working age Japanese adults, even though some reported a willingness to be tested. Opportunities for VCT during workplace health checkups might offer an immediate and positive way forwards in the fight against HIV; however, privacy protection for test results and the acceptance of HIV-positive employees should be carefully considered in the workplace. PMID- 26423334 TI - Dynamics of leaf gas exchange, chlorophyll fluorescence and stem diameter changes during freezing and thawing of Scots pine seedlings. AB - Boreal trees experience repeated freeze-thaw cycles annually. While freezing has been extensively studied in trees, the dynamic responses occurring during the freezing and thawing remain poorly understood. At freezing and thawing, rapid changes take place in the water relations of living cells in needles and in stem. While freezing is mostly limited to extracellular spaces, living cells dehydrate, shrink and their osmotic concentration increases. We studied how the freezing thawing dynamics reflected on leaf gas exchange, chlorophyll fluorescence and xylem and living bark diameter changes of Scots pine (Pinus sylvestris L.) saplings in controlled experiments. Photosynthetic rate quickly declined following ice nucleation and extracellular freezing in xylem and needles, almost parallel to a rapid shrinking of xylem diameter, while that of living bark followed with a slightly longer delay. While xylem and living bark diameters responded well to decreasing temperature and water potential of ice, the relationship was less consistent in the case of increasing temperature. Xylem showed strong temporal swelling at thawing suggesting water movement from bark. After thawing xylem diameter recovered to a pre-freezing level but living bark remained shrunk. We found that freezing affected photosynthesis at multiple levels. The distinct dynamics of photosynthetic rate and stomatal conductance reveals that the decreased photosynthetic rate reflects impaired dark reactions rather than stomatal closure. Freezing also inhibited the capacity of the light reactions to dissipate excess energy as heat, via non-photochemical quenching, whereas photochemical quenching of excitation energy decreased gradually with temperature in agreement with the gas exchange data. PMID- 26423335 TI - In situ 13CO2 pulse labelling of field-grown eucalypt trees revealed the effects of potassium nutrition and throughfall exclusion on phloem transport of photosynthetic carbon. AB - Potassium (K) is an important limiting factor of tree growth, but little is known of the effects of K supply on the long-distance transport of photosynthetic carbon (C) in the phloem and of the interaction between K fertilization and drought. We pulse-labelled 2-year-old Eucalyptus grandis L. trees grown in a field trial combining K fertilization (+K and -K) and throughfall exclusion (+W and -W), and we estimated the velocity of C transfer by comparing time lags between the uptake of (13)CO2 and its recovery in trunk CO2 efflux recorded at different heights. We also analysed the dynamics of the labelled photosynthates recovered in the foliage and in the phloem sap (inner bark extract). The mean residence time of labelled C in the foliage was short (21-31 h). The time series of (13)C in excess in the foliage was affected by the level of fertilization, whereas the effect of throughfall exclusion was not significant. The velocity of C transfer in the trunk (0.20-0.82 m h(-1)) was twice as high in +K trees than in -K trees, with no significant effect of throughfall exclusion except for one +K W tree labelled in the middle of the drought season that was exposed to a more pronounced water stress (midday leaf water potential of -2.2 MPa). Our results suggest that besides reductions in photosynthetic C supply and in C demand by sink organs, the lower velocity under K deficiency is due to a lower cross sectional area of the sieve tubes, whereas an increase in phloem sap viscosity is more likely limiting phloem transport under drought. In all treatments, 10 times less (13)C was recovered in inner bark extracts at the bottom of the trunk when compared with the base of the crown, suggesting that a large part of the labelled assimilates has been exported out of the phloem and replaced by unlabelled C. This supports the 'leakage-retrieval mechanism' that may play a role in maintaining the pressure gradient between source and sink organs required to sustain high velocity of phloem transport in tall trees. PMID- 26423336 TI - Root tip morphology, anatomy, chemistry and potential hydraulic conductivity vary with soil depth in three temperate hardwood species. AB - Root traits in morphology, chemistry and anatomy are important to root physiological functions, but the differences between shallow and deep roots have rarely been studied in woody plants. Here, we selected three temperate hardwood species, Juglans mandshurica Maxim., Fraxinus mandschurica Rupr. and Phellodendron amurense Rupr., in plantations in northeastern China and measured morphological, anatomical and chemical traits of root tips (i.e., the first-order roots) at surface (0-10 cm) and subsurface (20-30 cm) soil layers. The objectives of this study were to identify how those traits changed with soil depth and to reveal potential functional differences. The results showed that root diameters in deep root tips were greater in J. mandshurica and F. mandschurica, but smaller in P. amurense. However, root stele diameter and the ratio of stele to root diameter in the subsurface layer were consistently greater in all three species, which may enhance their abilities to penetrate into soil. All deep roots exhibited lower tissue nitrogen concentration and respiration rate, which were possibly caused by lower nutrient availability in the subsurface soil layer. Significant differences between shallow and deep roots were observed in xylem structure, with deep roots having thicker stele, wider maximum conduit and greater number of conduits per stele. Compared with shallow roots, the theoretical hydraulic conductivities in deep roots were enhanced by 133% (J. mandshurica), 78% (F. mandschurica) and 217% (P. amurense), respectively, indicating higher efficiency of transportation. Our results suggest that trees' root tip anatomical structure and physiological activity vary substantially with soil environment. PMID- 26423337 TI - A Surface Plasmon Resonance Spectroscopy Method for Characterizing Small-Molecule Binding to Nerve Growth Factor. AB - Small-molecule inhibitors have been previously investigated to identify possible therapeutics for the treatment of chronic pain. In the present study, known nerve growth factor (NGF) inhibitors identified by (125)I-NGF binding were characterized using affinity and binding evaluations by surface plasmon resonance (SPR) spectroscopy. A novel strategy for characterizing NGF inhibitors was used to determine the binding affinity (KD) and saturation ability of each compound with immobilized NGF. Seventy-four percent of compounds screened demonstrated a positive binding event to NGF. A KD less than 10 MUM and a percent saturation greater than 50% were used as thresholds to identify inhibitors that would warrant further investigation. This study details for the first time a methodology that can be used to directly characterize the binding event between small-molecule inhibitors and NGF. PMID- 26423338 TI - Construction of a Semisynthetic Human VH Single-Domain Antibody Library and Selection of Domain Antibodies against alpha-Crystalline of Mycobacterium tuberculosis. AB - The use of human variable heavy (VH) domain antibodies has been on the rise due to their small scaffold size and simple folding mechanism. A highly diverse library is largely dependent on the diversity introduced within the complementarity-determining region (CDR) cassettes. Here we introduced diversity with the use of a single framework diversifying all three CDRs using tailored codons consisting of degenerate trinucleotides (NNK). The length of the degeneracy in the CDRs was also taken into consideration based on the most frequently occurring length of CDRs and the canonical confirmation for each antibody subfamily. The semisynthetic human VH domain genes were assembled in a single pot using a temperature cascading process. The affinity selection process with Mycobacterium tuberculosis (MTb) alpha-crystalline was done using a semiautomated process. Enrichment of target-specific clones was observed with successful identification of monoclonal VH domain antibodies for MTb alpha crystalline. In short, the semisynthetic library generated was able to select monoclonal VH domain antibodies against full MTb alpha-crystalline protein with complete semisynthetic CDRs displayed on a single scaffold. The library has the potential to be applied for the isolation of antibodies against other pathogenic proteins. PMID- 26423339 TI - Screening and Identification of a Phage Display Derived Peptide That Specifically Binds to the CD44 Protein Region Encoded by Variable Exons. AB - CD44, especially the isoforms with variable exons (CD44v), is a promising biomarker for the detection of cancer. To develop a CD44v-specific probe, we screened a 7-mer phage peptide library against the CD44v3-v10 protein using an improved subtractive method. The consensus sequences with the highest frequency (designated CV-1) emerged after four rounds of panning. The binding affinity and specificity of the CV-1 phage and the synthesized peptide for the region of CD44 encoded by the variable exons were confirmed using enzyme-linked immunosorbent assay and competitive inhibition assays. Furthermore, the binding of the CV-1 probe to gastric cancer cells and tissues was validated using immunofluorescence and immunohistochemistry assays. CV-1 sensitively and specifically bound to CD44v on cancer cells and tissues. Thus, CV-1 has the potential to serve as a promising probe for cancer molecular imaging and target therapy. PMID- 26423340 TI - Recent innovations in the USA National Cancer Institute-sponsored investigator initiated Phase I and II anticancer drug development. AB - Exciting recent advancements in deep-sequencing technology have enabled a rapid and cost-effective molecular characterization of patient-derived tumor samples. Incorporating these innovative diagnostic technologies into early clinical trials could significantly propel implementation of precision medicine by identifying genetic markers predictive of sensitivity to agents. It may also markedly accelerate drug development and subsequent regulatory approval of novel agents. Particularly noteworthy, a high-response rate in a Phase II trial involving a biomarker-enriched patient cohort could result in a regulatory treatment approval in rare histologies, which otherwise would not be a candidate for a large randomized clinical trial. Furthermore, even if a trial does not meet its statistical endpoint, tumors from a few responders should be molecularly characterized as part of the new biomarker-mining processes. In order to accommodate patient screening and accelerate the accrual process, institutions conducting early clinical trials need to be a part of a multi-institution clinical trials network. Future clinical trial design will incorporate new biomarkers discovered by a 'phenotype-to-genotype' effort with an appropriate statistical design. To help advance such changes, the National Cancer Institute has recently reformed the existing early phase clinical trials network. A new clinical trial network, the Experimental Therapeutics Clinical Trials Network (ET CTN), was begun and, in addition to its pre-existing infrastructure, an up-to date clinical trial registration system, clinical trial monitoring system including electronic database and a central Institutional Review Board were formed. Ultimately, these reforms support identifying the most appropriate therapy for each tumor type by incorporating state-of-the-art molecular diagnostic tools into early clinical trials. PMID- 26423341 TI - Safety and efficacy of concurrent carboplatin plus radiotherapy for locally advanced head and neck cancer patients ineligible for treatment with cisplatin. AB - OBJECTIVE: Cisplatin-based chemoradiotherapy is the standard treatment for patients with locally advanced squamous cell carcinoma of the head and neck. However, patients with advanced age, renal, cardiac or neurogenic dysfunction seem ineligible for cisplatin treatment. We evaluated the safety and efficacy of concurrent carboplatin plus radiotherapy in patients ineligible for cisplatin usage. METHODS: We retrospectively analyzed the records of 25 consecutive locally advanced squamous cell carcinoma of the head and neck patients who received concurrent carboplatin plus radiotherapy at Shizuoka Cancer Center between August 2006 and March 2014. Carboplatin was administered tri-weekly or weekly. RESULTS: Patient characteristics were analyzed. The median age was 75 years (range, 54 82), male:female ratio, 24:1; performance status, 0-1 (23) or 2 (2); primary tumor site, oropharynx (10), hypopharynx (12), larynx (1) or oral cavity (2); Stage III (3), IVa (19) or IVb (3); induction chemotherapy, with (2) or without (23); and a median creatinine clearance of 62 ml/min (range, 37-117). The main reasons for choosing carboplatin were age (40%), renal impairment (36%) and cardiac dysfunction (20%). All patients received a planned irradiation dose of 70 Gy. Median follow-up was 30.9 months. Complete response was observed 70% patients. Median progression-free survival duration was 42.7 months. Median overall survival could not be analyzed. The 2-year progression-free and overall survival rates were 68 and 74%, respectively. The main toxicity Grade 3 or 4 was oral mucositis (56%), thrombocytopenia (34%), neutropenia (28%) and infection (24%). CONCLUSIONS: Concurrent carboplatin plus radiotherapy is tolerated and may be an option in treating locally advanced squamous cell carcinoma of the head and neck patients ineligible for treatment with cisplatin. PMID- 26423342 TI - A novel risk stratification model, involving preoperative lymphocyte-monocyte ratio and standard pathological factors, for overall survival in patients with bladder cancer undergoing radical cystectomy. AB - OBJECTIVE: To evaluate the ability of preoperative lymphocyte-monocyte ratio to predict prognosis and determine post-operative risk stratification in patients with bladder cancer undergoing radical cystectomy. METHODS: A retrospective review of the 210 patients who had undergone radical cystectomy for bladder cancer from 2006 to 2013 identified 181 patients with sufficient data to evaluate the prognostic significance of the lymphocyte-monocyte ratio. Overall survival was assessed by the Kaplan-Meier method. The association of clinicopathological findings with overall survival was evaluated by a multivariate Cox proportional model, and a novel risk stratification model to predict prognosis was established. RESULTS: Median follow-up after radical cystectomy was 6.0 years. The 5-year overall survival rate was significantly lower for patients with low than high lymphocyte-monocyte ratio (27.6 vs 80.7%, P < 0.001). Multivariable analyses showed that pT >=2, pN >=1, positive margins and low lymphocyte-monocyte ratio were independent predictors of overall survival. A post-operative risk stratification model using these factors showed significant differences among the three subgroups (low, intermediate and high risk) with a concordance index of 0.84. The 5-year overall survival rates in patients at low, intermediate and high risk were 85.4, 45.5 and 0%, respectively (P < 0.001). CONCLUSIONS: Preoperative lymphocyte-monocyte ratio, pathological tumor and lymph node stage and positive margins are significantly associated with overall survival in patients who have undergone radical cystectomy for bladder cancer. PMID- 26423344 TI - Cortical hyperostosis as a side-effect of prolonged use of prostaglandins. AB - Cortical hyperostosis is a very uncommon side-effect of prolonged prostaglandin therapy with distinctive radiological signs that may be accompanied by painful swelling of the limbs and responds rapidly to withdrawal of therapy. PMID- 26423343 TI - Retinotopic organization of extrastriate cortex in the owl monkey--dorsal and lateral areas. AB - Dense retinotopy data sets were obtained by microelectrode visual receptive field mapping in dorsal and lateral visual cortex of anesthetized owl monkeys. The cortex was then physically flatmounted and stained for myelin or cytochrome oxidase. Retinotopic mapping data were digitized, interpolated to a uniform grid, analyzed using the visual field sign technique-which locally distinguishes mirror image from nonmirror image visual field representations-and correlated with the myelin or cytochrome oxidase patterns. The region between V2 (nonmirror) and MT (nonmirror) contains three areas-DLp (mirror), DLi (nonmirror), and DLa/MTc (mirror). DM (mirror) was thin anteroposteriorly, and its reduced upper field bent somewhat anteriorly away from V2. DI (nonmirror) directly adjoined V2 (nonmirror) and contained only an upper field representation that also adjoined upper field DM (mirror). Retinotopy was used to define area VPP (nonmirror), which adjoins DM anteriorly, area FSTd (mirror), which adjoins MT ventrolaterally, and TP (mirror), which adjoins MT and DLa/MTc dorsoanteriorly. There was additional retinotopic and architectonic evidence for five more subdivisions of dorsal and lateral extrastriate cortex-TA (nonmirror), MSTd (mirror), MSTv (nonmirror), FSTv (nonmirror), and PP (mirror). Our data appear quite similar to data from marmosets, though our field sign-based areal subdivisions are slightly different. The region immediately anterior to the superiorly located central lower visual field V2 varied substantially between individuals, but always contained upper fields immediately touching lower visual field V2. This region appears to vary even more between species. Though we provide a summary diagram, given within- and between-species variation, it should be regarded as a guide to parsing complex retinotopy rather than a literal representation of any individual, or as the only way to agglomerate the complex mosaic of partial upper and lower field, mirror- and nonmirror-image patches into areas. PMID- 26423345 TI - A Bayesian approach for inducing sparsity in generalized linear models with multi category response. AB - BACKGROUND: The dimension and complexity of high-throughput gene expression data create many challenges for downstream analysis. Several approaches exist to reduce the number of variables with respect to small sample sizes. In this study, we utilized the Generalized Double Pareto (GDP) prior to induce sparsity in a Bayesian Generalized Linear Model (GLM) setting. The approach was evaluated using a publicly available microarray dataset containing 99 samples corresponding to four different prostate cancer subtypes. RESULTS: A hierarchical Sparse Bayesian GLM using GDP prior (SBGG) was developed to take into account the progressive nature of the response variable. We obtained an average overall classification accuracy between 82.5% and 94%, which was higher than Support Vector Machine, Random Forest or a Sparse Bayesian GLM using double exponential priors. Additionally, SBGG outperforms the other 3 methods in correctly identifying pre metastatic stages of cancer progression, which can prove extremely valuable for therapeutic and diagnostic purposes. Importantly, using Geneset Cohesion Analysis Tool, we found that the top 100 genes produced by SBGG had an average functional cohesion p-value of 2.0E-4 compared to 0.007 to 0.131 produced by the other methods. CONCLUSIONS: Using GDP in a Bayesian GLM model applied to cancer progression data results in better subclass prediction. In particular, the method identifies pre-metastatic stages of prostate cancer with substantially better accuracy and produces more functionally relevant gene sets. PMID- 26423346 TI - Enantiomeric switching of chiral metamaterial for terahertz polarization modulation employing vertically deformable MEMS spirals. AB - Active modulation of the polarization states of terahertz light is indispensable for polarization-sensitive spectroscopy, having important applications such as non-contact Hall measurements, vibrational circular dichroism measurements and anisotropy imaging. In the terahertz region, the lack of a polarization modulator similar to a photoelastic modulator in the visible range hampers expansion of such spectroscopy. A terahertz chiral metamaterial has a huge optical activity unavailable in nature; nevertheless, its modulation is still challenging. Here we demonstrate a handedness-switchable chiral metamaterial for polarization modulation employing vertically deformable Micro Electro Mechanical Systems. Vertical deformation of a planar spiral by a pneumatic force creates a three dimensional spiral. Enantiomeric switching is realized by selecting the deformation direction, where the polarity of the optical activity is altered while maintaining the spectral shape. A polarization rotation as high as 28 degrees is experimentally observed, thus providing a practical and compact polarization modulator for the terahertz range. PMID- 26423347 TI - Bootstrap percolation on spatial networks. AB - Bootstrap percolation is a general representation of some networked activation process, which has found applications in explaining many important social phenomena, such as the propagation of information. Inspired by some recent findings on spatial structure of online social networks, here we study bootstrap percolation on undirected spatial networks, with the probability density function of long-range links' lengths being a power law with tunable exponent. Setting the size of the giant active component as the order parameter, we find a parameter dependent critical value for the power-law exponent, above which there is a double phase transition, mixed of a second-order phase transition and a hybrid phase transition with two varying critical points, otherwise there is only a second-order phase transition. We further find a parameter-independent critical value around -1, about which the two critical points for the double phase transition are almost constant. To our surprise, this critical value -1 is just equal or very close to the values of many real online social networks, including LiveJournal, HP Labs email network, Belgian mobile phone network, etc. This work helps us in better understanding the self-organization of spatial structure of online social networks, in terms of the effective function for information spreading. PMID- 26423348 TI - Translating CESD-20 and PHQ-9 Scores to PROMIS Depression. AB - This study examined the accuracy of depression cross-walk tables in a sample of people with multiple sclerosis (MS). The tables link scores of two commonly used depression measures to the Patient Reported Outcome Measurement Information System Depression (PROMIS-D) scale metric. We administered the 8-item PROMIS-D (Short-Form 8b; PROMIS-D-8), the 20-item Center for Epidemiologic Studies Depression Scale (CESD-20), and the 9-item Patient Health Questionnaire (PHQ-9) to 459 survey participants with MS. We examined correlations between actual PROMIS-D-8 scores and the scores predicted by cross-walks based on PHQ-9 and CESD 20 scores. Intraclass correlation coefficients were used to assess correspondence. Consistency in severity classification was also calculated. Finally, we used Bland-Altman plots to graphically examine the levels of agreement. The correlations between actual and cross-walked PROMIS-D-8 scores were strong (CESD-20 = .82; PHQ-9 = .74). The intraclass correlation was moderate (.77). Participants were consistently classified as having or not having at least moderate depressive symptoms by both actual and cross-walked scores derived from the CESD-20 (90%) and PHQ-9 (85%). Bland-Altman plots suggested the smaller differences between actual and cross-walked scores with greater-than-average depression severity. PROMIS cross-walk tables can be used to translate depression scores of people with MS to the PROMIS-D metric, promoting continuity with previous research. PMID- 26423349 TI - Representation of the Cattell-Horn-Carroll Theory of Cognitive Abilities in the Factor Structure of the Dutch-Language Version of the WAIS-IV. AB - The Cattell-Horn-Carroll (CHC) theory of cognitive abilities has been guiding in the revision of the Wechsler Adult Intelligence Scale-Fourth edition (WAIS-IV). Especially the measurement of fluid reasoning (Gf) is improved. A total of five CHC abilities are included in the WAIS-IV subtests. Using confirmatory factor analysis, a five-factor model based on these CHC abilities is evaluated and compared with the four index scores in the Dutch-language version of the WAIS-IV. Both models demonstrate moderate fit, preference is given to the five-factor CHC model both on statistical and theoretical grounds. Evaluation of the WAIS-IV according to CHC terminology enhances uniformity, and can be important when interpreting possible sources of index discrepancies. To optimally assemblage CHC and WAIS-IV, more knowledge of the interaction of abilities is needed. This can be done by incorporating intelligence testing in neuropsychological assessment. Using this functional approach contributes to a better understanding of an individual's cognitive profile. PMID- 26423350 TI - Improving the Detection of Feigned Knowledge Deficits in Defendants Adjudicated Incompetent to Stand Trial. AB - Malingering is relatively common in criminal forensic evaluations as base rates of malingering have ranged from 20% to 30%. Given that the most prevalent criminal forensic evaluation is the assessment of competency to stand trial, the assessment of feigning during competency evaluations is necessary for accurate findings. Most of the response style literature focuses on feigning mental health symptoms, but in competency evaluations, individuals may attempt to feign legal knowledge deficits in order to be found incompetent to stand trial. The current investigation includes two studies: 195 students instructed to simulate feigned mental illness or incompetence to stand trial and one using a sample of 130 state psychiatric hospital residents who had been adjudicated incompetent to stand trial. The purpose of the study was to evaluate the Inventory of Legal Knowledge's (ILK; Musick & Otto, 2010) ability to detect individuals who are feigning legal knowledge deficits. Classification utility statistics, including sensitivity, specificity, positive predictive power, and negative predictive power are provided for each cut-score on the ILK beginning with a cut-score of 24 (which is the lower end of the range of chance) are provided. The current cut score of 47 provided in the professional manual of the ILK was shown to create a large number of false positives and suggests that modifications to this cut-score are required. PMID- 26423351 TI - Longitudinal Measurement Invariance of Beck Depression Inventory-II in Early Adolescents. AB - This study explored the longitudinal measurement invariance in the Beck Depression Inventory-II (BDI-II) in early adolescents (junior high school students). The participants were 730 early adolescents (330 boys and 400 girls), who were followed up over 3 years (in six waves). To reduce the size of longitudinal model and verify the stability of the findings, the Fall and Spring series data sets were analyzed separately. Each series includes three waves of data with about 1-year apart. It was found that the three-factor model (Negative Attitude, Performance Difficulty, and Somatic Elements) best fitted the data. Results of both data sets provided support for the longitudinal measurement invariance (threshold invariance) of the three-factor model, suggesting that the BDI-II measured the same construct over 3 years. The study also examined the category function of the BDI-II on the basis of the pattern of threshold estimates. Finally, the implications of the findings on the continuing use of the BDI-II are discussed. PMID- 26423352 TI - The protein kinase 2 inhibitor tetrabromobenzotriazole protects against renal ischemia reperfusion injury. AB - Protein kinase 2 (CK2) activation was reported to enhance reactive oxygen species production and activate the nuclear factor kappaB (NF-kappaB) pathway. Because oxidative stress and inflammation are critical events for tissue destruction during ischemia reperfusion (I/R), we sought to determine whether CK2 was important in the renal response to I/R. Mice underwent 25 min of renal ischemia and were then reperfused. We confirmed an increased expression of CK2alpha during the reperfusion period, while expression of CK2beta remained consistent. We administered tetrabromobenzotriazole (TBBt), a selective CK2alpha inhibitor before inducing I/R injury. Mice subjected to I/R injury showed typical patterns of acute kidney injury; blood urea nitrogen and serum creatinine levels, tubular necrosis and apoptosis, inflammatory cell infiltration and proinflammatory cytokine production, and oxidative stress were markedly increased when compared to sham mice. However, pretreatment with TBBt abolished these changes and improved renal function and architecture. Similar renoprotective effects of CK2alpha inhibition were observed for emodin. Renoprotective effects of CK2alpha inhibition were associated with suppression of NF-kappaB and mitogen activated protein kinase (MAPK) pathways. Taken together, these results suggest that CK2alpha mediates proapoptotic and proinflammatory signaling, thus the CK2alpha inhibitor may be used to prevent renal I/R injuries observed in clinical settings. PMID- 26423354 TI - Authors' reply. PMID- 26423353 TI - An optogenetic system for interrogating the temporal dynamics of Akt. AB - The dynamic activity of the serine/threonine kinase Akt is crucial for the regulation of diverse cellular functions, but the precise spatiotemporal control of its activity remains a critical issue. Herein, we present a photo-activatable Akt (PA-Akt) system based on a light-inducible protein interaction module of Arabidopsis thaliana cryptochrome2 (CRY2) and CIB1. Akt fused to CRY2phr, which is a minimal light sensitive domain of CRY2 (CRY2-Akt), is reversibly activated by light illumination in several minutes within a physiological dynamic range and specifically regulates downstream molecules and inducible biological functions. We have generated a computational model of CRY2-Akt activation that allows us to use PA-Akt to control the activity quantitatively. The system provides evidence that the temporal patterns of Akt activity are crucial for generating one of the downstream functions of the Akt-FoxO pathway; the expression of a key gene involved in muscle atrophy (Atrogin-1). The use of an optical module with computational modeling represents a general framework for interrogating the temporal dynamics of biomolecules by predictive manipulation of optogenetic modules. PMID- 26423355 TI - Long-term manure amendments reduced soil aggregate stability via redistribution of the glomalin-related soil protein in macroaggregates. AB - Glomalin-related soil protein (GRSP) contributes to the formation and maintenance of soil aggregates, it is however remains unclear whether long-term intensive manure amendments alter soil aggregates stability and whether GRSP regulates these changes. Based on a three-decade long fertilization experiment in northeast China, this study examined the impact of long-term manure input on soil organic carbon (SOC), total and easily extractable GRSP (GRSPt and GRSPe) and their respective allocations in four soil aggregates (>2000 MUm; 2000-250 MUm; 250-53 MUm; and <53 MUm). The treatments include no fertilization (CK), low and high manure amendment (M1, M2), chemical nitrogen, phosphorus and potassium fertilizers (NPK), and combined manure and chemical fertilizers (NPKM1, NPKM2). Though SOC, GRSPe and GRSPt in soil and SOC in each aggregate generally increased with increasing manure input, GRSPt and GRSPe in each aggregate showed varying changes with manure input. Both GRSP in macroaggregates (2000-250 MUm) were significantly higher under low manure input, a pattern consistent with changes in soil aggregate stability. Constituting 38~49% of soil mass, macroaggregates likely contributed to the nonlinear changes of aggregate stability under manure amendments. The regulatory process of GRSP allocations in soil aggregates has important implications for manure management under intensive agriculture. PMID- 26423356 TI - Synergistic algicidal effect and mechanism of two diketopiperazines produced by Chryseobacterium sp. strain GLY-1106 on the harmful bloom-forming Microcystis aeruginosa. AB - A potent algicidal bacterium isolated from Lake Taihu, Chryseobacterium sp. strain GLY-1106, produces two algicidal compounds: 1106-A (cyclo(4-OH-Pro-Leu)) and 1106-B (cyclo(Pro-Leu)). Both diketopiperazines showed strong algicidal activities against Microcystis aeruginosa, the dominant bloom-forming cyanobacterium in Lake Taihu. Interestingly, these two algicidal compounds functioned synergistically. Compared with individual treatment, combined treatment with cyclo(4-OH-Pro-Leu) and cyclo(Pro-Leu) significantly enhanced algicidal activity, accelerated the increase in intracellular reactive oxygen species (ROS) levels in M. aeruginosa, and further decreased the activities of antioxidases, effective quantum yield and maximal electron transport rate of M. aeruginosa. The results also showed that the algicidal characteristics of cyclo(4 OH-Pro-Leu) are distinct from those of cyclo(Pro-Leu). Cyclo(4-OH-Pro-Leu) mainly interrupted the flux of electron transport in the cyanobacterial photosynthetic system, whereas cyclo(Pro-Leu) mainly inhibited the activity of cyanobacterial intracellular antioxidases. A possible algicidal mechanism for the synergism between cyclo(4-OH-Pro-Leu) and cyclo(Pro-Leu) is proposed, which is in accordance with their distinct algicidal characteristics in individual and combined treatment. These findings suggest that synergism between algicidal compounds might be used as an effective strategy for the future control of Microcystis blooms. PMID- 26423357 TI - Dietary intake and food sources of choline in European populations. AB - Choline is an important nutrient for humans. Choline intake of the European population was assessed considering the European Food Safety Authority European Comprehensive Food Consumption Database and the United States Department of Agriculture Nutrient Database. Average choline intake ranges were 151-210 mg/d among toddlers (1 to <=3 years old), 177-304 mg/d among other children (3 to <=10 years old), 244-373 mg/d among adolescents (10 to <=18 years old), 291-468 mg/d among adults (18 to <=65 years old), 284-450 mg/d among elderly people (65 to <=75 years old) and 269-444 mg/d among very elderly people (>=75 years old). The intakes were higher among males compared with females, mainly due to larger quantities of food consumed per day. In most of the population groups considered, the average choline intake was below the adequate intake (AI) set by the Institute of Medicine in the USA. The main food groups contributing to choline intake were meat, milk, grain, egg and their derived products, composite dishes and fish. The main limitations of this study are related to the absence of choline composition data of foods consumed by the European population and the subsequent assumption made to assess their intake levels. Given the definition of AI, no conclusion on the adequacy of choline intake can be drawn for most European population groups. Such results improve the knowledge on choline intake in Europe that could be further refined by the collection of choline composition data for foods as consumed in Europe. PMID- 26423358 TI - Dinucleotide circular codes and bijective transformations. AB - The presence of circular codes in mRNA coding sequences is postulated to be involved in informational mechanisms aimed at detecting and maintaining the normal reading frame during protein synthesis. Most of the recent research is focused on trinucleotide circular codes. However, also dinucleotide circular codes are important since dinucleotides are ubiquitous in genomes and associated to important biological functions. In this work we adopt the group theoretic approach used for trinucleotide codes in Fimmel et al. (2015) to study dinucleotide circular codes and highlight their symmetry properties. Moreover, we characterize such codes in terms of n-circularity and provide a graph representation that allows to visualize them geometrically. The results establish a theoretical framework for the study of the biological implications of dinucleotide circular codes in genomic sequences. PMID- 26423359 TI - Alternative adaptive immunity strategies: coelacanth, cod and shark immunity. AB - The advent of high throughput sequencing has permitted to investigate the genome and the transcriptome of novel non-model species with unprecedented depth. This technological advance provided a better understanding of the evolution of adaptive immune genes in gnathostomes, revealing several unexpected features in different fish species which are of particular interest. In the present paper, we review the current understanding of the adaptive immune system of the coelacanth, the elephant shark and the Atlantic cod. The study of coelacanth, the only living extant of the long thought to be extinct Sarcopterygian lineage, is fundamental to bring new insights on the evolution of the immune system in higher vertebrates. Surprisingly, coelacanths are the only known jawed vertebrates to lack IgM, whereas two IgD/W loci are present. Cartilaginous fish are of great interest due to their basal position in the vertebrate tree of life; the genome of the elephant shark revealed the lack of several important immune genes related to T cell functions, which suggest the existence of a primordial set of TH1-like cells. Finally, the Atlantic cod lacks a functional major histocompatibility II complex, but balances this evolutionary loss with the expansion of specific gene families, including MHC I, Toll-like receptors and antimicrobial peptides. Overall, these data point out that several fish species present an unconventional adaptive immune system, but the loss of important immune genes is balanced by adaptive evolutionary strategies which still guarantee the establishment of an efficient immune response against the pathogens they have to fight during their life. PMID- 26423360 TI - Trafficking regulates the subcellular distribution of voltage-gated sodium channels in primary sensory neurons. AB - Voltage-gated sodium channels (Navs) comprise at least nine pore-forming alpha subunits. Of these, Nav1.6, Nav1.7, Nav1.8 and Nav1.9 are the most frequently studied in primary sensory neurons located in the dorsal root ganglion and are mainly localized to the cytoplasm. A large pool of intracellular Navs raises the possibility that changes in Nav trafficking could alter channel function. The molecular mediators of Nav trafficking mainly consist of signals within the Navs themselves, interacting proteins and extracellular factors. The surface expression of Navs is achieved by escape from the endoplasmic reticulum and proteasome degradation, forward trafficking and plasma membrane anchoring, and it is also regulated by channel phosphorylation and ubiquitination in primary sensory neurons. Axonal transport and localization of Navs in afferent fibers involves the motor protein KIF5B and scaffold proteins, including contactin and PDZ domain containing 2. Localization of Nav1.6 to the nodes of Ranvier in myelinated fibers of primary sensory neurons requires node formation and the submembrane cytoskeletal protein complex. These findings inform our understanding of the molecular and cellular mechanisms underlying Nav trafficking in primary sensory neurons. PMID- 26423361 TI - Zfp553 Is Essential for Maintenance and Acquisition of Pluripotency. AB - Pluripotent cells are promising tools in the arena of regenerative medicine. For many years, research efforts have been directed toward uncovering the underlying mechanisms that govern the pluripotent state and this involves identifying new pluripotency-associated factors. Zinc finger protein 553 (Zfp553) has been hypothesized to be one such factor because of its predominant expression in inner cell mass of the mouse early embryo. In this study, we have identified Zfp553 as a regulator of pluripotency. Zfp553 knockdown downregulates pluripotency markers and triggers differentiation in mouse embryonic stem cells (mESCs). Further investigation revealed that Zfp553 regulates pluripotency in mESCs through the transcriptional activation of Pou5f1 and Nanog. Microarray results revealed that depletion of Zfp553 downregulates many pluripotency genes, as well as genes associated with metabolism-related processes. ChIP-sequencing (ChIP-seq) depicted the genomic binding sites of Zfp553 in mESCs and its binding motif. In addition, we found that depletion of Zfp553 could impair somatic cell reprogramming, evidenced by reduced reprogramming efficiency and cell viability. Together, our preliminary findings provide novel insights to a newly identified pluripotency factor Zfp553 and its role in pluripotency regulation. PMID- 26423362 TI - Retinal development impairment and degenerative alterations in adult rats subjected to post-natal malnutrition. AB - BACKGROUND: The early stages of central nervous system (CNS) development are extremely important. Key events such as neurogenesis, gliogenesis, synaptogenesis, and ontogenesis occur. Malnutrition promotes alterations in CNS development, including the retinal development. During retinal development, malnutrition can induce a delay in some important events, such as neurotransmitter expression and neurogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Postpartum Wistar rats were fed either a commercial diet or a multideficient diet. Pups were breastfed by these rats, and from PND21 were kept with the same diet until PND45. We investigated the effects of malnutrition on adult retinal tissue with regard to (1) endogenous gamma-amino butyric acid (GABA) release induced by excitatory amino acids (EAAs) and (2) the expression of cellular markers related to degenerative events, such as reactive gliosis, microglial activation, cell proliferation and cell death. Endogenous GABA release induced by EAAs was higher in the retina of malnourished rats. The Muller cell population was reduced and displayed alterations in their phenotype profile compatible with reactive gliosis. The expression of glutamine synthetase and markers of cellular proliferation were higher in the retina of malnourished rats. Additionally, retinal dysplasia-like structures were present, indicating disturbance in the cell cycle machinery. CONCLUSION/SIGNIFICANCE: The current study provides evidence that the adult retina shows degenerative processes induced by long-term malnutrition during the postnatal development. These findings have high clinical significance with regard to the identification of possible targets for interventions in malnourished patients. PMID- 26423363 TI - From perceived autonomy support to intentional behaviour: Testing an integrated model in three healthy-eating behaviours. AB - A motivational model integrating self-determination theory, the theory of planned behaviour, and the health action process approach was tested in three samples in three behavioural contexts: fruit and vegetable, breakfast, and snack consumption. Perceived support for autonomous (self-determined) forms of motivation from parents and autonomous motivation from self-determination theory were hypothesised to predict intention and behaviour indirectly via the mediation of attitude and perceived behavioural control from the theory of planned behaviour. It was also expected that planning strategies would mediate the effect of intention on behaviour. Relations in the proposed models were expected to be similar across the behaviours. A two-wave prospective design was adopted. Three samples of high-school students (total N = 1041; 59.60% female; M age = 17.13 years +/- 1.57) completed measures of perceived autonomy support, autonomous motivation, theory of planned behaviour constructs, planning strategies and behaviour for each of the three behavioural contexts. Three months later, 816 participants (62,24% female; M age: 17.13 years, SD = 1.58) of the initial sample self-reported their behaviour referred to the previous three months. Structural equation models provided support for the key hypothesised effects of the proposed model for the three health-related behaviours. Two direct effects were significantly different across the three behaviours: the effect of perceived autonomy support on perceived behavioural control and the effect of attitude on intention. In addition, planning strategies mediated the effect of intention on behaviour in fruit and vegetable sample only. Findings extend knowledge of the processes by which psychological antecedents from the theories affect energy balance related behaviours. PMID- 26423365 TI - Quercetin interacts with Cry1Ac protein to affect larval growth and survival of Helicoverpa armigera. AB - BACKGROUND: Bt cotton has been widely planted in China for over a decade to control H. armigera, but field surveys indicate increasing resistance in the pest. It has been speculated that accumulating plant secondary compounds in mature cotton may interact with Bt toxins and affect the toxicity of Bt to H. armigera. RESULTS: Both quercetin, one of the main flavonoids in cotton, and the Bt toxin Cry1Ac protein had significant negative effects on the growth, development and survival of H. armigera when added singly to artificial diet, but their effects were inhibited when added in combination. Quercetin was antagonistic to Cry1Ac toxicity at all tested concentrations. CONCLUSION: The accumulation of quercetin might be one factor contributing to the reduced toxicity of mature Bt cotton plants to H. armigera, and could partially explain the reduced efficacy of Cry1Ac in controlling this pest in the field. (c) 2015 Society of Chemical Industry. PMID- 26423364 TI - Item banks for substance use from the Patient-Reported Outcomes Measurement Information System (PROMIS((r))): Severity of use and positive appeal of use. AB - BACKGROUND: Two item banks for substance use were developed as part of the Patient-Reported Outcomes Measurement Information System (PROMIS((r))): severity of substance use and positive appeal of substance use. METHODS: Qualitative item analysis (including focus groups, cognitive interviewing, expert review, and item revision) reduced an initial pool of more than 5300 items for substance use to 119 items included in field testing. Items were written in a first-person, past tense format, with 5 response options reflecting frequency or severity. Both 30 day and 3-month time frames were tested. The calibration sample of 1336 respondents included 875 individuals from the general population (ascertained through an internet panel) and 461 patients from addiction treatment centers participating in the National Drug Abuse Treatment Clinical Trials Network. RESULTS: Final banks of 37 and 18 items were calibrated for severity of substance use and positive appeal of substance use, respectively, using the two-parameter graded response model from item response theory (IRT). Initial calibrations were similar for the 30-day and 3-month time frames, and final calibrations used data combined across the time frames, making the items applicable with either interval. Seven-item static short forms were also developed from each item bank. CONCLUSIONS: Test information curves showed that the PROMIS item banks provided substantial information in a broad range of severity, making them suitable for treatment, observational, and epidemiological research in both clinical and community settings. PMID- 26423366 TI - Prevalence and predictors of patient no-shows to outpatient endoscopic procedures scheduled with anesthesia. AB - BACKGROUND: Demand for endoscopic procedures scheduled with anesthesia is increasing and no-show to appointments carries significant patient health and financial impact, yet little is known about predictors of no-show. METHODS: We performed a 16-month retrospective observational cohort study of patients scheduled for outpatient endoscopy with anesthesia at a county hospital serving the safety-net healthcare system of San Francisco. Multivariate logistic regression analysis was performed to evaluate associations between attendance and predictors of no-show. RESULTS: In total, 511 patients underwent endoscopy with anesthesia during the study period. Twenty-seven percent of patients failed to attend an appointment and were considered "no-show". In multivariate analysis, higher no-show rates were associated with patients with a prior history of no show (odds ratio [OR] 6.4; 95% confidence interval [CI], 2.4- 17.5), those with active substance abuse within the past year (OR 2.2; 95% CI 1.4-3.6), those with heavy prescription opioids/benzodiazepines use (OR 1.6; 95% CI 1.0-2.6) and longer wait-times (OR 1.05; 95% CI 1.00-1.09). Inversely associated with patient no-show were active employment (OR 0.38; 95% CI 0.18-0.81), patients who attended a pre-operative appointment with an anesthesiologist (OR 0.52; CI 0.32-0.85), and those undergoing an advanced endoscopic procedure (OR 0.43; 95% CI 0.19-0.94). CONCLUSION: In a safety-net healthcare population, behavioral and social determinants of health, including missed appointments, active substance abuse, homelessness, and unemployment are associated with no-shows to endoscopy with anesthesia. PMID- 26423367 TI - An end to AIDS is possible, but not without an end to HIV. PMID- 26423368 TI - Treatment of hepatitis C in patients with HIV. PMID- 26423369 TI - When is the best time to initiate antiretroviral therapy? PMID- 26423370 TI - Registries and syndemics: untapped potential for global health. PMID- 26423371 TI - Light and shade behind the opt-out system for the HIV screening. PMID- 26423372 TI - Light and shade behind the opt-out system for the HIV screening. PMID- 26423373 TI - Light and shade behind the opt-out system for the HIV screening - Authors' reply. PMID- 26423374 TI - Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non randomised, open-label trial. AB - BACKGROUND: Hepatitis C virus (HCV) infection is a leading cause of morbidity and mortality in patients with HIV-1. The C-EDGE CO-INFECTION study assessed the efficacy, safety, and tolerability of grazoprevir (MK-5172) plus elbasvir (MK 8742) in patients with HCV and HIV co-infection. METHODS: In this uncontrolled, non-randomised, phase 3, open-label, single-arm study, treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection and HIV co-infection, with or without cirrhosis, were enrolled from 37 centres in nine countries across Europe, the USA, and Australia. Patients were either naive to treatment with any antiretroviral therapy (ART) or stable on ART for at least 8 weeks. All patients received grazoprevir 100 mg plus elbasvir 50 mg in a fixed-dose combination tablet once daily for 12 weeks. The primary endpoint was sustained virological response (HCV RNA <15 IU/mL) 12 weeks after the end of therapy (SVR12). The primary population for efficacy analyses was all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT02105662. FINDINGS: Between June 11, 2014, and Aug 29, 2014, 218 patients were enrolled and received grazoprevir plus elbasvir for 12 weeks, all of whom completed follow-up at week 12. SVR12 was achieved by 210 (96%) of 218 patients (95% CI 92.9-98.4). One patient did not achieve SVR12 because of a non virological reason, and seven patients without cirrhosis relapsed (two subsequently confirmed as reinfections). All 35 patients with cirrhosis achieved SVR12. The most common adverse events were fatigue (29; 13%), headache (27; 12%), and nausea (20; 9%). No patient discontinued treatment because of an adverse event. Two patients receiving ART had transient HIV viraemia. INTERPRETATION: This HCV treatment regimen seems to be effective and well tolerated for patients co-infected with HIV with or without cirrhosis. These data are consistent with previous trials of this regimen in the monoinfected population. This regimen continues to be studied in phase 3 trials. FUNDING: Merck Sharp & Dohme Corp. PMID- 26423375 TI - Nurse-led palliative care for HIV-positive patients taking antiretroviral therapy in Kenya: a randomised controlled trial. AB - BACKGROUND: People with HIV accessing antiretroviral therapy (ART) have persistent physical, psychological, social, and spiritual problems, which are associated with poor quality of life and treatment outcomes. We assessed the effectiveness of a nurse-led palliative care intervention on patient-reported outcomes. METHODS: We did this randomised controlled trial at a clinic in Kenya for adults with HIV, established on ART, and reporting moderate-to-severe pain or symptoms. We randomly assigned participants (1:1) either to a palliative care intervention (including assessments of physical, emotional, and spiritual wellbeing and quality of life) given six times over 4 months, or to usual care. Participants and investigators were not masked to allocation. The primary outcome was pain (scored on the African Palliative Care Association's African Palliative Outcome Scale). This trial is registered with ClinicalTrials.gov, number NCT01608802. FINDINGS: We screened 2070 patients, of whom we enrolled 120: 60 allocated to each group. In the control group, median pain score improved from 1.0 (IQR 0.0-2.0) at baseline to 5.0 (3.0-5.0) at 4 months; in the intervention group, it improved from 1.0 (0.0-2.0) at baseline to 4.5 (3.0-5.0) at 4 months. Compared with standard care, the intervention had no significant effect on pain (coefficient -0.01, 95% CI -0.36 to 0.34, p=0.95). INTERPRETATION: A nurse-led palliative care intervention was not effective in reducing pain. However, person centred assessment and care delivered by staff who have received additional training had positive effects on self-reported mental health related quality of life and psychosocial wellbeing. FUNDING: Diana Princess of Wales Memorial Fund. PMID- 26423377 TI - Associations between HIV and schizophrenia and their effect on HIV treatment outcomes: a nationwide population-based cohort study in Denmark. AB - BACKGROUND: Associations between HIV and schizophrenia in people with and without substance use disorders and the effect on timeliness of HIV diagnosis, antiretroviral therapy (ART), and treatment outcomes are poorly understood. We aimed to assess the association between HIV and schizophrenia and the effect on HIV treatment outcomes in people with and without substance use disorders. METHODS: We did a population-based cohort study with data from nationwide registries in Denmark to investigate the risk of schizophrenia after a diagnosis of HIV and the risk of HIV after a diagnosis of schizophrenia, accounting for substance misuse, timeliness of HIV diagnosis, and treatment success in relation to schizophrenia. We selected the cohort from people born in Denmark between Jan 1, 1955, and Dec 31, 1995, who we followed up from their 16th birthday or Jan 1, 1995 (whichever occurred last) until their death, emigration from Denmark, onset of schizophrenia, or Dec 31, 2011 (whichever came first). We estimated incidence rate ratios (IRRs) with Poisson and Cox regression, with adjustment for calendar period, and age and its interaction with sex. FINDINGS: We identified 2,786,286 individuals, of whom we included 2,646,154 people in analyses of risk of schizophrenia diagnosis and 2,658,662 people in analyses of risk of HIV diagnosis. In 35,353,633 person-years of follow up, HIV was associated with an increased risk of schizophrenia (IRR 4.09, 95% CI 2.73-5.83) and acute psychosis (7.15, 4.45-10.8); the IRR was highest within the first year of HIV diagnosis for both disorders (8.24, 2.95-17.7 and 12.7, 3.15-32.9, respectively). Schizophrenia was not associated with an increased risk of HIV in individuals without substance misuse disorders (IRR 1.42, 95% CI 0.81-2.27). The risk of schizophrenia in individuals with HIV decreased after ART (IRR 0.53, 0.32-0.87). The risk of acute psychosis did not differ between HIV-infected individuals receiving antiretroviral regimens with and without efavirenz (IRR 0.70, 95% CI 0.32-1.54). We recorded no differences in CD4 cell counts, time to ART, or viral suppression between individuals with schizophrenia with HIV and those without schizophrenia when substance use was taken into account. Between 1999 and 2011, the mortality rate ratio comparing HIV-infected individuals with schizophrenia with HIV negative individuals without schizophrenia was 25.8 (95% CI 18.8-34.3). INTERPRETATION: Our findings emphasise the need for interventions to prevent HIV in people with schizophrenia, especially for those with substance use disorders, and for accessible mental health services for individuals with HIV. FUNDING: Stanley Medical Research Institute, Lundbeck Foundation, Preben and Anna Simonsen Fund, Novo Nordisk Foundation, The Danish AIDS Foundation, and the Augustinus Foundation. PMID- 26423379 TI - Quadri F et al (Clin Infect Dis 2015; 60:1737-42). PMID- 26423378 TI - Body image and weight control in South Africans 15 years or older: SANHANES-1. AB - BACKGROUND: South African studies have suggested that differences in obesity prevalence between groups may be partly related to differences in body image and body size dissatisfaction. However, there has never been a national study that measured body image and its relationship to weight control in the country. Hence, the main aim of the study was to examine body image in relation to body mass index and weight control in South Africa. METHODS: A cross-sectional survey and a secondary analyses of data were undertaken for 6 411 South Africans (15+ years) participating in the first South African National Health and Nutrition Examination Survey. Body image was investigated in relation to weight status and attempts to lose or gain weight. Data were analysed using STATA version 11.0. Descriptive statistics are presented as counts (numbers), percentages, means, standard error of means, and 95 % confidence intervals. Any differences in values were considered to be significantly different if the confidence intervals did not overlap. RESULTS: Overall, 84.5 % participants had a largely distorted body image and 45.3 % were highly dissatisfied about their body size. Overweight and obese participants under estimated their body size and desired to be thinner. On the other hand, normal- and under-weight participants over estimated their body size and desired to be fatter. Only 12.1 and 10.1 % of participants attempted to lose or gain weight, respectively, mainly by adjusting dietary intake and physical activity. DISCUSSION: Body mass index appears to influence body image and weight adjustment in South Africa. CONCLUSIONS: South Africans at the extreme ends of the body mass index range have a largely distorted body image and are highly dissatisfied by it. This suggests a need for health education and beneficial weight control strategies to halt the obesity epidemic in the country. PMID- 26423380 TI - Butel MJ et al (Clin Infect Dis 2015; 61:1116-8). PMID- 26423382 TI - HIV Infection: Still a Disease for Experts. PMID- 26423381 TI - Nasal Skin Necrosis: An Unexpected New Finding in Severe Chikungunya Fever. AB - Three adult Venezuelan patients with virologically confirmed Chikungunya fever, who developed extensive acute nasal skin necrosis early in the course of a life threatening illness characterized by shock and multiple organ dysfunction syndrome, are discussed. One patient survived and fully recovered. Nasal necrosis has not previously been associated with the disease. PMID- 26423383 TI - The HIV Workforce in New York State: Does Patient Volume Correlate with Quality? AB - BACKGROUND: Knowledge of care practices among clinicians who annually treat <20 human immunodeficiency virus (HIV)-positive patients with antiretroviral therapy (ART) is insufficient, despite their number, which is likely to increase given shifting healthcare policies. We analyze the practices, distribution and quality of care provided by low-volume prescribers (LVPs) based on available data sources in New York State. METHODS: We communicated with 1278 (66%) of the LVPs identified through a statewide claims database to determine the circumstances under which they prescribed ART in federal fiscal year 2009. We reviewed patient records from 84 LVPs who prescribed ART routinely and compared their performance with that of experienced clinicians practicing in established HIV programs. RESULTS: Of the surveyed LVPs, 368 (29%) provided routine ambulatory care for 2323 persons living with HIV/AIDS, and 910 LVPs cited other reasons for prescribing ART. Although the majority of LVPs (73%) practiced in New York City, patients living upstate were more likely to be cared for by a LVP (odds ratio, 1.7; 95% confidence interval, 1.4-1.9). Scores for basic HIV performance measures, including viral suppression, were significantly higher in established HIV programs than for providers who wrote prescriptions for <20 persons living with HIV/AIDS (P < .01). We estimate that 33% of New York State clinicians who provide ambulatory HIV care are LVPs. CONCLUSIONS: Our findings suggest that the quality of care associated with providers who prescribe ART for <20 patients is lower than that provided by more experienced providers. Access to experienced providers as defined by patient volume is an important determinant of delivering high-quality care and should guide HIV workforce policy decisions. PMID- 26423384 TI - Access and Quality of HIV-Related Point-of-Care Diagnostic Testing in Global Health Programs. AB - Access to point-of-care testing (POCT) improves patient care, especially in resource-limited settings where laboratory infrastructure is poor and the bulk of the population lives in rural settings. However, because of challenges in rolling out the technology and weak quality assurance measures, the promise of human immunodeficiency virus (HIV)-related POCT in resource-limited settings has not been fully exploited to improve patient care and impact public health. Because of these challenges, the Joint United Nations Programme on HIV/AIDS (UNAIDS), in partnership with other organizations, recently launched the Diagnostics Access Initiative. Expanding HIV programs, including the "test and treat" strategies and the newly established UNAIDS 90-90-90 targets, will require increased access to reliable and accurate POCT results. In this review, we examine various components that could improve access and uptake of quality-assured POC tests to ensure coverage and public health impact. These components include evaluation, policy, regulation, and innovative approaches to strengthen the quality of POCT. PMID- 26423385 TI - Standardizing 25-hydroxyvitamin D values from the Canadian Health Measures Survey. AB - BACKGROUND: The Canadian Health Measures Survey (CHMS) is an ongoing cross sectional national survey that includes a measure of 25-hydroxyvitamin D [25(OH)D] by immunoassay. For cycles 1 and 2, the collection period occurred approximately every 2 y, with a new sample of ~5600 individuals. OBJECTIVE: The goal was to standardize the original 25(OH)D CHMS values in cycles 1 and 2 to the internationally recognized reference measurement procedures (RMPs) developed by the US National Institute for Standards and Technology (NIST) and Ghent University, Belgium. DESIGN: Standardization was accomplished by using a 2-step procedure. First, serum samples corresponding to the original plasma samples were remeasured by using the currently available immunoassay method. Second, 50 serum samples with known 25(OH)D values assigned by the NIST and Ghent reference method laboratories were measured by using the currently available immunoassay method. The mathematical models for each step-i.e., 1) YCurrent = XOriginal and 2) YNIST Ghent = XCurrent -were estimated by using Deming regression, and the 2 models were solved to obtain a single equation for converting the "original" values to NIST-Ghent RMP values. RESULTS: After standardization (cycles 1 and 2 combined), the percentage of Canadians with 25(OH)D values <40 nmol/L increased from 16.4% (original) to 19.4% (standardized), and values <50 nmol/L increased from 29.0% (original) to 36.8% (standardized). The 25(OH)D standardized distributions (cycles 1 and 2 analyzed separately) were similar across age and sex groups; slightly higher values were associated with cycle 2 in the young and old. This finding contrasts with the original data, which indicated that cycle 2 values were lower for all age groups. CONCLUSION: The shifts in 25(OH)D distribution brought about by standardization indicate its importance in drawing correct conclusions about potential population deficiencies and insufficiencies and in permitting the comparison of distributions between national surveys. PMID- 26423387 TI - Gender perceptions predict sex differences in growth patterns of indigenous Guatemalan infants and young children. AB - BACKGROUND: Nearly one-half of Guatemalan children experience growth faltering, more so in indigenous than in nonindigenous children. OBJECTIVES: On the basis of ethnographic interviews in Totonicapan, Guatemala, which revealed differences in maternal perceptions about food needs in infant girls and boys, we predicted a cumulative sex difference in favor of girls that occurred at ~6 mo of age and diminished markedly thereafter. We examined whether the predicted differences in age-sex patterns were observed in the village, replicated the examination nationally for indigenous children, and examined whether the pattern in nonindigenous children was different. DESIGN: Ethnographic interviews (n = 24) in an indigenous village were conducted. Anthropometric measurements of the village children aged 0-35 mo (n = 119) were obtained. National-level growth patterns were analyzed for indigenous (n = 969) and nonindigenous (n = 1374) children aged 0-35 mo with the use of Demographic and Health Survey (DHS) data. RESULTS: Mothers reported that, compared with female infants, male infants were hungrier, were not as satisfied with breastfeeding alone, and required earlier complementary feeding. An anthropometric analysis confirmed the prediction of healthier growth in indigenous girls than in indigenous boys throughout the first year of life, which resulted in a 2.98-cm height-for-age difference (HAD) between sexes in the village and a 1.61-cm HAD (P < 0.001) in the DHS data between 6 and 17 mo of age in favor of girls. In both data sets, the growth sex differences diminished in the second year of life (P < 0.05). No such pattern was seen in nonindigenous children. CONCLUSIONS: We propose that the differences in the HAD that first favor girls and then favor boys in the indigenous growth patterns are due to feeding patterns on the basis of gendered cultural perceptions. Circumstances that result in differential sex growth patterns need to be elucidated, in particular the favorable growth in girls in the first year of life. PMID- 26423386 TI - Postdiagnostic intake of one-carbon nutrients and alcohol in relation to colorectal cancer survival. AB - BACKGROUND: Observational data have suggested that intakes of nutrients involved in one-carbon metabolism are inversely associated with risk of colorectal carcinoma and adenomas. In contrast, results from some preclinical studies and cardiovascular and chemoprevention trials have raised concerns that high folate intake may promote carcinogenesis by facilitating the progression of established neoplasia. OBJECTIVE: We tested the hypothesis that higher total folate intake (including food folate and folic acid from fortified foods and supplements) or other one-carbon nutrient intakes might be associated with poorer survival after a diagnosis of colorectal cancer. DESIGN: We used rectal and colon cancer cases within the following 2 US prospective cohort studies: the Nurses' Health Study and the Health Professionals Follow-Up Study. Biennial questionnaires were used to gather information on medical history and lifestyle factors, including smoking and alcohol consumption. B-vitamin and methionine intakes were derived from food frequency questionnaires. Data on tumor molecular characteristics (including microsatellite instability, CpG island methylator phenotype, KRAS, BRAF, and PIK3CA mutations, and long interspersed nucleotide element 1 methylation level) were available for a subset of cases. We assessed colorectal cancer-specific mortality according to postdiagnostic intakes of one-carbon nutrients with the use of multivariable Cox proportional hazards regression models. RESULTS: In 1550 stage I-III colorectal cancer cases with a median follow-up of 14.9 y, we documented 641 deaths including 176 colorectal cancer-specific deaths. No statistically significant associations were observed between postdiagnostic intakes of folate or other one-carbon nutrients and colorectal cancer-specific mortality (multivariate P-trend >= 0.21). In an exploratory molecular pathologic epidemiology survival analysis, there was no significant interaction between one carbon nutrients or alcohol and any of the tumor molecular biomarkers examined. CONCLUSIONS: Higher postdiagnostic intakes of one-carbon nutrients are not associated with the prognosis in stage I-III colorectal cancer. Our findings do not support the hypothesis that higher folate intake after colorectal cancer diagnosis might increase risk of cancer-related death. PMID- 26423388 TI - Associations of gestational glycemia and prepregnancy adiposity with offspring growth and adiposity in an Asian population. AB - BACKGROUND: Maternal obesity and hyperglycemia increase risk of obesity and diabetes in offspring later in life. OBJECTIVE: We examined the relation between gestational glycemia and prepregnancy body mass index (ppBMI) with offspring growth in an Asian mother-offspring cohort. DESIGN: Pregnant mothers undertook a 75-g 2-h oral-glucose-tolerance test at 26-28 wk of gestation. In 937 singleton offspring, <=9 serial measurements of weight and length were obtained from birth until 36 mo of age. RESULTS: Gestational fasting plasma glucose (FPG) was positively associated with birth weight (B: 0.17; 95% CI: 0.10, 0.24; P < 0.001) and birth BMI (B: 0.15; 95% CI: 0.06, 0.40; P = 0.001) but not at >=3 mo of age. In contrast, maternal ppBMI was positively associated with birth variables and conditional growth in weight and BMI in the first 36 mo of life. However, gestational FPG and prepregnancy obesity status interacted significantly for the association with offspring growth and overweight status in the first 36 mo of life (P-interaction < 0.01). In nonobese mothers, each unit increase in gestational FPG was associated with increased offspring weight (B: 0.08; 95% CI: 0.008, 0.16; P = 0.03) and BMI (B: 0.08; 95% CI: 0.003, 0.15; P = 0.04) as well as increased risk of overweight in the first 36 mo of life (OR: 1.36; 95% CI: 1.10, 1.68). However, in obese mothers, each unit increase in gestational FPG was associated with decreased offspring weight (B: -0.01; 95% CI: -0.02, -0.003) and BMI (B: -0.008; 95% CI: -0.01, -0.002) velocity (P < 0.01 for both) and decreased risk of overweight (OR: 0.59; 95% CI: 0.41, 0.86) in the first 36 mo of life. CONCLUSIONS: Prepregnancy adiposity was associated with offspring growth in early childhood. Although pooled analyses showed no demonstrable difference by 3 mo of age, there were contrasting and opposite associations of gestational glycemia with weight and BMI in the first 36 mo of life in offspring of nonobese and obese mothers separately. This study was registered at clinicaltrials.gov as NCT01174875. PMID- 26423389 TI - Time course of postprandial hepatic phosphorus metabolites in lean, obese, and type 2 diabetes patients. AB - BACKGROUND: Impaired energy metabolism is a possible mechanism that contributes to insulin resistance and ectopic fat storage. OBJECTIVE: We examined whether meal ingestion differently affects hepatic phosphorus metabolites in insulin sensitive and insulin-resistant humans. DESIGN: Young, lean, insulin-sensitive humans (CONs) [mean +/- SD body mass index (BMI; in kg/m(2)): 23.2 +/- 1.5]; insulin-resistant, glucose-tolerant, obese humans (OBEs) (BMI: 34.3 +/- 1.7); and type 2 diabetes patients (T2Ds) (BMI: 32.0 +/- 2.4) were studied (n = 10/group). T2Ds (61 +/- 7 y old) were older (P < 0.001) than were OBEs (31 +/- 7 y old) and CONs (28 +/- 3 y old). We quantified hepatic gammaATP, inorganic phosphate (Pi), and the fat content [hepatocellular lipids (HCLs)] with the use of (31)P/(1)H magnetic resonance spectroscopy before and at 160 and 240 min after a high caloric mixed meal. In a subset of volunteers, we measured the skeletal muscle oxidative capacity with the use of high-resolution respirometry. Whole-body insulin sensitivity (M value) was assessed with the use of hyperinsulinemic euglycemic clamps. RESULTS: OBEs and T2Ds were similarly insulin resistant (M value: 3.5 +/- 1.4 and 1.9 +/- 2.5 mg . kg(-1) . min(-1), respectively; P = 0.9) and had 12-fold (P = 0.01) and 17-fold (P = 0.002) higher HCLs, respectively, than those of lean persons. Despite comparable fasting hepatic gammaATP concentrations, the maximum postprandial increase of gammaATP was 6-fold higher in OBEs (0.7 +/- 0.2 mmol/L; P = 0.03) but only tended to be higher in T2Ds (0.6 +/- 0.2 mmol/L; P = 0.09) than in CONs (0.1 +/- 0.1 mmol/L). However, in the fasted state, muscle complex I activity was 53% lower (P = 0.01) in T2Ds but not in OBEs (P = 0.15) than in CONs. CONCLUSIONS: Young, obese, nondiabetic humans exhibit augmented postprandial hepatic energy metabolism, whereas elderly T2Ds have impaired fasting muscle energy metabolism. These findings support the concept of a differential and tissue-specific regulation of energy metabolism, which can occur independently of insulin resistance. This trial was registered at clinicaltrials.gov as NCT01229059. PMID- 26423390 TI - Alcohol consumption and risk of cutaneous basal cell carcinoma in women and men: 3 prospective cohort studies. AB - BACKGROUND: Alcohol consumption has been associated with an increased prevalence of sunburn, which is an established skin cancer risk factor. OBJECTIVE: We investigated whether alcohol consumption is associated with risk of cutaneous basal cell carcinoma (BCC). DESIGN: We conducted a prospective analysis on alcohol consumption and risk of BCC on the basis of data from 167,765 women in the NHS (Nurses' Health Study) (1984-2010) and NHS II (1991-2011) and 43,697 men in the Health Professionals Follow-Up Study (1986-2010). Alcohol intake was repeatedly assessed every 2-4 y over the follow-up period. HRs and 95% CIs for BCC in association with alcohol intake were computed with the use of Cox proportional hazards models with adjustment for sun exposure and other skin cancer risk factors. RESULTS: A total of 28,951 incident BCC cases were documented over 3.74 million person-years of follow-up. Increased alcohol intake was associated with increased BCC risk in both women and men (both P-trend < 0.0001). Pooled multivariable-adjusted HRs over increasing cumulative averaged alcohol intake categories were 1.00 (reference) for nondrinkers, 1.13 (95% CI: 1.06, 1.20) for 0.1-9.9 g/d, 1.24 (95% CI: 1.14, 1.35) for 10.0-19.9 g/d, 1.27 (95% CI: 1.20, 1.35) for 20.0-29.9 g/d, and 1.22 (95% CI: 1.15, 1.30) for >=30.0 g/d (P-trend < 0.0001, P-heterogeneity by study = 0.10 ). The association remained consistent when we used alcohol intakes over different latency periods (0-4, 4-8, 8-12, and 12-16 y) as exposures and over categories of sun exposure related factors. In the individual alcoholic beverages, white wine and liquor were positively associated with BCC risk. CONCLUSION: Alcohol consumption is associated with increased risk of cutaneous BCC in both women and men. PMID- 26423391 TI - Real-time toxicity and metabolic activity tracking of human cells exposed to Escherichia coli O157:H7 in a mixed consortia. AB - Escherichia coli O157:H7 is a significant human pathogen that is continually responsible for sickness, and even death, on a worldwide scale. While the pathology of E. coli O157:H7 infection has been well studied, the effect of it's multiple resulting cytotoxic mechanisms on host metabolic activity has not been well characterized. To develop a more thorough understanding of these effects, several bioluminescence assays were evaluated for their ability to track both toxicity and host metabolic activity levels in real-time. The use of continuously autobioluminescent human cells was determined to be the most favorable method for tracking these metrics, as its self-sufficient autobioluminescent phenotype was unaffected by the presence of the infecting bacteria and its signal could be measured without cellular destruction. Using this approach, it was determined that infection with as few as 10 CFU of E. coli O157:H7 could elicit cytotoxic effects. Regardless of the initial infective dose, an impact on metabolic expression was not observed until bacterial populations reached levels between 5 * 10(5) and 1 * 10(6) (R(2) = 0.933), indicating that a critical bacterial infection level must be reached prior to the onset of cytotoxic effects. Supporting this hypothesis, it was found that cells displaying infection-mediated metabolic activity reductions could recover to wild type metabolic activity levels if the infecting bacteria were removed prior to cell death. These results indicate that rapid treatment of E. coli O157:H7 infection could serve to limit host metabolic impact and reduce overall host cell death. PMID- 26423393 TI - Towards multi-level biomonitoring of nematodes to assess risk of nitrogen and phosphorus pollution in Jinchuan Wetland of Northeast China. AB - Cultivation for agricultural production often poses threats to nearby wetlands ecosystems in fertile landscapes. In this study, nematode ecological indexes were assessed through the main soil properties of the wetlands, farmlands, and edges of wetlands and farmlands in Jinchuan Wetland by the random sampling. Behavior and reproduction in Caenorhabditis elegans (C. elegans) exposed to the sampled waters were also examined. Stress proteins Hsp70 and Hsp90 were measured both in the living field samples of C. elegans and the lab-tested C. elegans. Our results suggested that disturbance to wetland ecosystems by nitrogen and phosphorus reduced nematode richness and proportions of bacterivore nematodes. Bacterivore nematode diversity and plant-parasitic ecological index were proven to be sensitive indicators of the ecological health of wetlands. Nematode Hsp70 were useful biosensors to monitor and assess the levels of nitrogen and phosphorus pollutions in wetlands. Furthermore, multi-level soil faunal assessments by canonical correspondence analysis showed that Jinchuan Wetland is threatened with non-point source pollution from nearby farmlands. PMID- 26423392 TI - Toxicological challenges to microbial bioethanol production and strategies for improved tolerance. AB - Bioethanol production output has increased steadily over the last two decades and is now beginning to become competitive with traditional liquid transportation fuels due to advances in engineering, the identification of new production host organisms, and the development of novel biodesign strategies. A significant portion of these efforts has been dedicated to mitigating the toxicological challenges encountered across the bioethanol production process. From the release of potentially cytotoxic or inhibitory compounds from input feedstocks, through the metabolic co-synthesis of ethanol and potentially detrimental byproducts, and to the potential cytotoxicity of ethanol itself, each stage of bioethanol production requires the application of genetic or engineering controls that ensure the host organisms remain healthy and productive to meet the necessary economies required for large scale production. In addition, as production levels continue to increase, there is an escalating focus on the detoxification of the resulting waste streams to minimize their environmental impact. This review will present the major toxicological challenges encountered throughout each stage of the bioethanol production process and the commonly employed strategies for reducing or eliminating potential toxic effects. PMID- 26423394 TI - Acclimation of Hydrilla verticillata to sediment anoxia in vegetation restoration in eutrophic waters. AB - Sediment anoxia generally results from intense organic enrichment and is a limiting factor in the restoration of vegetation in eutrophic waters. To investigate the effect of sediment anoxia on a typical pollution-tolerant submerged macrophyte species, Hydrilla verticillata, and acclimation mechanisms in the plant, a gradient of sediment anoxia was simulated with additions of sucrose to the sediment, which can stimulate increased concentrations of total nitrogen, NH4(+) and Fe in pore water. H. verticillata growth was significantly affected by highly anoxic conditions, as indicated by reduced total biomass in the 0.5 and 1% sucrose treatments. However, slight anoxia (0.1% sucrose addition) promoted growth, and the shoot biomass was 22.64% higher than in the control. In addition to morphologic alterations, H. verticillata showed physiological acclimations to anoxia, including increased anaerobic respiration and changes in carbon and nitrogen metabolism in roots. The soluble protein and soluble carbohydrate contents in roots of the 1% treatment were both significantly higher compared with those in the control. The increase in alcohol dehydrogenase activity and pyruvate content in the roots suggested that H. verticillata has a well-developed capacity for anaerobic fermentation. This study suggests that highly anoxic sediments inhibit the growth of H. verticillata and the species has a degree of tolerance to anoxic conditions. Further in situ investigations should be conducted on the interactions between sediment conditions and macrophytes to comprehensively evaluate the roles of sediment in the restoration of vegetation in eutrophic waters. PMID- 26423395 TI - Metagenomic insights into tetracycline effects on microbial community and antibiotic resistance of mouse gut. AB - Antibiotics have been widely used for disease prevention and treatment of the human and animals, and for growth promotion in animal husbandry. Antibiotics can disturb the intestinal microbial community, which play a fundamental role in animals' health. Misuse or overuse of antibiotics can result in increase and spread of microbial antibiotic resistance, threatening human health and ecological safety. In this study, we used Illumina Hiseq sequencing, (1)H nuclear magnetic resonance spectroscopy and metagenomics approaches to investigate intestinal microbial community shift and antibiotic resistance alteration of the mice drinking the water containing tetracycline hydrochloride (TET). Two-week TET administration caused reduction of gut microbial diversity (from 194 to 89 genera), increase in Firmicutes abundance (from 24.9 to 39.8%) and decrease in Bacteroidetes abundance (from 69.8 to 51.2%). Metagenomic analysis showed that TET treatment affected the intestinal microbial functions of carbohydrate, ribosomal, cell wall/membrane/envelope and signal transduction, which is evidenced by the alteration in the metabolites of mouse serum. Meanwhile, in the mouse intestinal microbiota, TET treatment enhanced the abundance of antibiotic resistance genes (ARGs) (from 307.3 to 1492.7 ppm), plasmids (from 425.4 to 3235.1 ppm) and integrons (from 0.8 to 179.6 ppm) in mouse gut. Our results indicated that TET administration can disturb gut microbial community and physiological metabolism of mice, and increase the opportunity of ARGs and mobile genetic elements entering into the environment with feces discharge. PMID- 26423396 TI - Workload, time and costs of the informal cares in patients with tele-monitoring of pacemakers: the PONIENTE study. AB - OBJECTIVES: The purpose of this study was to assess the burden borne by and the costs to informal caregivers of patients with remotely monitored (RM) pacemakers. METHODS: The PONIENTE study was a controlled, non-randomised clinical trial, with data collected from informal caregivers, 12 months after implantation of pacemakers. The survey on disabilities, personal autonomy, and dependency situations was used to gather information on demographic and social characteristics, levels of professionalism, time and types of care, difficulties in providing care, health status, professional aspects, economic and family or leisure impacts due to informal caregiving for patients with pacemakers. RESULTS: During 14 months, 76 caregivers were enrolled in the PONIENTE trial. Of which, 26 were included in the RM group and 50 in the hospital-monitored group (HM). The mean ages were 58.62 +/- 16.51 and 61.10 +/- 12.67 years, respectively (p = 0.56) in the groups, and 69.7 % were females. The majority (96.1 %) of the caregivers declared that they had to provide their services between 6 and 7 days per week (88.5 % in RM group versus 100 % in HM group; p = 0.037). The costs related to care provided by the informal caregivers were 21.38 % lower in the RM group than in the HM group (p = 0.033). CONCLUSIONS: The PONIENTE study shows a significant impact of informal care on relatives and friends of patients with pacemakers in terms of their well-being and costs. TRIAL REGISTRATION: ClinicalTrials.gov NCT02234245. PMID- 26423398 TI - Analysis of the usage of continence pads and help-seeking behavior of women with stress urinary incontinence in Poland. AB - BACKGROUND: Urinary incontinence (UI) in women is a chronic disorder which has a negative impact on health-related quality of life. Only 45 % of the affected individuals report the problem with continence to their doctor. The aim of the study was to assess the duration of stress urinary incontinence (SUI), time from disease onset to the first medical consultation and in-depth diagnosis, as well as the need for using continence pads in various grades of SUI. METHODS: We conducted a cross-sectional study in women who presented at the urogynecologic ambulatory center and reported urinary incontinence. A total of 420 subjects were interviewed and underwent urogynecologic and urodynamic examinations. A group of 147 patients with urodynamic SUI was enrolled in the study. RESULTS: All women were graded according to the Stamey severity score: grade 1 - 56 (38.1 %), grade 2 - 68 (46.3 %), and grade 3 - 23 (15.6 %). Mean time elapsed between disease onset and presentation at the urogynecologic ambulatory center was 17.4 +/- 11.8 years (grades 1, 2 and 3 for 11.6 +/- 11.8, 14.9 +/- 10.8, and 22.2 +/- 12.1 years, respectively; p = 0.0002). Patients with SUI started perceiving their condition as a problem 4.7 +/- 5.4 years before referral to urodynamics; 58.3 % of the SUI patients reported their problems with continence to a physician. Average time between the onset of UI symptoms and seeking medical help was 13.28 +/- 12.3 years. Mean duration of using continence pads during the day was 4.2, 5.4 and 10.2 years in grades 1, 2 and 3, respectively (p = 0.0002). The number of patients using continence pads in and outside the home, as compared to outside only, was: grade 1 - 44.6 % vs. 28.6 %, grade 2 - 77.6 % vs. 13.4 %, and grade 3 86.4 % vs. 9.1 % (p = 0.004). Mean use of continence pads at night was 3.3, 6.1, and 9.1 years in grades 1, 2 and 3, respectively. The differences were not statistically significant. Protective continence products were used at night by 26.7 % of the SUI patients: 16.1 %, 25 % and 59.1 % in grades 1, 2 and 3, respectively (p = 0.004). CONCLUSIONS: Women with SUI delay seeking medical help for over a decade. The severity of SUI is associated with duration and increased use of continence pads. PMID- 26423397 TI - [Management of complications in endoscopic interventions of the upper gastrointestinal tract]. AB - Endoscopic procedures are frequently performed interventions in the clinical routine. Whereas endoscopy was initially regarded as being a secondary diagnostic tool, over the last decades endoscopic procedures have now become an integral part of various treatment strategies. The appeal of these methods is without any doubt the minimally invasive approach in contrast to open surgery. Endoscopic interventions per se necessitate representative technical equipment and the various components are continually being refined. Considering the complexity of the method, profound skills in endoscopic diagnostic procedures and therapeutic interventions are essential prerequisites for adequate procedural quality and patient safety. Endoscopic examinations are in fact invasive interventions in the same way as surgical procedures and are associated with a certain risk of potential complications. The awareness about potential complications and their respective risk factors is of crucial importance for both the patient and the physician. Complications may harm patients and may lead to increased mortality rates; therefore, it is not only important to be aware of them but also to have an efficient management strategy in order to minimize the damage. Recognition and consistent actions are the basic pillars of correct complication management. These aspects are addressed in this article. PMID- 26423399 TI - Repression of PES1 expression inhibits growth of gastric cancer. AB - Gastric cancer is one of the leading causes of cancer death worldwide. However, precise molecular mechanisms underlining its development are far from clear. We recently reported that PES1 promoted development of breast cancer and ovarian cancer as an oncogene. In this study, we reported that ablation of endogenous PES1 resulted in significant suppression of cell proliferation and growth and led to cell cycle arrest in G2 or G1 phase, respectively, in two gastric cancer cell lines (AGS and N87) in vitro. Meanwhile, silencing of PES1 obviously decreased expressions of cyclin D1, HIF-1alpha, and vascular endothelial growth factor (VEGF) expressions and increased p21WAF1 expression. Re-expression of PES1 in these two kinds of PES1 knockdown cells rescued these effects. In vivo, repression of endogenous PES1 expression suppressed gastric tumor growth in nude mice. In addition, 40.7 % (24/59) of gastric cancer tissues showed PES1 expression via immunohistochemical (IHC) staining. However, there were not any positive PES1 stainings in matched adjacent tissues. Our results demonstrated that repression of PES1 changed expressions of some cell proliferation- and angiogenesis-related genes and inhibited gastric cancer growth, and PES1 expression increased in gastric cancer tissues. These results suggest that PES1 may play an important role in development of gastric cancer. PES1 may be a potential target for gastric cancer therapy. PMID- 26423400 TI - ZNRF3 contributes to the growth of lung carcinoma via inhibiting Wnt/beta-catenin pathway and is regulated by miR-93. AB - Lung carcinoma is the most common cancer with increasing morbidity, inefficient therapeutic modality, and poor prognosis, due to the lack of understanding of its related molecular mechanism. ZNRF3 is a newly identified negative regulator of Wnt signaling. In this study, we found that ZNRF3 level is reduced in lung carcinoma compared with normal lung tissue and its expression level is positively correlated with the survival of lung cancer patients. Restoration of ZNRF3 suppressed the proliferation and cell cycle progression of lung cancer cell lines. Suppression of ZNRF3 expression in normal lung cells increased the proliferation rates. In an animal model, ZNRF3 was shown to suppress the growth of lung cancer xenografts. ZNRF3 was shown to negatively regulate the activation of Wnt signaling in lung cancerous and normal cells. Further studies revealed that ZNRF3 is a target of miR-93, an oncogenic microRNA (miRNA) for lung cancer progression. Collectively, we found that miR-93/ZNRF3/Wnt/beta-catenin regulatory network contributes to the growth of lung carcinoma. Targeting this pathway may be a promising strategy for lung cancer therapy. PMID- 26423401 TI - PMS2 expression in epithelial ovarian cancer is posttranslationally regulated by Akt and essential for platinum-induced apoptosis. AB - Epithelial ovarian cancer (EOC) is the most lethal of the gynecologic malignancies, mainly due to the advanced stage at diagnosis and development of cisplatin resistance. The sensitivity of tumor cells to cisplatin is frequently affected by defect in DNA mismatch repair (MMR), which repairs mispaired DNA sequences and regulates DNA-damage-induced apoptosis. However, the role of postmeiotic segregation increased 2 (PMS2), a member of MMR protein family, in cisplatin resistance remains elusive. In the present study, we demonstrated the frequent deficiency of PMS2 and phosphorylation of Akt in EOC cell lines and tissues. Results of complex immunoprecipitation (co-IP) and protein stability assay indicated that activated Akt could directly bind to PMS2 and cause degradation of PMS2 in EOC cells. In addition, functional experiments revealed that PMS2 was required for cisplatin-induced apoptosis and cell cycle arrest in G2/M phase. These findings provide a novel insight into molecular mechanisms linking MMR with chemoresistance and suggest that stabilization of PMS2 expression may be useful in overcoming the cisplatin resistance in EOC. PMID- 26423402 TI - Harnessing the immunomodulatory effect of thermal and non-thermal ablative therapies for cancer treatment. AB - Minimally invasive interventional therapies are evolving rapidly and their use for the treatment of solid tumours is becoming more extensive. The in situ destruction of solid tumours by such therapies is thought to release antigens that can prime an antitumour immune response. In this review, we offer an overview of the current evidence for immune response activation associated with the utilisation of the main thermal and non-thermal ablation therapies currently in use today. This is followed by an assessment of the hypothesised mechanisms behind this immune response priming and by a discussion of potential methods of harnessing this specific response, which may subsequently be applicable in the treatment of cancer patients. References were identified through searches of PubMed/MEDLINE and Cochrane databases to identify peer-reviewed original articles, meta-analyses and reviews. Papers were searched from 1850 until October 2014. Articles were also identified through searches of the authors' files. Only papers published in English were reviewed. Thermal and non-thermal therapies have the potential to stimulate antitumour immunity although the current body of evidence is based mostly on murine trials or small-scale phase 1 human trials. The evidence for this immune-modulatory response is currently the strongest in relation to cryotherapy and radiotherapy, although data is accumulating for related ablative treatments such as high-intensity focused ultrasound, radiofrequency ablation and irreversible electroporation. This effect may be greatly enhanced by combining these therapies with other immunostimulatory interventions. Evidence is emerging into the immunomodulatory effect associated with thermal and non-thermal ablative therapies used in cancer treatment in addition to the mechanism behind this effect and how it may be harnessed for therapeutic use. A potential exists for treatment approaches that combine ablation of the primary tumour with control and possible eradication of persistent, locally recurrent and metastatic disease. However, more work is needed into each of these modalities, initially in further animal studies and then subsequently in large-scale prospective human studies. PMID- 26423404 TI - The clinical significance of systemic inflammation score in esophageal squamous cell carcinoma. AB - The objective of this study was to investigate the clinical significance of systemic inflammation score (SIS) and prognostic nutritional index (PNI) in esophageal squamous cell carcinoma (ESCC) patients who underwent esophagectomy. Records from 206 patients with histologically diagnosed ESCC who underwent esophagectomy at Qilu Hospital of Shandong University from January 2007 to December 2008 were retrospectively reviewed. The median disease-free survival (DFS) of this cohort was 32.3 months and 5-year DFS was 34.5 %. The median overall survival (OS) was 39.5 months and 5-year OS was 40.8 %. We found that high SIS was significantly associated with increased tumor length (p = 0.021), increased depth of invasion (p = 0.001), lymph node metastasis (p = 0.038), and advanced pathological stage (p = 0.004). Kaplan-Meier survival analysis revealed that both high SIS and low PNI were significantly associated with inferior DFS (for the SIS, p = 0.005; for the PNI, p = 0.003) and OS (for the SIS, p = 0.007; for the PNI, p = 0.002). In multivariate analysis, SIS was an independent prognostic indicator for both DFS and OS. However, PNI was not an independent prognosticator in multivariate analysis. SIS was a novel and promising inflammation-based prognostic score than PNI in ESCC patients who underwent esophagectomy. PMID- 26423405 TI - Tissue expression levels of miR-29b and miR-422a in children, adolescents, and young adults' age groups and their association with prediction of poor prognosis in human osteosarcoma. AB - Osteosarcoma is the most common type of bone cancer in children and adolescents. MicroRNAs (miRNAs) play important roles in the development, differentiation, and function of different cell types and in the pathogenesis of various human diseases. miRNAs are differentially expressed in normal and cancer cells. The investigation of miRNA expression between healthy subjects and patients with osteosarcoma is crucial for future clinical trials. In this study, the expression levels of miRNAs were detected by qRT-PCR. Correlation between expression levels of tow miRNAs and different clinicopathological characteristics were analyzed using the chi (2) test. Survival rate was detected using the log-rank test and Kaplan-Meier method. qRT-PCR was shown that expression levels of miR-29b and miR 422a were strongly decreased in osteosarcoma bone tissue compared with noncancerous bone tissues. Our result indicated that the low expression levels of miR-29b and miR-422a showed strong correlation with large tumor size (P = 0.20; 0.029), advanced TNM stage (P = 0.001; 0.012), distant metastasis (P = 0.008; 0.019), and grade of tumor (P = 0.009; 0.016). Kaplan-Meier survival analysis showed that the low expressions of miR-29b/miR-422a were correlated with shorter time overall survival (log-rank test, P = 0.009; P = 0.013). Moreover, multivariate Cox proportional hazards model indicated that miR-29b and miR-422a (P = 0.024; P = 0.016) were independent prognostic markers of overall survival of patients. Our result indicated that downregulation of miR-29b and miR-422a may be linked to the prediction of poor prognosis, indicating that miR-29b and miR-422a may be a valuable prognostic marker for osteosarcoma patients. PMID- 26423403 TI - The potential role of the NEK6, AURKA, AURKB, and PAK1 genes in adenomatous colorectal polyps and colorectal adenocarcinoma. AB - Colorectal adenomatous polyp (CRAP) is a major risk factor for the development of sporadic colorectal cancer (CRC). Histone modifications are one of the epigenetic mechanisms that may have key roles in the carcinogenesis of CRC. The objective of the present study is to investigate the alternations in the defined histone modification gene expression profiles in patients with CRAP and CRC. Histone modification enzyme key gene expressions of the CRC, CRAP, and control groups were evaluated and compared using the reverse transcription PCR (RT-PCR) array method. Gene expression analysis was performed in the CRAP group after dividing the patients into subgroups according to the polyp diameter, pathological results, and morphological parameters which are risk factors for developing CRC in patients with CRAP. PAK1, NEK6, AURKA, AURKB, HDAC1, and HDAC7 were significantly more overexpressed in CRC subjects compared to the controls (p < 0.05). PAK1, NEK6, AURKA, AURKB, and HDAC1 were significantly more overexpressed in the CRAP group compared to the controls (p < 0.005). There were no significant differences between the CRAP and CRC groups with regards to PAK1, NEK6, AURKA, or AURKB gene overexpression. PAK1, NEK6, AURKA, and AURKB were significantly in correlation with the polyp diameter as they were more overexpressed in polyps with larger diameters. In conclusion, overexpressions of NEK6, AURKA, AURKB, and PAK1 genes can be used as predictive markers to decide the colonoscopic surveillance intervals after the polypectomy procedure especially in polyps with larger diameters. PMID- 26423406 TI - Denosumab increases sublesional bone mass in osteoporotic individuals with recent spinal cord injury. AB - Osteoporosis is a frequent complication related to spinal cord injury (SCI), and data on osteoporosis treatment after SCI is scarce. Treatment with denosumab increases lumbar and femoral BMD and decreases bone turnover markers in individuals with recent SCI. This drug may be a promising therapeutic option in SCI-related osteoporosis. INTRODUCTION: Osteoporosis development is a frequent complication related to SCI, especially at the sublesional level. Nevertheless, data on osteoporosis treatment after SCI is scarce, particularly short term after injury, when the highest bone loss is produced. The aim of this study was to analyze the efficacy of denosumab in the treatment of SCI-related osteoporosis. METHODS: Fourteen individuals aged 39 +/- 15 years with osteoporosis secondary to recent SCI (mean injury duration 15 +/- 4 months) were treated with denosumab for 12 months. Bone turnover markers (BTMs) (PINP, bone ALP, sCTx), 25-hydroxyvitamin D (25OHD) levels and bone mineral density (BMD) at the lumbar spine (LS), total hip (TH), and femoral neck (FN) were assessed at baseline and at 12 months. All participants received calcium and vitamin D supplementation. RESULTS: At 12 months, SCI denosumab-treated participants showed a significant increase in BMD at TH (+2.4 +/- 3.6 %, p = 0.042), FN (+3 +/- 3.6 %, p = 0.006), and LS (+7.8 +/- 3.7 %, p < 0.001) compared to baseline values. Denosumab treatment was associated with significant decreases in BTMs (bone ALP -42 %, p < 0.001; PINP -58 %, p < 0.001, sCTx -57 %, p = 0.002) at 12 months. BMD evolution was not related to BTM changes or 25OHD serum levels. No skeletal fractures or serious adverse events were observed during follow-up. CONCLUSIONS: Treatment with denosumab increases lumbar and femoral BMD and decreases bone turnover markers in individuals with recent SCI. This drug may be a promising therapeutic option in SCI-related osteoporosis. PMID- 26423408 TI - Deep shaving and transanal disc excision in large endometriosis of mid and lower rectum: the Rouen technique. AB - BACKGROUND: Colorectal resection is performed in a majority of patients presenting with large endometriosis of mid and lower rectum; however, it may negatively and irreversibly impact postoperative rectal function. To avoid such unfavourable outcomes, we propose an original technique combining laparoscopic deep rectal shaving and transanal disc excision using a semi-circular stapler. METHODS: The video presents the procedure performed in a 29-year-old nullipara referred with a large endometriotic nodule infiltrating the lower rectum on more than 30 mm length. The first step is laparoscopic and involves deep rectal shaving performed using exclusively the plasma energy. Then, transanal excision of shaved area is performed, by placing traction parachute sutures in the middle and outside the shaved area. Their traction induces the prolapse of shaved area that is resected using a semicircular stapler. Insufflating the rectum with air checks the integrity of the staple line. RESULTS: Operative time was 210 min. Immediate postoperative outcomes were uneventful, and bowel movements were normal beginning with day 6. Our technique is suitable in large rectal nodules located up to 10 cm above the anus, infiltrating the rectum on up to 6 cm length, and these parameters are preoperatively assessed using MRI and computed tomography. To date, it was successfully carried out in 29 women with large deep endometriosis of the mid and lower rectum. Rectovaginal fistula was recorded in one patient (3.6 %) and transitory bladder dysfunction in seven patients (25 %). Digestive function assessment using standardized questionnaires revealed an overall improvement, without de novo anal continence troubles. Postoperative pregnancy rate was 78 % with a majority of patients having conceived spontaneously. CONCLUSIONS: Based on our experience, we believe that our conservative technique is feasible and reproducible in large mid and lower rectal endometriosis and might avoid the risk of unfavourable outcomes related to low colorectal resection. PMID- 26423407 TI - Risk of Cardiovascular Disease in an Aging HIV Population: Where Are We Now? AB - With more effective and widespread antiretroviral treatment, the overall incidence of AIDS- or HIV-related death has decreased dramatically. Consequently, as patients are aging, cardiovascular disease (CVD) has emerged as an important cause of morbidity and mortality in the HIV population. The incidence of CVD overall in HIV is relatively low, but it is approximately 1.5-2-fold higher than that seen in age-matched HIV-uninfected individuals. Multiple factors are believed to explain this excess in risk such as overrepresentation of traditional cardiovascular risk factors (particularly smoking), toxicities associated with cumulative exposure to some antiretroviral agents, together with persistent chronic inflammation, and immune activation associated with HIV infection. Tools are available to calculate an individual's predicted risk of CVD and should be incorporated in the regular follow-up of HIV-infected patients. Targeted interventions to reduce this risk must be recommended, including life-style changes and medical interventions that might include changes in antiretroviral therapy. PMID- 26423409 TI - Intraperitoneal onlay mesh reinforcement of the abdominal wall: a new surgical option for treatment of anterior cutaneous nerve entrapment syndrome-a retrospective cohort analysis of 30 consecutive patients. AB - BACKGROUND: The aim of the study was to introduce a new surgical treatment for anterior cutaneous nerve entrapment syndrome, a frequently unrecognised disorder in the general population responsible for chronic abdominal wall pain with limited treatment options to date. We hypothesised that intraperitoneal onlay mesh reinforcement could dissipate excessive increases in intra-abdominal pressure and prevent entrapment of the neurovascular bundle. METHODS: Retrospective cohort analysis was performed between September 2002 and March 2014. All consecutive patients diagnosed with anterior cutaneous nerve entrapment syndrome refractory to conservative treatment (n = 30) underwent laparoscopic intraperitoneal onlay mesh reinforcement of the painful area in the abdominal wall. Planned follow-up took place at 2, 6 and 12 weeks after surgery and at time of analysis (March 2015). Primary outcome was patients' satisfaction after treatment at short and long term (last follow-up) using a verbal rating score as measurement (1 = I am very satisfied; I never experience pain, 2 = I am satisfied; I occasionally experience some pain, 3 = I have improved but experience pain on a regular basis, 4 = I have had no result on this treatment, 5 = my pain is worse after treatment). Scores 1 and 2 were classified as success, and scores 4 and 5 as failure of the treatment. RESULTS: Thirty patients underwent laparoscopic intraperitoneal onlay mesh reinforcement. None were lost to follow-up (mean 54 +/- 44 months, range 12-122, median 38). Short- and long term success rates were 90 and 71 %, respectfully. CONCLUSIONS: Intraperitoneal onlay mesh reinforcement of the abdominal wall seems to be a promising option for the treatment of intractable anterior cutaneous nerve entrapment syndrome. PMID- 26423410 TI - Backflow prevention mechanism of laparoscopic Toupet fundoplication using high resolution manometry. AB - BACKGROUND: The use of multichannel intraluminal impedance pH (MII-pH) and high resolution manometry (HRM), which are new devices used to examine the esophageal function, has recently become common in Europe and the USA, thus garnering much attention. There have not been enough studies as of yet, however, on the esophageal motor function and the benefits of treatment after these devices have been used in laparoscopic fundoplication. OBJECTIVE: To use MII-pH and HRM to study the treatment effectiveness of laparoscopic fundoplication and consider a backflow prevention mechanism for laparoscopic Toupet fundoplication. MATERIALS AND METHODS: The study looked at 27 of a total of 60 patients undergoing laparoscopic fundoplication due to reasons of either gastroesophageal reflux disease or esophageal hiatal hernia between October 2012 and February 2014, who underwent a postsurgical HRM examination. Of these, 25 patients whose symptoms disappeared following surgery and who were not orally administered gastric secretion inhibitor (of whom nine were male, average age 55.9 +/- 14.9 years, and of whom 76 % underwent MII-pH) were taken as the subjects of the study. The postsurgical evaluation was conducted 3 months after the operation. RESULTS: Using HRM, although no change was noted in the lower esophageal sphincter pressure (LESP) (p = 0.943), an increase in lower esophageal sphincter pressure integral (p = 0.024) and extensions in both overall length and abdominal length were noted (both p < 0.001), while a significant improvement was noted in the lower esophageal sphincter (LES). Furthermore, the cases subjected to MII-pH demonstrated a reduced gastroesophageal reflux time, total number of liquid reflux episodes, and total number of reflux episodes (p < 0.001, p = 0.008, p = 0.009). CONCLUSIONS: Backflow prevention mechanism of laparoscopic Toupet fundoplication is thus considered to improve the overall LES function without elevating LESP. PMID- 26423411 TI - A single-centre experience of relaparoscopy in complications of laparoscopic inguinal hernia repair-feasibility and outcomes. AB - BACKGROUND: Management of complications of laparoscopic inguinal hernia repair remains challenging as well as debatable. Relaparoscopy in management of these complications is relatively newer concept. We tried to analyse the feasibility of relaparoscopy (transabdominal preperitoneal approach) in management of complications of laparoscopic inguinal hernia repair. MATERIALS AND METHODS: The study group included 61 patients (referral cases) from a prospectively maintained database of previous laparoscopic inguinal hernia surgery with majority of the patients of recurrence (n = 39). Other complications were mesh infections (n = 15), pubic osteitis (n = 3), migration of mesh into adjacent viscera (n = 3) and meralgia paresthetica (n = 1). All patients underwent transabdominal preperitoneal approach (TAPP) between January 2007 and December 2013. RESULTS AND OUTCOME: Most of the patients had previous TEP repair (n = 49) with variable complications detected in the range of 9 days to 38 months. Small-sized mesh (n = 12) and rolled up mesh (n = 10) were the causes of recurrence in 57 % cases. Mycobacterium tuberculosis (40 %) and mixed bacterial infections (33 %) strains were detected in the infected mesh. Pubic osteitis and meralgia paresthetica were tackers induced. All patients dealt with TAPP approach. Recurrent hernia cases underwent mesh placement and infected mesh was removed in mesh infection. Tackers were removed in cases of osteitis pubis and meralgia paraesthesia. Median operative time was 62 min (42-126 min) and hospital stay 3 days (2-13 days). The relaparoscopy was accomplished in 95.1 % of cases with no major intraoperative complications and minimal postoperative morbidity. CONCLUSION: Relaparoscopy through TAPP approach remains safe and feasible option to deal with primary laparoscopic hernia repair complications. Surgical techniques during primary laparoscopic repair are important cause for aforementioned complications. Though, surgical expertize remains warranted for relaparoscopy. PMID- 26423412 TI - Transanal Hartmann reversal: a new technique. AB - BACKGROUND: Hartmann procedure consists in a sigmoidectomy followed by a terminal colostomy. However, the stoma is associated with complications and suboptimal quality of life, so the restoration of colonic continuity should be, at least, considered in any case. Open restoration has been associated with significant morbidity and mortality; therefore, many authors have described the advantages of laparoscopic Hartmann reversal. We want to go a step further showing our experience using a combined laparoscopic and transanal approach in an attempt to improve the surgical technique. METHODS: Patients with an end colostomy due to an emergency Hartmann procedure are selected for this intervention. This approach is performed simultaneously laparoscopically and transanally, with single-port devices, through the colostomy wound in the first case and trough anal canal in the second one. The previous stapler line is resected transanally and the proximal rectum and mesorectum are dissected until the peritoneal reflexion, where both teams work together to complete the adhesiolysis. Finally an end-to end anastomosis is performed under laparoscopic control. RESULTS: As in patients with rectal cancer, dissection of the stump in Hartmann reversal procedure may be better and associated with shorter operative time. CONCLUSIONS: As with any new surgical procedure, it is probably too early to draw conclusions, but nowadays transanal combined with laparoscopic approach seems to be a safe and feasible technique to perform a Hartmann reversal. PMID- 26423414 TI - The use of endoluminal vacuum (E-Vac) therapy in the management of upper gastrointestinal leaks and perforations. AB - INTRODUCTION: Upper intestinal leaks and perforations are associated with high morbidity and mortality rates. Despite the growing experience using endoscopically placed stents, the treatment of these leaks and perforations remain a challenge. Endoluminal vacuum (E-Vac) therapy is a novel treatment that has been successfully used in Germany to treat upper gastrointestinal leaks and perforations. There currently are no reports on its use in the USA. METHODS: E Vac therapy was used to treat 11 patients with upper gastrointestinal leaks and perforations from September 2013 to September 2014. Five patients with leaks following sleeve gastrectomy were excluded from this study. A total of six patients were treated with E-Vac therapy; these included: (n = 2) iatrogenic esophageal perforations, (n = 1) iatrogenic esophageal and gastric perforations, (n = 1) iatrogenic gastric perforation, (n = 1) gastric staple line leak following a surgical repair of a traumatic gastric perforation, and (n = 1) esophageal perforation due to an invasive fungal infection. Four patients had failed an initial surgical repair prior to starting E-Vac therapy. RESULTS: All six patients (100 %) had complete closure of their perforation or leak after an average of 35.8 days of E-Vac therapy requiring 7.2 different E-Vac changes. No deaths occurred in the 30 days following E-Vac therapy. One patient died following complete closure of his perforation and transfer to an acute care facility due to an unrelated complication. There were no complications directly related to the use of E-Vac therapy. Only one patient had any symptoms of dysphagia. This patient had severe dysphagia from an esophagogastric anastomotic stricture prior to her iatrogenic perforations. Following E-Vac therapy, her dysphagia had actually improved and she could now tolerate a soft diet. CONCLUSIONS: E-Vac therapy is a promising new method in the treatment of upper gastrointestinal leaks and perforations. Current successes need to be validated through future prospective controlled studies. PMID- 26423413 TI - Outcomes of endoscopic treatment of second recurrences of large nonpedunculated colorectal adenomas. AB - BACKGROUND AND AIMS: Piecemeal endoscopic mucosal resection (EMR) of large nonpedunculated colorectal adenomas is associated with significant recurrence rates. After salvage endoscopic treatment of recurrences, there is a significant rate of second recurrences. There is a paucity of data on the efficacy and safety of continued endoscopic treatment after a second recurrence. METHODS: Consecutive patients with recurrent adenomas after initial piecemeal EMR of nonpedunculated colorectal adenomas >2 cm were reviewed. We assessed the feasibility, safety and efficacy of continued endoscopic treatment in these patients. RESULTS: Sixty-four patients with 70 recurrent lesions were identified. All were retreated endoscopically. Follow-up colonoscopy (mean interval 6.4 months) was performed on 62/70 lesions (89 %), and a second recurrence was found in 21/62 (34 %). One patient underwent surgery for a circumferential adenoma of the ileocecal valve. The other 20 lesions were treated endoscopically. Follow-up colonoscopy was performed on 15/20 (75 %) and demonstrated a third recurrence in 3/15 (20 %). One was a deep T1 cancer; curative surgery was performed. The other two patients each had one additional endoscopic treatment and both had no recurrence on subsequent colonoscopy. There were two complications: Both were delayed bleeds after treatment of the first recurrence. A mean of 1.3 endoscopic procedures was required to achieve a cure (range 1-3) for recurrent adenomas after piecemeal EMR. CONCLUSION: Endoscopic treatment of patients with second recurrences is safe and effective, but is associated with a significant rate of additional recurrences. Continued endoscopic treatment of patients with multiple recurrences is associated with high cure rates, low complication rates and a low risk of progression to malignancy. PMID- 26423415 TI - Learning curve analysis of colorectal endoscopic submucosal dissection (ESD) for laterally spreading tumors by endoscopists experienced in gastric ESD. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) for various colorectal neoplasms is more technically difficult than gastric ESD. We evaluated treatment outcomes and the learning curve for colorectal ESD of laterally spreading tumors (LSTs) based on the experience of a single endoscopist. METHODS: We included 93 colorectal ESD procedures for colorectal LST that were performed between March 2009 and June 2012 by a single experienced endoscopist who previously performed hundreds of cases of gastric ESD. The cases were grouped chronologically into three periods by multi-dimensional analyses. For procedure time, the learning curve was analyzed using the moving average method, and for complication, the learning curve was analyzed using cumulative sum (cusum) method. RESULTS: The median procedure time for 93 colorectal ESD was 45 min, and the rates of en bloc resection and R0 resection were 89.25 and 83.87 %. When results were compared among three periods in order to determine the learning curve, the procedure time and en bloc resection rates were not significantly different. However, the procedure proficiency (about 0.16 cm(2)/min) was significantly faster during the second period, after about 25 cases of colorectal ESD. In the third period (about 50 cases), the number and rate of en bloc resection (over 90 %) reached the same as that of en bloc R0 resection. When comparing outcomes based on LST subtype, the procedure proficiency of LST-granular type (LST-G) was significantly faster than that of LST-non granular type (LST-NG) (LST-NG, 0.072 cm(2)/min; LST-G, 0.157 cm(2)/min; p = 0.01). CONCLUSION: Endoscopists fully experienced in gastric ESD need a relatively short learning period for colorectal ESD in terms of procedure time and complication. However, approximately 50 cases might be needed to acquire an adequate skill of colorectal ESD for LST in an experienced gastric ESD endoscopist. Colorectal ESD for LST-NG seems to have higher technical difficulty and a longer learning curve than LST-G. PMID- 26423416 TI - Risk factors for under-diagnosis of gastric intraepithelial neoplasia and early gastric carcinoma in endoscopic forceps biopsy in comparison with endoscopic submucosal dissection in Chinese patients. AB - Differences in pathologic diagnosis between endoscopic forceps biopsy (EFB) and endoscopic submucosal dissection (ESD) for gastric intraepithelial neoplasia (GIN) and early gastric carcinoma (EGC) in Chinese patients remain unknown. The aim of the study was to investigate risk factors for under-diagnosed pathology in initial EFB, compared to final ESD. We reviewed endoscopic and histopathologic findings for tumor location, size, macroscopic pattern, nodularity, erythema, erosion, GIN (low and high grade), and EGC diagnosed with the WHO criteria. Differences in those features between EFB and ESD were compared and risk factors for under-diagnosis by EFB were analyzed. Although concordant in most (74.9 %) cases between EFBs and ESDs, pathological diagnoses in 57 (25.1 %) cases were upgraded in ESDs. Compared to the concordant group, the lesion size >=2 cm, and depressed and excavated patterns were significantly more frequent in the upgraded group. Further multivariate regression analysis demonstrated the depressed pattern and lesion size >=2 cm as independent risk factors for upgraded pathology with the odds ratio of 5.778 (95 % confidence interval 2.893-11.542) and 2.535 (95 % confidence interval 1.257-5.111), respectively. Lesion size >=2.0 cm and the depressed pattern at initial EFB were independent risk factors for pathologic upgrade to advanced diseases in ESD. Therefore, these endoscopic characteristics should be considered together with the initial EFB diagnosis to guide the optimal clinical management of patients with GIN and EGC. PMID- 26423417 TI - Thoracoscopic management of volvulus of the gastric conduit following minimally invasive Ivor-Lewis esophagectomy. AB - BACKGROUND: We present a case of emergent thoracoscopic management of volvulus of the gastric conduit following minimally invasive Ivor-Lewis esophagectomy. The patient is a 69-year-old Caucasian male with a history of adenocarcinoma of the lower third of the esophagus. Initial presentation was dysphagia with solid foods, which progressed in severity until he was unable to swallow anything. EUS demonstrated a partially obstructing mass at 33 cm; biopsy revealed poorly differentiated adenocarcinoma, stage T3N2Mx. PET scan did not reveal any metastatic disease. Preoperative management included neo-adjuvant chemoradiation therapy (5-FU and cisplatin) and early placement of a jejunal feeding tube. Intra operative leak test was performed as a matter of routine following completion of the esophagogastric anastomosis. A nasogastric tube was placed intra-operatively and removed on POD2 according to our standard pathway. Postoperatively, the patient progressed without difficulty to POD4, when we routinely obtain an upper GI swallow study. This demonstrated a lack of transit of contrast through the distal neo-esophagus. Follow-up endoscopy revealed volvulus of the gastric conduit with obliteration of the lumen. METHOD: We immediately took the patient to the OR for thoracoscopic detorsion, which we accomplished successfully by entering the existing trochar sites and using blunt dissection.?Upon entering the thoracic cavity, the staple line that had been oriented anteriorly was now posterior. Attachments were gently teased away from the chest wall and the conduit was detorsed and anchored to the chest wall in the correct orientation with silk suture. Intra-operative endoscopy demonstrated a patent conduit. RESULTS: Postoperative upper GI fluoroscopy now showed good transit of contrast. The patient continued to improve and was eventually advanced to mechanical soft diet and discharged on postoperative day 9. CONCLUSIONS: Early intervention is indicated in cases of volvulus of the gastric conduit following Ivor-Lewis esophagectomy. PMID- 26423376 TI - Comparative effectiveness of immediate antiretroviral therapy versus CD4-based initiation in HIV-positive individuals in high-income countries: observational cohort study. AB - BACKGROUND: Recommendations have differed nationally and internationally with respect to the best time to start antiretroviral therapy (ART). We compared effectiveness of three strategies for initiation of ART in high-income countries for HIV-positive individuals who do not have AIDS: immediate initiation, initiation at a CD4 count less than 500 cells per MUL, and initiation at a CD4 count less than 350 cells per MUL. METHODS: We used data from the HIV-CAUSAL Collaboration of cohort studies in Europe and the USA. We included 55,826 individuals aged 18 years or older who were diagnosed with HIV-1 infection between January, 2000, and September, 2013, had not started ART, did not have AIDS, and had CD4 count and HIV-RNA viral load measurements within 6 months of HIV diagnosis. We estimated relative risks of death and of death or AIDS-defining illness, mean survival time, the proportion of individuals in need of ART, and the proportion of individuals with HIV-RNA viral load less than 50 copies per mL, as would have been recorded under each ART initiation strategy after 7 years of HIV diagnosis. We used the parametric g-formula to adjust for baseline and time varying confounders. FINDINGS: Median CD4 count at diagnosis of HIV infection was 376 cells per MUL (IQR 222-551). Compared with immediate initiation, the estimated relative risk of death was 1.02 (95% CI 1.01-1.02) when ART was started at a CD4 count less than 500 cells per MUL, and 1.06 (1.04-1.08) with initiation at a CD4 count less than 350 cells per MUL. Corresponding estimates for death or AIDS-defining illness were 1.06 (1.06-1.07) and 1.20 (1.17-1.23), respectively. Compared with immediate initiation, the mean survival time at 7 years with a strategy of initiation at a CD4 count less than 500 cells per MUL was 2 days shorter (95% CI 1-2) and at a CD4 count less than 350 cells per MUL was 5 days shorter (4-6). 7 years after diagnosis of HIV, 100%, 98.7% (95% CI 98.6-98.7), and 92.6% (92.2-92.9) of individuals would have been in need of ART with immediate initiation, initiation at a CD4 count less than 500 cells per MUL, and initiation at a CD4 count less than 350 cells per MUL, respectively. Corresponding proportions of individuals with HIV-RNA viral load less than 50 copies per mL at 7 years were 87.3% (87.3-88.6), 87.4% (87.4-88.6), and 83.8% (83.6-84.9). INTERPRETATION: The benefits of immediate initiation of ART, such as prolonged survival and AIDS-free survival and increased virological suppression, were small in this high-income setting with relatively low CD4 count at HIV diagnosis. The estimated beneficial effect on AIDS is less than in recently reported randomised trials. Increasing rates of HIV testing might be as important as a policy of early initiation of ART. FUNDING: National Institutes of Health. PMID- 26423418 TI - Minimally invasive approaches to resection of benign/low-grade gastric tumors. AB - BACKGROUND: Tumors in the stomach have traditionally been treated with either subtotal gastrectomy or total gastrectomy, depending on the location. However, many of these lesions are benign spindle cell tumors or adenomas and could be resected with margins. Here, we explore multiple minimally invasive methods for the resection of these tumors. We highlight a wedge resection, a circumferential resection with transverse closure, a transgastric resection, and an endoscopic/laparoscopic submucosal resection. The wedge resection was performed in a 71-year-old man found to have a mass in the stomach on screening upper endoscopy. The biopsy was not definitive, but on CT scan there was a 4.5-cm submucosal mass consistent with a gastrointestinal stromal tumor. The circumferential resection was performed for an 83-year-old woman who had abdominal discomfort which led to an upper endoscopy. She was found to have a mass in the lesser curve of her stomach. Biopsy revealed this to be a gastrointestinal stromal tumor. Ultimately, it was removed when serial CT scans showed that it was growing. The transgastric approach was used for a 75-year-old man who had upper endoscopy for reflux symptoms and was found to have a mass in the stomach. Biopsy showed that it was a gastrointestinal stromal tumor. Due to patient preference, it was initially observed but was eventually removed when it was found to be growing on serial CT scans. The endoscopic/laparoscopic approach was for a 65-year-old man who had an upper endoscopy performed for work-up of melena and was found to have a 5-cm mass at the gastroesophageal junction. The biopsy showed this to be an adenoma, and he went on to have it removed. METHODS: We identified representative videos from patients treated with each of the above techniques. Small exophytic lesions can be completely excised with a wedge resection using a stapler to fire across the base of the lesion. By contrast, if the lesion is in an awkward location or is too large to remove in this way, a vessel-sealing device can divide the mass from the stomach circumferentially (intragastric resection). The resultant defect in the gastric wall must be repaired transversely to avoid narrowing the lumen. Endophytic lesions can be treated with transgastric resection. Ports are placed directly into the stomach allowing excision from within the stomach. Finally, submucosal resection is ideal for lesions close to the GE junction. This combined endoscopic and laparoscopic approach allows the tumor to be lifted off the muscle fibers and to be resected without transmural injury to the stomach or esophagus. RESULTS: All four patients tolerated the procedure well and were discharged home by postoperative day 2. There were no complications. One patient, the one who underwent the endoscopic/laparoscopic approach and was preoperatively found to have an adenoma on biopsy, was ultimately found to have an invasive component and later underwent total gastrectomy. The other three patients all had gastrointestinal stromal tumors. CONCLUSIONS: Minimally invasive techniques should be considered more frequently for the management of benign gastric tumors. The four methods illustrated here can be used safely and result in faster recovery as well as shorter hospital stays compared to traditional approaches. PMID- 26423421 TI - A Sociological Perspective. PMID- 26423420 TI - Peer interviewing in medical education research: experiences and perceptions of student interviewers and interviewees. AB - BACKGROUND: Interviewing is one of the main methods used for data collection in qualitative research. This paper explores the use of semi-structured interviews that were conducted by students with other students in a research study looking at cultural diversity in an international medical school. Specifically this paper documents and gives 'voice' to the opinions and experiences of interviewees and interviewers (the peers and the communities) on the value of peer interviewing in the study and outlines (1) the preparation made to address some of the foreseen challenges, (2) the challenges still faced, and (3) the benefits of using peer interviews with respect to the research study, the individual and the institution. METHODS: Peer interviewing was used as part of a two-year phased study, 2012-2013, which explored and then measured the impact of cultural diversity on undergraduate students in a medical higher education institution in Ireland. In phase one 16 peer interviewers were recruited to conduct 29 semi structured interviews with fellow students. In order to evaluate the peer interviewing process two focus group discussions were he ld and an online survey conducted. RESULTS: Key findings were that substantial preparations in relation to training, informed consent processes and addressing positionality are needed if peer-interviewing is to be used. Challenges still faced included were related to power, familiarity, trust and practical problems. However many benefits accrued to the research, the individual interviewer and to the university. CONCLUSIONS: A more nuanced approach to peer interviewing, that recognises commonalities and differences across a range of attributes, is needed. While peer interviewing has many benefits and can help reduce power differentials it does not eliminate all challenges. As part of a larger research project and as a way in which to get 'buy-in' from the student body and improve a collaborative research partnership peer interviewing was extremely useful. PMID- 26423419 TI - Sports Injury Surveillance Systems: A Review of Methods and Data Quality. AB - BACKGROUND AND AIMS: Data from sports injury surveillance systems are a prerequisite to the development and evaluation of injury prevention strategies. This review aimed to identify ongoing sports injury surveillance systems and determine whether there are gaps in our understanding of injuries in certain sport settings. A secondary aim was to determine which of the included surveillance systems have evaluated the quality of their data, a key factor in determining their usefulness. METHODS: A systematic search was carried out to identify (1) publications presenting methodological details of sports injury surveillance systems within clubs and organisations; and (2) publications describing quality evaluations and the quality of data from these systems. Data extracted included methodological details of the surveillance systems, methods used to evaluate data quality, and results of these evaluations. RESULTS: Following literature search and review, a total of 15 sports injury surveillance systems were identified. Data relevant to each aim were summarised descriptively. Most systems were found to exist within professional and elite sports. Publications concerning data quality were identified for seven (47%) systems. Validation of system data through comparison with alternate sources has been undertaken for only four systems (27%). CONCLUSIONS: This review identified a shortage of ongoing injury surveillance data from amateur and community sport settings and limited information about the quality of data in professional and elite settings. More surveillance systems are needed across a range of sport settings, as are standards for data quality reporting. These efforts will enable better monitoring of sports injury trends and the development of sports safety strategies. PMID- 26423422 TI - Late administration of murine CTLA-4 blockade prolongs CD8-mediated anti-tumor effects following stimulatory cancer immunotherapy. AB - We have demonstrated that immunostimulatory therapies such as interleukin-2 (IL 2) and anti-CD40 (alphaCD40) can be combined to deliver synergistic anti-tumor effects. While this strategy has shown success, efficacy varies depending on a number of factors including tumor type and severe toxicities can be seen. We sought to determine whether blockade of negative regulators such as cytotoxic T lymphocyte antigen-4 (CTLA-4) could simultaneously prolong CD8(+) T cell responses and augment T cell anti-tumor effects. We devised a regimen in which anti-CTLA-4 was administered late so as to delay contraction and minimize toxicities. This late administration both enhanced and prolonged CD8 T cell activation without the need for additional IL-2. The quality of the T cell response was improved with increased frequency of effector/effector memory phenotype cells along with improved lytic ability and bystander expansion. This enhanced CD8 response translated to improved anti-tumor responses both at the primary and metastatic sites. Importantly, toxicities were not exacerbated with combination. This study provides a platform for rational design of immunotherapy combinations to maximize anti-tumor immunity while minimizing toxicities. PMID- 26423423 TI - Downstream mediators of the intratumoral interferon response suppress antitumor immunity, induce gemcitabine resistance and associate with poor survival in human pancreatic cancer. AB - The cancer microenvironment allows tumor cells to evade immune surveillance through a variety of mechanisms. While interferon-gamma (IFNgamma) is central to effective antitumor immunity, its effects on the microenvironment are not as clear and have in some cancers been shown to induce immune checkpoint ligands. The heterogeneity of these responses to IFNgamma remains poorly characterized in desmoplastic malignancies with minimal inflammatory cell infiltration, such as pancreatic cancer (PC). Thus, the IFNgamma response within and on key cells of the PC microenvironment was evaluated. IFNgamma induced expression of human leukocyte antigen (HLA) class I and II on PC cell lines, primary pancreatic cancer epithelial cells (PPCE) and patient-derived tumor-associated stroma, concomitant with an upregulation of PDL1 in the absence of CD80 and CD86 expression. As expected, IFNgamma also induced high levels of CXCL10 from all cell types. In addition, significantly higher levels of CXCL10 were observed in PC specimens compared to those from chronic pancreatitis, whereby intratumoral CXCL10 concentration was an independent predictor of poor survival. Immunohistochemical analysis revealed a subset of CXCR3-positive cancer cells in over 90 % of PC specimens, as well as on a subset of cultured PC cell lines and PPCE, whereby exposure to CXCL10 induced resistance to the chemotherapeutic gemcitabine. These findings suggest that IFNgamma has multiple effects on many cell types within the PC microenvironment that may lead to immune evasion, chemoresistance and shortened survival. PMID- 26423424 TI - A retrospective study of the incidence, clinical characteristics, identification, and antimicrobial susceptibility of bacteremic isolates of Acinetobacter ursingii. AB - BACKGROUND: Acinetobacter ursingii bacteremia is rarely reported. We investigated the incidence and clinical features of A. ursingii bacteremia, performance of the identification system, and antimicrobial susceptibility of the isolates. Acinetobacter ursingii bacteremia patients were compared with A. baumannii bacteremia patients. METHODS: In this 9-year retrospective study, A. ursingii was identified using 16S rRNA and 16S-23S rRNA internal transcribed spacer sequence analysis. The performances of the Vitek 2, Phoenix, and matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometer systems for identifying isolates were tested. Pulsed-field gel electrophoresis (PFGE) was used to determine the clonality of the isolates. The minimal inhibitory concentrations of the antimicrobials were determined using the Vitek 2 system. RESULTS: Nineteen patients were identified. Acinetobacter ursingii was noted in 1.5-5.2 % of all Acinetobacter bacteremia cases. For the PFGE analysis, two isolates had smeared DNA, two had 93 % similarity, and 15 had similarity <80 %. Among 16 patients with complete medical records, 10 (62.5 %) had no identifiable source of A. ursingii bacteremia. Most patients (n = 12) had underlying malignant disease. Patients with A. ursingii bacteremia had lower Acute Physiology and Chronic Health Evaluation II scores than those with A. baumannii bacteremia (median [interquartile range], 17.1 [10.0-24.7] vs. 24.9 [14.6-35.1]). Patients with A. ursingii bacteremia were also less likely admitted to the intensive care unit than patients with A. baumannii bacteremia (18.8 % vs 63.5 %, p value < 0.01). About half of the patients with A. ursingii (50.8 %) and A. baumannii bacteremia (62.5 %) had received inappropriate antimicrobial therapy within 48 h after bacteremia onset. However, patients with A. ursingii bacteremia had significantly lower 14-day (6.25 % vs 29.8 %, p value = 0.04) and 28-day mortality rates (6.25 % vs 37.3 %, p value = 0.02) than patients with A. baumannii bacteremia. Nine isolates (47.4 %) were correctly identified as A. ursingii and the other 10 isolates (52.6 %) were incorrectly identified as A. lwoffii by the Vitek 2 system. The Phoenix system incorrectly identified all 19 isolates. The MALDI-TOF mass spectrometer system correctly identified all 19 isolates. All the A. ursingii isolates were resistant or showed intermediate susceptibility to ceftriaxone and ceftazidime, but were susceptible to levofloxacin and imipenem. CONCLUSIONS: Acinetobacter ursingii is a rare pathogen that mostly caused primary bacteremia in patients with malignancies. Patients with A. ursingii bacteremia had significantly lower disease severity and mortality rates than patients with A. baumannii bacteremia. PMID- 26423425 TI - Effect of resistance training with different frequencies and detraining on muscular strength and oxidative stress biomarkers in older women. AB - The aim of this study was to compare the effect of resistance training (RT) performed with different frequencies followed by a detraining period on muscular strength and oxidative stress (OS) biomarkers in older women. Twenty-seven physically independent women (68.8 +/- 4.8 years, 69.1 +/- 14.3 kg, 156.0 +/- 6.5 cm, and 28.3 +/- 4.9 to kg.m(-2)) were randomly assigned to perform a RT program for 2 or 3 days per week (G2X = 13 vs. G3X = 14) for 12 weeks followed by 12 weeks of detraining period. One repetition maximum (1RM) tests were used as measures of muscular strength (three exercises, three attempts for each exercise, 3-5 min of rest between attempts, and 5 min of rest between exercises). Advanced oxidized protein products (AOPP) and total radical-trapping antioxidant parameter (TRAP) were used as oxidative stress indicators. Both groups increased muscular strength after 12 weeks of training (P < 0.05) in chest press (G2X = +11.9 % vs. G3X = +27.5 %, P < 0.05), knee extension (G2X = +18.4 % vs. G3X = +16.7 %, P > 0.05), and preacher curl (G2X = +37.6 % vs. G3X = +36.7 %, P > 0.05). On the other hand, 12 weeks of detraining were not sufficient to eliminate the major effects produced by RT on muscular strength, although a significant decrease (P < 0.05) has been observed for chest press (G3X = -9.1 % vs. G2X = -10.2 %, P > 0.05), knee extension (G2X = -14.9 % vs. G3X = -12.1 %, P > 0.05), and preacher curl (G2X = -20.5 % vs. G3X = -17.4 %, P > 0.05). Pre- to post-training, both groups showed significant (P < 0.05) increases in TRAP (G2X = +6.9 % vs. G3X = +15.1 %) with no statistical significant difference between the groups (P > 0.05), and the scores remained elevated compared to pre-training after 12 weeks of detraining. AOPP was not changed by RT or detraining (P > 0.05). The results suggest that a 12-week RT program with a frequency of 2 days per week may be sufficient to improve muscular strength and OS in older women and detraining for 12 weeks does not completely reverse the changes induced by RT. PMID- 26423426 TI - Clinical and serologic features of primary Sjogren's syndrome concomitant with autoimmune hemolytic anemia: a large-scale cross-sectional study. AB - Autoimmune hemolytic anemia (AIHA) is an uncommon but clinically significant disorder in primary Sjogren's syndrome (pSS). Among 565 pSS patients hospitalized in Peking University People's Hospital from January 2000 to March 2013, 16 patients were diagnosed with AIHA (2.8% prevalence). AIHA presented at the onset of pSS without overt sicca symptoms in 3 of the 16 patients. Primary biliary cirrhosis (PBC) was more prevalent in the patients with SS-AIHA than in those without (p = 0.007). Edema, fever, and liver involvement occurred significantly more frequently in pSS patients with AIHA than those without AIHA (p = 0.035, p = 0.029, p = 0.024, respectively). The pSS patients with AIHA were more vulnerable to leukopenia and thrombocytopenia than those without AIHA (p = 0.004 and p = 0.001, respectively). Additionally, the levels of complement component 3 (C3) and complement component 4 (C4) were significantly lower in the SS-AIHA group (p = 0.008 and p = 0.037, respectively). Taken together, our results indicate that pSS should be considered in the differential diagnosis of AIHA, even in the absence of sicca symptoms. Among pSS patients, the existence of PBC, cytopenia, or hypocomplementemia suggests a higher risk of suffering from AIHA. PMID- 26423427 TI - Resveratrol prevents renal lipotoxicity in high-fat diet-treated mouse model through regulating PPAR-alpha pathway. AB - Resveratrol (RSV) has beneficial effects on renal diseases, but its underlying mechanisms are still unclear. In the present study, we investigate the renoprotective effects of RSV on obesity-related renal diseases and clarify the potential mechanisms. Male C57BL/6J mice were fed with high-fat diet (HFD) with or without 400 mg/kg RSV treatment for 12 weeks. Feeding HFD induced renal injuries, but treating them with RSV significantly decreased glomerular volume (p < 0.05), glycogen (p < 0.01) and collagen (p < 0.05) in renal tissues. Although slightly changed body weight and fasting blood glucose, RSV attenuated renal dysfunction, including decreased levels of blood urea nitrogen (p < 0.05), urea protein (p < 0.01), and microalbuminuria (p < 0.01). Furthermore, RSV treatment markedly reduced gene expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and inducible nitric oxide synthase (iNOS) (all p < 0.05), 4 Hydroxynonenal expression (p < 0.01), and lipid accumulation. Mechanistically, RSV enhanced the expression of lipolytic genes, peroxisome proliferator-activated receptor (PPAR)-alpha (p < 0.001), carnitine palmitoyltransferase (CPT)-1 (p < 0.05), and medium-chain acyl-coenzyme A dehydrogenase (MCAD) (p < 0.01), but had no effect on lipogenic genes, PPAR-gamma and sterol regulatory element-binding protein (SREBP)-1c. RSV also obviously increased renal PPAR-alpha protein expression (p < 0.001) and the phosphorylation of AMPK level. Collectively, these results support the therapeutic effects of RSV on high-fat diet-induced renal damages at least partially through targeting on PPAR-alpha signaling pathway. PMID- 26423428 TI - A call for new attitudes on infection, vaccination, and childhood stroke. PMID- 26423429 TI - Migraine and cryptogenic stroke: The clot thickens. PMID- 26423430 TI - Delivery of epilepsy care to adults with intellectual and developmental disabilities. AB - Epilepsy is common in people with intellectual and developmental disabilities (IDD). In adulthood, patients with IDD and epilepsy (IDD-E) have neurologic, psychiatric, medical, and social challenges compounded by fragmented and limited care. With increasing neurologic disability, there is a higher frequency of epilepsy, especially symptomatic generalized and treatment-resistant epilepsies. The causes of IDD-E are increasingly recognized to be genetic based on chromosomal microarray analysis to identify copy number variants, gene panels (epilepsy, autism spectrum disorder, intellectual disability), and whole-exome sequencing. A specific genetic diagnosis may guide care by pointing to comorbid disorders and best therapy. Therapy to control seizures should be individualized, with drug selection based on seizure types, epilepsy syndrome, concomitant medications, and comorbid disorders. There are limited comparative antiepileptic drug data in the IDD-E population. Vagus nerve and responsive neural stimulation therapies and resective surgery should be considered. Among the many comorbid disorders that affect patients with IDD-E, psychiatric and sleep disorders are common but often unrecognized and typically not treated. Transition from holistic and coordinated pediatric to adult care is often a vulnerable period. Communication among adult health care providers is complex but essential to ensure best care when these patients are seen in outpatient, emergency room, and inpatient settings. We propose specific recommendations for minimum care standards for people with IDD-E. PMID- 26423431 TI - Age-specific association of migraine with cryptogenic TIA and stroke: Population based study. AB - OBJECTIVE: To determine whether there is an association between previous migraine and cryptogenic TIA or ischemic stroke at older ages. METHODS: We determined the age-specific associations of history of migraine and Trial of Org 10172 in Acute Stroke Treatment (TOAST) subtype of TIA and ischemic stroke in a population-based cohort study (Oxford Vascular Study; 2002-2012). RESULTS: Among 1,810 eligible patients with TIA or ischemic stroke, 668 (36.9%) had cryptogenic events, of whom 187 (28.0%) had previous migraine. Migraine was more commonly associated with cryptogenic events than with those of known etiology (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.38-2.16, p < 0.0001; cardioembolic 2.00, 1.50-2.66, p < 0.0001; large artery 1.75, 1.20-2.53, p = 0.003; small vessel 1.32, 0.95-1.83, p = 0.096). The association of migraine with cryptogenic events was independent of age, sex, and all measured vascular risk factors (RFs) (adjusted OR 1.68, 1.33 2.13, p < 0.0001) and was strongest at older ages (<55 years, OR 1.11, 0.55-2.23; 55-64 years, 1.48, 0.83-2.63; >=65 years, 1.81, 1.39-2.36) and in patients without vascular RFs (0 RFs OR 2.62, 1.33-5.15; 1 RF 2.01, 1.35-3.01; 2 RFs 1.80, 1.21-2.68; 3 RFs 1.21, 0.71-2.07; 4 RFs 0.92, 0.28-2.99). Results were consistent for migraine with or without aura and for analyses excluding TIA or stratified by sex or vascular territory of event. CONCLUSIONS: In this population-based study of stroke etiology stratified by age, migraine was most strongly associated with cryptogenic TIA and ischemic stroke, particularly at older ages, suggesting a causal role or a shared etiology. PMID- 26423432 TI - Structural MRI substrates of cognitive impairment in neuromyelitis optica. AB - OBJECTIVE: To identify the clinical and structural MRI markers for predicting cognitive impairment (CI) in patients with neuromyelitis optica (NMO). METHODS: Fifty-four patients with NMO and 27 healthy controls underwent extensive neuropsychological testing and multimodal 3.0T MRI. The patient group was classified as CI or cognitively preserved (CP), using a criterion of <=1.5 SD on at least 2 cognitive domains. MRI measurements included white matter (WM) lesion volume, gray matter (GM), WM, and deep GM (DGM) volume, cortical thickness, and the severity and extent of WM tract diffusion metric alterations based on fractional anisotropy and mean, axial, and radial diffusivity. Groups were compared using a multivariate general linear model, and clinical and MRI measurements were related to average cognition z scores by partial correlations and a stepwise linear regression model. RESULTS: Twenty-six patients with NMO (48.2%) were classified as CI and showed WM tract diffusion abnormalities, particularly increased radial diffusivity, and GM especially DGM atrophy compared with healthy controls. Patients classified as CP also showed alterations of WM tract diffusion but without significant GM atrophy. Compared with the CP group, patients with CI demonstrated a lower level of education and decreased hippocampal volume. In the whole patient group, average cognition z scores were best predicted by the level of education and hippocampal volume (R(2) = 0.46, p < 0.001). CONCLUSION: In patients with NMO, WM tract integrity disruption was identified in both CP and CI groups. GM atrophy, particularly in the DGM, was only found in the CI group. Hippocampal volume is the main MRI predictor of cognition in NMO. PMID- 26423433 TI - Comment: Improving the care of people with epilepsy and intellectual disabilities. PMID- 26423435 TI - Artificial fish skin of self-powered micro-electromechanical systems hair cells for sensing hydrodynamic flow phenomena. AB - Using biological sensors, aquatic animals like fishes are capable of performing impressive behaviours such as super-manoeuvrability, hydrodynamic flow 'vision' and object localization with a success unmatched by human-engineered technologies. Inspired by the multiple functionalities of the ubiquitous lateral line sensors of fishes, we developed flexible and surface-mountable arrays of micro-electromechanical systems (MEMS) artificial hair cell flow sensors. This paper reports the development of the MEMS artificial versions of superficial and canal neuromasts and experimental characterization of their unique flow-sensing roles. Our MEMS flow sensors feature a stereolithographically fabricated polymer hair cell mounted on Pb(Zr(0.52)Ti(0.48))O3 micro-diaphragm with floating bottom electrode. Canal-inspired versions are developed by mounting a polymer canal with pores that guide external flows to the hair cells embedded in the canal. Experimental results conducted employing our MEMS artificial superficial neuromasts (SNs) demonstrated a high sensitivity and very low threshold detection limit of 22 mV/(mm s(-1)) and 8.2 um s(-1), respectively, for an oscillating dipole stimulus vibrating at 35 Hz. Flexible arrays of such superficial sensors were demonstrated to localize an underwater dipole stimulus. Comparative experimental studies revealed a high-pass filtering nature of the canal encapsulated sensors with a cut-off frequency of 10 Hz and a flat frequency response of artificial SNs. Flexible arrays of self-powered, miniaturized, light weight, low-cost and robust artificial lateral-line systems could enhance the capabilities of underwater vehicles. PMID- 26423434 TI - Infection, vaccination, and childhood arterial ischemic stroke: Results of the VIPS study. AB - OBJECTIVES: Minor infection can trigger adult arterial ischemic stroke (AIS) and is common in childhood. We tested the hypotheses that infection transiently increases risk of AIS in children, regardless of stroke subtype, while vaccination against infection is protective. METHODS: The Vascular Effects of Infection in Pediatric Stroke study is an international case-control study that prospectively enrolled 355 centrally confirmed cases of AIS (29 days-18 years old) and 354 stroke-free controls. To determine prior exposure to infections and vaccines, we conducted parental interviews and chart review. RESULTS: Median (interquartile range) age was 7.6 years for cases and 9.3 for controls (p = 0.44). Infection in the week prior to stroke, or interview date for controls, was reported in 18% of cases, vs 3% of controls, conferring a 6.3-fold increased risk of AIS (p < 0.0001); upper respiratory infections were most common. Prevalence of preceding infection was similar across stroke subtypes: arteriopathic, cardioembolic, and idiopathic. Use of vasoactive cold medications was similarly low in both groups. Children with some/few/no routine vaccinations were at higher stroke risk than those receiving all or most (odds ratio [OR] 7.3, p = 0.0002). In an age-adjusted multivariate logistic regression model, independent risk factors for AIS included infection in the prior week (OR 6.3, p < 0.0001), undervaccination (OR 8.2, p = 0.0004), black race (compared to white; OR 1.9, p = 0.009), and rural residence (compared to urban; OR 3.0, p = 0.0003). CONCLUSIONS: Infection may act as a trigger for childhood AIS, while routine vaccinations appear protective. Hence, efforts to reduce the spread of common infections might help prevent stroke in children. PMID- 26423436 TI - Structural symmetry in evolutionary games. AB - In evolutionary game theory, an important measure of a mutant trait (strategy) is its ability to invade and take over an otherwise-monomorphic population. Typically, one quantifies the success of a mutant strategy via the probability that a randomly occurring mutant will fixate in the population. However, in a structured population, this fixation probability may depend on where the mutant arises. Moreover, the fixation probability is just one quantity by which one can measure the success of a mutant; fixation time, for instance, is another. We define a notion of homogeneity for evolutionary games that captures what it means for two single-mutant states, i.e. two configurations of a single mutant in an otherwise-monomorphic population, to be 'evolutionarily equivalent' in the sense that all measures of evolutionary success are the same for both configurations. Using asymmetric games, we argue that the term 'homogeneous' should apply to the evolutionary process as a whole rather than to just the population structure. For evolutionary matrix games in graph-structured populations, we give precise conditions under which the resulting process is homogeneous. Finally, we show that asymmetric matrix games can be reduced to symmetric games if the population structure possesses a sufficient degree of symmetry. PMID- 26423437 TI - DyNAMiC Workbench: an integrated development environment for dynamic DNA nanotechnology. AB - Dynamic DNA nanotechnology provides a promising avenue for implementing sophisticated assembly processes, mechanical behaviours, sensing and computation at the nanoscale. However, design of these systems is complex and error-prone, because the need to control the kinetic pathway of a system greatly increases the number of design constraints and possible failure modes for the system. Previous tools have automated some parts of the design workflow, but an integrated solution is lacking. Here, we present software implementing a three 'tier' design process: a high-level visual programming language is used to describe systems, a molecular compiler builds a DNA implementation and nucleotide sequences are generated and optimized. Additionally, our software includes tools for analysing and 'debugging' the designs in silico, and for importing/exporting designs to other commonly used software systems. The software we present is built on many existing pieces of software, but is integrated into a single package-accessible using a Web-based interface at http://molecular-systems.net/workbench. We hope that the deep integration between tools and the flexibility of this design process will lead to better experimental results, fewer experimental design iterations and the development of more complex DNA nanosystems. PMID- 26423438 TI - Emergent behavioural phenotypes of swarming models revealed by mimicking a frustrated anti-ferromagnet. AB - Self-propelled particle (SPP) models are often compared with animal swarms. However, the collective animal behaviour observed in experiments often leaves considerable unconstrained freedom in the structure of a proposed model. Essentially, multiple models can describe the observed behaviour of animal swarms in simple environments. To tackle this degeneracy, we study swarms of SPPs in non trivial environments as a new approach to distinguish between candidate models. We restrict swarms of SPPs to circular (periodic) channels where they polarize in one of two directions (like spins) and permit information to pass through windows between neighbouring channels. Co-alignment between particles then couples the channels (anti-ferromagnetically) so that they tend to counter-rotate. We study channels arranged to mimic a geometrically frustrated anti-ferromagnet and show how the effects of this frustration allow us to better distinguish between SPP models. Similar experiments could therefore improve our understanding of collective motion in animals. Finally, we discuss how the spin analogy can be exploited to construct universal logic gates, and therefore swarming systems that can function as Turing machines. PMID- 26423439 TI - Optics of cone photoreceptors in the chicken (Gallus gallus domesticus). AB - Vision is the primary sensory modality of birds, and its importance is evident in the sophistication of their visual systems. Coloured oil droplets in the cone photoreceptors represent an adaptation in the avian retina, acting as long-pass colour filters. However, we currently lack understanding of how the optical properties and morphology of component structures (e.g. oil droplet, mitochondrial ellipsoid and outer segment) of the cone photoreceptor influence the transmission of light into the outer segment and the ultimate effect they have on receptor sensitivity. In this study, we use data from microspectrophotometry, digital holographic microscopy and electron microscopy to inform electromagnetic models of avian cone photoreceptors to quantitatively investigate the integrated optical function of the cell. We find that pigmented oil droplets primarily function as spectral filters, not light collection devices, although the mitochondrial ellipsoid improves optical coupling between the inner segment and oil droplet. In contrast, unpigmented droplets found in violet-sensitive cones double sensitivity at its peak relative to other cone types. Oil droplets and ellipsoids both narrow the angular sensitivity of single cone photoreceptors, but not as strongly as those in human cones. PMID- 26423440 TI - Patterns of recruitment and injury in a heterogeneous airway network model. AB - In respiratory distress, lung airways become flooded with liquid and may collapse due to surface-tension forces acting on air-liquid interfaces, inhibiting gas exchange. This paper proposes a mathematical multiscale model for the mechanical ventilation of a network of occluded airways, where air is forced into the network at a fixed tidal volume, allowing investigation of optimal recruitment strategies. The temporal response is derived from mechanistic models of individual airway reopening, incorporating feedback on the airway pressure due to recruitment. The model accounts for stochastic variability in airway diameter and stiffness across and between generations. For weak heterogeneity, the network is completely ventilated via one or more avalanches of recruitment (with airways recruited in quick succession), each characterized by a transient decrease in the airway pressure; avalanches become more erratic for airways that are initially more flooded. However, the time taken for complete ventilation of the network increases significantly as the network becomes more heterogeneous, leading to increased stresses on airway walls. The model predicts that the most peripheral airways are most at risk of ventilation-induced damage. A positive-end-expiratory pressure reduces the total recruitment time but at the cost of larger stresses exerted on airway walls. PMID- 26423441 TI - Optimal allocation of the limited oral cholera vaccine supply between endemic and epidemic settings. AB - The World Health Organization (WHO) recently established a global stockpile of oral cholera vaccine (OCV) to be preferentially used in epidemic response (reactive campaigns) with any vaccine remaining after 1 year allocated to endemic settings. Hence, the number of cholera cases or deaths prevented in an endemic setting represents the minimum utility of these doses, and the optimal risk averse response to any reactive vaccination request (i.e. the minimax strategy) is one that allocates the remaining doses between the requested epidemic response and endemic use in order to ensure that at least this minimum utility is achieved. Using mathematical models, we find that the best minimax strategy is to allocate the majority of doses to reactive campaigns, unless the request came late in the targeted epidemic. As vaccine supplies dwindle, the case for reactive use of the remaining doses grows stronger. Our analysis provides a lower bound for the amount of OCV to keep in reserve when responding to any request. These results provide a strategic context for the fulfilment of requests to the stockpile, and define allocation strategies that minimize the number of OCV doses that are allocated to suboptimal situations. PMID- 26423443 TI - Liposheres as a Novel Carrier for Lipid Based Drug Delivery: Current and Future Directions. AB - Researchers are facing challenges to develop robust formulation and to enhance the bioavailability of poorly water-soluble drugs towards clinical applications. The development of new drug molecule alone is not adequate to assure ample pharmacotherapy of various diseases. Considerable results obtained from in vitro studies are not supported by in vivo data due to inadequate plasma drug concentrations. This may occur due to limited drug solubility and absorption. To resolve these problems, development of new drug delivery systems will be a promising approach. One of the promising pharmaceutical strategies is the use of lipospheres drug delivery system to deliver the poorly water-soluble drugs. Therefore, the present review described the methodology for manufacturing of lipospheres and factors influencing the formulation to deliver the drugs to the targeted site. Apart from that, this review also enlisted briefly the various applications of liposphers in medical and biomedical fields and critically discussed the recent patent system. PMID- 26423442 TI - In vitro degradability, bioactivity and primary cell responses to bone cements containing mesoporous magnesium-calcium silicate and calcium sulfate for bone regeneration. AB - Mesoporous calcium sulfate-based bone cements (m-CSBC) were prepared by introducing mesoporous magnesium-calcium silicate (m-MCS) with specific surface area (410.9 m2 g(-1)) and pore volume (0.8 cm3 g(-1)) into calcium sulfate hemihydrate (CSH). The setting time of the m-CSBC was longer with the increase of m-MCS content while compressive strength decreased. The degradation ratio of m CSBC increased from 48.6 w% to 63.5 w% with an increase of m-MCS content after soaking in Tris-HCl solution for 84 days. Moreover, the m-CSBC containing m-MCS showed the ability to neutralize the acidic degradation products of calcium sulfate and prevent the pH from dropping. The apatite could be induced on m-CSBC surfaces after soaking in SBF for 7 days, indicating good bioactivity. The effects of the m-CSBC on vitamin D3 sustained release behaviours were investigated. It was found that the cumulative release ratio of vitamin D3 from the m-CSBC significantly increased with the increase of m-MCS content after soaking in PBS (pH = 7.4) for 25 days. The m-CSBC markedly improved the cell positive responses, including the attachment, proliferation and differentiation of MC3T3-E1 cells, suggesting good cytocompatibility. Briefly, m-CSBC with good bioactivity, degradability and cytocompatibility might be an excellent biocement for bone regeneration. PMID- 26423444 TI - Evaluating the effectiveness of common disinfectants at preventing the propagation of Mycobacterium spp. isolated from zebrafish. AB - Mycobacteriosis is a bacterial disease that is common in captive, wild and research fish. There is no one causative agent of mycobacteriosis, as several strains and species of Mycobacterium have been identified in zebrafish. With increased usage and investment in wild-type and mutant zebrafish strains, considerable value is placed on preserving zebrafish health. One control measure used to prevent mycobacterial spread within and between zebrafish facilities is egg disinfection. Here we investigate the effectiveness of three disinfectants [chlorine bleach, hydrogen peroxide, and povidone-iodine (PVPI)] commonly included in egg disinfection protocols for laboratory fish as well as aquaculture fish and compare the knockdown effect of these treatments on Mycobacterium spp. in vitro. Despite current usage, comparison of these disinfection regimes' abilities to prevent mycobacterial growth has not been tested. We found that the germicidal effect of different disinfectants varies by Mycobacterium spp. Hydrogen peroxide was the least effective disinfectant, followed by unbuffered chlorine bleach, which is commonly used to disinfect embryos in zebrafish facilities. Disinfection with 25ppm PVPI for 5min was very effective, and may be an improved alternative to chlorine bleach for embryo disinfection. Results from this study can be utilized by laboratory fish facilities in order to prevent the spread of mycobacteriosis in research fish. PMID- 26423445 TI - Effect of the ionic product of bioglass 60s on osteoblastic activity in canines. AB - BACKGROUND: The objective of the present study was to evaluate the effect of the ionic product (IP) of BG60S on osteoblastic activity. The following media groups were created: DMEM, which is formed by osteoblasts in basal medium; IP DMEM, which is formed by osteoblasts in IP with basal medium; OST, which is formed by osteoblasts in osteogenic medium; and IP OST, which is formed by osteoblasts in IP with osteogenic medium. The osteoblasts were cultivated in an incubator at 37 degrees C and 5 % CO2 for 7, 14 and 21 days. After each period, the alkaline phosphatase (AP) activity, mineralised area per field and expression of osterix (OSX), bone sialoprotein (BSP), osteonectin (ON) and osteocalcin (OC) were evaluated by reverse transcription (RT)-PCR. RESULTS: The IP significantly increased the AP activity in the IP DMEM group at 7 and 14 days and reduced the AP activity in the IP OST group at 14 and 21 days relative to their respective controls (DMEM and OST). The groups that received the IP displayed a significant increase in the percentage of mineralised area per field and more advance maturation of the extracellular matrix relative to those that did not receive IP. The IP significantly increased the expression of OSX, BSP and ON in osteoblast cultures maintained in IP DMEM compared with the control (DMEM) for the majority of studied periods. In osteogenic medium, IP also significantly increased OSX, BSP, ON and OC expression compared with the control (OST) for the majority of studied periods. CONCLUSIONS: The IP of BG60S alters the gene expression of canine osteoblasts, favouring the synthesis and mineralisation of the extracellular matrix. PMID- 26423447 TI - The binding selectivity of vonoprazan (TAK-438) to the gastric H+, K+ -ATPase. AB - BACKGROUND: The gastric H(+) ,K(+) -ATPase is the preferred target for acid suppression. Until recently, the only drugs that effectively inhibited this ATPase were the proton pump inhibitors (PPIs). PPIs are acid-activated prodrugs that require acid protection. Once acid-activated, PPIs bind to cysteines of the ATPase, resulting in covalent, long-lasting inhibition. The short plasma half life of PPIs and continual de novo synthesis of the H(+) ,K(+) -ATPase result in difficulty controlling night-time acid secretion. A new alternative to PPIs is the pyrrolo-pyridine, vonoprazan (TAK-438), a potassium-competitive acid blocker (PCAB) that does not require acid protection. In contrast to other PCABs, vonoprazan has a long duration of action, resulting in 24-h control of acid secretion, a high pKa of 9.37 and high affinity (Ki = 3.0 etamol/L). AIM: To determine binding selectivity of vonoprazan for the gastric H(+) ,K(+) -ATPase and to explain its slow dissociation. METHODS: Gastric gland and parietal cell binding of vonoprazan was determined radiometrically. Molecular modelling explained the slow dissociation of vonoprazan from the H(+) ,K(+) -ATPase. RESULTS: Vonoprazan binds selectively to the parietal cell, independent of acid secretion. Vonoprazan binds in a luminal vestibule between the surfaces of membrane helices 4, 5 and 6. Exit of the drug to the lumen is hindered by asp137 and asn138 in the loop between TM1 and TM2, which presents an electrostatic barrier to movement of the sulfonyl group of vonoprazan. This may explain its slow dissociation from the H(+) ,K(+) -ATPase and long-lasting inhibition. CONCLUSION: The binding model provides a template for design of novel potassium competitive acid blockers. PMID- 26423448 TI - Ferritin heavy chain mediates the protective effect of heme oxygenase-1 against oxidative stress. AB - The phenomenon that heme oxygenase-1 (HO-1) protects cell from injury yet its enzymatic product, iron, may facilitate generation of free radical has been long puzzling. Here we establish a functional connection between ferritin heavy chain (FHC) and HO-1. In human lupus nephritis HO-1 and FHC are colocalized within the glomeruli. In rodent anti-Thy1 (thymocyte antigen 1) induced glomerulonephritis, heme oxygenase blockade lowers the expression of FHC and accelerates mesangial cell death. Stimulation of heme oxygenase in cultured rat mesangial cell enhances its resistance to hydrogen peroxide, whereas FHC knockdown by RNA interference compromises this salutary effect. RNA interference of HO-1 makes the cell more susceptible to hydrogen peroxide, which can be rescued by forced expression of wild-type FHC but not mutants that lose the capacity of iron storage and ferroxidase activity. Phosphorylation of JunD was not sustained in these cells. Microarray analysis identifies four candidate transcriptional factors that may regulate the HO-1-induced transcription of FHC. Our results support the role of FHC in neutralizing the iron toxicity as well as mediating the protective effect of HO-1 in response to oxidative stress. PMID- 26423449 TI - The effects of anesthesia on the morphoproteomic expression of head and neck squamous cell carcinoma: a pilot study. AB - The prognosis and disease-free survival rates for head and neck squamous cell carcinoma (HNSCC) have remained relatively stagnant for the last several decades. Moreover, as is the case with other malignancies, locoregional recurrence and distant metastasis are all too common even after seemingly successful oncologic surgery and adjuvant therapy. Recently, increased focus has been placed on understanding the influence of perioperative factors on tumor cell behavior and surgical outcomes. More specifically, emerging research suggests that anesthetic agents may play a role in cancer recurrence by interacting with prosurvival protein signaling pathways which harden tumor cells against oncologic treatments. In the present pilot study, we tested the hypothesis that inhalational anesthesia and total intravenous anesthesia (TIVA) exert differential effects on the proteomic expression of HNSCC. Ten patients with previously untreated oral cavity or oropharyngeal HNSCC were randomized to receive either sevoflurane and remifentanil or propofol and remifentanil for the duration of their respective surgeries. Morphoproteomic analysis using 10 pro-oncogenic protein markers was performed on both pre- and postanesthesia tumor samples to qualitatively grade changes in protein expression. The results of this analysis demonstrated differential expression of several protein markers. Specifically, the exposure to sevoflurane but not TIVA resulted in a statistically significant increase in the expression of cytoplasmic hypoxia-inducible factor-2alpha (P = 0.049) and nuclear p-p38 mitogenic-activated protein kinase (P = 0.041). This study represents one of the first to evaluate the effects of anesthesia on the molecular biology of HNSCC in vivo, and the results suggest that the exposure to sevoflurane may increase the expression of pro-oncogenic protein markers in HNSCC tumor cells. PMID- 26423446 TI - Longitudinal Weight Loss Patterns and their Behavioral and Demographic Associations. AB - BACKGROUND: Identification of weight change patterns may allow tailored interventions to improve long-term weight loss. PURPOSE: To identify patterns of weight change over 18 months, and assess participant characteristics and intervention adherence factors associated with weight change patterns in a sample of 359 overweight/obese adults. METHODS: Weight loss (0-6 months) was achieved with reduced energy intake and increased physical activity (PA). Maintenance (7 18 months) provided adequate energy to maintain weight and continued PA. RESULTS: Latent profile analysis identified three weight change profiles. During weight loss/maintenance, participants in profiles 2 and 3 (18-month weight loss ~14 %) attended more behavioral sessions and performed more PA compared with profile 1 (18-month weight loss <1 %). Self-efficacy for both weight management and exercise barriers were higher in profiles 2 and 3 compared with profile 1 following weight loss and during maintenance. CONCLUSION: Weight change patterns can be identified and are associated with both participant characteristics and intervention adherence. PMID- 26423450 TI - Correlation between prenatal ultrasound and postmortem findings in 1029 fetuses following termination of pregnancy. AB - OBJECTIVE: A prenatal ultrasound examination and a postmortem examination provide the basis for correct diagnosis in fetuses terminated due to congenital anomalies. The aim of this study was to correlate fetal anomalies detected by ultrasound examination with those identified at autopsy following termination of pregnancy (TOP) over a 30-year period, and to evaluate the correlation between findings at different gestational ages and assess these trends over time. METHODS: The study group consisted of 1029 TOPs performed over a 30-year period, from 1985 to 2014. The gestational age ranged between 11 and 33 weeks. Prenatal ultrasound examinations were performed at the National Center for Fetal Medicine, St Olavs Hospital, Trondheim, Norway. Autopsies were performed at the Department of Pathology and Medical Genetics at the same hospital or a collaborating hospital. RESULTS: There was full agreement between ultrasound and autopsy findings in 88.1% (907/1029) of TOPs, and the main diagnosis was correct in 97.9% (1007/1029). When comparing the 15-year period of 2000-2014 with that of 1985 1999, the difference in the rates of full agreement and agreement in the main diagnosis was statistically significant. In 1.3% (13/1029) of cases, ultrasound findings were not confirmed at autopsy. There were no false-positive diagnoses leading to TOP. Throughout the 30-year period, there was an increase in early TOPs, whereas late TOPs declined. CONCLUSIONS: Our study demonstrates that there is a clear correlation between ultrasound and autopsy findings, which is continuously improving. Despite this high correlation, there is reason to continue the practice of validation to ensure the safety of the diagnostic process leading to TOP. The trend towards an earlier termination emphasizes the necessity of such a practice. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26423451 TI - Outer retinal tubulations response to anti-VEGF treatment. AB - AIM: To review the longitudinal changes of outer retinal tubulations (ORTs) in wet age-related macular degeneration (AMD) and their response to anti-vascular endothelial growth factor (VEGF) therapy by spectral-domain optical coherence tomography (SD-OCT), and to correlate these observations with disease activity, presence or absence of fluid, and patients' demographics. METHODS: Retrospective study of wet AMD eyes treated with anti-VEGF agents and showing ORTs on SD-OCT, and the patients' fellow eye with wet AMD but without ORTs. RESULTS: Fifty-one wet AMD eyes from 31 patients diagnosed and treated for wet AMD were included in the review and analysis of data; 33 eyes showed ORTs at baseline, while 18 fellow eyes had no ORTs. During a median follow-up treatment period of 11 months, 23 eyes had stable ORTs and 10 eyes had ORT changes. Among the 10 eyes with ORTs changes, ORTs collapsed during anti-VEGF treatment in 5 eyes but then reappeared within 12 months after stopping treatment. In two eyes, ORTs increased in size during anti-VEGF treatment, while in two other eyes ORTs collapsed without any treatment. In a single eye, ORTs collapsed within 10 months of no treatment and did not reappear upon recurrence of fluid. Eyes with ORTs tended to have lower visual acuity than eyes with no ORTs due to greater disruption of the external limiting membrane in the fovea. CONCLUSIONS: ORTs documented by SD-OCT may exhibit multiple types of longitudinal changes, such as collapse, recurrence or enlargement, which could be associated with anti-VEGF treatment or spontaneous. Some ORTs may have a vascular component or may be vascular in nature, considering their response to anti-VEGF treatment, while other ORTs are likely composed only of degenerating photoreceptor cells and may collapse independently from anti-VEGF treatments. PMID- 26423452 TI - Corneal endothelium in xeroderma pigmentosum: clinical specular microscopy study. AB - AIMS: Xeroderma pigmentosum is a condition caused due to a defective DNA repair mechanism when exposed to ultraviolet radiation. Many of the patients with this disorder develop severely oedematous cornea with varying degrees of anterior corneal haze, which necessitates a full-thickness keratoplasty or selective endothelial keratoplasty. Presence of corneal oedema suggests that these patients have a dysfunctional endothelium. The purpose of this study is to evaluate the corneal endothelium in the patients with xeroderma pigmentosum when clinical specular microscopy was feasible. METHODS: Thirteen patients with classic skin changes of xeroderma pigmentosum were included in the study conducted during January 2010-December 2012. An age-matched group of 13 volunteers were included as controls who were emmetropes without any history of ocular or systemic illness. Corneal endothelium was assessed using specular microscopy from the central clear area of cornea. RESULTS: The mean age of the patients with xeroderma pigmentosum was 16.6+/-7.2 years and that of the controls was 17.4+/ 6.9 years (p=0.78). The number of analysed cells and endothelial cell density were significantly higher in controls (p<0.001), whereas the average cell area, coefficient of variation of cell area and maximum cell area were significantly higher in xeroderma pigmentosum (p<=0.007). CONCLUSIONS: The specular microscopic findings in patients with xeroderma pigmentosum are suggestive of an accelerated endothelial cell loss. It is pertinent that the treating physicians must be involved in emphasising proper ocular protection from ultraviolet radiation to prevent avoidable blindness from xeroderma pigmentosum. PMID- 26423453 TI - Maharashtra government launches mental health programme to reduce suicide in farmers. PMID- 26423454 TI - Importance of "default" intraoperative ventilator settings. PMID- 26423455 TI - Effect of a nasal clip on inhaling a sufficient cortico steroid powder dose. PMID- 26423456 TI - Does superficial fat affect metabolite concentrations determined by MR spectroscopy with water referencing? AB - It has recently been reported in this journal that local fat depots produce a sizable frequency-dependent signal attenuation in magnetic resonance spectroscopy (MRS) of the brain. If of a general nature, this effect would question the use of internal reference signals for quantification of MRS and the quantitative use of MRS as a whole. Here, it was attempted to verify this effect and pinpoint the potential causes by acquiring data with various acquisition settings, including two field strengths, two MR scanners from different vendors, different water suppression sequences, RF coils, localization sequences, echo times, and lipid/metabolite phantoms. With all settings tested, the reported effect could not be reproduced, and it is concluded that water referencing and quantitative MRS per se remain valid tools under common acquisition conditions. PMID- 26423457 TI - Genetic inhibition of JNK3 ameliorates spinal muscular atrophy. AB - Mutation of the Survival Motor Neuron 1 (SMN1) gene causes spinal muscular atrophy (SMA), an autosomal recessive neurodegenerative disorder that occurs in early childhood. Degeneration of spinal motor neurons caused by SMN deficiency results in progressive muscle atrophy and death in SMA. The molecular mechanism underlying neurodegeneration in SMA is unknown. No treatment is available to prevent neurodegeneration and reduce the burden of illness in SMA. We report that the c-Jun NH2-terminal kinase (JNK) signaling pathway mediates neurodegeneration in SMA. The neuron-specific isoform JNK3 is required for neuron degeneration caused by SMN deficiency. JNK3 deficiency reduces degeneration of cultured neurons caused by low levels of SMN. Genetic inhibition of JNK pathway in vivo by Jnk3 knockout results in amelioration of SMA phenotype. JNK3 deficiency prevents the loss of spinal cord motor neurons, reduces muscle degeneration, improves muscle fiber thickness and muscle growth, improves motor function and overall growth and increases lifespan of mice with SMA that shows a systemic rescue of phenotype by a SMN-independent mechanism. JNK3 represents a potential (non-SMN) therapeutic target for the treatment of SMA. PMID- 26423458 TI - Genome-wide disruption of 5-hydroxymethylcytosine in a mouse model of autism. AB - The autism spectrum disorders (ASD) comprise a broad group of behaviorally related neurodevelopmental disorders affecting as many as 1 in 68 children. The hallmarks of ASD consist of impaired social and communication interactions, pronounced repetitive behaviors and restricted patterns of interests. Family, twin and epidemiological studies suggest a polygenetic and epistatic susceptibility model involving the interaction of many genes; however, the etiology of ASD is likely to be complex and include both epigenetic and environmental factors. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive DNA modification that is highly enriched in post-mitotic neurons and is associated with active transcription of neuronal genes. Here, we used an established chemical labeling and affinity purification method coupled with high throughput sequencing technology to generate a genome-wide profile of striatal 5hmC in an autism mouse model (Cntnap2(-/-) mice) and found that at 9 weeks of age the Cntnap2(-/-) mice have a genome-wide disruption in 5hmC, primarily in genic regions and repetitive elements. Annotation of differentially hydroxymethylated regions (DhMRs) to genes revealed a significant overlap with known ASD genes (e.g. Nrxn1 and Reln) that carried an enrichment of neuronal ontological functions, including axonogenesis and neuron projection morphogenesis. Finally, sequence motif predictions identified associations with transcription factors that have a high correlation with important genes in neuronal developmental and functional pathways. Together, our data implicate a role for 5hmC-mediated epigenetic modulation in the pathogenesis of autism and represent a critical step toward understanding the genome-wide molecular consequence of the Cntnap2 mutation, which results in an autism-like phenotype. PMID- 26423460 TI - On Race and Time. AB - Arousal is known to shape time perception, and heightened arousal causes one to perceive that time has slowed (i.e., a given length of time feels longer than it actually is). The current experiments illustrate that among White people who experience arousal when contemplating race (specifically those for whom appearing biased is an ongoing concern), time perception slows when they observe faces of Black men. We asked participants to judge the duration of presentation for faces of White and Black men (shown for periods ranging from 300 to 1,200 ms) relative to a standard duration of 600 ms. Evidence of bias emerged when White participants concerned with bias saw faces of Black men (e.g., durations of less than 600 ms were perceived as being greater than 600 ms). The current findings have implications for intergroup interactions in which timing is essential-for example, length of job interviews, police officers' perception of the length of an encounter and when force should be initiated, and doctors' perception of the length of medical encounters. Racially biased time perception is a new form of implicit bias, one exerted at the perceptual level. PMID- 26423459 TI - Use of the HPRT gene to study nuclease-induced DNA double-strand break repair. AB - Understanding the mechanisms of chromosomal double-strand break repair (DSBR) provides insight into genome instability, oncogenesis and genome engineering, including disease gene correction. Research into DSBR exploits rare-cutting endonucleases to cleave exogenous reporter constructs integrated into the genome. Multiple reporter constructs have been developed to detect various DSBR pathways. Here, using a single endogenous reporter gene, the X-chromosomal disease gene encoding hypoxanthine phosphoribosyltransferase (HPRT), we monitor the relative utilization of three DSBR pathways following cleavage by I-SceI or CRISPR/Cas9 nucleases. For I-SceI, our estimated frequencies of accurate or mutagenic non homologous end-joining and gene correction by homologous recombination are 4.1, 1.5 and 0.16%, respectively. Unexpectedly, I-SceI and Cas9 induced markedly different DSBR profiles. Also, using an I-SceI-sensitive HPRT minigene, we show that gene correction is more efficient when using long double-stranded DNA than single- or double-stranded oligonucleotides. Finally, using both endogenous HPRT and exogenous reporters, we validate novel cell cycle phase-specific I-SceI derivatives for investigating cell cycle variations in DSBR. The results obtained using these novel approaches provide new insights into template design for gene correction and the relationships between multiple DSBR pathways at a single endogenous disease gene. PMID- 26423462 TI - Introduction. PMID- 26423463 TI - Bad science and how to avoid it, a movement analysis perspective: Study design, statistics and publication ethics. PMID- 26423461 TI - Decoding Visual Location From Neural Patterns in the Auditory Cortex of the Congenitally Deaf. AB - Sensory cortices of individuals who are congenitally deprived of a sense can exhibit considerable plasticity and be recruited to process information from the senses that remain intact. Here, we explored whether the auditory cortex of congenitally deaf individuals represents visual field location of a stimulus-a dimension that is represented in early visual areas. We used functional MRI to measure neural activity in auditory and visual cortices of congenitally deaf and hearing humans while they observed stimuli typically used for mapping visual field preferences in visual cortex. We found that the location of a visual stimulus can be successfully decoded from the patterns of neural activity in auditory cortex of congenitally deaf but not hearing individuals. This is particularly true for locations within the horizontal plane and within peripheral vision. These data show that the representations stored within neuroplastically changed auditory cortex can align with dimensions that are typically represented in visual cortex. PMID- 26423464 TI - The relationship between health and cell-mediated immunity measured in ecology: Phytohaemagglutinin skin-swelling test mirrors blood cellular composition. AB - The phytohaemagglutinin (PHA) skin-swelling test, a common ecological method for measuring immune responsiveness, uses a subcutaneous injection of PHA to induce an inflammatory response with metrically measurable swelling. Both the immunological basis of this response and the role of pre-exposure physiology remain poorly understood, however, preventing predictions of costs and benefits of immunity investments revealed by the test and their relationship to life history traits. In this study, we measure PHA-triggered tissue swelling, cellular infiltration into inflamed tissue, and haematological changes in zebra finches Taeniopygia guttata, with the aim of identifying those cell types involved in activation of PHA-induced skin swelling. We show that the inflammation underlying the swelling response is dependent on initial haematological state and alters the composition of circulating leukocytes. Injection of PHA decreased heterophil and monocyte frequency and increased basophil frequency, suggesting changes in leukocyte trafficking and haematopoiesis. Higher initial basophil and lymphocyte frequencies in peripheral blood were associated with increased swelling. High pre treatment blood lymphocyte levels led to intense lymphocyte migration into inflamed tissue, while high initial basophil levels resulted in lower cellular infiltration. Our results show two possible directions in the association between pre-exposure health and swelling response: (i) a lymphocyte-based pathway that leads to higher responsiveness in high-quality healthy individuals capable of higher energy and resource investment, or (ii) higher responsiveness in diseased individuals with initially elevated basophil levels and pre-activated immunity. Haematological investigation, therefore, facilitates interpretation of PHA skin swelling test results in ecological immunology, explaining ca. 20 % of variation in skin-swelling data. J. Exp. Zool. 323A: 767-777, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26423465 TI - Complementary and Alternative Health Practices in the Rehabilitation Nursing. AB - This article discusses the connection between the Theory of Integral Nursing and the use of complementary and alternative medicine to rehabilitation nursing. Complementary and alternative health practices refers to methods, practices, and modalities that are outside of the realm of biomedicine. Some of the types of treatments and practices that are considered to be alternative include folk medicine, herbal medicine, homeopathy, faith healing, massage, energy healing, acupuncture and acupressure, supplements, aromatherapy, and music therapy. The Theory of Integral Nursing is explained in some detail. Components of self-care, nursing-based complementary and alternative medicine practices, and supplement alternatives for pain and antidepressant medications used in the rehabilitation setting are also reviewed. PMID- 26423466 TI - Survey of anal sphincter dysfunction using anal manometry in patients with fecal incontinence: a possible guide to therapy. AB - BACKGROUND: Despite the surge of new medical and surgical approaches to treat fecal incontinence, the types of sphincter abnormalities in patients with incontinence have not been well characterized. We aimed to categorize anal sphincter dysfunction using anorectal manometry in patients with fecal incontinence as a potential guide for improved treatment. METHODS: A retrospective review of 162 consecutive patients with fecal incontinence referred for anorectal manometry was performed. Resting anal pressure and maximal squeeze pressure were considered as measures of internal anal sphincter and external anal sphincter function respectively. RESULTS: Mean age of the patients was 63 years (13-89); females (81.5%) and males (18.5%). 74% of the patients had sphincter dysfunction on anorectal manometry. Internal anal sphincter dysfunction was present in 62% patients vs. external anal sphincter dysfunction present in 44% patients. 80% females had abnormal manometry vs. 44% in males (P<0.0001). Internal anal sphincter dysfunction was present in 68% females vs. 37% in males (P=0.0026). CONCLUSIONS: Overall, abnormal anorectal manometry studies revealed that internal anal sphincter dysfunction is the most common finding, alone or in combination with external anal sphincter dysfunction. We suggest that anorectal manometry may be important to delineate anal sphincter function prior to using newer therapeutic mechanical devices. Future studies using pharmacological agents to increase internal anal sphincter tone may be of clinical importance. Finally, the classification of fecal incontinence based on the type of sphincter dysfunction may be an improved guide in the selection of newer agents in treating fecal incontinence. PMID- 26423467 TI - Partially desulfated heparin modulates the interaction between anti protamine/heparin antibodies and platelets. AB - Protamine (PRT) is the standard drug to neutralise heparin. PRT/heparin complexes induce an immune response similar to that observed in heparin-induced thrombocytopenia (HIT). Partially desulfated heparin (ODSH) was shown to interfere with anti-platelet factor 4/heparin antibodies (Abs), which are responsible for HIT. In this study, we analyse the impact of ODSH on the interaction between anti-PRT/heparin Abs and platelets. The ability of ODSH to prevent anti-PRT/heparin Ab-induced platelet destruction in vivo was investigated using the NOD/SCID mouse model. ODSH improved platelet survival in the presence of PRT, heparin and anti-PRT/heparin Abs (median platelet survival after 300 minutes (min) with 20 ug/ml ODSH: 75%, range 70-81% vs without ODSH: 49%, range 44-59%, p=0.006). Furthermore, when ODSH was applied 60 min after Ab injection platelet survival was improved (median platelet survival after 300 min with ODSH: 83%, range 77-93% vs without ODSH: 59%, range 29-61%, p=0.02). In in vitro experiments ODSH inhibited platelet activation at concentrations >16 ug/mL (p<0.001), as well as PRT/heparin complex binding to platelets (mean fluorescence intensity [MFI] without ODSH: 85 +/- 14 vs with ODSH: 15 +/- 0.6, p=0.013). ODSH also displaced pre-bound complexes from the platelet surface (MFI without ODSH: 324 +/- 43 vs with 32 ug/ml ODSH: 53 +/- 9, p<0.001). While interfering with platelet activation by anti-PRT/heparin Abs, up to a concentration of 16 ug/ml, ODSH had only minimal impact on neutralisation of heparin by PRT. In conclusion, our study shows that ODSH is able to inhibit platelet activation and destruction suggesting a potential clinical use to reduce anti-PRT/heparin Ab-mediated adverse effects. PMID- 26423470 TI - Water availability predicts forest canopy height at the global scale. AB - The tendency of trees to grow taller with increasing water availability is common knowledge. Yet a robust, universal relationship between the spatial distribution of water availability and forest canopy height (H) is lacking. Here, we created a global water availability map by calculating an annual budget as the difference between precipitation (P) and potential evapotranspiration (PET) at a 1-km spatial resolution, and in turn correlated it with a global H map of the same resolution. Across forested areas over the globe, Hmean increased with P-PET, roughly: Hmean (m) = 19.3 + 0.077*(P-PET). Maximum forest canopy height also increased gradually from ~ 5 to ~ 50 m, saturating at ~ 45 m for P-PET > 500 mm. Forests were far from their maximum height potential in cold, boreal regions and in disturbed areas. The strong association between forest height and P-PET provides a useful tool when studying future forest dynamics under climate change, and in quantifying anthropogenic forest disturbance. PMID- 26423471 TI - In response to: 'Folic acid levels in some food staples in Ireland are on the decline: implications for passive folic acid intakes?' (Kelly et al. 2016;38(2):265-9). PMID- 26423473 TI - The epidemiology of pituitary adenomas in Iceland, 1955-2012: a nationwide population-based study. AB - OBJECTIVE: Pituitary adenomas (PA) are among the most common human neoplasms. To describe the epidemiology and assess the disease burden of clinically significant PAs, population-based studies are needed. Iceland has a small well-defined population. The aim of this study is to describe the epidemiology of PAs in Iceland over an expanded period of time. DESIGN: This is a retrospective observational study, including all PAs diagnosed in Iceland from 1955 to 2012. METHODS: Extensive clinical information was gathered in a database. Prevalence rates for all PA subtypes were calculated along with standardized incidence rates (SIR). Sex ratios and relationships with adenoma size, age, and symptoms were assessed. RESULTS: We identified 471 individuals: 190 men and 281 women. Total prevalence in 2012 was 115.57/100, 000, prolactinomas were most prevalent (54.37/100, 000) followed by non-functioning adenomas (NFPAs) (42.32/100 ,000). Throughout the period, NFPAs were most common (43.0%) followed by prolactinomas (39.9%) and 11.3% had acromegaly and 5.7% Cushing's disease. Women are diagnosed younger with smaller adenomas. Total SIR has increased significantly and is now 5.8/100 000 per year. CONCLUSION: In this nationwide study spanning six decades, we have confirmed PAs rising prevalence and incidence rates noted in recent studies. We demonstrated higher overall prevalence and incidence rates than ever previously recorded with an increasing predominance of NFPAs, which is not explained by incidental findings alone. There is a relationship with the introduction of imaging modalities, but the vast majority of patients are symptomatic at diagnosis. This underlines the importance of increased awareness, education, and appropriate allocation of resources for this growing group of patients. PMID- 26423474 TI - Is Adult-Onset ADHD a Distinct Entity? PMID- 26423475 TI - Toward Improved Risk Prediction in Individuals at High Risk of Psychotic Disorders. PMID- 26423476 TI - Getting Past Proof of Concept For New Treatments. PMID- 26423477 TI - Addressing Patients' Psychic Pain. PMID- 26423478 TI - Domestic Violence Awareness. PMID- 26423479 TI - Reproductive Psychiatry: The Gap Between Clinical Need and Education. PMID- 26423480 TI - Rorschach Inkblot Invasion of Pop Culture. PMID- 26423481 TI - Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression. AB - OBJECTIVE: The authors conducted a systematic review and meta-analysis of ketamine and other N-methyl-d-aspartate (NMDA) receptor antagonists in the treatment of major depression. METHOD: Searches of MEDLINE, PsycINFO, and other databases were conducted for placebo-controlled, double-blind, randomized clinical trials of NMDA antagonists in the treatment of depression. Primary outcomes were rates of treatment response and transient remission of symptoms. Secondary outcomes included change in depression symptom severity and the frequency and severity of dissociative and psychotomimetic effects. Results for each NMDA antagonist were combined in meta-analyses, reporting odds ratios for dichotomous outcomes and standardized mean differences for continuous outcomes. RESULTS: Ketamine (seven trials encompassing 147 ketamine-treated participants) produced a rapid, yet transient, antidepressant effect, with odds ratios for response and transient remission of symptoms at 24 hours equaling 9.87 (4.37 22.29) and 14.47 (2.67-78.49), respectively, accompanied by brief psychotomimetic and dissociative effects. Ketamine augmentation of ECT (five trials encompassing 89 ketamine-treated participants) significantly reduced depressive symptoms following an initial treatment (Hedges' g=0.933) but not at the conclusion of the ECT course. Other NMDA antagonists failed to consistently demonstrate efficacy; however, two partial agonists at the NMDA coagonist site, d-cycloserine and rapastinel, significantly reduced depressive symptoms without psychotomimetic or dissociative effects. CONCLUSIONS: The antidepressant efficacy of ketamine, and perhaps D-cycloserine and rapastinel, holds promise for future glutamate modulating strategies; however, the ineffectiveness of other NMDA antagonists suggests that any forthcoming advances will depend on improving our understanding of ketamine's mechanism of action. The fleeting nature of ketamine's therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution. PMID- 26423482 TI - Brief CBT and Suicide Risk: Ruling Out Nonspecific Effects of Individual Therapy. PMID- 26423483 TI - Response to Stankiewicz et al. PMID- 26423484 TI - Cardiac Effects of Methylphenidate. PMID- 26423485 TI - Response to Roose and Rutherford. PMID- 26423486 TI - A Case of a Depressed Patient With Major Titanium Cranial Base Reconstruction Successfully Treated by ECT. PMID- 26423492 TI - CORRECTION. In the Wake of National Trauma: Psychological Reactions Following the Charlie Hebdo Terror Attack. PMID- 26423493 TI - APA Council Reports. AB - At the fall component meetings of the American Psychiatric Association in Crystal City, Va., September 9-12, 2015, the APA councils heard reports from their components. Following are summaries of the activities of the councils and their components. PMID- 26423494 TI - Scaling Up Nature: Large Area Flexible Biomimetic Surfaces. AB - The fabrication and advanced function of large area biomimetic superhydrophobic surfaces (SHS) and slippery lubricant-infused porous surfaces (SLIPS) are reported. The use of roll-to-roll nanoimprinting techniques enabled the continuous fabrication of SHS and SLIPS based on hierarchically wrinkled surfaces. Perfluoropolyether hybrid molds were used as flexible molds for roll-to roll imprinting into a newly designed thiol-ene based photopolymer resin coated on flexible polyethylene terephthalate films. The patterned surfaces exhibit feasible superhydrophobicity with a water contact angle around 160 degrees without any further surface modification. The SHS can be easily converted into SLIPS by roll-to-roll coating of a fluorinated lubricant, and these surfaces have outstanding repellence to a variety of liquids. Furthermore, both SHS and SLIPS display antibiofouling properties when challenged with Escherichia coli K12 MG1655. The current article describes the transformation of artificial biomimetic structures from small, lab-scale coupons to low-cost, large area platforms. PMID- 26423495 TI - Comparative Evaluation of Fracture Resistance and Mode of Failure of Zirconia and Titanium Abutments with Different Diameters. AB - AIM: The purpose of the current study was to compare the fracture resistance and mode of failure of zirconia and titanium abutments with different diameters. MATERIALS AND METHODS: Fourteen groups of abutments including prefabricated zirconia, copy-milled zirconia and titanium abutments of an implant system (XiVE, Dentsply) were prepared in different diameters. An increasing vertical load was applied to each specimen until failure occurred. Fracture resistance was measured in each group using the universal testing machine. Moreover, the failure modes were studied and categorized as abutment screw fracture, connection area fracture, abutment body fracture, abutment body distortion, screw distortion and connection area distortion. Groups were statistically compared using univariate and post-hoc tests. The level of statistical significance was set at 5%. RESULTS: Fabrication method (p = 0.03) and diameter (p < 0.001) had significant effect on the fracture resistance of abutments. Fracture resistance of abutments with 5.5 mm diameter was higher than other diameters (p < 0.001). The observed modes of failure were dependent on the abutment material as well. All of the prefabricated titanium abutments fractured within the abutment screw. Abutment screw distortion, connection area fracture, and abutment body fracture were the common failure type in other groups. CONCLUSION: Diameter had a significant effect on fracture resistance of implant abutments, as abutments with greater diameters were more resistant to static loads. Copy-milled abutments showed lower fracture resistance as compared to other experimental groups. CLINICAL SIGNIFICANCE: Although zirconia abutments have received great popularity among clinicians and even patients selecting them for narrow implants should be with caution. PMID- 26423496 TI - Comparison of Antimicrobial Activity between Chemical Disinfectants on Contaminated Orthodontic Pliers. AB - AIM: To compare the antimicrobial activity of the chemical substances--70% isopropyl alcohol, 2% glutaraldehyde (GTA) and 0.25% peracetic acid (PAA) in disinfecting orthodontic pliers contaminated in vitro with Streptococcui mutani, Staphylococci aureui and Candida albicani. MATERIALS AND METHODS: Distal end cutter pliers were divided into five groups: group 1 (negative control- sterilized pliers), group 2 (positive control--sterilized plier, subsequently contaminated), group 3 (disinfected with 70% isopropyl alcohol, friction method), group 4 (disinfected with 2% GTA, immersion method for 30 minutes), group 5 (disinfected with 0.25% peracetic acid (PAA), immersion method for 10 minutes). After the pliers were treated with one disinfectant and submitted to microbiological evaluation (by counting colony forming units), they were submitted to the same cleansing, sterilizing and contaminating processes, and were used in the following groups (crossover and washout study). The two-factor analysis of variance (ANOVA) test, followed by the Tukey test, was used to compare the groups. RESULTS: The results showed that there was no statistically significant difference between the three tested disinfectants. CONCLUSION: Although there were no statistically significant differences between the disinfectants, the chemical agents 2% glutaraldehyde and 0.25% PAA were effective in inhibiting the growth of the three microorganisms tested; however, 70% isopropyl alcohol was unable to completely eliminate S. aureui. CLINICAL SIGNIFICANCE: The chemical substances 2% glutaraldehyde and 0.25% PAA completely eliminated the microorganisms tested. PMID- 26423497 TI - Antimicrobial Activity and pH of Calcium Hydroxide and Zinc Oxide Nanoparticles Intracanal Medication and Association with Chlorhexidine. AB - AIM: To evaluate pH and antibacterial activity of pastes with calcium hydroxide [Ca(OH)2] and zinc oxide (ZnO) microparticles (micro) or nanoparticles (nano) and association with 0.4% chlorhexidine against Enterococcus faecalis. MATERIALS AND METHODS: The following pastes were analyzed: Ca(OH)2/ZnO micro, (2) Ca(OH)2/ZnO nano, (3) Ca(OH)2/ ZnO micro + 0.4% chlorhexidine, (4) Ca(OH)2/ZnO nano + 0.4% chlorhexidine. Antibacterial activity against E. faecalis was evaluated by agar diffusion test. The direct contact test on planktonic cells of E. faecalis was performed for 30 and 60 seconds. Root canals from bovine teeth were filled with the pastes and pH was evaluated after 1, 7, 14, 21, 30 and 60 days. The data obtained were submitted to the statistical tests analysis of variance (ANOVA) and Tukey or Kruskal-Wallis and Dunn test, with a 5% significance level. RESULTS: Calcium hydroxide and zinc oxide nano, and the pastes with 0.4% chlorhexidine were more effective in agar diffusion test. In the direct contact test, the pastes with chlorhexidine showed the highest effect after 30 seconds. All pastes eliminated E. faecalis after 60 seconds. All pastes promoted an increase in pH. The highest increase in pH was observed with nanoparticle medications after 1 and 7 days (p < 0.05). After this period, the pastes presented similar pH increase. CONCLUSION: It was concluded that calcium hydroxide and zinc oxide nanoparticles promoted greater initial alkalinization. The antimicrobial activity of the pastes against E. faecalis is favored by the association with chlorhexidine. CLINICAL SIGNIFICANCE: Although nanoparticles of calcium hydroxide and zinc oxide promoted antibacterial effect, the activity against E. faecalis is favored by association with chlorhexidine. PMID- 26423498 TI - Evaluation of Bone Thickness and Density in the Lower Incisors' Region in Adults with Different Types of Skeletal Malocclusion using Cone-beam Computed Tomography. AB - OBJECTIVES: To evaluate the bone thickness and density in the lower incisors' region in orthodontically untreated adults, and to examine any possible relationship between thickness and density in different skeletal patterns using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: The CBCT records of 48 patients were obtained from the archive of orthodontic department comprising three groups of malocclusion (class I, II and III) with 16 patients in each group. Using OnDemand 3D software, sagittal sections were made for each lower incisor. Thicknesses and densities were measured at three levels of the root (cervical, middle and apical regions) from the labial and lingual sides. Accuracy and reliability tests were undertaken to assess the intraobserver reliability and to detect systematic error. Pearson correlation coefficients were calculated and one-way analysis of variance (ANOVA) was employed to detect significant differences among the three groups of skeletal malocclusion. RESULTS: Apical buccal thickness (ABT) in the four incisors was higher in class II and I patients than in class III patients (p < 0.05). There were significant differences between buccal and lingual surfaces at the apical and middle regions only in class II and III patients. Statistical differences were found between class I and II patients for the cervical buccal density (CBD) and between class II and III patients for apical buccal density (ABD). Relationship between bone thickness and density values ranged from strong at the cervical regions to weak at the apical regions. CONCLUSIONS: Sagittal skeletal patterns affect apical bone thickness and density at buccal surfaces of the four lower incisors' roots. Alveolar bone thickness and density increased from the cervical to the apical regions. PMID- 26423499 TI - Is It Possible to induce Artificial Caries-affected Dentin using the Same Protocol to Primary and Permanent Teeth? AB - AIM: This in vitro study compared the mineral loss of natural and artificially created caries-affected dentin in primary and permanent teeth using the same protocol to induce caries lesions. MATERIALS AND METHODS: Twenty molars presenting natural occlusal dentin caries lesions (10 primary-PriC and 10 perma nent-PermC; control group), and 20 sound molars (10 primary -PripH and 10 permanent-PermpH; experimental group), were selected. Occlusal cavities were prepared in teeth of the experimental group that were submitted to pH-cycling for 14 days to simulate caries-affected dentin. All specimens were longitudinally sectioned and prepared in order to obtain Knoop micro-hardness values from 15 to 250 urn depth, starting in bottom of center of natural lesions or cavities. The microhardness (KHN) data were submitted to three-way repeated measures analysis of variance (ANOVA) and Tukey's tests (alpha = 0.05). RESULTS: Considering all depths, there was no statistically significant differences (p > 0.05) between the mineral loss of the control (PriC = 30.9 +/- 6.4 and PermC = 40.8 +/- 8.6) and experimental (PripH = 27.3 +/- 11.1 and PermpH = 35.5 +/- 14.0) groups, neither between primary and permanent teeth. CONCLUSION: The mineral loss of the artificially-created caries-affected dentin is similar to that from naturally developed dentin caries lesions. CLINICAL SIGNIFICANCE: The pH-cycling model may be a suitable method to simulate caries-affected dentin in both permanent and primary teeth. PMID- 26423500 TI - In vivo Evaluation of Proximal Resin Composite Restorations performed using Three Different Matrix Systems. AB - OBJECTIVE: The aim of this in vivo study was to radiographically evaluate the proximal contour of composite resin restorations performed using different matrix systems. MATERIALS AND METHODS: Patients with premolars needing class II type resin composite restorations involving the marginal ridge were selected. Thirty premolars were selected and randomly divided into three groups (n = 10 each) to receive restorations using different matrix systems: group 1: metal matrix coupled to a carrier matrix and wood wedge (G1-MMW); group 2: sectioned and precontoured metal matrix and elastic wedge (G2-SME); and group 3: a polyester strip and reflective wedge (G3-PMR). After the restorative procedure, bitewing radiographs were performed and analyzed by three calibrated professionals. The quality of the proximal contact and marginal adaptation of the proximal surfaces was classified as either correct or incorrect (undercontour/overcontour). RESULTS: The Pearson Chi-square statistical test (alpha = 5%) revealed a statistically difference between frequencies of correct and incorrect restorations (alpha(2) = 6.787, p < 0.05). The group G2 SME produced a higher frequency of correct proximal contours (90%), while G1-MMW and G3-PMR had a ratio of 40% correct and 60% incorrect contours respectively. CONCLUSION: None of the matrix systems was able to prevent the formation of incorrect proximal contours; however, the sectioned and precontoured metal matrix/elastic wedge configuration provided better results as compared to the other groups. PMID- 26423501 TI - An Evaluation of Inter- and Intraobserver Reliability of Cone-beam Computed Tomography- and Two Dimensional-based Interpretations of Maxillary Canine Impactions using a Panel of Orthodontically Trained Observers. AB - OBJECTIVES: To assess intra- and interobserver agreement when evaluating maxillary impacted canines using cone beam computed tomography (CBCT) and two dimensional (2D) images through a panel of orthodontically trained observers. MATERIALS AND METHODS: An adult skull with permanent dentition was employed to perform 15 simulated maxillary canine impactions. Two sets of 2D and three dimensional (3D) radiographic images were acquired. A panel of assessors including 11 PhD and MSc postgraduate orthodontic students evaluated maxillary impacted canines using a standard questionnaire with 11 categorical variables. Kappa (K) statistics as well as Krippendorff's alpha (alpha) coefficients were used for the analysis of reliability. RESULTS: A high level of intraobserver agreement was found for both the CBCT- and 2D-based interpretations. The 11 observers demonstrated a higher interobserver agreement for the CBCT-based interpretations than that of the 2D-based interpretations (alpha = 0.68 and 0.38 respectively). The employed 3D classifications canines was found to be reliable among observers on CBCT images for the labiopalatal position (K = 0.87), mesiodistal position, vertical position, labiopalatal inclination and mesiodistal inclination (alpha = 0.95, 0.83, 0.84 and 0.92 respectively). The 2D-based interpretations were not in agreement among the 11 observers, except for the mesiodistal position (alpha = 0.88) and mesiodistal inclination (alpha = 0.88). CONCLUSION: The intraobserver agreement was high for both the 2D- and the CBCT based interpretations. The interobserver agreement for the CBCT-based interpretations was remarkably higher than that of the 2D-based interpretations. The utilized CBCT-based 3D classifications for the location and inclination of maxillary impacted canines were found reliable among observers. PMID- 26423502 TI - The Efficacy of Calcium Hydroxide Powder mixed with 0.2% Chlorhexidine Digluconate or mixed with Normal Saline as Intracanal Medicament in the Treatment of Apical Periodontitis. AB - AIM: To compare the efficacy of calcium hydroxide powder mixed with 0.2% chlorhexidine digluconate or mixed with normal saline as intracanal medicament in the treatment of apical periodontitis. MATERIALS AND METHODS: Subjects were 55 in number aged 17 to 60 years. Two-visit conventional root canal treatment was performed on 70 teeth. The teeth were divided by randomization (balloting) into two groups: control group and experimental group, each with 35 teeth treated with calcium hydroxide mixed with normal saline or with 0.2% chlorhexidine digluconate as intracanal medicament respectively. All treated teeth were evaluated clinically and radiographically for signs and symptom of periapical infection at specified periods postoperatively. Overall efficacy of medicament was rated based on quality guidelines for endodontic treatment by the European Society of Endodontology 2006. RESULTS: A postoperative favorable outcome of 97.1% in the control group and 94.3% in the experimental group was observed at 6-month review. This difference was not statistically significant (p > 0.05). CONCLUSION: The use of normal saline or 0.2% chlorhexidine digluconate to mix calcium hydroxide used as intracanal medicament during endodontic treatment resulted in high postoperative favorable outcomes. CLINICAL SIGNIFICANCE: Efficacy of 0.2% chlorhexidine digluconate as a vehicle for mixing calcium hydroxide as an intracanal medicament in the treatment of apical periodontitis is comparable to the efficacy of calcium hydroxide mixed with normal saline. PMID- 26423503 TI - Biocorrosion of Endodontic Files through the Action of Two Species of Sulfate reducing Bacteria: Desulfovibrio desulfuricans and Desulfovibrio fairfieldensis. AB - AIM: This study assessed the biocorrosive capacity of two bacteria: Desulfovibrio desulfuricans and Desulfovibrio fairfieldensis on endodontic files, as a preliminary step in the development of a biopharmaceutical, to facilitate the removal of endodontic file fragments from root canals. MATERIALS AND METHODS: In the first stage, the corrosive potential of the artificial saliva medium (ASM), modified Postgate E medium (MPEM), 2.5 % sodium hypochlorite (NaOCl) solution and white medium (WM), without the inoculation of bacteria was assessed by immersion assays. In the second stage, test samples were inoculated with the two species of sulphur-reducing bacteria (SRB) on ASM and modified artificial saliva medium (MASM). In the third stage, test samples were inoculated with the same species on MPEM, ASM and MASM. All test samples were viewed under an infinite focus Alicona microscope. RESULTS: No test sample became corroded when immersed only in media, without bacteria. With the exception of one test sample between those inoculated with bacteria in ASM and MASM, there was no evidence of corrosion. Fifty percent of the test samples demonstrated a greater intensity of biocorrosion when compared with the initial assays. CONCLUSION: Desulfovibrio desulfuricans and D. fairfieldensis are capable of promoting biocorrosion of the steel constituent of endodontic files. CLINICAL SIGNIFICANCE: This study describes the initial development of a biopharmaceutical to facilitate the removal of endodontic file fragments from root canals, which can be successfully implicated in endodontic therapy in order to avoiding parendodontic surgery or even tooth loss in such events. PMID- 26423504 TI - Effectiveness of Oral Antiseptics on Tooth Biofilm: A Study in vivo. AB - AIM: To evaluate the effectiveness of five different mouthwashes through measurement of the plaque index. MATERIALS AND METHODS: Fifty subjects took part in this blind study, randomized into blocks of five groups according to the active ingredient of the mouthwash: CHX group (0.12% chlorhexidine gluconate), essential oils (EO) group, cetylpyridinium chloride (CPC) group, Tri group (triclosan) and Hamamelis virginiana (HV) group. All subjects were evaluated for a reduction in the bacterial plaque index at 7, 14 and 21 days. RESULTS: There was a significant reduction in the mean plaque index during the period of evaluation (p < 0.01), and the reduction during the period of evaluation was different between mouthwashes (p < 0.01). The reduction in the plaque index at the end of 21 days was, in decreasing order, CHX > EO > CPC > Tri > HV. CONCLUSION: The reduction in the plaque index during the period of evaluation was different between the types of mouth-wash. The mouthwash containing the active ingredient chlorhexidine was the most effective, followed by the essential oil, cetylpyridinium chloride, triclosan and H. virginiana. PMID- 26423505 TI - The Effects of Ionizing Radiation on the Oral Cavity. AB - AIM: The aim of this study is to present a literature review on the effects of the ionizing radiation from radiotherapy treatment on dental tissues. BACKGROUND: Among the effects of increasing global life expectancy and longevity of the teeth in the oral cavity, increasing rates of neoplastic diseases have been observed. One of the important treatment modalities for head and neck neoplastic diseases is radiotherapy, which uses ionizing radiation as the main mechanism of action. Therefore, it is essential for dentists to be aware of the changes in oral and dental tissues caused by ionizing radiation, and to develop treatment and prevention strategies. RESULTS: In general, there is still controversy about the effects of ionizing radiation on dental structures. However, qualitative and quantitative changes in saliva and oral microbiota, presence of oral mucositis and radiation-related caries are expected, as they represent the well-known side effects of treatment with ionizing radiation. Points that still remain unclear are the effects of radiotherapy on enamel and dentin, and on their mechanisms of bonding to contemporary adhesive materials. CONCLUSION: Ionizing radiation has shown important interaction with organic tissues, since more deleterious effects have been shown on the oral mucosa, salivary glands and dentin, than on enamel. CLINICAL SIGNIFICANCE: With the increasing number of patients with cancer seeking dental treatment before and after head and neck radiotherapy, it is important for dentists to be aware of the effects of ionizing radiation on the oral cavity. PMID- 26423506 TI - Effect of Three-wall Bony Defect along Various Root Surfaces on Position of Center of Resistance: A 3D Finite Element Analysis. AB - INTRODUCTION: Increase in adult orthodontic patients has increased the challenges faced by orthodontists, as they often present themselves with a varying degree of dental and peri-odontal compromise, in which the entire orthodontic treatment planning will revolve around maintenance and augmentation of supporting apparatus. One of the many factors to be considered during treating an adult patient is the height of alveolar bone and its effect on center of resistance (CRes). MATERIALS AND METHODS: Eight 3D analytical models of upper central incisor were designed using 'Solid Works Office Premium'. The models were subjected to 3 and 6 mm bone loss along all four surfaces, i.e. labial, lingual, mesial and distal. One Newton of retraction force was applied on labial surface of tooth on model number 1, 2, 5 and 6 and 1N of distalization force was applied to model number 3, 4, 7 and 8. The relative location of the CRes to the total root length was taken as 41.8% of total root length from the root apex. The ANSYS software was used to evaluate the change in CRes on all the models. RESULTS: It was observed that CRes shifted apically from its relative location (41.8% from apex); however, this shift was clinically insignificant. Minimum deflection of CRes, 0.0122 mm, was seen when a distalization force was applied on model with 6 mm bone loss on distal surface, while maximum deflection of 0.0245 mm was seen when retraction force was applied on model with 6 mm bone loss on labial surface. CONCLUSION: The resultant displacement in position of center of resistance is negligible; hence, there is no need of changing biomechanics during orthodontic treatment for a tooth with three wall infrabony defects. However, it is necessary to further study other infrabony defects like two wall or one wall defect, and their effect on position of CRes. PMID- 26423507 TI - Genotoxicity of Endodontic Materials: A Critical Review. AB - Genotoxicity is an action on cell's genetic material which may affect its integrity. This includes certain types of radiations and also certain chemical compounds. Genotoxic materials are those with affinity to interact with DNA but render them potentially carcinogenic or mutagenic. This review will address the genotoxicity of endodontic irrigants, medicaments and sealers. PMID- 26423508 TI - An Intraoperative Site-specific Bone Density Device: A Pilot Test Case. AB - AIM: This paper reports a case of all-on-four rehabilitation where bone density at implant sites was assessed both through preoperative computed tomographic (CT) scans and using a micromotor working as an intraoperative bone density measurement device. BACKGROUND: Implant-supported rehabilitation is a predictable treatment option for tooth replacement whose success depends on the clinician's experience, the implant characteristics and location and patient-related factors. Among the latter, bone density is a determinant for the achievement of primary implant stability and, eventually, for implant success. The ability to measure bone density at the placement site before implant insertion could be important in the clinical setting. CASE DESCRIPTION: A patient complaining of masticatory impairment was presented with a plan calling for extraction of all her compromised teeth, followed by implant rehabilitation. A week before surgery, she underwent CT examination, and the bone density on the CT scans was measured. When the implant osteotomies were created, the bone density was again measured with a micromotor endowed with an instantaneous torque-measuring system. The implant placement protocols were adapted for each implant, according to the intraoperative measurements, and the patient was rehabilitated following an all on-four immediate loading protocol. CONCLUSION: The bone density device provided valuable information beyond that obtained from CT scans, allowing for site specific, intraoperative assessment of bone density immediately before implant placement and an estimation of primary stability just after implant insertion. CLINICAL SIGNIFICANCE: Measuring jaw-bone density could help clinicians to select implant-placement protocols and loading strategies based on site-specific bone features. PMID- 26423509 TI - Management of Maxillary Deformity with Segmental Osteotomy followed by Implant Insertion in beta-Thalassemia Major Patient. AB - AIM: The aim of this report is to present the management of the maxillary deformity and subsequent implant therapy of a case with beta-thalassemia major. BACKGROUND: beta-thalassemia is a hematologic disorder that results from the abnormality of the beta-globulin chain synthesis. The best known thalassemia induced dentofacial problem is the maxillary enlargement, and this undesirable growth of maxilla affects not only the facial esthetics but also dental occlusion, and leads to functional deficiency. CASE DESCRIPTION: A 16-year-old female patient with beta-thalasse-mia major was referred with the complaints of severe facial deformity and malocclusion, resulting in psychosocial and functional problems for her. The dentofacial deformity was characterized by an excessive premaxillary growth both in sagittal and vertical planes. Anterior maxillary osteotomy was performed with bilateral canines extraction, and dental implants were inserted to the canine regions, following bone healing. Postoperative course was free of problems with the crown restorations in function. Recurrence has not been occurred at 6 years follow-up. CONCLUSION: With maintaining hemoglobin level over 10 gm/dl, correction of maxillary defects is stable for long-term in beta-thalassemia major patient. Implant application to these patients may lead to unforeseeable results. CLINICAL SIGNIFICANCE: Although having some difficulties, such as overbleeding and stability problems, maxillary enlargement can be treated by segmental osteotomies successfully in beta thalassemia major patient. Implant failure frequency may be higher, but many other studies are needed for determining implant survival rate in beta thalassemia major patients. PMID- 26423510 TI - Clinical Trials with Oncolytic Viruses: Current and Future Prospects. AB - Reviewing the research in the field of oncolytic virus therapy (OVT) of the past two decades, it is inspiring to see the enormous amount of success accomplished by the scholars of this innovative therapeutic technique. Though the experimental trials have been ongoing from 1990s, however, it took a leap forward with approval of the clinical trials in China, 2005. The world's first oncolytic virus to be approved by their government was adenovirus (with E1B 55K gene deletion) for head and neck cancer therapy along with chemotherapy. PMID- 26423511 TI - A cortical locus for anisotropic overlay suppression of stimuli presented at fixation. AB - Human contrast sensitivity for narrowband Gabor targets is suppressed when superimposed on narrowband masks of the same spatial frequency and orientation (referred to as overlay suppression), with suppression being broadly tuned to orientation and spatial frequency. Numerous behavioral and neurophysiological experiments have suggested that overlay suppression originates from the initial lateral geniculate nucleus (LGN) inputs to V1, which is consistent with the broad tuning typically reported for overlay suppression. However, recent reports have shown narrowly tuned anisotropic overlay suppression when narrowband targets are masked by broadband noise. Consequently, researchers have argued for an additional form of overlay suppression that involves cortical contrast gain control processes. The current study sought to further explore this notion behaviorally using narrowband and broadband masks, along with a computational neural simulation of the hypothesized underlying gain control processes in cortex. Additionally, we employed transcranial direct current stimulation (tDCS) in order to test whether cortical processes are involved in driving narrowly tuned anisotropic suppression. The behavioral results yielded anisotropic overlay suppression for both broadband and narrowband masks and could be replicated with our computational neural simulation of anisotropic gain control. Further, the anisotropic form of overlay suppression could be directly modulated by tDCS, which would not be expected if the suppression was primarily subcortical in origin. Altogether, the results of the current study provide further evidence in support of an additional overlay suppression process that originates in cortex and show that this form of suppression is also observable with narrowband masks. PMID- 26423512 TI - Fulminant BCG Disease in a 7 Month Old Healthy Male Infant. AB - A seven month old healthy male infant was brought with papular skin lesions all over the body, which became ulcerative with increasing fever and redness within 1 week duration. On examination, Bacilli Calmette Guerin (BCG) scar was ulcerated with discharge; infant was irritable with tachycardia and tachypnea. Investigations revealed pancytopenia, and acid fast bacilli was positive in skin lesions and at BCG scar site. There was progressive worsening of infant's condition, culminating in death. PMID- 26423514 TI - International Medical Teams of the Japan Medical Association: A Framework for Foreign Medical Teams. PMID- 26423513 TI - Breastfeeding Is Associated with Decreased Risk of Hospitalization among HIV Exposed, Uninfected Kenyan Infants. AB - BACKGROUND: Human immunodeficiency virus (HIV)-exposed uninfected (HEU) infants are a growing population in sub-Saharan Africa, with higher morbidity and mortality than HIV-unexposed infants. HEU infants may experience increased morbidity due to breastfeeding avoidance. OBJECTIVES: We sought to describe the burden and identify predictors of hospitalization among HEU infants in the first year of life. METHODS: Using a retrospective cohort of HIV-infected mothers and their HEU infants in Nairobi, Kenya, we identified infants who were HIV uninfected at birth and were followed monthly until their last negative HIV test, death, loss to follow-up, or study exit at 1 year of age. Incidence, timing, and reason for hospitalization was assessed overall as well as stratified by feeding method. Predictors of first infectious disease hospitalization were identified using competing risk regression, with HIV acquisition and death as competing risks. RESULTS: Among 388 infants, 113 hospitalizations were reported (35/100 infant-years [the combined years of observation contributed by all infants in the study]; 95% confidence interval [CI], 29-42). Ninety hospitalizations were due to 1 or more infectious diseases (26/100 infant-years; 95% CI, 21-32)-primarily pneumonia (n = 40), gastroenteritis (n = 17), and sepsis (n = 14). Breastfeeding was associated with decreased risk of infectious disease hospitalization (subhazard ratio = 0.39; 95% CI, 0.24-0.64), as was time-updated nutrition status (subhazard ratio = 0.73; 95% CI, 0.61-0.89). Incidence of infectious disease hospitalization among formula-fed infants was 51/100 infant-years (95% CI, 37-70) compared to 19/100 infant-years (95% CI, 14-25) among breastfed infants. CONCLUSION: Among HEU infants, breastfeeding and nutrition status were associated with reduced hospitalization during the first year of life. PMID- 26423515 TI - Efficient experimental design for uncertainty reduction in gene regulatory networks. AB - BACKGROUND: An accurate understanding of interactions among genes plays a major role in developing therapeutic intervention methods. Gene regulatory networks often contain a significant amount of uncertainty. The process of prioritizing biological experiments to reduce the uncertainty of gene regulatory networks is called experimental design. Under such a strategy, the experiments with high priority are suggested to be conducted first. RESULTS: The authors have already proposed an optimal experimental design method based upon the objective for modeling gene regulatory networks, such as deriving therapeutic interventions. The experimental design method utilizes the concept of mean objective cost of uncertainty (MOCU). MOCU quantifies the expected increase of cost resulting from uncertainty. The optimal experiment to be conducted first is the one which leads to the minimum expected remaining MOCU subsequent to the experiment. In the process, one must find the optimal intervention for every gene regulatory network compatible with the prior knowledge, which can be prohibitively expensive when the size of the network is large. In this paper, we propose a computationally efficient experimental design method. This method incorporates a network reduction scheme by introducing a novel cost function that takes into account the disruption in the ranking of potential experiments. We then estimate the approximate expected remaining MOCU at a lower computational cost using the reduced networks. CONCLUSIONS: Simulation results based on synthetic and real gene regulatory networks show that the proposed approximate method has close performance to that of the optimal method but at lower computational cost. The proposed approximate method also outperforms the random selection policy significantly. A MATLAB software implementing the proposed experimental design method is available at http://gsp.tamu.edu/Publications/supplementary/roozbeh15a/. PMID- 26423517 TI - Numerical study of achiral phase-change metamaterials for ultrafast tuning of giant circular conversion dichroism. AB - Control of the polarization of light is highly desirable for detection of material's chirality since biomolecules have vibrational modes in the optical region. Here, we report an ultrafast tuning of pronounced circular conversion dichroism (CCD) in the mid-infrared (M-IR) region, using an achiral phase change metamaterial (PCMM). Our structure consists of an array of Au squares separated from a continuous Au film by a phase change material (Ge2Sb2Te5) dielectric layer, where the Au square patches occupy the sites of a rectangular lattice. The extrinsically giant 2D chirality appears provided that the rectangular array of the Au squares is illuminated at an oblique incidence, and accomplishes a wide tunable wavelength range between 2664 and 3912 nm in the M-IR regime by switching between the amorphous and crystalline states of the Ge2Sb2Te5. A photothermal model is investigated to study the temporal variation of the temperature of the Ge2Sb2Te5 layer, and shows the advantage of fast transiting the phase of Ge2Sb2Te5 of 3.2 ns under an ultralow incident light intensity of 1.9 MUW/MUm(2). Our design is straightforward to fabricate and will be a promising candidate for controlling electromagnetic (EM) wave in the optical region. PMID- 26423516 TI - A deuterostome origin of the Spemann organiser suggested by Nodal and ADMPs functions in Echinoderms. AB - During development of chordates, establishment of the body plan relies on the activity of an organizing centre located on the dorsal side of the embryo that patterns the embryo and induces neural tissue. Intriguingly, the evolutionary origin of this crucial signalling centre remains unclear and whether analogous organizers regulate D/V patterning in other deuterostome or protostome phyla is not known. Here we provide evidence that the ventral ectoderm of the sea urchin embryo is a long-range organizing centre that shares several fundamental properties with the Spemann organizer: the ability to induce duplicated embryonic axes when ectopically induced, the ability to induce neural fate in neighbouring tissues and the ability to finely regulate the level of BMP signalling by using an autoregulatory expansion-repression mechanism. These findings suggest that the evolutionary origin of the Spemann organizer is more ancient than previously thought and that it may possibly be traced back to the common ancestor of deuterostomes. PMID- 26423518 TI - Pri-miR-124 rs531564 polymorphism and colorectal cancer risk. AB - MiR-124 functions as a tumor suppressor and plays an important role in tumorigenesis. A common polymorphism (rs531564, C>G) in the pri-miR-124 has been recently studied in connection with cancer risk. The aim of the present study was to investigate the association between pri-miR-124 rs531564 polymorphism and the risk and clinicopathological characteristics of colorectal cancer (CRC). Two case control studies involving 900 CRC patients and 1110 cancer-free controls showed that pri-miR-124 rs531564 polymorphism was significantly associated with the decreased risk of CRC in Xuzhou population [GG vs. CC: OR = 0.25, 95%CI = 0.09 0.67, P = 0.003; (CG+GG) vs. CC: OR = 0.73, 95%CI = 0.56-0.94, P = 0.01; GG vs. (CC+CG): OR = 0.27, 95%CI = 0.10-0.70, P = 0.004; G vs. C: OR = 0.70, 95%CI = 0.56-0.89, P = 0.003], Bengbu population [GG vs. CC: OR = 0.20, 95%CI = 0.04 0.90, P = 0.02; GG vs. (CC+CG): OR = 0.21, 95%CI = 0.05-0.95, P = 0.03; G vs. C: OR = 0.72, 95%CI = 0.54-0.98, P = 0.03] and pooled population [GG vs. CC: OR = 0.26, 95%CI = 0.11-0.59, P<0.001; (CG+GG) vs. CC: OR = 0.76, 95%CI = 0.62-0.93, P = 0.008; GG vs. (CC+CG): OR = 0.27, 95%CI = 0.12-0.62, P < 0.001; G vs. C: OR = 0.71, 95%CI = 0.59-0.85, P<0.001]. Additionally, pri-miR-124 rs531564 polymorphism was significantly associated with the decreased risk of poor differentiation and lymph node metastasis of CRC. Our results suggest that pri miR-124 rs531564 polymorphism may be a genetic modifier for developing CRC. However, further studies are needed to validate our findings. PMID- 26423519 TI - Origin of Self-preservation Effect for Hydrate Decomposition: Coupling of Mass and Heat Transfer Resistances. AB - Gas hydrates could show an unexpected high stability at conditions out of thermodynamic equilibrium, which is called the self-preservation effect. The mechanism of the effect for methane hydrates is here investigated via molecular dynamics simulations, in which an NVT/E method is introduced to represent different levels of heat transfer resistance. Our simulations suggest a coupling between the mass transfer resistance and heat transfer resistance as the driving mechanism for self-preservation effect. We found that the hydrate is initially melted from the interface, and then a solid-like water layer with temperature dependent structures is formed next to the hydrate interface that exhibits fractal feature, followed by an increase of mass transfer resistance for the diffusion of methane from hydrate region. Furthermore, our results indicate that heat transfer resistance is a more fundamental factor, since it facilitates the formation of the solid-like layer and hence inhibits the further dissociation of the hydrates. The self-preservation effect is found to be enhanced with the increase of pressure and particularly the decrease of temperature. Kinetic equations based on heat balance calculations is also developed to describe the self-preservation effect, which reproduces our simulation results well and provides an association between microscopic and macroscopic properties. PMID- 26423521 TI - In Memoriam: Alexander V. Nichols (1924 - 2015). PMID- 26423520 TI - Simplified assays of lipolysis enzymes for drug discovery and specificity assessment of known inhibitors. AB - Lipids are used as cellular building blocks and condensed energy stores and also act as signaling molecules. The glycerolipid/ fatty acid cycle, encompassing lipolysis and lipogenesis, generates many lipid signals. Reliable procedures are not available for measuring activities of several lipolytic enzymes for the purposes of drug screening, and this resulted in questionable selectivity of various known lipase inhibitors. We now describe simple assays for lipolytic enzymes, including adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL), sn-1-diacylglycerol lipase (DAGL), monoacylglycerol lipase, alpha/beta hydrolase domain 6, and carboxylesterase 1 (CES1) using recombinant human and mouse enzymes either in cell extracts or using purified enzymes. We observed that many of the reported inhibitors lack specificity. Thus, Cay10499 (HSL inhibitor) and RHC20867 (DAGL inhibitor) also inhibit other lipases. Marked differences in the inhibitor sensitivities of human ATGL and HSL compared with the corresponding mouse enzymes was noticed. Thus, ATGListatin inhibited mouse ATGL but not human ATGL, and the HSL inhibitors WWL11 and Compound 13f were effective against mouse enzyme but much less potent against human enzyme. Many of these lipase inhibitors also inhibited human CES1. Results describe reliable assays for measuring lipase activities that are amenable for drug screening and also caution about the specificity of the many earlier described lipase inhibitors. PMID- 26423522 TI - A single-nucleotide-polymorphism real-time PCR assay for genotyping of Mycobacterium tuberculosis complex in peri-urban Kampala. AB - BACKGROUND: Accurate and high-throughput genotyping of Mycobacterium tuberculosis complex (MTBC) may be important for understanding the epidemiology and pathogenesis of tuberculosis (TB). In this study, we report the development of a LightCycler(r) real-time PCR single-nucleotide-polymorphism (LRPS) assay for the rapid determination of MTBC lineages/sublineages in minimally processed sputum samples from TB patients. METHOD: Genotyping analysis of 70 MTBC strains was performed using the Long Sequence Polymorphism-PCR (LSP-PCR) technique and the LRPS assay in parallel. For targeted sequencing, 9 MTBC isolates (three isolates per MTBC lineage) were analyzed for lineage-specific single nucleotide polymorphisms (SNPs) in the following three genes to verify LRPS results: Rv004c for MTB Uganda family, Rv2962 for MTB lineage 4, and Rv0129c for MTB lineage 3. The MTBC lineages present in 300 smear-positive sputum samples were then determined by the validated LRPS method without prior culturing. RESULTS: The LSP PCR and LRPS assays produced consistent genotyping data for all 70 MTBC strains; however, the LSP-PCR assay was 10-fold less sensitive than the LRPS method and required higher DNA concentrations to successfully characterize the MTBC lineage of certain samples. Targeted sequencing of genes containing lineage-specific SNPs was 100 % concordant with the genotyping results and provided further validation of the LRPS assay. Of the 300 sputum samples analyzed, 58 % contained MTBC from the MTBC-Uganda family, 27 % from the MTBC lineage 4 (excluding MTBC Uganda family), 13 % from the MTBC lineage 3, and the remaining 2 % were of indeterminate lineage. CONCLUSION: The LRPS assay is a sensitive, high-throughput technique with potential application to routine genotyping of MTBC in sputum samples from TB patients. PMID- 26423523 TI - Associations between biosecurity and outbreaks of canine distemper on Danish mink farms in 2012-2013. AB - BACKGROUND: During 8 months from July 2012 to February 2013, a major outbreak of canine distemper involving 64 mink farms occurred on the Danish peninsula of Jutland. The canine distemper outbreak was associated with exposure of farmed mink to infected wild carnivores and could represent a deficit in biosecurity on the mink farms. The aim of this study was to investigate the extent and association of specific biosecurity measures with the outbreak. The study was carried out in an epidemiological case-control design. The case group consisted of the 61 farms, which had a confirmed outbreak of canine distemper from July 2012 to February 2013. The control group included 54 farms without an outbreak of canine distemper in 2012 or 2013, selected as the closest geographical neighbour to a case farm. RESULTS: The results showed that significantly more control than case farms had vaccinated their mink against canine distemper virus. Mortality was only assessed on the case farms, and there was a non-significantly lower mortality on vaccinated farms than on the non-vaccinated farms. Furthermore, the proportion of farms with observations of wild red foxes (Vulpes vulpes) inside the farm enclosures were larger for case farms, indicating that the control farms had a better biosecurity or were not equally exposed to canine distemper virus. Generally, all farms had very few specific precautions at the gate entrance in respect to human visitors as well as animals. The use of biosecurity measures was very variable in both case and control farms. Not using plastic boot covers, presence of dogs and cats, presence of demarcated area for changing clothes when entering and leaving the farm area and presence of hand washing facilities significantly lowered the odds of the farm having a canine distemper virus outbreak. CONCLUSIONS: The results of the study indicate that consistent use of correct vaccination strategies, implementation of biosecurity measures and limiting human and animal access to the mink farm can be important factors in reducing the risk for canine distemper outbreaks. PMID- 26423524 TI - Aerobic and strength exercises for youngsters aged 12 to 15: what do parents think? AB - BACKGROUND: Although strength exercises evidently have both physiological and psychological health benefits across all ages, they are erroneously considered to adversely affect health status in youngsters. The aim of this study was to examine parental attitudes towards their child's physical activity in general, as well as aerobic and strength exercises in particular. METHODS: In total, 314 parents from an online panel representative of the Dutch population completed an online survey about their own physical activity and that of their child (12-15 years old). The study also explored reasons for non-participation, and attitudes about the parents' own and their child's physical activity level. RESULTS: Parents consistently reported a positive attitude towards aerobic exercises, but a less positive attitude regarding strength exercises. Parents were more likely to indicate that their child was not allowed to participate in strength exercises (29.6 %) than aerobic exercises (4.0 %). They thought that strength exercises could interfere with optimal physical development. CONCLUSIONS: This study consistently shows that parents have a positive attitude towards aerobic exercises, but a less positive attitude regarding strength exercises. We suggest testing interventions to increase parental understanding of the advantages of and possibilities for (e.g., facilities) strength training on their child's health. PMID- 26423525 TI - Evaluation of wound healing and anti-inflammatory activity of the rhizomes of Rumex abyssinicus J. (Polygonaceae) in mice. AB - BACKGROUND: Rumex abyssinicus Jacq (Polygonaceae) is widely used in Ethiopia for treatment of wound and other diseases. Although reports are available in the literature on some of the claimed activities, nothing has so far been reported about the wound healing activity of R. abyssinicus. Thus, this work was initiated to investigate the wound healing and anti-inflammatory activities of 80% methanol extract of the rhizomes of R. abyssinicus in mice. METHODS: Following extraction of the rhizomes of the plant with 80% methanol, the extract was formulated as ointment (5% & 10% w/w) with simple ointment base B.P. The ointment was then evaluated for wound healing activity using excision and incision wound models. Parameters, including wound contraction, epithelization time and hydroxyproline content were determined using the excision model, whereas tensile strength was measured from the incision model. In parallel, anti-inflammatory activity of the rhizome was evaluated with carrageenan induced hind paw edema model by dissolving the 80% methanol extract in 1% carboxyl methyl cellulose and administering orally in various doses (250, 500 and 750 mg/kg). RESULTS: Wound treated with 5% and 10% (w/w) hydroalcoholic extract ointment exhibited significant wound healing activity in both models, as evidenced by increased wound contraction, shorter epithelization time, higher tissue breaking strength and increased hydroxyproline content. The hydroalcoholic extract also produced dose-related significant reduction (p < 0.05-0.001) of inflammation. CONCLUSIONS: The results of this study demonstrated that the hydroalcoholic extract of the rhizomes of R. abyssinicus facilitated wound healing at least in part via its anti-inflammatory activity, supporting its traditional claim as a wound healing agent. PMID- 26423526 TI - "Borderline" fluorotic region in Serbia: correlations among fluoride in drinking water, biomarkers of exposure and dental fluorosis in schoolchildren. AB - This study explores relation between dental fluorosis occurrence in schoolchildren, residents of Ritopek, a small local community near Belgrade, and fluoride exposure via drinking water. Additionally, fluoride levels were determined in children's urine and hair samples, and efforts were made to correlate them with dental fluorosis. Dental fluorosis and caries prevalence were examined in a total of 52 schoolchildren aged 7-15 years (29 boys and 23 girls). Fluoride levels in three types of samples were analyzed using composite fluoride ion-selective electrode. Results showed high prevalence of dental fluorosis (34.6 %) and low prevalence of dental caries (23.1 %, mean DMFT 0.96) among children exposed to wide range of water fluoride levels (0.11-4.14 mg/L, n = 27). About 11 % of water samples exceeded 1.5 mg/L, a drinking-water quality guideline value for fluoride given by the World Health Organization (2006). Fluoride levels in urine and hair samples ranged between 0.07-2.59 (n = 48) and 1.07-19.83 mg/L (n = 33), respectively. Severity of dental fluorosis was positively and linearly correlated with fluoride levels in drinking water (r = 0.79). Fluoride levels in urine and hair were strongly and positively correlated with levels in drinking water (r = 0.92 and 0.94, respectively). Fluoride levels in hair samples appeared to be a potentially promising biomarker of fluoride intake via drinking water on one hand, and severity of dental fluorosis on the other hand. Based on community fluorosis index value of 0.58, dental fluorosis revealed in Ritopek can be considered as "borderline" public health issue. PMID- 26423527 TI - Assessment of indoor heat stress variability in summer and during heat warnings: a case study using the UTCI in Berlin, Germany. AB - Humans spend most of their time in confined spaces and are hence primarily exposed to the direct influence of indoor climate. The Universal Thermal Climate Index (UTCI) was obtained in 31 rooms (eight buildings) in Berlin, Germany, during summer 2013 and 2014. The indoor UTCI was determined from measurements of both air temperature and relative humidity and from data of mean radiant temperature and air velocity, which were either measured or modeled. The associated outdoor UTCI was obtained through facade measurements of air temperature and relative humidity, simulation of mean radiant temperature, and wind data from a central weather station. The results show that all rooms experienced heat stress according to UTCI levels, especially during heat waves. Indoor UTCI varied up to 6.6 K within the city and up to 7 K within building. Heat stress either during day or at night occurred on 35 % of all days. By comparing the day and night thermal loads, we identified maximum values above the 32 degrees C threshold for strong heat stress during the nighttime. Outdoor UTCI based on facade measurements provided no better explanation of indoor UTCI variability than the central weather station. In contrast, we found a stronger relationship of outdoor air temperature and indoor air temperature. Building characteristics, such as the floor level or window area, influenced indoor heat stress ambiguously. We conclude that indoor heat stress is a major hazard, and more effort toward understanding the causes and creating effective countermeasures is needed. PMID- 26423528 TI - Clinically effective OCD treatment prevents 5-HT1B receptor-induced repetitive behavior and striatal activation. AB - RATIONALE: Serotonin-1B receptor (5-HT1BR) agonist treatment induces obsessive compulsive disorder (OCD)-like behaviors including locomotor stereotypy, prepulse inhibition deficits, and delayed alternation disruptions, which are selectively prevented by clinically effective OCD treatment. However, the role of 5-HT1BRs in modulating other repetitive behaviors or OCD-like patterns of brain activation remains unclear. OBJECTIVES: We assessed the effects of 5-HT1BR agonism on digging, grooming, and open field behaviors in mice. We also quantified effects on neuronal activation in brain regions overactivated in OCD. Finally, we assessed whether effects of the 5-HT1BR challenge could be blocked by clinically effective, but not ineffective, drug treatments. METHODS: Mice were tested in open field, dig, and splash tests after acute treatment with saline, 1, 3, 5, or 10 mg/kg RU24969 (5-HT1B/1A agonist). Behavioral effects of RU24969 were also tested following co-treatment with vehicle, 1 mg/kg WAY100635 (5-HT1A antagonist) and 5 or 10 mg/kg GR127935 (5HT1B/D antagonist). Separate mice were behaviorally assessed following chronic pretreatment with vehicle with 10 mg/kg fluoxetine or 20 mg/kg desipramine and acute treatment with saline or 10 mg/kg RU24969. Brains were analyzed for Fos expression in the orbitofrontal cortex, the dorsal striatum, and the cerebellum. RESULTS: RU24969 induced robust locomotor stereotypy and decreased rearing, digging, and grooming. Effects were blocked by GR127935 but not by WAY100635. RU24969 also increased Fos expression in the dorsal striatum. Chronic fluoxetine, but not desipramine, alleviated 5-HT1BR induced effects. CONCLUSIONS: We report novel 5-HT1BR-induced behaviors and striatal activation that were alleviated only by clinically effective pharmacological OCD treatment. Studying the mechanisms underlying these effects could provide insight into OCD pathophysiology. PMID- 26423529 TI - Exercise for Hypertension: A Prescription Update Integrating Existing Recommendations with Emerging Research. AB - Hypertension is the most common, costly, and preventable cardiovascular disease risk factor. Numerous professional organizations and committees recommend exercise as initial lifestyle therapy to prevent, treat, and control hypertension. Yet, these recommendations differ in the components of the Frequency, Intensity, Time, and Type (FITT) principle of exercise prescription (Ex Rx); the evidence upon which they are based is only of fair methodological quality; and the individual studies upon which they are based generally do not include people with hypertension, which are some of the limitations in this literature. The purposes of this review are to (1) overview the professional exercise recommendations for hypertension in terms of the FITT principle of Ex Rx; (2) discuss new and emerging research related to Ex Rx for hypertension; and (3) present an updated FITT Ex Rx for adults with hypertension that integrates the existing recommendations with this new and emerging research. PMID- 26423530 TI - RAP1-GTPase signaling and platelet function. AB - Platelets are critical for hemostasis, i.e., the body's ability to prevent blood loss at sites of vascular injury. They patrol the vasculature in a quiescent, non adhesive state for approximately 10 days, after which they are removed from circulation by phagocytic cells of the reticulo-endothelial system. At sites of vascular injury, they promptly shift to an activated, adhesive state required for the formation of a hemostatic plug. The small GTPase RAP1 is a critical regulator of platelet adhesiveness. Our recent studies demonstrate that the antagonistic balance between the RAP1 regulators, CalDAG-GEFI and RASA3, is critical for the modulation of platelet adhesiveness, both in circulation and at sites of vascular injury. The RAP1 activator CalDAG-GEFI responds to small changes in the cytoplasmic calcium concentration and thus provides sensitivity and speed to the activation response, essential for efficient platelet adhesion under conditions of hemodynamic shear stress. The RAP1 inhibitor RASA3 ensures that circulating platelets remain quiescent by restraining CalDAG-GEFI-dependent RAP1 activation. Upon cellular stimulation, it is turned off by P2Y12 signaling to enable sustained RAP1 activation, required for the formation of a stable hemostatic plug. This review will summarize important studies that elucidated the signaling pathways that control RAP1 activation in platelets. PMID- 26423532 TI - Familial inflammatory bowel diseases in Northwest Greece. PMID- 26423533 TI - Inhibition of HIV-1 assembly by coiled-coil domain containing protein 8 in human cells. AB - Human Immunodeficiency Virus type 1 (HIV-1) major structure protein Gag is synthesized in the cytoplasm, assembles on the plasma membrane, subsequently buds and releases. HIV-1 viral particles incorporate a number of host proteins to facilitate or inhibit HIV-1 replication. Here we identify a new host protein, coiled-coil domain containing protein 8 (CCDC8), in HIV-1 particles. Incorporation of CCDC8 into virions is dependent on the interaction between CCDC8 and Gag matrix region. Exogenous overexpression of CCDC8 can strongly inhibit HIV 1 production, up to ~30 fold. CCDC8 is a membrane-associated protein. The interaction between exogenously expressed CCDC8 and Gag on the plasma membrane changes the assembly of Gag, and redirects it into intracellular sites, or causes Gag endocytosis. CCDC8, along with cytoskeleton protein obscuring-like1 (Obsl1) and E3 ligase Cul7, induces Gag polyubiquitination and degradation. Thus we identify a new host protein and a new pathway for HIV-1 Gag polyubiquitination and degradation. This pathway presents potential therapeutic strategies against HIV infection. PMID- 26423534 TI - Typical evanescent and atypical persistent polymorphic cutaneous rash in an adult Brazilian with Still's disease: a case report and review of the literature. AB - Adult onset Still's disease (AOSD) is a systemic auto-inflammatory condition of unknown etiology, characterized by high fever, an evanescent, salmon-pink maculopapular skin rash, arthralgia or arthritis and leukocytosis. AOSD can also present with atypical cutaneous manifestations, such as persistent pruritic coalescent papules or plaques and linear lesions that have highly distinctive pathological features and are usually associated with severe disease. Herein, we present a 31-year-old Brazilian man with both typical Still's rash and atypical persistent polymorphic cutaneous manifestations associated with severe systemic inflammatory response syndrome. Eosinophils that are consistently lacking in the AOSD-associated skin lesions were evident in the skin biopsy of the persistent atypical cutaneous manifestations and were either drug-related or AOSD associated. PMID- 26423535 TI - HLA-genotyping of clinical specimens using Ion Torrent-based NGS. AB - We have evaluated and validated the NXTypeTM workflow (One Lambda, Inc.) and the accompanying TypeStreamTM software on the Ion Torrent Next Generation Sequencing (NGS) platform using a comprehensive testing panel. The panel consisted of 285 genomic DNA (gDNA) samples derived from four major ethnic populations and contained 59 PT samples and 226 clinical specimens. The total number of alleles from the six loci interrogated by NGS was 3420. This validation panel provided a wide range of HLA sequence variations including many rare alleles, new variants and homozygous alleles. The NXTypeTM system (reagents and software) was able to correctly genotype the vast majority of these specimens. The concordance rate between SBT-derived genotypes and those generated by TypeStreamTM auto-analysis ranged from 99.5% to 99.8% for the HLA-A, B, C, DRB1 and DQB1 loci, and was 98.9% for HLA-DPB1. A strategy for data review was developed that would allow correction of most of the few remaining typing errors. The entire NGS workflow from gDNA amplification to genotype assignment could be completed within 3 working days. Through this validation study, the limitations and shortcomings of the platform, specific assay system, and software algorithm were also revealed for further evaluation and improvement. PMID- 26423531 TI - Dissecting the multiple myeloma-bone microenvironment reveals new therapeutic opportunities. AB - Multiple myeloma is a plasma cell skeletal malignancy. While therapeutic agents such as bortezomib and lenalidomide have significantly improved overall survival, the disease is currently incurable with the emergence of drug resistance limiting the efficacy of chemotherapeutic strategies. Failure to cure the disease is in part due to the underlying genetic heterogeneity of the cancer. Myeloma progression is critically dependent on the surrounding microenvironment. Defining the interactions between myeloma cells and the more genetically stable hematopoietic and mesenchymal components of the bone microenvironment is critical for the development of new therapeutic targets. In this review, we discuss recent advances in our understanding of how microenvironmental elements contribute to myeloma progression and, therapeutically, how those elements can or are currently being targeted in a bid to eradicate the disease. PMID- 26423536 TI - Advances in DNA sequencing technologies for high resolution HLA typing. AB - This communication describes our experience in large-scale G group-level high resolution HLA typing using three different DNA sequencing platforms - ABI 3730 xl, Illumina MiSeq and PacBio RS II. Recent advances in DNA sequencing technologies, so-called next generation sequencing (NGS), have brought breakthroughs in deciphering the genetic information in all living species at a large scale and at an affordable level. The NGS DNA indexing system allows sequencing multiple genes for large number of individuals in a single run. Our laboratory has adopted and used these technologies for HLA molecular testing services. We found that each sequencing technology has its own strengths and weaknesses, and their sequencing performances complement each other. HLA genes are highly complex and genotyping them is quite challenging. Using these three sequencing platforms, we were able to meet all requirements for G group-level high resolution and high volume HLA typing. PMID- 26423538 TI - How achievable is immediate ART for all? PMID- 26423539 TI - Mortality risk in older people on antiretroviral therapy. PMID- 26423537 TI - Infections, inflammation and epilepsy. AB - Epilepsy is the tendency to have unprovoked epileptic seizures. Anything causing structural or functional derangement of brain physiology may lead to seizures, and different conditions may express themselves solely by recurrent seizures and thus be labelled "epilepsy." Worldwide, epilepsy is the most common serious neurological condition. The range of risk factors for the development of epilepsy varies with age and geographic location. Congenital, developmental and genetic conditions are mostly associated with the development of epilepsy in childhood, adolescence and early adulthood. Head trauma, infections of the central nervous system (CNS) and tumours may occur at any age and may lead to the development of epilepsy. Infections of the CNS are a major risk factor for epilepsy. The reported risk of unprovoked seizures in population-based cohorts of survivors of CNS infections from developed countries is between 6.8 and 8.3 %, and is much higher in resource-poor countries. In this review, the various viral, bacterial, fungal and parasitic infectious diseases of the CNS which result in seizures and epilepsy are discussed. The pathogenesis of epilepsy due to brain infections, as well as the role of experimental models to study mechanisms of epileptogenesis induced by infectious agents, is reviewed. The sterile (non-infectious) inflammatory response that occurs following brain insults is also discussed, as well as its overlap with inflammation due to infections, and the potential role in epileptogenesis. Furthermore, autoimmune encephalitis as a cause of seizures is reviewed. Potential strategies to prevent epilepsy resulting from brain infections and non-infectious inflammation are also considered. PMID- 26423540 TI - Does early ART in sub-Saharan Africa decrease mortality? PMID- 26423541 TI - Antiretroviral therapy and perinatal outcomes. PMID- 26423542 TI - Making the economic case for universal ART access. PMID- 26423543 TI - Addressing barriers to the end of AIDS by 2030. PMID- 26423544 TI - Ensuring new medicines reach those in most need. PMID- 26423545 TI - Interpretation, communication, and mechanisms of associations between injectable contraception and HIV risk. PMID- 26423546 TI - Interpretation, communication, and mechanisms of associations between injectable contraception and HIV risk. PMID- 26423547 TI - Interpretation, communication, and mechanisms of associations between injectable contraception and HIV risk - Authors' reply. PMID- 26423548 TI - Interpretation, communication, and mechanisms of associations between injectable contraception and HIV risk. PMID- 26423549 TI - Interpretation, communication, and mechanisms of associations between injectable contraception and HIV risk - Authors' reply. PMID- 26423550 TI - Age in antiretroviral therapy programmes in South Africa: a retrospective, multicentre, observational cohort study. AB - BACKGROUND: As access to antiretroviral therapy (ART) expands, increasing numbers of older patients will start treatment and need specialised long-term care. However, the effect of age in ART programmes in resource-constrained settings is poorly understood. The HIV epidemic is ageing rapidly and South Africa has one of the highest HIV population prevalences worldwide. We explored the effect of age on mortality of patients on ART in South Africa and whether this effect is mediated by baseline immunological status. METHODS: In this retrospective cohort analysis, we studied HIV-positive patients aged 16-80 years who started ART for the first time in six large South African cohorts of the International Epidemiologic Databases to Evaluate AIDS-Southern Africa collaboration, in KwaZulu-Natal, Gauteng, and Western Cape (two primary care clinics, three hospitals, and a large rural cohort). The primary outcome was mortality. We ascertained patients' vital status through linkage to the National Population Register. We used inverse probability weighting to correct mortality for loss to follow-up. We estimated mortality using Cox's proportional hazards and competing risks regression. We tested the interaction between baseline CD4 cell count and age. FINDINGS: Between Jan 1, 2004, and Dec 31, 2013, 84,078 eligible adults started ART. Of these, we followed up 83,566 patients for 174,640 patient-years. 8% (1817 of 23,258) of patients aged 16-29 years died compared with 19% (93 of 492) of patients aged 65 years or older. The age adjusted mortality hazard ratio was 2.52 (95% CI 2.01-3.17) for people aged 65 years or older compared with those 16-29 years of age. In patients starting ART with a CD4 count of less than 50 cells per MUL, the adjusted mortality hazard ratio was 2.52 (2.04-3.11) for people aged 50 years or older compared with those 16-39 years old. Mortality was highest in patients with CD4 counts of less than 50 cells per MUL, and 15% (1103 of 7295) of all patients aged 50 years or older starting ART were in this group. The proportion of patients aged 50 years or older enrolling in ART increased with successive years, from 6% (290 of 4999) in 2004 to 10% (961 of 9657) in 2012-13, comprising 9% of total enrolment (7295 of 83 566). At the end of the study, 6304 (14%) of 44,909 patients still alive and in care were aged 50 years or older. INTERPRETATION: Health services need reorientation towards HIV diagnosis and starting of ART in older individuals. Policies are needed for long-term care of older people with HIV. FUNDING: National Institutes of Health (National Institute of Allergy and Infectious Diseases), US Agency for International Development, and South African Centre for Epidemiological Modelling and Analysis. PMID- 26423551 TI - Effect of baseline CD4 cell count at linkage to HIV care and at initiation of antiretroviral therapy on mortality in HIV-positive adult patients in Rwanda: a nationwide cohort study. AB - BACKGROUND: Continued debate exists about whether initiation of antiretroviral therapy (ART) in symptom-free patients at higher baseline CD4 cell counts results in important clinical benefits. We aimed to examine to what extent baseline CD4 cell count at linkage to HIV care and at ART initiation predicts mortality in adults with HIV in Rwanda. METHODS: We included data for patients with HIV in Rwanda who were aged 15 years or older and linked to care or initiated ART between Jan 1, 1997, and April 30, 2014, from nationally representative databases. We analysed the effect on mortality of baseline CD4 cell count at ART initiation and at linkage to care. Follow-up time was measured from time of ART initiation and from linkage to HIV care to study exit. To account for effect modification by time, we stratified by era of linkage (before 2008 vs 2008 or after) and for other indications for initiation of ART. We also stratified CD4 cell count by indication to initiate ART other than CD4 cell count status. We used Cox proportional hazard regressions to examine the effect of CD4 cell count at linkage and at ART initiation on mortality. FINDINGS: Our analysis was based on data from 50,147 patients who initiated ART and 72,061 patients linked to care. In the late era (2008 and after), linkage to care at a CD4 cell count of 100-199 cells per MUL without any further indication was associated with higher mortality than linkage at 200-349 cells per MUL (hazard ratio [HR] 1.37, 95% CI 0.95-1.97); the effect was much the same for initiation of ART in this CD4 stratum (1.37, 0.92-2.04). For higher CD4 strata, linkage to care at 500 cells per MUL or more was protective (0.53, 0.39-0.72), whereas the reported effect of initiation of ART on mortality was not distinguishable from chance alone (0.82, 0.21-3.20). INTERPRETATION: Efforts are needed to link and retain patients early in pre-ART HIV care. In settings where ART is not yet available for immediate treatment, retention in a strong pre-ART programme is effective at improving survival. FUNDING: The Bill & Melinda Gates Foundation. PMID- 26423552 TI - Pregnancy outcomes in HIV-positive women in Ukraine, 2000-12 (European Collaborative Study in EuroCoord): an observational cohort study. AB - BACKGROUND: Women living with HIV are potentially at increased risk of adverse pregnancy outcomes, due to a range of factors, including immunosuppression, use of combination antiretroviral therapy (ART), and injecting drug use. Rates of mother-to-child transmission of HIV in Ukraine have declined to around 2-4%, but little is known about other pregnancy outcomes in this setting. We used data from an observational prospective cohort study to assess pregnancy outcomes among HIV positive women in Ukraine. METHODS: The European Collaborative Study (ECS) in EuroCoord is a continuing cohort study, established in Ukraine in 2000. Eligible women are those with a diagnosis of HIV infection before or during pregnancy (including intrapartum) who deliver liveborn babies at seven sites. Maternal sociodemographic, HIV-related, and delivery (mother and infant) data were collected with study-specific questionnaires. We used Poisson regression models to identify factors associated with preterm delivery (before 37 weeks' gestation) and small weight for gestational age (less than the tenth percentile of weight for gestational age), based on complete cases. FINDINGS: Between January, 2000, and July, 2012, data were collected on 8884 HIV-positive mother and liveborn infant pairs. Median maternal age was 26.5 years (IQR 23.1-30.3). 832 (11%) women had WHO stage 3 or 4 HIV and 1474 (17%) had a history of injecting drug use. 7348 (83%) had received antenatal ART. Among 7435 for whom ART type was available, 4396 (50%) had received zidovudine monotherapy and 2949 (33%) combination ART. Preterm delivery was seen in 780 (9%, 95% CI 8-9) of 8860 births overall and in 77 (9%, 7-11) of 889 babies with small size for gestational age. Factors associated with preterm delivery were history of injecting drug use (adjusted risk ratio 1.64, 95% CI 1.38-1.95), no ART (2.94, 2.43-3.57 vs zidovudine monotherapy), antenatal combination ART (1.40, 1.14-1.73 vs zidovudine monotherapy), WHO stage 4 HIV (2.42, 1.71-3.41 vs WHO stage 1), and being in the most socially deprived group (1.38, 1.11-1.71). Small size for gestational age was associated with history of injecting drug use (adjusted RR 1.39, 95% CI 1.16 1.65), most socially deprived (1.32, 1.09-1.61), no ART (1.60, 1.32-1.94 vs zidovudine monotherapy), and antenatal combination ART (1.33, 1.12-1.60 vs zidovudine monotherapy). INTERPRETATION: Some risk factors for adverse pregnancy outcomes were directly associated with HIV and treatment and others were shared with the general antenatal population. Monitoring of pregnancy outcomes in Ukraine will be important as use of antenatal combination ART increases. FUNDING: European Union Seventh Framework Programme, Wellcome Trust. PMID- 26423553 TI - Cost-effectiveness of population-level expansion of highly active antiretroviral treatment for HIV in British Columbia, Canada: a modelling study. AB - BACKGROUND: Widespread HIV screening and access to highly active antiretroviral treatment (ART) were cost effective in mathematical models, but population-level implementation has led to questions about cost, value, and feasibility. In 1996, British Columbia, Canada, introduced universal coverage of drug and other health care costs for people with HIV/AIDS and and began extensive scale-up in access to ART. We aimed to assess the cost-effectiveness of ART scale-up in British Columbia compared with hypothetical scenarios of constrained treatment access. METHODS: Using comprehensive linked population-level data, we populated a dynamic, compartmental transmission model to simulate the HIV/AIDS epidemic in British Columbia from 1997 to 2010. We estimated HIV incidence, prevalence, mortality, costs (in 2010 CAN$), and quality-adjusted life-years (QALYs) for the study period, which was 1997-2010. We calculated incremental cost-effectiveness ratios from societal and third-party-payer perspectives to compare actual practice (true numbers of individuals accessing ART) to scenarios of constrained expansion (75% and 50% probability of accessing ART). We also investigated structural and parameter uncertainty. FINDINGS: Actual practice resulted in 263 averted incident cases compared with 75% of observed access and 676 averted cases compared with 50% of observed access to ART. From a third-party-payer perspective, actual practice resulted in incremental cost-effectiveness ratios of $23 679 per QALY versus 75% access and $24 250 per QALY versus 50% access. From a societal perspective, actual practice was cost saving within the study period. When the model was extended to 2035, current observed access resulted in cumulative savings of $25.1 million compared with the 75% access scenario and $65.5 million compared with the 50% access scenario. INTERPRETATION: ART scale-up in British Columbia has decreased HIV-related morbidity, mortality, and transmission. Resulting incremental cost-effectiveness ratios for actual practice, derived within a limited timeframe, were within established cost effectiveness thresholds and were cost saving from a societal perspective. FUNDING: BC Ministry of Health, National Institute of Drug Abuse at the US National Institutes of Health. PMID- 26423554 TI - Campylobacter jejuni PflB is required for motility and colonisation of the chicken gastrointestinal tract. AB - Campylobacter jejuni is the leading cause of foodborne bacterial gastroenteritis worldwide. Although the mechanisms by which C. jejuni causes disease are not completely understood, the presence of functional flagella appears to be required for colonisation of the gastrointestinal tract of humans and animals. Therefore much attention has been given to understanding the synthesis and role of flagella in C. jejuni. In this study we report insights into the function of PflB that is essential for Campylobacter motility. We have explored the function of this gene by constructing deletion mutants in C. jejuni strains NCTC11168 and M1, in the genes cj0390 and CJM1_0368, respectively. The mutants were non-motile yet assembled flagella that appeared structurally identical to the wild type. Furthermore the protein is required for C. jejuni colonisation of caeca in a two week old chicken colonisation model. PMID- 26423555 TI - Identification of CD4+ T-cell epitopes on iron-regulated surface determinant B of Staphylococcus aureus. AB - Iron-regulated surface determinant B (IsdB) of Staphylococcus aureus (S. aureus) is a highly conserved surface protein that can induce protective CD4(+) T-cell immune response. A pivotal role of CD4(+) T-cells in effective immunity against S. aureus infection has been proved, but CD4(+) T-cell epitopes on the S. aureus IsdB have not been well identified. In this study, MHC binding assay was firstly used to predict CD4(+) T-cell epitopes on S. aureus IsdB protein, and six peptides were synthesized to validate the probable epitopes. Two novel IsdB CD4(+) T-cell epitopes, P1 (residues 159-178) and P4 (residues 287-306), were for the first time identified using CD4(+) T-cells obtained from IsdB-immunized C57BL/6 (H-2(b)) and BALB/c (H-2(d)) mice spleen based on cell proliferation and cytokines response. The results showed that P1 and P4 emulsified in Freund's adjuvant (FA) induced much higher cell proliferation compared with PBS emulsified in FA. CD4(+) T-cells stimulated with peptides P1 and P4 secreted significantly higher levels of IFN-gamma and IL-17A. However, the level of the cytokine IL-4 almost remained unchanged, suggesting that P1 and P4 preferentially elicited polarized Th1-type responses. In addition, BALB/c mice just respond to P4 not P1, while C57BL/6 mice respond to P1 not P4, implying that epitope P1 and P4 were determined as H-2(b) and H-2(d) restricted epitope, respectively. Taken together, our data may provide an explanation of the IsdB-induced protection against S. aureus and highlight the possibility of developing the epitope-based vaccine against the S. aureus. PMID- 26423556 TI - A 10 year survey of acaricide residues in beeswax analysed in Italy. AB - BACKGROUND: The aim of this work was to provide an overview of the prevalence and level of acaricides in beeswax used in Italy in the past 10 years by analysing 1319 beeswax samples processed by the certified laboratory of the Italian Bee Research Institute. RESULTS: The proportion of samples positive to at least one active ingredient decreased between 2005 and 2009 (from 69 to 32%) and then increased again between 2009 and 2014 (from 32 to 91%). This trend is in agreement with reports from beekeepers that the use of synthetic acaricides decreased in the second half of the past decade and increased after the beginning of the colony losses phenomenon. The active ingredient with the greatest overall proportion of positive samples was coumaphos (49%), followed by fluvalinate (38%) and chlorphenvinphos (25%). The indicator for amitraz, 2,4 dimethylphenylformamide (DMPF), was detected in a very small proportion of samples (6%), while residues of cymiazole were never found. CONCLUSIONS: In more than half of the analysed samples, residues of at least one active ingredient were detected. The mean levels of residues of all the considered active ingredients in the positive samples may represent a source of accumulation in beeswax and pose risks to honey bee health. (c) 2015 Society of Chemical Industry. PMID- 26423557 TI - The associations of BMI trajectory and excessive weight gain with demographic and socio-economic factors: the Adolescent Nutritional Assessment Longitudinal Study cohort. AB - Assessing changes in adolescents' BMI over brief periods could contribute to detection of acute changes in weight status and prevention of overweight. The objective of this study was to analyse the BMI trajectory and the excessive weight gain of Brazilian adolescents over 3 years and the association with demographic and socio-economic factors. Data regarding the BMI of 1026 students aged between 13 and 19 years were analysed over 3 consecutive years (2010, 2011 and 2012) from the Adolescent Nutritional Assessment Longitudinal Study. Linear mixed effects models were used to assess the BMI trajectory according to the type of school attended (public or private), skin colour, socio-economic status and level of maternal schooling by sex. Associations between excessive weight gain and socio-economic variables were identified by calculation of OR. Boys attending private schools (beta coefficient: 0.008; P=0.01), those with white skin (beta coefficient: 0.007; P=0.04) and those whose mothers had >8 years of schooling (beta coefficient: 0.009; P=0.02) experienced greater BMI increase than boys and girls in other groups. Boys in private schools also presented higher excessive weight gain compared with boys attending public schools (P=0.03). Boys attending private schools experienced greater BMI increase and excessive weight gain, indicating the need to develop specific policies for the prevention and reduction of overweight in this population. PMID- 26423558 TI - Quantitative electron phase imaging with high sensitivity and an unlimited field of view. AB - As it passes through a sample, an electron beam scatters, producing an exit wavefront rich in information. A range of material properties, from electric and magnetic field strengths to specimen thickness, strain maps and mean inner potentials, can be extrapolated from its phase and mapped at the nanoscale. Unfortunately, the phase signal is not straightforward to obtain. It is most commonly measured using off-axis electron holography, but this is experimentally challenging, places constraints on the sample and has a limited field of view. Here we report an alternative method that avoids these limitations and is easily implemented on an unmodified transmission electron microscope (TEM) operating in the familiar selected area diffraction mode. We use ptychography, an imaging technique popular amongst the X-ray microscopy community; recent advances in reconstruction algorithms now reveal its potential as a tool for highly sensitive, quantitative electron phase imaging. PMID- 26423560 TI - Effects of Particle Size, Electronic Connectivity, and Incoherent Nanoscale Domains on the Sequence of Lithiation in LiFePO4 Porous Electrodes. AB - High-resolution X-ray microscopy is used to investigate the sequence of lithiation in LiFePO4 porous electrodes. For electrodes with homogeneous interparticle electronic connectivity via the carbon black network, the smaller particles lithiate first. For electrodes with heterogeneous connectivity, the better-connected particles preferentially lithiate. Correlative electron and X ray microscopy also reveal the presence of incoherent nanodomains that lithiate as if they are separate particles. PMID- 26423559 TI - Adherence to common cardiovascular medications in patients with schizophrenia vs. patients without psychiatric illness. AB - OBJECTIVE: The purpose of the study was to examine whether individuals with diagnoses of schizophrenia were differentially adherent to their statin or angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) medications compared to individuals without psychiatric illness. METHOD: Using electronic medical record data across 13 Mental Health Research Network sites, individuals with diagnoses of schizophrenia or schizoaffective disorder receiving two or more medication dispensings of a statin or an ACEI/ARB in 2011 (N=710) were identified and matched on age, sex and Medicare status to controls with no documented mental illness and two or more medication dispensings of a statin in 2011 (N=710). Medication adherence, and sociodemographic and clinical characteristics of the study population were assessed. RESULTS: Multivariable models indicated that having a schizophrenia diagnosis was associated with increased odds of statin medication adherence; the odds ratio suggested a small effect. After adjustment for medication regimen, schizophrenia no longer showed an association with statin adherence. Having a schizophrenia diagnosis was not associated with ACEI/ARB medication adherence. CONCLUSIONS: Compared to patients without any psychiatric illness, individuals with schizophrenia were marginally more likely to be adherent to their statin medications. Given that patterns of adherence to cardioprotective medications may be different from patterns of adherence to antipsychotic medications, improving adherence to the former may require unique intervention strategies. PMID- 26423561 TI - Nanomedicine of anastrozole for breast cancer: Physicochemical evaluation, in vitro cytotoxicity on BT-549 and MCF-7 cell lines and preclinical study on rat model. AB - AIM: Formulation and evaluation of anastrozole, an anti-cancer drug loaded in different biodegradable polymeric nanoparticles. MATERIALS AND METHODS: Different carrier systems such as poly(lactide-co-glycolide) (PLGA 50:50), poly(lactic acid) (PLA) and poly(epsilon-caprolactone) (PCL) are used to prepare nanoparticles by simple emulsion technique. The surfactants polyvinyl alcohol and sodium deoxycholate were studied for their use as stabilizing agents at varying concentrations. The formulations were studied for their particle size, zeta potential, entrapment efficiency and solid state characteristics, and also were tested for their in vitro cytotoxicity and in vivo behavior in rats. KEY FINDINGS: The entrapment ranged from 35 to 85%, depending on the drug-polymer ratio used. Particle size ranged from 100 to 350nm with optimal zeta potential. Accordingly, discrete spherical nanoparticles with smooth surface were obtained as evidence from Field Emission Scanning Electron Microscopy (FESEM) study. The solid state characteristics revealed dispersion of drug at the molecular level in the polymeric matrix of nanoparticles. A non-Fickian transport with initial burst release followed by slow release was observed with nanoparticles. The remarkable decrease in cell viability at various time points was observed for PLGA nanoparticles compared to other polymer matrices. The AUC(0->infinity) of PLGA, PLA and PCL nanoparticles were found to be 4.77, 19.31 and 19.81 fold higher than (p<0.05) anastrozole in solution, respectively. Also, pharmacokinetics study revealed the long time circulation of anastrozole loaded polymeric nanoparticles. SIGNIFICANCE: The results suggest that developed nanoparticles could be used successfully for effective management of breast cancer chemotherapy. PMID- 26423562 TI - A new cluster-based oversampling method for improving survival prediction of hepatocellular carcinoma patients. AB - Liver cancer is the sixth most frequently diagnosed cancer and, particularly, Hepatocellular Carcinoma (HCC) represents more than 90% of primary liver cancers. Clinicians assess each patient's treatment on the basis of evidence-based medicine, which may not always apply to a specific patient, given the biological variability among individuals. Over the years, and for the particular case of Hepatocellular Carcinoma, some research studies have been developing strategies for assisting clinicians in decision making, using computational methods (e.g. machine learning techniques) to extract knowledge from the clinical data. However, these studies have some limitations that have not yet been addressed: some do not focus entirely on Hepatocellular Carcinoma patients, others have strict application boundaries, and none considers the heterogeneity between patients nor the presence of missing data, a common drawback in healthcare contexts. In this work, a real complex Hepatocellular Carcinoma database composed of heterogeneous clinical features is studied. We propose a new cluster-based oversampling approach robust to small and imbalanced datasets, which accounts for the heterogeneity of patients with Hepatocellular Carcinoma. The preprocessing procedures of this work are based on data imputation considering appropriate distance metrics for both heterogeneous and missing data (HEOM) and clustering studies to assess the underlying patient groups in the studied dataset (K-means). The final approach is applied in order to diminish the impact of underlying patient profiles with reduced sizes on survival prediction. It is based on K means clustering and the SMOTE algorithm to build a representative dataset and use it as training example for different machine learning procedures (logistic regression and neural networks). The results are evaluated in terms of survival prediction and compared across baseline approaches that do not consider clustering and/or oversampling using the Friedman rank test. Our proposed methodology coupled with neural networks outperformed all others, suggesting an improvement over the classical approaches currently used in Hepatocellular Carcinoma prediction models. PMID- 26423563 TI - Organization and Development of Bone Marrow Donation and Transplantation in Poland. AB - This paper describes bone marrow donation and transplantation in Poland in terms of its history, current state, and information on the quality control system. Based on data gathered from the informatics systems of the Polish Central Unrelated Potential Bone Marrow Donor and Cord Blood Registry and the Polish transplant registries, as well as World Marrow Donor Association statistics, we performed an overview study to collect and compare numbers on hematopoietic stem cells donations and transplantations in Poland in the years 2010-2014. In the last 5 years, the number of registered potential hematopoietic stem cells donors in Poland increased by more than 4 times, from about 146,000 to over 750,000. During the same period, the number of patients qualified to hematopoietic stem cells transplantation from unrelated donor increased from 557 in 2010 to 817 in 2014. We observed a striking change in the percentage of transplantations performed in Polish centers using material collected from national donors--from 24% to 60%. This shift was also evident in the number of search procedures closed with acceptation of Polish donors--from 27% in 2010 to 58% in 2014. Another consequence of Polish registry growth is the increasing number of donations from Polish donors for international patients. Between 2010 and 2014, the percent of donation for non-national patient increased from 33% to 76%, placing Poland in 6th place in the ranking of the HSC "exporters" worldwide. Growth of transplantation rates involves standardization process, which is a natural way of development for national organizations in the field of HSCT because of its international character. PMID- 26423564 TI - The role of nutritional interventions in increasing fruit and vegetable intake in the elderlies: a systematic review. AB - BACKGROUND: The consumption of fruit and vegetables in old ages is particularly important, so that the appropriate consumption amount leads to reduction in the risk of chronic diseases. To increase consumption of fruit and vegetables and modify consumption pattern in the elderlies, training programs and appropriate intervention can be designed and implemented. AIMS: The study was done to assess and compare nutritional intervention-based training methods and education using theories and health education models for the consumption of fruits and vegetables in the elderlies. METHODS: Electronic search using keywords of Country Review Information Bank (Magiran), Scientific Information Database, Pub Med, Science direct, Science, Biomed central from the beginning of March 2014 to end of April 2015 was performed. RESULTS: Ten interventional studies were assessed in this systematic study. The interventions were divided into two groups of studies, a total of five studies, theories and health education models were the basis of training intervention and the other five studies that include their interventions without the use of theories and health education models was carried out. Of ten interventional studies, three studies as before and after and seven studies as the intervention and control was performed. DISCUSSION: The results showed that education-based theory and health education models have a greater impact on the consumption of fruit and vegetables in the elderlies. CONCLUSIONS: The duration and interventions performing method, environmental factors and educational programs using appropriate models and theories are important on the effectiveness of interventions to increase consumption of fruit and vegetables in the elderliness. PMID- 26423565 TI - Association of the COL1A1 gene polymorphisms in Mexican postmenopausal women with fracture or with low bone mineral density at the hip. AB - BACKGROUND AND AIMS: Osteoporosis leads to high fracture risk and evidence suggests that genetic factors play an important role in this disease. The aim was to evaluate the association of two polymorphisms (-1997G/T, +1245G/T) in the collagen type1 alpha 1 gene (COL1A1) with fracture or with low bone mineral density (BMD) at the hip in postmenopausal Mexican women. METHODS: BMD was determined by bone densitometry and the risk factors were collected with a questionnaire. Genotyping was performed by real-time PCR. RESULTS: The polymorphisms were in Hardy-Weinberg equilibrium. The -1997G/+1245T haplotype showed, after adjustment for confounders, a fourfold increased risk of hip fracture [OR 4.32; p = 0.041 (95 % CI 1.07-17.43)]; while in the women with low BMD at the hip, the risk was increased threefold [OR 3.36; p = 0.022 (95 % CI 1.20-9.40)]. CONCLUSIONS: The results support the association of COL1A1 gene polymorphisms with fracture and with low BMD at the hip in Mexican population. PMID- 26423567 TI - iBioChina and iBiology: spreading scientific knowledge together. PMID- 26423566 TI - Characteristics of the TCR Vbeta repertoire in imatinib-resistant chronic myeloid leukemia patients with ABL mutations. AB - Diversity in the T cell receptor (TCR) repertoire provides a miniature defense ability for the T cell immune system that may be related to tumor initiation and progression. Understanding the T cell immune status of leukemia patients is critical for establishing specific immunotherapies. Previous studies have reported abnormal TCR repertoires and clonally expanded TCR Vbeta T cells in chronic myeloid leukemia in chronic phase (CP-CML). In this study, we investigated the distribution and clonality of the TCR Vbeta repertoire in 4 cases with imatinib-resistant CML in blast crisis (BC-CML) with abelson murine leukemia viral oncogene homolog 1 (ABL1) kinase domain mutations (KDMs). Examination of TCR V expression and clonality was performed by reverse transcription-polymerase chain reaction (RT-PCR) and GeneScan analysis. Significantly skewed TCR Vbeta repertoires were observed in BC-CML patients with different KDMs, and 4 to 8 oligoclonally expanded TCR Vbeta subfamilies could be identified in each sample. Intriguingly, a relatively highly expanded Vbeta9 clone with the same length as complementarity- determining region 3 (CDR3) (139 bp) was found in all three CML patients in lymphoid blast crisis (LBC-CML) who had different KDMs, but the clone was not detected in the only CML patient in myeloid blast crisis (MBC-CML). In conclusion, restricted TCR Vbeta repertoire expression and decreased clone complexity was a general phenomenon observed in the BC-CML patients with different KDMs, indicating the T-cell immunodeficiency of these patients. In addition, clonally expanded Vbeta9 T cell clones may indicate a specific immune response to leukemia-associated antigens in LBC-CML patients. PMID- 26423568 TI - Public impact, prevention, and treatment of cataracts. PMID- 26423569 TI - Do Wildfires Promote Woody Species Invasion in a Fire-Adapted Ecosystem? Post fire Resprouting of Native and Non-native Woody Plants in Central Argentina. AB - We asked whether prescribed fire could be a useful management tool to reduce invasion by non-native plants in an ecosystem where native plants are supposed to be adapted to fires. Specifically, we compare the post-fire resprouting response of native and non-native woody species in Chaco Serrano forest of central Argentina. The measurements were carried out in five burnt areas where we selected ten native and seven non-native species. Our response variables were (1) post-fire survival, (2) types of resprouts, and (3) the growth of the resprouts. Our main results show that one year after the fire, survivals of native and non native species were 0.84 and 0.89, respectively, with variances in survival seven times smaller in the native species group. Type of resprout was also less variable in native species, while growth of the resprouts was similar in native and non-native groups. We interpret that in most cases, the burning a forest with mixed native and non-native plants through prescribed fires will not differentially stop the invasion by non-native woody species even in ecosystems which are presumed to be relatively resistant to fires such as our study area. PMID- 26423570 TI - Biomarkers of aging, life span and spontaneous carcinogenesis in the wild type and HER-2 transgenic FVB/N female mice. AB - FVB/N wild type and transgenic HER-2/neu FVB/N female mice breed at N.N. Petrov Research Institute of Oncology were under observation until natural death without any special treatment. Age-related dynamics of body weight, food consumption and parameters of carbohydrate and lipid metabolism, level of nitric oxide, malonic dialdehyde, catalase, Cu, Zn-superoxide dismutase, vascular endothelial growth factor were studied in both mice strains. The parameters of life span and tumor pathology were studied as well. Cancer-prone transgenic HER-2/neu mice developed in 100 % multiple mammary adenocarcinomas and died before the age of 1 year. Forty tree percent of long-lived wild type mice survived the age of 2 years and 19 %-800 days. The total tumor incidence in wild type mice was 34 %. The age associated changes in the level of serum IGF-1, glucose and insulin started much earlier in transgene HER-2/neu mice as compared with wild type FVB/N mice. It was suggested that transgenic HER-2/neu involves in initiation of malignization of mammary epithelial cells but also in acceleration of age-related hormonal and metabolic changes in turn promoting mammary carcinogenesis. PMID- 26423571 TI - The influence of Streptococcus pneumoniae nasopharyngeal colonization on the clinical outcome of the respiratory tract infections in preschool children. AB - BACKGROUND: Streptococcus pneumoniae (SPn) is an important pathogen causing a variety of clinical manifestations. The effects of SPn nasopharyngeal colonization on respiratory tract infections are poorly studied. We evaluated the association of SPn colonization with features of respiratory tract infections. METHODS: Children under the age of 6 years who visited a primary care physician because of respiratory tract infections were enrolled in the study. History was taken, children were clinically assessed by the physician, and nasopharyngeal swabs were obtained and cultured for SPn. Positive samples were serotyped. Associations of SPn colonization with clinical signs and symptoms, recovery duration, absence from day care centre, frequencies of specific diagnoses, and treatment with antimicrobials were evaluated. RESULTS: In total 900 children were enrolled. The prevalence of SPn colonization was 40.8 % (n = 367). There were minor differences between male and female subjects (199 of 492, 40.4 % vs 168 of 408, 41.2 %, p = 0.825). Children with and without siblings had similar colonization rates (145 of 334, 43.4 % vs 219 of 562, 39.0 %, p = 0.187). Clinical signs and symptoms were not associated with SPn colonization. Children colonized with SPn had longer recovery duration compared to non-colonized children (114 of 367, 31.1 % vs 98 of 533, 18.4 %, p < 0.001) and were longer absent from day care (270 of 608, 44.4 % vs 94 of 284, 33.1 %, p = 0.001). Pneumonia, sinusitis, and acute otitis media were more frequently diagnosed in children colonized with SPn. Children attending day care centres had significantly higher prevalence of SPn colonization (270 of 367, 44.4 % vs 338 of 533, 33.1 %, p = 0.001). Children with pneumonia, sinusitis and acute otitis media were more frequently treated with antimicrobials than children with other diagnoses. CONCLUSIONS: SPn nasopharyngeal colonization has a negative impact on the course of respiratory tract infection, likely because of SPn being the cause of the disease or a complicating factor. It is also associated with and may be responsible for higher frequencies of bronchitis, pneumonia, acute otitis media, sinusitis and the need of antimicrobial treatment. PMID- 26423572 TI - Thermal effects of lambda = 808 nm GaAlAs diode laser irradiation on different titanium surfaces. AB - Diode lasers are widely used in dental laser treatment, but little is known about their thermal effects on different titanium implant surfaces. This is a key issue because already a 10 degrees C increase over the normal body temperature can induce bone injury and compromise osseo-integration. The present study aimed at evaluating the temperature changes and surface alterations experienced by different titanium surfaces upon irradiation with a lambda = 808 nm diode laser with different settings and modalities. Titanium discs with surfaces mimicking different dental implant surfaces including TiUnite and anodized, machined surfaces were laser-irradiated in contact and non-contact mode, and with and without airflow cooling. Settings were 0.5-2.0 W for the continuous wave mode and 10-45 MUJ, 20 kHz, 5-20 MUs for the pulsed wave mode. The results show that the surface characteristics have a marked influence on temperature changes in response to irradiation. The TiUnite surface, corresponding to the osseous interface of dental implants, was the most susceptible to thermal rise, while the machined surfaces, corresponding to the implant collar, were less affected. In non-contact mode and upon continuous wave emission, the temperature rose above the 50 degrees C tissue damage threshold. Scanning electron microscopy investigation of surface alterations revealed that laser treatment in contact mode resulted in surface scratches even when no irradiation was performed. These findings indicate that the effects of diode laser irradiation on implant surfaces depend on physical features of the titanium coating and that in order to avoid thermal or physical damage to implant surface the irradiation treatment has to be carefully selected. PMID- 26423573 TI - Needs and Supports of People with Intellectual Disability and Their Families in Catalonia. AB - BACKGROUND: The study assesses the support needs of individuals with intellectual disability and their families in Catalonia. The present authors examine family quality of life (FQoL), identify the individual services required and assess families' perceptions of the extent to which their family member with intellectual disability and they themselves receive the services they need. MATERIALS AND METHODS: The N&S questionnaire (Needs and Supports for people with intellectual disability and their families) was administered to 2160 families with a family member with intellectual disability aged under 70 in Catalonia (Spain). RESULTS: Overall mean FQoL was quite high. FQoL was associated with family income, education, employment and percentage level of disability. Neither people with intellectual disability nor their families receive the specific support they need. CONCLUSIONS: Besides providing specific support for individuals with intellectual disability, local policymakers and practitioners should apply a family-centred approach to the provision of support for families in order to improve FQoL. PMID- 26423574 TI - Colectomy for constipation: time trends and impact based on the US Nationwide Inpatient Sample, 1998-2011. AB - BACKGROUND: Current guidelines include subtotal colectomy as treatment for refractory slow transit constipation. AIM: To use the US Nationwide Inpatient Sample (NIS) (1998-2011) and longitudinal data from the State Inpatient Database (2005-2011), comparable to NIS, to examine colectomy rates, in-hospital morbidity and emergency department (ED) visits or readmissions among patients treated for constipation. METHODS: Colectomies for any reason were identified based on the primary procedural code (ICD-9-CM 45.8x). Index hospitalisations were defined by the primary diagnosis of constipation (ICD-9-CM 564.x) associated with the primary procedural code for colectomy (ICD-9-CM45.8x) after exclusion of other diseases associated with colectomy. Demographic variables, comorbidities, complications and adverse events during the hospitalisation were captured, and ED visits and admissions were recorded for periods before and after colectomy. RESULTS: Nationally, colectomies for constipation rose from 104 procedures in 1998 (1.2% of annual colectomies) to 311 in 2011 (2.4% of annual colectomies). While there were no perioperative deaths, perioperative complications occurred in 42.7% of patients during the index hospitalisation. Longitudinal data were analysed for 181 patients, with similar perioperative complications and a readmission rate of 28.9% within the first 30 days after the index hospitalisation. Resource utilisation was tracked for a median time of 630 (0 2386) before and 463 (0-2204) days after colectomy with unchanged ED visits (median: 2 vs. 2, P = 0.21), but increased hospitalisations (median: 1 vs. 2, P = 0.003). CONCLUSIONS: Colectomy rates for constipation are rising, are associated with significant morbidity and do not decrease resource utilisation, raising questions about the true benefit of surgery for slow transit constipation. PMID- 26423575 TI - Bayesian network analysis of multi-compartmentalized immune responses in a murine model of sepsis and direct lung injury. AB - BACKGROUND: Inflammatory disease processes involve complex and interrelated systems of mediators. Determining the causal relationships among these mediators becomes more complicated when two, concurrent inflammatory conditions occur. In those cases, the outcome may also be dependent upon the timing, severity and compartmentalization of the insults. Unfortunately, standard methods of experimentation and analysis of data sets may investigate a single scenario without uncovering many potential associations among mediators. However, Bayesian network analysis is able to model linear, nonlinear, combinatorial, and stochastic relationships among variables to explore complex inflammatory disease systems. In these studies, we modeled the development of acute lung injury from an indirect insult (sepsis induced by cecal ligation and puncture) complicated by a direct lung insult (aspiration). To replicate multiple clinical situations, the aspiration injury was delivered at different severities and at different time intervals relative to the septic insult. For each scenario, we measured numerous inflammatory cell types and cytokines in samples from the local compartments (peritoneal and bronchoalveolar lavage fluids) and the systemic compartment (plasma). We then analyzed these data by Bayesian networks and standard methods. RESULTS: Standard data analysis demonstrated that the lung injury was actually reduced when two insults were involved as compared to one lung injury alone. Bayesian network analysis determined that both the severity of lung insult and presence of sepsis influenced neutrophil recruitment and the amount of injury to the lung. However, the levels of chemoattractant cytokines responsible for neutrophil recruitment were more strongly linked to the timing and severity of the lung insult compared to the presence of sepsis. This suggests that something other than sepsis-driven exacerbation of chemokine levels was influencing the lung injury, contrary to previous theories. CONCLUSIONS: To our knowledge, these studies are the first to use Bayesian networks together with experimental studies to examine the pathogenesis of sepsis-associated lung injury. Compared to standard statistical analysis and inference, these analyses elucidated more intricate relationships among the mediators, immune cells and insult-related variables (timing, compartmentalization and severity) that cause lung injury. Bayesian networks are an effective tool for evaluating complex models of inflammation. PMID- 26423576 TI - Financial toxicity: a potential side effect of prostate cancer treatment among Australian men. AB - The purpose of this study was to understand the extent, nature and variability of the current economic burden of prostate cancer among Australian men. An online cross-sectional survey was developed that combined pre-existing economic measures and new questions. With few exceptions, the online survey was viable and acceptable to participants. The main outcomes were self-reported out-of-pocket costs of prostate cancer diagnosis and treatment, changes in employment status and household finances. Men were recruited from prostate cancer support groups throughout Australia. Descriptive statistical analyses were undertaken. A total of 289 men responded to the survey during April and June 2013. Our study found that men recently diagnosed (within 16 months of the survey) (n = 65) reported spending a median AU$8000 (interquartile range AU$14 000) for their cancer treatment while 75% of men spent up to AU$17 000 (2012). Twenty per cent of all men found the cost of treating their prostate cancer caused them 'a great deal' of distress. The findings suggest a large variability in medical costs for prostate cancer treatment with 5% of men spending $250 or less in out-of-pocket expenses and some men facing very high costs. On average, respondents in paid employment at diagnosis stated that they had retired 4-5 years earlier than planned. PMID- 26423577 TI - Development of a pan-Babesia FRET-qPCR and a survey of livestock from five Caribbean islands. AB - BACKGROUND: Babesia spp. are tick-borne protozoan hemoparasites and the second most common blood-borne parasites of mammals, in particular domestic animals. We used the Clustal Multiple Alignment program and 18S rRNA gene sequences of 22 Babesia species from GenBank to develop a PCR that could detect a wide variety of Babesia spp. in a single reaction. The pan-Babesia FRET-qPCR we developed reliably detected B. gibsoni, B. canis, B. vogeli, B. microti, B. bovis, and B. divergens under controlled conditions but did not react with closely related species, mainly Hepatozoon americanum, Theileria equi, and Toxoplasma gondii. RESULTS: When we tested the pan-Babesia FRET-qPCR on DNA of whole blood from 752 cattle, sheep, goats, donkeys and horses from five Caribbean islands, we detected Babesia spp. expected to be present in the animals, mainly B. bovis and B. bigemina in cattle and B. caballi in horses and donkeys. Further, we found that animals were not uncommonly infected with species of Babesia usually associated with other hosts, mainly B. vogeli and B. gibsoni in cattle, sheep and goats, B. rossi in goats, and B. caballi in goats and sheep. Finally, the pan-Babesia FRET qPCR enabled us to identify unknown species of Babesia in cattle, goats, sheep and donkeys. CONCLUSIONS: Overall, 70 % (525/752) of the animals we tested were positive confirming earlier limited studies that infections with Babesia spp. are common in livestock in the Caribbean. PMID- 26423578 TI - Po2 cycling protects diaphragm function during reoxygenation via ROS, Akt, ERK, and mitochondrial channels. AB - Po2 cycling, often referred to as intermittent hypoxia, involves exposing tissues to brief cycles of low oxygen environments immediately followed by hyperoxic conditions. After experiencing long-term hypoxia, muscle can be damaged during the subsequent reintroduction of oxygen, which leads to muscle dysfunction via reperfusion injury. The protective effect and mechanism behind Po2 cycling in skeletal muscle during reoxygenation have yet to be fully elucidated. We hypothesize that Po2 cycling effectively increases muscle fatigue resistance through reactive oxygen species (ROS), protein kinase B (Akt), extracellular signal-regulated kinase (ERK), and certain mitochondrial channels during reoxygenation. Using a dihydrofluorescein fluorescent probe, we detected the production of ROS in mouse diaphragmatic skeletal muscle in real time under confocal microscopy. Muscles treated with Po2 cycling displayed significantly attenuated ROS levels (n = 5; P < 0.001) as well as enhanced force generation compared with controls during reperfusion (n = 7; P < 0.05). We also used inhibitors for signaling molecules or membrane channels such as ROS, Akt, ERK, as well as chemical stimulators to close mitochondrial ATP-sensitive potassium channel (KATP) or open mitochondrial permeability transition pore (mPTP). All these blockers or stimulators abolished improved muscle function with Po2 cycling treatment. This current investigation has discovered a correlation between KATP and mPTP and the Po2 cycling pathway in diaphragmatic skeletal muscle. Thus we have identified a unique signaling pathway that may involve ROS, Akt, ERK, and mitochondrial channels responsible for Po2 cycling protection during reoxygenation conditions in the diaphragm. PMID- 26423579 TI - Water transport running deep. Focus on "Deep proteomic profiling of vasopressin sensitive collecting duct cells". PMID- 26423581 TI - An Unusual Case of Reversible Empty Sella. AB - CONTEXT: An empty sella is a relatively common condition, often being an incidental finding at MRI or CT scan. It can develop because of the intrasellar herniation of Cerebro-spinal Fluid (CSF) and arachnoid membrane through an absent or rudimentary diaphragm sellae in concomitance of a sudden and even transient increment of intracranial pressure, leading to a picture in which the pituitary is flattened along the floor of the sella. CASE DESCRIPTION: A young female with headache, nausea, dizziness, diplopia and visual impairment showed an empty sella on MRI and increased CSF pressure at the lumbar puncture. After an initial improvement, there was a progressive worsening of the headache, especially in orthostatic position, with transient relief after bed rest and hydration. At MRI the empty sella was no longer evident, cerebellar tonsils were displaced in the occipital foramen and there was an impregnation of the meninges after contrast medium, a picture of CSF hypotension, probably due to the previously performed lumbar puncture causing a fistula with leak of CSF and consequent disappearance of the empty sella. The patient gradually improved after being submitted to epidural blood patch. CONCLUSIONS: The case here reported demonstrates that an empty sella can be a reversible condition in rare cases. Its disappearance can be due to the reduction in intracranial pressure caused by the lumbar puncture itself. The changes in the characteristics of the headache, in particular its worsening in the orthostatic position, should lead to the suspicion of CSF leak through a fistula and consequent intracranial hypotension, a dangerous and sometimes life-threatening condition. PMID- 26423580 TI - Purification, characterization and crystallization of the F-ATPase from Paracoccus denitrificans. AB - The structures of F-ATPases have been determined predominantly with mitochondrial enzymes, but hitherto no F-ATPase has been crystallized intact. A high-resolution model of the bovine enzyme built up from separate sub-structures determined by X ray crystallography contains about 85% of the entire complex, but it lacks a crucial region that provides a transmembrane proton pathway involved in the generation of the rotary mechanism that drives the synthesis of ATP. Here the isolation, characterization and crystallization of an integral F-ATPase complex from the alpha-proteobacterium Paracoccus denitrificans are described. Unlike many eubacterial F-ATPases, which can both synthesize and hydrolyse ATP, the P. denitrificans enzyme can only carry out the synthetic reaction. The mechanism of inhibition of its ATP hydrolytic activity involves a zeta inhibitor protein, which binds to the catalytic F1-domain of the enzyme. The complex that has been crystallized, and the crystals themselves, contain the nine core proteins of the complete F-ATPase complex plus the zeta inhibitor protein. The formation of crystals depends upon the presence of bound bacterial cardiolipin and phospholipid molecules; when they were removed, the complex failed to crystallize. The experiments open the way to an atomic structure of an F-ATPase complex. PMID- 26423582 TI - Unilateral sling transection for patients with postoperative voiding dysfunction after transobturator sling surgery. PMID- 26423583 TI - Modeling of T2* decay in vertebral bone marrow fat quantification. AB - Bone marrow fat fraction mapping using chemical shift encoding-based water-fat separation is becoming a useful tool in investigating the association between bone marrow adiposity and bone health and in assessing cancer treatment-induced bone marrow damage. Vertebral bone marrow is characterized by short T2* relaxation times, which are in general different for the water and fat components and can confound fat quantification. The purpose of the present study is to compare different approaches to T2* correction in chemical shift encoding-based water-fat imaging of vertebral bone marrow using single-voxel MRS as reference. Eight-echo gradient-echo imaging and single-voxel MRS measurements were made on the spine (L3-L5) of 25 healthy volunteers. Different approaches were evaluated for correction of T2* effects: (a) single-T2* correction, (b) dual-T2* correction, (c) T2' correction using the a priori-known T2 from the MRS at each vertebral body and (d) T2' correction using the a priori-known T2 equal to previously measured average values. Dual-T2* correction resulted in noisier imaging fat fraction maps than single-T2* correction or T2' correction using a priori-known T2. Linear regression analysis between imaging and MRS fat fraction showed a slope significantly different from 1 when using single-T2* correction (R(2) = 0.96) or dual-T2* correction (R(2) = 0.87). T2' correction using the a priori-known T2 resulted in a slope not significantly different from 1, an intercept significantly different from 0 (between 2.4% and 3%) and R(2) = 0.96. Therefore, a T2' correction using a priori-known T2 can remove the fat fraction bias induced by the difference in T2* between water and fat components without degrading noise performance in fat fraction mapping of vertebral bone marrow. PMID- 26423585 TI - Variation in outcome of acute myocardial infarction in Sweden and the UK may be due to population heterogeneity in the UK. PMID- 26423586 TI - Laser Microdissection. AB - Laser microdissection (LM) offers a relatively rapid and precise method of isolating and removing specified cells from complex tissues for subsequent analysis of their RNA, DNA, protein or metabolite content, thereby allowing assessment of the role of different cell types in the normal physiological or disease processes being studied. In this unit, protocols for the preparation of mammalian frozen tissues, fixed tissues, and cytologic specimens for LM, including tissue freezing, tissue processing and paraffin embedding, histologic sectioning, cell processing, hematoxylin and eosin staining, immunohistochemistry, and image-guided cell targeting are presented. Also provided are recipes for generating lysis buffers for the recovery of nucleic acids and proteins. The Commentary section addresses the types of specimens that can be utilized for LM and approaches to staining of specimens for cell visualization. Emphasis is placed on the preparation of tissue or cytologic specimens as this is critical to effective LM. PMID- 26423587 TI - Laser Microdissection-Mediated Isolation and In Vitro Transcriptional Amplification of Plant RNA. AB - Laser microdissection of cells allows for isolation of specific cells of interest for downstream analyses including transcriptional profiling. Plant cells present unique challenges for laser microdissection due to their cellulosic cell walls and large vacuoles. Here we present protocols for plant tissue preparation, laser microdissection of select plant cells, and linear amplification of RNA from dissected cells. Linear amplification of RNA from dissected cells allows sufficient RNA for subsequent quantitative analysis by RT-PCR, microarray, or RNA sequencing. PMID- 26423584 TI - Prophylactic antibiotic regimens in tumour surgery (PARITY): a pilot multicentre randomised controlled trial. AB - OBJECTIVE: Clinical studies of patients with bone sarcomas have been challenged by insufficient numbers at individual centres to draw valid conclusions. Our objective was to assess the feasibility of conducting a definitive multi-centre randomised controlled trial (RCT) to determine whether a five-day regimen of post operative antibiotics, in comparison to a 24-hour regimen, decreases surgical site infections in patients undergoing endoprosthetic reconstruction for lower extremity primary bone tumours. METHODS: We performed a pilot international multi centre RCT. We used central randomisation to conceal treatment allocation and sham antibiotics to blind participants, surgeons, and data collectors. We determined feasibility by measuring patient enrolment, completeness of follow-up, and protocol deviations for the antibiotic regimens. RESULTS: We screened 96 patients and enrolled 60 participants (44 men and 16 women) across 21 sites from four countries over 24 months (mean 2.13 participants per site per year, standard deviation 2.14). One participant was lost to follow-up and one withdrew consent. Complete data were obtained for 98% of eligible patients at two weeks, 83% at six months, and 73% at one year (the remainder with partial data or pending queries). In total, 18 participants missed at least one dose of antibiotics or placebo post operatively, but 93% of all post-operative doses were administered per protocol. CONCLUSIONS: It is feasible to conduct a definitive multi-centre RCT of post operative antibiotic regimens in patients with bone sarcomas, but further expansion of our collaborative network will be critical. We have demonstrated an ability to coordinate in multiple countries, enrol participants, maintain protocol adherence, and minimise losses to follow-up. Cite this article: Bone Joint Res;4:154-162. PMID- 26423588 TI - RNA Interference and MicroRNA-Mediated Silencing. AB - RNA interference (RNAi) and microRNA-mediated silencing cause sequence-specific silencing of target genes. This overview will give a brief description of how RNAi and microRNAs were discovered, how small RNAs silence their targets, and what the functions of small RNAs are. Since the discovery of RNAi, RNAi has been widely used in studies of gene function, including high-throughput screening. The unit will briefly describe how RNAi is used in different model systems, and how to analyze the function of endogenous small RNAs. PMID- 26423589 TI - Genome Editing in Human Cells Using CRISPR/Cas Nucleases. AB - The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated (Cas) system has been broadly adopted for highly efficient genome editing in a variety of model organisms and human cell types. Unlike previous genome editing technologies such as zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), CRISPR/Cas technology does not require complex protein engineering and can be utilized by any researcher proficient in basic molecular biology and cell culture techniques. This unit describes protocols for design and cloning of vectors expressing single or multiplex gRNAs, for transient transfection of human cell lines, and for quantitation of mutation frequencies by T7 endonuclease I assay. These protocols also include guidance for using two improvements that increase the specificity of CRISPR/Cas nucleases: truncated gRNAs and dimeric RNA-guided FokI nucleases. PMID- 26423590 TI - Transcriptome-Wide Identification of Pseudouridine Modifications Using Pseudo seq. AB - A diverse array of post-transcriptional modifications is found in RNA molecules from all domains of life. While the locations of RNA modifications are well characterized in abundant noncoding RNAs, modified sites in less abundant mRNAs are just beginning to be discovered. Recent work has revealed hundreds of previously unknown and dynamically regulated pseudouridines (Psi) in mRNAs from diverse organisms. This unit describes Pseudo-seq, an efficient, high-resolution method for identification of Psis genome-wide. This unit includes methods for isolation of RNA from S. cerevisiae, preparation of Pseudo-seq libraries from RNA samples, and identification of sites of pseudouridylation from the sequencing data. Pseudo-seq is applicable to any organism or cell type, facilitating rapid identification of novel pseudouridylation events. PMID- 26423591 TI - Overview of Target Enrichment Strategies. AB - Target enrichment is commonly used in next generation sequencing (NGS) workflows to eliminate genomic DNA regions that are not of interest for a particular experiment. By only targeting specific regions such as exons, one can obtain greater depth of DNA sequencing coverage for regions of interest or increase the sampling numbers of individuals, thereby saving both time and cost. This overview of target enrichment strategies provides a high-level review of distinct approaches to capture specific sequences: (a) hybridization-based strategies, (b) transposon-mediated fragmentation (tagmentation), (c) molecular inversion probes (MIPs), and (d) singleplex and multiplex polymerase chain reaction (PCR) target enrichment. Strategies for assay design and performance criteria are also discussed. Other platforms currently in development are also briefly described. PMID- 26423592 TI - Questions that need clarifying before implementation of the Ossebo balance training programme. PMID- 26423593 TI - Alternative competition-induced digestive strategies yield equal growth, but constrain compensatory growth in red-eyed treefrog larvae. AB - Compensatory growth is well documented across taxa and provides a fitness advantage to animals who would otherwise reach a smaller reproductive size. We investigated the role of competition-induced gut plasticity in facilitating a compensatory response in red-eyed treefrog larvae. We reared larvae at low, medium, and high densities with different per capita resources, environments known to produce individuals with long and short guts. We then transferred larvae to competitively equal environments to determine if longer guts provided an advantage when resources became available. We predicted that larvae from higher densities with longer guts would exhibit hyperphagia and compensatory growth. We measured growth over 1-week, as well as the time to and size at metamorphosis. To assess mechanisms underlying the growth response, we measured diet transit time and intake. Growth, development, and metamorph snout-vent length did not differ between larvae with long and short guts. Instead, different gut lengths were associated with dramatically different feeding strategies. Medium- and high density larvae fed at rates far below what their guts could accommodate. However, the combination of low intake and longer guts extended diet transit times, presumably increasing digestibility. This unexpected strategy achieved the same results as that of low-density larvae, which ate twice as much food, but passed it more quickly through a shorter gut. The lack of a compensatory response may be attributed to the costs of accelerated growth and weak seasonal time constraints in the tropics. This suggests that although compensatory growth is widespread among animals, expression of the response may vary with environmental context. J. Exp. Zool. 323A: 778-788, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26423594 TI - Histopathologic features of erythematous papulopustular eruption to epidermal growth factor receptor inhibitors in cancer patients. AB - BACKGROUND: Erythematous papulopustular eruption (EPPE) is the most frequent skin adverse event to epidermal growth factor receptor (EGFR) inhibitors but its histopathologic features have been poorly studied. As EPPE is a strong predictor of patient's treatment response, the EPPE histopathologic features and their correlations with skin eruption severity and involved drug were investigated. METHOD: An involved skin biopsy was carried out in 39 informed patients treated with EGFR inhibitors (mainly cetuximab and erlotinib). The cutaneous changes in hematoxylin-eosin stained sections were evaluated. RESULTS: The EPPE to EGFR inhibitors is histopathologically characterized by neutrophilic subcorneal or intraepidermal pustules and polymorphous infiltrate of the superficial dermis during the earliest phases and by lymphocytic perifolliculitis and/or suppurative folliculitis at a later phase. The widespread dermis inflammation was more frequent in severe EPPEs and in patients treated with cetuximab, while the hair follicle inflammation was observed only in mild/moderate EPPEs. CONCLUSION: Our study shows the histopathologic signs of EPPE and their correlation with clinical severity and the offending drug. PMID- 26423595 TI - Planned wedge size compared to achieved advancement in dogs undergoing the modified Maquet procedure. AB - OBJECTIVES: To evaluate the patellar ligament to tibial plateau angle (PL-TPA) and amount of achieved advancement in dogs that underwent the modified Maquet procedure; compare wedge sizes recommended using two different planning techniques (Orthomed and modified tibial tuberosity advancement); and evaluate anatomical factors that predict the wedge size required to obtain a 90 degrees PL-TPA. METHODS: Pre- and postoperative radiographs of dogs that had a modified Maquet procedure performed were evaluated for the following: calculated wedge size using two different planning techniques, the actual wedge size used, the achieved tibial tuberosity advancement, and the changes in PL-TPA. Anatomical measurements of the tibia were evaluated and correlated with the actual wedge size. RESULTS: Of the 38 modified Maquet procedures identified, 53% (n = 20) had a PL-TPA of 90 degrees +/- 5 degrees . Actual achieved advancement of the tibial tuberosity was 30% less than the wedge size used. Changes in PL-TPA and tibial width persisted at eight weeks postoperatively without loss of advancement. The two planning techniques did not result in a significantly different selection of wedge size. CLINICAL RELEVANCE: Current planning techniques for the modified Maquet procedure result in under-advancement of the tibial tuberosity. Both measurement techniques evaluated do not result in appropriate advancement. PMID- 26423596 TI - Potential estrogenic effects of wastewaters on gene expression in Pimephales promelas and fish assemblages in streams of southeastern New York. AB - Direct linkages between endocrine-disrupting compounds (EDCs) from municipal and industrial wastewaters and impacts on wild fish assemblages are rare. The levels of plasma vitellogenin (Vtg) and Vtg messenger ribonucleic acid (mRNA) in male fathead minnows (Pimephales promelas) exposed to wastewater effluents and dilutions of 17alpha-ethinylestradiol (EE2), estrogen activity, and fish assemblages in 10 receiving streams were assessed to improve understanding of important interrelations. Results from 4-d laboratory assays indicate that EE2, plasma Vtg concentration, and Vtg gene expression in fathead minnows, and 17beta estradiol equivalents (E2Eq values) were highly related to each other (R(2) = 0.98-1.00). Concentrations of E2Eq in most effluents did not exceed 2.0 ng/L, which was possibly a short-term exposure threshold for Vtg gene expression in male fathead minnows. Plasma Vtg in fathead minnows only increased significantly (up to 1136 MUg/mL) in 2 wastewater effluents. Fish assemblages were generally unaffected at 8 of 10 study sites, yet the density and biomass of 79% to 89% of species populations were reduced (63-68% were reduced significantly) in the downstream reach of 1 receiving stream. These results, and moderate to high E2Eq concentrations (up to 16.1 ng/L) observed in effluents during a companion study, suggest that estrogenic wastewaters can potentially affect individual fish, their populations, and entire fish communities in comparable systems across New York, USA. PMID- 26423597 TI - Does alvimopan enhance return of bowel function in laparoscopic gastrointestinal surgery? A meta-analysis. AB - BACKGROUND: Postoperative ileus (POI) remains a major impediment in patient recovery and leads to longer lengths of stay at the hospital, readmission rates, and hospital costs. Alvimopan, a mu-opioid receptor antagonist, lowers POI incidence following open gastrointestinal surgery, however, little is known about its role on POI prevention among patients undergoing laparoscopic gastrointestinal surgery. METHODS: A comprehensive search of PubMed/MEDLINE, Scopus, CINAHL, and Cochrane databases was performed (December 2014). Meta analysis was performed using the Mantel-Haenszel (fixed effects) model with odds ratio (OR) to assess prevention of POI and hospital readmission. RESULTS: Five studies were included in the final analysis. Pooling 4 of 5 studies, there was over a 75% relative risk reduction in POI development when patients were given alvimopan compared to placebo (OR 0.24, 95%CI 0.12-0.51, P=0.02). The number needed to treat with alvimopan to prevent one POI episode was 11 patients. There was a modest reduction in the length of hospitalization between 0.2 and 1.6 days. There did not appear to be a difference in frequency of 30-day readmission rate among the alvimopan group compared to placebo (OR 1.15, 95%CI 0.54-2.45, P=0.62). CONCLUSION: Overall, there was a 75% relative risk reduction in POI development among patients undergoing laparoscopic gastrointestinal surgery. However, there did not appear to be a significant reduction in all-cause 30-day readmission rate or length of hospitalization. Future studies will need to address which subset of patients undergoing laparoscopic gastrointestinal surgery will benefit most from alvimopan. PMID- 26423598 TI - Triaxial system in bronchial arterial embolization for haemoptysis using N-butyl 2-cyanoacrylate. AB - OBJECTIVE: The application of bronchial artery embolization (BAE) using N-butyl-2 cyanoacrylate (NBCA) for haemoptysis was recently reported to be useful. A triple co-axial (triaxial) system consisting of a 4-Fr catheter, 2.7-Fr microcatheter and 1.9-Fr no-taper microcatheter has been developed. The aim of the present study was to evaluate the usefulness of the triaxial system in BAE using NBCA. METHODS: 12 patients with haemoptysis, 8 males and 4 females with a median age of 64 years (range, 49-88 years), underwent BAE between August 2012 and October 2014. Medical records and images were reviewed, and the technical success rate, clinical success rate, haemoptysis-free rate and complications were evaluated. Technical success was defined as the complete cessation of the target artery as confirmed by digital subtraction angiography, whereas clinical success was defined as the cessation of haemoptysis within 24 h of BAE. Recurrent haemoptysis was defined as a total of >30 ml of bleeding per day. RESULTS: The target artery was embolized successfully in all patients, and the technical success rate was 100% (12/12). The cessation of haemoptysis was achieved in 11 out of 12 patients within 24 h, and thus, the clinical success rate was 92% (11/12). The 6-, 12- and 24-month haemoptysis-free rates were 89%, 89% and 76%, respectively. No patients exhibited any signs of complications such as spinal ischaemia. CONCLUSION: BAE using the triaxial system and NBCA appears to be a useful and safe procedure for haemoptysis. ADVANCES IN KNOWLEDGE: The triaxial system contributes to safe and effective BAE using NBCA. PMID- 26423599 TI - Perfusion-based assessment of disease activity in untreated and treated patients with aortitis and chronic periaortitis: correlation with CT morphological, clinical and serological data. AB - OBJECTIVE: To evaluate the role of perfusion-based assessment of inflammatory activity in patients with treated and untreated aortitis and chronic periaortitis as compared with clinical and serological markers. METHODS: 35 patients (20 females; median age 66 years) with (peri) aortitis were retrospectively evaluated. All patients had clinical symptoms prompting at the time of imaging. All patients first underwent whole-body contrast-enhanced CT and subsequently segmental volume perfusion CT for assessment of the degree of vascularization of (peri) aortitis as a surrogate marker for inflammatory activity. Blood flow, blood volume, volume transfer constant (k-trans), time to peak and mean transit time were determined. The thickness of the increased connective tissue formation was measured. Perfusion data were correlated with clinical symptoms and acute phase inflammatory parameters such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and leukocyte number. RESULTS: 21 of 35 patients were untreated and 14 of 35 had previous/ongoing immunosuppression. The interobserver agreement was good (kappa = 0.78) for all perfusion parameters. Average values of perfusion parameters were higher in untreated patients but remained abnormally elevated in treated patients as well. Perfusion data and ESR and CRP correlated well both in aortitis (p < 0.05) and in periaortitis (p < 0.05). In periaortitis, perfusion parameters agreed well with ESR and CRP values (p < 0.05) only in untreated patients. CONCLUSION: Perfusion CT parameters in untreated aortitis and chronic periaortitis correlate well with serological markers with respect to disease activity assessment. However, in treated periaortitis, correlations were weak, suggesting an increased role for (perfusion-based) imaging. ADVANCES IN KNOWLEDGE: Volume perfusion CT may be used for diagnosis of aortitis/periaortitis. PMID- 26423600 TI - Prepregnancy Body Mass Index and Gestational Weight Gain Have No Negative Impact on Maternal or Neonatal Iron Status. AB - OBJECTIVE: To assess the impact of maternal obesity and excessive gestational weight gain (GWG) on maternal and neonatal iron status and to explore the possible mediating role of inflammation on hepcidin. METHODS: This analysis included 230 pregnant adolescents (13-18 years) enrolled in either a longitudinal or a cross-sectional study. Prepregnancy body mass index (ppBMI) and GWG were obtained from medical records. Maternal iron status (hemoglobin, serum iron, ferritin, transferrin receptor, total body iron, and hepcidin) and inflammation (interleukin-6 [IL-6] and leptin) were assessed at midgestation (26.2 +/- 3.3 weeks) in the longitudinal cohort and at delivery (39.8 +/- 1.3 weeks) in both study cohorts. Cord blood was collected in both studies and analyzed for iron indicators. RESULTS: Approximately 40% of the adolescents entered pregnancy overweight or obese. Multivariate analysis identified ppBMI as a negative predictor of serum iron at midgestation (P = .009) and a positive predictor of serum hepcidin at delivery (P = .02). None of the other maternal iron status indicators were significantly associated with ppBMI or GWG. Serum IL-6 was significantly positively associated with hepcidin at delivery (P = .0001) but not at midgestation. There was a positive relationship between ppBMI and cord hemoglobin (P = .03). CONCLUSION: These results suggest that adiposity-related inflammation does not override the iron-mediated signals that regulate hepcidin production during pregnancy, and in this adolescent cohort, there is no strong evidence for a detrimental effect of maternal obesity and excessive weight gain on iron status in the offspring at birth. PMID- 26423601 TI - Proteoglycans in Leiomyoma and Normal Myometrium: Abundance, Steroid Hormone Control, and Implications for Pathophysiology. AB - Uterine leiomyoma are a common benign pelvic tumors composed of modified smooth muscle cells and a large amount of extracellular matrix (ECM). The proteoglycan composition of the leiomyoma ECM is thought to affect pathophysiology of the disease. To test this hypothesis, we examined the abundance (by immunoblotting) and expression (by quantitative real-time polymerase chain reaction) of the proteoglycans biglycan, decorin, and versican in leiomyoma and normal myometrium and determined whether expression is affected by steroid hormones and menstrual phase. Leiomyoma and normal myometrium were collected from women (n = 17) undergoing hysterectomy or myomectomy. In vitro studies were performed on immortalized leiomyoma (UtLM) and normal myometrial (hTERT-HM) cells with and without exposure to estradiol and progesterone. In leiomyoma tissue, abundance of decorin messenger RNA (mRNA) and protein were 2.6-fold and 1.4-fold lower, respectively, compared with normal myometrium. Abundance of versican mRNA was not different between matched samples, whereas versican protein was increased 1.8 fold in leiomyoma compared with myometrium. Decorin mRNA was 2.4-fold lower in secretory phase leiomyoma compared with proliferative phase tissue. In UtLM cells, progesterone decreased the abundance of decorin mRNA by 1.3-fold. Lower decorin expression in leiomyoma compared with myometrium may contribute to disease growth and progression. As decorin inhibits the activity of specific growth factors, its reduced level in the leiomyoma cell microenvironment may promote cell proliferation and ECM deposition. Our data suggest that decorin expression in leiomyoma is inhibited by progesterone, which may be a mechanism by which the ovarian steroids affect leiomyoma growth and disease progression. PMID- 26423602 TI - Afatinib, an irreversible ErbB family blocker, with protracted temozolomide in recurrent glioblastoma: a case report. AB - There are few effective treatments for recurrent glioblastoma multiforme (GBM). We present a patient with recurrent GBM who achieved a prolonged response to treatment with afatinib, an irreversible ErbB family blocker, plus temozolomide. A 58-year-old female patient was diagnosed with multifocal primary GBM. After surgical resection, first-line therapy comprised radiotherapy and temozolomide. Following disease progression after 3 temozolomide cycles, the patient entered a phase I/II clinical trial of afatinib (20-40 mg daily for 28 days) plus temozolomide (50 mg/m2 every 21/28 days). Next-generation sequencing analysis of the brain tumor specimen was performed. At the last assessment, 63 treatment cycles had been completed and the patient had survived for ~5 years since recurrence. Significant disease regression was observed after 5 cycles and was maintained during long-term follow-up. Adverse events were consistent with the known tolerability profile of afatinib and were managed by treatment interruption/dose reduction. The patient had several epidermal growth factor receptor (EGFR) aberrations, including gene amplification and EGFRvIII positivity. Three somatic mutations were identified, including an unprecedented extracellular-domain substitution (D247Y). The patient has survived ~6-fold longer than normally expected in patients with recurrent GBM. The complex EGFR genotype may underlie sustained response to afatinib plus temozolomide. PMID- 26423603 TI - Decline of gustatory sensitivity with the progression of Alzheimer's disease. AB - BACKGROUND: Patients with Alzheimer's disease (AD) manifest various impairments in eating behavior. However, few previous studies have directly investigated the gustatory function of AD patients, and results have been inconsistent. METHODS: Thirty-two AD patients (Clinical Dementia Rating (CDR) 0.5/1/2, respectively 11/15/6 patients) and 22 normal control participants were examined to measure detection and recognition thresholds of the four elemental tastes (sweet, salty, sour, and bitter), and their ability to discriminate between tastes. Effects of demographic and clinical factors (age, sex, histories of alcohol and tobacco consumption, and CDR grade) on gustatory threshold were examined using ordinal logistic regression analysis. Performance was compared between AD and control groups. RESULTS: Total threshold values (the sum of threshold grades for the four tastes) for detection and recognition of tastes were significantly higher in the AD group. Detection thresholds for sweet, salty, and bitter, and recognition thresholds for sweet and sour, were also significantly higher in the AD group. Ordinal logistic regression analysis revealed that CDR grade was the only factor that significantly affected both total threshold values. Regarding taste discrimination, there were no significant differences between the AD group and control group. CONCLUSIONS: These findings suggest that progression of dementia severity accompanies gustatory decline. Although it seemingly paradoxical, weight loss and preference for sweet tastes are frequently, often simultaneously, observed in AD. Gustatory dysfunction may be partially involved in these symptoms. Thus, the nutritional care of patients with AD could be improved by making the taste of meals stronger, while controlling calorie and mineral intake. PMID- 26423605 TI - Health care disparities among persons with comorbid schizophrenia and cardiovascular disease: a case-control epidemiological study. AB - AIMS: Studies showed health care disparities among persons with comorbid schizophrenia and cardiovascular disease (CVD), including in countries with universal health care. However, the potential positive effect of specific mental health legislation has not been reported. This study aimed to investigate the health care of persons with comorbid schizophrenia and CVD in a country with both a national health insurance and a comprehensive rehabilitation law for persons with mental disabilities. METHOD: This study builds on a large case-control epidemiological sample (N = 52 189) of service users. Within the sample we identified a sub-group of persons with CVD diagnoses (n = 8208) and compared service users with and without schizophrenia on drug utilisation, laboratory tests, visits to specialists and surgical interventions. RESULTS: Service users with schizophrenia were less likely to meet similar indexes of care as their counterparts: 91% cholesterol tests (p < 0.001), 60% stress tests (p < 0.001), 93% visits to specialists (p = 0.001), 93% drug utilisation (p < 0.001) and 55% CVD surgical interventions (odds ratio 0.55, 95% confidence intervals 0.49-0.61). CONCLUSIONS: In Israel, a country with a national health insurance and a rehabilitation law specific for persons with mental disabilities, service users with schizophrenia still fail to receive equitable levels of health care for CVD. However, the disparities appear to be smaller than in other countries with universal health insurance. PMID- 26423604 TI - Distinct preoptic-BST nuclei dissociate paternal and infanticidal behavior in mice. AB - Paternal behavior is not innate but arises through social experience. After mating and becoming fathers, male mice change their behavior toward pups from infanticide to paternal care. However, the precise brain areas and circuit mechanisms connecting these social behaviors are largely unknown. Here we demonstrated that the c-Fos expression pattern in the four nuclei of the preoptic bed nuclei of stria terminalis (BST) region could robustly discriminate five kinds of previous social behavior of male mice (parenting, infanticide, mating, inter-male aggression, solitary control). Specifically, neuronal activation in the central part of the medial preoptic area (cMPOA) and rhomboid nucleus of the BST (BSTrh) retroactively detected paternal and infanticidal motivation with more than 95% accuracy. Moreover, cMPOA lesions switched behavior in fathers from paternal to infanticidal, while BSTrh lesions inhibited infanticide in virgin males. The projections from cMPOA to BSTrh were largely GABAergic. Optogenetic or pharmacogenetic activation of cMPOA attenuated infanticide in virgin males. Taken together, this study identifies the preoptic-BST nuclei underlying social motivations in male mice and reveals unexpected complexity in the circuit connecting these nuclei. PMID- 26423606 TI - Dynamical modeling of uncertain interaction-based genomic networks. AB - BACKGROUND: Most dynamical models for genomic networks are built upon two current methodologies, one process-based and the other based on Boolean-type networks. Both are problematic when it comes to experimental design purposes in the laboratory. The first approach requires a comprehensive knowledge of the parameters involved in all biological processes a priori, whereas the results from the second method may not have a biological correspondence and thus cannot be tested in the laboratory. Moreover, the current methods cannot readily utilize existing curated knowledge databases and do not consider uncertainty in the knowledge. Therefore, a new methodology is needed that can generate a dynamical model based on available biological data, assuming uncertainty, while the results from experimental design can be examined in the laboratory. RESULTS: We propose a new methodology for dynamical modeling of genomic networks that can utilize the interaction knowledge provided in public databases. The model assigns discrete states for physical entities, sets priorities among interactions based on information provided in the database, and updates each interaction based on associated node states. Whenever uncertainty in dynamics arises, it explores all possible outcomes. By using the proposed model, biologists can study regulation networks that are too complex for manual analysis. CONCLUSIONS: The proposed approach can be effectively used for constructing dynamical models of interaction based genomic networks without requiring a complete knowledge of all parameters affecting the network dynamics, and thus based on a small set of available data. PMID- 26423608 TI - Large spin Hall magnetoresistance and its correlation to the spin-orbit torque in W/CoFeB/MgO structures. AB - The phenomena based on spin-orbit interaction in heavy metal/ferromagnet/oxide structures have been investigated extensively due to their applicability to the manipulation of the magnetization direction via the in-plane current. This implies the existence of an inverse effect, in which the conductivity in such structures should depend on the magnetization orientation. In this work, we report a systematic study of the magnetoresistance (MR) of W/CoFeB/MgO structures and its correlation with the current-induced torque to the magnetization. We observe that the MR is independent of the angle between the magnetization and current direction but is determined by the relative magnetization orientation with respect to the spin direction accumulated by the spin Hall effect, for which the symmetry is identical to that of so-called the spin Hall magnetoresistance. The MR of ~1% in W/CoFeB/MgO samples is considerably larger than those in other structures of Ta/CoFeB/MgO or Pt/Co/AlOx, which indicates a larger spin Hall angle of W. Moreover, the similar W thickness dependence of the MR and the current-induced magnetization switching efficiency demonstrates that MR in a non magnet/ferromagnet structure can be utilized to understand other closely correlated spin-orbit coupling effects such as the inverse spin Hall effect or the spin-orbit spin transfer torques. PMID- 26423607 TI - Non-invasive imaging and cellular tracking of pulmonary emboli by near-infrared fluorescence and positron-emission tomography. AB - Functional imaging of proteolytic activity is an emerging strategy to quantify disease and response to therapy at the molecular level. We present a new peptide based imaging probe technology that advances these goals by exploiting enzymatic activity to deposit probes labelled with near-infrared (NIR) fluorophores or radioisotopes in cell membranes of disease-associated proteolysis. This strategy allows for non-invasive detection of protease activity in vivo and ex vivo by tracking deposited probes in tissues. We demonstrate non-invasive detection of thrombin generation in a murine model of pulmonary embolism using our protease activated peptide probes in microscopic clots within the lungs with NIR fluorescence optical imaging and positron-emission tomography. Thrombin activity is imaged deep in tissue and tracked predominantly to platelets within the lumen of blood vessels. The modular design of our probes allows for facile investigation of other proteases, and their contributions to disease by tailoring the protease activation and cell-binding elements. PMID- 26423609 TI - Azo-Based Iridium(III) Complexes as Multicolor Phosphorescent Probes to Detect Hypoxia in 3D Multicellular Tumor Spheroids. AB - Hypoxia is an important characteristic of malignant solid tumors and is considered as a possible causative factor for serious resistance to chemo- and radiotherapy. The exploration of novel fluorescent probes capable of detecting hypoxia in solid tumors will aid tumor diagnosis and treatment. In this study, we reported the design and synthesis of a series of "off-on" phosphorescence probes for hypoxia detection in adherent and three-dimensional multicellular spheroid models. All of the iridium(III) complexes incorporate an azo group as an azo reductase reactive moiety to detect hypoxia. Reduction of non-phosphorescent probes Ir1-Ir8 by reductases under hypoxic conditions resulted in the generation of highly phosphorescent corresponding amines for detection of hypoxic regions. Moreover, these probes can penetrate into 3D multicellular spheroids over 100 MUm and image the hypoxic regions. Most importantly, these probes display a high selectivity for the detection of hypoxia in 2D cells and 3D multicellular spheroids. PMID- 26423610 TI - Stroboscopic phenomena in superconductors with dynamic pinning landscape. AB - Introducing artificial pinning centers is a well established strategy to trap quantum vortices and increase the maximal magnetic field and applied electric current that a superconductor can sustain without dissipation. In case of spatially periodic pinning, a clear enhancement of the superconducting critical current arises when commensurability between the vortex configurations and the pinning landscape occurs. With recent achievements in (ultrafast) optics and nanoengineered plasmonics it has become possible to exploit the interaction of light with superconductivity, and create not only spatially periodic imprints on the superconducting condensate, but also temporally periodic ones. Here we show that in the latter case, temporal matching phenomena develop, caused by stroboscopic commensurability between the characteristic frequency of the vortex motion under applied current and the frequency of the dynamic pinning. The matching resonances persist in a broad parameter space, including magnetic field, driving current, or material purity, giving rise to unusual features such as externally variable resistance/impedance and Shapiro steps in current-voltage characteristics. All features are tunable by the frequency of the dynamic pinning landscape. These findings open further exploration avenues for using flashing, spatially engineered, and/or mobile excitations on superconductors, permitting us to achieve advanced functionalities. PMID- 26423611 TI - Epirubicin-gold nanoparticles suppress hepatocellular carcinoma xenograft growth in nude mice. AB - We sought to investigate the effects of epirubicin-nanogold compounds (EPI-AuNP) on hepatocellular carcinoma xenograft growth in nude mice. EPI-AuNP was prepared and hepatoma xenograft model was established in nude mice. The mice were then randomly divided into four groups: the control group with injection of saline, the AuNP treatment group, the EPI treatment group and the EPI-AuNP treatment group. After two weeks, the hepatoma weight and volume of the xenografts were assessed. Our transmission electron microscopy revealed that epirubicin-gold nanoparticles caused significantly more structural changes of hepatocellular carcinoma cells HepG2. The tumor weight in the Epi-AuNP treatment group (0.80+/ 0.11g) was significantly lower than that of the control group (2.48+/-0.15 g), the AuNP treatment group (1.67+/-0.17 g), and the EPI treatment group (1.39+/ 0.10g) (P<0.01). Furthermore, the tumor volume of mice in the EPI-AuNP treatment group (0.27+/-0.06 cm3) was significantly smaller than that of the control group (2.23+/-0.34 cm3), the AuNP treatment group (1.21+/-0.25 cm3) and the EPI treatment group (0.81+/-0.11 cm3) (P<0.01). In conclusion, epirubicin-nanogold compounds (EPI-AuNP) have significant inhibitory effects on the growth of hepatocellular carcinoma cells in vivo. PMID- 26423612 TI - Generation of monoclonal antibodies against n-3 fatty acid desaturase. PMID- 26423613 TI - Retinol binding protein 4 correlates with and is an early predictor of carotid atherosclerosis in type 2 diabetes mellitus patients. AB - The association of retinol binding protein 4 (RBP4) with atherosclerosis of the carotid artery in type 2 diabetes mellitus (T2DM) remains undefined. We aimed to investigate the correlation of RBP4 expression with atherosclerosis of the carotid artery in T2DM. A total of 1,076 subjects were investigated for intima media thickness of the bilateral common carotid arteries, and they were divided into three groups: in group I, patients had normal neck vascular ultrasound, in group II, intimal carotid artery media thickness was equal to or more than 1 mm, and in group III, carotid artery plaque was present. Height, weight, blood pressure (BP), fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-1 (Apo A-1), apolipoprotein B (Apo B) and lipoprotein (a) (Lp(a)) were determined by routine laboratory methods. RBP4 and high sensitivity C reactive protein (HsCRP) were measured by an enzyme-linked immuno-sorbent assay, and insulin concentration was measured by an electrochemiluminescence sandwich immunoassay. Duration of diabetes, waist and BP, FPG, HbA1c, TG, TC, LDL-C, APOB, Lp(a), HsCRP, RBP4 and homeostasis model assessment insulin resistance index (HOMA-IR) were significantly lower in group I than in the other two groups (P<0.01, P<0.01). Plasma levels of HbA1c, RBP4, LDL-C, TC, HOMA-IR, HsCRP and Lp(a), waist and BP were significantly increased in group III than in group II (P<0.01). Multivariate logistic regression analysis showed that there were seven factors associated with the occurrence of carotid artery atherosclerosis and its risks in descending order were: high LDL-C, high waist, high HsCRP, duration of diabetes, high HOMA IR, HbA1c and high RBP4. Our finding supported that RBP4 was positively correlated with carotid atherosclerosis in patients with T2DM and could be used as an early predictor of cardiovascular disease. PMID- 26423614 TI - Scaphoid fracture non-union: a systematic review of surgical treatment using bone graft. AB - This systematic review assesses the quality and outcomes of published articles concerning bone graft surgery for scaphoid fracture non-union. Searches of the CENTRAL, MEDLINE, EMBASE, CINAHL and AMED databases captured 2710 articles. Each article was screened and 144 met our inclusion criteria. Data regarding source, study design, population, intervention, comparator and outcomes were extracted. There were 5464 scaphoid non-union outcomes within the 144 studies. Mean reported union rates for vascularized and non-vascularized bone graft were 84% and 80%, respectively. Avascular necrosis was diagnosed in several ways and, when present, the vascularized bone graft union rate was 74% compared with 62% with non vascularized bone graft. Reported union rates vary considerably. These differences may be due to patient factors, fracture factors, treatment factors or study design failures or bias. We recommend that future researchers take into account the deficiencies of previous studies and use the suggested minimum data set in future studies. LEVEL OF EVIDENCE: II. PMID- 26423615 TI - Peritoneal tuberculosis presenting with portal vein thrombosis and transudative Ascites - a diagnostic dilemma: case report. AB - BACKGROUND: Peritoneal tuberculosis is an important problem in regions of the world where tuberculosis is still prevalent (Chest 1991; 99:1134). Atypical presentations such as portal vein thrombosis can delay diagnosis or result in misdiagnosis (Gut 1990; 31:1130, Acta ClinBelg 2012; 67(2):137-9, J Cytol Histol 2014; 5:278, Digestive Diseases and Sciences 1991; 36(1):112-115). A high index of suspicion is required for the diagnosis of peritoneal tuberculosis, as the analysis of peritoneal fluid for tuberculous bacillus is often ineffective, and may increase mortality due to delayed diagnosis. (Clin Effect Dis 2002;35: 409 13) In light of new evidence, peritoneal biopsy through laparoscopy or laparotomy has emerged as the gold standard for diagnosis (Clin Effect Dis 2002; 35: 409 13). CASE PRESENTATION: We report a case of a 35 year old Sri Lankan female employed in a Middle - Eastern country who presented with progressive abdominal distention and constitutional symptoms for four months duration. She had been investigated abroad and diagnosed with ascites with chronic portal vein thrombosis following which warfarin therapy had been commenced suspecting an underlying thrombophilia. Despite treatment her symptoms had worsened. Therefore she had decided to return to Sri Lanka for further evaluation. After ruling out inherited thrombophilic states and the antiphospholipid syndrome, further investigations revealed a transudative ascites and high inflammatory markers. The tuberculosis work up on peritoneal fluid was negative. Therefore, we proceeded with laparoscopy which showed multiple nodular deposits on abdominal wall, bowel and omentum and peritoneal biopsy revealed granulomatous inflammation with caseous type necrosis compatible with mycobacterium tuberculosis infection. This was confirmed by tuberculosis genome identification on the biopsy sample confirming a diagnosis of peritoneal tuberculosis with secondary portal vein thrombosis and cavernous formation due to local inflammation. The patient was started on anti-tuberculosis treatment and warfarin was discontinued, following which she made a remarkable recovery. CONCLUSION: Peritoneal tuberculosis can present with unusual manifestations such as portal vein thrombosis and transudative ascites causing a diagnostic dilemma. Ascitic fluid analysis is generally not diagnostic. Under such circumstances peritoneal biopsy should be performed as it has a good diagnostic yield and accuracy. PMID- 26423616 TI - Semantic biomedical resource discovery: a Natural Language Processing framework. AB - BACKGROUND: A plethora of publicly available biomedical resources do currently exist and are constantly increasing at a fast rate. In parallel, specialized repositories are been developed, indexing numerous clinical and biomedical tools. The main drawback of such repositories is the difficulty in locating appropriate resources for a clinical or biomedical decision task, especially for non Information Technology expert users. In parallel, although NLP research in the clinical domain has been active since the 1960s, progress in the development of NLP applications has been slow and lags behind progress in the general NLP domain. The aim of the present study is to investigate the use of semantics for biomedical resources annotation with domain specific ontologies and exploit Natural Language Processing methods in empowering the non-Information Technology expert users to efficiently search for biomedical resources using natural language. METHODS: A Natural Language Processing engine which can "translate" free text into targeted queries, automatically transforming a clinical research question into a request description that contains only terms of ontologies, has been implemented. The implementation is based on information extraction techniques for text in natural language, guided by integrated ontologies. Furthermore, knowledge from robust text mining methods has been incorporated to map descriptions into suitable domain ontologies in order to ensure that the biomedical resources descriptions are domain oriented and enhance the accuracy of services discovery. The framework is freely available as a web application at ( http://calchas.ics.forth.gr/ ). RESULTS: For our experiments, a range of clinical questions were established based on descriptions of clinical trials from the ClinicalTrials.gov registry as well as recommendations from clinicians. Domain experts manually identified the available tools in a tools repository which are suitable for addressing the clinical questions at hand, either individually or as a set of tools forming a computational pipeline. The results were compared with those obtained from an automated discovery of candidate biomedical tools. For the evaluation of the results, precision and recall measurements were used. Our results indicate that the proposed framework has a high precision and low recall, implying that the system returns essentially more relevant results than irrelevant. CONCLUSIONS: There are adequate biomedical ontologies already available, sufficiency of existing NLP tools and quality of biomedical annotation systems for the implementation of a biomedical resources discovery framework, based on the semantic annotation of resources and the use on NLP techniques. The results of the present study demonstrate the clinical utility of the application of the proposed framework which aims to bridge the gap between clinical question in natural language and efficient dynamic biomedical resources discovery. PMID- 26423617 TI - A randomised controlled trial comparing the effects of a 12-week supervised exercise versus usual care on outcomes in haematological cancer patients. AB - PURPOSE: Following treatment, haematological cancer (HEM) patients exhibit significant physical deconditioning and psychological distress. Exercise has been shown as a clinically effective and safe intervention for cancer patients, with the potential to reverse the deleterious effects following treatment. Our aim was to investigate the efficacy of a 12-week exercise rehabilitation on cancer related fatigue (CRF) and associated outcomes in HEM patients post-treatment. METHODS: Patients with a HEM were recruited to participate in a 12-week exercise rehabilitation intervention post-treatment. Pre-, post- and follow-up assessments were conducted on outcome measures including CRF, quality of life (QoL), psychological distress, cardiovascular fitness, muscle strength (MS) and body composition. Patients were given tailored exercise programmes comprising aerobic and resistance exercises, carried out three times per week for 12 weeks in local gyms and clinics. Usual-care participants were offered a delayed, tailored 12 week exercise intervention after the initial study period. RESULTS: Thirty-seven patients (49 % recruitment rate) were randomly assigned to the 12-week exercise rehabilitation (n = 18) or usual care (n = 19) with a 91 % adherence to the exercise intervention. Following the exercise programme, significant improvements were seen in CRF (p = 0.01), cardiovascular fitness (p <= 0.001), QoL (p <= 0.001), MS (p <= 0.001) and body composition (p = 0.001), with moderate to large effects for all primary outcomes. Patient follow-up at 24 weeks demonstrated outcome maintenance in the exercise rehabilitation group and significant improvements in outcomes in usual-care patients following participation in a delayed exercise programme. There were no adverse reactions or study withdrawals. CONCLUSIONS: A 12-week exercise rehabilitation programme resulted in significant statistical (p <= 0.05) and clinical improvements in CRF and additional outcomes in HEM patients following treatment. Additionally, a 12-week delayed exercise programme showed similar significant improvements in patient outcomes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12609000450213. PMID- 26423620 TI - Special Collection: Emerging Concepts in Three-Dimensional Microtissues. AB - Over the past decade, the concept of tissue engineering has been extended to include technologies that use multicellular aggregates, not only to repair or replace tissue but also as a stand-alone in vitro device (e.g., "organ-on-a chip") with well-defined biological outputs. The advantage of such systems is that they allow for culture of one or more cell types in three dimensions, which may promote tissue function that is more mimetic of the in vivo state, while allowing high-throughput sample testing and a large degree of control of external culture factors that may lead to more reproducible results than that found in the more complex in vivo environment. While the means used to achieve these devices vary greatly, in this special collection, we focus our attention on formation and use of scaffold-free cellular aggregates (three-dimensional microtissues). PMID- 26423618 TI - A randomized, multicenter, phase II/III study to determine the optimal dose and to evaluate the efficacy and safety of pegteograstim (GCPGC) on chemotherapy induced neutropenia compared to pegfilgrastim in breast cancer patients: KCSG PC10-09. AB - PURPOSE: Pegylated granulocyte-colony-stimulating factor (G-CSF) is frequently used to prevent febrile neutropenia (FN) in patients undergoing chemotherapy with a high risk of myelosuppression. This phase II/III study was conducted to determine the adequate dose of pegteograstim, a new formulation of pegylated G CSF, and to evaluate the efficacy and safety of pegteograstim compared to pegfilgrastim. METHODS: In the phase II part, 60 breast cancer patients who were undergoing DA (docetaxel and doxorubicin) or TAC (docetaxel, doxorubicin, and cyclophosphamide) chemotherapy were randomly selected to receive a single subcutaneous injection of 3.6 or 6.0 mg pegteograstim on day 2 of each chemotherapy cycle. The phase III part was seamlessly started to compare the dose of pegteograstim at selected in phase II with 6.0 mg pegfilgrastim in 117 breast cancer patients. The primary endpoint of both the phase II and III parts was the duration of grade 4 neutropenia in the chemotherapy cycle 1. RESULTS: The mean duration of grade 4 neutropenia for the 3.6 mg pegteograstim (n = 33) was similar to that for the 6.0 mg pegteograstim (n = 26) (1.97 +/- 1.79 days vs. 1.54 +/- 0.95 days, p = 0.33). The 6.0 mg pegteograstim was selected to be compared with the 6.0 mg pegfilgrastim in the phase III part. In the phase III part, the primary analysis revealed that the efficacy of pegteograstim (n = 56) was non inferior to that of pegfilgrastim (n = 59) [duration of grade 4 neutropenia, 1.64 +/- 1.18 days vs. 1.80 +/- 1.05 days; difference, -0.15 +/- 1.11 (p = 0.36, 97.5 % confidence intervals = 0.57 and 0.26)]. The time to the absolute neutrophil count (ANC) recovery of pegteograstim (>=2000/MUL) was significantly shorter than that of pegfilgrastim (8.85 +/- 1.45 days vs. 9.83 +/- 1.20 days, p < 0.0001). Other secondary endpoints showed no significant difference between the two groups. The safety profiles of the two groups did not differ significantly. CONCLUSIONS: Pegteograstim was shown to be as effective as pegfilgrastim in the reduction of chemotherapy-induced neutropenia in the breast cancer patients who were undergoing chemotherapy with a high risk of myelosuppression. PMID- 26423619 TI - Linking individual medicare health claims data with work-life claims and other administrative data. AB - BACKGROUND: Researchers investigating health outcomes for populations over age 65 can utilize Medicare claims data, but these data include no direct information about individuals' health prior to age 65 and are not typically linkable to files containing data on exposures and behaviors during their worklives. The current paper is a proof-of-concept, of merging employers' administrative data and private, employment-based health claims with Medicare data. Characteristics of the linked data, including sensitivity and specificity, are evaluated with an eye toward potential uses of such linked data. This paper uses a sample of former manufacturing workers from an industrial cohort as a test case. The dataset created by this integration could be useful to research in areas such as social epidemiology and occupational health. METHODS: Medicare and employment administrative data were linked for a large cohort of manufacturing workers (employed at some point during 1996-2008) who transitioned onto Medicare between 2001-2009. Data on work-life health, including biometric indicators, were used to predict health at age 65 and to investigate the concordance of employment-based insurance claims with subsequent Medicare insurance claims. RESULTS: Chronic diseases were found to have relatively high levels of concordance between employment-based private insurance and subsequent Medicare insurance. Information about patient health prior to receipt of Medicare, including biometric indicators, were found to predict health at age 65. CONCLUSIONS: Combining these data allows for evaluation of continuous health trajectories, as well as modeling later-life health as a function of work-life behaviors and exposures. It also provides a potential endpoint for occupational health research. This is the first harmonization of its kind, providing a proof-of-concept. The dataset created by this integration could be useful for research in areas such as social epidemiology and occupational health. PMID- 26423621 TI - Establishing assay sensitivity in QT studies: experience with the use of moxifloxacin in an early phase clinical pharmacology study and comparison with its effect in a thorough QT study. AB - OBJECTIVE: To compare the effect of moxifloxacin as a positive control in a single ascending dose (SAD) study with that in a thorough QT (TQT) study. METHODS: Moxifloxacin was used as a positive control in a SAD study and a TQT study during the evaluation of the QT liability of a new drug. The SAD study had enrolled 24 males and the TQT study 25 males. Both studies intensively monitored electrocardiograms (ECGs) and pharmacokinetic sampling. Effect of moxifloxacin on QTc interval was analysed in each study by intersection union test (IUT) and by exposure-response (ER) analysis and the results compared. Cost-effectiveness of this approach was computed. RESULTS: Analysis by IUT revealed that the maximum mean (90 % confidence interval (CI)) placebo-corrected change from baseline (DeltaDeltaQTcF) in the SAD study and the TQT study were remarkably similar (10.7 (6.5; 14.9) ms vs. 9.09 (6.20; 11.98) ms, respectively). In both studies, assay sensitivity was established by the 90 % lower bound exceeding 5 ms. ER analysis revealed the slopes in both studies to be significantly different from zero and comparable. Bootstrap-predicted effects of moxifloxacin at geometric mean concentrations of ~3000 ng/mL were 8.19 (90 % CI 5.86; 10.7) ms in the SAD study and 7.33 (90 % CI 5.69; 9.70) ms in the TQT study. CONCLUSION: Moxifloxacin can be integrated effectively in a SAD study to establish assay sensitivity, and a TQT study may be replaced by a SAD study which has the required assay sensitivity. Further experience is warranted to verify this conclusion. PMID- 26423623 TI - Pulsed amperometric detection at glassy carbon electrodes: A new waveform for sensitive and reproducible determination of electroactive compounds. AB - In this work, the application of a new pulsed amperometric detection (PAD) waveform at a glassy carbon electrode, operating in typical chromatographic mobile phases, is proposed for the sensitive and reproducible determination of arylethanolaminic and phenolic moiety based compounds (e.g. beta-agonists and polyphenols). Preliminary experiments by cyclic voltammetry were carried out to investigate the electrochemical behaviour and to select the detection and cleaning electrode potentials. The proposed potential-time profile was designed to prevent the carbon electrode fouling under repeated analyses, thus ensuring a reproducible and sensitive quantitative determination, without the need of any mechanical or chemical electrode cleaning procedure. The waveform electrochemical parameters, including detection and delay times, were optimized in terms of sensitivity, limit of detection and response stability. The optimized waveform allowed the sensitive and stable detection of model compounds, such as clenbuterol and caffeic acid, that showed detection limits of 0.1 MUg L(-1) and 14 MUg L(-1), quantification limits of 0.4 MUg L(-1) and 46 MUg L(-1), and linearity up to 100 MUg L(-1) (r = 0.9993) and 10 mg L(-1) (r = 0.9998), respectively. Similar results were obtained for other compounds of the same classes, with precision values under repeatability conditions ranging from 3.0 to 5.9%. The proposed method can be then considered as an excellent alternative to the post-column detection of beta-agonists, phenols and polyphenols. PMID- 26423624 TI - Inductively coupled plasma - Tandem mass spectrometry (ICP-MS/MS): A powerful and universal tool for the interference-free determination of (ultra)trace elements - A tutorial review. AB - This paper is intended as a tutorial review on the use of inductively coupled plasma - tandem mass spectrometry (ICP-MS/MS) for the interference-free quantitative determination and isotope ratio analysis of metals and metalloids in different sample types. Attention is devoted both to the instrumentation and to some specific tools and procedures available for advanced method development. Next to the more typical reaction gases, e.g., H2, O2 and NH3, also the use of promising alternative gases, such as CH3F, is covered, and the possible reaction pathways with those reactive gases are discussed. A variety of published applications relying on the use of ICP-MS/MS are described, to illustrate the added value of tandem mass spectrometry in (ultra)trace analysis. PMID- 26423622 TI - Population pharmacokinetics of vancomycin in adult Chinese patients with post craniotomy meningitis and its application in individualised dosage regimens. AB - PURPOSE: Vancomycin (VCM) is a first-line antibacterial drug used to treat post craniotomy meningitis (PCM). VCM pharmacokinetic parameters are altered in PCM patients, compared to those in other patients. Although VCM population pharmacokinetics (PPK) has been reported, changes in VCM PPK in adult Chinese PCM patients remain unknown. We developed a VCM PPK model in adult Chinese PCM patients and proposed a new strategy for individualising VCM administration using this model. METHODS: Data was obtained from a prospective study of 100 adult PCM patients in the Neurosurgery Department of the First Affiliated Hospital of Fujian Medical University. The trough concentrations at steady state were determined by enzyme multiplied immunoassay. Nonlinear mixed-effect model software was employed to develop the PPK model. The final model was evaluated using the bootstrap method and normalised prediction error distribution and through the testing of 20 independent adult PCM patients. RESULTS: VCM clearance in PCM patients was higher than that observed in other patients. Creatinine clearance affected VCM clearance, whereas no co-administered drugs influenced VCM pharmacokinetics. Trough concentrations were accurately predicted by the final model, while the prediction errors were less than +/-32 %. Moreover, a new strategy for individualising VCM regimens using the PPK model was proposed and validated. CONCLUSIONS: A PPK model was developed to estimate the individual clearance in inpatients receiving intravenously infused VCM and could be used to develop individualised dosing of adult Chinese PCM patients. PMID- 26423625 TI - Methods for the experimental characterization and analysis of the efficiency and speed of chromatographic columns: A step-by-step tutorial. AB - Due to the developing insights in the theory of chromatography, column manufacturers of any kind (industrial, academic) nowadays have a broad array of experimental column testing tools at their disposal. The present tutorial aims at helping the novice in the field getting an overview of these tools and provides a fixed procedure to carry out the subsequent steps in the column quality analysis (guided via an Excel template file). After some brief introduction about the main equations, the reader is taken step by step through the theories underlying the measurement methods for the different column and performance parameters. In the final section, the reader is taken through the different items in the Excel template. PMID- 26423626 TI - Automated on-line liquid-liquid extraction system for temporal mass spectrometric analysis of dynamic samples. AB - Most real samples cannot directly be infused to mass spectrometers because they could contaminate delicate parts of ion source and guides, or cause ion suppression. Conventional sample preparation procedures limit temporal resolution of analysis. We have developed an automated liquid-liquid extraction system that enables unsupervised repetitive treatment of dynamic samples and instantaneous analysis by mass spectrometry (MS). It incorporates inexpensive open-source microcontroller boards (Arduino and Netduino) to guide the extraction and analysis process. Duration of every extraction cycle is 17 min. The system enables monitoring of dynamic processes over many hours. The extracts are automatically transferred to the ion source incorporating a Venturi pump. Operation of the device has been characterized (repeatability, RSD = 15%, n = 20; concentration range for ibuprofen, 0.053-2.000 mM; LOD for ibuprofen, ~0.005 mM; including extraction and detection). To exemplify its usefulness in real-world applications, we implemented this device in chemical profiling of pharmaceutical formulation dissolution process. Temporal dissolution profiles of commercial ibuprofen and acetaminophen tablets were recorded during 10 h. The extraction-MS datasets were fitted with exponential functions to characterize the rates of release of the main and auxiliary ingredients (e.g. ibuprofen, k = 0.43 +/- 0.01 h(-1)). The electronic control unit of this system interacts with the operator via touch screen, internet, voice, and short text messages sent to the mobile phone, which is helpful when launching long-term (e.g. overnight) measurements. Due to these interactive features, the platform brings the concept of the Internet-of-Things (IoT) to the chemistry laboratory environment. PMID- 26423627 TI - A strategy for fast screening and identification of sulfur derivatives in medicinal Pueraria species based on the fine isotopic pattern filtering method using ultra-high-resolution mass spectrometry. AB - Sulfurous compounds are commonly present in plants, fungi, and animals. Most of them were reported to possess various bioactivities. Isotopic pattern filter (IPF) is a powerful tool for screening compounds with distinct isotope pattern. Over the past decades, the IPF was used mainly to study Cl- and Br-containing compounds. To our knowledge, the algorithm was scarcely used to screen S containing compounds, especially when combined with chromatography analyses, because the (34)S isotopic ion is drastically affected by (13)C2 and (18)O. Thus, we present a new method for a fine isotopic pattern filter (FIPF) based on the separated M + 2 ions ((12)C(x)(1)H(y)(16)O(z)(32)S(13)C2(18)O, (12)C(x+2)(1)H(y)(16)O(z+1)(34)S, tentatively named M + 2OC and M + 2S) with an ultra-high-resolution mass (100,000 FWHM @ 400 m/z) to screen sulfur derivatives in traditional Chinese medicines (TCM).This finer algorithm operates through convenient filters, including an accurate mass shift of M + 2OC and M + 2S from M and their relative intensity compared to M. The method was validated at various mass resolutions, mass accuracies, and screening thresholds of flexible elemental compositions. Using the established FIPF method, twelve S-derivatives were found in the popular medicinal used Pueraria species, and 9 of them were tentatively identified by high-resolution multiple stage mass spectrometry (HRMS(n)). The compounds were used to evaluate the sulfurous compounds' situation in commercially purchased Pueraria products. The strategy presented here provides a promising application of the IPF method in a new field. PMID- 26423628 TI - Comprehensive profiling of mercapturic acid metabolites from dietary acrylamide as short-term exposure biomarkers for evaluation of toxicokinetics in rats and daily internal exposure in humans using isotope dilution ultra-high performance liquid chromatography tandem mass spectrometry. AB - Mercapturic acid metabolites from dietary acrylamide are important short-term exposure biomarkers for evaluating the in vivo toxicity of acrylamide. Most of studies have focused on the measurement of two metabolites, N-acetyl-S-(2 carbamoylethyl)-L-cysteine (AAMA) and N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L cysteine (GAMA). Thus, the comprehensive profile of acrylamide urinary metabolites cannot be fully understood. We developed an isotope dilution ultra high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous determination of all four mercapturic acid adducts of acrylamide and its primary metabolite glycidamide under the electroscopy ionization negative (ESI-) mode in the present study. The limit of detection (LOD) and limit of quantification (LOQ) of the analytes ranged 0.1-0.3 ng/mL and 0.4-1.0 ng/mL, respectively. The recovery rates with low, intermediate and high spiking levels were calculated as 95.5%-105.4%, 98.2%-114.0% and 92.2%-108.9%, respectively. Acceptable within-laboratory reproducibility (RSD<7.0%) substantially supported the use of current method for robust analysis. Rapid pretreatment procedures and short run time (8 min per sample) ensured good efficiency of metabolism profiling, indicating a wide application for investigating short-term internal exposure of dietary acrylamide. Our proposed UHPLC-MS/MS method was successfully applied to the toxicokinetic study of acrylamide in rats. Meanwhile, results of human urine analysis indicated that the levels of N-acetyl-S-(2-carbamoylethyl)-L-cysteine-sulfoxide (AAMA-sul), which did not appear in the mercapturic acid metabolites in rodents, were more than the sum of GAMA and N-acetyl-S-(1-carbamoyl-2-hydroxyethyl)-L-cysteine (iso-GAMA). Thus, AAMA-sul may alternatively become a specific biomarker for investigating the acrylamide exposure in humans. Current proposed method provides a substantial methodology support for comprehensive profiling of toxicokinetics and daily internal exposure evaluations of acrylamide in vivo. PMID- 26423629 TI - Increase the accessibility and scale of targeted metabolomics: Construction of a human urinary metabolome-wide multiple reaction monitoring library using directly coupled reversed-phase and hydrophilic interaction chromatography. AB - Multiple reaction monitoring (MRM) is wildly employed to research drug absorption, distribution, metabolism, excretion and pharmacokinetics in pharmaceutical and clinical laboratories. Recently, scientists in these areas have shown great interest in utilization of metabolomics to evaluate drug efficacy and toxicity. MRM-based targeted metabolomics is intrinsically more sensitive and selective than MS based untargeted metabolomics in complex biological samples. MRM also minimizes data complexity for fast and focused analysis of core metabolites. Nevertheless, to mitigate the intrinsic targeted nature of MRM and promote it as a discovery toolbox for metabolomics, larger scale MRM assays providing more comprehensive biological information are highly desirable. Here, we employed data-dependent and data-independent strategies to perform extensive MS/MS mapping of human urinary metabolome with the assistance of a directly-coupled reversed-phase liquid chromatography and hydrophilic interaction chromatography (RPLC-HILIC) for simultaneous profiling of hydrophilic and hydrophobic metabolites. RPLC-HILIC enables to save time, limit sample consumption and facilitate data interpretation by removing data redundancy occurring between separate RPLC and HILIC methods. Major product ions in the raw MS/MS spectra were used to build a human urinary metabolome-wide MRM library which contains 749 refined MRM tags in negative ion mode with 198 of them being unambiguously or tentatively assigned for particular metabolites. The library relieves researchers from the most time-consuming setup of massive MRM transitions and making an important step toward large-scale targeted urinary metabolomics. PMID- 26423630 TI - Fiber array based hyperspectral Raman imaging for chemical selective analysis of malaria-infected red blood cells. AB - A new setup for Raman spectroscopic wide-field imaging is presented. It combines the advantages of a fiber array based spectral translator with a tailor-made laser illumination system for high-quality Raman chemical imaging of sensitive biological samples. The Gaussian-like intensity distribution of the illuminating laser beam is shaped by a square-core optical multimode fiber to a top-hat profile with very homogeneous intensity distribution to fulfill the conditions of Koehler. The 30 m long optical fiber and an additional vibrator efficiently destroy the polarization and coherence of the illuminating light. This homogeneous, incoherent illumination is an essential prerequisite for stable quantitative imaging of complex biological samples. The fiber array translates the two-dimensional lateral information of the Raman stray light into separated spectral channels with very high contrast. The Raman image can be correlated with a corresponding white light microscopic image of the sample. The new setup enables simultaneous quantification of all Raman spectra across the whole spatial area with very good spectral resolution and thus outperforms other Raman imaging approaches based on scanning and tunable filters. The unique capabilities of the setup for fast, gentle, sensitive, and selective chemical imaging of biological samples were applied for automated hemozoin analysis. A special algorithm was developed to generate Raman images based on the hemozoin distribution in red blood cells without any influence from other Raman scattering. The new imaging setup in combination with the robust algorithm provides a novel, elegant way for chemical selective analysis of the malaria pigment hemozoin in early ring stages of Plasmodium falciparum infected erythrocytes. PMID- 26423631 TI - Fluorescence imaging for in situ detection of cell surface sialic acid by competitive binding of 3-(dansylamino)phenylboronic acid. AB - Sialic acid (SA) usually locates at the terminal position of the sugar chains on cell membranes, and its expression level is closely associated with cancer. Here polysialic acid (PSA) embedded gold nanoparticles (AuNPs) were prepared and functionalized with fluorescent 3-(dansylamino)phenylboronic acid (DAPB) for in situ imaging and detection of cell surface SA. The fluorescence resonance energy transfer (FRET) from DAPB to AuNPs quenched the fluorescence of DAPB. In the presence of additional SA or SA-abundant cells, the competitive binding of DAPB with SA and PSA led to the release of the assembled DAPB from the surface of PSA embedded AuNPs, resulting in fluorescence of DAPB on SA-abundant cell surface. The proposed methods realized the in situ imaging and monitoring of cell surface SA, and could also be applied to the quantification of cell number and the amounts of cell surface SA. This work not only proposed a convenient visualization method for the analysis of SA on cell membranes, but also provided a potential tool for accelerating the elucidation of the basic role of SA in various biological processes and development of anti-cancer therapies. PMID- 26423632 TI - Risk assessment of agricultural pesticides in water, sediment, and fish from Owan River, Edo State, Nigeria. AB - The distribution of pesticides in water, sediments, Clarias gariepinus, and Tilapia zilli from the Owan River was investigated to evaluate the pollution status and potential hazard in the river system. A total of 16 pesticides were analyzed using gas chromatography (GC) equipped with electron capture detector (ECD). The concentration of pesticide residues ranged from ND to 0.43 MUg/l for water samples, 0.82 to 2.14 MUg/kg/dw for sediment, 0.04 to 2.34 MUg/kg/ww for C. gariepinus, and 0.02 to 1.73 MUg/kg/ww for T. zilli. High concentrations of organochlorine pesticides, specifically benzenehexachloride (alpha-BHC, gamma BHC, and beta-BHC) observed in all environmental media, are an indication of the current illegal use of banned pesticides for agricultural activities in the region. Analysis of data showed a strong correlation (r (2) = 0.7) between total organic carbon (TOC) and total pesticide residues in sediment samples. Meanwhile, risk quotient estimates for heptachlor epoxide, dieldrin, endrin, dichlorodiphenyltrichloroethane (4,4'-DDT), endosulfan I, endosulfan II, endosulfan aldehyde, and phosphomethylglycine showed potential risk to aquatic organism under observed mean concentrations (risk quotient (RQ) >= 1). Estimated average daily intake (EADI) for organochlorine pesticides (gamma-BHC, heptachlor epoxide, aldrin, dieldrin, and endrin) was above their respective acceptable average daily intake (ADI), while hazard quotient for each of these pesticides was above the unity value (1). This indicates that there is a potential cancer risk for the local residents with life time consumption of pesticide-contaminated fish. PMID- 26423633 TI - The concentrations of five heavy metals in components of an economically important urban coastal wetland in Ghana: public health and phytoremediation implications. AB - Sakumo II is an urban wetland and a receptacle for domestic and industrial wastes from two cities in Ghana. It however supports viable populations of fish and crabs, is cultivated for food crops and grazed by farm animals. Components of the wetland can therefore accumulate pollutants, but the public health and phytoremediation implications of this are yet to be evaluated. We analysed Cd, As, Hg, Cu and Pb in the lagoon water, sediment, green algae, eight species of aquatic macrophytes, seven species of arthropods and one species of fish. The concentrations of Pb were generally below detection limit whilst Cu was detected only in the lagoon water and Pheropsophus vertialis. Cadmium ranged from 21 +/- 4 ppb in algae to 69 +/- 12 ppb in Typha domingensis and was generally higher than As and Hg. The highest concentration of As was 11.7 +/- 2.1 ppb in Pistia stratiotes whilst Hg was highest in lagoon water (4 +/- 2 ppb). The Cd concentrations generally, and Hg concentrations in macrophytes, were higher than US EPA guidelines indicating the wetland's resources were unsafe for regular consumption. Among the emergent aquatic macrophytes, T. domingensis, Ludwigia sp. and Paspalum vaginatum, respectively, had the highest accumulation capacity for Cd, As and Hg, but the floating aquatic plant P. stratiotes appeared to be a better accumulator of Cd and As. PMID- 26423634 TI - Sewage-fed aquaculture: a sustainable approach for wastewater treatment and reuse. AB - This study assesses the long-term sustainability for operation and maintenance (O&M) of sewage-fed aquaculture-based sewage treatment system. The study focused on the integrated assessment of an engineered pond system of 8 million liters per day capacity in the city of Karnal, the State of Haryana, northern India. Major areas during the assessment included health, environmental, societal and institutional views aspects as well as the quality of treated effluent subjected for reuse. The treatment facility met the Indian regulatory standards (downstream reuse and discharge into the legally permitted water bodies) in terms of physical chemical parameters. The total coliform and faecal coliform removal were up to 2 3 log units; nevertheless, it was not capable to come across the bacterial count requirement (<1,000 per 100 mL to minimise human health risk in aquaculture practices). The system was able to generate sufficient net income required for routine O&M. Annual revenue collected by the Municipal Corporation from the lease of the facility as well as selling of treated wastewater was $3,077 and $16,667 $25,000, respectively. The additional benefit from the facility for the farmers included the saving of fertilizers and cheapest source of water available for irrigation. Recycling of treated sewages for irrigation is also returned nutrients to the surrounding farms in Karnal. This exercise has saved significant quantities of chemical fertilizer (26-41 Ton of nitrogen, 10-18 Ton of phosphorous and 38-58 Ton of potassium per year) and the overall benefit for farmers during cultivation of one acre of crop was calculated to be approximately $133 per year. PMID- 26423635 TI - A reference-based approach for estimating leaf area and cover in the forest herbaceous layer. AB - Cover data are used to assess vegetative response to a variety of ecological factors. Estimating cover in the herbaceous layer of forests presents a problem because the communities are structurally complex and rich in species. The currently employed techniques for estimating cover are less than optimal for measuring such rich understories because they are inaccurate, slow, or impracticable. A reference-based approach to estimating cover is presented that compares the area of foliar surfaces to the area of an observer's hand. While this technique has been used to estimate cover in prior studies, its accuracy has not been tested. We tested this hand-area method at the individual plant, population, and community scales in a deciduous forest herbaceous layer, and in a separate farm experiment. The precision, accuracy, observer bias, and species bias of the method were tested by comparing the hand-estimated leaf area index values with actual leaf area index, measured using a leaf area meter. The hand area method was very precise when regressed against actual leaf area index at the plant, population, and community scales (R(2) of 0.97, 0.93, and 0.87). Among the deciduous sites, the hand-area method overestimated leaf area index consistently by 39.1% at all scales. There was no observer bias detected at any scale, but plant overestimation bias was detected in one species at the population scale. The hand-area method is a rapid and reliable technique for estimating leaf area index or cover in the forest herbaceous layer and should be useful to field ecologists interested in answering questions at the plant, population, or community level. PMID- 26423636 TI - Patient-reported Outcome Measures in Radiotherapy: Clinical Advances and Research Opportunities in Measurement for Survivorship. AB - Patient-reported outcome measures (PROMs) are a useful way of recording patient perceptions of the impact of their cancer and the consequences of treatment. Understanding the impact of radiotherapy longer term requires tools that are sensitive to change but also meaningful for patients. PROMs are useful in defining symptom severity but also the burden of illness for cancer patients. Patient-reported outcomes are increasingly being seen as a way to improve practice by enhancing communication, improving symptom management as well as identifying patient care needs. This paper provides an overview of the use of PROMs in radiotherapy and considerations for tool choice, analysis and the logistics of routine data collection. Consistent assessment is essential to detect patient problems as a result of radiotherapy, but also to address emerging symptoms promptly. PMID- 26423637 TI - Using Administrative Data to Examine Health Disparities and Outcomes in Neurological Diseases of the Elderly. AB - The fields of neurodegenerative disease and dementia research have grown considerably in the last several decades. Due to tremendous efforts of basic and clinical research scientists, we know a great deal about dementia risk factors and have multiple treatment options. Clinician recognition of cognitive impairment has increased considerably, national policies which support screening for and documenting cognitive dysfunction now exist, and public awareness of neurodegenerative disease has never been greater. These conditions promote (and demand) the growth of translational epidemiology and health services research, which focuses on examining outcomes in groups of individuals as a function of health care experiences. This review discusses the use of administrative data to answer health care outcomes and disparities questions in dementia. Of particular interest are publically available datasets that contain varying amounts of diagnostic, clinical, pharmacy, and patient information. Methodological challenges that are frequently encountered and must be understood to minimize biased inference are also discussed. PMID- 26423638 TI - Ex vivo tracing of pancreatic neuroendocrine tumors with bio-conjugated fluorescent quantum dots: a paradigm of nanoparticle-based diagnostics. PMID- 26423639 TI - Appetitive traits as behavioural pathways in genetic susceptibility to obesity: a population-based cross-sectional study. AB - The mechanisms through which genes influence body weight are not well understood, but appetite has been implicated as one mediating pathway. Here we use data from two independent population-based Finnish cohorts (4632 adults aged 25-74 years from the DILGOM study and 1231 twin individuals aged 21-26 years from the FinnTwin12 study) to investigate whether two appetitive traits mediate the associations between known obesity-related genetic variants and adiposity. The results from structural equation modelling indicate that the effects of a polygenic risk score (90 obesity-related loci) on measured body mass index and waist circumference are partly mediated through higher levels of uncontrolled eating (betaindirect = 0.030-0.032, P < 0.001 in DILGOM) and emotional eating (betaindirect = 0.020-0.022, P < 0.001 in DILGOM and betaindirect = 0.013-0.015, P = 0.043-0.044 in FinnTwin12). Our findings suggest that genetic predispositions to obesity may partly exert their effects through appetitive traits reflecting lack of control over eating or eating in response to negative emotions. Obesity prevention and treatment studies should examine the impact of targeting these eating behaviours, especially among individuals having a high genetic predisposition to obesity. PMID- 26423640 TI - RIFM fragrance ingredient safety assessment, linalyl isobutyrate, CAS registry number 78-35-3. AB - The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization potential, as well as, environmental safety. Reproductive toxicity was based on the Threshold of Toxicological Concern (TTC) of 0.03 mg/kg/day for a Cramer Class I material. The estimated systemic exposure is determined to be below this value while assuming 80% absorption from skin contact and 100% from inhalation. A systemic exposure below the TTC value is acceptable. PMID- 26423641 TI - PrEP: why are we waiting? PMID- 26423642 TI - Is monotherapy maintenance the way forward? PMID- 26423643 TI - BMS-663068, a safe and effective HIV-1 attachment inhibitor. PMID- 26423644 TI - Enhancing efforts to address infections. PMID- 26423645 TI - Methadone treatment in primary care. PMID- 26423646 TI - Is it time to abandon single intervention cure trials? PMID- 26423647 TI - Liver disease in patients with HIV in sub-Saharan Africa. PMID- 26423648 TI - HIV viral load messages should go viral in India. PMID- 26423650 TI - Safety and efficacy of the HIV-1 attachment inhibitor prodrug BMS-663068 in treatment-experienced individuals: 24 week results of AI438011, a phase 2b, randomised controlled trial. AB - BACKGROUND: BMS-663068 is an oral prodrug of BMS-626529, an attachment inhibitor that binds to HIV-1 gp120, blocking viral attachment to host CD4 cells. AI438011 is an ongoing trial investigating the efficacy, safety, and dose-response of BMS 663068 in treatment-experienced, HIV-1-infected patients. Herein we present the results of the primary analysis. METHODS: AI438011 is a phase 2b, randomised, active-controlled trial, at 53 hospitals and outpatient clinics across ten countries in North and South America, Europe, and Africa. Individuals with an HIV 1 RNA viral load of at least 1000 copies per mL and a BMS-626529 half-maximum inhibitory concentration lower than 100 nmol/L were randomly assigned (1:1:1:1:1) to receive either BMS-663068 at 400 mg twice daily, 800 mg twice daily, 600 mg once daily, or 1200 mg once daily or ritonavir-boosted atazanavir (300 mg of atazanavir and 100 mg of ritonavir once daily), each with 400 mg of raltegravir twice daily and 300 mg of tenofovir disoproxil fumarate once daily as a backbone. The sponsor, participants, and investigators were masked for BMS-663068 dose but not for allocation. Primary endpoints were the proportion of patients with an HIV 1 RNA viral load less than 50 copies per mL (response rate) at week 24 and the frequency of serious adverse events and adverse events leading to discontinuation, up to the week 24 analysis. The primary analyses included all patients who received at least one dose of study drug (modified intention-to treat population). This study is registered at ClinicalTrials.gov, NCT01384734. FINDINGS: Between July 26, 2011, and July 16, 2012, 581 participants were assessed for eligibility. Of these, 254 patients were randomly assigned to receive either BMS-663068 (n=52 for the 400 mg twice daily group, n=50 for the 800 mg twice daily group, n=51 for the 600 mg once daily group, and n=50 for the 1200 mg once daily group) or ritonavir-boosted atazanavir (n=51). 200 patients received at least one dose of BMS-663068, and 51 patients received at least one dose of ritonavir-boosted atazanavir. At week 24, 40 (80%) of 50 patients in the BMS-663068 400 mg twice daily group, 34 (69%) of 49 patients in the 800 mg twice daily group, 39 (76%) of 51 patients in the 600 mg once daily group, and 36 (72%) of 50 patients in the 1200 mg once daily group had an HIV-1 RNA viral load less than 50 copies per mL, compared with 38 (75%) of 51 patients in the ritonavir boosted atazanavir group. Serious adverse events were noted in 13 (7%) of 200 patients in the BMS-663068 groups and five (10%) of the 51 patients in the ritonavir-boosted atazanavir group. Four (2%) of the 200 patients in the BMS 663068 groups and two (4%) of the 51 patients in the ritonavir-boosted atazanavir group discontinued because of adverse events. No serious adverse events or adverse events leading to discontinuation were BMS-663068-related. Grade 2-4 adverse events related to study drug(s) occurred in 17 (9%) of 200 patients across the BMS-663068 groups and 14 (27%) of 51 patients in the ritonavir-boosted atazanavir group. For the BMS-663068 groups these events were mostly single instances with no dose relation and for the ritonavir-boosted atazanavir group these were mostly gastrointestinal or hepatobiliary disorders associated with hyperbilirubinaemia. INTERPRETATION: In a comparison with ritonavir-boosted atazanavir, efficacy and safety of BMS-663068 up to the week 24 analysis support continued development of BMS-663068, which is being assessed in a phase 3 trial in heavily treatment-experienced individuals. FUNDING: Bristol-Myers Squibb. PMID- 26423651 TI - Causes of hospital admission among people living with HIV worldwide: a systematic review and meta-analysis. AB - BACKGROUND: Morbidity associated with HIV infection is poorly characterised, so we aimed to investigate the contribution of different comorbidities to hospital admission and in-hospital mortality in adults and children living with HIV worldwide. METHODS: Using a broad search strategy combining terms for hospital admission and HIV infection, we searched MEDLINE via PubMed, Embase, Web of Science, LILACS, AIM, IMEMR and WPIMR from inception to Jan 31, 2015, to identify studies reporting cause of hospital admission in people living with HIV. We focused on data reported after 2007, the period in which access to antiretroviral therapy started to become widespread. We estimated pooled proportions of hospital admissions and deaths per disease category by use of random-effects models. We stratified data by geographical region and age. FINDINGS: We obtained data from 106 cohorts, with reported causes of hospital admission for 313 006 adults and 6182 children living with HIV. For adults, AIDS-related illnesses (25 119 patients, 46%, 95% CI 40-53) and bacterial infections (14 034 patients, 31%, 20 42) were the leading causes of hospital admission. These two categories were the most common causes of hospital admission for adults in all geographical regions and the most common causes of mortality. Common region-specific causes of hospital admission included malnutrition and wasting, parasitic infections, and haematological disorders in the Africa region; respiratory disease, psychiatric disorders, renal disorders, cardiovascular disorders, and liver disease in Europe; haematological disorders in North America; and respiratory, neurological, digestive and liver-related conditions, viral infections, and drug toxicity in South and Central America. For children, AIDS-related illnesses (783 patients, 27%, 95% CI 19-34) and bacterial infections (1190 patients, 41%, 26-56) were the leading causes of hospital admission, followed by malnutrition and wasting, haematological disorders, and, in the African region, malaria. Mortality in individuals admitted to hospital was 20% (95% CI 18-23, 12 902 deaths) for adults and 14% (10-19, 643 deaths) for children. INTERPRETATION: This review shows the importance of prompt HIV diagnosis and treatment, and the need to reinforce existing recommendations to provide chemoprophylaxis and vaccination against major preventable infectious diseases to people living with HIV to reduce serious AIDS and non-AIDS morbidity. FUNDING: None. PMID- 26423649 TI - Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial. AB - BACKGROUND: Standard-of-care antiretroviral therapy (ART) uses a combination of drugs deemed essential to minimise treatment failure and drug resistance. Protease inhibitors are potent, with a high genetic barrier to resistance, and have potential use as monotherapy after viral load suppression is achieved with combination treatment. We aimed to assess clinical risks and benefits of protease inhibitor monotherapy in long-term clinical use: in particular, the effect on drug resistance and future treatment options. METHODS: In this pragmatic, parallel-group, randomised, controlled, open-label, non-inferiority trial, we enrolled adults (>=18 years of age) positive for HIV attending 43 public sector treatment centres in the UK who had suppressed viral load (<50 copies per mL) for at least 24 weeks on combination ART with no change in the previous 12 weeks and a CD4 count of more than 100 cells per MUL. Participants were randomly allocated (1:1) to maintain ongoing triple therapy (OT) or to switch to a strategy of physician-selected ritonavir-boosted protease inhibitor monotherapy (PI-mono); we recommended ritonavir (100 mg)-boosted darunavir (800 mg) once daily or ritonavir (100 mg)-boosted lopinavir (400 mg) twice daily, with prompt return to combination treatment if viral load rebounded. All treatments were oral. Randomisation was with permuted blocks of varying size and stratified by centre and baseline ART; we used a computer-generated, sequentially numbered randomisation list. The primary outcome was loss of future drug options, defined as new intermediate-level or high-level resistance to one or more drugs to which the patient's virus was deemed sensitive at trial entry (assessed at 3 years; non inferiority margin of 10%). We estimated probability of rebound and resistance with Kaplan-Meier analysis. Analyses were by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISRCTN04857074. FINDINGS: Between Nov 4, 2008, and July 28, 2010, we randomly allocated 587 participants to OT (291) or PI-mono (296). At 3 years, one or more future drug options had been lost in two participants (Kaplan Meier estimate 0.7%) in the OT group and six (2.1%) in the PI-mono group: difference 1.4% (-0.4 to 3.4); non-inferiority shown. 49 (16.8%) participants in the OT group and 65 (22.0%) in the PI-mono group had grade 3 or 4 clinical adverse events (difference 5.1% [95% CI -1.3 to 11.5]; p=0.12); 45 (six treatment related) and 56 (three treatment related) had serious adverse events. INTERPRETATION: Protease inhibitor monotherapy, with regular viral load monitoring and prompt reintroduction of combination treatment for rebound, preserved future treatment options and did not change overall clinical outcomes or frequency of toxic effects. Protease inhibitor monotherapy is an acceptable alternative for long-term clinical management of HIV infection. FUNDING: National Institute for Health Research. PMID- 26423653 TI - Diethyl phthalate exposure is associated with embryonic toxicity, fatty liver changes, and hypolipidemia via impairment of lipoprotein functions. AB - Diethyl phthalates (DEPs) are notorious for their high potential toxicity in endocrinological and reproduction systems in humans and animals. In this study, we investigated the toxic effects of DEP on human lipoproteins, macrophages, and zebrafish embryos. Treatment of human high-density lipoprotein (HDL) with DEP caused oxidation, aggregation, and degradation of lipoproteins. DEP treatment promoted foam cell formation via accelerated phagocytosis of LDL by macrophages as well as exacerbated cellular senescence in human dermal fibroblasts. Injection of DEP (final 5 MUM and 10 MUM) into zebrafish embryos caused severe embryo death and slower developmental speed. Exposure of zebrafish embryos to water containing DEP (final 11 and 22 ppm) caused early embryonic death along with the increased oxidized products and impairment of skeletal development. Adult zebrafish exposed to water containing DEP (final 11 and 22 ppm) for 4 weeks showed severe loss of body weight under both normal diet (ND) and high cholesterol diet (HCD) conditions. ND and HCD groups showed 59% and 49% reduction of plasma total cholesterol (TC), respectively. Serum levels of hepatic inflammation enzymes along with fatty liver changes were significantly elevated by DEP exposure. In conclusion, DEP showed strong pro-atherogenic and pro-senescence effects via severe lipoprotein modification in human cells. DEP caused impairment of embryonic development and severe loss of body weight, hypolipidemia, and fatty liver changes in zebrafish. PMID- 26423652 TI - Effect of low-threshold methadone maintenance therapy for people who inject drugs on HIV incidence in Vancouver, BC, Canada: an observational cohort study. AB - BACKGROUND: HIV infection in people who inject drugs (PWID) is an international public health concern. We aimed to assess the effect of methadone maintenance therapy on HIV incidence in PWID in Vancouver, BC, Canada, where methadone is widely available through family physicians' offices and dispensed by community pharmacies. METHODS: Data were derived from the Vancouver Injection Drug Users Study (VIDUS), a prospective cohort of PWID in Vancouver. Individuals were eligible to enrol in VIDUS if they had injected illicit drugs at least once in the previous month and lived in the Greater Vancouver region. Participants responded to an interviewer-administered questionnaire and provided blood samples at enrolment and follow-up visits every 6 months. We estimated time to HIV seroconversion with Kaplan-Meier methods and used Cox proportional hazards methods to assess associations between methadone use and time to seroconversion. FINDINGS: 1639 HIV-negative individuals were recruited between May 1, 1996, and May 31, 2013. Of these individuals, 138 had HIV seroconversion during a median of 75.5 months (IQR 33.4-115.3) of follow-up. In multivariate Cox regression analyses, methadone maintenance therapy remained independently associated with a reduced hazard of HIV infection after adjustment for sociodemographic characteristics and drug use patterns (adjusted relative hazard 0.64, 95% CI 0.41 0.98). INTERPRETATION: Methadone maintenance therapy for PWID made available through primary care physicians and community pharmacies can help to achieve public health goals such as reducing the spread of HIV. FUNDING: US National Institutes of Health, Canada Research Chair, Canadian Institutes of Health Research. PMID- 26423654 TI - Dietary intake in adults with type 1 and type 2 diabetes: validation of the Dietary Questionnaire for Epidemiological Studies version 2 FFQ against a 3-d weighed food record and 24-h urinalysis. AB - The Dietary Questionnaire for Epidemiological Studies version 2 (DQES v2) FFQ has not been validated in adults with diabetes. The aim was to determine the agreement between the DQES v2 FFQ and a 3-d weighed food record (WFR) and 24-h urinalysis in adults with type 1 and type 2 diabetes. The DQES v2 FFQ and a 3-d WFR were completed on one occasion for measurement of food and nutrient intake. A 24-h urine sample was provided for measurement of Na and K excretion. Participants were sixty-seven adults with type 1 and type 2 diabetes recruited from the community. Nutrient intake reported in the FFQ was within 20 % of the corresponding intake level reported in the WFR for the majority of nutrients. However, the 95 % limits of agreement showed large variation at an individual level between the two methods. There was a weak to moderate correlation between nutrient intake measured using the two methods and a moderate to high correlation for food intake. Quintile analysis showed that for the majority of foods and nutrients >60 % of participants were ranked within 1 quintile of the WFR ranking. The weighted kappa values showed slight to moderate agreement between the two methods. Na intake was under-estimated in the FFQ by 25 % and K intake was over estimated by 5 % compared with the 24-h urinalysis. In adults with type 1 and type 2 diabetes, it is appropriate to use the DQES v2 FFQ to measure food and nutrient intake at a group level. PMID- 26423655 TI - Visible light and near-infrared-responsive chromophores for drug delivery-on demand applications. AB - The need for temporal-spatial control over the release of biologically active molecules has motivated efforts to engineer novel drug delivery-on-demand strategies actuated via light irradiation. Many systems, however, have been limited to in vitro proof-of-concept due to biocompatibility issues with the photo-responsive moieties or the light wavelength, intensity, and duration. To overcome these limitations, this paper describes a light actuated drug delivery on-demand strategy that uses visible and near-infrared (NIR) light and biocompatible chromophores: cardiogreen, methylene blue, and riboflavin. All three chromophores are capable of significant photothermal reaction upon exposure to NIR and visible light, and the amount of temperature change is dependent upon light intensity, wavelength as well as chromophore concentration. Pulsatile release of bovine serum albumin (BSA) from thermally responsive hydrogels was achieved over 4 days. These findings have the potential to translate light actuated drug delivery-on-demand systems from the bench to clinical applications that require explicit control over the presentation of biologically active molecules. PMID- 26423657 TI - Optimization of the score cutoff value for routine identification of Staphylococcus species by matrix-assisted laser desorption ionization-time-of flight mass spectrometry. AB - Staphylococcus species are important pathogens. We evaluated 2 score cutoffs (2.0 and 1.7) and the replicate number (a single or a duplicate test) on the identification of staphylococci using the Bruker matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). A collection of 440 clinical isolates (11 species) and 144 reference strains (36 species) was evaluated. For clinical isolates using a cutoff of 2.0 and duplicate tests, the rates of species, genus, and unreliable identifications were 93.4%, 5.7%, and 0.9% respectively, while the respective values were 99.3%, 0.2%, and 0.5% when the cutoff was 1.7. The species identification rates were significantly higher (P<0.01) when a cutoff of 1.7 or a duplicate test was used. Similar results were obtained for reference strains. In conclusion, a cutoff of 1.7 and duplicate tests are recommended for identification of staphylococci using MALDI-TOF MS. PMID- 26423656 TI - Copy number variation in the region harboring SOX9 gene in dogs with testicular/ovotesticular disorder of sex development (78,XX; SRY-negative). AB - Although the disorder of sex development in dogs with female karyotype (XX DSD) is quite common, its molecular basis is still unclear. Among mutations underlying XX DSD in mammals are duplication of a long sequence upstream of the SOX9 gene (RevSex) and duplication of the SOX9 gene (also observed in dogs). We performed a comparative analysis of 16 XX DSD and 30 control female dogs, using FISH and MLPA approaches. Our study was focused on a region harboring SOX9 and a region orthologous to the human RevSex (CanRevSex), which was located by in silico analysis downstream of SOX9. Two highly polymorphic copy number variable regions (CNVRs): CNVR1 upstream of SOX9 and CNVR2 encompassing CanRevSex were identified. Although none of the detected copy number variants were specific to either affected or control animals, we observed that the average number of copies in CNVR1 was higher in XX DSD. No copy variation of SOX9 was observed. Our extensive studies have excluded duplication of SOX9 as the common cause of XX DSD in analyzed samples. However, it remains possible that the causative mutation is hidden in highly polymorphic CNVR1. PMID- 26423658 TI - Comparison of three real-time PCR assays for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae in young pregnant women. AB - We compared 3 commercial real-time PCR assays, the Abbott RealTime CT/NG, the cobas(r) 4800 CT/NG, and the Cepheid Xpert(r) CT/NG, for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae in vaginal swabs collected prospectively from pregnant women aged <25 years. The overall agreement among 2 assays ranged from 98.9% to 99.5% with a kappa score between 0.94 and 0.97 for C. trachomatis. For N. gonorrhoeae, the overall agreement was 100%. All kits allowed prompt and specific results for C. trachomatis and N. gonorrhoeae in young pregnant women. PMID- 26423659 TI - The required minimum length of video sequences for obtaining a reliable interobserver diagnosis in wrist arthroscopies. AB - PURPOSE: To examine the relationship between video length for wrist arthroscopy and interobserver reliability. MATERIALS AND METHODS: 100 consecutive wrist arthroscopies were documented by long and short videos of the radiocarpal and the midcarpal joints. The long videos were about twice as long as the short videos. They were presented randomly to two independent and blinded examiners. Their diagnoses were compared to the diagnoses made by the surgeon who performed the arthroscopies. Kappa coefficients were calculated. RESULTS: Kappa statistics were inconsistent and did not show that the long video provided an obvious advantage over the short video. The Kappa coefficients of the two examiners for the assessment of the cartilage status were 0.524 and 0.700 for the long videos and 0.465 and 0.639 for the short videos, respectively. The examiners diagnosed twice as many false-positive cartilage lesions on short videos than on long videos. The assessment of ligament lesions was more accurate on long than on short videos. CONCLUSIONS: The results confirmed the hypothesis that the reproducibility of diagnoses based on video documents was influenced by the length of the video sequences. Therefore, it may be advisable for video documentation to be done diligently. The video sequence of the radiocarpal joint should last about 60 s, and that of a midcarpal joint should last about 45 s. Videos of difficult joints should last appropriately longer. LEVEL OF EVIDENCE: Diagnostic II. PMID- 26423660 TI - The combined CO2 laser and photodynamic therapy of multiple BCC's in a facial port wine stain. PMID- 26423661 TI - Radioprotective 105kDa protein (RP105): Is a critical therapeutic target for alleviating ischemia reperfusion induced myocardial damage via TLR4 signaling pathway. PMID- 26423662 TI - Ultrahigh and Broad Spectral Photodetectivity of an Organic-Inorganic Hybrid Phototransistor for Flexible Electronics. AB - The creation of new organic-inorganic phototransistors with high and broad spectral photosensitivity is reported. The extended charge transport and photoconductivity between the layers in the bilayer structure results in a notable detectivity of over 10(12) Jones and a linear dynamic range of over 100 dB at a broad spectral bandwidth across the UV-NIR range. Furthermore, the considerably reduced persistent photocurrent effect of In-Ga-Zn-O (IGZO)-based hybrid phototransistors is first demonstrated via an organic-inorganic bilayer approach. PMID- 26423663 TI - Developmental coordination disorder: core sensori-motor deficits, neurobiology and etiology. AB - Among developmental disorders, DCD is one of the least studied and less understood one (Bishop, 2010). This review summarizes the current understanding of developmental coordination disorder in neuropsychology with a focus mainly on high level sensorimotor impairments, its etiology and its neural bases. We summarize these core deficits in the framework of an influent motor control model (Blakemore et al., 2002). DCD has several environmental risk factors which probably interplay with genetic factors but those have not been sufficiently identified. High-level sensori-motor deficits are probably multifactorial in DCD and involve predictive coding deficits as well as weaknesses in perceptual and sensory integration. At the brain level, DCD is associated with impaired structure and functions within the motor network. Throughout the review we highlight exciting new findings as well as potential future lines of research to provide a more comprehensive understanding of this disorder. PMID- 26423664 TI - Brain response during the M170 time interval is sensitive to socially relevant information. AB - Deciphering the social meaning of facial displays is a highly complex neurological process. The M170, an event related field component of MEG recording, like its EEG counterpart N170, was repeatedly shown to be associated with structural encoding of faces. However, the scope of information encoded during the M170 time window is still being debated. We investigated the neuronal origin of facial processing of integrated social rank cues (SRCs) and emotional facial expressions (EFEs) during the M170 time interval. Participants viewed integrated facial displays of emotion (happy, angry, neutral) and SRCs (indicated by upward, downward, or straight head tilts). We found that the activity during the M170 time window is sensitive to both EFEs and SRCs. Specifically, highly prominent activation was observed in response to SRC connoting dominance as compared to submissive or egalitarian head cues. Interestingly, the processing of EFEs and SRCs appeared to rely on different circuitry. Our findings suggest that vertical head tilts are processed not only for their sheer structural variance, but as social information. Exploring the temporal unfolding and brain localization of non-verbal cues processing may assist in understanding the functioning of the social rank biobehavioral system. PMID- 26423667 TI - FASD Prevalence among Schoolchildren in Poland. AB - BACKGROUND: Prenatal Alcohol Exposure is a major cause of brain damage and developmental delay, known as Fetal Alcohol Spectrum Disorders (FASD) but in Poland is rarely diagnosed and the scale of problem is not known. METHODS: An active case ascertainment approach was applied to estimate the prevalence of FASD among 7-9 years olds. Pre-screening was conducted in 113 randomly selected regular and special schools. In the screening phase participated 280 children (54% from the risk group, 60% boys). The entire number of eligible students (N = 2500) was taken as a denominator. RESULTS: The prevalence of FASD is not lower than 2%, including 0.4% of Fetal Alcohol Syndrome. CONCLUSIONS: Neurodevelopmental disorders associated with PAE are a serious challenge for the public health system. Development of procedures and services to diagnose and to support individuals affected by PAE and their families is an urgent need in Poland. PMID- 26423666 TI - Expression and Significance of COX-2 and Ki-67 in Hepatolithiasis with Bile Duct Carcinoma. AB - BACKGROUND: As an induced enzyme, COX-2 expression is elevated under stimuli from inflammatory mediator or growth factor product. Ki-67, a cell cycle-related proliferative antigen, reflects the tissue proliferative activity. This study analyzed the expressional profile of cyclooxygenase-2 (COX-2) and Ki-67 in hepatolithiasis and bile duct carcinoma tissues, in an attempt to provide evidence for diagnosis and prognosis prediction of disease. MATERIAL AND METHODS: A cohort of tissue samples from hepatolithiasis with bile duct carcinoma (N=47) patients were analyzed using immunohistochemical (IHC) staining method for the expression of COX-2 and Ki-67, in parallel with hepatolithiasis (N=44) and normal bile duct tissues (N=30). The relationship between expression pattern of COX-2 and Ki-67 and pathological conditions was also analyzed, in addition to the correlation with positive expression in hepatolithiasis samples. RESULTS: The positive expression rate of COX-2 and Ki-67 in bile duct carcinoma was 76.6% and 80.9%, respectively, and was significantly higher than those in the hepatolithiasis group, which was also higher than the control group. Expression of both COX-2 and Ki-67 is closely related to TNM staging, lymph node metastasis, and differentiation stage. They were also correlated with the mortality rate of patients. CONCLUSIONS: Both COX-2 and Ki-67 are abundantly expressed in hepatolithiasis and bile duct carcinoma tissues and may play an important role in the disease occurrence, progression, and metastasis. PMID- 26423665 TI - Genetic variation in the serotonin transporter gene influences ERP old/new effects during recognition memory. AB - Recognition memory is defined as the ability to recognize a previously encountered stimulus and has been associated with spatially and temporally distinct event-related potentials (ERPs). Allelic variations of the serotonin transporter gene (SLC6A4) have recently been shown to impact memory performance. Common variants of the serotonin transporter-linked polymorphic region (5HTTLPR) of the SLC6A4 gene result in long (l) and short (s) allelic variants with carriers of the s allele having lowered transcriptional efficiency. Thus, the current study examines the effects polymorphisms of the SLC6A4 gene have on performance and ERP amplitudes commonly associated with recognition memory. Electroencephalogram (EEG), genetic, and behavioral data were collected from sixty participants as they performed an item and source memory recognition task. In both tasks, participants studied and encoded 200 words, which were then mixed with 200 new words during retrieval. Participants were monitored with EEG during the retrieval portion of each memory task. EEG electrodes were grouped into four ROIs, left anterior superior, right anterior superior, left posterior superior, and right posterior superior. ERP mean amplitudes during hits in the item and source memory task were compared to correctly recognizing new items (correct rejections). Results show that s-carriers have decreased mean hit amplitudes in both the right anterior superior ROI 1000-1500ms post stimulus during the source memory task and the left anterior superior ROI 300-500ms post stimulus during the item memory task. These results suggest that individual differences due to genetic variation of the serotonin transporter gene influences recognition memory. PMID- 26423668 TI - The Viable Violinist. AB - In the aftermath of the Kermit Gosnell trial and Giubilini and Minerva's article 'After-birth abortion', abortion-rights advocates have been pressured to provide an account of the moral difference between abortion, particularly late-term abortion, and infanticide. In response, some scholars have defended a moral distinction by appealing to an argument developed by Judith Jarvis Thomson in A defense of abortion. However, once Thomson's analogy is refined to account for the morally relevant features of late-term pregnancy, rather than distinguishing between late-term abortion and infanticide, it reinforces their moral similarity. This is because late-term abortion requires more than detachment - it requires an act of feticide to ensure the death of the viable fetus. As such, a Thomsonian account cannot be deployed successfully as a response to Giubilini and Minerva. Those wishing to defend late-term abortion while rejecting the permissibility of infanticide will need to provide an alternative account of the difference, or else accept Giubilini and Minerva's conclusion. PMID- 26423669 TI - Genetic diversity within ITS-1 region of Eimeria species infecting chickens of north India. AB - Coccidiosis, caused by apicomplexan parasites of the genus Eimeria, inflicts severe economic losses to the poultry industry around the globe. In the present study, ITS-1 based species specific nested PCR revealed prevalence of E. acervulina, E. brunetti, E. maxima, E. mitis, E. praecox, E. necatrix and E. tenella in 79.2%, 12.5%, 64.6%, 89.6%, 60.4%, 64.6% and 97.9% poultry farms of north India, respectively. The ITS-1 sequences of different Eimeria spp. from north India were generated and analyzed to establish their phylogenetic relationship. The sequence identity with available sequences ranged from 80 to 100% in E. tenella, 95 to 100% in E. acervulina, 64 to 97% in E. necatrix, 96 to 99% in E. brunetti and 97 to 98% in E. mitis. Only long ITS-1 sequences of E. maxima could be generated in the present study and it had 80-100% identity with published sequences. Two out of the four ITS-1 sequences of E. maxima had mismatches in the published nested primer sequences from Australia, while one sequence of E. necatrix had a mismatch near 3' end of both forward and reverse published nested primer sequences, warranting for the need of designing new set of degenerate primers for these two species of Eimeria. In the phylogenetic tree, all isolates of E. acervulina, E. brunetti, E. mitis, E. tenella and E. necatrix clustered in separate clades with high bootstrap value. E. maxima sequences of north Indian isolates grouped in a long form of E. maxima clade. Complete ITS-1 sequences of E. necatrix and E. mitis are reported for the first time from India. Further studies are required with more number of isolates to verify whether these differences are unique to geographical locations. PMID- 26423670 TI - Genotyping and molecular analysis of Enterocytozoon bieneusi isolated from immunocompromised patients in Iran. AB - Microsporidia are known as opportunistic unicellular pathogens, particularly so in individuals with congenital or acquired immunodeficiency. Enterocytozoon bieneusi is one of the most common species infecting both immunocompromised and immunocompetent individuals. The aim of this study was to assess the distribution of E. bieneusi genotypes among immunocompromised patients in Iran. From 329 stool samples referred for parasitological analysis during 2011-2014, 14 samples from immunocompromised patients proving positive for E. bieneusi by SSU rDNA analysis were selected. Genotyping was carried out using specific primers targeting the Internal Transcribed Spacer (ITS) region. Subsequently, all samples were sequenced and results queried against the GenBank database. Moreover, sequences were subject to phylogenetic analysis. The expected amplification product was generated for all samples. Genotype D was identified in patients with HIV+/AIDS, transplant recipients, and cancer patients, while Genotype E was identified only in cancer and HIV+/AIDS patients. Phylogenetic analysis revealed that there was no relationship between genotypes and types of immunosuppression, whereas most genotype D isolates grouped with those described previously from cattle, horses, birds, and humans. E. bieneusi genotype D appears to be the most frequent genotype in immunocompromised patients, while Genotype E was observed only in HIV+/AIDS patients and cancer patients, not transplant recipients. PMID- 26423671 TI - Approaches to characterize extended spectrum beta-lactamase/beta-lactamase producing Escherichia coli in healthy organized vis-a-vis backyard farmed pigs in India. AB - The study was undertaken to investigate the occurrence and to characterize the ESBL/beta-lactamase producing-Escherichia coli in healthy pigs of organized and backyard farms in West Bengal, India. Total 200 rectal swabs were collected randomly from healthy pigs maintained in four organized farms and 10 backyard farms (n=100 each) and 76 isolates were identified as E. coli from organized (48/100, 48%) and backyard pigs (28/100, 28%). Twelve E. coli isolates (6%) in the present study were detected to possess any of the ESBL/beta-lactamase genes studied. ESBL/beta-lactamase producers were isolated with significantly more frequency from backyard pigs than the organized farm pigs (p=0.026). Six of ESBL/beta-lactamase producing isolates were phenotypically confirmed as CTX-M producers and ten of them were confirmed as TEM/SHV producers. PCR and sequencing of the amplified product from representative isolates revealed the presence of blaCTX-M-9, blaSHV-12 and blaTEM-1. No unique combination of the studied beta lactamase genes for organized and backyard farm pig isolates was noted. The ESBL isolates belonged to O13, O55, O133, O153, O157, O158, O166, rough and OUT serogroups. The association of heat labile toxin (elt) (p<0.0005) with organized farm isolates and heat stable toxin (estA) (p=0.0143) with backyard piggery sector was significantly higher. The ESBL/beta-lactamase producers from organized farm (Ak/Ex) and indigenous pigs (Ak/Ex/Te; Ak/CoT/G) showed a characteristic phenotypical antibiotic resistance pattern. Two pairs of isolates from organized and backyard farm pigs showed clonal relationship indicating a possible transmission between the farms which were situated adjacently. Thus the present study revealed backyard farm pigs as major source of ESBL/beta-lactamase producing-E. coli associated with STa and characteristic antibiotic resistance pattern in India. PMID- 26423672 TI - Measurement of Foveal Avascular Zone Dimensions and its Reliability in Healthy Eyes Using Optical Coherence Tomography Angiography. AB - PURPOSE: To measure foveal avascular zone (FAZ) dimensions in healthy eyes using optical coherence tomography angiography (OCTA) and calculate interobserver variability. DESIGN: Reliability analysis. METHODS: Thirty-four eyes of 17 healthy subjects underwent OCTA at the Retina Service of Wills Eye Hospital. Two masked graders performed measurements of FAZ dimensions including area, perimeter, and maximum horizontal and vertical diameters using ImageJ. Intraclass correlation coefficient (ICC) between graders was calculated. RESULTS: Mean area (mm(2)), perimeter (mm), and maximum horizontal and vertical diameters (mm) were 0.27 +/- 0.101, 2.21 +/- 0.451, 0.59 +/- 0.126, and 0.56 +/- 0.118, respectively, at the superficial and 0.34 +/- 0.116, 2.50 +/- 0.462, 0.69 +/- 0.123, and 0.63 +/- 0.110 at the deep network. Interobserver agreement was high for all superficial FAZ measurements (ICC >=0.90) but did not meet the lowest acceptable grader agreement for the deep vascular network (ICC <0.85). Fellow eyes had statistically similar values (P > .05). CONCLUSION: Manual measurement of FAZ dimensions using OCTA is a noninvasive and reliable method for quantifying FAZ at the superficial vascular network. Assessing FAZ alterations in the deep vascular network may be subject to greater interobserver variability. PMID- 26423673 TI - Interpreters' subjective experiences of interpreting for refugees in person and via telephone in health and behavioural health settings in the United States. AB - Interpreters, whether in person or via telephonic means, are used in healthcare settings to aid communication between clinicians and clients when the same language is not shared. Refugees seeking health and behavioural healthcare often have multiple needs and experiences of trauma that can complicate the provision of services. Little is known about the interpreters' experiences in providing in person and telephonic interpreting for refugees. This qualitative study sought to understand the subjective experiences of interpreters in providing in-person and telephone interpretations to refugees in healthcare settings in the United States. Constant comparative analysis was used to analyse the transcribed, audio taped individual, semi-structured interviews of 36 interpreters. These interviews were conducted between July 2013 and July 2014. Two themes were identified: (i) the importance for the interpreter to develop trust with the client; and (ii) working with refugees requires more attention from the interpreter. The interpreters of this study describe experiencing additional challenges in working with refugees versus other clients. Recommendations based on the findings are made. PMID- 26423675 TI - Mesh Location in Open Ventral Hernia Repair: A Systematic Review and Network Meta analysis. AB - There is no consensus on the ideal location for mesh placement in open ventral hernia repair (OVHR). We aim to identify the mesh location associated with the lowest rate of recurrence following OVHR using a systematic review and meta analysis. A search was performed for studies comparing at least two of four locations for mesh placement during OVHR (onlay, inlay, sublay, and underlay). Outcomes assessed were hernia recurrence and surgical site infection (SSI). Pairwise meta-analysis was performed to compare all direct treatment of mesh locations. A multiple treatment meta-analysis was performed to compare all mesh locations in the Bayesian framework. Sensitivity analyses were planned for the following: studies with a low risk of bias, incisional hernias, by hernia size, and by mesh type (synthetic or biologic). Twenty-one studies were identified (n = 5,891). Sublay placement of mesh was associated with the lowest risk for recurrence [OR 0.218 (95% CI 0.06-0.47)] and was the best of the four treatment modalities assessed [Prob (best) = 94.2%]. Sublay was also associated with the lowest risk for SSI [OR 0.449 (95% CI 0.12-1.16)] and was the best of the 4 treatment modalities assessed [Prob (best) = 77.3%]. When only assessing studies at low risk of bias, of incisional hernias, and using synthetic mesh, the probability that sublay had the lowest rate of recurrence and SSI was high. Sublay mesh location has lower complication rates than other mesh locations. While additional randomized controlled trials are needed to validate these findings, this network meta-analysis suggests the probability of sublay being the best location for mesh placement is high. PMID- 26423674 TI - The Learning Curve of Robotic-Assisted Low Rectal Resection of a Novice Rectal Surgeon. AB - BACKGROUND: With the increasing availability of the surgical robotic system, the young generation colorectal surgeons may learn robotic-assisted rectal surgery upfront. There are currently very limited studies evaluating the learning curve of novice rectal surgeons. OBJECTIVE: This study aimed to evaluate the learning curve of a surgeon who had limited experience in open and laparoscopic rectal surgery. METHODS: Thirty-nine consecutive robotic-assisted total mesorectal excisions were performed from March 2013 to October 2014. All cases were performed by a single surgeon whose prior experience in open or laparoscopic low rectal cancer resections was <5 cases. The learning curve was analyzed using the cumulative sum method. RESULTS: Thirty-four low anterior resections, four abdomino-perineal resections, and one Hartmann's operation were performed. The mean total operating time was 397.2 +/- 184.3 min. There was no conversion. The major complication rate was 10.3 %. When total operating time was analyzed with the CUSUM method, three phases could be identified. They are the initial eight cases, middle 17 cases, and the final 14 cases. The first phase consisted of more proximal tumors (86.3 +/- 20.7 vs. 58.0 +/- 34.9 mm from anal verge, p = 0.04) and was associated with a shorter total operating time (243.5 +/- 38.0 vs. 540.9 +/- 133.4 min, p = 0.000) and less estimated blood loss (81.3 +/- 25.9 vs. 168.8 +/- 99.5 ml, p = 0.02) compared to the second phase. When the third phase is compared with the first and second phase, it has shorter total operating time (310.6 +/- 164.5 vs. 44 5.7 +/- 179.8 min, p = 0.03). Complications rate were 12.5, 17.6, and 0 % for phase one, two, and three respectively. CONCLUSIONS: In this study, the learning curve for a novice rectal surgeon was 25 cases. This is comparable to those who have already mastered the technique with laparoscopic or open approach. Surgical robotic system may have a role in shortening the learning curve for low rectal resection. PMID- 26423677 TI - Behavioral and Social Sciences for Personalized Medicine: Teaching with Novel Methods. PMID- 26423676 TI - Memory deficits associated with khat (Catha edulis) use in rodents. AB - Khat products and chewing practices are common in East Africa, Middle East for centuries with concomitant socio-economic and public health repercussions. We assessed memory deficits associated with khat use in rodents. Young male CBA mice, 5-7 weeks old (n = 20), weighing 25-35 g were used. Mice were treated with either 40, 120 or 360 mg/kg body weight (bw) methanolic khat extract, or 0.5 ml saline for 10 days. Spatial acquisition, reversal and reference memory were assessed using modified Morris Water maze (MMWM). Mice treated with 40 mg/kg khat extract had longer (t4 = 4.12 p = 0.015) and t4 = 2.28 p = 0.065) escape latency on first and second day during reversal relative to the baseline. Under 120 mg/kg khat dose, the escape latency was shorter (t4 = -2.49 p = 0.05) vs (t3 = -2.5 p = 0.05) on third and fourth day. Further, treatment with 360 mg/kg khat extract resulted in significantly longer time (49.13, 33.5, 40.2 and 35.75) vs. (23.5 s), compared to baseline. Mice treated with khat or control preferred the target quadrant post acquisition while differential pattern was seen during reversal phase. Mice treated with 40 or 120 mg/kg khat showed significant preference for target quadrant. Substantial time (19.9) was spent in the old target compared to the new (16.9 s) by animals treated with highest dose however, the difference was not significant. There is a biological plausibility that chronic khat use may induce memory deficits and impair cognitive flexibility. The differential patterns of memory deficits may reflect the differences in dose effect as well as time dependent impairment. PMID- 26423678 TI - A Novel Resident-as-Teacher Rotation for Second-Year Psychiatry Residents. PMID- 26423679 TI - Considerations of Ethics While Allowing Flexibility for Trainees: The Model and The Rationale for the Model of the Yale Global Mental Health Program. PMID- 26423680 TI - Exploring the Intersection of Mental Health and Humanities: the Dalhousie Psychiatry Student Writing Competition. PMID- 26423681 TI - Effects of Fatty Acids on CYP2A5 and Nrf2 Expression in Mouse Primary Hepatocytes. AB - Abnormal fatty acid metabolism is observed throughout nonalcoholic fatty liver disease (NAFLD) pathogenesis, and fatty acid storage is an important inducing factor in insulin resistance, lipid oxidation, hepatic cell damage, and inflammation. During NAFLD pathogenesis, changes in blood and liver contents of different fatty acid types also vary. Cytochrome P450 2A5 (CYP2A5), an important enzyme in mouse liver, metabolizes many drugs and activates multiple pro carcinogens with widely varying structures. According to the changes in liver fatty acid profiles observed in NAFLD animal models developed in our laboratory and others, saturated (PA/palmitic, and SA/stearic acids) and unsaturated (OA/oleic, LA/linoleic, ALA/alpha-linolenic and AA/arachidonic acids) fatty acids were selected to induce mouse primary hepatocytes, at concentrations under 1 mM, as detected by MTT assay. After 24 h treatment with various fatty acid concentrations and types, CYP2A5 mRNA and protein amounts, and enzyme activity were determined by real-time PCR, Western blot, and Coumarin 7-hydroxylation, respectively. Meanwhile, Nrf2 mRNA and protein levels were evaluated by real-time PCR and Western blot. The results indicated that saturated fatty acids are more potent in inducing CYP2A5 than unsaturated ones, except arachidonic acid. In addition, the changes in CYP2A5 expression were consistent with the alterations observed in Nrf2 expression, indicating that Nrf2 might play a regulatory role in CYP2A5 expression. PMID- 26423682 TI - A computer aided measurement method for unstable pelvic fractures based on standardized radiographs. AB - BACKGROUND: To set up a method for measuring radiographic displacement of unstable pelvic ring fractures based on standardized X-ray images and then test its reliability and validity using a software-based measurement technique. METHODS: Twenty-five patients that were diagnosed as AO/OTA type B or C pelvic fractures with unilateral pelvis fractured and dislocated were eligible for inclusion by a review of medical records in our clinical centre. Based on the input pelvic preoperative CT data, the standardized X-ray images, including inlet, outlet, and anterior-posterior (AP) radiographs, were simulated using Armira software (Visage Imaging GmbH, Berlin, Germany). After representative anatomic landmarks were marked on the standardized X-ray images, the 2 dimensional (2D) coordinates of these points could be revealed in Digimizer software (Model: Mitutoyo Corp., Tokyo, Japan). Subsequently, we developed a formula that indicated the translational and rotational displacement patterns of the injured hemipelvis. Five separate observers calculated the displacement outcomes using the established formula and determined the rotational patterns using a 3D-CT model based on their overall impression. We performed 3D reconstruction of all the fractured pelvises using Mimics (Materialise, Haasrode, Belgium) and determined the translational and rotational displacement using 3 matic suite. The interobserver reliability of the new method was assessed by comparing the continuous measure and categorical outcomes using intraclass correlation coefficient (ICC) and kappa statistic, respectively. RESULT: The interobserver reliability of the new method for translational and rotational measurement was high, with both ICCs above 0.9. Rotational outcome assessed by the new method was the same as that concluded by 3-matic software. The agreement for rotational outcome among orthopaedic surgeons based on overall impression was poor (kappa statistic, 0.250 to 0.426). Compared with the 3D reconstruction outcome, the interobserver reliability of the formula method for translational and rotational measures was perfect with both ICCs more than 0.9. CONCLUSIONS: The new method for measuring displacement using a formula was reliable, and could minimise the measurement errors and maximise the precision of pelvic fracture description. Furthermore, this study was useful for standardising the operative plan and establishing a theoretical basis for robot-assisted pelvic fracture surgery based on 2-D radiographs. PMID- 26423683 TI - Long term quality of life in patients with Hirschsprung's disease who underwent heart-shaped anastomosis during childhood: A twenty-year follow-up in China. AB - OBJECTIVE: The aim of this study was to evaluate the long term quality of life among adults who had undergone heart-shaped anastomosis for Hirschsprung's disease (HD) during childhood. METHODS: Ninety-two cases with HD who had undergone heart-shaped anastomosis between January 1986 and January 1995 were investigated, and 90 adults with pediatric surgical and gastrointestinal disorders during the same period were randomly collected to serve as controls. They were to complete bowel function score (BFS) and WHO Quality of Life-BREF (QLB). RESULTS: In BFS, there was significant difference in soiling between the HD group and the control group. Eight patients presented occasional soiling, with six of them having undergone two or more operations. Comparing persons without soiling in the HD group and controls, no significant difference was found in each area of QLB, and there was significant difference in psychology and low quality of life subjective feelings in the soiling group compared with the other HD persons and controls, respectively. CONCLUSION: The long-term outcome of heart shaped anastomosis for Hirschsprung's disease is satisfying. Recurrent operation is a high risk for soiling occurrence. It should be emphasized to remove all the lesion segment in the first operation. PMID- 26423684 TI - Surgical intervention strategies for pediatric congenital cystic lesions of the lungs: A 20-year single-institution experience. AB - BACKGROUND: The aim of this study was to assess surgical intervention strategies for congenital cystic lesions of the lungs (CCL), focusing on the safety of lung resection. MATERIALS AND METHODS: The clinical features of 27 children (CCAM, n=16; bronchial atresia, n=4; bronchogenic cyst, n=3; pulmonary sequestration, n=3; lobar emphysema, n=1) who were treated at our institution between 1995 and 2014 were analyzed. RESULTS: Of the 27 patients, 14 were asymptomatic, and 13 were symptomatic. The youngest symptomatic patient presented with pneumonia at 9months of age. The mean age at surgery was 4months in the asymptomatic group and 4.1years in the symptomatic group. The mean operating time was 167minutes in the asymptomatic group and 275minutes in the symptomatic group (P<0.001). The mean amount of intraoperative bleeding was 15g in the asymptomatic group and 83.4g in the symptomatic group (P<0.05). All of the prenatally diagnosed patients underwent surgery within six months of birth. Three patients had remnant cystic lesions, all of which involved cystic lesions located over the lobulation anomalies of the lung. CONCLUSIONS: To minimize surgical invasiveness, surgery for CCL should be performed during the asymptomatic period or within six months after birth. PMID- 26423685 TI - Acceleration of Proteinuria without Significant Impact on Renal Function and Its Protection by Angiotensin II Receptor Blocker in Rats Treated with Axitinib. AB - BACKGROUND: Proteinuria is a dose-associated adverse event induced by anti angiogenic agents; however, the mechanism mediating the induction of proteinuria by this type of agent remains largely unknown. The objective of this study was to assess the effects of treatment with axitinib and/or angiotensin II receptor blocker (ARB) on urinary protein excretion and renal function. MATERIALS AND METHODS: Thirty-five rats were randomly selected for treatment with following agents for 4 weeks: vehicle (group A), candesartan (group B), axitinib (group C), axitinib plus candesartan (group D), or axitinib and no treatment for subsequent 2 weeks (group E). RESULTS: After completion of treatment schedule, urine protein to-creatinine ratio (UPC) in group C was significantly higher than those in groups A and B, while the additional administration of candesartan resulted in the significant reduction of UPC in group D compared with group C. Following the no treatment interval for 2 weeks, UPC in group E significantly decreased compared with that in group C. There were no significant differences in serum creatinine or blood urea nitrogen level among the five groups. Furthermore, semiquantitative evaluation of immunofluorescence findings showed that the expression levels of both nephrin and podocin in rat kidneys were inversely associated with the UPC value throughout these five groups. CONCLUSIONS: Despite the acceleration of proteinuria involving the downregulation of slit diaphragm associated proteins, axitinib may not have an adverse impact on renal function, and axitinib-induced proteinuria can be partially prevented by additional treatment with ARB and reversibly recovered by its transient dose-interruption. PMID- 26423686 TI - Influence of endurance exercise training on antioxidant enzymes, tight junction proteins, and inflammatory markers in the rat ileum. AB - BACKGROUND: This study investigated the effects of endurance exercise training on ileum antioxidant status, as well as tight junction, inflammatory, and nutrient transporter gene expression. METHODS: Sprague-Dawley rats (4 month old) were assigned to sedentary (SED) or endurance exercise-training (EXE) groups (n = 8/group). EXE animals were trained on the treadmill for 10 days at a speed of 30 m/min at 0 degrees incline for 60 min/day. SED and EXE animals were sacrificed (24 h after the final training bout) and the ileum was stored for analyses. RESULTS: The ileum of EXE had higher (p < 0.05) antioxidant protein levels of manganese superoxide dismutase and catalase compared to SED with no change (p > 0.05) in the lipid peroxidation biomarker 4-hydroxynonenal. Ileum mRNA expression of the tight junction gene zonulin increased (p < 0.05) and claudin 1 decreased (p < 0.05) in EXE compared to SED, but occludin and zonula occluden 1 were not different (p > 0.05) between SED and EXE. The ileum mRNA expressions of seven nutrient transporters (SLC5A8, SLC7A6, SLC6A19, SLC7A7, SLC27A2, SLC16A10, and SLC15A1) were not different between the two groups (p > 0.05). EXE had lower ileum TNFalpha mRNA expression (p < 0.05) compared to SED. No changes (p > 0.05) were found in the other inflammatory mRNAs including NFkappaB, IFNgamma, IL6, CCL2, TLR4, and IL10. In addition, no changes in p-p65:p65 were detected. CONCLUSIONS: These findings suggest that 10 days of endurance exercise training up-regulates key endogenous antioxidant enzymes, decreases select inflammation markers, and alters select markers of tight junction permeability. PMID- 26423688 TI - Synergy of ambroxol with vancomycin in elimination of catheter-related Staphylococcus epidermidis biofilm in vitro and in vivo. AB - Central venous catheters are widely used in neonatal intensive care units (NICUs) nowadays. The commonest cause of catheter-related bloodstream infections (CRBSIs) is coagulase-negative staphylococci (CoNS). Ambroxol, an active metabolite of bromhexine, exhibits antimicrobial activity against strains producing biofilm and enhances the bactericidal effect of some antibiotic by breaking the structure of biofilm. In this study, we aimed to determine the effect of ambroxol with vancomycin on the biofilm of Staphylococcus epidermidis (S. epidermidis) in vitro and in vivo. In the in vitro study, the biofilm of S. epidermidis was assessed by XTT reduction assay and analysed by confocal laser scanning microscopy (CLSM). In the in vivo study, a rabbit model of CRBSIs was created by intravenous intubation with a tube covered with S. epidermidis biofilm. The rabbits received one of the following four treatments by means of antibiotic lock therapy: normal heparin, ambroxol, vancomycin, or vancomycin plus ambroxol each for 3 days. The microstructure of the biofilm was assessed by scanning electron microscopy (SEM). The number of bacterial colonies in the organs (liver, heart, and kidney) and on the intravenous tubes was measured on agar plates. Pathological changes in the organs (liver, heart, and kidney) were observed with Hematoxylin-Eosin staining. The ambroxol exhibits significant efficacy to potentiate the bactericidal effect of vancomycin on S. epidermidis biofilm both in vitro and in vivo. The antibiotic lock therapy using a combination of ambroxol and vancomycin reveals a high ability to eradicate S. epidermidis biofilms in vivo. These results provide the basis of a useful anti-infection strategy for the treatment of CRBSIs. PMID- 26423687 TI - Appropriateness of Prostate Cancer Imaging among Veterans in a Delivery System without Incentives for Overutilization. AB - OBJECTIVE: To determine the frequency of appropriate and inappropriate prostate cancer imaging in an integrated health care system. DATA SOURCES/STUDY SETTING: Veterans Health Administration Central Cancer Registry linked to VA electronic medical records and Medicare claims (2004-2008). STUDY DESIGN: We performed a retrospective cohort study of VA patients diagnosed with prostate cancer (N = 45,084). Imaging (CT, MRI, bone scan, PET) use was assessed among patients with low-risk disease, for whom guidelines recommend against advanced imaging, and among high-risk patients for whom guidelines recommend it. PRINCIPAL FINDINGS: We found high rates of inappropriate imaging among men with low-risk prostate cancer (41 percent) and suboptimal rates of appropriate imaging among men with high-risk disease (70 percent). Veterans utilizing Medicare-reimbursed care had higher rates of inappropriate imaging [OR: 1.09 (1.03-1.16)] but not higher rates of appropriate imaging. Veterans treated in middle [OR: 0.51 (0.47-0.56)] and higher [OR: 0.50 (0.46-0.55)] volume medical centers were less likely to undergo inappropriate imaging without compromising appropriate imaging. CONCLUSIONS: Our results highlight the overutilization of imaging, even in an integrated health care system without financial incentives encouraging provision of health care services. Paradoxically, imaging remains underutilized among high-risk patients who could potentially benefit from it most. PMID- 26423689 TI - Fulminant adenovirus hepatitis after hematopoietic stem cell transplant: Retrospective real-time PCR analysis for adenovirus DNA in two cases. AB - BACKGROUND: Viral infection is one of the major causes of mortality in patients undergoing hematopoietic stem cell transplant (HSCT). Systemic infection of adenovirus (AdV) has emerged as a not uncommon viral infection with significant morbidity and mortality as with cytomegalovirus and Epstein-Barr virus infection. Routine surveillance for these viruses has become a clinical practice and subsequent preemptive therapy improves patients' outcomes; however, the effectiveness of preemptive therapy for AdV has not been fully investigated in patients with a lethal form of AdV infection. METHODS: Sequential AdV loads were retrospectively analyzed in children with fulminant AdV hepatitis after HSCT. RESULTS: The AdV DNA became detectable (1 * 10(4) copies/mL) as early as 2 weeks after HSCT. These levels reached >1 * 10(8) copies/mL at the onset of fulminant hepatitis. However, we determined that gamma-glutamyltransferase levels were elevated to >100 IU/L at least 2 weeks before the diagnosis of hepatitis. CONCLUSIONS: Our observation raises the possibility that elevated gamma glutamyltransferase could be a sentinel marker for AdV hepatitis, which prompts elaborated monitoring of AdV load and targeted treatment. PMID- 26423690 TI - Fatal acute cardiac vasculopathy during cisplatin-gemcitabine-bevacizumab (CGB) chemotherapy for advanced urothelial carcinoma. AB - BACKGROUND: Bladder cancer (BC) accounts for ~14,680 deaths annually in the U.S. The prognosis of advanced disease remains dismal with current therapies. A phase III intergroup trial for metastatic BC adding bevacizumab to first-line cisplatin gemcitabine chemotherapy (GCB regimen) is currently ongoing. We report the clinical-pathologic findings of a patient who developed fatal acute cardiac microvascular toxicity while receiving this regimen. CASE REPORT: A 66 year old man consulted for epigastric pain, nausea, intermittent diarrhea and lightheadedness two weeks after receiving the first cycle of GCB chemotherapy for metastatic BC. Physical evaluation, laboratory studies and electrocardiogram (EKG) were within normal limits except for marked thrombocytopenia that was attributed to his recent chemotherapy. The patient was admitted for observation, rehydrated and started on a proton pump inhibitor. The following day, however, he experienced sudden severe chest and right upper quadrant pain. EKG showed tachycardia, ST elevations in leads V2 and V3, laboratory analyses revealed marked elevation of cardiac troponin I, and an echocardiogram showed a markedly reduced ejection fraction of 10-20%, consistent with rapidly progressive cardiogenic shock. Emergent cardiac catheterization showed no significant coronary artery disease. Sepsis work-up was negative. He became progressively hypotensive, developed multi-organ failure, and died 48 h after admission. Postmortem examination showed diffuse microvasculopathy and changes due to global hypoperfusion of 12-48 h evolution. CONCLUSIONS: We present the first case of acute, fatal cardiac failure due to microvasculopathy most consistent with bevacizumab-associated toxicity. The findings are discussed in light of the existing literature. PMID- 26423691 TI - Low Vitamin D Levels and Genetic Polymorphism in the Vitamin D Receptor are Associated with Increased Risk of Statin-Induced Myopathy. AB - The main aim of this study was to test the hypothesis whether 25-hydroxyvitamin D (25OHD) levels <50 nmol/L at baseline could predict statin-induced myopathy during the course of treatment. In addition, we analysed the association between a genetic polymorphism in the vitamin D receptor (VDR) and the risk of statin induced myopathy. We used serum samples from a prospective, observational study in statin-treated patients in Sweden who were thoroughly followed with interviews and questionnaires regarding muscular symptoms (n = 127). In this cohort, 16 developed muscular symptoms and 111 had no muscular symptoms associated with statin treatment during the first year of follow-up. Patients with 25OHD levels <50 nmol/L before starting on statin treatment had four times higher risk of developing muscular symptoms compared with individuals having 25OHD levels >50 nmol/L (RR 4.2; 95% CI 1.7-10.2; p < 0.01). The mean levels of 25OHD at baseline were 50 +/- 4 nmol/L among patients developing myopathy and 60 +/- 2 nmol/L among patients without myopathy (p < 0.01). Individuals homozygous for the C allele in the VDR polymorphism TaqI (rs731236) had a four times higher risk of developing muscular symptoms; (RR 4.37, 95% CI 1.9-10.1, p < 0.01). In conclusion, 25OHD levels <50 nmol/L might be a useful marker to predict muscular adverse events during statin treatment. In addition, the finding that the VDR polymorphism TaqI was associated with myopathy may indicate a causal relationship between vitamin D function and myopathy, but larger studies are needed before firm conclusions can be drawn. PMID- 26423692 TI - Microscopic Investigation of Protein Function in C. elegans Using Fluorescent Imaging. AB - Caenorhabditis elegans is a powerful model organism for studying human biology and disease due to its surprisingly high genetic homology to Homo sapiens. Its genetic amenability, small size, short generation time, and transparent body make it an ideal organism for multiple scientific disciplines. Fluorescent microscopy is essential for studying protein biological function. However, C. elegans, mainly due to its high motility, has been more difficult to adapt to fluorescence imaging, especially live-imaging. We present here several protocols for the study of protein location, function and dynamics in context of a whole animal. These protocols, especially when combined with existing genetic procedures, can yield a great deal of insight in the physiological roles of proteins in C. elegans, which can be directly translated into mammalian systems. PMID- 26423693 TI - In Vivo Immuno-Spin Trapping: Imaging the Footprints of Oxidative Stress. AB - A plethora of disease processes are associated with elevated reactive species formation and allied reactions with biomolecules that alter cell signaling, induce overt damage, and promote dysfunction of tissues. Unfortunately, effective detection of reactive species in tissues is wrought with issues that significantly limit capacity for validating species identity, establishing accurate concentrations, and identifying anatomic sites of production. These shortcomings reveal the pressing need for new approaches to more precisely assess reactive species generation in vivo. Herein, we describe an in vivo immuno-spin trapping method for indirectly assessing oxidant levels by detecting free radicals resulting from reaction of oxidants with biomolecules to form stable, immunologically detectable nitrone-biomolecular adducts. This process couples the reactivity and sensitivity of an electron paramagnetic resonance spin trap with the resolution of confocal imaging to visualize the extent of cell and tissue oxidation and anatomic sites of production by detecting resultant free radical formation. PMID- 26423694 TI - Getting a Handle on RAS-targeted Therapies: Cysteine Directed Inhibitors. AB - Directly inhibiting oncogenic RAS proteins has proven to be an arduous task, as after more than thirty years of intensive investigation, no clinically relevant therapies exist. Recently, two classes of selective small molecule inhibitors that target a cysteine-containing RAS mutant have been developed, representing the first directed approaches to specifically inhibit an oncogenic KRAS mutant. In this mini-review, we first assess the development and targeting strategies associated with novel cysteine-directed RAS inhibitors. Next, we describe the variable oncogenic potency of the KRAS G12C mutant when compared to other KRAS G12 mutants. Lastly, we evaluate how the redox properties of KRAS G12C may play a role in differential signaling and tumorigenic potency of the oncogene, the efficacy of small molecules targeting this specific RAS mutant and further development of directed oncogenic RAS inhibitors. PMID- 26423695 TI - Past, Present, and Future of Targeting Ras for Cancer Therapies. AB - For decades, mutant Ras (mut-Ras) proteins have been identified as drivers of multiple cancers including pancreatic, lung, and colon cancers. However, targeting this oncogene has been challenging and no Ras inhibitors are on the market to date. Lately several candidates targeting the downstream pathways of Ras signaling, including PI3K and Raf, were approved for cancer treatment. However, they do not present promising therapeutic effects on patients harboring Ras mutations. Recently, a variety of compounds have been reported to impair the activity of Ras, and these exciting discoveries reignite the hope for development of novel drugs targeting mut-Ras. In this article, we will review the progress made in this field and the current state-of-the-art technologies to develop Ras inhibitors. Also we will discuss the future direction of targeting Ras. PMID- 26423698 TI - Arene ruthenium(II) Complexes: The Promising Chemotherapeutic Agent in Inhibiting the Proliferation, Migration and Invasion. AB - Arene ruthenium(II) complexes have been widely investigated as one of the most promising candidates in chemotherapy because of their low toxicity and high inhibiting activity against the proliferation, invasion, migration, and angiogenesis of various tumors in vitro and in vivo. This review highlights the recent developments in different chemical types of arene Ru(II) complexes, as well as their biological activity and underlying mechanisms. The sustained efforts in this aspect of arene Ru(II) complexes would be essential in developing novel anti-tumor agents in the near future. PMID- 26423699 TI - Ruthenium Complexes: An Emerging Ground to the Development of Metallopharmaceuticals for Cancer Therapy. AB - GLOBOCAN 2012 estimates 14.1 million new cancer cases and 8.2 million cancer related deaths worldwide. Cancer is rapidly becoming a major public health concern in India as well, with the number of new cancer cases anticipated to double within the next 20 years. The percentage of currently approved metallodrugs is very low, in contrast to the majority of drugs available as organic compounds. The search for alternative drugs to cisplatin, carboplatin and other derivatives is highly needed due to their severe side effects including nephrotoxicity and neurotoxicity. Ruthenium, among other transition metal complexes appears to be a possible candidate for cancer therapy in the near future. The most significant rationale is ruthenium's octahedral chemistry and greater propensity to undergo redox reactions. The hypoxic environment of tumors favors the reduction of inert ruthenium (III) to active ruthenium (II) which opens new prospects for the development of novel prodrugs. Although studies suggest that ruthenium complexes penetrate well within the tumor cells and bind effectively to DNA, its binding to proteins is not very well explained. Ruthenium complexes are presently receiving great attention in the fields of biological, pharmaceutical and medicinal chemistry as anticancer agents. This review poses a comprehensive overview of the studies on competent anticancer ruthenium complexes and the role of these metal complexes in relation to their anticancer properties as well as those under clinical trials. PMID- 26423697 TI - Ras Dimer Formation as a New Signaling Mechanism and Potential Cancer Therapeutic Target. AB - The K-, N-, and HRas small GTPases are key regulators of cell physiology and are frequently mutated in human cancers. Despite intensive research, previous efforts to target hyperactive Ras based on known mechanisms of Ras signaling have been met with little success. Several studies have provided compelling evidence for the existence and biological relevance of Ras dimers, establishing a new mechanism for regulating Ras activity in cells additionally to GTP-loading and membrane localization. Existing data also start to reveal how Ras proteins dimerize on the membrane. We propose a dimer model to describe Ras-mediated effector activation, which contrasts existing models of Ras signaling as a monomer or as a 5-8 membered multimer. We also discuss potential implications of this model in both basic and translational Ras biology. PMID- 26423696 TI - How to Target Activated Ras Proteins: Direct Inhibition vs. Induced Mislocalization. AB - Oncogenic Ras proteins are a driving force in a significant set of human cancers and wildtype, unmutated Ras proteins likely contribute to the malignant phenotype of many more. The overall challenge of targeting activated Ras proteins has great promise to treat cancer, but this goal has yet to be achieved. Significant efforts and resources have been committed to inhibiting Ras, but these energies have so far made little impact in the clinic. Direct attempts to target activated Ras proteins have faced many obstacles, including the fundamental nature of the gain-of-function oncogenic activity being produced by a loss-of-function at the biochemical level. Nevertheless, there has been very promising recent pre clinical progress. The major strategy that has so far reached the clinic aimed to inhibit activated Ras indirectly through blocking its post-translational modification and inducing its mislocalization. While these efforts to indirectly target Ras through inhibition of farnesyl transferase (FTase) were rationally designed, this strategy suffered from insufficient attention to the distinctions between the isoforms of Ras. This led to subsequent failures in large-scale clinical trials targeting K-Ras driven lung, colon, and pancreatic cancers. Despite these setbacks, efforts to indirectly target activated Ras through inducing its mislocalization have persisted. It is plausible that FTase inhibitors may still have some utility in the clinic, perhaps in combination with statins or other agents. Alternative approaches for inducing mislocalization of Ras through disruption of its palmitoylation cycle or interaction with chaperone proteins are in early stages of development. PMID- 26423700 TI - RAS/Effector Interactions from Structural and Biophysical Perspective. AB - RAS is a molecular switch that regulates a large number of pathways through interactions with many effector proteins. Most RAS/effector complexes are short lived, demonstrating fast association and fast dissociation rate and Kds ranging from 10(-8)-10(-5) M, compatible with the signaling function of these interactions in the cell. RAS effectors share little sequence homology but all contain an RAS binding domain that exhibits ubiquitin fold. All effectors bind to the same epitope on RAS by forming an intermolecular beta sheet and creating a number of favorable hydrogen bonds and salt bridges across the binding interface. Several hot-spots on both RAS and effector molecules constitute a general recognition mode. RAS/effector interactions occur only when RAS is found in the active, GTP-bound state, and are disrupted upon GTP hydrolysis, most probably due to increased flexibility of the RAS molecule. Recent NMR studies demonstrate how in the presence of multiple binding partners, RAS prefers certain effectors to others. The hierarchy of these interactions could be altered for RAS oncogenic mutants, thus perturbing the network of the downstream signaling. Insights obtained through biophysical and structural studies of effectors interacting with RAS and its mutants establish the basic principles that could be used for designing drugs in RAS-associated diseases. PMID- 26423701 TI - Direct Inhibitors of Ras-Effector Protein Interactions. AB - Activating Ras mutations are associated with ~30% of all human cancers, which often respond poorly to standard therapies. The four Ras isoforms are therefore highly attractive targets for anticancer drug discovery. However, Ras proteins function through protein-protein interactions and their surfaces lack any major pockets for small molecules to bind; as a result they have been declared "undruggable" for the past 30 years. Several breakthroughs during the past few years may finally remove Ras from the list of undruggable proteins. This mini review discusses the current approaches to developing inhibitors especially cyclic peptides that physically block the interaction between Ras and its downstream effector proteins, which is potentially the most effective approach for treating Ras mutant cancers. PMID- 26423702 TI - Outcomes of Treatment in Slovene Follicular Lymphoma Patients. AB - BACKGROUND: The outcome of follicular lymphoma (FL) patients has dramatically improved over the last 2 decades by introduction of rituximab in combination chemotherapy and into maintenance setting. We retrospectively analyzed the treatment outcomes in Slovene FL patients in the era of rituximab and compared them to the results reported by pivotal clinical studies. PATIENTS AND METHODS: Two hundred seventy-eight patients with FL treated in Slovenia between 2000 and 2010 with a median follow-up of 5.7 years were included in our retrospective analysis. One hundred ninety-three (69%) received systemic treatment (ST). RESULTS: With a median follow-up of 5.7 years, the 5- and 10-year overall survival (OS) rates for the whole series were 77% and 53%, respectively. The 5 year progression-free survival (PFS) for 193 FL patients treated with ST was 37%. Patients treated with rituximab chemotherapy had a significantly better OS than patients treated with chemotherapy alone, with a 5-year OS of 79% versus 53% (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.22-0.67; P = .001). Adding rituximab to the first-line chemotherapy significantly improved PFS compared to chemotherapy alone (HR, 0.26; 95% CI 0.18-0.36; P < .001). Maintenance rituximab after immunochemotherapy in first-line treatment reduced the risk for progression by 61% and significantly prolonged the time to progression (HR, 0.39; 95% CI 0.20-0.73; P < .003). CONCLUSION: The outcomes in our routinely treated FL patients confirm the benefit of adding rituximab to chemotherapy and are comparable to the results of pivotal clinical studies. The outcome of our FL patients was improved in terms of both PFS and OS. PMID- 26423703 TI - Circulating Levels of Urokinase-Type Plasminogen Activator Receptor and D-Dimer in Patients With Hematological Malignancies. AB - BACKGROUND: Patients with cancer exhibit changes in their hemostatic mechanisms. The D-dimer (D-D) is the most important subproduct of fibrinolysis, and urokinase plasminogen activator receptor (uPAR) is related to invasiveness and metastases, and is overexpressed in neoplastic cells. The objective of this study was to identify in patients with hematological neoplasia, the serum levels of uPAR and D D, and to determine their effects on outcome. PATIENTS AND METHODS: A cross sectional study was performed. Clinical and demographic data were obtained from the clinical chart. Determination of uPAR in serum (pg/L) was performed using an enzyme-linked immunosorbent assay, and D-D (MUg/dL) using nephelometry. RESULTS: We included 42 patients (35 with lymphomas). Statistically significant differences were found in D-D (P < .001) and uPAR (P < .01) between patients and control participants. Response was an accumulated clinical outcome. We observed statistical differences between groups (P < .001). D-D was positive in 70% of cases. CONCLUSION: We found differences in D-D serum levels and soluble uPAR between control participants and patients with lymphoma. These results indicate that D-D serum levels and soluble uPAR should be considered biomarkers of response and survival in patients with lymphoma. PMID- 26423704 TI - In Silico Design of Highly Selective Mo-V-Te-Nb-O Mixed Metal Oxide Catalysts for Ammoxidation and Oxidative Dehydrogenation of Propane and Ethane. AB - We used density functional theory quantum mechanics with periodic boundary conditions to determine the atomistic mechanism underlying catalytic activation of propane by the M1 phase of Mo-V-Nb-Te-O mixed metal oxides. We find that propane is activated by Te?O through our recently established reduction-coupled oxo activation mechanism. More importantly, we find that the C-H activation activity of Te?O is controlled by the distribution of nearby V atoms, leading to a range of activation barriers from 34 to 23 kcal/mol. On the basis of the new insight into this mechanism, we propose a synthesis strategy that we expect to form a much more selective single-phase Mo-V-Nb-Te-O catalyst. PMID- 26423705 TI - Indolent CD8-positive lymphoid proliferation of acral sites: three further cases of a rare entity and an update on a unique patient. AB - BACKGROUND: Primary cutaneous indolent CD8-positive lymphoid proliferation is an emerging entity characterized by slowly enlarging papules and nodules that are pathologically comprised of clonal nonepidermotropic medium-sized atypical CD8(+) T-cells. Although the majority of lesions are solitary and located on the ears, bilateral symmetrical presentations have been described and lesions may arise at other peripheral or 'acral' sites. Patients follow a benign clinical course and systemic involvement has not yet been observed. Despite this, some medical practitioners classify such lesions as peripheral T-cell lymphoma, NOS, a category implying aggressive disease. OBJECTIVES: We present three cases seen in our institutions and provide an update on a previously reported unique patient who continues to develop recurrent and multifocal skin lesions. RESULTS: Systemic disease progression has not been observed, even in the presence of recurrent and multifocal cutaneous disease. CONCLUSIONS: Indolent CD8-positive lymphoid proliferation of acral sites is a distinctive and readily identifiable entity and should be included in the next consensus revision of cutaneous lymphoma classification. Although cases described thus far have followed an indolent clinical course, dermatologists should remain guarded about the prognosis and full staging and longitudinal observation are recommended until this condition is better understood. PMID- 26423707 TI - Liam Smeeth: Still hoping for Olympic gold. PMID- 26423708 TI - Developing interventions in child and adolescent mental health services: Do we really know what works for whom? PMID- 26423706 TI - Monitoring the athlete training response: subjective self-reported measures trump commonly used objective measures: a systematic review. AB - BACKGROUND: Monitoring athlete well-being is essential to guide training and to detect any progression towards negative health outcomes and associated poor performance. Objective (performance, physiological, biochemical) and subjective measures are all options for athlete monitoring. OBJECTIVE: We systematically reviewed objective and subjective measures of athlete well-being. Objective measures, including those taken at rest (eg, blood markers, heart rate) and during exercise (eg, oxygen consumption, heart rate response), were compared against subjective measures (eg, mood, perceived stress). All measures were also evaluated for their response to acute and chronic training load. METHODS: The databases Academic search complete, MEDLINE, PsycINFO, SPORTDiscus and PubMed were searched in May 2014. Fifty-six original studies reported concurrent subjective and objective measures of athlete well-being. The quality and strength of findings of each study were evaluated to determine overall levels of evidence. RESULTS: Subjective and objective measures of athlete well-being generally did not correlate. Subjective measures reflected acute and chronic training loads with superior sensitivity and consistency than objective measures. Subjective well-being was typically impaired with an acute increase in training load, and also with chronic training, while an acute decrease in training load improved subjective well-being. SUMMARY: This review provides further support for practitioners to use subjective measures to monitor changes in athlete well-being in response to training. Subjective measures may stand alone, or be incorporated into a mixed methods approach to athlete monitoring, as is current practice in many sport settings. PMID- 26423709 TI - Emergency department visits and revisits for nontraumatic dental conditions in Iowa. AB - OBJECTIVES: To examine the characteristics associated with emergency department (ED) utilization in Iowa for nontraumatic dental conditions (NTDCs), and those associated with having multiple visits to the ED for NTDCs before the Medicaid expansion program in Iowa. METHODS: State Emergency Department Database for Iowa was used for 2012, which comprised of all outpatient ED visits in the state. Logistic regression was used for bivariate and multivariable analyses to model the odds of visiting the ED for NTDCs, relative to other conditions, and odds of visiting the ED multiple times relative to a single time in 2012 for NTDCs. The hospital charges associated with the NTDC ED visits were also examined. RESULTS: ED visits for NTDCs comprised 1.41% of all ED visits in Iowa during 2012 with a mean charge of $557. Of the patients presenting for NTDCs in 2012, 17% presented multiples times. Young adults, Medicaid enrollees or uninsured, and those residing in metropolitan areas had greater odds of presenting to the EDs for NTDCs compared with other conditions, and presenting multiple times to EDs for NTDCs. Those with more chronic conditions also had greater odds of repeatedly visiting the ED for NTDCs. CONCLUSIONS: Low-income young adults in Iowa rely on EDs for their dental needs that can have substantial costs. The Dental Wellness Plan (DWP) is intended to facilitate dental care access by providing dental coverage to low-income Iowans. This study provides baseline data that will be used to evaluate the success of DWP in improving access to dental care. PMID- 26423710 TI - Positive effect of combined exercise training in a model of metabolic syndrome and menopause: autonomic, inflammatory, and oxidative stress evaluations. AB - It is now well established that after menopause cardiometabolic disorders become more common. Recently, resistance exercise has been recommended as a complement to aerobic (combined training, CT) for the treatment of cardiometabolic diseases. The aim of this study was to evaluate the effects of CT in hypertensive ovariectomized rats undergoing fructose overload in blood pressure variability (BPV), inflammation, and oxidative stress parameters. Female rats were divided into the following groups (n = 8/group): sedentary normotensive Wistar rats (C), and sedentary (FHO) or trained (FHOT) ovariectomized spontaneously hypertensive rats undergoing and fructose overload. CT was performed on a treadmill and ladder adapted to rats in alternate days (8 wk; 40-60% maximal capacity). Arterial pressure (AP) was directly measured. Oxidative stress and inflammation were measured on cardiac and renal tissues. The association of risk factors (hypertension + ovariectomy + fructose) promoted increase in insulin resistance, mean AP (FHO: 174 +/- 4 vs. C: 108 +/- 1 mmHg), heart rate (FHO: 403 +/- 12 vs. C: 352 +/- 11 beats/min), BPV, cardiac inflammation (tumor necrosis factor-alpha FHO: 65.8 +/- 9.9 vs. C: 23.3 +/- 4.3 pg/mg protein), and oxidative stress cardiac and renal tissues. However, CT was able to reduce mean AP (FHOT: 158 +/- 4 mmHg), heart rate (FHOT: 303 +/- 5 beats/min), insulin resistance, and sympathetic modulation. Moreover, the trained rats presented increased nitric oxide bioavailability, reduced tumor necrosis factor-alpha (FHOT: 33.1 +/- 4.9 pg/mg protein), increased IL-10 in cardiac tissue and reduced lipoperoxidation, and increased antioxidant defenses in cardiac and renal tissues. In conclusion, the association of risk factors promoted an additional impairment in metabolic, cardiovascular, autonomic, inflammatory, and oxidative stress parameters and combined exercise training was able to attenuate these dysfunctions. PMID- 26423711 TI - Chronic hypoxia during development does not trigger pathologic remodeling of the chicken embryonic heart but reduces cardiomyocyte number. AB - Fetal growth restriction programs an increased risk of cardiovascular disease in adulthood, but the actual mechanisms of this developmental programming are not fully understood. Previous studies in mammalian models suggest that hearts of growth-restricted fetuses have reduced cardiomyocyte number due to reduced proliferation and premature cardiomyocyte maturation. Chicken embryos incubated under chronic hypoxia are also growth-restricted, have smaller hearts, and show signs of cardiac insufficiency posthatching. The aim of the present study was to investigate how chronic hypoxia (14% O2) during development affects cardiomyocyte mass and how myocardial structure is altered. Hypoxic incubation reproduced the well-characterized embryonic growth restriction and an increased ventricle-to body mass ratio (at E11, E15, E17, and E19) with reduced absolute heart mass only at E19. Cell density, apoptosis, and cardiomyocyte size were insensitive to hypoxia at E15 and E19, and no signs of ventricular wall remodeling or myocardial fibrosis were detected. Bayesian modeling provided strong support for hypoxia affecting absolute mass and proliferation rates at E15, indicating that the growth impairment, at least partly, occurs earlier in development. Neither E15 nor E19 hearts contained binucleated cardiomyocytes, indicating that fetal hypoxia does not trigger early maturation of cardiomyocytes in the chicken, which contrasts with previous results from hypoxic rat pups. In conclusion, prenatal hypoxia in the chick embryo results in a reduction in the number of cardiomyocytes without inducing ventricular remodeling, cell hypertrophy, or premature cardiomyocyte maturation. PMID- 26423712 TI - Effect of doxycycline on contralateral canine cranial cruciate ligament rupture. A prospective randomized clinical trial in 69 dogs. AB - OBJECTIVE: To evaluate whether doxycycline administered to dogs with unilateral cranial cruciate ligament rupture (Uni-CCLR) would decrease the risk of contralateral-CCLR (Co-CCLR). To evaluate predictors for Co-CCLR survival. To evaluate if a predisposition of Labrador Retrievers to Co-CCLR exists when compared to other breeds. METHODS: In this prospective randomized controlled clinical trial, 69 client-owned dogs with Uni-CCLR were randomly assigned to a doxycycline (group-D: 7.5 mg/kg PO BID x 6 weeks) or non-doxycycline (group-ND: negative control). Medical and imaging data, time from Uni- to Co-CCLR and to follow-up were recorded. Statistics included chi-squared test, logistic regression, Kaplan-Meier survival analysis, log rank test, survival curves, and frailty model (p <0.05). RESULTS: This study included 32 dogs in group-D, and 37 dogs in group-ND. Median follow-up was 54.5 and 61 months, respectively. Contralateral CCLR occurred in 53.1% and 48.6% at medians of 20 and 11 months, respectively. Doxycycline did not significantly decrease the risk of Co-CCLR (p = 0.83). This risk was decreased by 14.2% with each year of age but increased with each increasing kilogram of body weight and each increasing degree of tibial plateau angle by 5.4% and 9.7%, respectively. Labrador Retrievers were not significantly predisposed (p = 0.37). CLINICAL SIGNIFICANCE: At the dose regimen investigated doxycycline does not decrease the risk for Co-CCLR. PMID- 26423713 TI - Cystic Tumor of the Intra-Atrial Septum. PMID- 26423714 TI - Boceprevir for chronic HCV genotype 1 infection in treatment-experienced patients with severe fibrosis or cirrhosis: The Greek real-life experience. AB - BACKGROUND: The aim of our study was to evaluate the safety and efficacy of triple therapy using boceprevir (BOC) with pegylated interferon (pIFN)/ribavirin (RBV) in chronic hepatitis C (CHC) genotype 1 (G1) treatment-experienced patients with advanced fibrosis or compensated cirrhosis. METHODS: We report the Greek experience on the first CHC patients who received BOC-based regimen. From September 2011 to June 2012, 26 treatment-experienced CHC patients and G1 with bridging fibrosis or compensated cirrhosis received 48 weeks of BOC+pIFN+RBV antiviral therapy. Data on complete blood counts and HCV RNA levels were obtained prior to therapy, at treatment weeks 4, 8, 12, 24, 36, 48 and 24 weeks after the end of treatment. RESULTS: A full set analysis was performed in 25 of 26 patients. Nine patients (36%) achieved sustained viral response (SVR). Ten patients (40%) stopped the therapy because of futility rules and 3 (12%) due to adverse events. Four patients (16%) developed a virological breakthrough (3 of those presented futility rules as well) and 2 (8%) relapse. All patients who achieved SVR had G 1b, 6 (67%) were non-cirrhotic and 5 (55%) had >1 log decline in baseline HCV RNA levels at week 4 of the treatment. There were no deaths, while two patients were hospitalized due to side effects. CONCLUSION: The triple therapy with BOC+pIFN+RBV in this cohort of real-life treatment-experienced CHC G1 patients and advanced liver disease was safe offering cure in the majority of those who could tolerate and complete treatment under a close monitoring. PMID- 26423715 TI - Free Triiodothyronine Concentrations are Inversely Associated with Elevated Carotid Intima-Media Thickness in Middle-Aged and Elderly Chinese Population. AB - AIM: Increased carotid artery intima media thickness (C-IMT) is an early feature of atherosclerosis. It has been reported to be altered in patients with thyroid dysfunction, and the evidence is still controversial. The present study aimed to explore the relationship between C-IMT and possible variations in thyroid function in Chinese adults aged 40 years and above. METHODS: A community-based cross-sectional study was conducted among 2276 non-diabetic participants. Serum free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) were determined by chemiluminescent microparticle immunoassay. RESULTS: The prevalence of elevated C-IMT decreased according to FT3 quartiles (29.8%, 24.3%, 24.2%, and 22.2%, P for trend=0.005). In both univariate and multivariate linear regression analyses, FT3 levels were inversely associated with C-IMT (both P values <= 0.002). Multivariate-adjusted logistic regression analysis showed that high FT3 levels were associated with low prevalent elevated C-IMT. The adjusted odds ratio for elevated C-IMT was 0.71 (95% confidence interval, 0.52-0.99, P=0.04) when comparing the highest with the lowest quartile of FT3. CONCLUSIONS: Serum FT3 levels were inversely associated with elevated C IMT in middle-aged and elderly Chinese adults without diabetes, independent of traditional risk factors for atherosclerosis. PMID- 26423716 TI - Cytochrome P450 Genetic Variants and Their Metabolite Levels Associated with Plaque Stability in Patients with Ischemic Stroke. AB - AIM: Cytochrome P450s (CYP450) enzymes regulate inflammation and atherosclerosis and can affect carotid plaque stability in patients with ischemic stroke (IS). This study aimed to investigate the association of CYP450 genetic variants with CYP plasma metabolite levels and plaque stability in patients with IS. METHODS: Eleven single nucleotide polymorphisms (SNPs) of CYP genes and their plasma metabolite [20-hydroxyeicosatetraenoic acid (HETE), total epoxyeicosatrienoic acids (EETs), and dihydroxyeicosatrienoic acids (DiHETEs)] levels were measured in 396 patients with IS who underwent high-resolution B-mode ultrasound carotid plaque detection and were stratified into the following groups: non-carotid plaque and carotid plaque groups. The carotid plaque was further classified into subgroups of echolucent plaque (ELP) and echogenic plaque (EGP). RESULTS: Among the 396 patients with IS, 294 cases (74%) had plaques. The frequency of rs17110453CC, rs751141 GG, and rs9333025 GG genotypes was significantly higher in patients with plaque than those without plaque. The CC, GG, GG, and GG genotypes of rs17110453, rs776746, rs751141, and rs9333025 polymorphisms were independently associated with ELP (OR, 2.62 [1.34-5.26]; OR, 1.89 [1.16-3.58]; OR, 3.12 [1.27 7.13]; and OR, 2.06 [1.34-6.33], respectively). These polymorphisms were also associated with CYP plasma metabolite levels. Patients with ELP have also shown significantly higher levels of 20-HETE and DiHETEs, but lower levels of EETs. CONCLUSIONS: Our data demonstrates that CYP450 SNPs are associated with plasma CYP450 metabolite levels and echolucent plaques, indicating that these SNPs may be potential markers for plaque instability. PMID- 26423717 TI - Waist Circumference is Better Than Other Anthropometric Indices for Predicting Cardiovascular Disease Risk Factors in Chinese Children--a Cross-Sectional Study in Guangzhou. AB - AIM: To determine the best anthropometric index among body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-stature ratio (WSR) and to derive optimal thresholds for predicting CVD risk factors in Chinese children. METHODS: A total of 2563 children aged 8-12 years were recruited in Guangzhou, China. Anthropometric indices were measured in all participants. Systolic and diastolic blood pressure (SBP and DBP, respectively), glucose, triglyceride (TG), total cholesterol, high-density lipoprotein cholesterol (HDLC) and low-density lipoprotein cholesterol (LDL-C) were measured in a subsample of 1609 children. RESULTS: In partial correlation analyses, the highest coefficients were found for WC in four risk factors in both genders. The receiver operating characteristic (ROC) analyses showed that WC was comparably consistent among the best in predicting BP and risk factor clustering, WC and WSR were the best in predicting HDL-C and TG in boys; WC, slightly better than BMI, was the best in distinguishing high BP and risk factor clustering in girls. In contrast, WHR was consistently the poorest index in both genders. Optimal age- and gender-specific thresholds to identify individual and clustering risk factors were provided; the thresholds for WC were 57.4-80.4 cm and 55.8-69.6 cm in boys and girls, respectively. CONCLUSIONS: WC was the comparatively consistent and best predictor of CVD risk factors compared with WSR and BMI, although the differences were small and depended on the type of risk factor and gender, and WHR was consistently the poorest predictor in Chinese children. PMID- 26423718 TI - CDH13 Polymorphisms are Associated with Adiponectin Levels and Metabolic Syndrome Traits Independently of Visceral Fat Mass. AB - AIM: Visceral fat accumulation contributes to the development of metabolic syndrome. As visceral fat accumulation increases, adiponectin levels decrease; therefore, adiponectin provides a link between visceral fat accumulation and metabolic disorders. Genome-wide association studies (GWASs) have identified genetic variations in the cadherin 13 (CDH13) gene that are associated with adiponectin levels. METHODS: We investigated whether single nucleotide polymorphisms (SNPs) in CDH13 was associated with adiponectin levels and metabolic syndrome traits independent of the visceral fat area (VFA), as measured using computed tomography (CT) in 945 Japanese individuals. RESULTS: We found that three CDH13 SNPs reported by recent GWASs (i.e., rs3865188, rs4783244, and rs12051272) were significantly associated with higher adiponectin levels (P < 1 * 10 (-14)), even after adjustment for VFA. However, these adiponectin-inducing alleles of CDH13 SNPs were significantly associated with traits consistent with deteriorating metabolic symptoms, such as higher fasting insulin, homeostasis model assessment-insulin resistance (HOMA-IR) scores, and triglycerides and lower high-density lipoprotein (HDL)-cholesterol levels, similar to increasing VFA and decreasing adiponectin levels. CONCLUSION: These results suggested that CDH13 SNPs cause an adiponectin-resistant status to compensate for increasing adiponectin levels and could result in the deterioration of metabolic syndrome traits. PMID- 26423720 TI - Exciting opportunities to publish your analytical research: Analytical Chemistry, ACS Sensors, and the Journal of Proteome Research. PMID- 26423719 TI - Pteridine-2,4-diamine derivatives as radical scavengers and inhibitors of lipoxygenase that can possess anti-inflammatory properties. AB - BACKGROUND: Reactive oxygen species are associated with inflammation implicated in cancer, atherosclerosis and autoimmune diseases. The complex nature of inflammation and of oxidative stress suggests that dual-target agents may be effective in combating diseases involving reactive oxygen species. RESULTS: A novel series of N-substituted 2,4-diaminopteridines has been synthesized and evaluated as antioxidants in several assays. Many exhibited potent lipid antioxidant properties, and some are inhibitors of soybean lipoxygenase, IC50 values extending down to 100 nM for both targets. Several pteridine derivatives showed efficacy at 0.01 mmol/kg with little tissue damage in a rat model of colitis. 2-(4-methylpiperazin-1-yl)-N-(thiophen-2-ylmethyl)pteridin-4-amine (18f) at 0.01 mmol/kg exhibited potent anti-inflammatory activity (reduction by 41%). CONCLUSION: The 2,4-diaminopteridine core represents a new scaffold for lipoxygenase inhibition as well as sustaining anti-inflammatory properties. PMID- 26423721 TI - Cognitive and functional status predictors of delirium and delirium severity after coronary artery bypass graft surgery: an interim analysis of the Neuropsychiatric Outcomes After Heart Surgery study. AB - BACKGROUND: Cognitive and functional impairment increase risk for post-coronary artery bypass graft (CABG) surgery delirium (PCD), but how much impairment is necessary to increase PCD risk remains unclear. METHODS: The Neuropsychiatric Outcomes After Heart Surgery (NOAHS) study is a prospective, observational cohort study of participants undergoing elective CABG surgery. Pre-operative cognitive and functional status based on Clinical Dementia Rating (CDR) scale and neuropsychological battery are assessed. We defined mild cognitive impairment (MCI) based on either (1) CDR global score 0.5 (CDR-MCI) or (2) performance 1.5 SD below population means on any cognitive domain on neurocognitive battery (MCI NC). Delirium was assessed daily post-operative day 2 through discharge using the confusion assessment method (CAM) and delirium index (DI). We investigate whether MCI - either definition - predicts delirium or delirium severity. RESULTS: So far we have assessed 102 participants (mean age 65.1 +/- 9; male: 75%) for PCD. Twenty six participants (25%) have MCI-CDR; 38 (62% of those completing neurocognitive testing) met MCI-NC criteria. Fourteen participants (14%) developed PCD. After adjusting for age, sex, comorbidity, and education, MCI-CDR, MMSE, and Lawton IADL score predicted PCD on logistic regression (OR: 5.6, 0.6, and 1.5, respectively); MCI-NC did not (OR [95% CI]: 11.8 [0.9, 151.4]). Using similarly adjusted linear regression, MCI-CDR, MCI-NC, CDR sum of boxes, MMSE, and Lawton IADL score predicted delirium severity (adjusted R(2): 0.26, 0.13, 0.21, 0.18, and 0.32, respectively). CONCLUSIONS: MCI predicts post-operative delirium and delirium severity, but MCI definition alters these relationships. Cognitive and functional impairment independently predict post-operative delirium and delirium severity. PMID- 26423722 TI - DMAP: a connectivity map database to enable identification of novel drug repositioning candidates. AB - BACKGROUND: Drug repositioning is a cost-efficient and time-saving process to drug development compared to traditional techniques. A systematic method to drug repositioning is to identify candidate drug's gene expression profiles on target disease models and determine how similar these profiles are to approved drugs. Databases such as the CMAP have been developed recently to help with systematic drug repositioning. METHODS: To overcome the limitation of connectivity maps on data coverage, we constructed a comprehensive in silico drug-protein connectivity map called DMAP, which contains directed drug-to-protein effects and effect scores. The drug-to-protein effect scores are compiled from all database entries between the drug and protein have been previously observed and provide a confidence measure on the quality of such drug-to-protein effects. RESULTS: In DMAP, we have compiled the direct effects between 24,121 PubChem Compound ID (CID), which were mapped from 289,571 chemical entities recognized from public literature, and 5,196 reviewed Uniprot proteins. DMAP compiles a total of 438,004 chemical-to-protein effect relationships. Compared to CMAP, DMAP shows an increase of 221 folds in the number of chemicals and 1.92 fold in the number of ATC codes. Furthermore, by overlapping DMAP chemicals with the approved drugs with known indications from the TTD database and literature, we obtained 982 drugs and 622 diseases; meanwhile, we only obtained 394 drugs with known indication from CMAP. To validate the feasibility of applying new DMAP for systematic drug repositioning, we compared the performance of DMAP and the well known CMAP database on two popular computational techniques: drug-drug-similarity based method with leave-one-out validation and Kolmogorov-Smirnov scoring based method. In drug-drug-similarity-based method, the drug repositioning prediction using DMAP achieved an Area-Under-Curve (AUC) score of 0.82, compared with that using CMAP, AUC = 0.64. For Kolmogorov-Smirnov scoring based method, with DMAP, we were able to retrieve several drug indications which could not be retrieved using CMAP. DMAP data can be queried using the existing C2MAP server or downloaded freely at: http://bio.informatics.iupui.edu/cmaps CONCLUSIONS: Reliable measurements of how drug affect disease-related proteins are critical to ongoing drug development in the genome medicine era. We demonstrated that DMAP can help drug development professionals assess drug-to-protein relationship data and improve chances of success for systematic drug repositioning efforts. PMID- 26423723 TI - SiR-Hoechst is a far-red DNA stain for live-cell nanoscopy. AB - Cell-permeable DNA stains are popular markers in live-cell imaging. Currently used DNA stains for live-cell imaging are either toxic, require illumination with blue light or are not compatible with super-resolution microscopy, thereby limiting their utility. Here we describe a far-red DNA stain, SiR-Hoechst, which displays minimal toxicity, is applicable in different cell types and tissues, and is compatible with super-resolution microscopy. The combination of these properties makes this probe a powerful tool for live-cell imaging. PMID- 26423725 TI - Clinical Trials With Mesenchymal Stem Cells: An Update. AB - In the last year, the promising features of mesenchymal stem cells (MSCs), including their regenerative properties and ability to differentiate into diverse cell lineages, have generated great interest among researchers whose work has offered intriguing perspectives on cell-based therapies for various diseases. Currently the most commonly used adult stem cells in regenerative medicine, MSCs, can be isolated from several tissues, exhibit a strong capacity for replication in vitro, and can differentiate into osteoblasts, chondrocytes, and adipocytes. However, heterogeneous procedures for isolating and cultivating MSCs among laboratories have prompted the International Society for Cellular Therapy (ISCT) to issue criteria for identifying unique populations of these cells. Consequently, the isolation of MSCs according to ISCT criteria has produced heterogeneous, nonclonal cultures of stromal cells containing stem cells with different multipotent properties, committed progenitors, and differentiated cells. Though the nature and functions of MSCs remain unclear, nonclonal stromal cultures obtained from bone marrow and other tissues currently serve as sources of putative MSCs for therapeutic purposes, and several findings underscore their effectiveness in treating different diseases. To date, 493 MSC-based clinical trials, either complete or ongoing, appear in the database of the US National Institutes of Health. In the present article, we provide a comprehensive review of MSC-based clinical trials conducted worldwide that scrutinizes biological properties of MSCs, elucidates recent clinical findings and clinical trial phases of investigation, highlights therapeutic effects of MSCs, and identifies principal criticisms of the use of these cells. In particular, we analyze clinical trials using MSCs for representative diseases, including hematological disease, graft-versus-host disease, organ transplantation, diabetes, inflammatory diseases, and diseases in the liver, kidney, and lung, as well as cardiovascular, bone and cartilage, neurological, and autoimmune diseases. PMID- 26423724 TI - Pre-amyloid oligomers of the proteotoxic RepA-WH1 prionoid assemble at the bacterial nucleoid. AB - Upon binding to short specific dsDNA sequences in vitro, the N-terminal WH1 domain of the plasmid DNA replication initiator RepA assembles as amyloid fibres. These are bundles of single or double twisted tubular filaments in which distorted RepA-WH1 monomers are the building blocks. When expressed in Escherichia coli, RepA-WH1 triggers the first synthetic amyloid proteinopathy in bacteria, recapitulating some of the features of mammalian prion diseases: it is vertically transmissible, albeit non-infectious, showing up in at least two phenotypically distinct and interconvertible strains. Here we report B3h7, a monoclonal antibody specific for oligomers of RepA-WH1, but which does not recognize the mature amyloid fibres. Unlike a control polyclonal antibody generated against the soluble protein, B3h7 interferes in vitro with DNA-promoted or amyloid-seeded assembly of RepA-WH1 fibres, thus the targeted oligomers are on pathway amyloidogenic intermediates. Immuno-electron microscopy with B3h7 on thin sections of E. coli cells expressing RepA-WH1 consistently labels the bacterial nucleoid, but not the large cytoplasmic aggregates of the protein. This observation points to the nucleoid as the place where oligomeric amyloid precursors of RepA-WH1 are generated, and suggests that, once nucleated by DNA, further growth must continue in the cytoplasm due to entropic exclusion. PMID- 26423726 TI - Mass loss and chemical structures of wheat and maize straws in response to ultraviolet-B radiation and soil contact. AB - The role of photodegradation, an abiotic process, has been largely overlooked during straw decomposition in mesic ecosystems. We investigated the mass loss and chemical structures of straw decomposition in response to elevated UV-B radiation with or without soil contact over a 12-month litterbag experiment. Wheat and maize straw samples with and without soil contact were exposed to three radiation levels: a no-sunlight control, ambient solar UV-B, and artificially elevated UV-B radiation. A block control with soil contact was not included. Compared with the no-sunlight control, UV-B radiation increased the mass loss by 14-19% and the ambient radiation by 9-16% for wheat and maize straws without soil contact after 12 months. Elevated UV-B exposure decreased the decomposition rates of both wheat and maize straws when in contact with soil. Light exposure resulted in decreased O-alkyl carbons and increased alkyl carbons for both the wheat and maize straws compared with no-sunlight control. The difference in soil contact may influence the contribution of photodegradation to the overall straw decomposition process. These results indicate that we must take into account the effects of photodegradation when explaining the mechanisms of straw decomposition in mesic ecosystems. PMID- 26423727 TI - Experimental Validation of Bacillus anthracis A16R Proteogenomics. AB - Anthrax, caused by the pathogenic bacterium Bacillus anthracis, is a zoonosis that causes serious disease and is of significant concern as a biological warfare agent. Validating annotated genes and reannotating misannotated genes are important to understand its biology and mechanisms of pathogenicity. Proteomics studies are, to date, the best method for verifying and improving current annotations. To this end, the proteome of B. anthracis A16R was analyzed via one dimensional gel electrophoresis followed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). In total, we identified 3,712 proteins, including many regulatory and key functional proteins at relatively low abundance, representing the most complete proteome of B. anthracis to date. Interestingly, eight sequencing errors were detected by proteogenomic analysis and corrected by resequencing. More importantly, three unannotated peptide fragments were identified in this study and validated by synthetic peptide mass spectrum mapping and green fluorescent protein fusion experiments. These data not only give a more comprehensive understanding of B. anthracis A16R but also demonstrate the power of proteomics to improve genome annotations and determine true translational elements. PMID- 26423728 TI - Development of a Bayesian response-adaptive trial design for the Dexamethasone for Excessive Menstruation study. AB - It is often unclear what specific adaptive trial design features lead to an efficient design which is also feasible to implement. This article describes the preparatory simulation study for a Bayesian response-adaptive dose-finding trial design. Dexamethasone for Excessive Menstruation aims to assess the efficacy of Dexamethasone in reducing excessive menstrual bleeding and to determine the best dose for further study. To maximise learning about the dose response, patients receive placebo or an active dose with randomisation probabilities adapting based on evidence from patients already recruited. The dose-response relationship is estimated using a flexible Bayesian Normal Dynamic Linear Model. Several competing design options were considered including: number of doses, proportion assigned to placebo, adaptation criterion, and number and timing of adaptations. We performed a fractional factorial study using SAS software to simulate virtual trial data for candidate adaptive designs under a variety of scenarios and to invoke WinBUGS for Bayesian model estimation. We analysed the simulated trial results using Normal linear models to estimate the effects of each design feature on empirical type I error and statistical power. Our readily-implemented approach using widely available statistical software identified a final design which performed robustly across a range of potential trial scenarios. PMID- 26423729 TI - Choriocarcinoma-associated pulmonary thromboembolism and pulmonary hypertension: a case report. AB - Cases of pulmonary embolism and pulmonary artery hypertension caused by choriocarcinoma represent a rare clinical emergency. We report a case of a 25 year-old woman who presented with pulmonary embolism and hypertension and died soon after complete pulmonary embolectomy. A related literature review revealed that almost all of these patients had previously experienced a spontaneous abortion (average, 6 months) and were not pregnant. PMID- 26423730 TI - Circulating thrombospondine-2 in patients with moderate-to-severe chronic heart failure due to coronary artery disease. AB - Chronic heart failure (CHF) remains a leading cause of morbidity and mortality. In the current study, we aimed to evaluate the predictive value of circulating thrombospondin-2 (TSP-2) for cumulative survival in patients with ischemic CHF due to coronary artery disease (CAD). The results showed that during a median follow-up of 2.18 years, 21 participants died and 106 subjects were hospitalized repeatedly. The median circulating levels of TSP-2 in patients who survived and those who died were 0.63 ng/mL (95%CI=0.55-0.64 ng/mL) and 1.03 ng/mL (95% CI=0.97-1.07 ng/mL) (P<0.001). Circulating TSP-2 independently predicted all cause mortality (OR=1.27; 95%CI=1.08-1.59; P=0.002), CHF-related death (OR=1.16; 95%CI=1.02-1.50; P<0.001), and also CHF-related rehospitalization (OR=1.12; 95%CI=1.07-1.25; P<0.001). In conclusion, among CAD patients with symptomatic CHF, increased circulating TSP-2 is correlated with increased 3-year CHF-related death, all-cause mortality, and risk for recurrent hospitalization. PMID- 26423731 TI - Molecular docking simulation analysis of the interaction of dietary flavonols with heat shock protein 90. AB - Hsp90 is a major protein involved in the stabilization of various proteins in cancer cells. The present investigation focused on the molecular docking simulation studies of flavanols as inhibitors of Hsp90 at the high affinity adenosine triphosphate (ATP) binding site and analyzed absorption, distribution, metabolism, excretion and toxicity (ADME-toxicity). The molecular docking analysis revealed that the flavanols showed competitive inhibition with ATP molecule at the active site and enhanced pharmacological parameters. PMID- 26423732 TI - A Single Meal Containing Raw, Crushed Garlic Influences Expression of Immunity- and Cancer-Related Genes in Whole Blood of Humans. AB - BACKGROUND: Preclinical and epidemiologic studies suggest that garlic intake is inversely associated with the progression of cancer and cardiovascular disease. OBJECTIVE: We designed a study to probe the mechanisms of garlic action in humans. METHODS: We conducted a randomized crossover feeding trial in which 17 volunteers consumed a garlic-containing meal (100 g white bread, 15 g butter, and 5 g raw, crushed garlic) or a garlic-free control meal (100 g white bread and 15 g butter) after 10 d of consuming a controlled, garlic-free diet. Blood was collected before and 3 h after test meal consumption for gene expression analysis in whole blood. Illumina BeadArray was used to screen for genes of interest, followed by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) on selected genes. To augment human study findings, Mono Mac 6 cells were treated with a purified garlic extract (0.5 MUL/mL), and mRNA was measured by qRT-PCR at 0, 3, 6, and 24 h. RESULTS: The following 7 genes were found to be upregulated by garlic intake: aryl hydrocarbon receptor (AHR), aryl hydrocarbon receptor nuclear translocator (ARNT), hypoxia-inducible factor 1alpha (HIF1A), proto-oncogene c-Jun (JUN), nuclear factor of activated T cells (NFAT) activating protein with immunoreceptor tyrosine-based activation motif 1 (NFAM1), oncostatin M (OSM), and V-rel avian reticuloendotheliosis viral oncogene homolog (REL). Fold-increases in mRNA transcripts ranged from 1.6 (HIF1A) to 3.0 (NFAM1) (P < 0.05). The mRNA levels of 5 of the 7 genes that were upregulated in the human trial were also upregulated in cell culture at 3 and 6 h: AHR, HIF1A, JUN, OSM, and REL. Fold-increases in mRNA transcripts in cell culture ranged from 1.7 (HIF1A) to 12.1 (JUN) (P < 0.01). OSM protein was measured by ELISA and was significantly higher than the control at 3, 6, and 24 h (24 h: 19.5 +/- 1.4 and 74.8 +/- 1.4 pg/mL for control and garlic, respectively). OSM is a pleiotropic cytokine that inhibits several tumor cell lines in culture. CONCLUSION: These data indicate that the bioactivity of garlic is multifaceted and includes activation of genes related to immunity, apoptosis, and xenobiotic metabolism in humans and Mono Mac 6 cells. This trial is registered at clinicaltrials.gov as NCT01293591. PMID- 26423733 TI - Metabolically Healthy Obesity Is Not Associated with Food Intake in White or Black Men. AB - BACKGROUND: Healthy obese individuals may be protected against adverse health outcomes. Diet and race might influence healthy obesity, but data on their roles and interactions on the phenotype are limited. OBJECTIVE: We compared the food intake of metabolically healthy obese men to those of other weight status metabolic health phenotypes. METHODS: Men (n = 4855) aged >= 45 y with BMI >= 18.5 kg/m(2) and free of cardiovascular diseases, diabetes, and cancer were evaluated in a cross-sectional study of the REGARDS (REasons for Geographic And Racial Differences in Stroke) study cohort. Food intake was assessed with the use of a food frequency questionnaire. Weight status-metabolic health phenotypes were defined by using metabolic syndrome (MetS) and homeostasis model assessment of insulin resistance (HOMA-IR) criteria. Mean differences in food intake among weight status-metabolic health phenotypes were compared with the use of linear regression. RESULTS: MetS-defined healthy obesity was present in 44% of white obese men and 58% of black obese men; the healthy obese phenotype, based on HOMA IR, was equally prevalent in both white (20%) and black (21%) obese men. Among white men, MetS-defined healthy and unhealthy obesity were associated with lower wholegrain bread intake and higher consumption of red meat (P < 0.001), whereas HOMA-IR-defined healthy and unhealthy obesity were associated with lower red meat intake (P < 0.0001) compared with healthy normal weight in multivariable-adjusted analyses that adjusted for sociodemographic, lifestyle, and clinical confounders. However, results were attenuated and became nonsignificant after further adjustment for BMI. Healthy and unhealthy overweight, defined by both criteria, were associated with lower whole grain bread intake (P < 0.001) in all models. Among black men, weight status-metabolic health phenotypes were not associated with food intake in all models. CONCLUSION: Healthy obesity in men is not associated with a healthier diet. Future studies need to consider dietary patterns, which may better inform the holistic effect of diet on healthy obesity, in prospective analyses. PMID- 26423734 TI - Higher Intakes of Fruits and Vegetables, beta-Carotene, Vitamin C, alpha Tocopherol, EPA, and DHA Are Positively Associated with Periodontal Healing after Nonsurgical Periodontal Therapy in Nonsmokers but Not in Smokers. AB - BACKGROUND: Periodontitis is a chronic inflammatory disease and a significant risk factor for tooth loss. Although a link between diet and periodontal health exists, the relation between diet and healing after periodontal therapy has yet to be investigated. OBJECTIVE: The objective was to determine whether higher intakes of fruits and vegetables or nutrients with antioxidant or anti inflammatory activity are associated with greater healing, measured as reduced probing depth (PD), after scaling and root planing (SRP), a cost-effective treatment to manage periodontal disease and prevent tooth loss. METHODS: Patients (63 nonsmokers, 23 smokers) with chronic generalized periodontitis who were undergoing SRP participated. Healing was evaluated based on PD, assessed at baseline and 8-16 wk after SRP. Intakes of fruits, vegetables, beta-carotene, vitamin C, alpha-tocopherol, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) were estimated using the Block 2005 food frequency questionnaire and a supplement questionnaire. Serum 25-hydroxyvitamin D concentrations were also measured. PD (% sites >3 mm) was modeled in multiple linear regression and analysis of covariance by tertile of intake and adjusted for age, sex, body mass index (BMI), baseline PD, examiner, gingival bleeding, and study duration. RESULTS: In nonsmokers, PD was associated with fruit and vegetable, beta-carotene, vitamin C, alpha-tocopherol, EPA, and DHA intakes (P < 0.05). PD was not significantly associated with ALA intake or serum 25 hydroxyvitamin D concentration. Significant associations that included supplements (beta-carotene, vitamin C, alpha-tocopherol) were attenuated or lost, depending on the statistical model used. There were no significant associations within the group of smokers. CONCLUSIONS: Dietary intakes of fruits and vegetables, beta-carotene, vitamin C, alpha-tocopherol, EPA, and DHA are associated with reduced PD after SRP in nonsmokers, but not smokers, with chronic generalized periodontitis. These findings may lead to the development of dietary strategies to optimize healing after periodontal procedures. This trial was registered at clinicaltrials.gov as NCT02291835. PMID- 26423735 TI - Protein-Energy Malnutrition Causes Deficits in Motor Function in Adult Male Rats. AB - BACKGROUND: Adult protein-energy malnutrition (PEM) often occurs in combination with neurological disorders affecting hand use and walking ability. The independent effects of PEM on motor function are not well characterized and may be obscured by these comorbidities. OBJECTIVE: Our goal was to undertake a comprehensive evaluation of sensorimotor function with the onset and progression of PEM in an adult male rat model. METHODS: In Expt. 1 and Expt. 2, male Sprague Dawley rats (14-15 wk old) were assigned ad libitum access for 4 wk to normal protein (NP) or low-protein (LP) diets containing 12.5% and 0.5% protein, respectively. Expt. 1 assessed muscle strength, balance, and skilled walking ability on days 2, 8, and 27 by bar-holding, cylinder, and horizontal ladder walking tasks, respectively. In addition to food intake and body weight, nutritional status was determined on days 3, 9, and 28 by serum acute-phase reactant and corticosterone concentrations and liver lipids. Expt. 2 addressed the effect of an LP diet on hindlimb muscle size. RESULTS: PEM evolved over time in rats consuming the LP diet. Total food intake decreased by 24% compared with the NP group. On day 28, body weight and serum albumin decreased by 31% and 26%, respectively, and serum alpha2-macroglobulin increased by 445% (P < 0.05) in the LP group compared with the NP group. Forelimb dysfunction (173% increase in adaptive flexed-arm-hang score) developed on day 2 in rats fed the LP diet (P < 0.001), whereas abnormal walking (34% decreased incidence of correct hindlimb placement) developed by day 27 (P < 0.05). Relative to the NP diet, the LP diet reduced the cross-sectional area of gastrocnemius medialis (P < 0.05). CONCLUSIONS: PEM in adult male rats causes a variety of sensorimotor abnormalities that develop at different stages of malnutrition. This model can be used in combination with disease models of sensorimotor deficits to examine the interactions between nutritional status, other treatments, and disease progression. PMID- 26423737 TI - Severe and Moderate Acute Malnutrition Can Be Successfully Managed with an Integrated Protocol in Sierra Leone. AB - BACKGROUND: Global acute malnutrition (GAM) is the sum of moderate acute malnutrition (MAM) and severe acute malnutrition (SAM). The use of different foods and protocols for MAM and SAM treatment can be cumbersome in emergency settings. OBJECTIVE: Our objective was to determine the recovery and coverage rates for GAM of an integrated protocol with a single food product, ready-to-use therapeutic food (RUTF), compared with standard management. METHODS: This was a cluster-randomized controlled trial in Sierra Leone conducted in 10 centers treating GAM in children aged 6-59 mo. The integrated protocol used midupper arm circumference (MUAC) as the criterion for admission and discharge, with a MUAC <12.5 cm defining malnutrition. The protocol included a decreasing ration of RUTF and health maintenance messages delivered by peers. Standard therapy treated MAM with a fortified blended flour and SAM with RUTF and used weight-for-height to determine admission to the treatment program. Coverage rates were the number of children who received treatment/number of children in the community eligible for treatment. RESULTS: Most of the children receiving integrated management had MAM (774 of 1100; 70%), whereas among those receiving standard management, SAM predominated (537 of 857; 63%; P = 0.0001). Coverage was 71% in the communities served by integrated management and 55% in the communities served by standard care (P = 0.0005). GAM recovery in the integrated management protocol was 910 of 1100 (83%) children and was 682 of 857 (79%) children in the standard therapy protocol. CONCLUSION: Integrated management of GAM in children is an acceptable alternative to standard management and provides greater community coverage. This trial was registered at clinicaltrials.gov as NCT01785680. PMID- 26423736 TI - Maternal Obesity and Excessive Gestational Weight Gain Are Associated with Components of Child Cognition. AB - BACKGROUND: Maternal overweight and obesity affect two-thirds of women of childbearing age and may increase the risk of impaired child cognition. OBJECTIVE: Our objective was to test the hypothesis that high/low gestational weight gain (GWG) and high/low prepregnancy BMI were associated with offspring intelligence quotient (IQ) and executive function at age 10. METHODS: Mother infant dyads (n = 763) enrolled in a birth cohort study were followed from early pregnancy to 10 y postpartum. IQ was assessed by trained examiners with the use of the Stanford Binet Intelligence Scale-4th edition. Executive function was assessed by the number of perseverative errors on the Wisconsin Card Sorting Test and time to complete Part B on the Trail Making Test. Self-reported total GWG was converted to gestational-age-standardized GWG z score. Multivariable linear regression and negative binomial regression were used to estimate independent and joint effects of GWG and BMI on outcomes while adjusting for covariates. RESULTS: At enrollment, the majority of women in the Maternal Health Practices and Child Development cohort were unmarried and unemployed, and more than one-half reported their race as black. The mean +/- SD GWG z score was -0.5 +/- 1.8, and 27% of women had a pregravid BMI >= 25. The median (IQR) number of perseverative errors was 23 (17, 29), the mean +/- SD time on Part B was 103 +/- 42.6 s, and 44% of children had a low average IQ (<= 89). Maternal obesity was associated with 3.2 lower IQ points (95% CI: -5.6, -0.8) and a slower time to complete the executive function scale Part B (adjusted beta: 12.7 s; 95% CI: 2.8, 23 s) compared with offspring of normal-weight mothers. Offspring of mothers whose GWG was >+1 SD, compared with -1 to +1 SD, performed 15 s slower on the executive function task (95% CI: 1.8, 28 s). There was no association between GWG z score and offspring composite IQ score (adjusted beta: -0.32; 95% CI: -0.72, 0.10). Prepregnancy BMI did not modify these associations. CONCLUSIONS: Although GWG may be important for executive function, maternal BMI has a stronger relation than GWG to both offspring intelligence and executive function. Our findings contribute to evidence linking maternal obesity to long-term child outcomes. PMID- 26423739 TI - Young Children's Food Neophobia Characteristics and Sensory Behaviors Are Related to Their Food Intake. AB - BACKGROUND: Food neophobia in children has been associated with poor dietary variety and nutrient intakes. Underlying characteristics that may predispose a child to neophobia have not been widely studied. OBJECTIVE: We investigated the associations between children's food neophobia, sensory sensitivity, and dietary intake in a diverse sample of typically developing preschoolers. METHODS: Caregiver reports of children's food neophobia and sensory behaviors (SBs) as measured by the Food Neophobia Scale and the Sensory Profile, children's observed weight outcome [body mass index z score (BMIz)], and children's food intake as estimated from the Block Kids Food Screener were collected at baseline in the Colorado LEAP (Longitudinal Eating and Physical Activity Study) study of childhood obesity. Preschool-aged children (n = 249; 136 girls, 113 boys; aged 55.6 +/- 4.7 mo; BMIz = 0.54 +/- 1.14) and caregivers [n = 180; 57 Hispanic, 119 non-Hispanic white (NHW), 4 unknown] participated. Data were analyzed by Pearson correlations and multivariate hierarchical linear regression analyses. RESULTS: Lower scores for children's oral sensory characteristics (i.e., more atypical) were related to higher neophobia ratings (r = -0.53, P < 0.001), and neophobia was negatively associated with reported vegetable intake (r = -0.31, P = 0.001) and dietary variety (r = -0.22, P < 0.001). Hispanic caregivers reported more atypical child SB scores (46.2 +/- 8.8) than did NHW caregivers (50.5 +/- 7.6; P = 0.006); however, no differences were noted for neophobia and SB scores by parent income and education or child sex. Neophobia was negatively associated with vegetable intake and dietary variety (P < 0.001 for both). SBs were associated with children's energy intake from sugar-sweetened beverages in bivariate analyses (r = -0.18, P < 0.05); however, in regression models, only ethnicity was significantly associated with energy from sugar-sweetened beverages (P < 0.001). Hispanic ethnicity was positively associated with sugar-sweetened beverage consumption (P < 0.001). CONCLUSIONS: Children's neophobia and sensory sensitivity may be important in understanding underlying issues related to limited food acceptance in typically developing young children and for helping caregivers facilitate healthy dietary intake patterns for their children. This trial was registered at clinicaltrials.gov as NCT01937481. PMID- 26423738 TI - Short Maternal Stature Increases Risk of Small-for-Gestational-Age and Preterm Births in Low- and Middle-Income Countries: Individual Participant Data Meta Analysis and Population Attributable Fraction. AB - BACKGROUND: Small-for-gestational-age (SGA) and preterm births are associated with adverse health consequences, including neonatal and infant mortality, childhood undernutrition, and adulthood chronic disease. OBJECTIVES: The specific aims of this study were to estimate the association between short maternal stature and outcomes of SGA alone, preterm birth alone, or both, and to calculate the population attributable fraction of SGA and preterm birth associated with short maternal stature. METHODS: We conducted an individual participant data meta analysis with the use of data sets from 12 population-based cohort studies and the WHO Global Survey on Maternal and Perinatal Health (13 of 24 available data sets used) from low- and middle-income countries (LMIC). We included those with weight taken within 72 h of birth, gestational age, and maternal height data (n = 177,000). For each of these studies, we individually calculated RRs between height exposure categories of < 145 cm, 145 to < 150 cm, and 150 to < 155 cm (reference: >= 155 cm) and outcomes of SGA, preterm birth, and their combination categories. SGA was defined with the use of both the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) birth weight standard and the 1991 US birth weight reference. The associations were then meta analyzed. RESULTS: All short stature categories were statistically significantly associated with term SGA, preterm appropriate-for-gestational-age (AGA), and preterm SGA births (reference: term AGA). When using the INTERGROWTH-21st standard to define SGA, women < 145 cm had the highest adjusted risk ratios (aRRs) (term SGA-aRR: 2.03; 95% CI: 1.76, 2.35; preterm AGA-aRR: 1.45; 95% CI: 1.26, 1.66; preterm SGA-aRR: 2.13; 95% CI: 1.42, 3.21). Similar associations were seen for SGA defined by the US reference. Annually, 5.5 million term SGA (18.6% of the global total), 550,800 preterm AGA (5.0% of the global total), and 458,000 preterm SGA (16.5% of the global total) births may be associated with maternal short stature. CONCLUSIONS: Approximately 6.5 million SGA and/or preterm births in LMIC may be associated with short maternal stature annually. A reduction in this burden requires primary prevention of SGA, improvement in postnatal growth through early childhood, and possibly further intervention in late childhood and adolescence. It is vital for researchers to broaden the evidence base for addressing chronic malnutrition through multiple life stages, and for program implementers to explore effective, sustainable ways of reaching the most vulnerable populations. PMID- 26423740 TI - Modeling Demonstrates That Folic Acid Fortification of Whole-Wheat Flour Could Reduce the Prevalence of Folate Inadequacy in Canadian Whole-Wheat Consumers. AB - BACKGROUND: Mandatory folic acid fortification of white-wheat flour and selected other grain products has reduced the prevalence of neural tube defects in Canada; however, the fortification of whole-wheat flour is not permitted. OBJECTIVE: The objective of this study was to model the impact of adding folic acid to whole wheat flour on the folate intake distribution of Canadians. METHODS: Twenty-four hour dietary recall and supplement intake data (n = 35,107) collected in the 2004 Canadian Community Health Survey 2.2 were used to calculate the prevalence of folate inadequacy (POFI) and the proportion of folic acid intakes above the Tolerable Upper Intake Level (UL). In model 1, folic acid was added to whole wheat flour-containing foods in amounts comparable to those that are mandatory for white-wheat flour-containing foods. In model 2, a 50% overage of folic acid fortification was considered. Models 3 and 4 included assessment of folate intake distributions in adult whole-wheat consumers with or without a fortification overage. SIDE (Software for Intake Distribution Estimation; Department of Statistics and Center for Agricultural and Rural Development, Iowa State University) was used to estimate usual folate intakes. RESULTS: Mean folate intakes increased by ~ 5% in all sex and age groups when whole-wheat foods were fortified (models 1 and 2; P < 0.0001). Folic acid fortification of whole-wheat flour-containing foods did not change the POFI or percentage of intakes above the UL in the general population, whether in supplement users or nonusers. Among whole-wheat consumers, the POFI was reduced by 10 percentage points after fortification of whole-wheat flour-containing foods (95% CIs did not overlap). The percentage of whole-wheat consumers with intakes above the UL did not change. CONCLUSION: Although folic acid fortification of whole-wheat flour-containing foods is unlikely to change the POFI or proportion of folic acid intakes above the UL in the general Canadian population, this fortification strategy may reduce the POFI in adult whole-wheat consumers. PMID- 26423741 TI - Urinary Phytoestrogens Are Associated with Subtle Indicators of Semen Quality among Male Partners of Couples Desiring Pregnancy. AB - BACKGROUND: Phytoestrogens have been associated with subtle hormonal changes, although effects on male fecundity are largely unknown. OBJECTIVE: We evaluated associations between male urinary phytoestrogen (isoflavone and lignan) concentrations and semen quality. METHODS: This study was a prospective cohort study of 501 male partners of couples desiring pregnancy and discontinuing contraception. Each participant provided up to 2 semen samples that were analyzed for 35 semen quality endpoints the following day. Linear mixed-effects models were used to estimate associations between baseline urinary phytoestrogen concentrations and semen quality parameters, adjusted for age, body mass index (BMI), research site, and serum lipid and cotinine concentrations. RESULTS: Most associations between urinary phytoestrogens and semen quality parameters were null. However, select individual phytoestrogens were associated with semen quality parameters, with associations dependent on the class of phytoestrogens and modified by BMI. Specifically, genistein and daidzein were associated with a lower percentage of normal sperm and increased abnormalities in semen morphology, with reduced associations observed as BMI increased (P < 0.05) [percentages (95% CIs) of normal morphology by WHO traditional criteria: genistein, main effect: 5.61% (-9.42%, -1.79%); interaction: 0.19% (0.06%, 0.31%) per log unit increase; daidzein, main effect: -5.35% (-9.36%, -1.34%); interaction: 0.18% (0.05%, 0.32%) per log unit increase]. Enterolactone was associated with fewer abnormalities in semen morphometry and morphology and decreased DNA fragmentation, with reduced associations observed as BMI increased (P < 0.05) [percentages (95% CIs) of abnormalities in the neck and midpiece: enterolactone, main effect: -3.35% ( 6.51%, -0.19%); interaction: 0.11% (0.01%, 0.21%) per log unit increase]. CONCLUSIONS: These results suggest that male urinary phytoestrogen concentrations characteristic of the US population may be associated with subtle indicators of male fecundity and semen quality but were not associated with couple fecundity. PMID- 26423742 TI - Preventive Effects of Long-Term Supplementation with 2 Nutritious Food Supplements in Young Children in Niger. AB - BACKGROUND: In nutritional crises, large-scale preventive distributions of specialized nutritious foods are recommended to prevent acute and chronic malnutrition in young children. Among the available specialized nutritious foods, the World Food Programme and UNICEF recommend lipid-based nutrient supplements (LNSs) and Super Cereal Plus (SC+). Although the effectiveness of short-term distributions for prevention of severe acute malnutrition (SAM) is well documented, evidence for long-term strategies and the role of distribution of specialized nutritious foods for prevention of stunting is weaker. OBJECTIVE: The objective of this study was to compare long-term supplementation of LNSs and SC+ on the incidence of acute malnutrition and stunting in young children. METHODS: We conducted two 15-mo-long supplementation interventions with the use of LNSs (500 kcal/d) and SC+ (810 kcal/d) and half rations during 5 mo of the nonlean season, for the prevention of acute malnutrition and stunting in children aged 6 23 mo. The study was designed as a prospective cohort in 11 villages in Madarounfa, Niger. We compared the incidence of acute malnutrition and stunting with the use of Cox proportional hazards models and report on sharing and use of these food supplements. RESULTS: Characteristics of children at baseline were similar across groups. A total of 1967 children were included in the analysis (845 in the SC+ group and 1122 in the LNS group). No significant differences in the incidence of moderate acute malnutrition (SC+ compared with LNS: adjusted HR: 0.79; 95% CI: 0.61, 1.02) or SAM (HR: 0.84; 95% CI: 0.52, 1.34) were found. No difference in the incidence of stunting (HR: 1.08; 95% CI: 0.95, 1.24) or severe stunting (HR: 0.94; 95% CI: 0.71, 1.22) over the follow-up period were found. CONCLUSIONS: These findings in young children in Niger suggest that both products should be considered when planning preventive distributions and choice of long term supplementation should be guided by context-specific factors such as acceptability, cost, and operational feasibility, among others. Additional research is essential to improving child health. The study was registered at clinicaltrials.gov as NCT01828814. PMID- 26423743 TI - Appropriate initial antibiotic therapy in hospitalized patients with gram negative infections: systematic review and meta-analysis. AB - BACKGROUND: The rapid global spread of multi-resistant bacteria and loss of antibiotic effectiveness increases the risk of initial inappropriate antibiotic therapy (IAT) and poses a serious threat to patient safety. We conducted a systematic review and meta-analysis of published studies to summarize the effect of appropriate antibiotic therapy (AAT) or IAT against gram-negative bacterial infections in the hospital setting. METHODS: MEDLINE, EMBASE, and Cochrane CENTRAL databases were searched until May 2014 to identify English-language studies examining use of AAT or IAT in hospitalized patients with Gram-negative pathogens. Outcomes of interest included mortality, clinical cure, cost, and length of stay. Citations and eligible full-text articles were screened in duplicate. Random effect models meta-analysis was used. RESULTS: Fifty-seven studies in 60 publications were eligible. AAT was associated with lower risk of mortality (unadjusted summary odds ratio [OR] 0.38, 95 % confidence interval [CI] 0.30-0.47, 39 studies, 5809 patients) and treatment failure (OR 0.22, 95 % CI 0.14-0.35; 3 studies, 283 patients). Conversely, IAT increased risk of mortality (unadjusted summary OR 2.66, 95 % CI 2.12-3.35; 39 studies, 5809 patients). In meta-analyses of adjusted data, AAT was associated with lower risk of mortality (adjusted summary OR 0.43, 95 % CI 0.23-0.83; 6 studies, 1409 patients). Conversely, IAT increased risk of mortality (adjusted summary OR 3.30, 95 % CI 2.42-4.49; 16 studies, 2493 patients). A limited number of studies suggested higher cost and longer hospital stay with IAT. There was considerable heterogeneity in the definition of AAT or IAT, pathogens studied, and outcomes assessed. DISCUSSION: Using a large set of studies we found that IAT is associated with a number of serious consequences,including an increased risk of hospital mortality. Infections caused by drug-resistant, Gram-negative organisms represent a considerable financial burden to healthcare systems due to the increased costs associated with the resources required to manage the infection, particularly longer hospital stays. However, there were insufficient data that evaluated AAT for the outcome of costs among patients with nosocomialGram negative infections. CONCLUSIONS: IAT in hospitalized patients with Gram-negative infections is associated with adverse outcomes. Technological advances for rapid diagnostics to facilitate AAT along with antimicrobial stewardship, surveillance, infection control, and prevention is needed. PMID- 26423745 TI - The Diagnostic and Therapeutic Impact of Point-of-Care Ultrasonography in the Intensive Care Unit. AB - PURPOSE: In light of point-of-care ultrasonography's (POCUS) recent rise in popularity, assessment of its impact on diagnosis and treatment in the intensive care unit (ICU) is of key importance. METHODS: Ultrasound examinations were collected through an ultrasound reporting software in 6 multidisciplinary ICU units from 3 university hospitals in Canada and the United States. This database included a self-reporting questionnaire to assess the impact of the ultrasound findings on diagnosis and treatment. We retrieved the results of these questionnaires and analyzed them in relation to which organs were assessed during the ultrasound examination. RESULTS: One thousand two hundred and fifteen ultrasound studies were performed on 968 patients. Intensivists considered the image quality of cardiac ultrasound to be adequate in 94.7% compared to 99.7% for general ultrasound ( P < .001). The median duration of a cardiac examination was 10 (interquartile range [IQR] 10) minutes compared to 5 (IQR 8) minutes for a general examination ( P < .001). Overall, ultrasound findings led to a change in diagnosis in 302 studies (24.9%) and to a change in management in 534 studies (44.0%). A change in diagnosis or management was reported more frequently for cardiac ultrasound than for general ultrasound (108 [37.1%] vs 127 [16.5%], P < .001) and (170 [58.4%] vs 270 [35.1%], P < .001). Assessment of the inferior vena cava for fluid status emerged as the critical care ultrasound application associated with the greatest impact on management. CONCLUSION: Point-of-care ultrasonography has the potential to optimize care of the critically ill patients when added to the clinical armamentarium of the intensive care physician. PMID- 26423744 TI - Trends in hospital and intensive care admissions in the Netherlands attributable to the very elderly in an ageing population. AB - INTRODUCTION: The Dutch population is ageing and it is unknown how this is affecting trends in the percentage of hospital and intensive care unit (ICU) admissions attributable to patients aged 80 years or older, the very elderly. METHODS: We present data on the percentage of the very elderly in the general population and the percentage of hospital admissions attributable to the very elderly. We subsequently performed a longitudinal cross-sectional study on ICU admissions from hospitals participating in the National Intensive Care Evaluation registry for the period 2005 to 2014. We modeled the percentage of adult ICU admissions and treatment days attributable to the very elderly separately for ICU admissions following cardiac surgery and other reasons. RESULTS: The percentage of Dutch adults aged 80 years and older, increased from 4.5 % in 2005 to 5.4 % in 2014 (p-value < 0.0001) and with this ageing of the population, the percentage of hospital admissions attributable to very elderly increased from 9.0 % in 2005 to 10.6 % in 2014 (p-value < 0.0001). The percentage of ICU admissions following cardiac surgery attributable to the very elderly increased from 6.7 % in 2005 to 11.0 % in 2014 in nine hospitals (p-value < 0.0001), while the percentage of treatment days attributable to this group rose from 8.6 % in 2005 to 11.7 % in 2014 (p-value = 0.0157). In contrast, the percentage of very elderly patients admitted to the ICU for other reasons than following cardiac surgery remained stable at 13.8 % between 2005 and 2014 in 33 hospitals (p-value = 0.1315). The number of treatment days attributable to the very elderly rose from 11,810 in 2005 to 15,234 in 2014 (p-value = 0.0002), but the percentage of ICU treatment days attributable to this group remained stable at 12.0 % (p-value = 0.1429). CONCLUSIONS: As in many European countries the Dutch population is ageing and the percentage of hospital admissions attributable to the very elderly rose between 2005 and 2014. However, the percentage of ICU admissions and treatment days attributable to very elderly remained stable. The percentage of ICU admissions following cardiac surgery attributable to this group increased between 2005 and 2014. PMID- 26423746 TI - A cross-sectional study on health differences between rural and non-rural U.S. counties using the County Health Rankings. AB - BACKGROUND: By examining 2013 County Health Rankings and Roadmaps data from the University of Wisconsin and the Robert Wood Johnson Foundation, this paper seeks to add to the available literature on health variances between United States residents living in rural and non-rural areas. We believe this is the first study to use the Rankings data to measure rural and urban health differences across the United States and therefore highlights the national need to address shortfalls in rural healthcare and overall health. The data indicates that U.S. residents living in rural counties are generally in poorer health than their urban counterparts. METHODS: We used 2013 County Health Rankings data to evaluate differences across the six domains of interest (mortality, morbidity, health behaviors, clinical care, social and economic factors, and physical environment) for rural and non-rural U.S. counties. This is a cross-sectional study employing chi-square analysis and logit regression. RESULTS: We found that residents living in rural U.S. counties are more likely to have poorer health outcomes along a variety of measurements that comprise the County Health Rankings' indexed domains of health quality. These populations have statistically significantly (p <= 0.05) lower scores in such areas as health behavior, morbidity factors, clinical care, and the physical environment. We attribute the differences to a variety of factors including limitations in infrastructure, socioeconomic differences, insurance coverage deficiencies, and higher rates of traffic fatalities and accidents. DISCUSSIONS: The largest differences between rural and non-rural counties were in the indexed domains of mortality and clinical care. CONCLUSIONS: Our analysis revealed differences in health outcomes in the County Health Rankings' indexed domains between rural and non-rural U.S. counties. We also describe limitations and offer commentary on the need for more uniform measurements in the classification of the terms rural and non-rural. These results can influence practitioners and policy makers in guiding future research and when deciding on funding allocation. PMID- 26423747 TI - Epidemiology and associated radiographic spinopelvic parameters of symptomatic degenerative lumbar scoliosis: are radiographic spinopelvic parameters associated with the presence of symptoms or decreased quality of life in degenerative lumbar scoliosis? AB - OBJECTIVES: To investigate the epidemiology of radiographic degenerative lumbar scoliosis (DLS) and symptomatic DLS and clarify the impact of radiographic spinopelvic parameters on the presence of symptoms and quality of life (QOL) in DLS subjects. METHODS: We obtained the age, gender, screening for chronic low back pain (CLBP) and lumbar spinal stenosis (LSS), QOL assessments and X-rays of the thoracolumbar spine from 254 patients from the general population for this study. The prevalence of DLS and symptomatic DLS were estimated and factors associated with symptoms, and the QOL in the DLS subjects was analysed. RESULTS: The prevalence of radiographic and symptomatic DLS was 19.2 and 7.8 %, respectively. A female gender (p = 0.018) and decreased sacral slope (p = 0.025) were associated with the presence of CLBP in the DLS subjects. A higher age was also associated with the presence of LSS in these subjects (p = 0.007), whereas the Cobb angle was found to be close the limit for significance (p = 0.063). The sacro-femoral-pubic angle and Cobb angle correlated with the EuroQol-5 dimensions utility score (r = 0.314, p = 0.014) and EuroQol-visual analogue scale score (r = -0.291, p = 0.043), respectively. Lumbar lordosis and body mass index correlated with the lumbar function (r = 0.285, p = 0.047) and visual analogue scale for leg pain (r = 0.328, p = 0.022) on the Japanese Orthopaedic Association Back Pain Questionnaire, respectively. CONCLUSIONS: The prevalence of radiographic DLS in this study was approximately 20 % and roughly 40 % of the DLS subjects had symptoms. Some spinopelvic parameters may impact the occurrence of symptoms and the QOL in DLS subjects. PMID- 26423748 TI - Radiographic measurement error of the scoliotic curve angle depending on positioning of the patient and the side of scoliotic curve. AB - BACKGROUND: The Cobb angle measurement is well established for the measurement of coronal deformity aspect of scoliotic curves. The effect of positional differences in relation to the apex side of the scoliosis is not yet fully quantified. While theoretically plausible that positioning error with rotation toward the apex of the scoliosis would decrease the Cobb angle, the relations are not investigated yet and were object of this study. MATERIALS AND METHODS: Multiple measurements of the Cobb angle were performed, while turning a spine pelvic cadaveric specimen with a right-sided thoracic scoliosis of 47 degrees (in neutral position) from 45 degrees to -45 degrees in steps of 5 degrees using biplanar radiography. Statistical methods were applied to find the critical position, in which measurement errors potentially become clinically relevant (Cobb angle deviation >5 degrees ). RESULTS: Turning the specimen to the right (toward the apex of the scoliosis) produced during the first -15 degrees of rotation, a Cobb angle ranging from 47 degrees to 45 degrees . At -20 degrees , the Cobb angle was 42 degrees , at -25 degrees rotation 37 degrees and at -30 degrees rotation 36 degrees . Above -30 degrees rotation, the measured Cobb angle decreased to 36 degrees (77 % of the original Cobb angle). No relevant differences were found by rotating the specimen to the left (away from the apex) (47 degrees at neutral rotation and 44 degrees at maximal error rotation of +45 degrees ). CONCLUSION: The influence of rotational misplacement of the patient at the time of image acquisition on Cobb angle measurements is negligible for a rotational misplacement of +/-20 degrees of rotation for a idiopathic right sided thoracic scoliosis of 47 degrees . Over 20 degrees of rotational misplacement of the patient toward the apex of the scoliosis falsely decreases the Cobb angle. PMID- 26423749 TI - Celiac disease detection in hypothyroid patients requiring elevated thyroid supplementation: A prospective cohort study. AB - BACKGROUND: Celiac disease (CD) is associated with hypothyroidism, but the disease prevalence is not thought to be great enough to warrant testing all hypothyroid patients. We hypothesized that hypothyroid patients with concomitant CD would require elevated doses of levothyroxine, and there is a threshold daily dose, above which, hypothyroid patients should be tested for CD. METHODS: Hypothyroid patients presenting to the endoscopy or endocrinology clinics at the University of Vermont Medical Center were included. Patients were categorized by whether or not they required >=125mcg/day of levothyroxine. A serum tissue transglutaminase (tTG) was performed on enrolled patients. Patients with an elevated serum tTG underwent endoscopy with duodenal biopsies. Symptoms were assessed by the Gastrointestinal Symptom Rating Scale. RESULTS: Overall, 500 patients were enrolled and 29% (144 patients) required >=125mcg/day of levothyroxine. CD was detected in 9 patients. The prevalence of CD ranged from 1.8% in our entire cohort to 12.5% in patients requiring >=200mcg/day of levothyroxine. Eight patients with CD (89%) required >=125mcg/day of levothyroxine. Patients who required >=125mcg/day of levothyroxine had a significantly increased risk of CD (p<0.001). CD was detected in 5.6% of patients requiring >=125mcg/day of levothyroxine. CONCLUSIONS: Hypothyroid patients requiring elevated daily doses of levothyroxine are more likely to have CD. Hypothyroid patients requiring >=125mcg/day of levothyroxine should undergo serologic testing for CD. PMID- 26423751 TI - RETRACTED ARTICLE: Net Fluorescein Flux Across Corneal Endothelium Suggests Fluid Transport is Driven by Electroosmosis. PMID- 26423750 TI - Understanding low colorectal cancer screening uptake in South Asian faith communities in England--a qualitative study. AB - BACKGROUND: Colorectal cancer screening uptake within the South Asian population in England is approximately half that of the general population (33 % vs 61 %), and varies by Muslim (31.9 %), Sikh (34.6 %) and Hindu (43.7 %) faith background. This study sought to explore reasons for low uptake of CRC screening in South Asian communities and for the variability of low uptake between three faith communities; and to identify strategies by which uptake might be improved. METHODS: We interviewed 16 'key informants' representing communities from the three largest South Asian faith backgrounds (Islam, Hinduism and Sikhism) in London, England. RESULTS: Reasons for low colorectal cancer screening uptake were overwhelmingly shared across South Asian faith groups. These were: limitations posed by written English; limitations posed by any written language; reliance on younger family members; low awareness of colorectal cancer and screening; and difficulties associated with faeces. Non-written information delivered verbally and interactively within faith or community settings was preferred across faith communities. CONCLUSIONS: Efforts to increase accessibility to colorectal cancer screening in South Asian communities should use local language broadcasts on ethnic media and face-to-face approaches within community and faith settings to increase awareness of colorectal cancer and screening, and address challenges posed by written materials. PMID- 26423752 TI - Health solutions for the poor. AB - The International Union Against Tuberculosis and Lung Disease (The Union) is the oldest international non-governmental organisation involved in the fight against tuberculosis. In 2008, the Institute of The Union was challenged to think boldly about the future and to develop a diverse work portfolio covering a wide spectrum of lung health and other disease-related problems. The vision adopted by The Union at that time was 'Health solutions for the poor'. More recently, there has been lengthy debate about the need for the Union to concentrate just on its core mandate of tuberculosis and lung health and for the Union's vision to reflect this narrower spectrum of activity as 'Lung health solutions for the poor'. In this viewpoint article we outline our reasons for believing that this narrower vision is incompatible with The Union's mission statement, and we argue that making such a change would be a mistake. PMID- 26423753 TI - Measles in the Democratic Republic of Congo: an urgent wake-up call to adapt vaccination implementation strategies. AB - All countries in Africa have made a commitment to eliminate measles by 2020. This is laudable, as measles elimination will have a crucial impact on reducing childhood mortality. An important operational challenge is the resurgence of measles outbreaks in a number of countries; one of the main reasons for this is that many children are being missed by vaccination programmes. In the Democratic Republic of Congo (DRC), outbreaks continue unabated despite repeated vaccination campaigns and high reported coverage by the Ministry of Health. This paper brings into question the effectiveness of the current approach and the need for better reflection on bottlenecks and strategies that can address this issue. If we are to eliminate measles by 2020, there will be a need for impetus, a need for decisive action to reach that goal and prevent unnecessary childhood deaths in countries such as the DRC. PMID- 26423754 TI - Childhood immunisation in Bungoma County, Kenya, from 2008 to 2011: need for improved uptake. AB - Uptake of immunisations in children aged 1-2 years in Bungoma County, Kenya, was determined as part of the 6-monthly Health and Demographic Surveillance System surveys. A total of 2699 children were assessed between 2008 and 2011. During this time period, full immunisation declined significantly from 84% to 58%, and measles vaccine declined uptake from 89% to 60% (P < 0.001). Each year there was a significant fall-off for the third doses of the oral polio and pentavalent vaccines (P < 0.001). These findings are of concern, as low immunisation coverage may lead to vaccine-preventable disease outbreaks. Further investigations into the reasons for declining immunisation trends are required. PMID- 26423755 TI - Do non-monetary incentives for pregnant women increase antenatal attendance among Ethiopian pastoralists? AB - In a pastoralist setting in Ethiopia, we assessed changes in attendance between the first and subsequent antenatal care (ANC) visits following the implementation of non-monetary incentives in a primary health care centre over a 3-year period from October 2009 to September 2012. Incentives included the provision of a bar of soap, a bucket, a mosquito net, sugar, cooking oil, a jerrycan and a delivery kit. The first ANC visits increased by 48% in the first year to 60% in the second. Subsequent visits did not show a similar pattern due to ruptures in incentive stocks. Incentives appear to increase ANC attendance; however, ruptures in stock should be avoided to sustain the effect. PMID- 26423756 TI - Active and passive case detection strategies for the control of leishmaniasis in Bangladesh. AB - SETTING: Two subdistricts in Bangladesh, Fulbaria and Trishal, which are hyperendemic for leishmaniasis. OBJECTIVE: To determine 1) the numbers of patients diagnosed with visceral leishmaniasis (VL) and post-kala azar dermal leishmaniasis (PKDL) using an active case detection (ACD) strategy in Fulbaria and a passive case detection (PCD) strategy in Trishal, and 2) the time taken from symptoms to diagnosis in the ACD subdistrict. DESIGN: A cross-sectional descriptive study of patients diagnosed from May 2010 to December 2011. The ACD strategy involved community education and outreach workers targeting households of index patients using symptom-based screening and rK-39 tests for suspected cases. RESULTS: In the ACD subdistrict (Fulbaria) and PCD sub-district (Trishal), respectively 1088 and 756 residents were diagnosed with VL and 1145 and 37 with PKDL. In the ACD subdistrict, the median time to diagnosis for patients directly referred by outreach workers or self-referred was similar, at 60 days for VL and respectively 345 and 360 days for PKDL. CONCLUSION: An ACD strategy at the subdistrict level resulted in an increased yield of VL and a much higher yield of PKDL. As PKDL acts as a reservoir for infection, a strategy of ACD and treatment can contribute to the regional elimination of leishmaniasis in the Indian sub continent. PMID- 26423757 TI - Providing a gateway to prevention and care for the most at-risk populations in Bhutan: is this being achieved? AB - SETTING: Two free-standing urban human immunodeficiency virus (HIV) testing and counselling (HCT) centres in Bhutan offering services to the general population and targeting the most at-risk populations (MARPs). OBJECTIVES: To assess the trend in testing for HIV, hepatitis B and syphilis in both the general population and MARPs, and to determine if sociodemographic and risk behaviour characteristics are associated with HIV, hepatitis B and syphilis seropositivity. DESIGN: Cross-sectional study using client records, 2009 - 2012. RESULTS: Of 7894 clients, 3009 (38%) were from the general population, while 4885 (62%) were from MARPs. Over the 4-year period, testing declined progressively among the general population, while it increased or remained static for MARPs. Of 4885 MARPs, seropositivity was respectively 0.7%, 1.3% and 1.2% for HIV, hepatitis B and syphilis. Female sex workers (FSWs) (relative risk [RR] 4.4, P = 0.03) and partners of person living with HIV (RR 25.9, P < 0.001) had a higher risk of being HIV-positive. FSWs had also a greater risk of being syphilis-positive (RR 9.1, P < 0.001). CONCLUSION: The increase in uptake of HCT services by MARPs is a welcome finding; however, the relatively static trends call for the introduction of community outreach approaches. The critical gateway being provided to MARPs is an 'opportunity' for the expansion of the current service package. PMID- 26423758 TI - Retention and HIV seroconversion among drug users on methadone maintenance treatment in Yunnan, China. AB - SETTING: Thirteen methadone maintenance treatment (MMT) clinics across Yunnan, the province with the highest human immunodeficiency virus (HIV) burden in China. OBJECTIVES: To determine, among HIV-negative participants on MMT, the proportion lost to follow-up (defined as those who missed the 6-monthly follow-up examination), factors associated with loss to follow-up (LFU), HIV seroconversion rate and factors associated with seroconversion. DESIGN: Prospective cohort study from October 2008 to April 2011. All participants were administered a pre-tested structured questionnaire to capture associated factors and offered HIV testing every 6 months. chi(2) test and log-binomial regression were used for data analysis. RESULTS: Of 1146 participants, 541 (47%) were lost to follow-up in 2.5 years. Factors associated with higher LFU proportion include <6 months of previous MMT, inconvenient location of the MMT clinic and average methadone dose ?60 mg/day, with adjusted relative risks (RRs) of respectively 1.4 (95%CI 1.2 1.5), 1.2 (95%CI 1.0-1.4) and 1.1 (95%CI 1.0-1.3). The overall HIV seroconversion rate was 6.6 (95%CI 3.7-11.0) per 1000 person-years. Not living with a partner contributed to higher HIV rates, with an adjusted RR of 3.6 (95%CI 1.0-12.8). CONCLUSION: The retention rate of MMT participants in Yunnan was not satisfactory. Decentralising service delivery in the community and making directly observed treatment more convenient has the potential to improve retention. PMID- 26423759 TI - Infection control in households of drug-resistant tuberculosis patients co infected with HIV in Mumbai, India. AB - BACKGROUND: Mumbai has a population of 21 million, and an increasingly recognised epidemic of drug-resistant tuberculosis (DR-TB). OBJECTIVE: To describe TB infection control (IC) measures implemented in households of DR-TB patients co infected with the human immunodeficiency virus (HIV) under a Medecins Sans Frontieres programme. METHODS: IC assessments were carried out in patient households between May 2012 and March 2013. A simplified, standardised assessment tool was utilised to assess the risk of TB transmission and guide interventions. Administrative, environmental and personal protective measures were tailored to patient needs. RESULTS: IC assessments were carried out in 29 houses. Measures included health education, segregating sleeping areas of patients, improving natural ventilation by opening windows, removing curtains and obstacles to air flow, installing fans and air extractors and providing surgical masks to patients for limited periods. Environmental interventions were carried out in 22 houses. CONCLUSIONS: TB IC could be a beneficial component of a comprehensive TB and HIV care programme in households and communities. Although particularly challenging in slum settings, IC measures that are feasible, affordable and acceptable can be implemented in such settings using simplified and standardised tools. Appropriate IC interventions at household level may prevent new cases of DR-TB, especially in households of patients with a lower chance of cure. PMID- 26423760 TI - The trend of tuberculosis cases over 60 years in Fiji's largest treatment centre: 1950-2010. AB - SETTING: P J Twomey Hospital, National Tuberculosis Programme, Fiji. OBJECTIVES: To review the trend in numbers of tuberculosis (TB) cases registered each year from 1950 to 2010 at P J Twomey Hospital, Fiji's largest TB treatment centre and central TB unit, and to consider trends in the context of key TB control events in Fiji. DESIGN: Descriptive study of data from medical records and TB registers, including age, sex, ethnicity, TB diagnosis and smear result. RESULTS: Between 1950 and 2010, 14 616 cases were registered at P J Twomey Hospital. Of these, 58% were male, 70% were indigenous Fijians (i-taukei) and 64% were aged 15-49 years. The caseload dropped sharply in the 1960s, and has fallen steadily since 1990. Smear results were available for the majority of cases (91%). Between 1950 and 1985, smear-positive cases accounted for 19% of cases overall; this increased to 41% after 1985 following laboratory training. The numbers of sputum smear positive cases recorded each year has been increasing in the last decade. CONCLUSION: There have been marked changes in TB caseload over the last 60 years at Fiji's largest TB treatment centre. The recent increase in smear-positive cases while total TB cases have been falling needs further evaluation. PMID- 26423761 TI - Using tuberculosis patient characteristics to predict future cases with matching genotype results. AB - SETTING: United States. BACKGROUND: It is unknown whether tuberculosis (TB) case or patient characteristics can predict the likelihood of future related TB cases. OBJECTIVE: To estimate the likelihood for future related cases, i.e., cases with matching TB genotypes within the same county diagnosed within the 2 years following the year of reporting of each included case. DESIGN: We considered all TB cases with genotyping results reported in the United States during 2004-2010. Predictive scores were calculated based on patient characteristics by dividing the number of patients who were not the last case in a county-level TB genotype cluster by the total number of patients. RESULTS: Overall, there was a 30.8% chance that a future related case would be detected during the 2 years following the report year of any given case. Future related cases were detected in 34.7% of instances following the diagnosis of smear-positive cases, 51.9% of instances following the diagnosis of a homeless patient and 45.2% of instances following the diagnosis of a patient who reported substance abuse. Predictive scores ranged by race (White 13.9%, Native Hawaiian 43.8%) and age group (?65 years 13.1%, 0-4 years 43%), and were higher for US-born patients. CONCLUSIONS: Behavioral and sociodemographic factors can help predict the likelihood of future related cases and can be used to prioritize contact investigations. PMID- 26423762 TI - Effectiveness of reporting on latent tuberculous infection in Massachusetts, 2006 2008. AB - Massachusetts is one of five states that mandate the reporting of latent tuberculous infection (LTBI). We assessed 2006-2008 Massachusetts surveillance data for LTBI to describe the system and examine the characteristics of persons with LTBI. Over 3 years, 15 301 LTBI cases were reported (4742-5398/year). Among those with known country of birth (n = 11 655), 9983 (85.7%) were foreign-born. Substantial under-ascertainment and/or under-reporting appear likely; mandatory reporting does not appear sufficient for LTBI detection. Enhanced targeted testing, active LTBI surveillance, or laboratory-based surveillance may be needed to eliminate tuberculosis disease in the United States. PMID- 26423763 TI - Does task shifting in tuberculosis microscopy services to non-certified technicians in Afghanistan affect quality? AB - SETTING: Tuberculosis microscopy centres in 30 provinces in Afghanistan. OBJECTIVE: To compare the quality of sputum smear examinations in microscopy centres with microscopists who are fully certified as laboratory technicians with those performed in centres with technicians who do not have such certification (high school graduates). DESIGN: Cross-sectional record review of sputum smear microscopy slides examined by technicians and cross-checked by trained assessors as part of routine external quality assurance between July and September 2009. RESULTS: Of 129 non-certified technicians, 118 (91%) were stationed in rural health centres compared with 217/257 (84%) certified technicians. From 386 microscopy centres, 7313 slides were cross-checked. Of 257 microscopy centres with certified technicians, 42 (16%) had at least one slide with a major error compared to 23 (18%) of 129 microscopy centres staffed with non-certified technicians. The difference was not statistically significant (OR 1.11, 95%CI 0.64-1.94). The number of slides showing major errors was also similar between the centres with both certified and non-certified technicians. CONCLUSION: This study confirms the deployment of non-certified microscopy technicians to peripheral health centres throughout the country and that their performance with sputum smear microscopy is similar to that of certified technicians with 3 years of training. PMID- 26423764 TI - Screening retreatment tuberculosis patients for drug resistance in mid-west Nepal: how well are we doing? AB - SETTING: Multidrug-resistant tuberculosis (MDR-TB, defined as resistance to isoniazid and rifampicin) is poorly detected in Nepal; one reason may be poor functioning of culture and drug susceptibility testing (CDST) services for retreatment tuberculosis (TB) patients. OBJECTIVES: To determine, among retreatment TB patients in mid-west Nepal, 1) the number of patients registered for treatment between July 2011 and July 2012; 2) the number submitting sputum specimens for CDST to the Central Reference Laboratory (CRL), Kathmandu, along with the results; and 3) the length of time for submission and receipt of specimens. DESIGN: Retrospective cohort study involving the review of treatment and laboratory registers from the Nepalgunj TB Referral Centre and the CRL. RESULTS: Of 431 retreatment patients, 66 (15%) submitted sputum samples, of which 63 reached the CRL. Of these, 39 (62%) were culture-positive; 13 (33%) patients had MDR-TB. The CDST results of 19 patients were received back at the TB Referral Centre. The median turnaround time from sending specimens to receipt of results at the TB Referral Centre was 119 days. CONCLUSION: Less than 10% of retreatment TB patients in mid-West Nepal had CDST results recorded, leading to the underdiagnosis of MDR-TB in the region. Urgent solutions are needed to rectify this problem. PMID- 26423765 TI - Sex-related trends in non-conversion of new smear-positive tuberculosis patients in the Free State, South Africa. AB - SETTING: Free State Province, South Africa. OBJECTIVE: To examine sex-specific trends in 2-month sputum smear non-conversion in new sputum smear-positive tuberculosis (TB) cases during a period when the DOTS strategy was operative. DESIGN: A retrospective cohort study of TB cases registered between 2003 and 2009 was conducted. Non-conversion was indicated by a positive 2-month sputum smear result. Descriptive and generalised linear model analyses were performed and sex specific trends in 2-month sputum smear non-conversion rates estimated. RESULTS: Overall, 2-month sputum smear non-conversion rates were 12.5% in males and 9.3% in females. Non-conversion was significantly associated with age in males (P < 0.001). Non-conversion rates declined significantly between 2003 and 2009: from 15.9% to 10.8% in males (P < 0.001) and from 12.0% to 6.6% in females (P < 0.001). The average rate of decline of non-conversion was higher among females (1.0%, 95%CI 0.8-1.2) than among males (0.8%, 95%CI 0.5-1.0). By 2009, males had a 60% higher risk of non-conversion than females (RR 1.60, CI 1.37-1.86). CONCLUSION: The decline in the trend of 2-month sputum smear non-conversion confirms the relative success of the DOTS strategy in TB control, with better performance among females than males. Interventions should consider the sex and age of patients to improve the 2-month sputum smear-conversion rate. PMID- 26423766 TI - Activation of the AMPK-ULK1 pathway plays an important role in autophagy during prion infection. AB - AMPK is a serine/threonine protein kinase that acts as a positive regulator of autophagy, by phosphorylating ULK1 at specific sites. A previous study demonstrated activation of the macroautophagic system in scrapie-infected experimental rodents and in certain human prion diseases, in which the essential negative regulator mTOR is severely inhibited. In this study, AMPK and ULK1 in the brains of hamsters infected with scrapie strain 263 K and in the scrapie infected cell line SMB-S15 were analysed. The results showed an up-regulated trend of AMPK and AMPK-Thr172, ULK1 and ULK1-Ser555. Increases in brain AMPK and ULK1 occurred at an early stage of agent 263 K infection. The level of phosphorylated ULK1-Ser757 decreased during mid-infection and was only negligibly present at the terminal stage, a pattern that suggested a close relationship of the phosphorylated protein with altered endogenous mTOR. In addition, the level of LKB1 associated with AMPK activation was selectively increased at the early and middle stages of infection. Knockdown of endogenous ULK1 in SMB-S15 cells inhibited LC3 lipidation. These results showed that, in addition to the abolishment of the mTOR regulatory pathway, activation of the AMPK-ULK1 pathway during prion infection contributes to autophagy activation in prion-infected brain tissues. PMID- 26423767 TI - What Ethical Issues Really Arise in Practice at an Academic Medical Center? A Quantitative and Qualitative Analysis of Clinical Ethics Consultations from 2008 to 2013. AB - As the field of clinical ethics consultation sets standards and moves forward with the Quality Attestation process, questions should be raised about what ethical issues really do arise in practice. There is limited data on the type and number of ethics consultations conducted across different settings. At Loyola University Medical Center, we conducted a retrospective review of our ethics consultations from 2008 through 2013. One hundred fifty-six cases met the eligibility criteria. We analyzed demographic data on these patients and conducted a content analysis of the ethics consultation write-ups coding both the frequency of ethical issues and most significant, or key, ethical issue per case. Patients for whom ethics consultation was requested were typically male (55.8 %), white (57.1 %), between 50 and 69 years old (38.5 %), of non-Hispanic origin (85.9 %), and of Roman Catholic faith (43.6 %). Nearly half (47.4 %) were in the intensive care unit and 44.2 % died in the hospital. The most frequent broad ethical categories were decision-making (93.6 %), goals of care/treatment (80.8 %), and end-of-life (73.1 %). More specifically, capacity (57.1 %), patient's wishes/autonomy (54.5 %), and surrogate decision maker (51.3 %) were the most frequent particular ethical issues. The most common key ethical issues were withdrawing/withholding treatment (12.8 %), patient wishes/autonomy (12.2 %), and capacity (11.5 %). Our findings provide additional data to inform the training of clinical ethics consultants regarding the ethical issues that arise in practice. A wider research agenda should be formed to collect and compare data across institutions to improve education and training in our field. PMID- 26423768 TI - A ventilation technique for oxygenation and carbon dioxide elimination in CPR: Continuous insufflation of oxygen at three levels of pressure in a pig model. AB - AIM: Pulmonary ventilation remains an important part of cardiopulmonary resuscitation, affecting gas exchange and haemodynamics. We designed and studied an improved method of ventilation for CPR, constructed specifically to support both gas exchange and haemodynamics. This method uses continuous insufflation of oxygen at three levels of pressure, resulting in tri-level pressure ventilation (TLPV). We hypothesized that TLPV improves gas exchange and haemodynamics compared to manual gold standard ventilation (GSV). METHODS: In 14 pigs, ventricular fibrillation was induced and automated CPR performed for 10 min with either TLPV or GSV. After defibrillation, CPR was repeated with the other ventilation method. Gas exchange and haemodynamics were monitored. Data are presented as mean+/-standard error of the mean. RESULTS: TLPV was superior to GSV for PaO2 (163+/-36 mmHg difference; P=0.001), and peak AWP (-20+/-2 cmH2O difference; P=0.000) and higher for mean AWP (8+/-0.2 cmH2O difference; P=0.000). TLPV was comparable to GSV for CPP (5+/-3 mmHg difference; P=0.012), VCO2 (0.07+/ 0.3 mL/min/kg difference; P=0.001), SvO2 (4+/-3%-point; P=0.001), mean carotid flow (-0.5+/-4 mL/min difference; P=0.016), and pHa (0.00+/-0.03 difference; P=0.002). The PaCO2 data do not provide a conclusive result (4+/-4 mmHg difference). CONCLUSION: We conclude that the ventilation strategy with a tri level pressure cycle performs comparable to an expert, manual ventilator in an automated-CPR swine model. PMID- 26423771 TI - The arduous task of differentiating takotsubo syndrome from myocardial infarction with normal coronary arteries. PMID- 26423769 TI - Immunotherapy in Sarcoma: Future Horizons. AB - Immunologic approaches to cancer are over a century old. Over the years, the strategy has been fine-tuned from inciting infections in subjects to inhibiting negative regulatory signals from the innate immune system. Sarcomas are among the first tumors to be considered for immune interventions. From Coley's toxin to cytokine-based therapies to adoptive cell therapy, there have been numerous immunotherapeutic investigations in this patient population. A promising strategy includes adoptive T cell therapy which has been studied in small cohorts of synovial sarcoma, a subtype that is known to widely express the cancer testis antigen, NY-ESO-1. Additionally, recent data in metastatic melanoma and renal cell carcinoma demonstrate the utility and tremendous efficacy of immune checkpoint blockade with increased rates of durable responses compared to standard therapies. Responses in traditionally "non-immunogenic" tumors, such as lung and bladder cancers, provide ample rationale for the study of immune checkpoint inhibitors in sarcoma. While immunotherapy has induced some responses in sarcomas, further research will help clarify optimal patient selection for future clinical trials and new combinatorial immunotherapeutic strategies. PMID- 26423772 TI - Incident diabetes mellitus, hypertension, and cardiovascular disease risk in exercising hypercholesterolemic patients. AB - Exercise may be an important treatment for hypercholesterolemic patients, particularly in statin users who are at increased diabetes risk. We therefore used Cox proportional hazard analyses to compare running and walking dose (metabolic equivalent hours/day [MET-h/d]) to diabetes, hypertension, and cardiovascular disease (CVD) risk in hypercholesterolemic patients. There were 60 diabetic- and 373 CVD-related deaths during a 10.1-year mortality surveillance of 6,688 hypercholesterolemic patients. In addition, there were 177 incident nonfatal diabetes, 815 incident nonfatal hypertensions, and 323 incident nonfatal CVD events during a 6.4-year follow-up of 6,971 hypercholesterolemic patients who supplied follow-up questionnaires. Fatal and nonfatal diabetes risk decreased 26% (p = 0.002) and 19% (p <=0.0001) per MET-h/d, respectively, and relative to <1.07 MET-h/d decreased 35% (p = 0.19) and 55% (p <=0.0001), respectively, for 1.8 to 3.6 MET-h/d and 73% (p = 0.02) and 71% (p <=0.0001), respectively, for >=3.6 MET h/d. Fatal and nonfatal CVD risk decreased 8% (p = 0.008) and 3% (p = 0.22) per MET-h/d, respectively, and relative to <1.07 MET-h/d decreased 10% (p = 0.45) and 36% (p = 0.008) for 1.8 to 3.6 MET-h/d, respectively, and 37% (p = 0.009) and 26% (p = 0.10), respectively, for >=3.6 MET-h/d. Incident hypertension risk decreased 4% (p = 0.01) per MET-h/d, and relative to <1.07 MET-h/d decreased 29% (p = 0.002) for 1.8 to 3.6 MET-h/d and 31% (p = 0.001) for >=3.6 MET-h/d. In conclusion, running and walking for exercise lowers diabetes, hypertension, and CVD risk in hypercholesterolemic patients and should more than compensate for the purported 9% increase in diabetes risk from statin use. By preventing morbidity and mortality for a specific existing medical condition, some exercise expenses may qualify for flexible spending account expenditures in hypercholesterolemic patients when prescribed by a physician. PMID- 26423773 TI - Juvenile exposure to vinclozolin shifts sex ratios and impairs reproductive capacity of zebrafish. AB - Exposure to endocrine disruptors during critical periods of development can impact the sustainability of wild fish populations. Anti-androgenic compounds have received less attention, but are capable of modulating gonad differentiation and maturation, and impairing reproduction in fish. The fungicide vinclozolin (VZ) has been shown to impair reproduction in adult fish, but less is known about its effects following exposure earlier in development. Here we show that waterborne exposure to 400MUg VZ/L during critical periods of sex differentiation (21-35 days post fertilization) permanently shifts sex ratios towards females, and alters the maturation of the gonad. Both fecundity and fertility were reduced, even when oogenesis and spermatogenesis recover and sperm motility is not altered. These results demonstrate the need to better understand the impacts of early exposure to anti-androgenic compounds on fish. PMID- 26423774 TI - Brain substrates of perceived spatial separation between speech sources under simulated reverberant listening conditions in schizophrenia. AB - BACKGROUND: People with schizophrenia recognize speech poorly under multiple people-talking (informational masking) conditions. In reverberant environments, direct-wave signals from a speech source are perceptually integrated with the source reflections (the precedence effect), forming perceived spatial separation (PSS) between different sources and consequently improving target-speech recognition against informational masking. However, the brain substrates underlying the schizophrenia-related vulnerability to informational masking and whether schizophrenia affects the unmasking effect of PSS are largely unknown. METHOD: Using psychoacoustic testing and functional magnetic resonance imaging, respectively, the speech recognition under either the PSS or perceived spatial co location (PSC) condition and the underlying brain substrates were examined in 20 patients with schizophrenia and 16 healthy controls. RESULTS: Speech recognition was worse in patients than controls. Under the PSS (but not PSC) condition, speech recognition was correlated with activation of the superior parietal lobule (SPL), and target speech-induced activation of the SPL, precuneus, middle cingulate cortex and caudate significantly declined in patients. Moreover, the separation (PSS)-against-co-location (PSC) contrast revealed (1) activation of the SPL, precuneus and anterior cingulate cortex in controls, (2) suppression of the SPL and precuneus in patients, (3) activation of the pars triangularis of the inferior frontal gyrus and middle frontal gyrus in both controls and patients, (4) activation of the medial superior frontal gyrus in patients, and (5) impaired functional connectivity of the SPL in patients. CONCLUSIONS: Introducing the PSS listening condition efficiently reveals both the brain substrates underlying schizophrenia-related speech-recognition deficits against informational masking and the schizophrenia-related neural compensatory strategy for impaired SPL functions. PMID- 26423776 TI - [Ibn al Haizam and the International Year of Light]. PMID- 26423775 TI - A robust screening method for dietary agents that activate tumour-suppressor microRNAs. AB - Certain dietary agents, such as natural products, have been reported to show anti cancer effects. However, the underlying mechanisms of these substances in human cancer remain unclear. We recently found that resveratrol exerts an anti-cancer effect by upregulating tumour-suppressor microRNAs (miRNAs). In the current study, we aimed to identify new dietary products that have the ability to activate tumour-suppressor miRNAs and that therefore may serve as novel tools for the prevention and treatment of human cancers. We describe the generation and use of an original screening system based on a luciferase-based reporter vector for monitoring miR-200c tumour-suppressor activity. By screening a library containing 139 natural substances, three natural compounds - enoxolone, magnolol and palmatine chloride - were identified as being capable of inducing miR-200c expression in breast cancer cells at 10 MUM. Moreover, these molecules suppressed the invasiveness of breast cancer cells in vitro. Next, we identified a molecular pathway by which the increased expression of miR-200c induced by natural substances led to ZEB1 inhibition and E-cadherin induction. These results indicate that our method is a valuable tool for a fast identification of natural molecules that exhibit tumour-suppressor activity in human cancer through miRNA activation. PMID- 26423777 TI - Patients with cirrhosis in the ED: early predictors of infection and mortality. AB - BACKGROUND: Patients with cirrhosis have high risk of bacterial infections and cirrhosis decompensation, resulting in admission to emergency department (ED). However, there are no criteria developed in the ED to identify patients with cirrhosis with bacterial infection and with high mortality risk. STUDY OBJECTIVE: The objective of the study is to identify variables from ED arrival associated with bacterial infections and inhospital mortality. METHODS: This is a retrospective single-center study using a tertiary hospital's database to identify consecutive ED patients with decompensated cirrhosis. Clinical variables and laboratory results were obtained by chart review. Logistic regression models were built to determine variables independently associated with bacterial infection and mortality. Scores using these variables were designed. RESULTS: One hundred forty-nine patients were enrolled, most of them males (77.9%) with alcoholic cirrhosis (53%) and advanced liver disease (Child-Pugh C, 47.2%). Bacterial infections were diagnosed in 72 patients (48.3%), and 36 (24.2%) died during hospital stay. Variables independently associated with bacterial infection were lymphocytes less than or equal to 900/mm(3) (odds ratio [OR], 3.85 [95% confidence interval {CI}, 1.47-10]; P = .006) and C-reactive protein greater than 59.4 mg/L (OR, 5.05 [95% CI, 1.93-13.2]; P = .001). Variables independently associated with mortality were creatinine greater than 1.5 mg/dL (OR, 4.35 [95% CI, 1.87-10.1]; P = .001) and international normalized ratio greater than 1.65 (OR, 3.71 [95% CI, 1.6-8.61]; P = .002). Scores designed to predict bacterial infection and mortality (Mortality in Cirrhosis Emergency Department Score) had an area under the receiver operating characteristic curve of 0.82 and 0.801, respectively. The Mortality in Cirrhosis Emergency Department Score performed better than Model for End-Stage Liver Disease score. CONCLUSIONS: In this cohort of ED patients with decompensated cirrhosis, lymphopenia and elevated C-reactive protein were related to bacterial infections, and elevated creatinine and international normalized ratio were related to mortality. Scores built with these variables should be prospectively validated. PMID- 26423779 TI - [Management of hepatitis B virus and hepatitis C virus infection in chronic kidney failure]. AB - Chronic infections by hepatitis B (HBV) and C virus (HCV) result in diagnosis and therapeutic issues in dialysis and kidney recipients patients. The exposure to nosocomial, including blood transfusion, risk explains the high prevalence of HBV and HCV infection in this setting. Chronic infection reduces the survival of both patients and allografts, including a specific risk of de novo glomerulonephritis. Cirrhosis was considered as a contra-indication to renal transplantation given the high risk of decompensation and death, questionning the indication of a combined liver and kidney transplantation. Thus, it is mandatory to screen HBV and HCV markers in all dialysis patients, whether or not they are candidates to transplantation. Liver biopsy allows evaluating the severity of the liver disease since the noninvasive markers of fibrosis appear to be less accurate in "renal" patients than in the general population and to better define antiviral therapeutic indications. HCV treatment was mainly based on pegylated interferon alpha (and low doses of ribavirin), which is contra-indicated in kidney recipients given the risk of graft rejection; HCV treatment is now based on the use of oral direct acting antivirals, which are very potent and well tolerated. HBV replication is now easily suppressed by second-generation nucleos(t)tidic analogues (entecavir and tenofovir), which will be indicated in all the dialysis patients with significant fibrosis (F2,3 or 4 according to the Metavir scoring system) and in any candidate to renal transplantation and to any HBsAg-positive kidney recipients. The best treatment remains preventive by anti-HBV vaccination for HBV and by the respect of universal hygiene rules for HCV. PMID- 26423778 TI - A trend analysis of antimicrobial resistance in commensal Escherichia coli from several livestock species in Belgium (2011-2014). AB - A temporal trend analysis was performed on antimicrobial resistance data collected over 4 consecutive years (2011-2014) in the official Belgian antimicrobial resistance monitoring programme. Commensal Escherichia coli strains were isolated from faecal samples of four livestock categories (veal calves, young beef cattle, broiler chickens and slaughter pigs) and the trends of resistance profiles were analysed. The resistance prevalence remained high (>50%) during the study period for ampicillin in veal calves and chickens, for ciprofloxacin and nalidixic acid in chickens, for sulfamethoxazole in veal calves, chickens and pigs and for tetracycline in veal calves. Using logistic regression and Generalized Estimating Equation and after p value adjustment for multiple testing (Linear step-up method), statistically significant decreasing temporal trends were observed for several of the 11 tested antimicrobials in several livestock categories: in veal calves (10/11), in chickens (6/11) and in pigs (5/11). A significant increasing trend was observed for the prevalence of resistance to ciprofloxacin in chickens. Multi-resistance, considered as the resistance to at least three antimicrobials of different antibiotic classes, was observed in the four livestock categories but was significantly decreasing in veal calves, chickens and pigs. Overall, the prevalence of resistance and of multi-resistance was lowest in the beef cattle livestock category and highest in broiler chickens. These decreasing temporal trends of antimicrobial resistance might be due to a decrease of the total antimicrobial consumption for veterinary use in Belgium which was reported for the period between 2010 and 2013. The methodology and statistical tools developed in this study provide outputs which can detect shifts in resistance levels or resistance trends associated with particular antimicrobial classes and livestock categories. Such outputs can be used as objective evidence to evaluate the possible efficacy of measures taken by animal health authorities and stakeholders in the livestock sector to limit antimicrobial resistance occurrence. PMID- 26423780 TI - Influence of the Homopolar Dihydrogen Bonding C-H???H-C on Coordination Geometry: Experimental and Theoretical Studies. AB - The reaction of the N-thiophosphorylated thiourea (HOCH2 )(Me)2 CNHC(S)NHP(S)(OiPr)2 (HL), deprotonated by the thiophosphorylamide group, with NiCl2 leads to green needles of the pseudotetrahedral complex [Ni(L-1,5-S,S')2 ]?0.5 (n-C6 H14 ) or pale green blocks of the trans square-planar complex trans [Ni(L-1,5-S,S')2 ]. The former complex is stabilized by homopolar dihydrogen C H???H-C interactions formed by n-hexane solvent molecules with the [Ni(L-1,5 S,S')2 ] unit. Furthermore, the dispersion-dominated C-H??? H-C interactions are, together with other noncovalent interactions (C-H???N, C-H???Ni, C-H???S), responsible for pseudotetrahedral coordination around the Ni(II) center in [Ni(L 1,5-S,S')2 ]?0.5 (n-C6 H14 ). PMID- 26423781 TI - First report on the bacterial diversity in the distal gut of dholes (Cuon alpinus) by using 16S rRNA gene sequences analysis. AB - The aim of this study was to investigate the bacterial community in the distal gut of dholes (Cuon alpinus) based on the analysis of bacterial 16S rRNA gene sequences. Fecal samples were collected from five healthy unrelated dholes captured from Qilian Mountain in Gansu province of China. The diversity of the fecal bacteria community was investigated by constructing a polymerase chain reaction (PCR)-amplified 16S rRNA gene clone library. Bacterial 16S rRNA gene was amplified by using universal bacterial primers 27F and 1492R. A total of 275 chimera-free near full length 16S rRNA gene sequences were collected, and 78 non redundant bacteria phylotypes (operational taxonomical units, OTUs) were identified according to the 97 % sequence similarity. Forty-two OTUs (53.8 %) showed less than 98 % sequence similarity to 16S rRNA gene sequences reported previously. Phylogenetic analysis demonstrated that dhole bacterial community comprised five different phyla, with the majority of sequences being classified within the phylum Bacteroidetes (64.7 %), followed by Firmicutes (29.8 %), Fusobacteria (4.7 %),Proteobacteria (0.4 %), and Actinobacteria (0.4 %). The only order Bacteroidales in phylum Bacteroidetes was the most abundant bacterial group in the intestinal bacterial community of dholes. Firmicutes and Bacteroidetes were the two most diverse bacterial phyla with 46.2 and 44.9 % of OTUs contained, respectively. Bacteroidales and Clostridiales were the two most diverse bacterial orders that contained 44.9 and 39.7 % of OTUs, respectively. PMID- 26423782 TI - A lack of Wolbachia-specific DNA in samples from apollo butterfly (Parnassius apollo, Lepidoptera: Papilionidae) individuals with deformed or reduced wings. AB - Various insects contain maternally inherited endosymbiotic bacteria which can cause reproductive alterations, modulation of some physiological responses (like immunity, heat shock response, and oxidative stress response), and resistance to viral infections. In butterflies, Wolbachia sp. is the most frequent endosymbiont from this group, occurring in about 30 % of species tested to date. In this report, the presence of Wolbachia-specific DNA has been detected in apollo butterfly (Parnassius apollo). In the isolated population of this insect occurring in Pieniny National Park (Poland), malformed individuals with deformed or reduced wings appear with an exceptionally high frequency. Interestingly, while total DNA isolated from most (about 85 %) normal insects contained Wolbachia-specific sequences detected by PCR, such sequences were absent in a large fraction (70 %) of individuals with deformed wings and in all tested individuals with reduced wings. These results indicate for the first time the correlation between malformation of wings and the absence of Wolbachia sp. in insects. Although the lack of the endosymbiotic bacteria cannot be considered as the sole cause of the deformation or reduction of wings, one might suggest that Wolbachia sp. could play a protective role in the ontogenetic development of apollo butterfly. PMID- 26423783 TI - PCR method for the rapid detection and discrimination of Legionella spp. based on the amplification of pcs, pmtA, and 16S rRNA genes. AB - Legionella bacteria are organisms of public health interest due to their ability to cause pneumonia (Legionnaires' disease) in susceptible humans and their ubiquitous presence in water supply systems. Rapid diagnosis of Legionnaires' disease allows the use of therapy specific for the disease. L. pneumophila serogroup 1 is the most common cause of infection acquired in community and hospital environments. The non-L. pneumophila infections are likely under detected because of a lack of effective diagnosis. In this work, simplex and duplex PCR assays with the use of new molecular markers pcs and pmtA involved in phosphatidylcholine synthesis were specified for rapid and cost-efficient identification and distinguishing Legionella species. The sets of primers developed were found to be sensitive and specific for reliable detection of Legionella belonging to the eight most clinically relevant species. Among these, four primer sets I, II, VI, and VII used for duplex-PCRs proved to have the highest identification power and reliability in the detection of the bacteria. Application of this PCR-based method should improve detection of Legionella spp. in both clinical and environmental settings and facilitate molecular typing of these organisms. PMID- 26423784 TI - Intrapleural Fibrinolysis with Urokinase Versus Alteplase in Complicated Parapneumonic Pleural Effusions and Empyemas: A Prospective Randomized Study. AB - BACKGROUND: Pleurofibrinolysis has been reported to be potentially beneficial in the management of complicated parapneumonic effusions (CPPE) and empyemas in the adult population. METHODS: Prospective, controlled, randomized, and double-blind study, to evaluate intrapleural alteplase 10 mg (initially 20 mg was considered but bleeding events forced dose reduction) versus 100,000 UI urokinase every 24 h for a maximum of 6 days in patients with CPPE or empyemas. The primary aim was to evaluate the success rate of each fibrinolytic agent at 3 and 6 days. Success of therapy was defined as the presence of both clinical and radiological improvement, making additional fibrinolytic doses unnecessary, and eventually leading to resolution. Secondary outcomes included the safety profile of intrapleural fibrinolytics, referral for surgery, length of hospital stay, and mortality. RESULTS: A total of 99 patients were included, of whom 51 received alteplase and 48 urokinase. Success rates for urokinase and alteplase at 3 and 6 days were not significantly different, but when only the subgroup of CPPE was considered, urokinase resulted in a high proportion of cures. There were no differences in mortality or surgical need (overall, 3 %). Five (28 %) patients receiving 20 mg of alteplase and 4 (12 %) receiving 10 mg presented serious bleeding events. CONCLUSIONS: If intrapleural fibrinolytics are intended to be used, urokinase may be more effective than alteplase in patients with non purulent CPPE and have a lower rate of adverse events. PMID- 26423785 TI - Maternal high fat diet programs stress-induced behavioral disorder in adult offspring. AB - Early life exposure to specific environmental factors can contribute to development of behavioral disorders in adulthood. Although maternal high fat diet (HFD) consumption during the perinatal period has been reported to program offspring behavior, the underlying mechanisms remain to be elucidated. The present study was designed to evaluate the influence of maternal HFD on offspring behavior under nonstressed and stressful conditions, using male Sprague-Dawley offspring, which mothers were fed with HFD or normal diet (ND), receiving chronic unpredictable mild stress (CUMS) in the adulthood. We found that although the detrimental effects of maternal HFD consumption on offspring depressive behavior did not persist into adulthood, it markedly aggravated the behavioral disorder response to stressful challenge in adult offspring. Moreover, calcitonin gene related peptide (CGRP) concentration in CSF and hippocampus were increased in the HFD+CUMS rats, compared to the ND+CUMS subjects. Another separate groups were fitted with intracerebroventricular (icv) cannulae. Central infusion of alphaCGRP8-37, a CGRP antagonist, produced antidepressant effects in HFD+CUMS rats, implying that the programming of maternal HFD on offspring behavior responses to stress may be mediated partially by endogenous central CGRP signaling. Moreover, we found that maternal HFD significantly exacerbated HPA profile response to acute restraint stress and attenuated the habituation of HPA responses to repeated restraint stress, suggesting that maternal HFD may program the changes of HPA-regulatory mechanisms. Overall, our findings suggest that maternal HFD influence adult depressive disorder response to stressful challenge, through the modulation of endogenous central CGRP signaling and HPA-regulatory components. PMID- 26423786 TI - Effects of environmental stress following myocardial infarction on behavioral measures and heart failure progression: The influence of isolated and group housing conditions. AB - BACKGROUND: Heart failure (HF) prognosis is negatively influenced by adverse environmental conditions associated with psychological distress and depression. The underlying mechanisms are not well understood because of insufficient experimental control in prior clinical and epidemiological studies. Using a validated animal model we examined whether distress-producing environmental manipulations (social isolation and crowding) increase HF progression following myocardial infarction (MI). METHODS: MI was induced using coronary artery ligation in 8-week old male Wistar rats (N=52) and results were compared to sham surgery (N=24). Housing conditions were randomly assigned at 5 days post MI or sham surgery (1/cage=isolation, 2/cage=standard reference condition, or 4/cage=crowding) and continued for 17 weeks until the end of observation. The open field test was used to test behavioral responses. Echocardiograms were obtained at weeks 8 and 16, and left ventricular (LV) weight at week 17. RESULTS: Housing conditions increased behavioral markers of distress (p=0.046) with the strongest effects for the isolated (1/cage) (p=0.022). MI did not increase distress-related behaviors compared to sham. MI-surgery resulted in characteristic HF indices (left ventricular ejection fraction (LVEF) at week 16=46 +/- 12% vs. 80 +/- 7% in sham, p<0.001). Housing condition was not related to LVEF or LV weight (p>0.10). CONCLUSIONS: Adverse environmental conditions, particularly isolated housing, produce increases in some of the behavioral indicators of distress. No effects of housing were found on post-MI progression of HF. The distress-HF associations observed in humans may therefore reflect common underlying factors rather than an independent causal pathway. Stronger environmental challenges may be needed in future animal research examining distress as related HF progression. PMID- 26423788 TI - Metabolic approaches to antihypertensive treatment in diabetic patients. PMID- 26423787 TI - Pre-existing differences in motivation for food and sensitivity to cocaine induced locomotion in obesity-prone rats. AB - Obesity is a significant problem in the United States, with roughly one third of adults having a body mass index (BMI) over thirty. Recent evidence from human studies suggests that pre-existing differences in the function of mesolimbic circuits that mediate motivational processes may promote obesity and hamper weight loss. However, few preclinical studies have examined pre-existing neurobehavioral differences related to the function of mesolimbic systems in models of individual susceptibility to obesity. Here, we used selectively bred obesity-prone and obesity-resistant rats to examine 1) the effect of a novel "junk-food" diet on the development of obesity and metabolic dysfunction, 2) over consumption of "junk-food" in a free access procedure, 3) motivation for food using instrumental procedures, and 4) cocaine-induced locomotor activity as an index of general mesolimbic function. As expected, eating a sugary, fatty, "junk food" diet exacerbated weight gain and increased fasted insulin levels only in obesity-prone rats. In addition, obesity-prone rats continued to over-consume junk-food during discrete access testing, even when this same food was freely available in the home cage. Furthermore, when asked to press a lever to obtain food in an instrumental task, rates of responding were enhanced in obesity-prone versus obesity-resistant rats. Finally, obesity-prone rats showed a stronger locomotor response to 15 mg/kg cocaine compared to obesity-resistant rats prior to any diet manipulation. This enhanced sensitivity to this dose of cocaine is indicative of basal differences in the function of mesolimbic circuits in obesity prone rats. We speculate that pre-existing differences in motivational systems may contribute to over-consumption and enhanced motivation in susceptible individuals. PMID- 26423789 TI - Multifunctional L/N- and L/T-type calcium channel blockers for kidney protection. PMID- 26423790 TI - A Defence of the Counterfactual Account of Harm. AB - In order to determine whether a particular course of conduct is ethically permissible it is important to have a concept of what it means to be harmed. The dominant theory of harm is the counterfactual account, most famously proposed by Joel Feinberg. This determines whether harm is caused by comparing what actually happened in a given situation with the 'counterfacts' i.e. what would have occurred had the putatively harmful conduct not taken place. If a person's interests are worse off than they otherwise would have been, then a person will be harmed. This definition has recently faced challenges from bioethicists such as John Harris, Guy Kahane and Julian Savulescu who, believing it to be severely flawed, have proposed their own alternative theories of the concept. In this article I will demonstrate that the shortcomings Harris, Kahane and Savulescu believe are present in Feinberg's theory are illusory and that it is their own accounts of harm that are fraught with logical errors. I maintain that the arguments presented to refute Feinberg's theory not only fail to achieve this goal and can be accommodated within the counterfactual account but that they actually undermine the theories presented by their respective authors. The final conclusion will be that these challenges are misconceived and fail to displace the counterfactual theory. PMID- 26423791 TI - Getting past the dual logic: findings from a pilot asset mapping exercise in Sheffield, UK. AB - Asset-based approaches seek to identify and mobilise the personal, social and organisational resources available to communities. Asset mapping is a recognised method of gathering an inventory of neighbourhood assets and is underpinned by a fundamentally different logic to traditional needs assessments. The aim of this paper is to explore how asset mapping might be used as a tool for health improvement. It reports on a qualitative evaluation of a pilot asset mapping project carried out in two economically disadvantaged neighbourhoods in Sheffield, UK. The project involved community health champions working with two community organisations to identify assets linked to the health and wellbeing of their neighbourhoods. The evaluation was undertaken in 2012 after mapping activities had been completed. A qualitative design, using theory of change methodology, was used to explore assumptions between activities, mechanisms and outcomes. Semi structured interviews were undertaken with a purposive sample of 11 stakeholders including champions, community staff and strategic partners. Thematic analysis was used and themes were identified on the process of asset mapping, the role of champions and the early outcomes for neighbourhoods and services. Findings showed that asset mapping was developmental and understandings grew as participatory activities were planned and implemented. The role of the champions was limited by numbers involved, nonetheless meaningful engagement occurred with residents which led to personal and social resources being identified. Most early outcomes were focused on the lead community organisations. There was less evidence of results feeding into wider planning processes because of the requirements for more quantifiable information. The paper discusses the importance of relational aspects of asset mapping both within communities and between communities and services. The conclusions are that it is insufficient to switch from the logic of needs to assets without building asset mapping as part of a broader planning process. PMID- 26423792 TI - Yeast Bud27 modulates the biogenesis of Rpc128 and Rpc160 subunits and the assembly of RNA polymerase III. AB - Yeast Bud27, an unconventional prefoldin is reported to affect the expression of nutrient-responsive genes, translation initiation and assembly of the multi subunit eukaryotic RNA polymerases (pols), at a late step. We found that Bud27 associates with pol III in active as well as repressed states. Pol III transcription and occupancy at the target genes reduce with the deletion of BUD27. It promotes the interaction of pol III with the chromatin remodeler RSC found on most of the pol III targets, and with the heat shock protein Ssa4, which helps in nuclear import of the assembled pol III. Under nutrient-starvation, Ssa4 pol III interaction increases, while pol III remains inside the nucleus. Bud27 but not Ssa4 is required for RSC-pol III interaction, which reduces under nutrient-starvation. In the bud27Delta cells, total protein level of the largest pol III subunit Rpc160 but not of Rpc128, Rpc34 and Rpc53 subunits is reduced. This is accompanied by lower transcription of RPC128 gene and lower RPC160 translation due to reduced association of mRNA with the ribosomes. The resultant alteration in the normal cellular ratio of the two largest subunits of pol III core leads to reduced association of other pol III subunits and hampers the normal assembly of pol III at an early step in the cytoplasm. Our results show that Bud27 is required in multiple activities responsible for pol III biogenesis and activity. PMID- 26423793 TI - Tinea Incognito. PMID- 26423794 TI - Examining the locations of medical marijuana dispensaries in Los Angeles. AB - INTRODUCTION AND AIMS: Little is known about the spatial distribution of medical marijuana dispensaries, particularly whether or not sites are disproportionately located in minority or communities with younger populations. This paper will assess if there is a relationship between medical marijuana dispensaries and neighbourhood characteristics. DESIGN AND METHODS: This study used an ecological, cross-sectional design of 1000 census tracts from Los Angeles city in 2012 to explore the relationship between neighbourhood sociodemographics, structural features of neighbourhoods and density of medical marijuana dispensaries. Locations of dispensaries were obtained through a premise survey of all listed dispensaries. Data on neighbourhood characteristics were obtained from Geolytics. The study used Bayesian conditionally autoregressive models that include controls for spatial heterogeneity to analyse the data. RESULTS: Findings show that dispensaries are located in areas that allow for commercial establishments. Results indicate a positive relationship between dispensaries and percent commercially zoned, areas with highway ramp access, density of on- and off premise alcohol outlets and percent Hispanic residents. DISCUSSION AND CONCLUSIONS: In sum, the findings suggest that, likely because of zoning regulations, dispensaries were located in primarily commercially zoned areas with greater road access (as measured by the presence of highway ramps). Given that areas with higher densities of dispensaries also have higher densities of alcohol outlets, future work should examine how this co-location affects neighbourhood problems such as crime and violence. [Thomas C, Freisthler B. Examining the locations of medical marijuana dispensaries in Los Angeles. Drug Alcohol Rev 2016;35:334-337]. PMID- 26423795 TI - Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors. AB - PURPOSE: To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with advanced nonhematologic malignancies. EXPERIMENTAL DESIGN: Pevonedistat was administered via 60-minute intravenous infusion on days 1 to 5 (schedule A, n = 12), or days 1, 3, and 5 (schedules B, n = 17, and C, n = 19) of 21-day cycles. Schedule B included oral dexamethasone 8 mg before each pevonedistat dose. Dose escalation proceeded using a Bayesian continual reassessment method. Tumor response was assessed by RECIST 1.0. RESULTS: Schedule A MTD was 50 mg/m(2); based on the severity of observed hepatotoxicity, this schedule was discontinued. Schedules B and C MTDs were 50 and 67 mg/m(2), respectively. DLTs on both these schedules included hyperbilirubinemia and elevated aspartate aminotransferase. There were no grade >= 3 treatment-related serious adverse events reported on schedules B or C. Twenty-three (74%) evaluable patients on schedules B and C had stable disease. Intermittent dexamethasone use did not significantly influence pevonedistat pharmacokinetics. NAE inhibition by pevonedistat was demonstrated in multiple tumor types via IHC detection of pevonedistat-NEDD8 adduct and accumulation of Cullin-RING ligase substrates CDT1 and NRF2 in tumor biopsies. CONCLUSIONS: Pevonedistat was generally well tolerated on a day 1, 3, 5 schedule every 3 weeks with an MTD between 50 mg/m(2) and 67 mg/m(2). DLTs were predominantly hepatic enzyme elevations. Pharmacodynamic studies demonstrated that pevonedistat inhibited NAE in tumors. PMID- 26423796 TI - The IL-15-Based ALT-803 Complex Enhances FcgammaRIIIa-Triggered NK Cell Responses and In Vivo Clearance of B Cell Lymphomas. AB - PURPOSE: Anti-CD20 monoclonal antibodies (mAb) are an important immunotherapy for B-cell lymphoma, and provide evidence that the immune system may be harnessed as an effective lymphoma treatment approach. ALT-803 is a superagonist IL-15 mutant and IL-15Ralpha-Fc fusion complex that activates the IL-15 receptor constitutively expressed on natural killer (NK) cells. We hypothesized that ALT 803 would enhance anti-CD20 mAb-directed NK-cell responses and antibody-dependent cellular cytotoxicity (ADCC). EXPERIMENTAL DESIGN: We tested this hypothesis by adding ALT-803 immunostimulation to anti-CD20 mAb triggering of NK cells in vitro and in vivo. Cell lines and primary human lymphoma cells were utilized as targets for primary human NK cells. Two complementary in vivo mouse models were used, which included human NK-cell xenografts in NOD/SCID-gammac (-/-) mice. RESULTS: We demonstrate that short-term ALT-803 stimulation significantly increased degranulation, IFNgamma production, and ADCC by human NK cells against B-cell lymphoma cell lines or primary follicular lymphoma cells. ALT-803 augmented cytotoxicity and the expression of granzyme B and perforin, providing one potential mechanism for this enhanced functionality. Moreover, in two distinct in vivo B-cell lymphoma models, the addition of ALT-803 to anti-CD20 mAb therapy resulted in significantly reduced tumor cell burden and increased survival. Long term ALT-803 stimulation of human NK cells induced proliferation and NK-cell subset changes with preserved ADCC. CONCLUSIONS: ALT-803 represents a novel immunostimulatory drug that enhances NK-cell antilymphoma responses in vitro and in vivo, thereby supporting the clinical investigation of ALT-803 plus anti-CD20 mAbs in patients with indolent B-cell lymphoma. PMID- 26423797 TI - Subtype-Specific Metagene-Based Prediction of Outcome after Neoadjuvant and Adjuvant Treatment in Breast Cancer. AB - PURPOSE: In spite of improvements of average benefit from adjuvant/neoadjuvant treatments, there are still individual patients with early breast cancer at high risk of relapse. We explored the association with outcome of robust gene cluster based metagenes linked to proliferation, ER-related genes, and immune response to identify those high-risk patients. EXPERIMENTAL DESIGN: A total of 3,847 publicly available gene-expression profiles were analyzed (untreated, N = 826; tamoxifen treated, N = 685; chemotherapy-treated, N = 1,150). Genes poorly performing in formalin-fixed samples were removed. Outcomes of interest were pathologic complete response (pCR) and distant metastasis-free survival (DMFS). In ER(+)HER2(-), the proliferation and ER-related metagenes were combined to define three risk groups. In HER2(+) and ER(-)HER2(-) risk groups were defined by tertiles of an immune-related metagene. RESULTS: The high-proliferation/low-ER group of ER(+)HER2(-) breast cancer had significantly higher pCR rate [OR, 5.01 (1.76-17.99), P = 0.005], but poorer outcome [HR = 3.73 (1.63-8.51), P = 0.0018] than the low-proliferation/high-ER. A similar association with outcome applied to patients with residual disease (RD) after neoadjuvant chemotherapy (P = 0.01). In ER(-)HER2(-) and HER2(+) breast cancer, immune metagene in the high tertile was linked to higher pCR [33.7% vs. 11.6% in high and low tertile, respectively; OR, 3.87 (1.79-8.95); P = 0.0009]. In ER(-)HER2(-), after adjuvant/neoadjuvant chemotherapy, 5-year DMFS was 85.4% for high-tertile immune metagene, and 43.9% for low tertile. The outcome association was similar in patients with RD (P = 0.0055). In HER2(+) breast cancer treated with chemotherapy the association with risk of relapse was not significant. CONCLUSIONS: We developed metagene-based predictors able to define low and high risk of relapse after adjuvant/neoadjuvant therapy. High-risk patients so defined should be preferably considered for trials with investigational agents. PMID- 26423799 TI - Comparative metabolic study between two selective estrogen receptor modulators, toremifene and tamoxifen, in human liver microsomes. AB - Toremifene (TOR) and Tamoxifen (TAM) are widely used as endocrine therapy for estrogen receptor positive breast cancer. Poor metabolizers of TAM are likely to have worse clinical outcomes than patients who exhibit normal TAM metabolism due to lower plasma level of its active metabolite, 4-hydroxy-N-desmethyl (4OH-NDM) tamoxifen (endoxifen). In this study, we examined the role of individual cytochrome P450 (CYP) isoforms in the metabolism of TOR to N-desmethyl (NDM), 4 hydroxy (4OH) and 4OH-NDM metabolites in comparison with TAM using human liver microsomes (HLMs) with selective chemical inhibitors for each CYP isoform and recombinant CYP proteins. Similar levels of NDM metabolites were formed for both TOR and TAM, and N-demethylation of both compounds was primarily carried out by CYP3A4. We found that the formation of 4OH-NDM-TOR was catalyzed both by CYP2C9 and CYP2D6, whereas the formation of 4OH-TAM and endoxifen was specifically catalyzed by CYP2D6 in HLMs. Our results suggest that the potential contribution of CYP2D6 in the bioactivation pathway of TOR may be lower compared to TAM, and may have a different impact on clinical outcome than CYP2D6 polymorphisms. PMID- 26423800 TI - Allelic polymorphism of KIR2DL2/2DL3 in a southern Chinese population. AB - KIR2DL2 and KIR2DL3 segregate as alleles of the same killer cell immunoglobulin like receptor (KIR) gene locus. They have been associated with viral infectious diseases and certain cancers and their allelic information may help to better comprehend mechanisms. The allelic polymorphism of KIR2DL2/2DL3 has been shown to influence their binding specificity and affinity to the HLA-C1 ligands. The present study aims to investigate the distribution of the allelic polymorphism of KIR2DL2/2DL3 in a southern Chinese population using sequence-specific primer polymerase chain reaction (PCR-SSP) and PCR-sequence-based typing (SBT) at the entire coding sequence. Of the 306 tested individuals, 1.96% were positive for KIR2DL2 only, 78.10% for KIR2DL3 only, and 19.93% for both KIR2DL2 and 2DL3. KIR2DL3 showed a high degree of diversity in the study population with 15 alleles detected including 8 novel ones. The predominant 2DL3 allele in the study population is 2DL3*00101 (92.81%) followed by 2DL3*00201 (24.18%), 2DL3*023 (4.25%), and 2DL3*00109 (1.31%). The remaining 11 2DL3 alleles all had a frequency below 1%. Three detected 2DL2 alleles were 2DL2*00301 (18.95%), 2DL2*00101 (3.59%), and the novel 2DL2*013 (0.33%). These results provide further insight into the KIR gene diversity in Southern Chinese and may help to better understand the role played by KIR genes in associated diseases. PMID- 26423798 TI - A vaccine formulated with the major outer membrane protein can protect C3H/HeN, a highly susceptible strain of mice, from a Chlamydia muridarum genital challenge. AB - C3H/HeN female mice were vaccinated with native Chlamydia muridarum major outer membrane protein (MOMP), using Montanide+CpG or Alum+CpG as adjuvants. Negative control groups were immunized with ovalbumin (OVA) and the same adjuvants. As positive control, mice were inoculated intranasally with live Chlamydia. Mice were challenged in the ovarian bursa with 10(5) C. muridarum inclusion forming units. Six weeks after the genital challenge the animals were caged with male mice and monitored for pregnancy. Mice vaccinated with MOMP+Montanide+CpG developed high levels of C. muridarum-specific antibodies, with a high IgG2a/IgG1 ratio and neutralizing titres. Animals immunized using Alum+CpG had low antibody levels. Cellular immune responses were significantly higher in mice vaccinated with MOMP and Montanide+CpG, but not with Alum+CpG, when compared with negative controls. Following the genital challenge, only 20% (4/20) of mice vaccinated with MOMP+CpG+Montanide had positive vaginal cultures whereas 100% (9/9) of mice immunized with MOMP+CpG+Alum had positive cultures. Of the positive control animals inoculated with live Chlamydia only 15% (3/20) had positive vaginal cultures. In contrast, 100% (20/20) of mice immunized with OVA+CpG+Montanide, or minimal essential medium, had positive cultures. Following mating, 80% (16/20) of mice vaccinated with MOMP+CpG+Montanide, and 85% (17/20) of animals inoculated intranasally with live C. muridarum carried embryos in both uterine horns. No protection against infertility was observed in mice immunized with MOMP and CpG+Alum or OVA. In conclusion, this is the first time that a subunit vaccine has been shown to elicit a protective immune response in the highly susceptible C3H/HeN strain of mice against an upper genital challenge. PMID- 26423802 TI - Endoplasmic reticulum stress and autophagy participate in apoptosis induced by bortezomib in cervical cancer cells. AB - OBJECTIVES: To determine the role of endoplasmic reticulum (ER) stress and autophagy in apoptosis induced by bortezomib in human cervical cancer-derived HeLa cells and CaSki cells. RESULTS: Bortezomib treatment activated apoptosis, evidenced by increased expression of cleaved caspase-3 and cleaved PARP in both HeLa cells and CaSki cells. Bortezomib also induced the loss of the mitochondrial membrane potential, increased the level of ER stress-associated proteins GRP78, ATF4, and CCAAT-enhancer-binding protein homologous protein, and affected the expression of autophagy-related proteins; increasing the levels of LC3-II and ATG5-ATG12 and decreasing the level of p62. When we combined bortezomib with the ER stress activator tunicamycin, or autophagy inhibitors 3-methyladenine or chloroquine, cell growth inhibition and apoptosis were markedly enhanced. CONCLUSIONS: Bortezomib activates apoptosis signaling, and activation of ER stress and inhibition of autophagy enhances the cytotoxicity of bortezomib, suggesting that these combination treatments may be potential chemotherapy strategies for treating cervical cancer. PMID- 26423801 TI - Predictors of survival and effect of short (40 Gy) or standard-course (60 Gy) irradiation plus concomitant temozolomide in elderly patients with glioblastoma: a multicenter retrospective study of AINO (Italian Association of Neuro Oncology). AB - The efficacy of temozolomide (TMZ) plus radiation therapy (RT) in elderly patients with glioblastoma is unclear. We performed a large multicenter retrospective study to analyze prognostic factors and clinical outcome in these patients. Inclusion criteria were age >=65 years, newly histologically confirmed glioblastoma, ECOG PS 0-2, adjuvant treatment with RT plus TMZ. We enrolled 237 patients; the average age was 71 and ECOG PS was 0-1 in 196 patients; gross total resection was performed in 174 cases. MGMT was analyzed in 151 persons and was methylated in 56 %. IDH1 was assessed in 100 patients and was mutated in 6 %. Seventy-one patients were treated with RT 40 Gy and 166 with RT 60 Gy. Progression-free survival and overall survival (OS) were 11.3 and 17.3 months, respectively. Overall survival was 19.4 vs 13.8 months for patients treated with RT 60 Gy and 40 Gy (p = 0.02); OS was 17.7 versus 16.1 months for patients treated with gross total resection vs partial surgery (p = 0.02); OS was 21.2 versus 13.6 months for methylated and unmethylated MGMT (p < 0.001). On multivariate analysis, gross total resection, RT 60 Gy, methylated MGMT and ECOG PS 0-1 were independent predictors of longer survival. Twenty-five patients (10 %) had grade 3-4 haematological toxicity during the concomitant treatment. We showed that, in elderly patients in good clinical condition treated with concomitant treatment, standard-course irradiation might be more effective than short-course irradiation. Methylated MGMT remains the most important prognostic factor. PMID- 26423803 TI - Epidermal growth factor receptor inhibition with erlotinib ameliorates anti-Thy 1.1-induced experimental glomerulonephritis. AB - BACKGROUND: Mesangial proliferative glomerulonephritis is a common glomerular disorder that may lead to end-stage renal disease. Epidermal growth factor (EGF) plays an important role in the regulation of cell growth, proliferation, and differentiation and in the pathology of various renal diseases. Erlotinib is a novel, oral, highly selective tyrosine kinase inhibitor of the EGF receptor. It is clinically used to treat non-small cell lung and pancreatic cancers. Here, we investigated the effect of erlotinib on the progression of mesangioproliferative glomerulonephritis in an experimental model. METHODS: Mesangial glomerulonephritis was induced with anti-rat Thy-1.1 antibody in male Wistar rats weighing 150-160 g. Rats were treated with erlotinib (10 mg/kg/day p.o.) or vehicle only (polyethylene glycol). Native Wistar rat kidneys were used as histological controls. Serum creatinine levels were measured at day 7. Kidneys were harvested 7 days after antibody administration for histology. RESULTS: Native controls showed no histological signs of glomerular pathology. In the vehicle group, intense glomerular inflammation developed after 7 days and prominent mesangial cell proliferation and glomerular matrix accumulation was seen. Erlotinib was well tolerated and there were no adverse effects during the follow-up period. Erlotinib significantly prevented progression of the glomerular inflammatory response and glomerular mesangial cell proliferation as well as matrix accumulation when compared with the vehicle group. Erlotinib also preserved renal function. CONCLUSION: These results indicate that erlotinib prevents the early events of experimental mesangial proliferative glomerulonephritis. Therefore, inhibition of the EGF receptor with erlotinib could prevent the progression of glomerulonephritis also in clinical nephrology. PMID- 26423804 TI - Cattell-Braasch Maneuver Combined with Artery-First Approach for Superior Mesenteric-Portal Vein Resection During Pancreatectomy. AB - Pancreatectomy associated with superior mesenteric-portal vein (SMPV) resection is currently considered the standard of care for patients with pancreatic tumors involving the major peripancreatic veins. However, a standard approach for resection and reconstruction is not defined yet. The aim of this study is to analyze the feasibility and short-term results of an original Cattell-Braasch artery-first approach (CBAF) for the resection of SMPV during pancreatectomy. Of 144 pancreatectomies with vascular resection undertaken from 2008 to 2013 at Karolinska University Hospital, 45 (31.2 %) were performed combining a Cattell Braasch maneuver with an artery-first approach (from 2011 to 2013). The mean patient age was 65.2 years. Thirty-seven (82.2 %) patients underwent pancreatoduodenectomy and 8 (17.8 %) total pancreatectomy. Histology showed pancreatic ductal adenocarcinoma in 42 patients (93.3 %). The median length of the resected SMPV segment was 4.6 cm (range 3-7). In all patients, a direct end to-end anastomosis was performed without graft interposition. In nine cases (20 %), an arterial resection was also performed. There was no mortality in this series, and the morbidity rate was 35.5 %. Combined CBAF for the resection of SMPV during pancreatectomy seems to be safe and effective. The reconstruction of the resected vessels is possible in many cases without graft interposition, even if the resected vein segment is of considerable length. PMID- 26423805 TI - Effect of rituximab on adult Burkitt's lymphoma: a systematic review and meta analysis. AB - The treatment of Burkitt's lymphoma with rituximab is controversial, and studies that compared the efficacy of chemotherapy alone with chemotherapy plus rituximab have not been powered to test differences in overall survival (OS). We conducted this systematic review and meta-analysis to identify the value of rituximab for the treatment of BL to guide treatment decisions. Based on the PubMed, Web of Science, and Cochrane library online electronic databases, all retrospective and randomized clinical trial studies that compared the aforementioned two regimens were included. The pooled hazard ratio and odds ratio were analyzed using Review Manager 5.3. The primary outcome was the 2-year OS. A total of 581 publications were identified using a predetermined search strategy. One randomized controlled trial (RCT) and five retrospective studies, which included 646 cases (351 cases for the chemotherapy with rituximab group and 295 cases for the chemotherapy alone group), fulfilled the selection criteria and were included in the meta analysis. The chemotherapy with rituximab group was associated with a higher 2 year OS (hazard ratio 0.62, 95 % CI 0.45-0.85, P = 0.003), 2-year progression free survival (hazard ratio 0.46, 95 % CI 0.43-0.50, P < 0. 001), and complete remission rate (odds ratios 3.26, 95 % CI 1.22-8.66, P = 0.02). In addition, the treatment-related mortality did not significantly differ between the two treatment regimens (odds ratio 1.16, 95 % CI 0.55-2.45, P = 0.69). The meta analysis indicates that the addition of rituximab to the treatment regimen for Burkitt's lymphoma may be associated with a significant survival benefit and did not increase the mortality compared with chemotherapy alone. PMID- 26423807 TI - Postnatal depressive symptoms amongst women in Central Vietnam: a cross-sectional study investigating prevalence and associations with social, cultural and infant factors. AB - BACKGROUND: This study investigated the prevalence and socio-cultural correlates of postnatal mood disturbance amongst women 18-45 years old in Central Vietnam. Son preference and traditional confinement practices were explored as well as factors such as poverty, parity, family and intimate partner relationships and infant health. METHODS: A cross-sectional study was conducted in twelve randomly selected Commune Health Centres from urban and rural districts of Thua Thien Hue Province, Vietnam. Mother-infant dyads one to six months postpartum were invited to participate. Questionnaires from 431 mothers (urban n = 216; rural n = 215) assessed demographic and family characteristics, traditional confinement practices, son preference, infant health and social capital. The Edinburgh Postnatal Depression Scale (EPDS) and WHO5 Wellbeing Index indicated depressive symptoms and emotional wellbeing. Data were analysed using general linear models. RESULTS: Using an EPDS cut-off of 12/13, 18.1% (n = 78, 95% CI 14.6-22.1) of women had depressive symptoms (20.4% urban; 15.8% rural). Contrary to predictions, infant gender and traditional confinement were unrelated to depressive symptoms. Poverty, food insecurity, being frightened of family members, and intimate partner violence increased both depressive symptoms and lowered wellbeing. The first model accounted for 30.2% of the variance in EPDS score and found being frightened of one's husband, husband's unemployment, breastfeeding difficulties, infant diarrhoea, and cognitive social capital were associated with higher EPDS scores. The second model had accounted for 22% of the variance in WHO5 score. Living in Hue city, low education, poor maternal competence and a negative family response to the baby lowered maternal wellbeing. CONCLUSIONS: Traditional confinement practices and son preference were not linked to depressive symptoms among mothers, but were correlates of family relationships and wellbeing. Poverty, food insecurity, violence, infant ill health, and discordant intimate and family relationships were linked with depressive symptoms in Central Vietnam. PMID- 26423809 TI - The Lancet HIV: a journal for a new era of AIDS. PMID- 26423806 TI - White matter deficits assessed by diffusion tensor imaging and cognitive dysfunction in psychostimulant users with comorbid human immunodeficiency virus infection. AB - BACKGROUND: Psychostimulant drug use is commonly associated with drug-related infection, including the human immunodeficiency virus (HIV). Both psychostimulant use and HIV infection are known to damage brain white matter and impair cognition. To date, no study has examined white matter integrity using magnetic resonance imaging (MRI) diffusion tensor imaging (DTI) in chronic psychostimulant users with comorbid HIV infection, and determined the relationship of white matter integrity to cognitive function. METHODS: Twenty-one subjects (mean age 37.5 +/- 9.0 years) with a history of heavy psychostimulant use and HIV infection (8.7 +/- 4.3 years) and 22 matched controls were scanned on a 3T MRI. Fractional anisotropy (FA) values were calculated with DTI software. Four regions of interest were manually segmented, including the genu of the corpus callosum, left and right anterior limbs of the internal capsule, and the anterior commissure. Subjects also completed a neurocognitive battery and questionnaires about physical and mental health. RESULTS: The psychostimulant using, HIV positive group displayed decreased white matter integrity, with significantly lower FA values for all white matter tracts (p < 0.05). This group also exhibited decreased cognitive performance on tasks that assessed cognitive set-shifting, fine motor speed and verbal memory. FA values for the white matter tracts correlated with cognitive performance on many of the neurocognitive tests. CONCLUSIONS: White matter integrity was thus impaired in subjects with psychostimulant use and comorbid HIV infection, which predicted worsened cognitive performance on a range of tests. Further study on this medical comorbidity is required. PMID- 26423808 TI - Methicillin-resistant Staphylococcus pseudintermedius (MRSP) from healthy dogs in Norway - occurrence, genotypes and comparison to clinical MRSP. AB - The aim of the study was to investigate the occurrence of methicillin-resistant Staphylococcus pseudintermedius (MRSP) in healthy dogs and further to determine genetic relatedness between carrier isolates and clinical MRSP from dogs in Norway. A total of 189 healthy dogs visiting ten veterinary clinics were screened for MRSP during the period February to April 2013. Carrier isolates were susceptibility tested with disk diffusion and genotyped using multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE). Forty-nine clinical MRSP were characterized for comparison. These isolates were collected from July 2008 to April 2013 and represent all MRSP index isolates from each MRSP-positive dog detected in Norway until April 2013. Geographical distribution of all MRSP cases was investigated using the ArcGIS 9.3 Software. MRSP was detected from five (2.6%) healthy dogs, sampled at three different clinics. The isolates grouped into three sequence types (STs): ST252 (two isolates), ST71 (two isolates) and ST306 (one isolate). MRSP from dogs sampled at the same animal clinic belonged to the same ST and produced identical PFGE pattern. The 49 clinical MRSP grouped into 15 STs; ST258 (n = 17), ST71 (n = 10), and ST305 (n = 4) were the most prevalent. The MRSP carrier isolates were genetically related to MRSP variants from dogs with infections as ST306 (from a carrier) is related to ST258. MRSP ST252, found in two carriers, was also present among the clinical MRSP isolates. Altogether the MRSP isolates were genetically diverse and MRSP of other lineages than ST71 continues to disseminate in Norway. Susceptibility testing showed that MRSP isolates of the ST71 lineage were the most multiresistant. Our study showed that MRSP could be detected in healthy dogs without infections and with no recent history of antimicrobial therapy stressing the need for future monitoring, infection control and prudent use of antimicrobial agents. PMID- 26423810 TI - 90-90-90: how do we get there? PMID- 26423811 TI - Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial. AB - BACKGROUND: Activating the expression of latent virus is an approach that might form part of an HIV cure. We assessed the ability of the histone deacetylase inhibitor panobinostat to disrupt HIV-1 latency and the safety of this strategy. METHODS: In this phase 1/2 clinical trial, we included aviraemic adults with HIV treated at Aarhus University Hospital, Denmark. Participants received oral panobinostat (20 mg) three times per week every other week for 8 weeks while maintaining combination antiretroviral therapy. The primary outcome was change from baseline of cell-associated unspliced HIV RNA. Secondary endpoints were safety, plasma HIV RNA, total and integrated HIV DNA, infectious units per million CD4 T cells, and time to viral rebound during an optional analytical treatment interruption of antiretroviral therapy. This trial is registered with ClinicalTrial.gov, number NCT01680094. FINDINGS: We enrolled 15 patients. The level of cell-associated unspliced HIV RNA increased significantly at all timepoints when patients were taking panobinostat (p < 0.0001). The median maximum increase in cell-associated unspliced HIV RNA during panobinostat treatment was 3.5-fold (range 2.1-14.4). Panobinostat induced plasma viraemia with an odds ratio of 10.5 (95% CI 2.2-50.3; p = 0.0002) compared with baseline. We recorded a transient decrease in total HIV DNA, but no cohort-wide reduction in total HIV DNA, integrated HIV DNA, or infectious units per million. Nine patients participated in the analytical treatment interruption, median time to viral rebound was 17 days (range 14-56). Panobinostat was well tolerated. 45 adverse events were reported, but only 16 (all grade 1) were presumed related to panobinostat. INTERPRETATION: Panobinostat effectively disrupts HIV latency in vivo and is a promising candidate for future combination clinical trials aimed at HIV eradication. However, panobinostat did not reduce the number of latently infected cells and this approach may need to be combined with others to significantly affect the latent HIV reservoir. FUNDING: The Danish Council for Strategic Research and Aarhus University. PMID- 26423812 TI - Tentative first steps to eradicate latent HIV. PMID- 26423813 TI - Recreational drug use, polydrug use, and sexual behaviour in HIV-diagnosed men who have sex with men in the UK: results from the cross-sectional ASTRA study. AB - BACKGROUND: Recreational drug use in men who have sex with men (MSM) is of concern because it might be linked to the transmission of HIV and other sexually transmitted infections. Evidence about drug use in HIV-diagnosed MSM in the UK is limited by representativeness of the study populations. We describe patterns of drug use and associations with sexual behaviours in HIV-diagnosed MSM in the UK. METHODS: We used data from the cross-sectional ASTRA study, which recruited participants aged 18 years or older with HIV from eight HIV outpatient clinics in the UK between Feb 1, 2011, and Dec 31, 2012. We examined data for MSM, assessing the prevalence of recreational drug use and polydrug use in the previous 3 months and associations with sociodemographic and HIV-related factors. We examined the association of polydrug use with measures of condomless sex in the previous 3 months and with other sexual behaviours. FINDINGS: Our analysis included data for 2248 MSM: 2136 (95%) were gay, 1973 (89%) were white, 1904 (85%) were on antiretroviral treatment (ART), and 1682 (76%) had a viral load of 50 copies per mL or lower. 1138 (51%) used recreational drugs in the previous 3 months; 608 (27%) used nitrites, 477 (21%) used cannabis, 460 (21%) used erectile dysfunction drugs, 453 (20%) used cocaine, 280 (13%) used ketamine, 258 (12%) used 3,4 methylenedioxy-N-methylamphetamine (MDMA), 221 (10%) used gamma-hydroxybutyrate or gamma-butyrolactone, 175 (8%) used methamphetamine, and 162 (7%) used mephedrone. In the 1138 individuals who used drugs, 529 (47%) used three or more drugs and 241 (21%) used five or more. Prevalence of injection drug use was 3% (n = 68). Drug use was independently associated with younger age (p < 0.0001), not being religious (p = 0.001), having an HIV-positive stable partner (p = 0.0008), HIV-serostatus disclosure (p = 0.009), smoking (p < 0.0001), evidence of harmful alcohol drinking (p = 0.0001), and ART non-adherence (p < 0.0001). Increasing polydrug use was associated with increasing prevalence of condomless sex (prevalence range from no drug use to use of five or more drugs was 24% to 78%), condomless sex with HIV-seroconcordant partners (17% to 69%), condomless sex with HIV-serodiscordant partners (10% to 25%), and higher-HIV-risk condomless sex after taking viral load into account (4% to 16%; p <= 0.005 for all). Associations were similar after adjustment for sociodemographic and HIV-related factors. Methamphetamine was more strongly associated with higher-HIV-risk condomless sex than were other commonly used drugs. INTERPRETATION: Polydrug use is prevalent in HIV-diagnosed MSM and is strongly associated with condomless sex. Specialist support services for MSM with HIV who use recreational drugs might be beneficial in the reduction of harm and prevention of ongoing transmission of HIV and other sexually transmitted infections. FUNDING: National Institute for Health Research. PMID- 26423814 TI - Health-related quality-of-life of people with HIV in the era of combination antiretroviral treatment: a cross-sectional comparison with the general population. AB - BACKGROUND: Combination antiretroviral therapy has substantially increased life expectancy in people living with HIV, but the effects of chronic infection on health-related quality of life (HRQoL) are unclear. We aimed to compare HRQoL in people with HIV and the general population. METHODS: We merged two UK cross sectional surveys: the ASTRA study, which recruited participants aged 18 years or older with HIV from eight outpatient clinics in the UK between Feb 1, 2011, and Dec 31, 2012; and the Health Survey for England (HSE) 2011, which measures health and health-related behaviours in individuals living in a random sample of private households in England. The ASTRA study has data for 3258 people (response rate 64%) and HSE for 8503 people aged 18 years or older (response rate 66%). HRQoL was assessed with the Euroqol 5D questionnaire 3 level (EQ-5D-3L) instrument that measures health on five domains, each with three levels. The responses are scored on a scale where a value of 1 represents perfect health and a value of 0 represents death, known as the utility score. We used multivariable models to compare utility scores between the HIV and general population samples with adjustment for several sociodemographic factors. FINDINGS: 3151 (97%) of 3258 of participants in ASTRA and 7424 (87%) of 8503 participants in HSE had complete EQ 5D-3L data. The EQ-5D-3L utility score was lower for people with HIV compared with that in the general population (marginal effect in utility score adjusted for age, and sex/sexuality -0.11; 95% CI -0.13 to -0.10; p < 0.0001). HRQoL was lower for people with HIV for all EQ-5D-3L domains, particularly for anxiety/depression. The difference in utility score was significant after adjustment for several additional sociodemographic variables (ethnic origin, education, having children, and smoking status) and was apparent across all CD4 cell count, antiretroviral therapy, and viral load strata, but was greatest for those people diagnosed with HIV in earlier calendar periods. Reduction in HRQoL with age was not greater in people with HIV than in the general population (pinteraction > 0.05). INTERPRETATION: People living with HIV have significantly lower HRQoL than do the general population, despite most HIV positive individuals in this study being virologically and immunologically stable. Although this difference could in part be due to factors other than HIV, this study provides additional evidence of the loss of health that can be avoided through prevention of further HIV infections. FUNDING: UK National Institute for Health Research. PMID- 26423815 TI - Sex, drugs, and HIV: let's avoid panic. PMID- 26423816 TI - Characterisation of long-term non-progression of HIV-1 infection after seroconversion: a cohort study. AB - BACKGROUND: Some individuals remain AIDS-free with a high and stable CD4 cell count without antiretroviral therapy (ART) for many years. We estimated long-term progression-free survival after HIV seroconversion and aimed to identify factors associated with loss of long-term non-progression (LTNP) status. METHODS: For this cohort study, we used data for individuals with well-estimated dates of HIV 1 seroconversion from the CASCADE Collaboration a network of 28 HIV seroconverter cohort studies in Europe, Australia, Canada, and sub-Saharan Africa. The first cohort began enrolling patients in 1979, and for this analysis we used data pooled in May 1, 2011. We defined non-progression as being HIV-positive without AIDS, ART-naive, and with CD4 counts of 500 cells per MUL or higher. We defined LTNP as non-progression during the first 10 years after seroconversion. We used longitudinal methods to characterise LTNP. FINDINGS: Of the 4979 HIV seroconverters in our dataset, 3708 (75%) were men. Median time to progression was 2.07 years (95% CI 1.96-2.17), giving estimated progression-free survivals of 18.4% (17.2-19.6) 5 years, 4.0% (3.6-4.5) 10 years, and 1.4% (0.9-1.5) 15 years after seroconversion. The rate of progression did not change beyond 10 years after seroconversion (0.28 [95%CI 0.26-0.31] per person-year at 10 years after seroconversion, 0.24 [0.19-0.29] per person-year at 15 years, and 0.18 [0.10 0.33] per person-year at 20 years). At 10 years since HIV seroconversion, 283 individuals had LTNP, of whom 202 subsequently lost this status (median time to loss of status 2.49 years [2.05-2.92]). In univariable analyses, loss of LTNP status was associated with CD4 cell count at 10 years after seroconversion (p < 0.0001) and HIV RNA load at 10 years after seroconversion (p = 0.005), but not age (p = 0.544), mode of infection (p = 0.621), sex (p = 0.676), or calendar year of seroconversion (p = 0.397). In the multivariable analyses, loss of LTNP status was associated with lower CD4 counts at 10 years after seroconversion (p < 0.0001). After exclusion of CD4 cell counts from the model, higher HIV RNA load at 10 years after seroconversion was independently associated with loss of LTNP status (p = 0.009). INTERPRETATION: Progression-free survival is rare. Most individuals with LTNP eventually lose immunological and clinical control of HIV infection eventually. FUNDING: European Union Seventh Framework Programme. PMID- 26423817 TI - Quality of life in chronic HIV infection. PMID- 26423818 TI - The death of HIV long-term non-progression? PMID- 26423819 TI - High burden of malaria infection in pregnant women in a rural district of Zambia: a cross-sectional study. AB - BACKGROUND: Malaria continues to be a major health problem in low-income countries. Consequently, malaria control remains a public health priority in endemic countries such as Zambia. Pregnant women and children under 5 years of age are among groups at high risk of malaria infection. Malaria infection is associated with adverse birth outcomes that affect the mother, foetus, and infant. Infection with HIV has been shown to increase the risk of malaria infection in pregnancy. The prevalence and the predictors of malaria infection among pregnant women resident in the Nchelenge District of northern Zambia were investigated. METHODS: Between November 2013 and April 2014, pregnant women in the catchment areas of two health centres were recruited during their first antenatal care visit. HIV testing was conducted as part of routine care. In addition, blood samples were collected from 1086 participants and tested for malaria infection using standard microscopy and polymerase chain reaction (PCR) techniques specific for Plasmodium falciparum. Multivariate logistic regression were conducted to examine the predictors of malaria infection. RESULTS: The prevalence of malaria identified by microscopy was 31.8 % (95 % confidence intervals [CI], 29.0-34.5; N = 1079) and by PCR was 57.8 % (95 % CI, 54.9-60.8; N = 1074). HIV infection was 13.2 % among women on their first antenatal visit; the prevalence of malaria detected by PCR among HIV-uninfected and HIV-infected women was 56.7 % (531/936) and 65.2 % (90/138), respectively. In the final model, the risk of malaria infection was 81 % higher among pregnant women recruited from Nchelenge health centre compared to those attending the Kashikishi health centre (adjusted odds ratio = 1.81; 95 % CI, 1.38-2.37, P < 0.001), and HIV-infected women across health centres had a 46 % greater risk of malaria infection compared to HIV-uninfected women (adjusted odds ratio = 1.46; 95 %, 1.00-2.13, P = 0.045). CONCLUSION: High burden of malaria detected by PCR in these pregnant women suggests that past prevention efforts have had limited effect. To reduce this burden of malaria sustainably, there is clear need to strengthen existing interventions and, possibly, to change approaches so as to improve targeting of groups most affected by malaria. PMID- 26423820 TI - Scattered atypical melanocytes with hyperchromatic nuclei in the nail matrix: diagnostic clue for early subungual melanoma in situ. AB - BACKGROUND: The lack of highly specific clinical and histopathological criteria has contributed to the delay in diagnosis of subungual melanoma in situ in its early stages. METHODS: Eighteen cases of subungual melanoma in situ, the largest series reported to date, were analyzed to characterize the clinical and histopathological findings of early stages of subungual melanoma in situ along with five cases of nail matrix nevus and five cases of subungual lentigo serving as histologic control. RESULTS: Clinically, longitudinal melanonychia was present in all 18 cases of subungual melanoma in situ, consisting of irregular dark brown to black streaks within a brown background with (11 cases) or without Hutchinson's sign. Histopathologically, variable shaped and sized, hyperchromatic nuclei surrounded by retraction artifact were present in all cases. Nine cases showed a significant increase in the number of atypical melanocytes with marked nuclear atypia, while the rest of the cases showed less noticeable changes in nail matrix including lower density of melanocytes and/or mild nuclear atypia. In 15 cases, the nuclear enlargement in some of the melanocytes was greater than two times that of the neighboring matrix cells. In the remaining three cases, the nuclei were enlarged to a much lesser degree. All cases displayed areas of haphazard and uneven distribution of solitary melanocytes and, although not observed in all cases, some degree of pagetoid spread was present in majority of the cases. In contrast, nail matrix nevi showed well-formed nests consisting of relatively monomorphous melanocytes with abundant cytoplasm and subungual lentigos consisted of subtle increase in the number of dendritic melanocytes in solitary units within the lower layers of the nail matrix. CONCLUSION: Increase in the number of scattered atypical melanocytes with large hyperchromatic nuclei in a partial nail matrix may provide a diagnostic clue to subungual melanoma in situ in concert with its clinical suspicion. PMID- 26423821 TI - Segmental HOG: new descriptor for glomerulus detection in kidney microscopy image. AB - BACKGROUND: The detection of the glomeruli is a key step in the histopathological evaluation of microscopic images of the kidneys. However, the task of automatic detection of the glomeruli poses challenges owing to the differences in their sizes and shapes in renal sections as well as the extensive variations in their intensities due to heterogeneity in immunohistochemistry staining. Although the rectangular histogram of oriented gradients (Rectangular HOG) is a widely recognized powerful descriptor for general object detection, it shows many false positives owing to the aforementioned difficulties in the context of glomeruli detection. RESULTS: A new descriptor referred to as Segmental HOG was developed to perform a comprehensive detection of hundreds of glomeruli in images of whole kidney sections. The new descriptor possesses flexible blocks that can be adaptively fitted to input images in order to acquire robustness for the detection of the glomeruli. Moreover, the novel segmentation technique employed herewith generates high-quality segmentation outputs, and the algorithm is assured to converge to an optimal solution. Consequently, experiments using real world image data revealed that Segmental HOG achieved significant improvements in detection performance compared to Rectangular HOG. CONCLUSION: The proposed descriptor for glomeruli detection presents promising results, and it is expected to be useful in pathological evaluation. PMID- 26423822 TI - Stratifying the outcome after neoadjuvant treatment using pathological response classification by the Japanese Breast Cancer Society. AB - BACKGROUNDS: Neoadjuvant chemotherapy (NAC) is one of the standard treatment for patients with operable and locally advanced breast cancer. Pathological response after NAC has been assessed according to the Japanese Breast Cancer Society (JBCS) classification in Japan. This classification that was first established in 1998 and revised in 2007 has been used in routine clinical practice in Japan. In the present study, we investigated whether the assessment of pathological response according to this classification could stratify the long-term outcome of patients with breast cancer. METHODS: Patients with breast cancer who had received neoadjuvant chemotherapy between January 2003 and December 2005 in 6 hospitals participating in this study were identified. Patients whose response was judged to be Grade 2 was reassessed into Grades 2a and 2b according to the updated JBCS classification revised in 2007. Then, the association of pathological response and recurrence-free survival (RFS) was analyzed. RESULTS: 635 patients received NAC and 154 relapses (24 %) were observed during a median follow-up of 41.5 months (range 4.2-69.5 months). There was a statistically significant difference in RFS among each pathological response. 5-year RFS of patients with Grade 3 without residual ductal carcinoma in situ was 94 %. 5-year RFS were 88 % in Grade 3, 95 % in Grade 2b, 80 % in Grade 2a, 73 % in Grade 1b, 67 % in Grade 1a, 59 % in Grade 0, respectively. CONCLUSIONS: An outcome could be stratified by assessing tumor burden following NAC according to the JBCS classification. PMID- 26423824 TI - Locking compression plate stabilization of 20 distal radial and ulnar fractures in toy and miniature breed dogs. AB - OBJECTIVE: To evaluate retrospectively the effectiveness of the Locking Compression Plate(r) (LCP), in the form of either a straight or notched head T plate, for the treatment of fractures of the distal radius and ulna in a series of 20 toy and miniature breed dogs. METHODS: The medical records of toy and miniature breed dogs (<6 kg), greater than six months of age, with fractures of the distal radius and ulna from two veterinary hospitals were reviewed. The inclusion criteria included: fractures of the distal 1/3 of the radius and ulna and repair with open reduction and internal fixation utilizing an LCP (straight or notched head T-plate). RESULTS: Twenty fractures (20 dogs) satisfied the inclusion criteria; eight straight and 12 notched head T-plates were used, either 2.0 mm (n = 13) or 2.4 mm (n = 7). Hybrid fixation was performed in all dogs in one or both fragments. Mean time to radiographic union was 6.9 +/- 2.5 weeks (range: 4-12 weeks) in 18/20 dogs with radiographic follow-up. One complication was observed: infection that resolved with antibiotic medication and implant removal. No other major complications occurred by the time of last follow-up. In all cases (mean follow-up: 15 +/- 7 months), the reported limb function as evaluated by the referring veterinarian or owner was excellent. CLINICAL SIGNIFICANCE: The LCP, used as a hybrid construct for the treatment of distal radial and ulnar fractures was shown to yield excellent clinical results with both uncomplicated healing and excellent functional outcomes in this series of toy and miniature breed dogs. PMID- 26423823 TI - Positively biased self-perceptions of peer acceptance and subtypes of aggression in children. AB - There is a growing body of research linking children's positively biased self perceptions with higher levels of aggression. This study extended this area of research by examining prospective associations of positively biased self perceptions of peer acceptance with overt and relational aggression. In addition, moderating effects of peer rejection were examined to test the "disputed overestimation hypothesis," which posits that the link between bias and aggression is limited to children who are rejected by their peers. Using a two wave longitudinal design, measures of peer-rated and self-perceived peer acceptance and peer-rated overt and relational aggression were obtained for 712 children in 3rd through 5th grades (386 girls and 326 boys). Positively biased perceptions led to increases in relational, but not overt, aggression. This pattern was observed even when the effects of gender, race, peer rejection, and overt aggression on relational aggression were controlled. Contrary to the disputed overestimation hypothesis, the prospective associations between bias and aggression did not vary as a function of children's peer rejection status, thus supporting the view that positive bias predicts future aggressive behavior, regardless of social status. The results are discussed in terms of the comparability with previous findings and practical implications. PMID- 26423825 TI - Imprecision Investigation and Analysis of Routine Chemistry in China. AB - BACKGROUND: This study aims to investigate the imprecision of internal quality control of routine chemistry analytes so that we can have an overall knowledge of imprecision level of measurement in laboratories in China. METHODS: The internal quality control information including two kinds of coefficient of variations (CVs) of 22 analytes were collected via an on-line questionnaire. Then, the percentages of laboratories meeting the quality requirement for each analyte were calculated according to five imprecision criteria. RESULTS: Among these 22 analytes, creatine kinase got the most satisfied result, the percentages of laboratories whose current CV met 1/3 total allowable error (1/3TEa), 1/4TEa, and the specifications based on biological variation were 99.3%, 95.9%, 99.6%, 99.9%, and 90.6%, respectively, while Na got the lowest satisfaction rate according to these specifications, which were 4.15%, 22.4%, 4.2%, 9.0%, and 1.3%, respectively. From an overall perspective, most of the 22 analytes got a satisfied result when applying the criteria defined by CLIA'88, while only a small amount of laboratories can meet the requirement when applying the specifications derived from biological variation. CONCLUSIONS: There is huge space for us to enhance and substantial effort is needed in improving and implementing quality management in China. PMID- 26423826 TI - A trial to find appropriate animal models of dichloropropane-induced cholangiocarcinoma based on the hepatic distribution of glutathione S transferases. AB - OBJECTIVES: It has been reported that 1,2-Dichloropropane (DCP) induced cholangiocarcinoma (CCA) in offset color proof-printing workers. However, exposure to DCP by inhalation or gavage for 2 year did not induce CCA in mice and rats. The present study mapped the hepatic distribution of GST, which is known to activate dihalogenated alkanes, and proliferative and fibrotic changes in bile ducts in various species to find the most appropriate animal model of DCP-induced CCA. METHODS: First, 12 each of C57BL/6J mice, Balb/cA mice, F344 rats, Syrian hamsters, and guinea pigs were divided into four equal groups and exposed to DCP at 0, 300, 1,000, or 3,000 ppm 8 hours/day for 7 days. Second, 32 Balb/cA mice and 32 Syrian hamsters were each divided into four equal groups and exposed to DCP at 0, 200, 400, and 800 ppm 6 hours/day for 14 days. After the last exposure, the animals were decapitated, and the livers were dissected out for histopathological evaluation. Immunostaining was conducted to determine the distribution of GSTT1, GSTM1, and GSTPi, as well as the expression of proliferation marker Ki67. RESULTS: GSTT1, GSTM1, and GSTPi were expressed in both hepatocytes and bile duct cells in all control and exposed animals. There was no clear difference in the expression of Ki67 between the exposed groups and the control. No fibrotic changes were observed in any species or strains examined. CONCLUSIONS: Expression of GSTT1 or other GST isozymes might not explain the difference in sensitivity of hepatocytes and the bile duct to DCP between humans and rodents. PMID- 26423827 TI - Determinants of workplace violence against clinical physicians in hospitals. AB - OBJECTIVES: Workplace violence in the health sector is a worldwide concern. Physicians play an essential role in health-care teamwork; thus, understanding how organizational factors influence workplace violence against physicians is critical. METHODS: A total of 189 physicians from three public hospitals and one private hospital in Northern Taiwan completed a survey, and the response rate was 47.1%. This study was approved by the institutional review board of each participating hospital. The 189 physicians were selected from the Taipei area, Taiwan. RESULTS: The results showed that 41.5% of the respondents had received at least one workplace-related physical or verbal violent threat, and that 9.8% of the respondents had experienced at least one episode of sexual harassment in the 3 months before the survey. Logistic regression analysis revealed that physicians in psychiatry or emergency medicine departments received more violent threats and sexual harassment than physicians in other departments. Furthermore, physicians with a lower workplace safety climate (OR=0.89; 95% CI=0.81-0.98) and more job demands (OR=1.15; 95% CI=1.02-1.30) were more likely to receive violent threats. CONCLUSIONS: This study found that workplace violence was associated with job demands and the workplace safety climate. Therefore, determining how to develop a workplace safety climate and ensure a safe job environment for physicians is a crucial management policy issue for health-care systems. PMID- 26423828 TI - Associations of neighborhood-level workplace violence with workers' mental distress problems: a multilevel analysis of Taiwanese employees. AB - OBJECTIVE: Workplace violence is known to pose mental health risks. However, whether or not workplace violence in a surrounding area might further increase the risk of mental distress in workers has rarely been examined. METHODS: The study subjects were 9,393 male and 7,716 female employees who participated in a nationwide survey in 2010. Their personal experiences of workplace violence over the past 1 year were ascertained by a standardized questionnaire. Also assessed were their psychosocial work characteristics and mental distress problems. Neighborhood-level workplace violence was computed based on aggregated data at the county level and was categorized into low-, medium-, and high-level categories. Multilevel logistic regression models were constructed to examine the associations between neighborhood-level workplace violence and individual-level mental distress problems, with adjustment of individual-level experience of workplace violence. FINDINGS: The neighborhood-level prevalence of workplace violence ranged from 4.7 to 14.7% in men and from 6.4 to 14.8% in women across 22 counties. As compared with those who live in counties of the lowest tertile of workplace violence, female workers who lived in counties of the highest tertile of workplace violence had a 1.72-fold increased risk for mental distress problems after controlling for individual experience of workplace violence and other psychosocial work characteristics. CONCLUSION: Neighborhood-level workplace violence was associated with poor mental health in female workers. Preventative strategies targeting workplace violence should pay attention to neighborhood factors and gender-specific effects that might influence societal tolerance of abusive work practices and workers' vulnerability to mental health impacts of workplace violence. PMID- 26423829 TI - Pancreatic cysts suspected to be branch duct intraductal papillary mucinous neoplasm without concerning features have low risk for development of pancreatic cancer. AB - BACKGROUND: The risk of developing pancreatic cancer is uncertain in patients with clinically suspected branch duct intraductal papillary mucinous neoplasm (BD IPMN) based on the "high-risk stigmata" or "worrisome features" criteria proposed in the 2012 international consensus guidelines ("Fukuoka criteria"). METHODS: Retrospective case series involving patients referred for endoscopic ultrasound (EUS) of indeterminate pancreatic cysts with clinical and EUS features consistent with BD-IPMN. Rates of pancreatic cancer occurring at any location in the pancreas were compared between groups of patients with one or more Fukuoka criteria ("Highest-Risk Group", HRG) and those without these criteria ("Lowest Risk Group", LRG). RESULTS: After exclusions, 661 patients comprised the final cohort (250 HRG and 411 LRG patients), 62% female with an average age of 67 years and 4 years of follow up. Pancreatic cancer, primarily adenocarcinoma, occurred in 60 patients (59 HRG, 1 LRG). Prevalent cancers diagnosed during EUS, immediate surgery, or first year of follow up were found in 48/661 (7.3%) of cohort and exclusively in HRG (33/77, 42.3%). Using Kaplan-Meier method, the cumulative incidence of cancer at 7 years was 28% in HRG and 1.2% in LRG patients (P<0.001). CONCLUSIONS: This study supports using Fukuoka criteria to stratify the immediate and long-term risks of pancreatic cancer in presumptive BD-IPMN. The risk of pancreatic cancer was highest during the first year and occurred exclusively in those with "high-risk stigmata" or "worrisome features" criteria. After the first year all BD-IPMN continued to have a low but persistent cancer risk. PMID- 26423832 TI - India has low doctor to patient ratio, study finds. PMID- 26423830 TI - Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms. AB - Essential thrombocythemia (ET) and primary myelofibrosis (PMF) are chronic diseases characterized by clonal hematopoiesis and hyperproliferation of terminally differentiated myeloid cells. The disease is driven by somatic mutations in exon 9 of CALR or exon 10 of MPL or JAK2-V617F in >90% of the cases, whereas the remaining cases are termed "triple negative." We aimed to identify the disease-causing mutations in the triple-negative cases of ET and PMF by applying whole-exome sequencing (WES) on paired tumor and control samples from 8 patients. We found evidence of clonal hematopoiesis in 5 of 8 studied cases based on clonality analysis and presence of somatic genetic aberrations. WES identified somatic mutations in 3 of 8 cases. We did not detect any novel recurrent somatic mutations. In 3 patients with clonal hematopoiesis analyzed by WES, we identified a somatic MPL-S204P, a germline MPL-V285E mutation, and a germline JAK2-G571S variant. We performed Sanger sequencing of the entire coding region of MPL in 62, and of JAK2 in 49 additional triple-negative cases of ET or PMF. New somatic (T119I, S204F, E230G, Y591D) and 1 germline (R321W) MPL mutation were detected. All of the identified MPL mutations were gain-of-function when analyzed in functional assays. JAK2 variants were identified in 5 of 57 triple-negative cases analyzed by WES and Sanger sequencing combined. We could demonstrate that JAK2 V625F and JAK2-F556V are gain-of-function mutations. Our results suggest that triple-negative cases of ET and PMF do not represent a homogenous disease entity. Cases with polyclonal hematopoiesis might represent hereditary disorders. PMID- 26423833 TI - Antisense oligonucleotide drugs for Duchenne muscular dystrophy: how far have we come and what does the future hold? PMID- 26423834 TI - The 2015 International Psychogeriatric Association Junior Research Awards in Psychogeriatrics. PMID- 26423836 TI - Density-based parallel skin lesion border detection with webCL. AB - BACKGROUND: Dermoscopy is a highly effective and noninvasive imaging technique used in diagnosis of melanoma and other pigmented skin lesions. Many aspects of the lesion under consideration are defined in relation to the lesion border. This makes border detection one of the most important steps in dermoscopic image analysis. In current practice, dermatologists often delineate borders through a hand drawn representation based upon visual inspection. Due to the subjective nature of this technique, intra- and inter-observer variations are common. Because of this, the automated assessment of lesion borders in dermoscopic images has become an important area of study. METHODS: Fast density based skin lesion border detection method has been implemented in parallel with a new parallel technology called WebCL. WebCL utilizes client side computing capabilities to use available hardware resources such as multi cores and GPUs. Developed WebCL parallel density based skin lesion border detection method runs efficiently from internet browsers. RESULTS: Previous research indicates that one of the highest accuracy rates can be achieved using density based clustering techniques for skin lesion border detection. While these algorithms do have unfavorable time complexities, this effect could be mitigated when implemented in parallel. In this study, density based clustering technique for skin lesion border detection is parallelized and redesigned to run very efficiently on the heterogeneous platforms (e.g. tablets, SmartPhones, multi-core CPUs, GPUs, and fully-integrated Accelerated Processing Units) by transforming the technique into a series of independent concurrent operations. Heterogeneous computing is adopted to support accessibility, portability and multi-device use in the clinical settings. For this, we used WebCL, an emerging technology that enables a HTML5 Web browser to execute code in parallel for heterogeneous platforms. We depicted WebCL and our parallel algorithm design. In addition, we tested parallel code on 100 dermoscopy images and showed the execution speedups with respect to the serial version. Results indicate that parallel (WebCL) version and serial version of density based lesion border detection methods generate the same accuracy rates for 100 dermoscopy images, in which mean of border error is 6.94%, mean of recall is 76.66%, and mean of precision is 99.29% respectively. Moreover, WebCL version's speedup factor for 100 dermoscopy images' lesion border detection averages around ~491.2. CONCLUSIONS: When large amount of high resolution dermoscopy images considered in a usual clinical setting along with the critical importance of early detection and diagnosis of melanoma before metastasis, the importance of fast processing dermoscopy images become obvious. In this paper, we introduce WebCL and the use of it for biomedical image processing applications. WebCL is a javascript binding of OpenCL, which takes advantage of GPU computing from a web browser. Therefore, WebCL parallel version of density based skin lesion border detection introduced in this study can supplement expert dermatologist, and aid them in early diagnosis of skin lesions. While WebCL is currently an emerging technology, a full adoption of WebCL into the HTML5 standard would allow for this implementation to run on a very large set of hardware and software systems. WebCL takes full advantage of parallel computational resources including multi-cores and GPUs on a local machine, and allows for compiled code to run directly from the Web Browser. PMID- 26423837 TI - Asymmetric synthesis of syn-propargylamines and unsaturated beta-amino acids under Bronsted base catalysis. AB - Propargylamines are important intermediates for the synthesis of polyfunctional amino derivatives and natural products and biologically active compounds. The classic method of synthesizing chiral propargylamines involves the asymmetric alkynylation of imines. Here, we report a significant advance in the catalytic asymmetric Mannich-type synthesis of propargylamines through catalytic asymmetric addition of carbon nucleophiles to C-alkynyl imines, culminating in a highly syn selective catalytic asymmetric Mannich reaction of C-alkynyl imines that provide syn-configured propargylamines with two adjacent stereogenic centres and a transition metal-free organocatalytic asymmetric approach to beta-alkynyl-beta amino acids with high efficiency and practicality, via a chiral Bronsted base catalysed asymmetric Mannich-type reaction of in situ generated challenging N-Boc C-alkynyl imines from previously unreported C-alkynyl N-Boc-N,O-acetals, with alpha-substituted beta-keto esters and less-acidic malonate (thio)esters as nucleophiles, respectively. A catalytic activation strategy is also disclosed, which may have broad implications for use in catalysis and synthesis. PMID- 26423835 TI - Attenuation of p38alpha MAPK stress response signaling delays the in vivo aging of skeletal muscle myofibers and progenitor cells. AB - Functional competence and self-renewal of mammalian skeletal muscle myofibers and progenitor cells declines with age. Progression of the muscle aging phenotype involves the decline of juvenile protective factorsi.e., proteins whose beneficial functions translate directly to the quality of life, and self-renewal of progenitor cells. These characteristics occur simultaneously with the age associated increase of p38alpha stress response signaling. This suggests that the maintenance of low levels of p38alpha activity of juvenile tissues may delay or attenuate aging. We used the dominant negative haploinsufficient p38alpha mouse (DN-p38alpha(AF/+)) to demonstrate that in vivo attenuation of p38alpha activity in the gastrocnemius of the aged mutant delays age-associated processes that include: a) the decline of the juvenile protective factors, BubR1, aldehyde dehydrogenase 1A (ALDH1A1), and aldehyde dehydrogenase 2 (ALDH2); b) attenuated expression of p16(Ink4a) and p19(Arf) tumor suppressor genes of the Cdkn2a locus; c) decreased levels of hydroxynonenal protein adducts, expression of COX2 and iNOS; d) decline of the senescent progenitor cell pool level and d) the loss of gastrocnemius muscle mass. We propose that elevated P-p38alpha activity promotes skeletal muscle aging and that the homeostasis of p38alpha impacts the maintenance of a beneficial healthspan. PMID- 26423838 TI - Mass spectrometric identification and toxicity assessment of degraded products of aflatoxin B1 and B2 by Corymbia citriodora aqueous extracts. AB - This study explores the detoxification potential of Corymbia citriodora plant extracts against aflatoxin B1 and B2 (AFB1; 100 MUg L(-1) and AFB2; 50 MUg L(-1)) in In vitro and In vivo assays. Detoxification was qualitatively and quantitatively analyzed by TLC and HPLC, respectively. The study was carried out by using different parameters of optimal temperature, pH and incubation time period. Results indicated that C. citriodora leaf extract(s) more effectively degrade AFB1 and AFB2 i.e. 95.21% and 92.95% respectively than C. citriodora branch extract, under optimized conditions. The structural elucidation of degraded toxin products was done by LCMS/MS analysis. Ten degraded products of AFB1 and AFB2 and their fragmentation pathways were proposed based on molecular formulas and MS/MS spectra. Toxicity of these degraded products was significantly reduced as compared to that of parent compounds because of the removal of double bond in the terminal furan ring. The biological toxicity of degraded toxin was further analyzed by brine shrimps bioassay, which showed that only 17.5% mortality in larvae was recorded as compared to untreated toxin where 92.5% mortality was observed after 96hr of incubation. Therefore, our finding suggests that C. citriodora leaf extract can be used as an effective tool for the detoxification of aflatoxins. PMID- 26423839 TI - Social interactions elicit rapid shifts in functional connectivity in the social decision-making network of zebrafish. AB - According to the social decision-making (SDM) network hypothesis, SDM is encoded in a network of forebrain and midbrain structures in a distributed and dynamic fashion, such that the expression of a given social behaviour is better reflected by the overall profile of activation across the different loci rather than by the activity of a single node. This proposal has the implicit assumption that SDM relies on integration across brain regions, rather than on regional specialization. Here we tested the occurrence of functional localization and of functional connectivity in the SDM network. For this purpose we used zebrafish to map different social behaviour states into patterns of neuronal activity, as indicated by the expression of the immediate early genes c-fos and egr-1, across the SDM network. The results did not support functional localization, as some loci had similar patterns of activity associated with different social behaviour states, and showed socially driven changes in functional connectivity. Thus, this study provides functional support to the SDM network hypothesis and suggests that the neural context in which a given node of the network is operating (i.e. the state of its interconnected areas) is central to its functional relevance. PMID- 26423840 TI - Dopamine is a key regulator in the signalling pathway underlying predator-induced defences in Daphnia. AB - The waterflea Daphnia is a model to investigate the genetic basis of phenotypic plasticity resulting from one differentially expressed genome. Daphnia develops adaptive phenotypes (e.g. morphological defences) thwarting predators, based on chemical predator cue perception. To understand the genomic basis of phenotypic plasticity, the description of the precedent cellular and neuronal mechanisms is fundamental. However, key regulators remain unknown. All neuronal and endocrine stimulants were able to modulate but not induce defences, indicating a pathway of interlinked steps. A candidate able to link neuronal with endocrine responses is the multi-functional amine dopamine. We here tested its involvement in trait formation in Daphnia pulex and Daphnia longicephala using an induction assay composed of predator cues combined with dopaminergic and cholinergic stimulants. The mere application of both stimulants was sufficient to induce morphological defences. We determined dopamine localization in cells found in close association with the defensive trait. These cells serve as centres controlling divergent morphologies. As a mitogen and sclerotization agent, we anticipate that dopamine is involved in proliferation and structural formation of morphological defences. Furthermore, dopamine pathways appear to be interconnected with endocrine pathways, and control juvenile hormone and ecdysone levels. In conclusion, dopamine is suggested as a key regulator of phenotypic plasticity. PMID- 26423841 TI - An exceptionally preserved Late Devonian actinopterygian provides a new model for primitive cranial anatomy in ray-finned fishes. AB - Actinopterygians (ray-finned fishes) are the most diverse living osteichthyan (bony vertebrate) group, with a rich fossil record. However, details of their earliest history during the middle Palaeozoic (Devonian) 'Age of Fishes' remains sketchy. This stems from an uneven understanding of anatomy in early actinopterygians, with a few well-known species dominating perceptions of primitive conditions. Here we present an exceptionally preserved ray-finned fish from the Late Devonian (Middle Frasnian, ca 373 Ma) of Pas-de-Calais, northern France. This new genus is represented by a single, three-dimensionally preserved skull. CT scanning reveals the presence of an almost complete braincase along with near-fully articulated mandibular, hyoid and gill arches. The neurocranium differs from the coeval Mimipiscis in displaying a short aortic canal with a distinct posterior notch, long grooves for the lateral dorsal aortae, large vestibular fontanelles and a broad postorbital process. Identification of similar but previously unrecognized features in other Devonian actinopterygians suggests that aspects of braincase anatomy in Mimipiscis are apomorphic, questioning its ubiquity as stand-in for generalized actinopterygian conditions. However, the gill skeleton of the new form broadly corresponds to that of Mimipiscis, and adds to an emerging picture of primitive branchial architecture in crown gnathostomes. The new genus is recovered in a polytomy with Mimiidae and a subset of Devonian and stratigraphically younger actinopterygians, with no support found for a monophyletic grouping of Moythomasia with Mimiidae. PMID- 26423842 TI - Multimodal signalling in the North American barn swallow: a phenotype network approach. AB - Complex signals, involving multiple components within and across modalities, are common in animal communication. However, decomposing complex signals into traits and their interactions remains a fundamental challenge for studies of phenotype evolution. We apply a novel phenotype network approach for studying complex signal evolution in the North American barn swallow (Hirundo rustica erythrogaster). We integrate model testing with correlation-based phenotype networks to infer the contributions of female mate choice and male-male competition to the evolution of barn swallow communication. Overall, the best predictors of mate choice were distinct from those for competition, while moderate functional overlap suggests males and females use some of the same traits to assess potential mates and rivals. We interpret model results in the context of a network of traits, and suggest this approach allows researchers a more nuanced view of trait clustering patterns that informs new hypotheses about the evolution of communication systems. PMID- 26423843 TI - Early development of rostrum saw-teeth in a fossil ray tests classical theories of the evolution of vertebrate dentitions. AB - In classical theory, teeth of vertebrate dentitions evolved from co-option of external skin denticles into the oral cavity. This hypothesis predicts that ordered tooth arrangement and regulated replacement in the oral dentition were also derived from skin denticles. The fossil batoid ray Schizorhiza stromeri (Chondrichthyes; Cretaceous) provides a test of this theory. Schizorhiza preserves an extended cartilaginous rostrum with closely spaced, alternating saw teeth, different from sawfish and sawsharks today. Multiple replacement teeth reveal unique new data from micro-CT scanning, showing how the 'cone-in-cone' series of ordered saw-teeth sets arrange themselves developmentally, to become enclosed by the roots of pre-existing saw-teeth. At the rostrum tip, newly developing saw-teeth are present, as mineralized crown tips within a vascular, cartilaginous furrow; these reorient via two 90 degrees rotations then relocate laterally between previously formed roots. Saw-tooth replacement slows mid rostrum where fewer saw-teeth are regenerated. These exceptional developmental data reveal regulated order for serial self-renewal, maintaining the saw edge with ever-increasing saw-tooth size. This mimics tooth replacement in chondrichthyans, but differs in the crown reorientation and their enclosure directly between roots of predecessor saw-teeth. Schizorhiza saw-tooth development is decoupled from the jaw teeth and their replacement, dependent on a dental lamina. This highly specialized rostral saw, derived from diversification of skin denticles, is distinct from the dentition and demonstrates the potential developmental plasticity of skin denticles. PMID- 26423844 TI - Convergent evolution of vascular optimization in kelp (Laminariales). AB - Terrestrial plants and mammals, although separated by a great evolutionary distance, have each arrived at a highly conserved body plan in which universal allometric scaling relationships govern the anatomy of vascular networks and key functional metabolic traits. The universality of allometric scaling suggests that these phyla have each evolved an 'optimal' transport strategy that has been overwhelmingly adopted by extant species. To truly evaluate the dominance and universality of vascular optimization, however, it is critical to examine other, lesser-known, vascularized phyla. The brown algae (Phaeophyceae) are one such group--as distantly related to plants as mammals, they have convergently evolved a plant-like body plan and a specialized phloem-like transport network. To evaluate possible scaling and optimization in the kelp vascular system, we developed a model of optimized transport anatomy and tested it with measurements of the giant kelp, Macrocystis pyrifera, which is among the largest and most successful of macroalgae. We also evaluated three classical allometric relationships pertaining to plant vascular tissues with a diverse sampling of kelp species. Macrocystis pyrifera displays strong scaling relationships between all tested vascular parameters and agrees with our model; other species within the Laminariales display weak or inconsistent vascular allometries. The lack of universal scaling in the kelps and the presence of optimized transport anatomy in M. pyrifera raises important questions about the evolution of optimization and the possible competitive advantage conferred by optimized vascular systems to multicellular phyla. PMID- 26423845 TI - The alignment between phenotypic plasticity, the major axis of genetic variation and the response to selection. AB - Phenotypic plasticity is the ability of a genotype to produce more than one phenotype in order to match the environment. Recent theory proposes that the major axis of genetic variation in a phenotypically plastic population can align with the direction of selection. Therefore, theory predicts that plasticity directly aids adaptation by increasing genetic variation in the direction favoured by selection and reflected in plasticity. We evaluated this theory in the freshwater crustacean Daphnia pulex, facing predation risk from two contrasting size-selective predators. We estimated plasticity in several life history traits, the G matrix of these traits, the selection gradients on reproduction and survival, and the predicted responses to selection. Using these data, we tested whether the genetic lines of least resistance and the predicted response to selection aligned with plasticity. We found predator environment specific G matrices, but shared genetic architecture across environments resulted in more constraint in the G matrix than in the plasticity of the traits, sometimes preventing alignment of the two. However, as the importance of survival selection increased, the difference between environments in their predicted response to selection increased and resulted in closer alignment between the plasticity and the predicted selection response. Therefore, plasticity may indeed aid adaptation to new environments. PMID- 26423846 TI - Wildlife-friendly farming increases crop yield: evidence for ecological intensification. AB - Ecological intensification has been promoted as a means to achieve environmentally sustainable increases in crop yields by enhancing ecosystem functions that regulate and support production. There is, however, little direct evidence of yield benefits from ecological intensification on commercial farms growing globally important foodstuffs (grains, oilseeds and pulses). We replicated two treatments removing 3 or 8% of land at the field edge from production to create wildlife habitat in 50-60 ha patches over a 900 ha commercial arable farm in central England, and compared these to a business as usual control (no land removed). In the control fields, crop yields were reduced by as much as 38% at the field edge. Habitat creation in these lower yielding areas led to increased yield in the cropped areas of the fields, and this positive effect became more pronounced over 6 years. As a consequence, yields at the field scale were maintained--and, indeed, enhanced for some crops--despite the loss of cropland for habitat creation. These results suggested that over a 5 year crop rotation, there would be no adverse impact on overall yield in terms of monetary value or nutritional energy. This study provides a clear demonstration that wildlife-friendly management which supports ecosystem services is compatible with, and can even increase, crop yields. PMID- 26423847 TI - Artificial light at night desynchronizes strictly seasonal reproduction in a wild mammal. AB - Change in day length is an important cue for reproductive activation in seasonally breeding animals to ensure that the timing of greatest maternal investment (e.g. lactation in mammals) coincides with favourable environmental conditions (e.g. peak productivity). However, artificial light at night has the potential to interfere with the perception of such natural cues. Following a 5 year study on two populations of wild marsupial mammals exposed to different night-time levels of anthropogenic light, we show that light pollution in urban environments masks seasonal changes in ambient light cues, suppressing melatonin levels and delaying births in the tammar wallaby. These results highlight a previously unappreciated relationship linking artificial light at night with induced changes in mammalian reproductive physiology, and the potential for larger-scale impacts at the population level. PMID- 26423848 TI - Spring or string: does tendon elastic action influence wing muscle mechanics in bat flight? AB - Tendon springs influence locomotor movements in many terrestrial animals, but their roles in locomotion through fluids as well as in small-bodied mammals are less clear. We measured muscle, tendon and joint mechanics in an elbow extensor of a small fruit bat during ascending flight. At the end of downstroke, the tendon was stretched by elbow flexion as the wing was folded. At the end of upstroke, elastic energy was recovered via tendon recoil and extended the elbow, contributing to unfurling the wing for downstroke. Compared with a hypothetical 'string-like' system lacking series elastic compliance, the tendon spring conferred a 22.5% decrease in muscle fascicle strain magnitude. Our findings demonstrate tendon elastic action in a small flying mammal and expand our understanding of the occurrence and action of series elastic actuator mechanisms in fluid-based locomotion. PMID- 26423849 TI - Peer review comments on drug trials submitted to medical journals differ depending on sponsorship, results and acceptance: a retrospective cohort study. AB - OBJECTIVE: During peer review, submitted manuscripts are scrutinised by independent experts to assist journal editors in their decision-making and to help improve the quality of articles. In this retrospective cohort study, peer review comments for drug trials submitted to medical journals were analysed to investigate whether there is a relation between the content of these comments and sponsorship, direction of results and decision about acceptance. DESIGN/SETTING: Descriptive content analysis of reviewer comments made on manuscripts on drug trials submitted to eight medical journals (January 2010-April 2012). For each manuscript, the number of reviewers, decision about acceptance, sponsorship and direction of results were extracted. Reviewer comments were classified using a predefined checklist. RESULTS: Reviewer reports for 246 manuscripts were assessed. Industry-sponsored trials were more likely to receive comments about lack of novelty (8.9%) than industry-supported (2.5%) and non-industry trials (6.1%, overall p=0.038). Non-industry trials more often received comments about poor experimental design (69.7%) than industry-supported (58.8%) and industry sponsored trials (52.9%, overall p=0.019). Non-industry trials were also more likely to receive comments regarding inappropriate statistical analyses (28.4%) than industry-supported (23.5%) and industry-sponsored trials (15.1%, overall p=0.006). Manuscripts with negative results were more likely to receive comments about inappropriate conclusions (29.3%) than those with positive results (18.9%, p=0.010). Rejected manuscripts had more often received comments on the research question not being clinically relevant (7.8%) than accepted manuscripts (1.6%, p=0.002), and also on lack of novelty (8.3% vs 2.6%, p=0.008) and poor experimental design (68.6% vs 50.5%, p<0.001). CONCLUSIONS: Reviewers identified fewer shortcomings regarding design and statistical analyses in industry-related trials, but commented more often on a lack of novelty in industry-sponsored trials. Negative trial results did not significantly influence the nature of comments other than appropriateness of the conclusion. Manuscript acceptance was primarily related to the research question and methodological robustness of studies. PMID- 26423850 TI - Process evaluation of the impact and acceptability of a polypill for prevention of cardiovascular disease. AB - IMPORTANCE: The Use of a Multidrug Pill In Reducing cardiovascular Events (UMPIRE) trial has shown improved adherence with the use of a polypill strategy when compared with usual medications for cardiovascular disease (CVD) prevention. To advance from efficacy to impact, we need a better understanding of why and how such a strategy might be deployed in complex health systems. OBJECTIVE: To understand, from the perspective of UMPIRE trial participants and professionals, how and why a polypill strategy improves adherence compared with usual care, why improvement is greater in some subgroups, and to explore the acceptability of a polypill strategy among trial participants and healthcare professionals. DESIGN, SETTING AND PARTICIPANTS: A preplanned process evaluation, based on qualitative interviews, was conducted with a subsample of 102 trial participants and 41 healthcare professionals at the end of the UMPIRE trial in India and Europe. RESULTS: Most patients contrasted the simplicity of the polypill with usual medications that they found complex and, for many in India, expensive. Patients with low baseline adherence struggled most with complex medication lists, and those without established disease described less motivation to adhere when compared with people who had already been diagnosed with CVD; people in the latter group had already undertaken self-directed measures to adhere to CVD preventive medicines prior to entering the trial. Taking medication was one of many adaptations described by patients; these included dietary changes, stopping smoking and maintaining exercise. Most patients liked the polypill strategy, although some participants and health professionals were concerned that it would provide less tailored therapy for individual needs. CONCLUSIONS: Adherence to treatment lists with multiple medications is complex and influenced by several factors. Simplifying medication by using a once-daily polypill is one approach to CVD prevention that may enhance adherence. Prescribers should also consider the wide variety of adjustments that individuals need to make to cope with daily medication. PMID- 26423851 TI - Efficacy of advice from healthcare professionals to pregnant women on avoiding constrictive clothing around the trunk: a study protocol for a randomised controlled trial. AB - INTRODUCTION: As a component of midwife care, eliminating clothing that constricts the trunk has been shown to markedly elevate the uterine fundus, soften the uterus and abdomen, and reduce the abdominal wall tension in women admitted to hospital due to the risk of miscarriage or premature delivery. However, no prospective study has conclusively verified the efficacy of avoiding constrictive clothes around the trunk in pregnant women. We aim to verify the efficacy of instructing pregnant women to wear loose clothing that does not constrict the trunk to reduce the risk of premature birth and improve quality of life (QoL) during pregnancy. METHODS AND ANALYSIS: We will conduct a randomised controlled trial of pregnant women scheduled to deliver at the National Center for Child Health and Development in Tokyo, Japan. A total of 616 pregnant women, from whom written informed consent will be obtained, will be allocated randomly to an intervention group or a control group. Women in the control group will be provided with anaemia prevention leaflets at 20 weeks' gestation and skin-care leaflets at 30 weeks' gestation. Women in the intervention group will be provided with the same leaflets and will also receive health advice from health professionals to avoid constrictive clothing around the trunk. The primary outcome will be a difference between these groups in the frequency of any one of the following category variables: (1) cervical length <30 mm up to 28 weeks' gestation, (2) hospital admission for threatened premature delivery, or (3) premature delivery. Secondary outcomes will include QoL during pregnancy, maternal state of health, and status of fetal development. ETHICS AND DISSEMINATION: The Institutional Review Board and Ethics Committee at the National Center for Child Health and Development, Japan, has approved this study. Our findings will be widely disseminated through conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: UMIN000016853. PMID- 26423852 TI - Providing immediate neonatal care and resuscitation at birth beside the mother: clinicians' views, a qualitative study. AB - OBJECTIVES: The aims of this study were to assess clinicians' views and experiences of providing immediate neonatal care at birth beside the mother, and of using a mobile trolley designed to facilitate this bedside care. DESIGN: Qualitative interview study with semistructured interviews. RESULTS: The results were analysed using thematic analysis. SETTING: A large UK maternity unit. PARTICIPANTS: Clinicians (n=20) from a range of disciplines who were present when the trolley was used to provide neonatal care at birth at the bedside. Five clinicians provided/observed advanced resuscitation by the bedside. RESULTS: Five themes were identified: (1) Parents' involvement, which included 'Contact and involvement', 'Positive emotions for parents' and 'Staff communication'; (2) Reservations about neonatal care at birth beside the mother, which included 'Impact on clinicians' and 'Impact on parents'; (3) Practical challenges in providing neonatal care at the bedside, which included 'Cord length' and 'Caesarean section'; (4) Comparison of the trolley with usual resuscitation equipment and (5) Training and integration of bedside care into clinical routine, which included 'Teething problems' and 'Training'. CONCLUSIONS: Overall, most clinicians were positive about providing immediate neonatal care at the maternal bedside, particularly in terms of the clinicians' perceptions of the parents' experience. Clinicians also perceived that their close proximity to parents improved communication. However, there was some concern about performing more intensive interventions in front of parents. Providing immediate neonatal care and resuscitation at the bedside requires staff training and support. PMID- 26423853 TI - Promoting professional behaviour change in healthcare: what interventions work, and why? A theory-led overview of systematic reviews. AB - OBJECTIVES: Translating research evidence into routine clinical practice is notoriously difficult. Behavioural interventions are often used to change practice, although their success is variable and the characteristics of more successful interventions are unclear. We aimed to establish the characteristics of successful behaviour change interventions in healthcare. DESIGN: We carried out a systematic overview of systematic reviews on the effectiveness of behaviour change interventions with a theory-led analysis using the constructs of normalisation process theory (NPT). MEDLINE, CINAHL, PsychINFO and the Cochrane Library were searched electronically from inception to July 2015. SETTING: Primary and secondary care. PARTICIPANTS: Participants were any patients and healthcare professionals in systematic reviews who met the inclusion criteria of having examined the effectiveness of professional interventions in improving professional practice and/or patient outcomes. INTERVENTIONS: Professional interventions as defined by the Cochrane Effective Practice and Organisation of Care Review Group. PRIMARY AND SECONDARY OUTCOME MEASURES: Success of each intervention in changing practice or patient outcomes, and their mechanisms of action. Reviews were coded as to the interventions included, how successful they had been and which NPT constructs its component interventions covered. RESULTS: Searches identified 4724 articles, 67 of which met the inclusion criteria. Interventions fell into three main categories: persuasive; educational and informational; and action and monitoring. Interventions focusing on action or education (eg, Audit and Feedback, Reminders, Educational Outreach) acted on the NPT constructs of Collective Action and Reflexive Monitoring, and reviews using them tended to report more positive outcomes. CONCLUSIONS: This theory-led analysis suggests that interventions which contribute to normative restructuring of practice, modifying peer group norms and expectations (eg, educational outreach) and relational restructuring, reinforcing modified peer group norms by emphasising the expectations of an external reference group (eg, Reminders, Audit and Feedback), offer the best chances of success. Combining such interventions is most likely to change behaviour. PMID- 26423854 TI - Clinical value of lncRNA MALAT1 as a prognostic marker in human cancer: systematic review and meta-analysis. AB - BACKGROUND: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is found to be overexpressed and associated with clinicopathological features in patients with cancer. OBJECTIVES: To evaluate the clinical value of MALAT1 as a prognostic marker in human cancers by a comprehensive meta-analysis of published studies. DATA SOURCES: The data on the prognostic impact of MALAT1 in cancer were collected from 11 September 2003 to 10 July 2015. SETTING AND PARTICIPANTS: Fourteen eligible studies with a total of 1373 patients conducted in 3 countries (9 in China, 3 in Japan and 2 in Germany) were matched to our inclusion criteria. OUTCOME MEASURES: Pooled HRs with 95% CIs were calculated to estimate the strength of the link between MALAT1 and clinical prognoses. The combined HRs heterogeneity was tested using a chi(2)-based Cochran Q test and Higgins I(2) statistic. Publication bias was evaluated using a funnel plot with Egger's bias indicator test. RESULTS: A significant association between MALAT1 overexpression and poor overall survival (OS) (HR=1.95; 95% CI 1.57 to 2.41) was observed. Residence region (Germany and China), cancer type (respiratory, digestive or other system disease), sample size and paper quality did not alter the predictive value of MALAT1 on OS in investigated cancers. MALAT1 expression was an independent prognostic marker for OS in patients with cancer using univariate and multivariate analyses. Subgroup analysis showed that the elevated MALAT1 appeared to be a powerful prognostic marker for patients with respiratory, digestive and other system cancers. A similar effect was also seen in different regions. Furthermore, the overexpression of MALAT1 was associated with disease-free, recurrence-free and progression-free survivals. CONCLUSIONS: MALAT1 may potentially be used as a new prognostic marker to predict poorer survival of patients with cancer. More clinical studies on the different types of human cancer not yet investigated need to be conducted. PMID- 26423855 TI - Retrospective analysis of the quality of reports by author-suggested and non author-suggested reviewers in journals operating on open or single-blind peer review models. AB - OBJECTIVES: To assess whether reports from reviewers recommended by authors show a bias in quality and recommendation for editorial decision, compared with reviewers suggested by other parties, and whether reviewer reports for journals operating on open or single-blind peer review models differ with regard to report quality and reviewer recommendations. DESIGN: Retrospective analysis of the quality of reviewer reports using an established Review Quality Instrument, and analysis of reviewer recommendations and author satisfaction surveys. SETTING: BioMed Central biology and medical journals. BMC Infectious Diseases and BMC Microbiology are similar in size, rejection rates, impact factors and editorial processes, but the former uses open peer review while the latter uses single blind peer review. The Journal of Inflammation has operated under both peer review models. SAMPLE: Two hundred reviewer reports submitted to BMC Infectious Diseases, 200 reviewer reports submitted to BMC Microbiology and 400 reviewer reports submitted to the Journal of Inflammation. RESULTS: For each journal, author-suggested reviewers provided reports of comparable quality to non-author suggested reviewers, but were significantly more likely to recommend acceptance, irrespective of the peer review model (p<0.0001 for BMC Infectious Diseases, BMC Microbiology and the Journal of Inflammation). For BMC Infectious Diseases, the overall quality of reviewer reports measured by the Review Quality Instrument was 5% higher than for BMC Microbiology (p=0.042). For the Journal of Inflammation, the quality of reports was the same irrespective of the peer review model used. CONCLUSIONS: Reviewers suggested by authors provide reports of comparable quality to non-author-suggested reviewers, but are significantly more likely to recommend acceptance. Open peer review reports for BMC Infectious Diseases were of higher quality than single-blind reports for BMC Microbiology. There was no difference in quality of peer review in the Journal of Inflammation under open peer review compared with single blind. PMID- 26423856 TI - Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE): a prospective multicountry study. AB - INTRODUCTION: Despite cooling, adverse outcomes are seen in up to half of the surviving infants after neonatal encephalopathy. A number of novel adjunct drug therapies with cooling have been shown to be highly neuroprotective in animal studies, and are currently awaiting clinical translation. Rigorous evaluation of these therapies in phase II trials using surrogate MR biomarkers may speed up their bench to bedside translation. A recent systematic review of single-centre studies has suggested that MR spectroscopy biomarkers offer the best promise; however, the prognostic accuracy of these biomarkers in cooled encephalopathic babies in a multicentre setting using different MR scan makers is not known. METHODS AND ANALYSIS: The MR scanners (3 T; Philips, Siemens, GE) in all the participating sites will be harmonised using phantom experiments and healthy adult volunteers before the start of the study. We will then recruit 180 encephalopathic infants treated with whole body cooling from the participating centres. MRI and spectroscopy will be performed within 2 weeks of birth. Neurodevelopmental outcomes will be assessed at 18-24 months of age. Agreement between MR cerebral biomarkers and neurodevelopmental outcome will be reported. The sample size is calculated using the 'rule of 10', generally used to calculate the sample size requirements for developing prognostic models. Considering 9 parameters, we require 9*10 adverse events, which suggest that a total sample size of 180 is required. ETHICS AND DISSEMINATION: Human Research Ethics Committee approvals have been received from Brent Research Ethics Committee (London), and from Imperial College London (Sponsor). We will submit the results of the study to relevant journals and offer national and international presentations. TRIAL REGISTRATION NUMBER: Clinical Trials.gov Number: NCT01309711. PMID- 26423857 TI - German Cranial Reconstruction Registry (GCRR): protocol for a prospective, multicentre, open registry. AB - INTRODUCTION: Owing to increasing numbers of decompressive craniectomies in patients with malignant middle cerebral artery infarction, cranioplastic surgery becomes more relevant. However, the current literature mainly consists of retrospective single-centre (evidence class III) studies. This leads to a wide variability of technical approaches and clinical outcomes. To improve our knowledge about the key elements of cranioplasty, which may help optimising clinical treatment and long-term outcome, a prospective multicentre registry across Germany, Austria and Switzerland will be established. METHODS: All patients undergoing cranioplastic surgery in participating centres will be invited to join the registry. Technical methods, materials, medical history, adverse events and clinical outcome measures, including modified Rankin scale and EQ-5D, will be assessed at several time points. Patients will be accessible to inclusion either at initial decompressive surgery or when cranioplasty is planned. Scheduled monitoring will be carried out at time of inclusion and subsequently at time of discharge, if any readmission is necessary, and at follow up presentation. Cosmetic results and patient satisfaction will also be assessed. Collected data will be managed and statistically analysed by an independent biometric institute. The primary endpoint will be mortality, need for operative revision and neurological status at 3 months following cranioplasty. ETHICS AND DISSEMINATION: Ethics approval was obtained at all participating centres. The registry will provide reliable prospective evidence on surgical techniques, used materials, adverse events and functional outcome, to optimise patient treatment. We expect this study to give new insights in the treatment of skull defects and to provide a basis for future evidence-based therapy regarding cranioplastic surgery. TRIAL REGISTRATION NUMBER: This trial is indexed in the German Clinical Trials Register (DRKS-ID: DRKS00007931). The Universal Trial Number (UTN) is U1111-1168-7425. PMID- 26423858 TI - Reporting, handling and assessing the risk of bias associated with missing participant data in systematic reviews: a methodological survey. AB - OBJECTIVES: To describe how systematic reviewers are reporting missing data for dichotomous outcomes, handling them in the analysis and assessing the risk of associated bias. METHODS: We searched MEDLINE and the Cochrane Database of Systematic Reviews for systematic reviews of randomised trials published in 2010, and reporting a meta-analysis of a dichotomous outcome. We randomly selected 98 Cochrane and 104 non-Cochrane systematic reviews. Teams of 2 reviewers selected eligible studies and abstracted data independently and in duplicate using standardised, piloted forms with accompanying instructions. We conducted regression analyses to explore factors associated with using complete case analysis and with judging the risk of bias associated with missing participant data. RESULTS: Of Cochrane and non-Cochrane reviews, 47% and 7% (p<0.0001), respectively, reported on the number of participants with missing data, and 41% and 9% reported a plan for handling missing categorical data. The 2 most reported approaches for handling missing data were complete case analysis (8.5%, out of the 202 reviews) and assuming no participants with missing data had the event (4%). The use of complete case analysis was associated only with Cochrane reviews (relative to non-Cochrane: OR=7.25; 95% CI 1.58 to 33.3, p=0.01). 65% of reviews assessed risk of bias associated with missing data; this was associated with Cochrane reviews (relative to non-Cochrane: OR=6.63; 95% CI 2.50 to 17.57, p=0.0001), and the use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (OR=5.02; 95% CI 1.02 to 24.75, p=0.047). CONCLUSIONS: Though Cochrane reviews are somewhat less problematic, most Cochrane and non-Cochrane systematic reviews fail to adequately report and handle missing data, potentially resulting in misleading judgements regarding risk of bias. PMID- 26423859 TI - Increased urothelial paracellular transport promotes cystitis. AB - Changes in the urothelial barrier are observed in patients with cystitis, but whether this leads to inflammation or occurs in response to it is currently unknown. To determine whether urothelial barrier dysfunction is sufficient to promote cystitis, we employed in situ adenoviral transduction to selectively overexpress the pore-forming tight junction-associated protein claudin-2 (CLDN 2). As expected, the expression of CLDN-2 in the umbrella cells increased the permeability of the paracellular route toward ions, but not to large organic molecules. In vivo studies of bladder function revealed higher intravesical basal pressures, reduced compliance, and increased voiding frequency in rats transduced with CLDN-2 vs. controls transduced with green fluorescent protein. While the integrity of the urothelial barrier was preserved in the rats transduced with CLDN-2, we found that the expression of this protein in the umbrella cells initiated an inflammatory process in the urinary bladder characterized by edema and the presence of a lymphocytic infiltrate. Taken together, these results are consistent with the notion that urothelial barrier dysfunction may be sufficient to trigger bladder inflammation and to alter bladder function. PMID- 26423860 TI - Alternative channels for urea in the inner medulla of the rat kidney. AB - The ascending thin limbs (ATLs) and lower descending thin limbs (DTLs) of Henle's loop in the inner medulla of the rat are highly permeable to urea, and yet no urea transporters have been identified in these sections. We hypothesized that novel, yet-unidentified transporters in these tubule segments could explain the high urea permeability. cDNAs encoding for Na(+)-glucose transporter 1a (SGLT1a), Na(+)-glucose transporter 1 (NaGLT1), urea transporter (UT)-A2c, and UT-A2d were isolated and cloned from the Munich-Wistar rat inner medulla. SGLT1a is a novel NH2-terminal truncated variant of SGLT1. NaGLT1 is a Na(+)-dependent glucose transporter primarily located in the proximal tubules and not previously described in the thin limbs. UT-A2c and UT-A2d are novel variants of UT-A2. UT A2c is truncated at the COOH terminus, and UT-A2d has one exon skipped. When rats underwent water restriction for 72 h, mRNA levels of SGLT1a increased in ATLs, NaGLT1 levels increased in both ATLs and DTLs, and UT-A2c increased in ATLs. [(14)C]urea uptake assays performed on Xenopus oocytes heterologously expressing these proteins revealed that despite having structural differences from their full-length versions, SGLT1a, UT-A2c, and UT-A2d enhanced urea uptake. NaGLT1 also facilitated urea uptake. Uptakes were Na(+) independent and inhibitable by phloretin and/or phloridzin. Our data indicate that there are several alternative channels for urea in the rat inner medulla that could potentially contribute to the high urea permeabilities in thin limb segments. PMID- 26423862 TI - [Lessons Learned after 25 Years of Studies on the Physiological Roles of the Peroxisome Proliferator-activated Receptor]. AB - The peroxisome proliferator-activated receptor (PPAR) was discovered a quarter of a century ago. PPAR was soon recognized as a general transcriptional regulator of lipid homeostasis, and several hypolipidemic and antidiabetic agents were shown to be effective ligands for it. Since then, many attempts to develop more potent drugs have been made worldwide, but most were unsuccessful due to serious side effects. It appears that the PPAR boom has ended. This review summarizes the short history of PPAR studies, including our own results, and discusses the lessons learned from the rise and fall of studies in this field for next generation basic studies and drug development research. PMID- 26423861 TI - Bridging the translational divide: identical cognitive touchscreen testing in mice and humans carrying mutations in a disease-relevant homologous gene. AB - Development of effective therapies for brain disorders has been hampered by a lack of translational cognitive testing methods. We present the first example of using the identical touchscreen-based cognitive test to assess mice and humans carrying disease-related genetic mutations. This new paradigm has significant implications for improving how we measure and model cognitive dysfunction in human disorders in animals, thus bridging the gap towards effective translation to the clinic. PMID- 26423863 TI - [Search for Structurally Unique Bioactive Natural Products]. AB - In our continuing search for structurally and biologically interesting metabolites from marine organisms and plants, we investigated the constituents of Okinawan marine sponges and Hypericum plants, resulting in the isolation of several new and unique natural products. Their structures were elucidated on the basis of spectroscopic analyses and chemical conversions. Novel bromopyrrole alkaloids, nagelamides X-Z, were isolated from a sponge Agelas sp. Heteroaromatic alkaloids, hyrtimomines A and B, were isolated from a sponge Hyrtios sp. together with bisindole alkaloids, hyrtimomines C-E. An oxylipin with a trimeric structure, manzamenone O, was obtained from a sponge Plakortis sp. Dimeric eudesmane sesquiterpenes connected through various linker moieties, halichonadins K-L, were isolated from a sponge Halichondria sp., and isomalabaricane triterpenes, stelliferins J-N, were obtained from a sponge Rhabdastrella sp. The investigation for the extracts of Hypericum plants gave new meroterpenes, acylphloroglucinols, and xanthones. Biyoulactones A-E are meroterpenoids from the roots of Hypericum chinense. Acylphloroglucinols, chipericumines A-D, and highly prenylated xanthones, biyouxanthones A-D, were also isolated from the same origin. Tricyclic meroterpenes, yezo'otogirins A-C, and liner meroterpenos, yojironins A and B, were isolated from Hypericum yezoense and Hypericum yojiroanum, respectively. PMID- 26423864 TI - [Total Synthesis of Biologically Active Natural Products toward Elucidation of the Mode of Action]. AB - Total synthesis of biologically active cyclodepsipeptide destruxin E using solid- and solution-phase synthesis is described. The solid-phase synthesis of destruxin E was initially investigated for the efficient synthesis of destruxin analogues. Peptide elongation from polymer-supported beta-alanine was efficiently performed using DIC/HOBt or PyBroP/DIEA, and subsequent cleavage from the polymer-support under weakly acidic conditions furnished a cyclization precursor in moderate yield. Macrolactonization of the cyclization precursor was smoothly performed using 2-methyl-6-nitrobenzoic anhydride (MNBA)/4-(dimethylamino)pyridine N-oxide (DMAPO) to afford macrolactone in moderate yield. Finally, formation of the epoxide in the side chain via three steps provided destruxin E, and the stereochemistry of the epoxide was determined to be S. Its diastereomer, epi destruxin E, was also synthesized in the same manner used to synthesize the natural product. The stereochemistry of the epoxide was critical for the V-ATPase inhibition; natural product destruxin E exhibited 10-fold more potent V-ATPase inhibition than epi-destruxin E. Next, the scalable synthesis of destruxin E for in vivo study was also performed via solution-phase synthesis. The scalable synthesis of a key component, (S)-HA-Pro-OH, was achieved using osmium-catalyzed diastereoselective dihydroxylation with (DHQD)2PHAL as a chiral ligand; peptide synthesis using Cbz-protected amino acid derivatives furnished the cyclization precursor on a gram-scale. Macrolactonization smoothly provided the macrolactone without forming a dimerized product, even at 6 mM, and the synthesis of destruxin E was achieved via three steps on a gram scale in high purity (>98%). PMID- 26423865 TI - [Discovery of Novel Biologically Active Compounds of Natural Origin, with a Focus on Anti-tumor Activity]. AB - Numerous clinically valuable medicines, including anticancer drugs, have been developed from biologically active natural compounds and their structurally related derivatives. This review discusses novel natural compounds with promising biological activities and those with novel chemical structures. Glaziovianin A, an isoflavone isolated from the leaves of Ateleia glazioviana (Legminosae), inhibited cell cycle progression at the M-phase with an abnormal spindle structure. AU-1 and YG-1, 5beta-steroidal glycosides isolated from the whole plants of Agave utahensis and the underground parts of Yucca glauca (Agavaceae), induced apoptosis of HL-60 cells via caspase-3 activation. Lycolicidinol, an alkaloid isolated from the bulbs of Lycoris albiflora (Amaryllidaceae), induced transient autophagy and morphological changes in mitochondria in the early stage of the apoptotic cell death process in HSC-2 cells. Taccasterosides isolated from the rhizomes of Tacca chantrieri (Taccaceae) and stryphnosides isolated from the pericarps of Stryphnodendron fissuratum (Legminosae) are steroidal and triterpene glycosides with unique chemical structures having novel sugar sequences. PMID- 26423866 TI - [Effects of Xenobiotics on Drug Pharmacokinetics and Safety]. AB - The use of nanotechnology has increased over the past 10 years, and various nanomaterials with a wide range of applications have been developed. Carbon nanotubes (CNTs), which are cylindrical molecules consisting of hexagonally arranged carbon atoms, are nanomaterials with high utility. Recently, applications of single-walled CNT (SWCNT) in the medical field for drug-delivery and as gene-delivery agents have been proposed. Due to its structural characteristics and physicochemical properties, the inhalation of SWCNT could be considered as one route for targeted drug delivery into the lungs. Therefore, it is necessary to investigate the effects of SWCNT on the physiological state and response of the cells upon delivery into the lung. We clarified the different response of two carcinoma cell lines to SWCNT exposure, and determined these differences may be due to different cell functions. Furthermore, SWCNT exposure resulted in a global downregulation of stress-responsive genes in normal human bronchial epithelial cells, thereby indicating that the factors involved in the stress responses were not activated by SWCNT. We then tried to ascertain the possible effect of SWCNT on the fate of drugs delivered with SWCNT. Exposure to SWCNT down-regulated the mRNA expression and enzymatic activity of CYP1A1 and CYP1B1 by preventing the binding of activated aryl hydrocarbon receptors to the enhancer region of these genes. This review provides basic information for the prediction of human responses to SWCNT exposure by inhalation, and in its use as a drug delivery carrier. PMID- 26423867 TI - [Optimization of Immunosuppression and the Prevention of Fungal Infection in Autoimmune Diseases]. AB - Mycophenolate mofetil (MMF) has recently been reported to be effective in the treatment of systemic lupus erythematosus (SLE). The therapeutic range of mycophenolic acid (MPA) and its 7-O-glucuronide (MPAG), and factors affecting their pharmacokinetics, remain to be clarified. The influence of the pharmacokinetics of MPA and MPAG on the activity of inosine 5'-monophosphate dehydrogenase (IMPDH), a target of the MPA, also remains to be revealed. The pharmacokinetic variability of hydroxy-itraconazole (OH-ITZ), an active metabolite of itraconazole frequently co-administered with immunosuppressants in immunocompromised patients, is not fully known. The aim of this study was to establish the optimal dosage and administration of immunosuppressants and antifungal agents. MMF improved clinical laboratory markers and reduced prednisolone dosage in 31 SLE patients, with a pre-dose plasma concentration of MPA and MPAG in the interquartile ranges of 0.94-2.96 and 18.6-53.7 MUg/mL, respectively. Renal function and co-administered metal influenced the pharmacokinetics of MPA and MPAG in 31 SLE patients in the remission maintenance phase. IMPDH activity was induced in 29 SLE patients receiving the MMF therapy. This induction was dependent on the plasma concentration of MPAG, but not MPA. In addition, IMPDH activity was negatively correlated with complement fraction C3. MPA exposure and disease activity in SLE patients may determine IMPDH activity. The pharmacokinetic variability of OH-ITZ was associated with saturated metabolism to keto-itraconazole, serum concentration of albumin, and renal function in 46 immunocompromised patients. Prevention of fungal infections and drug-drug interactions in immunocompromised patients can be obtained by considering these identified confounding factors. PMID- 26423868 TI - [Efficient Pharmaceutical Formulation Designs and Their Development Using Mathematical and Statistical Analysis]. AB - With the aim of directly predicting the functionality and mechanism of pharmaceutical excipients, we investigated an analysis method based on available surface area (S(t)), which is the surface area of a drug in direct contact with the external solvent during dissolution. First, to study the effect of lubricant concentration on the dissolution rate of acetaminophen (APAP), the dissolution behaviors as well as the change over time in S(t) of APAP tablets were examined. In the dissolution tests, a retarded dissolution of APAP was not observed with new lubricant triglycerin full behenate (TR-FB), whereas magnesium stearate (Mg St) retarded the dissolution. The S(t) profiles for APAP with Mg-St at>0.5% showed downward curvature indicating a gradual decrease in surface area over time. Conversely, with TR-FB, even when its concentration was increased, the S(t) profile for APAP had a maximum value. The differences between Mg-St and TR-FB could be explained by the differences in extensibility deriving from their morphology. Next, we evaluated the effect of disintegtant concentration using five disintegrants. When disintegrant was added to ethenzamide tablet formulation, an increase in the dissolution rate and S(t) dependent on disintegrant concentration was observed, according to the type of disintegrant. It was found that the water absorption ability of disintegrants had strong correlations with the parameters of S(t). Taken together, this study demonstrates that analysis of S(t) can directly provide useful information, especially about the functionality of pharmaceutical excipients. PMID- 26423869 TI - [Carrier-mediated Transport of Cationic Drugs across the Blood-Tissue Barrier]. AB - Studies of neurological dysfunction have revealed the neuroprotective effect of several cationic drugs, suggesting their usefulness in the treatment of neurological diseases. In the brain and retina, blood-tissue barriers such as blood-brain barrier (BBB) and blood-retinal barrier (BRB) are formed to restrict nonspecific solute transport between the circulating blood and neural tissues. Therefore study of cationic drug transport at these barriers is essential to achieve systemic delivery of neuroprotective agents into the neural tissues. In the retina, severe diseases such as diabetic retinopathy and macular degeneration can cause neurological dysfunction that dramatically affects patients' QOL. The BRB is formed by retinal capillary endothelial cells (inner BRB) and retinal pigment epithelial cells (outer BRB). Blood-to-retina transport of cationic drugs was investigated at the inner BRB, which is known to nourish two thirds of the retina. Blood-to-retinal transport of verapamil suggested that the barrier function of the BRB differs from that of the BBB. Moreover, carrier-mediated transport of verapamil and pyrilamine revealed the involvement of novel organic cation transporters at the inner BRB. The identified transport systems for cationic drugs are sensitive to several cationic neuroprotective and anti angiogenic agents such as clonidine and propranolol, and the involvement of novel transporters was also suggested in their blood-to-retina transport across the inner BRB. PMID- 26423870 TI - [Establishment of a Method of Hepatocyte Differentiation from Human Pluripotent Stem Cells for Innovative Drug Development]. AB - Hepatocyte-like cells differentiated from human pluripotent stem cells (such as human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells) are expected to be utilized in drug screening. However, the hepatocyte differentiation efficiency and hepatic functions of hepatocyte-like cells were not sufficient to perform ES/iPS cell-based drug discovery. Therefore, we decided to improve the method of hepatocyte differentiation from human ES/iPS cells. To enhance this hepatocyte differentiation efficiency, hepatocyte-related transcription factors, such as forkhead box protein A2 (FOXA2) and hepatocyte nuclear factor 1 alpha (HNF1alpha), were overexpressed during the hepatocyte differentiation process. In addition, to enhance the functions of hepatocyte-like cells, these cells were cultured in three dimensional (3D) conditions using a Nanopillar plate. By FOXA2 and HNF1alpha overexpression, human ES/iPS cells could efficiently (more than 80%) differentiate into albumin-positive hepatocyte-like cells. Various hepatic functions, including albumin secretion and drug metabolism capacities, of the hepatocyte-like cells were significantly enhanced by performing 3D cell culture. These results suggest that the method of hepatocyte differentiation could be improved by using gene transfer and 3D cell culture technologies. We believe that these new hepatocyte-like cells would be useful tools in drug development. PMID- 26423871 TI - [Search of Neurotrophin-mimic Natural Products for Prevention and Treatment of Neurodegenerative Disease]. AB - As part of our continuing studies on neurotrophin-mimic active compounds in natural products, we investigated the chemical constituents of the pericarps of Illicium jiadifengpi and the roots of Indonesian ginger Zingiber purpureum, resulting in the isolation of new seco-prezizaane-type sesquiterpenoid 1 and phenylbutenoid dimer 3-4 and two new curcuminoids 5-6. The MeOH extract of I. jiadifengpi was fractionated, leading to the isolation of compound 1. Compound 1 significantly enhanced neurite outgrowth in primary cell cultures of fetal rat cortical neurons. It is noteworthy that compound 1 has potential significantly to promote differentiation of multipotent neural stem cell line (MEB5 cells) into neurons. Additionally, we investigated the MeOH extract of the root of Bangle (Z. purpureum) that exhibited neuritogenesis activity in PC12 cells at 25 MUg/mL, resulting in the isolation of neurotrophic phenylbutenoid dimers 3-4 and new compounds 5-6. Compounds 3 and 4 were found not only significantly to induce neurite sprouting of PC12 cells but also to increase the neurite length and number of neurites in primary cultured rat cortical neurons, and also showed protective activity against cell death caused by deprivation of serum. Furthermore, chronic treatment with these compounds enhanced hippocampal neurogenesis in dementia model olfactory bulbectomized (OBX) mice. Compounds 5 and 6 had significant NGF-potentiating effects on PC12 cells whereas compound 5 enhanced prevention of amyloid beta (Abeta) 42 aggregation. PMID- 26423872 TI - [Effects of Bioactive Substances from Citrus on the Central Nervous System and Utilization as Food Material]. AB - We have recently shown that 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF) and auraptene (AUR) have neuroprotective effects on the central nervous system. HMF, a citrus flavonoid, altered NMDA-type glutamate receptor antagonist MK-801 induced memory dysfunction and schizophrenia-positive symptom-like behavior. HMF also showed a protective effect against ischemia-induced short-term memory dysfunction. In the ischemic brain, HMF induced the following protective effects against brain dysfunction: 1) rescue of neuronal cell death in the hippocampus; 2) increased production of brain-derived neurotrophic factor; 3) stimulation of neurogenesis in the dentate gyrus subgranular zone; 4) activation of the autophosphorylation of calcium-calmodulin-dependent protein kinase II; and 5) suppression of microglial activation. On the other hand, AUR, a citrus coumarin, ameliorated lipopolysaccharide-induced inflammation in the brain as shown by inhibition of microglial activation and inhibition of cyclooxygenase (COX)-2 expression in the hippocampus. AUR also showed antiinflammatory effects on the ischemic brain by inhibiting microglial activation, COX-2 expression, and neuronal cell death in the hippocampus. The peel of kawachibankan (Citrus kawachiensis), a noted citrus product of Ehime prefecture, Japan, contains AUR, HMF, naringin, and narirutin. The dried powder of both the peel and juice had antiinflammatory effects in the mouse hippocampus, suggesting that citrus compounds may be beneficial as neuroprotective agents in the treatment of neurological disorders. PMID- 26423874 TI - [Effect of Water Intake on Allergy-like Events Associated with Non-ionic Iodine Contrast Agents]. AB - The use of iodine contrast agents occasionally causes serious allergic symptoms including anaphylaxis. At Kyoto University Hospital to prevent nephropathy we began recommending water intake before and after administration of iodine contrast agents in September 2012. In the present study we investigated the effect of water intake on the incidence of allergy-like events after the use of non-ionic iodine contrast agents. We extracted the occurrence of allergy-like events from the incident report system in our hospital from January 2011 to September 2014, and classified these events into the following 3 grades: 1+ (follow-up); 2+ (medication treatment); and 3+ (hospitalization). The allergy like incidence rate was calculated for subsequent evaluation according to season and water intake. Allergy-like events significantly decreased from 0.49% before the recommendation of water intake to 0.26% at 1 year and 0.20% at 2 years after implementing the recommendation. The incidence of allergy-like events was significantly higher in summer than in winter before water intake was recommended. After implementing the recommendation, the value for summer significantly decreased to an incidence similar to that of winter. Respiratory and gastrointestinal allergy-like symptoms were dramatically decreased after implementing the recommendation. Water intake may be useful for preventing allergy-like events associated with non-ionic iodine contrast agents, especially during the summer. PMID- 26423873 TI - [The Xanthine Oxidase Inhibitory Activity and Hypouricemic Effects of Crude Drugs Obtained from the Silkworm in Mice]. AB - This study evaluated the effects of crude drugs obtained from the silkworm in mice with oxonic acid-induced hyperuricemia using xanthine oxidase inhibitory activity and plasma uric acid levels. The plasma uric acid level was analyzed using an improved HPLC with UV detection (HPLC-UV) method, which enabled high sensitivity analysis of a microliter of plasma. Using this method, we evaluated natural products administered orally to the hypouricemic mice. The plasma uric acid level of mice administered a water-soluble extract from silkworm larvae with botrytis (used in traditional Chinese medicine to reduce wind, lower blood pressure, and change platelet coagulation) was significantly lower than in the control group 1, 2, and 3 h after treatment. In addition, water soluble extracts from a fungus (NBRC 31161) metabolite and silkworm pupae and larvae reduced the plasma uric acid levels in mice compared with the control group. PMID- 26423875 TI - [Aryl Hydrocarbon Receptor Ligand Activity of Extracts from 62 Herbal Medicines and Effect on Cytochrome P450 Activity]. AB - Aryl hydrocarbon receptor (AhR) ligand activity of the extracts of 62 herbal medicines was examined using yeast reporter assay. Fifty-eight herbal extracts exhibited AhR ligand activity. The highest activity was observed with Ogon (Scutellariae Radix), followed by Oren (Coptidis Rhizoma), Kujin (Sophorae Radix) and Shoma (Cimicifiigae Rhizoma). When these extracts were treated with hesperinase, a hydrolase for sugar conjugates, the aglycones showed higher activity than the parent extracts. Among the constituents of Ogon extract, baicalein and wogonin showed AhR ligand activity, while the sugar conjugate of baicalein, baicalin, was inactive. Among the flavonoid components of these herbal medicines, flavone and chrysin exhibited high ligand activity for AhR. Ethoxyresorufin O-dealkylase (EROD) activity due to CYP1A1 in HepG2 cells was enhanced by the addition of baicalein. Baicalein also decreased the 3 methylcholanthrene-induced increase of EROD activity, but this effect was not statistically significant. When wogonin or baicalein was orally administered at the dose of 100 mg/kg to mice, EROD activity in liver was only slightly changed. Furthermore, when Ogon extract was co-administered with 3-methylcholanthrene, the EROD and methoxyresorufin O-dealkylase activities were not significantly changed. These results indicate that many herbal extracts have AhR ligand activity, and their inducing effect on CYP1A1/2 can be evaluated in HepG2 cells. PMID- 26423876 TI - [Editorial]. PMID- 26423877 TI - [Suicide - ethical and juridical aspects]. AB - This paper discusses the phenomenon of suicidality with regard to patient autonomy on the one hand and the obligation of medical professionals to provide support and treatment on the other hand. The continuation of a broad debate on these issues within the whole of society is mandatory also in the future. Suicide and assisted suicide are topics with high relevance for medicine in general and for psychiatry in particular. They can, however, not be handled by medical specialists alone. PMID- 26423878 TI - [Suicide - background, epidemiology, risk factors]. AB - Suicide research, in particular epidemiology, comprises a huge amount of data. However, the theoretical understanding clearly lags behind the empirical knowledge. Suicide, suicide attempts and other suicidal behaviors are more heterogeneous than most explanatory approaches would assume. The most important recent contributions to a better understanding have come from selected epidemiological findings and, interestingly, prevention. This article provides an overview of epidemiological findings, the most relevant risk factors and conclusions related to successful preventive efforts. PMID- 26423879 TI - [Suicidality in mental illness - prevention and therapy]. AB - The great majority of suicides and suicide attempts are related to mental illness. Special risk has been attributed to depression, psychosis, substance use, personality, and trauma-related disorders. Many affected persons seek medical attention prior to taking action. Primary care therefor plays an outstanding role in suicide prevention. Doctors should pay attention to potential risk constellations and actively address the issue. This paper presents possibly helpful models and instruments for everyday use. Most importantly, however, professionals' empathy and time are required as well as appropriate decisions concerning a referral to a psychiatrist or psychiatric inpatient treatment. PMID- 26423880 TI - [Prevention and interventions for suicidal youth considerations for health professionionals in Switzerland]. AB - Adolescence is associated with a dramatic surge in suicide rate. While worldwide age-adjusted suicides rate per 100'000 in under 14-year olds are relatively low around 0.6, a dramatic increase to 7.4 can be observed in 15 - 19 year olds with suicide being one of the three leading causes of mortality in most countries in this age group. From 2000 to 2013 the Swiss annual average of completed suicides in 15 - 19 year olds was 33.1 (minimum 24; maximum 47). This corresponds to an average age-specific death rate of 7.6, which is slightly above the global mean. Suicide prevention and treatment of suicidality in adolescents is a complex underpinning. Subjectively experienced feelings of insufficiency, hopelessness and the feeling of worthlessness combined with concrete suicidal ideations and the capacity to act out are important indicators for assessing suicidal risk. Suicide attempts as the strongest risk factor for suicide should always be taken seriously, even if they occur in the context of situational crisis. Narcissistic personality traits or increased impulsivity are further indicators of risk. The early detection and effective treatment of mental disorders such as depression, anxiety disorders, bipolar-affective disorders or psychotic disorders provide a great opportunity to reduce the frequency of suicide attempts and suicide. Particular caution is required when co-morbid addictions are present. The maintenance or establishment of sustainable relationships with significant others is considered a key protecting factor. Increasing withdrawal from significant others is an important warning sign and needs urgent involvement of experts. In acute suicidality, the admission to a psychiatric hospital must be considered, if necessary against the will of affected adolescent and their relatives. Personality-related recurrent suicidal behavior requires specific treatment approaches taking into account the prevention of iatrogenic worsening of suicidal patterns. PMID- 26423881 TI - [Suicide in the elderly - risk factors and prevention]. AB - Suicide rates are highest among the elderly in Switzerland. The estimated number of unreported cases is particularly high in this age group. The risk factors are multidimensional, including depression and social isolation. The detection and management of the controllable risk factors, foremost depression, is of particular importance for suicide prevention. Old age depression often shows an atypical presentation, is misinterpreted as a normal process of aging and is not adequately treated. PMID- 26423882 TI - [Suicidality at the general hospital - perspective of consultation and liaison psychiatry]. AB - Suicidality is a common problem in the general hospital. Patients with comorbid psychiatric disorders or during a psychosocial crisis can develop suicidal ideation during their stay at the general hospital, especially if they suffer from chronic disease. Some somatic disorders, such as cancer, epilepsy, chronic obstructive pulmonary disease, asthma, stroke and chronic pain conditions are associated with an increased risk of suicide. The fact that (1) a major part of patients are treated in the emergency room (ER) after a suicide attempt and (2) a suicide attempt is the strongest predictor for later completed suicide emphasizes the importance of expertise in dealing with suicidal patients in the ER. In order to improve prevention of suicides and suicide attempts within the general hospital and after discharge it is important to educate staff concerning suicidality and enhance detection of suicidal patients. A consultation and liaison psychiatrist should always be involved when there are suicidal patients on wards and in the ER. Assessment of suicidal patients has always to include clear recommendations concerning patient safety and treatment of the underlying condition as well as specific approaches in dealing with suicidal thoughts. Safety measures can include close monitoring, constant observation, restriction to means of suicide, referral to a psychiatric clinic and treatment with sedatives, generally benzodiazepines. Psychiatric disorders are ideally treated according to guidelines and clear recommendations should be given concerning treatment after discharge. Specific psychotherapy for suicidal behaviour possibly reduces the risk of future suicides. A special situation is created by assisted suicides which attribute to suicides in the elderly with a recent increase in the Swiss population. In some cases, undiagnosed depression may contribute to the decision making process, hence, underlining the importance of improved detection and treatment of depression in the elderly. PMID- 26423883 TI - ["I want to die" - dealing with suicidal wishes in primary palliative care]. AB - Different attitudes towards, and ideas about the end of life, represent an often experienced challenge in palliative care provided by family doctors. If values diverge too strongly, considerable strain can originate from it for the health care professionals, in particular if it is about assisted suicide. How do family doctors experience the incompatibility between patients' wishes and personal values? How do they succeed to bridge value divergences? Based on group discussions with family doctors in Switzerland the contribution focusses on these questions and identifies different strategies of family doctors. The results indicate that in particular 'convergence of perspectives' with patients can reduce the strain for family doctors and can at the same time guarantee high quality of care. PMID- 26423884 TI - [Suicide and suicidality in immigrant populations - transcultural aspects]. AB - To live as an immigrant in a foreign environment trying to restart his/her life is a major challenge for an individual and requires outstanding coping capacities. Some categories of immigrants suffer therefore from significant psychological stress and are at elevated risk for attempted or completed suicide: e. g. asylum seekers, second generation immigrants, uprooted refugees. In order to evaluate correctly the suicide risk and to offer effective treatment, a comprehensive assessment of the patient's history of migration is required. Only through a careful exploration of a patient's history and actual reality of life an effective approach is possible. The involvement of trained interpreters is essential if clinician and patient have no common language. Makeshifts like family members or friends as interpreters are not qualified and must be avoided. To approach the patient in an open minded, not judgmental, empathetic attitude is the key, and even culturally very different patients will be contactable. PMID- 26423885 TI - [Managment of the suicidal patient in the out-patient practice]. AB - Appropriate handling of suicidal tendencies is for certain one of the most important duties within ambulant treatment. As various examples show, occurrence of a suicidal tendency can be chronical as well as acute. Well-known risk factors including current psychopathology and psychodynamics help to identify and assess a suicidal tendency and to take necessary therapeutic options. Some of these can be applied in general, others have to be tailored specifically with respect to the mental disorder in question. Suicide often occurs in an interpersonal context. This fact underlines on one hand the importance and the therapeutic potential of the relationship between the patient and the therapist, on the other hand it results in many cases in a highly stressful situation for the therapist. Significant attention has to be paid to counter transference and its control. Development of an emergency plan and challenges of a "non-suicidal-contract" are discussed. We recommend an agreement with the patient to contact the therapist in case of not feeling able to control his/her own actions. This agreement includes our guarantee of permanent reachability. PMID- 26423886 TI - Berry intake changes hepatic gene expression and DNA methylation patterns associated with high-fat diet. AB - The liver is a critical organ for regulation of energy homeostasis and fatty liver disease is closely associated with obesity and insulin resistance. We have previously found that lingonberries, blackcurrants and bilberries prevent, whereas acai berries exacerbate, the development of hepatic steatosis and obesity in the high-fat (HF)-fed C57BL/6J mouse model. In this follow-up study, we investigated the mechanisms behind these effects. Genome-wide hepatic gene expression profiling indicates that the protective effects of lingonberries and bilberries are accounted for by several-fold downregulation of genes involved in acute-phase and inflammatory pathways (e.g. Saa1, Cxcl1, Lcn2). In contrast, acai fed mice exhibit marked upregulation of genes associated with steatosis (e.g. Cfd, Cidea, Crat) and lipid and cholesterol biosynthesis, which is in line with the exacerbation of HF-induced hepatic steatosis in these mice. In silico transcription factor analysis together with immunoblot analysis identified NF kappaB, STAT3 and mTOR as upstream regulators involved in mediating the observed transcriptional effects. To gain further insight into mechanisms involved in the gene expression changes, the HELP-tagging assay was used to identify differentially methylated CpG sites. Compared to the HF control group, lingonberries induced genome-wide hypermethylation and specific hypermethylation of Ncor2, encoding the corepressor NCoR/SMRT implicated in the regulation of pathways of metabolic homeostasis and inflammation. We conclude that the beneficial metabolic effects of lingonberries and bilberries are associated with downregulation of inflammatory pathways, whereas for blackcurrants, exerting similar metabolic effects, different mechanisms of action appear to dominate. NF kappaB, STAT3 and mTOR are potential targets of the health-promoting effects of berries. PMID- 26423887 TI - Table grape consumption reduces adiposity and markers of hepatic lipogenesis and alters gut microbiota in butter fat-fed mice. AB - Our objective was to determine if consuming table grapes reduces adiposity and its metabolic consequences and alters gut microbiota in mice fed a high-fat (HF), butter-rich diet. C57BL/6J mice were fed a low-fat (LF) diet or HF diet with 3% or 5% grapes for 11weeks. Total body and inguinal fat were moderately but significantly reduced in mice fed both levels of grapes compared to their controls. Mice fed 5% grapes had lower liver weights and triglyceride levels and decreased expression of glycerol-3-phosphate acyltransferase (Gpat1) compared to the 5% controls. Mice fed 3% grapes had lower hepatic mRNA levels of peroxisome proliferator-activated receptor gamma 2, sterol-CoA desaturase 1, fatty-acid binding protein 4 and Gpat1 compared to the 3% controls. Although grape feeding had only a minor impact on markers of inflammation or lipogenesis in adipose tissue or intestine, 3% of grapes decreased the intestinal abundance of sulfidogenic Desulfobacter spp. and the Bilophila wadsworthia-specific dissimilatory sulfite reductase gene and tended to increase the abundance of the beneficial bacterium Akkermansia muciniphila compared to controls. In addition, Bifidobacterium, Lactobacillus, Allobaculum and several other genera correlated negatively with adiposity. Allobaculum in particular was increased in the LF and 3% grapes groups compared to the HF-fed controls. Notably, grape feeding attenuated the HF-induced impairment in epithelial localization of the intestinal tight junction protein zonula occludens. Collectively, these data indicate that some of the adverse health consequences of consuming an HF diet rich in saturated fat can be attenuated by table grape consumption. PMID- 26423889 TI - IgA-Dominant Postinfectious Glomerulonephritis. PMID- 26423888 TI - Precision of the Kalon Herpes Simplex Virus Type 2 IgG ELISA: an international inter-laboratory assessment. AB - BACKGROUND: The commercial Kalon HSV-2 IgG ELISA is currently recommended for research use in sub-Saharan Africa because of its superior accuracy compared to other serologic assays. However, there are no data on key precision parameters of Kalon such as inter-operator variation, repeatability, and reproducibility, thus contributing to a barrier for its acceptance and use in clinical trials in sub Saharan Africa. We evaluated the analytical and field precision of the Kalon HSV 2 IgG ELISA. METHODS: A total of 600 HIV-infected and uninfected serum samples from South Africa and Zambia, previously tested by the gold standard University of Washington HSV western blot (UW-WB), were tested using Kalon by two technologists in an United States reference laboratory. Aliquots of 183 samples were retested using Kalon by an on-site technologist in a South African laboratory and a Zambian laboratory. RESULTS: Intra-assay variation was below 10 %. Intra-assay, intra-laboratory, and inter-laboratory correlation and agreement were significantly high (p < 0.01). In comparison to the UW-WB, accurate performance of Kalon was reproducible by each operator and laboratory. Receiver operating characteristic curve analysis indicated high selectivity of Kalon in the overall study population (area under the curve = 0.95, 95%CI = 0.92-0.97). DISCUSSION: Kalon is a robust assay with high precision and reproducibility. Accordingly, operator errorlikely does not contribute to the variability observed in Kalon's specificity throughout sera from sub-Saharan Africa. CONCLUSIONS: In populations with optimal diagnostic accuracy, Kalon is a reliable stand-alone method for on-site HSV-2 IgG antibody detection. PMID- 26423890 TI - A Comparison of Bladder Catheterization and Suprapubic Aspiration Methods for Urine Sample Collection From Infants With a Suspected Urinary Tract Infection. AB - This study compares 2 sampling methods for urine cultures in young infants. We analyzed data on urine samples obtained from 83 infants using 2 sources of urine: suprapubic bladder aspiration (SPA) and bladder catheterization. All specimens were subjected to both urinalysis and culture, and the results compared. Eighty three infants with positive urine culture results obtained by bladder catheterization were subjected to SPA. Of these, only 24 (28.9%) and 20 (24%) yielded positive urine culture and abnormal urinalysis data, respectively. Samples obtained via catheterization had a high false-positive rate (71.1%). The sensitivity and specificity of urinalysis were 66.7% (95% CI, 44.68% to 84.33%) and 93.22% (95% CI, 83.53% to 98.08%), respectively. In infants younger than 12 months, SPA is the best method to avoid bacterial contamination, showing better results than transurethral catheterization. PMID- 26423891 TI - An 8-Year-Old Boy With Abdominal Distension and Constipation. PMID- 26423892 TI - Effect of end-stage renal disease on long-term survival after a first-ever mechanical ventilation: a population-based study. AB - INTRODUCTION: Patients with end-stage renal disease (ESRD(Pos)) usually have multiple comorbidities and are predisposed to acute organ failure and in-hospital mortality. We assessed the effect of ESRD on the poorly understood long-term mortality risk after a first-ever mechanical ventilation (1-MV) for acute respiratory failure. METHODS: The data source was Taiwan's National Health Insurance (NHI) Research Database. All patients given a 1-MV between 1999 and 2008 from one million randomly selected NHI beneficiaries were identified (n = 38,659). Patients with or without ESRD (ESRD(Neg)) after a 1-MV between 1999 and 2008 were retrospectively compared and followed from the index admission date to death or the end of 2011. ESRD(Pos) patients (n = 1185; mean age: 65.9 years; men: 51.5 %) were individually matched to ESRD(Neg) patients (ratio: 1:8) using a propensity score method. The primary outcome was death after a 1-MV. The effect of ESRD on the risk of death after MV was assessed. A Cox proportional hazard regression model was used to assess how ESRD affected the mortality risk after a 1-MV. RESULTS: The baseline characteristics of the two cohorts were balanced, but the incidence of mortality was higher in ESRD(Pos) patients than in ESRD(Neg) patients (342.30 versus 179.67 per 1000 person-years; P <0.001; covariate adjusted hazard ratio: 1.43; 95 % confidence interval: 1.31-1.51). For patients who survived until discharge, ESRD was not associated with long-term (>4 years) mortality. CONCLUSIONS: ESRD increased the mortality risk after a 1-MV, but long term survival seemed similar. PMID- 26423893 TI - Piezoresistive effects in controllable defective HFTCVD graphene-based flexible pressure sensor. AB - In this work, the piezoresistive effects of defective graphene used on a flexible pressure sensor are demonstrated. The graphene used was deposited at substrate temperatures of 750, 850 and 1000 degrees C using the hot-filament thermal chemical vapor deposition method in which the resultant graphene had different defect densities. Incorporation of the graphene as the sensing materials in sensor device showed that a linear variation in the resistance change with the applied gas pressure was obtained in the range of 0 to 50 kPa. The deposition temperature of the graphene deposited on copper foil using this technique was shown to be capable of tuning the sensitivity of the flexible graphene-based pressure sensor. We found that the sensor performance is strongly dominated by the defect density in the graphene, where graphene with the highest defect density deposited at 750 degrees C exhibited an almost four-fold sensitivity as compared to that deposited at 1000 degrees C. This effect is believed to have been contributed by the scattering of charge carriers in the graphene networks through various forms such as from the defects in the graphene lattice itself, tunneling between graphene islands, and tunneling between defect-like structures. PMID- 26423894 TI - Childhood trauma and parental style: Relationship with markers of inflammation, oxidative stress, and aggression in healthy and personality disordered subjects. AB - Recent studies suggest that early life trauma is associated with elevations in circulating markers of inflammation in human subjects. History of aggression as a behavior, or aggression as a personality trait, is also associated with elevations of these inflammatory markers. Since early life trauma is associated with the development and maintenance of aggression in later life we examined the relationship of early life adversity, plasma inflammation markers (IL-6 and CRP) and oxidative stress markers (8-OH-DG and 8-ISO), and aggression in adult subjects with (n=79) and without (n=55) personality disorder. We used a series of mediated and moderated path models to test whether the effects of early adversity on later aggression may be mediated through markers of inflammation. Childhood abuse and parental control were associated with basal IL-6 and CRP concentrations. Path modeling suggested that childhood abuse was associated with aggression indirectly through CRP while parental control influenced aggression indirectly through IL-6 and CRP. Furthermore, these effects were independent of the effect of current depression. The results suggest that disruption of inflammatory processes represent one pathway by which early adversity influences aggression. PMID- 26423895 TI - Has variation in length of stay in acute hospitals decreased? Analysing trends in the variation in LOS between and within Dutch hospitals. AB - BACKGROUND: We aimed to get better insight into the development of the variation in length of stay (LOS) between and within hospitals over time, in order to assess the room for efficiency improvement in hospital care. METHODS: Using Dutch national individual patient-level hospital admission data, we studied LOS for patients in nine groups of diagnoses and procedures between 1995 and 2010. We fitted linear mixed effects models to the log-transformed LOS to disentangle within and between hospital variation and to evaluate trends, adjusted for case mix. RESULTS: We found substantial differences between diagnoses and procedures in LOS variation and development over time, supporting our disease-specific approach. For none of the diagnoses, relative variance decreased on the log scale, suggesting room for further LOS reduction. Except for two procedures in the same specialty, LOS of individual hospitals did not correlate between diagnoses/procedures, indicating the absence of a hospital wide policy. We found within-hospital variance to be many times greater than between-hospital variance. This resulted in overlapping confidence intervals across most hospitals for individual hospitals' performances in terms of LOS. CONCLUSIONS: The results suggest room for efficiency improvement implying lower costs per patient treated. It further implies a possibility to raise the number of patients treated using the same capacity or to downsize the capacity. Furthermore, policymakers and health care purchasers should take into account statistical uncertainty when benchmarking LOS between hospitals and identifying inefficient hospitals. PMID- 26423906 TI - Increased colorectal cancer incidence in Iran: a systematic review and meta analysis. AB - BACKGROUND: Colorectal cancer is the third most common cancer in Iran. The increasing trend of colorectal cancer incidence in Iran and the close relationship with the geographical location are the underlying reasons for this study. METHODS: DATA SOURCE: Eleven databases, including MEDLINE, EMBASE, SCOPUS, and four other databases, for articles in Persian were searched from April 2014 to October 2014. Additional data were obtained from an online survey of the Central Library of Tabriz Faculty of Medicine. STUDY ELIGIBILITY CRITERIA: In this systematic review and meta-analysis, we included studies reporting different measures of incidence, age-standardized incidence rates, and crude incidence rates. All rates (per 100,000 person-years) were standardized to the world standard population. STUDY APPRAISAL AND SYNTHESIS METHODS: A preliminary review of the title and abstracts of these articles was used to exclude any that were clearly irrelevant. The full text review determined whether the article was relevant to our topic. All the potentially relevant manuscripts were reviewed by two other investigators (S.D., M.G.). A total of 39 studies (10 Persian and 29 English articles) from different provinces and diverse areas of Iran, were analyzed in this study using comprehensive meta-analysis software. For accuracy studies, we used estimated rates for males and females with 95 % confidence intervals. RESULTS: Age-standardized incidence rates were obtained based on the random effects model and were 8.16 (95 % CI: 6.64 to 9.68) and 6.17 (95 % CI: 5.01 to 7.32) for males and females, respectively. The random crude rates were 5.58 (95 % CI: 4.22 to 6.94) for males and 4.01 (95 % CI: 3.06 to 4.97) for females. CONCLUSIONS: Colorectal cancer incidence rates rise due to individual and environmental risk factors as well as improvement in the registry system and increase in access to health services. A more executed organized and structured system for collecting cancer data, in all cities and rural areas of the country, is an essential priority. PMID- 26423907 TI - Superior cervical ganglion mimicking retropharyngeal adenopathy in head and neck cancer patients: MRI features with anatomic, histologic, and surgical correlation. AB - INTRODUCTION: To describe the unique MRI findings of superior cervical ganglia (SCG) that may help differentiate them from retropharyngeal lymph nodes (RPLNs). METHODS: A retrospective review of post-treatment NPC patients from 1999 to 2012 identified three patients previously irradiated for NPC that were suspected of having recurrent nodal disease in retropharyngeal lymph nodes during surveillance MRI. Subsequent surgical exploration revealed enlarged SCG only; no retropharyngeal nodal disease was found. A cadaveric head specimen was also imaged with a 3T MRI before and after dissection. In addition, SCG were also harvested from three cadaveric specimens and subjected to histologic analysis. RESULTS: The SCG were found at the level of the C2 vertebral body, medial to the ICA. They were ovoid on axial images and fusiform and elongated with tapered margins in the coronal plane. T2-weighted (T2W) signal was hyperintense. No central elevated T1-weighted (T1W) signal was seen within the ganglia in non-fat saturated sequences to suggest the presence of a fatty hilum. Enhancement after gadolinium was present. A central "black dot" was seen on axial T2W and post contrast images in two of the three SCG demonstrated. Histology showed the central black line was comprised of venules and interlacing neurites within the central portion of the ganglion. CONCLUSIONS: The SCG can be mistaken for enlarged RPLNs in post-treatment NPC patients. However, there are features which can help differentiate them from RPLNs, preventing unnecessary therapy. These imaging findings have not been previously described. PMID- 26423908 TI - Poly(N-isopropylacrylamide-co-allylamine) (PNIPAM-co-ALA) nanospheres for the thermally triggered release of Bacteriophage K. AB - Due to the increased prevalence of resistant bacterial isolates which are no longer susceptible to antibiotic treatment, recent emphasis has been placed on finding alternative modes of treatment of wound infections. Bacteriophage have long been investigated for their antimicrobial properties, yet the utilization of phage therapy for the treatment of wound infections relies on a suitable delivery system. Poly(N-isopropylacrylamide) (PNIPAM) is a thermally responsive polymer which undergoes a temperature dependent phase transition at a critical solution temperature. Bacteriophage K has been successfully formulated with PNIPAM nanospheres copolymerized with allylamine (PNIPAM-co-ALA). By utilizing a temperature responsive polymer it has been possible to engineer the nanospheres to collapse at an elevated temperature associated with a bacterial skin infection. The nanogels were reacted with surface deposited maleic anhydride in order to anchor the nanogels to non-woven fabric. Bacteriophage incorporated PNIPAM-co-ALA nanospheres demonstrated successful bacterial lysis of a clinically relevant bacterial isolate - Staphylococcus aureus ST228 at 37 degrees C, whilst bacterial growth was unaffected at 25 degrees C, thus providing a thermally triggered release of bacteriophage. PMID- 26423911 TI - Three-Dimensional Modeling May Improve Surgical Education and Clinical Practice. AB - BACKGROUND: Three-dimensional (3D) printing has been used in the manufacturing industry for rapid prototyping and product testing. The aim of our study was to assess the feasibility of creating anatomical 3D models from a digital image using 3D printers. Furthermore, we sought face validity of models and explored potential opportunities for using 3D printing to enhance surgical education and clinical practice. METHODS: Computed tomography and magnetic resonance images were reviewed, converted to computer models, and printed by stereolithography to create near exact replicas of human organs. Medical students and surgeons provided feedback via survey at the 2014 Surgical Education Week conference. RESULTS: There were 51 respondents, and 95.8% wanted these models for their patients. Cost was a concern, but 82.6% found value in these models at a price less than $500. All respondents thought the models would be useful for integration into the medical school curriculum. CONCLUSION: Three-dimensional printing is a potentially disruptive technology to improve both surgical education and clinical practice. As the technology matures and cost decreases, we envision 3D models being increasingly used in surgery. PMID- 26423910 TI - Altered serotonin transporter binding potential in patients with obsessive compulsive disorder under escitalopram treatment: [11C]DASB PET study. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic, relapsing mental illness. Selective serotonin reuptake inhibitors block serotonin transporters (SERTs) and are the mainstay of treatment for OCD. SERT abnormalities are reported in drug-free patients with OCD, but it is not known what happens to SERT levels during treatment. This is important as alterations in SERT levels in patients under treatment could underlie poor response, or relapse during or after treatment. The aim of the present study was first to validate a novel approach to measuring SERT levels in people taking treatment and then to investigate SERT binding potential (BP) using [11C]DASB PET in patients with OCD currently treated with escitalopram in comparison with healthy controls. METHOD: Twelve patients and age- and sex-matched healthy controls were enrolled. The patients and healthy controls underwent serial PET scans after administration of escitalopram and blood samples for drug concentrations were collected simultaneously with the scans. Drug-free BPs were obtained by using an inhibitory E max model we developed previously. RESULTS: The inhibitory E max model was able to accurately predict drug-free SERT BP in people taking drug treatment. The drug-free BP in patients with OCD currently treated with escitalopram was significantly different from those in healthy volunteers [Cohen's d = 0.03 (caudate), 1.16 (putamen), 1.46 (thalamus), -5.67 (dorsal raphe nucleus)]. CONCLUSIONS: This result extends previous findings showing SERT abnormalities in drug-free patients with OCD by indicating that altered SERT availability is seen in OCD despite treatment. This could account for poor response and the high risk of relapse in OCD. PMID- 26423909 TI - Myocardial interstitial remodelling in non-ischaemic dilated cardiomyopathy: insights from cardiovascular magnetic resonance. AB - Myocardial remodelling involves not only the myocytes, but also non-myocyte cells and the extracellular matrix, which constitutes around 6 % of the normal heart and includes fluid, collagen and glycoproteins. In non-ischaemic dilated cardiomyopathy (DCM), the cardiac interstitium increases as a result of diffuse interstitial (microscopic) fibrosis, post-necrotic replacement (macroscopic) fibrosis or myocardial oedema. The activation of the renin-angiotensin aldosterone system is a major determinant of fibroblasts activation and collagen deposition, with the transforming growth factor beta as the downstream signal mediator. Endomyocardial biopsy still represents the current reference method for interstitial and replacement myocardial fibrosis assessment, but cardiovascular magnetic resonance (CMR) allows in vivo detection of macroscopic fibrosis with post-contrast late enhancement imaging. Moreover, recent pre- and post-contrast T1 mapping techniques provide a quantitative estimation of myocardial interstitial remodelling, with potential diagnostic and prognostic clinical utility. Here, we review the pathophysiological mechanisms of myocardial interstitial remodelling in DCM, its non-invasive characterization with biomarkers and with CMR, as well as the most recent studies about their clinical utility. PMID- 26423912 TI - Electrical Impedance Spectroscopy to Aid Parathyroid Identification and Preservation in Central Compartment Neck Surgery: A Proof of Concept in a Rabbit Model. AB - BACKGROUND: Accurate identification of parathyroid glands during thyroid surgery is crucial to avoid postthyroidectomy hypocalcemia. Electrical impedance spectroscopy has the potential to differentiate between tissues of different morphology. The aim of this study was to determine the electrical impedance patterns of the thyroid, parathyroid, and other soft tissue structures in the rabbit neck. METHODS: The central compartments were exposed in 9 freshly culled New Zealand White rabbits. In situ and ex vivo electrical impedance was measured from thyroid lobes, external parathyroid glands, adipose tissue, and strap muscle using the APX100 device. Specimens of all identified glands were sent for histopathology examination. RESULTS: Histology confirmed correct identification of all excised thyroid and parathyroid glands. The impedance was higher for thyroid tissue at lower frequencies and for parathyroid tissue at higher frequencies. Ex vivo electrical impedance spectra were significantly higher compared with the in situ spectra across all frequencies for thyroid and parathyroid tissues (P < .001). The ratio of low to high frequency in situ impedance of thyroid, parathyroid, and muscle was significantly different (P < .001), allowing for differentiation between these tissues. CONCLUSION: The electrical impedance spectra of rabbit thyroid and parathyroid glands are distinct and different from each other and from skeletal muscle. If these results are replicated in human tissue, they have the potential to improve patient outcomes by achieving early identification and preservation of parathyroid glands. PMID- 26423913 TI - Risk of Adverse Vascular Events in Newly Diagnosed Glioblastoma Multiforme Patients Treated with Bevacizumab: a Systematic Review and Meta-Analysis. AB - Previous evidence suggests that the humanized anti-VEGF antibody bevacizumab increases thrombosis risk in glioma patients. Here, we comprehensively assessed the risk of adverse vascular events in adult glioma patients receiving bevacizumab therapy. Systematic searches of MEDLINE, EMBASE, and the Cochrane Library were conducted to find prospective phase II/III clinical trials on adult bevacizumab-treated glioma patients and non-bevacizumab-treated controls that reported data on adverse vascular events. Four high-quality trials were finally included in the systematic review, scoring greater than or equal to 7/8 on the Newcastle-Ottawa Scale. Three trials provided sufficient data for four meta analytical comparisons between bevacizumab-treated and control groups of newly diagnosed glioblastoma multiforme (GBM) patients: all-cause discontinuation, thrombocytopenia, deep vein thrombosis (DVT), and pulmonary embolism. None of these adverse outcomes were found to be significantly different between bevacizumab-treated and control groups (P > 0.05); however, there was a trend toward significance with regard to bevacizumab therapy and the risk of pulmonary embolism (P = 0.07). As there was a trend toward significance with regard to bevacizumab therapy and the risk of pulmonary embolism, anticoagulation may be advisable in certain newly diagnosed adult GBM patients who display a history of thromboembolism and/or more serious risk factors for thromboembolic events. PMID- 26423914 TI - Telemedicine for Monitoring MS Activity and Progression. AB - OPINION STATEMENT: Telemedicine (TM) is defined as the exchange of medical information between two different physical places. The aims of TM are to provide services that cannot easily be provided face-to-face and improve the efficiency of existing ones. Multiple sclerosis (MS) is a chronic demyelinating disease characterized by a heterogeneous array of symptoms that can lead to severe impairment and may impact on accessibility to medical services, patient's ability to function, and overall health-related quality of life (HRQoL). The use of TM to clinically monitor MS patients has demonstrated benefits by improving HRQoL and reducing associated medical costs. Patient-reported outcome (PRO) measures have been used in TM interventions, registries, and cost-efficiency studies because they offer valuable information about patient's perspective of MS disease burden. Moreover, TM has shown acceptable reliability in the assessment of the neurological impairment by Kurtzke expanded disability status scale (EDSS) and has the potential to develop more sensitive measures, such as average daily walking activity, to closely monitor MS disease progression in real environment. It is likely that the use of TM will continue to increase in the following years but larger and controlled studies are necessary to confirm the beneficial effects of TM to deliver an optimal care for patients with MS. PMID- 26423916 TI - [Osteoporosis]. PMID- 26423915 TI - A Randomized Controlled Trial of an Emergency Department Intervention for Patients with Chronic Noncancer Pain. AB - BACKGROUND: Emergency Departments (EDs) are beginning to notify their physicians of patients reporting chronic noncancer pain (CNCP) who frequent EDs, and are suggesting that the physicians not prescribe opioids to these patients. OBJECTIVES: We hypothesized that this intervention would reduce both the number of opioids prescribed to these patients by their ED physicians and the number of these patients' return visits to the ED. METHODS: We conducted a randomized controlled trial of this intervention in 13 electronically linked EDs. Patients eligible for the study were characterized by CNCP, lacked evidence of sickle cell anemia and suicide ideation, and made frequent (>10) visits to the EDs over a 12 month period. We randomly assigned 411 of these patients to either an intervention group or a control group. Our intervention comprised both an alert placed in eligible patients' medical files and letters sent to the patients and their community-based providers. The alert suggested that physicians decline requests for opioid analgesic prescriptions and instead refer these patients to community-based providers to manage their ongoing pain. RESULTS: During the 12 months after randomization, patients in the intervention and control groups averaged 11.9 and 16.6 return visits, and received prescriptions for opioids on 16% and 26% of those visits, respectively. Altogether, patients in the intervention group made 1033 fewer return visits to the EDs in the follow-up year than those in the control group. CONCLUSION: This intervention constitutes a promising practice that EDs should consider to reduce the number of visits made by frequent visitors with CNCP. PMID- 26423917 TI - [Penetrating stab injury to the lumbar spinal cord in a child]. AB - This article reports the case of an 8-year-old boy with a knife stab injury to the lumbar spine without neurological deficits. The computed tomography (CT) scan revealed a longitudinal penetration of the conus medullaris at the level of the first lumbar vertebra. The knife blade was extracted and primary closure was carried out on the stab wound. The immediately postoperative magnetic resonance imaging (MRI) as well as the follow-up examinations after 1 and 6 weeks showed no evidence of compressive spinal bleeding, myelopathy or cerebrospinal fluid leakage. In addition, no secondary changes of the neurological status developed. Consequently, in cases of neurologically asymptomatic patients without concomitant injuries the surgical exploration of a stab wound does not seem to be absolutely necessary. PMID- 26423918 TI - [Omission of osteoporosis diagnostics and therapy after fractures in the elderly : an avoidable treatment error?]. AB - Through a more consistent diagnostics and treatment of osteoporosis, subsequent fractures and associated complications could be reduced in aged patients. Whereas anticoagulants are now standard in the treatment of fractures of the lower extremities to prevent thromboembolic complications in orthopedic surgery and an omission of anticoagulation can be regarded as medical malpractice, the management of osteoporosis following such fractures is very frequently disregarded. Although guidelines for osteoporosis, such as those from the governing body on osteology (Dachverband Osteologie, DVO) from 2014 are not legally binding as such, the breach of this standard of care can constitute a breach of medical obligation by the physician. The omission of osteoporosis diagnostics and initiation of treatment despite appropriate findings after fractures in aged patients, could represent a diagnostic assessment error and severe malpractice in the legal sense. In this case, evidence of a serious malpractice could be associated with civil, criminal and professional claims which could be linked with relevant legal consequences. Regardless of the legal consequences for omission of osteoporosis management following multiple fractures in aged patients, the management of osteoporosis should be an integral component in the treatment of these patients in the future. PMID- 26423919 TI - Variations in peak nasal inspiratory flow among healthy students after using saline solutions. AB - INTRODUCTION: Nasal hygiene with saline solutions has been shown to relieve congestion, reduce the thickening of the mucus and keep nasal cavity clean and moist. OBJECTIVE: Evaluating whether saline solutions improve nasal inspiratory flow among healthy children. METHODS: Students between 8 and 11 years of age underwent 6 procedures with saline solutions at different concentrations. The peak nasal inspiratory flow was measured before and 30 min after each procedure. Statistical analysis was performed by means of t test, analysis of variance, and Tukey's test, considering p<0.05. RESULTS: We evaluated 124 children at all stages. There were differences on the way a same concentration was used. There was no difference between 0.9% saline solution and 3% saline solution by using a syringe. CONCLUSION: The 3% saline solution had higher averages of peak nasal inspiratory flow, but it was not significantly higher than the 0.9% saline solution. It is important to offer various options to patients. PMID- 26423920 TI - Reactivity of the Donor-Stabilized Silylenes [iPrNC(Ph)NiPr]2 Si and [iPrNC(NiPr2 )NiPr]2 Si: Activation of CO2 and CS2. AB - Activation of CO2 by the bis(amidinato)silylene 1 and the analogous bis(guanidinato)silylene 2 leads to the structurally analogous six-coordinate silicon(IV) complexes 4 (previous work) and 8, respectively, the first silicon compounds with a chelating carbonato ligand. Likewise, CS2 activation by silylene 1 affords the analogous six-coordinate silicon(IV) complex 10, the first silicon compound with a chelating trithiocarbonato ligand. CS2 activation by silylene 2, however, yields the five-coordinate silicon(IV) complex 13 with a carbon-bound CS2 (2-) ligand, which also represents an unprecedented coordination mode in silicon coordination chemistry. Treatment of the dinuclear silicon(IV) complexes 5 and 6 with CO2 also affords the six-coordinate carbonatosilicon(IV) complexes 4 and 8, respectively. PMID- 26423921 TI - Patients' Experiences Using a Brief Screening Tool for Medication-Related Problems in a Community Pharmacy Setting. AB - OBJECTIVES: The objective of this study was to explore patient perceptions and the practical implication of using a brief 9-item scale to screen for medication related problems in community pharmacies. METHODS: Semistructured, audio recorded, telephonic interviews were conducted with 40 patients who completed the scale and reviewed its results with their pharmacist. Audio recordings were transcribed verbatim and analyzed using qualitative methods to identify themes. RESULTS: Patients generally reported the scale was simple to complete and could be used easily in other community pharmacies. Participants shared they had increased understanding of their medications and confidence that their medication therapy was appropriate. Several patients reported having actual medication related problems identified and resolved through the use of the scale. Patients also reported improved relationships with pharmacists and heightened belief in the value provided by pharmacists. CONCLUSIONS: This screening tool may have value in increasing patients' understanding of and confidence in their medications, enhancing pharmacist-patient relationships, and identifying problems requiring additional interventions. PMID- 26423922 TI - Comments on: Validity and Reliability of a Systematic Database Search Strategy to Identify Publications Resulting From Pharmacy Residency Research Projects. PMID- 26423923 TI - Localizing Carbohydrate Binding Sites in Proteins Using Hydrogen/Deuterium Exchange Mass Spectrometry. AB - The application of hydrogen/deuterium exchange mass spectrometry (HDX-MS) to localize ligand binding sites in carbohydrate-binding proteins is described. Proteins from three bacterial toxins, the B subunit homopentamers of Cholera toxin and Shiga toxin type 1 and a fragment of Clostridium difficile toxin A, and their interactions with native carbohydrate receptors, GM1 pentasaccharides (beta Gal-(1->3)-beta-GalNAc-(1->4)[alpha-Neu5Ac-(2->3)]-beta-Gal-(1->4)-Glc), Pk trisaccharide (alpha-Gal-(1->4)-beta-Gal-(1->4)-Glc) and CD-grease (alpha-Gal-(1 >3)-beta-Gal-(1->4)-beta-GlcNAcO(CH2)8CO2CH3), respectively, served as model systems for this study. Comparison of the differences in deuterium uptake for peptic peptides produced in the absence and presence of ligand revealed regions of the proteins that are protected against deuterium exchange upon ligand binding. Notably, protected regions generally coincide with the carbohydrate binding sites identified by X-ray crystallography. However, ligand binding can also result in increased deuterium exchange in other parts of the protein, presumably through allosteric effects. Overall, the results of this study suggest that HDX-MS can serve as a useful tool for localizing the ligand binding sites in carbohydrate-binding proteins. However, a detailed interpretation of the changes in deuterium exchange upon ligand binding can be challenging because of the presence of ligand-induced changes in protein structure and dynamics. PMID- 26423924 TI - Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing. AB - Sudden unexpected death in epilepsy (SUDEP) is defined as the abrupt, no traumatic, witnessed or unwitnessed death, occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus (seizure duration >= 30 min or seizures without recovery), and in which postmortem examination does not reveal a cause of death. Although the physiopathological mechanisms that underlie SUDEP remain to be clarified, the genetic background has been described to play a role in this disorder. Pathogenic variants in genes associated with epilepsy and encoding cardiac ion channels could explain the SUDEP phenotype. To test this we use the next-generation sequencing technology to sequence a cohort of SUDEP cases and its translation into clinical and forensic fields. A panel target resequencing was used to study 14 SUDEP cases from both postmortem (2 cases) and from living patients (12 cases). Genes already associated with SUDEP and also candidate genes had been investigated. Overall, 24 rare genetic variants were identified in 13 SUDEP cases. Four cases showed rare variants with complete segregation in the SCN1A, FBN1, HCN1, SCN4A, and EFHC1 genes, and one case with a rare variant in KCNQ1 gene showed incomplete pattern of inheritance. In four cases, rare variants were detected in CACNA1A, SCN11A and SCN10A, and KCNQ1 genes, but familial segregation was not possible due to lack of DNA from relatives. Finally, in the four remaining cases, the rare variants did not segregate in the family. This study confirms the link between epilepsy, sudden death, and cardiac disease. In addition, we identified new potential candidate genes for SUDEP: FBN1, HCN1, SCN4A, EFHC1, CACNA1A, SCN11A, and SCN10A. Further confirmation in larger cohorts will be necessary especially if genetic screening for SUDEP is applied to forensic and clinical medicine. Nevertheless, this study supports the emerging concept of a genetically determined cardiocerebral channelopathy. PMID- 26423925 TI - Hereditary spastic paraplegia with recessive trait caused by mutation in KLC4 gene. AB - We report an association between a new causative gene and spastic paraplegia, which is a genetically heterogeneous disorder. Clinical phenotyping of one consanguineous family followed by combined homozygosity mapping and whole-exome sequencing analysis. Three patients from the same family shared common features of progressive complicated spastic paraplegia. They shared a single homozygous stretch area on chromosome 6. Whole-exome sequencing revealed a homozygous mutation (c.853_871del19) in the gene coding the kinesin light chain 4 protein (KLC4). Meanwhile, the unaffected parents and two siblings were heterozygous and one sibling was homozygous wild type. The 19 bp deletion in exon 6 generates a stop codon and thus a truncated messenger RNA and protein. The association of a KLC4 mutation with spastic paraplegia identifies a new locus for the disease. PMID- 26423926 TI - Comparison of genetic variation in drug ADME-related genes in Thais with Caucasian, African and Asian HapMap populations. AB - The objectives of this study are to investigate allele frequencies of drug absorption, distribution, metabolism and elimination (ADME)-related genes in the Thai population and to compare these genes to HapMap populations including Caucasians (CEU), Africans (YRI) and Asians (CHB/JPT). Genetic variations of drug ADME-related genes in 190 Thais were investigated using drug metabolizing enzymes and transporters (DMET) plus genotyping system. We examined 1936 single nucleotide polymorphisms (SNPs) of 225 genes that have documented functional and clinical significances in phase I and phase II drug metabolism enzymes, drug transporters and other genes involved in ADME processes. Distributions of genotyping data from Thai were compared with other HapMap populations including Caucasian, African and Asian populations. The analysis demonstrated 43 SNPs with statistical significance comparing among five populations. However, only 26 SNPs showed statistical significance in pair-wise comparisons between Thai versus CEU and Thai versus CHB/JPT. These 26 SNPs belong to 13 groups of drug ADME-related genes which are CYP2A6, CYP3A5, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, VKORC1, COMT, NAT2, TPMT, UGT1A1 and SLCO1B1. These genes demonstrated clinical significances as previously observed in many studies. The results could explain clinical variability in pharmacokinetics and pharmacodynamics of drugs in Thais based on genetic variations in drug ADME-related gene emphasized in this article. PMID- 26423927 TI - Environmentally persistent free radical-containing particulate matter competitively inhibits metabolism by cytochrome P450 1A2. AB - Combustion processes generate different types of particulate matter (PM) that can have deleterious effects on the pulmonary and cardiovascular systems. Environmentally persistent free radicals (EPFRs) represent a type of particulate matter that is generated after combustion of environmental wastes in the presence of redox-active metals and aromatic hydrocarbons. Cytochromes P450 (P450/CYP) are membrane-bound enzymes that are essential for the phase I metabolism of most lipophilic xenobiotics. The EPFR formed by chemisorption of 2-monochlorophenol to silica containing 5% copper oxide (MCP230) has been shown to generally inhibit the activities of different forms of P450s without affecting those of cytochrome P450 reductase and heme oxygenase-1. The mechanism of inhibition of rat liver microsomal CYP2D2 and purified rabbit CYP2B4 by MCP230 has been shown previously to be noncompetitive with respect to substrate. In this study, MCP230 was shown to competitively inhibit metabolism of 7-benzyl-4-trifluoromethylcoumarin and 7 ethoxyresorufin by the purified, reconstituted rabbit CYP1A2. MCP230 is at least 5- and 50-fold more potent as an inhibitor of CYP1A2 than silica containing 5% copper oxide and silica, respectively. Thus, even though PM generally inhibit multiple forms of P450, PM interacts differently with the forms of P450 resulting in different mechanisms of inhibition. P450s function as oligomeric complexes within the membrane. We also determined the mechanism by which PM inhibited metabolism by the mixed CYP1A2-CYP2B4 complex and found that the mechanism was purely competitive suggesting that the CYP2B4 is dramatically inhibited when bound to CYP1A2. PMID- 26423929 TI - Addiction, Voluntary Choice, and Informed Consent: A Reply to Uusitalo and Broers. AB - In an earlier article in this journal I argued that the question of whether heroin addicts can give voluntary consent to take part in research which involves giving them a choice of free heroin does not - in contrast with a common assumption in the bioethics literature - depend exclusively on whether or not they possess the capacity to resist their desire for heroin. In some cases, circumstances and beliefs might undermine the voluntariness of the choices a person makes even if they do possess a capacity for self-control. Based on what I took to be a plausible definition of voluntariness, I argued that the circumstances and beliefs typical of many vulnerable heroin addicts are such that we have good reasons to suspect they cannot give voluntary consent to take part in such research, even assuming their desire for heroin is not irresistible. In a recent article in this journal, Uusitalo and Broers object to this on the grounds that I misdescribe heroin addicts' options set, that the definition of voluntariness on which I rely is unrealistic and too demanding, and, more generally, that my view of heroin addiction is flawed. I think their arguments derive from a misunderstanding of the view I expressed in my article. In what follows I hope therefore to clarify my position. PMID- 26423928 TI - Increased risk of stroke with darbepoetin alfa in anaemic heart failure patients with diabetes and chronic kidney disease. AB - AIMS: The use of an erythropoesis-stimulating agent, darbepoetin alfa (DA), to treat anaemia in patients with diabetes mellitus and chronic kidney disease was associated with a heightened risk of stroke and neutral efficacy in the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), despite epidemiological data suggesting the contrary. However, this association has not been evaluated in another randomized, placebo-controlled trial. METHODS AND RESULTS: Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) was a randomized placebo-controlled trial of DA in 2278 patients with systolic heart failure and anaemia, enrolled from 2006 to 2012 and followed for a median of 28 months. Within RED-HF, 816 patients had diabetes mellitus and chronic kidney disease [estimated glomerular filtration rate (eGFR) 20-60 mL/min/1.73 m(2) ] and met inclusion criteria for TREAT. TREAT-like RED-HF patient data were analysed alone and combined at the patient level with the 4038 TREAT patients. In RED-HF, the annualized event rate of stroke was 2.3 in patients on DA and 1.1 in patients randomized to placebo (P = 0.051). Analysis of the combined group (n = 4854) confirmed a nearly two-fold increase in stroke risk [hazard ratio (HR) 1.94, 95% confidence interval (CI) 1.43-2.63] and an overall neutral effect on mortality (HR 1.00, 95% CI 0.89-1.12) of raising haemoglobin with DA. CONCLUSION: The placebo-controlled cohort of heart failure patients with anaemia, diabetes mellitus, and chronic kidney disease from RED-HF provides confirmation of the increased stroke risk associated with DA use identified in TREAT. PMID- 26423930 TI - Centrocentral Short Circuiting for Management of Stump Neuroma Pain in Amputees. PMID- 26423931 TI - Microsurgical Fenestration and Paraspinal Muscle Pedicle Flaps for the Treatment of Symptomatic Sacral Tarlov Cysts. AB - OBJECTIVE: Sacral Tarlov cysts are rare causes of sciatic and sacrococcygeal pain and neurologic deficits. Although several microsurgical treatments have been described, the optimal treatment has yet to be determined. We describe our initial experience with symptomatic lesions combining 1) cyst fenestration and imbrication and 2) filling the epidural space using vascularized paraspinous muscle flaps rotated into the cystic cavity. METHODS: We retrospectively reviewed all consecutive cases of symptomatic giant sacral Tarlov cysts treated with microsurgery at our institution between 2003 and 2011. The main outcome measure was self-reported symptom relief. Postoperative imaging, surgical complications, and subsequent treatments were also recorded. RESULTS: Thirty-five patients were treated. Mean age was 52 years. All patients presented with a chief complaint of sacral-perineal pain. The mean cyst size was 3.6 cm (largest diameter). Follow-up beyond the initial hospital stay was available in 86% (median 8 months). Ninety three percent reported improvement in pain at some point during the postoperative course but 50% of those developed recurrent pain symptoms. Postoperative imaging was available in 69% of the patients in whom 92% showed complete obliteration (25%) or reduction in cyst size (67%). CONCLUSIONS: The combination of microsurgical cyst fenestration and the use of vascularized muscle pedicle flaps to fill the cystic cavity and the epidural space results in obliteration or reduction in size of the majority of cysts and is associated with initial improvement in pain in most patients. However, delayed recurrence of pain was common with this technique. PMID- 26423932 TI - The immunomodulatory oligodendrocyte. AB - Oligodendrocytes, the myelinating glial cells of the central nervous system (CNS), are due to their high specialization and metabolic needs highly vulnerable to various insults. This led to a general view that oligodendrocytes are defenseless victims during brain damage such as occurs in acute and chronic CNS inflammation. However, this view is challenged by increasing evidence that oligodendrocytes are capable of expressing a wide range of immunomodulatory molecules. They express various cytokines and chemokines (e.g. Il-1beta, Il17A, CCL2, CXCL10), antigen presenting molecules (MHC class I and II) and co stimulatory molecules (e.g. CD9, CD81), complement and complement receptor molecules (e.g. C1s, C2 and C3, C1R), complement regulatory molecules (e.g. CD46, CD55, CD59), tetraspanins (e.g. TSPAN2), neuroimmune regulatory proteins (e.g. CD200, CD47) as well as extracellular matrix proteins (e.g. VCAN) and many others. Their potential immunomodulatory properties can, at specific times and locations, influence ongoing immune processes as shown by numerous publications. Therefore, oligodendrocytes are well capable of immunomodulation, especially during the initiation or resolution of immune processes in which subtle signaling might tip the scale. A better understanding of the immunomodulatory oligodendrocyte can help to invent new, innovative therapeutic interventions in various diseases such as Multiple Sclerosis. This article is part of a Special Issue entitled SI: Myelin Evolution. PMID- 26423933 TI - MicroRNA-574 is involved in cognitive impairment in 5-month-old APP/PS1 mice through regulation of neuritin. AB - Alzheimer's disease (AD) is the most common form of dementia in the elderly. The recent evidence in AD research suggests that alterations in the microRNA (miRNA) could contribute to risk for the disease. However, little is understood about the roles of miRNAs in cognitive impairment of early Alzheimer's disease (AD). Here, we used 5-month-old APP/PS1 mice, which mimic many of the salient features of the early stage of AD pathological process, to further investigate the roles of miRNAs in synaptic loss involved in learning and memory. We used miRNA expression microarrays on RNA extracted from the hippocampus of 5-month-old APP/PS1 mice and wild type mice. Real-time reverse transcription PCR was conducted to verify the candidate miRNAs discovered by microarray analysis. The data showed that miR-574 was increased significantly in the hippocampus of 5-month-old APP/PS1 mice, which were concomitant with that APP/PS1 mice at the same age displayed a significant synaptic loss and cognitive deficits. Bioinformatic analysis predicted that neuritin (Nrn1) mRNA is targeted by miR-574. Overexpression of miR-574 lowers the levels of neuritin and synaptic proteins expression in primary hippocampal neurons damage induced by Abeta25-35. And the expression of miR-574 was also up regulated in the hippocampal neurons from APP/PS1 mice compared with WT littermates. In contrast, suppression of miR-574 by miR-574 inhibitor significantly results in higher levels of neuritin and synaptic proteins expression. Taken together, miR-574 is involved in cognitive impairment in 5 month-old APP/PS1 mice through regulation of neuritin. PMID- 26423934 TI - Reverse engineering human neurodegenerative disease using pluripotent stem cell technology. AB - With the technology of reprogramming somatic cells by introducing defined transcription factors that enables the generation of "induced pluripotent stem cells (iPSCs)" with pluripotency comparable to that of embryonic stem cells (ESCs), it has become possible to use this technology to produce various cells and tissues that have been difficult to obtain from living bodies. This advancement is bringing forth rapid progress in iPSC-based disease modeling, drug screening, and regenerative medicine. More and more studies have demonstrated that phenotypes of adult-onset neurodegenerative disorders could be rather faithfully recapitulated in iPSC-derived neural cell cultures. Moreover, despite the adult-onset nature of the diseases, pathogenic phenotypes and cellular abnormalities often exist in early developmental stages, providing new "windows of opportunity" for understanding mechanisms underlying neurodegenerative disorders and for discovering new medicines. The cell reprogramming technology enables a reverse engineering approach for modeling the cellular degenerative phenotypes of a wide range of human disorders. An excellent example is the study of the human neurodegenerative disease amyotrophic lateral sclerosis (ALS) using iPSCs. ALS is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs), culminating in muscle wasting and death from respiratory failure. The iPSC approach provides innovative cell culture platforms to serve as ALS patient-derived model systems. Researchers have converted iPSCs derived from ALS patients into MNs and various types of glial cells, all of which are involved in ALS, to study the disease. The iPSC technology could be used to determine the role of specific genetic factors to track down what's wrong in the neurodegenerative disease process in the "disease in-a-dish" model. Meanwhile, parallel experiments of targeting the same specific genes in human ESCs could also be performed to control and to complement the iPSC based approach for ALS disease modeling studies. Much knowledge has been generated from the study of both ALS iPSCs and ESCs. As these methods have advantages and disadvantages that should be balanced on experimental design in order for them to complement one another, combining the diverse methods would help build an expanded knowledge of ALS pathophysiology. The goals are to reverse engineer the human disease using ESCs and iPSCs, generate lineage reporter lines and in vitro disease models, target disease related genes, in order to better understand the molecular and cellular mechanisms of differentiation regulation along neural (neuronal versus glial) lineages, to unravel the pathogenesis of the neurodegenerative disease, and to provide appropriate cell sources for replacement therapy. This article is part of a Special Issue entitled SI: PSC and the brain. PMID- 26423935 TI - Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer's and Parkinson's diseases. AB - Several neurological and psychiatric disorders present hyperexcitability of neurons in specific regions of the brain or spinal cord, partly because of some loss and/or dysfunction of gamma-amino butyric acid positive (GABA-ergic) inhibitory interneurons. Strategies that enhance inhibitory neurotransmission in the affected brain regions may therefore ease several or most deficits linked to these disorders. This perception has incited a huge interest in testing the efficacy of GABA-ergic interneuron cell grafting into regions of the brain or spinal cord exhibiting hyperexcitability, dearth of GABA-ergic interneurons or impaired inhibitory neurotransmission, using preclinical models of neurological and psychiatric disorders. Interneuron progenitors from the embryonic ventral telencephalon capable of differentiating into diverse subclasses of interneurons have particularly received much consideration because of their ability for dispersion, migration and integration with the host neural circuitry after grafting. The goal of this review is to discuss the premise, scope and advancement of GABA-ergic cell therapy for easing neurological deficits in preclinical models of schizophrenia, chronic neuropathic pain, Alzheimer's disease and Parkinson's disease. As grafting studies in these prototypes have so far utilized either primary cells from the embryonic medial and lateral ganglionic eminences or neural progenitor cells expanded from these eminences as donor material, the proficiency of these cell types is highlighted. Moreover, future studies that are essential prior to considering the possible clinical application of these cells for the above neurological conditions are proposed. Particularly, the need for grafting studies utilizing medial ganglionic eminence like progenitors generated from human pluripotent stem cells via directed differentiation approaches or somatic cells through direct reprogramming methods are emphasized. This article is part of a Special Issue entitled SI: PSC and the brain. PMID- 26423937 TI - Schwann cells and their transcriptional network: Evolution of key regulators of peripheral myelination. AB - As derivatives of the neural crest, Schwann cells represent a vertebrate invention. Their development and differentiation is under control of a newly constructed, vertebrate-specific regulatory network that contains Sox10, Oct6 and Krox20 as cornerstones and central regulators of peripheral myelination. In this review, we discuss the function and relationship of these transcription factors among each other and in the context of their regulatory network, and present ideas of how neofunctionalization may have helped to recruit them to their novel task in Schwann cells. This article is part of a Special Issue entitled SI: Myelin Evolution. PMID- 26423936 TI - Exacerbation of Charcot-Marie-Tooth type 2E neuropathy following traumatic nerve injury. AB - Charcot-Marie-Tooth disease (CMT) is the most commonly inherited peripheral neuropathy. CMT disease signs include distal limb neuropathy, abnormal gait, sensory defects, and deafness. We generated a novel line of CMT2E mice expressing hNF-L(E397K), which displayed muscle atrophy of the lower limbs without denervation, proximal reduction in large caliber axons, and decreased nerve conduction velocity. In this study, we challenged wild type, hNF-L and hNF L(E397K) mice with crush injury to the sciatic nerve. We analyzed functional recovery by measuring toe spread and analyzed gait using the Catwalk system. hNF L(E397K) mice demonstrated reduced recovery from nerve injury consistent with increased susceptibility to neuropathy observed in CMT patients. In addition, hNF L(E397K) developed a permanent reduction in their ability to weight bear, increased mechanical allodynia, and premature gait shift in the injured limb, which led to increasingly disrupted interlimb coordination in hNF-L(E397K). Exacerbation of neuropathy after injury and identification of gait alterations in combination with previously described pathology suggests that hNF-L(E397K) mice recapitulate many of clinical signs associated with CMT2. Therefore, hNF-L(E397K) mice provide a model for determining the efficacy of novel therapies. PMID- 26423938 TI - Acute Ebola virus disease patient treatment and health-related quality of life in health care professionals: A controlled study. AB - OBJECTIVE: This study aimed to identify predictors of health-related quality of life (HrQoL) and to investigate infection-related concerns in health professionals during the acute treatment episode for one Ebola virus disease (EVD) patient in tertiary care. METHODS: In a cross-sectional controlled study, validated self-report questionnaires were completed by three groups of health care professionals: (1) staff from standard internal medicine inpatient wards of a tertiary care center, (2) staff from the isolation unit of the same center responsible for Ebola patient treatment, and (3) staff from a research laboratory with contact to the Ebola virus and other highly infectious pathogens. Outcomes were HrQoL (SF-12), infection-related concerns, global health status, fatigue (FACIT), depression (PHQ-9), anxiety (GAD-7), and somatic symptoms (SSS-8). RESULTS: Comparisons between groups (n1=42, n2=32, n3=12) yielded no significant differences in HrQoL, subjective risk of infection, and most other psychosocial variables. However, the Ebola patient treatment group experienced significantly higher levels of social isolation than both other groups. The best predictors of poor physical and mental HrQoL were perceived lack of knowledge about the Ebola virus disease (physical: B=-1.2, p=0.05; mental: B=-1.3, p=0.03) and fatigue (physical: B=-0.3, p=0.02; mental: B=-0.53, p<0.001). CONCLUSION: Ebola patient treatment in tertiary care does not seem to be associated with lower HrQoL and enhanced subjective risk of infection, but seems to yield feelings of social isolation in health-care professionals. PMID- 26423939 TI - Predicting client attendance at further treatment following drug and alcohol detoxification: Theory of Planned Behaviour and Implementation Intentions. AB - INTRODUCTION AND AIMS: Despite clinical recommendations that further treatment is critical for successful recovery following drug and alcohol detoxification, a large proportion of clients fail to attend treatment after detoxification. In this study, individual factors and constructs based on motivational and volitional models of health behaviour were examined as predictors of post detoxification treatment attendance. DESIGN AND METHODS: The sample consisted of 220 substance-dependent individuals participating in short-term detoxification programs provided by The Australian Salvation Army. The Theory of Planned Behaviour and Implementation Intentions were used to predict attendance at subsequent treatment. RESULTS: Follow-up data were collected for 177 participants (81%), with 104 (80%) of those participants reporting that they had either attended further formal treatment (e.g. residential rehabilitation programs, outpatient counselling) or mutual support groups in the 2 weeks after leaving the detoxification program. Logistic regression examined the predictors of further treatment attendance. The full model accounted for 21% of the variance in treatment attendance, with attitude and Implementation Intentions contributing significantly to the prediction. DISCUSSION AND CONCLUSIONS: Findings from the present study would suggest that assisting clients to develop a specific treatment plan, as well as helping clients to build positive perceptions about subsequent treatment, will promote greater attendance at further treatment following detoxification. [Kelly PJ, Leung J, Deane FP, Lyons GCB. Predicting client attendance at further treatment following drug and alcohol detoxification: Theory of Planned Behaviour and Implementation Intentions. Drug Alcohol Rev 2016;35:678-685]. PMID- 26423940 TI - Induction and Antagonism of Antiviral Responses in Respiratory Syncytial Virus Infected Pediatric Airway Epithelium. AB - Airway epithelium is the primary target of many respiratory viruses. However, virus induction and antagonism of host responses by human airway epithelium remains poorly understood. To address this, we developed a model of respiratory syncytial virus (RSV) infection based on well-differentiated pediatric primary bronchial epithelial cell cultures (WD-PBECs) that mimics hallmarks of RSV disease in infants. RSV is the most important respiratory viral pathogen in young infants worldwide. We found that RSV induces a potent antiviral state in WD-PBECs that was mediated in part by secreted factors, including interferon lambda 1 (IFN lambda1)/interleukin-29 (IL-29). In contrast, type I IFNs were not detected following RSV infection of WD-PBECs. IFN responses in RSV-infected WD-PBECs reflected those in lower airway samples from RSV-hospitalized infants. In view of the prominence of IL-29, we determined whether recombinant IL-29 treatment of WD PBECs before or after infection abrogated RSV replication. Interestingly, IL-29 demonstrated prophylactic, but not therapeutic, potential against RSV. The absence of therapeutic potential reflected effective RSV antagonism of IFN mediated antiviral responses in infected cells. Our data are consistent with RSV nonstructural proteins 1 and/or 2 perturbing the Jak-STAT signaling pathway, with concomitant reduced expression of antiviral effector molecules, such as MxA/B. Antagonism of Jak-STAT signaling was restricted to RSV-infected cells in WD-PBEC cultures. Importantly, our study provides the rationale to further explore IL-29 as a novel RSV prophylactic. IMPORTANCE: Most respiratory viruses target airway epithelium for infection and replication, which is central to causing disease. However, for most human viruses we have a poor understanding of their interactions with human airway epithelium. Respiratory syncytial virus (RSV) is the most important viral pathogen of young infants. To help understand RSV interactions with pediatric airway epithelium, we previously developed three dimensional primary cell cultures from infant bronchial epithelium that reproduce several hallmarks of RSV infection in infants, indicating that they represent authentic surrogates of RSV infection in infants. We found that RSV induced a potent antiviral state in these cultures and that a type III interferon, interleukin IL-29 (IL-29), was involved. Indeed, our data suggest that IL-29 has potential to prevent RSV disease. However, we also demonstrated that RSV efficiently circumvents this antiviral immune response and identified mechanisms by which this may occur. Our study provides new insights into RSV interaction with pediatric airway epithelium. PMID- 26423941 TI - Infection of Mouse Macrophages by Seasonal Influenza Viruses Can Be Restricted at the Level of Virus Entry and at a Late Stage in the Virus Life Cycle. AB - Airway epithelial cells are susceptible to infection with seasonal influenza A viruses (IAV), resulting in productive virus replication and release. Macrophages (MPhi) are also permissive to IAV infection; however, virus replication is abortive. Currently, it is unclear how productive infection of MPhi is impaired or the extent to which seasonal IAV replicate in MPhi. Herein, we compared mouse MPhi and epithelial cells for their ability to support genomic replication and transcription, synthesis of viral proteins, assembly of virions, and release of infectious progeny following exposure to genetically defined IAV. We confirm that seasonal IAV differ in their ability to utilize cell surface receptors for infectious entry and that this represents one level of virus restriction. Following virus entry, we demonstrate synthesis of all eight segments of genomic viral RNA (vRNA) and mRNA, as well as seven distinct IAV proteins, in IAV infected mouse MPhi. Although newly synthesized hemagglutinin (HA) and neuraminidase (NA) glycoproteins are incorporated into the plasma membrane and expressed at the cell surface, electron microscopy confirmed that virus assembly was defective in IAV-infected MPhi, defining a second level of restriction late in the virus life cycle. IMPORTANCE: Seasonal influenza A viruses (IAV) and highly pathogenic avian influenza viruses (HPAI) infect macrophages, but only HPAI replicate productively in these cells. Herein, we demonstrate that impaired virus uptake into macrophages represents one level of restriction limiting infection by seasonal IAV. Following uptake, seasonal IAV do not complete productive replication in macrophages, representing a second level of restriction. Using murine macrophages, we demonstrate that productive infection is blocked late in the virus life cycle, such that virus assembly is defective and newly synthesized virions are not released. These studies represent an important step toward identifying host-encoded factors that block replication of seasonal IAV, but not HPAI, in macrophages. PMID- 26423942 TI - MDA5 Is Critical to Host Defense during Infection with Murine Coronavirus. AB - Infection with the murine coronavirus mouse hepatitis virus (MHV) activates the pattern recognition receptors melanoma differentiation-associated gene 5 (MDA5) and Toll-like receptor 7 (TLR7) to induce transcription of type I interferon. Type I interferon is crucial for control of viral replication and spread in the natural host, but the specific contributions of MDA5 signaling to this pathway as well as to pathogenesis and subsequent immune responses are largely unknown. In this study, we use MHV infection of the liver as a model to demonstrate that MDA5 signaling is critically important for controlling MHV-induced pathology and regulation of the immune response. Mice deficient in MDA5 expression (MDA5(-/-) mice) experienced more severe disease following MHV infection, with reduced survival, increased spread of virus to additional sites of infection, and more extensive liver damage than did wild-type mice. Although type I interferon transcription decreased in MDA5(-/-) mice, the interferon-stimulated gene response remained intact. Cytokine production by innate and adaptive immune cells was largely intact in MDA5(-/-) mice, but perforin induction by natural killer cells and levels of interferon gamma, interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) in serum were elevated. These data suggest that MDA5 signaling reduces the severity of MHV-induced disease, at least in part by reducing the intensity of the proinflammatory cytokine response. IMPORTANCE: Multicellular organisms employ a wide range of sensors to detect viruses and other pathogens. One such sensor, MDA5, detects viral RNA and triggers induction of type I interferons, chemical messengers that induce inflammation and help regulate the immune responses. In this study, we sought to determine the role of MDA5 during infection with mouse hepatitis virus, a murine coronavirus used to model viral hepatitis as well as other human diseases. We found that mice lacking the MDA5 sensor were more susceptible to infection than were mice with MDA5 and experienced decreased survival. Viral replication in the liver was similar in mice with and without MDA5, but liver damage was increased in MDA5(-/-) mice, suggesting that the immune response is causing the damage. Production of several proinflammatory cytokines was elevated in MDA5(-/-) mice, suggesting that MDA5 may be responsible for keeping pathological inflammatory responses in check. PMID- 26423943 TI - Contribution of Epidemiological Predictors in Unraveling the Phylogeographic History of HIV-1 Subtype C in Brazil. AB - The phylogeographic history of the Brazilian HIV-1 subtype C (HIV-1C) epidemic is still unclear. Previous studies have mainly focused on the capital cities of Brazilian federal states, and the fact that HIV-1C infections increase at a higher rate than subtype B infections in Brazil calls for a better understanding of the process of spatial spread. A comprehensive sequence data set sampled across 22 Brazilian locations was assembled and analyzed. A Bayesian phylogeographic generalized linear model approach was used to reconstruct the spatiotemporal history of HIV-1C in Brazil, considering several potential explanatory predictors of the viral diffusion process. Analyses were performed on several subsampled data sets in order to mitigate potential sample biases. We reveal a central role for the city of Porto Alegre, the capital of the southernmost state, in the Brazilian HIV-1C epidemic (HIV-1C_BR), and the northward expansion of HIV-1C_BR could be linked to source populations with higher HIV-1 burdens and larger proportions of HIV-1C infections. The results presented here bring new insights to the continuing discussion about the HIV-1C epidemic in Brazil and raise an alternative hypothesis for its spatiotemporal history. The current work also highlights how sampling bias can confound phylogeographic analyses and demonstrates the importance of incorporating external information to protect against this. IMPORTANCE: Subtype C is responsible for the largest HIV infection burden worldwide, but our understanding of its transmission dynamics remains incomplete. Brazil witnessed a relatively recent introduction of HIV-1C compared to HIV-1B, but it swiftly spread throughout the south, where it now circulates as the dominant variant. The northward spread has been comparatively slow, and HIV-1B still prevails in that region. While epidemiological data and viral genetic analyses have both independently shed light on the dynamics of spread in isolation, their combination has not yet been explored. Here, we complement publically available sequences and new genetic data from 13 cities with epidemiological data to reconstruct the history of HIV-1C spread in Brazil. The combined approach results in more robust reconstructions and can protect against sampling bias. We found evidence for an alternative view of the HIV-1C spatiotemporal history in Brazil that, contrary to previous explanations, integrates seamlessly with other observational data. PMID- 26423944 TI - Intercellular Transmission of Viral Populations with Vesicles. AB - A common paradigm holds that during cell-to-cell transmission, viruses behave as lone soldiers. Recently, we discovered not only that enteroviruses are transmitted via vesicles as populations of viral particles but also that this type of transmission enhances their infection efficiency (Y. H. Chen et al., Cell 160: 619-630, 2015). This mechanism could be advantageous for the overall fitness of the viral population, promoting genetic interplay by enabling viral quasispecies to collectively infect a susceptible host cell. Here, we discuss these findings in the context of viral pathogenesis and also propose that this novel type of vesicular transmission is widespread among different virus families and includes populations of both viral particles and naked viral genomes. PMID- 26423945 TI - Differential Inhibition of Macrophage Activation by Lymphocytic Choriomeningitis Virus and Pichinde Virus Is Mediated by the Z Protein N-Terminal Domain. AB - Several arenavirus pathogens, such as Lassa and Junin viruses, inhibit macrophage activation, the molecular mechanism of which is unclear. We show that lymphocytic choriomeningitis virus (LCMV) can also inhibit macrophage activation, in contrast to Pichinde and Tacaribe viruses, which are not known to naturally cause human diseases. Using a recombinant Pichinde virus system, we show that the LCMV Z N terminal domain (NTD) mediates the inhibition of macrophage activation and immune functions. PMID- 26423946 TI - Flavivirus Infection Impairs Peroxisome Biogenesis and Early Antiviral Signaling. AB - Flaviviruses are significant human pathogens that have an enormous impact on the global health burden. Currently, there are very few vaccines against or therapeutic treatments for flaviviruses, and our understanding of how these viruses cause disease is limited. Evidence suggests that the capsid proteins of flaviviruses play critical nonstructural roles during infection, and therefore, elucidating how these viral proteins affect cellular signaling pathways could lead to novel targets for antiviral therapy. We used affinity purification to identify host cell proteins that interact with the capsid proteins of West Nile and dengue viruses. One of the cellular proteins that formed a stable complex with flavivirus capsid proteins is the peroxisome biogenesis factor Pex19. Intriguingly, flavivirus infection resulted in a significant loss of peroxisomes, an effect that may be due in part to capsid expression. We posited that capsid protein-mediated sequestration and/or degradation of Pex19 results in loss of peroxisomes, a situation that could result in reduced early antiviral signaling. In support of this hypothesis, we observed that induction of the lambda interferon mRNA in response to a viral RNA mimic was reduced by more than 80%. Together, our findings indicate that inhibition of peroxisome biogenesis may be a novel mechanism by which flaviviruses evade the innate immune system during early stages of infection. IMPORTANCE: RNA viruses infect hundreds of millions of people each year, causing significant morbidity and mortality. Chief among these pathogens are the flaviviruses, which include dengue virus and West Nile virus. Despite their medical importance, there are very few prophylactic or therapeutic treatments for these viruses. Moreover, the manner in which they subvert the innate immune response in order to establish infection in mammalian cells is not well understood. Recently, peroxisomes were reported to function in early antiviral signaling, but very little is known regarding if or how pathogenic viruses affect these organelles. We report for the first time that flavivirus infection results in significant loss of peroxisomes in mammalian cells, which may indicate that targeting of peroxisomes is a key strategy used by viruses to subvert early antiviral defenses. PMID- 26423947 TI - AP-2 Is the Crucial Clathrin Adaptor Protein for CD4 Downmodulation by HIV-1 Nef in Infected Primary CD4+ T Cells. AB - HIV-1 Nef-mediated CD4 downmodulation involves various host factors. We investigated the importance of AP-1, AP-2, AP-3, V1H-ATPase, beta-COP, and ACOT8 for CD4 downmodulation in HIV-1-infected short hairpin RNA (shRNA)-expressing CD4(+) T cells and characterized direct interaction with Nef by Forster resonance energy transfer (FRET). Binding of lentiviral Nefs to CD4 and AP-2 was conserved, and only AP-2 knockdown impaired Nef-mediated CD4 downmodulation from primary T cells. Altogether, among the factors tested, AP-2 is the most important player for Nef-mediated CD4 downmodulation. PMID- 26423948 TI - Differentiation-Coupled Induction of Human Cytomegalovirus Replication by Union of the Major Enhancer Retinoic Acid, Cyclic AMP, and NF-kappaB Response Elements. AB - Triggers and regulatory pathways that effectively link human cytomegalovirus (HCMV) major immediate early (MIE) latent-lytic switch activation with progeny production are incompletely understood. In the quiescently infected human NTera2 cell model of primitive neural stem cells, we found that costimulation with vasoactive intestinal peptide (V) and phorbol ester (P) synergistically activated viral infection, but this effect waned over time. Coupling retinoic acid (R), an inducer of neuronal differentiation, to VP pulse stimulation attenuated the decline in viral activity and promoted the spread of the active infection through concentric layers of neighboring cells as cellular differentiation progressed. R stimulation alone was unable to activate the infection. The MIE enhancer cis regulatory mechanisms responsible for this result were characterized by a strategy of combinatorial mutagenesis of five cis-acting element types (retinoic acid receptor binding elements [RARE], cyclic AMP [cAMP] response elements [CRE], NF-kappaB binding sites [kB], serum response element, and ETS/ELK-1 binding site) and multiple methods of assessment. We found that the CRE and kB combination sets the preinduction enhancer tone, is the major initiator and amplifier of RVP induced MIE gene expression, and cooperates with RARE during cellular differentiation to enhance viral spread. In predifferentiated NTera2, we also found that the CRE-kB combination functions as initiator and amplifier of unstimulated HCMV MIE gene expression and cooperatively interacts with RARE to enhance viral spread. We conclude that RVP-stimulated signaling cascades and cellular differentiation operate through the enhancer CRE-kB-RARE core in strengthening induction of HCMV MIE gene expression in linkage with viral propagation. IMPORTANCE: Cytomegalovirus-seropositive persons commonly lack detectable levels of cytomegalovirus replication, even when profoundly immunocompromised. In a human NTera2 cell model of primitive neural stem cells carrying resting cytomegalovirus genomes, we show that costimulation of protein kinase A and C-delta signaling cascades in conjunction with retinoic acid-induced neuronal differentiation brings about progeny virus propagation. Iterated DNA binding sites for retinoic acid receptor, CREB, and NF-kappaB family members in the cytomegalovirus major enhancer are at the crux in the pathway to HCMV activation. The stimulated CREB and NF-kappaB binding site combination vigorously initiates and amplifies the active cytomegalovirus infection and cooperates with activated retinoic acid receptor binding sites to further promote viral proliferation and spread between differentiated cells. These results support a paradigm in which a specific combination of stimuli coupled with cellular differentiation satisfies a core cis-activating code that unlocks enhancer silence to repower the cycle of cytomegalovirus propagation. PMID- 26423949 TI - The Fusion Protein Specificity of the Parainfluenza Virus Hemagglutinin Neuraminidase Protein Is Not Solely Defined by the Primary Structure of Its Stalk Domain. AB - Virus-specific interaction between the attachment protein (HN) and the fusion protein (F) is prerequisite for the induction of membrane fusion by parainfluenza viruses. This HN-F interaction presumably is mediated by particular amino acids in the HN stalk domain and those in the F head domain. We found in the present study, however, that a simian virus 41 (SV41) F-specific chimeric HPIV2 HN protein, SCA, whose cytoplasmic, transmembrane, and stalk domains were derived from the SV41 HN protein, could not induce cell-cell fusion of BHK-21 cells when coexpressed with an SV41 HN-specific chimeric PIV5 F protein, no. 36. Similarly, a headless form of the SV41 HN protein failed to induce fusion with chimera no. 36, whereas it was able to induce fusion with the SV41 F protein. Interestingly, replacement of 13 amino acids of the SCA head domain, which are located at or around the dimer interface of the head domain, with SV41 HN counterparts resulted in a chimeric HN protein, SCA-RII, which induced fusion with chimera no. 36 but not with the SV41 F protein. More interestingly, retroreplacement of 11 out of the 13 amino acids of SCA-RII with the SCA counterparts resulted in another chimeric HN protein, IM18, which induced fusion either with chimera no. 36 or with the SV41 F protein, similar to the SV41 HN protein. Thus, we conclude that the F protein specificity of the HN protein that is observed in the fusion event is not solely defined by the primary structure of the HN stalk domain. IMPORTANCE: It is appreciated that the HN head domain initially conceals the HN stalk domain but exposes it after the head domain has bound to the receptors, which allows particular amino acids in the stalk domain to interact with the F protein and trigger it to induce fusion. However, other regulatory roles of the HN head domain in the fusion event have been ill defined. We have shown in the current study that removal of the head domain or amino acid substitutions in a particular region of the head domain drastically change the F protein specificity of the HN protein, suggesting that the ability of a given HN protein to interact with an F protein is defined not only by the primary structure of the HN stalk domain but also by its conformation. This notion seems to account for the unidirectional substitutability among rubulavirus HN proteins in triggering noncognate F proteins. PMID- 26423950 TI - Deer Prion Proteins Modulate the Emergence and Adaptation of Chronic Wasting Disease Strains. AB - Transmission of chronic wasting disease (CWD) between cervids is influenced by the primary structure of the host cellular prion protein (PrP(C)). In white tailed deer, PRNP alleles encode the polymorphisms Q95 G96 (wild type [wt]), Q95 S96 (referred to as the S96 allele), and H95 G96 (referred to as the H95 allele), which differentially impact CWD progression. We hypothesize that the transmission of CWD prions between deer expressing different allotypes of PrP(C) modifies the contagious agent affecting disease spread. To evaluate the transmission properties of CWD prions derived experimentally from deer of four PRNP genotypes (wt/wt, S96/wt, H95/wt, or H95/S96), transgenic (tg) mice expressing the wt allele (tg33) or S96 allele (tg60) were challenged with these prion agents. Passage of deer CWD prions into tg33 mice resulted in 100% attack rates, with the CWD H95/S96 prions having significantly longer incubation periods. The disease signs and neuropathological and protease-resistant prion protein (PrP-res) profiles in infected tg33 mice were similar between groups, indicating that a prion strain (Wisc-1) common to all CWD inocula was amplified. In contrast, tg60 mice developed prion disease only when inoculated with the H95/wt and H95/S96 CWD allotypes. Serial passage in tg60 mice resulted in adaptation of a novel CWD strain (H95(+)) with distinct biological properties. Transmission of first passage tg60CWD-H95(+) isolates into tg33 mice, however, elicited two prion disease presentations consistent with a mixture of strains associated with different PrP-res glycotypes. Our data indicate that H95-PRNP heterozygous deer accumulated two CWD strains whose emergence was dictated by the PrP(C) primary structure of the recipient host. These findings suggest that CWD transmission between cervids expressing distinct PrP(C) molecules results in the generation of novel CWD strains. IMPORTANCE: CWD prions are contagious among wild and captive cervids in North America and in South Korea. We present data linking the amino acid variant Q95H in white-tailed deer cellular prion protein (PrP(C)) to the emergence of a novel CWD strain (H95(+)). We show that, upon infection, deer expressing H95-PrP(C) molecules accumulated a mixture of CWD strains that selectively propagated depending on the PRNP genotype of the host in which they were passaged. Our study also demonstrates that mice expressing the deer S96-PRNP allele, previously shown to be resistant to various cervid prions, are susceptible to H95(+) CWD prions. The potential for the generation of novel strains raises the possibility of an expanded host range for CWD. PMID- 26423951 TI - Comparison of the Life Cycles of Genetically Distant Species C and Species D Human Adenoviruses Ad6 and Ad26 in Human Cells. AB - Our understanding of adenovirus (Ad) biology is largely extrapolated from human species C Ad5. Most humans are immune to Ad5, so lower-seroprevalence viruses like human Ad6 and Ad26 are being tested as therapeutic vectors. Ad6 and Ad26 differ at the DNA level by 34%. To better understand how this might impact their biology, we examined the life cycle of the two viruses in human lung cells in vitro. Both viruses infected A549 cells with similar efficiencies, executed DNA replication with identical kinetics within 12 h, and began killing cells within 72 h. While Ad6-infected cells remained adherent until death, Ad26-infected cells detached within 12 h of infection but remained viable. Next-generation sequencing (NGS) of mRNA from infected cells demonstrated that viral transcripts constituted 1% of cellular mRNAs within 6 h and 8 to 16% within 12 h. Quantitative PCR and NGS revealed the activation of key early genes at 6 h and transition to late gene activation by 12 h by both viruses. There were marked differences in the balance of E1A and E1B activation by the two viruses and in the expression of E3 immune evasion mRNAs. Ad6 was markedly more effective at suppressing major histocompatibility complex class I (MHC I) display on the cell surface and in evading TRAIL-mediated apoptosis than was Ad26. These data demonstrate shared as well as divergent life cycles in these genetically distant human adenoviruses. An understanding of these differences expands the knowledge of alternative Ad species and may inform the selection of related Ads for therapeutic development. IMPORTANCE: A burgeoning number of adenoviruses (Ads) are being harnessed as therapeutics, yet the biology of these viruses is generally extrapolated from Ad2 and Ad5. Here, we are the first to compare the transcriptional programs of two genetically distant Ads by mRNA next-generation sequencing (NGS). Species C Ad6 and Ad26 are being pursued as lower-seroprevalence Ad vectors but differ at the DNA level by 34%. Head-to-head comparison in human lung cells by NGS revealed that the two viruses generally conform to our general understanding of the Ad transcriptional program. However, fine mapping revealed subtle and strong differences in how these two viruses execute these programs, including differences in the balance of E1A and E1B mRNAs and in E3 immune evasion genes. This suggests that not all adenoviruses behave like Ad2 and Ad5 and that they may have unique strategies to infect cells and evade the immune system. PMID- 26423952 TI - Whole-Genome Sequencing of Kaposi's Sarcoma-Associated Herpesvirus from Zambian Kaposi's Sarcoma Biopsy Specimens Reveals Unique Viral Diversity. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent for Kaposi's sarcoma (KS). Both KSHV and KS are endemic in sub-Saharan Africa where approximately 84% of global KS cases occur. Nevertheless, whole-genome sequencing of KSHV has only been completed using isolates from Western countries-where KS is not endemic. The lack of whole-genome KSHV sequence data from the most clinically important geographical region, sub-Saharan Africa, represents an important gap since it remains unclear whether genomic diversity has a role on KSHV pathogenesis. We hypothesized that distinct KSHV genotypes might be present in sub-Saharan Africa compared to Western countries. Using a KSHV-targeted enrichment protocol followed by Illumina deep-sequencing, we generated and analyzed 16 unique Zambian, KS-derived, KSHV genomes. We enriched KSHV DNA over cellular DNA 1,851 to 18,235-fold. Enrichment provided coverage levels up to 24,740-fold; therefore, supporting highly confident polymorphism analysis. Multiple alignment of the 16 newly sequenced KSHV genomes showed low level variability across the entire central conserved region. This variability resulted in distinct phylogenetic clustering between Zambian KSHV genomic sequences and those derived from Western countries. Importantly, the phylogenetic segregation of Zambian from Western sequences occurred irrespective of inclusion of the highly variable genes K1 and K15. We also show that four genes within the more conserved region of the KSHV genome contained polymorphisms that partially, but not fully, contributed to the unique Zambian KSHV whole-genome phylogenetic structure. Taken together, our data suggest that the whole KSHV genome should be taken into consideration for accurate viral characterization. IMPORTANCE: Our results represent the largest number of KSHV whole-genomic sequences published to date and the first time that multiple genomes have been sequenced from sub Saharan Africa, a geographic area where KS is highly endemic. Based on our new sequence data, it is apparent that whole-genome KSHV diversity is greater than previously appreciated and differential phylogenetic clustering exists between viral genomes of Zambia and Western countries. Furthermore, individual genes may be insufficient for KSHV genetic characterization. Continued investigation of the KSHV genetic landscape is necessary in order to effectively understand the role of viral evolution and sequence diversity on KSHV gene functions and pathogenesis. PMID- 26423953 TI - Breakthrough Virus Neutralization Resistance as a Correlate of Protection in a Nonhuman Primate Heterologous Simian Immunodeficiency Virus Vaccine Challenge Study. AB - Comprehensive assessments of immune correlates of protection in human immunodeficiency virus (HIV) vaccine trials are essential to vaccine design. Neutralization sieve analysis compares the neutralization sensitivity of the breakthrough transmitted/founder (TF) viruses from vaccinated and control animals to infer the molecular mechanisms of vaccine protection. Here, we report a robust neutralization sieve effect in a nonhuman primate simian immunodeficiency virus (SIV) vaccine trial (DNA prime/recombinant adenovirus type 5 [rAd5] boost) (VRC 10-332) that demonstrated substantial protective efficacy and revealed a genetic signature of neutralization resistance in the C1 region of env. We found significant enrichment for neutralization resistance in the vaccine compared to control breakthrough TF viruses when tested with plasma from vaccinated study animals, plasma from chronically SIV-infected animals, and a panel of SIV specific monoclonal antibodies targeting six discrete Env epitopes (P < 0.008 for all comparisons). Neutralization resistance was significantly associated with the previously identified genetic signature of resistance (P < 0.0001), and together, the results identify virus neutralization as a correlate of protection. These findings further demonstrate the in vivo relevance of our previous in vitro analyses of the SIVsmE660 challenge stock, which revealed a broad range of neutralization sensitivities of its component viruses. In sum, this report demonstrates proof-of-concept that phenotypic sieve analyses can elucidate mechanistic correlates of immune protection following vaccination and raises a cautionary note for SIV and SHIV (simian-human immunodeficiency virus) vaccine studies that employ challenge strains with envelope glycoproteins that fail to exhibit neutralization resistance profiles typical of TF viruses. IMPORTANCE: With more than 2 million new infections annually, the development of an effective vaccine against HIV-1 is a global health priority. Understanding immunologic correlates of protection generated in vaccine trials is critical to advance vaccine development. Here, we assessed the role of vaccine-elicited neutralizing antibodies in a recent nonhuman primate study of a vaccine that showed significant protection against simian immunodeficiency virus (SIV) challenge and suggested a genetic signature of neutralization sensitivity. We found that breakthrough viruses able to establish infection in vaccinated animals were substantially more resistant to antibody-mediated neutralization than were viruses from controls. These findings suggest that vaccine-elicited neutralizing antibodies selectively blocked the transmission of more sensitive challenge viruses. Sieve analysis also corroborated a genetic signature of neutralization sensitivity and highlighted the impact of challenge swarm diversity. Our findings suggest an important role for neutralization sieve analyses as an informative component of comprehensive immune-correlates analyses. PMID- 26423954 TI - A Unique 5' Translation Element Discovered in Triticum Mosaic Virus. AB - Several plant viruses encode elements at the 5' end of their RNAs, which, unlike most cellular mRNAs, can initiate translation in the absence of a 5' m7GpppG cap. Here, we describe an exceptionally long (739-nucleotide [nt]) leader sequence in triticum mosaic virus (TriMV), a recently emerged wheat pathogen that belongs to the Potyviridae family of positive-strand RNA viruses. We demonstrate that the TriMV 5' leader drives strong cap-independent translation in both wheat germ extract and oat protoplasts through a novel, noncanonical translation mechanism. Translation preferentially initiates at the 13th start codon within the leader sequence independently of eIF4E but involves eIF4G. We truncated the 5' leader to a 300-nucleotide sequence that drives cap-independent translation from the 5' end. We show that within this sequence, translation activity relies on a stem loop structure identified at nucleotide positions 469 to 490. The disruption of the stem significantly impairs the function of the 5' untranslated region (UTR) in driving translation and competing against a capped RNA. Additionally, the TriMV 5' UTR can direct translation from an internal position of a bicistronic mRNA, and unlike cap-driven translation, it is unimpaired when the 5' end is blocked by a strong hairpin in a monocistronic reporter. However, the disruption of the identified stem structure eliminates such a translational advantage. Our results reveal a potent and uniquely controlled translation enhancer that may provide new insights into mechanisms of plant virus translational regulation. IMPORTANCE: Many members of the Potyviridae family rely on their 5' end for translation. Here, we show that the 739-nucleotide-long triticum mosaic virus 5' leader bears a powerful translation element with features distinct from those described for other plant viruses. Despite the presence of 12 AUG start codons within the TriMV 5' UTR, translation initiates primarily at the 13th AUG codon. The TriMV 5' UTR is capable of driving cap-independent translation in vitro and in vivo, is independent of eIF4E, and can drive internal translation initiation. A hairpin structure at nucleotide positions 469 to 490 is required for the cap independent translation and internal translation initiation abilities of the element and plays a role in the ability of the TriMV UTR to compete against a capped RNA in vitro. Our results reveal a novel translation enhancer that may provide new insights into the large diversity of plant virus translation mechanisms. PMID- 26423955 TI - Ultrastructural Characterization of Turnip Mosaic Virus-Induced Cellular Rearrangements Reveals Membrane-Bound Viral Particles Accumulating in Vacuoles. AB - Positive-strand RNA [(+) RNA] viruses remodel cellular membranes to facilitate virus replication and assembly. In the case of turnip mosaic virus (TuMV), the viral membrane protein 6K2 plays an essential role in endomembrane alterations. Although 6K2-induced membrane dynamics have been widely studied by confocal microscopy, the ultrastructure of this remodeling has not been extensively examined. In this study, we investigated the formation of TuMV-induced membrane changes by chemical fixation and high-pressure freezing/freeze substitution (HPF/FS) for transmission electron microscopy at different times of infection. We observed the formation of convoluted membranes connected to rough endoplasmic reticulum (rER) early in the infection process, followed by the production of single-membrane vesicle-like (SMVL) structures at the midstage of infection. Both SMVL and double-membrane vesicle-like structures with electron-dense cores, as well as electron-dense bodies, were found late in the infection process. Immunogold labeling results showed that the vesicle-like structures were 6K2 tagged and suggested that only the SMVL structures were viral RNA replication sites. Electron tomography (ET) was used to regenerate a three-dimensional model of these vesicle-like structures, which showed that they were, in fact, tubules. Late in infection, we observed filamentous particle bundles associated with electron-dense bodies, which suggests that these are sites for viral particle assembly. In addition, TuMV particles were observed to accumulate in the central vacuole as membrane-associated linear arrays. Our work thus unravels the sequential appearance of distinct TuMV-induced membrane structures for viral RNA replication, viral particle assembly, and accumulation. IMPORTANCE: Positive strand RNA viruses remodel cellular membranes for different stages of the infection process, such as protein translation and processing, viral RNA synthesis, particle assembly, and virus transmission. The ultrastructure of turnip mosaic virus (TuMV)-induced membrane remodeling was investigated over several days of infection. The first change that was observed involved endoplasmic reticulum-connected convoluted membrane accumulation. This was followed by the formation of single-membrane tubules, which were shown to be viral RNA replication sites. Later in the infection process, double-membrane tubular structures were observed and were associated with viral particle bundles. In addition, TuMV particles were observed to accumulate in the central vacuole as membrane-associated linear arrays. This work thus unravels the sequential appearance of distinct TuMV-induced membrane structures for viral RNA replication, viral particle assembly, and accumulation. PMID- 26423956 TI - An RNA Domain Imparts Specificity and Selectivity to a Viral DNA Packaging Motor. AB - During assembly, double-stranded DNA viruses, including bacteriophages and herpesviruses, utilize a powerful molecular motor to package their genomic DNA into a preformed viral capsid. An integral component of the packaging motor in the Bacillus subtilis bacteriophage phi29 is a viral genome-encoded pentameric ring of RNA (prohead RNA [pRNA]). pRNA is a 174-base transcript comprised of two domains, domains I and II. Early studies initially isolated a 120-base form (domain I only) that retains high biological activity in vitro; hence, no function could be assigned to domain II. Here we define a role for this domain in the packaging process. DNA packaging using restriction digests of phi29 DNA showed that motors with the 174-base pRNA supported the correct polarity of DNA packaging, selectively packaging the DNA left end. In contrast, motors containing the 120-base pRNA had compromised specificity, packaging both left- and right-end fragments. The presence of domain II also provides selectivity in competition assays with genomes from related phages. Furthermore, motors with the 174-base pRNA were restrictive, in that they packaged only one DNA fragment into the head, whereas motors with the 120-base pRNA packaged several fragments into the head, indicating multiple initiation events. These results show that domain II imparts specificity and stringency to the motor during the packaging initiation events that precede DNA translocation. Heteromeric rings of pRNA demonstrated that one or two copies of domain II were sufficient to impart this selectivity/stringency. Although phi29 differs from other double-stranded DNA phages in having an RNA motor component, the function provided by pRNA is carried on the motor protein components in other phages. IMPORTANCE: During virus assembly, genome packaging involves the delivery of newly synthesized viral nucleic acid into a protein shell. In the double-stranded DNA phages and herpesviruses, this is accomplished by a powerful molecular motor that translocates the viral DNA into a preformed viral shell. A key event in DNA packaging is recognition of the viral DNA among other nucleic acids in the host cell. Commonly, a DNA-binding protein mediates the interaction of viral DNA with the motor/head shell. Here we show that for the bacteriophage phi29, this essential step of genome recognition is mediated by a viral genome-encoded RNA rather than a protein. A domain of the prohead RNA (pRNA) imparts specificity and stringency to the motor by ensuring the correct orientation of DNA packaging and restricting initiation to a single event. Since this assembly step is unique to the virus, DNA packaging is a novel target for the development of antiviral drugs. PMID- 26423957 TI - Prion Infectivity Plateaus and Conversion to Symptomatic Disease Originate from Falling Precursor Levels and Increased Levels of Oligomeric PrPSc Species. AB - In lethal prion neurodegenerative diseases, misfolded prion proteins (PrP(Sc)) replicate by redirecting the folding of the cellular prion glycoprotein (PrP(C)). Infections of different durations can have a subclinical phase with constant levels of infectious particles, but the mechanisms underlying this plateau and a subsequent exit to overt clinical disease are unknown. Using tandem biophysical techniques, we show that attenuated accumulation of infectious particles in presymptomatic disease is preceded by a progressive fall in PrP(C) level, which constricts replication rate and thereby causes the plateau effect. Furthermore, disease symptoms occurred at the threshold associated with increasing levels of small, relatively less protease-resistant oligomeric prion particles (oPrP(Sc)). Although a hypothetical lethal isoform of PrP cannot be excluded, our data argue that diminishing residual PrP(C) levels and continuously increasing levels of oPrP(Sc) are crucial determinants in the transition from presymptomatic to symptomatic prion disease. IMPORTANCE: Prions are infectious agents that cause lethal brain diseases; they arise from misfolding of a cell surface protein, PrP(C) to a form called PrP(Sc). Prion infections can have long latencies even though there is no protective immune response. Accumulation of infectious prion particles has been suggested to always reach the same plateau in the brain during latent periods, with clinical disease only occurring when hypothetical toxic forms (called PrP(L) or TPrP) begin to accumulate. We show here that infectivity plateaus arise because PrP(C) precursor levels become downregulated and that the duration of latent periods can be accounted for by the level of residual PrP(C), which transduces a toxic effect, along with the amount of oligomeric forms of PrP(Sc). PMID- 26423958 TI - Erianthus arundinaceus HSP70 (EaHSP70) Acts as a Key Regulator in the Formation of Anisotropic Interdigitation in Sugarcane (Saccharum spp. hybrid) in Response to Drought Stress. AB - Plant growth during abiotic stress is a long sought-after trait especially in crop plants in the context of global warming and climate change. Previous studies on leaf epidermal cells have revealed that during normal growth and development, adjacent cells interdigitate anisotropically to form cell morphological patterns known as interlocking marginal lobes (IMLs), involving the cell wall-cell membrane-cortical actin continuum. IMLs are growth-associated cell morphological changes in which auxin-binding protein (ABP), Rho GTPases and actin are known to play important roles. In the present study, we investigated the formation of IMLs under drought stress and found that Erianthus arundinaceus, a drought-tolerant wild relative of sugarcane, develops such growth-related cell morphological patterns under drought stress. Using confocal microscopy, we showed an increasing trend in cortical F-actin intensity in drought-tolerant plants with increasing soil moisture stress. In order to check the role of drought tolerance-related genes in IML formation under soil moisture stress, we adopted a structural data mining strategy and identified indirect connections between the ABPs and heat shock proteins (HSPs). Initial experimental evidence for this connection comes from the high transcript levels of HSP70 observed in drought-stressed Erianthus, which developed anisotropic interdigitation, i.e. IMLs. Subsequently, by overexpressing the E. arundinaceus HSP70 gene (EaHSP70) in sugarcane (Saccharum spp. hybrid), we confirm the role of HSP70 in the formation of anisotropic interdigitation under drought stress. Taken together, our results suggest that EaHSP70 acts as a key regulator in the formation of anisotropic interdigitation in drought-tolerant plants (Erianthus and HSP70 transgenic sugarcane) under moisture stress in an actin-mediated pathway. The possible biological significance of the formation of drought-associated interlocking marginal lobes (DaIMLs) in sugarcane plants upon drought stress is discussed. PMID- 26423959 TI - Arabidopsis INCURVATA2 Regulates Salicylic Acid and Abscisic Acid Signaling, and Oxidative Stress Responses. AB - Epigenetic regulatory states can persist through mitosis and meiosis, but the connection between chromatin structure and DNA replication remains unclear. Arabidopsis INCURVATA2 (ICU2) encodes the catalytic subunit of DNA polymerase alpha, and null alleles of ICU2 have an embryo-lethal phenotype. Analysis of icu2 1, a hypomorphic allele of ICU2, demonstrated that ICU2 functions in chromatin mediated cellular memory; icu2-1 strongly impairs ICU2 function in the maintenance of repressive epigenetic marks but does not seem to affect ICU2 polymerase activity. To better understand the global function of ICU2 in epigenetic regulation, here we performed a microarray analysis of icu2-1 mutant plants. We found that the genes up-regulated in the icu2-1 mutant included genes encoding transcription factors and targets of the Polycomb Repressive Complexes. The down-regulated genes included many known players in salicylic acid (SA) biosynthesis and accumulation, ABA signaling and ABA-mediated responses. In addition, we found that icu2-1 plants had reduced SA levels in normal conditions; infection by Fusarium oxysporum induced SA accumulation in the En-2 wild type but not in the icu2-1 mutant. The icu2-1 plants were also hypersensitive to salt stress and exogenous ABA in seedling establishment, post-germination growth and stomatal closure, and accumulated more ABA than the wild type in response to salt stress. The icu2-1 mutant also showed high tolerance to the oxidative stress produced by 3-amino-1,2,4-triazole (3-AT). Our results uncover a role for ICU2 in the regulation of genes involved in ABA signaling as well as in SA biosynthesis and accumulation. PMID- 26423960 TI - The C-Terminal Sequence and PI motif of the Orchid (Oncidium Gower Ramsey) PISTILLATA (PI) Ortholog Determine its Ability to Bind AP3 Orthologs and Enter the Nucleus to Regulate Downstream Genes Controlling Petal and Stamen Formation. AB - This study focused on the investigation of the effects of the PI motif and C terminus of the Oncidium Gower Ramsey MADS box gene 8 (OMADS8), a PISTILLATA (PI) ortholog, on floral organ formation. 35S::OMADS8 completely rescued and 35S::OMADS8-PI (with the PI motif deleted) partially rescued petal/stamen formation, whereas these deficiencies were not rescued by 35S::OMADS8-C (C terminal 29 amino acids deleted) in pi-1 mutants. OMADS8 could interact with Arabidopsis APETALA3 (AP3) and enter the nucleus. The nuclear entry efficiency was reduced for OMADS8-PI/AP3 and OMADS8-C/AP3. OMADS8 could also interact with OMADS5/OMADS9 (the Oncidium AP3 ortholog) and enter the nucleus with an efficiency only slightly affected by the deletion of the C-terminal sequence or PI motif. However, the stability of the OMADS8/OMADS5 and OMADS8/OMADS9 complexes was significantly reduced by deletion of the C-terminal sequence or PI motif. Further analysis indicated that the expression of genes downstream of AP3/PI (BNQ1/BNQ2/GNC/At4g30270) was compensated by 35S::OMADS8 and 35S::OMADS8-PI to a level similar to wild-type plants but was not affected by 35S::OMADS8-C in the pi 1 mutants. A similar FRET (fluorescence resonance energy transfer) efficiency was observed for Arabidopsis AGAMOUS (AG) and the Oncidium AG ortholog OMADS4 for OMADS8, OMADS8-PI and OMADS8-C. These results indicated that the OMADS8 PI motif and C-terminus were valuable for the interaction of OMADS8 with the AP3 orthologs to form higher order heterotetrameric complexes that regulated petal/stamen formation in both Oncidium orchids and transgenic Arabidopsis. However, the C terminal sequence and PI motif were dispensable for the interaction of OMADS8 with the AG orthologs. PMID- 26423961 TI - Effects of Elevated Atmospheric CO2 on Primary Metabolite Levels in Arabidopsis thaliana Col-0 Leaves: An Examination of Metabolome Data. AB - Elevated atmospheric CO(2) concentrations ([CO(2)]) affect primary metabolite levels because CO(2) is a direct substrate for photosynthesis. In several studies, the responses of primary metabolite levels have been examined using Arabidopsis thaliana leaves, but these results have not been comprehensively discussed. Here, we examined metabolome data for A. thaliana accession Col-0 leaves that were grown at elevated [CO(2)] with sufficient nitrogen (N) nutrition. At elevated [CO(2)], starch, monosaccharides and several major amino acids accumulated in leaves. The degree of accumulation depended on whether the rooting medium contained NH(4) (+) or only NO(3) (-). Because low N conditions induce an increase in carbohydrates similar to that of elevated [CO(2)], we compared the responses of primary metabolite levels between elevated [CO(2)] and low N conditions. Levels of the tricarboxylic acid (TCA) cycle-associated organic acids and major amino acids decreased with low N, but not with elevated [CO(2)]. Even at elevated [CO(2)], the low N induced the decreases in the levels of organic acids and major amino acids. A small sink size also affects the primary metabolite response patterns in leaves under elevated [CO(2)] conditions. Thus, care is necessary when interpreting primary metabolite changes in leaves of field grown plants. PMID- 26423962 TI - Neuroprotective Effect of Calpeptin on Acrylamide-Induced Neuropathy in Rats. AB - Acrylamide (ACR) is a vinyl monomer with established human neurotoxic effects, which is characterized by the accumulation of neurofilaments (NFs) in the distal swellings of large axons in peripheral and central nervous systems. However, the mechanisms of neurotoxicity remain unclear. The objective is to investigate the neuroprotective effect of calpeptin (CP) on ACR-induced neuropathy and its mechanism. Female adult Wistar rats were randomly divided into four groups (control, CP, ACR, and ACR + CP group). Control group received 0.9 % saline, ACR and ACR + CP groups received 30 mg/kg ACR by intraperitoneal injection. In addition, CP and ACR + CP groups also received 200 ug/kg CP. Gait analysis and hind limb splay were measured weekly to analyze neurobehavioral changes. The calpain activity and the changes of NFs protein levels in spinal cord are determined. Compared with control group, body weight of rats in ACR group decreased by 11.3 % (P < 0.01), while in ACR + CP group body weight increased significantly by 8.3 % (P < 0.01) compared with ACR group by the end of the 4th week; gait score of rats in both ACR and ACR + CP groups increased significantly by 167 % and 100 % (P < 0.01) compared with control group, while it decreased significantly by 25.1 % (P < 0.01) in ACR + CP group compared with ACR group; the distance of hind limb splay in both ACR and ACR + CP groups increased by 76.7 % and 49.5 % (P < 0.01) compared with control group, while it decreased by 15.4 % (P < 0.01) in ACR + CP group compared with ACR group; calpain activity of spinal cord at ACR and ACR + CP groups increased significantly by 14.9 % and 10.0 % (P < 0.01) compared with control group, while it decreased 4.2 % (P < 0.01) in ACR + CP group compared with ACR group; compared with control group, the levels of light NF (NF-L), medium NF (NF-M) and heavy NF (NF-H) subunits increased by 81.2 %, 263.6 % and 22.6 % (P < 0.01) in the supernatant of ACR group in spinal cord tissue and increased by 28.4 %, 96.6 % and 10.6 % (P < 0.01) in ACR + CP group, while the levels of NF-L, NF-M and NF-H subunits decreased by 29.1 %, 45.9 % and 9.8 % (P < 0.01) in ACR + CP group compared with ACR group. The present results suggested that CP can relieve ACR neuropathy by decrease calpain activity and NFs degradation. The changes of calpain activity and NFs may be one of the mechanisms of ACR-induced neuropathy. PMID- 26423963 TI - Library Construction for Mutation Identification by Whole-Genome Sequencing. AB - Next-generation sequencing provides a rapid and powerful method for mutation identification. Herein is described a workflow for sample preparation to allow the simultaneous mapping and identification of candidate mutations by whole genome sequencing in Caenorhabditis elegans. The protocol is designed for small numbers of worms to accommodate classes of mutations, such as lethal and sterile alleles, that are difficult to identify by traditional means. PMID- 26423964 TI - Fundamentals of Comparative Genome Analysis in Caenorhabditis Nematodes. AB - The genome of the nematode Caenorhabditis elegans was the first of any animal to be sequenced completely, and it remains the "gold standard" for completeness and annotations. Even before the C. elegans genome was completed, however, biologists began examining the generality of its features in the genomes of other Caenorhabditis species. With many such genomes now sequenced and available via WormBase, C. elegans researchers are often confronted with how to interpret comparative genomic data. In this article, we present practical approaches to addressing several common issues, including possible sources of error in homology annotations, the often complex relationships between sequence similarity, orthology, paralogy, and gene family evolution, the impact of sexual mode on genome assemblies and content, and the determination and use of synteny as a tool. PMID- 26423965 TI - Genetic Methods for Cellular Manipulations in C. elegans. AB - Neuron manipulation in vivo by ablation, activation, or inactivation, and regulation of gene expression, is essential for dissecting nervous system function. Here we describe genetic means for neuron manipulation in the nematode C. elegans, and provide protocols for generating transgenic animals containing these genetic tools. PMID- 26423966 TI - A Fusion PCR Method for Expressing Genetic Tools in C. elegans. AB - C. elegans offer a unique opportunity for understanding computation in neural networks. This is largely due to their relatively compact neural network for which a wiring diagram is available. Recent advances in genetic tools for interrogating neural activity (e.g., optogenetics) make C. elegans particularly compelling as they can be expressed in many different combinations in target individual neurons. Thus, the prospect to decipher principles underlying functionality in neural networks largely depends on the ease by which transgenic animals can be generated. Traditionally, to generate transgenic animals one would inject a plasmid containing the gene of interest under the regulation of the cell or lineage-specific promoter. This often requires laborious cloning steps of both the gene and the promoter. The Hobert lab has developed a simpler protocol in which linear PCR fragments can be injected to generate transgenic animals. Relying on this PCR fusion-based method, here we provide a detailed protocol that we have optimized for expressing various genetically encoded calcium indicators and optogenetic tools in individual or sets of neurons. We use these simple procedures to generate multiple constructs within a very short time frame (typically 1-2 days). PMID- 26423967 TI - Transposon-Assisted Genetic Engineering with Mos1-Mediated Single-Copy Insertion (MosSCI). AB - Transgenesis in model organisms is necessary to determine the function, expression, and subcellular localization of gene products. In Caenorhabditis elegans, injected DNA can be propagated as multicopy extrachromosomal arrays but transgenes in arrays are mosaic, over-expressed in some tissues and silenced in the germline. Here, a method to insert a transgene into a specific genomic location called Mos1-mediated single-copy insertion (MosSCI) is described. Single copy insertion allows transgene expression at levels that approximate endogenous gene expression as well as expression in the germline. PMID- 26423968 TI - Creating Genome Modifications in C. elegans Using the CRISPR/Cas9 System. AB - The clustered, regularly interspaced, short, palindromic repeat (CRISPR) associated (CAS) nuclease Cas9 has been used in many organisms to generate specific mutations and transgene insertions. Here we describe a method using the S. pyogenes Cas9 in C. elegans that provides a convenient and effective approach for making heritable changes to the worm genome. PMID- 26423969 TI - Observing and Quantifying Fluorescent Reporters. AB - Genetically encoded fluorescent reporters take advantage of C. elegans' transparency to allow noninvasive, in vivo observation and recording of physiological processes in intact animals. Here, I discuss the basic microscope components required to observe, image, and measure fluorescent proteins in live animals for students and researchers who work with C. elegans but have limited experience with fluorescence imaging and analysis. PMID- 26423970 TI - Microbial Rhodopsin Optogenetic Tools: Application for Analyses of Synaptic Transmission and of Neuronal Network Activity in Behavior. AB - Optogenetics was introduced as a new technology in the neurosciences about a decade ago (Zemelman et al., Neuron 33:15-22, 2002; Boyden et al., Nat Neurosci 8:1263-1268, 2005; Nagel et al., Curr Biol 15:2279-2284, 2005; Zemelman et al., Proc Natl Acad Sci USA 100:1352-1357, 2003). It combines optics, genetics, and bioengineering to render neurons sensitive to light, in order to achieve a precise, exogenous, and noninvasive control of membrane potential, intracellular signaling, network activity, or behavior (Rein and Deussing, Mol Genet Genomics 287:95-109, 2012; Yizhar et al., Neuron 71:9-34, 2011). As C. elegans is transparent, genetically amenable, has a small nervous system mapped with synapse resolution, and exhibits a rich behavioral repertoire, it is especially open to optogenetic methods (White et al., Philos Trans R Soc Lond B Biol Sci 314:1-340, 1986; De Bono et al., Optogenetic actuation, inhibition, modulation and readout for neuronal networks generating behavior in the nematode Caenorhabditis elegans, In: Hegemann P, Sigrist SJ (eds) Optogenetics, De Gruyter, Berlin, 2013; Husson et al., Biol Cell 105:235-250, 2013; Xu and Kim, Nat Rev Genet 12:793-801, 2011). Optogenetics, by now an "exploding" field, comprises a repertoire of different tools ranging from transgenically expressed photo-sensor proteins (Boyden et al., Nat Neurosci 8:1263-1268, 2005; Nagel et al., Curr Biol 15:2279-2284, 2005) or cascades (Zemelman et al., Neuron 33:15-22, 2002) to chemical biology approaches, using photochromic ligands of endogenous channels (Szobota et al., Neuron 54:535 545, 2007). Here, we will focus only on optogenetics utilizing microbial rhodopsins, as these are most easily and most widely applied in C. elegans. For other optogenetic tools, for example the photoactivated adenylyl cyclases (PACs, that drive neuronal activity by increasing synaptic vesicle priming, thus exaggerating rather than overriding the intrinsic activity of a neuron, as occurs with rhodopsins), we refer to other literature (Weissenberger et al., J Neurochem 116:616-625, 2011; Steuer Costa et al., Photoactivated adenylyl cyclases as optogenetic modulators of neuronal activity, In: Cambridge S (ed) Photswitching proteins, Springer, New York, 2014). In this chapter, we will give an overview of rhodopsin-based optogenetic tools, their properties and function, as well as their combination with genetically encoded indicators of neuronal activity. As there is not "the" single optogenetic experiment we could describe here, we will focus more on general concepts and "dos and don'ts" when designing an optogenetic experiment. We will also give some guidelines on which hardware to use, and then describe a typical example of an optogenetic experiment to analyze the function of the neuromuscular junction, and another application, which is Ca(2+) imaging in body wall muscle, with upstream neuronal excitation using optogenetic stimulation. To obtain a more general overview of optogenetics and optogenetic tools, we refer the reader to an extensive collection of review articles, and in particular to volume 1148 of this book series, "Photoswitching Proteins." PMID- 26423972 TI - High-Pressure Freeze and Freeze Substitution Electron Microscopy in C. elegans. AB - While traditional chemical fixation methods for C. elegans electron microscopy (EM) have provided invaluable anatomical and structural information, the development of high-pressure freeze (HPF) and freeze substitution (FS) protocols offers advantages for high-resolution imaging. Specimens prepared using HPF methodology exhibit fewer distortion artifacts due to fixation and dehydration, have improved antigenicity, and result in a more physiologically accurate structural representation of the worm. In the HPF technique, freely moving worms are frozen at high-pressure (2100 bar) and low temperature (-180 degrees C) within milliseconds. These conditions prevent the formation of ice crystals that can damage cellular structures. Samples then undergo FS, during which worms are slowly brought to room temperature while substituting amorphous ice with organic solvents to preserve tissue in its near native state and provide contrast for imaging. FS can be performed in an automatic freeze substitution (AFS) machine or in makeshift, temperature controlled chambers. Fixed worms can be embedded in plastic resin and further processed for a variety of imaging techniques. Samples then viewed using scanning (SEM) or transmission electron microscopy (TEM) will show enhanced preservation of organelles, cell morphology, and antigenicity for immunocytochemistry. PMID- 26423971 TI - Simultaneous Optogenetic Stimulation of Individual Pharyngeal Neurons and Monitoring of Feeding Behavior in Intact C. elegans. AB - Optogenetic approaches have proven powerful for examining the role of neural circuits in generating behaviors, especially in systems where electrophysiological manipulation is not possible. Here we describe a method for optogenetically manipulating single pharyngeal neurons in intact C. elegans while monitoring pharyngeal behavior. This approach provides bidirectional and dynamic control of pharyngeal neural activity simultaneously with a behavioral readout and has allowed us to test hypotheses about the roles of individual pharyngeal neurons in regulating feeding behavior. PMID- 26423973 TI - Electron Tomography Methods for C. elegans. AB - Methods for electron tomography of the nematode C. elegans are explained in detail, including a brief introduction to specimen preparation, methods for image collection, and a comparison of several general methods for producing dual-axis tomograms, with or without external fiducial reference objects. New electron tomograms highlight features in software for data display, annotation, and analysis. This chapter discusses the ultrastructural analysis of cells and tissues, rather than molecular studies. PMID- 26423974 TI - Microfluidic Devices for Behavioral Analysis, Microscopy, and Neuronal Imaging in Caenorhabditis elegans. AB - Microfluidic devices offer several advantages for C. elegans research, particularly for presenting precise physical and chemical environments, immobilizing animals during imaging, quantifying behavior, and automating screens. However, challenges to their widespread adoption in the field include increased complexity over conventional methods, operational problems (such as clogging, leaks, and bubbles), difficulty in obtaining or fabricating devices, and the need to characterize biological results obtained from new assay formats. Here we describe the preparation and operation of simple, reusable microfluidic devices for quantifying behavioral responses to chemical patterns, and single-use devices to arrange animals for time-lapse microscopy and to measure neuronal activity. We focus on details that eliminate or reduce the frustrations commonly experienced by new users of microfluidic devices. PMID- 26423975 TI - Tracking Single C. elegans Using a USB Microscope on a Motorized Stage. AB - Locomotion and gross morphology have been important phenotypes for C. elegans genetics since the inception of the field and remain relevant. In parallel with developments in genome sequencing and editing, phenotyping methods have become more automated and quantitative, making it possible to detect subtle differences between mutants and wild-type animals. In this chapter, we describe how to calibrate a single-worm tracker consisting of a USB microscope mounted on a motorized stage and how to record and analyze movies of worms crawling on food. The resulting quantitative phenotypic fingerprint can sensitively identify differences between mutant and wild-type worms. PMID- 26423976 TI - An Imaging System for C. elegans Behavior. AB - Many experiments in C. elegans neurobiology and development benefit from automated imaging of worm behavior. Here we describe procedures for building a flexible and inexpensive imaging system using standard optical and mechanical components. PMID- 26423977 TI - A Method for Obtaining Large Populations of Synchronized Caenorhabditis elegans Dauer Larvae. AB - The C. elegans dauer is an attractive model with which to investigate fundamental biological questions, such as how environmental cues are sensed and are translated into developmental decisions through a series of signaling cascades that ultimately result in a transformed animal. Here we describe a simple method of using egg white plates to obtain highly synchronized purified dauers that can be used in downstream applications requiring large quantities of dauers or postdauer animals. PMID- 26423978 TI - Sampling and Isolation of C. elegans from the Natural Habitat. AB - Wild populations of the model organism C. elegans allow characterization of natural genetic variation underlying diverse phenotypic traits. Here we provide a simple protocol on how to sample and rapidly identify C. elegans wild isolates. We outline how to find suitable habitats and organic substrates, followed by describing isolation and identification of C. elegans live cultures based on easily recognizable morphological characteristics, molecular barcodes and/or mating tests. This protocol uses standard laboratory equipment and requires no prior knowledge of C. elegans biology. PMID- 26423979 TI - A Primer on Prototyping. AB - Standard mechanical components, such as adapters or mounts, are ubiquitous in research laboratories, C. elegans labs included. Recently, in-house prototyping and fabricating both standard and custom mechanical parts has become simple and cost effective. Here we describe the basic steps, equipment, and considerations required for rapid prototyping of a handful of simple yet useful designs. These examples were chosen for their simplicity, as well as for demonstrating specific practicalities. They are thus appropriate as training exercises. PMID- 26423980 TI - A Primer on Quantitative Modeling. AB - Caenorhabditis elegans is particularly suitable for obtaining quantitative data about behavior, neuronal activity, gene expression, ecological interactions, quantitative traits, and much more. To exploit the full potential of these data one seeks to interpret them within quantitative models. Using two examples from the C. elegans literature we briefly explore several types of modeling approaches relevant to worm biology, and show how they might be used to interpret data, formulate testable hypotheses, and suggest new experiments. We emphasize that the choice of modeling approach is strongly dependent on the questions of interest and the type of available knowledge. PMID- 26423981 TI - Comments on the review article 'Time trends in the incidence and prevalence of multiple sclerosis in Norway during eight decades'. PMID- 26423982 TI - Physical examination tests for screening and diagnosis of cervicogenic headache: A systematic review. AB - It has been suggested that differential diagnosis of headaches should consist of a robust subjective examination and a detailed physical examination of the cervical spine. Cervicogenic headache (CGH) is a form of headache that involves referred pain from the neck. To our knowledge, no studies have summarized the reliability and diagnostic accuracy of physical examination tests for CGH. The aim of this study was to summarize the reliability and diagnostic accuracy of physical examination tests used to diagnose CGH. A systematic review following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines was performed in four electronic databases (MEDLINE, Web of Science, Embase and Scopus). Full text reports concerning physical tests for the diagnosis of CGH which reported the clinometric properties for assessment of CGH, were included and screened for methodological quality. Quality Appraisal for Reliability Studies (QAREL) and Quality Assessment of Studies of Diagnostic Accuracy (QUADAS-2) scores were completed to assess article quality. Eight articles were retrieved for quality assessment and data extraction. Studies investigating diagnostic reliability of physical examination tests for CGH scored poorer on methodological quality (higher risk of bias) than those of diagnostic accuracy. There is sufficient evidence showing high levels of reliability and diagnostic accuracy of the selected physical examination tests for the diagnosis of CGH. The cervical flexion-rotation test (CFRT) exhibited both the highest reliability and the strongest diagnostic accuracy for the diagnosis of CGH. PMID- 26423983 TI - The effects of a self-observation-based meditation intervention on acceptance or rejection of the other. AB - Research has demonstrated the many benefits of mindfulness training programmes for individual health and well-being. This study, however, explored whether mindfulness training might have effects on intergroup interaction. We tested the effects of a self-observation-based mindfulness course on several dimensions of acceptance of the other (i.e., non-judgement, non-reaction and observation). An initial study test a mindfulness course training (N = 197). A second study then tested its effect on intergroup relationships (N = 120). A control group was used in both studies, and the subjects were tested before and after the course. Results indicate that participation in the course favoured intergroup acceptance of the other and suggest that mindfulness training represents a useful educational method for reducing social discrimination. PMID- 26423984 TI - Time for the UK to get ready for PrEP. PMID- 26423985 TI - Therapeutic CCR5 blockade illuminates IRIS pathogenesis. PMID- 26423986 TI - Home HIV testing and counselling: answers raising questions. PMID- 26423987 TI - Which strategy for ART in resource-limited settings? PMID- 26423988 TI - Churning in and out of HIV care. PMID- 26423989 TI - Effect of the CCR5 antagonist maraviroc on the occurrence of immune reconstitution inflammatory syndrome in HIV (CADIRIS): a double-blind, randomised, placebo-controlled trial. AB - BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) is a common complication of antiretroviral therapy (ART) in patients with HIV. IRIS is associated with an increased risk of admission to hospital and death. We assessed whether CCR5 blockade with maraviroc reduces the risk of IRIS. METHODS: The CADIRIS study was a double-blind, randomised, placebo-controlled trial that recruited participants from five clinical sites in Mexico and one in South Africa and followed them for 1 year. Patients were eligible if they were adults with HIV, who were naive to ART, had CD4 count lower than 100 cells per MUL and HIV RNA greater than 1000 copies per mL. Participants were randomly assigned (1:1) by permuted block randomisation to receive either maraviroc (600 mg twice daily) or placebo in addition to an ART regimen that included tenofovir, emtricitabine, and efavirenz for 48 weeks. Patients, care providers, and members of the research team were masked to treatment allocation. Clinical and laboratory evaluations were done at baseline, and weeks 2, 4, 8, 12, 16, 24, 48, and 60. The primary outcome was time to an IRIS event by 24 weeks. All patients who were randomly assigned contributed to the primary time-to-event analysis from the date of ART initiation until week 24, the time of an IRIS event or death. This trial is registered with ClinicalTrials.gov, number NCT00988780. FINDINGS: Between Dec 10, 2009, and Jan 17, 2012, we screened 362 patients; of whom 279 met the inclusion criteria and three refused to participate; thus 276 participants were randomly assigned (140 to receive maraviroc and 136 to receive placebo). 64 (23%) patients had IRIS events, 33 (24%) in the maraviroc group and 31 (23%) in the placebo group (p=0.74). No difference in the time to IRIS events was noted between the treatment groups (HR 1.08, 95% CI 0.66-1.77; log-rank test p=0.74). 37 participants (26%) in the maraviroc group had grade 3 or 4 adverse events compared with 24 (18%) in placebo group; p=0.072); 25 (18%) in the maraviroc group and 21 (15%) in the placebo group had serious treatment emergent adverse events (p=0.63). INTERPRETATION: Maraviroc had no significant effect on development of IRIS after ART initiation. Inclusion of this CCR5 inhibitor in an initial treatment regimen does not confer a meaningful protection from the occurrence of IRIS in people with advanced HIV infection. FUNDING: Pfizer. PMID- 26423990 TI - Effectiveness and cost-effectiveness of potential responses to future high levels of transmitted HIV drug resistance in antiretroviral drug-naive populations beginning treatment: modelling study and economic analysis. AB - BACKGROUND: With continued roll-out of antiretroviral therapy (ART) in resource limited settings, evidence is emerging of increasing levels of transmitted drug resistant HIV. We aimed to compare the effectiveness and cost-effectiveness of different potential public health responses to substantial levels of transmitted drug resistance. METHODS: We created a model of HIV transmission, progression, and the effects of ART, which accounted for resistance generation, transmission, and disappearance of resistance from majority virus in the absence of drug pressure. We simulated 5000 ART programmatic scenarios with different prevalence levels of detectable resistance in people starting ART in 2017 (t0) who had not previously been exposed to antiretroviral drugs. We used the model to predict cost-effectiveness of various potential changes in policy triggered by different prevalence levels of resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) measured in the population starting ART. FINDINGS: Individual level resistance testing before ART initiation was not generally a cost-effective option, irrespective of the cost-effectiveness threshold. At a cost-effectiveness threshold of US$500 per quality-adjusted life-year (QALY), no change in policy was cost effective (ie, no change in policy would involve paying less than $500 per QALY gained), irrespective of the prevalence of pretreatment NNRTI resistance, because of the increased cost of the policy alternatives. At thresholds of $1000 or higher, and with the prevalence of pretreatment NNRTI resistance greater than 10%, a policy to measure viral load 6 months after ART initiation became cost effective. The policy option to change the standard first line treatment to a boosted protease inhibitor regimen became cost effective at a prevalence of NNRTI resistance higher than 15%, for cost-effectiveness thresholds greater than $2000. INTERPRETATION: Cost-effectiveness of potential policies to adopt in response to different levels of pretreatment HIV drug resistance depends on competing budgetary claims, reflected in the cost-effectiveness threshold. Results from our model will help inform WHO recommendations on monitoring of HIV drug resistance in people starting ART. FUNDING: WHO (with funds provided by the Bill & Melinda Gates Foundation), CHAIN (European Commission). PMID- 26423991 TI - Capsule Commentary on Richman et al., Colorectal Cancer Screening in the Era of the Affordable Care Act. PMID- 26423992 TI - A Systematic Review of Conceptual Frameworks of Medical Complexity and New Model Development. AB - BACKGROUND: Patient complexity is often operationalized by counting multiple chronic conditions (MCC) without considering contextual factors that can affect patient risk for adverse outcomes. OBJECTIVE: Our objective was to develop a conceptual model of complexity addressing gaps identified in a review of published conceptual models. DATA SOURCES: We searched for English-language MEDLINE papers published between 1 January 2004 and 16 January 2014. Two reviewers independently evaluated abstracts and all authors contributed to the development of the conceptual model in an iterative process. RESULTS: From 1606 identified abstracts, six conceptual models were selected. One additional model was identified through reference review. Each model had strengths, but several constructs were not fully considered: 1) contextual factors; 2) dynamics of complexity; 3) patients' preferences; 4) acute health shocks; and 5) resilience. Our Cycle of Complexity model illustrates relationships between acute shocks and medical events, healthcare access and utilization, workload and capacity, and patient preferences in the context of interpersonal, organizational, and community factors. CONCLUSIONS/IMPLICATIONS: This model may inform studies on the etiology of and changes in complexity, the relationship between complexity and patient outcomes, and intervention development to improve modifiable elements of complex patients. PMID- 26423995 TI - CCL22 Prevents Rejection of Mouse Islet Allografts and Induces Donor-Specific Tolerance. AB - Manipulation of regulatory T cell (Treg) migration by islet expression of the chemokine CCL22 prevents diabetes in NOD mice and delays recurrent autoimmunity in syngeneic islet transplants. We sought to determine whether attracting Tregs with CCL22 also prevents islet allograft rejection. Isolated Bl/6 mouse islets were transduced overnight with adenovirus expressing CCL22 (Ad-CCL22) downstream of the CMV promoter. Islets were transplanted under the renal capsule of Balb/c recipients made diabetic by streptozotocin. To assess immunologic tolerance, graft-bearing kidneys from recipients of CCL22-expressing islet grafts were removed, and mice received a second transplant of naive islets from the same donor strain or third-party islets into the contralateral kidney. Adenoviral expression of CCL22 conferred prolonged protection of islet allografts in MHC mismatched, diabetic recipients, maintaining normoglycemia in 75% of recipients for at least 80 days. Increased frequency of Treg cells was observed in islet grafts transduced with Ad-CCL22 compared with untreated grafts. Normoglycemic recipients of CCL22-expressing islet grafts showed complete absence of antidonor antibodies and no lymphocyte proliferation after exposure to donor splenocytes. After removal of the primary graft at day 80, mice that received a second transplant with untreated islets from the same donor strain did not reject the grafts, suggesting the development of tolerance. Expression of CCL22 recruits Treg cells to transplanted islets, prevents activation of alloreactive T-cells and islet allograft failure and induces alloantigen-specific tolerance. Manipulation of Treg cells by CCL22 in transplanted islets may be a novel therapeutic strategy for diabetes. PMID- 26423993 TI - The continuing evolution of targeted therapy for inflammatory skin disease. AB - Treatment of inflammatory skin disease has evolved from non-specific suppression of immune cells to increasingly precise targeting and modulation of immune mechanisms at all levels. This has led to dramatic treatment successes and deepened understanding of the pathophysiology. The cycle of in vitro studies, animal models, clinical trials, and case series of non-primary indications is a feedback loop that informs and guides the design of ever better disease models and therapeutic targets. Not only are we constantly discovering new molecules driving skin inflammation, we have also found that psoriasis and other autoimmune conditions are driven by distinct mediators occurring in early and late phases, which could be an opportunity for phase-specific or multipronged interventions. The deeper our mechanistic understanding, the more likely we will be able to discover subtle strategies to reprogram each patients' immune cells without having to dampen or eliminate their protective effects against pathogens and tumors. Lastly, ongoing genomic studies might soon confirm interesting genetic markers for predictive personalized medicine, the earliest currently being evaluated in psoriasis such as HLA-Cw6 and TNFAIP3. Taken together, the continued evolution of immune therapies in skin will potentially allow an unprecedented form of medicine that is not bent on silencing the pathogenic mechanism, but rather aims at using subtle interventions to shepherd the immune cell swarm back on the correct path. PMID- 26423996 TI - Small bowel varices secondary to chronic superior mesenteric vein thrombosis in a patient with heterozygous Factor V Leiden mutation: a case report. AB - INTRODUCTION: Bleeding ectopic small bowel varices pose a clinical dilemma for the physician, given their diagnostic obscurity and the lack of evidence-based medicine to guide therapy. They often occur in the context of portal hypertension, secondary to either liver disease or extrahepatic causes. Rarely is their presence associated with chronic superior mesenteric vein thrombosis and hereditary coagulopathies. CASE PRESENTATION: A 74-year-old white woman, with a heterozygous Factor V Leiden mutation and no underlying liver disease or portal hypertension, presented over the course of 13 months for recurrent episodes of melena and per rectal bleeding. An initial endoscopy showed a clean-based chronic gastric ulcer, while colonoscopies showed multiple, non-bleeding angioectasias which were treated with argon plasma coagulation. Subsequent video capsule endoscopy and double balloon enteroscopy revealed red wale marks overlying engorged submucosal veins in her distal ileum, consistent with ectopic varices. A chronic superior mesenteric vein thrombus, found via computed tomography venogram, was the cause of the ileal varices. She underwent curative surgical resection of the affected bowel, with no re-bleeding episodes 17 months post surgery, despite needing lifelong anticoagulation for recurrent venous thromboembolisms. CONCLUSIONS: Clinicians should consider ectopic varices in patients who present with obscure gastrointestinal bleeding, even in the absence of portal hypertension or liver disease. In those with a known thrombophilia, patients should be screened for splanchnic thrombosis, which may precipitate ectopic varices. PMID- 26423994 TI - HIV-1 tuberculosis-associated immune reconstitution inflammatory syndrome. AB - Patients co-infected with HIV-1 and tuberculosis (TB) are at risk of developing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) following commencement of antiretroviral therapy (ART). TB-IRIS is characterized by transient but severe localized or systemic inflammatory reactions against Mycobacterium tuberculosis antigens. Here, we review the risk factors and clinical management of TB-IRIS, as well as the roles played by different aspects of the immune response in contributing to TB-IRIS pathogenesis. PMID- 26423997 TI - Factors associated with postpartum hemorrhage maternal death in referral hospitals in Senegal and Mali: a cross-sectional epidemiological survey. AB - BACKGROUND: Postpartum hemorrhage (PPH) is the leading cause of maternal mortality in Sub-Saharan-Africa (SSA). Although clinical guidelines treating PPH are available, their implementation remains a great challenge in resource poor settings. A better understanding of the factors associated with PPH maternal mortality is critical for preventing risk of hospital-based maternal death. The purpose of this study was thus to assess which factors contribute to maternal death occurring during PPH. The factors were as follows: women's characteristics, aspects of pregnancy and delivery; components of PPH management; and organizational characteristics of the referral hospitals in Senegal and Mali. METHODS: A cross-sectional survey nested in a cluster randomized trial (QUARITE trial) was carried out in 46 referral hospitals during the pre-intervention period from October 2007 to September 2008 in Senegal and Mali. Individual and hospital characteristics data were collected through standardized questionnaires. A multivariable logistic mixed model was used to identify the factors that were significantly associated with PPH maternal death. RESULTS: Among the 3,278 women who experienced PPH, 178 (5.4%) of them died before hospital discharge. The factors that were significantly associated with PPH maternal mortality were: age over 35 years (adjusted OR = 2.16 [1.26-3.72]), living in Mali (adjusted OR = 1.84 [1.13-3.00]), residing outside the region location of the hospital (adjusted OR = 2.43 [1.29-4.56]), pre-existing chronic disease before pregnancy (adjusted OR = 7.54 [2.54-22.44]), prepartum severe anemia (adjusted OR = 6.65 [3.77 11.74]), forceps or vacuum delivery (adjusted OR = 2.63 [1.19-5.81]), birth weight greater than 4000 grs (adjusted OR = 2.54 [1.26-5.10]), transfusion (adjusted OR = 2.17 [1.53-3.09]), transfer to another hospital (adjusted OR = 13.35 [6.20-28.76]). There was a smaller risk of PPH maternal death in hospitals with gynecologist-obstetrician (adjusted OR = 0.55 [0.35-0.89]) than those with only a general practitioner trained in emergency obstetric care (EmOC). CONCLUSIONS: Our findings may have direct implications for preventing PPH maternal death in resource poor settings. In particular, we suggest anemia should be diagnosed and treated before delivery and inter-hospital transfer of women should be improved, as well as the management of blood banks for a quicker access to transfusion. Finally, an extent training of general practitioners in EmOC would contribute to the decrease of PPH maternal mortality. PMID- 26423998 TI - Identification and characterization of TIFY family genes in Brachypodium distachyon. AB - The TIFY family is a plant-specific gene family encoding proteins characterized by a conserved TIFY domain. This family encodes four subfamilies of proteins, including ZIM-like (ZML), TIFY, PPD and JASMONATE ZIM-Domain (JAZ) proteins. TIFY proteins play important roles in plant development and stress responses. In this study, 21 BdTIFYs were identified in Brachypodium distachyon through genome-wide analysis, including 15 JAZ and 6 ZML genes. Analysis of the distribution of conserved domains showed that there are three additional domains (CCT domain, GATA domain and Jas domain) in the BdTIFY proteins besides the TIFY domain. Phylogenetic analysis indicated that these 21 proteins were classified into two major groups. Expression profile of BdTIFY genes in response to abiotic stresses and phytohormones was analyzed using quantitative real-time RT-PCR. Among 21 BdTIFY genes, 12 of them were induced by JA treatment, and 4 of them were induced by ABA treatment. Most of BdTIFY genes were responsive to one or more abiotic stresses including drought, salinity, low temperature and heat. Especially, BdTIFY5, 9a, 9b, 10c and 11a were significantly up-regulated by multiple abiotic stresses. These results provided important clues for functional analysis of TIFY family genes in B. distachyon. PMID- 26423999 TI - Multiple and mass introductions from limited origins: genetic diversity and structure of Solidago altissima in the native and invaded range. AB - Understanding the origins and diversity of invasive species can reveal introduction and invasion pathways, and inform an effective management of invasive species. Tall goldenrod, Solidago altissima, is a herbaceous perennial plant native to North America and it has become a widespread invasive weed in East Asian countries. We used microsatellite and chloroplast DNA markers to obtain information on neutral processes and on genetic diversity in native and invaded populations of S. altissima and to infer how it invaded and spread in Japan. We found that introduced (n = 12) and native (n = 20) populations had similar levels of genetic diversity at nuclear SSR loci. Genetic structure analysis indicated that at least two independent colonization events gave rise to current S. altissima populations in Japan. The majority (68%) of the Japanese S. altissima were genetically similar and likely shared a common origin from a single or a small number of populations from the southern USA populations, while the populations in Hokkaido were suggested to arise from a different source. Our results suggest that multiple and mass introductions have contributed to the persistence and rapid adaptation of S. altissima promoting its widespread establishment throughout Japan. PMID- 26424001 TI - Maternal exposure to GOS/inulin mixture prevents food allergies and promotes tolerance in offspring in mice. AB - BACKGROUND: Food allergies affect 4-8% of children and are constantly on the rise, thus making allergies a timely issue. Most importantly, prevention strategies are nonexistent, and current therapeutic strategies have limited efficacy and need to be improved. One alternative to prevent or reduce allergies, particularly during infancy, could consist of modulating maternal immunity and microbiota using nondigestible food ingredients, such as prebiotics. For this purpose, we studied the preventive effects of prebiotics in Balb/c mothers during pregnancy and breastfeeding on food allergy development in offspring mice. METHODS: After weaning, the offspring from mothers that were exposed to GOS/inulin mixture or fed a control diet were intraperitoneally sensitized to wheat proteins to induce a systemic allergic response and orally exposed to the same allergen. Immunological, physiological, and microbial parameters were analyzed. RESULTS: GOS/inulin mixture diet modified the microbiota of mothers and their offspring. Offspring from mothers that received GOS/inulin prebiotics were protected against food allergies and displayed lower clinical scores, specifically of IgE and histamine levels, compared to offspring from mothers fed a control diet. Moreover, GOS/inulin supplementation for the mother resulted in stronger intestinal permeability in the offspring. Enhancement of the regulatory response to allergic inflammation and changes in the Th2/Th1 balance toward a dampened Th2 response were observed in mice from GOS/inulin mixture-exposed mothers. CONCLUSION: The treatment of pregnant and lactating mice with nondigestible GOS/inulin prebiotics promotes a long-term protective effect against food allergies in the offspring. PMID- 26424002 TI - Beginnings-The Kidney and Nephrology in Ancient Mesopotamian Culture. AB - A defining period in the history of civilization occurred in ancient Mesopotamia. While some of Mesopotamian contributions to knowledge (writing, mathematics, astronomy) have been recognized, those made to medicine are just beginning to be studied and appreciated. The medicine of the time developed in a theocratic society where local gods controlled all aspects of life and their healers were learned scribes who established the priestly medicine of old. For their use of prayers and incantations as a component of therapy Mesopotamian medicine has been belittled and relegated to magic. In fact, the Mesopotamian healers established the basic medical skills of observation, diagnosis, prognosis and treatment and, over time, systematically produced an expanding corpus of medical knowledge that had not existed theretofore. The kidney as an organ, the components of the urogenital tract, some signs and symptoms of renal diseases, and the art of urinalysis were first conceptualized, studied, and codified in Mesopotamia. In doing so, the Mesopotamians set the foundations of rational medicine that would follow after the introduction of the phonetic alphabet and the Socratic method of questioning and debate to stimulate critical analysis. PMID- 26424000 TI - The epidemiology of subclinical malaria infections in South-East Asia: findings from cross-sectional surveys in Thailand-Myanmar border areas, Cambodia, and Vietnam. AB - BACKGROUND: The importance of the submicroscopic reservoir of Plasmodium infections for malaria elimination depends on its size, which is generally considered small in low transmission settings. The precise estimation of this reservoir requires more sensitive parasite detection methods. The prevalence of asymptomatic, sub-microscopic malaria was assessed by a sensitive, high blood volume quantitative real-time polymerase chain reaction method in three countries of the Greater Mekong Sub-region. METHODS: Cross-sectional surveys were conducted in three villages in western Cambodia, four villages along the Thailand-Myanmar border and four villages in southwest Vietnam. Malaria parasitaemia was assessed by Plasmodium falciparum/pan malaria rapid diagnostic tests (RDTs), microscopy and a high volume ultra-sensitive real-time polymerase chain reaction (HVUSqPCR: limit of detection 22 parasites/mL). All villagers older than 6 months were invited to participate. RESULTS: A census before the surveys identified 7355 residents in the study villages. Parasite prevalence was 224/5008 (4 %) by RDT, 229/5111 (5 %) by microscopy, and 988/4975 (20 %) when assessed by HVUSqPCR. Of these 164 (3 %) were infected with P. falciparum, 357 (7 %) with Plasmodium vivax, 56 (1 %) with a mixed infection, and 411 (8 %) had parasite densities that were too low for species identification. A history of fever, male sex, and age of 15 years or older were independently associated with parasitaemia in a multivariate regression model stratified by site. CONCLUSION: Light microscopy and RDTs identified only a quarter of all parasitaemic participants. The asymptomatic Plasmodium reservoir is considerable, even in low transmission settings. Novel strategies are needed to eliminate this previously under recognized reservoir of malaria transmission. PMID- 26424003 TI - Gastric Sarcina ventriculi: incidental or pathologic? PMID- 26424004 TI - Photoprotection as a Trait for Rice Yield Improvement: Status and Prospects. AB - Solar radiation is essential for photosynthesis and global crop productivity but it is also variable in space and time, frequently being limiting or in excess of plant requirements depending on season, environment and microclimate. Photoprotective mechanisms at the chloroplast level help to avoid oxidative stress and photoinhibition, which is a light-induced reduction in photosynthetic quantum efficiency often caused by damage to photosystem II. There is convincing evidence that photoinhibition has a large impact on biomass production in crops and this may be especially high in rice, which is typically exposed to high tropical light levels. Thus far there has been little attention to photoinhibition as a target for improvement of crop yield. However, we now have sufficient evidence to examine avenues for alleviation of this particular stress and the physiological and genetic basis for improvement in rice and other crops. Here we examine this evidence and identify new areas for attention. In particular we discuss how photoprotective mechanisms must be optimised at both the molecular and the canopy level in order to coordinate with efficient photosynthetic regulation and realise an increased biomass and yield in rice. PMID- 26424005 TI - High genetic abundance of Rpi-blb2/Mi-1.2/Cami gene family in Solanaceae. AB - BACKGROUND: Three NBS-LRR genes, Rpi-blb2, Mi-1.2, and Cami, constitute a very special plant resistance gene family. These genes confer resistance against 4 distantly related pathogen species in 3 different Solanaceae hosts. To characterize this noted resistance, we conducted a series of studies on this gene family. RESULTS: First, homologs of this gene family were identified in the pepper, tomato and potato genomes. This revealed a large variation in copy number within this gene family among species and a great divergence was found both between and within species. To gain more information pertaining to gene resistance within this family, 121 LRR regions were cloned in 16 different wild/cultivated potato accessions. Again, frequent copy number variations and a high level of divergence between homolog were observed common among accessions. The divergence within species was so high that it reaches the level of divergence between species. Also, frequent frameshift mutations and abundant gene conversion events were identified in these LRR regions. CONCLUSIONS: Our findings suggest that this family harbors an unusually high level of genetic abundance, making it of particular interest. Together with other reported examples, our study also provides evidence that multi-resistance is a common trait in R gene families like this. PMID- 26424006 TI - High blood pressure is linked to increased risk of diabetes. PMID- 26424007 TI - Biorevitalizing effect of a novel facial serum containing apple stem cell extract, pro-collagen lipopeptide, creatine, and urea on skin aging signs. AB - BACKGROUND: Epithelial regeneration in skin is achieved by the constant turnover and differentiation of keratinocytes. Epidermal and dermal stem cells compartments are fundamental for the continuous renewal of the skin. Adult stem cells are the unique source for skin tissue renewal. Plants have stem cells and plant derived stem cell extracts are now used in topical products for their potential anti-ageing and anti-wrinkle effects. A new dermocosmetic product containing apple stem cell extract, urea, creatine and palmitoyl tripeptide-38 (Ureadin Fusion Serum Lift Antiarrugas, ISDIN S.A), has been recently developed to target different aspects involved in skin aging. STUDY AIM: To assess in vitro the effects of this new serum on the metabolic functions of human senescent fibroblasts and in vivo the anti-aging effects by clinical and instrumental evaluation. METHODS: We evaluated the effects of the serum on the mitochondrial ROS (reactive oxygen species) production in human senescent cultured fibroblasts measured at 0.1% and 1% using the Mitoread AntiOx mtROS method. In addition we evaluated the anti-ageing in vivo effect of this new serum applied on the face twice daily for 28 consecutive days and assessed by clinical and instrumental evaluation in 32 women with sensitive skin bearing wrinkles on crow's feet. RESULTS: The tested serum both at 0.1% and 1% induces a significant increase in 02 consumption, cellular ATP level and a reduction in extra-cellular lactate concentration. The product reduces also significantly the mitochondrial ROS production. The clinical study shows a relevant anti-wrinkle effect in 71% of the treated women with visible effects in 68% of the subjects as soon as 7 days of treatment. A significant increase in dermal density and skin elasticity was also observed. CONCLUSION: The use of this novel anti-aging serum demonstrated a significant improvement of aging skin signs with first visible results achieved after one week of use. The product seemed to optimize the metabolic functions in human senescent cultured fibroblast restoring a more efficient cell metabolism therefore contributing to the anti-aging properties of the product. PMID- 26424008 TI - The garden in our gut. PMID- 26424009 TI - Osthole Upregulates BDNF to Enhance Adult Hippocampal Neurogenesis in APP/PS1 Transgenic Mice. AB - Adult hippocampal neurogenesis occurs in the dentate gyrus (DG) of the mouse hippocampus, and plays roles in learning and memory progresses. In amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice, a rodent model of Alzheimer's disease (AD), severe impairment of neurogenesis in the dentate subgranular zone (SGZ) of the DG has been reported. Osthole, an active constituent of Cnidium monnieri (L.) CUSSON, has been reported to exert neuroprotective effects and may promote neural stem cell proliferation. However, whether osthole ameliorates spatial memory deficits and improves hippocampal neurogenesis in APP/PS1 mice remains unknown. In this study we found that osthole (30 mg/kg intraperitoneally (i.p.) once daily) treatment dramatically ameliorated the cognitive impairments by Morris Water Maze test and passive avoidance test, and augmented neurogenesis in the DG of hippocampus in APP/PS1 mice. Furthermore, osthole treatment upregulated expression of brain-derived neurotrophic factor (BDNF) and enhanced activation of the BDNF receptor tyrosine receptor kinase B (TrkB) following increased phosphorylation of cyclic AMP response element-binding protein (CREB), indicating that osthole improves neurogenesis via stimulating BDNF/TrkB/CREB signaling in APP/PS1 transgenic mice. PMID- 26424010 TI - SPATA4 Counteracts Etoposide-Induced Apoptosis via Modulating Bcl-2 Family Proteins in HeLa Cells. AB - Spermatogenesis associated 4 (SPATA4) is a testis-specific gene first cloned by our laboratory, and plays an important role in maintaining the physiological function of germ cells. Accumulated evidence suggests that SPATA4 might be associated with apoptosis. Here we established HeLa cells that stably expressed SPATA4 to investigate the function of SPATA4 in apoptosis. SPATA4 protected HeLa cells from etoposide-induced apoptosis through the mitochondrial apoptotic pathway, in the way that SPATA4 suppressed decrease of the mitochondrial membrane potential, the release of cytochrome c, and subsequent activation of caspase-9 and -3. We further demonstrated that SPATA4 upregulated anti-apoptotic members of Bcl-2 family proteins, Bcl-2, and downregulated the pro-apoptotic member of Bcl-2 family proteins, Bax. Knockdown of SPATA4 in HeLa/SPATA4 cells could partially rescue expression levels of bcl-2 and bax. In conclusion, SPATA4 protects HeLa cells against etoposide-induced apoptosis through the mitochondrial apoptotic pathway. Our findings provide further evidence that SPATA4 plays a role in regulating apoptosis. PMID- 26424011 TI - Relaxin Inhibits High Glucose-Induced Matrix Accumulation in Human Mesangial Cells by Interfering with TGF-beta1 Production and Mesangial Cells Phenotypic Transition. AB - Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). DN is characterized by glomerular extracellular matrix accumulation, mesangial expansion, basement membrane thickening, and renal interstitial fibrosis. To date, mounting evidence has shown that H2 relaxin possesses powerful antifibrosis properties; however, the mechanisms of H2 relaxin on diabetic nephropathy remain unknown. Here, we aimed to explore whether H2 relaxin can reduce production of extracellular matrix (ECM) secreted by human mesangial cells (HMC). HMC were exposed to 5.5 mM glucose (NG) or 30 mM glucose (HG) with or without H2 relaxin. Fibronectin (FN) and collagen type IV levels in the culture supernatants were examined by solid-phase enzyme-linked immunoadsorbent assay (ELISA). Western blot was used to detect the expression of alpha-smooth muscle actin (alpha-SMA) protein. Quantitative polymerase chain reaction (qPCR) method was employed to analyze transforming growth factor (TGF)-beta1 mRNA expression. Compared with the normal glucose group, the levels of fibronectin and collagen type were markedly increased after being cultured in high glucose medium. Compared with the high glucose group, remarkable decreases of fibronectin, collagen type IV, alpha smooth muscle actin, and TGF-beta1 mRNA expression were observed in the H2 relaxin-treated group. The mechanism by which H2 relaxin reduced high glucose induced overproduction of ECM may be associated with inhibition of TGF-beta1 mRNA expression and mesangial cells' phenotypic transition. H2 relaxin is a potentially effective modality for the treatment of DN. PMID- 26424012 TI - Mechanism of Action of Panaxytriol on Midazolam 1'-Hydroxylation and 4 Hydroxylation Mediated by CYP3A in Liver Microsomes and Rat Primary Hepatocytes. AB - In our previous study, panaxytriol (PXT) was shown to enhance midazolam (MDZ) 1' hydroxylation significantly but to inhibit MDZ 4-hydroxylation. To explore the underlying mechanism, we investigated the effects of PXT on cytochrome P450 3A (CYP3A)-mediated MDZ metabolic pathways using rat liver microsomes (RLM), human liver microsomes (HLM), and rat primary hepatocytes. In the presence of PXT, the Vmax of 4-OH MDZ decreased from 0.72 to 0.51 nmol/min.mg pro in RLM and from 0.32 to 0.12 nmol/min.mg pro in HLM, and the Km value increased from 5.12 to 7.26 uM in RLM and from 27.87 to 32.80 uM in HLM. But the presence of PXT reduced the Km and increased the Vmax values of MDZ 1'-hydroxylation in RLM and HLM. Interestingly, the differential effect of PXT on MDZ 4-hydroxylation and 1' hydroxylation was also observed in primary rat hepatocytes after 45-min culture. PXT did not affect the expression levels of CYP3A1/2 mRNA in rat hepatocytes. With extension of the culture time to 6 h, however, PXT significantly inhibited both MDZ 4-hydroxylation and 1'-hydroxylation, and the expression level of CYP3A1/2 mRNA was decreased to 87% and 80% (CYP3A1) and to 89% and 85% (CYP3A2) of those in controls in the presence of PXT 4.0 and 8.0 ug/mL, respectively. These results suggest that PXT could activate MDZ 1'-hydroxylation but inhibit MDZ 4-hydroxylation by changing the CYP3A enzyme affinity and metabolic rate after a short-term intervention. However, long-term treatment with PXT could inhibit both the 4-hydroxylation and 1'-hydroxylation of MDZ by downregulating CYP3A1/2 mRNA expression. PMID- 26424013 TI - Electron Paramagnetic Resonance Study of the Free Radical Scavenging Capacity of Curcumin and Its Demethoxy and Hydrogenated Derivatives. AB - The quantitative free radical scavenging capacity of curcumin and its demethoxy derivatives (demethoxycurcumin (Dmc) and bisdemethoxycurcumin (Bdmc)) and hydrogenated derivatives (tetrahydrocurcumin (THC), hexahydrocurcumin (HHC) and octahydrocurcumin (OHC)) towards 1,1-diphenyl-2-picryl hydrazyl (DPPH), nitric oxide radical (NO), hydroxyl radical (HO(.)) and superoxide anion radical (O2(.)) were investigated by electron paramagnetic resonance (EPR) spectroscopy. One mole of the hydrogenated derivatives scavenged about 4 mol of the DPPH radical, while curcumin and Dmc scavenged about 3 mol of the DPPH radical. Curcumin and THC showed moderate scavenging activity towards NO, yielding 200 mmol of NO scavenged per 1 mol of the scavenger. In contrast, curcumin and its derivatives showed very low scavenging activity towards HO(.) and O2(.), yielding approximately only 3-12 mmol scavenged per 1 mol of the tested compounds. Our results suggest that curcumin and its derivatives principally act as chain breaking antioxidants rather than as direct free radical scavengers. Furthermore, we showed that the ortho-methoxyphenolic group and the heptadione linkage of these molecules greatly contributed to their DPPH and NO scavenging activity. PMID- 26424014 TI - Dioxin-Produced Alteration in the Profiles of Fecal and Urinary Metabolomes: A Change in Bile Acids and Its Relevance to Toxicity. AB - This study investigated dioxin-induced changes in metabolomes in pubertal rat excrement. The administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or restricting dietary intake (pair-fed group) markedly altered the metabolomic profile including lipids, hormones, and vitamins in the urine and feces. TCDD caused an increase in the fecal chenodeoxycholic acid and taurocholic acid content and in urinary adrenaline and 17beta-estradiol, while the urinary melatonin level was reduced by TCDD. These changes were not observed in the pair fed group. In accordance with the elevated level of fecal bile acids, TCDD reduced the intestinal expression of the apical sodium-dependent bile salt transporter, which plays a role in resorbing bile acids from the bile duct. In addition, CYP7A1, a rate-limiting enzyme for bile acid biosynthesis, was attenuated by TCDD treatment, although TCDD induced hepatic CYP8B1, an enzyme essential for cholic acid synthesis. Supplying cholic acid or chenodeoxycholic acid to TCDD-exposed rats tended to restore the TCDD-produced reduction in serum triglycerides, whereas no similar trend was observed in wasting syndrome and lipid accumulation in the liver. These results suggest that: 1) TCDD alters the circulating levels of bile acids and hormones via a mechanism distinct from an attenuation in dietary intake, although the majority of TCDD-induced changes in nutrient contents in the excrement is due to a reduction in food intake; and 2) TCDD facilitates the excretion of bile acids and disrupts their biosynthesis, resulting in the disturbance of lipid homeostasis. PMID- 26424015 TI - Saturated Metabolism of Voriconazole N-Oxidation Resulting in Nonlinearity of Pharmacokinetics of Voriconazole at Clinical Doses. AB - Metabolic saturation of voriconazole based on the trough plasma concentrations of voriconazole and its major metabolite N-oxide were evaluated according to CYP2C19 genotypes in 58 Japanese patients receiving voriconazole (median dose; 200 mg twice daily) for prophylaxis or treatment. Predose trough plasma concentrations of voriconazole and N-oxide were monitored on day 5 d or later after initiation of voriconazole treatment. Large interindividual variations in trough plasma concentrations of voriconazole and N-oxide were observed. Dose-normalized trough plasma concentrations of voriconazole were strongly correlated with its absolute trough concentrations, and the straight regression line between them intersected close to the origin of the coordinates. No significant correlation was observed between the trough plasma concentrations of voriconazole and N-oxide. The inverse value of the metabolic ratio of N-oxide to voriconazole was strongly correlated with the absolute trough voriconazole concentrations. No significant differences in the trough plasma concentrations of voriconazole and N-oxide or the metabolic ratio of N-oxide to voriconazole between the CYP2C19 genotypes were observed. Saturated metabolism of voriconazole N-oxidation rather than CYP2C19 genotypes contributed to the nonlinear pharmacokinetics. The metabolic process converting voriconazole to N-oxide was saturated at the clinical dose. PMID- 26424016 TI - Borrelidin Isolated from Streptomyces sp. Inhibited Adipocyte Differentiation in 3T3-L1 Cells via Several Factors Including GATA-Binding Protein 3. AB - An inhibitor of 3T3-L1 adipocyte differentiation was isolated from Streptomyces sp. TK08330 and identified by spectroscopy as the 18-membered macrolide borrelidin. Treatment with 1.0 MUM borrelidin suppressed intracellular lipid accumulation by 80% and inhibited the expression of adipocyte-specific genes. Borrelidin suppressed the mRNA expression of two master regulators of adipocyte differentiation, peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein (C/EBPalpha). Studies on well-known upstream regulators of PPARgamma revealed that borrelidin down-regulated C/EBPdelta mRNA expression but did not affect expression of C/EBPbeta. Borrelidin increased mRNA expression of negative regulators of differentiation such as GATA-binding protein (GATA) 3, Kruppel-like factor (KLF) 3 and KLF7, as well as positive regulators, KLF4, KLF6 and KLF15, at early stages of differentiation. To elucidate a primary mediator of borrelidin differentiation inhibitory activity, small interfering RNA (siRNA) transfection experiments were performed. The mRNA expression of PPARgamma, which was down-regulated by borrelidin, was not changed by KLF3 and KLF7 siRNA treatment. In contrast, expression of PPARgamma in GATA-3 siRNA treated cells was not significantly different from that of control siRNA-treated cells. Borrelidin significantly inhibited lipid accumulation in control siRNA treated cells, and treatment with GATA-3 siRNA slightly reduced the inhibitory effect of borrelidin. These results indicate that borrelidin inhibited adipocyte differentiation partially via GATA-3. PMID- 26424017 TI - PI3-Kinase Inhibitor LY294002 Repressed the Expression of Thrombin-Activatable Fibrinolysis Inhibitor in Human Hepatoma HepG2 Cells. AB - Thrombin-activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase B-like proenzyme biosynthesized in the liver and released into the blood circulation. Activated TAFI (TAFIa) has been implicated as an important player in maintaining the balance between blood coagulation and fibrinolysis. In the present study, regulation of TAFI (CPB2) gene expression was investigated using cultured human hepatoma HepG2 cells. HepG2 cells were treated with the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, and the levels of TAFI antigen and CPB2 mRNA were measured. HepG2 cells treated with LY29400 decreased their release of TAFI antigen into the conditioned medium (CM). In parallel, there were decreased levels of CPB2 mRNA and TAFI antigen in the cells. However, CPB2 gene promoter activity was not influenced by treatment of the cells with LY294002. The half life of the CPB2 transcript was shortened by treatment with LY294002 compared with control. The present results suggest that the PI3K inhibitor LY294002 suppresses expression of TAFI, a prothrombotic factor, by decreasing the stability of CPB2 transcripts. PMID- 26424018 TI - Vasodilator Effects of Elcatonin, a Synthetic Eel Calcitonin, on Retinal Blood Vessels in Rats. AB - The aim of this study was to examine the effects of elcatonin, a synthetic derivative of eel calcitonin, on rat retinal blood vessels, and to determine how diabetes affects the retinal vascular responses. Ocular fundus images were captured with an original high-resolution digital fundus camera in vivo. The retinal vascular responses were evaluated by measuring the diameter of retinal blood vessels contained in the digital images. Both systemic blood pressure and heart rate were continuously recorded. Elcatonin increased the diameter of retinal blood vessels but decreased mean blood pressure in a dose-dependent manner, whereas it had no significant effect on heart rate. A diminished retinal vasodilator response and significant pressor response to elcatonin were observed in rats injected intravenously with N(G)-nitro-L-arginine methyl ester, a nitric oxide (NO) synthase inhibitor. Intravitreal injection of indomethacin, a non selective cyclooxygenase (COX) inhibitor, and SQ22536, an adenylyl cyclase inhibitor, markedly attenuated the vasodilator effects of elcatonin on retinal blood vessels. The retinal vasodilator responses to elcatonin were unaffected 2 weeks after the induction of diabetes by a combination of streptozotocin treatment and D-glucose feeding. These results suggest that elcatonin dilates rat retinal blood vessels via NO- and COX-dependent mechanisms and that the adenylyl cyclase-adenosine 3',5'-cyclic monophosphate system plays a major role in the vasodilator mechanisms. The retinal vasodilatory effects of elcatonin seem to be preserved at early stages of diabetes. PMID- 26424019 TI - Excessive Interleukin 18 Relate the Aggravation of Indomethacin-Induced Intestinal Ulcerogenic Lesions in Adjuvant-Induced Arthritis Rat. AB - It is well known that rheumatoid arthritis patients taking nonsteroidal anti inflammatory drugs (NSAIDs) are more susceptible to NSAIDs-induced gastroenteropathy in comparison with other patients. In this study we demonstrate that expression levels of interleukin (IL)-18 are related to aggravation of intestinal ulcerogenic lesions in adjuvant-induced arthritis (AA) rats following oral administration of indomethacin. AA rats were administered oral indomethacin (40 mg/kg) and killed under deep isoflurane anesthesia after 24 h. The small intestinal mucosa was then examined. Oral administration of indomethacin caused hemorrhagic lesions in the small intestinal mucosa of AA rats, and the lesion score of AA rats 24 h after indomethacin treatment was approximately 5.6-fold higher than for normal rats administered indomethacin. IL-18 expression in the small intestinal mucosa of AA rats administered indomethacin was also higher in comparison with normal rats receiving indomethacin. In addition, interferon-gamma and nitric oxide levels in the small intestinal mucosa of AA rats were increased following oral administration of indomethacin. It is possible that IL-18 expression in AA rats renders the small intestinal mucosa more sensitive to indomethacin, and that IL-18 may play a role in aggravating intestinal ulcerogenic lesions in AA rats treated with this drug. PMID- 26424020 TI - Obligatory Role of Early Ca(2+) Responses in H2O2-Induced beta-Cell Apoptosis. AB - Our previous study using apoptosis analysis suggested that Ca(2+) release through inositol 1,4,5-trisphosphate (IP3) receptors and the subsequent Ca(2+) influx through store-operated channels (SOCs) constitute a triggering signal for H2O2 induced beta-cell apoptosis. In the present study, we further examined the obligatory role of early Ca(2+) responses in beta-cell apoptosis induction. H2O2 induced elevation of the cytosolic Ca(2+) concentration ([Ca(2+)]c) consisting of two phases: an initial transient [Ca(2+)]c elevation within 30 min and a slowly developing one thereafter. The first phase was almost abolished by 2 aminoethoxydiphenylborate (2-APB), which blocks IP3 receptors and cation channels including SOCs, while the second phase was only partially inhibited by 2-APB. The inhibition by 2-APB of the second phase was not observed when 2-APB was added 30 min after the treatment with H2O2. 2-APB also largely inhibited elevation of the mitochondrial Ca(2+) concentration ([Ca(2+)]m) induced by H2O2 when 2-APB was applied simultaneously with H2O2, but not when applied 30 min after H2O2 application. In addition, 2-APB inhibited the release of mitochondrial cytochrome c to the cytosol induced by H2O2 when 2-APB was applied simultaneously with H2O2 but not 30 min post-treatment. H2O2-induced [Ca(2+)]m elevation and cell death were not inhibited by Ru360, an inhibitor of the mitochondrial calcium uniporter (MCU). These results suggest that the H2O2-induced initial [Ca(2+)]c elevation, occurring within 30 min and mediated by Ca(2+) release through IP3 receptors and subsequent Ca(2+) influx through SOCs, leads to [Ca(2+)]m elevation, possibly through a mechanism independent of MCU, thereby inducing cytochrome c release and consequent apoptosis. PMID- 26424021 TI - Biological Responsiveness and Metabolic Performance of Liposome-Encapsulated Hemoglobin (Hemoglobin-Vesicles) in Apolipoprotein E-Deficient Mice after Massive Intravenous Injection. AB - The hemoglobin-vesicle (HbV), a vesicle in which a concentrated human hemoglobin solution is encapsulated, was developed as an artificial oxygen carrier. Although HbV has a favorable safety, metabolic, and excretion performance in healthy animals, the effect of a massive amount of HbV, which also contains a large amount of a lipid component including cholesterol, on physiological response and metabolic performance under hyperlipidemic conditions is unclear. The aim of this study was to evaluate whether administration of HbV causes toxicity in apolipoprotein E-deficient mice (hyperlipidemic model mice). Apolipoprotein E deficient mice were given a single injection of HbV (2000 mg hemoglobin/kg), and physiological responses and metabolic profiles were monitored for 14 d thereafter. All the mice tolerated the massive amount of HbV and survived, and adequate biocompatibility was observed. Serum biochemical parameters indicate that liver and kidney function were not remarkably affected, and morphological changes in the liver and spleen were negligible. Lipid parameters in serum were significantly increased until 3 d after HbV administration, but recovered within 7 d after the administration. In a pharmacokinetic study, HbV was mainly found distributed in the liver and spleen, and disappeared from the body within 14 d. In conclusion, even under conditions of hyperlipidemia, a massive dose of HbV and its components resulted in favorable biological compatibility, metabolic, and excretion profiles. These findings provide further support for the safety of HbV for clinical use. PMID- 26424022 TI - Preparation of a Monoclonal Antibody against Gintonin and Its Use in an Enzyme Immunoassay. AB - Gintonin is a novel ginseng-derived G protein-coupled lysophosphatidic acid (LPA) receptor ligand. Gintonin elicits an [Ca(2+)]i transient in animal cells via activation of LPA receptors. In vitro studies have shown that gintonin regulates various calcium-dependent ion channels and receptors. In in vivo studies, gintonin elicits anti-Alzheimer's disease activity through the activation of the non-amyloidogenic pathway and anti-metastatic effects through the inhibition of autotaxin. However, a method for gintonin quantitation in ginseng has not been developed. In the present study, we developed an enzyme immunoassay (EIA) to measure gintonin. A monoclonal antibody was raised in a mouse using gintonin as the immunogen, and an indirect competitive EIA was used to measure gintonin. The working range was 0.01-10 ug per assay. The anti-gintonin monoclonal antibody did not cross-react with the ginsenosides Ra, Rb1, Rb2, Rc, Rd, Re, Rf, Rg1, and Rg3 or with LPAs such as LPA C16:0, LPA C18:0, LPA C18:1, and LPA C18:2. Using a standard curve, we measured the amount of gintonin in various ginseng extract fractions. Interestingly, we only detected a little amount of gintonin in conventional hot water extracts of Korean red ginseng. However, we can measure gintonin after ethanol extraction of Korean red ginseng marc. Thus, gintonin can be extracted from ginseng with ethanol but not water, and the remaining Korean red ginseng marc can be used to obtain gintonin. These results indicate that the EIA with the anti-gintonin monoclonal antibody can be used to quantify gintonin in various ginseng preparations, including commercial ginseng products. PMID- 26424023 TI - Analysis of Neuropsychiatric Adverse Events in Patients Treated with Oseltamivir in Spontaneous Adverse Event Reports. AB - There have been concerns that oseltamivir causes neuropsychiatric adverse events (NPAEs). We analyzed the association of age and gender with NPAEs in patients treated with oseltamivir using a logistic regression model. NPAE data were obtained from the U.S. Food and Drug Administration Adverse Event Reporting System (2004 to 2013). The lower limit of the reporting odds ratio (ROR) 95% confidence interval (CI) of "abnormal behavior" in Japan, Singapore, and Taiwan was >=1. The effects of the interaction terms for oseltamivir in male patients aged 10-19 years were statistically significant. The adjusted ROR of "abnormal behavior" was 96.4 (95% CI, 77.5-119.9) in male patients aged 10-19 years treated with osletamivir. In female patients, the results of the likelihood ratio test for "abnormal behavior" were not statistically significant. The adjusted NPAE RORs were increased in male and female patients under the age of 20 years. Oseltamivir use could be associated with "abnormal behavior" in males aged 10-19 years. After considering the causality restraints of the current analysis, further epidemiological studies are recommended. PMID- 26424024 TI - Penetration of Ufenamate into Intact, Stripped, or Delipidized Skin Using Different Vehicles. AB - The purpose of this study was to clarify the effect of skin condition on skin penetration of the very high lipophilic drug, ufenamate (UF). UF was applied to stripped or delipidized skin using liquid paraffin (LP) or purified water containing polysorbate 80 at a dose of 2 uL/cm(2). We found that UF penetration into intact and stripped skin using a water vehicle was respectively 5 and 10 times higher than that using LP. UF is freely soluble in oil and insoluble in water; thus, activity in water is higher than that in LP. Therefore, it is useful to use a water-based vehicle for both intact sites and those with defective stratum corneum (SC). Conversely, we found that delipidization of SC decreased the penetration of UF significantly with both LP and water, and the amount measured in the epidermis was 1 ug/cm(2) with both vehicles. This indicates that UF is not suitable for so-called "dry skin." This study revealed clinically relevant differences in the penetration of UF into intact, stripped, or delipidized skin conditions. PMID- 26424025 TI - Evaluation of Phosphatidylserine-Specific Peptide-Conjugated Liposomes Using a Model System of Malaria-Infected Erythrocytes. AB - Malaria is one of the most prevalent parasitic diseases and is most widespread in tropical regions. The malarial parasite grows and reproduces in erythrocytes during its life cycle, resulting in programmed erythrocyte death, termed eryptosis. Lipid scrambling, which occurs following the exposure of anionic lipids such as phosphatidylserine (PS) on the outer surface of erythrocytes, is a characteristic physical change that occurs early during eryptosis. Here, we prepared "PS specific peptide (PSP)"-conjugated liposomes (PSP-liposomes) and investigated whether PSP-liposomes hold promise as a novel strategy for actively targeting eryptosis. Eryptosis was induced by exposing red blood cells (RBCs) to ionomycin, a known calcium ionophore. When PSP liposomes were mixed with either RBCs or RBCs undergoing eryptosis (E-RBCs), the amount of PSP-liposome bound to E RBCs was much higher than the amount bound to RBCs. However, the amount of PSP liposome bound to E-RBCs was significantly inhibited by the presence of annexin V protein, which binds specifically to PS. These results suggest that PSP-liposomes could be an effective drug nanocarrier for treating E-RBCs and malaria-infected erythrocytes. PMID- 26424026 TI - Preparation of Antibodies and Development of an Enzyme-Linked Immunosorbent Assay for the Tyrosine Kinase Inhibitors Lapatinib and Nilotinib. AB - In this paper, we describe the production of the first specific antibodies against the tyrosine kinase inhibitors lapatinib and nilotinib. Anti-lapatinib antibody was obtained by immunizing rabbits with an antigen conjugated with bovine serum albumin using 3-chloro-4-((3-fluorobenzyl)oxy)aniline. Anti nilotinib antibody was produced by immunizing mice with an antigen conjugated with bovine serum albumin using 2-(5-amino-2-methylanilino)-4-(3 pyridyl)pyrimidine. The generated antibodies were used to develop highly sensitive and specific enzyme-linked immunosorbent assays (ELISAs) for lapatinib and nilotinib in human serum. The assays were capable of detecting lapatinib and nilotinib at serum concentrations as low as 40 and 8 ng/mL, respectively. Using the two ELISAs, drugs levels were easily measured in the serum of rats after a single dose oral administration of lapatinib or nilotinib. The assays are therefore expected be valuable tools for therapeutic drug monitoring in the clinical setting and pharmacokinetic studies of lapatinib and nilotinib. PMID- 26424027 TI - Pomegranate Seed Oil Exerts Synergistic Effects with trans-Resveratrol in a Self nanoemulsifying Drug Delivery System. AB - Pomegranate seed oil (PSO) has diverse bioactivities. It was hyphothesized that if PSO were employed to construct a trans-resveratrol-loaded self-nanoemulsifying drug delivery system (RES SNEDDS-PSO), not only could PSO serve as an oil phase but also exert synergistic effects with resveratrol to yield better therapeutic outcomes. In this study, we prepared RES SNEDDS-PSO for the first time to validate that hypothesis. The anti-inflammatory and anticancer activities of RES SNEDDS-PSO were compared with another SNEDDS composed of oil phase isopropyl palmitate (RES SNEDDS-IP). The results showed that upon exposure to a 10-fold amount of water, RES SNEDDS-PSO was converted into nanoemulsions with a mean size of 44 nm. Nanoemulsions enhanced the water solubility of resveratrol by 20-fold, significantly improved resveratrol stability in intestinal fluid, and slowed the decomposition of resveratrol in water by 1-fold. An in vivo anti-infection test showed that the degree of inflammatory swelling in mice given RES SNEDDS-PSO was only 60 and 76% that of the group fed with RES SNEDDS-IP at doses of 10 and 20 mg/kg, respectively. An in vitro anticancer study showed that the inhibitory rate of RES SNEDDS-PSO against MCF-7 breast cancer cells was 2.03- and 1.24-fold that of RES SNEDDS-IP at a concentration of 12.5 and 25 ug/mL, respectively. This study demonstrated that the newly developed SNEDDS may be a prospective formulation in the functional food and clinical fields. PMID- 26424028 TI - Antimelanogenic Effects of Picrionoside A Isolated from the Leaves of Korean Ginseng. AB - This study was initiated to isolate active metabolites from the leaves of Panax ginseng. Among them, picrionoside A, a megastigmane glucoside, was isolated from the leaves of P. ginseng C. A. MAYER and its chemical structure was determined based on spectroscopic methods, including FAB-MS, one-dimensional (1D)-NMR, 2D NMR, and IR spectroscopy. Picrionoside A from P. ginseng has not been investigated previously, and its biological or pharmaceutical activities have not been reported elsewhere. The IC50 value of mushroom tyrosinase-inhibitory activity of picrionoside A was 9.8 uM, and the rate of inhibition of synthesized melanin content in melan-a cells was 17.1% at a concentration of 80 uM without cytotoxicity. Furthermore, picrionoside A dramatically reduced body pigmentation in the zebrafish model. Taken together, the results suggest that picrionoside A isolated from the leaves of P. ginseng may be an effective skin-whitening agent that could be a potent candidate material in the cosmetic industry. PMID- 26424029 TI - Conformational Effects of the A21G Flemish Mutation on the Aggregation of Amyloid beta Peptide. AB - Among the various hereditary mutants of amyloid beta (Abeta) in familial Alzheimer's disease (AD), the A21G Flemish-type mutant has unique properties showing a low aggregation propensity but progressive deposition in vascular walls. Moreover, in contrast to other familial AD cases that show extensive Abeta1-42 deposition in the brain, patients with Flemish AD predominantly exhibit the deposition of the Abeta1-40 isoform. Here we report the structural characterization of the Flemish-type mutant (A21G) in comparison with the wild type Abeta1-40 peptide to examine the possible effects of the A21G mutation on the conformation of the Abeta1-40 isoform. The kinetic analysis of the aggregation of the peptides monitored by thioflavin T fluorescence measurement indicates that the mutation precludes the initial nucleation process of amyloid fibril formation by Abeta1-40. Spectroscopic data indicate that the Flemish-type mutant bound to aqueous micelles composed of lyso-GM1, in which the mobile N terminal segment is tethered through the C-terminal helical segment, has reduced alpha-helical structure compared to the wild-type peptide. Our findings suggest that the mutational perturbation to the membrane binding properties is coupled with the changes in nucleation behavior of Abeta during its fibril formation. PMID- 26424030 TI - Simultaneous Determination Method of Epoxyeicosatrienoic Acids and Dihydroxyeicosatrienoic Acids by LC-MS/MS System. AB - Epoxyeicosatrienoic acids (EETs) are produced primarily by CYPs from arachidonic acid (AA) and then further metabolized to the corresponding dihydroxyeicosatrienoic acids (DHETs). EETs play important roles in physiological processes such as regulating vasodilation and inflammation. Thus, the drug inhibition of CYP-mediated AA metabolism could reduce production of EETs, potentially resulting in adverse cardiovascular events. The aim of this study was to develop a simple method to simultaneously determine the concentrations of both EETs and DHETs using a conventional LC-MS/MS system to evaluate drug-endogenous substance interactions, including eicosanoids. Eight eicosanoids (5,6-EET, 8,9 EET, 11,12-EET, 14,15-EET, 5,6-DHET, 8,9-DHET, 11,12-DHET, and 14,15-DHET) were detected with their corresponding deuterium-labeled eicosanoids as internal standards. The samples were purified by solid-phase extraction columns. Liquid chromatographic separation was achieved on a C18 column. DHETs and EETs were eluted at 4-7 and 18-26 min, respectively. The weighted (1/y(2)) calibration curves were linear over a range of 5-2000 nmol/L for EETs and 2-2000 nmol/L for DHETs. In quality control (QC) samples, the recoveries of eicosanoids were 95.2 118%. The intra-day precisions were within 6% in all three QC samples, and the inter-day precisions were <16.7% at 50 nmol/L, <8.6% at 200 nmol/L, and <9.8% at 1000 nmol/L. We have applied this method for the determination of the eicosanoid levels in samples from incubation studies of AA by using human recombinant CYP enzyme (rCYP), and confirmed that the method has sensitivity sufficient for assessment of rCYP incubation study. PMID- 26424031 TI - Comments on torsional testing. PMID- 26424032 TI - Quantitative Bioimaging to Investigate the Uptake of Mercury Species in Drosophila melanogaster. AB - The uptake of mercury species in the model organism Drosophila melanogaster was investigated by elemental bioimaging using laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS). The mercury distribution in Drosophila melanogaster was analyzed for the three species mercury(II) chloride, methylmercury chloride, and thimerosal after intoxication. A respective analytical method was developed and applied to the analysis of the entire Drosophila melanogaster first, before a particular focus was directed to the cerebral areas of larvae and adult flies. For quantification of mercury, matrix matched standards based on gelatin were prepared. Challenges of spatially dissolved mercury determination, namely, strong evaporation issues of the analytes and an inhomogeneous distribution of mercury in the standards due to interactions with cysteine containing proteins of the gelatin were successfully addressed by complexation with meso-2,3-dimercaptosuccinic acid (DMSA). No mercury was detected in the cerebral region for mercury(II) chloride, whereas both organic species showed the ability to cross the blood-brain barrier. Quantitatively, the mercury level in the brain exceeded the fed concentration indicating mercury enrichment, which was approximately 3 times higher for methylmercury chloride than for thimerosal. PMID- 26424033 TI - Correlates and predictors of loneliness in older-adults: a review of quantitative results informed by qualitative insights. AB - BACKGROUND: Older persons are particularly vulnerable to loneliness because of common age-related changes and losses. This paper reviews predictors of loneliness in the older population as described in the current literature and a small qualitative study. METHODS: Peer-reviewed journal articles were identified from psycINFO, MEDLINE, and Google Scholar from 2000-2012. Overall, 38 articles were reviewed. Two focus groups were conducted asking older participants about the causes of loneliness. RESULTS: Variables significantly associated with loneliness in older adults were: female gender, non-married status, older age, poor income, lower educational level, living alone, low quality of social relationships, poor self-reported health, and poor functional status. Psychological attributes associated with loneliness included poor mental health, low self-efficacy beliefs, negative life events, and cognitive deficits. These associations were mainly studied in cross-sectional studies. In the focus groups, participants mentioned environmental barriers, unsafe neighborhoods, migration patterns, inaccessible housing, and inadequate resources for socializing. Other issues raised in the focus groups were the relationship between loneliness and boredom and inactivity, the role of recent losses of family and friends, as well as mental health issues, such as shame and fear. CONCLUSIONS: Future quantitative studies are needed to examine the impact of physical and social environments on loneliness in this population. It is important to better map the multiple factors and ways by which they impact loneliness to develop better solutions for public policy, city, and environmental planning, and individually based interventions. This effort should be viewed as a public health priority. PMID- 26424034 TI - Experimental and Calculated Spectra of pi-Stacked Mild Charge-Transfer Complexes: Jet-Cooled Perylene.(Tetrachloroethene)n, n = 1,2. AB - The S0 <-> S1 spectra of the mild charge-transfer (CT) complexes perylene.tetrachloroethene (P.4ClE) and perylene.(tetrachloroethene)2 (P.(4ClE)2) are investigated by two-color resonant two-photon ionization (2C-R2PI) and dispersed fluorescence spectroscopy in supersonic jets. The S0 -> S1 vibrationless transitions of P.4ClE and P.(4ClE)2 are shifted by deltanu = -451 and -858 cm(-1) relative to perylene, translating to excited-state dissociation energy increases of 5.4 and 10.3 kJ/mol, respectively. The red shift is ~30% larger than that of perylene.trans-1,2-dichloroethene; therefore, the increase in chlorination increases the excited-state stabilization and CT character of the interaction, but the electronic excitation remains largely confined to the perylene moiety. The 2C-R2PI and fluorescence spectra of P.4ClE exhibit strong progressions in the perylene intramolecular twist (1au) vibration (42 cm(-1) in S0 and 55 cm(-1) in S1), signaling that perylene deforms along its twist coordinate upon electronic excitation. The intermolecular stretching (Tz) and internal rotation (Rc) vibrations are weak; therefore, the P.4ClE intermolecular potential energy surface (IPES) changes little during the S0 <-> S1 transition. The minimum-energy structures and inter- and intramolecular vibrational frequencies of P.4ClE and P.(4ClE)2 are calculated with the dispersion-corrected density functional theory (DFT) methods B97-D3, omegaB97X-D, M06, and M06-2X and the spin-consistent-scaled (SCS) variant of the approximate second-order coupled cluster method, SCS-CC2. All methods predict the global minima to be pi-stacked centered coplanar structures with the long axis of tetrachloroethene rotated by tau ~ 60 degrees relative to the perylene long axis. The calculated binding energies are in the range of -D0 = 28-35 kJ/mol. A second minimum is predicted with tau ~ 25 degrees , with ~1 kJ/mol smaller binding energy. Although both monomers are achiral, both the P.4ClE and P.(4ClE)2 complexes are chiral. The best agreement for adiabatic excitation energies and vibrational frequencies is observed for the omegaB97X-D and M06-2X DFT methods. PMID- 26424035 TI - Expanding Indications of Gastric Electrical Stimulation. PMID- 26424036 TI - Modulation of the Bitter Taste to Reduce Calorie Intake. PMID- 26424037 TI - Is Interstitial Cells of Cajal-opathy Present in Gastroparesis? AB - Gastroparesis (GP), defined as delayed gastric emptying in the absence of any mechanical obstruction, is a challenging clinical condition, mainly because of limited treatment options. Studies in animal models of delayed gastric emptying as well as patients with gastroparesis revealed depletion or ultrastructural changes of interstitial cells of Cajal (ICC) in the gastric tissue, recently termed ICC-opathy. ICC are the pacemakers of the gastrointestinal tract and are involved in the transmission of the neuronal signaling to the smooth muscles. Therefore, lack of ICC could be one explanation of delayed gastric emptying in gastroparetic patients. How frequently ICC changes are observed in gastroparesis is not yet clear. In this review, the data on gastric ICC counts and morphology in animal models and patients with gastroparesis are discussed. PMID- 26424038 TI - Targeting Ion Channels: An Important Therapeutic Implication in Gastrointestinal Dysmotility in Patients With Spinal Cord Injury. AB - Gastrointestinal (GI) dysmotility is a severe, and common complication in patients with spinal cord injury (SCI). Current therapeutic methods using acetylcholine analogs or laxative agents have unwanted side effects, besides often fail to have desired effect. Various ion channels such as ATP-sensitive potassium (KATP) channel, calcium ions (Ca(2+))-activated potassium ions (K(+)) channels, voltage-sensitive Ca(2+) channels and chloride ion (Cl(-)) channels are abundantly expressed in GI tissues, and play an important role in regulating GI motility. The release of neurotransmitters from the enteric nerve terminal, innervating GI interstitial cells of Cajal (ICC), and smooth muscle cells (SMC), causes inactivation of K(+) and Cl(-) channels, increasing Ca(2+) influx into cytoplasm, resulting in membrane depolarization and smooth muscle contraction. Thus, agents directly regulating ion channels activity either in ICC or in SMC may affect GI peristalsis and would be potential therapeutic target for the treatment of GI dysmotility with SCI. PMID- 26424039 TI - Association of the Extent of Atrophic Gastritis With Specific Dyspeptic Symptoms. AB - BACKGROUND/AIMS: It remains unclear whether atrophic gastritis can affect dyspeptic symptoms. We aimed to investigate whether the extent of atrophic gastritis is associated with specific dyspeptic symptoms. METHODS: Consecutive adults in a routine health-checkup program were enrolled in the study. The extent of atrophic gastritis was classified into 3 groups based on the Kimura-Takemoto criteria; the gastritis with no or little atrophy (group A: C0), the gastritis with atrophy mainly in the antrum (group B: C1 and C2), and the gastritis with atrophy in the large area of the corpus (group C: C3 and O). Upper gastrointestinal symptoms were categorized into "typical reflux symptoms," "epigastric pain syndrome (EPS)-related symptoms," and "postprandial distress syndrome (PDS)-related symptoms." RESULTS: A total of 1827 patients (1009 males, mean age 45.1 years) were included in the analysis. The subgroups of atrophic gastritis were as follows: group A (n = 1218, 66.7%), group B (n = 392, 21.4%), and group C (n = 217, 11.9%). Typical reflux, EPS-related, and PDS-related symptoms were present in 10.5%, 19.8%, and 16.2% of the subjects, respectively. PDS-related and EPS-related symptoms were significantly more prevalent in the group C of male patients and the group B of female patients, respectively, compared with other groups. PDS-related and EPS-related symptoms were independently associated with the group C in males (OR, 2.123; 95% CI, 1.090 4.136) and the group B in females (OR, 2.571; 95% CI, 1.319-5.025), respectively. CONCLUSIONS: The extent of atrophic gastritis appears to affect the generation of specific dyspeptic symptoms in a gender-dependent manner. PMID- 26424040 TI - Surgical Intervention to Rescue Hirschsprung Disease in a Rat Model. AB - BACKGROUND/AIMS: Rats with a spontaneous null mutation in endothelin receptor type B or Ednrb (sl/sl; spotting lethal) lack enteric neurons in the distal bowel and usually die within the first week after birth. This early postnatal lethality limits their use for examining the potential of cell therapy to treat Hirschsprung disease, and for studies of the influence of EDNRB on the mature CNS and vascular systems. METHODS: We have developed a surgical intervention to prolong the life of the spotting lethal sl/sl rat, in which we perform a colostomy on postnatal (P) day 4-6 rats to avoid the fatal obstruction caused by the lack of colonic enteric neurons. RESULTS: The stomas remained patent and functional and the rats matured normally following surgery. Weight gains were comparable between control and Hirschsprung phenotype (sl/sl) rats, which were followed until 4 weeks after surgery (5 weeks old). We confirmed the absence of enteric neurons in the distal colon of rats whose lives were saved by the surgical intervention. CONCLUSIONS: This study provides a novel approach for studying EDNRB signalling in multiple organ systems in mature rats, including an animal model to study the efficacy of cell therapy to treat Hirschsprung disease. PMID- 26424041 TI - Molecular and Cellular Characteristics of the Colonic Pseudo-obstruction in Patients With Intractable Constipation. AB - BACKGROUND/AIMS: Chronic intestinal pseudo-obstruction (CIPO) is a disorder characterized by recurrent symptoms suggestive of obstruction such as abdominal pain, proximal distension with extremely suppressed motility in the absence of lumen-occluding lesion, whose etiology/ pathophysiology is poorly understood. In this study we investigated a functionally obstructive lesion that could underlie symptoms of CIPO. METHODS: We studied colons surgically removed from 13 patients exhibiting clinical/pathological features of pseudo-obstruction but were unresponsive to standard medical treatments. The colons were characterized morphologically, functionally and molecularly, which were compared between regions and to 28 region-matched controls obtained from colon cancer patients. RESULTS: The colons with pseudo-obstruction exhibited persistent luminal distension proximally, where the smooth muscle was hypertrophied with changes in the cell phenotypes. Distinct luminal narrowing was observed near the distal end of the dilated region, close to the splenic flexure, previously referred to as the "transition zone (TZ)" between the dilated and non-dilated loops. Circular muscles from the TZ responded less to depolarization and cholinergic stimulation, which was associated with downregulation of L-type calcium channel expression. Smooth muscle contractile protein was also downregulated. Myenteric ganglia and neuronal nitric oxide synthase (nNOS) positive cells were deficient, more severely in the TZ region. Interstitial cells of Cajal was relatively less affected. CONCLUSIONS: The TZ may be the principal site of functional obstruction, leading to proximal distension and smooth muscle hypertrophy, in which partial nNOS depletion could play a key role. The neuromuscular abnormalities probably synergistically contributed to the extremely suppressed motility observed in the colonic pseudo-obstruction. PMID- 26424042 TI - Corticotropin-releasing Factor Changes the Phenotype and Function of Dendritic Cells in Mouse Mesenteric Lymph Nodes. AB - BACKGROUND/AIMS: Dendritic cells (DCs) are a significant contributor to the pathology of numerous chronic inflammatory autoimmune disorders; however, the effects of Corticotropin-releasing factor (CRF) on intestinal DCs are poorly understood. In this study, we investigated the role of CRF in alterations of intestinal dendritic cell phenotype and function. METHODS: Mouse mesenteric lymph node dendritic cells (MLNDCs) were obtained using magnetic bead sorting. Surface expression of CRF receptor type 1 (CRF-R1) and CRF-R2 was determined by double labeling immunofluorescence and quantitative polymerase chain reaction (qPCR) and MLNDCs were subsequently exposed to CRF in the presence or absence of CRF-R1 and CRF-R2 antagonists. Expression of surface molecules (MHC-I and MHC-II) and co stimulatory molecules (CD80 and CD86) was determined by flow cytometric and western blot analyses, and the T cell stimulatory capacity of MLNDCs was evaluated by mixed lymphocyte reaction. RESULTS: Immunofluorescent staining and quatitative polymerase chain reaction indicated that both the CRF receptors (CRF R1 and CRF-2) are expressed on the surface of MLNDCs. Exposure to CRF increased the expression of MHC-II on MLNDCs as well as their capacity to stimulate T cell proliferation. MLNDCs treated with CRF-R1 antagonist exhibited a phenotype characterized by a less activated state and reduced surface expression of MHC-II, and consequently showed reduced capacity to stimulate T cells. In contrast, treatment of MLNDCs with CRF-R2 antagonist yielded an opposite result. CONCLUSIONS: CRF can alter the phenotype and function of intestinal DCs through direct action on CRF-R1 and CRF-R2, and activation of the CRF-R1 and CRF-R2 pathways yields opposing outcomes. PMID- 26424043 TI - Visceral Hypersensitivity and Altered Colonic Motility in Type 2 Diabetic Rat. AB - BACKGROUND/AIMS: Abnormal visceral sensitivity and disordered motility are common in patients with diabetes mellitus. The purpose of the present study was to investigate whether visceral sensation and bowel motility were altered in a rat model of type 2 diabetes mellitus accompanied by weight loss. METHODS: A type 2 diabetic rat model in adulthood was developed by administrating streptozotocin (STZ; 90 mg/kg, i.p.) to neonatal rats. Eight weeks after STZ administration, rats with blood glucose level of 200 mg/dL or higher were selected and used as diabetic group (n = 35) in this study. Abdominal withdrawal reflex and arterial pulse rate were measured to examine visceral nociception induced by colorectal distension (0.1-1.0 mL). The amplitude, frequency, and area under the curve (AUC) of spontaneous phasic contractions of colonic circular muscles were recorded in vitro to examine colonic motility. RESULTS: STZ-treated diabetic rats gained significantly less weight for 8 weeks than control (P < 0.01). Forty-eight percent of the diabetic rats showed enhanced visceral nociceptive response to colorectal distension. Diabetic rats did not differ from control rats in colorectal compliance. However, the frequency and AUC, not the amplitude, of colonic spontaneous contraction in vitro was significantly decreased in diabetic rats compared to control rats (P < 0.01 in frequency and P < 0.05 in AUC). CONCLUSIONS: These results demonstrate visceral hypersensitivity and colonic dysmotility in a rat model of type 2 diabetes mellitus accompanied by weight loss. PMID- 26424046 TI - Clinical Significance of Esophageal Hypertensive Peristaltic Contractions on High resolution Manometry(Neurogastroenterol Motil 2015;27:229-236). PMID- 26424045 TI - Dysmotility Symptoms Are Independently Associated With Weight Change: A Population-based Study of Australian Adults. AB - BACKGROUND/AIMS: Weight loss is a recognized alarm symptom for organic gastrointestinal (GI) disease, yet the association between weight change (loss or gain) and specific GI symptoms remains poorly described. We assess the associations between GI symptoms and weight change in a population-based sample of Australian adults. METHODS: The prevalence of 26 GI symptoms was determined by a postal survey to 5000 residents in western Sydney, Australia (60% response rate). These were classified a priori into 5 symptom groups-abdominal pain, esophageal symptoms, dysmotility symptoms, diarrhea and constipation. Weight change was measured by two items which assessed weight loss and weight gain. Clinically relevant weight change was defined as a loss or gain of 3 or more kilograms in the past 3 months. RESULTS: Prevalence estimates for clinically relevant weight loss and gain in the past 3 months were 10.3% and 8.1%, respectively. When the 5 symptom groups were evaluated simultaneously, the dysmotility symptoms of fullness after meals emerged as a predictor of both weight loss (OR, 1.57; 95% CI, 1.32-1.88; P < 0.001) and weight gain (OR, 0.85; 95% CI, 0.72-0.99; P = 0.040), which also included bloating (OR, 1.64; 95% CI 1.46-1.84; P < 0.001). The associations remained significant following adjustment for socio-economic status, body mass index, and eating behaviors. CONCLUSIONS: Specific dysmotility symptoms are independently predictive of both weight loss and weight gain. Different pathogenic mechanisms may be involved. PMID- 26424044 TI - Serum Response Factor Is Essential for Prenatal Gastrointestinal Smooth Muscle Development and Maintenance of Differentiated Phenotype. AB - BACKGROUND/AIMS: Smooth muscle cells (SMCs) characteristically express serum response factor (SRF), which regulates their development. The role of SRF in SMC plasticity in the pathophysiological conditions of gastrointestinal (GI) tract is less characterized. METHODS: We generated SMC-specific Srf knockout mice and characterized the prenatally lethal phenotype using ultrasound biomicroscopy and histological analysis. We used small bowel partial obstruction surgeries and primary cell culture using cell-specific enhanced green fluorescent protein (EGFP) mouse lines to study phenotypic and molecular changes of SMCs by immunofluorescence, Western blotting, and quantitative polymerase chain reaction. Finally we examined SRF change in human rectal prolapse tissue by immunofluorescence. RESULTS: Congenital SMC-specific Srf knockout mice died before birth and displayed severe GI and cardiac defects. Partial obstruction resulted in an overall increase in SRF protein expression. However, individual SMCs appeared to gradually lose SRF in the hypertrophic muscle. Cells expressing low levels of SRF also expressed low levels of platelet-derived growth factor receptor alpha (PDGFRalpha(low)) and Ki67. SMCs grown in culture recaptured the phenotypic switch from differentiated SMCs to proliferative PDGFRalpha(low) cells. The immediate and dramatic reduction of Srf and Myh11 mRNA expression confirmed the phenotypic change. Human rectal prolapse tissue also demonstrated significant loss of SRF expression. CONCLUSIONS: SRF expression in SMCs is essential for prenatal development of the GI tract and heart. Following partial obstruction, SMCs down-regulate SRF to transition into proliferative PDGFRalpha(low) cells that may represent a phenotype responsible for their plasticity. These findings demonstrate that SRF also plays a critical role in the remodeling process following GI injury. PMID- 26424047 TI - Opioid-induced Lower Esophageal Sphincter Dysfunction. PMID- 26424048 TI - Measuring Gastrointestinal Electrical Activity With Extracellular Electrodes: Author's Reply. PMID- 26424049 TI - Polyamine-oligonucleotide conjugates: a promising direction for nucleic acid tools and therapeutics. AB - Chemical modification and/or the conjugation of small functional molecules to oligonucleotides have significantly improved their biological and biophysical properties, addressing issues such as poor cell penetration, stability to nucleases and low affinity for their targets. Here, the authors review the literature reporting on the biophysical, biochemical and biological properties of one particular class of modification - polyamine-oligonucleotide conjugates. Naturally derived and synthetic polyamines have been grafted onto a variety of oligonucleotide formats, including antisense oligonucleotides and siRNAs. In many cases this has had beneficial effects on their properties such as target hybridization, nuclease resistance, cellular uptake and activity. Polyamine oligonucleotide conjugation, therefore, represents a promising direction for the further development of oligonucleotide-based therapeutics and tools. PMID- 26424051 TI - Creation of identical multiple focal spots with prescribed axial distribution. AB - We present a scheme for the construction of coaxially equidistant multiple focal spots with identical intensity profiles for each individual focus and a predetermined number and spacing. To achieve this, the radiation field from an antenna is reversed and then gathered by high numerical aperture objective lenses. Radiation patterns from three types of line sources, i.e., the electric current, magnetic current and electromagnetic current distributions, with cosine squared taper are respectively employed to generate predominately longitudinally polarized bright spots, azimuthally polarized doughnuts, and focal spots with a perfect spherically symmetric intensity distribution. The required illuminations at the pupil plane of a 4Pi focusing configuration for the creation of these identical multiple focal spots can be easily derived by solving the inverse problem of the antenna radiation field. These unique focal field distributions may find potential applications in laser direct writing and optical microscopy, as well as multiple-particle trapping, alignment, and acceleration along the optical axis. PMID- 26424052 TI - An adverse event capture and management system for cancer studies. AB - BACKGROUND: Comprehensive capture of Adverse Events (AEs) is crucial for monitoring for side effects of a therapy while assessing efficacy. For cancer studies, the National Cancer Institute has developed the Common Terminology Criteria for Adverse Events (CTCAE) as a required standard for recording attributes and grading AEs. The AE assessments should be part of the Electronic Health Record (EHR) system; yet, due to patient-centric EHR design and implementation, many EHR's don't provide straightforward functions to assess ongoing AEs to indicate a resolution or a grade change for clinical trials. METHODS: At UAMS, we have implemented a standards-based Adverse Event Reporting System (AERS) that is integrated with the Epic EHR and other research systems to track new and existing AEs, including automated lab result grading in a regulatory compliant manner. Within a patient's chart, providers can launch AERS, which opens the patient's ongoing AEs as default and allows providers to assess (resolution/ongoing) existing AEs. In another tab, it allows providers to create a new AE. Also, we have separated symptoms from diagnoses in the CTCAE to minimize inaccurate designation of the clinical observations. Upon completion of assessments, a physician would submit the AEs to the EHR via a Health Level 7 (HL7) message and then to other systems utilizing a Representational State Transfer Web Service. CONCLUSIONS: AERS currently supports CTCAE version 3 and 4 with more than 65 cancer studies and 350 patients on those studies. This type of standard integrated into the EHR aids in research and data sharing in a compliant, efficient, and safe manner. PMID- 26424050 TI - Genome-wide association study identifies multiple susceptibility loci for glioma. AB - Previous genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of glioma. To identify new glioma susceptibility loci, we conducted a meta-analysis of four GWAS (totalling 4,147 cases and 7,435 controls), with imputation using 1000 Genomes and UK10K Project data as reference. After genotyping an additional 1,490 cases and 1,723 controls we identify new risk loci for glioblastoma (GBM) at 12q23.33 (rs3851634, near POLR3B, P=3.02 * 10(-9)) and non-GBM at 10q25.2 (rs11196067, near VTI1A, P=4.32 * 10(-8)), 11q23.2 (rs648044, near ZBTB16, P=6.26 * 10(-11)), 12q21.2 (rs12230172, P=7.53 * 10(-11)) and 15q24.2 (rs1801591, near ETFA, P=5.71 * 10(-9)). Our findings provide further insights into the genetic basis of the different glioma subtypes. PMID- 26424053 TI - Recent advances in Helicobacter pylori eradication. PMID- 26424056 TI - Providing a lifeline for rural doctors. PMID- 26424057 TI - Pain, pregnancy or Pilates - there is plenty to peruse. PMID- 26424054 TI - MiR-125a-5p Decreases the Sensitivity of Treg cells Toward IL-6-Mediated Conversion by Inhibiting IL-6R and STAT3 Expression. AB - The transcription factor FOXP3 is essential for the differentiation and function of regulatory T cells (Treg). It is established that the transcription factor GATA-3 is induced in Treg cells under inflammatory conditions. GATA-3 stabilizes FOXP3 levels to avoid the differentiation of Treg cells into inflammatory-like T cells. The IL-6 signal pathway influences the sensitivity of Treg cells towards instability. The mechanism of GATA-3 in regulating FOXP3 and its relation to the IL-6 pathway remains unclear. Here we report how miR-125a-5p plays an important role in regulating the conversion of Treg cells by IL-6. miR-125a-5p expression is low in Treg cells under steady state conditions and can be induced by GATA-3 to inhibit the expression of IL-6R and STAT3. This finding reveals a GATA3/miR 125a-5p/IL-6R and STAT3/FOXP3 regulatory pathway, which determines how Treg cells respond to inflammatory IL-6-rich conditions. PMID- 26424058 TI - Match of the decade: risk management of concussion versus high-speed collisions in the football codes. PMID- 26424059 TI - Co-creation: a new approach to optimising research impact? PMID- 26424060 TI - Teledermatologists' management of emergency skin conditions. PMID- 26424061 TI - Hypoadrenalism secondary to topical corticosteroid-containing skin-lightening cream: danger of over-the-counter cosmetic agents. PMID- 26424062 TI - Rural v metro: geographical differences in sports injury hospital admissions across Victoria. PMID- 26424063 TI - Recent advances in type 1 diabetes. AB - Type 1 diabetes (T1D) is caused by an autoimmune attack on pancreatic beta cells that leads to insulin deficiency. The incidence of T1D in Australia has doubled over the past 20 years. T1D treatment focuses on physiological insulin replacement, aiming for near-normal blood glucose levels. Hypoglycaemia is a significant cause of morbidity and mortality in T1D. Optimal T1D management is complex, and is enhanced by empowering individuals in all aspects of managing diabetes. New technologies, including insulin pumps, continuous glucose monitors and sensor-augmented pumps, can assist people achieve better glycaemic control and reduce the risk of severe hypoglycaemia. Women with T1D can achieve significantly better outcomes during pregnancy and for their infants by planning for their pregnancy and by intensive glycaemic control. Several trials are underway that seek to identify the determinants of autoimmunity and to develop therapies that prevent T1D in at-risk individuals. Pancreatic and islet cell transplants are proven therapies, but are only offered to individuals with diabetes and renal failure (pancreas) or severe hypoglycaemia unawareness (islet cell transplants). Although T1D is still associated with considerable premature mortality, recent findings show that a significant improvement in life expectancy has occurred. PMID- 26424064 TI - Unconventional natural gas development and human health: thoughts from the United States. AB - If unconventional gas development (UGD) continues to expand in Australia, the potential health and environmental impacts should be adequately addressed and preventive public health measures should be implemented. The United States has embraced UGD and has decades of experience that could be beneficial to Australia as stakeholders debate the potential benefits and harms of the technique. Additional research on the health impacts of UGD is necessary. Baseline and trend morbidity and mortality data need to be collected to assess changes in population health over time. To date, few health or epidemiological studies have been conducted, so it remains difficult to assess actual health outcomes. In the absence of scientific consensus, there are two possible risks: failing to develop unconventional natural gas when the harms are manageable; or developing it when the harms are substantial. Many government bodies around the world have chosen to minimise the risk of the latter until the impacts of UGD are better understood. Policies should be informed by empirical evidence based on actual experience rather than assurance of best practices. There is a strong rationale for precautionary measures based on the health and environmental risks identified in the scientific literature. PMID- 26424065 TI - The stability of rural outreach services: a national longitudinal study of specialist doctors. AB - OBJECTIVE: To explore the characteristics of specialists who provide ongoing rural outreach services and whether the nature of their service patterns contributes to ongoing outreach. DESIGN, PARTICIPANTS AND SETTING: Specialist doctors providing rural outreach in a large longitudinal survey of Australian doctors in 2008, together with new entrants to the survey in 2009, were followed up to 2011. MAIN OUTCOME MEASURES: Providing outreach services to the same rural town for at least 3 years. RESULTS: Of 953 specialists who initially provided rural outreach services, follow-up data were available for 848. Overall, 440 specialists (51.9%) provided ongoing outreach services. Multivariate analysis found that participation was associated with being male (odds ratio [OR], 1.82; 95% CI, 1.28-2.60), in mid-career (45-64 years old; OR, 1.44; 95% CI, 1.04-1.99), and working in mixed, mainly private practice (OR, 1.73; 95% CI, 1.18-2.53). Specialists working only privately were less likely to provide ongoing outreach (OR 0.51; 95% CI, 0.32-0.82), whereas metropolitan and rural-based specialists were equally likely to do so. Separate univariate analysis showed travelling further to remote towns had no effect on ongoing service provision. Outreach to smaller towns was associated with improved stability. CONCLUSIONS: Around half of specialists providing rural outreach services continue to visit the same town on an ongoing basis. More targeted outreach service strategies should account for career stage and practice conditions to help sustain access. Financial incentives may increase ongoing service provision by specialists only working privately. There is some indication that outreach services delivered to smaller communities are more stable. PMID- 26424066 TI - Safety of opioid patch initiation in Australian residential aged care. AB - OBJECTIVE: To explore opioid use by aged care facility residents before and after initiation of transdermal opioid patches. DESIGN: A cross-sectional cohort study, analysing pharmacy data on individual patient supply between 1 July 2008 and 30 September 2013. SETTING: Sixty residential aged care facilities in New South Wales. PARTICIPANTS: Residents receiving an initial opioid patch during the study period. MAIN OUTCOME MEASURE: The proportion of residents who were opioid-naive in the 4 weeks prior to patch initiation was determined. In addition, the patch strength at initiation and the daily dose of transdermal patches and of additional opioids 1 month after initiation were determined. RESULTS: An opioid patch was initiated in 596 of 5297 residents (11.3%: 2.6% fentanyl, 8.7% buprenorphine) in the 60 residential aged care facilities. The mean age at initiation was 87 years, and 74% of the recipients were women. The proportion of recipients who were opioid-naive before patch initiation was 34% for fentanyl and 49% for buprenorphine. Most were initiated at the lowest available patch strength, and the dose was up-titrated after initiation. Around 15% of fentanyl users and 10% of buprenorphine users needed additional regular opioids after patch initiation. CONCLUSIONS: The results suggest some inappropriate initiation of opioid patches in Australian residential aged care facilities. Contrary to best practice, a third of residents initiated on fentanyl patches were opioid naive in the 4 weeks before initiation. PMID- 26424067 TI - Trends and characteristics of accidental and intentional codeine overdose deaths in Australia. AB - OBJECTIVES: To examine trends in codeine-related mortality rates in Australia, and the clinical and toxicological characteristics of codeine-related deaths. DESIGN AND SETTING: Analysis of prospectively collected data from the National Coronial Information System on deaths where codeine toxicity was determined to be an underlying or contributory cause of death. The study period was 2000-2013. MAIN OUTCOME MEASURES: Population-adjusted numbers (per million persons) of (1) codeine-related deaths, classified by intent (accidental or intentional); and (2) heroin- and Schedule 8 opioid-related deaths (as a comparator). RESULTS: The overall rate of codeine-related deaths increased from 3.5 per million in 2000 to 8.7 per million in 2009. Deaths attributed to accidental overdoses were more common (48.8%) than intentional deaths (34.7%), and their proportion increased during the study period. High rates of prior comorbid mental health (53.6%), substance use (36.1%) and chronic pain (35.8%) problems were recorded for these deaths. For every two Schedule 8 opioid-related deaths in 2009, there was one codeine-related death. Most codeine-related deaths (83.7%) were the result of multiple drug toxicity. CONCLUSIONS: Codeine-related deaths (with and without other drug toxicity) are increasing as the consumption of codeine-based products increases. Educational messages are needed to better inform the public about the potential harms of chronic codeine use, especially in the context of polypharmacy. PMID- 26424068 TI - Klebsiella pneumoniae liver abscess complicated by endogenous endophthalmitis: the importance of early diagnosis and intervention. PMID- 26424069 TI - Catecholamine-induced cardiomyopathy resulting from life-threatening funnel-web spider envenoming. PMID- 26424070 TI - Every year eventually becomes the year for the older person. PMID- 26424072 TI - Quantification of regional leachate variance from municipal solid waste landfills in China. AB - The quantity of leachate is crucial when assessing pollution emanating from municipal landfills. In most cases, existing leachate quantification measures only take into account one source - precipitation, which resulted in serious underestimation in China due to its waste properties: high moisture contents. To overcome this problem, a new estimation method was established considering two sources: (1) precipitation infiltrated throughout waste layers, which was simulated with the HELP model, (2) water squeezed out of the waste itself, which was theoretically calculated using actual data of Chinese waste. The two sources depended on climate conditions and waste characteristics, respectively, which both varied in different regions. In this study, 31 Chinese cities were investigated and classified into three geographic regions according to landfill leachate generation performance: northwestern China (China-NW) with semi-arid and temperate climate and waste moisture content of about 46.0%, northern China (China-N) with semi-humid and temperate climate and waste moisture content of about 58.2%, and southern China (China-S) with humid and sub-tropical/tropical climate and waste moisture content of about 58.2%. In China-NW, accumulated leachate amounts were very low and mainly the result of waste degradation, implying on-site spraying/irrigation or recirculation may be an economic approach to treatment. In China-N, water squeezed out of waste by compaction totaled 22 45% of overall leachate amounts in the first 40 years, so decreasing the initial moisture content of waste arriving at landfills could reduce leachate generation. In China-S, the leachate generated by infiltrated precipitation after HDPE geomembranes in top cover started failing, contributed more than 60% of the overall amounts over 100 years of landfilling. Therefore, the quality and placing of HDPE geomembranes in the top cover should be controlled strictly for the purpose of mitigation leachate generation. PMID- 26424073 TI - The diverse impact of advance care planning: a long-term follow-up study on patients' and relatives' experiences. AB - BACKGROUND: Advance care planning (ACP) is a process of discussing and recording patients' preferences for future care, aiming to guide healthcare decisions at the end of life (EOL). AIM: To explore nuances in the long-term impact of ACP by studying patient and relative experiences. DESIGN: A qualitative follow-up interview study. Interviews were recorded, transcribed and analysed using thematic synthesis. SETTING/PARTICIPANTS: 3 patients with a life-limiting disease (lung or heart disease), affiliated with a major Danish hospital, and 7 relatives were interviewed 1 year after participating in an ACP discussion. RESULTS: The experiences were diverse. Some patients and relatives felt 'relieved', 'more secure' and more in control due to ACP. To some, ACP had led to open communication rather than 'beating around the bush', and to spending more quality time together. However, others perceived ACP as irrelevant. Some stated that the patient's wishes had not been met regardless of ACP. Others felt that EOL questions cannot be realistically considered until 'you're in the middle of it', because many factors are involved. In one case, participating in ACP led to a patient-relative conflict, resulting in EOL issues being 'tucked away'. CONCLUSIONS: The study reveals great diversity in patient and relative experiences of ACP. The study challenges previous research which mainly emphasises ACP as a valuable tool to optimise EOL care. This study stresses the importance of awareness of the highly individual nature of preferences and needs of patients and relatives regarding information, involvement and communication about EOL care. PMID- 26424074 TI - Impact of Periconceptional Use of Nitrosatable Drugs on the Risk of Neural Tube Defects. AB - Nitrosatable drugs (NSDs) can, in the presence of nitrosating agents and highly acidic conditions, form N-nitroso compounds that have been found to be teratogenic in animal models. Using data from the Slone Epidemiology Center Birth Defects Study collected from 1998 to 2012, we compared maternal periconceptional NSD use between 334 neural tube defect cases and 7,619 nonmalformed controls. We categorized NSDs according to their functional group (secondary amine, tertiary amine, and amide). With logistic regression models, we estimated adjusted odds ratios and 95% confidence intervals. Neural tube defect risk was associated with maternal periconceptional use of secondary (adjusted odds ratio (aOR) = 1.7, 95% confidence interval (CI): 1.1, 2.4) and tertiary (aOR = 1.7, 95% CI: 1.2, 2.5) amines; an association was observed for amides, but the 95% confidence interval included the null (aOR = 1.4, 95% CI: 0.7, 2.5). Within the secondary amine group, elevated adjusted odds ratios were observed for 3 drugs but were null for the remaining medications. Increases in risk were observed for both strata of folic acid intake (<400 ug/day, >=400 ug/day), with a slightly higher risk in the >=400-ug/day stratum. Our findings support previously reported positive associations between neural tube defects and periconceptional exposure to NSDs containing a secondary or tertiary amine or amide. PMID- 26424076 TI - Assessing vibratory stimulation-induced cortical activity during a motor task--A randomized clinical study. AB - Effects of vibratory stimulation on motor performance have been widely investigated. Many theories have been applied, in order to evaluate its influence on individuals; however, very few studies have researched vibratory stimulation induced cortical behavior. The aim of the present study is to investigate behavioral changes, such as reaction time and index finger movements, as well as electrophysiological changes, using beta band absolute power, in subjects submitted to vibratory stimulation. For this study, 30 healthy subjects were randomly selected and divided into two groups, experimental and control, and were submitted to a right index finger task, before and after vibratory stimulation, which was applied to the right upper limb, while their standard cerebral activity was recorded through electroencephalogram. No significant difference was found among behavioral variables. On the other hand, beta band absolute power significantly increased in the experimental group for the C3, C4 and P4 derivations, while it decreased at P3. The results suggest that electrophysiological changes were induced by vibratory stimulation, while reaction time and task-related movements were not affected by it. PMID- 26424075 TI - Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the second-leading cause of cancer-related death worldwide, and the factors influencing HCC progression are poorly understood. Here we reveal that HCC progression via induction of epithelial mesenchymal transition (EMT) is closely associated with the expression of CD36/fatty acid translocase and elevated free fatty acid (FFA) levels. Although obesity is manifested as elevated FFA levels, the degree of EMT was not associated with the body mass index of the patients, highlighting the specific roles of CD36 and FFA uptake. Treatment of human liver cancer cell lines with FFAs exacerbated the EMT phenotype, whereas chemical inhibition of CD36 mitigated these effects. Furthermore, the Wnt and TGF-beta signaling pathways were activated upon FFA treatment, potentially acting as upstream activators of the EMT program. These results provide the first direct evidence associating CD36 and elevated FFAs with HCC progression. PMID- 26424077 TI - Tetrodotoxin suppresses thermal hyperalgesia and mechanical allodynia in a rat full thickness thermal injury pain model. AB - Burn injuries have been identified as the primary cause of injury in 5% of U.S. military personnel evacuated from Operations Iraqi Freedom and Enduring Freedom. Severe burn-associated pain is typically treated with opioids such as fentanyl, morphine, and methadone. Side effects of opioids include respiratory depression, cardiac depression, decrease in motor and cognitive function, as well as the development of hyperalgesia, tolerance and dependence. These effects have led us to search for novel analgesics for the treatment of burn-associated pain in wounded combat service members. Tetrodotoxin (TTX) is a selective voltage-gated sodium channel blocker currently in clinical trials as an analgesic. A phase 3 clinical trial for cancer-related pain has been completed and phase 3 clinical trials on chemotherapy-induced neuropathic pain are planned. It has also been shown in mice to inhibit the development of chemotherapy-induced neuropathic pain. TTX was originally identified as a neurotoxin in marine animals but has now been shown to be safe in humans at therapeutic doses. The antinociceptive effects of TTX are thought to be due to inhibition of Na(+) ion influx required for initiation and conduction of nociceptive impulses. One TTX sensitive sodium channel, Nav1.7, has been shown to be essential in lowering the heat pain threshold after burn injuries. To date, the analgesic effect of TTX has not been tested in burn-associated pain. Male Sprague-Dawley rats were subjected to a full thickness thermal injury on the right hind paw. TTX (8 MUg/kg) was administered once a day systemically by subcutaneous injection beginning 3 days post thermal injury and continued through 7 days post thermal injury. Thermal hyperalgesia and mechanical allodynia were assessed 60 and 120 min post injection on each day of TTX treatment. TTX significantly reduced thermal hyperalgesia at all days tested and had a less robust, but statistically significant suppressive effect on mechanical allodynia. These results suggest that systemic TTX may be an effective, rapidly acting analgesic for battlefield burn injuries and has the potential for replacing or reducing the need for opioid analgesics. PMID- 26424079 TI - The epidemiology of sepsis: questioning our understanding of the role of race. AB - Race has been identified as an important risk factor for the development of sepsis and as a predictor of poor outcomes in sepsis. For example, black individuals have been demonstrated to be nearly twice as likely to develop sepsis and to have greater mortality from sepsis than white individuals. Recent data from a longitudinal cohort, which examined incident hospitalizations for infections occurring among participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, contradicts this prior research. Investigators determined that black participants were significantly less likely than white participants to present to the hospital with either infection or sepsis. Although these results are intriguing, they highlight our inadequate understanding of the relationship between race and sepsis and motivate the need for higher quality epidemiologic research to isolate the true role of race in the development of sepsis. PMID- 26424078 TI - The role of vancomycin in addition with colistin and meropenem against colistin sensitive multidrug resistant Acinetobacter baumannii causing severe infections in a Paediatric Intensive Care Unit. AB - BACKGROUND: Acinetobacter baumannii has been associated with high morbidity and mortality rates, even in pediatric patients. Therapeutic options are limited, especially when the strain is multidrug resistant. METHODS: Clinical and microbiological analyses of 4 cases of systemic infections caused by multi drug resistant A. baumannii treated with colistin/vancomycin combination at a Pediatric Intensive Care Unit were performed in order to explore the potential synergistic activity of colistin plus vancomycin. All the patients were treated with colistin, meropenem and vancomycin. RESULTS: Four severe infections due to MDR A. baumannii were observed. All patients treated with colistin/vancomycin combination had a positive outcome with no infection relapses. Most importantly, no significant adverse events related to the simultaneous administration of COL plus VAN were observed. In our in-vitro experiments, the synergistic effect of the combination COL plus VAN showed an early bactericidal activity even at VAN concentration of 16 mg/L, which reflects the serum trough concentrations obtained in patients. DISCUSSION: An antimicrobial strategy based on the activity of colistin plus vancomycin was in-vitro and in-vivo effective in life-threatening infections caused by multidrug-resistant A. baumannii in a Pediatric Intensive Care Unit, in the absence of adverse effects. Colistin plus vancomycin were highly synergic and bactericidal against carbapenem-resistant, colistin sensitive A. baumannii whereas the addition of meropenem did not enhance the in-vitro activity of colistin plus vancomycin. CONCLUSIONS: Our results confirm existing data on the potential synergistic activity of a therapeutic strategy including colistin plus vancomycin and provide important new clinical information for its potential use as a therapeutic option against MDR A. baumannii infections, especially in the pediatric population. PMID- 26424080 TI - JRC GMO-Amplicons: a collection of nucleic acid sequences related to genetically modified organisms. AB - The DNA target sequence is the key element in designing detection methods for genetically modified organisms (GMOs). Unfortunately this information is frequently lacking, especially for unauthorized GMOs. In addition, patent sequences are generally poorly annotated, buried in complex and extensive documentation and hard to link to the corresponding GM event. Here, we present the JRC GMO-Amplicons, a database of amplicons collected by screening public nucleotide sequence databanks by in silico determination of PCR amplification with reference methods for GMO analysis. The European Union Reference Laboratory for Genetically Modified Food and Feed (EU-RL GMFF) provides these methods in the GMOMETHODS database to support enforcement of EU legislation and GM food/feed control. The JRC GMO-Amplicons database is composed of more than 240 000 amplicons, which can be easily accessed and screened through a web interface. To our knowledge, this is the first attempt at pooling and collecting publicly available sequences related to GMOs in food and feed. The JRC GMO-Amplicons supports control laboratories in the design and assessment of GMO methods, providing inter-alia in silico prediction of primers specificity and GM targets coverage. The new tool can assist the laboratories in the analysis of complex issues, such as the detection and identification of unauthorized GMOs. Notably, the JRC GMO-Amplicons database allows the retrieval and characterization of GMO related sequences included in patents documentation. Finally, it can help annotating poorly described GM sequences and identifying new relevant GMO-related sequences in public databases. The JRC GMO-Amplicons is freely accessible through a web-based portal that is hosted on the EU-RL GMFF website. Database URL: http://gmo-crl.jrc.ec.europa.eu/jrcgmoamplicons/. PMID- 26424081 TI - Sample data processing in an additive and reproducible taxonomic workflow by using character data persistently linked to preserved individual specimens. AB - We present the model and implementation of a workflow that blazes a trail in systematic biology for the re-usability of character data (data on any kind of characters of pheno- and genotypes of organisms) and their additivity from specimen to taxon level. We take into account that any taxon characterization is based on a limited set of sampled individuals and characters, and that consequently any new individual and any new character may affect the recognition of biological entities and/or the subsequent delimitation and characterization of a taxon. Taxon concepts thus frequently change during the knowledge generation process in systematic biology. Structured character data are therefore not only needed for the knowledge generation process but also for easily adapting characterizations of taxa. We aim to facilitate the construction and reproducibility of taxon characterizations from structured character data of changing sample sets by establishing a stable and unambiguous association between each sampled individual and the data processed from it. Our workflow implementation uses the European Distributed Institute of Taxonomy Platform, a comprehensive taxonomic data management and publication environment to: (i) establish a reproducible connection between sampled individuals and all samples derived from them; (ii) stably link sample-based character data with the metadata of the respective samples; (iii) record and store structured specimen-based character data in formats allowing data exchange; (iv) reversibly assign sample metadata and character datasets to taxa in an editable classification and display them and (v) organize data exchange via standard exchange formats and enable the link between the character datasets and samples in research collections, ensuring high visibility and instant re-usability of the data. The workflow implemented will contribute to organizing the interface between phylogenetic analysis and revisionary taxonomic or monographic work. DATABASE URL: http://campanula.e taxonomy.net/. PMID- 26424082 TI - RegNetwork: an integrated database of transcriptional and post-transcriptional regulatory networks in human and mouse. AB - Transcriptional and post-transcriptional regulation of gene expression is of fundamental importance to numerous biological processes. Nowadays, an increasing amount of gene regulatory relationships have been documented in various databases and literature. However, to more efficiently exploit such knowledge for biomedical research and applications, it is necessary to construct a genome-wide regulatory network database to integrate the information on gene regulatory relationships that are widely scattered in many different places. Therefore, in this work, we build a knowledge-based database, named 'RegNetwork', of gene regulatory networks for human and mouse by collecting and integrating the documented regulatory interactions among transcription factors (TFs), microRNAs (miRNAs) and target genes from 25 selected databases. Moreover, we also inferred and incorporated potential regulatory relationships based on transcription factor binding site (TFBS) motifs into RegNetwork. As a result, RegNetwork contains a comprehensive set of experimentally observed or predicted transcriptional and post-transcriptional regulatory relationships, and the database framework is flexibly designed for potential extensions to include gene regulatory networks for other organisms in the future. Based on RegNetwork, we characterized the statistical and topological properties of genome-wide regulatory networks for human and mouse, we also extracted and interpreted simple yet important network motifs that involve the interplays between TF-miRNA and their targets. In summary, RegNetwork provides an integrated resource on the prior information for gene regulatory relationships, and it enables us to further investigate context specific transcriptional and post-transcriptional regulatory interactions based on domain-specific experimental data. Database URL: http://www.regnetworkweb.org. PMID- 26424083 TI - MGDB: a comprehensive database of genes involved in melanoma. AB - The Melanoma Gene Database (MGDB) is a manually curated catalog of molecular genetic data relating to genes involved in melanoma. The main purpose of this database is to establish a network of melanoma related genes and to facilitate the mechanistic study of melanoma tumorigenesis. The entries describing the relationships between melanoma and genes in the current release were manually extracted from PubMed abstracts, which contains cumulative to date 527 human melanoma genes (422 protein-coding and 105 non-coding genes). Each melanoma gene was annotated in seven different aspects (General Information, Expression, Methylation, Mutation, Interaction, Pathway and Drug). In addition, manually curated literature references have also been provided to support the inclusion of the gene in MGDB and establish its association with melanoma. MGDB has a user friendly web interface with multiple browse and search functions. We hoped MGDB will enrich our knowledge about melanoma genetics and serve as a useful complement to the existing public resources. Database URL: http://bioinfo.ahu.edu.cn:8080/Melanoma/index.jsp. PMID- 26424084 TI - miRSponge: a manually curated database for experimentally supported miRNA sponges and ceRNAs. AB - In this study, we describe miRSponge, a manually curated database, which aims at providing an experimentally supported resource for microRNA (miRNA) sponges. Recent evidence suggests that miRNAs are themselves regulated by competing endogenous RNAs (ceRNAs) or 'miRNA sponges' that contain miRNA binding sites. These competitive molecules can sequester miRNAs to prevent them interacting with their natural targets to play critical roles in various biological and pathological processes. It has become increasingly important to develop a high quality database to record and store ceRNA data to support future studies. To this end, we have established the experimentally supported miRSponge database that contains data on 599 miRNA-sponge interactions and 463 ceRNA relationships from 11 species following manual curating from nearly 1200 published articles. Database classes include endogenously generated molecules including coding genes, pseudogenes, long non-coding RNAs and circular RNAs, along with exogenously introduced molecules including viral RNAs and artificial engineered sponges. Approximately 70% of the interactions were identified experimentally in disease states. miRSponge provides a user-friendly interface for convenient browsing, retrieval and downloading of dataset. A submission page is also included to allow researchers to submit newly validated miRNA sponge data. Database URL: http://www.bio-bigdata.net/miRSponge. PMID- 26424085 TI - Characteristics of young people with long term conditions close to transfer to adult health services. AB - BACKGROUND: For many young people with long term conditions (LTC), transferring from paediatric to adult health services can be difficult and outcomes are often reported to be poor. We report the characteristics and representativeness of three groups of young people with LTCs as they approach transfer to adult services: those with autism spectrum disorder with additional mental health problems (ASD); cerebral palsy (CP); or diabetes. METHODS: Young people aged 14 years-18 years 11 months with ASD, or those with diabetes were identified from children's services and those with CP from population databases. Questionnaires, completed by the young person and a parent, included the 'Mind the Gap' Scale, the Rotterdam Transition Profile, and the Warwick and Edinburgh Mental Wellbeing Scale. RESULTS: Three hundred seventy four young people joined the study; 118 with ASD, 106 with CP, and 150 with diabetes. Participants had a significant (p < 0.001) but not substantial difference in socio-economic status (less deprived) compared to those who declined to take part or did not respond. Condition specific severity of participants was similar to that of population data. Satisfaction with services was good as the 'gap' scores (the difference between their ideal and current care) reported by parents and young people were small. Parents' satisfaction was significantly lower than their children's (p < 0.001). On every domain of the Rotterdam Transition Profile, except for education and employment, significant differences were found between the three groups. A larger proportion of young people with diabetes were in a more independent phase of participation than those with ASD or CP. The wellbeing scores of those with diabetes (median = 53, IQR: 47-58) and CP (median = 53, IQR: 48-60) were similar, and significantly higher than for those with ASD (median = 47, IQR: 41-52; p < 0.001). CONCLUSIONS: Having established that our sample of young people with one of three LTCs recruited close to transfer to adult services was representative, we have described aspects of their satisfaction with services, participation and wellbeing, noting similarities and differences by LTC. This information about levels of current functioning is important for subsequent evaluation of the impact of service features on the health and wellbeing of young people with LTCs following transfer from child services to adult services. PMID- 26424086 TI - A new protocol to accurately determine microtubule lattice seam location. AB - Microtubules (MTs) are cylindrical polymers of alphabeta-tubulin that display pseudo-helical symmetry due to the presence of a lattice seam of heterologous lateral contacts. The structural similarity between alpha- and beta-tubulin makes it difficult to computationally distinguish them in the noisy cryo-EM images, unless a marker protein for the tubulin dimer, such as kinesin motor domain, is present. We have developed a new data processing protocol that can accurately determine alphabeta-tubulin register and seam location for MT segments. Our strategy can deal with difficult situations, where the marker protein is relatively small or the decoration of marker protein is sparse. Using this new seam-search protocol, combined with movie processing for data from a direct electron detection camera, we were able to determine the cryo-EM structures of MT at 3.5 A resolution in different functional states. The successful distinction of alpha- and beta-tubulin allowed us to visualize the nucleotide state at the E site and the configuration of lateral contacts at the seam. PMID- 26424087 TI - Contextual representations of negative images modulate intrusion frequency in an intrusion provocation paradigm. AB - BACKGROUND AND OBJECTIVES: To understand how memories of negative events become highly accessible in the context of trauma, we tested the hypothesis that contextual information modulates how easily intrusions can be provoked by perceptual stimuli.. METHODS: Healthy participants viewed pictures depicting trauma scenes either with or without accompanying moderate (i.e. survival, recovery) or severe (i.e. fatality, permanent injury) outcome information. All participants viewed the same depictions of trauma scenes. Involuntary memories for the pictures were assessed using self-report diaries and an adapted version of the Impact of Event Scales (IES). A blurred picture perceptual priming paradigm was adapted to be used as an intrusion provocation task. RESULTS: The severe outcome group experienced a significantly higher frequency of intrusions on the intrusion provocation task in comparison to both moderate outcome and control (no-context) conditions. The severe outcome condition did not increase intrusions on the self-report diaries or the adapted IES. There was no effect of condition on ratings for the emotionality, self-relevance, valence, or seriousness of the trauma scenes. LIMITATIONS: The analogue method should not be generalized directly to incidences of real-life trauma. It was unclear why differences in intrusion frequency were found in the provocation task only. The relative amount of individual conceptual and data-driven processing adopted by the participants was not assessed. CONCLUSIONS: Manipulating contextual information that determines the meaning of sensory-perceptual features for a trauma scene can modulate subsequent intrusion frequency in response to visually similar cues. PMID- 26424088 TI - Glycosaminoglycans in subdural fluid and CSF after meningeal injury. AB - BACKGROUND: Inflammatory mechanisms have an acknowledged role in the progression of chronic subdural hematoma (CSDH) and in tissue response after subarachnoid hemorrhage (SAH). The participation of extracellular matrix, especially glycosaminoglycans, in the cellular events during tissue repair is known to be important. We studied the production of glycosaminoglycans after two types of meningeal injury-one caused by rupture of the dural border cell layer after head injury, and the other caused by SAH. METHODS: Patients with CSDH (n = 28), subdural effusion (n = 8), and SAH (n = 33) were included in the study. Samples from subdural fluid or cerebrospinal fluid (CSF) were assayed for hyaluronic acid (HA) with an enzyme-linked assay and for sulfated glycosaminoglycans (sGAGs) with a dye-binding assay. RESULTS: The median HA concentration was 3021 (range, 408 14,012) ng/ml in the CSDH fluid, 668 (392-3607) ng/ml in the effusion fluid, and 21.7 (5.8-195) ng/ml in the serum. In lumbar CSF after SAH, the median HA concentration was 246 (47-3686) ng/ml being 1.5-fold higher than that in control CSF. The median sGAG concentration was 52.8 (0-144) MUg/ml in CSDH fluid, but only 5.32 (0-20.5) MUg/ml in the effusion fluid, where the concentration was similar to that in the serum. CONCLUSIONS: We found high, but variable, concentrations of sGAGs and HA in the CSDH and effusion fluid after head injury and HA in the CSF after SAH. Our results show that HA and sGAGs are induced after meningeal injury and that these proteins may participate in a reactive process. PMID- 26424090 TI - Carbapenem-Resistant Enterobacteriaceae: A Major Prevalence Difference due to the High Performance of Carbapenemase Producers when compared to the Nonproducers. PMID- 26424089 TI - MeSiC: A Model-Based Method for Estimating 5 mC Levels at Single-CpG Resolution from MeDIP-seq. AB - As the fifth base in mammalian genome, 5-methylcytosine (5 mC) is essential for many biological processes including normal development and disease. Methylated DNA immunoprecipitation sequencing (MeDIP-seq), which uses anti-5 mC antibodies to enrich for methylated fraction of the genome, is widely used to investigate methylome at a resolution of 100-500 bp. Considering the CpG density-dependent bias and limited resolution of MeDIP-seq, we developed a Random Forest Regression (RFR) model method, MeSiC, to estimate DNA methylation levels at single-base resolution. MeSiC integrated MeDIP-seq signals of CpG sites and their surrounding neighbors as well as genomic features to construct genomic element-dependent RFR models. In the H1 cell line, a high correlation was observed between MeSiC predictions and actual 5 mC levels. Meanwhile, MeSiC enabled to calibrate CpG density-dependent bias of MeDIP-seq signals. Importantly, we found that MeSiC models constructed in the H1 cell line could be used to accurately predict DNA methylation levels for other cell types. Comparisons with methylCRF and MEDIPS showed that MeSiC achieved comparable and even better performance. These demonstrate that MeSiC can provide accurate estimations of 5 mC levels at single CpG resolution using MeDIP-seq data alone. PMID- 26424091 TI - Nicotine delivery, tolerability and reduction of smoking urge in smokers following short-term use of one brand of electronic cigarettes. AB - BACKGROUND: This randomized, partially single-blinded, 6-period crossover clinical study of adult smokers compared the nicotine pharmacokinetics, impacts on smoking urge and tolerability of various formulations of one brand of e cigarettes with that of a tobacco cigarette. METHODS: Five e-cigarettes with different e-liquid formulations containing 1.6 % and 2.4 % nicotine and a conventional tobacco cigarette were randomized among 24 subjects under two exposure sessions consisting of a 30-min controlled and a one-hour ad lib use period to assess plasma nicotine levels, impacts on smoking urge and adverse events. The 30-min controlled use session comprised an intensive use of the e cigarettes with a total of 50 puffs taken every 30 s for comparison to a single conventional cigarette having a typical machine-measured nicotine yield (~0.8 mg). Ad lib product use conditions provided insight into more naturalistic product use behaviors and their accompanying smoking urge reductions. Adverse events (AEs) were assessed by the Principal Investigator. RESULTS: Significant (p < 0.05) increases in plasma nicotine concentrations occurred within 10 min of controlled e-cigarette use and significant (p < 0.001) reductions from baseline smoking urge were observed within 5 min. E-cigarette and cigarette nicotine plasma levels were comparable for up to one hour of use. After both sessions (90 min), nicotine exposure was the highest for the cigarette, with all e-cigarettes showing 23 % to 53 % lower plasma concentrations. During controlled use, peak reduction in smoking urge for e-cigs occurred later than for the cigarette. After completion of both sessions, significant smoking urge reduction persisted for most of the tested e-cigarettes, albeit at levels lower than that provided by the tobacco cigarette. Nicotine content, vehicle differences, and the presence of menthol did not significantly affect smoking urge reduction by the e-cigarettes. No subjects were discontinued due to AEs. The most frequently reported AEs events included cough, throat irritation, headache, and dizziness. CONCLUSIONS: Blood plasma nicotine levels obtained from short-term use of e-cigarettes containing 1.6 % and 2.4 % nicotine were significant, but lower than those of conventional tobacco cigarettes, yet the reduction in craving symptoms were broadly comparable. The types of AEs were consistent with other research studies of longer duration that have reported that use of e-cigarettes by adult smokers is well-tolerated. TRIAL REGISTRATION: http://ClinicalTrials.gov identifier: NCT02210754 . Registered 8 August 2014. PMID- 26424092 TI - In vitro inhibition of calcium oxalate crystallization and crystal adherence to renal tubular epithelial cells by Terminalia arjuna. AB - Urolithiasis is a multifactorial disease and remains a public health problem around the world. Of all types of renal stones, calcium oxalate (CaOx) is the most common composition formed in the urinary system of the patients with urolithiasis. The present study is aimed at evaluating the antiurolithiatic properties of the Tris-Cl extract (TE) of Terminalia arjuna (T. arjuna). The antilithiatic activity of TE of T. arjuna was investigated on nucleation, aggregation, and growth of the CaOx crystals, as well as its protective potency was tested on oxalate-induced cell injury of NRK-52E renal epithelial cells. Also, in vitro antioxidant activity of TE T. arjuna bark was also determined. The TE of T. arjuna exhibited a concentration-dependent inhibition of nucleation and growth of CaOx crystals. Inhibition of aggregation of CaOx crystals remains constant. When NRK-52E cells were injured by exposure to oxalate for 48 h, the TE prevented the cells from injury and CaOx crystal adherence resulting in increased cell viability in a dose-dependent manner. The TE also scavenged the 2,2-diphenyl 1-picrylhydrazyl (DPPH) free radicals with an IC50 at 51.72 ug/mL. The results indicated that T. arjuna is a potential candidate for phytotherapy against urolithiasis as it attains the ability to inhibit CaOx crystallization and scavenge DPPH free radicals in vitro along with a cytoprotective role. PMID- 26424093 TI - Food handlers as potential sources of dissemination of virulent strains of Staphylococcus aureus in the community. AB - Food handlers may constitute a reservoir of virulent strains of Staphylococcus aureus and may be vehicles of their transmission to food. One hundred and sixty two volunteers were assessed for the presence of S. aureus on the hands and in the nose. S. aureus was isolated by routine procedures, and the isolates were tested for susceptibility against a panel of nine antimicrobial agents. The isolates were further characterized by SmaI-PFGE profiling and the presence of virulence factors. RESULTS: The prevalence of S. aureus was 19.8% in the nose and 11.1% on the hands; 6.2% of the individuals carried S. aureus both in their noses and hands, and three individuals had the same strain (PFGE type) in the nose and on the hands. Although 82% of the isolates were resistant to at least one antibiotic, none demonstrated the presence of either mecA gene or resistance to oxacillin (none identified as MRSA). Sixty-eight percent of the isolates from the nose and hands possessed enterotoxin genes. This study revealed a high prevalence of antibiotic resistance and virulence determinants among the isolates, including not only classical and novel enterotoxin genes but also major virulence factors such as tst. Potential dissemination of these strains in the community is a matter of concern. PMID- 26424094 TI - Does Oral Beta-Blocker Therapy Improve Long-Term Survival in ST-Segment Elevation Myocardial Infarction With Preserved Systolic Function? A Meta-Analysis. AB - BACKGROUND: The effect of oral beta-blocker therapy on long-term mortality in patients with ST-segment elevation myocardial infarction (STEMI) who are treated with primary percutaneous coronary intervention (PCI) and who have preserved left ventricular ejection fraction (LVEF) remains unclear. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for studies evaluating the effect of oral beta-blocker therapy in patients with STEMI who underwent primary PCI and who had preserved LVEF. The primary outcome was all cause mortality. Randomized controlled trials and the observational studies that reported an adjusted hazard ratio (or hazard ratio in the propensity score matched patients) with follow-up duration equal to or more than 6 months were included. Pooled hazard ratio with 95% confidence interval (CI) was calculated using a random effect model. RESULTS: No randomized controlled trials met the inclusion criteria. Seven observational studies totaling 10 857 patients met the inclusion criteria. Follow-up duration ranged from 6 months to 5.2 years. Preserved LVEF was defined as 40% in 4 studies and 50% in 3 studies. Based on the pooled estimate, oral beta-blocker therapy was associated with a reduction in all cause mortality (combined hazard ratio 0.79, 95% CI 0.65-0.97). CONCLUSION: This meta-analysis demonstrates that oral beta-blocker therapy is associated with decreased all-cause mortality in patients with STEMI who are treated with primary PCI and who have preserved LVEF. This supports the current American College of Cardiology Foundation/American Heart Association 2013 Guideline for the Management of STEMI. PMID- 26424095 TI - Treatment of CIA Mice with FGF21 Down-regulates TH17-IL-17 Axis. AB - Recently, FGF21 was reported to play an important role in anti-inflammation. The aim of the study is to explore the mechanism for FGF21 alleviating inflammation of CIA. CIA mice were injected with FGF21 once a day for 28 days after first booster immunization. The results showed that FGF21 alleviates arthritis severity and decreases serum anti-CII antibodies levels in CIA mice. Compared with CIA model, the number of the splenic TH17 cells was significantly decreased in FGF21 treated mice. FGF21 treatment reduced the mRNA expression of IL-17, TNF-alpha, IL 1beta, IL-6, IL-8, and MMP3 and increased level of IL-10 in the spleen tissue. The expression of STAT3 and phosphorylated STAT3 was suppressed in FGF21-treated group. The mRNA expression of RORgammat and IL-23 also decreased. In conclusion, these findings suggest that the beneficial effects of FGF21 on CIA mice were achieved by down-regulating Th17-IL-17 axis through STAT3/RORgammat pathway. Modulating of Th17-mediated inflammatory response may be one of the mechanisms for FGF21 attenuating inflammation in CIA. PMID- 26424096 TI - Fli-1, a Functional Factor Performed in Autoimmune Lupus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease. The friend leukemia insertion site 1 (Fli-1) belongs to the Ets family of transcription factors. Recent findings suggested that expression of Fli-1 was abnormal in SLE patients and lupus mice. In addition, functional analysis indicated that Fli-1 plays a key role in the development of this complex autoimmune disorder. Here, we review the updated evidence indicating the roles of Fli-1 in autoimmune lupus. Hopefully, the information obtained may result in a better understanding of the pathogenesis of the systemic autoimmune disease. PMID- 26424097 TI - Total Synthesis and Configurational Assignment of Ascospiroketal A. AB - The total synthesis of the marine fungus-derived natural product ascospiroketal is described. This concise synthesis relies on a unique Ag(I) -promoted tandem cascade cyclization that provides direct access to the correctly configured tricyclic core of the natural product from a linear precursor. The synthesis of candidate stereostructures of ascospiroketal A allowed for the confident assignment of both the relative and absolute stereochemistry of this unusual octaketide. PMID- 26424098 TI - Production of Optically Pure D-Lactic Acid by the Combined use of Weissella sp. S26 and Bacillus sp. ADS3. AB - Optically pure D-lactic acid was produced from glucose, xylose, or starch by the combined use of Weissella sp. S26 and Bacillus sp. ADS3, two native bacterial strains isolated from Singapore environment. Weissella sp. S26 was used to ferment various sugars to lactic acid rich in D-isomer followed by sterilization of the broth and inoculation of Bacillus sp. ADS3 cells to selectively degrade acetic acid (if any) and L-lactic acid. In a simultaneous saccharification and fermentation of starch by Weissella sp. S26 in 1 L of modified MRS medium containing 50 g/L starch at 30 degrees C, lactic acid reached 24.2 g/L (23.6 g/L of D-isomers and 0.6 g/L of L-isomers), and acetic acid was 11.8 g/L at 37 h. The fermentation broth was sterilized at 100 degrees C for 20 min and cooled down to 30 degrees C followed by inoculation of Bacillus sp. ADS3 (10 %, v/v), and the mixture was kept at 30 degrees C for 115 h. Acetic acid was completely removed, and L-lactic acid was largely removed giving an optical purity of D-lactic acid as high as 99.5 %. PMID- 26424099 TI - [Experimental and therapeutic neuromodulation of emotion and social cognition with non-invasive brain stimulation]. AB - Transcranial magnetic stimulation (TMS) is not only a highly elegant method for basic neuroscientific research that employs transient lesions to explore the relationship between brain structure and function but in a clinical context it is also a very promising approach to augmentation therapy in middle to severe grade depressive episodes. This overview illustrates the methodological basis of TMS and illuminates its neuromodulatory potential with reference to findings from recent studies on emotion regulation and social cognition. Against this empirical background, it becomes clear that preclinical studies on healthy participants are extremely important to develop innovative stimulation protocols and define functionally relevant target regions to be tested in clinical studies for therapeutic efficacy. Finally, the perspectives and limitations of functionally guided, individualized TMS neuronavigation will be explored based on task independent connectivity and task-dependent activity measurements. PMID- 26424100 TI - Different effect of alcohol consumption on hypertension according to metabolic health status. AB - We aimed to investigate whether the effect of problematic alcohol drinking on hypertension differed according to metabolic health statuses. Male participants from the fifth Korea National Health and Nutrition Examination Survey were recruited. Problematic alcohol drinkers were designated as subjects with heavy drinking (?30 g per day), binge drinking (?7 glasses per day) or a high alcohol use disorders identification test score (?20). Metabolically obese status was defined as having ?1 or ?2 components of the diagnostic criteria for metabolic syndrome, excluding the blood pressure component. Because the prevalence of problematic alcohol drinking and the prevalence of hypertension largely differed by age groups, separate analyses were performed for the two age groups (<50 and ?50 years). Among a total of 6329 subjects, 37.04% had hypertension. In the younger age group, subjects with problematic alcohol drinking demonstrated a higher prevalence of hypertension in both nonobese and obese individuals compared with subjects who were nonobese and who were not problematic alcohol drinkers. Of note, problematic alcohol drinking increased the risk of having hypertension ~3 times in young nonobese individuals who demonstrated a metabolically obese phenotype compared with those who were metabolically healthy. However, metabolic health status did not have a significant impact on the risk for having hypertension in obese participants, regardless of their age groups. For the prevention of hypertension, avoidance of problematic alcohol drinking should be emphasized, especially in young subjects who show poor metabolic health status despite being nonobese. PMID- 26424101 TI - The significance of micro- and macrovascular biomarkers on cardiovascular outcome in chronic kidney disease: a prospective cohort study. AB - Measures of small and large artery dysfunction have not been investigated in a single cohort for the prediction of cardiovascular (CV) events in patients with nondialysed (ND) chronic kidney disease (CKD). This prospective cohort study aimed to determine whether central pulse wave velocity (cPWV), central pulse pressure (CPP) or microvascular post-occlusive reactive hyperaemia area (PORHHA) independently predict CV events and mortality in CKD-ND. A total of 94 stage 1-5 CKD-ND (65.3+/-13.1 years; estimated glomerular filtration rate 35.3 (22.8-49.4) ml min(-1) per 1.73 m(2)) patients were followed-up for a median of 52 (36-65) months and had baseline cPWV and CPP measured by applanation tonometry and PORHHA by laser Doppler flowmetry. Multiple failure time Cox regression models were used to determine the predictive role of vascular parameters on CV mortality and events. Based on multiple linear regressions, baseline age, diabetes, CV disease, and systolic blood pressure (SBP) were independently related to cPWV (R(2)=0.3), SBP and PORHHA to CPP (R(2)=0.45), whereas CPP was the only parameter independently related to PORHHA (R(2)=0.16, all P<0.05). During follow-up, 41 CV events occurred (14 CV deaths). In univariate analyses, cPWV (1.07 (1.02-1.13) per m s(-1)), CPP (1.04 (1.01-1.07) per mm Hg) and lnPORHHA (0.70 (0.58-0.85) per ln(PU * s)) were all related to the outcome. Baseline diabetes (HR 3.07 (1.65 5.68)), lnFGF23 (fibroblast growth factor-23; 1.86 (1.13-3.06) per RU ml(-1)) and CPP (1.04 (1.01-1.07) per mm Hg) were independent predictors of CV events. The impaired pulsatile component of large arteries (CPP) independently of other vascular markers (cPWV, PORHHA) predicted CV outcomes in CKD-ND. CPP may integrate the information provided by cPWV and PORHHA. PMID- 26424102 TI - A HEALth Promotion and STRESS Management Program (HEAL-STRESS study) for prehypertensive and hypertensive patients: a quasi-experimental study in Greece. AB - Current hypertension guidelines advocate strategies encouraging healthy lifestyle behaviours. So far, there is a paucity of studies for the efficacy of such multifaceted programmes. The aim of this study is to investigate the efficacy of an 8-week health-promotion programme for lowering blood pressure (BP) in prehypertensive and hypertensive patients in the community. This was a quasi experimental study using wait-list controls of 548 patients. The intervention group was administered with an 8-week health-promotion intervention. Measurements included home BP, smoking, body mass index (BMI), perceived stress, depression, anxiety and Health Locus of Control. After adjusting for confounders, the intervention group had a significant reduction in both systolic BP (SBP; mean 2.62 mm Hg, 95% confidence interval (CI): -1.29 to -3.96) and diastolic BP (DBP; mean -1.0, 95% CI: -0.93 to -1.9) compared with controls. In all, 14.9% of patients in the intervention group had >10 mm Hg reduction in SBP vs 4.4% in the control group (P<0.001, numbers needed to treat (NNT)=10). With regards to DBP, 21.7% of patients in the intervention group had >5 mm Hg reduction vs 12.5% in the control group (P=0.01, NNT=11). In terms of effect size, moderate-to-large improvements of BMI, perceived stress, anxiety, depression, external and chance Health Locus of Control were recorded. Changes in SBP and DBP were attributed to BMI and depressive symptom reductions, respectively. Comprehensive non pharmaceutical programmes for BP management are strongly encouraged. Their long term benefits on cardiovascular morbidity and mortality remain to be established by future research. PMID- 26424103 TI - Identification of okadaic acid binding protein 2 in reconstituted sponge cell clusters from Halichondria okadai and its contribution to the detoxification of okadaic acid. AB - Okadaic acid (OA) and OA binding protein 2 (OABP2) were previously isolated from the marine sponge Halichondria okadai. Because the amino acid sequence of OABP2 is completely different from that of protein phosphatase 2A, a well-known target of OA, we have been investigating the production and function of OABP2. In the present study, we hypothesized that OABP2 plays a role in the detoxification of OA in H. okadai and that the OA concentrations are in proportional to the OABP2 concentrations in the sponge specimens. Based on the OA concentrations and the OABP2 concentrations in the sponge specimens collected in various places and in different seasons, however, we could not determine a positive correlation between OA and OABP2. We then attempted to determine distribution of OA and OABP2 in the sponge specimen. When the mixture of dissociated sponge cells and symbiotic species were separated with various pore-sized nylon meshes, most of the OA and OABP2 was detected from the same 0-10 MUm fraction. Next, when sponge cell clusters were prepared from a mixture of dissociated sponge cells and symbiotic species in the presence of penicillin and streptomycin, we identified the 18S rDNA of H. okadai and the gene of OABP2 in the analysis of genomic DNA but could not detect OA by LC-MS/MS. We thus concluded that the sponge cells express OABP2, and that OA was not apparently present in the sponge cells but could be colocalized with OABP2 in the sponge cells at a concentration less than the limit of detection. PMID- 26424104 TI - Ambiguities and Asymmetries in Consent and Refusal: Reply to Manson. AB - John Harris claims that is it 'palpable nonsense' to suggest that 'a child (or anyone) might competently consent to a treatment but not be competent to refuse it.' In 'Transitional Paternalism: How Shared Normative Powers Give Rise to the Asymmetry of Adolescent Consent and Refusal' Neil Manson aims to explain away the apparent oddness of this asymmetry of consent and refusal, by appealing to the idea of shared normative powers, presenting joint bank accounts as an example. In this article, I will argue that Manson's account fails to explain away the oddness. Rather, I will argue that there are ambiguities to which Manson has not paid sufficient attention. In fact, as odd as it may sound, I argue that Manson actually agrees with Harris (at least in relation to the asymmetry of competence). He fails to recognize that he agrees with Harris because he is not careful enough to distinguish between different asymmetries, which I have labelled the asymmetries of choice, permissibility and competence. PMID- 26424105 TI - Effectiveness of an interactive platform, and the ESC/HFA heartfailurematters.org website in patients with heart failure: design of the multicentre randomized e Vita heart failure trial. AB - AIMS: Electronic health support (e-health) may improve self-care of patients with heart failure (HF). We aim to assess whether an adjusted care pathway with replacement of routine consultations by e-health improves self-care as compared with usual care. In addition, we will determine whether the ESC/HFA (European Society of Cardiology/Heart Failure Association) website heartfailurematters.org (HFM website) improves self-care when added to usual care. Finally, we aim to evaluate the cost-effectiveness of these interventions. METHODS: A three-arm parallel randomized trial will be conducted. Arm 1 consists of usual care; arm 2 consists of usual care plus the HFM website; and arm 3 is the adjusted care pathway with an interactive platform for disease management (e-Vita platform), with a link to the HFM website, which replaces routine consultations with HF nurses at the outpatient clinic. In total, 414 patients managed in 10 Dutch HF outpatient clinics or in general practice will be included and followed for 12 months. Participants are included if they have had an established diagnosis of HF for at least 3 months. The primary outcome is self-care as measured by the European Heart Failure Self-care Behaviour scale (EHFScB scale). Secondary outcomes are quality of life, cardiovascular- and HF-related mortality, hospitalization, and its duration as captured by hospital and general practitioner registries, use of and user satisfaction with the HFM website, and cost-effectiveness. PERSPECTIVE: This study will provide important prospective data on the impact and cost-effectiveness of an interactive platform for disease management and the HFM website. CLINICAL TRIAL REGISTRATION: unique identifier: NCT01755988. PMID- 26424106 TI - Supporting children's well-being: Outcomes of a rural child-focused education program for separating or divorced parents. PMID- 26424108 TI - Inflammatory Myopathy Causing Leg Pain in a Soccer Player: Case Report and Return to-Play Considerations. AB - Leg pain is a common condition in athletes as well as in the general population, and has a broad differential diagnosis that includes musculoskeletal, vascular, rheumatologic, and neurologic etiologies. Idiopathic inflammatory myopathy (IM) is a relatively uncommon but recognized etiology of leg pain. In this case, we describe an acute presentation of IM in an athlete resulting in leg pain and activity limitation. The available literature suggests that moderate-intensity exercise is safe and beneficial in idiopathic IM, but studies to date have not assessed the effects of high-intensity exercise in IM or provided recommendations for return to competitive contact sport in this population. PMID- 26424107 TI - Effects of HIV and childhood trauma on brain morphometry and neurocognitive function. AB - A wide spectrum of neurocognitive deficits characterises HIV infection in adults. HIV infection is additionally associated with morphological brain abnormalities affecting neural substrates that subserve neurocognitive function. Early life stress (ELS) also has a direct influence on brain morphology. However, the combined impact of ELS and HIV on brain structure and neurocognitive function has not been examined in an all-female sample with advanced HIV disease. The present study examined the effects of HIV and childhood trauma on brain morphometry and neurocognitive function. Structural data were acquired using a 3T Magnetom MRI scanner, and a battery of neurocognitive tests was administered to 124 women: HIV positive with ELS (n = 32), HIV-positive without ELS (n = 30), HIV-negative with ELS (n = 31) and HIV-negative without ELS (n = 31). Results revealed significant group volumetric differences for right anterior cingulate cortex (ACC), bilateral hippocampi, corpus callosum, left and right caudate and left and right putamen. Mean regional volumes were lowest in HIV-positive women with ELS compared to all other groups. Although causality cannot be inferred, findings also suggest that alterations in the left frontal lobe, right ACC, left hippocampus, corpus callosum, left and right amygdala and left caudate may be associated with poorer neurocognitive performance in the domains of processing speed, attention/working memory, abstraction/executive functions, motor skills, learning and language/fluency with these effects more pronounced in women living with both HIV and childhood trauma. This study highlights the potential contributory role of childhood trauma to brain alterations and neurocognitive decline in HIV-infected individuals. PMID- 26424110 TI - Gender-related drug effect on several markers of oxidation stress in diabetes patients with and without complications. AB - We previously reported that circulating lipid (malondialdehyde, MDA) and protein oxidation (carbonyl residues, CO) products can be used as markers of risk for complications in poorly controlled type 2 diabetics. Now, we aimed to evaluate the existence of a gender effect on classical disease markers and oxidative stress parameters and on the effectiveness of metformin and/or statins in reducing CV risk in poorly controlled type 2 diabetics with and without complications. Our results show that diabetics with complications had higher plasma levels of FRAP, SOD and hs-CRP than those without complications, with FRAP and SOD found increased in both genders. Interestingly, male and female patients with complications had higher plasma levels of hs-CRP and MDA respectively, over patients without complications. Multivariate analysis indicated metformin and statin treatments effective in reducing plasma hs-CRP only in female and not in male diabetics with complications. In these latter females, a positive correlation between hs-CRP and triglycerides (TG) levels was found suggesting a causal relationship between them. Statin treatment was effective in reducing MDA in diabetics with complications irrespective of the gender. These data support the addition of statins to diabetic standard therapy to control oxidation injury and inflammation and, for the first time, indicate female patients with complications more responsive than males to the CV protection offered by metformin. PMID- 26424111 TI - Human perivascular adipose tissue dysfunction as a cause of vascular disease: Focus on vascular tone and wall remodeling. AB - Obesity is one of the major risk factors for the development of cardiovascular diseases. It is characterized by excessive or abnormal accumulation of adipose tissue, including depots which surround the blood vessels named perivascular adipose tissue (PVAT). PVAT plays endocrine and paracrine roles by producing large numbers of metabolically vasoactive adipokines. The present review outlines our current understanding of the beneficial roles of PVAT in vascular tone and remodeling in healthy subjects supported by clinical studies, highlighting different factors or mechanisms that could mediate protective effects of PVAT on vascular function. Most studies in humans show that adiponectin is the best candidate for the advantageous effect of PVAT. However, in pathological conditions especially obesity-related cardiovascular diseases, the beneficial effects of PVAT on vascular functions are impaired and transform into detrimental roles. This change is defined as PVAT dysfunction. In the current review, the contribution of PVAT dysfunction to obesity-related cardiovascular diseases has been discussed with a focus on possible mechanisms including an imbalance between beneficial and detrimental adipokines (commonly described as decreased levels of adiponectin and increased levels of leptin or tumor necrosis factor-alpha (TNFalpha)), increased quantity of adipose tissue, inflammation, cell proliferation and endothelial dysfunction. Finally, novel pharmacotherapeutic targets for the treatment of cardiovascular and metabolic disorders are addressed. PMID- 26424112 TI - Suture, synthetic, or biologic in contaminated ventral hernia repair. AB - BACKGROUND: Data are lacking to support the choice between suture, synthetic mesh, or biologic matrix in contaminated ventral hernia repair (VHR). We hypothesize that in contaminated VHR, suture repair is associated with the lowest rate of surgical site infection (SSI). METHODS: A multicenter database of all open VHR performed at from 2010-2011 was reviewed. All patients with follow-up of 1 mo and longer were included. The primary outcome was SSI as defined by the Centers for Disease Control and Prevention. The secondary outcome was hernia recurrence (assessed clinically or radiographically). Multivariate analysis (stepwise regression for SSI and Cox proportional hazard model for recurrence) was performed. RESULTS: A total of 761 VHR were reviewed for a median (range) follow-up of 15 (1-50) mo: there were 291(38%) suture, 303 (40%) low-density and/or mid-density synthetic mesh, and 167(22%) biologic matrix repair. On univariate analysis, there were differences in the three groups including ethnicity, ASA, body mass index, institution, diabetes, primary versus incisional hernia, wound class, hernia size, prior VHR, fascial release, skin flaps, and acute repair. The unadjusted outcomes for SSI (15.1%; 17.8%; 21.0%; P = 0.280) and recurrence (17.8%; 13.5%; 21.5%; P = 0.074) were not statistically different between groups. On multivariate analysis, biologic matrix was associated with a nonsignificant reduction in both SSI and recurrences, whereas synthetic mesh associated with fewer recurrences compared to suture (hazard ratio = 0.60; P = 0.015) and nonsignificant increase in SSI. CONCLUSIONS: Interval estimates favored biologic matrix repair in contaminated VHR; however, these results were not statistically significant. In the absence of higher level evidence, surgeons should carefully balance risk, cost, and benefits in managing contaminated ventral hernia repair. PMID- 26424113 TI - Following the money: Mapping the sources and funding flows of alcohol and other drug treatment in Australia. AB - INTRODUCTION AND AIMS: The structures of health systems impact on patient outcomes. We present and analyse the first detailed mapping of who funds alcohol and other drug (AOD) treatment and the channels and intermediaries through which funding flows from the funding sources to treatment providers. DESIGN AND METHODS: The study involved a literature review of AOD treatment financing and existing diagrammatic representations of the structure of the Australian health system. We interviewed 190 key informants to particularise the AOD treatment sector, and undertook two case examples of government funded non-government organisations providing AOD treatment. RESULTS: Funding sources include the Australian and state and territory governments, philanthropy, fund-raising and clients themselves. While funding sources align with the health sector generally and the broader social services sector, the complexity of flows from source to treatment service and the number of intermediaries are noteworthy. So too are the many sources of funding drawn on by some treatment providers. Diversification is both beneficial and disadvantageous for non-government treatment providers, adding to administrative workloads, but smoothing the risk of funding shortfalls. Government funders benefit from sharing risk. DISCUSSION AND CONCLUSIONS: Circuitous funding flows multiply the funding sources drawn on by services and put distance between the funding source and the service provider. This leads to concerns over lack of transparency about what is being purchased and challenges for the multiply funded service provider in maintaining programs and service models amid multiple and sometimes competing funding and accountability frameworks. [Chalmers J, Ritter A, Berends L, Lancaster K. Following the money: Mapping the sources and funding flows of alcohol and other drug treatment in Australia. Drug Alcohol Rev 2016;35:255-262]. PMID- 26424109 TI - NADPH oxidases-do they play a role in TRPC regulation under hypoxia? AB - In the lung, acute alveolar hypoxia causes hypoxic pulmonary vasoconstriction (HPV) to maintain ventilation perfusion matching and thus optimal oxygenation of blood. In contrast, global chronic hypoxia triggers a pathological thickening of pulmonary arterial walls, called pulmonary vascular remodelling, leading to persistence of pulmonary hypertension (PH). Moreover, ischaemia or hypoxia can lead to a damage of pulmonary endothelial cells with subsequent oedema formation. Alterations in reactive oxygen species (ROS) have been suggested as a crucial mediator of such responses. Among the various sources of cellular ROS production, NADPH oxidases (NOXs) have been found to contribute to these physiological and pathophysiological signalling processes. NOXs are the only known examples that generate ROS as the primary function of the enzyme system. However, the downstream targets of NOX-derived ROS signalling in hypoxia are still not known. Canonical transient receptor potential (TRPC) channels recently have been recognised as directly or indirectly ROS-activated channels and have been shown to be essential for hypoxia-dependent vascular regulatory processes in the lung. Against this background, we here summarise the current knowledge on NOX-mediated TRPC channel signalling during hypoxia in the pulmonary circulation. PMID- 26424114 TI - FGF9-induced changes in cellular redox status and HO-1 upregulation are FGFR dependent and proceed through both ERK and AKT to induce CREB and Nrf2 activation. AB - Our previous studies demonstrated that fibroblast growth factor 9 (FGF9) protects cortical and dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP(+)) induced oxidative insult by upregulation of gamma-glutamylcysteine synthetase (gamma-GCS) and heme oxygenase-1 (HO-1). However, the mechanisms responsible for FGF9-induced gamma-GCS and HO-1 upregulation remain uncharacterized. In the present study, we demonstrate the signaling pathways by which FGF9 upregulates HO 1 and gamma-GCS expression. We found that FGF9-induced HO-1 and gamma-GCS expression was prevented by PD173014, an inhibitor of the FGF receptor (FGFR). FGF9 treatment induced the phosphorylation of FGFR downstream signals of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT in a dose- and time dependent manner. The inhibition of MEK/ERK1/2 or PI3K/AKT activity by U0126 or wortmannin, but not the inhibition of phospholipase Cgamma by U73122, prevented FGF9-induced gamma-GCS and HO-1 upregulation, changes in cellular redox status, and neuroprotection against MPP(+) toxicity in primary cortical and dopaminergic neurons. Furthermore, FGF9 treatment enhanced the promoter activity of the cAMP response element binding protein (CREB) and nuclear factor erythroid-derived 2 like 2 (Nrf2), and this phenomenon was blocked by PD173014 or U0126 or wortmannin. Knockdown of CREB and Nrf2 by shRNA blocked FGF9-induced gamma-GCS and HO-1 upregulation, but not ERK and AKT phosphorylation. An in vivo study consistently showed that FGF9 overexpression using a lentivirus delivery system induced ERK1/2 phosphorylation and HO-1 upregulation and protected dopaminergic neurons against MPP(+) toxicity in rat substantia nigra. These results indicate that FGF9-induced HO-1 and gamma-GCS upregulation is mediated by binding to FGFR and activation of two parallel downstream signaling pathways, ERK and AKT, which reconverge to induce CREB and Nrf2 transcriptional activity. PMID- 26424115 TI - Sound envelope processing in the developing human brain: A MEG study. AB - OBJECTIVE: This study investigated auditory cortical processing of linguistically relevant temporal modulations in the developing brains of young children. METHODS: Auditory envelope following responses to white noise amplitude modulated at rates of 1-80 Hz in healthy children (aged 3-5 years) and adults were recorded using a paediatric magnetoencephalography (MEG) system and a conventional MEG system, respectively. RESULTS: For children, there were envelope following responses to slow modulations but no significant responses to rates higher than about 25 Hz, whereas adults showed significant envelope following responses to almost the entire range of stimulus rates. CONCLUSION: Our results show that the auditory cortex of preschool-aged children has a sharply limited capacity to process rapid amplitude modulations in sounds, as compared to the auditory cortex of adults. SIGNIFICANCE: These neurophysiological results are consistent with previous psychophysical evidence for a protracted maturational time course for auditory temporal processing. The findings are also in good agreement with current linguistic theories that posit a perceptual bias for low frequency temporal information in speech during language acquisition. These insights also have clinical relevance for our understanding of language disorders that are associated with difficulties in processing temporal information in speech. PMID- 26424117 TI - Ebola and HIV: managing febrile times. PMID- 26424116 TI - Structural brain alterations in hemifacial spasm: A voxel-based morphometry and diffusion tensor imaging study. AB - OBJECTIVE: Hemifacial spasm (HFS) is characterized by involuntary, irregular clonic or tonic movement of muscles innervated by the facial nerve. We evaluated structural reorganization in brain gray matter and white matter and whether neuroplasticity is linked to clinical features in HFS patients. METHODS: High resolution structural magnetic resonance imaging and diffusion tensor imaging data were acquired by 3.0 T MRI from 42 patients with HFS and 30 healthy subjects. The severity of the spasm was assessed according to Jankovic disability rating scale. Voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) analysis were performed to identify regional grey matter volume (GMV) changes and whole-brain microstructural integrity disruption measured by fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). RESULTS: The VBM analysis showed that patients with HFS reduced GMV in the right inferior parietal lobule and increased GMV in the cerebellar lobule VIII, when compared with healthy subjects. Furthermore, within the HFS disease group, GMV decreased with the disease duration in the right inferior parietal lobule. TBSS did not identify group differences in diffusivity parameters. CONCLUSIONS: While no white matter integrity disruption was detected in the brain of patients with HFS, our study identified evident GMV changes in brain areas which were known to be involved in motor control. SIGNIFICANCE: Our results suggest that HFS, a chronic neurovascular conflict disease, is related to structural reorganization in the brain. PMID- 26424118 TI - Panobinostat clinical trial highlights the challenges towards an HIV cure. PMID- 26424120 TI - Temporal trends in prognostic markers of HIV-1 virulence and transmissibility: an observational cohort study. AB - BACKGROUND: Measures of CD4 T-cell count and HIV-1 plasma viral load before antiretroviral therapy are proxies for virulence. Whether these proxies are changing over time has implications for prevention and treatment. The aim of this study was to investigate those trends. METHODS: Data were derived from the Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) collaboration of mainly European seroconverter cohorts. Longitudinal CD4 cell counts and plasma viral load measurements before the initiation of antiretroviral therapy or AIDS onset were analysed by use of linear or fractional polynomials mixed models adjusting for all available potential confounders. Calendar time effects were modelled through natural cubic splines. FINDINGS: 15 875 individuals seroconverting from 1979 to 2008 fulfilled the inclusion criteria; 3215 (20.3%) were women; median follow-up was 31 months (IQR 14-62); dropout before starting antiretroviral therapy or AIDS onset was 8.1%. Estimated CD4 counts at seroconversion for a typical individual declined from about 770 cells per MUL (95% CI 750-800) in the early 1980s to a plateau of about 570 cells per MUL (555 585) after 2002. CD4 cell rate of loss increased up to 2002. Estimated set-point plasma viral loads increased from 4.05 log10 copies per mL (95% CI 3.98-4.12) in 1980 to 4.50 log10 copies per mL (4.45-4.54) in 2002 with a tendency of returning to lower loads thereafter. Results were similar when we restricted analyses to various subsets, including adjusting for plasma viral load assay, censored follow up at 3 years, or used variations of the main statistical approach. INTERPRETATION: Our results provide strong indications of increased HIV-1 virulence and transmissibility during the course of the epidemic and a potential plateau effect after about 2002. FUNDING: European Union Seventh Framework Programme. PMID- 26424121 TI - The first step on the continuum of care. PMID- 26424119 TI - Interventions to promote adherence to antiretroviral therapy in Africa: a network meta-analysis. AB - BACKGROUND: Adherence to antiretroviral therapy (ART) is necessary for the improvement of the health of patients and for public health. We sought to determine the comparative effectiveness of different interventions for improving ART adherence in HIV-infected people living in Africa. METHODS: We searched for randomised trials of interventions to promote antiretroviral adherence within adults in Africa. We searched AMED, CINAHL, Embase, Medline (via PubMed), and ClinicalTrials.gov from inception to Oct 31, 2014, with the terms "HIV", "ART", "adherence", and "Africa". We created a network of the interventions by pooling the published and individual patients' data for comparable treatments and comparing them across the individual interventions with Bayesian network meta analyses. The primary outcome was adherence defined as the proportion of patients meeting trial defined criteria; the secondary endpoint was viral suppression. FINDINGS: We obtained data for 14 randomised controlled trials, with 7110 patients. Interventions included daily and weekly short message service (SMS; text message) messaging, calendars, peer supporters, alarms, counselling, and basic and enhanced standard of care (SOC). Compared with SOC, we found distinguishable improvement in self-reported adherence with enhanced SOC (odds ratio [OR] 1.46, 95% credibility interval [CrI] 1.06-1.98), weekly SMS messages (1.65, 1.25-2.18), counselling and SMS combined (2.07, 1.22-3.53), and treatment supporters (1.83, 1.36-2.45). We found no compelling evidence for the remaining interventions. Results were similar when using viral suppression as an outcome, although the network contained less evidence than that for adherence. Treatment supporters with enhanced SOC (1.46, 1.09-1.97) and weekly SMS messages (1.55, 1.01-2.38) were significantly better than basic SOC. INTERPRETATION: Several recommendations for improving adherence are unsupported by the available evidence. These findings can inform future intervention choices for improving ART adherence in low-income settings. FUNDING: None. PMID- 26424122 TI - Network meta-analyses: powerful but not without perils. PMID- 26424123 TI - The HIV care continuum in black MSM in the USA. PMID- 26424124 TI - The changing virulence of HIV. PMID- 26424125 TI - Large-Scale Conformational Dynamics Control H5N1 Influenza Polymerase PB2 Binding to Importin alpha. AB - Influenza A RNA polymerase complex is formed from three components, PA, PB1, and PB2. PB2 is independently imported into the nucleus prior to polymerase reconstitution. All crystallographic structures of the PB2 C-terminus (residues 536-759) reveal two globular domains, 627 and NLS, that form a tightly packed heterodimer. The molecular basis of the affinity of 627-NLS for importins remained unclear from these structures, apparently requiring large-scale conformational changes prior to importin binding. Using a combination of solution state NMR, small-angle neutron scattering, small-angle X-ray scattering (SAXS), and Forster resonance energy transfer (FRET), we show that 627-NLS populates a temperature-dependent dynamic equilibrium between closed and open states. The closed state is stabilized by a tripartite salt bridge involving the 627-NLS interface and the linker, that becomes flexible in the open state, with 627 and NLS dislocating into a highly dynamic ensemble. Activation enthalpies and entropies associated with the rupture of this interface were derived from simultaneous analysis of temperature-dependent chemical exchange saturation transfer measurements, revealing a strong temperature dependence of both open state population and exchange rate. Single-molecule FRET and SAXS demonstrate that only the open-form is capable of binding to importin alpha and that, upon binding, the 627 domain samples a dynamic conformational equilibrium in the vicinity of the C-terminus of importin alpha. This intrinsic large-scale conformational flexibility therefore enables 627-NLS to bind importin through conformational selection from a temperature-dependent equilibrium comprising both functional forms of the protein. PMID- 26424127 TI - A telephone interview version of the middle childhood HOME Observation Measurement of the Environment. AB - BACKGROUND: The Home Observation Measurement of the Environment (HOME) is a 59 item observation and interview tool used to measure how suitable a child's home is for a child of his or her developmental age and has been used extensively in research. The HOME is usually performed in the child's home, which has cost implications. We wished to develop a telephone version of the HOME. METHODS: We developed a 54-item telephone interview version of the HOME and used it to measure the home environment in 77 children aged 6-10 years inclusive attending a child and adolescent mental health clinic, followed by a home visit and HOME assessment. The results of the telephone home assessment were then compared with the results of the original HOME. RESULTS: Our sample had a mean HOME score of 47.6, standard deviation (SD) = 5.5 and a mean telephone home score of 42.6, SD = 5.1. No difference was found in comparison of the subscale mean scores of the HOME with the telephone home assessment. The agreement of 54 items in common between the HOME and telephone home assessment ranged from 73% agreement to 100% agreement. Forty-three of 50 items had moderate to almost perfect agreement using kappa analysis (kappa = 0.41-0.99); three had 100% agreement. CONCLUSIONS: The telephone version of the HOME compares favourably with the HOME. PMID- 26424126 TI - Cubical Shape Enhances the Interaction of Layer-by-Layer Polymeric Particles with Breast Cancer Cells. AB - Blood-borne objects display a nonspherical shape with in-flow dimensions much larger than the vascular endothelial fenestrations, yet, at the diseased state, are able to traverse through these fenestrations owing to their elasticity. The role of physical parameters including shape and elasticity in the behavior of objects found in the tumor microenvironment needs to be understood to ultimately enhance chemotherapy and minimize its side effects. In this study, sphere- and cube-shaped biocompatible elastic microparticles (EM) made via layer-by-layer assembly of hydrogen-bonded tannic acid/poly(N-vinylpyrrolidone) (TA/PVPON) as hollow polymer shells and their rigid core-shell precursors (RM) are explored. In contrast to rigid five-bilayer (TA/PVPON) core shells, hollow elastic shells are unrecognized by J774A.1 macrophages, yet interact with endothelial and breast cancer cells. Internalization of cubical shells is fivefold more efficient by HMVEC (human microvascular endothelial cells) and sixfold and 2.5-fold more efficient by MDA-MB-231 and by SUM159 (breast cancer cells), respectively, compared to spherical shells. The interaction of cubical (TA/PVPON)5 shells with endothelial cells is similar under 10 s(-1) (characteristic of tumor vasculature) and 100 s(-1) shear rate (normal vasculature) while it is decreased at 100 s(-1) shear rate for the spherical shells. Our data suggest that cubical geometry promotes interaction of particles with breast cancer cells, while elasticity prevents engulfment by phagocytic cells in the tumor microenvironment. PMID- 26424128 TI - Association of BAFF, APRIL serum levels, BAFF-R, TACI and BCMA expression on peripheral B-cell subsets with clinical manifestations in systemic lupus erythematosus. AB - OBJECTIVE: B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) signaling pathways regulate B-cell survival through interactions with their receptors BAFF-R, TACI and BCMA. We evaluated the association of these ligands/receptors on B-cell subsets according to clinical manifestations of systemic lupus erythematosus (SLE). METHODS: BAFF and APRIL serum concentrations were measured in 30 SLE patients by enzyme-linked immunosorbent assay. The BAFF R, TACI and BCMA expression was analyzed on each B cell subset (CD19 + CD27-CD38 / + naive; CD19 + CD27 + CD38-/ + memory; CD19 + CD27-CD38 + + immature and CD19 + CD27 + CD38 + + plasma cells) by flow cytometry, and compared among patients with different clinical manifestations as well as healthy controls (HCs). RESULTS: Serum BAFF and APRIL levels were high in SLE patients and correlated with the Mex-SLEDAI disease activity index (r = 0.584; p = 0.001 and r = 0.456; p = 0.011, respectively). The SLE patients showed an increased proportion of memory and plasma B cells (p < 0.05). BAFF-R, TACI and BCMA expression in SLE patients was decreased in almost all B cell subsets compared to HCs (p < 0.05). A lower BCMA expression was associated with severe disease activity, glomerulonephritis, serositis and hemolytic anemia (p < 0.01). BCMA expression showed a negative correlation with Mex-SLEDAI score (r = -0.494, p = 0.006). CONCLUSIONS: Decreased BCMA expression on peripheral B cells according to severe disease activity suggests that BCMA plays an important regulating role in B-cell hyperactivity and immune tolerance homeostasis in SLE patients. PMID- 26424129 TI - Low bone mass and carotid atherosclerosis in lupus erythematosus patients from Granada, a city in the south of Spain. PMID- 26424131 TI - Effect of sesamin against cytokine production from influenza type A H1N1-induced peripheral blood mononuclear cells: computational and experimental studies. AB - In 2009, swine flu (H1N1) had spread significantly to levels that threatened pandemic influenza. There have been many treatments that have arisen for patients since the WHO first reported the disease. Although some progress in controlling influenza has taken place during the last few years, the disease is not yet under control. The development of new and less expensive anti-influenza drugs is still needed. Here, we show that sesamin from the seeds of the Thai medicinal plant Sesamum indicum has anti-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs) induced by 2009 influenza virus type A H1N1. In this study, the combinatorial screening method combined with the computational approach was applied to investigate the new molecular binding structures of sesamin against the 2009 influenza virus type A H1N1 (p09N1) crystallized structure. Experimental methods were applied to propose the mechanisms of sesamin against cytokine production from H1N1-induced human PBMC model. The molecular dynamics simulation of sesamin binding with the p09N1 crystallized structure showed new molecular binding structures at ARG118, ILE222, ARG224, and TYR406, and it has been proposed that sesamin could potentially be used to produce anti H1N1 compounds. Furthermore, the mechanisms of sesamin against cytokine production from influenza type A H1N1-induced PBMCs by ELISA and signaling transduction showed that sesamin exhibits the ability to inhibit proinflammatory cytokines, IL-1beta and TNF-alpha, and to enhance the activity of the immune cell cytokine IL-2 via downregulating the phosphorylated JNK, p38, and ERK1/2 MAPK signaling pathways. This information might very well be useful in the prevention and treatment of immune-induced inflammatory disorders. PMID- 26424132 TI - The role of microRNA-1 and microRNA-206 in the proliferation and differentiation of bovine skeletal muscle satellite cells. AB - MicroRNAs (miRNAs) have been found to play essential roles in muscle cell proliferation and differentiation. MicroRNA-1 (miR-1) and microRNA-206 (miR-206), which are similar and have the same seed sequence, have specific roles in modulating skeletal muscle proliferation and differentiation in vitro and in vivo. However, there is no information about their function during bovine skeletal muscle satellite cell development. In this study, the profiles of miR-1 and miR-206 and their biological functions in bovine skeletal muscle cell development was investigated. The target genes were predicted, and we used a dual luciferase reporter assay to demonstrate that miR-1 and miR-206 directly targeted the 3' untranslated region (3'UTR) of paired-box transcription factor Pax7 and histone deacetylase 4 (HDAC4). We showed that miR-1 and miR-206 facilitate bovine skeletal muscle satellite cell myogenic differentiation by restricting the expression of their target gene and that inhibition of miR-1 and miR-206 increased the Pax7 and HDAC4 protein levels and substantially enhanced satellite cell proliferation. Therefore, our results revealed the mechanism in which miR-1 and miR-206 positively regulate bovine skeletal muscle satellite cell myogenic differentiation via Pax7 and HDAC4 downregulation. PMID- 26424133 TI - RETROSPECTIVE METHOD VALIDATION AND UNCERTAINTY ESTIMATION FOR ACTINIDES DETERMINATION IN EXCRETA BY ALPHA SPECTROMETRY. AB - Two essential technical requirements of ISO 17025 guide for accreditation of testing and calibration laboratories are the validation of methods and the estimation of all sources of uncertainty that may affect the analytical result. Bioelimination Laboratory from Radiation Dosimetry Service of CIEMAT (Spain) uses alpha spectrometry to quantify alpha emitters (Pu, Am, Th, U and Cm isotopes) in urine and faecal samples from workers exposed to internal radiation. Therefore and as a step previous to achieving the ISO 17025 accreditation, the laboratory has performed retrospective studies based on the obtained results in the past few years to validate the analytical method. Uncertainty estimation was done identifying and quantifying all the contributions, and finally the overall combined standard uncertainty was calculated. PMID- 26424134 TI - RADON AND PROGENY SOURCED DOSE ASSESSMENT OF SPA EMPLOYEES IN BALNEOLOGICAL SITES. AB - This study was conducted in the scope of IAEA project with the name 'Establishing a Systematic Radioactivity Survey and Total Effective Dose Assessment in Natural Balneological Sites' (TUR/9/018), at the Health Physics department of Saraykoy Nuclear Research and Training Center (SANAEM). The aim of this study is estimation of radon and progeny sourced effective dose for the people who are working at the spa facilities by measuring radon activity concentration (RAC) at the ambient air of indoor spa pools and dressing rooms. As it is known, the source of the radon gas is the radium content of the earth crust. Therefore, thermal waters coming from ground may contain dissolved radon and the radon can diffuse water to air. So the ambient air of spa pools can contain serious RAC that depends on a lot of parameters. In this regard, RAC measurements were executed at the 70 spa facilities in Turkey. The measurements were done with both active and passive methods at ambient air of spa pools and dressing rooms. Thus, active measurements were carried out by using the Alphaguard((r)) with diffusion mode during half an hour, and passive measurements were carried out by using the humidity resistive CR-39 radon detectors during 2 months. Results show that RAC values at ambient air of spa pools varies between 13 Bq m(-3) and 10 kBq m(-3) Because long-term measurements are more reliable, if it is available, for dose calculations passive radon measurements (with CR-39 detectors) at ambient air of spa pools and dressing rooms were used, otherwise active measurement results were used. With the measurement by the conversion coefficients of ICRP 65 and occupational data of the employees has got from questionary forms, effective dose values were calculated. According to the calculations, spa employees are exposed to annual average dose between 0.05 and 29 mSv because of radon and progeny. PMID- 26424135 TI - PROPERTIES OF THE BEOSL DOSIMETRY SYSTEM IN THE FRAMEWORK OF A LARGE-SCALE PERSONAL MONITORING SERVICE. AB - The Individual Monitoring Service of the Helmholtz Zentrum Munchen is currently using the BeOSL dosimetry system for monitoring ~15 000 persons per month. This dosimetry system has a modular structure and represents a complete new concept on handling dosemeters in a large-scale dosimetry service. It is based on optically stimulated luminescence dosemeters made of beryllium oxide. The dosimetric and operational properties of the system are shown and discussed. PMID- 26424136 TI - CORRECTIONS ASSOCIATED WITH ON-PHANTOM CALIBRATIONS OF NEUTRON PERSONAL DOSEMETERS. AB - The response of neutron personal dosemeters as a function of neutron energy and angle of incidence is typically measured by mounting the dosemeters on a slab phantom and exposing them to neutrons from an accelerator-based or radionuclide source. The phantom is placed close to the source (75 cm) so that the effect of scattered neutrons is negligible. It is usual to mount several dosemeters on the phantom together. Because the source is close, the source distance and the neutron incidence angle vary significantly over the phantom face, and each dosemeter may receive a different dose equivalent. This is particularly important when the phantom is angled away from normal incidence. With accelerator-produced neutrons, the neutron energy and fluence vary with emission angle relative to the charged particle beam that produces the neutrons, contributing further to differences in dose equivalent, particularly when the phantom is located at other than the straight-ahead position (0 degrees to the beam). Corrections for these effects are quantified and discussed in this article. PMID- 26424137 TI - NATIONAL DOSE REGISTER IN FRANCE WITHIN THE NATIONAL INFORMATION SYSTEM SISERI. AB - Over the past decade, France has developed an electronic dose register at national level called SISERI. Institute for Radiological Protection and Nuclear Safety is in charge of the management of this information system. Besides the main purpose of being a central register of any doses measured for the individual dosimetric monitoring of all exposed workers, SISERI has been developed so as to constitute a tool for occupational physicians and radiation protection officers allowing access in real-time to the results of the individual monitoring. The SISERI information system centralises, verifies and keeps the records of all personal dosimetric results of the 370 000 workers annually monitored in France. Moreover, since the publication of a new order in 2013, employers shall declare any new workers in SISERI before the beginning of their occupation and they shall upload data concerning in particular the activity field/sector and the occupation of each worker. The enforcement of this new order is going to enrich the individual dosimetric information stored in SISERI. Thus, it is expected that more precise and accurate statistics on occupational exposure to ionising radiation in France will be established in the next few years. PMID- 26424138 TI - ESTABLISHMENT OF A NATIONAL DOSE REGISTER AND A DOSIMETRY SERVICE APPROVAL SYSTEM IN IRELAND. AB - Until the end of 2012, the Radiological Protection Institute of Ireland (RPII) operated a personal dosimetry service for workers in the medical, industrial, education and research sectors in Ireland. The data recorded by the RPII service were used to generate national dose statistics and as such acted as a National Dose Register (NDR). In preparation for the closure of the RPII dosimetry service in 2012, a formal NDR was introduced for the first time in Ireland and data on all monitored workers are now supplied to it annually by Approved Dosimetry Services. A new system for approving dosimetry services operating in Ireland was also introduced in 2012. The criteria for approval are based on the recommendations given in the European Commission's publication, 'Radiation Protection No. 160'. This paper describes the steps involved and the operational experience gained in establishing both the NDR and the system for approval of dosimetry services. PMID- 26424139 TI - Environmental Isolate of Rahnella aquatilis Harbors Class 1 Integron. AB - The paper presents first description of class 1 integron in an environmental strain of Rahnella aquatilis, a rarely isolated Gram-negative bacterium of the family Enterobacteriaceae. The strain was isolated from the Warta river water, Poland. Class 1 integrase gene was detected by a PCR assay. Sequencing of the integron's variable region showed the presence of a dfrA1-aadA1 gene cassette array. The integron was located in a 54-kbp plasmid that was transferable to Escherichia coli J-53 recipient strain in a conjugation assay. The integron bearing R. aquatilis strain was resistant to aminoglycosides, penicillins, trimethoprim, sulfamethoxazole, and trimethoprim/sulfamethoxazole. This paper confirms that water environment play a major role in the spread of integrons and, consequently, antimicrobial resistance, among bacteria of various genera. PMID- 26424140 TI - Bacterial Diversity in Bohai Bay Solar Saltworks, China. AB - The microbiota in solar salterns plays an important role in salt production quantitatively and qualitatively. Bohai Bay coast is the major sea salt producing area in China. However, few ecological characterization studies of the Bohai Bay salt ponds, particularly of their microbial diversity, have been conducted. This study investigated the structure and diversity of the bacterial community in Hangu saltworks in response to environmental factors. The brine water was sampled from five selected saltponds within a salinity range of 5.0-19.3% in May, July, and October, 2012. Phylogenetic analysis based on the denaturing gradient gel electrophoresis (DGGE) patterns of the PCR-amplified 16S rRNA gene fragment showed that, rather than pond salinity, especially the month of sampling influenced the structure of the bacterial community in the saltponds, which may be related to the water temperature or other factors fluctuating over the months. Moreover, canonical correspondence analysis of biological and physico-chemical parameters indicated that especially other environmental factors such as nitrogenous and phosphorous nutrient contents and pH structured the microbial community. The relatively high range-weighted richness index and Shannon-Wiener index (H') observed in this study reflect the high level of richness and biodiversity present, though there were substantial fluctuations over the months and salinities of sampling. The fragment of 16S rRNA gene sequence recovered from DGGE bands indicated that the bacterial assemblage in Hangu Saltworks was dominated by members of gamma-Proteobacteria (34% of total sequences obtained), followed by Firmicutes (14%) and Bacteroidetes (9%). PMID- 26424142 TI - Erratum to: Switching of mesodermal and endodermal properties in hTERT-modified and expanded fetal human pancreatic progenitor cells. PMID- 26424141 TI - Vitamin D and Clinical Outcomes in Dialysis. AB - Most dialysis patients are vitamin D deficient, including deficiencies in both activated vitamin D (1, 25-dihydroxyvitamin D) and the less active 25 hydroxyvitamin D. These and other abnormalities associated with chronic kidney disease (CKD), if they remain untreated, lead to secondary hyperparathyroidism and bone changes, such as osteitis fibrosa cystica. Activated vitamin D has been proven to decrease parathyroid hormone (PTH) levels in dialysis patients and is currently used for this indication. There are multiple other potential "pleotrophic" effects associated with vitamin D therapy. These include associations with lower all-cause and cardiovascular mortality, lower rates of infections and improved glycemic indexes. Meta-analyses of multiple observational studies have shown activated vitamin D therapy to be associated with improved survival. Observational data also suggest fewer infections and better glucose control. There have been no randomized clinical trials powered to evaluate mortality or other clinical outcomes. Small trials of nutritional vitamin D (ergocalciferol and cholecalciferol) showed increases in 25-hydroxyvitamin D levels without hypercalcemia or hyperphosphatemia, even when given in addition to activated vitamin D therapy. While activated vitamin D therapy is associated with improved outcomes, it also leads to higher fibroblast growth factor 23 (FGF-23) levels, which may be detrimental in dialysis patients. Further research is needed to evaluate whether activated or nutritional vitamin D therapy are beneficial in dialysis patients for outcomes other than secondary hyperparathyroidism. PMID- 26424143 TI - Small bowel tuberculosis causing massive obscure gastrointestinal bleeding in an immunocompromised patient. PMID- 26424144 TI - Intragenic KANSL1 mutations and chromosome 17q21.31 deletions: broadening the clinical spectrum and genotype-phenotype correlations in a large cohort of patients. AB - BACKGROUND: The 17q21.31 deletion syndrome phenotype can be caused by either chromosome deletions or point mutations in the KANSL1 gene. To date, about 60 subjects with chromosome deletion and 4 subjects with point mutation in KANSL1 have been reported. Prevalence of chromosome deletions compared with point mutations, genotype-phenotype correlations and phenotypic variability have yet to be fully clarified. METHODS: We report genotype-phenotype correlations in 27 novel subjects with 17q21.31 deletion and in 5 subjects with KANSL1 point mutation, 3 of whom were not previously reported. RESULTS: The prevalence of chromosome deletion and KANSL1 mutation was 83% and 17%, respectively. All patients had similar clinical features, with the exception of macrocephaly, which was detected in 24% of patients with the deletion and 60% of those with the point mutation, and congenital heart disease, which was limited to 35% of patients with the deletion. A remarkable phenotypic variability was observed in both categories, mainly with respect to the severity of ID. Cognitive function was within normal parameters in one patient in each group. Craniosynostosis, subependymal heterotopia and optic nerve hypoplasia represent new component manifestations. CONCLUSIONS: In KANSL1 haploinsufficiency syndrome, chromosome deletions are greatly prevalent compared with KANSL1 mutations. The latter are sufficient in causing the full clinical phenotype. The degree of intellectual disability (ID) appears to be milder than expected in a considerable number of subjects with either chromosome deletion or KANSL1 mutation. Striking clinical criteria for enrolling patients into KANSL1 analysis include speech delay, distinctive facial dysmorphism, macrocephaly and friendly behaviour. PMID- 26424145 TI - HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome. AB - BACKGROUND: The genetic aetiology of neurodevelopmental defects is extremely diverse, and the lack of distinctive phenotypic features means that genetic criteria are often required for accurate diagnostic classification. We aimed to identify the causative genetic lesions in two families in which eight affected individuals displayed variable learning disability, spasticity and abnormal gait. METHODS: Autosomal recessive inheritance was suggested by consanguinity in one family and by sibling recurrences with normal parents in the second. Autozygosity mapping and exome sequencing, respectively, were used to identify the causative gene. RESULTS: In both families, biallelic loss-of-function mutations in HACE1 were identified. HACE1 is an E3 ubiquitin ligase that regulates the activity of cellular GTPases, including Rac1 and members of the Rab family. In the consanguineous family, a homozygous mutation p.R219* predicted a truncated protein entirely lacking its catalytic domain. In the other family, compound heterozygosity for nonsense mutation p.R748* and a 20-nt insertion interrupting the catalytic homologous to the E6-AP carboxyl terminus (HECT) domain was present; western blot analysis of patient cells revealed an absence of detectable HACE1 protein. CONCLUSION: HACE1 mutations underlie a new autosomal recessive neurodevelopmental disorder. Previous studies have implicated HACE1 as a tumour suppressor gene; however, since cancer predisposition was not observed either in homozygous or heterozygous mutation carriers, this concept may require re evaluation. PMID- 26424147 TI - Biogeographic distribution and metric dental variation of fossil and living orangutans (Pongo spp.). AB - The genus Pongo has a relatively richer Quaternary fossil record than those of the African great apes. Fossil materials are patchy in terms of anatomical parts represented, limited almost exclusively to isolated teeth, jaw and bone fragments. Fossil evidence indicates that the genus Pongo had a broadly continuous distribution across the southern part of the Indomalayan biogeographic region, ranging in time from Early Pleistocene to Holocene: southern China (77 fossil sites), Vietnam (15), Laos (6), Cambodia (2), Thailand (4), Peninsular Malaysia (6), Sumatra (4), Borneo (6) and Java (4). Within this distribution range, there are major geographical gaps with no known orangutan fossils, notably central and southern Indochina, central and southern Thailand, eastern Peninsular Malaysia, northern and southern Sumatra, and Kalimantan. The geological time and place of origin of the genus remain unresolved. Fossil orangutan assemblages usually show greater extent of dental metrical variation than those of modern-day populations. Such variability shown in prehistoric populations has partially contributed to confusion regarding past taxonomic diversity and systematic relationships among extinct and living forms. To date, no fewer than 14 distinct taxa have been identified and named for Pleistocene orangutans. Clear cases suggestive of predation by prehistoric human are few in number, and limited to terminal Pleistocene-Early Holocene sites in Borneo and a Late Pleistocene site in Vietnam. PMID- 26424146 TI - Aberrant activation of NF-kappaB signaling in mammary epithelium leads to abnormal growth and ductal carcinoma in situ. AB - BACKGROUND: Approximately 1 in 5 women diagnosed with breast cancer are considered to have in situ disease, most often termed ductal carcinoma in situ (DCIS). Though recognized as a risk factor for the development of more invasive cancer, it remains unclear what factors contribute to DCIS development. It has been shown that inflammation contributes to the progression of a variety of tumor types, and nuclear factor kappa B (NF-kappaB) is recognized as a master-regulator of inflammatory signaling. However, the contributions of NF-kappaB signaling to tumor initiation are less well understood. Aberrant up-regulation of NF-kappaB activity, either systemically or locally within the breast, could occur due to a variety of commonly experienced stimuli such as acute infection, obesity, or psychological stress. In this study, we seek to determine if activation of NF kappaB in mammary epithelium could play a role in the formation of hyperplastic ductal lesions. METHODS: Our studies utilize a doxycycline-inducible transgenic mouse model in which constitutively active IKKbeta is expressed specifically in mammary epithelium. All previously published models of NF-kappaB modulation in the virgin mammary gland have been constitutive models, with transgene or knock out present throughout the life and development of the animal. For the first time, we will induce activation at later time points after normal ducts have formed, thus being able to determine if NF-kappaB activation can promote pre malignant changes in previously normal mammary epithelium. RESULTS: We found that even a short pulse of NF-kappaB activation could induce profound remodeling of mammary ductal structures. Short-term activation created hyperproliferative, enlarged ducts with filled lumens. Increased expression of inflammatory markers was concurrent with the down-regulation of hormone receptors and markers of epithelial differentiation. Furthermore, the oncoprotein mucin 1, known to be up regulated in human and mouse DCIS, was over-expressed and mislocalized in the activated ductal tissue. CONCLUSIONS: These results indicate that aberrant NF kappaB activation within mammary epithelium can lead to molecular and morphological changes consistent with the earliest stages of breast cancer. Thus, inhibition of NF-kappaB signaling following acute inflammation or the initial signs of hyperplastic ductal growth could represent an important opportunity for breast cancer prevention. PMID- 26424148 TI - Inhibitory effect of novel iron chelator, 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2 methylpyridin-4-one (CM1) and green tea extract on growth of Plasmodium falciparum. AB - BACKGROUND: Iron is an essential micronutrient required by all living organisms including malaria parasites (Plasmodium spp.) for many biochemical reactions, especially growth and multiplication processes. Therefore, malaria parasite needs to take up the iron from outside or/and inside the parasitized red blood cells (PRBC). Iron chelators are widely used for the treatment of thalassaemia-related iron overload and also inhibit parasite growth at levels that are non-toxic to mammalian cells. METHODS: Inhibitory effect of 1-(N-acetyl-6-aminohexyl)-3 hydroxy-2-methylpyridin-4-one (CM1) and green tea extract (GTE) on the growth of malaria parasite Plasmodium falciparum was compared with standard chelators including desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX). A flow cytometric technique was used to enumerate PRBC stained with SYBR Green I fluorescent dye. The labile iron pool (LIP) was assayed using the calcein acetoxymethyl fluorescent method. RESULTS: The IC50 values of DFO, GTE, CM1, DFX and DFP against P. falciparum were 14.09, 21.11, 35.14, 44.71 and 58.25 uM, respectively. Importantly, CM1 was more effective in reducing LIP levels in the P. falciparum culture than DFP (p < 0.05). CONCLUSIONS: CM1 and GTE exhibit anti malarial activity. They could interfere with uptake of exogenous iron or deplete the intracellular labile iron pool in malaria parasites, leading to inhibition of their growth. PMID- 26424149 TI - Type 5 adenylyl cyclase disruption leads to enhanced exercise performance. AB - The most important physiological mechanism mediating enhanced exercise performance is increased sympathetic, beta adrenergic receptor (beta-AR), and adenylyl cyclase (AC) activity. This is the first report of decreased AC activity mediating increased exercise performance. We demonstrated that AC5 disruption, that is, knock out (KO) mice, a longevity model, increases exercise performance. Importantly for its relation to longevity, exercise was also improved in old AC5 KO. The mechanism resided in skeletal muscle rather than in the heart, as confirmed by cardiac- and skeletal muscle-specific AC5 KO's, where exercise performance was no longer improved by the cardiac-specific AC5 KO, but was by the skeletal muscle-specific AC5 KO, and there was no difference in cardiac output during exercise in AC5 KO vs. WT. Mitochondrial biogenesis was a major mechanism mediating the enhanced exercise. SIRT1, FoxO3a, MEK, and the anti-oxidant, MnSOD were upregulated in AC5 KO mice. The improved exercise in the AC5 KO was blocked with either a SIRT1 inhibitor, MEK inhibitor, or by mating the AC5 KO with MnSOD hetero KO mice, confirming the role of SIRT1, MEK, and oxidative stress mechanisms. The Caenorhabditis elegans worm AC5 ortholog, acy-3 by RNAi, also improved fitness, mitochondrial function, antioxidant defense, and lifespan, attesting to the evolutionary conservation of this pathway. Thus, decreasing sympathetic signaling through loss of AC5 is not only a mechanism to improve exercise performance, but is also a mechanism to improve healthful aging, as exercise also protects against diabetes, obesity, and cardiovascular disease, which all limit healthful aging. PMID- 26424150 TI - Nonintubated Transareolar Endoscopic Thoracic Sympathectomy with a Flexible Endoscope: Experience of 58 Cases. AB - OBJECTIVE: Natural orifice transluminal endoscopic surgery (NOTES) has recently become a hot spot in the field of minimally invasive surgery. But, most of the procedures are still in the early stages of development and limited to animal experiments. Transareolar endoscopic surgery could work as a viable intermediate step before thoracic NOTES. Under intravenous anesthesia without endotracheal intubation, transareolar endoscopic thoracic sympathectomy (ETS) with a flexible endoscope has rarely been attempted. The objective of this study is to evaluate the feasibility and safety of this novel minimally invasive technique in managing primary palmar hyperhidrosis (PPH). METHODS: From June 2012 to July 2014, a total of 58 male patients with severe PPH underwent transareolar ETS by use of a flexible endoscope. Under intravenous anesthesia without endotracheal intubation, a flexible endoscope was introduced through the incision on the edge of the areola into the thoracic cavity. The thoracic sympathetic chain was ablated at the level of the fourth rib. RESULTS: All procedures were successfully performed with a mean operating time of 33.6 +/- 8.3 min. All patients regained consciousness rapidly and none of them complained about sore throat after surgery. There were no operative mortality and conversion to open procedure. The symptoms of all patients disappeared as soon as the sympathetic chain was cut off. Fifty six patients (96.6%) were discharged from the hospital on the first postoperative day. The postoperative complications were minor, and no patients developed Horner's syndrome. At 3 months postoperatively, there was no obvious surgical scar on the chest wall, and none of the patients complained about postoperative pain. Compensatory hyperhidrosis (CH) appeared in 19 patients. No recurrent symptoms were observed in our study. One year follow-up revealed an excellent cosmetic result and degree of satisfaction. CONCLUSION: Nonintubated transareolar ETS with a flexible endoscope is a safe, effective and minimally invasive therapeutic procedure, which has the possible advantages of thoracic NOTES and can be performed in routine clinical practice for male PPH patients. PMID- 26424151 TI - Climbing fibers mediate vestibular modulation of both "complex" and "simple spikes" in Purkinje cells. AB - Climbing and mossy fibers comprise two distinct afferent paths to the cerebellum. Climbing fibers directly evoke a large multispiked action potential in Purkinje cells termed a "complex spike" (CS). By logical exclusion, the other class of Purkinje cell action potential, termed "simple spike" (SS), has often been attributed to activity conveyed by mossy fibers and relayed to Purkinje cells through granule cells. Here, we investigate the relative importance of climbing and mossy fiber pathways in modulating neuronal activity by recording extracellularly from Purkinje cells, as well as from mossy fiber terminals and interneurons in folia 8-10. Sinusoidal roll-tilt vestibular stimulation vigorously modulates the discharge of climbing and mossy fiber afferents, Purkinje cells, and interneurons in folia 9-10 in anesthetized mice. Roll-tilt onto the side ipsilateral to the recording site increases the discharge of both climbing fibers (CSs) and mossy fibers. However, the discharges of SSs decrease during ipsilateral roll-tilt. Unilateral microlesions of the beta nucleus (beta nucleus) of the inferior olive blocks vestibular modulation of both CSs and SSs in contralateral Purkinje cells. The blockage of SSs occurs even though primary and secondary vestibular mossy fibers remain intact. When mossy fiber afferents are damaged by a unilateral labyrinthectomy (UL), vestibular modulation of SSs in Purkinje cells ipsilateral to the UL remains intact. Two inhibitory interneurons, Golgi and stellate cells, could potentially contribute to climbing fiber-induced modulation of SSs. However, during sinusoidal roll-tilt, only stellate cells discharge appropriately out of phase with the discharge of SSs. Golgi cells discharge in phase with SSs. When the vestibularly modulated discharge is blocked by a microlesion of the inferior olive, the modulated discharge of CSs and SSs is also blocked. When the vestibular mossy fiber pathway is destroyed, vestibular modulation of ipsilateral CSs and SSs persists. We conclude that climbing fibers are primarily responsible for the vestibularly modulated discharge of both CSs and SSs. Modulation of the discharge of SSs is likely caused by climbing fiber evoked stellate cell inhibition. PMID- 26424152 TI - Plastic changes in spinal synaptic transmission following botulinum toxin A in patients with post-stroke spasticity. AB - OBJECTIVE: The therapeutic effects of intramuscular injections of botulinum toxin type A on spasticity can largely be explained by its blocking action at the neuromuscular junction. Botulinum toxin-type A is also thought to have a central action on the functional organization of the central nervous system. This study assessed the action of botulinum toxin-type A on spinal motor networks by investigating post-activation depression of the soleus H-reflex in post-stroke patients. Post-activation depression, a presynaptic mechanism controlling the synaptic efficacy of Ia-motoneuron transmission, is involved in the pathophysiology of spasticity. PATIENTS: Eight patients with chronic hemiplegia post-stroke presenting with lower limb spasticity and requiring botulinum toxin type A injection in the ankle extensor muscle. METHODS: Post-activation depression of soleus H-reflex assessed as frequency-related depression of H reflex was investigated before and 3, 6 and 12 weeks after botulinum toxin-type A injections in the triceps surae. Post-activation depression was quantified as the ratio between H-reflex amplitude at 0.5 and 0.1 Hz. RESULTS: Post-activation depression of soleus H-reflex, which is reduced on the paretic leg, was affected 3 weeks after botulinum toxin-type A injection. Depending on the residual motor capacity of the post-stroke patients, post-activation depression was either restored in patients with preserved voluntary motor control or further reduced in patients with no residual voluntary control. CONCLUSION: Botulinum toxin treatment induces synaptic plasticity at the Ia-motoneuron synapse in post-stroke paretic patients, which suggests that the effectiveness of botulinum toxin-type A in post-stroke rehabilitation might be partly due to its central effects. PMID- 26424153 TI - Transcriptome sequencing and analysis of major genes involved in calcium signaling pathways in pear plants (Pyrus calleryana Decne.). AB - BACKGROUND: Pears (Pyrus spp. L.) are an important genus of trees that produce one of the world's oldest fruit crops. Salinity stress is a common limiting factor for plant productivity that significantly affects the flavor and nutritional quality of pear fruits. Much research has shown that calcium signaling pathways, mediated by Calcineurin B-like proteins (CBLs) and their interacting kinases (CIPKs), are closely associated with responses to stresses, including salt. However, little is known about the molecular mechanisms that govern the relationship between salt stress and calcium signaling pathways in pear plants. The available genomic information for pears has promoted much functional genomic analysis and molecular breeding of the genus. This provided an ample foundation for characterizing the transcriptome of pear under salt stress. RESULTS: A high-throughput Illumina RNA-seq technology was used to identify a total of 78,695 unigenes that were successfully annotated by BLASTX analysis, using the publicly available protein database. Additionally, 2,855 novel transcripts, 218,167 SNPs, 23,248 indels and 18,322 alternative splicing events occurred. Assembled unique sequences were annotated and classified with Gene Ontology (GO), Clusters of Orthologous Group (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, which revealed that the main activated genes in pear are predominately involved in functions such as basic physiological processes, metabolic pathways, operation of cellular components, signal transduction mechanisms, and other molecular activities. Through targeted searches of the annotations, the majority of the genes involved in calcium signaling pathways were identified, among which, four genes were validated by molecular cloning, while 11 were validated by RT-qPCR expression profiles under salt stress treatment. CONCLUSIONS: These results facilitate a better understanding of the molecular genetics and functional genomic mechanisms of salt stress in pear plants. Furthermore, they provide a valuable foundation for additional research on the molecular biology and functional genomics of pear and related species. PMID- 26424154 TI - Suspension Array of Ionic Liquid or Ionic Liquid-Quantum Dots Conjugates for the Discrimination of Proteins and Bacteria. AB - It is of great importance to develop novel and sensitive sensing materials for the detection of proteins and microorganisms to fulfill the demand of disease diagnosis. As the selectivity and sensitivity of sensing systems are highly dependent on the receptor, the fluorescent sensor array with imidazolium ionic liquids (ILs) and ionic liquid-quantum dots conjugates as semiselective receptors is developed for protein/bacteria differential sensing or discrimination. The IL sensing system formed by 1,3-dibutylimidazolium chloride (BBimCl), 1,3 diethylimidazolium bromine (EEimBr), 1,3-dibutylimidazolium bromine (BBimBr), 1,3 dihexylimidazolium bromine (HHimBr), and 1,3-dioctylimidazolium bromine (OOimBr) and the IL@QDs/QDs sensing system formed by CdTe, BBimCl@CdTe, EEimBr@CdTe, BBimBr@CdTe, and HHimBr@CdTe are tested, by transferring the interaction binding difference between receptors and proteins to the fluorescent response pattern. The IL sensing system is applied to the identification of 48 samples (8 proteins at 500 nM) with an accuracy of 91.7%. For the IL@QDs/QDs sensing system, 8 proteins are completely distinguished with 100% accuracy at a very low concentration level of 10 nM. Remarkably, 36 training cases (6 strains of bacteria from 3 different species) are discriminated with 100% (OD600 of 0.1). PMID- 26424155 TI - Sleep and agitation in nursing home residents with and without dementia. AB - BACKGROUND: The prevalence of dementia in Australian nursing homes is high. A large proportion of residents express themselves through agitated behaviors, with substantial interpersonal and day-to-day variance. One factor that may increase agitation is poor sleep. The current study aimed to determine if sleep influences symptoms of agitation in nursing home residents, and whether this effect differed by dementia status. As benzodiazepines are used widely as hypnotic medication, their impact was also considered. METHODS: Actigraph devices worn on residents' non-dominant wrists for three days were used to obtain objective measures of sleep. Symptoms of agitation were assessed using staff responses to two standardized questionnaires - the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory - nursing home version (NPI-NH). Presence of dementia and benzodiazepine use were obtained from resident medical charts. RESULTS: Forty-nine residents (mean age: 85.57 years) from four nursing homes in Tasmania were included in the study. Results indicated that residents were in bed for an average of 11.04 h and slept for 10.14 h per day. Significant relationships between sleep and verbal as well as non-aggressive agitation were found. No relationships between sleep and aggressive agitation were detected. A significant moderation effect of dementia was found, in which residents without dementia expressed verbal agitation when obtaining less sleep, but not residents with dementia. Benzodiazepine use did not result in significantly more sleep. CONCLUSIONS: These results suggest that sleep could play an important role in explaining agitation, but more research is needed to explore the relationship between sleep and benzodiazepines in nursing home residents. PMID- 26424156 TI - GP is struck off for dishonestly providing sick notes for children. PMID- 26424157 TI - Rice SPX-Major Facility Superfamily3, a Vacuolar Phosphate Efflux Transporter, Is Involved in Maintaining Phosphate Homeostasis in Rice. AB - To maintain a stable cytosol phosphate (Pi) concentration, plant cells store Pi in their vacuoles. When the Pi concentration in the cytosol decreases, Pi is exported from the vacuole into the cytosol. This export is mediated by Pi transporters on the tonoplast. In this study, we demonstrate that SYG1, PHO81, and XPR1 (SPX)-Major Facility Superfamily (MFS) proteins have a similar structure with yeast (Saccharomyces cerevisiae) low-affinity Pi transporters Phosphatase87 (PHO87), PHO90, and PHO91. OsSPX-MFS1, OsSPX-MFS2, and OsSPX-MFS3 all localized on the tonoplast of rice (Oryza sativa) protoplasts, even in the absence of the SPX domain. At high external Pi concentration, OsSPX-MFS3 could partially complement the yeast mutant strain EY917 under pH 5.5, which lacks all five Pi transporters present in yeast. In oocytes, OsSPX-MFS3 was shown to facilitate Pi influx or efflux depending on the external pH and Pi concentrations. In contrast to tonoplast localization in plants cells, OsSPX-MFS3 was localized to the plasma membrane when expressed in both yeast and oocytes. Overexpression of OsSPX-MFS3 results in decreased Pi concentration in the vacuole of rice tissues. We conclude that OsSPX-MFS3 is a low-affinity Pi transporter that mediates Pi efflux from the vacuole into cytosol and is coupled to proton movement. PMID- 26424160 TI - Constructing a representative sample of out-of-care HIV patients from a representative sample of in-care patients. AB - Individuals infected with HIV who are out of care are at a higher risk of HIV related morbidity and mortality. It has been difficult to recruit a representative sample of out-of-care patients for epidemiological studies. Using a novel weighting method, we constructed a representative sample of out-of-care HIV patients from a representative sample of in-care patients. In-care patients were weighted based on the probability of receiving care during the study period and the probability of selection to participate in the study, and out-of-care patients were represented by those who were previously out of care and recently returned. The method can be used in other patient populations, if every patient in the population has a known, non-zero probability of receiving care and a known, non-zero probability of participating in the study. PMID- 26424158 TI - OsMADS26 Negatively Regulates Resistance to Pathogens and Drought Tolerance in Rice. AB - Functional analyses of MADS-box transcription factors in plants have unraveled their role in major developmental programs (e.g. flowering and floral organ identity) as well as stress-related developmental processes, such as abscission, fruit ripening, and senescence. Overexpression of the rice (Oryza sativa) MADS26 gene in rice has revealed a possible function related to stress response. Here, we show that OsMADS26-down-regulated plants exhibit enhanced resistance against two major rice pathogens: Magnaporthe oryzae and Xanthomonas oryzae. Despite this enhanced resistance to biotic stresses, OsMADS26-down-regulated plants also displayed enhanced tolerance to water deficit. These phenotypes were observed in both controlled and field conditions. Interestingly, alteration of OsMADS26 expression does not have a strong impact on plant development. Gene expression profiling revealed that a majority of genes misregulated in overexpresser and down-regulated OsMADS26 lines compared with control plants are associated to biotic or abiotic stress response. Altogether, our data indicate that OsMADS26 acts as an upstream regulator of stress-associated genes and thereby, a hub to modulate the response to various stresses in the rice plant. PMID- 26424161 TI - Correlates of HIV infection among street-based and venue-based sex workers in Vietnam. AB - Commercial sex work is one of the driving forces of the HIV epidemic across the world. In Vietnam, although female sex workers (FSWs) carry a disproportionate burden of HIV, little is known about the risk profile and associated factors for HIV infection among this population. There is a need for large-scale research to obtain reliable and representative estimates of the measures of association. This study involved secondary data analysis of the 'HIV/STI Integrated Biological and Behavioral Surveillance' study in Vietnam in 2009-2010 to examine the correlates of HIV among FSWs. Data collected from 5298 FSWs, including 2530 street-based sex workers and 2768 venue-based sex workers from 10 provinces in Vietnam, were analyzed using descriptive statistics and bivariate and multivariate logistic regression analyses. HIV prevalence among the overall FSW population was 8.6% (n = 453). However, when stratified by FSW subpopulations, HIV prevalence was 10.6% (n = 267) for street-based sex workers and 6.7% (n = 186) for venue-based sex workers. Factors independently associated with HIV infection in the multivariate analysis, regardless of sex work types, were injecting drug use, high self perceived HIV risk, and age >= 25 years. Additional factors independently associated with HIV risk within each FSW subpopulation included having ever been married among street-based sex workers and inconsistent condom use with clients and having sex partners who injected drugs among venue-based sex workers. Apart from strategies addressing modifiable risk behaviours among all FSWs, targeted strategies to address specific risk behaviours within each FSW subpopulation should be adopted. PMID- 26424159 TI - Metabolite Profiles of Maize Leaves in Drought, Heat, and Combined Stress Field Trials Reveal the Relationship between Metabolism and Grain Yield. AB - The development of abiotic stress-resistant cultivars is of premium importance for the agriculture of developing countries. Further progress in maize (Zea mays) performance under stresses is expected by combining marker-assisted breeding with metabolite markers. In order to dissect metabolic responses and to identify promising metabolite marker candidates, metabolite profiles of maize leaves were analyzed and compared with grain yield in field trials. Plants were grown under well-watered conditions (control) or exposed to drought, heat, and both stresses simultaneously. Trials were conducted in 2010 and 2011 using 10 tropical hybrids selected to exhibit diverse abiotic stress tolerance. Drought stress evoked the accumulation of many amino acids, including isoleucine, valine, threonine, and 4 aminobutanoate, which has been commonly reported in both field and greenhouse experiments in many plant species. Two photorespiratory amino acids, glycine and serine, and myoinositol also accumulated under drought. The combination of drought and heat evoked relatively few specific responses, and most of the metabolic changes were predictable from the sum of the responses to individual stresses. Statistical analysis revealed significant correlation between levels of glycine and myoinositol and grain yield under drought. Levels of myoinositol in control conditions were also related to grain yield under drought. Furthermore, multiple linear regression models very well explained the variation of grain yield via the combination of several metabolites. These results indicate the importance of photorespiration and raffinose family oligosaccharide metabolism in grain yield under drought and suggest single or multiple metabolites as potential metabolic markers for the breeding of abiotic stress-tolerant maize. PMID- 26424163 TI - Junior doctors' dispute is result of financial mismanagement, Labour says. PMID- 26424162 TI - Design, synthesis and antiviral evaluation of 2'-C-methyl branched guanosine pronucleotides: the discovery of IDX184, a potent liver-targeted HCV polymerase inhibitor. AB - BACKGROUND: Ribonucleoside analogs possessing a beta-methyl substituent at the 2' position of the d-ribose moiety have been previously discovered to be potent and selective inhibitors of hepatitis C virus (HCV) replication, their triphosphates acting as alternative substrate inhibitors of the HCV RdRp NS5B. Results/methodology: In this article, the authors detail the synthesis, anti-HCV evaluation in cell-based replicon assays and structure-activity relationships of several phosphoramidate diester derivatives of 2'-C-methylguanosine (2'-MeG). CONCLUSION: The most promising compound, namely the O-[S-(hydroxyl)pivaloyl-2 thioethyl]{abbreviated as O-[(HO)tBuSATE)]} N-benzylamine phosphoramidate diester derivative (IDX184), was selected for further in vivo studies, and was the first clinical pronucleotide evaluated for the treatment of chronic hepatitis C up to Phase II trials. PMID- 26424164 TI - The Stomach-Derived Hormone Ghrelin Increases Impulsive Behavior. AB - Impulsivity, defined as impaired decision making, is associated with many psychiatric and behavioral disorders, such as attention-deficit/hyperactivity disorder as well as eating disorders. Recent data indicate that there is a strong positive correlation between food reward behavior and impulsivity, but the mechanisms behind this relationship remain unknown. Here we hypothesize that ghrelin, an orexigenic hormone produced by the stomach and known to increase food reward behavior, also increases impulsivity. In order to assess the impact of ghrelin on impulsivity, rats were trained in three complementary tests of impulsive behavior and choice: differential reinforcement of low rate (DRL), go/no-go, and delay discounting. Ghrelin injection into the lateral ventricle increased impulsive behavior, as indicated by reduced efficiency of performance in the DRL test, and increased lever pressing during the no-go periods of the go/no-go test. Central ghrelin stimulation also increased impulsive choice, as evidenced by the reduced choice for large rewards when delivered with a delay in the delay discounting test. In order to determine whether signaling at the central ghrelin receptors is necessary for maintenance of normal levels of impulsive behavior, DRL performance was assessed following ghrelin receptor blockade with central infusion of a ghrelin receptor antagonist. Central ghrelin receptor blockade reduced impulsive behavior, as reflected by increased efficiency of performance in the DRL task. To further investigate the neurobiological substrate underlying the impulsivity effect of ghrelin, we microinjected ghrelin into the ventral tegmental area, an area harboring dopaminergic cell bodies. Ghrelin receptor stimulation within the VTA was sufficient to increase impulsive behavior. We further evaluated the impact of ghrelin on dopamine-related gene expression and dopamine turnover in brain areas key in impulsive behavior control. This study provides the first demonstration that the stomach-produced hormone ghrelin increases impulsivity and also indicates that ghrelin can change two major components of impulsivity-motor and choice impulsivity. PMID- 26424166 TI - Explicating perceived barriers to mammography for the USCREEN project: concerns about breast implants, faith violations, and perceived recommendations. AB - In line with the health belief model, perceived barriers have proven to be a key determinant of intentions to screen for breast cancer. The standard measure of perceived barriers to breast cancer screening is an 11 item scale developed by Victoria Champion. However, perceived barriers emerge and change over time, and Champion's perceived barriers scale was last revised in 1999. Moreover, the original scale did not address barriers which may be more pronounced in particular populations, such as congruity of action with faith. As part of the Utah Screening Project, a sample of women 40-74 (N = 341, Mage = 51.19, SD = 8.11) were recruited from four Utah counties in 2014 to complete a survey. The results revealed that the four new perceived barrier items explained 6.4 % of intentions to screen, above and beyond other predictors. In addition to barriers identified in past research, the current study identified several novel barriers including (a) concerns about negative effects to breast implants, (b) perceived conflict with faith, and the (c) perception that mammography is no longer recommended. The new perceived barriers items are useful to researchers interested in exploring barriers not addressed by the original instrument. The barriers also suggest potential belief-based targets and channels (e.g., plastic surgery clinics, faith-based interventions) for delivering mammography interventions. PMID- 26424165 TI - Metabolic and anthropometric changes in early breast cancer patients receiving adjuvant therapy. AB - Weight gain and metabolic changes have been related to survival of early breast cancer patients (EBC). ''However, factors influencing metabolism post-diagnosis are not fully understood. We measured anthropometric [body mass index (BMI), body weight, waist and hip circumferences, and waist-to-hip ratio] and metabolic (levels of insulin, glucose, H1Ac, total, HDL, and LDL cholesterol, triglycerides, and the homeostasis model assessment score [HOMA]) parameters in 433 pre- and post-menopausal women with EBC at diagnosis and 3, 6, 9, 12, and 24 months thereafter. At diagnosis, compared with post-menopausal women, pre menopausal patients were more likely to be leaner and to have a lower BMI, smaller waist and hip circumferences, and waist-to-hip ratio. They had also lower glucose, HbA1c, and triglyceride levels and a lower HOMA score. Furthermore, they were more likely to have an estrogen- and/or progesterone-positive tumor and a higher proliferating breast cancer. During the first two post-diagnosis years, all women showed a significant increase of weight (+0.72 kg/year, P < 0.001), waist circumference (+1.53 cm/year, P < 0.001), and plasma levels of LDL cholesterol (+5.4 mg/dl per year, P = 0.045) and triglycerides (+10.73 mg/dl per year, P = 0.017). In patients receiving chemotherapy only, there was a significant increase in hip circumference (+3.16 cm/year, P < 0.001) and plasma cholesterol levels (+21.26 mg/dl per year, P < 0.001). We showed that weight, body fat distribution, and lipid profile changed in EBC patients receiving adjuvant therapy. These changes occurred during the first 2 years after diagnosis and were not specifically related to chemotherapy, menopausal status, or initial body weight. PMID- 26424167 TI - Molecular subtyping improves diagnostic stratification of patients with primary breast cancer into prognostically defined risk groups. AB - Combined use of MammaPrint and a molecular subtyping profile (BluePrint) identifies disease subgroups with marked differences in long-term outcome and response to neo-adjuvant therapy. The aim of this study was to evaluate the prognostic value of molecular subtyping using MammaPrint and BluePrint in women with early-stage breast cancer (BC) treated at US institutions following National Comprehensive Cancer Network standard guidelines. Tumor samples were collected from stage 1-2B consecutively diagnosed BC patients (n = 373) who underwent lumpectomy or mastectomy with an axillary staging procedure between 1992 and 2010 at two institutes (NorthShore University HealthSystem and Fox Chase Cancer Center) in the United States of America, with a median follow-up time of 9.5 years. MammaPrint low-risk patients had a 10-year DMFS of 96 % (95 %CI 92.8 99.4), while MammaPrint high-risk patients had a 10-year DMFS of 87 % (95 %CI 81.9-92.1) with a hazard ratio of 3.62 (95 %CI 1.38-9.50) (p = 0.005). Uni- and multivariate analyses included age, tumor size, grade, ER, and Her2; in multivariate analysis, MammaPrint reached near-significance (HR 3.01; p 0.08). When comparing BluePrint molecular subtyping with clinical stratification, the prognosis (10-year DMFS) was significantly different in 10-year DMFS between the different molecular subtypes (p < 0.001). This retrospective study with 10-year follow-up data provides valuable insight into prognosis of patients with primary BC comparing clinical with molecular subtyping. The BluePrint molecular stratification assay identifies patients with significantly different outcomes compared with standard clinical molecular stratification. PMID- 26424168 TI - Cognitive deficits and anxiety induced by diisononyl phthalate in mice and the neuroprotective effects of melatonin. AB - Diisononyl phthalate (DINP) is a plasticizer that is frequently used as a substitute for other plasticizers whose use is prohibited in certain products. In vivo studies on the neurotoxicity of DINP are however, limited. This work aims to investigate whether DINP causes neurobehavioral changes in mice and to provide useful advice on preventing the occurrence of these adverse effects. Behavioral analysis showed that oral administration of 20 or 200 mg/kg/day DINP led to mouse cognitive deficits and anxiety. Brain histopathological observations, immunohistochemistry assays (cysteine-aspartic acid protease 3 [caspase-3], glial fibrillary acidic protein [GFAP]), oxidative stress assessments (reactive oxygen species [ROS], glutathione [GSH], superoxide dismutase [SOD] activities, 8 hydroxy-2-deoxyguanosine [8-OH-dG] and DNA-protein crosslinks [DPC]), and assessment of inflammation (tumor necrosis factor alpha [TNF-a] and interleukin-1 beta [IL-1beta]) of mouse brains showed that there were histopathological alterations in the brain and increased levels of oxidative stress, and inflammation for these same groups. However, some of these effects were blocked by administration of melatonin (50 mg/kg/day). Down-regulation of oxidative stress was proposed to explain the neuroprotective effects of melatonin. The data suggests that DINP could cause cognitive deficits and anxiety in mice, and that melatonin could be used to avoid these adverse effects. PMID- 26424170 TI - Treatment satisfaction in type 2 diabetes patients taking empagliflozin compared with patients taking glimepiride. AB - PURPOSE: This exploratory analysis assessed and compared patients' treatment satisfaction with empagliflozin plus metformin versus glimepiride plus metformin, using data obtained from the Diabetes Treatment Satisfaction Questionnaire, status version (DTSQs) collected in a randomized, double-blind, double-dummy clinical trial. METHODS: Observed values for DTSQs scale score and each of its eight items were summarized by visit and treatment arm. Changes from baseline in these scores were analyzed using linear mixed models for repeated measures. RESULTS: The baseline scale score and item scores were comparable between empagliflozin plus metformin (n = 765) and glimepiride plus metformin (n = 780). Compared with baseline, patients reported significant treatment satisfaction increases and significant decreases in perceived hyperglycemia with both treatments at all visits. Also, compared with baseline, a significant increase in perceived frequency of hypoglycemia was observed in the glimepiride treatment group at all visits. No statistically significant treatment difference was observed in DTSQs scale score and its items at week 104. The difference between the treatment groups was significant and in favor of empagliflozin from week 28 onward for perceived frequency of hyperglycemia (P <= 0.006) and perceived frequency of hypoglycemia (P <= 0.011). CONCLUSIONS: Despite positive trends in favor of empagliflozin, there was no significant difference in DTSQs scale score between empagliflozin and glimepiride at 104 weeks. However, when compared with glimepiride, empagliflozin demonstrated significantly lower perceived frequency of hyperglycemia and hypoglycemia at all visits from week 28 onward. This finding is consistent with the clinical results reported for the EMPA-REG H2H-SU trial. PMID- 26424169 TI - Linkage between the PROMIS(r) pediatric and adult emotional distress measures. AB - PURPOSE: Research studies that measure health-related quality of life (HRQOL) in both children and adults and longitudinal studies that follow children into adulthood need measures that can be compared across these age groups. This study links the PROMIS pediatric and adult emotional distress measures using data from participants with diverse health conditions and disabilities. METHODS: Analyses were conducted and compared in two separate samples to confirm the stability of results. One sample (n = 874) included individuals aged 14-20 years with special health care needs and who require health services. The other sample (n = 641) included individuals aged 14-25 years who have a physical or cognitive disability. Participants completed both PROMIS pediatric and adult measures. Item response theory-based scores were linked using the linear approximation to calibrated projection. RESULTS: The estimated latent-variable correlation between pediatric and adult PROMIS measures ranged from 0.87 to 0.94. Regression coefficients beta 0 (intercept) and beta 1 (slope), and mean squared error are provided to transform scores from the pediatric to the adult measures, and vice versa. CONCLUSIONS: This study used a relatively new linking method, calibrated projection, to link PROMIS pediatric and adult measure scores, thus expanding the use of PROMIS measures to research that includes both populations. PMID- 26424171 TI - Enhancing cancer clonality analysis with integrative genomics. AB - INTRODUCTION: It is understood that cancer is a clonal disease initiated by a single cell, and that metastasis, which is the spread of cancer from the primary site, is also initiated by a single cell. The seemingly natural capability of cancer to adapt dynamically in a Darwinian manner is a primary reason for therapeutic failures. Survival advantages may be induced by cancer therapies and also occur as a result of inherent cell and microenvironmental factors. The selected "more fit" clones outmatch their competition and then become dominant in the tumor via propagation of progeny. This clonal expansion leads to relapse, therapeutic resistance and eventually death. The goal of this study is to develop and demonstrate a more detailed clonality approach by utilizing integrative genomics. METHODS: Patient tumor samples were profiled by Whole Exome Sequencing (WES) and RNA-seq on an Illumina HiSeq 2500 and methylation profiling was performed on the Illumina Infinium 450K array. STAR and the Haplotype Caller were used for RNA-seq processing. Custom approaches were used for the integration of the multi-omic datasets. RESULTS: Reported are major enhancements to CloneViz, which now provides capabilities enabling a formal tumor multi-dimensional clonality analysis by integrating: i) DNA mutations, ii) RNA expressed mutations, and iii) DNA methylation data. RNA and DNA methylation integration were not previously possible, by CloneViz (previous version) or any other clonality method to date. This new approach, named iCloneViz (integrated CloneViz) employs visualization and quantitative methods, revealing an integrative genomic mutational dissection and traceability (DNA, RNA, epigenetics) thru the different layers of molecular structures. CONCLUSION: The iCloneViz approach can be used for analysis of clonal evolution and mutational dynamics of multi-omic data sets. Revealing tumor clonal complexity in an integrative and quantitative manner facilitates improved mutational characterization, understanding, and therapeutic assignments. PMID- 26424172 TI - Diversifying crop rotations with pulses enhances system productivity. AB - Agriculture in rainfed dry areas is often challenged by inadequate water and nutrient supplies. Summerfallowing has been used to conserve rainwater and promote the release of nitrogen via the N mineralization of soil organic matter. However, summerfallowing leaves land without any crops planted for one entire growing season, creating lost production opportunity. Additionally, summerfallowing has serious environmental consequences. It is unknown whether alternative systems can be developed to retain the beneficial features of summerfallowing with little or no environmental impact. Here, we show that diversifying cropping systems with pulse crops can enhance soil water conservation, improve soil N availability, and increase system productivity. A 3 yr cropping sequence study, repeated for five cycles in Saskatchewan from 2005 to 2011, shows that both pulse- and summerfallow-based systems enhances soil N availability, but the pulse system employs biological fixation of atmospheric N2, whereas the summerfallow-system relies on 'mining' soil N with depleting soil organic matter. In a 3-yr cropping cycle, the pulse system increased total grain production by 35.5%, improved protein yield by 50.9%, and enhanced fertilizer-N use efficiency by 33.0% over the summerfallow system. Diversifying cropping systems with pulses can serve as an effective alternative to summerfallowing in rainfed dry areas. PMID- 26424173 TI - Clinical profiles of moderate and severe Crohn's disease patients and use of anti tumor necrosis factor agents: Greek expert consensus guidelines. AB - Crohn's disease (CD) is a chronic idiopathic inflammatory bowel disease (IBD) which affects any site of the gastrointestinal tract and occasionally extraintestinal organs. The natural history of CD varies remarkably but a considerable proportion of patients develop complications leading to hospitalizations and surgeries, impaired quality of life, and disability. In these patients, effective medical therapy should aim beyond control of clinical symptoms to include induction and maintenance of steroid-free clinical and serological remission and mucosal healing, as this has shown to reduce complications, hospitalizations and surgeries, and to decrease the risk of colorectal cancer, at least in the short term. This therapeutic goal can be achieved in a considerable proportion of patients with anti-tumor necrosis factor (TNF)-alpha agents if applied early in the disease course. Clinical recommendations from a panel of Greek IBD experts are herein provided, regarding the clinical profiles and the use of anti-TNF-alpha therapy in patients with moderate and severe CD, based on literature review and personal experience. The objectives of this advisory workshop were to define the profiles of patients with moderate and severe CD using routine clinical and laboratory parameters, as well as the clinical profiles of patients with moderate CD, severe CD, perianal CD, and/or extra-intestinal manifestations, who are candidates for biologic therapies. Emphasis was given on patients with newly diagnosed CD. The proposed recommendations may provide a useful and practical approach for improving therapeutic strategies with anti-TNF-alpha in patients with active moderate and severe CD. PMID- 26424174 TI - Radioactive iodine (RAI) therapy for distantly metastatic differentiated thyroid cancer (DTC) in juvenile versus adult patients. AB - In general, juvenile differentiated thyroid carcinoma (DTC) demonstrate indolent characteristics and favorable prognosis are observed in comparison with many other carcinomas. However, recurrence is frequent, necessitating additional treatment, including radioactive iodine (RAI) therapy. In this report, the probability of recurrence, prognostic factors, treatment, and outcomes in both juvenile- and adult-onset DTC were analyzed and compared. At our institution, a total of 1552 DTC patients underwent thyroidectomy and/or lymph node dissection. The patients included 23 in their teens, 118 in their twenties, and 1412 in their thirties or older. The risk factors for distant metastases for DTC were male gender, follicular carcinoma, size of the PTC primary tumor, cervical lymph node metastases from PTC, and the presence of more than two distant metastatic foci. Patients with the highest risk underwent RAI ablation in line with institutional guidelines. Although the overall outcome in our juvenile patients was excellent, during follow-up, 4 (17.4%) of the 23 patients developed recurrent disease: 91.3% achieved complete remission, 4.35% partial remission, and 4.35% stable disease, with no disease-related deaths. Among the 118 patients in their twenties to thirties, 1 (0.8%) experienced progressive disease and disease-related death. A younger age at diagnosis and less radical primary surgery without subsequent RAI ablation are factors strongly predictive of distant metastases in patients with juvenile-onset DTC. To reduce the rate of relapse and improve surveillance for recurrent disease, total thyroidectomy followed by RAI appears to be the most beneficial initial treatment for patients with high- and intermediate-risk juvenile DTC. PMID- 26424175 TI - Resonant Scanning with Large Field of View Reduces Photobleaching and Enhances Fluorescence Yield in STED Microscopy. AB - Photobleaching is a major limitation of superresolution Stimulated Depletion Emission (STED) microscopy. Fast scanning has long been considered an effective means to reduce photobleaching in fluorescence microscopy, but a careful quantitative study of this issue is missing. In this paper, we show that the photobleaching rate in STED microscopy can be slowed down and the fluorescence yield be enhanced by scanning with high speed, enabled by using large field of view in a custom-built resonant-scanning STED microscope. The effect of scanning speed on photobleaching and fluorescence yield is more remarkable at higher levels of depletion laser irradiance, and virtually disappears in conventional confocal microscopy. With >=6 GW?cm(-2) depletion irradiance, we were able to extend the fluorophore survival time of Atto 647N and Abberior STAR 635P by ~80% with 8-fold wider field of view. We confirm that STED Photobleaching is primarily caused by the depletion light acting upon the excited fluorophores. Experimental data agree with a theoretical model. Our results encourage further increasing the linear scanning speed for photobleaching reduction in STED microscopy. PMID- 26424176 TI - Linezolid Induced Adverse Drug Reactions - An Update. AB - Treatment regimen recommended for resistant tuberculosis consists of various drugs and these drugs are prescribed for at least 12-15 months. Such a long duration therapy and high dose of antibiotics result in adverse drug reactions (ADRs). ADRs may lead to various complications in disease management like replacement of drugs, dose increment, therapy withdrawal, etc. Linezolid is one of those drugs, practiced as an anti-mycobacterial agent and it is an important member of drug regimen for MDR and XDR tuberculosis. Linezolid is a broad spectrum antibiotic known for its unique mechanism of inhibition of resistant pathogenic strains. However, it causes serious adverse effects like thrombocytopenia, optic neuropathy, peripheral neuropathy, lactic acidosis, etc. Literature suggests that Linezolid can cause severe ADRs which affect patient compliance and hinder in therapy to a larger extent. Recent studies confirm the possibility of ADRs to be predicted with genetic make-up of individuals. To effectively deliver the available treatment regimen and ensure patient compliance, it is important to manage ADRs more efficiently. The role of pharmacogenomics in reducing adverse drug effects has been recently explored. In the present review, we discussed about Linezolid induced adverse drug reactions, mechanisms and genetic associations. PMID- 26424177 TI - Pharmacokinetic and Pharmacodynamic Properties of Anti-VEGF Drugs After Intravitreal Injection. AB - Subretinal neovascularization and pathologic ocular angiogenesis are common causes of progressive, irreversible impairment of central vision, and dramatically affect quality of life. Anti-vascular endothelial growth factor (anti-VEGF) therapy has improved the quality of life for many patients with age related macular degeneration, diabetic retinopathy, and other ocular diseases involving neovascularization and edema. In these pathologies, the inhibition of intraocular VEGF is the only therapy that can preserve vision. Four anti-VEGF drugs are currently used to treat ocular neovascularization; pegaptanib, ranibizumab, and aflibercept have been approved for this condition, while bevacizumab can be used off-label. Anti-VEGF therapy is administered regularly for many months or years because its suspension or discontinuation may cause recurrence of neovascularization. On the other hand, VEGF is necessary for the survival of retinal and choroidal endothelial cells. Experimental studies in animal models have shown that local inhibition of VEGF causes thinning and atrophy of the choriocapillaris and degeneration of photoreceptors, primarily cones. These studies combined with clinical experience indicated that prolonged VEGF inhibition could impair retinal function. Moreover, anti-VEGF compounds can cross the blood-retina barrier, enter the systemic circulation, and inhibit serum VEGF. Since circulating VEGF protects blood vessel integrity, prolonged anti-VEGF treatment could induce thromboembolic adverse events from vascular causes such as heart attack and stroke, and even death. The ocular dosing regimen and systemic toxicity of anti-VEGF compounds are therefore central concerns. A better understanding of this topic requires knowledge of the metabolism, tissue distribution, and clearance of anti-VEGF compounds. This manuscript reviews the properties of anti-VEGF compounds following intravitreal administration. PMID- 26424178 TI - Comparison of sedation and general anaesthesia for transcatheter aortic valve implantation on cerebral oxygen saturation and neurocognitive outcome?. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a treatment strategy for patients with severe aortic stenosis. Although general anaesthesia (TAVI-GA) and sedation (TAVI-S) have previously been described for TAVI, the difference in safety and efficacy of both methods has not been studied in a randomized trial. METHODS: The INSERT trial was a single centre, controlled parallel-group trial with balanced randomization. Sixty-six patients (68-94 yr) with acquired aortic stenosis undergoing transfemoral CoreValveTM were assigned to TAVI-GA or TAVI-S. Comparable operative risk was determined from risk-scores (EUROscore, STS-Score). Monitoring and anaesthetic drugs were standardized. Near Infrared-Spectroscopy was used to monitor cerebral-oxymetry blinded. Primary outcome was the perioperative cumulative cerebral desaturation. As secondary outcomes, changes in neurocognitive function and respiratory and haemodynamic adverse events were evaluated. RESULTS: Of 66 included patients, 62 (TAVI-GA: n=31, TAVI-S: n=31) were finally analysed. Baseline characteristics were comparable. In 24 patients (39%) cerebral desaturation was observed. Cumulative cerebral desaturation was comparable (TAVI-GA:(median [IQR]) (0[0/1308] s%) vs. TAVI-S:(0[0/276] s%); P=0.505) between the groups. Neurocognitive function did not change within and between groups. Adverse events were more frequently observed in TAVI-S patients (P<0.001). Bradypnoea (n=16, 52%) and the need for airway manoeuvres (n=11, 36%) or bag-mask-ventilation (n=6, 19%) were the most common respiratory adverse events. CONCLUSIONS: Cerebral desaturation occurred in both patient groups, but there was no significant difference between the two groups. Based on primary outcome, both methods were shown to be comparable. Neurocognitive outcome was similar. The higher incidence of adverse events in the sedation group suggests a potential advantage of general anaesthesia. CLINICAL TRIAL REGISTRATION: NCT 01251328. PMID- 26424179 TI - Reaching with the sixth sense: Vestibular contributions to voluntary motor control in the human right parietal cortex. AB - The vestibular system constitutes the silent sixth sense: It automatically triggers a variety of vital reflexes to maintain postural and visual stability. Beyond their role in reflexive behavior, vestibular afferents contribute to several perceptual and cognitive functions and also support voluntary control of movements by complementing the other senses to accomplish the movement goal. Investigations into the neural correlates of vestibular contribution to voluntary action in humans are challenging and have progressed far less than research on corresponding visual and proprioceptive involvement. Here, we demonstrate for the first time with event-related TMS that the posterior part of the right medial intraparietal sulcus processes vestibular signals during a goal-directed reaching task with the dominant right hand. This finding suggests a qualitative difference between the processing of vestibular vs. visual and proprioceptive signals for controlling voluntary movements, which are pre-dominantly processed in the left posterior parietal cortex. Furthermore, this study reveals a neural pathway for vestibular input that might be distinct from the processing for reflexive or cognitive functions, and opens a window into their investigation in humans. PMID- 26424180 TI - Topology of genetic associations between regional gray matter volume and intellectual ability: Evidence for a high capacity network. AB - Intelligence is associated with a network of distributed gray matter areas including the frontal and parietal higher association cortices and primary processing areas of the temporal and occipital lobes. Efficient information transfer between gray matter regions implicated in intelligence is thought to be critical for this trait to emerge. Genetic factors implicated in intelligence and gray matter may promote a high capacity for information transfer. Whether these genetic factors act globally or on local gray matter areas separately is not known. Brain maps of phenotypic and genetic associations between gray matter volume and intelligence were made using structural equation modeling of 3T MRI T1 weighted scans acquired in 167 adult twins of the newly acquired U-TWIN cohort. Subsequently, structural connectivity analyses (DTI) were performed to test the hypothesis that gray matter regions associated with intellectual ability form a densely connected core. Gray matter regions associated with intellectual ability were situated in the right prefrontal, bilateral temporal, bilateral parietal, right occipital and subcortical regions. Regions implicated in intelligence had high structural connectivity density compared to 10,000 reference networks (p=0.031). The genetic association with intelligence was for 39% explained by a genetic source unique to these regions (independent of total brain volume), this source specifically implicated the right supramarginal gyrus. Using a twin design, we show that intelligence is genetically represented in a spatially distributed and densely connected network of gray matter regions providing a high capacity infrastructure. Although genes for intelligence have overlap with those for total brain volume, we present evidence that there are genes for intelligence that act specifically on the subset of brain areas that form an efficient brain network. PMID- 26424181 TI - Extracellular polysaccharide from Bordetella species reduces high glucose-induced macrophage apoptosis via regulating interaction between caveolin-1 and TLR4. AB - Microphage apoptosis is a critical event in atherosclerotic lesions in patients with diabetes. In the present investigation, high glucose treatment inhibited Akt phosphorylation and activated caspase 3 in primary peritoneal macrophage, leading to cell apoptosis. Hypoxia prolonged macrophage survival in high glucose condition. Extracellular polysaccharide from Bordetella species (EPS) further decreased cell apoptosis in response to high glucose during hypoxia. Under high glucose and hypoxic condition, EPS treatment promoted caveolin-1 phosphorylation by recognizing TLR4. Caveolin-1 phosphorylation elevated membrane Glut1 level to accelerate glucose consumption, which should be the reason for protective effect of EPS on macrophage exposed to high glucose. Further investigation demonstrated that TLR4-dependent caveolin-1 phosphorylation induced by EPS promoted association of caveolin-1 with TLR4, which should be critical for activation of TLR4 signaling pathway. PMID- 26424182 TI - Erysipelas, a large retrospective study of aetiology and clinical presentation. AB - BACKGROUND: Erysipelas is a common and severe infection where the aetiology and optimal management is not well-studied. Here, we investigate the clinical features, bacteriological aetiology, and treatment of erysipelas. METHODS: Episodes of erysipelas in a seven-years period in our institution were studied retrospectively using a pre-specified protocol and is presented with descriptive and comparative statistics. RESULTS: 1142 episodes of erysipelas were identified in 981 patients. Patients had a median age of 61 years, 59 % were male, a majority had underlying diseases or predisposing conditions, and the leg was most often affected. Wound cultures were taken in 343 episodes and 56 grew group A streptococci (GAS), 53 grew group G streptococci (GGS), 11 grew group C streptococci (GCS), and 153 grew Staphylococcus aureus. Blood cultures were drawn in 49 % of episodes and 50 cultures were positive with GGS as the most common finding (21 cultures) followed by GAS in 13, group B streptococci in 5, S. aureus in 4, and GCS in 3 cultures. In 45 % of episodes, patients received antibiotics with activity against S. aureus. CONCLUSIONS: GGS is the most common streptococcus isolated in erysipelas and the role of S. aureus in erysipelas remains elusive. PMID- 26424183 TI - Health-related quality of life measurement in chronic liver disease patients. AB - BACKGROUND AND OBJECTIVE: Health-related quality of life (HRQOL) is an important health indicator in medical outcome research and clinical practice. This issue tends to attract even more attention with the recent improvements of patient survival after liver transplantation. This review article aims at providing a deeper insight into practices used for evaluating HRQOL in chronic liver diseases (CLDs) and especially cirrhosis patients during different stages of the disease including liver transplantation. MATERIALS AND METHODS: A systematic review of the MEDLINE database and Cochrane library was conducted. A search using the Medical Subject Headings (MeSH) major terms "liver disease" AND "quality of life" was applied for the period from 1966 to 2012. RESULTS: Our review identified 1483 publications. The searched showed that significant increase of publications (from 362 to 1018) was observed during last decade (period 2003-2012) in comparison with previous. The majority of publications were in English (n=1179). The literature search and analysis provided information on the most common generic and disease-specific HRQOL instruments, which are used in CLD patients: Medical Outcomes Study Short Form-36, the National Institute of Diabetes and Digestive and Kidney Diseases Quality of Life questionnaire, the Chronic Liver Disease questionnaire, the Liver Disease Quality of Life questionnaire, and other. CONCLUSIONS: Quality of life instruments are potentially powerful tools for evaluating the functional status, presenting gains of treatment and reflecting patients' ability to return to a normal lifestyle in CLD patients. More attention should be paid by clinicians for integrated use of clinical tests together with HRQOL instruments in liver transplantation for establishing the reference levels of mental, physical, and role-social functioning. PMID- 26424184 TI - Left ventricular function by speckle-tracking echocardiography in patients with low-T3 syndrome and acute myocardial infarction. AB - BACKGROUND AND OBJECTIVE: Low-T3 syndrome is common in patients with acute myocardial infarction (AMI). Recent experimental and clinical data have suggested a potential negative impact of low-T3 syndrome on myocardial function in patients with AMI. The aim of this study was to assess left ventricular (LV) myocardial function in patients with low-T3 syndrome and to investigate the association between hormonal profile and the severity of LV dysfunction using speckle tracking echocardiography (STE). MATERIALS AND METHODS: In 130 patients with first-onset ST-segment elevation acute myocardial infarction (STEMI), conventional 2D and speckle-tracking echocardiography within 48-72h after the hospitalization was performed, and blood samples for TSH, fT4, fT3, and anti-TPO levels were obtained to investigate thyroid hormone production within 24h and on the fourth day after the onset of STEMI symptoms. RESULTS: The patients were divided into two groups according to their serum level of fT3: group 1 with fT3 concentration below 3.2pmol/L (n=34) and group 2 with normal fT3 (>3.2pmol/L) level (n=96). LV ejection fraction (EF) tended to be lower in the low fT3 group. The systolic longitudinal strain did not differ between the groups, but the late diastolic longitudinal strain rate was lower in group 1 (P=0.011). The systolic basal LV rotation positively correlated with the level of fT3 (r=0.4; P<0.001), while a negative correlation was detected between myocardial rotational parameters - systolic apical rotation (r=-0.2; P<0.05), torsion (r=-0.3; P<0.001), and diastolic apical rotation rate (r=-0.3; P<0.01) - and fT3 levels. CONCLUSIONS: The late diastolic longitudinal LV strain rate and LV rotation evaluated by speckle-tracking echocardiography were impaired in patients with low T3 syndrome after AMI. PMID- 26424185 TI - Comparison of the improvement in myocardial perfusion and function in cases of rapid and slow electrocardiographic stage dynamics between patients with TIMI-3 flow after primary angioplasty for acute myocardial infarction. AB - BACKGROUND AND OBJECTIVE: Post-PCI TIMI flow grade 3 in infarct-related artery not always is associated with follow-up improvement in myocardial perfusion and function. We compared the improvement in myocardial perfusion and function in cases of rapid and slow electrocardiographic (ECG) stage dynamics between patients with TIMI-3 flow after primary angioplasty for acute myocardial infarction (MI). MATERIALS AND METHODS: Ten patients with post-PCI TIMI-3 flow were divided into group A (n=50, no rapid change of ECG stages) and group B (n=50, with a >=2 ECG stages per 2 days change rate). RESULTS: There were no significant changes after 3 months in scintigraphic (ejection fraction 44.6+/ 9.3% vs. 42.0+/-3.4%, P=0.4; perfusion deficit severity 3.0+/-0.7 vs. 2.3+/-0.8, P=0.1) and echocardiographic (dysfunction score 1.9+/-0.2 vs. 1.6+/-0.5, P=0.2) data in group A. Scintigraphic data improved (ejection fraction 34.6+/-3.9% vs. 52.0+/-7.3, P=0.03; perfusion deficit severity 2.8+/-0.6 vs. 1.5+/-0.8, P=0.03) and changes in echocardiographic data were of borderline significance (dysfunction score 1.8+/-0.2 vs. 1.4+/-0.4, P=0.06) in group B. CONCLUSIONS: There was not any change in myocardial perfusion and function in a case of slow change of ECG stages after reached post-PCI TIMI flow grade 3, while myocardial perfusion improved and function tended to improve in a case of the rate at least two ECG stages in 2 days after primary angioplasty for acute MI. PMID- 26424186 TI - Prevalence and etiology of midfacial fractures: a study of 799 cases. AB - BACKGROUND AND OBJECTIVE: The prevalence and etiology of midfacial fractures varies among countries. Until now, knowledge about such type of injuries in the region of the Baltic countries was rather scarce. The purpose of the study was to analyze the prevalence, etiology and localization of midfacial fractures treated at the Vilnius University Hospital Zalgiris Clinic, Vilnius, Lithuania. MATERIALS AND METHODS: The medical records of patients treated for midfacial fractures during the period January 2005 to December 2010 were analyzed for gender, age distribution, frequency and type of injury, cause of fractures, consciousness status and alcohol abuse during trauma. RESULTS: The records of 799 patients were analyzed. The male-to-female ratio was 4.4:1. The mean age of the patients was 33.16+/-14.0 years (min 1, max 87). As much as 68.8% of injuries were zygomatic fractures, 27.9% were maxillary, and 3.3% were isolated orbital floor fractures. The most frequent causes for injury were interpersonal violence (64%), followed by falls (16.3%) and traffic accidents (8.3%). Most midfacial fractures (65.3%) occurred between April and October (P<0.05), on weekends (58.2%; P<0.05) and at night (62.0%; P<0.05). In 14%, trauma reports indicated the abuse of alcohol. More often such persons received more than one midfacial bone fracture (P<0.05) concurrently. CONCLUSIONS: This study revealed that the main cause of midfacial fractures was assault. Male patients, aged 15-34 years, more often sustain midfacial fractures. Preventive health care programs should seek measures in the reduction of aggression and violence in close future involving family, school and community institutions. PMID- 26424187 TI - Oral bony outgrowths: prevalence and genetic factor influence. Study of twins. AB - OBJECTIVE: The aim of the study was to verify the influence of a genetic factor on the etiology of oral bony outgrowths and to determine the prevalence and type of oral bony outgrowths (tori and exostoses) among a group of Lithuanian twins. MATERIALS AND METHODS: In total, 162 twins (81 twin pairs) were analyzed for the presence or absence, type, and size of oral bony outgrowths. Statistical analysis was carried out to find the prevalence of bony protuberances and the relationship between zygosity and occurrence of oral bony enlargements. Zygosity of twins was confirmed by DNA analysis. RESULTS: 59.9% of the subjects had oral bony outgrowths. Mandibular tori were found in 56.8% and palatal tori in 1.8% of the sample. Palatal exostoses and mandibular exostoses were present in 1.8% and 3.1% of the sample, respectively, whereas maxillary exostoses were not found. A higher percentage of tori and exostoses were found in the group of older subjects (>18 years old, p=0.025). No significant difference was found between men and women in the prevalence of bony outgrowths. High kappa and r values (0.91+/-0.062) showed very good concordance of oral bony outgrowths between monozygotic and moderate concordance (0.58+/-0.141) between dizygotic co-twins (p<0.001). The calculation of heritability estimate verifies dominant influence of genetic factor on the etiology of oral bony outgrowths (h(2)=0.658). CONCLUSION: The most common bony outgrowth was torus mandibularis. Our results show that the genetic factor is dominant in the etiology of oral bony outgrowths. PMID- 26424188 TI - Impact of left ventricular function on health-related quality of life in coronary artery disease patients. AB - OBJECTIVE: The aim of the study was to investigate the relation between health related quality of life (HRQoL) and left ventricular systolic and diastolic function parameters in stable coronary artery disease (CAD) patients with mild and moderate heart failure. MATERIALS AND METHODS: This study included 758 CAD patients. Left ventricular ejection fraction (LVEF) and ratio of peak velocities of early (E) and late (A) diastolic mitral inflow, ratio E/A, deceleration time, isovolumic relaxation time were assessed. Patients completed the SF-36 questionnaire. RESULTS: There were no strong and significant associations between echocardiographic measures and HRQoL in NYHA I-II class patients. In NYHA III class in univariate linear regression analyses significant associations were found between LVEF and physical functioning (beta=0.230, P=0.009) and role limitations due to physical problems (beta=0.230, P=0.009) and these associations remain significant after adjustment for age, gender, hypertension, angina pectoris class, nitrate, ACE inhibitors and diuretics use. E/A ratio was significantly associated only with mental health domain (beta=0.188, P=0.048), and this association remains significant after all adjustments. CONCLUSIONS: In stable CAD patients with NYHA I-II functional class HRQoL was not strongly associated with left ventricular function; in NYHA III functional class patients' greater systolic function mainly was associated with better physical health and better diastolic function, with better mental health. PMID- 26424189 TI - Management of coronary artery disease patients in Latvia compared with practice in Central-Eastern Europe and globally: analysis of the CLARIFY registry. AB - BACKGROUND AND OBJECTIVE: Management of outpatients with stable coronary artery disease (CAD) is important in secondary prevention. The objective was to describe differences in the characteristics of CAD patients in Latvia compared with other countries. MATERIALS AND METHODS: CLARIFY is an ongoing international, prospective, observational, longitudinal registry of outpatients with CAD. Data regarding treated outpatients with established CAD from the CLARIFY registry in Latvia (n=120) were compared with those from the rest of Central-Eastern Europe (CEE) (n=2888) and worldwide (n=33,163). RESULTS: Patients in Latvia had a larger waist circumference (101 [95-109] vs. 99 [91-106] in CEE, 96.5 [88-105]cm worldwide; P=0.023 and P<0.001, respectively) and higher blood pressure (systolic: 138.28+/-17.13 vs. 133.77+/-16.47 in CEE and 130.97+/-16.65mm Hg worldwide, P=0.003 and P<0.001; diastolic: 82.98+/-8.58 vs. 80.01+/-9.61 in CEE and 77.22+/-9.97mm Hg worldwide, P<0.001 and P<0.001, respectively). Body mass index in Latvia did not differ significantly from that in CEE (P=0.422), but was higher than worldwide (28.8 [26.2-32.0] vs. worldwide 27.3 [24.8-30.3]kg/m(2), P<0.001). The history of percutaneous coronary intervention was more frequent in Latvia (74.17% vs. 59.34% in CEE and 58.61% worldwide, P=0.001 and P<0.001, respectively). Latvian patients more frequently used aspirin (97.50% in Latvia vs. 89.75% in CEE and 87.64% worldwide, P=0.005 and P=0.001, respectively). CONCLUSIONS: Latvian CAD patients are well managed in terms of aspirin use and frequency of percutaneous coronary intervention. Control of obesity and high BP is poorer and needs further improvement. PMID- 26424190 TI - Body physique and dominant somatotype in elite and low-profile athletes with different specializations. AB - BACKGROUND AND OBJECTIVE: Somatotyping is helpful in sports in which the body shape could influence the resulting performance. The purpose of this study was to determine the somatotype of high profile Lithuanian athletes in kayaking, basketball and football and to compare between disciplines and with low level sportsmen of the same age. MATERIALS AND METHODS: A total of 72 young male sportsmen aged from 18 to 24 years were divided into three groups (kayakers, basketball and football players). Each group contained almost equal numbers of low level and elite, international level sportsmen. Anthropometric measurements of the players were used to establish somatotypes. RESULTS: The greatest difference was observed in the mesomorphic component of elite kayakers compared to the low profile sportsmen. Mesomorphy could also be used to predict sport ability. The range of mesomorphy for elite footballers was from 0 to 4.6, for basketball players from 4.6 to 5.9, and for kayaking, from 5.9 and higher. Individual groups of elite sportsmen displayed different modes of somatotype. The kayakers were predominantly endomorphic; the basketball players mostly endomorphic and the footballers most often ectomorphic. No distinguishable patterns of somatotype were displayed by the low level sportsmen. CONCLUSIONS: Morphometric characteristics of the athlete's body and the fractional somatotype can be used as guiders and markers of the chosen sport and method of training. The results emphasize the necessity for a specific somatotype to reach a high profile in the selected area of sport and thus support morphometric oriented studies. Further studies could elucidate differentiation by age and sex. PMID- 26424191 TI - Temperature influencing permeation pattern of alfuzosin: an investigation using DoE. AB - BACKGROUND AND OBJECTIVE: There has been relatively little investigation of the effect of temperature on skin permeation compared to other methods of penetration enhancement. A principal physicochemical factor which controls the passive diffusion of a solute from a vehicle into the skin arises from the skin temperature. The aim of this ex vivo study was to probe into the effect of heat on transdermal absorption of alfuzosin hydrochloride from ethyl cellulose polyvinyl pyrrolidone (EC-PVP) based transdermal systems. MATERIALS AND METHODS: Principles of design of experiment (DoE) were used to systematically study the influence of temperature on transdermal permeation of alfuzosin. Ex vivo transdermal permeation studies were carried out at varied donor compartment temperatures. Permeation data analysis was carried out and activation energy for transdermal permeation was estimated. RESULTS: Temperature found to enhance ex vivo permeation parameters of alfuzosin hydrochloride from its transdermal systems. It was also noted that chemical permeation enhancers potentiate permeation enhancing effect of temperature. The permeation flux values approximately doubled after exposure to 45 degrees C. The activation energy for transdermal permeation was found lower for the runs with chemical permeation enhancers indicating existence of a lower energy barrier in the presence of chemical permeation enhancers. CONCLUSION: The method reported here is a simple and useful tool for studying the effect of heat on percutaneous absorption. Such temperature dependent enhancement of flux can be more pronounced at skin surface temperatures >45 degrees C. PMID- 26424192 TI - An automated fitting procedure and software for dose-response curves with multiphasic features. AB - In cancer pharmacology (and many other areas), most dose-response curves are satisfactorily described by a classical Hill equation (i.e. 4 parameters logistical). Nevertheless, there are instances where the marked presence of more than one point of inflection, or the presence of combined agonist and antagonist effects, prevents straight-forward modelling of the data via a standard Hill equation. Here we propose a modified model and automated fitting procedure to describe dose-response curves with multiphasic features. The resulting general model enables interpreting each phase of the dose-response as an independent dose dependent process. We developed an algorithm which automatically generates and ranks dose-response models with varying degrees of multiphasic features. The algorithm was implemented in new freely available Dr Fit software (sourceforge.net/projects/drfit/). We show how our approach is successful in describing dose-response curves with multiphasic features. Additionally, we analysed a large cancer cell viability screen involving 11650 dose-response curves. Based on our algorithm, we found that 28% of cases were better described by a multiphasic model than by the Hill model. We thus provide a robust approach to fit dose-response curves with various degrees of complexity, which, together with the provided software implementation, should enable a wide audience to easily process their own data. PMID- 26424193 TI - Rising Incidence of Clostridium difficile Related Discharges among Hospitalized Children in the United States. AB - Using a national database, we report an increasing trend in Clostridium difficile incidence among hospitalized children in the United States from 2003 to 2012. The incidence rate of CDI increased from 24.0 to 58.0 per 10,000 discharges per year (P<0.001) across all age groups, with the greatest increase in children 15 years and older. Infect. Control Hosp. Epidemiol. 2015;37(1):104-106. PMID- 26424194 TI - New genes drive the evolution of gene interaction networks in the human and mouse genomes. AB - BACKGROUND: The origin of new genes with novel functions creates genetic and phenotypic diversity in organisms. To acquire functional roles, new genes must integrate into ancestral gene-gene interaction (GGI) networks. The mechanisms by which new genes are integrated into ancestral networks, and their evolutionary significance, are yet to be characterized. Herein, we present a study investigating the rates and patterns of new gene-driven evolution of GGI networks in the human and mouse genomes. RESULTS: We examine the network topological and functional evolution of new genes that originated at various stages in the human and mouse lineages by constructing and analyzing three different GGI datasets. We find a large number of new genes integrated into GGI networks throughout vertebrate evolution. These genes experienced a gradual integration process into GGI networks, starting on the network periphery and gradually becoming highly connected hubs, and acquiring pleiotropic and essential functions. We identify a few human lineage-specific hub genes that have evolved brain development-related functions. Finally, we explore the possible underlying mechanisms driving the GGI network evolution and the observed patterns of new gene integration process. CONCLUSIONS: Our results unveil a remarkable network topological integration process of new genes: over 5000 new genes were integrated into the ancestral GGI networks of human and mouse; new genes gradually acquire increasing number of gene partners; some human-specific genes evolved into hub structure with critical phenotypic effects. Our data cast new conceptual insights into the evolution of genetic networks. PMID- 26424195 TI - Costs of HIV/AIDS treatment in Indonesia by time of treatment and stage of disease. AB - BACKGROUND: We report an economic analysis of Human Immunodeficiency Virus (HIV) care and treatment in Indonesia to assess the options and limitations of costs reduction, improving access, and scaling up services. METHODS: We calculated the cost of providing HIV care and treatment in a main referral hospital in West Java, Indonesia from 2008 to 2010, differentiated by initiation of treatment at different CD4 cell count levels (0-50, 50-100, 100-150, 150-200, and >200 cells/mm(3)); time of treatment; HIV care and opportunistic infections cost components; and the costs of patients for seeking and undergoing care. DISCUSSION: Before antiretroviral treatment (ART) initiation, costs were dominated by laboratory tests (>65 %), and after initiation, by antiretroviral drugs (>=60 %). Average treatment costs per patient decreased with time on treatment (e.g. from US$580 per patient in the first 6 month to US$473 per patient in months 19-24 for those with CD4 cell counts under 50 cells/mm(3)). Higher CD4 cell counts at initiation resulted in lower laboratory and opportunistic infection treatment costs. Transportation cost dominated the costs of patients for seeking and undergoing care (>40 %). CONCLUSIONS: Costs of providing ART are highest during the early phase of treatment. Costs reductions can potentially be realized by early treatment initiation and applying alternative laboratory tests with caution. Scaling up ART at the community level in certain high prevalence settings may improve early uptake, adherence, and reduce transportation costs. PMID- 26424197 TI - Biology and management of sugarcane yellow leaf virus: an historical overview. AB - Sugarcane yellow leaf virus (SCYLV) is one of the most widespread viruses causing disease in sugarcane worldwide. The virus has been responsible for drastic economic losses in most sugarcane-growing regions and remains a major concern for sugarcane breeders. Infection with SCYLV results in intense yellowing of the midrib, which extends to the leaf blade, followed by tissue necrosis from the leaf tip towards the leaf base. Such symptomatic leaves are usually characterized by increased respiration, reduced photosynthesis, a change in the ratio of hexose to sucrose, and an increase in starch content. SCYLV infection affects carbon assimilation and metabolism in sugarcane, resulting in stunted plants in severe cases. SCYLV is mainly propagated by planting cuttings from infected stalks. Phylogenetic analysis has confirmed the worldwide distribution of at least eight SCYLV genotypes (BRA, CHN1, CHN3, CUB, HAW, IND, PER, and REU). Evidence of recombination has been found in the SCYLV genome, which contains potential recombination signals in ORF1/2 and ORF5. This shows that recombination plays an important role in the evolution of SCYLV. PMID- 26424196 TI - The Assessment and Non-Pharmacologic Treatment of Procedural Pain From Infancy to School Age Through a Developmental Lens: A Synthesis of Evidence With Recommendations. AB - The 2011 IOM report stated that pain management in children is often lacking especially during routine medical procedures. The purpose of this review is to bring a developmental lens to the challenges in assessment and non-pharmacologic treatment of pain in young children. METHOD: A synthesis of the findings from an electronic search of PubMed and the university library using the keywords pain, assessment, treatment, alternative, complementary, integrative, infant, toddler, preschool, young, pediatric, and child was completed. A targeted search identified additional sources for best evidence. RESULTS: Assessment of developmental cues is essential. For example, crying, facial expression, and body posture are behaviors in infancy that indicate pain: however in toddlers these same behaviors are not necessarily indicative of pain. Preschoolers need observation scales in combination with self-report while for older children self report is the gold standard. Pain management in infants includes swaddling and sucking. However for toddlers, preschoolers and older children, increasingly sophisticated distraction techniques such as easily implemented non-pharmacologic pain management strategies include reading stories, watching cartoons, or listening to music. DISCUSSION: A developmental approach to assessing and treating pain is critical. Swaddling, picture books, or blowing bubbles are easy and effective when used at the appropriate developmental stage and relieve both physical and emotional pain. Untreated pain in infants and young children may lead to increased pain perception and chronic pain in adolescents and adults. Continued research in the non-pharmacological treatment of pain is an important part of the national agenda. PMID- 26424198 TI - Complete genome sequence of a novel endornavirus isolated from hot pepper. AB - The complete genome of a putative new endornavirus infecting hot peppers (Capsicum annuum) was determined to be 14,729 nt in size, including 12 cytosines at the 3' end. The hot pepper-infecting virus has the highest nucleotide sequence similarity (94% query cover and 72% identity) to bell pepper endornavirus (BPEV) isolated from the cultivar Yolo Wonder in the USA (GenBank accession no. JN019858). The putative single, large open reading frame encodes a 4,884-amino acid-long polyprotein that contains four putative functional domains: a viral methyltransferase, a viral RNA helicase, a glycosyltransferase, and an RNA dependent RNA polymerase. A phylogenetic tree based on whole polyprotein sequences confirmed the close evolutionary relationship of the studied endornavirus to BPEV. The hot pepper-infecting virus also has a nick at nt position 975. Taken together, these results suggest that this virus belongs to a new species in the genus Endornavirus (family Endornaviridae), for which the name hot pepper endornavirus (HPEV) is proposed. PMID- 26424199 TI - Key Findings from Preclinical and Clinical Drug Interaction Studies Presented in New Drug and Biological License Applications Approved by the Food and Drug Administration in 2014. AB - Regulatory approval documents contain valuable information, often not published, to assess the drug-drug interaction (DDI) profile of newly marketed drugs. This analysis aimed to systematically review all drug metabolism, transport, pharmacokinetics, and DDI data available in the new drug applications and biologic license applications approved by the U.S. Food and Drug Administration in 2014, using the University of Washington Drug Interaction Database, and to highlight the significant findings. Among the 30 new drug applications and 11 biologic license applications reviewed, 35 new molecular entities (NMEs) were well characterized with regard to drug metabolism, transport, and/or organ impairment and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. In vivo, when NMEs were considered as victim drugs, 16 NMEs had at least one in vivo DDI study with a clinically significant change in exposure (area under the time-plasma concentration curve or Cmax ratio >=2 or <=0.5), with 6 NMEs shown to be sensitive substrates of cytochrome P450 enzymes (area under the time-plasma concentration curve ratio >=5 when coadministered with potent inhibitors): paritaprevir and naloxegol (CYP3A), eliglustat (CYP2D6), dasabuvir (CYP2C8), and tasimelteon and pirfenidone (CYP1A2). As perpetrators, seven NMEs showed clinically significant inhibition involving both enzymes and transporters, although no clinically significant induction was observed. Physiologically based pharmacokinetic modeling and pharmacogenetics studies were used for six and four NMEs, respectively, to optimize dosing recommendations in special populations and/or multiple impairment situations. In addition, the pharmacokinetic evaluations in patients with hepatic or renal impairment provided useful quantitative information to support drug administration in these fragile populations. PMID- 26424200 TI - Integrating neuroscience into psychiatric residency training. PMID- 26424201 TI - VapeCons: E-cigarette user conventions. AB - INTRODUCTION: E-cigarette 'vaping conventions' provide a venue for user social networking, parties, and 'try before you buy' access to a wide range of e cigarette products. This study identifies and describes vaping conventions, raising awareness of this potentially problematic practice. METHODS: Conventions were identified via Google searches in April and May 2014 and August 2015. Details captured included location, sponsors, admission cost, event features, and promotions. RESULTS: 41 distinct organizations have planned 90 vaping conventions in 37 different locations since 2010. Conventions promoted access to a wide range of product vendors, seminars, social interactions with other users, parties, gifts, vaping contests, and other events. E-cigarette use at conventions was encouraged. CONCLUSIONS: Vaping conventions promote e-cigarette use and social norms without public health having a voice to educate attendees about negative consequences of use. Future research should focus on the effects of attending these conventions on attendees and on indoor air quality in vapor-filled convention rooms. PMID- 26424202 TI - Child toy safety: An interdisciplinary approach to unravel the microbiological hazard posed by soap bubbles. AB - In 2012 some children developed sepsis after playing together with a soap bubble toy. Microbiological testing revealed heavy contamination of the soap solution, which reasonably represented the vehicle of infection. We investigated the issue with a multidisciplinary approach: review of toy safety legislation; microbiological testing of additional samples; query of the RAPEX database for non-compliant soap bubbles; identification of major manufacturing districts. Microbiological contamination of industrial soap bubbles was widespread. Sixty three notifications of batches contaminated by environmental microorganisms and opportunistic pathogens had been reported. The Chinese had a virtual monopoly of the soap bubble market. We identified two main manufacturing districts in Guangdong Province, both notable for degradation of their water resources. The use of untreated water for the industrial production of soap bubbles may explain the bacterial contamination. Existing legislation provides an unsatisfactory approach for managing microbiological hazards in sensitive toy categories and for identifying responsible parties in import and export of the products. PMID- 26424203 TI - A comparative analysis of how the media in the United Kingdom and India represented the emergence of NDM-1. AB - Research papers on New Delhi metallo-beta-lactamase (NDM-1) provoked considerable but very different media coverage in the United Kingdom (UK) and India. We describe how the media represented this research using qualitative thematic analysis of contemporary coverage by daily newspapers in the UK and India. Fifty four UK and 187 Indian articles mentioned NDM-1, describing it as the 'new super superbug' resistant to most antibiotics. They emphasised the role of medical tourism to the Indian subcontinent. In both countries, blame was framed abstractly as arising from the general misuse of antibiotics. In India, controversy about using New Delhi to name the organism dominated coverage, with officials seeking to discredit the two studies and media coverage characterised by denial and outrage, developing into theories of conspiracies to undermine tourism. Researchers must seek to anticipate the way that their work may be reported and proactively engage with the media to maximise the public health impact of their findings. PMID- 26424204 TI - Time for a regional alcohol policy - A literature review of the burden of normative alcohol use in the Caribbean. AB - Alcohol use is deeply engrained in the socio-cultural fabric of the Caribbean where heavy episodic drinking is an accepted and common drinking pattern. This article aims to create awareness of the tremendous negative impact on population health in the English-speaking Caribbean from culturally customary levels of alcohol consumption. It advocates for the urgent development and implementation of a regional alcohol policy in the English-speaking Caribbean, and emphasizes the importance of crafting and implementing the policy without cultural offence. PMID- 26424205 TI - Minimizing Aryloxy Elimination in Rh(I) -Catalyzed Asymmetric Hydrogenation of beta-Aryloxyacrylic Acids using a Mixed-Ligand Strategy. AB - The first example of efficient asymmetric hydrogenation of challenging beta aryloxyacrylic acids was realized using a Rh(I) -complex based on the heterocombination of a readily available chiral monodentate secondary phosphine oxide (SPO) and an achiral monodentate phosphine ligand as the catalyst. Excellent enantioselectivities (92->99 % ee) were achieved for a wide variety of chiral beta-aryloxypropionic acids with minor aryloxy elimination in most cases. The resultant products were readily transformed into biologically active compounds through simple synthetic manipulations. PMID- 26424206 TI - Antioxidant and anticoagulant activity of sulfated polysaccharide from Gracilaria debilis (Forsskal). AB - Sulfated polysaccharide was isolated from Gracilaria debilis and purified through gel chromatography and their molecular weight was determined through AGE and PAGE. The total sugars in the crude, fractionated and purified polysaccharide were estimated as 52.65%, 59.70% and 67.60%, respectively. The ash and moisture content of crude and purified polysaccharide was found to be 14.2% and 23.5% and the polysaccharide was free from protein contamination. The sulfate and uronic acid contents in the crude, fractionated and purified were estimated as 14.08%, 15.33% and 16.01% and 10.12%, 13.56%, 16.70%. The elemental composition including carbon (crude - 23.12%, purified - 21.05%), hydrogen (crude - 3.4%, purified - 4.13%) and nitrogen (crude - 1.22%, purified - 0.56%) were also analyzed. The anticoagulant activity of the sulfated polysaccharide through APTT and PT was estimated at 14.11 and 8.23IU/mg. The purified polysaccharide with the molecular mass of 20kDa showed highest antioxidant activity (38.57%, 43.48% and 38.88%) in all the assays tested such as DPPH hydroxyl radical, superoxide radical, hydroxyl radical scavenging activities and the structural property was analyzed through FT IR and (1)H NMR spectrum. The results together suggest that the isolated low molecular weight sulfated polysaccharide will demonstrate as a enormously available alternative natural source of antioxidant for industrial uses. PMID- 26424207 TI - Synthesis, characterization, DNA binding, DNA cleavage, protein binding and cytotoxic activities of Ru(II) complexes. AB - We report on the synthesis of novel Ru(II) compounds (Ru-1 to Ru-8) bearing R pdc, 4-Cl-pbinh ligands (where R=4-CF3, 4-F, 4-OH pdc=3-phenyl-5-(1H-pyrrol-2-yl) 4,5-dihydro-1H-pyrazole-1-carbothioamide, pbinh=phenoxybenzylidene isonicotinyl hydrazides) and their in vitro antitumor activity toward the cell lines murine leukemia L1210, human lymphocyte CEM, human epithelial cervical carcinoma HeLa, BEL-7402 and Molt4/C8. Some of the complexes exhibited more potent antiproliferative activity against cell lines than the standard drug cisplatin. Ruthenium complex Ru-2 displayed potent cytotoxicity with than that of cisplatin. DNA-binding, DNA cleavage and protein binding properties of ruthenium complexes with these ligands are reported. Interactions of these ruthenium complexes with DNA revealed an intercalative mode of binding between them. Synchronous fluorescence spectra proved that the interaction of ruthenium complexes with bovine serum albumin (BSA) resulted in a conformational change of the latter. PMID- 26424209 TI - Plasma biomarker signature associated with improved survival in advanced non small cell lung cancer patients on linifanib. AB - OBJECTIVES: Linifanib, a potent and selective inhibitor of the tyrosine kinase activity of vascular endothelial growth factor and platelet-derived growth factor receptors, has clinical activity in advanced non-small cell lung cancer (NSCLC) both as monotherapy in the relapsed setting or with carboplatin and paclitaxel in the first-line setting. Though benefit was observed in unselected patient populations, identification of predictive biomarkers is critical for further development of this novel agent. MATERIALS AND METHODS: Data from 4 randomized studies in relapsed NSCLC with linifanib (n=116) or other treatments (n=125) were examined in an exploratory analysis to identify a biomarker profile predictive of favorable survival. RESULTS: A signature combining the established tumor markers carcinoembryonic antigen (CEA) and cytokeratin 19 fragments (CYFRA 21-1) was predictive of a favorable outcome. This signature was associated with improved survival in patients receiving linifanib monotherapy (hazard ratio [HR]=0.51 vs signature negative; p=0.002), but not in those receiving other anti-cancer treatments (p=0.716). This signature was validated on baseline plasma samples from patients enrolled in a randomized trial of daily linifanib 7.5 mg, linifanib 12.5 mg, or placebo added to first-line carboplatin and paclitaxel chemotherapy for advanced, nonsquamous NSCLC. Only linifanib-treated signature-positive patients had significant improvement in progression-free survival (PFS). Median PFS with placebo was 5.2 months versus 10.2 months (HR=0.49, p=0.049) for those receiving linifanib 7.5mg, and 8.3 months (HR=0.38, p=0.029) for linifanib 12.5 mg. Overall survival for signature-positive patients was 11.3 months with placebo, 12.5 months with linifanib 7.5mg (HR=1.02, p=0.758), and 17.4 months with linifanib 12.5 mg (HR=0.54, p=0.137). CONCLUSION: This baseline plasma biomarker signature is associated with improved outcome in advanced NSCLC patients receiving linifanib. Utility of the biomarker signature in patient selection for linifanib therapy in NSCLC merits evaluation in larger, prospective trials that are powered to detect a survival benefit. PMID- 26424208 TI - From genotype to phenotype: Are there imaging characteristics associated with lung adenocarcinomas harboring RET and ROS1 rearrangements? AB - INTRODUCTION: Recurrent gene rearrangements are important drivers of oncogenesis in non-small cell lung cancers. RET and ROS1 rearrangements are each found in 1 2% of lung adenocarcinomas and represent distinct molecular subsets. This study assessed the computed tomography (CT) imaging features of patients with RET- and ROS1-rearranged lung cancers. METHODS: Eligible patients included pathologically confirmed lung adenocarcinomas of any stage with a RET or ROS1 rearrangement via fluorescence in-situ hybridization or next-generation sequencing, and available pre-treatment baseline imaging for review. A cohort of EGFR-mutant lung cancers was identified as a control group. CT features assessed included location, consistency, contour, presence of cavitation, and calcification of the primary tumor. Presence of an effusion, lung metastases, adenopathy and extrathoracic disease were recorded. The Wilcoxon rank-sum/Kruskal-Wallis and Fisher's exact tests were used to compare features between groups. RESULTS: 73 patients with lung adenocarcinomas were identified: 17 (23%) with ROS1 fusions, 25 (34%) with RET fusions and 31 (43%) with EGFR mutations. ROS1-rearranged lung cancers were more likely to present as peripheral tumors in comparison to EGFR-mutant lung cancers (32% vs. 65%, p=0.04). RET-rearranged lung cancers did not significantly differ from EGFR-mutant lung cancers radiographically. The consistency of the primary lesion for RET and ROS fusions and EGFR mutations were most frequently solid and spiculated. CONCLUSIONS: Lung adenocarcinomas with RET and ROS1 fusions share many radiographic features and those with ROS1 fusions are more likely to present as peripheral lesions in comparison to EGFR-mutant lung cancers. PMID- 26424210 TI - The Third Pillar. PMID- 26424211 TI - Opportunities in Reform: Bioethics and Mental Health Ethics. AB - Last year marks the first year of implementation for both the Patient Protection and Affordable Care Act and the Mental Health Parity and Addiction Equity Act in the United States. As a result, healthcare reform is moving in the direction of integrating care for physical and mental illness, nudging clinicians to consider medical and psychiatric comorbidity as the expectation rather than the exception. Understanding the intersections of physical and mental illness with autonomy and self-determination in a system realigning its values so fundamentally therefore becomes a top priority for clinicians. Yet Bioethics has missed opportunities to help guide clinicians through one of medicine's most ethically rich and challenging fields. Bioethics' distancing from mental illness is perhaps best explained by two overarching themes: 1) An intrinsic opposition between approaches to personhood rooted in Bioethics' early efforts to protect the competent individual from abuses in the research setting; and 2) Structural forces, such as deinstitutionalization, the Patient Rights Movement, and managed care. These two themes help explain Bioethics' relationship to mental health ethics and may also guide opportunities for rapprochement. The potential role for Bioethics may have the greatest implications for international human rights if bioethicists can re-energize an understanding of autonomy as not only free from abusive intrusions but also with rights to treatment and other fundamental necessities for restoring freedom of choice and self-determination. Bioethics thus has a great opportunity amid healthcare reform to strengthen the important role of the virtuous and humanistic care provider. PMID- 26424212 TI - Serum uric acid is associated with mortality and heart failure hospitalizations in patients with complicated myocardial infarction: findings from the High-Risk Myocardial Infarction Database Initiative. AB - AIMS: Serum uric acid (SUA) levels are associated with poorer outcomes in healthy cohorts and patients with stable and unstable coronary heart disease. We investigated the relationship between SUA and clinical outcomes in subjects with acute myocardial infarction (MI) complicated by reduced left ventricular (LV) function, heart failure (HF), or both. METHODS AND RESULTS: Univariable and multivariable Cox proportional hazards modelling was performed to study the association of baseline SUA and all-cause mortality, cardiovascular (CV) mortality, and HF hospitalization in an individual patient meta-analysis of four merged large randomized trials (CAPRICORN, EPHESUS, OPTIMAAL, and VALIANT). Three trials (excluding VALIANT) reported SUA, which was available in a total of 12 677 subjects. The ranges of SUA for quartiles I-IV were 45-280, 281-344, 345-420, and 420-1640 mmol/L, respectively. While almost 90% of patients in the lowest SUA quartile were alive after a mean follow-up of 23 +/- 11 months, <70% were alive in the highest SUA quartile. Compared with the lowest SUA quartile as reference, hazard ratios (HRs) and 95% confidence intervals (CIs) of SUA quartiles III and IV showed an increase in all-cause mortality [HR 1.18, 95% CI 0.95-1.46, and HR 1.36, 95% CI 1.11-1.67) and CV mortality (HR 1.27, 95% 1.01-1.61, and HR 1.47, 95% CI 1.17-1.83). SUA quartiles III and IV also exhibited increased HF hospitalization (HR 1.22, 95% CI 1.09-1.36, and HR 1.28, 95% CI 1.14-1.43; P < 0.001 for all comparisons) in multivariable analyses. The addition of SUA was associated with a significant improvement in reclassification to predict CV mortality (net reclassification improvement 17.6%, 95% CI 14.9-20.5%, P < 0.001). CONCLUSIONS: Elevated SUA is associated with poor outcomes in patients after MI complicated by reduced LV function, HF, or both. The quantification of SUA, a low cost routinely available biomarker, could improve risk stratification of patients with complicated MI. PMID- 26424213 TI - Effect of distal sugar and interglycosidic linkage of disaccharides on the activity of proline rich antimicrobial glycopeptides. AB - The effect of glycosylation on protein structure and function depends on a variety of intrinsic factors including glycan chain length. We have analyzed the effect of distal sugar and interglycosidic linkage of disaccharides on the properties of proline-rich antimicrobial glycopeptides, formaecin I and drosocin. Their glycosylated analogs-bearing lactose, maltose and cellobiose, as a glycan side chain on their conserved threonine residue, were synthesized where these disaccharides possess identical proximal sugar and vary in the nature of distal sugar and/or interglycosidic linkage. The structural and functional properties of these disaccharide-containing formaecin I and drosocin analogs were compared with their corresponding monoglycosylated forms, beta-D-glucosyl-formaecin I and beta D-glucosyl-drosocin, respectively. We observed neither major secondary structural alterations studied by circular dichroism nor substantial differences in the toxicity with mammalian cells among all of these analogs. The comparative analyses of antibacterial activities of these analogs of formaecin I and drosocin displayed that beta-D-maltosyl-formaecin I and beta-D-maltosyl-drosocin were more potent than that of respective beta-D-Glc-analog, beta-D-cellobiosyl-analog and beta-D-lactosyl-analog. Despite the differences in their antibacterial activity, all the analogs exhibited comparable binding affinity to DnaK that has been reported as one of the targets for proline-rich class of antibacterial peptides. The comparative-quantitative internalization studies of differentially active analogs revealed the differences in their uptake into bacterial cells. Our results exhibit that the sugar chain length as well as interglycosidic linkage of disaccharide may influence the antibacterial activity of glycosylated analogs of proline-rich antimicrobial peptides and the magnitude of variation in antibacterial activity depends on the peptide sequence. PMID- 26424214 TI - Plasma Chemokine signature correlates with lung goblet cell hyperplasia in smokers with and without chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is characterized by lung and systemic inflammation as well as airway goblet cell hyperplasia (GCH). Mucin production is activated in part by stimulation of the epidermal growth factor (EGF) receptor pathway through neutrophils and macrophages. How circulating cytokine levels relate to GCH is not clear. METHODS: We performed phlebotomy and bronchoscopy on 25 subjects (six nonsmokers, 11 healthy smokers, and eight COPD subjects FEV1 30-60 %). Six endobronchial biopsies per subject were performed. GCH was measured by measuring mucin volume density (MVD) using stereological techniques on periodic acid fast-Schiff stained samples. We measured the levels of chemokines CXCL8/IL-8, CCL2/MCP-1, CCL7/MCP-3, CCL22/MCD, CCL3/MIP-1alpha, and CCL4/MIP-1beta, and the cytokines IL-1, IL-4, IL-6, IL-9, IL-17, EGF, and vascular endothelial growth factor (VEGF). Differences between groups were assessed using one-way ANOVA, t test, or Chi squared test. Post hoc tests after ANOVA were performed using Bonferroni correction. RESULTS: MVD was highest in healthy smokers (27.78 +/- 10.24 MUL/mm(2)) compared to COPD subjects (16.82 +/- 16.29 MUL/mm(2), p = 0.216) and nonsmokers (3.42 +/- 3.07 MUL/mm(2), p < 0.0001). Plasma CXCL8 was highest in healthy smokers (11.05 +/- 8.92 pg/mL) compared to nonsmokers (1.20 +/- 21.92 pg/mL, p = 0.047) and COPD subjects (6.01 +/- 5.90 pg/mL, p = 0.366). CCL22 and CCL4 followed the same trends. There were no significant differences in the other cytokines measured. When the subjects were divided into current smokers (healthy smokers and COPD current smokers) and non/ex-smokers (nonsmokers and COPD ex-smokers), plasma CXCL8, CCL22, CCL4, and MVD were greater in current smokers. No differences in other cytokines were seen. Plasma CXCL8 moderately correlated with MVD (r = 0.552, p = 0.003). DISCUSSION: In this small cohort, circulating levels of the chemokines CXCL8, CCL4, and CCL22, as well as MVD, attain the highest levels in healthy smokers compared to nonsmokers and COPD subjects. These findings seem to be driven by current smoking and are independent of airflow obstruction. CONCLUSIONS: These data suggest that smoking upregulates a systemic pattern of neutrophil and macrophage chemoattractant expression, and this correlates significantly with the development of goblet cell hyperplasia. PMID- 26424215 TI - Vasoactive Inotropic Score (VIS) as Biomarker of Short-Term Outcomes in Adolescents after Cardiothoracic Surgery. AB - Our aim was to evaluate the Vasoactive Inotropic Score (VIS) as a prognostic marker in adolescents following surgery for congenital heart disease. This single center retrospective chart review included patients 10-18 years of age, who underwent cardiac surgery from 2009 to 2014. Hourly VIS was calculated for the initial 48 postoperative hours using standard formulae and incorporating doses of six pressors. The composite adverse outcome was defined as any one of death, resuscitation or mechanical support, arrhythmia, infection requiring antibacterial therapy, acute kidney injury or neurologic injury. Surgeries were risk-stratified by the type of surgical repair using the validated STAT score. Statistical analysis (SPSS 19.0) included Mann-Whitney U test, Chi-square test, ROC curves, and binary regression analysis. Our cohort (n = 149) had a mean (SD) age of 13.9 (2.4) years and included 97 (65.1 %) males. Maximal VIS at 24 and 48 h following surgery was significantly higher in subjects (n = 27) who suffered an adverse outcome. Subjects with adverse outcome had longer bypass and cross-clamp times, durations of stay in the hospital, and a higher rate of acute kidney injury, compared to those (n = 122) without postoperative adverse outcomes. The area under the ROC for maximum VIS at 24-48 h after surgery was 0.76, with sensitivity, specificity, and positive and negative predictive values with 95 % CI of 67 (48-82) %, 74 (70-77) %, and 36 (26-44) % and 91 (86-95) %, respectively, at a cutoff >4.75. On binary logistic regression, maximum VIS on second postoperative day remained significantly associated with adverse outcome (OR 1.35; 95 % CI> 1.12-1.64, p = 0.002). Maximal VIS at 24 and 48 h correlated significantly with length of stay and time to extubation. Maximal VIS on the second postoperative day predicts adverse outcome in adolescents following cardiac surgery. This simple yet robust prognostic indicator may aid in risk stratification and targeted interventions in this population. PMID- 26424216 TI - Reproducibility of compartmental subchondral bone morphometry in the mouse tibiofemoral joint. AB - AIM: Evidence suggests that subchondral bone can be used as a predictor for the onset of osteoarthritis. As such, there is a need to accurately and reproducibly quantify subchondral bone in areas where osteoarthritis develops. In this paper, we present a novel technique for the segmentation of subchondral bone in the tibiofemoral joint and assess the reproducibility of this method with multiple measures and users. METHODS: The right hind leg of seven C57BL/6 mice were excised and imaged in MUCT. The menisci and patella were manually segmented and the image data was Gaussian filtered and binarized. An in-house algorithm was used to generate cortical and epiphyseal volumes of interest and standard morphometric indices for bone were computed. The intraclass correlation coefficient (ICC), absolute precision error (PE(SD)), and precision error as a percentage of the coefficient of variation of the repeated measurements (PE(%CV)) were calculated for each index. Additionally, an inter-user study was performed using the same indices and statistics. RESULTS: For repeated measures, ICC ranged from 0.869 (cortical bone volume fraction, femur) to 0.994 (degree of anisotropy, femur). Similarly, PE(%CV) ranged from 0.84% (cortical bone volume fraction, femur) to 5.11% (connectivity density, tibia). For repeated users, no effect was seen in the femur with a slight effect in the tibia. CONCLUSIONS: A novel method for the automatic segmentation of cortical and epiphyseal bone is presented and is shown to be reproducible in C57BL/6 mice. This tool will allow for high throughput studies of osteoarthritis in animal models. PMID- 26424217 TI - Physiological and Behavioral Vulnerability Markers Increase Risk to Early Life Stress in Preschool-Aged Children. AB - The study examined whether child physiological (cortisol reactivity) and behavioral (negative emotionality) risk factors moderate associations between the early rearing environment, as measured by child exposure to maternal depression and stressful life events, and preschool psychopathology and psychosocial functioning. A sample of 156 preschool-aged children (77 boys, 79 girls; age M = 49.80 months, SD = 9.57, range: 36-71) participated in an observational assessment of temperament and was exposed to a stress-inducing laboratory task, during which we obtained five salivary cortisol samples. Parents completed clinical interviews to assess child and parent psychopathology and stressful life events. Results indicated that the combination of a blunted pattern of cortisol reactivity and recent stressful life events was associated with higher levels of preschoolers' externalizing symptoms and lower psychosocial functioning. In addition, greater life stress was associated with higher levels of preschoolers' internalizing symptoms. Lastly, children with high levels of negative emotionality and who were exposed to maternal depression had the lowest social competence. Our findings highlight the critical role of the early environment, particularly for children with identified risk factors, and add to our understanding of pathways involved in early emerging psychopathology and impairment. PMID- 26424218 TI - Anti-Apoptotic and Anti-Oxidant Effects of Caffeic Acid Phenethyl Ester on Cadmium-Induced Testicular Toxicity in Rats. AB - Cadmium (Cd) is a serious environmental and occupational contaminant and may represent a serious health hazard to humans and other animals. Cd is reported to induce the generation of reactive oxygen species, and induces testicular damage in many species of animals. The goal of our study was to examine the anti apoptotic and anti-oxidant effects of caffeic acid phenethyl ester (CAPE) on Cd induced oxidative stress, apoptosis, and testicular injury in rats. A total of 40 male Wistar albino rats were divided into four groups: control, CAPE alone, Cd treated, and Cd-treated with CAPE; each group consisted of 10 animals. To induce toxicity, Cd (1 mg/kg body weight) was dissolved in normal saline and subcutaneously injected into rats for 30 days. The rats in CAPE-treated group were given a daily dose of 10 MUmol/kg body weight of CAPE by using intraperitoneal injection. This application was continued daily for a total of 30 days. To date, no examinations of the anti-apoptotic and anti-oxidant properties of CAPE on Cd-induced apoptosis, oxidative damage, and testicular injury in rat testes have been reported. CAPE-treated animals showed an improved histological appearance and serum testosterone levels in Cd-treated group. Our data indicate a significant reduction in the number of apoptotic cells in testis tissues of the Cd-treated group with CAPE treatment. Moreover, CAPE significantly suppressed lipid peroxidation, compensated deficits in the anti-oxidant defenses in testes tissue resulted from Cd administration. These findings suggest that the protective potential of CAPE in Cd toxicity might be due to its anti-oxidant and anti-apoptotic properties, which could be useful for achieving optimum effects in Cd-induced testicular injury. PMID- 26424219 TI - Topical trans-resveratrol ameliorates steroid-induced anterior and posterior segment changes in rats. AB - Steroid-induced hypertension and glaucoma is associated with increased extracellular meshwork (ECM) deposition in trabecular meshwork (TM). Previous studies have shown that single drop application of trans-resveratrol lowers IOP in steroid-induced ocular hypertensive (SIOH) rats. This IOP lowering is attributed to activation of adenosine A1 receptors, which may lead to increased matrix metalloproteinase (MMP)-2 activity. This study evaluated the effect of repeated topical application of trans-resveratrol for 21 days in SIOH animals on IOP, changes in MMP-2 level in aqueous humor, trabecular meshwork and retinal morphology and retinal redox status. We observed that treatment with trans resveratrol results in significant and sustained IOP reduction in SIOH rats. This IOP reduction is associated with significantly higher aqueous humor total MMP-2 level; significantly reduced TM thickness and increased number of TM cells. Treatment with trans-resveratrol also significantly increased ganglion cell layer (GCL) thickness, the linear cell density in the GCL and inner retina thickness; and significantly reduced retinal oxidative stress compared to the SIOH vehicle treated group. In conclusion, repeated dose topical application of trans resveratrol produces sustained IOP lowering effect, which is associated with increased level of aqueous humor MMP-2, normalization of TM and retinal morphology and restoration of retinal redox status. PMID- 26424220 TI - An easy, rapid method to isolate RPE cell protein from the mouse eye. AB - The retinal pigment epithelium (RPE) is essential for maintaining the health of the neural retina. RPE cell dysfunction plays a critical role in many common blinding diseases including age-related macular degeneration (AMD), diabetic retinopathy, retinal dystrophies. Mouse models of ocular disease are commonly used to study these blinding diseases. Since isolating the RPE from the choroid has been challenging, most techniques separate the RPE from the retina, but not the choroid. As a result, the protein signature actually represents a heterogeneous population of cells that may not accurately represent the RPE response. Herein, we describe a method for separating proteins from the RPE that is free from retinal and choroidal contamination. After removing the anterior segment and retina from enucleated mouse eyes, protein from the RPE was extracted separately from the choroid by incubating the posterior eyecup with a protein lysis buffer for 10 min. Western blot analysis identified RPE65, an RPE specific protein in the RPE lysates, but not in choroidal lysates. The RPE lysates were devoid of rhodopsin and collagen VI, which are abundant in the retina and choroid, respectively. This technique will be very helpful for measuring the protein signal from the RPE without retinal or choroidal contamination. PMID- 26424221 TI - More heads choose better than one: Group decision making can eliminate probability matching. AB - Probability matching is a robust and common failure to adhere to normative predictions in sequential decision making. We show that this choice anomaly is nearly eradicated by gathering individual decision makers into small groups and asking the groups to decide. The group choice advantage emerged both when participants generated responses for an entire sequence of choices without outcome feedback (Exp. 1a) and when participants made trial-by-trial predictions with outcome feedback after each decision (Exp. 1b). We show that the dramatic improvement observed in group settings stands in stark contrast to a complete lack of effective solitary deliberation. These findings suggest a crucial role of group discussion in alleviating the impact of hasty intuitive responses in tasks better suited to careful deliberation. PMID- 26424222 TI - Probing the interface theory of perception: Reply to commentaries. AB - We propose that selection favors nonveridical perceptions that are tuned to fitness. Current textbooks assert, to the contrary, that perception is useful because, in the normal case, it is veridical. Intuition, both lay and expert, clearly sides with the textbooks. We thus expected that some commentators would reject our proposal and provide counterarguments that could stimulate a productive debate. We are pleased that several commentators did indeed rise to the occasion and have argued against our proposal. We are also pleased that several others found our proposal worth exploring and have offered ways to test it, develop it, and link it more deeply to the history of ideas in the science and philosophy of perception. To both groups of commentators: thank you. Point and counterpoint, backed by data and theory, is the essence of science. We hope that the exchange recorded here will advance the scientific understanding of perception and its evolution. In what follows, we respond to the commentaries in alphabetical order. PMID- 26424224 TI - Diving behaviour of wildlife impacted by an oil spill: A clean-up and rehabilitation success? AB - The value of rehabilitating oiled wildlife is an on-going global debate. On October 5, 2011, the cargo vessel C/V Rena grounded on Astrolabe Reef, New Zealand (NZ), spilling over 300 tonnes of heavy fuel oil. As part of the Rena oil spill response, 383 little blue penguins (LBP, Eudyptula minor) were captured, cleaned, rehabilitated and released back into a cleaned environment. This research investigates foraging behaviour changes due either to the oil spill or by the rehabilitation process by comparing the diving behaviour of rehabilitated (n=8) and non-rehabilitated (n=6) LBPs and with LBP populations throughout NZ. Stabile isotope analysis of feathers was also used to investigate diet. There were no foraging behaviour differences between rehabilitated and non rehabilitated LBPs and the overall diving behaviour of these LBPs have similar, if not less energetic, foraging behaviour than other LBPs in NZ. This suggests the rehabilitation process and clean-up undertaken after the Rena appears effective and helps justify the rehabilitation of oiled wildlife across the world. PMID- 26424223 TI - Volume Matters: Returning Home After Hip Fracture. AB - OBJECTIVES: To examine the effect of the relationship between volume (number of hip fracture admissions during the 12 months before participant's fracture) and other facility characteristics on outcomes. DESIGN: Prospective observational study. SETTING: U.S. skilled nursing facilities (SNFs) admitting individuals discharged from the hospital after treatment for hip fracture between 2000 and 2007 (N = 15,439). PARTICIPANTS: Community-dwelling fee-for-service Medi-care beneficiaries aged 75 and older admitted to U.S. hospitals for their first hip fracture and discharged to a SNF for postacute care from 2000 to 2007 (N = 512,967). MEASUREMENTS: Successful discharge from SNF to community, defined as returning to the community within 30 days of hospital discharge to the SNF and remaining in the community without being institutionalized for at least 30 days, was examined using Medicare administrative data, propensity score matching, and instrumental variables. RESULTS: The overall rate of successful discharge to the community was 31%. Of the 15,439 facilities, the facility interquartile range varied from 0% (25th percentile) to 42% (75th percentile). An important determinant of variation in discharge rate was SNF volume of hip fracture admissions. Unadjusted successful discharge from SNF to community was 43.7% in high-volume facilities (>24 admissions/year), versus 18.8% in low-volume facilities (1-6 admissions/year). This facility volume effect persisted after adjusting for participant and facility characteristics associated with outcomes (e.g., adjusted odds ratio = 2.06, 95% confidence interval = 1.91-2.21 for volume of 25 vs 3 admissions per year). CONCLUSION: In community-dwelling persons with their first hip fracture, successful return to the community varies substantially according to SNF provider volume and staffing characteristics. PMID- 26424225 TI - The alcohol policy environment, enforcement and consumption in the United States. AB - INTRODUCTION AND AIMS: Many studies of alcohol policies examine the presence or absence of a single policy without considering policy strength or enforcement. We developed measures for the strength of 18 policies (from Alcohol Policy Information System) and levels of enforcement of those policies for the 50 US states, and examined their associations with alcohol consumption. DESIGN AND METHODS: We grouped policies into four domains (underage alcohol use, provision of alcohol to underage, alcohol serving, general availability) and used latent class analysis to assign states to one of four classes based on the configuration of policies-weak except serving policies (6 states), average (29 states), strong for underage use (11 states) and strong policies overall (4 states). We surveyed 1082 local enforcement agencies regarding alcohol enforcement across five domains. We used multilevel latent class analysis to assign states to classes in each domain and assigned each state to an overall low (15 states), moderate (19 states) or high (16 states) enforcement group. Consumption outcomes (past month, binge and heavy) came from the Behavioral Risk Factor Surveillance System. RESULTS: Regression models show inverse associations between alcohol consumption and policy class, with past month alcohol consumption at 54% in the weakest policy class and 34% in the strongest. In adjusted models, the strong underage use policy class was consistently associated with lower consumption. Enforcement group did not affect the policy class and consumption associations. DISCUSSION AND CONCLUSIONS: Results suggest strong alcohol policies, particularly underage use policies, may help to reduce alcohol consumption and related consequences. [Erickson DJ, Lenk KM, Toomey TL, Nelson TF, Jones-Webb R. The alcohol policy environment, enforcement, and consumption in the United States. Drug Alcohol Rev 2015;??:??-??]. PMID- 26424226 TI - Beneficial effects of fluid resuscitation via the rectum on hemodynamic disorders and multiple organ injuries in an experimental severe acute pancreatitis model. AB - OBJECTIVES: Exaggerated hydration is harmful for patients with severe acute pancreatitis (SAP), and it can increase mortality rate. In this study, we investigated the role of fluid resuscitation via the rectum (FRVR) on the hemodynamic state and compared FRVR with intravenous fluid resuscitation (IVFR) on resuscitation effect and organ function in an early stage of SAP. METHODS: We studied whether FRVR corrects hemodynamic disorders at an early stage of SAP in Spraque-Dawley (SD) rats and whether it mitigates organ dysfunction and whether FRVR is superior to IVFR. RESULTS: In both IVFR and FRVR groups, we observed a rebound in the mean arterial pressure (MAP) after 5 h and 6 h of administration (p < 0.05), respectively. MAP of the FRVR group reached the same level as the SHAM group at the end of the treatment, with hematocrit declining compared with the non-fluid resuscitation (NFR) group (p < 0.05). A concomitant increase in abdominal ascites and the lung wet/dry ratio by IVFR was depressed in the FRVR group (p < 0.05). Liver function was ameliorated in both fluid resuscitation groups (p < 0.05), consistent with histopathological improvement. TNF-alpha in serum and MPO in the lungs and jejunum of the FRVR group were lower than the IVFR group (p < 0.05). Pancreas histopathological injuries were ameliorated by both IVFR and FRVR (p < 0.05). CONCLUSIONS: Our findings suggested FRVR is a potential supplementary method for fluid management in an early stage of SAP and FRVR should be studied further. PMID- 26424227 TI - The Cognitive Advantages of Counting Specifically: A Representational Analysis of Verbal Numeration Systems in Oceanic Languages. AB - The domain of numbers provides a paradigmatic case for investigating interactions of culture, language, and cognition: Numerical competencies are considered a core domain of knowledge, and yet the development of specifically human abilities presupposes cultural and linguistic input by way of counting sequences. These sequences constitute systems with distinct structural properties, the cross linguistic variability of which has implications for number representation and processing. Such representational effects are scrutinized for two types of verbal numeration systems-general and object-specific ones-that were in parallel use in several Oceanic languages (English with its general system is included for comparison). The analysis indicates that the object-specific systems outperform the general systems with respect to counting and mental arithmetic, largely due to their regular and more compact representation. What these findings reveal on cognitive diversity, how the conjectures involved speak to more general issues in cognitive science, and how the approach taken here might help to bridge the gap between anthropology and other cognitive sciences is discussed in the conclusion. PMID- 26424228 TI - Factors preventing the performance of oxygen isotope ratios as indicators of grain yield in maize. AB - MAIN CONCLUSION: This paper provides new insights into source-sink relationships and transpiration processes which will eventually help to interpret delta (18) O as a genotype selection and ecophysiological tool for maize adaptation to drought. Oxygen isotope composition (delta(18)O) has been proposed as a phenotyping tool to integrate leaf transpiration in C4 crops, such as maize. Within this context we hypothesize that delta(18)O in leaves may reflect primarily environmental and genetic variability in evaporative processes, but that this signal may become dampened in transit from source to sink tissues. The aim of this study was to assess the relative importance of transpirative or translocation-related factors affecting delta(18)O in plant tissues of maize. We performed two water regime experiments, one with two varieties under semi controlled conditions, and another in the field with 100 genotypes during two consecutive years. The delta(18)O in organic matter at the leaf base was strongly correlated with the delta(18)O in stem water, indicating that it could be a good proxy for source water in extensive samplings. Compared to leaves, we observed an (18)O depletion in silks and grains, but not in stem-soluble organic matter. We interpret this as evidence of exchange with unenriched water from source to sink, but mainly occurring within sink tissues. Although grain yield (GY) and physiological variables did not show clear intra-trial patterns against delta(18)O, the only tissues that correlated with GY in the linear regression approach were that of silks, giving an insight of evapotranspirative demand during female flowering and thus of potential maize lines that are better adapted to drought. This finding will eventually help to interpret delta(18)O as a genotype selection and ecophysiological tool for the adaption of maize and other crops to drought, offering insight into source-sink relationships and transpiration processes. PMID- 26424230 TI - Fast track to 2030: granularity at a global scale. PMID- 26424229 TI - Protein profile of cotyledon, tegument, and embryonic axis of mature acorns from a non-orthodox plant species: Quercus ilex. AB - MAIN CONCLUSION: Contrary to the orthodox seeds, recalcitrant Holm oak seeds possess the enzymatic machinery to start germination during the maturation phase. The protein profile of the different parts, mature seeds, of the Holm oak, a non orthodox plant species, has been characterized using one- and two-dimensional gel electrophoresis coupled to matrix-assisted laser desorption ionization-time of flight mass spectrometry. Protein content and profiles of the three seed tissues (cotyledon, embryonic axis and tegument) were quite different. The embryonic axis showed 4-fold and 20-fold higher protein content than the cotyledon and the tegument, respectively. Two hundred and twenty-six variable proteins among the three seed parts were identified, being classified according to their function into eight main groups. The cotyledon presented the highest number of metabolic and storage proteins (89% of them are legumin) compared to the embryonic axis and tegument. The embryonic axis had the highest number of the species within the protein fate group. The tegument presented the largest number of the defense /stress-related and cytoskeleton proteins. This distribution is in good agreement with the biological role of the tissues. The study of the seed tissue proteome demonstrated a compartmentalization of pathways and a division of metabolic tasks between embryonic axis, cotyledon and tegument. This compartmentalization uncovered in our study should provide a starting point for understanding, at the molecular level, the particularities of the recalcitrant seeds. PMID- 26424231 TI - A reality check for aspirational targets to end HIV. PMID- 26424233 TI - Unlocking adherence: is gender the key? PMID- 26424232 TI - Partner-based adherence intervention for second-line antiretroviral therapy (ACTG A5234): a multinational randomised trial. AB - BACKGROUND: Adherence is key to the success of antiretroviral therapy. Enhanced partner support might benefit patients with previous treatment failure. We aimed to assess whether an enhanced partner-based support intervention with modified directly observed therapy would improve outcomes with second-line therapy in HIV infected patients for whom first-line therapy had failed. METHODS: We did a multicentre, international, randomised clinical trial at nine sites in Botswana, Brazil, Haiti, Peru, South Africa, Uganda, Zambia, and Zimbabwe. Participants aged 18 years or older for whom first-line therapy had failed, with HIV RNA concentrations greater than 1000 copies per mL and with a willing partner, were randomly assigned (1:1), via computer-generated randomisation, to receive partner based modified directly observed therapy or standard of care. Randomisation was stratified by screening HIV RNA concentration (<=10 000 copies per mL vs >10 000 copies per mL). Participants and site investigators were not masked to group assignment. Primary outcome was confirmed virological failure (viral load >400 copies per mL) by week 48. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00608569. FINDINGS: Between April 23, 2009, and Sept 29, 2011, we randomly assigned 259 participants to the modified directly observed therapy group (n=129) or the standard-of-care group (n=130). 34 (26%) participants in the modified directly observed therapy group achieved the primary endpoint of virological failure by week 48 compared with 23 (18%) participants in the standard-of-care group. The Kaplan-Meier estimated cumulative probability of virological failure by week 48 was 25.1% (95% CI 17.7 32.4) in the modified directly observed therapy group and 17.3% (10.8-23.7) in the standard-of-care group, for a weighted difference in standard of care versus modified directly observed therapy of -6.6% (95% CI -16.5% to 3.2%; p=0.19). 36 (14%) participants reported at least one grade 3 or higher adverse event or laboratory abnormality (n=21 in the modified directly observed therapy group and n=15 in the standard-of-care group). INTERPRETATION: Partner-based training with modified directly observed therapy had no effect on virological suppression. The intervention does not therefore seem to be a promising strategy to increase adherence. Intensive follow-up with clinic staff might be a viable approach in this setting. FUNDING: AIDS Clinical Trials Group and the National Institute of Allergy and Infectious Diseases, US National Institutes of Health. PMID- 26424234 TI - Maximising the benefits of home-based HIV testing. PMID- 26424235 TI - Tailoring biomedical interventions for key populations. PMID- 26424236 TI - Postthrombolytic Antiplatelet Use for Patients with Intercerebral Hemorrhage without Extensive Parenchymal Involvement Does Not Worsen Outcome. AB - BACKGROUND AND PURPOSE: It is unclear whether postthrombolytic antiplatelet (AP) therapy after thrombolytic-related hemorrhage without extensive parenchymal involvement (THEPI) affects the clinical outcome. This study explored whether AP administration in patients with THEPI affects short- and long-term outcomes. METHODS: All of the data for this study were collected from the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China) registry. Patients with THEPI were assigned to either the AP (AP therapy should be commenced 24 h after intravenous thrombolysis) or AP-naive groups. THEPI was defined according to European-Australasian Acute Stroke Study II criteria. The 90 day functional outcome, 7-day National Institutes of Health Stroke Scale (NIHSS) score, and 7-day and 90-day mortalities were compared between the AP and AP-naive groups. Logistic regression analysis wy on the short- and long-term clinical outcomes. RESULTS: Of the 928 patients enrolled from those in the TIMS-China registry (n=1,440), 89 (9.6%) had nonsymptomatic intracerebral hemorrhage (ICH) within 24-36 h after thrombolysis; 33 (37%) of these patients were given AP therapy (AP group) and 56 (63%) were not (AP-naive group). No significant differences were found for the risk of 7-day aggravated ICH (p=0.998), 7-day NIHSS score (p=0.5491), 7-day mortality [odds ratio (OR)=3.427; 95% confidence interval (95% CI)=0.344-34.160; p=0.294], 90-day mortality (OR=0.788, 95% CI=0.154-4.040, p=0.775), or modified Rankin score 5 or 6 at 90-days (OR=1.108, 95% CI=0.249-4.928, p=0.893) between the AP and AP-naive groups after THEPI. CONCLUSIONS: Early administration of postthrombolytic AP therapy after THEPI does not worsen either the short- or long-term outcome. AP therapy may be a reasonable treatment option for patients with THEPI to reduce the risk of ischemic stroke recurrence. PMID- 26424237 TI - Prognostic Role of Serum Levels of Uric Acid in Amyotrophic Lateral Sclerosis. AB - BACKGROUND AND PURPOSE: It has been suggested that oxidative stress is one of the pathomechanisms underlying amyotrophic lateral sclerosis (ALS), and thus antioxidants such as uric acid (UA) that could reduce oxidative stress might be beneficial in the prevention or treatment of this disease. The objective of this study was to prospectively investigate serum UA levels in Korean ALS patients and to relate them to disease progression. METHODS: ALS patients and healthy controls who were individually well-matched for sex, age, and body mass index (BMI) underwent blood testing for serum UA levels, and analyzed whether UA levels were correlated with the disease status of the patients, as defined by the ALS Functional Rating Scale-Revised (ALSFRS-R). RESULTS: The study included 136 ALS patients and 136 matched controls. The UA level was lower in the ALS patients (4.50+/-1.17 mg/dL, mean+/-SD) than in the controls (5.51+/-1.22 mg/dL; p<0.001). Among the ALS patients, the level of UA acid was inversely correlated with the rate of disease progression (decrease in ALSFRS-R score). Kaplan-Meier analysis revealed that a better survival rate was more strongly correlated with top tertile levels of serum UA than with bottom-tertile levels (log-rank test: p=0.035). CONCLUSIONS: ALS patients had lower serum UA levels than did healthy individuals. UA levels in ALS were negatively correlated with the rate of disease progression and positively associated with survival, suggesting that UA levels contribute to the progression of ALS. UA levels could be considered a biomarker of disease progression in the early phase in ALS patients. PMID- 26424238 TI - Comments on "Improved Serum Leptin and Ghrelin Following Bariatric Surgery Predict better Postoperative Cognitive Function". PMID- 26424239 TI - Acute-Onset Altitudinal Visual Field Defect Caused by Optic Canal Meningioma. PMID- 26424240 TI - Surveillance of the System Accuracy of Two Systems for Self-Monitoring of Blood Glucose After Market Approval. PMID- 26424241 TI - Development of a Smartphone Application to Capture Carbohydrate, Lipid, and Protein Contents of Daily Food: Need for Integration in Artificial Pancreas for Patients With Type 1 Diabetes? AB - BACKGROUND: Meal lipids (LIP) and proteins (PRO) may influence the effect of insulin doses based on carbohydrate (CHO) counting in patients with type 1 diabetes (T1D). We developed a smartphone application for CHO, LIP, and PRO counting in daily food and assessed its usability in real-life conditions and potential usefulness. METHODS: Ten T1D patients used the android application for 1 week to collect their food intakes. Data included meal composition, premeal and 2-hour postmeal blood glucose, corrections for hypo- or hyperglycemia after meals, and time for entering meals in the application. Meal insulin doses were based on patients' CHO counting (application in blinded mode). Linear mixed models were used to assess the statistical differences. RESULTS: In all, 187 meals were analyzed. Average computed CHO amount was 74.37 +/- 31.78 grams; LIP amount: 20.26 +/- 14.28 grams and PRO amount: 25.68 +/- 16.68 grams. Average CHO, LIP, and PRO contents were significantly different between breakfast and lunch/dinner. The average time for meal entry in the application moved from 3-4 minutes to 2.5 minutes during the week. No significant impact of LIP and PRO was found on available blood glucose values. CONCLUSION: Our study shows CHO, LIP, and PRO intakes can be easily captured by an application on smartphone for meal entry used by T1D patients. Although LIP and PRO meal contents did not influence glucose levels when insulin doses were based on CHO in this pilot study, this application could be used for further investigation of this topic, including in closed-loop conditions. PMID- 26424242 TI - Relationship between Plasma Albumin Concentration and Plasma Volume in 5 Inbred Rat Strains. AB - Using the Evans Blue procedure, we previously found strain-related differences in plasma volumes in 5 inbred rat strains. Because albumin binds strongly with Evans blue, this protein is important in the Evans blue method of plasma volume determination. Therefore, we speculated that interstrain differences in plasma albumin concentration (PAC) could distort calculated plasma volumes. To address this concern, we used ELISA techniques to measure PAC in these inbred rat strains. In study A, the blood volume was measured by using Evans blue dye, and albumin was measured at the start of hemorrhage. In study B, blood volume was not measured, and albumin was measured twice, near the start and end of hemorrhage (approximately 14 min apart). Neither study revealed any interstrain differences in PAC, which decreased after hemorrhage in all 5 strains. No correlation was found between PAC and plasma volume, survival time, blood lactate, or blood base excess. Percentage changes in PAC during hemorrhage were greater in salt sensitive compared with Lewis rats. Moreover, these percentage changes were associated with survival time in Fawn hooded hypertensive rats. Our data show that the plasma volumes we measured previously were not misrepresented due to variations in PAC. PMID- 26424243 TI - Biochemical and Hematologic Reference Intervals for Aged Xenopus laevis in a Research Colony. AB - Xenopus laevis, the African clawed frog, is commonly used in developmental and toxicology research studies. Little information is available on aged X. laevis; however, with the complete mapping of the genome and the availability of transgenic animal models, the number of aged animals in research colonies is increasing. The goals of this study were to obtain biochemical and hematologic parameters to establish reference intervals for aged X. laevis and to compare results with those from young adult X. laevis. Blood samples were collected from laboratory reared, female frogs (n = 52) between the ages of 10 and 14 y. Reference intervals were generated for 30 biochemistry analytes and full hematologic analysis; these data were compared with prior results for young X. laevis from the same vendor. Parameters that were significantly higher in aged compared with young frogs included calcium, calcium:phosphorus ratio, total protein, albumin, HDL, amylase, potassium, CO2, and uric acid. Parameters found to be significantly lower in aged frogs included glucose, AST, ALT, cholesterol, BUN, BUN:creatinine ratio, phosphorus, triglycerides, LDL, lipase, sodium, chloride, sodium:potassium ratio, and anion gap. Hematology data did not differ between young and old frogs. These findings indicate that chemistry reference intervals for young X. laevis may be inappropriate for use with aged frogs. PMID- 26424244 TI - Microsurgical and Percutaneous Epididymal Sperm Aspiration for Sperm Collection from Live Mice. AB - Spermatozoa for in vitro fertilization of mouse oocytes and other methods of assisted reproduction typically are collected from the cauda epididymis of euthanized male mice. As an alternative to this terminal protocol, we developed and examined 2 methods for collecting sperm from anesthetized male mice without decreasing subsequent fertility: microsurgical epididymal sperm aspiration and, as a refinement, percutaneous epididymal sperm aspiration. Collected sperm was evaluated in terms of motility, concentration and in vitro fertilization ability. After recovery, both treated and untreated control male mice underwent in vivo fertility testing and subsequent histologic analysis of the treated male reproductive tract (epididymis and testis). In vitro fertilization using sperm recovered by the 2 collection methods was successfully achieved in all cases. The in vivo fertility test and the histologic analysis revealed no impairment of fertility and no permanent histologic alteration in the treated mice. Therefore, we recommend both techniques as simple and effective methods for recovering high quality epididymal mouse sperm without having to euthanize fertile male mice. PMID- 26424245 TI - Nasal Histopathology and Intracage Ammonia Levels in Female Groups and Breeding Mice Housed in Static Isolation Cages. AB - Many factors influence ammonia levels in rodent cages, and high intracage ammonia has been associated with specific types of abnormal nasal pathology in mice. The use of autoclaved corncob bedding and the maintenance of low room humidity reduce the accumulation of ammonia in mouse cages. However, there are no engineering standards that define the limits of ammonia exposure for mice housed in static isolation cages. Regulatory guidance indicates that solid bottom cages must be sanitized at least weekly and that cage components in direct contact with animals must be sanitized at least every 2 wk. Common practice is to replace the bottoms and bedding of static isolation cages once weekly. To determine whether changing static isolation cages once weekly is an appropriate performance standard for mice, we prospectively evaluated the relationship between ammonia levels, nasal histopathology, and housing densities in various grouping strategies of mice housed in static isolation cages. Here, we report that the average nasal pathology score per cage and intracage ammonia levels were correlated, but nasal pathology scores did not differ among mice housed in breeding pairs, breeding trios, or female groups. In light of ammonia levels and histopathology scores as performance standards, these results suggest that a weekly cage-change frequency for static isolation cages does not result in adverse effects. Our results provide evidence to support current practices in the use of static isolation cages for housing laboratory mice in modern vivaria. PMID- 26424246 TI - Ulcerative Dermatitis in C57BL/6NCrl Mice on a Low-Fat or High-Fat Diet With or Without a Mineralized Red-Algae Supplement. AB - Ulcerative dermatitis (UD) is a spontaneous idiopathic disease that often affects C57BL/6 mice or mice on a C57BL/6 background. UD is characterized by intense pruritus and lesion formation, most commonly on the head or dorsal thorax. Self trauma likely contributes to wound severity and delayed wound healing. Histologically, changes are nonspecific, consisting of ulceration with neutrophilic and mastocytic infiltration and epithelial hyperplasia and hyperkeratosis. Diet appears to have a profound effect on the development and progression of UD lesions. We investigated the incidence and severity of UD in C57BL/6NCrl mice on a high-fat western-style diet (HFWD) compared with a standard rodent chow. In addition, we examined the protective effects of dietary supplementation with a multimineral-rich product derived from marine red algae on UD in these 2 diet groups. HFWD-fed mice had an increased incidence of UD. In addition, mice on a HFWD had significantly more severe clinical and histologic lesions. Dietary mineral supplementation in mice on a HFWD decreased the histologic severity of lesions and reduced the incidence of UD in female mice in both diets. In conclusion, a high-fat western-style diet may potentiate UD in C57BL/6NCrl mice. Insufficient mineral supply and mineral imbalance may contribute to disease development. Mineral supplementation may be beneficial in the treatment of UD. PMID- 26424247 TI - Effect of Cage Space on Behavior and Reproduction in Crl:CD(SD) and BN/Crl Laboratory Rats. AB - The 2011 Guide for the Care and Use of Laboratory Animals contains recommendations regarding the amount of cage space for mothers with litters. Literature on cage-space use in breeding rats is sparse. We hypothesized that, if present, differences in behavior and reproduction would be detected between the smallest and largest cages tested. BN/Crl and Crl:CD(SD) rats were assigned to a cage treatment (580 cm(2), 758 cm(2), 903 cm(2), or 1355 cm(2)) and breeding configuration (single: male removed after birth of pups; pair: 1 male, 1 female) in a factorial design for 12 wk. All cages received 20 to 25 g of nesting material, and nests were scored weekly. Pups were weaned, sexed, and weighed between postnatal days 18 and 26. Adult behavior and location in the cage were videorecorded by scan-sampling on the litter's postnatal days 0 through 8 and 14 through 21. Press posture in adults and play behavior in pups were recorded according to a 1-0 sampling method. Differences in reproductive parameters were limited to expected differences related to rat genetic background and weaning weight in pups, which was lowest in the pair-bred CD rats in the smallest cages. Press posture in adults in the smaller cages increased as the pups became mobile. Pair-housed outbred rats in the smallest commercially available cage we tested showed behavioral changes and a lower pup weaning weight. Both laboratory animal scientists and caging manufacturers should address the challenge of providing more biologically relevant cage complexity rather than merely increasing floor space. PMID- 26424248 TI - Effects of Autoclaving Soy-Free and Soy-Containing Diets for Laboratory Rats on Protein and Energy Values Determined In Vitro and In Vivo. AB - Autoclaving diminishes the nutritional value of rat diets, depending on the duration and temperature of the process and the type of dietary protein. We evaluated in vivo and in vitro the effects of autoclaving on the protein and energy values of soy-free and soy-containing rat diets. The true digestibility and biological value of the dietary protein were determined in a 10-d experiment involving 28-d-old Wistar Crl:WI(Han) male rats fed casein- or soy-containing diet that was autoclaved for 20 min at 121 degrees C (T1), 10 min at 134 degrees C (T2), or not autoclaved (T0). The apparent protein digestibility and metabolizable energy concentration of experimental diets were assayed during an 18-d trial involving 6-wk-old Wistar-Crl:WI(Han) male rats and compared with a commercial diet. The neutral detergent fiber (NDF) content, amount of protein bound to NDF, protein solubility, and in vitro ileal protein digestibility were determined. Autoclaving decreased protein solubility, with the T2 condition having a greater effect than that of T1, and decreased the protein parameters determined in vivo, except for the apparent digestibility of the standard rat diet. Autoclaving decreased metabolizable energy slightly. The Atwater formula yielded higher values than those determined in rats, in vitro, and calculated according to the pig equation. We conclude that autoclaving diets according to the T1 program was less detrimental to dietary protein than was T2 and that the NDF content and protein solubility may be helpful in assessing the effect of autoclaving. The pig formula and in vitro method appear to be valid for estimating the metabolizable energy of rat diets. PMID- 26424249 TI - Severity and Distribution of Wounds in Rhesus Macaques (Macaca mulatta) Correlate with Observed Self-Injurious Behavior. AB - Self-injurious behavior (SIB) occurs within laboratory-housed NHP at low frequency but can have a devastating effect on animal research and wellbeing. One barrier to the study and clinical management of these cases is the cost of equipment and personnel time to quantify the behavior according to the current standard of observation and to score remotely obtained video recordings. In studies of human SIB, in which direct observation is difficult or prohibited, researchers have demonstrated that quantifying the tissue damage resulting from SIB can be a useful proxy to represent the underlying behavior. We hypothesized that the nature of wounds resulting from SIB in NHP could be used in a similar manner to measure the abnormal behavior. Using a cohort of rhesus macaques with high-incidence SIB, we examined severity, distribution, and number of wounds and compared them with observed incidences of SIB during a 12-wk experiment. We found that the number, severity, and distribution of physical wounds were associated with the incidences of biting behavior observed during the 2 wk prior to measurement. We also found that an increased number of wounds was associated with increased severity. Animals with wounds of moderate severity were more likely to also have severe wounds than were macaques with wounds that were lower than moderate in severity. This work is the first representative study in NHP to find that behavioral SIB correlates with physical wounding and that increases in the frequency and number of the body regions affected correlates with the severity of wounding. PMID- 26424250 TI - Effect of Room Ventilation Rates in Rodent Rooms with Direct-Exhaust IVC Systems. AB - When IVC are directly exhausted from a rodent housing room, the air quality of the room can become independent of the intracage air quality and may reduce the need for high room ventilation rates. This study assessed the effect of decreasing the ventilation rate in rodent rooms using direct-exhaust IVC systems. The study was conducted over 16 wk and compared conditions in 8 rodent rooms that had ventilation rates of 5 to 6 air changes per hour (ACH) with those in rooms at 10 to 12 ACH. At the low ventilation rate, rooms had higher CO2 concentrations, higher dew point temperature, and lower particulate levels and spent a greater percentage of time above the temperature set point than did rooms at the high rate. The levels of allergens and endotoxins in room air were the same regardless of the ventilation rate. Differences seen in parameters within cages at the 2 ventilation rates were operationally irrelevant. We detected no total volatile organic compounds in the room that were attributable to ammonia, regardless of the ventilation rate. Clearing the air of ethanol after a spill took longer at the low compared with high rate. However, ethanol clearance was faster at the low rate when the demand-control system was activated than at the high ventilation rate alone. Air quality in the room and in the cages were acceptable with room ventilation rates of 5 to 6 ACH in rodent rooms that use direct-exhaust IVC systems. PMID- 26424251 TI - Comparison of Indoor Air Quality between 2 Ventilation Strategies in a Facility Housing Rhesus Macaques (Macaca mulatta). AB - Adequate indoor-air quality (IAQ)--defined by the temperature, relative humidity, and the levels of carbon dioxide, small particles, and total volatile organic compounds (TVOC)--is crucial in laboratory animal facilities. The ventilation standards for controlling these parameters are not well defined. This study assessed the effect of 2 ventilation strategies on IAQ in 2 rooms housing rhesus macaques (Macaca mulatta). We hypothesized that using a demand-controlled ventilation (DCV) system with a baseline ventilation rate of less than 3 fresh air changes per hour (ACH) would maintain IAQ comparable to or better than the traditional constant flow rate (CFR) system at 12 fresh ACH. During a 60-d study period, each of the 2 rooms operated 30 d on DCV and 30 d on CFR ventilation. In both rooms, temperatures remained more consistently within the established setpoint during the DCV phase than during the CFR phase. Relative humidity did not differ significantly between rooms or strategies. CO2 was lower during the CFR phase than DCV phase. Small-particle and TVOC levels were lower during CFR in the larger (3060 ft(3)) room but not the smaller (2340 ft(3)) room. During the DCV phase, the larger room was at the baseline airflow rate over 99% of the time and the smaller room over 96% of the time. The DCV strategy resulted in a baseline airflow rate of less than 3 ACH, which in turn provided acceptable IAQ over 96% of the time; higher ventilation rates were warranted only during sanitation periods. PMID- 26424253 TI - 3D-Printed Small-Animal Immobilizer for Use in Preclinical Radiotherapy. AB - We have designed a method for immobilizing the subjects of small-animal studies using a study group-specific 3D-printed immobilizer that significantly reduces interfraction rotational variation. A cone-beam CT scan acquired from a single specimen in a study group was used to create a 3D-printed immobilizer that can be used for all specimens in the same study group. 3D printing allows for the incorporation of study-specific features into the immobilizer design, including geometries suitable for use in MR and CT scanners, holders for fiducial markers, and anesthesia nose cones of various sizes. Using metrics of rotational setup variations, we compared the current setup in our small-animal irradiation system, a half-pipe bed, with the 3D-printed device. We also assessed translational displacement within the immobilizer. The printed design significantly reduced setup variation, with average reductions in rotational displacement of 76% +/- 3% (1.57 to 0.37 degrees ) in pitch, 78% +/- 3% (1.85 to 0.41 degrees ) in yaw, and 87% +/- 3% (5.39 to 0.70 degrees ) in roll. Translational displacement within the printed immobilizer was less than 1.5 +/- 0.3 mm. This method of immobilization allows for repeatable setup when using MR or CT scans for the purpose of radiotherapy, streamlines the workflow, and places little burden on the study subjects. PMID- 26424252 TI - Comparison of Heart Rate and Blood Pressure with Toe Pinch and Bispectral Index for Monitoring the Depth of Anesthesia in Piglets. AB - Determining depth of anesthesia (DOA) is a clinical challenge in veterinary medicine, yet it is critical for the appropriate oversight of animals involved in potentially painful experimental procedures. Here, we investigated various parameters used to monitor conscious awareness during surgical procedures and refined the application of noxious stimuli to anesthetized animals. Specifically we used a common stimulus, a compressive toe pinch (TP), to determine physiologic changes that accompanied a positive or negative motion response in isoflurane anesthetized piglets. A positive response was defined as any reflexive withdrawal, whereas a negative response was defined as the absence of motion after stimulation. We also assessed the utility of the bispectral index (BIS) for its ability to predict a motion response to TP. The average of BIS values over 1 min (BISmean) was recorded before and after TP. In piglets with a positive response to TP, heart rate (HR), but not blood pressure (BP), increased significantly, but receiver operating characteristic (ROC) analysis revealed that HR was not a sensitive, specific predictor of TP motion response. Both before and after TP, BISmean was a strong predictor of a positive motion response. We conclude that HR and noninvasive BP changes are not clinically reliable indicators of anesthetic depth when assessed immediately after a peripherally applied compressive force as an indicator stimulus; however, BISmean and response TP are acceptable for assessing DOA in piglets maintained under isoflurane anesthesia. PMID- 26424254 TI - Voluntary Oral Administration of Losartan in Rats. AB - Gavage is a widely performed technique for daily dosing in laboratory rodents. Although effective, gavage comprises a sequence of potentially stressful procedures for laboratory animals that may introduce bias into experimental results, especially when the drugs to be tested interfere with stress-dependent parameters. We aimed to test vehicles suitable for drug delivery by voluntary ingestion in rats. Specifically, Male Wistar rats (age, 2 to 3 mo) were used to test nut paste (NUT), peanut butter (PB), and sugar paste (SUG) as vehicles for long-term voluntary oral administration of losartan, an angiotensin II receptor blocker. Vehicles were administered for 28 d without drug to assess effects on the glucose level and serum lipid profile. Losartan was mixed with vehicles and either offered to the rats or administered by gavage (14 d) for subsequent quantification of losartan plasma levels by HPLC. After a 2-d acclimation period, all rats voluntarily ate the vehicles, either alone or mixed with losartan. NUT administration reduced blood glucose levels. The SUG group had higher concentrations of losartan than did the gavage group, without changes in lipid and glucose profiles. Our results showed that NUT, PB, and SUG all are viable for daily single-dose voluntary ingestion of losartan and that SUG was the best alternative overall. Drug bioavailability was not reduced after voluntary ingestion, suggesting that this method is highly effective for chronic oral administration of losartan to laboratory rodents. PMID- 26424255 TI - Pharmacokinetics of Ceftiofur Crystalline Free Acid in Male Rhesus Macaques (Macaca mulatta) after Subcutaneous Administration. AB - Trauma is a common sequela to agonistic social encounters in rhesus macaques (Macaca mulatta), and veterinarians often prescribe antibiotics as part of a balanced treatment plan. Long-acting, single-dose, injectable antibiotics for use in rhesus macaques are unavailable currently. Ceftiofur crystalline free acid (CCFA) is a long-acting, single-dose, injectable third-generation cephalosporin that provides at least 7 d of ceftiofur therapeutic plasma concentrations in swine (Sus scrofa domesticus). We hypothesized that CCFA would achieve similar therapeutic concentrations (>= 0.2 MUg/mL) in rhesus macaques. We describe the pharmacokinetic profile of CCFA in healthy, adult male rhesus macaques ( n = 6) in this 2-period, 2-treatment crossover study of 5 and 20 mg/kg SC administered once. Plasma ceftiofur metabolite concentrations were determined prior to and for a maximum of 21 d after administration. Noncompartmental pharmacokinetic analysis was performed. The 5-mg dose achieved a maximal plasma concentration of 2.24 +/- 0.525 MUg/mL at 2.59 +/- 1.63 h, an AUC of 46.9 +/- 17.6 h/MUg/mL, and a terminal elimination half-life of 56.5 +/- 21.7 h; for the 20-mg/kg dose, these parameters were 9.18 +/- 4.90 MUg/mL at 1.82 +/- 1.30 h, 331 +/- 84.4 h/MUg/mL, and 69.7 +/- 8.86 h, respectively. No adverse effects were noted after either dose. Macaques maintained plasma ceftiofur concentrations of 0.2 MUg/mL or greater for at least 2 d after 5 mg/kg SC and at least 7 d after 20 mg/kg SC. PMID- 26424256 TI - Effects of Clove Oil as a Euthanasia Agent on Blood Collection Efficiency and Serum Cortisol Levels in Danio rerio. AB - Zebrafish are an important laboratory animal model for biomedical research and are increasingly being used for behavioral neuroscience. Tricaine methanesulfonate (MS222) is the standard agent used for euthanasia of zebrafish. However, recent studies of zebrafish behavior suggest that MS222 may be aversive, and clove oil might be a possible alternative. In this study, we compared the effects of MS222 or clove oil as a euthanasia agent in zebrafish on the volume of blood collected and on serum levels of cortisol. Greater amounts of serum could be collected and lower serum levels of cortisol were present in fish euthanized with clove oil compared with equipotent dose of MS222. Euthanasia with clove oil did not blunt the expected elevation of serum cortisol levels elicited by an acute premortem stress. According to our findings, clove oil is a fast-acting agent that minimizes the cortisol response to euthanasia in zebrafish and allows the collection of large volumes of blood postmortem. These results represent a significant refinement in euthanasia methods for zebrafish. PMID- 26424257 TI - Peptide Antibodies: Past, Present, and Future. AB - Peptide antibodies recognize epitopes with amino acid residues adjacent in sequence ("linear" epitopes). Such antibodies can be made to virtually any sequence and have been immensely important in all areas of molecular biology and diagnostics due to their versatility and to the rapid growth in protein sequence information. Today, peptide antibodies can be routinely and rapidly made to large numbers of peptides, including peptides with posttranslationally modified residues, and are used for immunoblotting, immunocytochemistry, immunohistochemistry, and immunoassays. In the future, peptide antibodies will continue to be immensely important for molecular biology, TCR- and MHC-like peptide antibodies may be produced routinely, peptide antibodies with predetermined conformational specificities may be designed, and peptide-based vaccines may become part of vaccination programs. PMID- 26424258 TI - The Structure of Natural and Recombinant Antibodies. AB - Immunoglobulins (Ig) isotypes A, D, E, G, and M are glycoproteins which are mainly composed of a "Y"-shaped Ig monomer (~150 kDa), consisting of two light and two heavy chains. Both light and heavy chains contain variable (N-terminal) and constant regions (C-terminal). Each light chain consists of one variable domain and one constant domain, whereas each heavy chain has one variable domain and three constant domains. However, heavy-chain antibodies consisting of only heavy chains and lacking the light chains are found in camelids and cartilaginous fishes. Unlike other immunoglobulins, the heavy chain of avian antibody IgY (~180 kDa) consists of four constant domains. The single-chain variable fragment (scFv; ~25 kDa) of an antibody contains variable regions of antibody heavy and light chains. The fragment antigen-binding (Fab; ~50 kDa) region has the full antibody light chain but the heavy chain is composed of a variable region and one constant domain. PMID- 26424259 TI - Prediction of Antigenic B and T Cell Epitopes via Energy Decomposition Analysis: Description of the Web-Based Prediction Tool BEPPE. AB - Unraveling the molecular basis of immune recognition still represents a challenging task for current biological sciences, both in terms of theoretical knowledge and practical implications. Here, we describe the physical-chemistry methods and computational protocols for the prediction of antibody-binding epitopes and MHC-II loaded epitopes, starting from the atomic coordinates of antigenic proteins (PDB file). These concepts are the base of the Web tool BEPPE (Binding Epitope Prediction from Protein Energetics), a free service that returns a list of putative epitope sequences and related blast searches against the Uniprot human complete proteome. BEPPE can be employed for the study of the biophysical processes at the basis of the immune recognition, as well as for immunological purposes such as the rational design of biomarkers and targets for diagnostics, therapeutics, and vaccine discovery. PMID- 26424260 TI - Prediction of Antibody Epitopes. AB - Antibodies recognize their cognate antigens in a precise and effective way. In order to do so, they target regions of the antigenic molecules that have specific features such as large exposed areas, presence of charged or polar atoms, specific secondary structure elements, and lack of similarity to self-proteins. Given the sequence or the structure of a protein of interest, several methods exploit such features to predict the residues that are more likely to be recognized by an immunoglobulin. Here, we present two methods (BepiPred and DiscoTope) to predict linear and discontinuous antibody epitopes from the sequence and/or the three-dimensional structure of a target protein. PMID- 26424261 TI - Fmoc Solid-Phase Peptide Synthesis. AB - Synthetic peptides are important as drugs and in research. Currently, the method of choice for producing these compounds is solid-phase peptide synthesis. In this nonspecialist review, we describe the scope and limitations of Fmoc solid-phase peptide synthesis. Furthermore, we provide a detailed protocol for Fmoc peptide synthesis. PMID- 26424262 TI - Peptide-Carrier Conjugation. AB - To produce antibodies against synthetic peptides it is necessary to couple them to a protein carrier. This chapter provides a nonspecialist overview of peptide carrier conjugation. Furthermore, a protocol for coupling cysteine-containing peptides to bovine serum albumin is outlined. PMID- 26424263 TI - Solid-Phase Peptide-Carrier Conjugation. AB - Conjugation to carrier proteins is necessary for peptides to be able to induce antibody formation when injected into animals together with a suitable adjuvant. This is usually performed by conjugation in solution followed by mixing with the adjuvant. Alternatively, the carrier may be adsorbed onto a solid support followed by activation and conjugation with the peptide by solid-phase chemistry. Different reagents can be used for conjugation through peptide functional groups (-SH, -NH2, -COOH) and various carrier proteins may be used depending on the peptides and the intended use of the antibodies. The solid phase may be an ion exchange matrix, from which the conjugate can subsequently be eluted and mixed with adjuvant. Alternatively, the adjuvant aluminum hydroxide may be used as the solid-phase matrix, whereupon the carrier is immobilized and conjugated with peptide. The resulting adjuvant-carrier-peptide complexes may then be used directly for immunization. PMID- 26424264 TI - Analysis of Peptides and Conjugates by Amino Acid Analysis. AB - Amino acid analysis is a highly accurate method for characterization of the composition of synthetic peptides. Together with mass spectrometry, it gives a reliable control of peptide quality and quantity before conjugation and immunization. Peptides are hydrolyzed, preferably in gas phase, with 6 M HCl at 110 degrees C for 20-24 h and the resulting amino acids analyzed by ion-exchange chromatography with post-column ninhydrin derivatization. Depending on the hydrolysis conditions, tryptophan is destroyed, and cysteine also, unless derivatized, and the amides, glutamine and asparagine, are deamidated to glutamic acid and aspartic acid, respectively. Three different ways of calculating results are suggested, and taking the above limitations into account, a quantitation better than 5% can usually be obtained. PMID- 26424265 TI - Characterization of Synthetic Peptides by Mass Spectrometry. AB - Mass spectrometry (MS) is well suited for analysis of the identity and purity of synthetic peptides. The sequence of a synthetic peptide is most often known, so the analysis is mainly used to confirm the identity and purity of the peptide. Here, simple procedures are described for MALDI-TOF-MS and LC-MS of synthetic peptides. PMID- 26424266 TI - Interpretation of Tandem Mass Spectrometry (MSMS) Spectra for Peptide Analysis. AB - The aim of this chapter is to give a short introduction to peptide analysis by mass spectrometry (MS) and interpretation of fragment mass spectra. Through examples and guidelines we demonstrate how to understand and validate search results and how to perform de novo sequencing based on the often very complex fragmentation pattern obtained by tandem mass spectrometry (also referred to as MSMS). The focus is on simple rules for interpretation of MSMS spectra of tryptic as well as non-tryptic peptides. PMID- 26424267 TI - Polyclonal Peptide Antisera. AB - Polyclonal antibodies are relatively easy to produce and may supplement monoclonal antibodies for some applications or even have some advantages. The choice of species for production of (peptide) antisera is based on practical considerations, including availability of immunogen (vaccine) and animals. Two major factors govern the production of antisera: the nature of adaptive immune responses, which take place over days/weeks and ethical guidelines for animal welfare. Here, simple procedures for immunization of mice, rabbits, sheep, goats, pigs, horses, and chickens are presented. PMID- 26424268 TI - Production and Screening of Monoclonal Peptide Antibodies. AB - Hybridoma technology is a remarkable and indispensable tool for generating high quality monoclonal antibodies. Hybridoma-derived monoclonal antibodies not only serve as powerful research and diagnostic reagents, but have also emerged as the most rapidly expanding class of therapeutic biologicals. In this chapter, an overview of hybridoma technology and the laboratory procedures used routinely for hybridoma production and antibody screening are presented, including characterization of peptide antibodies. PMID- 26424269 TI - Production of Epitope-Specific Antibodies by Immunization with Synthetic Epitope Peptide Formulated with CpG-DNA-Liposome Complex Without Carriers. AB - Antibody production using synthetic peptides has been investigated extensively to develop therapeutic antibodies and prophylactic vaccines. Previously, we reported that a complex of CpG-DNA and synthetic peptides corresponding to B cell epitopes, encapsulated in a phosphatidyl-beta-oleoyl-gamma-palmitoyl ethanolamine (DOPE):cholesterol hemisuccinate (CHEMS) complex, significantly enhanced the synthetic peptide-specific IgG production. Here, we describe synthetic peptide based epitope screening and antibody production without conventional carriers. PMID- 26424270 TI - Thioredoxin-Displayed Multipeptide Immunogens. AB - Fusion to carrier proteins is an effective strategy for stabilizing and providing immunogenicity to peptide epitopes. This is commonly achieved by cross-linking of chemically synthesized peptides to carrier proteins. An alternative approach is internal grafting of selected peptide epitopes to a scaffold protein via double stranded-oligonucleotide insertion or gene synthesis, followed by recombinant expression of the resulting chimeric polypeptide. The scaffold protein should confer immunogenicity to the stabilized and structurally constrained peptide, but also afford easy production of the antigen in recombinant form. A macromolecular scaffold that meets the above criteria is the redox protein thioredoxin, especially bacterial thioredoxin. Here we describe our current methodology for internal grafting of selected peptide epitopes to thioredoxin as tandemly arranged multipeptide repeats ("Thioredoxin Displayed Multipeptide Immunogens"), bacterial expression and purification of the recombinant thioredoxin-multipeptide fusion proteins and their use as antigens for the production of anti-peptide antibodies for prophylactic vaccine as well as diagnostic purposes. PMID- 26424271 TI - The Purification of Natural and Recombinant Peptide Antibodies by Affinity Chromatographic Strategies. AB - The purification of peptide antibodies (e.g., IgG, IgY, scFv, and Fab) are described in this chapter. Affinity chromatographic purification, a very convenient and effective antibody purification strategy, is used to isolate peptide antibodies based on specific binding, i.e., binding of the antibody to a column on which its specific ligand is immobilized with subsequent elution of the purified antibody. In addition, the application of purification methods based on the use of proteins A, G, and L, each of which bind to specific domains on an antibody/fragment, or the use of specific tags (e.g., histidine and biotin) attached to antibodies or antigens are also described. PMID- 26424272 TI - Isolation of Camelid Single-Domain Antibodies Against Native Proteins Using Recombinant Multivalent Peptide Ligands. AB - Generation of antibodies against desired epitopes on folded proteins may be hampered by various characteristics of the target protein, including antigenic and immunogenic dominance of irrelevant epitopes and/or steric occlusion of the desired epitope. In such cases, peptides encompassing linear epitopes of the native protein represent attractive alternative reagents for immunization and screening. Peptide antigens are typically prepared by fusing or conjugating the peptide of interest to a carrier protein. The utility of such antigens depends on many factors including the peptide's amino acid sequence, display valency, display format (synthetic conjugate vs. recombinant fusion) and characteristics of the carrier. Here we provide detailed protocols for: (1) preparation of DNA constructs encoding peptides fused to verotoxin (VT) multimerization domain; (2) expression, purification, and characterization of the multivalent peptide-VT ligands; (3) concurrent panning of a non-immune phage-displayed camelid VHH library against the peptide-VT ligands and native protein; and (4) identification of VHHs enriched via panning using next-generation sequencing techniques. These methods are simple, rapid and can be easily adapted to yield custom peptide-VT ligands that appear to maintain the antigenic structures of the peptide. However, we caution that peptide sequences should be chosen with great care, taking into account structural, immunological, and biophysical information on the protein of interest. PMID- 26424274 TI - Structural Characterization of Peptide Antibodies. AB - The role of proteins as very effective immunogens for the generation of antibodies is indisputable. Nevertheless, cases in which protein usage for antibody production is not feasible or convenient compelled the creation of a powerful alternative consisting of synthetic peptides. Synthetic peptides can be modified to obtain desired properties or conformation, tagged for purification, isotopically labeled for protein quantitation or conjugated to immunogens for antibody production. The antibodies that bind to these peptides represent an invaluable tool for biological research and discovery. To better understand the underlying mechanisms of antibody-antigen interaction here we present a pipeline developed by us to structurally classify immunoglobulin antigen binding sites and to infer key sequence residues and other variables that have a prominent role in each structural class. PMID- 26424273 TI - Generation of TCR-Like Antibodies Using Phage Display. AB - The adaptive immune response against cancer consists of two arms: the humoral response from B cells, and the cell-mediated response from T cells. The humoral response has the advantage of diversity, theoretically recognizing antigens of any type (sugar, protein, lipid, etc.), but is generally limited to surface expressed targets. T cells on the other hand, can recognize intracellular targets, but only if they are proteins, and presented as small peptide fragments on major histocompatibility complex (MHC) cell surface antigens. However, with advances in protein engineering and phage display, it has become feasible to quickly identify and generate antibodies or single-chain variable fragments against peptide-MHC, thus bridging the two arms, and allowing for recognition, identification, and effector responses against cells expressing intracellular targets. PMID- 26424275 TI - Automated High-Throughput Mapping of Linear B-Cell Epitopes Using a Statistical Analysis of High-Density Peptide Microarray Data. AB - Detailed information of antibodies' specificity is often missing or inadequate even for continuous (i.e., linear) epitopes. Recent developments in peptide microarray technology has enabled the synthesis of up to two million peptides per array thereby allowing linear peptide epitopes to be examined by a systematic amino acid substitution and positional scanning approach. This kind of analysis generates a very large body of data, which needs to be analyzed and interpreted in a robust and automated manner. Here, we describe a rational systematic approach to define linear antibody epitopes using ANOVA statistics to identify not only significant but also important residues involved in antibody recognition. This statistical approach can be used to perform a comprehensive linear epitope discovery. For polyclonal antibodies, this could be extended to entire proteins pinpointing critical residues for each epitope. We argue that the ANOVA analysis levels out issues of unknown peptide concentration/quality and unknown antibody titers leading to identification of epitopes that otherwise would be neglected if the evaluation was based merely on signal strength. PMID- 26424276 TI - Characterization of Peptide Antibodies by Epitope Mapping Using Resin-Bound and Soluble Peptides. AB - Characterization of peptide antibodies through identification of their target epitopes is of utmost importance. Understanding antibody specificity at the amino acid level provides the key to understand the specific interaction between antibodies and their epitopes and their use as research and diagnostic tools as well as therapeutic agents. This chapter describes a straightforward strategy for mapping of continuous peptide antibody epitopes using resin-bound and soluble peptides. The approach combines three different types of peptide sets for full characterization of peptide antibodies: (1) overlapping peptides, used to locate antigenic regions; (2) truncated peptides, used to identify the minimal peptide length required for antibody binding; and (3) substituted peptides, used to identify the key residues important for antibody binding and to determine the specific contribution of key residues. For initial screening resin-bound peptides are used for epitope estimation, while soluble peptides subsequently are used for fine mapping. The combination of resin-bound peptides and soluble peptides for epitope mapping provides a time-sparing and straightforward approach for characterization of peptide antibodies. PMID- 26424277 TI - Screening and Characterization of Linear B-Cell Epitopes by Biotinylated Peptide Libraries. AB - Identification of B-cell epitopes is important for the use of antibodies as therapeutic agents, the design of epitope-based vaccines against infectious diseases, and immunological assays based on peptide antibodies. A large number of methods are available for epitope mapping, but many of them require specialized laboratories and are expensive. In this chapter, we describe a high-throughput approach for epitope mapping of peptide antibodies by use of a library of soluble, overlapping, biotinylated peptides. As example, we present characterization of monoclonal and polyclonal antibodies specific for peptides of Mycobacterium tuberculosis acyl carrier protein AcpM and the Chlamydia trachomatis chaperone Ct043 by ELISA. PMID- 26424278 TI - Bead-Based Peptide Arrays for Profiling the Specificity of Modification State Specific Antibodies. AB - Modification state-specific antibodies are powerful tools for investigating posttranslational modifications in proteins. The majority of these antibodies have been generated against peptide-antigen conjugates. They are useful in a plethora of methods, such as Western blotting, immunohistochemistry, sandwich immunoassay, immunoprecipitation, and immunoprecipitation coupled with mass spectrometry. Phosphorylation, acetylation, methylation, sulfation, nitrosylation, ubiquitination, and sumoylation are some of the modifications that can be studied using such antibodies. However, investigating the on- and off target binding of antibodies is crucial to the interpretation of experimental data. Peptide arrays are excellent tools for such in-depth studies of off-target and on-target binding of antibodies. Dozens or even hundreds of modified peptides can be integrated into a single experimental setup to analyze the antibody's binding behavior. Here, we propose three different protocols for peptide bead array generation and describe their suitability for such types of assay. PMID- 26424279 TI - Surface Plasmon Resonance Method to Evaluate Anti-citrullinated Protein/Peptide Antibody Affinity to Citrullinated Peptides. AB - Surface plasmon resonance (SPR) technique is extremely interesting in immunology because it has the potential to directly visualize biomolecular interactions in real-time monitoring antibody affinity, one of the parameters affecting pathogenicity in autoimmune diseases. Herein we describe the affinity evaluation of anti-citrullinated peptide antibodies (ACPA) to a peptide-based biosensor by SPR. The method describes the purification of ACPA isolated from rheumatoid arthritis (RA) patients using affinity columns, the strategy employed for the immobilization of citrullinated peptides onto a sensor chip, and the evaluation of the specific binding of purified ACPA to immobilized peptides. PMID- 26424280 TI - Specificity Analysis of Histone Modification-Specific Antibodies or Reading Domains on Histone Peptide Arrays. AB - Histone posttranslational modifications (PTMs) have a crucial role in chromatin regulation and dynamics. They are specifically bound by so-called reading domains, which mediate the biological effects of histone PTMs. On a similar note, antibodies are invaluable reagents in chromatin biology for the detection, characterization, and mapping of histone PTMs. Despite these central roles in chromatin research and biology, the specificity of many antibodies and reading domains has been insufficiently characterized and documented. Here we describe in detail the application of the MODifiedTM Histone Peptide Array for the investigation of the binding specificity of histone binding antibodies or domains. The array contains 384 histone tail peptides carrying 59 posttranslational modifications in different combinations which can be used to study the primary binding specificity, but at the same time also allow to determine the combinatorial effect of secondary marks on antibody or reading domain binding. PMID- 26424281 TI - Prion-Specific Antibodies Produced in Wild-Type Mice. AB - Peptide-specific antibodies produced against synthetic peptides are of high value in probing protein structure and function, especially when working with challenging proteins, including not readily available, non-immunogenic, toxic, and/or pathogenic proteins. Here, we present a straightforward method for production of mouse monoclonal antibodies (MAbs) against peptides representing two sites of interest in the bovine prion protein (boPrP), the causative agent of bovine spongiform encephalopathy ("mad cow disease") and new variant Creutzfeldt Jakob's disease (CJD) in humans, as well as a thorough characterization of their reactivity with a range of normal and pathogenic (misfolded) prion proteins. It is demonstrated that immunization of wild-type mice with ovalbumin-conjugated peptides formulated with Freund's adjuvant induces a good immune response, including high levels of specific anti-peptide antibodies, even against peptides very homologous to murine protein sequences. In general, using the strategies described here for selecting, synthesizing, and conjugating peptides and immunizing 4-5 mice with 2-3 different peptides, high-titered antibodies reacting with the target protein are routinely obtained with at least one of the peptides after three to four immunizations with incomplete Freund's adjuvant. PMID- 26424282 TI - Immunoblotting with Peptide Antibodies: Differential Immunoreactivities Caused by Certain Amino Acid Substitutions in a Short Peptide and Possible Effects of Differential Refolding of the Peptide on a Nitrocellulose or PVDF Membrane. AB - Immunodetection using antibodies, e.g., Western blotting, is generally utilized to measure the amount of a certain protein in a protein mixture. For valid interpretation of results observed by immunodetection, strict attention must be paid to the factors affecting the immunoreactivities of the antibodies. We here describe the step-by-step procedures to demonstrate that substitution of certain amino acids in a peptide can cause remarkable differences in its immunoreactivity with antibodies against epitope tags in the immobilized peptide. Refolding of the peptide on the membrane in a way that masks the epitope to different degrees was the possible reason for their distinct immunoreactivities with the antibodies. The results in this chapter suggest that we need to interpret carefully the experimental results involving immunodetection. PMID- 26424283 TI - Immunocytochemical and Immunohistochemical Staining with Peptide Antibodies. AB - Peptide antibodies are particularly useful for immunocytochemistry (ICC) and immunohistochemistry (IHC), where antigens may denature due to fixation of tissues and cells. Peptide antibodies can be made to any defined sequence, including unknown putative proteins and posttranslationally modified sequences. Moreover, the availability of large amounts of the antigen (peptide) allows inhibition/adsorption controls, which are important in ICC/IHC, due to the many possibilities for false-positive reactions caused by immunoglobulin Fc receptors, nonspecific reactions, and cross-reactivity of primary and secondary antibodies with other antigens and endogenous immunoglobulins, respectively. Here, simple protocols for ICC and IHC are described together with recommendations for appropriate controls. PMID- 26424284 TI - Designing B-Cell Epitopes for Immunotherapy and Subunit Vaccines. AB - Rationally designed subunit vaccines mainly consist of small peptides or B-cell epitopes, which can stimulate the body's immune response. Development of subunit vaccines is a very tedious and costly process. One of the imperative and crucial steps of vaccine development is the identification of highly competent B-cell epitopes as most of the proteins and fragments of proteins are immunologically irrelevant. With the advances in bioinformatics tools, it can be possible to precisely narrow down potential B-cell epitopes from the whole proteome of any pathogen. This chapter sheds light on prediction and designing of B-cell epitopes using two in silico tools LBtope and IgPred. PMID- 26424285 TI - Enterovirus-Specific Anti-peptide Antibodies. AB - Enterovirus 71 (EV-71) is the main causative agent of hand, foot, and mouth disease (HFMD) which is generally regarded as a mild childhood disease. In recent years, EV71 has emerged as a significant pathogen capable of causing high mortalities and severe neurological complications in large outbreaks in Asia. A formalin-inactivated EV71 whole virus vaccine has completed phase III trial in China but is currently unavailable clinically. The high cost of manufacturing and supply problems may limit practical implementations in developing countries. Synthetic peptides representing the native primary structure of the viral immunogen which is able to elicit neutralizing antibodies can be made readily and is cost effective. However, it is necessary to conjugate short synthetic peptides to carrier proteins to enhance their immunogenicity. This review describes the production of cross-neutralizing anti-peptide antibodies in response to immunization with synthetic peptides selected from in silico analysis, generation of B-cell epitopes of EV71 conjugated to a promiscuous T-cell epitope from Poliovirus, and evaluation of the neutralizing activities of the anti-peptide antibodies. Besides neutralizing EV71 in vitro, the neutralizing antibodies were cross-reactive against several Enteroviruses including CVA16, CVB4, CVB6, and ECHO13. PMID- 26424286 TI - Therapeutic HIV Peptide Vaccine. AB - Therapeutic vaccines aim to control chronic HIV infection and eliminate the need for lifelong antiretroviral therapy (ART). Therapeutic HIV vaccine is being pursued as part of a functional cure for HIV/AIDS. We have outlined a basic protocol for inducing new T cell immunity during chronic HIV-1 infection directed to subdominant conserved HIV-1 epitopes restricted to frequent HLA supertypes. The rationale for selecting HIV peptides and adjuvants are provided. Peptide subunit vaccines are regarded as safe due to the simplicity, quality, purity, and low toxicity. The caveat is reduced immunogenicity and hence adjuvants are included to enhance and direct the immune response. Although the vaccine has been tested in ART naive individuals, we recommend future testing of the vaccine during (early started) ART that improves immune function and to select individuals likely to benefit. Peptides representing other epitopes may be used. PMID- 26424287 TI - Protein biomarkers and microbial profiles in peri-implantitis. AB - OBJECTIVES: The aim of the present investigation was to determine the profile of peri-implant crevicular fluid (PICF) biomarkers combined with microbial profiles from implants with healthy peri-implant tissues and peri-implantitis to assess real-time disease activity. MATERIAL AND METHODS: Sixty-eight patients were included in this cross-sectional study. They were divided into two groups: 34 patients with at least one healthy implant (control) and 34 with at least one peri-implantitis affected implant (test). Total DNA content and qPCR analysis for periodontal bacteria obtained from subgingival plaque samples (Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola) and a PICF analysis for IL-1beta, VEGF, MMP-8, TIMP-2, and OPG were performed. The individual and combined diagnostic ability of each biomarker for peri-implantitis and target bacterial species were analyzed. RESULTS: The mean concentration of IL-1beta (44.6 vs. 135.8 pg/ml; P < 0.001), TIMP-2 (5488.3 vs. 9771.8 pg/ml; P = 0.001), VEGF (59.1 vs. 129.0 pg/ml; P = 0.012), and OPG (66.5 vs. 111.7 pg/ml; P = 0.050) was increased in the peri-implantitis patients. The mean expression of MMP-8 (6029.2 vs. 5943.1 pg/ml; P = 0.454) and did not reveal a meaningful difference among groups. Total bacterial DNA of selected microorganisms was associated with a threefold or greater increase in peri-implantitis although no statistical significant difference. The ability to diagnose diseased sites was enhanced by T. denticola combined with IL-1beta, VEGF, and TIMP-2 PICF levels. CONCLUSION: The present data suggest that the increased levels of the selected PICF-derived biomarkers of periodontal tissue inflammation, matrix degradation/regulation, and alveolar bone turnover/resorption combined with site-specific microbial profiles may be associated with peri-implantitis and could have potential as predictors of peri-implant diseases. PMID- 26424288 TI - Betauried bumper syndrome presenting with hematemesis two weeks after percutaneous endoscopic gastrostomy placement. PMID- 26424289 TI - Vulval symptoms after the menopause - Not all atrophy! AB - Vulval and vaginal symptoms are common after the menopause and are frequently assumed to be due to the normal physiological changes that occur at this time. However, there are several important dermatoses that can occur in this patient group which need accurate diagnosis and appropriate management. This review discusses the clinical features and basic management of some of the common vulval problems occurring after the menopause. PMID- 26424290 TI - Effect of Qiguiyin Decoction on multidrug-resistant Pseudomonas aeruginosa infection in rats. AB - OBJECTIVE: To investigate the effect of Qiguiyin Decoction, QGYD) on multidrug resistant Pseudomonas aeruginosa infection in Sprague-Dawley (SD) rats. METHODS: A pseudomonal infection model in SD rats was established by injecting multidrug resistant P. aeruginosa intraperitoneally. Infected rats were randomized into four groups treated with Pure water, QGYD, ceftazidime, or combined QGYD and ceftazidime. Blood samples were obtained from the abdominal aorta. Serum was then collected and analyzed by peptide array for immune responsiveness to multidrug resistant beta-lactamase proteins, including Verona integronen-coded metallo-beta lactamase 1 (VIM-1), Sao Paulo metallo-beta-lactamase 1 (SPM-1), and Temoniera (TEMs). Blood levels of interleukin-1beta (IL-1beta), interleukin-4 (IL-4), and interferon-gamma (IFN-gamma) were assessed by enzyme-linked immunosorbent assay. RESULTS: QGYD enhanced antibody reactivity against VIM-1 [epitopes 7-11 and 36 40] and TEM-1 [epitopes 26-27, 52-55, and 66-70]. QGYD treatment restored the compromised antibody reactivity against VIM-1 [epitopes 53-54 and 56-58] and SPM 1 [epitopes 16-19 and 82-85] following pseudomonal infection. Serum levels of IL 1beta and Th1/Th2 in the rats were significantly elevated following pseudomonal infection (P<0.05 orP<0.01). In contrast, QGYD and combination QGYD and ceftazidime treatment restored the elevated serum IL-1beta and Th1/Th2 levels to normal (P>0.05). CONCLUSIONS: QGYD improves the immune response to pseudomonal infection in rats by stimulating the production of protective antibodies against drug-resistant proteins VIM-1, SPM-1, and TEM-1. In addition, it protects the immune system and maintains immune responsiveness by restoring IL-1beta and Th1/Th2 levels. PMID- 26424291 TI - Effect of ligustrazine nanoparticles nano spray on transforming growth factor beta/Smad signal pathway of rat peritoneal mesothelial cells induced by tumor necrosis factor-alpha. AB - OBJECTIVE: To study the effect of ligustrazine nanoparticles nano spray (LNNS) on transforming growth factor beta (TGF-beta)/Smad signal protein of rat peritoneal mesothelial cells (RPMC) induced by tumor necrosis factor alpha (TNF-alpha), and the anti-adhesion mechanism of LNNS in the abdominal cavity. METHODS: The primary culture and subculture of rat peritoneal mesothelial cells (RPMC) was processed by trypsin digestion method in vitro. The third generation was identifified for experiment and divided into 5 groups: a blank group: RPMC without treatment; a control group: RPMC stimulated with TNF-alpha; RPMC treated by a low-dosage LNNS group (2.5 mg/L); RPMC treated by a medium-dosage LNNS group (5 mg/L); and RPMC treated by a high-dosage LNNS group (10 mg/L). Reverse transcription-polymerase chain reaction was applied to test the expression of fifibronectin, collagen I (COL-I), TGF-beta mRNA, and Western blot method to test the Smad protein 7 expression of RPMC. RESULTS: Compared with the blank group, a signifificant elevation in fifibronectin (FN), COL-I and TGF-beta mRNA expression of RPMC were observed in the control group (P<0.05). Compared with the control group, LNNS suppressed the expressions of FN, COL-I and TGF-beta mRNA in a concentrationdependent manner (P<0.05). The expression of Smad7 protein of RPMC was down-regulated by TNF-alpha stimulation, and up-regulated with the increase of LNNS dose (P<0.05). CONCLUSIONS: TNF-alpha may induce changes in RPMC's viability, leading to peritoneal injury. LNNS could reverse the induction of fifibrosis related cytokine FN, COL-I and TGF-beta, up-regulating the expression of Smad7 by TNF-alpha in RPMC, thus attenuate peritoneal injury by repairing mesothelial cells. PMID- 26424292 TI - Randomized double-blind clinical trial of Moluodan () for the treatment of chronic atrophic gastritis with dysplasia. AB - OBJECTIVE: To assess the efficacy and safety of Moluodan () in treating dysplasia in chronic atrophic gastritis (CAG) patients. METHODS: This was a multi-centered, double-blind, randomized controlled trial. The total of 196 subjects were assigned to receive either Moluodan or folic acid in a 2:1 ratio by blocked randomization. Mucosa marking targeting biopsy (MTB) was used to insure the accuracy and consistency between baseline and after 6-month treatment. Primary outcomes were histological score, response rate of pathological lesions and dysplasia disappearance rate. Secondary endpoints included gastroscopic findings, clinical symptom and patient reported outcome (PRO) instrument. RESULTS: Dysplasia score decreased in Moluodan group (P =0.002), significance was found between groups (P =0.045). Dysplasia disappearance rates were 24.6% and 15.2% in Moluodan and folic acid groups respectively, no significant differences were found (P =0.127). The response rate of atrophy and intestinal metaplasia were 34.6% and 23.0% in Moluodan group, 24.3% and 13.6% in folic acid group. Moluodan could improve erythema (P =0.044), and bile reflux (P =0.059), no significance between groups. Moluodan was better than folic acid in improving epigastric pain, epigastric suffocation, belching and decreased appetite (P <0.05), with symptom disappearance rates of 37% to 83%. CONCLUSIONS: Moluodan improved dysplasia score in histopathology, and erythema and bile reflux score in endoscopy, and superior to folic acid in improving epigastric pain, epigastric suffocation, belching and decreased appetite. [ChiCTR-TRC-00000169]. PMID- 26424294 TI - [How should cytopathology be taught?]. AB - Cytopathology is not excessively employed in the whole faculty of pathology in Germany, in contrast to some neighboring countries. Cytopathology also suffers from a lack of next generation cytologists, because experienced and interested specialists as well as assistants actively engaged in cytology (ZTA, cytological technical assistant and MTLA medical laboratory technical assistant) are only available in limited numbers. However, cytopathological expertise is urgently needed, not only in the diagnostics of gynecological cancer screening but also for assessment of many non-gynecological preparations, which have nowadays become more demanding and more complex particularly due to the technical developments in internal medicine. In addition, adjuvant methods have become incorporated into cytopathology, the interpretation of which must be carried out within this specialty.This article gives a review of the status quo of cytopathology in Germany and sketches how training and advanced education opportunities are organized and if necessary could be improved. The course of specialist medical training as well as the ZTA and MTLA training are described, also as a teaching concept (e.g. microscopy of current cases, microscopy of case collections and online microscopy). In order to provide cytopathology in Germany with a wider perspective, a paradigm shift in the internal approach to cytology is suggested so that the next generation can perceive this specialty not as a burden but as a chance. PMID- 26424293 TI - Effects of acupuncture at Baihui (GV 20) and Zusanli (ST 36) on peripheral serum expression of MicroRNA 124, laminin and integrin beta1 in rats with cerebral ischemia reperfusion injury. AB - OBJECTIVE: To explore the effects of acupuncture at Baihui (GV 20) and Zusanli (ST 36) on the peripheral serum expression of microRNA 124 (miRNA 124), laminin and integrin beta1 in rats with cerebral ischemia reperfusion injury (CIRI). METHODS: Seventy-two healthy male Sprague-Dawley rats were randomized into a model group, an acupuncture group, and a sham-operated group using a random digits table, with 24 rats per group. Each group was further randomly divided into 1-, 3-, 5-, and 7-day subgroups based on the reperfusion time according to a random digits table, with 6 rats in each subgroup. In the model and acupuncture groups, CIRI was induced using the thread occlusion method. Electroacupuncture stimulation was applied daily to GV 20 and left ST 36 for 20 min at the indicated time points after successful operations. Serum was sampled for detecting laminin and integrin beta1 protein via enzyme-linked immunosorbent assay, and serum miRNA 124 was examined using quantitative polymerase chain reaction. RESULTS: The serum level of miRNA 124 in the cerebral ischemia rats increased significantly, and the peak expression of miRNA 124 in both the model and acupuncture groups occurred at 3 days. The expression of miRNA 124 in the acupuncture group was higher than in the model group at the same time point (5.96+/-0.01 vs. 3.11+/-0.04, P <0.05). Laminin expression in serum from the cerebral ischemia group was higher than that in the sham-operated group. Compared with the model group, the level of laminin in the serum of the acupuncture group was significantly lower at each time point, especially at the 3-day, and 7-day time points (589.12+/-3.57 vs. 793.05+/-5.28, and 600.53+/-3.05 vs. 899.06+/-5.74, P <0.05). The level of integrin beta1 in the serum from the acupuncture group was lower than that in the model group particularly at the 3-day and 7-day time points (208.66+/-0.95 vs. 280.83+/-1.77, and 212.36+/-0.95 vs. 316.77+/-2.42, P <0.05). Additionally, the model group and the acupuncture group showed dual peaks of integrin beta1 and laminin expression at 3-day and 7-day. CONCLUSIONS: Acupuncture at GV 20 and ST 36 in rats alleviated CIRI and was associated with upregulated expression of miRNA 124 and with downregulated expression of integrin beta1 and laminin in peripheral serum. These changes may represent one of the mechanisms underlying acupuncture's attenuation of CIRI. PMID- 26424295 TI - Diagnostic cutoff for pressure drop coefficient in relation to fractional flow reserve and coronary flow reserve: A patient-level analysis. AB - OBJECTIVES AND BACKGROUND: Functional assessment of intermediate coronary stenosis during cardiac catheterization is conducted using diagnostic parameters like fractional flow reserve (FFR), coronary flow reserve (CFR), hyperemic stenosis resistance index (HSR), and hyperemic microvascular resistance (HMR). CDP (ratio of pressure drop across a stenosis to distal dynamic pressure), a nondimensional index derived from fundamental fluid dynamic principles, based on a combination of intracoronary pressure, and flow measurements may improve the functional assessment of coronary lesion severity. METHODS: Patient-level data pertaining to 350 intracoronary pressure and flow measurements across coronary stenoses was assessed to evaluate CFR, FFR, HSR, HMR, and CDP. CDP was calculated as (DeltaP)/(0.5 * rho * APV(2)). The density of blood (rho) was assumed to be 1.05 g/cm(3). The correlation of current diagnostic parameters (CFR, FFR, HSR, and HMR) with CDP was evaluated. The receiver operating characteristic (ROC) curve was used to identify the optimal cut-off point of CDP, corresponding to the clinically used cut-off values (FFR = 0.80 and CFR = 2.0). RESULTS: CDP correlated significantly with FFR (r = 0.81, P < 0.05) and had significant diagnostic efficiency (ROC-area under curve of 86%), specificity (72%) and sensitivity (85%) at FFR < 0.8. The corresponding cut-off value for CDP to detect FFR < 0.8 was at CDP>25.4. CDP also correlated significantly (r = 0.98, P < 0.05) with epicardial-specific parameter, HSR. CONCLUSIONS: CDP, a functional parameter based on both intracoronary pressure and flow measurements, has close agreement (area under ROC curve = 86%) with FFR, the frequently used method of evaluating stenosis severity. PMID- 26424297 TI - Serum Cholinesterase Is Inversely Associated with Body Weight Change in Men Undergoing Routine Health Screening. AB - OBJECTIVE: The purpose of this study is to investigate the relationships between serum cholinesterase and body weight change, in addition to incident obesity defined as a body mass index (BMI) of 25 kg/m(2) or greater. METHODS: A retrospective 5-year follow-up study was conducted. The crude incidence and hazard ratios (HRs) of obesity adjusted for the BMI and other confounders were calculated for cholinesterase quartiles in 1,412 men and 921 women. Partial correlation coefficients (PCCs) were calculated between cholinesterase and changes in the BMI during the 5-year follow-up period adjusted for age and other confounders and the change in the BMI were compared among cholinesterase quartiles in 1,223 men and 681 women. RESULTS: During the 5-year follow-up period, 149 men (10.6%) and 65 women (7.1%) developed obesity. The adjusted HRs of obesity decreased, although the crude incidence of obesity increased along the quartiles of cholinesterase in men. The adjusted HRs of obesity for the first (lowest), second and third quartiles of cholinesterase were 2.02 (p=0.006), 1.45 (p=0.122), and 1.28 (p=0.265), respectively compared with the highest quartile in men. The PCC between the baseline level of cholinesterase and change in the BMI was -0.16 (p<0.001) in men. The mean changes in BMI for 5 years were 0.31 kg/m(2), 0.17 kg/m(2), 0.01 kg/m(2) and -0.04 kg/m(2), respectively in the first, second, third and fourth quartiles of cholinesterase in men (p=0.005). Neither incident obesity nor weight gain was significantly associated with cholinesterase in women. CONCLUSION: The serum cholinesterase level was inversely associated with body weight change, as well as incident obesity, after adjusted for the BMI in men. PMID- 26424296 TI - Interventions for preventing or treating malnutrition in problem drinkers who are homeless or vulnerably housed: protocol for a systematic review. AB - BACKGROUND: Problem alcohol drinking in homeless and vulnerably housed people can lead to malnutrition, which is associated with complications such as alcohol related brain damage. Homeless alcohol drinkers are likely to have worse health outcomes and different nutritional needs compared with housed alcohol-drinking persons. It is not clear whether interventions to improve nutritional status in this population have been effective. The purpose of this review is to assess the effectiveness and cost-effectiveness of interventions for preventing or correcting micronutrient deficiencies and other forms of malnutrition and related comorbidities in this population. METHODS/DESIGN: A systematic search for studies of a nutrition-based intervention applied in the homeless or vulnerably housed population with problem drinking will be conducted. The following electronic databases will be systematically searched for relevant studies: MEDLINE, EMBASE, Web of Science, PsycINFO, CAB abstracts, CINAHL, Cochrane Public Health Group Register and Cochrane Drugs and Alcohol Group Register. Screening of identified abstracts for relevance and assessment of papers for inclusion will be done in duplicate. One reviewer will extract data from the studies and assess quality, and this will be checked by another reviewer. Discrepancies will be resolved by consensus. The primary outcomes are (mal)nutrition status or micronutrient deficiencies or change in (mal)nutrition status or micronutrient deficiencies, measures of liver damage and cognitive function. Secondary outcomes include comorbidities, quality of life and functional scales, resources used to deliver treatment, uptake/acceptability of the intervention and engagement with treatment services. Results will be analysed descriptively, and, if appropriate, meta analyses will be performed. DISCUSSION: The results of this review should help to inform the development of effective interventions that can be implemented in the community to improve the health of homeless people who are problem drinkers. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015024247. PMID- 26424298 TI - Clinical Features of Ischemic Stroke during Treatment with Dabigatran: An Association between Decreased Severity and a Favorable Prognosis. AB - OBJECTIVE: Anticoagulation therapy with warfarin is associated with a favorable prognosis in ischemic stroke. Dabigatran, a new oral anticoagulant, is widely used to prevent ischemic stroke in non-valvular atrial fibrillation (NVAF) patients. However, its association with decreased severity and a favorable prognosis once ischemic stroke has occurred remains unknown. METHODS: We retrospectively reviewed all the patients with NVAF-associated ischemic stroke admitted to our hospital from April 2011 to December 2014 and included those who received dabigatran therapy. We assessed whether the patients were under regular use of the drug or discontinuance and classified them into 2 groups, the treatment and discontinuation groups. Clinical data, including the age, sex, ASCOD stroke phenotype, NVAF type, prescribed drug dose, comorbidities, CHADS2 score, renal function, National Institute of Health Stroke Scale (NIHSS) score on admission, modified Rankin scale (mRS) score at discharge, D-dimer, and brain natriuretic peptide, were investigated and compared between the groups. RESULTS: Nine patients were under regular dabigatran therapy, and 6 were under discontinuance of the drug. The age, sex, ASCOD stroke phenotype, NVAF type, comorbidities, renal function, and CHADS2 scores did not differ between the 2 groups; however, the NIHSS scores were significantly lower in the treatment group. The mRS scores at discharge were additionally decreased in the treatment group. Moreover, the D-dimer scores were lower in the treatment group, thus suggesting a possible role in the decreased stroke severity. CONCLUSION: Dabigatran may therefore decrease the severity of ischemic stroke, even if ischemic stroke occurs. PMID- 26424299 TI - True Primary Enterolith Treated by Balloon-assisted Enteroscopy. AB - Primary enterolith is a rare condition that can induce ileus and intestinal perforation. We report the first case of a true primary enterolith treated by balloon-assisted enteroscopy. The patient presented with a small intestinal ileus. After its improvement following the insertion of an ileus tube, radiography with amidotrizoate sodium meglumine detected a round, movable defect in the ileum measuring 42 mm diameter. The patient was diagnosed with a primary enterolith based on her past history. The enterolith was fractured and removed using balloon-assisted enteroscopy. This case suggests that balloon-assisted enteroscopy may be an effective non-invasive treatment option for enteroliths. PMID- 26424300 TI - Acute Liver Failure Complicated with Severe Heart Failure. AB - A young pregnant woman was hospitalized due to hepatitis B virus (HBV)-related acute liver failure (ALF). The cardiac function was normal on admission. However, she developed ALF concurrently with a coma and severe cardiac failure. The patient was diagnosed with severe acute cardiomyopathy due to diffuse hypokinesis of the left ventricle wall on ultrasound cardiography. Following intensive treatment, both the liver and cardiac function dramatically recovered. Although some factors, such as HBV, pregnancy and systemic inflammatory response syndrome, are possible causes of acute cardiomyopathy in the present case, ALF itself may be a risk factor for heart failure. PMID- 26424301 TI - Rate-dependent Loss of Capture during Ventricular Pacing. AB - A 63-year-old patient who had undergone atrial septal defect surgical repair received implantation of a single chamber VVI pacemaker for long RR intervals during atrial fibrillation. One week later, an intermittent loss of capture and sensing failure was detected at a pacing rate of 70 beats/min. However, a successful capture was observed during rapid pacing. Consequently, the pacing rate was temporarily adjusted to 90 beats/min. At the 3-month follow-up, the pacemaker was shown to be functioning properly independent of the pacing rate. An echocardiogram showed that the increased pacing rates were accompanied by a reduction in the right ventricular outflow tract dimension. The pacemaker was then permanently programmed at a lower rate of 60 beats/min. PMID- 26424302 TI - Coronary Artery Pseudoaneurysm due to Medial Mucoid Degeneration Mimicking an Intra-atrial Mass. AB - Coronary artery aneurysms are frequently asymptomatic and may be difficult to diagnose by cardiac imaging. We herein present a case of a coronary artery aneurysm of the right coronary artery due to medial mucoid degeneration mimicking an intra-atrial mass on echocardiography and magnetic resonance imaging, with the cause being diagnosed after surgery. PMID- 26424303 TI - A Sickle Cell Disease Patient with Severe Tricuspid Regurgitation and Early Developed Pulmonary Hypertension. AB - Pulmonary hypertension (PH) worsens the mortality of the patients with sickle cell disease (SCD). The exact mechanism of PH development/progression in SCD, including the role of tricuspid regurgitation (TR), remains unclear. We herein report an unusual SCD case, complicated by chronic thromboembolic disorder, who developed severe TR and an accelerated progression of PH. Tricuspid valve surgery significantly ameliorated the patient's symptoms and reduced hospital readmission. The early detection and management of the reversible disorder accelerating the PH development in SCD patients may alter the clinical course, improve the quality of life, and potentially affect the long-term outcome. PMID- 26424304 TI - Isolated Atrial Septal Defect Complicated by Tricuspid Valve Infective Endocarditis. AB - Infective endocarditis (IE) associated with atrial septal defect (ASD) is extremely rare. However, tricuspid regurgitation (TR) secondary to right ventricular overload is a potential cause of IE, and once it occurs, the development of a paradoxical embolism may lead to fatal complications. We herein report the case of a 50-year-old woman who was admitted due to a persistent fever resistant to antibiotics. Echocardiography showed secundum ASD, moderate TR and a mobile vegetation measuring 15*10 mm attached to the tricuspid valve. Given the risk of developing a paradoxical embolism, urgent surgery was successfully performed. PMID- 26424305 TI - Successful Treatment with an Antihypertensive Drug Regimen Including Eplerenone in a Patient with Malignant Phase Hypertension with Renal Failure. AB - A 28-year-old man was referred to our hospital for the treatment of congestive heart failure and severe hypertension. The patient was diagnosed with malignant phase hypertension based on the presence of marked hypertension with left ventricular hypertrophy, exudate retinopathy, and renal failure. Intensive therapy for hypertension and heart failure with a combination of antihypertensive drugs including nitroglycerin, nifedipine, eplerenone and candesartan successfully lowered his blood pressure and further improved the renal function. Eplerenone could be one of the choices of antihypertensive drugs in combination therapy in patients with malignant phase hypertension with progressive heart and renal failure. PMID- 26424306 TI - Dramatic Improvement of Diabetes Mellitus Following the Treatment of Coexisting Acromegaly and Cushing's Syndrome. AB - Endocrine diseases are frequently accompanied by diabetes mellitus and treatment of an underlying endocrine disease often improves glucose control. The co occurrence of acromegaly and Cushing's syndrome is extremely rare. We herein describe a patient who showed a dramatic improvement in glucose control following treatment for co-existing acromegaly and Cushing's syndrome. An adrenal mass was incidentally discovered during a routine evaluation of a 56-year-old woman who was subsequently diagnosed with acromegaly and a unilateral cortisol-producing adrenal adenoma. Her blood glucose was poorly controlled despite receiving high dose insulin therapy. After undergoing adrenalectomy for Cushing's syndrome, her insulin dosage was decreased by almost 50%. The insulin treatment was discontinued following the treatment of acromegaly. PMID- 26424307 TI - A Novel Missense Mutation of the MEN1 Gene in a Patient with Multiple Endocrine Neoplasia Type 1 with Glucagonoma and Obesity. AB - A 35-year-old obese diabetic man presented with recurrent primary hyperparathyroidism during a three-year outpatient follow-up. He was clinically diagnosed with multiple endocrine neoplasia type 1 (MEN1) due to the presence of a pituitary adenoma and multiple glucagonomas. The glucagonomas may have affected his glycemic control. However, he did not demonstrate weight loss, suggesting that the patient's obesity could have obscured the early diagnosis of a glucagonoma. Genetic testing revealed a novel missense mutation at codon 561 in exon 10, resulting in an amino acid substitution from methionine to arginine (M561R) in the MEN1 gene. This mutation appeared to be responsible for the MEN1 pathogenicity. PMID- 26424308 TI - Pulmonary Sarcoidosis Presenting with Miliary Opacities. AB - Lung lesions often appear in patients with sarcoidosis; however, miliary opacities are rare. We herein report the case of a 40-year-old woman with pulmonary sarcoidosis who presented with dyspnea on exertion. Subsequent computed tomography showed miliary opacities, and the presence of granulomas was confirmed by a transbronchial lung biopsy. Glucocorticoid therapy was initiated and the symptoms and miliary opacities rapidly improved. Although miliary sarcoidosis is uncommon, physicians should consider sarcoidosis in addition to tuberculosis, malignancy, and pneumoconiosis when presented with miliary opacities. PMID- 26424309 TI - Life-threatening and Rapidly Growing Teratoma in the Anterior Mediastinum. AB - This report describes the case of a 23-year-old man with a mediastinal teratoma. Five months before admission, a chest radiograph during a routine health checkup was normal. Four months before admission, the patient developed sudden onset of mild right-sided chest pain. He gradually developed dyspnea and was admitted to our hospital. Computed tomography revealed a giant tumor that was markedly compressing the right atrium. Urgent surgery was performed, and a ruptured, benign mature teratoma was diagnosed. Mature mediastinal teratomas are benign tumors, but they can rupture and have the potential to grow rapidly, potentially leading to life-threatening complications. PMID- 26424310 TI - An Autopsy Case of Two Distinct, Acquired Drug Resistance Mechanisms in Epidermal Growth Factor Receptor-mutant Lung Adenocarcinoma: Small Cell Carcinoma Transformation and Epidermal Growth Factor Receptor T790M Mutation. AB - We herein describe the case of a 63-year-old man who died from relapsed epidermal growth factor receptor gene (EGFR) exon 19 deletion lung adenocarcinoma treated with erlotinib. According to the autopsy results, he was confirmed to have small cell carcinoma without the EGFR T790M mutation in his pancreas and left kidney metastatic specimens, while the adenocarcinoma metastatic lesion in his right kidney had the EGFR T790M mutation; both retained the somatic EGFR exon 19 deletion. We herein report an autopsy case of resistance to an EGFR tyrosine kinase inhibitor via small cell carcinoma transformation and the EGFRT790M mutation in separate metastatic organs. PMID- 26424311 TI - Anti-MuSK Antibody-positive Myasthenia Gravis Mimicking Amyotrophic Lateral Sclerosis. AB - We herein investigated the clinical features of three patients with anti-muscle specific tyrosine kinase (MuSK) antibody-positive myasthenia gravis (MG), which was initially difficult to distinguish from amyotrophic lateral sclerosis (ALS). The patients exhibited dropped head syndrome or dysphagia as initial symptoms. Although their clinical findings were compatible with the revised El Escorial Criteria for ALS, their progression appeared to be more rapid than that of ALS. Both the edrophonium and repetitive nerve stimulation tests yielded negative results, and diurnal fluctuation was not confirmed. The patients were ultimately diagnosed with anti-MuSK antibody-positive MG. We therefore recommend the measurement of anti-MuSK antibodies when encountering such cases. PMID- 26424312 TI - A Patient with the GLA p.E66Q Mutation Exhibiting Vascular Parkinsonism and Bilateral Pulvinar Lesions. AB - A 76-year-old man was admitted to our hospital due to gait difficulty. Brain imaging indicated bilateral pulvinar lesions and moderate white matter lesions. The serum alpha-galactosidase A levels were measured for the differential diagnosis of bilateral pulvinar lesions and were found to be abnormally low. Therefore, the patient was suspected to have variant Fabry disease. A GLA mutation analysis showed the p.E66Q mutation, which is speculated to be a functional polymorphism rather than a disease-causing mutation of Fabry disease. Enzyme replacement therapy did not result in a marked improvement, however, the disease progression stopped. PMID- 26424313 TI - Refractory Dermatomyositis Complicated with Myelodysplastic Syndrome. AB - We herein describe a case of refractory dermatomyositis (DM) complicated with myelodysplastic syndrome (MDS). Despite intensive immunosuppressive therapies, the activity of myositis, skin ulcers, and interstitial pneumonia did not improve. The patient ultimately died following the progression of interstitial pneumonia. There are few reports of DM accompanying MDS to date, and any association in the pathogenesis between the two is still unclear. However, underlying MDS may have the potential to influence the therapeutic response of DM. PMID- 26424314 TI - Falciparum Malaria Incidentally Pretreated with Azithromycin. AB - A 65-year-old man, who recently returned from Liberia, visited a clinic complaining of fever, and azithromycin was prescribed. The patient presented to a general hospital 5 days after the onset of symptoms, however, a blood smear examination failed to detect malaria. Contrary to the blood smear result, a rapid antigen test in our hospital was strongly-positive for falciparum malaria, indicating a high level of malarial antigen in the blood. Moreover, laboratory examinations on admission showed a tendency for improvement. We assumed that the administration of azithromycin partially treated malaria, thus complicating the blood smear diagnosis. We should be careful in prescribing azithromycin, which is widely used in clinics, to travelers returning from malaria-endemic countries. PMID- 26424315 TI - Pregnant Woman Bitten by a Japanese Mamushi (Gloydius blomhoffii). AB - We herein report the fourth case of a pregnant woman bitten by a mamushi. A 33 year-old pregnant woman in the 25th week of gestation was bitten by a mamushi. Her vital signs were stable; however, biochemical analyses of the blood showed mild deterioration of anemia and hypoproteinemia. The effects of envenomation were limited to the extremities, the administration of supportive therapy without antivenom fortunately resulted in a favorable outcome. As there are differences in the maternal medical condition and weeks of gestation, further research is needed to clarify the optimal management strategy for administering antivenom in pregnancy. PMID- 26424316 TI - Multiple Osteonecrosis with Systemic Lupus Erythematosus. PMID- 26424317 TI - Uterine Leiomyosarcoma Presenting with a Fever of Unknown Origin. PMID- 26424318 TI - Othello Pica: A Clue of Recurrent Rectal Cancer. PMID- 26424319 TI - Deep Vein Thrombosis due to Metastatic Bladder Cancer. PMID- 26424320 TI - Dumping Syndrome due to the Misplacement of the Gastrostomy Feeding Tube. PMID- 26424321 TI - Human Papillomavirus (HPV) Vaccination Safety Assessment: The Methods Matter. PMID- 26424322 TI - Human Papillomavirus (HPV) Vaccination Safety Assessment: The Methods Matter. PMID- 26424323 TI - Reciprocal Alterations in Regulator of G Protein Signaling 4 and microRNA16 in Schizophrenia. AB - N-methyl-d-aspartate receptor (NMDAR) hypofunction in the dorsolateral prefrontal cortex (DLPFC) has been implicated in the pathology of schizophrenia. NMDAR activity is negatively regulated by some G protein-coupled receptors (GPCRs). Signaling through these GPCRs is reduced by Regulator of G protein Signaling 4 (RGS4). Thus, lower levels of RGS4 would enhance GPCR-mediated reductions in NMDAR activity and could contribute to NMDAR hypofunction in schizophrenia. In this study, we quantified RGS4 mRNA and protein levels at several levels of resolution in the DLPFC from subjects with schizophrenia and matched healthy comparison subjects. To investigate molecular mechanisms that could contribute to altered RGS4 levels, we quantified levels of small noncoding RNAs, known as microRNAs (miRs), which regulate RGS4 mRNA integrity after transcription. RGS4 mRNA and protein levels were significantly lower in schizophrenia subjects and were positively correlated across all subjects. The RGS4 mRNA deficit was present in pyramidal neurons of DLPFC layers 3 and 5 of the schizophrenia subjects. In contrast, levels of miR16 were significantly higher in the DLPFC of schizophrenia subjects, and higher miR16 levels predicted lower RGS4 mRNA levels. These findings provide convergent evidence of lower RGS4 mRNA and protein levels in schizophrenia that may result from increased expression of miR16. Given the role of RGS4 in regulating GPCRs, and consequently the strength of NMDAR signaling, these findings could contribute to the molecular substrate for NMDAR hypofunction in DLPFC pyramidal cells in schizophrenia. PMID- 26424324 TI - Distribution and transmission of Mycobacterium tuberculosis complex lineages among children in peri-urban Kampala, Uganda. AB - BACKGROUND: To gain insight into the transmission of tuberculosis (TB) in peri urban Kampala-Uganda, we performed a household contact study using children as a surrogate for recent transmission of Mycobacterium tuberculosis (MTB). Using this approach, we sought to understand M. tuberculosis complex (MTBC) lineage diversity, distribution and how these relate to TB transmission to exposed children. METHOD: MTBC isolates from children aged <= 15 years, collected from 2002 to 2010 in a household-contact study, were analyzed using a LightCycler RT PCR SNP genotyping assay (LRPS). The resultant genotypic data was used to determine associations between MTBC lineage and the children's clinical and epidemiological characteristics. RESULTS AND DISCUSSION: Of the 761 children surveyed, 9% (69/761) had culture-positive TB an estimate in the range of global childhood TB; of these 71% (49/69) were infected with an MTBC strain of the "Uganda family", 17% (12/69) infected with MTBC lineage 4 strains other than MTBC Uganda family and 12% (8/69) infected with MTBC lineage 3, thereby disproportionately causing TB in the study area. Overall the data showed no correlation between the MTBC lineages studied and transmission (OR = 0.304; P value = 0.251; CI: 95%; 0.039-2.326) using children a proxy for TB transmission. CONCLUSIONS: Our findings indicate that MTBC Uganda family strains are the main cause of TB in children in peri-urban Kampala. Furthermore, MTBC lineages did not differ in their transmissibility to children. PMID- 26424325 TI - Impact of the Surveillance Interval on the Survival of Patients Who Undergo Curative Surgery for Gastric Cancer. AB - BACKGROUND: For patients who undergo gastrectomy for gastric cancer, systematic follow-up evaluation to detect recurrent lesions is recommended, although the benefits of a surveillance program using short-term imaging studies have not been evaluated. METHODS: This study reviewed the clinical data of patients who underwent curative surgery for gastric cancer using a prospective database. Patients with recurrence were classified according to surveillance interval as follows: <=3, 3-6, and 6-12 months. RESULTS: Of the 2785 patients who underwent curative surgery for gastric cancer, 376 (13.5 %) had intraabdominal recurrences, excluding the stomach. Multivariable analysis showed that a short surveillance interval did not increase the post-recurrence survival duration (with 6-12 months as the reference: <=3 months: hazard ratio [HR] 0.954; 95 % confidence interval [CI] 0.689-1.323; 3-6 months: HR 0.994, 95 % CI 0.743-1.330). In addition, short surveillance intervals did not increase overall survival (with 6-12 months as the reference: <=3 months: HR 0.969; 95 % CI 0.699-1.342; 3-6 months: HR 0.955; 95 % CI 0.711-1.285). In contrast to the surveillance interval, age, cancer stage, symptoms at recurrence, and recurrence time after gastrectomy were factors associated with both post-recurrence survival and overall survival. CONCLUSIONS: Although the detection of recurrence before symptoms helped to prolong both post recurrence survival and overall survival, shortening the surveillance interval to less than 6 months did not improve either the patient's post-recurrence survival or overall survival. Hence, it is not recommended that asymptomatic patients undergo surveillance involving imaging studies more often than once a year. PMID- 26424327 TI - Effectiveness of the Restore4Stroke self-management intervention "Plan ahead!": A randomized controlled trial in stroke patients and partners. AB - OBJECTIVE: To investigate the effectiveness of a self-management intervention aimed at proactive coping for stroke patients and partners, compared with an education intervention. DESIGN: Multicentre randomized controlled trial. PARTICIPANTS: The study included 113 stroke patients (mean age 57.0 years (standard deviation (SD) 9.0), mean 18.8 months after stroke (SD 28.4)) and 57 partners (mean age 59.2 years (SD 8.3)). METHODS: Participants were randomized to a self-management intervention, or an education intervention, both 10 weeks' duration, outpatient, stroke-specific, and group-based. Main patient inclusion criteria were symptomatic stroke (>= 6 weeks previously) and reporting >= 2 restrictions on the Restriction subscale of the Utrecht Scale for Evaluation of Rehabilitation Participation. Measurements were performed immediately after intervention, and at 3 and 9 months follow-up. Primary patient and partner outcomes were proactive coping and participation restrictions. Analyses were based on linear mixed modelling. RESULTS: A significant effect was found only in partners' increased proactive coping at T2 (compared with education intervention). Beneficial trends were found for the self-manage-ment intervention in partners' self-efficacy and patients' health-related quality of life, mood complaints and participation restriction. CONCLUSION: Little convincing evidence was found favouring our self-management intervention over the education intervention; therefore, the self-management intervention should not be implemented yet in clinical practice. Further research is needed to explore beneficial trends. PMID- 26424326 TI - Mosquito age and avian malaria infection. AB - BACKGROUND: The immune system of many insects wanes dramatically with age, leading to the general prediction that older insects should be more susceptible to infection than their younger counterparts. This prediction is however challenged by numerous studies showing that older insects are more resistant to a range of pathogens. The effect of age on susceptibility to infections is particularly relevant for mosquitoes given their role as vectors of malaria and other diseases. Despite this, the effect of mosquito age on Plasmodium susceptibility has been rarely explored, either experimentally or theoretically. METHODS: Experiments were carried out using the avian malaria parasite Plasmodium relictum and its natural vector in the field, the mosquito Culex pipiens. Both innate immune responses (number and type of circulating haemocytes) and Plasmodium susceptibility (prevalence and burden) were quantified in seven- and 17-day old females. Whether immunity or Plasmodium susceptibility are modulated by the previous blood feeding history of the mosquito was also investigated. To ensure repeatability, two different experimental blocks were carried out several weeks apart. RESULTS: Haemocyte numbers decrease drastically as the mosquitoes age. Despite this, older mosquitoes are significantly more resistant to a Plasmodium infection than their younger counterparts. Crucially, however, the age effect is entirely reversed when old mosquitoes have taken one previous non infected blood meal. CONCLUSIONS: The results agree with previous studies showing that older insects are often more resistant to infections than younger ones. These results suggest that structural and functional alterations in mosquito physiology with age may be more important than immunity in determining the probability of a Plasmodium infection in old mosquitoes. Possible explanations for why the effect is reversed in blood-fed mosquitoes are discussed. The reversal of the age effect in blood fed mosquitoes implies that age is unlikely to have a significant impact on mosquito susceptibility in the field. PMID- 26424328 TI - Trends of patient referral to a memory clinic and towards earlier diagnosis from 1985-2009. AB - BACKGROUND: It may be assumed that increased public awareness of dementia due to Alzheimer's disease (AD) together with the availability of efficacious treatment will result in diagnostic evaluation at earlier stages of cognitive decline and diagnosis of dementia due to AD at earlier stages. METHODS: All persons that were examined at a university based memory clinic, in Germany, between 1985 and 2009 were included. RESULTS: In the 3,951 persons identified, linear regression analysis revealed a positive association between Mini Mental State Examination (MMSE) score and year of initial examination (yearIE) (beta = 0.266; p < 0.001). In the 1,821 patients diagnosed with dementia due to AD, a positive association between MMSE score and yearIE (beta = 0.230; p < 0.001) was revealed. MMSE scores were higher (beta = 0.195; p < 0.001) after the introduction of cholinesterase inhibitors in Germany in 1997. CONCLUSIONS: Diagnostic evaluation of individuals occurred at progressively earlier stages of cognitive decline. Dementia due to AD was diagnosed at progressively earlier stages, and this trend was associated with the availability of efficacious treatment. This is the first study on changes in patient referral and diagnosis based on a continuous 25 years period. PMID- 26424329 TI - Detection of Tetrodotoxins in Puffer Fish by a Self-Assembled Monolayer-Based Immunoassay and Comparison with Surface Plasmon Resonance, LC-MS/MS, and Mouse Bioassay. AB - The increasing occurrence of puffer fish containing tetrodotoxin (TTX) in the Mediterranean could represent a major food safety risk for European consumers and threaten the fishing industry. The work presented herein describes the development of a new enzyme linked immunosorbent assay (mELISA) based on the immobilization of TTX through dithiol monolayers self-assembled on maleimide plates, which provides an ordered and oriented antigen immobilization and favors the antigen-antibody affinity interaction. The mELISA was found to have a limit of detection (LOD) of TTX of 0.23 mg/kg of puffer fish matrix. The mELISA and a surface plasmon resonance (SPR) immunosensor previously developed were employed to establish the cross-reactivity factors (CRFs) of 5,6,11-trideoxy-TTX, 5,11 deoxy-TTX, 11-nor-TTX-6-ol, and 5,6,11-trideoxy-4-anhydro-TTX, as well as to determine TTX equivalent contents in puffer fish samples. Results obtained by both immunochemical tools were correlated (R(2) = 0.977). The puffer fish samples were also analyzed using liquid chromatography-tandem mass spectrometry (LC MS/MS), and the corresponding CRFs were applied to the individual TTX contents. Results provided by the immunochemical tools, when compared with those obtained by LC-MS/MS, showed a good degree of correlation (R(2) = 0.991 and 0.979 for mELISA and SPR, respectively). The mouse bioassay (MBA) slightly overestimated the CRF adjusted TTX content of samples when compared with the data obtained from the other techniques. The mELISA has been demonstrated to be fit for the purpose for screening samples in monitoring programs and in research activities. PMID- 26424330 TI - Effectiveness and Persistence with Liraglutide Among Patients with Type 2 Diabetes in Routine Clinical Practice--EVIDENCE: A Prospective, 2-Year Follow-Up, Observational, Post-Marketing Study. AB - INTRODUCTION: The aim of this study was to investigate whether the efficacy of liraglutide observed in randomized controlled trials translates into therapeutic benefits in the French population during routine clinical practice. METHODS: This observational, prospective, multicenter study included 3152 adults with type 2 diabetes who had recently started or were about to start liraglutide treatment. During 2 years of follow-up, an evaluation of the reasons for prescribing liraglutide, maintenance dose of liraglutide, changes in combined antidiabetic treatments, level of glycemic control, change in body weight and body mass index (BMI), patient satisfaction with diabetes treatment and safety of liraglutide were investigated. The primary study endpoint was the proportion of patients still receiving liraglutide and presenting with HbA1c <7.0% after 2 years of follow-up. RESULTS: At the end of the study, 29.5% of patients maintained liraglutide treatment and reached the HbA(1c) target. Mean (+/-SD) HbA(1c), fasting plasma glucose concentration, body weight and BMI were significantly reduced from baseline [8.46% (+/-1.46) to 7.44% (+/-1.20); 180 (+/-60) to 146 (+/ 44) mg/dL; 95.2 (+/-20.0) to 91.1 (+/-19.6) kg; 34.0 (+/-7.2) to 32.5 (+/-6.9) kg/m(2); respectively, all P < 0.0001]. Patient treatment satisfaction increased, with the mean diabetes treatment satisfaction questionnaire status version score increasing from 22.17 (+/-7.64) to 28.55 (+/-5.79), P < 0.0001. The main adverse event type was gastrointestinal, with a frequency of 10.9%, and the percentage of patients suffering >=1 hypoglycemic episode decreased from 6.9% to 4.4%. CONCLUSION: The results of the EVIDENCE study suggest that the effectiveness of liraglutide in real-world clinical practice is similar to that observed in randomized controlled trials. FUNDING: Novo Nordisk A/S. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01226966. PMID- 26424331 TI - Fixed Combination of Travoprost and Timolol Maleate Reduces Intraocular Pressure in Japanese Patients with Primary Open-Angle Glaucoma or Ocular Hypertension: A Prospective Multicenter Open-Label Study. AB - INTRODUCTION: The efficacy of lowering intraocular pressure (IOP) and safety of switching to travoprost/timolol fixed combination ophthalmic solution (Duotrav((r)), Alcon Laboratories, Inc., Fort Worth, TX, USA) in patients with primary open-angle glaucoma, normal tension glaucoma or ocular hypertension undergoing prostaglandin analog (PGA) monotherapy was investigated. METHODS: Patients treated with travoprost, latanoprost, tafluprost, or bimatoprost for >=3 months and requiring additional medication were switched to Duotrav without washout. Baseline IOP was calculated from measurements at two visits during PGA monotherapy. IOP reductions at 4, 8, and 12 weeks after switching to Duotrav and adverse events were assessed. RESULTS: Of 162 patients enrolled, 157 patients (96.9%) with >=4 weeks of follow-up after switching to Duotrav were analyzed. The mean IOP decreased significantly (baseline = 16.3 +/- 3.1 mmHg; 4 weeks = 14.6 +/ 3.1 mmHg, 8 weeks = 14.7 +/- 3.3 mmHg, 12 weeks = 14.6 +/- 3.2 mmHg; all P < 0.0001). When study eyes were divided into three groups according to baseline IOP (>=19 mmHg: 33 eyes, 21.0%; >=15 to <19 mmHg: 78 eyes, 49.7%; <15 mmHg: 46 eyes, 29.3%), all groups showed significant IOP reductions (P = 0.0324 ~ P < 0.0001) after switching to Duotrav. Twenty-seven of 166 patients (16.3%) in the safety analysis experienced adverse events and 26/166 patients (15.7%) experienced adverse events, for which a relationship to Duotrav could not be ruled out. Adverse events in five patients led to treatment discontinuation (eye pruritus; eye irritation; increased blood pressure and rash; increased blurred vision; deepening of the eyelid sulcus and blepharoptosis). Twelve weeks after treatment switching, eyelash changes, blepharal pigmentation and deepening of the eyelid sulcus occurred in 42 (26.8%), 29 (18.5%), and 13 (8.3%) cases, respectively, among 157 patients with follow-up. There was no significant worsening from baseline for superficial punctate keratopathy (SPK) or conjunctival hyperemia after switching (SPK score: baseline = 0.58 +/- 1.31; 12 weeks = 0.92 +/- 1.76, P = 0.1819; conjunctival hyperemia score: baseline = 0.41 +/- 0.64; 12 weeks = 0.49 +/- 0.63, P = 0.3774). CONCLUSION: Our findings confirm that switching to Duotrav((r)) in PGA monotherapy patients shows IOP-lowering effect with minimal safety concerns. FUNDING: Japan Association of Health Service and Alcon Japan. Ltd. TRIAL REGISTRATION: UMIN Clinical Trials Registry identifier, UMIN000007028. PMID- 26424333 TI - Introduction: Complications of lumbar spine surgery. PMID- 26424332 TI - Role of the major antigenic membrane protein in phytoplasma transmission by two insect vector species. AB - BACKGROUND: Phytoplasmas are bacterial plant pathogens (class Mollicutes), transmitted by phloem feeding leafhoppers, planthoppers and psyllids in a persistent/propagative manner. Transmission of phytoplasmas is under the control of behavioral, environmental and geographical factors, but molecular interactions between membrane proteins of phytoplasma and vectors may also be involved. The aim of the work was to provide experimental evidence that in vivo interaction between phytoplasma antigenic membrane protein (Amp) and vector proteins has a role in the transmission process. In doing so, we also investigated the topology of the interaction at the gut epithelium and at the salivary glands, the two barriers encountered by the phytoplasma during vector colonization. METHODS: Experiments were performed on the 'Candidatus Phytoplasma asteris' chrysanthemum yellows strain (CYP), and the two leafhopper vectors Macrosteles quadripunctulatus Kirschbaum and Euscelidius variegatus Kirschbaum. To specifically address the interaction of CYP Amp at the gut epithelium barrier, insects were artificially fed with media containing either the recombinant phytoplasma protein Amp, or the antibody (A416) or both, and transmission, acquisition and inoculation efficiencies were measured. An abdominal microinjection protocol was employed to specifically address the interaction of CYP Amp at the salivary gland barrier. Phytoplasma suspension was added with Amp or A416 or both, injected into healthy E. variegatus adults and then infection and inoculation efficiencies were measured. An internalization assay was developed, consisting of dissected salivary glands from healthy E. variegatus exposed to phytoplasma suspension alone or together with A416 antibody. The organs were then either observed in confocal microscopy or subjected to DNA extraction and phytoplasma quantification by qPCR, to visualize and quantify possible differences among treatments in localization/presence/number of CYP cells. RESULTS: Artificial feeding and abdominal microinjection protocols were developed to address the two barriers separately. The in vivo interactions between Amp of 'Candidatus Phytoplasma asteris' Chrysanthemum yellows strain (CYP) and vector proteins were studied by evaluating their effects on phytoplasma transmission by Euscelidius variegatus and Macrosteles quadripunctulatus leafhoppers. An internalization assay was developed, consisting of dissected salivary glands from healthy E. variegatus exposed to phytoplasma suspension alone or together with anti-Amp antibody. To visualize possible differences among treatments in localization/presence of CYP cells, the organs were observed in confocal microscopy. Pre-feeding of E. variegatus and M. quadripunctulatus on anti-Amp antibody resulted in a significant decrease of acquisition efficiencies in both species. Inoculation efficiency of microinjected E. variegatus with CYP suspension and anti-Amp antibody was significantly reduced compared to that of the control with phytoplasma suspension only. The possibility that this was due to reduced infection efficiency or antibody-mediated inhibition of phytoplasma multiplication was ruled out. These results provided the first indirect proof of the role of Amp in the transmission process. CONCLUSION: Protocols were developed to assess the in vivo role of the phytoplasma native major antigenic membrane protein in two phases of the vector transmission process: movement through the midgut epithelium and colonization of the salivary glands. These methods will be useful also to characterize other phytoplasma-vector combinations. Results indicated for the first time that native CYP Amp is involved in vivo in specific crossing of the gut epithelium and salivary gland colonization during early phases of vector infection. PMID- 26424334 TI - Lumbar pseudarthrosis: a review of current diagnosis and treatment. AB - OBJECT Failed solid bony fusion, or pseudarthrosis, is a well-known complication of lumbar arthrodesis. Recent advances in radiographic technology, biologics, instrumentation, surgical technique, and understanding of the local biology have all aided in the prevention and treatment of pseudarthrosis. Here, the current literature on the diagnosis and management of lumbar pseudarthroses is reviewed. METHODS A systematic literature review was conducted using the MEDLINE and Embase databases in order to search for the current radiographie diagnosis and surgical treatment methods published in the literature (1985 to present). Inclusion criteria included: 1) published in English; 2) level of evidence I-III; 3) diagnosis of degenerative lumbar spine conditions and/or history of lumbar spine fusion surgery; and 4) comparative studies of 2 different surgical techniques or comparative studies of imaging modality versus surgical exploration. RESULTS Seven studies met the inclusion criteria for current radiographie imaging used to diagnose lumbar pseudarthrosis. Plain radiographs and thin-cut CT scans were the most common method for radiographie diagnosis. PET has been shown to be a valid imaging modality for monitoring in vivo active bone formation. Eight studies compared the surgical techniques for managing and preventing failed lumbar fusion. The success rates for the treatment of pseudarthrosis are enhanced with the use of rigid instrumentation. CONCLUSIONS Spinal fusion rates have improved secondary to advances in biologies, instrumentation, surgical techniques, and understanding of local biology. Treatment of lumbar pseudarthrosis includes a variety of surgical options such as replacing loose instrumentation, use of more potent biologies, and interbody fusion techniques. Prevention and recognition are important tenets in the algorithm for the management of spinal pseudarthrosis. PMID- 26424335 TI - Complications from the use of intrawound vancomycin in lumbar spinal surgery: a systematic review. AB - OBJECT The use of intrawound vancomycin is rapidly being adopted for the prevention of surgical site infection (SSI) in spinal surgery. At operative closure, the placement of vancomycin powder in the wound bed-in addition to standard infection prophylaxis-can provide high concentrations of antibiotics with minimal systemic absorption. However, despite its popularity, to date the majority of studies on intrawound vancomycin are retrospective, and there are no prior reports highlighting the risks of routine treatment. METHODS A MEDLINE search for pertinent literature was conducted for studies published between 1966 and May 2015 using the following MeSH search terms: "intrawound vancomycin," "operative lumbar spine complications," and "nonoperative lumbar spine complications." This was supplemented with references and known literature on the topic. RESULTS An advanced MEDLINE search conducted on May 6, 2015, using the search string "intrawound vancomycin" found 22 results. After a review of all abstracts for relevance to intrawound vancomycin use in spinal surgery, 10 studies were reviewed in detail. Three meta-analyses were evaluated from the initial search, and 2 clinical studies were identified. After an analysis of all of the identified manuscripts, 3 additional studies were included for a total of 16 studies. Fourteen retrospective studies and 2 prospective studies were identified, resulting in a total of 9721 patients. A total of 6701 (68.9%) patients underwent treatment with intrawound vancomycin. The mean SSI rate among the control and vancomycin-treated patients was 7.47% and 1.36%, respectively. There were a total of 23 adverse events: nephropathy (1 patient), ototoxicity resulting in transient hearing loss (2 patients), systemic absorption resulting in supratherapeutic vancomycin exposure (1 patient), and culture-negative seroma formation (19 patients). The overall adverse event rate for the total number of treated patients was 0.3%. CONCLUSIONS Intrawound vancomycin use appears to be safe and effective for reducing postoperative SSIs with a low rate of morbidity. Study disparities and limitations in size, patient populations, designs, and outcomes measures contribute significant bias that could not be fully rectified by this systematic review. Moreover, care should be exercised in the use of intrawound vancomycin due to the lack of well-designed, prospective studies that evaluate the efficacy of vancomycin and include the appropriate systems to capture drug-related complications. PMID- 26424336 TI - Complications of intraoperative epidural steroid use in lumbar discectomy: a systematic review and meta-analysis. AB - OBJECT The authors' aim in this paper was to review the intraoperative use of epidural steroids in lumbar discectomy surgery with a focus on surgical complications. METHODS A comprehensive literature search was done using PubMed, MEDLINE, and the Cochrane Central Registry of Controlled Trials. Relevant papers were retrieved and analyzed. The authors performed a meta-analysis of all available data. Search terms included epidural, steroids, discectomy, lumbar disc surgery, herniated lumbar disc, methylprednisolone, and perioperative.The primary outcome was surgical complications such as wound infection or need for reoperation. Secondary outcomes were pain and postoperative narcotic usage. RESULTS Sixteen trials and 1 retrospective study (a total of 1933 patients) were eligible for inclusion in this study. In all studies, steroids were added epidurally over the nerve root before closure in cases, and control patients underwent discectomy alone. The mean age (42.7 years vs 42.4 years; RR 0.30 [95% CI -0.30 to 0.90], p = 0.32), overall complication rates (2.69% vs 1.18%; RR 1.94 [95% CI 0.72-5.26], p = 0.19), and infectious complication rates (0.94% vs 0.08%; RR 4.58 [95% CI 0.75-27.95], p = 0.10) were similar between the steroid group and control group, respectively. CONCLUSIONS There is good evidence that epidural steroids can decrease pain in the short term and decrease the usage of postoperative narcotics after lumbar spinal surgery for degenerative spinal disease. The authors' results demonstrate a trend toward increased infection with epidural steroid use, but there was not a statistically significant difference. More studies are needed to validate the long-term risk/benefit ratio of epidural steroids in lumbar discectomy. PMID- 26424337 TI - A population-based review of bone morphogenetic protein: associated complication and reoperation rates after lumbar spinal fusion. AB - OBJECT The authors compared the rates of postoperative adverse events and reoperation of patients who underwent lumbar spinal fusion with bone morphogenetic protein (BMP) to those of patients who underwent lumbar spinal fusion without BMP. METHODS The authors retrospectively analyzed the PearlDiver Technologies, Inc., database, which contains the Medicare Standard Analytical Files, the Medicare Carrier Files, the PearlDiver Private Payer Database (UnitedHealthcare), and select state all-payer data sets, from 2005 to 2010. They identified patients who underwent lumbar spinal fusion with and without BMP. The ICD-9-CM code 84.52 was used to identify patients who underwent spinal fusion with BMP. ICD-9-CM diagnosis codes identified complications that occurred during the initial hospital stay. ICD-9-CM procedural codes were used to identify reoperations within 90 days of the index procedure. The relative risks (and 95% CIs) of BMP use compared with no BMP use (control) were calculated for the association of any complication with BMP use compared with the control. RESULTS Between 2005 and 2010, 460,773 patients who underwent lumbar spinal fusion were identified. BMP was used in 30.7% of these patients. The overall complication rate in the BMP group was 18.2% compared with 18.7% in the control group. The relative risk of BMP use compared with no BMP use was 0.976 (95% CI 0.963-0.989), which indicates a significantly lower overall complication rate in the BMP group (p < 0.001). In both treatment groups, patients older than 65 years had a statistically significant higher rate of postoperative complications than younger patients (p < 0.001). CONCLUSIONS In this large-scale institutionalized database study, BMP use did not seem to increase the overall risk of developing a postoperative complication after lumbar spinal fusion surgery. PMID- 26424338 TI - Failure rates and complications of interspinous process decompression devices: a European multicenter study. AB - OBJECT Spacers placed between the lumbar spinous processes represent a promising surgical treatment alternative for a variety of spinal pathologies. They provide an unloading distractive force to the stenotic motion segment, restoring foraminal height, and have the potential to relieve symptoms of degenerative disc disease. The authors performed a retrospective, multicenter nonrandomized study consisting of 1108 patients to evaluate implant survival and failure modes after the implantation of 8 different interspinous process devices (IPDs). METHODS The medical records of patients who had undergone placement of an IPD were retrospectively evaluated, and demographic information, diagnosis, and preoperative pain levels were recorded. Preoperative and postoperative clinical assessments in the patients were based on the visual analog scale. A minimum of 3 years after IPD placement, information on long-term outcomes was obtained from additional follow-up or from patient medical and radiological records. RESULTS One thousand one hundred eight patients affected by symptomatic 1- or 2-level segmental lumbar spine degenerative disease underwent placement of an IPD. The complication rate was 7.8%. There were 27 fractures of the spinous process and 23 dura mater tears with CSF leakage. The ultimate failure rate requiring additional surgery was 9.6%. The reasons for revision, which always involved removal of the original implant, were acute worsening of low-back pain or lack of improvement (45 cases), recurrence of symptoms after an initial good outcome (42 cases), and implant dislocation (20 cases). CONCLUSIONS The IPD is not a substitute for a more invasive 3-column fusion procedure in cases of major instability and spondylolisthesis. Overdistraction, poor bone density, and poor patient selection may all be factors in the development of complications. Preoperatively, careful attention should be paid to bone density, appropriate implant size, and optimal patient selection. PMID- 26424339 TI - Complications related to the use of spinal cord stimulation for managing persistent postoperative neuropathic pain after lumbar spinal surgery. AB - OBJECT Structural spinal surgery yields improvement in pain and disability for selected patients with spinal stenosis, spondylolisthesis, or a herniated intervertebral disc. A significant fraction of patients exhibit persistent postoperative neuropathic pain (PPNP) despite technically appropriate intervention, and such patients can benefit from spinal cord stimulation (SCS) to alleviate suffering. The complication profile of this therapy has not been systematically assessed and, thus, was the goal of this review. METHODS A comprehensive literature search was performed to identify prospective cohorts of patients who had PPNP following structurally corrective lumbar spinal surgery and who underwent SCS device implantation. Data about study design, technique of SCS lead introduction, and complications encountered were collected and analyzed. Comparisons of complication incidence were performed between percutaneously and surgically implanted systems, with the level of significance set at 0.05. RESULTS Review of 11 studies involving 542 patients formed the basis of this work: 2 randomized controlled trials and 9 prospective cohorts. Percutaneous implants were used in 4 studies and surgical implants were used in 4 studies; in the remainder, the types were undefined. Lead migration occurred in 12% of cases, pain at the site of the implantable pulse generator occurred in 9% of cases, and wound-related complications occurred in 5% of cases; the latter 2 occurred more frequently among surgically implanted devices. CONCLUSIONS Spinal cord stimulation can provide for improved pain and suffering and for decreased narcotic medication use among patients with PPNP after lumbar spinal surgery. This study reviewed the prospective studies forming the evidence base for this therapy, to summarize the complications encountered and, thus, best inform patients and clinicians considering its use. There is a significant rate of minor complications, many of which require further surgical intervention to manage, including lead migration or implant infection, although such complications do not directly threaten patient life or function. PMID- 26424340 TI - Lumbar spine surgery positioning complications: a systematic review. AB - OBJECT There are a variety of surgical positions that provide optimal exposure of the dorsal lumbar spine. These include the prone, kneeling, knee-chest, knee elbow, and lateral decubitus positions. All are positions that facilitate exposure of the spine. Each position, however, is associated with an array of unique complications that result from excessive pressure applied to the torso or extremities. The authors reviewed clinical studies reporting complications that arose from positioning of the patient during dorsal exposures of the lumbar spine. METHODS MEDLINE, Scopus, and Web of Science database searches were performed to find clinical studies reporting complications associated with positioning during lumbar spine surgery. For articles meeting inclusion criteria, the following information was obtained: publication year, study design, sample size, age, operative time, type of surgery, surgical position, frame or table type, complications associated with positioning, time to first observed complication, long-term outcomes, and evidence-based recommendations for complication avoidance. RESULTS Of 3898 articles retrieved from MEDLINE, Scopus, and Web of Science, 34 met inclusion criteria. Twenty-four studies reported complications associated with use of the prone position, and 7 studies investigated complications after knee-chest positioning. Complications associated with the knee-elbow, lateral decubitus, and supine positions were each reported by a single study. Vision loss was the most commonly reported complication for both prone and knee-chest positioning. Several other complications were reported, including conjunctival swelling, Ischemic orbital compartment syndrome, nerve palsies, thromboembolic complications, pressure sores, lower extremity compartment syndrome, and shoulder dislocation, highlighting the assortment of possible complications following different surgical positions. For prone-position studies, there was a relationship between increased operation time and position complications. Only 3 prone-position studies reported complications following procedures of less than 120 minutes, 7 studies reported complications following mean operative times of 121-240 minutes, and 9 additional studies reported complications following mean operative times greater than 240 minutes. This relationship was not observed for knee-chest and other surgical positions. CONCLUSIONS This work presents a systematic review of positioning-related complications following prone, knee-chest, and other positions used for lumbar spine surgery. Numerous evidence-based recommendations for avoidance of these potentially severe complications associated with intraoperative positioning are discussed. This investigation may serve as a framework to educate the surgical team and decrease rates of intraoperative positioning complications. PMID- 26424341 TI - Reconstruction of open wounds as a complication of spinal surgery with flaps: a systematic review. AB - OBJECT A systematic review of the available evidence on the prophylactic and therapeutic use of flaps for the coverage of complex spinal soft-tissue defects was performed to determine if the use of flaps reduces postoperative complications and improves patient outcomes. METHODS A PubMed database search was performed to identify English-language articles published between 1990 and 2014 that contained the following phrases to describe postoperative wounds ("wound," "complex back wound," "postoperative wound," "spine surgery") and intervention ("flap closure," "flap coverage," "soft tissue reconstruction," "muscle flap"). RESULTS In total, 532 articles were reviewed with 17 articles meeting the inclusion criteria of this study. The risk factors from the pooled analysis of 262 patients for the development of postoperative complex back wounds that necessitated muscle flap coverage included the involvement of instrumentation (77.6%), a previous history of radiotherapy (33.2%), smoking (20.6%), and diabetes mellitus (17.2%). In patients with instrumentation, prophylactic coverage of the wound with a well-vascularized flap was shown to result in a lower incidence of wound complications. One study showed a statistically significant decrease in complications compared with patients where prophylactic coverage was not performed (20% vs 45%). The indications for flap coverage after onset of wound complications included hardware exposure, wound infection, dehiscence, seroma, and hematoma. Flap coverage was shown to decrease the number of surgical debridements needed and also salvage hardware, with the rate of hardware removal after flap coverage ranging from 0% to 41.9% in 4 studies. CONCLUSIONS Prophylactic coverage with flaps in high-risk patients undergoing spine surgery reduces complications, while therapeutic coverage following wound complications allows the salvage of hardware in the majority of patients. PMID- 26424342 TI - Perioperative morbidity and mortality after lumbar trauma in the elderly. AB - OBJECT Traumatic fractures of the thoracolumbar spine are common injuries, accounting for approximately 90% of all spinal trauma. Lumbar spine trauma in the elderly is a growing public health problem with relatively little evidence to guide clinical management. The authors sought to characterize the complications, morbidity, and mortality associated with surgical and nonsurgical management in elderly patients with traumatic fractures of the lumbar spine. METHODS Using the National Sample Program of the National Trauma Data Bank, the authors performed a retrospective analysis of patients >= 55 years of age who had traumatic fracture to the lumbar spine. This group was divided into middle-aged (55-69 years) and elderly (>= 70 years) cohorts. Cohorts were subdivided into nonoperative, vertebroplasty or kyphoplasty, noninstrumented surgery, and instrumented surgery. Univariate and multivariable analyses were used to characterize and identify predictors of medical and surgical complications, mortality, hospital length of stay, ICU length of stay, number of days on ventilator, and hospital discharge in each subgroup. Adjusted odds ratios, mean differences, and associated 95% CIs were reported. Statistical significance was assessed at p < 0.05, and the Bonferroni correction for multiple comparisons was applied for each outcome analysis. RESULTS Between 2003 and 2012, 22,835 people met the inclusion criteria, which represents 94,103 incidents nationally. Analyses revealed a similar medical and surgical complication profile between age groups. The most prevalent medical complications were pneumonia (7.0%), acute respiratory distress syndrome (3.6%), and deep venous thrombosis (3%). Surgical site infections occurred in 6.3% of cases. Instrumented surgery was associated with the highest odds of each complication (p < 0.001). The inpatient mortality rate was 6.8% for all subjects. Multivariable analyses demonstrated that age >= 70 years was an independent predictor of mortality (OR 3.16, 95% CI 2.77-3.60), whereas instrumented surgery (multivariable OR 0.38, 95% CI 0.28-0.52) and vertebroplasty or kyphoplasty (OR 0.27, 95% CI 0.17-0.45) were associated with decreased odds of death. In surviving patients, both older age (OR 0.32, 95% CI 0.30-0.34) and instrumented fusion (OR 0.37, 95% CI 0.33-0.41) were associated with decreased odds of discharge to home. CONCLUSIONS The present study confirms that lumbar surgery in the elderly is associated with increased morbidity. In particular, instrumented fusion is associated with periprocedural complications, prolonged hospitalization, and a decreased likelihood of being discharged home. However, fusion surgery is also associated with reduced mortality. Age alone should not be an exclusionary factor in identifying surgical candidates for instrumented lumbar spinal fusion. Future studies are needed to confirm these findings. PMID- 26424343 TI - The safety profile of lumbar spinal surgery in elderly patients 85 years and older. AB - OBJECT The aging of the population will require that surgeons increasingly consider operating on elderly patients. Performing surgery safely in the elderly will require an understanding of the factors that predict successful outcomes and avoid complications. METHODS Records of patients 85 years and older undergoing elective lumbar spinal surgery were retrospectively reviewed. Microdiscectomies were excluded. Preexisting medical illnesses measured using the Charlson Comorbidity Index (CCI), American Society of Anesthesiologists (ASA) Physical Status class, age, and surgical parameters were analyzed as factors potentially predictive of complications. Ambulatory function was rated on a 4-point scale. RESULTS During the study 26 consecutive patients (mean age 87 years) with a mean ASA class of 2.6 +/- 0.65 and CCI of 1.1 +/- 1.27 were enrolled. The average number of levels treated was 2.17 +/- 1.23, and 73% underwent fusion. The mean follow-up was 41.9 months with a minimum of 24 months, and all patients were alive at last follow-up. Average blood loss was 142 +/- 184 ml, and the operative time was 183.3 +/- 80.6 minutes. The mean number of levels treated was 2.17 +/- 1.13 (range 1-4). Ambulatory function improved significantly by 0.59 +/- 1.0 points. Five complications (19.2%) occurred in 4 patients, 2 major and 3 minor. Four complications were temporary and 1 was permanent. Patient age, blood loss, CCI score, ASA class, the number of levels treated, and fusion surgery were not statistically associated with a complication. Operative time of longer than 180 minutes (p = 0.0134) was associated with complications. CONCLUSIONS Lumbar spine surgery in patients 85 years and older can be accomplished safely if careful attention is paid to preoperative selection. Prolonged operative times are associated with a higher risk of complications. PMID- 26424344 TI - Comparison of complication rates of minimally invasive transforaminal lumbar interbody fusion and lateral lumbar interbody fusion: a systematic review of the literature. AB - OBJECT Minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) and lateral lumbar interbody fusion (LLIF) are 2 currently popular techniques for lumbar arthrodesis. The authors compare the total risk of each procedure, along with other important complication outcomes. METHODS This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Relevant studies (up to May 2015) that reported complications of either MI-TLIF or LLIF were identified from a search in the PubMed database. The primary outcome was overall risk of complication per patient. Secondary outcomes included risks of sensory deficits, temporary neurological deficit, permanent neurological deficit, intraoperative complications, medical complications, wound complications, hardware failure, subsidence, and reoperation. RESULTS Fifty-four studies were included for analysis of MI-TLIF, and 42 studies were included for analysis of LLIF. Overall, there were 9714 patients (5454 in the MI-TLIF group and 4260 in the LLIF group) with 13,230 levels fused (6040 in the MI-TLIF group and 7190 in the LLIF group). A total of 1045 complications in the MI-TLIF group and 1339 complications in the LLIF group were reported. The total complication rate per patient was 19.2% in the MI-TLIF group and 31.4% in the LLIF group (p < 0.0001). The rate of sensory deficits and temporary neurological deficits, and permanent neurological deficits was 20.16%, 2.22%, and 1.01% for MI-TLIF versus 27.08%, 9.40%, and 2.46% for LLIF, respectively (p < 0.0001, p < 0.0001, p = 0.002, respectively). Rates of intraoperative and wound complications were 3.57% and 1.63% for MI-TLIF compared with 1.93% and 0.80% for LLIF, respectively (p = 0.0003 and p = 0.034, respectively). No significant differences were noted for medical complications or reoperation. CONCLUSIONS While there was a higher overall complication rate with LLIF, MI-TLIF and LLIF both have acceptable complication profiles. LLIF had higher rates of sensory as well as temporary and permanent neurological symptoms, although rates of intraoperative and wound complications were less than MI-TLIF. Larger, prospective comparative studies are needed to confirm these findings as the current literature is of relative poor quality. PMID- 26424345 TI - Morphometrics as a predictor of perioperative morbidity after lumbar spine surgery. AB - OBJECT Improved objective assessments of perioperative risk after spine surgery are necessary to decrease postoperative morbidity and mortality rates. Morphometric analysis has proven utility in predicting postoperative morbidity and mortality in surgical disciplines. The aim of the present study was to evaluate whether morphometrics can be applied to the cases of patients undergoing lumbar spine surgery. METHODS The authors performed a retrospective review of the perioperative course of 395 patients who underwent lumbar surgery at their institution from 2013 to 2014. Preoperative risk factors such as age, diabetes, smoking, coronary artery disease, and body mass index (BMI) were recorded. Preoperative MRI was used to measure the psoas muscle area at the L-4 vertebra and paraspinal muscle area at the T-12 vertebra. Primary outcomes included unplanned return to the operating room, 30- and 90-day readmissions, surgical site infection, wound dehiscence, new neurological deficit, deep vein thrombosis, pulmonary embolism, myocardial infarction, urinary tract infection, urinary retention, hospital-acquired pneumonia, stroke, and prolonged stay in the intensive care unit. RESULTS The overall rate of adverse events was 30%, the most common event being urinary retention (12%). Greater age (p = 0.015) and tobacco usage (p = 0.026) were both significantly associated with complications for all patients, while diabetes, coronary artery disease, and high BMI were not. No surgery-related characteristics were associated with postoperative morbidity, including whether surgery required instrumentation, whether it was a revision, or the number of vertebral levels treated. Using multivariate regression analysis, male and female patients with the lowest psoas tertile had an OR of 1.70 (95% CI 1.04-2.79, p = 0.035) for having postoperative complications. Male patients in the lowest psoas tertile had an OR of 2.42 (95% CI 1.17-5.01, p = 0.016) for having a postoperative complication. The paraspinal muscle groups did not provide any significant data for postoperative morbidity, even after multivariate analysis. CONCLUSIONS The morphometric measurement of psoas muscle size may be a sensitive predictive tool compared with other risk factors for perioperative morbidity in male patients undergoing lumbar surgery. PMID- 26424346 TI - Lumbar microdiscectomy complication rates: a systematic review and meta-analysis. AB - OBJECT Lumbar microdiscectomy and its various minimally invasive surgical techniques are seeing increasing popularity, but a systematic review of their associated complications has yet to be performed. The authors sought to identify all prospective clinical studies reporting complications associated with lumbar open microdiscectomy, microendoscopic discectomy (MED), and percutaneous microdiscectomy. METHODS The authors conducted MEDLINE, Scopus, Web of Science, and Embase database searches for randomized controlled trials and prospective cohort studies reporting complications associated with open, microendoscopic, or percutaneous lumbar microdiscectomy. Studies with fewer than 10 patients and published before 1990 were excluded. Overall and interstudy median complication rates were calculated for each surgical technique. The authors also performed a meta-analysis of the reported complications to assess statistical significance across the various surgical techniques. RESULTS Of 9504 articles retrieved from the databases, 42 met inclusion criteria. Most studies screened were retrospective case series, limiting the number of studies that could be included. A total of 9 complication types were identified in the included studies, and these were analyzed across each of the surgical techniques. The rates of any complication across the included studies were 12.5%, 13.3%, and 10.8% for open, MED, and percutaneous microdiscectomy, respectively. New or worsening neurological deficit arose in 1.3%, 3.0%, and 1.6% of patients, while direct nerve root injury occurred at rates of 2.6%, 0.9%, and 1.1%, respectively. Hematoma was reported at rates of 0.5%, 1.2%, and 0.6%, respectively. Wound complications (infection, dehiscence, orseroma) occurred at rates of 2.1%, 1.2%, and 0.5%, respectively. The rates of recurrent disc complications were 4.4%, 3.1%, and 3.9%, while reoperation was indicated in 7.1%, 3.7%, and 10.2% of operations, respectively. Meta-analysis calculations revealed a statistically significant higher rate of intraoperative nerve root injury following percutaneous procedures relative to MED. No other significant differences were found. CONCLUSIONS This review highlights complication rates among various microdiscectomy techniques, which likely reflect real-world practice and conceptualization of complications among physicians. This investigation sets the framework for further discussions regarding microdiscectomy options and their associated complications during the informed consent process. PMID- 26424347 TI - Thirty-day readmission rates in spine surgery: systematic review and meta analysis. AB - OBJECT The rate of 30-day readmissions is rapidly gaining significance as a quality metric and is increasingly used to evaluate performance. An analysis of the present 30-day readmission rate in the spine literature is needed to aid the development of policies to decrease the frequency of readmissions. The authors examine 2 questions: 1) What is the 30-day readmission rate as reported in the spine literature? 2) What study factors impact the rate of 30-day readmissions? METHODS This study was registered with Prospera (CRD42014015319), and 4 electronic databases (PubMed, Cochrane Library, Web of Science, and Google Scholar) were searched for articles. A systematic review and meta-analysis was performed to assess the current 30-day readmission rate in spine surgery. Thirteen studies met inclusion criteria. The readmission rate as well as data source, time from enrollment, sample size, demographics, procedure type and spine level, risk factors for readmission, and causes of readmission were extrapolated from each study. RESULTS The pooled 30-day readmission rate was 5.5% (95% CI 4.2% 7.4%). Studies from single institutions reported the highest 30-day readmission rate at 6.6% (95% CI 3.8%-11.1%), while multicenter studies reported the lowest at 4.7% (95% CI 2.3%-9.7%). Time from enrollment had no statistically significant effect on the 30-day readmission rate. Studies including all spinal levels had a higher 30-day readmission rate (6.1%, 95% CI 4.1%-8.9%) than exclusively lumbar studies (4.6%, 95% CI 2.5%-8.2%); however, the difference between the 2 rates was not statistically significant (p = 0.43). The most frequently reported risk factors associated with an increased odds of 30-day readmission on multivariate analysis were an American Society of Anesthesiology score of 4+, operative duration, and Medicare/Medicaid insurance. The most common cause of readmission was wound complication (39.3%). CONCLUSIONS The 30-day readmission rate following spinal surgery is between 4.2% and 7.4%. The range, rather than the exact result, should be considered given the significant heterogeneity among studies, which indicates that there are factors such as demographics, procedure types, and individual institutional factors that are important and affect this outcome variable. The pooled analysis of risk factors and causes of readmission is limited by the lack of reporting in most of the spine literature. PMID- 26424348 TI - Unintended durotomy in lumbar degenerative spinal surgery: a 10-year systematic review of the literature. AB - OBJECT Unintended durotomy is a common occurrence during lumbar spinal surgery, particularly in surgery for degenerative spinal conditions, with the reported incidence rate ranging from 0.3% to 35%. The authors performed a systematic literature review on unintended lumbar spine durotomy, specifically aiming to identify the incidence of durotomy during spinal surgery for lumbar degenerative conditions. In addition, the authors analyzed the incidence of durotomy when minimally invasive surgical approaches were used as compared with that following a traditional midline open approach. METHODS A MEDLINE search using the term "lumbar durotomy" (under the 2015 medical subject heading [MeSH] "cerebrospinal fluid leak") was conducted on May 13, 2015, for English-language medical literature published in the period from January 1, 2005, to May 13, 2015. The resulting papers were categorized into 3 groups: 1) those that evaluated unintended durotomy rates during open-approach lumbar spinal surgery, 2) those that evaluated unintended durotomy rates during minimally invasive spine surgery (MISS), and 3) those that evaluated durotomy rates in comparable cohorts undergoing MISS versus open-approach lumbar procedures for similar lumbar pathology. RESULTS The MEDLINE search yielded 116 results. A review of titles produced 22 potentially relevant studies that described open surgical procedures. After a thorough review of individual papers, 19 studies (comprising 15,965 patients) pertaining to durotomy rates during open-approach lumbar surgery were included for analysis. Using the Oxford Centre for Evidence-Based Medicine (CEBM) ranking criteria, there were 7 Level 3 prospective studies and 12 Level 4 retrospective studies. In addition, the authors also included 6 studies (with a total of 1334 patients) that detailed rates of durotomy during minimally invasive surgery for lumbar degenerative disease. In the MISS analysis, there were 2 prospective and 4 retrospective studies. Finally, the authors included 5 studies (with a total of 1364 patients) that directly compared durotomy rates during open approach versus minimally invasive procedures. Studies of open-approach surgery for lumbar degenerative disease reported a total of 1031 durotomies across all procedures, for an overall durotomy rate of 8.11% (range 2%-20%). Prospectively designed studies reported a higher rate of durotomy than retrospective studies (9.57% vs 4.32%, p = 0.05). Selected MISS studies reported a total of 93 durotomies for a combined durotomy rate of 6.78%. In studies of matched cohorts comparing open-approach surgery with MISS, the durotomy rates were 7.20% (34 durotomies) and 7.02% (68), respectively, which were not significantly different. CONCLUSIONS Spinal surgery for lumbar degenerative disease carries a significant rate of unintended durotomy, regardless of the surgical approach selected by the surgeon. Interpretation of unintended durotomy rates for lumbar surgery is limited by a lack of prospective and cohort-matched controlled studies. PMID- 26424349 TI - Iatrogenic spondylolisthesis following laminectomy for degenerative lumbar stenosis: systematic review and current concepts. AB - OBJECT Decompression without fusion for degenerative lumbar stenosis is an effective treatment for both the pain and disability of neurogenic claudication. Iatrogenic instability following decompression may require further intervention to stabilize the spine. The authors review the incidence of postsurgical instability following lumbar decompression, and assess the impact of surgical technique as well as study design on the incidence of instability. METHODS A comprehensive literature search was performed to identify surgical cohorts of patients with degenerative lumbar stenosis, with and without preexisting spondylolisthesis, who were treated with laminectomy or minimally invasive decompression without fusion. Data on patient characteristics, surgical indications and techniques, clinical and radiographic outcomes, and reoperation rates were collected and analyzed. RESULTS A systematic review of 24 studies involving 2496 patients was performed, assessing both open laminectomy and minimally invasive bilateral canal enlargement. Postoperative pain and functional outcomes were similar across the various studies, and postoperative radiographie instability was seen in 5.5% of patients. Instability was seen more frequently in patients with preexisting spondylolisthesis (12.6%) and in those treated with open laminectomy (12%). Reoperation for instability was required in 1.8% of all patients, and was higher for patients with preoperative spondylolisthesis (9.3%) and for those treated with open laminectomy (4.1%). CONCLUSIONS Instability following lumbar decompression is a common occurrence. This is particularly true if decompression alone is selected as a surgical approach in patients with established spondylolisthesis. This complication may occur less commonly with the use of minimally invasive techniques; however, larger prospective cohort studies are necessary to more thoroughly explore these findings. PMID- 26424350 TI - Heart drug pushes outcome-based pricing plans. PMID- 26424351 TI - Cancer drug developers counteract kinase gatekeeper mutations. PMID- 26424352 TI - FDA approves ultra-orphan drug on a 4-patient trial. PMID- 26424353 TI - FDA approves female sexual dysfunction drug. PMID- 26424354 TI - Off-label targeted cancer drugs fail in first randomized trial. PMID- 26424355 TI - Infectious diseases: Vaccine for Middle East respiratory syndrome. PMID- 26424356 TI - Cancer: Small-molecule FGF trap shrinks tumours. PMID- 26424360 TI - Electric-field-induced local and mesoscale structural changes in polycrystalline dielectrics and ferroelectrics. AB - The atomic-scale response of dielectrics/ferroelectrics to electric fields is central to their functionality. Here we introduce an in situ characterization method that reveals changes in the local atomic structure in polycrystalline materials under fields. The method employs atomic pair distribution functions (PDFs), determined from X-ray total scattering that depends on orientation relative to the applied field, to probe structural changes over length scales from sub-Angstrom to several nanometres. The PDF is sensitive to local ionic displacements and their short-range order, a key uniqueness relative to other techniques. The method is applied to representative ferroelectrics, BaTiO3 and Na1/2Bi1/2TiO3, and dielectric SrTiO3. For Na1/2Bi1/2TiO3, the results reveal an abrupt field-induced monoclinic to rhombohedral phase transition, accompanied by ordering of the local Bi displacements and reorientation of the nanoscale ferroelectric domains. For BaTiO3 and SrTiO3, the local/nanoscale structural changes observed in the PDFs are dominated by piezoelectric lattice strain and ionic polarizability, respectively. PMID- 26424361 TI - Authors' reply to Bonten. PMID- 26424362 TI - Coping with Work-Related Stress through Guided Imagery and Music (GIM): Randomized Controlled Trial. AB - BACKGROUND: Long-term stress-related sick leave constitutes a serious health threat and an economic burden on both the single worker and the society. Effective interventions for the rehabilitation and facilitation of return to work are needed. OBJECTIVE: The aim of the study was to examine the effects of Guided Imagery and Music (GIM), a psychotherapy intervention including relaxation, music listening, and imagery, on biopsychosocial measures of work-related stress. METHODS: Twenty Danish workers on sick leave were randomized to music therapy versus wait-list control. Data collection was carried out at an occupational health ward in the period 2008-2010. Changes in salivary cortisol, testosterone, and melatonin were explored, and self-reported data on psychological stress symptoms (perceived stress, mood disturbance, sleep quality, physical distress symptoms, work readiness, well-being, anxiety, depression, immediate stress) were collected. Data regarding sick leave situation and job return were collected from participants throughout the study. RESULTS: Significant beneficial effects of GIM compared to wait-list after nine weeks with large effect sizes were found in well being, mood disturbance, and physical distress, and in cortisol concentrations with a medium effect size. A comparison between early and late intervention as related to the onset of sick leave showed faster job return and significantly improved perceived stress, well-being, mood disturbance, depression, anxiety, and physical distress symptoms in favor of early intervention. In the whole sample, 83% of the participants had returned to work at nine weeks' follow-up. CONCLUSIONS: The results indicate that GIM is a promising treatment for work related chronic stress, and further studies are recommended. PMID- 26424364 TI - A heuristic approach to determine an appropriate number of topics in topic modeling. AB - BACKGROUND: Topic modelling is an active research field in machine learning. While mainly used to build models from unstructured textual data, it offers an effective means of data mining where samples represent documents, and different biological endpoints or omics data represent words. Latent Dirichlet Allocation (LDA) is the most commonly used topic modelling method across a wide number of technical fields. However, model development can be arduous and tedious, and requires burdensome and systematic sensitivity studies in order to find the best set of model parameters. Often, time-consuming subjective evaluations are needed to compare models. Currently, research has yielded no easy way to choose the proper number of topics in a model beyond a major iterative approach. METHODS AND RESULTS: Based on analysis of variation of statistical perplexity during topic modelling, a heuristic approach is proposed in this study to estimate the most appropriate number of topics. Specifically, the rate of perplexity change (RPC) as a function of numbers of topics is proposed as a suitable selector. We test the stability and effectiveness of the proposed method for three markedly different types of grounded-truth datasets: Salmonella next generation sequencing, pharmacological side effects, and textual abstracts on computational biology and bioinformatics (TCBB) from PubMed. CONCLUSION: The proposed RPC-based method is demonstrated to choose the best number of topics in three numerical experiments of widely different data types, and for databases of very different sizes. The work required was markedly less arduous than if full systematic sensitivity studies had been carried out with number of topics as a parameter. We understand that additional investigation is needed to substantiate the method's theoretical basis, and to establish its generalizability in terms of dataset characteristics. PMID- 26424363 TI - Health economic modeling of the potential cost saving effects of Neurally Adjusted Ventilator Assist. AB - OBJECTIVES: Asynchrony between patient and ventilator breaths is associated with increased duration of mechanical ventilation (MV). Neurally Adjusted Ventilatory Assist (NAVA) controls MV through an esophageal reading of diaphragm electrical activity via a nasogastric tube mounted with electrode rings. NAVA has been shown to decrease asynchrony in comparison to pressure support ventilation (PSV). The objective of this study was to conduct a health economic evaluation of NAVA compared with PSV. METHODS: We developed a model based on an indirect link between improved synchrony with NAVA versus PSV and fewer days spent on MV in synchronous patients. Unit costs for MV were obtained from the Swedish intensive care unit register, and used in the model along with NAVA-specific costs. The importance of each parameter (proportion of asynchronous patients, costs, and average MV duration) for the overall results was evaluated through sensitivity analyses. RESULTS: Base case results showed that 21% of patients ventilated with NAVA were asynchronous versus 52% of patients receiving PSV. This equals an absolute difference of 31% and an average of 1.7 days less on MV and a total cost saving of US$7886 (including NAVA catheter costs). A breakeven analysis suggested that NAVA was cost effective compared with PSV given an absolute difference in the proportion of asynchronous patients greater than 2.5% (49.5% versus 52% asynchronous patients with NAVA and PSV, respectively). The base case results were stable to changes in parameters, such as difference in asynchrony, duration of ventilation and daily intensive care unit costs. CONCLUSION: This study showed economically favorable results for NAVA versus PSV. Our results show that only a minor decrease in the proportion of asynchronous patients with NAVA is needed for investments to pay off and generate savings. Future studies need to confirm this result by directly relating improved synchrony to the number of days on MV. PMID- 26424365 TI - Molecular Insights into Aqueous NaCl Electrolytes Confined within Vertically oriented Graphenes. AB - Vertically-oriented graphenes (VGs) are promising active materials for electric double layer capacitors (EDLCs) due to their unique morphological and structural features. This study, for the first time, reports the molecular dynamics (MD) simulations on aqueous NaCl electrolytes confined within VG channels with different surface charge densities and channel widths. Simulation results show that the accessibility of ions and the structure of EDLCs are determined by the ion type/size, surface charging, and VG channel width. For relatively narrow VG channels with the same width, the threshold charge density (to compensate the energy penalty for shedding hydration shell) and the dehydration rate of Cl(-) ions are larger than those of Na(+) ions. To achieve the highest ion concentration coefficient, the effective VG channel width should be between the crystal and hydration diameters of the ions. The results are further quantified and elucidated by calculating the electrolyte density profiles. The molecular insights obtained in the current work are useful in guiding the design and fabrication of VGs for advancing their EDLC applications. PMID- 26424366 TI - Emergency readmissions are highest in patients discharged at weekends. PMID- 26424367 TI - Oncological emergencies associated with gastrointestinal tumors. AB - Oncological emergencies are defined as acute life-threatening conditions in cancer patients either as a result of the malignancy or as a result of its treatment. In this review, we focus on oncological emergencies associated with gastrointestinal tumors. They can be categorized by their system of origin as hematologic, neurologic or metabolic. Furthermore, we discuss mechanical emergencies such as intestinal obstruction and vena cava superior syndrome as well as acute gastrointestinal bleeding and pulmonary embolism. The patients' performance status as well as prognosis are essential during decision making for optimal treatment. PMID- 26424369 TI - Focus on the surgical approach to transcatheter aortic valve implantation: Complications, outcome, and preoperative risk adjustment. AB - OBJECTIVE: Perioperative complications in patients undergoing transcatheter aortic valve implantation remain a major issue affecting outcome. Because preoperative risk adjustment remains challenging and a valid scoring system is missing, we sought to determine the incidence of peri- and postprocedural complications of transapical (TA) or transaortic (TAO) access to define the influence of specific complications on early safety, 30-day mortality, and 1-year survival. Furthermore, we aimed to develop a risk-stratification model to allow an estimation of the perioperative risk and the 1-year survival rate, based on the individual preoperative condition of each patient. METHODS: We performed an outcome analysis of 230 consecutive patients who underwent aortic valve implantation via transapical or transaortic access between 2008 and 2012, with regard to Valve Academic Research Consortium II criteria, including univariate and multivariable regression analysis, to develop a risk-stratification model. RESULTS: Thirty-day mortality was 12.7%. Estimated 1-year survival was 0.69 (95% confidence interval [CI], 0.631-0.757), and 3-year survival was 0.554 (95% CI, 0.474-0.634). Univariate logistic regression analysis revealed a significant influence on 30-day mortality in case of life-threatening bleeding (16.1-fold), abdominal complications (8.5-fold), and acute kidney injury (3.2-fold). Pacemaker implantation (odds ratio, 1.55; 95% CI, 0.42-5.81; P = .512) was not a significant predictor. Concerning use of intraprocedural hemodynamic bridging therapy via cardiopulmonary bypass (CPB), Cox regression analysis revealed no significant survival difference after 1 year. A preoperative risk-stratification model for 1-year survival revealed that a logistic European System for Cardiac Operative Risk Evaluation score >20%, preoperative existing coronary artery disease, and prior myocardial infarction appeared to be significant predictors for diminished survival. CONCLUSIONS: Concerning intraprocedural complications, CPB support for hemodynamic stabilization is a safe treatment option. Therefore, the heart team approach with CPB standby represents a life-saving option. Attention should also be drawn to specialized and individual postoperative care, because nonprocedure-specific complications clearly affect postoperative short- and long-term outcome. In addition, the risk-stratification model might facilitate preoperative decision making. PMID- 26424368 TI - Determinants of the t(14;18) translocation and their role in t(14;18)-positive follicular lymphoma. AB - PURPOSE: The strong association between t(14;18) translocation and follicular lymphoma (FL) is well known. However, the determinants of this chromosomal aberration and their role in t(14;18) associated FL remain to be established. METHODS: t(14;18) frequency within the B cell lymphoma 2 major breakpoint region was determined for 135 incident FL cases and 251 healthy controls as part of a nested case-control study within the European Prospective Investigation into Cancer cohort. Quantitative real-time PCR was performed in DNA extracted from blood samples taken at recruitment. The relationship between prevalence and frequency of the translocation with baseline anthropometric, lifestyle, and dietary factors in cases and controls was determined. Unconditional logistic regression was used to explore whether the risk of FL associated with these factors differed in t(14;18)(+) as compared to t(14;18)(-) cases. RESULTS: Among incident FL cases, educational level (chi(2) p = 0.021) and height (chi(2) p = 0.025) were positively associated with t(14;18) prevalence, and cases with high frequencies [t(14;18)(HF)] were significantly taller (t test p value = 0.006). These findings were not replicated in the control population, although there were a number of significant associations with dietary variables. Further analyses revealed that height was a significant risk factor for t(14;18)(+) FL [OR 6.31 (95% CI 2.11, 18.9) in the tallest versus the shortest quartile], but not t(14;18)(-) cases. CONCLUSIONS: These findings suggest a potential role for lifestyle factors in the prevalence and frequency of the t(14;18) translocation. The observation that the etiology of FL may differ by t(14;18) status, particularly with regard to height, supports the subdivision of FL by translocation status. PMID- 26424370 TI - Efforts to improve bypass graft patency have not been "in vein". PMID- 26424371 TI - Internal thoracic artery grafting in the elderly and the challenge to conventional wisdom. PMID- 26424372 TI - Neopulmonary reconstruction: Operam do. PMID- 26424373 TI - Septal myectomy in context: Clinical acumen and procedural expertise. PMID- 26424374 TI - On biostatisticians and their role in cardiothoracic surgery research. PMID- 26424375 TI - Biostatisticians and the future of cardiovascular research. PMID- 26424376 TI - JBP485 promotes corneal epithelial wound healing. AB - Proper wound healing is vital for maintenance of corneal integrity and transparency. Corneal epithelial damage is one of the most frequently observed ocular disorders. Because clinical options are limited, further novel treatments are needed to improve clinical outcomes for this type of disease. In the present study, it was found that placental extract-derived dipeptide (JBP485) significantly increased the proliferation and migration of corneal epithelial cells (CECs). Moreover, JBP485 accelerated corneal epithelial wound healing in vivo without inflammation and neovascularization and was found to be effective for the treatment of corneal damage. These data indicate that JBP485 efficiently activates the viability of CECs and has potential as a novel treatment for various kinds of corneal epithelial disease. PMID- 26424378 TI - Paradoxical (rapid eye movement) sleep-on neurons in the laterodorsal pontine tegmentum in mice. AB - A total of 211 neurons that discharged at the highest rate during sleep (sleep active neurons) were recorded in non-anesthetized, head-restrained mice during the complete wake-sleep cycle in, and around, the laterodorsal (LDT) and sublaterodorsal (SubLDT) tegmental nuclei, which contain both cholinergic and non cholinergic neurons. For the first time in mice, I reveal the presence, mainly in the SubLDT, of sleep-specific neurons displaying sustained tonic discharge either (i) just prior to, and during, paradoxical sleep (PS) (PS-on neurons) or (ii) during both slow-wave sleep (SWS) and PS (SWS/PS-on neurons). Both the PS-on and SWS/PS-on neurons showed either a low (< 10 Hz) or high (? 10 Hz) rate of spontaneous firing and exhibited a biphasic narrow or medium-to-broad action potential, a characteristic of non-cholinergic neurons. At the transition from SWS to waking (W), the PS-on and SWS/PS-on neurons simultaneously ceased firing shortly before the onset of W, whereas, at the transition from W to SWS, only the SWS/PS-on neurons fired shortly after the onset of sleep. At the transition from SWS to PS, only the PS-on neurons exhibited a significant increase in discharge rate before PS onset, while, at the transition from PS to W, the SWS/PS-on neurons, then the PS-on neurons, displayed a significant decrease in the discharge rate before the end of PS. The SWS/PS-on neurons were more sensitive to the change in the electroencephalogram (EEG) than the PS-on neurons, as, during a PS episode, the slightest interruption of rhythmic theta activity resulted in cessation of discharge of the SWS/PS-on neurons. These findings support the view that, in the mouse SubLDT, PS-on neurons play an important role in the induction, maintenance, and cessation of PS, while SWS/PS-on neurons play a role in the maintenance of the PS state in particular and the sleep state in general. PMID- 26424377 TI - Comparative aspects of immunity and vaccination in human and bovine trichomoniasis: a review. AB - Trichomonas vaginalis and Tritrichomonas foetus are important extracellular protozoans that cause, respectively, human and bovine venereal diseases. Trichomonads are extracellular parasites that primarily inhabit the genital tracts of the mammalian hosts where they overcome the mucus barrier and parasitize mucosa by contact-dependent or contact-independent cytotoxicity. Transient immunity is usually achieved by the host after clinical infection. At present, vaccination in cattle reduces infection rates and reproductive wastage in affected herds. After vaccination, immunoglobulin G (IgG) levels increase in systemic circulation while immunoglobulin A (IgA) levels rise in the vagina. Only moderate protection is conferred by means of vaccination. Future vaccine development strategies are needed for cattle to enhance the antigenic component or use adjuvant that strongly activates the innate immune response to produce safe and potent vaccines. This paper reviews the current knowledge of the immunology of trichomoniasis infection and the challenges and potential of vaccines in the control of the infection in human and bovine trichomoniasis. PMID- 26424379 TI - Effects of facial color on the subliminal processing of fearful faces. AB - Recent studies have suggested that both configural information, such as face shape, and surface information is important for face perception. In particular, facial color is sufficiently suggestive of emotional states, as in the phrases: "flushed with anger" and "pale with fear." However, few studies have examined the relationship between facial color and emotional expression. On the other hand, event-related potential (ERP) studies have shown that emotional expressions, such as fear, are processed unconsciously. In this study, we examined how facial color modulated the supraliminal and subliminal processing of fearful faces. We recorded electroencephalograms while participants performed a facial emotion identification task involving masked target faces exhibiting facial expressions (fearful or neutral) and colors (natural or bluish). The results indicated that there was a significant interaction between facial expression and color for the latency of the N170 component. Subsequent analyses revealed that the bluish colored faces increased the latency effect of facial expressions compared to the natural-colored faces, indicating that the bluish color modulated the processing of fearful expressions. We conclude that the unconscious processing of fearful faces is affected by facial color. PMID- 26424380 TI - Distribution of serotonin receptor 5-HT6 mRNA in rat neuronal subpopulations: A double in situ hybridization study. AB - The 5-HT6 receptor (5-HT6R) is almost exclusively expressed in the brain and has emerged as a promising target for cognitive disorders, including Alzheimer's disease. In the present study, we have determined the cell types on which the 5 HT6R is expressed by colocalizing 5-HT6R mRNA with that of a range of neuronal and interneuronal markers in the rat brain. Here, we show that 5-HT6R mRNA was expressed at high levels in medium spiny neurons in caudate putamen and in nucleus accumbens, as well as in the olfactory tubercle. Striatal 5-HT6R mRNA was colocalized with both dopamine D1 and D2 receptor mRNA. 5-HT6R mRNA was moderately expressed in the hippocampus and throughout cortical regions in glutamatergic neurons coexpressing vGluT1. A subset of GAD67-positive GABAergic interneurons (approximately 15%) expressed 5-HT6R mRNA in the cortex and hippocampus, the majority of which belonged to the 5-HT3a receptor (5-HT3aR) expressing subpopulation. In contrast, 5-HT6R mRNA was only expressed to a minor extent in the parvalbumin and somatostatin subpopulations. A subset of calbindin- and calretinin-positive GABAergic interneurons expressed 5-HT6R mRNA while only a very minor fraction of VIP or NPY interneurons in forebrain structures expressed 5-HT6R mRNA. Serotonergic, dopaminergic or cholinergic neurons did not express 5 HT6R mRNA. These data indicate that the 5-HT6R is located on GABAergic and glutamatergic principal neurons, and on a subset of interneurons mainly belonging to the 5-HT3aR subgroup suggesting that the 5-HT6R is positioned to regulate the balance between excitatory and inhibitory signaling in the brain. These data provide new insights into the mechanisms of 5-HT6R signaling. PMID- 26424382 TI - Phylogeography of the European sturgeon (Acipenser sturio): A critically endangered species. AB - The European sturgeon (Acipenser sturio) was once a common species throughout Europe, but the sole remaining natural population presently inhabits the Gironde Estuary in France (Atlantic coast). The species was classified as 'Critically Endangered' in 1996, and the Gironde population is now on the verge of extinction. In this setting, and for the first time, we present the past phylogeographical features of this species throughout Europe along with an assessment of its former genetic diversity. This study was based on a molecular analysis (mtDNA CR sequencing) of 10 living specimens from the Gironde Estuary, 55 museum specimens that had been caught along 19th and 20th centuries, and 59 archaeological remains dating back to 260-5000years BP, from which mitochondrial DNA was extracted and amplified. Although discontinuous, the produced data provided a realistic image of the former structure of A. sturio in Europe. Reconstruction of the phylogenetic trees and haplotypes network led to the identification of several clades. The mitochondrial genetic diversity of this species was found to be much greater at the core (Iberian Peninsula, Mediterranean and Adriatic regions) than along the margins (Atlantic-Northern Europe, Black Sea) of its range. A series of hypotheses on the dates and causes of changes in the species' major structures are put forward on the basis of these data. Finally, competition with A. oxyrinchus, a sibling species whose presence in Northern Europe was recently reconsidered, is presented as a major factor in the evolution of this species. PMID- 26424383 TI - Late-Life Depression and Antidepressants. PMID- 26424381 TI - Ontogeny of tight junction protein expression in the ovine cerebral cortex during development. AB - Tight junctions of the blood-brain barrier are composed of transmembrane and associated cytoplasmic proteins. The transmembrane claudin proteins form the primary seal between endothelial cells and junctional adhesion molecules (JAMs) regulate tight junction formation. We have previously shown that claudin-1, claudin-5, zonula occludens (ZO)-1, and ZO-2 exhibit differential developmental regulation from 60% of gestation up to maturity in adult sheep. The purpose of the current study was to examine developmental changes in claudin-3, -12, and JAM A protein expression in cerebral cortices of fetuses at 60%, 80%, and 90% gestation, and in newborn and adult sheep. We also examined correlations between changes in endogenous cortisol levels and tight junction protein expression in cerebral cortices of the fetuses. Claudin-3, -12 and JAM-A expressions were determined by Western immunoblot. Claudin-3 and -12 were lower (P<0.01) at 60%, 80%, 90% and in newborns than in adults, and JAM-A was lower in adults than in fetuses at 80% and 90% gestation. Claudin-3 expression demonstrated a direct correlation with increasing plasma cortisol levels (r=0.60, n=15, P<0.02) in the fetuses. We conclude that: claudin-3, -12 and JAM-A are expressed as early as 60% of gestation in ovine cerebral cortices, exhibit differential developmental regulation, and that increasing endogenous glucocorticoids modulate claudin-3 expression in the fetus. PMID- 26424384 TI - Natural occurrence of pure nano-polycrystalline diamond from impact crater. AB - Consolidated bodies of polycrystalline diamond with grain sizes less than 100 nm, nano-polycrystalline diamond (NPD), has been experimentally produced by direct conversion of graphite at high pressure and high temperature. NPD has superior hardness, toughness and wear resistance to single-crystalline diamonds because of its peculiar nano-textures, and has been successfully used for industrial and scientific applications. Such sintered nanodiamonds have, however, not been found in natural mantle diamonds. Here we identified natural pure NPD, which was produced by a large meteoritic impact about 35 Ma ago in Russia. The impact diamonds consist of well-sintered equigranular nanocrystals (5-50 nm), similar to synthetic NPD, but with distinct [111] preferred orientation. They formed through the martensitic transformation from single-crystal graphite. Stress-induced local fragmentation of the source graphite and subsequent rapid transformation to diamond in the limited time scale result in multiple diamond nucleation and suppression of the overall grain growth, producing the unique nanocrystalline texture of natural NPD. A huge amount of natural NPD is expected to be present in the Popigai crater, which is potentially important for applications as novel ultra-hard material. PMID- 26424385 TI - Cryptosporidiosis outbreak in visitors of a UK industry-compliant petting farm caused by a rare Cryptosporidium parvum subtype: a case-control study. AB - A case-control study was conducted to investigate an outbreak of 46 cases of cryptosporidiosis in visitors to a petting farm in England. Details of exposures on the farm were collected for 38 cases and 39 controls, recruited through snowball sampling. Multivariable logistic regression identified that cases were 5.5 times more likely than controls to have eaten without washing their hands [95% confidence interval (CI) 1.51-19.9, P = 0.01] and 10 times less likely to report being informed of risk of infection on arrival (odds ratio 0.10, 95% CI 0.01-0.71, P = 0.02). An uncommon Cryptosporidium parvum gp60 subtype (IIaA19G1R1) was identified in a lamb faecal sample and all subtyped cases (n = 22). We conclude that lack of verbal advice and non-compliance with hand washing are significantly associated with a risk of cryptosporidiosis on open farms. These findings highlight the public health importance of effectively communicating risk to petting farm visitors in order to prevent future outbreaks of zoonotic infections. PMID- 26424386 TI - To Bleed or Not to Bleed: That is the Question. The Side Effects of Apixaban. AB - Apixaban is a new oral anticoagulant (NOACs: Novel Oral Anticoagulant), like dabigatran, rivaroxaban, and edoxaban. All of them are prescribed to patients with non valvular atrial fibrillation or venous thromboembolism, to replace warfarin, because of the lower probability of bleeding, however they can cause bleeding by themselves. Bleeding is an adverse event in patients taking anticoagulants. It is associated with a significant increase of morbidity and risk of death. However, these drugs should be used only for the time when anticoagulation is strictly required, especially when used for preventing deep vein thrombosis. Prolonged use increases the risk of bleeding. In the ARISTOTLE Trial Apixaban, compared with warfarin, was associated with a lower rate of intracranial hemorrhages and less adverse consequences following extracranial hemorrhage. Many physicians still have limited experience with new oral anticoagulants and about bleeding risk managment. We reviewed the available literature on extracranial and intracranial bleeding concerning apixaban. PMID- 26424387 TI - Stress Hormone-Mediated DNA Damage Response--Implications for Cellular Senescence and Tumour Progression. AB - When DNA damage occurs, cells stop the cell cycle and DNA repair can take place. However, if DNA damage exceeds DNA repair capacities, cells undergo either apoptosis or senescence. These mechanisms preclude the proliferation of cells with heavily damaged DNA, thus protecting the organism against tumour development. When individuals are exposed to stress, the hypothalamic-pituitary adrenal (HPA) axis and the sympathetic- adrenal-medullary (SAM) system can be activated leading to secretion of corticosteroids and catecholamines, respectively. The influences of these stress-related hormones have been proposed to promote cellular senescence. But paradoxically, chronic stimulation of the HPA axis is associated with higher risk of developing cancer. Focusing on the DNA damage response pathway, this review discusses whether stress hormones induce senescence or tumour progression or both and presents historical and recent data that might help resolve some of these controversies. PMID- 26424388 TI - Polysaccharide based Copolymers as Supramolecular Systems in Biomedical Applications. AB - Polysaccharides are natural polymers, obtained from a large variety of sources ranging from fungi to more complex organisms such as birds and whales. Their use for pharmaceutical and biomedical applications has been the subject of numerous researches by the world's academia. Polysaccharide chemical/physical modifications leading to graft copolymers are discussed in this review, focusing on those nanosystems that are potential candidates for drug delivery applications. Therefore, this review focuses on the biomedical application of polysaccharide based copolymers, particularly as nanocarriers. Copolymer of polysaccharides such as alginate, cellulose, chitosan, dextran, guar, hyaluronic acid, pullulan and starch as drug delivery nanocarriers will be discussed. PMID- 26424389 TI - Metallothionein as a Scavenger of Free Radicals - New Cardioprotective Therapeutic Agent or Initiator of Tumor Chemoresistance? AB - Cardiotoxicity is a serious complication of anticancer therapy by anthracycline antibiotics. Except for intercalation into DNA/RNA structure, inhibition of DNA topoisomerase and histone eviction from chromatin, the main mechanism of their action is iron-mediated formation of various forms of free radicals, which leads to irreversible damage to cancer cells. The most serious adverse effect of anthracyclines is, thus, cardiomyopathy leading to congestive heart failure, which is caused by the same mechanisms. Here, we briefly summarize the basic types of free radicals formed by anthracyclines and the main processes how to scavenge them. From these, the main attention is paid to metallothioneins. These low-molecular cysteine-rich proteins are introduced and their functions and properties are reviewed. Further, their role in detoxification of metals and drugs is discussed. Based on these beneficial roles, their use as a new therapeutic agent against oxidative stress and for cardioprotection is critically evaluated with respect to their ability to increase chemoresistance against some types of commonly used cytostatics. PMID- 26424390 TI - From "An Enzyme Able to Destroy Penicillin" to Carbapenemases: 70 Years of Beta lactamase Misbehaviour. AB - As early as 1940, Abraham and Chain described "an enzyme able to destroy penicillin". In the late 1940's, penicillin-resistant strains of Staphylococcus aureus were found to be a clinical problem. They produced a penicillinase that could hydrolyze the amide bond in the beta-lactam ring. Later, an enzyme mediated by an R-factor was isolated from Enterobacteriaceae. Methicillin and cephalosporins, both very poor substrates of the S. aureus enzyme, were found to be sensitive to this new enzyme. Third generation cephalosporins appeared to solve the problem, but further enzymes were selected that exhibited extended spectra and could for instance hydrolyze cefotaxime and/or ceftazidime. The discovery of carbapenems constituted a major advance for our antimicrobial arsenal: they inactivated most of the essential penicillin binding proteins effectively and escaped the activity of nearly all known -beta lactamases. However, the metallo-beta-lactamases, which had not been recognised as a major danger before 1990, were found to act as effective carbapenemases and started to spread in a worrying way. Moreover, carbapenem-hydrolyzing enzymes were found in each of the 3 classes of active-site serine beta-lactamases. PMID- 26424391 TI - Sphingosine-1-Phosphate Receptors in the Central Nervous and Immune Systems. AB - Sphingosine-1-phosphate receptor (S1PR) modulators have entered clinical practice as immune-modulators for the treatment of multiple sclerosis (MS). Pharmacologic modulation of S1PR expression on lymphocytes inhibits these cells capacity to respond to the S1P gradient within regional lymph nodes (LNs) (and thymus) that promotes their exit into peripheral circulation. The resultant peripheral blood restricted lymphopenia is considered to underlie the capacity of S1PR modulators to reduce new inflammatory lesion formation in MS in the absence of global immune suppression. These modulators also regulate entry of selective lymphocyte populations and dendritic cells (DCs) into LNs and modulate sphingosine-1 phosphate (S1P) cell signaling networks that govern the generation of specific cell subsets within LNs. S1PR modulators that access the CNS can also have functional effects within this compartment since S1PRs are expressed by cells comprising the blood brain barrier (BBB) and by those within the parenchyma, including neurons, astrocytes, oligodendrocytes and microglia. Absence of S1P1 receptor (S1PR1) on astrocytes reduces disease severity in experimental autoimmune encephalomyelitis (EAE). Even under conditions that inhibit cell responses to the natural ligand, S1PR modulators can continue to induce active signaling responses; such responses may be relevant for promoting neuroprotection and augmenting tissue repair within the CNS. PMID- 26424392 TI - Alginate Bead-Encapsulated PEDF Induces Ectopic Bone Formation In Vivo in the Absence of Co-Administered Mesenchymal Stem Cells. AB - BACKGROUND: Bone defects can be severely debilitating and reduce quality of life. Osteoregeneration can alleviate some of the complications in bony defects. For therapeutic use in future, a single factor that can cause potent bone regeneration is highly preferred as it will be more costeffective, any off-target effects will be more easily monitored and potentially managed, and for ease of administration which would lead to better patient compliance and satisfaction. OBJECTIVE: We demonstrate that pigment epithelium-derived factor (PEDF), one such factor that is known to be potent against angiogenesis, promotes osteoblastogenesis in mesenchymal stem cells in vitro, but does not need co encapsulation of cells in alginate bead scaffolds for osteogeneration in vivo. RESULTS: Osteogenic differentiation by PEDF in vitro was confirmed with immunoblotting and immunocytochemical staining for bone markers (alkaline phosphatase, osteocalcin, osteopontin, collagen I), calcified mineral deposition, and assay for alkaline phosphatase activity. PEDF-mediated bone formation in a muscle pocket in vivo model was confirmed by microcomputed tomography (microCT), histology (haematoxylin and eosin, Alcian blue staining), immunostaining for bone markers and for collagen I-processing proteins (heat shock protein 47 and membrane type I matrix metalloproteinase). CONCLUSION: PEDF therefore presents itself as a promising biological for osteogeneration. PMID- 26424393 TI - Gastrin-Releasing Peptide Receptor Targeting in Cancer Treatment: Emerging Signaling Networks and Therapeutic Applications. AB - Growth factors of the bombesin/gastrin releasing peptide (BN/GRP) family play a critical role in proliferation and progression of malignancies. Inhibitors targeting GRP signalling have been developed and tested as anticancer compounds showing promising preclinical and early phase clinical results. In this review, we will discuss the molecular signaling, expression and the functional role of BN/GRP-GRPR in different cancer models and will focus on the available strategies to target BN/GRP-GRPR in cancer treatment as well as in tumour diagnosis and follow up. PMID- 26424394 TI - New Pharmacological Approaches to the Prevention of Myocardial Ischemia- Reperfusion Injury. AB - BACKGROUND: Early reperfusion of the blocked vessel is critical to restore the blood flow to the ischemic myocardium to salvage myocardial tissue and improve clinical outcome. This reperfusion strategy after a period of ischemia, however, may elicit further myocardial damage named myocardial reperfusion injury. The manifestations of reperfusion injury include arrhythmias, myocardial stunning and micro-vascular dysfunction, in addition to significant cardiomyocyte death. It is suggested that an overproduction of reactive oxygen species, intracellular calcium overload and inflammatory cell infiltration are the most important features of myocardial ischemia-reperfusion injury. OBJECTIVE: In this review, various pharmacological interventions to treat myocardial reperfusion injury including the antioxidant flavonols, hydrogen sulfide, adenosine, opioids, incretin-based therapies and cyclosporin A which targets the mitochondrial permeability transition pore are discussed. CONCLUSION: The processes involved in reperfusion injury might provide targets for improved outcomes after myocardial infarction but thus far that aim has not been met in the clinic. PMID- 26424395 TI - Effect of Genetic Polymorphisms (SNPs) in CHRNA7 Gene on Response to Acetylcholinesterase Inhibitors (AChEI) in Patients with Alzheimer's Disease. AB - BACKGROUND: Cholinergic transmission loss is one of the major features in Alzheimer's Disease (AD). Acetylcholinesterase inhibitors (AChEI) are moderately active in AD. alpha7nAChR (alpha-7 nicotinic acetylcholine receptor), encoded by CHRNA7 (Nicotinic Cholinergic Receptor Alpha-7 gene), is involved in the cholinergic neurotransmission and AD pathogenesis. alpha7nAChR is a putative receptor of amyloid beta (Abeta). The complex alpha7nAChR-Abeta is found in neuritic plaques and AD cortical neurons. In normal physiologic conditions, alpha7nAChR-Abeta interaction leads to receptor activation. Genetic polymorphisms (SNPs) of CHRNA7 and/or CHRFAM7A (fusion gene containing CHRNA7 partial duplication) may be a possible susceptibility trait to dementia, potentially useful to identify high risk or responder individuals. CHRFAM7A-2-bp deletion or CHRNA7 SNPs (rs1514246, rs2337506, rs8027814) seem protective factors in different forms of dementia including AD. OBJECTIVE: Correlation between(SNPs) of CHRNA7 and/or CHRFAM7A and cholinesterase inhibitors in AD. METHODS: Literature review. RESULTS: Among the leading AD therapeutics, Donepezil (DP) and galantamine (AChEI) induce upregulation of alpha7nAChR protein levels, protecting neurons from degeneration. Patients carrying rs8024987 (C/G) or rs6494223 (C/T) respond better to AChEI. In the caucasic population rs6494223 TT subjects are 7 15% of the total. alpha7nAChR upregulation induced by DP is higher in lymphocytes from TT subjects than in CC or CT as well as calcium uptake. CONCLUSION: The correlation between genetic and functionality data may have an impact on several aspects of disease presentation and therapy, helping in prediction pattern of AD presentation and treatment efficacy. As a consequence it may lead to better patients quality of life and longer periods of self- sufficiency. Moreover, it may contribute to clarify AChEI mechanisms of action. PMID- 26424396 TI - Withdrawn: The chemopreventive activity of beta-ionone involves modulation of Rxralpha, Rarbeta and Coup-Tf1 expression in liver pre-neoplastic lesions in rats. AB - Withdrawn by the publisher. PMID- 26424397 TI - The Contribution of Extracellular Nef to HIV-Induced Pathogenesis. AB - Nef is an accessory protein expressed exclusively in primate lentiviruses. It is devoid of enzymatic activities while interacting with several cell proteins as an adaptor/scaffold protein. Intracellular functions of Nef largely account for many pathogenic effects observed in AIDS disease. Nef, despite lacking known secretory pathways, can be detected in plasma of HIV-1-infected patients at the concentration varing from 5 to 10 ng/ml. Remarkably, the levels of Nef in plasma of HIV patients do not correlate with viral load or number of CD4(+) T lymphocytes, and persist during antiretroviral therapy. Here, we review literature data describing how Nef can be transmitted from HIV-1- infected cells to bystander ones, and the effects of extracellular Nef in different cell types. Overall, large part of experimental evidences supports the idea that extracellular Nef plays a relevant role in AIDS pathogenesis. Hence, efforts focused on the identification of Nef-inhibiting drugs would be of relevance to establish new therapeutic approaches supporting current antiretroviral therapies. PMID- 26424399 TI - Nanosponge Carriers- An Archetype Swing in Cancer Therapy: A Comprehensive Review. AB - Nanotechnology and nanomedicines are emerging research meadows; which chiefly focuses on creating and manipulating materials at a nanometer level for the betterment in imaging, diagnosis and treatment of a range of diseases together with cancer. Cyclodextrin-based nanosponges, anticipated as a new-fangled nanosized delivery system, are ground-breaking hyper-crosslinked cyclodextrin polymers nanostructured within a three-dimensional network. Nanosponges based systems hold the potential of elevating the solubility, absorption, penetration, bioavailability, in vivo stability, targeted as well as sustained delivery, and therapeutic efficiency of numerous anticancer agents. The extension of nanosponges based drug delivery systems is an exhilarating and demanding research pasture, predominantly to overcome aforementioned problems allied to existing anticancer formulations and for the further progressions in cancer therapies. Nanosponges in cancer therapy, particularly cyclodextrin based nanosponges are brought up in this review. By quoting diverse attempts made in pertinent direction, efforts have been made to exemplify the characteristics, suitability and versatility of cyclodextrin based nanosponges for their promising applications in cancer treatment. PMID- 26424400 TI - Possible Effects of Dietary Anthocyanins on Diabetes and Insulin Resistance. AB - Diabetes is reaching epidemic proportions worldwide. Many dietary compounds have been found to exert health beneficial effects against different pathologies including diabetes. Most bioactive compounds have been identified in fruits and vegetables and their mechanisms of action explored both in vitro and in vivo. In particular, great interest has been given to polyphenols and especially to a specific subset of molecules, i.e. anthocyanins. Several lines of evidence suggest that anthocyanins have positive effects on human health by inducing a number of biological activities. This review will give an overview on the influence of dietary anthocyanins on preventing and managing type 2 diabetes. In particular, in vitro and in vivo studies will be presented. The article also reviews the potential clinical impact of the antidiabetic activity of anthocyanins and outlines the major challenges of using anthocyanins for diabetes treatment. PMID- 26424401 TI - Decoding the Structural Basis For Carbapenem Hydrolysis By Class A beta lactamases: Fishing For A Pharmacophore. AB - Nowadays clinical therapy witnesses a challenging bacterial resistance limiting the available armament of antibiotics. Over the decades strains resistant to all antibiotics have been selected while medicinal chemists were not able to develop agents capable of destroying them or to prevent their extension. In particular, carbapenem-resistant Enterobacteriaceae (CRE), representing one of the most common human pathogens, have been reported with increased frequency since their first identification twenty years ago. The enterobacterial carbapenemases differ from the extended spectrum beta-lactamases (ESBL) in their ability to hydrolyze beta-lactams, cephalosporins and most importantly monobactams and carbapenems. They are progressively spreading throughout the world, therefore leaving no effective beta-lactam to cure bacterial infections. Several BLs-carbapenemase Xray structures have been determined making these enzymes attractive targets for structure-based drug design studies. However, very little has been done so far to powerfully address the inhibitor design issues for this emerging type of BLs. Here, we focus on the structural basis for molecular recognition and for broad spectrum activity of class A carbapenemases: based on available 3-dimensional structural information we identify a theoretical pharmacophoric model as a starting point for the development of needed carbapenemases inhibitors. PMID- 26424398 TI - B1-Metallo-beta-Lactamases: Where Do We Stand? AB - Metallo-beta-Lactamases (MBLs) are class Bbeta-lactamases that hydrolyze almost all clinically-availablebeta-lactam antibiotics. MBLs feature the distinctive alphabeta/betaalpha sandwich fold of the metallo-hydrolase/oxidoreductase superfamily and possess a shallow active-site groove containing one or two divalent zinc ions, flanked by flexible loops. According to sequence identity and zinc ion dependence, MBLs are classified into three subclasses (B1, B2 and B3), of which the B1 subclass enzymes have emerged as the most clinically significant. Differences among the active site architectures, the nature of zinc ligands, and the catalytic mechanisms have limited the development of a common inhibitor. In this review, we will describe the molecular epidemiology and structural studies of the most prominent representatives of class B1 MBLs (NDM-1, IMP-1 and VIM-2) and describe the implications for inhibitor design to counter this growing clinical threat. PMID- 26424402 TI - Targeting Receptor Tyrosine Kinases Using Monoclonal Antibodies: The Most Specific Tools for Targeted-Based Cancer Therapy. AB - Receptor tyrosine kinases (RTKs) family is comprised of different cell surface glycoproteins. These enzymes participate in and regulate vital processes such as cell proliferation, polarity, differentiation, cell to cell interactions, signaling, and cell survival. Dysregulation of RTKs contributes to the development of different types of tumors. RTKs deregulation in different types of cancer has been reported for more than 30 RTKs. Due to their critical roles, the specific targeting of RTKs in malignancies is a promising approach. Targeted cellular and molecular therapies (personalized medicine) have been known as new types of therapeutics, which prevent tumor cell proliferation and invasion by interfering with molecules essential for tumor growth and survival. Specific targeting of RTKs using monoclonal antibodies (mAbs) in malignancies as well as in autoimmune disorders is of great interest. The growing number of mAbs approved by the authorities implies on the increasing attentions and applications of these therapeutic tools. Due to the high specificity, mAbs are the most promising substances that target RTKs expressed on the tumor cell surface. In this communication, we review the recent progresses in the development of mAbs targeting oncogenic RTKs for cancer treatment. PMID- 26424403 TI - Efflux Pump Inhibitors: A Novel Approach to Combat Efflux-Mediated Drug Resistance in Bacteria. AB - The increasing multi-drug resistance has become a major threat to the public health. Overexpression of multidrug efflux pumps is one of the major mechanisms of drug resistance in bacteria. Since active efflux of antibacterial agents plays a significant role in mediating drug resistance in bacteria, the inhibition of efflux pumps appears to be a promising strategy to restore antibacterial potency. In recent years, in order to address this grave problem of multiple drug resistance mediated by efflux pump, a large number of efflux pump inhibitors have been discovered and tested, including natural products, antibiotics and synthetic molecules. This review mainly describes recent achievements in the search for new molecules that are able to inhibit efflux pumps in both Gram-positive and Gram negative bacteria, in particular emphasis on natural and synthetic inhibitors of the NorA efflux pump in Staphylococcus aureus, MexAB-OprM efflux pump in Pseudomonas aeruginosa, and AcrAB-TolC efflux pump in Enterobacteriaceae, giving special attention to their mechanisms of action, structure-activity relationships and synergetic effect with clinically available antibiotics. PMID- 26424405 TI - In Vivo Wear Performance of Cobalt-Chromium Versus Oxidized Zirconium Femoral Total Knee Replacements. AB - This study examines the damage and wear on the polyethylene (PE) inserts from 52 retrieved Genesis II total knee replacements to identify differences in tribological performance between matched pairs of cobalt-chromium (CoCr) and oxidized zirconium (OxZr) femoral components. Observer damage scoring and microcomputed tomography were used to quantify PE damage and wear, respectively. No significant differences were found between CoCr and OxZr groups in terms of PE insert damage, surface penetration, or wear. No severe damage such as cracking or delamination was noted on any of the 52 PE inserts. Observer damage scoring did not correlate with penetrative or volumetric PE wear. The more costly OxZr femoral component does not demonstrate clear tribological benefit over the standard CoCr component in the short term with this total knee replacement design. PMID- 26424404 TI - Genotypic distribution and hepatic fibrosis among HIV/HCV co-infected individuals in Southern China: a retrospective cross-sectional study. AB - BACKGROUND: End-stage liver disease and hepatocellular carcinoma due to hepatitis C virus (HCV) co-infection are increasingly common causes of death among HIV infected individuals. However, there are few clinical investigations of HIV/HCV co-infected individuals from low and middle-income nations. Here, we compare the epidemiology of HCV-infected and HIV/HCV co-infected individuals in Southern China and examine hepatic fibrosis scores in co-infected individuals. METHODS: We conducted a retrospective cross-sectional study of treatment-naive HIV/HCV co infected and HCV mono-infected subjects. Bivariate and multivariate models were used to examine the association between demographics and HCV genotype. Among co infected individuals, we also studied the relationship between fibrosis scores derived from non-invasive studies and HCV genotype. RESULTS: Data were collected from 175 HCV-infected individuals, including 89 (51 %) HIV/HCV co-infected individuals. HIV/HCV co-infection was correlated with intravenous drug use (AOR 46.25, p < 0.001) and not completing high school (AOR 17.39, p < 0.001) in a multivariate model. HIV/HCV co-infected individuals were more likely to be infected with HCV genotype 6a (p < 0.0001) or 3a (p < 0.023), whereas increased fibrosis (FIB-4 score) was associated with HCV genotype 3a infection (beta 2.18, p < 0.001). DISCUSSION: Our results suggest that intravenous drug use is driving HIV/HCV co-infection in Southern China. While additional studies are needed, HCV genotype 6a is more common and genotype 3a appears to be associated with more severe hepatic fibrosis in co-infected individuals. CONCLUSIONS: Future HIV/HCV co-infection research in China should focus on at risk populations, HCV testing uptake, and genotype-specific treatment. PMID- 26424406 TI - Total Synthesis of (-)-Isoschizogamine. AB - The total synthesis of (-)-isoschizogamine was accomplished, featuring the construction of the quaternary carbon center by the modified Johnson-Claisen rearrangement in basic media and the facile assembly of the key tetracyclic quinolone intermediate through a cascade cyclization. The characteristic cyclic aminal was constructed by late-stage C-H functionalization at the position adjacent to the lactam nitrogen using a combination of CrO3 and nBu4 NIO4 and subsequent Bi(OTf)3 -mediated cyclization. PMID- 26424407 TI - Clonal dynamics in a single AML case tracked for 9 years reveals the complexity of leukemia progression. AB - Most types of cancers are made up of heterogeneous mixtures of genetically distinct subclones. In particular, acute myeloid leukemia (AML) has been shown to undergo substantial clonal evolution over the course of the disease. AML tends to harbor fewer mutations than solid tumors, making it challenging to infer clonal structure. Here, we present a 9-year, whole-exome sequencing study of a single case at 12 time points, from the initial diagnosis until a fourth relapse, including 6 remission samples in between. To the best of our knowledge, it covers the longest time span of any data set of its kind. We used these time series data to track the hierarchy and order of variant acquisition, and subsequently analyzed the evolution of somatic variants to infer clonal structure. From this, we postulate the development and extinction of subclones, as well as their anticorrelated expansion via varying drug responses. In particular, we show that new subclones started appearing after the first complete remission. The presence and absence of different subclones during remission and relapses implies differing drug responses among subclones. Our study shows that time series analysis contrasting remission and relapse periods provides a much more comprehensive view of clonal structure and evolution. PMID- 26424408 TI - Determinants of hospital length of stay for people with serious mental illness in England and implications for payment systems: a regression analysis. AB - BACKGROUND: Serious mental illness (SMI), which encompasses a set of chronic conditions such as schizophrenia, bipolar disorder and other psychoses, accounts for 3.4 m (7 %) total bed days in the English NHS. The introduction of prospective payment to reimburse hospitals makes an understanding of the key drivers of length of stay (LOS) imperative. Existing evidence, based on mainly small scale and cross-sectional studies, is mixed. Our study is the first to use large-scale national routine data to track English hospitals' LOS for patients with a main diagnosis of SMI over time to examine the patient and local area factors influencing LOS and quantify the provider level effects to draw out the implications for payment systems. METHODS: We analysed variation in LOS for all SMI admissions to English hospitals from 2006 to 2010 using Hospital Episodes Statistics (HES). We considered patients with a LOS of up to 180 days and estimated Poisson regression models with hospital fixed effects, separately for admissions with one of three main diagnoses: schizophrenia; psychotic and schizoaffective disorder; and bipolar affective disorder. We analysed the independent contribution of potential determinants of LOS including clinical and socioeconomic characteristics of the patient, access to and quality of primary care, and local area characteristics. We examined the degree of unexplained variation in provider LOS. RESULTS: Most risk factors did not have a differential effect on LOS for different diagnostic sub-groups, however we did find some heterogeneity in the effects. Shorter LOS in the pooled model was associated with co-morbid substance or alcohol misuse (4 days), and personality disorder (8 days). Longer LOS was associated with older age (up to 19 days), black ethnicity (4 days), and formal detention (16 days). Gender was not a significant predictor. Patients who self-discharged had shorter LOS (20 days). No association was found between higher primary care quality and LOS. We found large differences between providers in unexplained variation in LOS. CONCLUSIONS: By identifying key determinants of LOS our results contribute to a better understanding of the implications of case-mix to ensure prospective payment systems reflect accurately the resource use within sub-groups of patients with SMI. PMID- 26424409 TI - Variation in the ribosome interacting loop of the Sec61alpha from Giardia lamblia. AB - The interaction between the ribosome and the endoplasmic reticulum-located Sec61 protein translocon is mediated through an arginine residue of Sec61alpha, which is conserved in all prokaryotic and eukaryotic orthologues characterized to date. Using in silico approaches we report that instead of arginine, this ribosome interaction function is most likely discharged by a lysine residue in the protist Giardia lamblia. This functional substitution of the R with a K in GlSec61alpha may have taken place to accommodate a G-rich rRNA. PMID- 26424410 TI - Active ghrelin and the postpartum. AB - Postpartum depression (PPD) occurs in 10-15 % of women. The appetite hormone ghrelin, which fluctuates during pregnancy, is associated with depression in nonpregnant samples. Here, we examine the association between PPD and active ghrelin from pregnancy to postpartum. We additionally examine whether ghrelin changes from pregnancy to postpartum and differs between breastfeeding and non breastfeeding women. Sixty women who participated in a survey examining PPD and had information in regard to ghrelin concentrations were included in the study. The Edinburgh Postnatal Depression Scale was used to assess symptoms of PPD. Raw ghrelin levels and ghrelin levels adjusted for creatinine were included as outcomes. Women screening positive for PPD at 12 weeks postpartum had higher pregnancy ghrelin concentrations. Ghrelin concentrations significantly decreased from pregnancy to 6 weeks postpartum and this change differed based on pregnancy depression status. Finally, ghrelin levels were lower in women who breastfed compared with women who were bottle-feeding. No significant findings remained once ghrelin levels were adjusted for creatinine. Although results do not suggest an association between PPD and ghrelin after adjusting for creatinine, future research should continue to explore this possibility extending further across the postpartum period with larger sample sizes. PMID- 26424411 TI - Prediction of biochemical recurrence after radical prostatectomy. New tool for selecting candidates for adjuvant radiation therapy. AB - OBJECTIVE: To design a risk summation to select patients for adjuvant radiation therapy after prostatectomy. MATERIALS AND METHOD: A retrospective study was conducted on 629 patients with localised prostate cancer (pN0-pNx) who were treated with prostatectomy and with a prostate-specific antigen (PSA) value <0.2ng/mL at 2-3 months. Biochemical recurrence was defined as a PSA >0.4ng/mL. A multivariate Cox regression analysis was performed. A score (0-2) was assigned according to the hazard ratio of the significant variables. The score summation defined the risk summation. RESULTS: A total of 19.7% of the patients were pT3, 24.2% had a Gleason score >= 8, and 26.3% had positive surgical margins. The median follow-up was 82 months. Some 26.6% of the patients experienced biochemical recurrence. The identified prognostic variables independent of biochemical recurrence were a Gleason score =7 (4+3) (HR, 2.01; P=.008), a Gleason score >= 8 (HR, 3.07; P <.001), a pT3b stage (HR, 1.93; p=.008) and a positive surgical margin (HR, 2.20; P<.001). We assigned 0 points to patients without risk prognosis variables; 1 point to patients with Gleason scores =7 (4+3), pT3b or positive surgical margins; and 2 points to patients with Gleason scores >= 8. The patients with a risk summation <= 2 had >50% survival free of biochemical recurrence at 5 and 8 years. In contrast, the patients with a risk summation >= 3 had <44% survival free of biochemical recurrence. CONCLUSION: The patients with a risk summation <= 2 did not benefit from adjuvant radiation therapy, while the patients with a risk summation >= 3 might benefit from adjuvant radiation therapy. PMID- 26424413 TI - p53 Mutants Access Epigenetic Pathways to Promote Tumor Growth. AB - Mutations in p53 cause cancer cell growth by upregulating chromatin-modifying enzymes. PMID- 26424414 TI - High-Affinity PD-1 Protein Has Potential. AB - A small, engineered protein that selectively binds to PD-L1 with very high affinity was more effective in shrinking tumors in preclinical studies than existing antibody-based immune checkpoint inhibitors, and it may overcome some the drawbacks of these agents, according to data presented at the CRI-CIMT-EATI AACR International Cancer Immunotherapy Conference. PMID- 26424412 TI - Conceptualizing the neurobiology of non-suicidal self-injury from the perspective of the Research Domain Criteria Project. AB - Non-suicidal self-injury (NSSI) commonly starts in adolescence and is associated with an array of negative outcomes. Neurobiological research investigating NSSI is in its early stages and most studies have examined this behavior within the context of specific diagnoses. However, the Research Domain Criteria (RDoC) initiative encourages researchers to examine brain-behavior relationships across diagnoses. This review on the neurobiology associated with NSSI is organized using the domains proposed by RDoC: Negative Valence, Positive Valence, Cognitive, Social Processes, and Arousal/Regulatory Systems. Evidence of neurobiological anomalies is found in each of these domains. We also propose future research directions, especially in regard to human development. Future NSSI studies should address this behavior independent of diagnosis, examine relevant constructs across multiple units of analysis, and assess how systems change across development and course of illness. These advances will be essential for guiding neurobiologically informed intervention and prevention strategies to target NSSI. In doing so, we may prevent the associated negative outcomes across the lifespan. PMID- 26424415 TI - Avoiding the Personhood Issue: Abortion, Identity, and Marquis's 'Future-Like Ours' Argument. AB - One reason for the persistent appeal of Don Marquis' 'future like ours' argument (FLO) is that it seems to offer a way to approach the debate about the morality of abortion while sidestepping the difficult task of establishing whether the fetus is a person. This essay argues that in order to satisfactorily address both of the chief objections to FLO - the 'identity objection' and the 'contraception objection' - Marquis must take a controversial stand on what is most essential to being the kind of entity that an adult human being is. Such a stand amounts to a controversial account of personhood. To the extent that FLO's success depends on accepting such a controversial metaphysical view, one apparent attraction of FLO proves illusory. PMID- 26424418 TI - Do common genotypes of FK506 binding protein 5 (FKBP5) moderate the effects of childhood maltreatment on cognition in schizophrenia and healthy controls? AB - Common variants of the FK506 binding protein 5 (FKBP5) gene are implicated in psychotic and other disorders, via their role in regulating glucocorticoid receptor (GR) receptor sensitivity and effects on the broader function of the HPA system in response to stress. In this study, the effects of four FKBP5 polymorphisms (rs1360780, rs9470080, rs4713902, rs9394309) on IQ and eight other cognitive domains were examined in the context of exposure to childhood maltreatment in 444 cases with schizophrenia and 292 healthy controls (from a total sample of 617 cases and 659 controls obtained from the Australian Schizophrenia Research Bank; ASRB). Participants subjected to any kind of maltreatment (including physical, emotional, or sexual abuse or physical or emotional neglect) in childhood were classified as 'exposed'; cognitive functioning was measured with Repeatable Battery for the Assessment of Neuropsychological Status, the Controlled Oral Word Association Test, and IQ was estimated with the Weschler Test of Adult Reading. Hierarchical regressions were used to test the main effects of genotype and childhood maltreatment, and their additive interactive effects, on cognitive function. For rs1360870, there were significant main effects of genotype and childhood maltreatment, and a significant interaction of genotype with childhood trauma affecting attention in both schizophrenia and healthy participants (C-homozygotes in both groups showed worse attention in the context of maltreatment); in SZ, this SNP also affected global neuropsychological function regardless of exposure to childhood trauma, with T-homozygotes showing worse cognition than other genotypes. The mechanisms of trauma-dependent effects of FKBP5 following early life trauma deserve further exploration in healthy and psychotic samples, in the context of epigenetic effects and perhaps epistasis with other genes. Study of these processes may be particularly informative in subgroups exposed to various other forms of early life adversity (i.e., birth complications, immigration). PMID- 26424417 TI - Mood dysregulation and affective instability in emerging adults with childhood maltreatment: An ecological momentary assessment study. AB - Childhood maltreatment increases risk for mood, anxiety, substance use and personality disorders and is associated with alterations in structure, function and connectivity of brain regions involved in emotional regulation. We sought to assess whether maltreatment was specifically associated with disturbances in positive or negative mood regulation. Ecological momentary ratings were collected with a wristwatch-like device with joy-stick (Seiko ecolog) approximately six times per day over a week in 60 unmedicated participants (22 control, 38 maltreated, 18-25 years old). Forty-five percent of maltreated subjects had a history of major depression but all were currently euthymic. Principal component analysis with varimax rotation was used to provide orthogonal measures of positive and negative valence, which were analyzed for indices of variability, circadian rhythmicity and persistence, using linear and non-linear hierarchical modeling and Hurst analysis. Groups did not differ in mean levels of positive or negative affect. Maltreated subjects had increased variability and circadian and hemicircadian abnormalities in ratings of positive but not negative affect. Conversely, they had higher estimated Hurst exponents for negative but not positive affect ratings indicating a greater degree of persistence. Abnormalities in variability, rhythmicity and persistence were present in both maltreated subjects with and without histories of major depression. These findings suggest that both positive and negative valence systems may be dysregulated in individuals with childhood maltreatment. However the nature of the dysregulation appears to differ fundamentally in these domains, as positive mood ratings were more variable and negative ratings more persistent. PMID- 26424416 TI - Low unesterified:esterified eicosapentaenoic acid (EPA) plasma concentration ratio is associated with bipolar disorder episodes, and omega-3 plasma concentrations are altered by treatment. AB - OBJECTIVES: Omega (n)-3 and n-6 polyunsaturated fatty acids (PUFAs) are molecular modulators of neurotransmission and inflammation. We hypothesized that plasma concentrations of n-3 PUFAs would be lower and those of n-6 PUFAs higher in subjects with bipolar disorder (BD) compared to healthy controls (HCs), and would correlate with symptom severity in subjects with BD, and that effective treatment would correlate with increased n-3 but lower n-6 PUFA levels. Additionally, we explored clinical correlations and group differences in plasma levels of saturated and monounsaturated fatty acids. METHODS: This observational, parallel group study compared biomarkers between HCs (n = 31) and symptomatic subjects with BD (n = 27) when ill and after symptomatic recovery (follow-up). Plasma concentrations of five PUFAs [linoleic acid (LA), arachidonic acid (AA), alpha linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA)], two saturated fatty acids (palmitic acid and stearic acid) and two monounsaturated fatty acids (palmitoleic acid and oleic acid) were measured in esterified (E) and unesterified (UE) forms. Calculated ratios included UE:E for the five PUFAs, ratios of n-3 PUFAs (DHA:ALA, EPA:ALA and EPA:DHA), and the ratio of n-6:n-3 AA:EPA. Comparisons of plasma fatty acid levels and ratios between BD and HC groups were made with Student t-tests, and between the BD group at baseline and follow-up using paired t-tests. Comparison of categorical variables was performed using chi-square tests. Pearson's r was used for bivariate correlations with clinical variables, including depressive and manic symptoms, current panic attacks, and psychosis. RESULTS: UE EPA was lower in subjects with BD than in HCs, with a large effect size (Cohen's d = 0.86, p < 0.002); however, it was not statistically significant after correction for multiple comparisons. No statistically significant difference was seen in any plasma PUFA concentration between the BD and HC groups after Bonferroni correction for 40 comparisons, at p < 0.001. Neither depressive severity nor mania severity was correlated significantly with any PUFA concentration. Exploratory comparison showed lower UE:E EPA in the BD than the HC group (p < 0.0001). At follow-up in the BD group, UE, E DHA:ALA, and UE EPA:ALA were decreased (p < 0.002). Exploratory correlations of clinical variables revealed that mania severity and suicidality were positively correlated with UE:E EPA ratio, and that several plasma levels and ratios correlated with panic disorder and psychosis. Depressive severity was not correlated with any ratio. No plasma fatty acid level or ratio correlated with self-reported n-3 PUFA intake or use of medication by class. CONCLUSIONS: A large effect size of reduced UE EPA, and a lower plasma UE:E concentration ratio of EPA in the symptomatic BD state may be important factors in vulnerability to a mood state. Altered n-3 PUFA ratios could indicate changes in PUFA metabolism concurrent with symptom improvement. Our findings are consistent with preclinical and postmortem data and suggest testing interventions that increase n-3 and decrease n-6 dietary PUFA intake. PMID- 26424419 TI - Dysregulation of the NF-kappaB pathway as a potential inducer of bipolar disorder. AB - A century of investigations enhanced our understanding of bipolar disorder although it remains a complex multifactorial disorder with a mostly unknown pathophysiology and etiology. The role of the immune system in this disorder is one of the most controversial topics in genetic psychiatry. Though inflammation has been consistently reported in bipolar patients, it remains unclear how the immunologic process influences the disorder. One of the core components of the immune system is the NF-kappaB pathway, which plays an essential role in the development of innate and adaptive immunity. Remarkably, the NF-kappaB pathway received only little attention in bipolar studies, as opposed to studies of related psychiatric disorders where immune dysregulation has been proposed to explain the neurodegeneration in patient conditions. If immune dysregulation can also explains the neurodegeneration in bipolar disorder, it will underscore the role of the immune system in the chronicity and pathophysiology of the disorder and may promote personalized therapeutic strategies. This is the first review to summarize the current knowledge of the pathophysiological functions of NF-kappaB in bipolar disorder. PMID- 26424420 TI - The exclusion of people with psychiatric disorders from medical research. AB - People with psychiatric disorders are excluded from medical research to an unknown degree with unknown effects. We examined the prevalence of reported psychiatric exclusion criteria using a sample of 400 highly-cited randomized trials (2002-2010) across 20 common chronic disorders (6 psychiatric and 14 other medical disorders). Two coders rated the presence of psychiatric exclusion criteria for each trial. Half of all trials (and 84% of psychiatric disorder treatment trials) reported possible or definite psychiatric exclusion criteria, with significant variation across disorders (p < .001). Non-psychiatric conditions with high rates of reported psychiatric exclusion criteria included low back pain (75%), osteoarthritis (57%), COPD (55%), and diabetes (55%). The most commonly reported type of psychiatric exclusion criteria were those related to substance use disorders (reported in 48% of trials reporting at least one psychiatric exclusion criteria). General psychiatric exclusions (e.g., "any serious psychiatric disorder") were also prevalent (38% of trials). Psychiatric disorder trials were more likely than other medical disorder trials to report each specific type of psychiatric exclusion (p's < .001). Because published clinical trial reports do not always fully describe exclusion criteria, this study's estimates of the prevalence of psychiatric exclusion criteria are conservative. Clinical trials greatly influence state-of-the-art medical care, yet individuals with psychiatric disorders are often actively excluded from these trials. This pattern of exclusion represents an under-recognized and worrisome cause of health inequity. Further attention should be paid to how individuals with psychiatric disorders can be safely included in medical research to address this important clinical and social justice issue. PMID- 26424421 TI - De novo cost-utility analysis of oral paliperidone in the treatment of schizoaffective disorder. AB - OBJECTIVES: The aim of this analysis is to compare costs and effectiveness of paliperidone ER vs. placebo in the treatment of schizoaffective disorder (SAD) in the Czech Republic based on pooled clinical trial data. METHODS: A de novo micro simulation model was developed to assess the cost-utility analysis of paliperidone vs. placebo as there is lack of clinical data comparing paliperidone to other interventions. There are no studies primarily evaluating the efficacy of treatment of SAD with other antipsychotics. The model estimated effectiveness and costs of patients with SAD every week during 24-week time horizon. The effectiveness was defined as improvement of a patient's PANSS score where utilities were assigned to each modelled PANSS score. Based on the patient level data a linear mixed-effects model was used to estimate the regression equations of percentage decrease of PANSS score from the baseline. Utilities were computed using a regression function of patients' age, sex and PANSS score, which was adapted from a clinical study of patients with schizophrenia as there are no QoL data on SAD patients. Among relevant costs, reflecting the payer's perspective, costs of pharmacotherapy, concomitant medications and outpatient care were considered. RESULTS: The average ICER of paliperidone compared to placebo reached 28,935 EUR/QALY. The probability of paliperidone being cost-effective compared to placebo was 99.5%. CONCLUSIONS: Treatment of SAD with paliperidone results in acceptable ICER and high probability of being cost-effective compared to placebo. Thus, it can be considered as a cost-effective treatment of patients with SAD in the Czech Republic. PMID- 26424422 TI - The relationship between cortisol, stress and psychiatric illness: New insights using hair analysis. AB - BACKGROUND: Stress is an established important contributor to the development of mental illness and stress related disorders. The biology implicated in the homeostasis of pathological stress mechanisms is not fully established. One of the difficulties with current techniques is the limitation in capturing chronic levels of cortisol as an expression of stress levels in humans. Hair samples can be used to evaluate cortisol levels averaged over relatively long periods of time, therefore providing a more valid measure of chronic levels of this hormone. A highly replicable technique to measure long-term cortisol could prove pivotal in improving our understanding of the role of stress in psychiatric disorders. METHODS: This review synthesises all the published studies relating hair cortisol concentration (HCC) to stress and to psychiatric disorders. It describes and summarises their findings with the aim of providing a summary picture of the current state of this line of research. RESULTS: The strongest finding to date is the replicable increases in hair cortisol associated with stressful life events. Findings in psychiatric disorders are more sparse and inconsistent. There is some support for the presence of raised HCC in major depressive disorders, and for lowered HCC in posttraumatic stress disorder, suggesting chronic hypercortisolaemia and hypocortisolaemia respectively. CONCLUSIONS: HCC is a promising methodology to study chronic cortisol levels with the potential to help characterise psychiatric and stress related disorders. The combination of chronic and acute cortisol measurements has the potential for more accurately determining different aspects of the stress response, and ultimately for the development of a biological marker to aid diagnosis and response to treatment. PMID- 26424423 TI - Effect of tyrosine supplementation on clinical and healthy populations under stress or cognitive demands--A review. AB - Consuming the amino-acid tyrosine (TYR), the precursor of dopamine (DA) and norepinephrine (NE), may counteract decrements in neurotransmitter function and cognitive performance. However, reports on the effectiveness of TYR supplementation vary considerably, with some studies finding beneficial effects, whereas others do not. Here we review the available cognitive/behavioral studies on TYR, to elucidate whether and when TYR supplementation can be beneficial for performance. The potential of using TYR supplementation to treat clinical disorders seems limited and its benefits are likely determined by the presence and extent of impaired neurotransmitter function and synthesis. Likewise, the potential of TYR supplementation for enhancing physical exercise seems minimal as well, perhaps because the link between physical exercise and catecholamine function is mediated by many other factors. In contrast, TYR does seem to effectively enhance cognitive performance, particularly in short-term stressful and/or cognitively demanding situations. We conclude that TYR is an effective enhancer of cognition, but only when neurotransmitter function is intact and DA and/or NE is temporarily depleted. PMID- 26424425 TI - Prevalence of postpartum depression among immigrant women: A systematic review and meta-analysis. AB - The aims of this systematic review and meta-analysis were threefold: to estimate the prevalence of postpartum depressive symptoms in immigrant women, compare this prevalence to non-immigrant women, and determine risk factors for postpartum depressive symptoms in immigrant women. Literature searches were conducted in PubMed, Embase, PsycINFO, Web of Science, Scopus, ResearchGate and Google Scholar databases from 1950 until October 2014. Twenty-four studies met the inclusion criteria of which 22 (12 cross-sectional and 10 prospective cohort) contributed data for meta-analyses. Heterogeneity and publication bias were assessed. The prevalence of postpartum depressive symptoms in immigrant women was 20% (95% confidence interval [CI] 17-23%, 18 studies, N = 13,749 women). Immigrant women were twice more likely to experience depressive symptoms in the postpartum period than non-immigrant women (pooled unadjusted odds ratio [OR] = 2.10 [95% CI 1.62 2.73, 15 studies, N = 50,519 women] and adjusted OR = 2.18 [95% CI 1.60-2.96, 7 studies, N = 35,557 women]). There was, however, evidence of publication bias with the pooled adjusted OR reduced to 1.63 (95% CI 1.22-2.17) after adjustment for bias. Risk factors associated with postpartum depressive symptoms among immigrant women included shorter length of residence in the destination country, lower levels of social support, poorer marital adjustment, and perceived insufficient household income. This study suggests that postpartum depression is a common condition among immigrant women. Moreover, immigrant women are at higher risk of postpartum depression than non-immigrant women. Further prospective studies on the risk factors of postpartum depression among immigrant women verified by a clinical diagnosis are needed. PMID- 26424424 TI - Burning odor-elicited anxiety in OEF/OIF combat veterans: Inverse relationship to gray matter volume in olfactory cortex. AB - Despite the anatomical overlap between the brain's fear/threat and olfactory systems, a very limited number of investigations have considered the role of odors and the central olfactory system in the pathophysiology of PTSD. The goal of the present study was to assess structural differences in primary and secondary olfactory cortex between combat veterans with and without PTSD (CV + PTSD, CV-PTSD, respectively). An additional goal was to determine the relationship between gray matter volume (GMV) in olfactory cortex and the distressing properties of burning-related odors. A region of interest voxel-based morphometric (VBM) approach was used to measure GMV in olfactory cortex in a well characterized group of CV + PTSD (n = 20) and CV-PTSD (n = 25). Prior to the MRI exam, combat-related (i.e., burning rubber) and control odors were systematically sampled and rated according to their potential for eliciting PTSD symptoms. Results showed that CV + PTSD exhibited significantly reduced GMV in anterior piriform (primary olfactory) and orbitofrontal (secondary olfactory) cortices compared to CV-PTSD (both p < .01). For the entire group, GMV in bilateral anterior piriform cortex was inversely related to burning rubber odor-elicited memories of trauma (p < .05). GMV in orbitofrontal cortex was inversely related to both clinical and laboratory measures of PTSD symptoms (all p < .05). In addition to replicating an established inverse relationship between GMV in anxiety-associated brain structures and PTSD symptomatology, the present study extends those findings by being the first report of volumetric decreases in olfactory cortex that are inversely related to odor-elicited PTSD symptoms. Potential mechanisms underlying these findings are discussed. PMID- 26424426 TI - Interacting effects of maternal responsiveness, infant regulatory problems and dopamine D4 receptor gene in the development of dysregulation during childhood: A longitudinal analysis. AB - Recent longitudinal studies have indicated that affective and behavioral dysregulation in childhood is associated with an increased risk for various negative outcomes in later life. However, few studies to date have examined early mechanisms preceding dysregulation during early childhood. Aim of this study was to elucidate early mechanisms relating to dysregulation in later life using data from an epidemiological cohort study on the long-term outcome of early risk factors from birth to adulthood. At age 3 months, mothers and infants were videotaped during a nursing and playing situation. Maternal responsiveness was evaluated by trained raters. Infant regulatory problems were assessed on the basis of a parent interview and direct observation by trained raters. At age 8 and 11 years, 290 children (139 males) were rated on the Child Behavior Checklist (CBCL). Additionally, participants were genotyped for the dopamine D4 receptor (DRD4) exon 3 VNTR polymorphism. A significant three-way interaction between maternal responsiveness, DRD4 genotype and infant regulatory problems was detected predicting the CBCL-dysregulation profile (CBCL-DP). Carriers of the DRD4 7r allele with regulatory problems at age 3 months showed significantly more behavior problems associated with the CBCL-DP during childhood when exposed to less maternal responsiveness. In contrast, no effect of maternal responsiveness was observed in DRD4 7r carriers without infant regulatory problems and in non carriers of the DRD4 7r allele. This prospective longitudinal study extends earlier findings regarding the association of the CBCL-DP with early parenting and later psychopathology, introducing both DRD4 genotype and infant regulatory problems as important moderators. PMID- 26424428 TI - Efficacy and safety of a form of cranial electrical stimulation (CES) as an add on intervention for treatment-resistant major depressive disorder: A three week double blind pilot study. AB - We examined efficacy and safety of one specific cranial electrical stimulator (CES) device at a fixed setting in subjects with treatment-resistant major depressive disorder (MDD). Thirty subjects (57% female, mean age 48.1 +/- 12.3 years) with MDD and inadequate response to standard antidepressants were randomized to 3 weeks of treatment with CES (15/500/15,000 Hz, symmetrical rectangular biphasic current of 1-4 mAmp, 40 V) or sham CES (device off) for 20 min, 5 days per week. The primary outcome measure was improvement in the 17-item Hamilton Depression Rating Scale (HAM-D-17). Adverse effects (AEs) were assessed using the Patient Related Inventory of Side Effects (PRISE). Completion rates were 88% for CES, 100% for sham. Both treatment groups demonstrated improvement of about 3-5 points in HAM-D-17 scores (p < 0.05 for both), and no significant differences were observed between groups. Remission rates were 12% for CES, and 15% for sham, a nonsignificant difference. CES was deemed safe, with good tolerability; poor concentration and malaise were the only distressing AEs that differed significantly between CES and sham (p = 0.019 and p = 0.043, respectively). Limitations include a small sample and lack of an active comparator therapy. Although both treatment groups improved significantly, this CES at the setting chosen did not separate from sham in this sample. Thus we cannot rule out that the benefit from this setting used in this particular form of CES was due to placebo effects. Since this form of CES has other settings, future studies should test these settings and compare it against other CES devices. Clinicaltrials.gov ID: NCT01325532. PMID- 26424427 TI - The pro-inflammatory profile of depressed patients is (partly) related to obesity. AB - Many people with major depressive disorder (MDD) show evidence of systemic inflammation, including elevations in inflammatory factors, but the cause is unclear. The purpose of this analysis was to determine if obesity might contribute to the pro-inflammatory state in MDD patients. Blood was obtained from 135 MDD patients and 50 controls. Serum was extracted and assayed for interleukin (IL) -1beta, IL-2, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, interferon-gamma (IFNgamma), tumor necrosis factor alpha (TNFalpha), C-reactive protein (CRP), leptin, and adiponectin using single- or multi-plex human immunoassay kits. The primary analysis contrasted IL-6, TNFalpha, and CRP between MDD and control groups with body mass index (BMI) as a covariate. The other analytes were compared in an exploratory fashion. IL-6 (but not TNFalpha or CRP) showed significant differences between MDD and controls even after covarying for BMI. Obese controls and obese MDD groups were significantly higher in IL-6 than both lean groups, but the two obese groups did not differ from each other. In the exploratory analyses, the IL-2 level showed robust and significant differences between MDD and controls even after covarying for BMI. Both lean and obese MDD were higher than lean and obese controls. Adiponectin levels were also lower in the MDD sample than controls. Prior findings of higher IL-6, and CRP in MDD patients may be explained, at least in part, based on obesity. High IL-2, however, was associated with depression and not obesity. The results have significant implications for the understanding of pathophysiology and, potentially treatment of MDD. PMID- 26424429 TI - Comparing cognitive functions in medication adherent and non-adherent patients with schizophrenia. AB - BACKGROUND: Medication non-adherence presents a considerable problem in patients with schizophrenia. Cognitive and executive functions can affect adherence. The association between medication non-adherence and cognitive impairment in schizophrenia is under investigated with limited and conflicting research data. PURPOSE OF THE STUDY: To prospectively assess the rate of drug adherence among a sample of patients with schizophrenia and to compare the cognitive and executive functions between adherent and non-adherent patients. SUBJECTS AND METHODS: 109 patients with schizophrenia diagnosed according to the DSM-IV classification were initially assessed by the Wechsler Adult Intelligence Scale (WAIS), Wechsler Memory Scale-Revised (WMS-R) and Wisconsin Card Sorting Test (WCST) and six months later by the Brief Adherence Rating Scale (BARS). RESULTS: 68.8% were non adherent to their antipsychotic medication. Adherent patients (31.2%) had significantly higher mean scores for the total, verbal and performance IQ. They had significantly higher mean scores in most of WMS subtests (orientation, information, verbal paired association, digit span, visual memory span), and higher mean scores for; total correct, conceptual level response, percentage and categories completed on the WSCT subscales (P < 0.0001). Whereas the non-adherent group had higher mean scores in; trials administered, total errors, perseverative responses, and perseverative errors (P < 0.0001). In a step regression analysis, digit span, conceptualization, total and percentage of errors were putative predictors of non-adherence. CONCLUSION: Cognitive deficits, especially verbal memory and executive functions were the strongest patients' related factors associated with non adherence to medication. Psychiatrists ought to consider possible cognitive factors influencing adherence to enable offering proper interventions. PMID- 26424430 TI - The emerging field of retinal electrophysiological measurements in psychiatric research: A review of the findings and the perspectives in major depressive disorder. AB - Major depressive disorder (MDD) is a severe mental illness leading to long-term disabilities. One of the current challenges in psychiatric research is to develop new approaches to investigate the pathophysiology of MDD and monitor drug response in order to provide better therapeutic strategies to the patients. Since the retina is considered as part of the central nervous system, it was suggested that it constitutes an appropriate site to investigate mental illnesses. In the past years, several teams assessed the retinal function of patients with mood disorders and many relevant abnormalities have been reported. Investigation of the retinal electrophysiological abnormalities in MDD remains a young emerging field, but we believe that the current findings are very promising and we argue that objective retinal electrophysiological measurements may eventually become relevant tools to investigate the pathophysiology of MDD. Here, we review the retinal abnormalities detected with objective electrophysiological measurements such as the flash electroretinogram (fERG), the pattern electroretinogram (PERG) and the electrooculogram (EOG) in patients with MDD. We discuss how these changes might reflect the pathophysiology of MDD in both clinical and scientific points of view, according especially to the monoamine neurotransmission deficiency hypothesis. We also discuss the technical details that must be taken into consideration for a potential use of the objective retinal electrophysiological measurements as tools to investigate the pathophysiology of MDD. PMID- 26424431 TI - Amygdala network dysfunction in late-life depression phenotypes: Relationships with symptom dimensions. AB - The amygdala, a crucial hub of the emotional processing neural system, has been implicated in late-life depression (LLD) pathophysiology. However, the overlapping and diverging amygdala network function abnormalities underlying two clinical LLD phenotypes (i.e., LLD alone and LLD with mild cognitive impairment [LLD-MCI]) are unknown. The aim of this study is to investigate the amygdala functional connectivity (FC) differences between LLD alone, LLD-MCI and healthy controls, and to examine the relationships between amygdala network dysfunction and symptom dimensions. A resting-state functional connectivity magnetic resonance imaging study was conducted to probe amygdala FC in a total of 63 elderly participants (LLD [n = 22], LLD-MCI [n = 15], and age- and gender-equated healthy older adults [n = 26]) using a seed-based voxelwise R-fcMRI approach. LLD only adults showed increased FC in the posterior default mode and vermis, and diminished connections in the fronto-parietal, salience and temporal areas, relative to controls. The LLD-MCI participants showed diminished FC in the default mode, cognitive control, salience and visual regions, whereas increased FC was limited to lateral parietal cortex compared with healthy controls. The LLD MCI group also showed diminished FC in the occipital and posterior default mode areas, relative to the LLD-only group. Distinct amygdala FC abnormalities that explain depressive and anxiety symptom severity, and executive functioning were identified. The amygdala FC impairments may distinguish LLD phenotypes. These functional network abnormalities may also explain the heterogeneity seen in the LLD clinical presentations. PMID- 26424432 TI - Childhood trauma as a risk factor for psychosis: A sib-pair study. AB - BACKGROUND: Childhood trauma, cannabis use and certain personality traits have been related to the development of psychosis. This study uses a sib-pair design to examine the association between childhood trauma and psychosis controlling for cannabis use and neuroticism. METHODS: We evaluated 60 patient-sibling pairs, conformed by patients with functional psychosis in the first five years of their illness matched with a non-psychotic sibling. In univariate analyses, patients and siblings were compared with McNemar tests and paired-sample t tests. A conditional logistic regression model of the risk of developing psychosis was built. The dependent variable of this model was the patient-sibling status (patient = 1, sibling = 0). RESULTS: After controlling for cannabis use and neuroticism, the odds of suffering psychosis for subjects who experienced a childhood trauma were 7.3 times higher than the odds for subjects who did not experience a childhood trauma [95% CI, (1.06-50.01); P = 0.04]. Also, after controlling for experiencing childhood trauma and neuroticism, subjects who were heavy cannabis users had odds of suffering psychosis that were 6.4 times higher than the odds of the remaining subjects [95% CI, (1.2-35.2); P = 0.03]. CONCLUSION: Both childhood trauma and cannabis use were significantly associated with an increased risk of suffering functional psychosis. A neurotic personality also contributed independently to this risk. These findings might help improve the prevention of psychosis and the development of specific treatment strategies on this specific population. PMID- 26424433 TI - Serum B cell-activating factor (BAFF) level in connective tissue disease associated interstitial lung disease. AB - BACKGROUND: Interstitial lung diseases (ILDs) are common in patients with connective tissue diseases (CTDs). Although the diagnosis of an underlying CTD in ILD (CTD-ILD) affects both prognosis and treatment, it is sometimes difficult to distinguish CTD-ILD from chronic fibrosing interstitial pneumonia (CFIP). B cell activating factor belonging to the tumour necrosis factor family (BAFF) plays a crucial role in B cell development, survival, and antibody production. METHODS: We examined serum levels of BAFF, surfactant protein D (SP-D), and Krebs von den Lungen-6 (KL-6) in 33 patients with CTD-ILD, 16 patients with undifferentiated CTD-ILD, 19 patients with CFIP, and 26 healthy volunteers. And we analysed the relationship between serum BAFF levels and pulmonary function, as well as the expression of BAFF in the lung tissue of patients with CTD-ILD. RESULTS: Serum levels of BAFF were significantly higher in CTD-ILD patients compared to healthy subjects and CFIP patients. However, there were no significant differences in serum levels of SP-D and KL-6. Furthermore, serum BAFF levels in CTD-ILD patients were inversely correlated with pulmonary function. BAFF was strongly expressed in the lungs of CTD-ILD patients, but weakly in normal lungs. DISCUSSION: This is the first study to demonstrate that serum BAFF levels were significantly higher in CTD-ILD patients compared to healthy subjects and CFIP patients. Furthermore, serum BAFF levels were correlated with pulmonary function. We consider that serum BAFF levels in patients with CTD-ILD reflect the presence of ILDs disease activity and severity. CONCLUSION: These finding suggest that BAFF may be a useful marker for distinguishing CTD-ILD from CFIP. PMID- 26424434 TI - Similarities and Contrasts in the Archaeal Community of Two Japanese Mountains: Mt. Norikura Compared to Mt. Fuji. AB - The community ecology, abundance, and diversity patterns of soil archaea are poorly understood-despite the fact that they are a major branch of life that is ubiquitous and important in nitrogen cycling in terrestrial ecosystems. We set out to investigate the elevational patterns of archaeal ecology, and how these compare with other groups of organisms. Many studies of different groups of organisms (plants, birds, etc.) have shown a series of distinct communities with elevation, and often a diversity maximum in mid-elevations. We investigated the soil archaeal communities on Mt. Norikura, Japan, using 454 pyrosequencing of the 16S ribosomal RNA (rRNA) gene. There was a strong mid-elevation maximum in diversity, and a mid-elevation maximum in abundance of soil archaea 16S rRNA and amoA genes. These diversity and abundance maximums could not be correlated with any identifiable soil parameter, nor plant diversity. Discrete, predictable communities of archaea occurred at each elevational level, also not explicable in terms of pH or major nutrients. When we compared the archaeal community and diversity patterns with those found in an earlier study of Mt Fuji, both mountains showed mid-elevation maximums in diversity and abundance of archaea, possibly a result of some common environmental factor such as soil disturbance frequency. However, they showed distinct sets of archaeal communities at similar elevational sampling points. Presumably, the difference reflects their distinct geology (Norikura being andesitic, while Fuji is basaltic) and the resulting combinations of soil chemistry and environmental conditions, although no explanatory variable was found. Clearly, many soil archaea have strongly defined niches and will only occur in a narrow subset of the range of possible climate and soil conditions. The findings of a mid-elevation diversity maximum on Norikura provides a further instance of how widespread this unexplained pattern is in nature, in a wide variety of groups of organisms. PMID- 26424435 TI - Drug-induced systemic lupus erythematosus in a child after 3 years of treatment with carbamazepine. AB - Drug-induced lupus erythematosus (DILE) is a less severe variant of systemic lupus erythematosus (SLE) that generally resolves within weeks or months after the withdrawal of the implicated drug. DILE is unusual during childhood, with the most frequent age of presentation being at 50-70 years of age. Among different drugs, most commonly procainamide and hydralazine have been implicated as a cause of DILE. However carbamazepine (CBZ) is considered a low-risk drug and very few cases have been reported in children. We describe the case of CBZ-induced SLE in a 9-year-old girl following 3 years of CBZ therapy. This case report shows that drug-induced SLE is an important side-effect to be considered, even after long term treatment with CBZ, and also during childhood. PMID- 26424437 TI - The Basic Empathy Scale adapted to French middle childhood: Structure and development of empathy. AB - We adapted the adult French version of the Basic Empathy Scale to French children aged 6-11 years, in order to probe the factorial structure underlying empathy. A total of 410 children (189 girls and 221 boys) were instructed to fill out the resulting Basic Empathy Scale in Children (BES-C). Results showed that, as in adulthood, the three-factor model of empathy (i.e., emotional contagion, cognitive empathy, and emotional disconnection) was more relevant than the one- and two-factor ones. This means that as early as 6 years of age, children's responses should reflect the same organization of the three components of empathy as those of adults. In line with the literature, cognitive empathy increased and emotional disconnection decreased in middle childhood, while emotional contagion remained stable. Moreover, girls exhibited greater emotional contagion than boys, with the reverse pattern being observed for emotional disconnection. No sex difference was found regarding cognitive empathy. PMID- 26424439 TI - Erratum to: Efficient simulation of diffusion-based choice RT models on CPU and GPU. PMID- 26424438 TI - The Novel Object and Unusual Name (NOUN) Database: A collection of novel images for use in experimental research. AB - Many experimental research designs require images of novel objects. Here we introduce the Novel Object and Unusual Name (NOUN) Database. This database contains 64 primary novel object images and additional novel exemplars for ten basic- and nine global-level object categories. The objects' novelty was confirmed by both self-report and a lack of consensus on questions that required participants to name and identify the objects. We also found that object novelty correlated with qualifying naming responses pertaining to the objects' colors. The results from a similarity sorting task (and a subsequent multidimensional scaling analysis on the similarity ratings) demonstrated that the objects are complex and distinct entities that vary along several featural dimensions beyond simply shape and color. A final experiment confirmed that additional item exemplars comprised both sub- and superordinate categories. These images may be useful in a variety of settings, particularly for developmental psychology and other research in the language, categorization, perception, visual memory, and related domains. PMID- 26424436 TI - Novel p75 neurotrophin receptor ligand stabilizes neuronal calcium, preserves mitochondrial movement and protects against HIV associated neuropathogenesis. AB - Human immunodeficiency virus (HIV) rapidly penetrates into the brain and establishes a persistent infection of macrophages/microglia. Activation of these cells by HIV results in the secretion of soluble factors that destabilize neuronal calcium homeostasis, encourage oxidative stress and result in neural damage. This damage is thought to underlie the cognitive-motor dysfunction that develops in many HIV-infected patients. Studies have suggested that neurotrophins may protect neurons from the toxic effects of HIV-associated proteins. To better understand the pathogenic mechanisms and the neuroprotective potential of neurotrophin ligands, we evaluated neuronal damage, calcium homeostasis and mitochondrial functions after exposure of cultured rat neurons directly to HIV gp120 or to conditioned medium from human monocyte-derived macrophages treated with gp120. We then assessed the ability of a new non-peptide p75 neurotrophin receptor ligand, LM11A-31, to stabilize calcium homeostasis and prevent the development of pathology. Each toxic challenge resulted in a delayed accumulation of intracellular calcium coupled to a decrease in the rate of calcium clearance from the cell. The delayed calcium accumulation correlated with the development of focal dendritic swellings (beading), cytoskeletal damage and impaired movement of mitochondria. Addition of LM11A-31 to the cultures at nanomolar concentrations eliminated cell death, significantly reduced the pathology, suppressed the delayed accumulation of calcium and restored mitochondrial movements. The potent neuroprotection and the stabilization of calcium homeostasis indicate that LM11A 31 may have excellent potential for the treatment of HIV-associated neurodegeneration. PMID- 26424440 TI - Evidence-based recommendations for designing free-sorting experiments. AB - The card-sorting task is a flexible research tool that is widely used across many of the subfields of psychology. Yet this same great flexibility requires researchers to make several (seemingly arbitrary) decisions in their designs, such as fixing a sufficient number of objects to sort, setting task requirements, and creating task instructions for participants. In the present research, we provide a systematic empirical investigation of the consequences of typical researcher design choices while administering sorting tasks. Specifically, we studied the effects of seven sorting task design factors by collecting data from over 1,000 online participants assigned to one of 36 sorting tasks, as part of a fractional factorial experimental design. Analyses show the effects of the various researcher decisions on the probability that participants would quit the task, the amount of time spent on the task, the number of piles made, and posttask measures such as satisfaction and depletion. Research design recommendations are provided. PMID- 26424441 TI - Normative study of theme identifiability: Instructions with and without explanation of the false memory effect. AB - False-memory illusions have been widely studied using the Deese/Roediger McDermott paradigm (DRM). In this paradigm, words semantically related to a single nonpresented critical word are studied. In a later memory test, critical words are often falsely recalled and recognized. The present normative study was conducted to measure the theme identifiability of 60 associative word lists in Spanish that include six words (e.g., stove, coat, blanket, scarf, chill, and bonnet) that are simultaneously associated with three critical words (e.g., HEAT, COLD, and WINTER; Beato & Diez, Psicothema, 26, 457-463, 2011). Different levels of backward associative strength were used in the construction of the DRM lists. In addition, we used two types of instructions to obtain theme identifiability. In the without-explanation condition, traditional instructions were used, requesting participants to write the theme list. In the with-explanation condition, the false-memory effect and how the lists were built were explained, and an example of a DRM list and critical words was shown. Participants then had to discover the critical words. The results showed that all lists produced theme identifiability. Moreover, some lists had a higher theme identifiability rate (e.g., 61 % for the critical words LOVE, BOYFRIEND, COUPLE) than others (e.g., 24 % for CITY, PLACE, VILLAGE). After comparing the theme identifiabilities in the different conditions, the results indicated higher theme identifiability when the false-memory effect was explained than without such an explanation. Overall, these new normative data provide a useful tool for those experiments that, for example, aim to analyze the wide differences observed in false memory with DRM lists and the role of theme identifiability. PMID- 26424442 TI - CRIE: An automated analyzer for Chinese texts. AB - Textual analysis has been applied to various fields, such as discourse analysis, corpus studies, text leveling, and automated essay evaluation. Several tools have been developed for analyzing texts written in alphabetic languages such as English and Spanish. However, currently there is no tool available for analyzing Chinese-language texts. This article introduces a tool for the automated analysis of simplified and traditional Chinese texts, called the Chinese Readability Index Explorer (CRIE). Composed of four subsystems and incorporating 82 multilevel linguistic features, CRIE is able to conduct the major tasks of segmentation, syntactic parsing, and feature extraction. Furthermore, the integration of linguistic features with machine learning models enables CRIE to provide leveling and diagnostic information for texts in language arts, texts for learning Chinese as a foreign language, and texts with domain knowledge. The usage and validation of the functions provided by CRIE are also introduced. PMID- 26424443 TI - The EU-Emotion Stimulus Set: A validation study. AB - The EU-Emotion Stimulus Set is a newly developed collection of dynamic multimodal emotion and mental state representations. A total of 20 emotions and mental states are represented through facial expressions, vocal expressions, body gestures and contextual social scenes. This emotion set is portrayed by a multi ethnic group of child and adult actors. Here we present the validation results, as well as participant ratings of the emotional valence, arousal and intensity of the visual stimuli from this emotion stimulus set. The EU-Emotion Stimulus Set is available for use by the scientific community and the validation data are provided as a supplement available for download. PMID- 26424444 TI - Depressive symptom trajectories over a 6-year period following myocardial infarction: predictive function of cognitive appraisal and coping. AB - The association between distinct patterns of depression and coping variables in myocardial infarction (MI) survivors over the long-term is unclear. The study aims to evaluate depressive trajectories and their covariates, including coping and cognitive appraisal, following MI over a period of 6 years. Depressive symptoms were assessed in 200 patients a few days after the first MI, and 1 month, 6 months and 6 years later. Cognitive appraisal and coping were assessed during the first three time points. Three latent depressive trajectories were identified: chronic (high; increasing then decreasing; n = 49), rising (moderate; decreasing then increasing; n = 121) and low (low; decreasing then stabilizing; n = 30). The chronic trajectory was associated with higher negative appraisal and emotion-focused coping. The findings clarify the long-term longitudinal trajectories of post-MI depressive symptoms and their association with coping variables, revealing the unfavorable impact of negative cognition and palliative coping. PMID- 26424445 TI - Cow hair allergen concentrations in dairy farms with automatic and conventional milking systems: From stable to bedroom. AB - Bovine hair and dander are considered to be a notable risk factor for sensitization and allergic symptoms in occupationally exposed cattle farmers due to various IgE binding proteins. Farmers are suspected not only to be exposed during their work inside the stables but also inside their homes as allergens could be transferred via hair and clothes resulting in continued bovine allergen exposure in private areas. In recent years a new sensitive sandwich ELISA (enzyme linked immunosorbent assay) test has been developed to measure the cow hair allergen (CHA) concentration in dust. The aim of the present study was to determine the CHA concentration in airborne and settled dust samples in stables and private rooms of dairy cattle farms with automatic milking systems (AM) and conventional milking systems (CM), also with respect to questionnaire data on farming characteristics. For this purpose different sampling techniques were applied, and results and practicability of the techniques were compared. Dust sampling was performed in the stable, computer room (only AM), changing room, living room and bedroom (mattress) of 12 dairy farms with automatic milking systems (AM group) and eight dairy farms with conventional milking systems (CM group). Altogether, 90 samples were taken by ALK filter dust collectors from all locations, while 32 samples were collected by an ion charging device (ICD) and 24 samples by an electronic dust fall collector (EDC) in computer rooms (AM) and/or changing and living rooms (not stables). The dust samples were extracted and analyzed for CHA content with a sandwich ELISA. At all investigated locations, CHA concentrations were above the limit of detection (LOD) of 0.1 ng/ml dust extract. The median CHA concentrations in dust collected by ALK filters ranged from 63 to 7154 MUg/g dust in AM farms and from 121 to 5627 MUg/g dust in CM farms with a steep concentration gradient from stables to bedrooms. ICD sampling revealed median CHA contents of 112 MUg/g airborne dust in the computer rooms of the AM farms and median CHA loads of 5.6 MUg/g (AM farms) and 19.8 MUg/g (CM farms) in the living rooms. Passive dust sampling by EDC was performed only at two locations in the AM group resulting in median CHA values of 116 MUg/m(2) (computer room) and 55.0 MUg/m(2) (changing room). Except for the stable samples the median CHA load was lower in AM farms compared to CM farms. The CHA contents of ALK filter samples were significantly correlated in most locations. Differences between the farming types were not significant. Although allergen transfer to the private area of the farmers has been found and results from several locations were correlated, differences in CHA concentrations were not significant with respect to questionnaire data such as the wearing of stable clothes in living room, free access of pets to stable and home, frequency of hair washing. All sampling techniques seem to being practicable for simple and effective CHA measurement. PMID- 26424447 TI - X-ray microtomography using correlation of near-field speckles for material characterization. AB - Nondestructive microscale investigation of objects is an invaluable tool in life and materials sciences. Currently, such investigation is mainly performed with X ray laboratory systems, which are based on absorption-contrast imaging and cannot access the information carried by the phase of the X-ray waves. The phase signal is, nevertheless, of great value in X-ray imaging as it is complementary to the absorption information and in general more sensitive to visualize features with small density differences. Synchrotron facilities, which deliver a beam of high brilliance and high coherence, provide the ideal condition to develop such advanced phase-sensitive methods, but their access is limited. Here we show how a small modification of a laboratory setup yields simultaneously quantitative and 3D absorption and phase images of the object. This single-shot method is based on correlation of X-ray near-field speckles and represents a significant broadening of the capabilities of laboratory-based X-ray tomography. PMID- 26424448 TI - STIM1-Ca2+ signaling modulates automaticity of the mouse sinoatrial node. AB - Cardiac pacemaking is governed by specialized cardiomyocytes located in the sinoatrial node (SAN). SAN cells (SANCs) integrate voltage-gated currents from channels on the membrane surface (membrane clock) with rhythmic Ca(2+) release from internal Ca(2+) stores (Ca(2+) clock) to adjust heart rate to meet hemodynamic demand. Here, we report that stromal interaction molecule 1 (STIM1) and Orai1 channels, key components of store-operated Ca(2+) entry, are selectively expressed in SANCs. Cardiac-specific deletion of STIM1 in mice resulted in depletion of sarcoplasmic reticulum (SR) Ca(2+) stores of SANCs and led to SAN dysfunction, as was evident by a reduction in heart rate, sinus arrest, and an exaggerated autonomic response to cholinergic signaling. Moreover, STIM1 influenced SAN function by regulating ionic fluxes in SANCs, including activation of a store-operated Ca(2+) current, a reduction in L-type Ca(2+) current, and enhancing the activities of Na(+)/Ca(2+) exchanger. In conclusion, these studies reveal that STIM1 is a multifunctional regulator of Ca(2+) dynamics in SANCs that links SR Ca(2+) store content with electrical events occurring in the plasma membrane, thereby contributing to automaticity of the SAN. PMID- 26424449 TI - Fibonacci family of dynamical universality classes. AB - Universality is a well-established central concept of equilibrium physics. However, in systems far away from equilibrium, a deeper understanding of its underlying principles is still lacking. Up to now, a few classes have been identified. Besides the diffusive universality class with dynamical exponent [Formula: see text], another prominent example is the superdiffusive Kardar Parisi-Zhang (KPZ) class with [Formula: see text]. It appears, e.g., in low dimensional dynamical phenomena far from thermal equilibrium that exhibit some conservation law. Here we show that both classes are only part of an infinite discrete family of nonequilibrium universality classes. Remarkably, their dynamical exponents [Formula: see text] are given by ratios of neighboring Fibonacci numbers, starting with either [Formula: see text] (if a KPZ mode exist) or [Formula: see text] (if a diffusive mode is present). If neither a diffusive nor a KPZ mode is present, all dynamical modes have the Golden Mean [Formula: see text] as dynamical exponent. The universal scaling functions of these Fibonacci modes are asymmetric Levy distributions that are completely fixed by the macroscopic current density relation and compressibility matrix of the system and hence accessible to experimental measurement. PMID- 26424450 TI - ACHT4-driven oxidation of APS1 attenuates starch synthesis under low light intensity in Arabidopsis plants. AB - The regulatory mechanisms that use signals of low levels of reactive oxygen species (ROS) could be obscured by ROS produced under stress and thus are better investigated under homeostatic conditions. Previous studies showed that the chloroplastic atypical thioredoxin ACHT1 is oxidized by 2-Cys peroxiredoxin (2 Cys Prx) in Arabidopsis plants illuminated with growth light and in turn transmits a disulfide-based signal via yet unknown target proteins in a feedback regulation of photosynthesis. Here, we studied the role of a second chloroplastic paralog, ACHT4, in plants subjected to low light conditions. Likewise, ACHT4 reacted in planta with 2-Cys Prx, indicating that it is oxidized by a similar disulfide exchange reaction. ACHT4 further reacted uniquely with the small subunit (APS1) of ADP-glucose pyrophosphorylase (AGPase), the first committed enzyme of the starch synthesis pathway, suggesting that it transfers the disulfides it receives from 2-Cys Prx to APS1 and turns off AGPase. In accordance, ACHT4 participated in an oxidative signal that quenched AGPase activity during the diurnal transition from day to night, and also in an attenuating oxidative signal of AGPase in a dynamic response to small fluctuations in light intensity during the day. Increasing the level of expressed ACHT4 or of ACHT4DeltaC, a C terminus-deleted form that does not react with APS1, correspondingly decreased or increased the level of reduced APS1 and decreased or increased transitory starch content. These findings imply that oxidative control mechanisms act in concert with reductive signals to fine tune starch synthesis during daily homeostatic conditions. PMID- 26424452 TI - Extreme events in computational turbulence. AB - We have performed direct numerical simulations of homogeneous and isotropic turbulence in a periodic box with 8,192(3) grid points. These are the largest simulations performed, to date, aimed at improving our understanding of turbulence small-scale structure. We present some basic statistical results and focus on "extreme" events (whose magnitudes are several tens of thousands the mean value). The structure of these extreme events is quite different from that of moderately large events (of the order of 10 times the mean value). In particular, intense vorticity occurs primarily in the form of tubes for moderately large events whereas it is much more "chunky" for extreme events (though probably overlaid on the traditional vortex tubes). We track the temporal evolution of extreme events and find that they are generally short-lived. Extreme magnitudes of energy dissipation rate and enstrophy occur simultaneously in space and remain nearly colocated during their evolution. PMID- 26424451 TI - Drosophila E-cadherin is required for the maintenance of ring canals anchoring to mechanically withstand tissue growth. AB - Intercellular bridges called "ring canals" (RCs) resulting from incomplete cytokinesis play an essential role in intercellular communication in somatic and germinal tissues. During Drosophila oogenesis, RCs connect the maturing oocyte to nurse cells supporting its growth. Despite numerous genetic screens aimed at identifying genes involved in RC biogenesis and maturation, how RCs anchor to the plasma membrane (PM) throughout development remains unexplained. In this study, we report that the clathrin adaptor protein 1 (AP-1) complex, although dispensable for the biogenesis of RCs, is required for the maintenance of the anchorage of RCs to the PM to withstand the increased membrane tension associated with the exponential tissue growth at the onset of vitellogenesis. Here we unravel the mechanisms by which AP-1 enables the maintenance of RCs' anchoring to the PM during size expansion. We show that AP-1 regulates the localization of the intercellular adhesion molecule E-cadherin and that loss of AP-1 causes the disappearance of the E-cadherin-containing adhesive clusters surrounding the RCs. E-cadherin itself is shown to be required for the maintenance of the RCs' anchorage, a function previously unrecognized because of functional compensation by N-cadherin. Scanning block-face EM combined with transmission EM analyses reveals the presence of interdigitated, actin- and Moesin-positive, microvilli like structures wrapping the RCs. Thus, by modulating E-cadherin trafficking, we show that the sustained E-cadherin-dependent adhesion organizes the microvilli meshwork and ensures the proper attachment of RCs to the PM, thereby counteracting the increasing membrane tension induced by exponential tissue growth. PMID- 26424454 TI - Testing spatial measures of alcohol outlet density with self-rated health in the Australian context: Implications for policy and practice. AB - INTRODUCTION AND AIMS: Reducing access to alcohol is an important and cost effective strategy for decreasing alcohol consumption and associated harm. Yet this is a less common approach to alcohol control in Australia. The aim of this research was to ascertain which alcohol outlet density spatial measures were related to long-term health outcomes, and the extent to which this differs for those living in more or less disadvantaged neighbourhoods. DESIGN AND METHODS: Existing Australian state-level spatial alcohol policies were reviewed. No appropriate spatial policies were identified; therefore, the literature was used to identify potential alcohol-related spatial measures. Spatial measures of alcohol outlet density were generated in a geographical information system and linked with health survey data drawn from 3141 adults living in metropolitan Melbourne. Logistic regression analysis was used to examine associations between alcohol outlet density measures, self-rated health and area-level disadvantage. RESULTS: Twelve spatial measures of alcohol outlet density were generated. Alcohol outlet density and self-rated health associations varied by area-level disadvantage. For those living in more disadvantaged areas, not having off licenses available within 800 m, or on-licenses available within 400 m were protective of self-rated health. DISCUSSION AND CONCLUSIONS: Local alcohol outlet density may have a more detrimental effect on self-rated health for those living in more disadvantaged neighbourhoods, compared with those living in more advantaged areas. There is a need for spatial alcohol policies to help reduce alcohol-related harm. This research proposes a set of spatial measures to generate a more consistent understanding of alcohol availability in Australia. [Badland H, Mavoa S, Livingston M, David S, Giles-Corti B. Testing spatial measures of alcohol outlet density with self-rated health in the Australian context: Implications for policy and practice. Drug Alcohol Rev 2016;35:298-306]. PMID- 26424455 TI - The long shadows of past mistakes. PMID- 26424453 TI - Splicing noncoding RNAs from the inside out. AB - Eukaryotic precursor-messenger RNAs (pre-mRNAs) undergo splicing to remove intragenic regions (introns) and ligate expressed regions (exons) together. Unlike exons in the mature messenger RNAs (mRNAs) that are used for translation, introns that are spliced out of pre-mRNAs were generally believed to lack function and to be degraded. However, recent studies have revealed that a large group of spliced introns can escape complete degradation and are processed to generate noncoding RNAs (ncRNAs), including different types of small RNAs, long noncoding RNAs, and circular RNAs. Strikingly, exonic sequences can be also back spliced from pre-mRNAs to form stable circular RNAs. Together, the findings that ncRNAs can be spliced out of mRNA precursors not only expand the ever-growing repertoire of ncRNAs that originate from different genomic regions, but also reveal the unexpected transcriptomic complexity and functional capacity of eukaryotic genomes. PMID- 26424456 TI - Second-line antiretroviral therapy and the human factor. PMID- 26424457 TI - Should everyone ageing with HIV take a statin? PMID- 26424458 TI - HIV in Thai men who have sex with men: a sustained emergency. PMID- 26424459 TI - HIV surveys in older adults: better data, better health. PMID- 26424462 TI - Temporal trends in HIV-1 incidence and risk behaviours in men who have sex with men in Bangkok, Thailand, 2006-13: an observational study. AB - BACKGROUND: HIV-1 incidence in men who have sex with men (MSM) is often difficult to estimate. We therefore assessed temporal trends in HIV-1 incidence and behavioural risk factors in MSM in Bangkok, Thailand, from 2006 to 2013. METHODS: In this observational study, we used data for clients attending the Silom Community Clinic for voluntary counselling and testing (VCT) services and from the Bangkok MSM Cohort Study (BMCS) to investigate trends in HIV incidence per 100 person-years per quarter in both cohorts. During VCT, basic demographic data were gathered at registration. However, no behavioural risk data were gathered. In the BMCS, we gathered demographic and behavioural data at baseline and at regular study visits using audio computer-assisted self-interviewing. Questions were included about potential risk factors such as drug use, sexual practices, and how often condoms were used. We also analysed behavioural risk factors in the BMCS cohort, using a restricted cubic spline function for time. FINDINGS: From 2006 to 2013, 8176 MSM came for VCT; 1999 (24%) clients were initially seronegative and returned for another test. 235 (12%) individuals seroconverted. The overall HIV-1 incidence was 5.5 per 100 person-years (95% CI 4.8-6.3), with an increasing trend (adjusted p=0.02). In the BMCS, 1372 people were seronegative at baseline; 1259 (92%) had more than one follow-up test and 238 (17%) seroconverted. The overall HIV-1 incidence was 5.3 per 100 person-years (95% CI 4.7-6.1), with an increase and then a decline (inverted U-shaped curve, p=0.0001). Individuals aged 21 years and younger were at significantly higher risk of HIV infection than were those aged 30 years and older in the in the VCT (rate ratio 2.29, 95% CI 1.88-2.78, p<0.0001) and BMCS cohorts (1.99, 1.50-2.65, p<0.0001). Overall, drug use (p=0.03), drug use to enhance sex (p=0.0006), use of drugs for erectile dysfunction (p<0.0001), and 100% condom use (p<0.0001) increased over time, whereas the proportion of individuals reporting receptive anal intercourse decreased (p=0.004). INTERPRETATION: With a sustained high HIV-1 incidence and increasing drug use in MSM in Bangkok, we urgently need innovative and acceptable HIV prevention interventions, especially for young MSM. FUNDING: US Centers for Disease Control and Prevention. PMID- 26424460 TI - Baseline HIV-1 resistance, virological outcomes, and emergent resistance in the SECOND-LINE trial: an exploratory analysis. AB - BACKGROUND: WHO-recommended second-line antiretroviral therapy (ART) of a pharmacologically enhanced (boosted) protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NtRTIs) might be compromised by resistance. Results of the 96 week SECOND-LINE randomised trial showed that NtRTI sparing ART with ritonavir-boosted lopinavir and raltegravir (raltegravir-group) provided non-inferior efficacy to ritonavir-boosted lopinavir and two or three NtRTIs (NtRTI-group) in participants with virological failure composed of a first line regimen of a non-nucleoside reverse transcriptase inhibitor plus two NtRTIs. We report the relation of baseline virological resistance with virological failure and emergent resistance on study. METHODS: As part of the randomised open label SECOND-LINE trial, second-line ART NtRTI selection was made by either genotype (local laboratory) or algorithm. Genotypic resistance for the entire cohort at baseline was assessed on stored samples at a central laboratory. Virological failure was defined as plasma viral load greater than 200 copies per mL. Baseline viral isolates were assigned genotypic sensitivity scores (GSSs) by use of the Stanford HIV Database version 6.3.1: a global GSS (gGSS), defined as the combined GSS for lamivudine or emtricitabine, abacavir, zidovudine, stavudine, didanosine, and tenofovir and a specific GSS (sGSS) defined as the GSS for the ART regimen initiated by a specific participant. Emergent resistance was reported on samples with a viral load greater than 500 copies per mL. We used multivariate logistic regression with backward elimination to assess predictors of virological failure and emergent resistance. FINDINGS: From April 19, 2010, to July 22, 2013, 271 patients were included in the NtRTI group and and 270 in the raltegravir group. In the NtRTI group 215 had available baseline sequence data, and 240 had viral load measurements at 96 weeks; in the raltegravir group 236 had baseline sequence data and 255 had viral load measurements at 96 weeks. Median (IQR) gGSS was 3.0 (1.3-4.3) in the NtRTI group and 3.0 (1.0-4.3) in the raltegravir group. The median sGSS in the NtRTI group was 1.0 (0.5-1.8). Multivariate analysis showed significant associations between virological failure and less than complete adherence at week 4 (odds ratio [OR] 2.18, 95%CI 1.07 4.47; p=0.03) and week 48 (2.49, 1.09-5.69; p=0.03), baseline plasma viral load greater than 100,000 copies per mL (3.43, 1.70-6.94; p=0.0006), baseline gGSS >4.25 (4.73, 1.94-11.6; p=0.0007), and being Hispanic (3.13, 1.21-8.13; p=0.02) or African (3.49, 1.68-7.28; p=0.0008) rather than Asian. We observed emergent major mutations in one (1%) of 129 participants for protease (both groups), eight (13%) of 64 for reverse transcriptase (NtRTI group) and 16 (20%) of 79 for integrase. Emergent resistance was associated with the raltegravir group (OR 2.47, 95% CI 1.02-5.99; p=0.05), baseline log10 viral load (1.83, 1.12-2.97; p=0.02), and absence of the Lys65Arg (K65R) or Lys70Glu (K70E) mutation at baseline (3.18, 1.12-9.02; p=0.03). INTERPRETATION: Poor adherence was a major determinant of virological failure in people on second-line ART. In settings with limited resources, investment in optimisation of adherence rather than implementation of drug resistance testing might be advisable. FUNDING: University of New South Wales Australia, Merck, AbbVie, and the Foundation for AIDS Research. PMID- 26424461 TI - Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: HIV-infected patients have a high risk of myocardial infarction. We aimed to assess the ability of statin treatment to reduce arterial inflammation and achieve regression of coronary atherosclerosis in this population. METHODS: In a randomised, double-blind, placebo-controlled trial, 40 HIV-infected participants with subclinical coronary atherosclerosis, evidence of arterial inflammation in the aorta by fluorodeoxyglucose (FDG)-PET, and LDL-cholesterol concentration of less than 3.37 mmol/L (130 mg/dL) were randomly assigned (1:1) to 1 year of treatment with atorvastatin or placebo. Randomisation was by the Massachusetts General Hospital (MGH) Clinical Research Pharmacy with a permuted block algorithm, stratified by sex with a fixed block size of four. Study codes were available only to the MGH Research Pharmacy and not to study investigators or participants. The prespecified primary endpoint was arterial inflammation as assessed by FDG-PET of the aorta. Additional prespecified endpoints were non calcified and calcified plaque measures and high risk plaque features assessed with coronary CT angiography and biochemical measures. Analysis was done by intention to treat with all available data and without imputation for missing data. The trial is registered with ClinicalTrials.gov, number NCT00965185. FINDINGS: The study was done from Nov 13, 2009, to Jan 13, 2014. 19 patients were assigned to atorvastatin and 21 to placebo. 37 (93%) of 40 participants completed the study, with equivalent discontinuation rates in both groups. Baseline characteristics were similar between groups. After 12 months, change in FDG-PET uptake of the most diseased segment of the aorta was not different between atorvastatin and placebo, but technically adequate results comparing longitudinal changes in identical regions could be assessed in only 21 patients (atorvastatin Delta -0.03, 95% CI -0.17 to 0.12, vs placebo Delta -0.06, -0.25 to 0.13; p=0.77). Change in plaque could be assessed in all 37 people completing the study. Atorvastatin reduced non-calcified coronary plaque volume relative to placebo: median change -19.4% (IQR -39.2 to 9.3) versus 20.4% (-7.1 to 94.4; p=0.009, n=37). The number of high-risk plaques was significantly reduced in the atorvastatin group compared with the placebo group: change in number of low attenuation plaques -0.2 (95% CI -0.6 to 0.2) versus 0.4 (0.0, 0.7; p=0.03; n=37); and change in number of positively remodelled plaques -0.2 (-0.4 to 0.1) versus 0.4 (-0.1 to 0.8; p=0.04; n=37). Direct LDL-cholesterol (-1.00 mmol/L, 95% CI -1.38 to 0.61 vs 0.30 mmol/L, 0.04 to 0.55, p<0.0001) and lipoprotein associated phospholipase A2 (-52.2 ng/mL, 95% CI -70.4 to -34.0, vs -13.3 ng/mL, 32.8 to 6.2; p=0.005; n=37) decreased significantly with atorvastatin relative to placebo. Statin therapy was well tolerated, with a low incidence of clinical adverse events. INTERPRETATION: No significant effects of statin therapy on arterial inflammation of the aorta were seen as measured by FDG-PET. However, statin therapy reduced non-calcified plaque volume and high-risk coronary plaque features in HIV-infected patients. Further studies should assess whether reduction in high-risk coronary artery disease translates into effective prevention of cardiovascular events in this at-risk population. FUNDING: National Institutes of Health, Harvard Clinical and Translational Science Center, National Center for Research Resources. PMID- 26424464 TI - Naturally together: pitch-height and brightness as coupled factors for eliciting the SMARC effect in non-musicians. AB - Pitch-height is often labeled spatially (i.e., low or high) as a function of the fundamental frequency of the tone. This correspondence is highlighted by the so called Spatial-Musical Association of Response Codes (SMARC) effect. However, the literature suggests that the brightness of the tone's timbre might contribute to this spatial association. We investigated the SMARC effect in a group of non musicians by disentangling the role of pitch-height and the role of tone brightness. In three experimental conditions, participants were asked to judge whether the tone they were listening to was (or was not) modulated in amplitude (i.e., vibrato). Participants were required to make their response in both the horizontal and the vertical axes. In a first condition, tones varied coherently in pitch (i.e., manipulation of the tone's F0) and brightness (i.e., manipulation of the tone's spectral centroid); in a second condition, pitch-height varied whereas brightness was fixed; in a third condition, pitch-height was fixed whereas brightness varied. We found the SMARC effect only in the first condition and only in the vertical axis. In contrast, we did not observe the effect in any of the remaining conditions. The present results suggest that, in non-musicians, the SMARC effect is not due to the manipulation of the pitch-height alone, but arises because of a coherent change of pitch-height and brightness; this effect emerges along the vertical axis only. PMID- 26424465 TI - Rectal bleeding due to rectal erosion of vaginal mesh. PMID- 26424466 TI - The LysR-type regulator LeuO regulates the acid tolerance response in Vibrio cholerae. AB - Vibrio cholerae is a neutrophilic enteric pathogen that is extremely sensitive to acid. As V. cholerae passages through the host gastrointestinal tract it is exposed to a variety of environmental stresses including low pH and volatile fatty acids. Exposure to acidic environments induces expression of the V. cholerae acid tolerance response. A key component of the acid tolerance response is the cad system, which is encoded by cadC and the cadBA operon. CadB is a lysine/cadaverine antiporter and CadA is a lysine decarboxylase and these function together to counter low intracellular and extracellular pH. CadC is a membrane-associated transcription factor that activates cadBA expression in response to acidic conditions. Herein we investigated the role of the LysR-type transcriptional regulator LeuO in the V. cholerae acid tolerance response. Transcriptional reporter assays revealed that leuO expression repressed cadC transcription, indicating that LeuO was a cadC repressor. Consistent with this, leuO expression was inversely linked to lysine decarboxylase production and leuO overexpression resulted in increased sensitivity to organic acids. Overexpression of leuO in a cadA mutant potentiated killing by organic acids, suggesting that the function of leuO in the acid tolerance response extended beyond its regulation of the cad system. Collectively, these studies have identified a new physiological role for LeuO in V. cholerae acid tolerance. PMID- 26424467 TI - Recanalization of chronic total coronary occlusions--high success rate despite a restrictive use of the retrograde approach. AB - AIM: The retrograde approach in chronic total occlusion (CTO) percutaneous coronary intervention (PCI) is increasingly being used as a first-line intervention despite a higher radiation exposure, contrast volume, and a higher major adverse cardiac event (MACE) rate compared with the antegrade approach. It was aimed to evaluate the overall success rate of CTO-PCI over time when the retrograde approach was restrictively used only after a failed antegrade attempt. METHODS AND RESULTS: In a prospective single operator registry from January 2008 to December 2012 about 436 consecutive patients underwent a CTO-PCI. Mean age was 63.4 +/- 10.3 years, and 86% were male. The overall success rate improved significantly over time [68% (first quartile) to 91% (fourth quartile), P < 0.001] due to a significant increase of the antegrade success rate. This could be achieved by a retrograde approach of less than 20% with no change over time. The overall in-hospital MACE rate was 0.69% with no difference between antegrade and retrograde procedures. CONCLUSIONS: A high CTO-PCI success rate of above 90% could be achieved with a restrictive use of the retrograde technique. PMID- 26424468 TI - Effects of an anesthetic mixture of medetomidine, midazolam, and butorphanol in rats-strain difference and antagonism by atipamezole. AB - An anesthetic mixture of medetomidine (MED), midazolam (MID), and butorphanol (BUT) has been used in laboratory animals. We previously reported that this anesthetic mixture produced closely similar anesthetic effects in BALB/c and C57BL/6J strains. We also demonstrated the efficacy of atipamezole (ATI), an antagonist of MED that produced quick recovery from anesthesia in mice. Anesthetics have various anesthetic effects among animal strains. However, the differences in the effects of anesthetic mixtures in rats are unclear. In the present study, we first examined effects of the abovementioned anesthetic mixture using three different rat strains: Wistar (WST), Sprague-Dawley (SD), and Fischer 344 (F344). Second, we examined how different dosages and optimum injection timing of ATI affected recovery from anesthesia in rats. We used the anesthetic score to measure anesthetic duration and a pulse oximeter to monitor vital signs. We found no significant differences in anesthetic duration among the three different strains. However, recovery from anesthesia in the SD strain took significantly longer than in the other strains. The antagonistic effects of ATI (0.15 mg/kg and 0.75 mg/kg) were equivalent when administered at 30 min after anesthetic mixture administration. The antagonistic effects of ATI 0.75 mg/kg were stronger than those of ATI 0.15 mg/kg at 10 min after anesthetic mixture administration. This anesthetic mixture is a useful drug that can induce similar anesthetic effects in three different strains and has an antagonist, ATI, that makes rats quickly recover from anesthesia. These results may contribute to the welfare of laboratory animals. PMID- 26424469 TI - Accelerated pathway evolution in mouse-like rodents involves cell cycle control. AB - Rodents include both the cancer-susceptible short-lived mouse and the two unrelated cancer-resistant long-lived mole-rats. In this work, their genomes were analyzed with the goal to reveal pathways enriched in genes, which are more similar between the mole-rats than between the mouse and the naked mole-rat. The pathways related to cell cycle control were prominent. They include external signal transduction and all cell cycle stages. There are several stem cell pathways among them. The other enriched pathways involve ubiquitin-dependent protein degradation, immunity, mRNA splicing, and apoptosis. The ubiquitin dependent protein degradation is a core of network of enriched pathways. However, this phenomenon is not specific for the mouse and the mole-rats. The other muroid species show features similar to the mouse, whereas the non-muroid rodents and the human show features similar to the mole-rats. The higher ratio of non synonymous to synonymous nucleotide substitutions (dN/dS) indicates the accelerated evolution of revealed pathways in the muroid rodents (except the blind mole-rat). Paradoxically, the dN/dS averaged over the whole genome is lower in the muroids, i.e., the purifying selection is generally stronger in them. In practical sense, these data suggest caveat for using muroid rodents (mouse, rat, and hamsters) as biomedical models of human conditions involving cell cycle and show the network of pathways where muroid genes are most different (compared with non-muroid) from human genes. The guinea pig is emphasized as a more suitable rodent model for biomedical research involving cell cycle. PMID- 26424470 TI - Relationships between self-reported lifetime physical activity, estimates of current physical fitness, and aBMD in adult premenopausal women. AB - Osteoporosis is common, and physical activity is important in its prevention and treatment. Of the categories of historical physical activity (PA) examined, we found that weight-bearing and very hard physical activity had the strongest relationships with areal bone mineral density (aBMD) throughout growth and into adulthood, while for measures of strength, only grip strength proved to be an independent predictor of aBMD. PURPOSE/INTRODUCTION: To examine relationships between aBMD (total body, lumbar spine, proximal femur, tibial shaft, distal radius) and estimates of historical PA, current strength, and cardiovascular fitness in adult premenopausal women. METHODS: One hundred fifty-two adult premenopausal women (40 +/- 9.6 years) undertook aBMD (dual-energy X-ray absorptiometry (DXA)) and completed surveys to estimate historical physical activity representative of three decades (Kriska et al. [1]), while subsets underwent functional tests of isokinetic strength (hamstrings and quadriceps), grip strength (hand dynamometer), and maximum oxygen uptake (MaxV02; cycle ergometer). Historical PA was characterized by demand (metabolic equivalents, PA > 3 METS; PA > 7 METS) and type (weight-bearing; high impact). RESULTS: Significant positive independent predictors varied by decade and site, with weight-bearing exercise and PA > 3 METS significant for the tibial shaft (10-19 decade) and only PA > 7 METS significant for the final two decades (20-29 and 30 39 years; total body and total hip). A significant negative correlation between high impact activity and tibial shaft aBMD appeared for the final decade. For strength measures, only grip strength was an independent predictor (total body, total hip), while MaxV02 provided a significant independent prediction for the tibial shaft. CONCLUSIONS: Past PA > 7 METS was positively associated with aBMD, and such activity should probably constitute a relatively high proportion of all weekly PA to positively affect aBMD. The findings warrant more detailed investigations in a prospective study, specifically also investigating the potentially negative effects of high impact PA on tibial aBMD. PMID- 26424471 TI - Factors impacting the quality of peer relationships of youth with Tourette's syndrome. AB - BACKGROUND: Tourette's syndrome (TS) is a poorly understood neurodevelopmental disorder consistently associated with impaired peer relationships. This research aimed to investigate the relationship between TS and the ability of diagnosed youth to form secure attachment relationships with peers. A quantitative study examined differences between youth with TS and typically developing peers in social functioning, relationship problems and attachment security. Qualitative studies sought to identify factors that enhanced or impeded the ability to form secure peer relationships, including the impact of tic severity, comorbidity and personality traits. All research was conducted from the parental perspective. METHODS: The research consisted of a controlled, survey-based qualitative and quantitative study (Study One) of parents of youth with TS (n = 86) and control group peers (n = 108), and a qualitative telephone interview-based study of TS group parents (Study Two, n = 22). Quantitative assessment of social functioning, peer problems and peer attachment security was conducted using the Paediatric Quality of Life inventory, the Strengths and Difficulties Questionnaire and the Attachment Questionnaire for Children. Qualitative data relating to personality was classified using the Five Factor Model. RESULTS: Results revealed significantly higher rates of insecure peer attachment, problems in peer relationships, difficulty making friends, stigmatisation and lower levels of social functioning for the TS group. Significant between-group differences in number and type of factors impacting peer relationships were also determined with 'personality' emerging as the most prevalent factor. Whilst Extraversion and Agreeableness facilitated friendships for both groups, higher rates of Neuroticism were barriers to friendship for individuals with TS. The TS group also identified multiple 'non-personality' factors impacting peer relationships, including TS and comorbid symptom severity, the child's psychological and behavioural adjustment to their disorder, coping strategies and the behaviour and attitudes of peers. DISCUSSION: Our findings suggest that, whilst Extraversion and Agreeableness facilitated friendships for both groups, higher rates of Neuroticism were barriers to friendship for individuals with TS. Notwithstanding the fact that these findings are based on parental report and not the perceptions of youth themselves, this study may help clinicians to identify youth at increased risk of developing insecure peer relationships and guide the development of targeted supports. CONCLUSIONS: The findings from the study may help clinicians, parents and individuals with TS to better understand and cope with the difficulties experienced in interactions with peers. PMID- 26424472 TI - Response to commentary: Anomalous origin of the left pulmonary artery from the internal carotid artery. PMID- 26424473 TI - Utility and feasibility of integrating pulse oximetry into the routine assessment of young infants at primary care clinics in Karachi, Pakistan: a cross-sectional study. AB - BACKGROUND: Hypoxemia may occur in young infants with severe acute illnesses or congenital cardiac anomalies, but is not reliably detected on physical exam. Pulse oximetry (PO) can be used to detect hypoxemia, but its application in low income countries has been limited, and its feasibility in the routine assessment of young infants (aged 0-59 days) has not been previously studied. The aim of this study was to characterize the operational feasibility and parent/guardian acceptability of incorporating PO into the routine clinical assessment of young infants in a primary care setting in a low-income country. METHODS: This was a cross-sectional study of 862 visits by 529 infants at two primary care clinics in Karachi, Pakistan (March to June, 2013). After clinical assessment, oxygen saturation (Sp02) was measured by a handheld PO device (Rad-5v, Masimo Corporation) according to a standardized protocol. Performance time (PT) was the time between sensor placement and attainment of an acceptable PO reading (i.e., stable SpO2 + 1% for at least 10 s, heart rate displayed, and adequate signal indicators). PT included the time for one repeat attempt at a different anatomical site if the first attempt did not yield an acceptable reading within 1 min. Parent/guardian acceptability of PO was based on a questionnaire and unprompted comments about the procedure. All infants underwent physician assessment. RESULTS: Acceptable PO readings were obtained in <= 1 and <= 5 min at 94.4% and 99.8% of visits, respectively (n = 862). Median PT was 42 s (interquartile range 37; 50). Parents/guardians overwhelmingly accepted PO (99.6% overall satisfaction, n = 528 first visits). Of 10 infants with at least one visit with Sp02 <92% on a first PO attempt, 3 did not have a significant acute illness on physician assessment. There were no PO-related adverse events. DISCUSSION: Using a commercially available handheld pulse oximeter, acceptable Sp02 measurements were obtained in nearly all infants in under 1 minute. The procedure was readily integrated into existing assessment pathways and parents/guardians had positive views of the technology. CONCLUSIONS: When incorporated into routine clinical assessment of young infants at primary care clinics in a low-income country, PO was feasible and acceptable to parents/guardians. Future research is needed to determine if the introduction of routine PO screening of young infants will improve outcomes in low-resource settings. PMID- 26424474 TI - Tissue-Engineered External Anal Sphincter Using Autologous Myogenic Satellite Cells and Extracellular Matrix: Functional and Histological Studies. AB - The aim of the present study was to demonstrate the regaining histological characteristics of bioengineered external anal sphincters (EAS) in rabbit fecal incontinence model. The EAS of 16 rabbits were resected and decellularized. The decellularized scaffolds were transplanted to the terminal rectum following a period of 6 months of fecal incontinency (5 days after sterilization). The rabbits were divided into two groups: in group 1 (n = 8), myogenic satellite cells were injected into the transplanted sphincters. In group 2 (n = 8), the transplanted scaffolds remained in situ without cellular injection. The histological evaluation was performed with desmin, myosin, smooth muscle actin, CD31, and CD34 at 3-month intervals. The rabbits were followed for 2 years. Electromyography (EMG) with needle and electrical stimulation, pudendal and muscle electrical stimulation were also performed after 2 years of transplantation. At the time of biopsy, no evidence of inflammation or rejection was observed and the transplanted EAS appeared histologically and anatomically normal. The immunohistochemistry staining validated that the histological features of EAS was more satisfactory in group 1 in short-term follow-up. However, no statistically significant difference was detected between two groups in long-term follow-ups (p value > 0.05). In both groups, grafted EAS contracted in response to electrical signals delivered to the muscle and the pudendal nerve. However, more signals were detected in group 1 in EMG evaluation. In conclusion, bioengineered EAS with myogenic satellite cells can gain more satisfactory histological outcomes in short-term follow-ups with better muscle electrical stimulation outcomes. PMID- 26424475 TI - From Finite Element Meshes to Clouds of Points: A Review of Methods for Generation of Computational Biomechanics Models for Patient-Specific Applications. AB - It has been envisaged that advances in computing and engineering technologies could extend surgeons' ability to plan and carry out surgical interventions more accurately and with less trauma. The progress in this area depends crucially on the ability to create robustly and rapidly patient-specific biomechanical models. We focus on methods for generation of patient-specific computational grids used for solving partial differential equations governing the mechanics of the body organs. We review state-of-the-art in this area and provide suggestions for future research. To provide a complete picture of the field of patient-specific model generation, we also discuss methods for identifying and assigning patient specific material properties of tissues and boundary conditions. PMID- 26424476 TI - Image-Based Personalization of Cardiac Anatomy for Coupled Electromechanical Modeling. AB - Computational models of cardiac electromechanics (EM) are increasingly being applied to clinical problems, with patient-specific models being generated from high fidelity imaging and used to simulate patient physiology, pathophysiology and response to treatment. Current structured meshes are limited in their ability to fully represent the detailed anatomical data available from clinical images and capture complex and varied anatomy with limited geometric accuracy. In this paper, we review the state of the art in image-based personalization of cardiac anatomy for biophysically detailed, strongly coupled EM modeling, and present our own tools for the automatic building of anatomically and structurally accurate patient-specific models. Our method relies on using high resolution unstructured meshes for discretizing both physics, electrophysiology and mechanics, in combination with efficient, strongly scalable solvers necessary to deal with the computational load imposed by the large number of degrees of freedom of these meshes. These tools permit automated anatomical model generation and strongly coupled EM simulations at an unprecedented level of anatomical and biophysical detail. PMID- 26424478 TI - The spectrum of expert reports on clinical biochemical toxicology and medicine from an Irish practice. AB - The compounds which generated an expert opinion report in the area of medical toxicology in the period 1999 to 2015 are presented from the toxicological case files of a specialist in chemical pathology and general internal medicine. There were 132 different compounds from 86 cases. Alcohol was involved in 43%, drugs of abuse in 18.6%, volatile carbon compounds in 17.4%, metals in 9.3%, and carbon monoxide in 4.6%. Many compounds appeared once. The duty of the medical expert witness to provide an objective report for the court irrespective of the payer is stated. The addition of references from peer reviewed literature to substantiate the pros and cons of each case is recommended as a standard operating procedure in completing each report. PMID- 26424479 TI - Non-vehicular homicides masquerading as road traffic accidents. AB - Interfering with or planting evidence to disguise the cause of a death is not uncommon in forensic practice. Homicides staged as road accidents are, however, rarely encountered by crime scene investigators. We report two homicides which were presented as road traffic accidents. Case 1: Dead body of a 35-year-old male was brought for autopsy with history of road traffic accident. Primary police inquiry suggested that the victim was knocked down by a speeding four-wheeler, while walking by the side of a high way with his friends. On postmortem examination the deceased's death was found due to homicidal smothering staged as a road traffic accident. Case 2: Dead body of 40-year-old male was brought for autopsy with history of road traffic accident. It was an unwitnessed crush by a speeding four-wheeler. However, on postmortem examination, the deceased was found to have died from homicidal multiple stab wounds with his death staged as a road traffic accident. Importance of meticulous autopsy to determine accurately the cause of death is emphasized. PMID- 26424477 TI - Effects of different arachidonic acid supplementation on psychomotor development in very preterm infants; a randomized controlled trial. AB - BACKGROUND & AIMS: Nutritional supplementation with polyunsaturated fatty acids is important in preterm infants neurodevelopment, but it is not known if the omega-6/omega-3 ratio affects this process. This study was designed to determine the effects of a balanced contribution of arachidonic acid in very preterm newborns fed with formula milk. METHODS: This was a randomized trial, in which newborns <1500 g and/or <32 weeks gestational age were assigned to one of two groups, based on the milk formula they would receive during the first year of life. Initially, 60 newborns entered the study, but ultimately, group A was composed of 24 newborns, who were given formula milk with an omega-6/omega-3 ratio of 2/1, and Group B was composed of 21 newborns, given formula milk with an omega-6/omega-3 ratio of 1/1. The infants were followed up for two years: growth, visual-evoked potentials, brainstem auditory-evoked potentials, and plasma fatty acids were periodically measured, and psychomotor development was assessed using the Brunet Lezine scale at 24 months corrected age. A control group, for comparison of Brunet Lezine score, was made up of 25 newborns from the SEN1500 project, who were fed exclusively with breast milk. RESULTS: At 12 months, arachidonic acid values were significantly higher in group A than in group B (6.95 +/- 1.55% vs. 4.55 +/- 0.78%), as were polyunsaturated fatty acids (41.02 +/- 2.09% vs. 38.08 +/- 2.32%) achieved a higher average. Group A achieved a higher average Brunet Lezine score at 24 months than group B (99.9 +/- 9 vs. 90.8 +/- 11, p =0.028). The Brunet Lezine results from group A were compared with the control group results, with very similar scores registered between the two groups (99.9 +/- 9 vs. 100.5 +/- 7). There were no significant differences in growth or evoked potentials between the two formula groups. CONCLUSIONS: Very preterm infants who received formula with an omega-6/omega-3 ratio of 2/1 had higher blood levels of essential fatty acids during the first year of life, and better psychomotor development, compared with very preterm newborns who consumed formula with an omega-6/omega-3 of 1/1. Therefore, formula milk with an arachidonic acid quantity double that of docosahexaenoic acid should be considered for feeding very preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02503020. PMID- 26424480 TI - Chronic mercury exposure in Late Neolithic/Chalcolithic populations in Portugal from the cultural use of cinnabar. AB - Cinnabar is a natural mercury sulfide (HgS) mineral of volcanic or hydrothermal origin that is found worldwide. It has been mined prehistorically and historically in China, Japan, Europe, and the Americas to extract metallic mercury (Hg(0)) for use in metallurgy, as a medicinal, a preservative, and as a red pigment for body paint and ceramics. Processing cinnabar via combustion releases Hg(0) vapor that can be toxic if inhaled. Mercury from cinnabar can also be absorbed through the gut and skin, where it can accumulate in organs and bone. Here, we report moderate to high levels of total mercury (THg) in human bone from three Late Neolithic/Chalcolithic (5400-4100 B.P.) sites in southern Portugal that were likely caused by cultural use of cinnabar. We use light stable isotope and Hg stable isotope tracking to test three hypotheses on the origin of mercury in this prehistoric human bone. We traced Hg in two individuals to cinnabar deposits near Almaden, Spain, and conclude that use of this mineral likely caused mild to severe mercury poisoning in the prehistoric population. Our methods have applications to bioarchaeological investigations worldwide, and for tracking trade routes and mobility of prehistoric populations where cinnabar use is documented. PMID- 26424481 TI - Ciliary subcompartments and cysto-proteins. AB - Renal cystic diseases are conditions in which parts of or entire nephrons become enlarged and create fluid-filled cysts. These cysts occur in many genetic diseases. Most of the products of causative genes, termed cysto-proteins, are localized in cilia and/or centrioles. In addition, mutant mice lacking cilia develop renal cysts. Therefore, cilia are thought to have an important role in renal cystogenesis. The cilium is a tiny projection from the cell surface; however, it can be divided into several subcompartments. These subcompartments have specific roles. This review attempts to classify cysto-proteins based on their localization in ciliary subcompartments with the aim of defining relationships among them and of identifying their exact intraciliary functions. PMID- 26424482 TI - A Chlamydia trachomatis strain with a chemically generated amino acid substitution (P370L) in the cthtrA gene shows reduced elementary body production. AB - BACKGROUND: Chlamydia (C.) trachomatis is the most prevalent bacterial sexually transmitted infection worldwide and the leading cause of preventable blindness. Genetic approaches to investigate C. trachomatis have been only recently developed due to the organism's intracellular developmental cycle. HtrA is a critical stress response serine protease and chaperone for many bacteria and in C. trachomatis has been previously shown to be important for heat stress and the replicative phase of development using a chemical inhibitor of the CtHtrA activity. In this study, chemically-induced SNVs in the cthtrA gene that resulted in amino acid substitutions (A240V, G475E, and P370L) were identified and characterized. METHODS: SNVs were initially biochemically characterized in vitro using recombinant protein techniques to confirm a functional impact on proteolysis. The C. trachomatis strains containing the SNVs with marked reductions in proteolysis were investigated in cell culture to identify phenotypes that could be linked to CtHtrA function. RESULTS: The strain harboring the SNV with the most marked impact on proteolysis (cthtrA P370L) was detected to have a significant reduction in the production of infectious elementary bodies. CONCLUSIONS: This provides genetic evidence that CtHtrA is critical for the C. trachomatis developmental cycle. PMID- 26424483 TI - Understanding and predicting binding between human leukocyte antigens (HLAs) and peptides by network analysis. AB - BACKGROUND: As the major histocompatibility complex (MHC), human leukocyte antigens (HLAs) are one of the most polymorphic genes in humans. Patients carrying certain HLA alleles may develop adverse drug reactions (ADRs) after taking specific drugs. Peptides play an important role in HLA related ADRs as they are the necessary co-binders of HLAs with drugs. Many experimental data have been generated for understanding HLA-peptide binding. However, efficiently utilizing the data for understanding and accurately predicting HLA-peptide binding is challenging. Therefore, we developed a network analysis based method to understand and predict HLA-peptide binding. METHODS: Qualitative Class I HLA peptide binding data were harvested and prepared from four major databases. An HLA-peptide binding network was constructed from this dataset and modules were identified by the fast greedy modularity optimization algorithm. To examine the significance of signals in the yielded models, the modularity was compared with the modularity values generated from 1,000 random networks. The peptides and HLAs in the modules were characterized by similarity analysis. The neighbor-edges based and unbiased leverage algorithm (Nebula) was developed for predicting HLA peptide binding. Leave-one-out (LOO) validations and two-fold cross-validations were conducted to evaluate the performance of Nebula using the constructed HLA peptide binding network. RESULTS: Nine modules were identified from analyzing the HLA-peptide binding network with a highest modularity compared to all the random networks. Peptide length and functional side chains of amino acids at certain positions of the peptides were different among the modules. HLA sequences were module dependent to some extent. Nebula archived an overall prediction accuracy of 0.816 in the LOO validations and average accuracy of 0.795 in the two-fold cross-validations and outperformed the method reported in the literature. CONCLUSIONS: Network analysis is a useful approach for analyzing large and sparse datasets such as the HLA-peptide binding dataset. The modules identified from the network analysis clustered peptides and HLAs with similar sequences and properties of amino acids. Nebula performed well in the predictions of HLA peptide binding. We demonstrated that network analysis coupled with Nebula is an efficient approach to understand and predict HLA-peptide binding interactions and thus, could further our understanding of ADRs. PMID- 26424484 TI - Hierarchical ferroelectric and ferrotoroidic polarizations coexistent in nano metamaterials. AB - Tailoring materials to obtain unique, or significantly enhanced material properties through rationally designed structures rather than chemical constituents is principle of metamaterial concept, which leads to the realization of remarkable optical and mechanical properties. Inspired by the recent progress in electromagnetic and mechanical metamaterials, here we introduce the concept of ferroelectric nano-metamaterials, and demonstrate through an experiment in silico with hierarchical nanostructures of ferroelectrics using sophisticated real-space phase-field techniques. This new concept enables variety of unusual and complex yet controllable domain patterns to be achieved, where the coexistence between hierarchical ferroelectric and ferrotoroidic polarizations establishes a new benchmark for exploration of complexity in spontaneous polarization ordering. The concept opens a novel route to effectively tailor domain configurations through the control of internal structure, facilitating access to stabilization and control of complex domain patterns that provide high potential for novel functionalities. A key design parameter to achieve such complex patterns is explored based on the parity of junctions that connect constituent nanostructures. We further highlight the variety of additional functionalities that are potentially obtained from ferroelectric nano-metamaterials, and provide promising perspectives for novel multifunctional devices. This study proposes an entirely new discipline of ferroelectric nano-metamaterials, further driving advances in metamaterials research. PMID- 26424485 TI - Improvement of an enzyme-linked immunosorbent assay for equine herpesvirus type 4 by using a synthetic-peptide 24-mer repeat sequence of glycoprotein G as an antigen. AB - To increase the sensitivity of an enzyme-linked immunosorbent assay (ELISA) for equine herpesvirus type 4 (EHV-4) that uses a 12-mer peptide of glycoprotein G (gG4-12-mer: MKNNPIYSEGSL) [4], we used a longer peptide consisting of a 24-mer repeat sequence (gG4-24-mer: MKNNPIYSEGSLMLNVQHDDSIHT) as an antigen. Sera of horses experimentally infected with EHV-4 reacted much more strongly to the gG4 24-mer peptide than to the gG4-12-mer peptide. We used peptide ELISAs to test paired sera from horses naturally infected with EHV-4 (n=40). gG4-24-mer ELISA detected 37 positive samples (92.5%), whereas gG4-12-mer ELISA detected only 28 (70.0%). gG4-24-mer ELISA was much more sensitive than gG4-12-mer ELISA. PMID- 26424486 TI - Three questions about study on treatments for pyoderma gangrenosum. PMID- 26424488 TI - Ultralow temperature terahertz magnetic thermodynamics of perovskite-like SmFeO3 ceramic. AB - The terahertz magnetic properties of perovskite-like SmFeO3 ceramic are investigated over a broad temperature range, especially at ultralow temperatures, using terahertz time-domain spectroscopy. It is shown that both resonant frequencies of quasi-ferromagnetic and quasi-antiferromagnetic modes have blue shifts with the decreasing temperature due to the enhancement of effective magnetic field. The temperature-dependent magnetic anisotropy constants are further estimated using the resonant frequencies, under the approximation of omitting the contribution of Sm(3+) magnetic moments to the effective field. Specially, the effective anisotropy constants in the ca and cb planes at 3 K are 6.63 * 10(5) erg/g and 8.48 * 10(5) erg/g, respectively. This thoroughly reveals the terahertz magnetic thermodynamics of orthoferrites and will be beneficial to the application in terahertz magnetism. PMID- 26424487 TI - Percutaneous ablation therapies of inoperable pancreatic cancer: a systematic review. AB - Initial studies about ablation therapies of the pancreas were associated with significant morbidity and mortality, which limited widespread adoption. Development of techniques with high quality imaging used as guidance improve outcomes reducing complications. Moreover, only few experiences of percutaneous pancreatic ablations are reported. They are performed by very skilled operators in highly specialized centers. This review presents the current status of percutaneous local ablative therapies in the treatment of advanced pancreatic cancer. PMID- 26424489 TI - Conceptualization in pigeons: The evolution of a paradigm. AB - Keller and Schoenfeld (1950) proposed a unique behavioral perspective on conceptualization. They suggested that concepts refer solely to an organism's behavior and to the conditions under which it occurs; as such, conceptual behavior need be neither verbal nor uniquely human. Herrnstein and Loveland (1964) advanced that behavioral perspective by deploying an elegant training procedure to teach visual concepts to pigeons. Keller and Schoenfeld's perspective and Herrnstein and Loveland's methodology have inspired my own research into conceptualization by pigeons. Using a system of arbitrary visual tokens, my colleagues and I have built ever-expanding nonverbal "vocabularies" in pigeons through a variety of different concept learning tasks. Pigeons have reliably categorized as many as 2000 individual photographs from as many as 16 different human object categories, even without the benefit of seeing an item twice. Our formal model of conceptualization effectively embraces 25 years of empirical evidence as well as generates novel predictions for both pigeon and human conceptual behavior. Comparative study should continue to elucidate the commonalities and disparities between human and nonhuman conceptual behavior; it should also explicate the relationship between associative learning, object recognition, conceptualization, and language. PMID- 26424490 TI - The problem with categorical thinking by psychologists. AB - Continua abound in the natural world, but the treatment of these continua in the psychological study of behavior is often categorical. Four practices and their consequences are considered: limited sampling of a continuum, turning continuous predictors into categories through dichotomization and similar practices, treating continuous predictors as categorical in an analysis, and overuse of the analysis of variance. Concrete examples illustrate the consequences of these practices. Recommendations to improve the treatment of continua, both in the design and analysis of data, are provided. PMID- 26424491 TI - Prognostic evaluation in obese patients using a dedicated multipinhole cadmium zinc telluride SPECT camera. AB - The purpose of this study is to evaluate the prognostic value of myocardial perfusion SPECT obtained in CZT cameras (CZT-SPECT) with multipinhole collimation in obese patients. CZT-SPECT may be technically challenging in the obese, and its prognostic value remains largely unknown. Patients underwent single-day, rest/stress (supine and prone) imaging. Images were visually inspected and graded as poor, fair or good/excellent. Summed stress and difference scores (SSS and SDS, respectively) were converted into percentages of total perfusion defect and of ischemic defect by division by the maximum possible score. Obesity was defined as a body mass index (BMI) >= 30 kg/m(2) and classified as class I (BMI 30-34.9 kg/m(2)), II (BMI 35-39.9 kg/m(2)), or III (BMI >= 40 kg/m(2)). Patients were followed-up by telephone interview for the occurrence of all-cause death, myocardial infarction or revascularization. A Cox proportional hazards analysis was used to assess the independent predictors of death. Among 1396 patients, 365 (26.1 %) were obese (mean BMI 33.9 +/- 3.6; 17.5 % class I, 3.4 % class II, and 3.4 % class III). Image quality was good/excellent in 94.5 % of the obese patients. The annualized mortality rates were not significantly different among obese and non-obese patients, being <1 % with normal CZT-SPECT, and increased with the degree of scan abnormality in both obese and non-obese patients. Age, the use of pharmacologic stress and an abnormal CZT-SPECT, but not obesity, were independent predictors of death. In obese patients, single-day rest/stress CZT SPECT with a multipinhole camera provides prognostic discrimination with high image quality. PMID- 26424492 TI - 3D-Dixon MRI based volumetry of peri- and epicardial fat. AB - There is growing evidence that pericardial and epicardial fat volume (PFV, EFV) are associated with cardiovascular risk. We evaluated a novel method for accurate measurement of PFV and EFV using a 3D-Dixon based cardiac magnetic resonance (CMR) approach. An electrocardiography triggered and respiratory navigator gated 3D-gradient echo pulse sequence was used for cardiac Dixon imaging. Based on this sequence, voxels predominantly containing fat were identified and added up for volumetry. After accuracy assessment in phantoms, consisting of muscle tissue and seven different fat samples (50-200 ml), the sequence was acquired in 34 healthy volunteers (22 male, BMI range 14-42 kg/m(2), age range 21-79 years) at 1.5 T. Analysis was performed independently by two readers who draw two 3D-regions of interest, one for EFV and one for PFV. Additionally, EFV and PFV were compared between overweighted and non-overweighted subjects. The phantom study showed an excellent agreement of measured and true fat volumes (maximum difference = 6 %, linear correlation coefficient R = 1.00). PFV over all volunteers was 158.0 +/- 126.4 ml and EFV was 77.0 +/- 55.3 ml. PFV and EFV were highly correlated (R = 0.96). Inter-reader agreement was good with a mean difference of 0.2 +/- 5.6 and 4.5 +/- 4.2 ml for PFV/EFV, (R > 0.99, each). EFV and PFV differed significantly between subjects with BMI > 25 kg/m(2) and BMI < 25 kg/m(2), n = 17 each (PFV 219.0 +/- 151.8 vs. 96.9 +/- 44.7 ml and EFV 102.3 +/- 66.3 vs. 51.7 +/- 23.6 ml, p < 0.001, each). The proposed 3D-Dixon based method allows accurate measurement of cardiac fat volumes. It provides a valuable tool for cardiovascular risk stratification by CMR. PMID- 26424493 TI - Lipomatous hypertrophy of the right ventricle and interventricular septum associated with ventricular arrhythmia. PMID- 26424494 TI - Rebranding public health as "soft healing" is not necessary. PMID- 26424495 TI - PAX3 and PAX7 as upstream regulators of myogenesis. AB - Like other subclasses within the PAX transcription factor family, PAX3 and PAX7 play important roles in the emergence of a number of different tissues during development. PAX3 regulates neural crest and, together with its orthologue PAX7, is also expressed in parts of the central nervous system. In this chapter we will focus on their role in skeletal muscle. Both factors are key regulators of myogenesis where Pax3 plays a major role during early skeletal muscle formation in the embryo while Pax7 predominates during post-natal growth and muscle regeneration in the adult. We review the expression and functions of these factors in the myogenic context. We also discuss mechanistic aspects of PAX3/7 function and modulation of their activity by interaction with other proteins, as well as the post-transcriptional and transcriptional regulation of their expression. PMID- 26424496 TI - Age-associated changes in regenerative capabilities of mesenchymal stem cell: impact on chronic wounds repair. AB - Mesenchymal stem cells (MSCs) represent an ideal source of autologous cell-based therapy for chronic wounds. Functional characteristics of MSCs may benefit wound healing by exerting their multi-regenerative potential. However, cell ageing resulting from chronic degenerative diseases or donor age could cause inevitable effects on the regenerative abilities of MSCs. A variety of studies have shown the relationship between MSC ageing and age-related dysfunction, but few associate these age-related impacts on MSCs with their ability of repairing chronic wounds, which are common in the elderly population. Here, we discuss the age-associated changes of MSCs and describe the potential impacts on MSC-based therapy for chronic wounds. Furthermore, critical evaluation of the current literatures is necessary for understanding the underlying mechanisms of MSC ageing and raising the corresponding concerns on considering their possible use for chronic wound repair. PMID- 26424497 TI - Association between use of proton pump inhibitors and non-typhoidal salmonellosis identified following investigation into an outbreak of Salmonella Mikawasima in the UK, 2013. AB - In November 2013, national public health agencies in England and Scotland identified an increase in laboratory-confirmed Salmonella Mikawasima. The role of proton pump inhibitors (PPIs) as a risk factor for salmonellosis is unclear; we therefore captured information on PPI usage as part of our outbreak investigation. We conducted a case-control study, comparing each case with two controls. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. Thirty-nine of 61 eligible cases were included in the study. The median age of cases was 45 years; 56% were female. Of these, 33% were admitted to hospital and 31% reported taking PPIs. We identified an association between PPIs and non-typhoidal salmonellosis (aOR 8.8, 95% CI 2.0-38.3). There is increasing evidence supporting the existence of an association between salmonellosis and PPIs; however, biological studies are needed to understand the effect of PPIs in the pathogenesis of Salmonella. We recommend future outbreak studies investigate PPI usage to strengthen evidence on the relevance of PPIs in Salmonella infection. These findings should be used to support the development of guidelines for patients and prescribers on the risk of gastrointestinal infection and PPI usage. PMID- 26424498 TI - Giant Optical Activity of Quantum Dots, Rods, and Disks with Screw Dislocations. AB - For centuries mankind has been modifying the optical properties of materials: first, by elaborating the geometry and composition of structures made of materials found in nature, later by structuring the existing materials at a scale smaller than the operating wavelength. Here we suggest an original approach to introduce optical activity in nanostructured materials, by theoretically demonstrating that conventional achiral semiconducting nanocrystals become optically active in the presence of screw dislocations, which can naturally develop during the nanocrystal growth. We show the new properties to emerge due to the dislocation-induced distortion of the crystal lattice and the associated alteration of the nanocrystal's electronic subsystem, which essentially modifies its interaction with external optical fields. The g-factors of intraband transitions in our nanocrystals are found comparable with dissymmetry factors of chiral plasmonic complexes, and exceeding the typical g-factors of chiral molecules by a factor of 1000. Optically active semiconducting nanocrystals-with chiral properties controllable by the nanocrystal dimensions, morphology, composition and blending ratio-will greatly benefit chemistry, biology and medicine by advancing enantiomeric recognition, sensing and resolution of chiral molecules. PMID- 26424499 TI - Man and VAD: Deus Ex Machina. PMID- 26424500 TI - Renoprotective effects of continuous positive airway pressure in chronic kidney disease patients with sleep apnea. AB - PURPOSE: Chronic kidney disease (CKD) is associated with a high incidence of obstructive sleep apnea (OSA). We assessed the effect of continuous positive airway pressure (CPAP) on renal function in patients with CKD and OSA. METHODS: In this retrospective cohort study, 42 patients with Stage 3-5 CKD and OSA were stratified into two groups: patients who use CPAP more (average >4 h/night on >70 % of nights) and patients who use CPAP less (average <=4 h/night on <=70 % of nights). Median follow-up time was 2.3 (1.6-2.9) years for greater and 2.0 (0.6 3.5) years for lesser CPAP users. Chart reviews were carried out to record clinical characteristics, proteinuria measurements by urine dipstick, and eGFR values calculated by CKD-EPI equations. Univariate analyses were performed using Wilcoxon rank-sum and Kruskal-Wallis tests. Multivariate logistic regression models were applied to assess eGFR decline after CPAP prescription. RESULTS: Twelve (29 %) of the 42 subjects used CPAP more. Groups were similar with respect to age, body mass index, blood pressure, Charlson Comorbidity Index, and baseline eGFR and proteinuria. The median rate of decline of eGFR was significantly slower at -0.07 mL/min/1.73 m(2)/year (range -30 to 13) in those who used more CPAP compared to those who used it less at -3.15 mL/min/1.73 m(2)/year (range -27 to 7) (p = 0.027).Greater use of CPAP was also associated with a significantly reduced level of proteinuria at 0.15 (range 0.0-3.0) versus 0.70 g/L (range 0.0 3.0) (p = 0.046). Less compliant CPAP users were more likely to have progressive decline of eGFR (decline >3 mL/min/1.73 m(2)/year), with unadjusted OR 5.0 (95 % CI 0.93-26.8) and adjusted OR 8.9 (95 % CI 1.1-72.8), adjusting for CCI and baseline eGFR. CONCLUSIONS: Compliance to CPAP therapy is associated with a slower rate of progression of CKD in patients with CKD and OSA. PMID- 26424501 TI - The Clinical Outcome of Hypofractionated Stereotactic Radiotherapy With CyberKnife Robotic Radiosurgery for Perioptic Pituitary Adenoma. AB - Stereotactic radiation technique including single fraction radiosurgery and conventional fractionated stereotactic radiotherapy is widely reported as an effective treatment of pituitary adenomas. Because of the restricted radiation tolerance dose of the optic pathway, single fraction radiosurgery has been accepted for small tumor located far away from the optic apparatus, while fractionated stereotactic radiotherapy may be suitable for larger tumor located close to the optic pathway. More recently, hypofractionated stereotactic radiotherapy has become an alternative treatment option that provides high rate of tumor control and visual preservation for the perioptic lesions within 2 to 3 mm of the optic pathway. The objective of the study was to analyze the clinical outcomes of perioptic pituitary adenomas treated with hypofractionated stereotactic radiotherapy. From 2009 to 2012, 40 patients with perioptic pituitary adenoma were treated with CyberKnife robotic radiosurgery. The median tumor volume was 3.35 cm3 (range, 0.82-25.86 cm3). The median prescribed dose was 25 Gy (range, 20-28 Gy) in 5 fractions (range, 3-5). After the median follow-up time of 38.5 months (range, 14-71 months), 1 (2.5%) patient with prolactinoma had tumor enlargement, 31 (77.5%) were stable, and the remaining 8 (20%) tumors were smaller in size. No patient's vision deteriorated after hypofractionated stereotactic radiotherapy. Hormone normalization was observed in 7 (54%) of 13 patients. No newly developed hypopituitarism was detected in our study. These data confirmed that hypofractionated stereotactic radiotherapy achieved high rates of tumor control and visual preservation. Because of the shorter duration of treatment, it may be preferable to use hypofractionated stereotactic radiotherapy over fractionated stereotactic radiotherapy for selected pituitary adenomas immediately adjacent to the optic apparatus. PMID- 26424502 TI - Stereotactic Radiotherapy in the Retreatment of Recurrent Cervical Cancers, Assessment of Toxicity, and Treatment Response: Initial Results and Literature Review. AB - AIM: To evaluate the role of stereotactic body radiation therapy in the retreatment of locally recurrent cervical cancers. Brachytherapy is the main choice to treat gynecologic cancers. METHODS: Patients with recurrent cervical cancer, previously submitted to radiotherapy, were treated with stereotactic body radiation therapy using a CyberKnife system (Accuray Incorporated, Sunnyvale, California) with a fiducial tracking system. RESULTS: From August 2011 to October 2014, 5 patients have been treated. Median age was 81 years (range, 70-84 years). Two patients were diagnosed with adenocarcinoma endometrioid and 3 with squamous cell carcinoma. Toxicity was scored according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. After a median follow-up of 12 months (range, 8-34 months), no severe (>grade 3) acute/late genitourinary or low gastrointestinal toxicity was observed. CONCLUSION: Our preliminary results of stereotactic body radiation therapy "simulating" high dose rate for recurrent cervical cancers confirm a minimal toxicity and an optimal outcome. The stereotactic body radiation therapy is an alternative to high dose rate brachytherapy for gynecologic tumors. PMID- 26424503 TI - Dynamical preparation of Floquet Chern insulators. AB - Realizing topological insulators is of great current interest because of their remarkable properties and possible future applications. There are recent proposals based on Floquet analyses that one can generate topologically non trivial insulators by periodically driving topologically trivial ones. Here we address what happens if one follows the dynamics in such systems. Specifically, we present an exact study of the time evolution of a graphene-like system subjected to a circularly polarized electric field. We prove that for infinite (translationally invariant) systems the Chern number is conserved under unitary evolution. For systems with boundaries, on the other hand, we show that a properly defined topological invariant, the Bott index, can change. Hence, it should be possible to experimentally prepare topological states starting from non topological ones. We show that the chirality of the edge current in such systems can be controlled by adjusting the filling. PMID- 26424504 TI - No weak days? Impact of day in the week on surgical mortality. AB - BACKGROUND: Studies show increased rates of mortality for admissions on the weekend (WE) versus the weekday (WD). However, scepticism exists of this so called 'weekend effect' on patient outcome. It remains poorly investigated, particularly the timing of the day of surgery and post-operative outcomes. A UK study found higher odds of death when operated on Friday and the WE, versus WD. This relationship was investigated by interrogating the Australian and New Zealand Audit of Surgical Mortality database. METHODS: A standardized tool is used to collect data after every surgical death. Data in this retrospective cohort study from participating private and public hospitals in Australia on elective and emergency operations were extracted and included 7718 patients who had a surgical procedure within 30 days of admission and who subsequently died. A proxy measure of early surgical mortality, namely odds of dying within the first 48 h following surgery, was used to compare surgical mortality across days of the week. RESULTS: Unadjusted and adjusted odds of early surgical mortality were higher on the WE compared to WD, unadjusted and adjusted OR 1.30 (P < 0.001) and 1.19 (P = 0.026), respectively. When separated by day of week, there was a trend for higher surgical mortality on Friday, Saturday and Sunday versus all other days, although this did not reach statistical significance. ASA grade and specialty of surgery were important predictors of outcome. CONCLUSION: There appears to be an association between day of surgery and surgical outcome. The exact cause and contributing factors requires further investigation. PMID- 26424506 TI - A zinc fixative for 3D visualization of cerebral capillaries and pericytes. AB - BACKGROUND: A large volume of data indicates that disturbances in the morphology and function of the capillary wall may play a causal role in several types of neurodegenerative disorders. We present a highly reproducible staining method for investigating the cerebral capillary network and the pericyte cells within the basement membrane in mice - a specie specific challenging task when uniform staining in thick sections was needed for confocal microscopy or a quantitative analysis, e.g. stereological investigation using 3D probes. NEW METHOD: We perfused C57BL6/Jbom mice and immersion fixated the brains with an aldehyde free zinc fixative, which is normally used for paraffin embedded tissues, and stained for CD31 and Collagen Type IV positive capillaries in 100MUm thick sections. RESULTS: Using the milder zinc fixative allowed complete immunohistochemical visualization of the cerebral capillary network in 100MUm thick sections using CD31 or Collagen Type IV antibodies. Moreover CD31 or Collagen Type IV staining revealed the presence of pericytes, which was confirmed by a fluorescent co localization with the NG2 pericyte marker. COMPARISON WITH EXISTING METHODS: Compared with conventional aldehyde-based fixative, this method resulted in a homogeneous staining through the entire depth of thick sections with very limited background staining and well-preserved morphology. CONCLUSIONS: This method is suitable for 3D stereological analysis of capillary networks and pericytes within thick brain sections using CD31 or Collagen Type IV antibodies. PMID- 26424505 TI - High rates of unplanned interruptions from HIV care early after antiretroviral therapy initiation in Nigeria. AB - BACKGROUND: Unplanned care interruption (UCI) challenges effective HIV treatment. We determined the frequency and risk factors for UCI in Nigeria. METHODS: We conducted a retrospective-cohort study of adults initiating antiretroviral therapy (ART) between January 2009 and December 2011. At censor, patients were defined as in care, UCI, or inactive. Associations between baseline factors and UCI rates were quantified using Poisson regression. RESULTS: Among 2,496 patients, 44 % remained in care, 35 % had >=1 UCI, and 21 % became inactive. UCI rates were higher in the first year on ART (39/100PY), than the second (19/100PY), third (16/100PY), and fourth (14/100PY) years (p < 0.001). In multivariate analysis, baseline CD4 > 350/uL (IRR 3.21, p < 0.0001), being a student (IRR 1.95, p < 0.0001), and less education (IRR 1.58, p = 0.001) increased risk for UCI. Fifty-five percent of patients with UCI and viral load data had HIV viral load > 1,000 copies/ml upon return to care. DISCUSSION: UCI were observed in over one-third of patients treated, and were most common in the first year on ART. High baseline CD4 count at ART initiation was the greatest predictor of subsequent UCI. CONCLUSIONS: Interventions focused on the first year on ART are needed to improve continuity of HIV care. PMID- 26424508 TI - A fully parallel in time and space algorithm for simulating the electrical activity of a neural tissue. AB - BACKGROUND: The resolution of a model describing the electrical activity of neural tissue and its propagation within this tissue is highly consuming in term of computing time and requires strong computing power to achieve good results. NEW METHOD: In this study, we present a method to solve a model describing the electrical propagation in neuronal tissue, using parareal algorithm, coupling with parallelization space using CUDA in graphical processing unit (GPU). RESULTS: We applied the method of resolution to different dimensions of the geometry of our model (1-D, 2-D and 3-D). The GPU results are compared with simulations from a multi-core processor cluster, using message-passing interface (MPI), where the spatial scale was parallelized in order to reach a comparable calculation time than that of the presented method using GPU. A gain of a factor 100 in term of computational time between sequential results and those obtained using the GPU has been obtained, in the case of 3-D geometry. Given the structure of the GPU, this factor increases according to the fineness of the geometry used in the computation. COMPARISON WITH EXISTING METHOD(S): To the best of our knowledge, it is the first time such a method is used, even in the case of neuroscience. CONCLUSION: Parallelization time coupled with GPU parallelization space allows for drastically reducing computational time with a fine resolution of the model describing the propagation of the electrical signal in a neuronal tissue. PMID- 26424507 TI - In vivo imaging of axonal transport in murine motor and sensory neurons. AB - BACKGROUND: Axonal transport is essential for neuronal function and survival. Defects in axonal transport have been identified as an early pathological feature in several disorders of the nervous system. The visualisation and quantitative analysis of axonal transport in vivo in rodent models of neurological disease is therefore crucial to improve our understanding of disease pathogenesis and for the identification of novel therapeutics. NEW METHOD: Here, we describe a method for the in vivo imaging of axonal transport of signalling endosomes in the sciatic nerve of live, anaesthetised mice. RESULTS: This method allows the multiparametric, quantitative analysis of in vivo axonal transport in motor and sensory neurons of adult mice in control conditions and during disease progression. COMPARISON WITH EXISTING METHODS: Previous in vivo imaging of the axonal transport of signalling endosomes has been limited to studies in nerve explant preparations or non-invasive approaches using magnetic resonance imaging; techniques that are hampered by major drawbacks such as tissue damage and low temporal and spatial resolution. This new method allows live imaging of the axonal transport of single endosomes in the sciatic nerve in situ and a more sensitive analysis of axonal transport kinetics than previous approaches. CONCLUSIONS: The method described in this paper allows an in-depth analysis of the characteristics of axonal transport in both motor and sensory neurons in vivo. It enables the detailed study of alterations in axonal transport in rodent models of neurological diseases and can be used to identify novel pharmacological modifiers of axonal transport. PMID- 26424509 TI - The challenges of reshaping disease specific and care oriented community based services towards comprehensive goals: a situation appraisal in the Western Cape Province, South Africa. AB - BACKGROUND: Similar to other countries in the region, South Africa is currently reorienting a loosely structured and highly diverse community care system that evolved around HIV and TB, into a formalized, comprehensive and integrated primary health care outreach programme, based on community health workers (CHWs). While the difficulties of establishing national CHW programmes are well described, the reshaping of disease specific and care oriented community services, based outside the formal health system, poses particular challenges. This paper is an in-depth case study of the challenges of implementing reforms to community based services (CBS) in one province of South Africa. METHODS: A multi method situation appraisal of CBS in the Western Cape Province was conducted over eight months in close collaboration with provincial stakeholders. The appraisal mapped the roles and service delivery, human resource, financing and governance arrangements of an extensive non-governmental organisation (NGO) contracted and CHW based service delivery infrastructure that emerged over 15-20 years in this province. It also gathered the perspectives of a wide range of actors - including communities, users, NGOs, PHC providers and managers - on the current state and future visions of CBS. RESULTS: While there was wide support for new approaches to CBS, there are a number of challenges to achieving this. Although largely government funded, the community based delivery platform remains marginal to the formal public primary health care (PHC) and district health systems. CHW roles evolved from a system of home based care and are limited in scope. There is a high turnover of cadres, and support systems (supervision, monitoring, financing, training), coordination between CHWs, NGOs and PHC facilities, and sub-district capacity for planning and management of CBS are all poorly developed. CONCLUSIONS: Reorienting community based services that have their origins in care responses to HIV and TB presents an inter-related set of resource mobilisation, system design and governance challenges. These include not only formalising community based teams themselves, but also the forging of new roles, relationships and mind-sets within the primary health care system, and creating greater capacity for contracting and engaging a plural set of actors - government, NGO and community - at district and sub-district level. PMID- 26424510 TI - A comparison of intervention and conservative treatment for angulated fractures of the distal forearm in children (AFIC): study protocol for a randomized controlled trial. AB - BACKGROUND: Angulated fractures of the distal forearm are very frequent lesions in childhood. Currently, there are no standard guidelines on whether these children should be treated conservatively with a cast; with reduction and a cast; or with reduction, pinning and a cast under anesthesia. Minor prospective and retrospective studies have shown that the distal physis of the forearm possesses high remodeling capacity leading to reliable correction of malalignment. The aim of this trial is to answer the question about whether operative and conservative treatment show equivocal results. METHODS/DESIGN: This is a prospective, multinational, multicenter, randomized, observer-blinded, actively controlled, parallel group trial, with 24 months of observation. The primary objective of this trial is to assess whether or not the long-term functional outcome in remodeling patients is inferior to patients receiving closed reduction and K-wire pinning. The trial should include 742 patients with acute fracture. The patients will be included in 30 medical centers in Germany, Switzerland and Austria. All patients 5 to 11 years of age presenting at the emergency department with an angulated distal fracture of the forearm will be randomized online after informed consent. The primary endpoint is the Cooney Score after 24 months. The secondary endpoint is the grade of radiological displacement at 12/24 months. DISCUSSION: Therapy of angulated fractures is a matter of intensive debate. Primary manipulation and pinning under general anesthesia is recommended in order to avoid malalignment. No major study has proven the advantage of manipulation and pinning over immobilization alone. Should remodeling appear to be a safe alternative, manipulation under general anesthesia, K-wire pinning and removal of pins could be avoided, thus sparing significant costs. TRIAL REGISTRATION: DRKS00004874 , 30 October 2013. PMID- 26424512 TI - Medical Researchers' Ancillary Care Obligations: The Relationship-Based Approach. AB - In this article, I provide a new account of the basis of medical researchers' ancillary care obligations. Ancillary care in medical research, or medical care that research participants need but that is not required for the validity or safety of a study or to redress research injuries, is a topic that has drawn increasing attention in research ethics over the last ten years. My view, the relationship-based approach, improves on the main existing theory, Richardson and Belsky's 'partial-entrustment model', by avoiding its problematic restriction on the scope of health needs for which researchers could be obligated to provide ancillary care. Instead, it grounds ancillary care obligations in a wide range of morally relevant features of the researcher-participant relationship, including the level of engagement between researchers and participants, and weighs these factors against each other. I argue that the level of engagement, that is, the duration and intensity of interactions, between researchers and participants matters for ancillary care because of its connection to the meaningfulness of a relationship, and I suggest that other morally relevant features can be grounded in researchers' role obligations. PMID- 26424511 TI - Psychiatric symptoms in adolescents: FKBP5 genotype--early life adversity interaction effects. AB - Psychiatric disorders are multi-factorial and their symptoms overlap. Constitutional and environmental factors influence each other, and this contributes to risk and resilience in mental ill-health. We investigated functional genetic variation of stress responsiveness, assessed as FKBP5 genotype, in relation to early life adversity and mental health in two samples of adolescents. One population-based sample of 909 12-year-old adolescents was assessed using the Life Incidence of Traumatic Events scale and the Strengths and Difficulties Questionnaire. One sample of 398 17-year-old adolescents, enriched for poly-victimized individuals (USSS), was assessed using the Juvenile Victimization Questionnaire and the Trauma Symptom Checklist for Children (TSCC). The FKBP5 rs1360780 and rs3800373 polymorphisms were genotyped using a fluorescence-based competitive allele-specific PCR. Most prominently among poly victimized older male adolescents, the least common alleles of the polymorphisms, in interaction with adverse life events, were associated with psychiatric symptoms, after controlling for ethno-socio-economic factors. The interaction effect between rs3800373 and adverse life events on the TSCC sub-scales-anxiety, depression, anger, and dissociation-and with the rs1360780 on dissociation in the USSS cohort remained significant after Bonferroni correction. This pattern of association is in line with the findings of clinical and neuroimaging studies, and implies interactive effects of FKBP5 polymorphisms and early life environment on several psychiatric symptoms. These correlates add up to provide constructs that are relevant to several psychiatric symptoms, and to identify early predictors of mental ill-health. PMID- 26424514 TI - Brain activity modifications following spinal cord stimulation for chronic neuropathic pain: A systematic review. AB - BACKGROUND AND OBJECTIVE: Spinal cord stimulation (SCS) is believed to exert supraspinal effects; however, these mechanisms are still far from fully elucidated. This systematic review aims to assess existing neurophysiological and functional neuroimaging literature to reveal current knowledge regarding the effects of SCS for chronic neuropathic pain on brain activity, to identify gaps in knowledge, and to suggest directions for future research. DATABASES AND DATA TREATMENT: Electronic databases and hand-search of reference lists were employed to identify publications investigating brain activity associated with SCS in patients with chronic neuropathic pain, using neurophysiological and functional neuroimaging techniques (fMRI, PET, MEG, EEG). Studies investigating patients with SCS for chronic neuropathic pain and studying brain activity related to SCS were included. Demographic data (age, gender), study factors (imaging modality, patient diagnoses, pain area, duration of SCS at recording, stimulus used) and brain areas activated were extracted from the included studies. RESULTS: Twenty four studies were included. Thirteen studies used neuroelectrical imaging techniques, eight studies used haemodynamic imaging techniques, two studies employed both neuroelectrical and haemodynamic techniques separately, and one study investigated cerebral neurobiology. CONCLUSIONS: The limited available evidence regarding supraspinal mechanisms of SCS does not allow us to develop any conclusive theories. However, the studies included appear to show an inhibitory effect of SCS on somatosensory evoked potentials, as well as identifying the thalamus and anterior cingulate cortex as potential mediators of the pain experience. The lack of substantial evidence in this area highlights the need for large-scale controlled studies of this kind. PMID- 26424513 TI - LUCID: A Quantitative Assay of ESCRT-Mediated Cargo Sorting into Multivesicular Bodies. AB - Endosomes are transportation nodes, mediating selective transport of soluble and transmembrane cargos to and from the Golgi apparatus, plasma membrane and lysosomes. As endosomes mature to become multivesicular bodies (MVBs), Endosomal Sorting Complexes Required for Transport (ESCRTs) selectively incorporate transmembrane cargos into vesicles that bud into the endosome lumen. Luminal vesicles and their cargoes are targeted for destruction when MVBs fuse with lysosomes. Common assays of endosomal luminal targeting, including fluorescence microscopy and monitoring of proteolytic cargo maturation, possess significant limitations. We present a quantitative assay system called LUCID (LUCiferase reporter of Intraluminal Deposition) that monitors exposure of chimeric luciferase-cargo reporters to cytosol. Luciferase-chimera signal increases when sorting to the endosome lumen is disrupted, and silencing of signal from the chimera depends upon luminal delivery of the reporter rather than proteolytic degradation. The system presents several advantages, including rapidity, microscale operation and a high degree of reproducibility that enables detection of subtle phenotypic differences. Luciferase reporters provide linear signal over an extremely broad dynamic range, allowing analysis of reporter traffic even at anemic levels of expression. Furthermore, LUCID reports transport kinetics when applied to inducible trafficking reporters. PMID- 26424515 TI - The influence of sun exposure on the DNA methylation status of MMP9, miR-137, KRT14 and KRT19 genes in human skin. AB - BACKGROUND: Studies have shown that a variety of environmental factors and habits are associated with epigenetic changes. In addition, various genes are also found to respond to UV radiation. OBJECTIVES: The aim of this study was to investigate the sun exposure influence on the DNA methylation profile on the matrix metalloprotease-9 (MMP9), microRNA 137 (miR-137), cytokeratin 14 (KRT14) and 19 (KRT19) genes of skin cells of subjects with no history of skin diseases. METHODS: Skin biopsies (5mm) were obtained using a punch technique on sun-exposed (outer forearm) and sun-protected areas (inner arm) from 30 corpses from the Brazilian Service of Death Investigation. Skin types were ranked according to Fitzpatrick's criteria. Genomic DNA was extracted and a DNA methylation analysis was performed using Methylation Specific PCR (MSP) or Methylation-Sensitive Restriction Enzymes (MSRE) of sun-exposed and sun-protected skin areas. RESULTS: No differences were found among the areas (p>0.05; McNemar), with the partially methylated condition found to be a common event in skin for both MMP9 and miR-137 genes and the methylated condition for both KRT14 and KRT19 genes. Additional analysis showed no differences in the methylation status when age, gender and skin type were considered, however, the methylation status of miR-137 gene seems to be gender-related. CONCLUSIONS: We conclude that sun exposure does not induce changes in the DNA methylation status in MMP9, miR-137, KRT14 and KRT19 genes. PMID- 26424517 TI - The 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: a practical chronicle of progress. PMID- 26424518 TI - The 2015 guidelines for idiopathic pulmonary fibrosis: an important chapter in the evolution of the management of patients with IPF. PMID- 26424516 TI - From stem cells to the law courts: DNA methylation, the forensic epigenome and the possibility of a biosocial archive. PMID- 26424519 TI - Classification of antituberculosis drugs: a new proposal based on the most recent evidence. PMID- 26424520 TI - Multitasking basal cells: combining stem cell and innate immune duties. PMID- 26424521 TI - The double-edged sword of neutrophilic inflammation in bronchiectasis. PMID- 26424522 TI - Should COPD stand for "comorbidity-related obstructive pulmonary disease"? PMID- 26424523 TI - Comorbidities in idiopathic pulmonary fibrosis patients: a systematic literature review. AB - Idiopathic pulmonary fibrosis (IPF) is associated with a fatal prognosis and manifests in patients over 60 years old who may have comorbidities. The prevalence and impact of comorbidities on the clinical course of IPF is unclear.This systematic literature review examined the prevalence of comorbidities and mortality associated with comorbidities in IPF patients. Relevant observational studies published in English from January 1990 to January 2015 identified via MEDLINE and EMBASE were included; bibliographies of articles were also searched.Among the 126 studies included, prevalence of pulmonary hypertension (PH) was 3-86%, 6-91% for obstructive sleep apnoea, 3-48% for lung cancer and 6-67% for chronic obstructive pulmonary disease (COPD). Nonrespiratory comorbidities included ischaemic heart disease (IHD) (3-68%) and gastro oesophageal reflux (GER) (0-94%). Mortality was highest among patients with IPF and lung cancer. Most studies assessed relatively small samples of patients with IPF.PH, COPD, lung cancer, GER and IHD are significant comorbidities; differences in IPF severity, case definitions and patient characteristics limited the comparability of findings. The identification and prompt treatment of comorbidities may have a clinically significant impact on overall outcome that is meaningful for patients with IPF. PMID- 26424524 TI - Pulse oximetry oxygen saturation during the 6-min walk test: a limit for stopping the test without resuming it. PMID- 26424525 TI - Guidance for the regulatory status of allergen extracts in clinical trials. PMID- 26424526 TI - "Dead space: the physiology of wasted ventilation." H. Thomas Robertson. Eur Respir J 2015; 45: 1704-1716. PMID- 26424528 TI - Dermoscopy and reflectance confocal microscopy in cutaneous leishmaniasis on the face. PMID- 26424529 TI - The effect of the phytol-rich fraction from Lacistema pubescens against Leishmania amazonensis is mediated by mitochondrial dysfunction. AB - Leishmaniasis is a complex disease caused by protozoan parasite Leishmania and the treatment remains a serious problem since the available drugs exhibited high toxicity and side effects. Plant-derived natural products are promising leads for the development of novel chemotherapeutics. In this work the phytol-rich hexane fraction (PRF) from the leaves of Lacistema pubescens was obtained and identified by GC-MS analysis. When assayed for antileishmanial effects, PRF was active against promastigote and amastigote forms of Leishmania amazonensis (IC50 values of 44.0 and 25.8 MUg/mL respectively). Furthermore, PRF did not show significant cytotoxicity on peritoneal macrophages being more destructive to the intracellular parasite than to mammalian cells. In addition, possible targets of PRF were investigated against L. amazonensis promastigotes. The results showed that PRF exerted its antipromastigote activity by marked depolarization of the mitochondrial membrane potential followed by the increase of ROS levels in L. amazonensis promastigotes. During these events, no rupture of the cell membrane integrity was observed. Our results indicated that PRF was effective and selective against L. amazonensis, and that this effect was mainly mediated by mitochondrial dysfunction associated to ROS production. PMID- 26424530 TI - Real life management of community-acquired Pneumonia in adults in the Gulf region and comparison with practice guidelines: a prospective study. AB - BACKGROUND: Very few data exist on the management of community-acquired pneumonia (CAP) in patients admitted to hospitals in the Gulf region. The objectives of this study were to describe treatment patterns for CAP in 38 hospitals in five Gulf countries (United Arab Emirates, Kuwait, Bahrain, Oman, and Qatar) and to compare the findings to the most recent Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) guidelines. METHODS: This was a prospective, observational study conducted between January 2009 and February 2011. Adult patients hospitalised (excluding intensive care units) for CAP and subsequently discharged were included. Data were collected retrospectively at hospital discharge, and prospectively during two follow-up visits. Data on medical history, mortality-risk scores, diagnostic criteria, antibiotic treatment, isolated pathogens and clinical and radiographic outcomes were collected. Care practices were compared to the IDSA/ATS guidelines. RESULTS: A total of 684 patients were included. The majority (82.9 %) of patients were classified as low risk for mortality (pneumonia severity index II and III). The majority of patients fulfilled criteria for treatment success at discharge, although only 77.6 % presented a normalised leukocyte count. Overall, the management of CAP in Gulf countries is in line with the IDSA/ATS guidelines. This applied to the diagnosis of CAP, to the identification of high-risk CAP patients, to the identification of etiologic agent responsible for CAP and to the type of treatment despite the fact that combinations of antimicrobial agents were not consistent with the guidelines in 10 % of patients. In all patients, information about Gram's staining was not captured as recommended by the IDSA/ATS and in the majority of patients (>85 %) chest radiography was not systematically performed at the post-discharge follow-up visits. DISCUSSION: The management of CAP in the Gulf region is globally in line with current IDSA/ATS guidelines, although rates of pathogen characterisation and post-discharge follow-up need to be improved. CONCLUSION: Compliance with established guidelines should be encouraged in order to improve the management of the disease in this region. PMID- 26424531 TI - University Students Intend to Eat Better but Lack Coping Self-Efficacy and Knowledge of Dietary Recommendations. AB - OBJECTIVE: To assess university students' knowledge, intentions, and coping self efficacy related to dietary recommendations. DESIGN: The study used a cross sectional online survey. SETTING: Large university campus. PARTICIPANTS: Students (n = 6,638; 22% response). VARIABLES MEASURED: Self-efficacy and intentions were measured using 11-point scales. Students' perceived dietary recommendations were evaluated as correct or incorrect. ANALYSIS: Categorical variables were analyzed using chi-square and continuous variables by t tests or ANOVAs. Significance was set at P <= .05 and multiple comparisons at P <= .01. RESULTS: Respondents believed that they need fewer vegetables and fruit and more milk or alternatives servings/d than recommended; eg, males aged >= 19 years perceived milk or alternatives recommendations to be 4.3 +/- 2.1 servings/d, significantly more than the 2 servings/d recommended (P < .001). Students in health sciences or with a food or nutrition course were significantly more likely to claim that they met recommendations (eg, 56% with vs 47% without a food or nutrition course for vegetables and fruit; P < .001); however, they were no more likely to identify them correctly. Males aged < 19 years had higher coping self-efficacy than females aged < 19 years to consume vegetables (68.3 +/- 24.2 vs 64.0 +/- 24.7; P < .01) and avoid high-calorie foods and beverages (HCFB) (56.2 +/- 27.2 vs 49.0 +/- 25.2; P < .01) when under stress; however, they had significantly lower intentions to consume vegetables (72.1 +/- 24.5 vs 80.9 +/- 20.3; P < .01) and avoid HCFB (60.5 +/- 30.3 vs 77.7 +/- 22.8; P < .01). CONCLUSIONS AND IMPLICATIONS: Students do not have adequate knowledge of age- and sex-specific food guide recommendations. Simpler food guide recommendations or age- and sex targeted campaigns may enhance knowledge. Students intend to consume more vegetables and less HCFB; however, they have low coping self-efficacy, all of which could be targeted in nutrition interventions. PMID- 26424532 TI - Bonding and Bridging Social and Cultural Capitals: Perceived Factors Associated With Family Eating Practices Among Hmong, Latino, and White Mothers and Fathers. AB - OBJECTIVE: To examine perceived social and cultural capitals associated with family eating practices among Hmong, Latino, and white mothers and fathers. METHODS: Six focus groups composed of 52 Hmong, Latino, and white mothers and fathers of young children were conducted to examine parental perceptions of social and cultural capitals associated with eating practices. RESULTS: Whereas Hmong participants unanimously emphasized the healthfulness of their traditional food, Latino groups had divergent views on their traditional foods' healthfulness. Hmong parents highly valued their traditional foods whereas white and Latino mothers were more accepting of new foods from other cultures. Participants noted divergent views on gender roles in family eating practices and food culture preservation efforts. CONCLUSIONS AND IMPLICATIONS: Identifying and promoting bonding and bridging of cultural assets for healthy dietary practices among different cultural groups may be important for developing successful nutrition education programs across ethnicities in the community. PMID- 26424533 TI - Unit cell structure of water-filled monoolein in inverted hexagonal mesophase in the presence of incorporated tricaprylin and entrapped lysozyme. AB - Molecular dynamics (MD) was employed by means of a specific simulation protocol to investigate the equilibrium structure at 25 degrees C of the hexagonal inverted (HII) mesophase composed from water, 1-monoolein (GMO), and tricaprylin, with or without entrapped lysozyme. Based on robust and fast MD simulations, the study provides a comprehensive analysis and visualization of the local structure of HII mesophase containing admixtures. The most important physical insight is the possibility to observe the strong self-recovery capacity of the GMO layer, which allows the HII mesophase tubes to reorganize and host lysozyme molecules with a size bigger than the diameter of the water channel. This is a direct message to the experimenters that the HII mesophase has the potential to host molecules larger than the diameter of the water channel. Collective character of the interlipid interactions is outlined, which is not affected by the presence of the cargo and may be the reason for the efficient GMO reorganization. Another important result is the possible explanation of the role of triacylglycerols on the low-temperature stabilization of the HII mesophase. The analysis shows that despite the low amount of tricaprylin, its molecules prevent the extreme inclination of the lipid tails and thus optimize the alignment capacity of the lipid tails layer. The study also reveals that the packing frustration does not depend on the temperature and the presence of admixtures. Hence, it might be numerically defined as a universal invariant parameter of a stable HII mesophase composed of a certain lipid. PMID- 26424534 TI - [Patient Blood Management: where to start?]. PMID- 26424536 TI - Regulatory RNAs discovered in unexpected places. AB - Recent studies have discovered both small and long noncoding RNAs (ncRNAs) encoded in unexpected places. These ncRNA genes were surprises at the time of their discovery, but many quickly became well-accepted families of functional regulatory RNA species. Even after years of extensive gene annotation studies using high-throughput sequencing technologies, new types of ncRNA genes continue to be discovered in unexpected places. We highlight ncRNAs that have atypical structures and that are encoded in what are generally considered 'junk' sequences, such as spacers and introns. We also discuss current bottlenecks in the approaches for identifying novel ncRNAs and the possibility that many remain to be discovered. PMID- 26424538 TI - Night-time assaults in Newcastle 6-7 years after trading hour restrictions. PMID- 26424537 TI - Narrow pH Range of Surface Water Bodies Receiving Pesticide Input in Europe. AB - Fate and toxicity of the active ingredients (AI's) of plant protection products in surface waters is often influenced by pH. Although a general range of pH values is reported in literature, an evaluation targeting aquatic ecosystems with documented AI inputs is lacking at the larger scale. Results show 95% of European surface waters (n = 3075) with a documented history of AI exposure fall within a rather narrow pH range, between 7.0 and 8.5. Spatial and temporal variability in the data may at least be partly explained by the calcareous characteristics of parental rock material, the affiliation of the sampling site to a freshwater ecoregion, and the photosynthetic activity of macrophytes (i.e., higher pH values with photosynthesis). Nonetheless, the documented pH range fits well with the standard pH of most ecotoxicological test guidelines, confirming the fate and ecotoxicity of AIs are usually adequately addressed. PMID- 26424539 TI - Non-motor symptoms and quality of life in patients with Parkinson's disease in Northeastern Mexico. AB - Parkinson's disease (PD) is a multisystem disorder, and besides the classical motor symptoms it is now known that patients also suffer from a variety of non motor symptoms that adversely affect quality of life (QOL). Since data on Hispanic populations on this issue are scarce, our aim was to study the association of non-motor symptoms and QOL in patients with PD. This study is a cross-sectional observational study involving patients with PD using the following instruments: Quality of Life Questionnaire (PDQ-8), Unified Parkinson's Disease Rating Scale part III (UPDRS part III), and Non-Motor Symptom Scale (NMSS). We included 52 patients, with a median age of 64 years. Sleep/fatigue and mood/cognitive domains were the most common non-motor symptoms. Only sleep/fatigue, mood/cognition and gastrointestinal domains were associated with worse PDQ-8 scores. After adjusting for confounding variables, NMSS scores were significantly associated with a high PDQ-8 score. Higher NMSS scores were associated with and predicted higher PDQ-8 scores. The focus of management in PD should shift to a comprehensive strategy that incorporates care of non-motor symptoms and improves QOL. PMID- 26424535 TI - Choices for Induction of Pluripotency: Recent Developments in Human Induced Pluripotent Stem Cell Reprogramming Strategies. AB - The ability to generate human induced pluripotent stem cells (iPSCs) from somatic cells provides tremendous promises for regenerative medicine and its use has widely increased over recent years. However, reprogramming efficiencies remain low and chromosomal instability and tumorigenic potential are concerns in the use of iPSCs, especially in clinical settings. Therefore, reprogramming methods have been under development to generate safer iPSCs with higher efficiency and better quality. Developments have mainly focused on the somatic cell source, the cocktail of reprogramming factors, the delivery method used to introduce reprogramming factors and culture conditions to maintain the generated iPSCs. This review discusses the developments on these topics and briefly discusses pros and cons of iPSCs in comparison with human embryonic stem cells generated from somatic cell nuclear transfer. PMID- 26424540 TI - Hereditary multiple exostoses: an unusual cause of spinal cord compression. PMID- 26424541 TI - Wireless non-invasive continuous respiratory monitoring with FMCW radar: a clinical validation study. AB - Altered respiratory rate is one of the first symptoms of medical conditions that require timely intervention, e.g., sepsis or opioid-induced respiratory depression. To facilitate continuous respiratory rate monitoring on general hospital wards a contactless, non-invasive, prototype monitor was developed using frequency modulated continuous wave radar. We aimed to study whether radar can reliably measure respiratory rate in postoperative patients. In a diagnostic cross-sectional study patients were monitored with the radar and the reference monitor (pneumotachograph during mechanical ventilation and capnography during spontaneous breathing). Eight patients were included; yielding 796 min of observation time during mechanical ventilation and 521 min during spontaneous breathing. After elimination of movement artifacts the bias and 95 % limits of agreement for mechanical ventilation and spontaneous breathing were -0.12 (-1.76 to 1.51) and -0.59 (-5.82 to 4.63) breaths per minute respectively. The radar was able to accurately measure respiratory rate in mechanically ventilated patients, but the accuracy decreased during spontaneous breathing. PMID- 26424543 TI - The end of AIDS? PMID- 26424542 TI - Estimation of mortality among HIV-infected people on antiretroviral treatment in East Africa: a sampling based approach in an observational, multisite, cohort study. AB - BACKGROUND: Mortality in HIV-infected people after initiation of antiretroviral treatment (ART) in resource-limited settings is an important measure of the effectiveness and comparative effectiveness of the global public health response. Substantial loss to follow-up precludes accurate accounting of deaths and limits our understanding of effectiveness. We aimed to provide a better understanding of mortality at scale and, by extension, the effectiveness and comparative effectiveness of public health ART treatment in east Africa. METHODS: In 14 clinics in five settings in Kenya, Uganda, and Tanzania, we intensively traced a sample of patients randomly selected using a random number generator, who were infected with HIV and on ART and who were lost to follow-up (>90 days late for last scheduled visit). We incorporated the vital status outcomes for these patients into analyses of the entire clinic population through probability weighted survival analyses. FINDINGS: We followed 34 277 adults on ART from Mbarara and Kampala in Uganda, Eldoret, and Kisumu in Kenya, and Morogoro in Tanzania. The median age was 35 years (IQR 30-42), 11 628 (34%) were men, and median CD4 count count before therapy was 154 cells per MUL (IQR 70-234). 5780 patients (17%) were lost to follow-up, 991 (17%) were selected for tracing between June 10, 2011, and Aug 27, 2012, and vital status was ascertained for 860 (87%). With incorporation of outcomes from the patients lost to follow-up, estimated 3 year mortality increased from 3.9% (95% CI 3.6-4.2) to 12.5% (11.8 13.3). The sample-corrected, unadjusted 3 year mortality across settings was lowest in Mbarara (7.2%) and highest in Morogoro (23.6%). After adjustment for age, sex, CD4 count before therapy, and WHO stage, the sample-corrected hazard ratio comparing the settings with highest and lowest mortalities was 2.2 (95% CI 1.5-3.4) and the risk difference for death at 3 years was 11% (95% CI 5.0-17.7). INTERPRETATION: A sampling-based approach is widely feasible and important to an understanding of mortality after initiation of ART. After adjustment for measured biological drivers, mortality differs substantially across settings despite delivery of a similar clinical package of treatment. Implementation research to understand the systems, community, and patients' behaviours driving these differences is urgently needed. FUNDING: The US National Institutes of Health and President's Emergency Fund for AIDS Relief. PMID- 26424544 TI - Trying to cure HIV with immunotherapy: not so simple. PMID- 26424545 TI - End of AIDS on the horizon, but innovation needed to end HIV. PMID- 26424546 TI - CD4/CD8 ratio: an emerging biomarker for HIV. PMID- 26424547 TI - Where have all the patients gone? PMID- 26424548 TI - How can we end paediatric AIDS? PMID- 26424549 TI - Effect of therapeutic intensification followed by HIV DNA prime and rAd5 boost vaccination on HIV-specific immunity and HIV reservoir (EraMune 02): a multicentre randomised clinical trial. AB - BACKGROUND: Achievement of a cure for HIV infection might need reactivation of latent virus and improvement of HIV-specific immunity. As an initial step, in this trial we assessed the effect of antiretroviral therapy intensification and immune modulation with a DNA prime and recombinant adenovirus 5 (rAd5) boost vaccine. METHODS: In this multicentre, randomised, open-label, non-comparative, phase 2 clinical trial, we enrolled eligible adults 18-70 years of age with chronic HIV-1 infection on suppressive antiretroviral therapy with current CD4 count of at least 350 cells per MUL and HIV DNA between 10 and 1000 copies per 10(6) peripheral blood mononuclear cells. After an 8 week lead-in of antiretroviral intensification therapy (standard dose raltegravir and dose adjusted maraviroc based on baseline antiretroviral therapy), patients were randomly assigned (1:1) to receive antiretroviral therapy intensification alone or intensification plus injections of HIV DNA prime vaccine (4 mg VRC-HIVDNA016 00-VP) at weeks 8, 12, and 16, followed by HIV rAd5 boost vaccine (10(10) particle units of VRC-HIVADV014-00-VP) at week 32. Randomisation was computer generated in permuted blocks of six and was stratified by study site. The primary endpoint was a 0.5 log10 or greater decrease in HIV DNA in peripheral blood mononuclear cells at week 56. This study is registered with ClinicalTrials.gov, number NCT00976404. FINDINGS: Between Nov 29, 2010, and Oct 28, 2011, we enrolled 28 eligible patients from three academic HIV clinics in the USA. After the 8 week lead-in of antiretroviral intensification therapy, 14 patients were randomly assigned to continue antiretroviral therapy intensification alone and 14 to intensification plus vaccine. Enrolled participants had median CD4 count of 636 cells per MUL, median HIV DNA 170 copies per 10(6) peripheral blood mononuclear cells, and duration of antiretroviral therapy of 13 years. The median amount of HIV DNA did not change significantly between baseline and week 56 in the antiretroviral therapy intensification plus vaccine group. One participant in the antiretroviral therapy intensification alone group reached the primary endpoint, with 0.55 log10 decrease in HIV DNA in peripheral blood mononuclear cells. Both treatments were well tolerated. No severe or systemic reactions to vaccination occurred, and five serious adverse events were recorded during the study, most of which resolved spontaneously or were judged unrelated to study treatments. INTERPRETATION: Antiretroviral therapy intensification followed by DNA prime and rAd5 boost vaccine did not significantly increase HIV expression or reduce the latent HIV reservoir. A multifaceted approach that includes stronger activators of HIV expression and novel immune modulators will probably be needed to reduce the latent HIV reservoir and allow for long-term control in patients off antiretroviral therapy. FUNDING: Objectif Recherche Vaccin SIDA (ORVACS). PMID- 26424551 TI - Metabolic Engineering of Wheat Provitamin A by Simultaneously Overexpressing CrtB and Silencing Carotenoid Hydroxylase (TaHYD). AB - Increasing the provitamin A content in staple crops via carotenoid metabolic engineering is one way to address vitamin A deficiency. In this work a combination of methods was applied to specifically increase beta-carotene content in wheat by metabolic engineering. Endosperm-specific silencing of the carotenoid hydroxylase gene (TaHYD) increased beta-carotene content 10.5-fold to 1.76 MUg g( 1) in wheat endosperm. Overexpression of CrtB introduced an additional flux into wheat, accompanied by a beta-carotene increase of 14.6-fold to 2.45 MUg g(-1). When the "push strategy" (overexpressing CrtB) and "block strategy" (silencing TaHYD) were combined in wheat metabolic engineering, significant levels of beta carotene accumulation were obtained, corresponding to an increase of up to 31 fold to 5.06 MUg g(-1). This is the first example of successful metabolic engineering to specifically improve beta-carotene content in wheat endosperm through a combination of methods and demonstrates the potential of genetic engineering for specific nutritional enhancement of wheat. PMID- 26424552 TI - Down-regulation of PAR1 activity with a pHLIP-based allosteric antagonist induces cancer cell death. AB - Even though abnormal expression of G protein-coupled receptors (GPCRs) and of their ligands is observed in many cancer cells of various origins, only a few anti-cancer compounds directly act on their signalling. One promising approach to modulate their activity consists of targeting the receptor cytoplasmic surfaces interacting with the associated G-proteins using peptides mimicking the intracellular loops of the receptor. Thus, to be fully effective, the peptide mimics must be selectively targeted to the tumour while sparing healthy tissues, translocated across the cell membrane and stay anchored to the cytoplasmic leaflet of the plasma membrane. In the present study, we introduce a novel way to selectively target and inhibit the activity of a GPCR in cancer cells under acidic conditions, such as those found in solid tumours. We find that the conjugation of a peptide fragment derived from the third intracellular loop (i3) of the protease-activated receptor 1 (PAR1) to a peptide that can selectively target tumours solely based on their acidity [pH(Low) Insertion Peptide (pHLIP)], produces a construct capable of effectively down-regulating PAR1 activity in a concentration- and pH-dependent manner and of inducing a potent cytotoxic effect in a panel of cancer cells that is proportional to the relative level of receptor expression at the cell surface. This strategy not only allows for a more selective targeting and specific intracellular delivery than current approaches, but also offers new possibilities for developing novel anti-cancer drugs targeting GPCRs. PMID- 26424553 TI - Salvaging lowermost deployment of an acurate device during transcatheter aortic valve replacement with balloon and lasso pull techniques. AB - Transcatheter aortic valve replacement (TAVR), also known as transcatheter aortic valve implantation (TAVI), is being used with increasing frequency in patients with severe aortic stenosis at high or prohibitive surgical risk. A number of devices are becoming available for TAVR, and competence in using them is mandatory to maximize the safety and efficacy of TAVR, while individualizing device selection in keeping with patient features. The ACURATE TF is a novel promising device for transfemoral TAVR. However, its peculiar features may require additional maneuvers in case of complications. We hereby report the case of a patient undergoing transfemoral TAVR with the ACURATE TF device, in whom lowermost deployment was complicated by massive aortic regurgitation. With two separate remedial actions, the balloon pull and lasso techniques, we were able to pull back the device and significantly reduce post-TAVR aortic regurgitation. Awareness of this complication and the possible use of these two techniques may increase the safety and efficacy of TAVR with this and other new devices. (c) 2015 Wiley Periodicals, Inc. PMID- 26424554 TI - Gastric-type extremely well-differentiated adenocarcinoma arising in the blind pouch of a bypassed stomach, presenting as colonic pseudo-obstruction. AB - Gastric carcinoma after gastric bypass is rare. Extremely well-differentiated adenocarcinoma (EWDA) of the stomach is a rare variant that has been mostly reported in Japan. We present a case of a 68-year-old man with EWDA arising in the bypassed stomach that presented as a colonic pseudo-obstruction (CPO). Several imaging, endoscopic and pathologic studies performed in the course of 2 months were non-diagnostic. An iatrogenic duodenal perforation during a diagnostic procedure led to an emergent exploratory laparotomy in which the dilated colonic segment was resected. Pathologic examination showed metastatic EWDA in the colonic wall. Post-operative complications led to the patient's demise. At autopsy the primary tumor was identified in the blind pouch of the bypassed stomach. A literature review on gastric EWDA and carcinomas arising in bypassed stomachs is discussed. EWDA of the stomach is rare, difficult to diagnose, and shows an aggressive clinical course discordant with its near-benign histology. Gastric cancer arising in a bypassed stomach is uncommon; when it occurs it is usually diagnosed at advanced stage. Surveillance of the blind pouch is not currently recommended. Malignant infiltration of the colonic wall should be included in the differential diagnosis of CPO of unclear etiology. PMID- 26424550 TI - CD4/CD8 ratio normalisation and non-AIDS-related events in individuals with HIV who achieve viral load suppression with antiretroviral therapy: an observational cohort study. AB - BACKGROUND: In patients with HIV, immune reconstitution after antiretroviral therapy (ART) is often incomplete. We assessed the probability of patients reaching a CD4/CD8 ratio of 1 or more after the start of ART and its association with the onset of non-AIDS-defining events and death. METHODS: We did an analysis of the ICONA cohort, which recruited treatment-naive patients with HIV in Italy. We included participants in the cohort who started ART, reached an undetectable viral load (<=80 copies per mL), and had a CD4/CD8 ratio of less than 0.8 at the time of an undetectable viral load. We defined ratio normalisation in patients as two consecutive values of 1 or more. We used Kaplan-Meier curves to estimate the cumulative probability of ratio normalisation. We then used Poisson regression models to identify factors independently associated with normalisation and with progression to non-AIDS-defining events or death. FINDINGS: We included 3236 participants, enrolled between Jan 22, 1997, and Feb 25, 2013. At the start of ART, median CD4/CD8 ratio in our population was 0.39 (IQR 0.26-0.55). 458 (14%) patients reached a CD4/CD8 ratio of 1 or more; the estimated probability of normalisation was 4.4% (95% CI 3.7-5.2) by 1 year from baseline, 11.5% (10.2 13.0) by 2 years, and 29.4% (26.7-32.4) by 5 years. Factors associated with normalisation were high pre-ART CD4 cell counts, a high CD4/CD8 ratio at baseline, and negative cytomegalovirus serological findings. The incidence rate of non-AIDS-defining events for patients with a CD4/CD8 ratio of less than 0.30 (4.2 per 100 patient-years, 95% CI 3.4-5.3) was double that for those with a ratio of 0.30-0.45 (2.3, 2.1-2.5) or more than 0.45 (2.2, 1.7-2.9). A ratio of less than 0.30 was independently associated with an increased risk of non-AIDS defining events or death compared with one of more than 0.45. INTERPRETATION: Few patients had normalised CD4/CD8 ratios, even though they had viral suppression. Low ratios were associated with increased risk of serious events and deaths. The CD4/CD8 ratio could be used by clinicians to identity patients at risk of non AIDS-related events. FUNDING: AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp & Dohme, ViiV Italy. PMID- 26424556 TI - Erratum to: Long-term liposteroid therapy for idiopathic pulmonary hemosiderosis. PMID- 26424555 TI - Relationship between histology, development and tumorigenesis of mammary gland in female rat. AB - The mammary gland is a dynamic organ that undergoes structural and functional changes associated with growth, reproduction, and post-menopausal regression. The postnatal transformations of the epithelium and stromal cells of the mammary gland may contribute to its susceptibility to carcinogenesis. The increased cancer incidence in mammary glands of humans and similarly of rodents in association with their development is believed to be partly explained by proliferative activity together with lesser degree of differentiation, but it is not completely understood how the virgin gland retains its higher susceptibility to carcinogenesis. During its developmental cycle, the mammary gland displays many of the properties associated with breast cancer. An early first full-term pregnancy may have a protective effect. Rodent models are useful for investigating potential breast carcinogens. The purpose of this review is to help recognizing histological appearance of the epithelium and the stroma of the normal mammary gland in rats, and throughout its development in relation to tumorigenic potential. PMID- 26424557 TI - Kaiso represses the expression of glucocorticoid receptor via a methylation dependent mechanism and attenuates the anti-apoptotic activity of glucocorticoids in breast cancer cells. AB - Kaiso is a Pox Virus and Zinc Finger (POZ-ZF) transcription factor with bi-modal DNA-binding specificity. Here, we demonstrated that Kaiso expression is inversely correlated with glucocorticoid receptor (GR) expression in breast carcinomas. Knockdown of Kaiso increased GR expression, while overexpression of Kaiso inhibited GR expression in breast cancer cells. Furthermore, Kaiso repressed GR proximal promoter-reporter activity in a dose-dependent manner. Remarkably, ChIP experiments demonstrated that endogenous Kaiso was associated with the GR promoter sequence in a methylation-dependent manner. Since glucocorticoids inhibit chemotherapyinduced apoptosis and have been widely used as a co-treatment of patients with breast cancer, we assessed the role of Kasio in GR-mediated anti apoptotic effects. We found that overexpression of Kaiso attenuated the anti apoptotic effects of glucocorticoids in breast cancer cells. Our findings suggest that GR is a putative target gene of Kaiso and suggest Kaiso to be a potential therapeutic target in GC-combination chemotherapy in breast cancer. [BMB Reports 2016; 49(3): 167-172]. PMID- 26424559 TI - Implications of NQO1 in cancer therapy. AB - NAD(P)H: quinone oxidoreductase (NQO1), an obligatory two-electron reductase, is a ubiquitous cytosolic enzyme that catalyzes the reduction of quinone substrates. The NQO1- mediated two-electron reduction of quinones can be either chemoprotection/detoxification or a chemotherapeutic response, depending on the target quinones. When toxic quinones are reduced by NQO1, they are conjugated with glutathione or glucuronic acid and excreted from the cells. Based on this protective effect of NQO1, the use of dietary compounds to induce the expression of NQO1 has emerged as a promising strategy for cancer prevention. On the other hand, NQO1-mediated two-electron reduction converts certain quinone compounds (such as mitomycin C, E09, RH1 and ?-lapachone) to cytotoxic agents, leading to cell death. It has been known that NQO1 is expressed at high levels in numerous human cancers, including breast, colon, cervix, lung, and pancreas, as compared with normal tissues. This implies that tumors can be preferentially damaged relative to normal tissue by cytotoxic quinone drugs. Importantly, NQO1 has been shown to stabilize many proteins, including p53 and p33ING1b, by inhibiting their proteasomal degradation. This review will summarize the biological roles of NQO1 in cancer, with emphasis on recent findings and the potential of NQO1 as a therapeutic target for the cancer therapy. PMID- 26424558 TI - Stanniocalcin 2 enhances mesenchymal stem cell survival by suppressing oxidative stress. AB - To overcome the disadvantages of stem cell-based cell therapy like low cell survival at the disease site, we used stanniocalcin 2 (STC2), a family of secreted glycoprotein hormones that function to inhibit apoptosis and oxidative damage and to induce proliferation. STC2 gene was transfected into two kinds of stem cells to prolong cell survival and protect the cells from the damage by oxidative stress. The stem cells expressing STC2 exhibited increased cell viability and improved cell survival as well as elevated expression of the pluripotency and self-renewal markers (Oct4 and Nanog) under sub-lethal oxidative conditions. Up-regulation of CDK2 and CDK4 and down-regulation of cell cycle inhibitors p16 and p21 were observed after the delivery of STC2. Furthermore, STC2 transduction activated pAKT and pERK 1/2 signal pathways. Taken together, the STC2 can be used to enhance cell survival and maintain long-term stemness in therapeutic use of stem cells. PMID- 26424561 TI - Eighth International Symposium on Intensive Care and Emergency Medicine for Latin America. PMID- 26424560 TI - MYC and BCL-2 adjusted-International Prognostic Index (A-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. AB - The International Prognostic Index (IPI) has been the basis for determining prognosis in patients with diffuse large B-cell lymphoma (DLBCL) for the past 20 years. The utility of the IPI must be reassessed in the era of immunochemotherapy. Seven risk factors at diagnosis were identified, and a maximum of 7 points were assigned to each patient. Four risk groups were created: low (0-1), low-intermediate (2-3), high-intermediate (4), and high (5-7). Using MYC and BCL-2 clinical data from the Drum Tower Hospital collected during the rituximab era, we performed a retrospective analysis of patients with DLBCL treated with R-CHOP and built an biological markers adjusted IPI with the goal of improving risk stratification.Clinical features from 60 adults with de novo DLBCL diagnosed from 2008-2013 were assessed for their prognostic significance. The IPI remains predictive, but it cannot identify the high-risk subgroup. Compared with the IPI, the MYC and BCL-2 adjusted-IPI (A-IPI) better discriminated patients in the high-risk subgroup (4-year overall survival [OS]: 33.3%) than did the IPI (4 year OS: 48.0%). In the era of R-CHOP treatment, MYC and BCL-2 adjusted-IPI is more powerful than the IPI for helping guide treatment planning and interpretation of clinical trials. PMID- 26424562 TI - Potentially fatal arrhythmias in two cases of adult Kawasaki disease. AB - Fatal arrhythmias in asymptomatic Kawasaki disease patients with normal left ventricular function have rarely been reported. In this study, we report the cases of two adult patients with largely unpredictable sudden cardiac arrest, despite almost-normal left ventricular function even after the diagnosis of presumed Kawasaki disease, as well as consider the mechanisms involved with reference to the literature. PMID- 26424563 TI - Androgen deprivation therapy for prostate cancer: friend or foe to the cardiovascular system? PMID- 26424565 TI - Asthma: Undoing millions of years of coevolution in early life? PMID- 26424564 TI - Hippocampal volume and cingulum bundle fractional anisotropy are independently associated with verbal memory in older adults. AB - The objective of this study was to investigate the relationship of medial temporal lobe and posterior cingulate cortex (PCC) volumetrics as well as fractional anisotropy of the cingulum angular bundle (CAB) and the cingulum cingulate gyrus (CCG) bundle to performance on measures of verbal memory in non demented older adults. The participants were 100 non-demented adults over the age of 70 years from the Einstein Aging Study. Volumetric data were estimated from T1 weighted images. The entire cingulum was reconstructed using diffusion tensor MRI and probabilistic tractography. Association between verbal episodic memory and MRI measures including volume of hippocampus (HIP), entorhinal cortex (ERC), PCC and fractional anisotropy of CAB and CCG bundle were modeled using linear regression. Relationships between atrophy of these structures and regional cingulum fractional anisotropy were also explored. Decreased HIP volume on the left and decreased fractional anisotropy of left CAB were associated with lower memory performance. Volume changes in ERC, PCC and CCG disruption were not associated with memory performance. In regression models, left HIP volume and left CAB-FA were each independently associated with episodic memory. The results suggest that microstructural changes in the left CAB and decreased left HIP volume independently influence episodic memory performance in older adults without dementia. The importance of these findings in age and illness-related memory decline require additional exploration. PMID- 26424566 TI - Endogenous retroviruses in ALS: A reawakening? PMID- 26424567 TI - Early infancy microbial and metabolic alterations affect risk of childhood asthma. AB - Asthma is the most prevalent pediatric chronic disease and affects more than 300 million people worldwide. Recent evidence in mice has identified a "critical window" early in life where gut microbial changes (dysbiosis) are most influential in experimental asthma. However, current research has yet to establish whether these changes precede or are involved in human asthma. We compared the gut microbiota of 319 subjects enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) Study, and show that infants at risk of asthma exhibited transient gut microbial dysbiosis during the first 100 days of life. The relative abundance of the bacterial genera Lachnospira, Veillonella, Faecalibacterium, and Rothia was significantly decreased in children at risk of asthma. This reduction in bacterial taxa was accompanied by reduced levels of fecal acetate and dysregulation of enterohepatic metabolites. Inoculation of germ free mice with these four bacterial taxa ameliorated airway inflammation in their adult progeny, demonstrating a causal role of these bacterial taxa in averting asthma development. These results enhance the potential for future microbe-based diagnostics and therapies, potentially in the form of probiotics, to prevent the development of asthma and other related allergic diseases in children. PMID- 26424568 TI - Human endogenous retrovirus-K contributes to motor neuron disease. AB - The role of human endogenous retroviruses (HERVs) in disease pathogenesis is unclear. We show that HERV-K is activated in a subpopulation of patients with sporadic amyotrophic lateral sclerosis (ALS) and that its envelope (env) protein may contribute to neurodegeneration. The virus was expressed in cortical and spinal neurons of ALS patients, but not in neurons from control healthy individuals. Expression of HERV-K or its env protein in human neurons caused retraction and beading of neurites. Transgenic animals expressing the env gene developed progressive motor dysfunction accompanied by selective loss of volume of the motor cortex, decreased synaptic activity in pyramidal neurons, dendritic spine abnormalities, nucleolar dysfunction, and DNA damage. Injury to anterior horn cells in the spinal cord was manifested by muscle atrophy and pathological changes consistent with nerve fiber denervation and reinnervation. Expression of HERV-K was regulated by TAR (trans-activation responsive) DNA binding protein 43, which binds to the long terminal repeat region of the virus. Thus, HERV-K expression within neurons of patients with ALS may contribute to neurodegeneration and disease pathogenesis. PMID- 26424569 TI - Human IFNAR2 deficiency: Lessons for antiviral immunity. AB - Type I interferon (IFN-alpha/beta) is a fundamental antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-alpha/beta in immunity, although validation of these findings in humans has been limited. We investigated a previously healthy child with fatal encephalitis after inoculation of the live attenuated measles, mumps, and rubella (MMR) vaccine. By targeted resequencing, we identified a homozygous mutation in the high-affinity IFN alpha/beta receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-alpha/beta. Reconstitution of the proband's cells with wild-type IFNAR2 restored IFN-alpha/beta responsiveness and control of IFN-attenuated viruses. Despite the severe outcome of systemic live vaccine challenge, the proband had previously shown no evidence of heightened susceptibility to respiratory viral pathogens. The phenotype of IFNAR2 deficiency, together with similar findings in STAT2-deficient patients, supports an essential but narrow role for IFN-alpha/beta in human antiviral immunity. PMID- 26424570 TI - DEL-1 restrains osteoclastogenesis and inhibits inflammatory bone loss in nonhuman primates. AB - DEL-1 (developmental endothelial locus-1) is an endothelial cell-secreted protein that regulates LFA-1 (lymphocyte function-associated antigen-1) integrin dependent leukocyte recruitment and inflammation in various tissues. We identified a novel regulatory mechanism of DEL-1 in osteoclast biology. Specifically, we showed that DEL-1 is expressed by human and mouse osteoclasts and regulates their differentiation and resorptive function. Mechanistically, DEL 1 inhibited the expression of NFATc1, a master regulator of osteoclastogenesis, in a Mac-1 integrin-dependent manner. In vivo mechanistic analysis has dissociated the anti-inflammatory from the anti-bone-resorptive action of DEL-1 and identified structural components thereof mediating these distinct functions. Locally administered human DEL-1 blocked inflammatory periodontal bone loss in nonhuman primates-a relevant model of human periodontitis. The ability of DEL-1 to regulate both upstream (inflammatory cell recruitment) and downstream (osteoclastogenesis) events that lead to inflammatory bone loss paves the way to a new class of endogenous therapeutics for treating periodontitis and perhaps other inflammatory disorders. PMID- 26424573 TI - The epigenetic regulator UHRF1 promotes ubiquitination-mediated degradation of the tumor-suppressor protein promyelocytic leukemia protein. PMID- 26424572 TI - Lessons from Ebola: Improving infectious disease surveillance to inform outbreak management. AB - The current Ebola virus disease outbreak in West Africa has revealed serious shortcomings in national and international capacity to detect, monitor, and respond to infectious disease outbreaks as they occur. Recent advances in diagnostics, risk mapping, mathematical modeling, pathogen genome sequencing, phylogenetics, and phylogeography have the potential to improve substantially the quantity and quality of information available to guide the public health response to outbreaks of all kinds. PMID- 26424571 TI - Efficient modification of CCR5 in primary human hematopoietic cells using a megaTAL nuclease and AAV donor template. AB - Genetic mutations or engineered nucleases that disrupt the HIV co-receptor CCR5 block HIV infection of CD4(+) T cells. These findings have motivated the engineering of CCR5-specific nucleases for application as HIV therapies. The efficacy of this approach relies on efficient biallelic disruption of CCR5, and the ability to efficiently target sequences that confer HIV resistance to the CCR5 locus has the potential to further improve clinical outcomes. We used RNA based nuclease expression paired with adeno-associated virus (AAV)-mediated delivery of a CCR5-targeting donor template to achieve highly efficient targeted recombination in primary human T cells. This method consistently achieved 8 to 60% rates of homology-directed recombination into the CCR5 locus in T cells, with over 80% of cells modified with an MND-GFP expression cassette exhibiting biallelic modification. MND-GFP-modified T cells maintained a diverse repertoire and engrafted in immune-deficient mice as efficiently as unmodified cells. Using this method, we integrated sequences coding chimeric antigen receptors (CARs) into the CCR5 locus, and the resulting targeted CAR T cells exhibited antitumor or anti-HIV activity. Alternatively, we introduced the C46 HIV fusion inhibitor, generating T cell populations with high rates of biallelic CCR5 disruption paired with potential protection from HIV with CXCR4 co-receptor tropism. Finally, this protocol was applied to adult human mobilized CD34(+) cells, resulting in 15 to 20% homologous gene targeting. Our results demonstrate that high-efficiency targeted integration is feasible in primary human hematopoietic cells and highlight the potential of gene editing to engineer T cell products with myriad functional properties. PMID- 26424574 TI - Anterior Cruciate Ligament Injury Prevention and Rehabilitation: Let's Get It Right. AB - Anterior cruciate ligament (ACL) injuries are among the most common and functionally disabling conditions in orthopaedics and sports medicine. As professionals, we need to do a better job of screening individuals to determine who is at greatest risk of sustaining an ACL injury, as well as implementing injury prevention programs. We also need to do a better job with programs that return individuals to their preinjury activity levels, including implementing thorough functional testing to determine if a patient is ready to return to sports or strenuous activities post-ACLR. PMID- 26424575 TI - Chondrosarcoma of the Hip. AB - The patient was a 27-year-old woman who was being evaluated by a physical therapist 1 month following a right Achilles tendon repair. She reported the presence of a painful firm mass in her left hip that she first noticed approximately 6 months prior. As an initial assessment of the mass, the physical therapist ordered radiographs of the left hip, which revealed a mass projecting off the left lateral iliac bone. The radiologist recommended contrast-enhanced magnetic resonance imaging for further characterization, which revealed a large lobulated mass that was consistent with an osteochondroma. PMID- 26424576 TI - Split-belt walking adaptation recalibrates sensorimotor estimates of leg speed but not position or force. AB - Motor learning during reaching not only recalibrates movement but can also lead to small but consistent changes in the sense of arm position. Studies have suggested that this sensory effect may be the result of recalibration of a forward model that associates motor commands with their sensory consequences. Here we investigated whether similar perceptual changes occur in the lower limbs after learning a new walking pattern on a split-belt treadmill--a task that critically involves proprioception. Specifically, we studied how this motor learning task affects perception of leg speed during walking, perception of leg position during standing or walking, and perception of contact force during stepping. Our results show that split-belt adaptation leads to robust motor aftereffects and alters the perception of leg speed during walking. This is specific to the direction of walking that was trained during adaptation (i.e., backward or forward). The change in leg speed perception accounts for roughly half of the observed motor aftereffect. In contrast, split-belt adaptation does not alter the perception of leg position during standing or walking and does not change the perception of stepping force. Our results demonstrate that there is a recalibration of a sensory percept specific to the domain of the perturbation that was applied during walking (i.e., speed but not position or force). Furthermore, the motor and sensory consequences of locomotor adaptation may be linked, suggesting overlapping mechanisms driving changes in the motor and sensory domains. PMID- 26424577 TI - The mammalian efferent vestibular system plays a crucial role in the high frequency response and short-term adaptation of the vestibuloocular reflex. AB - Although anatomically well described, the functional role of the mammalian efferent vestibular system (EVS) remains unclear. Unlike in fish and reptiles, the mammalian EVS does not seem to play a role in modulation of primary afferent activity in anticipation of active head movements. However, it could play a role in modulating long-term mechanisms requiring plasticity such as vestibular adaptation. We measured the efficacy of vestibuloocular reflex (VOR) adaptation in alpha9-knockout mice. These mice carry a missense mutation of the gene encoding the alpha9 nicotinic acetylcholine receptor (nAChR) subunit. The alpha9 nAChR subunit is expressed in the vestibular and auditory periphery, and its loss of function could compromise peripheral input from the predominantly cholinergic EVS. We measured the VOR gain (eye velocity/head velocity) in 26 alpha9-knockout mice and 27 cba129 control mice. Mice were randomly assigned to one of three groups: gain-increase adaptation (1.5*), gain-decrease adaptation (0.5*), or no adaptation (baseline, 1*). After adaptation training (horizontal rotations at 0.5 Hz with peak velocity 20 degrees /s), we measured the sinusoidal (0.2-10 Hz, 20 100 degrees /s) and transient (1,500-6,000 degrees /s(2)) VOR in complete darkness. alpha9-Knockout mice had significantly lower baseline gains compared with control mice. This difference increased with stimulus frequency (~ 5% <1 Hz to ~ 25% >1 Hz). Moreover, vestibular adaptation (difference in VOR gain of gain increase and gain-decrease adaptation groups as % of gain increase) was significantly reduced in alpha9-knockout mice (17%) compared with control mice (53%), a reduction of ~ 70%. Our results show that the loss of alpha9 nAChRs moderately affects the VOR but severely affects VOR adaptation, suggesting that the EVS plays a crucial role in vestibular plasticity. PMID- 26424578 TI - Changes in sensory reweighting of proprioceptive information during standing balance with age and disease. AB - With sensory reweighting, reliable sensory information is selected over unreliable information during balance by dynamically combining this information. We used system identification techniques to show the weight and the adaptive process of weight change of proprioceptive information during standing balance with age and specific diseases. Ten healthy young subjects (aged between 20 and 30 yr) and 44 elderly subjects (aged above 65 yr) encompassing 10 healthy elderly, 10 with cataract, 10 with polyneuropathy, and 14 with impaired balance, participated in the study. During stance, proprioceptive information of the ankles was disturbed by rotation of the support surface with specific frequency content where disturbance amplitude increased over trials. Body sway and reactive ankle torque were measured to determine sensitivity functions of these responses to the disturbance amplitude. Model fits resulted in a proprioceptive weight (changing over trials), time delay, force feedback, reflexive stiffness, and damping. The proprioceptive weight was higher in healthy elderly compared with young subjects and higher in elderly subjects with cataract and with impaired balance compared with healthy elderly subjects. Proprioceptive weight decreased with increasing disturbance amplitude; decrease was similar in all groups. In all groups, the time delay was higher and the reflexive stiffness was lower compared with young or healthy elderly subjects. In conclusion, proprioceptive information is weighted more with age and in patients with cataract and impaired balance. With age and specific diseases the time delay was higher and reflexive stiffness was lower. These results illustrate the opportunity to detect the underlying cause of impaired balance in the elderly with system identification. PMID- 26424580 TI - The role of vibration in tactile speed perception. AB - The relative motion between the surface of an object and our fingers produces patterns of skin deformation such as stretch, indentation, and vibrations. In this study, we hypothesized that motion-induced vibrations are combined with other tactile cues for the discrimination of tactile speed. Specifically, we hypothesized that vibrations provide a critical cue to tactile speed on surfaces lacking individually detectable features like dots or ridges. Thus masking vibrations unrelated to slip motion should impair the discriminability of tactile speed, and the effect should be surface-dependent. To test this hypothesis, we measured the precision of participants in discriminating the speed of moving surfaces having either a fine or a ridged texture, while adding masking vibratory noise in the working range of the fast-adapting mechanoreceptive afferents. Vibratory noise significantly reduced the precision of speed discrimination, and the effect was much stronger on the fine-textured than on the ridged surface. On both surfaces, masking vibrations at intermediate frequencies of 64 Hz (65-MUm peak-to-peak amplitude) and 128 Hz (10 MUm) had the strongest effect, followed by high-frequency vibrations of 256 Hz (1 MUm) and low-frequency vibrations of 32 Hz (50 and 25 MUm). These results are consistent with our hypothesis that slip induced vibrations concur to the discrimination of tactile speed. PMID- 26424579 TI - Spinal electro-magnetic stimulation combined with transgene delivery of neurotrophin NT-3 and exercise: novel combination therapy for spinal contusion injury. AB - Our recent terminal experiments revealed that administration of a single train of repetitive spinal electromagnetic stimulation (sEMS; 35 min) enhanced synaptic plasticity in spinal circuitry following lateral hemisection spinal cord injury. In the current study, we have examined effects of repetitive sEMS applied as a single train and chronically (5 wk, every other day) following thoracic T10 contusion. Chronic studies involved examination of systematic sEMS administration alone and combined with exercise training and transgene delivery of neurotrophin [adeno-associated virus 10-neurotrophin 3 (AAV10-NT3)]. Electrophysiological intracellular/extracellular recordings, immunohistochemistry, behavioral testing, and anatomical tracing were performed to assess effects of treatments. We found that administration of a single sEMS train induced transient facilitation of transmission through preserved lateral white matter to motoneurons and hindlimb muscles in chronically contused rats with effects lasting for at least 2 h. These physiological changes associated with increased immunoreactivity of GluR1 and GluR2/3 glutamate receptors in lumbar neurons. Systematic administration of sEMS alone for 5 wk, however, was unable to induce cumulative improvements of transmission in spinomuscular circuitry or improve impaired motor function following thoracic contusion. Encouragingly, chronic administration of sEMS, followed by exercise training (running in an exercise ball and swimming), induced the following: 1) sustained strengthening of transmission to lumbar motoneurons and hindlimb muscles, 2) better retrograde transport of anatomical tracer, and 3) improved locomotor function. Greatest improvements were seen in the group that received exercise combined with sEMS and AAV-NT3. PMID- 26424581 TI - Intermanual transfer characteristics of dynamic learning: direction, coordinate frame, and consolidation of interlimb generalization. AB - Intermanual transfer, i.e., generalization of motor learning across hands, is a well-accepted phenomenon of motor learning. Yet, there are open questions regarding the characteristics of this transfer, particularly the intermanual transfer of dynamic learning. In this study, we investigated intermanual transfer in a force field adaptation task concerning the direction and the coordinate frame of transfer as well as the influence of a 24-h consolidation period on the transfer. We tested 48 healthy human subjects for transfer from dominant to nondominant hand, and vice versa. We considered two features of transfer. First, we examined transfer to the untrained hand using force channel trials that suppress error feedback and learning mechanisms to assess intermanual transfer in the form of a practice-dependent bias. Second, we considered transfer by exposing the subjects to the force field with the untrained hand to check for faster learning of the dynamics (interlimb savings). Half of the subjects were tested for transfer immediately after adaptation, whereas the other half were tested after a 24-h consolidation period. Our results showed intermanual transfer both from dominant to nondominant hand and vice versa in extrinsic coordinates. After the consolidation period, transfer effects were weakened. Moreover, the transfer effects were negligible compared with the subjects' ability to rapidly adapt to the force field condition. We conclude that intermanual transfer is a bidirectional phenomenon that vanishes with time. However, the ability to transfer motor learning seems to play a minor role compared with the rapid adaptation processes. PMID- 26424582 TI - A leech model for homeostatic plasticity and motor network recovery after loss of descending inputs. AB - Motor networks below the site of spinal cord injury (SCI) and their reconfiguration after loss of central inputs are poorly understood but remain of great interest in SCI research. Harley et al. (J Neurophysiol 113: 3610-3622, 2015) report a striking locomotor recovery paradigm in the leech Hirudo verbena with features that are functionally analogous to SCI. They propose that this well established neurophysiological system could potentially be repurposed to provide a complementary model to investigate basic principles of homeostatic compensation relevant to SCI research. PMID- 26424583 TI - Associations between fruit and vegetable consumption and psychological distress: results from a population-based study. AB - BACKGROUND: Several studies observed associations of various aspects of diet with mental health, but little is known about the relationship between following the 5 a-day recommendation for fruit and vegetables consumption and mental health. Thus, we examined the associations of the Swiss daily recommended fruit and vegetable intake with psychological distress. METHODS: Data from 20,220 individuals aged 15+ years from the 2012 Swiss Health Survey were analyzed. The recommended portions of fruit and vegetables per day were defined as 5-a-day (at least 2 portions of fruit and 3 of vegetables). The outcome was perceived psychological distress over the previous 4 weeks (measured by the 5-item mental health index [MHI-5]). High distress (MHI-5 score <= 52), moderate distress (MHI 5 > 52 and <= 72) and low distress (MHI-5 > 72 and <= 100) were differentiated and multinomial logistic regression analyses adjusted for known confounding factors were performed. RESULTS: The 5-a-day recommendation was met by 11.6 % of the participants with low distress, 9.3 % of those with moderate distress, and 6.2 % of those with high distress. Consumers fulfilling the 5-a-day recommendation had lower odds of being highly or moderately distressed than individuals consuming less fruit and vegetables (moderate vs. low distress: OR = 0.82, 95 % confidence interval [CI] 0.69-0.97; high vs. low distress: OR = 0.55, 95 % CI 0.41-0.75). CONCLUSIONS: Daily intake of 5 servings of fruit and vegetable was associated with lower psychological distress. Longitudinal studies are needed to further determine the causal nature of this relationship. PMID- 26424584 TI - Stable expression and functional characterisation of the diamondback moth ryanodine receptor G4946E variant conferring resistance to diamide insecticides. AB - Diamides, such as flubendiamide and chlorantraniliprole, belong to a new chemical class of insecticides that act as conformation-sensitive activators of insect ryanodine receptors (RyRs). Both compounds are registered for use against lepidopteran species such as the diamondback moth, Plutella xylostella, a notorious global pest of cruciferous crops. Recently acquired resistance to diamide insecticides in this species is thought to be due to a target-site mutation conferring an amino acid substitution (G4946E), located within the trans membrane domain of the RyR, though the exact role of this mutation has not yet been fully determined. To address this we have cloned a full-length cDNA encoding the P. xylostella RyR and established clonal Sf9 cell lines stably expressing either the wildtype RyR or the G4946E variant, in order to test the sensitivity to flubendiamide and chlorantraniliprole on the recombinant receptor. We report that the efficacy of both diamides was dramatically reduced in clonal Sf9 cells stably expressing the G4946E modified RyR, providing clear functional evidence that the G4946E RyR mutation impairs diamide insecticide binding. PMID- 26424585 TI - Population Density and Moment-based Approaches to Modeling Domain Calcium mediated Inactivation of L-type Calcium Channels. AB - We present a population density and moment-based description of the stochastic dynamics of domain [Formula: see text]-mediated inactivation of L-type [Formula: see text] channels. Our approach accounts for the effect of heterogeneity of local [Formula: see text] signals on whole cell [Formula: see text] currents; however, in contrast with prior work, e.g., Sherman et al. (Biophys J 58(4):985 995, 1990), we do not assume that [Formula: see text] domain formation and collapse are fast compared to channel gating. We demonstrate the population density and moment-based modeling approaches using a 12-state Markov chain model of an L-type [Formula: see text] channel introduced by Greenstein and Winslow (Biophys J 83(6):2918-2945, 2002). Simulated whole cell voltage clamp responses yield an inactivation function for the whole cell [Formula: see text] current that agrees with the traditional approach when domain dynamics are fast. We analyze the voltage-dependence of [Formula: see text] inactivation that may occur via slow heterogeneous domain [[Formula: see text]]. Next, we find that when channel permeability is held constant, [Formula: see text]-mediated inactivation of L-type channels increases as the domain time constant increases, because a slow domain collapse rate leads to increased mean domain [[Formula: see text]] near open channels; conversely, when the maximum domain [[Formula: see text]] is held constant, inactivation decreases as the domain time constant increases. Comparison of simulation results using population densities and moment equations confirms the computational efficiency of the moment-based approach, and enables the validation of two distinct methods of truncating and closing the open system of moment equations. In general, a slow domain time constant requires higher order moment truncation for agreement between moment-based and population density simulations. PMID- 26424586 TI - 8th International Congress of Familial Mediterranean Fever and Systemic Autoinflammatory Diseases. PMID- 26424587 TI - The effect of melatonin treatment on postural stability, muscle strength, and quality of life and sleep in postmenopausal women: a randomized controlled trial. AB - BACKGROUND: Melatonin is often used as a sleeping aid in elderly adults. As previous studies suggest a protective role of melatonin against osteoporosis, it is important to document its safety. Treatment should not cause any hangover effect that could potentially lead to falls and fractures. We therefore aimed to evaluate the effect of melatonin on balance- and muscle function. METHODS AND PATIENTS: In a double-blind placebo-controlled study, we randomized 81 postmenopausal women with osteopenia to receive 1 or 3 mg melatonin, or placebo nightly for 12 months. Postural balance as well as muscle function was measured. In addition, we assessed quality of life and sleep at baseline and after 12 months treatment. RESULTS: Compared to placebo, one-year treatment with melatonin did not affect postural balance or risk of falls. Furthermore, no significant changes between groups were observed in muscle strength in neither upper- nor lower extremities. Treatment did not affect quality of life or sleep. However, in the subgroup of women with sleep disturbances at baseline, a trend towards an improved sleep quality was seen (p = 0.08). CONCLUSION: Treatment with melatonin is safe in postmenopausal women with osteopenia. There is no hangover effect affecting balance- and muscle function following the intake of melatonin. In women with a good quality of sleep, melatonin has no effect, however in poor quality of sleep, small doses of melatonin trended towards improving the quality. TRIAL REGISTRATION: (# NCT01690000). PMID- 26424588 TI - Fabrication of 3-nm-thick Si3N4 membranes for solid-state nanopores using the poly-Si sacrificial layer process. AB - To improve the spatial resolution of solid-state nanopores, thinning the membrane is a very important issue. The most commonly used membrane material for solid state nanopores is silicon nitride (Si3N4). However, until now, stable wafer scale fabrication of Si3N4 membranes with a thickness of less than 5 nm has not been reported, although a further reduction in thickness is desired to improve spatial resolution. In the present study, to fabricate thinner Si3N4 membranes with a thickness of less than 5 nm in a wafer, a new fabrication process that employs a polycrystalline-Si (poly-Si) sacrificial layer was developed. This process enables the stable fabrication of Si3N4 membranes with thicknesses of 3 nm. Nanopores were fabricated in the membrane using a transmission electron microscope (TEM) beam. Based on the relationship between the ionic current through the nanopores and their diameter, the effective thickness of the nanopores was estimated to range from 0.6 to 2.2 nm. Moreover, DNA translocation through the nanopores was observed. PMID- 26424590 TI - Does the capsaicin-sensitive local neural circuit constitutively regulate vagally evoked esophageal striated muscle contraction in rats? AB - To determine whether a capsaicin-sensitive local neural circuit constitutively modulates vagal neuromuscular transmission in the esophageal striated muscle or whether the neural circuit operates in a stimulus-dependent manner, we compared the motility of esophageal preparations isolated from intact rats with those in which capsaicin-sensitive neurons had been destroyed. Electrical stimulation of the vagus nerve trunk evoked contractile responses in the esophagus isolated from a capsaicin-treated rat in a manner similar to those in the esophagus from a control rat. No obvious differences were observed in the inhibitory effects of D tubocurarine on intact and capsaicin-treated rat esophageal motility. Destruction of the capsaicin-sensitive neurons did not significantly affect latency, time to peak and duration of a vagally evoked twitch-like contraction. These findings indicate that the capsaicin-sensitive neural circuit does not operate constitutively but rather is activated in response to an applied stimulus. PMID- 26424589 TI - Gastrointestinal microbiome modulator improves glucose tolerance in overweight and obese subjects: A randomized controlled pilot trial. AB - OBJECTIVE: The objective of this study was to examine the effects of a gastrointestinal microbiome modulator (GIMM) containing inulin, beta-glucan, blueberry anthocyanins, and blueberry polyphenols on metabolic parameters, fecal markers of gut microbiota, and satiety. DESIGN AND METHODS: Thirty overweight or obese individuals aged 18 to 70years, were enrolled in a randomized controlled trial. Participants consumed the test product or placebo daily for four weeks. Stool samples were collected and blood was drawn at baseline and week four for assessments of gut microbiota, satiety hormones, glucose control, and lipid measures. Subjective satiety was assessed weekly. Linear models were used to compare differences from baseline to week four. RESULTS: GIMM consumption improved blood glucose tolerance (p=0.008), and increased satiety (p=0.03). There were no statistically significant differences in insulin sensitivity, fecal markers of gut microbiota, plasma satiety hormones, or serum lipid concentrations between the groups. However, plasma satiety hormones and fecal short chain fatty acid concentrations increased in the test group compared to the placebo. CONCLUSIONS: GIMM consumption for four weeks, increases satiety, and improves glucose tolerance possibly through insulin-independent pathways. PMID- 26424591 TI - Changes to the Intestinal Microbiome With Parenteral Nutrition: Review of a Murine Model and Potential Clinical Implications. AB - Parenteral nutrition (PN) dependence, while life sustaining, carries a significant risk of septic complications associated with epithelial barrier dysfunction and translocation of gut-derived microbiota. Increasing evidence suggests that PN-associated changes in the intestinal microbiota play a central role in the breakdown of the intestinal epithelial barrier. This review outlines the clinical and experimental evidence of epithelial barrier dysfunction with PN, the role of gut inflammatory dysregulation in driving this process, and the role of the intestinal microbiome in modulating inflammation in the gut and systemically. The article summarizes the most current work of our laboratory and others and describes many of the laboratory findings behind our current understanding of the PN enteral environment. Understanding the interaction between nutrient delivery, the intestinal microbiome, and PN-associated complications may lead to the development of novel therapies to enhance safety and quality of life for patients requiring PN. PMID- 26424592 TI - Evidence of cAMP involvement in cellobiohydrolase expression and secretion by Trichoderma reesei in presence of the inducer sophorose. AB - BACKGROUND: The signaling second messenger cyclic AMP (cAMP) regulates many aspects of cellular function in all organisms. Previous studies have suggested a role for cAMP in the regulation of gene expression of cellulolytic enzymes in Trichoderma reesei (anamorph of Hypocrea jecorina). METHODS: The effects of cAMP in T. reesei were analyzed through both activity and expression of cellulase, intracellular cAMP level measurement, western blotting, indirect immunofluorescence and confocal microscopy. RESULTS: To elucidate the involvement of cAMP in the cellulase expression, we analyzed the growth of the mutant strain ?acy1 and its parental strain QM9414 in the presence of the inducers cellulose, cellobiose, lactose, or sophorose, and the repressor glucose. Our results indicated that cAMP regulates the expression of cellulase in a carbon source dependent manner. The expression cel7a, and cel6a genes was higher in the presence of sophorose than in the presence of cellulose, lactose, cellobiose, or glucose. Moreover, intracellular levels of cAMP were up to four times higher in the presence of sophorose compared to other carbon sources. Concomitantly, our immunofluorescence microscopy and western blot data suggest that in the presence of sophorose, cAMP may regulate secretion of cellulolytic enzymes in T. reesei. CONCLUSIONS: These results allow us to better understand the role of cAMP and expand our knowledge on the signal transduction pathways involved in the regulation of cellulase expression in T. reesei. Finally, our data may help develop new strategies to improve the expression of cel7a and cel6a genes, and therefore, favor their application in several biotechnology fields. PMID- 26424593 TI - NSAIDs Ibuprofen, Indometacin, and Diclofenac do not interact with Farnesoid X Receptor. AB - The nuclear farnesoid X receptor (FXR) is a ligand activated transcription factor and acts as cellular sensor for bile acids. In this role, FXR is a highly important liver protector and FXR inhibition by antagonists or knockout has shown several deleterious effects. A recent report characterized non-steroidal anti rheumatic drugs (NSAIDs) such as ibuprofen or diclofenac as FXR antagonists and linked hepatotoxic effects of these drugs with antagonistic activity on FXR. Since this would guide a way to develop safer anti-inflammatory agents by sparing FXR, we intended to further characterize the reported antagonistic activity and intensively investigated ibuprofen, indometacin and diclofenac. However, we conclude that these agents do not interact with FXR and that the reported reduced FXR signaling induced by CDCA in presence of NSAIDs is merely a consequence than a cause of hepatotoxicity. PMID- 26424595 TI - Transcriptome analysis of Solanum melongena L. (eggplant) fruit to identify putative allergens and their epitopes. AB - Eggplant is the third most important Solanaceae crop after tomato and potato, particularly in India and China. A transcriptome analysis of eggplant's fruit was performed to study genes involved in medicinal importance and allergies. Illumina HiSeq 2000 system generated 89,763,638 raw reads (~18 Gb) from eggplant. High quality reads (59,039,694) obtained after trimming process, were assembled into a total of 149,224 non redundant set of transcripts. Out of 80,482 annotated sequences of eggplant fruit (BLASTx results against nr-green plant database), 40,752 transcripts showed significant similarity with predicted proteins of Solanum tuberosum (51%) followed by Solanum lycopersicum (34%) and other sequenced plant genomes. With BLASTx top hit analysis against existing allergens, a total of 1986 homologous allergen sequences were found, which had >37% similarity with 48 different allergens existing in the database. From the 48 putative allergens, 526 B-cell linear epitopes were identified using BepiPred linear epitope prediction tool. Transcript sequences generated from this study can be used to map epitopes of monoclonal antibodies and polyclonal sera from patients. With the support of this whole transcriptome catalogue of eggplant fruit, complete list of genes can be predicted based on which secondary structures of proteins may be modeled. PMID- 26424594 TI - Depression and suicide ideation in chronic hepatitis C patients untreated and treated with interferon: prevalence, prevention, and treatment. AB - Interferon-based therapies were until recently the standard of care in chronic hepatitis C (CHC), despite their side effects. We aimed to review the available data on the depression and suicide in CHC patients receiving or not antiviral therapy based on interferon treatment. A PubMed search was performed, identifying relevant papers published between 1991 and January 2015 concerning major depressive disorders and suicidal risk in patients under interferon. A total of 21 relevant papers were retrieved. Prospective studies reported depression as the most common side effect of interferon, with an incidence peak between weeks 8 and 12 of therapy. Suicide risk was analyzed in 7 of the reviewed articles, and case reports of attempted suicide were discussed. Moreover, studies have shown that pretreatment with serotonin reuptake inhibitors is a good strategy for the prevention of interferon-induced depression. PMID- 26424596 TI - Frequency of PTEN alterations, TMPRSS2-ERG fusion and their association in prostate cancer. AB - BACKGROUND: Phosphatase and tensin homolog (PTEN) gene aberration and trans membrane protease, serine 2 (TMPRSS2)-v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusion are the most prevalent genomic events in prostate cancer. In this study we aimed to evaluate the frequency of PTEN alteration and TMPRSS2-ERG fusion and possible link between these two biomarkers in Iranian men. METHODS: We assessed 42 fresh frozen tissue samples of prostate cancer (PCA) obtained by radical prostatectomy, interrogating the TMPRSS2-ERG fusion gene along with PTEN gene status using Real Time PCR and FISH methods. RESULTS: Using Real Time PCR we identified the TMPRSS2-ERG fusion in 64% (27/42) of tumor samples, which was confirmed by FISH technique, giving 21 positive samples with deletion, suggesting the presence of TMPRSS2-ERG fusion gene. By contrast, PTEN deletion was detected in 52% (11/21) of PCA samples, which all showed low expression in Real Time. Concomitance of PTEN deletion or low expression and TMPRSS2-ERG fusion was present in PCA samples (P=0.005). All of the PTEN deletion samples showed TMPRSS2-ERG fusion, (11/11, 100%) while not all of the TMPRSS2-ERG fusion positive samples showed PTEN deletion. None of 29 cases of BPH and 8 cases of normal zone of tumor tissue showed TMPRSS2-ERG fusion. CONCLUSIONS: These results indicate that PTEN loss occurs in cooperation with TMPRSS2-ERG fusion in PCA. While the majority of PCA samples harbor TMPRSS2-ERG fusion as well as PTEN gene deletion, normal tissues do not show these molecular aberrations. PMID- 26424597 TI - Structural signature of Ser83Leu and Asp87Asn mutations in DNA gyrase from enterotoxigenic Escherichia coli and impact on quinolone resistance. AB - Enterotoxigenic Escherichia coli (ETEC) is among the most frequent microorganisms causing traveler's diarrhea (TD). Quinolones are potent antimicrobial agents used for the treatment of TD. Resistance to quinolones is typically caused by substitutions in QRDR region of gyrA subunit of DNA gyrase. The aim of this study was to seek insights into the effect of these substitutions at structural level and their association with observed quinolone resistance. Majority of the ETEC strains have gyrA mutations at amino acid position 83 and 87. To understand the quinolone resistance mechanism at molecular level, we have studied the interaction of wild type and mutant forms of ETEC gyrA with nalidixic acid and ciprofloxacin by molecular modeling using Discovery Studio and LeadIt. All the mutants had reduced affinity towards both ciprofloxacin and nalidixic acid relative to the wild type due to the mutations introduced in gyrA. Besides Ser83 and Asp87, for nalidixic acid binding Arg91 and His45 residues were observed to be critical while in ciprofloxacin binding Lys42 and Arg91 residues played a significant role. Amino acid substitutions contribute to the emergence of drug resistance in sensitive strains by causing structural alterations leading to reduced affinity of the drug towards receptor. Analysis of the effect of amino acid substitutions at structural level is of utmost importance to establish possible associations between mutations and the diseases. These studies accelerate the identification of pharmaceutical targets for relevant treatments and could also be helpful in guiding the design of further experimental research. PMID- 26424598 TI - Analysis of the coding potential of the ORF in the control region of the female transmitted Mytilus mtDNA. AB - Key elements in determining the sex-specific transmission of the female and male mitochondrial genomes in Mytilus species with doubly uniparental inheritance of mtDNA are suspected to be contained in the control region. A novel F genome specific open reading frame (ORF) identified in this region has previously been hypothesized to be involved in the DUI mechanism. In their recent work Kyriakou et al. (2014a) questioned the functionality of this ORF. Here, we present evidence that this ORF is transcribed and may thus code for a functional product. PMID- 26424599 TI - Top-down and Middle-down Protein Analysis Reveals that Intact and Clipped Human Histones Differ in Post-translational Modification Patterns. AB - Post-translational modifications (PTMs) of histone proteins play a fundamental role in regulation of DNA-templated processes. There is also growing evidence that proteolytic cleavage of histone N-terminal tails, known as histone clipping, influences nucleosome dynamics and functional properties. Using top-down and middle-down protein analysis by mass spectrometry, we report histone H2B and H3 N terminal tail clipping in human hepatocytes and demonstrate a relationship between clipping and co-existing PTMs of histone H3. Histones H2B and H3 undergo proteolytic processing in primary human hepatocytes and the hepatocellular carcinoma cell line HepG2/C3A when grown in spheroid (3D) culture, but not in a flat (2D) culture. Using tandem mass spectrometry we localized four different clipping sites in H3 and one clipping site in H2B. We show that in spheroid culture clipped H3 proteoforms are mainly represented by canonical histone H3, whereas in primary hepatocytes over 90% of clipped H3 correspond to the histone variant H3.3. Comprehensive analysis of histone H3 modifications revealed a series of PTMs, including K14me1, K27me2/K27me3, and K36me1/me2, which are differentially abundant in clipped and intact H3. Analysis of co-existing PTMs revealed negative crosstalk between H3K36 methylation and H3K23 acetylation in clipped H3. Our data provide the first evidence of histone clipping in human hepatocytes and demonstrate that clipped H3 carry distinct co-existing PTMs different from those in intact H3. PMID- 26424600 TI - Novel Molecular Insights into Classical and Alternative Activation States of Microglia as Revealed by Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC)-based Proteomics. AB - Microglia, the resident immune cells of the brain, have been shown to display a complex spectrum of roles that span from neurotrophic to neurotoxic depending on their activation status. Microglia can be classified into four stages of activation, M1, which most closely matches the classical (pro-inflammatory) activation stage, and the alternative activation stages M2a, M2b, and M2c. The alternative activation stages have not yet been comprehensively analyzed through unbiased, global-scale protein expression profiling. In this study, BV2 mouse immortalized microglial cells were stimulated with agonists specific for each of the four stages and total protein expression for 4644 protein groups was quantified using SILAC-based proteomic analysis. After validating induction of the various stages through a targeted cytokine assay and Western blotting of activation states, the data revealed novel insights into the similarities and differences between the various states. The data identify several protein groups whose expression in the anti-inflammatory, pro-healing activation states are altered presumably to curtail inflammatory activation through differential protein expression, in the M2a state including CD74, LYN, SQST1, TLR2, and CD14. The differential expression of these proteins promotes healing, limits phagocytosis, and limits activation of reactive nitrogen species through toll like receptor cascades. The M2c state appears to center around the down regulation of a key member in the formation of actin-rich phagosomes, SLP-76. In addition, the proteomic data identified a novel activation marker, DAB2, which is involved in clathrin-mediated endocytosis and is significantly different between M2a and either M1 or M2b states. Western blot analysis of mouse primary microglia stimulated with the various agonists of the classical and alternative activation states revealed a similar trend of DAB2 expression compared with BV2 cells. PMID- 26424602 TI - Next generation dengue vaccines: A review of the preclinical development pipeline. AB - Dengue represents a significant and growing public health problem across the globe, with approximately half of the world's population at risk. The increasing and expanding burden of dengue has highlighted the need for new tools to prevent dengue, including development of dengue vaccines. Recently, the first dengue vaccine candidate was evaluated in Phase 3 clinical trials, and other vaccine candidates are under clinical evaluation. There are also a number of candidates in preclinical development, based on diverse technologies, with promising results in animal models and likely to move into clinical trials and could eventually be next-generation dengue vaccines. This review provides an overview of the various technological approaches to dengue vaccine development with specific focus on candidates in preclinical development and with evaluation in non-human primates. PMID- 26424603 TI - A systematic review and meta-analysis of management options for adults who respond poorly to hepatitis B vaccination. AB - An estimated 5-10% of adults do not seroconvert after a three-dose primary course of hepatitis B vaccines, and are considered non-responders. Many approaches have been used to induce immunity in healthy adult non-responders, but few studies have compared their relative effectiveness. We conducted a systematic review and meta-analysis of seroconversion rates after additional doses of four approaches: 20 mcg or 40 mcg intramuscular (IM), and 5 mcg or 20 mcg intradermal (ID). The search identified 13 articles encompassing 16 studies (N=1067) that met the eligibility criteria. Seroconversion rates after additional doses of each approach were pooled and estimated. After one additional dose, the four approaches produced very similar seroconversion rates and we did not find any evidence to support the use of 40 mcg IM in healthy adults. PMID- 26424601 TI - Integrated Metabolomics, Transcriptomics and Proteomics Identifies Metabolic Pathways Affected by Anaplasma phagocytophilum Infection in Tick Cells. AB - Anaplasma phagocytophilum is an emerging zoonotic pathogen that causes human granulocytic anaplasmosis. These intracellular bacteria establish infection by affecting cell function in both the vertebrate host and the tick vector, Ixodes scapularis. Previous studies have characterized the tick transcriptome and proteome in response to A. phagocytophilum infection. However, in the postgenomic era, the integration of omics datasets through a systems biology approach allows network-based analyses to describe the complexity and functionality of biological systems such as host-pathogen interactions and the discovery of new targets for prevention and control of infectious diseases. This study reports the first systems biology integration of metabolomics, transcriptomics, and proteomics data to characterize essential metabolic pathways involved in the tick response to A. phagocytophilum infection. The ISE6 tick cells used in this study constitute a model for hemocytes involved in pathogen infection and immune response. The results showed that infection affected protein processing in endoplasmic reticulum and glucose metabolic pathways in tick cells. These results supported tick-Anaplasma co-evolution by providing new evidence of how tick cells limit pathogen infection, while the pathogen benefits from the tick cell response to establish infection. Additionally, ticks benefit from A. phagocytophilum infection by increasing survival while pathogens guarantee transmission. The results suggested that A. phagocytophilum induces protein misfolding to limit the tick cell response and facilitate infection but requires protein degradation to prevent ER stress and cell apoptosis to survive in infected cells. Additionally, A. phagocytophilum may benefit from the tick cell's ability to limit bacterial infection through PEPCK inhibition leading to decreased glucose metabolism, which also results in the inhibition of cell apoptosis that increases infection of tick cells. These results support the use of this experimental approach to systematically identify cell pathways and molecular mechanisms involved in tick pathogen interactions. Data are available via ProteomeXchange with identifier PXD002181. PMID- 26424604 TI - Immune modulation of T regulatory cells and IgE responses in horses vaccinated with West Nile virus vaccine combined with a CpG ODN. AB - Hypersensitivity reactions, such as hives or fatal anaphylactic shock, in response to vaccination constitute a health hazard for horses that develop allergies to vaccine components. In such horses vaccination with viral vaccines stimulates an IgE response to non-target antigens. Viral vaccines share contaminating non-target proteins, such as bovine serum albumin (BSA); these antigens can stimulate IgE production with each exposure. We hypothesized that the addition of a CpG oligodeoxynucleotide (ODN) administered in conjunction with a West Nile virus vaccine would decrease the IgE response; through up-regulation of T regulatory cells and T helper 1 cells thus decreasing the potential to induce a type 1 hypersensitivity response. Thirty adult horses were injected with either CpG ODN or control GpC ODN with a killed WNV vaccine. T regulatory cell numbers and BSA specific IgE concentrations were determined pre and post vaccination. Multicolor flow cytometry was used to evaluate expression of CD4, CD25, and intracellular Foxp3 on PBMCs. Serum concentrations of BSA specific IgE were determined by ELISA. Cell culture supernatants from BSA re-stimulated lymphocytes were evaluated for concentrations of IL-2, IL-4, IL-10, and IFN gamma. The inclusion of the CpG ODN significantly increased the differentiation of T regulatory cells in response to antigen in vitro and in vivo. A significant inverse correlation was found between T regulatory cell numbers and serum BSA specific IgE concentrations. These results suggest that we can provide a safer alternate vaccination strategy, particularly for horses that have demonstrated a pro-allergic phenotype. PMID- 26424605 TI - Dengue human infection models to advance dengue vaccine development. AB - Dengue viruses (DENV) currently infect approximately 400 million people each year causing millions to seek care and overwhelming the health care infrastructure in endemic areas. Vaccines to prevent dengue and therapeutics to treat dengue are not currently available. The efficacy of the most advanced candidate vaccine against symptomatic dengue in general and DENV-2 in particular was much lower than expected, despite the ability of the vaccine to induce neutralizing antibody against all four DENV serotypes. Because seroconversion to the DENV serotypes following vaccination was thought to be indicative of induced protection, these results have made it more difficult to assess which candidate vaccines should or should not be evaluated in large studies in endemic areas. A dengue human infection model (DHIM) could be extremely valuable to down-select candidate vaccines or therapeutics prior to engaging in efficacy trials in endemic areas. Two DHIM have been developed to assess the efficacy of live attenuated tetravalent (LATV) dengue vaccines. The first model, developed by the Laboratory of Infectious Diseases at the U. S. National Institutes of Health, utilizes a modified DENV-2 strain DEN2Delta30. This virus was derived from the DENV-2 Tonga/74 that caused only very mild clinical infection during the outbreak from which it was recovered. DEN2Delta30 induced viremia in 100%, rash in 80%, and neutropenia in 27% of the 30 subjects to whom it was given. The Walter Reed Army Institute of Research (WRAIR) is developing a DHIM the goal of which is to identify DENV that cause symptomatic dengue fever. WRAIR has evaluated seven viruses and has identified two that meet dengue fever criteria. Both of these models may be very useful in the evaluation and down-selection of candidate dengue vaccines and therapeutics. PMID- 26424606 TI - A bivalent virus-like particle based vaccine induces a balanced antibody response against both enterovirus 71 and norovirus in mice. AB - Noroviruses are the main cause of severe viral gastroenteritis, which results in estimated 200,000 deaths each year, primarily in children in the developing world. Genogroup II.4 (GII.4) strains are responsible for the majority of norovirus outbreaks. Enterovirus 71 (EV71), the leading causative agent of hand, foot and mouth disease, has recently been prevalent in Asia-Pacific regions, resulting in significant morbidity and mortality in young children. However, no vaccine is commercially available for either norovirus GII.4 or EV71. Recombinant virus-like particles (VLPs) derived from either GII.4 or EV71 have been shown to be promising monovalent vaccine candidates. In this study, we investigate the possibility to formulate a VLP-based bivalent vaccine for both norovirus GII.4 and EV71. The GII.4- and EV71-VLPs were produced in a baculovirus-insect cell expression system. A bivalent combination vaccine comprised of GII.4 and EV71 VLPs was formulated and compared with monovalent GII.4- and EV71-VLPs for their immunogenicity in mice. We found that the bivalent vaccine elicited durable antibody responses toward both GII.4 and EV71, and the antibody titers were comparable to that induced by the monovalent vaccines, indicating there is no immunological interference between the two antigens in the combination vaccine. More significantly, the bivalent vaccine-immunized mouse sera could efficiently neutralize EV71 infection and block GII.4-VLP binding to mucin. Together, our results demonstrate that the experimental combination vaccine comprised of GII.4 and EV71-VLPs is able to induce a balanced protective antibody response, and therefore strongly support further preclinical and clinical development of such a bivalent VLP vaccine targeting both norovirus GII.4 and EV71. PMID- 26424607 TI - Text message reminders for timely routine MMR vaccination: A randomized controlled trial. AB - OBJECTIVE: Measles-mumps-rubella (MMR) vaccination is important for preventing disease outbreaks, yet pockets of under-vaccination persist. Text message reminders have been employed successfully for other pediatric vaccines, but studies examining their use for MMR vaccination are limited. This study assessed the impact of text message reminders on timely MMR vaccination. STUDY DESIGN: Parents (n=2054) of 9.5-10.5-month-old children from four urban academically affiliated pediatric clinics were randomized to scheduling plus appointment text message reminders, appointment text message reminder-only, or usual care. The former included up to three text reminders to schedule the one-year preventive care visit. Both text messaging arms included a text reminder sent 2 days before that visit. Outcomes included appointment scheduling, appointment attendance, and MMR vaccination by age 13 months, the standard of care at study sites. RESULTS: Children of parents in the scheduling plus appointment text message reminders arm were more likely to have a scheduled one-year visit than those in the other arms (71.9% vs. 67.4%, relative risk ratio (RRR) 1.07 [95% CI 1.005-1.13]), particularly if no appointment was scheduled before randomization (i.e., no baseline appointment) (62.1% vs. 54.7%, RRR 1.14 [95% CI 1.04-1.24]). One-year visit attendance and timely MMR vaccination were similar between arms. However, among children without a baseline appointment, those with parents in the scheduling plus appointment text message reminders arm were more likely to undergo timely MMR vaccination (61.1% vs. 55.1%, RRR 1.11 [95% CI 1.01-1.21]). CONCLUSION: Text message reminders improved timely MMR vaccination of high-risk children without a baseline one-year visit. PMID- 26424608 TI - Dietary glutamine supplementation effects on amino acid metabolism, intestinal nutrient absorption capacity and antioxidant response of gilthead sea bream (Sparus aurata) juveniles. AB - A study was undertaken to evaluate dietary glutamine supplementation effects on gilthead sea bream performance, intestinal nutrient absorption capacity, hepatic and intestinal glutamine metabolism and oxidative status. For that purpose gilthead sea bream juveniles (mean weight 13.0g) were fed four isolipidic (18% lipid) and isonitrogenous (43% protein) diets supplemented with 0, 0.5, 1 and 2% glutamine for 6weeks. Fish performance, body composition and intestinal nutrient absorption capacity were not affected by dietary glutamine levels. Hepatic and intestinal glutaminase (GlNase), glutamine synthetase (GSase), alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase activities were also unaffected by dietary glutamine supplementation. In the intestine GlNase activity was higher and GSase/GlNase ratio was two-fold lower than in the liver, suggesting a higher use of glutamine for energy production by the intestine than by the liver. The liver showed higher catalase and glucose-6 phosphate dehydrogenase activities, while the intestine presented higher glutathione peroxidase and glutathione reductase activities and oxidised glutathione content, which seems to reveal a higher glutathione dependency of the intestinal antioxidant response. Total and reduced glutathione contents in liver and intestine and superoxide dismutase activity in the intestine were enhanced by dietary glutamine, though lipid peroxidation values were not affected. Overall, differences between liver and intestine glutamine metabolism and antioxidant response were identified and the potential of dietary glutamine supplementation to gilthead sea bream's antioxidant response was elucidated. PMID- 26424610 TI - Authors' reply to Whitlock and Saied and colleagues. PMID- 26424609 TI - Improving wound healing and preventing surgical site complications of closed surgical incisions: a possible role of Incisional Negative Pressure Wound Therapy. A systematic review of the literature. AB - Advances in preoperative care, surgical techniques and technologies have enabled surgeons to achieve primary closure in a high percentage of surgical procedures. However, often, underlying patient comorbidities in addition to surgical-related factors make the management of surgical wounds primary closure challenging because of the higher risk of developing complications. To date, extensive evidence exists, which demonstrate the benefits of negative pressure dressing in the treatment of open wounds; recently, Incisional Negative Pressure Wound Therapy (INPWT) technology as delivered by PrevenaTM (KCI USA, Inc., San Antonio, TX) and Pico (Smith & Nephew Inc, Andover, MA) systems has been the focus of a new investigation on possible prophylactic measures to prevent complications via application immediately after surgery in high-risk, clean, closed surgical incisions. A systematic review was performed to evaluate INPWT's effect on surgical sites healing by primary intention. The primary outcomes of interest are an understanding of INPWT functioning and mechanisms of action, extrapolated from animal and biomedical engineering studies and incidence of complications (infection, dehiscence, seroma, hematoma, skin and fat necrosis, skin and fascial dehiscence or blistering) and other variables influenced by applying INPWT (re operation and re-hospitalization rates, time to dry wound, cost saving) extrapolated from human studies. A search was conducted for published articles in various databases including PubMed, Google Scholar and Scopus Database from 2006 to March 2014. Supplemental searches were performed using reference lists and conference proceedings. Studies selection was based on predetermined inclusion and exclusion criteria and data extraction regarding study quality, model investigated, epidemiological and clinical characteristics and type of surgery, and the outcomes were applied to all the articles included. 1 biomedical engineering study, 2 animal studies, 15 human studies for a total of 6 randomized controlled trials, 5 prospective cohort studies, 7 retrospective analyses, were included. Human studies investigated the outcomes of 1042 incisions on 1003 patients. The literature shows a decrease in the incidence of infection, sero haematoma formation and on the re-operation rates when using INPWT. Lower level of evidence was found on dehiscence, decreased in some studies, and was inconsistent to make a conclusion. Because of limited studies, it is difficult to make any assertions on the other variables, suggesting a requirement for further studies for proper recommendations on INPWT. PMID- 26424611 TI - Direct chemotherapeutic dual drug delivery through intra-articular injection for synergistic enhancement of rheumatoid arthritis treatment. AB - The effectiveness of systemic rheumatoid arthritis (RA) treatments is limited by difficulties in achieving therapeutic doses within articular joints. We evaluated the ability of intra-articular administration of injectable formulations to synergistically enhance repair of RA joints. Methotrexate-loaded hyaluronic acid (Met-HA), dexamethasone-loaded microcapsules (Dex-M), and Dex-M dispersed inside Met-HA were prepared as viscous emulsions and injected into articular joints using a needle to form a drug depot. By near-infrared (NIR) fluorescence imaging, we confirmed the local release of NIR from the depot injected into the articular joint over an extended period. In comparison with the subjects treated with Met HA or Dex-M alone, subjects treated simultaneously with Met-HA and Dex-M exhibited faster and more significant RA repair. Collectively, these results indicated that the drug depot formed after intra-articular injection of Met HA/Dex-M induced long-lasting drug release and allowed Met and Dex to effectively act in the articular joint, resulting in enhanced RA repair. PMID- 26424613 TI - Mandatory submission of patient identifiable information to third parties: FGM now, what next? PMID- 26424612 TI - Identification of the centromeric repeat in the threespine stickleback fish (Gasterosteus aculeatus). AB - Centromere sequences exist as gaps in many genome assemblies due to their repetitive nature. Here we take an unbiased approach utilizing centromere protein A (CENP-A) chomatin immunoprecipitation followed by high-throughput sequencing to identify the centromeric repeat sequence in the threespine stickleback fish (Gasterosteus aculeatus). A 186-bp, AT-rich repeat was validated as centromeric using both fluorescence in situ hybridization (FISH) and immunofluorescence combined with FISH (IF-FISH) on interphase nuclei and metaphase spreads. This repeat hybridizes strongly to the centromere on all chromosomes, with the exception of weak hybridization to the Y chromosome. Together, our work provides the first validated sequence information for the threespine stickleback centromere. PMID- 26424614 TI - Hemoperitoneum Due to Left Inferior Phrenic Artery Injury During Pericardiocentesis. PMID- 26424616 TI - Epidural abscess from prolotherapy: a cautionary tale. PMID- 26424615 TI - Properties of ATP-gated ion channels assembled from P2X2 subunits in mouse cochlear Reissner's membrane epithelial cells. AB - In the cochlea, Reissner's membrane separates the scala media endolymphatic compartment that sustains the positive endocochlear potential and ion composition necessary for sound transduction, from the scala vestibuli perilymphatic compartment. It is known that with sustained elevated sound levels, adenosine 5' triphosphate (ATP) is released into the endolymph and ATP-gated ion channels on the epithelial cells lining the endolymphatic compartment shunt the electrochemical driving force, contributing to protective purinergic hearing adaptation. This study characterises the properties of epithelial cell P2X(2) type ATP-activated membrane conductance in the mouse Reissner's membrane, which forms a substantial fraction of the scale media surface. The cells were found to express two isoforms (a and b) of the P2X(2) subunit arising from alternative splicing of the messenger RNA (mRNA) transcript that could contribute to the trimeric subunit assembly. The ATP-activated conductance demonstrated both immediate and delayed desensitisation consistent with incorporation of the combination of P2X(2) subunit isoforms. Activation by the ATP analogue 2meSATP had equipotency to ATP, whereas alpha,beta-meATP and adenosine 5'-diphosphate (ADP) were ineffective. Positive allosteric modulation of the P2X(2) channels by protons was profound. This native conductance was blocked by the P2X(2)-selective blocker pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) and the conductance was absent in these cells isolated from mice null for the P2rX2 gene encoding the P2X(2) receptor subunit. The activation and desensitisation properties of the Reissner's membrane epithelial cell ATP-gated P2X(2) channels likely contribute to the sensitivity and kinetics of purinergic control of the electrochemical driving force for sound transduction invoked by noise exposure. PMID- 26424617 TI - Retinal and choroidal alterations in patients with anorexia nervosa without vision loss. AB - OBJECTIVE: Evaluate the alterations of retinal anatomy and function, as well as choroidal thickness changes, in patients with anorexia nervosa (AN). METHOD: 13 female AN patients (26 eyes) and 20 female controls (40 eyes) were included. Assessment of the retinal and choroidal anatomy was performed by optical coherence-tomography, while multifocal-electroretinogram was used for measurements of the electrical activity of the macula. Statistical analysis was performed using t-test. RESULTS: Central macular thickness was found to be thinner in AN (140.04 +/- 14.45, 150.85 +/- 16.03, p = 0.007), likewise the ganglion cell complex and outer retinal layer (ORL) at most areas. ORL superiorly was thicker in AN (169.12 +/- 2.55, 163.00 +/- 8.70, p < 0.001), while retinal nerve fiber layer was not different between the two groups, except the inferior region (121.08 +/- 18.52, 137.60 +/- 7.30, p < 0.001). Choroidal thickness was evenly diminished in the anorectic group (p = 0.001-0.027). Multifocal electroretinogram showed lower P1-retinal response density amplitude of ring 1 in AN (159.04 +/- 60.83, 292.43 +/- 11.59, p < 0.001), but no significant difference concerning the P1-response density amplitude of ring 2 (79.04 +/- 21.89, 82.63 +/ 9.10, p = 0.36). DISCUSSION: In AN patients, even without vision loss, significant changes occur in retinal and choroidal thickness, as well as in the electrical activity of the macula. However, this is a pilot study in a small sample that needs replication. PMID- 26424618 TI - Next-generation sequencing (NGS) in the identification of encephalitis-causing viruses: Unexpected detection of human herpesvirus 1 while searching for RNA pathogens. AB - BACKGROUND: Encephalitis is a severe neurological syndrome usually caused by viruses. Despite significant progress in diagnostic techniques, the causative agent remains unidentified in the majority of cases. The aim of the present study was to test an alternative approach for the detection of putative pathogens in encephalitis using next-generation sequencing (NGS). METHODS: RNA was extracted from cerebrospinal fluid (CSF) from a 60-year-old male patient with encephalitis and subjected to isothermal linear nucleic acid amplification (Ribo-SPIA, NuGen) followed by next-generation sequencing using MiSeq (Illumina) system and metagenomics data analysis. RESULTS: The sequencing run yielded 1,578,856 reads overall and 2579 reads matched human herpesvirus I (HHV-1) genome; the presence of this pathogen in CSF was confirmed by specific PCR. In subsequent experiments we found that the DNAse I treatment, while lowering the background of host derived sequences, lowered the number of detectable HHV-1 sequences by a factor of 4. Furthermore, we found that the routine extraction of total RNA by the Chomczynski method could be used for identification of both DNA and RNA pathogens in typical clinical settings, as it results in retention of a significant amount of DNA. CONCLUSION: In summary, it seems that NGS preceded by nucleic acid amplification could supplement currently used diagnostic methods in encephalitis. PMID- 26424620 TI - Graphitic Carbon Nitride Polymers toward Sustainable Photoredox Catalysis. AB - As a promising two-dimensional conjugated polymer, graphitic carbon nitride (g-C3 N4 ) has been utilized as a low-cost, robust, metal-free, and visible-light active photocatalyst in the field of solar energy conversion. This Review mainly describes the latest advances in g-C3 N4 photocatalysts for water splitting. Their application in CO2 conversion, organosynthesis, and environmental purification is also briefly discussed. The methods to modify the electronic structure, nanostructure, crystal structure, and heterostructure of g-C3 N4 , together with correlations between its structure and performance are illustrated. Perspectives on the challenges and opportunities for the future exploration of g C3 N4 photocatalysts are provided. This Review will promote the utilization of g C3 N4 materials in the fields of photocatalysis, energy conversion, environmental remediation, and sensors. PMID- 26424619 TI - Assembly and characterization of gp160-nanodiscs: A new platform for biochemical characterization of HIV envelope spikes. AB - The human immunodeficiency virus (HIV) is the causative agent of acquired immune deficiency syndrome (AIDS) and is thus responsible for significant morbidity and mortality worldwide. Despite considerable effort, preparation of an effective vaccine for AIDS has been elusive and it has become clear that a fundamental understanding of the relevant antigenic targets on HIV is essential. The Env trimer spike is the only viral antigen present on the surface of the viral particle and it is the target of all broadly neutralizing antibodies isolated to date. Thus, a soluble, homogeneous, and well-defined preparation of Env trimers is an important first step toward biochemical and structural characterization of the antigenic spike. Phospholipid bilayer nanodiscs represent a relatively new technology that can serve as a platform for the assembly of membrane proteins into a native membrane-like environment. Here we describe the preparation and characterization of unprocessed full-length, natively glycoslyated gp160 Env proteins incorporated into nanodiscs (gp160-ND). The particles are soluble and well defined in the absence of detergent, and possess a morphology anticipated of Env incorporated into a lipid ND. Importantly, the gp160-NDs retain CD4 and Env antibody binding characteristics expected of a functional trimer spike and their incorporation into a lipid membrane allows interrogation of epitopes associated with the membrane-proximal ectodomain region of gp41. These studies provide the groundwork for the use of gp160-ND in more detailed biochemical and structural studies that may set the stage for their use in vaccine development. PMID- 26424621 TI - Malaria Chemoprophylaxis and Self-Reported Impact on Ability to Work: Mefloquine Versus Doxycycline. AB - BACKGROUND: It is well known that both mefloquine and doxycycline are commonly associated with adverse effects when taken for malaria chemoprophylaxis. However, the relative impact of these on travelers' ability to work is not so well understood. The aim of this study was to identify which drug has a lesser impact on the ability to work as measured by self-reported severity of adverse effects via a questionnaire. METHODS: This was a questionnaire-based two-arm cohort study. Participants were soldiers selected from 10 consecutive units training in Kenya during 2012 and 2013. The exposure was either doxycycline or mefloquine and the main outcome measure was impact upon ability to work. Each cohort was advised to take doxycycline or mefloquine with exceptions at the individual level where medically or occupationally advised. RESULTS: Significantly more (p < 0.0001) doxycycline users reported that one or more adverse effects had interfered with their ability to do their job than mefloquine users. Of the 867 mefloquine users, who reported on the impact of adverse effects, 109 (12.6%) reported that one or more adverse effects had impacted upon their ability to do their job, compared to 152 (22.2%) of the 685 doxycycline users who had reported on the impact of any adverse effects. Doxycycline symptoms were predominantly gastrointestinal and dermatological, whereas mefloquine symptoms were neuropsychiatric. CONCLUSIONS: Self-reported symptoms were common in those that responded and, while the true background rate of adverse effects (off any medication) is unknown, doxycycline had a significantly increased rate compared with mefloquine and was associated with a greater occupational impact. Therefore, this study supports the view that, for organizations which provide malaria chemoprophylaxis to employees free of charge, mefloquine should be the first-choice antimalarial drug where the only alternative is doxycycline. PMID- 26424622 TI - Abnormal heart rate recovery in patients with heart failure: an important target for exercise training treatment. PMID- 26424623 TI - Vitamin D and heart: A not so sunny pathway. PMID- 26424624 TI - Achilles' heel of coil occlusion procedure: Anticoagulant therapy. PMID- 26424625 TI - Transcatheter ventricular septal defect closure: Should we feel comfortable after many years? PMID- 26424626 TI - Squeezed heart. PMID- 26424627 TI - Is echocardiographic epicardial adipose tissue thickness measurement a reliable and reproducible method for risk stratification? PMID- 26424628 TI - What is the real predictive value of red cell distribution width for the mortality in non-ST elevation acute coronary syndrome? PMID- 26424629 TI - Arterial stiffness evaluation in patients with irritable bowel syndrome: Role of antihypertensive drugs and statins. PMID- 26424630 TI - Can epicardial adipose tissue predict coronary artery plaque? PMID- 26424631 TI - Preoperative oral pentoxifylline in case of coronary artery bypass grafting with left ventricular dysfunction (ejection fraction equal to/less than 30%). PMID- 26424632 TI - Cardiogenic shock due to occlusion of left main coronary in a cocaine user. PMID- 26424633 TI - An alternative malpractice system suggestion for Turkey: Patient compensation system. PMID- 26424634 TI - Clopidogrel and morphine: Aggregation disturbance? PMID- 26424635 TI - Interview with Carlo Di Mario. PMID- 26424637 TI - A case of an atypically located cardiac hydatid cyst. PMID- 26424638 TI - An unpredictable complication of a transcatheter closure device and surgical treatment. PMID- 26424640 TI - Why and How Epstein-Barr Virus Was Discovered 50 Years Ago. AB - An account is given of the experiences and events which led to a search being undertaken for a causative virus in the recently described Burkitt's lymphoma and of the steps which ultimately culminated in the discovery of the new human herpesvirus which came to be known as Epstein-Barr virus (EBV). PMID- 26424641 TI - Tumor Associations of EBV--Historical Perspectives. AB - This is a brief history of our collaborative work with Werner and Gertrude Henle, Francis Wiener, George and Yanke Manolov, and others on the association of Epstein-Barr virus (EBV) with Burkitt lymphoma and other human tumors. Special emphasis is put on the question where EBV is a true cancer virus. PMID- 26424639 TI - Enhancing assertive community treatment with cognitive behavioral social skills training for schizophrenia: study protocol for a randomized controlled trial. AB - BACKGROUND: Schizophrenia leads to profound disability in everyday functioning (e.g., difficulty finding and maintaining employment, housing, and personal relationships). Medications can effectively reduce positive symptoms (e.g., hallucinations and delusions), but they do not meaningfully improve daily life functioning. Psychosocial evidence-based practices (EBPs) improve functioning, but these EBPs are not available to most people with schizophrenia. The field must close the research and service delivery gap by adapting EBPs for schizophrenia to facilitate widespread implementation in community settings. Our hybrid effectiveness and implementation study represents an initiative to bridge this divide. In this study we will test whether an existing EBP (i.e., Cognitive Behavioral Social Skills Training (CBSST)) modified to work in practice settings (i.e., Assertive Community Treatment (ACT) teams) commonly available to persons with schizophrenia results in better consumer outcomes. We will also identify key factors relevant to developing future CBSST implementation strategies. METHODS/DESIGN: For the effectiveness study component, persons with schizophrenia will be recruited from existing publicly funded ACT teams operating in community settings. Participants will be randomized to one of the 2 treatments (ACT alone or ACT + Adapted CBSST) and followed longitudinally for 18 months with assessments every 18 weeks after baseline (5 in total). The primary outcome domain is psychosocial functioning (e.g., everyday living skills and activities related to employment, education, and housing) as measured by self-report, testing, and observation. Additional outcome domains of interest include mediators of change in functioning, symptoms, and quality of services. Primary analyses will be conducted using linear mixed-effects models for continuous data. The implementation study component consists of a structured, mixed qualitative quantitative methodology (i.e., Concept Mapping) to characterize and assess the implementation experience from multiple stakeholder perspectives in order to inform future implementation initiatives. DISCUSSION: Adapting CBSST to fit into the ACT service delivery context found throughout the United States creates an opportunity to substantially increase the number of persons with schizophrenia who could have access to and benefit from EBPs. As part of the implementation learning process training materials and treatment workbooks have been revised to promote easier use of CBSST in the context of brief community-based ACT visits. TRIAL REGISTRATION: ClinicalTrials.gov NCT02254733 . Date of registration: 25 April 2014. PMID- 26424642 TI - EBV-Specific Immune Response: Early Research and Personal Reminiscences. AB - Early research on Epstein-Barr virus (EBV) developed from serological observations that were made soon after the discovery of the virus. Indeed, the definition of the humoral response to a variety of EBV proteins dominated the early literature and was instrumental in providing the key evidence for the association of the virus with infectious mononucleosis (IM), Burkitt's lymphoma (BL), and nasopharyngeal carcinoma (NPC). Each of these disease associations involved a distinct pattern of serological reactivity to the EBV membrane antigens (MA), early antigens (EA), and the EBV nuclear antigen (EBNA). When it became generally accepted that the marked lymphocytosis , which is a hallmark of acute IM, was dominated by T cells, considerable effort was directed toward untangling the specificities that might be associated with restricting the proliferation of newly infected B cells. Early evidence was divided between support for both EBV non-specific and/or HLA non-restricted components. However, all results needed to be reassessed in light of the observation that T cells died by apoptosis within hours of separation from fresh blood from acute IM patients. The observation that EBV-infected cultures from immune (but not non-immune) individuals began to die (termed regression) about 10 days post-seeding, provided the first evidence of a specific memory response which was apparently capable of controlling the small pool of latently infected B cells which all immune individuals possess. In this early era, CD8(+) T cells were thought to be the effector population responsible for this phenomenon, but later studies suggested a role for CD4(+) cells. This historical review includes reference to key early observations in regard to both the specific humoral and cellular responses to EBV infection from the time of the discovery of the virus until 1990. As well, we have included personal recollections in regard to the events surrounding the discovery of the memory T cell response since we believe they add a human dimension to a chapter focussed on early history. PMID- 26424643 TI - Epstein-Barr Virus Strain Variation. AB - What is wild-type Epstein-Barr virus and are there genetic differences in EBV strains that contribute to some of the EBV-associated diseases? Recent progress in DNA sequencing has resulted in many new Epstein-Barr virus (EBV) genome sequences becoming available. EBV isolates worldwide can be grouped into type 1 and type 2, a classification based on the EBNA2 gene sequence. Type 1 transforms human B cells into lymphoblastoid cell lines much more efficiently than type 2 EBV and molecular mechanisms that may account for this difference in cell transformation are now becoming understood. Study of geographic variation of EBV strains independent of the type 1/type 2 classification and systematic investigation of the relationship between viral strains, infection and disease are now becoming possible. So we should consider more directly whether viral sequence variation might play a role in the incidence of some EBV-associated diseases. PMID- 26424644 TI - Chromatin Structure of Epstein-Barr Virus Latent Episomes. AB - EBV latent infection is characterized by a highly restricted pattern of viral gene expression. EBV can establish latent infections in multiple different tissue types with remarkable variation and plasticity in viral transcription and replication. During latency, the viral genome persists as a multi-copy episome, a non-integrated-closed circular DNA with nucleosome structure similar to cellular chromosomes. Chromatin assembly and histone modifications contribute to the regulation of viral gene expression, DNA replication, and episome persistence during latency. This review focuses on how EBV latency is regulated by chromatin and its associated processes. PMID- 26424645 TI - The Epigenetic Life Cycle of Epstein-Barr Virus. AB - Ever since the discovery of Epstein-Barr virus (EBV) more than 50 years ago, this virus has been studied for its capacity to readily establish a latent infection, which is the prominent hallmark of this member of the herpesvirus family. EBV has become an important model for many aspects of herpesviral latency, but the molecular steps and mechanisms that lead to and promote viral latency have only emerged recently. It now appears that the virus exploits diverse facets of epigenetic gene regulation in the cellular host to establish a latent infection. Most viral genes are transcriptionally repressed, and viral chromatin is densely compacted during EBV's latent phase, but latent infection is not a dead end. In order to escape from this phase, epigenetic silencing must be reverted efficiently and quickly. It appears that EBV has perfected a clever strategy to overcome transcriptional repression of its many lytic genes to initiate virus de novo synthesis within a few hours after induction of its lytic cycle. This review tries to summarize the known molecular mechanisms, the current models, concepts, and ideas underlying this viral strategy. This review also attempts to identify and address gaps in our current understanding of EBV's epigenetic mechanisms within the infected cellular host. PMID- 26424646 TI - Epstein-Barr Virus: From the Detection of Sequence Polymorphisms to the Recognition of Viral Types. AB - The Epstein-Barr virus is etiologically linked with the development of benign and malignant diseases, characterized by their diversity and a heterogeneous geographic distribution across the world. The virus possesses a 170-kb-large genome that encodes for multiple proteins and non-coding RNAs. Early on there have been numerous attempts to link particular diseases with particular EBV strains, or at least with viral genetic polymorphisms. This has given rise to a wealth of information whose value has been difficult to evaluate for at least four reasons. First, most studies have looked only at one particular gene and missed the global picture. Second, they usually have not studied sufficient numbers of diseased and control cases to reach robust statistical significance. Third, the functional significance of most polymorphisms has remained unclear, although there are exceptions such as the 30-bp deletion in LMP1. Fourth, different biological properties of the virus do not necessarily equate with a different pathogenicity. This was best illustrated by the type 1 and type 2 viruses that markedly differ in terms of their transformation abilities, yet do not seem to cause different diseases. Reciprocally, environmental and genetic factors in the host are likely to influence the outcome of infections with the same virus type. However, with recent developments in recombinant virus technology and in the availability of high throughput sequencing, the tide is now turning. The availability of 23 complete or nearly complete genomes has led to the recognition of viral subtypes, some of which possess nearly identical genotypes. Furthermore, there is growing evidence that some genetic polymorphisms among EBV strains markedly influence the biological and clinical behavior of the virus. Some virus strains are endowed with biological properties that explain crucial clinical features of patients with EBV-associated diseases. Although we now have a better overview of the genetic diversity within EBV genomes, it has also become clear that defining phenotypic traits evinced by cells infected by different viruses usually result from the combination of multiple polymorphisms that will be difficult to identify in their entirety. However, the steadily increasing number of sequenced EBV genomes and cloned EBV BACS from diseased and healthy patients will facilitate the identification of the key polymorphisms that condition the biological and clinical behavior of the viruses. This will allow the development of preventative and therapeutic approaches against highly pathogenic viral strains. PMID- 26424649 TI - Primary Immunodeficiencies Associated with EBV Disease. AB - Epstein-Barr virus (EBV) infects nearly all humans and usually is asymptomatic, or in the case of adolescents and young adults, it can result in infectious mononucleosis. EBV-infected B cells are controlled primarily by NK cells, iNKT cells, CD4 T cells, and CD8 T cells. While mutations in proteins important for B cell function can affect EBV infection of these cells, these mutations do not result in severe EBV infection. Some genetic disorders affecting T and NK cell function result in failure to control EBV infection, but do not result in increased susceptibility to other virus infections. These include mutations in SH2D1A, BIRC4, ITK, CD27, MAGT1, CORO1A, and LRBA. Since EBV is the only virus that induces proliferation of B cells, the study of these diseases has helped to identify proteins critical for interactions of T and/or NK cells with B cells. Mutations in three genes associated with hemophagocytic lymphohistocytosis, PRF1, STXBP2, and UNC13D, can also predispose to severe chronic active EBV disease. Severe EBV infection can be associated with immunodeficiencies that also predispose to other viral infections and in some cases other bacterial and fungal infections. These include diseases due to mutations in PIK3CD, PIK3R1, CTPS1, STK4, GATA2, MCM4, FCGR3A, CARD11, ATM, and WAS. In addition, patients with severe combined immunodeficiency, which can be due to mutations in a number of different genes, are at high risk for various infections as well as EBV B cell lymphomas. Identification of proteins important for control of EBV may help to identify new targets for immunosuppressive therapies. PMID- 26424650 TI - Burkitt's Lymphoma. AB - Endemic Burkitt's lymphoma (BL) remains the most prevalent pediatric cancer in sub-Saharan Africa even though it was the first human cancer with a viral etiology described over 50 years ago. Epstein-Barr virus (EBV) was discovered in a BL tumor in 1964 and has since been implicated in other malignancies. The etiology of endemic BL has been linked to EBV and Plasmodium falciparum malaria co-infection. While epidemiologic studies have yielded insight into EBV infection and the etiology of endemic BL, the modulation of viral persistence in children by malaria and deficits in EBV immunosurveillance has more recently been reified. Renewed efforts to design prophylactic and therapeutic EBV vaccines provide hope of preventing EBV-associated BL as well as increasing the ability to cure this cancer. PMID- 26424648 TI - Infectious Mononucleosis. AB - Infectious mononucleosis is a clinical entity characterized by sore throat, cervical lymph node enlargement, fatigue, and fever most often seen in adolescents and young adults and lasting several weeks. It can be caused by a number of pathogens, but this chapter only discusses infectious mononucleosis due to primary Epstein-Barr virus (EBV) infection. EBV is a gamma-herpesvirus that infects at least 90% of the population worldwide. The virus is spread by intimate oral contact among teenagers and young adults. How preadolescents acquire the virus is not known. A typical clinical picture with a positive heterophile test is usually sufficient to make the diagnosis, but heterophile antibodies are not specific and do not develop in some patients. EBV-specific antibody profiles are the best choice for staging EBV infection. In addition to causing acute illness, there can also be long-term consequences as the result of acquisition of the virus. Several EBV-related illnesses occur including certain cancers and autoimmune diseases, as well as complications of primary immunodeficiency in persons with the certain genetic mutations. A major obstacle to understanding these sequelae has been the lack of an efficient animal model for EBV infection, although progress in primate and mouse models has recently been made. Key future challenges are to develop protective vaccines and effective treatment regimens. PMID- 26424651 TI - Contribution of the Epstein-Barr Virus to the Pathogenesis of Hodgkin Lymphoma. AB - The morphology of the pathognomonic Hodgkin and Reed-Sternberg cells (HRS) of Hodgkin lymphoma was described over a century ago, yet it was only relatively recently that the B-cell origin of these cells was identified. In a proportion of cases, HRS cells harbour monoclonal forms of the B lymphotropic Epstein-Barr virus (EBV). This review summarises current knowledge of the pathogenesis of Hodgkin lymphoma with a particular emphasis on the contribution of EBV. PMID- 26424647 TI - EBV Persistence--Introducing the Virus. AB - Persistent infection by EBV is explained by the germinal center model (GCM) which provides a satisfying and currently the only explanation for EBVs disparate biology. Since the GCM touches on every aspect of the virus, this chapter will serve as an introduction to the subsequent chapters. EBV is B lymphotropic, and its biology closely follows that of normal mature B lymphocytes. The virus persists quiescently in resting memory B cells for the lifetime of the host in a non-pathogenic state that is also invisible to the immune response. To access this compartment, the virus infects naive B cells in the lymphoepithelium of the tonsils and activates these cells using the growth transcription program. These cells migrate to the GC where they switch to a more limited transcription program, the default program, which helps rescue them into the memory compartment where the virus persists. For egress, the infected memory cells return to the lymphoepithelium where they occasionally differentiate into plasma cells activating viral replication. The released virus can either infect more naive B cells or be amplified in the epithelium for shedding. This cycle of infection and the quiescent state in memory B cells allow for lifetime persistence at a very low level that is remarkably stable over time. Mathematically, this is a stable fixed point where the mechanisms regulating persistence drive the state back to equilibrium when perturbed. This is the GCM of EBV persistence. Other possible sites and mechanisms of persistence will also be discussed. PMID- 26424652 TI - The Role of EBV in the Pathogenesis of Diffuse Large B Cell Lymphoma. AB - Epstein-Barr virus (EBV) infection is a common feature of B cell lymphoproliferative disorders (LPDs), including diffuse large B cell lymphoma. Approximately 10 % of DLBCLs are EBV-positive, with the highest incidence in immunocompromised and elderly patients. Here, we review the clinical, genetic, and pathologic characteristics of DLBCL and discuss the molecular role of EBV in lymphoma tumorigenesis. Using EBV-positive DLBCL of the elderly as a model, we describe the key features of EBV-positive DLBCL. Studies of EBV-positive DLBCL of the elderly demonstrate that EBV-positive DLBCL has a distinct biology, related to both viral and host factors. The pathogenic mechanisms noted in EBV-positive DLBCL of the elderly, including enhanced NFkappaB activity, are likely to be a generalizable feature of EBV-positive DLBCL. Therefore, we review how this information might be used to target the EBV or its host response for the development of novel treatment strategies. PMID- 26424653 TI - Nasopharyngeal Carcinoma: An Evolving Role for the Epstein-Barr Virus. AB - The Epstein-Barr herpesvirus (EBV) is an important human pathogen that is closely linked to several major malignancies including the major epithelial tumor, undifferentiated nasopharyngeal carcinoma (NPC). This important tumor occurs with elevated incidence in specific areas, particularly in southern China but also in Mediterranean Africa and some regions of the Middle East. Regardless of tumor prevalence, undifferentiated NPC is consistently associated with EBV. The consistent detection of EBV in all cases of NPC, the maintenance of the viral genome in every cell, and the continued expression of viral gene products suggest that EBV is a necessary factor for the malignant growth in vivo. However, the molecular characterization of the infection and identification of critical events have been hampered by the difficulty in developing in vitro models of NPC. Epithelial cell infection is difficult in vitro and in contrast to B-cell infection does not result in immortalization and transformation. Cell lines established from NPC usually do not retain the genome, and the successful establishment of tumor xenografts is difficult. However, critical genetic changes that contribute to the onset and progression of NPC and key molecular properties of the viral genes expressed in NPC have been identified. In some cases, viral expression becomes increasingly restricted during tumor progression and tumor cells may express only the viral nuclear antigen EBNA1 and viral noncoding RNAs. As NPC develops in the immunocompetent, the continued progression of deregulated growth likely reflects the combination of expression of viral oncogenes in some cells and viral noncoding RNAs that likely function synergistically with changes in cellular RNA and miRNA expression. PMID- 26424654 TI - EBV and Autoimmunity. AB - Although a role of EBV in autoimmunity is biologically plausible and evidence of altered immune responses to EBV is abundant in several autoimmune diseases, inference on causality requires the determination that disease risk is higher in individuals infected with EBV than in those uninfected and that in the latter it increases following EBV infection. This determination has so far been possible only for multiple sclerosis (MS) and, to some extent, for systemic lupus erythematosus (SLE), whereas evidence is either lacking or not supportive for other autoimmune conditions. In this chapter, we present the main epidemiological findings that justify the conclusion that EBV is a component cause of MS and SLE and possible mechanisms underlying these effects. PMID- 26424655 TI - Incidence and predictors of annual chlamydia testing among 15-29 year olds attending Aboriginal primary health care services in New South Wales, Australia. AB - BACKGROUND: For the past two decades, chlamydia has been the most commonly notified infectious disease among young people (15-29 year olds) in Australia, the United States of America and the United Kingdom and rates have increased annually in these three countries. In Australia, rates of chlamydia are three times higher in Aboriginal compared with non-Aboriginal people. Australian sexually transmissible infection guidelines recommend annual chlamydia testing for 15-29 year old females and males. This analysis will examine the incidence and predictors of annual chlamydia testing in 15-29 year olds attending four Aboriginal Community Controlled Health Services (ACCHS) in Australia. METHODS: From 2009-2011, attendance and chlamydia testing data were extracted from the patient system to calculate the number and proportion of 15-29 year olds that were tested for chlamydia and that tested positive for chlamydia by gender (male, female), age-group (15-19, 20-24, 25-29 years), Aboriginal status (Aboriginal, non-Aboriginal people) and by the four ACCHSs sites (1, 2, 3 and 4). A cohort was created to calculate the incidence rate per 100 person-years (PY) and predictors of an annual chlamydia test (a test within 12-months of a previous test/visit) by the above factors using Cox regression. Unadjusted and adjusted hazard ratios (AHR) and their 95 % confidence intervals (CIs) and p-values were calculated with significance at p < 0.05. RESULTS: From 2009-2011, there were 2896 individuals who attended the four ACCHSs. Overall , 17 % (22 % of females and 10 % of males) were tested for chlamydia and 9 % tested positive (8 % of females and 14 % of males). The median time to an annual chlamydia test was 10.7 months. The cohort included 2318 individuals. Overall the incidence rate of an annual chlamydia test was 9.1 per 100 PY (11.6 in females and 5.8 in males). Predictors of an annual chlamydia test were being female (AHR: 1.7, 95 % CI: 1.2-2.2, p < 0.01), being 15 19 years old (AHR: 1.6, 95 % CI: 1.1-2.3, p < 0.01) and attending ACCHS site 2 (AHR: 3.8, 95 % CI: 1.8-8.0, p < 0.01). CONCLUSIONS: This analysis highlights that opportunistic STI testing strategies are needed to increase annual chlamydia testing in young people; especially males. PMID- 26424656 TI - A good patient? How notions of 'a good patient' affect patient-nurse relationships and ART adherence in Zimbabwe. AB - BACKGROUND: While patient-provider interactions are commonly understood as mutually constructed relationships, the role of patient behaviour, participation in interactions, and characteristics, particularly ideals surrounding notions of 'good' and 'bad' patients, are under-examined. This article examines social representations of 'a good patient' and how these representations affect patient healthcare provider relationships and antiretroviral treatment (ART) for people living with HIV. METHODS: Using thematic network analysis, we examined interview and focus group transcripts involving 25 healthcare staff, 48 ART users, and 31 carers of HIV positive children, as well as field notes from over 100 h of ethnographic observation at health centres in rural Zimbabwe. RESULTS: Characteristics of a good patient include obedience, patience, politeness, listening, enthusiasm for treatment, intelligence, physical cleanliness, honesty, gratitude and lifestyle adaptations (taking pills correctly and coming to the clinic when told). As healthcare workers may decide to punish patients who do not live up the 'good patient persona', many patients seek to perform within the confines of the 'good patient persona' to access good care and ensure continued access to ART. DISCUSSION: The notion of a 'good ART patient' can have positive effects on patient health outcomes. It is one of the only arenas of the clinic experience that ART patients can influence in their favour. However, for people not conforming to the norms of the 'good patient persona', the productive and health-enabling patient-nurse relationship may break down and be detrimental to the patient. CONCLUSION: We conclude that policy makers need to take heed of the social representations that govern patient-nurse relationships and their role in facilitating or undermining ART adherence. PMID- 26424657 TI - The regulatory role of B cells in autoimmunity, infections and cancer: Perspectives beyond IL10 production. AB - The term regulatory B cells (B regs) is ascribed to a heterogeneous population of B cells with the function of suppressing inflammatory responses. They have been described mainly during the last decade in the context of different immune mediated diseases. Most of the work on B regs has been focused on IL-10-producing B cells. However, B cells can exert regulatory functions independently of IL-10 production. Here we discuss the phenotypes, development and effector mechanisms of B regs and advances in their role in autoimmunity, infections and cancer. PMID- 26424658 TI - The zinc-finger protein SPT4 interacts with SPT5L/KTF1 and modulates transcriptional silencing in Arabidopsis. AB - The Arabidopsis multidomain protein SPT5L/KTF1 (which has similarity to the transcript elongation factor SPT5) associates with RNA polymerase V (RNAPV) and is an accessory factor in RNA-directed DNA methylation. The zinc-finger protein SPT4 was found to interact with SPT5L (and SPT5) both in vivo and in vitro. Here, we show that plants depleted of SPT4 relative to wild type display reduced DNA methylation and the locus specificity is shared with SPT5L, suggesting a cooperation of SPT4 and SPT5L. Unlike observed for SPT5, no reduced protein level of SPT5L is determined in SPT4-deficient plants. These experiments demonstrate that in addition to the RNA polymerase II-associated SPT4/SPT5 that is generally conserved in eukaryotes, flowering plants have SPT4/SPT5L that is involved in RNAPV-mediated transcriptional silencing. PMID- 26424659 TI - O-Fucosylation of CCN1 is required for its secretion. AB - The matricellular protein CCN1, also known as Cyr61, is a secreted ligand and has numerous functions. Human CCN1 contains one predicted O-fucosylation site in the thrombospondin type-1 repeat (TSR1) domain at Thr(242). In this report, we demonstrated that CCN1 is O-fucosylated at Thr(242) using mass spectrometry. Deficiency of O-fucosylation resulted in the decrement of the cell surface localization and the secretion of CCN1. Furthermore, knockdown of protein O fucosyltransferase 2, which modifies a specific Ser/Thr residue in the TSR1 domain, decreased secreted levels of CCN1. These results demonstrated that O fucosylation of CCN1 at Thr(242) regulates its secretion. PMID- 26424660 TI - Disease-modifying effects of phosphocitrate and phosphocitrate-beta-ethyl ester on partial meniscectomy-induced osteoarthritis. AB - BACKGROUND: It is believed that phosphocitrate (PC) exerts its disease-modifying effects on osteoarthritis (OA) by inhibiting the formation of crystals. However, recent findings suggest that PC exerts its disease-modifying effect, at least in part, through a crystal-independent action. This study sought to examine the disease-modifying effects of PC and its analogue PC-beta-ethyl ester (PC-E) on partial meniscectomy-induced OA and the structure-activity relationship. METHODS: Calcification- and proliferation-inhibitory activities were examined in OA fibroblast-like synoviocytes (FLSs) culture. Disease-modifying effects were examined using Hartley guinea pigs undergoing partial meniscectomy. Cartilage degeneration was examined with Indian ink, safranin-O, and picrosirius red. Levels of matrix metalloproteinase-13 (MMP-13), ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5), chemokine (C-C motif) ligand 5 (CCL5), and cyclooxygenase-2 (Cox-2) were examined with immunostaining. The effects of PC E and PC on gene expressions in OA FLSs were examined with microarray. Results are expressed as mean +/- standard deviation and analyzed using Student's t test or Wilcoxon rank sum test. RESULTS: PC-E was slightly less powerful than PC as a calcification inhibitor but as powerful as PC in the inhibition of OA FLSs proliferation. PC significantly inhibited cartilage degeneration in the partial meniscectomied right knee. PC-E was less powerful than PC as a disease-modifying drug, especially in the inhibition of cartilage degeneration in the non-operated left knee. PC significantly reduced the levels of ADAMTS5, MMP-13 and CCL5, whereas PC-E reduced the levels of ADAMTS5 and CCL5. Microarray analyses revealed that PC-E failed to downregulate the expression of many PC-downregulated genes classified in angiogenesis and inflammatory response. CONCLUSIONS: PC is a disease-modifying drug for posttraumatic OA therapy. PC exerts its disease modifying effect through two independent actions: inhibiting pathological calcification and modulating the expression of many genes implicated in OA. The beta-carboxyl group of PC plays an important role in the inhibition of cartilage degeneration, little role in the inhibition of FLSs proliferation, and a moderate role in the inhibition of FLSs-mediated calcification. PMID- 26424661 TI - Osteochondroma of the fifth rib resulting in recurrent hemothorax. AB - A 48-year-old man presented with recurrent spontaneous hemothoraces, which ultimately were found to be secondary to a pedunculated costal osteochondroma causing vascular injury. After initially undergoing endovascular coil embolization, he ultimately required segmental rib resection containing the offending lesion for definite treatment. Although a few cases of symptomatic costal osteochondromas have been reported in the literature, as far as we know, no previous reports have provided direct radiologic confirmation of active bleeding or the role of angiographic intervention. In this report, we highlight the importance of CT angiography in establishing a direct link between an osteochondroma and recurrent hemothorax. We also discuss the diagnostic imaging challenges associated with this condition and the use of a multidisciplinary treatment strategy involving both angiographic and operative management. PMID- 26424662 TI - Developing a system to monitor family planning and HIV service integration: results from a pilot test of indicators. AB - OBJECTIVES: To determine the feasibility of collecting data to calculate six indicators of family planning (FP) and HIV integration using existing health information systems (HIS); obtain information to refine indicators; and identify changes needed in existing HIS to calculate indicators. DESIGN: Data abstraction from HIS in a purposive sample of 39 health facilities in Ethiopia, Rwanda, Tanzania and Uganda to analyse data availability and quality undertaken between November 2010 and March 2011. METHODS: Teams reviewed patient record cards, registers, monthly and quarterly reports for the most recent complete month. Teams recorded all possible sources for each data element, indicated whether data are collated monthly, and whether disaggregation by age, sex and originating service was possible. RESULTS: With the exception of Uganda, all countries were able to report the proportion of service delivery points offering integrated services. Ethiopia was able to calculate the indicator for fixed sites but not for home-based care services. In most cases we were able to calculate the proportion of HIV clients receiving FP services or referral, and the proportion of FP clients receiving an HIV test or referral. It is feasible to collect data for these indicators under current circumstances in some countries. CONCLUSIONS: Several actions are proposed for national health systems, including adopting a system of unique client identifiers. Age group reporting bands should be aligned across services. More accurate counts of daily and active client loads are needed to provide programme managers with information to inform programme monitoring. PMID- 26424663 TI - Equine Embryo Sexing and Ultrasonographic Foetal Sexing - Interests and Applicability. AB - The ability to choose the sex of the offspring is of upmost economic importance for horse breeders. Unlike other species, horses present several reproductive peculiarities that interfere with assisted reproductive technologies used in other large animals (such as bovine) and make them difficult to apply. Thus, there is a great interest to determine the sex of the offspring as soon as possible. This has led to the development of several technologies to serve this purpose, which can be classified into two categories. One is equine embryo sexing by either non-invasive biotechnological methods, such as monitoring of X-linked enzymes before X chromosome inactivation and detection of sex-specific antigen, or by invasive biotechnological methods, such as cytogenetic analysis and polymerase chain reaction (PCR). The other one is equine foetus sexing using ultrasound scanning in different stages of its development (early, mid or late), by different approaches (transrectally or transabdominally). This can be performed with classic B-mode ultrasound machines or using 3D-mode and Doppler mode scanners. This review article offers a comprehensive overview of the current status of these procedures as well as an assessment of their interests and applicability. PMID- 26424664 TI - Concepts and Molecular Aspects in the Polypharmacology of PARP-1 Inhibitors. AB - Recent years have witnessed a renewed interest in PARP-1 inhibitors as promising anticancer agents with multifaceted functions. Particularly exciting developments include the approval of olaparib (Lynparza) for the treatment of refractory ovarian cancer in patients with BRCA1/2 mutations, and the increasing understanding of the polypharmacology of PARP-1 inhibitors. The aim of this review article is to provide the reader with a comprehensive overview of the distinct levels of the polypharmacology of PARP-1 inhibitors, including 1) inter family polypharmacology, 2) intra-family polypharmacology, and 3) multi-signaling polypharmacology. Progress made in gaining insight into the molecular basis of these multiple target-independent and target-dependent activities of PARP-1 inhibitors are discussed, with an outlook on the potential impact that a better understanding of polypharmacology may have in aiding the explanation as to why some drug candidates work better than others in clinical settings, albeit acting on the same target with similar inhibitory potency. PMID- 26424666 TI - Co-ingestion of energy drinks with alcohol and other substances among a sample of people who regularly use ecstasy. AB - INTRODUCTION AND AIMS: Despite the potential harms of mixing unregulated drugs with energy drinks (ED), research to date has primarily been focused on EDs co ingested with alcohol. Consequently, the aim of the present study was to explore the rate of use, harms and correlates of EDs co-ingested with alcohol and other drugs among a sample of people who regularly use illicit stimulant drugs. DESIGN AND METHODS: In 2010, 693 Australians who regularly used ecstasy completed a 1-h interview about their past six-month ED and drug use. RESULTS: Three-quarters of the sample (77%) had recently consumed EDs with other substances, primarily alcohol (70%) and ecstasy (57%). People who consumed ED with alcohol versus those who had consumed ED with ecstasy and with alcohol (only 8% reported only consuming ED with ecstasy) had similar profiles in regards to demographics, drug use, mental health and drug-related problems. Primary motives for consuming ED with alcohol included increased alertness (59%), the taste (25%), to party for longer (23%) and to combat fatigue (16%). One-half (52%) and one-quarter (27%) of participants who consumed EDs with alcohol and with ecstasy respectively had recently experienced adverse outcomes post-consumption, primarily headaches (24% and 11%) and heart palpitations (21% and 14%). DISCUSSION AND CONCLUSIONS: Co ingestion of EDs with licit and illicit drugs is common among people who regularly use ecstasy and related drugs. Adverse outcomes of co-ingestion suggest that targeted education regarding negative interactive drug effects is crucial for harm reduction. [Peacock A, Sindicich N, Dunn M, Whittaker E, Sutherland R, Entwistle G, Burns L, Bruno R. Co-Ingestion of Energy Drinks with Alcohol and Other Substances among a Sample of People Who Regularly Use Ecstasy. Drug Alcohol Rev 2016;35:352-358]. PMID- 26424667 TI - Antiretroviral gels: facing the FACTS. PMID- 26424665 TI - A Comprehensive Overview on Myositis-Specific Antibodies: New and Old Biomarkers in Idiopathic Inflammatory Myopathy. AB - Autoantibodies specific for idiopathic inflammatory myopathy (myositis-specific autoantibodies (MSAs)) are clinically useful biomarkers to help the diagnosis of polymyositis/dermatomyositis (PM/DM). Many of these are also associated with a unique clinical subset of PM/DM, making them useful in predicting and monitoring certain clinical manifestations. Classic MSAs known for over 30 years include antibodies to Jo-1 (histidyl transfer RNA (tRNA) synthetase) and other aminoacyl tRNA synthetases (ARS), anti-Mi-2, and anti-signal recognition particle (SRP). Anti-Jo-1 is the first autoantibodies to ARS detected in 15-25 % of patients. In addition to anti-Jo-1, antibodies to seven other aminoacyl tRNA synthetases (ARS) have been reported with prevalence, usually 1-5 % or lower. Patients with any anti-ARS antibodies are associated with anti-synthetase syndrome characterized by myositis, interstitial lung disease (ILD), arthritis, Raynaud's phenomenon, and others. Several recent studies suggested heterogeneity in clinical features among different anti-ARS antibody-positive patients and anti-ARS may also be found in idiopathic ILD without myositis. Anti-Mi-2 is a classic marker for DM and associated with good response to steroid treatment and good prognosis. Anti-SRP is specific for PM and associated with treatment-resistant myopathy histologically characterized as necrotizing myopathy. In addition to classic MSAs, several new autoantibodies with strong clinical significance have been described in DM. Antibodies to transcription intermediary factor 1gamma/alpha (TIF1gamma/alpha, p155/140) are frequently found in DM associated with malignancy while anti-melanoma differentiation-associated gene 5 (MDA5; CADM140) are associated with clinically amyopathic DM (CADM) complicated by rapidly progressive ILD. Also, anti-MJ/nuclear matrix protein 2 (NXP-2) and anti-small ubiquitin-like modifier-1 (SUMO-1) activating enzyme (SAE) are recognized as new DM-specific autoantibodies. Addition of these new antibodies to clinical practice in the future will help in making earlier and more accurate diagnoses and better management for patients. PMID- 26424668 TI - FLAMINGO: still in the pink? PMID- 26424669 TI - Co-trimoxazole prophylaxis: the debates continue. PMID- 26424670 TI - Maintenance of antiretroviral efficacy in children. PMID- 26424671 TI - Cost-effectiveness of community-based strategies for HIV. PMID- 26424672 TI - Viral co-infections in high-risk communities of Pakistan. PMID- 26424674 TI - Co-trimoxazole prophylaxis in adults, including pregnant women, with HIV: a systematic review and meta-analysis. AB - INTRODUCTION: Co-trimoxazole prophylaxis is used to reduce morbidity and mortality in people with HIV. We systematically reviewed three topics related to co-trimoxazole prophylaxis to update WHO guidelines: initiation, discontinuation, and dose. METHODS: We searched PubMed, Embase, WHO Global Index Medicus, and clinical trial registries in November, 2013, for randomised controlled trials and observational studies including co-trimoxazole prophylaxis and a comparator group. Studies were eligible if they reported death, WHO clinical stage 3 or 4 events, admittance to hospital, severe bacterial infections, tuberculosis, pneumonia, diarrhoea, malaria, or treatment-limiting adverse events. Infant mortality, low birthweight, and placental malaria were additional outcomes for the comparison of co-trimoxazole prophylaxis and intermittent preventive treatment for malaria in pregnant women (IPTp). We compared a dose of 480 mg co trimoxazole once a day with one of 960 mg co-trimoxazole once a day. We used a 10% margin for non-inferiority and equivalence analyses. We used random-effects models for all meta-analyses. This study is registered with PROSPERO, number CRD42014007163. FINDINGS: 19 articles, published from 1995 to 2014 and including 35 328 participants, met the inclusion criteria. Co-trimoxazole prophylaxis reduced rates of death (hazard ratio [HR] 0.40, 95% CI 0.26-0.64) when started at CD4 counts of 350 cells per MUL or lower with antiretroviral therapy (ART) worldwide. Co-trimoxazole prophylaxis started at higher than 350 cells per MUL without ART reduced rates of death (0.50, 0.30-0.83) and malaria (0.25, 0.10 0.57) in Africa. Co-trimoxazole prophylaxis was non-inferior to IPTp with respect to infant mortality (risk difference [RD] -0.05, 95% CI -0.12 to 0.02), low birthweight (0.00, -0.07 to 0.07), and placental malaria (0.00, -0.10 to 0.10). Co-trimoxazole prophylaxis continuation after ART-induced recovery with CD4 counts higher than 350 cells per MUL reduced admittances to hospital (HR 0.42, 95% CI 0.22-0.80), pneumonia (0.73, 0.61-0.88), malaria (0.03, 0.01-0.10), and diarrhoea (0.61, 0.48-0.78) in Africa. A dose of 480 mg co-trimoxazole prophylaxis once a day did not reduce treatment-limiting adverse events compared with 960 mg once a day (RD -0.07, 95% CI -0.52 to 0.39). INTERPRETATION: Co trimoxazole prophylaxis should be given with ART in people with CD4 counts of 350 cells per MUL or lower in low-income and middle-income countries. Co-trimoxazole prophylaxis should be provided irrespective of CD4 count in settings with a high burden of infectious diseases. Pregnant women with HIV in Africa should use co trimoxazole rather than IPTp to prevent malaria complications in infants. Further research is needed to inform dose optimisation and co-trimoxazole use in the context of expanded ART in different epidemiological settings. FUNDING: None. PMID- 26424675 TI - Role of Amylin in Type 1 and Type 2 Diabetes. AB - PURPOSE: The pathophysiology of diabetes has historically focused on alterations in insulin secretion and function; however, diabetes involves multiple hormonal alterations, including abnormal regulation of amylin. This review discusses the physiologic functions of amylin in glucose homeostasis and the rationale for amylin replacement in type 1 and 2 diabetes. The use of pramlintide, a synthetic amylin analog, is also discussed. CONCLUSIONS: Amylin, formed primarily in pancreatic islet beta cells, is cosecreted with insulin in response to caloric intake. Patients with type 1 diabetes have lower baseline amylin serum concentrations, and amylin response to caloric intake is absent. Patients with type 2 diabetes requiring insulin also have a diminished amylin response to caloric intake, potentially related to the degree of beta-cell impairment. Key physiologic functions of amylin in maintaining glucose homeostasis include suppressing glucagon release in response to caloric intake, delaying the rate of gastric emptying, and stimulating the satiety center in the brain to limit caloric intake. Pramlintide is indicated for adults with type 1 and 2 diabetes who have not achieved adequate glucose control despite optimal insulin therapy. As an adjunct to insulin therapy, pramlintide demonstrated significant reductions in A1C in patients with type 1 and 2 diabetes, with favorable effects on body weight. It is administered subcutaneously before each major meal. There is an increased risk of hypoglycemia with insulin when used in combination with pramlintide. Other adverse effects may include nausea, vomiting, anorexia, reduced appetite, and headache. Proper patient selection and education are essential to successful pramlintide use. PMID- 26424673 TI - Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open label, phase 3b study. AB - BACKGROUND: The primary analysis of the FLAMINGO study at 48 weeks showed that patients taking dolutegravir once daily had a significantly higher virological response rate than did those taking ritonavir-boosted darunavir once daily, with similar tolerability. We present secondary efficacy and safety results analysed at 96 weeks. METHODS: FLAMINGO was a multicentre, open-label, phase 3b, non inferiority study of HIV-1-infected treatment-naive adults. Patients were randomly assigned (1:1) to dolutegravir 50 mg or darunavir 800 mg plus ritonavir 100 mg, with investigator-selected combination tenofovir and emtricitabine or combination abacavir and lamivudine background treatment. The main endpoints were plasma HIV-1 RNA less than 50 copies per mL and safety. The non-inferiority margin was -12%. If the lower end of the 95% CI was greater than 0%, then we concluded that dolutegravir was superior to ritonavir-boosted darunavir. This trial is registered with ClinicalTrials.gov, number NCT01449929. FINDINGS: Of 595 patients screened, 488 were randomly assigned and 484 included in the analysis (242 assigned to receive dolutegravir and 242 assigned to receive ritonavir boosted darunavir). At 96 weeks, 194 (80%) of 242 patients in the dolutegravir group and 164 (68%) of 242 in the ritonavir-boosted darunavir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 12.4, 95% CI 4.7-20.2; p=0.002), with the greatest difference in patients with high viral load at baseline (50/61 [82%] vs 32/61 [52%], homogeneity test p=0.014). Six participants (three since 48 weeks) in the dolutegravir group and 13 (four) in the darunavir plus ritonavir group discontinued because of adverse events. The most common drug-related adverse events were diarrhoea (23/242 [10%] in the dolutegravir group vs 57/242 [24%] in the darunavir plus ritonavir group), nausea (31/242 [13%] vs 34/242 [14%]), and headache (17/242 [7%] vs 12/242 [5%]). INTERPRETATION: Once-daily dolutegravir is associated with a higher virological response rate than is once daily ritonavir-boosted darunavir. Dolutegravir compares favourably in efficacy and safety to a boosted darunavir regimen with nucleoside reverse transcriptase inhibitor background treatment for HIV-1-infected treatment-naive patients. FUNDING: ViiV Healthcare and Shionogi & Co. PMID- 26424676 TI - Diabetes Education as a Career Choice. AB - PURPOSE: The purpose of the study was to examine the field of diabetes education along with identifying facilitators and barriers for future health care professionals entering the specialty field of diabetes education. METHOD: Faculty members who were currently teaching in a health-related discipline, the students of those faculty members, and nursing students who were members of the National Student Nursing Association were surveyed to gather descriptive data. RESULTS: While faculty members reported they are promoting diabetes education to their health professions students, many nursing students are not aware of this career path. Nursing students understand that diabetes is a significant problem and will be something they encounter in all areas of their careers, but many were not sure they wanted to specialize in it. CONCLUSIONS: There is a gap between what faculty members and students report as far as awareness of the diabetes education specialty. In addition, misinformation about diabetes and people living with diabetes may be a deterrent for potential future diabetes educators. American Association of Diabetes Educators, health professions faculty members, and practicing diabetes educators can do more to clear up misconceptions and promote diabetes education as a career path for students in the health professions. PMID- 26424677 TI - Grandparent Education Through Simulation-Diabetes. AB - PURPOSE: The purpose of this study was to explore the feasibility of using human patient simulation (HPS) to teach type 1 diabetes (T1DM) management to grandparents of grandchildren with T1DM. METHODS: Thirty grandparents (11 male, 19 female) of young grandchildren (aged 12 and under) with T1DM were recruited from an urban medical center. Experimental group (n = 14) grandparents received hands-on visual T1DM management education using an HPS intervention, and control group (n = 16) grandparents received similar education using a non-HPS intervention. FINDINGS: This study demonstrated the feasibility of recruiting and retaining grandparents into a clinical trial using HPS to teach T1DM management. Post intervention, all grandparent scores for T1DM knowledge, confidence, and fear showed significant improvement from time 1 to time 2, with HPS group grandparent scores showing consistently larger improvement. CONCLUSIONS: The consistency of larger HPS-taught grandparent score improvement is suggestive of a benefit for the HPS teaching method. Early multimethod Certified Diabetes Educator (CDE)-provided T1DM education is an important point of entry for inducting grandparent members onto the grandchild's diabetes care team. PMID- 26424679 TI - Transcatheter aortic valve implantation for paradoxical low-flow low-gradient aortic stenosis patients. AB - OBJECTIVES: We compared the outcomes of transcatheter aortic valve implantation (TAVI) in three different aortic stenosis syndromes: paradoxical low-flow low gradient aortic stenosis (PLFLG), high-gradient aortic stenosis (HGAS), and low ejection fraction low-gradient severe aortic stenosis (LEF-LG). BACKGROUND: Outcomes for PLFLG patients after TAVI procedure are not well known. METHODS: Between 2010 and 2013, patients with severe (indexed aortic valve area iAVA<=0.6 cm(2)/m(2)) symptomatic aortic stenosis were consecutively referred to our institution for TAVI because of multiple comorbidities and excessive surgical risk. About 262 patients were split into three groups as following, PLFLG: mean gradient MG<=40 mm Hg, stroke volume index SVI<=35 mL/m(2), ejection fraction EF>=55%, valvuloarterial impedance Zva>4.5 mm Hg/mL/m(2), maximal aortic jet velocity MaxV<4 m/s; LEF-LG: MG<=40 mm Hg, MaxV<4 m/s, EF<=50%, SVI<=35 mL/m(2); and HGAS: MaxV>4 m/s, MG>40 mm Hg, EF>55%. The primary endpoint of our study was to evaluate mid-term global and cardiovascular mortalities; secondary endpoints included recommended VARC-2 variables. RESULTS: PLFLG (n = 31) mid-term survival was similar to HGAS (n = 172) (mean follow-up = 13.2 months [4.6-26]). Conversely LEF-LG patients (n = 59) displayed significant higher rates of all-cause (P = 0.01) and cardiovascular mortalities (P = 0.05). Postprocedural outcomes (VARC-2 criteria) were similar in the PLFLG and HGAS groups except regarding major bleeding (P = 0.02), while the LEF-LG group had more congestive heart failure and a higher BNP before discharge (both P < 0.001) than the other groups. 30-days deaths were significantly more frequent in LEF-LG and PLFLG in comparison to HGAS (P = 0.03). CONCLUSION: As opposed to LEF-LG patients, mid-term prognosis after TAVI procedure in PLFLG patients is similar to HGAS patients despite higher perioperative mortality. PMID- 26424681 TI - Finally, a time and place for electrophysiological testing in critically ill patients? PMID- 26424680 TI - Cytomegalovirus reactivation in ICU patients. AB - INTRODUCTION: Approximately 20 years have passed since we reported our results of histologically proven cytomegalovirus (CMV) pneumonia in non-immunocompromised ICU patients. Even if there are more recent reports suggesting that CMV may worsen the outcomes for ICU patients, there is no definite answer to this question: is CMV a potential pathogen for ICU patients or is it simply a bystander? METHODS: We will describe the pathophysiology of active CMV infection and the most recent insights concerning the epidemiological aspects of these reactivations. MAJOR FINDINGS: Cytomegalovirus can be pathogenic by a direct organ insult (such as for the lung), by decreasing host defences against other microorganisms and/or by enhancing the body's inflammatory response (as in acute respiratory distress syndrome). The incidence of active CMV infection is dependent on the diagnostic method used. Using the most sophisticated available biological tools, the incidence can reach 15-20% of ICU patients (20-40% in ICU patients with positive CMV serology). In adequately powered cohorts of patients, active CMV infection appears to be associated with worse outcomes for mechanically ventilated ICU patients. DISCUSSION: There is no absolute direct proof of a negative impact of active CMV infection on the health outcomes of mechanically ventilated patients. Prospective randomized trials are lacking. Future trials should examine the potential benefits for health outcomes of using antiviral treatments. Such treatments could be prophylactic, pre-emptive or used only when there is an end-organ disease. CONCLUSION: Cytomegalovirus infection may affect health outcomes for ICU patients. Additional prospective trials are necessary to confirm this hypothesis. PMID- 26424682 TI - What's new in bacterial meningitis. PMID- 26424683 TI - Bacteremic pneumococcal pneumonia: clinical outcomes and preliminary results of inflammatory response. AB - PURPOSE: Further examination of clinical outcomes and inflammatory response of bacteremic pneumococcal community-acquired pneumonia (CAP) is of great interest to enhance the care of patients with pneumococcal CAP. METHODS: This is a secondary analysis of the Community Acquired Pneumonia Organization (CAPO) to compare the time to clinical stability (TCS), length of hospital stay (LOS), and in-hospital mortality of hospitalized pneumococcal CAP patients with and without bacteremia. To measure the effect of bacteremia in pneumococcal CAP patients on outcomes, we modeled all-cause in-hospital mortality using a Poisson regression model, and TCS and LOS using Cox proportional hazards models. Adjusted multivariate regression models were also used to predict the probability of occurrence of each of the study outcomes. To investigate the inflammatory response, we measured the plasma levels of pro- and anti-inflammatory cytokines [tumor necrosis factor (TNF)-alpha, interleukin (IL)-1ralpha, IL-6, IL-8, IL-10], inflammatory biomarkers [C-reactive protein (CRP), pro-calcitonin (PCT), and B type natriuretic peptide (BNP)], and peripheral blood neutrophil responses in 10 patients, 4 bacteremic and 6 non-bacteremic pneumococcal CAP, upon admission and every other day during the first 6 days of hospitalization. Functional data were presented as median and standard error of the median (SEM); due to small number of samples no statistical comparisons were performed between groups. RESULTS: From 833 pneumococcal CAP patients, 394 patients (47 %) were bacteremic. Bacteremic pneumococcal CAP were less likely to reach TCS with an adjusted hazard ratio (AHR) of 0.82 (95 % CI 0.69-0.97; p = 0.02) and had higher in-hospital mortality with an AHR of 1.63 (95 % CI 1.06-2.50, p = 0.026). Bacteremic pneumococcal CAP patients had a longer LOS than non-bacteremic pneumococcal CAP (p < 0.003). Higher plasma levels of CRP, PCT, and BNP were found in bacteremic than in non-bacteremic patients. The bacteremic group had consistently higher plasma levels of both pro- and anti-inflammatory cytokines. The blood neutrophil functional responses were similar in both groups of patients. CONCLUSIONS: Bacteremic pneumococcal CAP patients were significantly associated with higher in hospital mortality, lower TCS, and longer LOS. HIV-infected patients showed a greater mortality which was not statistically significant. Bacteremic pneumococcal CAP patients had higher levels of biomarkers and systemic cytokines. PMID- 26424684 TI - Corynebacterium diphtheriae in a free-roaming red fox: case report and historical review on diphtheria in animals. AB - OBJECTIVES: Corynebacterium diphtheriae, the classical causative agent of diphtheria, is considered to be nearly restricted to humans. Here we report the first finding of a non-toxigenic C. diphtheriae biovar belfanti strain in a free roaming wild animal. METHODS: The strain obtained from the subcutis and mammary gland of a dead red fox (Vulpes vulpes) was characterized by biochemical and molecular methods including MALDI-TOF and Multi Locus Sequence Typing. Since C. diphtheriae infections of animals, usually with close contact to humans, are reported only very rarely, an intense review comprising also scientific literature from the beginning of the 20th century was performed. RESULTS: Besides the present case, only 11 previously reported C. diphtheriae animal infections could be verified using current scientific criteria. CONCLUSIONS: Our report is the first on the isolation of C. diphtheriae from a wildlife animal without any previous human contact. In contrast, the very few unambiguous publications on C. diphtheriae in animals referred to livestock or pet animals with close human contact. C. diphtheriae carriage in animals has to be considered as an exceptionally rare event. PMID- 26424685 TI - The Effects of Diesel Exhaust Pollution on Floral Volatiles and the Consequences for Honey Bee Olfaction. AB - There is growing evidence of a substantial decline in pollinators within Europe and North America, most likely caused by multiple factors such as diseases, poor nutrition, habitat loss, insecticides, and environmental pollution. Diesel exhaust could be a contributing factor to this decline, since we found that diesel exhaust rapidly degrades floral volatiles, which honey bees require for flower recognition. In this study, we exposed eight of the most common floral volatiles to diesel exhaust in order to investigate whether it can affect volatile mediated plant-pollinator interaction. Exposure to diesel exhaust altered the blend of common flower volatiles significantly: myrcene was considerably reduced, beta-ocimene became undetectable, and beta-caryophyllene was transformed into its cis-isomer isocaryophyllene. Proboscis extension response (PER) assays showed that the alterations of the blend reduced the ability of honey bees to recognize it. The chemically reactive nitrogen oxides fraction of diesel exhaust gas was identified as capable of causing degradation of floral volatiles. PMID- 26424686 TI - The importance of tailoring physicians' trauma care training needs in rural environments. AB - SUMMARY: Gaps in the provision of care exist in the initial evaluation and management of patients first cared for in the most rural settings. We designed a survey to explore what unmet educational needs might exist so as to improve the care of patients before transfer. Here we discuss opportunities for tailored training that will enhance learning capacity, narrow the trauma education gap and improve trauma care, particularly in rural environments. PMID- 26424687 TI - Providing mentorship support to general surgery residents: a model for structured group facilitation. AB - SUMMARY: Mentorship is foundational to surgical training, with recognized benefits for both mentees and mentors. The University of Ottawa General Surgery Mentorship Program was developed as a module-based group facilitation program to support inclusive personal and professional development of junior general surgery residents. The group format provided an opportunity for both vertical and horizontal mentorship relationships between staff mentors and resident mentees. Perceived benefits of program participants were evaluated at the conclusion of the first year of the program. The program was well-received by staff and resident participants and may provide a time-efficient and inclusive mentorship structure with the additional benefit of peer support. We review the development and implementation of the program to date and share our mentorship experience to encourage the growth of formal mentorship opportunities within general surgery training programs. PMID- 26424688 TI - Current perioperative practice in Canadian vascular surgery. AB - BACKGROUND: The Enhanced Recovery After Surgery (ERAS) Society has set out to improve patient recovery by developing evidence-based perioperative practices. Many institutions and other specialties have begun to apply their principles with great success; however, ERAS principles focus mostly on general surgery, and their applicability to other specialties, such as vascular surgery, is less clear. We sought to investigate the current standard of perioperative care in Canadian vascular surgery by assessing surgeons' perceptions of evidence supporting ERAS practices, identifying barriers to aligning them and identifying aspects of perioperative care that require research specific to vascular surgery before they could be broadly applied. METHODS: We administered an online survey with 26 questions to all Canadian Society for Vascular Surgery members. RESULTS: Respondents varied largely in perioperative practice, most notably in the use of nasogastric tubes, Foley catheters and neck drains. Familiarity with supporting evidence was poor. Approximately half (44%) of respondents were not familiar with contrary evidence, while those who were often perceived institutional barriers to change. Finally, one-third (30%) of respondents felt that relevant evidence did not exist to support changing their practice. CONCLUSION: The variability of perioperative practice in Canadian vascular surgery is likely due to multiple factors, including a lack of specific evidence. Further research in areas of perioperative vascular care where the current standard of practice varies most greatly may help improve recovery after vascular surgery in Canada over simply adopting existing ERAS principles. PMID- 26424689 TI - Trends in the Canadian Surgery Forum (CSF): analysis of the CSF program over the past decade. AB - SUMMARY: Numerous clinical and basic science-related innovations have been presented at the Canadian Surgery Forum (CSF). We sought to define changes in both the content and methodology of the CSF scientific program over the past decade. While the total volume of CSF abstract presentations has increased dramatically, the methodological quality has remained static, with few randomized trials and minimal prospective work. Although the majority of the scientific content is associated with urban university centres, the program also encourages content from community practices. Surgical education, hepatopancreatobiliary and bariatric content have increased substantially, but remain secondary to colorectal diseases. PMID- 26424690 TI - Significance of CD4+ T-cell count in the management of appendicitis in patients with HIV. AB - SUMMARY: Identification of complicated appendicitis (CA) is critical to the management of appendicitis. However, previous studies have not investigated indicators of CA among patients with HIV or whether it is safe to use conservative treatment for appendicitis in these patients. Among 322 patients with appendicitis, we identified 14 who had HIV. Six of them were operated and 8 were treated with antibiotics; CA was diagnosed in 4. Patients with HIV and CA had a significantly lower CD4+ T-cell count than those with uncomplicated appendicitis. A white blood cell count lower than 7.4 * 10(9)/L was observed exclusively in patients with CA. No patient with HIV whose appendicitis was treated conservatively died or experienced a recurrence. We discuss our findings, which suggest the possibility of conservative treatment of appendicitis in patients with HIV and identification of CA by low CD4+ T-cell count. PMID- 26424691 TI - Proceedings of the 2015 MidSouth Computational Biology and Bioinformatics Society (MCBIOS) Conference. PMID- 26424694 TI - VI International Congress of Histology and Tissue Engineering - XVIII Congress of the Spanish Society of Histology and Tissue Engineering - II Iberoamerican Congress of Histology. 16-18 September, 2015, Bilbao, Spain. PMID- 26424692 TI - Risk factors for outcome in refractory acute myeloid leukemia patients treated with a combination of fludarabine, cytarabine, and amsacrine followed by a reduced-intensity conditioning and allogeneic stem cell transplantation. AB - INTRODUCTION: Hematopoietic stem cell transplantation (HCT) is considered a standard treatment for high-risk acute myeloid leukemia (AML) in first or second complete remission (CR). Unfortunately, not all patients achieve complete remission prior to HCT. We sought to establish predictive factors for survival after HCT for refractory AML after FLAMSA-RIC. PATIENTS AND METHODS: We analyzed the outcome of 44 consecutive patients aged between 21 and 65 years transplanted at the University Hospitals of Jena and Leipzig for refractory AML between 2006 and January 2013. Conditioning for HCT was performed with chemotherapy consisting of fludarabine, cytarabine, and amsacrine followed by total body irradiation or busulfan combined with cyclophosphamide. Antithymocyte globulin was given when transplanting from unrelated donors (FLAMSA-RIC). RESULTS: Estimated overall survival (OS) and event-free survival (EFS) at 3 years after a median follow-up of 34 (range 6-71) months were 15 and 12 %, respectively. Causes of death were relapse in 66 %, infection in 11 %, and graft-versus-host disease (GvHD) in 7 % of all patients. Twenty-five from 42 evaluable patients (60 %) achieved CR 4 weeks after HCT, while eight patients had partial remission (PR), and nine patients had stable disease (SD). Another six patients with PR and SD achieved CR (overall CR rate 74 %) from 4 weeks to day 90 after HCT following reduction in immunosuppression. The strongest favorable factors in univariate analysis for OS, EFS, and RI were >=98 % total donor chimerism 2-4 weeks after HCT and <3 lines of pretreatment prior to HCT. In addition, better OS was detected in patients with <20 % bone marrow blasts alone (32 vs. 5 % at 3 years) and in combination with <3 lines of pretreatment (38 vs. 4 % at 3 years). Only a trend for better EFS and lower RI was observed in patients with limited chronic GvHD. In addition, a lower RI was seen in patients with <5 % blasts 4 weeks after HCT. Multivariate analysis revealed that >=98 % donor chimerism 2-4 weeks after HCT for OS, EFS, and RI and <3 lines of pretreatment for OS and EFS are the strongest predictors for better outcome. CONCLUSION: FLAMSA-RIC shows long-term survival in refractory AML patients. Factors for favorable outcome are <20 % bone marrow blasts prior to HCT, <3 lines of pretreatment and complete donor chimerism after HCT. PMID- 26424693 TI - Comparison of nine prognostic scores in patients with brain metastases of breast cancer receiving radiotherapy of the brain. AB - PURPOSE: Several prognostic indices (PI) have been developed to stratify patients with brain metastases in groups with good or bad prognosis. The aim of our study was to compare nine prognostic scores for patients with brain metastases (BM) of breast cancer receiving radiotherapy. METHODS: The clinical data of 139 breast cancer patients with BM were collected retrospectively. All patients were treated with cerebral radiotherapy or surgery followed by radiotherapy between January 2007 and December 2012. The prognostic value and accuracy of recursive partitioning analysis (RPA), RPA II, graded prognostic assessment (GPA), basic score for BM, Breast-RPA, Breast-GPA, Rades Score 2011, Germany Score and Breast Rades Score were assessed. RESULTS: The median survival after BM diagnosis in our cohort was 14 months. The overall 6-month, 1-, 2- and 3-year survival rates were 49.6, 37.4, 20.9 and 13.7 %, respectively. Most of the PI were associated with OS, but univariate analysis favored GPA regarding OS. GPA was the most accurate score to identify patients with long (longer than 12 months) and Breast-GPA patients with short (<3 months) life expectancy. CONCLUSIONS: GPA and Breast-GPA seem to be the most useful scores and perform better than other PI for breast cancer patients with BM receiving radiotherapy. PMID- 26424695 TI - Hypoxia-Induced WSB1 Promotes the Metastatic Potential of Osteosarcoma Cells. AB - Intratumoral hypoxia occurs in many solid tumors, where it is associated with the development of metastatic character. However, the connections between these phenomena are not fully understood. In this study, we define an integrative role for the E3 ubiquitin ligase subunit WSB1. In primary osteosarcomas, increased levels of WSB1 correlated with pulmonary metastatic potential. RNAi-mediated attenuation of WSB1 or disruption of its E3 ligase activity potently suppressed tumor metastasis. Quantitative proteomic and functional analyses revealed that WSB1 ubiquitylates the Rho-binding protein RhoGDI2 and promotes its proteasomal degradation, thereby activating Rac1 to stimulate tumor cell motility and invasion. Our findings show how WSB1 regulates key steps of the metastatic cascade in hypoxia-driven osteosarcoma, and they highlight a candidate therapeutic target to potentially improve the survival of patients with metastatic disease. PMID- 26424696 TI - Fluorophore-NanoLuc BRET Reporters Enable Sensitive In Vivo Optical Imaging and Flow Cytometry for Monitoring Tumorigenesis. AB - Fluorescent proteins are widely used to study molecular and cellular events, yet this traditionally relies on delivery of excitation light, which can trigger autofluorescence, photoxicity, and photobleaching, impairing their use in vivo. Accordingly, chemiluminescent light sources such as those generated by luciferases have emerged, as they do not require excitation light. However, current luciferase reporters lack the brightness needed to visualize events in deep tissues. We report the creation of chimeric eGFP-NanoLuc (GpNLuc) and LSSmOrange-NanoLuc (OgNLuc) fusion reporter proteins coined LumiFluors, which combine the benefits of eGFP or LSSmOrange fluorescent proteins with the bright, glow-type bioluminescent light generated by an enhanced small luciferase subunit (NanoLuc) of the deep-sea shrimp Oplophorus gracilirostris. The intramolecular bioluminescence resonance energy transfer that occurs between NanoLuc and the fused fluorophore generates the brightest bioluminescent signal known to date, including improved intensity, sensitivity, and durable spectral properties, thereby dramatically reducing image acquisition times and permitting highly sensitive in vivo imaging. Notably, the self-illuminating and bifunctional nature of these LumiFluor reporters enables greatly improved spatiotemporal monitoring of very small numbers of tumor cells via in vivo optical imaging and also allows the isolation and analyses of single cells by flow cytometry. Thus, LumiFluor reporters are inexpensive, robust, noninvasive tools that allow for markedly improved in vivo optical imaging of tumorigenic processes. PMID- 26424697 TI - Sublethal vancomycin-induced ROS mediating antibiotic resistance in Staphylococcus aureus. AB - Staphylococcus aureus is the leading cause of many human infectious diseases. Besides infectious dangers, S. aureus is well-known for the quickly developed drug resistance. Although great efforts have been made, mechanisms underlying the antibiotic effects of S. aureus are still not well clarified. Recently, reports have shown that oxidative stress connects with bactericidal antibiotics [Dwyer et al. (2009) Curr. Opin. Microbiol. 12: , 482-489]. Based on this point, we demonstrate that reactive oxygen species (ROS) induced by sublethal vancomycin may be partly responsible for the antibiotic resistance in heterogeneous vancomycin resistant S. aureus (hVRSA). Sublethal vancomycin treatment may induce protective ROS productions in hVRSA, whereas reduction in ROS level in hVRSA strains may increase their vancomycin susceptibility. Moreover, low dose of ROS in VSSA (vancomycin susceptible S. aureus) strains may promote their survival under vancomycin conditions. Our findings reveal that modest ROS generation may be protective for vancomycin resistance in hVRSA. These results recover novel insights into the relationship between oxidative stress and bacterial resistance, which has important applications for further use of antibiotics and development of therapeutics strategies for hVRSA. PMID- 26424698 TI - Chronic aerobic swimming exercise promotes functional and morphological changes in rat ileum. AB - Several studies have reported the gastrointestinal (GI) effects promoted by the physical exercise. Thus, we aimed to evaluate the influence of swimming exercise on the contractile reactivity, lipid peroxidation and morphology of rat ileum. Wistar rats were divided into sedentary (SED) and groups exercised for two (EX2), four (EX4), six (EX6) or eight (EX8) weeks, 5 days/week. Animals were killed; the ileum was removed and suspended in organ baths where the isotonic contractions were recorded. Lipid peroxidation was evaluated by MDA (malondialdehyde) measurement with TBARS (thiobarbituric acid reactive substances) assay and morphology by histological staining. Cumulative concentration-response curves to KCl were attenuated, as the Emax values were changed from 100% (SED) to 63.1+/ 3.9 (EX2), 48.8+/-3.8 (EX4), 19.4+/-1.8 (EX6) and 59.4+/-2.8% (EX8). Similarly, cumulative concentration-response curves to carbamylcholine hydrochloride (CCh) were attenuated, as the Emax values were changed from 100% (SED) to 74.1+/-5.4 (EX2), 75.9+/-5.2 (EX4) and 62.9+/-4.6 (EX6), but not in the EX8 (89.7+/-3.4%). However, CCh potency was increased in this latter, as the EC50 was altered from 1.0+/-0.1*10(-6) (SED) to 2.1+/-0.4*10(-7) (EX8). MDA concentration was altered only in EX4 (44.3+/-4.4) compared with SED (20.6+/-3.6 MUmol/l). Circular layer was reduced in SED when compared with the exercised groups. Conversely, longitudinal layer was increased. In conclusion, chronic swimming exercise reduces the ileum contraction, equilibrates the oxidative damage and promotes changes in tissue size to establish an adaptation to the exercise. PMID- 26424699 TI - Impact of working 48 h per week on opportunities for training and patient contact: the experience of Irish interns. AB - OBJECTIVE: The European Working Time Regulations (EWTR) have been criticized for its purported negative impact on the training of junior doctors. The aim of this study was to examine the amount of time interns spent engaging in various work activities. DESIGN: An online time-use diary was used to collect data from interns. SETTING: Two teaching hospitals in the Republic of Ireland. PARTICIPANTS: A total of 45 interns logged at least one 24-h period. The logs were obtained from 67 shifts from a surgical rotation and 83 shifts from a medical rotation. MAIN OUTCOME MEASURES: The amount of time interns spent engaging in direct patient care, indirect patient care, educational activities and personal activities. RESULTS: On day shift, medical interns spent a significantly smaller proportion of the shift on direct care (159/613 min, 25.9% versus 214/636 min, 33.6%) and a greater proportion on education (195/613 min, 31.8% versus 139/636 min, 21.9%) than surgical interns. On extended days, medical interns spent a significantly larger proportion of the shift on education than surgical interns (243/814 min, 29.9% versus 126/804, 15.7% min). On night shift, medical interns spent a significantly greater proportion of the shift on direct care (590/720 min, 81.9% versus 346/727 min, 47.6%) and education (33/720 min, 4.6% versus 6/727 min, 0.8%) than surgical interns. CONCLUSIONS: The interns in the study reported spending more time on direct patient care and educational activities, and less time on indirect patient care activities than interns in other countries. PMID- 26424700 TI - Is accreditation linked to hospital infection rates? A 4-year, data linkage study of Staphylococcus aureus rates and accreditation scores in 77 Australian acute hospitals. AB - OBJECTIVES: To test our hypothesis that hospitals with higher accreditation scores, specifically in infection control, would be associated with lower Staphylococcus aureus bacteraemia (SAB) rates. DESIGN: A retrospective cohort study. SETTING AND PARTICIPANTS: Acute public hospitals (n = 77) in New South Wales, Australia, with reported SAB rates, results from two accreditation surveys and results from at least four hand hygiene audits. METHODS: We linked three separate data sets comprising SAB rates, accreditation scores and hand hygiene rates. SAB rates were regressed against accreditation scores, hand hygiene audit rates and hospital demographics using a generalized linear model to account for the non-linear nature of our outcome variable. RESULTS: Significant (P < 0.05) findings included the following: SAB rates across all hospitals fell from 1.34 per 10 000 bed days in 2009 to 0.77 per 10 000 bed days in 2012; mean SAB rates in small hospitals (0.62/10 000 bed days) over the study period were lower than those for principal referral hospitals (1.52/10 000 bed days); smaller hospitals with higher accreditation scores had lower SAB rates, but larger hospitals with higher overall accreditation scores had higher SAB rates, although the effect size was small (<2%). CONCLUSIONS: There is a strong evidence base for using SAB rates to measure the impact of infection control programs that are assessed during accreditation. However, there is less evidence to support whether accreditation scores accurately reflect implementation of the infection control accreditation standards. This impacts identification of indicators to measure patient safety and quality of care, especially in ensuring these are appropriate across a range of hospital size and activities. PMID- 26424701 TI - Bradycardia as an early warning sign for cardiac arrest during routine laparoscopic surgery. AB - OBJECTIVES: The aim of this study was to identify clinical patterns of occurrence, management and outcomes surrounding cardiac arrest during laparoscopic surgery using the Australian Incident Monitoring Study (AIMS) database to guide possible prevention and treatment. SETTING: The AIMS database includes incident reports from participating clinicians from secondary and tertiary healthcare centres across Australia and New Zealand. PARTICIPANTS: The AIMS database holds over 11 000 peri- and intraoperative incidents. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was to characterize the pattern of events surrounding cardiac arrest. The secondary outcome was to identify successful management strategies in the possible prevention and treatment of cardiac arrest during laparoscopic surgery. RESULTS: Fourteen cases of cardiac arrest during laparoscopic surgery were identified. The majority of cases occurred in 'fit and healthy' patients during elective gynaecological and general surgical procedures. Twelve cases of cardiac arrest were directly associated with pneumoperitoneum with bradycardia preceding cardiac arrest in 75% of these. Management included deflation of pneumoperitoneum, atropine administration and cardiopulmonary resuscitation with circulatory restoration in all cases. The results imply vagal mechanisms associated with peritoneal distension as the predominant contributor to bradycardia and subsequent cardiac arrest during laparoscopy. CONCLUSIONS: Bradycardia during gas insufflation is not necessarily a benign event and appears to be a critical early warning sign for possible impending and unexpected cardiac arrest. Immediate deflation of pneumoperitoneum and atropine administration are effective measures that may alleviate bradycardia and possibly avert progression to cardiac arrest. PMID- 26424702 TI - The missing evidence: a systematic review of patients' experiences of adverse events in health care. AB - PURPOSE: Preventable patient harm due to adverse events (AEs) is a significant health problem today facing contemporary health care. Knowledge of patients' experiences of AEs is critical to improving health care safety and quality. A systematic review of studies of patients' experiences of AEs was conducted to report their experiences, knowledge gaps and any challenges encountered when capturing patient experience data. DATA SOURCES: Key words, synonyms and subject headings were used to search eight electronic databases from January 2000 to February 2015, in addition to hand-searching of reference lists and relevant journals. STUDY SELECTION: Titles and abstracts of publications were screened by two reviewers and checked by a third. Full-text articles were screened against the eligibility criteria. DATA EXTRACTION: Data on design, methods and key findings were extracted and collated. RESULTS: Thirty-three publications demonstrated patients identifying a range of problems in their care; most commonly identified were medication errors, communication and coordination of care problems. Patients' income, education, health burden and marital status influence likelihood of reporting. Patients report distress after an AE, often exacerbated by receiving inadequate information about the cause. Investigating patients' experiences is hampered by the lack of large representative patient samples, data over sufficient time periods and varying definitions of an AE. CONCLUSION: Despite the emergence of policy initiatives to enhance patient engagement, few studies report patients' experiences of AEs. This information must be routinely captured and utilized to develop effective, patient-centred and system-wide policies to minimize and manage AEs. PMID- 26424704 TI - Analysis of the Information Quality of Bariatric Surgery Smartphone Applications Using the Silberg Scale. AB - There is a paucity of literature that has evaluated the information quality of the current bariatric and obesity applications. Our objective was to evaluate the quality of currently available smartphone applications for bariatric-patient care using the Silberg scale. The two most widely used smartphone application online stores were searched in June 2014 and a total of 39 applications were evaluated. The average Silberg score of the 39 applications was 4.0 +/- 1.76. The current gaps of information quality include the lack of provision of appropriate references, full disclosure of sponsorship, and accurate disclosure whether the application has been modified in the past month. PMID- 26424703 TI - Response of lactate metabolism in brain glucosensing areas of rainbow trout (Oncorhynchus mykiss) to changes in glucose levels. AB - There is no evidence in fish brain demonstrating the existence of changes in lactate metabolism in response to alterations in glucose levels. We induced in rainbow trout through intraperitoneal (IP) treatments, hypoglycaemic or hyperglycaemic changes to assess the response of parameters involved in lactate metabolism in glucosensing areas like hypothalamus and hindbrain. To distinguish those effects from those induced by peripheral changes in the levels of metabolites or hormones, we also carried out intracerebroventricular (ICV) treatments with 2-deoxy-D-glucose (2-DG, a non-metabolizable glucose analogue thus inducing local glucopenia) or glucose. Finally, we also incubated hypothalamus and hindbrain in vitro in the presence of increased glucose concentrations. The changes in glucose availability were in general correlated to changes in the amount of lactate in both areas. However, when we assessed in these areas the response of parameters related to lactate metabolism, the results obtained were contradictory. The increase in glucose levels did not produce in general the expected changes in those pathways with only a minor increase in their capacity of lactate production. The decrease in glucose levels was, however, more clearly related to a decreased capacity of the pathways involved in the production and use of lactate, and this was especially evident after ICV treatment with 2-DG in both areas. In conclusion, the present results while addressing the existence of changes in lactate metabolism after inducing changes in glucose levels in brain glucosensing areas only partially support the possible existence of an astrocyte-neuron lactate shuttle in hypothalamus and hindbrain of rainbow trout relating glucose availability to lactate production and use. PMID- 26424705 TI - Increased Prevalence of Irritable Bowel Syndrome in a Cohort of French Morbidly Obese Patients Candidate for Bariatric Surgery. AB - BACKGROUND: Only a few recent reports have suggested a correlation between obesity and irritable bowel syndrome (IBS). We aimed to determine the prevalence and severity of IBS in a prospective cohort of obese patients undergoing bariatric surgery in Nice Hospital (France). METHODS: One hundred obese patients were included prospectively before bariatric surgery. A diagnosis of IBS and each subtype was performed according to Rome-III criteria using a Bristol scale for stool consistency. Patients provided information on IBS-related comorbidities, including chronic fatigue, migraine, lower back pain, gastroesophageal reflux disease (GERD), genitourinary problems, and dyspepsia. Patients completed questionnaires to assess the severity of IBS, GERD, psychological factors (anxiety, depression), fatigue, and quality of life. RESULTS: Thirty patients fulfilled the Rome-III criteria for IBS. There was no difference in age, gender, or BMI between obese patients with or without IBS. Obese patients with IBS reported a significantly higher prevalence of GERD, migraines, lower back pain, genitourinary problems, chronic fatigue, and dyspepsia. Obese patients with IBS had significant higher scores of fatigue, anxiety, depression, and poorer quality of life. Obese patients that had both IBS and GERD had significantly higher IBS severity scores than those without GERD. In a logistic regression model including BMI, anxiety, depression, gender, and GERD score, only anxiety was significantly and independently associated with IBS. CONCLUSIONS: Thirty percent of obese patients had IBS: its severity was not correlated with BMI. However, anxiety was independently associated with IBS, suggesting that psychological factors are key features of IBS, whatever the presence of obesity. PMID- 26424706 TI - A Comment on "Obesity Surgery and Ramadan: a Prospective Analysis of Nutritional Intake, Hunger and Satiety and Adaptive Behaviours During Fasting". PMID- 26424707 TI - Economic costs of outbreaks of acute viral gastroenteritis due to norovirus in Catalonia (Spain), 2010-2011. AB - BACKGROUND: To determine the direct and indirect costs of outbreaks of acute viral gastroenteritis (AVG) due to norovirus in closed institutions (hospitals, social health centers or nursing homes) and the community in Catalonia in 2010 11. METHODS: Information on outbreaks were gathered from the reports made by epidemiological surveillance units. Direct costs (medical visits, hospital stays, drug treatment, sample processing, transport, diagnostic tests, monitoring and control of the outbreaks investigated) and indirect costs (lost productivity due to work absenteeism, caregivers time and working hours lost due to medical visits) were calculated. RESULTS: Twenty-seven outbreaks affecting 816 people in closed institutions and 74 outbreaks affecting 1,940 people in the community were detected. The direct and indirect costs of outbreaks were ? 131,997.36 (? 4,888.79 per outbreak) in closed institutions and ? 260,557.16 (? 3,521.04 per outbreak) in community outbreaks. The cost per case was ? 161.76 in outbreaks in closed institutions and ? 134.31 in community outbreaks. The main costs were surveillance unit monitoring (? 116,652.93), laboratory diagnoses (? 119,950.95), transport of samples (? 69,970.90), medical visits (? 25,250.50) and hospitalization (? 13,400.00). CONCLUSIONS: The cost of outbreaks of acute viral gastroenteritis due to norovirus obtained in this study was influenced by the number of people affected and the severity of the outbreak, which determined hospitalizations and work absenteeism. Urgent reporting of outbreaks would allow the implementation of control measures that could reduce the numbers affected and the duration of the illness and thus the costs derived from them. PMID- 26424708 TI - Preoperative neutrophil/lymphocyte ratio and prognostic nutritional index predict survival in patients with non-small cell lung cancer. AB - BACKGROUND: The immunological status, consisting of "inflammation status" and "nutritional condition," is important for the survival of patients with various cancers, including non-small cell lung cancer (NSCLC). The neutrophil/lymphocyte ratio (NLR) reflects the inflammation status, and the prognostic nutritional index (PNI) reflects the immunological nutritional condition. In the present study, the correlation between the NLR and the PNI as well as the consistency and magnitude of the prognostic impact of the NLR and the PNI were investigated. METHODS: We conducted a retrospective review of data from 334 patients who had undergone a curative resection for NSCLC. The NLR and the PNI were calculated, which was routinely performed before surgery. The correlations between the NLR and the PNI and survival were then evaluated. RESULTS: A clear inverse correlation was observed between the NLR and the PNI. The NLR was associated with sex, smoking history, the CEA level, tumor size, and vascular invasion. The PNI was associated with sex, age, smoking history, tumor size, histological type, tumor differentiation, and vascular invasion. Patients with NLR >=2.5 had a significantly poorer survival outcome, and patients with PNI <50 had a significantly poorer survival outcome. A multivariate analysis demonstrated that age, nodal metastasis, tumor differentiation, NLR, and PNI were independent predictors of disease-free and overall survival. CONCLUSIONS: Our study demonstrated a significant inverse correlation between the NLR and the PNI, and a high NLR and a low PNI were significantly associated with a poor survival among patients who had undergone a complete resection for NSCLC. PMID- 26424709 TI - The Relationship Between Distance and Post-operative Visit Attendance Following Medical Male Circumcision in Nyanza Province, Kenya. AB - To date, there is no research on voluntary medical male circumcision (VMMC) catchment areas or the relationship between distance to a VMMC facility and attendance at a post-operative follow-up visit. We analyzed data from a randomly selected subset of males self-seeking circumcision at one of 16 participating facilities in Nyanza Province, Kenya between 2008 and 2010. Among 1437 participants, 46.7 % attended follow-up. The median distance from residence to utilized facility was 2.98 km (IQR 1.31-5.38). Nearly all participants (98.8 %) lived within 5 km from a facility, however, 26.3 % visited a facility more than 5 km away. Stratified results demonstrated that among those utilizing fixed facilities, greater distance was associated with higher odds of follow-up non attendance (OR5.01-10km vs. 0-1km = 1.71, 95 % CI 1.08, 2.70, p = 0.02; OR>10km vs. 0-1 km = 2.80, 95 % CI 1.26, 6.21, p = 0.01), adjusting for age and district of residence. We found 5 km marked the threshold distance beyond which follow-up attendance significantly dropped. These results demonstrate distance is an important predictor of attending follow-up, and this relationship appears to be modified by facility type. PMID- 26424710 TI - Symbiosis dependent accumulation of primary metabolites in arbuscule-containing cells. AB - BACKGROUND: The arbuscular mycorrhizal symbiosis is characterized by the presence of different symbiotic structures and stages within a root system. Therefore tools allowing the analysis of molecular changes at a cellular level are required to reveal insight into arbuscular mycorrhizal (AM) symbiosis development and functioning. RESULTS: Here we describe the analysis of metabolite pools in arbuscule-containing cells, which are the site of nutrient transfer between AM fungus and host plant. Laser capture microdissection (LCM) combined with gas chromatography mass spectrometry (GC-EI/TOF-MS) enabled the analysis of primary metabolite levels,which might be of plant or fungal origin, within these cells. CONCLUSIONS: High levels of the amino acids, aspartate, asparagine, glutamate, and glutamine, were observed in arbuscule-containing cells. Elevated amounts of sucrose and the steady-state of hexose levels indicated a direct assimilation of monosaccharides by the fungal partner. PMID- 26424711 TI - Incompatibility of busulfan with 1 ml Luer-Lock syringes. PMID- 26424712 TI - Respondent-driven sampling as a recruitment method for men who have sex with men in southern sub-Saharan Africa: a cross-sectional analysis by wave. AB - OBJECTIVES: Respondent-driven sampling (RDS) is a popular method for recruiting men who have sex with men (MSM). Our objective is to describe the ability of RDS to reach MSM for HIV testing in three southern African nations. METHODS: Data collected via RDS among MSM in Lesotho (N=318), Swaziland (N=310) and Malawi (N=334) were analysed by wave in order to characterise differences in sample characteristics. Seeds were recruited from MSM-affiliated community-based organisations. Men were interviewed during a single study visit and tested for HIV. chi(2) tests for trend were used to examine differences in the proportions across wave category. RESULTS: A maximum of 13-19 recruitment waves were achieved in each study site. The percentage of those who identified as gay/homosexual decreased as waves increased in Lesotho (49% to 27%, p<0.01). In Swaziland and Lesotho, knowledge that anal sex was the riskiest type of sex for HIV transmission decreased across waves (39% to 23%, p<0.05, and 37% to 19%, p<0.05). The percentage of participants who had ever received more than one HIV test decreased across waves in Malawi (31% to 12%, p<0.01). In Lesotho and Malawi, the prevalence of testing positive for HIV decreased across waves (48% to 15%, p<0.01 and 23% to 11%, p<0.05). Among those living with HIV, the proportion of those unaware of their status increased across waves in all study sites although this finding was not statistically significant. CONCLUSIONS: RDS that extends deeper into recruitment waves may be a promising method of reaching MSM with varying levels of HIV prevention needs. PMID- 26424714 TI - No reduction in fibreoptic intubation rates with universal video laryngoscopy. PMID- 26424713 TI - Sexually transmitted infections associated with alcohol use and HIV infection among men who have sex with men in Kampala, Uganda. AB - OBJECTIVES: Few studies have been conducted in Africa to assess prevalence of sexually transmitted infections (STIs) and risk factors among men who have sex with men (MSM). We report findings from the first behavioural survey to include STI testing among MSM in Kampala, Uganda. METHODS: Respondent-driven sampling (RDS) was used to recruit MSM for a biobehavioural survey. Eligible participants were men who reported anal sex with another man in the previous 3 months, were 18 years or older, and resided in Kampala. Information was collected on demographics, sexual behaviour, alcohol and drug use, and STI symptoms. Blood, urine and rectal specimens were tested for syphilis, HIV, rectal and urethral gonorrhoea, and chlamydia. Analyses weighted for RDS were conducted to assess associations with STI diagnosis. RESULTS: A total of 295 MSM participated in the survey. Almost half (weighted percentage: 47.3%) reported STI symptoms in the last 6 months and 12.9% tested HIV-positive. Prevalence of non-HIV STI was 13.5%; syphilis prevalence was 9.0%. Adjusting for age and education, STI was associated with HIV (adjusted OR (AOR)=3.46, 95% CI 1.03 to 11.64), alcohol use before sex (AOR=4.99, 95% CI 1.86 to 13.38) and having sold sex in the last 3 months (AOR=3.17, 95% CI 1.25 to 8.07), and inversely associated with having anonymous sex partners (AOR=0.20, 95% CI 0.07 to 0.61). CONCLUSIONS: We observed high levels of self-reported STI symptoms and STI prevalence associated with alcohol use and HIV among MSM in Kampala. Public health interventions supporting MSM are needed to address STI risk and facilitate access to diagnosis and treatment services. PMID- 26424715 TI - In reply: No reduction in fibreoptic intubation rates with universal video laryngoscopy. PMID- 26424717 TI - Intraoperative protective ventilation: too early to redefine management parameters? PMID- 26424718 TI - Permission fees for reproducing tables in journal articles are exorbitant. PMID- 26424716 TI - The Emergence of 2-Oxoglutarate as a Master Regulator Metabolite. AB - The metabolite 2-oxoglutarate (also known as alpha-ketoglutarate, 2-ketoglutaric acid, or oxoglutaric acid) lies at the intersection between the carbon and nitrogen metabolic pathways. This compound is a key intermediate of one of the most fundamental biochemical pathways in carbon metabolism, the tricarboxylic acid (TCA) cycle. In addition, 2-oxoglutarate also acts as the major carbon skeleton for nitrogen-assimilatory reactions. Experimental data support the conclusion that intracellular levels of 2-oxoglutarate fluctuate according to nitrogen and carbon availability. This review summarizes how nature has capitalized on the ability of 2-oxoglutarate to reflect cellular nutritional status through evolution of a variety of 2-oxoglutarate-sensing regulatory proteins. The number of metabolic pathways known to be regulated by 2 oxoglutarate levels has increased significantly in recent years. The signaling properties of 2-oxoglutarate are highlighted by the fact that this metabolite regulates the synthesis of the well-established master signaling molecule, cyclic AMP (cAMP), in Escherichia coli. PMID- 26424719 TI - In Vitro and In Vivo Comparison of Selected Ga-68 and Zr-89 Labelled Siderophores. AB - PURPOSE: Some [(68)Ga]siderophores show promise in specific and sensitive imaging of infection. Here, we compare the in vitro and in vivo behaviour of selected Ga 68 and Zr-89 labelled siderophores. PROCEDURES: Radiolabelling was performed in HEPES or sodium acetate buffer systems. Radiochemical purity of labelled siderophores was determined using chromatography. Partition coefficients, in vitro stability and protein binding affinities were determined. Ex vivo biodistribution and animal imaging was studied in mice. RESULTS: Certain differences among studied siderophores were observed in labelling efficiency. Protein binding and stability tests showed highest stabilities and lowest protein binding affinities for Ga-68 and [(89)Zr]triacetylfusarinine C (TAFC). All studied Ga-68 and [(89)Zr]siderophores exhibited a similar biodistribution and pharmacokinetics in mice with the exception of [(89)Zr]ferrioxamine E (FOXE). CONCLUSIONS: Zr-89 and [(68)Ga]siderophores showed analogous in vitro and in vivo behaviour. Tested [(89)Zr]siderophores could be applied for longitudinal positron emission tomography (PET) studies of fungal infections and especially TAFC for the development of novel bioconjugates. PMID- 26424721 TI - Implementation and Use of State-of-the-Art, Cell-Based In Vitro Assays. AB - The impressive advances in the generation and interpretation of functional omics data have greatly contributed to a better understanding of the (patho-)physiology of many biological systems and led to a massive increase in the number of specific targets and phenotypes to investigate in both basic and applied research. The obvious complexity revealed by these studies represents a major challenge to the research community and asks for improved target characterisation strategies with the help of reliable, high-quality assays. Thus, the use of living cells has become an integral part of many research activities because the cellular context more closely represents target-specific interrelations and activity patterns. Although still predominant, the use of traditional two dimensional (2D) monolayer cell culture models has been gradually complemented by studies based on three-dimensional (3D) spheroid (Sutherland 1988) and other 3D tissue culture systems (Santos et al. 2012; Matsusaki et al. 2014) in an attempt to employ model systems more closely representing the microenvironment of cells in the body. Hence, quite a variety of state-of-the-art cell culture models are available for the generation of novel chemical probes or the identification of starting points for drug development in translational research and pharma drug discovery. In order to cope with these information-rich formats and their increasing technical complexity, cell-based assay development has become a scientific research topic in its own right and is used to ensure the provision of significant, reliable and high-quality data outlasting any discussions related to the current "irreproducibility epidemic" (Dolgin 2014; Prinz et al. 2011; Schatz 2014). At the same time the use of cells in microplate assay formats has become state of the art and greatly facilitates rigorous cell-based assay development by providing the researcher with the opportunity to address the multitude of factors affecting the actual assay results in a systematic fashion and a timely manner. This microplate-based assay development strategy should result in the setting up of more robust and reliable test systems that ensure and increase the confidence in the statistical significance of the actual data generated. And, although assay miniaturisation is essential in order to achieve this, most, if not all, cell based assays can be easily reformatted and adapted to be used in this format in a straightforward manner. This synopsis aims at summarising valuable, general observations made when implementing a diverse set of functional cellular in vitro assays at Bayer Pharma AG without claiming to deeply review all of the literature available in each and every detail. In addition, phenotypic assays (Moffat et al. 2014) or label-free detection methods (Minor 2008) are not discussed. Although this essay tries to cover the most relevant technological developments in the field, it nevertheless may express personal preferences and peculiarities of the author's approach to state-of-the-art cell-based assay development. For additional reviews covering the actual field, see Wunder et al. (2008) and Michelini et al. (2010). PMID- 26424720 TI - Psychometric Properties of the Screen for Child Anxiety Related Emotional Disorders (SCARED) in a Non-Clinical Sample of Children and Adolescents in Saudi Arabia. AB - This paper examined the reliability, convergent validity and factor structure of the self-report Screen for Child Anxiety Disorders (SCARED; Birmaher et al. in J Am Acad Child Adolesc Psychiatry 36:545-553, 1997) in a large community sample of children and adolescents in Saudi Arabia. The questionnaire showed moderate to high internal consistency and satisfactory test-retest reliability over a 2 week period. In addition, there were significant positive correlations between reported anxiety symptoms with parent report behavioural difficulties. The five factor structure model of the SCARED also had a good model fit in this population. The results showed that self-report anxiety symptoms decreased with age (for boys and not girls) and were higher in adolescent girls. The results suggest that the SCARED could be useful in this population to identify individuals who are at risk of developing anxiety disorders in childhood with a view to implementing prevention and intervention methods to ensure positive developmental outcome over time. PMID- 26424722 TI - The engagement of FDG PET/CT image quality and harmonized quantification: from competitive to complementary. AB - The use of (18)F-FDG PET/CT as a quantitative imaging biomarker requires standardization and harmonization of imaging procedures and PET/CT system performance to obtain repeatable and reproducible quantitative data. However, a PET/CT system optimized to meet international quantitative standards is not necessarily optimized for use as a diagnostic tool (i.e. for lesion detectability). Several solutions have been proposed and validated, but until recently none of them had been implemented commercially. Vendor-provided solutions allowing the use of PET/CT both as a diagnostic tool and as a quantitative imaging biomarker are therefore greatly needed and would be highly appreciated. In this invited perspective one such solution is highlighted. PMID- 26424723 TI - Evaluation of two methods for the use of diatoms in drowning cases. AB - In this study, we compare digestive methods used in a forensic context to extract diatoms (37 % hydrochloric acid) to a method recently described in Italian protocols for analysis of benthic diatoms for ecological assessment of surface water (hydrogen peroxide digestion). The two digestive methods were performed using 5 g of brain, lung, liver, kidney, and bone marrow taken from the bodies of 10 drowning victims recovered from three different aquatic environments (ocean, lakes, and rivers). Postmortem examination was performed on all bodies, but aquatic samples were only analyzed in two cases. Tissue digestion was equal by both methods. Hydrogen peroxide (H2O2) digestion resulted in better diatom preservation, enabling identification of nine genera in all samples examined versus three obtained using hydrochloride digestion. The ideal digestive method to provide evidence for corroboration of a diagnosis of drowning still needs to be established. However, the benthic diatoms protocol can be useful because it is less chemically hazardous to the laboratory operator and supports better diatom preservation for reliable taxonomic analysis. PMID- 26424724 TI - GPs' adherence to guidelines for structured assessments of stroke survivors in the community and care homes. AB - BACKGROUND: Clinical practice guidelines recommend that stroke survivors' needs be assessed at regular intervals after stroke. The extent to which GPs comply with national guidance particularly for patients in care homes who have greatest clinical complexity is unknown. OBJECTIVES: This study aimed to establish the current clinical practice in the UK of needs assessment by GPs for stroke survivors after hospital discharge for acute stroke. METHODS: Cross-sectional online survey of current practice of GPs, using the national doctors.net network. RESULTS: The survey was completed by 300 GPs who had on average been working for 14 years. The structured assessment of stroke survivors' needs was not offered by 31% of GPs, with no significant difference for level of provision in community or care home settings. The outputs of reviews were added to patients' notes by 89% of GPs and used to change management by 57%. Only half the GPs reported integrating the information obtained into care plans and only a quarter of GPs had a protocol for follow-up of identified needs. Analysis of free-text comments indicated that patients in some care homes may receive more regular and structured reviews. CONCLUSIONS: This survey suggests that at least one-third of GPs provide no formal review of the needs of stroke patients and that in only a minority are identified needs addressed in a structured way. Standardization is required for what is included in reviews and how needs are being identified and met. PMID- 26424725 TI - Fixation of the Proximal Metatarsal Crescentic Osteotomy Using a Head Locking X Plate. AB - BACKGROUND: We present a new method to stabilize proximal crescentic osteotomies (PCOs) for the correction of moderate to severe hallux valgus. METHODS: A single center prospective study with a consecutive series of 72 patients (94 feet) with a PCO was performed using a head locking X-plate. The primary aim was to investigate the stability of the osteotomy, measuring the dorsal elevation of the first metatarsal head, first cuneiform height, talus-first metatarsal angle, and first metatarsal inclination pre- and postoperatively. A secondary outcome assessed weight distribution during gait, quality of life, and radiologically documented bone healing process. RESULTS: Ninety-three percent of the feet were within +/-2 mm change for dorsal elevation of the first metatarsal head, and 72% for the medial cuneiform height. Eighty-nine percent were within +/-4 degrees change for the first metatarsal inclination, 73% for the talus-first metatarsal angle, and 100% for the calcaneus pitch angle. The mean changes between pre- and 1-year postoperative were not significantly different for any of the stability measurements except for the first metatarsal inclination angle. The SF36 showed a significant improvement of physical function, general health, and decreased bodily pain. Harris mat footprints showed a decrease of 46% underneath the second and a pressure decrease of 40% underneath the third metatarsal head. CONCLUSION: This technique, of using a head locking X-plate to stabilize the PCO, showed satisfactory and reproducible results in terms of stability, clinical outcome, bone healing, and patient satisfaction. The plate provided substantial support for the PCO resulting in adequate and easy fixation. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 26424726 TI - Polymerase chain reaction blood tests for the diagnosis of invasive aspergillosis in immunocompromised people. AB - BACKGROUND: Invasive aspergillosis (IA) is the most common life-threatening opportunistic invasive mould infection in immunocompromised people. Early diagnosis of IA and prompt administration of appropriate antifungal treatment are critical to the survival of people with IA. Antifungal drugs can be given as prophylaxis or empirical therapy, instigated on the basis of a diagnostic strategy (the pre-emptive approach) or for treating established disease. Consequently there is an urgent need for research into both new diagnostic tools and drug treatment strategies. Newer methods such as polymerase chain reaction (PCR) to detect fungal nucleic acids are increasingly being investigated. OBJECTIVES: To provide an overall summary of the diagnostic accuracy of PCR-based tests on blood specimens for the diagnosis of IA in immunocompromised people. SEARCH METHODS: We searched MEDLINE (1946 to June 2015) and EMBASE (1980 to June 2015). We also searched LILACS, DARE, Health Technology Assessment, Web of Science and Scopus to June 2015. We checked the reference lists of all the studies identified by the above methods and contacted relevant authors and researchers in the field. SELECTION CRITERIA: We included studies that: i) compared the results of blood PCR tests with the reference standard published by the European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG); ii) reported data on false-positive, true-positive, false negative and true-negative results of the diagnostic tests under investigation separately; and iii) evaluated the test(s) prospectively in cohorts of people from a relevant clinical population, defined as a group of individuals at high risk for invasive aspergillosis. Case-control studies were excluded from the analysis. DATA COLLECTION AND ANALYSIS: Authors independently assessed quality and extracted data. For PCR assays, we evaluated the requirement for either one or two consecutive samples to be positive for diagnostic accuracy. We investigated heterogeneity by subgroup analyses. We plotted estimates of sensitivity and specificity from each study in receiver operating characteristics (ROC) space and constructed forest plots for visual examination of variation in test accuracy. We performed meta-analyses using the bivariate model to produce summary estimates of sensitivity and specificity. MAIN RESULTS: Eighteen primary studies, corresponding to 19 cohorts and 22 data sets, published between 2000 and 2013 were included in the meta-analyses, with a median prevalence of IA (proven or probable) of 12.0% (range 2.5 to 30.8 %). The majority of people had received chemotherapy for a haematological malignancy or had undergone a hematopoietic stem cell transplant. Several PCR techniques were used among the included studies. The sensitivity and specificity of PCR for the diagnosis of IA varied according to the interpretative criteria used to define a test as positive. The mean sensitivity and specificity were 80.5% (95% CI; 73.0 to 86.3) and 78.5% (67.8 to 86.4) for a single positive test result, and 58.0% (36.5 to 76.8) and 96.2% (89.6 to 98.6) for two consecutive positive test results. AUTHORS' CONCLUSIONS: PCR shows moderate diagnostic accuracy when used as screening tests for IA in high-risk patient groups. Importantly the sensitivity of the test confers a high negative predictive value (NPV) such that a negative test allows the diagnosis to be excluded. Consecutive positives show good specificity in diagnosis of IA and could be used to trigger radiological and other investigations or for pre-emptive therapy in the absence of specific radiological signs when the clinical suspicion of infection is high. When a single PCR positive test is used as diagnostic criterion for IA in a population of 100 people with a disease prevalence of 13.0% (overall mean prevalence), three people with IA would be missed (sensitivity 80.5%, 19.5% false negatives), and 19 people would be unnecessarily treated or referred for further tests (specificity of 78.5%, 21.5% false positives). If we use the two positive test requirement in a population with the same disease prevalence, it would mean that six IA people would be missed (sensitivity 58.0%, 42.1% false negatives) and three people would be unnecessarily treated or referred for further tests (specificity of 96.2%, 3.8% false positives). Galactomannan and PCR have good NPV for excluding disease but the low prevalence of disease limits the ability to rule in a diagnosis. The biomarkers are detecting different aspects of disease and the combination of both together is likely to be more useful. PMID- 26424728 TI - The Impact of Fractional Flow Reserve on Revascularization. AB - INTRODUCTION: Fractional flow reserve (FFR) is recommended by society guidelines for assessment of the hemodynamic significance of intermediate coronary lesions when non-invasive evidence of myocardial ischemia is unavailable. However, the prevalence of FFR usage in current practice and how FFR values impact revascularization decisions are not well known. METHODS: At a single-center Veterans Administration Hospital, all subjects referred for coronary angiography for any indication from the period from May 2012 until January 2014 were prospectively entered into a database. FFR was measured in all intermediate coronary lesions (30-70% stenosis). Based on the FFR results, the lesions were categorized into 3 different groups: FFR > 0.80 (non-ischemic), FFR 0.75-0.80 (gray zone), and FFR < 0.75 (ischemic). RESULTS: A total of 1482 cardiac catheterizations were performed during the study period. FFR was performed in 347 (23%) of these procedures. The total numbers of intermediate coronary lesions evaluated with FFR were 429. The mean FFR value was 0.79 (median = 0.80; interquartile range 0.64-0.96). Among 211 non-ischemic lesions, revascularization was deferred in 201 (95%). In the gray-zone group (73 lesions), 35 (48%) lesions were treated with percutaneous coronary intervention (PCI), 11 (15%) lesions were referred for coronary artery bypass grafting surgery (CABG), and 27 (37%) lesions were treated medically. In the ischemic group (145 lesions), 82 (57%) lesions were treated with PCI, 41 (28%) lesions were referred for CABG, and 22 (15%) lesions were treated medically. CONCLUSION: At a Veterans Administration Hospital, FFR was performed in approximately one out of four total catheterizations. FFR documented lack of ischemia in about half of the intermediate coronary lesions, and thus reduced the need for many revascularization procedures. PMID- 26424727 TI - Fast Dating Using Least-Squares Criteria and Algorithms. AB - Phylogenies provide a useful way to understand the evolutionary history of genetic samples, and data sets with more than a thousand taxa are becoming increasingly common, notably with viruses (e.g., human immunodeficiency virus (HIV)). Dating ancestral events is one of the first, essential goals with such data. However, current sophisticated probabilistic approaches struggle to handle data sets of this size. Here, we present very fast dating algorithms, based on a Gaussian model closely related to the Langley-Fitch molecular-clock model. We show that this model is robust to uncorrelated violations of the molecular clock. Our algorithms apply to serial data, where the tips of the tree have been sampled through times. They estimate the substitution rate and the dates of all ancestral nodes. When the input tree is unrooted, they can provide an estimate for the root position, thus representing a new, practical alternative to the standard rooting methods (e.g., midpoint). Our algorithms exploit the tree (recursive) structure of the problem at hand, and the close relationships between least-squares and linear algebra. We distinguish between an unconstrained setting and the case where the temporal precedence constraint (i.e., an ancestral node must be older that its daughter nodes) is accounted for. With rooted trees, the former is solved using linear algebra in linear computing time (i.e., proportional to the number of taxa), while the resolution of the latter, constrained setting, is based on an active-set method that runs in nearly linear time. With unrooted trees the computing time becomes (nearly) quadratic (i.e., proportional to the square of the number of taxa). In all cases, very large input trees (>10,000 taxa) can easily be processed and transformed into time-scaled trees. We compare these algorithms to standard methods (root-to-tip, r8s version of Langley-Fitch method, and BEAST). Using simulated data, we show that their estimation accuracy is similar to that of the most sophisticated methods, while their computing time is much faster. We apply these algorithms on a large data set comprising 1194 strains of Influenza virus from the pdm09 H1N1 Human pandemic. Again the results show that these algorithms provide a very fast alternative with results similar to those of other computer programs. These algorithms are implemented in the LSD software (least-squares dating), which can be downloaded from http://www.atgc montpellier.fr/LSD/, along with all our data sets and detailed results. An Online Appendix, providing additional algorithm descriptions, tables, and figures can be found in the Supplementary Material available on Dryad at http://dx.doi.org/10.5061/dryad.968t3. PMID- 26424729 TI - Non-utilization of the Pap Test Among Women with Frequent Health System Contact. AB - Despite improvements in health access, many underserved women abstain from cervical cancer screening. A self-administered questionnaire was used to identify factors determining whether medically underserved women attending a safety net health system regularly are screened for cervical cancer. Approximately 11 % of study subjects had never received a Pap test despite an average of nearly four clinic visits in the preceding 12 months. Never screeners were significantly younger, more likely to be Hispanic, non-U.S. born and less likely to have healthcare continuity. In multivariable analysis, odds for never screening were independently lower among women with male partner support (aOR 0.29) and physician's recommendation for screening (aOR 0.34) and higher among women who believed screening visits are too long (aOR 2.53). Educating male partners of Hispanic and immigrant women in addition to addressing recognized situational barriers may help to improve cervical cancer screening rates. PMID- 26424730 TI - Acanthocephalan-related variation in the pattern of energy storage of a behaviorally and physiologically modified host: field data. AB - The acanthocephalan parasite Acanthocephalus dirus infects the freshwater isopod Caecidotea intermedius as an intermediate host before completing its life cycle in a fish. Transmission to the definitive host occurs after the parasite has reached the cystacanth stage, and development into this stage is associated with changes in several behavioral and physiological traits of the host. Given the potential importance of host energy availability to trait modification, we examined the relationship between cystacanth-stage infection and energy storage of adult isopods. Six samples of infected and uninfected male C. intermedius were collected from a population in March, April, and May during which time cystacanth stage A. dirus dominate infections and modification of behavior and physiology occurs in nature. Biochemical assays revealed that infected male C. intermedius contained more glycogen and more lipid than uninfected males and that this difference was present throughout the sampling period, which represents the entire adult phase of the host's life. Additional analysis revealed that infected and uninfected males differed in their pattern of allocation to each energy source and that host lipid levels were negatively correlated with parasite intensity. We propose that the typical pattern of allocation and storage of host energy appears to be disrupted by A. dirus infection and that the changes are more likely to favor the parasite than the host. PMID- 26424731 TI - Dissociation between exercise-induced reduction in liver fat and changes in hepatic and peripheral glucose homoeostasis in obese patients with non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is associated with multi-organ (hepatic, skeletal muscle, adipose tissue) insulin resistance (IR). Exercise is an effective treatment for lowering liver fat but its effect on IR in NAFLD is unknown. We aimed to determine whether supervised exercise in NAFLD would reduce liver fat and improve hepatic and peripheral (skeletal muscle and adipose tissue) insulin sensitivity. Sixty nine NAFLD patients were randomized to 16 weeks exercise supervision (n=38) or counselling (n=31) without dietary modification. All participants underwent MRI/spectroscopy to assess changes in body fat and in liver and skeletal muscle triglyceride, before and following exercise/counselling. To quantify changes in hepatic and peripheral insulin sensitivity, a pre-determined subset (n=12 per group) underwent a two-stage hyperinsulinaemic euglycaemic clamp pre- and post-intervention. Results are shown as mean [95% confidence interval (CI)]. Fifty participants (30 exercise, 20 counselling), 51 years (IQR 40, 56), body mass index (BMI) 31 kg/m(2) (IQR 29, 35) with baseline liver fat/water % of 18.8% (IQR 10.7, 34.6) completed the study (12/12 exercise and 7/12 counselling completed the clamp studies). Supervised exercise mediated a greater reduction in liver fat/water percentage than counselling [Delta mean change 4.7% (0.01, 9.4); P<0.05], which correlated with the change in cardiorespiratory fitness (r=-0.34, P=0.0173). With exercise, peripheral insulin sensitivity significantly increased (following high-dose insulin) despite no significant change in hepatic glucose production (HGP; following low-dose insulin); no changes were observed in the control group. Although supervised exercise effectively reduced liver fat, improving peripheral IR in NAFLD, the reduction in liver fat was insufficient to improve hepatic IR. PMID- 26424732 TI - The effectiveness of microsurgical fenestration for middle fossa arachnoid cysts in children. AB - OBJECTIVE: Although middle fossa arachnoid cysts (MFACs) are common, the optimal surgical treatment for these lesions remains controversial. In this study, we present our experiences of treating MFACs by microsurgical fenestration and evaluate its effectiveness. METHODS: We performed retrospective review of 28 patients who underwent microsurgical fenestration for MFACs between May 2003 and December 2014. We reviewed patient characteristics and treatment outcomes including age, sex, symptoms, complicating hydrocephalus, Gallasi classification, change in cyst size after surgery, complicating subdural hygroma, symptom resolution, regrowth of the cyst, and reoperation (including additional CSF diversion). RESULTS: Twenty-eight MFACs in 28 patients were investigated. The average age at the time of surgery was 61.6 months. The average follow-up duration was 53.5 months. After surgery, 19 (90.5 %) of 21 patients with symptomatic MFACs experienced improvements. The cysts decreased in size in all cases (100 %, 28/28) and disappeared in three cases (11 %, 3/28). None of the cases experienced regrowth of the cyst. Subdural hygroma was identified in 23 cases (82.1 %) at the immediate postoperative period. Hygroma was asymptomatic in all cases but one. Hygroma disappeared in 19 cases (83 %) and decreased in size in three cases (13 %) in the long term. Only one case (4 %) required an additional subdural-peritoneal shunt. The rate of CSF diversion after the fenestration was significantly higher in patients with preoperative ventricular dilation (p = 0.0002). CONCLUSION: Microsurgical fenestration for pediatric MFACs was considered to be safe and effective. Although subdural hygroma developed in significant number of patients at the immediate postoperative period, it was mostly asymptomatic and disappeared or decreased in size in the long term. PMID- 26424734 TI - Suicide Risk of Heroin Dependent Subjects in Lebanon. AB - The aim is to determine the frequency of suicidal behavior and associated factors among heroin dependent inpatients. 61 heroin dependent inpatients (vs. 61 controls) were assessed on their pattern of substance use, impulsivity, depression and suicidal behavior. 37.7 % of patients had a personal history of suicidal attempt (SA), 14.8 % had current suicidal ideation. SA was associated to younger age at first substance use and to higher rates of depression and impulsivity. IV heroin overdose was the most frequent mode of SA (47.8 %). Long duration, multiple drug use, and family history of suicide were associated with higher risk of suicide among lebanese patients. PMID- 26424733 TI - Elevated low-density lipoprotein cholesterol is independently associated with obstructive sleep apnea: evidence from a large-scale cross-sectional study. AB - BACKGROUND: Lipid metabolism disorder is recognized to be associated with obstructive sleep apnea (OSA); however, inconsistent results have been reported. The aim of this study was to evaluate the association between lipid profile and OSA with adjustments for multiple confounding factors. METHODS: In total, 2983 subjects were recruited from the Shanghai Sleep Health Study (SSHS) during 2007 2013. Data for overnight polysomnography (PSG) parameters, serum lipids, fasting blood glucose, insulin levels, and anthropometric measurements were collected. Multivariable logistic regression analyses were used to determine the correlation between lipid profile and OSA with adjustments for confounders including lipids, age, gender, Epworth sleepiness scale, body mass index, waist/hip ratio, glucose, insulin resistance, hypertension, and smoking. RESULTS: The prevalence of hyper total cholesterol (TC), hyper triglycerides, hypo high-density lipoprotein cholesterol, hyper low-density lipoprotein cholesterol (LDL-C), hyper apolipoprotein (apo) A-I, and hyper apoB differed significantly between the non OSA and OSA patients. Without considering the interaction across different lipids, TC, LDL-C, and apoB were independently associated with OSA in primary multivariable logistic regression analyses; the odds ratios (ORs) and 95 % confidence intervals (CIs) were 1.262 (1.109-1.438), 1.432 (1.233-1.664), and 5.582 (2.643-11.787), respectively. However, only LDL-C (OR = 1.430, 95 % CI = 1.221-1.675) was found to be an independent risk factor for OSA in further multivariable logistic regression analyses. CONCLUSIONS: We demonstrated that patients with OSA had a higher percentage of dyslipidemia than subjects without OSA. Of the various components in serum lipid, only LDL-C was independently associated with OSA. PMID- 26424735 TI - Middle School as a Developmental Niche for Civic Engagement. AB - The present study investigated how school climate, school connectedness and academic efficacy beliefs inform emergent civic engagement behaviors among middle school youth of color. These associations were examined both concurrently and longitudinally using a developmentally appropriate measure of civic engagement. Data were drawn from two subsamples of a larger study of social/emotional development in middle school (cross-sectional sample n = 324; longitudinal sample n = 232), M = 12 years old, 46 % female, 53 % male. Forty-two percent (42.2 %) of the sample self-identified as African American, 19.8 % as Multiracial or Mixed, 19.4 % as Latino, 11.6 % as Asian American or Pacific Islander, 11.6 % identified as Other, and 5.2 % as Native American. The study tested and found support for a latent mediation model in which more positive perceptions of school climate were positively related to school connectedness, and this in turn, was positively associated with civic engagement; school climate was also positively associated with academic-self-efficacy beliefs, but such beliefs did not mediate the climate civic engagement association. Implications for future research and practice are discussed. PMID- 26424736 TI - Effects of treadmill running and rutin on lipolytic signaling pathways and TRPV4 protein expression in the adipose tissue of diet-induced obese mice. AB - To explore the effects of rutin and exercise on high-fat diet (HFD)-induced disrupted lipolytic signaling, adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling, transient receptor potential cation channel subfamily V member 4 (TRPV4) and its associated protein expression, and whether depot specific effects existed. C57BL/6J mice were randomized into five groups: chow group, HFD, HFD plus rutin intervention group (HR), HFD combined with treadmill running group (HE), and HFD combined with treadmill running and rutin intervention group (HRE). At the end of the 16-week intervention, lipolytic markers, AMPK signaling pathways, TRPV4, and peroxisome proliferator-activated receptor gamma coactivator 1alpha + beta (PGC-1alpha + beta) from adipose tissue were measured by western blotting. In epididymal adipose tissue, HFD resulted in significant reduction in the phosphorylation of hormone sensitive lipase at serine660 (p-HSL660), perilipin A, phosphoenolpyruvate carboxykinase (PEPCK), p AMPK, and p-acetyl-CoA carboxylase (ACC) protein expression. Exercise intervention and exercise plus rutin completely restored p-HSL660, perilipin A, PEPCK, p-AMPK, and p-ACC protein expression to normal level. HFD and HR groups have reduced expression of PGC-1alpha + beta, exercise, and exercise plus rutin completely restored PGC-1alpha + beta expression to normal level. In subcutaneous adipose tissue, HFD elevated TRPV4, exercise, and exercise plus rutin completely reduced TRPV4 to normal level. HR, HE, and HRE group have increased PGC-1alpha + beta. In conclusion, depot-specific effects existed in regards to how rutin and exercise affect lipolytic signaling and p-AMPK, as well as TRPV4 and PGC-1alpha + beta expression. PMID- 26424738 TI - ASCO Reveals Additional Promising Results With Immunotherapies. PMID- 26424737 TI - Molecular epidemiology of MRSA in 13 ICUs from eight European countries. AB - OBJECTIVES: The European epidemiology of MRSA is changing with the emergence of community-associated MRSA (CA-MRSA) and livestock-associated MRSA (LA-MRSA). In this study, we investigated the molecular epidemiology of MRSA during 2 years in 13 ICUs in France, Greece, Italy, Latvia, Luxemburg, Portugal, Slovenia and Spain. METHODS: Surveillance cultures for MRSA from nose and wounds were obtained on admission and twice weekly from all patients admitted to an ICU for >=3 days. The first MRSA isolate per patient was genotyped in a central laboratory by MLST, spa typing, agr typing and SCCmec (sub)typing. Risk factors for patients with an unknown history of MRSA colonization were identified. RESULTS: Overall, 14 390 ICU patients were screened, of whom 8519 stayed in an ICU for >=3 days. Overall MRSA admission prevalence was 3.9% and ranged from 1.0% to 7.0% for individual ICUs. Overall MRSA acquisition rate was 2.5/1000 patient days at risk and ranged from 0.2 to 8/1000 patient days at risk per ICU. In total, 557 putative MRSA isolates were submitted to the central laboratory for typing, of which 511 (92%) were confirmed as MRSA. Each country had a distinct epidemiology, with ST8-IVc (UK-EMRSA-2/-6, USA500) being most prevalent, especially in France and Spain, and detected in ICUs in five of eight countries. Seventeen (3%) and three (<1%) isolates were categorized as CA-MRSA and LA-MRSA, respectively. Risk factors for MRSA carriage on ICU admission were age >70 years and hospitalization within 1 year prior to ICU admission. CONCLUSIONS: The molecular epidemiology of MRSA in 13 European ICUs in eight countries was homogeneous within, but heterogeneous between, countries. CA-MRSA and LA-MRSA genotypes and Panton-Valentine leucocidin producing isolates were detected sporadically. PMID- 26424739 TI - Study Finds Black Women Have Denser Breast Tissue Than White Women. PMID- 26424740 TI - Elective Neck Dissection in Early Oral Cancer: Debate Resolved. PMID- 26424743 TI - Banked Donor T-Cells Treat Virus-Related B Cell Disorder when Rituximab Fails. PMID- 26424744 TI - Authors' reply to Elshimy. PMID- 26424745 TI - Plymouth medical school is committed to producing GPs of the future. PMID- 26424746 TI - Frozen elephant trunk procedure for extensive pneumococcal thoracic aortitis. AB - Infectious arteritis is an insidious condition commonly associated with a long diagnostic delay. We report the management of extensive pneumococcal thoracic aortitis in a 64-year-old woman. The frozen elephant trunk procedure was performed to repair the aortic arch. Prolonged aortic wall cultures were positive for Streptococcus pneumoniae. Late follow-up imaging at 36 months demonstrated no sign of recurrence around the hybrid vascular graft in the thoracic aorta. PMID- 26424747 TI - Prognostic Indicators for Salvage Surgery of Recurrent Sinonasal Malignancy. AB - OBJECTIVE: Identify prognostic factors after salvage surgery for recurrent sinonasal malignancy (SNM). STUDY DESIGN: Case series with chart review. SETTING: University of Pittsburgh Medical Center. SUBJECTS: Forty-two patients who underwent curative surgery for locally recurrent SNM +/- adjuvant therapy from June 5, 2000, to December 19, 2012. Patients without follow-up were excluded. METHODS: Chart review with established prognostic indicators for primary malignancies. Statistical analysis included Kaplan-Meier log-rank test, Fisher's exact test, Student's t test, and Cox regression. RESULTS: Forty-two patients met inclusion criteria: 38.5% developed a second recurrence, and 21.4% had metastases following treatment. The average disease-free interval (DFI) was 26.9 months (range, 2-90 months). DFI was significantly affected by ethmoid versus nonethmoid site (P = .049), histology (P = .012), carotid artery involvement (P = .008), perineural extension (P = .006), and clival invasion (P = .015). The overall survival rates at 6 months, 12 months, and 5 years following surgery were 83.3%, 69%, and 47.6%, respectively. Survival was affected by histology (P = .014), stratified grade (P = .042), tumor extension into the orbit (P = .019), carotid artery (P = .001), perineural space (P = .028), and clivus (P = .022). Complications occurred in 28.6% of patients and were associated with histology (P = .04). Length of hospital stay related to treatment was affected by histology (P = .009), grade (P = .013), and postoperative complication (P < .001). The median percentage of time hospitalized was 8%, and 43% of patients who died within 12 months spent >10% of their remaining days in the hospital. CONCLUSION: High-risk histologic subtype (melanoma, sinonasal undifferentiated carcinoma, adenocarcinoma, neuroendocrine cancer, sarcoma, and squamous cell carcinoma), grade, and orbital and skull base involvement negatively affect survival and/or DFI for patients with local recurrence of SNM. Improved stratification of patients can be used to guide decision making for patients with recurrent SNM and to avoid inappropriate surgery. PMID- 26424748 TI - Marketing a Healthy Mind, Body, and Soul: An Analysis of How African American Men View the Church as a Social Marketer and Health Promoter of Colorectal Cancer Risk and Prevention. AB - The Centers for Disease Control and Prevention ranks colorectal cancer (CRC) as the third most commonly diagnosed cancer among men in the United States; African American (AA) men are at even greater risk. The present study was from a larger study that investigates the church's role as a social marketer of CRC risk and prevention messages, and whether religiously targeted and tailored health promotion materials will influence screening outcome. We used an integrated theoretical approach to explore participants' perceptions of CRC risk and prevention and how promotion messages should be developed and socially marketed by the church. Six focus groups were conducted with men from predominately AA churches in the Midwest. Themes from focus group discussions showed participants lacked knowledge about CRC, feared cancer diagnosis, and feared the procedure for screening. Roles of masculinity and the mistrust of physicians were also emergent themes. Participants did perceive the church as a trusted marketer of CRC but believed that promotional materials should be cosponsored and codeveloped by reputable health organizations. Employing the church as a social marketer of CRC screening promotion materials may be useful in guiding health promotions and addressing barriers that are distinct among African American men. PMID- 26424749 TI - The NC11 domain of human collagen XVI induces vasculogenic mimicry in oral squamous cell carcinoma cells. AB - Collagen XVI, a fibril-associated collagen with interrupted triple helix (FACIT) collagen, is involved in oral squamous cell carcinoma (OSCC) and glioblastoma progression. The NC11 domain of collagen XVI has been described previously with a strong implication in physiological processes. We detected the non-collagenous (NC) 11-domain in supernatants of OSCC cells after recombinant expression of full length collagen XVI and in sera from OSCC patients and healthy individuals. Stable expression of NC11-green fluorescent protein (GFP) fusion protein in OSCC cells initiated proliferation control and block of anchorage-independent growth. Moreover, the NC11 domain triggered the generation of tubular-like net structures on laminin-rich matrix in contrast to mock-GFP control cells and cells expressing full-length collagen XVI. Taqman(r) quantitative PCR and diaminobenzidine staining in 2D- and 3D cell culture revealed a significantly increased gene and protein expression of VEGFR1, VEGFR2 and uPAR in recombinant NC11-GFP-expressing cells. Specific VEGF receptor inhibition with Axitinib or fetal calf serum heat inactivation prevented formation of tubular-like net structures. Accordantly, NC11-GFP coated culture slides led to an increase of focal adhesion contact formation and the upregulation of VEGFR1 and uPAR in three different non transfected OSCC cell lines. In summary, we suggest that the NC11 domain of collagen XVI is a potential biomarker for OSCC and triggers vasculogenic mimicry via upregulation of endothelial receptors VEGFR1, VEGFR2 and uPAR in 2D- and 3D OSCC cell culture conditions. PMID- 26424750 TI - The mycotoxin aflatoxin B1 stimulates Epstein-Barr virus-induced B-cell transformation in in vitro and in vivo experimental models. AB - Although Epstein-Barr virus (EBV) infection is widely distributed, certain EBV driven malignancies are geographically restricted. EBV-associated Burkitt's lymphoma (eBL) is endemic in children living in sub-Saharan Africa. This population is heavily exposed to food contaminated with the mycotoxin aflatoxin B1 (AFB1). Here, we show that exposure to AFB1 in in vitro and in vivo models induces activation of the EBV lytic cycle and increases EBV load, two events that are associated with an increased risk of eBL in vivo. AFB1 treatment leads to the alteration of cellular gene expression, with consequent activations of signaling pathways, e.g. PI3K, that in turn mediate reactivation of the EBV life cycle. Finally, we show that AFB1 triggers EBV-driven cellular transformation both in primary human B cells and in a humanized animal model. In summary, our data provide evidence for a role of AFB1 as a cofactor in EBV-mediated carcinogenesis. PMID- 26424752 TI - To Cut ... or Not? PMID- 26424753 TI - Biomechanical Analysis of Simulated Clinical Testing and Reconstruction of the ALL: Letter to the Editor. PMID- 26424754 TI - Biomechanical Analysis of Simulated Clinical Testing and Reconstruction of the ALL: Response. PMID- 26424755 TI - The Effectiveness of ESWT in Lower Limb Tendinopathy: Letter to the Editor. PMID- 26424756 TI - The Effectiveness of ESWT in Lower Limb Tendinopathy: Response. PMID- 26424757 TI - Is there a role yet for new direct oral anticoagulants in cancer patients? PMID- 26424751 TI - Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer. AB - Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P <= 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1*10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72*10( 8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70*10( 8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene. PMID- 26424759 TI - The Association Between PD-L1 Expression and the Clinical Outcomes to Vascular Endothelial Growth Factor-Targeted Therapy in Patients With Metastatic Clear Cell Renal Cell Carcinoma. AB - BACKGROUND: Vascular endothelial growth factor pathway (VEGF)-tyrosine kinase inhibitors (TKIs) are used as the first-line treatment for patients with metastatic clear cell renal cell carcinoma (mCCRCC). Recently, programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) blockade emerged as promising therapy for renal cell carcinoma. However, the expression pattern and prognostic implication of programmed death-ligands (PD-Ls) in mCCRCC patients receiving VEGF TKI remain unclear. PATIENTS AND METHODS: PD-L1 and PD-L2 expression in tumor cells and the quantities of PD-1+ tumor-infiltrating lymphocytes were immunohistochemically evaluated in 91 mCCRCC patients treated with VEGF-TKI, and their associations with VEGF-TKI responsiveness and clinical outcome were analyzed. RESULTS: PD-L1 immunopositivity was observed in 17.6% and significantly associated with a high International Society of Urological Pathology grade (p = .031) and sarcomatoid features (p = .014). PD-L2 immunopositivity was observed in 39.6% and was not associated with any of the assessed clinicopathological variables. PD-L1-positive cases showed poor VEGF-TKI responsiveness (p = .012) compared with PD-L1-negative cases. In univariate survival analysis, PD-L1 immunopositivity was significantly associated with shorter overall survival (OS) (p = .037) and progression-free survival (PFS) (p = .043). Multivariate survival analysis revealed that PD-L1 expression was independently associated with poor OS (p = .038) and PFS (p = .013) in addition to tumor necrosis (p = .006; p = .029, respectively) and Memorial Sloan Kettering Cancer Center score (p = .018; p = .032, respectively). PD-L2 expression was neither associated with VEGF-TKI responsiveness nor patients' outcome. CONCLUSION: PD-L1 expression was significantly related to lack of VEGF-TKI responsiveness and independently associated with shorter survival in mCCRCC patients after VEGF-TKI treatment. PD L1 may have a predictive and prognostic value for determining the value of VEGF TKI treatment in patients with mCCRCC. IMPLICATIONS FOR PRACTICE: Vascular endothelial growth factor pathway (VEGF)-tyrosine kinase inhibitors (TKIs) are essential for the treatment of metastatic renal cell carcinoma patients, but the treatment suffers from a lack of predictive markers. This study demonstrates that PD-L1 expression is a predictor for unfavorable response to VEGF-TKI and a prognostic indicator for poor overall survival and progression-free survival in patients with metastatic clear cell renal cell carcinoma receiving VEGF-TKI. PMID- 26424758 TI - Familial Gastric Cancers. AB - Although the majority of gastric carcinomas are sporadic, approximately 10% show familial aggregation, and a hereditary cause is determined in 1%-3% cases. Of these, hereditary diffuse gastric cancer is the most recognized predisposition syndrome. Although rare, the less commonly known syndromes also confer a markedly increased risk for development of gastric cancer. Identification and characterization of these syndromes require a multidisciplinary effort involving oncologists, surgeons, genetic counselors, biologists, and pathologists. This article reviews the molecular genetics, clinical and pathologic features, surveillance guidelines, and preventive measures of common and less common hereditary gastric cancer predisposition syndromes. PMID- 26424760 TI - Phase II Trial of Nilotinib in Patients With Metastatic Malignant Melanoma Harboring KIT Gene Aberration: A Multicenter Trial of Korean Cancer Study Group (UN10-06). AB - BACKGROUND: KIT has been suggested to be a potential therapeutic target for malignant melanoma. We evaluated the antitumor activity and safety of the KIT inhibitor nilotinib in metastatic melanoma patients harboring KIT gene mutations or amplifications. METHODS: We conducted a phase II multicenter trial of nilotinib in metastatic malignant melanoma with KIT mutations or amplifications. Patients received 400 mg oral nilotinib twice daily. The primary endpoint was response rate, and if seven or more responders were observed from the cumulative 36 patients, nilotinib would be considered worthy of further testing in this study population. RESULTS: Between October 2009 and June 2013, 176 patients underwent molecular screening for KIT gene aberrations, and 42 patients harboring KIT gene mutations and/or amplification were enrolled in the study. Overall, 25 (59.5%), 15 (35.7%), and 2 (4.8%) patients had KIT mutations, KIT amplifications, and both KIT mutations and amplification, respectively. Of the 42 enrolled patients, 1 patient achieved complete response, 6 patients achieved partial response, and 17 patients achieved stable disease, resulting in an overall response rate of 16.7% (95% confidence interval [CI]: 5.4%-28.0%) and a disease control rate of 57.1% (95% CI: 42.1%-72.1%). The median duration of response was 34 weeks (range: 5-55 weeks). Of the 7 responders, 6 patients had KIT mutations (exon 11: 5 patients; exon 17: 1 patient), and 1 patient had KIT amplification only. CONCLUSION: Although this study did not meet its primary endpoint of response rate, nilotinib showed durable response in a subset of metastatic melanoma patients with specific KIT mutations. IMPLICATIONS FOR PRACTICE: KIT aberration can be detected in a subset of metastatic melanoma patients. This phase II trial showed that nilotinib demonstrates durable response in a subset of patients with KIT mutations. The safety profile was very tolerable. This study suggests that a KIT inhibitor may benefit a small subset of metastatic melanoma patients with KIT mutations. PMID- 26424761 TI - Assessing patient-centred care through direct observation of clinical encounters. PMID- 26424762 TI - Observation for assessment of clinician performance: a narrative review. AB - BACKGROUND: Video recorded and in-person observations are methods of quality assessment and monitoring that have been employed in high risk industries. In the medical field, observations have been used to evaluate the quality and safety of various clinical processes. This review summarises studies utilising video recorded or in-person observations for assessing clinician performance in medicine and surgery. METHODS: A search of MEDLINE (PubMed) was conducted using a combination of medical subject headings (MeSH) terms. Articles were included if they described the use of in-person or video recorded observations to assess clinician practices in three categories: (1) teamwork and communication between clinicians; (2) errors and weaknesses in practice; and (3) compliance and adherence to interventions or guidelines. RESULTS: The initial search criteria returned 3215 studies, 223 of which were identified for full text review. A total of 69 studies were included in the final set of literature. Observations were most commonly used in data dense and high risk environments, such as the emergency department or operating room. The most common use was for assessing teamwork and communication factors. CONCLUSIONS: Observations are useful for the improvement of healthcare delivery through the identification of clinician lapses and weaknesses that affect quality and safety. Limitations of observations include the Hawthorne effect and the necessity of trained observers to capture and analyse the notes or videos. The comprehensive, subtle and sensitive information observations provided can supplement traditional quality assessment methods and inform targeted interventions to improve patient safety and the quality of care. PMID- 26424763 TI - Point-of-care decision support for reducing inappropriate test use: easier said than done. PMID- 26424764 TI - Community Palliative Care Nurses' Challenges and Coping Strategies on Delivering Home-Based Pediatric Palliative Care. AB - OBJECTIVE: The aim of this study was to explore the experience of community palliative care nurses providing home care to children. METHOD: A qualitative study was conducted at the 3 community palliative care provider organizations in greater Kuala Lumpur from August to October 2014. Data were collected with semistructured interviews with 16 nurses who have provided care to children and was analyzed using thematic analysis. Two categories were identified: (1) challenges nurses faced and (2) coping strategies. The themes identified from the categories are (1) communication challenges, (2) inadequate training and knowledge, (3) personal suffering, (4) challenges of the system, (5) intrapersonal coping skills, (6) interpersonal coping strategies, and (7) systemic supports. CONCLUSIONS: These results reinforces the need for integration of pediatric palliative care teaching and communication skills training into all undergraduate health care programs. Provider organizational support to meet the specific needs of the nurses in the community can help retain them in their role. It will also be important to develop standards for current and new palliative care services to ensure delivery of quality pediatric palliative care. PMID- 26424765 TI - Genomic manipulations in alkaliphilic haloarchaea demonstrated by a gene disruption in Natrialba magadii. AB - Alkaliphilic haloarchaea, a distinct physiological group from the closely related neutrophilic haloarchaea, represent an underutilized resource for basic research and industrial applications. In contrast to the neutrophilic haloarchaea, no reports on genomic manipulations in haloalkaliphiles have been published until now. Genomic manipulations via homologous recombination are useful for basic research. In this study, we demonstrate the possibility for this strategy in alkaliphilic haloarchaea for the first time. In a previous study, we developed a PEG-mediated transformation technique for alkaliphilic haloarchaea that was deployed in this study to deliver a gene disruption cassette into the model organism Natrialba magadii. The gene encoding for the well-studied Natrialba extracellular protease was successfully disrupted by a recombination marker gene, demonstrating a proof of principle for the usability of homologous recombination for genomic manipulations in alkaliphilic haloarchaea. Since halo(alkali)philic Archaea are polyploid, a selection process was applied in order to obtain a mutant strain containing exclusively disrupted genes. The resulting strain exhibited no proteolytic activity measurable by an azo-casein assay. Complementation was able to restore proteolytic activity. The expression pattern of the Natrialba extracellular protease was different in the complemented strain. PMID- 26424766 TI - High temperature microbial activity in upper soil layers. AB - Biomineralization at high temperatures in upper soil layers has been largely ignored, although desertification and global warming have led to increasing areas of soils exposed to high temperatures. Recent publications evidenced thermophilic bacteria ubiquity in soils as viable cells, and their role in nutrient cycling and seedling development. High temperature events, frequently observed at medium and low latitudes, locate temporal niches for thermophiles to grow in soils. There, at temperatures inhibitory for common mesophiles, thermophilic bacteria could perform biogeochemical reactions important to the soil food web. Nutrient cycling analyses in soils at medium and low latitudes would benefit from considering the potential role of thermophiles. PMID- 26424767 TI - Prevalence and population analysis of Vibrio parahaemolyticus in aquatic products from South China markets. AB - Vibrio parahaemolyticus is a common foodborne pathogen in aquatic products. To investigate the prevalence of Vibrio parahaemolyticus in aquatic products in South China, 224 samples were collected from markets in four provinces (11 cities) from May 2013 to January 2014. One hundred and fifty isolates were isolated from 98 samples. All isolates were analyzed for the presence of thermostable direct haemolysin (TDH) and TDH-related haemolysin (TRH) by PCR, antibiotic susceptibility analysis by disk diffusion method, serotyping by multiplex PCR and molecular typing by enterobacterial repetitive intergenic consensus sequence PCR (ERIC-PCR) typing. Although all 150 isolates were negative for tdh, 61 strains were trh positive (40.67%). Antimicrobial susceptibility results indicated that most strains were resistant to streptomycin (88.67%), cefazolin (66.00%) and ampicillin (62.67%). All strains were susceptible to chloramphenicol. Forty percent of all isolates were O2 type. The 150 isolates were grouped into three clusters by ERIC-PCR typing. The results demonstrated the presence of V. parahaemolyticus in aquatic products from the retail market and this methodology can be used for microbiological risk assessment in China. PMID- 26424768 TI - Revisiting bacterial cyclic nucleotide phosphodiesterases: cyclic AMP hydrolysis and beyond. AB - Cyclic-3',5'-adenosine monophosphate (cAMP) is a universal second messenger that regulates vital activities in bacteria and eukaryotes. Enzymes that hydrolyze cAMP, called phosphodiesterases (PDEs), negatively regulate the levels of this messenger molecule and are therefore crucial for signal 'termination'. In this minireview, I shall summarize the available literature on bacterial cAMP-PDEs, with particular emphasis on enzymes belonging to the ubiquitously encoded Class III PDE family exemplified by CpdA from Escherichia coli and Rv0805 from Mycobacterium tuberculosis. Using available biochemical, structural and biological information, I shall make a case for re-examining the functions of these enzymes as merely regulators of intrabacterial cAMP levels and suggest that some members of this class may have evolved cAMP-independent functions as well. Finally, I shall highlight the major lacunae in our understanding of these enzymes and present unanswered questions in the area. PMID- 26424769 TI - Urinary uroplakin expression in cyclophosphamide-induced rat cystitis model. AB - Cyclophosphamide (CYP) induces urothelial injury and causes excretion of cellular exudates at 24 h, followed by rapid restoration at 72 h. We investigated the role of urinary uroplakin II (UPII) levels in a CYP-induced cystitis model. For the purpose of this study, 10 controls and 26 CYP-injected female Sprague Dawley rats were killed at 24 h and 72 h postinjection. The vesical weight, severity of hematuria, and expression of UPII in the urinary bladder and urine were measured. CYP decreased the level of vesical UPII messenger RNA at 24 h, followed by rapid recovery at 72 h. Contrary to the negligible levels of urinary UPII and hematuria in controls, CYP treatment abruptly increased the excretion of urinary UPII at 24 h. The excretion had subsided at 72 h. Similarly, severe hematuria was observed at 24 h, with improvement at 72 h. However, some rats still exhibited hematuria at 72 h. CYP caused increase in vesical weight. The vesical weight at 24 h after CYP injection was negatively correlated with the vesical UPII level. Rats with significant hematuria demonstrated higher urinary UPII levels than those with insignificant hematuria. Vesical UPII could be an important barrier for early CYP related injury, while the levels of urinary UPII may be associated with the severity of hematuria during dynamic periods in the urothelium. PMID- 26424770 TI - Effect of agmatine on experimental vascular endothelial dysfunction. AB - This study was designed to investigate the effect of agmatine sulfate (AG, CAS2482-00-0) in nicotine (NIC)-induced vascular endothelial dysfunction (VED) in rabbits. NIC was administered to produce VED in rabbits with or without AG for 6 weeks. Serum lipid profile, serum thiobarbituric acid reactive substances, reduced glutathione, superoxide dismutase generation, serum nitrite/nitrate, serum vascular cellular adhesion molecule-1 (VCAM-1), and aortic nuclear factor kappaB (NF-kappaB) levels were analyzed.Treatment with AG markedly improves lipid profile and prevented NIC-induced VED and oxidative stress. The mechanism of AG in improving NIC-induced VED may be due to the significant reduction in serum VCAM-1 levels and aortic NF-kappaB. Thus, it may be concluded that AG reduces the oxidative stress, nitric oxide production, VCAM-1 levels, and aortic NF-kappaB expression, thereby consequently improving the integrity of vascular endothelium. PMID- 26424771 TI - Disturbance of autophagic pathway may be involved in the diabetes-induced oxidative response in brain. PMID- 26424772 TI - Flavocoxid Protects Against Cadmium-Induced Disruption of the Blood-Testis Barrier and Improves Testicular Damage and Germ Cell Impairment in Mice [corrected]. AB - Cadmium (Cd) causes male infertility. There is the need to identify safe treatments counteracting this toxicity. Flavocoxid is a flavonoid that induces a balanced inhibition of cyclooxygenase (COX)-1 and COX-2 peroxidase moieties and of 5-lipoxygenase (LOX) and has efficacy in the male genitourinary system. We investigated flavocoxid effects on Cd-induced testicular toxicity in mice. Swiss mice were divided into 4 groups: 2 control groups received 0.9% NaCl (vehicle; 1 ml/kg/day) or flavocoxid (20 mg/kg/day ip); 2 groups were challenged with cadmium chloride (CdCl2; 2 mg/kg/day ip) and administered with vehicle or flavocoxid. The treatment lasted for 1 or 2 weeks. The testes were processed for biochemical and morphological studies. CdCl2 increased phosphorylated extracellular signal regulated kinase (p-ERK) 1/2, tumor necrosis factor (TNF)-alpha, COX-2, 5-LOX, malondialdehyde (MDA), B-cell-lymphoma (Bcl)-2-associated X protein (Bax), follicle-stimulating hormone (FSH), luteinizing hormone (LH), transforming growth factor (TGF) -beta3, decreased Bcl-2, testosterone, inhibin-B, occludin, N Cadherin, induced structural damages in the testis and disrupted the blood-testis barrier. Many TUNEL-positive germ cells and changes in claudin-11, occludin, and N-cadherin localization were present. Flavocoxid administration reduced, in a time-dependent way, p-ERK 1/2, TNF-alpha, COX-2, 5-LOX, MDA, Bax, FSH, LH, TGF beta3, augmented Bcl-2, testosterone, inhibin B, occludin, N-Cadherin, and improved the structural organization of the testis and the blood-testis barrier. Few TUNEL-positive germ cells were present and a morphological retrieval of the intercellular junctions was observed. In conclusion, flavocoxid has a protective anti-inflammatory, antioxidant, and antiapoptotic function against Cd-induced toxicity in mice testis. We suggest that flavocoxid may play a relevant positive role against environmental levels of Cd, otherwise deleterious to gametogenesis and tubular integrity. PMID- 26424773 TI - Acute and Long-Term Effects of Brief Sevoflurane Anesthesia During the Early Postnatal Period in Rats. AB - The possibility that exposure to general anesthetics during early life results in long-term impairment of neural function attracted considerable interest over the past decade. Extensive laboratory data suggest that administration of these drugs during critical stages of central nervous system development can lead to cell death, impaired neurogenesis, and synaptic growth as well as cognitive deficits. These observations are corroborated by several recent human epidemiological studies arguing that such cognitive impairment might also occur in humans. Despite the potential public health importance of this issue, several important questions remain open. Amongst them, how the duration of anesthesia exposure impact on outcome is as yet not fully elucidated. To gain insight into this question, here we focused on the short- and long-term impact of a 30-min-long exposure to clinically relevant concentrations of sevoflurane in rat pups at 2 functionally distinct stages of the brain growth spurt. We show that this treatment paradigm induced developmental stage-dependent and brain region specific acute but not lasting changes in dendritic spine densities. Electrophysiological recordings in hippocampal brain slices from adult animals exposed to anesthesia in the early postnatal period revealed larger paired-pulse facilitation but no changes in the long-term potentiation paradigm when compared with nonanesthetized controls. 5-bromo-2-deoxyuridine pulse and pulse-chase experiments demonstrated that neither proliferation nor differentiation and survival of hippocampal progenitors were affected by sevoflurane exposure. In addition, behavioral testing of short- and long-term memory showed no differences between control and sevoflurane-exposed animals. Overall, these results suggest that brief sevoflurane exposure during critical periods of early postnatal development, although it does not seem to exert major long-term effects on brain circuitry development, can induce subtle changes in synaptic plasticity and spine density of which the physiological significance remains to be determined. PMID- 26424774 TI - Therapeutic Potential and Critical Analysis of the PCSK9 Monoclonal Antibodies Evolocumab and Alirocumab. AB - OBJECTIVE: To review the mechanism of action for PCSK9 monoclonal antibodies and critically evaluate the therapeutic potential of evolocumab and alirocumab in the treatment of hypercholesterolemia. DATA SOURCES: Ovid MEDLINE search from 1980 to August 2015 using the terms PCSK9, evolocumab, and alirocumab with forward and backward citation tracking. STUDY SELECTION AND DATA EXTRACTION: English-language trials and studies assessing the mechanism, efficacy, or safety of PCSK9 monoclonal antibodies were included. DATA SYNTHESIS: PCSK9 monoclonal antibodies have a potent ability to reduce low-density lipoprotein (LDL) by almost 50% in controlled trials: -47.49% (95% CI = -69.6% to -25.4%). They have an acceptable safety profile with no significant elevations in Creatine Kinase (CK) (odds ratio [OR] = 0.72; 95% CI = 0.54 to 0.96) or serious adverse events (OR = 1.01; 95% CI = 0.87 to 1.18), and preliminary evidence suggests reductions in myocardial infarction (OR = 0.49; 95% CI = 0.26 to 0.93). Although it is effective in several familial hypercholesterolemia (FH) patient types, it does not work in homozygous patients with dual allele LDL receptor negative polymorphisms or those who are homozygous for autosomal recessive hypercholesterolemia. CONCLUSIONS: Although not preferred over statins because of limited clinical trial evidence of cardiovascular event reductions, dosing convenience, and expense, PCSK9 monoclonal antibodies will have a prominent role to play in the treatment of hypercholesterolemia, especially in patients needing large LDL reductions, including patients with many types of FH. PMID- 26424775 TI - Influence of Input Hardware and Work Surface Angle on Upper Limb Posture in a Hybrid Computer Workstation. AB - OBJECTIVE: We evaluated the effect of work surface angle and input hardware on upper-limb posture when using a hybrid computer workstation. BACKGROUND: Offices use sit-stand and/or tablet workstations to increase worker mobility. These workstations may have negative effects on upper-limb joints by increasing time spent in non-neutral postures, but a hybrid standing workstation may improve working postures. METHOD: Fourteen participants completed office tasks in four workstation configurations: a horizontal or sloped 15 degrees working surface with computer or tablet hardware. Three-dimensional right upper-limb postures were recorded during three tasks: reading, form filling, and writing e-mails. Amplitude probability distribution functions determined the median and range of upper-limb postures. RESULTS: The sloped-surface tablet workstation decreased wrist ulnar deviation by 5 degrees when compared to the horizontal-surface computer when reading. When using computer input devices (keyboard and mouse), the shoulder, elbow, and wrist were closest to neutral joint postures when working on a horizontal work surface. The elbow was 23 degrees and 15 degrees more extended, whereas the wrist was 6 degrees less ulnar deviated, when reading compared to typing forms or e-mails. CONCLUSION: We recommend that the horizontal surface computer configuration be used for typing and the sloped-surface tablet configuration be used for intermittent reading tasks in this hybrid workstation. APPLICATION: Offices with mobile employees could use this workstation for alternating their upper-extremity postures; however, other aspects of the device need further investigation. PMID- 26424776 TI - Trends in Treatment Patterns and Outcomes for Ductal Carcinoma In Situ. AB - BACKGROUND: Impact of contemporary treatment of pre-invasive breast cancer (ductal carcinoma in situ [DCIS]) on long-term outcomes remains poorly defined. We aimed to evaluate national treatment trends for DCIS and to determine their impact on disease-specific (DSS) and overall survival (OS). METHODS: The Surveillance, Epidemiology, and End Results (SEER) registry was queried for patients diagnosed with DCIS from 1991 to 2010. Treatment pattern trends were analyzed using Cochran-Armitage trend test. Survival analyses were performed using inverse probability weights (IPW)-adjusted competing risk analyses for DSS and Cox proportional hazard regression for OS. All tests performed were two sided. RESULTS: One hundred twenty-one thousand and eighty DCIS patients were identified. The greatest proportion of patients was treated with lumpectomy and radiation therapy (43.0%), followed by lumpectomy alone (26.5%) and unilateral (23.8%) or bilateral mastectomy (4.5%) with significant shifts over time. The rate of sentinel lymph node biopsy increased from 9.7% to 67.1% for mastectomy and from 1.4% to 17.8% for lumpectomy. Compared with mastectomy, OS was higher for lumpectomy with radiation (hazard ratio [HR] = 0.79, 95% confidence interval [CI] = 0.76 to 0.83, P < .001) and lower for lumpectomy alone (HR = 1.17, 95% CI = 1.13 to 1.23, P < .001). IPW-adjusted ten-year DSS was highest in lumpectomy with XRT (98.9%), followed by mastectomy (98.5%), and lumpectomy alone (98.4%). CONCLUSIONS: We identified substantial shifts in treatment patterns for DCIS from 1991 to 2010. When outcomes between locoregional treatment options were compared, we observed greater differences in OS than DSS, likely reflecting both a prevailing patient selection bias as well as clinically negligible differences in breast cancer outcomes between groups. PMID- 26424777 TI - Long-term Realism and Cost-effectiveness: Primary Prevention in Combatting Cancer and Associated Inequalities Worldwide. AB - The global figure of 14 million new cancer cases in 2012 is projected to rise to almost 22 million by 2030, with the burden in low- and middle-income countries (LMICs) shifting from 59% to 65% of all cancer cases worldwide over this time. While the overheads of cancer care are set to rapidly increase in all countries worldwide irrespective of income, the limited resources to treat and manage the growing number of cancer patients in LMICs threaten national economic development. Current data collated in the recent second edition of The Cancer Atlas by the American Cancer Society and International Agency for Research on Cancer show that a substantial proportion of cancers are preventable and that prevention is cost-effective. Therefore, cancer control strategies within countries must prioritize primary and secondary prevention, alongside cancer management and palliative care and integrate these measures into existing health care plans. There are many examples of the effectiveness of prevention in terms of declining cancer rates and major risk factors, including an 80% decrease in liver cancer incidence rates among children and young adults following universal infant hepatitis B vaccination in Taiwan and a 46% reduction in smoking prevalence in Brazil after the implementation of a more aggressive tobacco control program beginning in 1989. Prevention can bring rich dividends in net savings but actions must be promoted and implemented. The successful approaches to combatting certain infectious diseases provide a model for implementing cancer prevention, particularly in LMICs, via the utilization of existing infrastructures for multiple purposes. PMID- 26424779 TI - Prevalence and Predictors of Inappropriate Delivery of Palliative Thoracic Radiotherapy for Metastatic Lung Cancer. AB - BACKGROUND: High-level evidence has established well-recognized standard treatment regimens for patients undergoing palliative chest radiotherapy (RT) for stage IV non-small cell lung cancer (NSCLC), including treating with fewer than 15 fractions of RT, and not delivering concurrent chemoradiation (CRT) because of its increased toxicity and limited efficacy in the palliative setting. METHODS: The study included patients in the National Cancer Database from 2004 to 2012 with stage IV lung cancer who received palliative chest radiation therapy. Logistic regression was performed to determine predictors of standard vs nonstandard regimens (>15 fractions or CRT). All statistical tests were two sided. RESULTS: There were 46 803 patients in the analysis and 49% received radiotherapy for longer than 15 fractions, and 28% received greater than 25 fractions. Approximately 19% received CRT. The strongest independent predictors of long-course RT were private insurance (odds ratio [OR] = 1.40 vs uninsured, 95% confidence interval [CI] = 1.28 to 1.53) and treatment in community cancer programs (OR = 1.49, 95% CI = 1.38 to 1.58) compared with academic research programs. The strongest factors that predicted for concurrent chemoradiotherapy were private insurance (OR = 1.38 95% CI = 1.23 to 1.54) compared with uninsured patients and treatment in community cancer programs (OR = 1.44, 95% CI = 1.33 to 1.56) compared with academic programs. CONCLUSIONS: Approximately half of all patients with metastatic lung cancer received a higher number of radiation fractions than recommended. Patients with private insurance and treated in community cancer centers were more likely to receive longer courses of RT or CRT. This demonstrates that a substantial number of patients requiring palliative thoracic radiotherapy are overtreated and further work is necessary to ensure these patients are treated according to evidenced-based guidelines. PMID- 26424778 TI - Weight Gain After Breast Cancer Diagnosis and All-Cause Mortality: Systematic Review and Meta-Analysis. AB - BACKGROUND: Overweight and obesity are associated with breast cancer mortality. However, the relationship between postdiagnosis weight gain and mortality is unclear. We conducted a systematic review and meta-analysis of weight gain after breast cancer diagnosis and breast cancer-specific, all-cause mortality and recurrence outcomes. METHODS: Electronic databases identified articles up through December 2014, including: PubMed (1966-present), EMBASE (1974-present), CINAHL (1982-present), and Web of Science. Language and publication status were unrestricted. Cohort studies and clinical trials measuring weight change after diagnosis and all-cause/breast cancer-specific mortality or recurrence were considered. Participants were women age 18 years or older with stage I-IIIC breast cancer. Fixed effects analysis summarized the association between weight gain (>=5.0% body weight) and all-cause mortality; all tests were two-sided. RESULTS: Twelve studies (n = 23 832) were included. Weight gain (>=5.0%) compared with maintenance (<+/-5.0%) was associated with increased all-cause mortality (hazard ratio [HR] = 1.12, 95% confidence interval [CI] = 1.03 to 1.22, P = .01, I(2) = 55.0%). Higher risk of mortality was apparent for weight gain >=10.0% (HR = 1.23, 95% CI = 1.09 to 1.39, P < .001); 5% to 10.0% weight gain was not associated with all-cause mortality (P = .40). The association was not statistically significant for those with a prediagnosis body mass index (BMI) of less than 25 kg/m(2) (HR = 1.14, 95% CI = 0.99 to 1.31, P = .07) or with a BMI of 25 kg/m(2) or higher (HR = 1.00, 95% CI = 0.86 to 1.16, P = .19). Weight gain of 10.0% or more was not associated with hazard of breast cancer-specific mortality (HR = 1.17, 95% CI = 1.00 to 1.38, P = .05). CONCLUSIONS: Weight gain after diagnosis of breast cancer is associated with higher all-cause mortality rates compared with maintaining body weight. Adverse effects are greater for weight gains of 10.0% or higher. PMID- 26424780 TI - Addressing Overtreatment in DCIS: What Should Physicians Do Now? PMID- 26424781 TI - Tinnitus Annoyance in Normal-Hearing Individuals: Correlation With Depression and Anxiety. AB - OBJECTIVE: To assess and correlate tinnitus annoyance in normal-hearing patients with auditory brainstem response and with anxiety/depression. METHODS: A sample of 84 individuals with tinnitus and normal hearing levels (pure-tone thresholds <=25 dB HL) was compared to a matched control group of 47 normal-hearing individuals without tinnitus. All participants underwent auditory brainstem response testing. Tinnitus annoyance was assessed using the Tinnitus Handicap Inventory and depression and anxiety using the Beck Depression Inventory and Beck Anxiety Inventory, respectively. We compared auditory brainstem response and anxiety/depression symptoms between groups. In the study group, we correlated the degree of tinnitus annoyance with normal/abnormal auditory brainstem response and presence/level of anxiety/depression symptoms. RESULTS: All controls had normal auditory brainstem response; 30 patients with tinnitus had abnormal results. Thirty-five patients with tinnitus had depression and 41 anxiety, while only 2 controls had depression and none had anxiety, with a significant between-group difference (P < .001). Normal/abnormal auditory brainstem response showed no association with tinnitus annoyance, anxiety, or depression. A higher degree of tinnitus annoyance was associated with severity of depression and anxiety. CONCLUSIONS: Increased tinnitus annoyance was positively correlated with greater severity of anxiety and depression in normal-hearing patients but was unrelated to normal/abnormal auditory brainstem response. PMID- 26424782 TI - Intraspecific variation in stomatal traits, leaf traits and physiology reflects adaptation along aridity gradients in a South African shrub. AB - BACKGROUND AND AIMS: Trait-environment relationships are commonly interpreted as evidence for local adaptation in plants. However, even when selection analyses support this interpretation, the mechanisms underlying differential benefits are often unknown. This study addresses this gap in knowledge using the broadly distributed South African shrub Protea repens. Specifically, the study examines whether broad-scale patterns of trait variation are consistent with spatial differences in selection and ecophysiology in the wild. METHODS: In a common garden study of plants sourced from 19 populations, associations were measured between five morphological traits and three axes describing source climates. Trait-trait and trait-environment associations were analysed in a multi-response model. Within two focal populations in the wild, selection and path analyses were used to test associations between traits, fecundity and physiological performance. KEY RESULTS: Across 19 populations in a common garden, stomatal density increased with the source population's mean annual temperature and decreased with its average amount of rainfall in midsummer. Concordantly, selection analysis in two natural populations revealed positive selection on stomatal density at the hotter, drier site, while failing to detect selection at the cooler, moister site. Dry-site plants with high stomatal density also had higher stomatal conductances, cooler leaf temperatures and higher light-saturated photosynthetic rates than those with low stomatal density, but no such relationships were present among wet-site plants. Leaf area, stomatal pore index and specific leaf area in the garden also co-varied with climate, but within population differences were not associated with fitness in either wild population. CONCLUSIONS: The parallel patterns of broad-scale variation, differences in selection and differences in trait-ecophysiology relationships suggest a mechanism for adaptive differentiation in stomatal density. Densely packed stomata may improve performance by increasing transpiration and cooling, but predominately in drier, hotter climates. This study uniquely shows context dependent benefits of stomatal density--a trait rarely linked to local adaptation in plants. PMID- 26424783 TI - Phylogeography and modes of reproduction in diploid and tetraploid halophytes of Limonium species (Plumbaginaceae): evidence for a pattern of geographical parthenogenesis. AB - BACKGROUND AND AIMS: The genus Limonium (Plumbaginaceae) has long been recognized to have sexual and apomictic (asexual seed formation) modes of reproduction. This study aimed to elucidate phylogeographical patterns and modes of reproduction in diploid and tetraploid Limonium species, namely three putative sexual diploid species with morphological affinities (L. nydeggeri, L. ovalifolium, L. lanceolatum) and three related, probably apomict tetraploid species (L. binervosum, L. dodartii, L. multiflorum). METHODS: cpDNA diversity and differentiation between natural populations of the species were investigated using two chloroplast sequence regions (trnL intron and trnL-trnF intergenic spacer). Floral heteromorphies, ovule cytoembryological analyses and pollination and crossing tests were performed in representative species of each ploidy group, namely diploid L. ovalifolium and tetraploid L. multiflorum, using plants from greenhouse collections. KEY RESULTS AND CONCLUSIONS: Genetic analyses showed that diploid species have a higher haplotype diversity and a higher number of unique (endemic) haplotypes than tetraploid species. Network analysis revealed correlations between cpDNA haplotype distribution and ploidy groups, species groups and geographical origin, and haplotype sharing within and among species with distinct ploidy levels. Reproductive biology analyses showed that diploid L. ovalifolium mainly forms meiotically reduced tetrasporic embryo sacs of Gagea ova, Adoxa and Drusa types. Limonium multiflorum, however, has only unreduced, diplosporic (apomictic) embryo sacs of Rudbeckia type, and autonomous apomictic development seems to occur. Taken together, the findings provide evidence of a pattern of 'geographical parthenogenesis' in which quaternary climatic oscillations appear to be involved in the geographical patterns of coastal diploid and tetraploid Limonium species. PMID- 26424784 TI - Lower plasticity exhibited by high- versus mid-elevation species in their phenological responses to manipulated temperature and drought. AB - BACKGROUND AND AIMS: Recent global changes, particularly warming and drought, have had worldwide repercussions on the timing of flowering events for many plant species. Phenological shifts have also been reported in alpine environments, where short growing seasons and low temperatures make reproduction particularly challenging, requiring fine-tuning to environmental cues. However, it remains unclear if species from such habitats, with their specific adaptations, harbour the same potential for phenological plasticity as species from less demanding habitats. METHODS: Fourteen congeneric species pairs originating from mid and high elevation were reciprocally transplanted to common gardens at 1050 and 2000 m a.s.l. that mimic prospective climates and natural field conditions. A drought treatment was implemented to assess the combined effects of temperature and precipitation changes on the onset and duration of reproductive phenophases. A phenotypic plasticity index was calculated to evaluate if mid- and high-elevation species harbour the same potential for plasticity in reproductive phenology. KEY RESULTS: Transplantations resulted in considerable shifts in reproductive phenology, with highly advanced initiation and shortened phenophases at the lower (and warmer) site for both mid- and high-elevation species. Drought stress amplified these responses and induced even further advances and shortening of phenophases, a response consistent with an 'escape strategy'. The observed phenological shifts were generally smaller in number of days for high-elevation species and resulted in a smaller phenotypic plasticity index, relative to their mid-elevation congeners. CONCLUSIONS: While mid- and high-elevation species seem to adequately shift their reproductive phenology to track ongoing climate changes, high-elevation species were less capable of doing so and appeared more genetically constrained to their specific adaptations to an extreme environment (i.e. a short, cold growing season). PMID- 26424785 TI - Optimizing tiller production and survival for grain yield improvement in a bread wheat * spelt mapping population. AB - BACKGROUND AND AIMS: Tiller production and survival determine final spike number, and play key roles in grain yield formation in wheat (Triticum aestivum). This study aimed to understand the genetic and physiological basis of the tillering process, and its trade-offs with other yield components, by introducing genetic variation in tillering patterns via a mapping population of wheat * spelt (Triticum spelta). METHODS: The dynamics of tillering and red/far-red ratio (R:FR) at the base of a canopy arising from neighbouring plants in a bread wheat (Triticum aestivum 'Forno') * spelt (Triticum spelta 'Oberkulmer') mapping population were measured in the field in two growing seasons. Additional thinning and shading experiments were conducted in the field and glasshouse, respectively. Yield components were analysed for all experiments, followed by identification of quantitative trait loci (QTL) associated with each trait. KEY RESULTS: Large genetic variation in tillering was observed, and more fertile shoots per plant were associated with more total shoots initiated, faster tillering rate, delayed tillering onset and cessation, and higher shoot survival. A total of 34 QTL for tillering traits were identified, and analysis of allelic effects confirmed the above associations. Low R:FR was associated with early tillering cessation, few total shoots, high infertile shoot number and shoot abortion, and these results concurred with the thinning and shading experiments. These effects probably resulted from an assimilate shortage for tiller buds or developing tillers, due to early stem elongation and enhanced stem growth induced by low R:FR. More fertile tillers normally contributed to plant yield and grain number without reducing yield and grain set of individual shoots. However, there was a decrease in grain weight, partly because of smaller carpels and fewer stem water-soluble carbohydrates at anthesis caused by pleiotropy or tight gene linkages. CONCLUSIONS: Tillering is under the control of both genetic factors and R:FR. Genetic variation in tillering and tolerance to low R:FR can be used to optimize tillering patterns for yield improvement in wheat. PMID- 26424787 TI - Persistent pupillary membrane. PMID- 26424786 TI - G Protein-Coupled Bile Acid Receptor TGR5 Activation Inhibits Kidney Disease in Obesity and Diabetes. AB - Obesity and diabetes mellitus are the leading causes of renal disease. In this study, we determined the regulation and role of the G protein-coupled bile acid receptor TGR5, previously shown to be regulated by high glucose and/or fatty acids, in obesity-related glomerulopathy (ORG) and diabetic nephropathy (DN). Treatment of diabetic db/db mice with the selective TGR5 agonist INT-777 decreased proteinuria, podocyte injury, mesangial expansion, fibrosis, and CD68 macrophage infiltration in the kidney. INT-777 also induced renal expression of master regulators of mitochondrial biogenesis, inhibitors of oxidative stress, and inducers of fatty acid beta-oxidation, including sirtuin 1 (SIRT1), sirtuin 3 (SIRT3), and Nrf-1. Increased activity of SIRT3 was evidenced by normalization of the increased acetylation of mitochondrial superoxide dismutase 2 (SOD2) and isocitrate dehydrogenase 2 (IDH2) observed in untreated db/db mice. Accordingly, INT-777 decreased mitochondrial H2O2 generation and increased the activity of SOD2, which associated with decreased urinary levels of H2O2 and thiobarbituric acid reactive substances. Furthermore, INT-777 decreased renal lipid accumulation. INT-777 also prevented kidney disease in mice with diet-induced obesity. In human podocytes cultured with high glucose, INT-777 induced mitochondrial biogenesis, decreased oxidative stress, and increased fatty acid beta-oxidation. Compared with normal kidney biopsy specimens, kidney specimens from patients with established ORG or DN expressed significantly less TGR5 mRNA, and levels inversely correlated with disease progression. Our results indicate that TGR5 activation induces mitochondrial biogenesis and prevents renal oxidative stress and lipid accumulation, establishing a role for TGR5 in inhibiting kidney disease in obesity and diabetes. PMID- 26424788 TI - The clinical, occupational and financial outcomes associated with a bespoke specialist clinic for military aircrew-a cohort study. AB - OBJECTIVES: To assess the clinical, occupational and financial outcomes of a new Clinical Aviation Medicine Service (CAMS) for UK military personnel. METHODS: Consecutive patients over a 2 year period were included. Predictors of flying restrictions at referral and final outcome following consultation were modelled using logistic regression. National Health Service (NHS) Payment by Results tariffs and Defence capitation data were used to assess the financial impact of the service. RESULTS: Eight hundred and sixteen new referrals (94.5% male, median age 45 years (range 19-75)) were received and 1025 consultations performed. Cardiovascular disease was the commonest reason for referral. CAMS clinical activity cost at NHS tariff was L453 310 representing a saving of L316 173 (L137 137 delivery cost). In total, 310/816 (38%) patients had employment restrictions on referral and 49.0% of this group returned to full employment following their initial consultation. Compared with cardiology, general medicine and respiratory patients were more likely to have been occupationally restricted prior to referral (50 vs. 35%, OR 1.81; 95% CI 1.18-2.76, P values=0.006 and 53 vs. 35%, OR 2.12; 95% CI 1.15-3.90, P values = 0.016, respectively). Overall 581/816 (71.2%) of patients returned to unrestricted employment while 98/816 (12.0%) were unable to continue in any aircrew role. The service saved 7000 lost working days per year at an estimated occupational saving of ~L1 million per annum. CONCLUSIONS: This bespoke service has allowed rapid, occupationally relevant clinical care to be delivered with both time and financial savings. The model may have significant occupational and financial relevance for other environmental and occupational medical organizations. PMID- 26424789 TI - Pulmonary Langerhans Cell Histiocytosis in pre-existing chronic myelomonocytic leukaemia: a rare association. PMID- 26424790 TI - Epigenetic Control of Skeletal Development by the Histone Methyltransferase Ezh2. AB - Epigenetic control of gene expression is critical for normal fetal development. However, chromatin-related mechanisms that activate bone-specific programs during osteogenesis have remained underexplored. Therefore, we investigated the expression profiles of a large cohort of epigenetic regulators (>300) during osteogenic differentiation of human mesenchymal cells derived from the stromal vascular fraction of adipose tissue (AMSCs). Molecular analyses establish that the polycomb group protein EZH2 (enhancer of zeste homolog 2) is down-regulated during osteoblastic differentiation of AMSCs. Chemical inhibitor and siRNA knockdown studies show that EZH2, a histone methyltransferase that catalyzes trimethylation of histone 3 lysine 27 (H3K27me3), suppresses osteogenic differentiation. Blocking EZH2 activity promotes osteoblast differentiation and suppresses adipogenic differentiation of AMSCs. High throughput RNA sequence (mRNASeq) analysis reveals that EZH2 inhibition stimulates cell cycle inhibitory proteins and enhances the production of extracellular matrix proteins. Conditional genetic loss of Ezh2 in uncommitted mesenchymal cells (Prrx1-Cre) results in multiple defects in skeletal patterning and bone formation, including shortened forelimbs, craniosynostosis, and clinodactyly. Histological analysis and mRNASeq profiling suggest that these effects are attributable to growth plate abnormalities and premature cranial suture closure because of precocious maturation of osteoblasts. We conclude that the epigenetic activity of EZH2 is required for skeletal patterning and development, but EZH2 expression declines during terminal osteoblast differentiation and matrix production. PMID- 26424791 TI - Characterization of the Pseudomonas aeruginosa Glycoside Hydrolase PslG Reveals That Its Levels Are Critical for Psl Polysaccharide Biosynthesis and Biofilm Formation. AB - A key component of colonization, biofilm formation, and protection of the opportunistic human pathogen Pseudomonas aeruginosa is the biosynthesis of the exopolysaccharide Psl. Composed of a pentameric repeating unit of mannose, glucose, and rhamnose, the biosynthesis of Psl is proposed to occur via a Wzx/Wzy dependent mechanism. Previous genetic studies have shown that the putative glycoside hydrolase PslG is essential for Psl biosynthesis. To understand the function of this protein, the apo-structure of the periplasmic domain of PslG (PslG(31-442)) and its complex with mannose were determined to 2.0 and 1.9 A resolution, respectively. Despite a domain architecture and positioning of catalytic residues similar to those of other family 39 glycoside hydrolases, PslG(31-442) exhibits a unique 32-A-long active site groove that is distinct from other structurally characterized family members. PslG formed a complex with two mannose monosaccharides in this groove, consistent with binding data obtained from intrinsic tryptophan fluorescence. PslG was able to catalyze the hydrolysis of surface-associated Psl, and this activity was abolished in a E165Q/E276Q double catalytic variant. Surprisingly, P. aeruginosa variants with these chromosomal mutations as well as a pslG deletion mutant were still capable of forming Psl biofilms. However, overexpression of PslG in a pslG deletion background impaired biofilm formation and resulted in less surface-associated Psl, suggesting that regulation of this enzyme is important during polysaccharide biosynthesis. PMID- 26424792 TI - Reciprocal Phosphorylation and Palmitoylation Control Dopamine Transporter Kinetics. AB - The dopamine transporter is a neuronal protein that drives the presynaptic reuptake of dopamine (DA) and is the major determinant of transmitter availability in the brain. Dopamine transporter function is regulated by protein kinase C (PKC) and other signaling pathways through mechanisms that are complex and poorly understood. Here we investigate the role of Ser-7 phosphorylation and Cys-580 palmitoylation in mediating steady-state transport kinetics and PKC stimulated transport down-regulation. Using both mutational and pharmacological approaches, we demonstrate that these post-translational modifications are reciprocally regulated, leading to transporter populations that display high phosphorylation-low palmitoylation or low phosphorylation-high palmitoylation. The balance between the modifications dictates transport capacity, as conditions that promote high phosphorylation or low palmitoylation reduce transport Vmax and enhance PKC-stimulated down-regulation, whereas conditions that promote low phosphorylation or high palmitoylation increase transport Vmax and suppress PKC stimulated down-regulation. Transitions between these functional states occur when endocytosis is blocked or undetectable, indicating that the modifications kinetically regulate the velocity of surface transporters. These findings reveal a novel mechanism for control of DA reuptake that may represent a point of dysregulation in DA imbalance disorders. PMID- 26424793 TI - DISC1 Protein Regulates gamma-Aminobutyric Acid, Type A (GABAA) Receptor Trafficking and Inhibitory Synaptic Transmission in Cortical Neurons. AB - Association studies have suggested that Disrupted-in-Schizophrenia 1 (DISC1) confers a genetic risk at the level of endophenotypes that underlies many major mental disorders. Despite the progress in understanding the significance of DISC1 at neural development, the mechanisms underlying DISC1 regulation of synaptic functions remain elusive. Because alterations in the cortical GABA system have been strongly linked to the pathophysiology of schizophrenia, one potential target of DISC1 that is critically involved in the regulation of cognition and emotion is the GABAA receptor (GABAAR). We found that cellular knockdown of DISC1 significantly reduced GABAAR-mediated synaptic and whole-cell current, whereas overexpression of wild-type DISC1, but not the C-terminal-truncated DISC1 (a schizophrenia-related mutant), significantly increased GABAAR currents in pyramidal neurons of the prefrontal cortex. These effects were accompanied by DISC1-induced changes in surface GABAAR expression. Moreover, the regulation of GABAARs by DISC1 knockdown or overexpression depends on the microtubule motor protein kinesin 1 (KIF5). Our results suggest that DISC1 exerts an important effect on GABAergic inhibitory transmission by regulating KIF5/microtubule-based GABAAR trafficking in the cortex. The knowledge gained from this study would shed light on how DISC1 and the GABA system are linked mechanistically and how their interactions are critical for maintaining a normal mental state. PMID- 26424794 TI - The Silent Sway of Splicing by Synonymous Substitutions. AB - Alternative splicing diversifies mRNA transcripts in human cells. This sequence driven process can be influenced greatly by mutations, even those that do not change the protein coding potential of the transcript. Synonymous mutations have been shown to alter gene expression through modulation of splicing, mRNA stability, and translation. Using a synonymous position mutation library in SMN1 exon 7, we show that 23% of synonymous mutations across the exon decrease exon inclusion, suggesting that nucleotide identity across the entire exon has been evolutionarily optimized to support a particular exon inclusion level. Although phylogenetic conservation scores are insufficient to identify synonymous positions important for exon inclusion, an alignment of organisms filtered based on similar exon/intron architecture is highly successful. Although many of the splicing neutral mutations are observed to occur, none of the exon inclusion reducing mutants was found in the filtered alignment. Using the modified phylogenetic comparison as an approach to evaluate the impact on pre-mRNA splicing suggests that up to 45% of synonymous SNPs are likely to alter pre-mRNA splicing. These results demonstrate that coding and pre-mRNA splicing pressures co-evolve and that a modified phylogenetic comparison based on the exon/intron architecture is a useful tool in identifying splice altering SNPs. PMID- 26424795 TI - Homocitrullination Is a Novel Histone H1 Epigenetic Mark Dependent on Aryl Hydrocarbon Receptor Recruitment of Carbamoyl Phosphate Synthase 1. AB - The aryl hydrocarbon receptor (AhR), a regulator of xenobiotic toxicity, is a member of the eukaryotic Per-Arnt-Sim domain protein family of transcription factors. Recent evidence identified a novel AhR DNA recognition sequence called the nonconsensus xenobiotic response element (NC-XRE). AhR binding to the NC-XRE in response to activation by the canonical ligand 2,3,7,8-tetrachlorodibenzo-p dioxin resulted in concomitant recruitment of carbamoyl phosphate synthase 1 (CPS1) to the NC-XRE. Studies presented here demonstrate that CPS1 is a bona fide nuclear protein involved in homocitrullination (hcit), including a key lysine residue on histone H1 (H1K34hcit). H1K34hcit represents a hitherto unknown epigenetic mark implicated in enhanced gene expression of the peptidylarginine deiminase 2 gene, itself a chromatin-modifying protein. Collectively, our data suggest that AhR activation promotes CPS1 recruitment to DNA enhancer sites in the genome, resulting in a specific enzyme-independent post-translational modification of the linker histone H1 protein (H1K34hcit), pivotal in altering local chromatin structure and transcriptional activation. PMID- 26424796 TI - Adrenocorticotropic Hormone (ACTH) Responses Require Actions of the Melanocortin 2 Receptor Accessory Protein on the Extracellular Surface of the Plasma Membrane. AB - The melanocortin-2 (MC2) receptor is a G protein-coupled receptor that mediates responses to ACTH. The MC2 receptor acts in concert with the MC2 receptor accessory protein (MRAP) that is absolutely required for ACTH binding and signaling. MRAP has a single transmembrane domain and forms a highly unusual antiparallel homodimer that is stably associated with MC2 receptors at the plasma membrane. Despite the physiological importance of the interaction between the MC2 receptor and MRAP, there is little understanding of how the accessory protein works. The dual topology of MRAP has made it impossible to determine whether highly conserved and necessary regions of MRAP are required on the intracellular or extracellular face of the plasma membrane. The strategy used here was to fix the orientation of two antiparallel MRAP molecules and then introduce inactivating mutations on one side of the membrane or the other. This was achieved by engineering proteins containing tandem copies of MRAP fused to the amino terminus of the MC2 receptor. The data firmly establish that only the extracellular amino terminus (Nout) copy of MRAP, oriented with critical segments on the extracellular side of the membrane, is essential. The transmembrane domain of MRAP is also required in only the Nout orientation. Finally, activity of MRAP MRAP-MC2-receptor fusion proteins with inactivating mutations in either MRAP or the receptor was rescued by co-expression of free wild-type MRAP or free wild type receptor. These results show that the basic MRAP-MRAP-receptor signaling unit forms higher order complexes and that these multimers signal. PMID- 26424797 TI - PP2A/B56 and GSK3/Ras suppress PKB activity during Dictyostelium chemotaxis. AB - We have previously shown that the Dictyostelium protein phosphatase 2A regulatory subunit B56, encoded by psrA, modulates Dictyostelium cell differentiation through negatively affecting glycogen synthase kinase 3 (GSK3) function. Our follow-up research uncovered that B56 preferentially associated with GDP forms of RasC and RasD, but not with RasG in vitro, and psrA(-) cells displayed inefficient activation of multiple Ras species, decreased random motility, and inefficient chemotaxis toward cAMP and folic acid gradient. Surprisingly, psrA(-) cells displayed aberrantly high basal and poststimulus phosphorylation of Dictyostelium protein kinase B (PKB) kinase family member PKBR1 and PKB substrates. Expression of constitutively active Ras mutants or inhibition of GSK3 in psrA(-) cells increased activities of both PKBR1 and PKBA, but only the PKBR1 activity was increased in wild-type cells under the equivalent conditions, indicating that either B56- or GSK3-mediated suppressive mechanism is sufficient to maintain low PKBA activity, but both mechanisms are necessary for suppressing PKBR1. Finally, cells lacking RasD or RasC displayed normal PKBR1 regulation under GSK3-inhibiting conditions, indicating that RasC or RasD proteins are essential for GSK3-mediated PKBR1 inhibition. In summary, B56 constitutes inhibitory circuits for PKBA and PKBR1 and thus heavily affects Dictyostelium chemotaxis. PMID- 26424798 TI - Basic mechanism for biorientation of mitotic chromosomes is provided by the kinetochore geometry and indiscriminate turnover of kinetochore microtubules. AB - Accuracy of chromosome segregation relies on the ill-understood ability of mitotic kinetochores to biorient, whereupon each sister kinetochore forms microtubule (MT) attachments to only one spindle pole. Because initial MT attachments result from chance encounters with the kinetochores, biorientation must rely on specific mechanisms to avoid and resolve improper attachments. Here we use mathematical modeling to critically analyze the error-correction potential of a simplified biorientation mechanism, which involves the back-to-back arrangement of sister kinetochores and the marked instability of kinetochore-MT attachments. We show that a typical mammalian kinetochore operates in a near optimal regime, in which the back-to-back kinetochore geometry and the indiscriminate kinetochore-MT turnover provide strong error-correction activity. In human cells, this mechanism alone can potentially enable normal segregation of 45 out of 46 chromosomes during one mitotic division, corresponding to a mis segregation rate in the range of 10(-1)-10(-2) per chromosome. This theoretical upper limit for chromosome segregation accuracy predicted with the basic mechanism is close to the mis-segregation rate in some cancer cells; however, it cannot explain the relatively low chromosome loss in diploid human cells, consistent with their reliance on additional mechanisms. PMID- 26424799 TI - Spontaneous and electric field-controlled front-rear polarization of human keratinocytes. AB - It has long been known that electrical fields (EFs) are able to influence the direction of migrating cells, a process commonly referred to as electrotaxis or galvanotaxis. Most studies have focused on migrating cells equipped with an existing polarity before EF application, making it difficult to delineate EF specific pathways. Here we study the initial events in front-rear organization of spreading keratinocytes to dissect the molecular requirements for random and EF controlled polarization. We find that Arp2/3-dependent protrusive forces and Rac1/Cdc42 activity were generally required for both forms of polarization but were dispensable for controlling the direction of EF-controlled polarization. By contrast, we found a crucial role for extracellular pH as well as G protein coupled-receptor (GPCR) or purinergic signaling in the control of directionality. The normal direction of polarization toward the cathode was reverted by lowering extracellular pH. Polarization toward the anode was also seen at neutral pH when GPCR or purinergic signaling was inhibited. However, the stepwise increase of extracellular pH in this scenario led to restoration of cathodal polarization. Overall our work puts forward a model in which the EF uses distinct polarization pathways. The cathodal pathway involves GPCR/purinergic signaling and is dominant over the anodal pathway at neutral pH. PMID- 26424800 TI - gp78 functions downstream of Hrd1 to promote degradation of misfolded proteins of the endoplasmic reticulum. AB - Eukaryotic cells eliminate misfolded proteins from the endoplasmic reticulum (ER) via a conserved process termed ER-associated degradation (ERAD). Central regulators of the ERAD system are membrane-bound ubiquitin ligases, which are thought to channel misfolded proteins through the ER membrane during retrotranslocation. Hrd1 and gp78 are mammalian ubiquitin ligases homologous to Hrd1p, an ubiquitin ligase essential for ERAD in Saccharomyces cerevisiae. However, the functional relevance of these proteins to Hrd1p is unclear. In this paper, we characterize the gp78-containing ubiquitin ligase complex and define its functional interplay with Hrd1 using biochemical and recently developed CRISPR-based genetic tools. Our data show that transient inactivation of the gp78 complex by short hairpin RNA-mediated gene silencing causes significant stabilization of both luminal and membrane ERAD substrates, but unlike Hrd1, which plays an essential role in retrotranslocation and ubiquitination of these ERAD substrates, knockdown of gp78 does not affect either of these processes. Instead, gp78 appears to act downstream of Hrd1 to promote ERAD via cooperation with the BAG6 chaperone complex. We conclude that the Hrd1 complex forms an essential retrotranslocation module that is evolutionarily conserved, but the mammalian ERAD system uses additional ubiquitin ligases to assist Hrd1 during retrotranslocation. PMID- 26424801 TI - Probability-based particle detection that enables threshold-free and robust in vivo single-molecule tracking. AB - Single-molecule detection in fluorescence nanoscopy has become a powerful tool in cell biology but can present vexing issues in image analysis, such as limited signal, unspecific background, empirically set thresholds, image filtering, and false-positive detection limiting overall detection efficiency. Here we present a framework in which expert knowledge and parameter tweaking are replaced with a probability-based hypothesis test. Our method delivers robust and threshold-free signal detection with a defined error estimate and improved detection of weaker signals. The probability value has consequences for downstream data analysis, such as weighing a series of detections and corresponding probabilities, Bayesian propagation of probability, or defining metrics in tracking applications. We show that the method outperforms all current approaches, yielding a detection efficiency of >70% and a false-positive detection rate of <5% under conditions down to 17 photons/pixel background and 180 photons/molecule signal, which is beneficial for any kind of photon-limited application. Examples include limited brightness and photostability, phototoxicity in live-cell single-molecule imaging, and use of new labels for nanoscopy. We present simulations, experimental data, and tracking of low-signal mRNAs in yeast cells. PMID- 26424802 TI - Reorganization of actin filaments by ADF/cofilin is involved in formation of microtubule structures during Xenopus oocyte maturation. AB - We examined the reorganization of actin filaments and microtubules during Xenopus oocyte maturation. Surrounding the germinal vesicle (GV) in immature oocytes, the cytoplasmic actin filaments reorganized to accumulate beneath the vegetal side of the GV, where the microtubule-organizing center and transient microtubule array (MTOC-TMA) assembled, just before GV breakdown (GVBD). Immediately after GVBD, both Xenopus ADF/cofilin (XAC) and its phosphatase Slingshot (XSSH) accumulated into the nuclei and intranuclear actin filaments disassembled from the vegetal side with the shrinkage of the GV. As the MTOC-TMA developed well, cytoplasmic actin filaments were retained at the MTOC-TMA base region. Suppression of XAC dephosphorylation by anti-XSSH antibody injection inhibited both actin filament reorganization and proper formation and localization of both the MTOC-TMA and meiotic spindles. Stabilization of actin filaments by phalloidin also inhibited formation of the MTOC-TMA and disassembly of intranuclear actin filaments without affecting nuclear shrinkage. Nocodazole also caused the MTOC-TMA and the cytoplasmic actin filaments at its base region to disappear, which further impeded disassembly of intranuclear actin filaments from the vegetal side. XAC appears to reorganize cytoplasmic actin filaments required for precise assembly of the MTOC and, together with the MTOC-TMA, regulate the intranuclear actin filament disassembly essential for meiotic spindle formation. PMID- 26424803 TI - Intraflagellar transport is essential for mammalian spermiogenesis but is absent in mature sperm. AB - Drosophila sperm are unusual in that they do not require the intraflagellar transport (IFT) system for assembly of their flagella. In the mouse, the IFT proteins are very abundant in testis, but we here show that mature sperm are completely devoid of them, making the importance of IFT to mammalian sperm development unclear. To address this question, we characterized spermiogenesis and fertility in the Ift88(Tg737Rpw) mouse. This mouse has a hypomorphic mutation in the gene encoding the IFT88 subunit of the IFT particle. This mutation is highly disruptive to ciliary assembly in other organs. Ift88(-/-) mice are completely sterile. They produce ~ 350-fold fewer sperm than wild-type mice, and the remaining sperm completely lack or have very short flagella. The short flagella rarely have axonemes but assemble ectopic microtubules and outer dense fibers and accumulate improperly assembled fibrous sheath proteins. Thus IFT is essential for the formation but not the maintenance of mammalian sperm flagella. PMID- 26424804 TI - Dual pulse-chase microscopy reveals early divergence in the biosynthetic trafficking of the Na,K-ATPase and E-cadherin. AB - Recent evidence indicates that newly synthesized membrane proteins that share the same distributions in the plasma membranes of polarized epithelial cells can pursue a variety of distinct trafficking routes as they travel from the Golgi complex to their common destination at the cell surface. In most polarized epithelial cells, both the Na,K-ATPase and E-cadherin are localized to the basolateral domains of the plasma membrane. To examine the itineraries pursued by newly synthesized Na,K-ATPase and E-cadherin in polarized MDCK epithelial cells, we used the SNAP and CLIP labeling systems to fluorescently tag temporally defined cohorts of these proteins and observe their behaviors simultaneously as they traverse the secretory pathway. These experiments reveal that E-cadherin is delivered to the cell surface substantially faster than is the Na,K-ATPase. Furthermore, the surface delivery of newly synthesized E-cadherin to the plasma membrane was not prevented by the 19 degrees C temperature block that inhibits the trafficking of most proteins, including the Na,K-ATPase, out of the trans Golgi network. Consistent with these distinct behaviors, populations of newly synthesized E-cadherin and Na,K-ATPase become separated from one another within the trans-Golgi network, suggesting that they are sorted into different carrier vesicles that mediate their post-Golgi trafficking. PMID- 26424806 TI - A Comparison of Two Strategies for Building an Exposure Prediction Model. AB - Cost-efficient assessments of job exposures in large populations may be obtained from models in which 'true' exposures assessed by expensive measurement methods are estimated from easily accessible and cheap predictors. Typically, the models are built on the basis of a validation study comprising 'true' exposure data as well as an extensive collection of candidate predictors from questionnaires or company data, which cannot all be included in the models due to restrictions in the degrees of freedom available for modeling. In these situations, predictors need to be selected using procedures that can identify the best possible subset of predictors among the candidates. The present study compares two strategies for selecting a set of predictor variables. One strategy relies on stepwise hypothesis testing of associations between predictors and exposure, while the other uses cluster analysis to reduce the number of predictors without relying on empirical information about the measured exposure. Both strategies were applied to the same dataset on biomechanical exposure and candidate predictors among computer users, and they were compared in terms of identified predictors of exposure as well as the resulting model fit using bootstrapped resamples of the original data. The identified predictors were, to a large part, different between the two strategies, and the initial model fit was better for the stepwise testing strategy than for the clustering approach. Internal validation of the models using bootstrap resampling with fixed predictors revealed an equally reduced model fit in resampled datasets for both strategies. However, when predictor selection was incorporated in the validation procedure for the stepwise testing strategy, the model fit was reduced to the extent that both strategies showed similar model fit. Thus, the two strategies would both be expected to perform poorly with respect to predicting biomechanical exposure in other samples of computer users. PMID- 26424805 TI - Emissions from a Diesel Engine using Fe-based Fuel Additives and a Sintered Metal Filtration System. AB - A series of laboratory tests were conducted to assess the effects of Fe containing fuel additives on aerosols emitted by a diesel engine retrofitted with a sintered metal filter (SMF) system. Emission measurements performed upstream and downstream of the SMF system were compared, for cases when the engine was fueled with neat ultralow sulfur diesel (ULSD) and with ULSD treated with two formulations of additives containing Fe-based catalysts. The effects were assessed for four steady-state engine operating conditions and one transient cycle. The results showed that the SMF system reduced the average total number and surface area concentrations of aerosols by more than 100-fold. The total mass and elemental carbon results confirmed that the SMF system was indeed very effective in the removal of diesel aerosols. When added at the recommended concentrations (30 p.p.m. of iron), the tested additives had minor adverse impacts on the number, surface area, and mass concentrations of filter-out (FOut) aerosols. For one of the test cases, the additives may have contributed to measurable concentrations of engine-out (EOut) nucleation mode aerosols. The additives had only a minor impact on the concentration and size distribution of volatile and semi-volatile FOut aerosols. Metal analysis showed that the introduction of Fe with the additives substantially increased Fe concentration in the EOut, but the SMF system was effective in removal of Fe-containing aerosols. The FOut Fe concentrations for all three tested fuels were found to be much lower than the corresponding EOut Fe concentrations for the case of untreated ULSD fuel. The results support recommendations that these additives should not be used in diesel engines unless they are equipped with exhaust filtration systems. Since the tested SMF system was found to be very efficient in removing Fe introduced by the additives, the use of these additives should not result in a measurable increase in emissions of de novo generated Fe-containing aerosols. The findings from this study should promote a better understanding of the benefits and challenges of using sintered metal systems and fuel additives to control the exposure of underground miners and other workers to diesel aerosols and gases. PMID- 26424807 TI - Early adolescent Depo-Provera exposure increases stillbirths in adult sooty mangabeys. AB - The 3-month injectable contraceptive medroxyprogesterone acetate (MPA; Depo Provera) is a synthetic progestin that protects against pregnancy by suppressing ovulation. Studies have focused on the resumption of ovulation after MPA treatment cessation but neglected potential long-term effects of MPA exposure on future successful reproduction. MPA is frequently administered to adolescent girls; however, long-term fertility effects of adolescent MPA exposure have not been explored. We investigated fertility after extended MPA exposure in a species of old world primate, the sooty mangabey (Cercocebus atys). Female sooty mangabeys (n=31) received chronic MPA-treatment for 4-8 years. At MPA-treatment onset, subjects were either parous adults (n=14) or nulliparous adolescents (n=17), with adolescent-treated subjects being further divided into those who had reached first ovulation (n=10) and those who had not (n=7). After MPA-treatment cessation, adolescent-treated females had a significantly higher incidence of stillbirth than did age-matched and parity-matched controls, whereas adult treated females did not differ from their matched controls. Females placed on MPA treatment prior to first ovulation had a significantly higher incidence of stillbirth post-treatment than did females placed on MPA-treatment after first ovulation. Diabetic females had an increased incidence of stillbirth as compared to nondiabetic females; however, when controlling for diabetes, MPA exposure prior to first ovulation was still a significant positive predictor of stillbirth. These findings suggest that the post-treatment fertility effects of chronic MPA exposure vary with the developmental timing of treatment onset and raise concern about the use of MPA as a contraceptive for adolescent girls. PMID- 26424808 TI - Potential role of autophagy in the bactericidal activity of human PMNs for Bacillus anthracis. AB - Bacillus anthracis, the causative agent of anthrax, is acquired by mammalian hosts from the environment, as quiescent endospores. These endospores must germinate inside host cells, forming vegetative bacilli, before they can express the virulence factors that enable them to evade host defenses and disseminate throughout the body. While the role of macrophages and dendritic cells in this initial interaction has been established, the role of polymorphonuclear leukocytes (PMNs) has not been adequately defined. We discovered that while B. anthracis 34F2 Sterne endospores germinate poorly within non-activated human PMNs, these phagocytes exhibit rapid microbicidal activity toward the outgrown vegetative bacilli, independent of superoxide and nitric oxide. These findings suggest that a non-free radical pathway kills B. anthracis bacilli. We also find in PMNs an autophagic mechanism of bacterial killing based on the rapid induction of LC-3 conversion, beclin-1 expression, sequestosome 1 (SQSTM1) degradation and inhibition of bactericidal activity by the inhibitor, 3-methyladenine. These findings extend to PMNs an autophagic bactericidal mechanism previously described for other phagocytes. PMID- 26424809 TI - Factors affecting well-being in adults recently diagnosed with rheumatoid arthritis. AB - This article examines role stress, key psychosocial variables, and well-being in adults recently diagnosed with rheumatoid arthritis. Patients recently diagnosed with rheumatoid arthritis must often learn to balance disease and role-related responsibilities. This was cross-sectional, descriptive study ( N = 80). Data were analyzed using correlation coefficients and linear regression models. Participants were predominantly female (78%), married, and employed. Mean age and disease duration were 54.2 years and 24.2 months, respectively. The findings suggest that well-being is influenced by feelings of being self-efficacious and having balance in their roles and less to do with social support received from others. PMID- 26424810 TI - Exploring gender and identity issues among female adolescent and young adults who connect in an anonymous platform. AB - There has been an increased usage of online cancer support groups as a resource for health-related information and social support. This work analyzes message blog posts from an anonymous online support community to better understand issues related to gender and identity among female adolescent and young adults. This work sheds further light into the nuances of gender and identity issues including motherhood and reproductive issues, physical appearance, and romantic relationships. Specifically, findings reveal that female adolescent and young adults experience issues pertaining to infertility, feeling like a bad mom, hair loss, scarring, dating, and intimacy. These findings of this work offer further guidance about how healthcare providers and caregivers can attempt to meet the needs of female adolescent and young adults. PMID- 26424811 TI - Anxiety prior to breast biopsy: Relationships with length of time from breast biopsy recommendation to biopsy procedure and psychosocial factors. AB - This study investigated how time from breast biopsy recommendation to biopsy procedure affected pre-biopsy anxiety ( N = 140 women), and whether the relationship between wait time and anxiety was affected by psychosocial factors (chronic life stress, traumatic events, social support). Analyses showed a significant interaction between wait time and chronic life stress. Increased time from biopsy recommendation was associated with greater anxiety in women with low levels of life stress. Women with high levels of life stress experienced increased anxiety regardless of wait time. These results suggest that women may benefit from shorter wait times and receiving strategies for managing anxiety. PMID- 26424813 TI - Antiphospholipid syndrome presenting as cerebral venous sinus thrombosis: a case series and a review. AB - The cerebral venous sinus system is a rare site for venous thrombosis except in patients with antiphospholipid syndrome. We describe three patients presenting with cerebral venous thrombosis in association with other thrombotic sites in two patients and as an only site in one patient. Antiphospholipid syndrome has varied clinical manifestations but the defining feature is the persistent presence of antiphospholipid antibodies. In this report we will review the clinical and laboratory diagnostic criteria and the management of patients with antiphospholipid syndrome. PMID- 26424812 TI - Following the Footsteps of Chlamydial Gene Regulation. AB - Regulation of gene expression ensures an organism responds to stimuli and undergoes proper development. Although the regulatory networks in bacteria have been investigated in model microorganisms, nearly nothing is known about the evolution and plasticity of these networks in obligate, intracellular bacteria. The phylum Chlamydiae contains a vast array of host-associated microbes, including several human pathogens. The Chlamydiae are unique among obligate, intracellular bacteria as they undergo a complex biphasic developmental cycle in which large swaths of genes are temporally regulated. Coupled with the low number of transcription factors, these organisms offer a model to study the evolution of regulatory networks in intracellular organisms. We provide the first comprehensive analysis exploring the diversity and evolution of regulatory networks across the phylum. We utilized a comparative genomics approach to construct predicted coregulatory networks, which unveiled genus- and family specific regulatory motifs and architectures, most notably those of virulence associated genes. Surprisingly, our analysis suggests that few regulatory components are conserved across the phylum, and those that are conserved are involved in the exploitation of the intracellular niche. Our study thus lends insight into a component of chlamydial evolution that has otherwise remained largely unexplored. PMID- 26424814 TI - Adverse histological features in malignant colorectal polyps: a contemporary series of 239 cases. AB - AIMS: Screening colonoscopy has led to more colorectal carcinomas presenting at an early stage potentially curable by endoscopic resection. In this study, we examined the clinical and histological features of a contemporary series of malignant colorectal polyps (MCPs) with subsequent surgical resection. METHODS: We conducted a retrospective study on a consecutive series of MCPs from 239 patients, predominantly males (57.7%) with a median age of 66 years, and assessed histological parameters associated with residual disease on the surgical specimens. RESULTS: Median MCP size was 18.6 mm, with 23.1% polyps measuring <=10 mm. From the 140 surgical resection specimens, residual disease was identified in 20 cases, including 12 cases with metastatic lymph nodes and/or 9 cases with residual carcinoma in the large bowel wall. Histological parameters associated with nodal metastases were greater width and greater depth of the invasive component (p=0.001 and 0.006, respectively), poor differentiation (p=0.003) and a cribriform pattern (p=0.01). The risk of nodal metastases was 23.3% if two or three of these features were identified, while it was 0% and 4.5% if none or one was present, respectively. A positive margin was not associated with nodal metastasis and might be adequately treated by local endoscopic resection. CONCLUSIONS: Surgical resection should be recommended if >=2 of these adverse histological features are present and may be warranted if one feature is present. A positive margin may require additional local resection but not necessarily surgery if no other adverse factors are present. PMID- 26424815 TI - Curculigo orchioides Gaertn Effectively Ameliorates the Uro- and Nephrotoxicities Induced by Cyclophosphamide Administration in Experimental Animals. AB - Background Curculigo orchioides Gaertn is an ancient medicinal plant (Family: Amaryllidaceae), well known for its immunomodulatory and rejuvenating effects. Cyclophosphamide (CPA) is an alkylating agent widely used for treating a variety of human malignancies, but associated with different toxicities too. Our previous reports regarding the hemoprotective and hepatoprotective effects of the plant against CPA toxicities provide the background for the present study, which is designed to analyze the ameliorative effect of the methanolic extract of C orchioides on the urotoxicity and nephrotoxicity induced by CPA. Methods CPA was administered to male Swiss albino mice at a single dose of 1.5 mmol/kg body weight to induce urotoxicity after 5 days of prophylactic treatment with C orchioides extract (20 mg/kg body weight). Mesna (2-mercaptoethanesulfonate) was used as a control drug. Serum, tissue, and urine levels of kidney function markers and antioxidant levels were checked along with the serum cytokine levels. Results The plant extract was found to be effective in ameliorating the urotoxic and nephrotoxic side effects of CPA. Upregulation of serum interferon-gamma and interleukin-2 levels were observed with C orchioides treatment, which was decreased by CPA administration. Besides these, serum tumor necrosis factor-alpha level was also downregulated by C orchioides treatment. Conclusion Curculigo orchioides was found to be effective against the CPA-induced bladder and renal toxicities by its antioxidant capability and also by regulating the pro inflammatory cytokine levels. PMID- 26424817 TI - Pool palms. PMID- 26424816 TI - AMPK Inhibits the Stimulatory Effects of TGF-beta on Smad2/3 Activity, Cell Migration, and Epithelial-to-Mesenchymal Transition. AB - AMP-activated protein kinase (AMPK), an important downstream effector of the tumor suppressor liver kinase 1 (LKB1) and pharmacologic target of metformin, is well known to exert a preventive and inhibitory effect on tumorigenesis; however, its role in cancer progression and metastasis has not been well characterized. The present study investigates the potential roles of AMPK in inhibiting cancer cell migration and epithelial-to-mesenchymal transition (EMT) by regulating the canonical transforming growth factor beta (TGF-beta) signaling pathway, an important promoting factor for cancer progression. Our results showed that activation of AMPK by metformin inhibited TGF-beta-induced Smad2/3 phosphorylation in cancer cells in a dose-dependent manner. The effect of metformin is dependent on the presence of LKB1. A similar effect was obtained by expressing a constitutive active mutant of AMPKalpha1 subunit, whereas the expression of a dominant negative mutant of AMPKalpha1 or ablation of AMPKalpha subunits greatly enhanced TGF-beta stimulation of Smad2/3 phosphorylation. As a consequence, expression of genes downstream of Smad2/3, including plasminogen activator inhibitor-1, fibronectin, and connective tissue growth factor, was suppressed by metformin in a LKB1-dependent fashion. In addition, metformin blocked TGF-beta-induced inteleukin-6 expression through both LKB1-dependent and independent mechanisms. Our results also indicate that activation of LKB1/AMPK inhibits TGF-beta-stimulated cancer cell migration. Finally, TGF-beta induction of EMT was inhibited by phenformin and enhanced by knockdown of LKB1 expression with shRNA. Together, our data suggest that AMPK could be a drug target for controlling cancer progression and metastasis. PMID- 26424818 TI - Granulomatous-lymphocytic interstitial lung disease and recurrent sinopulmonary infections in a patient with Good's syndrome. AB - Good's syndrome is a rare primary immunodeficiency associated with adult thymoma. Complications are mainly autoimmune manifestations and recurrent infections with encapsulated bacteria. Only one possible case of combined granulomatous lymphocytic interstitial lung disease (GL-ILD) and Good's syndrome have been described earlier, but the patient died at the time of diagnosis. This is the first case of GL-ILD in Good's syndrome with a successful outcome. We present a case of a 43-year-old man with GL-ILD, who suffered from recurrent infections of Haemophilus influenzae and Pneumocystis jirovecii, with 8-year follow-up. After a thymectomy, he was diagnosed with Good's syndrome and GL-ILD. He was treated with prophylactic pivampicillin, quinolones and cephalosporins for his recurrent P. jirovecii and H. influenzae infections, an approach that proved unsuccessful due to resistance, with relapse after cessation. He was stabilised with oral diaminodiphenyl-sulfone for P. jirovecii and colistimethate-sodium inhalations for H. influenzae, which is a new approach to prophylactic treatment. PMID- 26424819 TI - Transscleral cyclophotocoagulation in refractory acute and chronic angle closure glaucoma. AB - Angle closure glaucoma, both acute and chronic, is a major cause of blindness worldwide. Transscleral cyclophotocoagulation (TSCP) is conventionally undertaken non-urgently in patients with advanced glaucoma and poor visual potential with poor control of intraocular pressure (IOP). We describe a case of a patient with refractory acute angle closure glaucoma and severe pain in whom emergency TSCP was undertaken 12 h after presentation, reducing the IOP from 68 to 10 mm Hg. Further, a patient with chronic angle closure glaucoma underwent TSCP, reducing the IOP from 78 to 14 mm Hg. Both patients consequently underwent uneventful phacoemulsification cataract surgery with preservation of visual acuity and long term IOP control. TSCP may achieve prompt IOP control and symptomatic relief in the acute setting in patients with acute and chronic forms of angle closure glaucoma refractory to medical therapy. TSCP may reduce the risk of definitive surgical intervention by temporising phacoemulsification or trabeculectomy surgery until the IOP is well controlled. PMID- 26424820 TI - Dysplasia epiphysealis hemimelica of the ankle: a fracture-like rare developmental disorder. AB - Dysplasia epiphysealis hemimelica is a rare developmental disorder which affects the epiphyses. We report a case of the disease located in the ankle joint, referred to our clinic with the initial misdiagnosis of a Salter-Harris 3 type fracture of the distal epiphysis of the tibia. After correct diagnosis, the patient was treated surgically with the excision of the cartilaginous masses. Taking an accurate medical history and performing adequate imaging studies is essential in diagnosing and treating this disease. Fracture-like epiphyseal configurations in patients with no history of injury should raise suspicion of periarticular developmental disorders. PMID- 26424821 TI - A case of metastatic adenocarcinoma on a background of penoscrotal extramammary Paget's disease. AB - A 77-year-old man presented with a chronic lesion located in the left penoscrotal area. Apart from pruritus, bleeding and an occasional discharge from this area, he also reported reduced appetite and weight loss. Examination revealed an ulcerated skin lesion attached to a firm subcutaneous mass. Wide local excision of the lesion revealed invasive adenocarcinoma on a background of extramammary Paget's disease. Staging studies showed disseminated metastatic disease within the lymph nodes, and liver and bone metastases. He was treated with carboplatin and paclitaxel chemotherapy initially, but then continued only on Carboplatin chemotherapy due to side effects from Paclitaxel. Eleven weeks after the start of his chemotherapy, his restaging imaging showed reduced lymphadenopathy, unchanged liver metastasis and sclerosis of bone metastasis. With completion of chemotherapy, repeat imaging showed stable disease. The patient is currently on follow-up. PMID- 26424822 TI - Neglected partial denture in the lower oesophagus presenting after 7 days. AB - Accidental ingestion of a denture is an acute emergency, and the denture is usually removed on the same day it is discovered. We present a patient who had a seizure while asleep, during which his denture broke; he accidentally swallowed a major part of it, which had a clasp attached. He was unaware that he had ingested the denture, since he was asymptomatic, but he started developing symptoms after 5 days and presented to us on the eighth day of ingestion. With much difficulty, the impacted section of the denture in the distal oesophagus was removed with the combined effort of flexible endoscopy and a rigid oesophagoscopy. Post-procedure, the patient developed mediastinitis, which was managed conservatively; he is doing well on follow-up. PMID- 26424823 TI - A painless pelvic wall ectopic pregnancy. AB - A 38-year-old woman presented with light vaginal bleeding at approximately 8 weeks gestation. Although she initially presented to accident and emergency with vaginal bleeding and menstrual-like pain, this rapidly settled and both symptoms resolved over the following days. An initial ultrasound scan revealed an empty uterus, with no adnexal masses or free fluid. Miscarriage was presumed. However, following suboptimal beta-human chorionic gonadotropin decline, further ultrasonography noted a mass next to the right ovary. The patient underwent laparoscopy, revealing an ectopic pregnancy closely adherent to the peritoneum of the right pelvic wall. The patient was treated with systemic methotrexate and responded well. This rare form of ectopic pregnancy has a high maternal morbidity and mortality, and its optimal management is not definitively decided, due to the scarcity of the condition and subsequent lack of high-powered data. We present a case of successful medical management. PMID- 26424824 TI - An interesting case of an antihypertensive causing post-prostatectomy incontinence. AB - A 70-year-old man underwent a laparoscopic radical prostatectomy with preservation of bladder neck for T3aN0R0 prostate cancer in December 2009, (Gleason 4+3, negative surgical margin). His postoperative prostate-specific antigen rose from 0.01 to 0.05 ng/mL over 19 months. He had salvage radiotherapy in May 2012. Following radiotherapy, his urinary control worsened and he needed to wear up to four pads per day. He was being considered for an artificial urinary sphincter placement. He was also taking doxazosin for hypertension, which was discontinued. After stopping the doxazosin, his urinary control improved and he did not require any further intervention. Doctors should be aware of the effect of alpha-blockers on the internal sphincter and the risk of incontinence in patients post-prostate cancer treatment. PMID- 26424826 TI - A predictable but life-threatening complication of hydroxyurea in a patient with sickle cell anaemia: an experience learned from a Jehovah's Witness. AB - It is well known that hydroxyurea can cause pancytopaenia secondary to bone marrow suppression, which is reversible with short-term discontinuation of the therapy. However, it is important to note that bone marrow suppressive effects caused by hydroxyurea could be easily potentiated in patients with sickle cell anaemia complicated by chronic kidney disease (CKD). We present a case of a Jehovah's Witness with sickle cell anaemia, who developed severe bone marrow suppression due to the combined effects of hydroxyurea and CKD, resulting in a prolonged recovery period after discontinuation of hydroxyurea. PMID- 26424825 TI - Intestinal ganglioneuromatosis: an unusual aetiology for occult gastrointestinal bleeding. AB - Intestinal ganglioneuromatosis is a rare disorder of the enteric nervous system. It is often associated with neurofibromatosis type 1 and multiple endocrine neoplasia type 2b but, more rarely, it can present in a sporadic and isolated form. A 66-year-old man presented with a 14-year history of iron deficiency anaemia, with no visible bleeding, requiring occasional blood transfusions. Haematological causes of anaemia were thoroughly excluded, and conventional endoscopic and radiological examinations showed no lesions. Capsule enteroscopy identified an ulcerated stenosis in the small bowel, but the biopsies taken at balloon enteroscopy were inconclusive. The patient underwent a laparotomy, which revealed a stiff and ulcerated stenosis in the ileum. Histological analysis demonstrated the presence of diffuse intestinal ganglioneuromatosis. Three years after surgery, the patient is asymptomatic, with normal haemoglobin levels. This case demonstrates an isolated form of intestinal ganglioneuromatosis, with an atypical presentation, difficult to diagnose despite an exhaustive evaluation. PMID- 26424827 TI - Renal fibromuscular dysplasia. PMID- 26424828 TI - Treatment of peritoneal metastases from colorectal cancer. AB - Peritoneal seedings of a colorectal tumor represent the second most frequent site of metastasis (after the liver). In the era of 5-fluorouracil (5-FU)-only chemotherapy, the prognosis was poor for colorectal cancer with peritoneal metastases. Within the last few years, new chemotherapeutic and targeted agents have improved the prognosis; however, the response to these treatments seems to be lower than that for liver metastases. The combination of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have further improved both disease free survival and overall survival. Keeping this in mind, every patient presenting with peritoneal metastases from colorectal cancer should be evaluated and receive adequate treatment, if possible in the above-mentioned combination. This paper reviews recent advancements in the therapy of peritoneal carcinomatosis. PMID- 26424830 TI - Insulin-Like Growth Factor-1 Related to Disability Among Older Adults. AB - BACKGROUND: Disability is a crucial health problem in aging. Identifying a biological contributory factor would be useful. Serum insulin-like growth factor 1 (IGF-1) plays an important role in the endocrine system and is associated with frailty. However, there is no consensus about the relationship between IGF-1 and disability. This study aimed to examine whether IGF-1 related to incident disability among older adults. METHODS: The study included 4,133 older adults (mean age, 71.8+/-5.4 years) who were participants in the "Obu Study of Health Promotion for the Elderly" cohort study. We collected information on demographic variables, measured gait speed, Mini Mental State Examination score, and serum IGF-1 at baseline. During follow-up, incident disability was monitored by Long Term Care Insurance certification. RESULTS: Disability was observed in 212 participants during a mean follow-up duration period of 29.2 months. A log rank test indicated that lower levels of serum IGF-1 were related to incident disability (p = .004). A Cox hazard regression showed a lower quartile in IGF-1 related to disability compared with the highest quartile (Q4), even when adjusting for covariates including gait speed and Mini Mental State Examination score (Q1: hazard ratio = 1.72, 95% confidence intervals: 1.06-2.81; Q2: hazard ratio = 1.64, 95% confidence intervals: 0.99-2.71; Q3: hazard ratio = 1.31, 95% confidence intervals: 0.76-2.25). In the analysis, stratified by sex, there was also significant relationship between IGF-1 and disability among women, but not men. CONCLUSIONS: Lower serum IGF-1 was independently related to disability among older adults. PMID- 26424829 TI - Budding off: bringing functional genomics to Candida albicans. AB - Candida species are the most prevalent human fungal pathogens, with Candida albicans being the most clinically relevant species. Candida albicans resides as a commensal of the human gastrointestinal tract but is a frequent cause of opportunistic mucosal and systemic infections. Investigation of C. albicans virulence has traditionally relied on candidate gene approaches, but recent advances in functional genomics have now facilitated global, unbiased studies of gene function. Such studies include comparative genomics (both between and within Candida species), analysis of total RNA expression, and regulation and delineation of protein-DNA interactions. Additionally, large collections of mutant strains have begun to aid systematic screening of clinically relevant phenotypes. Here, we will highlight the development of functional genomics in C. albicans and discuss the use of these approaches to addressing both commensalism and pathogenesis in this species. PMID- 26424831 TI - Cytomegalovirus IgG Level and Avidity in Breastfeeding Infants of HIV-Infected Mothers in Malawi. AB - Cytomegalovirus (CMV) infection is common among infants of HIV-infected mothers in resource-limited settings. We examined the prevalence and timing of infant CMV infection during the first year of life using IgG antibody and avidity among HIV exposed infants in Malawi and correlated the results with the presence of detectable CMV DNA in the blood. The Breastfeeding, Antiretrovirals and Nutrition (BAN) study randomized 2,369 mothers and their infants to maternal antiretrovirals, infant nevirapine, or neither for 28 weeks of breastfeeding, followed by weaning. Stored plasma specimens were tested for CMV IgG and antibody avidity from a random subset of infants who had been previously tested with blood CMV PCR and had available specimens at birth and at 24 and 48 weeks of age. Ninety-four of 127 infants (74.0%) tested at 24 weeks of age had CMV IgG of low or intermediate avidity, signifying primary CMV infections. An additional 22 infants (17.3%) had IgG of high avidity; 19 of them had CMV DNA detected in their blood, indicating infant infections. Taken together, these results show that the estimated prevalence of CMV infection at 24 weeks was 88.9%. By 48 weeks of age, 81.3% of infants had anti-CMV IgG; most of them (70.9%) had IgG of high avidity. The CMV serology and avidity testing, combined with the PCR results, confirmed a high rate of primary CMV infection by 6 months of life among breastfeeding infants of HIV-infected mothers. The CMV PCR in blood detected most, but not all, infant CMV infections. PMID- 26424832 TI - Susceptibility of Meningococcal Strains Responsible for Two Serogroup B Outbreaks on U.S. University Campuses to Serum Bactericidal Activity Elicited by the MenB 4C Vaccine. AB - In 2013 and 2014, two U.S. universities had meningococcal serogroup B outbreaks (a total of 14 cases) caused by strains from two different clonal complexes. To control the outbreaks, students were immunized with a serogroup B meningococcal vaccine (Novartis) that was not yet licensed in the United States. The vaccine (referred to as MenB-4C) contains four components capable of eliciting bactericidal activity. Both outbreak strains had high expression levels of two of the vaccine antigens (subfamily B factor H binding protein [FHbp] and neisserial heparin binding antigen [NHba]); the university B outbreak strain also had moderate expression of a third antigen, NadA. We investigated the bactericidal activity of sera from mice immunized with FHbp, NHba, or NadA and sera from MenB 4C-immunized infant macaques and an adult human. The postimmunization bactericidal activity of the macaque or human serum against isolates from university B with FHbp identification (ID) 1 that exactly matched the vaccine FHbp sequence variant was 8- to 21-fold higher than that against isolates from university A with FHbp ID 276 (96% identity to the vaccine antigen). Based on the bactericidal activity of mouse antisera to FHbp, NadA, or NHba and macaque or human postimmunization serum that had been depleted of anti-FHbp antibody, the bactericidal activity against both outbreak strains largely or entirely resulted from antibodies to FHbp. Thus, despite the high level of strain expression of FHbp from a subfamily that matched the vaccine antigen, there can be large differences in anti-FHbp bactericidal activity induced by MenB-4C vaccination. Further, strains with moderate to high NadA and/or NHba expression can be resistant to anti-NadA or anti-NHba bactericidal activity elicited by MenB-4C vaccination. PMID- 26424834 TI - Vasculopathy-related clinical and pathological features are associated with severe juvenile dermatomyositis. AB - OBJECTIVE: Outcome of JDM is highly heterogeneous. Our objective was to determine clinical and muscle biopsy features associated with poor outcome and response to treatment. METHODS: Clinical data and muscle biopsy were obtained from a monocentric cohort of 29 patients. Clinical subgroups were defined by latent class model analysis of initial and follow-up parameters. Myopathological features were analysed using validated scores. Capillary loss was determined on reconstructions of transversal sections and assessed in the different age groups to take into account variations of muscle capillarization during post-natal development. Regression models were used to identify initial predictors of therapeutic response. RESULTS: Two distinct homogeneous subgroups of patients were identified according to clinical severity and pathological findings. The smallest group of patients (7/29) presented with severe JDM. Compared with the other group (22/29), patients had more severe muscle weakness at disease onset, low remission rate at 12 months, frequent subcutaneous limb oedema or gastrointestinal (GI) involvement and higher myopathological scores (capillary dropout, perifascicular necrosis/regeneration, fibres with internal myonuclei and fibrosis subscores). Relevance of capillary dropout to JDM severity was substantiated by age-based analysis, confirming its major role in JDM pathophysiology. Most of these manifestations could be related to vasculopathy (limb oedema, GI involvement, capillary dropout). Furthermore, Childhood Myositis Assessment Scale <34 with either GI involvement or muscle endomysial fibrosis at disease onset were the best predictors of poor response to treatment. CONCLUSION: Vasculopathy is prominent in severe JDM. Simple criteria can be used at initial evaluation to identify patients requiring a more intensive therapy. PMID- 26424833 TI - Perceived Control Moderates the Effects of Functional Limitation on Older Adults' Social Activity: Findings From the Australian Longitudinal Study of Ageing. AB - Objectives: Research has shown that functional limitation is related to reduced social activity in older adults; however, individuals with high perceived control have greater confidence in their ability to achieve outcomes and are more likely to show persistence and employ strategies to overcome challenges. The aim of this study was to examine whether perceived control protects against the negative effects of functional limitation on older adults' social activity. Method: Participants were 835 older adults aged 69 to 103 years at baseline from the Australian Longitudinal Study of Ageing. Multilevel modeling was used to examine baseline and within-person change in functional limitation and perceived control as predictors of 18-year trajectories of social activity. Results: An interaction between baseline functional limitation and perceived control indicated that having greater functional limitation was associated with less social activity and greater decline over time for those with lower perceived control, but not for those with higher control. Within-person change in functional limitation was not reliably associated with social activity. Discussion: This study highlights the importance of perceived control as a protective psychological resource and may have implications for developing interventions aimed at enabling older adults to maintain their social activity as they experience functional decline. PMID- 26424835 TI - Risk of myocardial infarction and ischaemic stroke in adults with polymyositis and dermatomyositis: a general population-based study. AB - OBJECTIVE: Limited data are available on the risk of cardiovascular disease in DM and PM. The purpose of this study was to estimate the risk of incident myocardial infarction (MI) and ischaemic stroke in adults with incident PM/DM at the general population level. METHODS: We assembled a retrospective cohort of all adults with incident PM/DM in British Columbia, and we matched up to 10 adults randomly selected from the general population. We estimated the incidence rates (IRs) per 1000 person-years for MI and stroke. We calculated hazard ratios (HRs), adjusting for potential confounders. RESULTS: Among 774 new cases of inflammatory myopathies, 424 had PM (59% female, mean age 60 years) and 350 had DM (65% female, mean age 56 years). IRs for MI and stroke in PM were 22.52 and 10.15 events per 1000 person-years, respectively, vs 5.50 and 5.58 events in the comparison cohort, respectively. Fully adjusted HRs (95% CI) were 3.89 (95% CI: 2.28, 6.65) for MI and 1.76 (95% CI: 0.91, 3.40) for stroke. The age-, sex- and entry time-matched HRs for MI and stroke were highest in the first year after PM diagnosis (6.51, [95% CI: 3.15, 13.47] and 3.48 [95% CI: 1.26, 9.62], respectively). Similar trends were seen for DM. CONCLUSION: Our study demonstrates that PM and DM are both associated with an increased risk of MI but not ischaemic stroke. Our findings support increased vigilance in cardiovascular prevention, surveillance and risk modification in adults with PM and DM. PMID- 26424836 TI - Increased risk of papillary thyroid cancer in systemic sclerosis associated with autoimmune thyroiditis. AB - OBJECTIVES: Patients with SSc have an increased risk of malignancy compared with the general population. Before now, no study has evaluated the risk of thyroid cancer (TC) in SSc patients. The aim of the study was to evaluate the prevalence of TC in SSc patients. METHODS: We studied the prevalence of TC in 327 unselected SSc patients in comparison with two population-based, gender- and age-matched control groups (654 subjects from an iodine-deficient area and 654 subjects from an iodine-sufficient area). Thyroid status was assessed by measurement of circulating thyroid hormones and autoantibodies, thyroid ultrasonography and fine needle aspiration cytology (when necessary). RESULTS: Circulating thyroid stimulating hormone, anti-thyroglobulin and anti-thyroperoxidase antibody levels, and the prevalence of hypothyroidism were significantly higher in SSc patients (P < 0.01, for all). Six patients with papillary TC (PTC) were detected among SSc patients, whereas only one case was observed in each of controls 1 and 2 (P = 0.007, for both). In SSc all patients with TC had evidence of thyroid autoimmunity vs 40% of the other SSc patients (P = 0.001). CONCLUSION: These data suggest a high prevalence of papillary TC in SSc patients, in particular in the presence of thyroid autoimmunity; careful thyroid monitoring would be opportune during the follow-up of these patients. PMID- 26424837 TI - Biologic efficacy optimization--a step towards personalized medicine. AB - This following is a review of the factors that influence the outcome of biologic agents in the treatment of adult RA and, when synthesized into the clinical decision-making process, enhance optimization. Adiposity can exacerbate inflammatory diseases; patients with high BMI have worse outcomes from RA, including TNF inhibitors (TNFis), whereas the efficacy of abatacept and tocilizumab is unaffected. Smoking adversely affects TNFi outcomes but has less or no effect on the efficacy of rituximab and tocilizumab, and the effect on abatacept is unknown. Patients who are positive for ACPA and RF have better efficacy with rituximab and abatacept than those who are seronegative, whereas the influence of serotype is less significant for tocilizumab and more complex for TNFis. All biologics seem to do better when co-prescribed with MTX, whereas in monotherapy, tocilizumab is superior to adalimumab and prescription of a non MTX DMARD has advantages over no DMARD for rituximab and adalimumab. Monitoring of TNFi drug levels is an exciting new field, correlating closely with efficacy in RA and PsA, and is influenced by BMI, adherence, co-prescribed DMARDs and anti drug antibodies. The measurement of trough levels provides a potential tool for patients who are not doing well to determine early whether to switch within the TNFi class (if levels are low) or to a biologic with an alternative mode of action (if levels are normal or high). Conversely, the finding of supratherapeutic levels has the potential to enable individual patient selection for dose reduction without the risk of flare. PMID- 26424838 TI - Use of biologics in SLE: a review of the evidence from a clinical perspective. AB - With the explosion in biologics use in rheumatology, newer and smarter ways of using these drugs in different diseases have been advocated. SLE has to date been at the back of the biologics algorithms. Recently, the US Food and Drug Administration and European Medicines Evaluation Agency licensed belimumab for use in SLE, the first drug in >30 years. A clinical review of the evidence that underlies the use of belimumab and other biologics in SLE reveals possible reasons why the results are not as spectacular as they are in other diseases. PMID- 26424839 TI - Selective oestrogen receptor modulators lasofoxifene and bazedoxifene inhibit joint inflammation and osteoporosis in ovariectomised mice with collagen-induced arthritis. AB - OBJECTIVE: RA predominantly affects post-menopausal women and is strongly associated with development of generalised osteoporosis. To find treatments that target both joint manifestations and osteoporosis in RA is desirable. The third generation of selective oestrogen receptor modulators (SERMs) [lasofoxifene (LAS) and bazedoxifene (BZA)] are new treatment options for post-menopausal osteoporosis. The aim of this study was to investigate the effects of LAS and BZA on arthritic disease and inflammation-associated bone loss using CIA in mice. METHODS: Female DBA/1 mice were ovariectomised and subjected to CIA as a model of post-menopausal RA. Mice received treatment with LAS, BZA, 17beta-estradiol (E2) as reference or vehicle. Arthritis development was assessed and BMD was determined by peripheral quantitative CT of the femurs. Serologic markers of inflammation and cartilage destruction were analysed. Immune cells in lymph nodes were studied by flow cytometry. RESULTS: LAS and BZA reduced the clinical severity of arthritis as well as the grade of histologic synovitis and erosions on cartilage and bone. Moreover, SERMs protected against generalised bone loss in CIA by increasing trabecular BMD. Both SERMs decreased serum marker of cartilage destruction and LAS reduced serum IL-6 levels. SERMs did not alter Th17 cells in lymph nodes as E2 did. CONCLUSION: The anti-osteoporotic drugs LAS and BZA were found to be potent inhibitors of joint inflammation and bone destruction in experimental arthritis. This study provides new important knowledge regarding the treatment regimen of post-menopausal women with RA who suffer from increased risk for osteoporosis. PMID- 26424840 TI - Evaluation of the Rapidec Carba NP Test for Detection of Carbapenemases in Enterobacteriaceae. AB - This study evaluated the performance of the Rapidec Carba NP test, which was introduced recently into the market for the detection of carbapenemase production in a broad spectrum of beta-lactamase-producing Enterobacteriaceae clinical isolates. In total, 252 clinical Enterobacteriaceae isolates that had been genetically characterized with respect to carbapenemase, extended-spectrum beta lactamase (ESBL), and AmpC genes were analyzed; 51/252 isolates (20.2%) were genetically confirmed to be carbapenemase producers, whereas 201/252 isolates (79.8%) were genetically negative for the presence of carbapenemase genes. The Rapidec Carba NP test was applied according to the manufacturer's instructions, and results were read after 30 and 120 min of incubation. The overall sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the Rapidec Carba NP test were 90.2%, 100%, 100%, and 97.6%, respectively, when the manufacturer's instructions were followed. Four of 5 false-negative results occurred with OXA-48-like enzymes. After an incubation time of 30 min, the sensitivity was 49%. The sensitivity increased to 100% when the recommended bacterial inoculum was doubled and the test was read strictly after 120 min of incubation. The Rapidec Carba NP test is a useful tool for the reliable confirmation of carbapenemase-producing Enterobacteriaceae isolates. The test should be read strictly after 120 min of incubation and the inoculum should be larger than recommended by the manufacturer. PMID- 26424841 TI - Simplified Protocol for Carba NP Test for Enhanced Detection of Carbapenemase Producers Directly from Bacterial Cultures. AB - We compared carbapenemase detection among 266 Gram-negative bacilli (161 carbapenemase producers) using the Carba NP tests issued by the CLSI (CNPt-CLSI) and a novel protocol (CNPt-direct) designed for carbapenemase detection direct from bacterial cultures (instead of bacterial extracts required by the CLSI tests). The specificities were comparable (100%), but the CNPt-direct was more sensitive (98% versus 84%). The CNPt-direct was easier to perform due to the direct use of colonies and offered a more robust detection of carbapenemase producers. PMID- 26424842 TI - Comparative Evaluation of Three Nucleic Acid-Based Assays for BK Virus Quantification. AB - With the growing importance of BK virus (BKV), effective and efficient screening for BKV replication in plasma and urine samples is very important for monitoring renal transplant and hematopoietic stem cell transplant recipients, who are at increased risk of BKV-associated diseases. However, recent assays proposed by many manufacturers have not been tested, and the available tests have not been standardized. The aim of the present study was to evaluate and compare the performances of three commercially available kits, R-gene, GeneProof, and RealStar, on plasma and urine specimens from patients infected with various genotypes and to determine the correlations with the results from a reference laboratory. A qualitatively excellent global agreement (96.8%) was obtained. RealStar PCR tended to give a higher sensitivity, especially for subtype Ib1 samples. Comparison of 30 plasma samples and 53 urine samples showed a good agreement between the three assays, with Spearman's Rho correlation coefficient values falling between 0.92 and 0.98 (P < 0.001). Moreover, a perfect correlation was obtained for comparison of the assay performances with the AcroMetrix BKV panel (P < 0.001 for all comparisons). According to Bland-Altman analysis, more than 95% (240/249 comparisons) of sample comparisons were situated in the range of the mean +/- 2 standard deviations (SD). The greatest variability between assays was observed for 10.2% of subtype Ib2 samples, with differences of >1 log10 copies/ml. In conclusion, this study demonstrated the reliable and comparable performances of the R-gene, GeneProof, and RealStar real-time PCR systems for quantification of BKV in urine and plasma samples. All three real time PCR assays are appropriate for screening of BKV replication in patients. PMID- 26424844 TI - Characterization of Five Zoonotic Streptococcus suis Strains from Germany, Including One Isolate from a Recent Fatal Case of Streptococcal Toxic Shock-Like Syndrome in a Hunter. AB - A Streptococcus suis isolate from a German hunter with streptococcal toxic shock like syndrome (STSLS) and four additional zoonotic isolates were genotyped as mrp(+) epf* (variant 1890) sly(+) cps2(+). All five zoonotic German strains were characterized by high multiplication in human blood samples ex vivo, but induction of only low levels of proinflammatory cytokines compared to a Chinese STSLS strain. PMID- 26424843 TI - Development of a Multiplex PCR Assay for Rapid Molecular Serotyping of Haemophilus parasuis. AB - Haemophilus parasuis causes Glasser's disease and pneumonia in pigs. Indirect hemagglutination (IHA) is typically used to serotype this bacterium, distinguishing 15 serovars with some nontypeable isolates. The capsule loci of the 15 reference strains have been annotated, and significant genetic variation was identified between serovars, with the exception of serovars 5 and 12. A capsule locus and in silico serovar were identified for all but two nontypeable isolates in our collection of >200 isolates. Here, we describe the development of a multiplex PCR, based on variation within the capsule loci of the 15 serovars of H. parasuis, for rapid molecular serotyping. The multiplex PCR (mPCR) distinguished between all previously described serovars except 5 and 12, which were detected by the same pair of primers. The detection limit of the mPCR was 4.29 * 10(5) ng/MUl bacterial genomic DNA, and high specificity was indicated by the absence of reactivity against closely related commensal Pasteurellaceae and other bacterial pathogens of pigs. A subset of 150 isolates from a previously sequenced H. parasuis collection was used to validate the mPCR with 100% accuracy compared to the in silico results. In addition, the two in silico-nontypeable isolates were typeable using the mPCR. A further 84 isolates were analyzed by mPCR and compared to the IHA serotyping results with 90% concordance (excluding those that were nontypeable by IHA). The mPCR was faster, more sensitive, and more specific than IHA, enabling the differentiation of 14 of the 15 serovars of H. parasuis. PMID- 26424845 TI - Vancomycin-Variable Enterococcal Bacteremia. AB - Vancomycin-variable enterococcus (VVE) is an emerging pathogen. VVE isolates initially appear phenotypically susceptible to vancomycin but possesses the vanA gene and can develop in vitro and in vivo resistance to vancomycin. We report a case of VVE bacteremia and describe how VVE poses diagnostic and therapeutic dilemmas. PMID- 26424846 TI - Social contacts, vaccination decisions and influenza in Japan. AB - BACKGROUND: Contact patterns and vaccination decisions are fundamental to transmission dynamics of infectious diseases. We report on age-specific contact patterns in Japan and their effect on influenza vaccination behaviour. METHODS: Japanese adults (N=3146) were surveyed in Spring 2011 to assess the number of their social contacts within a 24 h period, defined as face-to-face conversations within 2 m, and gain insight into their influenza-related behaviour. We analysed the duration and location of contacts according to age. Additionally, we analysed the probability of vaccination and influenza infection in relation to the number of contacts controlling for individual's characteristics. RESULTS: The mean and median reported numbers of daily contacts were 15.3 and 12.0, respectively. School-aged children and young adults reported the greatest number of daily contacts, and individuals had the most contacts with those in the same age group. The age-specific contact patterns were different between men and women, and differed between weekdays and weekends. Children had fewer contacts between the same age groups during weekends than during weekdays, due to reduced contacts at school. The probability of vaccination increased with the number of contacts, controlling for age and household size. Influenza infection among unvaccinated individuals was higher than for those vaccinated, and increased with the number of contacts. CONCLUSIONS: Contact patterns in Japan are age and gender specific. These contact patterns, as well as their interplay with vaccination decisions and infection risks, can help inform the parameterisation of mathematical models of disease transmission and the design of public health policies, to control disease transmission. PMID- 26424847 TI - The rise of neoliberalism: how bad economics imperils health and what to do about it. AB - The 2008 global financial crisis, precipitated by high-risk, under-regulated financial practices, is often seen as a singular event. The crisis, its recessionary consequences, bank bailouts and the adoption of 'austerity' measures can be seen as a continuation of a 40-year uncontrolled experiment in neoliberal economics. Although public spending and recapitalisation of failing banks helped prevent a 1930s-style Great Depression, the deep austerity measures that followed have stifled a meaningful recovery for the majority of populations. In the short term, these austerity measures, especially cuts to health and social protection systems, pose major health risks in those countries under its sway. Meanwhile structural changes to the global labour market, increasing under-employment in high-income countries and economic insecurity elsewhere, are likely to widen health inequities in the longer term. We call for four policy reforms to reverse rising inequalities and their harms to public health. First is re-regulating global finance. Second is rejecting austerity as an empirically and ethically unjustified policy, especially given now clear evidence of its deleterious health consequences. Third, there is a need to restore progressive taxation at national and global scales. Fourth is a fundamental shift away from the fossil fuel economy and policies that promote economic growth in ways that imperil environmental sustainability. This involves redistributing work and promoting fairer pay. We do not suggest these reforms will be politically feasible or even achievable in the short term. They nonetheless constitute an evidence-based agenda for strong, public health advocacy and practice. PMID- 26424848 TI - Nucleotide sequence of miRNA precursor contributes to cleavage site selection by Dicer. AB - The ribonuclease Dicer excises mature miRNAs from a diverse group of precursors (pre-miRNAs), most of which contain various secondary structure motifs in their hairpin stem. In this study, we analyzed Dicer cleavage in hairpin substrates deprived of such motifs. We searched for the factors other than the secondary structure, which may influence the length diversity and heterogeneity of miRNAs. We found that the nucleotide sequence at the Dicer cleavage site influences both of these miRNA characteristics. With regard to cleavage mechanism, we demonstrate that the Dicer RNase IIIA domain that cleaves within the 3' arm of the pre-miRNA is more sensitive to the nucleotide sequence of its substrate than is the RNase IIIB domain. The RNase IIIA domain avoids releasing miRNAs with G nucleotide and prefers to generate miRNAs with a U nucleotide at the 5' end. We also propose that the sequence restrictions at the Dicer cleavage site might be the factor that contributes to the generation of miRNA duplexes with 3' overhangs of atypical lengths. This finding implies that the two RNase III domains forming the single processing center of Dicer may exhibit some degree of flexibility, which allows for the formation of these non-standard 3' overhangs. PMID- 26424849 TI - Dynamic modulation of Dnmt2-dependent tRNA methylation by the micronutrient queuine. AB - Dnmt2 enzymes are cytosine-5 methyltransferases that methylate C38 of several tRNAs. We report here that the activities of two Dnmt2 homologs, Pmt1 from Schizosaccharomyces pombe and DnmA from Dictyostelium discoideum, are strongly stimulated by prior queuosine (Q) modification of the substrate tRNA. In vivo tRNA methylation levels were stimulated by growth of cells in queuine-containing medium; in vitro Pmt1 activity was enhanced on Q-containing RNA; and queuine stimulated in vivo methylation was abrogated by the absence of the enzyme that inserts queuine into tRNA, eukaryotic tRNA-guanine transglycosylase. Global analysis of tRNA methylation in S. pombe showed a striking selectivity of Pmt1 for tRNA(Asp) methylation, which distinguishes Pmt1 from other Dnmt2 homologs. The present analysis also revealed a novel Pmt1- and Q-independent tRNA methylation site in S. pombe, C34 of tRNA(Pro). Notably, queuine is a micronutrient that is scavenged by higher eukaryotes from the diet and gut microflora. This work therefore reveals an unanticipated route by which the environment can modulate tRNA modification in an organism. PMID- 26424850 TI - Femtosecond near-infrared laser microirradiation reveals a crucial role for PARP signaling on factor assemblies at DNA damage sites. AB - Laser microirradiation is a powerful tool for real-time single-cell analysis of the DNA damage response (DDR). It is often found, however, that factor recruitment or modification profiles vary depending on the laser system employed. This is likely due to an incomplete understanding of how laser conditions/dosages affect the amounts and types of damage and the DDR. We compared different irradiation conditions using a femtosecond near-infrared laser and found distinct damage site recruitment thresholds for 53BP1 and TRF2 correlating with the dose dependent increase of strand breaks and damage complexity. Low input-power microirradiation that induces relatively simple strand breaks led to robust recruitment of 53BP1 but not TRF2. In contrast, increased strand breaks with complex damage including crosslinking and base damage generated by high input power microirradiation resulted in TRF2 recruitment to damage sites with no 53BP1 clustering. We found that poly(ADP-ribose) polymerase (PARP) activation distinguishes between the two damage states and that PARP activation is essential for rapid TRF2 recruitment while suppressing 53BP1 accumulation at damage sites. Thus, our results reveal that careful titration of laser irradiation conditions allows induction of varying amounts and complexities of DNA damage that are gauged by differential PARP activation regulating protein assembly at the damage site. PMID- 26424851 TI - KSHV but not MHV-68 LANA induces a strong bend upon binding to terminal repeat viral DNA. AB - Latency-associated nuclear antigen (LANA) is central to episomal tethering, replication and transcriptional regulation of gamma2-herpesviruses. LANA binds cooperatively to the terminal repeat (TR) region of the viral episome via adjacent LANA binding sites (LBS), but the molecular mechanism by which LANA assembles on the TR remains elusive. We show that KSHV LANA and MHV-68 LANA proteins bind LBS DNA using strikingly different modes. Solution structure of LANA complexes revealed that while kLANA tetramer is intrinsically bent both in the free and bound state to LBS1-2 DNA, mLANA oligomers instead adopt a rigid linear conformation. In addition, we report a novel non-ring kLANA structure that displays more flexibility at its assembly interface than previously demonstrated. We identified a hydrophobic pivot point located at the dimer-dimer assembly interface, which gives rotational freedom for kLANA to adopt variable conformations to accommodate both LBS1-2 and LBS2-1-3 DNA. Alterations in the arrangement of LBS within TR or at the tetramer assembly interface have a drastic effect on the ability of kLANA binding. We also show kLANA and mLANA DNA binding functions can be reciprocated. Although KSHV and MHV-68 are closely related, the findings provide new insights into how the structure, oligomerization, and DNA binding of LANA have evolved differently to assemble on the TR DNA. PMID- 26424852 TI - BacDive--The Bacterial Diversity Metadatabase in 2016. AB - BacDive-the Bacterial Diversity Metadatabase (http://bacdive.dsmz.de) provides strain-linked information about bacterial and archaeal biodiversity. The range of data encompasses taxonomy, morphology, physiology, sampling and concomitant environmental conditions as well as molecular biology. The majority of data is manually annotated and curated. Currently (with release 9/2015), BacDive covers 53 978 strains. Newly implemented RESTful web services provide instant access to the content in machine-readable XML and JSON format. Besides an overall increase of data content, BacDive offers new data fields and features, e.g. the search for gene names, plasmids or 16S rRNA in the advanced search, as well as improved linkage of entries to external life science web resources. PMID- 26424853 TI - RNA binding to APOBEC3G induces the disassembly of functional deaminase complexes by displacing single-stranded DNA substrates. AB - APOBEC3G (A3G) DNA deaminase activity requires a holoenzyme complex whose assembly on nascent viral reverse transcripts initiates with A3G dimers binding to ssDNA followed by formation of higher-order A3G homo oligomers. Catalytic activity is inhibited when A3G binds to RNA. Our prior studies suggested that RNA inhibited A3G binding to ssDNA. In this report, near equilibrium binding and gel shift analyses showed that A3G assembly and disassembly on ssDNA was an ordered process involving A3G dimers and multimers thereof. Although, fluorescence anisotropy showed that A3G had similar nanomolar affinity for RNA and ssDNA, RNA stochastically dissociated A3G dimers and higher-order oligomers from ssDNA, suggesting a different modality for RNA binding. Mass spectrometry mapping of A3G peptides cross-linked to nucleic acid suggested ssDNA only bound to three peptides, amino acids (aa) 181-194 in the N-terminus and aa 314-320 and 345-374 in the C-terminus that were part of a continuous exposed surface. RNA bound to these peptides and uniquely associated with three additional peptides in the N- terminus, aa 15-29, 41-52 and 83-99, that formed a continuous surface area adjacent to the ssDNA binding surface. The data predict a mechanistic model of RNA inhibition of ssDNA binding to A3G in which competitive and allosteric interactions determine RNA-bound versus ssDNA-bound conformational states. PMID- 26424854 TI - Similar clinical results of influenza vaccination in peritoneal dialysis and haemodialysis patients. PMID- 26424855 TI - missMethyl: an R package for analyzing data from Illumina's HumanMethylation450 platform. AB - DNA methylation is one of the most commonly studied epigenetic modifications due to its role in both disease and development. The Illumina HumanMethylation450 BeadChip is a cost-effective way to profile >450 000 CpGs across the human genome, making it a popular platform for profiling DNA methylation. Here we introduce missMethyl, an R package with a suite of tools for performing normalization, removal of unwanted variation in differential methylation analysis, differential variability testing and gene set analysis for the 450K array. AVAILABILITY AND IMPLEMENTATION: missMethyl is an R package available from the Bioconductor project at www.bioconductor.org. CONTACT: alicia.oshlack@mcri.edu.au SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26424856 TI - smallWig: parallel compression of RNA-seq WIG files. AB - CONTRIBUTIONS: We developed a new lossless compression method for WIG data, named smallWig, offering the best known compression rates for RNA-seq data and featuring random access functionalities that enable visualization, summary statistics analysis and fast queries from the compressed files. Our approach results in order of magnitude improvements compared with bigWig and ensures compression rates only a fraction of those produced by cWig. The key features of the smallWig algorithm are statistical data analysis and a combination of source coding methods that ensure high flexibility and make the algorithm suitable for different applications. Furthermore, for general-purpose file compression, the compression rate of smallWig approaches the empirical entropy of the tested WIG data. For compression with random query features, smallWig uses a simple block based compression scheme that introduces only a minor overhead in the compression rate. For archival or storage space-sensitive applications, the method relies on context mixing techniques that lead to further improvements of the compression rate. Implementations of smallWig can be executed in parallel on different sets of chromosomes using multiple processors, thereby enabling desirable scaling for future transcriptome Big Data platforms. MOTIVATION: The development of next generation sequencing technologies has led to a dramatic decrease in the cost of DNA/RNA sequencing and expression profiling. RNA-seq has emerged as an important and inexpensive technology that provides information about whole transcriptomes of various species and organisms, as well as different organs and cellular communities. The vast volume of data generated by RNA-seq experiments has significantly increased data storage costs and communication bandwidth requirements. Current compression tools for RNA-seq data such as bigWig and cWig either use general-purpose compressors (gzip) or suboptimal compression schemes that leave significant room for improvement. To substantiate this claim, we performed a statistical analysis of expression data in different transform domains and developed accompanying entropy coding methods that bridge the gap between theoretical and practical WIG file compression rates. RESULTS: We tested different variants of the smallWig compression algorithm on a number of integer and real- (floating point) valued RNA-seq WIG files generated by the ENCODE project. The results reveal that, on average, smallWig offers 18-fold compression rate improvements, up to 2.5-fold compression time improvements, and 1.5-fold decompression time improvements when compared with bigWig. On the tested files, the memory usage of the algorithm never exceeded 90 KB. When more elaborate context mixing compressors were used within smallWig, the obtained compression rates were as much as 23 times better than those of bigWig. For smallWig used in the random query mode, which also supports retrieval of the summary statistics, an overhead in the compression rate of roughly 3-17% was introduced depending on the chosen system parameters. An increase in encoding and decoding time of 30% and 55% represents an additional performance loss caused by enabling random data access. We also implemented smallWig using multi-processor programming. This parallelization feature decreases the encoding delay 2-3.4 times compared with that of a single-processor implementation, with the number of processors used ranging from 2 to 8; in the same parameter regime, the decoding delay decreased 2 5.2 times. AVAILABILITY AND IMPLEMENTATION: The smallWig software can be downloaded from: http://stanford.edu/~zhiyingw/smallWig/smallwig.html, http://publish.illinois.edu/milenkovic/, http://web.stanford.edu/~tsachy/. CONTACT: zhiyingw@stanford.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26424857 TI - ANARCI: antigen receptor numbering and receptor classification. AB - MOTIVATION: Antibody amino-acid sequences can be numbered to identify equivalent positions. Such annotations are valuable for antibody sequence comparison, protein structure modelling and engineering. Multiple different numbering schemes exist, they vary in the nomenclature they use to annotate residue positions, their definitions of position equivalence and their popularity within different scientific disciplines. However, currently no publicly available software exists that can apply all the most widely used schemes or for which an executable can be obtained under an open license. RESULTS: ANARCI is a tool to classify and number antibody and T-cell receptor amino-acid variable domain sequences. It can annotate sequences with the five most popular numbering schemes: Kabat, Chothia, Enhanced Chothia, IMGT and AHo. AVAILABILITY AND IMPLEMENTATION: ANARCI is available for download under GPLv3 license at opig.stats.ox.ac.uk/webapps/anarci. A web-interface to the program is available at the same address. CONTACT: deane@stats.ox.ac.uk. PMID- 26424858 TI - regioneR: an R/Bioconductor package for the association analysis of genomic regions based on permutation tests. AB - MOTIVATION: Statistically assessing the relation between a set of genomic regions and other genomic features is a common challenging task in genomic and epigenomic analyses. Randomization based approaches implicitly take into account the complexity of the genome without the need of assuming an underlying statistical model. SUMMARY: regioneR is an R package that implements a permutation test framework specifically designed to work with genomic regions. In addition to the predefined randomization and evaluation strategies, regioneR is fully customizable allowing the use of custom strategies to adapt it to specific questions. Finally, it also implements a novel function to evaluate the local specificity of the detected association. AVAILABILITY AND IMPLEMENTATION: regioneR is an R package released under Artistic-2.0 License. The source code and documents are freely available through Bioconductor (http://www.bioconductor.org/packages/regioneR). CONTACT: rmalinverni@carrerasresearch.org. PMID- 26424859 TI - Warpgroup: increased precision of metabolomic data processing by consensus integration bound analysis. AB - MOTIVATION: Current informatic techniques for processing raw chromatography/mass spectrometry data break down under several common, non-ideal conditions. Importantly, hydrophilic liquid interaction chromatography (a key separation technology for metabolomics) produces data which are especially challenging to process. We identify three critical points of failure in current informatic workflows: compound specific drift, integration region variance, and naive missing value imputation. We implement the Warpgroup algorithm to address these challenges. RESULTS: Warpgroup adds peak subregion detection, consensus integration bound detection, and intelligent missing value imputation steps to the conventional informatic workflow. When compared with the conventional workflow, Warpgroup made major improvements to the processed data. The coefficient of variation for peaks detected in replicate injections of a complex Escherichia Coli extract were halved (a reduction of 19%). Integration regions across samples were much more robust. Additionally, many signals lost by the conventional workflow were 'rescued' by the Warpgroup refinement, thereby resulting in greater analyte coverage in the processed data. AVAILABILITY AND: I: MPLEMENTATION: Warpgroup is an open source R package available on GitHub at github.com/nathaniel-mahieu/warpgroup. The package includes example data and XCMS compatibility wrappers for ease of use. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. CONTACT: nathaniel.mahieu@wustl.edu or gjpattij@wustl.edu. PMID- 26424860 TI - A mandibular advancement device did not affect daytime sleepiness and quality of life in obstructive sleep apnoea. PMID- 26424861 TI - Paediatric pain-related conditions impact healthcare expenditures. PMID- 26424862 TI - Dialectical behaviour therapy with skills training seems to be more effective in reducing non-suicidal self-injury. PMID- 26424863 TI - Burden of bullying: enduring effects of early victimisation on depression in adulthood. PMID- 26424864 TI - Improving methadone maintenance therapy for prisoner populations. PMID- 26424867 TI - Erratum. PMID- 26424865 TI - The ORBIT bleeding score: a simple bedside score to assess bleeding risk in atrial fibrillation. AB - BACKGROUND: Therapeutic decisions in atrial fibrillation (AF) are often influenced by assessment of bleeding risk. However, existing bleeding risk scores have limitations. OBJECTIVES: We sought to develop and validate a novel bleeding risk score using routinely available clinical information to predict major bleeding in a large, community-based AF population. METHODS: We analysed data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF), a prospective registry that enrolled incident and prevalent AF patients at 176 US sites. Using Cox proportional hazards regression, we identified factors independently associated with major bleeding among patients taking oral anticoagulation (OAC) over a median follow-up of 2 years (interquartile range = 1.6-2.5). We also created a numerical bedside risk score that included the five most predictive risk factors weighted according to their strength of association with major bleeding. The predictive performance of the full model, the simple five-item score, and two existing risk scores (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly, HAS-BLED, and anticoagulation and risk factors in atrial fibrillation, ATRIA) were then assessed in both the ORBIT-AF cohort and a separate clinical trial population, Rivaroxaban Once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET-AF). RESULTS: Among 7411 ORBIT-AF patients taking OAC, the rate of major bleeding was 4.0/100 person-years. The full continuous model (12 variables) and five-factor ORBIT risk score (older age [75+ years], reduced haemoglobin/haematocrit/history of anaemia, bleeding history, insufficient kidney function, and treatment with antiplatelet) both had good ability to identify those who bled vs. not (C-index 0.69 and 0.67, respectively). These scores both had similar discrimination, but markedly better calibration when compared with the HAS-BLED and ATRIA scores in an external validation population from the ROCKET-AF trial. CONCLUSIONS: The five-element ORBIT bleeding risk score had better ability to predict major bleeding in AF patients when compared with HAS BLED and ATRIA risk scores. The ORBIT risk score can provide a simple, easily remembered tool to support clinical decision making. PMID- 26424868 TI - Erratum. PMID- 26424866 TI - Imaging of congenital heart disease in adults. AB - Imaging is fundamental to the lifelong care of adult congenital heart disease (ACHD) patients. Echocardiography remains the first line imaging for inpatient, outpatient, or perioperative care. Cross-sectional imaging with cardiovascular magnetic resonance (CMR) or computed tomography (CT) provides complementary and invaluable information on cardiac and vascular anatomy and other intra-thoracic structures. Furthermore, CMR provides quantification of cardiac function and vascular flow. Cardiac catheterization is mostly reserved for assessment of pulmonary vascular resistance, ventricular end-diastolic pressure, and percutaneous interventions. There have been further advances in non-invasive imaging for ACHD including the application of advanced echocardiographic techniques, faster automated CMR imaging, and radiation dose reduction in CT. As a result ACHD, a heterogeneous population, benefit from appropriate application of multiple imaging modalities matched with tertiary ACHD expertise. PMID- 26424869 TI - Blood transfusion and the benefit/harm inflection point. PMID- 26424870 TI - Reply to Fisher et al. PMID- 26424871 TI - Are intraoperative flow measurements sufficient to allay concerns about flow capacity of skeletonized internal thoracic arteries? PMID- 26424872 TI - Early dysfunction of a tricuspid valve-in-valve replacement due to papillary muscle overgrowth. PMID- 26424873 TI - Intraoperative bleeding control by uniportal video-assisted thoracoscopic surgery?. AB - Owing to advances in video-assisted thoracic surgery (VATS), the majority of pulmonary resections can currently be performed by VATS in a safe manner with a low level of morbidity and mortality. The majority of the complications that occur during VATS can be minimized with correct preoperative planning of the case as well as careful pulmonary dissection. Coordination of the whole surgical team is essential when confronting an emergency such as major bleeding. This is particularly important during the VATS learning curve, where the occurrence of intraoperative complications, particularly significant bleeding, usually ends in a conversion to open surgery. However, conversion should not be considered as a failure of the VATS approach, but as a resource to maintain the patient's safety. The correct assessment of any bleeding is of paramount importance during major thoracoscopic procedures. Inadequate management of the source of bleeding may result in major vessel injury and massive bleeding. If bleeding occurs, a sponge stick should be readily available to apply pressure immediately to control the haemorrhage. It is always important to remain calm and not to panic. With the bleeding temporarily controlled, a decision must be made promptly as to whether a thoracotomy is needed or if the bleeding can be solved through the VATS approach. This will depend primarily on the surgeon's experience. The operative vision provided with high-definition cameras, specially designed or adapted instruments and the new sealants are factors that facilitate the surgeon's control. After experience has been acquired with conventional or uniportal VATS, the rate of complications diminishes and the majority of bleeding events are controlled without the need for conversion to thoracotomy. PMID- 26424874 TI - Hard and Soft Selection Revisited: How Evolution by Natural Selection Works in the Real World. AB - The modern synthesis of evolutionary biology unified Darwin's natural selection with Mendelian genetics, but at the same time it created the dilemma of genetic load. Lewontin and Hubby's (1966) and Harris's (1966) characterization of genetic variation in natural populations increased the apparent burden of this load. Neutrality or near neutrality of genetic variation was one mechanism proposed for the revealed excessive genetic variation. Bruce Wallace coined the term "soft selection" to describe an alternative way for natural selection to operate that was consistent with observed variation. He envisioned nature as presenting ecological vacancies that could be filled by diverse genotypes. Survival and successful reproduction was a combined function of population density, genotype, and genotype frequencies, rather than a fixed value of the relative fitness of each genotype. My goal in this review is to explore the importance of soft selection in the real world. My motive and that of my colleagues as described here is not to explain what maintains genetic variation in natural populations, but rather to understand the factors that shape how organisms adapt to natural environments. We characterize how feedbacks between ecology and evolution shape both evolution and ecology. These feedbacks are mediated by density- and frequency-dependent selection, the mechanisms that underlie soft selection. Here, I report on our progress in characterizing these types of selection with a combination of a consideration of the published literature and the results from my collaborators' and my research on natural populations of guppies. PMID- 26424875 TI - Disrupting the Perception of Effort with Continuous Theta Burst Stimulation. PMID- 26424876 TI - Opioid Inhibition of Intercalated Input to the Central Amygdala. PMID- 26424877 TI - Neuronal Store-Operated Calcium Entry and Mushroom Spine Loss in Amyloid Precursor Protein Knock-In Mouse Model of Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most common reason for elderly dementia in the world. We proposed that memory loss in AD is related to destabilization of mushroom postsynaptic spines involved in long-term memory storage. We demonstrated previously that stromal interaction molecule 2 (STIM2)-regulated neuronal store-operated calcium entry (nSOC) in postsynaptic spines play a key role in stability of mushroom spines by maintaining activity of synaptic Ca(2+)/calmodulin kinase II (CaMKII). Furthermore, we demonstrated previously that the STIM2-nSOC-CaMKII pathway is downregulated in presenilin 1 M146V knock in (PS1-M146V KI) mouse model of AD, leading to loss of hippocampal mushroom spines in this model. In the present study, we demonstrate that hippocampal mushroom postsynaptic spines are also lost in amyloid precursor protein knock-in (APPKI) mouse model of AD. We demonstrated that loss of mushroom spines occurs as a result of accumulation of extracellular beta-amyloid 42 in APPKI culture media. Our results indicate that extracellular Abeta42 acts by overactivating mGluR5 receptor in APPKI neurons, leading to elevated Ca(2+) levels in endoplasmic reticulum, compensatory downregulation of STIM2 expression, impaired synaptic nSOC, and reduced CaMKII activity. Pharmacological inhibition of mGluR5 or overexpression of STIM2 rescued synaptic nSOC and prevented mushroom spine loss in APPKI hippocampal neurons. Our results indicate that downregulation of synaptic STIM2-nSOC-CaMKII pathway causes loss of mushroom synaptic spines in both presenilin and APPKI mouse models of AD. We propose that modulators/activators of this pathway may have a potential therapeutic value for treatment of memory loss in AD. Significance statement: A direct connection between amyloid-induced synaptic mushroom spine loss and neuronal store-operated calcium entry pathway is shown. These results provide strong support for the calcium hypothesis of neurodegeneration and further validate the synaptic store operated calcium entry pathway as a potential therapeutic target for Alzheimer's disease. PMID- 26424878 TI - Gaze Direction Modulates the Relation between Neural Responses to Faces and Visual Awareness. AB - Gaze direction and especially direct gaze is a powerful nonverbal cue that plays an important role in social interactions. Here we studied the neural mechanisms underlying the privileged access of direct gaze to visual awareness. We performed functional magnetic resonance imaging in healthy human volunteers who were exposed to faces with direct or averted gaze under continuous flash suppression, thereby manipulating their awareness of the faces. A gaze processing network comprising fusiform face area (FFA), superior temporal sulcus, amygdala, and intraparietal sulcus showed overall reduced neural responses when participants reported to be unaware of the faces. Interestingly, direct gaze elicited greater responses than averted gaze when participants were aware of the faces, but smaller responses when they were unaware. Additional between-subject correlation and single-trial analyses indicated that this pattern of results was due to a modulation of the relationship between neural responses and awareness by gaze direction: with increasing neural activation in the FFA, direct-gaze faces entered awareness more readily than averted-gaze faces. These findings suggest that for direct gaze, lower levels of neural activity are sufficient to give rise to awareness than for averted gaze, thus providing a neural basis for privileged access of direct gaze to awareness. Significance statement: Another person's eye gaze directed at oneself is a powerful social signal acting as a catalyst for further communication. Here, we studied the neural mechanisms underlying the prioritized access of direct gaze to visual awareness in healthy human volunteers and show that with increasing neural activation, direct-gaze faces enter awareness more readily than averted-gaze faces. This suggests that for a socially highly relevant cue like direct gaze, lower levels of neural activity are sufficient to give rise to awareness compared with averted gaze, possibly because the human brain is attuned to the efficient neural processing of direct gaze due to the biological importance of eye contact for social interactions. PMID- 26424879 TI - Sleep Regulates Incubation of Cocaine Craving. AB - After withdrawal from cocaine, chronic cocaine users often experience persistent reduction in total sleep time, which is accompanied by increased sleep fragmentation resembling chronic insomnia. This and other sleep abnormalities have long been speculated to foster relapse and further drug addiction, but direct evidence is lacking. Here, we report that after prolonged withdrawal from cocaine self-administration, rats exhibited persistent reduction in nonrapid-eye movement (NREM) and rapid-eye-movement (REM) sleep, as well as increased sleep fragmentation. In an attempt to improve sleep after cocaine withdrawal, we applied chronic sleep restriction to the rats during their active (dark) phase of the day, which selectively decreased the fragmentation of REM sleep during their inactive (light) phase without changing NREM or the total amount of daily sleep. Animals with improved REM sleep exhibited decreased incubation of cocaine craving, a phenomenon depicting the progressive intensification of cocaine seeking after withdrawal. In contrast, experimentally increasing sleep fragmentation after cocaine self-administration expedited the development of incubation of cocaine craving. Incubation of cocaine craving is partially mediated by progressive accumulation of calcium-permeable AMPA receptors (CP AMPARs) in the nucleus accumbens (NAc). After withdrawal from cocaine, animals with improved REM sleep exhibited reduced accumulation of CP-AMPARs in the NAc, whereas increasing sleep fragmentation accelerated NAc CP-AMPAR accumulation. These results reveal a potential molecular substrate that can be engaged by sleep to regulate cocaine craving and relapse, and demonstrate sleep-based therapeutic opportunities for cocaine addiction. Significance statement: Sleep abnormalities are common symptoms in chronic drug users long after drug withdrawal. These withdrawal-associated sleep symptoms, particularly reduction in total sleep time and deteriorating sleep quality, have been speculated to foster relapse and further drug addiction, but direct evidence is lacking. Here we show in rats that the sleep pattern was persistently changed long after withdrawal from cocaine self-administration, and demonstrate that sleep interventions can bidirectionally regulate cocaine craving and seeking after withdrawal. We further demonstrate that glutamatergic synapses in the nucleus accumbens are potential neuronal targets for sleep intervention to influence cocaine craving after withdrawal. These results provide a strong rationale supporting sleep-based therapies for cocaine addiction. PMID- 26424880 TI - Distinct Functional Modules for Discrete and Rhythmic Forelimb Movements in the Mouse Motor Cortex. AB - Movements of animals are composed of two fundamental dynamics: discrete and rhythmic movements. Although the movements with distinct dynamics are thought to be differently processed in the CNS, it is unclear how they are represented in the cerebral cortex. Here, we investigated the cortical representation of movement dynamics by developing prolonged transcranial optogenetic stimulation (pTOS) using awake, channelrhodopsin-2 transgenic mice. We found two domains that induced discrete forelimb movements in the forward and backward directions, and these sandwiched a domain that generated rhythmic forelimb movements. The forward discrete movement had an intrinsic velocity profile and the rhythmic movement had an intrinsic oscillation frequency. Each of the forward discrete and rhythmic domains possessed intracortical synaptic connections within its own domain, independently projected to the spinal cord, and weakened the neuronal activity and movement induction of the other domain. pTOS-induced movements were also classified as ethologically relevant movements. Forepaw-to-mouth movement was mapped in a part of the forward discrete domain, while locomotion-like movement was in a part of the rhythmic domain. Interestingly, photostimulation of the rhythmic domain resulted in a nonrhythmic, continuous lever-pull movement when a lever was present. The motor cortex possesses functional modules for distinct movement dynamics, and these can adapt to environmental constraints for purposeful movements. Significance statement: Animal behavior has discrete and rhythmic components, such as reaching and locomotion. It is unclear how these movements with distinct dynamics are represented in the cerebral cortex. We investigated the dynamics of movements induced by long-duration transcranial photostimulation on the dorsal cortex of awake channelrhodopsin-2 transgenic mice. We found two domains causing forward and backward discrete forelimb movements and a domain for rhythmic forelimb movements. A domain for forward discrete movement and a domain for rhythmic movement mutually weakened neuronal activity and movement size. The photostimulation of the rhythmic domain also induced nonrhythmic, lever-pull movement, when the lever was present. Thus, the motor cortex has functional modules with distinct dynamics, and each module retains flexibility for adaptation to different environments. PMID- 26424881 TI - Bidirectional Modulation of Recognition Memory. AB - Perirhinal cortex (PER) has a well established role in the familiarity-based recognition of individual items and objects. For example, animals and humans with perirhinal damage are unable to distinguish familiar from novel objects in recognition memory tasks. In the normal brain, perirhinal neurons respond to novelty and familiarity by increasing or decreasing firing rates. Recent work also implicates oscillatory activity in the low-beta and low-gamma frequency bands in sensory detection, perception, and recognition. Using optogenetic methods in a spontaneous object exploration (SOR) task, we altered recognition memory performance in rats. In the SOR task, normal rats preferentially explore novel images over familiar ones. We modulated exploratory behavior in this task by optically stimulating channelrhodopsin-expressing perirhinal neurons at various frequencies while rats looked at novel or familiar 2D images. Stimulation at 30-40 Hz during looking caused rats to treat a familiar image as if it were novel by increasing time looking at the image. Stimulation at 30-40 Hz was not effective in increasing exploration of novel images. Stimulation at 10-15 Hz caused animals to treat a novel image as familiar by decreasing time looking at the image, but did not affect looking times for images that were already familiar. We conclude that optical stimulation of PER at different frequencies can alter visual recognition memory bidirectionally. Significance statement: Recognition of novelty and familiarity are important for learning, memory, and decision making. Perirhinal cortex (PER) has a well established role in the familiarity-based recognition of individual items and objects, but how novelty and familiarity are encoded and transmitted in the brain is not known. Perirhinal neurons respond to novelty and familiarity by changing firing rates, but recent work suggests that brain oscillations may also be important for recognition. In this study, we showed that stimulation of the PER could increase or decrease exploration of novel and familiar images depending on the frequency of stimulation. Our findings suggest that optical stimulation of PER at specific frequencies can predictably alter recognition memory. PMID- 26424883 TI - Fast Learning with Weak Synaptic Plasticity. AB - New sensory stimuli can be learned with a single or a few presentations. Similarly, the responses of cortical neurons to a stimulus have been shown to increase reliably after just a few repetitions. Long-term memory is thought to be mediated by synaptic plasticity, but in vitro experiments in cortical cells typically show very small changes in synaptic strength after a pair of presynaptic and postsynaptic spikes. Thus, it is traditionally thought that fast learning requires stronger synaptic changes, possibly because of neuromodulation. Here we show theoretically that weak synaptic plasticity can, in fact, support fast learning, because of the large number of synapses N onto a cortical neuron. In the fluctuation-driven regime characteristic of cortical neurons in vivo, the size of membrane potential fluctuations grows only as ?N, whereas a single output spike leads to potentiation of a number of synapses proportional to N. Therefore, the relative effect of a single spike on synaptic potentiation grows as ?N. This leverage effect requires precise spike timing. Thus, the large number of synapses onto cortical neurons allows fast learning with very small synaptic changes. Significance statement: Long-term memory is thought to rely on the strengthening of coactive synapses. This physiological mechanism is generally considered to be very gradual, and yet new sensory stimuli can be learned with just a few presentations. Here we show theoretically that this apparent paradox can be solved when there is a tight balance between excitatory and inhibitory input. In this case, small synaptic modifications applied to the many synapses onto a given neuron disrupt that balance and produce a large effect even for modifications induced by a single stimulus. This effect makes fast learning possible with small synaptic changes and reconciles physiological and behavioral observations. PMID- 26424882 TI - The Synaptic and Morphological Basis of Orientation Selectivity in a Polyaxonal Amacrine Cell of the Rabbit Retina. AB - Much of the computational power of the retina derives from the activity of amacrine cells, a large and diverse group of GABAergic and glycinergic inhibitory interneurons. Here, we identify an ON-type orientation-selective, wide-field, polyaxonal amacrine cell (PAC) in the rabbit retina and demonstrate how its orientation selectivity arises from the structure of the dendritic arbor and the pattern of excitatory and inhibitory inputs. Excitation from ON bipolar cells and inhibition arising from the OFF pathway converge to generate a quasi-linear integration of visual signals in the receptive field center. This serves to suppress responses to high spatial frequencies, thereby improving sensitivity to larger objects and enhancing orientation selectivity. Inhibition also regulates the magnitude and time course of excitatory inputs to this PAC through serial inhibitory connections onto the presynaptic terminals of ON bipolar cells. This presynaptic inhibition is driven by graded potentials within local microcircuits, similar in extent to the size of single bipolar cell receptive fields. Additional presynaptic inhibition is generated by spiking amacrine cells on a larger spatial scale covering several hundred microns. The orientation selectivity of this PAC may be a substrate for the inhibition that mediates orientation selectivity in some types of ganglion cells. Significance statement: The retina comprises numerous excitatory and inhibitory circuits that encode specific features in the visual scene, such as orientation, contrast, or motion. Here, we identify a wide field inhibitory neuron that responds to visual stimuli of a particular orientation, a feature selectivity that is primarily due to the elongated shape of the dendritic arbor. Integration of convergent excitatory and inhibitory inputs from the ON and OFF visual pathways suppress responses to small objects and fine textures, thus enhancing selectivity for larger objects. Feedback inhibition regulates the strength and speed of excitation on both local and wide field spatial scales. This study demonstrates how different synaptic inputs are regulated to tune a neuron to respond to specific features in the visual scene. PMID- 26424884 TI - Motor Cortex Activity Organizes the Developing Rubrospinal System. AB - The corticospinal and rubrospinal systems function in skilled movement control. A key question is how do these systems develop the capacity to coordinate their motor functions and, in turn, if the red nucleus/rubrospinal tract (RN/RST) compensates for developmental corticospinal injury? We used the cat to investigate whether the developing rubrospinal system is shaped by activity dependent interactions with the developing corticospinal system. We unilaterally inactivated M1 by muscimol microinfusion between postnatal weeks 5 and 7 to examine activity-dependent interactions and whether the RN/RST compensates for corticospinal tract (CST) developmental motor impairments and CST misprojections after M1 inactivation. We examined the RN motor map and RST cervical projections at 7 weeks of age, while the corticospinal system was inactivated, and at 14 weeks, after activity returned. During M1 inactivation, the RN on the same side showed normal RST projections and reduced motor thresholds, suggestive of precocious development. By contrast, the RN on the untreated/active M1 side showed sparse RST projections and an immature motor map. After M1 activity returned later in adolescent cat development, RN on the active M1/CST side continued to show a substantial loss of spinal terminations and an impaired motor map. RN/RST on the inactivated side regressed to a smaller map and fewer axons. Our findings suggest that the developing rubrospinal system is under activity dependent regulation by the corticospinal system for establishing mature RST connections and RN motor map. The lack of RS compensation on the non-inactivated side can be explained by development of ipsilateral misprojections from the active M1 that outcompete the RST. Significance statement: Skilled movements reflect the activity of multiple descending motor systems and their interactions with spinal motor circuits. Currently, there is little insight into whether motor systems interact during development to coordinate their emerging functions and, if so, the mechanisms underlying this process. This study examined activity dependent interactions between the developing corticospinal and rubrospinal systems, two key systems for skilled limb movements. We show that the developing rubrospinal system competes with the corticospinal system in establishing the red nucleus motor map and rubrospinal tract connections. This is the first demonstration of one motor system steering development, and ultimately function, of another. Knowledge of activity-dependent competition between these two systems helps predict the response of the rubrospinal system following corticospinal system developmental injury. PMID- 26424885 TI - Astrocyte Ca2+ Signaling Drives Inversion of Neurovascular Coupling after Subarachnoid Hemorrhage. AB - Physiologically, neurovascular coupling (NVC) matches focal increases in neuronal activity with local arteriolar dilation. Astrocytes participate in NVC by sensing increased neurotransmission and releasing vasoactive agents (e.g., K(+)) from perivascular endfeet surrounding parenchymal arterioles. Previously, we demonstrated an increase in the amplitude of spontaneous Ca(2+) events in astrocyte endfeet and inversion of NVC from vasodilation to vasoconstriction in brain slices obtained from subarachnoid hemorrhage (SAH) model rats. However, the role of spontaneous astrocyte Ca(2+) signaling in determining the polarity of the NVC response remains unclear. Here, we used two-photon imaging of Fluo-4-loaded rat brain slices to determine whether altered endfoot Ca(2+) signaling underlies SAH-induced inversion of NVC. We report a time-dependent emergence of endfoot high-amplitude Ca(2+) signals (eHACSs) after SAH that were not observed in endfeet from unoperated animals. Furthermore, the percentage of endfeet with eHACSs varied with time and paralleled the development of inversion of NVC. Endfeet with eHACSs were present only around arterioles exhibiting inversion of NVC. Importantly, depletion of intracellular Ca(2+) stores using cyclopiazonic acid abolished SAH-induced eHACSs and restored arteriolar dilation in SAH brain slices to two mediators of NVC (a rise in endfoot Ca(2+) and elevation of extracellular K(+)). These data indicate a causal link between SAH-induced eHACSs and inversion of NVC. Ultrastructural examination using transmission electron microscopy indicated that a similar proportion of endfeet exhibiting eHACSs also exhibited asymmetrical enlargement. Our results demonstrate that subarachnoid blood causes a delayed increase in the amplitude of spontaneous intracellular Ca(2+) release events leading to inversion of NVC. Significance statement: Aneurysmal subarachnoid hemorrhage (SAH)--strokes involving cerebral aneurysm rupture and release of blood onto the brain surface--are associated with high rates of morbidity and mortality. A common complication observed after SAH is the development of delayed cerebral ischemia at sites often remote from the site of rupture. Here, we provide evidence that SAH-induced changes in astrocyte Ca(2+) signaling lead to a switch in the polarity of the neurovascular coupling response from vasodilation to vasoconstriction. Thus, after SAH, signaling events that normally lead to vasodilation and enhanced delivery of blood to active brain regions cause vasoconstriction that would limit cerebral blood flow. These findings identify astrocytes as a key player in SAH-induced decreased cortical blood flow. PMID- 26424886 TI - Dickkopf 3 Promotes the Differentiation of a Rostrolateral Midbrain Dopaminergic Neuronal Subset In Vivo and from Pluripotent Stem Cells In Vitro in the Mouse. AB - Wingless-related MMTV integration site 1 (WNT1)/beta-catenin signaling plays a crucial role in the generation of mesodiencephalic dopaminergic (mdDA) neurons, including the substantia nigra pars compacta (SNc) subpopulation that preferentially degenerates in Parkinson's disease (PD). However, the precise functions of WNT1/beta-catenin signaling in this context remain unknown. Stem cell-based regenerative (transplantation) therapies for PD have not been implemented widely in the clinical context, among other reasons because of the heterogeneity and incomplete differentiation of the transplanted cells. This might result in tumor formation and poor integration of the transplanted cells into the dopaminergic circuitry of the brain. Dickkopf 3 (DKK3) is a secreted glycoprotein implicated in the modulation of WNT/beta-catenin signaling. Using mutant mice, primary ventral midbrain cells, and pluripotent stem cells, we show that DKK3 is necessary and sufficient for the correct differentiation of a rostrolateral mdDA neuron subset. Dkk3 transcription in the murine ventral midbrain coincides with the onset of mdDA neurogenesis and is required for the activation and/or maintenance of LMX1A (LIM homeobox transcription factor 1alpha) and PITX3 (paired-like homeodomain transcription factor 3) expression in the corresponding mdDA precursor subset, without affecting the proliferation or specification of their progenitors. Notably, the treatment of differentiating pluripotent stem cells with recombinant DKK3 and WNT1 proteins also increases the proportion of mdDA neurons with molecular SNc DA cell characteristics in these cultures. The specific effects of DKK3 on the differentiation of rostrolateral mdDA neurons in the murine ventral midbrain, together with its known prosurvival and anti-tumorigenic properties, make it a good candidate for the improvement of regenerative and neuroprotective strategies in the treatment of PD. Significance statement: We show here that Dickkopf 3 (DKK3), a secreted modulator of WNT (Wingless-related MMTV integration site)/beta-catenin signaling, is both necessary and sufficient for the proper differentiation and survival of a rostrolateral (parabrachial pigmented nucleus and dorsomedial substantia nigra pars compacta) mesodiencephalic dopaminergic neuron subset, using Dkk3 mutant mice and murine primary ventral midbrain and pluripotent stem cells. The progressive loss of these dopamine-producing mesodiencephalic neurons is a hallmark of human Parkinson's disease, which can up to now not be halted by clinical treatments of this disease. Thus, the soluble DKK3 protein might be a promising new agent for the improvement of current protocols for the directed differentiation of pluripotent and multipotent stem cells into mesodiencephalic dopaminergic neurons and for the promotion of their survival in situ. PMID- 26424888 TI - Modulation of Neuronal Responses by Exogenous Attention in Macaque Primary Visual Cortex. AB - Visual perception is influenced by attention deployed voluntarily or triggered involuntarily by salient stimuli. Modulation of visual cortical processing by voluntary or endogenous attention has been extensively studied, but much less is known about how involuntary or exogenous attention affects responses of visual cortical neurons. Using implanted microelectrode arrays, we examined the effects of exogenous attention on neuronal responses in the primary visual cortex (V1) of awake monkeys. A bright annular cue was flashed either around the receptive fields of recorded neurons or in the opposite visual field to capture attention. A subsequent grating stimulus probed the cue-induced effects. In a fixation task, when the cue-to-probe stimulus onset asynchrony (SOA) was <240 ms, the cue induced a transient increase of neuronal responses to the probe at the cued location during 40-100 ms after the onset of neuronal responses to the probe. This facilitation diminished and disappeared after repeated presentations of the same cue but recurred for a new cue of a different color. In another task to detect the probe, relative shortening of monkey's reaction times for the validly cued probe depended on the SOA in a way similar to the cue-induced V1 facilitation, and the behavioral and physiological cueing effects remained after repeated practice. Flashing two cues simultaneously in the two opposite visual fields weakened or diminished both the physiological and behavioral cueing effects. Our findings indicate that exogenous attention significantly modulates V1 responses and that the modulation strength depends on both novelty and task relevance of the stimulus. Significance statement: Visual attention can be involuntarily captured by a sudden appearance of a conspicuous object, allowing rapid reactions to unexpected events of significance. The current study discovered a correlate of this effect in monkey primary visual cortex. An abrupt, salient, flash enhanced neuronal responses, and shortened the animal's reaction time, to a subsequent visual probe stimulus at the same location. However, the enhancement of the neural responses diminished after repeated exposures to this flash if the animal was not required to react to the probe. Moreover, a second, simultaneous, flash at another location weakened the neuronal and behavioral effects of the first one. These findings revealed, beyond the observations reported so far, the effects of exogenous attention in the brain. PMID- 26424887 TI - Simple Learned Weighted Sums of Inferior Temporal Neuronal Firing Rates Accurately Predict Human Core Object Recognition Performance. AB - To go beyond qualitative models of the biological substrate of object recognition, we ask: can a single ventral stream neuronal linking hypothesis quantitatively account for core object recognition performance over a broad range of tasks? We measured human performance in 64 object recognition tests using thousands of challenging images that explore shape similarity and identity preserving object variation. We then used multielectrode arrays to measure neuronal population responses to those same images in visual areas V4 and inferior temporal (IT) cortex of monkeys and simulated V1 population responses. We tested leading candidate linking hypotheses and control hypotheses, each postulating how ventral stream neuronal responses underlie object recognition behavior. Specifically, for each hypothesis, we computed the predicted performance on the 64 tests and compared it with the measured pattern of human performance. All tested hypotheses based on low- and mid-level visually evoked activity (pixels, V1, and V4) were very poor predictors of the human behavioral pattern. However, simple learned weighted sums of distributed average IT firing rates exactly predicted the behavioral pattern. More elaborate linking hypotheses relying on IT trial-by-trial correlational structure, finer IT temporal codes, or ones that strictly respect the known spatial substructures of IT ("face patches") did not improve predictive power. Although these results do not reject those more elaborate hypotheses, they suggest a simple, sufficient quantitative model: each object recognition task is learned from the spatially distributed mean firing rates (100 ms) of ~60,000 IT neurons and is executed as a simple weighted sum of those firing rates. Significance statement: We sought to go beyond qualitative models of visual object recognition and determine whether a single neuronal linking hypothesis can quantitatively account for core object recognition behavior. To achieve this, we designed a database of images for evaluating object recognition performance. We used multielectrode arrays to characterize hundreds of neurons in the visual ventral stream of nonhuman primates and measured the object recognition performance of >100 human observers. Remarkably, we found that simple learned weighted sums of firing rates of neurons in monkey inferior temporal (IT) cortex accurately predicted human performance. Although previous work led us to expect that IT would outperform V4, we were surprised by the quantitative precision with which simple IT-based linking hypotheses accounted for human behavior. PMID- 26424889 TI - Zac1 Regulates the Differentiation and Migration of Neocortical Neurons via Pac1. AB - Imprinted genes are dosage sensitive, and their dysregulated expression is linked to disorders of growth and proliferation, including fetal and postnatal growth restriction. Common sequelae of growth disorders include neurodevelopmental defects, some of which are indirectly related to placental insufficiency. However, several growth-associated imprinted genes are also expressed in the embryonic CNS, in which their aberrant expression may more directly affect neurodevelopment. To test whether growth-associated genes influence neural lineage progression, we focused on the maternally imprinted gene Zac1. In humans, either loss or gain of ZAC1 expression is associated with reduced growth rates and intellectual disability. To test whether increased Zac1 expression directly perturbs neurodevelopment, we misexpressed Zac1 in murine neocortical progenitors. The effects were striking: Zac1 delayed the transition of apical radial glial cells to basal intermediate neuronal progenitors and postponed their subsequent differentiation into neurons. Zac1 misexpression also blocked neuronal migration, with Zac1-overexpressing neurons pausing more frequently and forming fewer neurite branches during the period when locomoting neurons undergo dynamic morphological transitions. Similar, albeit less striking, neuronal migration and morphological defects were observed on Zac1 knockdown, indicating that Zac1 levels must be regulated precisely. Finally, Zac1 controlled neuronal migration by regulating Pac1 transcription, a receptor for the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP). Pac1 and Zac1 loss- and gain-of function presented as phenocopies, and overexpression of Pac1 rescued the Zac1 knockdown neuronal migration phenotype. Thus, dysregulated Zac1 expression has striking consequences on neocortical development, suggesting that misexpression of this transcription factor in the brain in certain growth disorders may contribute to neurocognitive deficits. Significance statement: Altered expression of imprinted genes is linked to cognitive dysfunction and neuropsychological disorders, such as Angelman and Prader-Willi syndromes, and autism spectrum disorder. Mouse models have also revealed the importance of imprinting for brain development, with chimeras generated with parthenogenetic (two maternal chromosomes) or androgenetic (two paternal chromosomes) cells displaying altered brain sizes and cellular defects. Despite these striking phenotypes, only a handful of imprinted genes are known or suspected to regulate brain development (e.g., Dlk1, Peg3, Ube3a, necdin, and Grb10). Herein we show that the maternally imprinted gene Zac1 is a critical regulator of neocortical development. Our studies are relevant because loss of 6q24 maternal imprinting in humans results in elevated ZAC1 expression, which has been associated with neurocognitive defects. PMID- 26424891 TI - Tonic Local Brain Blood Flow Control by Astrocytes Independent of Phasic Neurovascular Coupling. AB - According to the current model of neurovascular coupling, blood flow is controlled regionally through phasic changes in the activity of neurons and astrocytes that signal to alter arteriole diameter. Absent in this model, however, is how brain blood flow is tonically regulated independent of regional changes in activity. This is important because a large fraction of brain blood flow is required to maintain basal metabolic needs. Using two-photon fluorescence imaging combined with patch-clamp in acute rat brain slices of sensory-motor cortex, we demonstrate that reducing resting Ca(2+) in astrocytes with intracellular BAPTA causes vasoconstriction in adjacent arterioles. BAPTA-induced vasoconstriction was eliminated by a general COX blocker and the effect is mimicked by a COX-1, but not COX-2, antagonist, suggesting that astrocytes provide tonic, steady-state vasodilation by releasing prostaglandin messengers. Tonic vasodilation was insensitive to TTX, as well as a variety of synaptic and extrasynaptic receptor antagonists, indicating that the phenomenon operates largely independent of neural activity. Using in vivo two-photon fluorescence imaging of the barrel cortex in fully awake mice, we reveal that acute COX-1 inhibition reduces resting arteriole diameter but fails to affect vasodilation in response to vibrissae stimulation. Our findings demonstrate that astrocytes provide tonic regulation of arterioles using resting intracellular Ca(2+) in a manner that is independent of phasic, neuronal-evoked vasodilation. Significance statement: The brain requires both phasic and tonic regulation of its blood supply to service energy needs over various temporal windows. While many mechanisms have been described for phasic blood flow regulation, how the brain accomplishes tonic control is largely unknown. Here we describe a way in which astrocytes contribute to the management of basal brain blood flow by providing steady-state vasodilation to arterioles via resting astrocyte Ca(2+) and the continuous release of prostaglandin messengers. This phenomenon may be important for understanding the declines in basal brain blood flow that occur in aging and dementia, as well as for the interpretation of fMRI data. PMID- 26424890 TI - Modeling of Age-Dependent Epileptogenesis by Differential Homeostatic Synaptic Scaling. AB - Homeostatic synaptic plasticity (HSP) has been implicated in the development of hyperexcitability and epileptic seizures following traumatic brain injury (TBI). Our in vivo experimental studies in cats revealed that the severity of TBI mediated epileptogenesis depends on the age of the animal. To characterize mechanisms of these differences, we studied the properties of the TBI-induced epileptogenesis in a biophysically realistic cortical network model with dynamic ion concentrations. After deafferentation, which was induced by dissection of the afferent inputs, there was a reduction of the network activity and upregulation of excitatory connections leading to spontaneous spike-and-wave type seizures. When axonal sprouting was implemented, the seizure threshold increased in the model of young but not the older animals, which had slower or unidirectional homeostatic processes. Our study suggests that age-related changes in the HSP mechanisms are sufficient to explain the difference in the likelihood of seizure onset in young versus older animals. Significance statement: Traumatic brain injury (TBI) is one of the leading causes of intractable epilepsy. Likelihood of developing epilepsy and seizures following severe brain trauma has been shown to increase with age. Specific mechanisms of TBI-related epileptogenesis and how these mechanisms are affected by age remain to be understood. We test a hypothesis that the failure of homeostatic synaptic regulation, a slow negative feedback mechanism that maintains neural activity within a physiological range through activity-dependent modulation of synaptic strength, in older animals may augment TBI-induced epileptogenesis. Our results provide new insight into understanding this debilitating disorder and may lead to novel avenues for the development of effective treatments of TBI-induced epilepsy. PMID- 26424892 TI - Intracortical and Thalamocortical Connections of the Hand and Face Representations in Somatosensory Area 3b of Macaque Monkeys and Effects of Chronic Spinal Cord Injuries. AB - Brains of adult monkeys with chronic lesions of dorsal columns of spinal cord at cervical levels undergo large-scale reorganization. Reorganization results in expansion of intact chin inputs, which reactivate neurons in the deafferented hand representation in the primary somatosensory cortex (area 3b), ventroposterior nucleus of the thalamus and cuneate nucleus of the brainstem. A likely contributing mechanism for this large-scale plasticity is sprouting of axons across the hand-face border. Here we determined whether such sprouting takes place in area 3b. We first determined the extent of intrinsic corticocortical connectivity between the hand and the face representations in normal area 3b. Small amounts of neuroanatomical tracers were injected in these representations close to the electrophysiologically determined hand-face border. Locations of the labeled neurons were mapped with respect to the detailed electrophysiological somatotopic maps and histologically determined hand-face border revealed in sections of the flattened cortex stained for myelin. Results show that intracortical projections across the hand-face border are few. In monkeys with chronic unilateral lesions of the dorsal columns and expanded chin representation, connections across the hand-face border were not different compared with normal monkeys. Thalamocortical connections from the hand and face representations in the ventroposterior nucleus to area 3b also remained unaltered after injury. The results show that sprouting of intrinsic connections in area 3b or the thalamocortical inputs does not contribute to large-scale cortical plasticity. Significance statement: Long-term injuries to dorsal spinal cord in adult primates result in large-scale somatotopic reorganization due to which chin inputs expand into the deafferented hand region. Reorganization takes place in multiple cortical areas, and thalamic and medullary nuclei. To what extent this brain reorganization due to dorsal column injuries is related to axonal sprouting is not known. Here we show that reorganization of primary somatosensory area 3b is not accompanied with either an increase in intrinsic cortical connections between the hand and face representations, or any change in thalamocortical inputs to these areas. Axonal sprouting that causes reorganization likely takes place at subthalamic levels. PMID- 26424894 TI - Signal Propagation in the Human Visual Pathways: An Effective Connectivity Analysis. AB - Although the visual system has been extensively investigated, an integrated account of the spatiotemporal dynamics of long-range signal propagation along the human visual pathways is not completely known or validated. In this work, we used dynamic causal modeling approach to provide insights into the underlying neural circuit dynamics of pattern reversal visual-evoked potentials extracted from concurrent EEG-fMRI data. A recurrent forward-backward connectivity model, consisting of multiple interacting brain regions identified by EEG source localization aided by fMRI spatial priors, best accounted for the data dynamics. Sources were first identified in the thalamic area, primary visual cortex, as well as higher cortical areas along the ventral and dorsal visual processing streams. Consistent with hierarchical early visual processing, the model disclosed and quantified the neural temporal dynamics across the identified activity sources. This signal propagation is dominated by a feedforward process, but we also found weaker effective feedback connectivity. Using effective connectivity analysis, the optimal dynamic causal modeling revealed enhanced connectivity along the dorsal pathway but slightly suppressed connectivity along the ventral pathway. A bias was also found in favor of the right hemisphere consistent with functional attentional asymmetry. This study validates, for the first time, the long-range signal propagation timing in the human visual pathways. A similar modeling approach can potentially be used to understand other cognitive processes and dysfunctions in signal propagation in neurological and neuropsychiatric disorders. Significance statement: An integrated account of long range visual signal propagation in the human brain is currently incomplete. Using computational neural modeling on our acquired concurrent EEG-fMRI data under a visual evoked task, we found not only a substantial forward propagation toward "higher-order" brain regions but also a weaker backward propagation. Asymmetry in our model's long-range connectivity accounted for the various observed activity biases. Importantly, the model disclosed the timing of signal propagation across these connectivity pathways and validates, for the first time, long-range signal propagation in the human visual system. A similar modeling approach could be used to identify neural pathways for other cognitive processes and their dysfunctions in brain disorders. PMID- 26424893 TI - The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory Neuron Responses to TRPV1 by Activation of TLR4. AB - Peripheral neuropathy is dose limiting in paclitaxel cancer chemotherapy and can result in both acute pain during treatment and chronic persistent pain in cancer survivors. The hypothesis tested was that paclitaxel produces these adverse effects at least in part by sensitizing transient receptor potential vanilloid subtype 1 (TRPV1) through Toll-like receptor 4 (TLR4) signaling. The data show that paclitaxel-induced behavioral hypersensitivity is prevented and reversed by spinal administration of a TRPV1 antagonist. The number of TRPV1(+) neurons is increased in the dorsal root ganglia (DRG) in paclitaxel-treated rats and is colocalized with TLR4 in rat and human DRG neurons. Cotreatment of rats with lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides (LPS RS), a TLR4 inhibitor, prevents the increase in numbers of TRPV1(+) neurons by paclitaxel treatment. Perfusion of paclitaxel or the archetypal TLR4 agonist LPS activated both rat DRG and spinal neurons directly and produced acute sensitization of TRPV1 in both groups of cells via a TLR4-mediated mechanism. Paclitaxel and LPS sensitize TRPV1 in HEK293 cells stably expressing human TLR4 and transiently expressing human TRPV1. These physiological effects also are prevented by LPS-RS. Finally, paclitaxel activates and sensitizes TRPV1 responses directly in dissociated human DRG neurons. In summary, TLR4 was activated by paclitaxel and led to sensitization of TRPV1. This mechanism could contribute to paclitaxel-induced acute pain and chronic painful neuropathy. Significance statement: In this original work, it is shown for the first time that paclitaxel activates peripheral sensory and spinal neurons directly and sensitizes these cells to transient receptor potential vanilloid subtype 1 (TRPV1)-mediated capsaicin responses via Toll-like receptor 4 (TLR4) in multiple species. A direct functional interaction between TLR4 and TRPV1 is shown in rat and human dorsal root ganglion neurons, TLR4/TRPV1-coexpressing HEK293 cells, and in both rat and mouse spinal cord slices. Moreover, this is the first study to show that this interaction plays an important role in the generation of behavioral hypersensitivity in paclitaxel-related neuropathy. The key translational implications are that TLR4 and TRPV1 antagonists may be useful in the prevention and treatment of chemotherapy-induced peripheral neuropathy in humans. PMID- 26424895 TI - Trace Fear Conditioning Differentially Modulates Intrinsic Excitability of Medial Prefrontal Cortex-Basolateral Complex of Amygdala Projection Neurons in Infralimbic and Prelimbic Cortices. AB - Neuronal activity in medial prefrontal cortex (mPFC) is critical for the formation of trace fear memory, yet the cellular mechanisms underlying these memories remain unclear. One possibility involves the modulation of intrinsic excitability within mPFC neurons that project to the basolateral complex of amygdala (BLA). The current study used a combination of retrograde labeling and in vitro whole-cell patch-clamp recordings to examine the effect of trace fear conditioning on the intrinsic excitability of layer 5 mPFC-BLA projection neurons in adult rats. Trace fear conditioning significantly enhanced the intrinsic excitability of regular spiking infralimbic (IL) projection neurons, as evidenced by an increase in the number of action potentials after current injection. These changes were also associated with a reduction in spike threshold and an increase in h current. In contrast, trace fear conditioning reduced the excitability of regular spiking prelimbic (PL) projection neurons, through a learning-related decrease of input resistance. Interestingly, the amount of conditioned freezing was (1) positively correlated with excitability of IL-BLA projection neurons after conditioning and (2) negatively correlated with excitability of PL-BLA projection neurons after extinction. Trace fear conditioning also significantly enhanced the excitability of burst spiking PL-BLA projection neurons. In both regions, conditioning-induced plasticity was learning specific (observed in conditioned but not in pseudoconditioned rats), flexible (reversed by extinction), and transient (lasted <10 d). Together, these data suggest that intrinsic plasticity within mPFC-BLA projection neurons occurs in a subregion- and cell-type-specific manner during acquisition, consolidation, and extinction of trace fear conditioning. Significance statement: Frontal lobe-related function is vital for a variety of important behaviors, some of which decline during aging. This study involves a novel combination of electrophysiological recordings from fluorescently labeled mPFC-to-amygdala projection neurons in rats with acquisition and extinction of trace fear conditioning to determine how specific neurons change during behavior. This is the first study to demonstrate that trace fear conditioning significantly alters the intrinsic excitability of mPFC-to amygdala projection neurons in a subregion- and cell-type-specific manner, which is also transient and reversed by extinction. These data are of broad interest to the neuroscientific community, and the results will inspire additional studies investigating the cellular mechanisms underlying circuit-specific changes within the brain as a result of associative learning and memory. PMID- 26424897 TI - Subthalamic nucleus stimulation improves Parkinson's disease-associated camptocormia in parallel to its preoperative levodopa responsiveness. AB - OBJECTIVE: The aim of this work was to identify factors predictive of postoperative improvement of camptocormia in patients with Parkinson's disease (PD) treated by subthalamic nucleus (STN) stimulation. BACKGROUND: Camptocormia, one of the most disabling features of PD, often responds poorly to medical therapies. The reported effects of deep brain stimulation on PD-associated camptocormia vary, and preoperative characteristics affecting the surgical outcome remain unclear. METHODS: We evaluated 17 patients with camptocormia whose preoperative off-medication thoracolumbar angle exceeded 45 degrees . We used photographs to measure their thoracolumbar angle preoperatively, 3 months after surgery, and at the last follow-up (mean 36.5 months postoperatively) in status on-medication and off-medication. The patient age, duration of PD and camptocormia, daily medications, Unified Parkinson's Disease Rating Scale (UPDRS) subscores and the Schwab-England activity of daily living scale (S-E) were also recorded. Univariate analysis was performed to identify factors predictive of the postoperative improvement of camptocormia. RESULTS: STN stimulation significantly improved the UPDRS subscores and S-E, and resulted in a reduction of daily medications 3 months post-treatment. The preoperative thoracolumbar angle (mean+/ SD) in status off-medication (84.0+/-29.5 degrees ) was significantly ameliorated 3 months postoperatively (49.8+/-29.3 degrees ) and at the last follow-up (54.8+/ 28.3 degrees ). There was no correlation between the postoperative camptocormia improvement rate and preoperative parameters other than the duration and severity of camptocormia and the levodopa responsiveness of the thoracolumbar angle. Symptom duration negatively affected levodopa responsiveness. CONCLUSIONS: STN stimulation improves PD-associated camptocormia in parallel with preoperative levodopa responsiveness. Long symptom duration interferes with levodopa responsiveness. PMID- 26424896 TI - TRPV4 and AQP4 Channels Synergistically Regulate Cell Volume and Calcium Homeostasis in Retinal Muller Glia. AB - Brain edema formation occurs after dysfunctional control of extracellular volume partly through impaired astrocytic ion and water transport. Here, we show that such processes might involve synergistic cooperation between the glial water channel aquaporin 4 (AQP4) and the transient receptor potential isoform 4 (TRPV4), a polymodal swelling-sensitive cation channel. In mouse retinas, TRPV4 colocalized with AQP4 in the end feet and radial processes of Muller astroglia. Genetic ablation of TRPV4 did not affect the distribution of AQP4 and vice versa. However, retinas from Trpv4(-/-) and Aqp4(-/-) mice exhibited suppressed transcription of genes encoding Trpv4, Aqp4, and the Kir4.1 subunit of inwardly rectifying potassium channels. Swelling and [Ca(2+)]i elevations evoked in Muller cells by hypotonic stimulation were antagonized by the selective TRPV4 antagonist HC-067047 (2-methyl-1-[3-(4-morpholinyl)propyl]-5-phenyl-N-[3 (trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide) or Trpv4 ablation. Elimination of Aqp4 suppressed swelling-induced [Ca(2+)]i elevations but only modestly attenuated the amplitude of Ca(2+) signals evoked by the TRPV4 agonist GSK1016790A [(N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3 hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2 carboxamide]. Glial cells lacking TRPV4 but not AQP4 showed deficits in hypotonic swelling and regulatory volume decrease. Functional synergy between TRPV4 and AQP4 during cell swelling was confirmed in the heterologously expressing Xenopus oocyte model. Importantly, when the swelling rate was osmotically matched for AQP4-positive and AQP4-negative oocytes, TRPV4 activation became independent of AQP4. We conclude that AQP4-mediated water fluxes promote the activation of the swelling sensor, whereas Ca(2+) entry through TRPV4 channels reciprocally modulates volume regulation, swelling, and Aqp4 gene expression. Therefore, TRPV4 AQP4 interactions constitute a molecular system that fine-tunes astroglial volume regulation by integrating osmosensing, calcium signaling, and water transport and, when overactivated, triggers pathological swelling. Significance statement: We characterize the physiological features of interactions between the astroglial swelling sensor transient receptor potential isoform 4 (TRPV4) and the aquaporin 4 (AQP4) water channel in retinal Muller cells. Our data reveal an elegant and complex set of mechanisms involving reciprocal interactions at the level of glial gene expression, calcium homeostasis, swelling, and volume regulation. Specifically, water influx through AQP4 drives calcium influx via TRPV4 in the glial end foot, which regulates expression of Aqp4 and Kir4.1 genes and facilitates the time course and amplitude of hypotonicity-induced swelling and regulatory volume decrease. We confirm the crucial facets of the signaling mechanism in heterologously expressing oocytes. These results identify the molecular mechanism that contributes to dynamic regulation of glial volume but also provide new insights into the pathophysiology of glial reactivity and edema formation. PMID- 26424898 TI - Bilateral adaptive deep brain stimulation is effective in Parkinson's disease. AB - INTRODUCTION & OBJECTIVES: Adaptive deep brain stimulation (aDBS) uses feedback from brain signals to guide stimulation. A recent acute trial of unilateral aDBS showed that aDBS can lead to substantial improvements in contralateral hemibody Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and may be superior to conventional continuous DBS in Parkinson's disease (PD). We test whether potential benefits are retained with bilateral aDBS and in the face of concurrent medication. METHODS: We applied bilateral aDBS in 4 patients with PD undergoing DBS of the subthalamic nucleus. aDBS was delivered bilaterally with independent triggering of stimulation according to the amplitude of beta activity at the corresponding electrode. Mean stimulation voltage was 3.0+/-0.1 volts. Motor assessments consisted of double-blinded video-taped motor UPDRS scores that included both limb and axial features. RESULTS: UPDRS scores were 43% (p=0.04; Cohen's d=1.62) better with aDBS than without stimulation. Motor improvement with aDBS occurred despite an average time on stimulation (ToS) of only 45%. Levodopa was well tolerated during aDBS and led to further reductions in ToS. CONCLUSION: Bilateral aDBS can improve both axial and limb symptoms and can track the need for stimulation across drug states. PMID- 26424900 TI - Stress Concentration of Periodic Collinear Square Holes in an Infinite Plate in Tension. AB - A numerical approach for the stress concentration of periodic collinear holes in an infinite plate in tension is presented. It involves the fictitious stress method and a generalization of Bueckner's principle. Numerical examples are concluded to show that the numerical approach is very efficient and accurate for analyzing the stress concentration of periodic collinear holes in an infinite plate in tension. The stress concentration of periodic collinear square holes in an infinite plate in tension is studied in detail by using the numerical approach. The calculated stress concentration factor is proven to be accurate. PMID- 26424899 TI - Heat Transfer in Health and Healing. AB - Our bodies depend on an exquisitely sensitive and refined temperature control system to maintain a state of health and homeostasis. The exceptionally broad range of physical activities that humans engage in and the diverse array of environmental conditions we face require remarkable strategies and mechanisms for regulating internal and external heat transfer processes. On the occasions for which the body suffers trauma, therapeutic temperature modulation is often the approach of choice for reversing injury and inflammation and launching a cascade of healing. The focus of human thermoregulation is maintenance of the body core temperature within a tight range of values, even as internal rates of energy generation may vary over an order of magnitude, environmental convection, and radiation heat loads may undergo large changes in the absence of any significant personal control, surface insulation may be added or removed, all occurring while the body's internal thermostat follows a diurnal circadian cycle that may be altered by illness and anesthetic agents. An advanced level of understanding of the complex physiological function and control of the human body may be combined with skill in heat transfer analysis and design to develop life-saving and injury healing medical devices. This paper will describe some of the challenges and conquests the author has experienced related to the practice of heat transfer for maintenance of health and enhancement of healing processes. PMID- 26424901 TI - A Novel Screening and Diagnostic Tool for Child and Adolescent Psychiatric Disorders for Telepsychiatry. AB - BACKGROUND: A diagnostic tool designed as part of a telepsychiatry application for diagnosis and management of child and adolescent psychiatric disorders in India was developed considering the paucity of trained child psychiatrists and mental health professionals in India. MATERIALS AND METHODS: The diagnostic tool consisted of screening and 10(th) revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) criteria-based diagnostic algorithms for 18 psychiatric disorders seen in childhood and adolescence. Accuracy of diagnoses and feasibility of use of the tool was examined by comparing it with detailed semi-structured clinical evaluations by a qualified psychiatrist with 50 psychiatric patients (children and adolescents). STATISTICAL ANALYSIS: Descriptive analyses and paired t-tests were conducted to compare the mean number of diagnosis generated by the two interviews. Sensitivity, specificity, positive and negative predictive values were computed for the screening and the diagnostic sub-modules of the tool, compared to the clinical diagnoses. Kappa coefficients were computed to assess agreement between the diagnoses generated by the diagnostic sub-module and the clinical diagnoses. RESULTS: The screening sub-module had high sensitivity, high specificity and negative predictive values for all disorders. For the diagnostic sub-module, there was moderate (kappa-0.4-0.6) to substantial agreement (kappa > 0.6) for all the disorders, (except psychosis) and high sensitivity (barring a few disorders) and specificity for almost all the disorders. Positive predictive values were found to be acceptable to high for most disorders, with consistently high negative predictive values. CONCLUSION: The new tool was found to be comprehensive, reasonably short and feasible. Results showed acceptable level of accuracy in diagnosis generated by the tool. PMID- 26424902 TI - Clinical Significance of SASH1 Expression in Glioma. AB - OBJECTIVE: SAM and SH3 domain containing 1 (SASH1) is a recently discovered tumor suppressor gene. The role of SASH1 in glioma has not yet been described. We investigated SASH1 expression in glioma cases to determine its clinical significance on glioma pathogenesis and prognosis. METHODS: We produced tissue microarrays using 121 patient-derived glioma samples and 30 patient-derived nontumor cerebral samples. Immunohistochemistry and Western blotting were used to evaluate SASH1 expression. We used Fisher's exact tests to determine relationships between SASH1 expression and clinicopathological characteristics; Cox regression analysis to evaluate the independency of different SASH1 expression; Kaplan-Meier analysis to determine any correlation of SASH1 expression with survival rate. RESULTS: SASH1 expression was closely correlated with the WHO glioma grade. Of the 121 cases, 66.9% with low SASH1 expression were mostly grade III-IV cases, whereas 33.1% with high SASH1 expression were mostly grades I-II. Kaplan-Meier analysis revealed a significant positive correlation between SASH1 expression and postoperative survival. CONCLUSIONS: SASH1 was widely expressed in normal and low-grade glioma tissues. SASH1 expression strongly correlated with glioma grades, showing higher expression at a lower grade, which decreased significantly as grade increased. Furthermore, SASH1 expression was positively correlated with better postoperative survival in patients with glioma. PMID- 26424903 TI - Aerobic Glycolysis as a Marker of Tumor Aggressiveness: Preliminary Data in High Grade Human Brain Tumors. AB - OBJECTIVES: Glucose metabolism outside of oxidative phosphorylation, or aerobic glycolysis (AG), is a hallmark of active cancer cells that is not directly measured with standard (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET). In this study, we characterized tumor regions with elevated AG defined based on PET measurements of glucose and oxygen metabolism. METHODS: Fourteen individuals with high-grade brain tumors underwent structural MR scans and PET measurements of cerebral blood flow (CBF), oxygen (CMRO2) and glucose (CMRGlu) metabolism, and AG, using (15)O-labeled CO, O2 and H2O, and FDG, and were compared to a normative cohort of 20 age-matched individuals. RESULTS: Elevated AG was observed in most high-grade brain tumors and it was associated with decreased CMRO2 and CBF, but not with significant changes in CMRGlu. Elevated AG was a dramatic and early sign of tumor growth associated with decreased survival. AG changes associated with tumor growth were differentiated from the effects of nonneoplastic processes such as epileptic seizures. CONCLUSIONS: Our findings demonstrate that high-grade brain tumors exhibit elevated AG as a marker of tumor growth and aggressiveness. AG may detect areas of active tumor growth that are not evident on conventional FDG PET. PMID- 26424904 TI - Exploring Discrimination and Mental Health Disparities Faced By Black Sexual Minority Women Using a Minority Stress Framework. AB - Black sexual minority women are triply marginalized due to their race, gender, and sexual orientation. We compared three dimensions of discrimination-frequency (regularity of occurrences), scope (number of types of discriminatory acts experienced), and number of bases (number of social statuses to which discrimination was attributed)-and self-reported mental health (depressive symptoms, psychological well-being, and social well-being) between 64 Black sexual minority women and each of two groups sharing two of three marginalized statuses: (a) 67 White sexual minority women and (b) 67 Black sexual minority men. Black sexual minority women reported greater discrimination frequency, scope, and number of bases and poorer psychological and social well-being than White sexual minority women and more discrimination bases, a higher level of depressive symptoms, and poorer social well-being than Black sexual minority men. We then tested and contrasted dimensions of discrimination as mediators between social status (race or gender) and mental health outcomes. Discrimination frequency and scope mediated the association between race and mental health, with a stronger effect via frequency among sexual minority women. Number of discrimination bases mediated the association between gender and mental health among Black sexual minorities. Future research and clinical practice would benefit from considering Black sexual minority women's mental health in a multidimensional minority stress context. PMID- 26424905 TI - Association of increased rate of condemnation of broiler carcasses due to hepatic abnormalities with immunosuppressive diseases in the broiler chicken industry in Saskatchewan. AB - The objective of this study was to identify the causative agents of hepatitis observed in broiler chickens at processing. Livers of chickens from 16 broiler farms in Saskatchewan with gross lesions of hepatitis were collected at processing. In addition to routine bacterial isolation and histopathological examination, serologic studies for infectious bursal disease virus (IBDV) and Chicken anaemia virus (CAV), calculation of the ratio of the weight of the bursa of Fabricius (BF) to body weight (BBW), and histopathological examination of the BF were done. Of the 264 livers with gross lesions, 83% had multifocal to coalescing necrotizing hepatitis, 16% had perihepatitis, and 1% had hemorrhages. No definitive causative microorganisms were isolated from the hepatic lesions; however, no significant bacterial isolations were made. Bursal atrophy, low BBW ratio, and high titer of antibody against IBDV each correlated with the rate of total condemnations (P = 0.0188, P = 0.0001, and P = 0.0073, respectively). Nucleotide sequencing of IBDV isolated from the BF identified the variant strains Delaware-E and 586. Condemnation because of hepatic lesions was correlated with titer of antibody against IBDV and BBW (P = 0.016 and P = 0.027). The results of this study demonstrate that hepatic lesions in Saskatchewan chickens are not currently caused by a primary bacterial pathogen but are associated with indicators of immunosuppression that is likely due to variant IBDV. PMID- 26424906 TI - Descriptive analysis and spatial epidemiology of porcine reproductive and respiratory syndrome (PRRS) for swine sites participating in area regional control and elimination programs from 3 regions of Ontario. AB - The objectives of this study were to describe demographics, basic biosecurity practices, ownership structure, and prevalence of porcine reproductive and respiratory syndrome (PRRS) in swine sites located in 3 regions in Ontario, and investigate the presence of spatial clustering and clusters of PRRS positive sites in the 3 regions. A total of 370 swine sites were enrolled in Area Regional Control and Elimination projects in Niagara, Watford, and Perth from 2010 to 2013. Demographics, biosecurity, and site ownership data were collected using a standardized questionnaire and site locations were obtained from an industry organization. Status was assigned on the basis of available diagnostic tests and/or assessment by site veterinarians. Spatial dependence was investigated using the D-function, the spatial scan statistic test and the spatial relative risk method. Results showed that the use of strict all-in all-out (AIAO) pig flow and shower before entry are uncommon biosecurity practices in swine sites, but a larger proportion of sites reported having a Danish entry. The prevalence of PRRS in the 3 regions ranged from 17% to 48% and localized high and low risk clusters were detected. Sites enrolled in the PRRS control projects were characterized by membership in multiple and overlapping ownership structures and networks, which complicates the way the results of monitoring and disease management measures are communicated to the target population. PMID- 26424907 TI - Streptococcus suis in employees and the environment of swine slaughterhouses in Sao Paulo, Brazil: Occurrence, risk factors, serotype distribution, and antimicrobial susceptibility. AB - Streptococcus suis is an important pathogen in the swine industry. This article is the first to report the occurrence, risk factors, serotype distribution, and antimicrobial susceptibility of S. suis recovered from employees and environmental samples of swine slaughterhouses in Brazil. Tonsillar swabs from all 139 pig-slaughtering employees and 261 environmental swabs were collected for detection of S. suis and serotyping by monoplex and multiplex polymerase chain reaction, respectively. Antimicrobial susceptibility was determined by the disk diffusion method. Although S. suis was not detected in any of the tested employees, it was isolated from 25% of the environmental samples. Significant differences (P < 0.05) in the occurrence of S. suis were observed between slaughterhouses and between areas of low, medium, and high risk. The most frequent serotypes were 4 and 29, each accounting for 12% of the isolates, followed by 5, 12, 21, and 31, each accounting for 6%. High rates of susceptibility to the antimicrobials doxycycline (100%), ceftiofur (94%), ampicillin (81%), and cephalexin (75%) were observed. However, multidrug resistance was observed in all the isolates. Because S. suis is present in the environment of swine slaughterhouses, on carcasses and knives, as well as on the hands of employees in all areas, all employees are at risk of infection. PMID- 26424908 TI - Antimicrobial effect against different bacterial strains and bacterial adaptation to essential oils used as feed additives. AB - The aim of this study was to evaluate the antimicrobial activity and determine the minimum bactericidal concentration (MBC) of the essential oils derived from Origanum vulgare (oregano), Melaleuca alternifolia (tea tree), Cinnamomum cassia (cassia), and Thymus vulgaris (white thyme) against Salmonella Typhimurium, Salmonella Enteritidis, Escherichia coli, Staphylococcus aureus and Enterococcus faecalis. The study also investigated the ability of these different bacterial strains to develop adaptation after repetitive exposure to sub-lethal concentrations of these essential oils. The MBC of the essential oils studied was determined by disc diffusion and broth dilution methods. All essential oils showed antimicrobial effect against all bacterial strains. In general, the development of adaptation varied according to the bacterial strain and the essential oil (tea tree > white thyme > oregano). Therefore, it is important to use essential oils at efficient bactericidal doses in animal feed, food, and sanitizers, since bacteria can rapidly develop adaptation when exposed to sub lethal concentrations of these oils. PMID- 26424909 TI - Prevalence of internal parasites in beef cows in the United States: Results of the National Animal Health Monitoring System's (NAHMS) beef study, 2007-2008. AB - During the United States Department of Agriculture (USDA) National Animal Health Monitoring System's (NAHMS) 2007-2008 beef study, 567 producers from 24 US States were offered the opportunity to collect fecal samples from weaned beef calves and have them evaluated for the presence of parasite eggs (Phase 1). Participating producers were provided with instructions and materials for sample collection. Up to 20 fresh fecal samples were collected from each of the 99 participating operations. Fresh fecal samples were submitted to one of 3 randomly assigned laboratories for evaluation. Upon arrival at the laboratories, all samples were processed for the enumeration of strongyle, Nematodirus, and Trichuris eggs using the modified Wisconsin technique. The presence or absence of coccidian oocysts and tapeworm eggs was also noted. In submissions where the strongyle eggs per gram exceeded 30, aliquots from 2 to 6 animals were pooled for DNA extraction. Extracted DNA was subjected to genus level polymerase chain reaction (PCR) identification for the presence of Ostertagia, Cooperia, Haemonchus, Oesophagostomum, and Trichostrongylus. In this study, 85.6% of the samples had strongyle type, Nematodirus, and Trichuris eggs. Among the samples evaluated, 91% had Cooperia, 79% Ostertagia, 53% Haemonchus, 38% Oesophagostomum, 18% Nematodirus, 7% Trichuris, and 3% Trichostrongylus. The prevalence of coccidia and tapeworm eggs was 59.9% and 13.7%, respectively. PMID- 26424910 TI - Effectiveness of current anthelmintic treatment programs on reducing fecal egg counts in United States cow-calf operations. AB - During the United States Department of Agriculture (USDA) National Animal Health Monitoring System's (NAHMS) 2007-2008 beef study, producers from 24 states were offered the opportunity to evaluate their animals for internal parasites and for overall responses to treatment with anthelmintics. A lapse of 45 d was required between initial sampling and any previous treatments. Choice of anthelmintic (oral benzimidazoles, and both injectable and pour-on endectocides) was at the discretion of the producer so as not to alter the local control programs. Fresh fecal samples were collected from 20 animals, or from the entire group if less than 20, then randomly assigned to 1 of 3 participating laboratories for examination. Analyses consisted of double centrifugation flotation followed by enumeration of strongyle, Nematodirus, and Trichuris eggs (the presence of coccidian oocysts and tapeworm eggs was also noted). Where strongyle eggs per gram (epg) exceeded 30, aliquots from 2 to 6 animals were pooled for egg isolation and polymerase chain reaction (PCR) analysis for the presence of Ostertagia, Cooperia, Haemonchus, Oesophagostomum, and Trichostrongylus. Results from 72 producers (19 States) indicated that fecal egg count reductions were < 90% in 1/3 of the operations. All operations exhibiting less than a 90% reduction had used pour-on macrocyclic lactones as the anthelmintic treatment. While some of these less than expected reductions could have been the result of improper drug application, PCR analyses of the parasite populations surviving treatment, coupled with follow-up studies at a limited number of sites, indicated that less than expected reductions were most likely due to anthelmintic resistance in Cooperia spp. and possibly Haemonchus spp. PMID- 26424911 TI - Efficacy of a topical bovine-derived thrombin solution as a hemostatic agent in a rodent model of hepatic injury. AB - Hemorrhage is a major concern in patients undergoing hepatic surgery or in those with hepatic trauma. In these cases, employing traditional hemostatic strategies can be problematic due to the diffuse nature of hepatic hemorrhage and limited opportunities for direct hemostasis. This study assessed the efficacy of a bovine derived thrombin solution, (BT), as a topical liquid agent to augment hemostasis and survival following severe hepatic hemorrhage in a rat model. Heart rate (HR), arterial blood pressure (ABP), packed cell volume (PCV), and overall survival were evaluated in 54 rats randomly assigned to receive topical application of BT, saline, or suture ligation applied immediately to a liver lobe following controlled laceration. Six additional rats received liver laceration with no applied treatment. Intravenous fluid resuscitation was initiated and HR and ABP were recorded for 60 min, after which survivors were recovered from anesthesia. Rats were then monitored for 72 h, after which survivors were euthanized. There was no significant difference in survival time, percentage survival, intra operative ABP or HR, or post-operative PCV between treatment groups. There is insufficient evidence to recommend BT as the sole therapy using this delivery method for mitigating severe hemorrhage from liver injury. PMID- 26424912 TI - Hemodynamic effects of target-controlled infusion of propofol alone or in combination with a constant-rate infusion of remifentanil in dogs. AB - The objective of this study was to evaluate the hemodynamic effects of target controlled infusion (TCI) of propofol alone or in combination with a constant rate infusion (CRI) of remifentanil. Six adult dogs were given 2 treatments in a randomized crossover study with a 7-day interval between treatments. Treatment 1 was propofol (P) and treatment 2 was propofol and remifentanil (P-Rem), without any premedication. Propofol was induced using a TCI system with a predicted plasma concentration (Cp) of 6.0 MUg/mL. Anesthesia was maintained within the Cp range (0.65 to 3.0 MUg/mL) for 120 min and remifentanil was administered at a rate of 0.3 MUg/kg body weight (BW) per minute, CRI. Cardiopulmonary variables were recorded before (baseline), during, and 120 min after drug administration. Heart rate (HR) decreased significantly in the P-Rem group (46%) compared with baseline values. In the P-Rem group, the cardiac index (CI) decreased significantly (49% to 58%) and the stroke volume (SV) decreased compared with baseline values. The systemic vascular resistance index (SVRI) increased significantly in the P-Rem group compared with baseline values. There was no difference in mean arterial pressure (MAP) between the groups. Central venous pressure (CVP) and pulmonary artery occlusion pressure (PAOP) significantly increased in the P-Rem group compared with baseline values. In conclusion, the hemodynamic changes observed in this study indicate a compromise of the cardiovascular system, although the dogs in this study were healthy/euvolemic and there was no change in preload. More studies are required in order to evaluate the actual safety of the combination of propofol and remifentanil in patients with reduced cardiac reserve. PMID- 26424913 TI - Use of ImageJ software for histomorphometric evaluation of normal and severely affected canine ear canals. AB - Morphological studies comparing normal and diseased ear canals use primarily subjective scoring. The aim of this study was to compare normal and severely affected ears in dogs with objective measurements using ImageJ software. Ear canals were harvested from cadavers with normal ears and from dogs that underwent total ear canal ablation for unresolved otitis. Histopathology samples from ear canals were evaluated by semi-quantitative scoring and also by using ImageJ software for histomorphometric measurements. The normal ears were compared to the severely affected ears using the 2 methods. The 2 methods were significantly (P < 0.0001) correlated for epidermal hyperplasia, ceruminous gland dilation, and hyperplasia and tissue inflammation, which were significantly greater in the severely affected ears (P < 0.0001). This study demonstrated that there is a very high correlation between the 2 methods for the most markedly affected components of otitis externa and that ImageJ software can be efficiently used to measure and evaluate ear canal histomorphometry. PMID- 26424914 TI - Comparative study of 2 surgical techniques for castration of guinea pigs (Cavia porcellus). AB - The objective of this study was to compare 2 surgical approaches (scrotal or abdominal) for castration of guinea pigs and to investigate post-operative infection rates with either technique. Forty-eight guinea pigs were castrated by scrotal or abdominal technique after being randomly assigned to 1 of 2 groups (n = 24). Individuals were either castrated by an experienced exotic animal surgeon (n = 12) or by an experienced small animal surgeon (n = 12). Surgical wounds were evaluated daily before euthanasia for histological evaluation 2 wks after surgery. Post-operative infection rate was significantly higher in the scrotal group than in the abdominal group, with a higher rate for the experienced small animal surgeon. Castration of guinea pigs with the abdominal technique is significantly faster and has a significantly lower post-operative infection rate than the scrotal technique. PMID- 26424915 TI - Relationship of oxidative stress in skeletal muscle with obesity and obesity associated hyperinsulinemia in horses. AB - In horses, hyperinsulinemia and insulin resistance (insulin dysregulation) are associated with the development of laminitis. Although obesity is associated with insulin dysregulation, the mechanism of obesity-associated insulin dysregulation remains to be established. We hypothesized that oxidative stress in skeletal muscle is associated with obesity-associated hyperinsulinemia in horses. Thirty five light breed horses with body condition scores (BCS) of 3/9 to 9/9 were studied, including 7 obese, normoinsulinemic (BCS >= 7, resting serum insulin < 30 MUIU/mL) and 6 obese, hyperinsulinemic (resting serum insulin >= 30 MUIU/mL) horses. Markers of oxidative stress (oxidative damage, mitochondrial function, and antioxidant capacity) were evaluated in skeletal muscle biopsies. A Spearman's rank correlation coefficient was used to determine relationships between markers of oxidative stress and BCS. Furthermore, to assess the role of oxidative stress in obesity-related hyperinsulinemia, markers of antioxidant capacity and oxidative damage were compared among lean, normoinsulinemic (L-NI); obese, normoinsulinemic (O-NI); and obese, hyperinsulinemic (O-HI) horses. Increasing BCS was associated with an increase in gene expression of a mitochondrial protein responsible for mitochondrial biogenesis (estrogen-related receptor alpha, ERRalpha) and with increased antioxidant enzyme total superoxide dismutase (TotSOD) activity. When groups (L-NI, O-NI, and O-HI) were compared, TotSOD activity was increased and protein carbonyls, a marker of oxidative damage, decreased in the O-HI compared to the L-NI horses. These findings suggest that a protective antioxidant response occurred in the muscle of obese animals and that obesity-associated oxidative damage in skeletal muscle is not central to the pathogenesis of equine hyperinsulinemia. PMID- 26424916 TI - Identification of immunodominant proteins from Mannheimia haemolytica and Histophilus somni by an immunoproteomic approach. AB - Mannheimia haemolytica and Histophilus somni are frequently isolated from diseased cattle with bovine respiratory disease (BRD). They compromise animal lung function and the immune responses generated are not sufficient to limit infection. Identification of specific immunogenic antigens for vaccine development represents a great challenge. Immunogenic proteins were identified by immunoproteomic approach with sera from cattle immunized with a commercial cellular vaccine of M. haemolytica and H. somni. Proteins of M. haemolytica were identified as solute ABC transporter, iron-binding protein, and hypothetical protein of capsular biosynthesis. Histophilus somni proteins correspond to porin, amino acid ABC transporter, hypothetical outer membrane protein, cysteine synthase, and outer membrane protein P6. Although these antigens share strong similarities with other proteins from animal pathogens, the ABC system proteins have been associated with virulence and these proteins could be considered as potential vaccine candidates for BRD. PMID- 26424917 TI - Clonal distribution of Streptococcus suis isolated from diseased pigs in the central region of Chile. AB - The characteristics of 29 Chilean field strains of Streptococcus suis recovered between 2007 and 2011 from pigs with clinical signs at different farms were studied. Serotyping with use of the coagglutination test revealed that all but 1 strain belonged to serotype 6; the remaining strain was serotype 22. All the serotype-6 strains were suilysin (hemolysin)-negative; in addition, they were found to be genotypically homogeneous by enterobacterial repetitive intergenic consensus sequence-based polymerase chain reaction (ERIC-PCR) and sensitive to ampicillin, ceftiofur, penicillin, and trimethoprim/sulfamethoxazole. The results indicate that, in contrast to what is generally observed in other countries, a single clone of S. suis was isolated from diseased pigs in the central region of Chile. PMID- 26424919 TI - Aerobic training increases the expression of adiponectin receptor genes in the peripheral blood mononuclear cells of young men. AB - Little is known about the effect of exercise training on the expression of adiponectin receptor genes in peripheral blood mononuclear cells (PBMCs). In this study, we investigated the effects of aerobic training on the expression of AdipoR1 and AidpoR2 mRNAs in PBMCs, whole body insulin sensitivity, and circulating adiponectins in men. Thirty young men were randomly assigned to either a control (n=15) or an exercise (n=15) group. Subjects assigned to the exercise group underwent a 12-week jogging and/or running programme on a motor driven treadmill at an intensity of 60%-75% of the age-based maximum heart rate with duration of 40 minutes per session and a frequency of 5 days per week. Two way mixed ANOVA with repeated measures was used to test any significant time-by group interaction effects for the measured variables at p=0.05. We found significant time-by-group interaction effects for waist circumference (p=0.001), VO2max (p<0.001), fasting insulin (p=0.016), homeostasis model assessment for insulin resistance (HOMA-IR) (p=0.010), area under the curve (AUC) for insulin response during the 75-g oral glucose tolerance test (p=0.002), high-molecular weight (HMW) adiponectin (p=0.016), and the PBMC mRNA levels of AdipoR1 (p<0.001) and AdipoR2 (p=0.001). The exercise group had significantly increased mRNA levels of AdipoR1 and AdipoR2 in PBMCs, along with increased whole body insulin sensitivity and HMW adiponectin, decreased waist circumference, and increased VO2max compared with the control group. In summary, the current findings suggest that exercise training modulates the expression of AdipoR1 and AdipoR2 mRNAs in PBMCs, implying that manipulation of the expression of these genes could be a potential surrogate for lifestyle intervention-mediated improvements of whole body insulin sensitivity and glucose homeostasis. PMID- 26424918 TI - Enhanced inactivation of avian influenza virus at -20 degrees C by disinfectants supplemented with calcium chloride or other antifreeze agents. AB - Avian influenza outbreaks have occurred during winter months, and effective disinfection of poultry premises at freezing temperatures is needed. The commercial disinfectants Virkon and Accel, supplemented with an antifreeze agent [propylene glycol (PG), methanol (MeOH), or calcium chloride (CaCl2)], were evaluated for their effectiveness in killing avian influenza virus (AIV) at -20 degrees C or 21 degrees C. An AIV suspension was applied to stainless steel disks, air-dried, and covered with a disinfectant or antifreeze agent for 5 to 30 min. Virkon (2%) and Accel (6.25%) with 30% PG, 20% MeOH, or 20% CaCl2 inactivated 6 log10 AIV within 5 min at -20 degrees C and 21 degrees C. At these temperatures PG and MeOH alone did not kill AIV, but the 20% CaCl2 solution alone inactivated 5 log10 AIV within 10 min. The results suggested that CaCl2 is potentially useful to enhance the effectiveness of disinfection of poultry facilities after outbreaks of AIV infection in warm and cold seasons. PMID- 26424920 TI - Increased extracellular dopamine and 5-hydroxytryptamine levels contribute to enhanced subthalamic nucleus neural activity during exhausting exercise. AB - The purpose of the study was to explore the mechanism underlying the enhanced subthalamic nucleus (STN) neural activity during exhausting exercise from the perspective of monoamine neurotransmitters and changes of their corresponding receptors. Rats were randomly divided into microdialysis and immunohistochemistry study groups. For microdialysis study, extracellular fluid of the STN was continuously collected with a microdialysis probe before, during and 90 min after one bout of exhausting exercise. Dopamine (DA) and 5-hydroxytryptamine (5-HT) levels were subsequently detected with high-performance liquid chromatography (HPLC). For immunohistochemistry study, the expression of DRD2 and HT2C receptors in the STN, before, immediately after and 90 min after exhaustion was detected through immunohistochemistry technique. Microdialysis study results showed that the extracellular DA and 5-HT neurotransmitters increased significantly throughout the procedure of exhausting exercise and the recovery period (P<0.05 or P<0.01). Immunohistochemistry study results showed that the expression levels of DRD2 and HT2C in the rat STN immediately after exhausting exercise and at the time point of 90 min after exhaustion were both higher than those of the rest condition, but the difference was not significant (P>0.05). Our results suggest that the increased extracellular DA and 5-HT in the STN might be one important factor leading to the enhanced STN neural activity and the development of fatigue during exhausting exercise. This study may essentially offer useful evidence for better understanding of the mechanism of the central type of exercise-induced fatigue. PMID- 26424921 TI - The effect of estrogen on muscle damage biomarkers following prolonged aerobic exercise in eumenorrheic women. AB - This study assessed the influence of estrogen (E2) on muscle damage biomarkers [skeletal muscle - creatine kinase (CK); cardiac muscle - CK-MB] responses to prolonged aerobic exercise. Eumenorrheic women (n=10) who were physically active completed two 60-minute treadmill running sessions at ~60-65% maximal intensity during low E2 (midfollicular menstrual phase) and high E2 (midluteal menstrual phase) hormonal conditions. Blood samples were collected prior to exercise (following supine rest), immediately post-, 30 min post-, and 24 hours post exercise to determine changes in muscle biomarkers. Resting blood samples confirmed appropriate E2 hormonal levels Total CK concentrations increased following exercise and at 24 hours post-exercise were higher in the midfollicular low E2 phase (p<0.001). However, CK-MB concentrations were unaffected by E2 level or exercise (p=0.442) resulting in the ratio of CK-MB to total CK being consistently low in subject responses (i.e., indicative of skeletal muscle damage). Elevated E2 levels reduce the CK responses of skeletal muscle, but had no effect on CK-MB responses following prolonged aerobic exercise. These findings support earlier work showing elevated E2 is protective of skeletal muscle from exercise-induced damage associated with prolonged aerobic exercise. PMID- 26424922 TI - Reduced susceptibility to eccentric exercise-induced muscle damage in resistance trained men is not linked to resistance training-related neural adaptations. AB - The purpose of this study was to examine the acute effects of maximal concentric vs. eccentric exercise on the isometric strength of the elbow flexor, as well as the biceps brachii muscle electromyographic (EMG) responses in resistance-trained (RT) vs. untrained (UT) men. Thirteen RT men (age: 24 +/- 4 years; height: 180.2 +/- 7.7 cm; body weight: 92.2 +/- 16.9 kg) and twelve UT men (age: 23 +/- 4 years; height: 179.2 +/- 5.0 cm; body weight: 81.5 +/- 8.6 kg) performed six sets of ten maximal concentric isokinetic (CON) or eccentric isokinetic (ECC) elbow flexion exercise in two separate visits. Before and after the exercise interventions, maximal voluntary contractions (MVCs) were performed for testing isometric strength. In addition, bipolar surface EMG signals were detected from the biceps brachii muscle during the strength testing. Both CON and ECC caused isometric strength to decrease, regardless of the training status. However, ECC caused greater isometric strength decline than CON did for the UT group (p = 0.006), but not for the RT group. Both EMG amplitude and mean frequency significantly decreased and increased, respectively, regardless of the training status and exercise intervention. Resistance-trained men are less susceptible to eccentric exercise-induced muscle damage, but this advantage is not likely linked to the chronic resistance training-induced neural adaptations. PMID- 26424923 TI - Aerobic and anaerobic determinants of repeated sprint ability in team sports athletes. AB - The aim of this study was to examine in team sports athletes the relationship between repeated sprint ability (RSA) indices and both aerobic and anaerobic fitness components. Sixteen team-sport players were included (age, 23.4 +/- 2.3 years; weight, 71.2 +/- 8.3 kg; height, 178 +/- 7 cm; body mass index, 22.4 +/- 2 kg . m(-2); estimated VO2max, 54.16 +/- 3.5 mL . kg(-1) . min(-1)). Subjects were licensed in various team sports: soccer (n = 8), basketball (n = 5), and handball (n = 3). They performed 4 tests: the 20 m multi-stage shuttle run test (MSRT), the 30-s Wingate test (WingT), the Maximal Anaerobic Shuttle Running Test (MASRT), and the RSA test (10 repetitions of 30 m shuttle sprints (15 + 15 m with 180 degrees change of direction) with 30 s passive recovery in between). Pearson's product moment of correlation among the different physical tests was performed. No significant correlations were found between any RSA test indices and WingT. However, negative correlations were found between MASRT and RSA total sprint time (TT) and fatigue index (FI) (r = -0.53, p < 0.05 and r = -0.65, p < 0.01, respectively). No significant relationship between VO2max and RSA peak sprint time (PT) and total sprint time (TT) was found. Nevertheless, VO2max was significantly correlated with the RSA FI (r = -0.57, p < 0.05). In conclusion, aerobic fitness is an important factor influencing the ability to resist fatigue during RSA exercise. Our results highlighted the usefulness of MASRT, in contrast to WingT, as a specific anaerobic testing procedure to identify the anaerobic energy system contribution during RSA. PMID- 26424924 TI - Epidemiology of training injuries in amateur taekwondo athletes: a retrospective cohort study. AB - The objectives of this study were to estimate the incidence and describe the pattern and severity of training injuries in taekwondo, and to compare pattern and severity of training injuries with competition injuries. One hundred and fifty-two active Australian amateur taekwondo athletes, aged 12 years or over, completed an online survey comprising questions on training exposure and injury history over the preceding 12 months. The main outcome measures were: overall injury incidence rate per athlete-year; training injury incidence rate per athlete-year, per 1000 athlete-training-sessions, and per 1000 athlete-hours of training; injury severity; and injury proportions by anatomical region and by type of injury. Injury incidence rates were calculated with 95% confidence intervals using standard methods, while injury proportions were compared using Fisher's exact test. The vast majority (81.5%) of taekwondo injuries in an average athlete-year occurred during training. The training injury incidence rate was estimated to be 1.6 (95% CI: 1.4, 1.9) per athlete-year, 11.8 (95% CI: 10.4, 13.4) per 1000 athlete-training-sessions, and 7.0 (95% CI: 6.1, 7.9) per 1000 athlete-hours of training. Among athletes with five or fewer injuries, the severity and injury pattern of training injuries were, by and large, the same as for competition injuries. Approximately sixty percent (60.3%) of training injuries required treatment by a health professional. Considering the burden of training injuries exceeds that of competition injuries, taekwondo governing bodies and stakeholders are encouraged to devote more efforts towards the identification of risk factors for, and prevention of, training injuries in the sport of taekwondo. PMID- 26424925 TI - Long-term effects of graduated compression stockings on cardiorespiratory performance. AB - The use of graduated compression stockings (GCS) in sport has been increasing in the last years due to their potential positive effects for athletes. However, there is little evidence to support whether these types of garments actually improve cardiorespiratory performance. The aim of this study was to examine the cardiorespiratory responses of GCS during running after three weeks of regular use. Twenty recreational runners performed three tests on different days: test 1) - a 5-min maximal effort run in order to determine the participants' maximal aerobic speed; and tests 2) and 3) - a fatigue running test of 30 minutes at 80% of their maximal aerobic speed with either GCS or PLACEBO stockings at random. Cardiorespiratory parameters (minute ventilation, heart rate, relative oxygen consumption, relative carbon dioxide production, ventilatory equivalents for oxygen and carbon dioxide, and oxygen pulse) were measured. Before each test in the laboratory, the participants trained with the randomly assigned stockings (GCS or PLACEBO) for three weeks. No significant differences between GCS and PLACEBO were found in any of the cardiorespiratory parameters. In conclusion, the present study provides evidence that running with GCS for three weeks does not influence cardiorespiratory parameters in recreational runners. PMID- 26424926 TI - Alternative to traditional stretching methods for flexibility enhancement in well trained combat athletes: local vibration versus whole-body vibration. AB - This study aimed to compare the effect of local vibration (LV) and whole body vibration (WBV) on lower body flexibility and to assess whether vibration treatments were more effective than traditionally used static and dynamic stretching methods. Twenty-four well-trained male combat athletes (age: 22.7 +/- 3.3 years) performed four exercise protocols - LV (30 Hz, 4 mm), WBV (30 Hz, 4 mm), static stretching (SS), and dynamic stretching (DS) - in four sessions of equal duration 48 hours apart in a randomized, balanced order. During a 15-minute recovery after each protocol, subjects performed the stand and reach test (S&R) at the 15th second and the 2(nd), 4(th), 6(th), 8(th), 10(th) and 15(th) minute. There was a similar change pattern in S&R scores across the 15-minute recovery after each protocol (p = 0.572), remaining significantly elevated throughout the recovery. A significant main protocol effect was found for absolute change in S&R scores relative to baseline (p = 0.015). These changes were statistically greater in LV than WBV and DS. Changes in SS were not significantly different from LV, but were consistently lower than LV with almost moderate effect sizes. After LV, a greater percentage of subjects increased flexibility above the minimum detectable change compared to other protocols. Subjects with high flexibility (n = 12) benefited more from LV compared with other methods (effect size >= 0.862). In conclusion, LV was an effective alternative exercise modality to acutely increase lower extremity flexibility for well-trained athletes compared with WBV and traditional stretching exercises. PMID- 26424927 TI - The acute effects of different training loads of whole body vibration on flexibility and explosive strength of lower limbs in divers. AB - The purpose of this study was to examine the acute effects of different vibration loads (frequency and amplitude) of whole-body vibration (WBV) on flexibility and explosive strength of lower limbs in springboard divers. Eighteen male and female divers, aged 19 +/- 2 years, volunteered to perform 3 different WBV protocols in the present study. To assess the vibration effect, flexibility and explosive strength of lower limbs were measured before (Pre), immediately after (Post 1) and 15 min after the end of vibration exposure (Post 15). Three protocols with different frequencies and amplitudes were used in the present study: a) low vibration frequency and amplitude (30 Hz/2 mm); b) high vibration frequency and amplitude (50 Hz/4 mm); c) a control protocol (no vibration). WBV protocols were performed on a Power Plate platform, whereas the no vibration divers performed the same protocol but with the vibration platform turned off. A two-way ANOVA 3 x 3 (protocol * time) with repeated measures on both factors was used. The level of significance was set at p < 0.05. Univariate analyses with simple contrasts across time were selected as post hoc tests. Intraclass coefficients (ICC) were used to assess the reliability across time. The results indicated that flexibility and explosive strength of lower limbs were significantly higher in both WBV protocols compared to the no vibration group (NVG). The greatest improvement in flexibility and explosive strength, which occurred immediately after vibration treatment, was maintained 15 min later in both WBV protocols, whereas NVG revealed a significant decrease 15 min later, in all examined strength parameters. In conclusion, a bout of WBV significantly increased flexibility and explosive strength in competitive divers compared with the NVG. Therefore, it is recommended to incorporate WBV as a method to increase flexibility and vertical jump height in sports where these parameters play an important role in the success outcome of these sports. PMID- 26424928 TI - Effect of whole body vibration frequency on neuromuscular activity in ACL deficient and healthy males. AB - Whole-body vibration (WBV) has been shown to enhance muscle activity via reflex pathways, thus having the potential to contrast muscle weakness in individuals with rupture of the anterior cruciate ligament (ACL). The present study aimed to compare the magnitude of neuromuscular activation during WBV over a frequency spectrum from 20 to 45 Hz between ACL-deficient and healthy individuals. Fifteen males aged 28+/-4 with ACL rupture and 15 age-matched healthy males were recruited. Root mean square (RMS) of the surface electromyogram from the vastus lateralis in both limbs was computed during WBV in a static half-squat position at 20, 25, 30, 35, 40 and 45 Hz, and normalized to the RMS while maintaining the half-squat position without vibration. The RMS of the vastus lateralis in the ACL deficient limb was significantly greater than in the contralateral limb at 25, 30, 35 and 40 Hz (P<0.05) and in both limbs of the healthy participants (dominant limb at 25, 30, 35, 40 and 45 Hz, P<0.05; non dominant limb at 20, 25, 30, 35, 40 and 45 Hz, P<0.05). The greater neuromuscular activity in the injured limb compared to the uninjured limb of the ACL-deficient patients and to both limbs of the healthy participants during WBV might be due to either augmented excitatory or reduced inhibitory neural inflow to motoneurons of the vastus lateralis through the reflex pathways activated by vibratory stimuli. The study provides optimal WBV frequencies which might be used as reference values for ACL-deficient patients. PMID- 26424929 TI - Sweat gland density and response during high-intensity exercise in athletes with spinal cord injuries. AB - Sweat production is crucial for thermoregulation. However, sweating can be problematic for individuals with spinal cord injuries (SCI), as they display a blunting of sudomotor and vasomotor responses below the level of the injury. Sweat gland density and eccrine gland metabolism in SCI are not well understood. Consequently, this study examined sweat lactate (S-LA) (reflective of sweat gland metabolism), active sweat gland density (SGD), and sweat output per gland (S/G) in 7 SCI athletes and 8 able-bodied (AB) controls matched for arm ergometry VO2peak. A sweat collection device was positioned on the upper scapular and medial calf of each subject just prior to the beginning of the trial, with iodine sweat gland density patches positioned on the upper scapular and medial calf. Participants were tested on a ramp protocol (7 min per stage, 20 W increase per stage) in a common exercise environment (21+/-1 degrees C, 45-65% relative humidity). An independent t-test revealed lower (p<0.05) SGD (upper scapular) for SCI (22.3 +/-14.8 glands . cm(-2)) vs. AB. (41.0 +/- 8.1 glands . cm(-2)). However, there was no significant difference for S/G between groups. S-LA was significantly greater (p<0.05) during the second exercise stage for SCI (11.5+/ 10.9 mmol . l(-1)) vs. AB (26.8+/-11.07 mmol . l(-1)). These findings suggest that SCI athletes had less active sweat glands compared to the AB group, but the sweat response was similar (SLA, S/G) between AB and SCI athletes. The results suggest similar interglandular metabolic activity irrespective of overall sweat rate. PMID- 26424930 TI - Selected anthropometric variables and aerobic fitness as predictors of cardiovascular disease risk in children. AB - The aim of this study was to assess the suitability of body mass index, waist circumference, waist-to-height ratio and aerobic fitness as predictors of cardiovascular risk factor clustering in children. A cross-sectional study was conducted with 290 school boys and girls from 6 to 10 years old, randomly selected. Blood was collected after a 12-hour fasting period. Blood pressure, waist circumference (WC), height and weight were evaluated according to international standards. Aerobic fitness (AF) was assessed by the 20-metre shuttle-run test. Clustering was considered when three of these factors were present: high systolic or diastolic blood pressure, high low-density lipoprotein (LDL) cholesterol, high triglycerides, high plasma glucose, high insulin concentrations and low high-density lipoprotein (HDL) cholesterol. A ROC curve identified the cut-off points of body mass index (BMI), WC, waist-to-height ratio (WHtR) and AF as predictors of risk factor clustering. BMI, WC and WHR resulted in significant areas under the ROC curves, which was not observed for AF. The anthropometric variables were good predictors of cardiovascular risk factor clustering in both sexes, whereas aerobic fitness should not be used to identify cardiovascular risk factor clustering in these children. PMID- 26424931 TI - Changes in the acid-base balance and lactate concentration in the blood in amateur ultramarathon runners during a 100-km run. AB - The aim of this study was to analyse the acid-base balance and partial pressure of blood gases of participants during a 100-km run. Fourteen experienced amateur ultramarathon runners (age: 43.36+/-11.83 years; height: 175.29+/-6.98 cm; weight: 72.12+/-7.36 kg) completed the 100-km run. Blood samples were taken before the run; after 25, 50, 75, and 100 km; and 12 and 24 hours after the run. There were significant differences (p<0.05) between the mean values registered for acid-alkaline balance, buffering alkalies, and current bicarbonate in each segment of the run, especially during the third, fourth, and fifth segments of the run (i.e., between 50 and 100 km), and there were only significant differences associated with buffering alkalies and current bicarbonate during the recovery. However, all the changes were within the physiological norm. A significant decrease in the compressibility of oxygen was observed after 100 km (from 92.80+/-15.67 to 88.36+/-13.71 mmHg) and continued during the recovery to 75.06+/-8.60 mmHg 12 h after the run. Also there was a decrease in saturation to a mean value of 93.78+/-3.10 at 12 h after the run. Generally the amateurs runners are able to adjust their running speed so as not to provoke a significant acid-base imbalance or lactate acid accumulation. PMID- 26424932 TI - The effect of uphill stride manipulation on race walking gait. AB - Stride length analysis represents an easy method for assessing race walking kinematics. However, the stride parameters emerging from such an analysis have never been used to design a training protocol aimed at increasing stride length. With this aim, we investigated the effects of stride frequency manipulation during three weeks of uphill (2%) training on stride length at iso-efficiency speed. Twelve male race walkers were randomly allocated to one of two training groups: stride frequency manipulation (RWM, n=6) and free stride frequency (RWF, n=6). RESULTS: Kinematic parameters measured before and after the 3-week training in RWM showed increased stride length (4.54%; p<0.0001) and contact time (4.58%; p<0.001); inversely, a decreased stride frequency (4.44%; p<0.0001) and internal work (7.09%; p<0.05) were found. In RWF the effect of the training showed a decrease in stride length (1.18%; p<0.0001) and contact time (<1%; p<0.0001) with respect to baseline conditions and an increased stride frequency and internal work of 1.19% (p<0.0001). These results suggest that using slopes (2%) as RWM could help coaches to provide some training methods that would improve an athlete's performance, through increasing stride length without altering his or her race walking technique or metabolic demands. PMID- 26424933 TI - On the Question of Effective Sample Size in Network Modeling: An Asymptotic Inquiry. AB - The modeling and analysis of networks and network data has seen an explosion of interest in recent years and represents an exciting direction for potential growth in statistics. Despite the already substantial amount of work done in this area to date by researchers from various disciplines, however, there remain many questions of a decidedly foundational nature - natural analogues of standard questions already posed and addressed in more classical areas of statistics - that have yet to even be posed, much less addressed. Here we raise and consider one such question in connection with network modeling. Specifically, we ask, "Given an observed network, what is the sample size?" Using simple, illustrative examples from the class of exponential random graph models, we show that the answer to this question can very much depend on basic properties of the networks expected under the model, as the number of vertices nV in the network grows. In particular, adopting the (asymptotic) scaling of the variance of the maximum likelihood parameter estimates as a notion of effective sample size, say neff, we show that whether the networks are sparse or not under our model (i.e., having relatively few or many edges between vertices, respectively) is sufficient to yield an order of magnitude difference in neff, from O(nV ) to [Formula: see text]. We then explore some practical implications of this result, using both simulation and data on food-sharing from Lamalera, Indonesia. PMID- 26424934 TI - Hepatitis prevention project in the Korean American community in Killeen, Texas. AB - Educational efforts related to viral hepatitis have the potential to increase awareness and identify chronically infected individuals and can lead to successful vaccination strategies. However, in underserved semirural communities, such as the Korean American community in Killeen, Texas, these outreach activities are lacking. The GanYum ("hepatitis" in Korean) Prevention Project aimed to evaluate thoughts/behaviors, assess vulnerability, and educate Korean Americans on hepatitis B and C. Two outreach events were held at a Korean church and a Korean market (O'Mart) to provide education, screening, and outreach about viral hepatitis. Ninety-six patients were screened at two events. Five patients were found to be positive for hepatitis B surface antigen and were referred to their primary care physicians and the liver clinic at Scott & White Healthcare in Temple, Texas. Fifty-one patients (53%) were found to be immune to hepatitis B, and 40 patients (42%) were hepatitis B vulnerable. We demonstrated that the prevalence of chronic hepatitis B in Koreans in our study is similar to the previously documented prevalence (5%). Our educational efforts were successful in changing perceptions regarding the modes of transmission and exacerbating factors of chronic viral hepatitis and encouraged participants to seek care for their liver diseases, if needed. We found that both venues (the church and Korean market) were appropriate to screen and educate participants; churches seemed to have a more engaged audience. PMID- 26424935 TI - Screening for hepatitis B in patients with lymphoma. AB - Chronic hepatitis B virus (HBV) infection can be reactivated during lymphoma chemotherapy, specifically with rituximab. In 2008, the Centers for Disease Control and Prevention and, in 2010, the American Society of Clinical Oncology made recommendations that anyone who received cytotoxic or immunosuppressive therapy should be tested for serologic markers of HBV infection. In our study, we wanted to determine the screening rates for HBV infection at our institution and if simply adding a checkbox onto the rituximab order would improve HBV screening. We performed a retrospective chart review of two cohorts of lymphoma patients at Scott & White Health Clinic. Cohort 1 included patients from 1993 to 2008. Cohort 2 included patients who received rituximab after an institutionwide protocol (rituximab order checkbox) was initiated in 2011. A total of 452 patients treated for lymphoma were reviewed. Only 15 of the 404 Cohort 1 patients received HBV screening (3.7%; 95% confidence interval, 2.1%-6.1%). Screening rates were statistically higher if baseline liver laboratory values were elevated (P < 0.0001). HBV was also checked more frequently if patients' liver function tests became elevated while on chemotherapy, 85.7% (12/14). Of the 48 patients in Cohort 2, 33 patients (68.7%) received HBV screening. No patients in either cohort had a positive HBV surface antigen or developed reactivation of HBV during chemotherapy. The addition of a checkbox on the rituximab order form significantly increased our screening for HBV infection in lymphoma patients initiating chemotherapy. PMID- 26424936 TI - Invited Commentary: Screening for hepatitis B in the immigrant population and individuals who are in need of immunosuppressive drug therapy. AB - Chronic hepatitis B (CHB) afflicts approximately 300 million people in the world. Hepatitis B virus (HBV) is a known carcinogenic virus and continues to be the leading cause of hepatocellular carcinoma (HCC) (1). Approximately 70% of hepatitis B surface antigen (HBsAg) carriers reside in intermediate (>2% prevalence) to high-risk (>8% prevalence) areas such as Asia, the Pacific Islands, Africa, India, and parts of Southern Europe (1). There is a common misperception that this disorder is not very common in the United States. However, 63% of the nearly 28 million immigrants who entered the US between 1974 and 2008 were born in countries of intermediate or high prevalence (2). The Immigrant Refugee and Migrant Health Branch of the Centers for Disease Control and Prevention (CDC) estimated that an average of 53,000 CHB cases were imported to the US yearly from 2004 to 2008. Forty percent of these cases originated from China, Vietnam, and the Philippines (2). The CDC has recently revised its prevalence estimates and concluded that 2.2 million US residents are likely to have chronic HBV infection, of which 1.3 million are judged to be foreign-born individuals. Even these figures are likely to be too low, however, because the estimates do not take into account illegal immigrants and other socially disadvantaged patients. Importantly, HBsAg testing is not required as part of the process of immigrating into the United States (3). This lack of a requirement for HBV screening is an important missed opportunity to programmatically diagnose this condition. PMID- 26424937 TI - Dual antiplatelet compared to triple antithrombotic therapy in anterior wall acute myocardial infarction complicated by depressed left ventricular ejection fraction. AB - Current guidelines recommend triple antithrombotic therapy (TT) consisting of warfarin, aspirin, and a P2Y12 inhibitor following an anterior ST elevation myocardial infarction (STEMI) complicated by extensive wall motion abnormalities. This recommendation, however, is based on data collected before percutaneous coronary intervention (PCI) became the standard of care for the treatment of STEMI. We designed a retrospective study of patients who received PCI for anterior STEMI over an 8-year period to compare rates of thromboembolic and bleeding events between patients receiving dual antiplatelet therapy (DAPT) and those receiving TT, including warfarin. Patients were included if the predischarge echocardiogram showed extensive wall motion abnormality and an ejection fraction <=35%. Patients with known left ventricular thrombus were excluded. A total of 124 patients met the criteria, with 80 patients in the DAPT group and 44 in the TT group. The median age was 58 years in the TT group and 64 years in the DAPT group (P < 0.04), with an average ejection fraction of 31%. Thromboembolic events occurred in 4 patients (5%) in the DAPT group compared with 3 patients (6.8%) in the TT group (P = 0.70). Bleeding occurred in 2 patients in the DAPT group and 4 patients in the TT group (2.5% in DAPT vs. 9.1% in TT group, P = 0.18). No differences in rates of clinical embolism or left ventricular thrombus were found. Our data support recent findings that warfarin may not be indicated for patients following PCI for anterior STEMI, even when significant wall motion abnormalities and reduced ejection fraction <=35% are present. PMID- 26424938 TI - Improving compliance with cervical cancer screening guidelines. AB - Current cervical cancer screening guidelines for the care of healthy women include HPV cotesting with all Papanicolaou (Pap) smears after the age of 30. To improve compliance with current guidelines, we instituted two processes: first, simplifying the ordering process to a single order for Pap smear plus HPV cotesting using an electronic medical record system (EMR); and second, providing education for clinic staff. Baseline and postintervention data were collected by retrospective chart review. Patients were selected during three intervals: prior to the transition to Epic EMR, after the transition to Epic, and after an educational intervention. Compliance with standard guidelines was evaluated in relation to the trial intervals, type of provider, patient age, and duration from the previous Pap smear. Provider type was analyzed by considering gynecologists versus nongynecologist providers, and physicians versus mid-level providers. Overall, the percentage of compliance with HPV test ordering did not differ (P = 0.21) between intervals. Univariate analyses performed to identify factors likely to be associated with the practice of ordering HPV cotesting only involved the type of provider. In conclusion, transition to Epic and a training session had minimal impact on compliance with ordering HPV cotesting at the time of a Pap smear except among family practice physicians, who did significantly improve their compliance rate. Gynecologists and mid-level providers were more compliant with ordering HPV cotesting throughout, but did not significantly improve after the interventions. PMID- 26424939 TI - Replacement of the aortic valve with a bioprosthesis at the time of continuous flow ventricular assist device implantation for preexisting aortic valve dysfunction. AB - Left ventricular assist device (LVAD) implantation has become a mainstay of therapy for advanced heart failure patients who are either ineligible for, or awaiting, cardiac transplantation. Controversy remains over the optimal therapeutic strategy for preexisting aortic valvular dysfunction in these patients at the time of LVAD implant. In patients with moderate to severe aortic regurgitation, surgical approaches are center specific and range from variable leaflet closure techniques to concomitant aortic valve replacement (AVR) with a bioprosthesis. In the present study, we retrospectively analyzed our outcomes in patients who underwent simultaneous AVR and LVAD implantation secondary to antecedent aortic valve pathology. Between January 2004 and June 2010, 144 patients underwent LVAD implantation at a single institution. Of these, 7 patients (4.8%) required concomitant AVR. Five of the 7 patients (71%) survived to hospital discharge and suffered no adverse events in the perioperative period. One-year survival for the discharged patients was 80%, and no prosthetic valve related adverse events were observed in long-term follow-up. Given our experience, we conclude that bioprosthetic AVR is a plausible alternative for end stage heart failure patients at the time of LVAD implantation. PMID- 26424940 TI - The gender of authors in the Baylor Proceedings: a reflection of both current staff composition and lesser number of publications by female physicians. AB - Gender parity has been achieved in entrance to medical school, but women still constitute only 32% of the physicians licensed to practice in the state of Texas. Similarly, female physicians lag behind in scholarly publications. This gender imbalance appears to be improving, although parity has yet to be achieved in many journals. We could reliably obtain the gender of both the physician staff of the North Division of Baylor Scott & White Health and of the authors in Baylor University Medical Center Proceedings. Of the Baylor authors, 19% were female physicians, while 65% were male physicians (others were nonphysicians). The gender makeup of the total staff was 27% female and 73% male physicians. Thus, female authorship is only 70% as great as the number of female staff physicians. We suggest ways to encourage more women to submit publications. PMID- 26424941 TI - Acral vesicles and bullae in a patient with severe rheumatoid arthritis. AB - We present the case of a 56-year-old black woman with rheumatoid arthritis who developed worsening fatigue, fever, weight loss, and a vesiculobullous skin eruption while being treated with certolizumab pegol for her arthritis. Microscopic findings confirmed the diagnosis of a neutrophilic dermatosis. PMID- 26424942 TI - Diagnosing and managing peripartum headache. AB - A 38-year-old gravida 7 para 5 Hispanic woman at 36 weeks and 4 days gestation presented with a postpartum headache following vaginal delivery complicated by an unintentional dural puncture for epidural analgesia. Due to the positional nature of the headache and its frontal and occipital origin, a postdural puncture headache was diagnosed. After failure of conservative treatment, an epidural blood patch was used, which offered immediate relief. However, shortly following the procedure, the parturient's neurological condition deteriorated due to an unrecognized intraparenchymal and subarachnoid hemorrhage requiring an emergent craniectomy. This case highlights the importance of diligence when evaluating and treating postpartum headache despite a classic presentation. PMID- 26424943 TI - A triad of linezolid toxicity: hypoglycemia, lactic acidosis, and acute pancreatitis. AB - We present a case of suspected linezolid toxicity in a 34-year-old man with sickle cell disease and line-related vancomycin-resistant enterococcal bacteremia and tricuspid valve endocarditis. The patient developed sudden-onset hypoglycemia, lactic acidosis, and acute pancreatitis 11 days after initiation of linezolid. All adverse effects quickly resolved with drug cessation. The pathophysiology underlying this triad of linezolid toxicity is unclear, but may be related to mitochondrial dysfunction. PMID- 26424944 TI - Microscopic polyangiitis causing diffuse alveolar hemorrhage and rapidly progressive glomerulonephritis. AB - Diffuse alveolar hemorrhage complicating small vessel vasculitis is a life threatening emergency and should be considered in the differential diagnosis of patients who develop rapidly progressive dyspnea with alveolar opacities on chest imaging. In these patients, the coexistence of pulmonary and renal involvement suggests a multisystem disease. We present a case of a man who presented to our hospital with diffuse alveolar hemorrhage, severe anemia, and rapidly progressive glomerulonephritis. PMID- 26424945 TI - Noncirrhotic hyperammonemia causing relapsing altered mental status. AB - Hyperammonemia is a recognized cause of encephalopathy. However, it is commonly seen in patients with liver disease. The clinical entity of noncirrhotic hyperammonemia is now being increasingly recognized. We report a man who presented to our hospital with relapsing altered mental status later diagnosed as noncirrhotic hyperammonemia. PMID- 26424946 TI - Synthetic cannabinoids and acute kidney injury. AB - Synthetic cannabinoids (SCB) are a family of chemicals that bind to cannabinoid receptors and cause psychoactive effects. Over the past few years, they have been increasingly used for recreational purposes, especially by young adults, and have been reported to have many adverse effects. Acute kidney injury (AKI) has been recently reported; the pathophysiology of SCB-induced AKI is unknown. We report three cases of AKI in the setting of SCB use. The peak serum creatinine levels ranged from 3.0 to 5.7 mg/dL; one patient required hemodialysis. SCB can induce AKI. PMID- 26424947 TI - Gastropericardial fistula as a delayed complication of a Nissen fundoplication. AB - A 41-year-old man presented to the emergency department with substernal chest pain and was found to have ST elevations in the inferior leads on his electrocardiogram. An emergent cardiac catheterization did not identify significant coronary narrowing. Computed tomography of the thorax demonstrated a pneumopericardium and a hiatal hernia. The patient had a complicated past surgical history, including a Nissen fundoplication and three additional surgeries for postoperative complications. An esophagram later revealed an ulcer and possible fistula, and the patient underwent gastropericardial fistula resection after the fistula failed to close with fibrin sealant application. Enteropericardial fistulas occur infrequently but have high morbidity and mortality rates. This possibility is much more likely in patients with prior gastroesophageal surgery, including laparoscopic Nissen fundoplication. PMID- 26424948 TI - Fatal pulmonary tumor thrombotic microangiopathy caused by undiagnosed metastatic gastric adenocarcinoma. AB - Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare cause of rapidly progressive dyspnea in a background of metastatic cancer. Gastric adenocarcinoma is the neoplasm most frequently associated with PTTM. Unfortunately, PTTM is difficult to identify clinically and is most commonly a postmortem diagnosis. We present the case of a woman with no previous diagnosis of cancer who presented with rapidly progressive shortness of breath. She was diagnosed with severe pulmonary arterial hypertension and rapidly succumbed to her illness. A postmortem diagnosis of PTTM was established based on autopsy results. PMID- 26424949 TI - Transjugular intrahepatic portosystemic shunt creation using a three-dimensional fluoroscopy guidance system in patients with the Budd-Chiari syndrome. AB - When performed for Budd-Chiari syndrome (BCS), transjugular intrahepatic portosystemic shunt (TIPS) creation can be technically difficult due to hepatic congestion and asymmetric hypertrophy. We present three female patients with decompensated BCS in whom TIPS were created using a three-dimensional fluoroscopy guidance system. On a dedicated workstation using three-dimensional volumes of computed tomography imaging, a virtual needle path was created by the operator extending from the needle entry point (hepatic vein stump or inferior vena cava) to the target portal vein. Subsequently, the virtual needle path was overlaid on the fluoroscopy image for guidance of portal venous cannulation. This technology can be used for TIPS procedures in patients with BCS and other complex TIPS cases, as it may help delimit the trajectory of the needle pass and optimally result in more efficient procedures with decreased radiation dose. PMID- 26424950 TI - Late presentation of adenovirus-induced hemorrhagic cystitis and ureteral obstruction in a kidney-pancreas transplant recipient. AB - We report a late presentation of adenovirus-induced renal allograft and bladder infection causing azotemia and hemorrhagic cystitis in a patient 5 years after simultaneous kidney-pancreas transplantation. Adenovirus has been increasingly recognized as a cause of morbidity and mortality in both solid organ and stem cell transplant recipients. We wish to emphasize the importance of early detection, as treatment options involve reduction of immunosuppression, followed by the addition of antiviral agents and supportive care. PMID- 26424952 TI - Iron deficiency and hemolytic anemia reversed by ventricular septal myectomy. AB - Hemolytic anemia has been reported to occur in the setting of aortic stenosis and prosthetic heart valves, but much more rarely in association with obstructive hypertrophic cardiomyopathy (HC). Of the few descriptions of hemolytic anemia secondary to HC, all but one case involved bacterial endocarditis contributing to left ventricular outflow tract obstruction. We present the case of a 67-year-old man with recurrent hemolytic anemia and HC, without infective endocarditis. Attempts at iron repletion and augmentation of beta-blocker therapy proved his anemia to be refractory to medical management. Ventricular septal myectomy led to the resolution of hemolysis, anemia, and its coexisting symptoms. PMID- 26424951 TI - Heart transplantation in the Ehlers-Danlos syndrome. AB - We describe a woman with Ehlers-Danlos syndrome and aortic aneurysm who experienced a myocardial infarction due to spontaneous left circumflex coronary artery dissection 3 weeks postpartum. She developed end-stage heart failure and subsequently underwent a successful orthotopic heart transplantation. To our knowledge, this is the first report of a heart transplant performed in an individual with Ehlers-Danlos syndrome. PMID- 26424953 TI - Unruptured sinus of Valsalva aneurysm presenting with concurrent Morgagni hernia. AB - We describe a patient with dyspnea and intermittent cyanosis who was found to have concurrent right diaphragmatic and right atrial masses, initially thought to have advanced vascular sarcoma. She was ultimately diagnosed with an unruptured sinus of Valsalva aneurysm, a Morgagni hernia, and a patent foramen ovale. Her dyspnea and cyanosis resolved after sequential surgical correction of these defects. PMID- 26424954 TI - Surgical repair of renal artery aneurysms. AB - The pathogenesis of renal artery aneurysms (RAAs) is degenerative, which eventually leads to weakening of the vessel wall and, in extreme cases, rupture. RAAs are a rare occurrence. Patients generally are asymptomatic, with a small number presenting with uncontrollable hypertension or hematuria. Most RAAs are discovered incidentally on imaging and do not pose an immediate health threat. However, the risk of rupture is an indication for prophylactic repair in certain patients. Interest in interventional radiologic procedures in the management of RAAs has recently increased; however, open repair should still be considered in select instances. In this case series, we present three patients for whom an open approach was indicated and performed. PMID- 26424955 TI - Effectiveness of balloon valvuloplasty for stenosis of a bioprosthesis in the tricuspid valve position. AB - A 67-year-old man underwent percutaneous balloon valvuloplasty for bioprosthetic tricuspid stenosis. He had undergone two tricuspid valve replacements over a period of 39 years and became symptomatic. After the valvuloplasty, his symptoms were resolved. Stenosis of a bioprosthetic tricuspid valve can be successfully and safely treated with balloon valvuloplasty. PMID- 26424956 TI - Multivessel transradial percutaneous coronary angioplasty in a single coronary artery originating from the right sinus of Valsalva. AB - Percutaneous coronary intervention in patients with an anomalous coronary artery is technically challenging. Selective cannulation and coaxial positioning in the anomalous artery and optimum stability during the procedure are pivotal for successful completion of the procedure. Selection of the appropriate guide catheter is of paramount importance in these situations. In patients with congenital coronary artery anomalies, increasing use of multidetector computed tomography for cardiac imaging may yield diagnostic information not obtained with coronary angiography. Axial, multiplanar, and three-dimensional volume-rendered reconstructions aid in detecting and interpreting such anomalies and in selecting appropriate hardware during percutaneous coronary intervention in these patients. We report a case of successful stent implantation in the right coronary artery and proximal circumflex coronary artery in a patient with a single coronary artery arising from the right sinus of Valsalva. PMID- 26424957 TI - Two-time recurrence of a right atrial myxoma. AB - We report a case of a second recurrence of a right atrial myxoma in a 38-year-old woman who had surgical excision in March 2008 and excision of a recurrence in August 2012. She presented with a similar clinical picture in December 2014 and again underwent surgical excision. The case is unusual both for its location in the right atrium and its multiple recurrences in a sporadic form without any sign of the myxoma complex. PMID- 26424958 TI - Myxedema coma with cardiac tamponade and severe cardiomyopathy. AB - Myxedema coma is an infrequent but potentially fatal complication of hypothyroidism. We present a rare case of previously undiagnosed hypothyroidism presenting in cardiogenic shock from pericardial tamponade and depressed myocardial contractility in myxedema coma. Here, we focus on cardiovascular complications associated with the condition. PMID- 26424959 TI - Myocardial infarction with ventricular septal rupture and cardiogenic shock. PMID- 26424960 TI - Morphologic demonstration of spontaneous and surgical closure of membranous ventricular septal defect. AB - This report demonstrates morphologic features of membranous ventricular septal defect that was closed spontaneously in one patient and operatively in the other. PMID- 26424962 TI - What my cancer taught me. PMID- 26424961 TI - A review of spontaneous closure of ventricular septal defect. AB - Ventricular septal defect (VSD) is the most common congenital heart malformation and can be detected during the prenatal and postnatal period, in childhood, and in adulthood. Spontaneous closure of VSD can be determined through a variety of methods-echocardiography, Doppler color flow imaging, angiography, auscultation, and cardiac catheterization-and can be proven by pathological evidence at necropsy. There are two major types of VSD, membranous and muscular, as well as the perimembranous variety, which comprises variable portions of the adjacent muscular septum but lacks the membranous septum. VSD appears either as an isolated cardiac defect without other abnormalities or with several complex malformations. It has long been recognized that VSD can close spontaneously, but the incidence of spontaneous VSD closure is still uncertain. Since necropsy study of the hearts with VSD has rarely been reported, information on morphological features of spontaneous VSD closure remains limited. In addition, the mechanisms for spontaneous VSD closure are not fully understood. Herein, we present a brief review of the incidence of spontaneous VSD closure, morphological characteristics of the closure, and the main mechanisms responsible for the closure. PMID- 26424963 TI - Reflections on Sir Roger Bannister and his autobiography, Twin Tracks. PMID- 26424964 TI - Feroze Novroji Ghadially, 1920-2014: a personal remembrance. PMID- 26424965 TI - A week in Havana, Cuba, in February 2015. PMID- 26424966 TI - Facts and ideas from anywhere. PMID- 26424968 TI - Proinflammatory Cytokines Increase Vascular Endothelial Growth Factor Expression in Alveolar Epithelial Cells. AB - Vascular endothelial growth factor (VEGF) is an endothelial permeability mediator that is highly expressed in lung epithelium. In nonlung cells proinflammatory cytokines have been shown to increase VEGF expression, but their effects on lung epithelium remain unclear. We hypothesized that increases in alveolar epithelial cell VEGF RNA and protein expression occur after exposure to proinflammatory cytokines. We tested this using human alveolar epithelial cells (A549) stimulated with 5 proinflammatory cytokines. VEGF RNA expression was increased 1.4-2.7-fold in response to IL-1, IL-6, IL-8, TNF-alpha, or TGF-beta over 6 hours, with TGF beta having the largest response. TNF-alpha increased VEGF RNA as early as 1 hour. A mix of IL-1, IL-6, and IL-8 had effects similar to IL-1. TNF-alpha increased protein expression as early as 4 hours and had a sustained effect at 16 hours, whereas IL-1 did not increase protein expression. Only VEGF165 was present in cultured A549 cells, yet other isoforms were seen in human lung tissue. Increased expression of VEGF in alveolar epithelial cells occurs in response to proinflammatory cytokines. Increased VEGF expression likely contributes to the pathogenesis of inflammatory lung diseases and to the angiogenic phenotype of lung cancer, a disease typically preceded by chronic inflammation. PMID- 26424970 TI - Protecting our specialty. PMID- 26424971 TI - Dr. Fernando Ortiz-Monasterio. PMID- 26424967 TI - Intracellular Cleavage of the Cx43 C-Terminal Domain by Matrix-Metalloproteases: A Novel Contributor to Inflammation? AB - The coordination of tissue function is mediated by gap junctions (GJs) that enable direct cell-cell transfer of metabolic and electric signals. GJs are formed by connexin (Cx) proteins of which Cx43 is most widespread in the human body. Beyond its role in direct intercellular communication, Cx43 also forms nonjunctional hemichannels (HCs) in the plasma membrane that mediate the release of paracrine signaling molecules in the extracellular environment. Both HC and GJ channel function are regulated by protein-protein interactions and posttranslational modifications that predominantly take place in the C-terminal domain of Cx43. Matrix metalloproteases (MMPs) are a major group of zinc dependent proteases, known to regulate not only extracellular matrix remodeling, but also processing of intracellular proteins. Together with Cx43 channels, both GJs and HCs, MMPs contribute to acute inflammation and a small number of studies reports on an MMP-Cx43 link. Here, we build further on these reports and present a novel hypothesis that describes proteolytic cleavage of the Cx43 C-terminal domain by MMPs and explores possibilities of how such cleavage events may affect Cx43 channel function. Finally, we set out how aberrant channel function resulting from cleavage can contribute to the acute inflammatory response during tissue injury. PMID- 26424972 TI - Vascularised composite allotransplants: Transplant of upper extremities and face. AB - Transplantation of solid organs and bone marrow has become a highly acceptable and often the only available clinical solution in many situations. It has been practiced across the globe for quite a long time since the first kidney transplant in 1954. Transplantation of tissues other than these, which was termed composite tissue allotransplantation and currently as vascularised composite allotransplantation (VCA) is gaining acceptance as a solution for complex reconstructive problems. This involves the transfer of multiple types of tissue such as bone, muscle, nerve, skin and blood vessels. The advantage of these over the conventional reconstructive methods is its ability to give aesthetically and functionally superior equal composite substitute to the missing or deformed part. The composite tissues transplanted commonly include the upper extremities, face and abdominal wall. Among these, hand transplants were the first to be done and have been carried out more than any other VCA. This article reviews the current scenario of VCA especially of the hand and face, in the light of experience of the two bilateral hand transplants done recently in India. PMID- 26424973 TI - Namaste (counterbalancing) technique: Overcoming warping in costal cartilage. AB - BACKGROUND: Indian noses are broader and lack projection as compared to other populations, hence very often need augmentation, that too by large volume. Costal cartilage remains the material of choice in large volume augmentations and repair of complex primary and secondary nasal deformities. One major disadvantage of costal cartilage grafts (CCG) which offsets all other advantages is the tendency to warp and become distorted over a period of time. We propose a simple technique to overcome this menace of warping. MATERIALS AND METHODS: We present the data of 51 patients of rhinoplasty done using CCG with counterbalancing technique over a period of 4 years. RESULTS: No evidence of warping was found in any patient up to a maximum follow-up period of 4 years. CONCLUSION: Counterbalancing is a useful technique to overcome the problem of warping. It gives liberty to utilize even unbalanced cartilage safely to provide desired shape and use the cartilage without any wastage. PMID- 26424974 TI - Magnetic resonance neurography of the brachial plexus. AB - Magnetic Resonance Imaging (MRI) is being increasingly recognised all over the world as the imaging modality of choice for brachial plexus and peripheral nerve lesions. Recent refinements in MRI protocols have helped in imaging nerve tissue with greater clarity thereby helping in the identification, localisation and classification of nerve lesions with greater confidence than was possible till now. This article on Magnetic Resonance Neurography (MRN) is based on the authors' experience of imaging the brachial plexus and peripheral nerves using these protocols over the last several years. PMID- 26424975 TI - Magnetic resonance neurography of the brachial plexus. PMID- 26424969 TI - Trachoma and Ocular Chlamydial Infection in the Era of Genomics. AB - Trachoma is a blinding disease usually caused by infection with Chlamydia trachomatis (Ct) serovars A, B, and C in the upper tarsal conjunctiva. Individuals in endemic regions are repeatedly infected with Ct throughout childhood. A proportion of individuals experience prolonged or severe inflammatory episodes that are known to be significant risk factors for ocular scarring in later life. Continued scarring often leads to trichiasis and in turning of the eyelashes, which causes pain and can eventually cause blindness. The mechanisms driving the chronic immunopathology in the conjunctiva, which largely progresses in the absence of detectable Ct infection in adults, are likely to be multifactorial. Socioeconomic status, education, and behavior have been identified as contributing to the risk of scarring and inflammation. We focus on the contribution of host and pathogen genetic variation, bacterial ecology of the conjunctiva, and host epigenetic imprinting including small RNA regulation by both host and pathogen in the development of ocular pathology. Each of these factors or processes contributes to pathogenic outcomes in other inflammatory diseases and we outline their potential role in trachoma. PMID- 26424976 TI - How were lipofilling cannulae designed and are they as safe as we believe? AB - BACKGROUND: Most practitioners in plastic surgery believe that blunt tipped cannulae are safer. Interestingly, there is no study about their safety, and the problem is exactly this. As the use of blunt tipped cannulae is somehow difficult, some surgeons try other extreme alternatives, such as sharp and cutting tipped injection needles. But, they can cause complications such as vessel damage. According to these hypotheses, we tried to design a cannula which would ease the application of lipofilling and which would minimise the trauma. Contrary to the injection needle, the tips of the cannula would be blunter, and trauma would be diminished. OBJECTIVES: After designing such a cannula, we compared it with the most frequently used Coleman type cannulae with regard to ease in utilisation, and safety. We also tried to evaluate the potential for trauma, of the regularly used cannulae. MATERIALS AND METHODS: In the first part, the penetration capacity of all cannulae was measured and compared, and in the second part, the tissue damage was evaluated in an experimental model. RESULTS: According to the statistical and histological findings, the pointed-tip cannulae, blunted to a certain degree, can be applied easily through the tissues. The surgeon works more comfortably and we have noted that these cannulae cause less tissue damage. PMID- 26424977 TI - Objective analysis of microtia reconstruction in Indian patients and modifications in management protocol. AB - INTRODUCTION: An ideal ear, with representation of all anatomic landmarks, is the aim of any reconstructive surgeon embarking on reconstructing the ear in a microtia patient. The literature is abundant with the description of techniques, but these have been reported mainly in Caucasian and Oriental population. There have been very few publications on results in the population belonging to the Indian subcontinent. In spite of strictly adhering to the recommended techniques of reconstruction, the results obtained in these patients have often been marred by problems that are not reported with the Oriental or Caucasian populations. This may necessitate a relook into the management strategy of these cases. Hindering the assessment of the results, their reporting and auditing the improvement obtained by such change in the management strategy, is the lack of a standardized method for assessment of the outcome. Hence, an attempt was made in a series of patients who underwent microtia reconstruction to assess the outcome using a new tool based on the attained definition of anatomical components of the reconstructed pinna. Further effort was made to document the modifications in the technical execution of the reconstruction during the period of the study. MATERIALS AND METHODS: A retrospective review of 44 patients and a prospective analysis of 11 patients, who underwent ear reconstruction for microtia from December 2003 to September 2014 at a tertiary care teaching hospital, was undertaken. Taking a cue from Nagata's description of an 'ideal reconstructed ear' which should show all the anatomical components, we developed an objective grading system to assess our results. The technique had undergone several changes during these years combining the principles of three universally accepted methods, that is, those described by Nagata, Brent, and Firmin. These changes, as well as the reasons behind them, were documented. RESULTS: On objectively measuring and analysing the replication of normal morphologic characteristics of the reconstructed ears, we documented progressive improvement of our results. Good or excellent results could be achieved in 70% of cases in the second group compared to a poor outcome in more than 2/3(rd) of the cases carried out during the initial period. Based on these results and the changes adopted in our practice we propose suggestions for management of microtia cases in the Indian population. CONCLUSIONS: An objective, weighted grading system has further enabled us to critically evaluate the outcomes and to further improve upon the existing results. Our amalgamation of the salient features of the established techniques as well as changes made based on our experience has enabled us to get good results more consistently in our attempts at microtia reconstruction. We believe that the adoption of such amalgamated methods will be more suitable in Indian patients. PMID- 26424978 TI - Thoracodorsal artery perforator flap: Indeed a versatile flap. AB - INTRODUCTION: The thoracodorsal artery perforator (TDAP) flap has emerged as one of the ideal perforator flaps. We, hereby, describe its versatility in indications (free/pedicled), methods of harvest (patient position and paddle orientation) and perforator consistency. MATERIALS AND METHODS: We have performed a total of six TDAP flaps-five free and one pedicled, over a period of 1-year from March 2014 to February 2015 at a single centre. Our indications have been: Reconstruction of oral cavity, breast and upper and lower extremities. RESULTS: We had neither any failures nor any re-explorations. The average perforator length is about 6 cm and the pedicle length can be extended to 12-14 cm by including the thoracodorsal artery. There is inconsistency in perforator position; however, the presence of a perforator is certain. It can be harvested in lateral, prone or supine position, thus, does not require any position change allowing a two-team approach to reconstruction. The paddle can be oriented vertically or horizontally, both healing with scars in inconspicuous locations. Apart from providing a good colour match for extremities, this flap can be thinned primarily. CONCLUSION: The versatility of TDAP has several advantages that make it a workhorse flap for most reconstructions requiring soft tissue cover. Further, the ease of harvest makes it a good perforator flap for beginners. Its use in chimerism with the underlying latissimus dorsi muscle provides reconstruction for coverage and volume replacement. PMID- 26424979 TI - Single nucleotide polymorphism of bone morphogenetic protein 4 gene: A risk factor of non-syndromic cleft lip with or without palate. AB - BACKGROUND: The bone morphogenetic protein (BMP) signalling pathway is crucial in a number of developmental processes and is critical in the formation of variety of craniofacial elements including cranial neural crest, facial primordium, tooth, lip and palate. It is an important mediator in regulation of lip and palate fusion, cartilage and bone formation. AIM: To study the role of mutation of BMP4 genes in the aetiology of non-syndromic cleft lip with or without palate (NSCL +/- P) and identify it directly from human analyses. MATERIALS AND METHODS: A case-control study was done to evaluate whether BMP4T538C polymorphism, resulting in an amino acid change of Val=Ala (V152A) in the polypeptide, is associated with NSCL +/- P in an Indian paediatric population. Genotypes of 100 patients with NSCL +/- P and 100 controls (in whom absence of CL +/- P was confirmed in three generations) were detected using a polymerase chain reaction restriction fragment length polymorphism strategy. Logistic regression was performed to evaluate allele and genotype association with NSCLP. RESULTS: Results showed significant association between homozygous CC genotype with CL +/- P (odds ratio [OR]-5.59 and 95% confidence interval [CI] = 2.85-10.99). The 538C allele carriers showed an increased risk of NSCL +/- P as compared with 538 T allele (OR - 4.2% CI = 2.75-6.41). CONCLUSION: This study suggests an association between SNP of BMP4 gene among carriers of the C allele and increased risk for NSCLP in an Indian Population. Further studies on this aspect can scale large heights in preventive strategies for NSCLP that may soon become a reality. PMID- 26424980 TI - Single nucleotide polymorphism of BMP4 Gene: A risk factor of non-syndromic cleft lip with or without cleft palate. PMID- 26424981 TI - Arterial segments as microvascular interposition grafts in venous anastomosis in digital replantations. AB - INTRODUCTION: Microvascular anastomosis is a crucial procedure in replantation surgeries. Venous insufficiency is one of the most consistent cause of failure or re-exploration in these surgeries necessitating the use of venous grafts. MATERIALS AND METHODS: We discuss our study of 9 such replantation surgeries executed in calendar year 2013-2014, including a double finger replantation done in the same patient having total amputation of 4 fingers of the same (right) hand, in which an arterial segment was used as a microvascular interposition graft for venous anastomosis. Out of these 9 surgeries, 3 were re-exploration procedures for venous compromise and 6 were successful primary replantations. RESULTS: In all, 8 replants were successful and one failed due to arterial compromise. DISCUSSION: In our experience and extensive review of the previously available literature, we would like to portray the advantages of arterial segments as microvascular grafts in replant surgeries. Specifically, in a crush amputation injury for which the use of a vascular interposition graft is being contemplated. If any other digit is also amputated and is unsuitable for replantation, it can act as a potential donor site to harvest the arterial segment. However, when dealing with single finger amputation, the surgeon must be confident about the single digital arterial anastomosis, before harvesting the second digital artery as a microvascular graft. CONCLUSION: In our study, we found the use of arterial grafts in microvascular anastomosis of veins advantageous, as arterial segments have better ability to resist spasm due to environmental changes, better pressure tolerance as compared to venous segments, and provide an appropriate calibre match and ease of harvest in the same operative field. PMID- 26424982 TI - "Ride-on" technique and other simple and logical solutions to counter most common complications of silicone implants in augmentation rhinoplasty. AB - Augmentation rhinoplasty can be carried out using a wide range of materials including autologous bone and/or cartilage as well as alloplasts. Use of biologic bone and cartilage grafts results in lower infection rates, but they are associated with long-term resorption and donor-site morbidity. Alloplastic materials, in particular silicone, have been associated in literature with extrusion, necrosis of the tip, mobility and deviation or displacement of the implant, immobile nasal tip and infection. However, they have the advantages of being readily available and easy to reshape with no requirement for harvesting autografts. AIM: To overcome these problems associated with silicone implants for which the authors have devised a novel technique, the "rideon technique". MATERIALS AND METHODS: The present study was carried out on 11 patients over a period of 4 years. The authors have devised a simple technique to fix the silicone implant and retain it in place. Restricting the implant to only dorsum avoided common complications related to the silicone implant. RESULTS: The authors have used this technique in 11 patients with encouraging results. Follow up ranged from 12 months to 36 months during which patients were assessed for implant mobility, implant extrusion and tip necrosis. There was no incidence of above mentioned complications in these patients. CONCLUSION: The "rideon technique" provides excellent stability to silicone implants and restricting the implant only to dorsum not only eliminates chances of tip necrosis and thus implant extrusion but also maintains natural shape, feel and mobility of the tip. PMID- 26424983 TI - White Roll Vermilion turn down flap in primary unilateral cleft lip repair: A novel approach. AB - AIM: Numerous modifications of Millard's technique of rotation - advancement repair have been described in literature. This article envisions a new modification in Millard's technique of primary unilateral chieloplasty. MATERIAL AND METHODS: Eliminating or reducing the secondary deformities in children with cleft lip has been a motivating factor for the continual refinement of cleft lip surgical techniques through the years. Vermilion notching, visibility of paramedian scars and scar contracture along the white roll are quite noticeable in close-up view even in good repairs. Any scar is less noticeable if it is in midline or along the lines of embryological closure. White Roll Vermilion turn down Flap (WRV Flap), a modification in the Millard's repair is an attempt to prevent these secondary deformities during the primary cleft lip sugery. This entails the use of white roll and the vermilion from the lateral lip segment for augmenting the medial lip vermilion with the final scar in midline at the vermilion. RESULT: With an experience of more than 100 cases of primary cleft lip repair with this technique, we have achieved a good symmetry and peaking of cupid's bow with no vermilion notching of the lips. CONCLUSION: WRV flap aims to high light the importance of achieving a near normal look of the cleft patient with the only drawback of associated learning curve with this technique. PMID- 26424984 TI - White roll vermilion-turn down flap in primary unilateral cleft lip repair: A novel approach. PMID- 26424985 TI - Tunica vaginalis flap following 'Tubularised Incised Plate' urethroplasty to prevent urethrocutaneous fistulaa. AB - INTRODUCTION: Surgery for hypospadias has been continuously evolving, implying thereby that no single technique is perfect and suitable for all types of hypospadias. Snodgrass technique is presently the most common surgical procedure performed for hypospadias. MATERIALS AND METHODS: We analysed the results of tunica vaginalis flap (TVF) as an additional cover to the tubularised incised plate (TIP) repair. RESULTS: A total of 35 patients of hypospadias were repaired using TIP urethroplasty and TVF as a second layer. Mean age at the time of presentation was 6.63 +/- 3.4 years. Post-operative complications namely wound infection, flap necrosis, scrotal haematoma, scrotal abscess, urethral fistula, meatal stenosis were recorded and analysed during follow-up period. Need for re do surgery was considered as failure of the operative procedure. Out of 35 patients, 8 (22.85%) patients had proximal penile hypospadias and 27 (77.14%) patients had distal penile hypospadias. Mean post-operative follow-up was 24.53 months. During the follow-up complications noticed included wound infection (n = 2), urethrocutaneous fistula (n = 1) and meatal stenosis (n = 1). Wound infection was managed with appropriate antibiotics as per hospital policy/culture and sensitivity reports. Meatal stenosis responded to bougie dilatation/calibration during follow-up. CONCLUSION: To conclude, TVF as an additional cover is associated with an acceptable complication rate and good cosmetic results if performed with meticulous tissue handling. PMID- 26424986 TI - Surgical revirgination: Four vaginal mucosal flaps for reconstruction of a hymen. AB - INTRODUCTION: Over centuries, virginity has been given social, religious and moral importance. It is widely believed as a state of a female who has never engaged in sexual intercourse, and her hymen is intact. Hymenoplasty for torn hymen is carried out not only for the sake of cultural and religious traditions but also for the social status and interpersonal relationships. MATERIALS AND METHODS: 2.5 cm long and 1 cm wide four vaginal mucosal flaps were raised from the anterior vaginal wall just behind labia minora. Two flaps were based proximally, and their two opposing flaps were based distally. These flaps were overlapped in a crisscross fashion and were sutured with 5/0 Polyglactin (Vicryl((r))) sutures leaving no area raw. The donor area was closed primarily. When some remains of a torn hymen were found, one to three vaginal mucosal flaps were added to its remains as per the need for reconstruction. RESULTS: We operated upon 11 patients. In nine cases, the hymen was reconstructed with four flaps. In remaining two, it was reconstructed from the remains using vaginal mucosal flaps. All flaps healed without any infection or disruption. Sutures got absorbed in 25-35 days. In all cases, this newly constructed barrier broke with only moderate pressure at the time of penetrative sex serving the purpose of the surgery completely. CONCLUSION: Erasing evidence of the sexual history simply by 'Surgical Revirgination' is extremely important to women contemplating marriage in cultures where a high value is placed on virginity. PMID- 26424987 TI - Extended effect after a single dose of type A botulinum toxin for asymmetric masseter muscle hypertrophy. AB - Facial asymmetry can either be physiological or pathological and is a common cosmetic concern. A 35-year-old Indian male presented with broad appearing lower face and prominent left jaw since adolescence. Parotid enlargement and other local disorders were ruled out. Ultrasonographic thickness of right masseter muscle was 13 mm while that of left was 14.9 mm, in unclenched state. Type-A botulinum toxin (T-ABT) was injected, evenly at five points, in both muscles within the "safe zone". Using a 29 gauge needle, 15 and 25 international units were delivered to right and left masseters, respectively. Six months post - injection, a reduction of 2.9 mm and 4.4 mm was observed along with a reduced external facial asymmetry. At 24 months, patient maintains a satisfactory facial contour with no significant early or late post-injection complications. Intra massteric injection of T-ABT can be used effectively as a primary or adjunct procedure for holistic oculo-facial sculpting. PMID- 26424988 TI - Bony tumour in an unusual location on the mandible. AB - Osteomas are benign osteogenic tumors that are seen in the facial bones, but uncommonly in the mandible. In the facial bones, both central and peripheral osteomas have been described. Peripheral osteomas have been described to occur in the frontal, ethmoid, and maxillary sinuses but are not common in jawbones. When in the mandible, they are usually found over the angle and inferior border of the mandible. We report on a solitary peripheral osteoma located unusually in the sigmoid notch of the left mandible causing facial asymmetry. PMID- 26424989 TI - Congenital urethrocutaneous fistula in an adolescent male. AB - A urethrocutaneous fistula is a common complication after hypospadias repair, but congenital fistula is a rare anomaly. We present a 16-year-old boy with this unusual anomaly. Its etiology, embryology, and management are discussed in brief. PMID- 26424990 TI - A rare case of plexiform schwannoma of the lower lip: Treatment and management. AB - An 18-year-old female presented with a swelling on the lower lip, which was insidious in onset and gradually progressive. The mass was completely excised under local anaesthesia. Complete histopathologic and immunohistochemical studies were conducted. The Antoni A areas were found along with typical verocay bodies composed of palisading nuclei and surrounding spaces filled with eosinophilic filaments. No necrosis was noted and there were no atypical mitotic figures. In the Antoni B region, a closely textured matrix with areas of edema, myxomatous changes, cystic degeneration and dilated vessels were noted. On the basis of the histopathologic and immunohistochemical staining with S-100 protein, a diagnosis of plexiform schwannoma was made and has been reported in this study. The post operative view confirmed complete recovery after 6 weeks of surgery. This is a rare case with the tumour located in the lower lip, as very few cases have been reported in literature and it may be the first one reported from India. PMID- 26424991 TI - Intraosseous keratin cyst of the distal phalanx. AB - Keratin or epidermoid cysts of the phalanges are rare lesions mimicking osteolytic lesions such as infection, malignancy and other tumours. Definitive diagnosis can be made by histopathology only and treatment is by simple excision and curettage. We present a case of intraosseous keratin cyst of the distal phalanx and review of literature. PMID- 26424992 TI - A word of caution. PMID- 26424993 TI - Hyperbaric oxygen and topical oxygen are different treatments. PMID- 26424994 TI - Innovation and beyond: Dangers in improvised negative pressure wound therapy systems. PMID- 26424995 TI - The levels of evidence of articles published by Indian authors in Indian journal of plastic surgery. PMID- 26424996 TI - Giant lipoma of the back. PMID- 26424997 TI - Extended uses of scalp vein set in plastic surgery. PMID- 26424998 TI - Universal Splint for upper limb support during reconstruction by pedicled abdominal flap. PMID- 26424999 TI - Temporal artery rupture following firework rocket injury. PMID- 26425000 TI - Mayo clinic. PMID- 26425002 TI - Controversies in contraception for women with epilepsy. AB - Contraception is an important choice that offers autonomy to women with regard to prevention of unintended pregnancies. There is wide variation in the contraceptive practices between continents, countries, and societies. The medical eligibility for contraception for sexually active women with epilepsy (WWE) is determined by the type of anti-epileptic drugs (AEDs) that they use. Enzyme inducing AEDs such as phenobarbitone, phenytoin, carbamazepine, and oxcarbazepine increase the metabolism of orally administered estrogen (and progesterone to a lesser extent). Estrogen can increase the metabolism of certain AEDs, such as lamotrigine, leading to cyclical variation in its blood level with resultant adverse effect profile or seizure dyscontrol. AEDs and sex hormones can increase the risk of osteoporosis and fracture in WWE. The potential interactions between AEDs and hormonal contraception need to be discussed with all women in reproductive age-group. The alternate options of oral contraception such as intrauterine copper device, intrauterine levonorgestrel release system, and supplementary protection with barriers need to be presented to them. World Health Organization has recommended to avoid combination contraceptive pills containing estrogen and progesteron in women who desire contraception and in breastfeeding mothers. Care providers need to consider the option of non-enzyme-inducing AEDs while initiating long-term treatment in adolescent and young WWE. PMID- 26425001 TI - Epilepsy in India I: Epidemiology and public health. AB - Of the 70 million persons with epilepsy (PWE) worldwide, nearly 12 million PWE are expected to reside in India; which contributes to nearly one-sixth of the global burden. This paper (first of the two part series) provides an in-depth understanding of the epidemiological aspects of epilepsy in India for developing effective public health prevention and control programs. The overall prevalence (3.0-11.9 per 1,000 population) and incidence (0.2-0.6 per 1,000 population per year) data from recent studies in India on general population are comparable to the rates of high-income countries (HICs) despite marked variations in population characteristics and study methodologies. There is a differential distribution of epilepsy among various sociodemographic and economic groups with higher rates reported for the male gender, rural population, and low socioeconomic status. A changing pattern in the age-specific occurrence of epilepsy with preponderance towards the older age group is noticed due to sociodemographic and epidemiological transition. Neuroinfections, neurocysticercosis (NCC), and neurotrauma along with birth injuries have emerged as major risk factors for secondary epilepsy. Despite its varied etiology (unknown and known), majority of the epilepsy are manageable in nature. This paper emphasizes the need for focused and targeted programs based on a life-course perspective and calls for a stronger public health approach based on equity for prevention, control, and management of epilepsy in India. PMID- 26425004 TI - Single small enhancing CT Lesions, with special reference to neurocysticercosis: How I treat. AB - Single small enhancing CT lesions (SSECTL) have been very commonly encountered in clinical practice. These lesions typically are small (often < 20 mm), enhancing as a ring lesion or a disc and with varying amounts of surrounding edema. Most SSECTL present as focal seizures. Once the diagnosis of SSECTL and likely to be a solitary cysticercus lesion is made, the patient is given appropriate AED therapy. Depending on the resolution pattern on repeat imaging performed at intervals not less than six months if patient remains asymptomatic, cysticidal therapy is instituted along with AEDs. Any deviation from the classical clinical or radiological patterns needs further evaluation and other etiologies described for the SSECTL will need to be ruled out, including that of tuberculosis. Largely these lesions resolve and the clinical condition remains benign and in most patients AEDs can be withdrawn in two to three years period. PMID- 26425003 TI - Ipsipulsion: A forgotten sign of lateral medullary syndrome. AB - Ipsipulsion is a clinical sign specifically seen in lateral medullary syndrome. It is characterized by two involuntary phenomenons. One is static eye deviation ipsilateral to the side of lesion especially in the absence of visual fixation. Second is the saccadic lateropulsion whereby voluntary saccades towards the side of lesion are hypermetric and saccades towards opposite side are hypometric. The vertical saccades may also appear oblique. Ipsipulsion is produced due to damage to the contralateral olivocerebellar pathways that crosses midline in medulla and pass through the ipsilateral inferior cerebellar peduncle to supply ipsilateral cerebellar hemisphere. PMID- 26425005 TI - Joseph Godwin Greenfield: The father of neuropathology (1884-1958). AB - The systematic study of neuropathology was initiated by Godwin Greenfield in the early part of the 20(th) century. He worked at the National Hospital, Queen Square, London for the major period of his life and worked on various subjects like cerebrospinal fluid, intracranial tumours, cerebellar ataxias, dystrophia myotonica, disseminated sclerosis, subacute combined degeneration of the spinal cord, and the like. After his retirement he visited the National Institute of Neurological Diseases and Blindness in Bethesda, Maryland, USA, from time to time and there he died suddenly from myocardial infarction. PMID- 26425006 TI - Pure neuritic leprosy: Resolving diagnostic issues in acid fast bacilli (AFB) negative nerve biopsies: A single centre experience from South India. AB - BACKGROUND AND PURPOSE: Demonstration of lepra bacilli is essential for definite or unequivocal diagnosis of pure neuritic leprosy (PNL) on nerve biopsy. However, nerves always do not show bacilli owing to the changes of previous therapy or due to low bacillary load in tuberculoid forms. In absence of granuloma or lepra bacilli, other morphologic changes in endoneurium and perineurium can be of help in making a probable diagnosis of PNL and treating the patient with multidrug therapy. MATERIALS AND METHODS: Forty-six biopsies of PNL were retrospectively reviewed and histologic findings were compared with 25 biopsies of non leprosy neuropathies (NLN) including vasculitic neuropathy and chronic inflammatory demyelinating polyneuropathy (CIDP). The distribution of endoneurial infiltrate and fibrosis, perineurial thickening, and myelin abnormalities were compared between PNL and NLN biopsies and analyzed by Chi-square test. RESULTS: Out of 46 PNL casses, 24 (52.17 %) biopsies were negative for acid fast bacilli (AFB). In these cases, the features which favor a diagnosis of AFB-negative PNL were endoneurial infiltrate (51.1%), endoneurial fibrosis (54.2%), perineurial thickening (70.8%), and reduced number of myelinated nerve fibers (75%). INTERPRETATION AND CONCLUSION: Nerve biopsy is an efficient tool to diagnose PNL and differentiate it from other causes of NLN. In absence of AFB, the diagnosis of PNL is challenging. In this article, we have satisfactorily evaluated the various hisopthological features and found that endoneurial inflammation, dense fibrosis, and reduction in the number of myelinated nerve fibers are strong supportive indicators of PNL regardless of AFB positivity. PMID- 26425007 TI - Sleep changes during prophylactic treatment of migraine. AB - AIMS: To assess sleep quality in patients with primary headaches before and after prophylactic treatment using a validated sleep-screening instrument. MATERIALS AND METHODS: A total of 147 patients, including 63 tension type headache (TTH) and 84 migraine patients were included. Patients were examined in terms of frequency and severity of headaches and sleep quality before and 12 weeks after prophylactic treatment with either propranolol or amitriptyline. RESULTS: Baseline Visual Analogue Score (VAS) in migraine patients was 7.99 +/- 1.39 compared with 6.86 +/- 1.50 in TTH group (P < 0.001). VAS score after the first month of treatment was 6.08 +/- 1.88 in migraine patients and 5.40 +/- 1.61 in TTH (P = 0.023). VAS scores decreased after the third month of treatment to 4.32 +/- 2.29 in migraine patients and 4.11 +/- 1.66 in TTH patients (P = 0.344). The decrease was significant for patients treated with amitriptyline but not for those with propranolol. Baseline Pittsburgh Sleep Quality (PSQI) scores were 5.93 +/- 2.43 in migraine patients and 6.71 +/- 2.39 in TTH patients. Poor quality of sleep (PSQI >= 6) prior to prophylactic treatment was observed in 61.4% of migraine patients and in 77.7% of TTH patients. Comparison of PSQI scores before and 3 months following treatment showed significantly improved quality of sleep in all treatment groups; the greatest significance was detected in migraine patients with initial PSQI scores of >=6 and treated with amitriptyline (P < 0.001). CONCLUSIONS: Increased understanding of routine objective sleep measures in migraine patients is needed to clarify the nature of sleep disturbances associated with primary headaches. This may in turn lead to improvements in headache treatments. PMID- 26425008 TI - Hindi translation and validation of Cambridge-Hopkins Diagnostic Questionnaire for RLS (CHRLSq). AB - BACKGROUND: Restless legs syndrome also known as Willis-Ekbom's Disease (RLS/WED) is a common illness. Cambridge-Hopkins diagnostic questionnaire for RLS (CHRLSq) is a good diagnostic tool and can be used in the epidemiological studies. However, its Hindi version is not available. Thus, this study was conducted to translate and validate it in the Hindi speaking population. MATERIALS AND METHODS: After obtaining the permission from the author of the CHRLSq, it was translated into Hindi language by two independent translators. After a series of forward and back translations, the finalized Hindi version was administered to two groups by one of the authors, who were blinded to the clinical diagnosis. First group consisted of RLS/WED patients, where diagnosis was made upon face to face interview and the other group - the control group included subjects with somatic symptoms disorders or exertional myalgia or chronic insomnia. Each group had 30 subjects. Diagnosis made on CHRLSq was compared with the clinical diagnosis. STATISTICAL ANALYSIS: Analysis was done using Statistical Package for Social Sciences (SPSS) v 21.0. Descriptive statistics was calculated. Proportions were compared using chi-square test; whereas, categorical variables were compared using independent sample t-test. Sensitivity, specificity, and positive predictive value of the translated version of questionnaire were calculated. RESULTS: Average age was comparable between the cases and control group (RLS/WED = 39.1 +/- 10.1 years vs 36.2 +/- 11.4 years in controls; P = 0.29). Women outnumbered men in the RLS/WED group (87% in RLS/WED group vs 57% among controls; chi(2) = 6.64; P = 0.01). Both the sensitivity and specificity of the translated version was 83.3%. It had the positive predictive value of 86.6%. CONCLUSION: Hindi version of CHRLSq has positive predictive value of 87% and it can be used to diagnose RLS in Hindi speaking population. PMID- 26425009 TI - Serial macro-architectural alterations with levodopa in Parkinson's disease: Polysomnography (PSG)-based analysis. AB - PURPOSE: We studied the sleep macroarchitecture with polysomnography (PSG) in drug naive patients with Parkinson's disease (PD) and reassessed them following treatment with levodopa. MATERIALS AND METHODS: This prospective hospital-based study included 15 patients with PD (age: 59 +/- 11.2 years, duration of PD: 11.8 +/- 12.3 months; and male: female (M:F) = 11:4). They were assessed for demography, phenotype, modified Hoehn and Yahr staging (H & Y); Schwab and England and Activities of Daily Living (S and E ADL) Scale; and Unified PDRating Scale (UPDRS). Sleep was assessed using Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and National Institute of Mental Health and Neurosciences (NIMHANS) comprehensive sleep disorder questionnaire. They underwent overnight PSG at baseline and after13.3 +/- 5.7 months of levodopa (440 mg/day). RESULTS: Patients with PD had responded to levodopa as indicated by the significant improvement in UPDRS motor score in ON state compared to OFF state. Nocturnal sleep quality indices did not vary significantly, but the excessive daytime somnolence improved (P = 0.04) with levodopa. Sleep efficiency (P = 0.65), latency to sleep onset (P = 0.19), latency to stage 1 (P = 0.12), and duration of stage 1 (P = 0.55) had increased. Duration of 'awake in bed' (P = 0.24), slow wave sleep (P = 0.29), and rapid eye movement (REM) sleep (P = 0.24) decreased with treatment. Periodic leg movements (PLMs) had reduced (P = 0.68) and mean oxygen saturation during sleep improved (P = 0.002). Surprisingly, snore index (P < 0.03) during sleep had increased with levodopa. CONCLUSIONS: Sleep alterations in PD occur even in early stages due to the disease process. There was improvement in most of the parameters of sleep macroarchitecture with levodopa. PMID- 26425010 TI - Vitamin D as a marker of cognitive decline in elderly Indian population. AB - OBJECTIVES: Very few studies in India have addressed the role of vitamin D in cognitive function. The present study was conducted to assess the serum levels of 25-hydroxyvitamin D (25(OH)D) and its association with markers of cognitive impairment and homocysteine levels in the elderly Indian population. MATERIALS AND METHODS: The study population consisted of patients with dementia (Group A, n = 32), mild cognitive impairment (MCI; Group B, n = 24), and elderly age-matched controls (Group C, n = 30). Measurement of serum levels of 25(OH)D and total homocysteine were done. RESULTS: Significant decreased concentration of 25(OH)D and increased concentration of homocysteine was observed. Association of serum levels of vitamin D with markers of cognitive decline as well as serum homocysteine levels was observed in patients with dementia and MCI when compared to controls. CONCLUSION: Correlation of vitamin D with markers of cognitive decline and homocysteine opens a new door for early diagnosis of cognitive impairment. PMID- 26425011 TI - Effect of apolipoprotein E (APO E) polymorphism on leptin in Alzheimer's disease. AB - BACKGROUND: Leptin, a 16 kDa peptide hormone synthesized and secreted specifically from white adipose cells protects neurons against amyloid beta induced toxicity, by increasing Apolipoprotein E (APO E)-dependent uptake of beta amyloid into the cells, thereby, protect individuals from developing Alzheimer's disease (AD). The APO E epsilon4 allele is a known genetic risk factor for AD by accelerating onset. It is estimated that the lifetime risk of developing AD increases to 29% for carriers with one epsilon4 allele and 9% for those with no epsilon4 allele. OBJECTIVES: To determine the levels of serum leptin, cholesterol, low density lipoprotein (LDL-C), and high density lipoprotein (HDL C) in the diagnosed cases of AD and the association of them with cognitive decline and Apolipoprotein E (APO E) genotypes in AD. MATERIALS AND METHODS: Serum levels of serum leptin, cholesterol, LDL-C, and HDL-C along with APO E polymorphism were studied in 39 subjects with probable AD and 42 cognitive normal individuals. RESULTS: AD group showed significantly lower levels of leptin (P = 0.00) as compared to control group. However, there was no significant difference in cholesterol, triglycerides, LDL-C, and HDL-C levels in AD and control groups. The frequency of epsilon4 allele in AD (38.5%) was found to be significantly higher than in control (10.3%). epsilon3 allele was more frequent than epsilon4 allele in AD and control group. PMID- 26425012 TI - Treatment of pediatric chronic inflammatory demyelinating polyneuropathy: Challenges, controversies and questions. AB - Pediatric chronic inflammatory demyelinating polyneuropathy (CIDP) is an uncommon acquired disorder of unknown cause, presumed to have an immunological basis. We report 20 patients seen at Children's Hospital Los Angeles over a period of 10 years. The outcome of our patients was favorable in a vast majority with good response to various treatments instituted. However, residual neurologic deficit was common. The choice of treatment modality was empirical and selected by the treating neurologist. Intravenous immunoglobulin (IVIG) and corticosteroids were most commonly utilized for treatment. Plasmapheresis, mycophenolate mofetil, rituximab, cyclophosphamide, azathioprine, and abatacept were added if the patients were refractory to IVIG or became corticosteroid dependent. The spectrum of disease severity ranged from a single monophasic episode, to multiphasic with infrequent relapses with good response to IVIG, to progressive disease refractory to multiple therapies. PMID- 26425014 TI - "Nine" syndrome: A new neuro-ophthalmologic syndrome: Report of two cases. AB - "Eight-and-a-half" syndrome is a rare condition involving the ipsilateral abducens nucleus or paramedian pontine reticular formation (PPRF), the ipsilateral medial longitudinal fasciculus (MLF), and the adjacent facial colliculus/facial nerve fascicle. The condition is often caused by a lesion (vascular or demyelinating) in the dorsal tegmentum of the caudal pons. There are new variants of this syndrome caused by extension of lesion to involve new adjacent structures in pontine tegmentum. We report two patients with different etiology presenting with clinical features suggestive of eight-and-a-half syndrome associated with hemiataxia representing "nine" syndrome (81/2 + 1/2 = 9) adding new dimension to "eight-and-a-half" syndrome. PMID- 26425013 TI - Statin-induced bilateral foot drop in a case of hypothyroidism. AB - Muscle involvement is a common manifestation of both clinical and subclinical hypothyroidism, with serum creatine kinase (CK) elevation being probably the most common manifestation, and is seen in up to 90% of patients, but is usually mild (less than 10 times the upper limit of normal). Rhabdomyolysis is a distinctively uncommon presentation of hypothyroidism described usually in the setting of precipitating events such as strenuous exercise, alcohol, or statin use. Rarely rhabdomyolysis and myoedema seen in hypothyroidism can be complicated by the development of anterior compartment syndrome leading to neurovascular compression. We describe a case of a patient with hypothyroidism who developed acute onset bilateral foot drop on initiation of statins. This case highlights the need for cautious use of statins in patients at risk for rhabdomyolysis. PMID- 26425015 TI - A case of Erdheim Chester disease with central nervous system involvement. AB - Erdheim Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, commonly involving the musculoskeletal system. Other tissue can also be involved, including the central nervous system with wide spectrum of clinical features, at times being nonspecific. This can cause diagnostic dilemmas with delay in diagnosis and initiation of therapy. Here we describe a 63-year-old man who had presented with ataxia and behavioral changes, bony pains, weight loss, and fatigue. His computed tomography (CT), 99Tc scintigraphy and histopathological features on bone biopsy were consistent with ECD. Thus, ECD should be considered as a differential diagnosis in patients presenting with bony pain and nonspecific features of multiorgan involvement. PMID- 26425016 TI - Diffusion MRI features of acute encephalopathy due to stopping steroid medication abruptly in congenital adrenal hyperplasia. AB - Congenital adrenal hyperplasia (CAH) is characterized by adrenal steroid biosynthesis defect. Steroid replacement therapy should be performed regularly in these patients. Adrenal crisis may be present in acute stress due to increased cortisol requirements or in steroid deficiency due to stopping steroid medication abruptly. In patients with acute adrenal insufficiency, severe hypotension or hypovolemic shock occurs typically. Acute encephalopathy can be seen due to hypoxia, hypervolemia, or hypoglycemia. Diffusion restriction can be seen in cortical-subcortical regions of frontal and parieto-occipital lobes and in splenium of corpus callosum. In CAH patients with neurologic symptoms, Diffusion weighted images (DWI) is very important in the diagnosis and follow-up of acute encephalopathy. PMID- 26425017 TI - Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): A case report and review of literature. AB - Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently described inflammatory disease of central nervous system with distinct clinical and radiological features. The etiopathogenesis of this rare entity remains to be understood. The histopathological findings closely resemble chronic inflammatory diseases like sarcoidosis and malignancies like lymphoma. With advancements in serology, immunopathology and radiology CLIPPERS is identified as a distinct entity that differs considerably in its clinical presentation, immunopathology, radiological findings and response to steroids. We describe a case that presented to us with progressive quadriparesis and lower cranial nerve deficits whose radiological and pathological findings were consistent with CLIPPERS. The patient had a good outcome with long term immunosuppression. PMID- 26425018 TI - An uncommon initial presentation of snake bite-subarachnoid hemorrhage: A case report with literature review. AB - Snake bites are very common in India, particularly in West Bengal. Snake bite can cause various hematological, neuromyopathical complications. It can be very fatal if not detected and treated early. Timely intervention can save the patient. We are reporting a case of hematotoxic Russell viper snake bite presented with subarachnoid hemorrhage. Patient was successfully treated with antivenom serum (AVS) along with other conservative management. Subarachnoid hemorrhage as an initial presentation in viper bite is very rare and we discuss the case with proper literature review. PMID- 26425019 TI - An unusual case of bloody tears. AB - Conjunctival bleeding although occurs in many pathological conditions enlisting diseases like purulent conjunctivitis, infection with epstian bar virus, and accidental damage to conjunctiva. We report here a rare case of bloody tears which was accompanied with severe headache in a12-years school-going girl. PMID- 26425020 TI - Moyamoya disease; suspecting on conventional MRI brain without angiography. PMID- 26425021 TI - A unique presentation of atypical SREDA pattern in a young healthy woman. AB - Subclinical rhythmic electrographic discharge of adults (SREDA) is an EEG pattern seen in normal individuals and others with different diseases. we report a case of healthy young woman with alleged epilepsy but normal responsiveness during sustained SREDA. SREDA is a rare EEG variant with variable clinical significance. This is the first report of atypical SREDA in a 25 year-old woman. PMID- 26425022 TI - Montelukast-associated Churg-Strauss syndrome with mononeuritis multiplex. PMID- 26425023 TI - Bilateral symmetrical parieto occipital involvement in dengue infection. PMID- 26425024 TI - Antiphospholipid syndrome is an important modifiable risk factor of stroke in the young. PMID- 26425025 TI - Conducting case control study on a cross-sectional database. PMID- 26425026 TI - "Comments on intravenous thrombolysis in acute ischemic stroke in a known case of left atrial myxoma". PMID- 26425027 TI - Intravenous thrombolysis in a patient with left atrial myxoma with acute ischemic stroke. PMID- 26425028 TI - Sleep quality and health complaints among nursing students. PMID- 26425029 TI - Electroconvulsive therapy for refractory status epilepticus in a child: A case report. PMID- 26425030 TI - Erratum: Impulse control disorders and related behaviours (ICD-RBs) in Parkinson's disease patients: Assessment using "Questionnaire for impulsive compulsive disorders in Parkinson's disease" (QUIP): Erratum. AB - [This corrects the article on p. 49 in vol. 18, PMID: 25745311.]. PMID- 26425031 TI - Vogt-Koyanagi-Harada syndrome presenting with encephalopathy: Retraction. AB - [This retracts the article on p. 128 in vol. 17, PMID: 24753681.]. PMID- 26425032 TI - Histone Deacetylases and Their Regulatory MicroRNAs in Hepatocarcinogenesis. AB - A growing body of evidence suggests that epigenetic modifications are promising potential mechanisms in cancer research. Among the molecules that mediate epigenetic mechanisms, histone deacetylases (HDACs) are critical regulators of gene expression that promote formation of heterochromatin by deacetylating histone and non-histone proteins. Aberrant regulation of HDACs contributes to malignant transformation and progression in a wide variety of human cancers, including hepatocellular carcinoma (HCC), gastric cancer, lung cancer, and other cancers. Thus, the roles of HDACs have been extensively studied because of their potential as therapeutic targets. However, the underlying mechanism leading to deregulation of individual HDACs remains largely unknown. Some reports have suggested that functional microRNAs (miRNAs) modulate epigenetic effector molecules including HDACs. Here, we describe the oncogenic or tumor suppressive functions of HDAC families and their regulatory miRNAs governing HDAC expression in hepatocarcinogenesis. PMID- 26425033 TI - Essential Components of Educational Programs on Biomedical Writing, Editing, and Publishing. AB - The primary objective of educational programs on biomedical writing, editing, and publishing is to nurture ethical skills among local and international researchers and editors from diverse professional backgrounds. The mechanics, essential components, and target outcomes of these programs are described in this article. The mechanics covers the objectives, design, benefits, duration, participants and qualifications, program formats, administrative issues, and mentorship. The essential components consist of three core schedules: Schedule I Basic aspects of biomedical writing, editing, and communications; Schedule II Essential skills in biomedical writing, editing, and publishing; and Schedule III Interactive lectures on relevant topics. The target outcomes of the programs comprise knowledge acquisition, skills development, paper write-up, and journal publication. These programs add to the prestige and academic standing of the host institutions. PMID- 26425034 TI - HIF-1alpha Upregulation due to Depletion of the Free Ubiquitin Pool. AB - Hypoxia-inducible factor 1alpha (HIF-1alpha), which transactivates a variety of hypoxia-induced genes, is rapidly degraded under nomoxia through the hydroxylation-ubiquitination-proteasome pathway. In this study, we addressed how HIF-1alpha is stabilized by proteasome inhibitors. The ubiquitin pool was rapidly reduced after proteasome inhibition, followed by the accumulation of non ubiquitinated HIF-1alpha. The poly-ubiquitination of HIF-1alpha was resumed by restoration of free ubiquitin, which suggests that the HIF-1alpha stabilization under proteasome inhibition is attributed to depletion of the free ubiquitin pool. Ni(2+) and Zn(2+) also stabilized HIF-1alpha with depletion of the free ubiquitin pool and these effects of metal ions were attenuated by restoration of free ubiquitin. Ni(2+) and Zn(2+) may disturb the recycling of free ubiquitin, as MG132 does. Based on these results, the state of the ubiquitin pool seems to be another critical factor determining the cellular level of HIF-1alpha. PMID- 26425035 TI - Presumed Regional Incidence Rate of Out-of-Hospital Cardiac Arrest in Korea. AB - The regional incidence rates of out-of-hospital cardiac arrest (OHCA) were traditionally calculated with the residential population as the denominator. The aim of this study was to estimate the true incidence rate of OHCA and to investigate characteristics of regions with overestimated and underestimated OHCA incidence rates. We used the national OHCA database from 2006 to 2010. The nighttime residential and daytime transient populations were investigated from the 2010 Census. The daytime population was calculated by adding the daytime influx of population to, and subtracting the daytime outflow from, the nighttime residential population. Conventional age-standardized incidence rates (CASRs) and daytime corrected age-standardized incidence rates (DASRs) for OHCA per 100,000 person-years were calculated in each county. A total of 97,291 OHCAs were eligible. The age-standardized incidence rates of OHCAs per 100,000 person-years were 34.6 (95% CI: 34.3-35.0) in the daytime and 24.8 (95% CI: 24.5-25.1) in the nighttime among males, and 14.9 (95% CI: 14.7-15.1) in the daytime, and 10.4 (95% CI: 10.2-10.6) in the nighttime among females. The difference between the CASR and DASR ranged from 35.4 to -11.6 in males and from 6.1 to -1.0 in females. Through the Bland-Altman plot analysis, we found the difference between the CASR and DASR increased as the average CASR and DASR increased as well as with the larger daytime transient population. The conventional incidence rate was overestimated in counties with many OHCA cases and in metropolitan cities with large daytime population influx and nighttime outflow, while it was underestimated in residential counties around metropolitan cities. PMID- 26425036 TI - Therapeutic Effects of Mesenchymal Stem Cells for Patients with Chronic Liver Diseases: Systematic Review and Meta-analysis. AB - Based on their ability to differentiate into multiple cell types including hepatocytes, the transplantation of mesenchymal stem cells (MSCs) has been suggested as an effective therapy for chronic liver diseases. The aim of this study was to evaluate the safety, efficacy and therapeutic effects of MSCs in patients with chronic liver disease through a literature-based examination. We performed a systematic review (SR) and meta-analysis (MA) of the literature using the Ovid-MEDLINE, EMBASE and Cochrane Library databases (up to November 2014) to identify clinical studies in which patients with liver diseases were treated with MSC therapy. Of the 568 studies identified by the initial literature search, we analyzed 14 studies and 448 patients based on our selection criteria. None of the studies reported the occurrence of statistically significant adverse events, side effects or complications. The majority of the analyzed studies showed improvements in liver function, ascites and encephalopathy. In particular, an MA showed that MSC therapy improved the total bilirubin level, the serum albumin level and the Model for End-stage Liver Disease (MELD) score after MSC treatment. Based on these results, MSC transplantation is considered to be safe for the treatment of chronic liver disease. However, although MSCs are potential therapeutic agents that may improve liver function, in order to obtain meaningful insights into their clinical efficacy, further robust clinical studies must be conducted to evaluate the clinical outcomes, such as histological improvement, increased survival and reduced liver-related complications, in patients with chronic liver disease. PMID- 26425037 TI - Oral Maintenance Chemotherapy with 6-Mercaptopurine and Methotrexate in Patients with Acute Myeloid Leukemia Ineligible for Transplantation. AB - For decades, maintenance chemotherapy has failed to improve the cure rate or prolong the survival of patients with acute myeloid leukemia (AML), other than those with acute promyelocytic leukemia. Immediately after the first complete remission following consolidation therapy was obtained, oral maintenance chemotherapy (daily 6-mercaptopurine and weekly methotrexate) was given and continued for two years in transplant-ineligible AML patients. Leukemia-free survival (LFS) and overall survival (OS) were studied and compared between these patients and the historical control group who did not receive maintenance therapy. Consecutive 52 transplant-ineligible AML patients were analyzed. Among these patients, 27 received oral maintenance chemotherapy. No significant difference was found in the patients' characteristics between the maintenance and the control groups. The median OS was 43 (95% CI, 19-67) and 19 (95% CI, 8-30) months in the maintenance and the control groups, respectively (P = 0.202). In the multivariate analysis, the presence of maintenance therapy was an independent prognostic factor for better OS (P = 0.021) and LFS (P = 0.024). Clinical benefit from maintenance chemotherapy was remarkable in older patients (>= 60 yr) (P = 0.035), those with intermediate or unfavorable cytogenetics (P = 0.006), those with initial low blast count in peripheral blood (P = 0.044), and those receiving less than two cycles of consolidation therapy (P = 0.017). Maintenance oral chemotherapy as a post-remission therapy can prolong the survival of patients with AML who are not eligible for transplantation, particularly older patients, those with intermediate or unfavorable cytogenetics, those with initial low blast count, and those receiving less than two cycles of consolidation therapy. PMID- 26425038 TI - TERT Polymorphism rs2853669 Influences on Lung Cancer Risk in the Korean Population. AB - Short telomeres are known as one of the risk factors for human cancers. The present study was conducted to evaluate the association between 6 polymorphisms, which were related with short telomere length in the Korean population, and lung cancer risk using 1,100 cases and 1,096 controls. Among the 6 polymorphisms, TERT rs2853669 was significantly associated with increased lung cancer risk under a recessive model (odds ratio [OR]=1.38, 95% confidence interval [CI]=1.05-1.81, P=0.02). The effect of rs2853669 on lung cancer risk was significant in younger individuals (OR=1.73, 95% CI=1.18-2.54, P=0.005) and adenocarcinoma (OR=1.50, 95% CI=1.07-2.07, P=0.02). Our results suggest that a common functional promoter polymorphism, TERT rs2853669, may influence both telomere length and lung cancer risk in the Korean population. PMID- 26425040 TI - Clinico-pathological Analysis of the Lungs from Patients with Lung Transplantation in a Single Institute in Korea. AB - Recently, the numbers of lung transplantation (LT) has been increased in Korea. However, post-LT outcome has not been successful in all patients, which may be partially affected by the primary lung disease. Therefore comprehensive understanding in original pathological diagnosis of patients with LT would be needed for achieving better clinical outcome. To address this issue, we performed clinico-pathological analysis of the explanted lungs from 29 patients who underwent LT over a 9-yr period in Seoul National University Hospital. Among them, 26 patients received single (1/26) or double (25/26) LT, while heart-lung transplantation was performed in 3 patients. The final clinico-pathological diagnoses were idiopathic pulmonary fibrosis/usual interstitial pneumonia (UIP) (n = 6), acute interstitial pneumonia (AIP)/diffuse alveolar damage (DAD) (n = 4), AIP/non-specific interstitial pneumonia with DAD (n = 1), collagen vascular disease-related interstitial lung disease (CVD-ILD)/DAD (n = 3), CVD-ILD/UIP (n = 1), lymphangioleiomyomatosis (n = 1), bronchiectasis (n = 4), pulmonary arterial hypertension (n = 2), tuberculosis (n = 1), bronchiolitis obliterans (BO) (n = 1), and lung cancer (n = 1). Moreover, 4 patients who had chemotherapy and hematopoietic stem cell transplantation due to hematologic malignancy showed unclassifiable interstitial pneumonia with extensive fibrosis in the lungs. Our study demonstrates that pathology of the explanted lungs from Korean patients with LT is different from that of other countries except for interstitial lung disease and bronchiectasis, which may be helpful for optimization of selecting LT candidates for Korean patients. PMID- 26425039 TI - Baseline Characteristics of the Korean Registry of Pulmonary Arterial Hypertension. AB - Despite recent advances in understanding of the pathobiology and targeted treatments of pulmonary arterial hypertension (PAH), epidemiologic data from large populations have been limited to western countries. The aim of the Korean Registry of Pulmonary Arterial Hypertension (KORPAH) was to examine the epidemiology and prognosis of Korean patients with PAH. KORPAH was designed as a nationwide, multicenter, prospective data collection using an internet webserver from September 2008 to December 2011. A total of 625 patients were enrolled. The patients' mean age was 47.6 +/- 15.7 yr, and 503 (80.5%) were women. The diagnostic methods included right heart catheterization (n = 249, 39.8%) and Doppler echocardiography (n = 376, 60.2%). The etiologies, in order of frequency, were connective tissue disease (CTD), congenital heart disease, and idiopathic PAH (IPAH) (49.8%, 25.4%, and 23.2%, respectively). Patients with WHO functional class III or IV at diagnosis were 43.4%. In total, 380 (60.8%) patients received a single PAH-specific treatment at the time of enrollment, but only 72 (18.9%) patients received combination therapy. Incident cases during the registry represented 297 patients; therefore, the incidence rate of PAH was 1.9 patients/yr/million people. The 1st-, 2nd-, and 3rd-yr estimated survival rates were 90.8%, 87.8%, and 84.4%, respectively. Although Korean PAH patients exhibited similar age, gender, and survival rate compared with western registries, they showed relatively more CTD-PAH in the etiology and also systemic lupus erythematosus among CTD-PAH. The data suggest that earlier diagnosis and more specialized therapies should be needed to improve the survival of PAH patients. PMID- 26425041 TI - Role of Atypical Pathogens and the Antibiotic Prescription Pattern in Acute Bronchitis: A Multicenter Study in Korea. AB - The role of atypical bacteria and the effect of antibiotic treatments in acute bronchitis are still not clear. This study was conducted at 22 hospitals (17 primary care clinics and 5 university hospitals) in Korea. Outpatients (aged >= 18 yr) who had an acute illness with a new cough and sputum (<= 30 days) were enrolled in 2013. Multiplex real-time polymerase chain reaction (RT-PCR) was used to detect five atypical bacteria. A total of 435 patients were diagnosed as having acute bronchitis (vs. probable pneumonia, n = 75), and 1.8% (n = 8) were positive for atypical pathogens (Bordetella pertussis, n = 3; B. parapertussis, n = 0; Mycoplasma pneumoniae, n = 1; Chlamydophila pneumoniae, n = 3; Legionella pneumophila, n = 1). Among clinical symptoms and signs, only post-tussive vomiting was more frequent in patients with atypical pathogens than those without (P = 0.024). In all, 72.2% of the enrolled patients received antibiotic treatment at their first visits, and beta-lactams (29.4%) and quinolones (20.5%) were the most commonly prescribed agents. In conclusion, our study demonstrates that the incidence of atypical pathogens is low in patients with acute bronchitis, and the rate of antibiotic prescriptions is high. PMID- 26425042 TI - Effect of Indacaterol on Cough and Phlegm in Chronic Obstructive Pulmonary Disease Patients: A Meta-Analysis of Five Randomized Controlled Trials. AB - We investigated the effects of indacaterol on cough and phlegm in patients with stable chronic obstructive pulmonary disease (COPD). We performed a meta-analysis with five randomized controlled trials (RCTs) of indacaterol in stable COPD patients. The symptom severity was defined using the St. George's Respiratory Questionnaire (SGRQ). We analyzed patients treated with 150 ug (n = 945) and 300 ug (n = 832) out of 3,325 patients who completed the SGRQ from five RCTs. After a 12-week treatment of 150 ug indacaterol, cough improvement was reported in 36.5% (316/866) of patients treated with indacaterol vs. 32.2% (259/804) patients treated with placebo (Relative Ratio [RR], 1.13; 95% confidence interval [CI], 0.99-1.29). Phlegm improvement was reported in 31.0% (247/798) of patients treated with indacaterol vs. 30.6% (225/736) of patients treated with placebo (RR, 1.01; 95% CI, 0.87-1.18). Dyspnea improvement was reported in 39.5% (324/820) of patients treated with indacaterol vs. 31.5% (237/753) patients treated with placebo (RR, 1.33; 95% CI, 1.03-1.71; P = 0.001, I(2) = 55.1%). Only dyspnea improvement was significant compared to placebo even at the 300 ug indacaterol dose. Compared to placebo, a 12-week treatment of the long-acting beta-agonist, indacaterol might not have a significant effect on cough or phlegm in stable COPD. PMID- 26425043 TI - The Prognostic Value of Residual Volume/Total Lung Capacity in Patients with Chronic Obstructive Pulmonary Disease. AB - The prognostic role of resting pulmonary hyperinflation as measured by residual volume (RV)/total lung capacity (TLC) in chronic obstructive pulmonary disease (COPD) remains poorly understood. Therefore, this study aimed to identify the factors related to resting pulmonary hyperinflation in COPD and to determine whether resting pulmonary hyperinflation is a prognostic factor in COPD. In total, 353 patients with COPD in the Korean Obstructive Lung Disease cohort recruited from 16 hospitals were enrolled. Resting pulmonary hyperinflation was defined as RV/TLC >= 40%. Multivariate logistic regression analysis demonstrated that older age (P = 0.001), lower forced expiratory volume in 1 second (FEV1) (P < 0.001), higher St. George Respiratory Questionnaire (SGRQ) score (P = 0.019), and higher emphysema index (P = 0.010) were associated independently with resting hyperinflation. Multivariate Cox regression model that included age, gender, dyspnea scale, SGRQ, RV/TLC, and 6-min walking distance revealed that an older age (HR = 1.07, P = 0.027), a higher RV/TLC (HR = 1.04, P = 0.025), and a shorter 6-min walking distance (HR = 0.99, P < 0.001) were independent predictors of all cause mortality. Our data showed that older age, higher emphysema index, higher SGRQ score, and lower FEV1 were associated independently with resting pulmonary hyperinflation in COPD. RV/TLC is an independent risk factor for all-cause mortality in COPD. PMID- 26425044 TI - Risk Factors of Discharged Against Medical Advice among Adolescents Self inflicted Injury and Attempted Suicide in the Korean Emergency Department. AB - Suicide is a leading cause of death among Korean adolescents. Many suicide attempting adolescents often are discharged against medical advice in the emergency department. The aim of the present study was to determine the risk factors for discharge against medical advice (DAMA) after self-inflicted injury or attempted suicide in the emergency department. We extracted data on adolescents (10-19 yr old) from the national emergency department information system; we used data from 2007 and 2011. A total of 6,394 adolescents visited EDs after self-inflicted injury or attempted suicide. Among these patients, the median age was 17 yr (Interquatile range, 15-18 yr), 83.2% were between 15-19 yr of age, and 63.3% were female. Poisoning was the most common method of attempted suicide, while hanging and fall were the most common methods of fatality. The rate of DAMA from the ED was 22.8%. Independent risk factors for DAMA included female gender (odds ratio [OR], 1.49), older age adolescents (OR, 1.96), residence in a metropolitan/large city area (OR, 1.49), and discharge at night (OR, 1.38). These risk factors should be considered in establishing management and counseling plans for patients discharged against medical advice by community services and EDs. PMID- 26425045 TI - Detection of Rotavirus Genotypes in Korea 5 Years after the Introduction of Rotavirus Vaccines. AB - Rotavirus (RV) is one of the most important viral etiologic agents of acute gastroenteritis (AGE) in children. Although effective RV vaccines (RVVs) are now used worldwide, novel genotypes and outbreaks resulting from rare genotype combinations have emerged. This study documented RV genotypes in a Korean population of children with AGE 5 yr after the introduction of RVV and assessed potential genotype differences based on vaccination status or vaccine type. Children less than 5-yr-old diagnosed with AGE between October 2012 and September 2013 admitted to 9 medical institutions from 8 provinces in Korea were prospectively enrolled. Stool samples were tested for RV by enzyme immunoassay and genotyped by multiplex reverse-transcription polymerase chain reaction. In 346 patients, 114 (32.9%) were RV-positive. Among them, 87 (76.3%) patients were infected with RV alone. Eighty-six of 114 RV-positive stool samples were successfully genotyped, and their combinations of genotypes were G1P[8] (36, 41.9%), G2P[4] (12, 14.0%), and G3P[8] (6, 7.0%). RV was detected in 27.8% of patients in the vaccinated group and 39.8% in the unvaccinated group (P=0.035). Vaccination history was available for 67 of 86 cases with successfully genotyped RV-positive stool samples; RotaTeq (20, 29.9%), Rotarix (7, 10.4%), unvaccinated (40, 59.7%). The incidence of RV AGE is lower in the RV-vaccinated group compared to the unvaccinated group with no evidence of substitution with unusual genotype combinations. PMID- 26425046 TI - Neonatal Morbidities Associated with Histologic Chorioamnionitis Defined Based on the Site and Extent of Inflammation in Very Low Birth Weight Infants. AB - Conflicting results on the influences of histologic chorioamnionitis (HC) on neonatal morbidities might be partly originated from using different definition of HC. The aim of this study was to determine the relationship between HC and neonatal morbidities using definition of HC that reflects the site and extent of inflammation. This was a retrospective cohort study of 261 very low birth weight (VLBW) infants admitted at a tertiary academic center. Based on the site of inflammation, HC was categorized: any HC; amnionitis; funisitis; amnionitis+funisitis. The extent of inflammation in each site was reflected by sub-defining high grade (HG). The incidences of morbidities in infants with and without HC were compared. The bronchopulmonary dysplasia (BPD) rate was significantly higher in infants with amnionitis and the severe retinopathy of prematurity (ROP) rate was significantly higher in infants with any HC and funisitis. After adjustment for both gestational age and birth weight, the respiratory distress syndrome (RDS) rate was significantly lower in infants with all categories of HC except for HG amnionitis and HG funisitis, which are not associated with lower RDS rate. HG amnionitis was significantly associated with increased BPD rate but the association of HC with severe ROP disappeared. In conclusion, HC is significantly associated with decreased RDS and HG amnionitis with increased BPD while lacking association with other neonatal morbidities in VLBW infants. The association with HC and neonatal morbidities differs by the site and extent of chorioamnionitis. PMID- 26425047 TI - Preoperative Underweight Patients with Upper Tract Urothelial Carcinoma Survive Less after Radical Nephroureterectomy. AB - The prognostic impact of body mass index (BMI) in patients with upper tract urothelial carcinoma (UTUC) is an ongoing debate. Our study aimed to investigate the prognostic role of BMI in patients treated with radical nephroureterectomy (RNU) for UTUC from a multi-institutional Korean collaboration. We retrospectively reviewed data from 440 patients who underwent RNU for UTUC at four institutions in Korea. To avoid biasing the survival estimates, patients who had previous or concomitant muscle-invasive bladder tumors were excluded. BMI was categorized into approximate quartiles with the lowest quartile assigned to the reference group. Kaplan-Meier and multivariate Cox regression analyses were performed to assess the influence of BMI on survival. The lower quartile BMI group showed significantly increased overall mortality (OM) and cancer specific mortality (CSM) compared to the 25%-50% quartiles and upper quartile BMI groups. Kaplan-Meier estimates showed similar results. Based on multivariate Cox regression analysis, preoperative BMI as a continuous variable was an independent predictor for OM and CSM. In conclusion, preoperative underweight patients with UTUC in Korea survive less after RNU. Preoperative BMI may provide additional prognostic information to establish risk factors. PMID- 26425048 TI - Clinical Characteristics of the Suicide Attempters Who Refused to Participate in a Suicide Prevention Case Management Program. AB - Case management interventions for suicide attempters aimed at helping adjust their social life to prevent reattempts have high nonparticipation and dropout rates. We analyzed the clinical characteristics of the group who refused to participate in the suicide prevention program in Korea. A total of 489 patients with a suicide attempt who visited Uijeongbu St. Mary's Hospital, the Catholic University of Korea, from December 2009 to December 2013 were analyzed. All patients were divided into the participation group (n = 262) and the refusal group (n = 227) according to their participation in the case management program. Demographic and clinical characteristics of each group were examined. Results showed that the refusal group had low risks for suicide in terms of risk factors related with psychopathologies and presenting suicide behavior. That is, the refusal group had less patients with co-morbid medical illnesses and more patients with mild severity of depression compared to the participation group. However, the refusal group had more interpersonal conflict, more isolation of social integrity, and more impaired insight about suicide attempt. The results suggest that nonparticipation in the case management program may depend upon the patient's impaired insight about the riskiness of suicide and lack of social support. PMID- 26425049 TI - Effects of Repetitive Transcranial Magnetic Stimulation on Behavioral Recovery during Early Stage of Traumatic Brain Injury in Rats. AB - Repetitive transcranial magnetic stimulation (rTMS) is a promising technique that modulates neural networks. However, there were few studies evaluating the effects of rTMS in traumatic brain injury (TBI). Herein, we assessed the effectiveness of rTMS on behavioral recovery and metabolic changes using brain magnetic resonance spectroscopy (MRS) in a rat model of TBI. We also evaluated the safety of rTMS by measuring brain swelling with brain magnetic resonance imaging (MRI). Twenty male Sprague-Dawley rats underwent lateral fluid percussion and were randomly assigned to the sham (n=10) or the rTMS (n=10) group. rTMS was applied on the fourth day after TBI and consisted of 10 daily sessions for 2 weeks with 10 Hz frequency (total pulses=3,000). Although the rTMS group showed an anti-apoptotic effect around the peri-lesional area, functional improvements were not significantly different between the two groups. Additionally, rTMS did not modulate brain metabolites in MRS, nor was there any change of brain lesion or edema after magnetic stimulation. These data suggest that rTMS did not have beneficial effects on motor recovery during early stages of TBI, although an anti-apoptosis was observed in the peri-lesional area. PMID- 26425050 TI - Effect of Propofol and Desflurane on Immune Cell Populations in Breast Cancer Patients: A Randomized Trial. AB - Several factors can affect the perioperative immune function. We evaluated the effect of propofol and desflurane anesthesia on the surgery-induced immune perturbation in patients undergoing breast cancer surgery. The patients were randomly assigned to receive propofol (n = 20) or desflurane (n = 20) anesthesia. The total and differential white blood cell counts were determined with lymphocyte subpopulations before and 1 hr after anesthesia induction and at 24 hr postoperatively. Plasma concentrations of interleukin (IL)-2 and IL-4 were also measured. Both propofol and desflurane anesthesia preserved the IL-2/IL-4 and CD4(+)/CD8(+) T cell ratio. Leukocytes were lower in the propofol group than in the desflurane group at 1 hr after induction (median [quartiles], 4.98 [3.87 6.31] vs. 5.84 [5.18-7.94] 10(3)/uL) and 24 hr postoperatively (6.92 [5.54-6.86] vs. 7.62 [6.22-9.21] 10(3)/uL). NK cells significantly decreased 1 hr after induction in the propofol group (0.41 [0.34-0.53] to 0.25 [0.21-0.33] 10(3)/uL), but not in the desflurane group (0.33 [0.29-0.48] to 0.38 [0.30-0.56] 10(3)/uL). Our findings indicate that both propofol and desflurane anesthesia for breast cancer surgery induce a favorable immune response in terms of preservation of IL 2/IL-4 and CD4(+)/CD8(+) T cell ratio in the perioperative period. With respect to leukocytes and NK cells, desflurane anesthesia is associated with less adverse immune responses than propofol anesthesia during surgery for breast cancer. (Clinical trial registration at https://cris.nih.go.kr/cris number: KCT0000939). PMID- 26425051 TI - Relationship between Serum Uric Acid Concentration and Acute Kidney Injury after Coronary Artery Bypass Surgery. AB - An elevated serum concentration of uric acid may be associated with an increased risk of acute kidney injury (AKI). The aim of this study was to investigate the impact of preoperative uric acid concentration on the risk of AKI after coronary artery bypass surgery (CABG). Perioperative data were evaluated from patients who underwent CABG. AKI was defined by the AKI Network criteria based on serum creatinine changes within the first 48 hr after CABG. Multivariate logistic regression was utilized to evaluate the association between preoperative uric acid and postoperative AKI. We evaluated changes in C statistic, the net reclassification improvement, and the integrated discrimination improvement to determine whether the addition of preoperative uric acid improved prediction of AKI. Of the 2,185 patients, 787 (36.0%) developed AKI. Preoperative uric acid was significantly associated with postoperative AKI (odds ratio, 1.18; 95% confidence interval, 1.10-1.26; P<0.001). Adding uric acid levels improved the C statistic and had significant impact on risk reclassification and integrated discrimination for AKI. Preoperative uric acid is related to postoperative AKI and improves the predictive ability of AKI. This finding suggests that preoperative measurement of uric acid may help stratify risks for AKI in in patients undergoing CABG. PMID- 26425052 TI - Common Pesticides Used in Suicide Attempts Following the 2012 Paraquat Ban in Korea. AB - To determine the change in pesticides used during suicide attempts after the 2012 paraquat (PQ) ban, we evaluated the annual number of suicide attempts by pesticide ingestion between 2011 and 2014. We extracted demographic, clinical outcome, and pesticide class data from the medical records of 1,331 patients that attempted suicide by pesticide ingestion. Pesticides were sorted into 5 groups: herbicides, insecticides, fungicides, other pesticides, and combined pesticides. Each group was subdivided into various classes based on publications by the respective Resistance Action Committees. The chi-square test for trends was used to compare the annual incidence of categorical variables. The total number of suicide attempts decreased each year, from 399 in 2011 to 245 in 2014. Simultaneously, PQ ingestion decreased from 253 patients in 2011 to 60 in 2014. The proportion of PQ to pesticides also decreased from 63.4% in 2011 to 24.5% in 2014. Furthermore, the rate of decrease in the proportion of PQ to all herbicide categories increased by calendar year. In conclusion, there is a significant trend in increased annual number of suicides and proportion of suicides using glyphosates and glufosinates versus total herbicides. However, the number of suicide attempts using glyphosate and glufosinate is lower than that using PQ. The ratio of persons completing suicide to those attempting suicide after pesticide ingestion has decreased every year after the PQ ban. PMID- 26425053 TI - Dosimetric Effects of Magnetic Resonance Imaging-assisted Radiotherapy Planning: Dose Optimization for Target Volumes at High Risk and Analytic Radiobiological Dose Evaluation. AB - Based on the assumption that apparent diffusion coefficients (ADCs) define high risk clinical target volume (aCTVHR) in high-grade glioma in a cellularity dependent manner, the dosimetric effects of aCTVHR-targeted dose optimization were evaluated in two intensity-modulated radiation therapy (IMRT) plans. Diffusion-weighted magnetic resonance (MR) images and ADC maps were analyzed qualitatively and quantitatively to determine aCTVHR in a high-grade glioma with high cellularity. After confirming tumor malignancy using the average and minimum ADCs and ADC ratios, the aCTVHR with double- or triple-restricted water diffusion was defined on computed tomography images through image registration. Doses to the aCTVHR and CTV defined on T1-weighted MR images were optimized using a simultaneous integrated boost technique. The dosimetric benefits for CTVs and organs at risk (OARs) were compared using dose volume histograms and various biophysical indices in an ADC map-based IMRT (IMRTADC) plan and a conventional IMRT (IMRTconv) plan. The IMRTADC plan improved dose conformity up to 15 times, compared to the IMRTconv plan. It reduced the equivalent uniform doses in the visual system and brain stem by more than 10% and 16%, respectively. The ADC based target differentiation and dose optimization may facilitate conformal dose distribution to the aCTVHR and OAR sparing in an IMRT plan. PMID- 26425054 TI - Therapeutic Plasmapheresis Enabling Radioactive Iodine Treatment in a Patient with Thyrotoxicosis. AB - Therapeutic plasma exchange (TPE) is one possible treatment for patients resistant to conventional antithyroid drugs or requiring urgent attention for thyrotoxicosis. We report a 35-yr-old man with thyrotoxicosis, ultimately attributed to Graves' disease in whom antithyroid drug used initially was soon discontinued, due to abnormal liver function, and replaced by Lugol's solution. Three weeks later, an escape phenomenon (to Lugol's solution) was apparent, so we performed TPE to control the thyrotoxicosis. Two courses of TPE by a centrifugal type machine resulted in diminished levels of thyroid hormone levels, which then rebounded after another two courses of membrane filtration type TPE. However, the patient could be treated with radioactive iodine therapy without any complications at present. PMID- 26425055 TI - Predatory Publishing Practices Corrode the Credibility of Science. PMID- 26425056 TI - Pain experience and expression in Rett syndrome: Subjective and objective measurement approaches. AB - Rett syndrome (RTT) is associated with myriad debilitating health issues and significant motor and communicative impairments. Because of the former there is concern about the possibility of recurrent and chronic pain but because of the latter it remains difficult to determine what pain 'looks like' in RTT. This study investigated pain experience and expression using multiple complementary subjective and objective approaches among a clinical RTT sample. Following informed consent, 18 participants (all female) with RTT (mean age= 12.8 years, SD= 6.32) were characterized in terms of pain experience and interference, typical pain expression, and elicited pain behavior during a passive range of motion-like examination procedure. Parents completed the Dalhousie Pain Interview (DPI; pain type, frequency, duration, intensity), the Brief Pain Inventory (BPI; pain interference), and the Non-Communicating Children's Pain Checklist - Revised (NCCPC-R; typical pain expression). A Pain Examination Procedure (PEP) was conducted and scored using the Pain and Discomfort Scale (PADS). The majority of the sample (89%) were reported to experience pain in the previous week which presented as gastrointestinal (n=8), musculoskeletal (n=5), and seizure related pain (n=5) that was intense (scored 0-10; M= 5.67, SD= 3.09) and long in duration (M= 25.22 hours, SD= 53.52). Numerous pain-expressive behaviors were inventoried (e.g., vocal, facial, mood/interaction changes) when parents reported their child's typical pain behaviors and based on independent direct observation during a reliably coded pain exam. This study provides subjective and objective evidence that individuals with RTT experience recurring and chronic pain for which pain expression appears intact. PMID- 26425057 TI - Socio-Cultural Context and Bulling Others in Childhood. AB - The objective of this epidemiological study was to examine, using an ecological perspective, which individual and distal contextual factors (familial, social and cultural) are associated with bullying other children across two different sites. Our sample included 1,271 Puerto Rican children 10 and older years of age at baseline residing in the South Bronx in New York and in the Standard Metropolitan Area in San Juan and Caguas, Puerto Rico. Bullying others was assessed through parents' and children's response to one item in the conduct disorder section of the Diagnostic Interview Schedule for Children Version IV (DISC IV). Child, family, social and cultural factors were examined as independent variables with bullying others as dependent variable in hierarchical models adjusting for gender, maternal education, poverty, single parent household and site. Prevalence of bullying others was 15.2% in South Bronx versus 4.6% in Puerto Rico (p<0.0001). Poor social adjustment and academic achievement, parental harsh discipline, negative school environment, exposure to violence, peer delinquency and level of acculturation in the child were all risk factors for bullying others. Child acculturation accounted for site differences in rates of bullying others. We conclude that, besides the school context, specific aspects of the community, family, and culture influence the development of bullying perpetration and should be targets for interventions and prevention programs. Minority youth living in at-risk contexts may benefit from contextually sensitive preventive interventions that address how assimilation into a high-risk context may increase involvement in bullying perpetration. PMID- 26425058 TI - Regional Myocutaneous Flaps for Head and Neck Reconstruction: Experience of a Head and Neck Cancer Unit. AB - BACKGROUND: Pectoralis major myocutaneous pedicle flap and other regional myocutaneous pedicle flaps (RMF), despite the superiority shown by free flaps, have remained relevant in the reconstruction of major head and neck oncologic defects. It has continued to find relevance as the preferred reconstruction of choice in some general head and neck reconstructive applications. While its role has been defined in developed environment, the same cannot be said for developing environment. The aim thus, was to review our experiences with RMFs in head and neck reconstructions, with a view to evaluating the indications and outcomes in a limited opportunity environment with some free flaps expertise. MATERIALS AND METHODS: This was a retrospective cohort study from records of RMF cases performed for head and neck reconstruction, at the study institution. Eligibility for study inclusion comprised case cohorts with advanced head and neck diseases requiring ablative surgery and reconstruction with pectoralis major flaps and other RMFs. RESULTS: A total of 17 cases were treated with RMFs. 10 were pectoralis major flaps while 7 were other RMFs. The main indications were failed free flaps and financial constraints. No regional pedicle flap failure was recorded; however, complication rate was 35.5% (6/17). CONCLUSION: Pectoralis major flaps and other RMFs were very reliable option for head and neck reconstruction. Free flap failure and financial constraints were the main indications for RMF reconstruction indications in head and neck reconstruction in a developing environment with some free flap expertise. PMID- 26425059 TI - Management of Chest Drains: A National Survey on Surgeons-in-training Experience and Practice. AB - BACKGROUND: Chest tube insertion is a simple and sometimes life-saving procedure performed mainly by surgical residents. However with inadequate knowledge and poor expertise, complications may be life threatening. OBJECTIVE: We aimed to determine the level of experience and expertise of resident surgeons in performing tube thoracostomy. METHODOLOGY: Four tertiary institutions were selected by simple random sampling. A structured questionnaire was administered to 90 residents after obtaining consent. RESULTS: The majority of respondents were between 31 and 35 years. About 10% of respondents have not observed or performed tube thoracostomy while 77.8% of respondents performed tube thoracostomy for the first time during residency training. The mean score was 6.2 +/- 2.2 and 59.3% of respondents exhibited good experience and practice. Rotation through cardiothoracic surgery had an effect on the score (P = 0.034). About 80.2% always obtained consent while 50.6% always used the blunt technique of insertion. About 61.7% of respondents routinely inserted a chest drain in the Triangle of safety. Only 27.2% of respondents utilized different sizes of chest tubes for different pathologies. Most respondents removed chest drains when the output is <50 mL. Twenty-six respondents (32.1%) always monitored air leak before removal of tubes in cases of pneumothorax. Superficial surgical site infection, tube dislodgement, and tube blockage were the most common complications. CONCLUSION: Many of the surgical resident lack adequate expertise in this lifesaving procedure and they lose the opportunity to learn it as interns. There is a need to stress the need to acquire this skill early, to further educate and evaluate them to avoid complications. PMID- 26425060 TI - Ethnicity and Prostate Cancer in Southern Nigeria: A Preliminary Report. AB - INTRODUCTION: The natural history of prostate cancer varies among patients. The aim of this study is to detect any variations in clinical and pathological characteristics of the tumor in patients from different ethnic groups in Southern Nigeria. PATIENTS AND METHODS: Consecutive patients who presented with features of prostatic diseases at the Urology Units of University of Port Harcourt Teaching Hospital, Port Harcourt and Nnamdi Azikiwe University Teaching Hospital, Nnewi, were evaluated prospectively with history, physical examination, and relevant investigations using a proforma. Data obtained were collated and analyzed statistically using the Chi-square test and Microsoft Excel. RESULTS: Of 187 patients studied, 169 were analyzed. Eighty-six were Ibos, 31 Ijaws, 25 Ikwerres, and 12 Ogonis. Two were from each Etche, Urhobo, Opobo, and Effik; 4 from Andoni, and 3 Ibibio. Fifty-seven (66.3%) Ibos presented with the disease at higher ages (70-80 years) than 19 (61.3%) Ijaws and 11 (91.7%) Ogonis. These age differences were statistically significant with 95% and 99.9% confidence, respectively. All cases were adenocarcinomas. Clinical features, pattern of serum prostate-specific antigen levels, grades of the tumors, tumor metastases, and complications were similar for all ethnic groups. Although more Ibos had tumors with relatively more aggressive metastatic features, there was no statistical significance. CONCLUSION: Clinical and pathological features of adenocarcinoma of the prostate in Ibos, Ikwerres, Ijaws, and Ogonis were found to be similar. However, Ibos presented with the disease at older ages than Ijaws and Ogonis. PMID- 26425061 TI - Preoperative Ultrasonography as a Predictor of Difficult Laparoscopic Cholecystectomy that Requires Conversion to Open Procedure. AB - AIM: The present study was conducted to see whether preoperative ultrasonography can be used as a predictor of difficult lapariscopic cholecystectomy or not. METHODS: 50 patients of cholelithiasis, selected from surgical OPD of Rajindra Hospital Patiala, who fulfilled all inclusion and exclusion criteria for the study underwent elective cholecystectomy. Ultrasonography was done pre operatively on all cases in the same setup and with same probe and patients underwent laparoscopic cholecystectomy in same setup. RESULTS: A significant prediction was found between ultrasonographic parameters and conversion of the procedure to open cholecystectomy which proved that pre-operative ultrasonography is a good predictor of difficulty in laparoscopic cholecystectomy in majority of the cases and should be used as a screening procedure. CONCLUSION: Preoperative ultrasonography should be used as a screening procedure as it is a good predictor of difficulty in laparoscopic cholecystectomy in majority of the cases. It can help surgeon to get an idea of potential difficulty that he can face in the particular patient. PMID- 26425062 TI - Endoscopic Evaluation of Upper and Lower Gastro-Intestinal Bleeding. AB - INTRODUCTION: A myriad of pathologies lead to gastro-intestinal bleeding (GIB). The common clinical presentations are hematemesis, melena, and hematochezia. Endoscopy aids localization and treatment of these lesions. AIMS: The aim was to study the differential diagnosis of GIB emphasizing the role of endoscopy in diagnosis and treatment of GIB. PATIENTS AND METHODS: A prospective study of patients with GIB referred to the Endoscopy unit of two health facilities in Port Harcourt Nigeria from February 2012 to August 2014. The variables studied included: Demographics, clinical presentation, risk score, endoscopic findings, therapeutic procedure, and outcome. Data were collated and analyzed using SPSS version 20 software. RESULTS: A total of 159 upper and lower gastro-intestinal (GI) endoscopies were performed during the study period with 59 cases of GI bleeding. There were 50 males and 9 females with an age range of 13-86 years (mean age 52.4 +/- 20.6 years). The primary presentations were hematochezia, hematemesis, and melena in 44 (75%), 9 (15%), and 6 (10%) cases, respectively. Hemorrhoids were the leading cause of lower GIB seen in 15 cases (41%). The majority of pathologies in upper GIB were seen in the stomach (39%): Gastritis and benign gastric ulcer. Injection sclerotherapy was successfully performed in the hemorrhoids and a case of gastric varices. The mortality recorded was 0%. CONCLUSION: Endoscopy is vital in the diagnosis and treatment of GIB. Gastritis and Haemorrhoid are the most common causes of upper and lower GI bleeding respectively, in our environment. PMID- 26425063 TI - The Utility of Digital Rectal Examination in Estimating Prostate Volume in a Rural Hospital Setting. AB - OBJECTIVES: To determine the correlation between prostate volume estimated by digital rectal examination (DRE) and that estimated by abdominal ultrasound in the same patients. PATIENTS AND METHODS: Men who presented to our urology outpatient clinic with lower urinary tract symptoms were recruited in this study. We estimated the prostate size by digital rectal examination using the sliding scale as a guide and subsequently measured the prostate volume by transabdominal ultrasound. RESULTS: A total of 100 patients completed this study. The mean age was 65.6 +/- 9.84 years. The Kappa's reliability test comparing the prostate size estimated by DRE and the prostate size measured by transabdominal ultrasound was 0.579832, the Kappa's standard error was 0.097768 and Kappa's t value was 5.93. The Kappa's reliability test fell into good agreement range (0.4-0.75). This is further validated by the Pearson's correlation test ascertaining correlation between Ultrasound and DRE and generated a correlation coefficient((r)) of 0.59 (P = 0.00). This implies a high positive correlation between ultrasound estimated prostate volume and that estimated by DRE that is statistically significant (P < 0.01). CONCLUSION: Estimation of prostate volume by digital rectal examination is reliable. This is very important in an environment where esoteric laboratory facilities are not readily available, and the clinician has to depend mainly on his clinical acumen. PMID- 26425064 TI - A Survey of the Awareness of Prostate Cancer and its Screening among Men Attending the Outpatient Clinics of a Tertiary Health Center in Lagos, Nigeria. AB - BACKGROUND: Prostate cancer is the most common cancer among Nigerian men and the second most common cause of death from cancer in men worldwide. The aim of this study was to assess the level of awareness of prostate cancer among men attending the various outpatients' clinics of the Lagos State University Teaching Hospital, Ikeja. MATERIALS AND METHODS: This study is a descriptive cross-sectional study. Self-administered structured questionnaires were used to collect information from consecutives patients attending the various outpatient clinics of the hospital. RESULTS: One hundred and forty-six respondents with an age range of 40-80 years participated in this study. Sixty-nine (47.3%) respondents were aware of prostate cancer while 77 (52.7%) have never heard of the disease. Twenty (13.7%) participants were aware of the availability of a screening test for the disease and only 12 (8.2%) have had any form of screening for prostate cancer. CONCLUSION: There is a low level of awareness of prostate cancer among patients seen at our center and also level of voluntary screening for the disease is low. PMID- 26425065 TI - Does Improvised Waterbed Reduce the Incidence of Pressure Ulcers in Patients with Spinal Injury? AB - BACKGROUND: Pressure ulcers are lesions caused by unrelieved pressure over bony prominences, resulting in damage to underlying tissues. The etiology is multifactorial including prolonged immobility. They usually complicate spinal cord injuries with long periods of bed confinement. The use of bed replacements markedly reduces the incidence of pressure ulcers, but the unaffordability of these replacements in low-income countries has necessitated the need to explore cheaper alternatives. AIM AND OBJECTIVE: The aim of this study was to ascertain whether the use of our cheap and locally improvised waterbeds would reduce the incidence of pressure ulcers in patients on prolonged bed confinement due to spinal injury. METHODOLOGY: Over a 16-month period, 51 patients (age range 1-80 years) with spinal injuries were managed conservatively in our service using improvised waterbeds in 21 (41.2%), while using the regular hospital bed/foam in 30 (58.8%). Biodata, the time interval between injury and presentation to the hospital, nature of the injury, use of improvised waterbed and development of pressure ulcer, were collected, collated, and analyzed. Statistical significance was calculated with the Chi-square test. RESULTS: Most were males (98%), in the age range of 21-30 years (25.5%), and due to fall from heights (35.3%). Of 21 patients who were managed on improvised waterbeds, 6 (28.6%) had pressure ulcers, and of the 30 who did not use the waterbed, 17 (56.7%) developed ulcers. The chi(2) = 3.9381, while P = 0.0472. This difference was statistically significant. CONCLUSION: The improvised waterbed, which is much cheaper than the standard waterbed, was observed to have significantly reduced the incidence of pressure ulcers among our patients. Nonetheless, further studies would still be needed to confirm this observation. PMID- 26425066 TI - One-stage Anastomotic Urethroplasty for Traumatic Urethral Strictures. January 2004-January 2013. AB - PURPOSE: One-stage anastomotic urethroplasty is an attractive procedure for reconstructing the urethra following trauma. This prospective study highlights the advantages of the procedure and outcome of treatment. MATERIALS AND METHODS: A total of 87 patients, age range 11-68 years with a mean of 35.4 years were included in the study. These patients were seen at two tertiary Institutions in South East Nigeria. The stricture lengths varied between 0.8 cm and 3.2 cm. All had suprapubic cystostomy initially followed by an end to end perineal anastomosis after thorough work up. Preoperatively 9 (10.3%) patients had impotence from the trauma. Postoperatively the patients were assessed with peri catheter retrograde urethrogram, micturating cystourethrogram, and uroflowmetery. RESULTS: All the patients were males. At 6 months, 13 out of 21 (62%) patients who had bulbo-prostatic anastomosis and 62 out of 66 (94%) patients that had bulbo-membranous, bulbo-bulbar anastomosis had satisfactory micturition with urine flow rate >15 ml/s. Totally, 12 (13.8%) patients had urine flow rate of <12 ml/s. At 1-year, there were 12 re-strictures, no urinary incontinence and four cases of a decrease in the strength of penile erection that needed no treatment. CONCLUSION: Delayed one-stage anastomotic urethroplasty provides for decreased incidence of postoperative morbidity, re-stricture, impotence and urinary incontinence for most short segment posttraumatic urethral strictures. PMID- 26425067 TI - Preoperative Prediction of Difficult Laparoscopic Cholecystectomy: A Scoring Method. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) has become the procedure of choice for management of symptomatic gallstone disease. At times, it is difficult and takes longer time or has to be converted to an open procedure. This study is undertaken to determine the predictive factors for difficult LC. AIM: The aim was to evaluate a scoring method to predict difficult LC preoperatively. MATERIALS AND METHODS: There were 30 cases operated by a single experienced surgeon. There are total 15 score from history, clinical and sonological findings. Score up to 5 predicted easy, 6-10 difficult and >10 are very difficult. RESULTS: Prediction came true in 76.4% for easy and 100% difficult cases; there were no cases with a score above 10. The factors like previous history of hospitalization (P - 0.004), clinically palpable gallbladder (GB) (P - 0.009), impacted GB stone (P - 0.001), pericholecystic collection (P - 0.04), and abdominal scar due to previous abdominal surgery (P - 0.009) were found statistically significant in predicting difficult LC. CONCLUSION: The proposed scoring system is reliable with a sensitivity of 76.47% and specificity of 100%. PMID- 26425068 TI - Clinical Parameters and Challenges of Managing Cervicofacial Necrotizing Fasciitis in a Sub-Saharan Tertiary Hospital. AB - INTRODUCTION: Necrotizing fasciitis is a severe soft tissue infection. In our environment, patients presenting with this infection are usually financially incapacitated and, therefore, their management can be challenging. This paper aimed to document the pattern and challenges encountered in the management of cervicofacial necrotizing fasciitis (CNF) in the University College Hospital, Ibadan. MATERIALS AND METHODS: Information such as biodata, site of infection, systemic conditions, widest span of defect, management provided, hospital stay, and outcome of management was prospectively collected on all patients with CNF who presented at the Department of Oral and Maxillofacial Surgery between January 2007 and December 2013. The patients were managed according to a devised protocol of antibiotic therapy, serial debridement and honey dressings. RESULTS: Twenty four cases of CNF were seen. There were 9 males and 15 females while 70.9% of the patients belonged to the low socioeconomic class. The mean span of wound defect was 12.2 (+/-8.844) cm. The mean hospital stay was 27.8 (+/-23.1) days, and scar formation was the most common complication encountered. CONCLUSION: Our study represents the largest series of CNF from a Nigerian health facility presently. The management of necrotizing fascitis in the maxillofacial region poses a significant challenge to both the surgeon and the patient. However, the mortality rate of CNF in our center appears comparatively low. PMID- 26425069 TI - Early Experience with Stapled Gastrointestinal Anastomoses in a Nigerian Hospital. AB - BACKGROUND: Hand-sewn gastrointestinal anastomoses has been the traditional approach to gastrointestinal anastomosis in Nigeria while stapled anastomoses are infrequently performed in few centers. OBJECTIVES: To describe the outcome of our initial experience with stapled gastrointestinal anastomoses in a semi-urban patient population. PATIENTS AND METHODS: Consecutive patients who had stapled gastrointestinal anastomoses between January 2011 and June 2014 in a Nigerian tertiary hospital were prospectively evaluated. Indications for operation, procedures performed and anastomoses constructed and postoperative outcome of each patient were documented. RESULTS: Nineteen patients including seven males and 12 females had stapled anastomoses within the period. Their ages ranged between 41 and 68 (mean 52.5) years. Six (31.6%) Roux-en-Y gastrojejunostomies, 6 (31.6%) ileo-colic, 3 (15.8%) ileo-ileal, 2 (10.5%) colo-colic, and 2 (10.5%) colo-anal anastomoses were performed. Indications include antral gastric cancer in 4 (21.1%), right colon cancer 4 (21.1%), ileal perforations in 3 (15.8%) while 2 (10.5%) each had left colon cancer, common bile duct obstruction, rectal cancer and ruptured appendix. Mean duration of operation was 108 +/- 46 min and mean duration of postoperative stay was 5 +/- 2.6 days. No intraoperative complications were recorded and no anastomotic leakage occurred. At a median follow-up of 5 months no staple related stricture had occurred. CONCLUSIONS: Stapled gastrointestinal anastomoses are associated with a good outcome in our center. We propose a prospective, large-population randomized comparison of the technique with hand-sewn anastomoses. PMID- 26425070 TI - Long-Term Outcome of Endoprosthetic Replacement for Proximal Femur Giant Cell Tumor. AB - INTRODUCTION: Giant cell tumor (GCT) of bone is locally aggressive benign tumor involving the epiphysis of long bones in young adults. Various treatment options include intralesional curettage, extended curettage, wide resection, resection and reconstruction and amputation. The main variables to be considered for planning treatment include the site of involvement and Campanacci stage of the tumor. Functional and oncological outcomes of these treatment options vary widely, the predominant detrimental factor being tumor recurrence rate. AIM: A study was conducted to evaluate the long-term oncological and functional outcome of patients with GCT of the proximal femur that underwent tumor resection and endoprosthetic replacement. MATERIALS AND METHODS: Eleven patients with Campanacci stage-III GCT of proximal femur who underwent wide excision of tumor and endoprosthesis replacement with a mean follow-up the duration of 10.6 years were assessed using standard proforma. The treatment outcome was evaluated using the Revised Musculoskeletal Tumor Society Rating Scale for the lower extremity. RESULTS: At mean follow-up the duration of 10.6 years, none of the cases had tumor recurrence, infection, prosthesis loosening or dislocation. All the patients were community ambulators among whom eight patients were walking without support while three patients were using a cane for support. The mean total Musculoskeletal Tumor Society Score was 26.8 out of 30 indicating the good outcome. CONCLUSIONS: The authors recommend that wide resection and endoprosthetic replacement should be considered as a preferred treatment option for proximal femur GCT as the functional, and oncological outcome is satisfactory with this modality of treatment. PMID- 26425071 TI - Urethroplasty Practices among Reconstructive Urologists in Nigeria. AB - OBJECTIVES: To determine the national practice patterns in the management of male urethral stricture disease by the open urethroplasty technique. MATERIALS AND METHODS: A questionnaire-based national survey of Nigerian urologists was performed during the 19(th) Annual General Meeting and Scientific Conference of the National Association of Urological Surgeons of Nigeria, held at Ibadan, Southwest Nigeria in 2013. RESULTS: A total of 55 respondents (67.1%) completed the questionnaire. About 43.6% were between the ages of 40 and 49 years. Almost 41.8% had between 5 and 9 years of experience as a reconstructive urologist, and 50.9% performed 1-9 urethroplasties/year. A total of 80 responders reported trauma as the most common etiology for their strictures. About 63.7% preferred to treat strictures after 3-6 months of diagnosis and 67.3% of respondents preferred the combination of retrograde urethrography and voiding cystourethrography for the diagnosis of urethral stricture. Stenting of the urethra was done after urethroplasty using size 16 Fr of 18 Fr silastic catheter; however, the duration of stenting varied among urologists. About 41.8% followed up their patients for a year, and uroflowmetry was used by 36.6% of the responders to follow-up their patients. Stricture recurrence was the most common reported complication by 36.4% of the respondents. CONCLUSIONS: In Nigeria, most urethral stricture diseases are treated by open urethroplasties. Very few of these surgeries are performed annually by young urologists. There is no uniformity in the method of diagnosis, stenting, and follow-up after treatment. PMID- 26425072 TI - Posterior Urethral Valves in Children: Pattern of Presentation and Outcome of Initial Treatment in Ile-Ife, Nigeria. AB - BACKGROUND: The management of posterior urethral valves (PUV) and its sequelae is still a challenge to most pediatric surgeons in our environment due to late presentation and inadequate facilities for long-term evaluation and treatment. Despite initial successful treatment about 40% would develop chronic renal failure. The aim is to describe the presentation, management and outcome of the initial treatment in boys with PUV. MATERIALS AND METHODS: It is a retrospective analysis of PUV in boys 8 years and below over a 17 years period. Demographic characteristics, clinical features, investigations, and treatment outcome were reviewed. RESULTS: Thirty-seven cases were analyzed. The median age was 5 months (range from birth to 8 years). Three (8.1%) patients had prenatal ultrasound diagnosis. The most common presentation was voiding dysfunction 37 (100%). Part of the preoperative investigation included micturating cystourethrogram (n = 31: 83.8%) and abdomino-pelvic ultrasonography (n = 37:(100%). The mean serum creatinine value of those who presented within the first 30 days of life and those who presented afterwards were 325 (+/-251) umol/L and 141 (+/-100) umol/L respectively, P = 0.003. Surgical interventions included trans-vesical excision of valves (n = 9: 28.1%), valvotomy (n = 10: 31.3%), balloon avulsion (n = 8: 25.0%), vesicostomy (n = 4: 12.5%) and endoscopic valve avulsion (n = 1: 3.1%). Seventeen (56.7%) patients had serum creatinine >70.4 umol/L after 1-month of valve excision. Five (13.5%) patients had postrelief complications and 5 (13.5%) died on admission. Ninety percentage (27/30) of patients had poor prognostic indices. CONCLUSIONS: The initial treatment outcome was good but most had poor prognostic factors. PMID- 26425073 TI - Carotid Body Tumor Presenting as Parotid Swelling Misdiagnosed as Pleomorphic Adenoma: A Rare Presentation. AB - Carotid body tumor (CBT) also known as chemodectoma is a rare tumor of neuroendocrine tissue of carotid body and is the most commonly seen jugular paraganglioma. In most cases, it is benign but it can be malignant. Extra adrenal paraganglioma is rare. We present such a rare case where unusual presentation of chemodectoma was seen as a parotid swelling. This swelling was misdiagnosed as a pleomorphic adenoma on clinical examination, ultrasonography, and fine-needle aspiration cytology and superficial parotidectomy was done for the same, but on histopathological examination it was found to be CBT presenting as a parotid swelling. PMID- 26425074 TI - Surgical repair of orbital fat prolapse by conjunctival fixation to the sclera. AB - PURPOSE: The aim of the study described here was to report the outcomes of surgery for orbital fat prolapse by conjunctival fixation to the sclera. PATIENTS AND METHODS: Twenty-three consecutive eyes of 19 patients with orbital fat prolapse were retrospectively reviewed. All cases were treated with the same simple procedure without resection through conjunctival incision: fixation of conjunctiva to the sclera with interrupted sutures of 10-0 nylon in two rows located approximately 12-14 mm posterior to the limbus. These sutures formed an embankment to keep the prolapsed fat posteriorly. Postoperative results were determined by slit-lamp examination and recurrence of prolapse was defined as the presence of orbital fat anterior to the embankment. RESULTS: During the mean follow-up period of 19 months (range: 1-59 months), one case experienced recurrence which required further surgery. None of the other cases experienced recurrence, and there were no intraoperative or postoperative complications. CONCLUSION: Conjunctival fixation to the sclera was a simple and effective surgical technique for orbital fat prolapse, with less invasion compared to the conventional method that requires conjunctival incision. PMID- 26425075 TI - Clinical utility and patient considerations in the use of ofatumumab in chronic lymphocytic leukemia. AB - Treatment aim for chronic lymphocytic leukemia has been radically changed over the past years from providing only a palliative approach to reaching disease eradication and improving survival. Ofatumumab is a monoclonal humanized antibody with peculiar in vitro and in vivo properties, at present approved for double fludarabine and alemtuzumab refractory chronic lymphocytic leukemia. Its efficacy in this subset of patients, who typically have an unfavorable prognosis, facilitated its use in different Phase II and III trials. Ofatumumab as single agent or combined with chemotherapeutic or biologic agents, led to sundry results in the setting of both previously treated or untreated patients. Its role in maintenance therapy is also under investigation. Further advances concerning ofatumumab administration as first line therapy in combination with chlorambucil, came recently from the COMPLEMENT 1 study. Results from this trial will open the door to new perspectives of its use in treatment-naive patients. Ofatumumab was well tolerated in almost all the studies, with the main adverse events relating mostly to infusion reaction. Hematologic toxicity, especially neutropenia, was also common. A significant improvement in patients' quality of life was reported following ofatumumab treatment and this was mainly due to its effect on constitutional symptoms. Nevertheless, some concerns remain regarding the long term efficacy of the drug in terms of response duration and survival. The real strength of this drug needs to be confirmed by further studies and direct comparative trials. PMID- 26425076 TI - Improvement of oral bioavailability of lovastatin by using nanostructured lipid carriers. AB - Nanostructured lipid carriers (NLCs) have been one of the systems of choice for improving the oral bioavailability of drugs with poor water solubility. In the present study, lovastatin (LVT)-loaded NLCs (LVT-NLCs) were successfully prepared by hot high-pressure homogenization method with high entrapment efficiency, drug loading, and satisfactory particle size distribution. The particles had almost spherical and uniform shapes and were well dispersed with a particle size of <50 nm (23.5 +/- 1.6 nm) and a low polydispersity index (0.17 +/- 0.05 mV). The result of stability showed that the LVT-NLCs dispersion maintained excellent stability without exhibiting any aggregation, precipitation, or phase separation at 4 degrees C for 6 months of storage. The LVT release data from all developed solid lipid nanoparticles (SLNs) and NLCs were best fitted to a Ritger-Peppas kinetic model (0.9832 and 0.9783 for NLCs and SLNs, respectively). This indicated that the release of LVT from the SLNs and NLCs was due to a combination of drug diffusion and erosion from the lipid matrix. The pharmacokinetic and pharmacodynamic results show that LVT-NLCs were better compared to free drug, which could be attributed to an increase in bioavailability. PMID- 26425077 TI - Clinicopathological significance and potential drug target of CDH1 in breast cancer: a meta-analysis and literature review. AB - CDH1, as a tumor suppressor gene, contributes sporadic breast cancer (BC) progression. However, the association between CDH1 hypermethylation and BC, and its clinicopathological significance remains unclear. We conducted a meta analysis to investigate the relationship between the CDH1 methylation profile and the major clinicopathological features. A detailed literature was searched through the electronic databases PubMed, Web of ScienceTM, and EMBASETM for related research publications. The data were extracted and assessed by two reviewers independently. Odds ratios (ORs) with corresponding confidence intervals (CIs) were calculated and summarized respectively. The frequency of CDH1 methylation was significantly higher in invasive ductal carcinoma than in normal breast tissues (OR =5.83, 95% CI 3.76-9.03, P<0.00001). CDH1 hypermethylation was significantly higher in estrogen receptor (ER)-negative BC than in ER-positive BC (OR =0.62, 95% CI 0.43-0.87, P=0.007). In addition, we found that the CDH1 was significantly methylated in HER2-negative BC than in HER2 positive BC (OR =0.26, 95% CI 0.15-0.44, P<0.00001). However, CDH1 methylation frequency was not associated with progesterone receptor (PR) status, or with grades, stages, or lymph node metastasis of BC patients. Our results indicate that CDH1 hypermethylation is a potential novel drug target for developing personalized therapy. CDH1 hypermethylation is strongly associated with ER negative and HER2-negative BC, respectively, suggesting CDH1 methylation status could contribute to the development of novel therapeutic approaches for the treatment of ER-negative or HER2-negative BC with aggressive tumor biology. PMID- 26425078 TI - Effects of exercise intensity on postexercise hypotension after resistance training session in overweight hypertensive patients. AB - Among all nonpharmacological treatments, aerobic or resistance training (RT) has been indicated as a significantly important strategy to control hypertension. However, postexercise hypotension responses after intensity alterations in RT are not yet fully understood. The purpose of this study was to compare the outcomes of differing intensities of RT on hypertensive older women. Twenty hypertensive older women participated voluntarily in this study. After a maximum voluntary contraction test (one repetition maximum) and determination of 40% and 80% experimental loads, the protocol (3 sets/90" interset rest) was performed in a single session with the following exercises: leg press, leg extension, leg curl, chest press, elbow flexion, elbow extension, upper back row, and abdominal flexion. Systolic and diastolic blood pressures were evaluated at rest, during exercise peak, and after 5, 10, 15, 30, 45, and 60 minutes of exercise and compared to the control. Both experimental loads were effective (P<0.01) in promoting postexercise systolic hypotension (mmHg) compared to controls, after 30, 45, and 60 minutes, respectively, at 40% (113+/-2, 112+/-4, and 110+/-3 mmHg) and 80% (111+/-3, 111+/-4, and 110+/-4 mmHg). Both procedures promoted hypotension with similar systolic blood pressures (40%: -11%+/-1.0% and 80%: 13%+/-0.5%), mean arterial blood pressures (40%: -12%+/-5.5% and 80%: -12%+/ 3.4%), and rate-pressure products (40%: -15%+/-2.1% and 80%: -17%+/-2.4%) compared to control measures (systolic blood pressure: 1%+/-1%, mean arterial blood pressure:? 0.6%+/-1.5%, rate-pressure product: 0.33%+/-1.1%). No differences were found in diastolic blood pressure and heart rate measures. In conclusion, hypertensive older women exhibit postexercise hypotension independently of exercise intensity without expressed cardiovascular overload during the session. PMID- 26425079 TI - History of falls, gait, balance, and fall risks in older cancer survivors living in the community. AB - Older cancer survivors may be predisposed to falls because cancer-related sequelae affect virtually all body systems. The use of a history of falls, gait speed, and balance tests to assess fall risks remains to be investigated in this population. This study examined the relationship of previous falls, gait, and balance with falls in community-dwelling older cancer survivors. At the baseline, demographics, health information, and the history of falls in the past year were obtained through interviewing. Participants performed tests including gait speed, Balance Evaluation Systems Test, and short-version of Activities-specific Balance Confidence scale. Falls were tracked by mailing of monthly reports for 6 months. A "faller" was a person with >=1 fall during follow-up. Univariate analyses, including independent sample t-tests and Fisher's exact tests, compared baseline demographics, gait speed, and balance between fallers and non-fallers. For univariate analyses, Bonferroni correction was applied for multiple comparisons. Baseline variables with P<0.15 were included in a forward logistic regression model to identify factors predictive of falls with age as covariate. Sensitivity and specificity of each predictor of falls in the model were calculated. Significance level for the regression analysis was P<0.05. During follow-up, 59% of participants had one or more falls. Baseline demographics, health information, history of falls, gaits speed, and balance tests did not differ significantly between fallers and non-fallers. Forward logistic regression revealed that a history of falls was a significant predictor of falls in the final model (odds ratio =6.81; 95% confidence interval =1.594-29.074) (P<0.05). Sensitivity and specificity for correctly identifying a faller using the positive history of falls were 74% and 69%, respectively. Current findings suggested that for community-dwelling older cancer survivors with mixed diagnoses, asking about the history of falls may help detect individuals at risk of falling. PMID- 26425081 TI - Targeting delivery of Radix Ophiopogonis polysaccharide to ischemic/reperfused rat myocardium by long-circulating macromolecular and liposomal carriers. AB - Drug delivery to ischemic myocardium is an enormous challenge. This work aimed to characterize cardiac delivery behaviors of mono-polyethylene glycosylated (PEGylated) conjugates and long-circulating liposomes (L-Lps) with Radix Ophiopogonis polysaccharide (ROP) as drug. The results showed that compared to native ROP, 32-, 52-, and 45-fold increases in blood half-life were achieved by 20-kDa PEG mono-modified ROP (P(20k)-R), 40-kDa PEG mono-modified ROP (P(40k)-R), and ROP-loaded L-Lp, respectively. With comparable blood pharmacokinetics, ROP loaded L-Lp showed both significantly higher targeting efficacy and drug exposure in infarcted myocardium than P(40k)-R. With regard to P(20k)-R, both its targeting efficacy and its level in infarcted myocardium at 3 hours postdose were comparable to P(40k)-R, but its level in blood and myocardium reduced obviously faster. As a whole, the results indicate that both loading in L-Lps and mono PEGylation are effective in targeting drug to ischemic myocardium, but the former appears to induce stronger effects. PMID- 26425080 TI - Delivery of DNAzyme targeting aurora kinase A to inhibit the proliferation and migration of human prostate cancer. AB - Herein, a polyethylenimine derivative N-acetyl-L-leucine-polyethylenimine (N-Ac-L Leu-PEI) was employed as a carrier to achieve the delivery of DNAzyme targeting aurora kinase A using PC-3 cell as a model. Flow cytometry and confocal laser scanning microscopy demonstrated that the derivative could realize the cellular uptake of nanoparticles in an energy-dependent and clathrin-mediated pathway and obtain a high DNAzyme concentration in the cytoplasm through further endosomal escape. After DNAzyme transfection, expression level of aurora kinase A would be downregulated at the protein level. Meanwhile, the inhibition of cell proliferation was observed through 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide and cell colony formation assay, attributing to the activation of apoptosis and cell cycle arrest. Through flow cytometric analysis, an early apoptotic ratio of 25.93% and G2 phase of 22.58% has been detected after N-Ac-L-Leu-PEI-mediated DNAzyme transfection. Finally, wound healing and Transwell migration assay showed that DNAzyme transfection could efficiently inhibit the cell migration. These results demonstrated that N-Ac-L-Leu-PEI could successfully mediate the DNAzyme delivery and downregulate the expression level of aurora kinase A, triggering a significant inhibitory effect of excessive proliferation and migration of tumor cells. PMID- 26425082 TI - Cytotoxicity and physicochemical characterization of iron-manganese-doped sulfated zirconia nanoparticles. AB - Iron-manganese-doped sulfated zirconia nanoparticles with both Lewis and Bronsted acidic sites were prepared by a hydrothermal impregnation method followed by calcination at 650 degrees C for 5 hours, and their cytotoxicity properties against cancer cell lines were determined. The characterization was carried out using X-ray diffraction, thermogravimetric analysis, Fourier transform infrared spectroscopy, Brauner-Emmett-Teller (BET) surface area measurements, X-ray fluorescence, X-ray photoelectron spectroscopy, zeta size potential, and transmission electron microscopy (TEM). The cytotoxicity of iron-manganese-doped sulfated zirconia nanoparticles was determined using 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assays against three human cancer cell lines (breast cancer MDA-MB231 cells, colon carcinoma HT29 cells, and hepatocellular carcinoma HepG2 cells) and two normal human cell lines (normal hepatocyte Chang cells and normal human umbilical vein endothelial cells [HUVECs]). The results suggest for the first time that iron-manganese-doped sulfated zirconia nanoparticles are cytotoxic to MDA-MB231 and HepG2 cancer cells but have less toxicity to HT29 and normal cells at concentrations from 7.8 MUg/mL to 500 MUg/mL. The morphology of the treated cells was also studied, and the results supported those from the cytotoxicity study in that the nanoparticle treated HepG2 and MDA-MB231 cells had more dramatic changes in cell morphology than the HT29 cells. In this manner, this study provides the first evidence that iron-manganese-doped sulfated zirconia nanoparticles should be further studied for a wide range of cancer applications without detrimental effects on healthy cell functions. PMID- 26425083 TI - Endothelial cell-targeted pVEGF165 polyplex plays a pivotal role in inhibiting intimal thickening after vascular injury. AB - Upregulation of vascular endothelial growth factor (VEGF) expression can inhibit intimal thickening after vascular injury. However, the lack of efficient gene delivery systems leads to insufficient VEGF expression, which prevents its application in gene therapy. In the present study, to improve the delivery of the plasmid vector with the VEGF gene (pVEGF165) to the injured vessel wall, we explored the potentially important difference between endothelial cell-targeted and nontargeted polymeric carriers. The alphavbeta3 integrin is overexpressed on activated endothelial cells but not on normal quiescent vessels. In this study, CDG2-cRGD, synthesized by conjugating an alphavbeta3 integrin-binding cyclic arginylglycylaspartic acid (cRGD) peptide with the Generation 2 polycation polyamidoamine (PAMAMG2)-g-cyclodextrin (termed as CDG2), was developed as a targetable carrier. It was observed that the specific integrin-ligand interactions greatly enhanced cellular internalization of CDG2-cRGD in human umbilical vein endothelial cells (HUVECs), which are notoriously difficult to transfect. Consequently, HUVECs were found to show remarkably high levels of VEGF165 expression induced by the CDG2-cRGD polyplex. Interestingly, VEGF165 overexpression in vivo was more complex than that in vitro, and in vivo assays demonstrated that the stimulus response to balloon injury in arteries could obviously upregulate VEGF165 expression in the saline-treated group, although it was not enough to prevent intimal thickening. In gene-transfected groups, intravascular delivery of pVEGF165 with the CDG2-cRGD polyplex into rabbits after vascular injury resulted in a significant inhibition of intimal thickening at 4 weeks, whereas the low therapeutic efficacy in the nontargeted CDG2-treated group was only comparable to that in the saline-treated group. It is becoming clear that the conflicting results of VEGF165 gene therapy in two gene-transfected groups are reflective of the pivotal role of the cRGD-conjugated carriers in achieving the beneficial therapeutic effects of vascular gene therapy. PMID- 26425084 TI - Preparation and characterization of anti-HIV nanodrug targeted to microfold cell of gut-associated lymphoid tissue. AB - The human immunodeficiency virus 1 (HIV-1) still remains one of the leading life threatening diseases in the world. The introduction of highly active antiretroviral therapy has significantly reduced disease morbidity and mortality. However, most of the drugs have variable penetrance into viral reservoir sites, including gut-associated lymphoid tissue (GALT). Being the largest lymphoid organ, GALT plays a key role in early HIV infection and host-pathogen interaction. Many different treatment options have been proposed to eradicate the virus from GALT. However, it becomes difficult to deliver traditional drugs to the GALT because of its complex physiology. In this regard, we developed a polymer-based Pluronic nanocarrier containing anti-HIV drug called efavirenz (EFV) targeting Microfold cells (M-cells) in the GALT. M-cells are specialized epithelial cells that are predominantly present in the GALT. In this work, we have exploited this paracellular transport property of M-cells for targeted delivery of Pluronic nanocarrier tagged EFV, bioconjugated with anti-M-cell specific antibodies to the GALT (nanodrug). Preliminary characterization showed that the nanodrug (EFV-F12-COOH) is of 140 nm size with 0.3 polydispersion index, and the zeta potential of the particles was -19.38+/-2.2 mV. Further, drug dissolution study has shown a significantly improved sustained release over free drugs. Binding potential of nanodrug with M-cell was also confirmed with fluorescence microscopy and in vitro uptake and release studies. The anti-HIV activity of the nanodrug was also significantly higher compared to that of free drug. This novel formulation was able to show sustained release of EFV and inhibit the HIV-1 infection in the GALT compared to the free drug. The present study has potential for our in vivo targeted nanodrug delivery system by combining traditional enteric-coated capsule technique via oral administration. PMID- 26425085 TI - Development, characterization, and skin delivery studies of related ultradeformable vesicles: transfersomes, ethosomes, and transethosomes. AB - Ultradeformable vesicles (UDV) have recently become a promising tool for the development of improved and innovative dermal and transdermal therapies. The aim of this work was to study three related UDV: transfersomes, ethosomes, and transethosomes for the incorporation of actives of distinct polarities, namely, vitamin E and caffeine, and to evaluate the effect of the carrier on skin permeation and penetration. These actives were incorporated in UDV formulations further characterized for vesicles imaging by transmission electron microscopy; mean vesicle size and polydispersity index by photon correlation spectroscopy; zeta potential by laser-Doppler anemometry; deformability by pressure-driven transport; and incorporation efficiency (IE) after actives quantification by high performance liquid chromatography. Topical delivery studies were performed in order to compare UDV formulations regarding the release, skin permeation, and penetration profiles. All UDV formulations showed size values within the expected range, except transethosomes prepared by "transfersomal method", for which size was smaller than 100 nm in contrast to that obtained for vesicles prepared by "ethosomal method". Zeta potential was negative and higher for formulations containing sodium cholate. The IE was much higher for vitamin E- than caffeine loaded UDV as expected. For flux measurements, the following order was obtained: transethosomes (TE) > ethosomes (E) >= transfersomes (T). This result was consistent with the release and skin penetration profiles for Vitamin E-loaded UDV. However, the releasing results were totally the opposite for caffeine-loaded UDV, which might be explained by the solubility and thermodynamic activity of this active in each formulation instead of the UDV deformability attending to the higher non-incorporated fraction of caffeine. Anyway, a high skin penetration and permeation for all caffeine-loaded UDV were obtained. Transethosomes were more deformable than ethosomes and transfersomes due to the presence of both ethanol and surfactant in their composition. All these UDV were suitable for a deeper skin penetration, especially transethosomes. PMID- 26425086 TI - Neurite outgrowth stimulatory effects of myco synthesized AuNPs from Hericium erinaceus (Bull.: Fr.) Pers. on pheochromocytoma (PC-12) cells. AB - BACKGROUND: Hericium erinaceus has been reported to have a wide range of medicinal properties such as stimulation of neurite outgrowth, promotion of functional recovery of axonotmetic peroneal nerve injury, antioxidant, antihypertensive, and antidiabetic properties. In recent years, the green synthesis of gold nanoparticles (AuNPs) has attracted intense interest due to the potential use in biomedical applications. The aim of this study was to investigate the effects of AuNPs from aqueous extract of H. erinaceus on neurite outgrowth of rat pheochromocytoma (PC-12) cells. METHODS: The formation of AuNPs was characterized by UV-visible spectrum, energy dispersive X-ray (EDX), field emission scanning electron microscope (FESEM), transmission electron microscopy (TEM), particle size distribution, and Fourier transform-infrared spectroscopy (FTIR). Furthermore, the neurite extension study of synthesized AuNPs was evaluated by in vitro assay. RESULTS: The AuNPs exhibited maximum absorbance between 510 and 600 nm in UV-visible spectrum. FESEM and TEM images showed the existence of nanoparticles with sizes of 20-40 nm. FTIR measurements were carried out to identify the possible biomolecules responsible for capping and efficient stabilization of the nanoparticles. The purity and the crystalline properties were confirmed by EDX diffraction analysis, which showed strong signals with energy peaks in the range of 2-2.4 keV, indicating the existence of gold atoms. The synthesized AuNPs showed significant neurite extension on PC-12 cells. Nerve growth factor 50 ng/mL was used as a positive control. Treatment with different concentrations (nanograms) of AuNPs resulted in neuronal differentiation and neuronal elongation. AuNPs induced maximum neurite outgrowth of 13% at 600 ng/mL concentration. CONCLUSION: In this study, the AuNPs synthesis was achieved by a simple, low-cost, and rapid bioreduction approach. AuNPs were shown to have potential neuronal differentiation and stimulated neurite outgrowth. The water soluble bioconstituents could be responsible for the neuroactivity. This is the first report for the biosynthesis of AuNPs using the hot aqueous extract of H. erinaceus. PMID- 26425087 TI - Probing insulin bioactivity in oral nanoparticles produced by ultrasonication assisted emulsification/internal gelation. AB - Alginate-dextran sulfate-based particles obtained by emulsification/internal gelation technology can be considered suitable carriers for oral insulin delivery. A rational study focused on the emulsification and particle recovery steps was developed in order to reduce particles to the nanosize range while keeping insulin bioactivity. There was a decrease in size when ultrasonication was used during emulsification, which was more pronounced when a cosurfactant was added. Ultrasonication add-on after particle recovery decreased aggregation and led to a narrower nanoscale particle-size distribution. Insulin encapsulation efficiency was 99.3%+/-0.5%, attributed to the strong pH-stabilizing electrostatic effect between insulin and nanoparticle matrix polymers. Interactions between these polymers and insulin were predicted using molecular modeling studies through quantum mechanics calculations that allowed for prediction of the interaction model. In vitro release studies indicated well preserved integrity of nanoparticles in simulated gastric fluid. Circular dichroism spectroscopy proved conformational stability of insulin and Fourier transform infrared spectroscopy technique showed rearrangements of insulin structure during processing. Moreover, in vivo biological activity in diabetic rats revealed no statistical difference when compared to nonencapsulated insulin, demonstrating retention of insulin activity. Our results demonstrate that alginate-dextran sulfate-based nanoparticles efficiently stabilize the loaded protein structure, presenting good physical properties for oral delivery of insulin. PMID- 26425088 TI - Synthesis and in vivo magnetic resonance imaging evaluation of biocompatible branched copolymer nanocontrast agents. AB - Branched copolymer nanoparticles (D(h) =20-35 nm) possessing 1,4,7, 10 tetraazacyclododecane-N,N',N",N'''-tetraacetic acid macrocycles within their cores have been synthesized and applied as magnetic resonance imaging (MRI) nanosized contrast agents in vivo. These nanoparticles have been generated from novel functional monomers via reversible addition-fragmentation chain transfer polymerization. The process is very robust and synthetically straightforward. Chelation with gadolinium and preliminary in vivo experiments have demonstrated promising characteristics as MRI contrast agents with prolonged blood retention time, good biocompatibility, and an intravascular distribution. The ability of these nanoparticles to perfuse and passively target tumor cells through the enhanced permeability and retention effect is also demonstrated. These novel highly functional nanoparticle platforms have succinimidyl ester-activated benzoate functionalities within their corona, which make them suitable for future peptide conjugation and subsequent active cell-targeted MRI or the conjugation of fluorophores for bimodal imaging. We have also demonstrated that these branched copolymer nanoparticles are able to noncovalently encapsulate hydrophobic guest molecules, which could allow simultaneous bioimaging and drug delivery. PMID- 26425090 TI - Today's diverse nano-theranostic applications and tomorrow's promises. PMID- 26425089 TI - Microwave-assisted fibrous decoration of mPE surface utilizing Aloe vera extract for tissue engineering applications. AB - Developing multifaceted, biocompatible, artificial implants for tissue engineering is a growing field of research. In recent times, several works have been reported about the utilization of biomolecules in combination with synthetic materials to achieve this process. Accordingly, in this study, the ability of an extract obtained from Aloe vera, a commonly used medicinal plant in influencing the biocompatibility of artificial material, is scrutinized using metallocene polyethylene (mPE). The process of coating dense fibrous Aloe vera extract on the surface of mPE was carried out using microwaves. Then, several physicochemical and blood compatibility characterization experiments were performed to disclose the effects of corresponding surface modification. The Fourier transform infrared spectrum showed characteristic vibrations of several active constituents available in Aloe vera and exhibited peak shifts at far infrared regions due to aloe-based mineral deposition. Meanwhile, the contact angle analysis demonstrated a drastic increase in wettability of coated samples, which confirmed the presence of active components on glazed mPE surface. Moreover, the bio-mimic structure of Aloe vera fibers and the influence of microwaves in enhancing the coating characteristics were also meticulously displayed through scanning electron microscopy micrographs and Hirox 3D images. The existence of nanoscale roughness was interpreted through high-resolution profiles obtained from atomic force microscopy. And the extent of variations in irregularities was delineated by measuring average roughness. Aloe vera-induced enrichment in the hemocompatible properties of mPE was established by carrying out in vitro tests such as activated partial thromboplastin time, prothrombin time, platelet adhesion, and hemolysis assay. In conclusion, the Aloe vera-glazed mPE substrate was inferred to attain desirable properties required for multifaceted biomedical implants. PMID- 26425091 TI - Magnetic microparticle-based multimer detection system for the detection of prion oligomers in sheep. AB - Transmissible spongiform encephalopathies (TSEs) are zoonotic fatal neurodegenerative diseases in animals and humans. TSEs are commonly known as bovine spongiform encephalopathy in cattle, scrapie in sheep and goats, chronic wasting disease in cervids, and Creutzfeldt-Jakob disease in humans. The putative transmissible agents are infectious prion proteins (PrP(Sc)), which are formed by the conversion of the normal prion protein on the glycoprotein cell surface in the presence of other PrP(Sc). Reports of the transmission of TSEs through blood raised considerable concern about the safety of blood and blood products. To address this issue, many laboratories attempted to develop a sensitive and accurate blood diagnostic test to detect PrP(Sc). Previously, we reported that, compared to normal controls, the multimer detection system (MDS) was more efficient in detecting PrP(Sc) in infected hamster brain homogenate, mouse plasma spiked with purified PrP(Sc) from scrapie mouse brain, and scrapie-infected hamster plasmas. MDS differentiates prion multimers from the cellular monomer through the multimeric expression of epitopes on prion multimers, in contrast to the monomeric form. In this study, MDS detected PrP(Sc) in plasma samples from scrapie-infected sheep expressing clinical symptoms, demonstrating 100% sensitivity and specificity in these samples. Plasma samples from asymptomatic lambs at the preclinical stage (8-month-old naturally infected offspring of scrapie-infected parents expressing a highly susceptible genotype) tested positive with 50% sensitivity and 100% specificity. In the first of two coded analyses using clinical scrapie-infected sheep and normal healthy samples, MDS successfully identified all but one of the clinical samples with 92% sensitivity and 100% specificity. Similar results were obtained in the second coded analysis using preclinical samples. MDS again successfully identified all but one of the samples with 87% sensitivity and 100% specificity. The false-negative sample was subjected to a protease pretreatment. In conclusion, MDS could accurately detect scrapie in plasma samples at both preclinical and clinical stages. From these studies, we conclude that MDS could be a promising tool for the early diagnosis of TSEs from blood samples. PMID- 26425093 TI - Comparative hyperthermia effects of silica-gold nanoshells with different surface coverage of gold clusters on epithelial tumor cells. AB - Silica-gold nanoshell (SGNS), which is a silica core surrounded by a gold layer, was synthesized by seed-mediated coalescence of gold clusters in an electroless plating solution. SGNS variations with different surface coverage of gold clusters were prepared by adjusting the amounts of gold salts in the presence of formaldehyde-reducing agents. Fully covered SGNS (f-SGNS) with connected gold clusters exhibited stronger intensity and more redshift of plasmon bands located around 820 nm than those of partially covered SGNS (p-SGNS) with disconnected gold clusters. Upon irradiation with near-infrared light (30 W/cm(2), 700-800 nm), f-SGNS caused a larger hyperthermia effect, generating a large temperature change (DeltaT =42 degrees C), as compared to the relatively small temperature change (DeltaT =24 degrees C) caused by p-SGNS. The therapeutic antibody, ErbituxTM (ERB), was further conjugated to SGNS for specific tumor cell targeting. The f-ERB-SGNS showed excellent therapeutic efficacy based on the combined effect of both the therapeutic antibody and the full hyperthermia dose under near-infrared irradiation. Thus, SGNS with well-controlled surface morphology of gold shells may be applicable for near-infrared-induced hyperthermia therapy with tunable optical properties. PMID- 26425094 TI - An innovative intervention for the treatment of cognitive impairment-Emisymmetric bilateral stimulation improves cognitive functions in Alzheimer's disease and mild cognitive impairment: an open-label study. AB - BACKGROUND AND AIMS: In the last decade, the development of different methods of brain stimulation by electromagnetic fields (EMF) provides a promising therapeutic tool for subjects with impaired cognitive functions. Emisymmetric bilateral stimulation (EBS) is a novel and innovative EMF brain stimulation, whose working principle is to introduce very weak noise-like stimuli through EMF to trigger self-arrangements in the cortex of treated subjects, thereby improving cognitive faculties. The aim of this pilot study was to investigate in patients with cognitive impairment the effectiveness of EBS treatment with respect to global cognitive function, episodic memory, and executive functions. METHODS: Fourteen patients with cognitive decline (six with mild cognitive impairment and eight with Alzheimer's disease) underwent three EBS applications per week to both the cerebral cortex and auricular-specific sites for a total of 5 weeks. At baseline, after 2 weeks and 5 weeks, a neuropsychological assessment was performed through mini-mental state examination, free and cued selective reminding tests, and trail making test. As secondary outcomes, changes in behavior, functionality, and quality of life were also evaluated. RESULTS: After 5 weeks of standardized EBS therapy, significant improvements were observed in all neurocognitive assessments. Mini-mental state examination score significantly increased from baseline to end treatment (+3.19, P=0.002). Assessment of episodic memory showed an improvement both in immediate and delayed recalls (immediate recall =+7.57, P=0.003; delayed recall =+4.78, P<0.001). Executive functions significantly improved from baseline to end stimulation (trail making test A 53.35 seconds; P=0.001). Of note, behavioral disorders assessed through neuropsychiatric inventory significantly decreased (-28.78, P<0.001). The analysis concerning the Alzheimer's disease and mild cognitive impairment group confirmed a significant improvement of cognitive functions and behavior after EBS treatment. CONCLUSION: This pilot study has shown EBS to be a promising, effective, and safe tool to treat cognitive impairment, in addition to the drugs presently available. Further investigations and controlled clinical trials are warranted. PMID- 26425092 TI - Targeting cancer stem cells by using the nanoparticles. AB - Cancer stem cells (CSCs) have been shown to be markedly resistant to conventional cancer treatments such as chemotherapy and radiation therapy. Therefore, therapeutic strategies that selectively target CSCs will ultimately lead to better cancer treatments. Currently, accessible conventional therapeutic agents mainly eliminate the bulk tumor but do not eliminate CSCs. Therefore, the discovery and improvement of CSC-targeting therapeutic agents are necessary. Nanoparticles effectively inhibit multiple types of CSCs by targeting specific signaling pathways (Wnt/beta-catenin, Notch, transforming growth factor-beta, and hedgehog signaling) and/or specific markers (aldehyde dehydrogenases, CD44, CD90, and CD133) critically involved in CSC function and maintenance. In this review article, we summarized a number of findings to provide current information about their therapeutic potential of nanoparticles in various cancer cell types and CSCs. PMID- 26425095 TI - Intractable and highly active relapsing multiple sclerosis - role of alemtuzumab. AB - Alemtuzumab is a humanized recombinant monoclonal antibody that was recently approved by the US Food and Drug Administration and the European Medicines Agency for the management of relapsing forms of multiple sclerosis (MS). It has been utilized for the management of chronic lymphocytic leukemia, bone marrow and renal transplantation, or graft versus host disease. Because of its immunomodulatory properties, it was brought into clinical development in MS. One Phase II (CAMMS223) and two Phase III clinical trials (CARE-MSI and -II) have evaluated the safety and efficacy of alemtuzumab in patients with relapsing remitting MS. Even though its efficacy profile and long-lasting effect have attracted much interest among physicians and patients, it has significant potential adverse effects that may limit its use to patients with active disease. Here, we review the history of drug development of alemtuzumab. Furthermore, we outline the postulated mechanisms of action, clinical evidence, and safety of alemtuzumab for its use as a disease-modifying agent in active and highly active MS. PMID- 26425096 TI - Anatomical and functional brain abnormalities in unmedicated major depressive disorder. AB - BACKGROUND: Using magnetic resonance imaging (MRI) and resting-state functional magnetic resonance imaging (rsfMRI) to explore the mechanism of brain structure and function in unmedicated patients with major depressive disorder (MDD). PATIENTS AND METHODS: Fifty patients with MDD and 50 matched healthy control participants free of psychotropic medication underwent high-resolution structural and rsfMRI scanning. Optimized diffeomorphic anatomical registration through exponentiated lie algebra and the Data Processing Assistant for rsfMRI were used to find potential differences in gray-matter volume (GMV) and regional homogeneity (ReHo) between the two groups. A Pearson correlation model was used to analyze associations of morphometric and functional changes with clinical symptoms. RESULTS: Compared to healthy controls, patients with MDD showed significant GMV increase in the left posterior cingulate gyrus and GMV decrease in the left lingual gyrus (P<0.001, uncorrected). In ReHo analysis, values were significantly increased in the left precuneus and decreased in the left putamen (P<0.001, uncorrected) in patients with MDD compared to healthy controls. There was no overlap between anatomical and functional changes. Linear correlation suggested no significant correlation between mean GMV values within regions with anatomical abnormality and ReHo values in regions with functional abnormality in the patient group. These changes were not significantly correlated with symptom severity. CONCLUSION: Our study suggests a dissociation pattern of brain regions with anatomical and functional alterations in unmedicated patients with MDD, especially with regard to GMV and ReHo. PMID- 26425097 TI - The MGuard coronary stent: safety, efficacy, and clinical utility. AB - Atheromatous and thrombotic embolization during percutaneous coronary revascularization is a feared complication that may cause impaired myocardial reperfusion even with a patent epicardial vessel. The MGuard stent is a cobalt chromium bare metal stent with a porous net attached to its outer surface that has been designed to prevent thrombus fragmentation and distal embolization during stent implantation. This review summarizes the available evidence supporting the use of the MGuard stent in different scenarios such as lesions with high thrombus burden, saphenous vein graft interventions, coronary perforations, or carotid lesions. PMID- 26425099 TI - Comparing two assays for clinical genomic profiling: the devil is in the data [Letter of clarification]. PMID- 26425098 TI - A comparative cohort study of totally laparoscopic and open aortobifemoral bypass for the treatment of advanced atherosclerosis. AB - BACKGROUND: Totally laparoscopic aortobifemoral bypass (LABF) procedure has been shown to be feasible for the treatment of advanced aortoiliac occlusive disease (AIOD). This study compares the LABF with the open aortobifemoral bypass (OABF) operation. METHODS: In this prospective comparative cohort study, 50 consecutive patients with type D atherosclerotic lesions in the aortoiliac segment were treated with an LABF operation. The group was compared with 30 patients who were operated on with the OABF procedure for the same disease and time period. We had an explanatory strategy, and our research hypothesis was to compare the two surgical procedures based on a composite event (all-cause mortality, graft occlusion, and systemic morbidity). Stratification analysis was performed by using the Mantel-Haenszel method with the patient-time model. Cox multivariate regression method was used to adjust for confounding effect after considering the proportional hazard assumption. Cox proportional cause-specific hazard regression model was used for competing risk endpoint. RESULTS: There was a higher frequency of comorbidity in the OABF group. A significant reduction of composite event, 82% (hazard ratio 0.18; 95% CI 0.08-0.42, P=0.0001) was found in the LABF group when compared with OABF group, during a median follow-up time period of 4.12 years (range from 1 day to 9.32 years). In addition, less operative bleeding and shorter length of hospital stay were observed in the LABF group when compared with the OABF group. All components of the composite event showed the same positive effect in favor of LABF procedure. CONCLUSION: LABF for the treatment of AIOD, Trans-Atlantic Inter-Society Consensus II type D lesions, seems to result in a less composite event when compared with the OABF procedure. To conclude, our results need to be replicated by a randomized clinical trial. PMID- 26425100 TI - Combination of BCL-2 and MYC protein expression improves high-risk stratification in diffuse large B-cell lymphoma. AB - PURPOSE: To evaluate whether the addition of two biological markers (MYC and BCL 2 protein overexpression) improves the stratification of high-risk patients with diffuse large B-cell lymphoma (DLBCL). METHOD: Seven risk factors were identified at diagnosis, and a maximum of 7 points were assigned to each patient. The patients were classified according to four risk groups: low (0-1), low intermediate (2-3), high-intermediate (4), and high (5-7). Only high-risk patients with DLBCL were included in this analysis. We retrospectively examined 20 cases from 2008 to 2013 at the Nanjing Drum Tower Hospital. RESULTS: The median expression of MYC protein was 60%, and 17 of 20 (65%) evaluable cases overexpressed MYC. The median expression of BCL-2 protein was also 60%. Eighteen of 20 (90%) evaluable cases showed BCL-2 overexpression. Additionally, 12 out of 20 cases (60%) demonstrated coexpression of MYC and BCL-2 proteins. The percentages of overall survival and progression-free survival at the median follow-up time (36 months) were 33.3%+/-16.1% and 16.9%+/-13.5%, respectively. By comparison, nine, four, and 20 patients were classified as high risk based on the International Prognostic Index (IPI), National Comprehensive Cancer Network(NCCN) IPI, and revised IPI criteria, respectively. According to the IPI and NCCN-IPI stratification, the risk groups demonstrated closely overlapping survival curves. In addition, four out of 20 cases were identified as low-intermediate risk according to the NCCN-IPI criteria. CONCLUSION: The addition of MYC and BCL-2 protein expression to the IPI could identify a subset of DLBCL patients with high risk clinicopathological characteristics and poor clinical outcome. PMID- 26425101 TI - Diarrhea as initial manifestation of pulmonary artery intimal sarcoma: a case report and literature review. AB - Pulmonary artery intimal sarcoma (PAIS) is a rare malignant tumor that presents with nonspecific symptoms and may be misdiagnosed as thromboembolic disease. We report a case of a 40-year-old female who presented with diarrhea as the initial symptom, was misdiagnosed and received thrombolytic therapy for presumed pulmonary embolism. Progressive symptoms and subsequent surgery led to the diagnosis of PAIS, and early relapse after pulmonary endarterectomy. Her survival time was 17 months after pulmonary endarterectomy. To our knowledge, diarrhea as initial manifestation of PAIS has not been described. PMID- 26425102 TI - An exploratory retrospective assessment of a quantitative measure of diabetes risk: medical management and patient impact in a primary care setting. AB - BACKGROUND: Primary care providers with limited time and resources bear a heavy responsibility for chronic disease prevention or progression. Reliable clinical tools are needed to risk stratify patients for more targeted care. This exploratory study examined the care of patients who had been risk stratified regarding their likelihood of clinically progressing to type 2 diabetes. METHODS: This was a retrospective chart review pilot study conducted to assess a primary care provider's use of a risk screening test. In this quality improvement project, the result of the risk screening was examined in relation to its influence on medical management and clinical impact on patients at risk for diabetes. All providers were board certified in family medicine and had more than 10 years clinical experience in managing diabetes and prediabetes. No specific clinical practice guidelines were mandated for patient care in this pilot study. Physicians in the practice group received an orientation to the diabetes risk measure and its availability for use in a pilot study to be conducted over a 6 month period. We identified the 696 nondiabetic adults in family practices who received a risk screening test (PreDx((r)), a multi-marker blood test that estimates the 5-year likelihood of conversion to type 2 diabetes) between June and November 2011 for a 6-month sample. A comparison group of 2,002 patients from a total database of 3.2 million patients who did not receive the risk test was randomly selected from the same clinical database after matching for age, sex, selected diagnoses, and metabolic risk factors. Patient groups were compared for intensity of care provided and clinical impact. RESULTS: Compared to patients with a similar demographic and diagnostic profile, patients who had the risk test received more intensive primary care and had better clinical outcome than comparison patients. Risk-tested patients were more likely to return for follow up visits, be monitored for relevant cardio-metabolic risk factors, and receive prescription medications with P<0.001. Further, intensity of care was associated with the level of risk test result: patients with moderate or high scores were more likely to return for follow-up visits and receive prescription medications than patients with low scores. All P-values for comparison patients between the low and moderate groups, low and high groups, and moderate and high groups resulted in P<0.001. Risk-tested patients were more likely than their comparison group counterparts to achieve weight reduction, lowered blood pressure, and improved blood glucose and cholesterol as demonstrated by P-values of <0.001. CONCLUSION: Use of a risk stratification test in primary care may help providers to more effectively identify high risk patients, manage diabetes risk, increase patient involvement in diabetes risk management, and improve clinical outcomes. A randomized controlled study is the next step to investigate the impact of diabetes risk stratification in primary care. PMID- 26425103 TI - Bariatric surgery outcomes: a single-center study in the United Arab Emirates. AB - BACKGROUND: Bariatric surgery has become an attractive treatment for severe obesity over the last decade, due to its impacts on weight loss and remission of type 2 diabetes and metabolic syndrome. In the United Arab Emirates, a country where the rate of obesity is dramatically increasing bariatric surgery has gained popularity in recent years; however, published data on its outcomes in the Emirati population are lacking. METHODS: We retrospectively reviewed the medical records of 95 patients who underwent bariatric surgery (ie, laparoscopic Roux-en Y gastric bypass [RYGB] or laparoscopic sleeve gastrectomy) at the Rashid Center for Diabetes and Research in Ajman, United Arab Emirates. Weight outcomes and metabolic marker data were abstracted at baseline and at 3, 6, and 12 months postoperatively. RESULTS: Laparoscopic RYGB was the main procedure performed by our bariatric unit. All variables demonstrated postoperative improvement. An average excess weight loss of 68% was observed at 12 months. Fat mass was the body component that decreased the most, with an average reduction of 46%. Additionally, lipid profiles were significantly different (P<0.01) at 12 months, with triglyceride levels improving by 27% and low-density lipoprotein levels improving by 21%. Similarly, glycated hemoglobin (HbA1c) levels decreased significantly (P<0.001) in patients with type 2 diabetes, with an average reduction of 73%. CONCLUSION: Our results show that a substantial short-term reduction in weight and significant improvements in metabolic markers followed bariatric surgery in severely obese Emirati patients. Our results are consistent with the outcomes of other internationally published studies. Additional studies are warranted to determine whether the favorable impacts of bariatric surgery can be sustained over the long term. PMID- 26425104 TI - The clinical utility of aflibercept for diabetic macular edema. AB - The treatment of center-involving diabetic macular edema (DME) has improved because of the proven efficacy of drugs that inhibit the effects of vascular endothelial growth factor (VEGF). The newest anti-VEGF drug, aflibercept, has recently been approved by the United States Food and Drug Administration for the treatment of center-involving DME and for diabetic retinopathy in eyes with DME. In the pivotal Phase III VISTA and VIVID trials, intravitreal aflibercept 2 mg injections every 4 or 8 weeks (after 5 monthly loading doses) produced superior gains in BCVA compared to laser/sham injections. In the Diabetic Retinopathy Clinical Research Network Protocol T trial, which featured monthly anti-VEGF monotherapy for 6 months, followed by monthly pro re nata anti-VEGF injections with laser rescue therapy from months 6 through 12, aflibercept 2 mg monthly was superior to bevacizumab 1.25 mg and ranibizumab 0.5 mg in eyes with BCVA of 20/50 or worse (aflibercept versus bevacizumab: P<0.001; aflibercept versus ranibizumab: P=0.003), but the three regimens were comparable for eyes with VA of 20/40 or better. Only in the 20/50 or worse subgroup did aflibercept achieve clinical superiority (>5 letter difference) to bevacizumab. Each treatment regimen led to significant macular thinning, with aflibercept being superior to bevacizumab in both visual acuity subgroups (P<0.001 for each), but it was not statistically superior to ranibizumab in either group. In diabetic patients, aflibercept has an excellent safety profile that does not appear to differ from laser/sham or other VEGF inhibitory drugs. PMID- 26425106 TI - Atypical teratoid rhabdoid tumors: a population-based clinical outcomes study involving 174 patients from the Surveillance, Epidemiology, and End Results database (1973-2010). AB - INTRODUCTION: Atypical teratoid rhabdoid tumors (ATRTs) are rare, highly malignant embryonal tumors of the central nervous system (CNS) accounting for 20% of CNS tumors in children under the age of 3. This study examines a large cohort of ATRT patients to determine demographic, clinical, and pathologic factors which impact prognosis and survival. METHODS: Demographic and clinical data were abstracted on 174 ATRT patients (171 pediatric patients age <20 and 3 adult patients age >=20) from the Surveillance, Epidemiology, and End Results database (1973-2010). Standard statistical methodology was used. RESULTS: A total of 174 ATRT cases (mean age of 2.84 years) were identified. ATRT had a higher incidence in males (56.3%), Caucasians (59.1%), and children <3 years of age (80.5%), P<0.001. The most common primary sites were the cerebellum (17.8%), ventricles (16.1%), and frontal lobe (12.6%). Mean overall survival was 3.2+/-0.4 years, while overall and cancer-specific mortality were 63.2% and 56.3%, respectively, P=0.005. Most ATRT cases were treated with surgery alone (58.0%), followed by a combination of surgery and radiation (34.3%), no treatment (6.5%), and radiation alone (1.2%). The use of combination therapy has increased significantly (16.1%) since 2005 (P<0.001), while primary surgical resection and radiation therapy rates remain relatively unchanged. The longest survival was observed among ATRT patients receiving combination therapy (5.9+/-0.7 years), followed by radiation alone (2.8+/-1.2 years), and surgery alone (1.9+/-0.4 years), P<0.001. Multivariable analysis identified only distant metastases (OR =4.6) as independently associated with increased mortality, whereas combination therapy (OR =0.4) was associated with reduced mortality, P<0.005. CONCLUSION: ATRT is a rare and highly aggressive embryonal malignancy of the CNS that presents more often as locoregional tumors >4 cm in male Caucasian children of age <3 years, involving the cerebellum, ventricles, or frontal lobe. Combination therapy significantly improves survival, and its use has been increasing since 2005. PMID- 26425107 TI - Relapsing polychondritis with different types of ocular inflammations. AB - We were presented with two cases of relapsing polychondritis (RP) associated with different types of ocular inflammation. The first case was a 35-year-old man who had bilateral hyperemic conjunctiva and ocular pain, and was referred to Chiba University Hospital with a diagnosis of episcleritis refractory. He was treated with dexamethasone eye drops. He developed tinnitus, deafness in both ears, and left auriculitis. A left auricular biopsy showed an infiltration of lymphocytes surrounding the cartilage. He was diagnosed with RP and treated with 30 mg/day oral prednisolone. After tapering the prednisolone, the scleritis in both eyes improved. The second case was a 71-year-old man who was deaf in both ears and had bilateral scleritis. At the first visit to our hospital, his left eyelid and right auricula were reddish and swollen, and he reported some pain. He was treated with intravenous antibiotics, and the left orbital cellulitis quickly improved. However, he developed right scleritis and left gonitis. Magnetic resonance imaging showed bilateral posterior scleritis and right auricular perichondritis. Auricular biopsy showed an infiltration of lymphocytes into the periauricular tissue. He was diagnosed with RP, and 40 mg/day oral prednisolone was given and his symptoms improved. Although RP is rare, it is a life threatening disease. Thus, ophthalmologists should consider RP in patients with both ocular and auricular inflammation. PMID- 26425108 TI - Optical coherence tomography imaging of chorioretinal folds associated with hypotony maculopathy following pars plana vitrectomy. AB - Chorioretinal folds may occur as a consequence of hypotony and can be a cause of vision loss when associated with macular involvement. In this report, the spectral domain ocular coherence tomography imaging of three patients with chorioretinal folds before and after management are presented. The cases had unique presentations and each underwent different management approaches, but the results included improved visual acuities and lessened chorioretinal folds. PMID- 26425105 TI - Genetics of inherited primary arrhythmia disorders. AB - A sudden unexplained death is felt to be due to a primary arrhythmic disorder when no structural heart disease is found on autopsy, and there is no preceding documentation of heart disease. In these cases, death is presumed to be secondary to a lethal and potentially heritable abnormality of cardiac ion channel function. These channelopathies include congenital long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and short QT syndrome. In certain cases, genetic testing may have an important role in supporting a diagnosis of a primary arrhythmia disorder, and can also provide prognostic information, but by far the greatest strength of genetic testing lies in the screening of family members, who may be at risk. The purpose of this review is to describe the basic genetic and molecular pathophysiology of the primary inherited arrhythmia disorders, and to outline a rational approach to genetic testing, management, and family screening. PMID- 26425109 TI - Evaluation of an automated single-channel sleep staging algorithm. AB - BACKGROUND: We previously published the performance evaluation of an automated electroencephalography (EEG)-based single-channel sleep-wake detection algorithm called Z-ALG used by the Zmachine((r)) sleep monitoring system. The objective of this paper is to evaluate the performance of a new algorithm called Z-PLUS, which further differentiates sleep as detected by Z-ALG into Light Sleep, Deep Sleep, and Rapid Eye Movement (REM) Sleep, against laboratory polysomnography (PSG) using a consensus of expert visual scorers. METHODS: Single night, in-lab PSG recordings from 99 subjects (52F/47M, 18-60 years, median age 32.7 years), including both normal sleepers and those reporting a variety of sleep complaints consistent with chronic insomnia, sleep apnea, and restless leg syndrome, as well as those taking selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor antidepressant medications, previously evaluated using Z-ALG were re-examined using Z-PLUS. EEG data collected from electrodes placed at the differential-mastoids (A1-A2) were processed by Z-ALG to determine wake and sleep, then those epochs detected as sleep were further processed by Z-PLUS to differentiate into Light Sleep, Deep Sleep, and REM. EEG data were visually scored by multiple certified polysomnographic technologists according to the Rechtschaffen and Kales criterion, and then combined using a majority-voting rule to create a PSG Consensus score file for each of the 99 subjects. Z-PLUS output was compared to the PSG Consensus score files for both epoch-by-epoch (eg, sensitivity, specificity, and kappa) and sleep stage-related statistics (eg, Latency to Deep Sleep, Latency to REM, Total Deep Sleep, and Total REM). RESULTS: Sensitivities of Z-PLUS compared to the PSG Consensus were 0.84 for Light Sleep, 0.74 for Deep Sleep, and 0.72 for REM. Similarly, positive predictive values were 0.85 for Light Sleep, 0.78 for Deep Sleep, and 0.73 for REM. Overall, kappa agreement of 0.72 is indicative of substantial agreement. CONCLUSION: This study demonstrates that Z-PLUS can automatically assess sleep stage using a single A1 A2 EEG channel when compared to the sleep stage scoring by a consensus of polysomnographic technologists. Our findings suggest that Z-PLUS may be used in conjunction with Z-ALG for single-channel EEG-based sleep staging. PMID- 26425110 TI - Rate and predictors of low serum ferritin levels among healthy parturient women in Enugu, Nigeria. AB - BACKGROUND: Low serum ferritin levels signify low iron stores and this could predispose to iron deficiency anemia. OBJECTIVE: To determine the rate and predictors of low serum ferritin levels during the puerperium in Enugu, Southeast Nigeria. STUDY DESIGN: A hospital-based prospective longitudinal study involving parturient women who delivered singleton fetuses at term. Venous blood samples were collected to determine the serum ferritin concentration at 48 hours and 6 weeks postpartum. Data analysis involved descriptive and inferential statistics at 95% confidence interval (CI) using Statistical Package for Social Sciences (SPSS) computer software version 20.0. RESULTS: Two-hundred and two women who carried singleton pregnancies to term were studied. The mean serum ferritin levels at 48 hours and 6 weeks were 27.82+/-18.41 ug/L and 36.12+/-21.53 ug/L, respectively. Forty-eight hours postdelivery, 29.2% had low ferritin levels and this decreased to 12.4% at 6 weeks postpartum. There was a significant positive correlation between the serum ferritin level at 48 hours postdelivery and the serum ferritin level at 6 weeks postpartum (r=0.89, P<0.001). Predictors of the low ferritin level at 6 weeks included age <20 years (odds ratio [OR] =0.70, 95% CI =0.53, 0.93), multiparity (OR =63.7, 95% CI =3.18, 127.5), anemia at 48 hours postpartum (OR =61.7, 95% CI =13.27, 116.6), a low ferritin level at 48 hours (OR =78.1, 95% CI =8.8, 108.3), and intake of antenatal hematinics for <3 months (OR =0.04, 95% CI =0.01, 0.20). CONCLUSION: There was a significant occurrence of low ferritin levels during the puerperium in the study centers, and this was associated mainly with pregnancy and delivery factors. Efforts to improve the iron stores in parturient women could benefit from early booking and compliance with antenatal hematinics and optimizing hemoglobin and iron levels before delivery. PMID- 26425112 TI - Beverage- and Brand-Specific Binge Alcohol Consumption among Underage Youth in the U.S. AB - BACKGROUND AND OBJECTIVES: Binge drinking is a common and risky pattern of alcohol consumption among youth; beverage and brand-specific consumption during binge drinking is poorly understood. The objective was to characterize beverage- and brand-specific consumption associated with binge drinking among underage youth in the U.S. METHODS: An internet panel was used to obtain a sample of 1,032 underage youth aged 13-20, who drank alcohol in the past 30 days. For each brand consumed, youth reported drinking quantity and frequency, and whether they engaged in binge drinking with that brand (>=5 drinks for males, >=4 for females). Each youth reporting binge drinking with a brand constituted a binge drinking report. RESULTS: Overall, 50.9% of youth binge drank with >=1 brand, and 36.5% of youth who consumed any particular brand reported binge drinking with it. Spirits accounted for 43.8% of binge drinking reports. Twenty-five brands accounted for 46.2% of binge drinking reports. Many of these brands were disproportionately associated with binge drinking relative to their youth market share. CONCLUSIONS: Binge drinking among youth is most commonly involves spirits, and binge drinking is concentrated within a relatively small number of brands. Understanding factors underlying beverage and brand preference among binge drinking youth could assist prevention efforts. PMID- 26425111 TI - Cadmium induces apoptosis in primary rat osteoblasts through caspase and mitogen activated protein kinase pathways. AB - Exposure to cadmium (Cd) induces apoptosis in osteoblasts (OBs); however, little information is available regarding the specific mechanisms of Cd-induced primary rat OB apoptosis. In this study, Cd reduced cell viability, damaged cell membranes and induced apoptosis in OBs. We observed decreased mitochondrial transmembrane potentials, ultrastructure collapse, enhanced caspase-3 activity, and increased concentrations of cleaved PARP, cleaved caspase-9 and cleaved caspase-3 following Cd treatment. Cd also increased the phosphorylation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases (ERK)1/2 and c-jun N-terminal kinase (JNK) in OBs. Pretreatment with the caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, ERK1/2 inhibitor (U0126), p38 inhibitor (SB203580) and JNK inhibitor (SP600125) abrogated Cd induced cell apoptosis. Furthermore, Cd-treated OBs exhibited signs of oxidative stress protection, including increased antioxidant enzymes superoxide dismutase and glutathione reductase levels and decreased formation of reactive oxygen species. Taken together, the results of our study clarified that Cd has direct cytotoxic effects on OBs, which are mediated by caspase- and MAPK pathways in Cd induced apoptosis of OBs. PMID- 26425113 TI - A study protocol for a cluster randomised trial for the prevention of chronic suppurative otitis media in children in Jumla, Nepal. AB - BACKGROUND: Chronic Suppurative Otitis Media (CSOM) is the commonest cause of preventable deafness, affecting 164 million people worldwide, 90 % of whom live in low resource countries, such as Nepal. Simple, inexpensive treatment of acute otitis media can prevent the development of CSOM and its sequelae: deafness, abscess, encephalitis, and, rarely, death. CSOM is a disease of poverty and its social determinants: low parental education, overcrowding, poor hygiene and malnutrition. Previous studies have established economic, socio-cultural and geographic barriers to care seeking for childhood illness in the developing world and, in particular, in Nepal. The ultimate aim of this research is to improve the ear health of the children in Jumla, Nepal. The primary outcome is an increase in mother's knowledge, attitude and practice regarding ear disease in their children. The secondary outcome is a reduction in the prevalence of CSOM in their children. METHODS/DESIGN: Using 56 existing women's self-help groups, sample size, adjusting for clustering and data analysis, is set at 15 groups per arm. A baseline survey of 30 randomly selected groups will be performed, consisting of a knowledge, attitude and practice questionnaire aimed at women who participate in self-help groups, as well as examination of their children's ears. This will be followed by random allocation, stratified by geography, into 15 intervention and 15 control groups. The intervention groups will participate in three interactive educational sessions at their regular monthly meetings based on World Health Organisation Primary Ear and Hearing Resource, Basic Level. The control groups will continue their usual monthly group meetings. At 12 months, a follow-up assessment of both control and intervention groups will be performed, with a repeat women's survey and repeat ear examination of the children. Data analysis will be by intention to treat and clustering will be considered at every stage. Cluster level data will be analysed using t-test and individual level data using mixed effects linear regression and logistic regression random effects model as appropriate. DISCUSSION: Despite its remote location, Jumla has a vibrant network of health posts and community workers. This project uses existing, local resources and will be undertaken in a way that is consistent with the cultural understanding of the local community in Jumla and acceptable to local care givers. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register, ACTRN12614000231640. PMID- 26425115 TI - Losing trust in the world: Humiliation and its consequences. AB - The author identifies acts of humiliation as a specific and often traumatic way of exercising power, with a set of consistently occurring elements and predictable consequences, including a loss of the ability to trust others. It is argued that these consequences are serious and long-lasting. The article makes a distinction between 'shame' as a state of mind and 'humiliation' as an act perpetrated against a person or group. The interplay between humiliation and shame after a humiliating act is discussed. It is argued that the patient's recovery of the capacity to resume a relatively normal life is made more likely if the therapist acknowledges the specificity of humiliation, the impossibility of reversing a humiliating act and the importance of focussing on the consequences of humiliation. PMID- 26425114 TI - Implications of miR cluster 143/145 as universal anti-oncomiRs and their dysregulation during tumorigenesis. AB - Tumorigenesis is a multistep process, de-regulated due to the imbalance of oncogenes as well as anti-oncogenes, resulting in disruption of tissue homeostasis. In many cases the effect of oncogenes and anti-oncogenes are mediated by various other molecules such as microRNAs. microRNAs are small non coding RNAs established to post-transcriptionally regulate more than half of the protein coding genes. miR cluster 143/145 is one such cancer-related microRNA cluster which is down-regulated in most of the cancers and is able to hinder tumorigenesis by targeting tumor-associated genes. The fact that they could sensitize drug-resistant cancer cells by targeting multidrug resistant genes makes them potent tools to target cancer cells. Their low levels precede events which lead to cancer progression and therefore could be considered also as biomarkers to stage the disease. Interestingly, evidence suggests the existence of several in vivo mechanisms by which this cluster is differentially regulated at the molecular level to keep their levels low in cancer. In this review, we summarize the roles of miR cluster 143/145 in cancer, their potential prognostic applications and also their regulation during tumorigenesis. PMID- 26425117 TI - The importance of regional availability of health care for old age survival - Findings from German reunification. AB - BACKGROUND: This article investigates the importance of regional health care availability for old age survival. Using German reunification as a natural experiment, we show that spatial variation in health care in East Germany considerably influenced the convergence of East German life expectancy toward West German levels. METHOD: We apply cause-deleted life tables and continuous mortality decomposition for the years 1982-2007 to show how reductions in circulatory mortality among the elderly affected the East German catch-up in life expectancy. RESULTS: Improvements in remaining life expectancy at older ages were first seen in towns with university hospitals, where state-of-the-art services became available first. CONCLUSION: Our results suggest that the modernization of the health care system had a substantial effect on old-age life expectancy and helped to significantly reduce circulatory diseases as the main cause of death in East Germany. PMID- 26425116 TI - Effects of exercise on brain and peripheral inflammatory biomarkers induced by total sleep deprivation in rats. AB - BACKGROUND: Physical exercise induces neuroprotection through anti-inflammatory effects and total sleep deprivation is reported an inflammatory process. We examined whether 7 weeks of exercise training attenuates markers of inflammation during total sleep deprivation (24-h wakefulness) in the rat brain and periphery. METHODS: Four groups of 10 rats were investigated: Sedentary control, Sedentary sleep-deprived, Exercised control, and Exercised sleep-deprived. Sleep deprivation and exercise training were induced using slowly rotating wheels and a motorized treadmill. We examined mRNA expression of pro-inflammatory (IL-1beta, TNF-alpha, and IL-6) cytokine-related genes using real-time PCR, and protein levels in the hippocampus and frontal cortex, as well as circulating concentrations. RESULTS: Compared to Sedentary control rats, hippocampal and cortical IL-1beta mRNA expressions in Sedentary sleep-deprived rats were up regulated (p < 0.05 and p < 0.01 respectively). At the protein level, hippocampal IL-1beta and TNF-alpha and cortical IL-6 contents were higher in Sedentary sleep deprived rats (p < 0.001, p < 0.05, p < 0.05, respectively). Peripherally, TNF alpha, IL-6 and norepinephrine concentrations were higher in Sedentary sleep deprived rats compared to Sedentary control (p < 0.01, p < 0.001, p < 0.01, respectively). Exercise training reduced the sleep deprivation-induced hippocampal IL-1beta increases (mRNA expression and protein content) (p < 0.05 and p < 0.001), and TNF-alpha content (p < 0.001). At the periphery, exercise reduced sleep deprivation-induced increase of IL-6 concentration (p < 0.05) without effect on TNF-alpha and norepinephrine. CONCLUSIONS: We demonstrate that a 7-week exercise training program before acute total sleep deprivation prevents pro-inflammatory responses in the rat hippocampus, particularly the IL-1beta cytokine at the gene expression level and protein content. PMID- 26425118 TI - American trypanosomiasis and associated risk factors in owned dogs from the major city of Yucatan, Mexico. AB - BACKGROUND: The American trypanosomiasis is a zoonosis caused by the protozoa Trypanosoma cruzi (T. cruzi). The disease is widely distributed throughout the American continent, affecting a wide range of hosts, including dogs. It is present in the canine population in the State of Yucatan, Mexico. However, no significant studies in owned dogs have been performed in the metropolitan area of Merida. A transversal study was conducted in 370 owned dogs from Merida, Yucatan, Mexico. METHODS: A cross-sectional study including 370 dogs was performed in a major city of Yucatan, Mexico, to detect IgG antibodies against T. cruzi. A commercial ELISA test kit was used and a chi-square test used to evaluate associated risk factors; odds ratio (OR) and 95 % confidence interval (CI) were also estimated. RESULTS: The indirect ELISA and western blot (WB) tests were used to detect specific immunoglobulin G antibodies against T. cruzi in serum samples. A prevalence of 12.2 % was found; age and area of residence were statistically associated with seropositivity in dogs (p <0.05). CONCLUSIONS: Results from the present study suggests the presence and abundance of the vector in urban conditions where a high number of seropositive cases of T. cruzi cases were found. PMID- 26425119 TI - Sun Protection Behaviors Associated with Self-Efficacy, Susceptibility, and Awareness among Uninsured Primary Care Patients Utilizing a Free Clinic. AB - Background. Skin cancer is the most commonly diagnosed form of cancer in the United States (US). However, knowledge, behaviors, and attitudes regarding sun protection vary among the general population. The purpose of this study is to examine sun protection behaviors of low-income primary care patients and assess the association between these health behaviors and the self-efficacy, susceptibility, and skin cancer awareness. Methods. Uninsured primary care patients utilizing a free clinic (N = 551) completed a self-administered survey in May and June 2015. Results. Using sunscreen was the least common tactic among the participants of this study. Skin cancer awareness and self-efficacy are important to improve sun protection behaviors. Spanish speakers may have lower levels of skin care awareness compared to US born and non-US born English speakers. Male and female participants use different sun protection methods. Conclusion. It is important to increase skin cancer awareness with self-efficacy interventions as well as education on low-cost sun protection methods. Spanish speaking patients would be a target population for promoting awareness. Male and female patients would need separate gender-specific sun protection education. Future studies should implement educational programs and assess the effectiveness of the programs to further promote skin cancer prevention among underserved populations. PMID- 26425120 TI - Dissecting the Potential Interplay of DEK Functions in Inflammation and Cancer. AB - There is a long-standing correlation between inflammation, inflammatory cell signaling pathways, and tumor formation. Understanding the mechanisms behind inflammation-driven tumorigenesis is of great research and clinical importance. Although not entirely understood, these mechanisms include a complex interaction between the immune system and the damaged epithelium that is mediated by an array of molecular signals of inflammation-including reactive oxygen species (ROS), cytokines, and NFkappaB signaling-that are also oncogenic. Here, we discuss the association of the unique DEK protein with these processes. Specifically, we address the role of DEK in chronic inflammation via viral infections and autoimmune diseases, the overexpression and oncogenic activity of DEK in cancers, and DEK-mediated regulation of NFkappaB signaling. Combined, evidence suggests that DEK may play a complex, multidimensional role in chronic inflammation and subsequent tumorigenesis. PMID- 26425121 TI - Pulmonary Venous Obstruction in Cancer Patients. AB - Background. We study the clinical significance and management of pulmonary venous obstruction in cancer patients. Methods. We conducted a prospective cohort study to characterize the syndrome that we term "pulmonary vein obstruction syndrome" (PVOS) between January 2005 and March 2014. The criteria for inclusion were (1) episodes of shortness of breath; (2) chest X-ray showing abnormal pulmonary hilum shadow with or without presence of pulmonary edema and/or pleural effusion; (3) CT scan demonstrating pulmonary vein thrombosis/tumor with or without tumor around the vein. Results. Two hundred and twenty-two patients developed PVOS. Shortness of breath was the main symptom, which was aggravated by chemotherapy in 28 (13%), and medical/surgical procedures in 21 (9%) and showed diurnal change in intensity in 32 (14%). Chest X-rays all revealed abnormal pulmonary hilum shadows and presence of pulmonary edema in 194 (87%) and pleural effusion in 192 (86%). CT scans all showed pulmonary vein thrombosis/tumor (100%) and surrounding the pulmonary veins by tumor lesions in 140 patients (63%). PVOS was treated with low molecular weight heparin in combination with dexamethasone, and 66% of patients got clinical/image improvement. Conclusion. Physicians should be alert to PVOS when shortness of breath occurs and chest X-ray reveals abnormal pulmonary hilum shadows. PMID- 26425122 TI - Epithelial to Mesenchymal Transition in a Clinical Perspective. AB - Tumor growth and metastatic dissemination rely on cellular plasticity. Among the different phenotypes acquired by cancer cells, epithelial to mesenchymal transition (EMT) has been extensively illustrated. Indeed, this transition allows an epithelial polarized cell to acquire a more mesenchymal phenotype with increased mobility and invasiveness. The role of EMT is quite clear during developmental stage. In the neoplastic context in many tumors EMT has been associated with a more aggressive tumor phenotype including local invasion and distant metastasis. EMT allows the cell to invade surrounding tissues and survive in the general circulation and through a stem cell phenotype grown in the host organ. The molecular pathways underlying EMT have also been clearly defined and their description is beyond the scope of this review. Here we will summarize and analyze the attempts made to block EMT in the therapeutic context. Indeed, till today, most of the studies are made in animal models. Few clinical trials are ongoing with no obvious benefits of EMT inhibitors yet. We point out the limitations of EMT targeting such tumor heterogeneity or the dynamics of EMT during disease progression. PMID- 26425124 TI - Frequency of Red Cell Alloimmunization and Autoimmunization in Thalassemia Patients: A Report from Eastern India. AB - Introduction. Red blood cell (RBC) alloimmunization and autoimmunization remain a major problem in transfusion dependent thalassemic patients. There is a paucity of data on the incidence of RBC alloimmunization and autoimmunization in thalassemic patients from eastern part of India, as pretransfusion antibody screening is not routinely performed. Aims. To assess the incidence of RBC alloimmunization and autoimmunization in transfusion dependent thalassemic patients in eastern India. Materials and Methods. Total 500 thalassemia cases were evaluated. The antibody screening and identification were performed with commercially available panel cells (Diapanel, Bio-rad, Switzerland) by column agglutination method. To detect autoantibodies, autocontrol and direct antiglobulin tests were carried out using polyspecific coombs (IgG + C3d) gel cards in all patients. Results. A total of 28 patients developed RBC alloimmunization (5.6%) and 5 patients had autoantibodies (1%). Alloantibody against c had the highest incidence (28.57%) followed by E (21.42%). Five out of 28 (17.85%) patients had developed antibodies against both c and E. Conclusion. Data from this study demonstrate that the RBC alloantibody and autoantibody development rates are significant in our region. Thus, pretransfusion antibody screening needs to be initiated in eastern India in order to ensure safe transfusion practice. PMID- 26425123 TI - Occupational Exposure to Diesel Motor Exhaust and Lung Cancer: A Dose-Response Relationship Hidden by Asbestos Exposure Adjustment? The ICARE Study. AB - Background. In a French large population-based case-control study we investigated the dose-response relationship between lung cancer and occupational exposure to diesel motor exhaust (DME), taking into account asbestos exposure. Methods. Exposure to DME was assessed by questionnaire. Asbestos was taken into account through a global indicator of exposure to occupational carcinogens or by a specific JEM. Results. We found a crude dose response relationship with most of the indicators of DME exposure, including with the cumulative exposure index. All results were affected by adjustment for asbestos exposure. The dose response relationships between DME and lung cancer were observed among subjects never exposed to asbestos. Conclusions. Exposure to DME and to asbestos is frequently found among the same subjects, which may explain why dose-response relationships in previous studies that adjusted for asbestos exposure were inconsistent. PMID- 26425125 TI - The Association of Polymorphisms in Leptin/Leptin Receptor Genes and Ghrelin/Ghrelin Receptor Genes With Overweight/Obesity and the Related Metabolic Disturbances: A Review. AB - CONTEXT: Leptin and ghrelin are two important appetite and energy balance regulating peptides. Common polymorphisms in the genes coding these peptides and their related receptors are shown to be associated with body weight, different markers of obesity and metabolic abnormalities. This review article aims to investigate the association of common polymorphisms of these genes with overweight/obesity and the metabolic disturbances related to it. EVIDENCE ACQUISITION: The keywords leptin, ghrelin, polymorphism, single-nucleotide polymorphism (SNP), obesity, overweight, Body Mass Index, metabolic syndrome, and type 2 diabetes mellitus (T2DM) (MeSH headings) were used to search in the following databases: Pubmed, Sciencedirect (Elsevier), and Google scholar. Overall, 24 case-control studies, relevant to our topic, met the criteria and were included in the review. RESULTS: The most prevalent leptin/leptin receptor genes (LEP/LEPR) and ghrelin/ghrelin receptor genes (GHRL/GHSR) single nucleotide polymorphisms studied were LEP G-2548A, LEPR Q223R, and Leu72Met, respectively. Nine studies of the 17 studies on LEP/LEPR, and three studies of the seven studies on GHRL/GHSR showed significant relationships. CONCLUSIONS: In general, our study suggests that the association between LEP/LEPR and GHRL/GHSR with overweight/obesity and the related metabolic disturbances is inconclusive. These results may be due to unidentified gene-environment interactions. More investigations are needed to further clarify this association. PMID- 26425126 TI - The Association of Dairy Intake With Metabolic Syndrome and Its Components in Adolescents: Tehran Lipid and Glucose Study. AB - BACKGROUND: Epidemiological studies have shown that consumption of dairy product plays an important role in prevention and treatment of Metabolic Syndrome (MetS). OBJECTIVES: The objective of this study was to examine the association of dairy intake with MetS and its components in Tehranian adolescents. PATIENTS AND METHODS: In this cross-sectional study, 785 adolescent aged 10 to 19 years, participated from the fourth phase of the Tehran Lipid and Glucose Study. Usual dietary intake was assessed using a valid semi quantitative food frequency questionnaire. Total dairy, low fat and high fat dairy, milk, yoghurt and cheese were evaluated. Assessment of anthropometric, biochemical and blood pressure was performed and MetS was defined according to the de Ferranti criteria. RESULTS: The mean age of subjects was 14.8 +/- 2.9 years. The prevalence of MetS was 22.2% (girls: 19.5% and boys: 25.2%). The most prevalent risk factor for MetS in boys was high waist circumference (53.4%) and among girls was low HDL-C (53.1%). Energy density and intake of protein, total fat, saturated fat, cholesterol, calcium and phosphor were higher in the highest quartile of dairy consumption than the lowest quartile. After adjustments for confounders, odds ratios with 95% confidence interval for MetS in the highest quartile of total dairy, low fat dairy, high fat dairy, milk, yoghurt and cheese compared with lowest quartile were respectively 0.97 (0.57 - 1.66), 1.44 (0.83 - 2.49), 0.97 (0.56 - 1.67), 0.70 (0.42 - 1.18), 1.62 (0.99 - 2.64) and 0.72 (0.44 - 1.18). CONCLUSIONS: Results of this study did not support the hypothesis that dairy products consumption protects against MetS and its components. PMID- 26425127 TI - A Longitudinal Study of Adherence to the Mediterranean Dietary Pattern and Metabolic Syndrome in a Non-Mediterranean Population. AB - BACKGROUND: Adherence to the Mediterranean diet (MedDiet) has been proposed to reduce the risk of metabolic syndrome (MetS), but the association of the diet on MetS in non-Mediterranean populations remains unclear. OBJECTIVES: The aim of this study was to investigate whether adherence to the MedDiet is related to the incident MetS and its components during a 3-year follow-up among Iranian adults. PATIENTS AND METHODS: Longitudinal associations between the MedDiet and MetS components were investigated on 2241 adults, aged 18 - 74 years, without type 2 diabetes selected from participants of the Tehran lipid and glucose study (TLGS). The association between the MedDiet and MetS incidence was also examined in 1661 participants, free of Mets at baseline. Adherence to the MedDiet was assessed using the traditional Mediterranean diet score (MDS) and a recently posteriori adaptation of the MDS of Sofi et al. (Sofi-MDS). MetS was defined according to the recent interim consensus. RESULTS: After adjusting for potential confounders, neither higher MDS nor higher Sofi-MDS were significantly associated with the mean values of MetS components and the risk of metabolic abnormalities incidence after 3 years follow-up. During the 3 years of follow-up, 246 developed MetS were identified. In multivariable model, the adjusted odds ratio (OR) of developing MetS did not differ significantly in participants with the highest tertile of the MDS (OR (95% CI): 0.88 (0.62 - 1.23)) or sofi-MDS (OR (95% CI):1.12 (0.77 - 1.62)) compared to those in the lowest tertiles. CONCLUSIONS: Adherence to the MedDiet, according to MDS and Sofi-MDS, may not predict MetS components and MetS incidence after 3 years of follow-up in Iranian adult populations. PMID- 26425128 TI - Development of an In-House TaqMan Real Time RT-PCR Assay to Quantify Hepatitis C Virus RNA in Serum and Peripheral Blood Mononuclear Cells in Patients With Chronic Hepatitis C Virus Infection. AB - BACKGROUND: Viral load measurements are commonly used to monitor HCV infection in patients with chronic diseases or determining the number of HCV-genomes in serum samples of patients after sustained virological response. However, in some patients, HCV viral load in serum samples is too low to be detected by PCR, especially after treatment. OBJECTIVES: The aim of this study was to develop a highly specific, sensitive, and reproducible in-house quantitative PCR using specific primers and probe cited in highly conservative region of HCV genome that allows simultaneous detection of HCV genotypes 1 - 4. MATERIALS AND METHODS: In this study, three sets of primer pairs and a TaqMan probe for amplification and detection of selected region within 5'-non-coding (5'NCR) of four HCV genotypes were used. Using plasmid containing 5'NCR region of HCV, standard curve, threshold, and threshold cycle (CT) values were determined. Real-time and nested PCR were performed on HCV genotypes 1 - 4 extracted from plasma and peripheral blood mononuclear cells (PBMCs) samples collected from patients with chronic HCV infection. RESULTS: The lower limit detection of this in-house HCV real-time RT PCR was determined as 100 RNA copies/mL. Inter- and intra-assay coefficient of variation (CV) of this in-house HCV real-time RT-PCR ranged from 0.9% to 1.8% and 1.76% to 3.94%, respectively. The viral load of the genotyped samples ranged from 2.0 * 10(6) +/- 0.31 to 2.7 * 10(5) +/- 0.46 copies/mL in serum samples and 5 * 10(2) +/- 0.36 to 4.0 * 10(3) +/- 0.51 copies/10(6) cells/mL of PBMCs. CONCLUSIONS: The quite sensitive in-house TaqMan real time RT-PCR assay was able to detect and quantify all four main HCV genotypes prevailing around all geographical regions of Iran. PMID- 26425129 TI - Tocotrienol-Rich Fraction from Rice Bran Demonstrates Potent Radiation Protection Activity. AB - The vitamin E analogs delta-tocotrienol (DT3) and gamma-tocotrienol (GT3) have significant protective and mitigative capacity against the detrimental effects of ionizing radiation (IR). However, the expense of purification limits their potential use. This study examined the tocotrienol-rich fraction of rice bran (TRFRB) isolated from rice bran deodorizer distillate, a rice oil refinement waste product, to determine its protective effects against IR induced oxidative damage and H2O2. Several cell lines were treated with tocotrienols or TRFRB prior to or following exposure to H2O2 or IR. To determine the radioprotective capacity cells were analyzed for morphology, mitochondrial bioenergetics, clonogenic survival, glutathione oxidation, cell cycle, and migration rate. TRFRB displayed similar antioxidant activity compared to pure tocotrienols. Cells pretreated with TRFRB or DT3 exhibited preserved cell morphology and mitochondrial respiration when exposed to H2O2. Oxidized glutathione was decreased in TRFRB treated cells exposed to IR. TRFRB reversed mitochondrial uncoupling and protected cells migration rates following IR exposure. The protective antioxidant capacity of TRFRB treated cells against oxidative injury was similar to that of purified DT3. TRFRB effectively protects normal cells against IR induced injury suggesting that rice bran distillate may be an inexpensive and abundant alternate source. PMID- 26425130 TI - The Efficacy of Acupuncture for the Treatment of Sciatica: A Systematic Review and Meta-Analysis. AB - Background. Sciatica is one of the most frequently reported complaints; it affects quality of life and reduces social and economic efficacy. Clinical studies on the efficacy of acupuncture therapy in sciatica are increasing, while systematic reviews assessing the efficacy of acupuncture therapy are still lacking. Objective. This study aims to assess the effectiveness of acupuncture therapy for sciatica. Methods. Comprehensive searches of 8 databases were conducted up until April 2015. Outcomes included effectiveness (proportion of patients who improved totally or partly in clinical symptoms), pain intensity, and pain threshold. Effect sizes were presented as risk ratio (RR) and mean difference (MD). Pooled effect sizes were calculated by fixed effects or random effects model. Results. A total of 12 studies (involving 1842 participants) were included. Results showed that acupuncture was more effective than conventional Western medicine (CWM) in outcomes effectiveness (RR 1.21, 95% CI: 1.16-1.25), pain intensity (MD -1.25, 95% CI: -1.63 to -0.86), and pain threshold (MD: 1.08, 95% CI: 0.98-1.17). Subgroup and sensitivity analysis found that the results did not change in different treatment method and drug categories substantially. The reported adverse effects were acceptable. Conclusions. Acupuncture may be effective in treating the pain associated with sciatica. PMID- 26425131 TI - Anti-Inflammatory Effects of Cumin Essential Oil by Blocking JNK, ERK, and NF kappaB Signaling Pathways in LPS-Stimulated RAW 264.7 Cells. AB - Cumin seeds (Cuminum cyminum L.) have been commonly used in food flavoring and perfumery. In this study, cumin essential oil (CuEO) extracted from seeds was employed to investigate the anti-inflammatory effects in lipopolysaccharide- (LPS ) stimulated RAW 264.7 cells and the underlying mechanisms. A total of 26 volatile constituents were identified in CuEO by GC-MS, and the most abundant constituent was cuminaldehyde (48.773%). Mitochondrial-respiration-dependent 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) reduction assay demonstrated that CuEO did not exhibit any cytotoxic effect at the employed concentrations (0.0005-0.01%). Real-time PCR tests showed that CuEO significantly inhibited the mRNA expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), interleukin- (IL-) 1, and IL-6. Moreover, western blotting analysis revealed that CuEO blocked LPS-induced transcriptional activation of nuclear factor-kappa B (NF-kappaB) and inhibited the phosphorylation of extracellular signal regulated kinase (ERK) and c-Jun N terminal kinase (JNK). These results suggested that CuEO exerted anti inflammatory effects in LPS-stimulated RAW 264.7 cells via inhibition of NF kappaB and mitogen-activated protein kinases ERK and JNK signaling; the chemical could be used as a source of anti-inflammatory agents as well as dietary complement for health promotion. PMID- 26425132 TI - Erratum to: The effect of aging on the frequency, phenotype and cytokine production of human blood CD4 + CXCR5 + T follicular helper cells: comparison of aged and young subjects. AB - [This corrects the article DOI: 10.1186/1742-4933-11-12.]. PMID- 26425133 TI - Development of cryptococcal immune reconstitution inflammatory syndrome 41 months after the initiation of antiretroviral therapy in an AIDS patient. AB - Cryptococcal meningitis is one of the most lethal fungal infections in patients with acquired immune deficiency syndrome (AIDS). The incidence of and mortality from cryptococcal meningitis have markedly decreased since the introduction of combination antiretroviral therapy (cART). However, despite its benefits, the initiation of cART results in immune reconstitution inflammatory syndrome (IRIS) in some patients. Although IRIS is occasionally difficult to distinguish from relapse or treatment failure, the distinction is important because IRIS requires a different treatment. Here, we present the case of a patient with AIDS who developed symptoms of cryptococcal IRIS 41 months after starting cART. To the best of our knowledge, the time between cART initiation and the onset of cryptococcal IRIS in this patient is the longest that has been reported in the literature. PMID- 26425134 TI - Is DOG1 really useful in the diagnosis of salivary gland acinic cell carcinoma? - A DOG1 (clone K9) analysis in fine needle aspiration cell blocks and the review of the literature. AB - INTRODUCTION: DOG1 is a transmembrane protein originally "discovered on gastrointestinal stromal tumors," works as a calcium-activated chloride channel protein. There is a limited number of studies on the potential usage of this antibody in the diagnosis of salivary gland tumors on routine practice in cell blocks. The aim of this study was to search for the usefulness of K9 clone in oncocytic type tumors and review of the literature. MATERIALS AND METHODS: Sixty nine fine needle aspiration (FNA) cytologic materials of predominantly oncocytic morphology salivary gland tumors; acinic cell carcinoma (AciCC) (n = 8), adenoid cystic carcinoma (n = 2), pleomorphic adenoma (PA) (n = 22), Warthin tumor (WT) (n = 20), myoepithelioma (ME) (n = 5), benign oncocytoma (BeO) (n = 3), mucoepidermoid carcinoma (MEC) (n = 7), mammary analog salivary gland carcinoma (n = 2) were immunostained with DOG1 (clone K9) stain. RESULTS: Of the 8 AciCCs, 7 were observed apical-luminal positive staining, demonstrating 1-3 + intensity, and involving 40-70% of the tumor cells. One MEC of 7 (14%), 1 ME of 5 (20%), and 4 PA of 22 (18%) showed weak (1+) cytoplasmic granular staining in 5-10% of the tumor cells. Pure oncocytic neoplasms (WT, BeO) showed no expression with DOG1 K9. CONCLUSIONS: FNA is a common tool in the diagnosis and management of salivary gland tumors. DOG1-K9 clone was very useful with a unique staining pattern of apical-luminal positivity in the differential diagnosis of AciCC from other oncocytic salivary gland tumors. PMID- 26425135 TI - Merkel cell carcinoma presenting as malignant ascites: A case report and review of literature. AB - The most common site of metastasis to ascitic fluid in females is from a mullerian (ovarian) primary, whereas in males it is from the gastrointestinal tract. Metastatic Merkel cell carcinoma (MCC) to the ascitic fluid is extremely rare and may present as a diagnostic challenge on effusion cytology. In a review of the literature, there are only two case reports of metastatic MCC in pleural effusion. To the best of our knowledge, we present the first cytological diagnosis of MCC metastatic to the ascitic fluid. We describe the cytologic findings as well as the immunohistochemical stains supportive of the diagnosis. Given the fatal prognosis of this tumor compared to melanoma and rarity of its occurrence in ascitic fluid, awareness of this tumor and use of immunohistochemical stains are critical in arriving at the diagnosis. PMID- 26425136 TI - Applying the Bradford Hill criteria in the 21st century: how data integration has changed causal inference in molecular epidemiology. AB - In 1965, Sir Austin Bradford Hill published nine "viewpoints" to help determine if observed epidemiologic associations are causal. Since then, the "Bradford Hill Criteria" have become the most frequently cited framework for causal inference in epidemiologic studies. However, when Hill published his causal guidelines-just 12 years after the double-helix model for DNA was first suggested and 25 years before the Human Genome Project began-disease causation was understood on a more elementary level than it is today. Advancements in genetics, molecular biology, toxicology, exposure science, and statistics have increased our analytical capabilities for exploring potential cause-and-effect relationships, and have resulted in a greater understanding of the complexity behind human disease onset and progression. These additional tools for causal inference necessitate a re evaluation of how each Bradford Hill criterion should be interpreted when considering a variety of data types beyond classic epidemiology studies. Herein, we explore the implications of data integration on the interpretation and application of the criteria. Using examples of recently discovered exposure response associations in human disease, we discuss novel ways by which researchers can apply and interpret the Bradford Hill criteria when considering data gathered using modern molecular techniques, such as epigenetics, biomarkers, mechanistic toxicology, and genotoxicology. PMID- 26425138 TI - Is whole gland salvage cryotherapy effective as palliative treatment of haematuria in patients with locally advanced prostate cancer? Results of a preliminary case series. AB - OBJECTIVES: Locally advanced prostate cancer may cause several complications such as haematuria, bladder outlet obstruction, and renal failure due to the ureteral obstruction. Various treatments have been suggested, including radiotherapy, antifibrinolytics, bladder irrigation with alum solution, transurethral surgery and angioembolization, none of which have proven effectiveness. In the last years cryoablation has become a valid therapeutic option for prostate cancer. In our experience we used this 'new' technique as haemostatic therapy. METHODS: We selected four patients with gross haematuria affected by locally advanced hormone refractory prostate cancer, who had already been treated with primary radiotherapy. We used third-generation cryotherapy: under ultrasonographic guidance, we inserted six cryoprobes, two in each of the vascular pedicles reaching at least -60 degrees C, and three thermometers. We then induced two freeze-thaw cycles. RESULTS: After the operation the haematuria stopped in all patients and at 9-month follow up we observed a mean of four red cells (range three to five) in the urinary sediment with no evidence of bacteriuria. Prostate volume, prostate-specific antigen and postmicturition residue were significantly reduced. Qmax improved significantly too. CONCLUSION: Our experience has given us good results with minimal intra- and postoperative complications. We think that haemostatic cryotherapy as a palliative approach for locally advanced prostate cancer could represent a valid treatment option and more consideration could be given to its use. PMID- 26425139 TI - Clinical use of the beta3 adrenoceptor agonist mirabegron in patients with overactive bladder syndrome. AB - Mirabegron is a beta3 adrenoceptor agonist licensed for the treatment of overactive bladder symptoms, such as urinary urgency or urgency incontinence. beta3 adrenoceptor activation causes detrusor muscle relaxation, but mirabegron may also act by binding other targets in the bladder, and it may also reduce activity in sensory nerves. Phase III clinical trials (SCORPIO, ARIES, and CAPRICORN) evaluated mirabegron at various doses, demonstrating reduction from baseline to endpoint in mean incontinence episodes and mean number of micturitions per 24 h (coprimary endpoints), along with health-related quality of life and a range of secondary measures. Efficacy was seen in many patients who had previously discontinued antimuscarinic therapy on the grounds of lack of efficacy or poor tolerability. Treatment emergent adverse effects were documented in a long-term study (TAURUS), mostly being of mild or moderate severity. The most frequent adverse effects were hypertension, dry mouth, constipation, and headache, with a lower incidence of dry mouth than for the antimuscarinic active comparator. Efficacy and safety are not substantially different in older patients. A urodynamic safety study in men showed no consistent effect on voiding function, but a small increase in postvoid residual. Use of mirabegron in combination with alpha-adrenergic blockers does not appear to increase adverse effects. Dose reduction is needed in people with severe renal failure, or moderate hepatic failure. Dose adjustment is not needed in relation to food intake. Ongoing research is evaluating the potential for combination therapy with antimuscarinics. PMID- 26425140 TI - Tadalafil for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a review of clinical data in Asian men and an update on the mechanism of action. AB - Tadalafil, a phosphodiesterase type 5 (PDE5) inhibitor, is approved worldwide for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH-LUTS). The purpose of this narrative review is to summarize the clinical data on tadalafil 5 mg once-daily, primarily focusing on Asian men with BPH-LUTS, and to update the current understanding of the mechanism of action underlying PDE5 inhibition. Findings from studies have demonstrated that PDE5 is highly expressed in the lower urinary tract and supporting vasculature, and that PDE5 inhibition potentially decreases smooth muscle cell proliferation in the prostate, relaxes smooth muscle in the prostate, bladder neck and supporting vasculature, increases blood perfusion to the lower urinary tract, and modulates bladder afferent nerve activity. A total of 11 larger, 12-week, double-blind, randomized, placebo-controlled studies of tadalafil, including four Asian studies, have been conducted globally, enrolling >3000 men with BPH-LUTS. In addition, two long-term (42- and 52-week) studies enrolled 394 Japanese and 428 North American men, respectively, with BPH-LUTS. Overall, tadalafil 5 mg once daily resulted in significant improvements in the change from baseline to endpoint in total International Prostate Symptom Scores (IPSS), IPSS storage and voiding subscores, and IPSS quality of life index compared with placebo. Tadalafil was well tolerated and had a favorable safety profile. These findings support tadalafil 5 mg once-daily for treating men, including Asian men, with BPH LUTS. PMID- 26425141 TI - Percutaneous biopsy for risk stratification of renal masses. AB - The increased use of abdominal imaging has led to identification of more patients with incidental renal masses, and renal mass biopsy (RMB) has become a popular method to evaluate unknown renal masses prior to definitive treatment. Pathologic data obtained from biopsy may be used to guide decisions for treatment and may include the presence or absence of malignant tumor, renal cell cancer subtype, tumor grade and the presence of other aggressive pathologic features. However, prior to using RMB for risk stratification, it is important to understand whether RMB findings are equivalent to pathologic analysis of surgical specimens and to identify any potential limitations of this approach. This review outlines the advantages and limitations of the current studies that evaluate RMB as a guide for treatment decision in patients with unknown renal masses. In multiple series, RMB has demonstrated low morbidity and a theoretical reduction in cost, if patients with benign tumors are identified from biopsy and can avoid subsequent treatment. However, when considering the routine use of RMB for risk stratification, it is important to note that biopsy may underestimate risk in some patients by undergrading, understaging or failing to identify aggressive tumor features. Future studies should focus on developing treatment algorithms that integrate RMB to identify the optimal use in risk stratification of patients with unknown renal masses. PMID- 26425142 TI - Cytoreductive nephrectomy and its role in the present-day period of targeted therapy. AB - The beneficial effect of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma in the immunotherapy era was based on two prospective randomized trials. Unfortunately, such evidence does not yet exist in the present-day period of targeted therapy. Despite this, cytoreductive nephrectomy remains integral in the multimodal management of patients with metastatic renal cell carcinoma. Multiple retrospective studies as well as data from prospective studies examining targeted therapy support the continued use of cytoreductive nephrectomy in the properly selected patient. Ongoing studies will hopefully fine-tune the role and timing of cytoreductive nephrectomy in the context of targeted therapy. PMID- 26425143 TI - Clinical experience with everolimus in the second-line treatment of advanced renal cell carcinoma. AB - Everolimus is an oral inhibitor of mammalian target of rapamycin (mTOR-I) and is currently approved for the treatment of metastatic renal cell carcinoma (mRCC) after failure of first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI). In this narrative review, we aim to report the available evidence about the use of everolimus as second-line therapy for mRCC. A literature search was performed using PubMed/MEDLINE and abstracts from major conferences on clinical oncology as sources. We report data from prospective as well as retrospective and real world data studies and we analyze the safety and efficacy profile of everolimus as second-line therapy for mRCC. Although different drugs are currently available for the second-line treatment of mRCC, everolimus represents a feasible and safe option in this setting, especially for patients who have experienced high-grade toxicity or are still carrying TKI related toxicities from first-line treatment. PMID- 26425144 TI - Sterile pyuria: a forgotten entity. AB - Sterile pyuria is a common entity. Yet there are no guidelines to address this issue. We have conducted a systematic review over 20 years and reviewed the results. Guidelines for assessment, diagnosis and management are developed based on these results. PMID- 26425145 TI - Mechanisms of immunological tolerance in central nervous system inflammatory demyelination. AB - Multiple sclerosis is a complex autoimmune disease of the central nervous system that results in a disruption of the balance between pro-inflammatory and anti inflammatory signals in the immune system. Given that central nervous system inflammation can be suppressed by various immunological tolerance mechanisms, immune tolerance has become a focus of research in the attempt to induce long lasting immune suppression of pathogenic T cells. Mechanisms underlying this tolerance induction include induction of regulatory T cell populations, anergy and the induction of tolerogenic antigen-presenting cells. The intravenous administration of encephalitogenic peptides has been shown to suppress experimental autoimmune encephalomyelitis and induce tolerance by promoting the generation of regulatory T cells and inducing apoptosis of pathogenic T cells. Safe and effective methods of inducing long-lasting immune tolerance are essential for the treatment of multiple sclerosis. By exploring tolerogenic mechanisms, new strategies can be devised to strengthen the regulatory, anti inflammatory cell populations thereby weakening the pathogenic, pro-inflammatory cell populations. PMID- 26425147 TI - Atherosclerosis in psoriatic disease: latest evidence and clinical implications. AB - It is widely accepted that atherosclerosis is caused by chronic low-grade inflammation that results from an interaction between immune mechanisms and metabolic abnormalities within the vessel wall. Population-based studies have found an increased cardiovascular risk in patients with psoriasis and psoriatic arthritis (PsA). This risk is higher in patients with severe disease phenotypes, such as those with severe psoriasis and with musculoskeletal inflammation. Higher levels of inflammatory biomarkers also predict the development of clinical cardiovascular events in these patients. The effect of medications used for PsA on cardiovascular risk is limited to observational studies. Antitumor necrosis factor agents and methotrexate have been associated with reduced cardiovascular risk. These data highlight the importance of screening for cardiovascular risk factors in these patients. PMID- 26425146 TI - Making the next steps in psoriatic arthritis management: current status and future directions. AB - Psoriatic arthritis (PsA) is a chronic inflammatory condition with articular and extra-articular manifestations: peripheral arthritis, axial disease, enthesitis, dactylitis, and skin and nail disease. It is associated with cardiovascular comorbidities. It is now recognized as a new entity, different from rheumatoid arthritis and other spondyloarthritis in terms of clinical manifestations, pathogenesis, and response to therapies. Anti-tumor necrosis factors (anti-TNFs) have demonstrated clinical efficacies exceeding that of conventional disease modifying antirheumatic drugs (DMARDs). The current treatment paradigms recommend early diagnosis and treatment, and a strategic and target orientated approach, aiming at a low disease activity status. New understanding in the immunopathogenesis of PsA has led to new treatment targets. This review addresses the evidence of current treatment for each of the domains as an aid to the clinician managing these patients in the clinic. Some new therapeutic targets are presented. We highlight the importance of development and validation in outcome measures, including that of composite scores that capture various disease domains that will facilitate future clinical trials to inform the best treatment. PMID- 26425148 TI - Sarcoidosis: a rheumatologist's perspective. AB - Sarcoidosis is a systemic disorder of unknown etiology, which may involve various tissues and organs and is characterized by a noncaseating granuloma reaction. While pathogenesis is not yet clear, cellular immune system activation and nonspecific inflammatory response occur secondarily to several genetic and environmental factors. T helper 1-cells and macrophage-derived pro-inflammatory cytokines stimulate the inflammatory cascade and formation of granuloma occurs as a result of tissue permeability, cell influx, and local cell proliferation. The different prevalence, clinical results, and disease course observed in different races and ethnic groups, is an indicator of the heterogeneous nature of the disease. Sarcoidosis may mimic and/or may occur concomitantly with numerous primary rheumatic diseases. This disease most commonly presents with bilateral hilar lymphadenopathy, pulmonary infiltrations, and skin and eye lesions. Locomotor system involvement is observed at a range of 15% and 25%. Two major joint involvements have been described: acute and chronic form. The most common form, the acute form, may be the first sign of sarcoidosis and present with arthralgia, arthritis, or periarthritis. Chronic sarcoid arthritis is usually associated with pulmonary parenchymal disease or other organ involvement and occurs rarely. While asymptomatic muscular involvement is reported between 25% and 75%, symptomatic muscular involvement is very rare. Symptomatic myopathy may present as three different types: chronic myopathy, palpable nodular myositis, or acute myositis. Even if rare, 2-5% of cases may exhibit osseous involvement and it is frequently associated with lupus pernio, chronic uveitis, and multisystemic disease. Sarcoidosis was reported together with different rheumatologic diseases. There are studies showing that sarcoidosis may mimic the clinical and laboratory findings of these disorders. Nonsteroidal anti-inflammatory drugs and corticosteroids are used for treating the symptoms of rheumatologic findings. In patients who are unresponsive to corticosteroids, immunosuppressive and anti tumor necrosis factor alpha drugs may be used. In this review, the incidence of rheumatologic symptoms, the clinical findings, and the treatment of rheumatologic manifestations of sarcoidosis are discussed. PMID- 26425149 TI - Towards an understanding of the role of DNA methylation in rheumatoid arthritis: therapeutic and diagnostic implications. AB - The term 'epigenetics' loosely describes DNA-templated processes leading to heritable changes in gene activity and expression, which are independent of the underlying DNA sequence. Epigenetic mechanisms comprise of post-translational modifications of chromatin, methylation of DNA, nucleosome positioning as well as expression of noncoding RNAs. Major advances in understanding the role of DNA methylation in regulating chromatin functions have been made over the past decade, and point to a role of this epigenetic mechanism in human disease. Rheumatoid arthritis (RA) is an autoimmune disorder where altered DNA methylation patterns have been identified in a number of different disease-relevant cell types. However, the contribution of DNA methylation changes to RA disease pathogenesis is at present poorly understood and in need of further investigation. Here we review the current knowledge regarding the role of DNA methylation in rheumatoid arthritis and indicate its potential therapeutic implications. PMID- 26425150 TI - Volume change theory for syringomyelia: A new perspective. AB - BACKGROUND: The etiopathogenesis of syringomyelia is still an enigma. The authors present a novel theory based on fluid dynamics at the craniovertebral (CV) junction to explain the genesis of syringomyelia (SM). The changes in volume of spinal canal, spinal cord, central canal and spinal subarachnoid space (SSS) in relation to the posterior fossa have been analysed, specifically during postural movements of flexion and extension. The effect of fluctuations in volume of spinal canal and its contents associated with cerebrospinal fluid (CSF) flow dynamics at the CV junction have been postulated to cause the origin and propagation of the syringomyelia. The relevant literature on the subject has been reviewed and the author's theory has been discussed. CONCLUSION: Volume of spinal canal in flexion is always greater than that in extension. Flexion of spine causes narrowing of the ventral subarachnoid space (SAS) and widening of dorsal SAS while extension causes reverse changes leading to fluid movement in dorsal spinal SAS in flexion and ventral spinal SAS in extension. Cervical and lumbar spinal region with maximum bulk hence maximum area and volume undergo maximum deformation during postural changes. SSS CSF is the difference between the volume of spinal canal and spinal cord, varies in flexion and extension which is compensated by changes in posterior fossa (CSF) volume in normal circumstances. Blocked SAS at foramen magnum donot permit spinal SAS CSF exchange which during postural changes is compensated by cavitatory/cystic (syrinx) change at locations in cervical and lumbar spine with propensity for maximum deformation. Augmentation of posterior fossa volume by decompression helps by normalization of this CSF exchange dynamics but immobilizing the spinal movement theoretically will cease any dynamic volume changes thereby minimizing the destructive influence of the fluid exchange on the cord. Thus, this theory strengthens the rational of treating patients by either methodology. PMID- 26425151 TI - Outcome of revascularization in moyamoya disease: Evaluation of a new angiographic scoring system. AB - BACKGROUND: Moyamoya disease (MMD) is a chronic progressive cerebrovascular occlusive disease affecting commonly the anterior circle of Willis. Matushima grade inadequately reflects the angiographic changes postrevascularization procedure. AIMS: To analyze the clinical and angiographic outcome of revascularization procedures (direct [ST-middle cerebral artery (MCA) anastomosis] and indirect [encephalo-duro-arterio-myo-synangiosis (EDAMS)]) in MMD and validate a new angiographic scoring system. MATERIALS AND METHODS: Retrospective study included symptomatic patients of MMD who underwent revascularization; both indirect and combined methods between January 2002 and April 2012. Follow-up angiography was done after at least 3 months. We devised a novel scoring system the "angiographic outcome score" (AOS) including reformation of distal MCA and anterior cerebral artery, regression of basal moyamoya vessels, leptomeningeal collaterals and overall perfusion. AOS was applied to the angiograms independently by a neuroradiologist and a neurosurgeon that were blinded toward its preoperative or postoperative status. RESULTS: Totally 33 patients underwent 36 EDAMS and 4 combined procedures (EDAMS + ST-MCA bypass). The mean follow-up was 20 months. None had recurrent transient ischemic attack or fresh infarct. Postoperative AOS was significantly higher than preoperative AOS. The Spearman rho showed positive correlation between Matushima grade and postoperative AOS. Significant regression of basal moyamoya vessels and increase in number of loci of transdural collaterals was seen. CONCLUSIONS: EDAMS is a simple yet effective method of revascularization in both pediatric as well as adult age groups. AOS is a simple, precise and easily reproducible scoring system, which reflects the favorable angiographic changes after revascularization. PMID- 26425152 TI - Attention and executive functions in microsurgically treated patients after subarachnoid hemorrhage. AB - OBJECTIVES: This research aimed to assess attention and executive functions in subarachnoid hemorrhage (SAH) patients. METHODS: The prospective, controlled, longitudinal study was conducted. There were two groups of patients (SAH and lumbar microdiscectomy groups), and all of them were operated on by a single neurosurgeon (KD) in the same institution. Preoperatively, SAH patients were in the Hunt-Hess Grade I and II. They did not develop any focal neurological deficit or hydrocephalus postoperatively. The patients were tested in 2-time points: 15 and 45 days after microsurgery with a battery of tests and questioners consisting of the Trail Making Test, the Sustained Attention to Response Task, the Hayling Sentence Completion Test, The Attention/Concentration test of Attention, the Wechsler Adult Intelligence Scale (verbal part). Results between groups were compared (sex, age; years of education and verbal IQ). RESULTS: It was found the presence of lower attention and executive function test scores in the SAH group of patients with a trend of improving during the time. CONCLUSION: The detailed neuropsychological assessment of operated patients who sustained SAH and were without the focal neurological deficit postoperatively, showed declination in their attention and executive function with a trend of cognitive recovery as time passes by. PMID- 26425153 TI - Multiple glioblastomas: Are they different from their solitary counterparts? AB - CONTEXT: Multiple glioblastomas (GBMs) have a reported incidence of 2-20%. AIMS: We intend to study these subsets of GBMs to know whether these are similar to their solitary counterparts. SETTING AND DESIGN: A retrospective study. MATERIALS AND METHODS: We analyzed 7 cases of biopsy-proven multiple GBMs. Multiple GBMs were described if there were >1 lesion which was at least 1 cm apart. The clinical data, radiological features, histopathological and immunohistochemical analysis and follow-up were recorded. RESULTS: The mean age was 45 years (range 17-69 years). All cases presented with features of raised intracranial pressure (ICP). Totally, 3 cases presented with hemiparesis and 2 cases with altered sensorium and generalized tonic clonic seizures each. The median Karnofsky performance status (KPS) was 50. Mean duration of symptoms was 40 days. All lesions were contrast enhancing (2 with homogenous enhancement and 5 had ring enhancement). Total excision of the lesion causing mass effect was done in all cases. Histopathologically, small cells were significantly present in 4 cases, and satellitosis was seen in 5 cases. Glial fibrillary acidic protein (GFAP) was absent in all cases in which small cells were significant. In these 4 cases, the proliferation index ranged from 40% to 95%. Totally, 3 patients died within 2 months of surgery, whereas remaining 4 patients underwent chemo-radiotherapy. CONCLUSIONS: We conclude that the cases usually present with features of raised ICP and poor KPS. Histopathologically these lesions show significant small cell population, satellitosis, and GFAP negativity. PMID- 26425155 TI - Imaging characteristics of supratentorial ependymomas: Study on a large single institutional cohort with histopathological correlation. AB - BACKGROUND: Supratentorial ependymoma (STE) is a tumor whose unique clinical and imaging characteristics have not been studied. Histopathologically, they resemble ependymoma elsewhere. We retrospectively reviewed the imaging findings with clinicopathological correlation in a large number of patients with STE to identify these characteristics. MATERIALS AND METHODS: Computed tomography (CT) magnetic resonance images (MRI), pathology reports, and clinical information from 41 patients with pathology-confirmed STE from a single institution were retrospectively reviewed. CT and MRI findings including location, size, signal intensity, hemorrhage, and enhancement pattern were tabulated and described separately in intraventricular and intraparenchymal forms. RESULTS: STE was more common in pediatric age group and intraparenchymal was more common than intraventricular form. The most common presentation was features of raised intracranial tension. There were equal numbers of Grade II and Grade III tumors. The imaging characteristics in adult and pediatric age group were similar. The tumor was large and had both solid and cystic components. Advanced imaging such as diffusion, perfusion, and spectroscopy were suggestive of high-grade tumor. Only differentiating factor between Grade II and Grade III was the presence of calcification. 1234 rule and periwinkle sign which we have described in this article may help characterize this tumor on imaging. CONCLUSION: This series expands the clinical and imaging spectrum of STE and identifies characteristics that should suggest consideration of this uncommon diagnosis. PMID- 26425154 TI - Safe and accurate placement of thoracic and thoracolumbar percutaneous pedicle screws without image-navigation. AB - BACKGROUND: Percutaneous pedicle screw placement is now commonly used to treat spinal instability. It is imperative, especially at thoracic levels, to avoid damage to adjacent neurovascular structures. Although more technically demanding when compared with the lumbar spine, we believe that the percutaneous placement of thoracic pedicle screws can be performed safely without image-navigation. PURPOSE: The purpose was to evaluate the safety of percutaneous pedicle screw placement in the thoracic and thoracolumbar spine without image-navigation. STUDY DESIGN/SETTING: A retrospective study at a single institution. PATIENT SAMPLE: Patients over the age of 18 years who presented with degenerative disease, trauma or tumor that required surgical stabilization. OUTCOME MEASURES: Our outcomes included postoperative plain film X-rays and computerized tomography (CT). MATERIALS AND METHODS: We performed a retrospective study of patients who underwent percutaneous pedicle screw placement without image-navigation between T2 and L2. RESULTS: Between 2005 and 2011, a total of 507 pedicle screws were placed in 120 patients. The indications included trauma (17%), tumor (8%), and degenerative conditions (75%). The mean age was 61.3 years (range: 20-81 years). Fifty-seven percent were male, and 43% were female. The mean blood loss was 297 +/- 40 ml. All patients underwent postoperative anterior-posterior and lateral films that showed safe placement of pedicle screws. Moreover, 57% of patients underwent postoperative CT imaging. There was 1 (0.4%) medial breach and 13 (5%) lateral breaches of the pedicle screw patients who underwent CT imaging as read by an independent neuroradiologist. None of the breaches resulted in adverse neurological sequelae either immediately after or at most recent follow-up. CONCLUSION: Thoracic and thoracolumbar percutaneous pedicle screw placement can be performed safely and accurately without image-navigation. PMID- 26425156 TI - The AOSpine thoracolumbar spine injury classification system: A reliability and agreement study. AB - AIM: Recently, AOSpine trauma knowledge forum proposed the AOSpine thoracolumbar injury classification (AOSTLIC) system and suggested that it was reliable. However, reliability data from additional institutions for the AOSTLIC system are not available. This study was to examine the reliability of the AOSTLIC system in patients with thoracolumbar (TL) fractures. MATERIALS AND METHODS: Between August 2009 and June 2012, 56 patients with 74 levels traumatic TL spinal injuries were recruited. Two classifiers, consisting of two spine surgeons, assessed clinical and imaging data. Initially, one surgeon reviewed the data in order to classify and calculate injury severity score according to the AOSTSIC system. This process was repeated on a 5-week interval by another surgeon. Then we analyzed data for intra-observer and inter-observer reliability using the kappa statistic (k). Finally, validity was assessed using the known-groups comparison. RESULTS: The mean age of patients was 59.5 +/- 11.5 years. The kappa values for the AOSTSIC system for intra-observer and inter-observer reliability ranged from 0.83 to 0.89, indicating nearly perfect agreement agreements. Known-groups analysis showed satisfactory results. The AOSTSIC system discriminated well between sub groups of patients who differed in Oswestry disability index. CONCLUSION: The findings showed that the morphologic classification in AOSTSIC system appears to be reliable and reproducible classification. PMID- 26425158 TI - The long-term efficacy of pedicular screw fixation in patients suffering from thoracolumbar burst fractures without neurological deficit. PMID- 26425157 TI - The long-term efficacy of pedicular screw fixation at patients suffering from thoracolumbar burst fractures without neurological deficit. AB - OBJECTIVES: Treatment of choice at stable burst fracture is still a matter of debate. The aim of this study is assessment of health-related quality of life (HRQOL) regarding short form-36 (SF-36) and its correlation with kyphosis in patients affected by thoracolumbar burst fracture without neurological deficit undergoing posterior short segment pedicular screw fixation. MATERIALS AND METHODS: Twenty patients with thoracolumbar burst fractures without neurological deficits, meeting our criteria were enrolled in this study. The patients underwent short segment pedicular screw fixation. After 2 years of follow-up, the outcome assessment was performed with evaluating HRQOL; SF-36. The mean +/- standard deviation was measured at each eight category of SF-36 and compared with normative values of Iran. The correlation of Cobb angle and body pain was analyzed by linear regression. RESULTS: The study detected reduced quality of life (QOL), with total mean of 49.7 +/- 14 and physical function grade of 61.2 +/ 22 which was significantly lower than Iran normative reported as 85.9 +/- 19. Fifty percent still suffered from moderate to severe pain and Cobb angle had no statistically significant correlation with body pain. CONCLUSIONS: It seems that surgical treatment could not improve pain related disability of patients with stable thoracolumbar burst fracture at long term follow up. PMID- 26425159 TI - Spinal tumors: Trends from Northern India. AB - INTRODUCTION AND METHODS: We retrospectively analyzed 111 patients with spinal tumors operated over a period of 9 years to observe the relative frequency of different lesions, their clinical profile, functional outcome and prognostic factors. 30/111 (27%) were extradural, 40/111 (36.1%) were intradural extramedullary (IDEM) and 41/111 (36.9%) were intramedullary spinal cord tumors (IMSCTs). Mean age at surgery was 30.81 years (range 1-73 years). The average preoperative duration of symptoms was 16.17 months (15 days to 15 years). Major diagnoses were ependymomas and astrocytomas in IMSCT group, schwanommas and neurofibromas in IDEM group, and metastasis, lymphoma in extradural group. The common clinical features were motor weakness in 78/111 (70.27%), sensory loss in 55/111 (49.54%), pain 46/111 (41.44%), and sphincter involvement in 47/111 (42.43%) cases. RESULTS: Totally, 88/111 (79.27%) patients had improvement in their functional status, 17/111 (15.31%) remained same, and 6/111 (5.4%) were worse at time of their last follow-up. The mean follow-up was 15.64 months (1.5 m(-10) years). Totally, 59 out of 79 patients, who were dependent initially, were ambulatory with or without the aid. Most common complication was persistent pain in 10/111 (9%) patients and nonimprovement of bladder/bowel symptoms in 7/111 (6.3%). One patient died 3 months after surgery. CONCLUSIONS: (1) Congenital malformative tumors like epidermoids/dermoids (unrelated to spina bifida) occur more frequently, whereas the incidence of spinal meningioma is less in developing countries than western populations. (2) The incidence of intramedullary tumors approaches to that of IDEM tumors. Intramedullary tumors present at a younger age in developing countries. (3) Rare histological variants like primitive neuroectodermal tumors should also be considered for histological differential diagnosis of spinal tumors. (4) Preoperative neurologic status is the most important factor related to outcome in spinal tumors. PMID- 26425160 TI - Clinical profile and outcomes in brainstem glioma: An institutional experience. AB - AIM OF THE STUDY: This study was to analyze the clinical outcomes of brain stem glioma treated with radiation therapy (RT) in our institution. MATERIAL AND METHODS: Records of 48 patients with brainstem glioma treated between January 2007 and January 2013 were reviewed. Demographic variables, clinical variables, radiological findings and treatment details with respect to age, sex, location of tumor ( pontine Vs non pontine ), signs and symptoms, RT dose, follow up period and outcomes were recorded. Patients were subdivided into two groups based on their age, age <15 years (Group I) and age >=15 yrs (Group II). RESULTS: The median age at diagnosis was 10 years (range 4-50). Male to female ratio was 11:10. Of the 48 cases analyzed, 27 patients (56%) were in group I and 21 (44%) were in group II. Radiologically, 90.5% had involvement of pons. 10 (21%) patients received RT dose >60 Gy and 38 (79 %) patients received RT dose of 54-60 Gy. Median overall survival was 7months (range 3-44 months). Median overall survival in Group I and Group II was 4 months and 10 months respectively (P = 0.042). CONCLUSIONS: Brain stem glioma in pediatric age group is associated with worse outcomes than in adults. PMID- 26425161 TI - Extracranial to intracranial by-pass anastomosis: Review of our preliminary experience from a low volume center in Egypt. AB - BACKGROUND: Cerebral revascularization is a useful microsurgical technique for the treatment of steno-occlusive intracranial ischemic disease, complex intracranial aneurysms that require deliberate occlusion of a parent artery and invasive skull base tumors. We describe our preliminary experience with extracranial-to-intracranial by-passes at a low volume center; and discuss clinical indications and microsurgical techniques, challenges in comparison to large advanced referral centers. MATERIALS AND METHODS: Twenty-seven patients with hemodynamic ischemia or complex aneurysms or skull base tumors were operated at Cairo University Hospitals in the period between May 2009 and June 2014. All patients operated by a low flow by-pass were operated through a superficial temporal artery to middle cerebral artery (MCA) anastomosis. All patients chosen for a high flow by-pass were operated using a radial artery graft interposed between the MCAs distally and the common or the external carotid artery proximally. Patency was confirmed at the end of surgery using appearance on the table and confirmed after surgery by transcranial color-coded duplex or computed tomography angiography. All patient data were prospectively collected and retrospectively analyzed at the end of surgery. RESULTS: Nineteen patients (70.4%) were operated upon for flow augmentation and eight patients (29.6%) were operated upon for flow replacement. A total of 30 anastomoses were performed. All except one were patent which gives a patency rate of 96.3%. There was one death in the present series resulting from a hyperperfusion syndrome. 89.5% of patients with hemodynamic ischemia stopped having symptoms after surgery. All but one patient operated for hemodynamic ischemia showed a considerable cognitive improvement after surgery. None of the patients operated upon for flow replacement showed improvement of oculomotor nerve function in spite of adequate intraoperative decompression. All patients treated for flow replacement showed the absence of recurrence on follow-up. CONCLUSION: Our initial results for both low and high flow by-pass procedures in our low volume center indicate that such complex surgical procedures are possible with results comparable to those obtained in other larger referral centers throughout the world. This procedure not only represents a more definitive treatment when compared to other endovascular or radiation treatments but is also much less costly when compared to other treatment modalities. PMID- 26425162 TI - Treatment of arteriovenous malformation with high-flow fistula and bilateral transverse-sigmoid sinuses stenosis resulting diffuse cortical vein engorgement and symptoms resembling carotid-cavernous fistula. AB - Patients harboring arteriovenous malformations (AVMs) may present with focal neurological deficit, seizures, hemorrhage or be completely asymptomatic. This diversity in manifestation of AVM is related to the individual characteristics of AVMs such as size, location, configuration of feeding arteries, and drainage veins. Treating the AVMs with high-flow fistula and downstream sinuses occlusion is challenging. The authors reported their experience of treating this kind of AVM. The high venous pressure caused diffuse cortical venous regurgitation and engorgement of left superior ophthalmic vein and symptoms resembling carotid venous fistula. To avoid possible reflux of embolization materials to cortical veins and facilitate surgical treatment, the bilateral transverse sinuses were re canalized first. The venous pressure was measured through left transverse sinus, and it decreased significantly from 50 mmHg to 20 mmHg after bilateral sinus stenting. The AVM was then embolized and excised uneventfully. PMID- 26425163 TI - Ruptured concomitant dermoid cysts of conus medullaris and cervico medullary junction. AB - Cranio spinal dermoid tumors are rare, benign, slow growing congenital, cystic uni or multi locular tumors, which arise from the inclusion of epithelial tissue within the neural grove during embryonic development.[1] In this case report, we present an uncommon presentation, of a case of concomitant dermoid cysts at conus medullaris and cervico medullary junction that ruptured into the central canal. PMID- 26425164 TI - Enigmatic intracranial cyst causing diplopia and trigeminal neuralgia. AB - Chronic compression by intracranial cystic lesions can cause cranial nerve palsies and bony changes. With the advent of imaging techniques, grossly accurate diagnosis is possible. However, few cases do surprise the clinicians both intra, and postoperatively. A 27-year-old male presented to us with complaints of double vision for 4 months followed by sharp, shooting pain in the left V1 and V2 distribution for 1-month duration, on examination, he had left lateral palsy and decreased pin prick and temperature sensation in V1 distribution. On computed tomography scan, a cystic lesion noted which is isodense in the middle cranial fossa with erosion of the underlying bone. On magnetic resonance imaging lesion was iso to hyperintense on T1-Weighted and hyperintense on T2-Weighted, brilliantly enhancing on contrast administration. Provisional diagnosis was trigeminal schwannoma, left temporal craniotomy and total excision of the cyst done. Histopathological examination showed cyst wall lined with collagen. Postoperatively patient neuralgic pain subsided with persisting sixth nerve palsy. PMID- 26425165 TI - Rare occurrence of intracranial epidermoid tumor in an unusual location with atypical radiological features. AB - Intracranial epidermoid tumors are benign rare tumors that arise due to dysembryogenesis. Thought rare, they have characteristic radiological features such as their magnetic resonance imaging signal intensities and a typical location. We present a rare case of intracranial epidermoid tumor in a young female patient that was unusually located within the left frontal lobe and had certain atypical radiological findings. Preoperatively, this lesion was erroneously presumed to be a low grade glioma or a dermoid. Therefore, this case report prompts us to include atypical epidermoid cyst in the list of differential diagnosis for nonenhancing lobar tumors. PMID- 26425166 TI - Giant hydatid cyst in the posterior fossa of a child. AB - The hydatid cyst (HC) is endemic in Mediterranean region including Syria. The central nervous system is involved in 2-3% of cases. HC in cerebellum is very rare. We report a case that presented as an emergency for high intracranial pressure and deteriorating Glascow coma scale. Close monitoring and precise surgical management using Dowling's technique resulted in very good outcome with full recovery. We highlight the need for very careful surgical treatment because cyst rupture and secondary hydatidosis due to spillage of the cyst contents can dramatically worsen the outcome. HC should be taken into consideration in countries where hydatid infestation is endemic. PMID- 26425167 TI - Rhabdoid meningioma in the petroclival region: An atypical meningioma in an atypical site. PMID- 26425168 TI - The unusual angiographic course of intracranial pseudoaneurysms. AB - Although rare, traumatic intracranial pseudoaneurysms remain one of the most difficult vascular lesions to diagnose and treat. A 55-year-old male patient underwent endoscopic endonasal transphenoidal resection for a pituitary macroadenoma. The operation was complicated by an arterial bleed. The initial angiogram revealed pseudoaneurysm of the anterior choroidal artery. Although the pseudoaneurysm completely disappeared on the second angiogram, it was surprisingly found to have enlarged on the third angiogram. The lesion was successfully treated with flow-diversion using a pipeline embolization device. The present case demonstrates that the natural history of iatrogenic pseudoaneurysms may be unpredictable and misleading. Traumatic pseudoaneurysms should, therefore, be carefully followed when conservative treatment is elected or when the lesion seems to have spontaneously regressed. Flow-diversion seems to be a reasonable treatment option. PMID- 26425169 TI - A case of early extraneural medulloblastoma metastases in a young adult. AB - Extraneural metastases are a relatively rare manifestation of the primary brain tumors, and a major part of the cases has been associated with initial medulloblastoma. Herein, we present the case of a young female adult diagnosed and operated for medulloblastoma. The patient developed extraneural metastases in the first postoperative year. The condition exhibited an aggressive course of development, and the applied treatment approaches were unable to halt its progression. A short literature review identifies the predictive factors determining both prognosis and treatability of the condition; the current limitations and future perspectives of the treatment options are discussed. PMID- 26425170 TI - Enchondroma of the cervical spine in young woman: A rare case report. AB - Enchondroma is a type of benign cartilaginous bone tumor. Enchondroma of the spine is very rare. There are only a few cases of enchondromas located in the lamina of the cervical spine have been reported. Therefore, we report a case of enchondroma in the cervical spine. A 24-year-old female patient presented with a history of neck pain, restriction of neck movement, pain and numbness along the right scapula, and weakness accompanied by wasting of the right hand. Presumptive diagnoses included bony tumors such as an aneurysmal bone cyst or a giant cell tumor. Radiologic examinations revealed a round tumor in the right lamina of C4 with extracortical extension and foramen of C4-5. C4 right hemilaminectomy and facetectomy were performed with near complete removal of the tumor. On histological examination, the tumor was confirmed to be an enchondroma. At the 6 month follow-up, a computed tomography scan showed no recurrence with good alignment. PMID- 26425171 TI - Incidental frontal lobe mixed density epidermoid tumor in a patient of head injury: A rare case report. AB - The incidence of the epidermoid tumor is approximately 0.2-1.8% of all intracranial tumors. Epidermoid tumors are typically intradural, but extra-axial in location and only rarely found within the brain substance. We are reporting the first case of incidental mixed density frontal epidermoid tumor in a patient of head injury. Difficulty in the preoperative diagnosis and uncommon presentation of the intracranial epidermoid tumor prompted us to report this case. PMID- 26425172 TI - Spinal neural fibrolipoma: A case report and review of the literature. AB - Neural fibrolipoma is characterized by infiltration of the epineurium by adipose and fibrous tissue. Intradural spinal cases are extremely rare. We report an unusual case of spinal neural fibrolipoma. A 31-year-old pregnant woman presented due to weakness of right leg (muscle strength 2/5). Magnetic resonance (MR) evaluation of the spine revealed an extramedullary intradural mass at the T1-T4 level. MR findings were suggesting a dermoid cyst or a lipoma. Subtotal surgical excision of the tumor was done. Histopathological examination showed enlarged nerve bundles infiltrated by fibroadipose tissue. Thus, the diagnosis of neural fibrolipoma was established. One month after surgery, lumbar MR showed residual tumor tissue, but successful decompression of the spinal cord. Six months after surgery, the neurological examination, muscle strength 4/5 evaluated. Neural fibrolipoma is characterized by infiltration of the epineurium by adipose and fibrous tissue. The tissue grows between and around nerve bundles thereby causing enlargement of the affected nerve. Neural fibrolipoma is a benign lesion with no effective therapy. Surgical excision usually causes severe damage of the involved nerve. Although spinal cases are extremely rare, it should be included in the differential diagnosis of extramedullary intradural masses. PMID- 26425173 TI - A rare case of neurofibromatosis - type 1. AB - Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is an autosomal dominant familial tumor syndrome. Glioblastoma is a malignant brain tumor but is a rare occurrence in patients with NF1. Here, we report a rare occurrence of glioblastoma in a 60-year-old man with NF1, who presented with headache, neck pain, and gait unsteadiness of 3 days duration. He also had postural hypotension. Motor examination revealed left hemiparesis. Multiple subcutaneous soft swellings and multiple cafe-au-lait spots were seen all over his body. He also had inguinal and axillary freckling. Abdominal imaging revealed a right suprarenal mass suggestive of cystic pheochromocytoma. Brain imaging revealed a predominantly cystic intra-axial right frontal space occupying lesion (SOL) with enhancing solid component, perilesional edema, and mass effect. The patient underwent laparoscopic removal of right adrenal mass after being adequately "blocked" by an alpha blocker-prazosin. Thereafter, he underwent right frontal craniotomy and gross total excision of right frontal infiltrative SOL. The postoperative period was uneventful. Patient underwent adjuvant radiotherapy and chemotherapy. PMID- 26425174 TI - Multiple meningiomas consisting of fibrous meningioma, transitional meningioma, and meningotheliomatous meningioma in one adult patient. AB - Multiple histopathology of meningioma is a condition in which the patient has more than one histopathology feature of meningioma in different intracranial locations, with or without sign of neurofibromatosis. Meningiomas are the most common, non-glial, primitive intracranial tumors; their prevalence among operated tumors is around 13-19%. They may occur at any age, but have a peak incidence around 45 years of age. The incidence of multiple intracranial meningiomas varies from 1% to 10% in different series, and the frequency of multiple meningiomas without neurofibromatosis was reported to be <3%. PMID- 26425175 TI - "Giant" terminal myelocystocele: A rare variant of spinal dysraphism. AB - Terminal myelocystocele (TMC) is a rare form of spinal dysraphism. They constitute approximately 5% of skin covered lumbosacral masses. The TMC is composed of a low-lying conus medullaris with cystic dilatation of caudal central canal and a surrounding meningocele that extends from the conus to the skin. A 2 year-old female child presented with a large lumbosacral mass and weakness of both lower limbs since birth. Magnetic resonance imaging revealed a giant TMC. The child was operated on successfully. This is an interesting and rare case of "giant" TMC with partial sacral agenesis. PMID- 26425177 TI - New depsidones and isoindolinones from the mangrove endophytic fungus Meyerozyma guilliermondii (HZ-Y2) isolated from the South China Sea. AB - Three new depsidones, botryorhodines E-G (1-3), and two new isoindolinones, meyeroguillines A and B (7 and 9), along with five known compounds were isolated from an endophytic fungus Meyerozyma guilliermondii, derived from the mangrove plant Kandelia obovata. Their structures were elucidated by 1D and 2D NMR spectroscopy and high resolution mass spectrometry (HREIMS). Compounds 1-6 exhibited strong alpha-glucosidase inhibitory activity with IC50 values ranging from 2.1 to 13.3 MUM. Moreover, kinetic studies of compounds 2 and 6 showed that both of them were noncompetitive inhibitors of alpha-glucosidase. PMID- 26425176 TI - New palladium-oxazoline complexes: Synthesis and evaluation of the optical properties and the catalytic power during the oxidation of textile dyes. AB - The present paper describes the synthesis of new palladium-oxazoline complexes in one step with good to high yields (68-95%). The oxazolines were prepared from enantiomerically pure alpha-aminoalcohols. The structures of the synthesized palladium complexes were confirmed by NMR, FTIR, TOFMS, UV-visible spectroscopic analysis and X-ray diffraction. The optical properties of the complexes were evaluated by the determination of the gap energy values (E g) ranging between 2.34 and 3.21 eV. Their catalytic activities were tested for the degradation of Eriochrome Blue Black B (a model of azo dyes) in the presence of an ecological oxidant (H2O2). The efficiency of the decolorization has been confirmed via UV visible spectroscopic analysis and the factors affecting the degradation phenomenon have been studied. The removal of the Eriochrome reached high yields. We have found that the complex 9 promoted 84% of color elimination within 5 min (C 0 = 30 mg/L, T = 22 degrees C, pH 7, H2O2 = 0.5 mL) and the energetic parameters have been also determined. PMID- 26425178 TI - The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry. AB - The implementation of continuous flow processing as a key enabling technology has transformed the way we conduct chemistry and has expanded our synthetic capabilities. As a result many new preparative routes have been designed towards commercially relevant drug compounds achieving more efficient and reproducible manufacture. This review article aims to illustrate the holistic systems approach and diverse applications of flow chemistry to the preparation of pharmaceutically active molecules, demonstrating the value of this strategy towards every aspect ranging from synthesis, in-line analysis and purification to final formulation and tableting. Although this review will primarily concentrate on large scale continuous processing, additional selected syntheses using micro or meso-scaled flow reactors will be exemplified for key transformations and process control. It is hoped that the reader will gain an appreciation of the innovative technology and transformational nature that flow chemistry can leverage to an overall process. PMID- 26425180 TI - Intermolecular addition reactions of N-alkyl-N-chlorosulfonamides to unsaturated compounds. AB - N-Alkyl-N-chlorosulfonamides add to alkenes under copper(I) catalysis. In reactions of styrene derivatives with terminal double bonds the addition products were obtained in excellent yield and high regioselectivity. Lower yields are obtained in addition reactions to non-aromatic alkenes. The reaction most likely proceeds via a redox catalysis and amidyl radicals, a concerted mechanism has been ruled out and a polar mechanism via chloronium ions would lead to the opposite regiochemistry. PMID- 26425179 TI - Synthesis of icariin from kaempferol through regioselective methylation and para Claisen-Cope rearrangement. AB - The hemisynthesis of the naturally occurring bioactive flavonoid glycoside icariin (1) has been accomplished in eleven steps with 7% overall yield from kaempferol. The 4'-OH methylation of kaempferol, the 8-prenylation of 3-O methoxymethyl-4'-O-methyl-5-O-prenyl-7-O-benzylkaempferol (8) via para-Claisen Cope rearrangement catalyzed by Eu(fod)3 in the presence of NaHCO3, and the glycosylation of icaritin (3) are the key steps. PMID- 26425181 TI - A new and efficient procedure for the synthesis of hexahydropyrimidine-fused 1,4 naphthoquinones. AB - A new and efficient method for the synthesis of hexahydropyrimidine-fused 1,4 naphthoquinones in one step with high yields from the reaction of lawsone with 1,3,5-triazinanes was developed. PMID- 26425182 TI - Development of variously functionalized nitrile oxides. AB - N-Methylated amides (N,4-dimethylbenzamide and N-methylcyclohexanecarboxamide) were systematically subjected to chemical transformations, namely, N-tosylation followed by nucleophilic substitution. The amide function was converted to the corresponding carboxylic acid, esters, amides, aldehyde, and ketone upon treatment with hydroxide, alkoxide, amine, diisobutylaluminium hydride and Grignard reagent, respectively. In these transformations, N-methyl-N tosylcarboxamides behave like a Weinreb amide. Similarly, N-methyl-5 phenylisoxazole-3-carboxamide was converted into 3-functionalized isoxazole derivatives. Since the amide was prepared by the cycloaddition reaction of ethynylbenzene and N-methylcarbamoylnitrile oxide, the nitrile oxide served as the equivalent of the nitrile oxides bearing a variety of functional groups such as carboxy, alkoxycarbonyl, carbamoyl, acyl and formyl moieties. PMID- 26425183 TI - The chemical behavior of terminally tert-butylated polyolefins. AB - The chemical behavior of various oligoenes 2 has been studied. The catalytic hydrogenation of diene 3 yielded monoene 4. Triene 7 was hydrogenated to diene 8, monoene 9 and saturated hydrocarbon 10. Bromine addition to 3 and 7 yielded the dibromides 17 and 18, respectively, i.e., the oligoene system has been attacked at its terminal olefinic carbon atoms. Analogously, the higher vinylogs 19 and 20 yielded the 1,8- and 1,10-bromine adduts 23 and 24, respectively, when less than 1 equivalent of bromine was employed. Treatment of tetraene 19 with excess bromine provided tetrabromide 25. In epoxidation reactions, both with meta chloroperbenzoic acid (MCPBA) and dimethyldioxirane (DMDO) two model oligoenes were studied: triene 7 and tetraene 19. Whereas 7 furnished the rearrangement product 31 with MCPBA, it yielded the symmetrical epoxide 32 with DMDO. Analogously, 19 was converted to mono-epoxide 33 with MCPBA and to 34 with DMDO. Diels-Alder addition of 7 with N-phenyltriazolinedione (PTAD) did not take place. Extension of the conjugated pi-system to the next higher vinylog, 19, caused NPTD addition to the symmetrical adduct 37 in good yield. Comparable results were observed on adding NPTD (equivalent amount) to pentaene 20 and hexaene 21. Using 36 in excess provided the 2:1-adduct 40 from 21 and led to a complex mixture of adducts from heptaene 22. With tetracyanoethylene (TCNE) as the dienophile, tetraolefin 19 yielded the symmetrical adduct 43, although the reaction temperature had to be increased. Pentaene 20 and hexaene 21 led to corresponding results, adducts 44 and 45 being produced in acceptable yields. With nonaene 42 and TCNE the 2:1-adduct 48 was generated according to its spectroscopic data. Exploratory photochemical studies were carried out with tetraene 19 as the model compound. On irradiation this reacted with oxygen to the stable endo-peroxide 52. PMID- 26425184 TI - Design and synthesis of fused polycycles via Diels-Alder reaction and ring rearrangement metathesis as key steps. AB - Atom efficient processes such as the Diels-Alder reaction (DA) and the ring rearrangement metathesis (RRM) have been used to design new polycycles. In this regard, ruthenium alkylidene catalysts are effective in realizing the RRM of bis norbornene derivatives prepared by DA reaction and Grignard addition. Here, fused polycycles are assembled which are difficult to produce by conventional synthetic routes. PMID- 26425185 TI - One-pot odourless synthesis of thioesters via in situ generation of thiobenzoic acids using benzoic anhydrides and thiourea. AB - An efficient and odourless procedure for a one-pot synthesis of thioesters by the reaction of benzoic anhydrides, thiourea and various organic halides (primary, allylic, and benzylic) or structurally diverse, electron-deficient alkenes (ketones, esters, and nitriles) in the presence of Et3N has been developed. In this method, thiobenzoic acids were in situ generated from the reaction of thiourea with benzoic anhydrides, which were subjected to conjugate addition with electron-deficient alkenes or a nucleophilic displacement reaction with alkyl halides. PMID- 26425187 TI - Synthesis of gamma-hydroxypropyl P-chirogenic (+/-)-phosphorus oxide derivatives by regioselective ring-opening of oxaphospholane 2-oxide precursors. AB - The synthesis of P-chirogenic (+/-)-phosphine oxides and phosphinates via selective nucleophilic ring opening of the corresponding oxaphospholanes is described. Two representative substrates: the phosphonate 2-ethoxy-1,2 oxaphospholane 2-oxide and the phosphinate 2-phenyl-1,2-oxaphospholane 2-oxide were reacted with various Grignard reagents to produce a single alkyl/aryl product. These products may possess further functionalities in addition to the phosphorus center such as the gamma-hydroxypropyl group which results from the ring opening and pi-donor moieties such as aryl, allyl, propargyl and allene which originates from the Grignard reagent. PMID- 26425186 TI - Selected synthetic strategies to cyclophanes. AB - In this review we cover various approaches to meta- and paracyclophanes involving popular reactions. Generally, we have included a strategy where the reaction was used for assembling the cyclophane skeleton for further functionalization. In several instances, after the cyclophane is made several popular reactions are used and these are not covered here. We included various natural products related to cyclophanes. To keep the length of the review at a manageable level the literature related to orthocyclophanes was not included. PMID- 26425188 TI - Surprisingly facile CO2 insertion into cobalt alkoxide bonds: A theoretical investigation. AB - Exploiting carbon dioxide as co-monomer with epoxides in the production of polycarbonates is economically highly attractive. More effective catalysts for this reaction are intensively being sought. To promote better understanding of the catalytic pathways, this study uses density functional theory calculations to elucidate the reaction step of CO2 insertion into cobalt(III)-alkoxide bonds, which is also the central step of metal catalysed carboxylation reactions. It was found that CO2 insertion into the cobalt(III)-alkoxide bond of [(2 hydroxyethoxy)Co(III)(salen)(L)] complexes (salen = N,N"-bis(salicyliden-1,6 diaminophenyl)) is exothermic, whereby the exothermicity depends on the trans ligand L. The more electron-donating this ligand is, the more exothermic the insertion step is. Interestingly, we found that the activation barrier decreases with increasing exothermicity of the CO2 insertion. Hereby, a linear Bronsted Evans-Polanyi relationship was found between the activation energy and the reaction energy. PMID- 26425189 TI - Synthesis and evaluation of the biostability and cell compatibility of novel conjugates of nucleobase, peptidic epitope, and saccharide. AB - This article reports the synthesis of a new class of conjugates containing a nucleobase, a peptidic epitope, and a saccharide and the evalution of their gelation, biostability, and cell compatibility. We demonstrate a facile synthetic process, based on solid-phase peptide synthesis of nucleopeptides, to connect a saccharide with the nucleopeptides for producing the target conjugates. All the conjugates themselves (1-8) display excellent solubility in water without forming hydrogels. However, a mixture of 5 and 8 self-assembles to form nanofibers and results in a supramolecular hydrogel. The proteolytic stabilities of the conjugates depend on the functional peptidic epitopes. We found that TTPV is proteolytic resistant and LGFNI is susceptible to proteolysis. In addition, all the conjugates are compatible to the mammalian cells tested. PMID- 26425190 TI - Pd(OAc)2-catalyzed dehydrogenative C-H activation: An expedient synthesis of uracil-annulated beta-carbolinones. AB - An intramolecular dehydrogenative C-H activation enabled an efficient synthesis of an uracil-annulated beta-carbolinone ring system. The reaction is simple, efficient and high yielding (85-92%). PMID- 26425191 TI - Spiro annulation of cage polycycles via Grignard reaction and ring-closing metathesis as key steps. AB - A simple synthetic strategy to C 2-symmetric bis-spiro-pyrano cage compound 7 involving ring-closing metathesis is reported. The hexacyclic dione 10 was prepared from simple and readily available starting materials such as 1,4 naphthoquinone and cyclopentadiene. The synthesis of an unprecedented octacyclic cage compound through intramolecular Diels-Alder (DA) reaction as a key step is described. The structures of three new cage compounds 7, 12 and 18 were confirmed by single crystal X-ray diffraction studies. PMID- 26425192 TI - Design and synthesis of polycyclic sulfones via Diels-Alder reaction and ring rearrangement metathesis as key steps. AB - Here, we describe a new and simple synthetic strategy to various polycyclic sulfones via Diels-Alder reaction and ring-rearrangement metathesis (RRM) as the key steps. This approach delivers tri- and tetracyclic sulfones with six (n = 1), seven (n = 2) or eight-membered (n = 3) fused-ring systems containing trans-ring junctions unlike the conventional all cis-ring junctions generally obtained during the RRM sequence. Interestingly the starting materials used are simple and commercially available. PMID- 26425193 TI - Tetrathiafulvalene-based azine ligands for anion and metal cation coordination. AB - The synthesis and full characterization of two tetrathiafulvalene-appended azine ligands, namely 2-([2,2'-bi(1,3-dithiolylidene)]-4-yl)-6-((2,4 dinitrophenyl)hydrazono)methyl)pyridine (L1) and 5-([2,2'-bi(1,3-dithiolylidene)] 4-yl)-2-((2,4-dinitrophenyl)hydrazono)methyl)pyridine (L2) are described. The crystal structure of ligand L1 indicates that the ligand is completely planar with the presence of a strong intramolecular N3-H3...O1 hydrogen bonding. Titration experiments with inorganic anions showed that both ligands are suitable candidates for the sensing of fluoride anions. Ligand L2 was reacted with a Re(I) cation to yield the corresponding rhenium tricarbonyl complex 3. In the crystal structure of the newly prepared electroactive rhenium complex the TTF is neutral and the rhenium cation is hexacoordinated. The electrochemical behavior of the three compounds indicates that they are promising for the construction of crystalline radical cation salts. PMID- 26425194 TI - Cross-metathesis reaction of alpha- and beta-vinyl C-glycosides with alkenes. AB - Cross-metathesis of alpha- and beta-vinyl C-deoxyribosides and alpha-vinyl C galactoside with various terminal alkenes under different conditions was studied. The cross-metathesis of the former proceeded with good yields of the corresponding products in ClCH2CH2Cl the latter required the presence of CuI in CH2Cl2 to achieve good yields of the products. A simple method for the preparation of alpha- and beta-vinyl C-deoxyribosides was also developed. In addition, feasibility of deprotection and further transformations were briefly explored. PMID- 26425195 TI - Antioxidant potential of curcumin-related compounds studied by chemiluminescence kinetics, chain-breaking efficiencies, scavenging activity (ORAC) and DFT calculations. AB - This study compares the ability to scavenge different peroxyl radicals and to act as chain-breaking antioxidants of monomers related to curcumin (1): dehydrozingerone (2), zingerone (3), (2Z,5E)-ethyl 2-hydroxy-6-(4-hydroxy-3 methoxyphenyl)-4-oxohexa-2,5-dienoate (4), ferulic acid (5) and their corresponding C 2-symmetric dimers 6-9. Four models were applied: model 1 - chemiluminescence (CL) of a hydrocarbon substrate used for determination of the rate constants (k A) of the reactions of the antioxidants with peroxyl radicals; model 2 - lipid autoxidation (lipidAO) used for assessing the chain-breaking antioxidant efficiency and reactivity; model 3 - oxygen radical absorbance capacity (ORAC), which yields the activity against peroxyl radicals generated by an azoinitiator; model 4 - density functional theory (DFT) calculations at UB3LYP/6-31+G(d,p) level, applied to explain the structure-activity relationship. Dimers showed 2-2.5-fold higher values of k A than their monomers. Model 2 gives information about the effects of the side chains and revealed much higher antioxidant activity for monomers and dimers with alpha,beta-unsaturated side chains. Curcumin and 6 in fact are dimers of the same monomer 2. We conclude that the type of linkage between the two "halves" by which the molecule is made up does not exert influence on the antioxidant efficiency and reactivity of these two dimers. The dimers and the monomers demonstrated higher activity than Trolox (10) in aqueous medium (model 3). A comparison of the studied compounds with DL alpha-tocopherol (11), Trolox and curcumin is made. All dimers are characterized through lower bond dissociation enthalpies (BDEs) than their monomers (model 4), which qualitatively supports the experimental results. PMID- 26425196 TI - A novel and widespread class of ketosynthase is responsible for the head-to-head condensation of two acyl moieties in bacterial pyrone biosynthesis. AB - The biosynthesis of photopyrones, novel quorum sensing signals in Photorhabdus, has been studied by heterologous expression of the photopyrone synthase PpyS catalyzing the head-to-head condensation of two acyl moieties. The biochemical mechanism of pyrone formation has been investigated by amino acid exchange and bioinformatic analysis. Additionally, the evolutionary origin of PpyS has been studied by phylogenetic analyses also revealing homologous enzymes in Pseudomonas sp. GM30 responsible for the biosynthesis of pseudopyronines including a novel derivative. Moreover this novel class of ketosynthases is only distantly related to other pyrone-forming enzymes identified in the biosynthesis of the potent antibiotics myxopyronin and corallopyronin. PMID- 26425197 TI - A new method for the synthesis of alpha-aminoalkylidenebisphosphonates and their asymmetric phosphonyl-phosphinyl and phosphonyl-phosphinoyl analogues. AB - A convenient approach has been developed to alpha-aminoalkylidenebisphosphonates and their asymmetric phosphonyl-phosphinyl and phosphonyl-phosphinoyl analogues by alpha-phosphonylation, alpha-phosphinylation or alpha-phosphinoylation of 1-(N acylamino)alkylphosphonates, that, in turn, are easily accessible from N-acyl alpha-amino acids. Effective electrophilic activation of the alpha-position of 1 (N-acetylamino)alkylphosphonates was achieved by electrochemical alpha methoxylation of these compounds in methanol, mediated with NaCl, followed by displacement of the methoxy group with triphenylphosphonium tetrafluoroborate to give hitherto unknown 1-(N-acetylamino)-1-triphenylphosphoniumalkylphosphonate tetrafluoroborates. The latter compounds react smoothly with trialkyl phosphites, dialkyl phosphonites or alkyl phosphinites in the presence of Hunig's base and methyltriphenylphosphonium iodide in a Michaelis-Arbuzov-like reaction to give the expected alkylidenebisphosphonates, 1-phosphinylalkylphosphonates or 1 phosphinoylalkylphosphonates, respectively, in good yields. PMID- 26425198 TI - Synthesis of alpha-tetrasubstituted triazoles by copper-catalyzed silyl deprotection/azide cycloaddition. AB - Propargylamines are popular substrates for triazole formation, but tetrasubstituted variants have required multistep syntheses involving stoichiometric amounts of metal. A recent cyclohexanone-amine-silylacetylene coupling forms silyl-protected tetrasubstituted propargylamines in a single copper-catalyzed step. The development of the tandem silyl deprotection-triazole formation reported herein offers rapid access to alpha-tetrasubstituted triazoles. A streamlined two-step approach to this uncommon class of hindered triazoles will accelerate exploration of their therapeutic potential. The superior activity of copper(II) triflate in the formation of triazoles from sensitive alkyne substrates extends to simple terminal alkynes. PMID- 26425199 TI - Synthesis and spectroscopic properties of beta-triazoloporphyrin-xanthone dyads. AB - A novel series of beta-triazoloporphyrin-xanthone conjugates and xanthone-bridged beta-triazoloporphyrin dyads has been synthesized in moderate to good yields through Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of copper(II) 2-azido-5,10,15,20-tetraphenylporphyrin or zinc(II) 2-azidomethyl-5,10,15,20 tetraphenylporphyrin with various alkyne derivatives of xanthones in DMF containing CuSO4 and ascorbic acid at 80 degrees C. Furthermore, these metalloporphyrins underwent demetalation under acidic conditions to afford the corresponding free-base porphyrins in good to excellent yields. After successful spectroscopic characterization, these porphyrins have been evaluated for their photophysical properties. The preliminary results revealed a bathochromic shift in the UV-vis and fluorescence spectra of these porphyrin-xanthone dyads. PMID- 26425200 TI - Why base-catalyzed isomerization of N-propargyl amides yields mostly allenamides rather than ynamides. AB - The base-catalyzed isomerization of N-propargylamides or carbamates may furnish N allenyl compounds (allenamides/allencarbamates) or further evolve to N-alkynyl compounds (ynamides or yncarbamates). The particular fate of this reaction varies from experiment to experiment and there is no clear rule for predicting the reaction outcome for a particular structure. With the support of ab initio and DFT computations, this work shows that observed results can be explained by assuming an exchange equilibrium between energetically close N-propargyl, allenyl and N-alkynyl forms and that the reaction outcome correlates to a particular equilibrium mixture. Due to the very small energy gap between the N-allenyl and N alkynyl forms, small structural changes may easily alter the equilibrium position, explaining the variety of observed experimental results. Based on CBS QB3 computations, the omegaB97 functional provided reasonably accurate isomerization energies and could successfully predict the experimentally observed behavior for several examples from the literature. PMID- 26425201 TI - Structure and conformational analysis of spiroketals from 6-O-methyl-9(E) hydroxyiminoerythronolide A. AB - Three novel spiroketals were prepared by a one-pot transformation of 6-O-methyl 9(E)-hydroxyiminoerythronolide A. We present the formation of a [4.5]spiroketal moiety within the macrolide lactone ring, but also the unexpected formation of a 10-C=11-C double bond and spontaneous change of stereochemistry at position 8-C. As a result, a thermodynamically stable structure was obtained. The structures of two new diastereomeric, unsaturated spiroketals, their configurations and conformations, were determined by means of NMR spectroscopy and molecular modelling. The reaction kinetics and mechanistic aspects of this transformation are discussed. These rearrangements provide a facile synthesis of novel macrolide scaffolds. PMID- 26425202 TI - Consequences of the electronic tuning of latent ruthenium-based olefin metathesis catalysts on their reactivity. AB - Two ruthenium olefin metathesis initiators featuring electronically modified quinoline-based chelating carbene ligands are introduced. Their reactivity in RCM and ROMP reactions was tested and the results were compared to those obtained with the parent unsubstituted compound. The studied complexes are very stable at high temperatures up to 140 degrees C. The placement of an electron-withdrawing functionality translates into an enhanced activity in RCM. While electronically modified precatalysts, which exist predominantly in the trans-dichloro configuration, gave mostly the RCM and a minor amount of the cycloisomerization product, the unmodified congener, which preferentially exists as its cis-dichloro isomer, shows a switched reactivity. The position of the equilibrium between the cis- and the trans-dichloro species was found to be the crucial factor governing the reactivity of the complexes. PMID- 26425203 TI - Thermal properties of ruthenium alkylidene-polymerized dicyclopentadiene. AB - Differential scanning calorimetry (DSC) analysis of ring opening methatesis polymerization (ROMP) derived polydicyclopentadiene (PDCPD) revealed an unexpected thermal behavior. A recurring exothermic signal can be observed in the DSC analysis after an elapsed time period. This exothermic signal was found to be proportional to the resting period and was accompanied by a constant increase in the glass-transition temperature. We hypothesize that a relaxation mechanism within the cross-linked scaffold, together with a long-lived stable ruthenium alkylidene species are responsible for the observed phenomenon. PMID- 26425204 TI - Deproto-metallation of N-arylated pyrroles and indoles using a mixed lithium-zinc base and regioselectivity-computed CH acidity relationship. AB - The synthesis of N-arylated pyrroles and indoles is documented, as well as their functionalization by deprotonative metallation using the base in situ prepared from LiTMP and ZnCl2.TMEDA (1/3 equiv). With N-phenylpyrrole and -indole, the reactions were carried out in hexane containing TMEDA which regioselectively afforded the 2-iodo derivatives after subsequent iodolysis. With pyrroles and indoles bearing N-substituents such as 2-thienyl, 3-pyridyl, 4-methoxyphenyl and 4-bromophenyl, the reactions all took place on the substituent, at the position either adjacent to the heteroatom (S, N) or ortho to the heteroatom-containing substituent (OMe, Br). The CH acidities of the substrates were determined in THF solution using the DFT B3LYP method in order to rationalize the experimental results. PMID- 26425205 TI - Tandem cross enyne metathesis (CEYM)-intramolecular Diels-Alder reaction (IMDAR). An easy entry to linear bicyclic scaffolds. AB - A new tandem cross enyne metathesis (CEYM)-intramolecular Diels-Alder reaction (IMDAR) has been carried out. It involves conjugated ketones, esters or amides bearing a remote olefin and aromatic alkynes as the starting materials. The overall process enables the preparation of a small family of linear bicyclic scaffolds in a very simple manner with moderate to good levels of diastereoselectivity. This methodology constitutes one of the few examples that employ olefins differently than ethylene in tandem CEYM-IMDAR protocols. PMID- 26425206 TI - Pyridine-promoted dediazoniation of aryldiazonium tetrafluoroborates: Application to the synthesis of SF5-substituted phenylboronic esters and iodobenzenes. AB - Pyridine promotes dediazoniation of aryldiazonium tetrafluoroborates. The formed aryl radicals were trapped with B2pin2, iodine, or tetrahydrofuran to afford boronic esters, iodobenzenes and benzenes, respectively. The application to the synthesis of (pentafluorosulfanyl)phenylboronic esters, iodo(pentafluorosulfanyl)benzenes and (pentafluorosulfanyl)benzene is shown. PMID- 26425207 TI - Synthesis of a tricyclic lactam via Beckmann rearrangement and ring-rearrangement metathesis as key steps. AB - A tricyclic lactam is reported in a four step synthesis sequence via Beckmann rearrangement and ring-rearrangement metathesis as key steps. Here, we used a simple starting material such as dicyclopentadiene. PMID- 26425208 TI - The enantioselective synthesis of (S)-(+)-mianserin and (S)-(+)-epinastine. AB - A simple enantioselective synthetic procedure for the preparation of mianserin and epinastine in optically pure form is described. The key step in the synthetic pathway is the asymmetric reduction of the cyclic imine using asymmetric transfer hydrogenation conditions. PMID- 26425209 TI - Design and synthesis of hybrid cyclophanes containing thiophene and indole units via Grignard reaction, Fischer indolization and ring-closing metathesis as key steps. AB - We demonstrate a new synthetic strategy to cyclophanes containing thiophene and indole moieties via Grignard addition, Fischer indolization and ring-closing metathesis as key steps. PMID- 26425210 TI - Ruthenium indenylidene "1(st) generation" olefin metathesis catalysts containing triisopropyl phosphite. AB - The reaction of triisopropyl phosphite with phosphine-based indenylidene pre catalysts affords "1(st) generation" cis-complexes. These have been used in olefin metathesis reactions. The cis-Ru species exhibit noticeable differences with the trans-Ru parent complexes in terms of structure, thermal stability and reactivity. Experimental data underline the importance of synergistic effects between phosphites and L-type ligands. PMID- 26425211 TI - Tetrathiafulvalene chemistry. PMID- 26425212 TI - Qualitative evaluation of regioselectivity in the formation of di- and tri-6-O tritylates of alpha-cyclodextrin. AB - The quantitative analysis of reaction products showed that the reaction of 6(A),6(D)-di-O-trityl-alpha-cyclodextrin (CD), AD-isomer, with trityl chloride in pyridine at 55 degrees C gave 6(A),6(B),6(E)-tri-O-trityl-alpha-CD, the amount of which was only 25% of that of simultaneously formed 6(A),6(B),6(D)-tri-O trityl-alpha-CD. This indicates that the bulky trityl groups of glucopyranose-A and -D (Glu-A and -D, respectively) in the AD-isomer mainly retard the additional tritylation of the C(6)-OH of the adjacent glucopyranoses in a counter-clockwise direction (Glu-F and -C, respectively). (1)H NMR spectra of the AD-isomer showed that the O(6)-H and C(6)-H signals of Glu-C and -F are shifted upfield due to the ring current of the trityl groups. Thus, it is concluded that the bulky trityl groups on Glu-A and Glu-D are oriented to Glu-F and Glu-C, respectively, and sterically retard additional tritylation on Glu-F and Glu-C. Similar steric hindrance was also observed in the additional tritylations of mono-6-O-trityl alpha-CD, 6(A),6(B)-di- and 6(A),6(C)-di-O-trityl-alpha-CD's. PMID- 26425213 TI - Latent ruthenium-indenylidene catalysts bearing a N-heterocyclic carbene and a bidentate picolinate ligand. AB - A silver-free methodology was developed for the synthesis of unprecedented N heterocyclic carbene ruthenium indenylidene complexes bearing a bidentate picolinate ligand. The highly stable (SIPr)(picolinate)RuCl(indenylidene) complex 4a (SIPr = 1,3-bis(2-6-diisopropylphenyl)imidazolidin-2-ylidene) demonstrated excellent latent behaviour in ring closing metathesis (RCM) reaction and could be activated in the presence of a Bronsted acid. The versatility of the catalyst 4a was subsequently demonstrated in RCM, cross-metathesis (CM) and enyne metathesis reactions. PMID- 26425214 TI - Towards inhibitors of glycosyltransferases: A novel approach to the synthesis of 3-acetamido-3-deoxy-D-psicofuranose derivatives. AB - A novel synthetic strategy leading to 3-acetamido-3-deoxy-D-psicofuranose 9 is presented. The latter compound, after some manipulations, was transformed into fully protected 3-acetamido-3-deoxy-D-psicofuranose 11 as a potential substrate for the synthesis of N-acetylglucosaminyltransferase inhibitors designed by computational methods. After the attempted thioglycosylation of 11 with EtSH in the presence of BF3.OEt2, 2-methyloxazoline derivatives 13 and 14 were isolated. PMID- 26425215 TI - Assessing value of innovative molecular diagnostic tests in the concept of predictive, preventive, and personalized medicine. AB - Molecular diagnostic tests drive the scientific and technological uplift in the field of predictive, preventive, and personalized medicine offering invaluable clinical and socioeconomic benefits to the key stakeholders. Although the results of diagnostic tests are immensely influential, molecular diagnostic tests (MDx) are still grudgingly reimbursed by payers and amount for less than 5 % of the overall healthcare costs. This paper aims at defining the value of molecular diagnostic test and outlining the most important components of "value" from miscellaneous assessment frameworks, which go beyond accuracy and feasibility and impact the clinical adoption, informing healthcare resource allocation decisions. The authors suggest that the industry should facilitate discussions with various stakeholders throughout the entire assessment process in order to arrive at a consensus about the depth of evidence required for positive marketing authorization or reimbursement decisions. In light of the evolving "value-based healthcare" delivery practices, it is also recommended to account for social and ethical parameters of value, since these are anticipated to become as critical for reimbursement decisions and test acceptance as economic and clinical criteria. PMID- 26425216 TI - Perception, career choice and self-efficacy of UK medical students and junior doctors in urology. AB - INTRODUCTION: There is a growing concern about the reduced clinical exposure to urology at undergraduate level in the United Kingdom. As a consequence, the competencies of junior doctors are considered inadequate. The views of these doctors in training towards urology remain under reported. METHODS: A modified Delphi method was employed to construct a questionnaire. Given the rise of social media as a platform for scientific discussion, participants were recruited via a social networking site. Outcomes assessed included career preference, exposure to urology, perceived male dominance, and confidence at core procedures. RESULTS: In total, 412 and 66 responses were collected from medical students and junior doctors, respectively. Overall, 41% of participants felt that they had received a good level of clinical exposure to urology as part of their training and 15% were considering a career in this speciality. Female students were significantly less likely to consider urology as a career option (p < 0.01). Of these, 37% of the students felt confident at male catheterization and 46% of students regarded urology as a male-dominated speciality. CONCLUSIONS: Urology is perceived as male dominated and is the least likely surgical speciality to be pursued as a career option according to our survey. Increased exposure to urology at the undergraduate level and dedicated workshops for core urological procedures are needed to address these challenges. PMID- 26425217 TI - Predictors of improvement in semen parameters after varicocelectomy for male subfertility: A prospective study. AB - INTRODUCTION: We aim to predict results of varicocelectomy on sperm density and progressive motility using preoperative clinical, laboratory and radiological data and to propose cut-off values for significant parameters. METHODS: This prospective study was carried out between July 2011 and June 2014. We included 123 patients in our study. They were diagnosed with primary infertility with varicocele, were scheduled for varicocelectomy, and completed their follow-up. We excluded patients with azoospermia, total necrospermia, recurrent varicocele, and pituitary hormonal abnormalities. Varicocele was diagnosed and graded by physical examination and colour Doppler ultrasound. Semen analyses were completed preoperatively and 6 months postoperatively. Microscopic subinguinal varicocelectomy was done in all cases. Patient demographics, pre- and postoperative clinical data (varicocele grade and semen parameters) were statistically analyzed. RESULTS: The mean +/- standard deviation of age, body mass index, and subfertility duration was 28.3 +/- 7.4 years, 29.1 +/- 2.7 kg/m(2), and 21.9 +/- 7.1 months, respectively. About 53% of our patients (n = 66) had bilateral varicocele, and unilateral disease was found in the other 57 (46.3%) cases. Varicocele grade I was diagnosed in 42 (34.1%) patients, while the other 81 (65.9%) patients had grade II or III. Higher grades of varicocele, preoperative total testosterone level, sperm density, and progressive motility had a statistically significant impact on the outcome of varicocelectomy in univariate testing. Multivariate logistic analysis revealed that grade of preoperative varicocele (95% confidence interval [CI] 5.6-6.3, p = 0.007) and sperm density (95% CI 2.7-1.6, p = 0.0035), and progressive motility (95% CI 1.1 2.3, p = 0.0123) are independent predictors of semen parameters improvement after varicocelectomy. CONCLUSION: The grade of the varicocele, sperm density, and progressive motility are major predictors of outcome in varicocelectomy. Cut-off values of >8 million/mL and >18% for sperm density and progressive motility, respectively, in men with varicocele grade II or III, indicate a successful outcome. PMID- 26425218 TI - Comparative effectiveness of adrenal sparing radical nephrectomy and non-adrenal sparing radical nephrectomy in clear cell renal cell carcinoma: Observational study of survival outcomes. AB - INTRODUCTION: We compare the survival outcomes of patients with clear cell renal cell carcinoma (RCC) treated with adrenal sparing radical nephrectomy (ASRN) and non-adrenal sparing radical nephrectomy (NASRN). METHODS: We conducted an observational study based on a composite patient population from two university teaching hospitals who underwent RN for RCC between January 2000 and December 2012. Only patients with pathologically confirmed RCC were included. We excluded patients undergoing cytoreductive nephrectomy, with loco-regional lymph node involvement. In total, 579 patients (ASRN = 380 and NASRN = 199) met our study criteria. Patients were categorized by risk groups (all stage, early stage and locally advanced RCC). Overall survival (OS) and cancer-specific survival (CSS) were analyzed for risk groups. Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards regression. RESULTS: The median follow-up was 41 months (range: 12-157). There were significant benefits in OS (ASRN 79.5% vs. NASRN 63.3%; p = 0.001) and CSS (84.3% vs. 74.9%; p = 0.001), with any differences favouring ASRN in all stage. On multivariate analysis, there was a trend towards worse OS (hazard ratio [HR] 1.759, 95% confidence interval [CI] 0.943-2.309, p = 0.089) and CSS (HR 1.797, 95% CI 0.967-3.337, p = 0.064) in patients with NASRN (although not statistically significant). Of these patients, only 11 (1.9%) had adrenal involvement. CONCLUSIONS: The inherent limitations in our study include the impracticality of conducting a prospective randomized trial in this scenario. Our observational study with a 13-year follow-up suggests ASRN leads to better survival than NASRN. ASRN should be considered the gold standard in treating patients with RCC, unless it is contraindicated. PMID- 26425219 TI - Collecting (Bellini) duct carcinoma: A clinical study of a rare tumour and review of the literature. AB - INTRODUCTION: We report our 15-year experience of Collecting (Bellini) duct carcinoma (CDC). We retrospectively analyzed patient and tumour characteristics, clinical manifestations, surgical techniques, clinical outcomes, and salvage therapies. METHODS: From January 1999 to December 2013, 1042 patients underwent surgical resection of renal neoplasm. We examined all renal tumors and identified 10 cases (0.96%) of CDC. RESULTS: The study group included 8 men and 2 women, with a median age of 62.5 years. Of these 10 patients, 9 were symptomatic (90%). All patients were treated with open nephrectomy. The mean tumour size was 5.7 cm. The pathologic stages were distributed as follows: pT1b in 2 patients (20%); pT2a in 1 patient (10%); pT3a in 3 patients (30%); and pT3b in 4 patients (40%). Grading was assessed according to Fuhrman scale as follows: grade II in 1 patient (10%); grade III in 3 patients (30%); grade IV in 5 patients (50%); undetermined grade in 1 patient (10%). Four patients (40%) relapsed locally. The median time of local recurrence was 4.9 months. Distant metastases occurred in 9 patients (90%): 4/9 at the time of diagnosis and 5/9 after nephrectomy. The median time of distant metastases after surgery was 8.1 months. Six patients received chemotherapy (gemcitabine plus platinum salts). Radiotherapy was performed in 5 patients. One patient had surgery because of local recurrence and 2 patients were irradiated in the area of the local recurrence. The median overall survival was 7.6 months, and only 2 patients survived more than 2 years after the nephrectomy. CONCLUSIONS: CDCs of the kidney are aggressive and they have a low survival rate. All patients in our study experienced a relapse of their disease. Local recurrence preceded distant metastases. Results of salvage treatments were poor. PMID- 26425220 TI - Risk factors for hemorrhage requiring embolization after percutaneous nephrolithotomy. AB - INTRODUCTION: Percutaneous nephrolithotomy (PCNL) is the primary surgical intervention in kidney stone management. Even though it is performed quite often, the complication rates are also high. Arteriovenous fistulas following extended hemorrhages after PCNL are one of the most serious complications of this operation. Our main objective was to review the data of patients who required angiography and embolization. METHODS: In total, we included 1405 patients who underwent PCNL between 2007 and 2014. All patient data were retrospectively reviewed. All patients went under PCNL using fluoroscopy. Following informed consent, all hemorrhagic patients underwent angiography in the interventional radiology department and embolization was performed in patients with a hemorrhage focus point. RESULTS: A total of 147 patients (10.4%) required transfusion for post-PCNL hemorrhages. Of them, 14 (0.99%) underwent angiography and embolization (9 [64.2%] were male and 5 [35.8%] were female, with a mean age of 39.4 +/- 10.2). The remaining 133 patients were conservatively managed (81 [60.9%] males and 52 [39.1%] females, with a mean age of 42.3 +/- 12.4). When the predicting factors for angiography and embolization were reviewed, renal abnormalities and the mean size of stones were significant in both univariate and multivariate analysis (p < 0.001). CONCLUSION: Patients with extended and intermittent hematuria should be monitored closely for hemodynamics; if there is an ongoing necessity for transfusion, angiography should be considered. PMID- 26425221 TI - Optimization of the current self-assembled urinary bladder model: Organ-specific stroma and smooth muscle inclusion. AB - INTRODUCTION: Due to the complications associated with the use of non-native biomaterials and the lack of local tissues, bioengineered tissues are required for surgical reconstruction of complex urinary tract diseases, including those of the urinary bladder. The self-assembly method of matrix formation using autologous stromal cells obviates the need for exogenous biomaterials. We aimed at creating novel ex-vivo multilayer urinary tissue from a single bladder biopsy. METHODS: After isolating urothelial, bladder stromal and smooth muscle cells from bladder biopsies, we produced 2 models of urinary equivalents: (1) the original one with dermal fibroblasts and (2) the new one with bladder stromal cells. Dermal fibroblasts and bladder stromal cells were stimulated to form an extracellular matrix, followed by sequential seeding of smooth muscle cells and urothelial cells. Stratification and cellular differentiation were assessed by histology, immunostaining and electron microscopy. Barrier function was checked with the permeability test. Biomechanical properties were assessed with uniaxinal tensile strength, elastic modulus, and failure strain. RESULTS: Both urinary equivalents could be handled easily and did not contract. Stratified epithelium, intact basement membrane, fused matrix, and prominent muscle layer were detected in both urinary equivalents. Bladder stromal cell-based constructs had terminally differentiated urothelium and more elasticity than dermal fibroblasts-based equivalents. Permeation studies showed that both equivalents were comparable to native tissues. CONCLUSIONS: Organ-specific stromal cells produced urinary tissues with more terminally differentiated urothelium and better biomechanical characteristics than non-specific stromal cells. Smooth muscle cells could be incorporated into the self-assembled tissues effectively. This multilayer tissue can be used as a urethral graft or as a bladder model for disease modelling and pharmacotherapeutic testing. PMID- 26425222 TI - Radiation therapy after radical prostatectomy: A single-centre radiation oncology experience in trends of referral and treatment practices. AB - INTRODUCTION: Our objective was to assess whether referral and treatment practices have changed since publication of the Southwest Oncology Group (SWOG) 8794 Trial in 2009, the first randomized study to demonstrate an overall survival advantage of adjuvant radiation therapy (RT) after radical prostatectomy (RP). METHODS: We retrospectively reviewed all medical charts of men who received RT at our institution between 2004 and 2014 following RP. All RT was conducted by a single radiation oncologist (DT). We divided the cohort into 2 groups according to first referral date before or after the SWOG 8794 trial publication (i.e., before 2010 and after 2010). RESULTS: Medical charts were available for 161/165 patients (97.6%). RP was performed at the same institution in 58% of cases. The median time between surgery and first referral for RT decreased significantly from 672 days (interquartile range [IQR] 295-1449) before 2010 to 300 days (IQR 225-1023) after 2010 (p = 0.04). This trend was associated with lower median prostate-specific antigen (PSA) at RT referral (0.26 MUg/L [IQR 0.17-0.48] vs. 0.46 MUg/L [IQR 0.25-0.90], respectively; p = 0.001). Androgen-deprivation therapy with RT nearly tripled over time from 13% before 2010 to 37% after 2010 (p = 0.003). Throughout the study period, the time interval between surgery and RT initiation was positively correlated with pT-stage (p = 0.001), Gleason score (p = 0.005) and PSA doubling time (p < 0.001). CONCLUSIONS: At our tertiary referral academic institution, post-RP patients are notably referred earlier for RT and at lower PSA values compared to men treated prior to 2010. Further study is necessary to evaluate this impact on biochemical recurrence-free survival. PMID- 26425223 TI - Demonstration of the direct impact of ketamine on urothelium using a tissue engineered bladder model. AB - INTRODUCTION: Ketamine is a common recreational drug. Severe lower urinary tract symptoms associated with its consumption have been reported, but little is known about the involved mechanisms. The effect of ketamine, which is excreted in urine, was evaluated by its application on an in vitro three-dimensional human tissue-engineered bladder model composed of an urothelium and a submucosa. METHODS: Human urothelial cells were cultured with medium containing various concentrations of ketamine and harvested at different times to obtain growth curves. Using this model, specific activity of caspase-3 was measured to assess the level of apoptosis induced by ketamine. Finally, a human tissue-engineered bladder model was used. Urothelial cells were plated on a stromal layer made of dermal fibroblasts and incubated at the air/liquid interface to allow their differentiation. Ketamine was then put on the mature urothelium using paper or agarose vectors for 48 hours. RESULTS: The presence of ketamine increased cells' doubling times from 1.26 days for control to 1.38 days (p = 0.14) and 1.78 days (p < 0.01) for the 0.5 mM and 1.5 mM concentrations, respectively. 5 mM and 10 mM of ketamine led to decline in the major cell population. Exposure to 5 mM ketamine induced apoptosis, confirmed by a 2.5-fold increase in capase-3 specific activity from control (p = 0.03). The structure and cellular cohesion of the urothelium on the three-dimensional model, especially in the intermediate layers, were severely affected in a concentration dependant fashion with both vectors. CONCLUSION: The presence of ketamine in the bladder directly damages the urothelium through the induction of apoptosis. PMID- 26425224 TI - Towards optimizing prostate tissue retrieval following holmium laser enucleation of the prostate (HoLEP): Assessment of two morcellators and review of literature. AB - INTRODUCTION: We assess different approaches to retrieve the enucleated adenoma after transurethral enucleation of the prostate, particularly using the holmium laser. METHODS: A retrospective review through our prospectively maintained database was performed looking for safety and efficacy of two morcellators. The enucleation phase of the holmium laser enucleation of the prostate (HoLEP) was classically performed followed by retrieval of the intravesical adenoma using either the Piranha (Wolf Inc., Knittlingen, Germany) or VersaCut (Lumenis) morcellator. A PubMed-MEDLINE search was conducted for all transurethral enucleation procedures and relevant data regarding methods of prostate tissue retrieval were extracted. RESULTS: Strictly limiting the study to 3 reusable blades with each morcellator, we performed 67 and 55 consecutive procedures with Piranha and VersaCut, respectively. There was no significant difference between the two morcellators regarding perioperative complications, apart from 5 bladder mucosal injuries with the VersaCut (9%). Furthermore, there were similar retrieved tissue weight, mechanical problems-rate, catheter-time and hospital stay in both morcellators. However, the Piranha morcellator needed significantly less morcellation-time, needed to use cold loop to remove non-morcellated pieces and to score the adenoma by laser for better bite of the adenoma, and had a higher median morcellation-rate 6.2 (rate: 2.8-12) g/min. Despite little reporting on morcellation, we had data on the tissue retrieval rate (2.6 to 6.5 g/min with Piranha and 1.9 to 11 g/min with VersaCut. Furthermore, bladder mucosal injury was reported in 1.4% and 0.7 to 5.7% with Piranha and VersaCut, respectively; bladder perforation with VersaCut was experienced in about 0.1 to 1.5% of patients. Our study is limited by its non-randomization. CONCLUSION: The Piranha morcellator was the most efficient and safe way to retrieve tissue after a transurethral enucleation of a prostate adenoma. PMID- 26425225 TI - Initial Canadian experience with robotic simple prostatectomy: Case series and literature review. AB - INTRODUCTION: Robotic-assisted simple prostatectomy (RASP) has been touted as an alternative to open simple prostatectomy (OSP) to treat large gland benign prostatic hyperplasia. Our study assesses our institution's experience with RASP and reviews the literature. METHODS: We performed a retrospective chart review from January 2011 to November 2013 of all patients undergoing RASP and OSP. Operative and 90-day outcomes, including operation time, intraoperative blood loss, length of hospital stay (LOS), transfusion requirements, and complication rates, were assessed. RESULTS: Thirty-two patients were identified: 4 undergoing RASP and 28 undergoing OSP. There was no difference in mean age at surgery (69.3 vs. 75.2 years; p = 0.17), mean Charlson Comorbidity Index (2.5 vs. 3.5; p = 0.19), and mean prostate volume on TRUS (239 vs. 180 mL; p = 0.09) in the robotic and open groups, respectively. There was a significant difference in the mean length of operation, with RASP exceeding OSP (161 vs. 79 min; p = 0.008). The mean intraoperative blood loss was significantly higher in the open group (835.7 vs. 218.8 mL; p = 0.0001). Mean LOS was shorter in the RASP group (2.3 vs. 5.5 days; p = 0.0001). No significant differences were noted in the 90-day transfusion rate (p = 0.13), or overall complication rate at 0% with RASP vs. 57.1% with OSP (p = 0.10). CONCLUSIONS: Our data suggest RASP has a shorter LOS and lower intraoperative volume of blood loss, with the disadvantage of a longer operating time, compared to OSP. It is a feasible technique and deserves further investigation and consideration at Canadian centres performing robotic prostatectomies. PMID- 26425227 TI - The influence of membranous stretched urethral length and urethral circumference on postoperative recovery of continence after radical prostatectomy: A pilot study. PMID- 26425226 TI - Treatment and outcome of fibroepithelial ureteral polyps: A systematic literature review. AB - INTRODUCTION: Fibroepithelial polyps of the ureter are rare. Cases and small series are reported in the literature. The treatment of choice, outcome and appropriate follow-up regimen remain unclear. METHODS: We conducted a systematic literature review of papers reporting fibroepithelial polyps of the ureter in adult patients. Articles published before 1980 were excluded. RESULTS: The search yielded 144 papers, of which 68 met the inclusion criteria. A reference scan from the included 68 yielded an additional 7 new articles. In total, our study included 75 articles (68 + 7). A total of 134 patients were described. Most patients had a single lesion (range: 1-10). The median length of the polyp was 4.0 cm (range: 0.4-17.0). The percentage of polyps resected endoscopically increased from 0% before 1985 to 67% after 2005. Two perioperative complications were reported in 72 procedures (2.8%): a deep venous thrombosis and a case of mesenteric lymphadenopathy. Both of these occurred after open surgery. Follow-up data were available for 57 patients. The median follow-up was 12 months (range: 1 180). Four patients (7.0%) developed recurrent complaints: 2 had urinary stones, 1 had a ureteral stricture and 1 had recurrence of the polyp. Three of these events followed endoscopic resection, and occurred within a year after the procedure. CONCLUSION: Endoscopic resection of fibroepithelial polyps seems to be safe and effective. It is minimally invasive and should be considered the gold standard where endoscopic expertise is available. We advise follow-up imaging by computed tomographic intravenous urography after 3 months and ultrasound after 1 year to detect late complications. PMID- 26425228 TI - More work needed in examining the relationship between mean platelet volume and inflammation in varicocele pathophysiology. PMID- 26425229 TI - Author response: The relationship between mean platelet volume and inflammation in varicocele pathophysiology. PMID- 26425230 TI - Renal cancer seeding metastases following retroperitoneoscopic-assisted cryoablation: A case report. AB - Nephron-sparing laparoscopy is the standard surgical treatment for clinical T1a renal tumours. However, the laparoscopic technique brings in its specific oncological safety concerns. Seeding metastases are reported: peritoneal metastases, port-tract metastases, and (sub-) cutaneous metastases. The method of laparoscopic assisted renal mass cryoablation is marked by the fact that traumatic tumour tissue handling is unavoidable. This case report reviews the rare occasion of seeding metastases in the retroperitoneal space following laparoscopic cryoablation of a small renal mass. The primary tumour showed no focal recurrence as reported by histological examination. The combination of two events as harming the integrity of cancer tissue and gas-circulation leading to the development of metastases in the retroperitoneal cavity is discussed. The combination of iatrogenic harming cancer tissue integrity and CO2-circulation leads to metastases in the retroperitoneal cavity. Therefore, we recommend performing image-guided renal mass biopsies before considering cryoablative surgery. PMID- 26425231 TI - Androgen secreting giant adrenocortical carcinoma with no metastases: A case report and review of the literature. AB - Functional adrenocortical carcinoma (ACC) is a very rare disease with a poor prognosis. Over half (60%) of ACCs bigger than 6 cm synthesize hormones; hormone secreting ACCs generally include virilization, feminization or Cushing syndrome. Besides, 82% of ACCs are metastatic at the time of diagnosis. While a 48-year-old female patient was examined for abdominal pain and flushing, we detected a non metastasizing mass (23 * 18 * 16 cm) in the adrenal lodge. The mass was extracted en bloc during open exploration and its histopathology was reported as ACC. We review the literature and report the largest androgen-producing, clinically silent ACC mass cited in the literature so far. PMID- 26425232 TI - Wunderlich syndrome as the first manifestation of an extraskeletal Ewing sarcoma. AB - We recently encountered an extremely rare case of spontaneous perirenal hemorrhage in a 34-year-old man. He initially had undergone radical nephrectomy owing to suspicion of renal cell carcinoma. The final diagnosis was extraskeletal Ewing sarcoma. PMID- 26425233 TI - Sorafenib treatment for recurrent stage T1 bilateral renal cell carcinoma in patients with Von Hippel- Lindau disease: A case report and literature review. AB - Renal cell carcinoma (RCC) with Von Hippel-Lindau (VHL) syndrome is associated with multiple recurrences and a young age at diagnosis. Therefore the primary goal of treatment is to stabilize the disease, minimizing the surgical resection and preserving the renal function in the patients with VHL who have developing RCC nodules after initial treatment. This is the first case report of VHL disease, with long-term stable disease, treated with a half dose of sorafenib after surgical resection and radiofrequency ablation for multiple recurrent stage T1 masses. We discuss the efficacy and safety of low-dose sorafenib treatment and review RCC in a patient with VHL disease. PMID- 26425234 TI - Tubulocystic renal cell carcinoma: Report of a rare case. AB - Cystic neoplasms of the kidney are rare, and present a unique diagnostic challenge. We report the case of an elderly male who presented with a large cystic neoplasm, which was a diagnostic dilemma clinically and radiologically. Histopathological examination showed a tumour composed of variably sized tubules lined by atypical cells having large round nuclei with prominent nucleoli. Hobnailing was seen at places. Tumour cells were immunopositive for pancytokeratin, vimentin, CD10, CK19 and AMACR, confirming a diagnosis of tubulocystic renal cell carcinoma (TC-RCC). PMID- 26425235 TI - Paradoxical air embolism during percutaneous nephrolithotomy due to patent foramen ovale: Case report. AB - Paradoxical air embolism is a very rare complication associated with percutaneous nephrolithotomy (PCNL). Incidence may be higher if patients also suffer from a septal heart defect. We report the case of a 76-year old male who presented for PCNL treatment of a right kidney lower calyceal calculus. During the procedure, the patient developed signs and symptoms consistent with that of air embolism. Intraoperative echocardiography confirmed the diagnosis. Subsequent intraoperative and postoperative medical management was carried out and the patient was discharged after recovery three days later. This case highlights the importance of a rare but potentially fatal complication of PCNL. PMID- 26425236 TI - Intracardiac migration of ureteral double-J stent: A case report and review. AB - Ureteral double-J (DJ) stenting is a common urologic procedure in several ureteral surgeries and has been used to manage ureteral obstructions during pregnancy. It may result in early and late complications. We review a rare case of migration of the DJ stent into the cardiovascular system in a pregnant female. We also review the literature. The endoscopic procedure to remove this displacement has been done postnatally with no adverse effects. PMID- 26425237 TI - Ectopic scrotum: A unique case report. AB - Ectopic scrotum is a rare congenital anomaly. Most common location is supra inguinal. We present a case of left ectopic scrotum in a three year old boy with no associated congenital anomalies, who underwent successful scrotoplasty and orchiopexy. PMID- 26425238 TI - Reproductive outcomes in men with karyotype abnormalities: Case report and review of the literature. AB - Reciprocal translocations of autosomal chromosomes are present in about 1/625 men, yet often there are no symptoms except primary infertility. Abnormal segregation during meiosis often produces sperm and subsequent embryos with unbalanced translocations that often ultimately result in spontaneous abortions. We report on a 37-year-old man and his 39-year-old wife who complained of primary infertility. Previous in vitro fertilization (IVF) had resulted in pregnancy, but two spontaneous abortions. Upon chromosomal testing, the man was diagnosed with a reciprocal translocation and his wife was diagnosed with mosaic Turner's syndrome. Through testicular sperm extraction (TESE) and IVF with preimplantation genetic screening (PGS), they succeeded in having two healthy children. Since men with different karyotype abnormalities can have male infertility, we reviewed the literature and summarized the reproductive outcomes for men with both autosome and sex chromosomal karyotype abnormalities. PMID- 26425239 TI - Salvage HIFU for biopsy confirmed local prostate cancer recurrence after radical prostatectomy and radiation therapy: Case report and literature review. AB - High-intensity focused ultrasound (HIFU) is a treatment option for low- and intermediate-risk prostate cancer and more recently has been used as salvage therapy after failed radiation therapy. We present a case of local recurrence with biochemical failure after radical prostatectomy and salvage external beam radiation therapy with salvage HIFU without biochemical recurrence at 20 months. PMID- 26425240 TI - Upper urinary tract lipoma: A case report. AB - Upper urinary tract (UUT) benign tumours are rare. We present a case of UUT lipoma in a 41-year-old man with left flank pain. A computed tomographic urography scan revealed an irregular thickening of the left renal collecting system wall extending from the upper calices to the renal pelvis. The diagnosis of UUT was made and the patient underwent a nephroureterectomy with bladder cuff excision, as standard treatment. However, macroscopic and histological examination revealed a lipomatous tumour with no sign of malignancy. To our knowledge this is the first reported case of its kind of a UUT managed first with a minimally invasive approach. PMID- 26425241 TI - A novel approach for manual de-torsion of an atypical (outward) testicular torsion with bedside Doppler ultrasonography guidance. AB - A 17-year-old boy presented with right testicular torsion to the lateral side. Torsion was diagnosed by physical examination; the colour Doppler ultrasonography (CDU) confirmed right testicular torsion with minimal peripheral hydrocele. Transverse and longitudinal examination of the spermatic cord with ultrasound and CDU revealed a counter-clockwise testicular torsion. Manual de-torsion was performed in a clockwise direction (720o) and testicular blood flow and the neutral position of the spermatic cord were confirmed by CDU. We did not encounter a residual twist of the spermatic cord upon surgical exploration. In our experience, ultrasound and CDU may predict the direction of testicular torsion and may allow appropriate management of cases prior to surgery. PMID- 26425242 TI - Conservative treatment for Brucella testicular abscesses: A case report and literature review. AB - Brucellosis is a multi-organ infectious disease that can cause genitourinary manifestations.1-4 The most common genitourinary manifestation is orchitis;2,4 however, intratesticular abscesses are a rare complication. Although surgery is the standard treatment for intratesticular abscesses, medical therapy alone can be successful. We report the case of a 36-year-old man with multiple testicular abscesses caused by relapse of systemic brucellosis. The patient presented after a history of treated systemic brucellosis with left testicular swelling and pain. An ultrasound showed multiple small testicular abscesses, and the repeat diluted brucella titer demonstrated the causative pathogen. The patient was successfully treated with 3 months of oral targeted antibiotics, with no need for drainage or orchiectomy. PMID- 26425243 TI - Fungus ball and emphysematous cystitis secondary to Candida tropicalis: A case report. AB - Fungus ball and fungal emphysematous cystitis are two rare complications of fungal urinary tract infection. A 53-year-old male patient presented with these complications caused by Candida tropicalis simultaneously. The predisposing factors were diabetes mellitus and usage of broad-spectrum antibiotics. The fungus ball, measuring 3.5 * 2.0 cm on the left wall of the urinary bladder, shrank significantly to 1.6 * 0.8 cm after 5 days of intermittent irrigation with saline before surgery. With transurethral removal of the fungus ball and antifungal treatment with fluconazole, the patient fully recovered. We conclude that a bladder fungus ball and fungal emphysematous cystitis should always be suspected in patients with diabetes mellitus with uncontrolled funguria and abnormal imaging. Treatment should include a systemic antifungal therapy and thorough surgical removal of the fungus ball. A systemic antifungal therapy combined with a local irrigation with saline or antifungal drugs might help decrease the dissemination of fungemia during an invasive manipulation. PMID- 26425245 TI - The Origins of Jewish Guilt: Psychological, Theological, and Cultural Perspectives. AB - The idea that guilt and Judaism are closely interlinked has a long historical legacy. After discussing recent work on anthropology and emotion focusing on shame and guilt, we examine three theories purporting to account for this link: psychoanalytic, theological, and guilt as a cultural stereotype particularly the notion of the Jewish mother. PMID- 26425244 TI - Chromophobe renal cell carcinoma recurrence in the ureter: A late presentation of a rare metastasis. AB - We describe a case of recurrence of chromophobe renal cell carcinoma 8 years after successful surgical treatment of primary localized disease in the left kidney. The primary tumour had exhibited neither gross nor histological evidence of lymphovascular infiltration. The recurrence occurred in the residual left ureteric stump - a finding that, to the best of our knowledge, has not previously been reported. PMID- 26425246 TI - Prophylactic Fresh Frozen Plasma Infusion is Ineffective in Reversing Warfarin Anticoagulation and Preventing Delayed Intracranial Hemorrhage After Falls. AB - BACKGROUND: Elderly patients, with considerable fall risk, are increasingly anticoagulated to prevent thromboembolic disease. We hypothesized that a policy of prophylactic fresh frozen plasma (FFP) infusion in patients having falls would reverse vitamin K antagonists (VKAs) and that reversal would decrease delayed intracranial hemorrhage (ICH). METHODS: A retrospective review of patients with trauma admitted to a level 2 community trauma center was performed from January 2010 until November 2012. Inclusion criteria were: ground level fall (GLF) with suspected head trauma, on VKA, an international normalized ratio (INR) of >1.5, and a negative head computed tomography (CT). Patients were transfused with FFP to a goal INR of <1.5 while observed. Patients were classified as reversed (REV) if the lowest INR achieved within 4 to 24 hours after initial INR was <1.5 or unreversed (NREV) if lowest INR achieved was >1.5. Chi-square and logistic regression were performed. RESULTS: A total of 194 patients met the criteria. In all, 43 (22%) patients were able to be REV, and 151 (78%) patients remained NREV. Unreversed patients were male and younger (P < .05). There was no difference in mean FFP received. Unreversed patients had a higher initial INR of 3.0 compared to REV patients (2.5; P = .018). One patient developed a delayed ICH and belonged to the REV group. CONCLUSION: The incidence of delayed hemorrhage was 0.5%. A strategy of prophylactic FFP infusion was ineffective in VKA reversal. We recommend against prophylactic infusion of FFP during a period of observation for patients on VKA with suspected head trauma and a negative initial CT. PMID- 26425247 TI - Facilitating Early-In-Day Discharge for Multiple Sclerosis Patients Treated With Intravenous Methylprednisolone: A Quality Improvement Project. AB - BACKGROUND AND PURPOSE: Delays in patient hospital discharge affect care value through costs of prolonged length of stay and barriers to patient flow within the hospital. We sought to facilitate early-in-day discharges (EIDDs) without extending length of stay for inpatients with multiple sclerosis admitted for acute exacerbations and treated with intravenous (IV) methylprednisolone. METHODS: We developed a standardized admission order set, a provider checklist, and a patient checklist to better coordinate in-hospital care and discharge planning for patients with multiple sclerosis admitted for IV methylprednisolone treatment. The order set allowed providers to enter an accelerated dosing schedule of methylprednisolone, as appropriate, to ensure administration of the final dose of methylprednisolone in the morning on the anticipated day of discharge. We compared a prospective intervention cohort to a retrospective, preintervention baseline cohort. RESULTS: At baseline (N = 25), 12.0% of patients were EIDD compared to 40.7% of intervention patients (N = 27; P = .03). In all, 85.2% of intervention patients compared to 64.0% of baseline patients were discharged on the same day as last methylprednisolone treatment (P = .11). No difference was observed in median length of stay and 30-day readmission rate between groups. CONCLUSIONS: Use of a standard admission order set as well as provider and patient checklists can facilitate EIDD and hospital bed availability without compromising care quality for a select group of neurology inpatients. PMID- 26425248 TI - Cervical Myelopathy Caused by Injections into the Neck. AB - Three cases of longitudinally extensive cervical myelopathies temporally associated with neck injections are presented. The spinal cord injury was similar radiographically, despite a number of different needle approaches and substances injected. In recent years, there have been reports of an acute cervical myelopathy immediately following an injection procedure in the neck. Various explanations have been offered for this unfortunate complication, including (1) direct injection into the cord leading to traumatic injury, (2) injection of particulate matter into the arterial supply of the cord causing microvascular embolism and spinal cord infarction, and (3) intraneural injection of the chemical with centripetal spread of the injectant from the nerve trunk to the substance of the cord. The merits of each of these 3 mechanisms in explaining these cases are discussed. Albeit rare, acute cervical myelopathy should be considered a potential complication from any deep injection of chemicals into the neck. PMID- 26425249 TI - Direct Invasion of the Optic Nerves, Chiasm, and Tracts by Cryptococcus neoformans in an Immunocompetent Host. AB - Cryptococcus spp is a common fungal infection and frequent cause of meningitis in immunocompromised patients; however, immunocompetent patients are also at risk of infection. Visual loss often occurs via elevated intracranial hypertension but can rarely occur through direct optic nerve, chiasm, or tract invasion. We report a case of a 38-year-old woman who presented with decreased acuity in both eyes. She had generalized visual field constriction in the right eye and temporal hemianopsia in the left eye. Magnetic resonance imaging of the brain and orbits showed multiple areas of ill-defined enhancement in the optic chiasm and tracts as well as in the diaphragmatic sella, prepontine and interpeduncular cisterns, and along cranial nerves VI, VII, and VIII bilaterally. Initial cerebrospinal fluid (CSF) showed 34 white blood cells, hypoglycorrhachia, and negative cryptococcal antigen and bacterial and fungal cultures. A transphenoidal biopsy of the dura and pituitary gland was unremarkable. Empiric steroids resulted in marked improvement in visual acuity in both eyes, but while tapering steroids, she developed rapid visual loss bilaterally. Repeat CSF performed 6 weeks later demonstrated a cryptococcal antigen titer of 1:512. Retroactive staining of the pituitary biopsy was positive for mucicarmine, a component of the polysaccharide capsule of Cryptococcus spp. After induction therapy with amphotericin B and flucytosine and 1 year of fluconazole, her visual acuity was 20/20 in both eyes. In summary, Cryptococcus can affect immunocompetent patients and often presents with insidious, chronic meningitis. Visual loss is common in cryptococcal meningitis but usually results from fulminant papilledema related to elevated intracranial pressure. In rare cases, direct nerve or chiasm infiltration by the fungus results in vision loss. PMID- 26425251 TI - Dabigatran-Associated Intracranial Hemorrhage: Literature Review and Institutional Experience. AB - Dabigatran etexilate is an oral direct thrombin inhibitor approved for prevention of stroke and systemic embolization in patients with nonvalvular atrial fibrillation and for the treatment of venous thromboembolism. Although dabigatran has a favorable safety profile, predictable pharmacokinetics, fewer drug interactions than warfarin, and does not require monitoring, clinical data regarding dabigatran reversal are limited. In addition, currently available laboratory assays allow measurement of the presence, but not extent, of dabigatran-associated anticoagulation. Patient age, renal function, weight, concurrent drug therapy, adherence, and concomitant disease states can affect dabigatran's efficacy and safety. Management of dabigatran-related intracranial hemorrhage must be approached on a case-by-case basis and include assessment of degree of anticoagulation, severity of hemorrhage, renal function, timing of last dabigatran dose, and risk of thromboembolic events. Initial management includes dabigatran discontinuation and general supportive measures. Oral activated charcoal should be administered in those who ingested dabigatran within 2 hours. Four-factor prothrombin complex concentrates (4PCCs), activated PCC, or recombinant activated factor VII use may be reasonable but is not evidence based. Reserve fresh frozen plasma for patients with dilutional coagulopathy. If readily available, hemodialysis should be considered, particularly in patients with advanced kidney injury or excessive risk of thromboembolic events. More clinical studies are needed to determine a standardized approach to treating dabigatran associated intracranial hemorrhage. Institutional protocol development will facilitate safe, efficacious, and timely use of the limited management options. PMID- 26425250 TI - Neuro-Ophthalmological Emergencies. AB - Neuro-ophthalmological emergencies constitute vision or life-threatening conditions if diagnosis and treatment are not promptly undertaken. Even with immediate therapy, these clinical entities carry a high rate of morbidity. They may present with diplopia, visual loss, and/or anisocoria. Arteritic anterior ischemic optic neuropathy is an ominous condition, which can cause permanent and severe vision loss, stroke, or aortic dissection, requiring immediate steroid therapy. Pituitary apoplexy may go unnoticed if only computed axial tomography is performed. Diseases affecting the cavernous sinus and orbital apex region, such as cavernous sinus thrombosis or mucormycosis, can give rise to simultaneous vision loss and diplopia and, if not treated, may extend to the brain parenchyma causing permanent neurological sequela. An isolated third nerve palsy may be the harbinger of a cerebral aneurysm, carrying a significant risk of mortality. Horner syndrome can be the initial presentation of a carotid dissection, an important cause of stroke in the young adult. The neurohospitalist should be familiar with the workup and management of neuro-ophthalmological emergencies. PMID- 26425253 TI - The Reversal Sign: An Ominous Imaging Finding. PMID- 26425252 TI - A 61-Year-Old Woman With Headaches and Aphasia. PMID- 26425254 TI - A Tangled Web. PMID- 26425255 TI - Differential Diagnosis of Restricted Diffusion of the Thalamus-Focus on Viral Encephalitis. PMID- 26425256 TI - Ictal Asystole in Focal Epilepsy: To Pace or Not to Pace? AB - Ictal bradyarrhythmias are rare episodes occurring in patients with or without a past cardiac history. These episodes go unnoticed unless the patient is monitored on simultaneous video-electroencephalogram and 1-lead electrocardiogram. Recognizing ictal bradyarrhythmias is important, since episodes may predispose patients to sudden, unexplained death in epilepsy. We present 2 cases of ictal asystole in patients with right temporal lobe epilepsy. The first patient had seizures refractory to medical therapy and received a pacemaker. The seizures in the second patient responded well to antiepileptic medication, and a pacemaker was deferred. These cases highlight the differing cardiovascular treatment options for ictal asystole. PMID- 26425257 TI - The Use of Osteochondral Allograft Transplantation for Primary Treatment of Cartilage Lesions in the Knee. AB - OBJECTIVE: To assess the outcome of osteochondral allograft (OCA) transplantation as the primary treatment for cartilage injury in patients with no previous surgical treatment. STUDY DESIGN: Case series. Patients were identified in our outcomes database. Patients undergoing primary OCA transplantation with no prior surgical treatment and a minimum of 2 years follow-up were selected. Pain and function were evaluated preoperatively and postoperatively. Patient satisfaction was assessed. Reoperations following OCA transplantation were captured. Failure was defined as revision OCA or conversion to arthroplasty. RESULTS: Fifty-five patients (61 knees) were included in the analysis. The study consisted of 30 males and 25 females (mean age = 32.9 years; range = 15.7-67.8 years). The most common diagnoses for the OCA transplantation were osteochondritis dissecans (44.3%) and avascular necrosis (31.1%). Pain and function improved preoperatively to postoperatively on all outcome scales (P < 0.01). The majority of patients (86%) were "extremely satisfied" or "satisfied." OCA survivorship was 89.5% at 5 years and 74.7% at 10 years. At latest follow-up (mean = 7.6 years; range = 1.9 22.6 years), OCA remained in situ in 50 knees (82%). Eighteen knees (29.5%) had further surgery; 11 OCA failures and 7 other surgical procedure(s). Of the failed knees (mean time to failure = 3.5 years; range = 0.5-13.7 years), 8 were converted to arthroplasty, 2 had OCA revisions, and 1 had a patellectomy. CONCLUSIONS: OCA transplantation is an acceptable primary treatment method for some chondral and osteochondral defects of the knee. Failure of previous treatment(s) is not a prerequisite for OCA transplantation. PMID- 26425258 TI - Cartilage Degeneration and Alignment in Severe Varus Knee Osteoarthritis. AB - OBJECTIVES: The aim of this study was to examine the relationship between cartilage, ligament, and meniscus degeneration and radiographic alignment in severe varus knee osteoarthritis in order to understand the development of varus knee osteoarthritis. DESIGN: Fifty-three patients (71 knees) with primary varus knee osteoarthritis and who underwent total knee arthroplasty were selected for this study. There were 6 men and 47 women, with 40 right knees and 31 left knees studied; their mean age at operation was 73.5 years. The ligament, meniscus, degeneration of joint cartilage, and radiographic alignments were examined visually. RESULTS: The tibial plateau-tibial shaft angle was larger if the condition of the cartilage in the lateral femoral condyle was worse. The femorotibial angle and tibial plateau-tibial shaft angle were larger if the conditions of the lateral meniscus or the cartilage in the lateral tibial plateau were worse. CONCLUSION: Based on the results of this study, progression of varus knee osteoarthritis may occur in the following manner: medial knee osteoarthritis starts in the central portion of the medial tibial plateau, and accompanied by medial meniscal extrusion and anterior cruciate ligament rupture, cartilage degeneration expands from the anterior to the posterior in the medial tibial plateau. Bone attrition occurs in the medial tibial plateau, and the femoro tibial angle and tibial plateau-tibial shaft angle increase. Therefore, the lateral intercondylar eminence injures the cartilage of the lateral femoral condyle in the longitudinal fissure type. Thereafter, the cartilage degeneration expands in the whole of the knee joints. PMID- 26425259 TI - Depth-Dependent Glycosaminoglycan Concentration in Articular Cartilage by Quantitative Contrast-Enhanced Micro-Computed Tomography. AB - OBJECTIVE: A quantitative contrast-enhanced micro-computed tomography (qCECT) method was developed to investigate the depth dependency and heterogeneity of the glycosaminoglycan (GAG) concentration of ex vivo cartilage equilibrated with an anionic radiographic contrast agent, Hexabrix. DESIGN: Full-thickness fresh native (n = 19 in 3 subgroups) and trypsin-degraded (n = 6) articular cartilage blocks were imaged using micro-computed tomography (MUCT) at high resolution (13.4 MUm(3)) before and after equilibration with various Hexabrix bathing concentrations. The GAG concentration was calculated depth-dependently based on Gibbs-Donnan equilibrium theory. Analysis of variance with Tukey's post hoc was used to test for statistical significance (P < 0.05) for effect of Hexabrix bathing concentration, and for differences in bulk and zonal GAG concentrations individually and compared between native and trypsin-degraded cartilage. RESULTS: The bulk GAG concentration was calculated to be 74.44 +/- 6.09 and 11.99 +/- 4.24 mg/mL for native and degraded cartilage, respectively. A statistical difference was demonstrated for bulk and zonal GAG between native and degraded cartilage (P < 0.032). A statistical difference was not demonstrated for bulk GAG when comparing Hexabrix bathing concentrations (P > 0.3214) for neither native nor degraded cartilage. Depth-dependent GAG analysis of native cartilage revealed a statistical difference only in the radial zone between 30% and 50% Hexabrix bathing concentrations. CONCLUSIONS: This nondestructive qCECT methodology calculated the depth-dependent GAG concentration for both native and trypsin degraded cartilage at high spatial resolution. qCECT allows for more detailed understanding of the topography and depth dependency, which could help diagnose health, degradation, and repair of native and contrived cartilage. PMID- 26425260 TI - Characterization of Tissue Response to Impact Loads Delivered Using a Hand-Held Instrument for Studying Articular Cartilage Injury. AB - OBJECTIVE: The objective of this study was to fully characterize the mechanics of an in vivo impactor and correlate the mechanics with superficial cracking of articular surfaces. DESIGN: A spring-loaded impactor was used to apply energy controlled impacts to the articular surfaces of neonatal bovine cartilage. The simultaneous use of a load cell and displacement sensor provided measurements of stress, stress rate, strain, strain rate, and strain energy density. Application of India ink after impact was used to correlate the mechanical inputs during impact with the resulting severity of tissue damage. Additionally, a signal processing method to deconvolve inertial stresses from impact stresses was developed and validated. RESULTS: Impact models fit the data well (root mean square error average ~0.09) and provided a fully characterized impact. Correlation analysis between mechanical inputs and degree of superficial cracking made visible through India ink application provided significant positive correlations for stress and stress rate with degree of surface cracking (R (2) = 0.7398 and R (2) = 0.5262, respectively). Ranges of impact parameters were 7 to 21 MPa, 6 to 40 GPa/s, 0.16 to 0.38, 87 to 236 s(-1), and 0.3 to 1.1 MJ/m(3) for stress, stress rate, strain, strain rate, and strain energy density, respectively. Thresholds for damage for all inputs were determined at 13 MPa, 15 GPa/s, 0.23, 160 s(-1), and 0.59 MJ/m(3) for this system. CONCLUSIONS: This study provided the mechanical basis for use of a portable, sterilizable, and maneuverable impacting device. Use of this device enables controlled impact loads in vitro or in vivo to connect mechanistic studies with long-term monitoring of disease progression. PMID- 26425261 TI - In Vitro Toxicity of Local Anesthetics and Corticosteroids on Chondrocyte and Synoviocyte Viability and Metabolism. AB - OBJECTIVE: There is growing concern that intra-articular injection of local anesthetic and/or corticosteroids may cause significant morbidity, including potential toxicity to chondrocytes and synoviocytes, after even a single exposure. We demonstrate that full thickness canine chondral and synovial samples exposed to various local anesthetics and corticosteroids exhibit decreased loss of cell viability compared with prior in vitro studies using monolayer culture, due to the protective effects of intact extracellular matrix and cell heterogeneity. METHODS: Full-thickness cartilage and synovial explants were obtained from canine cadavers and exposed in culture media to the following for 24 hours: 1% lidocaine, 0.5% lidocaine, 0.25% bupivacaine, 0.125% bupvacaine, 0.0625% bupivacaine, betamethasone acetate, methylprednisolone acetate, triamcinolone acetonide, or culture media only (control). Cell viability was determined on days 1 and 7 of culture using a microscopic live-dead and alamar blue metabolic assays. RESULTS: Complete loss of chondrocyte and synoviocyte viability was noted in the 1% and 0.5% lidocaine group, 0.25% and 0.125% bupivacaine group, betamethasone group, and methylprednisolone groups after 1 and 7 days of culture. Treatment with 0.0625% bupivacaine and triamcinolone demonstrated no decrease in cell viability or metabolism when compared to negative control. CONCLUSIONS: In this canine explant model, 1% and 0.5% lidocaine, 0.25% and 0.125% bupivacaine, betamethasone acetate, and methylpresdnisolone acetate were severely chondrotoxic and synoviotoxic after a single exposure, despite intact extracellular matrix. In contrast, chondrocytes and synoviocytes exposed to 0.0625% bupivacaine and triamcinolone remained viable after treatment. Further in vivo study is needed before definitive recommendations can be made. PMID- 26425262 TI - Repairing Osteochondral Defects of Critical Size Using Multiple Costal Grafts: An Experimental Study. AB - OBJECTIVE: To investigate the feasibility of repairing osteochondral defects of critical size by performing mosaicplasty using multiple sliced costal cartilage grafts, which enables repair of extensively injured knees using grafts from a single rib. DESIGN: Critical osteochondral defects were prepared on the femoral groove of skeletally mature Japanese white rabbits. Costal cartilage grafts from a single rib were harvested and sliced into multiple segments (approximately 3-5 mm in length). The defects were left untreated or repaired by performing mosaicplasty using costal cartilage grafts (with or without a longitudinal cut along the middle). At 4 and 12 weeks after transplantation, International Cartilage Repair Society macroscopic and histological grading was performed. RESULTS: The macroscopic score and visual histological score were significantly higher in the repaired groups than in the untreated group at 4 and 12 weeks after surgery. Histological continuous integration between grafted costal cartilage and host bone was observed in both repaired groups. CONCLUSIONS: The findings suggest that costal cartilage might be a useful alternative source for chondral grafting. We were able to repair large osteochondral defects by performing mosaicplasty using multiple sliced costal cartilage grafts from a single rib. PMID- 26425263 TI - An In Vitro Comparison of the Incorporation, Growth, and Chondrogenic Potential of Human Bone Marrow versus Adipose Tissue Mesenchymal Stem Cells in Clinically Relevant Cell Scaffolds Used for Cartilage Repair. AB - AIM: To compare the incorporation, growth, and chondrogenic potential of bone marrow (BM) and adipose tissue (AT) mesenchymal stem cells (MSCs) in scaffolds used for cartilage repair. METHODS: Human BM and AT MSCs were isolated, culture expanded, and characterised using standard protocols, then seeded into 2 different scaffolds, Chondro-Gide or Alpha Chondro Shield. Cell adhesion, incorporation, and viable cell growth were assessed microscopically and following calcein AM/ethidium homodimer (Live/Dead) staining. Cell-seeded scaffolds were treated with chondrogenic inducers for 28 days. Extracellular matrix deposition and soluble glycosaminoglycan (GAG) release into the culture medium was measured at day 28 by histology/immunohistochemistry and dimethylmethylene blue assay, respectively. RESULTS: A greater number of viable MSCs from either source adhered and incorporated into Chondro-Gide than into Alpha Chondro Shield. In both cell scaffolds, this incorporation represented less than 2% of the cells that were seeded. There was a marked proliferation of BM MSCs, but not AT MSCs, in Chondro Gide. MSCs from both sources underwent chondrogenic differentiation following induction. However, cartilaginous extracellular matrix deposition was most marked in Chondro-Gide seeded with BM MSCs. Soluble GAG secretion increased in chondrogenic versus control conditions. There was no marked difference in GAG secretion by MSCs from either cell source. CONCLUSION: Chondro-Gide and Alpha Chondro Shield were permissive to the incorporation and chondrogenic differentiation of human BM and AT MSCs. Chondro-Gide seeded with BM MSCs demonstrated the greatest increase in MSC number and deposition of a cartilaginous tissue. PMID- 26425264 TI - Comparison of Efficacy of Endogenous and Exogenous IGF-I in Stimulating Matrix Production in Neonatal and Mature Chondrocytes. AB - OBJECTIVE: The goal of this study was to compare the efficacy of endogenous upregulation of IGF-I by gene therapy and exogenous addition of insulin-like growth factor I (IGF-I) in enhancing proteoglycan synthesis by skeletally mature and neonatal chondrocytes. Chondrocyte transplantation therapy is a common treatment for focal cartilage lesions, with both mature and neonatal chondrocytes used as a cell source. Additionally, gene therapy strategies to upregulate growth factors such as IGF-I have been proposed to augment chondrocyte transplantation therapies. METHODS: Both skeletally mature and neonatal chondrocytes were exposed to either an adeno-associated virus-based plasmid containing the IGF-I gene or exogenous IGF-I. RESULTS: Analysis of IGF-I and glycosaminoglycan production using a 4-parameter dose-response model established a clear connection between the amount of IGF-I produced by cells and their biosynthetic response. Both neonatal and mature chondrocytes showed this relationship, but the sensitivities were quite different, with EC50 of 0.57 ng/mL for neonatal chondrocytes and EC50 of 8.70 ng/mL IGF-I for skeletally mature chondrocytes. CONCLUSIONS: These data suggest that IGF-I gene therapy may be more effective with younger cell sources. Both cell types were less sensitive to exogenous IGF-I than endogenous IGF-I. PMID- 26425265 TI - Detection methods and clinical significance of free peritoneal tumor cells found during colorectal cancer surgery. AB - Peritoneal washing is now part of the standard clinical practice in several abdominal and pelvic neoplasias. However, in colorectal cancer surgery, intra peritoneal free cancer cells (IFCC) presence is not routinely investigated and their prognostic meaning is still unclear. When peritoneal washing results are positive for the presence of IFCC a worse outcome is usually expected in these colorectal cancer operated patients, but it what is not clear is whether it is associated with an increased risk of local recurrence. It is authors' belief that one of the main reasons why IFCC are not researched as integral part of the routine staging system for colon cancer is that there still isn't a diagnostic or detection method with enough sensibility and specificity. However, the potential clinical implications of a routine research for the presence IFCC in colon neoplasias are enormous: not only to obtain a more accurate clinical staging but also to offer different therapy protocols, based on the presence of IFCC. Based on this, adjuvant chemotherapy could be offered to those patients found to be positive for IFCC; also, protocols of proactive intraperitoneal chemotherapy could be applied. Although presence of IFCC appears to have a valid prognostic significance, further studies are needed to standardize detection and examination procedures, to determine if there are and which are the stages more likely to benefit from routine search for IFCC. PMID- 26425266 TI - Need for simulation in laparoscopic colorectal surgery training. AB - The dissemination of laparoscopic colorectal surgery (LCS) has been slow despite increasing evidence for the clinical benefits, with a prolonged learning curve being one of the main restrictions for a prompt uptake. Performing advanced laparoscopic procedures requires dedicated surgical skills and new simulation methods designed precisely for LCS have been established: These include virtual reality simulators, box trainers, animal and human tissue and synthetic materials. Studies have even demonstrated an improvement in trainees' laparoscopic skills in the actual operating room and a staged approach to surgical simulation with a combination of various training methods should be mandatory in every colorectal training program. The learning curve for LCS could be reduced through practice and skills development in a riskfree setting. PMID- 26425267 TI - Management of afferent loop obstruction: Reoperation or endoscopic and percutaneous interventions? AB - Afferent loop obstruction is a purely mechanical complication that infrequently occurs following construction of a gastrojejunostomy. The operations most commonly associated with this complication are gastrectomy with Billroth II or Roux-en-Y reconstruction, and pancreaticoduodenectomy with conventional loop or Roux-en-Y reconstruction. Etiology of afferent loop obstruction includes: (1) entrapment, compression and kinking by postoperative adhesions; (2) internal herniation, volvulus and intussusception; (3) stenosis due to ulceration at the gastrojejunostomy site and radiation enteritis of the afferent loop; (4) cancer recurrence; and (5) enteroliths, bezoars and foreign bodies. Acute afferent loop obstruction is associated with complete obstruction of the afferent loop and represents a surgical emergency, whereas chronic afferent loop obstruction is associated with partial obstruction. Abdominal multiple detector computed tomography is the diagnostic study of choice. CT appearance of the obstructed afferent loop consists of a C-shaped, fluid-filled tubular mass located in the midline between the abdominal aorta and the superior mesenteric artery with valvulae conniventes projecting into the lumen. The cornerstone of treatment is surgery. Surgery includes: (1) adhesiolysis and reconstruction for benign causes; and (2) by-pass or excision and reconstruction for malignant causes. However, endoscopic enteral stenting, transhepatic percutaneous enteral stenting and direct percutaneous tube enterostomy have the principal role in management of malignant and radiation-induced obstruction. Nevertheless, considerable limitations exist as a former Roux-en-Y reconstruction limits endoscopic access to the afferent loop and percutaneous approaches for enteral stenting and tube enterostomy have only been reported in the literature as isolated cases. PMID- 26425268 TI - Response to chemoradiotherapy and lymph node involvement in locally advanced rectal cancer. AB - AIM: To establish the association between lymph node involvement and the response to neoadjuvant therapy in locally advanced rectal cancer. METHODS: Data of 130 patients with mid and low locally advanced rectal adenocarcinoma treated with neoadjuvant chemoradiation followed by radical surgery over a 5-year period were reviewed. Tumor staging was done by endorectal ultrasound and/or magnetic resonance imaging. Tumor response to neoadjuvant therapy was determined by T downstaging and tumor regression grading (TRG). Pathologic complete response (pCR) is defined as the absence of tumor cells in the surgical specimen (ypT0N0). The varying degrees TRG were classified according to Mandard's scoring system. The evaluation of the response is based on the comparison between previous clinico-radiological staging and the results of pathological evaluation. chi (2) and Spearman's correlation tests were used for the comparison of variables. RESULTS: Pathologic complete response (pCR, ypT0N0, TRG1) was observed in 19 cases (14.6%), and other 18 (13.8%) had only very few residual malignant cells in the rectal wall (TRG2). T-downstaging was found in 63 (48.5%). Mean lymph node retrieval was 9.4 (range 0-38). In 37 cases (28.5%) more than 12 nodes were identified in the surgical specimen. Preoperative lymph node involvement was seen in 77 patients (59.2%), 71 N1 and 6 N2. Postoperative lymph node involvement was observed in 41 patients (31.5%), 29 N1 and 12 N2, while the remaining 89 were N0 (68.5%). In relation to ypT stage, we found nodal involvement of 9.4% in ypT0-1, 22.2% in ypT2 and 43.7% in ypT3-4. Of the 37 patients considered "responders" to neoadjuvant therapy (TRG1 and 2), there were only 4 N+ (10.8%) and the remainder N0 (89.2%). In the "non responders" group (TRG 3, 4 and 5), 37 cases were N+ (39.8%) and 56 (60.2%) were N0 (P < 0.001). CONCLUSION: Response to neoadjuvant chemoradiation in rectal cancer is associated with lymph node involvement. PMID- 26425269 TI - Validation of a new scoring system: Rapid assessment faecal incontinence score. AB - AIM: To implement a quick and simple test - rapid assessment faecal incontinence score (RAFIS) and show its reliability and validity. METHODS: From March 2008 through March 2010, we evaluated a total of 261 consecutive patients, including 53 patients with faecal incontinence. Demographic and comorbidity information was collected. In a single visit, patients were administered the RAFIS. The results obtained with the new score were compared with those of both Wexner score and faecal incontinence quality of life scale (FIQL) questionnaire. The patient without influence of the surgeon completed the test. The role of surgeon was explaining the meaning of each section and how he had to fill. Reliability of the RAFIS score was measured using intra-observer agreement and Cronbach's alpha (internal consistency) coefficient. Multivariate analysis of the main components within the different scores was performed in order to determine whether all the scores measured the same factor and to conclude whether the information could be encompassed in a single factor. A sample size of 50 patients with faecal incontinence was estimated to be enough to detect a correlation of 0.55 or better at 5% level of significance with 80% power. RESULTS: We analysed the results obtained by 53 consecutive patients with faecal incontinence (median age 61.55 +/ 12.49 years) in the three scoring systems. A total of 208 healthy volunteers (median age 58.41 +/- 18.41 years) without faecal incontinence were included in the study as negative controls. Pearson's correlation coefficient between "state" and "leaks" was excellent (r = 0.92, P < 0.005). Internal consistency in the comparison of "state" and "leaks" yielded also excellent correlation (Cronbach's alpha = 0.93). Results in each score were compared using regression analysis and a correlation value of r = 0.98 was obtained with Wexner score. As regards FIQL questionnaire, the values of "r" for the different subscales of the questionnaire were: "lifestyle" r = -0.87, "coping/behaviour" r = -0.91, "depression" r = -0.36 and "embarrassment" r = -0.90, (P < 0.01). A multivariate analysis showed that all the scoring systems measured the same factor. A single factor may explain 80.84% of the variability of FI, so all the scoring systems measure the same factor. Patient's continence improves when RAFIS and Jorge-Wexner scores show low values and when the values obtained in the FIQL questionnaire are high. CONCLUSION: RAFIS is a valid and reliable tool to assess Faecal Incontinence. PMID- 26425270 TI - Impact of surgical delay on outcomes in elderly patients undergoing emergency surgery: A single center experience. AB - AIM: To determine predisposing factors leading to surgical delay in elderly patients with acute abdominal conditions and its impact on surgical outcomes. METHODS: A retrospective review of a total of 144 patients aged 60 years and older who had undergone emergency abdominal surgery between 2010 and 2013 at a regional general hospital was analysed. The operations analysed were limited to perforated or gangrenous viscus and strangulated hernia. Patient demographic features, time taken to obtain a computed tomography scan, time taken to surgery and the impact on postoperative morbidity and mortality were analysed. RESULTS: The mean age was 70.5 +/- 9.1 years and median time taken to surgery was 9 h. The overall mortality and complication rates (Clavien Dindo 3 and above) were 9% and 13.1% respectively. Diabetes mellitus was a significant predisposing factor which had an impact on surgical delays. Delays in surgery more than 24 h led to higher complication rates at 38.9% (P = 0.003), with multivariate analysis confirming it as an independent factor. Delays in obtaining a computed tomography (CT) scan was also shown to result in higher complication rates (Clavien Dindo 3 and above). CONCLUSION: Delays in performing emergency surgery in elderly lead to higher complication rates. Obtaining CT scans early also may facilitate prompt diagnosis of certain abdominal emergencies where presentation is more equivocal and this may lead to improved surgical outcomes. PMID- 26425271 TI - Laying open (deroofing) and curettage under local anesthesia for pilonidal disease: An outpatient procedure. AB - AIM: To test the efficacy of lay open (deroofing, not excision) with curettage under local anesthesia (LOCULA) for pilonidal sinus as an outpatient procedure. METHODS: LOCULA procedure was done for all types of pilonidal disease. The primary outcome measure was cure rate. The secondary outcome measures were hospital stay, operating time, return to work, healing time and complication rate. RESULTS: Thirty-three (M/F-30/3, mean age-23.4 +/- 5.8 years) consecutive patients were operated and followed for 24 mo (6-46 mo). Eleven were pilonidal abscess and 22 were chronic pilonidal disease. Six had recurrent disease. Operating time and the hospital stay was 22.3 +/- 5.6 min and 63.8 +/- 22.3 min respectively. The patients could resume normal work in 4.3 +/- 3.2 d and the healing time was 42.9 +/- 8.1 d. Thirty (93.8%) patients had complete resolution of the disease and two (6.2%) had a recurrence. Both the recurrences happened in patients who had complete healing but ignored the prescribed recommendations. One out of these got cured after getting operated again with the same procedure. Thus the overall success rate of this procedure was 96.9%. CONCLUSION: Lay open (deroofing) with curettage procedure under local anesthesia is an effective procedure to treat both simple and complicated pilonidal sinus and abscess. It is a simple procedure, has a high cure rate (up to 97%), doesn't require admission and is associated with minimal morbidity and scarring. Considering the distinct advantages, this procedure has the potential to become the first line procedure for treating pilonidal disease. PMID- 26425272 TI - Acute pancreatitis complicated with splenic rupture: A case report. AB - Atraumatic splenic rupture is an uncommon complication of acute pancreatitis. This report describes the case of a 30-year-old man with acute pancreatitis and splenic vein thrombosis complicated by splenic rupture. The patient was admitted to the emergency department with pain in the upper abdomen that had been present for six hours and was associated with vomiting and sweating. He was diagnosed with acute pancreatitis of alcoholic etiology. Upon computed tomography (CT) of the abdomen, the pancreatitis was scored as Balthazar C grade, and a suspicious area of necrosis affecting 30% of the pancreas with splenic vein thrombosis was revealed. Seventy-two hours after admission, the patient had significant improvement in symptoms. However, he showed clinical worsening on the sixth day of hospitalization, with increasing abdominal distension and reduced hemoglobin levels. A CT angiography showed a large amount of free fluid in the abdominal cavity, along with a large splenic hematoma and contrast extravasation along the spleen artery. The patient subsequently underwent laparotomy, which showed hemoperitoneum due to rupture of the splenic parenchyma. A splenectomy was then performed, followed by ultrasound-guided percutaneous drainage. PMID- 26425273 TI - Hematopoietic effect of deer antler extract fermented by Bacillus subtilis on murine marrow cells. AB - BACKGROUND/OBJECTIVES: We examined the chemical composition and the effect of fermented deer antler on hematopoietic factors in bone marrow cells. MATERIALS/METHODS: For the preparation of fermented deer antler extract (FAB), fermentation was carried out using Bacillus subtilis at 30C for 7 days. The hematopoietic effect of FAB was investigated hematopoietic factors in marrow cells. RESULTS: The contents of total sugar, sulfated glycosaminoglycans, and uronic acid and the dry weight gradually increased with fermentation time. The sialic acid content (from 0.14 mg/mL to 0.54 mg/mL) was the highest on the 4th day of fermentation after which it decreased. The proliferating activity of bone marrow cells increased with fermentation times. The levels of various hematopoietic growth factors were determined to verify the beneficial effect of deer antler extract fermented by B. subtilis on hematopoiesis. FAB increased the number of stem cell factors and granulocyte colony-stimulating factor in bone marrow cells. In addition, FAB augmented the burst-forming unit erythroid and total colonies in splenocyte-conditioned medium compared with non-fermented antler extract (NFA). However, FAB did not affect the mRNA levels of erythropoietin, an important factor for erythropoiesis. CONCLUSIONS: FAB, like NFA, did not directly affect hematopoiesis, but contributed to hematopoiesis by stimulating the production of hematopoietic factors. PMID- 26425274 TI - St. John's Wort (Hypericum perforatum) stimulates human osteoblastic MG-63 cell proliferation and attenuates trabecular bone loss induced by ovariectomy. AB - BACKGROUND/OBJECFTIVES: The effect of St. John's Wort extract (SJW) on MG-63 cell proliferation and trabecular bone loss induced by ovariectomy was examined. MATERIALS/METHODS: Proliferation, expression of estrogen receptor (ER) alpha and ER beta, and gene expressions of osteoprotegerin (OPG), osteocalcin (OC) and alkaline phosphatase (ALP) were examined in MG-63 cells treated with or without SJW. Ovariectomized rats were treated with SJW at the dose of 100 or 200 mg/kg/day, beta-estradiol-3-benzoate (E2), or vehicle only (OVX-C), and sham operated rats were treated with vehicle only (Sham-C). Serum ALP and C telopeptide (CTX), and femoral trabecular bone loss were examined. RESULTS: SJW increased MG-63 cell proliferation and expression of ER alpha and ER beta, and positive effect was shown on gene expressions of ALP, OC and OPG. SJW also showed estrogen like effect on bone associated with slowing down in trabecular bone loss. Histopathology by H&E showed rats treated with SJW displayed denser structure in metaphyseal region of distal femur compared with rats in OVX-C. SJW was shown to reduce serum CTX in OVX rats. CONCLUSION: The present study provides new insight in preventing estrogen deficiency induced bone loss of SJW and possibility for its application in bone health supplement. PMID- 26425275 TI - Protective effects of Artemisia arborescens essential oil on oestroprogestative treatment induced hepatotoxicity. AB - BACKGROUND: Currently, natural products have been shown to exhibit interesting biological and pharmacological activities and are used as chemotherapeutic agents. The purpose of this study, conducted on Wistar rats, was to evaluate the beneficial effects of Artemisia arborescens oil on oestroprogestative treatment induced damage on liver. MATERIALS/METHODS: A total of 36 Wistar rats were divided into 4 groups; a control group (n = 9), a group of rats who received oestroprogestative treatment by intraperitoneal injection (n = 9), a group pre treated with Artemisia arborescens then injected with oestroprogestative treatment (n = 9), and a group pre-treated with Artemisia arborescens (n = 9). To minimize the handling stress, animals from each group were sacrificed rapidly by decapitation. Blood serum was obtained by centrifugation and the livers were removed, cleaned of fat, and stored at -80C until use. RESULTS: In the current study, oestroprogestative poisoning resulted in oxidative stress, which was demonstrated by 1) a significant increase of lipid peroxidation level in hepatic tissue 2) increased levels of serum transaminases (aspartate amino transferase and serum alanine amino transferase), alkaline phosphatase, glycemia and triglycerides and a decrease in the level of cholesterol 3) alteration of hepatic architecture. Pre-administration of Artemisia arborescens oil was found to alleviate oestroprogestative treatment induced damage by lowering lipid peroxidation level and by increasing activity of catalase, superoxide-dismutase, and glutathione-peroxidase in liver and by reducing disruption of biochemical parameters. CONCLUSION: Therefore, the results obtained in this study confirmed that Artemisia essential oil protects against oestroprogestative administration induced hepatotoxicity by restoration of liver activities. PMID- 26425276 TI - Sargassum coreanum extract alleviates hyperglycemia and improves insulin resistance in db/db diabetic mice. AB - BACKGROUND/OBJECTIVES: The goal of this study was to examine the effect of Sargassum coreanum extract (SCE) on blood glucose concentration and insulin resistance in C57BL-KsJ-db/db mice. MATERIALS/METHODS: For 6 weeks, male C57BL/KsJ-db/db mice were administrated SCE (0.5%, w/w), and rosiglitazone (0.005%, w/w). RESULTS: A supplement of the SCE for 6 weeks induced a significant reduction in blood glucose and glycosylated hemoglobin concentrations, and it improved hyperinsulinemia compared to the diabetic control db/db mice. The glucokinase activity in the hepatic glucose metabolism increased in the SCE supplemented db/db mice, while phosphoenolpyruvate carboxykinase and glucose-6 phosphatase activities in the SCE-supplemented db/db mice were significantly lower than those in the diabetic control db/db mice. The homeostatic index of insulin resistance was lower in the SCE-supplemented db/db mice than in the diabetic control db/db mice. CONCLUSIONS: These results suggest that a supplement of the SCE lowers the blood glucose concentration by altering the hepatic glucose metabolic enzyme activities and improves insulin resistance. PMID- 26425278 TI - The effects of Momordica charantia on obesity and lipid profiles of mice fed a high-fat diet. AB - BACKGROUND/OBJECTIVES: The present study was conducted to investigate the effects of dried Momordica charantia aqueous extracts (MCA) and ethanol extracts (MCE) on obesity and lipid profiles in mice fed a high-fat diet. MATERIALS/METHODS: Forty two ICR mice were randomly divided into six groups. The normal group was fed a basal diet, and other groups were fed a 45% high-fat diet (HFD) for 7 weeks. The normal and HFD groups were also orally administered distilled water each day for 7 weeks. The remaining groups received Momordica charantia extract (0.5 or 1.0 g/kg/day MCA, and 0.5 or 1.0 g/kg/day MCE). In order to measure the anti-obesity and lipid profile improvement effects, body and visceral tissue weight, lipid profiles, plasma insulin levels, hepatic malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity were measured. RESULTS: Both MCA and MCE significantly decreased body and visceral tissue weight relative to those of the HFD group (P < 0.05). Additionally high doses of MCE and MCA significantly reduced the plasmatic insulin levels compared to the HFD groups (P < 0.05) to concentrations comparable to those found in the normal group. MCA and MCE supplementation also significantly modulated the lipid profiles in plasma, liver, and feces compared to mice fed the HFD (P < 0.05). Furthermore MCA and MCE significantly increased hepatic SOD activity, and reduced MDA generation in the liver of the HFD mice (P < 0.05). CONCLUSIONS: Results from the present study suggest that Momordica charantia extracts have anti-obesity effects and the ability to modulate lipid prolife of mice fed a HFD by suppressing body weight gain, visceral tissue weight, plasma and hepatic lipid concentrations, and lipid peroxidation along with increasing lipid metabolism. PMID- 26425277 TI - Protective role of caffeic acid in an Abeta25-35-induced Alzheimer's disease model. AB - BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) is characterized by deficits in memory and cognitive functions. The accumulation of amyloid beta peptide (Abeta) and oxidative stress in the brain are the most common causes of AD. MATERIALS/METHODS: Caffeic acid (CA) is an active phenolic compound that has a variety of pharmacological actions. We studied the protective abilities of CA in an Abeta25-35-injected AD mouse model. CA was administered at an oral dose of 10 or 50 mg/kg/day for 2 weeks. Behavioral tests including T-maze, object recognition, and Morris water maze were carried out to assess cognitive abilities. In addition, lipid peroxidation and nitric oxide (NO) production in the brain were measured to investigate the protective effect of CA in oxidative stress. RESULTS: In the T-maze and object recognition tests, novel route awareness and novel object recognition were improved by oral administration of CA compared with the Abeta25-35-injected control group. These results indicate that administration of CA improved spatial cognitive and memory functions. The Morris water maze test showed that memory function was enhanced by administration of CA. In addition, CA inhibited lipid peroxidation and NO formation in the liver, kidney, and brain compared with the Abeta25-35-injected control group. In particular, CA 50 mg/kg/day showed the stronger protective effect from cognitive impairment than CA 10 mg/kg/day. CONCLUSIONS: The present results suggest that CA improves Abeta25-35-induced memory deficits and cognitive impairment through inhibition of lipid peroxidation and NO production. PMID- 26425279 TI - Association between fish and shellfish, and omega-3 PUFAs intake and CVD risk factors in middle-aged female patients with type 2 diabetes. AB - BACKGROUND/OBJECTIVES: This study was performed to investigate the association between the dietary intake of fish and shellfish, and omega-3 polyunsaturated fatty acids (PUFAs) and cardiovascular disease (CVD) risk factors in the middle aged Korean female patients with Type 2 diabetes (T2D). SUBJECTS/METHODS: A cross sectional analysis was performed with 356 female patients (means age: 55.5 years), who were recruited from the Huh's Diabetes Clinic in Seoul, Korea between 2005 and 2011. The dietary intake was assessed by a validated semi-quantitative food frequency questionnaire and analyzed using the Computer Aided Nutritional Analysis program (CAN-Pro) version 4.0 software. RESULTS: In a multiple regression analysis after the adjustment for confounding factors such as age, BMI, duration of diagnosed T2D, alcohol consumption, fiber intake, sodium intake, and total energy intake, fish and shellfish intake of the subjects was negatively associated with triglyceride and pulse wave velocity (PWV). Omega-3 PUFAs intake was negatively associated with triglyceride, systolic blood pressures, diastolic blood pressures, and PWV. The multiple logistic regression analysis with the covariates showed a significant inverse relationship between the omega-3 PUFAs consumption and prevalence of hypertriglyceridemia [OR (95% CI) for greater than the median compared to less than the median: 0.395 (0.207-0.753)]. CONCLUSIONS: These results suggest that the consumption of fish and shellfish, good sources of omega-3 PUFAs, may reduce the risk factors for CVD in the middle-aged female patients with T2D. PMID- 26425280 TI - Poor nutrition and alcohol consumption are related to high serum homocysteine level at post-stroke. AB - BACKGROUND/OBJECTIVES: Increased serum homocysteine (Hcy) levels have been reported to be related to the occurrence of cardio- and cerebrovascular diseases. High serum Hcy levels are also related to the development of secondary stroke and all-cause mortality. The purpose of this study was to investigate the prevalence of high serum homocysteine level and relating factors, and the change over the 10 month period post-stroke. SUBJECTS/METHODS: Consecutive stroke patients who were admitted to the Asan Medical Center were enrolled. Ten months after the onset of stroke, an interview with a structured questionnaire was performed and blood samples were obtained for the biochemical parameters. Nutritional status was determined using the mini nutritional assessment (MNA) score and dietary nutrient intakes were also obtained using a 24 hour recall method. RESULTS: Out of 203 patients, 84% were malnourished or at risk of malnutrition, and 26% had high homocysteine levels at 10 months post-stroke. Using logistic regression, the factors related with high homocysteine levels at 10 months post-stroke included heavy alcohol consumption (P = 0.020), low MNA scores (P = 0.026), low serum vitamin B12 (P = 0.021) and low serum folate levels (P = 0.003). Of the 156 patients who had normal homocysteine levels at admission, 36 patients developed hyperhomocysteinemia 10 months post-stroke, which was related to heavy alcohol consumption (P = 0.013). Persistent hyperhomocysteinemia, observed in 22 patients (11%), was related to male sex (P = 0.031), old age (P = 0.042), low vitamin B6 intake (P = 0.029), and heavy alcohol consumption (P = 0.013). CONCLUSION: Hyperhomocysteinemia is common in post-stroke, and is related to malnutrition, heavy alcohol drinking and low serum level of folate and vitamin B12. Strategies to prevent or manage high homocysteine levels should consider these factors. PMID- 26425281 TI - Evaluation of diet quality and its associated factors among adolescents in Kuala Lumpur, Malaysia. AB - BACKGROUND/OBJECTIVES: This study aims to determine contribution of meal frequency, self-efficacy for healthy eating, and availability of healthy foods towards diet quality of adolescents in Kuala Lumpur, Malaysia. SUBJECTS/METHODS: This study was conducted among 373 adolescents aged from 13 to 16 years old. Diet quality of the respondents was assessed using the Healthy Eating Index for Malaysians. Meal frequency, self-efficacy for healthy eating, and availability of healthy foods were assessed through the Eating Behaviours Questionnaire (EBQ), self-efficacy for healthy eating scale, and availability of healthy foods scale, respectively. RESULTS: The majority of the respondents (80.7%) were at risk of poor diet quality. Males (mean = 34.2 +/- 8.2%) had poorer diet quality than females (mean = 39.9 +/- 9.0%) (t = -5.941, P < 0.05). Malay respondents (mean = 36.9 +/- 8.7%) had poorer diet quality than Indian respondents (mean = 41.3 +/- 10.0%) (F = 2.762, P < 0.05). Age (r = 0.123, P < 0.05), self-efficacy for healthy eating (r = 0.129, P < 0.05), and availability of healthy foods (r = 0.159, P < 0.05) were positively correlated with the diet quality of the respondents. However, meal frequency was not correlated with the diet quality of the respondents. Multiple linear regression analysis showed that being a male, being a Malay, low self-efficacy for healthy eating, and low availability of healthy foods contributed significantly towards poor diet quality among respondents. CONCLUSIONS: In short, sex, ethnicity, self-efficacy for healthy eating, and availability of healthy foods were associated with diet quality among adolescents. Health practitioners should take into consideration of differences in sex and ethnicity during implementation of nutrition-related intervention programs. Self-efficacy for healthy eating and availability of healthy foods should be included as important components in improving diet quality of adolescents. PMID- 26425282 TI - Attitudes and preferences of consumers toward food allergy labeling practices by diagnosis of food allergies. AB - BACKGROUND/OBJECTIVES: The objective of this study was to investigate food allergens and prevalence rates of food allergies, followed by comparison of consumer attitudes and preferences regarding food allergy labeling by diagnosis of food allergies. SUBJECTS/METHODS: A total of 543 individuals living in Seoul and Gyeonggi area participated in the survey from October 15 to 22 in 2013. RESULTS: The results show that the prevalence of doctor-diagnosed food allergies was 17.5%, whereas 6.4% of respondents self-reported food allergies. The most common allergens of doctor-diagnosed and self-reported food allergy respondents were peaches (30.3%) and eggs (33.3%), respectively, followed by peanuts, cow's milk, and crab. Regarding consumer attitudes toward food labeling, checking food allergens as an item was only significantly different between allergic and non allergic respondents among all five items (P < 0.001). All respondents reported that all six items (bold font, font color, box frame, warning statement, front label, and addition of potential allergens) were necessary for an improved food allergen labeling system. PLSR analysis determined that the doctor-diagnosed group and checking of food allergens were positively correlated, whereas the non allergy group was more concerned with checking product brands. CONCLUSIONS: An effective food labeling system is very important for health protection of allergic consumers. Additionally, government agencies must develop policies regarding prevalence of food allergies in Korea. Based on this information, the food industry and government agencies should provide clear and accurate food labeling practices for consumers. PMID- 26425283 TI - Perceptions and practices of commensality and solo-eating among Korean and Japanese university students: A cross-cultural analysis. AB - BACKGROUND/OBJECTIVES: Commensality, eating together with others, is a major representation of human sociality. In recent time, environments around commensality have changed significantly due to rapid social changes, and the decline of commensality is perceived as a serious concern in many modern societies. This study employs a cross-cultural analysis of university students in two East Asian countries, and examines cross-cultural variations of perceptions and actual practices of commensality and solo-eating. SUBJECTS/METHODS: The analysis was drawn from a free-list survey and a self-administrative questionnaires of university students in urban Korea and Japan. The free-listing survey was conducted with a small cohort to explore common images and meanings of commensality and solo-eating. The self-administrative questionnaire was developed based on the result of the free-list survey, and conducted with a larger cohort to examine reasons and problems of practices and associated behaviors and food intake. RESULTS: We found that Korean subjects tended to show stronger associations between solo-eating and negative emotions while the Japanese subjects expressed mixed emotions towards the practice of solo-eating. In the questionnaire, more Korean students reported they prefer commensality and tend to eat more quantities when they eat commensally. In contrast, more Japanese reported that they do not have preference on commensality and there is no notable difference in food quantities when they eat commensally and alone. Compared to the general Korean cohort finding, more proportion of overweight and obese groups of Korean subjects reported that they tend to eat more when they are alone than normal and underweight groups. This difference was not found in the overweight Japanese subjects. CONCLUSION: Our study revealed cross-cultural variations of perceptions and practices of commensality and solo-eating in a non-western setting. PMID- 26425284 TI - Nutrition knowledge, outcome expectations, self-efficacy, and eating behaviors by calcium intake level in Korean female college students. AB - BACKGROUND/OBJECTIVES: Calcium is important but deficient in diets of young adult women. This study aimed to examine if cognitive factors and eating behaviors differ according to calcium intake based on the Social Cognitive Theory. SUBJECTS/METHODS: Subjects were female college students in Seoul, Korea. Three hundred students completed the questionnaire regarding calcium intake, nutrition knowledge, outcome expectations, self-efficacy and eating behaviors. Data on 240 students were analyzed using t-test or chi(2)-test. Subjects were categorized into two groups, high calcium intake (HC, >= 650 mg/day) and low calcium intake (LC, < 650 mg/day), according to recommended intakes of calcium for women aged 19 29 years. RESULTS: The LC group constituted 77.9% of total subjects. Nutrition knowledge was not different according to calcium intake. Three out of 12 outcome expectations items were significantly different between the HC and LC groups. Subjects in the HC group agreed more strongly with the practical benefits of consuming calcium-rich foods, including 'taste' (P < 0.01) and 'going well with other snacks' (P < 0.05), compared to those in the LC group. Negative expectations of 'indigestion' were stronger in the LC group than HC group (P < 0.001). Among self-efficacy items, perceived ability of 'eating dairy foods for snacks' (P < 0.001), 'eating dairy foods every day' (P < 0.01), and 'eating calcium-rich side dishes at meals' (P < 0.05) differed significantly between the HC and LC groups. Eating behaviors including more frequent consumption of dairy foods, fruits or fruit juice (P < 0.001), anchovy, seaweeds, green vegetables, protein-rich foods (P < 0.05), and less frequent consumption of sweets or soft drinks (P < 0.01) were significantly related to calcium intake. CONCLUSIONS: This study found that outcome expectations, self-efficacy in consuming calcium-rich foods, and eating behaviors are important in explaining calcium intake. Nutrition education needs to address practical benefits, reduce negative expectations of calcium-rich foods, increase self-efficacy, and modify eating behaviors contributing to calcium intake. PMID- 26425285 TI - Prevalence of osteoporosis according to nutrient and food group intake levels in Korean postmenopausal women: using the 2010 Korea National Health and Nutrition Examination Survey Data. AB - BACKGROUND/OBJECTIVES: Women's bone health status is closely related with environmental factors and lifestyle factors. The purpose of this study is to evaluate the dietary risks of osteoporosis and osteopenia for Korean postmenopausal women. SUBJECTS/METHODS: The data from 1,433 subjects from the 2010 KNHANES were used and divided into three groups: normal, osteopenia, and osteoporosis group using bone mineral density (BMD). Nutrient intakes and food intake frequency were evaluated. Logistic regression analysis was applied to determine the odds ratios for osteoporosis and osteopenia. RESULTS: The RNI percentage of each nutrient and food intake frequency from 12 food groups decreased as bone mineral density status deteriorated. Risk for osteoporosis of low calcium (Ca) intake, under the EAR, showed an odds ratio of 2.13(95% CI; 1.26 3.61, P < 0.05). Higher intake frequency showed preventive effect from osteoporosis compared to lower intake frequency in such food group as dairy products (ORs 0.40, CI 0.21-0.75), beans (ORs 0.49, CI 0.29-0.83), seaweeds (ORs 0.55, CI 0.32-0.94), fish (ORs 0.56, CI 0.32-0.98), and fruits (ORs 0.42, CI 0.23 0.79) after adjusting for age. CONCLUSION: To prevent osteoporosis in later life, sufficient Ca intake and more frequent intakes of foods containing Ca such as dairy products, beans, fish, seaweeds, and fruits, which help in Ca absorption, should be stressed for Korean postmenopausal women. PMID- 26425286 TI - Nutritional status of toddlers and preschoolers according to household income level: overweight tendency and micronutrient deficiencies. AB - BACKGROUNDS/OBJECTIVES: The effects of malnutrition on growth of toddlers and preschoolers by socioeconomic status are not well known. This study aimed to examine the effects of dietary intake on growth outcomes in toddlers and preschoolers by household income level. SUBJECTS/METHODS: The study population was a total of 1,687 children aged 1 to 5 years that participated in the KNHANES from 2009 to 2011. Growth of children was assessed by height for age (HFA) and weight for height (WFH). Children were classified into three groups according to children's HFA and WFH compared to the 10(th) and 90(th) percentiles of the 2007 Korean Children and Adolescent Growth Standard. Average monthly household income was divided into quartile groups. Dietary intake data were obtained by using the one day 24-hr recall method. Risks of inadequate intake of nutrients and unfavorable growth were estimated by using a multiple logistic regression model adjusted for sex, age, region, and energy intake. RESULTS: The low HFA group (< 10(th) percentile) had significantly lower intakes of energy, carbohydrate, and thiamin as compared with the high group (>= 90(th) percentile). For WFH status, vitamin C intake was lower in the low group than in the high group. Household income level was related to WFH status but not HFA. Children from lower income households were more likely to have high WFH than those from higher income households (P for trend = 0.038). Household income status was also significantly related with risk of inadequate intake of micronutrients such as thiamin (P for trend = 0.032) and vitamin C (P for trend = 0.002), showing higher odds of inadequate intakes in children from lower income households. CONCLUSIONS: Children from lower income households were prone to be overweight and to have inadequate intakes of micronutrients such as thiamin and vitamin C. To reduce nutritional and health disparities, collective action in the public sector is required from early life. PMID- 26425288 TI - Providing holistic care for older people. PMID- 26425287 TI - Low consumption of fruits and dairy foods is associated with metabolic syndrome in Korean adults from outpatient clinics in and near Seoul. AB - BACKGROUND/OBJECTIVES: The aim of this study was to examine differences in nutrient intake and food consumption by the presence of metabolic syndrome in Korean adults. SUBJECTS/METHODS: Study subjects in this cross-sectional study were recruited from four outpatient clinics in and near the Seoul metropolitan area of South Korea between 2006 and 2012. A total of 668 subjects (413 men and 255 women) aged >= 30 y were included in the final data analyses. For each subject, daily nutrient intake and food consumption were calculated using three days of dietary intake data obtained from a combination of 24-hour recalls and dietary records. To evaluate food consumption, mean number of servings consumed per day and percentages of recommended number of servings for six food groups were calculated. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. The general linear model was performed to examine differences in nutrient intake and food consumption by sex and the presence of metabolic syndrome after adjustment for potential confounding variables. RESULTS: Nutrient intake did not differ by the presence of metabolic syndrome in both men and women. Men with metabolic syndrome had lower consumption and percentage of the recommendation for fruits compared with those without metabolic syndrome (1.6 vs. 1.1 servings/day, P-value = 0.001; 63.5 vs. 49.5%, P-value = 0.013). Women with metabolic syndrome showed lower consumption and percentage of the recommendation for dairy foods than those without metabolic syndrome (0.8 vs. 0.5 servings/day, P-value = 0.001; 78.6 vs. 48.9%, P-value = 0.001). CONCLUSIONS: Low intakes of fruits and dairy foods might be associated with the risk of having metabolic syndrome among Korean adults. Dietary advice on increasing consumption of these foods is needed to prevent and attenuate the risk of metabolic syndrome. PMID- 26425289 TI - Health screening for older people-what are the current recommendations? AB - The world population of older people is on the rise with improved health services. With longevity, older people are at increased risk of chronic non communicable diseases (NCDs), which are also leading causes of death among older people. Screening through case finding in primary care would allow early identification of NCDs and its risk factors, which could lead to the reduction of related complications as well as mortality. However, direct evidence for screening older people is lacking and the decision to screen for diseases should be made based on comorbidity, functional status and life expectancy, and has to be individualised. PMID- 26425290 TI - Correlation between cognitive impairment and depressive mood of Thai elderly with type 2 diabetes in a primary care setting. AB - OBJECTIVE: The objective of this study was to evaluate the relationship between cognitive impairment and depressive mood in Thai elderly with type 2 diabetes at primary care centres. MATERIALS AND METHODS: Two-hundred and eighty three (283) older people with type 2 diabetes were enrolled in this study. Mini-Cog and mini mental state examination (MMSE) Thai 2002 were used to measure cognitive impairment while Thai geriatric screening test (TGDS) was used to measure depressive mood in all participants. Spearmen correlation was applied to determine the relationship between cognitive function and depressive mood. RESULTS: There was a positive relationship between cognitive impairment and depressive mood in older people with type 2 diabetes. The scores from Mini-Cog and MMSE Thai 2002 were negatively correlated with TGDS scores while adjusting for the effects of age and years of education with rs = -0.1, p = 0.06 and rs = 0.2, p<0.01, respectively. Although it showed an inverse relationship of the scores between cognitive and depressive mood screening tests, the results between the tests were positive when interpreting the test scores. It means that the higher score in Mini-Cog and MMSE Thai 2002 (non-cognitive impairment) were associated with the lower score in TGDS (non-depressed mood). CONCLUSION: The finding of this study showed that older people with type 2 diabetes who had cognitive impairment seemed to have depressive mood. Hence, these two co morbidities should be considered in order to give an optimal care to older people with diabetes. PMID- 26425291 TI - Poor blood pressure control and its associated factors among older people with hypertension: A cross-sectional study in six public primary care clinics in Malaysia. AB - INTRODUCTION: Hypertension is highly prevalent in the older people. Chronic disease care is a major burden in the public primary care clinics in Malaysia. Good blood pressure (BP) control is needed to reduce the morbidity and mortality of cardiovascular disease (CVD). This study aimed to determine the status of BP control and its associated factors among older people with hypertension in public primary care clinics. MATERIALS AND METHODS: A cross-sectional study on hypertensive patients aged 18 years and above was conducted in six public primary care clinics in Federal Territory, Malaysia. A total of 1107 patients were selected via systematic random sampling. Data from 441 (39.8%) patients aged 60 years and more were used in this analysis. BP control was determined from the average of two BP readings measured twice at an interval of 5 min. For patients without diabetes, poor BP control was defined as BP of >=140/90 mm Hg and >=150/90 for the patients aged 80 years and more. For patients with diabetes, poor control was defined as BP of >=140/80 mm Hg. RESULTS: A total of 51.7% (n = 228) of older patients had poor BP control. The factors associated with BP control were education level (p = 0.003), presence of comorbidities (p = 0.015), number of antihypertensive agents (p = 0.001) and number of total medications used (p = 0.002). Patients with lower education (less than secondary education) (OR = 1.7, p = 0.008) and the use of three or more antihypertensive agents (OR = 2.0, p = 0.020) were associated with poor BP control. CONCLUSION: Among older people with hypertension, those having lower education level, or using three or more antihypertensive agents would require more attention on their BP control. PMID- 26425292 TI - Management of pulmonary tuberculosis in health clinics in the Gombak district: How are we doing so far? AB - This audit report assessed the structure, processes and outcome of the pulmonary tuberculosis (PTB) management in adults conducted at eight government health clinics within the high TB burden Gombak district. All newly diagnosed PTB patients from November 2012 to November 2013 were identified from the tuberculosis registry. Patients less than 18 years old, were transferred out or extrapulmonary tuberculosis was excluded from the study. The assessment criteria for PTB were defined according to the latest Malaysian TB clinical practice guidelines (TB CPG) 2012. A total of 117 patients were included in this report and data were extracted and analysed using SPSS version 20.0. The mean age of patients was 40.4 +/- 14.4 SD. Majority was men (63.2%). Out of 117 patients, 82.1% were Malaysian citizens and 17.9% were foreigners. Malays were the majority (65%) followed by 7.7% Chinese, 10.3% Indian and 17.1% others. The most common clinical feature was cough (88.0%) followed by loss of weight (58.1%), loss of appetite (57.3%), fever (56.4%), night sweat (30.8%) and haemoptysis (32.5%). Acid-fast bacilli (AFB) smear was positive in 94% of cases. Chest X-ray and human immunodeficiency virus (HIV) screening results were available for 89.1 and 82.1% cases respectively. The results for the sputum culture were available in 27.4% of patients and 54.7% were documented as done but pending results. The clinics have a successful directly observed therapy (DOT) program with 94.0% patients documented under DOT. Out of 53 patients on maintenance phase, 47.2% were identified as cured. Cure rate for those completed treatment was 100%. The defaulter rate was 17.1%. This audit demonstrated the attempt made by the clinics to adhere to the recommended guidelines. However, improvements are to be made in the documentation of medical records, tracing of investigation results and reduction of the number of defaulters. PMID- 26425294 TI - A case study of human immunodeficiency virus with positive seroconversion to negative. AB - This case study demonstrates a 36-year-old ex-intravenous drug user (IVDU) who had been initially tested positive for human immunodeficiency virus (HIV) twice using Enzyme Immunoassay (EIA) method (Particle agglutination, PA done), but a year later he was tested HIV-negative. The patient was asymptomatic for HIV and T helper cells (CD4) count remained stable throughout this period. In light of this case, there may be a need to retest by molecular methods for high risk category patients who were initially diagnosed HIV-positive, but later showing an unexpected clinical course, such as a rising or stable CD4 titre over the years. PMID- 26425295 TI - Night market contact lens-related corneal ulcer: Should we increase public awareness? PMID- 26425293 TI - Social support and self-care activities among the elderly patients with diabetes in Kelantan. AB - INTRODUCTION: Diabetes is common among the elderly and can significantly affect their lives including the issues related with social support and diabetic self care activities. OBJECTIVES: The objective of this study was to examine the social support and self-care activities among the elderly patients with diabetes. METHODS: A survey involving 200 patients was conducted from March 2013 to May 2013 in three hospitals in Kelantan. Data were obtained through self-administered questionnaires and clinical characteristics were acquired from the patients' records. RESULTS: The scores for social support (mean = 19.26; SD = 2.63) and self-care activities (mean = 14.83; SD = 4.92) were moderate. Higher social support was associated with high levels of glycated haemoglobin (HbA1c), fasting blood sugar (FBS) level, the duration of diabetes and a decrease in body mass index (BMI) (p<0.05). It was observed that the patients with low educational, Hb1Ac and FBS level, with other chronic diseases and who have had diabetes for some time had low self-care activities (p<0.05). There was a significant negative relationship between an increase in social support and decrease in self-care activity (p<0.05). CONCLUSION: Healthcare providers, family and friends have to strengthen their relationship with the elderly patients with diabetes to provide more social support and promote the compliance with diabetic self-care activities to improve clinical outcomes. PMID- 26425296 TI - A boy with bluish neck swelling on screaming. PMID- 26425297 TI - A boy with blue sclera and recurrent fractures. PMID- 26425298 TI - The challenging task of gatekeeping. PMID- 26425299 TI - Factors influencing the role of primary care providers as gatekeepers in the Malaysian public healthcare system. AB - Primary care providers play an important gatekeeping role in ensuring appropriate referrals to secondary care facilities. This cross-sectional study aimed to determine the level, pattern and rate of referrals from health clinics to hospitals in the public sector, and whether the placement of resident family medicine specialist (FMS) had made a significant difference. The study was carried out between March and April in 2012, involving 28 public primary care clinics. It showed that the average referral rate was 1.56% for clinics with resident FMS and 1.94% for those without resident FMS, but it was not statistically significant. Majority of referred cases were considered appropriate (96.1%). Results of the multivariate analysis showed that no prior consultation with senior healthcare provider and illnesses that were not severe and complex were independently associated with inappropriate referrals. Severity, complexity or uncertain diagnosis of patients' illness or injury significantly contributed to unavoidable referrals. Adequate facilities or having more experienced doctors could have avoided 14.5% of the referrals. The low referral rate and very high level of appropriate referrals could indicate that primary care providers in the public sector played an effective role as gatekeepers in the Malaysian public healthcare system. PMID- 26425300 TI - Prevalence, awareness, treatment and control of diabetes mellitus among the elderly: The 2011 National Health and Morbidity Survey, Malaysia. AB - Diabetes mellitus is an important cardiovascular risk factor. The objective of this study was to provide population-based estimates on the prevalence, awareness, treatment and control rate of diabetes among the older persons in Malaysia. Analysis of secondary data from a cross-sectional national population based survey was done, which was conducted in 2011 throughout Malaysia. A total of 2764 respondents (15.5%) were older persons. The overall prevalence of diabetes among older persons was 34.4% in which 65.2% were aware of their diabetes status. Out of those who were aware, 87.5% had been treated. Only 21.8% of those treated had their diabetes controlled. The results of multiple logistic regression showed that the factors associated with higher awareness rates were women, Indians and higher income groups; factors associated with higher treatment rates were urban residents and those who were married and widow/widower/ divorcee. There was a high overall prevalence, awareness and treatment rate of diabetes among older persons in Malaysia but with suboptimal control rate. PMID- 26425301 TI - Risk factors for women attending pre-pregnancy screening in selected clinics in Selangor. AB - BACKGROUND: The Ministry of Health is committed to achieve Millenium Development Goal (MDG) MDG 4 and 5 by 2015 and include pre-pregnancy care as a strategy. This study evaluates the risk factors detected during the pre-pregnancy screening at selected public primary care clinics in Selangor. OBJECTIVES: The objectives of this study were to determine the proportion of women with risk factors receiving pre-pregnancy care in selected clinics in Selangor, their socio demographic features, the types of risk factors detected and their significance. METHODS: A retrospective review using secondary data was carried out from the month of March until June 2013 in four public primary care clinics in Klang and Petaling districts of Selangor. Data were obtained through non-probability sampling, using the pre-pregnancy screening form utilised in 2012, which is a standard questionnaire to determine the presence of risk factors. Women with at least one defined risk factor were considered as being at risk of an adverse obstetric outcome. Data were analysed using SPSS version 16. RESULTS: A total of 840 pre pregnancy screening forms were collected. However only 614 (73.1%) were analysed and studied. The proportion of women with at least one risk factor was 68.8% (95% CI: 65.1, 72.5). The majority was Malays who had tertiary education and earned more than RM 1000. Most were in the reproductive age group of 18-35 years old (350, 82.9%). The mean age was 28.68 + 5.78 years. Most of the women were parous (259, 65.1%) and did not practice any form of contraception (308, 80.8%) despite having risks. The percentage of those not receiving any form of immunisation was small i.e. 9.8% but it was of importance and needed to be addressed prior to the conception. This study did not reveal any person with mental disorder or those who endured domestic abuse. Additionally, 3% (12) of them had unhealthy lifestyle habits, which include smoking, alcohol and substance abuse. Approximately one third (212, 35.2%) of the women screened were overweight and obese, putting them at risk of developing gestational diabetes mellitus, pregnancy induced hypertension or deep vein thrombosis. The mean body mass index (BMI) for those at risk was 25.36 + 5.94 compared to 21.06 +/- 1.46 for those with no risk. This study also found a small percentage of women with raised blood pressure (3.9%), abnormal physical examination (1.5%) and anaemia (14.4%), which need to be investigated and treated prior to conception. CONCLUSION: More than half of the women who attended the pre-pregnancy screening were found to have at least one risk factor. PMID- 26425302 TI - Low vision rehabilitation and ocular problems among industrial workers in a developing country. AB - AIM: Work-related ocular injuries and illnesses were among the major causes of job absenteeism. This study was conducted to determine if low vision rehabilitation was provided following work-related ocular problems among industrial workers in a developing country. This was a retrospective analysis of case records. METHOD: Randomly selected records of all employees from the Social Security Organization (SOCSO) Medical Board for 2004 who suffered from ocular injuries and illnesses were selected. Rates of ocular injuries and illnesses according to age, gender, races, types of injuries, types of industries, visual rehabilitation and types of medical interventions were tabulated and analysed. RESULTS: A total of 26 cases of ocular injuries and illnesses were identified where 46.2% suffered from ocular injuries. The remaining 53.8% had ocular and/or systemic diseases. The 40-49-yearold age group suffered the greatest number of injuries (26.92%). Ocular perforating injuries (66.67%) and ocular contusions (33.33%) were the most common types of ocular injury among industrial workers in Kuala Lumpur. Most injuries occurred among workers in the service industry (50%). Almost 60% of these injured workers did not receive any low vision rehabilitation after medical intervention while 25% were given contact lenses or spectacles as rehabilitation and remaining had surgery. CONCLUSION: The low vision rehabilitation is still unexplored in the management of ocular injuries and illnesses among industrial workers. Introducing low vision rehabilitation can benefit both workers and employers as it provides care beyond spectacles or contact lens prescriptions. PMID- 26425303 TI - Tuberculosis in adults. AB - Tuberculosis (TB) in Malaysia is rising due to multiple factors and issues related to its management are addressed in the updated evidence-based clinical practice guidelines. Screening for active TB should be considered in high risk groups. Light emitting diode-based fluorescence microscopy and nucleic acid amplification tests are recommended investigations. Health education and standardised 6-month daily antituberculosis (antiTB) regimen are among important elements for successful treatment. Latent TB infection screening should only be performed on high risk individuals. AntiTB regimen offered to HIV-positive adults should be the same as for HIV-negative adults and timing to initiate highly active antiretroviral therapy in patients with TB is based on CD4 count. All patients on antiTB treatment should be monitored to assess their response to treatment and to identify problems associated with it. PMID- 26425304 TI - Isolation of Mycobacterium fortuitum in sputum specimens of a patient with chronic cough: Is it clinically significant? AB - Managing chronic cough is diagnostically challenging especially in primary care. This case report highlights the difficulties experienced in approaching a case of chronic cough from a primary care perspective. The discussion also involves the clinical significance and treatment dilemma of M. fortuitum chelonae complex that was isolated from the sputum cultures of an elderly woman who presented with chronic cough for more than a year. PMID- 26425305 TI - Full thickness macular hole: Early intervention is an important factor in visual prognosis. AB - Full thickness macular hole is an eye disease, which can cause permanent visual impairment. Current advancement in vitreoretinal surgery has high success rates in repairing them, leading to a significant visual improvement, especially if patient presents early. In this article, three cases of idiopathic full thickness macular hole with different visual outcomes have been presented. All cases were referred by the primary care practitioners and had undergone macular hole surgery with the same vitreoretinal surgeon. The visual outcome was best in the patient who had the earliest presentation and referral. Early detection and referral of these patients is vital so that early surgical intervention can be carried out to improve their vision. PMID- 26425306 TI - An intravenous drug abuser with painless neck masses. PMID- 26425307 TI - Common Molecular Challenges in Glaucoma. PMID- 26425308 TI - Conjunctival Lesions; a Histopathologic Review in Fars Province, Iran. AB - PURPOSE: To determine the prevalence of various types of conjunctival lesions, at a tertiary ophthalmic center in Fars Province, South of Iran. METHODS: Histopathologic slides and medical records of conjunctival lesions submitted to the pathology department of Khalili Hospital, Shiraz, Iran were reviewed from April, 2009 to July, 2013. The histopathologic diagnoses were categorized into benign, pre-malignant, and malignant lesions. The prevalence of various types of conjunctival lesions was calculated. RESULTS: Histologic sections of 631 conjunctival lesions were reviewed. Benign lesions were most prevalent (81.8%), followed by premalignant (10.8%) and malignant (7.4%) lesions. Pterygia were the most common benign lesions (69.2%), intraepithelial dysplasia constituted most cases of premalignant lesions (94.1%), and squamous cell carcinoma was the most frequent malignant lesion (93.6%). Benign lesions were the most common type of lesions in all age groups, however the prevalence of malignant lesions increased significantly with age (P < 0.001). CONCLUSION: Benign lesions were the most common conjunctival lesions with pterygia on top of the list, while intraepithelial neoplasia and squamous cell carcinoma were the most common premalignant and malignant lesions, respectively. Conjunctival malignant lesions were more prevalent with older age. PMID- 26425309 TI - Is Corneal Sensitivity Sex Dependent? AB - PURPOSE: To determine whether corneal sensitivity is different between the two genders. METHODS: Corneal sensitivity of 130 normal volunteers, including 77 women and 53 men aged 20-35 years, with no history of previous ocular surgery was measured using the Cochet-Bonnet esthesiometer. Measurements were done on five corneal regions: central, nasal, inferior, temporal and superior. The findings were compared between men and women using the non-parametric Mann-Whitney U test. RESULTS: Mean age of male subjects was 28.0 years and that of female participants was 26.8 years (P = 0.063). There was a significant difference in corneal sensitivity between men and women in the superior (P = 0.013), temporal (P = 0.020) and inferior (P = 0.046) regions. There was no significant difference in corneal sensitivity in the central (P = 0.862) and nasal (P = 0.273) regions. CONCLUSION: Except for the central and nasal regions, corneal sensitivity is significantly higher in men as compared to women. The reason for this difference is not yet evident. PMID- 26425310 TI - Chlorhexidine Monotherapy with Adjunctive Topical Corticosteroids for Acanthamoeba Keratitis. AB - PURPOSE: To assess the efficacy of chlorhexidine monotherapy for Acanthamoeba keratitis, and to determine the therapeutic outcomes of concomitant topical corticosteroids. METHODS: In this prospective interventional case series, 31 eyes of 31 patients with Acanthamoeba keratitis (AK) were treated with chlorhexidine 0.02% as monotherapy, from April 2010 to April 2011. The diagnosis of AK was made based on clinical manifestations and positive confocal microscopic (confoscan 3.4, Nidek Co. Ltd., Gamagori, Japan) results. We report the percentage of a favorable clinical response within two weeks of initiating treatment, worsening of the infection while receiving chlorhexidine, recovery of visual acuity (VA), duration of treatment with chlorhexidine and corticosteroids, necessity for addition of other anti-Acanthamoeba agents, presence of corneal scar at the end of the treatment, and need for penetrating keratoplasty (PK). RESULTS: Two weeks after initiation of chlorhexidine, improvement in signs and symptoms was observed in 26 (83.9%) patients but 3 eyes required the addition of propamidine. After initial improvement in one patient, the infection worsened, necessitating the addition of Polyhexamethylene Biguanide (PHMB) and propamidine. A total of 26 (83.9%) patients received topical corticosteroids with mean duration of 65.8 +/- 45.1 days. In 22 (71%) eyes, final visual acuity was >=0.80. Improved VA occurred in 29 eyes (93.5%). Optical PK was considered in 3 (9.7%) eyes and a corneal scar developed in 8 (25.8%) eyes. CONCLUSION: Chlorhexidine is effective for monotherapy in AK and could be a good choice for initiating treatment. After the initial response to anti-Acanthamoeba agents, corticosteroids can be used as adjunctive therapy depending on the clinical condition. PMID- 26425311 TI - Deep Anterior Lamellar Keratoplasty in Keratoconic Patients with versus without Vernal Keratoconjunctivitis. AB - PURPOSE: To compare the clinical outcomes of deep anterior lamellar keratoplasty (DALK) for keratoconus in patients with vernal keratoconjunctivitis (VKC) versus those without VKC. METHODS: In this retrospective comparative study, records of 262 eyes with keratoconus (Group 1) and 28 keratoconic eyes with VKC (Group 2) that had undergone DALK were compiled. Reviewed parameters included length of follow-up, best-corrected visual acuity (BCVA), refractive error, complications and cumulative graft survival. RESULTS: Mean duration of follow-up was 38.6 +/- 20.2 and 34.4 +/- 20.9 months in groups 1 and 2, respectively (P = 0.21). Mean post-operative BCVA was 0.19 +/- 0.11 and 0.20 +/- 0.15 logMAR, in groups 1 and 2 (P = 0.79). BCVA>=20/40 was achieved in 91.6 and 88.5% of eyes in groups 1 and 2, respectively (P = 0.48). Epithelial problems were encountered in 31.3 and 42.9% of operated eyes, respectively (P = 0.16). Vascularization of suture tracts and stitch abscesses were encountered more frequently in the eyes with VKC (P = 0.01 and <0.001, respectively). At the 33-month follow-up examination, rejection-free graft survival rates were 56.0% in group 1 and 33.3% in group 2, with mean durations of 41.0 and 32.1 months, respectively (P = 0.15). Graft survival rates were 98.1% in group 1 and 95.0% in group 2, with mean durations of 88.6 and 88.4 months, respectively (P = 0.74). CONCLUSION: Clinical outcomes of DALK in keratoconic eyes with VKC were comparable to those in eyes with keratoconus alone. However, complications such as suture tract vascularization and stitch abscesses were more common when VKC coexisted, necessitating closer monitoring. PMID- 26425312 TI - Lens Densitometry after Corneal Cross-linking in Patients with Keratoconus Using a Scheimpflug Camera. AB - PURPOSE: To evaluate changes in crystalline lens densitometry following corneal cross-linking (CXL) in keratoconic patients. METHODS: In a quasi-experimental study, three-dimensional lens densitometry was performed using the Pentacam Scheimpflug camera (Oculus Optikgerate GmbH, Wetzlar, Germany) at baseline and six months after CXL. Densitometry was performed in a fixed area of 2 inch * 1 inch of the anterior capsule and anterior lens cortex. The subject group included patients with progressive keratoconus who underwent CXL (n = 40) and the control group was comprised of aged-matched patients with non-progressive keratoconus (n = 36). RESULTS: Mean age of the case and control groups was 25.8 +/- 4.0 and 25.0 +/- 4.1 years, respectively (P = 0.392). Mean lens density in the CXL group was 6.68% +/- 0.58% at baseline and 6.77% +/- 0.53% at the last visit (P = 0.352). Corresponding figures in the control group were 6.53% +/- 0.27% and 6.39% +/- 0.31%, respectively (P = 0.213). There was no significant difference between the study groups at baseline or six months later (P = 0.96). CONCLUSION: In this short term study with six months' follow-up, we observed no significant impact on lens density following exposure of the crystalline lens to ultraviolet A and riboflavin free radicals in the CXL procedure. PMID- 26425314 TI - Prevalence of Color Vision Deficiency and its Correlation with Amblyopia and Refractive Errors among Primary School Children. AB - PURPOSE: To determine the prevalence of color vision deficiency (CVD) and its correlation with amblyopia and refractive errors among primary school children. METHODS: In this population-based cross-sectional study, 2160 children were selected from 36 primary schools; 60 students were from each school (10 students in each grade), with equal sex distribution. A complete eye examination including refraction using a photorefractometer, determination of visual acuity (VA) and color vision using a Yang vision tester, and evaluation of ocular media opacity using a direct ophthalmoscope was performed. Children who could not answer at least 4 plates of the Ishihara color test were considered as color vision deficient subjects. Amblyopia was determined if pinhole VA was worse than 0.3 LogMAR (equal to 20/40). RESULTS: The prevalence of CVD was 2.2% (95% CI: 1.5% to 3%) which was higher in male subjects (37 [3.5%] boys vs. 11 [1.0%] girls, P < 0.001). Mean VA was lower among students with CVD as compared to normal color vision children (P = 0.035) and amblyopia was observed in 8.3% (95% CI: 0.2% to 16.4%) of patients with CVD versus 2.1% (95% CI: 1.5% to 2.08%) of children with normal color vision perception (P = 0.005). A statistically significant correlation between lower VA and CVD was observed (P = 0.023). CONCLUSION: Although CVD was correlated with lower VA and amblyopia, there was no relationship between CVD and the type of amblyopia, refractive error, anisometropia or strabismus. PMID- 26425313 TI - A Possible Role for LTBP2 in the Etiology of Primary Angle Closure Glaucoma. AB - PURPOSE: To assess the association of LTBP2 mutations with primary angle closure glaucoma (PACG). METHODS: We studied 54 unrelated patients with PACG and one individual with pseudoexfoliation accompanied with angle closure glaucoma; these consisted of 28 female and 27 male subjects aged 27 to 82 (mean, 63) years. The 36 exons and flanking intronic sequences of LTBP2 in all patients were amplified by PCR and sequenced by the Sanger protocol. The sequences were compared to LTBP2 reference sequences. A total of 100 to 400 controls aged at least 60 years old were screened for various variations. RESULTS: Out of 24 observed sequence variations, ten were in amino acid coding regions; of these four created synonymous codons while six caused amino acid changes. Based on allele frequencies, biochemical parameters, absence in control individuals, evolutionary conservation of affected amino acids, and bioinformatic predictions on the effects on protein function, it was concluded that only two mutations causing p. Gln1417Arg and p. Gly1660Trp may contribute to PACG. The p. Gly1660Trp mutation was observed in a patient with both PACG and PEX syndrome. P. Gln1417Arg had previously been reported only in a subject with POAG. CONCLUSION: LTBP2 may contribute to PACG. This finding emphasizes that there may be an overlap in the etiology of various forms of glaucoma and the overlaps likely contribute to common features in various forms of glaucoma. PMID- 26425315 TI - Bilateral Vitreous Hemorrhage in Children: Clinical Features and Outcomes. AB - PURPOSE: To determine the etiology, clinical features and outcomes of bilateral vitreous hemorrhage (VH) in children. METHODS: This retrospective chart review was performed on patients with bilateral VH under the age of 18 at a tertiary eye care center in India. Data included demographics, details of history and ocular examination, reports of investigations, surgeries or other interventions performed, and final anatomical and visual outcomes. Patients were divided into two groups i.e., traumatic and non-traumatic (spontaneous). RESULTS: The traumatic group was comprised of 37 patients including 27 male and 10 female subjects with mean age of 13.47 +/- 5.31 years, the most common complaint was decreased vision (96.45%) and the most prevalent etiology was firecracker injury in 16 (43.2%) patients. Mean baseline visual acuity (VA) was 2.34 +/- 1.31 logMAR which was significantly improved to 1.08 +/- 0.23 logMAR (P = 0.042). The mean number of surgeries was 2.72 +/- 1.43 in the traumatic VH and mean follow up period was 23.14 +/- 6.54 months. The spontaneous group included 48 subjects comprised of 27 male and 21 female cases with mean age of 14.48 +/- 2.03 years. The most common cause was vasculitis in 21 (43.75%) subjects including four patients with tuberculosis. Mean baseline VA was 1.97 +/- 1.13 logMAR which showed a significant improvement to 0.82 +/- 0.24 logMAR (P = 0.012) after mean follow up of 34.2 +/- 11.2 months. Eleven patients required at least one major surgery. CONCLUSION: Vasculitis was the most common cause of spontaneous bilateral VH; traumatic VH most prevalently occurred due to firecracker injury. Final VA was better in the spontaneous group. PMID- 26425316 TI - Effect of Monocular Deprivation on Rabbit Neural Retinal Cell Densities. AB - PURPOSE: To describe the effect of monocular deprivation on densities of neural retinal cells in rabbits. METHODS: Thirty rabbits, comprised of 18 subject and 12 control animals, were included and monocular deprivation was achieved through unilateral lid suturing in all subject animals. The rabbits were observed for three weeks. At the end of each week, 6 experimental and 3 control animals were euthanized, their retinas was harvested and processed for light microscopy. Photomicrographs of the retina were taken and imported into FIJI software for analysis. RESULTS: Neural retinal cell densities of deprived eyes were reduced along with increasing period of deprivation. The percentage of reductions were 60.9% (P < 0.001), 41.6% (P = 0.003), and 18.9% (P = 0.326) for ganglion, inner nuclear, and outer nuclear cells, respectively. In non-deprived eyes, cell densities in contrast were increased by 116% (P < 0.001), 52% (P < 0.001) and 59.6% (P < 0.001) in ganglion, inner nuclear, and outer nuclear cells, respectively. CONCLUSION: In this rabbit model, monocular deprivation resulted in activity-dependent changes in cell densities of the neural retina in favour of the non-deprived eye along with reduced cell densities in the deprived eye. PMID- 26425317 TI - Endothelin-1 and Nitric Oxide Levels in Exudative Age-Related Macular Degeneration. AB - PURPOSE: To evaluate plasma levels of endothelin-1 (ET-1) and nitric oxide (NO) in patients with exudative age-related macular degeneration (AMD). METHODS: In this study, ET-1 levels, as well as nitrite plus nitrate concentrations as an indicator of plasma NO level, were measured in the plasma of 20 subjects with exudative AMD and compared with 20 healthy age and sex matched controls. RESULTS: Mean plasma ET-1 level was significantly higher in exudative AMD patients as compared to control subjects (0.35 +/- 0.06 fmol/ml versus 0.17 +/- 0.03 fmol/ml, P = 0.015). Patients with exudative AMD also showed significantly lower mean plasma levels of nitrite plus nitrate as compared to the controls (58.9 +/- 2.7 umol/l versus 82.6 +/- 5.9 umol/l, P = 0.001). CONCLUSION: Increased concentrations of ET-1 and reduced levels of NO in the plasma may suggest an imbalance between vasoconstrictor and vasodilator agents, respectively, as a reflection of endothelial dysfunction in the pathogenesis of AMD. These findings may also imply the role of vasoconstriction in exudative AMD. PMID- 26425318 TI - Tumor Necrosis Factor Gene Polymorphisms in Advanced Non-exudative Age-related Macular Degeneration. AB - PURPOSE: To investigate tumor necrosis factor (TNF)-alpha gene polymorphisms in advanced dry-type age-related macular degeneration (AMD) in a population from Northeastern Iran. METHODS: In this case-control study, 50 patients with geographic macular atrophy and 73 gender-matched controls were enrolled. Genomic deoxyribonucleic acid (DNA) was extracted from the peripheral blood. Polymerase chain reaction was performed to analyze 2 candidate single nucleotide polymorphisms in the TNF-alpha gene, namely -1031 thymine (T)/cytosine (C) and 308 guanine (G)/adenine (A). RESULTS: The distribution of the - 1031 T/C genotype was TT, 62%; TC, 36%; CC, 2% in the patients and TT, 60%; TC, 36%; CC, 4% in the controls (P = 0.94). Genotype analysis of TNF-alpha -308 also revealed no significant difference in distribution between patients (G, 78%; GA, 22%; AA, 0%) and controls (GG, 74%; GA, 23%; AA, 3%) (P = 0.51). None of the haplotypes nor alleles of studied TNF-alpha polymorphisms were significantly associated with advanced dry-type AMD. CONCLUSION: The findings of this study show that polymorphisms in the TNF-alpha gene, do not play an important role in dry-type AMD in the studied population. PMID- 26425319 TI - Retinal Sensitivity over Hard Exudates in Diabetic Retinopathy. AB - PURPOSE: To evaluate retinal sensitivity over hard exudates in correlation with the spectral domain optical coherence tomography (SD-OCT) findings in eyes with diabetic retinopathy. METHODS: Twelve eyes of 10 patients with hard exudates associated with diabetic retinopathy were enrolled in this study. All subjects underwent a complete ophthalmic examination including SD-OCT (Copernicus, Zawiercie, Poland) and microperimetry (MP1; Nidek Technologies, Padova, Italy). Retinal sensitivity was measured, over the areas with hard exudates and compared to corresponding locations devoid of hard exudates, using a semi-automatic program. The size of the hard exudate plaque was measured using the measurement software in the microperimeter. Retinal thickness in the area of the hard exudates and foveal thickness were measured using SD-OCT. RESULTS: Mean retinal sensitivity over hard exudates was 4.97 +/- 4.17 dB which was significantly (P = 0.0001) reduced as compared to locations devoid of hard exudates. No significant correlation (r=-0.23, P = 0.45) was found between the size of the hard exudates and retinal sensitivity. A significant negative correlation was found between retinal sensitivity and retinal thickness at the area of the hard exudates (r= 0.65, P = 0.05), and between retinal sensitivity and foveal thickness (r=-0.91, P = 0.001). CONCLUSION: In eyes with diabetic retinopathy, retinal sensitivity was reduced due to the presence of hard exudates in the outer retinal layers and retinal thickening but this was not correlated with the size of the hard exudates. PMID- 26425320 TI - Multifocal Electroretinogram in Diabetic Macular Edema; Correlation with Visual Acuity and Optical Coherence Tomography. AB - PURPOSE: To evaluate multifocal electroretinogram (mfERG) changes in eyes with diabetic macular edema (DME) and investigate any possible correlation with optical coherence tomography (OCT) features and visual acuity (VA). METHODS: Twenty-nine right eyes of 29 subjects with DME due to non-proliferative diabetic retinopathy and 30 eyes of 30 normal subjects were evaluated. All patients underwent a complete ophthalmic examination. Sixty-one scaled hexagon mfERG responses were recorded. Components of the first order kernel of N1, N2, and P1 in five concentric rings centered on the fovea, were measured in both groups. Correlation and regression analyses were performed among VA, central macular thickness (CMT) based on OCT, mfERG amplitude, and latency of the N1, N2 and P1 waves. RESULTS: Significant differences were observed in all mfERG parameters in five-ring regions of the retina between eyes with DME versus controls (P < 0.05). There were significant correlations among VA with N2 (P = 0,001, b = 0.73) and P1 amplitudes (P = 0.001, b = -0.84) in the central macular area, and there was a borderline association between VA and CMT (P = 0.042, b = 0.392). CONCLUSION: Amplitudes of mfERG components (N1, P1, and N2) are significantly reduced and their latencies are delayed in eyes with DME indicating functional impairment in the outer retina. The mfERG total amplitude was significantly correlated with VA even more than CMT, therefore the combined use of OCT and mfERG for macular evaluation may better evaluate visual status in DME patients. PMID- 26425321 TI - Foveal Structure in Macula-off Rhegmatogenous Retinal Detachment after Scleral Buckling or Vitrectomy. AB - PURPOSE: To evaluate foveal microstructural changes and to determine its association with visual outcomes after reattachment of rhegmatogenous retinal detachments (RRDs) by scleral buckling (SB) or pars plana vitrectomy (PPV). METHODS: Using spectral domain optical coherence tomography (SD-OCT), foveal microstructure in eyes with macula-off RRD were studied 1, 3, 6, 9, 12 and 15 months after PPV or SB and correlated with visual outcomes. RESULTS: Forty-two eyes were included in the final analysis. Even with improved microstructural changes and normalization of retinal structures on OCT, final visual acuity was not correlated with microstructural changes in eyes undergoing PPV. In the SB group, final visual acuity was significantly correlated with an intact inner segment/outer segment (IS/OS) junction (P = 0.013). There was no significant correlation between final visual acuity and presence of subretinal fluid (SRF) in either group. CONCLUSION: After SB, eyes with an intact IS/OS junction had better final visual acuity. In the PPV group, there was no significant correlation between microstructural changes and visual acuity. The presence of SRF did not influence final visual acuity in both groups. PMID- 26425322 TI - Senile Dementia and Glaucoma: Evidence for a Common Link. AB - Dementia and glaucoma are both neurodegenerative conditions characterized by neuronal loss leading to cognitive and visual dysfunction, respectively. A variety of evidence exists linking the two diseases including structural signs, specifically degenerative changes within ganglion cells. Both diseases become more prevalent with increased age, but that alone is unlikely to account for the increased co-prevalence of the diseases found in various studies. Neurotoxic substances including abnormal hyperphosphorylated tau and amyloid-beta have been found in both disease processes suggesting possible pathophysiologic links between the diseases. The exact mechanism of apoptosis, whether by direct toxicity or potentiation, still needs to be established, but could prove important for both diseases. Another potential link relates to low intracranial pressure in patients with both diseases causing a high translaminar pressure gradient and optic nerve damage in certain patients. While this alone may not account for direct optic nerve damage, it could lead to cerebrospinal fluid (CSF) circulatory failure causing increased neurotoxins along the optic nerves with resultant damage. All of this evidence suggests the need to further study links between the two diseases, as this could prove instrumental in understanding their overlapping pathophysiology and developing directed therapies for both diseases. While this is more thoroughly investigated, it may be prudent to have a lower threshold for a glaucoma work-up in patients with pre-existing dementia. PMID- 26425323 TI - Herpes Simplex Virus Endotheliitis following Descemet's Membrane Endothelial Keratoplasty. AB - PURPOSE: To report a case of herpes simplex virus (HSV) endotheliitis following simultaneous phacoemulsification, intraocular lens (IOL) implantation and descemet's membrane endothelial keratoplasty (DMEK). CASE REPORT: A;45 year-old female with corneal endothelial decompensation and a mature cataract, and history of anterior uveitis underwent simultaneous phacoemulsification, IOL implantation and DMEK. Increased corneal edema and descemet's membrane (DM) detachment occurred on postoperative day 3 and 5, respectively. One week after surgery, active keratic precipitates (KPs) appeared. Polymerase chain reaction (PCR) analysis was performed on an aqueous sample which was positive for herpes simplex virus (HSV). After initiating oral acyclovir and frequent topical corticosteroids, the corneal edema resolved and the donor tissue became spontaneously reattached to the recipient corneal stroma. CONCLUSION: HSV endotheliitis may occur in the early postoperative period after DMEK and manifest as endothelial dysfunction leading to donor detachment. Anti-viral medication may help treat the acute phase and reduce the risk of recurrence. PMID- 26425325 TI - Optical Coherence Tomography Features in Idiopathic Retinal Vasculitis, Aneurysms and Neuroretinitis Syndrome. PMID- 26425324 TI - Optic Nerve Aplasia: Case Report and Literature Review. AB - PURPOSE: To report three cases of optic nerve aplasia (ONA). CASE REPORT: Herein three subjects with ONA are described, two subjects had unilateral involvement. In one of these cases, the fellow eye had an associated persistent hyperplastic primary vitreous (PHPV). The third patient had bilateral ONA with multiple intracranial anomalies. Previous reports are reviewed and reported findings are summarized. Orbital and brain magnetic resonance imaging (MRI) were normal in two of our cases and loss of corpus callosum in the third case. Narrow optic nerve was observed on the right side and normal appearance in other two patients. CONCLUSION: The diagnosis of optic nerve abnormalities in children requires a thorough ophthalmic examination and proper ancillary testing. Although MRI is valuable in the diagnosis of associated central nervous system anomalies, the optic nerve may appear in normal size and course on MRI images and thus one may not be able to diagnose ONA in eyes with opaque media. PMID- 26425326 TI - Multimodal Imaging of Posterior Dislocation of Crystalline Lens Nucleus following Vitrectomy. PMID- 26425327 TI - Public Health Interventions to Reduce the Prevalence of Blindness in Developing Countries. PMID- 26425328 TI - Erratum: Central Corneal Thickness in Highly Myopic Eyes: Interdevice Agreement of Ultrasonic Pachymetry, Pentacam and Orbscan II Before and After Photorefractive Keratectomy: Erratum. AB - [This corrects the article on p. 14 in vol. 9, PMID: 24982727.]. PMID- 26425329 TI - Quit Smoking Experts' Opinions toward Quality and Results of Quit Smoking Methods Provided in Tobacco Cessation Services Centers in Iran. AB - BACKGROUND: One of the core responsibilities of health system is to treat tobacco dependence. This treatment includes different methods such as simple medical consultation, medication, and telephone counseling. To assess physicians' opinions towards quality and result of different quit smoking methods provided in tobacco cessation services centers in Iran. METHODS: In this cross-sectional and descriptive study, random sampling of all quit centers at country level was used to obtain a representative sample size of 100 physicians. Physicians completed a self-administered questionnaire which contained 10 questions regarding the quality, cost, effect, side effects, and the results of quitting methods using a 5-point Likert-type scale. Percentages, frequencies, mean, T-test, and variance analyses were computed for all study variables. RESULTS: Most experts preferred to use combination quit smoking methods and then Nicotine Replacement Therapy (NRT) with 26 and 23, respectively. The least used methods were quit line and some methods without medication with 3 cases. The method which gained the maximum scores were telephone consultation, acupuncture, Willpower, Champix, combined method, and Interactive Voice Response (IVR) with the mean of 23.3, 23, 22.5, 22, 21.7 and 21.3, respectively. The minimum scores were related to e-cigarette, some methods without medication, and non-NRT medication with the mean of 12.3, 15.8 and 16.2, respectively. There were no significant differences in the mean of scores based on different cities (P = 0.256). Analysis of variance in mean scores showed significant differences in the means scores of different methods (P < 0.000). CONCLUSIONS: According to physicians acupuncture, personal methods and Champix are the most effective methods and these methods could be much more feasible and cost effective than other methods. PMID- 26425330 TI - Analyzing Short Message Services Application Effect on Diabetic Patients' Self caring. AB - BACKGROUND: Diabetes is the most prevalent metabolic disease with a growing spread rate in word wide. Short message service (SMS) is of the most common public communication networks, which have brought about a broad spectrum of applications like social, cultural and service products in the late decade. The objective of this research is, the investigate of using SMS on diabetes patients self-caring. METHODS: In an interventional study, 228 diabetes patients have been selected from a community charity. With using of random sampling method, they were divided into two groups of 114 subjects as the control and case. The case group was sent messages reminding them about sports, caring foot, taking insulin and oral tablet for 4 weeks via mobile phone. After 4 weeks, a posttest questionnaire was completed. The data analysis was performed using a descriptive statistic, Chi-square, independent t-test, and paired t-test. RESULTS: There are not significant differences between case and control groups before intervention by studied dependent variables (P > 0.05). Performance score mean of taking care of foot, sport and taking oral tablet and insulin in case group before intervention were 29.90, 10, 11.16 and 3.75 respectively and after intervention were 20.11, 41.36, 13.09 and 4.90, respectively. Furthermore, the performance scores mean difference after intervention, taking care of foot (P < 0.001), sport (P < 0.001), taking oral tablet (P = 0.020) was meaningful in case and control groups. CONCLUSIONS: Regarding the study results on using cell phone, to utilize virtual training methods is recommended as an appropriate procedure for different health care, self-caring and follow-up training plans for various groups in society, especially diabetic and chronic patients. PMID- 26425331 TI - Spatial Analysis of Neonatal Congenital Hypothyroidism and Nitrate as an Environmental Pollutant in Isfahan Province During 2010-2013. AB - BACKGROUND: Thyroid absorption of iodine could be encumbered by nitrate drinking water when it is transported to the fetal thyroid gland. Therefore, nitrate potentially causes congenital hypothyroidism (CH) due to thyroid dysfunction. In this study, we have not only aimed at spatial determination of CH distribution and nitrate concentration (NC) existing in drinking water, but also we intended to evaluate the probable impact of nitrate on CH incidence. METHODS: Annual average of nitrate in drinking-water as well as number of CH infants diagnosed through the screening program were applied to determine the incidence ratio of the disease for each town (from 2010 to 2013). Afterward, Arc GIS 9.3 was used to draw choropleth maps with quantile classification. Data were entered into SPSS 16.0 and Excel 2010 software. Finally, linear regression was applied for data analysis. RESULTS: The incidence rate of CH (considering transient and permanent cases) was about one in every 413 births. Khansar, Golpaygan, Naein, and Ardestan had the highest incidence rate of CH respectively. On the other hand, Tiran, Dehaghan, Khansar, and Fereydan had the highest level of nitrate drinking water. There was a strong relationship between the NC and incidence of CH in Khansar; however, this relationship was not significant (P = 0.392) in Isfahan province. CONCLUSIONS: Since there was not a significant relationship between NC in drinking-water and incidence of CH through linear regression analysis, more studies should be implemented to confirm or refute our observations. PMID- 26425332 TI - Methodology and Early Findings of the Assessment of Determinants of Weight Disorders among Iranian Children and Adolescents: The Childhood and Adolescence Surveillance and PreventIon of Adult Noncommunicable Disease-IV Study. AB - BACKGROUND: This paper presents the methodology and primary findings of a national project on determinants of weight disorders among Iranian children and adolescents at national and sub-national levels. METHODS: This nationwide study was conducted in 2011-2012 in Iran as part of the fourth phase of a national surveillance program entitled Childhood and Adolescence Surveillance and PreventIon of Adult Noncommunicable disease-IV study. It had two phases of qualitative and quantitative study. This multicentric study was conducted among 25,000 students aged 6-18 years, living in urban and rural areas of 30 provinces of Iran. Students were selected by multistage cluster sampling method. Data regarding weight disorders including sociodemographic variables, perinatal factors, lifestyle factors, family and student dietary habits, quality of life, and family history of chronic diseases as well as body image were gathered via validated questionnaires. RESULTS: Overall, 23043 students completed the survey (participation rate: 92.17%). The mean age of participants was 12.55 +/- 3.31 years; 50.8% were boys, and 73.4% were from urban areas. Underweight was found in 10.4% of boys and 9.2% of girls, the corresponding figure for overweight and obesity was 21% and 18.3%. Abdominal obesity was found in 17.6% of students. Among parents, obesity was more frequent than other weight disorders, with higher prevalence in parents of girls than boys (24.5% vs. 21.5%, respectively, P < 0.001). Overweight and obesity were more prevalent in urban than in rural parents (66.7% vs. 59.7%, respectively, P < 0.001). CONCLUSIONS: This survey serves as confirmatory evidence on the prevalence of dual burden of weight disorders in Iran. Its findings on determinants of weight disorders would help policymakers to implement relevant programs at national and sub-national levels. PMID- 26425333 TI - Validation of Perceptual Strain Index to Evaluate the Thermal Strain in Experimental Hot Conditions. AB - BACKGROUND: The incidence of heat stress is one of the most common problems in workplaces and industries. Many heat stress indices have been developed, and these indices have some disadvantages. The purpose of this study is to validate the perceptual strain index (PeSI) in experimental hot conditions. METHODS: This study is of cross-sectional carried out on 15 men at five different thermal conditions (35 degrees C, 30 degrees C, 27 degrees C, 24 degrees C, and 21 degrees C) in a climate chamber and on a treadmill at three levels of light (2.4 kph), medium (4.8 kph) and heavy activity (6.3 kph). Heart rate and oral temperature were respectively measured to calculate the physiological strain index. Also, thermal sensation and rate perceive exertion were respectively measured to calculate the PeSI. Finally, the correlation between the indices was analyzed using Pearson correlation test and regression analysis. RESULTS: Pearson correlation test showed a high correlation (r = 0.94) between the PeSI and physiological strain index (P = 0/001). It was also observed a high correlation between the PeSI and the oral temperature (r = 0.78, P = 0/001) and the heart rate (r = 0.90, P = 0/001). In addition, there was found a moderate correlation (r = 0.71) between the PeSI and the wet bulb glob temperature (P = 0/001). However, there was no correlation between the PeSI and the body mass index (r = 0.0009, P = 0.79). CONCLUSIONS: The research findings showed when there is no access to other forms of methods to evaluate the heat stress, it can be used the PeSI in evaluating the strain because of its favorable correlation with the thermal strain. PMID- 26425334 TI - Psycho-social Needs Impact on Hookah Smoking Initiation among Women: A Qualitative Study from Iran. AB - BACKGROUND: In Iranian women, the use of hookah is the most common method of tobacco smoking. This study aimed to find the role of psycho-social needs and gaps as a possible risk factor for hookah smoking initiation in women. METHODS: This qualitative study was conducted during 2012-2013 in Tehran, Iran. Thirty-six women participated in the study. They were current or former users of hookah. Data were collected through in-depth individual interviews and was analyzed through content analysis. RESULTS: Four main categories were identified from the data. This study focused on the category: Psycho-social needs and gaps. This category has five sub-categories which explain why women begin to smoke hookah including curiosity; desire for non-feminine, forbidden, and negative activities; need for amusement and recreation; for others: To show off; attract attention; satisfy and join others and protection. CONCLUSIONS: From this study, a variety of factors which contribute to the initiation of hookah smoking among women have been identified. Keeping young girls and women away from seemingly happy gatherings of hookah smokers; Providing appropriate recreational facilities for young women and training families on how to help their children in the event of a crisis-like intention to take up smoking behavior, can be some effective ways for reducing hookah smoking initiation among women. PMID- 26425335 TI - Demographic and other characteristics of nodal non-Hodgkin's lymphoma managed in academic versus non-academic centers. AB - BACKGROUND: Cancer therapy and outcomes are known to be affected by various demographic features and hospital types. We aimed to identify the characteristics of non-Hodgkin's lymphoma (NHL) patients associated with receipt of care at academic centers. METHOD: This is a retrospective study of all patients diagnosed with nodal NHL between 2000 and 2011 in the National Cancer Database (NCDB), who received the diagnosis, and all or part of their initial therapy in the reporting hospital (n = 243,436). Characteristics of patients receiving care in academic versus nonacademic centers were compared using the Chi-square test. RESULTS: Approximately 27% received care in academic centers. Patients receiving care in nonacademic centers, compared with academic centers, were more likely to be ?60 years (69% versus 58%, p < .0001), White (89% versus 80%, p < .0001) and have lower educational attainment (>12% without high school diploma: 72% versus 69%, p < .0001) and economic status (household income <$49,000: 66% versus 61%, p < 0.0001). Patients receiving care in nonacademic centers were less likely to travel ?25 miles (21% versus 26%, p < 0.0001). White patients, compared with non Whites, were more likely to be ?60 years (70% versus <50%, p < 0.0001), which probably explains less care in academic centers. CONCLUSIONS: Patients ?60 years and those with poorer educational attainment and economic status were less likely to receive care in academic centers. Care in academic centers required a longer commute. Elderly patients frequently have inferior outcomes and may benefit from clinical trials with novel agents and expertise at academic centers. PMID- 26425336 TI - CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL). AB - Relapsed and chemotherapy-refractory B-cell acute lymphoblastic leukemia (B-ALL) remain significant causes of cancer-associated morbidity and mortality for children and adults. Development of new molecularly targeted treatment strategies for patients with high-risk B-ALL is thus a major preclinical and clinical priority. Adoptive cellular therapy with patient-derived human T cells genetically engineered to express CD19 redirected chimeric antigen receptors (CD19 CAR T cells) is one immunotherapeutic modality that has recently demonstrated remarkable efficacy in re-inducing remission in patients with multiply relapsed B-ALL. Investigative teams at several major cancer centers are currently conducting phase I clinical trials in children and/or adults with relapsed/refractory B-ALL to assess the safety and to identify the maximally tolerated dose of each group's CD19 CAR T-cell product. All groups have reported major clinical toxicities associated with CD19 CAR T-cell treatment, including cytokine release syndrome (CRS) and macrophage activation syndrome, neurologic dysfunction and aplasia of normal B lymphocytes, while CD19 CAR T cells persist in vivo. Toxicities have generally been transient or manageable with supportive care measures. Some patients with life-threatening CD19 CAR T-cell induced sequelae have received anti-cytokine receptor antibody treatment to diminish CRS symptoms and/or corticosteroids to terminate CAR T-cell proliferation. Remarkably, 67-90% of children and adults with B-ALL treated with CD19 CAR T cells in these trials have achieved morphologic leukemia remission with many patients also in molecular remission. The duration of CD19 CAR T cell persistence in vivo has varied appreciably among treated patients and likely reflects differences in the CD19 CAR constructs utilized at each institution. CD19 positive and CD19-negative B-ALL relapses after CD19 CAR T-cell treatment have occurred in some patients. Phase II trials to assess the efficacy of CD19 CAR T cell immunotherapy in larger cohorts of patients with relapsed/refractory B-ALL are ongoing or planned. PMID- 26425338 TI - The clinical potential of inotuzumab ozogamicin in relapsed and refractory acute lymphocytic leukemia. AB - Antibody-drug conjugates (ADCs) are likely to make a significant contribution in the treatment of acute lymphoblastic leukemia (ALL) by combining the cytotoxicity of chemotherapy with the specificity of monoclonal antibodies. CD22, an endocytic receptor expressed by the majority of B cells, is an excellent target for ADCs. Inotuzumab ozogamicin (INO) is an ADC that consists of a cytotoxic moiety (derivative of calicheamicin) attached to a humanized monoclonal anti-CD22 antibody. As a single agent, INO, was shown to be effective with an objective response rate of 50% in the treatment of relapsed and refractory CD22 positive ALL patients. Clinical trials investigating the combination of INO with the conventional chemotherapies are ongoing. This review summarizes the clinical potential of INO in treatment of relapsed and refractory ALL, based on currently available data in the literature. PMID- 26425337 TI - Ibrutinib in mantle cell lymphoma patients: glass half full? Evidence and opinion. AB - Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin's lymphoma typically marked by an aggressive clinical course and a predilection for relapse. The B cell receptor (BCR) signaling survival pathway is chronically activated in MCL, contributing to its pathogenesis. Ibrutinib is an inhibitor of Bruton's tyrosine kinase, a vital component of this pathway. This article details the current clinical experience with ibrutinib in the treatment of patients with MCL, including completed and published clinical trials and reviews potential adverse events (AEs) and pitfalls associated with ibrutinib therapy. Although most AEs experienced by patients treated with ibrutinib are mild, some can be severe and treatment limiting and may be attributed to off-target effects. Ibrutinib is a very promising agent for patients with MCL with notable response rates. However, when used as a single agent, around one third of patients relapse in the first 2 years of treatment. Recently reported combination therapies have shown significant activity. Emerging data evaluating potential mechanisms of drug resistance and the poor clinical outcomes after treatment failure are also discussed. Further understanding of resistance and its implications not only in relapsed disease but in the frontline setting are needed. Investigation of strategies to overcome resistance remains an area of high unmet clinical need. Evaluation of the impact of shorter treatment duration, effects on minimal residual disease, and incorporation of novel combinations are also warranted. PMID- 26425340 TI - Kvik: three-tier data exploration tools for flexible analysis of genomic data in epidemiological studies. AB - Kvik is an open-source framework that we developed for explorative analysis of functional genomics data from large epidemiological studies. Creating such studies requires a significant amount of time and resources. It is therefore usual to reuse the data from one study for several research projects. Often each project requires implementing new analysis code, integration with specific knowledge bases, and specific visualizations. Although existing data exploration tools are available for single study data exploration, no tool provides all the required functionality for multistudy data exploration. We have therefore used the Kvik framework to develop Kvik Pathways, an application for exploring gene expression data in the context of biological pathways. We have used Kvik Pathways to explore data from both a cross-sectional study design and a case-control study within the Norwegian Women and Cancer (NOWAC) cohort. Kvik Pathways follows the three-tier architecture in web applications using a powerful back-end for statistical analyses and retrieval of metadata.In this note, we describe how we used the Kvik framework to develop the Kvik Pathways application. Kvik Pathways was used by our team of epidemiologists toexplore gene expression data from healthy women with high and low plasma ratios of essential fatty acids. PMID- 26425339 TI - The role of IL-33 and mast cells in allergy and inflammation. AB - Interleukin-33 (IL-33) is a member of the interleukin-1 (IL-1) cytokine family. It is preferentially and constitutively expressed in different structural cells such as epithelial cells, endothelial cells, and smooth muscle cells. During necrosis of these cells (after tissue injury or cell damage), the IL-33 that is released may be recognized by different types of immune cells, such as eosinophils, basophils and, especially, mast cells. IL-33 needs the specific receptor ST2 (membrane-bound receptor) and Interleukin-1 receptor accessory protein heterodimer for its binding, which instigates the production of different types of cytokines and chemokines that have crucial roles in the exacerbation of allergic diseases and inflammation. IL-33 and mast cells have been influentially associated to the pathophysiology of allergic diseases and inflammation. IL-33 is a crucial regulator of mast cell functions and might be an attractive therapeutic target for the treatment of allergic and inflammatory diseases. In this review, we summarize the current knowledge regarding the roles of IL-33 and mast cells in the pathogenesis of allergies and inflammation. PMID- 26425341 TI - Water immersion for post incident cooling of firefighters; a review of practical fire ground cooling modalities. AB - Rapidly cooling firefighters post emergency response is likely to increase the operational effectiveness of fire services during prolonged incidents. A variety of techniques have therefore been examined to return firefighters core body temperature to safe levels prior to fire scene re-entry or redeployment. The recommendation of forearm immersion (HFI) in cold water by the National Fire and Protection Association preceded implementation of this active cooling modality by a number of fire services in North America, South East Asia and Australia. The vascularity of the hands and forearms may expedite body heat removal, however, immersion of the torso, pelvis and/or lower body, otherwise known as multi segment immersion (MSI), exposes a greater proportion of the body surface to water than HFI, potentially increasing the rates of cooling conferred. Therefore, this review sought to establish the efficacy of HFI and MSI to rapidly reduce firefighters core body temperature to safe working levels during rest periods. A total of 38 studies with 55 treatments (43 MSI, 12 HFI) were reviewed. The core body temperature cooling rates conferred by MSI were generally classified as ideal (n = 23) with a range of ~0.01 to 0.35 degrees C min(-1). In contrast, all HFI treatments resulted in unacceptably slow core body temperature cooling rates (~0.01 to 0.05 degrees C min(-1)). Based upon the extensive field of research supporting immersion of large body surface areas and comparable logistics of establishing HFI or MSI, it is recommended that fire and rescue management reassess their approach to fireground rehabilitation of responders. Specifically, we question the use of HFI to rapidly lower firefighter core body temperature during rest periods. By utilising MSI to restore firefighter Tc to safe working levels, fire and rescue services would adopt an evidence based approach to maintaining operational capability during arduous, sustained responses. While the optimal MSI protocol will be determined by the specifics of an individual response, maximising the body surface area immersed in circulated water of up to 26 degrees C for 15 min is likely to return firefighter Tc to safe working levels during rest periods. Utilising cooler water temperatures will expedite Tc cooling and minimise immersion duration. PMID- 26425344 TI - UEG E-learning: The future has arrived. PMID- 26425342 TI - Effects of different colloid infusions on ROTEM and Multiplate during elective brain tumour neurosurgery. AB - BACKGROUND: The European Medicines Agency does not recommend the use of hydroxyethyl starch-based volume replacement solutions in critically ill patients due to an increased risk of renal failure. However, this recommendation is questionable for its perioperative use. Several recent randomised controlled studies do not indicate a risk for renal failure-not even after high-risk surgery. Human albumin is used in our neurointensive care unit as a part of the "Lund concept" of brain injury resuscitation, and albumin has been introduced in elective neurosurgery instead of starch. The aim of our prospective unblinded observational cohort study was to compare the degree of dilutive coagulopathy after albumin and starch intra-operative fluid therapy. METHODS: Thirty-nine patients undergoing elective brain tumour surgery with craniotomy received either 130/0.42 hydroxyethyl starch or 5 % albumin infusions. The first 18 patients received starch, whereas the rest received albumin. Rotational thromboelastometry with ROTEM and platelet aggregometry with Multiplate were performed before surgery, after the first and second consecutive colloid infusions (250/500 ml albumin or 500/1000 ml starch) and at the end of surgery. RESULTS: Both intra- and inter-group comparisons showed more deranged ROTEM parameters after the higher doses of starch. Multiplate detected changes only in the albumin group after 500-ml infusion. Blood los did not differ between groups, nor did haemoglobin preoperatively or at end of surgery. Lower volumes of albumin were required to maintain stable intra-operative haemodynamic parameters; 250/500 ml albumin corresponded to 500/1000 ml starch. CONCLUSIONS: Hydroxyethyl starch affected coagulation at lower volumes, with a more prominent effect on clot structure at the end of surgery, corroborating previous research. Only albumin decreased platelet aggregation, and 5 % albumin had a more potential volume effect than 130/0.42 hydroxyethyl starch. PMID- 26425345 TI - What it means to receive the UEG Rising Star Award. PMID- 26425346 TI - Young Talent Group introduces young guest editors for UEG Journal. PMID- 26425343 TI - New developments and future opportunities in biomarkers for amyotrophic lateral sclerosis. AB - Modern technology has improved the ability to probe effectively the underlying biology of ALS by examination of genomic, proteomic and physiological changes in patients with ALS, as well as to monitor functional and structural changes during the course of disease. While effective treatments for ALS are lacking, the discovery of sensitive biomarkers to disease activity offers clinicians tools for rapid diagnosis and insights into the pathophysiology of ALS. The ultimate aim is to lessen reliance on clinical measures and survival as trial endpoints and broaden the therapeutic options for patients with this disease. PMID- 26425347 TI - Effect of therapeutic plasma exchange on plasma levels and total removal of adipokines and inflammatory markers. AB - BACKGROUND: Aside from well-established inflammatory mediators adipokines have recently been found to play an important role in a variety of immunologic diseases. Therapeutic plasma exchange (TPE) is an established treatment modality for the acute removal of pathophysiological relevant disease mediators. The aim of this study was to determine adipokine removal during TPE therapy. METHODS: 21 Caucasian patients (10 females, 11 males) with an indication for TPE using albumin as exchange fluid received two consecutive TPE sessions. Blood samples for measurement of resistin, leptin, sICAM-1, sCD40L, MCP-1, and sTNF-R were drawn before and at the end of each TPE session. Samples from the total removed plasma were collected at the end of every treatment. RESULTS: We found a significant reduction in pre- vs. post-TPE plasma concentrations for sICAM-1 (517 +/- 246 vs. 260 +/- 159 ng/ml, p < 0.0001), sTNF-R (8.1 +/- 6.4 vs. 5.7 +/- 3.9 ng/ml, p < 0.05), and resistin plasma levels (14.3 +/- 6.9 vs. 9.5 +/- 4.7 ng/ml, p < 0.001). Solely sICAM-1 reduction persisted for 25 +/- 5 h between the first and second TPE treatment, while the other investigated mediators increased to baseline levels. Substantial amounts of all measured mediators could be recovered from the removed plasma. CONCLUSIONS: TPE provides a persistent reduction in sICAM-1 levels and temporarily affects several adipokine and cytokine plasma levels. Our findings are of importance not only for the interpretation of blood levels of cytokines in patients undergoing TPE but provide solid evidence that TPE markedly decreases sICAM-1. PMID- 26425348 TI - Vitreomacular Interface: From Anterior to Tangential Traction. PMID- 26425349 TI - The Vitreomacular Interface in Diabetic Retinopathy. AB - Diabetic retinopathy (DR) is a leading health concern and a major cause of blindness. DR can be complicated by scar tissue formation, macular edema, and tractional retinal detachment. Optical coherence tomography has found that patients with DR often have diffuse retinal thickening, cystoid macular edema, posterior hyaloid traction, and tractional retinal detachment. Newer imaging techniques can even detect fine tangential folds and serous macular detachment. The interplay of the vitreous and the retina in the progression of DR involves multiple chemokine and other regulatory factors including VEGF. Understanding the cells infiltrating pathologic membranes at the vitreomacular interface has opened up the possibility of new targets for pharmacotherapy. Vitrectomies for DR remain a vital tool to help relieve tension on the macula by removing membranes, improving edema absorption, and eliminating the scaffold for new membrane formation. Newer treatments such as triamcinolone acetonide and VEGF inhibitors have become essential as a rapid way to control DR at the vitreomacular interface, improve macular edema, and reduce retinal neovascularization. These treatments alone, and in conjunction with PRP, help to prevent worsening of the VMI in patients with DR. PMID- 26425350 TI - Correlative Microscopy of Lamellar Hole-Associated Epiretinal Proliferation. AB - Purpose. To describe morphology of lamellar hole-associated epiretinal proliferation (LHEP) removed from eyes with lamellar macular holes (LMH). Methods. Based on optical coherence tomography data, 10 specimens of LHEP were removed from 10 eyes with LMH during standard vitrectomy. Specimens were prepared for correlative light and electron microscopy (CLEM) using an immunonanogold particle of 1.4 nm diameter that was combined with a fluorescein moiety, both having been attached to a single antibody fragment. As primary antibodies, we used antiglial fibrillary acidic protein (GFAP), anti-CD45, anti-CD64, anti-alpha smooth muscle actin (alpha-SMA), and anticollagen type I and type II. Results. In LHEP, GFAP-positive cells possess ultrastructural characteristics of fibroblasts and hyalocytes. They represent the major cell types and were densely packed in cell agglomerations on vitreous collagen strands. Epiretinal cells of LHEP rarely demonstrated contractive properties as alpha-SMA-positive myofibroblasts were an infrequent finding. Conclusion. CLEM indicates that epiretinal cells in LHEP might originate from the vitreous and that remodelling processes of vitreous collagen may play an important role in pathogenesis of eyes with LMH. PMID- 26425353 TI - Is the Memory Effect of the Blind Spot Involved in Negative Dysphotopsia after Cataract Surgery? AB - We present novel clinical observations on negative dysphotopsia (ND) in eyes that have undergone cataract surgery. In the past, shadow effects were alleged to be located in the far peripheral temporal visual field 50 degrees to 100 degrees away from the optical axis. In a small series of eight patients we found evidence of photic effects, described by the patients as shadows in the periphery that were objectively located much more centrally. In all cases, we could find an association of these phenomena with the blind spot. We hypothesize that the memory effect of the blind spot which is dislocated and changed in magnification due to replacement of the crystalline lens could be one determinant for pseudophakic ND. The scotoma of the optic nerve head and the main arteries and veins of the phakic eye are displaced in the pseudophakic eye depending on the specific characteristics and position of the intraocular lens within the eye. PMID- 26425352 TI - Current Trends about Inner Limiting Membrane Peeling in Surgery for Epiretinal Membranes. AB - The inner limiting membrane (ILM) is the basement membrane of the Muller cells and can act as a scaffold for cellular proliferation in the pathophysiology of disorders affecting the vitreomacular interface. The atraumatic removal of the macular ILM has been proposed for treating various forms of tractional maculopathy in particular for macular pucker. In the last decade, the removal of ILM has become a routine practice in the surgery of the epiretinal membranes (ERMs), with good anatomical results. However many recent studies showed that ILM peeling is a procedure that can cause immediate traumatic effects and progressive modification on the underlying inner retinal layers. Moreover, it is unclear whether ILM peeling is helpful to improve vision after surgery for ERM. In this review, we describe the current understanding about ILM peeling and highlight the beneficial and adverse effects associated with this surgical procedure. PMID- 26425354 TI - Effects of Vitreomacular Adhesion on Age-Related Macular Degeneration. AB - Herein, we review the association between vitreomacular adhesion (VMA) and neovascular age-related macular degeneration (AMD). Meta-analyses have shown that eyes with neovascular AMD are twice as likely to have VMA as normal eyes. VMA in neovascular AMD may induce inflammation, macular traction, decrease in oxygenation, sequestering of vascular endothelial growth factor (VEGF), and other cytokines or may directly stimulate VEGF production. VMA may also interfere with the treatment effects of anti-VEGF therapy, which is the standard treatment for neovascular AMD, and releasing VMA can improve the treatment response to anti VEGF treatment in neovascular AMD. We also reviewed currently available methods of relieving VMA. PMID- 26425355 TI - Retinal Damage Induced by Internal Limiting Membrane Removal. AB - The internal limiting membrane (ILM), the basement membrane of the Muller cells, serves as the interface between the vitreous body and the retinal nerve fiber layer. It has a fundamental role in the development, structure, and function of the retina, although it also is a pathologic component in the various vitreoretinal disorders, most notably in macular holes. It was not until understanding of the evolution of idiopathic macular holes and the advent of idiopathic macular hole surgery that the idea of adjuvant ILM peeling in the treatment of tractional maculopathies was explored. Today intentional ILM peeling is a commonly applied surgical technique among vitreoretinal surgeons as it has been found to increase the rate of successful macular hole closure and improve surgical outcomes in other vitreoretinal diseases. Though ILM peeling has refined surgery for tractional maculopathies, like all surgical procedures it is not immune to perioperative risk. The essential role of the ILM to the integrity of the retina and risk of trauma to retinal tissue spurs suspicion with regard to its routine removal. Several authors have investigated the retinal damage induced by ILM peeling and these complications have been manifested across many different diagnostic studies. PMID- 26425356 TI - Advances in atomic physics: Four decades of contribution of the Cairo University Atomic Physics Group. AB - In this review article, important developments in the field of atomic physics are highlighted and linked to research works the author was involved in himself as a leader of the Cairo University - Atomic Physics Group. Starting from the late 1960s - when the author first engaged in research - an overview is provided of the milestones in the fascinating landscape of atomic physics. PMID- 26425351 TI - Complications of Macular Peeling. AB - Macular peeling refers to the surgical technique for the removal of preretinal tissue or the internal limiting membrane (ILM) in the macula for several retinal disorders, ranging from epiretinal membranes (primary or secondary to diabetic retinopathy, retinal detachment...) to full-thickness macular holes, macular edema, foveal retinoschisis, and others. The technique has evolved in the last two decades, and the different instrumentations and adjuncts have progressively advanced turning into a safer, easier, and more useful tool for the vitreoretinal surgeon. Here, we describe the main milestones of macular peeling, drawing attention to its associated complications. PMID- 26425358 TI - New algorithms for solving third- and fifth-order two point boundary value problems based on nonsymmetric generalized Jacobi Petrov-Galerkin method. AB - Two families of certain nonsymmetric generalized Jacobi polynomials with negative integer indexes are employed for solving third- and fifth-order two point boundary value problems governed by homogeneous and nonhomogeneous boundary conditions using a dual Petrov-Galerkin method. The idea behind our method is to use trial functions satisfying the underlying boundary conditions of the differential equations and the test functions satisfying the dual boundary conditions. The resulting linear systems from the application of our method are specially structured and they can be efficiently inverted. The use of generalized Jacobi polynomials simplify the theoretical and numerical analysis of the method and also leads to accurate and efficient numerical algorithms. The presented numerical results indicate that the proposed numerical algorithms are reliable and very efficient. PMID- 26425357 TI - Synthesis, cloning and expression of a novel pre-miniproinsulin analogue gene in Escherichia coli. AB - In the present study, a novel pre-miniproinsulin analogue was designed to have a short 9 residue sequence replacing the 35 residue C-chain, one lysine and one arginine added to the C-terminus of the B-chain in combination with glycine and arginine substitution at A21 and B29, respectively, and a 16-residue fusion partner comprising the pentapeptide sequence (PSDKP) of the N-terminus of human tumor necrosis factor-alpha (TNF-alpha), 6 histidine residues for Ni(2+) chelated affinity purification and a pentapeptide ending with methionine for ease of chemical cleavage fused at the N-terminus. Homology modeling of the designed protein against miniproinsulin (protein databank file 1 efeA) as a template showed that the distance between the alpha-carbons of the C-terminus of the B chain and the N-terminus of the A-chain did not change; the root-mean-square deviation of the backbone atoms between the structures of modeled miniproinsulin and miniproinsulin template was 0.000 A. DNA sequencing of the synthesized gene showed 100% identity with theoretical sequence. The gene was constructed taking into account the codon preference of Escherichia coli (CAI value 0.99) in order to increase the expression rate of the DNA in the host strain. The designed gene was synthesized using DNA synthesis technology and then cloned into the expression plasmid pET-24a(+) and propagated in E. coli strain JM109. Gene expression was successful in two E. coli strains: namely JM109(DE3) and BL21(DE3)pLysS. SDS-PAGE analysis was carried out to check protein size and to check and optimize expression. Rapid screening and purification of the resulting protein was carried out by Ni-NTA technology. The identity of the expressed protein was verified by immunological detection method of western blot using polyclonal rabbit antibody against insulin. PMID- 26425360 TI - Statistical analysis of the effective factors on the 28 days compressive strength and setting time of the concrete. AB - In this study, the effects of various factors (weight fraction of the SiO2, Al2O3, Fe2O3, Na2O, K2O, CaO, MgO, Cl, SO3, and the Blaine of the cement particles) on the concrete compressive strength and also initial setting time have been investigated. Compressive strength and setting time tests have been carried out based on DIN standards in this study. Interactions of these factors have been obtained by the use of analysis of variance and regression equations of these factors have been obtained to predict the concrete compressive strength and initial setting time. Also, simple and applicable formulas with less than 6% absolute mean error have been developed using the genetic algorithm to predict these parameters. Finally, the effect of each factor has been investigated when other factors are in their low or high level. PMID- 26425359 TI - An intelligent approach for variable size segmentation of non-stationary signals. AB - In numerous signal processing applications, non-stationary signals should be segmented to piece-wise stationary epochs before being further analyzed. In this article, an enhanced segmentation method based on fractal dimension (FD) and evolutionary algorithms (EAs) for non-stationary signals, such as electroencephalogram (EEG), magnetoencephalogram (MEG) and electromyogram (EMG), is proposed. In the proposed approach, discrete wavelet transform (DWT) decomposes the signal into orthonormal time series with different frequency bands. Then, the FD of the decomposed signal is calculated within two sliding windows. The accuracy of the segmentation method depends on these parameters of FD. In this study, four EAs are used to increase the accuracy of segmentation method and choose acceptable parameters of the FD. These include particle swarm optimization (PSO), new PSO (NPSO), PSO with mutation, and bee colony optimization (BCO). The suggested methods are compared with other most popular approaches (improved nonlinear energy operator (INLEO), wavelet generalized likelihood ratio (WGLR), and Varri's method) using synthetic signals, real EEG data, and the difference in the received photons of galactic objects. The results demonstrate the absolute superiority of the suggested approach. PMID- 26425361 TI - Bearing capacity of shell strip footing on reinforced sand. AB - In this paper, the ultimate load capacities of shell foundations on unreinforced and reinforced sand were determined by laboratory model tests. A series of loading tests were carried out on model shell footing with and without single layer of reinforcement. The tests were done for shell foundation at different shell embedment depth and subgrade density. The results were compared with those for flat foundations without reinforcement. The model test results were verified using finite element analysis using program PLAXIS. The experimental studies indicated that, the ultimate load capacity of shell footing on reinforced subgrade is higher than those on unreinforced cases and the load settlement curves were significantly modified. The shell foundation over reinforced subgrade can be considered a good method to increase the effective depth of the foundation and decrease the resulting settlement. Also the rupture surface of shell reinforced system was significantly deeper than both normal footing and shell footing without reinforcement. The numerical analysis helps in understanding the deformation behavior of the studied systems and identifies the failure surface of reinforced shell footing. PMID- 26425362 TI - Principal component analysis of cardiovascular risk traits in three generations cohort among Indian Punjabi population. AB - The current study focused to determine significant cardiovascular risk factors through principal component factor analysis (PCFA) among three generations on 1827 individuals in three generations including 911 males (378 from offspring, 439 from parental and 94 from grand-parental generations) and 916 females (261 from offspring, 515 from parental and 140 from grandparental generations). The study performed PCFA with orthogonal rotation to reduce 12 inter-correlated variables into groups of independent factors. The factors have been identified as 2 for male grandparents, 3 for male offspring, female parents and female grandparents each, 4 for male parents and 5 for female offspring. This data reduction method identified these factors that explained 72%, 84%, 79%, 69%, 70% and 73% for male and female offspring, male and female parents and male and female grandparents respectively, of the variations in original quantitative traits. The factor 1 accounting for the largest portion of variations was strongly loaded with factors related to obesity (body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR), and thickness of skinfolds) among all generations with both sexes, which has been known to be an independent predictor for cardiovascular morbidity and mortality. The second largest components, factor 2 and factor 3 for almost all generations reflected traits of blood pressure phenotypes loaded, however, in male offspring generation it was observed that factor 2 was loaded with blood pressure phenotypes as well as obesity. This study not only confirmed but also extended prior work by developing a cumulative risk scale from factor scores. Till today, such a cumulative and extensive scale has not been used in any Indian studies with individuals of three generations. These findings and study highlight the importance of global approach for assessing the risk and need for studies that elucidate how these different cardiovascular risk factors interact with each other over the time to create clinical disease. The findings also added depth to the negligible amount of literature of factor analysis of cardiovascular risk in any Indian ethnic population. PMID- 26425363 TI - Expression, genetic localization and phylogenic analysis of NAPlr in piscine Streptococcus dysgalactiae subspecies dysgalactiae isolates and their patterns of adherence. AB - Streptococcus dysgalactiae, the long recognized mammalian pathogen, has currently received a major concern regarding fish bacterial infection. Adhesion to host epithelial cells and the presence of wall-associated plasminogen binding proteins are prerequisites to Streptococcus infection. This is the first study of the occurrence of nephritis-associated plasminogen-binding receptor (NAPlr) and alpha enolase genes in piscine S. dysgalactiae subspecies dysgalactiae (SDSD) isolates. Further characterization of surface localized NAPlr of fish SDSD revealed a similar immune-reactive band of 43 KDa as that from porcine S. dysgalactiae subsp. equisimilis (SDSE). The phylogenetic analysis revealed that NAPlr of fish SDSD is more associated with those of mammalian SDSE and Streptococcus pyogenes rather than of other streptococci. Our findings warrant public attention to the possible implication of these virulence genes in dissemination of SDSD to different tissues of infected hosts and to get advantage to new niches. The SDSD adherence patterns were also studied to better understand their pathogenicity. The patterns of adherence of SDSD on two different cell lines showed a different pattern of adherence. Such difference gives an insight about the variance in host susceptibility to infection. PMID- 26425364 TI - Effect of laser acupuncture combined with a diet-exercise intervention on metabolic syndrome in post-menopausal women. AB - This study aimed to evaluate the effect of laser acupuncture combined with a diet exercise intervention on features of the metabolic syndrome (MetS). Twenty-eight obese post-menopausal women were randomly distributed to the control and laser acupuncture group. The control group received the diet-exercise intervention and the study group received the same intervention and sessions of laser acupuncture, 3 times/week for 12 weeks. Anthropometric measurement, fasting blood glucose and insulin levels, homeostatic model assessment-insulin resistance (HOMA-IR), and lipid profile were assessed before and after the treatment course. Both groups showed a significant decrease in the anthropometric and metabolic parameters. However, laser acupuncture group showed a greater decrease in the waist (P = 0.001) and hip (P = 0.001) circumferences, cholesterol (P = 0.04), and insulin levels (P = 0.043) than the control group. These results suggest that laser acupuncture is a valuable approach that could be added to the diet-exercise intervention to correct features of the MetS. PMID- 26425365 TI - The MANGUA Project: A Population-Based HIV Cohort in Guatemala. AB - Introduction. The MANGUA cohort is an ongoing multicenter, observational study of people living with HIV/AIDS in Guatemala. The cohort is based on the MANGUA application which is an electronic database to capture essential data from the medical records of HIV patients in care. Methods. The cohort enrolls HIV-positive adults >=16 years of age. A predefined set of sociodemographic, behavioral, clinical, and laboratory data are registered at entry to the cohort study. Results. As of October 1st, 2012, 21 697 patients had been included in the MANGUA cohort (median age: 33 years, 40.3% female). At enrollment 74.1% had signs of advanced HIV infection and only 56.3% had baseline CD4 cell counts. In the first 12 months after starting antiretroviral treatment 26.9% (n = 3938) of the patients were lost to the program. Conclusions. The implementation of a cohort of HIV-positive patients in care in Guatemala is feasible and has provided national HIV indicators to monitor and evaluate the HIV epidemic. The identified percentages of late presenters and high rates of LTFU will help the Ministry to target their current efforts in improving access to diagnosis and care. PMID- 26425366 TI - Open and Closed Endotracheal Suctioning and Arterial Blood Gas Values: A Single Blind Crossover Randomized Clinical Trial. AB - Aim. This study was aimed at comparing the effects of the open and closed suctioning techniques on the arterial blood gas values in patients undergoing open-heart surgery. Methods. In a clinical trial, we recruited 42 patients after open-heart surgery in an educational hospital. Each patient randomly underwent both open and closed suctioning. ABGs, PaO2, SaO2, PaCO2, were analyzed before and one, five, and fifteen minutes after each suctioning episode. Results. At first the pressure of oxygen in arterial blood increased; however, this increase in the open technique was greater than that of the closed system (P < 0.001). The pressure of oxygen decreased five and fifteen minutes after both suctioning techniques (P < 0.05). The trends of carbon dioxide variations after the open and closed techniques were upward and downward, respectively. Moreover, the decrease in the level of oxygen saturation five and fifteen minutes after the open suctioning was greater than that of the closed suctioning technique (P < 0.05). Conclusion. Arterial blood gas disturbances in the closed suctioning technique were less than those of the open technique. Therefore, to eliminate the unwanted effects of endotracheal suctioning on the arterial blood gases, the closed suctioning technique is recommended. PMID- 26425367 TI - Influence of Individual Surgeon Volume on Oncological Outcome of Colorectal Cancer Surgery. AB - BACKGROUND: Surgery performed by a high-volume surgeon improves short-term outcomes. However, not much is known about long-term effects. Therefore we performed the current study to evaluate the impact of high-volume colorectal surgeons on survival. METHODS: We conducted a retrospective analysis of our prospectively collected colorectal cancer database between 2004 and 2011. Patients were divided into two groups: operated on by a high-volume surgeon (>25 cases/year) or by a low-volume surgeon (<25 cases/year). Perioperative data were collected as well as follow-up, recurrence rates, and survival data. RESULTS: 774 patients underwent resection for colorectal malignancies. Thirteen low-volume surgeons operated on 453 patients and 4 high-volume surgeons operated on 321 patients. Groups showed an equal distribution for preoperative characteristics, except a higher ASA-classification in the low-volume group. A high-volume surgeon proved to be an independent prognostic factor for disease-free survival in the multivariate analysis (P = 0.04). Although overall survival did show a significant difference in the univariate analysis (P < 0.001) it failed to reach statistical significance in the multivariate analysis (P = 0.09). CONCLUSIONS: In our study, a higher number of colorectal cases performed per surgeon were associated with longer disease-free survival. Implementing high-volume surgery results in improved long-term outcome following colorectal cancer. PMID- 26425368 TI - Central Sensitization and Perceived Indoor Climate among Workers with Chronic Upper-Limb Pain: Cross-Sectional Study. AB - Monitoring of indoor climate is an essential part of occupational health and safety. While questionnaires are commonly used for surveillance, not all workers may perceive an identical indoor climate similarly. The aim of this study was to evaluate perceived indoor climate among workers with chronic pain compared with pain-free colleagues and to determine the influence of central sensitization on this perception. Eighty-two male slaughterhouse workers, 49 with upper-limb chronic pain and 33 pain-free controls, replied to a questionnaire with 13 items of indoor climate complaints. Pressure pain threshold (PPT) was measured in muscles of the arm, shoulder, and lower leg. Cross-sectional associations were determined using general linear models controlled for age, smoking, and job position. The number of indoor climate complaints was twice as high among workers with chronic pain compared with pain-free controls (1.8 [95% CI: 1.3-2.3] versus 0.9 [0.4-1.5], resp.). PPT of the nonpainful leg muscle was negatively associated with the number of complaints. Workers with chronic pain reported more indoor climate complaints than pain-free controls despite similar actual indoor climate. Previous studies that did not account for musculoskeletal pain in questionnaire assessment of indoor climate may be biased. Central sensitization likely explains the present findings. PMID- 26425369 TI - Naegele Forceps Delivery and Association between Morbidity and the Number of Forceps Traction Applications: A Retrospective Study. AB - OBJECTIVE: To present the method of Naegele forceps delivery clinically practiced by the lead author, its success rate, and morbidity and to evaluate the relationship between morbidity and the number of forceps traction applications. METHODS: Naegele forceps delivery was performed when the fetal head reached station +2 cm, the forceps were applied in the maternal pelvic application, and traction was slowly and gently performed. In the past two years, Naegele forceps delivery was attempted by the lead author in 87 cases, which were retrospectively reviewed. RESULTS: The numbers of traction applications were one in 64.7% of cases, two in 24.7%, and three or more in 10.7%. The success rate was 100%. No severe morbidity was observed in mothers or neonates. Neonatal facial injury occurred most commonly in cases with fetal head malrotation, elevated numbers of traction applications, and maternal complications. Umbilical artery acidemia most commonly occurred in cases with nonreassuring fetal status. The significant crude odds ratio for three or more traction applications was 20 in cases with malrotation. CONCLUSION: Naegele forceps delivery has a high success rate, but multiple traction applications will sometimes be required, particularly in cases with malrotation. Malrotation and elevated numbers of traction applications may lead to neonatal head damage. PMID- 26425371 TI - Constrictive Pericarditis: A Challenging Diagnosis in Paediatrics. AB - Constrictive pericarditis is an uncommon disease in children, usually difficult to diagnose. We present the case of a 14-year-old boy with a previous history of tuberculosis and right heart failure, in whom constrictive pericarditis was diagnosed. The case highlights the need to integrate all information, including clinical data, noninvasive cardiac imaging, and even invasive hemodynamic evaluation when required, in order to establish the correct diagnosis and proceed to surgical treatment. PMID- 26425372 TI - Conventional Complete Denture in Patients with Ectodermal Dysplasia. AB - Ectodermal dysplasia is described as heritable conditions that involve anomalies of structures derived from the ectoderm, including hypodontia. In the cases of edentulous young patients, who did not finish their craniofacial growth, treatment with conventional complete denture is a suitable alternative. The aim of this study was to report a case of mandibular edentulism treated with conventional complete denture in a thirteen-year-old patient diagnosed with hidrotic ectodermal dysplasia. Typical features, such as frontal bossing, depressed nasal bridge, protuberant lips, scarce hair, and brittle nails, were visualized during the extraoral examination. The intraoral inspection and radiographic analysis revealed oligodontia, dental malformation, and prolonged retention of deciduous teeth at maxilla and total edentulism at mandible. A conventional complete denture was planned and constructed following the same steps of technique as recommended in adults. Although this option is not a definitive treatment, the patient and his parents were satisfied with his improvement in chewing and speech, as well as with the aesthetic benefits. PMID- 26425370 TI - Audiomotor Integration in Minimally Conscious State: Proof of Concept! AB - Patients suffering from chronic disorders of consciousness (DOC) are characterized by profound unawareness and an impairment of large-scale cortical and subcortical connectivity. In this study, we applied an electrophysiological approach aimed at identifying the residual audiomotor connectivity patterns that are thought to be linked to awareness. We measured some markers of audiomotor integration (AMI) in 20 patients affected by DOC, before and after the application of a repetitive transcranial magnetic stimulation protocol (rTMS) delivered over the left primary motor area (M1), paired to a transauricular alternating current stimulation. Our protocol induced potentiating of the electrophysiological markers of AMI and M1 excitability, paired to a clinical improvement, in all of the patients with minimally conscious state (MCS) but in none of those suffering from unresponsive wakefulness syndrome (UWS). Our protocol could be a promising approach to potentiate the functional connectivity within large-scale audiomotor networks, thus allowing clinicians to differentiate patients affected by MCS from UWS, besides the clinical assessment. PMID- 26425373 TI - Interdisciplinary Approach to a Tooth with Open Apex and Persistent Sinus. AB - Traumatic injuries in childhood may disrupt root development leading to a tooth with open apex. Apexification procedures in such cases aim at root end closure after reasonable period of time. In some chronic cases, complete healing of the periapical area does not occur resulting in development of a nonhealing sinus. Failure of nonsurgical approach in such cases needs surgical intervention permitting thorough periapical curettage. In the present case, apexification procedure with MTA achieved root end closure but failed to heal the sinus for which surgical treatment was completed with thorough periapical curettage and application of platelet rich fibrin (PRF) and a combination of beta-tricalcium phosphate and hydroxyapatite resulted in healing. PMID- 26425374 TI - Reconstruction of a Large Anterior Ear Defect after Mohs Micrographic Surgery with a Cartilage Graft and Postauricular Revolving Door Flap. AB - A novel postauricular revolving door island flap and cartilage graft combination was employed to correct a large defect on the anterior ear of an 84-year-old man who underwent Mohs micrographic surgery for an antihelical squamous cell carcinoma. The defect measured 4.6 * 2.4 cm and spanned the antihelix, scapha, a small portion of the helix, and a large segment of underlying cartilage, with loss of structural integrity and anterior folding of the ear. The repair involved harvesting 1.5 cm(2) of exposed cartilage from the scaphoid fossa and then sculpting and suturing it to the remnant of the antihelical cartilage in order to recreate the antihelical crura. The skin of the posterior auricle was then incised just below the helical rim and folded anteriorly to cover the cartilage graft. The flap remained attached by a central subcutaneous pedicle, and an island designed using the full-thickness defect as a stencil template was pulled through the cartilage window anteriorly to resurface the anterior ear. This case demonstrates the use of the revolving door flap for coverage of large central ear defects with loss of cartilaginous support and illustrates how cartilage grafts may be used in combination with the flap to improve ear contour after resection. PMID- 26425375 TI - Lithium as an Alternative Option in Graves Thyrotoxicosis. AB - A 67-year-old woman was admitted with signs and symptoms of Graves thyrotoxicosis. Biochemistry results were as follows: TSH was undetectable; FT4 was >6.99 ng/dL (0.7-1.8); FT3 was 18 pg/mL (3-5); TSI was 658% (0-139). Thyroid uptake and scan showed diffusely increased tracer uptake in the thyroid gland. The patient was started on methimazole 40 mg BID, but her LFTs elevated precipitously with features of fulminant hepatitis. Methimazole was determined to be the cause and was stopped. After weighing pros and cons, lithium was initiated to treat her persistent thyrotoxicosis. Lithium 300 mg was given daily with a goal to maintain between 0.4 and 0.6. High dose Hydrocortisone and propranolol were also administered concomitantly. Free thyroid hormone levels decreased and the patient reached a biochemical and clinical euthyroid state in about 8 days. Though definitive RAI was planned, the patient has been maintained on lithium for more than a month to control her hyperthyroidism. Trial removal of lithium results in reemergence of thyrotoxicosis within 24 hours. Patient was maintained on low dose lithium treatment with lithium level just below therapeutic range which was sufficient to maintain euthyroid state for more than a month. There were no signs of lithium toxicity within this time period. Conclusion. Lithium has a unique physiologic profile and can be used to treat thyrotoxicosis when thionamides cannot be used while awaiting elective radioablation. Lithium levels need to be monitored; however, levels even at subtherapeutic range may be sufficient to treat thyrotoxicosis. PMID- 26425376 TI - Fatal Epstein-Barr Virus Reactivation in an Acquired Aplastic Anemia Patient Treated with Rabbit Antithymocyte Globulin and Cyclosporine A. AB - Epstein-Barr virus (EBV) associated lymphoproliferative disorder (LPD) after immunosuppressive therapy for aplastic anemia (AA) is extremely rare in a nontransplant setting and has not been well described. This report describes a severe AA patient in whom fatal EBV-LPD developed after being treated with rabbit antithymocyte globulins (ATG) and cyclosporine A (CsA). An 81-year-old man was diagnosed as having severe AA. He was started on CsA followed by administration of ATG for five consecutive days. One month after the start of ATG, persistent fever which was not responsive to antibiotics or antifungal agents developed and atypical lymphocytes emerged in peripheral blood. Repeated blood cultures were negative. An extremely high level of EBV virus in his peripheral blood plasma was detected by means of a quantitative real-time PCR assay. Even after the cessation of CsA, the fever persisted and the peripheral atypical lymphocytes proliferated rapidly. The patient suffered from respiratory failure, liver dysfunction, and metabolic acidosis. Rituximab was administered without success and he died. PMID- 26425377 TI - Behcet's Disease with Intracardiac Thrombus Presenting with Fever of Unknown Etiology. AB - A young male was referred to us for evaluation of fever of unknown origin (FUO). He had history of recurrent painful oral ulcers for one year and moderate to high grade fever, pustulopapular rash, and recurrent genital ulcers for 6 months and hemoptysis for 3 days. He was detected to have intracardiac thrombi and pulmonary arterial thrombosis along with underlying Behcet's disease (BD). Patient responded to high dose prednisolone (1 mg/Kg/day) along with monthly parenteral cyclophosphamide therapy. This case highlights the fact that BD is an important cause for pulmonary artery vasculitis with intracardiac thrombus formation, and such patients can present with FUO. PMID- 26425378 TI - Hyperchloremic Metabolic Acidosis due to Cholestyramine: A Case Report and Literature Review. AB - Cholestyramine is a bile acid sequestrant that has been used in the treatment of hypercholesterolemia, pruritus due to elevated bile acid levels, and diarrhea due to bile acid malabsorption. This medication can rarely cause hyperchloremic nonanion gap metabolic acidosis, a complication featured in this report of an adult male with concomitant acute kidney injury. This case emphasizes the caution that must be taken in prescribing cholestyramine to patients who may also be volume depleted, in renal failure, or taking spironolactone. PMID- 26425379 TI - STA-MCA Bypass as a "Bridge" to Pituitary Surgery in a Patient with an Adenoma Occluding the Internal Carotid Artery: Case Report and Review of the Literature. AB - Occlusion of the intracranial internal carotid artery (ICA) by a pituitary adenoma with resulting cerebral ischemia is a very rare but devastating occurrence. The authors present a case in which a condition of symptomatic ICA occlusion due to a giant pituitary adenoma was successfully treated using a preliminary extraintracranial bypass as a "bridge" to the tumor removal. A 52 year-old patient presented with a minor stroke followed by pressure-dependent transient ischemic attacks consistent with a condition of hypoperfusion. MR imaging and a digital subtraction angiography revealed a pituitary adenoma occluding the ICA on the right side. He underwent a superficial temporal artery to middle cerebral artery (STA-MCA) bypass with the aim of revascularizing the ischemic hemisphere and reducing the risk of perioperative stroke or stroke evolution. The patient was subsequently operated on to remove the adenoma through a transsphenoidal approach. The postoperative course was uneventful and the patient has suffered no further ischemic events. When there are no emergency indications to decompress the optical pathways but the patient is at risk of impending stroke because of ICA occlusion, a two-step strategy consisting of a bypass and subsequent removal of the pituitary adenoma may be a valuable option. PMID- 26425380 TI - Ledderhose Disease: Clinical, Radiological (Ultrasound and MRI), and Anatomopathological Findings. AB - Plantar fibromatosis, or Ledderhose disease, is a rare hyperproliferative disorder of the plantar aponeurosis. It may occur at any age, with the greatest prevalence at middle age and beyond. This disorder is more common in men than woman and it is sometimes associated with other forms of fibromatosis. Diagnosis is based on clinical examination. Ultrasound (US) and magnetic resonance imaging (MRI) can be useful to confirm the diagnosis. A 44-year-old man with Ledderhose disease who underwent ultrasound and MR is described in this paper. PMID- 26425381 TI - Bilateral Simultaneous Avulsion Fractures of the Proximal Tibia in a 14-Year-Old Athlete with Vitamin-D Deficiency. AB - Fractures involving the proximal tibial epiphysis are rare and form 0.5% of all epiphyseal injuries. The specific anatomical and developmental features of the proximal tibial epiphysis make it vulnerable to unique patterns of fractures. Vitamin-D plays a vital role in bone homeostasis and its deficiency has an impact on fracture risk and healing. We present the first ever reported case of simultaneous bilateral proximal tibial physeal fractures in an athlete with vitamin-D deficiency. Treatment consisted of plaster immobilisation, and the patient made a full recovery and returned to preinjury level of activities. We report this case for its uniqueness and as an educational review of the importance of the developmental anatomy of the proximal tibia. We review the literature and discuss how the stages of the growing physis determine the type of fracture sustained. PMID- 26425382 TI - Importance of NAB2-STAT6 Fusion in the Diagnosis of Pancreatic Solitary Fibrous Tumor with Hamartoma-Like Features: A Case Report and Review of the Literature. AB - We report a case of pancreatic hamartoma-like solitary fibrous tumor which was differentiated from pancreatic hamartoma with the detection of NAB2-STAT6 fusion, a specific mutation for solitary fibrous tumors. A pancreatic well-demarcated solid nodule, 21 * 17 mm, of 82-year-old man was surgically enucleated. Microscopic findings were close to a pancreatic hamartoma that consisted of sparsely distributed pancreatic ducts and acini in heavily collagenized fibrous stroma. Neither islet nor peripheral nerve existed in the tumor. The fibroblastic cells in the stroma were immune-positive for CD34, CD99, and bcl-2. But these expressions were not decisive in the differentiation between solitary fibrous tumor and pancreatic hamartoma, because CD34 was positive for both tumors, and CD99 and bcl-2 expressions were not elucidated in the previous cases of pancreatic hamartomas. Thus, we evaluated NAB2-STAT6 fusion. The fibroblastic cells were positive for STAT6 and sequencing analysis revealed the gene fusion between NAB2 exon 4 and STAT6 exon 2, with which the final diagnos is of solitary fibrous tumor was achieved. In conclusion, detection of NAB2-STAT6 fusion has a great diagnostic value for pancreatic solitary fibrous tumors with hamartoma-like features. PMID- 26425383 TI - Neuroimaging Features of San Luis Valley Syndrome. AB - A 14-month-old Hispanic female with a history of double-outlet right ventricle and developmental delay in the setting of recombinant chromosome 8 syndrome was referred for neurologic imaging. Brain MR revealed multiple abnormalities primarily affecting midline structures, including commissural dysgenesis, vermian and brainstem hypoplasia/dysplasia, an interhypothalamic adhesion, and an epidermoid between the frontal lobes that enlarged over time. Spine MR demonstrated hypoplastic C1 and C2 posterior elements, scoliosis, and a borderline low conus medullaris position. Presented herein is the first illustration of neuroimaging findings from a patient with San Luis Valley syndrome. PMID- 26425384 TI - THE FUNDAMENTAL SOLUTIONS FOR MULTI-TERM MODIFIED POWER LAW WAVE EQUATIONS IN A FINITE DOMAIN. AB - Fractional partial differential equations with more than one fractional derivative term in time, such as the Szabo wave equation, or the power law wave equation, describe important physical phenomena. However, studies of these multi term time-space or time fractional wave equations are still under development. In this paper, multi-term modified power law wave equations in a finite domain are considered. The multi-term time fractional derivatives are defined in the Caputo sense, whose orders belong to the intervals (1, 2], [2, 3), [2, 4) or (0, n) (n > 2), respectively. Analytical solutions of the multi-term modified power law wave equations are derived. These new techniques are based on Luchko's Theorem, a spectral representation of the Laplacian operator, a method of separating variables and fractional derivative techniques. Then these general methods are applied to the special cases of the Szabo wave equation and the power law wave equation. These methods and techniques can also be extended to other kinds of the multi-term time-space fractional models including fractional Laplacian. PMID- 26425385 TI - Possible Benefit of Dietary Carnosine towards Depressive Disorders. AB - Many stress-related and depressive disorders have been shown to be associated with one or more of the following; shortened telomeres, raised cortisol levels and increased susceptibility to age-related dysfunction. It is suggested here that insufficient availability of the neurological peptide, carnosine, may provide a biochemical link between stress- and depression-associated phenomena: there is evidence that carnosine can enhance cortisol metabolism, suppress telomere shortening and exert anti-aging activity in model systems. Dietary supplementation with carnosine has been shown to suppress stress in animals, and improve behaviour, cognition and well-being in human subjects. It is therefore proposed that the therapeutic potential of carnosine dietary supplementation towards stress-related and depressive disorders should be examined. PMID- 26425387 TI - SUMOylation: Novel Neuroprotective Approach for Alzheimer's Disease? AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized in the brain by the formation of amyloid-beta (Abeta)-containing plaques and neurofibrillary tangles containing the microtubule-associated protein tau. Neuroinflammation is another feature of AD and astrocytes are receiving increasing attention as key contributors. Although some progress has been made, the molecular mechanisms underlying the pathophysiology of AD remain unclear. Interestingly, some of the main proteins involved in AD, including amyloid precursor protein (APP) and tau, have recently been shown to be SUMOylated. The post-translational modification by SUMO (small ubiquitin-like modifier) has been shown to regulate APP and tau and may modulate other proteins implicated in AD. Here we present an overview of recent studies suggesting that protein SUMOylation might be involved in the underlying pathogenic mechanisms of AD and discuss how this could be exploited for therapeutic intervention. PMID- 26425386 TI - Metabolic Alterations Associated to Brain Dysfunction in Diabetes. AB - From epidemiological studies it is known that diabetes patients display increased risk of developing dementia. Moreover, cognitive impairment and Alzheimer's disease (AD) are also accompanied by impaired glucose homeostasis and insulin signalling. Although there is plenty of evidence for a connection between insulin resistant diabetes and AD, definitive linking mechanisms remain elusive. Cerebrovascular complications of diabetes, alterations in glucose homeostasis and insulin signalling, as well as recurrent hypoglycaemia are the factors that most likely affect brain function and structure. While difficult to study in patients, the mechanisms by which diabetes leads to brain dysfunction have been investigated in experimental models that display phenotypes of the disease. The present article reviews the impact of diabetes and AD on brain structure and function, and discusses recent findings from translational studies in animal models that link insulin resistance to metabolic alterations that underlie brain dysfunction. Such modifications of brain metabolism are likely to occur at early stages of neurodegeneration and impact regional neurochemical profiles and constitute non-invasive biomarkers detectable by magnetic resonance spectroscopy (MRS). PMID- 26425388 TI - The involvement of BDNF, NGF and GDNF in aging and Alzheimer's disease. AB - Aging is a normal physiological process accompanied by cognitive decline. This aging process has been the primary risk factor for development of aging-related diseases such as Alzheimer's disease (AD). Cognitive deficit is related to alterations of neurotrophic factors level such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and glial cell-derived neurotrophic factor (GDNF). These strong relationship between aging and AD is important to investigate the time which they overlap, as well as, the pathophysiological mechanism in each event. Considering that aging and AD are related to cognitive impairment, here we discuss the involving these neurotrophic factors in the aging process and AD. PMID- 26425389 TI - Does Infection-Induced Immune Activation Contribute to Dementia? AB - The central nervous system (CNS) is protected by a complex blood-brain barrier system; however, a broad diversity of virus, bacteria, fungi, and protozoa can gain access and cause illness. As pathogens replicate, they release molecules that can be recognized by innate immune cells. These molecules are pathogen associated molecular patterns (PAMP) and they are identified by pattern recognition receptors (PRR) expressed on antigen-presenting cells. Examples of PRR include toll-like receptors (TLR), receptors for advanced glycation endproducts (RAGE), nucleotide binding oligomerisation domain (NOD)-like receptors (NLR), c-type lectin receptors (CLR), RIG-I-like receptors (RLR), and intra-cytosolic DNA sensors. The reciprocal action between PAMP and PRR triggers the release of inflammatory mediators that regulate the elimination of invasive pathogens. Damage-associated molecular patterns (DAMP) are endogenous constituents released from damaged cells that also have the ability to activate the innate immune response. An increase of RAGE expression levels on neurons, astrocytes, microglia, and endothelial cells could be responsible for the accumulation of alphabeta-amyloid in dementia and related to the chronic inflammatory state that is found in neurodegenerative disorders. PMID- 26425391 TI - Carnosine and Related Peptides: Therapeutic Potential in Age-Related Disorders. AB - Imidazole dipeptides (ID), such as carnosine (beta-alanyl-L-histidine), are compounds widely distributed in excitable tissues of vertebrates. ID are also endowed of several biochemical properties in biological tissues, including antioxidant, bivalent metal ion chelating, proton buffering, and carbonyl scavenger activities. Furthermore, remarkable biological effects have been assigned to such compounds in age-related human disorders and in patients whose activity of serum carnosinase is deficient or undetectable. Nevertheless, the precise biological role of ID is still to be unraveled. In the present review we shall discuss some evidences from clinical and basic studies for the utilization of ID as a drug therapy for age-related human disorders. PMID- 26425390 TI - Dopamine Receptors and Neurodegeneration. AB - Dopamine (DA) is one of the major neurotransmitters and participates in a number of functions such as motor coordination, emotions, memory, reward mechanism, neuroendocrine regulation etc. DA exerts its effects through five DA receptors that are subdivided in 2 families: D1-like DA receptors (D1 and D5) and the D2 like (D2, D3 and D4). All DA receptors are widely expressed in the central nervous system (CNS) and play an important role in not only in physiological conditions but also pathological scenarios. Abnormalities in the DAergic system and its receptors in the basal ganglia structures are the basis Parkinson's disease (PD), however DA also participates in other neurodegenerative disorders such as Huntington disease (HD) and multiple sclerosis (MS). Under pathological conditions reorganization of DAergic system has been observed and most of the times, those changes occur as a mechanism of compensation, but in some cases contributes to worsening the alterations. Here we review the changes that occur on DA transmission and DA receptors (DARs) at both levels expression and signals transduction pathways as a result of neurotoxicity, inflammation and in neurodegenerative processes. The better understanding of the role of DA receptors in neuropathological conditions is crucial for development of novel therapeutic approaches to treat alterations related to neurodegenerative diseases. PMID- 26425393 TI - Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations. AB - Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism caused by the deficiency of phenylalanine hydroxylase. This deficiency leads to the accumulation of Phe and its metabolites in tissues and body fluids of PKU patients. The main signs and symptoms are found in the brain but the pathophysiology of this disease is not well understood. In this context, metabolic alterations such as oxidative stress, mitochondrial dysfunction, and impaired protein and neurotransmitters synthesis have been described both in animal models and patients. This review aims to discuss the main metabolic disturbances reported in PKU and relate them with the pathophysiology of this disease. The elucidation of the pathophysiology of brain damage found in PKU patients will help to develop better therapeutic strategies to improve quality of life of patients affected by this condition. PMID- 26425395 TI - Astounding recovery after resection of an intradural nerve sheath tumor in an adult male from Vietnam. AB - BACKGROUND: Spinal cord tumors can be classified as intramedullary, intradural extramedullary, or extradural. The differential diagnosis of spinal cord tumors includes meningiomas, astrocytomas, ependymomas, metastasis, nerve sheath tumors such as schwannomas or neurofibromas, and multiple sclerosis plaques. Radiology can provide clues to the type of tumor, but a pathology evaluation of a specimen is necessary to provide an accurate diagnosis. These tumors can cause a variety of neurological symptoms from spinal cord compression including pain, weakness, and paresthesia. They are treated by surgical resection, with a variety of outcomes possible depending on the severity of the preoperative symptoms, location and extent of the tumor, and efficacy of the surgery performed. CASE DESCRIPTION: A 59-year-old male from Vietnam came to the Atlanta Medical Center for evaluation of severe ride sided hemiparesis and paresthesias. He first noticed alterations in his handwriting and quickly deteriorated to the point of being unable to walk or move his right arm. A cervical spinal mass was identified and analyzed on magnetic resonance imaging. Surgical resection was performed under a microscope in a joint operation between an orthopedic surgeon and neurosurgeon. A specimen of the tumor was sent to pathology for further evaluation. CONCLUSION: The mass was determined to be an intradural extramedullary schwannoma. The severity of the patient's symptoms and the location and size of the tumor made full recovery unlikely and postoperative quadriplegia a real possibility. The tumor was surgically resected, which led surprisingly, however, to a full and prompt resolution of the patient's symptoms. Less than 2 weeks after surgery, the patient was able to walk and had almost fully regained use of his hands. PMID- 26425394 TI - Potential Therapeutical Contributions of the Endocannabinoid System towards Aging and Alzheimer's Disease. AB - Aging can lead to decline in cognition, notably due to neurodegenerative processes overwhelming the brain over time. As people live longer, numerous concerns are rightfully raised toward long-term slowly incapacitating diseases with no cure, such as Alzheimer's disease. Since the early 2000's, the role of neuroinflammation has been scrutinized for its potential role in the development of diverse neurodegenerative diseases notably because of its slow onset and chronic nature in aging. Despite the lack of success yet, treatment of chronic neuroinflammation could help alleviate process implicated in neurodegenerative disease. A growing number of studies including our own have aimed at the endocannabinoid system and unfolded unique effects of this system on neuroinflammation, neurogenesis and hallmarks of Alzheimer's disease and made it a reasonable target in the context of normal and pathological brain aging. PMID- 26425392 TI - Mechanisms of Muscle Denervation in Aging: Insights from a Mouse Model of Amyotrophic Lateral Sclerosis. AB - Muscle denervation at the neuromuscular junction (NMJ) is thought to be a contributing factor in age-related muscle weakness. Therefore, understanding the mechanisms that modulate NMJ innervation is a key to developing therapies to combat age-related muscle weakness affecting the elderly. Two mouse models, one lacking the Cu/Zn superoxide dismutase (SOD1) gene and another harboring the transgenic mutant human SOD1 gene, display progressive changes at the NMJ, including muscle endplate fragmentation, nerve terminal sprouting, and denervation. These changes at the NMJ share many of the common features observed in the NMJs of aged mice. In this review, research findings demonstrating the effects of PGC-1alpha, IGF-1, GDNF, MyoD, myogenin, and miR-206 on NMJ innervation patterns in the G93A SOD1 mice will be highlighted in the context of age-related muscle denervation. PMID- 26425396 TI - A completely thrombosed, nongiant middle cerebral artery aneurysm mimicking an intra-axial neoplasm. AB - BACKGROUND: Few reports exist regarding thrombosed aneurysms where the initial work up was concerning for a neoplasm. To date, no published reports exist regarding a nongiant thrombosed middle cerebral artery aneurysm, where the primary workup and treatment plan was directed toward a preliminary diagnosis of intra-axial neoplasm. CASE DESCRIPTION: We report a 43-year-old female who presented with a generalized tonic-clonic seizure attributed to a lesion along the right superior temporal gyrus. The lesion enhanced on initial magnetic resonance imaging (MRI) of the brain, as well as on follow-up MRI. Subsequent vascular studies and metastatic work up were negative. A craniotomy with image guidance was performed and an intraoperative diagnosis was made of a thrombosed aneurysm along a branch of the middle cerebral artery. The aneurysm was trapped and resected as there was no significant flow from the branch as seen on the prior cerebral angiogram. The patient had an uneventful postoperative course. CONCLUSION: Completely thrombosed, nongiant aneurysms can mimic an intra-axial neoplasm. Typical imaging features for thrombosed aneurysms may be missed, especially if the aneurysms are small, where imaging characteristics of the intraluminal contents is more difficult to appreciate. Although imaging may be consistent with a neoplastic lesion, there should be suspicion for a potential underlying aneurysm. PMID- 26425397 TI - Commentary on article: Laminoplasty versus laminectomy and fusion for multilevel cervical myelopathy: A meta-analysis of clinical and radiological outcomes by Chang-Hyun Lee et al. AB - BACKGROUND: This is a commentary on the article laminoplasty versus laminectomy and fusion (LF) for multilevel cervical myelopathy: A meta-analysis of clinical and radiological outcomes by Chang-Hyun Lee et al. Here, the authors utilized seven studies to compare the efficacy of cervical expansive laminoplasty (EL) versus laminectomy and fusion (LF) to address three or more level multilevel cervical spondylotic myelopathy (CSM). Both procedures led to similar degrees of neurological recovery and short-term loss of lordosis, but found that LF led to more favorable long-term results. METHODS: For patients with three or more level CSM, laminectomy followed by an instrumented fusion (LF) has major advantages; open bilateral decompression of the nerve roots, while minimizing the risk of inadvertent injury to the cord, and the fusion's maintenance of lordosis. RESULTS: Some would argue that inadvertent cord/root injury is greater utilizing any of the EL techniques; e.g., unilateral, bilateral, or spinous process splitting techniques. In short, why risk cord/root injury by manipulating the compressive posterior/posterolateral elements, which are already threatening neural function. CONCLUSION: Although the results of EL versus LF appeared comparable in the short-term in these seven articles, LF resulted in better long term outcomes. Some would also argue that LF, utilizing an open approach offers safer bilateral neural exposure and decompression. PMID- 26425398 TI - Unnecessary multiple epidural steroid injections delay surgery for massive lumbar disc: Case discussion and review. AB - BACKGROUND: Epidural steroid injections (ESI) in the lumbar spine are not effective over the long-term for resolving "surgical" lesions. Here, we present a patient with a massive L2-L3 lumbar disk herniation whose surgery was delayed for 4 months by multiple unnecessary ESI, resulting in a cauda equina syndrome. METHODS: A 54-year-old male acutely developed increased low back and radiating left leg pain in October of 2014. In December of 2014, a magnetic resonance imaging (MRI) scan showed a massive central/left sided disk herniation at the L2 L3 level resulting in marked thecal sac and left L2 foraminal and L3 lateral recess root compression. Despite the marked degree of neural compression, pain management treated him with 3 ESI over the next 3 months. RESULTS: At the end of April of 2015, he presented to spine surgeon with a cauda equina syndrome. When the new MRI scan confirmed the previously documented massive central-left sided L2-L3 disk herniation, the patient emergently underwent an L1-L3 laminectomy with central-left sided L2-L3 lateral/foraminal diskectomy. Postoperatively, the patient was neurologically intact. CONCLUSIONS: Pain specialists performed multiple unnecessary lumbar ESI critically delaying spinal surgery for 4 months in this patient with a massive lumbar disk herniation who ultimately developed a cauda equina syndrome. Unfortunately, pain specialists (e.g., radiologists, anesthesiologists, and physiatrists), not specifically trained to perform neurological examinations or spinal surgery, are increasingly mismanaging spinal disease with ESI/variants. It is time for spine surgeons to speak out against this, and "take back" the care of patients with spinal surgical disease. PMID- 26425399 TI - Synovial chondromatosis presenting as an epidural mass. AB - BACKGROUND: Synovial chondromatosis is an uncommon disorder characterized by the formation of multiple cartilaginous nodules in the synovium of the facet joint. It most commonly affects large joints such as hip or shoulder. Commonly seen features are bony erosion and calcifications. Synovial chondromatosis is rare in the spine and there are few previous reports of extension into the spinal canal. CASE DESCRIPTION: A 58-year-old man presented with a 2 year history of progressive numbness in the right upper extremity without objective weakness. A several month course of conservative management, including physical therapy, failed to alleviate symptoms. Magnetic resonance imaging of the cervical spine demonstrated the erosion of the right facet C5-C6 joint with listhesis and foraminal enlargement secondary to a lesion. Treatment was offered to the patient in the form of surgical resection. The lesion was removed in piecemeal fashion using curettes and Cavitron ultrasonic surgical aspirator. Histological examination demonstrated atypical well-differentiated cartilaginous proliferation. CONCLUSION: This patient had an uncomplicated postoperative course and experienced complete resolution of right upper extremity sensory symptoms. Synovial chondromatosis may compromise cervical spinal cord and nerve roots if it extends into the spinal canal. Although it remains rare, it should be included in the differential diagnosis for upper extremity radiculopathy and myelopathy. Surgical resection is a viable treatment option for symptomatic patients with this pathology. In some cases, adequate resection may necessitate stabilization with instrumentation. PMID- 26425400 TI - Medicare payment data for spine reimbursement; important but flawed data for evaluating utilization of resources. AB - BACKGROUND: Medicare data showing physician-specific reimbursement for 2012 were recently made public in the mainstream media. Given the ongoing interest in containing healthcare costs, we analyze these data in the context of the delivery of spinal surgery. METHODS: Demographics of 206 leading surgeons were extracted including state, geographic area, residency training program, fellowship training, and academic affiliation. Using current procedural terminology (CPT) codes, information was evaluated regarding the number of lumbar laminectomies, lumbar fusions, add-on laminectomy levels, and anterior cervical fusions reimbursed by Medicare in 2012. RESULTS: In 2012 Medicare reimbursed the average neurosurgeon slightly more than an orthopedic surgeon for all procedures ($142,075 vs. $110,920), but this was not found to be statistically significant (P = 0.218). Orthopedic surgeons had a statistical trend illustrating increased reimbursement for lumbar fusions specifically, $1187 versus $1073 (P = 0.07). Fellowship trained spinal surgeons also, on average, received more from Medicare ($125,407 vs. $76,551), but again this was not statistically significant (P = 0.112). A surgeon in private practice, on average, was reimbursed $137,495 while their academic counterparts were reimbursed $103,144 (P = 0.127). Surgeons performing cervical fusions in the Centers for Disease Control West Region did receive statistically significantly less reimbursement for that procedure then those surgeons in other parts of the country (P = 0.015). Surgeons in the West were reimbursed on average $849 for CPT code 22,551 while those in the Midwest received $1475 per procedure. CONCLUSION: Medicare reimbursement data are fundamentally flawed in determining healthcare expenditure as it shows a bias toward delivery of care in specific patient demographics. However, neurosurgeons, not just policy makers, must take ownership to analyze, investigate, and interpret these data as it will affect healthcare reimbursement and delivery moving forward. PMID- 26425401 TI - Hospital Disaster Preparedness Tools: a Systematic Review. AB - AIM: Evaluating hospital disaster preparedness is one the best ways for hospital accreditation. The aim of this study was to evaluate the quality of outcome measure that offer the level of measurement, reliability and validity that are known as the ' psychometric properties' of the current hospital disaster preparedness tools. METHODS: In total, 140 studies were retrieved. Studies which had been published from 2000 to 2014 and had used hospital disaster preparedness tools were appraised by using the PRISMA guideline. The content quality and the quality of the psychometric properties of the retrieved tools were assessed by using the World Health Organization Criteria for Hospital Preparedness as well as the COSMIN criteria. FINDINGS: Only 33 studies met the inclusion criteria. In total, eleven hospital disaster preparedness tools had been used in these 33 studies. These tools mainly focused on evaluating structural and non-structural aspects of hospital preparedness and paid little attention, if any, to the key functional aspect. CONCLUSION: Given the paramount importance of evaluating hospital disaster preparedness and the weaknesses of current preparedness evaluation tools, valid and reliable tools should be developed by using experts' knowledge and experience through the processes of tool development and psychometric evaluation. PMID- 26425402 TI - The Effect of Transient Local Anti-inflammatory Treatment on the Survival of Pig Retinal Progenitor Cell Allotransplants. AB - PURPOSE: The development of photoreceptor replacement therapy for retinal degenerative disorders requires the identification of the optimal cell source and immunosuppressive regimen in a large animal model. Allotransplants are not acutely rejected in swine subretinal space, although it is not known if survival can be improved with immunosuppression. Here we investigated the survival and integration of expanded pig retinal progenitor cells (pRPCs) in normal recipients with and without transient anti-inflammatory suppression. METHODS: pRPCs were derived from the neural retina of E60 GFP transgenic pigs, expanded for six passages, characterized, and transplanted into the subretinal space of 12 pigs. Six recipients received a single intravitreal injection of rapamycin and dexamethasone. RESULTS: pRPCs expressed the photoreceptor development genes Sox2, Pax6, Lhx2, Crx, Nrl, and Recoverin in vitro. Transplanted cells were identified in 9 out of 12 recipients 4 weeks after the injection. pRPCs integrated primarily into the photoreceptor inner segment layer and outer nuclear layer with single cells present in the inner nuclear layer. Donor cells remained recoverin-positive and acquired rhodopsin. We did not observe any signs of graft proliferation. The immunosuppression did not affect the survival or distribution of grafts. No macrophage infiltration or loss of retinal structure was observed in either group. CONCLUSIONS: Local immunosuppression with rapamycin and dexamethasone does not improve the outcome of pRPC allotransplantation into the subretinal space. TRANSLATIONAL RELEVANCE: Survival and integration of pRPC together with the lack of graft proliferation suggests that allogeneic RPC transplantation without transient immunosuppression is a favorable approach for photoreceptor cell replacement. PMID- 26425403 TI - Diabetes Complications in Childhood Diabetes-New Biomarkers and Technologies. AB - A major challenge in preventing vascular complications in diabetes is the inability to identify high-risk patients at an early stage, emphasizing the importance of discovering new risk factors, technologies and therapeutic targets to reduce the development and progression of complications. Promising biomarkers which may improve risk stratification and serve as therapeutic targets, include: uric acid, insulin sensitivity, copeptin, SGLT-2 and Klotho/FGF-23. Non-invasive measures of macrovasuclar disease in youth, include: 1) pulse wave velocity to examine arterial stiffness; 2) carotid intima-media thickness to evaluate arterial thickness; 3) cardiac MRI to investigate cardiac function and structure. Novel microvascular measures include: GFR by iohexol clearance using filter paper to directly measure GFR, retinal vascular geometry to predict early retinal changes and corneal confocal microscopy to improve detection of early nerve loss to better predict diabetic neuropathy. Herein we will review technologies, novel biomarkers, and therapeutic targets in relation to vascular complications of diabetes. PMID- 26425404 TI - Formation of pure Cu nanocrystals upon post-growth annealing of Cu-C material obtained from focused electron beam induced deposition: comparison of different methods. AB - In this paper we study in detail the post-growth annealing of a copper-containing material deposited with focused electron beam induced deposition (FEBID). The organometallic precursor Cu(II)(hfac)2 was used for deposition and the results were compared to that of compared to earlier experiments with (hfac)Cu(I)(VTMS) and (hfac)Cu(I)(DMB). Transmission electron microscopy revealed the deposition of amorphous material from Cu(II)(hfac)2. In contrast, as-deposited material from (hfac)Cu(I)(VTMS) and (hfac)Cu(I)(DMB) was nano-composite with Cu nanocrystals dispersed in a carbonaceous matrix. After annealing at around 150-200 degrees C all deposits showed the formation of pure Cu nanocrystals at the outer surface of the initial deposit due to the migration of Cu atoms from the carbonaceous matrix containing the elements carbon, oxygen, and fluorine. Post-irradiation of deposits with 200 keV electrons in a transmission electron microscope favored the formation of Cu nanocrystals within the carbonaceous matrix of freestanding rods and suppressed the formation on their surface. Electrical four-point measurements on FEBID lines from Cu(hfac)2 showed five orders of magnitude improvement in conductivity when being annealed conventionally and by laser-induced heating in the scanning electron microscope chamber. PMID- 26425405 TI - Continuum models of focused electron beam induced processing. AB - Focused electron beam induced processing (FEBIP) is a suite of direct-write, high resolution techniques that enable fabrication and editing of nanostructured materials inside scanning electron microscopes and other focused electron beam (FEB) systems. Here we detail continuum techniques that are used to model FEBIP, and release software that can be used to simulate a wide range of processes reported in the FEBIP literature. These include: (i) etching and deposition performed using precursors that interact with a surface through physisorption and activated chemisorption, (ii) gas mixtures used to perform simultaneous focused electron beam induced etching and deposition (FEBIE and FEBID), and (iii) etch processes that proceed through multiple reaction pathways and generate a number of reaction products at the substrate surface. We also review and release software for Monte Carlo modeling of the precursor gas flux which is needed as an input parameter for continuum FEBIP models. PMID- 26425406 TI - Possibilities and limitations of advanced transmission electron microscopy for carbon-based nanomaterials. AB - A major revolution for electron microscopy in the past decade is the introduction of aberration correction, which enables one to increase both the spatial resolution and the energy resolution to the optical limit. Aberration correction has contributed significantly to the imaging at low operating voltages. This is crucial for carbon-based nanomaterials which are sensitive to electron irradiation. The research of carbon nanomaterials and nanohybrids, in particular the fundamental understanding of defects and interfaces, can now be carried out in unprecedented detail by aberration-corrected transmission electron microscopy (AC-TEM). This review discusses new possibilities and limits of AC-TEM at low voltage, including the structural imaging at atomic resolution, in three dimensions and spectroscopic investigation of chemistry and bonding. In situ TEM of carbon-based nanomaterials is discussed and illustrated through recent reports with particular emphasis on the underlying physics of interactions between electrons and carbon atoms. PMID- 26425407 TI - Electrical properties and mechanical stability of anchoring groups for single molecule electronics. AB - We report on an experimental investigation of transport through single molecules, trapped between two gold nano-electrodes fabricated with the mechanically controlled break junction (MCBJ) technique. The four molecules studied share the same core structure, namely oligo(phenylene ethynylene) (OPE3), while having different aurophilic anchoring groups: thiol (SAc), methyl sulfide (SMe), pyridyl (Py) and amine (NH2). The focus of this paper is on the combined characterization of the electrical and mechanical properties determined by the anchoring groups. From conductance histograms we find that thiol anchored molecules provide the highest conductance; a single-level model fit to current-voltage characteristics suggests that SAc groups exhibit a higher electronic coupling to the electrodes, together with better level alignment than the other three groups. An analysis of the mechanical stability, recording the lifetime in a self-breaking method, shows that Py and SAc yield the most stable junctions while SMe form short-lived junctions. Density functional theory combined with non-equlibrium Green's function calculations help in elucidating the experimental findings. PMID- 26425410 TI - How decision analysis can further nanoinformatics. AB - The increase in nanomaterial research has resulted in increased nanomaterial data. The next challenge is to meaningfully integrate and interpret these data for better and more efficient decisions. Due to the complex nature of nanomaterials, rapid changes in technology, and disunified testing and data publishing strategies, information regarding material properties is often illusive, uncertain, and/or of varying quality, which limits the ability of researchers and regulatory agencies to process and use the data. The vision of nanoinformatics is to address this problem by identifying the information necessary to support specific decisions (a top-down approach) and collecting and visualizing these relevant data (a bottom-up approach). Current nanoinformatics efforts, however, have yet to efficiently focus data acquisition efforts on the research most relevant for bridging specific nanomaterial data gaps. Collecting unnecessary data and visualizing irrelevant information are expensive activities that overwhelm decision makers. We propose that the decision analytic techniques of multicriteria decision analysis (MCDA), value of information (VOI), weight of evidence (WOE), and portfolio decision analysis (PDA) can bridge the gap from current data collection and visualization efforts to present information relevant to specific decision needs. Decision analytic and Bayesian models could be a natural extension of mechanistic and statistical models for nanoinformatics practitioners to master in solving complex nanotechnology challenges. PMID- 26425408 TI - Influence of surface chemical properties on the toxicity of engineered zinc oxide nanoparticles to embryonic zebrafish. AB - Zinc oxide nanoparticles (ZnO NPs) are widely used in a variety of products, thus understanding their health and environmental impacts is necessary to appropriately manage their risks. To keep pace with the rapid increase in products utilizing engineered ZnO NPs, rapid in silico toxicity test methods based on knowledge of comprehensive in vivo and in vitro toxic responses are beneficial in determining potential nanoparticle impacts. To achieve or enhance their desired function, chemical modifications are often performed on the NPs surface; however, the roles of these alterations play in determining the toxicity of ZnO NPs are still not well understood. As such, we investigated the toxicity of 17 diverse ZnO NPs varying in both size and surface chemistry to developing zebrafish (exposure concentrations ranging from 0.016 to 250 mg/L). Despite assessing a suite of 19 different developmental, behavioural and morphological endpoints in addition to mortality in this study, mortality was the most common endpoint observed for all of the ZnO NP types tested. ZnO NPs with surface chemical modification, regardless of the type, resulted in mortality at 24 hours post-fertilization (hpf) while uncoated particles did not induce significant mortality until 120 hpf. Using eight intrinsic chemical properties that relate to the outermost surface chemistry of the engineered ZnO nanoparticles, the highly dimensional toxicity data were converted to a 2-dimensional data set through principal component analysis (PCA). Euclidean distance was used to partition different NPs into several groups based on converted data (score) which were directly related to changes in the outermost surface chemistry. Kriging estimations were then used to develop a contour map based on mortality data as a response. This study illustrates how the intrinsic properties of NPs, including surface chemical modifications and capping agents, are useful to separate and identify ZnO NP toxicity to zebrafish (Danio rerio). PMID- 26425409 TI - Experiences in supporting the structured collection of cancer nanotechnology data using caNanoLab. AB - The cancer Nanotechnology Laboratory (caNanoLab) data portal is an online nanomaterial database that allows users to submit and retrieve information on well-characterized nanomaterials, including composition, in vitro and in vivo experimental characterizations, experimental protocols, and related publications. Initiated in 2006, caNanoLab serves as an established resource with an infrastructure supporting the structured collection of nanotechnology data to address the needs of the cancer biomedical and nanotechnology communities. The portal contains over 1,000 curated nanomaterial data records that are publicly accessible for review, comparison, and re-use, with the ultimate goal of accelerating the translation of nanotechnology-based cancer therapeutics, diagnostics, and imaging agents to the clinic. In this paper, we will discuss challenges associated with developing a nanomaterial database and recognized needs for nanotechnology data curation and sharing in the biomedical research community. We will also describe the latest version of caNanoLab, caNanoLab 2.0, which includes enhancements and new features to improve usability such as personalized views of data and enhanced search and navigation. PMID- 26425411 TI - Materials for sustainable energy production, storage, and conversion. PMID- 26425412 TI - Simple and efficient way of speeding up transmission calculations with k-point sampling. AB - The transmissions as functions of energy are central for electron or phonon transport in the Landauer transport picture. We suggest a simple and computationally "cheap" post-processing scheme to interpolate transmission functions over k-points to get smooth well-converged average transmission functions. This is relevant for data obtained using typical "expensive" first principles calculations where the leads/electrodes are described by periodic boundary conditions. We show examples of transport in graphene structures where a speed-up of an order of magnitude is easily obtained. PMID- 26425413 TI - The eNanoMapper database for nanomaterial safety information. AB - BACKGROUND: The NanoSafety Cluster, a cluster of projects funded by the European Commision, identified the need for a computational infrastructure for toxicological data management of engineered nanomaterials (ENMs). Ontologies, open standards, and interoperable designs were envisioned to empower a harmonized approach to European research in nanotechnology. This setting provides a number of opportunities and challenges in the representation of nanomaterials data and the integration of ENM information originating from diverse systems. Within this cluster, eNanoMapper works towards supporting the collaborative safety assessment for ENMs by creating a modular and extensible infrastructure for data sharing, data analysis, and building computational toxicology models for ENMs. RESULTS: The eNanoMapper database solution builds on the previous experience of the consortium partners in supporting diverse data through flexible data storage, open source components and web services. We have recently described the design of the eNanoMapper prototype database along with a summary of challenges in the representation of ENM data and an extensive review of existing nano-related data models, databases, and nanomaterials-related entries in chemical and toxicogenomic databases. This paper continues with a focus on the database functionality exposed through its application programming interface (API), and its use in visualisation and modelling. Considering the preferred community practice of using spreadsheet templates, we developed a configurable spreadsheet parser facilitating user friendly data preparation and data upload. We further present a web application able to retrieve the experimental data via the API and analyze it with multiple data preprocessing and machine learning algorithms. CONCLUSION: We demonstrate how the eNanoMapper database is used to import and publish online ENM and assay data from several data sources, how the "representational state transfer" (REST) API enables building user friendly interfaces and graphical summaries of the data, and how these resources facilitate the modelling of reproducible quantitative structure-activity relationships for nanomaterials (NanoQSAR). PMID- 26425414 TI - Analysis of soil bacteria susceptibility to manufactured nanoparticles via data visualization. AB - The impact of ZnO and TiO2 manufactured nanoparticles (MNPs) on soil bacterial communities for different exposure periods and MNP doses was explored via data visualization techniques. Interrelationships between MNP treatments and responses of bacterial taxa were illustrated by bipartite graphs, allowing fast identification of important soil bacterial taxa that are susceptible to MNPs. Contribution biplots with subcompositional coherence property were generated via log-ratio analysis (LRA), which jointly display the treatment distribution and the variance (contribution) of bacterial taxa. The LRA contribution biplots and nonmetric multi-dimensional scaling (NMDS) of the dataset, along with hierarchical clustering, demonstrated that high doses of ZnO and TiO2 MNPs caused significant compositional changes in soil bacterial communities. The suitability of family level for MNP taxonomic impact assessment was demonstrated by both the LRA biplots and simplified NMDSs with quantification provided by the distance correlation between MNP impacts summarized at different taxonomic levels. The present study demonstrates that visual exploration could potentially assist in knowledge discovery and interpretation of data on soil bacterial communities exposed to MNPs and thus evaluate the potential for environmental impacts. PMID- 26425415 TI - Structural and magnetic properties of iron nanowires and iron nanoparticles fabricated through a reduction reaction. AB - The main goal of this work is to study the structural and magnetic properties of iron nanowires and iron nanoparticles, which have been fabricated in almost the same processes. The only difference in the synthesis is an application of an external magnetic field in order to form the iron nanowires. Both nanomaterials have been examined by means of transmission electron microscopy, energy dispersive X-ray spectrometry, X-ray diffractometry and Mossbauer spectrometry to determine their structures. Structural investigations confirm that obtained iron nanowires as well as nanoparticles reveal core-shell structures and they are composed of crystalline iron cores that are covered by amorphous or highly defected phases of iron and iron oxides. Magnetic properties have been measured using a vibrating sample magnetometer. The obtained values of coercivity, remanent magnetization, saturation magnetization as well as Curie temperature differ for both studied nanostructures. Higher values of magnetizations are observed for iron nanowires. At the same time, coercivity and Curie temperature are higher for iron nanoparticles. PMID- 26425416 TI - In situ SU-8 silver nanocomposites. AB - Nanocomposite materials containing metal nanoparticles are of considerable interest in photonics and optoelectronics applications. However, device fabrication of such materials always encounters the challenge of incorporation of preformed nanoparticles into photoresist materials. As a solution to this problem, an easy new method of fabricating silver nanocomposites by an in situ reduction of precursors within the epoxy-based photoresist SU-8 has been developed. AgNO3 dissolved in acetonitrile and mixed with the epoxy-based photoresist SU-8 forms silver nanoparticles primarily during the pre- and post exposure soft bake steps at 95 degrees C. A further high-temperature treatment at 300 degrees C resulted in the formation of densely homogeneously distributed silver nanoparticles in the photoresist matrix. No particle growth or agglomeration of nanoparticles is observed at this point. The reported new in situ silver nanocomposite materials can be spin coated as homogeneous thin films and structured by using UV lithography. A resolution of 5 um is achieved in the lithographic process. The UV exposure time is found to be independent of the nanoparticle concentration. The fabricated silver nanocomposites exhibit high plasmonic responses suitable for the development of new optoelectronic and optical sensing devices. PMID- 26425417 TI - Analyzing collaboration networks and developmental patterns of nano-enabled drug delivery (NEDD) for brain cancer. AB - The rapid development of new and emerging science & technologies (NESTs) brings unprecedented challenges, but also opportunities. In this paper, we use bibliometric and social network analyses, at country, institution, and individual levels, to explore the patterns of scientific networking for a key nano area - nano-enabled drug delivery (NEDD). NEDD has successfully been used clinically to modulate drug release and to target particular diseased tissues. The data for this research come from a global compilation of research publication information on NEDD directed at brain cancer. We derive a family of indicators that address multiple facets of research collaboration and knowledge transfer patterns. Results show that: (1) international cooperation is increasing, but networking characteristics change over time; (2) highly productive institutions also lead in influence, as measured by citation to their work, with American institutes leading; (3) research collaboration is dominated by local relationships, with interesting information available from authorship patterns that go well beyond journal impact factors. Results offer useful technical intelligence to help researchers identify potential collaborators and to help inform R&D management and science & innovation policy for such nanotechnologies. PMID- 26425418 TI - Synthesis, characterization and in vitro biocompatibility study of Au/TMC/Fe3O4 nanocomposites as a promising, nontoxic system for biomedical applications. AB - The unique properties and applications of iron oxide and Au nanoparticles have motivated researchers to synthesize and optimize a combined nanocomposite containing both. By using various polymers such as chitosan, some of the problems of classic core-shell structures (such as reduced saturation magnetization and thick coating) have been overcome. In the present study, chitosan and one of its well-known derivatives, N-trimethylchitosan (TMC), were applied to construct three-layer nanocomposites in an Au/polymer/Fe3O4 system. It was demonstrated that replacement of chitosan with TMC reasonably improved the properties of the final nanocomposites including their size, magnetic behavior and thermal stability. Moreover, the results of the MTT assay showed no significant cytotoxicity effect when the Au/TMC/Fe3O4 nanocomposites were applied in vitro. These TMC-containing magnetic nanoparticles are well-coated by Au nanoparticles and have good biocompatibility and can thus play the role of a platform or a label in various fields of application, especially the biomedical sciences and biosensors. PMID- 26425420 TI - Towards multifunctional inorganic materials: biopolymeric templates. PMID- 26425419 TI - Conductance through single biphenyl molecules: symmetric and asymmetric coupling to electrodes. AB - The contacts and the chemical bonds formed between metallic electrodes and molecules determine to a large extent the conductive properties of single molecular junctions, which represent the smallest possible active elements in an electronic circuit. We therefore investigated in a comparative study, using the break junction technique (MCBJ), the conductive properties of [1,1'-biphenyl] 4,4'-dithiol (M1) and of 4'-mercapto-[1,1'-biphenyl]-4-carbonitrile (M2) between gold electrodes. As a function of electrode separation, characterized by the conductance close to 0 V, we found several plateaus of relative stability, with those close to 0.01G0 being the most pronounced. The overall conductance of symmetric and asymmetric molecules were surprisingly similar, only the range of stability was smaller for M2. While M1 yielded symmetric I-V-curves, only small asymmetries were detected for M2. These are also reflected in the comparable values for coupling parameters using the single level resonance model. The high conductance for the asymmetric molecule is interpreted as a result of coherent coupling of electronic states through the whole molecule, so that the outcome cannot be predicted just by adding conductive properties of individual molecular groups. PMID- 26425421 TI - Radiation losses in the microwave Ku band in magneto-electric nanocomposites. AB - A study on radiation losses in conducting polymer nanocomposites, namely La-Co substituted barium hexaferrite and polyaniline, is presented. The study was performed by means of a vector network analyser, X-ray diffraction, Fourier transform infrared spectroscopy, transmission electron microscopy, electron spin resonance spectroscopy and a vibrating sample magnetometer. It is found that the maximum loss occurs at 17.9 GHz (-23.10 dB, 99% loss) which is due to the composition of a conducting polymer and a suitable magnetic material. A significant role of polyaniline has been observed in ESR. The influence of the magnetic properties on the radiation losses is explained. Further studies revealed that the prepared material is a nanocomposite. FTIR spectra show the presence of expected chemical structures such as C-H bonds in a ring system at 1512 cm(-1). PMID- 26425423 TI - Imaging of carbon nanomembranes with helium ion microscopy. AB - Carbon nanomembranes (CNMs) prepared from aromatic self-assembled monolayers constitute a recently developed class of 2D materials. They are made by a combination of self-assembly, radiation-induced cross-linking and the detachment of the cross-linked SAM from its substrate. CNMs can be deposited on arbitrary substrates, including holey and perforated ones, as well as on metallic (transmission electron microscopy) grids. Therewith, freestanding membranes with a thickness of 1 nm and macroscopic lateral dimensions can be prepared. Although free-standing CNMs cannot be imaged by light microscopy, charged particle techniques can visualize them. However, CNMs are electrically insulating, which makes them sensitive to charging. We demonstrate that the helium ion microscope (HIM) is a good candidate for imaging freestanding CNMs due to its efficient charge compensation tool. Scanning with a beam of helium ions while recording the emitted secondary electrons generates the HIM images. The advantages of HIM are high resolution, high surface sensitivity and large depth of field. The effects of sample charging, imaging of multilayer CNMs as well as imaging artefacts are discussed. PMID- 26425422 TI - Atomic scale interface design and characterisation. PMID- 26425424 TI - Lower nanometer-scale size limit for the deformation of a metallic glass by shear transformations revealed by quantitative AFM indentation. AB - We combine non-contact atomic force microscopy (AFM) imaging and AFM indentation in ultra-high vacuum to quantitatively and reproducibly determine the hardness and deformation mechanisms of Pt(111) and a Pt57.5Cu14.7Ni5.3P22.5 metallic glass with unprecedented spatial resolution. Our results on plastic deformation mechanisms of crystalline Pt(111) are consistent with the discrete mechanisms established for larger scales: Plasticity is mediated by dislocation gliding and no rate dependence is observed. For the metallic glass we have discovered that plastic deformation at the nanometer scale is not discrete but continuous and localized around the indenter, and does not exhibit rate dependence. This contrasts with the observation of serrated, rate-dependent flow of metallic glasses at larger scales. Our results reveal a lower size limit for metallic glasses below which shear transformation mechanisms are not activated by indentation. In the case of metallic glass, we conclude that the energy stored in the stressed volume during nanometer-scale indentation is insufficient to account for the interfacial energy of a shear band in the glassy matrix. PMID- 26425425 TI - A simple method for the determination of qPlus sensor spring constants. AB - qPlus sensors are widely used to measure forces at the atomic scale, however, confidence in these measurements is limited by inconsistent reports of the spring constant of the sensor and complications from finite tip heights. Here we combine a numerical investigation of the force reconstruction with an experimental characterization of the flexural mechanics of the qPlus sensor. Numerical studies reveal significant errors in reconstructed force for tip heights exceeding 400 MUm or one sixth of the cantilever length. Experimental results with a calibrated nanoindenter reveal excellent agreement with an Euler-Bernoulli beam model for the sensor. Prior to the attachment of a tip, measured spring constants of 1902 +/- 29 N/m are found to be in agreement with theoretical predictions for the geometry and material properties of the sensor once a peaked ridge in the beam cross section is included. We further develop a correction necessary to adjust the spring constant for the size and placement of the tip. PMID- 26425426 TI - A facile method for the preparation of bifunctional Mn:ZnS/ZnS/Fe3O4 magnetic and fluorescent nanocrystals. AB - Bifunctional magnetic and fluorescent core/shell/shell Mn:ZnS/ZnS/Fe3O4 nanocrystals were synthesized in a basic aqueous solution using 3 mercaptopropionic acid (MPA) as a capping ligand. The structural and optical properties of the heterostructures were characterized by X-ray diffraction (XRD), dynamic light scattering (DLS), transmission electron microscopy (TEM), UV-vis spectroscopy and photoluminescence (PL) spectroscopy. The PL spectra of Mn:ZnS/ZnS/Fe3O4 quantum dots (QDs) showed marked visible emission around 584 nm related to the (4)T1 -> (6)A1 Mn(2+) transition. The PL quantum yield (QY) and the remnant magnetization can be regulated by varying the thickness of the magnetic shell. The results showed that an increase in the thickness of the Fe3O4 magnetite layer around the Mn:ZnS/ZnS core reduced the PL QY but improved the magnetic properties of the composites. Nevertheless, a good compromise was achieved in order to maintain the dual modality of the nanocrystals, which may be promising candidates for various biological applications. PMID- 26425427 TI - The Nanomaterial Data Curation Initiative: A collaborative approach to assessing, evaluating, and advancing the state of the field. AB - The Nanomaterial Data Curation Initiative (NDCI), a project of the National Cancer Informatics Program Nanotechnology Working Group (NCIP NanoWG), explores the critical aspect of data curation within the development of informatics approaches to understanding nanomaterial behavior. Data repositories and tools for integrating and interrogating complex nanomaterial datasets are gaining widespread interest, with multiple projects now appearing in the US and the EU. Even in these early stages of development, a single common aspect shared across all nanoinformatics resources is that data must be curated into them. Through exploration of sub-topics related to all activities necessary to enable, execute, and improve the curation process, the NDCI will provide a substantive analysis of nanomaterial data curation itself, as well as a platform for multiple other important discussions to advance the field of nanoinformatics. This article outlines the NDCI project and lays the foundation for a series of papers on nanomaterial data curation. The NDCI purpose is to: 1) present and evaluate the current state of nanomaterial data curation across the field on multiple specific data curation topics, 2) propose ways to leverage and advance progress for both individual efforts and the nanomaterial data community as a whole, and 3) provide opportunities for similar publication series on the details of the interactive needs and workflows of data customers, data creators, and data analysts. Initial responses from stakeholder liaisons throughout the nanoinformatics community reveal a shared view that it will be critical to focus on integration of datasets with specific orientation toward the purposes for which the individual resources were created, as well as the purpose for integrating multiple resources. Early acknowledgement and undertaking of complex topics such as uncertainty, reproducibility, and interoperability is proposed as an important path to addressing key challenges within the nanomaterial community, such as reducing collateral negative impacts and decreasing the time from development to market for this new class of technologies. PMID- 26425428 TI - Template-controlled mineralization: Determining film granularity and structure by surface functionality patterns. AB - We present a promising first example towards controlling the properties of a self assembling mineral film by means of the functionality and polarity of a substrate template. In the presented case, a zinc oxide film is deposited by chemical bath deposition on a nearly topography-free template structure composed of a pattern of two self-assembled monolayers with different chemical functionality. We demonstrate the template-modulated morphological properties of the growing film, as the surface functionality dictates the granularity of the growing film. This, in turn, is a key property influencing other film properties such as conductivity, piezoelectric activity and the mechanical properties. A very pronounced contrast is observed between areas with an underlying fluorinated, low energy template surface, showing a much more (almost two orders of magnitude) coarse-grained film with a typical agglomerate size of around 75 nm. In contrast, amino-functionalized surface areas induce the growth of a very smooth, fine grained surface with a roughness of around 1 nm. The observed influence of the template on the resulting clear contrast in morphology of the growing film could be explained by a contrast in surface adhesion energies and surface diffusion rates of the nanoparticles, which nucleate in solution and subsequently deposit on the functionalized substrate. PMID- 26425429 TI - Nanotechnology in the real world: Redeveloping the nanomaterial consumer products inventory. AB - To document the marketing and distribution of nano-enabled products into the commercial marketplace, the Woodrow Wilson International Center for Scholars and the Project on Emerging Nanotechnologies created the Nanotechnology Consumer Products Inventory (CPI) in 2005. The objective of this present work is to redevelop the CPI by leading a research effort to increase the usefulness and reliability of this inventory. We created eight new descriptors for consumer products, including information pertaining to the nanomaterials contained in each product. The project was motivated by the recognition that a diverse group of stakeholders from academia, industry, and state/federal government had become highly dependent on the inventory as an important resource and bellweather of the pervasiveness of nanotechnology in society. We interviewed 68 nanotechnology experts to assess key information needs. Their answers guided inventory modifications by providing a clear conceptual framework best suited for user expectations. The revised inventory was released in October 2013. It currently lists 1814 consumer products from 622 companies in 32 countries. The Health and Fitness category contains the most products (762, or 42% of the total). Silver is the most frequently used nanomaterial (435 products, or 24%); however, 49% of the products (889) included in the CPI do not provide the composition of the nanomaterial used in them. About 29% of the CPI (528 products) contain nanomaterials suspended in a variety of liquid media and dermal contact is the most likely exposure scenario from their use. The majority (1288 products, or 71%) of the products do not present enough supporting information to corroborate the claim that nanomaterials are used. The modified CPI has enabled crowdsourcing capabilities, which allow users to suggest edits to any entry and permits researchers to upload new findings ranging from human and environmental exposure data to complete life cycle assessments. There are inherent limitations to this type of database, but these modifications to the inventory addressed the majority of criticisms raised in published literature and in surveys of nanotechnology stakeholders and experts. The development of standardized methods and metrics for nanomaterial characterization and labelling in consumer products can lead to greater understanding between the key stakeholders in nanotechnology, especially consumers, researchers, regulators, and industry. PMID- 26425430 TI - Nonlinear optical properties of near-infrared region Ag2S quantum dots pumped by nanosecond laser pulses. AB - This study investigates near-infrared region Ag2S quantum dots (QDs) and their nonlinear optical response under 532 nm nanosecond laser pulses. Our experimental result shows that nonlinear transmission is reduced from 0.084 to 0.04. The observed narrowing behavior of the output pulse width shows superior optical limiting. We discuss the physical mechanisms responsible for the nonlinear optical response of the QDs. The average size of the nanocrystals was 5.5 nm. Our results suggest the possibility of using these Ag2S QDs for photoelectric, biosensor, optical ranging, and self-adaptive technologies. PMID- 26425432 TI - Surface engineering of nanoporous substrate for solid oxide fuel cells with atomic layer-deposited electrolyte. AB - Solid oxide fuel cells with atomic layer-deposited thin film electrolytes supported on anodic aluminum oxide (AAO) are electrochemically characterized with varying thickness of bottom electrode catalyst (BEC); BECs which are 0.5 and 4 times thicker than the size of AAO pores are tested. The thicker BEC ensures far more active mass transport on the BEC side and resultantly the thicker BEC cell generates ~11 times higher peak power density than the thinner BEC cell at 500 degrees C. PMID- 26425433 TI - Two-phase equilibrium states in individual Cu-Ni nanoparticles: size, depletion and hysteresis effects. AB - In isolated bimetallic nanoscale systems the limit amount of matter and surface induced size effects can change the thermodynamics of first-order phase transformation. In this paper we present theoretical modification of Gibbs free energy concept describing first-order phase transformation of binary alloyed nanoparticles taking into account size effects as well as depletion and hysteresis effects. In such a way the hysteresis in a form of nonsymmetry for forth and back transforming paths takes place; compositional splitting and the loops-like splitted path on the size dependent temperature-composition phase diagram occur. Our calculations for individual Cu-Ni nanoparticle show that one must differentiate the solubility curves and the equilibrium loops (discussed here in term of solidification and melting loops). For the first time we have calculated and present here on the temperature-composition phase diagram the nanomelting loop at the size of 80 nm and the nanosolidification loop at the size of 25 nm for an individual Cu-Ni nanoparticle. So we observe the difference between the size-dependent phase diagram and solubility diagram, between two phase equilibrium curves and solubility curves; also intersection of nanoliquidus and nanosolidus is available. These findings lead to the necessity to reconsider such basic concepts in materials science as phase diagram and solubility diagram. PMID- 26425434 TI - Metal hydrides: an innovative and challenging conversion reaction anode for lithium-ion batteries. AB - The state of the art of conversion reactions of metal hydrides (MH) with lithium is presented and discussed in this review with regard to the use of these hydrides as anode materials for lithium-ion batteries. A focus on the gravimetric and volumetric storage capacities for different examples from binary, ternary and complex hydrides is presented, with a comparison between thermodynamic prediction and experimental results. MgH2 constitutes one of the most attractive metal hydrides with a reversible capacity of 1480 mA.h.g(-1) at a suitable potential (0.5 V vs Li(+)/Li(0)) and the lowest electrode polarization (<0.2 V) for conversion materials. Conversion process reaction mechanisms with lithium are subsequently detailed for MgH2, TiH2, complex hydrides Mg2MH x and other Mg-based hydrides. The reversible conversion reaction mechanism of MgH2, which is lithium controlled, can be extended to others hydrides as: MH x + xLi(+) + xe(-) in equilibrium with M + xLiH. Other reaction paths-involving solid solutions, metastable distorted phases, and phases with low hydrogen content-were recently reported for TiH2 and Mg2FeH6, Mg2CoH5 and Mg2NiH4. The importance of fundamental aspects to overcome technological difficulties is discussed with a focus on conversion reaction limitations in the case of MgH2. The influence of MgH2 particle size, mechanical grinding, hydrogen sorption cycles, grinding with carbon, reactive milling under hydrogen, and metal and catalyst addition to the MgH2/carbon composite on kinetics improvement and reversibility is presented. Drastic technological improvement in order to the enhance conversion process efficiencies is needed for practical applications. The main goals are minimizing the impact of electrode volume variation during lithium extraction and overcoming the poor electronic conductivity of LiH. To use polymer binders to improve the cycle life of the hydride-based electrode and to synthesize nanoscale composite hydride can be helpful to address these drawbacks. The development of high capacity hydride anodes should be inspired by the emergent nano-research prospects which share the knowledge of both hydrogen-storage and lithium-anode communities. PMID- 26425431 TI - NanoE-Tox: New and in-depth database concerning ecotoxicity of nanomaterials. AB - The increasing production and use of engineered nanomaterials (ENMs) inevitably results in their higher concentrations in the environment. This may lead to undesirable environmental effects and thus warrants risk assessment. The ecotoxicity testing of a wide variety of ENMs rapidly evolving in the market is costly but also ethically questionable when bioassays with vertebrates are conducted. Therefore, alternative methods, e.g., models for predicting toxicity mechanisms of ENMs based on their physico-chemical properties (e.g., quantitative (nano)structure-activity relationships, QSARs/QNARs), should be developed. While the development of such models relies on good-quality experimental toxicity data, most of the available data in the literature even for the same test species are highly variable. In order to map and analyse the state of the art of the existing nanoecotoxicological information suitable for QNARs, we created a database NanoE Tox that is available as Supporting Information File 1. The database is based on existing literature on ecotoxicology of eight ENMs with different chemical composition: carbon nanotubes (CNTs), fullerenes, silver (Ag), titanium dioxide (TiO2), zinc oxide (ZnO), cerium dioxide (CeO2), copper oxide (CuO), and iron oxide (FeO x ; Fe2O3, Fe3O4). Altogether, NanoE-Tox database consolidates data from 224 articles and lists altogether 1,518 toxicity values (EC50/LC50/NOEC) with corresponding test conditions and physico-chemical parameters of the ENMs as well as reported toxicity mechanisms and uptake of ENMs in the organisms. 35% of the data in NanoE-Tox concerns ecotoxicity of Ag NPs, followed by TiO2 (22%), CeO2 (13%), and ZnO (10%). Most of the data originates from studies with crustaceans (26%), bacteria (17%), fish (13%), and algae (11%). Based on the median toxicity values of the most sensitive organism (data derived from three or more articles) the toxicity order was as follows: Ag > ZnO > CuO > CeO2 > CNTs > TiO2 > FeO x . We believe NanoE-Tox database contains valuable information for ENM environmental hazard estimation and development of models for predicting toxic potential of ENMs. PMID- 26425435 TI - Optimized design of a nanostructured SPCE-based multipurpose biosensing platform formed by ferrocene-tethered electrochemically-deposited cauliflower-shaped gold nanoparticles. AB - The demand for on-site nanodevices is constantly increasing. The technology development for the design of such devices is highly regarded. In this work, we report the design of a disposable platform that is structured with cauliflower shaped gold nanoparticles (cfAuNPs) and we show its applications in immunosensing and enzyme-based detection. The electrochemical reduction of Au(III) allows for the electrodeposition of highly dispersed cauliflower-shaped gold nanoparticles on the surface of screen-printed carbon electrodes (SPCEs). The nanostructures were functionalized using ferrocenylmethyl lipoic acid ester which allowed for the tethering of the ferrocene group to gold, which serves as an electrochemical transducer/mediator. The bioconjugation of the surface with anti-human IgG antibody (alpha-hIgG) or horseradish peroxidase (HRP) enzyme yields biosensors, which have been applied for the selective electrochemical detection of human IgG (hIgG) or H2O2 as model analytes, respectively. Parameters such as the number of sweeps, amount of charge generated from the oxidation of the electrodeposited gold, time of incubation and concentration of the ferrocene derivatives have been studied using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and scanning electron microscopy (SEM). Selectivity and specificity tests have been also performed in the presence of potentially interfering substances to either hIgG or H2O2. Results showed that the devised immunosensor is endowed with good selectivity and specificity in the presence of several folds of competitive analytes. The enzyme-based platform showed a good catalytic activity towards H2O2 oxidation which predestined it to potential applications pertaining to enzymatic kinetics studies. The levels of hIgG in human serum and H2O2 in honey were successfully determined and served as assessment tools of the applicability of the platforms for real samples analysis. PMID- 26425436 TI - Large-voltage behavior of charge transport characteristics in nanosystems with weak electron-vibration coupling. AB - We study analytically the Full Counting Statistics of the charge transport through a nanosystem consisting of a few electronic levels weakly coupled to a discrete vibrational mode. In the limit of large transport voltage bias the cumulant generating function can be evaluated explicitly based solely on the intuitive physical arguments and classical master equation description of the vibration mode. We find that for the undamped vibrational modes mutual dynamical interplay between electronic and vibronic degrees of freedom leads to strongly nonlinear (in voltage) transport characteristics of the nanosystem. In particular, we find that for large voltages the k-th cumulant of the current grows as V (2k) to be contrasted with the linear dependence in case of more strongly externally damped and thus thermalized vibrational modes. PMID- 26425437 TI - Nanocuration workflows: Establishing best practices for identifying, inputting, and sharing data to inform decisions on nanomaterials. AB - There is a critical opportunity in the field of nanoscience to compare and integrate information across diverse fields of study through informatics (i.e., nanoinformatics). This paper is one in a series of articles on the data curation process in nanoinformatics (nanocuration). Other articles in this series discuss key aspects of nanocuration (temporal metadata, data completeness, database integration), while the focus of this article is on the nanocuration workflow, or the process of identifying, inputting, and reviewing nanomaterial data in a data repository. In particular, the article discusses: 1) the rationale and importance of a defined workflow in nanocuration, 2) the influence of organizational goals or purpose on the workflow, 3) established workflow practices in other fields, 4) current workflow practices in nanocuration, 5) key challenges for workflows in emerging fields like nanomaterials, 6) examples to make these challenges more tangible, and 7) recommendations to address the identified challenges. Throughout the article, there is an emphasis on illustrating key concepts and current practices in the field. Data on current practices in the field are from a group of stakeholders active in nanocuration. In general, the development of workflows for nanocuration is nascent, with few individuals formally trained in data curation or utilizing available nanocuration resources (e.g., ISA-TAB-Nano). Additional emphasis on the potential benefits of cultivating nanomaterial data via nanocuration processes (e.g., capability to analyze data from across research groups) and providing nanocuration resources (e.g., training) will likely prove crucial for the wider application of nanocuration workflows in the scientific community. PMID- 26425438 TI - A novel link between FMR gene and the JNK pathway provides clues to possible role in malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is an aggressive form of thoracic cancer with poor prognosis. While some studies have identified the molecular alterations associated with MPM, little is known about their role in MPM. For example, fragile X mental retardation (FMR) gene is up-regulated in MPM but its role in MPM is unknown. Here, utilizing Drosophila genetics, I investigate the possible role FMR may be playing in MPM. I provide evidence which suggests that FMR may contribute to tumorigenesis by up-regulating a matrix metalloprotease (MMP) and by degrading the basement membrane (BM), both important for tumor metastasis. I also demonstrate a novel link between FMR and the JNK pathway and suggest that the effects of FMR in MPM could in part be mediated by up-regulation of the JNK pathway. PMID- 26425440 TI - On the role of impulsivity and decision-making in suicidal behavior. AB - Suicide risk constitutes a complex set of interacting demographic, clinical, psychobiological and environmental variables. Impulsivity is a long-known risk factor for suicide attempts. However, research based on clearer conceptual refinement in this area is imperative. One emerging field of study is that of decision-making. Impulsivity involves a failure of higher-order control, including decision-making. Using standardized operational definitions that take into consideration relevant aspects of impulsivity, including state- and trait components and a deeper understanding of the process of decision-making in the suicidal mind, we may come a step closer to understanding suicidality and winning the fight in this scourge of human suffering. PMID- 26425439 TI - Detection of circulating IgG antibodies to apolipoprotein B100 in acute myocardial infarction. AB - A number of studies have reported an association between increased levels of antibodies against oxidized low-density lipoprotein (oxLDL) and cardiovascular disease, but the anti-oxLDL antibody has not been confirmed to serve as an effective biomarker for prediction of acute myocardial infarction (AMI). Apolipoprotein B100 (ApoB100)-derived peptide fragments generated by proteolytic degradation and aldehyde modification are the major antigens in oxLDL, and so the present work was undertaken to detect circulating IgG for Apo-B100-derived peptide antigens. An in-house enzyme-linked immunosorbent assay (ELISA) was developed with eight ApoB100-derived peptide antigens (Ag1-Ag8) to detect circulating anti-ApoB100 IgG levels in 267 patients with AMI and 201 control subjects. Binary logistic regression analysis revealed that circulating IgG for Ag1 was significantly higher in the patient group than the control group (P < 0.001) after adjustment for age, gender, smoking, hypertension, diabetes and circulating levels of cholesterol, HDL, LDL, ApoA and ApoB100. None of the other seven antigens detected an increase in IgG levels in AMI patients compared with control subjects. Spearman correlation analysis showed no correlation between IgG antibody for Ag1 and clinical characteristics. In conclusion, the linear peptide antigens derived from ApoB100 may be suitable for the development of an ELISA antibody test for prediction of AMI, although further confirmation is still needed in large-scale clinical studies. PMID- 26425441 TI - Role of presynaptic phosphoprotein synapsin II in schizophrenia. AB - Synapsin II is a member of the neuronal phosphoprotein family. These phosphoproteins are evolutionarily conserved across many organisms and are important in a variety of synaptic functions, including synaptogenesis and the regulation of neurotransmitter release. A number of genome-wide scans, meta analyses, and genetic susceptibility studies have implicated the synapsin II gene (3p25) in the etiology of schizophrenia (SZ) and other psychiatric disorders. Further studies have found a reduction of synapsin II mRNA and protein in the prefrontal cortex in post-mortem samples from schizophrenic patients. Disruptions in the expression of this gene may cause synaptic dysfunction, which can result in neurotransmitter imbalances, likely contributing to the pathogenesis of SZ. SZ is a costly, debilitating psychiatric illness affecting approximately 1.1% of the world's population, amounting to 51 million people today. The disorder is characterized by positive (hallucinations, paranoia), negative (social withdrawal, lack of motivation), and cognitive (memory impairments, attention deficits) symptoms. This review provides a comprehensive summary of the structure, function, and involvement of the synapsin family, specifically synapsin II, in the pathophysiology of SZ and possible target for therapeutic intervention/implications. PMID- 26425444 TI - Months backward test: A review of its use in clinical studies. AB - AIM: To review the use of the Months Backwards Test (MBT) in clinical and research contexts. METHODS: We conducted a systematic review of reports relating to the MBT based upon a search of PsychINFO and MEDLINE between January 1980 and December 2014. Only reports that specifically described findings pertaining to the MBT were included. Findings were considered in terms of rating procedures, testing performance, psychometric properties, neuropsychological studies and use in clinical populations. RESULTS: We identified 22 data reports. The MBT is administered and rated in a variety of ways with very little consistency across studies. It has been used to assess various cognitive functions including focused and sustained attention as well as central processing speed. Performance can be assessed in terms of the ability to accurately complete the test without errors ("MB accuracy"), and time taken to complete the test ("MB duration"). Completion time in cognitively intact subjects is usually < 20 s with upper limits of 60-90 s typically applied in studies. The majority of cognitively intact adults can complete the test without error such that any errors of omission are strongly suggestive of cognitive dysfunction. Coverage of clinical populations, including those with significant cognitive difficulties is high with the majority of subjects able to engage with MBT procedures. Performance correlates highly with other cognitive tests, especially of attention, including the digit span backwards, trailmaking test B, serial threes and sevens, tests of simple and complex choice reaction time, delayed story recall and standardized list learning measures. Test-retest and inter-rater reliability are high (both > 0.90). Functional magnetic resonance imaging studies comparing the months forward test and MBT indicate greater involvement of more complex networks (bilateral middle and inferior frontal gyri, the posterior parietal cortex and the left anterior cingulate gyrus) for backwards cognitive processing. The MBT has been usefully applied to the study of a variety of clinical presentations, for both cognitive and functional assessment. In addition to the assessment of major neuropsychiatric conditions such as delirium, dementia and Mild Cognitive Impairment, the MBT has been used in the assessment of concussion, profiling of neurocognitive impairments in organic brain disorders and Parkinson's disease, prediction of delirium risk in surgical patients and medication compliance in diabetes. The reported sensitivity for acute neurocognitive disturbance/delirium in hospitalised patients is estimated at 83%-93%. Repeated testing can be used to identify deteriorating cognitive function over time. CONCLUSION: The MBT is a simple, versatile tool that is sensitive to significant cognitive impairment. Performance can be assessed according to accuracy and speed of performance. However, greater consistency in administration and rating is needed. We suggest two approaches to assessing performance - a simple (pass/fail) method as well as a ten point scale for rating test performance (467). PMID- 26425443 TI - Usefulness of telepsychiatry: A critical evaluation of videoconferencing-based approaches. AB - Telepsychiatry, i.e., the use of information and communication technologies to provide psychiatric services from a distance, has been around for more than half a century now. Research over this period has shown that videoconferencing-based telepsychiatry is an enabling and empowering form of service delivery, which promotes equality of access, and high levels of satisfaction among patients. The range of services offered by videoconferencing-based telepsychiatry, potential users and points of delivery of such services are theoretically limitless. Telepsychiatry has both clinical utility and non-clinical uses such as administrative, learning and research applications. A large body of accumulated evidence indicates that videoconferencing-based telepsychiatric assessments are reliable, and clinical outcomes of telepsychiatric interventions are comparable to conventional treatment among diverse patient populations, ages and diagnostic groups, and on a wide range of measures. However, on many aspects of effectiveness, the evidence base is still relatively limited and often compromised by methodological problems. The lack of cost-effectiveness data in particular, is a major hindrance, raising doubts about the continued viability of telepsychiatric services. Added to this are the vagaries of technology, negative views among clinicians, poor uptake by providers, and several legal, ethical and administrative barriers. These hamper the widespread implementation of telepsychiatry and its integration with routine care. Though further advances in technology and research are expected to solve many of these problems, the way forward would be to promote telepsychiatry as an adjunct to conventional care, and to develop hybrid models, which incorporate both traditional and telepsychiatric forms of mental health-care. PMID- 26425442 TI - Psychiatric aspects of brain tumors: A review. AB - Infrequently, psychiatric symptoms may be the only manifestation of brain tumors. They may present with mood symptoms, psychosis, memory problems, personality changes, anxiety, or anorexia. Symptoms may be misleading, complicating the clinical picture. A comprehensive review of the literature was conducted regarding reports of brain tumors and psychiatric symptoms from 1956-2014. Search engines used include PubMed, Ovid, Psych Info, MEDLINE, and MedScape. Search terms included psychiatric manifestations/symptoms, brain tumors/neoplasms. Our literature search yielded case reports, case studies, and case series. There are no double blind studies except for post-diagnosis/-surgery studies. Early diagnosis is critical for improved quality of life. Symptoms that suggest work-up with neuroimaging include: new-onset psychosis, mood/memory symptoms, occurrence of new or atypical symptoms, personality changes, and anorexia without body dysmorphic symptoms. This article reviews the existing literature regarding the diagnosis and management of this clinically complex condition. PMID- 26425445 TI - Motor abilities of children and adolescents with a psychiatric condition: A systematic literature review. AB - AIM: To summarize research regarding the motor abilities of children and adolescents who suffer from a common psychiatric condition. METHODS: In order to outline the current knowledge regarding the motor abilities of children and adolescents with autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), disruptive behavior disorders (DBD) and depression, a comprehensive systematic literature search was carried out using PubMed, Medline and ERIC databases. The databases were searched for relevant English language articles published between January 1990 and April 2014. Only studies that conducted a quantitative evaluation of motor ability and concerned individuals aged 0-18 years were included. A separate search was conducted for each disorder (ASD, ADHD, DBD, depression) in conjunction with each of the following keywords: (psycho/perceptuo) motor/movement skill(s), (psycho/perceptuo) motor/movement abilities, (psycho/perceptuo) motor/movement impairment, (psycho/perceptuo) motor/movement problem(s), motor function, motor coordination, motor performance, motor deficit(s). To detect supplementary relevant literature, the reference lists of the retrieved articles were examined. RESULTS: The search strategy yielded 51 studies meeting the inclusion criteria. In total, 28 studies were included that examined the motor abilities of children and adolescents with ASD. All studies indicated that they performed below average on various standardized motor assessment instruments. The overall prevalence rate for impairment in motor abilities ranged from 33% to 100%. Twenty-seven studies examined the motor abilities of children and adolescents with ADHD. Depending on the type of motor assessment tool and the cut-off points used by different researchers, prevalence rates of impairment in motor abilities are highly variable and ranged from 8% to 73%. Remarkably, there is a paucity of research addressing the motor abilities of individuals with DBD or depression. Furthermore, methodological problems, such as measurement and comorbidity issues, complicate the generalization of the findings. CONCLUSION: Research suggests that motor impairment is highly prevalent in some psychiatric conditions, particularly ASD and ADHD. However, future work is necessary to draw sound conclusions. PMID- 26425448 TI - Video-assisted surgery for thyroid cancer patients. AB - BACKGROUND: Today is well known that endoscopic thyroidectomy could reach the same level of completeness as a conventional operation. We have been using minimally invasive video assisted thyroidectomy (MIVAT) as our favorite minimally invasive access to thyroid diseases from the late nineties. METHODS: Our experience with MIVAT is represented by 2,413 cases between 1998 and 2014: in particular 821 patients were operated with a total thyroidectomy for a papillary carcinoma (34.0%). Furthermore 967 patients underwent a MVAT for the presence of an undetermined lesion (40.0%). RESULTS: The conversion rate was very low: 24 patients (1.0%), mainly due to: unexpected posterior tracheal invasions (nine patients), involvement of lymph nodes not evident at echography (four patients), esophageal infiltration (three patients), strap muscles infiltration (three patients) and finally in five cases the presence of serious thyroiditis that had escaped to ultrasonographic evaluation. CONCLUSIONS: The minimally MIVAT to treat malignant thyroid tumors has today a very clear indication for malignancies. PMID- 26425447 TI - Influence of gender in the recognition of basic facial expressions: A critical literature review. AB - AIM: To conduct a systematic literature review about the influence of gender on the recognition of facial expressions of six basic emotions. METHODS: We made a systematic search with the search terms (face OR facial) AND (processing OR recognition OR perception) AND (emotional OR emotion) AND (gender or sex) in PubMed, PsycINFO, LILACS, and SciELO electronic databases for articles assessing outcomes related to response accuracy and latency and emotional intensity. The articles selection was performed according to parameters set by COCHRANE. The reference lists of the articles found through the database search were checked for additional references of interest. RESULTS: In respect to accuracy, women tend to perform better than men when all emotions are considered as a set. Regarding specific emotions, there seems to be no gender-related differences in the recognition of happiness, whereas results are quite heterogeneous in respect to the remaining emotions, especially sadness, anger, and disgust. Fewer articles dealt with the parameters of response latency and emotional intensity, which hinders the generalization of their findings, especially in the face of their methodological differences. CONCLUSION: The analysis of the studies conducted to date do not allow for definite conclusions concerning the role of the observer's gender in the recognition of facial emotion, mostly because of the absence of standardized methods of investigation. PMID- 26425446 TI - Pharmacologic approaches to treatment resistant depression: Evidences and personal experience. AB - AIM: To review evidence supporting pharmacological treatments for treatment resistant depression (TRD) and to discuss them according to personal clinical experience. METHODS: Original studies, clinical trials, systematic reviews, and meta-analyses addressing pharmacological treatment for TRD in adult patients published from 1990 to 2013 were identified by data base queries (PubMed, Google Scholar e Quertle Searches) using terms: "treatment resistant depression", "treatment refractory depression", "partial response depression", "non responder depression", "optimization strategy", "switching strategy", "combination strategy", "augmentation strategy", selective serotonin reuptake inhibitors antidepressants (SSRI), tricyclic antidepressants (TCA), serotonin norepinephrine reuptake inhibitors antidepressants, mirtazapine, mianserine, bupropione, monoamine oxidase inhibitor antidepressant (MAOI), lithium, thyroid hormones, second generation antipsychotics (SGA), dopamine agonists, lamotrigine, psychostimulants, dextromethorphan, dextrorphan, ketamine, omega-3 fatty acids, S adenosil-L-metionine, methylfolat, pindolol, sex steroids, glucocorticoid agents. Other citations of interest were further identified from references reported in the accessed articles. Selected publications were grouped by treatment strategy: (1) switching from an ineffective antidepressant (AD) to a new AD from a similar or different class; (2) combining the current AD regimen with a second AD from a different class; and (3) augmenting the current AD regimen with a second agent not thought to be an antidepressant itself. RESULTS: Switching from a TCA to another TCA provides only a modest advantage (response rate 9%-27%), while switching from a SSRI to another SSRI is more advantageous (response rate up to 75%). Evidence supports the usefulness of switching from SSRI to venlafaxine (5 positive trials out 6), TCA (2 positive trials out 3), and MAOI (2 positive trials out 2) but not from SSRI to bupropione, duloxetine and mirtazapine. Three reviews demonstrated that the benefits of intra- and cross-class switch do not significantly differ. Data on combination strategy are controversial regarding TCA-SSRI combination (positive results in old studies, negative in more recent study) and bupropion-SSRI combination (three open series studies but not three controlled trails support the useful of this combination) and positive regard mirtazapine (or its analogue mianserine) combination with ADs of different classes. As regards the augmentation strategy, available evidences supported the efficacy of TCA augmentation with lithium salts and thyroid hormone (T3), but are conflicting regard the SSRI augmentation with these two drugs (1 positive trial out of 4 for lithium and 3 out of 5 for thyroid hormone). Double-blind controlled studies showed the efficacy of AD augmentation with aripiprazole (5 positive trials out 5), quetiapine (3 positive trials out 3) and, at less extent, of fluoxetine augmentation with olanzapine (3 positive trials out 6), so these drugs received the FDA indication for the acute treatment of TRD. Results on AD augmentation with risperidone are conflicting (2 short term positive trials, 1 short-term and 1 long-term negative trials). Case series and open-label trials showed that AD augmentation with pramipexole or ropinirole, two dopamine agonists, could be an effective treatment for TRD (response rate to pramipexole 48%-74%, to ropinirole 40%-44%) although one recent double-blind placebo controlled study does not support the superiority of pramipexole over placebo. Evidences do not justify the use of psychostimulants, omega-3 fatty acids, S adenosil-L-metionine, methylfolate, pindolol, lamotrigine, and sex hormone as AD augmentation for TRD. Combining the available evidences with our experience we suggest treating non-responders to one SSRI bupropion or mirtazapine trial by switching to venlafaxine, and non-responders to one venlafaxine trial by switching to a TCA or, if TCA are not tolerated, combining mirtazapine with SSRI or venlafaxine. In non-responders to two or more ADs (including at least one TCA if tolerated) current AD regimen could be augmented with lithium salts (mainly in patients with bipolar depression or suicidality), SGAs (mostly aripiprazole) or DA-agonists (mostly pramipexole). In patients with severe TRD, i.e., non responders to combination and augmentation strategies as well as to electroconvulsive therapy if workable, we suggest to try a combination plus augmentation strategy. CONCLUSION: Our study identifies alternative effective treatment strategies for TRD. Further studies are needed to compare the efficacy of different strategies in more homogeneous subpopulations. PMID- 26425449 TI - Electrophysiological neural monitoring of the laryngeal nerves in thyroid surgery: review of the current literature. AB - Recurrent laryngeal nerve (RLN) injury is one of the most common complications of thyroid surgery. RLN injury can cause vocal cord paralysis, affecting the patient's voice and the quality of life. Injury of the external branch of the superior laryngeal nerve (EBSLN) can cause cricothyroid muscle denervation affecting high vocal tones. Thus, securing the laryngeal nerves in these surgeries is of utmost importance. Visual identification of the nerves has long been the standard method for this precaution. Intraoperative neuromonitoring (IONM) has been introduced as a novel technology to improve the protection of the laryngeal nerves and reduce the rate of RLN injury. The aim of this article is to provide a brief description of the technique and review the literature to illustrate the value of IONM. IONM can provide early identification of anatomical variations and unusual nerve routes, which carry a higher risk of injury if not detected. IONM helps in prognosticating postoperative nerve function. Moreover, by detecting nerve injury intraoperatively, it aids in staging bilateral surgeries to avoid bilateral vocal cord paralysis and tracheostomy. The article will discuss the value of continuous IONM (C-IOMN) that may prevent nerve injury by detecting EMG waveform changes indicating impending nerve injury. Herein, we are also discussing anatomy of laryngeal nerves and aspects of its injury. PMID- 26425450 TI - Remote access thyroid surgery. AB - Robot assisted thyroid surgery has been the latest advance in the evolution of thyroid surgery after endoscopy assisted procedures. The advantage of a superior field vision and technical advancements of robotic technology have permitted novel remote access (trans-axillary and retro-auricular) surgical approaches. Interestingly, several remote access surgical ports using robot surgical system and endoscopic technique have been customized to avoid the social stigma of a visible scar. Current literature has displayed their various advantages in terms of post-operative outcomes; however, the associated financial burden and also additional training and expertise necessary hinder its widespread adoption into endocrine surgery practices. These approaches offer excellent cosmesis, with a shorter learning curve and reduce discomfort to surgeons operating ergonomically through a robotic console. This review aims to provide details of various remote access techniques that are being offered for thyroid resection. Though these have been reported to be safe and feasible approaches for thyroid surgery, further evaluation for their efficacy still remains. PMID- 26425451 TI - Transaxillary single-incision robotic neck dissection for metastatic thyroid cancer. AB - In head and neck area, neck dissection (ND) is one of the most complex and precision-needed procedure. The long cervical scar and post-operative neck discomfort have been also inevitable brands after this procedure. Heretofore, few dare to try endoscopic surgical technique to the ND mainly due to its complexity and jeopardy of complication. Although, there have been several reports about the endoscopic approaches for functional ND or ND, they had so many technical and instrumental limitations. The dexterities of the surgical robotics have advanced the techniques of endoscopic surgery, and have facilitated the most precise and delicate endoscopic surgical procedure in head and neck area. The technical feasibility and early surgical outcomes of robotic ND using the transaxillary approach for the management of metastatic thyroid cancer have already been reported as satisfactory. Robotic ND can allow complete compartment-oriented lymph node (LN) dissection without any fatal complications, or compromising oncologic principles. We previously described a novel method of robotic thyroidectomy with ND using a gasless transaxillary approach for metastatic thyroid cancer, and here, we firstly introduce a less invasive robotic procedure which has been modified from the original one, which we refer to as the transaxillary single-incision robotic ND. PMID- 26425452 TI - Robotic transaxillary thyroid surgery. AB - Recent technological advances have led to a rapid progress in endocrine surgery. With the advent of minimally invasive techniques in thyroid surgery, robot assisted transaxillary thyroid surgery (RATS) has emerged as one of the most promising approaches. Its main advantages are improved cosmetic outcome, avoiding cervical incisions, increased patient satisfaction, improved visualization, arms articulations, eliminating surgeon's natural tremor, thereby increasing precision. The main disadvantages are longer operative time, and increased cost compared to conventional thyroidectomy, as well as potential injuries to the brachial plexus, skin flap, esophagus, and trachea. Large-scale studies, mainly from South-Korea, have proved that in skilled hands, RATS is a safe alternative to conservative thyroidectomy and should be presented to patients with aesthetic concerns. As with any new emerging technique, careful patient selection is crucial, and further evidence must be sought to confirm its indications. PMID- 26425453 TI - Robotic facelift thyroid surgery. AB - Techniques for thyroid surgery have advanced dramatically over the past two decades, driven by a better understanding of thyroid physiology, anatomy, and perioperative management strategies. Improvements in surgical technology have permitted surgeons to perform minimally invasive surgery associated with less dissection, decreased pain, smaller anterior cervical incisions, and most importantly a faster recovery. The advent of robotic surgical technology has allowed the development of remote access thyroidectomy for select patients who wish to avoid a visible cervical incision completely. The robotic facelift thyroidectomy (RFT) approach also offers the advantage of outpatient surgery without the need for postoperative drainage. A growing body of evidence supports the safety and efficacy of the approach, and as a result the technique is now being performed at several centers around the world. PMID- 26425454 TI - Minimally invasive parathyroid surgery. AB - Traditionally, bilateral cervical exploration for localization of all four parathyroid glands and removal of any that are grossly enlarged has been the standard surgical treatment for primary hyperparathyroidism (PHPT). With the advances in preoperative localization studies and greater public demand for less invasive procedures, novel targeted, minimally invasive techniques to the parathyroid glands have been described and practiced over the past 2 decades. Minimally invasive parathyroidectomy (MIP) can be done either through the standard Kocher incision, a smaller midline incision, with video assistance (purely endoscopic and video-assisted techniques), or through an ectopically placed, extracervical, incision. In current practice, once PHPT is diagnosed, preoperative evaluation using high-resolution radiographic imaging to localize the offending parathyroid gland is essential if MIP is to be considered. The imaging study results suggest where the surgeon should begin the focused procedure and serve as a road map to allow tailoring of an efficient, imaging guided dissection while eliminating the unnecessary dissection of multiple glands or a bilateral exploration. Intraoperative parathyroid hormone (IOPTH) levels may be measured during the procedure, or a gamma probe used during radioguided parathyroidectomy, to ascertain that the correct gland has been excised and that no other hyperfunctional tissue is present. MIP has many advantages over the traditional bilateral, four-gland exploration. MIP can be performed using local anesthesia, requires less operative time, results in fewer complications, and offers an improved cosmetic result and greater patient satisfaction. Additional advantages of MIP are earlier hospital discharge and decreased overall associated costs. This article aims to address the considerations for accomplishing MIP, including the role of preoperative imaging studies, intraoperative adjuncts, and surgical techniques. PMID- 26425455 TI - Robotic transaxillary and retroauricular parathyroid surgery. AB - Current advancement in robotic surgery has provided a safe, precise, 3 dimensional (3D) magnified dissection for parathyroid surgery without the need for CO2 insufflation, and with a better cosmetic outcome due to an invisible scar in the axillary or retroauricular region. Preoperative imaging studies that assist in the localization of lesions have been key elements in patients' selection for targeted parathyroid surgery. PMID- 26425456 TI - Transoral robotic thyroid surgery. AB - There is currently significant demand for minimally invasive thyroid surgery; however the majority of proposed surgical approaches necessitate a compromise between minimal tissue dissection with a visible cervical scar or extensive tissue dissection with a remote, hidden scar. The development of transoral endoscopic thyroid surgery however provides an approach which is truly minimally invasive, as it conceals the incision within the oral cavity without significantly increasing the amount of required dissection. The transoral endoscopic approach however presents multiple technical challenges, which could be overcome with the incorporation of a robotic operating system. This manuscript summarizes the literature on the feasibility and current clinical experience with transoral robotic thyroid surgery. PMID- 26425457 TI - Laparoscopic and robotic adrenal surgery: transperitoneal approach. AB - Recent advances in technology and the need to decrease surgical morbidity have led a rapid progress in laparoscopic adrenalectomy (LA) over the past decade. Robotics is attractive to the surgeon owing to the 3-dimensional image quality, articulating instruments, and stable surgical platform. The safety and efficacy of robotic adrenalectomy (RA) have been demonstrated by several reports. In addition, RA has been shown to provide similar outcomes compared to LA. Development of adrenal surgery has involved the description of several surgical approaches including the anterior transperitoneal, lateral transperitoneal (LT) and posterior retroperitoneal (PR). Among these, the most frequently preferred technique is LT adrenalectomy, primarily due to the surgeon's familiarity of the operative field, wider working space and visibility. The LT technique is suitable for the resection of larger, unilateral tumors and in scenarios where conversion to an open transperitoneal approach is warranted, it offers a lesser burden. Also, the larger view of the entire abdominal cavity and excellent exposure of both adrenal glands and surrounding structures provided by the LT technique render it safe and feasible in pediatric and pregnant individuals. PMID- 26425458 TI - Surgical approaches for liver metastases in carcinoid tumors. AB - Liver is the commonest site for metastasis in patients with neuroendocrine tumors (NETs); it occurs in 45-95% of patients. Available treatment options include surgical resection, liver transplantation, chemotherapy and biotherapy. Surgery is the gold standard for curative therapy. Typically, a multidisciplinary approach is a cornerstone for decision making while dealing with this aggressive disease. This review will focus on the performance and safety of open, laparoscopic, and liver transplant surgical approaches in NETs patients with liver metastases. PMID- 26425459 TI - Robotic-assisted laparoscopic adrenalectomy for an adrenal adenoma. AB - The patient was referred for management of a left adrenal incidentaloma. Preoperative CT scan and MRI showed focal calcification. Here we are presenting this video demonstrating robotic-assisted laparoscopic adrenalectomy for left adrenal mass. PMID- 26425460 TI - Role of bilateral adrenalectomy in adrenocorticotropic hormone-dependent Cushing's syndrome. PMID- 26425461 TI - Only generics (drugs/names): Is India ready? PMID- 26425462 TI - Statins: Cholesterol guidelines and Indian perspective. AB - Statins have become an important drug in preventing the occurrence of atherosclerotic cardiovascular disease (ASCVD). The effectiveness of statins in reducing ASCVD has been established in large-scale clinical trials. The lipid management guidelines have been periodically modified due to accumulating evidence about the proportionate benefit achieved with a progressive reduction in cholesterol levels with higher doses of statins and even in those at low risk of development of ASCVD. The current American College of Cardiology/American Heart Association guidelines have based its recommendations from data gathered exclusively from randomized controlled trials. It has simplified the use of statins, but also raised questions regarding the validity of its cardiovascular event risk prediction tool. Epidemiology of cardiovascular disease in India differs from the western population; there is an increased the prevalence of metabolic syndrome and atherogenic dyslipidemia phenotype a group not addressed in the current guidelines. The guidelines are based on trials, which do not have a representative South Asian population. This article reviews the relevant literature, and examines the issues involved in adopting the guidelines to the Indian population. PMID- 26425463 TI - Pleiotropic effects of statins. AB - Statins or 3-hydroxy-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors not only prevents the synthesis of cholesterol biosynthesis but also inhibits the synthesis of essential isoprenoid intermediates such as farnesyl pyrophosphate, geranylgeranyl pyrophosphate, isopentanyl adenosine, dolichols and polyisoprenoid side chains of ubiquinone, heme A, and nuclear lamins. These isoprenoid intermediates are required for activation of various intracellular/signaling proteins- small guanosine triphosphate bound protein Ras and Ras-like proteins like Rho, Rab, Rac, Ral, or Rap which plays an indispensible role in multiple cellular processes. Reduction of circulating isoprenoids intermediates as a result of HMG CoA reductase inhibition by statins prevents activation of these signalling proteins. Hence, the multiple effects of statins such as antiinflammatory effects, antioxidant effects, antiproliferative and immunomodulatory effects, plaque stability, normalization of sympathetic outflow, and prevention of platelet aggregation are due to reduction of circulating isoprenoids and hence inactivation of signalling proteins. These multiple lipid independent effects of statins termed as statin pleiotropy would potentially open floodgates for research in multiple treatment domains catching attentions of researchers and clinician across the globe. PMID- 26425464 TI - Bariatric surgery and diabetes remission: Who would have thought it? AB - Type 2 diabetes mellitus (T2DM) and obesity are increasingly common and major global health problems. The Edmonton obesity staging system clearly pointed towards increased mortality proportionate to the severity of obesity. Obesity itself triggers insulin resistance and thereby poses the risk of T2DM. Both obesity and T2DM have been associated with higher morbidity and mortality and this calls for institution of effective therapies to deal with the rising trend of complications arising out of this dual menace. Although lifestyle changes form the cornerstone of therapy for both the ailments, sustained results from this modalities is far from satisfactory. While Look AHEAD (action for HEAalth in diabetes) study showed significant weight loss, reduction in glycated hemoglobin and higher remission rate of T2DM at 1(st) year following intensive lifestyle measures; recurrence and relapse rate bounced back in half of subjects at 4 years, thereby indicating that weight loss and glycemic control is difficult to maintain in the long term with lifestyle interventions. Same recurrence phenomenon was also observed with pharmacotherapy with rimonabant, sibutramine and orlistat. Bariatric surgery has been seen to associate with substantial and sustained weight loss in morbidly obese patients. Interestingly, bariatric surgeries also induce higher rates of short and long-term diabetes remission. Although the exact mechanism behinds this diabetes remission are not well understood; improved insulin action, beta-cell function and complex interplay of hormones in the entero-insular axis appears to play a major role. This article reviews the effectiveness of bariatric procedures on remission or improvement in diabetes and put a perspective on its implicated mechanisms. PMID- 26425466 TI - Profile of liver enzymes in non-alcoholic fatty liver disease in patients with impaired glucose tolerance and newly detected untreated type 2 diabetes. AB - CONTEXT: The perception of non-alcoholic fatty liver disease (NAFLD) as an uncommon and benign condition is rapidly changing. Approximately, 70% type 2 diabetes mellitus (T2DM) patients have a fatty liver, which may follow an aggressive course with necroinflammation and fibrosis. AIMS: To assess the profile of liver enzymes in subjects with impaired glucose tolerance (IGT), new onset treatment naive T2DM and normal glucose tolerance (NGT) with and without NAFLD. SETTINGS AND DESIGN: Cross-sectional clinic-based study. SUBJECTS AND METHODS: 152 IGT and 158 recently detected T2DM subjects aged between 30 and 69 years, along with 160 age and gender matched controls with NGT. An ultrasonography scan of the upper abdomen was done in all patients in order to examine presence of fatty liver. Anthropometry, lipid profile, liver enzymes were also analyzed in all patients. STATISTICAL ANALYSIS USED: Unpaired t-test, Chi square/Fisher Exact test (for categorical variables), Pearson/Spearmen correlation test to find significant difference, association and correlation between two or more groups respectively. RESULTS: NAFLD was significantly associated with higher alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) but not ALP levels in IGT and T2DM patients. ALT, GGT significant correlated with waist circumference, body mass index, fasting insulin, homeostatic model assessment- insulin resistance, fasting blood glucose, high density lipoprotein cholesterol, triglyceride. 57% of NAFLD patients had normal ALT between 25 and 40 U/L, 53% of NAFLD subjects had normal GGT between 15 and 30 U/L. ALT <25 U/L and GGT <15 U/L had highest negative predictivity whereas ALT >40 U/L and GGT > 30 U/L had highest positive predictivity for presence of NAFLD in our study sample. CONCLUSIONS: Mild elevations of liver enzymes in the upper normal range are associated with features of metabolic syndrome and NAFLD even in IGT and recently detected T2DM patients. Novel cut-offs for liver enzymes are warranted in order to prevent unnecessary diagnostic work-ups and early detection of NAFLD to reduce the risk of cirrhosis, hepatocellular carcinoma and classical cardiovascular disease in T2DM and IGT patients. PMID- 26425467 TI - Iodine nutritional status in Himachal Pradesh state, India. AB - INTRODUCTION: Iodine deficiency (ID) is the preventable causes of mental retardation worldwide. Himachal Pradesh (HP) state is a known endemic region to ID. OBJECTIVE: the objective was to assess the current status of iodine nutrition in a population of HP, India. METHODOLOGY: There are three regions in HP namely: Kangra, Mandi, and Shimla. In each region, one district was selected namely: Kangra, Kullu, and Solan. In each district, 30 clusters were identified by utilizing population proportional-to-size cluster sampling methodology. A total of 5748 school-age children (SAC) (Kangra; 1864, Kullu; 1986, Solan: 1898), 1711 pregnant mothers (PMs) (Kangra; 647, Kullu; 551, Solan: 513), and 1934 neonates (Kangra; 613, Kullu; 638, Solan: 683), were included in study. Clinical examination of thyroid of each child and PM was conducted. Casual urine samples were collected from children and PMs. Cord blood samples were collected for estimation of thyroid stimulating hormone (TSH) among neonates. RESULTS: In SAC, total goiter rate (TGR) was 15.8% (Kangra), 23.4% (Kullu), and 15.4% (Solan). Median urinary iodine concentration (UIC) level was 200 MUg/l (Kangra), 175 MUg/l (Kullu), and 62.5 MUg/l (Solan). In PMs, TGR was 42.2% (Kangra), 42.0% (Kullu), and 19.9% (Solan). Median UIC level was 200 MUg/l (Kangra), 149 MUg/l (Kullu), and 130 MUg/l (Solan). In Neonates, TSH levels of > 5 mIU/L were found in 73.4 (Kangra), 79.8 (Kullu), and 63.2 (Solan) percent of neonates. CONCLUSION: As per, UIC level (<100 MUg/l) in SAC, ID was found in district Solan. In Kullu and Solan districts, there were ID (UIC level < 150 MUg/l) among PMs. TSH levels indicated ID in all districts surveyed. PMID- 26425465 TI - Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement. AB - Since their introduction in clinical practice in the 1950's, Sulfonylureas (SUs) have remained the main-stay of pharmacotherapy in the management of type 2 diabetes. Despite their well-established benefits, their place in therapy is inappropriately being overshadowed by newer therapies. Many of the clinical issues associated with the use of SUs are agent-specific, and do not pertain to the class as such. Modern SUs (glimepiride, gliclazide MR) are backed by a large body of evidence, experience, and most importantly, outcome data, which supports their role in managing patients with diabetes. Person-centred care, i.e., careful choice of SU, appropriate dosage, timing of administration, and adequate patient counseling, will ensure that deserving patients are not deprived of the advantages of this well-established class of anti-diabetic agents. Considering their efficacy, safety, pleiotropic benefits, and low cost of therapy, SUs should be considered as recommended therapy for the treatment of diabetes in South Asia. This initiative by SAFES aims to encourage rational, safe and smart prescription of SUs, and includes appropriate medication counseling. PMID- 26425469 TI - Vitamin D status and gestational diabetes mellitus. AB - CONTEXT: Vitamin D (Vit D) deficiency and gestational diabetes mellitus (GDM) are increasingly being seen in Indian women. The role of Vit D in causing GDM is not clear. AIMS: (1) To compare Vit D status in pregnant women with or without GDM. (2) Frequency of GDM in women with Vit D insufficiency and deficiency. (3) To reassess glucose tolerance after replacement of Vit D in those women with Vit D deficiency and GDM. SETTINGS AND DESIGN: Tertiary Care Hospital, Antenatal Care Department based prospective, controlled study. SUBJECTS AND METHODS: Seventy eight consecutive women (<28 weeks gestational period) were screened for GDM by glucose tolerance test (GTT) (75 g 2 h). Fifty-nine of these women were confirmed to have GDM (2 h postglucose > 140 mg/dl). Eight of these women were excluded as per laid exclusion criteria. Remaining 19 women with normal glucose tolerance (NGT) were included as controls. Serum 25-OH Vit D level was estimated by radioimmuno assay. Standard advice regarding diet, sunlight exposure, and exercise was given to all by the same dietician. Women with Vit D levels below 20 ng/ml were prescribed 60,000 IU of oral cholecalciferol to be administered twice weekly for 4 weeks. GTT was repeated after 6 weeks. Frequency of glucose intolerance was compared between Vit D sufficient and deficient groups. Women with GDM and Vit D deficiency who revert to NGT after supplementation with cholecalciferol were evaluated. STATISTICAL ANALYSIS USED: Paired t-test for comparing means, and Fisher's test for comparing proportions. RESULTS: Baseline characteristics of GDM and NGT with respect to their age, prepregnancy body mass index, and gestational period were comparable. Serum 25-OH Vit D levels were significantly lower in GDM 24.7 (+/-17.6) ng/ml versus NGT (45.8 +/- 28) group (P = 0.0004). Frequency of GDM was similar irrespective of Vit D status 67% versus 42% (P = 0.09). Standard advice on diet and exercise with or without Vit D supplementation did not significantly differ in the conversion of GDM to NGT (P = 0.63). CONCLUSION: Although Vit D deficiency is associated with GDM however its replacement does not reverse the glucose intolerance. There is no justification at present for routine screening for Vit D deficiency or its replacement in the management of GDM. PMID- 26425468 TI - Bone mineral content has stronger association with lean mass than fat mass among Indian urban adolescents. AB - INTRODUCTION: There are conflicting reports on the relationship of lean mass (LM) and fat mass (FM) with bone mineral content (BMC). Given the high prevalence of Vitamin D deficiency in India, we planned the study to evaluate the relationship between LM and FM with BMC in Indian children and adolescents. The objective of the study was to evaluate the relationship of BMC with LM and FM. MATERIALS AND METHODS: Total and regional BMC, LM, and FM using dual energy X-ray absorptiometry and pubertal staging were assessed in 1403 children and adolescents (boys [B]: 826; girls [G]: 577). BMC index, BMC/LM and BMC/FM ratio, were calculated. RESULTS: The age ranged from 5 to 18 years, with a mean age of 13.2 +/- 2.7 years. BMC adjusted for height (BMC index and BMC/height ratio) was comparable in both genders. There was no difference in total BMC between genders in the prepubertal group but were higher in more advanced stages of pubertal maturation. The correlation of total as well as regional BMC was stronger for LM (B: Total BMC - 0.880, trunk - 0.715, leg - 0.894, arm - 0.891; G: Total BMC - 0.827, leg - 0.846, arm - 0.815 (all value indicate r (2), P < 0.0001 for all) when compared with FM (B: Total BMC - 0.776, trunk - 0.676, leg - 0.772, arm - 0.728; G: Total BMC - 0.781, leg - 0.741, arm - 0.689; all P < 0.0001) except at trunk BMC (LM - 0.682 vs. FM - 0.721; all P < 0.0001), even after controlling for age, height, pubertal stage, and biochemical parameters. CONCLUSIONS: BMC had a stronger positive correlation with LM than FM. PMID- 26425470 TI - Thyroid autoimmunity in pregnant Nigerians. AB - CONTEXT: Thyroid autoimmunity is a recognized disorder in pregnancy and is associated with a number of adverse pregnancy outcomes. AIM: This study set out to determine the relationship between pregnancy and thyroid autoimmunity in Nigerian women. SETTINGS AND DESIGN: This was an analytical cross-sectional study carried out in a tertiary hospital in South Western Nigeria with a total study population of 108 pregnant and 52 nonpregnant women. SUBJECTS AND METHODS: Serum thyroid stimulating hormone, free thyroxine and thyroid peroxidase antibodies (TPO-Ab) were quantitatively determined using enzyme linked immuno-assays. Pregnant women were grouped into three categories (<14 weeks, 14-28 weeks and > 28 weeks). The relationship between pregnancy and thyroid autoimmunity was determined using Spearman correlation. Analysis of variance was used in comparison of means, Chi-square test used in analyzing proportions while P <= 0.05 was considered as significant. RESULTS: The mean age of the pregnant women was 30.4 +/- 6.0 years while the mean gestational age of all pregnant women was 20.6 +/- 9.6 weeks. The mean TPO-Ab of 11.58 IU/ml in the pregnant was significantly higher than that of the controls of 7.23 IU/ml (P < 0.001). Out of 108 pregnant women, 27 (25%) had elevated TPO-Ab as against about 2% of the nonpregnant women levels P < 0.001. The number of pregnant women with elevated TPO-Ab levels decreased from 33.3% in the first group to 25.6% and 15.2% in the second and third groups. CONCLUSION: Thyroid autoimmunity expressed by the presence of TPO-Ab is high among pregnant Nigerian women and the frequency of autoimmunity appears to decline with advancing gestational age. PMID- 26425471 TI - Posology of insulins: A review of standard textbooks and product inserts. AB - OBJECTIVES: The study is aimed to assess whether the information contained in standard pharmacology, endocrinology, and diabetology textbooks regarding timings of administration, frequency and dose of various insulins is adequate and also to see whether the information contained in these texts is concordant with product inserts. MATERIALS AND METHODS: Four standard textbooks of pharmacology, two of diabetology and three of endocrinology were assessed for the published information regarding dose, timing, and frequency of insulin administration. The product inserts of commonly available insulins in India were also studied for the same. RESULTS: Various omissions and disparities could be seen in the coverage of insulins in standard textbooks. Posology information about premixed insulins and basal insulins have been omitted by the majority of the textbooks. Details about dose, frequency and timings of ultra-short acting insulins have also not been covered by all textbooks. Some discrepancies regarding prescribing information was also noted in product inserts, especially in case of newer insulins. CONCLUSIONS: Thus, this article stresses upon the need of a uniform source of information for providing adequate and standardized knowledge regarding timing, frequency, and dose of insulins. PMID- 26425472 TI - Appropriateness of using prevalent national standards for assessment of growth parameters in children from Uttarakhand. AB - BACKGROUND: With distinct geographical and demographic conditions prevalent in the regions of Himalayan foothills, it seems questionable to assess the children from these areas using the standards based upon growth pattern of children from major central cities of the country. To answer this question, we compared the growth parameters of apparently healthy children, attending our out-patient clinic, with corresponding median values for age from national reference data. MATERIALS AND METHODS: The growth parameters of apparently healthy children were compared with the expected value for age that is, median value for the corresponding age from the recommended national reference data (Agarwal et al). RESULTS: Data from 205 boys and 200 girls, aged 5-18 years, were finally evaluated. The considerable difference was observed between growth parameters. Children from Uttarakhand were observed to be lighter, especially in older age groups and taller, especially in younger age groups, when compared with corresponding median values from reference data. CONCLUSION: It appears inappropriate to interpret the growth parameters of the children of this region in the background of index national reference. PMID- 26425473 TI - Plasma free metanephrine, normetanephrine, and 3-methoxytyramine for the diagnosis of pheochromocytoma/paraganglioma. AB - BACKGROUND: Pheochromocytomas (PHEO) and paragangliomas (PGL) are derived from paraganglia of the sympathetic and parasympathetic nervous system. Most of the sympathetic PHEO/PGL secrete either catecholamine or their metabolites, metanephrines, whereas parasympathetic PHEO/PGL are nonsecretory. We assessed the utility of plasma free 3-methoxytyramine (3MT), normetanephrine (NM), and metanephrine (MN) for the diagnosis of PHEO/PGL. MATERIALS AND METHODS: Sixty five patients referred to endocrine/ENT clinics were enrolled. Twelve patients with von Hippel-Lindau (VHL), neurofibromatosis type 1 (NF1) and multiple endocrine neoplasia type 2 (MEN2) syndromes were excluded. Remaining 53 patients (39 patients with adrenal, abdominal, cervical and thoracic PHEO/PGL and 14 patients with head and neck PGL (HNPGL) were taken for this study. Sixty-five age and sex-matched subjects were taken as controls. Plasma levels 3MT, NM, and MN were measured using high-performance liquid chromatography. Receivers operating characteristics was plotted and cut-off levels were established. RESULTS: When compared with controls, there was a 36-, 8.7- and 9.5-fold increase in levels of NM, 3MT and MN in the patients with PHEO/PGL and 7.2- and 2.7-fold increase in 3MT and NM, in the patients with HNPGL, respectively. In malignant PHEO/PGL, there was a 99-, 16- and 20-fold increase and in benign PHEO/PGL, there was 19-, 6.8- and 6.4-fold increase in levels of NM, 3MT, and MN, respectively. NM in combination with MN was high in 97% of the patients with PHEO/PGL. All three metabolites in combination were high in 83% of patients with HNPGL. In malignant PHEO/PGL, 50% subjects had increased levels of both NM and 3MT. CONCLUSIONS: Measurement of plasma-free NM along with 3MT and MN provides a better tool for the diagnosis of PHEO/PGL as well as HNPGL. Further, NM in combination with 3MT can be used for the diagnosis of malignant PHEO/PGL. PMID- 26425474 TI - Pioglitazone and the risk of bladder cancer: An Indian retrospective cohort study. AB - AIM: To determine whether pioglitazone is associated with an increased risk of bladder cancer among Indian type 2 diabetic patients. METHODS: A retrospective data analysis of 2222 type 2 diabetic patients was conducted. The study subjects were divided into two equal groups: 1111 pioglitazone users and 1111 pioglitazone non-users. The safety of pioglitazone therapy was analyzed in terms of occurrence of bladder and other types of cancers along with its efficacy in terms of glycemic control. Parameters for assessing safety were duration of disease, duration of usage and total dose of pioglitazone consumed across age groups, glycemic control, obesity and family history of any cancer. Bladder cancer prevalence was analyzed on the basis of urinary cytology, urine routine and microscopy, hematuria, urinary nuclear matrix protein 22 analysis and ultrasonography. RESULTS: Of the 2222 cases analysed, there was no evidence of bladder cancer in any of the studied groups, (p=not significant) which was also evident among 1111 patients on Pioglitazone therapy with a cumulative dose consumption of 2737 mg to 1,31,400 mg. On subgroup analysis, there was no evidence of bladder cancer amongst patients with age >60 years, duration of diabetes > 10 years and uncontrolled diabetics (HbA1c >8%) with cumulative pioglitazone consumption of >28,000 mg. A significant number of patients achieved good glycemic control (HbA1c <7.5%) with pioglitazone therapy. CONCLUSION: Pioglitazone therapy was not associated with occurrence of bladder cancer among Indian type 2 diabetic patients and demonstrated good glycemic control. PMID- 26425475 TI - Clinical profile and inheritance pattern of CYP21A2 gene mutations in patients with classical congenital adrenal hyperplasia from 10 families. AB - CONTEXT: Congenital adrenal hyperplasia (CAH) is an autosomal recessive metabolic disorder caused by mutations in the CYP21A2 gene. Genetic diagnosis of 21-OH deficiency causing CAH is more complicated than any other monogenic disorder due to high variability of the locus. The disease has a wide spectrum of clinical variants making it difficult to establish a genotyp-phenotype correlation. Therefore, family studies are necessary to ascertain parental genotype and segregation of the mutant allele among the offspring. AIM: The present study aimed to identify CYP21A2 gene mutations and analyze the segregation pattern in CAH trios (patients and their parents). MATERIALS AND METHODS: A total of ten families having at least one CAH child were recruited. RESULTS: Out of 31 children from ten families, 15 were affected with CAH and 13 of/them (12 females and 1 male) were available for genetic testing. One family had all the children affected with CAH. Compound heterozygous mutations were identified in seven patients (53.8%) whereas p.P30L, In2 and Delta8 bp mutations were present in homozygous state in three (23.1%), two (15.3 %) and one (7.6%) patient respectively. CONCLUSIONS: In majority of the families, mutant alleles observed in the patients were inherited from the parents whereas three families showed sporadic mutations without any paternal or maternal origin. This indicated their novel occurrence due to misalignment of the parental genes and/or large deletion of the gene. Female preponderance was noted in the CAH families and also among the patients raising the possibility of survival advantage among females. PMID- 26425476 TI - Prevalence of obesity and central obesity among adolescent girls in a district school in Bangladesh. AB - INTRODUCTION: The prevalence of childhood obesity has increased over the last two decades. Obesity is a major risk factor for chronic diseases and plays a central role in insulin resistance or metabolic syndrome. METHODS: The aim of the study was to assess the prevalence of obesity and abdominal obesity by means of body mass index (BMI) and waist-to-height ratio (WHtR) in adolescent girls in a district school in Bangladesh. Based on age and sex specific BMI percentiles, the students were classified as normal weight (5(th)-<85(th) percentile), overweight (85(th)-<95(th) percentiles), and obese (>=95(th) percentile). Central obesity was categorized as WHtR >= 0.5. Adolescent girls (aged 9-17 years) attending the sixth to twelfth grades (n = 501) in a Bengali medium school participated in the study. RESULTS: The prevalence of obesity and overweight were 23% and 14% among the girls. The prevalence of central obesity was 26%. Around 14% of girls in the normal weight group were centrally obese. There was a significant relationship between WHtR and BMI status (P = 0.0001). CONCLUSION: Our study provides evidence showing a high prevalence of overall and central obesity in adolescent girls in our population. We emphasize the need for further large scale surveillance programs and preventive strategies in our population to reduce the incidence of obesity. PMID- 26425477 TI - Effect of integrated approach of yoga therapy on autonomic functions in patients with type 2 diabetes. AB - BACKGROUND AND OBJECTIVES: Integrated approach of yoga therapy (IAYT) had shown beneficial effects in the management of type 2 diabetes mellitus (DM). Autonomic dysfunction is one of the major complications of type 2 DM. Research studies have demonstrated that yoga can modulate autonomic functions. Hence, the current study was designed to assess the effect of IAYT on autonomic functions in type 2 diabetics. MATERIALS AND METHODS: 15 patients of type 2 DM with ages ranging from 35 to 60 years were recruited for the study. They were diagnosed with type 2 diabetes from 1-year to 15 years. Assessments were made on day 1 (before yoga) and day 7 (after 1-week of yoga practice). Heart rate variability (HRV), blood pressure (BP) response to the isometric handgrip and heart rate response to deep breathing were assessed before and after 1-week of IAYT. RESULTS: There was a significant reduction in fasting plasma glucose from 154.67-130.27 mg/dL (Wilcoxon signed rank test, P = 0.029) following 1-week of IAYT. BP response to isometric hand grip improved significantly (Wilcoxon signed rank test, P = 0.01). There was no statistical significant change in HRV components and heart rate response to deep breathing test. However, there was a trend of increase in the low frequency power (41.07%), high frequency power (6.29%), total power (5.38%), and standard deviation of all NN intervals (SDNN) (6.29%). CONCLUSION: These findings suggest that, IAYT improved autonomic functions in type 2 diabetes patients. PMID- 26425478 TI - Insulin aspart in patients with gestational diabetes mellitus and pregestational diabetes mellitus. AB - AIMS: This study was undertaken to assess the effectiveness and safety of insulin aspart in patients with gestational and pregestational diabetes. SETTINGS AND DESIGN: An open-label, prospective, nonrandomized, comparative, and observational study conducted at single center in India. SUBJECTS AND METHODS: A total of 276 patients were in gestational diabetes mellitus (GDM) group, 79 were in the pre GDM group. Patients were started on insulin therapy (insulin aspart +/- neutral protamine hagedorn) once medical nutrition therapy for 2 weeks failed to achieve control, that is., fasting plasma glucose >=90 mg/dL and/or 1.0 h postprandial plasma glucose >=130 mg/dL. Insulin dose was titrated to keep the blood glucose values between 90 and 130 mg/dL. Patients were followed once every 4 weeks until the 28(th) week, then once every 2 weeks until 32(nd) week, then once every week until delivery, and the final visit was on 60 +/- 7 days. The final outcome was assessed in terms of incidence of macrosomia (>3.5 kg body weight) between the two groups and episodes of confirmed (blood glucose <56 mg/dL) minor or major maternal hypoglycemia. RESULTS: There was no statistically significant difference among the two groups in terms of incidence of macrosomia that is., it was 5.1%, 8.9% in GDM, pre-GDM group, respectively. CONCLUSIONS: Insulin aspart was found safe in pregnancy, however, more studies with double-blind, standard controlled studies are required to confirm the findings of this study. PMID- 26425479 TI - Metabolic syndrome among Jaffna Tamil community, Sri Lanka. AB - AIM: The prevalence and associated risk factors of metabolic syndrome (MS) among adults over 18 years old in Jaffna district. MATERIALS AND METHODS: It was community-based cross-sectional descriptive study. Multistage stratified cluster sampling technique was employed. An interviewer administered questionnaire was used to obtain the relevant information. Waist circumference (WC) and blood pressure (BP) measurements were recorded. Fasting plasma glucose (FPG), high density lipoprotein (HDL), and triacylglycerols were analyzed by the enzymatic colorimetric assay using semi-automated analyzer (Teco Diagnostics TC-3300). International Diabetic Federation guideline for Asians was used to identify MS. RESULTS: Sample response rate was 95.3% and of them, 43.8% (n = 224) was male. The prevalence of central obesity (WC for male >=90 cm, female >=80 cm) was 23.9%. Raised FPG (>=100 mg/dL, or previously diagnosed diabetes mellitus), hypertriacylglycerolemia (>=150 mg/dl), low level of HDL cholesterol (<40 mg/dL in males, <50 mg/dL in females), and raised BP (systolic BP >=130 or diastolic BP >=85 mmHg or previously diagnosed hypertension) were found in 23.9%, 25%, 79.3%, and 36.6% of the participants. The prevalence of MS was 15.8% (95% confidence interval [CI]: 12.8-19.3) and it was 17.4% in males and 14.6% in females. Participants living in the urban area had a higher prevalence of MS when compared with participants in a rural area (P = 0.015). Older age (P < 0.001) was a risk factor for development of MS. Smoking (P = 0.005) was a risk factor for the development of MS. Participants having sedentary, moderately active, and highly active lifestyle had the prevalence of MS 20.6% (95% CI: 13.2-29.7), 14.7% (95% CI: 10.6-19.5), and 14.7% (95% CI: 9.3-21.6), respectively (P = 0.247). CONCLUSION: Older age, urban living, and smoking carry a higher risk for development of MS among Jaffna Tamil community. PMID- 26425480 TI - Association of low educational status with microvascular complications in type 2 diabetes: Jaipur diabetes registry-1. AB - OBJECTIVE: To determine the association of educational status (ES), as a marker of socioeconomic status, with the prevalence of microvascular complications in diabetes. METHODS: Successive patients (n = 1214) presenting to our centre were evaluated for sociodemographic, anthropometric, clinical, and therapeutic variables. Subjects were classified according to ES into Group 1 (illiterate, 216); Group 2 (=25 kg/m(2) 64.0%, abdominal obesity 63.4%, hypertension 67.5%, high fat diet 14.5%, low fruits/vegetables 31.8%, low fibre intake 60.0%, high salt diet 16.9%, physical inactivity 27.5%, coronary, or cerebrovascular disease 3.0%, and microvascular disease (peripheral, ocular or renal) in 20.7%. Microvascular disease was significantly greater in illiterate (25.9%) and low (23.6%) compared to middle (15.0%) and high (14.7%) ES groups (P < 0.05). Age- and sex-adjusted logistic regression analysis revealed that in illiterate and low ES groups respectively, prevalence of smoking/tobacco use (odds ratio 3.84, confidence intervals 2.09-7.05 and 2.15, 1.36-3.41); low fruit/vegetable (2.51, 1.53-4.14 and 1.99, 1.30-3.04) and low fibre intake (4.02, 2.50-6.45 and 1.78, 1.23-2.59) was greater compared to high ES. Poor diabetes control (HbA1c >8.0%) was significantly greater in illiterate (38.0%), low (46.0%) and middle (41.0%) compared to high (31.5%) ES subjects (P < 0.05). CONCLUSIONS: There is a greater prevalence of the microvascular disease in illiterate and low ES diabetes patients in India. This is associated with the higher prevalence of smoking/tobacco use, poor quality diet and sub-optimal diabetes control. PMID- 26425481 TI - Clinical profile of diabetic ketoacidosis in tertiary care hospital of Eastern Nepal. AB - INTRODUCTION: Diabetes ketoacidoisis (DKA) is characterized by hyperketonaemia, metabolic acidosis, and hyperglycemia. AIMS: The aim of this study was to describe the demographic profile, clinical characterstics of patients admitted with diabetic ketoacidosis in BPKIHS, medical ward. SETTINGS AND DESIGN: The hospital based descriptive study. MATERIALS AND METHODS: We took all the patients admitted with a diagnosis of diabetic ketoacidosis (DKA) as defined ADA 2006 consensus statement in medical ward from January 2010 to December 2010. The statistical operations was done through Manufactured by IBM Corp. RESULTS: Only sixteen patients (7 type 1 and 9 type 2DM) were with DKA. When compared to the 16 subjects with type 1 DM, the type 2 were older (56.8 s 25.7 years) and had a significantly higher PH levels (7.11 s 7.28 P = 0.04). The mean body mass index was 20.5+/-2.44 in both Type 1 and type 2 DM. Four were on diet control and Insulin respectively. Five were on oral hypoglycemic agents (OHA) and three on both (insulin and OHA). Infection was most common precipitating factor (56.25%) followed by poor drug compliance (37.5%) and first presentation (6.25%). CONCLUSIONS: We found majority of patients were type 2 DM. Metabolic acidosis has significant association in both type of diabetic. We found infection was the most common precipitating factor for DKA. PMID- 26425482 TI - The making of an endocrinologist in India: Life and times at Institute of Post Graduate Medical Education and Research Calcutta. AB - Endocrinology is relatively one of the newer super-specialties of internal medicine. Following higher secondary schooling, it takes anywhere between 13 and 18 years to become a super-specialist in India, which holds true for endocrinology also. This article intends to highlight the life and the journey of making an endocrinologist in India, through personal experiences, focusing on Institute of Post Graduate Medical Education and Research (IPGMER) Calcutta, the largest super-specialty teaching hospital and research institute of Eastern India. In general, there is lack of adequate exposure to endocrinology during the Bachelor of Medicine, Bachelor of Surgery and MD Internal Medicine Training in India. Pre-Doctorate of Medicine (DM) senior residency goes a long way in developing an orientation for endocrinology. Endocrinology DM entrance examinations are usually a rigorous intimidating affair. Endocrinology training at IPGMER was a heady mix of managing huge number of patients with diverse endocrinopathies, laboratory work, academic presentations, and clinical research. The support and back up provided by the entire faculty enhanced the learning process. As I look back, the 3 years of DM residency flew by like the wink of the eye. The journey of endocrinology is the journey of a lifetime. PMID- 26425483 TI - Fasts, feasts, and festivals in diabetes: Glycemic management during Parsi rituals. AB - The article is one in the series of articles related to glycaemic management in festivals across all religions in India. The article discusses issues in glycaemic management among Parsi culture, which represent a small but ever important group of Indian population. PMID- 26425484 TI - Hemoglobin E disease and glycosylated hemoglobin. AB - Glycosylated hemoglobin (HbA1C) is a routinely measured parameter to monitor long term glycemic control in people with diabetes mellitus. The presence of hemoglobin (Hb) variants can affect the accuracy of HbA1C methods. Hb E variant is the most common Hb variant in South-east Asia and North-east India. In the presence of Hb E, HbA1C may not be detectable by ion-exchange chromatography (high-pressure liquid chromatography), but may be estimated by immunoassay technique and boronate affinity chromatography. However, the result may be underestimated when correlated with plasma glucose and serum fructosamine levels. Clinicians should be aware of this limitation of HbA1C estimation in patients with Hb E and other Hb variants. PMID- 26425485 TI - High-mix insulins. AB - Premix insulins are commonly used insulin preparations, which are available in varying ratios of different molecules. These drugs contain one short- or rapid acting, and one intermediate- or long-acting insulin. High-mix insulins are mixtures of insulins that contain 50% or more than 50% of short-acting insulin. This review describes the clinical pharmacology of high-mix insulins, including data from randomized controlled trials. It suggests various ways, in which high mix insulin can be used, including once daily, twice daily, thrice daily, hetero mix, and reverse regimes. The authors provide a rational framework to help diabetes care professionals, identify indications for pragmatic high-mix use. PMID- 26425486 TI - The resolution of anemia after curative parathyroidectomy is sustained even after a decade. PMID- 26425487 TI - Endocrine Society of India Fun Research Workshop 2015: The participants perspective. PMID- 26425488 TI - Endocrinology training in India: A student's perspective. PMID- 26425489 TI - Mid-Ventricular Variant of Dobutamine-Induced Stress Cardiomyopathy. AB - INTRODUCTION: Dobutamine stress testing is a commonly used modality in detecting and estimating the prognosis in coronary artery disease (CAD). Although it is well tolerated by most patients, adverse events have been reported. Rarely, transient wall motion abnormalities can occur in the absence of obstructive CAD to suggest stress cardiomyopathy. CASE PRESENTATION: We report a 48-year-old female with intermittent chest pain. Her physical exam, cardiac enzymes and transthoracic echocardiogram were unremarkable. She underwent dobutamine stress echocardiogram to rule out obstructive CAD. After 40 micrograms (mcg)/kg/minute and 0.5 mg atropine, she complained of intense chest pain and became hypertensive. Stress echocardiogram demonstrated mid-anterior and mid-septal hypokinesis. Emergent coronary angiogram demonstrated normal coronaries. Left ventricular angiogram in the right anterior oblique projection revealed mid ventricular ballooning during systole with apical and basal hypercontractility. Patient demonstrated excellent recovery with expectant management. CONCLUSIONS: The mechanism of mid-variant of Dobutamine-induced stress cardiomyopathy remains unclear. We think that multiple mechanisms are involved and this risk should be considered in patients with comorbid psychiatric conditions and with use of centrally acting stimulants. PMID- 26425490 TI - Community Priority Index: Utility, Applicability and Validation for Priority Setting in Community-Based Participatory Research. AB - BACKGROUND: Providing practitioners with an intuitive measure for priority setting that can be combined with diverse data collection methods is a necessary step to foster accountability of the decision-making process in community settings. Yet, there is a lack of easy-to-use, but methodologically robust measures, that can be feasibly implemented for reliable decision-making in community settings. To address this important gap in community based participatory research (CBPR), the purpose of this study was to demonstrate the utility, applicability, and validation of a community priority index in a community-based participatory research setting. DESIGN AND METHODS: Mixed-method study that combined focus groups findings, nominal group technique with six key informants, and the generation of a Community Priority Index (CPI) that integrated community importance, changeability, and target populations. Bootstrapping and simulation were performed for validation. RESULTS: For pregnant mothers, the top three highly important and highly changeable priorities were: stress (CPI=0.85; 95%CI: 0.70, 1.00), lack of affection (CPI=0.87; 95%CI: 0.69, 1.00), and nutritional issues (CPI=0.78; 95%CI: 0.48, 1.00). For non-pregnant women, top priorities were: low health literacy (CPI=0.87; 95%CI: 0.69, 1.00), low educational attainment (CPI=0.78; 95%CI: 0.48, 1.00), and lack of self-esteem (CPI=0.72; 95%CI: 0.44, 1.00). For children and adolescents, the top three priorities were: obesity (CPI=0.88; 95%CI: 0.69, 1.00), low self-esteem (CPI=0.81; 95%CI: 0.69, 0.94), and negative attitudes toward education (CPI=0.75; 95%CI: 0.50, 0.94). CONCLUSIONS: This study demonstrates the applicability of the CPI as a simple and intuitive measure for priority setting in CBPR. Significance for public healthCommunity-based participatory research (CBPR) has been credited to be a promising approach for the reduction of health disparities and as an effective way to create sustainable community outcomes. Priority setting is an essential decision-making step in community-based participatory research. Issue prioritization must be driven not just by the importance of the issue, but also what realistically can be changed with available funds. However, there is little guidance on how to approach priority setting with objective and subjective measures while implementing CBPR. This study depicts the invention of a Community Priority Index (CPI), which can be used to prioritize community health issues by combining subjective and objective markers into a single measure. The CPI shown in this study represents a viable systematic approach to improve the objectivity and reliability of community-based decision-making. PMID- 26425492 TI - Knowledge and Behavioural Factors Associated with Gender Gap in Acquiring HIV Among Youth in Uganda. AB - BACKGROUND: The increasing prevalence of HIV in Uganda during the last decade (7.5% in 2004-05 to 8.3% in 2011 among women and 5.0% in 2004-05 to 6.1% among men in 2011 of 15 to 49 years) clearly shows that women are disproportionately affected by HIV epidemic. Hence, we assessed the prevalence of HIV and focused on differences in risky sexual behaviour and knowledge of HIV among Ugandan youth. DESIGN AND METHODS: Uganda AIDS Indicator Survey 2011 data was used. The total samples of men and women (15 to 24 years), interviewed and tested for HIV, were 3450 and 4504 respectively. The analysis of risky sexual behaviour was based on 1941 men and 3127 women who had ever had sex and were tested for HIV. Pearson's Chi-square test and multivariate logistic regression analysis were used. RESULTS: Findings showed that young women were almost two times more vulnerable than young men in acquiring HIV (OR=1.762, P<0.001). Women who had first sex under age 15 (7.3%), had more than 2 sexual partners (9.2%) and did not use condom during last sex (6.4%) were more HIV-positive. Higher risk was found among women (6.3%) than men (2.2%). Significantly (P<0.01) less percentage (81.3%) of women as compared to men (83.8%) perceived that the probability of HIV transmission may be reduced by correct and consistent use of the condom during sex. CONCLUSIONS: Hence, there is an urgent need for effective strategies and programmes to raise awareness on sexual health and risky behaviour, particularly targeting the youth, which will reduce the gender gap in risky sexual behaviour and new transmission of HIV in Uganda. Significance for public healthThe present study represents the evidence of a recent increase in HIV infection in Uganda from the latest round of AIDs indicator survey. This manuscript describes how young women (15-24 years-old) are disproportionately HIV-infected compared to young men in Uganda. They are more vulnerable to HIV than young men. Moreover, it is also observed that young women are at greater risk of acquiring HIV because of their risky sexual behaviour and inappropriate knowledge of HIV transmission. Some educational programmes, growing gender equity in HIV/AIDS activities and services, dropping violence and coercion, addressing male norms and behaviours, improving women's legal protection, and rising women's access to income and productive resources can be very effective in minimising the vulnerability of young women to HIV/AIDS. PMID- 26425491 TI - Diabetic Peripheral Neuropathy and its Determinants among Patients Attending a Tertiary Health Care Centre in Mangalore, India. AB - BACKGROUND: The burden of diabetes mellitus (DM) is on the rise especially in developing countries like India. Due to its chronic nature DM tends to cause many debilitating complications and diabetic peripheral neuropathy (DPN) is one of them. The aim of this study is to determine the prevalence of DPN among patients attending a tertiary care hospital and to identify the determinants associated with it. DESIGN AND METHODS: A cross sectional study was conducted in Government Wenlock Hospital, Mangalore (India), during January-February 2014. A total of 208 patients with >5 year duration of DM were asked to respond to the patient history version of Michigan Neuropathy Screening Instrument (MNSI) and examinations were conducted after obtaining consent from them. The statistical analysis was done in terms of descriptive statistics and association between variables was tested using logistic regression test. RESULTS: The prevalence of DPN using the MNSI history version and MNSI examination were found to be 18.3% and 32.2% respectively. The major determinants associated with DPN were found to be male gender (OR: 2.7, CI: 1.4-5.1, P=0.001), smoking (OR: 5.8, CI: 1.9-17.3, P=0.001) and age >40 years (OR: 2.7, CI: 1.2-5.8, P=0.011). CONCLUSIONS: The burden of undetected DPN was found to be higher among diabetics, with an especially higher prevalence among males, smokers and those with long standing diabetes mellitus. Interventions in the form of early detection through routine screening, smoking cessation and regular follow up examinations would go a long way in reducing the burden of disability among diabetics and improve their quality of life significantly. Significance for public healthThe findings of the current research hold importance since diabetes is one of the leading causes of morbidity and mortality across the world. Due to its chronic nature and effects of hyperglycaemia, diabetes tends to be associated with many comorbidities, like peripheral neuropathy, nephropathy, retinopathy etc. The presence of diabetic peripheral neuropathy leads to a reduced quality of life among diabetic patients due to the trauma and consequent gangrenes andamputation. The concept of secondary prevention can be applied to the prevention of diabetic peripheral neuropathy using easy to apply screening tools and thus help in early diagnosis and treatment to reduce the burden of this debilitating illness. PMID- 26425493 TI - Investigation on the Trace Elemental Profile of Sewage Workers in Kolkata, an Indian Megacity. AB - BACKGROUND: Environmental pollution has become a global health risk. Exposure to pollutants at the work place, i.e. occupational exposure, is one of the areas that need immediate attention. The civic drainage workers are exposed to pollutants present in the wastewater they handle and most of them are toxic heavy metals. Exposure to such pollutants may be a health hazard, since it can lead to the imbalance in nutrient elements status. DESIGN AND METHODS: In the present study, profiling of trace elements in the blood of drainage worker population from an Indian megacity, Kolkata, was carried out by energy dispersive x-ray fluorescence (EDXRF) and compared with the control group population of the same area. RESULTS: The elements detected by EDXRF spectrometry include P, S, Cl, K, Fe, Cu, Zn, Se, Br, and Rb. By using ANOVA with 5% significance level, we observed significant alterations in the trace elements status, iron over loading, selenium deficiency, and in Cu-Zn ratio. Gender specific variations within the same population were also observed. CONCLUSIONS: The results indicate that the drainage workers have altered elemental profile in comparison to that of control population. Significance for public healthEnvironmental pollution is a global health risk and awareness among sewage workers is growing very slowly in many developing countries. Due to this fact, workers are often exposed to different pollutants which are responsible for several health complications. Imbalances in the presence of trace elements in blood are a symptom of different health status and could also indicate new health perspectives for the future. In the present scenario, this paper is essential since this kind of analysis has not been done yet, especially regarding the health status of sewage workers. We hope this initial study will be a starting point for future investigations. PMID- 26425494 TI - Predicting Malawian Women's Intention to Adhere to Antiretroviral Therapy. AB - BACKGROUND: With the increase in scaling up of antiretroviral therapy (ART), knowledge of the need for adherence to ART is pivotal for successful treatment outcomes. DESIGN AND METHODS: A cross-sectional study was carried out between October and December 2013. We administered theory of planned behaviour (TPB) and adherence questionnaires to 358 women aged 18-49 years, from a rural and urban ART-clinics in southern Malawi. Hierarchical linear regression models were used to predict intentions to adhere to ART. RESULTS: Regression models show that attitude (beta=0.47), subjective norm (beta=0.31) and perceived behavioural control (beta=0.12) explain 55% of the variance in intentions to adhere to ART. The relationship between both food insecurity and perceived side effects with intentions to adhere to ART is mediated by attitude, subjective norm, and perceived behavioural control. Household (r=0.20) and individual (r=0.21) food insecurity were positively and significantly correlated with perceived behavioural control. Household food insecurity had a negative correlation with perceived side effects (r=-0.11). Perceived side effects were positively correlated with attitude (r=0.25). There was no statistically significant relationship between intentions to adhere to ART in the future and one month self report of past month adherence. These interactions suggest that attitude predicted adherence only when food insecurity is high or perception of side effects is strong. CONCLUSIONS: This study shows that modification might be needed when using TPB constructs in resource constraint environments. Significance for public healthThe knowledge of the rates of adherence to antiretroviral therapy (ART) could be used to evaluate planning and project, which could lead to better outcomes predicted by treatment efficacy data. In addition, knowledge of adherence behaviour could help the development of interventions focusing on collaboration between healthcare providers and Malawian government to provide food support for patients on ART. The interventions could also focus on providing better counselling support to improve beliefs regarding control over taking the medication and perceived versus real side effects. It is relevant for public health professors to understand factors influencing women's ART adherence, in order to create interventions that are appropriate for increasing ART adherence, which may lead to improved outcomes among women with HIV living in endemic regions with limited treatment access. PMID- 26425495 TI - Physician Gender and Lifestyle Counselling to Prevent Cardiovascular Disease: A Nationwide Representative Study. AB - BACKGROUND: Primary care physicians (PCPs) have a key role in the prevention of cardiovascular diseases (CVD). However, it is not clear whether lifestyle counselling behaviour differs between female and male PCPs. Nonetheless, this information might be helpful to develop need-based advanced training for female and male PCPs. Therefore, our aim was to identify potential gender differences in the implementation of health promotion and the prevention of CVD in primary care. DESIGN AND METHODS: In a Germany-wide survey called the ASP-kardio Study, we collected data from 4074 PCPs (40% female; from October 2011 to March 2012). We compared the provision of prevention measures, the attitude towards counselling, and the potential barriers in counselling among female and male German PCPs. We used chi(2) tests, Mann-Whitney U tests, and logistic regression analysis. RESULTS: We found differences in all of the above-mentioned aspects. Female PCPs were less likely to perceive barriers than male and more likely to ask patients about lifestyle, for example, nutrition (OR=1.62, P<=0.001). Additionally, female PCPs were more likely to feel well prepared (84.2% vs. 76.0%, P<=0.001) and successful (75.6% vs. 68.0%, P<=0.001). Male PCPs were more likely to mention barriers in daily practice that hinder lifestyle counselling. CONCLUSIONS: Overall, both female and male PCPs had a positive attitude towards lifestyle counselling. Nevertheless, in view of the barriers that they indicated, incentives such as better reimbursement may help output-oriented PCPs to translate their positive attitude into action. Moreover, awareness of gender differences may help PCPs to acquire the specific advanced training that they need for effective lifestyle counselling in CVD. Significance for public healthLifestyle counselling is an important instrument to reduce the burden of cardiovascular disease. Here, primary care physicians (PCPs) play an important role as health advisors. Our study was able to identify deficits in the health promotion behaviour of PCPs. Because of the gender differences revealed in our study, male PCPs in particular should be sensitized to the importance and the potentials of prevention and health promotion. Overcoming the barriers of prevention and health promotion identified by the PCPs may be an important starting point. If, for instance, PCPs were better financially compensated for offering lifestyle counselling, which was rated as the most important barrier, it is conceivable that more PCPs would start to incorporate such measures into their daily routine. Additionally, a stronger focus on prevention and health promotion during advanced training programs for PCPs could increase the use of lifestyle counselling. PMID- 26425496 TI - From Disappointment to Holistic Ideals: A Qualitative Study on Motives and Experiences of Using Complementary and Alternative Medicine in Sweden. AB - BACKGROUND: Recent studies indicate increased use of complementary and alternative medicine (CAM) in western societies, to ameliorate health problems. Even if there is substantial research on general patterns of use, there is limited knowledge on individual motives. This study contributes to a qualitative understanding of experiences of choosing and using CAM. DESIGN AND METHODS: This study consists of in-depth interviews with 10 CAM users in Sweden. The participants represent different backgrounds and experiences of using CAM. The interviews have been analysed in accordance with content analysis. RESULTS: In analysing experiences of choosing and using CAM four main themes were identified: frustration and critique, values and ideology, individual responsibility, and combining treatments. In general, the participants were highly reflexive on issues concerning their health. They highlighted their own role and responsibility, combined a variety of treatments, and continuously dealt with questions on risks, even if they had relatively different approaches to if and when to use CAM. The results also show that motives may change over time. Even if initial choices were closely related to frustration and critique of conventional treatments (for example, by perceiving conventional health care as limited, not receiving proper diagnoses, or being critical to conventional drugs) was long term use motivated by ideological characteristics of CAM (such as holistic and individualized treatments, and extensive interaction with practitioners). CONCLUSIONS: Four main themes, concerning experiences of choosing and using CAM were identified. This study also supports the idea that initial motives for choosing CAM may differ from those explaining long-term use. Significance for public healthRecent studies indicate increased use of complementary and alternative medicine (CAM), both in general western populations and specific patient groups. Well-documented motives for choosing CAM are related to disappointment and failure of conventional health care. In addition, there are findings that demonstrate that certain basic values (such as individualism and holistic orientations) are related to the use of CAM. A better understanding of individual motives behind people's choice of CAM, and how this is related to their perception of the health care system, is important for policy makers and health care professionals alike. This study contributes to a qualitative understanding of experiences of choosing and using CAM and how motives may change over time. It also contributes with knowledge on how users combine CAM with conventional health care and deal with risks. PMID- 26425497 TI - The Relationship of Built Environment to Health-Related Behaviors and Health Outcomes in Elderly Community Residents in a Middle Income Country. AB - BACKGROUND: Few studies have examined the impact of the built environment (BE) on health behaviours and health outcomes in middle income countries. This study examines associations between self-assessed characteristics of the home and neighbourhood environment and health-related behaviours and health outcomes in an elderly population in Brazil. DESIGN AND METHODS: In a community sample of 6963 community dwellers 60 years old and older living in the state of Rio Grande do Sul, Brazil, associations between self-reported BE conditions and health behaviours and health outcomes were assessed using a structured questionnaire. Multivariate analysis was conducted to investigate these associations while accounting for other relevant characteristics. RESULTS: We found significant positive associations between adverse BE conditions and pulmonary, urinary conditions, gastrointestinal, problems, headache and depression. There were mixed associations between adverse BE conditions and musculoskeletal and sensory conditions, inverse associations with metabolic disorders. and no associations with dermatologic problems and cancer. After accounting for health related behaviours, results suggest a modest association between adverse BE conditions and hypertension, with no significant associations with other indicators of cardiovascular conditions (heart problems, stroke, varicose veins). CONCLUSIONS: The findings in this study suggest links between adverse conditions in the BE and health related behaviours in the hypothesized direction. Associations with the health conditions examined here are mixed. We find the strongest evidence for effects of adverse BE conditions for pulmonary and infectious conditions. Significant associations between the adverse BE indicators and health outcomes persist after accounting for health related behaviours, suggesting that BE conditions are linked to health pathways above and beyond the health related behaviours assessed in this study. Significance for public healthThe health outcomes for which we found most consistent evidence of associations with the built environment index (BEI) included respiratory conditions (bronchitis, pneumonia), urinary and renal conditions, gastrointestinal problems, headache, visual impairment and stroke. These health outcomes in the elderly may reflect exposures in the household environment associated with inadequate housing, such as mold, dust and damp. They may also be influenced by poor sanitary conditions, reflected in the absence of indoor plumbing and inadequate waste disposal facilities. Poor vision, headache and depression may all be associated with chronic exposure to poverty and stress, for which the measures of the household and neighborhood environmental conditions used in the BEI may be indicators. Assuring that the elderly in Brazil have access to adequate housing located in neighborhoods with access to basic sanitary conditions, water and lighting, will be increasingly important as the average age of Brazilians continues to increase, and increasing proportions of the population experience the adverse health effects associated with these conditions. PMID- 26425498 TI - A Stakeholder-Based System Dynamics Model of Return-to-Work: A Research Protocol. AB - BACKGROUND: Returning to work following a job-related injury or illness can be a complex process, influenced by a range of interrelated personal, psychosocial, and organizational components. System dynamics modelling (SDM) takes a sociotechnical systems perspective to view return-to-work (RTW) as a system made up of multiple feedback relationships between influential components. DESIGN AND METHODS: To build the RTW SDM, a mixed-method approach will be used. The first stage, that has already been completed, involved creating a baseline model using key informant interviews. Second, in two manufacturing companies, stakeholder based models will be developed through interviews and focus groups with senior management, frontline workers, and frontline supervisors. Participants will be asked about the RTW process in general and more targeted questions regarding influential components. Participants will also be led through a reference mode exercise where they will be asked to estimate the direction, shape and magnitude of relationships between influential components. Data will be entered into the software program Vensim that provides a platform for visualizing system-structure and simulating the effects of adapting components. Finally, preliminary model validity testing will be conducted to provide insights on model generalizability and sensitivity. EXPECTED IMPACT OF THE STUDY FOR PUBLIC HEALTH: The proposed methodology will create a SDM of the RTW process using feedback relationships of influential components. It will also provide an important simulation tool to understand system behaviour that underlies complex RTW cases, and examine anticipated and unanticipated consequences of disability management policies. Significance for public healthWhile the incidence of occupational injuries and illnesses has declined over the past two decades, the proportion resulting in sickness absence has actually increased. Implementing strategies to address sickness absences and promote return-to-work (RTW) can significantly benefit physical and mental health, and work outcomes like worker engagement, job satisfaction and job strain. As a key social determinant of health, participation in paid work can also ensure that work-disabled individuals generate income necessary for access to housing, education, food, and social services that also benefit health. Improving RTW outcomes can also have significant societal benefits such as a reduction in workers compensation costs, increased economic activity and less burden on social assistance programs. Despite its benefits, returning to work after injury or illness is not a straightforward process and can be complicated by the individual, psychosocial, organizational and regulatory components that influence a disabled person's ability to resume work activities. PMID- 26425499 TI - Medically Assisted Procreation and Fast-Moving Developments in Science and Law: Ethical and Legal Issues in Heterologous Procreation in Italy. AB - Significance for public healthContinual scientific progress is making new applications available, with significant medical, ethical, legal and social implications, not only for the persons directly concerned. In the area of medically assisted procreation, the use of heterologous techniques is able to overcome problems of sterility or infertility for those requesting access to methods of this kind. On the other hand, legislation is required to regulate the many correlated issues, also with regard to other parties such as ova or sperm donors and the offspring resulting from the use of these techniques: the protection of the health of the offspring; the management of laboratory results obtained during donor selection tests; the protection of confidentiality; the donor-child traceability; the number of donations; and individuals' rights to be fully informed about their biological origins are just some of the questions confirming that the implications of new procreation techniques are not restricted merely to the couples who access them. PMID- 26425500 TI - Barriers and Facilitators to Palliative Care of Patients with Chronic Heart Failure in Germany: A Study Protocol. AB - BACKGROUND: Despite its high prevalence, similar symptoms and symptom burden, people suffering from chronic heart failure receive less palliative care than patients with malignant diseases. Internationally, numerous barriers to palliative care of patients with chronic heart failure are known, however, there are no credible data regarding barriers and facilitators to palliative care of people suffering from chronic heart failure available for Germany. DESIGN AND METHODS: Tripartite study. First part of this study evaluates health care providers' (physicians and nurses) perceived barriers and facilitators to palliative care of patients with chronic heart failure using a qualitative approach. At least 18 persons will be interviewed. In the second part, based on the results of part one, a questionnaire about barriers and facilitators to palliative care of patients with chronic heart failure will be designed and applied to at least 150 physicians and nurses. In the last part a classic Delphi method will be used to develop specific measures to improve the palliative care for chronic heart failure patients. EXPECTED IMPACT FOR PUBLIC HEALTH: The results of this study will help to understand why patients with heart failure are seldom referred to palliative care and will provide solutions to overcome these barriers. Developed solutions will be the first step to improve palliative care in patients with heart failure in Germany. In addition, the results will help health care providers in other countries to take action to improve palliative care situations for heart failure patients. Significance for public healthPatients with chronic heart failure suffer from similar symptoms and symptom burden than patients with malignant diseases. However, palliative care differs between these groups in a quantitative and qualitative way. This study will help to understand why patients with chronic heart failure receive less palliative care than patients with malignant disease. In addition, measures to overcome barriers and to promote facilitators of palliative care in patients with chronic heart failure will be developed. These recommendations could provide a basis for quality improvement projects or studies aiming at improving symptoms and symptom burden of heart failure patients. The recommended measures could also be used to reduce caregiver burden. PMID- 26425502 TI - Food and Human Behaviour: Consumption, Waste and Sustainability. PMID- 26425503 TI - Endoscopic ultrasonography-guided portal injection chemotherapy for hepatic metastases. AB - INTRODUCTION: We hypothesized that endoscopic ultrasonography-guided portal injection chemotherapy (EPIC) using irinotecan-loaded microbeads may achieve increased intrahepatic concentrations, while decreasing systemic exposure. This may achieve enhanced efficacy for the treatment of diffuse liver metastases, while decreasing systemic toxicities. MATERIALS AND METHODS: In eight anesthetized 35 kg pigs, EPIC was performed transgastrically using the linear array echoendoscope and a 22 g fine-needle aspiration. In four animals, irinotecan (100 mg) loaded onto 75-150 micron liquid chromatography (LC) beads was injected. In four animals, saline was injected into the portal vein and unloaded irinotecan (100 mg) was injected into the jugular vein. Plasma (every 15 min), and at 1 h bone marrow, liver and skeletal muscle samples were obtained. Irinotecan and SN-38 (active metabolite) concentrations were assayed by LC/mass spectrometry. RESULTS: The procedure was performed safely in all eight animals. Compared with systemic administration, EPIC resulted in almost twice the hepatic concentration of irinotecan (6242 vs. 3692 ng/g) and half the systemic concentrations in plasma (1092 vs. 2762 ng/mL), bone marrow (815 vs. 1703 ng/mL) and skeletal muscle (521 vs. 1058 ng/g). SN-38 levels were lower with EPIC (liver: 166 vs. 681 ng/g; plasma: 1.8 vs. 2.4 ng/mL; bone marrow: 0.9 vs. 1.4 ng/mL; muscle 4.6 vs. 9.2 ng/g). Liver histology showed the beads within small portal venules. CONCLUSIONS: EPIC using irinotecan-loaded microbeads can enhance hepatic exposure to irinotecan, while decreasing systemic concentrations. SN-38 levels were lower with EPIC indicating that a substantial portion of the irinotecan was still loaded onto beads. The microbeads may act as a reservoir resulting in prolonged hepatic drug exposure. PMID- 26425501 TI - H1N1 Influenza Pandemic in Italy Revisited: Has the Willingness to Get Vaccinated Suffered in the Long Run? AB - BACKGROUND: The aim of the study is to assess the long-term secondary effects of personal experience with the H1N1 pandemic of 2009/2010 and the perception of the institutional reaction to it on Italians' willingness to get vaccinated in case of a novel influenza pandemic. DESIGN AND METHODS: We conducted 140 face-to-face interviews in the Registry Office of the Municipality of Milan, Italy, from October to December 2012. RESULTS: Willingness to get vaccinated during a novel influenza pandemic was best predicted by having been vaccinated against the seasonal flu in the past (OR=5.18; 95%CI: 1.40 to 19.13) and fear of losing one's life in case of an infection with H1N1 (OR=4.09; 95%CI: 1.68 to 9.97). It was unaffected by the assessment of institutional performance. CONCLUSIONS: The findings of this study do not point to long-term secondary effects of the institutional handling of the H1N1 pandemic. The results highlight the fact that behavioural intention is not the same as behaviour, and that the former cannot simply be taken as an indicator of the latter. Significance for public healthWhereas influenza pandemics occurred rather rarely in the last centuries, their frequency can be expected to increase in the future due to the enhanced globalisation and still raising importance of air travelling. Recent examples (Ebola, H1N1, SARS, avian influenza) demonstrate that initially local disease outbreaks often become worldwide health threats of international concern. National and international health authorities are consequently urged to present preparedness plans on how to manage such health crises. However, their success highly depends on their acceptance by the public. To ensure the public compliance with recommended actions, effective communication is needed. Since communication is most successful when it meets the needs of the target audience, a full understanding of the audience is crucial. This study can help public health experts to better understand the variables determining people's willingness to get vaccinated during influenza pandemic, in terms of behavioural and perceptual variables. This knowledge enables them to correctly address the public's concerns when having to communicate during the next outbreak of pandemic influenza. PMID- 26425504 TI - Characteristics of vessels wall, myocardium and epicardial fat in patients with heart failure with preserved ejection fraction with and without metabolic syndrome. AB - BACKGROUND: The structure of the vessels wall and myocardium is an independent predictor of cardiovascular events among patients with heart failure (HF). There is a data that metabolic syndrome (MS) accelerates the progression of structural and functional disorders of the vessel wall and myocardium. Epicardial fat thickness was shown to correlates with visceral fat thickness and to be an independent predictor of cardiovascular diseases. OBJECTIVES: To investigate the characteristics of vessels wall, myocardium and epicardial fat in patients with HF with preserved ejection fraction (HF-PEF) with and without MS. MATERIALS AND METHODS: A total of 59 patients with HF-PEF were included. First group - patients without MS (n = 29), second group - patients with MS (n = 30). Following characteristics were evaluated: Arterial stiffness (stiffness index [SI]), reflection index (RI), augmentation index (Alp). The function of big vessels was evaluated by phase shift (PS), of the small vessels - by the occlusion index (OI). Investigations were performed by the device "angioscan." Sizes of the heart chambers and the thickness of the myocardium wall and epicardial fat thickness were evaluated echocardiographically. RESULTS: Among the patients from both groups significant changes of the vessels wall and myocardial structure were found. SI at the first group was 8.26 +/- 1.72 m/s, at the second group - 9.62 +/ 5.61 m/s (non-significant, P = 0.25). RI at the first group was 39.79 +/- 18.12%, at the second - 31.43 +/- 17.23% (non-significant, P = 0.086). Alp at the first group was 23.47 +/- 14.69%, at the second - 11.16 +/- 17.14% (significant, P = 0.011). PS at the first group was 8.05 +/- 7.72 ms, at the second - 5.34 +/- 4.4 ms (non-significant, P = 0.36). OI at the first group was 1.34 +/- 0.58%, at the second - 1.46 +/- 0.54% (non-significant, P = 0.46). Significant intergroup differences were found in the interventricular septum thickness: 10.3 +/- 1.2 mm at the first group and 11.3 +/- 1.6 mm at the second (P = 0.01); left ventricle wall thickness: 10.1 +/- 1.1 mm at the first group and 11.3 +/- 1.6 mm - at the second (P = 0.001); left ventricle myocardium mass: 157.75 +/- 46.11 g at the first group and 201.19 +/- 58.82 g - at the second (P = 0.005). The epicardial fat thickness was 14.8 +/- 1.8 mm at the first group and 36.7 +/- 1.7 mm - at the second group (significant, P = 0.001). CONCLUSION: Among patients with hypertension and HF-PEF with and without MS significant changes in the structure of the vessel wall and myocardium were found. The presence of MS lead to more pronounced myocardial remodeling. The epicardial fat thickness is significantly higher among patients MS. PMID- 26425505 TI - Metallic stent in the endoscopic treatment of pancreatic fluid collections. AB - BACKGROUND AND AIMS: The endoscopic treatment of pancreatic fluid collections (PFCs) has become the preferred first-line approach. Fully covered self expandable metal stents (FCSEMS) were considered as an alternative to multiple double pigtail stents. The aim of this study was to evaluate the results of the endosonography guided drainage (EUS-GD) of PFCs with FCEMS. MATERIALS AND METHODS: A total of 33 consecutive patients were included. Cystogastrostomy and cystoduodenostomy were created with a linear echoendoscope under endosonographic and fluoroscopic control. Procedures were performed in a standard way of, puncture with a 19 gauge needle, bougie dilation and insertion of FCSEMS. RESULTS: A total of 33 patients (mean age 52 years, 21 men, range: 18-77 years), were included. PFCs were 22 non-infected symptomatic pseudocyst and 11 walled-off necrosis or abscess. EUS-GD was successful in 30 (90.9%) patients. Stent insertion failed in one patient. Two patients needed surgery. Complications were observed in 8 (25%) patients (stent dislocation in 3, perforation in 2, bleeding in 2 and pneumoperitoneum in 1 patient). Procedure related mortality was not seen. The mean cyst size was 11.3 cm (5-22). FCSEMS were successful in the treatment of pseudocysts (after 1 month mean cyst size is 6.2 cm, range: 0-15 cm, with 54.8% decrement rate). During a mean follow-up of 15 months complete resolution was 66.6% (20 patients) and recurrence due to stent malfunction was 10%. All these cases were submitted to a new session of endoscopic drainage. CONCLUSIONS: EUS-GD, FCSEMS insertion provides an effective, minimally invasive, and safe approach in the management of PFCs. PMID- 26425506 TI - Endosonographic features of unicentric Castleman Disease. AB - BACKGROUND: Castleman disease (CD) is a rare lymphoproliferative disorder most frequently occurring in the mediastinum. Peripancreatic forms are less frequent. Few cases of endoscopic ultrasonography-fine-needle aspiration (EUS-FNA) findings of this lesion have been reported, where no real-time tissue elastography (RTTE) has been described in the literature to our knowledge. METHODS: We describe the endosonographic, elastographic, cytologic and immunocytochemistry findings in two cases of unicentric CD of the hyaline vascular variant. RESULTS: Two females, aged 41 and 34 year were referred to our hospital for further EUS evaluation of a peripancreatic mass found incidentally on computed tomography. EUS examination revealed around, well-demarcated, uniformly hypoechoic mass measuring 52 and 23 mm respectively, with smaller adjacent hypoechoic lymph nodes. Doppler examination revealed intense peripheral vascularity, together with prominent penetrating feeding vessels entering a distinct hilum. RTTE revealed a relatively homogenous soft elastographic pattern. EUS-FNA provided smears with clusters of lymphocytes in a hemorrhagic background. Cell block preparation showed immature lymphocytes surrounding lymphocyte-poor centers with vascular proliferation. Immunohistochemical staining of the cell block sections showed CD45-leukocyte common antigen, CD20, CD23, CD79a, Bcl-2 and CD5 positivity in small lymphocytes. Cytology was suggestive of non-Hodgkin's lymphoma. Surgical excision was performed in both cases and histopathology was consistent with CD of the hyaline vascular type. CONCLUSION: The echo features of a solitary hypoechoic homogenous well-demarcated mass with prominent vasculature and increased elasticity should raise the possibility of unicentric CD. EUS-FNA usually cannot make a definitive distinction from certain kinds of lymphoma. PMID- 26425508 TI - Liver abscess as a first manifestation of colonic tumor. AB - INTRODUCTION: Male, 72-year-old, morbidly obese, diabetic, admitted for abdominal pain, prostration and fever that started last 3 days. Abdominal ultrasound and abdominal computed tomography scan showed liver injury in the transition of V and VI segments measuring 8.4 cm. Due to the possibility of liver abscess, initiate empirical antibiotic therapy with ampicillin and sulbactam and metronidazole and performed ultrasound-guided percutaneous drainage of liver injury. Negative for malignant cells, with the presence of leukocytes and negative culture. After 2 weeks of treatment, take control image without changing the lesion dimension. New percutaneous drainage with the same results. We opted for performing endoscopic ultrasound (EUS) with fine-needle aspiration (FNA). FNA pathology: Moderately differentiated adenocarcinoma. Immunohistochemistry suggestive of metastasis of the lower gastrointestinal tract. Due this finding, realized colonoscopy, which revealed a vegetating lesion with central ulceration, bleeding, filling almost the entire cecum. Patient was referred for surgical resection of the bowel tumor, which showed moderately differentiated adenocarcinoma infiltrating vegetative and possibly originated from villous adenoma with high-grade dysplasia. DISCUSSION: The finding of metastatic liver abscess of colonic neoplasia is not common. In most cases, the material from the abscess drainage allows the diagnosis, but in this case, even after two ultrasound-guided percutaneous drainage was not obtained conclusive bacteriological or histopathological. Opted for new puncture through EUS, which allowed definitive diagnosis of the condition. CONCLUSION: Metastatic colon neoplasm should be considered in cases of differential diagnosis of liver abscess. PMID- 26425507 TI - Endoscopic ultrasonography-fine-needle aspiration of solid pancreatic lesions: A prospective, randomized, single-blinded, comparative study using the 22 Gauge EchoTip(r) ProCoreTM HD (A) and the 22 Gauge EchoTip(r) Ultra HD (B) endoscopic ultrasound needles. AB - INTRODUCTION: In order to improve diagnostic efficacy of pancreatic masses, a new endoscopic ultrasonography-fine-needle aspiration (EUS-FNA) needle was developed (EchoTip((r)) ProCoreTM HD). Very few studies have compared these two needles and none could avoid selection biases. AIMS: The present study intends to compare the results obtained by these two needles when performing EUS-FNA of pancreatic solid lesions. PATIENTS AND METHODS: This was a prospective, single-blinded, randomized, controlled trial conducted at a tertiary care referral center. Thirty consecutive patients with solid pancreatic lesions were enrolled to have EUS-FNA performed with two different types of needle. All patients were punctured with the two needles and were randomized regarding the order of the needle to be used. RESULTS: After collecting data, we used the Fisher's exact test in order to compare the results P <0.05. There was no difference (P = 1.0) regarding introduction, exposition and removal of the needles. The values of sensitivity (92% for needles A and B), specificity (100% * 80%), positive predictive value (100% * 95.8%), negative predictive value (71.4% * 66.6%) and accuracy (93.3% for needle A and 90% for needle B) were not statistically different. The duration of the procedure was the only analyzed parameter, in which we observed a difference between the needles. For needle A, the average time was 2 min 26 s (1 min 30 s-4 min 0 s) and for needle B the average time was 11 min 7 s (6 min 0 s-17 min 0 s). CONCLUSION: Even though, the 22 gauge EchoTip((r)) ProCoreTM HD and the 22 gauge EchoTip((r)) Ultra HD endoscopic ultrasound needles had similar overall results, the ProCoreTM needle allowed a much quicker procedure. PMID- 26425509 TI - Diagnosis of ganglionar tuberculosis by endoscopic ultrasonography. AB - INTRODUCTION: The endoscopic ultrasonography (EUS) is an endoscopic technique of proven clinical validity today, having a significant impact on the diagnosis and evaluation of several diseases with a low complication rate. The EUS-fine-needle aspiration (FNA) allows the evaluation of subepithelial lesions, extra-luminal lymph nodes or the gastrointestinal tract that are difficult to access by other methods with safe and high diagnostic accuracy. AIMS AND METHODS: In the case reported, the EUS-FNA was useful for the differential diagnosis with residual biliary microlithiasis and the diagnosis of non-oncologic pathology. RESULTS: Male, white, 35-year-old, human immunodeficiency virus and tuberculosis treatment for about 5 months presented with jaundice. No fever, weight loss or abdominal pain. Choluria and hipocholia. History of cholecystectomy for about 1 year due to cholelithiasis. Laboratory tests showed cholestatic jaundice (direct hyperbilirrubinemia). Abdominal ultrasound showed liver without particularities, without biliary dilatation or filling defects. Initially suspected hepatitis due tuberculosis drugs so, the treatment was suspended. After a week with no drugs, no improvement in jaundice was observed. In contrast, a progressive increase indirect bilirubin. EUS performed with identification of mass along the distal common bile duct near the duodenal papilla. FNA performed with the presence of lymphocytes and tuberculosis bacile positive. After, endoscopic retrograde cholangiopancreatography was performed with sphincterotomy and placement of endoprosthesis for biliary drainage. The tuberculosis drugs were restarted with the plan to complete. The jaundice was resoluted. The patient completed 9 months of treatment and abdominal tomography has not identified a mass in that place. CONCLUSION: The EUS-FNA was proven to be a useful tool for diagnosis of non oncologic pathologies like tuberculosis. PMID- 26425510 TI - Solid pancreatic lesions: The choice of fine-needle aspiration-needle to optimize the diagnosis. AB - INTRODUCTION: Endoscopic ultrasonography (EUS)-guided fine-needle aspiration (FNA) have a better accuracy for the detection of pancreatic tumors compared with others images modalities. We assessed if the image criteria of elastography and contrast harmonic echo-endoscopic ultrasound could help in choosing the appropriate FNA-needle in the evaluation of focal pancreatic mass in other to maximize the diagnostic yield. This study prospectively included all new patients with focal pancreatic masses referred to be examined by EUS from October to December/2013. A total of 21 patients performed EUS with sequentially elastography and intravenous injection of a second-generation contrast agent (2.4 mL of SonoVue, Braco International, The Netherlands). The lesions which appear hipovascular were assessed with 22 gauge or 25 gauge FNA-needles. The hipervascular masses were biopsied with 19 gauge needles. RESULTS: The topography of the lesions varied on 13 at the head, 4 at the body and 1 on the tail. The finding of a hypoenhanced mass was found in 57% (12/21 patients). Hyperenhanced was detected in 28% (6/21 patients). There were 14% (three patients) which the data were not recorded. The cytological diagnosis was achieved in 81% (17/21 patients) on the first biopsy. The others four patients have reached the diagnosis on the second examination. Of those four patients, in one was used the ProCore 25 gauge (lesion on the uncinatus process), and another one was used both 22 gauge and 25 gauge in the first examination. CONCLUSION: A characterization of the pancreatic lesions with elastography and contrast agents might be useful for clinical decision of which needle is better to improve biopsy quality and minimize EUS-FNA negatives results. PMID- 26425512 TI - Feedback is the best way to see. AB - A 60-year-old man with past history of acute mild pancreatitis (AP) in 1997 and 2005, recently with repeated attacks of AP 5 times in last 2 years. Repeated endoscopic ultrasonography (EUS) showed 20 mm cyst in pancreatic body with 5 mm nodule, main pancreatic duct (MPD) 4-6 mm, fine-needle aspiration malignant cell negative, mucin positive. Computed tomography and magnetic resonance imaging of branch duct intraductal papillary mucosal neoplasms with 10 mm branch duct. From 2011 to 2013, the cyst was without progression in size or character. Due to clinical course of repeated AP, endoscopic retrograde cholangiopancreatography was recommended. It revealed dilated MPD 5-7 mm and 15 mm * 13 mm cyst in pancreatic body. Distal pancreatectomy was indicated because of clinical course and "worrisome EUS features" - MPD size and intramural nodule. In terms of having feedback, endosonographer use to examine every resected specimen of pancreas in our hospital just after surgery. The resected body with "sand glass" appearance of the cyst of size 3 cm was totally different from what we saw previously. We rewinded the previous EUS documentation and made a new evaluation. EUS is unique method for pancreatic tumors, but only in combination with real image of specimen makes endosonographer to bow up. PMID- 26425511 TI - Vascular image in autoimmune pancreatitis by contrast-enhanced color-Doppler endoscopic ultrasonography: Comparison with pancreatic cancer. AB - INTRODUCTION: In autoimmune pancreatitis (AIP), veins of various sizes are highly affected by obliterative phlebitis without damage to arteries, in contrast, the involvement of both arteries and veins is observed in the mass of pancreatic cancer. A vascular image without blooming artifact in the pancreas is clearly observed in the directional eFLOW (Prosound alpha10, Aloca Co., Tokyo, Japan) color mode using contrast-enhanced color-Doppler endoscopic ultrasonography (CC EUS) despite perfusion of the contrast media. AIMS AND METHODS: The aim of this study was to compare the vascular structure of AIP with that of pancreatic cancer using CC-EUS. We evaluated the perfusion image and the vascular image of the mass in AIP patients (11) with an increase in serum IgG4 levels (477.3 +/- 314.2 IU/mL) and in pancreatic cancer patients (11) with elevated serum CA19-9 levels (49839.0 +/- 80061.6 mg/dl), on CC-EUS. Perfusion images were obtained at 20-30 s after injection of a contrast agent, Sonazoid (GE Healthcare AG, Oslo, Norway), by extended pure harmonic detection mode and were assessed as to homogeneity or heterogeneity (containing partial low echoic areas or multiple spotty low echoic areas) enhancement. The vascular image was assessed in the directional eFLOW color mode despite perfusion of the contrast media (40-50 s after injection of Sonazoid) as to the presence of a dendritic vessel network or only a few feeder vessels. The parameters for imaging were as follows: Mechanical index, 0.22-0.24; transmission frequency, 5.0 MHz; and receiving frequency, 5.0 MHz. The Chi-square test or Fisher's exact test was used for comparison of categorical data of the two groups when appropriate. This study was approved by the institutional review board of Sendai City Medical Center. All subjects gave informed consent. RESULTS: A homogenous pattern in perfusion imaging was seen in 73% of patients with AIP (8/11) and 55% of those with pancreatic cancer (6/11). The rates were not significantly different between the two groups (P = 0.33). In the other patients with a heterogenous pattern, multiple spotty low echoic areas were seen in 33% (1/3) and 80% (4/5) in each group, respectively. A dendritic vascular pattern in the eFLOW color mode was seen in 82% (9/11) of patients with AIP, but was not seen in any of patients with pancreatic cancer. The other patients with AIP (18%) and all patients with pancreatic cancer showed only a few feeder vessels in the mass on CC-EUS. CONCLUSION: The eFLOW color mode using Sonazoid may be useful for evaluating the vascular structure of AIP for differential diagnosis from pancreatic cancer. PMID- 26425513 TI - Short-term results after hepaticogastrostomy guided by echo-endoscopy: Monocentric retrospective study. AB - BACKGROUND: Biliary drainage guided by echo-endoscopy (EUS) is a recent technique but expanding more and more in addition of retrograde and percutaneous approaches. METHODS: Seventy-three hepaticogastrostomy (HG) were carried out from 2000 to 2013. After exclusion of patients included in a randomized prospective study, data from 60 patients were retrospectively analyzed in order to study the feasibility and early results of this technique. RESULTS: During the study period, 60 patients (woman = 32; median age = 64 years [38-93]) were treated by HG. This technique was choose in the event of impossibility to reach the papilla, a failure of endoscopic retrograde cholangiopancreatography or to achieve drainage of the left hepatic biliary ducts in 35%, 15% and 50%, respectively. The biliary stricture was neoplasic in 85%. Sixty-four procedures were carried out: The technical success rate was 94%. Eighteen patients presented one or more adverse effects (28%) including: Infection (n = 14), pneumoperitoneum (n = 7), choleperitoneum/bilioma (n = 8), hemorrhage (n = 2), other (n = 2). Seven stents migration occurred (11%). The average duration of hospitalization was 9 days (0 61j). Three related deaths occurred, due to severe infection. During the period of the study, several types of stent were placed during the first procedure: Plastic stent (n = 12), one covered or uncovered metallic stent (n = 9), association of one uncovered metallic stent and one fully covered stent (SIS, n = 27), or one half covered metallic stent (n = 16). The rate of complications was respectively 33% (n = 4), 56% (n = 5), 26% (n = 7) and 13% (n = 2) according to the type of stent used. Three successive periods can thus be individualized according to the type of biliary stent used and the use of the CO2 insufflator [Table 1]. [Table: see text]. CONCLUSIONS: Hepaticogastric anastomosis guided by echo-endoscopy is an effective, useful technique when the retrograde way is not possible or to drain selectively left intrahepatic biliary ducts. The morbidity rate is quite high but seems to decrease. PMID- 26425514 TI - Safety and efficacy of nitrous oxide for endoscopic ultrasound procedures that need irrigation. AB - OBJECTIVE: Echo-endoscopes are much stiffer and thicker than regular endoscopes. During the procedure of endoscopic ultrasound (EUS) procedure, water irrigation is a very useful for imaging but very dangerous if the patient receive the procedure under anesthesia without intubation. In this study, we evaluated the safety and effectiveness of nitrous oxide (N2O) (<=70%) for EUS. METHODS: Among 4230 patients who underwent EUS from December 2012 to December 2013, 347 out patients who need irrigation during the procedure were enrolled and divided into Group A. Group A (N2O sedation group, n = 162) and Group B (no sedative group, n = 185). For Group A, patients received N2O by inhalation during the procedure. The mixture rate of N2O and O2 was 45-65% and controlled by nurses according to individual effect. The cardiorespiratory functions, procedure duration, complications, and visual analog scale (VAS) of the patient and examiner satisfaction were compared. RESULTS: Both group had comparable diagnostic accuracy, but VAS of the patients who received N2O sedation was higher than that in Group B (7.5 vs. 4.5, P < 0.05) and the examiner procedural satisfaction ratings of Group A was also better than that of Group B (8.1 vs. 5.1, P < 0.05); Most patients in Group A reported willingness to reconsider N2O for a future EUS. No pulmonary aspiration occurred in this study. CONCLUSIONS: N2O for EUS is comfortable, safe and feasible, especially for the procedures that need irrigation. PMID- 26425515 TI - Interobserver concordance for endoscopic ultrasonography-guided fine-needle aspiration on-site cytopathology. AB - INTRODUCTION: Endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) is an accurate method of diagnosing and staging gastrointestinal and thoracic malignancy. A key issue in maximizing FNA accuracy is to ensure that an adequate specimen is obtained. On-site cytopathology increases the diagnostic yield of EUS FNA. However, this increases the time and costs. Physicians trained in EUS and in pathology are capable of interpreting cytologic adequacy from EUS-FNA specimens. Furthermore, on-site interpretation by the endoscopist could reduce cost and procedure duration. The learning curve of endossonographers in on-site cytopathology and how they could contribute in EUS-FNA accuracy increase is unknown. OBJECTIVE: To determine the interobserver concordance of on-site cytopathology interpretation of EUS-FNA specimens by comparing endosonographers trained in cytology with a physician cytopathologist. METHODS: A prospective blinded study comparing one endossonographer with one physician cytopathologist. The study was developed in the Santa Casa Medical School, Brazil from February to November 2012. Fifteen different cases of EUS-FNA were analysed, in a total of 50 slides. Each observer described the slides for the adequate or not of tissue sampling, and classified as benign, suspicious, malign or undefined. The analyses were then matched. RESULTS: We analyzed the concordance of 50 slides description made by the endossonographer and physician cytopathologist, according to enough material, cellular group identification and final diagnosis. Kappa (kappa) indexes were: Presence of material kappa = 0.480 (P < 0.001); presence of malignance kappa = 0.808 (P < 0.001); in subepithelial lesions kappa = 0.615 (P = 0.06); in pancreatic lesions kappa = 0.675 (P < 0.001); in mediastinal lesions kappa = 0.243 (P = 0.128). CONCLUSION: Our study showed that endosonographers and cytopathologists had good concordance in EUS-FNA specimens on-site cytopathology interpretation, except in mediastinal/pulmonary cases. PMID- 26425516 TI - Relevance of endoscopic ultrasound in the management of esophagus cancer therapy. AB - INTRODUCTION: The objective of this case series study by retrospective analysis was to determine the relevance of endoscopic ultrasound (EUS) in therapeutic decision esophageal cancer. MATERIAL AND METHODS: Using medical records of the Department of Endoscopy of Santa Casa de Sao Paulo, we have collected data from 16 patients, in 4 years, diagnosed of esophageal cancer, and presented in the form of clinical cases to a specialist surgeon in esophageal cancer and a clinical oncologist, for therapeutic evaluation before and after the outcome of EUS. RESULTS: Both of them choose non-resective and not curative methods (68.8% by surgeon vs. 87.5% oncologist) before EUS. The best treatment by the surgeon was chemotherapy and palliative radiotherapy associated (25%) and palliative endoscopic prostheses (25%), and by the oncologist, neoadjuvant chemotherapy and radiotherapy associated (56.2%). After EUS, the resective surgical treatment was the both choice in only 6.2% of cases, and the rest of 93.8%, non-resective. The surgeon choice was chemotherapy and palliative radiotherapy associated (44%), and oncologist choice was neoadjuvant chemotherapy and radiotherapy associated (44%). Analysis by the Chi-square method, comparing respective versus non-resective treatment, surgeon versus oncologist, with and without the EUS, obtained values of P = 0.39 and P = 0.46, respectively. The comparison between healing and non healing treatment had the same P value. Regarding the change in behavior (resective vs. non-resective), there was a change of approach by the surgeon in 25% of cases (P = 0.17) and the oncologist moved conduct in 6.25% of cases. Comparing the changing of behavior among experts, the P value was 0.33. Despite evidence of behavior change after the EUS, the statistical point of view, the P value had no significant relevance. The main factor involved is probably due to a reduced number of sample cases. However, this is a pilot study, and is needed other with a larger number of cases. CONCLUSION: The data obtained allow us to conclude that EUS proved to be an important test for the change in staging and therapeutic management of esophageal cancer. PMID- 26425517 TI - Influence of layer, size and organ of subepithelial lesions of upper gastrointestinal tract in outcomes of endoscopic ultrasound-guided fine-needle aspiration. AB - INTRODUCTION: The endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has emerged as a minimally invasive and safe method for material procurement in the differential diagnosis of subepithelial lesions (SEL) of upper gastrointestinal tract (UGT), especially in suspicious lesions of gastrointestinal stromal tumors (GIST). There are few studies discussing the factors that influence the EUS-FNA in the diagnosis of SEL. AIM: To establish possible associations between lesion size, layer and organ of origin with the outcome of EUS-FNA in patients with SELs of UGT. METHODS: A retrospective analysis using data of patients referred to French-Brazilian Center of EUS of endoscopy Department of Santa Casa de Sao Paulo Hospital, with previous endoscopic diagnosis of SEL, which underwent EUS-FNA from May 2006 to August 2011. RESULTS: A total of 222 patients were submitted to EUS. 15 with extrinsic compressions and 207 with SEL. Of these, 89 underwent to EUS-FNA. Ninety-two SEL were diagnosed on EUS and punctured. The EUS-FNA was positive in 58.7%. In lesions measuring 2-3 cm and >3 cm, the EUS-FNA was positive in 80% and 72%, respectively (P < 0.001). CONCLUSION: The size of SELs was the only variable that influenced the outcome of EUS-FNA. Best results are achieved in lesions larger than 2 cm. PMID- 26425518 TI - Imaging of peritoneal ligament by endoscopic ultrasound. AB - INTRODUCTION: Double layered peritoneal folds, variously named as ligaments, omenta and mesenteries connect the intraperitoneal organs to the abdominal wall. Some of these ligaments contain blood vessels and lymph nodes while others are avascular. The peritoneal folds not only act as conduits for the passage of blood vessels from the retroperitoneum to reach intraperitoneal organs, but also provide a pathway for the spread of disease processes. It is difficult to identify these normal peritoneal folds at imaging. Computed tomography is the most common imaging modality used to detect diseases of the peritoneum to fully delineate peritoneal anatomy and the extent of disease. The endoscopic ultrasound (EUS) can be used to image peritoneal ligaments with the advantage of lack of ionizing radiation and lower cost. Though EUS is being increasingly used both for diagnostic and interventional purposes in the abdomen, it has not been used to assess the peritoneal ligaments till now. METHODS: We did this study in 50 patients using linear echo endoscope to delineate various peritoneal ligaments. The technique of evaluation of ligament has been described in this review. CONCLUSION: The peritoneal ligaments can be delineated with accuracy by EUS. PMID- 26425519 TI - To evaluate the role of novel fully covered self-expanding metal stent for endoscopic drainage of infected pancreatic pseudocyst. AB - INTRODUCTION: Endoscopic ultrasonography-guided transgastric drainage of pancreatic pseudocyst (PPC) is the mainstay of treatment. Drainage can be achieved either by plastic stents or fully covered self-expandable metal stent (FCSEMS). Plastic stents have small lumen diameter, which may limit drainage and may necessitate re-intervention. FCSEMS are easier to deploy and preclude the need to place multiple plastic stents. OBJECTIVE: To evaluate the role of novel FCSEMS for endoscopic drainage of infected PPC. METHODS: PATIENTS: 10 patients with single symptomatic pseudocyst in proximity to the stomach or duodenum and fever were treated. Pseudocyst drainage was done per protocol. Repeat computed tomography scan after 72 h. Nasocystic drain removed after 3-5 days. PATIENTS were followed-up at every 2 week interval. Stent was removed after complete disappearance of pseudocyst confirmed on imaging. Early (7 days) and late (>7 days) complications were noted and managed accordingly. RESULTS: Technical success and clinical success achieved in all. Early complication: 1/10 (pneumoperitoneum). No late complications observed. Stent were removed without complication after 6-7 week follow-up period ranges from 6 to 8 months. CONCLUSION: Use of FCSEMS for pseudocyst drainage is technically feasible and safe. PMID- 26425520 TI - A rare cause of hemosuccus pancreaticus diagnosed with endoscopic ultrasound. AB - INTRODUCTION: Hemosuccus pancreaticus (HP), hemorrhage from the papilla of Vater through the pancreatic duct (PD), is a rare cause of upper gastrointestinal bleeding. It may be caused by chronic pancreatitis, pseudoaneurism and pancreatic tumors. Only 2% of HP involves the hepatic arteries. Endoscopic ultrasound (EUS) may not only visualize the presence of HP, previously seen on computed tomography/magnetic resonance imaging (CT/MRI), but also reveal additional pathology. CASE REPORT: A 62-year-old man was admitted with severe intermittent gastrointestinal bleeding. He underwent gastroscopy, colonoscopy and capsule endoscopy without sign of bleeding. The patient had no previous history of pancreatitis or infection. On CT and MRI scan with angiography, an aneurism of the common hepatic artery (CHA) was found, with a dilatation of the main PD toward the tail of the pancreas, but no apparent source of bleeding. EUS was then performed, and could show a partial thrombosed aneurysm of a hepatica with a diameter of 5 cm. In addition, a narrow fistula between the hepatic artery and PD could be identified using power Doppler. The patient was subsequently operated, which revealed a thrombosed arteriosclerotic aneurysm in the CHA with fistula to the PD. CONCLUSION: To the best of our knowledge, this is the second reported case of a severe gastrointestinal bleeding due to a fistula between the CHA and PD. The use of EUS in diagnosing this rare condition has not been reported before, but seems feasible. PMID- 26425521 TI - Endoscopic ultrasonography-guided bi-lateral biliary drainage: A case series study. AB - INTRODUCTION: Biliary obstruction is preferentially managed by endoscopic retrograde cholangiopancreatography (ERCP). However, after ERCP failed, alternatives include percutaneous transhepatic drainage, surgery and more recently, endoscopic ultrasonography (EUS)-guided hepaticogastrostomy. The limitation of this technique is that the drainage is restricted to the left side. The aim of this study is to describe a new method of drainage of both hepatic ductal systems by hepaticogastrostomy in patients with hilar obstruction. RESULTS: Nine prospectively patients were included, all with hilar obstruction (metastasis of a pancreatic adenocarcinoma n = 4, cholangiocarcinoma n = 1, gallbladder cancer n = 2 and metastasis from a pancreatic neuroendocrine tumor n = 2). A total of four patients had previously Whipple surgery and the others five had duodenal involvement by the tumor. The topography of the stenosis varied from Bismuth type 2 (n = 7) and hilar infiltration in the others two. All of them were submitted a three-step drainage. The first one consisted in a transgastric EUS guided puncture of the left-side bile duct with a 19 gauge needle, insertion of a 0.0035 inch guide wire which was positioned at the right biliary tree crossing the bile bifurcation. After a dilatation with 6 Fr cystotome, a non-covered self expandable metal stent was placed communicating the right and left biliary ducts. Finally, a second stent, partially covered, was inserted at the left biliary duct, with the distal part inside the previously stent and the proximal edge positioned at the stomach. Successful drainage was observed in seven patients, two of them presented abdominal pain during the first 72 h. One patient developed sepsis and death 7 days after the procedure and the other one had drainage failure. Jaundice was reduced significatively in seven patients and a chemotherapy was started in 6/7 patients. CONCLUSION: This pilot study shows the feasibility of this new technique to drain the right biliary duct in patients with hilar obstruction, with few major complications rates. PMID- 26425522 TI - Endoscopic ultrasound guided confocal microscopy: Atlas of cystic pancreatic lesions. PMID- 26425523 TI - The observation of the formation of splenic artery pseudoaneurysms. AB - Pseudoaneurysms are infrequent, potentially fatal angiopathies. Because of a high mortality rate, pseudoaneurysms must be handled urgently, regardless of the size and symptoms at presentation. We report a case of chronic pancreatitis and a pseudocyst of the pancreas complicated with a splenic artery pseudoaneurysm. Endoscopic ultrasonography (EUS) was chosen as the device to observe the forming of a splenic artery pseudoaneurysm, which could provide timely, minimally invasive, precise lesion information. Early diagnosis and urgent measure are important when there is a high probability of splenic artery psedoaneurysm. In recent years, EUS has been extensively studied in the detection, diagnosis and treatment of pancreatic disease. The color-Doppler flow imaging (CDFI) can dynamically reflect the peripheral blood flow signal. EUS with a CDFI function can play an important role in the initial detection of pseudoaneurysms, especially when complicated with chronic pancreatitis with or without a pseudocyst. We recommend that EUS should be carried out if a pseudoaneurysm near the digestive tract is considered, then effective and timely measures can produce a favorable prognosis. PMID- 26425524 TI - Epicardial fat as the predictor for essential hypertension and early vascular damage in patients with metabolic syndrome and non-alcoholic fatty liver disease. AB - Increased visceral adiposity is a new marker of metabolic syndrome, early vascular damage, non-alcoholic fatty liver disease and also is associated with essential hypertension. Epicardial adipose tissue is a very important factor in the pathogenesis of coronary atherosclerosis. Hypertension is one of the most important risk factor for the development of coronary heart disease, stroke, congestive heart failure, and end-stage renal disease. Epicardial fat is an active endocrine organ producing a wide range of active molecules, which can affect vessels dramatically. PMID- 26425525 TI - Endoscopic ultrasound-guided needle confocal laser endomicroscopy in pancreatic masses. AB - INTRODUCTION: Endoscopic ultrasound (EUS) is an established tool in diagnosing pancreatic masses and enables guided fine-needle aspiration (FNA). Confocal laser endomicroscopy (CLE) has allowed in vivo microscopic analysis during on-going endoscopy. Recently, CLE has gone beyond luminal indications with the development of a new microprobe (nCLE). The aim of this case series was to study the feasibility of EUS-guided nCLE and to correlate the findings with microscopy. METHODS: A total of 25 patients with pancreatic masses were included. During the procedure, an nCLE fiber preloaded into a 19 gauge FNA needle was advanced into the lesion under EUS guidance. Fluorescein was administered intravenously and imaging performed. Afterwards EUS-FNA was performed in the same location. Safety and feasibility were evaluated and CLE structures were registered and correlated to the standard hematoxylin and eosin cytopathology specimens. Moreover, additional topical acriflavine-enhanced ex vivo examinations on fresh pancreatic specimens were conducted. RESULTS: EUS-guided nCLE procedures were accomplished in all patients. No adverse advents were registered. Furthermore, it was feasible to do nCLE inside pathological lesions and relatively easy to visualize organ specific tissue. Despite selecting predefined structures the diagnostic value was limited mainly due to the missing ability to elucidate the cell nuclei, In the ex vivo examinations, where acriflavine was administered topically on excised pancreatic tissue, the nuclei were clearly visualized, thus increasing the diagnostic value. CONCLUSION: EUS-guided nCLE procedures on focal pancreatic masses are feasible and safe, but the diagnostic value seems limited. Thus, further studies using different contrast agents are required to optimize the diagnostic accuracy. PMID- 26425526 TI - Gastric cancer-can we rely only on endoscopic ultrasonography? AB - BACKGROUND: Endoscopic ultrasonography (EUS) is considered to be the most precise method for locoregional staging, was commonly used for differentiating mucosal lesions from submucosal lesions. By contrast, computed tomography (CT) was used to detect the presence of distant metastasis. Both are valuable tools for the pre operative evaluation of gastric cancer. With the introduction of new therapeutic options and the recent improvements in CT technology, further evaluation of the diagnostic accuracy of EUS and multidetector CT (MDCT) is needed. AIM: The present study was conducted to compare the staging accuracy of EUS with that of MDCT in series of patients and to evaluate their usefulness in association with the clinicopathological factors. PATIENTS AND METHODS: In total, 277 patients with gastric lesions who underwent EUS and CT, hospitalized at Department of Gastroenterology and Hepatology, Clinical Center, University of Sarajevo. The results from the pre-operative EUS and MDCT were compared with the post-operative pathological findings. RESULTS: Among the 277 patients, the overall accuracy of EUS and MDCT for T staging was 74.7% and 76.9%, respectively. Among the 141 patients with visualized primary lesions on MDCT, the overall accuracy of EUS and MDCT for T staging was 61.7% and 63.8%, respectively. The overall accuracy for N staging was 66% and 62.8%, respectively. The performance of EUS and MDCT for large lesions and lesions at the cardia and angle had significantly lower accuracy than that of other groups. For EUS, the early gastric cancer lesions with ulcerative changes had significantly lower accuracy than those without ulcerative changes. CONCLUSIONS: For the pre-operative assessment of individual T and N staging in patients with gastric cancer, the accuracy of MDCT was close to that of EUS. Both EUS and MDCT are useful complementary modalities for the locoregional staging of gastric cancer. PMID- 26425527 TI - Utility of endoscopic ultrasonography in the evaluation of dilated common bile duct of undetermined etiology. AB - INTRODUCTION: Occasionally, common bile duct (CBD) dilatation is discovered while working up patients for various causes. Not infrequently, the usual imaging modalities fail to identify the cause and endoscopic ultrasonography (EUS) becomes necessary. The aim of this study is to assess the value of EUS in identifying the cause of CBD dilatation undiagnosed by transabdominal ultrasonography. PATIENTS AND METHODS: During 1 year, 152 consecutive patients who were referred for evaluation of dilated CBD (diameter >=7 mm) discovered incidentally during transabdominal ultrasonography were included. Final diagnoses were confirmed by endoscopic retrograde cholangiopancreatography, EUS-guided fine needle aspiration, surgical exploration, or clinical follow-up of at least 10 months. RESULTS: One hundred and fifty two patients (54% female) with dilated CBD were included. Mean age of patients was 60 +/- 17 years. The final diagnoses was choledocholithiasis in 32 (21.1%), passed CBD stone in 35 (23%), opium-induced CBD dilation in 14 (9.2%), post-cholecystectomy states in 20 (13.1%), ampullary neoplasia in 15 (15.8%), cholangiocarcinoma in 14 (9.2%) and pancreatic head cancer in 9 (5.9%). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EUS for patients with abnormal EUS was 89.5%, 100.0%, 100.0%, 91.2%, and 90.9%, respectively. CONCLUSION: After diagnosis of CBD dilation by transabdominal ultrasonography, EUS may be a reasonable next choice for determining the etiology of dilated CBD. PMID- 26425528 TI - Comparison of elastography methods in patients with pancreatic masses. AB - INTRODUCTION: Endoscopic ultrasonography (EUS) quantitative elastography methods are developed for non-invasive differentiation of pancreatic masses. AIMS: First: To evaluate the diagnostic value of strain ratio (SR) and hue histogram (HH) in patients with pancreatic masses and to determine the cut-off value between pancreatic cancer and focal pancreatitis using a pancreatic tissue close to the mass as a reference area. Second: To calculate new variable HH ratio (HHR) in an attempt to improve sensitivity, specificity and accuracy of the method. METHODS: In a prospective single center study, 149 patients were examined: 105 with the pancreatic masses and 44 controls using Pentax EUS linear probes in combination with Hitachi platforms. SR and HH were automatically calculated by machine software. Finally, two groups were formed: Pancreatic cancer group (58 patients) and focal pancreatitis group (47 patients). All statistical analysis has been made in SPSS 14.0 (SPSS Inc., Chicago, USA). CONCLUSION: Statistical analysis in our study showed that SR with a cut-off value of 7.59 reaches 100% sensitivity and 95% specificity with overall accuracy of 97% (confidence intervals [CI]: 92 97%) in detection of pancreatic cancer. Statistical analysis also showed that HH with a cut-off value of >=86 reaches 100% sensitivity and just 45% specificity with overall accuracy of 66% (CI: 61-66%) in detection of pancreatic cancer. New variable HHR with cut-off >=1.153 was slightly better with 98% sensitivity and 50% specificity, with overall accuracy of 69% (CI: 63-70%). SR showed significantly higher specificity compared with HH and HHR. More HH studies on Hitachi platforms are needed. PMID- 26425529 TI - The observation indicator induced from gastrointestinal stromal tumor under long term monitoring by endoscopic ultrasonography. AB - INTRODUCTION: We report a case of low-risk stomach gastrointestinal stromal tumor (GIST) which has been under a long-term observation, obtaining from this experience knowledge useful in determining the treatment formula for this disease. RESULTS: During the observation for 6 years, no such change as ulcer formation was observed in the appearance of the tumor. The measurement of tumor diameter, however, showed gradual growth of maximum tumor diameter from 2.7 to 5.0 cm. When the changes in the diameter of tumor during this period is plotted, taking the timeon the horizontal axis and the tumor diameter on the vertical axis, the growth of the tumor can be approximated with a secondary function, making it possible to estimate the developmental period of the GIST concerned from the approximated secondary function. Thus, the developmental period in this case was estimated to go back 19 years before the time when it was discovered for the 1(st) time. Further, it was considered that the coefficient of the secondary function represents the rate of tumor growth, and that comparison with this coefficient contributed to the evaluation of malignancy stage of the GIST concerned. CONCLUSION: The growth curve predicting the growth of tumor could be depicted by measuring the diameter of the tumor in GIST twice or more at an interval of 6-12 months with EUS, and it was thought that this was utilizable for determining treatment formula for GISTs. PMID- 26425530 TI - The analysis of endoscopic ultrasonographic finding for esophageal subepithelial lesion. AB - INTRODUCTION: The number of endoscopic ultrasonography (EUS) for esophageal subepithelial lesion (SEL) is on the increase recently. We retrospectively investigated the 230 patients who underwent EUS for esophageal SEL from July 2010 to June 2013. We analyzed EUS finding and assumptive diagnosis. RESULTS: Among 230 enrolled patients, subepithelial tumor (SET) was observed in 189 (82.2%) patients. Mean size of SET was 8.5 +/- 5.0 mm and mean distance from incisor tooth to lesion was 29.2 +/- 6.7 cm. The most common origin wall layer of the SET was muscularis mucosa (59.4%), followed by submucosa (15.8%) and muscularis propria (21.1%). 3.7% of SET was indetermined. In the analysis of primary assumptive diagnosis, 70.5% was leiomyoma, 16.8% was granular cell tumor, 6.8% was gastrointestinal stromal tumor, 1.6% was cyst and 2.1% was vascular ectasia. The tissue sample by biopsy was checked in only 14.2% (27 cases) and the result was mostly (81.5%) non-specific inflammation. 21 cases (9.1%) of 230 patients revealed extrinsic compression, 61.9% was compressed by vessel, 33.3% was due to spine and one case (4.8%) was bronchus. 20 patients (8.7%) was normal without SEL. 107 patients (46.5%) of enrolled 230 patients repeatedly underwent EUS at least twice but, 79.4% (85/107) of SET was no change in size or shape. CONCLUSIONS: Esophageal SEL is mostly benign nature and misdiagnosed as extrinsic compression or normal variation easily. Thus, meticulous inspection is essential to distinguish SET and extrinsic compression. EUS is a good modality to examine esophageal SEL but, EUS is limited to accurate diagnosis of SET. The tissue acquisition for accurate diagnosis of SET is an important issue. PMID- 26425531 TI - Evaluation of opium effect on pancreatobiliary system in opium addicted patients by endoscopic ultrasonography. AB - INTRODUCTION: Pancreatobiliary abnormalities in patients with opium addiction have not been widely evaluated by endoscopic ultrasonography before. MATERIALS AND METHODS: Patients without any pancreatobiliary disease or symptom during 10 months were enrolled in this study. Common bile duct (CBD), pancreatic duct (PD) and portal vein (PV) diameters, gallbladder wall thickness and surface area of the papilla and abnormalities were evaluated in both groups by endosonography. RESULTS: In total, 199 patients were evaluated. 36 (18.1%) cases were addicted to opium. Mean age of the patients was 56.0 +/- 14.2 years. Opium users had a statistically significant higher (all P < 0.001) mean diameters of distal CBD (4.6 +/- 1.9 vs. 3.1 +/- 1.0 mm), middle part of CBD (7.5 +/- 3.1 vs. 4.6 +/- 1.6 mm), PD in head (3.3 +/- 1.3 vs. 2.3 +/- 0.7 mm) and PV (10.3 +/- 2.3 vs. 8.9 +/- 2.1 mm). However, the difference in the diameters of PD in the body of pancreas and gallbladder wall thickness did not reach statistical significance. The size of the papilla as measured by the surface area of the papilla of Vater was also significantly larger in opium users (40.6 +/- 17.1 vs. 29.9 +/- 13.5, P < 0.001). CONCLUSION: Opium addicted persons have larger diameters of CBD, PV and a larger surface area of the papilla of Vater. Dilated PD only in the head of the pancreas might be an important clue to differentiate opium-induced CBD dilation from periampullary tumors and chronic pancreatitis. The clinical significance of these findings warrants further investigation. PMID- 26425532 TI - Role of high resolution ultrasonography/endoscopic ultrasonography and elastography in predicting lymph node malignancy. AB - OBJECTIVE: To evaluate the role of high resolution ultrasonography (US) and endoscopic ultrasonography (EUS)-elastography in predicting malignant lymphadenopathy. METHODS: This prospective study included 88 patients who underwent EUS or US examination of different groups of lymph nodes (LNs). The classification as benign or malignant based on the real-time elastography pattern and the B-mode US/EUS images was compared to the final diagnosis obtained by EUS or US guided fine-needle aspiration cytology (FNAC), Tru-Cut biopsy or excisional biopsy and follow-up in benign lesions not indicated for biopsy for at least 12 months. RESULTS: Regarding the echogenicity, 98.3% of the benign LNs were hyperechoic, 1.7% were hypoechoic, while 89.7% of the malignant LNs were hypoechoic, 3.4% were heterogenous and 6.9% were hyperechoic. With cut-off value of 1.93, the sensitivity of longitudinal to transverse ratio was 73% and the specificity was 100%. Score 1 elastography had specificity of 100% in diagnosis of benign LNs, sensitivity was 76.3%, positive predictive value (PPV) was 100%, negative predictive value (NPV) was 84.7% while Score 2 had a sensitivity of 60%, specificity of 31.5%, PPV of 15.3%, NPV of 79.3%. Score 3 had a sensitivity of 70.2%, specificity of 100%, PPV of 13.8%, NPV of 100% in detecting malignancy while Score 4 had a sensitivity of 85.5%, specificity of 100%, PPV of 100%, NPV of 65.5%. CONCLUSION: Elastography is a promising diagnostic modality that may complement standard ultrasound and EUS and help guide FNAC during staging of LNs. PMID- 26425533 TI - Gastric mucosa-associated lymphoid tissue lymphoma associated with pancreatic non Hodgkin's lymphoma: A case report. AB - Mucosa-associated lymphoid tissue (MALT) lymphomas are extranodal lymphomas that arise from B lymphocytes located in the marginal zone of lymphoid follicles. Although, there is a substantial amount of lymphoid tissue in the gastrointestinal tract, MALT lymphomas usually arise in chronically inflamed sites that are normally devoid of lymphoid tissue. The best example is gastric MALT lymphoma that is almost always associated with Helicobacter pylori. Primary pancreatic lymphoma (PPL) is an extremely rare tumor (1% incidence) and is often confused with pancreatic adenocarcinoma. By suspecting PPL on clinical and imaging grounds, surgery and its associated complications can be avoided, since the mainstay of the treatment is non-surgical strategies including chemotherapy. We represent a case of a 45-year-old male presented with abdominal pain and vomiting. Upper endoscopy showed multiple gastric ulcers, biopsies revealed non specific inflammatory ulcers. The patient was given 4-weeks course of proton pump inhibitor with no improvement. After few months, he complained of severe abdominal pain relieved by leaning forward and associated with repeated vomiting. Upper endoscopy revealed multiple umbilicated gastric masses, 10-20 mm in diameter. Biopsies were taken, histopathology and immunohistochemistry revealed MALT lymphoma. Endoscopic ultrasonography was done to the patient and it showed a pancreatic head mass, fine-needle aspiration was done, histopathology and immunohistochemistry revealed PPL. The patient received chemotherapy for MALT lymphoma with near total relief of symptoms and disappearance of gastric and pancreatic masses. CONCLUSION: This is a rare case having MALT lymphoma associated with PPL. PMID- 26425534 TI - A case of gastric aberrant pancreas with bleeding and diagnosed by endoscopic ultrasonography. AB - Aberrant pancreas is used to describe ectopic pancreatic tissue lying outside its normal location with no anatomic or vascular connection to the pancreas proper. Patients with aberrant pancreas are usually asymptomatic, so aberrant pancreas are typically discovered incidentally during endoscopy, surgery, or autopsy. This time, we report a case of gastric aberrant pancreas bleeding was repeated and endoscopic hemostasis was difficult. A 22-year-old man was admitted to a hospital with a complaint of epigastric pain and melena. Upper gastrointestinal endoscopy and endoscopic ultrasonography (EUS) revealed a submucosal tumor with a bleeding ulcer at the anterior wall of the antrum in the stomach, and diagnosed it as an aberrant pancreas. It was hard to stop bleeding by in total 7 times endoscopic hemostasis and anemia was gradually progressed, so partial gastrectomy was performed. This gastric tumor measured 40 mm * 30 mm * 20 mm and had a severe ulcerative change. The pathological diagnosis was aberrant pancreas with Langerhans islet, acinous cells and excretory duct. (Heinrich type) Until December 2013 in Japan, 13 cases of gastric aberrant pancreas with bleeding have been reported and in these, a surgery was done in 11 cases. In gastric aberrant pancreas cases with ulcer formation like this case, endoscopic hemostasis is expected to be difficult, and surgery is necessary. Hence, early accurate diagnosis by EUS is a very important to decide better treatment plan. PMID- 26425536 TI - Dynamic control of pH in esophagus diseases treatment. AB - During complete medical checkup of proximal gastrointestinal tract, the esophagus pH measurement is an adventive procedure that requires probes usage, which is introduced through the endoscope biopsy channel. Such procedure cannot be used for everyday dynamic treatment control because of its invasiveness. The main aim of this article is to develop an effective everyday quality control of esophagus diseases non-traumatic antisecretory treatment. We solve the problem by measuring the air-ionic esophagus internal environment characteristics with the help of the air exhaled by the patient analysis. Initial examination is provided during endoscopic research in the period of patient's planned checkup. Esophagus air tests are get through biopsy channel and analyzed by computer air-ionic complex. The range of air-ionic concentration in the esophagus air content is 0.060-0.040 (60-40%) in electrical voltage 0.020-0.050 V, which corresponds to pH 5.0-7.0. The esophagus air content indexes, received from primary samples are used as gauging for air-ionic characteristics of air exhausted by patient. Hereafter, during the therapy course we study only air samples exhausted by the patient on a daily basis. Air-ionic esophageal pH - measurement is used during checkup and treatment of 42 patients with gastroesophageal reflux disease diagnose. Parallel usage of invasive esophageal pH determination method demonstrated complete results match. Thus, the proposed method is an advanced non-invasive diagnostic method, which allows to measure intra-esophagus pH indexes and provides probable assessment of antisecretory drugs treatment efficacy with an ability of therapeutic course operative correction. PMID- 26425535 TI - Comparison of capillary versus aspiration technique in endoscopic ultrasound guided fine-needle aspiration: A preliminary report. AB - INTRODUCTION: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is widely used to diagnose pancreatic malignancies. Different EUS-FNA techniques have been described to improve sample quality. Recently, a new technique, using capillarity, has been proposed. AIM: To assess the quality of cytological samples, comparing two different FNA techniques, in order to optimize tissue acquisition. METHODS: All consecutive patients with solid pancreatic lesions, requiring an EUS-FNA, were included in the study between July and September 2013. All procedures were done under deep sedation. FNA was performed using a 25 gauge needle, using both capillary and aspiration technique. Patients were randomized to undergo firstly one or the other technique. Samples were evaluated "on site" by expert cytotechnologist. An expert cytopathologist, blinded for the technique used, reviewed the slides, for final diagnosis and assessed sampling quality. Quality of samples was evaluated through the assessment of the amount of blood, cellularity, tumoral versus normal cells ratio and adequacy for final diagnosis. Data were analyzed with Student's t-test and Chi-square test, assuming a significant P value of 0.05. RESULTS: A total of 30 consecutive patients (19 M, mean age 67.8 years) with an EUS finding of pancreatic solid lesion were included in the study. Cytological final diagnosis was adenocarcinoma in 25/30 (83.3%) cases, neuroendocrine tumor 1/30 (3.3%), intraductal papillary mucosal neoplasms with high-grade dysplasia 2/30 (6.7%), gastrointestinal stromal tumor in 1/30 (3.3%) and negative for malignant cells 1/30 (3.3%). The difference between the overall blood amount score per technique was not statistically significant (P = 0.61) as well as the cellularity score (P = 0.08). In 13/30 patients (43%) the two techniques reported concordant T/N ratio. In 6/30 patients (20%) final diagnosis was achieved only by capillary obtained smears. In 1/30 patients (3.3%) the diagnosis was done with aspiration. In the remnant, the ratio between the two techniques was similar. Adequacy was reached in 24/30 (80%) with aspiration and 29/30 (97%) with capillary technique (P = 0.04). CONCLUSIONS: Aspiration and capillary sampling techniques provided similar results in cellularity and blood amount. However, adequacy rate was significantly superior in capillary technique. Furthermore, in 20% of cases, final diagnosis was achieved only with capillary samples. PMID- 26425537 TI - True and false splenic artery aneurysm on endoscopic ultrasonography: Two-case analysis. AB - INTRODUCTION: The etiology of true and false splenic artery aneurysm is different, but the differential X-ray contrast diagnosis could be difficult. Purpose - to detect endoscopic ultrasonography (EUS) diagnostic capability for false and true splenic artery aneurysm by considering two clinical cases: With suspected stomach and pancreatic lesions. MATERIALS AND METHODS: FIRST CASE: Patient, female, 50-year-old with suspected stomach lesion, complicated by gastric bleeding. Endoscopy - acute gastric ulcer. X-ray - submucosal gastric tumor. The patient was sent to the EUS with fine-needle aspiration. SECOND CASE: Patient, male, 73-year-old with suspected pancreatic neoplasm. Ultrasound - pancreatic cysts. Computed tomography (CT) - neoplasm of the pancreas body. Celiacography - splenic artery aneurysm. The patient was sent to the EUS to clarify the diagnosis. RESULTS: First patient EUS - anechoic rounded lesion with thick wall close to the stomach. Stomach wall layers were not differentiated above the lesion. Doppler - turbulent blood flow. EUS excluded submucosal lesion and proved the presence of aneurysm. CT confirmed the aneurysm. Post-operative histology - splenic artery pseudoaneurysm, destruction of the stomach wall and pancreatic parenchyma. Second patient EUS - ovoid solid-cystic lesion with thin hyperechoic "capsule." Doppler in cystic part - arterial blood flow. EUS suspected saccular splenic artery aneurysm with the neck and the residual lumen. Post-operative histology - true splenic artery aneurysm with thrombotic masses near the wall, pancreatic parenchyma was intact. CONCLUSION: EUS can reliably differentiate splenic artery aneurysm from gastric submucosal lesion and differentiate true and false aneurysm with high probability. PMID- 26425538 TI - Combined endoscopic ultrasonography and endobronchial ultrasound-fine-needle aspiration for evaluation of mediastinal lymph nodes. AB - OBJECTIVES: Endoscopic ultrasonography (EUS) and endobronchial ultrasound-fine needle aspiration (EBUS-FNA), is an accurate technique for evaluation of mediastinal lymph nodes (MLN) and stadification of lung cancer. The aims of the study are to evaluate the feasibility and the efficacy of the combined technique compared with mediastinoscopy for the diagnosis of MLN. DESIGN AND METHODS: All patients with suspected malignant MLN and/or lung lesion identified by positron emission tomography-computed tomography underwent combined EUS-EBUS-FNA. The combined procedure was performed in outpatients under general anesthesia for EUS and sedation by intravenous midazolam for EBUS when performed separately, using linear-array echoendoscopes. The MLN were punctured during the EUS and EBUS-FNA procedures with a 22 gauge needle. RESULTS: Thirty-four patients underwent consecutively EUS and EBUS-FNA between September 2011 and November 2013 (8 women, 26 men, mean age of 65.9 year, range: 51-83). Combined EUS-EBUS-FNA was performed in a single time procedure in 26 patients (mean time 50 min) and in two different times in eight patients (mean delay 3 days). Twenty-five malignant and 9 inflammatory lesions were diagnosed. Mediastinoscopy was performed in nine patients and confirmed in eight patients the initial combined EUS-EBUS-FNA diagnosis. The diagnosis was obtained in 91.2% with EUS-FNA, 70.6% with EBUS-FNA and 97% when combined procedure was performed. The overall sensitivity, specificity, positive and negative predictive values of EUS-EBUS-FNA for diagnosing malignancy were 96.5%, 100%, 100% and 90% respectively. No complications related to the procedure were observed. CONCLUSION: Combined EUS EBUS-FNA represents an accurate technique in the diagnosis of MLN, can be done in a single time procedure and has the advantage of being less invasive than mediastinoscopy. PMID- 26425539 TI - Endoscopic ultrasonography for intra-abdominal textiloma. AB - INTRODUCTION: The term textiloma is used to describe foreign body (swab) forgotten during surgery. We don't know any case of the description of endoscopic ultrasonography (EUS) for intra-abdominal textiloma. OBJECTIVES: To determine the EUS capabilities in the topical diagnosis of intra-abdominal textiloma. MATERIALS AND METHODS: Patient, female, 57-year-old was admitted to our hospital with post operative hernia. 10 months before the patient underwent surgery (laparotomy, splenectomy) in another hospital. For ethical reasons, we do not name that hospital. Intra-abdominal lesion has been accidentally revealed by computed tomography during the pre-operative examination prior to hernioplasty. Ultrasound unclear detected hyperechoic lesion with a dense acoustic shadow. The patient was sent to the EUS to clarify the diagnosis and to determine the topography of the lesion, fine-needle aspiration - if required. RESULTS: EUS revealed a hyperechoic corrugated border of the lesion with a dense acoustic shadow - between the gastric wall and the lower surface of the liver. Taking into account preceding surgery EUS suspected textiloma. The patient underwent hernioplasty and revision of the abdominal cavity. Textiloma has been revealed between the stomach and liver. CONCLUSION: EUS correctly diagnosed textiloma and accurately determined its location. PMID- 26425540 TI - Do Panic Symptoms Affect the Quality of Life and Add to the Disability in Patients with Bronchial Asthma? AB - Background. Anxiety and panic are known to be associated with bronchial asthma with variety of impact on clinical presentation, treatment outcome, comorbidities, quality of life, and functional disability in patients with asthma. This study aims to explore the pattern of panic symptoms, prevalence and severity of panic disorder (PD), quality of life, and disability in them. Methods. Sixty consecutive patients of bronchial asthma were interviewed using semistructured proforma, Panic and Agoraphobia scale, WHO Quality of life (QOL) BREF scale, and WHO disability schedule II (WHODAS II). Results. Though 60% of the participants had panic symptoms, only 46.7% had diagnosable panic attacks according to DSM IV TR diagnostic criteria and 33.3% had PD. Most common symptoms were "sensations of shortness of breath or smothering," "feeling of choking," and "fear of dying" found in 83.3% of the participants. 73.3% of the participants had poor quality of life which was most impaired in physical and environmental domains. 55% of the participants had disability score more than a mean (18.1). Conclusion. One-third of the participants had panic disorder with significant effect on physical and environmental domains of quality of life. Patients with more severe PD and bronchial asthma had more disability. PMID- 26425541 TI - Prevalence and Factors Associated with Perceived Stigma among Patients with Epilepsy in Ethiopia. AB - Background. Epilepsy stigma is considered to be one of the most important factors that have a negative influence on people with epilepsy. Among all types of stigma perceived stigma further exerts stress and restricts normal participation in society. Methods. Hospital based cross-sectional study was conducted from May 1, 2013, to May 30, 2013. All patients with epilepsy in Ethiopia were source population. The sample size was determined using single population proportion formula and 347 subjects were selected by using systematic random sampling method. Data was analyzed by using SPSS version 20. Results. A total of 346 participants with mean age of 29.3 +/- 8.5 SD participated with a response rate of 99.7%. The prevalence of perceived stigma was 31.2%. Age range between 18 and 24 [AOR = 2.84, 95%CI: 1.02, 7.92], difficulty to attend follow-up because of stigma [AOR = 3.15, 95%CI: 1.19, 8.34], seizure related injury [AOR = 1.88, 95%CI: 1.12, 3.15], and contagion belief [AOR = 1.88, 95%CI: 1.10, 5.08] were significantly associated with perceived stigma. Conclusions. Perceived stigma was found to be a common problem among patients suffering from epilepsy. The results reinforce the need for creating awareness among patients with epilepsy and addressing misconceptions attached to epilepsy. PMID- 26425542 TI - The Contribution of Alexithymia to Obsessive-Compulsive Disorder Symptoms Dimensions: An Investigation in a Large Community Sample in Italy. AB - Poor attention has been dedicated to the relation between Alexithymia and specific OCD symptoms dimensions. Knowledge about which Alexithymia domains are the most affected ones in OCD dimensions could inform clinical practice, suggesting the need for the introduction of psychotherapeutic interventions targeting Alexithymia deficits. The current study aimed to investigate which OCD symptom dimension correlated with Alexithymia domains. A total of 425 community individuals (mean age = 27.80, SD = 9.89, 60% women) completed measures of Alexithymia, OCD symptoms dimensions, anxiety, and depression. Moderate correlations emerged between Difficulty Identifying Feelings and Hoarding (r = .36, p < .001) and Checking symptoms (r = .34, p < .001) and between Difficulty Describing Feelings and Pure Obsessing (r = .31, p < .001). Difficulty Identifying Feelings uniquely predicted OCD symptoms (beta = 0.20, t = 3.96, and p < .001), after controlling for anxiety and depression. A main effect emerged of Alexithymia on Ordering (beta = 0.70, t = 2.50, p < .05) and Pure Obsessing symptoms (beta = 0.043, t = 2.08, and p < .05). Psychotherapeutic interventions specifically targeting Alexithymia should be integrated in the treatment of Ordering and Pure Obsessing symptoms. Difficulty Identifying Feelings and Difficulty Describing Feelings should be addressed in the psychotherapeutic treatment of Hoarding, Checking, and Pure Obsessing, respectively. PMID- 26425543 TI - Exploring the Functional Disorder and Corresponding Key Transcription Factors in Intraductal Papillary Mucinous Neoplasms Progression. AB - This study has analyzed the gene expression patterns of an IPMN microarray dataset including normal pancreatic ductal tissue (NT), intraductal papillary mucinous adenoma (IPMA), intraductal papillary mucinous carcinoma (IPMC), and invasive ductal carcinoma (IDC) samples. And eight clusters of differentially expressed genes (DEGs) with similar expression pattern were detected by k-means clustering. Then a survey map of functional disorder in IPMN progression was established by functional enrichment analysis of these clusters. In addition, transcription factors (TFs) enrichment analysis was used to detect the key TFs in each cluster of DEGs, and three TFs (FLI1, ERG, and ESR1) were found to significantly regulate DEGs in cluster 1, and expression of these three TFs was validated by qRT-PCR. All these results indicated that these three TFs might play key roles in the early stages of IPMN progression. PMID- 26425546 TI - Comment on "Maternal Satisfaction on Delivery Service and Its Associated Factors among Mothers Who Gave Birth in Public Health Facilities of Debre Markos Town, Northwest Ethiopia". PMID- 26425545 TI - Yeast Actin-Related Protein ARP6 Negatively Regulates Agrobacterium-Mediated Transformation of Yeast Cell. AB - The yeasts, including Saccharomyces cerevisiae and Pichia pastoris, are single cell eukaryotic organisms that can serve as models for human genetic diseases and hosts for large scale production of recombinant proteins in current biopharmaceutical industry. Thus, efficient genetic engineering tools for yeasts are of great research and economic values. Agrobacterium tumefaciens-mediated transformation (AMT) can transfer T-DNA into yeast cells as a method for genetic engineering. However, how the T-DNA is transferred into the yeast cells is not well established yet. Here our genetic screening of yeast knockout mutants identified a yeast actin-related protein ARP6 as a negative regulator of AMT. ARP6 is a critical member of the SWR1 chromatin remodeling complex (SWR-C); knocking out some other components of the complex also increased the transformation efficiency, suggesting that ARP6 might regulate AMT via SWR-C. Moreover, knockout of ARP6 led to disruption of microtubule integrity, higher uptake and degradation of virulence proteins, and increased DNA stability inside the cells, all of which resulted in enhanced transformation efficiency. Our findings have identified molecular and cellular mechanisms regulating AMT and a potential target for enhancing the transformation efficiency in yeast cells. PMID- 26425547 TI - Chemotherapy-Induced Nausea and Vomiting. PMID- 26425544 TI - Targeted Therapies in Adult B-Cell Malignancies. AB - B-lymphocytes are programmed for the production of immunoglobulin (Ig) after antigen presentation, in the context of T-lymphocyte control within lymphoid organs. During this differentiation/activation process, B-lymphocytes exhibit different restricted or common surface markers, activation of cellular pathways that regulate cell cycle, metabolism, proteasome activity, and protein synthesis. All molecules involved in these different cellular mechanisms are potent therapeutic targets. Nowadays, due to the progress of the biology, more and more targeted drugs are identified, a situation that is correlated with an extended field of the targeted therapy. The full knowledge of the cellular machinery and cell-cell communication allows making the best choice to treat patients, in the context of personalized medicine. Also, focus should not be restricted to the immediate effects observed as clinical endpoints, that is, response rate, survival markers with conventional statistical methods, but it should consider the prediction of different clinical consequences due to other collateral drug targets, based on new methodologies. This means that new reflection and new bioclinical follow-up have to be monitored, particularly with the new drugs used with success in B-cell malignancies. This review discussed the principal aspects of such evident bioclinical progress. PMID- 26425548 TI - Clinical Safety and Immunogenicity of Tumor-Targeted, Plant-Made Id-KLH Conjugate Vaccines for Follicular Lymphoma. AB - We report the first evaluation of plant-made conjugate vaccines for targeted treatment of B-cell follicular lymphoma (FL) in a Phase I safety and immunogenicity clinical study. Each recombinant personalized immunogen consisted of a tumor-derived, plant-produced idiotypic antibody (Ab) hybrid comprising the hypervariable regions of the tumor-associated light and heavy Ab chains, genetically grafted onto a common human IgG1 scaffold. Each immunogen was produced in Nicotiana benthamiana plants using twin magnICON vectors expressing the light and heavy chains of the idiotypic Ab. Each purified Ab was chemically linked to the carrier protein keyhole limpet hemocyanin (KLH) to form a conjugate vaccine. The vaccines were administered to FL patients over a series of >=6 subcutaneous injections in conjunction with the adjuvant Leukine (GM-CSF). The 27 patients enrolled in the study had previously received non-anti-CD20 cytoreductive therapy followed by >=4 months of immune recovery prior to first vaccination. Of 11 patients who became evaluable at study conclusion, 82% (9/11) displayed a vaccine-induced, idiotype-specific cellular and/or humoral immune response. No patients showed serious adverse events (SAE) related to vaccination. The fully scalable plant-based manufacturing process yields safe and immunogenic personalized FL vaccines that can be produced within weeks of obtaining patient biopsies. PMID- 26425549 TI - The Implications of HIV Treatment on the HIV-Malaria Coinfection Dynamics: A Modeling Perspective. AB - Most hosts harbor multiple pathogens at the same time in disease epidemiology. Multiple pathogens have the potential for interaction resulting in negative impacts on host fitness or alterations in pathogen transmission dynamics. In this paper we develop a mathematical model describing the dynamics of HIV-malaria coinfection. Additionally, we extended our model to examine the role treatment (of malaria and HIV) plays in altering populations' dynamics. Our model consists of 13 interlinked equations which allow us to explore multiple aspects of HIV malaria transmission and treatment. We perform qualitative analysis of the model that includes positivity and boundedness of solutions. Furthermore, we evaluate the reproductive numbers corresponding to the submodels and investigate the long term behavior of the submodels. We also consider the qualitative dynamics of the full model. Sensitivity analysis is done to determine the impact of some chosen parameters on the dynamics of malaria. Finally, numerical simulations illustrate the potential impact of the treatment scenarios and confirm our analytical results. PMID- 26425551 TI - Expression of Translationally Controlled Tumor Protein in Human Kidney and in Renal Cell Carcinoma. AB - Translationally controlled tumor protein is a multifaceted protein involved in several physiological and biological functions. Its expression in normal kidney and in renal carcinomas, once corroborated by functional data, may add elements to elucidate renal physiology and carcinogenesis. In this study, translationally controlled tumor protein expression was evaluated by quantitative real time polymerase chain reaction and western blotting, and its localization was examined by immunohistochemistry on 84 nephrectomies for cancer. In normal kidney protein expression was found in the cytoplasm of proximal and distal tubular cells, in cells of the thick segment of the loop of Henle, and in urothelial cells of the pelvis. It was also detectable in cells of renal carcinoma with different pattern of localization (membranous and cytoplasmic) depending on tumor histotype. Our data may suggest an involvement of translationally controlled tumor protein in normal physiology and carcinogenesis. However, functional in vitro and in vivo studies are needed to verify this hypothesis. PMID- 26425550 TI - Reviving Lonidamine and 6-Diazo-5-oxo-L-norleucine to Be Used in Combination for Metabolic Cancer Therapy. AB - Abnormal metabolism is another cancer hallmark. The two most characterized altered metabolic pathways are high rates of glycolysis and glutaminolysis, which are natural targets for cancer therapy. Currently, a number of newer compounds to block glycolysis and glutaminolysis are being developed; nevertheless, lonidamine and 6-diazo-5-oxo-L-norleucine (DON) are two old drugs well characterized as inhibitors of glycolysis and glutaminolysis, respectively, whose clinical development was abandoned years ago when the importance of cancer metabolism was not fully appreciated and clinical trial methodology was less developed. In this review, a PubMed search using the words lonidamine and 6-diazo-5-oxo-L-norleucine (DON) was undertaken to analyse existing information on the preclinical and clinical studies of these drugs for cancer treatment. Data show that they exhibit antitumor effects; besides there is also the suggestion that they are synergistic. We conclude that lonidamine and DON are safe and potentially effective drugs that need to be reevaluated in combination as metabolic therapy of cancer. PMID- 26425552 TI - A Bayesian Outbreak Detection Method for Influenza-Like Illness. AB - Epidemic outbreak detection is an important problem in public health and the development of reliable methods for outbreak detection remains an active research area. In this paper we introduce a Bayesian method to detect outbreaks of influenza-like illness from surveillance data. The rationale is that, during the early phase of the outbreak, surveillance data changes from autoregressive dynamics to a regime of exponential growth. Our method uses Bayesian model selection and Bayesian regression to identify the breakpoint. No free parameters need to be tuned. However, historical information regarding influenza-like illnesses needs to be incorporated into the model. In order to show and discuss the performance of our method we analyze synthetic, seasonal, and pandemic outbreak data. PMID- 26425553 TI - Understanding Transcription Factor Regulation by Integrating Gene Expression and DNase I Hypersensitive Sites. AB - Transcription factors are proteins that bind to DNA sequences to regulate gene transcription. The transcription factor binding sites are short DNA sequences (5 20 bp long) specifically bound by one or more transcription factors. The identification of transcription factor binding sites and prediction of their function continue to be challenging problems in computational biology. In this study, by integrating the DNase I hypersensitive sites with known position weight matrices in the TRANSFAC database, the transcription factor binding sites in gene regulatory region are identified. Based on the global gene expression patterns in cervical cancer HeLaS3 cell and HelaS3-ifnalpha4h cell (interferon treatment on HeLaS3 cell for 4 hours), we present a model-based computational approach to predict a set of transcription factors that potentially cause such differential gene expression. Significantly, 6 out 10 predicted functional factors, including IRF, IRF-2, IRF-9, IRF-1 and IRF-3, ICSBP, belong to interferon regulatory factor family and upregulate the gene expression levels responding to the interferon treatment. Another factor, ISGF-3, is also a transcriptional activator induced by interferon alpha. Using the different transcription factor binding sites selected criteria, the prediction result of our model is consistent. Our model demonstrated the potential to computationally identify the functional transcription factors in gene regulation. PMID- 26425554 TI - iTRAQ-Based Quantitative Proteomic Analysis Identified HSC71 as a Novel Serum Biomarker for Renal Cell Carcinoma. AB - Renal cell carcinoma (RCC) is one of the most lethal urologic cancers and about 80% of RCC are of the clear-cell type (ccRCC). However, there are no serum biomarkers for the accurate diagnosis of RCC. In this study, we performed a quantitative proteomic analysis on serum samples from ccRCC patients and control group by using isobaric tag for relative and absolute quantitation (iTRAQ) labeling and LC-MS/MS analysis to access differentially expressed proteins. Overall, 16 proteins were significantly upregulated (ratio > 1.5) and 14 proteins were significantly downregulated (ratio < 0.67) in early-stage ccRCC compared to control group. HSC71 was selected and subsequently validated by Western blot in six independent sets of patients. ELISA subsequently confirmed HSC71 as a potential serum biomarker for distinguishing RCC from benign urologic disease with an operating characteristic curve (ROC) area under the curve (AUC) of 0.86 (95% confidence interval (CI), 0.76~0.96), achieving sensitivity of 87% (95% CI 69%~96%) at a specificity of 80% (95% CI 61~92%) with a threshold of 15 ng/mL. iTRAQ-based quantitative proteomic analysis led to identification of serum HSC71 as a novel serum biomarker of RCC, particularly useful in early diagnosis of ccRCC. PMID- 26425555 TI - Association of Tag SNPs and Rare CNVs of the MIR155HG/miR-155 Gene with Epilepsy in the Chinese Han Population. AB - BACKGROUND: miR-155 likely acts as an important modulator in the inflammatory mechanism of epilepsy, and this study investigated its association with epilepsy from the perspective of molecular genetics. METHODS: This study enrolled 249 epileptic patients and 289 healthy individuals of the Chinese Han population; 4 tag single-nucleotide polymorphisms (SNPs: rs969885, rs12483428, rs987195, and rs4817027) of the MIR155HG/miR-155 gene were selected, and their association with epilepsy was investigated. Additionally, this study determined the copy numbers of the MIR155HG/miR-155 gene. RESULTS: The TCA haplotype (rs12483428-rs987195 rs4817027) and the AA genotype at rs4817027 conferred higher vulnerability to epilepsy in males. Stratification by age of onset revealed that the CC haplotype (rs969885-rs987195) was a genetic susceptibility factor for early-onset epilepsy. Further stratification by drug-resistant status indicated the CC haplotype (rs969885-rs987195) and the AA genotype at rs4817027 were genetic susceptibility factors for drug-resistant epilepsy (DRE) but the CG haplotype (rs987195 rs969885) was a genetically protective factor against DRE. Besides, 3 epileptic patients with copy number variants of the MIR155HG/miR-155 gene were observed. CONCLUSIONS: This study first demonstrates the association of MIR155HG/miR-155 tag SNPs with epilepsy and shows that rare CNVs were found exclusively in epileptic patients, clarifying the genetic role of miR-155 in epilepsy. PMID- 26425557 TI - Prophylactic Management of Radiation-Induced Nausea and Vomiting. AB - The incidence of nausea and vomiting after radiotherapy is often underestimated by physicians, though some 50-80% of patients may experience these symptoms. The occurrence of radiotherapy-induced nausea and vomiting (RINV) will depend on radiotherapy-related factors, such as the site of irradiation, the dosing, fractionation, irradiated volume, and radiotherapy techniques. Patients should receive antiemetic prophylaxis as suggested by the international antiemetic guidelines based upon a risk assessment, taking especially into account the affected anatomic region and the planned radiotherapy regimen. In this field the international guidelines from the Multinational Association of Supportive Care in Cancer (MASCC)/European Society of Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) guidelines as well as the National Comprehensive Cancer Network (NCCN) are widely endorsed. The emetogenicity of radiotherapy regimens and recommendations for the appropriate use of antiemetics including 5-hydroxytryptamine (5-HT3) receptor antagonists, steroids, and other antiemetics will be reviewed in regard to the applied radiotherapy or radiochemotherapy regimen. PMID- 26425556 TI - MicroRNA Promoter Identification in Arabidopsis Using Multiple Histone Markers. AB - A microRNA is a small noncoding RNA molecule, which functions in RNA silencing and posttranscriptional regulation of gene expression. To understand the mechanism of the activation of microRNA genes, the location of promoter regions driving their expression is required to be annotated precisely. Only a fraction of microRNA genes have confirmed transcription start sites (TSSs), which hinders our understanding of the transcription factor binding events. With the development of the next generation sequencing technology, the chromatin states can be inferred precisely by virtue of a combination of specific histone modifications. Using the genome-wide profiles of nine histone markers including H3K4me2, H3K4me3, H3K9Ac, H3K9me2, H3K18Ac, H3K27me1, H3K27me3, H3K36me2, and H3K36me3, we developed a computational strategy to identify the promoter regions of most microRNA genes in Arabidopsis, based upon the assumption that the distribution of histone markers around the TSSs of microRNA genes is similar to the TSSs of protein coding genes. Among 298 miRNA genes, our model identified 42 independent miRNA TSSs and 132 miRNA TSSs, which are located in the promoters of upstream genes. The identification of promoters will provide better understanding of microRNA regulation and can play an important role in the study of diseases at genetic level. PMID- 26425558 TI - Rituximab as Single Agent in Primary MALT Lymphoma of the Ocular Adnexa. AB - Ocular Adnexal Lymphomas are the first cause of primary ocular malignancies, and among them the most common are MALT Ocular Adnexal Lymphomas. Recently systemic immunotherapy with anti-CD20 monoclonal antibody has been investigated as first line treatment; however, the optimal management for MALT Ocular Adnexal Lymphomas is still unknown. The present study evaluated retrospectively the outcome of seven consecutive patients with primary MALT Ocular Adnexal Lymphomas, of whom six were treated with single agent Rituximab. All patients received 6 cycles of Rituximab 375 mg/mq every 3 weeks intravenously. The overall response rate was 100%; four patients (67%) achieved a Complete Remission, and two (33%) achieved a partial response. In four patients an additional Rituximab maintenance every 2-3 months was given for two years. After a median follow-up of 29 months (range 8 34), no recurrences were observed, without of therapy- or disease-related severe adverse events. None of the patients needed additional radiotherapy or other treatments. Rituximab as a single agent is highly effective and tolerable in first-line treatment of primary MALT Ocular adnexal Lymphomas. Furthermore, durable responses are achievable with the same-agent maintenance. Rituximab can be considered the agent of choice in the management of an indolent disease in whom the "quality of life" matter is of primary importance. PMID- 26425559 TI - Orthostatic Intolerance Is Independent of the Degree of Autonomic Cardiovascular Adaptation after 60 Days of Head-Down Bed Rest. AB - Spaceflight and head-down bed rest (HDBR) can induce the orthostatic intolerance (OI); the mechanisms remain to be clarified. The aim of this study was to determine whether or not OI after HDBR relates to the degree of autonomic cardiovascular adaptation. Fourteen volunteers were enrolled for 60 days of HDBR. A head-up tilt test (HUTT) was performed before and after HDBR. Our data revealed that, in all nonfainters, there was a progressive increase in heart rate over the course of HDBR, which remained higher until 12 days of recovery. The mean arterial pressure gradually increased until day 56 of HDBR and returned to baseline after 12 days of recovery. Respiratory sinus arrhythmia and baroreflex sensitivity decreased during HDBR and remained suppressed until 12 days of recovery. Low-frequency power of systolic arterial pressure increased during HDBR and remained elevated during recovery. Three subjects fainted during the HUTT after HDBR, in which systemic vascular resistance did not increase and remained lower until syncope. None of the circulatory patterns significantly differed between the fainters and the nonfainters at any time point. In conclusion, our data indicate that the impaired orthostatic tolerance after HDBR could not be distinguished by estimation of normal hemodynamic and/or neurocardiac data. PMID- 26425560 TI - The Roles of Hedgehog Signaling in Upper Lip Formation. AB - Craniofacial development consists of a highly complex sequence of the orchestrated growth and fusion of facial processes. It is also known that craniofacial abnormalities can be detected in 1/3 of all patients with congenital diseases. Within the various craniofacial abnormalities, orofacial clefting is one of the most common phenotypic outcomes associated with retarded facial growth or fusion. Cleft lip is one of the representative and frequently encountered conditions in the spectrum of orofacial clefting. Despite various mechanisms or signaling pathways that have been proposed to be the cause of cleft lip, a detailed mechanism that bridges individual signaling pathways to the cleft lip is still elusive. Shh signaling is indispensable for normal embryonic development, and disruption can result in a wide spectrum of craniofacial disorders, including cleft lip. This review focuses on the current knowledge about the mechanisms of facial development and the etiology of cleft lip that are related to Shh signaling. PMID- 26425561 TI - Subcutaneous Administration of Bortezomib in Combination with Thalidomide and Dexamethasone for Treatment of Newly Diagnosed Multiple Myeloma Patients. AB - OBJECTIVE: To investigate the efficacy and safety of the treatment of the newly diagnosed multiple myeloma (MM) patients with the therapy of subcutaneous (subQ) administration of bortezomib and dexamethasone plus thalidomide (VTD) regimen. METHODS: A total of 60 newly diagnosed MM patients were analyzed. 30 patients received improved VTD regimen (improved VTD group) with the subQ injection of bortezomib and the other 30 patients received conventional VTD regimen (VTD group).The efficacy and safety of two groups were analyzed retrospectively. RESULTS: The overall remission (OR) after eight cycles of treatment was 73.3% in the VTD group and 76.7% in the improved VTD group (P > 0.05). No significant differences in time to 1-year estimate of overall survival (72% versus 75%, P = 0.848) and progression-free survival (median 22 months versus 25 months; P = 0.725) between two groups. The main toxicities related to therapy were leukopenia, neutropenia, thrombocytopenia, asthenia, fatigue, and renal and urinary disorders. Grade 3 and higher adverse events were significantly less common in the improved VTD group (50%) than VTD group (80%, P = 0.015). CONCLUSIONS: The improved VTD regimen by changing bortezomib from intravenous administration to subcutaneous injection has noninferior efficacy to standard VTD regimen, with an improved safety profile and reduced adverse events. PMID- 26425562 TI - Impact of CYP1A1 Polymorphisms on Susceptibility to Chronic Obstructive Pulmonary Disease: A Meta-Analysis. AB - OBJECTIVE: Several studies have evaluated the association between CYP1A1 polymorphisms and the susceptibility of chronic obstructive pulmonary disease (COPD) with inconclusive results. We performed the first comprehensive meta analysis to summarize the association between CYP1A1 polymorphisms and COPD risk. METHOD: A systematic literature search was conducted (up to April 2015) in five online databases: PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), WeiPu, and WanFang databases. The strength of association was calculated by odds ratio (OR) and corresponding 95% confidence interval (CI). RESULTS: Seven case control studies with 1050 cases and 1202 controls were included. Our study suggested a significant association between the MspI polymorphism and COPD risk (CC versus TC + TT: OR = 1.57, CI: 1.09-2.26, P = 0.02; CC versus TT: OR = 1.73, CI: 1.18-2.55, P = 0.005). For the Ile/Val polymorphism, a significant association with COPD risk was observed (GG versus AG + AA: OR = 2.75, CI: 1.29 5.84, P = 0.009; GG versus AA: OR = 3.23, CI: 1.50-6.93, P = 0.003; AG versus AA: OR = 1.39, CI: 1.01-1.90, P = 0.04). Subgroup analysis indicated a significant association between the MspI variation and COPD risk among Asians (CC versus TC + TT: OR = 1.70, CI: 1.06-2.71, P = 0.03; CC versus TT: OR = 1.84, CI: 1.11-3.06, P = 0.02). CONCLUSION: The MspI and Ile/Val polymorphisms might alter the susceptibility of COPD, and MspI polymorphism might play a role in COPD risk among Asian population. PMID- 26425563 TI - Management of Chemotherapy Induced Nausea and Vomiting in Patients on Multiday Cisplatin Based Combination Chemotherapy. AB - Introduction of cisplatin based chemotherapy has revolutionized the treatment of germ cell tumors. A common side effect of multiday cisplatin chemotherapy is severe nausea and vomiting. Considerable progress has been made in the control of these side effects since the introduction of cisplatin based chemotherapy in the 1970s. Germ cell tumor which is a model for a curable neoplasm has also turned into an excellent testing ground to develop effective strategies to prevent chemotherapy induced nausea and vomiting (CINV) in multiday cisplatin based regimens. The use of combination of a 5-hydroxytryptamine (HT)3 receptor antagonist, a neurokinin-1 (NK1) antagonist, and dexamethasone has greatly improved our ability to prevent and control acute and delayed CINV. Mechanism and pattern of CINV with multiday chemotherapy may differ from those in single day chemotherapy and therefore efficacy of antiemetic drugs as observed in single day chemotherapy may not be applicable. There are only few randomized clinical trials with special emphasis on multiday chemotherapy. Further studies are essential to determine the efficacy, optimal dose, and duration of the newer agents and combinations in multiday cisplatin based chemotherapy. PMID- 26425564 TI - Efficacy of Olanzapine Combined Therapy for Patients Receiving Highly Emetogenic Chemotherapy Resistant to Standard Antiemetic Therapy. AB - OBJECTIVE: Olanzapine is proved to be effective for chemotherapy induced nausea and vomiting (CINV). But its efficacy in combination with standard antiemetic therapy is unknown. The purpose of this study is to prove the preventive effect of olanzapine for the prevention of CINV caused by highly emetogenic chemotherapy when used with standard antiemetic therapy. METHOD: Gynecologic cancer patients receiving cisplatin-based chemotherapy who had grade 2 or 3 nausea in overall phase (0-120 h after chemotherapy) despite standard therapy were assigned to this study. From the next cycles to cycles in which patients developed grade 2 or 3 nausea, they received olanzapine with standard therapy. 5 mg oral olanzapine was administered for 7 days from the day before chemotherapy. The effectiveness of preventive administration of olanzapine was evaluated retrospectively. The primary endpoint was nausea control rate (grade 0 or 1) with olanzapine. RESULTS: Fifty patients were evaluable. The nausea control rate with olanzapine was improved from 58% to 98% in acute phase (0-24 h after chemotherapy) and 2% to 94% in delayed phase (24-120 h after chemotherapy). In overall phase, the nausea control rate improved from 0% to 92%, and it was statistically significant (P < 0.001). CONCLUSION: Preventive use of olanzapine combined with standard antiemetic therapy showed improvement in control of refractory nausea. PMID- 26425565 TI - Following Up Crack Users after Hospital Discharge Using Record Linkage Methodology: An Alternative to Find Hidden Populations. AB - This paper presents the probabilistic record linkage (PRL) methodology as an alternative way to find or follow up hard-to-reach population as crack users. PRL was based on secondary data from public health information systems and the strategy used from standardization; phonetic encoding and the rounds of matching data were described. A total of 293 patient records from medical database and two administrative datasets obtained from Ministry of Health Information Systems were used. Patient information from the medical database was the identifiers to the administrative datasets containing data on outpatient treatment and hospital admissions. 40% of patient records were found in the hospital database and 12% were found in the outpatient database; 95% of the patients were hospitalized up to 5 times, and only 10 out of them had outpatient information. The record linkage methodology by linking government databases may help to address research questions about the path of patients in the care network without spending time and financial resources with primary data collection. PMID- 26425567 TI - Prevalence, Clinical Correlates, and Use of Glucose-Lowering Drugs among Older Patients with Type 2 Diabetes Living in Long-Term Care Facilities. AB - Prevalence, clinical correlates, and use of glucose-lowering drugs were comprehensively evaluated among 863 nursing home older patients with diabetes (mean age 82.9 +/- 2.1 years): functional dependence and cognitive impairment were present in 84.1% and 68% of patients, respectively, and 66.3% of patients had 2-4 comorbidities. HbA1c values < 7.0% were documented in 54.9% of diabetic; significantly lower HbA1c levels were observed in demented patients than in nondemented subjects. Documented hypoglycemic episodes were reported for 57 patients (6.6%), without significant association with age, functional dependence, cognitive impairment, or HbA1c levels. About one-fifth of older long-term facilities residents have diabetes, with concomitant poor health conditions and high prevalence of cognitive impairment and functional dependence. Roughly three fourths of these older and frail diabetic patients have HbA1c values lower than optimal, suggesting a potential for hypoglycemic harm especially among patients with severe cognitive impairment. PMID- 26425566 TI - Active Microbial Communities Inhabit Sulphate-Methane Interphase in Deep Bedrock Fracture Fluids in Olkiluoto, Finland. AB - Active microbial communities of deep crystalline bedrock fracture water were investigated from seven different boreholes in Olkiluoto (Western Finland) using bacterial and archaeal 16S rRNA, dsrB, and mcrA gene transcript targeted 454 pyrosequencing. Over a depth range of 296-798 m below ground surface the microbial communities changed according to depth, salinity gradient, and sulphate and methane concentrations. The highest bacterial diversity was observed in the sulphate-methane mixing zone (SMMZ) at 250-350 m depth, whereas archaeal diversity was highest in the lowest boundaries of the SMMZ. Sulphide-oxidizing epsilon-proteobacteria (Sulfurimonas sp.) dominated in the SMMZ and gamma proteobacteria (Pseudomonas spp.) below the SMMZ. The active archaeal communities consisted mostly of ANME-2D and Thermoplasmatales groups, although Methermicoccaceae, Methanobacteriaceae, and Thermoplasmatales (SAGMEG, TMG) were more common at 415-559 m depth. Typical indicator microorganisms for sulphate methane transition zones in marine sediments, such as ANME-1 archaea, alpha-, beta- and delta-proteobacteria, JS1, Actinomycetes, Planctomycetes, Chloroflexi, and MBGB Crenarchaeota were detected at specific depths. DsrB genes were most numerous and most actively transcribed in the SMMZ while the mcrA gene concentration was highest in the deep methane rich groundwater. Our results demonstrate that active and highly diverse but sparse and stratified microbial communities inhabit the Fennoscandian deep bedrock ecosystems. PMID- 26425568 TI - Metastatic Insulinoma Following Resection of Nonsecreting Pancreatic Islet Cell Tumor: A Case Report and Review of the Literature. AB - A 56-year-old woman presented to our clinic for recurrent hypoglycemia after undergoing resection of an incidentally discovered nonfunctional pancreatic endocrine tumor 6 years ago. She underwent a distal pancreatectomy and splenectomy, after which she developed diabetes and was placed on an insulin pump. Pathology showed a pancreatic endocrine neoplasm with negative islet hormone immunostains. Two years later, computed tomography scan of the abdomen showed multiple liver lesions. Biopsy of a liver lesion showed a well differentiated neuroendocrine neoplasm, consistent with pancreatic origin. Six years later, she presented to clinic with 1.5 years of recurrent hypoglycemia. Laboratory results showed elevated proinsulin, insulin levels, and c-peptide levels during a hypoglycemic episode. Computed tomography scan of the abdomen redemonstrated multiple liver lesions. Repeated transarterial catheter chemoembolization and microwave thermal ablation controlled hypoglycemia. The unusual features of interest of this case include the transformation of nonfunctioning pancreatic endocrine tumor to a metastatic insulinoma and the occurrence of atrial flutter after octreotide for treatment. PMID- 26425569 TI - Obscure Severe Infrarenal Aortoiliac Stenosis With Severe Transient Lactic Acidosis. AB - A 57-year-old man presented with sudden onset of leg pain, right-sided weakness, aphasia, confusion, drooling, and severe lactic acidosis (15 mmol/L). He had normal peripheral pulses and demonstrated no pain, pallor, poikilothermia, paresthesia, or paralysis. Empiric antibiotics, aspirin, full-dose enoxaparin, and intravenous fluid were initiated. Lactic acid level decreased to 2.5 mmol/L. The patient was subsequently extubated and was alert and oriented with no complaints of leg or abdominal pain. Unexpectedly, the patient developed cardiac arrest, rebound severe lactic acidosis (8.13 mmol/L), and signs of acute limb ischemia. Emergent computed tomography of the aorta confirmed infrarenal aortoiliac thrombosis. Transient leg pain and transient severe lactic acidosis can be unusual presentations of severe infrarenal aortoiliac stenosis. When in doubt, vascular studies should be implemented without delay to identify this catastrophic diagnosis. PMID- 26425571 TI - Urticarial Vasculitis in a Teenage Girl. AB - This case involves a 13-year-old female who presented to the pediatrician for a routine check-up with complaints of a long history of intermittent diarrhea followed by a severe rash lasting for up to a week afterwards. The mother had described her daughter's condition to multiple physicians, several whom had seen her during flare-ups. The nonmigratory lesions resembled "hives" with a single lesion lasting for 48 to 72 hours and resolving into what her parent described as a bruise. They often diagnosed her daughter with urticaria and prescribed steroids, which did resolve the acute flare-ups. None of the physicians, however, focused on the disease's evolution and chronicity in an effort toward diagnosis and prevention. The patient was referred by her pediatrician to a dermatologist who diagnosed the patient with urticarial vasculitis. She was initially started on dapsone 25 mg and was increased over a period of months to a maintenance dose of 100 mg daily. She has had no recurrences in her cutaneous or systemic symptoms on this dose. She is closely monitored by her dermatologist on a regular basis with twice yearly complete blood counts. Several attempts have been made to discontinue the dapsone, resulting in a flare of her gastrointestinal symptoms. This patient suffered with this condition for almost 10 years. This is a reminder that spending extra time to think through a patient's problem early on may prevent years of suffering for patients and their families. PMID- 26425570 TI - Cyclophosphamide-Induced Cardiomyopathy: A Case Report, Review, and Recommendations for Management. AB - Cyclophosphamide is increasingly used to treat various types of cancers and autoimmune conditions. Higher doses of this drug may produce significant cardiac toxicity, including fatal hemorrhagic myocarditis. In this review, we present a case of cyclophosphamide-induced cardiomyopathy requiring mechanical circulatory support. We also describe the pathophysiology, clinical manifestations, and risk factors for this important clinical entity and propose early detection and management strategies. PMID- 26425572 TI - Two Metachronous Neoplasms in the Radiotherapy Fields of a Young Man With Familial Adenomatous Polyposis. AB - BACKGROUND: It is recognized that various radiation-induced malignancies often follow childhood radiotherapy. Radiation-induced neoplasms have been shown to occur with increased frequency in syndromes due to mutated tumor suppressor genes. There exist no recommendations for the management of cancer patients with germline APC gene mutations. Preclinical data suggest that APC gene mutations cause enhanced radiosensitivity, but no clinical observations exist that show that patients with this mutation are at higher risk for radiation-induced malignancies. RESULTS: We report the case of a 32-year-old man with a genetic diagnosis of familial adenomatous polyposis (FAP) who initially presented at age 10 with a medulloblastoma treated with radiotherapy and surgery. Radiation induced papillary thyroid carcinoma followed 13 years later. Finally, radiation induced soft tissue osteosarcoma occurred with widespread metastasis 20 years thereafter. CONCLUSIONS: This is the first report of 2 malignancies in the prior radiotherapy fields of a patient with a genetic diagnosis of FAP. More important, this suggests that APC-defective cells are at an enhanced sensitivity to the carcinogenic effects of radiotherapy compared with APC-proficient cells. This could argue for genetic screening in affected members of these families and for creation of treatment recommendations to more seriously consider the risks of radiation therapy. PMID- 26425573 TI - Spontaneous Atraumatic Mediastinal Hemorrhage: Challenging Management of a Life Threatening Condition and Literature Review. AB - Spontaneous atraumatic mediastinal hematomas are rare. We present a case of a previously fit and well middle-aged lady who presented with acute breathlessness and an increasing neck swelling and spontaneous neck bruising. On plain chest radiograph, widening of the mediastinum was noted. The bruising was later confirmed to be secondary to mediastinal hematoma. This life-threatening diagnostic conundrum was managed conservatively with a multidisciplinary team approach involving upper gastrointestinal and thoracic surgeons, gastroenterologists, radiologists, intensivists, and hematologists along with a variety of diagnostic modalities. A review of literature is also presented to help surgeons manage such challenging and complicated cases. PMID- 26425574 TI - Hypercalcemia, Renal Failure, and Skull Lytic Lesions: Follicular Lymphoma Masquerading as Multiple Myeloma. AB - The findings of hypercalcemia, skull lytic lesions, and renal failure are usually characteristic for multiple myeloma. We herein describe an interesting case of B cell follicular lymphoma that presented with many features mimicking multiple myeloma. PMID- 26425575 TI - Recurrent Early Thrombus Formation in HeartMate II Left Ventricular Assist Device. AB - Left ventricular assist devices are becoming an established treatment for end stage heart failure. In spite of their proven benefit, pump thrombosis remains a significant complication. Here we describe the challenging management of a patient with recurrent pump thrombosis. PMID- 26425576 TI - When Is "Pseudo-Ludwig's Angina" Associated With Coagulopathy Also a "Pseudo" Hemorrhage? AB - Sublingual hematoma secondary to short-acting anticoagulants such as warfarin has been labeled "pseudo-Ludwig's angina" to distinguish it from the classic syndrome of localized infection and swelling involving the upper airway. Sublingual hematoma with airway compromise secondary to brodifacoum, a common long-acting anticoagulant rodenticide, has only been reported in the veterinary literature. We report a case of massive tongue swelling and impending airway compromise in the context of an intentional long-acting anticoagulant ingestion leading to coagulopathy. The swelling was initially presumed to be due either to infection or hemorrhage, but this was not supported by computed tomography scan imaging. Instead, the patient's clinical course was consistent with corticosteroid responsive angioedema, temporally associated with the ingested brodifacoum. PMID- 26425577 TI - Transformation of a Silent Adrencorticotrophic Pituitary Tumor Into Central Nervous System Melanoma. AB - Silent adrenocorticotrophic pituitary adenomas are nonfunctioning pituitary adenomas that express adrenocorticotrophic hormone (ACTH) but do not cause the clinical or laboratory features of hypercortisolemia. Primary central nervous system (CNS) melanoma is well documented, but rarely originates in the sellar region or pituitary gland. Here we report transformation of an aggressive silent adrenocorticotrophic pituitary adenoma that transformed into CNS melanoma and review other presentations of pituitary melanoma. A 37-year-old woman initially presented with apoplexy and an invasive nonfunctioning pituitary macroadenoma for which she underwent transphenoidal surgery. The patient underwent 3 subsequent surgeries as the tumor continued to progress. Pathology from the first 3 operations showed pituitary adenoma or carcinoma. Pathology from the final surgery showed melanoma and the magnetic resonance imaging characteristics of the tumor had changed to become consistent with CNS melanoma. Dermatologic and ophthalmologic examinations did not identify cutaneous or ocular melanoma. The patient's disease progressed despite aggressive surgical, medical and radiologic treatment. To our knowledge, this is the first report demonstrating transformation of a primary pituitary tumor into melanoma. The mechanism of tumor transformation is unclear, but it is possible that a mutation in the original ACTH-producing tumor lead to increased cleavage of pro-opiomelanocortin or ACTH into alpha-melanocyte-stimulating hormone, which in turn stimulated the expression of microopthalmia transcription factor, leading to melanocytic phenotype transformation. PMID- 26425578 TI - An Unusual Presentation of Isolated Leptomeningeal Disease in Carcinoma of Unknown Primary With Pancreatic Features. AB - Leptomeningeal disease (LMD) can occur in a small percentage of patients with active metastatic cancer. However, we report a case of LMD occurring during disease remission in a patient with carcinoma of unknown primary with panreaticobiliary features. A 45-year-old woman was found with mediastinal and abdominal lymphadenopathy with lymph node biopsy consistent with adenocarcinoma, expressing immunomarkers CK7, CK20, and Ca19-9 along with markedly elevated serum Ca19-9 level. The patient was started on a pancreatic cancer directed chemotherapy regimen of Folfirinox (5-fluorouracil, leucovorin, oxaliplatin, irinotecan) and achieved complete response. She was then noted to have slowly rising Ca19-9 level that did not correlate with her lack of evidence of systemic disease progression. Eventually, she presented with neurologic symptoms and was found on imaging to have isolated LMD. PMID- 26425579 TI - Polypoid Gallbladder Lesion in the Context of Renal Cell Carcinoma: Is Laparoscopic Cholecystectomy a Reasonable Option? AB - Introduction. The only curative therapeutic approach for renal cell carcinoma (RCC) is surgery. Laparoscopic surgery for RCC has become an established surgical procedure with equivalent cancer-free survival rate, following the same surgical oncological principles as open surgery. Metastatic RCC of the gallbladder is a rare phenomenon. Hence, there are few reports regarding their management. Case Presentation. We report 2 cases of gallbladder metastasis from clear cell RCC treated by laparoscopic cholecystectomy. The first case was that of a 44-year-old male patient who underwent palliative cholecystectomy, the second case was that of an 83-year-old female patient who is doing well 55 months after surgery without evidence of disease recurrence. Conclusion. The outcome allows us to demonstrate the interest of surgical resection of RCC metastases in the gallbladder by laparoscopic cholecystectomy, respecting surgical oncological principles. Laparoscopic resection of an uncommon gallbladder metastasis can provide long-term favorable outcome. PMID- 26425580 TI - Salter Harris Fractures of the Distal Femur: Learning Points From Two Cases Compared. AB - Salter Harris-type injuries of the distal femur should be treated as a dislocation of the knee and therefore as a medical emergency. Senior medical staff should be involved early, ankle-brachial index ratio should be measured in all patients and the clinician should have a high index of suspicion for a vascular injury. Ideally reduction, stabilization, and vascular repair, if necessary, should be carried out within 6 hours of the initial event. There should be a low threshold for fasciotomies. These 2 cases demonstrate the importance of having a high index of suspicion for vascular injury and the need for continued reassessment. PMID- 26425581 TI - Clopidogrel-Induced Recurrent Polyarthritis. AB - Clopidogrel is an oral thienopyridine and together with aspirin is a component of dual antiplatelet therapy for the prevention of stent thrombosis after intracoronary stent placement. The common adverse effects from its use are an increased risk of bleeding, neutropenia, and rash. Arthralgia and backache are also known to occur with its use. There have been case reports linking arthritis with the use of clopidogrel. We describe the case of a 64-year-old man who reported symptoms of fever and joint pains following initiation of therapy with clopidogrel. Acute-phase reactants were elevated. Laboratory and radiologic testing were unremarkable. Incidentally, he reported experiencing a similar arthritis after he received a loading dose of clopidogrel prior to a diagnostic coronary angiography in the past. The symptoms improved dramatically on discontinuation of clopidogrel. There was no recurrence of symptoms with prasugrel. This describes possibly the second incidence of recurrent arthritis with clopidogrel therapy. PMID- 26425582 TI - An Intriguing Endoscopic Case of Asymptomatic Crohn's Disease. AB - We present the case of a 64-year old male with Crohn's disease, who has intriguing endoscopic findings. Upon initial diagnosis at age 20, he received steroid therapy, but has not required any further medical intervention. He has remained relatively asymptomatic and keeps a healthy lifestyle. At routine colonoscopy, we identified pseudopolyps as well as tissue bridges within the colon, giving an unusual "swiss cheese" appearance. This case exemplifies the heterogeneity of Crohn's disease, emphasizing the possibility of finding evidence of ongoing disease despite lack of symptoms. PMID- 26425583 TI - Thoracic Cavernous Lymphangioma Provoking Massive Chyloptysis: A Case Report. AB - Chyloptysis is a relatively rare embodiment of disease that encompasses a lengthy differential and provides many diagnostic and therapeutic challenges. Presented here is the case of a young woman with massive chyloptysis due to a thoracic cavernous lymphangioma arising in the peripartum period. The severity of her condition mandated the use of cardiopulmonary bypass to resect her lymphangioma. We believe that the extent of her symptoms, etiology of disease, and surgical management represent a unique scenario in the literature. PMID- 26425584 TI - rhIGF-1 Therapy for Growth Failure and IGF-1 Deficiency in Congenital Disorder of Glycosylation Ia (PMM2 Deficiency). AB - Background. Congenital disorders of glycosylation (CDG) are a group of rare disorders in which glycosylation required for proper protein-protein interactions and protein stability is disrupted, manifesting clinically with multiple system involvement and growth failure. The insulin-like growth factor (IGF) system plays an important role in childhood growth and has been shown to be dysfunctional with low IGF-1 levels in children with CDG type Ia (PMM2 deficiency). Case report. A 3 year-old Caucasian male with failure to thrive was diagnosed with PMM2-CDG at 5 months of age. Initially, his length and weight were less than -2 standard deviation score, IGF-1 <25 ng/mL (normal 55-327 ng/mL), IGFBP-3 1.0 ug/mL (normal 0.7-3.6 ng/mL), and acid-labile subunit 1.3 mg/L (normal 0.7-7.9 mg/L). Despite aggressive feeding, he continued to show poor linear growth and weight gain. At 17 months, he underwent an IGF-1 generation test with growth hormone (0.1 mg/kg/d) for 7 days; baseline IGF-1of 27 ng/mL (normal 55-327 ng/mL) stimulated to only 33 ng/mL. Recombinant human IGF-1 (rhIGF-1) therapy (up to 130 ug/kg/dose twice daily) was initiated at 21 months of age resulting in an excellent linear growth response with height increasing from -2.73 to -1.39 standard deviation score over 22 months. IGF-1 and IGFBP-3 levels also increased. Conclusion. This is the first case report of rhIGF-1 therapy in a patient with PMM2-CDG. The child had an excellent linear growth response. These results provide additional in vivo evidence for IGF dysfunction in PMM2-CDG and suggest that rhIGF-1 may be a novel treatment for growth failure in PMM2-CDG. PMID- 26425585 TI - Computed Tomography and Magnetic Resonance Imaging Findings of a Malignant Hepatic Epithelioid Hemangioendothelioma: A Rare Case of Solitary Small Nodular Form. AB - We report the case of a rare solitary small nodular form of malignant hepatic epithelioid hemangioendothelioma in a patient followed by computed tomography and gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging with histological analysis. This case showed early peripheral septal and nodular enhancement and delayed centripetal enhancing pattern with capsular retraction, mimicking peripheral cholangiocarcinoma, inflammatory pseudotumor, or metastases. The histological and immunohistochemical findings were diagnostic of a malignant hepatic epithelioid hemangioendothelioma. PMID- 26425587 TI - A Case of Adenomyosis with a High Titer of IgG Autoantibody to Calreticulin. AB - Background. High prevalence of autoantibodies to the calcium-binding, endoplasmic reticulum chaperone protein calreticulin has been reported in various autoimmune and parasitic diseases. It has been reported that adenomyosis is associated with the presence of autoantibodies, in particular to phospholipids; however, it is not known whether it is associated with autoimmunity to calreticulin. Results. A 35-year-old gravida 4 para 4 woman presented with a history of many years of intractable menorrhagia. Histopathological examination of a subsequent hysterectomy specimen revealed a bulky uterus, a poorly developed secretory endometrium with decidualization of the stroma and chronic endometritis, as well as the presence of adenomyosis uteri. IgG autoantibodies to calreticulin were measured in the plasma of this and 234 other patients. Nine (3.8%) patients tested positive. The titer of anticalreticulin IgG autoantibody in the sole case with adenomyosis was approximately 8 times the average of other positive-testing samples. Conclusions. The etiology of adenomyosis is unclear. The presence of a high titer, blocking anticalreticulin autoantibody may directly increase the risk that adenomyosis might develop. It is also possible that the expansion of endometrial glandular tissue, as well as elevated estrogens, during adenomyosis may lead to elevated calreticulin, which induces an autoimmune reaction to it. Further study is required to determine whether there is a significant association between adenomyosis and the prevalence of calreticulin autoantibodies. PMID- 26425586 TI - Clinical Correlates of Autosomal Chromosomal Abnormalities in an Electronic Medical Record-Linked Genome-Wide Association Study: A Case Series. AB - Although mosaic autosomal chromosomal abnormalities are being increasingly detected as part of high-density genotyping studies, the clinical correlates are unclear. From an electronic medical record (EMR)-based genome-wide association study (GWAS) of peripheral arterial disease, log-R-ratio and B-allele-frequency data were used to identify mosaic autosomal chromosomal abnormalities including copy number variation and loss of heterozygosity. The EMRs of patients with chromosomal abnormalities and those without chromosomal abnormalities were reviewed to compare clinical characteristics. Among 3336 study participants, 0.75% (n = 25, mean age = 74.8 +/- 10.7 years, 64% men) had abnormal intensity plots indicative of autosomal chromosomal abnormalities. A hematologic malignancy was present in 8 patients (32%), of whom 4 also had a solid organ malignancy while 2 patients had a solid organ malignancy only. In 50 age- and sex-matched participants without chromosomal abnormalities, there was a lower rate of hematologic malignancies (2% vs 32%, P < .001) but not solid organ malignancies (20% vs 24%, P = .69). We also report the clinical characteristics of each patient with the observed chromosomal abnormalities. Interestingly, among 5 patients with 20q deletions, 4 had a myeloproliferative disorder while all 3 men in this group had prostate cancer. In summary, in a GWAS of 3336 adults, 0.75% had autosomal chromosomal abnormalities and nearly a third of them had hematologic malignancies. A potential novel association between 20q deletions, myeloproliferative disorders, and prostate cancer was also noted. PMID- 26425588 TI - A Spontaneously Ruptured Hepatic Metastasis From a Gastric Gastrointestinal Stromal Tumor That Presented as Hemoperitoneum. AB - Spontaneous hepatic hemorrhage is a rare condition that may be caused by an underlying hepatic tumor, most commonly hepatocellular carcinoma or hepatic adenoma. A spontaneous rupture of a hepatic metastasis from a gastric gastrointestinal stromal tumor is also extremely rare, and the majority of affected patients present with hypovolemic shock or an acute abdomen. In this article, we report the case of a 65-year-old man with a spontaneous rupture of a hepatic metastasis from a gastric gastrointestinal stromal tumor that presented as hypovolemic shock. Cross-sectional imaging studies (computed tomography or magnetic resonance imaging) play a significant role in the diagnosis of this condition and guides its management. PMID- 26425589 TI - Fixed Drug Eruption in an Epileptic Patient Previously Receiving Treatment With Phenytoin for Seven Years. AB - A 52-year-old African American female presented with severe left thigh pain of unknown etiology. She had a past medical history of generalized seizure disorder treated with phenytoin for 7 years without incident. During admission a nurse witnessed a seizure, and consequently loading and maintenance doses of phenytoin were administered to obtain a therapeutic serum concentration. The patient had a history of noncompliance with multiple subtherapeutic phenytoin levels. Subsequently, unifocal blue discolored spots appeared, progressing to a bullous component that was positive for skin sloughing. Drug-induced fixed drug eruption was diagnosed and attributed to phenytoin. Clinicians should be cognizant of drug induced fixed drug eruption in patients just initiated and those receiving long term treatment with phenytoin. The administration rate of phenytoin may be associated with the development of fixed drug eruption. PMID- 26425590 TI - Isolated Pulmonary Valve Endocarditis Complicated With Septic Emboli to the Lung Causing Pneumothorax, Pneumonia, and Sepsis in an Intravenous Drug Abuser. AB - Intravenous drug users are at increased risk for developing right-sided infective endocarditis involving the tricuspid and pulmonary valves. Isolated pulmonary valve endocarditis in intravenous drug users is very rare, and these patients often have more complications, such as pulmonary embolism, sepsis, and pneumonia. We report a case with pulmonary valve endocarditis and extensive pulmonary complications, including sepsis, septic emboli, pneumonia, and pneumothorax. Early identification of pulmonic valve endocarditis and treatment with appropriate antibiotics with or without surgical management should provide better outcomes, and clinicians need to think about pulmonary valve endocarditis in patients with complex respiratory presentations. PMID- 26425591 TI - Drug-Induced Liver Injury by Glatiramer Acetate Used for Treatment of Multiple Sclerosis: A Case Report. AB - Glatiramer acetate (GA, Copaxone) is an approved drug for the treatment of relapsing-remitting multiple sclerosis. Most common side effects observed with GA are local injection site reactions, which can include pain, swelling, or redness. However, systemic adverse event such as hepatotoxicity related to GA is rarely seen. In this report, we present a case of GA-induced toxic hepatitis associated with cholestatic and hepatocellular damage. PMID- 26425592 TI - Late Onset of CSF Rhinorrhea in a Postoperative Transsphenoidal Surgery Patient Following Robotic-Assisted Abdominal Hysterectomy. AB - Cerebrospinal fluid (CSF) leak is the most commonly encountered perioperative complication in transsphenoidal surgery for pituitary lesions. Direct closure with a combination of autologous fat, local bone, and/or synthetic grafts remains the standard of care for leaks encountered at the time of surgery as well as postoperatively. The development of the vascularized nasoseptal flap as a closure technique has increased the surgeon's capacity to correct even larger openings in the dura of the sella as well as widely exposed anterior skull base defects. Yet these advances in the technical nuances for management of post-transsphenoidal CSF leak are useless without the ability to recognize a CSF leak by physical examination, clinical history, biochemical testing, or radiographic assessment. Here, we report a case of a patient who developed a CSF leak 28 years after transsphenoidal surgery, precipitated by a robotic-assisted hysterectomy during which increased intra-abdominal pressure and steep Trendelenberg positioning were both factors. Given the remote nature of the patient's transsphenoidal surgery and relative paucity of data regarding such a complication, the condition went unrecognized for several months. We review the available literature regarding risk and pathophysiology of CSF leak following abdominal surgery and propose the need for increased vigilance in identification of such occurrences with the increasing acceptance and popularity of minimally invasive abdominal and pelvic surgeries as standards in the field. PMID- 26425593 TI - Perioperative Outcome of Dyssomnia Patients on Chronic Methylphenidate Use. AB - Methylphenidate is frequently prescribed for attention deficit hyperactivity disorder, narcolepsy, and other sleep disorders requiring psychostimulants. Our report is based on 2 different clinical experiences of patients with chronic methylphenidate use, undergoing general anesthesia. These cases contrast different strategies of taking versus withholding the drug treatment on the day of surgery. From the standpoint of anesthetic management and patient safety, the concerns for perioperative methylphenidate use are mainly related to cardiovascular stability and possible counteraction of sedatives and anesthetics. PMID- 26425594 TI - Right-Sided Pleural Effusion in a Critically Ill Stroke Patient. AB - Pleural fluid collections are common in those critically ill. We report the case of a left middle cerebral artery stroke patient who developed respiratory distress and required intubation and mechanical ventilation. Although the patient's clinical status and oxygenation improved, there was persistence of right-sided opacity in the chest radiograph. Further workup proved a right-sided pleural effusion, which was drained and managed. Following extubation, a swallow study was ordered, which led to a fluoroscopic examination that demonstrated esophageal perforation. Thoracic surgery was consulted and did a primary repair of perforation and noted non-small cell carcinoma on the perforated site. PMID- 26425595 TI - Intravascular Large B-Cell Lymphoma: A Difficult Diagnostic Challenge. AB - Case Presentation. A 69-year-old Hispanic male, with a past history of diabetes and coronary disease, was admitted for fever, diarrhea, and confusion of 4 weeks duration. Physical examination showed a disoriented patient with multiple ecchymoses, possible ascites, and bilateral scrotal swelling. Hemoglobin was 6.7, prothrombin time (PT) 21.4 seconds with international normalized ratio 2.1, partial thromboplastin time (PTT) 55.6 seconds, fibrin split 10 ug/L, and lactate dehydrogenase (LDH) 1231 IU/L. Except for a positive DNA test for Epstein-Barr virus (EBV) infection, extensive diagnostic workup for infections, malignancy, or a neurological cause was negative. Mixing studies revealed a nonspecific inhibitor of PT and PTT but Factor VIII levels were normal. The patient was empirically treated with antibiotics but developed hypotension and died on day 27 of admission. At autopsy, patient was found to have intravascular diffuse large B cell lymphoma involving skin, testes, lung, and muscles. The malignant cells were positive for CD20, CD791, Mum-1, and Pax-5 and negative for CD3, CD5, CD10, CD30, and Bcl-6. The malignant cells were 100% positive for Ki-67. Discussion. Intravascular large cell B-cell lymphoma (IVLBCL) is rare form of diffuse large B cell lymphoma and tends to proliferate within small blood vessels, particularly capillaries and postcapillary venules. The cause of its affinity for vascular bed remains unknown. In many reports, IVLBCL was associated with HIV, HHV8, and EBV infections. The fact that our case showed evidence of EBV infection lends support to the association of this diagnosis to viral illness. The available literature on this subject is scant, and in many cases, the diagnosis was made only at autopsy. The typical presentation of this disorder is with B symptoms, progressive neurologic deficits, and skin findings. Bone marrow, spleen, and liver are involved in a minority of patients. Nearly all patients have elevated LDH, and about 65% are anemic. About 20% have hepatic and renal dysfunction. The treatment consists of systemic chemotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone plus rituximab (CHOP-R) and central nervous system prophylaxis. Retrospective data suggests that, with treatment, 51% to 82% of the patients achieve a complete remission and 27% to 56% are alive at 2-year follow up. Conclusion. IVLBCL is a difficult diagnosis to make as the disease remains confined to the vascular lumen. It may be associated with certain viral illnesses, and this association needs to be explored further. It is important to consider this diagnosis in the appropriate settings because patients may achieve durable remissions with therapy. PMID- 26425596 TI - Reversible Adrenal Insufficiency in Three Patients With Post-Roux-en-Y Gastric Bypass Noninsulinoma Pancreatogenous Hypoglycemia Syndrome. AB - Objective. Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) is a disorder of endogenous hyperinsulinemia that is clinically distinguishable from insulinoma, with a greater preponderance after Roux-en-Y gastric bypass (RYBG). Hyperinsulinemic hypoglycemia can predispose to attenuation of counterregulatory hormone responses to hypoglycemia, and consequent suppression of the hypothalamic pituitary-adrenal (HPA) axis. This case series describes 3 individuals who were diagnosed with adrenal insufficiency (AI) after undergoing RYGB, complicated by NIPHS. Methods. A retrospective chart review was performed for each individual. Chart review applied particular attention to the onset of hyperinsulinemic hypoglycemia following bariatric surgery and the dynamic testing leading to the diagnoses of NIPHS and AI. Results. In each case, reactive hypoglycemia ensued within months to years after RYGB. Cosyntropin stimulation testing confirmed the diagnosis of AI. Hydrocortisone therapy reduced the frequency and severity of hypoglycemia and was continued until successful medical and/or surgical management of hyperinsulinism occurred. Follow-up testing of the HPA axis demonstrated resolution of AI. In all cases, hydrocortisone therapy was finally discontinued without incident. Conclusion. We speculate that transient AI is a potential complication in patients who experience recurrent hyperinsulinemic hypoglycemia after RYGB. The putative mechanism for this observation may be attenuation of the HPA axis after prolonged exposure to severe, recurrent hypoglycemia. We conclude that biochemical screening for AI should be considered in individuals who develop post-RYGB hyperinsulinemic hypoglycemia. If AI is diagnosed, supportive treatment should be maintained until hyperinsulinemic hypoglycemia has been managed effectively. PMID- 26425597 TI - Long-Term Hypoparathyroidism and Hypophosphatemia in Dialysis Patients. AB - Background and Objectives. Hypoparathyroidism in patients with functioning kidneys leads to hyperphosphatemia. This article reviews data suggesting that hypoparathyroidism in patients on dialysis leads to hypophosphatemia. Design. Clinical data of the following were reviewed: (a) a patient with hypoparathyroidism before and during chronic dialysis; (b) patients on dialysis with surgically created hypoparathyroidism; (c) dialysis patients being treated with Cinacalcet, a calcium-sensing receptor agonist that lowers parathyroid hormone (PTH) levels; and (d) dialysis patients being treated with Velcalcetide, a new calcium-sensing receptor agonist that also lowers PTH. Results. In the patient presented in this study, in patients with surgically created hypoparathyroidism, and those receiving Cinacalcet or Velcalcetide, a fall in PTH was associated with hypophosphatemia or a fall in serum phosphorus. Conclusion. In patients on dialysis, hypoparathyroidism may lead to hypophosphatemia. PMID- 26425598 TI - Postural Orthostatic Tachycardia With Chronic Fatigue After HPV Vaccination as Part of the "Autoimmune/Auto-inflammatory Syndrome Induced by Adjuvants": Case Report and Literature Review. AB - We report the case of a 14-year-old girl who developed postural orthostatic tachycardia syndrome (POTS) with chronic fatigue 2 months following Gardasil vaccination. The patient suffered from persistent headaches, dizziness, recurrent syncope, poor motor coordination, weakness, fatigue, myalgias, numbness, tachycardia, dyspnea, visual disturbances, phonophobia, cognitive impairment, insomnia, gastrointestinal disturbances, and a weight loss of 20 pounds. The psychiatric evaluation ruled out the possibility that her symptoms were psychogenic or related to anxiety disorders. Furthermore, the patient tested positive for ANA (1:1280), lupus anticoagulant, and antiphospholipid. On clinical examination she presented livedo reticularis and was diagnosed with Raynaud's syndrome. This case fulfills the criteria for the autoimmune/auto-inflammatory syndrome induced by adjuvants (ASIA). Because human papillomavirus vaccination is universally recommended to teenagers and because POTS frequently results in long term disabilities (as was the case in our patient), a thorough follow-up of patients who present with relevant complaints after vaccination is strongly recommended. PMID- 26425599 TI - Ineffectual Medical Treatment of Cesarean Scar Ectopic Pregnancy With Systemic Methotrexate: A Report of Two Cases. AB - The implantation of a pregnancy within the scar of a previous cesarean section is known as a "cesarean scar pregnancy." Its incidence was reported to be 6.1%. However, with the increasing rates of cesarean sections, the incidence is expected to rise. A variety of conservative and surgical treatment modalities have been proposed for the management of cesarean scar pregnancy; however, there are no optimal universal treatment guidelines because of its rarity. Treatment should be tailored to the individual patient. It is obvious that more scar pregnancies will be seen in the future and therefore a set of criteria for the choice of various modes of management should be developed. Here, we present 2 cases of cesarean scar pregnancies treated with a local injection of potassium chloride after the failure of methotrexate administration. PMID- 26425600 TI - Pulmonary Artery Sarcoma: A Rare Entity. AB - Pulmonary artery sarcomas (PAS) are extremely rare sarcomas of uncertain histogenesis that often mimic pulmonary thromboemboli. This is a report of a 60 year-old female patient who presented with recurrent chest pain and cough. The patient was first diagnosed with pulmonary embolism but she did not improve on anticoagulant therapy. Follow-up imaging studies revealed a mass in the left hilar region extending into the pulmonary trunk and branches of the left pulmonary artery. The tru-cut biopsy revealed an undifferentiated sarcoma. The patient died 10 months after her initial presentation. PMID- 26425601 TI - Neuroborreliosis Mimicking Leptomeningeal Carcinomatosis in a Patient With Breast Cancer: A Case Report. AB - Leptomeningeal carcinomatosis is a serious complication of advanced cancer. Various clinical manifestations may present, such as headache, nausea, seizures, cranial neuropathies. In this article, we report the case of a 65-year-old woman with metastatic breast cancer who was admitted to hospital suffering from facial palsy, which was suspected to be caused by leptomeningeal tumor infiltration. Magnetic resonance imaging (MRI) scans of the head and spine showed meningeal enhancement of the facial nerve, conus medullaris, and fibers of the cauda equina, which were radiologically interpreted as leptomeningeal carcinomatosis. Assessment of cerebrospinal fluid found no malignant cells but investigation for infectious diseases established the diagnosis of neuroborreliosis. Antibiotic treatment with doxycycline was performed. After completion of treatment, follow up MRI scans found complete regression of meningeal enhancement. Several months later, the patient is still in good condition and without neurological symptoms. Hence, initial diagnosis of leptomeningeal carcinomatosis was rejected. This case report should alert oncologists to carefully rule out infectious diseases before leptomeningeal carcinomatosis is diagnosed. Cerebrospinal fluid analysis is strongly recommended due to low specificity of MRI images in this regard. PMID- 26425602 TI - Herpes Simplex Pneumonia in an Immunocompetent Patient With Progression to Organizing Pneumonia. AB - Background. Organizing pneumonia is an uncommon diffuse interstitial lung disease that affects the terminal and respiratory bronchioles, alveolar ducts, and alveoli. Most cases are idiopathic, but some are associated with infections. We present an uncommon case of organizing pneumonia associated with herpes simplex virus-1 (HSV-1). Case. A 39-year-old man with hypertension presented with dyspnea, fever, and productive cough for 2 weeks. He was treated for 5 days for acute bronchitis as an outpatient with no improvement. His examination revealed mild respiratory distress, O2 saturation 92% on room air, and right sided crackles. Labs included a white blood cell count of 19 300/uL. His chest x-ray showed bilateral infiltrates greater on the right. Bronchoalveolar lavage was positive for HSV-1; transbronchial biopsies showed focal pneumonitis with plentiful intra-alveolar macrophages. His respiratory status progressively deteriorated, and he was intubated for mechanical ventilation. He received 10 days of intravenous (IV) antibiotics and 14 days of IV acyclovir. He was readmitted 10 days later with worsening symptoms and was intubated for respiratory failure. His CT chest showed diffuse, patchy consolidation of both lungs, right more than left. Open lung biopsy showed extensive organizing pneumonia, diffuse alveolar damage, intra-alveolar macrophages, and pleural fibrosis; he was treated with IV corticosteroids. He was extubated after 10 days; within 2 weeks his chest x-ray was markedly improved. Discussion. Organizing pneumonia is usually idiopathic; infection is one of the secondary causes. To our knowledge this is only the second reported case associated with HSV. This association may have important pathogenic and therapeutic implications. PMID- 26425603 TI - Spontaneous Heterotopic Triplet Pregnancy With Tubal Rupture: A Case Report and Literature Review. AB - The recent increase in heterotopic pregnancies has been largely attributed to the increased use of assisted reproduction technologies. We report the rare case of a multiparous woman with a spontaneous conception resulting in a triplet heterotopic pregnancy: a twin intrauterine pregnancy and a single right tubal ectopic pregnancy. Heterotopic pregnancy is a rare and potentially life threatening condition in which simultaneous gestations occur at 2 or more implantation sites. It is infrequent in natural conception cycles, occurring in 1:30 000 pregnancies. However, the prevalence is rising with the increased use of assisted reproduction techniques to that of 1:100 to 1:500 in these patient subgroups, highlighting the need to incorporate it into a clinician's diagnostic algorithm. PMID- 26425604 TI - Medulloblastoma in an Adult With Late Extraneural Metastases to the Mediastinum. AB - Background. Medulloblastoma, although the most common brain tumor of childhood, is exceedingly rare in adults. These tumors have a propensity for local recurrence and to metastasize along the leptomeninges; however, extraneural metastases are very rare and typically occur in the bone or bone marrow. We have not come across any case in literature of medulloblastoma with mediastinal metastases in an adult. Case Presentation. We report a case of medulloblastoma in a 38-year-old lady who was treated with surgery followed by craniospinal radiation. Ten years later she presented with hoarseness from true vocal cord paralysis. She was diagnosed to have infiltrating metastases of her medulloblastoma to the mediastinum, which was confirmed by biopsy. There was no local recurrence. This was treated with chemotherapy followed by stem cell rescue, and she remained progression free for 2 years. Conclusion. Medulloblastomas are rare in adults and can present with late extraneural metastases following treatment. Although most common reported sites are bone and bone marrow, late metastases to other unexpected areas like the mediastinum are possible too and warrant awareness. This can be treated with chemotherapy followed by high-dose chemotherapy and stem cell rescue in a young patient with good performance status. PMID- 26425606 TI - Cholestatic Jaundice With the Use of Methylstenbolone and Dymethazine, Designer Steroids Found in Super DMZ Rx 2.0 "Nutritional Supplement": A Case Report. AB - "Nutritional supplements" that promise an increase in muscle mass and strength are becoming a go to item as enhancing one's physical appearance becomes a more important part of our society. This is alarming because many of these nutritional supplements rely on androgen precursors to deliver their promises, without adequately informing consumers of the potential side effects of such agents. These products may conceal the presence of potent androgens to avoid regulatory sanctions and become more appealing to consumers. Recent reports have shown that some products marketed as "nutritional supplements" have been found to contain androgenic anabolic steroids. Methylstenbolone and dymethazine are new androgenic anabolic steroids currently gaining popularity among body builders for their performance-enhancing properties and rapid effects on muscle mass. These agents are found together in Super DMZ Rx 2.0, a "dietary supplement" for bodybuilders. Here we report the first case of Super DMZ Rx 2.0-induced cholestatic jaundice in a 26-year-old previously healthy Caucasian male, who took the supplement according to the manufacturer's instructions for 30 days. PMID- 26425607 TI - Fever Through a Jaundiced Eye. AB - Pyogenic liver abscess (PLA) is an important clinical entity to consider in a patient with fever and abdominal pain. Previously, the condition was difficult to diagnose and treat, but with the introduction of widely available and reliable imaging techniques, its diagnosis has become more straightforward. Although uncommon, PLA should especially be considered in the differential diagnosis for patients with specific predisposing conditions such as underlying biliary tract disease, whether as a result of chronic inflammatory disease or malignancy. The introduction of percutaneous drainage has revolutionized the management of PLA, and thus, this disease has become largely correctable. PMID- 26425605 TI - Ultrasound Detection of Salmonella Septic Arthritis in a Rheumatoid Arthritis Patient on Anti-TNF Treatment. AB - We report a case of Salmonella septic arthritis detected by ultrasound in a 40 year-old man with rheumatoid arthritis while he was on anti-tumor necrosis factor alpha monoclonal antibody certolizumab. An aspirate of his left elbow joint showed Salmonella enteritidis infection that was sensitive to ceftraixone. This was preceded by a brief episode of loose stools following a visit to the Far East. He was treated with antibiotics and made a good recovery. There have only been a few case reports of Salmonella septic arthritis in a rheumatoid arthritis patient on anti-tumor necrosis factor treatment but none previously in association with certolizumab. PMID- 26425608 TI - Immune Reconstitution Inflammatory Syndrome in Acquired Immune Deficiency Syndrome related to Cryptococcal Meningoencephalitis. AB - Background. Highly active antiretroviral therapy (HAART) has contributed to reducing the occurrence of opportunistic infections and mortality in human immunodeficiency virus (HIV) infected patients. However, a paradoxical worsening of clinical signs and symptoms among patients during HAART may occur. Immune reconstitution inflammatory syndrome (IRIS) is described as a paradoxical deterioration of clinical status on initiation of HAART in patients with HIV infection. Case Report. We describe the case of a 41-year-old man with opportunistic cryptococcal encephalitis who exhibited neurological and radiological deterioration during the course of HAART. A diagnosis of central nervous system (CNS)-IRIS was based on a decrease of HIV-RNA viral load greater than 1 log, with an increase in CD4(+) T-cell count from baseline. Conclusions. Differential diagnosis of this paradoxical deterioration in clinical and neurological status from overwhelming opportunistic infection is important; it enables an avoidance of unnecessary diagnostic procedures and proper management of this HIV-associated CNS disorder. PMID- 26425609 TI - Brachial Neuritis With Phrenic Nerve Involvement in a Patient With a Possible Connective Tissue Disease. AB - Background. Brachial neuritis (BN) is a rare inflammatory condition of peripheral nerves, usually involving the cervicobrachial plexus. These patients present with sudden onset of shoulder and arm pain that evolves into muscle weakness and atrophy.. Case Report. A 33-year-old woman presented with a 1-month history of diffuse pain in her thorax. She had no trauma or inciting incident prior to the onset of this pain and was initially treated for muscle spasms. The patient was seen in the emergency room multiple times and was treated with several courses of antibiotics for pneumonia on the basis of clinical symptoms and abnormal x-rays. The pleuritic chest pain persisted for at least 4 months, and the patient was eventually admitted for worsening pain and dyspnea. On physical examination, crackles were heard at both lung bases, and chest inspection revealed increased expansion in the upper thorax but poor expansion of the lower thorax and mild paradoxical respiration. "Sniff" test revealed no motion of the left hemidiaphragm and reduced motion on the right hemidiaphragm. Her computed tomography scan revealed bilateral atelectasis, more severe at the left base. She reported no symptoms involving her joints or skin or abdomen. Her presentation and clinical course are best explained by BN with a bilateral diaphragmatic weakness. However, she had a positive ANA, RF, anti-RNP antibody, and anti SS-A. Conclusion. Patients with BN can present with diffuse thoracic pain, pleuritic chest pain, and diaphragmatic weakness. Our patient may represent a case of connective tissue disease presenting with brachial plexus neuritis. PMID- 26425610 TI - Tension Pneumothorax During Surgery for Thoracic Spine Stabilization in Prone Position: A Case Report and Review of Literature. AB - The intraoperative progression of a simple or occult pneumothorax into a tension pneumothorax can be a devastating clinical scenario. Routine use of prophylactic thoracostomy prior to anesthesia and initiation of controlled ventilation in patients with simple or occult pneumothorax remains controversial. We report the case of a 75-year-old trauma patient with an insignificant pneumothorax on the right who developed an intraoperative tension pneumothorax on the left side while undergoing thoracic spine stabilization surgery in the prone position. Management of an intraoperative tension pneumothorax requires prompt recognition and treatment; however, the prone position presents an additional challenge of readily accessing the standard anatomic sites for pleural puncture and air drainage. PMID- 26425611 TI - Mitral Valve Annuloplasty Ring Dehiscence Diagnosed Intraoperative With Real-Time 3D Transesophageal Echocardiogram. AB - Mitral annular calcification (MAC) is often a result of the accumulation of lipids around the annulus, which can lead to degeneration and calcification of the valve. Multiple risk factors have been associated with the progression of MAC and life-threatening complications such as the early mitral valve annuloplasty dehiscence. Our case describes the different risk factors for annuloplasty dehiscence in a patient with severe MAC, as well as the importance of its early recognition intraoperatively with 3D transesophageal echocardiography. PMID- 26425612 TI - Trousseau's Syndrome, a Previously Unrecognized Condition in Acute Ischemic Stroke Associated With Myocardial Injury. AB - Trousseau's syndrome is a well-known malignancy associated hypercoagulative state leading to venous or arterial thrombosis. The pathophysiology is however poorly understood, although multiple mechanisms are believed to be involved. We report a case of Trousseau's syndrome resulting in concomitant cerebral and myocardial microthrombosis, presenting with acute ischemic stroke and markedly elevated plasma troponin T levels suggesting myocardial injury. Without any previous medical history, the patient developed multiple cerebral infarctions and died within 11 days of admission. The patient was postmortem diagnosed with an advanced metastatic adenocarcinoma of the prostate with disseminated cerebral, pulmonary, and myocardial microthrombosis. Further analyses revealed, to the best of our knowledge for the first time in stroke patients, circulating microvesicles positive for the epithelial tumor marker CK18 and citrullinated histone H3 in thrombi, markers of the recently described cancer-associated procoagulant DNA based neutrophil extracellular traps. We also found tissue factor, the main in vivo initiator of coagulation, both in thrombi and in metastases. Troponin elevation in acute ischemic stroke is common and has repeatedly been associated with an increased risk of mortality. The underlying pathophysiology is however not fully clarified, although a number of possible explanations have been proposed. We now suggest that unexplainable high levels of troponin in acute ischemic stroke deserve special attention in terms of possible occult malignancy. PMID- 26425613 TI - Hepatic Dysfunction as a Paraneoplastic Manifestation of Metastatic Prostate Adenocarcinoma. AB - Cholestasis is a general feature of intrahepatic or extrahepatic biliary obstruction by various mechanisms including cirrhosis, stricture, choledocholithiasis, hepatitis, and neoplasms. Neoplasms can directly impinge on the hepatobiliary tree resulting in bile stasis. Stauffer's syndrome is another variant of this neoplastic process that can cause cholestasis and liver enzyme elevation without any direct hepatobiliary obstruction, and is thus categorized as a paraneoplastic syndrome of unclear pathophysiology. We report a first case of metastatic prostate adenocarcinoma with features of Stauffer's syndrome that reversed completely on androgen deprivation therapy. This is in contrast to a previously reported case of Stauffer's syndrome due to metastatic prostate adenocarcinoma, which reversed partially to androgen deprivation therapy. Our case demonstrates the importance of early recognition of Stauffer's syndrome and underlying neoplasms in patients who present with cholestasis without clear evidence of intrahepatic or extrahepatic biliary obstruction, which may lead to early initiation of treatment. PMID- 26425614 TI - Abnormal Origin of the Right Pulmonary Artery From Ascending Aorta (Hemitruncus Arteriosus). AB - Hemitruncus arteriosus is a rare congenital deformity that results in early infant mortality. Persistence into adulthood is very unusual and is associated with pulmonary hypertension. We report a case in an adult male with the associated clinical issues. PMID- 26425616 TI - Tumor Lysis Syndrome in a Retroperitoneal Sarcoma. AB - In the present case, a 49-year-old white female presented to the clinic with a 2 month history of nausea, vomiting, and right upper quadrant pain. On examination a 3-cm mass on the right anterior scalene muscle was noted. A computed tomography scan was performed revealing a 8.7 * 7.7 * 6.1 cm retroperitoneal mass with possible invasion of the inferior vena cava and right renal and left common iliac veins. An excisional biopsy was performed with pathology compatible with spindle cell sarcoma. The patient was then sent for follow-up at the sarcoma clinic as an outpatient. However, before chemotherapy was to be started the patient would be admitted to the hospital with progressively worse nausea and vomiting. At that time the patient's lab work showed lactic acidosis, acute renal failure, hyperuricemia, hyperphosphatemia, and hypocalcemia, which met the Cairo-Bishop criteria for tumor lysis syndrome (TLS). The patient was admitted to the intensive care unit and kidney dialysis initiated. The patient would become progressively obtunded at which time the family opted for hospice care. The patient eventually succumbed peacefully 3 days after her last admission. In this case report, we briefly review the literature on TLS in solid tumors, and we present a rare case of spontaneous TLS in a retroperitoneal sarcoma. PMID- 26425615 TI - Acute Surgical Abdomen: An Unusual Presentation of Pulmonary Embolus. AB - Background. Pulmonary embolism is a common and potentially lethal condition. Most patients who die from massive pulmonary embolism do so within the first few hours of the event. The clinical manifestations of pulmonary embolism are nonspecific, which makes the diagnosis difficult. Case Report. We present a case of massive pulmonary embolism presenting as an acute surgical abdomen that underwent exploratory laparotomy and made a complete recovery. Why should an emergency physician be aware of this? Emergency department physicians should be aware that massive pulmonary embolism could present as an acute surgical abdomen in young healthy individuals. PMID- 26425617 TI - Follicular Thyroid Carcinoma Presenting With Endobronchial Metastases: Case Report and Review of Literature. AB - Endobronchial metastasis is a rare manifestation of differentiated thyroid cancer. A 79-year-old male was admitted to the hospital with shortness of breath, chest pain, anemia, and weight loss. Computed tomography of chest revealed multiple lung nodules. Bronchoscopy showed an endobronchial lesion in the right upper lobe. The biopsy of the lesion demonstrated neoplastic cells stained positive for thyroglobulin, thyroid transcription factor-1, and cytokeratin-7, consistent with metastatic follicular thyroid cancer. Physical examination revealed a firm fixed thyroid nodule, which was confirmed by thyroid ultrasound. He subsequently underwent total thyroidectomy and neck exploration. Thyroid gland pathology revealed a nodule with features of high-grade follicular thyroid carcinoma. Metastatic thyroid cancer should be considered in workup of pulmonary nodules. We recommend an examination of thyroid gland in patients who present with pulmonary nodules associated with signs and symptoms of malignancy. PMID- 26425618 TI - Permanent Peripheral Neuropathy: A Case Report on a Rare but Serious Debilitating Side-Effect of Fluoroquinolone Administration. AB - The health risks and side effects of fluoroquinolone use include the risk of tendon rupture and myasthenia gravis exacerbation, and on August 15, 2013, the Food and Drug Administration updated its warning to include the risk of permanent peripheral neuropathy. We present a case of fluoroquinolone-induced peripheral neuropathy in a patient treated for clinically diagnosed urinary tract infection with ciprofloxacin antibiotic. PMID- 26425619 TI - Belatacept for Maintenance Immunosuppression in Lung Transplantation. AB - Belatacept is a novel immunosuppressant that blocks a T-cell costimulation pathway and is approved for use in adult kidney transplant recipients. Its safety and efficacy have not been established after lung transplantation. We present a case of a lung transplant recipient treated with belatacept. A 56-year-old man underwent bilateral lung retransplantation for bronchiolitis obliterans syndrome (BOS). In the third year posttransplant, he developed hemolytic uremic syndrome (HUS) attributed to tacrolimus. Tacrolimus was changed to sirolimus. One month later, he presented with worsening renal function and HUS attributed to sirolimus. Plasmapheresis and steroid pulse were initiated with clinical improvement, and sirolimus was switched to belatacept. He experienced no episodes of cellular rejection but developed recurrent BOS. Complications during treatment included anemia and recurrent pneumonias. The safety and efficacy of belatacept in lung transplantation remains unclear; further studies are needed. PMID- 26425620 TI - Carotid Stump Syndrome: Case Report and Endovascular Treatment. AB - Objectives. To highlight the case of a patient with multiple transient ischemic attacks and visual disturbances diagnosed with carotid stump syndrome and managed with endovascular approach. Case Presentation. We present the case of a carotid stump syndrome in an elderly patient found to have moderate left internal carotid artery stenosis in response to an advertisement for carotid screening. After a medical therapeutic approach and a close follow-up, transient ischemic attacks recurred. Computed tomographic angiography showed an occlusion of the left internal carotid artery and the presence of moderate stenosis in the right internal carotid artery, which was treated by endovascular stenting and balloon insertion. One month later, the patient presented with visual disturbances due to the left carotid stump and severe stenosis of the left external carotid artery that was reapproached by endovascular stenting. Conclusion. Considerations should be given to the carotid stump syndrome as a source of emboli for ischemic strokes, and vascular assessment could be used to detect and treat this syndrome. PMID- 26425621 TI - Severe Osteomalacia Related to Long-Term Intravenous Drug Abuse. AB - Objective. We present the clinical, biochemical, and imaging findings of a woman with vitamin D deficiency and severe osteomalacia related to intravenous heroin addiction. Results. A 54-year-old woman with a medical history significant for long-standing heroin abuse presented with complaints of bone pain, muscle cramping, and a left hip ulcer. She had been bed bound for approximately 1 year secondary to pain of uncertain etiology, and her husband was bringing her both food and drugs. She was admitted to the hospital for debridement of a right ischial ulcer. Further workup revealed osteomyelitis of the left hip and severe vitamin D deficiency. Radiologic evaluation demonstrated diffuse osteopenia with pseudofractures, as well as true fractures. Conclusion. This is the first case reported in the English literature of advanced osteomalacia resulting from a debilitating narcotic dependency. Vitamin D deficiency should be considered in patients with poor nutrition and prolonged sunlight deprivation from any cause. PMID- 26425622 TI - When Coke Is Not Hydrating: Cocaine-Induced Acute Interstitial Nephritis. AB - A 47-year-old African American man was admitted with 4 days of back pain, nausea and vomiting, and low urine output. There was no history of fever, dysuria, frequency, hesitancy, viral symptoms, trauma, rash, or constipation. Despite his past medical history of hypertension, diabetes mellitus, and hyperlipidemia he denied taking any medications for 18 months, including nonsteroidal anti inflammatory drugs, acetaminophen, or antacids. He denied smoking and alcohol but admitted to cocaine use. No significant FH. Physical examination results were as follows: BP 235/125 mm Hg, heart rate 90 beats/min, temperature 98 degrees F, O2 saturation normal; lungs and heart normal, abdomen soft but bilateral costovertebral angle tenderness. Neurological examination was normal. Laboratory tests yielded the following results: creatinine (Cr) 10.5 mg/dL (1.2 mg/dL in 2010), blood urea nitrogen 63 mg/dL, glucose 151 mg/dL, Ca 9.4 mg/dL, PO4 6.1 mg/dL, Hgb 15 g/dL, white blood cells (WBC) 9100, platelets 167 000, amylase/lipase normal, aspartate aminotransferase/alanine aminotransferase (AST/ALT) normal, bilirubin 1.4 mg/dL, alkaline phosphatase 39 IU/L, creatine phosphokinase 127 ug/L. Hepatic panel, C- and P-ANCA (cytoplasmic- and perinuclear-antineutrophil cytoplasm antibodies, respectively), anti-GBM (anti glomerular basement membrane), antimyeloperoxidase, antinuclear antibody, and Helicobacter pylori were all negative. C3, C4 normal, urinalysis: 2+ blood, no white blood cells or eosinophils, no casts, no albumin, negative for nitrate/leukocyte esterase and bacteria. Imaging: chest radiograph, abdominal radiograph, computed tomography of the abdomen, electrocardiography, and transthoracic echocardiography were all normal. Course. The patient's urine output declined from 700 to 400 cm(3)/d and the on third day he required hemodialysis with Cr 14 mg/dL. Renal biopsy showed typical findings of interstitial nephritis. The patient was dialyzed for 10 days and responded to steroids and went home with an improving Cr of 3.5 mg/dL, back to baseline of 1.5 in 8 weeks. Discussion. Internists encounter patients with acute kidney injury (AKI) on a daily basis, most of which can be explained by prerenal azotemia, acute tubular necrosis (ATN), obstruction, or rhabdomyolysis among other etiologies. Cocaine is only rarely implicated as an etiology of AKI and if it is, usually the injury is due to ATN or pigment effects. Acute interstitial nephritis (AIN) caused by cocaine, on the other hand, has only been described in a handful of cases. AIN is a renal lesion that causes a decline in creatinine clearance and is characterized by an inflammatory infiltrate in the kidney interstitium and is most often associated with drug therapy. AIN can also be seen in autoimmune disorders like systemic lupus erythematosus, Sjogren's syndrome, or sarcoidosis; or with infections remote to the kidney like Legionella, leptospirosis, and streptococcal disease. Our case was very similar to the other reported cases of AIN due to cocaine in that all have occurred in middle-aged African American males and all have responded to steroids. This case reminds clinicians to consider AIN in patients with AKI and a history of cocaine abuse. PMID- 26425623 TI - A Spotty Liver of Pregnancy. AB - Herpes simplex virus (HSV) hepatitis by definition constitutes disseminated herpes simplex infection; it is rare, with only approximately 130 cases reported in the literature. Although HSV hepatitis typically occurs in immunocompromised hosts, pregnancy-especially the third trimester, has been identified as a risk factor for its development. This is likely because of the fact that humoral and cell-mediated immunity decrease throughout pregnancy and nadir in the third trimester with decreased T-cell counts and altered B/T lymphocyte ratios. Here, we report on a patient with HSV 2 hepatitis in a previously healthy 27-year-old woman in her 23rd week of pregnancy. She initially presented with nausea, vomiting, and abdominal pain and was found to have acute hepatocellular liver injury and a systemic inflammatory response syndrome. Broad-spectrum antibiotics and acyclovir were promptly initiated. Liver biopsy, serum DNA polymerase chain reaction (PCR) as well as a labial ulcer culture and PCR were all positive for HSV 2. The patient recovered completely; however, her fetus did not survive. Review of the literature emphasizes that presentation with disseminated HSV infection typically occurs in the third trimester of pregnancy. This report emphasizes that abdominal pain combined with fever and hepatic dysfunction in pregnancy should prompt immediate consideration of the diagnosis of HSV hepatitis. Furthermore, given the high mortality rate and effective treatment, empiric treatment with acyclovir should be considered early in all potential cases. PMID- 26425625 TI - Cocaine Intoxication and Thyroid Storm: Similarity in Presentation and Implications for Treatment. AB - Introduction. Cocaine, a widely used sympathomimetic drug, causes thermoregulatory and cardiac manifestations that can mimic a life-threatening thyroid storm. Case. A man presented to the emergency department requesting only cocaine detoxification. He reported symptoms over the last few years including weight loss and diarrhea, which he attributed to ongoing cocaine use. On presentation he had an elevated temperature of 39.4 degrees C and a heart rate up to 130 beats per minute. Examination revealed the presence of an enlarged, nontender goiter with bilateral continuous bruits. He was found to have thyrotoxicosis by labs and was treated for thyroid storm and cocaine intoxication concurrently. The patient was ultimately diagnosed with Graves' disease and treated with iodine-131 therapy. Conclusion. Cocaine use should be considered a possible trigger for thyroid storm. Recognition of thyroid storm is critical because of the necessity for targeted therapy and the significant mortality associated with the condition if left untreated. PMID- 26425624 TI - Anesthetic Considerations for a Patient With Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome) Undergoing a Five-Box Thoracoscopic Maze Procedure for Atrial Fibrillation. AB - Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder involving the abnormal communication of vascular structures. HHT typically presents with recurrent epistaxis and telangiectasis of the nasal and buccal mucosa, tongue, and lips. More serious manifestations of this disease include cerebral, pulmonary, gastrointestinal, and hepatic arteriovenous malformations. This case report details a 55-year-old male with HHT undergoing a five-box maze procedure for curative treatment of atrial fibrillation. Particular anesthetic considerations are described to reduce morbidity and mortality in this patient population. PMID- 26425626 TI - Methimazole-Induced Goitrogenesis in an Adult Patient With the Syndrome of Resistance to Thyroid Hormone. AB - Patients with the syndrome of resistance to thyroid hormone (RTH) have clinical (tachycardia and anxiety) and biochemical (elevated thyroid hormones level) features of hyperthyroidism. Based on previous reports in pediatric patients with the RTH, antithyroid treatment in these patients is not indicated. Clinical and biochemical sequel of antithyroid therapy in an adult patient with RTH was not previously reported. A 63-year-old African American female with history of RTH was treated with a therapy consisting of methimazole 15 mg daily and atenolol. Methimazole treatment resulted in reduction in thyroid hormone level while the patient's TSH increased with a peak of 24.88 mIU/L. Having achieved biochemical euthyroidism, the patient developed thyroid gland enlargement associated with progressive symptoms of dysphagia and dyspnea. Examination demonstrated globally enlarged firm thyroid gland with areas of nodularity in both lobes. A computed tomography of the neck showed enlarged thyroid gland with extension around bilateral sternocleidomastoid muscles and compression onto the trachea. Methimazole therapy was discontinued and patient was treated just on atenolol. Over 12 months following discontinuation of methimazole, the patient experienced marked clinical and radiographic improvement of the goiter size associated with TSH reduction to 1.26 mIU/L and modest free thyroxine increase as expected in RTH. It seems appealing to treat patients with the RTH with antithyroid medications. However, in these patients decrease in thyroid hormone levels will stimulate TSH production, which can, in turn, predispose to goiter formation. Our report supports prior observations in children with RTH that treatment with methimazole is not indicated in adult patients with RTH. PMID- 26425627 TI - Adolescent Premature Ovarian Insufficiency Following Human Papillomavirus Vaccination: A Case Series Seen in General Practice. AB - Three young women who developed premature ovarian insufficiency following quadrivalent human papillomavirus (HPV) vaccination presented to a general practitioner in rural New South Wales, Australia. The unrelated girls were aged 16, 16, and 18 years at diagnosis. Each had received HPV vaccinations prior to the onset of ovarian decline. Vaccinations had been administered in different regions of the state of New South Wales and the 3 girls lived in different towns in that state. Each had been prescribed the oral contraceptive pill to treat menstrual cycle abnormalities prior to investigation and diagnosis. Vaccine research does not present an ovary histology report of tested rats but does present a testicular histology report. Enduring ovarian capacity and duration of function following vaccination is unresearched in preclinical studies, clinical and postlicensure studies. Postmarketing surveillance does not accurately represent diagnoses in adverse event notifications and can neither represent unnotified cases nor compare incident statistics with vaccine course administration rates. The potential significance of a case series of adolescents with idiopathic premature ovarian insufficiency following HPV vaccination presenting to a general practice warrants further research. Preservation of reproductive health is a primary concern in the recipient target group. Since this group includes all prepubertal and pubertal young women, demonstration of ongoing, uncompromised safety for the ovary is urgently required. This matter needs to be resolved for the purposes of population health and public vaccine confidence. PMID- 26425628 TI - Ischemic Hepatitis as the Presenting Manifestation of Cardiac Amyloidosis. AB - An abrupt elevation in aminotransferases without clear etiology may be attributed to hypoxic hepatitis. Underlying cardiac dysfunction, an important clinical clue, is often overlooked as a cause of hypoxic hepatitis, and understanding the interdependence of the heart and liver is crucial in making this diagnosis. Causes of cardiac dysfunction may include any of many different diagnoses; infiltrative heart disease is a rare cause of cardiac dysfunction, with amyloidosis being the most common among this category of pathologies. More advanced imaging techniques have improved the ability to diagnose infiltrative heart disease, thus allowing quicker diagnosis of conditions such as amyloidosis. PMID- 26425629 TI - Two Cases of Transcutaneous Electrical Nerve Stimulation of the Common Peroneal Nerve Successfully Treating Refractory, Multifactorial Leg Edema. AB - The treatment of leg edema often involves promoting venous blood flow but can be difficult in patients with comorbidities that prevent traditional management strategies such as limb elevation or mechanical compression devices. The geko device is a self-contained neuromuscular stimulation device that adheres to skin over the common peroneal nerve and delivers a low-voltage stimulus that activates the lower-leg musculature resulting in enhanced superficial femoral vein blood flow and velocity. Here we report 2 cases of multifactorial and refractory leg edema successfully treated with the geko device over a period of 4 to 16 weeks. The device also improved pain and chronic wound healing. Although the geko device is costly, it was well tolerated and may provide another treatment strategy for resistant leg swelling. PMID- 26425630 TI - Histological Regression of Giant Cell Tumor of Bone Following RANK Ligand Inhibition. AB - Lung metastases are a rare complication of giant cell tumors of bone. We herein describe an interesting case of histological regression and size reduction of lung metastases originating from a primary giant cell tumor of bone in response to the RANK ligand inhibitor denosumab. PMID- 26425631 TI - Embolic Stroke Diagnosed by Elevated D-Dimer in a Patient With Negative TEE for Cardioembolic Source. AB - We report a case of cerebrovascular accident with thromboembolic stroke etiology in a patient who had atrial flutter and negative transesophageal echocardiography (TEE) results. The increased D-dimer levels (1877 ng/mL) initiated referral for magnetic resonance imaging and magnetic resonance angiography of the brain that showed classic recanalization of an embolic thrombus in the angular branch of the left middle cerebral distribution. The D-dimer level of this patient was normalized after 3 months of anticoagulation therapy. Although TEE is considered the gold standard for evaluation of cardiac source of embolism, exclusion of intracardiac thrombus with TEE alone does not eliminate the risk of thromboembolic events. This case highlights the utility of D-dimer as a potential adjunct in the decision-making process to guide investigation of thromboembolism, determine subsequent therapy, and hence reduce the risk of embolic stroke recurrence. PMID- 26425632 TI - A Case of Sarcoidosis Associated With Anti-Tumor Necrosis Factor Treatment. AB - Sarcoidosis is a systemic chronic granulomatous disease of unknown etiology. It predominantly involves the lungs but can affect many organs or tissues in the body, such as the lymphatic system, skin, eyes, and liver. Typical histopathological lesions are noncaseating granulomas in the affected organ or tissue. Indications, type of treatment, and duration of sarcoidosis treatment is currently debated. Despite studies showing that anti-tumor necrosis factor-alpha (TNF-alpha) treatment can successfully be used in refractory sarcoidosis, there are some case reports regarding the development of sarcoidosis with these agents. There have been reports of 47 anti-TNF-associated cases of sarcoidosis until 2012. The patient is a 54-year-old Caucasian male. During routine examinations of the patient who had been followed for psoriasis vulgaris for 20 years and who had been on several anti-TNF regimens thereafter, new pulmonary pathologies due to sarcoidosis were detected. We present here a case of sarcoidosis that developed after infliximab treatment and showed obvious radiologic regression with discontinuation of treatment. During anti-TNF treatment, it should be kept in mind that autoimmune and granulomatous diseases may develop and particular care should be given to patient follow-ups. PMID- 26425633 TI - Cocaine: A Rare Cause of Left-Sided Renal Infarction. AB - Cocaine abuse is commonly associated with myocardial ischemia, mesenteric ischemia, and cerebrovascular accidents. Renal infarction is an uncommon complication of cocaine abuse. Various mechanisms have been postulated for this cocaine-related injury. There are only 15 cases reported on cocaine-induced renal infarction. Among the cases with available data, very few cases had left kidney involvement. We report a case of a 65-year-old African American man with history of cocaine abuse who presented with left flank pain and had left renal infarction. PMID- 26425634 TI - When Feeding Difficulties Are due to Genetics: The Case of Familial Partial 9q Duplication. AB - Chromosomal abnormalities may cause growth failure before or since birth. 9q duplication is reported as a cause of intrauterine growth restriction, mild dysmporphism, and intellectual disabilities. We report a case of a maternally inherited 9q21.31q21.33 duplication causing prenatal and postnatal growth restriction with feeding refusal and mild facial dysmorphisms, prenatally diagnosed by single-nucleotide polymorphism array analysis. Hypothesis of the possible pathogenic mechanisms are discussed. PMID- 26425635 TI - Acute Lymphoblastic Leukemia in a Man Treated With Fingolimod for Relapsing Multiple Sclerosis. AB - A man with relapsing multiple sclerosis, treated with fingolimod 0.5 mg/d for 15 months, developed acute lymphoblastic leukemia and died 4 months after immune ablation and bone marrow allograft, from graft versus host disease. To our knowledge, this is the first case of acute lymphoblastic leukemia reported in a patient treated with fingolimod. Although no causal relationship can be established between fingolimod use and acute lymphoblastic leukemia risk in this single case, future surveillance for lymphatic cell malignancies in patients treated with fingolimod appears justified. PMID- 26425636 TI - CT and MRI Findings of Autoimmune Polymorph Bifocal Pancreatitis Mimicking Pancreatic Adenocarcinoma: A Case Report and Review of the Literature. AB - Autoimmune pancreatitis is a rare type of chronic pancreatitis. It is supposed to be a pancreatic manifestation of an immune-complex modulated systemic disorder. In contrast, pancreatic adenocarcinoma is the most frequent malignant neoplasm of the pancreas. Within the rare type of focal autoimmune pancreatitis, only few presentations with multifocal pancreatic lesions have been described. Herein we report a case of a 58-year-old patient with autoimmune pancreatitis presenting with bifocal manifestations of the pancreatic head and tail, mimicking pancreatic adenocarcinoma clinically, on computed tomography and magnetic resonance imaging. Typical imaging findings of autoimmune pancreatitis are compared with typical findings in pancreatic carcinoma. The diagnostic dilemma of differentiating between both entities is discussed. A review of the present literature regarding multifocal presence of autoimmune pancreatitis is performed. PMID- 26425637 TI - Fever-Induced Brugada Syndrome. AB - Brugada syndrome is increasingly recognized as a cause of sudden cardiac death. Many of these patients do not get diagnosed due its dynamic and often hidden nature. We have come a long way in understanding the disease process, and its electrophysiology appears to be intimately linked with sodium channel mutations or disorders. The cardiac rhythm in these patients can deteriorate into fatal ventricular arrhythmias. This makes it important for the clinician to be aware of the conditions in which arrhythmogenicity of Brugada syndrome is revealed or even potentiated. We present such an instance where our patient's Brugada syndrome was unmasked by fever. PMID- 26425638 TI - Metastatic Adenocarcinoma of Unknown Origin Presenting as Small Bowel Perforation: A Case Report and Literature Review. AB - Metastatic malignant tumors that originate from occult primaries are defined as "cancers of unknown origin." We herein present the case of a 59-year-old man who presented with small bowel perforation secondary to metastatic adenocarcinoma of an unknown primary site. Imaging exhibited two pulmonary nodules, neither of which was dominant, along with mediastinal and retroperitoneal lymphadenopathy. Immunohistochemical profiling of the small bowel biopsy specimens revealed the tumor was most likely pulmonary in origin. PMID- 26425639 TI - Idiopathic Splenic Artery Pseudoaneurysm Rupture as an Uncommon Cause of Hemorrhagic Shock. AB - Splenic artery pseudoaneurysms are infrequently encountered but critical to recognize. Limited literature to date describes associations with pancreatitis, trauma, and rarely peptic ulcer disease. Hemorrhage and abdominal pain are the most common manifestations. There is typically overt gastrointestinal blood loss but bleeding can also extend into the peritoneum, retroperitoneum, adjacent organs, or even a pseudocyst. Most patients with ruptured splenic artery pseudoaneurysms present with hemodynamic instability. Here, we describe a patient recovering from acute illness in the intensive care unit but with otherwise no obvious risk factors or precipitants for visceral pseudoaneurysm. He presented with acute onset altered mental status, nausea, and worsening back and abdominal pain and was found to be in hypovolemic shock. The patient was urgently stabilized until more detailed imaging could be performed, which ultimately revealed the source of blood loss and explained his rapid decompensation. He was successfully treated with arterial coiling and embolization. Thus, we herein emphasize the importance of prompt recognition of hemorrhagic shock and of aggressive hemodynamic stabilization, as well as a focused diagnostic approach to this problem with specific treatment for splenic artery pseudoaneurysm. Finally, we recommend that multidisciplinary management should be the standard approach in all patients with splenic artery pseudoaneurysm. PMID- 26425640 TI - Double Cystic Duct in a Septated Gallbladder. AB - Double cystic duct in a single gallbladder is one of the least common variances encountered in the biliary system. This article presents a 54-year-old man who had a septated gallbladder with 2 separate cystic ducts. With intraoperative cholangiogram, he had successful laparoscopic cholecystectomy without any ductal injuries or complications. PMID- 26425642 TI - Metastasizing Bronchopulmonary Leiomyosarcoma. AB - An otherwise healthy 55-year-old female, nonsmoker, was seen in pulmonary consultation for progressively worsening shortness of breath. She had undergone a complete hysterectomy 7 years prior for bleeding leiomyomas. On presentation, her initial chest X-ray showed a large right-sided pleural effusion with multiple pulmonary nodules. Two thoracenteses failed to reveal any cytologic abnormalities. Bronchoscopy revealed smooth, round, endobronchial lesions. Histologic examination showed features consistent with leiomyosarcoma. We present a rare case of a patient that initially had possible leiomyomas of the uterus surgically removed and years later presented with bronchopulmonary leiomyosarcoma. PMID- 26425641 TI - Spilt Milk: An Unusual Cause of Bilateral Chylothorax. AB - We report a case of bilateral chylothorax without evidence of chylous fistula in a 62-year-old man following total laryngectomy and bilateral selective neck dissection for laryngeal cancer. Chylous fistulae, a well-known complication of neck dissection, occurs following 1% to 2% of these surgeries. On rare occasions, the chyle leak may communicate with the pleural space, resulting in chylothorax. This is a rare but potentially life-threatening complication. Bilateral chylothorax following neck dissection is even rarer, with less than 25 cases reported in the literature. Early diagnosis is essential to prevent complications. Physicians should have a high index of suspicion, especially when the postoperative effusions do not respond to diuretics. Though no evidence-based treatment guidelines exist, expert opinion recommends conservative management as first-line therapy. Our patient was effectively treated by conservative management. We postulate a mechanism whereby bilateral chylothorax occurred in our patient without a chylous fistula. PMID- 26425644 TI - Unusually Located Stroke After Chemotherapy in Testicular Germ Cell Tumors. AB - Testicular cancer is a type of malignancy that affects young adults and has high rates of cure; however, as any malignancy, it is associated with an increased risk of ischemic or hemorrhagic cerebrovascular disease, given the systemic tumor effects or side effects of chemotherapy, which in turn increases morbidity, functional impairment, and additional risk of early death. PMID- 26425643 TI - Vocal Hoarseness and a Subglottic Mass: An Uncommon Diagnosis for a Common Complaint. AB - We report a patient with tracheopathia osteoplastica (TPO), a rare or perhaps underrecognized disorder, detected in approximately 1 in every 2000 to 5000 patients who undergo bronchoscopy. TPO is marked by proliferation of bony and cartilaginous spurs leading to airway stenosis. Multiple submucosal cartilaginous and osseous nodules can develop in the respiratory tract and may involve the entire trachea and mainstem bronchi. Symptoms may range from a completely silent condition to life-threatening respiratory failure and diagnosis is made based on radiological and bronchoscopic findings. Although the etiology has not been established, TPO can be familial and is sometimes associated with chronic inflammation, such as seen with rheumatic diseases. This case highlights the need for understanding TPO so that it can be differentiated from potentially serious conditions such as necrotizing granulomatous diseases, invasive infections, and cancer. PMID- 26425645 TI - Acute Pancreatitis Induced by Methimazole in a Patient With Subclinical Hyperthyroidism. AB - We report here a unique case of methimazole (MMI)-induced pancreatitis. To our knowledge, this is the sixth case reported in the literature and the first diagnosed in a patient with toxic multinodular goiter. A 51-year-old Caucasian female with a history of benign multinodular goiter and subclinical hyperthyroidism was started on MMI 10 mg orally daily. Three weeks later, she developed sharp epigastric pain, diarrhea, lack of appetite, and fever. Her lipase was elevated 5 times the upper limit of normal, consistent with acute pancreatitis. There was no history of hypertriglyceridemia, or alcohol abuse. Abdominal computed tomography was consistent with acute uncomplicated pancreatitis, without evidence of gallstones or tumors. MMI was discontinued, and her hyperthyroid symptoms were managed with propranolol. Her acute episode of pancreatitis quickly resolved clinically and biochemically. One year later, she redeveloped mild clinical symptoms of hyperthyroidism with biochemical evidence of subclinical hyperthyroidism. MMI 10 mg orally daily was restarted. Five days later, she experienced progressive abdominal discomfort. Her lipase was elevated 12 times the upper limit of normal, and the abdominal computed tomography was again compatible with acute uncomplicated pancreatitis. MMI was again discontinued, which was followed by rapid resolution of her pancreatitis. The patient is currently considering undergoing definitive therapy with radioactive iodine ablation. Our case as well as previous case reports in the literature should raise awareness about the possibility of pancreatitis in subjects treated with MMI in the presence of suggestive symptoms. If the diagnosis is confirmed by elevated pancreatic enzymes, the drug should be discontinued. PMID- 26425646 TI - Gas6/Axl in arginine-starvation therapy. PMID- 26425647 TI - betaNp63 controls cellular redox status. PMID- 26425648 TI - miR-25, integrin and cancer invasiveness. PMID- 26425649 TI - BMI1, ATM and DDR. PMID- 26425651 TI - The many-faced KSR1: a tumor suppressor in breast cancer. PMID- 26425650 TI - Immunosuppression via Tenascin-C. PMID- 26425652 TI - Targeting ncRNAs in the 3q26.2 amplicon. PMID- 26425653 TI - ATP, a double-edged sword in cancer. PMID- 26425654 TI - Cell hierarchies in colorectal cancer: focus on APC and BRAF. PMID- 26425655 TI - NK cell modulation by JAK inhibition. PMID- 26425656 TI - Cell-ECM interactions control DDR. PMID- 26425657 TI - Right on TARGET: glutamine metabolism in cancer. AB - Recent studies highlight the importance of glutamine metabolism in metabolic reprogramming, which underlies cancer cell addiction to glutamine. Examples for the dependence on glutamine metabolism are seen across different tumor types as during different phases of cancer development, progression and response to therapy. In this perspective, we assess the possibility of targeting glutamine metabolism as a therapeutic modality for cancer. PMID- 26425659 TI - A novel telomerase substrate precursor rapidly induces telomere dysfunction in telomerase positive cancer cells but not telomerase silent normal cells. AB - Although telomerase is an almost universal target for cancer therapy, there has been no effective telomerase targeted inhibitor that has progressed to late stage human clinical trials. Recently, we reported that a telomerase-mediated telomere disrupting compound, 6-thio-2'-deoxyguanosine (6-thio-dG), was very effective at targeting telomerase positive cancer cells while sparing telomerase silent normal cells. 6-thio-dG, a nucleoside analogue of the already-approved drug 6 thioguanine, is incorporated into telomeres by telomerase, resulting in disruption of the telomere-protecting shelterin complex. This disruption leads to Telomere dysfunction-Induced Foci (TIFs) formation and rapid cell death for the vast majority of cancer cells. Since most chemotherapies eventually fail due to drug acquired resistance, novel drugs such as 6-thio-dG, as a single first line agent or in the maintenance setting, may represent an effective new treatment for cancer patients. PMID- 26425658 TI - How to target small cell lung cancer. AB - Small cell lung cancer (SCLC) is a highly malignant disease with dismal prognosis. Although great progress has been made in investigating genetic aberrations and putative drivers of this tumor entity, the mechanisms of rapid dissemination and acquisition of drug resistance are not clear. The majority of SCLC cases are characterized by inactivation of the tumor suppressors p53 and retinoblastoma (Rb) and, therefore, interchangeable drivers will be difficult to target successfully. Access to pure cultures of SCLC circulating tumor cells (CTCs) and study of their tumor biology has revealed a number of new potential targets. Most important, expression of chitinase-3-like-1/YKL-40 (CHI3L1) which controls expression of vascular epithelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP9) was newly described in these cells. The process switching CHI3L1-negative SCLC cells to CHI3L1-positive CTCs seems to be associated with cytokines released by inflammatory immune cells. Furthermore, these CTCs were found to promote monocyte-macrophage differentiation, most likely of the M2 tumor-promoting type, recently described to express PD-1 immune checkpoint antigen in SCLC. In conclusion, dissemination of SCLC seems to be linked to conversion of regular tumor cells to highly invasive CHI3L1-positive CTCs, which are protected by immune system suppression. Besides the classical targets VEGF, MMP-9 and PD-1, CHI3L1 constitutes a new possibly drugable molecule to retard down dissemination of SCLC cells, which may be similarly relevant for glioblastoma and other tumor entities. PMID- 26425660 TI - Doxycycline and therapeutic targeting of the DNA damage response in cancer cells: old drug, new purpose. AB - There is a small proportion of cells within a tumour with self-renewing properties, which is resistant to conventional therapy, and is responsible for tumour initiation, maintenance and metastasis. These cells are known as cancer stem cells (CSCs) or tumour-initiating cells (TICs) [1]. Recent publications identify several antibiotics, such as salinomycin or doxycycline, as selective CSCs inhibitors [2-4]. However, the mechanisms of action of these antibiotics on CSCs are not fully understood. PMID- 26425661 TI - PRMT5-dependent p53 escape in tumorigenesis. AB - Extensive studies have characterized mutational disruption of p53 signaling in human cancers. However, the mechanism for bypass of p53 function in tumors retaining wild-type p53 has remained ambiguous. Recent studies suggest that PRMT5, which is frequently elevated in human cancers, cooperates with oncogenic cyclin D1 and leaves marks on p53 by way of arginine methylation, promoting the bypass of wild-type p53, and in doing so, evade apoptosis. PMID- 26425664 TI - Dataset from the global phosphoproteomic mapping of early mitotic exit in human cells. AB - The presence or absence of a phosphorylation on a substrate at any particular point in time is a functional readout of the balance in activity between the regulatory kinase and the counteracting phosphatase. Understanding how stable or short-lived a phosphorylation site is required for fully appreciating the biological consequences of the phosphorylation. Our current understanding of kinases and their substrates is well established; however, the role phosphatases play is less understood. Therefore, we utilized a phosphatase dependent model of mitotic exit to identify potential substrates that are preferentially dephosphorylated. Using this method, we identified >16,000 phosphosites on >3300 unique proteins, and quantified the temporal phosphorylation changes that occur during early mitotic exit (McCloy et al., 2015 [1]). Furthermore, we annotated the majority of these phosphorylation sites with a high confidence upstream kinase using published, motif and prediction based methods. The results from this study have been deposited into the ProteomeXchange repository with identifier PXD001559. Here we provide additional analysis of this dataset; for each of the major mitotic kinases we identified motifs that correlated strongly with phosphorylation status. These motifs could be used to predict the stability of phosphorylated residues in proteins of interest, and help infer potential functional roles for uncharacterized phosphorylations. In addition, we provide validation at the single cell level that serine residues phosphorylated by Cdk are stable during phosphatase dependent mitotic exit. In summary, this unique dataset contains information on the temporal mitotic stability of thousands of phosphorylation sites regulated by dozens of kinases, and information on the potential preference that phosphatases have at both the protein and individual phosphosite level. The compellation of this data provides an invaluable resource for the wider research community. PMID- 26425662 TI - Mcl-1 protects prostate cancer cells from cell death mediated by chemotherapy induced DNA damage. AB - The anti-apoptotic protein Mcl-1 is highly expressed in castration-resistant prostate cancer (CRPC), resulting in resistance to apoptosis and association with poor prognosis. Although predominantly localized in the cytoplasm, there is evidence that Mcl-1 exhibits nuclear localization where it is thought to protect against DNA damage-induced cell death. The role of Mcl-1 in mediating resistance to chemotherapy-induced DNA damage in prostate cancer (PCa) is not known. We show in human PCa cell lines and in TRAMP, a transgenic mouse model of PCa, that the combination of the antimitotic agent ENMD-1198 (analog of 2-methoxyestradiol) with betulinic acid (BA, increases proteotoxic stress) targets Mcl-1 by increasing its proteasomal degradation, resulting in increased gammaH2AX (DNA damage) and apoptotic/necrotic cell death. Knockdown of Mcl-1 in CRPC cells leads to elevated gammaH2AX, DNA strand breaks, and cell death after treatment with 1198 + BA- or doxorubicin. Additional knockdowns in PC3 cells suggests that cytoplasmic Mcl-1 protects against DNA damage by blocking the mitochondrial release of apoptosis-inducing factor and thereby preventing its nuclear translocation and subsequent interaction with the cyclophilin A endonuclease. Overall, our results suggest that chemotherapeutic agents that target Mcl-1 will promote cell death in response to DNA damage, particularly in CRPC. PMID- 26425665 TI - SILAC-based quantification of changes in protein tyrosine phosphorylation induced by Interleukin-2 (IL-2) and IL-15 in T-lymphocytes. AB - This data article presents the first large-scale quantitative phosphoproteomics dataset generated to decipher the signaling networks initiated by IL-2 and IL-15 in T-lymphocytes. Data was collected by combining immunoprecipitation of tyrosine phosphorylated proteins and TiO2-based phosphopeptide enrichment with SILAC-based quantitative mass spectrometry. We report all the proteins and phosphotyrosine containing peptides identified and quantified in IL-2- and IL-15-stimulated T lymphocytes. The gene ontology analysis of IL-2 and IL-15 effector proteins detected in the present work is also included. The data supplied in this article is related to the research work entitled "Simultaneous dissection and comparison of IL-2 and IL-15 signaling pathways by global quantitative phosphoproteomics" [1]. All mass spectrometry data have been deposited in the ProteomeXchange with the identifier PXD001129. PMID- 26425663 TI - Quantitative evaluation of cell death response in vitro and in vivo using conventional-frequency ultrasound. AB - Previous studies using high-frequency ultrasound have suggested that radiofrequency (RF) spectral analysis can be used to quantify changes in cell morphology to detect cell death response to therapy non-invasively. The study here investigated this at conventional-frequencies, frequently used in clinical settings. Spectral analysis was performed using ultrasound RF data collected with a clinical ultrasound platform. Acute myeloid leukemia (AML-5) cells were exposed to cisplatinum for 0-72 hours in vitro and prepared for ultrasound data collection. Preclinical in vivo experiments were also performed on AML-5 tumour bearing mice receiving chemotherapy. The mid-band fit (MBF) spectral parameter demonstrated an increase of 4.4 +/- 1.5 dBr for in vitro samples assessed 48 hours after treatment, a statistically significant change (p < 0.05) compared to control. Further, in vitro concentration-based analysis of a mixture of apoptotic and untreated cells indicated a mean change of 10.9 +/- 2.4 dBr in MBF between 0% and 40% apoptotic cell mixtures. Similar effects were reproduced in vivo with an increase of 4.6 +/- 0.3 dBr in MBF compared to control, for tumours with considerable apoptotic areas within histological samples. The alterations in the size of cells and nuclei corresponded well with changes measured in the quantitative ultrasound (QUS) parameters. PMID- 26425666 TI - Reciprocal repression between Fgf8 and miR-133 regulates cardiac induction through Bmp2 signaling. AB - This data article contains complementary figures and results related to the research article entitled "Negative Fgf8-Bmp2 feed-back is controlled by miR-130 during early cardiac specification" [15], which reveals what specific role miR 130 plays during the cardiac induction process. This study evidenced miR-130 a putative microRNA that targets Erk1/2 (Mapk1) 3'UTR- as a necessary linkage in the control of Fgf8 signaling, mediated by Bmp2. Thus, miR-130 regulates a negative Fgf8-Bmp2 feed-back loop responsible to achieve early cardiac specification. A significant aspect supporting our conclusions is given by the expression pattern of miR-130 during early cardiac specification, as well as by those results obtained after the designed experimental procedures. The data presented here reveal that miR-133 is also expressed within the precardiac areas during early cardiogenesis, pattern which is comparable to that of FGFR1, receptor involved in the Fgf8/ERK signaling pathway. Interestingly, our miR-133 overexpression experiments resulted in a decrease of Fgf8 expression, whereas we observed an increase of Bmp2 and subsequently of cardiac specific markers Nkx-2.5 and Gata4. Additionally, our loss-of-function experiments -through Fgf8 siRNA electroporation- showed an increase of miR-133 expression. Finally, after our Bmp2 experiments, we observed that miR-133 is upstream-regulated by Bmp2. All those results suggest that miR-133 also constitutes a crucial linkage in the crosstalk between Fgf8 and Bmp2 signaling by regulating the Fgf8/ERK pathway during cardiac induction. PMID- 26425667 TI - Dissipated power and induced velocity fields data of a micro single dielectric barrier discharge plasma actuator for active flow control. AB - In recent years, single dielectric barrier discharge (SDBD) plasma actuators have gained great interest among all the active flow control devices typically employed in aerospace and turbomachinery applications [1,2]. Compared with the macro SDBDs, the micro single dielectric barrier discharge (MSDBD) actuators showed a higher efficiency in conversion of input electrical power to delivered mechanical power [3,4]. This article provides data regarding the performances of a MSDBD plasma actuator [5,6]. The power dissipation values [5] and the experimental and numerical induced velocity fields [6] are provided. The present data support and enrich the research article entitled "Optimization of micro single dielectric barrier discharge plasma actuator models based on experimental velocity and body force fields" by Pescini et al. [6]. PMID- 26425668 TI - A predictive toxicogenomics signature to classify genotoxic versus non-genotoxic chemicals in human TK6 cells. AB - Genotoxicity testing is a critical component of chemical assessment. The use of integrated approaches in genetic toxicology, including the incorporation of gene expression data to determine the DNA damage response pathways involved in response, is becoming more common. In companion papers previously published in Environmental and Molecular Mutagenesis, Li et al. (2015) [6] developed a dose optimization protocol that was based on evaluating expression changes in several well-characterized stress-response genes using quantitative real-time PCR in human lymphoblastoid TK6 cells in culture. This optimization approach was applied to the analysis of TK6 cells exposed to one of 14 genotoxic or 14 non-genotoxic agents, with sampling 4 h post-exposure. Microarray-based transcriptomic analyses were then used to develop a classifier for genotoxicity using the nearest shrunken centroids method. A panel of 65 genes was identified that could accurately classify toxicants as genotoxic or non-genotoxic. In Buick et al. (2015) [1], the utility of the biomarker for chemicals that require metabolic activation was evaluated. In this study, TK6 cells were exposed to increasing doses of four chemicals (two genotoxic that require metabolic activation and two non-genotoxic chemicals) in the presence of rat liver S9 to demonstrate that S9 does not impair the ability to classify genotoxicity using this genomic biomarker in TK6cells. PMID- 26425669 TI - Getting Healthier Through Microbiome Makeover. PMID- 26425670 TI - Flibanserin for Low Sexual Desire in Women: A Molecule From Bench to Bed? PMID- 26425671 TI - Neural Stem Cell Carriers for the Treatment of Glioblastoma Multiforme. PMID- 26425672 TI - New Brain Lymphatic Vessels Drain Old Concepts. PMID- 26425673 TI - Is it Possible to Predict Benefit from 5FU Adjuvant Therapy in Stage III Colon Cancer Patients? PMID- 26425674 TI - Deciphering Crosstalk Circuits in Non-small Cell Lung Cancers with an Increasing Interval Length of Low Dose CT Screening. PMID- 26425675 TI - Surrogate Prognostic Biomarkers in OSCC: The Paradigm of PA28gamma Overexpression. PMID- 26425676 TI - Suppress for Success: A JAK Inhibitor for Adjunct Therapy of Tuberculosis. PMID- 26425677 TI - How Much HIV is Alive? The Challenge of Measuring Replication Competent HIV for HIV Cure Research. PMID- 26425678 TI - Dormancy antigens as biomarkers of latent tuberculosis infection. PMID- 26425679 TI - Unpacking Vaccine Hesitancy Among Healthcare Providers. PMID- 26425680 TI - Is Psychosis a Disorder of XY Epigenetics? PMID- 26425681 TI - The Importance of Measuring Multi-level Risk and Illness Progression Markers in High-risk Youth From Well-characterized Bipolar Parents. PMID- 26425682 TI - DNA methylation signatures in circulating cell-free DNA for the monitoring of at risk populations progressing to lung cancer. PMID- 26425683 TI - Disappearing acts of ADAMTS13. PMID- 26425684 TI - How can clinical research help our understanding of trastuzumab-related cardiotoxicity? PMID- 26425685 TI - Predicting Risk at the End of the End: Telomere G-tail as a Biomarker. PMID- 26425686 TI - You Lose Some, You Win Some: Weight Loss Induces Microbiota and Metabolite Shifts. PMID- 26425687 TI - Inhibition of de novo Palmitate Synthesis by Fatty Acid Synthase Induces Apoptosis in Tumor Cells by Remodeling Cell Membranes, Inhibiting Signaling Pathways, and Reprogramming Gene Expression. AB - Inhibition of de novo palmitate synthesis via fatty acid synthase (FASN) inhibition provides an unproven approach to cancer therapy with a strong biological rationale. FASN expression increases with tumor progression and associates with chemoresistance, tumor metastasis, and diminished patient survival in numerous tumor types. TVB-3166, an orally-available, reversible, potent, and selective FASN inhibitor induces apoptosis, inhibits anchorage independent cell growth under lipid-rich conditions, and inhibits in-vivo xenograft tumor growth. Dose-dependent effects are observed between 20-200 nM TVB 3166, which agrees with the IC50 in biochemical FASN and cellular palmitate synthesis assays. Mechanistic studies show that FASN inhibition disrupts lipid raft architecture, inhibits biological pathways such as lipid biosynthesis, PI3K AKT-mTOR and beta-catenin signal transduction, and inhibits expression of oncogenic effectors such as c-Myc; effects that are tumor-cell specific. Our results demonstrate that FASN inhibition has anti-tumor activities in biologically diverse preclinical tumor models and provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers, including those expressing mutant K Ras, ErbB2, c-Met, and PTEN. The reported findings inform ongoing studies to link mechanisms of action with defined tumor types and advance the discovery of biomarkers supporting development of FASN inhibitors as cancer therapeutics. RESEARCH IN CONTEXT: Fatty acid synthase (FASN) is a vital enzyme in tumor cell biology; the over-expression of FASN is associated with diminished patient prognosis and resistance to many cancer therapies. Our data demonstrate that selective and potent FASN inhibition with TVB-3166 leads to selective death of tumor cells, without significant effect on normal cells, and inhibits in vivo xenograft tumor growth at well-tolerated doses. Candidate biomarkers for selecting tumors highly sensitive to FASN inhibition are identified. These preclinical data provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers. PMID- 26425688 TI - TP53 Mutational Status and Prediction of Benefit from Adjuvant 5-Fluorouracil in Stage III Colon Cancer Patients. AB - We investigated the hypothesis that the varying treatment efficacy of adjuvant 5 fluorouracil (5FU) in stage III colon cancer is linked to the TP53 mutational status. ABCSG-90 was a prospective randomized trial in which effect of adjuvant 5FU was studied in stage III colon cancer patients. Tumor material of 70% of these patients (389/572) was available for analysis of the biomarker TP53 using a TP53-gene-specific Sanger sequencing protocol. Median follow-up was 88 months. TP53 mutation frequency was 33%. A significant interaction between TP53 status, outcomes and nodal category was found (P = 0.0095). In the N1 category, TP53 wildtype patients had significantly better overall survival than TP53 mutated (81.0% vs. 62.0% overall survival at 5 years; HR = 2.131; 95% CI: 1.344-3.378; P = 0.0010). In the N2 category, the TP53 status did not affect survival (P = 0.4992). In TP53 wildtype patients, the prognostic significance of N category was significantly enhanced (P = 0.0002). In TP53 mutated patients, survival curves of N1 and N2 patients overlapped and nodal category was no longer prognostic. The biomarker TP53 independently predicted effect of adjuvant 5FU in N1 colon cancer patients. TP53 was not predictive in N2 patients, in whom 5FU is known to have no effect. PMID- 26425689 TI - Gene Signatures Stratify Computed Tomography Screening Detected Lung Cancer in High-Risk Populations. AB - BACKGROUND: Although screening programmes of smokers have detected resectable early lung cancers more frequently than expected, their efficacy in reducing mortality remains debatable. To elucidate the biological features of computed tomography (CT) screening detected lung cancer, we examined the mRNA signatures on tumours according to the year of detection, stage and survival. METHODS: Gene expression profiles were analysed on 28 patients (INT-IEO training cohort) and 24 patients of Multicentre Italian Lung Detection (MILD validation cohort). The gene signatures generated from the training set were validated on the MILD set and a public deposited DNA microarray data set (GSE11969). Expression of selected genes and proteins was validated by real-time RT-PCR and immunohistochemistry. Enriched core pathway and pathway networks were explored by GeneSpring GX10. FINDINGS: A 239-gene signature was identified according to the year of tumour detection in the training INT-IEO set and correlated with the patients' outcomes. These signatures divided the MILD patients into two distinct survival groups independently of tumour stage, size, histopathological type and screening year. The signatures can also predict survival in the clinically detected cancers (GSE11969). Pathway analyses revealed tumours detected in later years enrichment of the PI3K/PTEN/AKT pathway, with up-regulation of PDPK1, ITGB1 and down regulation of FOXO1A. Analysis of normal lung tissue from INT-IEO cohort produced signatures distinguishing patients with early from late detected tumours. INTERPRETATION: The distinct pattern of "indolent" and "aggressive" tumour exists in CT-screening detected lung cancer according to the gene expression profiles. The early development of an aggressive phenotype may account for the lack of mortality reduction by screening observed in some cohorts. PMID- 26425690 TI - Discovery and Validation of Predictive Biomarkers of Survival for Non-small Cell Lung Cancer Patients Undergoing Radical Radiotherapy: Two Proteins With Predictive Value. AB - Lung cancer is the most frequent cause of cancer-related death world-wide. Radiotherapy alone or in conjunction with chemotherapy is the standard treatment for locally advanced non-small cell lung cancer (NSCLC). Currently there is no predictive marker with clinical utility to guide treatment decisions in NSCLC patients undergoing radiotherapy. Identification of such markers would allow treatment options to be considered for more effective therapy. To enable the identification of appropriate protein biomarkers, plasma samples were collected from patients with non-small cell lung cancer before and during radiotherapy for longitudinal comparison following a protocol that carries sufficient power for effective discovery proteomics. Plasma samples from patients pre- and during radiotherapy who had survived > 18 mo were compared to the same time points from patients who survived < 14 mo using an 8 channel isobaric tagging tandem mass spectrometry discovery proteomics platform. Over 650 proteins were detected and relatively quantified. Proteins which showed a change during radiotherapy were selected for validation using an orthogonal antibody-based approach. Two of these proteins were verified in a separate patient cohort: values of CRP and LRG1 combined gave a highly significant indication of extended survival post one week of radiotherapy treatment. PMID- 26425691 TI - Associations between proteasomal activator PA28gamma and outcome of oral squamous cell carcinoma: Evidence from cohort studies and functional analyses. AB - BACKGROUND: PA28gamma was suggested to play a role in malignant progression. This paper aimed to investigate the association between PA28gamma and the prognosis of oral squamous cell carcinoma (OSCC) in cohort studies. METHODS: The PA28gamma expression level was assessed by immunohistochemistry in a total of 368 OSCC patients from three independent cohorts. The Cox proportional hazards regression model was used to determine multivariate hazard ratios for Overall Survival (OS). Model discrimination was measured using C Statistic. Additionally, OS was analyzed in Head Neck Squamous Cell Carcinoma (HNSCC) patients from The Cancer Genome Atlas (TCGA) data set. Functional analyses were conducted both in-vitro and in-vivo. FINDINGS: The median follow-up times of patients in the three studies were 60, 52, and 51 months. High expression of PA28gamma was identified in tumors from 179 of 368 patients (48.6%). Compared with low expression, high expression of PA28gamma was strongly associated with worse OS, with relative risks of 5.14 (95% CI, 2.51-10.5; P < 0.001), 2.82 (95% CI, 1.73-4.61; P < 0.001), and 3.85 (95% CI, 1.59-9.37; P = 0.003). PA28gamma expression was also associated with disease-free survival in all three cohorts (P < 0.005). These findings are consistent with TCGA HNSCC data (P < 0.006). The prediction of all cause mortality was significantly improved when PA28gamma was added to the traditional clinical factors (Model 3, C statistic value: 0.78 VS 0.73, P = 0.016). In functional analyses, we found that PA28gamma silencing dramatically inhibited the growth, proliferation and mobility of OSCC cells in vitro and reduced tumor growth and angiogenesis in tumor-bearing mice. INTERPRETATION: PA28gamma overexpression is associated with adverse prognosis in patients with OSCC. The aberrant expression of PA28gamma may contribute to the pathogenesis and progression of OSCC. RESEARCH IN CONTEXT: OSCC is one of the most common HNSCC, which have a high lethally rate. However, few prognostic markers have been applied in the clinical practice. We found that PA28gamma in OSCC tumor tissues were significantly high expression than those in normal tissues. As the results of the three cohorts from two independent research centers and from an additional validation cohort from a US population in the TCGA dataset, we demonstrate PA28gamma is a good predictor of the risk of death in OSCC. Meanwhile, we demonstrate PA28gamma have a potential role in OSCC tumorigenesis. PMID- 26425692 TI - Reverse Engineering of Vaccine Antigens Using High Throughput Sequencing-enhanced mRNA Display. AB - Vaccine reverse engineering is emerging as an important approach to vaccine antigen identification, recently focusing mainly on structural characterization of interactions between neutralizing monoclonal antibodies (mAbs) and antigens. Using mAbs that bind unknown antigen structures, we sought to probe the intrinsic features of antibody antigen-binding sites with a high complexity peptide library, aiming to identify conformationally optimized mimotope antigens that capture mAb-specific epitopes. Using a high throughput sequencing-enhanced messenger ribonucleic acid (mRNA) display approach, we identified high affinity binding peptides for a hepatitis C virus neutralizing mAb. Immunization with the selected peptides induced neutralizing activity similar to that of the original mAb. Antibodies elicited by the most commonly selected peptides were predominantly against specific epitopes. Thus, using mRNA display to interrogate mAbs permits high resolution identification of functional peptide antigens that direct targeted immune responses, supporting its use in vaccine reverse engineering for pathogens against which potent neutralizing mAbs are available. RESEARCH IN CONTEXT: We used a large number of randomly produced small proteins ("peptides") to identify peptides containing specific protein sequences that bind efficiently to an antibody that can prevent hepatitis C virus infection in cell culture. After the identified peptides were injected into mice, the mice produced their own antibodies with characteristics similar to the original antibody. This approach can provide previously unavailable information about antibody binding and could also be useful in developing new vaccines. PMID- 26425693 TI - Efficacy of Adjunctive Tofacitinib Therapy in Mouse Models of Tuberculosis. AB - The global tuberculosis (TB) epidemic and the spread of multi- and extensively drug resistant strains of Mycobacterium tuberculosis (M.tb) have been fueled by low adherence to following lengthy treatment protocols, and the rapid spread of HIV (Human Immunodeficiency Virus). Persistence of the infection in immunocompetent individuals follows from the ability of M.tb to subvert host immune responses in favor of survival within macrophages. Alternative host directed strategies are therefore being currently sought to improve treatment efficacy and duration. In this study, we evaluated tofacitinib, a new oral Janus kinase (JAK) blocker with anti-inflammatory properties, in shortening tuberculosis treatment. BALB/c mice, which are immunocompetent, showed acceleration of M.tb clearance achieving apparent sterilization after 16 weeks of adjunctive tofacitinib therapy at average exposures higher than recommended in humans, while mice receiving standard treatment alone did not achieve clearance until 24 weeks. True sterilization with tofacitinib was not achieved until five months. C3HeB/FeJ mice, which show reduced pro-inflammatory cytokines during M.tb infection, did not show improved clearance with adjunctive tofacitinib therapy, indicating that the nature of granulomatous lesions and host immunity may influence responsiveness to tofacitinib. Our findings suggest that the JAK pathway could be explored further for host-directed therapy in immunocompetent individuals. PMID- 26425694 TI - A Novel Assay to Measure the Magnitude of the Inducible Viral Reservoir in HIV infected Individuals. AB - BACKGROUND: Quantifying latently infected cells is critical to evaluate the efficacy of therapeutic strategies aimed at reducing the size of the long-lived viral reservoir, but the low frequency of these cells makes this very challenging. METHODS: We developed TILDA (Tat/rev Induced Limiting Dilution Assay) to measure the frequency of cells with inducible multiply-spliced HIV RNA, as these transcripts are usually absent in latently infected cells but induced upon viral reactivation. TILDA requires less than a million cells, does not require RNA extraction and can be completed in two days. FINDINGS: In suppressed individuals on ART, we found the median frequency of latently infected CD4 + T cells as estimated by TILDA to be 24 cells/million, which was 48 times more than the frequency measured by the quantitative viral outgrowth assay, and 6-27 times less than the frequencies of cells harbouring viral DNA measured by PCR-based assays. TILDA measurements strongly correlated with most HIV DNA assays. The size of the latent reservoir measured by TILDA was lower in subjects who initiated ART during the early compared to late stage of infection (p = 0.011). In untreated HIV disease, the frequency of CD4 + cells carrying latent but inducible HIV largely exceeded the frequency of actively producing cells, demonstrating that the majority of infected cells are transcriptionally silent even in the absence of ART. INTERPRETATIONS: Our results suggest that TILDA is a reproducible and sensitive approach to measure the frequency of productively and latently infected cells in clinical settings. We demonstrate that the latent reservoir represents a substantial fraction of all infected cells prior to ART initiation. RESEARCH IN CONTEXT: In this manuscript, we describe the development of a novel assay that measures the magnitude of the latent HIV reservoir, the main barrier to HIV eradication. This novel assay, termed TILDA for Tat/rev Induced Limiting Dilution Assay, requires only 10 ml of blood, does not necessitate extraction of viral nucleic acids, is highly reproducible, covers a wide dynamic range of reservoir sizes and can be completed in two days. As such, TILDA may represent an alternative to existing assays used to evaluate the efficacy of therapeutic strategies aimed at reducing the size of the latent HIV reservoir. PMID- 26425696 TI - Vaccine Hesitancy Among General Practitioners and Its Determinants During Controversies: A National Cross-sectional Survey in France. AB - BACKGROUND: This study aimed to assess: 1) vaccine hesitancy (VH) prevalence among French general practitioners (GPs) through the frequency of their vaccine recommendations, and 2) the determinants of these recommendations. METHODS: Cross sectional observational study in 2014 nested in a national panel of 1712 randomly selected GPs in private practice in France. We constructed a score of self reported recommendation frequency for 6 specific vaccines to target populations. RESULTS: 16% to 43% of GPs sometimes or never recommended at least one specific vaccine to their target patients. Multivariable logistic regressions of the dichotomized score showed that GPs recommended vaccines frequently when they felt comfortable explaining their benefits and risks to patients (OR = 1.87; 1.35 2.59), or trusted official sources of information highly (OR = 1.40; 1.01-1.93). They recommended vaccines infrequently when they considered that adverse effects were likely (OR = 0.71; 0.52-0.96) or doubted the vaccine's utility (OR = 0.21; 0.15-0.29). INTERPRETATION: Our findings show that after repeated vaccine controversies in France, some VH exists among French GPs, whose recommendation behaviors depend on their trust in authorities, their perception of the utility and risks of vaccines, and their comfort in explaining them. Further research is needed to confirm these results among health care workers in other countries. PMID- 26425695 TI - A Mycobacterium tuberculosis Dormancy Antigen Differentiates Latently Infected Bacillus Calmette-Guerin-vaccinated Individuals. AB - IFN-gamma release assays (IGRAs) are better indicators of Mycobacterium tuberculosis infection than the tuberculin skin test (TST) in Bacillus Calmette Guerin (BCG)-vaccinated populations. However, IGRAs do not discriminate active and latent infections (LTBI) and no gold standard for LTBI diagnosis is available. Thus, since improved tests to diagnose M. tuberculosis infection are required, we assessed the efficacy of several M. tuberculosis latency antigens. BCG-vaccinated healthy donors (HD) and tuberculosis (TB) patients were recruited. QuantiFERON-TB Gold In-Tube, TST and clinical data were used to differentiate LTBI. IFN-gamma production against CFP-10, ESAT-6, Rv2624c, Rv2626c and Rv2628 antigens was tested in peripheral blood mononuclear cells. LTBI subjects secreted significantly higher IFN-gamma levels against Rv2626c than HD. Additionally, Rv2626c peptide pools to which only LTBI responded were identified, and their cumulative IFN-gamma response improved LTBI discrimination. Interestingly, whole blood stimulation with Rv2626c allowed the discrimination between active and latent infections, since TB patients did not secrete IFN-gamma against Rv2626c, in contrast to CFP-10 + ESAT-6 stimulation that induced IFN-gamma response from both LTBI and TB patients. ROC analysis confirmed that Rv2626c discriminated LTBI from HD and TB patients. Therefore, since only LTBI recognizes specific epitopes from Rv2626c, this antigen could improve LTBI diagnosis, even in BCG-vaccinated people. PMID- 26425697 TI - Astroglial Control of the Antidepressant-Like Effects of Prefrontal Cortex Deep Brain Stimulation. AB - Although deep brain stimulation (DBS) shows promising efficacy as a therapy for intractable depression, the neurobiological bases underlying its therapeutic action remain largely unknown. The present study was aimed at characterizing the effects of infralimbic prefrontal cortex (IL-PFC) DBS on several pre-clinical markers of the antidepressant-like response and at investigating putative non neuronal mechanism underlying DBS action. We found that DBS induced an antidepressant-like response that was prevented by IL-PFC neuronal lesion and by adenosine A1 receptor antagonists including caffeine. Moreover, high frequency DBS induced a rapid increase of hippocampal mitosis and reversed the effects of stress on hippocampal synaptic metaplasticity. In addition, DBS increased spontaneous IL-PFC low-frequency oscillations and both raphe 5-HT firing activity and synaptogenesis. Unambiguously, a local glial lesion counteracted all these neurobiological effects of DBS. Further in vivo electrophysiological results revealed that this astrocytic modulation of DBS involved adenosine A1 receptors and K(+) buffering system. Finally, a glial lesion within the site of stimulation failed to counteract the beneficial effects of low frequency (30 Hz) DBS. It is proposed that an unaltered neuronal-glial system constitutes a major prerequisite to optimize antidepressant DBS efficacy. It is also suggested that decreasing frequency could heighten antidepressant response of partial responders. PMID- 26425698 TI - Over-expression of XIST, the Master Gene for X Chromosome Inactivation, in Females With Major Affective Disorders. AB - BACKGROUND: Psychiatric disorders are common mental disorders without a pathological biomarker. Classic genetic studies found that an extra X chromosome frequently causes psychiatric symptoms in patients with either Klinefelter syndrome (XXY) or Triple X syndrome (XXX). Over-dosage of some X-linked escapee genes was suggested to cause psychiatric disorders. However, relevance of these rare genetic diseases to the pathogenesis of psychiatric disorders in the general population of psychiatric patients is unknown. METHODS: XIST and several X-linked genes were studied in 36 lymphoblastoid cell lines from healthy females and 60 lymphoblastoid cell lines from female patients with either bipolar disorder or recurrent major depression. XIST and KDM5C expression was also quantified in 48 RNA samples from postmortem human brains of healthy female controls and female psychiatric patients. FINDINGS: We found that the XIST gene, a master in control of X chromosome inactivation (XCI), is significantly over-expressed (p = 1 * 10(- 7), corrected after multiple comparisons) in the lymphoblastoid cells of female patients with either bipolar disorder or major depression. The X-linked escapee gene KDM5C also displays significant up-regulation (p = 5.3 * 10(- 7), corrected after multiple comparisons) in the patients' cells. Expression of XIST and KDM5C is highly correlated (Pearson's coefficient, r = 0.78, p = 1.3 * 10(- 13)). Studies on human postmortem brains supported over-expression of the XIST gene in female psychiatric patients. INTERPRETATIONS: We propose that over-expression of XIST may cause or result from subtle alteration of XCI, which up-regulates the expression of some X-linked escapee genes including KDM5C. Over-expression of X linked genes could be a common mechanism for the development of psychiatric disorders between patients with those rare genetic diseases and the general population of female psychiatric patients with XIST over-expression. Our studies suggest that XIST and KDM5C expression could be used as a biological marker for diagnosis of psychiatric disorders in a significantly large subset of female patients. RESEARCH IN CONTEXT: Due to lack of biological markers, diagnosis and treatment of psychiatric disorders are subjective. There is utmost urgency to identify biomarkers for clinics, research, and drug development. We found that XIST and KDM5C gene expression may be used as a biological marker for diagnosis of major affective disorders in a significantly large subset of female patients from the general population. Our studies show that over-expression of XIST and some X-linked escapee genes may be a common mechanism for development of psychiatric disorders between the patients with rare genetic diseases (XXY or XXX) and the general population of female psychiatric patients. PMID- 26425700 TI - Diagnostic Performance of Plasma DNA Methylation Profiles in Lung Cancer, Pulmonary Fibrosis and COPD. AB - Disease-specific alterations of the cell-free DNA methylation status are frequently found in serum samples and are currently considered to be suitable biomarkers. Candidate markers were identified by bisulfite conversion-based genome-wide methylation screening of lung tissue from lung cancer, fibrotic ILD, and COPD. cfDNA from 400 MUl serum (n = 204) served to test the diagnostic performance of these markers. Following methylation-sensitive restriction enzyme digestion and enrichment of methylated DNA via targeted amplification (multiplexed MSRE enrichment), a total of 96 markers were addressed by highly parallel qPCR. Lung cancer was efficiently separated from non-cancer and controls with a sensitivity of 87.8%, (95%CI: 0.67-0.97) and specificity 90.2%, (95%CI: 0.65-0.98). Cancer was distinguished from ILD with a specificity of 88%, (95%CI: 0.57-1), and COPD from cancer with a specificity of 88% (95%CI: 0.64-0.97). Separation of ILD from COPD and controls was possible with a sensitivity of 63.1% (95%CI: 0.4-0.78) and a specificity of 70% (95%CI: 0.54-0.81). The results were confirmed using an independent sample set (n = 46) by use of the four top markers discovered in the study (HOXD10, PAX9, PTPRN2, and STAG3) yielding an AUC of 0.85 (95%CI: 0.72-0.95). This technique was capable of distinguishing interrelated complex pulmonary diseases suggesting that multiplexed MSRE enrichment might be useful for simple and reliable diagnosis of diverse multifactorial disease states. PMID- 26425701 TI - A Retrospective Analysis of the Significance of Haemoglobin SS and SC in Disease Outcome in Patients With Sickle Cell Disease and Dengue Fever. AB - BACKGROUND: Little is known about the significance of haemoglobin genotype in dengue fever severity. This study was undertaken to determine the case fatality ratio and the impact of genotype in patients with sickle cell disease and confirmed dengue fever. METHODS: This retrospective analysis included 40 patients with confirmed dengue and sickle cell disease, during the study period (2010 2012). FINDINGS: There was a significantly higher case fatality ratio, 12.5% among patients with either haemoglobin SC disease or homozygous SS disease when compared to that of the general population 0.41% (p < 0.0001). The unadjusted odds of dying among those with haemoglobin SC disease compared with the group with homozygous SS disease was OR = 4.4 (95% CI 0.6 to 31.7). The predictors of mortality independent of sickle cell disease genotype were haemoglobin concentration at presentation OR = 0.57 (95% CI, 0.35 to 0.94) and the change in haemoglobin concentration from steady state OR = 0.59 (95% CI, 0.37 to 0.94). Adjusting for haemoglobin concentration at presentation increased the risk of death for the SC genotype relative to SS genotype OR = 13.4 (95% CI 1.1 to 160.3). INTERPRETATION: The risk of fatal dengue may be higher among patients with a relatively mild genotype (haemoglobin SC). PMID- 26425699 TI - A Multi-Dimensional and Integrative Approach to Examining the High-Risk and Ultra High-Risk Stages of Bipolar Disorder. AB - BACKGROUND: Validating the high-risk (HR) and ultra-high-risk (UHR) stages of bipolar disorder (BP) may help enable early intervention strategies. METHODS: We followed up with 44 offspring of parents with BP, subdividing into the HR and UHR categories. The offspring were aged 8-28 years and were free of any current DSM IV diagnoses. Our multilevel, integrative approach encompassed gray matter (GM) volumes, brain network connectivity, neuropsychological performance, and clinical outcomes. FINDINGS: Compared with the healthy controls (HCs) (n = 33), the HR offspring (n = 26) showed GM volume reductions in the right orbitofrontal cortex. Compared with the HR offspring, the UHR offspring (n = 18) exhibited increased GM volumes in four regions. Both the HR and UHR offspring displayed abnormalities in the inferior occipital cortex regarding the measures of degree and centrality, reflecting the connections and roles of the region, respectively. In the UHR versus the HR offspring, the UHR offspring exhibited upwards-shifted small world topologies that reflect high clustering and efficiency in the brain networks. Compared with the HCs, the UHR offspring had significantly lower assortativity, which was suggestive of vulnerability. Finally, processing speed, visual-spatial, and general function were impaired in the UHR offspring but not in the HR offspring. INTERPRETATION: The abnormalities observed in the HR offspring appear to be inherited, whereas those associated with the UHR offspring represent stage specific changes predisposing them to developing the disorder. PMID- 26425702 TI - Pathogenicity of Anti-ADAMTS13 Autoantibodies in Acquired Thrombotic Thrombocytopenic Purpura. AB - BACKGROUND: Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disease in which anti-ADAMTS13 autoantibodies cause severe enzyme deficiency. ADAMTS13 deficiency causes the loss of regulation of von Willebrand factor multimeric size and platelet-tethering function, which results in the formation of disseminated microvascular platelet microthrombi. Precisely how anti-ADAMTS13 autoantibodies, or antibody subsets, cause ADAMTS13 deficiency (ADAMTS13 activity generally < 10%) has not been formally investigated. METHODS: We analysed 92 acquired TTP episodes at presentation, through treatment and remission/relapse using epitope mapping and functional analyses to understand the pathogenic mechanisms of anti-ADAMTS13 IgG. RESULTS: 89/92 of TTP episodes had IgG recognising the ADAMTS13 N-terminal domains. The central spacer domain was the only N-terminal antigenic target detected. 38/92 TTP episodes had autoantibodies recognising the N-terminal domains alone; 54/92 TTP episodes also had antibodies against the ADAMTS13 C-terminal domains (TSP2-8 and/or CUB domains). Changes in autoantibody specificity were detected in 9/16 patients at relapse, suggesting a continued development of the disease. Functional analyses on IgG from 43 patients revealed inhibitory IgG were limited to anti-spacer domain antibodies. However, 15/43 patients had autoantibodies with no detectable inhibitory action and as many as 32/43 patients had autoantibodies with inhibitory function that was insufficient to account for the severe deficiency state, suggesting that in many patients there is an alternative pathogenic mechanism. We therefore analysed plasma ADAMTS13 antigen levels in 91 acquired TTP presentation samples. We demonstrated markedly reduced ADAMTS13 antigen levels in all presentation samples, median 6% normal (range 0-47%), with 84/91 patients having < 25% ADAMTS13 antigen. ADAMTS13 antigen in the lowest quartile at first presentation was associated with increased mortality (odds ratio 5.7). CONCLUSIONS: Anti spacer domain autoantibodies are the major inhibitory antibodies in acquired TTP. However, depletion of ADAMTS13 antigen (rather than enzyme inhibition) is a dominant pathogenic mechanism. ADAMTS13 antigen levels at presentation have prognostic significance. Taken together, our results provide new insights into the pathophysiology of acquired TTP. PMID- 26425703 TI - Trastuzumab Induces an Immediate, Transient Volume Increase in Humans: A Randomised Placebo-Controlled Trial. AB - BACKGROUND: The exact extent of and the mechanism by which trastuzumab causes cardiac side effects are not completely unravelled. We investigated the (cardiotoxic) side effects of trastuzumab in a relatively large homogeneous population. METHODS: Healthy male volunteers (n = 54) with a left ventricle ejection fraction (LVEF) > 55% were administered 6 mg/kg trastuzumab (n = 46) IV in 90 min in a placebo-controlled, parallel study. Placebo consisted of 0 . 9% NaCl (n = 8). Assessments included body weight, routine and cardiac laboratory markers and serial echocardiographic examinations (8 placebo and 9 trastuzumab treated participants) up to 63 days after dosing. Statistical analysis was done using repeated measurements of variance. FINDINGS: Following trastuzumab infusion, fluid retention was observed: mean body weight increased over the first 4 days post-administration with 0 . 4 kg (95%-confidence interval: - 0 . 2, 0 . 9, p = 0 . 2261) compared to placebo, mean haemoglobin concentration decreased with 0 . 3 mM (- 0 . 6, - 0 . 1; p = 0 . 0043), as did haematocrit (- 0 . 013 L/L [- 0 . 024, - 0 . 002], p = 0 . 0216), and protein (- 2 g/L [- 4, - 0], p = 0 . 0443) and albumin (- 2 g/L [- 3, - 1], p < 0 . 0001) concentrations. Elevations in NT-proBNP levels, parallel to the weight increase, were observed in individual cases, but not on a group level. Troponin-T concentrations did not increase. The only echocardiographic parameter that changed significantly at all studied dose levels was E/A-ratio, a load-dependent parameter: from 1 . 81 (SD 0 . 42) to 1 . 98 (0 . 31) 3-5 days after administration, contrast to placebo of 0 . 57 (90%-CI: 0 . 21-0 . 93, p = 0 . 0034). Ejection fraction and pulsed-wave Doppler recorded parameters remained unchanged. INTERPRETATION: Single dose administration of trastuzumab in humans is associated with an immediate, transient extracellular volume increase, either as a primary or secondary (compensatory) response, which can be detected easily using routine clinical assessments. Echocardiographic changes, both short and long term, could not be found after single dose administration to drug-naive patients. PMID- 26425704 TI - Telomere G-tail Length is a Promising Biomarker Related to White Matter Lesions and Endothelial Dysfunction in Patients With Cardiovascular Risk: A Cross sectional Study. AB - BACKGROUND: The telomeric 3'-overhang (G-tail) length is essential for the biological effects of telomere dysfunction in vitro, but the association of length with aging and cardiovascular risk is unclear in humans. We investigated the association between the telomere G-tail length of leukocytes and cardiovascular risk, age-related white matter changes (ARWMCs), and endothelial function. METHODS: Patients with a history of cerebrovascular disease and comorbidity were enrolled (n = 102; 69 males and 33 females, 70.1 +/- 9.2 years). Total telomere and telomere G-tail lengths were measured using a hybridization protection assay. Endothelial function was evaluated by ultrasound assessment of brachial flow-mediated dilation (FMD). FINDINGS: Shortened telomere G-tail length was associated with age and Framingham risk score (P = 0.018 and P = 0.012). In addition, telomere G-tail length was positively correlated with FMD values (P = 0.031) and negatively with the severity of ARWMCs (P = 0.002). On multivariate regression analysis, telomere G-tail length was independently associated with FMD values (P = 0.022) and the severity of ARWMCs (P = 0.033), whereas total telomere length was not associated with these indicators. INTERPRETATION: Telomere G-tail length is associated with age and vascular risk factors, and might be superior to total telomere length as a marker of endothelial dysfunction and ARWMC severity. PMID- 26425708 TI - Brain metastasis in two patients with stage IA papillary serous carcinoma of the uterus. AB - We report two cases of brain metastasis in patients initially diagnosed with extremely early stage UPSC after extensive staging surgery. They did not receive either adjuvant chemotherapy or adjuvant pelvic or vaginal cuff radiation. At the same time that these patients were diagnosed with systemic metastasis, they both had a local "drop" metastasis in the vulva or the vaginal cuff. After the initial response to palliative chemotherapy, they both developed brain metastasis. The pattern of recurrence with the lack of adjuvant treatment underscores the urgent need in further evaluation of the potential benefits of adjuvant treatment, including chemotherapy and possibly in combination with radiation in this highly aggressive disease. PMID- 26425705 TI - Dietary Modulation of Gut Microbiota Contributes to Alleviation of Both Genetic and Simple Obesity in Children. AB - Gut microbiota has been implicated as a pivotal contributing factor in diet related obesity; however, its role in development of disease phenotypes in human genetic obesity such as Prader-Willi syndrome (PWS) remains elusive. In this hospitalized intervention trial with PWS (n = 17) and simple obesity (n = 21) children, a diet rich in non-digestible carbohydrates induced significant weight loss and concomitant structural changes of the gut microbiota together with reduction of serum antigen load and alleviation of inflammation. Co-abundance network analysis of 161 prevalent bacterial draft genomes assembled directly from metagenomic datasets showed relative increase of functional genome groups for acetate production from carbohydrates fermentation. NMR-based metabolomic profiling of urine showed diet-induced overall changes of host metabotypes and identified significantly reduced trimethylamine N-oxide and indoxyl sulfate, host bacteria co-metabolites known to induce metabolic deteriorations. Specific bacterial genomes that were correlated with urine levels of these detrimental co metabolites were found to encode enzyme genes for production of their precursors by fermentation of choline or tryptophan in the gut. When transplanted into germ free mice, the pre-intervention gut microbiota induced higher inflammation and larger adipocytes compared with the post-intervention microbiota from the same volunteer. Our multi-omics-based systems analysis indicates a significant etiological contribution of dysbiotic gut microbiota to both genetic and simple obesity in children, implicating a potentially effective target for alleviation. RESEARCH IN CONTEXT: Poorly managed diet and genetic mutations are the two primary driving forces behind the devastating epidemic of obesity-related diseases. Lack of understanding of the molecular chain of causation between the driving forces and the disease endpoints retards progress in prevention and treatment of the diseases. We found that children genetically obese with Prader Willi syndrome shared a similar dysbiosis in their gut microbiota with those having diet-related obesity. A diet rich in non-digestible but fermentable carbohydrates significantly promoted beneficial groups of bacteria and reduced toxin-producers, which contributes to the alleviation of metabolic deteriorations in obesity regardless of the primary driving forces. PMID- 26425709 TI - Fertility-sparing management of a stage IB1 small cell neuroendocrine cervical carcinoma with radical abdominal trachelectomy and adjuvant chemotherapy. AB - *Neuroendocrine (NEC) tumors of the cervix are very rare and aggressive.*We present a case of Stage IB1 disease managed with fertility-sparing surgery.*Further investigation into fertility-sparing surgery is warranted. PMID- 26425710 TI - Endometrioid adenocarcinoma associated with endometrial stromal sarcoma: A rare, often unrecognized collision tumor. AB - We are reporting 3 cases of the uterine corpus with collision of endometrioid adenocarcinoma (EAC) with endometrial stromal sarcoma (ESS). The patients' ages ranged from 36 to 59 years old. The major clinical presentation was abnormal uterine bleeding. Microscopically, all 3 cases presented with 2 separate components, EAC Grade 1 and ESS (one low grade and two high grades). The EAC component ranged from 10% to 70%, and the ESS component ranged from 30% to 70% of total tumor volume. The EAC component was stage 1A in two cases and stage II in one case. The ESS component was stages IA, IIB, and IIIB. Adjuvant hormonal therapy was administrated to one patient while a second patient was treated with chemo/radiation therapy. Two patients were still alive with no evidence of disease at 4 years post-therapy. One patient was lost for follow-up. Collision tumor should be distinguished from carcinosarcoma due to its different treatment modality, outcome and, prognosis. PMID- 26425706 TI - Interventions to Improve Neonatal Health and Later Survival: An Overview of Systematic Reviews. AB - BACKGROUND: Evidence-based interventions and strategies are needed to improve child survival in countries with a high burden of neonatal and child mortality. An overview of systematic reviews can focus implementation on the most effective ways to increase child survival. METHODS: In this overview we included published Cochrane and other systematic reviews of experimental and observational studies on antenatal, childbirth, postnatal and child health interventions aiming to prevent perinatal/neonatal and child mortality using the WHO list of essential interventions. We assessed the methodological quality of the reviews using the AMSTAR criteria and assessed the quality of the outcomes using the GRADE approach. Based on the findings from GRADE criteria, interventions were summarized as effective, promising or ineffective. FINDINGS: The overview identified 148 Cochrane and other systematic reviews on 61 reproductive, maternal, newborn and child health interventions. Of these, only 57 reviews reported mortality outcomes. Using the GRADE approach, antenatal corticosteroids for preventing neonatal respiratory distress syndrome in preterm infants; early initiation of breastfeeding; hygienic cord care; kangaroo care for preterm infants; provision and promotion of use of insecticide treated bed nets (ITNs) for children; and vitamin A supplementation for infants from six months of age, were identified as clearly effective interventions for reducing neonatal, infant or child mortality. Antenatal care, tetanus immunization in pregnancy, prophylactic antimalarials during pregnancy, induction of labour for prolonged pregnancy, case management of neonatal sepsis, meningitis and pneumonia, prophylactic and therapeutic use of surfactant, continuous positive airway pressure for neonatal resuscitation, case management of childhood malaria and pneumonia, vitamin A as part of treatment for measles associated pneumonia for children above 6 months, and home visits across the continuum of care, were identified as promising interventions for reducing neonatal, infant, child or perinatal mortality. INTERPRETATION: Comprehensive adoption of the above six effective and 11 promising interventions can improve neonatal and child survival around the world. Choice of intervention and degree of implementation currently depends on resources available and policies in individual countries and geographical settings. FUNDING: This review was part of doctoral thesis which was funded by University of Adelaide, Australia. PMID- 26425711 TI - Menopausal hormone therapy and mortality among women diagnosed with ovarian cancer in the NIH-AARP Diet and Health Study. AB - BACKGROUND: Although menopausal hormone therapy (MHT) use has been linked with an increased risk of ovarian cancer, whether pre-diagnosis MHT use affects ovarian cancer-specific mortality is unknown. METHODS: Our analysis included 395 incident epithelial ovarian cancer patients with data on pre-diagnosis MHT use from the National Institutes of Health-AARP (NIH-AARP) Diet and Health Study. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for MHT type and ovarian cancer-specific mortality, adjusted for tumor characteristics, treatment, and other risk factors. Effect modification by histology (serous vs. non-serous) was examined using likelihood ratio tests comparing models with and without interaction terms between MHT type and histology. RESULTS: Ovarian cancer-specific mortality was not associated with pre-diagnosis estrogen-only therapy (ET) (HR = 1.09, 95% CI = 0.70-1.68) or estrogen plus progestin-only therapy (EPT) (HR = 0.97, 95% CI = 0.68-1.38). Neither recency of use nor specific regimen of EPT-only (sequential vs. continuous) was related to mortality. In analyses stratified by histology, no significant association between MHT type and ovarian cancer-specific mortality was observed among serous or non-serous cases; however, a significant interaction between MHT type and histology was noted (p-heterogeneity = 0.01). CONCLUSION: Our results suggest that pre-diagnosis MHT use is not related to risk of ovarian cancer-specific death. PMID- 26425712 TI - Spontaneous ureteral rupture during concurrent chemoradiotherapy in a woman with uterine cervical cancer. AB - Spontaneous rupture of the renal pelvis and ureter is associated with obstruction of the urinary collecting system, but is rarely caused by tumors. We describe our experience with a patient who had uterine cervical cancer with mild hydroureter in whom spontaneous ureteral rupture occurred during concurrent chemoradiotherapy. The patient was a 66-year-old woman with stage IIIB uterine cervical cancer and mild hydroureter who received concurrent chemoradiotherapy. The patient felt uncontrolled right-side abdominal pain caused by ureteral rupture after she was given hydration and an intravenous bolus injection of furosemide during the first week of chemoradiotherapy. Contrast-enhanced computed tomography was more useful than ultrasonography for diagnosis of the ureteral rupture. The ureteral rupture in our patient was attributed to a rapid rise in the pressure of the urinary collecting system caused by hydration and the bolus injection of furosemide. Placement of a double-J stent before starting concurrent chemoradiotherapy may help to prevent ureteral rupture in patients who have uterine cervical cancer with mild hydroureter. PMID- 26425713 TI - Solitary ovarian plasmacytoma. A case report and review of literature. AB - *A patient with rare solitary ovarian plasmacytoma is reported*Diagnostic work-up is mandatory to rule out ovarian involvement as part of multiple myeloma.*After complete surgical resection, the prognosis appears to be very favorable. PMID- 26425714 TI - The problem of late ovarian metastases from primary cervical adenocarcinoma. AB - *Ovarian metastases can occur after hysterectomy for cervical adenocarcinoma.*Cervical adenocarcinoma and ovarian metastases showed common genetic profiles.*Most likely mechanism is trans-tubal spread of neoplastic cells via ovarian stroma. PMID- 26425715 TI - WWP2 and its association with PTEN in endometrial cancer. AB - We wished to determine if WWP2 gene expression and PTEN protein levels inversely correlate in human endometrial cancer tissues. Fifty-one endometrioid endometrial tumors and five normal endometrial controls were available for analysis. PTEN protein levels were assessed by immunohistochemistry (IHC). WWP2 and PTEN gene expression were quantitated by RT PCR. Clinical and pathologic information was collected by chart review. We found that in tumors with low PTEN protein but normal mRNA expression there were significantly higher levels of WWP2 expression (p = 0.0017). Increased WWP2 expression was not associated with clinical prognostic factors including lymphovascular space invasion, >= 50% myometrial invasion, grade, stage or recurrence. WWP2 expression was not different statistically between tumors and normal controls (p = NS). Therefore, in this cohort, tumors with low PTEN protein but normal mRNA expression had elevated levels of WWP2 expression. This suggests that WWP2 may be playing a role in PTEN degradation in endometrial cancer. PMID- 26425716 TI - Primary endometrial uterine Burkitt lymphoma in a 65-year-old woman. AB - *Primary Burkitt lymphoma of the uterus is a rare disease.*Differential of postmenopausal bleeding and night sweats should include lymphoma.*Outpatient endometrial sampling expedites diagnosis of endometrial malignancy. PMID- 26425717 TI - Breast cancer metastasis to the vulva 20 years remote from initial diagnosis: A case report and literature review. AB - *This is the 20th documented case of metastatic breast carcinoma to the vulva.*Greater than 21 years have passed from initial diagnosis to vulvar metastasis.*Existing literature supports long term surveillance in women with invasive lobular carcinoma of the breast. PMID- 26425719 TI - Palladium interstitial implant in combination with external beam radiotherapy and chemotherapy for the definitive treatment of a female urethral carcinoma. AB - Primary urethral cancer is a rare diagnosis, especially in females. This report presents the utilization of a palladium interstitial implant and a review of the retrospective data published on the management of female urethral cancer. Excellent local control and survival has been obtained with the use of a palladium interstitial implant in combination with external beam radiotherapy and concurrent chemotherapy. This modality represents a novel and effective way to treat primary urethral cancer in females. PMID- 26425718 TI - Characteristics of ovarian tumors of low malignant potential in BRCA mutation carriers: A case series. AB - *Tumor characteristics of 5 cases of ovarian tumor of low malignant potential (LMP) with BRCA mutation were examined.*Young age, BRCA1 mutation, and presence of invasive implants may be characteristics of BRCA carriers with ovarian LMP. PMID- 26425720 TI - Ureteroarterial fistula following retrograde ureteral stenting in a patient with a double-barreled wet colostomy for cervical cancer. AB - *Ureteroarterial fistula (UAF) is a rare cause of massive hematuria.*Percutaneous retrograde ureteral stents via DBWC can be done safely in the compliant patient for improved comfort.*Understanding the anatomy, risks, and minimally invasive treatment options for UAF is important for prompt patient care. PMID- 26425721 TI - The cost implications of the use of pegylated liposomal doxorubicin when choosing an anthracycline for the treatment of platinum-resistant ovarian cancer: A low value intervention? PMID- 26425722 TI - Lumbee Native American ancestry and the incidence of aggressive histologic subtypes of endometrial cancer. AB - OBJECTIVE: The Lumbee Indian tribe is the largest Native American tribe in North Carolina, with about 55,000 enrolled members who mostly reside in southeastern counties. We evaluated whether Lumbee heritage is associated with high-risk histologic subtypes of endometrial cancer. METHODS: We retrospectively analyzed the available records from IRB-approved endometrial cancer databases at two institutions of patients of Lumbee descent (year of diagnosis range 1980-2014). Each Lumbee case was matched by age, year of diagnosis, and BMI to two non-Lumbee controls. Chi-square test was used to compare categorical associations. Kaplan Meier methods and log-rank test were used to display and compare disease-free survival (DFS) and overall survival (OS). Multivariate Cox proportional hazards regression was used to adjust for age and BMI while testing cohort as a predictor of DFS and OS. RESULTS: Among 108 subjects, 10/35 (29%) Lumbee and 19/72 (26%) non-Lumbee subjects had high-risk (serous/clear cell/carcinosarcoma) histologic types (p = 0.8). 12/35 (34%) Lumbee and 24/72 (33%) non-Lumbee subjects had grade 3 tumors (p = 0.9). 5/33 (15%) Lumbee and 13/72 (18%) non-Lumbee had advanced stage endometrial cancer at diagnosis (p = 0.7). Lumbee ancestry was not associated with worse survival outcomes. OS (p = 0.054) and DFS (p = 0.01) were both worse in Blacks compared to Lumbee and White subjects. CONCLUSION: In this retrospective cohort analysis, Lumbee Native American ancestry was not a significant independent predictor of rates of high-risk histological subtypes of endometrial cancer or poor survival outcomes. PMID- 26425723 TI - FGFR3-TACC3: A novel gene fusion in cervical cancer. AB - Cervical cancer epitomizes the success of cancer prevention through the human papillomavirus (HPV) vaccine, but significant challenges remain in the treatment of advanced disease. We report the first three cases of cervical carcinoma harboring an FGFR3-TACC3 fusion, which serves as a novel therapeutic target. The fusion, identified by comprehensive genomic profiling, activates the FGFR pathway that has been implicated in HPV-driven carcinogenesis. One of the patients whose tumor contained the FGFR3-TACC3 fusion was treated with an investigational FGFR tyrosine kinase inhibitor. Concomitant molecular alterations involving the PI3K/AKT/mTOR and RAF/MEK pathways were also identified and suggest other treatment strategies that deserve investigation. This case series highlights the role of comprehensive genomic profiling in the identification of new therapeutic targets and in targeted therapy selection for patients with cervical cancer. PMID- 26425724 TI - Novel treatment of a central type, primitive neuroectodermal tumor of the ovary with postoperative pediatric medulloblastoma chemotherapy regimen: A case report and review of the literature. AB - *Central type primitive neuroectodermal tumor (cPNET) of the ovary is difficult to treat.*Etoposide, cisplatin and cyclophosphamide is a pediatric medulloblastoma regimen.*Our case with cPNET responded to this combination chemotherapy. PMID- 26425725 TI - Debulking surgery and hyperthermic intraperitoneal chemotherapy in the management of a recurrent aggressive uterine myxoid leiomyosarcoma with peritoneal dissemination. AB - *A rare case of recurrent peritoneal sarcomatosis (PS) arising from aggressive uterine myxoid leiomyosarcoma was described.*Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) has the potential to improve outcomes in PS from uterine sarcoma.*Careful patient selection for cytoreductive surgery with HIPEC is important to achieve better outcomes in PS. PMID- 26425726 TI - Hepatoid carcinoma of the ovary: A case report and review of the literature. AB - Primary hepatoid carcinoma of the ovary (HCO) is a rare aggressive tumor that typically presents at an advanced stage in postmenopausal women with unilateral or bilateral ovarian masses and elevated AFP and CA125. We report a case of HCO in a 73 year-old woman who presented with abdominal distention, weight loss, and a large lower abdominal mass. Postoperative serum AFP was markedly elevated and trended down with initiation of chemotherapy. Review of the literature revealed thirty-two reported cases with no consensus on histogenesis or consistent immunohistochemical profile other than positive AFP staining in all but one case. Although the optimal treatment has not yet been determined, tumor debulking surgery followed by a platinum and taxane based chemotherapy regimen has shown promise. Both serum AFP and CA125 appear to have prognostic value and can be used to follow response to treatment and screen for recurrence. PMID- 26425727 TI - Endometrioid adenocarcinoma arising from deep infiltrating endometriosis involving the bladder: A case report and review of the literature. AB - *Malignant transformation of deep infiltrating endometriosis involving the bladder is quite rare.*We review eight relevant cases which have been reported.*This is the second case fulfilling Sampson and Scott criteria. PMID- 26425728 TI - Almost half of women with endometrial cancer or hyperplasia do not know that obesity affects their cancer risk. PMID- 26425729 TI - Fatal cardiac tamponade following cytoreductive surgery for serous carcinoma of the ovary. AB - *Pericardial effusion may be present early in the disease process in patients with ovarian cancer.*Even a small pericardial effusion may become clinically apparent in the setting of concomitant pleural effusion(s).*Cardiac tamponade should be considered in the differential diagnosis of postoperative hemodynamic instability to facilitate timely intervention. PMID- 26425730 TI - In-vitro maturation and cryopreservation of oocytes at the time of oophorectomy. AB - A 27 year old female presented for fertility preservation prior to undergoing pelvic radiotherapy. She had previously undergone a radical laparoscopic hysterectomy for cervical carcinoma seven months earlier. A trans-vaginal oocyte aspiration was not advisable due to a vaginal recurrence of the disease. Due to a polycystic ovarian morphology (PCO), follicle stimulating hormone (FSH) priming with no human chorionic gonadotrophin (hCG) trigger was performed prior to oophorectomy followed by ex-vivo oocyte aspiration and in vitro maturation (IVM). All visualized follicles were punctured and follicular fluid aspirated. There were 22 immature oocytes identified and placed into maturation culture for 24 h. After this time, 15 oocytes were deemed to be mature and suitable for vitrification. Following an additional 24 h in maturation culture of the remaining 7 oocytes, three more were suitable for cryopreservation. The patient recovered well and progressed to radiotherapy three days later. This report demonstrates the use of IVM treatment to store oocytes for oncology patients in time-limited circumstances. PMID- 26425731 TI - The Use of Tutomesh for a Tension-Free and Tridimensional Repair of Uterovaginal and Vaginal Vault Prolapse: Preliminary Report. AB - Objective. To evaluate efficacy in terms of vaginal capacity, coital function, and recurrence prevention of a new biological mesh of bovine pericardium (Tutomesh) in the repair of severe POP. Methods. Thirty cases of patients suffering from stage III uterine or apical prolapse undergone surgical repair by means of a modified sacrospinous ligament suspension combined with mesh attachment to both the cardinal ligaments, posterior and anterior colporrhaphy, and perineal body fixation. The mesh was replaced inside the pelvis with the goal of reconstructing the tridimensional fascial disposition of the structures sustaining the correct axis of vagina. Follow-up was done at 12 months with POPIQ analysis. Results. One total mesh failure occurred early after surgery due to marked deficiency of anatomy. Two cystoceles were observed at 12 months in two patients treated for apical prolapse where anterior repair was not performed. Two other patients developed a de novo SUI at 12 months. No reported abnormalities of coital function or dyspareunia were ever found after surgery. Conclusions. It is possible that the utilization of a tension-free and tridimensional placement of Tutomesh might favor a more physiologic reconstruction of the vaginal axis as compared with traditional sacrospinous ligament suspension. PMID- 26425732 TI - Teamwork Assessment Tools in Modern Surgical Practice: A Systematic Review. AB - Introduction. Deficiencies in teamwork skills have been shown to contribute to the occurrence of adverse events during surgery. Consequently, several teamwork assessment tools have been developed to evaluate trainee nontechnical performance. This paper aims to provide an overview of these instruments and review the validity of each tool. Furthermore, the present paper aims to review the deficiencies surrounding training and propose several recommendations to address these issues. Methods. A systematic literature search was conducted to identify teamwork assessment tools using MEDLINE (1946 to August 2015), EMBASE (1974 to August 2015), and PsycINFO (1806 to August 2015) databases. Results. Eight assessment tools which encompass aspects of teamwork were identified. The Nontechnical Skills for Surgeons (NOTSS) assessment was found to possess the highest level of validity from a variety of sources; reliability and acceptability have also been established for this tool. Conclusions. Deficits in current surgical training pathways have prompted several recommendations to meet the evolving requirements of surgeons. Recommendations from the current paper include integration of teamwork training and assessment into medical school curricula, standardised formal training of assessors to ensure accurate evaluation of nontechnical skill acquisition, and integration of concurrent technical and nontechnical skills training throughout training. PMID- 26425733 TI - Current Status of Single-Site Robotic Cholecystectomy, its feasibility, economic and overall impact. AB - This paper reviews recent, though limited, articles on the topic of robotic single-site cholecystectomy (RSSC), a relatively new approach that is rapidly advancing in both research and clinical application. Laparoscopy has typically been the standard method of performing a cholecystectomy, but recent medical advances have led to usage of the da Vinci(r) Surgical System robot technology to assist in performing the procedure. Several studies have compared outcomes of the RSSC to single-port laparoscopic cholecystectomies and to the traditional multiport laparoscopic cholecystectomies. Single port advocates think it as a tool with better cosmetic results and questionable less post-operative pain; however, single port also limits the maneuverability of the instrument arms, making some tasks more difficult, bigger single incision, more chances of post operative hernia. Overall, the RSSC is considered as safe with no worse outcomes regarding pain, hospital stay length, operative time, and patient satisfaction when compared to other cholecystectomy methods. Future direction includes expanding use of the miniature instruments and further advanced tools to overcome manipulation and visualization limitations. Thus far, though, there may be enough evidence with these smaller studies to support lack of harm with more use of resources. PMID- 26425735 TI - Development of a polymer based fiberoptic magnetostrictive metal detector system. AB - This paper presents a new metal detector using a fiberoptic magnetostriction sensor. The metal sensor uses a fiber-optic Mach-Zehnder interferometer with a newly developed ferromagnetic polymer as the magnetostrictive sensing material. This polymeric magnetostrictive fiberoptic metal sensor is simple to fabricate, small in size, and resistant to RF interference (which is common in typical electromagnetic type metal detectors). Metal detection is based on disruption of the magnetic flux density across the magnetostriction sensor. In this paper, characteristics of the material being sensed and magnetic properties of the ferromagnetic polymers will be discussed. PMID- 26425736 TI - Synthesis and luminescence modulation of pyrazine-based gold(III) pincer complexes. AB - The first examples of pyrazine-based gold(III) pincer complexes are reported; their intense photoemissions can be modified by protonation, N-alkylation or metal ions, without the need for altering the ligand framework. Emissions shift from red (77 K) to blue (298 K) due to thermally activated delayed fluorescence (TADF). PMID- 26425737 TI - [Lassa fever and ribavirin]. PMID- 26425734 TI - Mast cell degranulation by a hemolytic lipid toxin decreases GBS colonization and infection. AB - Ascending infection of microbes from the lower genital tract into the amniotic cavity increases the risk of preterm birth, stillbirth, and newborn infections. Host defenses that are critical for preventing ascending microbial infection are not completely understood. Group B Streptococcus (GBS) are Gram-positive bacteria that frequently colonize the lower genital tract of healthy women but cause severe infections during pregnancy, leading to preterm birth, stillbirth, or early-onset newborn infections. We recently described that the GBS pigment is hemolytic, and increased pigment expression promotes GBS penetration of human placenta. Here, we show that the GBS hemolytic pigment/lipid toxin and hyperpigmented GBS strains induce mast cell degranulation, leading to the release of preformed and proinflammatory mediators. Mast cell-deficient mice exhibit enhanced bacterial burden, decreased neutrophil mobilization, and decreased immune responses during systemic GBS infection. In a vaginal colonization model, hyperpigmented GBS strains showed increased persistence in mast cell-deficient mice compared to mast cell-proficient mice. Consistent with these observations, fewer rectovaginal GBS isolates from women in their third trimester of pregnancy were hyperpigmented/hyperhemolytic. Our work represents the first example of a bacterial hemolytic lipid that induces mast cell degranulation and emphasizes the role of mast cells in limiting genital colonization by hyperpigmented GBS. PMID- 26425738 TI - Hormone crosstalk in plants. PMID- 26425739 TI - Preface. PMID- 26425740 TI - Homer Hupf (1933-2015): In memoriam. PMID- 26425741 TI - Central Retinal Artery Occlusion in a 21-Year-Old Boxer. PMID- 26425742 TI - Palisaded Encapsulated Neuroma of the Eyelid. PMID- 26425743 TI - Orbital Choristoma. PMID- 26425744 TI - Uveal Melanoma Presenting as a Pigmented Conjunctival Lesion. PMID- 26425745 TI - Retraction notice to 'Design and synthesis of CHAP31, trapoxin B and HC-toxin based bicyclic tetrapeptides disulfide as potent histone deacetylase inhibitors' [Bioorg Med Chem 22 (2014) 3850-3855]. PMID- 26425746 TI - 2nd International Conference on Biomedicine and Pharmaceutics (ICBP) 2014. PMID- 26425747 TI - From The Archives. PMID- 26425781 TI - Are general surgeons able to accurately self-assess their level of technical skills? AB - INTRODUCTION: Self-assessment is a way of improving technical capabilities without the need for trainer feedback. It can identify areas for improvement and promote professional medical development. The aim of this review was to identify whether self-assessment is an accurate form of technical skills appraisal in general surgery. METHODS: The PubMed, MEDLINE((r)), Embase(TM) and Cochrane databases were searched for studies assessing the reliability of self-assessment of technical skills in general surgery. For each study, we recorded the skills assessed and the evaluation methods used. Common endpoints between studies were compared to provide recommendations based on the levels of evidence. RESULTS: Twelve studies met the inclusion criteria from 22,292 initial papers. There was no level 1 evidence published. All papers compared the correlation between self appraisal versus an expert score but differed in the technical skills assessment and the evaluation tools used. The accuracy of self-assessment improved with increasing experience (level 2 recommendation), age (level 3 recommendation) and the use of video playback (level 3 recommendation). Accuracy was reduced by stressful learning environments (level 2 recommendation), lack of familiarity with assessment tools (level 3 recommendation) and in advanced surgical procedures (level 3 recommendation). CONCLUSIONS: Evidence exists to support the reliability of self-assessment of technical skills in general surgery. Several variables have been shown to affect the accuracy of self-assessment of technical skills. Future work should focus on evaluating the reliability of self-assessment during live operating procedures. PMID- 26425782 TI - A framework for the frontline: How hospitalists can improve healthcare value. AB - As healthcare costs continue to grow, hospitalists may be able to help patients and health system administrators make decisions that generate higher-value care. In this article, we discuss 3 ways hospitalists can contribute to the mission of delivering value-based healthcare: design innovative strategies to coordinate care, advocate for appropriate utilization of tests and treatments, and lead local value-improvement initiatives. We also describe specific tools hospitalists can use in their daily practice, including the Choosing Wisely lists and the COST (Culture, Oversight, Systems Change, Training) framework for value-improvement initiatives. PMID- 26425783 TI - Can attachment and peer relation constructs predict anxiety in ethnic minority youths? A longitudinal exploratory study. AB - Anxiety is the most prevalent psychiatric disturbance in childhood effecting typically 15-20% of all youth. It has been associated with attachment insecurity and reduced competence in peer relations. Prior work has been limited by including mainly White samples, relying on questionnaires, and applying a cross sectional design. The present study addressed these limitations by considering how at-risk non-White youth (n = 34) responded to the Friends and Family Interview (FFI) in middle childhood and how this linked up with anxiety symptoms and an anxiety diagnosis three years later in early adolescence. Five dimensions of secure attachment, namely, (i) to mother, (ii) to father, (iii) coherence, (iv) developmental understanding, and (v) social competence and quality of contact with best friend in middle childhood, were found to correlate significantly (and negatively) with self-reported anxiety symptoms. Linear regression results showed independent influences of female gender, and (low) quality of best friend contact as the most efficient model predicting anxiety symptoms. Logistic regression results suggested a model that included female gender, low social competence, and immature developmental understanding as efficient predictors of an anxiety diagnosis, evident in only 18% of the sample. These results point to the usefulness of after-school programs for at-risk minority youth in promoting peer competence, developmental awareness, and minimizing anxiety difficulties. PMID- 26425784 TI - Protostane Triterpenoids from the Rhizome of Alisma orientale Exhibit Inhibitory Effects on Human Carboxylesterase 2. AB - Twelve new and 10 known protostane triterpenoids were isolated from the rhizome of Alisma orientale. Their structures were elucidated based on physical data analyses, including UV, HRESIMS, NMR experiments ((1)H, (13)C NMR, (1)H-(1)H COSY, HSQC, HMBC, and NOESY), and induced electronic circular dichroism. New compounds 1-12 were classified as protostanes (1-10), 29-norprotostane (11), and 24-norprotostane (12) by structure analyses. Furthermore, the inhibitory effects on human carboxylesterases (hCE-1, hCE-2) of compounds 1-22 were evaluated. Compounds 2, 6, 9, and 11 showed moderate inhibitory activities and were selective toward hCE-2 enzymes, with IC50 values of 8.68, 4.72, 4.58, and 2.02 MUM, respectively. The inhibition kinetics of compound 11 toward hCE-2 were established, and the Ki value was determined as 1.76 MUM using a mixed inhibition model. The interaction of bioactive compound 11 with hCE-2 was shown using molecular docking. PMID- 26425786 TI - Fluorographane: a promising material for bipolar doping of MoS2. AB - Using first principles calculations we investigate the structural and electronic properties of interfaces between fluorographane and MoS2. Unsymmetrical functionalization of graphene with H and F results in an intrinsic dipole moment perpendicular to the plane of the buckled graphene skeleton. Depending on the orientation of this dipole moment, the electronic properties of a physically absorbed MoS2 monolayer can be switched from n- to p-type or vice versa. We show that one can realize vanishing n-type/p-type Schottky barrier heights when contacting MoS2 to fluorographane. By applying a perpendicular electric field, the size of the Schottky barrier and the degree of doping can be tuned. Our calculations indicate that a fluorographane monolayer is a promising candidate for bipolar doping of MoS2, which is vital in the design of novel technological applications based on two-dimensional materials. PMID- 26425787 TI - Direct costs of acute respiratory infections in a pediatric long-term care facility. AB - Acute respiratory tract infections (ARI) are a major burden in pediatric long term care. We analyzed the financial impact of ARI in 2012-2013. Costs associated with ARI during the respiratory viral season were ten times greater than during the non-respiratory viral season, $31 224 and $3242 per 1000 patient-days, respectively (P < 0.001). ARI are burdensome for pediatric long-term care facilities not only because of the associated morbidity and mortality, but also due to the great financial costs of prevention. PMID- 26425788 TI - Heteromerous Bistricyclic Aromatic Enes: Dynamic Stereochemistry of Xanthylidene Anthrones. AB - The heteromerous bistricyclic aromatic ene (BAE) 2,2'-dimethyl-10-(9H xanthylidene)-9(10H)-anthrone (DMXA) was synthesized by a condensation of 10,10 dichloro-2-methylxanthene with 2-methylanthrone. X-ray crystallography of (E) DMXA and xanthylidene-anthrone (XA) indicated that the molecules adopt anti folded conformations with folding dihedral angles of 44 degrees /44 degrees and 39 degrees /41 degrees , respectively. The crystal structure of anti-folded (E) DMXA does not indicate any xanthenylium-anthracenolate push-pull effect. E,Z diastereomerization of DMXA was studied by (1) H-NMR coalescence-temperature measurements at different magnetic field strengths and by kinetic equilibration experiments. Free energy of activation for this process was 81.5 (+/-1.3) kJ/mol. B3LYP/6-311+G(d,p) calculations showed that anti-folded conformers of XA, (E) DMXA, bianthrone (AA), and dixanthylene (XX) were global minima. The twisted conformers of XA, AA, and XX were local minima (DeltaG298 = 16, 18, and 24 kJ/mol) with a substantial dipolar xanthenylium-anthracenolate dipolar contribution for XA. Chirality 27:919-928, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26425785 TI - Voxel-Based Lesion Symptom Mapping of Coarse Coding and Suppression Deficits in Patients With Right Hemisphere Damage. AB - PURPOSE: This study examined right hemisphere (RH) neuroanatomical correlates of lexical-semantic deficits that predict narrative comprehension in adults with RH brain damage. Coarse semantic coding and suppression deficits were related to lesions by voxel-based lesion symptom mapping. METHOD: Participants were 20 adults with RH cerebrovascular accidents. Measures of coarse coding and suppression deficits were computed from lexical decision reaction times at short (175 ms) and long (1000 ms) prime-target intervals. Lesions were drawn on magnetic resonance imaging images and through normalization were registered on an age-matched brain template. Voxel-based lesion symptom mapping analysis was applied to build a general linear model at each voxel. Z score maps were generated for each deficit, and results were interpreted using automated anatomical labeling procedures. RESULTS: A deficit in coarse semantic activation was associated with lesions to the RH posterior middle temporal gyrus, dorsolateral prefrontal cortex, and lenticular nuclei. A maintenance deficit for coarsely coded representations involved the RH temporal pole and dorsolateral prefrontal cortex more medially. Ineffective suppression implicated lesions to the RH inferior frontal gyrus and subcortical regions, as hypothesized, along with the rostral temporal pole. CONCLUSION: Beyond their scientific implications, these lesion-deficit correspondences may help inform the clinical diagnosis and enhance decisions about candidacy for deficit-focused treatment to improve narrative comprehension in individuals with RH damage. PMID- 26425789 TI - Telehealth will supersede face-to-face consultations in rural Australia by 2025. PMID- 26425790 TI - Pathways to Remote Professional Practice: New release. PMID- 26425791 TI - Chronic disease must be confronted on two fronts. PMID- 26425792 TI - A Retrospective Review of Conjunctival Melanoma Presentation, Treatment, and Outcome and an Investigation of Features Associated With BRAF Mutations. AB - IMPORTANCE: Large studies investigating clinical presentation and treatment in primary conjunctival melanoma (CM) are rare. Clinicopathological characteristics of BRAF-mutated CM have not been studied thoroughly. OBJECTIVES: To determine the associations of clinicopathological tumor features and treatment with local recurrence, metastasis, and mortality and to determine the association of BRAF mutations with these features. DESIGN, SETTING, AND PARTICIPANTS: Population based cohort study at the Eye Pathology Institute, Copenhagen, Denmark. Participants included 139 patients with primary CM in Denmark from January 1, 1960, to December 31, 2012. For BRAF analysis, all patients with available formalin-fixed, paraffin-embedded tumor samples from January 1, 1994, to December 31, 2012, were included. MAIN OUTCOMES AND MEASURES: BRAF mutations, local recurrence, regional and distant metastasis, melanoma-related mortality, and all cause mortality were examined. RESULTS: A poor prognosis of tumors involving the extrabulbar conjunctiva and adjacent tissue structures was confirmed in multivariable Cox proportional hazards regression models. Patients undergoing incisional biopsy more frequently developed metastasis (hazard ratio [HR], 2.46; 95% CI, 1.08-5.58; P = .03). Excision without adjuvant treatment was associated with local recurrence (HR, 1.97; 95% CI, 0.11-3.48; P = .02), metastatic disease (HR, 2.51; 95% CI, 1.07-5.91; P = .03), and all-cause mortality (HR, 1.80; 95% CI, 1.05-3.08; P = .03). BRAF mutations were identified in 19 of 47 primary CMs (40.4%) and were more frequent in younger patients (P = .005), less frequent in the extrabulbar conjunctiva (P = .05), more frequently classified as T1 tumors (P = .03), and rarely manifested with primary acquired melanosis (P = .001) or with a uniformly pigmented lesion (P = .006). Distant metastases developed in 6 of 19 BRAF-mutated CMs (31.6%) as opposed to 1 of 28 BRAF wild-type CMs (3.6%). No definitive association with distant metastasis was seen in multivariable Cox proportional hazards regression models. CONCLUSIONS AND RELEVANCE: Incisional biopsy and excision without adjuvant therapy were associated with a poor outcome in patients with CM. Extrabulbar location was also associated with a poor outcome in multivariable analysis. BRAF-mutated CMs were frequent in younger patients and were rare in tumors involving the extrabulbar conjunctiva. Despite a more favorable location, BRAF-mutated tumors may be associated with more frequent distant metastasis. PMID- 26425793 TI - Learning curves for transfemoral transcatheter aortic valve replacement in the PARTNER-I trial: Success and safety. AB - OBJECTIVES: To identify number of cases needed to maximize device success and minimize adverse events after transfemoral transcatheter aortic valve replacement (TF-TAVR), and determine if adverse events were linked to the technical performance learning curve. BACKGROUND: TF-TAVR is a complex procedure with an incompletely characterized learning curve for clinical outcomes. METHODS: From 4/2007-2/2012, 1521 patients underwent TF-TAVR in the PARTNER-I trial. Outcomes learning curves were defined as number of cases needed to reach a plateau for device success, adverse events, and post-procedure length of stay. Institutional variation was accounted for by mixed-model non-linear techniques, which were also used to identify contribution of the procedure time learning curve to 30-day major adverse events and length of stay. RESULTS: Eighty percent device success was achieved after 22 cases; major vascular complications fell below 5% after 70 cases and major bleeding below 10% after 25 cases. It took an average of 28 cases to achieve a consistent low risk of 30-day major adverse events, but institutions entering in the middle of the trial achieved it after about 26. The most significant correlate of 30-day major adverse events and post-procedure length of stay was procedure time (P < 0.0001). However, this association was related to patient and unmeasured variables, not the procedure time learning curve (P = 0.6). CONCLUSIONS: By end of trial, a consistent low risk of adverse events was achieved after ~26 cases. However, these improved results were due to change in patient risk profile; outcomes were not linked to the technical performance learning curve. (c) 2015 Wiley Periodicals, Inc. PMID- 26425794 TI - The changing importance of key factors associated with anaemia in 6- to 59-month old children in a sub-Saharan African setting where malaria is on the decline: analysis of the Rwanda Demographic and Health Survey 2010. AB - OBJECTIVE: To estimate the relative contribution of malaria and other potential determinants to current anaemia prevalence in Rwanda. METHODS: The database for this study was the Rwanda Demographic and Health Survey 2010. Haemoglobin and malaria test results, and additional exposures ascertained through mothers' interviews, were analysed for all eligible children age 6-59 months (n = 4068), in addition to diet data available for the youngest under 5-year-old per household. We examined anaemia-exposure associations through forward logistic regression, first for the overall population (n = 3685), and second, for the subpopulation with diet data (n = 1934). RESULTS: In the overall study population, malaria was strongly associated with anaemia (OR = 6.83, 95% CI: 2.90 16.05), but population impact was modest (population-attributable fraction = 2.5%). Factors associated with lower odds of anaemia were recent de-worming medication (six months; OR = 0.60, 95% CI: 0.49-0.74), female sex (OR = 0.76, 95% CI: 0.66-0.87), increasing age, residence in North Province and educated mother. Being underweight and recent fever (two weeks) were associated with higher odds. In the subpopulation with diet data, odds were lower with consumption of vitamin A-rich foods (OR = 0.66, 95% CI: 0.50-0.88); and higher in households with many young children. CONCLUSIONS: Malaria remains a strong determinant of anaemia for the individual child: transmission control efforts must be maintained. At population level, to further reduce anaemia prevalence, promoting regular vitamin A intake from natural sources and reducing intestinal helminths burden appear the most promising strategies to explore; exploring potential hitherto unidentified sex-linked factors is warranted. PMID- 26425795 TI - A prospective observational study of needle-handling practices at a University Veterinary Teaching Hospital. AB - AIM: To determine the period prevalence of needlestick injury (NSI) at the Massey University Veterinary Teaching Hospital (VTH) and to identify handling and disposal practices that may contribute to the risk of NSI. METHODS: Observations of personnel were conducted in the equine (EVH) and companion animal (CAH) clinics of the VTH during scheduled clinical activities over 9- and 10-day periods, respectively. The number and type of NSI incidents, needle uncapping, capping and disposal events were recorded for veterinarians, nurses and other personnel (visitors and students). The number of needle-related practices, as a proportion of observations, were compared between CAH and EVH, and veterinarians, nurses and others using chi(2) tests. RESULTS: Needlestick injury was not observed during 190 and 163 needle handling and disposal observations in the CAH and EVH, respectively. Uncapping of needles by mouth was observed and was practised more by veterinarians (15/119; 13%) than nurses (2/42; 5%) and others (6/193; 3%) (p=0.001). Two-handed needle recapping after use was observed 265/354 times, and the one handed scooping technique was rarely observed (8/352). In the case of needle disposal, EVH workers used a container that was not purpose built for disposal more than CAH staff (p=0.02), or placed them in a pocket more frequently (p=0.003). Needle disposal containers were available on adjacent bench tops for 65/190 (34%) CAH observations, but no EVH observations. For 51/163 (31%) EVH observations the needle disposal containers were located on the ground, whereas none were observed there in the CAH. No approved sharps containers were observed in the immediate EVH and CAH work areas for 47/163 (28.8%) and 1/191 (0.5%) needle-handling activities, respectively. CONCLUSIONS: Unsafe needle handling practices must be reduced by policies and training programmes to encourage safe needle-related practices, and ensuring that approved sharps containers are available in close proximity to where needles are used. PMID- 26425797 TI - A Proton-Switchable Bifunctional Ruthenium Complex That Catalyzes Nitrile Hydroboration. AB - A new bifunctional pincer ligand framework bearing pendent proton-responsive hydroxyl groups was prepared and metalated with Ru(II) and subsequently isolated in four discrete protonation states. Stoichiometric reactions with H2 and HBPin showed facile E-H (E = H or BPin) activation across a Ru(II)-O bond, providing access to unusual Ru-H species with strong interactions with neighboring proton and boron atoms. These complexes were found to promote the catalytic hydroboration of ketones and nitriles under mild conditions, and the activity was highly dependent on the ligand's protonation state. Mechanistic experiments revealed a crucial role of the pendent hydroxyl groups for catalytic activity. PMID- 26425799 TI - The dysfunctional inner mirror: poor insight in obsessive-compulsive disorder, contributions to heterogeneity and outcome. PMID- 26425800 TI - Comorbidity of personality disorder in obsessive-compulsive disorder: special emphases on the clinical significance. PMID- 26425798 TI - A proteomics approach to identifying key protein targets involved in VEGF inhibitor mediated attenuation of bleomycin-induced pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a life expectancy of less than 5 years post diagnosis for most patients. Poor molecular characterization of IPF has led to insufficient understanding of the pathogenesis of the disease, resulting in lack of effective therapies. In this study, we have integrated a label-free LC-MS based approach with systems biology to identify signaling pathways and regulatory nodes within protein interaction networks that govern phenotypic changes that may lead to IPF. Ingenuity Pathway Analysis of proteins modulated in response to bleomycin treatment identified PI3K/Akt and Wnt signaling as the most significant profibrotic pathways. Similar analysis of proteins modulated in response to vascular endothelial growth factor (VEGF) inhibitor (CBO-P11) treatment identified natural killer cell signaling and PTEN signaling as the most significant antifibrotic pathways. Mechanistic/mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK) were identified to be key mediators of pro- and antifibrotic response, where bleomycin (BLM) treatment resulted in increased expression and VEGF inhibitor treatment attenuated expression of mTOR and ERK. Using a BLM mouse model of pulmonary fibrosis and VEGF inhibitor CBO-P11 as a therapeutic measure, we identified a comprehensive set of signaling pathways and proteins that contribute to the pathogenesis of pulmonary fibrosis that can be targeted for therapy against this fatal disease. PMID- 26425801 TI - Molecular identification and physiological characterization of yeasts, lactic acid bacteria and acetic acid bacteria isolated from heap and box cocoa bean fermentations in West Africa. AB - Yeast, lactic acid bacteria (LAB) and acetic acid bacteria (AAB) populations, isolated from cocoa bean heap and box fermentations in West Africa, have been investigated. The fermentation dynamicswere determined by viable counts, and 106 yeasts, 105 LAB and 82 AAB isolateswere identified by means of rep-PCR grouping and sequencing of the rRNA genes. During the box fermentations, the most abundant species were Saccharomyces cerevisiae, Candida ethanolica, Lactobacillus fermentum, Lactobacillus plantarum, Acetobacter pasteurianus and Acetobacter syzygii, while S. cerevisiae, Schizosaccharomyces pombe, Hanseniaspora guilliermondii, Pichia manshurica, C. ethanolica, Hanseniaspora uvarum, Lb. fermentum, Lb. plantarum, A. pasteurianus and Acetobacter lovaniensis were identified in the heap fermentations. Furthermore, the most abundant species were molecularly characterized by analyzing the rep-PCR profiles. Strains grouped according to the type of fermentations and their progression during the transformation process were also highlighted. The yeast, LAB and AAB isolates were physiologically characterized to determine their ability to grow at different temperatures, as well as at different pH, and ethanol concentrations, tolerance to osmotic stress, and lactic acid and acetic acid inhibition. Temperatures of 45 degrees C, a pH of 2.5 to 3.5, 12% (v/v) ethanol and high concentrations of lactic and acetic acid have a significant influence on the growth of yeasts, LAB and AAB. Finally, the yeastswere screened for enzymatic activity, and the S. cerevisiae, H. guilliermondii, H. uvarumand C. ethanolica species were shown to possess several enzymes that may impact the quality of the final product. PMID- 26425802 TI - Variation of the Pseudomonas community structure on oak leaf lettuce during storage detected by culture-dependent and -independent methods. AB - The genus Pseudomonas plays an important role in the lettuce leaf microbiota and certain species can induce spoilage. The aim of this study was to investigate the occurrence and diversity of Pseudomonas spp. on oak leaf lettuce and to follow their community shift during a six day cold storage with culture-dependent and culture-independent methods. In total, 21 analysed partial Pseudomonas 16S rRNA gene sequences matched closely (> 98.3%) to the different reference strain sequences, which were distributed among 13 different phylogenetic groups or subgroups within the genus Pseudomonas. It could be shown that all detected Pseudomonas species belonged to the P. fluorescens lineage. In the culture dependent analysis, 73% of the isolates at day 0 and 79% of the isolates at day 6 belonged to the P. fluorescens subgroup. The second most frequent group, with 12% of the isolates, was the P. koreensis subgroup. This subgroup was only detected at day 0. In the culture-independent analysis the P. fluorescens subgroup and P. extremaustralis could not be differentiated by RFLP. Both groups were most abundant and amounted to approximately 46% at day 0 and 79% at day 6. The phytopathogenic species P. salmonii, P. viridiflava and P. marginalis increased during storage. Both approaches identified the P. fluorescens group as the main phylogenetic group. The results of the present study suggest that pseudomonads found by plating methods indeed represent the most abundant part of the Pseudomonas community on oak leaf lettuce. PMID- 26425804 TI - Two-dimensional MoS2-assisted immediate aggregation of poly-3-hexylthiophene with high mobility. AB - Nanoscale morphology is of significance to the electronic properties of semiconducting polymers. Solution-processed poly-3-hexylthiophene (P3HT) has been demonstrated as a promising active-layer material in organic thin film transistors (OTFTs) and solar cells. Controlling the crystallinity of P3HT chains is critical for gaining high-performance devices. Here we demonstrated the immediate crystallization of P3HT induced by two-dimensional MoS2 nanosheets under ultrasonication. The resulting aggregation was attributed to the presence of interaction between the MoS2 nanosheets and P3HT, which could enhance the inter-chain ordering and association of P3HT. The crystallization of P3HT contributed to the 38-fold enhancement in the hole mobility of the thin film as compared to the non-crystallized thin films because of the absence of MoS2. Our approach of using 2D MoS2 nanosheets to induce immediate aggregation of P3HT provides a facile process to control the crystallization of conjugated polymers for the development of high-performance organic electronics. PMID- 26425803 TI - Assessing the Indirect Photochemical Transformation of Dissolved Combined Amino Acids through the Use of Systematically Designed Histidine-Containing Oligopeptides. AB - Photooxidation is an important abiotic transformation pathway for amino acids (AAs) in sunlit waters. Although dissolved free AAs are well studied, the photooxidation of dissolved combined AAs (DCAAs) remains poorly investigated. This study is a systematic investigation of the effect of neighboring photostable AA residues (i.e., aliphatic, cationic, anionic, or aromatic residues) on the environmental indirect photochemical transformation of histidine (His) in His containing oligopeptides. The pKa values of His residues in the studied oligopeptides were found to be between 4.3 and 8.1. Accordingly, the phototransformation rate constants of the His-containing oligopeptides were highly pH-dependent in an environmentally relevant pH range with higher reactivity for neutral His than for the protonated species. The photostable AA residues significantly modulated the photoreactivity of oligopeptides either through altering the accessibility of His to photochemically produced oxidants or through shifting the pKa values of His residues. In addition, the influence of neighboring photostable AA residues on the sorption-enhanced phototransformation of oligopeptides in solutions containing chromophoric dissolved organic matter (CDOM) was assessed. The constituent photostable AA residues promoted sorption of His-containing oligopeptides to CDOM macromolecules through electrostatic attraction, hydrophobic effects, and/or low-barrier hydrogen bonds, and subsequently increased the apparent phototransformation rate constants by up to 2 orders of magnitude. PMID- 26425805 TI - An overview of current knowledge concerning the health and environmental consequences of the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident. AB - Since 2011, the scientific community has worked to identify the exact transport and deposition patterns of radionuclides released from the accident at the Fukushima Daiichi Nuclear Power Plant (FDNPP) in Japan. Nevertheless, there still remain many unknowns concerning the health and environmental impacts of these radionuclides. The present paper reviews the current understanding of the FDNPP accident with respect to interactions of the released radionuclides with the environment and impacts on human and non-human biota. Here, we scrutinize existing literature and combine and interpret observations and modeling assessments derived after Fukushima. Finally, we discuss the behavior and applications of radionuclides that might be used as tracers of environmental processes. This review focuses on (137)Cs and (131)I releases derived from Fukushima. Published estimates suggest total release amounts of 12-36.7PBq of (137)Cs and 150-160PBq of (131)I. Maximum estimated human mortality due to the Fukushima nuclear accident is 10,000 (due to all causes) and the maximum estimates for lifetime cancer mortality and morbidity are 1500 and 1800, respectively. Studies of plants and animals in the forests of Fukushima have recorded a range of physiological, developmental, morphological, and behavioral consequences of exposure to radioactivity. Some of the effects observed in the exposed populations include the following: hematological aberrations in Fukushima monkeys; genetic, developmental and morphological aberrations in a butterfly; declines in abundances of birds, butterflies and cicadas; aberrant growth forms in trees; and morphological abnormalities in aphids. These findings are discussed from the perspective of conservation biology. PMID- 26425806 TI - Pre- and postnatal exposures to pesticides and neurodevelopmental effects in children living in agricultural communities from South-Eastern Spain. AB - BACKGROUND: Childrens exposure to neurotoxic compounds poses a major problem to public health because oftheir actively developing brain that makes them highly vulnerable. However, limited information is available on neuropsychological effects in children associated with pre- and postnatal exposures to pesticides. OBJECTIVE: To evaluate the association between current and pre- and postnatal exposures to pesticides and their effects on neurodevelopment in children aged 6 11 years living in agricultural communities from South-Eastern Spain. METHODS: An ambispective study was conducted on 305 children aged 6-11 years randomly selected from public schools of the study area. Current exposure to organophosphate pesticides was assessed measuring children's urinary levels of dialkylphosphates (DAPs). Both prenatal and postnatal residential exposure to pesticides was estimated by developing a geographical information system (GIS) technology-based index that integrated distance-weighted measure of agricultural surface, time-series of crop areas per municipality and year, and land-use maps. Neuropsychological performance was evaluated with the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV). The association of pre- and postnatal and current pesticide exposure with WISC-IV scale scores was assessed using multivariate linear regression models and generalized estimating equation (GEE) models, respectively. RESULTS: Greater urinary DAP levels were associated with a poorer performance on intelligence quotient and verbal comprehension domain, with effects being more prominent in boys than in girls. The influence of an increase in 10 ha per year in crop surface around the child's residence during the postnatal period was associated with decreased intelligence quotient, processing speed and verbal comprehension scores. As regards prenatal exposure to pesticides, a poor processing speed performance was observed. These effects were also more prominent in boys than in girls. CONCLUSIONS: Our results suggest that postnatal exposure to pesticides can negatively affect children's neuropsychological performance. Prenatal exposure was weakly associated to neurodevelopment impairment. PMID- 26425807 TI - Exposure to long-term air pollution and road traffic noise in relation to cholesterol: A cross-sectional study. AB - BACKGROUND: Exposure to traffic noise and air pollution have both been associated with cardiovascular disease, though the mechanisms behind are not yet clear. OBJECTIVES: We aimed to investigate whether the two exposures were associated with levels of cholesterol in a cross-sectional design. METHODS: In 1993-1997, 39,863 participants aged 50-64 year and living in the Greater Copenhagen area were enrolled in a population-based cohort study. For each participant, non fasting total cholesterol was determined in whole blood samples on the day of enrolment. Residential addresses 5-years preceding enrolment were identified in a national register and road traffic noise (Lden) were modeled for all addresses. For air pollution, nitrogen dioxide (NO2) was modeled at all addresses using a dispersion model and PM2.5 was modeled at all enrolment addresses using a land use regression model. Analyses were done using linear regression with adjustment for potential confounders as well as mutual adjustment for the three exposures. RESULTS: Baseline residential exposure to the interquartile range of road traffic noise,NO2 and PM2.5 was associated with a 0.58 mg/dl (95% confidence interval: 0.09; 1.25), a 0.68 mg/dl (0.22; 1.16) and a 0.78 mg/dl (0.22; 1.34) higher level of total cholesterol in single pollutant models, respectively. In two pollutant models with adjustment for noise in air pollution models and vice versa, the association between air pollution and cholesterol remained for both air pollution variables (NO2: 0.72 (0.11; 1.34); PM2.5: 0.70 (0.12; 1.28) mg/dl), whereas there was no association for noise (-0.08mg/dl). In three-pollutant models (NO2, PM2.5 and road traffic noise), estimates for NO2 and PM2.5 were slightly diminished (NO2: 0.58 (-0.05; 1.22); PM2.5: 0.57 (-0.02; 1.17) mg/dl). CONCLUSIONS: Air pollution and possibly also road traffic noise may be associated with slightly higher levels of cholesterol, though associations for the two exposures were difficult to separate. PMID- 26425809 TI - Chelating Surfaces for Native State Proteins Patterning: The Human Serum Albumin Case. AB - The paper reports a new "soft" surface functionalization strategy, based on a highly selective ion metal chelation process. The proposed stepwise methodology implies at first the construction of a monolayer of terpyridine-based thiol (Tpy), whose highly packed structuring has been followed in situ by using quartz crystal microbalance (QCM-D) measurements, showing that the monolayers consist of about 2.7 * 10(14) Tpy/cm(2). Then, the tridentate sites of the each Tpy moiety are employed to partially chelate divalent metal ions, providing an effective platform to anchoring proteins by completing the metal ion coordination with an available site on the protein of interest. We report the case study of the application of the process to the HSA immobilization onto various surfaces, including Tpy-Fe(II) and Tpy-Cu(II) complexes, as well as hydrophilic bare gold substrates and hydrophobic self-assembled Tpy-based monolayers. It is shown that the chelation interaction between Tpy-Cu(II) complexes and HSA produces the highest and most robust HSA immobilization, with an adsorbed mass at the steady state of ~800 ng/cm(2), with respect to an average adsorption of ~350 ng/cm(2) for the other surfaces. Furthermore, Cu(II)-chelated surfaces seem to promote a sort of protein "soft" landing, preventing the ubiquitous surface-induced major unfolding and transmitting an orientation information to the protein, owing to the highly specific symmetry coordination of the Tpy-Cu(II)-protein complex. Indeed, the interaction with a specific monoclonal antiboby (anti-HSA) indicated the lack of a significant protein denaturation, while a massive reorientation/denaturation process was found for all the remaining surfaces, including the Tpy-Fe(II) complex. Finally, the metal-ion-dependent HSA immobilization selectivity has been exploited to obtain micropatterned surfaces, based on the strikingly different strength of interaction and stability observed for Fe(II) and Cu(II) complexes. PMID- 26425810 TI - One-pot synthesis of cobalt-coordinated N-doped carbon catalysts via co-synthesis of ionic liquids and cobalt porphyrins. AB - Cobalt-coordinated N-doped carbon (CoNC) was fabricated by heating cobalt porphyrins and ionic liquids. The prepared catalysts displayed superior catalytic capacity for the direct oxidation of ethylbenzene, and unprecedented stability was obtained even after six runs with a similar catalytic performance. PMID- 26425808 TI - Using a 3D Culture System to Differentiate Visceral Adipocytes In Vitro. AB - It has long been recognized that body fat distribution and regional adiposity play a major role in the control of metabolic homeostasis. However, the ability to study and compare the cell autonomous regulation and response of adipocytes from different fat depots has been hampered by the difficulty of inducing preadipocytes isolated from the visceral depot to differentiate into mature adipocytes in culture. Here, we present an easily created 3-dimensional (3D) culture system that can be used to differentiate preadipocytes from the visceral depot as robustly as those from the sc depot. The cells differentiated in these 3D collagen gels are mature adipocytes that retain depot-specific characteristics, as determined by imaging, gene expression, and functional assays. This 3D culture system therefore allows for study of the development and function of adipocytes from both depots in vitro and may ultimately lead to a greater understanding of site-specific functional differences of adipose tissues to metabolic dysregulation. PMID- 26425811 TI - Rapid, specific, simple, in-field detection of Xanthomonas campestris pathovar musacearum by loop-mediated isothermal amplification. AB - AIMS: To develop and evaluate a loop-mediated isothermal amplification (LAMP) assay for Xanthomonas campestris pathovar musacearum (Xcm), the causal agent of banana Xanthomonas wilt, a major disease of banana in Africa. METHODS AND RESULTS: LAMP primers were designed to the general secretion pathway protein D gene and tested against 17 isolates of Xcm encompassing the known genetic and geographic diversity of the bacterium and all isolates were detected. Seventeen other Xanthomonas isolates, including closely related Xanthomonas vasicola, other bacterial pathogens/endophytes of Musa and two healthy Musa varieties gave negative results with the LAMP assay. The assay showed good sensitivity, detecting as little as 51 fg of Xcm DNA, a greater level of sensitivity than that of an Xcm PCR assay. Amplification with the LAMP assay was very rapid, typically within 9 min from bacterial cultures. Symptomatic field samples of Musa from Uganda were tested and all produced amplification in less than 13 min. CONCLUSIONS: The LAMP assay provides rapid, sensitive detection of the pathogen that is ideally suited for deployment in laboratories with basic facilities and in-field situations. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first LAMP assay for Xcm which provides a significant improvement compared to existing diagnostics. PMID- 26425812 TI - Randomized controlled multicenter study comparing short dental implants (6 mm) versus longer dental implants (11-15 mm) in combination with sinus floor elevation procedures. Part 2: clinical and radiographic outcomes at 1 year of loading. AB - AIM: To compare, clinically and radiographically, short dental implants (6 mm) to long implants (11-15 mm) placed with sinus grafting. METHODS: Participants with 5 7 mm of bone height in the posterior maxilla were randomly allocated to receive short implants (GS) or long implants with sinus grafting (GG). Implants were loaded with single crowns 6 months after placement (PR). Patients were re evaluated 12 months after loading (FU-1). Outcome variables included: Implant survival rate (CSR), marginal bone level alteration (MBL), periodontal probing depth (PPD), bleeding on probing (BoP), plaque control record (PCR) and crown-to implant ratios (C/I). Statistical analysis was performed using parametric tests. RESULTS: In 97 subjects, 132 implants were re-evaluated at FU-1. The CSR was 100%. The MBL from implant placement (IP) to (PR) was -0.22 +/- 0.4 mm for GG and -0.3 +/- 0.45 mm for GS (p < 0.001). MBL from IP to FU-1 was -0.37 +/- 0.59 mm for GG and -0.22 +/- 0.3 mm for GS (p < 0.001). Intergroup comparisons showed non significant differences for MBL (p > 0.05), PPD (p = 1) and PCR (p = 0.09). BoP was higher in the GS (p = 0.04). The C/I was 0.99 +/- 0.17 for GG and 1.86 +/- 0.23 for GS (p < 0.001). No correlation was observed between C/I and MBL, (GG: p = 0.13; GS: p = 0.38). CONCLUSIONS: Both treatment modalities provided similar outcomes. PMID- 26425817 TI - Lipophilic M(alpha,alpha'-OC5H11)8phthalocyanines (M = H2 and Ni(II)): synthesis, electronic structure, and their utility for highly efficient carbonyl reductions. AB - A lipophilic and electron-rich phthalocyanine (alpha,alpha'-n-OC5H11)8-H2Pc and its nickel(ii) complex (alpha,alpha'-n-OC5H11)8-Ni(ii)Pc have been synthesized and characterized. Detailed analyses of the electronic structure were carried out by spectroscopy, electrochemistry, spectroelectrochemistry, and TD-DFT calculations. A series of experiments demonstrate that the (alpha,alpha'-n OC5H11)8-Ni(ii)Pc complex can be used as a catalyst for highly efficient carbonyl reductions. PMID- 26425818 TI - The HOMO Nodal Arrangement in Polychromophoric Molecules and Assemblies Controls the Interchromophoric Electronic Coupling. AB - Triptycenes spontaneously assemble into two-dimensional networks in which long range charge transport is facilitated by the extensive electronic coupling through the triptycene framework (intramolecularly) and by cofacial pi-stacking (intermolecularly). While designing and synthesizing next-generation triptycenes containing polyaromatic chromophores, the electronic coupling amongst the chromophores was observed to be highly dependent on the nature and position of the substituents. Herein, we demonstrate using hexaalkoxytriptycenes that the electronic coupling amongst the chromophores is switched on and off by a simple repositioning of the substituents, which alters the nodal arrangement of the HOMOs of the individual chromophores. A visual inspection of the HOMOs can thus provide a ready evaluation of the electronic coupling in polychromophoric molecules/assemblies, and will serve as an important tool for the rational design of modern charge-transport materials. PMID- 26425819 TI - Isolation of cytotoxic diterpenoids from the Chilean medicinal plant Azorella compacta Phil from the Atacama Desert by high-speed counter-current chromatography. AB - BACKGROUND: Azorella compacta (Apiaceae) is a native Chilean cushion shrub which produces a resin containing mulinane and azorellane diterpenoids. This plant has been used since pre-Colombian times to treat inflammation and dental neuralgias. In this work the first preparative fractionation of diterpenoids present in this plant by means of high-speed counter-current chromatography (HSCCC) was applied, and cytotoxic effects of the isolated compounds were evaluated for the first time against a panel of MCF7 cells. RESULTS: The major compounds isolated were identified by means of spectroscopy as azorellanol, 13alpha, 14alpha dihydroxymulin-11-en-20-oic acid, mulinolic acid, mulin-11,13-dien-20-oic acid, 17-acetoxy-mulin-11,13-dien-20 oic acid, and 17-acetoxy-mulinic acid (compounds 7, 9-11 and 13, respectively), and four minor diterpenoids [7-deacetyl azorellanol (6), 13-epi-azorellanol, 7-acetoxy-mulin-9,12-diene, and 17-acetoxy mulin-11,13-dien-20-oic acid (compounds 4, 8 and 12)], together with three new minor diterpenoids: 13beta,14beta-dihydroxymulin-11-en-20-oic acid (1), 13 epiazorellanone (2) and 13-epi-7-deacetyl-azorellanol (3) were identified. Besides, compounds 4, 6, 7, 8 and 11 displayed good cytotoxic activity (less than 50% cell viability at 100 uM). Among them, compound 7, an acetylated azorellane, was the most active. CONCLUSIONS: HSCCC allowed the isolation of 13 diterpenoids present in A. compacta. Three compounds are reported for the first time. Isolated azorellanes are more potent cytotoxic agents than are mulinanes. (c) 2015 Society of Chemical Industry. PMID- 26425821 TI - Making the case for collaboration. PMID- 26425822 TI - Understanding the effects of rheumatoid arthritis. PMID- 26425820 TI - Interferon-gamma constrains cytokine production of group 2 innate lymphoid cells. AB - Group 2 innate lymphoid cells (ILC2s) produce a significant amount of interleukin 5 (IL-5), which supports eosinophil responses in various tissues; they also produce IL-13, which induces mucus production and contributes to tissue repair or fibrosis. The ILC2s are activated by alarmins, such as IL-33 released from epithelia, macrophages and natural killer T (NKT) cells in response to infection and allergen exposure, leading to epithelial injury. We examined gene expression in lung ILC2s and found that ILC2s expressed Ifngr1, the receptor for interferon gamma (IFN-gamma). Interferon-gamma severely inhibited IL-5 and IL-13 production by lung and kidney ILC2s. To evaluate the effects in vivo, we used alpha galactosylceramide (alpha-GalCer) to induce NKT cells to produce IL-33 and IFN gamma. Intraperitoneal injection of alpha-GalCer in mice induced NKT cell activation resulting in IL-5 and IL-13 production by ILC2s. Administration of anti-IFN-gamma together with alpha-GalCer significantly enhanced the production of IL-5 and IL-13 by ILC2s in lung and kidney. Conversely, cytokine production from ILC2s was markedly suppressed after injection of exogenous IL-33 in Il33(-/ ) mice pre-treated with alpha-GalCer. Hence, IFN-gamma induced or already present in tissues can impact downstream pleiotropic functions mediated by ILC2s, such as inflammation and tissue repair. PMID- 26425823 TI - The role of illness perceptions in adherence to surveillance in patients with familial adenomatous polyposis (FAP). AB - OBJECTIVE: The aim of the study was to examine patients' beliefs about having familial adenomatous polyposis (FAP), a hereditary colorectal cancer syndrome, and how these beliefs are associated with adherence to endoscopic surveillance. METHODS: Adult patients diagnosed with FAP on the national Swedish polyposis register who had undergone prophylactic colorectal surgery (n 209, response rate 76%) completed the Illness Perception Questionnaire (IPQ). Logistic regression analysis was used to investigate the relationships between illness perceptions and adherence, when controlling for demographic and clinical factors. RESULTS: FAP was less distressing in men and those with fewer symptoms, reporting less serious consequences and more coherent understanding of FAP. Non-adherence (14%) to surveillance was associated with being older, having undergone surgery less recently and no history of malignancy. Patients' beliefs about their FAP were able to explain unique variance in non-adherence, in particular those who believed FAP was less distressing. CONCLUSIONS: Patients who were non-adherent to endoscopic surveillance had more positive perceptions about their FAP and, in particular, were less emotionally affected compared to those who adhered. As non adherence implies a greater risk of future malignancies, special efforts are required to effectively prevent cancer in all patients with FAP. Those who have lived with the condition for a long time, and are not troubled by gastrointestinal symptoms or worried about their FAP, may be in need of specific information and support. Further prospective research is required to examine emotional predictors and consequences of non-adherence. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26425824 TI - Rhodium-catalyzed Asymmetric Hydrogenation of alpha-Dehydroamino Ketones: A General Approach to Chiral alpha-amino Ketones. AB - Rhodium/DuanPhos-catalyzed asymmetric hydrogenation of aliphatic alpha dehydroamino ketones has been achieved and afforded chiral alpha-amino ketones in high yields and excellent enantioselectives (up to 99 % ee), which could be reduced further to chiral beta-amino alcohols by LiAlH(tBuO)3 with good yields. This protocol provides a readily accessible route for the synthesis of chiral alpha-amino ketones and chiral beta-amino alcohols. PMID- 26425825 TI - Phase-Separation-Induced Anomalous Stiffening, Toughening, and Self-Healing of Polyacrylamide Gels. AB - Novel, tough, strong, and self-healable poly-acrylamide (PAAm) gels are fabricated by inducing an appropriate phase-separation structure using a poor solvent. The phase separation induces a gel-glass-like transition of the PAAm gels, providing the gels an anomalously high modulus (211 MPa), fracture stress (7.13 MPa), and fracture energy (4.16 * 10(4) J m(-2)), while keeping a high solvent content (~60 vol%). PMID- 26425826 TI - Micro-optical coherence tomography tracking of magnetic gene transfection via Au Fe3O4 dumbbell nanoparticles. AB - Heterogeneous Au-Fe3O4 dumbbell nanoparticles (NPs) are composed of Au NPs and Fe3O4 NPs that bring in optical and magnetic properties respectively. This article reports the engineering of Au-Fe3O4 NPs as gene carriers for magnetic gene transfection as well as contrast agents for micro-optical coherence tomography (MUOCT). As a proof-of-concept, Au-Fe3O4 NPs are used to deliver the green fluorescent protein to HEK 293T cells and their entrance into the cells is monitored through MUOCT. PMID- 26425828 TI - Brain sonography insight into the midbrain in myotonic dystrophy type 2. AB - INTRODUCTION: The aim of this study was to analyze transcranial sonography (TCS) findings in genetically confirmed myotonic dystrophy type 2 (DM2) patients. METHODS: Forty DM2 patients and 38 gender- and age-matched healthy controls (HCs) underwent TCS through the pre-auricular acoustic bone window. RESULTS: Substantia nigra hyperechogenicity was found in 20% of DM2 patients compared with 3% of HCs. Brainstem raphe (BR) hypoechogenicity was more common in DM2 patients compared with HCs (56% vs. 10%, P < 0.01), and it was more common in patients with fatigue and excessive daytime sleepiness (P < 0.05). Diameter of the third ventricle was increased in DM2 patients compared with HCs (5.8 +/- 1.7 vs. 5.1 +/- 1.0 mm, P < 0.05). CONCLUSIONS: Finding BR hypoechogenicity might have clinical implication because of the potential response to serotonin-reuptake inhibitors. TCS revealed alterations in brain structures previously not seen in MRI studies. PMID- 26425827 TI - Retinol binding protein and vitamin D associations with serum antibody isotypes, serum influenza virus-specific neutralizing activities and airway cytokine profiles. AB - Vitamin A supports the induction of immunoglobulin (Ig)A responses at mucosal surfaces in mice, but much less is known about the influence of vitamins on antibody isotype expression in humans. To address this knowledge gap, we examined 46 residual blood samples from adults and children, some of whom were experiencing influenza virus infections of the respiratory tract. Assays were performed for retinol binding protein (RBP, a surrogate for vitamin A), vitamin D (a related vitamin) and antibody isotypes. Results showed that all but two tested samples exhibited RBP and/or vitamin D insufficiencies or deficiencies. Vitamin D correlated with blood IgM and IgG3, while RBP correlated with IgG4 and IgA. RBP also correlated positively with age and with influenza virus-specific antibody neutralization titres. Individuals with low blood RBP levels exhibited the highest frequencies of over-expressed cytokines and growth factors in nasal wash samples, an indication of inflamed mucosal tissues. While cause-effect relationships were not discerned, results support a hypothesis that vitamins directly influence B cell isotype expression in humans, and by so doing may help protect mucosal surfaces from respiratory viral disease. PMID- 26425830 TI - The SUDEP Risk Inventory: Association with postictal generalized EEG suppression. AB - To help identify patients at greatest risk for sudden unexpected death in epilepsy (SUDEP), screening inventories like the SUDEP-7 Inventory can be useful. In this study, we examined the strength of association between this inventory's risk factors and postictal generalized EEG suppression (PGES), a biomarker of SUDEP risk. We reanalyzed data from an epilepsy monitoring unit study of 37 children. We performed a 2 by 2 contingency table analysis to determine the association between "yes" responses on the inventory questions and PGES following >=1 seizure. Having a history of >3 generalized tonic-clonic seizures (GTCS) in the past year had the strongest association with PGES (Pearson chi-square p<0.001, Cramer's V=0.75). Having >=1 GTCS in the past year was also strongly associated with PGES (Pearson chi-square p<0.001, Cramer's V=0.636). Histories of >50 seizures of any type/month (Pearson chi-square p=0.14, Cramer's V=0.241) and intellectual disability (Pearson chi-square p=0.04, Cramer's V=0.337) were not as robustly associated with PGES. Current use of >=3 AEDs had the weakest association with PGES (Pearson chi-square p=0.66, Cramer's V=0.072). Given that all study patients had >=1 seizure per year and epilepsy durations <30 years, the strength of association with these questions and PGES could not be analyzed. PMID- 26425829 TI - Volumetric and shape analysis of hippocampal subfields in unilateral mesial temporal lobe epilepsy with hippocampal atrophy. AB - OBJECTIVE: The hippocampus consists of several functionally and histologically different subfields that are known to be differentially affected in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE). Using automated MRI analyses, we aimed to investigate atrophy patterns of hippocampal subfields and their relationships with clinical characteristics in a homogenous group of unilateral MTLE. METHODS: Twenty-four left MTLE patients, 23 right MTLE patients, and 41 control subjects were scanned on a 3T MR scanner. Automated volumetry and shape analysis were used to assess volume and shape changes of hippocampal subfields in MTLE patients relative to controls. Within-group correlations were performed between subfield volumes and clinical variables in patients. RESULTS: Compared to controls, left and right MTLE patients exhibited significant volume reductions in ipsilateral whole hippocampus and subfields including CA1, CA2-3, CA4-DG, presubiculum, and subiculum (corrected p<0.05). Regional inward shape deformation mainly localized to ipsilateral CA1 and adjacent subiculum was found in left and right MTLE patients relative to controls (corrected p<0.05). Longer disease duration was related to smaller volumes of left CA1, presubiculum, and subiculum in left MTLE, and right CA1 in right MTLE. CONCLUSION: We found overall volume reductions in ipsilateral hippocampal subfields in patients with unilateral MTLE, in accordance with known pathologic findings. Our findings of regional atrophy in ipsilateral CA1 and subiculum on shape analysis and an inverse relationship between disease duration and ipsilateral CA1 volume implicate an important role of CA1 and subiculum in the pathogenesis underlying MTLE. PMID- 26425831 TI - Predicting toxicity to Hyalella azteca in pyrogenic-impacted sediments-Do we need to analyze for all 34 PAHs? AB - Polycyclic aromatic hydrocarbons (PAHs) are major drivers of risk at many urban and/or industrialized sediment sites. The US Environmental Protection Agency (USEPA) currently recommends using measurements of 18 parent + 16 groups of alkylated PAHs (PAH-34) to assess the potential for sediment-bound PAHs to impact benthic organisms at these sites. ASTM Method D7363-13 was developed to directly measure low-level sediment porewater PAH concentrations. These concentrations are then compared to ambient water criteria (final chronic values [FCVs]) to assess the potential for impact to benthic organisms. The interlaboratory validation study that was used to finalize ASTM D7363-13 was developed using 24 of the 2-, 3 , and 4-ring PAHs (PAH-24) that are included in the USEPA PAH-34 analyte list. However, it is the responsibility of the user of ASTM Method D7363 to establish a test method to quantify the remaining 10 higher molecular weight PAHs that make up PAH-34. These higher molecular weight PAHs exhibit extremely low saturation solubilities that make their detection difficult in porewater, which has proven difficult to implement in a contract laboratory setting. As a result, commercial laboratories are hesitant to conduct the method on the entire PAH-34 analyte list. This article presents a statistical comparison of the ability of the PAH-24 and PAH-34 porewater results to predict survival of the freshwater amphipod Hyalella azteca, using the original 269 sediment samples used to gain ASTM D7363 Method approval. The statistical analysis shows that the PAH-24 are statistically indistinguishable from the PAH-34 for predicting toxicity. These results indicate that the analysis of freely dissolved porewater PAH-24 is sufficient for making risk-based decisions based on benthic invertebrate toxicity (survival and growth). This reduced target analyte list should result in a cost-saving for stakeholders and broader implementation of the method at PAH-impacted sediment sites. Integr Environ Assess Manag 2016;12:493-499. (c) 2015 SETAC. PMID- 26425832 TI - Lifestyle and therapeutic interventions for hypertension. PMID- 26425833 TI - Salutary cardiovascular effects of antidiabetic drugs: myth or fact? PMID- 26425834 TI - Where there's smoke there might be hypertension. PMID- 26425835 TI - Updated classification of hypertensive retinopathy: which role for cardiovascular risk stratification? PMID- 26425836 TI - Night-time blood pressure and target organ damage: a comparative analysis of absolute blood pressure and dipping status. AB - BACKGROUND: The prognostic significance of abnormal circadian blood pressure (BP) patterns is well established. Research to date has focused on both nocturnal dipping and absolute night-time BP levels; however, which of these variables should be the primary target for therapy remains unclear. The aim of this study is to determine whether dipping status or absolute night-time BP levels have a stronger association with subclinical target organ damage (TOD). METHODS: The Mitchelstown Cohort was established to examine cardiovascular health in an adult population sample recruited from primary care. Night-time BP was categorized by dipping status. Subclinical TOD was defined as Cornell Product left ventricular hypertrophy (LVH) voltage criteria on ECG and urine albumin : creatinine ratio (ACR) at least 1.1 mg/mmol. Multivariable logistic regression analysis was used to assess the association between night-time BP and TOD. RESULTS: Of 2047 participants, 1207 (response rate 59%), underwent 24-h ambulatory BP monitoring. We excluded 161 studies due to incomplete data. Of 1046 participants, 178 (17%) had evidence of TOD. Each 10-mmHg rise in night-time SBP increased the odds of TOD. Odds ratio (OR) ACR at least 1.1 mg/mmol 1.5 [95% confidence interval (95% CI) 1.2-1.8] and OR LVH 1.4 (95% CI 1.1-1.8). CONCLUSION: Absolute BP level rather than dipping status may be a superior early marker of risk associated with night-time BP. Interventional studies are required to determine whether there is a benefit in specifically targeting absolute night-time BP levels to prevent clinically important outcomes. PMID- 26425837 TI - PTPRD gene associated with blood pressure response to atenolol and resistant hypertension. AB - OBJECTIVE: The aim of this study is to identify single-nucleotide polymorphisms (SNPs) influencing blood pressure (BP) response to the beta-blocker atenolol. METHODS: Genome-wide association analysis of BP response to atenolol monotherapy was performed in 233 white participants with uncomplicated hypertension in the pharmacogenomic evaluation of antihypertensive responses study. Forty-two polymorphisms with P less than 10 for association with either diastolic or systolic response to atenolol monotherapy were validated in four independent groups of hypertensive individuals (total n = 2114). RESULTS: In whites, two polymorphisms near the gene PTPRD (rs12346562 and rs1104514) were associated with DBP response to atenolol (P = 3.2 * 10 and P = 5.9 * 10, respectively) with directionally opposite association for response to hydrochlorothiazide in another group of 228 whites (P = 0.0018 and P = 0.00012). A different polymorphism (rs10739150) near PTPRD was associated with response to atenolol in 150 black hypertensive individuals (P = 8.25 * 10). rs12346562 had a similar trend in association with response to bisoprolol (a different beta-blocker) in 207 Finnish men in the genetics of drug responsiveness in essential hypertension study. In addition, an intronic single-nucleotide polymorphism (rs4742610) in the PTPRD gene was associated with resistant hypertension in whites and Hispanics in the international verapamil SR trandolapril study (meta-analysis P = 3.2 * 10). CONCLUSION: PTPRD was identified as a novel locus potentially associated with BP response to atenolol and resistant hypertension in multiple ethnic groups. PMID- 26425839 TI - Alkene anti-Dihydroxylation with Malonoyl Peroxides. AB - Malonoyl peroxide 1, prepared in a single step from the commercially available diacid, is an effective reagent for the anti-dihydroxylation of alkenes. Reaction of 1 with an alkene in the presence of acetic acid at 40 degrees C followed by alkaline hydrolysis leads to the corresponding diol (35-92%) with up to 13:1 anti selectivity. A mechanism consistent with experimental findings is proposed that accounts for the selectivity observed. PMID- 26425838 TI - Parasite molecules and host responses in cystic echinococcosis. AB - Cystic echinococcosis is the infection by the larvae of cestode parasites belonging to the Echinococcus granulosus sensu lato species complex. Local host responses are strikingly subdued in relation to the size and persistence of these larvae, which develop within mammalian organs as 'hydatid cysts' measuring up to tens of cm in diameter. In a context in which helminth-derived immune suppressive, as well as Th2-inducing, molecules garner much interest, knowledge on the interactions between E. granulosus molecules and the immune system lags behind. Here, we discuss what is known and what are the open questions on E. granulosus molecules and structures interacting with the innate and adaptive immune systems, potentially or in demonstrated form. We attempt a global biological approach on molecules that have been given consideration primarily as protective (Eg95) or diagnostic antigens (antigen B, antigen 5). We integrate glycobiological information, which traverses the discussions on antigen 5, the mucin-based protective laminated layer and immunologically active preparations from protoscoleces. We also highlight some less well-known molecules that appear as promising candidates to possess immune-regulatory activities. Finally, we point out gaps in the molecular-level knowledge of this infectious agent that hinder our understanding of its immunology. PMID- 26425840 TI - Metabolic profile of phillyrin in rats obtained by UPLC-Q-TOF-MS. AB - Forsythia suspensa Vahl (Oleaceae) is an important original plant in traditional Chinese medicine. The air-dried fruits of Forsythia suspensa have long been used to relieve respiratory symptoms. Phillyrin is one of the main chemical constituent of Forsythia suspensa. A clear understanding of the metabolism of phillyrin is very important in rational clinical use and pharmacological research. In this study, the metabolism of phillyrin in rat was investigated for the first time using an ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) method. Bile, urine and feces were collected from rats after single-dose (10 mg/kg) orally administered phillyrin. Liquid-liquid extraction and ultrasonic extraction were used to prepare samples. UPLC-Q-TOF-MS analysis of the phillyrin samples showed that phillyrin was converted to a major metabolite, M26, which underwent deglucosidation, further dehydration and desaturation. A total of 34 metabolites were detected including 30 phase I and four phase II metabolites. The conjugation types and structure skeletons of the metabolites were preliminarily determined. Moreover, 28 new metabolites were reported for the first time. The main biotransformation route of phillyrin was identified as hydrolysis, oxidation and sulfation. These findings enhance our understanding of the metabolism and the real active structures of phillyrin. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26425841 TI - Does lymphopenia or macrocytosis reflect 6-thioguanine levels in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine? AB - BACKGROUND: The thiopurine drugs, 6-mercaptopurine and azathioprine, remain the mainstay of immunomodulator therapy for inflammatory bowel disease (IBD). Optimal management depends on achieving therapeutic levels of 6-thioguanine (6-TGN), but measuring thiopurine metabolites is associated with significant cost. Thiopurines cause lymphopenia and an increase in mean corpuscular volume (MCV). It is unclear whether any clinically useful correlation exists between 6-TGN levels and lymphocyte count or MCV. AIMS: The aim of this study is to investigate the correlation between 6-TGN levels and lymphocyte count and MCV in thiopurine treated patients with IBD. METHODS: We analysed a prospectively acquired database of 67 patients with IBD treated with thiopurine therapy. The data were analysed looking at the relationship between 6-TGN levels and both lymphocyte count and MCV by using the Spearman's rank correlation coefficient. RESULTS: Twenty-seven (40%) patients had therapeutic 6-TGN levels. Thirty-three (49%) patients had sub therapeutic 6-TGN levels. A weak positive correlation between 6-TGN levels and lymphocyte count was demonstrated, but this was not statistically significant (Spearman's R = 0.14, P = 0.23). Spearman's rank correlation coefficient between 6-TGN levels and MCV was statistically significant (R = 0.42, P = 0.0005). MCV >101 fL excluded a subtherapeutic 6-TGN level with positive predictive value of 92%. CONCLUSIONS: There is no specific lymphopenia that can be assumed to indicate a therapeutic 6-TGN level. The relationship between 6-TGN levels and MCV is likely to be clinically relevant. If MCV is elevated, 6-TGN is unlikely to be sub-therapeutic. MCV is a potential surrogate marker which can rule out sub therapeutic thiopurine metabolites in patients with IBD treated with azathioprine or 6-mercaptopurine. PMID- 26425842 TI - Kidney Paired Donation Protocol for Participating Donors 2014. PMID- 26425843 TI - Smooth Muscle Cell Differentiation: Model Systems, Regulatory Mechanisms, and Vascular Diseases. AB - Smooth muscle cell (SMC) differentiation is an important process during vascular development. The highly differentiated mature SMCs play critical roles in maintaining structural and functional integrity of blood vessels. However, SMCs are not terminally differentiated, and their phenotype can be modulated between contractile and proliferative states in response to various environmental conditions. Alterations in SMC phenotype contribute to a number of major cardiovascular diseases such as atherosclerosis, hypertension and restenosis following angioplasty, etc. The goal of this review is to provide a brief overview of the recent advancements in our understanding of SMC differentiation and the development of in vitro SMC differentiation models, with a particular emphasis on examination of molecular mechanisms involved in the regulation of SMC differentiation and phenotypic modulation. J. Cell. Physiol. 231: 777-787, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26425844 TI - Therapeutic Potential of Date Palm Pollen for Testicular Dysfunction Induced by Thyroid Disorders in Male Rats. AB - Hyper- or hypothyroidism can impair testicular function leading to infertility. The present study was designed to examine the protective effect of date palm pollen (DPP) extract on thyroid disorder-induced testicular dysfunction. Rats were divided into six groups. Group I was normal control. Group II received oral DPP extract (150 mg kg(-1)), group III (hyperthyroid group) received intraperitoneal injection of L-thyroxine (L-T4, 300 MUg kg(-1); i.p.), group IV received L-T4 plus DPP extract, group V (hypothyroid group) received propylthiouracil (PTU, 10 mg kg(-1); i.p.) and group VI received PTU plus DPP extract. All treatments were given every day for 56 days. L-T4 or PTU lowered genital sex organs weight, sperm count and motility, serum levels of luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone (T), testicular function markers and activities of testicular 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD). Moreover, L-T4 or PTU increased estradiol (E2) serum level, testicular oxidative stress, DNA damage and apoptotic markers. Morphometric and histopathologic studies backed these observations. Treatment with DPP extract prevented LT4- or PTU induced changes. In addition, supplementation of DPP extract to normal rats augmented sperm count and motility, serum levels of LH, T and E2 paralleled with increased activities of 3beta-HSD and 17beta-HSD as well as testicular antioxidant status. These results provide evidence that DPP extract may have potential protective effects on testicular dysfunction induced by altered thyroid hormones. PMID- 26425845 TI - Addressing the Complications of Ebola and Other Viral Hemorrhagic Fever Infections: Using Insights from Bacterial and Fungal Sepsis. PMID- 26425846 TI - Glaucomatous-Type Optic Discs in High Myopia. AB - PURPOSE: To assess the prevalence of glaucoma in patients with high myopia defined as myopic refractive error of >-8 diopters or axial length >=26.5 mm. METHODS: The hospital-based observational study included 172 patients (336 eyes) with a mean age of 61.9+/-12.3 years and mean axial length of 30.1+/-2.3 mm (range: 24.7-39.1mm). Glaucomatous-type optic discs were defined by glaucomatous optic disc appearance. Glaucoma was defined by glaucomatous optic disc appearance and glaucomatous Goldmann visual field defects not corresponding with myopic macular changes. RESULTS: Larger disc area (mean: 3.18+/-1.94 mm2) was associated with longer axial length (P<0.001; standardized correlation coefficient: 0.45). Glaucoma was detected in 94 (28%; 95% Confidence intervals: 23%, 33%) eyes. In multivariate analysis, glaucoma prevalence was 3.2 times higher (P<0.001) in megalodiscs (>3.79 mm2) than in normal-sized discs or small discs (<1.51 mm2) after adjusting for older age. Axial length was not significantly (P = 0.38) associated with glaucoma prevalence in that model. Glaucoma prevalence increased by a factor of 1.39 for each increase in optic disc area by one mm2. Again, axial length was not significantly (P = 0.38) associated with glaucoma prevalence when added to this multivariate model. CONCLUSION: Within highly myopic individuals, glaucoma prevalence increased with larger optic disc size beyond a disc area of 3.8 mm2. Highly myopic megalodiscs as compared to normal sized discs or small discs had a 3.2 times higher risk for glaucomatous optic nerve neuropathy. The increased glaucoma prevalence in axial high myopia was primarily associated with axial myopia associated disc enlargement and not with axial elongation itself. PMID- 26425848 TI - Waist circumference cut-off in relation to body mass index and percentage of body fat in adult women from Merida, Mexico. AB - Waist circumference (WC) as an index of central obesity is related to body mass index (BMI) and percent body fat (PBF). Waist circumference data were analyzed to identify a WC cut-off for adult women with respect to BMI-based obesity (>= 30 kg/m2) and PBF. The sample was 138 women aged 22 to 41 years with Maya ancestry (based on surnames) in Merida, Yucatan, measured during 2011 - 2013. Anthropometric parameters included height, body weight (BW), and BMI. The PBF was estimated by bioelectrical impedance. Estimated cut-offs per centimeter WC (80 - 99 cm) were predicted by BMI for obesity (>= 30 kg m-2; binomial: Yes = 1, No = 0) and PBF (continuous variable) using binary logistic regression analyses. Mean age was 32 years, mean BMI was 29 kg m(-2) and mean WC was 89 cm. The sample exhibited high PBF (44 %), and high rates of overweight (44%) and obesity (40%). The threshold WC (>= 93 cm) had high sensitivity (80%), specificity (82%), Youden Index value (0.62), and correct classification rate (82%). The area under the receiver operating characteristic curve was 88 %. The WC >= 93 cm cut-off had corresponding values for mean BMI (34 kg m-2) and PBF (47%). The optimal WC cut off at 93 cm significantly identified central obesity for BMI >= 30 kg m-2 and PBF for this sample. PMID- 26425849 TI - Results of Automated Retinal Image Analysis for Detection of Diabetic Retinopathy from the Nakuru Study, Kenya. AB - OBJECTIVE: Digital retinal imaging is an established method of screening for diabetic retinopathy (DR). It has been established that currently about 1% of the world's blind or visually impaired is due to DR. However, the increasing prevalence of diabetes mellitus and DR is creating an increased workload on those with expertise in grading retinal images. Safe and reliable automated analysis of retinal images may support screening services worldwide. This study aimed to compare the Iowa Detection Program (IDP) ability to detect diabetic eye diseases (DED) to human grading carried out at Moorfields Reading Centre on the population of Nakuru Study from Kenya. PARTICIPANTS: Retinal images were taken from participants of the Nakuru Eye Disease Study in Kenya in 2007/08 (n = 4,381 participants [NW6 Topcon Digital Retinal Camera]). METHODS: First, human grading was performed for the presence or absence of DR, and for those with DR this was sub-divided in to referable or non-referable DR. The automated IDP software was deployed to identify those with DR and also to categorize the severity of DR. MAIN OUTCOME MEASURES: The primary outcomes were sensitivity, specificity, and positive and negative predictive value of IDP versus the human grader as reference standard. RESULTS: Altogether 3,460 participants were included. 113 had DED, giving a prevalence of 3.3% (95% CI, 2.7-3.9%). Sensitivity of the IDP to detect DED as by the human grading was 91.0% (95% CI, 88.0-93.4%). The IDP ability to detect DED gave an AUC of 0.878 (95% CI 0.850-0.905). It showed a negative predictive value of 98%. The IDP missed no vision threatening retinopathy in any patients and none of the false negative cases met criteria for treatment. CONCLUSIONS: In this epidemiological sample, the IDP's grading was comparable to that of human graders'. It therefore might be feasible to consider inclusion into usual epidemiological grading. PMID- 26425847 TI - Genome-Scale Mapping of Escherichia coli sigma54 Reveals Widespread, Conserved Intragenic Binding. AB - Bacterial RNA polymerases must associate with a sigma factor to bind promoter DNA and initiate transcription. There are two families of sigma factor: the sigma70 family and the sigma54 family. Members of the sigma54 family are distinct in their ability to bind promoter DNA sequences, in the context of RNA polymerase holoenzyme, in a transcriptionally inactive state. Here, we map the genome-wide association of Escherichia coli sigma54, the archetypal member of the sigma54 family. Thus, we vastly expand the list of known sigma54 binding sites to 135. Moreover, we estimate that there are more than 250 sigma54 sites in total. Strikingly, the majority of sigma54 binding sites are located inside genes. The location and orientation of intragenic sigma54 binding sites is non-random, and many intragenic sigma54 binding sites are conserved. We conclude that many intragenic sigma54 binding sites are likely to be functional. Consistent with this assertion, we identify three conserved, intragenic sigma54 promoters that drive transcription of mRNAs with unusually long 5' UTRs. PMID- 26425851 TI - Asia Pacific Stroke Conference 2015 Abstracts of the Annual Conference of the Asia Pacific Stroke Organization (APSO) Kuala Lumpur, Malaysia, October 2-4, 2015: Abstracts. PMID- 26425850 TI - Previous Exposure to Statin May Reduce the Risk of Subsequent Non-Hodgkin Lymphoma: A Nationwide Population-Based Case-Control Study. AB - BACKGROUND: The purpose of this study was to investigate the association between previous exposure to statins and the risk of non-Hodgkin lymphoma (NHL). METHODS: This nationwide population-based case-control study was conducted using the National Health Insurance Research Database of Taiwan. The NHL group consisted of the patients with a first-time diagnosis of NHL between 2005 and 2008. The cases of the control group were pair-matched to the NHL group according to sex, year of birth and date of NHL diagnosis (index date). The statin administration data from both groups were retrospectively collected from the index date to January 1, 1996. The cumulative defined daily dose (cDDD) was estimated to evaluate the statin exposure. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariate logistic regression. RESULTS: The study population was composed of 1715 NHL patients and 16942 control subjects. The analysis revealed that previous statin administration was associated with a reduced risk of subsequent NHL with an adjusted OR of 0.52 (95% CI, 0.43-0.62). Additionally, there was a dose-response relationship between statin administration and the risk of NHL. The adjusted ORs were 0.63 (95% CI, 0.46 0.86), 0.58 (95% CI, 0.42-0.79), 0.51 (95% CI, 0.38-0.67), and 0.36 (95% CI, 0.24 0.53) for the subjects with statin administrations of fewer than 28, 28 to 90, 91 to 365, and more than 365 cDDDs, respectively, relative to the subjects without any statin administration. CONCLUSIONS: The results of this study suggest that previous statin administration is associated with a lower risk of subsequent NHL. As statins are widely used medications, the magnitude of the risk reduction may have a substantial influence on public health. Further studies to confirm our findings are warranted. PMID- 26425852 TI - Correction: Novel Compound Heterozygous Mutations in MYO7A Associated with Usher Syndrome 1 in a Chinese Family. PMID- 26425853 TI - Monte Carlo simulation of prompt gamma-ray emission in proton therapy using a specific track length estimator. AB - A Monte Carlo (MC) variance reduction technique is developed for prompt-gamma emitters calculations in proton therapy. Prompt-gamma emitted through nuclear fragmentation reactions and exiting the patient during proton therapy could play an important role to help monitoring the treatment. However, the estimation of the number and the energy of emitted prompt-gamma per primary proton with MC simulations is a slow process. In order to estimate the local distribution of prompt-gamma emission in a volume of interest for a given proton beam of the treatment plan, a MC variance reduction technique based on a specific track length estimator (TLE) has been developed. First an elemental database of prompt gamma emission spectra is established in the clinical energy range of incident protons for all elements in the composition of human tissues. This database of the prompt-gamma spectra is built offline with high statistics. Regarding the implementation of the prompt-gamma TLE MC tally, each proton deposits along its track the expectation of the prompt-gamma spectra from the database according to the proton kinetic energy and the local material composition. A detailed statistical study shows that the relative efficiency mainly depends on the geometrical distribution of the track length. Benchmarking of the proposed prompt gamma TLE MC technique with respect to an analogous MC technique is carried out. A large relative efficiency gain is reported, ca. 10(5). PMID- 26425854 TI - Determinants of Default in P2P Lending. AB - This paper studies P2P lending and the factors explaining loan default. This is an important issue because in P2P lending individual investors bear the credit risk, instead of financial institutions, which are experts in dealing with this risk. P2P lenders suffer a severe problem of information asymmetry, because they are at a disadvantage facing the borrower. For this reason, P2P lending sites provide potential lenders with information about borrowers and their loan purpose. They also assign a grade to each loan. The empirical study is based on loans' data collected from Lending Club (N = 24,449) from 2008 to 2014 that are first analyzed by using univariate means tests and survival analysis. Factors explaining default are loan purpose, annual income, current housing situation, credit history and indebtedness. Secondly, a logistic regression model is developed to predict defaults. The grade assigned by the P2P lending site is the most predictive factor of default, but the accuracy of the model is improved by adding other information, especially the borrower's debt level. PMID- 26425855 TI - A Review of Scientific Topics and Literature in Abdominal Radiology in Germany- Part 2: Abdominal Parenchymal Organs. AB - The working group for abdominal and gastrointestinal diagnosis is a group of the German Radiological Society (DRG) focusing clinically and scientifically on the diagnosis and treatment of the gastrointestinal tract as well as the parenchymal abdominal organs. In this article we give an up-to-date literature review of scientific radiological topics especially covered by German radiologists. The working group experts cover the most recent relevant studies concerning liver specific contrast media with an emphasis on a new classification system for liver adenomas. Additionally studies regarding selective internal radiotherapy (SIRT) are reviewed. For the pancreas the most important tumors are described followed by an introduction to the most recently introduced functional imaging techniques. The manuscript concludes with some remarks on recent studies and concerning chronic pancreatitis as well as autoimmune pancreatitis. KEY POINTS: * Different subtypes of liver adenomas with different therapeutic consequences can be differentiated by MRI * Most recently published studies focus on liver imaging with extracellular liver specific contrast media as well as diffusion weighted imaging. They consider this new method having a high diagnostic potential. * For pancreatic neoplasm diagnosis diffusion--as well as perfusion--imaging is considered as a highly promising method. PMID- 26425856 TI - [Cardiac metastasis of a recurrent urothelial carcinoma of the bladder]. PMID- 26425857 TI - Changes in Meningococcal Strains in the Era of a Serogroup C Vaccination Campaign: Trends and Evolution in Belgium during the Period 1997-2012. AB - BACKGROUND: Invasive meningococcal disease (IMD) is a major cause of bacterial meningitides and septicaemia. This study shows the results of the laboratory based surveillance of IMD in Belgium over the period 1997-2012. METHODS: The results are based on microbiological and molecular laboratory surveillance of 2997 clinical isolates of N. meningitides received by the Belgian Meningococcal Reference Centre (BMRC) over the period 1997-2012. RESULTS: Serogroup B has always been a major cause of meningococcal disease in Belgium, with P3.4 as most frequent serotype till 2008, while an increase in non-serotypable strains has been observed in the last few years. Clonal complexes cc-41/44 and cc-269 are most frequently observed in serogroup B strains. In the late nineties, the incidence of serogroup C disease increased considerably and peaked in 2001, mainly associated with phenotypes C:2a:P1.5,2, C:2a:P1.5 and C:2a:P1.2 (ST-11/ET 37 clonal complex). The introduction of the meningococcal C conjugate vaccine has been followed by an 88% significant decrease in serogroup C disease from 2001 to 2004 nationally, yet sharper in Flanders (92%) compared to Wallonia (77%). Since 2008 a difference in incidence of serogroup C was observed in Flanders (0 0.1/100,000) versus Wallonia (0.1-0.3/100,000). CONCLUSION: This study showed the change in epidemiology and strain population over a 16 years period spanning an exhaustive vaccination campaign and highlights the influence of regional vaccination policies with different cohorts sizes on short and long-term IMD incidences. PMID- 26425859 TI - Fetal Cardiac Axis in Fetuses with Conotruncal Anomalies. AB - Purpose The purpose of this study was to assess the cardiac axis in fetuses with conotruncal anomalies during four-chamber view scanning. Materials and Methods We retrospectively evaluated the cardiac axis of 150 fetuses with conotruncal anomalies within the second and third trimester between October 2008 and August 2014. The cardiac axis was obtained by the angle of two lines in a transverse view of the fetal thorax at the level of the four-chamber view. The first line divided the thorax into two equal halves starting from the spine posteriorly ending at the sternum. The second line was placed through the interventricular septum of the fetal heart. The angle was calculated using OsiriX software. Results 23 had double outlet right ventricle (DORV), 17 had truncus arteriosus communis (TAC), 36 had tetralogy of Fallot (TOF), and 74 had complete transposition of the great arteries (d-TGA). In fetuses with DORV <= 24 + 6 weeks of gestation (wks), the mean cardiac axis was 52.5 degrees (p = 0.005), at >= 25 + 0 wks it was 51.1 degrees (p = 0.0003). In fetuses with TAC <= 24 + 6 wks, the mean cardiac axis was 56.8 degrees (p = 0.01), at >= 25 + 0 wks it was 50.0 degrees (p = 0.05). In fetuses with TOF <= 24 + 6 wks, the mean cardiac axis was 67.5 degrees (p < 0.0001), at >= 25 + 0 wks it was 63.8 degrees (p < 0.0001). In fetuses with d-TGA <= 24 + 6 wks, the mean cardiac axis was 45.6 degrees , at >= 25 + 0 wks it was 45.4 degrees (not significant). Throughout gestation, the cardiac axis did not show a difference in the two separate examinations. Conclusion In fetuses with DORV, TAC and TOF, the cardiac axis is significantly different from the normal axis, but in fetuses with TGA there is no significant difference compared to the normal axis. Therefore, analysis of the heart axis could be useful for screening for conotruncal anomalies. PMID- 26425858 TI - Idiopathic Pulmonary Fibrosis: Gender-Age-Physiology Index Stage for Predicting Future Lung Function Decline. AB - BACKGROUND: Idiopathic pulmonary fibrosis is a progressive lung disease with variable course. The Gender-Age-Physiology (GAP) Index and staging system uses clinical variables to stage mortality risk. It is unknown whether clinical staging predicts future decline in pulmonary function. We assessed whether the GAP stage predicts future pulmonary function decline and whether interval pulmonary function change predicts mortality after accounting for stage. METHODS: Patients with idiopathic pulmonary fibrosis (N = 657) were identified retrospectively at three tertiary referral centers, and baseline GAP stages were assessed. Mixed models were used to describe average trajectories of FVC and diffusing capacity of the lung for carbon monoxide (Dlco). Multivariable Cox proportional hazards models were used to assess whether declines in pulmonary function >= 10% in 6 months predict mortality after accounting for GAP stage. RESULTS: Over a 2-year period, GAP stage was not associated with differences in yearly lung function decline. After accounting for stage, a 10% decrease in FVC or Dlco over 6 months independently predicted death or transplantation (FVC hazard ratio, 1.37; Dlco hazard ratio, 1.30; both, P <= .03). Patients with GAP stage 2 with declining pulmonary function experienced a survival profile similar to patients with GAP stage 3, with 1-year event-free survival of 59.3% (95% CI, 49.4-67.8) vs 56.9% (95% CI, 42.2-69.1). CONCLUSIONS: Baseline GAP stage predicted death or lung transplantation but not the rate of future pulmonary function decline. After accounting for GAP stage, a decline of >= 10% over 6 months independently predicted death or lung transplantation. PMID- 26425860 TI - Image-based view-angle independent cardiorespiratory motion gating and coronary sinus catheter tracking for x-ray-guided cardiac electrophysiology procedures. AB - Determination of the cardiorespiratory phase of the heart has numerous applications during cardiac imaging. In this article we propose a novel view angle independent near-real time cardiorespiratory motion gating and coronary sinus (CS) catheter tracking technique for x-ray fluoroscopy images that are used to guide cardiac electrophysiology procedures. The method is based on learning CS catheter motion using principal component analysis and then applying the derived motion model to unseen images taken at arbitrary projections, using the epipolar constraint. This method is also able to track the CS catheter throughout the x ray images in any arbitrary subsequent view. We also demonstrate the clinical application of our model on rotational angiography sequences. We validated our technique in normal and very low dose phantom and clinical datasets. For the normal dose clinical images we established average systole, end-expiration and end-inspiration gating success rates of 100%, 85.7%, and 92.3%, respectively. For very low dose applications, the technique was able to track the CS catheter with median errors not exceeding 1 mm for all tracked electrodes. Average gating success rates of 80.3%, 71.4%, and 69.2% were established for the application of the technique on clinical datasets, even with a dose reduction of more than 10 times. In rotational sequences at normal dose, CS tracking median errors were within 1.2 mm for all electrodes, and the gating success rate was 100%, for view angles from RAO 90 degrees to LAO 90 degrees . This view-angle independent technique can extract clinically useful cardiorespiratory motion information using x-ray doses significantly lower than those currently used in clinical practice. PMID- 26425861 TI - Adolescents' Lived Experiences While Hospitalized After Surgery for Ulcerative Colitis. AB - Adolescents are in a transitional phase of life characterized by major physical, emotional, and psychological challenges. Living with ulcerative colitis is experienced as a reduction of their life quality. Initial treatment of ulcerative colitis is medical, but surgery may be necessary when medical treatment ceases to have an effect. No research-based studies of adolescents' experience of the hospital period after surgery for ulcerative colitis exist. The objective of the study was to identify and describe adolescents' lived experiences while hospitalized after surgery for ulcerative colitis. This qualitative study was based on interviews with eight adolescents. Analysis and interpretation were based on a hermeneutic interpretation of meaning. Three themes were identified: Body: Out of order; Seen and understood; and Where are all the others? The adolescents experience a postoperative period characterized by physical and mental impairment. Being mentally unprepared for such challenges, they shun communication and interaction. The findings demonstrate the importance of individualized nursing care on the basis of the adolescent's age, maturity, and individual needs. Further study of adolescent patients' hospital stay, focusing on the implications of being young and ill at the same time, is needed. PMID- 26425862 TI - Nursing Assessment Tool for People With Liver Cirrhosis. AB - The aim of this study was to describe the process of developing a nursing assessment tool for hospitalized adult patients with liver cirrhosis. A descriptive study was carried out in three stages. First, we conducted a literature review to develop a data collection tool on the basis of the Conceptual Model of Wanda Horta. Second, the data collection tool was assessed through an expert panel. Third, we conducted the pilot testing in hospitalized patients. Most of the comments offered by the panel members were accepted to improve the tool. The final version was in the form of a questionnaire with open closed questions. The panel members concluded that the tool was useful for accurate nursing diagnosis. Horta's Conceptual Model assisted with the development of this data collection tool to help nurses identify accurate nursing diagnosis in hospitalized patients with liver cirrhosis. We hope that the tool can be used by all nurses in clinical practice. PMID- 26425864 TI - Predicting attitudes toward seeking professional psychological help among Alaska Natives. AB - This study sought to examine the role of current/previous treatment experience, stigma (social and self), and cultural identification (Caucasian and Alaska Native [AN]) in predicting attitudes toward psychological help seeking for ANs. Results indicated that these variables together explained roughly 56% of variance in attitudes. In particular, while self-stigma and identification with the Caucasian culture predicted a unique amount of variance in help-seeking attitudes, treatment use and identification with AN culture did not. The results of this study indicate that efforts to address the experience of self-stigma may prove most useful to improving help-seeking attitudes in ANs. PMID- 26425863 TI - Post-traumatic stress disorder and HIV risk behaviors among rural American Indian/Alaska Native women. AB - We assessed the relationship between post-traumatic stress disorder (PTSD), binge drinking, and HIV sexual risk behavior by examining number of unprotected sex acts and number of sexual partners in the past 6 months among 129 sexually active American Indian women. A total of 51 (39.5%) young women met PTSD criteria. Among women who met the PTSD criteria, binge drinking was associated with a 35% increased rate of unprotected sex (IRR 1.35, p < .05), and there was a stronger association between increased binge drinking and risk of more sexual partners (IRR 1.21, p < .001) than among women who did not meet PTSD criteria (IRR 1.08, p < .01) with a difference of 13% (p < .05). HIV intervention and prevention interventions in this population likely would benefit from the inclusion of efforts to reduce binge drinking and increase treatment of PTSD symptoms. PMID- 26425865 TI - Systematic review of interventions focusing on Indigenous adolescent mental health and substance use. AB - Mental health and substance use are pressing public health concerns among Indigenous adolescent populations. This systematic review analyzed interventions focusing on mental health and substance use that utilize the Positive Youth Development (PYD) framework, incorporate culturally tailored programs, and are geared toward Indigenous adolescents. In total, 474 articles were retrieved from PSYCInfo and PubMed databases. Eight articles were eligible for analysis, with six focusing on AI/AN populations in the U.S. Most programs reported positive or expected outcomes. All the programs incorporated PYD variables, while all but one were culturally grounded or included deep structure adaptations. Implications are further discussed. PMID- 26425866 TI - Iron Complexes of Square Planar Tetradentate Polypyridyl-Type Ligands as Catalysts for Water Oxidation. AB - The tetradentate ligand, 2-(pyrid-2'-yl)-8-(1",10"-phenanthrolin-2"-yl)-quinoline (ppq) embodies a quaterpyridine backbone but with the quinoline C8 providing an additional sp(2) center separating the two bipyridine-like subunits. Thus, the four pyridine rings of ppq present a neutral, square planar host that is well suited to first-row transition metals. When reacted with FeCl3, a MU-oxo-bridged dimer is formed having a water bound to an axial metal site. A similar metal binding environment is presented by a bis-phenanthroline amine (dpa) which forms a 1:1 complex with FeCl3. Both structures are verified by X-ray analysis. While the Fe(III)(dpa) complex shows two reversible one-electron oxidation waves, the Fe(III)(ppq) complex shows a clear two-electron oxidation associated with the process H2O-Fe(III)Fe(III) -> H2O-Fe(IV)Fe(IV) -> O?Fe(V)Fe(III). Subsequent disproportionation to an Fe?O species is suggested. When the Fe(III)(ppq) complex is exposed to a large excess of the sacrificial electron-acceptor ceric ammonium nitrate at pH 1, copious amounts of oxygen are evolved immediately with a turnover frequency (TOF) = 7920 h(-1). Under the same conditions the mononuclear Fe(III)(dpa) complex also evolves oxygen with TOF = 842 h(-1). PMID- 26425867 TI - Comparing the Maryland Comprehensive Cancer Control Plan With Federal Cancer Prevention and Control Recommendations. AB - INTRODUCTION: Since the introduction of the Affordable Care Act (ACA) in 2012, 11 million more Americans now have access to preventive services via health care coverage. Several prevention-related recommendations issued by the US Preventive Services Task Force (USPSTF), Centers for Disease Control and Prevention (CDC), and Advisory Committee on Immunization Practices (ACIP) are covered under the ACA. State cancer plans often provide prevention strategies, but whether these strategies correspond to federal evidence-based recommendations is unclear. The objective of this article is to assess whether federal evidence-based recommendations, including those covered under the ACA, are included in the Maryland Comprehensive Cancer Control Plan (MCCCP). METHODS: A total of 19 federal recommendations pertaining to cancer prevention and control were identified. Inclusion of federal cancer-related recommendations by USPSTF, CDC, and ACIP in the MCCCP's goals, objectives, and strategies was examined. RESULTS: Nine of the federal recommendations were issued after the MCCCP's publication. MCCCP recommendations corresponded completely with 4 federal recommendations and corresponded only partially with 3. Reasons for partial correspondence included specification of less restrictive at-risk populations or different intervention implementers. Three federal recommendations were not mentioned in the MCCCP's goals, objectives, and strategies. CONCLUSION: Many cancer-related federal recommendations were released after the MCCCP's publication and therefore do not appear in the most current version. We recommend that the results of this analysis be considered in the update of the MCCCP. Our findings underscore the need for a periodic scan for changes to federal recommendations and for adjusting state policies and programs to correspond with federal recommendations, as appropriate for Marylanders. PMID- 26425868 TI - Using Photovoice to Understand Barriers to and Facilitators of Cardiovascular Health Among African American Adults and Adolescents, North Carolina, 2011-2012. AB - INTRODUCTION: Cardiovascular disease is the leading cause of death in the United States, and mortality rates are higher among African Americans than among people of other races/ethnicities. We aimed to understand how African American adults and adolescents conceptualize cardiovascular health and perceive related barriers and facilitators. METHODS: This qualitative study was conducted as formative research for a larger study, Heart Healthy Lenoir, which aimed to reduce cardiovascular disease disparities among African Americans in eastern North Carolina, part of the widely-known "stroke belt" that runs through the southeastern United States. Using photovoice, a community-based participatory research method, we conducted eight 90-minute photovoice sessions with 6 adults and 9 adolescents in Lenoir County, North Carolina. Topics for each discussion were selected by participants and reflected themes related to cardiovascular health promotion. All sessions were transcribed and coded using a data-driven, inductive approach. RESULTS: Participants conceptualized cardiovascular health to have mental, spiritual, and social health dimensions. Given these broad domains, participants acknowledged many ecological barriers to cardiovascular health; however, they also emphasized the importance of personal responsibility. Facilitators for cardiovascular health included using social health (eg, family/community relationships) and spiritual health dimensions (eg, understanding one's body and purpose) to improve health behaviors. CONCLUSION: The perspectives of African American adults and adolescents elicited through this formative research provided a strong foundation for Heart Healthy Lenoir's ongoing engagement of community members in Lenoir County and development and implementation of its intervention to prevent cardiovascular disease. PMID- 26425869 TI - Evaluating the Effects of Coping Style on Allostatic Load, by Sex: The Jackson Heart Study, 2000-2004. AB - The objective of this study was to examine the cross-sectional association between coping styles and allostatic load among African American adults in the Jackson Heart Study (2000-2004). Coping styles were assessed using the Coping Strategies Inventory-Short Form; allostatic load was measured by using 9 biomarkers standardized into z-scores. Sex-stratified multivariable linear regressions indicated that females who used disengagement coping styles had significantly higher allostatic load scores (beta = 0.016; 95% CI, 0.001-0.032); no such associations were found in males. Future longitudinal investigations should examine why disengagement coping style is linked to increased allostatic load to better inform effective interventions and reduce health disparities among African American women. PMID- 26425870 TI - New School Meal Regulations and Consumption of Flavored Milk in Ten US Elementary Schools, 2010 and 2013. AB - Milk is a source of shortfall nutrients in children's diets, but most children do not consume recommended amounts. We measured consumption of milk by elementary schoolchildren (grades 3-5) in a diverse sample of schools before and after implementation of the US Department of Agriculture's updated meal regulations requiring flavored milk to be fat-free. Flavored milk consumption did not change from 2010 to 2013; 52.2% of students in 2010 and 49.7% in 2013 consumed 7 ounces or more of an 8-ounce container. Updated regulations succeeded in lowering the amount of fat, added sugars, and calories in school milk but did not change overall milk consumption, thus improving children's diet quality. PMID- 26425872 TI - Detectability of hepatic tumors during 3D post-processed ultrafast cone-beam computed tomography. AB - To evaluate hepatic tumor detection using ultrafast cone-beam computed tomography (UCBCT) cross-sectional and 3D post-processed image datasets. 657 patients were examined using UCBCT during hepatic transarterial chemoembolization (TACE), and data were collected retrospectively from January 2012 to September 2014. Tumor detectability, diagnostic ability, detection accuracy and sensitivity were examined for different hepatic tumors using UCBCT cross-sectional, perfusion blood volume (PBV) and UCBCT-MRI (magnetic resonance imaging) fused image datasets. Appropriate statistical tests were used to compare collected sample data. Fused image data showed the significantly higher (all P < 0.05) diagnostic ability for hepatic tumors compared to UCBCT or PBV image data. The detectability of small hepatic tumors (<5 mm) was significantly reduced (all P < 0.05) using UCBCT cross-sectional images compared to MRI or fused image data; however, PBV improved tumor detectability using a color display. Fused image data produced 100% tumor sensitivity due to the simultaneous availability of MRI and UCBCT information during tumor diagnosis. Fused image data produced excellent hepatic tumor sensitivity, detectability and diagnostic ability compared to other datasets assessed. Fused image data is extremely reliable and useful compared to UCBCT cross-sectional or PBV image datasets to depict hepatic tumors during TACE. Partial anatomical visualization on cross-sectional images was compensated by fused image data during tumor diagnosis. PMID- 26425871 TI - Strategies to Support Tobacco Cessation and Tobacco-Free Environments in Mental Health and Substance Abuse Facilities. AB - We identified and described strategies for promoting smoking cessation and smoke free environments that were implemented in Oregon and Utah in treatment centers for mental illness and substance abuse. We reviewed final evaluation reports submitted by state tobacco control programs (TCPs) to the Centers for Disease Control and Prevention and transcripts from a call study evaluation. The TCPs described factors that assisted in implementing strategies: being ready for opportunity, having a sound infrastructure, and having a branded initiative. These strategies could be used by other programs serving high-need populations for whom evidence-based interventions are still being developed. PMID- 26425873 TI - Nephrologists' Perspectives on Recipient Eligibility and Access to Living Kidney Donor Transplantation. AB - BACKGROUND: Wide variations in access to living kidney donation are apparent across transplant centers. Such disparities may be in part explained by nephrologists' beliefs and decisions about recipient eligibility. This study aims to describe nephrologists' attitudes towards recipient eligibility and access to living kidney donor transplantation. METHODS: Face-to-face semistructured interviews were conducted from June to October 2013 with 41 nephrologists from Australia and New Zealand. Transcripts were analyzed thematically. RESULTS: We identified five major themes: championing optimal recipient outcomes (maximizing recipient survival, increasing opportunity, accepting justified risks, needing control and certainty of outcomes, safeguarding psychological wellbeing), justifying donor sacrifice (confidence in reasonable utility, sparing the donor, ensuring reciprocal donor benefit), advocating for patients (being proactive and encouraging, addressing ambivalence, depending on supportive infrastructure, avoiding selective recommendations), maintaining professional boundaries (minimizing conflict of interest, respecting shared decision-making, emphasizing patient accountability, restricted decisional power, protecting unit interests), and entrenched inequities (exclusivity of living donors, inherently advantaging self-advocates, navigating language barriers, increasing center transparency, inevitable geographical disadvantage, understanding cultural barriers). CONCLUSIONS: Nephrologists' decisions about recipient suitability for living donor transplantation aimed to achieve optimal recipient outcomes, but were constrained by competing priorities to ensure reasonable utility derived from the donor kidney and protect the integrity of the transplant program. Comprehensive guidelines that provide explicit recommendations for complex medical and psychosocial risk factors might promote more equitable and transparent decision making. Psychosocial support and culturally sensitive educational resources are needed to help nephrologists advocate for disadvantaged patients and address disparities in access to living kidney donor transplantation. PMID- 26425874 TI - Ventilatory Management During Normothermic Ex Vivo Lung Perfusion: Effects on Clinical Outcomes. AB - BACKGROUND: During ex vivo lung perfusion (EVLP), fixed ventilator settings and monitoring of compliance are used to prevent ventilator-induced lung injury (VILI). Analysis of the airway pressure-time curve (stress index) has been proposed to assess the presence of VILI. We tested whether currently proposed ventilator settings expose lungs to VILI during EVLP and whether the stress index could identify VILI better than compliance. METHODS: Flow, volume, and airway opening pressure were collected continuously during EVLP. Durations of mechanical ventilation, intensive care unit (ICU) and hospital lengths of stay were recorded in lung recipients. RESULTS: Fourteen lungs underwent EVLP and were transplanted. In 5 lungs, 95 +/- 2% of the stress index values were within the 0.95 to 1.05 range (protected); in the remaining nine lungs, 69 +/- 1% of the values were greater than 1.05 and 15 +/- 3% were less than 0.95 (nonprotected). There was a significant (P < 0.05) increase in cytokine concentrations after 4 hours of EVLP in the nonprotected lungs. Durations of mechanical ventilation, ICU, and hospital lengths of stay were shorter in recipients of protected than that of nonprotected lungs (P < 0.05). There was no correlation between compliance during EVLP and duration of mechanical ventilation or ICU and hospital lengths of stay in recipients, but the stress index during EVLP was significantly correlated with the duration of mechanical ventilation and with ICU and hospital lengths of stay (P < 0.05). CONCLUSIONS: This small, preliminary study shows that ventilator settings currently proposed for EVLP may expose lungs to VILI. Use of the stress index to personalize ventilator settings needs to be tested in further clinical studies. PMID- 26425875 TI - Quantifying the Race Stratified Impact of Socioeconomics on Graft Outcomes in Kidney Transplant Recipients. AB - BACKGROUND: Socioeconomic status (SES) is a significant determinant of health outcomes and may be an important component of the causal chain surrounding racial disparities in kidney transplantation. The social adaptability index (SAI) is a validated and quantifiable measure of SES, with a lack of studies analyzing this measure longitudinally or between races. METHODS: Longitudinal cohort study in adult kidney transplantation transplanted at a single-center between 2005 and 2012. The SAI score includes 5 domains (employment, education, marital status, substance abuse and income), each with a minimum of 0 and maximum of 3 for an aggregate of 0 to 15 (higher score -> better SES). RESULTS: One thousand one hundred seventy-one patients were included; 624 (53%) were African American (AA) and 547 were non-AA. African Americans had significantly lower mean baseline SAI scores (AAs 6.5 vs non-AAs 7.8; P < 0.001). Cox regression analysis demonstrated that there was no association between baseline SAI and acute rejection in non-AAs (hazard ratio [HR], 0.92; 95% confidence interval [95% CI], 0.81-1.05), whereas it was a significant predictor of acute rejection in AAs (HR, 0.89; 95% CI, 0.80 0.99). Similarly, a 2-stage approach to joint modelling of time to graft loss and longitudinal SAI did not predict graft loss in non-AAs (HR, 1.01; 95% CI, 0.28 3.62), whereas it was a significant predictor of graft loss in AAs (HR, 0.23; 95% CI, 0.06-0.93). CONCLUSIONS: After controlling for confounders, SAI scores were associated with a lower risk of acute rejection and graft loss in AA kidney transplant recipients, whereas neither baseline nor follow-up SAI predicted outcomes in non-AA kidney transplant recipients. PMID- 26425876 TI - Preconditioning Therapy in ABO-Incompatible Living Kidney Transplantation: A Systematic Review and Meta-Analysis. AB - BACKGROUND: ABO-incompatible (ABOi) kidney transplantation is now an established form of renal replacement therapy, but the efficacy and safety of the different types of preconditioning therapies are unclear. We aimed to synthesize the totality of the published evidence about the effects of any form of preconditioning therapies in living donor ABOi kidney transplantation on graft and patient outcomes. METHODS: We searched MEDLINE, Embase, and Clinicaltrial.gov databases (inception through June 2015) to identify all studies that described the outcomes of adult living donor ABOi kidney transplantations using any form of preconditioning therapies. Two independent reviewers identified studies, extracted data, and assessed the risk of bias. Data were summarized using the random effects model, and heterogeneity was explored using subgroup analyses. We assessed confidence in the evidence using the Grading of Recommendations Assessment, Development, and Evaluation framework. RESULTS: Eighty-three studies (54 case reports and case series, 25 cohort, 2 case-control, and 2 registry studies) involving 4810 ABOi transplant recipients were identified. Overall, confidence in the available evidence was low. During a mean follow-up time of 28 (standard deviation [SD], 26.6) months, the overall graft survival for recipients who received immunoadsorption or apheresis was 94.1% (95% confidence interval [95%CI], 88.2%-97.1%) and 88.0% (95% CI, 82.6%-91.8%), respectively. For those who received rituximab or underwent splenectomy, the overall graft survival was 94.5% (95% CI, 91.6%-96.5%) and 79.7% (95% CI, 72.9%-85.1%), respectively. Data on other longer-term outcomes, including malignancy, were sparse. CONCLUSIONS: Rituximab or immunoadsorption appeared to be promising preconditioning strategies before ABOi kidney transplantation. However, the overall quality of evidence and the confidence in the observed treatment effects are low. The increased use of ABOi kidney transplantation needs to be matched with randomized trials of different types, dosing, and frequency of preconditioning therapies so that this scarce resource can be used most effectively and efficiently. PMID- 26425877 TI - Pretransplant Recipient Circulating CD4+CD127lo/- Tumor Necrosis Factor Receptor 2+ Regulatory T Cells: A Surrogate of Regulatory T Cell-Suppressive Function and Predictor of Delayed and Slow Graft Function After Kidney Transplantation. AB - BACKGROUND: Delayed graft function (DGF) and slow graft function (SGF) are ischemia-reperfusion-associated acute kidney injuries (AKI) that decrease long term graft survival after kidney transplantation. Regulatory T (Treg) cells are protective in murine AKI, and their suppressive function predictive of AKI in kidney transplantation. The conventional Treg cell function coculture assay is however time-consuming and labor intensive. We sought a simpler alternative to measure Treg cell function and predict AKI. METHODS: In this prospective observational cohort study, pretransplant recipient circulating CD4+CD25+CD127lo/ and CD4+CD127lo/- tumor necrosis factor receptor 2 (TNFR2)+ Treg cells were measured by flow cytometry in 76 deceased donor kidney transplant recipients (DGF, n = 18; SGF, n = 34; immediate graft function [IGF], n = 24). In a subset of 37 recipients, pretransplant circulating Treg cell-suppressive function was also quantified by measuring the suppression of autologous effector T-cell proliferation by Treg cell in coculture. RESULTS: The TNFR2+ expression on CD4+CD127lo/- T cells correlated with Treg cell-suppressive function (r = 0.63, P < 0.01). In receiver operating characteristic curves, percentage and absolute number of CD4+CD127lo/-TNFR2+ Treg cell predicted DGF from non-DGF (IGF + SGF) with area under the curves of 0.75 and 0.77, respectively, and also AKI (DGF + SGF) from IGF with area under the curves of 0.76 and 0.72, respectively (P < 0.01). Prediction of AKI (DGF + SGF) from IGF remained significant in multivariate logistic regression accounting for cold ischemic time, donor age, previous transplant, and pretransplant dialysis modality. CONCLUSIONS: Pretransplant recipient circulating CD4+CD127lo/-TNFR2+ Treg cell is potentially a simpler alternative to Treg cell function as a pretransplant recipient immune marker for AKI (DGF + SGF), independent from donor and organ procurement characteristics. PMID- 26425878 TI - Transformation between Inverse Bicontinuous Cubic Phases of a Lipid from Diamond to Gyroid. AB - The transformation between inverse bicontinuous cubic phases of a lipid from diamond (QII(D)) to gyroid (QII(G)) in the single crystal region of monoolein was studied. X-ray diffraction data indicate that the single orientation of the QII(D) phase was converted into an almost single orientation of the QII(G) phase. The [111] and [110] directions of a single crystal of the QII(D) phase corresponded to the [202] and [040] directions of the QII(G) phase, respectively. This orientation relationship indicated that one direction in the four-branched water channels of the QII(D) phase was preserved in the three-branched water channels of the QII(G) phase. Using this relationship, a transformation model was constructed in which one direction of the water channels was preserved while another direction appeared. PMID- 26425879 TI - Cardiac Troponin Measurement in the Critically Ill: Potential for Guiding Clinical Management. AB - BACKGROUND: Elevated cardiac troponin (cTn) in the absence of acute coronary syndromes (ACS) is associated with increased mortality in critically ill patients. There are no evidence-based interventions that reduce mortality in this group. OBJECTIVES: We performed a retrospective investigation of the Veterans Administration Inpatient Evaluation Center database to determine whether drugs used in ACS (beta-blockers, aspirin, and statins) are associated with reduced mortality in critically ill patients. METHODS: Thirty-day mortality was determined for non-ACS patients admitted to any Veterans Administration Intensive Care Unit between October 1, 2007, and September 30, 2008, adjusted for severity of illness. Troponin assay values were normalized across institutions. RESULTS: Multivariate analyses for 30-day mortality showed an odds ratio (OR) of 1.82 for patients with high cTn (P < 0.0001, cTn > 10% coefficient of variation) and 1.18 for intermediate cTn (P = 0.0021, cTn between lowest limit detectable and 10% coefficient of variation) compared with patients with no elevation, adjusting for severity of illness (n = 19,979). Logistic regression models showed that patients with no or intermediate elevations of cTn taking statins within 24 hours of cTn measurement had a lower mortality than patients not taking statins (OR, 0.66; 95% confidence interval [95% CI], 0.53-0.82; P = 0.0003), whereas patients with high cTn had a lower mortality if they were taking beta-blockers or aspirin within 24 hours of cTn measurement compared to patients not taking beta-blockers or aspirin (beta-blockers: OR, 0.80; 95% CI, 0.68-0.94; P = 0.0077; aspirin: OR, 0.81;95% CI, 0.69-0.96; P = 0.0134). CONCLUSIONS: This retrospective study confirms an association between elevated troponin and outcomes in critically ill patients without ACS and identifies statins, beta-blockers, and aspirin as potential outcome modifiers in a cTn-dependent manner. PMID- 26425882 TI - Correction to Spectroscopy and Structure of the Simplest Actinide Bonds. PMID- 26425881 TI - Are You Missing an Entropion? The Test of Induced Entropion 2. AB - PURPOSE: Entropion is the inward turning of the eyelid. The most common type of entropion is involutional, a combination of eyelid laxity, lower eyelid retractor weakness, and orbicularis oculi override. Unfortunately, the condition can be intermittent and remain undiagnosed, leading to ocular surface damage. In suspected cases, clinicians can use provocation techniques to elicit the condition. These include the forced closure of the eyelids, the tetracaine provocation test, and the test of induced entropion (TIE). The authors present an alternative diagnostic test: the TIE-2. METHODS: The TIE-2 test is performed by asking the patient to look down while the examiner holds the upper eyelid open and high to prevent downward movement. The patient is then asked to close their eyelids as tightly as possible. An entropion will then be induced. To illustrate the technique, the authors present 2 patients seen in the oculoplastics clinic with symptoms and signs suggestive of intermittent entropion, in whom conventional provocation tests were unsuccessful. RESULTS: In both cases, conventional methods did not provoke an entropion. However, the TIE-2 test successfully induced an entropion, leading to the correct diagnosis and appropriate management. CONCLUSION: When there is suspicion of intermittent entropion that is not revealed with existing provocation tests, the TIE-2 is a simple and useful diagnostic tool. PMID- 26425883 TI - Intranasal Human Growth Hormone (hGH) Induces IGF-1 Levels Comparable With Subcutaneous Injection With Lower Systemic Exposure to hGH in Healthy Volunteers. AB - CONTEXT: The development of an improved, efficacious human GH (hGH) product administered by a noninjectable route of delivery such as the nasal route is highly desirable. We have developed a novel nasal hGH product (CP024) that showed excellent nasal absorption in animal models; however, the translation of these results into the clinical setting is essential because past attempts to develop such formulations by other groups have been unable to induce IGF-1 in man. OBJECTIVE: The objective of the study was to assess the pharmacokinetics, pharmacodynamics, and tolerability of CP024 compared with a sc hGH injection. DESIGN: This was a single-center, nonrandomized placebo-controlled, open-label, five-way crossover study in eight healthy volunteers. SETTING: The study was carried out at a contract research organization, Quotient Bioresearch. VOLUNTEERS: Eight healthy male volunteers, given an iv infusion of octreotide to suppress the endogenous GH secretion during the study period, participated in the study. No volunteers were withdrawn due to side effects. MAIN OUTCOME MEASURES: Measurement of hGH and IGF-1 levels and tolerability of the drug product was performed. RESULTS: No serious adverse events were reported and no subjects withdrawn from study due to the treatment. After the nasal administration of CP024, 3-fold higher hGH blood levels were obtained as compared with hGH nasal control. The relative bioavailability was about 3%. CP024 (given twice daily) induced a significant increase in IGF-1 levels up to 19 hours after administration, with no significant difference to those obtained after the sc injection of hGH. CONCLUSIONS: The study indicates that CP024 is a promising candidate for an efficacious nasal product for the treatment of GH deficiency due to induction of IGF-1 similar to that after a sc injection, despite the lower plasma hGH concentration obtained. A dose-response study is needed to evaluate the optimal nasal dose. PMID- 26425885 TI - Chenodeoxycholic Acid as a Potential Prognostic Marker for Roux-en-Y Gastric Bypass in Chinese Obese Patients. AB - CONTEXT: Bile acids (BAs) have been suggested as key mediators of the improvements in glucose metabolism after Roux-en-Y gastric bypass (RYGB). OBJECTIVE: The objective of the study was to test whether the individual or a group of BAs have potential value to predict diabetes remission after RYGB. DESIGN AND PATIENTS: A retrospective cohort of 38 Chinese obese patients with type 2 diabetes mellitus (T2DM) who had undergone RYGB and a cross-sectional cohort of 327 subjects from the Shanghai Obesity Study were involved in the study. MAIN OUTCOME AND MEASURES: We applied a targeted metabolomics approach to quantitatively measure 26 serum BAs. The relative proportion of each BA in total BAs was calculated. RESULTS: In the metabolic surgery study, RYGB was effective in the reduction of body weight in both remission and nonremission groups. The reductions of body mass index (BMI) in both groups were 7.34 +/- 2.10 kg/m(2) and 6.31 +/- 2.38 kg/m(2), respectively (P = .14). Patients in the remission group had a shorter duration of diabetes, lower glycated hemoglobin, and higher C peptide and chenodeoxycholic acid (CDCA) proportion at baseline compared with the nonremission group. Multiple logistic regression indicated that a higher level of CDCA relative to total BA (CDCA%) and shorter duration of diabetes at baseline were associated with a greater chance of diabetes remission. The odd ratios were 0.19 (95% confidence interval 0.05-0.74) and 1.77 (95% confidence interval 1.13 2.76), respectively, after adjustment for age, gender, and BMI. In the cross sectional study, CDCA% was significantly higher in obese individuals with T2DM than the normal glucose tolerance group. Correlation analysis showed CDCA% was positively correlated with BMI, glycated hemoglobin, triglycerides, and low density lipoprotein cholesterol and negatively correlated with high-density lipoprotein cholesterol and diabetes duration. CONCLUSION: Increased CDCA, a major primary BA, was correlated with a shorter duration of T2DM, which was associated with a higher possibility of remission after surgery. CDCA% might act as a potential prognostic marker of RYGB. PMID- 26425884 TI - Estradiol Priming Improves Gonadotrope Sensitivity and Pro-Inflammatory Cytokines in Obese Women. AB - CONTEXT: Obesity is associated with a pro-inflammatory state and relative hypogonadotropic hypogonadism. Estrogen (E2) is a potential link between these phenomena because it exhibits negative feedback on gonadotropin secretion and also inhibits production of pro-inflammatory cytokines. OBJECTIVE: We sought to examine the effect of estrogen priming on the hypothalamic-pituitary-ovarian axis in obesity. DESIGN, SETTING, AND PARTICIPANTS: This was an interventional study at an academic center of 11 obese and 10 normal-weight (NW) women. INTERVENTION: A frequent blood-sampling study and one month of daily urinary collection were performed before and after administration of transdermal estradiol 0.1 mg/d for one entire menstrual cycle. MAIN OUTCOME MEASURES: Serum LH and FSH before and after GnRH stimulation, and urinary estrogen and progesterone metabolites were measured. RESULTS: E2 increased LH pulse amplitude and FSH response to GnRH (P = .048, and P < .03, respectively) in obese but not NW women. After E2 priming, ovulatory obese but not NW women had a 25% increase in luteal progesterone (P = .01). Obese women had significantly higher baseline IL-6, IL-10, TGF-beta, and IL 12 compared with NW (all P < .05); these levels were reduced after E2 (-6% for IL 1beta, -21% for IL-8, -5% for TGF-beta, -5% for IL-12; all P < .05) in obese but not in NW women. CONCLUSIONS: E2 priming seems to improve hypothalamic-pituitary ovarian axis function and systemic inflammation in ovulatory, obese women. Reducing chronic inflammation at the pituitary level may decrease the burden of obesity on fertility. PMID- 26425891 TI - Author's reply to Performance of interferon-gamma release assay for tuberculosis screening in inflammatory bowel disease patients: disease activity as an influencing factor. PMID- 26425892 TI - Pyridine-Hydrazones as N,N'-Ligands in Asymmetric Catalysis: Pd(II)-Catalyzed Addition of Boronic Acids to Cyclic Sulfonylketimines. AB - The design, synthesis, and coordination features of a novel class of chiral pyridine-hydrazone ligands are described. As a first application, L/Pd(TFA)2 complexes served as catalysts in the 1,2-addition of arylboronic acids to saccharin-derived cyclic ketimines, affording products in high yields and enantioselectivities. The method was also applied to more challenging 3,4 disubstituted 1,2,5-thiadiazole 1,1-dioxides, affording again high yields and enantioselectivities along with high regioselectivities for unsymmetrically substituted derivatives. PMID- 26425886 TI - Timing of Estradiol Treatment After Menopause May Determine Benefit or Harm to Insulin Action. AB - CONTEXT: Type 2 diabetes (T2D) is reduced in postmenopausal women randomized to estrogen-based hormone therapy (HT) compared with placebo. Insulin sensitivity is a key determinant of T2D risk and overall cardiometabolic health, and studies indicate that estradiol (E2) directly impacts insulin action. OBJECTIVE: We hypothesized that the timing of E2 administration after menopause is an important determinant of its effect on insulin action. DESIGN: We performed a randomized, crossover, placebo-controlled study. PARTICIPANTS: Study participants were early postmenopausal (EPM; <= 6 years of final menses; n = 22) and late postmenopausal (LPM; >= 10 years since last menses; n = 24) women naive to HT. INTERVENTION: Study interventions included short-term (1 week) transdermal E2 and placebo. MAIN OUTCOMES AND MEASURES: The study's main outcome was insulin-mediated glucose disposal (glucose disposal rate [GDR]) via hyperinsulinemic-euglycemic clamp. RESULTS: Compared to EPM women, LPM women were older (mean +/- SD; 63 +/- 3 vs 56 +/- 4 years, P < .05) and more years past menopause (12 +/- 2 vs 3 +/- 2 years, P < .05). Body mass index (24 +/- 3 vs 25 +/- 7 kg/m(2)) and fat mass (25 +/- 7 vs 23 +/- 6 kg) did not differ between groups, but fat-free mass (FFM) was lower in LPM women compared to EPM women (40 +/- 4 vs 43 +/- 5 kg, P < .05). Baseline GDR did not differ between groups (11.7 +/- 2.8 vs 11.5 +/- 2.9 mg/kg FFM/min). In support of our hypothesis, 1 week of E2 decreased GDR in LPM women compared to an increase in EPM women (+0.44 +/- 1.7 vs - 0.76 +/- 2.1 mg/kg FFM/min, P < .05). CONCLUSIONS: There was not an apparent decline in GDR with age or time since menopause per se. However, E2 action on GDR was dependent on time since menopause, such that there was an apparent benefit early (<= 6 years) compared to harm later (>= 10 years) in menopause. E2-mediated effects on insulin action may be one mechanism by which HT reduces the incidence of T2D in early postmenopausal women. PMID- 26425893 TI - An Update on Hantaviruses. PMID- 26425894 TI - Molecular Characterization of Murine Monoclonal Antibody Variable Regions Specific for Hepatitis B Surface Antigen. AB - BACKGROUND: Hepatitis B virus (HBV) surface antigen (HBsAg) induces a vigorous neutralizing antibody response, which causes effective protection against HBV infection. Little is known about the profile of variable region genes of immunoglobuline heavy (VH) and light (VL) chains rearranged in anti-HBs antibodies, and also the possible association of this profile with specificity pattern of these antibodies to mutant forms of HBsAg. AIMS: The present study determined the nucleotide sequence of VH and VL genes of mouse monoclonal antibodies (MAbs) generated against HBsAg. METHODS: Hybridoma clones secreting anti-HBsAg MAbs were developed from hyperimmunized Balb/c mice. VH and VL gene sequences of all MAbs were determined by amplifying the genes using a panel of VH and VL family specific primers by reverse transcription polymerase chain reaction. The reactivity pattern of anti-HBs MAbs with different mutant forms of HBsAg was evaluated by enzyme-linked immunosorbent assay, and then the profile of antigen specificity and its association to VH/VL family expression was analyzed. RESULTS: Twenty-three murine hybridomas producing anti-HBs MAbs were generated. Nucleotide sequence analysis revealed that heavy chains of these MAbs were encoded by IGHV genes from the HV1 (52%), HV6 (22%), HV5 (17%), and HV3 (9%) families in combination with IGHJ2 (57%), HJ1 (26%), and HJ4 (17%). Besides, 56% of MAbs used IGHD1 genes in their VDJ rearrangements. Concerning the IGKV gene, 26% and 22% of clones used KV4 and KV10 gene families, while the rest of the clones used KV8, KV6, KV1, KV12, and KV14 gene families. Besides, the IGKJ2 gene was the most represented KJ gene (43%). No association was found between the specificity pattern of MAbs to mutant forms of HBsAg with their preferential V, D, and J genes usage for most of MAbs. CONCLUSION: The data suggest that heavy chains of anti-HBs MAbs preferentially use genes derived from the IGHV1, IGHV6, IGHJ2, and IGHD1 families. In contrast to heavy chains, which predominantly use four families of IGHV genes, light chains use more diverse IGKV gene families. PMID- 26425896 TI - The MCART Consortium Animal Model Series: MCART Animal Model Refinement and MCM Development: Defining organ dose, organ-specific tissue imaging, model validation and the natural history between the acute radiation syndrome (ARS) and the delayed effects of acute radiation exposure (DEARE). PMID- 26425897 TI - The Hematopoietic Syndrome of the Acute Radiation Syndrome in Rhesus Macaques: A Systematic Review of the Lethal Dose Response Relationship. AB - Well characterized animal models that mimic the human response to potentially lethal doses of radiation are required to assess the efficacy of medical countermeasures under the criteria of the U.S. Food and Drug Administration "animal rule." Development of a model requires the determination of the radiation dose response relationship and time course of mortality and morbidity across the hematopoietic acute radiation syndrome. The nonhuman primate, rhesus macaque, is a relevant animal model that may be used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality at selected lethal doses of total body irradiation. A systematic review of relevant studies that determined the dose response relationship for the hematopoietic acute radiation syndrome in the rhesus macaque relative to radiation quality, dose rate, and exposure uniformity has never been performed. The selection of data cohorts was made from the following sources: Ovid Medline (1957-present), PubMed (1954-present), AGRICOLA (1976-present), Web of Science (1954-present), and U.S. HHS REPORT (2002 to present). The following terms were used: Rhesus, total body irradiation, total body x irradiation, TBI, irradiation, gamma radiation, hematopoiesis, LD50/60, Macaca mulatta, whole-body irradiation, nonhuman primate, NHP, monkey, primates, hematopoietic radiation syndrome, mortality, and nuclear radiation. The reference lists of all studies, published and unpublished, were reviewed for additional studies. The total number of hits across all search sites was 3,001. There were a number of referenced, unpublished, non-peer reviewed government reports that were unavailable for review. Fifteen studies, 11 primary (n = 863) and four secondary (n = 153) studies [n = 1,016 total nonhuman primates (NHP), rhesus Macaca mulatta] were evaluated to provide an informative and consistent review. The dose response relationships (DRRs) were determined for uniform or non-uniform total body irradiation (TBI) with 250 kVp or 2 MeV x radiation, Co gamma radiation and reactor- and nuclear weapon-derived mixed gamma: neutron-radiation, delivered at various dose rates from a total body, bilateral, rotational, or unilateral exposure aspect. The DRRs established by a probit analysis vs. linear dose relationship were characterized by two main parameters or dependent variables: a slope and LD50/30. Respective LD50/30 values for studies that used 250 kVp x radiation (five primary studies combined, n = 338), 2 MeV x radiation, Co gamma radiation, and steady-state reactor-derived mixed gamma:neutron radiation for total body uniform exposures were 521 rad [498, 542], 671 rad [632, 715], 644 rad [613, 678], and 385 rad [357, 413]. The respective slopes were steep and ranged from 0.738 to 1.316. The DRR, LD50/30 values and slopes were also determined for total body, non-uniform, unilateral, pulse-rate exposures of mixed gamma:neutron radiation derived at reactor and nuclear weapon detonations. The LD50/30 values were, respectively, 395 rad [337, 432] and 412 rad [359, 460]. Secondary data sets of limited studies that did not describe a DRR were used to support the mid-to-high lethal dose range for the H ARS and the threshold dose range for the concurrent acute GI ARS. The available evidence provided a reliable and extensive database that characterized the DRR for the H-ARS in young rhesus macaques exposed to 250 kVp uniform total body x radiation without the benefit of medical management. A less substantial but consistent database demonstrated the DRR for total body exposure of differing radiation quality, dose rate and non-uniform exposure. The DRR for the H-ARS is characterized by steep slopes and relative LD50/30 values that reflect the radiation quality, exposure aspect, and dose rate over a range in time from 1954 2012. PMID- 26425898 TI - Mean Organ Doses Resulting From Non-Human Primate Whole Thorax Lung Irradiation Prescribed to Mid-Line Tissue. AB - Multi-organ dose evaluations and the effects of heterogeneous tissue dose calculations have been retrospectively evaluated following irradiation to the whole thorax and lung in non-human primates (NHP). A clinical-based approach was established to evaluate actual doses received in the heart and lungs during whole thorax lung irradiation. Anatomical structure and organ densities have been introduced in the calculations to show the effects of dose distribution through heterogeneous tissue. Mean organ doses received by non-human primates undergoing whole thorax lung irradiations were calculated using a treatment planning system that is routinely used in clinical radiation oncology. The doses received by non human primates irradiated following conventional dose calculations have been retrospectively reconstructed using computerized tomography-based, heterogeneity corrected dose calculations. The use of dose volume descriptors for irradiation to organs at risk and tissue exposed to radiation is introduced. Mean and partial volume doses to lung and heart are presented and contrasted. The importance of exact dose definitions is highlighted, and the relevance of precise dosimetry to establish organ-specific dose response relationships in NHP models of acute and delayed effects of acute radiation exposure is emphasized. PMID- 26425899 TI - Increased Expression of Connective Tissue Growth Factor (CTGF) in Multiple Organs After Exposure of Non-Human Primates (NHP) to Lethal Doses of Radiation. AB - Exposure to sufficiently high doses of ionizing radiation is known to cause fibrosis in many different organs and tissues. Connective tissue growth factor (CTGF/CCN2), a member of the CCN family of matricellular proteins, plays an important role in the development of fibrosis in multiple organs. The aim of the present study was to quantify the gene and protein expression of CTGF in a variety of organs from non-human primates (NHP) that were previously exposed to potentially lethal doses of radiation. Tissues from non-irradiated NHP and NHP exposed to whole thoracic lung irradiation (WTLI) or partial-body irradiation with 5% bone marrow sparing (PBI/BM5) were examined by real-time quantitative reverse transcription PCR, western blot, and immunohistochemistry. Expression of CTGF was elevated in the lung tissues of NHP exposed to WTLI relative to the lung tissues of the non-irradiated NHP. Increased expression of CTGF was also observed in multiple organs from NHP exposed to PBI/BM5 compared to non-irradiated NHP; these included the lung, kidney, spleen, thymus, and liver. These irradiated organs also exhibited histological evidence of increased collagen deposition compared to the control tissues. There was significant correlation of CTGF expression with collagen deposition in the lung and spleen of NHP exposed to PBI/BM5. Significant correlations were observed between spleen and multiple organs on CTGF expression and collagen deposition, respectively, suggesting possible crosstalk between spleen and other organs. These data suggest that CTGF levels are increased in multiple organs after radiation exposure and that inflammatory cell infiltration may contribute to the elevated levels of CTGF in multiple organs. PMID- 26425900 TI - The H-ARS Dose Response Relationship (DRR): Validation and Variables. AB - Manipulations of lethally-irradiated animals, such as for administration of pharmaceuticals, blood sampling, or other laboratory procedures, have the potential to induce stress effects that may negatively affect morbidity and mortality. To investigate this in a murine model of the hematopoietic acute radiation syndrome, 20 individual survival efficacy studies were grouped based on the severity of the administration (Admn) schedules of their medical countermeasure (MCM) into Admn 1 (no injections), Admn 2 (1-3 injections), or Admn 3 (29 injections or 6-9 oral gavages). Radiation doses ranged from LD30/30 to LD95/30. Thirty-day survival of vehicle controls in each group was used to construct radiation dose lethality response relationship (DRR) probit plots, which were compared statistically to the original DRR from which all LDXX/30 for the studies were obtained. The slope of the Admn 3 probit was found to be significantly steeper (5.190) than that of the original DRR (2.842) or Admn 2 (2.009), which were not significantly different. The LD50/30 for Admn 3 (8.43 Gy) was less than that of the original DRR (8.53 Gy, p < 0.050), whereas the LD50/30 of other groups were similar. Kaplan-Meier survival curves showed significantly worse survival of Admn 3 mice compared to the three other groups (p = 0.007). Taken together, these results show that stressful administration schedules of MCM can negatively impact survival and that dosing regimens should be considered when constructing DRR to use in survival studies. PMID- 26425901 TI - The Delayed Effects of Acute Radiation Syndrome: Evidence of Long-Term Functional Changes in the Clonogenic Cells of the Small Intestine. AB - Long term or residual damage post-irradiation has been described for many tissues. In hematopoietic stem cells (HSC), this is only revealed when the HSC are stressed and required to regenerate and repopulate a myeloablated host. Such an assay cannot be used to assess the recovery potential of previously irradiated intestinal stem cells (ISC) due to their incompatibility with transplantation. The best approximation to the HSC assay is the crypt microcolony assay, also based on clonogen survival. In the current study, the regenerative capacity of intestinal clonogenic cells in mice that had survived 13 Gy irradiation (with 5% bone marrow shielding to allow survival through the hematopoietic syndrome) and were then aged for 200 d was compared to previously unirradiated age-matched controls. Interestingly, at 200 d following 13 Gy, there remained a statistically significant reduction in crypts present in the various small intestinal regions (illustrating that the gastrointestinal epithelium had not fully recovered despite the 200-d interval). However, upon re-irradiation on day 196, those mice previously irradiated had improved crypt survival and regeneration compared to the age-matched controls. This was evident in all regions of the small intestine following 11-13 Gy re-exposure. Thus, there were either more clonogens per crypt within those previously irradiated and/or those that were present were more radioresistant (possibly because a subpopulation was more quiescent). This is contrary to the popular belief that previously irradiated animals may have an impaired/delayed regenerative response and be more radiosensitive. PMID- 26425902 TI - Lymphoid and Myeloid Recovery in Rhesus Macaques Following Total Body X Irradiation. AB - Recovery from severe immunosuppression requires hematopoietic stem cell reconstitution and effective thymopoiesis to restore a functional immune cell repertoire. Herein, a model of immune cell reconstitution consequent to potentially lethal doses of irradiation is described, which may be valuable in evaluating potential medical countermeasures. Male rhesus macaques were total body irradiated by exposure to 6.00 Gy 250 kVp x-radiation (midline tissue dose, 0.13 Gy min), resulting in an approximate LD10/60 (n = 5/59). Animals received medical management, and hematopoietic and immune cell recovery was assessed (n <= 14) through 370 d post exposure. A subset of animals (n <= 8) was examined through 700 d. Myeloid recovery was assessed by neutrophil and platelet-related parameters. Lymphoid recovery was assessed by the absolute lymphocyte count and FACS-based phenotyping of B- and T-cell subsets. Recent thymic emigrants were identified by T cell receptor excision circle quantification. Severe neutropenia, lymphopenia, and thrombocytopenia resolved within 30 d. Total CD3+ cells MUL required 60 d to reach values 60% of normal, followed by subsequent slow recovery to approximately normal by 180 d post irradiation. Recovery of CD3+4+ and CD3+8+ cell memory and naive subsets were markedly different. Memory populations were >= 100% of normal by day 60, whereas naive populations were only 57% normal at 180 d and never fully recovered to baseline post irradiation. Total (CD20+) B cells MUL were within normal levels by 77 d post exposure. This animal model elucidates the variable T- and B-cell subset recovery kinetics after a potentially lethal dose of total-body irradiation that are dependent on marrow-derived stem and progenitor cell recovery, peripheral homeostatic expansion, and thymopoiesis. PMID- 26425903 TI - The Effect of Radiation Dose and Variation in Neupogen(r) Initiation Schedule on the Mitigation of Myelosuppression during the Concomitant GI-ARS and H-ARS in a Nonhuman Primate Model of High-dose Exposure with Marrow Sparing. AB - A nonhuman primate (NHP) model of acute high-dose, partial-body irradiation with 5% bone marrow (PBI/BM5) sparing was used to assess the effect of Neupogen(r) [granulocyte colony stimulating factor (G-CSF)] to mitigate the associated myelosuppression when administered at an increasing interval between exposure and initiation of treatment. A secondary objective was to assess the effect of Neupogen(r) on the mortality or morbidity of the hematopoietic (H)- acute radiation syndrome (ARS) and concurrent acute gastrointestinal radiation syndrome (GI-ARS). NHP were exposed to 10.0 or 11.0 Gy with 6 MV LINAC-derived photons at approximately 0.80 Gy min. All NHP received medical management. NHP were dosed daily with control article (5% dextrose in water) initiated on day 1 post exposure or Neupogen(r) (10 MUg kg) initiated on day 1, day 3, or day 5 until recovery [absolute neutrophil count (ANC) >= 1,000 cells MUL for three consecutive days]. Mortality in both the 10.0 Gy and 11.0 Gy cohorts suggested that early administration of Neupogen(r) at day 1 post exposure may affect acute GI-ARS mortality, while Neupogen(r) appeared to mitigate mortality due to the H ARS. However, the study was not powered to detect statistically significant differences in survival. The ability of Neupogen(r) to stimulate granulopoiesis was assessed by evaluating key parameters for ANC recovery: the depth of nadir, duration of neutropenia (ANC < 500 cells MUL) and recovery time to ANC >= 1,000 cells MUL. Following 10.0 Gy PBI/BM5, the mean duration of neutropenia was 11.6 d in the control cohort vs. 3.5 d and 4.6 d in the day 1 and day 3 Neupogen(r) cohorts, respectively. The respective ANC nadirs were 94 cells MUL, 220 cells MUL, and 243 cells MUL for the control and day 1 and day 3 Neupogen(r) cohorts. Following 11.0 Gy PBI/BM5, the duration of neutropenia was 10.9 d in the control cohort vs. 2.8 d, 3.8 d, and 4.5 d in the day 1, day 3, and day 5 Neupogen(r) cohorts, respectively. The respective ANC nadirs for the control and day 1, day 3, and day 5 Neupogen(r) cohorts were 131 cells MUL, 292 cells MUL, 236 cells MUL, and 217 cells MUL, respectively. Therefore, the acceleration of granulopoiesis by Neupogen(r) in this model is independent of the time interval between radiation exposure and treatment initiation up to 5 d post-exposure. The PBI/BM5 model can be used to assess medical countermeasure efficacy in the context of the concurrent GI- and H-ARS. PMID- 26425904 TI - Citrulline as a Biomarker in the Non-human Primate Total- and Partial-body Irradiation Models: Correlation of Circulating Citrulline to Acute and Prolonged Gastrointestinal Injury. AB - The use of plasma citrulline as a biomarker for acute and prolonged gastrointestinal injury via exposure to total- and partial-body irradiation (6 MV LINAC-derived photons; 0.80 Gy min) in nonhuman primate models was investigated. The irradiation exposure covered gastrointestinal injuries spanning lethal, mid lethal, and sub-lethal doses. The acute gastrointestinal injury was assessed via measurement of plasma citrulline and small intestinal histopathology over the first 15 d following radiation exposure and included total-body irradiation at 13.0 Gy, 10.5 Gy, and 7.5 Gy and partial-body irradiation at 11.0 Gy with 5% bone marrow sparing. The dosing schemes of 7.5 Gy total-body irradiation and 11.0 Gy partial-body irradiation included time points out to day 60 and day 180, respectively, which allowed for correlation of plasma citrulline to prolonged gastrointestinal injury and survival. Plasma citrulline values were radiation dependent for all radiation doses under consideration, with nadir values ranging from 63-80% lower than radiation-naive NHP plasma. The nadir values were observed at day 5 to 7 post irradiation. Longitudinal plasma citrulline profiles demonstrated prolonged gastrointestinal injury resulting from acute high-dose irradiation had long lasting effects on enterocyte function. Moreover, plasma citrulline did not discriminate between total-body or partial-body irradiation over the first 15 d following irradiation and was not predictive of survival based on the radiation models considered herein. PMID- 26425905 TI - Citrulline as a Biomarker in the Murine Total-Body Irradiation Model: Correlation of Circulating and Tissue Citrulline to Small Intestine Epithelial Histopathology. AB - The use of plasma citrulline as a biomarker for gastrointestinal acute radiation syndrome via exposure to total-body irradiation in a murine model was investigated. The radiation exposure covered lethal, mid-lethal, and sub-lethal gastrointestinal acute radiation syndrome. Plasma citrulline profiles were generated over the first 6 d following total-body irradiation exposure of 6-15 Gy. In addition, plasma citrulline was comprehensively evaluated in the context of matching small intestine citrulline and histopathology. Higher plasma citrulline was significantly associated with lower irradiation doses over the first 6 d following the irradiation insult. Furthermore, higher plasma citrulline was significantly associated with higher crypt survival. The correlation of the plasma citrulline to crypt survival was more robust for higher irradiation doses and for later time points. The data suggested plasma citrulline was most informative for reflecting gastrointestinal injury resulting from exposure to 9 15 Gy total-body irradiation covering time-points 2-5 d post the irradiation insult. PMID- 26425906 TI - A MALDI-MSI Approach to the Characterization of Radiation-Induced Lung Injury and Medical Countermeasure Development. AB - Radiation-induced lung injury is highly complex and characterized by multiple pathologies, which occur over time and sporadically throughout the lung. This complexity makes biomarker investigations and medical countermeasure screenings challenging. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) has the ability to resolve differences spatially in molecular profiles within the lung following radiation exposure and can aid in biomarker identification and pharmaceutical efficacy investigations. MALDI-MSI was applied to the investigation of a whole-thorax lung irradiation model in non-human primates (NHP) for lipidomic analysis and medical countermeasure distribution. PMID- 26425907 TI - The Evolving Mcart Multimodal Imaging Core: Establishing a Protocol for Computed Tomography and Echocardiography in the Rhesus Macaque to Perform Longitudinal Analysis of Radiation-Induced Organ Injury. AB - Computed Tomography (CT) and Echocardiography (EC) are two imaging modalities that produce critical longitudinal data that can be analyzed for radiation induced organ-specific injury to the lung and heart. The Medical Countermeasures Against Radiological Threats (MCART) consortium has a well established animal model research platform that includes nonhuman primate (NHP) models of the acute radiation syndrome and the delayed effects of acute radiation exposure. These models call for a definition of the latency, incidence, severity, duration, and resolution of different organ-specific radiation-induced subsyndromes. The pulmonary subsyndromes and cardiac effects are a pair of interdependent syndromes impacted by exposure to potentially lethal doses of radiation. Establishing a connection between these will reveal important information about their interaction and progression of injury and recovery. Herein, the authors demonstrate the use of CT and EC data in the rhesus macaque models to define delayed organ injury, thereby establishing: a) consistent and reliable methodology to assess radiation-induced damage to the lung and heart; b) an extensive database in normal age-matched NHP for key primary and secondary endpoints; c) identified problematic variables in imaging techniques and proposed solutions to maintain data integrity; and d) initiated longitudinal analysis of potentially lethal radiation-induced damage to the lung and heart. PMID- 26425908 TI - Comparing the Hematopoetic Syndrome Time Course in the NHP Animal Model to Radiation Accident Cases From the Database Search. AB - Since controlled clinical studies on drug administration for the acute radiation syndrome are lacking, clinical data of human radiation accident victims as well as experimental animal models are the main sources of information. This leads to the question of how to compare and link clinical observations collected after human radiation accidents with experimental observations in non-human primate (NHP) models. Using the example of granulocyte counts in the peripheral blood following radiation exposure, approaches for adaptation between NHP and patient databases on data comparison and transformation are introduced. As a substitute for studying the effects of administration of granulocyte-colony stimulating factor (G-CSF) in human clinical trials, the method of mathematical modeling is suggested using the example of G-CSF administration to NHP after total body irradiation. PMID- 26425909 TI - An Interlaboratory Validation of the Radiation Dose Response Relationship (DRR) for H-ARS in the Rhesus Macaque. AB - The Medical Countermeasures against Radiological Threats (MCART) consortium has established a dose response relationship for the hematopoietic acute radiation syndrome (HARS) in the rhesus macaque conducted under an individualized supportive care protocol, including blood transfusions. Application of this animal model as a platform for demonstrating efficacy of candidate medical countermeasures is significantly strengthened when the model is independently validated at multiple institutions. The study reported here describes implementation of standard operating procedures at an institute outside the consortium in order to evaluate the ability to establish an equivalent radiation dose response relationship in a selected species. Validation of the animal model is a significant component for consideration of the model protocol as an FDA recommended drug development tool in the context of the "Animal Rule." In the current study, 48 male rhesus macaques (4-8 kg) were exposed to total-body irradiation (TBI) using 6 MV photon energy at a dose rate of approximately 0.8 Gy min. Results show that onset and duration of the hematological response, including anemia, neutropenia, and thrombocytopenia, following TBI ranging from 6.25 to 8.75 Gy correlate well with previously reported findings. The lethality values at 60 d following TBI were estimated to be 6.88 Gy (LD30/60), 7.43 Gy (LD50/60), and 7.98 Gy (LD70/60). These values are equivalent to those published previously of 7.06 Gy (LD30/60), 7.52 Gy (LD50/60), and 7.99 Gy (LD70/60); the DRR slope (p = 0.68) and y-intercepts show agreement along the complete dose range for HARS. The ability to replicate the previously established institutional lethality profile (PROBIT) and model outcomes through careful implementation of defined procedures is a testament to the robustness of the model and highlights the need for consistency in procedures. PMID- 26425910 TI - Delayed Effects of Acute Radiation Exposure in a Murine Model of the H-ARS: Multiple-Organ Injury Consequent to <10 Gy Total Body Irradiation. AB - The threat of radiation exposure from warfare or radiation accidents raises the need for appropriate animal models to study the acute and chronic effects of high dose rate radiation exposure. The goal of this study was to assess the late development of fibrosis in multiple organs (kidney, heart, and lung) in survivors of the C57BL/6 mouse model of the hematopoietic-acute radiation syndrome (H-ARS). Separate groups of mice for histological and functional studies were exposed to a single uniform total body dose between 8.53 and 8.72 Gy of gamma radiation from a Cs radiation source and studied 1-21 mo later. Blood urea nitrogen levels were elevated significantly in the irradiated mice at 9 and 21 mo (from ~22 to 34 +/- 3.8 and 69 +/- 6.0 mg dL, p < 0.01 vs. non-irradiated controls) and correlated with glomerosclerosis (29 +/- 1.8% vs. 64 +/- 9.7% of total glomeruli, p < 0.01 vs. non-irradiated controls). Glomerular tubularization and hypertrophy and tubular atrophy were also observed at 21 mo post-total body irradiation (TBI). An increase in interstitial, perivascular, pericardial and peribronchial fibrosis/collagen deposition was observed from ~9-21 mo post-TBI in kidney, heart, and lung of irradiated mice relative to age-matched controls. Echocardiography suggested decreased ventricular volumes with a compensatory increase in the left ventricular ejection fraction. The results indicate that significant delayed effects of acute radiation exposure occur in kidney, heart, and lung in survivors of the murine H-ARS TBI model, which mirrors pathology detected in larger species and humans at higher radiation doses focused on specific organs. PMID- 26425916 TI - Fibrinolytic system related to pulmonary arterial pressure and lung function of patients with idiopathic pulmonary fibrosis. AB - OBJECTIVES AND AIMS: To investigate urokinase-(uPA) and tissue-type (tPA) plasminogen activator and plasminogen activator inhibitor type-1 (PAI-1) levels in patients with idiopathic pulmonary fibrosis (IPF) and to determine the relationship between fibrinolytic system and pulmonary arterial pressure and pulmonary function. METHODS: Seventy-nine patients with IPF were included. Bronchoalveolar lavage fluid (BALF) and blood samples were collected. The concentrations of tPA, uPA and PAI-1 were measured using enzyme-linked immunosorbent assay. Doppler echocardiography was used to detect tricuspid regurgitation pressure gradient (TRPG) to estimate pulmonary arterial pressure. RESULTS: BALF tPA elevated (P < 0.005), circulatory PAI-1 decreased (P = 0.05) and the ratio of uPA and PAI-1 decreased (P = 0.01) in BALF in IPF patients with pulmonary hypertension (PH) compared to those without PH. Positive linear correlations were found: BALF tPA and TRPG (r = 0.558, P = 0.013); the predicted percentage of diffusion capacity of lung for carbon monoxide adjustments for alveolar volume and BALF uPA (r = 0.319, P = 0.035). Negative linear correlations were as follows: BALF PAI-1 and the predicted percentage of VCmax (r = -0.325, P = 0.020), or total lung capacity (r = -0.312, P = 0.033); circulatory PAI-1 and TRPG (r = -0.697, P = 0.003). CONCLUSIONS: The change of alveolar fibrolytic system in IPF, especially the uPA reduction and the PAI-1elevation, contributes to the deterioration of lung function. During the lung injury initiating fibrosis, tPA and PAI-1 might be leaked out of the pulmonary capillaries into alveoli, resulting in their elevation in alveoli and reduction in circulation, and finally contributing to the development of PH in IPF. PMID- 26425917 TI - Comparative study of reproductive skew and pair-bond stability using genealogies from 80 small-scale human societies. AB - OBJECTIVES: Genealogies contain information on the prevalence of different sibling types that result from past reproductive behavior. Full sibling sets stem from stable monogamy, paternal half siblings primarily indicate male reproductive skew, and maternal half siblings reflect unstable pair bonds. METHODS: Full and half sibling types are calculated for a total of 61,181 siblings from published genealogies for 80 small-scale societies, including foragers, horticulturalists, agriculturalists, and pastoralists from around the world. RESULTS: Most siblings are full (61%) followed by paternal half siblings (27%) and maternal half siblings (13%). Paternal half siblings are positively correlated with more polygynous marriages, higher at low latitudes, and slightly higher in nonforagers, Maternal half sibling fractions are slightly higher at low latitudes but do not vary with subsistence. Partible paternity societies in Amazonia have more paternal half siblings indicating higher male reproductive skew. CONCLUSIONS: Sibling counts from genealogies provide a convenient method to simultaneously investigate the reproductive skew and pair-bond stability dimensions of human mating systems cross-culturally. Am. J. Hum. Biol. 28:335 342, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26425918 TI - Chiral Inhibition of Rivaroxaban Derivatives Towards UDP-Glucuronosyltransferase (UGT) Isoforms. AB - Rivaroxaban is an oral direct factor Xa (FXa) inhibitor clinically used to prevent and treat thromboembolic disorders. Drug-drug interaction (DDI) exist for rivaroxaban and the inhibitors of CYP3A4/5. This study aims to investigate the inhibition of rivaroxaban and its derivatives with a chiral center towards UDP glucuronosyltransferases (UGTs). Chemical synthesis was performed to obtain rivaroxaban derivatives with different chiral centers. UGTs supersomes-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was employed to evaluate the inhibition potential towards various UGT isoforms. A significant influence of rivaroxaban derivatives towards UGT1A3 was observed. Chiral centers produce different effects towards the effect of four pairs of rivaroxaban derivatives towards UGT1A3 activity, with stronger inhibition potential of S1 than R1, but stronger inhibition capability of R2, R3, R4 than S2, S3, and S4. Competitive inhibition of R3 and R4 towards UGT1A3 was demonstrated by Dixon and Lineweaver Burk plots. In conclusion, the significant influence of rivaroxaban derivatives towards UGT1A3's activity was demonstrated in the present study. The chirality centers highly affected the inhibition behavior of rivaroxaban derivatives towards UGT1A3. PMID- 26425919 TI - Transcatheter aortic valve replacement for native aortic valve regurgitation as a bridge to liver transplantation. AB - Coexistence of end-stage liver disease (ESLD) and severe valvular heart disease conveyed substantial risk for patients, oftentimes leading to exclusion from liver transplantation candidacy due to inability to safely offer cardiac surgery prior to transplantation. Several approaches have been described, including performing transplantation and valve surgery concurrently, or in sequence. Both options, however, have associated complications: catastrophic repercussion of peri-operative coagulopathy and organ dysfunction post-transplantation, respectively. The introduction of transcatheter procedures offered a safer alternative for high-risk patients; however, its recognized indications remained limited. A novel approach to this surgical dilemma by performing transcatheter aortic valve replacement (TAVR) for severe native aortic valve regurgitation in a patient on the liver transplant list has been presented. The procedure proved to be an effective management for the aortic valve insufficiency, improving our patient's hemodynamics in preparation for the subsequent orthotopic liver transplantation (OLT). (c) 2015 Wiley Periodicals, Inc. PMID- 26425920 TI - Comparing two survey methods of measuring health-related indicators: Lot Quality Assurance Sampling and Demographic Health Surveys. AB - OBJECTIVES: Two common methods used to measure indicators for health programme monitoring and evaluation are the demographic and health surveys (DHS) and lot quality assurance sampling (LQAS); each one has different strengths. We report on both methods when utilised in comparable situations. METHODS: We compared 24 indicators in south-west Uganda, where data for prevalence estimations were collected independently for the two methods in 2011 (LQAS: n = 8876; DHS: n = 1200). Data were stratified (e.g. gender and age) resulting in 37 comparisons. We used a two-sample two-sided Z-test of proportions to compare both methods. RESULTS: The average difference between LQAS and DHS for 37 estimates was 0.062 (SD = 0.093; median = 0.039). The average difference among the 21 failures to reject equality of proportions was 0.010 (SD = 0.041; median = 0.009); among the 16 rejections, it was 0.130 (SD = 0.010, median = 0.118). Seven of the 16 rejections exhibited absolute differences of <0.10, which are clinically (or managerially) not significant; 5 had differences >0.10 and <0.20 (mean = 0.137, SD = 0.031) and four differences were >0.20 (mean = 0.261, SD = 0.083). CONCLUSION: There is 75.7% agreement across the two surveys. Both methods yield regional results, but only LQAS provides information at less granular levels (e.g. the district level) where managerial action is taken. The cost advantage and localisation make LQAS feasible to conduct more frequently, and provides the possibility for real-time health outcomes monitoring. PMID- 26425921 TI - The effect of a low radiation CT protocol on accuracy of CT guided implant migration measurement: A cadaver study. AB - The current study compared the impact of low radiation CT protocols on the accuracy, repeatability, and inter- and intra-observer variability of implant migration studies in total hip arthroplasty. Two total hip replacements were performed in two human cadavers and six tantalum beads were inserted into the femur similar to radiostereometric analysis. Six different 28 mm heads (-3 mm, 0 mm, 2.5 mm, 5.0 mm, 7.5 mm, and 10 mm) were added to simulate five reproducible translations (maximum total point migration) of the center of the head. Three CT scans with varying levels of radiation were performed for each head position. The effective dose (mSv) was 3.8 mSv for Protocol A (standard protocol), 0.7 mSv for Protocol B and 1.6 mSv for Protocol C. Implant migration was measured in a 3-D analysis software (Geomagic Studio 7). The accuracy was 0.16 mm for CT Protocol A, 0.13 mm for Protocol B and 0.14 mm for Protocol C; The repeatability was 0.22 mm for CT Protocol A, 0.18 mm for Protocol B and 0.20 mm for Protocol C; ICC for inter observer reliability was 0.89, intra observer reliability was 0.95. The difference in accuracy between standard protocol A and the two low radiation protocols (B, C) was less than 0.05 mm. The accuracy, inter- and intra-observer reliability of all three CT protocols is comparable to radiostereometric analysis. Reducing the CT radiation exposure to numbers similar to an AP Pelvis radiograph (0.7 mSv protocol B) does not affect the accuracy of implant migration measurements. PMID- 26425922 TI - Bioelectrical impedance vector analysis for evaluating zinc supplementation in prepubertal and healthy children. AB - BACKGROUND: The prevalence of abnormal nutritional status has increased in children and adolescents. Nutritional assessment is important for monitoring the health and nutritional status. Bioelectrical impedance vector analysis (BIVA) combines changes in tissue hydration and structure and body composition that can be assessed. OBJECTIVES: The objective of this study was to use BIVA to evaluate nutritional status in 60 prepubertal children, aged between 8 and 9 years, supplemented with zinc, to detect possible changes in body composition. DESIGN: We performed a randomized, controlled, triple-blind study. The children were divided into the control group (CG; sorbitol 10%, n=29) or the experimental group (EG; 10 mg Zn/day, n=31), and the duration of the experiment was 3 months. Anthropometric assessments were performed for all of the children. RESULTS: The body mass index-for-age increased after oral zinc supplementation in the EG (p=0.005). BIVA indicated that the CG demonstrated a tendency for dehydration and decreased soft tissue and the EG demonstrated a tendency for increased soft tissue, primarily the fat-free mass. After analyses of BIVA ellipses, we observed that this method could detect improvements in body composition in healthy children supplemented with zinc. CONCLUSIONS: These results suggest that BIVA could be an auxiliary method for studying a small population undergoing zinc intervention. PMID- 26425923 TI - Phenolic Acid-based Poly(anhydride-esters) as Antioxidant Biomaterials. AB - Poly(anhydride-esters) comprised of naturally occurring, non-toxic phenolic acids, namely syringic and vanillic acid, with antioxidant properties were prepared via solution polymerization methods. Polymer and polymer precursor physiochemical properties were characterized, including polymer molecular weight and thermal properties. In vitro release studies illustrated that polymer hydrolytic degradation was influenced by relative hydrophobicity and degree of methoxy substitution of the phenolic acids. Further, the released phenolic acids were found to maintain antioxidant potency relative to free phenolic acid controls as determined by a 2,2-diphenyl-1-picrylhydrazyl assay. Polymer cytotoxicity was assessed with L929 fibroblasts in polymer-containing media; appropriate cell morphology and high fibroblast proliferation were obtained for the polymers at the lower concentrations. These polymers deliver non-cytotoxic levels of naturally occurring antioxidants, which could be efficacious in topical delivery of antioxidant therapies. PMID- 26425924 TI - Time-Resolved Proteomic Visualization of Dendrimer Cellular Entry and Trafficking. AB - Our understanding of the complex cell entry pathways would greatly benefit from a comprehensive characterization of key proteins involved in this dynamic process. Here we devise a novel proteomic strategy named TITAN (Tracing Internalization and TrAfficking of Nanomaterials) to reveal real-time protein-dendrimer interactions using a systems biology approach. Dendrimers functionalized with photoreactive cross-linkers were internalized by HeLa cells and irradiated at set time intervals, then isolated and subjected to quantitative proteomics. In total, 809 interacting proteins cross-linked with dendrimers were determined by TITAN in a detailed temporal manner during dendrimer internalization, traceable to at least two major endocytic mechanisms, clathrin-mediated and caveolar/raft mediated endocytosis. The direct involvement of the two pathways was further established by the inhibitory effect of dynasore on dendrimer uptake and changes in temporal profiles of key proteins. PMID- 26425926 TI - High mobility, large linear magnetoresistance, and quantum transport phenomena in Bi2Te3 films grown by metallo-organic chemical vapor deposition (MOCVD). AB - We investigated the magnetotransport properties of Bi2Te3 films grown on GaAs (001) substrate by a cost-effective metallo-organic chemical vapor deposition (MOCVD). We observed the remarkably high carrier mobility and the giant linear magnetoresistance (carrier mobility ~ 22 000 cm(2) V(-1) s(-1), magnetoresistance ~ 750% at 1.8 K and 9 T for a 100 nm thick film) that depends on the film thickness. In addition, the Shubnikov-de Haas oscillation was observed, from which the effective mass was calculated to be consistent with the known value. From the thickness dependence of the Shubnikov-de Haas oscillation, it was found that a two dimensional electron gas with the conventional electron nature coexists with the topological Dirac fermion states and dominates the carrier transport in the Bi2Te3 film with thickness higher than 300 nm. These results are attributed to the intrinsic nature of Bi2Te3 in the high-mobility transport regime obtained by a deliberate choice of the substrate and the growth conditions. PMID- 26425925 TI - Dental maturation, eruption, and gingival emergence in the upper jaw of newborn primates. AB - In this report we provide data on dental eruption and tooth germ maturation at birth in a large sample constituting the broadest array of non-human primates studied to date. Over 100 perinatal primates, obtained from natural captive deaths, were screened for characteristics indicating premature birth, and were subsequently studied using a combination of histology and micro-CT. Results reveal one probable unifying characteristic of living primates: relatively advanced maturation of deciduous teeth and M1 at birth. Beyond this, there is great diversity in the status of tooth eruption and maturation (dental stage) in the newborn primate. Contrasting strategies in producing a masticatory battery are already apparent at birth in strepsirrhines and anthropoids. Results show that dental maturation and eruption schedules are potentially independently co opted as different strategies for attaining feeding independence. The most common strategy in strepsirrhines is accelerating eruption and the maturation of the permanent dentition, including replacement teeth. Anthropoids, with only few exceptions, accelerate mineralization of the deciduous teeth, while delaying development of all permanent teeth except M1. These results also show that no living primate resembles the altricial tree shrew (Tupaia) in dental development. Our preliminary observations suggest that ecological explanations, such as diet, provide an explanation for certain morphological variations at birth. These results confirm previous work on perinatal indriids indicating that these and other primates telegraph their feeding adaptations well before masticatory anatomy is functional. Quantitative analyses are required to decipher specific dietary and other influences on dental size and maturation in the newborn primate. PMID- 26425927 TI - The impact of a cancer diagnosis on health and well-being: a prospective, population-based study. AB - OBJECTIVE: Little is known about the trajectory of health and well-being from before to after a cancer diagnosis. This study aimed to examine changes in health and well-being across three time points (0-2 years before a cancer diagnosis, 0-2 years post-diagnosis and 2-4 years post-diagnosis) in individuals receiving a new cancer diagnosis, and at matched time points in a cancer-free comparison group. METHODS: Data were from waves 1-6 of the English Longitudinal Study of Ageing. Repeated-measures ANOVAs were used to examine differences in self-rated health, mobility impairments, activities of daily living impairments, quality of life, depressive symptoms and life satisfaction by group and time, and group-by-time interactions. RESULTS: Of the 4565 participants with data from three time points, 444 (9.7%) reported a new cancer diagnosis. Those in the cancer group reported poorer self-rated health (p < .001), quality of life (p < .001) and life satisfaction (p < .01) than participants in the comparison group, and a higher proportion reported depressive symptoms (p < .001) and impairments in mobility (p < .001) and activities of daily living (p < .001). All markers of health and well being worsened significantly over time. The group-by-time interaction was significant for self-rated health (p < .001), with a greater decline in health over time in the cancer group. CONCLUSIONS: Cancer survivors in this sample had poorer health and well-being than those with no diagnosis, and self-rated health deteriorated more rapidly following a cancer diagnosis. Screening for these factors around the time of a cancer diagnosis could allow for interventions to be targeted effectively and improve the health and well-being of cancer survivors. (c) 2015 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd. PMID- 26425928 TI - Referential Ambiguity in the Narrative Productions of African American Adults. AB - PURPOSE: The purpose of this study was to examine the production of referential ambiguities in two contrasting narrative conditions among age-defined groups of healthy African American women. METHOD: Twenty middle-aged adults (M = 51 years) and 20 older adults (M = 72 years) produced a complex story retelling and a personal narrative. All narratives were transcribed orthographically, parsed into T-units, and analyzed for surface structure markings of referents and the presence of ambiguities. RESULTS: The results demonstrated that older adults produced more ambiguities than middle-aged adults, were more compromised with task complexity, used more role or relation designations to refer to story characters while underusing proper names, and exhibited significant lexical retrieval deficits during ongoing narrative production. Middle-aged adults produced more proper names, but were also challenged by the complexity of the story-retelling task. Moreover, the results showed that older adults produced more African American English variants than middle-aged adults. CONCLUSION: This investigation revealed a pattern of age-related ambiguities during narrative production. The results demonstrated that lexical retrieval from long-term semantic memory was an important predictor of ambiguity, whereas African American English contributed negligibly. These results show that referential ambiguities may be a robust characteristic of cognitive-linguistic changes that occur with typical aging. PMID- 26425929 TI - The effect of training in mindfulness and affect consciousness on the therapeutic environment for patients with psychoses: an explorative intervention study. AB - RATIONALE: The ward atmosphere and the relationships between patients and staff contribute to the improvement in symptoms and psychiatric patient functioning and satisfaction. The quality of the therapeutic relationship is connected to the degree of self-reflection and self-awareness by the staff. OBJECTIVE: To examine the effect of two different training programmes for healthcare professionals on the ward atmosphere in wards for psychotic patients. DESIGN AND METHODS: Exploratory intervention study with two eight-week interventions of mindfulness training and affect-consciousness training. The outcome was measured on mindfulness and on relevant subscales of the Ward Atmosphere Scale. Data were collected by means of questionnaires and analysed using paired samples t-tests and repeated measures anova. RESULTS: Two groups professionals (n = 27 & n = 23) participated in the study. Improvements indicated that both interventions had a positive impact on the ward atmosphere. STUDY LIMITATIONS: The exploratory design and the small samples size make definitive conclusions difficult. Patient assessment on the ward atmosphere scale would have strengthened the validity of the results. CONCLUSION: The ward atmosphere in two different wards for psychotic patients improved after staff training in mindfulness or affect consciousness. There were differences in change profiles for the groups in accordance with the differences in the two interventions. PRACTICE IMPLICATIONS: We recommend awareness on the quality of the ward atmosphere in wards for psychotic patients. Both training in mindfulness and affect consciousness can support healthcare professionals in their awareness. PMID- 26425930 TI - Serotonergic or Anticholinergic Toxidrome: Case Report of a 9-Year-Old Girl. AB - OBJECTIVE: The aim of this study was to report an acute onset of symptoms erroneously attributed to serotonin syndrome in a child who had been given both anticholinergic and serotonergic agents. CASE SUMMARY: A 9-year-old girl with chronic anxiety and gastrointestinal problems was prescribed oral sertraline 6.25 mg daily, as well as hyoscyamine, ondansetron, montelukast, and a course of nitazoxanide. She was also routinely given diphenhydramine and omeprazole. Three days after increasing sertraline to 12.5 mg, she presented to the emergency department with altered mental status, hallucinations, mydriasis, tachycardia, and pyrexia. She was admitted to the pediatric intensive care unit and subsequently treated unsuccessfully for serotonin syndrome, with blurred vision and clonus persisting at discharge 4 days after admittance. Upon follow-up with her outpatient clinic, all anticholinergic agents were discontinued, and symptoms slowly resolved. CONCLUSIONS: This case illustrates the importance of differential diagnosis between toxidromes and how clinical presentation can be altered by preexisting conditions as well as the use of medications that affect multiple neurotransmitter systems. PMID- 26425931 TI - Child Abuse Mimic: Avulsion Injury in a Child With Penoscrotal Webbing. AB - Sexual abuse of children is prevalent in today's society. In 2012, approximately 686,000 children (9.2 per 1000) in the United States were determined to be victims of substantiated child abuse and neglect, according to national data compiled by child protective service agencies; victimization rates were highest for children younger than 1 year. Nearly 9.3% of maltreated children were victims of sexual abuse, this finding was reported by US Department of Health and Human Services (http://www.acf.hhs.gov/programs/cb/research-data-technology/statistics research/child-maltreatment). Previous research has shown that as many as 1 in 3 girls and 1 in 7 boys will be sexually abused during childhood (Child Abuse Negl. 2003;27:1205-1222). Although sexual abuse seems to be less common in boys than girls, this may be partly due to underdiagnosis and underreporting of sexual abuse in boys (Arch Dis Child. 2007;92:328-331). Clinicians should therefore consider the possibility of sexual abuse when boys present with genital injuries, because failing to recognize and diagnose sexual abuse can pose an ongoing safety risk to a child. However, an erroneous diagnosis of sexual abuse can have equally hazardous repercussions, including removal of a child from their caregivers or prosecution of an innocent individual. A number of medical conditions can mimic child sexual abuse injuries, including anal fissures, failure of midline fusion, perianal streptococcal dermatitis, and straddle injury (J Pediatr Health Care. 2009;23:283-288 and Acta Paediatr. 2011;100:590-593). The following case involves a 5-week-old male infant who presented to the pediatric emergency department with an avulsion injury to his penis concerning for sexual abuse. He was ultimately diagnosed with a relatively rare anatomic variant of the genitalia and determined to have sustained an accidental injury whose appearance mimicked abuse. PMID- 26425932 TI - Ultrasound-Assisted Lumbar Puncture in Pediatric Emergency Department. AB - BACKGROUND: Lumbar puncture (LP) is one of the essential diagnostic tools in pediatric emergency services. Recently, ultrasound-assisted LP was reported to be beneficial in the emergency service by facilitating the procedure and improving the successful procedure rates. In addition, this method may be effective in reducing patient and parent anxiety due to the LP procedure. OBJECTIVES: The aim of this study was to investigate the effect of ultrasound-assisted LP on the outcomes of puncture procedures and traumatic LP. METHODS: The study included patients younger than 18 years, who were admitted to the pediatric emergency service and underwent LP because of suspected central nervous system infection. The patients requiring LP were randomly divided into 2 groups designated as odd and even. One group received LP using the conventional method, whereas the other group had LP after spinal space measurement by ultrasound. The patients who did and who did not undergo ultrasound-assisted LP were compared for demographics, number of puncture attempts, and traumatic LP. Statistical analysis was performed using the Mann-Whitney U test and the Student t test. The chi test was used when nominal data were compared between the 2 groups. RESULTS: Ultrasound-assisted LP was performed in 56 patients, and LP by using conventional method was performed in 55 patients. There was traumatic LP in 5 (8.9%) of the patients who underwent ultrasound-assisted LP and 9 (16.3%) of the patients who underwent LP using the conventional method (P > 0.05). The number of puncture attempts was 2 or more in 2 (3.5%) of the patients who underwent ultrasound-assisted LP and 5 (9%) of the patients who had LP using the conventional method (P > 0.05). CONCLUSIONS: Ultrasound-assisted LP reduced traumatic LP and the number of puncture attempts in pediatric patients; however, the results were not statistically significant. PMID- 26425933 TI - An imputation-based genome-wide association study on traits related to male reproduction in a White Duroc * Erhualian F2 population. AB - Boar reproductive traits are economically important for the pig industry. Here we conducted a genome-wide association study (GWAS) for 13 reproductive traits measured on 205 F2 boars at day 300 using 60 K single nucleotide polymorphism (SNP) data imputed from a reference panel of 1200 pigs in a White Duroc * Erhualian F2 intercross population. We identified 10 significant loci for seven traits on eight pig chromosomes (SSC). Two loci surpassed the genome-wide significance level, including one for epididymal weight around 60.25 Mb on SSC7 and one for semen temperature around 43.69 Mb on SSC4. Four of the 10 significant loci that we identified were consistent with previously reported quantitative trait loci for boar reproduction traits. We highlighted several interesting candidate genes at these loci, including APN, TEP1, PARP2, SPINK1 and PDE1C. To evaluate the imputation accuracy, we further genotyped nine GWAS top SNPs using PCR restriction fragment length polymorphism or Sanger sequencing. We found an average of 91.44% of genotype concordance, 95.36% of allelic concordance and 0.85 of r(2) correlation between imputed and real genotype data. This indicates that our GWAS mapping results based on imputed SNP data are reliable, providing insights into the genetic basis of boar reproductive traits. PMID- 26425934 TI - Are Cellulose Nanofibers a Solution for a More Circular Economy of Paper Products? AB - This paper presents the study of the feasibility of incorporating lignocellulosic nanofibers (LCNF) to paper in order to maintain the relevant physical properties and increase the number of cycles that paper can be recycled in the technosphere in a more circular economy. For that purpose, the effect of mechanical refining in recycling processes was compared with that of the novel LCNF addition. In this sense, the behavior of a bleached kraft hardwood pulp when recycled was investigated, as well as the effects of each methodology. Since there are many issues to be considered when trying to replace a technology, the present paper analyses its feasibility from a technical and environmental point of view. Technically, LCNF present greater advantages against mechanical refining, such as higher mechanical properties and longer durability of the fibers. A preliminary life cycle assessment showed that the environmental impacts of both systems are very similar; however, changing the boundary conditions to some feasible future scenarios, led to demonstrate that the CNF technology may improve significantly those impacts. PMID- 26425935 TI - Oral Anticoagulation and the Risk of Stroke or Death in Patients With Atrial Fibrillation and One Additional Stroke Risk Factor: The Loire Valley Atrial Fibrillation Project. AB - BACKGROUND: It remains uncertain whether patients with atrial fibrillation (AF) and a single additional stroke risk factor (congestive heart failure, hypertension, age >= 75 years, diabetes mellitus, prior stroke or thromboembolism, vascular disease, age 65-74 years, and sex category [CHA2DS2 VASc] score = 1 in men, 2 in women) should be treated with oral anticoagulation (OAC). We investigated the risk of ischemic stroke, systemic embolism, and death in a community-based cohort of unselected patients with AF with zero to one stroke risk factor based on the CHA2DS2-VASc score. METHODS: Among 8,962 patients with AF seen between 2000 and 2010, 2,177 (24%) had zero or one additional stroke risk factor, of which 53% were prescribed OAC. RESULTS: Over a follow-up of 979 +/- 1,158 days, 151 (7%) had a major adverse event (stroke/systemic thromboembolism/death). Prescription of OAC was not associated with a better prognosis for stroke/systemic thromboembolism/death for patients in the "low risk" category (ie, CHA2DS2-VASc score = 0 for men or 1 for women; adjusted hazard ratio [HR], 0.68; 95% CI, 0.35-1.31; P = .25). OAC use was independently associated with a better prognosis in patients with AF with a single additional stroke risk factor (ie, CHA2DS2-VASc score = 1 in men, 2 in women; adjusted HR, 0.59; 95% CI, 0.40-0.86; P = .007). CONCLUSIONS: Among patients with AF with a single additional stroke risk factor (CHA2DS2-VASc score = 1 in men, 2 in women), OAC use was associated with an improved prognosis for stroke/systemic thromboembolism/death. PMID- 26425936 TI - Sensitive Detection of Deliquescent Bacterial Capsules through Nanomechanical Analysis. AB - Encapsulated bacteria usually exhibit strong resistance to a wide range of sterilization methods, and are often virulent. Early detection of encapsulation can be crucial in microbial pathology. This work demonstrates a fast and sensitive method for the detection of encapsulated bacterial cells. Nanoindentation force measurements were used to confirm the presence of deliquescent bacterial capsules surrounding bacterial cells. Force/distance approach curves contained characteristic linear-nonlinear-linear domains, indicating cocompression of the capsular layer and cell, indentation of the capsule, and compression of the cell alone. This is a sensitive method for the detection and verification of the encapsulation status of bacterial cells. Given that this method was successful in detecting the nanomechanical properties of two different layers of cell material, i.e. distinguishing between the capsule and the remainder of the cell, further development may potentially lead to the ability to analyze even thinner cellular layers, e.g. lipid bilayers. PMID- 26425938 TI - Self-organization of "fibro-axonal" composite tissue around unmodified metallic micro-electrodes can form a functioning interface with a peripheral nerve: A new direction for creating long-term neural interfaces. AB - INTRODUCTION: A long-term peripheral neural interface is an area of intense research. The use of electrode interfaces is limited by the biological response to the electrode material. METHODS: We created an electrode construct to harbor the rat sciatic nerve with interposition of autogenous adipose tissue between the nerve and the electrode. The construct was implanted for 10 weeks. RESULTS: Immunohistochemistry showed a unique laminar pattern of axonal growth layered between fibro-collagenous tissue, forming a physical interface with the tungsten micro-electrode. Action potentials transmitted across the intrerface showed mean conduction velocities varying between 6.99 +/- 2.46 and 20.14 +/- 4 m/s. CONCLUSIONS: We have demonstrated the feasibility of a novel peripheral nerve interface through modulation of normal biologic phenomena. It has potential applications as a chronic implantable neural interface. PMID- 26425939 TI - The effect of ferrous-chelating hairtail peptides on iron deficiency and intestinal flora in rats. AB - BACKGROUND: Chelating agents, such as small peptides, can decrease free iron content and increase iron bioavailability. They may have promising therapeutic potential and may prevent the pro-oxidant effects of low molecular weight iron. Hairtail is a species of fish that is rich in easily digestible proteins. We extended this strategy for iron delivery by using an enzymatic hydrolysate of hairtail as the chelating agent and found that the ferrous-chelating hairtail peptides have anti-anaemic activity in Sprague-Dawley rats with anaemia. RESULTS: The anti-anaemic activity of ferrous-chelating hairtail peptides prepared by enzymatic hydrolysis of the hairtail and ferrous chelation was studied in rat models of iron deficiency anaemia. After the end of the 35 d experiment, we noted significant differences in haemoglobin, mean corpuscular volume, haemoglobin distribution width, and ferritin concentrations between those animals supplemented with ferrous-chelating hairtail peptides and FeSO4 and healthy animals. There were no negative side effects on the animals' growth or behaviour. There was no obvious inflammation in the intestinal mucosa lamina propria and no unbalance of intestinal flora. CONCLUSION: The novel ferrous-chelating hairtail peptides may be a suitable fortificant for improving iron-deficiency status. Our findings demonstrated that this multi-tracer technique has many applications in nutritional research. (c) 2015 Society of Chemical Industry. PMID- 26425937 TI - Structures and Energetics of Four Adjacent G.U Pairs That Stabilize an RNA Helix. AB - Consecutive G.U base pairs inside RNA helices can be destabilizing, while those at the ends of helices are thermodynamically stabilizing. To determine if this paradox could be explained by differences in base stacking, we determined the high-resolution (1.32 A) crystal structure of (5'-GGUGGCUGUU-3')2 and studied three sequences with four consecutive terminal G.U pairs by NMR spectroscopy. In the crystal structure of (5'-GGUGGCUGUU-3')2, the helix is overwound but retains the overall features of A-form RNA. The penultimate base steps at each end of the helix have high base overlap and contribute to the unexpectedly favorable energetic contribution for the 5'-GU-3'/3'-UG-5' motif in this helix position. The balance of base stacking and helical twist contributes to the positional dependence of G.U pair stabilities. The energetic stabilities and similarity to A form RNA helices suggest that consecutive G.U pairs would be recognized by RNA helix binding proteins, such as Dicer and Ago. Thus, these results will aid future searches for target sites of small RNAs in gene regulation. PMID- 26425940 TI - Differences in major bacterial populations in the intestines of mature broilers after feeding virginiamycin or bacitracin methylene disalicylate. AB - AIMS: The purpose of this study was to compare the effects of feeding virginiamycin or bacitracin methylene disalicylate (BMD), two in-feed antibiotics typically used by commercial poultry producers in the United States, on the chicken gastrointestinal microbiota. METHODS AND RESULTS: 454 pyrosequencing of the V6-V8 region of the 16S rRNA gene and quantitative PCR were employed to examine the bacterial microbiota and Clostridium perfringens, respectively, in the jejunum and caecum of market-age broiler chickens over four replicate grow outs. CONCLUSIONS: Our results suggest that virginiamycin has a more pronounced impact on broiler gastrointestinal tract bacterial communities, relative to BMD, manifested primarily through significant enrichments in the genus Faecalibacterium in the caecum and a distinct population of Lactobacillus, OTU_02, in both the jejunum and caecum. No evidence for a difference among the diets in Cl. perfringens levels in the jejunum or caecum was observed. SIGNIFICANCE AND IMPACT OF THE STUDY: This work represents the highest resolution comparison to date of the jejunum and caecum microbiota in broilers fed either virginiamycin or BMD, and provides evidence for specific bacterial OTUs potentially involved in the health and performance benefits typically attributed to these in-feed antibiotics. PMID- 26425941 TI - Can Low-Cost Strategies Improve Attendance Rates in Brief Psychological Therapy? Double-Blind Randomized Controlled Trial. AB - OBJECTIVES: To assess if telephone text message appointment reminders and orientation leaflets can increase the proportion of patients who attend brief interventions after being assessed as suitable for guided self-help following cognitive behavioral therapy principles. METHOD: Attendance was operationally defined as having accessed at least 1 therapy appointment. A secondary outcome was the proportion of attenders who completed or dropped out of therapy. After initial assessment, 254 patients with depression and anxiety disorders were randomly assigned to 1 of 3 groups: (a) usual waitlist control, (b) leaflet, (c) leaflet plus text message. Differences in the proportions of patients who started and completed therapy across groups were assessed using chi-square and logistic regression analyses. RESULTS: Overall, 63% of patients in this sample attended therapy. Between-group differences were not significant for attendance, x(2) (2) = 3.94, p = .14, or completion rates, x(2) (2) = 2.98, p = .23. These results were not confounded by demographic or clinical characteristics. CONCLUSIONS: Low cost strategies appear to make no significant difference to therapy attendance and completion rates. PMID- 26425942 TI - Individual and combined effects of deoxynivalenol and alpha-zearalenol on cell proliferation and steroidogenesis of granulosa cells in cattle. AB - This study was conducted to evaluate the impact of deoxynivalenol (DON) and zearalenone (ZEA) metabolite, alpha-zearalenol (alpha-Zol), on cell proliferation and steroidogenesis of bovine large (LG) follicle granulosa cells (GC). LGGC were obtained from bovine ovarian follicles (8-22 mm) and were cultured for 2 days in medium containing 10% fetal bovine serum followed by 1 or 2 days in serum-free medium without (control) or with treatments. Three different experiments were performed using different dosages of DON and alpha-Zol and in different combinations and a fourth experiment evaluated estradiol effects on granulosa cell proliferation. DON inhibited progesterone (P4) and estradiol (E2) production at high dose. alpha-Zol alone and in combination with DON increased cell growth. Estradiol inhibited cell growth indicating alpha-Zol is not acting as an estrogen agonist. This study demonstrates that alpha-Zol and DON can impact in vitro GC function, however further studies will be required to better understand the mechanism of action and reproductive effects of Fusarium mycotoxins. PMID- 26425943 TI - Toxicological effects of silver nanoparticles. AB - Nanotechnology offers numerous biomedical applications and in so doing, exerts toxic effects. AgNPs, one of the metallic nanoparticles is known for its antibacterial applications and hence exposed to human through various healthcare products. Analysis of its toxic effects is necessary before its appliance into the biomedical field. Hence, this mini-review focuses on toxic effects of AgNPs related to human and his environment in vitro and in vivo. PMID- 26425944 TI - Frog-Leg Test Maneuver for the Diagnosis of Injuries to the Posterolateral Corner of the Knee: A Diagnostic Accuracy Study. AB - OBJECTIVE: To determine the sensitivity and specificity of a new clinical test for the diagnosis of injuries to the posterolateral corner of the knee by using magnetic resonance imaging (MRI) as the reference standard. DESIGN: Diagnostic accuracy study. SETTING: A tertiary care teaching hospital. PARTICIPANTS: Twelve subjects with chronic instability of the knee and posterolateral corner injury diagnosed by intraoperative findings and 9 subjects without posterolateral corner injury (used as controls). INTERVENTIONS: Injured and uninjured knees were assessed blindly by 2 examiners using a new clinical diagnostic test (the frog leg test) and the classic varus stress test. MAIN OUTCOME MEASURES: Injuries to the posterolateral corner of the knee identified by the 2 clinical tests. Findings were compared and examined for reproducibility, and kappa statistic was used to assess interobserver agreement. Test results were compared with those of MRI and intraoperative findings to determine diagnostic accuracy. RESULTS: The frog-leg test showed high interobserver agreement (kappa, 0.86), with a high rate (83%-100%) of agreement with the intraoperative diagnosis. The frog-leg test had high sensitivity (91.7%) and specificity (94.5%) for detecting posterolateral corner injuries. The sensitivity of the varus stress test increased from 83.3% to 90.0% when combined with the frog-leg test. CONCLUSIONS: Examiners were able to identify posterolateral corner injuries and differentiate injured from uninjured knees using the frog-leg test, which could potentially be used as an ancillary tool to the varus stress test in diagnosing injuries to the posterolateral corner of the knee. Larger studies are needed to confirm our findings. PMID- 26425954 TI - Category Index. PMID- 26425958 TI - Continuing Medical Education and Disclosures. PMID- 26425956 TI - Meeting-at-a-Glance. PMID- 26425959 TI - Poster Sessions. PMID- 26425962 TI - Organic Single-Crystal Semiconductor Films on a Millimeter Domain Scale. AB - Nucleation and growth processes can be effectively controlled in organic semiconductor films through a new concept of template-mediated molecular crystal seeds during the phase transition; the effective control of these processes ensures millimeter-scale crystal domains, as well as the performance of the resulting organic films with intrinsic hole mobility of 18 cm(2) V(-1) s(-1). PMID- 26425963 TI - Generation of Hydrogen by Visible Light-Induced Water Splitting with the Use of Semiconductors and Dyes. AB - Photosynthesis that occurs in plants involves both the oxidation of water and the reduction of carbon dioxide. Plants carry out these reactions with ease, by involving electron-transport chains. In this article, hydrogen generation by the reduction of water in the laboratory by using semiconductor nanostructures through artificial photosynthesis is examined. Dye-sensitized photochemical generation of hydrogen from water is also discussed. Hydrogen generation by these means has great technological relevance, since it is an environmentally friendly fuel. The way in which oxygen can be generated by the oxidation of water using metal oxide catalysts is also shown. PMID- 26425961 TI - Relationships Between Measures of the Ability to Perform Vision-Related Activities, Vision-Related Quality of Life, and Clinical Findings in Patients With Glaucoma. AB - IMPORTANCE: To our knowledge, few studies have combined an objective measure of vision-related performance (VRP) and subjective measures of vision-related quality of life (VRQoL) with clinically related visual parameters, particularly in a large, prospective, cohort study setting. OBJECTIVE: To examine the relationships between clinical visual assessments and both a VRP and 2 self reported VRQoL measurements. DESIGN, SETTING, AND PARTICIPANTS: Patients (N = 161) with moderate-stage glaucoma recruited from the Glaucoma Service at Wills Eye Hospital, Philadelphia, Pennsylvania, were enrolled from May 2012 to May 2014 in an ongoing prospective, 4-year longitudinal observational study. This report includes cross-sectional results from the baseline visit. Patients received a complete ocular examination, automated visual field (VF) test and Cirrus optical coherence tomographic scan. Contrast sensitivity was measured with the Pelli Robson and the Spaeth-Richman Contrast Sensitivity (SPARCS) tests. Vision-related performance was assessed by the Compressed Assessment of Ability Related to Vision (CAARV) test. Vision-related QoL was assessed by the National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ-25) and a modified Glaucoma Symptom Scale (MGSS). MAIN OUTCOMES AND MEASURES: Correlations between clinical measures and CAARV, NEI-VFQ-25, and MGSS scores. RESULTS: A total of 161 patients were enrolled in the study. The strongest correlation was found between SPARCS score in the better eye and total CAARV score (r = 0.398; 95% CI, 0.235-0.537; P < .001). The CAARV score also correlated with the Pelli-Robson score (r = 0.353; 95% CI, 0.186-0.499; P = .001), VF mean deviation (r = 0.366; 95% CI, 0.200 0.510; P < .001), and VA (r = -0.326, 95% CI = -0.476 to -0.157; P = .003) in the better eye. There were more statistically significant correlations between contrast sensitivity tests and VF mean deviation with VRQoL measurements than with other clinical measures (visual acuity, intraocular pressure, Disc Damage Likelihood Scale, and mean retinal nerve fiber layer thickness). The MGSS scores were lower (worse) in women compared with men (P = .03 for binocular, P = .01 for better eye, and P = .05 for the worse eye). Structural measures (eg, Disc Damage Likelihood Scale, and retinal nerve fiber layer thickness) were generally not informative with respect to VRP or VRQoL. CONCLUSIONS AND RELEVANCE: Contrast sensitivity tests and VF mean deviation were associated with both objective measures of the ability to act and subjective measurements of VRQoL. The strongest correlation was between SPARCS score (contrast sensitivity) in the better eye and total CAARV score. Therefore, measurement of contrast sensitivity should be considered when evaluating patients' VRQoL. The results of this study were limited by the patient population and apply only within the bounds of the tested cohort. PMID- 26425964 TI - The triplet-charge annihilation in copolymer-based organic light emitting diodes: through the "Scattering Channel" or the "Dissociation Channel"? AB - In organic semiconductors, the triplet-charge annihilation (TCA) is one of the most common excitonic interactions influencing the opto-electronic power conversion efficiency of the devices. However, it is still unclear whether the TCA reaction goes through the "Scattering Channel" or the "Dissociation Channel". In this work, by measuring the organic magneto-current (OMC) of the conjugated co polymer poly[{9,9-dioctyl-2,7-divinylene-fluorenylene}-alt-co-{2-methoxy-5-(2 ethylhexyloxy)-1,4-phenyene}] (PFOPV)-based organic light-emitting diodes (OLEDs) containing both localized exciton (LE) and charge-transfer-complex (CT), it is found that (3)LE and (3)CT play a crucial role in the "Scattering Channel" and the "Dissociation Channel" of TCA, respectively. This argument was supported by the simulations of Lorentzian and non-Lorentzian functions used, respectively, for intersystem crossing (or reverse intersystem crossing, RISC) and TCA effects. Moreover, by inserting a tris(2,4,6-trimethyl-3-(pyridin-3-yl)phenyl)borane (3TPYMB) layer between PFOPV and the cathode, we improved the electroluminescence efficiency of PFOPV-based OLEDs by suppressing the TCA when (3)CT involves in RISC. Our results give insights into the spin-dependent TCA limiting the efficiency of hotly discussed CT-based OLEDs. PMID- 26425966 TI - Classical Amphiphilic Behavior of Nonclassical Amphiphiles: A Comparison of Metallacarborane Self-Assembly with SDS Micellization. AB - The self-assembly of metallacarboranes, a peculiar family of compounds exhibiting surface activity and resembling molecular-scale Pickering stabilizers, has been investigated by comparison to the micellization of sodium dodecylsulfate (SDS). These studies have shown that molecules without classical amphiphilic topology but with an inherent amphiphilic nature can behave similarly to classical surfactants. As shown by NMR techniques, the self-assembly of both metallacarboranes and SDS obey a closed association model. However, the aggregation of metallacarboranes is found to be enthalpy-driven, which is very unusual for classical surfactants. Possible explanations of this fact are outlined. PMID- 26425965 TI - Simulation of biological therapies for degenerated intervertebral discs. AB - The efficacy of biological therapies on intervertebral disc repair was quantitatively studied using a three-dimensional finite element model based on a cell-activity coupled multiphasic mixture theory. In this model, cell metabolism and matrix synthesis and degradation were considered. Three types of biological therapies-increasing the cell density (Case I), increasing the glycosaminoglycan (GAG) synthesis rate (Case II), and decreasing the GAG degradation rate (Case III)-to the nucleus pulposus (NP) of each of two degenerated discs [one mildly degenerated (e.g., 80% viable cells in the NP) and one severely degenerated (e.g., 30% viable cells in the NP)] were simulated. Degenerated discs without treatment were also simulated as a control. The cell number needed, nutrition level demanded, time required for the repair, and the long-term outcomes of these therapies were analyzed. For Case I, the repair process was predicted to be dependent on the cell density implanted and the nutrition level at disc boundaries. With sufficient nutrition supply, this method was predicted to be effective for treating both mildly and severely degenerated discs. For Case II, the therapy was predicted to be effective for repairing the mildly degenerated disc, but not for the severely degenerated disc. Similar results were predicted for Case III. No change in cell density for Cases II and III were predicted under normal nutrition level. This study provides a quantitative guide for choosing proper strategies of biological therapies for different degenerated discs. PMID- 26425968 TI - Disruptive Innovation: Latest Buzzword or New Reality? AB - This is an inaugural department column focusing on disruptive healthcare innovations and the implications for nurse leaders and nursing practice. PMID- 26425967 TI - Certification as a Quality Initiative. AB - The vice president of the Certification and Measurement Services for the American Nurses Credentialing Center presents this month's column focused on the value of certification for both the patient and the organization. PMID- 26425969 TI - Creating Supportive Environments and Thriving in a Volatile, Uncertain, Complex, and Ambiguous World. AB - Nurse executives (NEs) are operating in a volatile, uncertain, complex, and ambiguous world. NEs must create supportive environments that promote staff empowerment, resilience, and alignment, to ensure organizational success. In addition, NEs need to be transparent and create a culture of partnership with their staff. The ability of NEs to create and sustain this environment is vital in supporting teams to successfully navigate in today's healthcare environment. PMID- 26425970 TI - Findings From the 2015 National Forum of State Nursing Workforce Centers Annual Meeting. AB - Estimating the future nursing workforce needs is critical to all aspects of nursing care. Currently, the healthcare system is undergoing chaotic change, and predicting the workforce needs over the next 10 years has been challenging. The efforts of Dr Peter Buerhaus and his associates in addressing nursing workforce issues over the last 25 years are a hallmark. Dr Buerhaus joined forces with the state nursing workforce centers to discuss new approaches to this critical issue. PMID- 26425971 TI - US Nurses' Perceptions Regarding Caring for Suspected, Probable, and Confirmed Ebola Virus Disease Patients, Part 1: A Quantitative Analysis. AB - OBJECTIVE: This study examined US hospital, ambulatory/outpatient facility, and clinic nurses' perceptions regarding care of persons under investigation (PUIs) and confirmed Ebola virus disease (EVD) patients and EVD nursing workforce impact. BACKGROUND: Timely research was warranted to better understand nurses' perceptions. METHODS: This survey research used convenience sampling of RNs, LPNs, and nurse technicians. Respondents completed a 45-item electronic validated survey. RESULTS: Overall average perceived risk with providing care was higher for confirmed EVD patients (5.2) than PUIs (4.8) (0 = no risk, 10 = highest risk). Few had cared for confirmed EVD patients (0.3%) or PUIs (0.7%). Whereas 48.4% felt prepared in protecting themselves from contracting EVD, 25.2% were concerned with contracting EVD. More nurses (45.9%) felt they should be able to opt out of caring for confirmed EVD patients as compared with those caring for PUIs (39.2%). EVD emergence had not affected (85.8%) nurses' willingness to provide direct patient care; however, 6.8% reported EVD has decreased years planned in the nursing workforce. CONCLUSIONS: Nurses reported moderate risk for EVD-related patient care; 6.8% may leave the workforce earlier. PMID- 26425972 TI - Models of Discharge Care in Magnet(r) Hospitals. AB - OBJECTIVE: The aim of this article is to describe how the discharge preparation process is operationalized in Magnet(r) hospitals. BACKGROUND: Nationally, there are intensive efforts toward improving discharge transitions and reducing readmissions. Discharge preparation is a core hospital function, yet there are few reports of operational models. METHODS: This was a descriptive, Web-based survey of 32 Magnet hospitals (64 units) participating in the Readiness Evaluation and Discharge Interventions study. RESULTS: Most hospitals have adopted 1 or more national readmission reduction initiatives. Most unit models include several discharge preparation roles; RN case managers, and discharging RNs lead the process. Nearly one-half of units actively screen for readmission risk. More than three-fourths report daily discharge rounds, but less than one third include the patient and family. More than two-thirds report a follow-up phone call, mostly to assess patient satisfaction. CONCLUSIONS: Magnet hospitals operationalize discharge preparation differently. Recommended practices from national discharge initiatives are inconsistently used. RNs play a central role in discharge planning, coordination, and teaching. PMID- 26425973 TI - A Phenomenological Study of Nurse Manager Interventions Related to Workplace Bullying. AB - OBJECTIVE: The aim of this study was to acquire nurse managers' perspectives as to the scope of workplace bullying, which interventions were deemed as effective and ineffective, and what environmental characteristics cultivated a healthy, caring work environment. BACKGROUND: Research has linked workplace bullying among RNs to medical errors, unsafe hospital environments, and negative patient outcomes. Limited research had been conducted with nurse managers to discern their perspectives. METHODS: Six nurse managers from hospital settings participated in in-depth, semistructured interviews. Ray's theory of bureaucratic caring guided the study. RESULTS: These themes emerged: (a) awareness, (b) scope of the problem, (c) quality of performance, and (d) healthy, caring environment. Findings indicated mandated antibullying programs were not as effective as individual manager interventions. CONCLUSIONS: Systems must be in place to hold individuals accountable for their behavior. Communication, collective support, and teamwork are essential to create environments that lead to the delivery of safe, optimum patient care. PMID- 26425974 TI - Major Predictors of Inpatient Falls: A Multisite Study. AB - OBJECTIVE: The purpose of this secondary data analysis was to identify key factors predictive of falls in hospitals. BACKGROUND: Patient falls remain a major concern for hospitals. Falls can increase patient morbidity/mortality and increase legal risk/cost for institutions. While a number of high-risk falls assessments are available, key predictors of falls have not been identified. METHODS: A secondary data analysis was performed on 281,865 high-risk falls assessments collected in a multisite study. RESULTS: For the total sample, logistic regression analyses demonstrated that 3 factors, falls within the past 6 months (OR=2.98), confusion (odds ratio, 2.05), taking a laxative (odds ratio, 1.54), are strong predictors of falling. Similar results were found for individual hospitals, different units within hospitals, and urban versus rural hospital locations. CONCLUSION: Findings suggest that assessments of fall risk should heavily weigh the 3 predictors identified in this study. Another approach would be to intervene based on these predictors. PMID- 26425975 TI - Interactive Care Model: A Framework for More Fully Engaging People in Their Healthcare. AB - Transformation of care delivery requires rethinking the relationship between the person and clinician. The model described provides a process to more fully engage patients in their care. Five encounters include assessing capacity for engagement, exchanging information and choices, planning, determining interventions, and evaluating the effectiveness of engagement interventions. Created by researchers and validated by experts, implications for practice, education, and policy are explored. PMID- 26425976 TI - Simulation-Based Mastery Learning Improves Central Line Maintenance Skills of ICU Nurses. AB - OBJECTIVE: This study evaluated the impact of a simulation-based mastery learning (SBML) curriculum on central line maintenance and care among a group of ICU nurses. METHODS: The intervention included 5 tasks: (a) medication administration, (b) injection cap (needleless connector) changes, (c) tubing changes, (d) blood drawing, and (e) dressing changes. All participants underwent a pretest, engaged in deliberate practice with directed feedback, and completed a posttest. We compared pretest and posttest scores and assessed correlations between demographics, self-confidence, and pretest performance. RESULTS: The number of nurses passing each task at pretest varied from 24 of 49 (49%) for dressing changes to 44 of 49 (90%) for tubing changes. At pretest, scores ranged from a median of 0.0% to 73.1%. At posttest, all scores rose to a median of 100.0%. Total years in nursing and ICU nursing had significant, negative correlations with medication administration pretest performance (r = -0.42, P = .003; r = -0.42, P = .003, respectively). CONCLUSION: ICU nurses displayed large variability in their ability to perform central line maintenance tasks. After SBML, there was significant improvement, and all nurses reached a predetermined level of competency. PMID- 26425977 TI - Design and Outcome of a Certification Preparation Program for Outpatient Nurses. AB - This article presents the design, implementation, and outcomes of a certification preparation program for nurses working in an outpatient clinic. A nurse educator designed curriculum using the Certified Breast Care Nurse test blueprint. Nurse administrators provided the resources and the staff coverage to allow all staff members to attend the sessions without disruption to patient care. This outpatient center has achieved and sustained 100% certification among eligible nurses over the past 5 years. PMID- 26425978 TI - Stability and toxicity of tris-tolyl bismuth(V) dicarboxylates and their biological activity towards Leishmania major. AB - A series of 29 tris-tolyl bismuth(v) di-carboxylato complexes of composition [Bi(Tol)3(O2CR)2] involving either ortho, meta or para substituted tolyl ligands have been synthesized and characterised. Of these 15 were assessed for their toxicity towards Leishmania promastigotes and human fibroblast cells, with ten then being subsequently assessed against parasite amastigotes. The carboxylate ligands are drawn from a series of substituted and biologically relevant benzoic acids which allow a comparison with earlier studies on [BiPh3(O2CR)2] and analogous Sb(v) [SbAr3(O2CR)2] (Ar = Ph and Tol) complexes. Twelve complexes have been structurally characterized by single crystal X-ray diffraction and shown to adopt a typical trigonal bipyramidal geometry in which the three tolyl ligands occupy the equatorial plane. NMR studies on two illustrative examples indicate that the complexes are stable in D2O and DMSO but only have a half-life of 1.2 hours in culture medium, with glucose being a contributing factor in decomposition and reduction to Bi(Tol)3. Despite their short lifetime many complexes show significant toxicity towards promastigotes at low concentration (<6 MUM) and at that concentration provide for good selectivity indices (parasite vs. mammalian cells), for example 114 for [Bi(o-Tol)3(O2CC6H3(2-OH,5-C6H3(2,4 F2)))2] and 838 for [Bi(m-Tol)3(O2CC6H4(2-OAc))2]. Best activity and selectivity is observed with complexes containing o- and m-tolyl ligands, and it appears the primary influence on fibroblast toxicity is the Ar ligand while the carboxylate influences promastigote toxicity. The complexes are less effective in vitro against the parasite amastigotes, where longer incubation times and harsher chemical and biological environments are encountered in the assay. Nevertheless, there were some statistically relevant differences at 1 MUM against the positive controls with the best performing complexes being [Bi(o-Tol)3(O2CC6H4(2-EtO))2] and [Bi(m-Tol)3(O2CC6H4(2-OAc))2]. PMID- 26425979 TI - The effect of pressure on cation-cellulose interactions in cellulose/ionic liquid mixtures. AB - Cation-cellulose interactions in binary mixtures of [EMIM][OAc] and cellulose have been investigated using high-pressure infrared spectroscopy. At low concentrations of cellulose, almost no changes were observed in the imidazolium C(2)-H frequency; on the other hand, at high concentrations of cellulose, increases in the C(2)-H vibration frequency were observed under ambient pressure. As the pressure was elevated, the imidazolium C(2)-H absorption of the [EMIM][OAc]/cellulose mixtures underwent band-narrowing and blue-shifts in the frequency. These observations suggest that high pressures may strengthen the hydrogen bonds formed between C(2)-H and cellulose, possibly forcing the cellulose to dissociate clusters of ionic liquid through enhanced cation cellulose interactions. In contrast to the cation-cellulose interaction results, the COO(-) absorption of the anion does not show dramatic changes under high pressures. Our results indicate the possibility of enhanced cation-cellulose interactions through pressure elevation, demonstrating that high pressures may have the potential to tune the relative contributions of cation-cellulose and anion-cellulose interactions in cellulose/ionic liquid mixtures. PMID- 26425980 TI - ORS Interview with Warren Snell. PMID- 26425981 TI - Proposal for a Simple and Efficient Monthly Quality Management Program Assessing the Consistency of Robotic Image-Guided Small Animal Radiation Systems. AB - Modern pre-clinical radiation therapy (RT) research requires high precision and accurate dosimetry to facilitate the translation of research findings into clinical practice. Several systems are available that provide precise delivery and on-board imaging capabilities, highlighting the need for a quality management program (QMP) to ensure consistent and accurate radiation dose delivery. An ongoing, simple, and efficient QMP for image-guided robotic small animal irradiators used in pre-clinical RT research is described. Protocols were developed and implemented to assess the dose output constancy (based on the AAPM TG-61 protocol), cone-beam computed tomography (CBCT) image quality and object representation accuracy (using a custom-designed imaging phantom), CBCT-guided target localization accuracy and consistency of the CBCT-based dose calculation. To facilitate an efficient read-out and limit the user dependence of the QMP data analysis, a semi-automatic image analysis and data representation program was developed using the technical computing software MATLAB. The results of the first 6-mo experience using the suggested QMP for a Small Animal Radiation Research Platform (SARRP) are presented, with data collected on a bi-monthly basis. The dosimetric output constancy was established to be within +/-1 %, the consistency of the image resolution was within +/-0.2 mm, the accuracy of CBCT-guided target localization was within +/-0.5 mm, and dose calculation consistency was within +/ 2 s (+/-3%) per treatment beam. Based on these results, this simple quality assurance program allows for the detection of inconsistencies in dosimetric or imaging parameters that are beyond the acceptable variability for a reliable and accurate pre-clinical RT system, on a monthly or bi-monthly basis. PMID- 26425982 TI - Technical Assessment of Internal Surface Smoothness and Particle Transmission to the American National Standard ANSI/HPS N13.1-2011. AB - Clause 6.4.4 in the American National Standard ANSI/HPS N13.1 standard "Sampling and Monitoring Releases of Airborne Radioactive Substances From the Stacks and Ducts of Nuclear Facilities" addresses the internal smoothness of sample transport lines present between the nozzle and the analyzer (or collector). The appropriateness of this clause is evaluated by comparing roughness length of various materials against the required relative roughness and by conducting computational fluid dynamic modeling. The results indicate that the inclusion of numerical criteria for the relative roughness of pipe by the ANSI/HPS N13.1-2011 (clause 6.4.4) is not appropriate. Recommended alternatives would be elimination of the numerical criteria or modification of the standard to include a variable criterion for relative roughness. PMID- 26425983 TI - Attenuation of X and Gamma Rays in Personal Radiation Shielding Protective Clothing. AB - A collection of personal radiation shielding protective clothing, suitable for use in case of accidents in nuclear facilities or radiological emergency situations involving radioactive agents, was gathered and tested at the Nuclear Protection Department of the National Institute for Nuclear, Chemical and Biological Protection, Czech Republic. Attenuating qualities of shielding layers in individual protective clothing were tested via spectra measurement of x and gamma rays, penetrating them. The rays originated from different radionuclide point sources, the gamma ray energies of which cover a broad energy range. The spectra were measured by handheld spectrometers, both scintillation and High Purity Germanium. Different narrow beam geometries were adjusted using a special testing bench and a set of various collimators. The main experimentally determined quantity for individual samples of personal radiation shielding protective clothing was x and gamma rays attenuation for significant energies of the spectra. The attenuation was assessed comparing net peak areas (after background subtraction) in spectra, where a tested sample was placed between the source and the detector, and corresponding net peak areas in spectra, measured without the sample. Mass attenuation coefficients, which describe attenuating qualities of shielding layers materials in individual samples, together with corresponding lead equivalents, were determined as well. Experimentally assessed mass attenuation coefficients of the samples were compared to the referred ones for individual heavy metals. PMID- 26425984 TI - Lessons Learned on the Presentation of Scan Data. AB - Technicians performed a radiological survey of a surplus metal tank to support disposition planning at an Oak Ridge, TN, site. The survey included radiation scans to identify contamination and, if identified, define the boundary and magnitude of contamination. Fixed-point 1-min measurements were also collected at randomly selected locations for comparison against the site's free release limit of 5,000 disintegrations per minute per 100 cm (dpm 100 cm) (0.83 Bq cm). Scan data were recorded using a data logger as a means to document surveyor observation-logged data captured at 1-s intervals and converted to counts per minute (cpm) by the data logger software were presented in the project report. Both the qualitative scan data (in cpm) and the quantitative direct measurements (in dpm 100 cm) were reported for completeness, so stakeholders had all available information to support disposition decisions. However, a new stakeholder introduced to the project at the reporting phase of work-used the instrument efficiency and background data to convert the scan data from cpm to dpm 100 cm, then compared the converted results to the site limit. Many of the converted values exceeded 5,000 dpm 100 cm. This resulted in delays in tank disposition and additional project costs that could have been avoided if the proper use and interpretation of scan data and implications of radon progeny buildup on oxidized metal surfaces had been better communicated. PMID- 26425985 TI - Occupational Exposure to Veterinary Workers from the Positron Emission Tomography Imaging Agent 64Cu-ATSM. AB - Cu-ATSM is an emerging radiopharmaceutical for diagnostic use in positron emission tomography (PET), but to date there are no studies that assess the potential occupational doses to workers in either human or veterinary medicine. This study was aimed at determining the external radiation dose to veterinary workers from clinical PET/CT (PET combined with computed tomography) procedures using Cu-ATSM. To determine the dose to the workers, each worker was assigned two Electronic Personal Dosimeters (EPDs) to be worn on the chest and waist during the entirety of each procedure. The workers monitored during this study included a radiobiologist, a nuclear medicine technologist, an anesthesiologist, and a veterinary surgeon. Seven canine patients were imaged with an average mass of 33.7 kg (a range of 20.0-55.1 kg) with an average injected activity of 5 MBq kg. The dose range for the radiobiologist was 2-17 MUSv (mean of 7.1 MUSv), for the nuclear medicine technologist 0-14 MUSv (mean of 5.6 MUSv), for the anesthesiologist 0-12 MUSv (mean of 4.0 MUSv), and for the surgeon 0-10 MUSv (mean of 3.6 MUSv). In a comparison between the results of this study and published literature on occupational exposures from veterinary FDG PET/CT procedures, Cu-ATSM veterinary PET/CT procedures, on a per patient bias, exposed workers to less radiation. PMID- 26425990 TI - Mitochondrial capture enriches mito-DNA 100 fold, enabling PCR-free mitogenomics biodiversity analysis. AB - Biodiversity analyses based on next-generation sequencing (NGS) platforms have developed by leaps and bounds in recent years. A PCR-free strategy, which can alleviate taxonomic bias, was considered as a promising approach to delivering reliable species compositions of targeted environments. The major impediment of such a method is the lack of appropriate mitochondrial DNA enrichment ways. Because mitochondrial genomes (mitogenomes) make up only a small proportion of total DNA, PCR-free methods will inevitably result in a huge excess of data (>99%). Furthermore, the massive volume of sequence data is highly demanding on computing resources. Here, we present a mitogenome enrichment pipeline via a gene capture chip that was designed by virtue of the mitogenome sequences of the 1000 Insect Transcriptome Evolution project (1KITE, www.1kite.org). A mock sample containing 49 species was used to evaluate the efficiency of the mitogenome capture method. We demonstrate that the proportion of mitochondrial DNA can be increased by approximately 100-fold (from the original 0.47% to 42.52%). Variation in phylogenetic distances of target taxa to the probe set could in principle result in bias in abundance. However, the frequencies of input taxa were largely maintained after capture (R(2) = 0.81). We suggest that our mitogenome capture approach coupled with PCR-free shotgun sequencing could provide ecological researchers an efficient NGS method to deliver reliable biodiversity assessment. PMID- 26425991 TI - Active biomonitoring with Corbicula for USEPA priority pollutant and metal sources in the Anacostia River (DC, Maryland, USA). AB - The freshwater Anacostia River watershed (Maryland, DC, USA) was surveyed for the sources of bioavailable US Environmental Protection Agency (USEPA) Priority Pollutants and toxic metals by active biomontoring (ABM) using the freshwater Asiatic clam Corbicula fluminea. The Anacostia River is a 456 km(2) tributary of the tidal freshwater Potomac River that includes the city of Washington, DC where edible fish are highly contaminated with PCBs and chlordane. From 1999 to 2011, Corbicula were collected for ABM from a Potomac reference site and translocated in cages placed at 45 sites in the tidal and nontidal Anacostia watershed. Minimum clam mortality and maximum contaminant bioaccumulation was with 2-week translocation. The clam tissues (28-50) were combined at sites and analyzed by TestAmerica for 66 USEPA Priority Pollutants plus technical chlordane, benz(e) pyrene, and 6 metals (As, Cd, Cr, Cu, Fe, Pb). Tissue contaminants reflected water, not sediment, levels. To compare sites, all contaminant data above detection or reference were grouped as total metals (TMET), total polycyclic aromatic hydrocarbons (TPAH), total PCB congeners (TPCB), total pesticides (TPEST), and total technical chlordane (TCHL). Tidal Anacostia ABM found highest TPAH and TCHL upstream at Bladensburg Marina (MD) except for TCHL at site PP near the confluence. Five nontidal MD subtributaries (94% of flow) had 17 sites with bioavailable TPAH, TPCB, or TCHL 2 to 3 times higher than found at the toxic sediment "hotspots" near Washington. The only TMET noted was Fe at 1 site. TPAH in MD subtributaries was highest near industrial parks and Metro stations. A naphthalene spill was detected in Watts Branch. TPCB (low molecular weight) originated upstream at 1 industrial park. Total technical chlordane (80% of TPEST) was 2 to 5 times the US Food and Drug Administration action in 4 nontidal tributaries where heptachlor indicated legacy chlordane dumpsites. Total technical chlordane fell to reference below a stormwater pond, suggesting transport via suspended sediment. Controlling the formation and movement of contaminated TSS in MD should enable the uncontaminated-sediment capping of Washington DC's toxic-sediment "hot-spots" that are presently considered responsible for fish contamination. Integr Environ Assess Manag 2016;12:548-558. (c) 2015 SETAC. PMID- 26425992 TI - The relationship between women's attitude towards menopause and menopausal symptoms among postmenopausal women. AB - OBJECTIVES: The purpose of this study is to assess the symptoms of menopausal women as well as the relationship between women's attitude towards menopause and menopausal symptoms. METHOD: This studied, following a cross-sectional method, included 349 selected postmenopausal women attending health care centers. The data was collected using the attitude toward menopause (ATM) checklist and Menopause-Specific Quality of Life (MENQOL) questionnaires. RESULTS: The most common menopausal symptoms were physical with joint and muscle pain. The highest mean score belongs to vasomotor symptoms (1.37 +/- 1.43), followed by psychosocial (1.32 +/- 1.16), physical (1.22 +/- 0.96), and sexual (0.91 +/- 0.94) symptoms. Attitude toward menopause was significantly influenced by sweat nights, poor memory, and sleeplessness. The marital status and educational level of the husband were the only demographic factors affecting the severity of menopausal symptoms. CONCLUSION: This study provides deeper insights about the relationship between attitudes towards menopause and menopausal symptoms, which can guide health-care professionals towards providing an optimal package. PMID- 26425993 TI - Statistical modeling of nitrogen-dependent modulation of root system architecture in Arabidopsis thaliana. AB - Plant root development is strongly affected by nutrient availability. Despite the importance of structure and function of roots in nutrient acquisition, statistical modeling approaches to evaluate dynamic and temporal modulations of root system architecture in response to nutrient availability have remained as widely open and exploratory areas in root biology. In this study, we developed a statistical modeling approach to investigate modulations of root system architecture in response to nitrogen availability. Mathematical models were designed for quantitative assessment of root growth and root branching phenotypes and their dynamic relationships based on hierarchical configuration of primary and lateral roots formulating the fishbone-shaped root system architecture in Arabidopsis thaliana. Time-series datasets reporting dynamic changes in root developmental traits on different nitrate or ammonium concentrations were generated for statistical analyses. Regression analyses unraveled key parameters associated with: (i) inhibition of primary root growth under nitrogen limitation or on ammonium; (ii) rapid progression of lateral root emergence in response to ammonium; and (iii) inhibition of lateral root elongation in the presence of excess nitrate or ammonium. This study provides a statistical framework for interpreting dynamic modulation of root system architecture, supported by meta analysis of datasets displaying morphological responses of roots to diverse nitrogen supplies. PMID- 26425996 TI - Plasticity in oscillatory coupling between hippocampus and cortex. AB - Neural oscillations observed in local field potentials (LFP) represent gross cellular activity near the recording electrode. Coupling of oscillations in distributed brain circuits has been proposed to enhance communication across the circuits, and the plasticity in oscillatory coupling can underlie flexible task learning, but the direct evidence has been lacking. Recently, evidence for plasticity in oscillatory coupling in theta, beta and gamma bands has been obtained in memory circuits consisted of the hippocampus and its connected areas, suggesting importance of oscillatory coupling plasticity in memory processing. I hypothesize that such plasticity in oscillatory coupling could be a key mechanism for enhancing inter-regional neural communication, especially in the entorhinal hippocampal and prefrontal-hippocampal memory circuits that underlie formation, control and retrieval of memory. PMID- 26425994 TI - HDL cholesterol and stroke risk: The Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND AND PURPOSE: Accurate identification of risk factors for stroke is important for public health promotion and disease prevention. HDL cholesterol is a potential risk factor, yet its role in stroke risk is unclear, as is whether HDL cholesterol content or particle number might be a better indicator of stroke risk. Furthermore, the degree to which ethnicity moderates the risk is unknown. As such, the current study examines the associations between incident stroke and both HDL cholesterol concentration and particle number, and assesses the moderating role of race and ethnicity. METHODS: The sample is a racially diverse cohort of US adults between the ages of 45-84 years enrolled in the Multi-Ethnic Study of Atherosclerosis between 2000 and 2002 and followed until December 2011. The associations among cholesterol content and stroke risk, particle number and stroke risk, and the interaction with race were explored. RESULTS: The incidence of stroke was 2.6%. HDL cholesterol concentration (mmol/L) (Hazard Ratio (HR) = .56; 95% Confidence Interval (CI): .312-.988) and number of large HDL particles (MUmol/L) (HR = .52, CI: .278-.956) were associated with lower stroke risk. When interactions with race were evaluated, the relationship between both HDL variables and stroke were significant in Blacks, but not other races. CONCLUSIONS: Higher HDL cholesterol and a higher concentration of large particles are associated with lower risk of stroke in Blacks. Further research is needed to elucidate the mechanisms by which HDL subfractions may differentially affect stroke outcome in different races/ethnicities. PMID- 26425998 TI - Hydroxymethyl Salicylaldehyde Auxiliary for a Glycine-Dependent Amide-Forming Ligation. AB - A new amide-forming ligation that requires a glycine or a primary amine at the linkage site is described herein. The distinguishing feature of this ligation is its reliance on an O-hydroxymethyl salicylaldehyde ester at the C-terminus which allows, via an N,O-acetal intermediate, the formation of a native peptide bond. PMID- 26425997 TI - Mainstream wastewater treatment in integrated fixed film activated sludge (IFAS) reactor by partial nitritation/anammox process. AB - In this study the system based on the combination of biofilm and activated sludge (IFAS - integrated fixed film activated sludge) was tested and compared with a system that relies only on biofilm (MBBR - moving bed biofilm reactor) for nitrogen removal from municipal wastewater by deammonification process. By introduction of suspended biomass into MBBR the nitrogen removal efficiency increased from 36 +/- 3% to 70 +/- 4% with simultaneous 3-fold increase of nitrogen removal rate. Results of batch tests and continuous reactor operation showed that organotrophic nitrate reduction to nitrite, followed by anammox reaction contributed to this high removal efficiency. After sCOD/NH4-N ratio decreased from 1.8 +/- 0.2 to 1.3 +/- 0.1 removal efficiency decreased to 52 +/- 4%, while still maintaining 150% higher removal rate, comparing to MBBR. Activity tests revealed that affinity of NOB to oxygen is higher than affinity of AOB with half-saturation constants of 0.05 and 0.41 mg/L, respectively. PMID- 26425999 TI - Bioassay-Guided Isolation and Identification of Xanthine Oxidase Inhibitory Constituents from the Leaves of Perilla frutescens. AB - Activity-directed fractionation and purification processes were employed to identify xanthine oxidase (XO) inhibitory compounds from the leaves of Perilla frutescens. The total extract was evaluated in vitro on XO inhibitory activity and in vivo in an experimental model with potassium oxonate-induced hyperuricemia in mice which was used to evaluate anti-hyperuricemic activity. The crude extract showed expressive urate-lowering activity results. Solvent partitioning of the total extract followed by macroporous resin column chromatography of the n butanol extract yielded four extracts and eluted parts. Among them, only the 70% ethanol eluted part of the n-butanol extract showed strong activity and therefore was subjected to separation and purification using various chromatographic techniques. Five compounds showing potent activity were identified by comparing their spectral data with literature values to be caffeic acid, vinyl caffeate, rosmarinic acid, methyl rosmarinate, and apigenin. These results indicate that pending further study, these compounds could be used as novel natural product agents for the treatment of hyperuricemia. PMID- 26426000 TI - Amination of Aryl Halides and Esters Using Intensified Continuous Flow Processing. AB - Significant process intensification of the amination reactions of aryl halides and esters has been demonstrated using continuous flow processing. Using this technology traditionally difficult amination reactions have been performed safely at elevated temperatures. These reactions were successfully conducted on laboratory scale coil reactor modules with 1 mm internal diameter (ID) and on a preparatory scale tubular reactor with 6 mm ID containing static mixers. PMID- 26426001 TI - Methanolic Extract of Ganoderma lucidum Induces Autophagy of AGS Human Gastric Tumor Cells. AB - Ganoderma lucidum is one of the most widely studied mushroom species, particularly in what concerns its medicinal properties. Previous studies (including those from some of us) have shown some evidence that the methanolic extract of G. lucidum affects cellular autophagy. However, it was not known if it induces autophagy or decreases the autophagic flux. The treatment of a gastric adenocarcinoma cell line (AGS) with the mushroom extract increased the formation of autophagosomes (vacuoles typical from autophagy). Moreover, the cellular levels of LC3-II were also increased, and the cellular levels of p62 decreased, confirming that the extract affects cellular autophagy. Treating the cells with the extract together with lysossomal protease inhibitors, the cellular levels of LC3-II and p62 increased. The results obtained proved that, in AGS cells, the methanolic extract of G. lucidum causes an induction of autophagy, rather than a reduction in the autophagic flux. To our knowledge, this is the first study proving that statement. PMID- 26426002 TI - Phytotoxic Potential and Biological Activity of Three Synthetic Coumarin Derivatives as New Natural-Like Herbicides. AB - Coumarin is a natural compound well known for its phytotoxic potential. In the search for new herbicidal compounds to manage weeds, three synthetic derivatives bearing the coumarin scaffold (1-3), synthesized by a carbonylative organometallic approach, were in vitro assayed on germination and root growth of two noxious weeds, Amaranthus retroflexus and Echinochloa crus-galli. Moreover, the synthetic coumarins 1-3 were also in vitro assayed on seedlings growth of the model species Arabidopsis thaliana to identify the possible physiological targets. All molecules strongly affected seed germination and root growth of both weeds. Interestingly, the effects of synthetic coumarins on weed germination were higher than template natural coumarin, pointing out ED50 values ranging from 50 115 uM. Moreover, all synthetic coumarins showed a strong phytotoxic potential on both Arabidopsis shoot and root growth, causing a strong reduction in shoot fresh weight (ED50 values <= 60 uM), accompanied by leaf development and a decrease in pigment content. Furthermore, they caused a strong alteration in root growth (ED50 values <= 170 uM) and morphology with evident alterations in root tip anatomy. Taken together, our results highlight the promising potential herbicidal activity of these compounds. PMID- 26426003 TI - Activity of Polyphenolic Compounds against Candida glabrata. AB - Opportunistic mycoses increase the morbidity and mortality of immuno-compromised patients. Five Candida species have been shown to be responsible for 97% of worldwide cases of invasive candidiasis. Resistance of C. glabrata and C. krusei to azoles has been reported, and new, improved antifungal agents are needed. The current study was designed to evaluatethe activity of various polyphenolic compounds against Candida species. Antifungal activity was evaluated following the M27-A3 protocol of the Clinical and Laboratory Standards Institute, and antioxidant activity was determined using the DPPH assay. Myricetin and baicalein inhibited the growth of all species tested. This effect was strongest against C. glabrata, for which the minimum inhibitory concentration (MIC) value was lower than that of fluconazole. The MIC values against C. glabrata for myricitrin, luteolin, quercetin, 3-hydroxyflavone, and fisetin were similar to that of fluconazole. The antioxidant activity of all compounds was confirmed, and polyphenolic compounds with antioxidant activity had the greatest activity against C. glabrata. The structure and position of their hydroxyl groups appear to influence their activity against C. glabrata. PMID- 26426004 TI - Potent Activities of Roemerine against Candida albicans and the Underlying Mechanisms. AB - Roemerine (RM) is an aporphine alkaloid isolated from the fresh rattan stem of Fibraurea recisa, and it has been demonstrated to have certain antifungal activity. This study aimed to investigate the antifungal activity of RM and the underlying mechanisms in Candida albicans (C. albicans). The in vitro antifungal activity of RM was evaluated by a series of experiments, including the XTT reduction assay, confocal laser scanning microscopy assay, scanning electron microscope assay. Results showed that 1 MUg/mL RM inhibited biofilm formation significantly (p < 0.01) both in Spider medium and Lee's medium. In addition, RM could inhibit yeast-to-hyphae transition of C. albicans in a dose-dependent manner. The biofilm-specific and hypha-specific genes such as YWP1, SAP5, SAP6, HWP1, ECE1 were up-regulated and EFG1 was down-regulated after 8 MUg/mL RM treatment. Furthermore, the toxicity of RM was investigated using C. elegans worms, three cancer cells and one normal cell. The date showed that RM had no significant toxicity. In conclusion, RM could inhibited the formation of C. albicans biofilm in vitro, but it had no fungicidal effect on planktonic C. albicans cells, and the anti-biofilm mechanism may be related to the cAMP pathway. PMID- 26426005 TI - Usefulness of Photodynamic Therapy as a Possible Therapeutic Alternative in the Treatment of Basal Cell Carcinoma. AB - Basal cell carcinoma (BCC) is the most common cancer in individuals with fair skin type (I-II) and steadily increasing in incidence (70% of skin malignancy). It is locally invasive but metastasis is usually very rare, with an estimated incidence of 0.0028%-0.55%. Conventional therapy is surgery, especially for the H region of the face and infiltrative lesions; in case of inoperable tumors, radiotherapy is a valid option. Recently, topical photodynamic therapy (PDT) has become an effective treatment in the management of superficial and small nodular BCC. PDT is a minimally invasive procedure that involves the administration of a photo-sensibilizing agent followed by irradiation at a pre-defined wavelength; this determines the creation of reactive oxygen species that specifically destroy target cells. The only major side effect is pain, reported by some patients during the irradiation. The high cure rate and excellent cosmetic outcome requires considering this possibility for the management of patients with both sporadic and hereditary BCC. In this article, an extensive review of the recent literature was made, in order to clarify the role of PDT as a possible alternative therapeutic option in the treatment of BCC. PMID- 26426006 TI - Evaluating Osteogenic Potential of Ligamentum Flavum Cells Cultivated in Photoresponsive Hydrogel that Incorporates Bone Morphogenetic Protein-2 for Spinal Fusion. AB - Regenerative medicine is increasingly important in clinical practice. Ligamentum flava (LF) are typically removed during spine-related surgeries. LF may be a source of cells for spinal fusion that is conducted using tissue engineering techniques. In this investigation, LF cells of rabbits were isolated and then characterized by flow cytometry, morphological observation, and immunofluorescence staining. The LF cells were also cultivated in polyethylene (glycol) diacrylate (PEGDA) hydrogels that incorporated bone morphogenetic protein-2 (BMP-2) growth factor, to evaluate their proliferation and secretion of ECM and differentiation in vitro. The experimental results thus obtained that the proliferation, ECM secretion, and differentiation of the PEGDA-BMP-2 group exceeded those of the PEGDA group during the period of cultivation. The mineralization and histological staining results differed similarly. A nude mice model was utilized to prove that LF cells on hydrogels could undergo osteogenic differentiation in vivo. These experimental results also revealed that the PEGDA BMP-2 group had better osteogenic effects than the PEGDA group following a 12 weeks after transplantation. According to all of these experimental results, LF cells are a source of cells for spinal fusion and PEGDA-BMP-2 hydrogel is a candidate biomaterial for spinal fusion by tissue engineering. PMID- 26426008 TI - Polyphosphate during the Regreening of Chlorella vulgaris under Nitrogen Deficiency. AB - Polyphosphate (Poly-P) accumulation has been reported in Chlorella vulgaris under nitrogen deficiency conditions with sufficient P supply, and the process has been demonstrated to have great impact on lipid productivity. In this article, the utilization of polyphosphates and the regreening process under N resupplying conditions, especially for lipid production reviving, were investigated. This regreening process was completed within approximately 3-5 days. Polyphosphates were first degraded within 3 days in the regreening process, with and without an external P supply, and the degradation preceded the assimilation of phosphate in the media with an external P offering. Nitrate assimilation was markedly influenced by the starvation of P after polyphosphates were exhausted in the medium without external phosphates, and then the reviving process of biomass and lipid production was strictly impeded. It is, thus, reasonable to assume that simultaneous provision of external N and P is essential for overall biodiesel production revival during the regreening process. PMID- 26426007 TI - Dangerous Liaisons: Caspase-11 and Reactive Oxygen Species Crosstalk in Pathogen Elimination. AB - Recently, the focus of murine caspase-11 and human orthologs caspase-4, -5 research has been on their novel function to induce noncanonical inflammasome activation in direct response to Gram-negative bacterial infection. On the other hand, a new role in anti-bacterial autophagy has been attributed to caspase-11, 4 and -5, which currently stands largely unexplored. In this review, we connect lately emerged evidence that suggests these caspases have a key role in anti bacterial autophagy and discuss the growing implications of a danger molecule- extracellular ATP--and NADPH oxidase-mediated ROS generation as novel inducers of human caspase-4, -5 signaling during infection. We also highlight the adeptness of persistent pathogens like Porphyromonas gingivalis, a Gram-negative anaerobe and successful colonizer of oral mucosa, to potentially interfere with the activated caspase-4 pathway and autophagy. While, the ability of caspase-4, -5 to promote autophagolysosomal fusion is not well understood, the abundance of caspase-4 in skin and other mucosal epithelial cells implies an important role for caspase-4 in mucosal defense, supporting the view that caspase-4, -5 may play a non-redundant part in innate immunity. Thus, this review will join the currently disconnected cutting-edge research thereby proposing a working model for regulation of caspase-4, -5 in pathogen elimination via cellular-trafficking. PMID- 26426009 TI - Alkyl Chain Growth on a Transition Metal Center: How Does Iron Compare to Ruthenium and Osmium? AB - Industrial Fischer-Tropsch processes involve the synthesis of hydrocarbons usually on metal surface catalysts. On the other hand, very few homogeneous catalysts are known to perform a Fischer-Tropsch style of reaction. In recent work, we established the catalytic properties of a diruthenium-platinum carbene complex, [(CpRu)2(MU2-H) (MU2-NHCH3)(MU3-C)PtCH3(P(CH3)3)2](CO)n+ with n=0, 2 and Cp=eta5-C5(CH3)5, and showed it to react efficiently by initial hydrogen atom transfer followed by methyl transfer to form an alkyl chain on the Ru-center. In particular, the catalytic efficiency was shown to increase after the addition of two CO molecules. As such, this system could be viewed as a potential homogeneous Fischer-Tropsch catalyst. Herein, we have engineered the catalytic center of the catalyst and investigated the reactivity of trimetal carbene complexes of the same type using iron, ruthenium and osmium at the central metal scaffold. The work shows that the reactivity should increase from diosmium to diruthenium to diiron; however, a non-linear trend is observed due to multiple factors contributing to the individual barrier heights. We identified all individual components of these reaction steps in detail and established the difference in reactivity of the various complexes. PMID- 26426010 TI - Combination of MiR-378 and MiR-210 Serum Levels Enables Sensitive Detection of Renal Cell Carcinoma. AB - Serum microRNAs are emerging as a clinically useful tool for early and non invasive detection of various cancer types including renal cell carcinoma (RCC). Based on our previous results, we performed the study to analyze circulating serum miR-378 and miR-210 in patients with various histological subtypes of RCC. RNA was purified from blood serum samples of 195 RCC patients and 100 healthy controls. The levels of miR-378 and miR-210 in serum were determined absolutely using quantitative real-time PCR. Pre- and postoperative levels of both microRNAs were compared in 20 RCC patients. Significantly increased serum levels of both miR-378 and miR-210 enabled to clearly distinguish RCC patients and healthy controls with 80% sensitivity and 78% specificity if analyzed in combination (p<0.0001), and their levels significantly decreased in the time period of three months after radical nephrectomy (p<0.0001). Increased level of miR-378 positively correlates with disease-free survival (p=0.036) and clinical stage (p=0.0476). The analysis of serum miR-378 and miR-210 proved their potential to serve as powerful non-invasive diagnostic and prognostic biomarkers in RCC. PMID- 26426011 TI - Heavy Metal Induced Antibiotic Resistance in Bacterium LSJC7. AB - Co-contamination of antibiotics and heavy metals prevails in the environment, and may play an important role in disseminating bacterial antibiotic resistance, but the selective effects of heavy metals on bacterial antibiotic resistance is largely unclear. To investigate this, the effects of heavy metals on antibiotic resistance were studied in a genome-sequenced bacterium, LSJC7. The results showed that the presence of arsenate, copper, and zinc were implicated in fortifying the resistance of LSJC7 towards tetracycline. The concentrations of heavy metals required to induce antibiotic resistance, i.e., the minimum heavy metal concentrations (MHCs), were far below (up to 64-fold) the minimum inhibition concentrations (MIC) of LSJC7. This finding indicates that the relatively low heavy metal levels in polluted environments and in treated humans and animals might be sufficient to induce bacterial antibiotic resistance. In addition, heavy metal induced antibiotic resistance was also observed for a combination of arsenate and chloramphenicol in LSJC7, and copper/zinc and tetracycline in antibiotic susceptible strain Escherichia coli DH5alpha. Overall, this study implies that heavy metal induced antibiotic resistance might be ubiquitous among various microbial species and suggests that it might play a role in the emergence and spread of antibiotic resistance in metal and antibiotic co contaminated environments. PMID- 26426012 TI - Nimbolide Induces ROS-Regulated Apoptosis and Inhibits Cell Migration in Osteosarcoma. AB - Osteosarcoma (OS) is a primary malignant tumor of bone and is most prevalent in children and adolescents. OS is frequently associated with pulmonary metastasis, which is the main cause of OS-related mortality. OS has a poor prognosis and is often unresponsive to conventional chemotherapy. In this study, we determined that Nimbolide, a novel anti-cancer therapy, acts by modulating multiple mechanisms in osteosarcoma cells. Nimbolide induces apoptosis by increasing endoplasmic reticulum (ER) stress, mitochondrial dysfunction, accumulation of reactive oxygen species (ROS), and finally, caspase activation. We also determined that Nimbolide inhibits cell migration, which is crucial for metastasis, by reducing the expression of integrin alphavbeta5. In addition, our results demonstrate that integrin alphavbeta5 expression is modulated by the PI3K/Akt and NF-kappaB signaling cascade. Nimbolide has potential as an anti tumor drug given its multifunctional effects in OS. Collectively, these results help us to understand the mechanisms of action of Nimbolide and will aid in the development of effective therapies for OS. PMID- 26426015 TI - Performance Evaluation of Wearable Sensor Systems: A Case Study in Moderate-Scale Deployment in Hospital Environment. AB - A wearable sensor system enables continuous and remote health monitoring and is widely considered as the next generation of healthcare technology. The performance, the packet error rate (PER) in particular, of a wearable sensor system may deteriorate due to a number of factors, particularly the interference from the other wearable sensor systems in the vicinity. We systematically evaluate the performance of the wearable sensor system in terms of PER in the presence of such interference in this paper. The factors that affect the performance of the wearable sensor system, such as density, traffic load, and transmission power in a realistic moderate-scale deployment case in hospital are all considered. Simulation results show that with 20% duty cycle, only 68.5% of data transmission can achieve the targeted reliability requirement (PER is less than 0.05) even in the off-peak period in hospital. We then suggest some interference mitigation schemes based on the performance evaluation results in the case study. PMID- 26426013 TI - Sunflower Oil but Not Fish Oil Resembles Positive Effects of Virgin Olive Oil on Aged Pancreas after Life-Long Coenzyme Q Addition. AB - An adequate pancreatic structure is necessary for optimal organ function. Structural changes are critical in the development of age-related pancreatic disorders. In this context, it has been reported that different pancreatic compartments from rats were affected according to the fat composition consumed. Since there is a close relationship between mitochondria, oxidative stress and aging, an experimental approach has been developed to gain more insight into this process in the pancreas. A low dosage of coenzyme Q was administered life-long in rats in order to try to prevent pancreatic aging-related alterations associated to some dietary fat sources. According to that, three groups of rats were fed normocaloric diets containing Coenzyme Q (CoQ) for two years, where virgin olive, sunflower, or fish oil was included as unique fat source. Pancreatic samples for microscopy and blood samples were collected at the moment of euthanasia. The main finding is that CoQ supplementation gives different results according to fat used in diet. When sunflower oil was the main fat in the diet, CoQ supplementation seems to improve endocrine pancreas structure and in particular beta-cell mass resembling positive effects of virgin olive oil. Conversely, CoQ intake does not seem to improve the structural alterations of exocrine compartment previously observed in fish oil fed rats. Therefore CoQ may improve pancreatic alterations associated to the chronic intake of some dietary fat sources. PMID- 26426016 TI - Rate Adaptive Based Resource Allocation with Proportional Fairness Constraints in OFDMA Systems. AB - Orthogonal frequency division multiple access (OFDMA), which is widely used in the wireless sensor networks, allows different users to obtain different subcarriers according to their subchannel gains. Therefore, how to assign subcarriers and power to different users to achieve a high system sum rate is an important research area in OFDMA systems. In this paper, the focus of study is on the rate adaptive (RA) based resource allocation with proportional fairness constraints. Since the resource allocation is a NP-hard and non-convex optimization problem, a new efficient resource allocation algorithm ACO-SPA is proposed, which combines ant colony optimization (ACO) and suboptimal power allocation (SPA). To reduce the computational complexity, the optimization problem of resource allocation in OFDMA systems is separated into two steps. For the first one, the ant colony optimization algorithm is performed to solve the subcarrier allocation. Then, the suboptimal power allocation algorithm is developed with strict proportional fairness, and the algorithm is based on the principle that the sums of power and the reciprocal of channel-to-noise ratio for each user in different subchannels are equal. To support it, plenty of simulation results are presented. In contrast with root-finding and linear methods, the proposed method provides better performance in solving the proportional resource allocation problem in OFDMA systems. PMID- 26426014 TI - An Overview of Predictors for Intrinsically Disordered Proteins over 2010-2014. AB - The sequence-structure-function paradigm of proteins has been changed by the occurrence of intrinsically disordered proteins (IDPs). Benefiting from the structural disorder, IDPs are of particular importance in biological processes like regulation and signaling. IDPs are associated with human diseases, including cancer, cardiovascular disease, neurodegenerative diseases, amyloidoses, and several other maladies. IDPs attract a high level of interest and a substantial effort has been made to develop experimental and computational methods. So far, more than 70 prediction tools have been developed since 1997, within which 17 predictors were created in the last five years. Here, we presented an overview of IDPs predictors developed during 2010-2014. We analyzed the algorithms used for IDPs prediction by these tools and we also discussed the basic concept of various prediction methods for IDPs. The comparison of prediction performance among these tools is discussed as well. PMID- 26426017 TI - Optimisation and Characterisation of Anti-Fouling Ternary SAM Layers for Impedance-Based Aptasensors. AB - An aptasensor with enhanced anti-fouling properties has been developed. As a case study, the aptasensor was designed with specificity for human thrombin. The sensing platform was developed on screen printed electrodes and is composed of a self-assembled monolayer made from a ternary mixture of 15-base thiolated DNA aptamers specific for human thrombin co-immobilised with 1,6-hexanedithiol (HDT) and further passivated with 1-mercapto-6-hexanol (MCH). HDT binds to the surface by two of its thiol groups forming alkyl chain bridges and this architecture protects from non-specific attachment of molecules to the electrode surface. Using Electrochemical Impedance Spectroscopy (EIS), the aptasensor is able to detect human thrombin as variations in charge transfer resistance (Rct) upon protein binding. After exposure to a high concentration of non-specific Bovine Serum Albumin (BSA) solution, no changes in the Rct value were observed, highlighting the bio-fouling resistance of the surface generated. In this paper, we present the optimisation and characterisation of the aptasensor based on the ternary self-assembled monolayer (SAM) layer. We show that anti-fouling properties depend on the type of gold surface used for biosensor construction, which was also confirmed by contact angle measurements. We further studied the ratio between aptamers and HDT, which can determine the specificity and selectivity of the sensing layer. We also report the influence of buffer pH and temperature used for incubation of electrodes with proteins on detection and anti fouling properties. Finally, the stability of the aptasensor was studied by storage of modified electrodes for up to 28 days in different buffers and atmospheric conditions. Aptasensors based on ternary SAM layers are highly promising for clinical applications for detection of a range of proteins in real biological samples. PMID- 26426018 TI - A Note on an Improved Self-Healing Group Key Distribution Scheme. AB - In 2014, Chen et al. proposed a one-way hash self-healing group key distribution scheme for resource-constrained wireless networks in the journal of Sensors (14(14):24358-24380, doi: 10.3390/ s141224358). They asserted that their Scheme 2 achieves mt-revocation capability, mt-wise forward secrecy, any-wise backward secrecy and has mt-wise collusion attack resistance capability. Unfortunately, this paper pointed out that their scheme does not satisfy the forward security, mt-revocation capability and mt-wise collusion attack resistance capability. PMID- 26426019 TI - A Feasibility Analysis of Land-Based SINS/GNSS Gravimetry for Groundwater Resource Detection in Taiwan. AB - The integration of the Strapdown Inertial Navigation System and Global Navigation Satellite System (SINS/GNSS) has been implemented for land-based gravimetry and has been proven to perform well in estimating gravity. Based on the mGal-level gravimetry results, this research aims to construct and develop a land-based SINS/GNSS gravimetry device containing a navigation-grade Inertial Measurement Unit. This research also presents a feasibility analysis for groundwater resource detection. A preliminary comparison of the kinematic velocities and accelerations using multi-combination of GNSS data including Global Positioning System, Global Navigation Satellite System, and BeiDou Navigation Satellite System, indicates that three-system observations performed better than two-system data in the computation. A comparison of gravity derived from SINS/GNSS and measured using a relative gravimeter also shows that both agree reasonably well with a mean difference of 2.30 mGal. The mean difference between repeat measurements of gravity disturbance using SINS/GNSS is 2.46 mGal with a standard deviation of 1.32 mGal. The gravity variation because of the groundwater at Pingtung Plain, Taiwan could reach 2.72 mGal. Hence, the developed land-based SINS/GNSS gravimetry can sufficiently and effectively detect groundwater resources. PMID- 26426020 TI - Quantitative Assessment of Parkinsonian Tremor Based on an Inertial Measurement Unit. AB - Quantitative assessment of parkinsonian tremor based on inertial sensors can provide reliable feedback on the effect of medication. In this regard, the features of parkinsonian tremor and its unique properties such as motor fluctuations and dyskinesia are taken into account. Least-square-estimation models are used to assess the severities of rest, postural, and action tremors. In addition, a time-frequency signal analysis algorithm for tremor state detection was also included in the tremor assessment method. This inertial sensor based method was verified through comparison with an electromagnetic motion tracking system. Seven Parkinson's disease (PD) patients were tested using this tremor assessment system. The measured tremor amplitudes correlated well with the judgments of a neurologist (r = 0.98). The systematic analysis of sensor-based tremor quantification and the corresponding experiments could be of great help in monitoring the severity of parkinsonian tremor. PMID- 26426021 TI - A Novel Fusion-Based Ship Detection Method from Pol-SAR Images. AB - A novel fusion-based ship detection method from polarimetric Synthetic Aperture Radar (Pol-SAR) images is proposed in this paper. After feature extraction and constant false alarm rate (CFAR) detection, the detection results of HH channel, diplane scattering by Pauli decomposition and helical factor by Barnes decomposition are fused together. The confirmed targets and potential target pixels can be obtained after the fusion process. Using the difference degree of the target, potential target pixels can be classified. The fusion-based ship detection method works accurately by utilizing three different features comprehensively. The result of applying the technique to measured Airborne Synthetic Radar (AIRSAR) data shows that the novel detection method can achieve better performance in both ship's detection and ship's shape preservation compared to the result of K-means clustering method and the Notch Filter method. PMID- 26426022 TI - Surface Plasmon Scattering in Exposed Core Optical Fiber for Enhanced Resolution Refractive Index Sensing. AB - Refractometric sensors based on optical excitation of surface plasmons on the side of an optical fiber is an established sensing architecture that has enabled laboratory demonstrations of cost effective portable devices for biological and chemical applications. Here we report a Surface Plasmon Resonance (SPR) configuration realized in an Exposed Core Microstructured Optical Fiber (ECF) capable of optimizing both sensitivity and resolution. To the best of our knowledge, this is the first demonstration of fabrication of a rough metal coating suitable for spectral interrogation of scattered plasmonic wave using chemical electroless plating technique on a 10 MUm diameter exposed core of the ECF. Performance of the sensor in terms of its refractive index sensitivity and full width at half maximum (FWHM) of SPR response is compared to that achieved with an unstructured bare core fiber with 140 MUm core diameter. The experimental improvement in FWHM, and therefore the detection limit, is found to be a factor of two (75 nm for ECF in comparison to 150 nm for the large core fiber). Refractive index sensitivity of 1800 nm/RIU was achieved for both fibers in the sensing range of aqueous environment (1.33-1.37) suitable for biosensing applications. PMID- 26426023 TI - The Video Collaborative Localization of a Miner's Lamp Based on Wireless Multimedia Sensor Networks for Underground Coal Mines. AB - Based on wireless multimedia sensor networks (WMSNs) deployed in an underground coal mine, a miner's lamp video collaborative localization algorithm was proposed to locate miners in the scene of insufficient illumination and bifurcated structures of underground tunnels. In bifurcation area, several camera nodes are deployed along the longitudinal direction of tunnels, forming a collaborative cluster in wireless way to monitor and locate miners in underground tunnels. Cap lamps are regarded as the feature of miners in the scene of insufficient illumination of underground tunnels, which means that miners can be identified by detecting their cap-lamps. A miner's lamp will project mapping points on the imaging plane of collaborative cameras and the coordinates of mapping points are calculated by collaborative cameras. Then, multiple straight lines between the positions of collaborative cameras and their corresponding mapping points are established. To find the three-dimension (3D) coordinate location of the miner's lamp a least square method is proposed to get the optimal intersection of the multiple straight lines. Tests were carried out both in a corridor and a realistic scenario of underground tunnel, which show that the proposed miner's lamp video collaborative localization algorithm has good effectiveness, robustness and localization accuracy in real world conditions of underground tunnels. PMID- 26426024 TI - Double Laser for Depth Measurement of Thin Films of Ice. AB - The use of thin films is extensive in both science and industry. We have created an experimental system that allows us to measure the thicknesses of thin films (with typical thicknesses of around 1 um) in real time without the need for any prior knowledge or parameters. Using the proposed system, we can also measure the refractive index of the thin film material exactly under the same experimental conditions. We have also obtained interesting results with regard to structural changes in the solid substance with changing temperature and have observed the corresponding behavior of mixtures of substances. PMID- 26426025 TI - Opioid Facilitation of beta-Adrenergic Blockade: A New Pharmacological Condition? AB - Recently, propranolol was suggested to prevent hyperlactatemia in a child with hypovolemic shock through beta-adrenergic blockade. Though it is a known inhibitor of glycolysis, propranolol, outside this observation, has never been reported to fully protect against lactate overproduction. On the other hand, literature evidence exists for a cross-talk between beta-adrenergic receptors (protein targets of propranolol) and delta-opioid receptor. In this literature context, it is hypothesized here that anti-diarrheic racecadotril (a pro-drug of thiorphan, an inhibitor of enkephalinases), which, in the cited observation, was co-administered with propranolol, might have facilitated the beta-blocker-driven inhibition of glycolysis and resulting lactate production. The opioid-facilitated beta-adrenergic blockade would be essentially additivity or even synergism putatively existing between antagonism of beta-adrenergic receptors and agonism of delta-opioid receptor in lowering cellular cAMP and dependent functions. PMID- 26426026 TI - Redox Status and Neuro Inflammation Indexes in Cerebellum and Motor Cortex of Wistar Rats Supplemented with Natural Sources of Omega-3 Fatty Acids and Astaxanthin: Fish Oil, Krill Oil, and Algal Biomass. AB - Health authorities worldwide have consistently recommended the regular consumption of marine fishes and seafood to preserve memory, sustain cognitive functions, and prevent neurodegenerative processes in humans. Shrimp, crabs, lobster, and salmon are of particular interest in the human diet due to their substantial provision of omega-3 fatty acids (n-3/PUFAs) and the antioxidant carotenoid astaxanthin (ASTA). However, the optimal ratio between these nutraceuticals in natural sources is apparently the key factor for maximum protection against most neuro-motor disorders. Therefore, we aimed here to investigate the effects of a long-term supplementation with (n-3)/PUFAs-rich fish oil, ASTA-rich algal biomass, the combination of them, or krill oil (a natural combination of both nutrients) on baseline redox balance and neuro-inflammation indexes in cerebellum and motor cortex of Wistar rats. Significant changes in redox metabolism were only observed upon ASTA supplementation, which reinforce its antioxidant properties with a putative mitochondrial-centered action in rat brain. Krill oil imposed mild astrocyte activation in motor cortex of Wistar rats, although no redox or inflammatory index was concomitantly altered. In summary, there is no experimental evidence that krill oil, fish oil, oralgal biomass (minor variation), drastically change the baseline oxidative conditions or the neuro-inflammatory scenario in neuromotor-associated rat brain regions. PMID- 26426027 TI - Photo-Oxidative Stress-Driven Mutagenesis and Adaptive Evolution on the Marine Diatom Phaeodactylum tricornutum for Enhanced Carotenoid Accumulation. AB - Marine diatoms have recently gained much attention as they are expected to be a promising resource for sustainable production of bioactive compounds such as carotenoids and biofuels as a future clean energy solution. To develop photosynthetic cell factories, it is important to improve diatoms for value-added products. In this study, we utilized UVC radiation to induce mutations in the marine diatom Phaeodactylum tricornutum and screened strains with enhanced accumulation of neutral lipids and carotenoids. Adaptive laboratory evolution (ALE) was also used in parallel to develop altered phenotypic and biological functions in P. tricornutum and it was reported for the first time that ALE was successfully applied on diatoms for the enhancement of growth performance and productivity of value-added carotenoids to date. Liquid chromatography-mass spectrometry (LC-MS) was utilized to study the composition of major pigments in the wild type P. tricornutum, UV mutants and ALE strains. UVC radiated strains exhibited higher accumulation of fucoxanthin as well as neutral lipids compared to their wild type counterpart. In addition to UV mutagenesis, P. tricornutum strains developed by ALE also yielded enhanced biomass production and fucoxanthin accumulation under combined red and blue light. In short, both UV mutagenesis and ALE appeared as an effective approach to developing desired phenotypes in the marine diatoms via electromagnetic radiation-induced oxidative stress. PMID- 26426028 TI - Blood Cadmium Is Associated with Osteoporosis in Obese Males but Not in Non-Obese Males: The Korea National Health and Nutrition Examination Survey 2008-2011. AB - Osteoporosis in males is becoming an important health concern in an aging society. The aim of this study was to investigate the associations between cadmium exposure and osteoporosis by considering the effect of obesity in aged males using a representative sample of the Korean population. Using the fourth and fifth Korea National Health and Nutrition Examination Survey data, 1098 males over 50 years of age were analyzed. The blood cadmium concentration was measured. The bone mineral density in the total hip, femur neck, and lumbar spine was measured using dual-energy X-ray absorptiometry. T-scores to determine the presence of osteoporosis were calculated using a Korean reference. Subjects were stratified into two groups according to obesity status (body mass index <25 kg/m2 and >=25 kg/m2). In comparison with obese subjects with blood cadmium <1.00 MUg/L, those with blood cadmium >1.50 MUg/L had odds ratios of 4.57 (95% confidence interval [CI] 1.49-14.01) and 5.71 (95% CI 1.99-16.38) at the femur neck and any site, respectively, after adjusting for potential confounders such as age, serum creatinine, vitamin D deficiency, smoking, alcohol drinking, and physical activity level. However, this association was not significant in non obese males. In conclusion, the effect of cadmium on osteoporosis was different by obesity status in aged males. PMID- 26426029 TI - Healthy Aging Promotion through Neuroscientific Information-Based Strategies. AB - To ensure the well-being of a rapidly growing elderly population, it is fundamental to find strategies to foster healthy brain aging. With this intention, we designed a program of scientific-based lectures aimed at dissemination by established neuroscientists about brain function, brain plasticity and how lifestyle influences the brain. We also carried out a pilot study on the impact of the lectures on attendees. The objective was to provide information to elderly people in order to encourage them to identify unhealthy and healthy daily habits, and more importantly, to promote behavioral changes towards healthy brain aging. Here we report on our experience. In order to determine the impact of the lectures in the daily routine of the attendees, we asked them to fill out questionnaires. Preliminary results indicate that neuroscientific information-based strategies can be a useful method to have a positive impact on the lives of elderly, increase their awareness on how to improve brain function and promote positive lifestyle modifications. Furthermore, based on self-reported data, we also found that through this strategy it is possible to promote behavioral changes related to nutrition, sleep, and realization of physical and cognitively stimulating activities. Finally, based on the results obtained, the importance of promoting self-efficacy and the empowerment of the older populations is highlighted. PMID- 26426030 TI - Temporal and Spatial Simulation of Atmospheric Pollutant PM2.5 Changes and Risk Assessment of Population Exposure to Pollution Using Optimization Algorithms of the Back Propagation-Artificial Neural Network Model and GIS. AB - PM2.5 pollution has become of increasing public concern because of its relative importance and sensitivity to population health risks. Accurate predictions of PM2.5 pollution and population exposure risks are crucial to developing effective air pollution control strategies. We simulated and predicted the temporal and spatial changes of PM2.5 concentration and population exposure risks, by coupling optimization algorithms of the Back Propagation-Artificial Neural Network (BP ANN) model and a geographical information system (GIS) in Xi'an, China, for 2013, 2020, and 2025. Results indicated that PM2.5 concentration was positively correlated with GDP, SO2, and NO2, while it was negatively correlated with population density, average temperature, precipitation, and wind speed. Principal component analysis of the PM2.5 concentration and its influencing factors' variables extracted four components that accounted for 86.39% of the total variance. Correlation coefficients of the Levenberg-Marquardt (trainlm) and elastic (trainrp) algorithms were more than 0.8, the index of agreement (IA) ranged from 0.541 to 0.863 and from 0.502 to 0.803 by trainrp and trainlm algorithms, respectively; mean bias error (MBE) and Root Mean Square Error (RMSE) indicated that the predicted values were very close to the observed values, and the accuracy of trainlm algorithm was better than the trainrp. Compared to 2013, temporal and spatial variation of PM2.5 concentration and risk of population exposure to pollution decreased in 2020 and 2025. The high-risk areas of population exposure to PM2.5 were mainly distributed in the northern region, where there is downtown traffic, abundant commercial activity, and more exhaust emissions. A moderate risk zone was located in the southern region associated with some industrial pollution sources, and there were mainly low-risk areas in the western and eastern regions, which are predominantly residential and educational areas. PMID- 26426031 TI - High Cancer Burden in Elderly Chinese, 2005-2011. AB - OBJECTIVE: Cancer risk increases with age, creating a challenge for the Chinese health system. To inform public health policy and research, we evaluated the cancer burden in elderly Chinese. METHODS: Based on the published Chinese Cancer Registry Annual Report or related literature and the China Population and Employment Statistics Yearbooks, we estimated the cancer burden of elderly Chinese, who were representative of the Chinese population. We calculated the cancer incidence, cancer-related mortality, potential years of life lost (PYLL), and disability-adjusted life years (DALYs) in 2005-2011 by age, sex, district (rural, urban), and calendar year using national cancer registry, publication, and census data. The relative ratios (RRs) were determined between the elderly (>=60 years) and young (<60 years). RESULTS: Cancer incidence and related mortality in the elderly were 8.47 and 13.96 times, respectively, those in the young. The PYLL and DALY rates of the elderly were 1.63 and 5.00 times, respectively, those in the young. The PYLL and DALY rates for elderly men and rural districts were higher than for elderly women and urban districts. The RRs for male sex and rural districts were higher than for female sex and urban districts. RRs increased sharply from 2005 to 2011. CONCLUSIONS: The cancer burden in elderly Chinese was higher in men and rural districts than in women and urban districts, which creates considerable challenges for the Chinese health care system. Comprehensive measures for cancer prevention and treatment in the elderly are needed. PMID- 26426032 TI - Water Environmental Capacity Analysis of Taihu Lake and Parameter Estimation Based on the Integration of the Inverse Method and Bayesian Modeling. AB - An integrated approach using the inverse method and Bayesian approach, combined with a lake eutrophication water quality model, was developed for parameter estimation and water environmental capacity (WEC) analysis. The model was used to support load reduction and effective water quality management in the Taihu Lake system in eastern China. Water quality was surveyed yearly from 1987 to 2010. Total nitrogen (TN) and total phosphorus (TP) were selected as water quality model variables. Decay rates of TN and TP were estimated using the proposed approach. WECs of TN and TP in 2011 were determined based on the estimated decay rates. Results showed that the historical loading was beyond the WEC, thus, reduction of nitrogen and phosphorus input is necessary to meet water quality goals. Then WEC and allowable discharge capacity (ADC) in 2015 and 2020 were predicted. The reduction ratios of ADC during these years were also provided. All of these enable decision makers to assess the influence of each loading and visualize potential load reductions under different water quality goals, and then to formulate a reasonable water quality management strategy. PMID- 26426033 TI - A Comparative Land Use-Based Analysis of Noise Pollution Levels in Selected Urban Centers of Nigeria. AB - Growth in the commercialization, mobility and urbanization of human settlements across the globe has greatly exposed world urban population to potentially harmful noise levels. The situation is more disturbing in developing countries like Nigeria, where there are no sacrosanct noise laws and regulations. This study characterized noise pollution levels in Ibadan and Ile-Ife, two urban areas of Southwestern Nigeria that have experienced significant increases in population and land use activities. Eight hundred noise measurements, taken at 20 different positions in the morning, afternoon, and evening of carefully selected weekdays, in each urban area, were used for this study. Findings put the average noise levels in the urban centers at between 53 dB(A) and 89 dB (A), a far cry from the World Health Organization (WHO) permissible limits in all the land use types, with highest noise pollution levels recorded for transportation, commercial, residential and educational land use types. The result of the one-way ANOVA test carried out on the dependent variable noise and fixed factor land use types reveals a statistically significant mean noise levels across the study area (F(3,34) = 15.13, p = 0.000). The study underscores noise pollution monitoring and the urgent need to control urban noise pollution with appropriate and effective policies. PMID- 26426034 TI - Nipple Pain in Breastfeeding Mothers: Incidence, Causes and Treatments. AB - BACKGROUND: Persistent nipple pain is one of the most common reasons given by mothers for ceasing exclusive breastfeeding. We aimed to determine the frequency of nipple pain as a reason for consultation, the most common attributed aetiologies, and the effectiveness of the advice and treatment given. METHODS: All consultations at the Breast Feeding Centre of Western Australia (WA) were audited over two six-month periods in 2011 (n = 469) and 2014 (n = 708). Attributed cause(s) of nipple pain, microbiology results, treatment(s) advised, and resolution of pain were recorded. RESULTS: Nipple pain was one of the reasons for consultation in 36% of cases. The most common attributed cause of nipple pain was incorrect positioning and attachment, followed by tongue tie, infection, palatal anomaly, flat or inverted nipples, mastitis, and vasospasm. Advice included correction of positioning and attachment, use of a nipple shield, resting the nipples and expressing breastmilk, frenotomy, oral antibiotics, topical treatments, and cold or warm compresses. Pain was resolving or resolved in 57% of cases after 18 days (range 2-110). CONCLUSION: The multiple attributed causes of nipple pain, possibly as a result of a cascade of events, suggests that effective early lactation management for prevention of nipple pain and early diagnosis and effective treatment are crucial to avoid early weaning. PMID- 26426035 TI - Comparison of Hourly PM2.5 Observations Between Urban and Suburban Areas in Beijing, China. AB - Hourly PM2.5 observations collected at 12 stations over a 1-year period are used to identify variations between urban and suburban areas in Beijing. The data demonstrates a unique monthly variation form, as compared with other major cities. Urban areas suffer higher PM2.5 concentration (about 92 MUg/m3) than suburban areas (about 77 MUg/m3), and the average PM2.5 concentration in cold season (about 105 MUg/m3) is higher than warm season (about 78 MUg/m3). Hourly PM2.5 observations exhibit distinct seasonal, diurnal and day-of-week variations. The diurnal variation of PM2.5 is observed with higher concentration at night and lower value at daytime, and the cumulative growth of nighttime (22:00 p.m. in winter) PM2.5 concentration maybe due to the atmospheric stability. Moreover, annual average PM2.5 concentrations are about 18 MUg/m3 higher on weekends than weekdays, consistent with driving restrictions on weekdays. Additionally, the nighttime peak in weekdays (21:00 p.m.) is one hour later than weekends (20:00 p.m.) which also shows the evidence of human activity. These observed facts indicate that the variations of PM2.5 concentration between urban and suburban areas in Beijing are influenced by complex meteorological factors and human activities. PMID- 26426036 TI - Filoviruses: One of These Things is (not) Like the Other. AB - The family Filoviridae contains several of the most deadly pathogens known to date and the current Ebola virus disease (EVD) outbreak in Western Africa, due to Ebola virus (EBOV) infection, highlights the need for active and broad research into filovirus pathogenesis. However, in comparison, the seven other known filovirus family members are significantly understudied. Many of these, including Marburgviruses and Ebolaviruses other than EBOV, are also highly virulent and fully capable of causing widespread epidemics. This review places the focus on these non-EBOV filoviruses, including known immunological and pathological data. The available animal models, research tools and currently available therapeutics will also be discussed along with an emphasis in the large number of current gaps in knowledge of these less highlighted filoviruses. It is evident that much research is yet to be done in order to bring the non-EBOV filovirus field to the forefront of current research and, importantly, to the development of more effective vaccines and therapeutics to combat potential future outbreaks. PMID- 26426037 TI - Differentially-Expressed Pseudogenes in HIV-1 Infection. AB - Not all pseudogenes are transcriptionally silent as previously thought. Pseudogene transcripts, although not translated, contribute to the non-coding RNA pool of the cell that regulates the expression of other genes. Pseudogene transcripts can also directly compete with the parent gene transcripts for mRNA stability and other cell factors, modulating their expression levels. Tissue specific and cancer-specific differential expression of these "functional" pseudogenes has been reported. To ascertain potential pseudogene:gene interactions in HIV-1 infection, we analyzed transcriptomes from infected and uninfected T-cells and found that 21 pseudogenes are differentially expressed in HIV-1 infection. This is interesting because parent genes of one-third of these differentially-expressed pseudogenes are implicated in HIV-1 life cycle, and parent genes of half of these pseudogenes are involved in different viral infections. Our bioinformatics analysis identifies candidate pseudogene:gene interactions that may be of significance in HIV-1 infection. Experimental validation of these interactions would establish that retroviruses exploit this newly-discovered layer of host gene expression regulation for their own benefit. PMID- 26426039 TI - Solid Microneedles for Transdermal Delivery of Amantadine Hydrochloride and Pramipexole Dihydrochloride. AB - The aim of this project was to study the influence of microneedles on transdermal delivery of amantadine hydrochloride and pramipexole dihydrochloride across porcine ear skin in vitro. Microchannel visualization studies were carried out and characterization of the microchannel depth was performed using confocal laser scanning microscopy (CLSM) to demonstrate microchannel formation following microneedle roller application. We also report, for the first time, the use of TA.XT Plus Texture Analyzer to characterize burst force in pig skin for transdermal drug delivery experiments. This is the force required to rupture pig skin. The mean passive flux of amantadine hydrochloride, determined using a developed LC-MS/MS technique, was 22.38 +/- 4.73 ug/cm2/h, while the mean flux following the use of a stainless steel microneedle roller was 49.04 +/- 19.77 ug/cm2/h. The mean passive flux of pramipexole dihydrochloride was 134.83 +/- 13.66 ug/cm2/h, while the flux following the use of a stainless steel microneedle roller was 134.04 +/- 0.98 ug/cm2/h. For both drugs, the difference in flux values following the use of solid stainless steel microneedle roller was not statistically significantly (p > 0.05). Statistical analysis was carried out using the Mann-Whitney Rank sum test. PMID- 26426038 TI - Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance. AB - The hepatitis C virus (HCV) is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The development of antiviral therapeutic agents has also been challenging, primarily due to the lack of efficient cell culture and animal models for all HCV genotypes, as well as the large genetic diversity between HCV strains. On the other hand, the use of interferon-alpha-based treatments in combination with the guanosine analogue, ribavirin, achieved limited success, and widespread use of these therapies has been hampered by prevalent side effects. For more than a decade, the HCV RNA dependent RNA polymerase (RdRp) has been targeted for antiviral development, and direct-acting antivirals (DAA) have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection. Here we review the different classes of RdRp inhibitors and their mode of action against HCV. Furthermore, the mechanism of antiviral resistance to each class is described, including naturally occurring resistance-associated variants (RAVs) in different viral strains and genotypes. Finally, we review the impact of these RAVs on treatment outcomes with the newly developed regimens. PMID- 26426040 TI - Methylene Blue-Loaded Dissolving Microneedles: Potential Use in Photodynamic Antimicrobial Chemotherapy of Infected Wounds. AB - Photodynamic therapy involves delivery of a photosensitising drug that is activated by light of a specific wavelength, resulting in generation of highly reactive radicals. This activated species can cause destruction of targeted cells. Application of this process for treatment of microbial infections has been termed "photodynamic antimicrobial chemotherapy" (PACT). In the treatment of chronic wounds, the delivery of photosensitising agents is often impeded by the presence of a thick hyperkeratotic/necrotic tissue layer, reducing their therapeutic efficacy. Microneedles (MNs) are an emerging drug delivery technology that have been demonstrated to successfully penetrate the outer layers of the skin, whilst minimising damage to skin barrier function. Delivering photosensitising drugs using this platform has been demonstrated to have several advantages over conventional photodynamic therapy, such as, painless application, reduced erythema, enhanced cosmetic results and improved intradermal delivery. The aim of this study was to physically characterise dissolving MNs loaded with the photosensitising agent, methylene blue and assess their photodynamic antimicrobial activity. Dissolving MNs were fabricated from aqueous blends of Gantrez((r)) AN-139 co-polymer containing varying loadings of methylene blue. A height reduction of 29.8% was observed for MNs prepared from blends containing 0.5% w/w methylene blue following application of a total force of 70.56 N/array. A previously validated insertion test was used to assess the effect of drug loading on MN insertion into a wound model. Staphylococcus aureus, Escherichia coli and Candida albicans biofilms were incubated with various methylene blue concentrations within the range delivered by MNs in vitro (0.1-2.5 mg/mL) and either irradiated at 635 nm using a Paterson Lamp or subjected to a dark period. Microbial susceptibility to PACT was determined by assessing the total viable count. Kill rates of >96%, were achieved for S. aureus and >99% for E. coli and C. albicans with the combination of PACT and methylene blue concentrations between 0.1 and 2.5 mg/mL. A reduction in the colony count was also observed when incorporating the photosensitiser without irradiation, this reduction was more notable in S. aureus and E. coli strains than in C. albicans. PMID- 26426041 TI - Anti-Tumor Effect of Steamed Codonopsis lanceolata in H22 Tumor-Bearing Mice and Its Possible Mechanism. AB - Although previous studies confirmed that steaming and the fermentation process could significantly improve the cognitive-enhancement and neuroprotective effects of Codonopsis lanceolata, the anti-tumor efficacy of steamed C. lanceolata (SCL) and what mechanisms are involved remain largely unknown. The present study was designed to evaluate the anti-tumor effect in vivo of SCL in H22 tumor-bearing mice. The results clearly indicated that SCL could not only inhibit the tumor growth, but also prolong the survival time of H22 tumor-bearing mice. Besides, the serum levels of cytokines, such as interferon gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-2 (IL-2), were enhanced by SCL administration. The observations of Hoechst 33258 staining demonstrated that SCL was able to induce tumor cell apoptosis. Finally, immunohistochemical analysis revealed that SCL treatment significantly increased Bax expression and decreased Bcl-2 and vascular endothelial growth factor (VEGF) expression of H22 tumor tissues in a dose-dependent manner. Moreover, LC/MS analysis of SCL indicated that it mainly contained lobetyolin and six saponins. Taken all together, the findings in the present study clearly demonstrated that SCL inhibited the H22 tumor growth in vivo at least partly via improving the immune functions, inducing apoptosis and inhibiting angiogenesis. PMID- 26426042 TI - Total and Differential Phylloquinone (Vitamin K1) Intakes of Preterm Infants from All Sources during the Neonatal Period. AB - All newborns require phylloquinone after birth to prevent vitamin K deficiency bleeding. Babies born prematurely may be at particular risk of deficiency without adequate supplementation during infancy. The main sources of phylloquinone in preterm babies during the neonatal period are the prophylactic dose of phylloquinone given at birth, and that derived from parenteral and/or enteral feeding. This observational study formed part of a prospective, multicentre, randomised, controlled trial that examined the vitamin K status of preterm infants after random allocation to one of three phylloquinone prophylactic regimens at birth (0.5 or 0.2 mg intramuscularly or 0.2 mg intravenously). In this nutritional sub-study we quantified the proportional and total phylloquinone intakes of preterm infants within the neonatal period from all sources. Almost all infants had average daily phylloquinone intakes that were in excess of the currently recommended amounts. In infants who did not receive parenteral nutrition, the bolus dose of phylloquinone given at birth was the major source of phylloquinone intake, whereas in infants who received parenteral nutrition, the intake from the parenteral preparation exceeded that from the bolus dose by a ratio of approximately 3:1. Our study supports the concern of others that preterm infants who receive current parenteral nutrition formulations may be receiving excessive vitamin K. PMID- 26426043 TI - Body Mass Index and Risk of Gallbladder Cancer: Systematic Review and Meta Analysis of Observational Studies. AB - OBJECTIVES: To provide a quantitative assessment of the association between excess body weight, interpreted as increased body mass index (BMI), and the risk of gallbladder cancer (GBC). METHODS: We identified eligible studies in Medline and EMBASE up to 1 February 2015, and reference lists of retrieved articles. Summary relative risks with their 95% confidence intervals were calculated in a random-effects model. Subgroup analyses were performed according to study design, gender, geographic location, ascertainment of exposure and adjustment for confounders. RESUITS: A total of 12 cohort studies and 8 case-control studies were included in the meta-analysis. Overall, compared with "normal" weight, the summary relative risks of GBC were 1.14 (95% CI, 1.04-1.25) for overweight individuals (BMI 25-30 kg/m2) and 1.56 (95% CI, 1.41-1.73) for obese individuals (BMI > 30 kg/m2). Obese women had a higher risk of GBC than men did (women: SRRs 1.67, 95% CI 1.38-2.02; men: SRRs 1.42, 95% CI 1.21-1.66), and there was significant association between overweight and GBC risk in women (SRRs 1.26, 95% CI 1.13-1.40), but not in men (SRRs 1.06, 95% CI 0.94-1.20). CONCLUSIONS: Findings from this meta-analysis indicate that obesity is associated with an increased risk of GBC, especially in women. Overweight is associated with GBC risk only in women. PMID- 26426044 TI - Effect of Probiotic Supplement on Cytokine Levels in HIV-Infected Individuals: A Preliminary Study. AB - Inflammation persists in patients infected with HIV. Reduction of inflammatory cytokines and microbial translocation might be one way that this could be managed. PURPOSE: The anti-inflammatory properties of certain probiotic strains prompted us to investigate whether a probiotic could reduce the inflammatory index of HIV-infected patients. METHODS: The study involved 30 HIV+ males on antiretroviral therapy, who were given one bottle of fermented milk Yakult Light(r) containing Lactobacillus casei Shirota (LcS) twice a day for four weeks. RESULTS: The probiotic LcS was associated with an increase of T lymphocytes and a significant increase of CD56+ cells (p = 0.04). There was also a significant decrease of mRNA levels of TGFbeta, IL-10 and IL-12 (p < 0.001) and IL-1beta expression (p < 0.001) and an increase of serum IL-23 (p = 0.03). In addition, decreased inflammation and cardiovascular risk were observed, as shown by a reduction of cystatin C (p < 0.001). CONCLUSIONS: These data provide preliminary evidence that probiotic supplementation may modulate certain immunological parameters and some of the cytokines that were analyzed. Thus, we propose that LcS may be an inexpensive and practical strategy to support the immune function of HIV+ patients. PMID- 26426046 TI - Development and Evaluation of Monoclonal Antibodies for Paxilline. AB - Paxilline (PAX) is a tremorgenic mycotoxin that has been found in perennial ryegrass infected with Acremonium lolii. To facilitate screening for this toxin, four murine monoclonal antibodies (mAbs) were developed. In competitive indirect enzyme-linked immunosorbent assays (CI-ELISAs) the concentrations of PAX required to inhibit signal development by 50% (IC50s) ranged from 1.2 to 2.5 ng/mL. One mAb (2-9) was applied to the detection of PAX in maize silage. The assay was sensitive to the effects of solvents, with 5% acetonitrile or 20% methanol causing a two-fold or greater increase in IC50. For analysis of silage samples, extracts were cleaned up by adsorbing potential matrix interferences onto a solid phase extraction column. The non-retained extract was then diluted with buffer to reduce solvent content prior to assay. Using this method, the limit of detection for PAX in dried silage was 15 ug/kg and the limit of quantification was 90 ug/kg. Recovery from samples spiked over the range of 100 to 1000 ug/kg averaged 106% +/- 18%. The assay was applied to 86 maize silage samples, with many having detectable, but none having quantifiable, levels of PAX. The results suggest the CI-ELISA can be applied as a sensitive technique for the screening of PAX in maize silage. PMID- 26426045 TI - Gut Function-Enhancing Properties and Metabolic Effects of Dietary Indigestible Sugars in Rodents and Rabbits. AB - Indigestible sugars (iS) have received particular interest in food and nutrition research due to their prebiotic properties and other health benefits in humans and animals. The main aim of this review article is to summarize the current knowledge regarding digestive and health-enhancing properties of iS such as sugar alcohols, oligosacharides, and polysaccharides, in rodents and rabbits. Besides ameliorating gut health, iS ingestion also elicits laxative effects and stimulate intestinal permeability and fluid secretions, thereby shortening digesta transit time and increasing stool mass and quality. In rodents and rabbits, as hindgut fermenters, consumption of iS leads to an improved nutrient digestibility, too. Cecal fermentation of iS reduces luminal pH and extends wall tissue facilitating absorption of key dietary minerals across hindgut. The microbial fermentation of iS also enhances excessive blood nitrogen (N) flowing into the cecum to be used as N source for bacterial growth, enhancing N retention in cecotrophic animals. This review also highlights the impact of iS on improving lipid metabolism, mainly by lowering cholesterol and triglycerides levels in the blood. The paper serves as an index of the current knowledge of iS effects in rodents and rabbits and also identifies gaps of knowledge that need to be addressed by future research. PMID- 26426048 TI - Exploring Protein Binding of Uremic Toxins in Patients with Different Stages of Chronic Kidney Disease and during Hemodialysis. AB - As protein binding of uremic toxins is not well understood, neither in chronic kidney disease (CKD) progression, nor during a hemodialysis (HD) session, we studied protein binding in two cross-sectional studies. Ninety-five CKD 2 to 5 patients and ten stable hemodialysis patients were included. Blood samples were taken either during the routine ambulatory visit (CKD patients) or from blood inlet and outlet line during dialysis (HD patients). Total (CT) and free concentrations were determined of p-cresylglucuronide (pCG), hippuric acid (HA), indole-3-acetic acid (IAA), indoxyl sulfate (IS) and p-cresylsulfate (pCS), and their percentage protein binding (%PB) was calculated. In CKD patients, %PB/CT resulted in a positive correlation (all p < 0.001) with renal function for all five uremic toxins. In HD patients, %PB was increased after 120 min of dialysis for HA and at the dialysis end for the stronger (IAA) and the highly-bound (IS and pCS) solutes. During one passage through the dialyzer at 120 min, %PB was increased for HA (borderline), IAA, IS and pCS. These findings explain why protein-bound solutes are difficult to remove by dialysis: a combination of the fact that (i) only the free fraction can pass the filter and (ii) the equilibrium, as it was pre-dialysis, cannot be restored during the dialysis session, as it is continuously disturbed. PMID- 26426049 TI - Detection of Dinophysistoxin-1 in Clonal Culture of Marine Dinoflagellate Prorocentrum foraminosum (Faust M.A., 1993) from the Sea of Japan. AB - For the first time the presence of dinophysistoxin-1 (DTX-1) in a culture of Prorocentrum foraminosum was revealed in cells and in the culture medium. The clone was isolated from coastal waters of the Sea of Japan and identified by molecular analyses of SSU and D1/D2 regions of LSU rDNA. The concentration of DTX 1 in cells was 8.4 +/- 2.5 pg/cell and, in cell-free media, 27.9 +/- 14.7 ug/L. The toxin presence was confirmed by HPLC with high-resolution tandem mass spectrometry. PMID- 26426047 TI - Conotoxin Interactions with alpha9alpha10-nAChRs: Is the alpha9alpha10-Nicotinic Acetylcholine Receptor an Important Therapeutic Target for Pain Management? AB - The alpha9alpha10-nicotinic acetylcholine receptor (nAChR) has been implicated in pain and has been proposed to be a novel target for analgesics. However, the evidence to support the involvement of the alpha9alpha10-nAChR in pain is conflicted. This receptor was first implicated in pain with the characterisation of conotoxin Vc1.1, which is highly selective for alpha9alpha10-nAChRs and is an efficacious analgesic in chronic pain models with restorative capacities and no reported side effects. Numerous other analgesic conotoxin and non-conotoxin molecules have been subsequently characterised that also inhibit alpha9alpha10 nAChRs. However, there is evidence that alpha9alpha10-nAChR inhibition is neither necessary nor sufficient for analgesia. alpha9alpha10-nAChR-inhibiting analogues of Vc1.1 have no analgesic effects. Genetically-modified alpha9-nAChR knockout mice have a phenotype that is markedly different from the analgesic profile of Vc1.1 and similar conotoxins, suggesting that the conotoxin effects are largely independent of alpha9alpha10-nAChRs. Furthermore, an alternative mechanism of analgesia by Vc1.1 and other similar conotoxins involving non-canonical coupling of GABAB receptors to voltage-gated calcium channels is known. Additional incongruities regarding alpha9alpha10-nAChRs in analgesia are discussed. A more comprehensive characterisation of the role of alpha9alpha10-nAChRs in pain is crucial for understanding the analgesic action of conotoxins and for improved drug design. PMID- 26426050 TI - Passive Immunotherapy Protects against Enteric Invasion and Lethal Sepsis in a Murine Model of Gastrointestinal Anthrax. AB - The principal portal for anthrax infection in natural animal outbreaks is the digestive tract. Enteric exposure to anthrax, which is difficult to detect or prevent in a timely manner, could be exploited as an act of terror through contamination of human or animal food. Our group has developed a novel animal model of gastrointestinal (GI) anthrax for evaluation of disease pathogenesis and experimental therapeutics, utilizing vegetative Bacillus anthracis (Sterne strain) administered to A/J mice (a complement-deficient strain) by oral gavage. We hypothesized that a humanized recombinant monoclonal antibody (mAb) * that neutralizes the protective antigen (PA) component of B. anthracis lethal toxin (LT) and edema toxin (ET) could be an effective treatment. Although the efficacy of this anti-anthrax PA mAb has been shown in animal models of inhalational anthrax, its activity in GI infection had not yet been ascertained. We hereby demonstrate that passive immunotherapy with anti-anthrax PA mAb, administered at the same time as gastrointestinal exposure to B. anthracis, prevents lethal sepsis in nearly all cases (>90%), while a delay of up to forty-eight hours in treatment still greatly reduces mortality following exposure (65%). Moreover, passive immunotherapy protects against enteric invasion, associated mucosal injury and subsequent dissemination by gastrointestinal B. anthracis, indicating that it acts to prevent the initial stages of infection. * Expired raxibacumab being cycled off the Strategic National Stockpile; biological activity confirmed by in vitro assay. PMID- 26426051 TI - Study of Adsorption and Flocculation Properties of Natural Clays to Remove Prorocentrum lima. AB - High accumulations of phytoplankton species that produce toxins are referred to as harmful algal blooms (HABs). HABs represent one of the most important sources of contamination in marine environments, as well as a serious threat to public health, fisheries, aquaculture-based industries, and tourism. Therefore, methods effectively controlling HABs with minimal impact on marine ecology are required. Marine dinoflagellates of the genera Dinophysis and Prorocentrum are representative producers of okadaic acid (OA) and dinophysistoxins responsible for the diarrhetic shellfish poisoning (DSP) which is a human intoxication caused by the consumption of shellfish that bioaccumulate those toxins. In this work we explore the use of natural clay for removing Prorocentrum lima. We evaluate the adsorption properties of clays in seawater containing the dinoflagellates. The experimental results confirmed the cell removal through the flocculation of algal and mineral particles leading to the formation of aggregates, which rapidly settle and further entrain cells during their descent. Moreover, the microscopy images of the samples enable one to observe the clays in aggregates of two or more cells where the mineral particles were bound to the outer membranes of the dinoflagellates. Therefore, this preliminary data offers promising results to use these clays for the mitigation of HABs. PMID- 26426053 TI - Clinical Implications of Hedgehog Pathway Signaling in Prostate Cancer. AB - Activity in the Hedgehog pathway, which regulates GLI-mediated transcription, is important in organogenesis and stem cell regulation in self-renewing organs, but is pathologically elevated in many human malignancies. Mutations leading to constitutive activation of the pathway have been implicated in medulloblastoma and basal cell carcinoma, and inhibition of the pathway has demonstrated clinical responses leading to the approval of the Smoothened inhibitor, vismodegib, for the treatment of advanced basal cell carcinoma. Aberrant Hedgehog pathway signaling has also been noted in prostate cancer with evidence suggesting that it may render prostate epithelial cells tumorigenic, drive the epithelial-to mesenchymal transition, and contribute towards the development of castration resistance through autocrine and paracrine signaling within the tumor microenvironment and cross-talk with the androgen pathway. In addition, there are emerging clinical data suggesting that inhibition of the Hedgehog pathway may be effective in the treatment of recurrent and metastatic prostate cancer. Here we will review these data and highlight areas of active clinical research as they relate to Hedgehog pathway inhibition in prostate cancer. PMID- 26426052 TI - Histone Modifications, Modifiers and Readers in Melanoma Resistance to Targeted and Immune Therapy. AB - The treatment of melanoma has been revolutionized by new therapies targeting MAPK signaling or the immune system. Unfortunately these therapies are hindered by either primary resistance or the development of acquired resistance. Resistance mechanisms involving somatic mutations in genes associated with resistance have been identified in some cases of melanoma, however, the cause of resistance remains largely unexplained in other cases. The importance of epigenetic factors targeting histones and histone modifiers in driving the behavior of melanoma is only starting to be unraveled and provides significant opportunity to combat the problems of therapy resistance. There is also an increasing ability to target these epigenetic changes with new drugs that inhibit these modifications to either prevent or overcome resistance to both MAPK inhibitors and immunotherapy. This review focuses on changes in histones, histone reader proteins and histone positioning, which can mediate resistance to new therapeutics and that can be targeted for future therapies. PMID- 26426054 TI - The Mesothelial Origin of Carcinoma Associated-Fibroblasts in Peritoneal Metastasis. AB - Solid tumors are complex and unstructured organs that, in addition to cancer cells, also contain other cell types. Carcinoma-associated fibroblasts (CAFs) represent an important population in the tumor microenviroment and participate in several stages of tumor progression, including cancer cell migration/invasion and metastasis. During peritoneal metastasis, cancer cells detach from the primary tumor, such as ovarian or gastrointestinal, disseminate through the peritoneal fluid and colonize the peritoneum. Tumor cells metastasize by attaching to and invading through the mesothelial cell (MC) monolayer that lines the peritoneal cavity, then colonizing the submesothelial compact zone where CAFs accumulate. CAFs may derive from different sources depending on the surrounding metastatic niche. In peritoneal metastasis, a sizeable subpopulation of CAFs originates from MCs through a mesothelial-to-mesenchymal transition (MMT), which promotes adhesion, invasion, vascularization and subsequent tumor growth. The bidirectional communication between cancer cells and MC-derived CAFs via secretion of a wide range of cytokines, growth factors and extracellular matrix components seems to be crucial for the establishment and progression of the metastasis in the peritoneum. This manuscript provides a comprehensive review of novel advances in understanding how peritoneal CAFs provide cancer cells with a supportive microenvironment, as well as the development of future therapeutic approaches by interfering with the MMT in the peritoneum. PMID- 26426055 TI - Intracellular Mono-ADP-Ribosylation in Signaling and Disease. AB - A key process in the regulation of protein activities and thus cellular signaling pathways is the modification of proteins by post-translational mechanisms. Knowledge about the enzymes (writers and erasers) that attach and remove post translational modifications, the targets that are modified and the functional consequences elicited by specific modifications, is crucial for understanding cell biological processes. Moreover detailed knowledge about these mechanisms and pathways helps to elucidate the molecular causes of various diseases and in defining potential targets for therapeutic approaches. Intracellular adenosine diphosphate (ADP)-ribosylation refers to the nicotinamide adenine dinucleotide (NAD+)-dependent modification of proteins with ADP-ribose and is catalyzed by enzymes of the ARTD (ADP-ribosyltransferase diphtheria toxin like, also known as PARP) family as well as some members of the Sirtuin family. Poly-ADP-ribosylation is relatively well understood with inhibitors being used as anti-cancer agents. However, the majority of ARTD enzymes and the ADP-ribosylating Sirtuins are restricted to catalyzing mono-ADP-ribosylation. Although writers, readers and erasers of intracellular mono-ADP-ribosylation have been identified only recently, it is becoming more and more evident that this reversible post translational modification is capable of modulating key intracellular processes and signaling pathways. These include signal transduction mechanisms, stress pathways associated with the endoplasmic reticulum and stress granules, and chromatin-associated processes such as transcription and DNA repair. We hypothesize that mono-ADP-ribosylation controls, through these different pathways, the development of cancer and infectious diseases. PMID- 26426057 TI - Non-Conserved Residues in Clostridium acetobutylicum tRNA(Ala) Contribute to tRNA Tuning for Efficient Antitermination of the alaS T Box Riboswitch. AB - The T box riboswitch regulates expression of amino acid-related genes in Gram positive bacteria by monitoring the aminoacylation status of a specific tRNA, the binding of which affects the folding of the riboswitch into mutually exclusive terminator or antiterminator structures. Two main pairing interactions between the tRNA and the leader RNA have been demonstrated to be necessary, but not sufficient, for efficient antitermination. In this study, we used the Clostridium acetobutylicum alaS gene, which encodes alanyl-tRNA synthetase, to investigate the specificity of the tRNA response. We show that the homologous C. acetobutylicum tRNA(Ala) directs antitermination of the C. acetobutylicum alaS gene in vitro, but the heterologous Bacillus subtilis tRNA(Ala) (with the same anticodon and acceptor end) does not. Base substitutions at positions that vary between these two tRNAs revealed synergistic and antagonistic effects. Variation occurs primarily at positions that are not conserved in tRNA(Ala) species, which indicates that these non-conserved residues contribute to optimal antitermination of the homologous alaS gene. This study suggests that elements in tRNA(Ala) may have coevolved with the homologous alaS T box leader RNA for efficient antitermination. PMID- 26426056 TI - Epigenetic Therapy for Solid Tumors: Highlighting the Impact of Tumor Hypoxia. AB - In the last few decades, epigenetics has emerged as an exciting new field in development and disease, with a more recent focus towards cancer. Epigenetics has classically referred to heritable patterns of gene expression, primarily mediated through DNA methylation patterns. More recently, it has come to include the reversible chemical modification of histones and DNA that dictate gene expression patterns. Both the epigenetic up-regulation of oncogenes and downregulation of tumor suppressors have been shown to drive tumor development. Current clinical trials for cancer therapy include pharmacological inhibition of DNA methylation and histone deacetylation, with the aim of reversing these cancer-promoting epigenetic changes. However, the DNA methyltransferase and histone deacetylase inhibitors have met with less than promising results in the treatment of solid tumors. Regions of hypoxia are a common occurrence in solid tumors. Tumor hypoxia is associated with increased aggressiveness and therapy resistance, and importantly, hypoxic tumor cells have a distinct epigenetic profile. In this review, we provide a summary of the recent clinical trials using epigenetic drugs in solid tumors, discuss the hypoxia-induced epigenetic changes and highlight the importance of testing the epigenetic drugs for efficacy against the most aggressive hypoxic fraction of the tumor in future preclinical testing. PMID- 26426058 TI - The Scalp Confounds Near-Infrared Signal from Rat Brain Following Innocuous and Noxious Stimulation. AB - Functional near-infrared imaging (fNIRI) is a non-invasive, low-cost and highly portable technique for assessing brain activity and functions. Both clinical and experimental evidence suggest that fNIRI is able to assess brain activity at associated regions during pain processing, indicating a strong possibility of using fNIRI-derived brain activity pattern as a biomarker for pain. However, it remains unclear how, especially in small animals, the scalp influences fNIRI signal in pain processing. Previously, we have shown that the use of a multi channel system improves the spatial resolution of fNIRI in rats (without the scalp) during pain processing. Our current work is to investigate a scalp effect by comparing with new data from rats with the scalp during innocuous or noxious stimulation (n = 6). Results showed remarkable stimulus-dependent differences between the no-scalp and intact-scalp groups. In conclusion, the scalp confounded the fNIRI signal in pain processing likely via an autonomic mechanism; the scalp effect should be a critical factor in image reconstruction and data interpretation. PMID- 26426059 TI - Hemodynamic and Light-Scattering Changes of Rat Spinal Cord and Primary Somatosensory Cortex in Response to Innocuous and Noxious Stimuli. AB - Neuroimaging technologies with an exceptional spatial resolution and noninvasiveness have become a powerful tool for assessing neural activity in both animals and humans. However, the effectiveness of neuroimaging for pain remains unclear partly because the neurovascular coupling during pain processing is not completely characterized. Our current work aims to unravel patterns of neurovascular parameters in pain processing. A novel fiber-optic method was used to acquire absolute values of regional oxy- (HbO) and deoxy-hemoglobin concentrations, oxygen saturation rates (SO2), and the light-scattering coefficients from the spinal cord and primary somatosensory cortex (SI) in 10 rats. Brief mechanical and electrical stimuli (ranging from innocuous to noxious intensities) as well as a long-lasting noxious stimulus (formalin injection) were applied to the hindlimb under pentobarbital anesthesia. Interhemispheric comparisons in the spinal cord and SI were used to confirm functional activation during sensory processing. We found that all neurovascular parameters showed stimulation-induced changes; however, patterns of changes varied with regions and stimuli. Particularly, transient increases in HbO and SO2 were more reliably attributed to brief stimuli, whereas a sustained decrease in SO2 was more reliably attributed to formalin. Only the ipsilateral SI showed delayed responses to brief stimuli. In conclusion, innocuous and noxious stimuli induced significant neurovascular responses at critical centers (e.g., the spinal cord and SI) along the somatosensory pathway; however, there was no single response pattern (as measured by amplitude, duration, lateralization, decrease or increase) that was able to consistently differentiate noxious stimuli. Our results strongly suggested that the neurovascular response patterns differ between brief and long-lasting noxious stimuli, and can also differ between the spinal cord and SI. Therefore, a use of multiple-parameter strategy tailored by stimulus modality (brief or long-lasting) as well as region-dependent characteristics may be more effective in detecting pain using neuroimaging technologies. PMID- 26426060 TI - Micelle-Based Adjuvants for Subunit Vaccine Delivery. AB - In the development of subunit vaccines with purified or recombinant antigens for cancer and infectious diseases, the design of improved and safe adjuvants able to efficiently target the antigen presenting cells, such as dendritic cells, represents a crucial challenge. Nanoparticle-based antigen delivery systems have been identified as an innovative strategy to improve the efficacy of subunit vaccines. Among them, self-assembled micellar nanoparticles from amphiphilic (macro)molecules have recently emerged as promising candidates. In this short review, we report on the recent research findings highlighting the versatility and potential of such systems in vaccine delivery. PMID- 26426061 TI - The Effect of the Nonlinearity of the Response of Lipid Membranes to Voltage Perturbations on the Interpretation of Their Electrical Properties. A New Theoretical Description. AB - Our understanding of the electrical properties of cell membranes is derived from experiments where the membrane is exposed to a perturbation (in the form of a time-dependent voltage or current change) and information is extracted from the measured output. The interpretation of such electrical recordings consists in finding an electronic equivalent that would show the same or similar response as the biological system. In general, however, there is no unique circuit configuration, which can explain a single electrical recording and the choice of an electric model for a biological system is based on complementary information (most commonly structural information) of the system investigated. Most of the electrophysiological data on cell membranes address the functional role of protein channels while assuming that the lipid matrix is an insulator with constant capacitance. However, close to their melting transition the lipid bilayers are no inert insulators. Their conductivity and their capacitance are nonlinear functions of both voltage, area and volume density. This has to be considered when interpreting electrical data. Here we show how electric data commonly interpreted as gating currents of proteins and inductance can be explained by the nonlinear dynamics of the lipid matrix itself. PMID- 26426062 TI - On the Recent Use of Membrane Technology for Olive Mill Wastewater Purification. AB - Many reclamation treatments as well as integrated processes for the purification of olive mill wastewaters (OMW) have already been proposed and developed but not led to completely satisfactory results, principally due to complexity or cost ineffectiveness. The olive oil industry in its current status, composed of little and dispersed factories, cannot stand such high costs. Moreover, these treatments are not able to abate the high concentration of dissolved inorganic matter present in these highly polluted effluents. In the present work, a review on the actual state of the art concerning the treatment and disposal of OMW by membranes is addressed, comprising microfiltration (MF), ultrafiltration (UF), nanofiltration (NF), and reverse osmosis (RO), as well as membrane bioreactors (MBR) and non-conventional membrane processes such as vacuum distillation (VD), osmotic distillation (OD) and forward osmosis (FO). Membrane processes are becoming extensively used to replace many conventional processes in the purification of water and groundwater as well as in the reclamation of wastewater streams of very diverse sources, such as those generated by agro-industrial activities. Moreover, a brief insight into inhibition and control of fouling by properly-tailored pretreatment processes upstream the membrane operation and the use of the critical and threshold flux theories is provided. PMID- 26426063 TI - Strong Static Magnetic Fields Increase the Gel Signal in Partially Hydrated DPPC/DMPC Membranes. AB - NIt was recently reported that static magnetic fields increase lipid order in the hydrophobic membrane core of dehydrated native plant plasma membranes [Poinapen, Soft Matter 9:6804-6813, 2013]. As plasma membranes are multicomponent, highly complex structures, in order to elucidate the origin of this effect, we prepared model membranes consisting of a lipid species with low and high melting temperature. By controlling the temperature, bilayers coexisting of small gel and fluid domains were prepared as a basic model for the plasma membrane core. We studied molecular order in mixed lipid membranes made of dimyristoyl-sn-glycero-3 phosphocholine (DMPC) and dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) using neutron diffraction in the presence of strong static magnetic fields up to 3.5 T. The contribution of the hydrophobic membrane core was highlighted through deuterium labeling the lipid acyl chains. There was no observable effect on lipid organization in fluid or gel domains at high hydration of the membranes. However, lipid order was found to be enhanced at a reduced relative humidity of 43%: a magnetic field of 3.5 T led to an increase of the gel signal in the diffraction patterns of 5%. While all biological materials have weak diamagnetic properties, the corresponding energy is too small to compete against thermal disorder or viscous effects in the case of lipid molecules. We tentatively propose that the interaction between the fatty acid chains' electric moment and the external magnetic field is driving the lipid tails in the hydrophobic membrane core into a better ordered state. PMID- 26426064 TI - Regulation of the Target of Rapamycin and Other Phosphatidylinositol 3-Kinase Related Kinases by Membrane Targeting. AB - Phosphatidylinositol 3-kinase-related kinases (PIKKs) play vital roles in the regulation of cell growth, proliferation, survival, and consequently metabolism, as well as in the cellular response to stresses such as ionizing radiation or redox changes. In humans six family members are known to date, namely mammalian/mechanistic target of rapamycin (mTOR), ataxia-telangiectasia mutated (ATM), ataxia- and Rad3-related (ATR), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), suppressor of morphogenesis in genitalia-1 (SMG-1), and transformation/transcription domain-associated protein (TRRAP). All fulfill rather diverse functions and most of them have been detected in different cellular compartments including various cellular membranes. It has been suggested that the regulation of the localization of signaling proteins allows for generating a locally specific output. Moreover, spatial partitioning is expected to improve the reliability of biochemical signaling. Since these assumptions may also be true for the regulation of PIKK function, the current knowledge about the regulation of the localization of PIKKs at different cellular (membrane) compartments by a network of interactions is reviewed. Membrane targeting can involve direct lipid-/membrane interactions as well as interactions with membrane anchored regulatory proteins, such as, for example, small GTPases, or a combination of both. PMID- 26426066 TI - T Cells in Fish. AB - Cartilaginous and bony fish are the most primitive vertebrates with a thymus, and possess T cells equivalent to those in mammals. There are a number of studies in fish demonstrating that the thymus is the essential organ for development of T lymphocytes from early thymocyte progenitors to functionally competent T cells. A high number of T cells in the intestine and gills has been reported in several fish species. Involvement of CD4+ and CD8alpha+ T cells in allograft rejection and graft-versus-host reaction (GVHR) has been demonstrated using monoclonal antibodies. Conservation of CD4+ helper T cell functions among teleost fishes has been suggested in a number studies employing mixed leukocyte culture (MLC) and hapten/carrier effect. Alloantigen- and virus-specific cytotoxicity has also been demonstrated in ginbuna and rainbow trout. Furthermore, the important role of cell-mediated immunity rather than humoral immunity has been reported in the protection against intracellular bacterial infection. Recently, the direct antibacterial activity of CD8alpha+, CD4+ T-cells and sIgM+ cells in fish has been reported. In this review, we summarize the recent progress in T cell research focusing on the tissue distribution and function of fish T cells. PMID- 26426065 TI - Antimicrobial Peptides as Mediators of Innate Immunity in Teleosts. AB - Antimicrobial peptides (AMPs) have been identified throughout the metazoa suggesting their evolutionarily conserved nature and their presence in teleosts is no exception. AMPs are short (18-46 amino acids), usually cationic, amphipathic peptides. While AMPs are diverse in amino acid sequence, with no two AMPs being identical, they collectively appear to have conserved functions in the innate immunity of animals towards the pathogens they encounter in their environment. Fish AMPs are upregulated in response to pathogens and appear to have direct broad-spectrum antimicrobial activity towards both human and fish pathogens. However, an emerging role for AMPs as immunomodulatory molecules has become apparent-the ability of AMPs to activate the innate immune system sheds light onto the multifaceted capacity of these small peptides to combat pathogens through direct and indirect means. Herein, this review focuses on the role of teleost AMPs as modulators of the innate immune system and their regulation in response to pathogens or other exogenous molecules. The capacity to regulate AMP expression by exogenous factors may prove useful in modulating AMP expression in fish to prevent disease, particularly in aquaculture settings where crowded conditions and environmental stress pre-dispose these fish to infection. PMID- 26426069 TI - Incidence of dentinal defects after preparation of severely curved root canals using the Reciproc single-file system with and without prior creation of a glide path. AB - AIM: To investigate the incidence of dentinal defects after preparation of severely curved root canals using the Reciproc single-file system with and without prior creation of a glide path. METHODOLOGY: Mesial roots from extracted mandibular first molars were collected and scanned with CBCT to assess the morphology of the root canal systems. Three groups of 20 anatomically comparable specimens were generated. The control group was left unprepared, whilst the experimental groups were prepared with Reciproc R25 with and without a glide path (groups RG and R, respectively). Roots were then sectioned perpendicular to the long axis at 2, 4, 6, 8 and 10 mm from the apex, and coloured photographs of the sections at 40* were obtained. Two blinded examiners registered the presence of dentinal defects twice at 2-week interval. Data were statistically analysed using the Fisher exact and Cochran's Q tests. RESULTS: No defects were observed in the control group. The overall incidence of dentinal defects was 26% in group R and 24% in group RG, with no significant differences between them (P > 0.05). Dentinal defects occurred significantly more often in the middle and coronal thirds compared to the apical third of the canals (P < 0.05). CONCLUSIONS: Prior preparation of a glide path had no impact on the incidence of dentinal defects when using Reciproc files. PMID- 26426070 TI - LM-CMA: An Alternative to L-BFGS for Large-Scale Black Box Optimization. AB - Limited-memory BFGS (L-BFGS; Liu and Nocedal, 1989 ) is often considered to be the method of choice for continuous optimization when first- or second-order information is available. However, the use of L-BFGS can be complicated in a black box scenario where gradient information is not available and therefore should be numerically estimated. The accuracy of this estimation, obtained by finite difference methods, is often problem-dependent and may lead to premature convergence of the algorithm. This article demonstrates an alternative to L-BFGS, the limited memory covariance matrix adaptation evolution strategy (LM-CMA) proposed by Loshchilov ( 2014 ). LM-CMA is a stochastic derivative-free algorithm for numerical optimization of nonlinear, nonconvex optimization problems. Inspired by L-BFGS, LM-CMA samples candidate solutions according to a covariance matrix reproduced from m direction vectors selected during the optimization process. The decomposition of the covariance matrix into Cholesky factors allows reducing the memory complexity to [Formula: see text], where n is the number of decision variables. The time complexity of sampling one candidate solution is also [Formula: see text] but scales as only about 25 scalar-vector multiplications in practice. The algorithm has an important property of invariance with respect to strictly increasing transformations of the objective function; such transformations do not compromise its ability to approach the optimum. LM-CMA outperforms the original CMA-ES and its large-scale versions on nonseparable ill-conditioned problems with a factor increasing with problem dimension. Invariance properties of the algorithm do not prevent it from demonstrating a comparable performance to L-BFGS on nontrivial large-scale smooth and nonsmooth optimization problems. PMID- 26426067 TI - Using Gene Essentiality and Synthetic Lethality Information to Correct Yeast and CHO Cell Genome-Scale Models. AB - Essentiality (ES) and Synthetic Lethality (SL) information identify combination of genes whose deletion inhibits cell growth. This information is important for both identifying drug targets for tumor and pathogenic bacteria suppression and for flagging and avoiding gene deletions that are non-viable in biotechnology. In this study, we performed a comprehensive ES and SL analysis of two important eukaryotic models (S. cerevisiae and CHO cells) using a bilevel optimization approach introduced earlier. Information gleaned from this study is used to propose specific model changes to remedy inconsistent with data model predictions. Even for the highly curated Yeast 7.11 model we identified 50 changes (metabolic and GPR) leading to the correct prediction of an additional 28% of essential genes and 36% of synthetic lethals along with a 53% reduction in the erroneous identification of essential genes. Due to the paucity of mutant growth phenotype data only 12 changes were made for the CHO 1.2 model leading to an additional correctly predicted 11 essential and eight non-essential genes. Overall, we find that CHO 1.2 was 76% less accurate than the Yeast 7.11 metabolic model in predicting essential genes. Based on this analysis, 14 (single and double deletion) maximally informative experiments are suggested to improve the CHO cell model by using information from a mouse metabolic model. This analysis demonstrates the importance of single and multiple knockout phenotypes in assessing and improving model reconstructions. The advent of techniques such as CRISPR opens the door for the global assessment of eukaryotic models. PMID- 26426071 TI - Perinatal outcomes after hypertensive disorders in pregnancy in a low resource setting. AB - OBJECTIVE: The objective of this study was to evaluate perinatal outcomes of pregnancies complicated by hypertensive disorders in pregnancy in an urban sub Saharan African setting. METHODS: A prospective cohort study of 1010 women of less than 17 weeks of gestation was conducted at two antenatal clinics in Accra, Ghana, between July 2012 and March 2014. Information about hypertensive disorders was available for analysis on 789 pregnancies. The main outcomes were pre-term birth, birthweight, Apgar scores, small for gestational age and mortality. Relative risk (RR, 95% confidence interval (CI)) for the association between hypertensive disorders of pregnancy and perinatal outcomes was assessed using logistic regression adjusting for potential confounders. RESULTS: A total of 88.7% of women remained normotensive, 7.5% developed pregnancy-induced hypertension, 2.0% had chronic hypertension, and 1.7% developed (pre-)eclampsia. No adverse effects were observed in women with pregnancy-induced hypertension. Women with chronic hypertension were more likely to have a lower gestational age at delivery (38.0 +/- 2.3 weeks vs. 39.0 +/- 1.9 weeks, P = 0.04) and higher risk of pre-term delivery (aRR 4.63, 95% CI 1.35-15.91). Women with pre-eclampsia had emergency Caesarean section significantly more often (88.9% vs. 50%, P = 0.04), with a higher risk for low birthweight infants (aRR 7.95, 95% CI 1.41-44.80) and a higher risk of neonatal death (aRR 18.41, 95% CI 1.20-283.22). CONCLUSION: Comparable to high-income countries, in Accra hypertensive disorders during pregnancy were associated with increased risk of adverse perinatal outcomes necessitating maternal and newborn care. PMID- 26426068 TI - Impact of Alcohol on Glycemic Control and Insulin Action. AB - Alcohol has profound effects on tissue and whole-body fuel metabolism which contribute to the increased morbidity and mortality in individuals with alcohol use disorder. This review focuses on the glucose metabolic effects of alcohol, primarily in the muscle, liver and adipose tissue, under basal postabsorptive conditions and in response to insulin stimulation. While there is a relatively extensive literature in this area, results are often discordant and extrapolating between models and tissues is fraught with uncertainty. Comparisons between data generated in experimental cell and animals systems will be contrasted with that obtained from human subjects as often times results differ. Further, the nutritional status is also an important component of the sometimes divergent findings pertaining to the effects of alcohol on the regulation of insulin and glucose metabolism. This work is relevant as the contribution of alcohol intake to the development or exacerbation of type 2 diabetes remains ill-defined and a multi-systems approach is likely needed as both alcohol and diabetes affect multiple targets within the body. PMID- 26426072 TI - The Network for Evaluation of One Health: evidence-based added value of One Health. PMID- 26426073 TI - A conversation with Helen Hobbs. PMID- 26426074 TI - Rescuing the physician-scientist workforce: the time for action is now. AB - The 2014 NIH Physician-Scientist Workforce (PSW) Working Group report identified distressing trends among the small proportion of physicians who consider research to be their primary occupation. If unchecked, these trends will lead to a steep decline in the size of the workforce. They include high rates of attrition among young investigators, failure to maintain a robust and diverse pipeline, and a marked increase in the average age of physician-scientists, as older investigators have chosen to continue working and too few younger investigators have entered the workforce to replace them when they eventually retire. While the policy debates continue, here we propose four actions that can be implemented now. These include applying lessons from the MD-PhD training experience to postgraduate training, shortening the time to independence by at least 5 years, achieving greater diversity and numbers in training programs, and establishing Physician-Scientist Career Development offices at medical centers and universities. Rather than waiting for the federal government to solve our problems, we urge the academic community to address these goals by partnering with the NIH and national clinical specialty and medical organizations. PMID- 26426075 TI - Proof-of-principle rapid noninvasive prenatal diagnosis of autosomal recessive founder mutations. AB - BACKGROUND: Noninvasive prenatal testing can be used to accurately detect chromosomal aneuploidies in circulating fetal DNA; however, the necessity of parental haplotype construction is a primary drawback to noninvasive prenatal diagnosis (NIPD) of monogenic disease. Family-specific haplotype assembly is essential for accurate diagnosis of minuscule amounts of circulating cell-free fetal DNA; however, current haplotyping techniques are too time-consuming and laborious to be carried out within the limited time constraints of prenatal testing, hampering practical application of NIPD in the clinic. Here, we have addressed this pitfall and devised a universal strategy for rapid NIPD of a prevalent mutation in the Ashkenazi Jewish (AJ) population. METHODS: Pregnant AJ couples, carrying mutation(s) in GBA, which encodes acid beta-glucosidase, were recruited at the SZMC Gaucher Clinic. Targeted next-generation sequencing of GBA flanking SNPs was performed on peripheral blood samples from each couple, relevant mutation carrier family members, and unrelated individuals who are homozygotes for an AJ founder mutation. Allele-specific haplotypes were constructed based on linkage, and a consensus Gaucher disease-associated founder mutation-flanking haplotype was fine mapped. Together, these haplotypes were used for NIPD. All test results were validated by conventional prenatal or postnatal diagnostic methods. RESULTS: Ten parental alleles in eight unrelated fetuses were diagnosed successfully based on the noninvasive method developed in this study. The consensus mutation-flanking haplotype aided diagnosis for 6 of 9 founder mutation alleles. CONCLUSIONS: The founder NIPD method developed and described here is rapid, economical, and readily adaptable for prenatal testing of prevalent autosomal recessive disease-causing mutations in an assortment of worldwide populations. FUNDING: SZMC, Protalix Biotherapeutics Inc., and Centogene AG. PMID- 26426076 TI - IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII. AB - The development of inhibitory antibodies to factor VIII (FVIII) is a major obstacle in using this clotting factor to treat individuals with hemophilia A. Patients with a congenital absence of FVIII do not develop central tolerance to FVIII, and therefore, any control of their FVIII-reactive lymphocytes relies upon peripheral tolerance mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulatory enzyme that supports Treg function and peripheral tolerance in adult life. Here, we investigated the association between IDO1 competence and inhibitor status by evaluating hemophilia A patients harboring F8-null mutations that were either inhibitor negative (n = 50) or positive (n = 50). We analyzed IDO1 induction, expression, and function for any relationship with inhibitor occurrence by multivariable logistic regression and determined that defective TLR9-mediated activation of IDO1 induction is associated with an inhibitor positive status. Evaluation of experimental hemophilic mouse models with or without functional IDO1 revealed that tryptophan metabolites, which result from IDO1 activity, prevent generation of anti-FVIII antibodies. Moreover, treatment of hemophilic animals with a TLR9 agonist suppressed FVIII-specific B cells by a mechanism that involves IDO1-dependent induction of Tregs. Together, these findings indicate that strategies aimed at improving IDO1 function should be further explored for preventing or eradicating inhibitors to therapeutically administered FVIII protein. PMID- 26426077 TI - Identifying local and descending inputs for primary sensory neurons. AB - Primary pain and touch sensory neurons not only detect internal and external sensory stimuli, but also receive inputs from other neurons. However, the neuronal derived inputs for primary neurons have not been systematically identified. Using a monosynaptic rabies viruses-based transneuronal tracing method combined with sensory-specific Cre-drivers, we found that sensory neurons receive intraganglion, intraspinal, and supraspinal inputs, the latter of which are mainly derived from the rostroventral medulla (RVM). The viral-traced central neurons were largely inhibitory but also consisted of some glutamatergic neurons in the spinal cord and serotonergic neurons in the RVM. The majority of RVM derived descending inputs were dual GABAergic and enkephalinergic (opioidergic). These inputs projected through the dorsolateral funiculus and primarily innervated layers I, II, and V of the dorsal horn, where pain-sensory afferents terminate. Silencing or activation of the dual GABA/enkephalinergic RVM neurons in adult animals substantially increased or decreased behavioral sensitivity, respectively, to heat and mechanical stimuli. These results are consistent with the fact that both GABA and enkephalin can exert presynaptic inhibition of the sensory afferents. Taken together, this work provides a systematic view of and a set of tools for examining peri- and extrasynaptic regulations of pain-afferent transmission. PMID- 26426078 TI - ZIC2-dependent OCT4 activation drives self-renewal of human liver cancer stem cells. AB - Liver cancer stem cells (CSCs) have been identified and shown to have self renewal and differentiation properties; however, the biology of these hepatic CSCs remains largely unknown. Here, we analyzed transcriptome gene expression profiles of liver CSCs and non-CSCs from hepatocellular carcinoma (HCC) cells lines and found that the transcription factor (TF) ZIC2 is highly expressed in liver CSCs. ZIC2 was required for the self-renewal maintenance of liver CSCs, as ZIC2 depletion reduced sphere formation and xenograft tumor growth in mice. We determined that ZIC2 acts upstream of the TF OCT4 and that ZIC2 recruits the nuclear remodeling factor (NURF) complex to the OCT4 promoter, thereby initiating OCT4 activation. In HCC patients, expression levels of the NURF complex were consistent with clinical severity and prognosis. Moreover, ZIC2 and OCT4 levels positively correlated to the clinicopathological stages of HCC patients. Altogether, our results indicate that levels of ZIC2, OCT4, and the NURF complex can be detected and used for diagnosis and prognosis prediction of HCC patients. Moreover, these factors may be potential therapeutic targets for eradicating liver CSCs. PMID- 26426080 TI - CTGF directs fibroblast differentiation from human mesenchymal stem/stromal cells and defines connective tissue healing in a rodent injury model. PMID- 26426081 TI - The tragic fate of group 3 innate lymphoid cells during HIV-1 infection. PMID- 26426082 TI - A New Strategy to Increase Scientific Publications and Facilitate Research Uptake in the Caribbean. PMID- 26426079 TI - Bacterial exploitation of phosphorylcholine mimicry suppresses inflammation to promote airway infection. AB - Regulation of neutrophil activity is critical for immune evasion among extracellular pathogens, yet the mechanisms by which many bacteria disrupt phagocyte function remain unclear. Here, we have shown that the respiratory pathogen Streptococcus pneumoniae disables neutrophils by exploiting molecular mimicry to degrade platelet-activating factor (PAF), a host-derived inflammatory phospholipid. Using mass spectrometry and murine upper airway infection models, we demonstrated that phosphorylcholine (ChoP) moieties that are shared by PAF and the bacterial cell wall allow S. pneumoniae to leverage a ChoP-remodeling enzyme (Pce) to remove PAF from the airway. S. pneumoniae-mediated PAF deprivation impaired viability, activation, and bactericidal capacity among responding neutrophils. In the absence of Pce, neutrophils rapidly cleared S. pneumoniae from the airway and impeded invasive disease and transmission between mice. Abrogation of PAF signaling rendered Pce dispensable for S. pneumoniae persistence, reinforcing that this enzyme deprives neutrophils of essential PAF mediated stimulation. Accordingly, exogenous activation of neutrophils overwhelmed Pce-mediated phagocyte disruption. Haemophilus influenzae also uses an enzyme, GlpQ, to hydrolyze ChoP and subvert PAF function, suggesting that mimicry-driven immune evasion is a common paradigm among respiratory pathogens. These results identify a mechanism by which shared molecular structures enable microbial enzymes to subvert host lipid signaling, suppress inflammation, and ensure bacterial persistence at the mucosa. PMID- 26426084 TI - Alexithymia in children with and without autism spectrum disorders. AB - Alexithymia refers to pronounced difficulty in identifying and describing one's own emotions and is associated with an externally oriented focus of thinking. Alexithymia is known to be much more common in adults with autism spectrum disorders (ASD) compared with the typically developing (TD) adult population. However, we know very little about alexithymia in young children with ASD and advancing our understanding of this topic may be of critical clinical and translational importance. Here, we present the first study to examine alexithymia in children with ASD. We find that alexithymia is substantially elevated in ASD on both self- and parent-report measures. Despite both measures being sensitive to on-average group differentiation, we find no evidence of correlation between such measures, indicating that children and their parents may be using different sources of information. Parent-rated alexithymia is also associated with increasing levels of autistic traits. Discrepancy between self and other alexithymia ratings are also associated with autistic traits, but only in ASD. These results underscore the idea that assessing alexithymia in ASD at younger ages may help identify important subgroups that have particular difficulties in the domain of emotion processing. Autism Res 2016, 9: 773-780. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26426085 TI - Boosting the sensitivity of Nd(3+)-based luminescent nanothermometers. AB - Luminescence thermal sensing and deep-tissue imaging using nanomaterials operating within the first biological window (ca. 700-980 nm) are of great interest, prompted by the ever-growing demands in the fields of nanotechnology and nanomedicine. Here, we show that (Gd1-xNdx)2O3 (x = 0.009, 0.024 and 0.049) nanorods exhibit one of the highest thermal sensitivity and temperature uncertainty reported so far (1.75 +/- 0.04% K(-1) and 0.14 +/- 0.05 K, respectively) for a nanothermometer operating in the first transparent near infrared window at temperatures in the physiological range. This sensitivity value is achieved using a common R928 photomultiplier tube that allows defining the thermometric parameter as the integrated intensity ratio between the (4)F5/2 > (4)I9/2 and (4)F3/2 -> (4)I9/2 transitions (with an energy difference between the barycentres of the two transitions >1000 cm(-1)). Moreover, the measured sensitivity is one order of magnitude higher than the values reported so far for Nd(3+)-based nanothermometers enlarging, therefore, the potential of using Nd(3+) ions in luminescence thermal sensing and deep-tissue imaging. PMID- 26426083 TI - Neisseria gonorrhoeae survives within and modulates apoptosis and inflammatory cytokine production of human macrophages. AB - The human-adapted organism Neisseria gonorrhoeae is the causative agent of gonorrhoea, a sexually transmitted infection. It readily colonizes the genital, rectal and nasalpharyngeal mucosa during infection. While it is well established that N. gonorrhoeae recruits and modulates the functions of polymorphonuclear leukocytes during infection, how N. gonorrhoeae interacts with macrophages present in infected tissue is not fully defined. We studied the interactions of N. gonorrhoeae with two human monocytic cell lines, THP-1 and U937, and primary monocytes, all differentiated into macrophages. Most engulfed bacteria were killed in the phagolysosome, but a subset of bacteria was able to survive and replicate inside the macrophages suggesting that those cells may be an unexplored cellular reservoir for N. gonorrhoeae during infection. N. gonorrhoeae was able to modulate macrophage apoptosis: N. gonorrhoeae induced apoptosis in THP-1 cells whereas it inhibited induced apoptosis in U937 cells and primary human macrophages. Furthermore, N. gonorrhoeae induced expression of inflammatory cytokines in macrophages, suggesting a role for macrophages in recruiting polymorphonuclear leukocytes to the site of infection. These results indicate macrophages may serve as a significant replicative niche for N. gonorrhoeae and play an important role in gonorrheal pathogenesis. PMID- 26426086 TI - Enhancing the Therapy Experience Using Principles of Video Game Design. AB - PURPOSE: This article considers the potential benefits that applying design principles from contemporary video games may have on enhancing therapy experiences. METHOD: Six principles of video game design are presented, and their relevance for enriching clinical experiences is discussed. RESULTS: The motivational and learning benefits of each design principle have been discussed in the education literature as having positive impacts on student motivation and learning and are related here to aspects of clinical practice. The essential experience principle suggests connecting all aspects of the experience around a central emotion or cognitive connection. The discovery principle promotes indirect learning in focused environments. The risk-taking principle addresses the uncertainties clients face when attempting newly learned skills in novel situations. The generalization principle encourages multiple opportunities for skill transfer. The reward system principle directly relates to the scaffolding of frequent and varied feedback in treatment. Last, the identity principle can assist clients in using their newly learned communication skills to redefine self perceptions. CONCLUSION: These principles highlight areas for research and interventions that may be used to reinforce or advance current practice. PMID- 26426087 TI - Plasma Xanthine Oxidase Activity Is Predictive of Cardiovascular Disease in Patients with Chronic Kidney Disease, Independently of Uric Acid Levels. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality. Oxidative stress seems to play a pivotal role in this process, and purine metabolism may be involved in CKD-related oxidative stress. Xanthine oxidase (XO) is an enzyme involved in purine metabolism and is also responsible for the production of reactive oxygen species. METHODS: This prospective study aimed to analyze the relation between plasma dosages of molecules involved in redox balance, purine metabolism and cardiovascular events in patients with non-diabetic CKD stages 3-5 or on chronic hemodialysis (HD). CKD (n = 51) and HD (n = 50) patients were compared to matched healthy controls (n = 38) and followed-up for 3 years. RESULTS: Both CKD and HD patients had decreased plasma levels of antioxidants (selenium, zinc, vitamin C). HD patients had decreased levels of the antioxidant enzyme superoxide dismutase and increased levels of oxidation products (ischemia-modified albumin, malondialdehyde [MDA]). The following substrates and enzymes involved in purine metabolism were increased in the HD cohort: adenosine, adenosine deaminase and the pro-oxidant XO. XO activity was negatively correlated with super oxide dismutase and positively with MDA. Interestingly, XO activity was an independent predictor of cardiovascular events in CKD and HD patients, regardless of uric acid levels. Uric acid was not predictive of events. CONCLUSION: This highlights a possible role of XO itself in CKD-related cardiovascular disease (CVD) and raises the hypothesis that beneficial effects observed with XO inhibitors on CVD in CKD may also be due to the reduction of oxidative stress. PMID- 26426088 TI - Why Do Patients with COPD Decline Rehabilitation. AB - AIM: This paper aimed to suggest possible answers to the question: Why do patients with COPD decline pulmonary rehabilitation (PR)? METHOD: The study is a metasynthesis inspired by Noblit of the existing qualitative research on the area. The data were collected during 2014. Six studies were found through a systematic literature search in relevant databases. In these six studies, 65 persons were identified as decliners of PR. Four themes were identified from these studies. RESULTS: The themes identified were as follows: the referral process, transport problems, perception of health and other obligations or priorities. The problems with the referral of patients relate to different areas: the referring health professional's conviction and commitment, and the patients' understanding of the referral. It seems that various transport problems cause decline, for example long distance to the PR centre or the expenses of getting back and forth. Perceptions of health cause decline. Decliners feel too sick to join PR or do not identify themselves as a sick person, and do not want undertake the 'patient role'. Other obligations or priorities such as work, family obligations and vacations are prioritised on behalf of PR causing decline. CONCLUSION: The studies included show patients' rational accounts and reflections on declining PR. The included studies tend to describe accounts for deselection of PR in relation to the preferences and beliefs of the patients rather than including the social and economic variables framing the behaviour and choices of the patients. PMID- 26426089 TI - Amidinate-Stabilized Group 9 Metal-Silicon(I) Dimer and -Silylene Complexes. AB - The coordination chemistry of the amidinate-stabilized silicon(I) dimer toward group 9 metal complexes is described. The reaction of [LSi:]2 (1, L = PhC(NtBu)2) with [Ir(cod)Cl]2 (cod = 1,5-cyclooctadiene) in toluene at ambient temperature afforded the base-stabilized silicon(I) dimer-iridium complex [LSi{Ir(cod)-MU-Cl Ir(cod)}SiL][(cod)IrCl2] (2). In contrast, the reaction of 1 with [Rh(cod)Cl]2 in toluene at ambient temperature afforded a mixture of the amidinate-stabilized silicon(I) dimer-rhodium complex [LSi{Rh(cod)-MU-Cl-Rh(cod)}SiL] (3) and the dimeric amidinate-stabilized rhodosilylene [(LSi)MU-{Rh(MU-Cl)2Rh(cod)}]2 (4). Moreover, the latter reacted with PPh3 to afford a mixture of the Wilkinson's catalyst [(PPh3)3RhCl] and the dimeric rhodosilylene complex [(LSi)MU {RhCl(PPh3)}]2 (5), which underwent a rearrangement to form the rhodosilylene phosphidorhodium dimer (LSi)[MU-{RhCl(PPh3)}MU-{RhCl(LSiPh)}](PPh2) (6). Compounds 2-6 were characterized by NMR spectroscopy and X-ray crystallography. In addition, DFT calculations of compound 4 were performed to understand its electronic structure. PMID- 26426091 TI - Computerized tomography scanning: are we optimizing catheter revision surgery in targeted drug delivery systems? PMID- 26426090 TI - Production of decellularized porcine lung scaffolds for use in tissue engineering. AB - There is a growing body of work dedicated to producing acellular lung scaffolds for use in regenerative medicine by decellularizing donor lungs of various species. These scaffolds typically undergo substantial matrix damage due to the harsh conditions required to remove cellular material (e.g., high pH, strong detergents), lengthy processing times, or pre-existing tissue contamination from microbial colonization. In this work, a new decellularization technique is described that maintains the global tissue architecture, key matrix components, mechanical composition and cell-seeding potential of lung tissue while effectively removing resident cellular material. Acellular lung scaffolds were produced from native porcine lungs using a combination of Triton X-100 and sodium deoxycholate (SDC) at low concentrations in 24 hours. We assessed the effect of matrix decellularization by measuring residual DNA, biochemical composition, mechanical characteristics, tissue architecture, and recellularization capacity. PMID- 26426092 TI - Subgroup analysis of Japanese patients in a phase 3 study of lenvatinib in radioiodine-refractory differentiated thyroid cancer. AB - Lenvatinib significantly prolonged progression-free survival (PFS) versus placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) in the phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial. This subanalysis evaluated the efficacy and safety of lenvatinib in Japanese patients who participated in SELECT. Outcomes for Japanese patients (lenvatinib, n = 30; placebo, n = 10) were assessed in relationship to the SELECT population (lenvatinib, n = 261; placebo, n = 131). The primary endpoint was PFS; secondary endpoints included overall survival, overall response rate, and safety. Lenvatinib PFS benefit was shown in Japanese patients (median PFS: lenvatinib, 16.5 months; placebo, 3.7 months), although significance was not reached, presumably due to sample size (hazard ratio, 0.39; 95% confidence interval, 0.10 1.57; P = 0.067). Overall response rates were 63.3% and 0% for lenvatinib and placebo, respectively. No significant difference was found in overall survival. The lenvatinib safety profile was similar between the Japanese and overall SELECT population, except for higher incidences of hypertension (any grade: Japanese, 87%; overall, 68%; grade >=3: Japanese, 80%; overall, 42%), palmar-plantar erythrodysesthesia syndrome (any grade: Japanese, 70%; overall, 32%; grade >=3: Japanese, 3%; overall, 3%), and proteinuria (any grade: Japanese, 63%; overall, 31%; grade >=3: Japanese, 20%; overall, 10%). Japanese patients had more dose reductions (Japanese, 90%; overall, 67.8%), but fewer discontinuations due to adverse events (Japanese, 3.3%; overall, 14.2%). There was no difference in lenvatinib exposure between the Japanese and overall SELECT populations after adjusting for body weight. In Japanese patients with radioiodine-refractory differentiated thyroid cancer, lenvatinib showed similar clinical outcomes to the overall SELECT population. Some differences in adverse event frequencies and dose modifications were observed. Clinical trial registration no.: NCT01321554. PMID- 26426093 TI - Remote Loading of (64)Cu(2+) into Liposomes without the Use of Ion Transport Enhancers. AB - Due to low ion permeability of lipid bilayers, it has been and still is common practice to use transporter molecules such as ionophores or lipophilic chelators to increase transmembrane diffusion rates and loading efficiencies of radionuclides into liposomes. Here, we report a novel and very simple method for loading the positron emitter (64)Cu(2+) into liposomes, which is important for in vivo positron emission tomography (PET) imaging. By this approach, copper is added to liposomes entrapping a chelator, which causes spontaneous diffusion of copper across the lipid bilayer where it is trapped. Using this method, we achieve highly efficient (64)Cu(2+) loading (>95%), high radionuclide retention (>95%), and favorable loading kinetics, excluding the use of transporter molecule additives. Therefore, clinically relevant activities of 200-400 MBq/patient can be loaded fast (60-75 min) and efficiently into preformed stealth liposomes avoiding subsequent purification steps. We investigate the molecular coordination of entrapped copper using X-ray absorption spectroscopy and demonstrate high adaptability of the loading method to pegylated, nonpegylated, gel- or fluid like, cholesterol rich or cholesterol depleted, cationic, anionic, and zwitterionic lipid compositions. We demonstrate high in vivo stability of (64)Cu liposomes in a large canine model observing a blood circulation half-life of 24 h and show a tumor accumulation of 6% ID/g in FaDu xenograft mice using PET imaging. With this work, it is demonstrated that copper ions are capable of crossing a lipid membrane unassisted. This method is highly valuable for characterizing the in vivo performance of liposome-based nanomedicine with great potential in diagnostic imaging applications. PMID- 26426094 TI - Ultrasound Guidance Facilitates Radial Artery Catheterization: A Meta-analysis With Trial Sequential Analysis of Randomized Controlled Trials. AB - BACKGROUND: Potential benefits and possible risks associated with ultrasound guidance compared with traditional palpation for radial artery catheterization are not fully understood. METHODS: We searched PubMed, Embase, and the Cochrane Library through July 2015 to identify randomized controlled trials that evaluated ultrasound guidance compared with traditional palpation for radial artery catheterization. Primary outcome was first-attempt failure. Secondary outcomes included mean attempts to success, mean time to success, and hematoma complications. A random-effects model was used to estimate relative risks (RRs) with 95% CIs. RESULTS: Twelve trials used dynamic two-dimensional (2-D) ultrasound guidance (N = 1,992) and two used Doppler ultrasound guidance (N = 666). Compared with traditional palpation, dynamic 2-D ultrasound guidance was associated with a reduced first-attempt failure (RR, 0.68; 95% CI, 0.52-0.87). Trial sequential analysis showed that the cumulative z curve crossed the trial sequential monitoring boundary for benefit establishing sufficient and conclusive evidence. Dynamic 2-D ultrasound guidance further reduced mean attempts to success, mean time to success, and hematoma complications. No evidence of publication bias was detected. Compared with traditional palpation, Doppler ultrasound guidance had no benefit on first-attempt failure (RR, 1.00; 95% CI, 0.87-1.15), which was confirmed by trial sequential analysis as the cumulative z curve entered the futility area. CONCLUSIONS: The use of dynamic 2-D ultrasound guidance for radial artery catheterization decreases first-attempt failure, mean attempts to success, mean time to success, and the occurrence of hematoma complications. Dynamic 2-D ultrasound guidance is recommended as an adjunct to aid radial arterial catheterization. PMID- 26426095 TI - Outcome and Prognostic Factors for Canine Splenic Lymphoma Treated by Splenectomy (1995-2011). AB - OBJECTIVE: To assess the outcome of canine splenic lymphoma treated with splenectomy and to evaluate prognostic factors, including involvement of other sites, adjuvant chemotherapy, and the effect of World Health Organization (WHO) histological classification of canine malignant lymphoma. DESIGN: Multi institutional, retrospective study. ANIMALS: Client-owned dogs (n = 28). METHODS: Medical records (1995-2011) of dogs with a histological diagnosis of splenic lymphoma and treated by splenectomy submitted by Veterinary Society of Surgical Oncology members were reviewed. Included were dogs treated with or without adjuvant therapy. Overall survival, disease-free interval, and cause of death were determined. Prognostic factors and the WHO histological classification of canine malignant lymphoma were evaluated with respect to outcome. RESULTS: Dogs with splenic lymphoma treated by splenectomy had a 1-year survival rate of 58.8%, after which no animals died of their disease. B cell lymphoma held a better prognosis for survival than other variants of splenic lymphoma. Marginal zone lymphoma and mantle cell lymphoma were the most common B cell lymphoma subtypes in our study. Hemoabdomen and clinical signs related to splenic lymphoma, including abdominal distention, lethargy, and anorexia, were poor prognostic indicators, whereas disease confined to the spleen was a positive prognostic indicator. Pre- or postoperative adjuvant chemotherapy did not provide a survival benefit. CONCLUSION: Based on our sample population, splenectomy alone was an effective treatment for splenic lymphoma in cases with disease confined to the spleen. Chemotherapy may not improve survival in cases of lymphoma restricted to the spleen. PMID- 26426096 TI - Degradation Mechanism Induced by Psoriasis in Human Fingernails-A Different Approach. PMID- 26426098 TI - In cellulo protein labelling with Ru-conjugate for luminescence imaging and bioorthogonal photocatalysis. AB - Labelling of proteins with a luminescent ruthenium complex enables the direct visualization and photocatalytic reduction of aryl azide in live cells. The confinement of catalysis to the labeled proteins was visualized using an azide based immolative linker releasing a precipitating dye. PMID- 26426099 TI - Infection of Penile Prostheses in Patients with Diabetes Mellitus. AB - BACKGROUND: Controversy still exists in some centers on whether diabetes mellitus is a risk factor for penile prosthesis infection. The aim of this review is to examine the evidence correlating penile implant infections to the presence of diabetes mellitus in patients with organic erectile dysfunction. METHODS: We performed a systematic review searching through Medline database from 1960 to 2014, using keywords; penile prosthesis(es), penile implant(s), and diabetes mellitus. We used the Prisma 2009 Flow diagram for systematic reviews. Thirty eight publications were selected for inclusion in this qualitative analysis. RESULTS: Most case series reporting a greater infection rate in patients with diabetes mellitus date from the 1970s to 1990s. These series reported an infection rate of 5.5 to 20% and contained small cohort of patients. In the 1990s larger case series reported a lower infection rate in patients with diabetes mellitus compared with patients with paraplegia, pelvic trauma, and patients on steroids, but still reported an infection rate as high as 10.6%. With the implementation of antibiotic coated implants in 2001, infection rates reduced further with reported rates becoming less than 2% in patients with diabetes mellitus. The latest and largest case series by Eid et al. (2012) reported an infection rate of 0.46% with antibiotic coated implants and "no touch" technique in a cohort of 1511 cases, out of which 41% were patients with diabetes mellitus. CONCLUSION: Strong evidence exists that the risk of penile prosthesis infection has reduced over the decades with device improvement and surgical expertise. In larger case series infection rates in patients with diabetes mellitus is not statistically significant from that experiences in the population at large. PMID- 26426100 TI - Impaired Performance of Pressure-Retarded Osmosis due to Irreversible Biofouling. AB - Next-generation pressure-retarded osmosis (PRO) approaches aim to harness the energy potential of streams with high salinity differences, such as wastewater effluent and seawater desalination plant brine. In this study, we evaluated biofouling propensity in PRO. Bench-scale experiments were carried out for 24 h using a model wastewater effluent feed solution and simulated seawater desalination brine pressurized to 24 bar. For biofouling tests, wastewater effluent was inoculated with Pseudomonas aeruginosa and artificial seawater desalination plant brine draw solution was seeded with Pseudoalteromonas atlantica. Our results indicate that biological growth in the feed wastewater stream channel severely fouled both the membrane support layer and feed spacer, resulting in ~50% water flux decline. We also observed an increase in the pumping pressure required to force water through the spacer-filled feed channel, with pressure drop increasing from 6.4+/-0.8 bar m(-1) to 15.1+/-2.6 bar m(-1) due to spacer blockage from the developing biofilm. Neither the water flux decline nor the increased pressure drop in the feed channel could be reversed using a pressure-aided osmotic backwash. In contrast, biofouling in the seawater brine draw channel was negligible. Overall, the reduced performance due to water flux decline and increased pumping energy requirements from spacer blockage highlight the serious challenges of using high fouling potential feed sources in PRO, such as secondary wastewater effluent. We conclude that PRO power generation using wastewater effluent and seawater desalination plant brine may become possible only with rigorous pretreatment or new spacer and membrane designs. PMID- 26426101 TI - Isolation and characterization of Leptolyngbya sp. KIOST-1, a basophilic and euryhaline filamentous cyanobacterium from an open paddle-wheel raceway Arthrospira culture pond in Korea. AB - AIMS: Cyanobacteria have been used as sustainable bioresource producers for foods, feeds and other valuable natural products. However, selection of a new species (other than Arthrospira), with advantageous properties for alimentary purposes, continues to be a challenge due to potential toxicity and low biomass productivity. In this study, we report a valuable filamentous cyanobacterium isolated from Korea. METHODS AND RESULTS: Morphological and phylogenetic analyses demonstrated that the isolate belongs to the genus Leptolyngbya, and consequently designated Leptolyngbya sp. KIOST-1. Interestingly, Leptolyngbya sp. KIOST-1 possessed numerous advantageous characteristics for biomass production, similar to Arthrospira. The isolate readily propagated in SOT medium with efficient biomass productivity, and its optimum growth was observed at 30 degrees C under alkaline and saline conditions. Moreover, more than half of the cellular components in Leptolyngbya sp. KIOST-1 were composed of protein, with approx. 40% of essential amino acids. Most importantly, no significant cytotoxicity was detected in the isolate. CONCLUSIONS: Leptolyngbya sp. KIOST-1 has a number of advantageous characteristics for alimentary purposes due to its efficient productivity, high protein content and lack of potential cytotoxicity. SIGNIFICANCE AND IMPACT OF THE STUDY: Leptolyngbya sp. KIOST-1 may be considered a potential candidate for industrial biomass production, similar to Arthrospira. PMID- 26426102 TI - Food consumption in patients referred for bariatric surgery with and without binge eating disorder. AB - INTRODUCTION: The prevalence of Binge Eating Disorder (BED) is high in obese patients referred to bariatric surgery. Although the total energy intake is increased, the risk of nutritional deficiencies in these patients is unknown. This study proposes to evaluate and compare the intakes of candidate patients for bariatric surgery with and without BED, using for this purpose the Dietary Reference Intakes. METHODS: 116 patients referred for bariatric surgery were submitted to nutritional, laboratory and psychological assessments. RESULTS: Among the patients, 46.6% had BED, of these, 25.9% had the severe form. The patients with current depression (31.9%) were more compulsive than those without depression (p < 0.001). The mean age was significantly higher in patients without BED (46.94 +/- 12.05 vs 42.32 +/- 10.60, p = 0.030). The only difference in anthropometric parameters individuals with and without BED was the mid-upper arm circumference (P = 0.047). The percentage of energy from carbohydrates was higher in patients with BED (53.78%) than without BED (48.88%) (U = 1222, P = 0.018, r = - 0.22). The percentage from total fat (13.63% versus 12.89%, U = 1201.0, P = 0.019, r = - 0.22) and from saturated fat (9.04% versus 8.15%, U = 1074.0, P = 0.023, r = - 0.21), was higher in patients without BED. When adjusted for the body weight of patients, these differences were not significant. CONCLUSION: Patients with BED eat more carbohydrates and have larger mid-upper arm circumference in the face of similar body weight, suggesting a higher percentage of fat mass. PMID- 26426104 TI - Jugular pit associated with 5q14.3 deletion incorporating the MEF2C locus: a recurrent clinical finding. PMID- 26426103 TI - Biometric Modeling of Gene-Environment Interplay: The Intersection of Theory and Method and Applications for Social Inequality. AB - For more than a decade, biometric moderation models have been used to examine whether genetic and environmental influences on individual differences might vary within the population. These quantitative Gene * Environment interaction models have the potential to elucidate not only when genetic and environmental influences on a phenotype might differ, but also why, as they provide an empirical test of several theoretical paradigms that serve as useful heuristics to explain etiology-diathesis-stress, bioecological, differential susceptibility, and social control. In the current article, we review how these developmental theories align with different patterns of findings from statistical models of gene-environment interplay. We then describe the extant empirical evidence, using work by our own research group and others, to lay out genetically informative plausible accounts of how phenotypes related to social inequality-physical health and cognition-might relate to these theoretical models. PMID- 26426113 TI - Population Prevalence of Need for Spectacles and Spectacle Ownership Among Urban Migrant Children in Eastern China. AB - IMPORTANCE: The number of urban migrants in China is 300 million and is increasing rapidly in response to government policies. Urban migrants have poor access to health care, but little is known about rates of correction of refractive error among migrant children. This is of particular significance in light of recent evidence demonstrating the educational impact of providing children with spectacles. OBJECTIVE: To measure prevalence of spectacle need and ownership among Chinese migrant children. DESIGN, SETTING, AND PARTICIPANTS: Population-based, cross-sectional study among children who failed vision testing (uncorrected visual acuity <=6/12 in either eye) between September 15 and 30, 2013, at 94 randomly selected primary schools in predominantly migrant communities in Shanghai, Suzhou, and Wuxi, China. MAIN OUTCOMES AND MEASURES: Refractive error by cycloplegic refraction; spectacle ownership, defined as producing glasses at school, having been told to bring them; and needing glasses, defined as uncorrected visual acuity of 6/12 or less correctable to greater than 6/12 in either eye, with myopia of -0.5 diopters (D) or less, hyperopia of +2.0 D or greater, or astigmatism of 0.75 D or greater in both eyes. RESULTS: Among 4409 children, 4376 (99.3%) completed vision screening (mean [SD] age, 11.0 [0.81] years; 55.3% boys; 4225 [96.5%] migrant and 151 [3.5%] local). Among 1204 children failing vision testing (total, 27.5%; 1147 migrant children [27.1%] vs 57 local children [37.7%]; P = .003), 850 (70.6%) completed refraction. Spectacle ownership in migrant children needing glasses (147 of 640 children [23.0%]) was less than among local children (12 of 34 children [35.3%]) (odds ratio = 0.55; 95% CI, 0.32-0.95; P = .03). Having uncorrected visual acuity less than 6/18 in both eyes was associated positively with baseline spectacle ownership (odds ratio = 5.73; 95% CI, 3.81-8.62; P < .001), but parental education and family wealth were not. CONCLUSIONS AND RELEVANCE: Among urban migrant children, there was a high prevalence of need for spectacles and a very low rate of spectacle ownership. Spectacle distribution programs are needed specifically targeting migrant children. PMID- 26426114 TI - Ultratrace DNA Detection Based on the Condensing-Enrichment Effect of Superwettable Microchips. AB - A sensitive nucleic acid detection platform based on superhydrophilic microwells spotted on a superhydrophobic substrate is fabricated. Due to the wettability differences, ultratrace DNA molecules are enriched and the fluorescent signals are amplified to allow more sensitive detection. The biosensing interface based on superwettable materials provides a simple and cost-effective way for ultratrace DNA sensing. PMID- 26426115 TI - Glycerol Production from Glucose and Fructose by 3T3-L1 Cells: A Mechanism of Adipocyte Defense from Excess Substrate. AB - Cultured adipocytes (3T3-L1) produce large amounts of 3C fragments; largely lactate, depending on medium glucose levels. Increased glycolysis has been observed also in vivo in different sites of rat white adipose tissue. We investigated whether fructose can substitute glucose as source of lactate, and, especially whether the glycerol released to the medium was of lipolytic or glycolytic origin. Fructose conversion to lactate and glycerol was lower than that of glucose. The fast exhaustion of medium glucose was unrelated to significant changes in lipid storage. Fructose inhibited to a higher degree than glucose the expression of lipogenic enzymes. When both hexoses were present, the effects of fructose on gene expression prevailed over those of glucose. Adipocytes expressed fructokinase, but not aldolase b. Substantive release of glycerol accompanied lactate when fructose was the substrate. The mass of cell triacylglycerol (and its lack of change) could not justify the comparatively higher amount of glycerol released. Consequently, most of this glycerol should be derived from the glycolytic pathway, since its lipolytic origin could not be (quantitatively) sustained. Proportionally (with respect to lactate plus glycerol), more glycerol was produced from fructose than from glucose, which suggests that part of fructose was catabolized by the alternate (hepatic) fructose pathway. Earlier described adipose glycerophophatase activity may help explain the glycolytic origin of most of the glycerol. However, no gene is known for this enzyme in mammals, which suggests that this function may be carried out by one of the known phosphatases in the tissue. Break up of glycerol-3P to yield glycerol, may be a limiting factor for the synthesis of triacylglycerols through control of glycerol-3P availability. A phosphatase pathway such as that described may have a potential regulatory function, and explain the production of glycerol by adipocytes in the absence of lipolytic stimulation. PMID- 26426116 TI - Transcytosis-Targeting Peptide: A Conductor of Liposomal Nanoparticles through the Endothelial Cell Barrier. AB - The ultimate goal in the area of drug-delivery systems is the development of a nanoparticle that can penetrate the endothelial cell monolayer for the targeting of tissue parenchyma. In the present study, we identify a transcytosis-targeting peptide (TTP) that permits polyethyleneglycol (PEG)-modified liposomes (PEG-LPs) to penetrate through monolayers of brain-derived endothelial cells. These endothelial cells were layered on a gelatin nanofiber sheet, a nanofiber meshwork that allows the evaluation of transcellular transport of nanosized particles (ca. 100 nm). Systematic modification of the sequences results in the identification of the consensus sequence of TTP as L(R/K)QZZZL, where Z denotes hydrophilic amino acids (R/K/S and partially D). The TTP-modified liposomes are bound on the heparin sulfate proteoglycan, and are then taken up via lipid raft-mediated endocytosis. Subsequent intracellular imaging of the particles reveals a unique intracellular sorting of TTP-modified PEG liposomes (TTP-PEG-LPs); namely the TTP LPs are not localized with the lysosomes, whereas this co-localization is dominant in the unmodified PEG liposomes (PEG-LPs). The in vivo endothelial penetration of liposomes in adipose tissue is conferred by the dual modification of the particles with TTP and tissue-targeting ligands. This technology promises innovations in intravenously available delivery system to tissue parenchyma. PMID- 26426117 TI - Development of a High-Content Orthopoxvirus Infectivity and Neutralization Assays. AB - Currently, a number of assays measure Orthopoxvirus neutralization with serum from individuals, vaccinated against smallpox. In addition to the traditional plaque reduction neutralization test (PRNT), newer higher throughput assays are based on neutralization of recombinant vaccinia virus, expressing reporter genes such as beta-galactosidase or green fluorescent protein. These methods could not be used to evaluate neutralization of variola virus, since genetic manipulations of this virus are prohibited by international agreements. Currently, PRNT is the assay of choice to measure neutralization of variola virus. However, PRNT assays are time consuming, labor intensive, and require considerable volume of serum sample for testing. Here, we describe the development of a high-throughput, cell based imaging assay that can be used to measure neutralization, and characterize replication kinetics of various Orthopoxviruses, including variola, vaccinia, monkeypox, and cowpox. PMID- 26426118 TI - Host Coenzyme Q Redox State Is an Early Biomarker of Thermal Stress in the Coral Acropora millepora. AB - Bleaching episodes caused by increasing seawater temperatures may induce mass coral mortality and are regarded as one of the biggest threats to coral reef ecosystems worldwide. The current consensus is that this phenomenon results from enhanced production of harmful reactive oxygen species (ROS) that disrupt the symbiosis between corals and their endosymbiotic dinoflagellates, Symbiodinium. Here, the responses of two important antioxidant defence components, the host coenzyme Q (CoQ) and symbiont plastoquinone (PQ) pools, are investigated for the first time in colonies of the scleractinian coral, Acropora millepora, during experimentally-induced bleaching under ecologically relevant conditions. Liquid chromatography-mass spectrometry (LC-MS) was used to quantify the states of these two pools, together with physiological parameters assessing the general state of the symbiosis (including photosystem II photochemical efficiency, chlorophyll concentration and Symbiodinium cell densities). The results show that the responses of the two antioxidant systems occur on different timescales: (i) the redox state of the Symbiodinium PQ pool remained stable until twelve days into the experiment, after which there was an abrupt oxidative shift; (ii) by contrast, an oxidative shift of approximately 10% had occurred in the host CoQ pool after 6 days of thermal stress, prior to significant changes in any other physiological parameter measured. Host CoQ pool oxidation is thus an early biomarker of thermal stress in corals, and this antioxidant pool is likely to play a key role in quenching thermally-induced ROS in the coral-algal symbiosis. This study adds to a growing body of work that indicates host cellular responses may precede the bleaching process and symbiont dysfunction. PMID- 26426119 TI - Striking Similarities in the Presentation and Duration of Illness of Influenza A and B in the Community: A Study Based on Sentinel Surveillance Networks in France and Turkey, 2010-2012. AB - Influenza B represents a high proportion of influenza cases in some seasons (even over 50%). The Influenza B study in General Practice (IBGP) is a multicenter study providing information about the clinical, demographic and socio-economic characteristics of patients affected by lab-confirmed influenza A or B. Influenza B patients and age-matched influenza A patients were recruited within the sentinel surveillance networks of France and Turkey in 2010-11 and 2011-12 seasons. Data were collected for each patient at the swab test day, after 9+/-2 days and, if not recovered, after 28+/-5 days. It was related to patient's characteristics, symptoms at presentation, vaccination status, prescriptions of antibiotics and antivirals, duration of illness, follow-up consultations in general practice or emergency room. We performed descriptive analyses and developed a multiple regression model to investigate the effect of patients and disease characteristics on the duration of illness. Overall, 774 influenza cases were included in the study: 419 influenza B cases (209 in France and 210 in Turkey) and 355 influenza A cases (205 in France and 150 in Turkey). There were no differences between influenza A and B patients in terms of clinical presentation and number of consultations with a practitioner; however, the use of antivirals was higher among influenza B patients in both countries. The average (median) reported duration of illness in the age groups 0-14 years, 15-64 years and 65+ years was 7.4 (6), 8.7 (8) and 10.5 (9) days in France, and 6.3 (6), 8.2 (7) and 9.2 (6) days in Turkey; it increased with age but did not differ by virus type; increased duration of illness was associated with antibiotics prescription. In conclusion, our findings show that influenza B infection appears not to be milder disease than influenza A infection. PMID- 26426121 TI - Interferon-gamma: The Jekyll and Hyde of Malaria. PMID- 26426120 TI - Classification of Rhinoentomophthoromycosis into Atypical, Early, Intermediate, and Late Disease: A Proposal. AB - BACKGROUND: Rhinoentomophthoromycosis, or rhino-facial conidiobolomycosis, is a rare, grossly disfiguring disease due to an infection with entomophthoralean fungi. We report a case of rhinoentomophthoromycosis from Gabon and suggest a staging system, which provides information on the prognosis and duration of antifungal therapy. METHODS: We present a case of rhinoentomophthoromycosis including the histopathology, mycology, and course of disease. For the suggested staging system, all cases on confirmed rhinoentomophthoromycosis published in the literature without language restriction were eligible. Exclusion criteria were missing data on (i) duration of disease before correct diagnosis, (ii) outcome, and (iii) confirmation of entomophthoralean fungus infection by histopathology and/or mycology. We classified cases into atypical (orbital cellulitis, severe pain, fever, dissemination), early, intermediate, and late disease based on the duration of symptoms before diagnosis. The outcome was evaluated for each stage of disease. FINDINGS: The literature search of the Medpilot database was conducted on January 13, 2014, (updated on January 18, 2015). The search yielded 8,333 results including 198 cases from 117 papers; of these, 145 met our inclusion criteria and were included in the final analysis. Median duration of treatment was 4, 3, 4, and 5 months in atypical, early, intermediate, and late disease, respectively. Cure rates were clearly associated with stage of disease and were 57%, 100%, 82%, and 43% in atypical, early, intermediate, and late disease, respectively. CONCLUSION: We suggest a clinical staging system that underlines the benefit of early case detection and may guide the duration of antifungal treatment. The scientific value of this classification is its capacity to structure and harmonize the clinical and research approach towards rhinoentomophthoromycosis. PMID- 26426125 TI - Non-thermal ion desorption from an acetonitrile (CH3CN) astrophysical ice analogue studied by electron stimulated ion desorption. AB - The incidence of high-energy radiation onto icy surfaces constitutes an important route for leading new neutral or ionized molecular species back to the gas phase in interstellar and circumstellar environments, especially where thermal desorption is negligible. In order to simulate such processes, an acetonitrile ice (CH3CN) frozen at 120 K is bombarded by high energy electrons, and the desorbing positive ions are analyzed by time-of-flight mass spectrometry (TOF MS). Several fragment and cluster ions were identified, including the Hn=1-3(+), CHn=0-3(+)/NHn=0-1(+); C2Hn=0-3(+)/CHn=0-3N(+), C2Hn=0-6N(+) ion series and the ion clusters (CH3CN)n=1-2(+) and (CH3CN)n=1-2H(+). The energy dependence on the positive ion desorption yield indicates that ion desorption is initiated by Coulomb explosion following Auger electronic decay. The results presented here suggest that non-thermal desorption processes, such as desorption induced by electronic transitions (DIET) may be responsible for delivering neutral and ionic fragments from simple nitrile-bearing ices to the gas-phase, contributing to the production of more complex molecules. The derived desorption yields per electron impact may contribute to chemical evolution models in different cold astrophysical objects, especially where the abundance of CH3CN is expected to be high. PMID- 26426123 TI - Acetylation of NDPK-D Regulates Its Subcellular Localization and Cell Survival. AB - Nucleoside diphosphate kinases (NDPK) are ubiquitous enzymes that catalyze the reversible phosphotransfer of gamma-phosphates between di- and triphosphonucleosides. NDPK-D (Nm23-H4) is the only member of the NDPK family with a mitochondrial targeting sequence. Despite the high expression of NDPK-D in the developing central nervous system, its function remains to be determined. In this study, we show that NDPK-D knockdown induces apoptosis in neuroblastoma cells as well as in mouse cortex, suggesting that NDPK-D is required for neuronal survival. We identified NDPK-D as a binding partner of NAD+-dependent histone deacetylase, SIRT1, by yeast two-hybrid screening. NDPK-D co-localized with SIRT1, and the association of these molecules was confirmed by co immunoprecipitation. Inhibition of SIRT1 increases the acetylation of NDPK-D. Overexpression of NDPK-D along with SIRT1, or mutation in the acetylated lysine residues in NDPK-D, increases its nuclear accumulation. Furthermore, the NDPK-D acetylation-mimic mutant increased apoptosis in N1E-115 cells. Our data demonstrate that acetylation regulates the shuttling of NDPK-D between nucleus and cytoplasm, and increased acetylation of NDPK-D causes apoptosis. PMID- 26426122 TI - Differential Translocation of Host Cellular Materials into the Chlamydia trachomatis Inclusion Lumen during Chemical Fixation. AB - Chlamydia trachomatis manipulates host cellular pathways to ensure its proliferation and survival. Translocation of host materials into the pathogenic vacuole (termed 'inclusion') may facilitate nutrient acquisition and various organelles have been observed within the inclusion, including lipid droplets, peroxisomes, multivesicular body components, and membranes of the endoplasmic reticulum (ER). However, few of these processes have been documented in living cells. Here, we survey the localization of a broad panel of subcellular elements and find ER, mitochondria, and inclusion membranes within the inclusion lumen of fixed cells. However, we see little evidence of intraluminal localization of these organelles in live inclusions. Using time-lapse video microscopy we document ER marker translocation into the inclusion lumen during chemical fixation. These intra-inclusion ER elements resist a variety of post-fixation manipulations and are detectable via immunofluorescence microscopy. We speculate that the localization of a subset of organelles may be exaggerated during fixation. Finally, we find similar structures within the pathogenic vacuole of Coxiella burnetti infected cells, suggesting that fixation-induced translocation of cellular materials may occur into the vacuole of a range of intracellular pathogens. PMID- 26426124 TI - Cost-Effectiveness of Including a Nurse Specialist in the Treatment of Urinary Incontinence in Primary Care in the Netherlands. AB - OBJECTIVE: Incontinence is an important health problem. Effectively treating incontinence could lead to important health gains in patients and caregivers. Management of incontinence is currently suboptimal, especially in elderly patients. To optimise the provision of incontinence care a global optimum continence service specification (OCSS) was developed. The current study evaluates the costs and effects of implementing this OCSS for community-dwelling patients older than 65 years with four or more chronic diseases in the Netherlands. METHOD: A decision analytic model was developed comparing the current care pathway for urinary incontinence in the Netherlands with the pathway as described in the OCSS. The new care strategy was operationalised as the appointment of a continence nurse specialist (NS) located with the general practitioner (GP). This was assumed to increase case detection and to include initial assessment and treatment by the NS. The analysis used a societal perspective, including medical costs, containment products (out-of-pocket and paid by insurer), home care, informal care, and implementation costs. RESULTS: With the new care strategy a QALY gain of 0.005 per patient is achieved while saving ?402 per patient over a 3 year period from a societal perspective. In interpreting these findings it is important to realise that many patients are undetected, even in the new care situation (36%), or receive care for containment only. In both of these groups no health gains were achieved. CONCLUSION: Implementing the OCSS in the Netherlands by locating a NS in the GP practice is likely to reduce incontinence, improve quality of life, and reduce costs. Furthermore, the study also highlighted that various areas of the continence care process lack data, which would be valuable to collect through the introduction of the NS in a study setting. PMID- 26426126 TI - Melatonin attenuates (-)-epigallocatehin-3-gallate-triggered hepatotoxicity without compromising its downregulation of hepatic gluconeogenic and lipogenic genes in mice. AB - (-)-Epigallocatehin-3-gallate (EGCG), a major constituent of green tea, can ameliorate metabolic syndrome at least in part through reducing gluconeogenesis and lipogenesis. Green tea extracts, of which EGCG is a key constituent, have been used for weight loss in humans. A potential adverse effect of high-dose EGCG or green tea extracts is hepatotoxicity. Melatonin, an endogenous antioxidant with a high safety profile, is effective in preventing various types of tissue damage. The current study investigated the influence of melatonin on EGCG triggered hepatotoxicity and EGCG-downregulated hepatic genes responsible for gluconeogenesis and lipogenesis in mice. We found that (i) melatonin extended survival time of mice intoxicated with lethal doses of EGCG; (ii) melatonin ameliorated acute liver damage and associated hepatic Nrf2 suppression caused by a nonlethal toxic dose of EGCG; (iii) melatonin reduced subacute liver injury and hepatic Nrf2 activation caused by lower toxic doses of EGCG; and (iv) melatonin did not compromise the action of pharmacological doses of EGCG in downregulating a battery of hepatic genes responsible for gluconeogenesis and lipogenesis, including G6Pc, PEPCK, FOXO1alpha, SCD1, Fasn, leptin, ACCalpha, ACCbeta, GAPT, and Srebp-1. Taken together, these results suggest that the combination of EGCG and melatonin is an effective approach for preventing potential adverse effects of EGCG as a dietary supplement for metabolic syndrome alleviation and body weight reduction. PMID- 26426127 TI - Patients' experience of partial tooth loss and expectations to treatment: a qualitative study in Danish and Swedish patients. AB - Knowledge of impairments, wishes and expectations is essential to make correct decisions regarding oral rehabilitation. The purpose of this study was to investigate discomforts, wishes and expectations in patients' with partial edentulism before entering oral rehabilitation. In Copenhagen, Denmark, and Malmo, Sweden, respectively, 20 patients with partial edentulism seeking rehabilitation were interviewed in a semistructured qualitative manner. The interviews were transcribed and analysed yielding overall domains. Six themes appeared as overall domains: (i) experienced impairments, (ii) experienced social awareness, (iii) expectation to treatment, (iv) expectation to durability/survival, (v) coping strategies dealing with the tooth loss including explanations of the tooth loss and (vi) modifications to experienced impairment. The impairments were mostly experienced as problems in social settings. Most participants expressed a simple wish to function normally; a fixed solution was preferred. Many Danish participants accepted a removable solution whereas only few Swedish participants did so. The domains 'coping strategies' and 'modifications' were not part of the chosen topics of interest, indicating a high wish of the participants to explain their tooth loss and how they coped with it. In conclusion, a large degree of social impairment was found in the patient group along with several coping strategies. The impairments were modified by a number of factors indicating that highly individualised care and treatment is needed. A state of normality was described as the primary treatment wish with a higher acceptance of removable solutions in Denmark than in Sweden. For final decision making, surrounding factors seemed to influence the patients' choices. PMID- 26426128 TI - Supramolecular Assays for Mapping Enzyme Activity by Displacement-Triggered Change in Hyperpolarized (129)Xe Magnetization Transfer NMR Spectroscopy. AB - Reversibly bound Xe is a sensitive NMR and MRI reporter with its resonance frequency being influenced by the chemical environment of the host. Molecular imaging of enzyme activity presents a promising approach for disease identification, but current Xe biosensing concepts are limited since substrate conversion typically has little impact on the chemical shift of Xe inside tailored cavities. Herein, we exploit the ability of the product of the enzymatic reaction to bind itself to the macrocyclic hosts CB6 and CB7 and thereby displace Xe. We demonstrate the suitability of this method to map areas of enzyme activity through changes in magnetization transfer with hyperpolarized Xe under different saturation scenarios. PMID- 26426129 TI - Nursing Workforce Trends Demand Transformational Leadership. PMID- 26426130 TI - Hospital Nursing Workforce Costs, Wages, Occupational Mix,and Resource Utilization. AB - BACKGROUND: The objective of the study was to better understand how hospitals use different types of RNs, LPNs, and nurse aides in proprietary (for-profit), nonprofit, and government-owned hospitals and to estimate the wages, cost, and intensity of nursing care using a national data set. METHOD: This is a cross sectional observational study of 3,129 acute care hospitals in all 50 states and District of Columbia using data from the 2008 Occupational Mix Survey administered by the Centers for Medicare &Medicaid Services (CMS). Nursing skill mix, hours, and labor costs were combined with other CMS hospital descriptive data, including type of hospital ownership, urban or rural location, hospital beds, and case-mix index. RESULTS: RN labor costs make up 25.5% of all hospital expenditures annually, and all nursing labor costs represent 30.1%, which is nearly a quarter trillion dollars ($216.7 billion) per year for inpatient nursing care. On average, proprietary hospitals employ 1.3 RNs per bed and 1.9 nursing personnel per bed in urban hospitals compared with 1.7 RNs per bed and 2.3 nursing personnel per bed for nonprofit and government-owned hospitals (P G .05). States with higher ratios of RN compared with LPN licenses used fewer LPNs in the inpatient setting. CONCLUSION: The findings from this study can be helpful in comparing nursing care across different types of hospitals, ownership, and geographic locations and used as a benchmark for future nursing workforce needs and costs. PMID- 26426131 TI - Mitigating Knowledge Loss: A Strategic Imperative for Nurse Leaders. AB - With the aging of the nursing workforce and expected retirement of large numbers of experienced nurses in the next decade, mitigating the impact that lost knowledge will have on organizational performance and patient outcomes is critical. The authors raise awareness of the problem, summarize observations procured from hospital nurse executive regarding approaches for knowledge transfer through workforce development, and pose proactive strategies for nurse leaders who can provide direction to offset the issue before it becomes a crisis. PMID- 26426132 TI - Retirement Financial Planning and the RN: An Integrative Literature Review. AB - This integrative literature review examined the current research on RN retirement. The review identified 3 critical gaps in knowledge: (a) minimal knowledge regarding the economic impact on RN retirement, (b) incomplete information regarding the demographics of RN retirement, and (c) a scarcity of prospective longitudinal RN workforce studies. Future research must address these gaps to better address RN workforce sustainability. PMID- 26426133 TI - Correlates of New Graduate Nurses' Experiences of Workplace Mistreatment. AB - OBJECTIVE: This study explores correlates of new graduate nurses' experiences of workplace mistreatment. BACKGROUND: New graduate nurses' experiences of workplace mistreatment, such as bullying, coworker incivility, and supervisor incivility, negatively influence nurses' work and health. It is unclear whether these forms of workplace mistreatment have similar precipitating factors and outcomes. METHODS: We surveyed 342 new graduate nurses in Ontario to explore correlates of 3 forms of workplace mistreatment. RESULTS: Workplace incivility and bullying were significantly related to authentic leadership, structural empowerment, worklife fit, and psychological capital. Bullying was more strongly related to job satisfaction, emotional exhaustion, and mental and physical health outcomes than supervisor and coworker incivility. CONCLUSIONS: New graduate nurses' experiences of 3 types of workplace mistreatment are related to organizational and health factors, although bullying appears to have stronger negative effects. PMID- 26426134 TI - Reflections on Nursing Workforce. PMID- 26426135 TI - New Nurses' Perceptions of Hostility and Job Satisfaction: Magnet(r) Versus Non Magnet. AB - PURPOSE: This study investigated the perceptions of nursing hostility and job satisfaction of new RNs, comparing the working settings of MagnetA and non-Magnet hospitals. METHODS: An online survey of new graduate RNs wasconducted using theNegative Acts QuestionnaireY Revised, the McCloskey/Mueller Satisfaction Survey, the Casey-Fink Graduate Nurse Experience Survey, and a demographic questionnaire. RESULTS: Findings indicated that RNs of Magnet and non-Magnet facilities experienced similar hostility and job satisfaction results. Magnet nurses (n = 226) perceived nursing hostility significantly different than non Magnet nurses (n = 939); however, both groups reported a global perception of nursing hostility as new RNs. CONCLUSION: Based on this study's findings, greater consideration should be placed on orientation/residency programs, collaborative partnerships between academia and service, zero tolerance for behaviors undermining culture safety, and addressing nursing hostility. PMID- 26426136 TI - Factors Influencing Critical Care Nurses' Perception of Their Overall Job Satisfaction: An Empirical Study. AB - OBJECTIVE: The aim of this study was to explore the factors influencing critical care nurses' perception of their overall job satisfaction. BACKGROUND: Nurses' job satisfaction is a key issue to consider in the retention of critical care nurses. Shortages of nurses result in unsafe patient care, increased expense, and increased stress levels among other nurses. METHOD: The Leadership Practices Inventory was used among a sample of critical care nurses to measure perceived leadership practices, the Organizational Commitment Questionnaire measured nurses commitment, and the Job in General scale was used to measure nurses' overall job satisfaction. Four different hypotheses were tested using bivariate and multivariate statistical analytical techniques. RESULTS: Statistically significant relationships were found among the following hypotheses: (a) perceived leadership and job satisfaction; (b) organizational commitment and job satisfaction; and (c) perceived leadership practices, organizational commitment, and job satisfaction. No significant relationships were found among critical care nurses' demographic variables and job satisfaction. Organizational commitment was the strongest predictor of job satisfaction. Encourage the heart (B = 0.116, P = .035) and organizational commitment (B = 0.353, P = .000) were found to be significantly associated with job satisfaction. CONCLUSION: These findings have implications for nurse educators, preceptors, administrators, recruiters, and managers in promoting satisfaction. PMID- 26426137 TI - Projections of the Long-Term Growth of the Registered Nurse Workforce: A Regional Analysis. PMID- 26426138 TI - Understanding the Role of the Professional Practice Environment on Quality of Care in Magnet(r) and Non-Magnet Hospitals. AB - OBJECTIVE: The aim of this study was to explore the relationship between Magnet RecognitionA and nurse-reported quality of care. BACKGROUND: MagnetA hospitals are recognized for nursing excellence and quality patient outcomes; however, few studies have explored contributing factors for these superior outcomes. METHODS: This was a secondary analysis of linked nurse survey data, hospital administrative data, and a listing of American Nurses Credentialing Center Magnet hospitals. Multivariate regressions were modeled before and after propensity score matching to assess the relationship between Magnet status and quality of care. A mediation model assessed the indirect effect of the professional practice environment on quality of care. RESULTS: Nurse-reported quality of care was significantly associated with Magnet Recognition after matching. The professional practice environment mediates the relationship between Magnet status and quality of care. CONCLUSION: A prominent feature of Magnet hospitals, a professional practice environment that is supportive of nursing, plays a role in explaining why Magnet hospitals have better nurse-reported quality of care. PMID- 26426139 TI - Explaining the mechanical mechanisms of zeolitic metal-organic frameworks: revealing auxeticity and anomalous elasticity. AB - The comprehensive elastic properties of Zeolitic Imidazolate Frameworks (ZIF-1 to ZIF-4) have been computed using density functional theory (DFT). We employed the periodic CRYSTAL14 code to calculate the single-crystal elastic coefficients (Cij) at the B3LYP level of theory. While the chemical compositions of ZIFs-1 to 4 are the same, each structure features a distinct network topology, crystal symmetry and porosity configuration, which translate into differential structure function mechanical correlations. We elucidate the anisotropic mechanical response with respect to the directionally dependent Young's and shear moduli properties. Our theoretical results suggest that ZIF-3 adopting a dft topology has an extremely low shear resistance (Gmin = 0.1 GPa), which is also underpinning the flexible mechanism responsible for its negative Poisson's ratio (auxetic numin = -0.43). Interestingly, we identified that ZIF-1, ZIF-2, and ZIF 4 could exhibit a nearly zero Poisson's ratio for certain crystal orientations, which is reminescent of a rare "cork-like" phenomenon where there is practically no lateral deformation corresponding to an applied axial strain. Furthermore, we determined the bulk moduli and linear compressibilities, alongside the averaged elastic properties of the ZIF polycrystals. PMID- 26426141 TI - The origin of a large apparent tortuosity factor for the Knudsen diffusion inside monoliths of a samaria-alumina aerogel catalyst: a diffusion NMR study. AB - Pulsed field gradient (PFG) NMR was applied to measure tortuosity factors for carbon dioxide diffusion in the Knudsen and gas regimes inside monoliths of a samaria-alumina aerogel catalyst, a high porosity material containing micropores in addition to meso- and macropores. The apparent tortuosity factor obtained from PFG NMR measurements for the Knudsen diffusion in the meso- and macropores of the catalyst has an unexpectedly large value of approximately 6 if carbon dioxide adsorption in the micropores and other types of surface adsorption sites of the catalyst is ignored. At the same time, the corresponding apparent tortuosity factor in the gas regime was found to be around 2. Application of a proposed model which describes fast molecular exchange between the surface adsorption sites and the main pore volume of the catalyst yields corrected tortuosity factors which depend only on the pore system geometry. Using this model, the corrected tortuosity factors were found to be around 2 for both diffusion regimes, in agreement with the expectations based on a high porosity of the studied catalyst. PMID- 26426140 TI - Synthesis and Evaluation of Cytosolic Phospholipase A(2) Activatable Fluorophores for Cancer Imaging. AB - Activatable fluorophores selective to cytosolic phospholipase A2 (cPLA2) were synthesized and evaluated for their ability to image triple negative breast cancer cells. The activatable constructs were synthesized by esterification of a small molecule fluorophore with a fatty acid resulting in ablated fluorescence. Selectivity for cPLA2 was generated through the choice of fluorophore and fatty acid. Esterification with arachidonic acid was sufficient to impart specificity to cPLA2 when compared to esterification with palmitic acid. In vitro analysis of probes incorporated into phosphatidylcholine liposomes demonstrated that a nonselective phospholipase (sPLA2 group IB) was able to hydrolyze both arachidonate and palmitate coupled fluorophores resulting in the generation of fluorescence. Of the four fluorophores tested, DDAO (7-hydroxy-9H-(1,3-dichloro 9,9-dimethylacridin-2-one)) was observed to perform optimally in vitro and was analyzed further in 4175-Luc+ cells, a metastatic triple negative human breast cancer cell line expressing high levels of cPLA2. In contrast to the in vitro analysis, DDAO arachidonate was shown to activate selectively in 4175-Luc+ cells compared to the control DDAO palmitate as measured by fluorescence microscopy and quantitated with fluorescence spectroscopy. The addition of two agents known to activate cPLA2 enhanced DDAO arachidonate fluorescence without inducing any change to DDAO palmitate. Inhibition of cPLA2 resulted in reduced fluorescence of DDAO arachidonate but not DDAO palmitate. Together, we report the synthesis of a cPLA2 selective activatable fluorophore capable of detecting cPLA2 in triple negative breast cancer cells. PMID- 26426143 TI - The Archean Nickel Famine Revisited. AB - Iron formations (IF) preserve a history of Precambrian oceanic elemental abundance that can be exploited to examine nutrient limitations on early biological productivity. However, in order for IF to be employed as paleomarine proxies, lumped-process distribution coefficients for the element of interest must be experimentally determined or assumed. This necessitates consideration of bulk ocean chemistry and which authigenic ferric iron minerals controlled the sorption reactions. It also requires an assessment of metal mobilization reactions that might have occurred in the water column during particle descent and during post-depositional burial. Here, we summarize recent developments pertaining to the interpretation and fidelity of the IF record in reconstructions of oceanic trace element evolution. Using an updated compilation, we reexamine and validate temporal trends previously reported for the nickel content in IF (see Konhauser et al., 2009 ). Finally, we reevaluate the consequences of methanogen Ni starvation in the context of evolving views of the Archean ocean climate system and how the Ni famine may have ultimately facilitated the rise in atmospheric oxygen. PMID- 26426144 TI - Modification Strategies with Inorganic Acids for Efficient Photocatalysts by Promoting the Adsorption of O2. AB - Efficient photocatalysis for degrading environmental organic pollutants on semiconductors requires photogenerated charge carrier separation to drive the photochemical processes. To ensure charge separation, it is indispensable to make charges captured effectively. Generally, the step for capturing the photogenerated electrons by the surface adsorbed O2 is relatively slow as compared to that for capturing holes by the surface adsorbed hydroxyl groups so that it is taken as the rate-determining step. However, it is frequently neglected. Thus, it is greatly desired to develop feasible strategies to promote the adsorption of O2 for efficient photocatalysts. In this paper, we have mainly discussed surface modification with inorganic acids, such as H3PO4, HF, and H3BO3, to enhance photogenerated charge carrier separation based on oxygen adsorption promotion for photocatalytic degradation of environmental pollutants. Among these acids, the function and mechanism of H3PO4 are highlighted because of its good performance and universality. Several important photocatalyst systems, mainly including TiO2, alpha-Fe2O3, and g-C3N4, along with the nanostructured carbons as electron acceptors in nanocomposites, are addressed to improve the ability to adsorb O2. A key consideration in this review is the development of a strategy for the promotion of adsorbed O2 for efficient photocatalysts, along with the process mechanisms by revealing the relationships among the adsorbed O2, photogenerated charge carrier separation, and photocatalytic performance. Interestingly, it is suggested that the enrichment in surface acidity be favorable for promotion of O2 adsorption, leading to the improved charge carrier separation and then to the enhanced photoactivities of various semiconductor photocatalysts. Moreover, several outlooks are put forward. PMID- 26426142 TI - Crystal structure of the Legionella pneumophila Lem10 effector reveals a new member of the HD protein superfamily. AB - Legionella pneumophila, the intracellular pathogen that can cause severe pneumonia known as Legionnaire's disease, translocates close to 300 effectors inside the host cell using Dot/Icm type IVB secretion system. The structure and function for the majority of these effector proteins remains unknown. Here, we present the crystal structure of the L. pneumophila effector Lem10. The structure reveals a multidomain organization with the largest C-terminal domain showing strong structural similarity to the HD protein superfamily representatives. However, Lem10 lacks the catalytic His-Asp residue pair and does not show any in vitro phosphohydrolase enzymatic activity, typical for HD proteins. While the biological function of Lem10 remains elusive, our analysis shows that similar distinct features are shared by a significant number of HD domains found in Legionella proteins, including the SidE family of effectors known to play an important role during infection. Taken together our data point to the presence of a specific group of non-catalytic Legionella HD domains, dubbed LHDs, which are involved in pathogenesis. PMID- 26426145 TI - Compartmentalization of Incompatible Catalytic Transformations for Tandem Catalysis. AB - In Nature, incompatible catalytic transformations are being carried out simultaneously through compartmentalization that allows for the combination of incompatible catalysts in tandem reactions. Herein, we take the compartmentalization concept to the synthetic realm and present an approach that allows two incompatible transition metal catalyzed transformations to proceed in one pot in tandem. The key is the site isolation of both catalysts through compartmentalization using a core-shell micellar support in an aqueous environment. The support is based on amphiphilic triblock copolymers of poly(2 oxazoline)s with orthogonal functional groups on the side chain that can be used to cross-link covalently the micelle and to conjugate two metal catalysts in different domains of the micelle. The micelle core and shell provide different microenvironments for the transformations: Co-catalyzed hydration of an alkyne proceeds in the hydrophobic core, while the Rh-catalyzed asymmetric transfer hydrogenation of the intermediate ketone into a chiral alcohol occurs in the hydrophilic shell. PMID- 26426146 TI - Fourier transform infrared microspectroscopy reveals biochemical changes associated with glioma stem cell differentiation. AB - According to the cancer stem cell theory malignant glioma is incurable because of the presence of the cancer stem cells - a subpopulation of cells that are resistant to therapy and cause the recurrence of a tumor after surgical resection. Several protein markers of cancer stem cell were reported but none of those is fully reliable to grade the content of stem cells in a tumor. Hereby we propose Fourier transform infrared (FTIR) microspectroscopy as an alternative, labelfree, non-damaging and fast method to identify glioma stem cells based on their own spectral characteristics. The analysis of FTIR data revealed that in NCH421k cells, a model of glioma stem cells, the relative content of lipids is higher than in their all-trans retinoic acid-differentiated counterparts. Moreover, it has been assessed that stem cells have more rigid cellular membranes and more phosphorylated proteins, whereas after differentiation glycogen level increases. The ability of FTIR to estimate the content of stem cells in a heterogeneous sample, on the base of the identified spectral markers, and to classify stem and non-stem cells into two separate populations was probed. Although it was not possible to calculate the exact percentage of each subpopulation, we could clearly see that with the increasing amount of differentiated cells in a sample, more hits occupy the PC space previously identified as a space of differentiated cells. The present study is therefore an initial step towards the development of a FTIR based protocol in clinical practice to estimate the content of stem cells in a tumor sample. PMID- 26426147 TI - The Irish living kidney donor program - why potential donors do not proceed to live kidney donation? AB - BACKGROUND: Living donation is not only a method to increase access to kidney transplantation but can also offer superior outcomes. We report the experience of the living donor (LD) program in the Republic of Ireland and explore reasons why potential donors do not proceed to live donation. METHODS: Retrospective cohort study of all potential donors from January 2000 to March 2014 who presented wishing to undergo donor work-up and their subsequent outcomes. RESULTS: A total of 956 donors for 496 recipients contacted the live kidney donation program of which 883 potential donors proceeded to the initial stage of assessment. The donor dropout rate at this stage was 64.2% (614/956 potential donors did not proceed to further evaluation). Thereafter, 269 (28.1%) donors underwent further assessment by the multidisciplinary team. In total, 93 (9.7%) donors were declined following this assessment with 176 (18.4%) donors ultimately proceeding to live kidney donation. The major reason for declining a donor was a medical contraindication (n = 63, 67.7%). In term of recipients, 54.2% (n = 269/496) had a potential donor proceed for further assessment of which 65.4% (n = 176/269) ultimately proceeding to live donation. CONCLUSION: Further evaluation of the declined donor group is warranted to allow for expansion of the LD program. PMID- 26426148 TI - The Effect of Breathing, Movement, and Meditation on Psychological and Physical Symptoms and Inflammatory Biomarkers in Inflammatory Bowel Disease: A Randomized Controlled Trial. AB - BACKGROUND: This study evaluated the effects of the Breath-Body-Mind Workshop (BBMW) (breathing, movement, and meditation) on psychological and physical symptoms and inflammatory biomarkers in inflammatory bowel disease (IBD). METHODS: Twenty-nine IBD patients from the Jill Roberts IBD Center were randomized to BBMW or an educational seminar. Beck Anxiety Inventory, Beck Depression Inventory, Brief Symptom Inventory 18, IBD Questionnaire, Perceived Disability Scale, Perceived Stress Questionnaire, Digestive Disease Acceptance Questionnaire, Brief Illness Perception Questionnaire, fecal calprotectin, C reactive protein, and physiological measures were obtained at baseline and weeks 6 and 26. RESULTS: The BBMW group significantly improved between baseline and week 6 on Brief Symptom Inventory 18 (P = 0.02), Beck Anxiety Inventory (P = 0.02), and IBD Questionnaire (P = 0.01) and between baseline and week 26 on Brief Symptom Inventory 18 (P = 0.04), Beck Anxiety Inventory (P = 0.03), Beck Depression Inventory (P = 0.01), IBD Questionnaire (P = 0.01), Perceived Disability Scale (P = 0.001), and Perceived Stress Questionnaire (P = 0.01) by paired t tests. No significant changes occurred in the educational seminar group at week 6 or 26. By week 26, median C-reactive protein values decreased significantly in the BBMW group (P = 0.01 by Wilcoxon signed-rank test) versus no significant change in the educational seminar group. CONCLUSIONS: In patients with IBD, participation in the BBMW was associated with significant improvements in psychological and physical symptoms, quality of life, and C-reactive protein. Mind-body interventions, such as BBMW, which emphasize Voluntarily Regulated Breathing Practices, may have significant long-lasting benefits for IBD symptoms, anxiety, depression, quality of life, and inflammation. BBMW, a promising adjunctive treatment for IBD, warrants further study. PMID- 26426153 TI - A tiered, integrated biological and chemical monitoring framework for contaminants of emerging concern in aquatic ecosystems. AB - The chemical-specific risk-based paradigm that informs monitoring and assessment of environmental contaminants does not apply well to the many thousands of new chemicals that are being introduced into ambient receiving waters. We propose a tiered framework that incorporates bioanalytical screening tools and diagnostic nontargeted chemical analysis to more effectively monitor for contaminants of emerging concern (CECs). The framework is based on a comprehensive battery of in vitro bioassays to first screen for a broad spectrum of CECs and nontargeted analytical methods to identify bioactive contaminants missed by the currently favored targeted analyses. Water quality managers in California have embraced this strategy with plans to further develop and test this framework in regional and statewide pilot studies on waterbodies that receive discharge from municipal wastewater treatment plants and stormwater runoff. In addition to directly informing decisions, the data obtained using this framework can be used to construct and validate models that better predict CEC occurrence and toxicity. The adaptive interplay among screening results, diagnostic assessment and predictive modeling will allow managers to make decisions based on the most current and relevant information, instead of extrapolating from parameters with questionable linkage to CEC impacts. Integr Environ Assess Manag 2016;12:540-547. (c) 2015 SETAC. PMID- 26426152 TI - High-throughput genotyping of Anopheles mosquitoes using intact legs by Agena Biosciences iPLEX. AB - Recent developments in genotyping technologies coupled with the growing desire to characterize genome variation in Anopheles populations open the opportunity to develop more effective genotyping strategies for high-throughput screening. A major bottleneck of this goal is nucleic acid extraction. Here, we examined the feasibility of using intact portions of a mosquito's leg as sources of template DNA for whole-genome amplification (WGA) by primer-extension preamplification. We used the Agena Biosciences MassARRAY((r)) platform (formerly Sequenom) to genotype 78 SNPs for 265 WGA leg samples. We performed nucleic acid extraction on 36 mosquito carcasses and compared the genotype call concordance with their corresponding legs and observed full concordance. Using three legs instead of one improved genotyping success rates (96% vs. 89%, respectively), although this difference was not significant. We provide a proof of concept that WGA reactions can be performed directly on mosquito legs, thereby eliminating the need to extract nucleic acid. This approach is straightforward and sensitive and allows both species determination and genotyping of Anopheles mosquitoes to be performed in a high-throughput manner. Our protocol also leaves the mosquito body intact facilitating other experimental analysis to be undertaken on the same sample. Based on our findings, this method would also be suitable for use with other insect species. PMID- 26426154 TI - Drosophila glob1 expresses dynamically and is required for development and oxidative stress response. AB - Biological significance of the globin protein family could be ascertained by their conservation through archaea to human. Globin(s) have been "classically" studied as oxygen binding protein(s), with recent implications in a host of other physiological functions. Drosophila melanogaster possesses three globin genes (glob1, glob2, glob3) located at different cytogenetic positions. We have performed a comprehensive investigation on the cellular expression profile and functional relevance of glob1 in Drosophila development. A profound level of maternally contributed glob1 gene products was found during early embryogenesis. Subsequently, commencement of zygotic transcription leads to its strong expression in somatic muscles, gut primordia, fat bodies, tracheal cells, etc. Similarly, dynamic expression of glob1 was evident in most of the larval tissues, interestingly with high expression in dividing cells. Reduced expression of glob1 leads to various impairments and lethality during embryogenesis and larval development. A substantial increase in level of cellular ROS was also evident due to reduced expression of glob1 which consequently leads to locomotor impairment and early aging in surviving adult flies. To best of our knowledge, this is the first report which demonstrates that in addition to oxygen management, globin gene(s) are also involved in regulating various aspects of development in Drosophila. PMID- 26426158 TI - Radiotracer investigations in pilot-scale soakers. AB - This paper describes a radiotracer investigation carried out to measure residence time distribution (RTD) of petroleum residues in pilot-scale soakers. The main objectives of the investigation were to evaluate the feasibility of using bromine 82 as dibromobiphenyl (DBBP) for tracing the petroleum residues (organic phase) as a radiotracer at elevated temperature and pressure, and to investigate the flow dynamics of the phase in the soaker at different operating and process conditions. The measured RTD was treated and mean residence times (MRTs) were determined. Tanks-in-series with backmixing model (TISBM) was used to simulate the measured RTD data. The results of model simulation indicated a high degree of backmixing in the soaker without baffles i.e. without sectionalizing the soaker. However, the introduction of perforated plates at various axial locations inside the soaker i.e. sectionalizing the soaker, reduces the extent of backmixing thus tending the flow towards plug flow. PMID- 26426155 TI - Expression of stem cell-related genes in the endometrium and endometriotic lesions: a pilot study. AB - OBJECTIVE: To compare the expression of stem cell-related genes in the endometrium (END), superficial endometriosis (SE), and deep infiltrating endometriosis (DIE). STUDY DESIGN: We performed a prospective pilot study of six women suffering from SE and DIE who gave consent for laparoscopy surgery, endometrial biopsies, and participation in this study. Quantitative RT-PCR analysis of 84 stem cell-related genes was performed in 18 biopsy samples. RESULTS: A total of 40 of 84 genes were expressed in SE and DIE, but were different from END as follows. Seven genes were over-expressed in SE and 33 genes were under-expressed in DIE compared with END. Two genes were only over-expressed in SE and three genes were only over-expressed in DIE. Six under-expressed genes were exclusively located in SE and one was only located in DIE. The remaining 31 genes were not different among the groups. There was no significant difference in gene expression between SE and DIE samples. CONCLUSION: Tissue of DIE and SE appears to have similar stem cell-related genes. Nevertheless, there are differences in gene expression between SE and DIE. PMID- 26426159 TI - Maxillofacial trauma in the emergency department: pearls and pitfalls in airway management. AB - Maxillofacial trauma poses a challenge for the anesthesiologist because injuries can often compromise the patient's airways. Airway maintenance is the first step in the American College of Surgeons Advance Trauma Life Support (ATLS(r)) protocol. However, clinical dilemmas may arise about the best way to manage a potentially life-threatening injury. There are no recommendations about the best time to intubate, the warning signs for deciding to intubate, or which device should be used when difficulty is expected. In this context the ATLS(r) approach is important but not sufficient. It is also necessary to recognize and be able to manage specific problems in this scenario where clinical priorities may be conflicting, may suddenly change or may be hidden. This clinical review discusses the complexity of this scenario, providing an overview of the conditions at greatest risk for airway obstruction and the options for airway management, on the basis of the recent literature. Clinicians must recognize the milestones and pitfalls of this topic in order to adopt a systematic approach for airway management, to identify specific characteristics associated with it, and to establish the utility of different instruments for airway management. PMID- 26426160 TI - Pulmonary pathophysiology in obesity: did we miss something? PMID- 26426161 TI - Influence of therapeutic cancer radiation on the bond strength of an epoxy- or an MTA-based sealer to root dentine. AB - AIM: To evaluate the influence of radiation on root canal sealer push-out bond strength to dentine and sealer/dentine interface in teeth filled with AH Plus (Dentsply Ind. Com. Ltda, Petropolis, RJ, Brazil) and MTA Fillapex (Angelus Ind. Prod. Odontologicos S/A, Londrina, PR, Brazil). METHODOLOGY: Thirty-two maxillary canines were selected and randomly assigned to 2 groups (n = 16): one group was not irradiated, and the other was subjected to a cumulative radiation dose of 60 Gy. Root canals were prepared with the Reciproc system (VDW GmbH, Munich, Germany), and each group was divided into 2 subgroups (n = 8) according to the sealer - AH Plus or MTA Fillapex - using the single-cone filling technique. Then, 1-mm-thick dentine slices were obtained from each root third for the push-out test to evaluate sealer bond strength to dentine and for scanning electron microscopy (SEM) to examine the sealer/dentine interface. Failure mode after debonding was determined with a stereomicroscope at *25 magnification. Bond strength data were analysed by two-way anova with a split-plot design and post hoc Tukey's test (alpha = 0.05). RESULTS: Significantly lower bond strength (P < 0.0001) was obtained after irradiation (0.71 +/- 0.20 versus 0.97 +/- 0.29 MPa) and in specimens filled with MTA Fillapex (0.70 +/- 0.18 MPa) compared with AH Plus (1.00 +/- 0.27 MPa). Percentage of adhesive failures increased after radiation in all root thirds in the teeth filled with AH Plus. SEM revealed more gap-containing regions and fewer tags at the sealer/dentine interface in irradiated specimens, with more tag formation and fewer gaps with AH Plus sealer. CONCLUSIONS: Radiation was associated with a decrease in the push-out bond strength of sealers to intraradicular dentine and formation of more gaps and fewer tags at the sealer/dentine interface regardless of the sealer. PMID- 26426162 TI - Identification of immunodominant antigens for the laboratory diagnosis of toxocariasis. AB - OBJECTIVES: To identify immunodominant antigens of Toxocara canis recognised by Toxocara-infected sera as recombinant reagents for immunodiagnosis of toxocariasis. METHODS: Pooled sera from human cases of toxocariasis were used to identify immunodominant antigens by immunoscreening a T. canis larval expression cDNA library. The positive clones were sequenced to reveal the identity of the antigens. The recombinant proteins were expressed in E. coli and then used to confirm their immunoreaction with sera of humans with toxocariasis. Two chosen antigens were also used to differentiate Toxocara infection from other helminth infections in mice. RESULTS: Eleven antigens with immunodiagnostic potential were identified, including two C-type lectins (CTLs) that reacted strongly with the Toxocara-positive serum pool. The first CTL (Tc-CTL-1) is the same as TES-32, previously identified as a major immunodominant component of TES; the second CTL (Tc-CTL-2) is a novel C-type lectin sharing 83% amino acid sequence identity within the functional domain of Tc-CTL-1. The E. coli-expressed recombinant Tc CTL-1 was strongly recognised by the Toxocara-positive serum pool or sera from animals experimentally infected with T. canis. Reactivity with recombinant Tc-CTL 1 was higher when the unreduced protein was used in an enzyme-linked immunosorbent assay (ELISA), dot-blot assay or Western blot test compared to the protein under reduced condition. Both recombinant Tc-CTL-1- and Tc-CTL-2-based ELISAs were able to differentiate T. canis infection from other helminth infections in experimentally infected mice. CONCLUSIONS: Both Tc-CTL-1 and Tc-CTL 2 were able to differentiate Toxocara infection from other helminth infections and could potentially be used as sensitive and specific immunodiagnostic antigens. PMID- 26426163 TI - Effects of particle size and hydro-thermal treatment of feed on performance and stomach health in fattening pigs. AB - Effects of grinding and hydro-thermal treatment of feed on growth performance, slaughter traits, nutrient digestibility, stomach content and stomach health were examined by using 96 crossbred fattening pigs. Pigs were fed a grain-soybean meal based diet processed by various technical treatments. Feeding groups differed in particle size after grinding (finely vs. coarsely ground feed) and hydro-thermal treatment (without hydro-thermal treatment, pelleting, expanding, expanding and pelleting). Fine grinding and hydro-thermal treatment showed significant improvements on the digestibility of crude nutrients and content of metabolisable energy. Hydro-thermal treatment influenced average daily gain (ADG) and average daily feed intake (DFI) significantly. Finely ground pelleted feed without expanding enhanced performances by increasing ADG and decreasing feed-to-gain ratio (FGR) of fattening pigs. Coarsely ground feed without hydro-thermal treatment resulted in the highest ADG and DFI, however also in the highest FGR. Expanded feed decreased DFI and ADG. Slaughter traits were not affected by treatments. Coarsely ground feed without hydro-thermal treatment had protective effects on the health of gastric pars nonglandularis, however, pelleting increased gastric lesions. Hydro-thermal treatment, especially expanding, resulted in clumping of stomach content which possibly induced satiety by slower ingesta passage rate and thus decreased feed intake. Pigs fed pelleted feed showed less pronounced development of clumps in stomach content compared with expanded feed. PMID- 26426165 TI - Priapism in Homozygous Sickle Cell Disease: A 40-year Study of the Natural History. AB - OBJECTIVES: To describe the incidence, pattern, and outcome of priapism in homozygous sickle cell (SS) disease. METHODS: Regular review, for periods up to 40 years, was done of all 162 males with SS disease detected during the screening of 100 000 consecutive non-operative deliveries at the main government maternity hospital in Kingston, Jamaica, between June 1973 and December 1981. RESULTS: Priapism occurred in 52 (32.7%) patients overall, the incidence rising steeply in late adolescence to 32% by age 20 years and a cumulative incidence of nearly 60% of patients by age 40 years. Many cases were elicited only on direct questioning because of embarrassment and the lack of realization that priapism complicates SS disease. Initial events were recurrent stuttering episodes in 39 patients, a single short-term event in six patients and a major attack (more than six hours) in seven patients. Erectile function was preserved in almost all patients with simple stuttering or single events. Major attacks (> 6 hours) occurred in 17 patients, preceded by stuttering episodes in nine, by a single event in one, and occurring de novo in seven. In these, erectile function was unknown in five, deemed satisfactory in five (sometimes improving over three years), weak in three and impotence persisted in four (two with major attacks three and six months previously). CONCLUSION: A history of stuttering priapism should be routinely enquired and prophylactic measures used if attacks exceed once weekly. Major events generally result in short-term impotence, but the late recovery of erectile function cautions against the early insertion of penile prostheses. PMID- 26426164 TI - Biosimilar Epoetin Zeta in Oncology and Haematology: Development and Experience following 6 Years of Use. AB - Chemotherapy-induced anaemia is frequent in cancer patients, with severity depending on the extent of the disease and intensity of treatment. Clinical guidelines recommend erythropoietin therapy to treat or prevent anaemia in some oncology/haematology patients being treated with chemotherapy. The patent expiry of the first-generation erythropoietins has led to the development of biosimilar products, i.e. therapeutic proteins exhibiting comparable quality, safety and efficacy to an existing reference biological medicine, the patent of which has expired. This review summarises the available data set supporting the use of one such biosimilar product, epoetin zeta (RetacritTM) in oncology/haematology. The body of evidence supporting the use of epoetin zeta continues to grow, with post marketing clinical studies underway to evaluate its longer-term clinical efficacy and safety. Biosimilar medicines have the potential to offer cost savings to health care providers, with the assurance of ongoing risk management programmes to ensure patient safety. PMID- 26426166 TI - Healthy Eating in Jamaica: The Cost Factor. AB - OBJECTIVE: This study was conducted to determine the importance of food cost in securing a healthy diet to combat non-communicable diseases. Several studies have evaluated whether healthier foods or diets cost more but a full range of health criteria has rarely been explored. Rather than merely comparing high and low energy dense foods, this study also included type of fat, vitamin, mineral and fibre content of foods in classifying them as healthy and less healthy. METHOD: Both 'commonly consumed' and 'all available' foods were ranked according to their nutritional value and potential positive or negative contribution to the development of major health problems in Jamaica such as obesity and chronic diseases. The costs of 158 food items were averaged from supermarkets, municipal markets and wholesale outlets in six parishes across Jamaica. Cost differentials were then assessed in comparing healthy and less healthy foods. RESULTS: The study found that among the commonly consumed foods in Jamaica, healthy options cost J$88 (US$0.78) more than less healthy ones. However, when all the available food items were considered, the less healthy options cost more. The cheapest daily cost of a nutritionally balanced diet in Jamaica varied considerably by parish but was on average J$269 (US$2.40) per person. For a family of three, this translates approximately to the total minimum wage per week. CONCLUSION: Eating healthy in Jamaica can be achieved at low cost if appropriate information on nutrient content/value for money is provided to consumers. Effective promotions by public and private sector agencies are essential for consumer choice to be optimal. PMID- 26426167 TI - The Protective Effect of Epigallocatechin-3-gallate on Paraquat-induced Haemolysis. AB - Epigallocatechin-3-gallate (EGCG) is a major ingredient present in green tea, which has a high antioxidant activity. In this study, the effect of EGCG was investigated on paraquat-induced haemolysis of erythrocyte membrane. Erythrocytes were incubated in 0.03, 0.3, 3.0 and 30 mg/mL EGCG, respectively and exposed to 30 mg/mL of paraquat for 10 minutes. The effect of paraquat was determined by an analysis of the osmotic fragility of the erythrocytes. The results showed that EGCG (30 mg/mL) significantly (p < 0.05) reduced the haemolysis of erythrocytes exposed to paraquat (5.0 mg/mL). This suggests that EGCG may have a protective effect on paraquat-induced erythrocyte membrane haemolysis and that consumption of green tea, with high EGCG concentration, could ameliorate the deleterious effect of paraquat toxicity on the haemolysis of erythrocyte membrane. PMID- 26426168 TI - Effect of L-ornithine L-aspartate on Liver Injury Due to Acute Ethyl Alcohol Intoxication in Rats. AB - OBJECTIVE: Ethyl alcohol is a substance that is widely used worldwide and known to exert toxic effects on liver. In this study, we aimed to examine the effect of L-ornithine L-aspartate (LOLA) on the toxicity of a single dose of ethyl alcohol in rats. SUBJECTS AND METHOD: We used 32 randomly selected male Sprague-Dawley rats weighing 200-250 g. The rats were grouped into four groups with each group containing eight rats: Group 1: the control group, Group 2: the ethyl alcohol group, Group 3: the LOLA group and Group 4: the ethyl alcohol+LOLA group. Ethyl alcohol was administered orally through a nasogastric tube at a dose of 6 g/kg after diluting with distilled water. One hour after ethyl alcohol administration, LOLA was administered to pre-specified groups orally through a nasogastric tube at a dose of 200 mg/kg after diluting with distilled water. Liver tissue and blood samples were obtained from all rats 24 hours later to study total antioxidant capacity (TAC), total oxidant status (TOS) and oxidative stress index (OSI) levels in liver samples, and aspartate aminotransferase (AST), alanine transferase (ALT), TAC, TOS and OSI levels in blood samples. RESULTS: Serum TAC, TOS and OSI levels were higher in the groups that were administered ethyl alcohol. In addition, tissue TAC level was higher and TOS and OSI levels were lower in groups that were given ethyl alcohol. No significant changes were observed in serum and tissue TAC, TOS, OSI, ALT and AST levels in the LOLA administered groups. CONCLUSION: This study showed that LOLA was not biochemically effective and exerts no oxidative stress reducing activity in liver injury due to acute ethyl alcohol toxicity. PMID- 26426169 TI - Alcoholic Extract of Lotus Leaves Improves Lipid Profile in Rats with HIV Protease Inhibitor-induced Dyslipidaemia. AB - OBJECTIVE: To examine the effect of the alcoholic extract of lotus leaves (AELL) on antiretroviral treatment-induced dyslipidaemia in a rat model. METHODS: Lotus leaves were extracted by 95% ethanol. Seventy male Sprague-Dawley rats were given lopinavir/ritonavir for six weeks. At week 0 and 6, sera were collected for measurement of total cholesterol (TC) and triglyceride (TG). Rats meeting the criteria for dyslipidaemia were assigned to four groups and received once daily for another four weeks lopinavir/ritonavir (group A), lopinavir/ritonavir plus 0.52 g/kg AELL (group B), lopinavir/ritonavir plus 0.26 g/kg AELL (group C), or lopinavir/ritonavir plus 0.13 g/kg AELL (group D), respectively. At weeks 8 and 10, blood samples were collected again for measurement of TC or TG. RESULTS: Both TC and TG increased over time in group A during the observation period (weeks 6 to 10), however, TC and TG decreased in group B, and TG declined in group C. Neither TC nor TG could be reduced to a level near baseline. CONCLUSION: Alcoholic extract of lotus leaves may have the potential to treat dyslipidaemia related to highly active antiretroviral therapy, but may not be potent enough to reduce TC or TG concentrations to goal levels when used alone. PMID- 26426170 TI - Prevalence of Chronic Kidney Disease among Patients Attending a Specialist Diabetes Clinic in Jamaica. AB - OBJECTIVE: To estimate the prevalence of chronic kidney disease (CKD) among patients attending the University Hospital of the West Indies (UHWI) Diabetes Clinic and to determine the proportion of patients at high risk for adverse outcomes. METHODS: We conducted a cross-sectional study among patients attending the UHWI Diabetes Clinic between 2009 and 2010. Trained nurses administered a questionnaire, reviewed dockets, and performed urinalyses. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Albuminuria was assessed using urine test strips for protein and microalbumin. Chronic kidney disease was defined as an eGFR < 60 ml/min/1.73m2 or albuminuria >= 30 mg/g creatinine. Risk of adverse outcome (all-cause mortality, cardiovascular disease and kidney failure) was determined using the Kidney Disease: Improving Global Outcome (KDIGO) 2012 prognosis grid. RESULTS: Participants included 100 women and 32 men (mean age, 55.4 +/- 12.9 years, mean duration of diabetes, 16.7 +/- 11.7 years). Twenty-two per cent of participants had eGFR < 60 ml/min/1.73m2. Moderate albuminuria (30-300 mg/g) was present in 20.5% of participants and severe albuminuria (> 300 mg/g) in 62.1%. Overall prevalence of CKD was 86.3% (95%CI 80.4%, 92.2%). Based on KDIGO risk categories, 50.8% were at high risk and 17.4% at very high risk of adverse outcomes. CONCLUSION: Most patients at the UHWI Diabetes Clinic had CKD and were at high or very high risk of adverse outcomes. Further studies to determine the burden of CKD in other clinical settings and to identify the best strategies for preventing adverse outcomes in developing countries need to be conducted. PMID- 26426171 TI - Application of Modified Glomerular Filtration Rate Estimation Equations in Chinese Diabetic Patients with Chronic Kidney Diseases. AB - OBJECTIVE: To evaluate the applicability of modified formulae based on plasma creatinine levels in Chinese diabetic patients with chronic kidney diseases (CKD). METHODS: A total of 294 diabetic patients were investigated. Glomerular filtration rate (GFR) was estimated with the Ruijin equation, Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulae. The accuracy of estimated GFR was compared with technetium-99m diethylene triamine pentaacetic acid (99mTc-DTPA)-GFR (sGFR). RESULTS: Bland-Altman analysis demonstrated that the Ruijin equation was more consistent with sGFR than the other equations. However, all the equations were not very consistent with sGFR. The analysis showed that the slope of the Ruijin equation was closer to the identical line and indicated that the bias of Ruijin equation was lowest. The 15%, 30% and 50% accuracies of the Ruijin equation were higher than those of the other equations; the 30% accuracy of Ruijin equation was more than 70%. CONCLUSION: Ruijin equation is more applicable in Chinese diabetic and CKD patients. PMID- 26426172 TI - Evaluation of Nutritional Biochemical Parameters in Haemodialysis Patients over a Ten-year Period. AB - AIM: Protein-energy malnutrition as well as systemic inflammation and metabolic disorders are common in patients with chronic kidney failure, who require renal replacement therapy (haemodialysis). Such malnutrition is a factor that significantly contributes to their morbidity and mortality. This study evaluated the nutritional status of haemodialysis patients by assessing biochemical and anthropometric parameters in order to determine whether these patients suffered disorders reflecting nutritional deterioration directly related to time on haemodialysis. SUBJECTS AND METHOD: This research comprised 90 patients of both genders with chronic kidney failure, who regularly received haemodialysis at our unit over a period of ten years. The patients' blood was tested quarterly for plasma albumin, total cholesterol and total proteins, and tested monthly for transferrin. The patients' weight, height and body mass index (BMI) were monitored. Body mass index was calculated using the formula: weight (kg)/height (m2 ) and classified in one of the following categories defined in the World Health Organization (WHO) Global Database on Body Mass Index: (i) underweight [BMI < 18.50], (ii) normal [BMI 18.50 - 24.99], (iii) overweight [BMI 25 - 29.99], (iv) obese [BMI > 30]. RESULTS: In the ten-year period of the study, the patients experienced a substantial decline in their biochemical parameters. Nevertheless, their BMI did not show any significant changes despite the patients' state of malnutrition. CONCLUSIONS: The prevalence of malnutrition in haemodialysis patients was evident. Nevertheless, the BMI of the subjects did not correspond to the biochemical parameters measured. Consequently, the results showed that the nutritional deterioration of these patients was mainly reflected in their biochemical parameters rather than in their anthropometric measurements. PMID- 26426173 TI - Treatment Experience of Severe Abdominal Infection after Orthotopic Liver Transplantation. AB - This study aims to investigate the causes and treatment experience of severe abdominal infection after orthotopic liver transplantation. Clinical data were retrospectively analysed in perioperative severe abdominal infection of 186 orthotopic liver transplantation cases from March 2004 to November 2011. Among the 186 patients, 16 cases had severe abdominal infection: five cases had bile duct anastomotic leakage-inducing massive hydrops and infection under liver interstice, 10 cases had extensive bleeding of surgical wound leading to massive haematocele and infection around the liver, and one case had postoperative lower oesophageal fistula leakage causing massive hydrops and infection under the left diaphragm. After definite diagnosis, 12 cases underwent surgery within three days, with no death. Among the four cases that underwent surgery three days after diagnosis, one case died of multiple-organ failure five days after abdominal cavity exploration, which was performed 21 days after liver transplantation. Severe abdominal infections after liver transplantation were the most common causes of death in perioperative liver transplantation. Comprehensive treatment with efficacious antibiotics, multiple-organ support, controlled surgical removal of the lesion, and adequate drainage establishment was the key to the entire treatment. PMID- 26426174 TI - Time-dependent Degradation Pattern of Cardiac Troponin T in Cases of Death by Burn. AB - OBJECTIVE: Death due to burn occurs frequently. This study investigated time dependent alterations in cardiac troponin T (cTnT) associated with fatal burns. METHODS: Cardiac tissue samples were collected from 10 medico-legal autopsies after informed consent from the relatives and post-mortem degradation by incubation of the cardiac tissue was studied at room temperature for different time periods. The cases included in this study were the subjects of burns without any prior history of disease who died in the hospital and their exact time of death was known. An efficient extraction protocol to analyse the banding pattern of cTnT in post-mortem tissue was developed. RESULTS: The data show a distinct time-dependent profile corresponding to the degradation of cTnT by proteases found in cardiac muscle. Both post-mortem interval and cardiac tissue of burned corpses had a statistically significant effect where the greatest amount of protein breakdown was observed within the first 41.20 hours, after which intact protein slowly disappears. The average molecular weight of all fragments showed intact cTnT to be rapidly degraded into smaller fragments. CONCLUSION: In cases of burns, such knowledge will assist in knowing if there were previous scars that might have mimicked a burn and also help to properly evaluate the real cause of death. PMID- 26426175 TI - Treatment of Parapelvic Cyst by Internal Drainage Technology Using Ureteroscope and Holmium Laser. AB - BACKGROUND: The aim of parapelvic cyst treatment is to have complete drainage of cyst fluid and prevent its further compression of the kidney and collective system. This study explores the efficacy and safety of surgical approaches with holmium laser ureteroscopic internal drainage in the treatment of parapelvic cyst. METHODS: The compression effect of parapelvic cyst on the renal collective system was observed by rigid ureteroscope using retrograde ureteroscopic technology. With direct vision, the cyst wall on the obvious parapelvic compression site was cut. The diameter of the cyst wall cut was about 1 cm. The internal drainage was obtained by double-J tubes. When the cyst was in the inferior pole of kidney or where the rigid ureteroscope could not reach, a flexible ureteroscope was used. RESULTS: In 28 cases of operation, 27 cases were successful. The cyst treatment time was eight to 40 minutes (average 26 minutes). During the operation, no massive haemorrhage, damage of nearby organ and ureter, or other complications happened. Time of follow-up was 10-72 months (average 39 months). The results of follow-up showed that in 22 cases, the cyst disappeared; the diameter of the cyst in four cases was reduced by more than half, and one case recurred. CONCLUSION: The treatment of parapelvic cyst by internal drainage operation using holmium laser and ureteroscopy was effective. The operation was safe with few complications. PMID- 26426176 TI - Ascites in Ovarian Carcinoma - Reliability and Limitations of Cytological Analysis. AB - OBJECTIVE: The objective of this study was to examine the validity of ascitic fluid cytology in the detection of pathological findings, to examine the percentage of false positive and false negative results in the cytology of ascitic fluid and to determine the validity of peritoneal cytology in relation to the histopathological type of the ovarian tumour. METHODS: This retrospective study included 170 peritoneal cytology findings. The study was conducted from January 2010 to December 2012. The experimental group included 76 cytology findings obtained from patients diagnosed with ovarian carcinoma, whereas the control group was composed of 94 cytology findings of benign ovarian tumours and liver cirrhosis ascites. The patients with ovarian carcinoma had grades III, as well as grades I and IIc but only in cases where operative and pathological finding indicated a ruptured or perforated tumour capsule. RESULTS: The sensitivity of peritoneal cytology is 68.92%, specificity is 93.61%, positive predictive value is 89.65% and negative predictive value is 78.57%. In 30.02% of patients, the peritoneal cytology showed false negative results, while in 6.38%, the results were false positive. The highest percentage of false negative findings was 77%, found in endometrioid carcinoma. CONCLUSION: Peritoneal cytology of ascitic fluid is highly specific but has relatively low sensitivity, particularly in the case of endometrioid ovarian carcinoma. In order to increase sensitivity, peritoneal cytology should be combined with monoclonal antibodies and other biochemical and immunohistochemical markers. PMID- 26426177 TI - Analysing Biological Rhythms in Fibromyalgia Syndrome. AB - AIM: This study evaluated biological rhythm disorders in patients with fibromyalgia syndrome (FMS). METHODS: The study enrolled 82 patients with FMS and 82 controls. Pain intensity was evaluated using a visual analogue scale (VAS). The psychological conditions of the patients were evaluated using the Beck Depression Inventory (BDI). The Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) was used to assess disturbances in biological rhythms (ie sleep, activity, social and eating patterns). RESULTS: There was no difference between the two groups at baseline (all p > 0.05). The BDI, BRIAN total, sleep, activity, social, and eating scores were higher in patients with FMS than in the controls (all p < 0.001). Further, a significant correlation was found between biological rhythms and BDI scores (p < 0.001) and there were positive correlations between the VAS score and BRIAN total, sleep, and eating and BDI in patients with FMS (all p < 0.001). CONCLUSION: There are marked biological rhythm disturbances in FMS. There is an important relationship between rhythm disorders and FMS. The disturbances in sleep, functional activities, social participation, and disordered rhythms like eating patterns show the need for a multidisciplinary approach to treating patients with FMS. PMID- 26426178 TI - Estimated Burden of Serious Fungal Infections in Jamaica by Literature Review and Modelling. AB - OBJECTIVE: Jamaica is one of the largest countries in the Caribbean with a population of 2 706 500. Prevalence of human immunodificency virus (HIV) in Jamaica is high, while that of tuberculosis (TB) is recorded to be low. In this study, we have estimated the burden of serious fungal infections and some other mycoses in Jamaica. METHODS: All published papers reporting on rates of fungal infections in Jamaica and the Caribbean were identified through extensive search of the literature. We also extracted data from published papers on epidemiology and from the World Health Organization (WHO) TB Programme and UNAIDS. Chronic pulmonary aspergillosis (CPA), allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS) rates were derived from asthma and TB rates. Where there were no available data on some mycoses, we used specific populations at risk and frequencies of fungal infection of each to estimate national prevalence. RESULTS: Over 57 600 people in Jamaica probably suffer from serious fungal infections each year, most related to 'fungal asthma' (ABPA and SAFS), recurrent vulvovaginal candidiasis and AIDS-related opportunistic infections. Histoplasmosis is endemic in Jamaica, though only a few clinical cases are known. Pneumocystis pneumonia is frequent while cryptococcosis and aspergillosis are rarely recorded. Tinea capitis is common in children. Recurrent vulvovaginal candidiasis is very common (3154/100 000) and candidaemia occurs. Subcutaneous mycoses such as chromoblastomycosis and mycetoma also seem to be relatively common. CONCLUSION: Local epidemiological studies are urgently required to validate or modify these estimates of serious fungal infections in Jamaica. PMID- 26426180 TI - Simvastatin Protects Osteoblasts from the Deleterious Effects of the Liquid Milieu of Multiple Myeloma. AB - Lytic bone lesions are the main clinical manifestation of multiple myeloma. The intense variety in this cell microenvironment, composed mainly of fibroblasts, osteoblasts, osteoclasts, immune cells and mesenchymal cells, is influenced by the massive presence of neoplastic plasma cells. Studies with statins have reported their action in stimulating the formation and reducing bone resorption. The aim of this study was to verify the in vitro response of human osteoblasts exposed to the supernatant (liquid milieu) of multiple myeloma. The data obtained indicate that simvastatin has positive effects on the growth of osteoblasts and protection against the anti-proliferative effects of multiple myeloma supernatant. PMID- 26426179 TI - Mini-review: Obesity in Caribbean Youth. AB - OBJECTIVE: Our focus was on the determination of the growing number of youths of every race and ethnicity, diagnosed with obesity and its co-morbidities in the Caribbean. We reviewed the causes and strategies to combat obesity, and the implications of the fast food industry in enabling the escalation of obesity. METHODS: We consulted several databases such as PubMed, MEDLINE, the Obesity Gene Map Database, and the USEPA Toxicity Reference Database. Organizations such as the World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), Organization for Economic Co-operation and Development (OECD) and the Pan American Health Organization (PAHO) were used as information sources. RESULTS: Transgenerational effects and triggers like obesogens, pathogens, environmental stress, antibiotics and gut microbiota are some of the causes of obesity, and some of these triggers are imprinted epigenetically early in embryonic development, leading to lifelong obesity. With an estimated population of 42 million in the Caribbean, the economic cost of obesity, including medical, absenteeism, presenteeism, insurance, disability, direct and indirect cost, was estimated cost of 68.5 billion USD with 88.2 million quality-adjusted life years lost. CONCLUSION: Genome-wide association studies have established that genetics play a role in the aetiology of this "non-communicable" disease. While the development of personalized interventions according to genotype is futuristic, we must focus on effective nutrition and physical education classes in schools and establishing monitoring programmes using simple tools such as scales and tape measures as suggested intervention. A Pigovian tax to control the fast food industry is mandatory. Nevertheless, lifestyle adjustment, including alterations in diet and increased physical activity, continues to be a sound recommendation. PMID- 26426181 TI - Oral Hygiene and Handwashing Practices among Middle School Students in 15 Latin American and Caribbean Countries. AB - OBJECTIVE: To examine the relationship between infrequent toothbrushing and infrequent handwashing among middle school students from 15 Latin American and Caribbean countries (Antigua and Barbuda, Argentina, British Virgin Islands, Cayman Islands, Costa Rica, Grenada, Guatemala, Guyana, Peru, Saint Kitts and Nevis, Saint Lucia, Saint Vincent and Grenadines, Suriname, Trinidad and Tobago, and Uruguay). METHODS: A secondary analysis was done of nationally-representative data from 33 174 middle school students who participated in the Global School based Student Health Survey (GSHS) between 2006 and 2011. RESULTS: In all 15 countries, the association between rarely brushing or cleaning teeth and rarely handwashing after using the toilet was significant for both boys and girls. The pooled odds ratio for this association was 6.7 (5.8, 7.7). CONCLUSION: Healthcare providers who notice signs of poor dental hygiene or infrequent bathing in adolescents should consider providing comprehensive hygiene education to their patients, since infrequent oral and body hygiene behaviours tend to co-exist and both are threats to health. PMID- 26426182 TI - Correlation of Radiographic Mental Foramen Position and Occulusion in Three Different Indian Populations. AB - BACKGROUND: The knowledge of the position of the mental foramen (MF) is important for administering local anaesthesia for diagnostic, surgical or operative procedures. AIMS: To determine the shape, position, symmetry of MF and its continuity with the inferior dental canal (IDC) on a digital panoramic view and to find its correlation with Angle's molar relations in three Indian subpopulations. The study also determines the correlation of inter-foramen distance in both genders of three Indian subpopulations. SUBJECTS AND METHODS: One hundred and twenty digital panoramic radiographs were evaluated from three Indian subpopulations (Punjab, Rajasthan and Northeast [NE]). The assessment of occlusion was based on Angle's molar relationships. The data obtained were statistically analysed. RESULTS: The commonest position of the MF in the Rajasthan and NE populations was position 4 bilaterally, while in the Punjab population, it was position 3 on the right and position 4 on the left side. The majority of the MF was round in shape followed by oval. The mean distance between two MF was highest among the Punjab male population and least among the NE female population. The most frequent pattern of MF continuity with IDC was diffuse in Rajasthan population, separated in NE and continuous in Punjab. Correlation between Angle's molar relation with MF position was significant for Classes I and II but not for Class III. Correlation of inter-foramen distance between genders was highly significant in the NE and Punjab populations. CONCLUSION: The commonest MF position was aligned with the 1st premolar and between the 1st and 2nd premolar. PMID- 26426184 TI - Amlodipine-induced Gingival Hyperplasia - A Case Report and Review. AB - Anticonvulsants, antihypertensive calcium channel blockers and immunosuppressants are the three main classes of drugs known to cause drug-induced gingival hypertrophy or hyperplasia. Among the calcium channel blockers, nifedipine administration has most frequently been associated with medication-related gingival hyperplasia. The incidence with amlodipine, which has a mode of action pharmacodynamically comparable to nifedipine, has rarely been reported. Here, we present a rare case of amlodipine-induced gingival hyperplasia in a hypertensive patient. PMID- 26426183 TI - Paroxysmal Complete Atrioventricular Block: A Rare Cause of Syncope in Children. AB - Paroxysmal atrioventricular block (PAVB) is a rare cause of syncope, mostly reported in adults. In the present study, a child with recurrent syncope due to PAVB is reported. A 12-year old boy was admitted due to syncope. Some syncopal episodes were consistent with vasovagal syncope, while others had atypical features. Electrocardiography, echocardiography and 24-hour electrocardiography monitoring were normal. Head-up tilt table test revealed mixed type vasovagal syncope. With beta-blocker treatment, the frequency of syncopal episodes decreased; however, the episodes with atypical features continued. Intracardiac electrophysiological study was normal, but repeated external loop recorder monitoring revealed transient AVB during a syncopal episode. In children with syncope with atypical features, PAVB should be kept in mind. Repeated external loop recorder monitoring may be useful in the diagnosis of such seldom seen arrhythmic causes. PMID- 26426185 TI - Functional Outcomes of the Surgery and Rehabilitation in a Challenging Case of Heterotopic Ossification after Encephalitis. AB - Heterotopic ossification is the formation of the lamellar bone where normally osseous tissue does not exist. Since heterotopic ossification can cause severe functional loss, it is a challenging condition for both clinicians and patients. Neurogenic heterotopic ossification is a rare condition after encephalitis. Likewise, in this paper, we have presented a challenging case of heterotopic ossification after viral encephalitis and functional outcomes after the management of heterotopic ossification. PMID- 26426186 TI - Rare Seagull Cooing Murmur from Acute Aortic Dissection. AB - Acute aortic dissection is a rare but potentially fatal disease. The early recognition of this disease is important for timely treatment. Some signs and symptoms, such as past history of hypertension, tearing pain and pulselessness, can provide valuable clues to the diagnosis of this disease. In this case study, the mechanism of a seagull murmur from aortic dissection is first described. This information is potentially useful for the differential diagnosis of dissection. PMID- 26426187 TI - Repeated Burkholderia cepacia Peritonitis in a Patient Undergoing Continuous Ambulatory Peritoneal Dialysis. AB - Burkholderia cepacia (B cepacia) is a rare opportunistic pathogen in continuous ambulatory peritoneal dialysis (CAPD) peritonitis. We describe the first case of repeated B cepacia CAPD peritonitis, occurring in an outpatient environment, treated with antimicrobial medication without peritoneal catheter removal. B cepacia may lead to repeat infection, therefore, we should insist on catheter removal during each peritonitis episode. PMID- 26426188 TI - A Reduction Grade of Lipodystrophy and Limited Side Effects after HAART Regimen with Raltegravir, Lamivudine, Darunavir and Ritonavir in an HIV-1 Infected Patient after Six Years of Antiretroviral Therapy. AB - HIV-associated lipodystrophy commonly presents with fat loss in the face, buttocks, arms and legs, hypocomplementaemia, glomerulonephritis, and autoimmune disorders. The exact mechanism of HIV-associated lipodystrophy is not fully elucidated. There is evidence indicating that it can be caused by both antiretroviral medications and HIV infection in the absence of antiretroviral medication. Lipodystrophy seems to be mainly due to HIV-1 protease inhibitors. Interference with lipid metabolism is postulated as pathophysiology. Also, the development of lipodystrophy is associated with specific nucleoside reverse transcriptase inhibitors (NRTI). Mitochondrial toxicity is postulated to be involved in the pathogenesis associated with NRTI. Here, we analyse the side effects and examine the impact of the highly active antiretroviral therapy (HAART) regimen including raltegravir, lamivudine, darunavir and ritonavir in an HIV-1 infected patient with severe lipodystrophy after six years of antiretroviral therapy. PMID- 26426189 TI - Tricuspid Atresia 18 Years Post Glenn: Is Fontan Necessary in All Cases? AB - Tricuspid atresia is a rare cyanotic congenital heart disease, first described by Kreysig (1817), has an incidence of 1% to 5%. It is incompatible with longevity without surgical intervention. Glenn (1958) was successful in using a superior vena cava to right pulmonary artery anastomosis. Fontan (1958) was successful in separating the right and left cardiac circulation; this is the surgical method of choice, with death of 17% by 20 years of age. The Fontan circulation has burdens of multisystem abnormalities, including ventricular dysfunction (72%), dysrhythmias (40%) and renal, hepatic, gastrointestinal and pulmonary complications. The index case is the oldest documented report of tricuspid atresia with rudimentary right ventricle and concordant ventriculo-arterial connections, 18 years post Glen only, from two years of age. She is asymptomatic, of high intellect, never used medications and is now functioning at New York Heart Association (NYHA) I-II, at 20 years of age. Her survival and function was secondary to an innate large atrial and ventricular communication with normal left ventricle, mitral, aortic and pulmonary valves, indicating Fontan may not be needed in all structural anatomic cases of tricuspid atresia. PMID- 26426190 TI - Valvar Pulmonary Atresia in Afro-Caribbean Adolescents: Echocardiographic Features. AB - Valvar pulmonary atresia is a rare congenital anomaly usually associated with ventricular septal defects or intact ventricular septum. The patent ductus arteriosus (56%) and systemic pulmonary collaterals maintain pulmonary blood flow. Presentation beyond childhood is unusual, as there is usually high morbidity in the first year of life. The two index cases highlight the rarity of adolescents with valvar pulmonary atresia and focusses on the transthoracic echocardiographic features, whose diagnoses provide definitive and curative options with adequate size pulmonary dimensions. Options available are transcatheter interventional radiofrequency pulmonary valvotomy, which is both diagnostic and therapeutic, and intraoperative valve replacement, thus eliminating the need for right ventricle pulmonary artery external valved conduit during corrective surgery. They are the first cases of adolescents with isolated cardiac anomaly of valvar pulmonary atresia, documented in Afro-Caribbeans. PMID- 26426191 TI - The Non-recurrent Laryngeal Nerve -- A Rare Phenomenon Which Requires Vigilance. PMID- 26426193 TI - Extradural Haematoma in Football. PMID- 26426192 TI - Parathyroid Carcinoma: A Case Report and Review of the Literature. PMID- 26426194 TI - The Significance of Evaluating the Variation of Mechanical Microstructure for Hypertrophic Cardiomyopathy Using Diffusion Tensor Magnetic Resonance Imaging. PMID- 26426195 TI - Adrenal Cystic Lymphangioma. PMID- 26426196 TI - Closing the Gap between Preclinical Biologic Development and Clinical Application in Rheumatoid Arthritis. PMID- 26426197 TI - Lack of awareness of treatment failure among HIV-1-infected patients in Guinea Bissau - a retrospective cohort study. AB - INTRODUCTION: With more people receiving antiretroviral treatment (ART), the need to detect treatment failure and switch to second-line ART has also increased. We assessed CD4 cell counts (as a marker of treatment failure), determined the rate of switching to second-line treatment and evaluated mortality related to treatment failure among HIV-infected patients in Guinea-Bissau. METHODS: In this retrospective cohort study, adult patients infected with HIV-1 receiving >=6 months of ART at an HIV clinic in Bissau were included from June 2005 to July 2014 and followed until January 2015. Treatment failure was defined as 1) a fall in CD4 count to baseline (or below) or 2) CD4 levels persistently below 100 cells/uL after >=6 months of ART. Cox hazard models, with time since six months of ART as the time-varying coefficient, were used to estimate the hazard ratio for death and loss to follow-up. RESULTS: We assessed 1,591 HIV-1-infected patients for immunological treatment failure. Treatment failure could not be determined in 594 patients (37.3%) because of missing CD4 cell counts. Among the remaining 997 patients, 393 (39.4%) experienced failure. Only 39 patients (9.9%) with failure were switched from first- to second-line ART. The overall switching rate was 3.1 per 100 person-years. Mortality rate was higher in patients with than without treatment failure, with adjusted hazard rate ratios (HRRs) 10.0 (95% CI: 0.9-107.8), 7.6 (95% CI: 1.6-35.5) and 3.1 (95% CI: 1.5-6.3) in the first, second and following years, respectively. During the first year of follow-up, patients experiencing treatment failure had a higher risk of being lost to follow up than patients not experiencing treatment failure (adjusted HRR 4.4; 95% CI: 1.7-11.8). CONCLUSIONS: We found a high rate of treatment failure, an alarmingly high number of patients for whom treatment failure could not be assessed, and a low rate of switching to a second-line therapy. These factors could lead to an increased risk of resistance development and excess mortality. PMID- 26426198 TI - Estimated and Measured GFR Associate Differently with Retinal Vasculopathy in the General Population. AB - BACKGROUND/AIMS: Estimated glomerular filtration rate (eGFR) is used extensively in epidemiological research. Validations of eGFR have demonstrated acceptable performance, but the dependence of creatinine and cystatin C on non-GFR factors could confound associations with disease. Few studies have investigated this issue in direct comparison with measured GFR (mGFR). We compared the associations between eGFR and mGFR and retinal vasculopathy, a marker of systemic microvasculopathy. METHODS: Iohexol clearance and retinal photography were examined in the Renal Iohexol Clearance Survey in Tromso 6, which consists of a representative sample of middle-aged persons from the general population. A total of 1,553 persons without self-reported kidney disease, cardiovascular disease or diabetes were investigated. Three eGFR equations based on creatinine and/or cystatin C from the Chronic Kidney Disease Epidemiology Collaboration were studied. Differences between eGFR and mGFR were analyzed with seemingly unrelated regression methods. RESULTS: mGFR in the lowest quartile was associated with an increased multivariable-adjusted odds ratio of retinopathy (OR 1.86, 95% CI 1.16 2.97), but not with retinal artery or vein diameters. eGFR based on cystatin C (eGFRcys) was consistently biased relative to mGFR in its associations with retinal vessel diameters across different models. eGFR based on creatinine (eGFRcrea) and eGFR based on both creatinine and cystatin C were also biased in several of these models (p < 0.05). For retinopathy, the differences between the 3 eGFR and mGFR measurements were not statistically significant. CONCLUSIONS: Low mGFR is associated with retinopathy in the general population. eGFR based on creatinine and/or cystatin C are not valid substitutes for mGFR in studies of the relationship between the retina and kidney function in healthy persons. PMID- 26426199 TI - Human Inducible Pluripotent Stem Cells and Autism Spectrum Disorder: Emerging Technologies. AB - Autism Spectrum Disorder (ASD) is a behaviorally defined neurodevelopmental condition. Symptoms of ASD cover the spectrum from mild qualitative differences in social interaction to severe communication and social and behavioral challenges that require lifelong support. Attempts at understanding the pathophysiology of ASD have been hampered by a multifactorial etiology that stretches the limits of current behavioral and cell based models. Recent progress has implicated numerous autism-risk genes but efforts to gain a better understanding of the underlying biological mechanisms have seen slow progress. This is in part due to lack of appropriate models for complete molecular and pharmacological studies. The advent of induced pluripotent stem cells (iPSC) has reinvigorated efforts to establish more complete model systems that more reliably identify molecular pathways and predict effective drug targets and candidates in ASD. iPSCs are particularly appealing because they can be derived from human patients and controls for research purposes and provide a technology for the development of a personalized treatment regimen for ASD patients. The pluripotency of iPSCs allow them to be reprogrammed into a number of CNS cell types and phenotypically screened across many patients. This quality is already being exploited in protocols to generate 2-dimensional (2-D) and three dimensional (3-D) models of neurons and developing brain structures. iPSC models make powerful platforms that can be interrogated using electrophysiology, gene expression studies, and other cell-based quantitative assays. iPSC technology has limitations but when combined with other model systems has great potential for helping define the underlying pathophysiology of ASD. Autism Res 2016, 9: 513 535. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26426200 TI - Bright-Yellow-Emissive N-Doped Carbon Dots: Preparation, Cellular Imaging, and Bifunctional Sensing. AB - Fluorescent carbon dots (CDs) have attracted much attention in recent years because of their superior optical and chemical properties, thus demonstrating many potential applications. However, the previously reported CDs mostly show strong emission only in the blue-light region, and the long-wavelength (i.e., yellow- to red-light) emissions are usually very weak. Such a drawback restricts their further applications, particularly in the biology-relevant fields. Herein, a rare example of N-doped CDs that emit bright-yellow fluorescence (i.e., y-CDs) is reported using 1,2,4-triaminobenzene as carbon precursor. The as-prepared y CDs exhibit not only respectable emission quantum yield and highly optical stabilities but superior biocompatibility and biolabeling potentials. In addition, the y-CDs are found to show an interesting "ON-OFF-ON" three-state emission with the stepwise addition of Ag(+) and cysteine (Cys), indicating potential applications as a bifunctional sensing platform. Thanks to the highly intense emission of y-CDs, the gradual quenching and restoration of their fluorescence with the addition of Ag(+) and further Cys could also be observed with the naked eye. More importantly, the ensemble of the y-CDs and Ag(+) demonstrates practicability for the highly selective and sensitive detection of Cys in human plasma samples with satisfactory results. PMID- 26426201 TI - Heterodimers formed through a partial anionic exchange process: scanning tunneling spectroscopy to monitor bands across the junction vis-a-vis photoinduced charge separation. AB - We report controlled formation of heterodimers and their charge separation properties. CdS|CdTe heterodimers were formed through an anionic exchange process of CdS nanostructures. With control over the duration of the anionic exchange process, bulk|dot, bulk|bulk, and then dot|bulk phases of the semiconductors could be observed to have formed. A mapping of density of states as derived from scanning tunneling spectroscopy (STS) brought out conduction and valence band edges along the nanostructures and heterodimers. The CdS|CdTe heterodimers evidenced a type-II band-alignment between the semiconductors along with the formation of a depletion region at the interface. The width (of the depletion region) and the energy-offset at the interface depended on the size of the semiconductors. We report that the width that is instrumental for photoinduced charge separation in the heterodimers has a direct correlation with the performance of hybrid bulk-heterojunction solar cells based on the nanostructures in a polymer matrix. PMID- 26426202 TI - Rust fungal effectors mimic host transit peptides to translocate into chloroplasts. AB - Parasite effector proteins target various host cell compartments to alter host processes and promote infection. How effectors cross membrane-rich interfaces to reach these compartments is a major question in effector biology. Growing evidence suggests that effectors use molecular mimicry to subvert host cell machinery for protein sorting. We recently identified chloroplast-targeted protein 1 (CTP1), a candidate effector from the poplar leaf rust fungus Melampsora larici-populina that carries a predicted transit peptide and accumulates in chloroplasts and mitochondria. Here, we show that the CTP1 transit peptide is necessary and sufficient for accumulation in the stroma of chloroplasts. CTP1 is part of a Melampsora-specific family of polymorphic secreted proteins. Two members of that family, CTP2 and CTP3, also translocate in chloroplasts in an N-terminal signal-dependent manner. CTP1, CTP2 and CTP3 are cleaved when they accumulate in chloroplasts, while they remain intact when they do not translocate into chloroplasts. Our findings reveal that fungi have evolved effector proteins that mimic plant-specific sorting signals to traffic within plant cells. PMID- 26426203 TI - Role of (H2O)(n) (n = 2-3) Clusters on the HO2 + O3 Reaction: A Theoretical Study. AB - We report a theoretical investigation on the role of the water dimer and trimer in the reaction between the hydroperoxyl radical and ozone. This study is part of an ongoing series of research endeavors that intend to deliver a comprehensive understanding on the role of water on this reaction. Due to the complexity of the potential energy surface, and to be able to make comparisons with our previous works, our calculations have employed model chemistries based on the Kohn-Sham DFT formalism. It is found that the calculated reaction paths share a common scheme, not only in the context of this work, but also in consideration of our previous studies. Also, oxygen-abstraction barriers are always submerged, with the relative energy between the hydrogen- and oxygen-abstraction saddle-points increasing with the number of water molecules, which maintain an apparent spectator role. Finally, we report novel HO2...(H2O)3 and HO3...(H2O)n complexes originating from our reaction schemes. PMID- 26426204 TI - The Effect of Luting Cement and Titanium Base on the Final Color of Zirconium Oxide Core Material. AB - PURPOSE: To evaluate the effects of different types of luting cements and different colors of zirconium cores on the final color of the restoration that simulates implant-supported fixed partial dentures (FPDs) by using a titanium base on the bottom. MATERIALS AND METHODS: One hundred and twenty zirconium oxide core plates (Zr-Zahn; 10 mm in width, 5 mm in length, 0.5 mm in height) were prepared in different shades (n = 20; noncolored, A2, A3, B1, C2, D2). The specimens were subdivided into two subgroups for the two types of luting cements (n = 10). The initial color measurements were made on zirconium oxide core plates using a spectrometer. To create the cement thicknesses, stretch strips with holes in the middle (5 mm in diameter, 70 MUm in height) were used. The second measurement was done on the zirconium oxide core plates after the application of the resin cement (U-200, A2 Shade) or polycarboxylate cement (Lumicon). The final measurement was done after placing the titanium discs (5 mm in diameter, 3 mm in height) in the bottom. The data were analyzed with two-way ANOVA and Tukey's honestly significant differences (HSD) tests (alpha = 0.05). RESULTS: The ?E*ab value was higher in the resin cement-applied group than in the polycarboxylate cement-applied group (p < 0.001). The highest ?E*ab value was recorded for the zirconium oxide core-resin cement-titanium base, and the lowest was recorded for the polycarboxylate cement-zirconium oxide core (p < 0.001). CONCLUSION: The luting cement, the presence of titanium, and the color of zirconium are all important factors that determine the final shade of zirconia cores in implant supported FPDs. PMID- 26426205 TI - DNA methylation status as a biomarker of anti-epidermal growth factor receptor treatment for metastatic colorectal cancer. AB - Anti-epidermal growth factor receptor (EGFR) treatment is an effective option for metastatic colorectal cancer (CRC) treatment. However, there are few reliable biomarkers to predict the clinical response to anti-EGFR treatment. We investigated the genome-wide DNA methylation status in metastatic colorectal cancer to identify associations between the methylation status and clinical response to anti-EGFR antibody. We retrospectively reviewed the medical records of 97 patients (45 patients for the first cohort and 52 patients for the second cohort) who received anti-EGFR treatment for KRAS wild-type metastatic CRC. Then we analyzed the associations between genome-wide DNA methylation status and clinical response to anti-EGFR treatment, and evaluated the predictive power and value of the methylation status statistically. As a result, each cohort was classified into highly methylated CRC and low methylated CRC subgroups by unsupervised clustering analyses. In the first cohort, clinical outcomes were significantly better in the low methylated CRC subgroup than in the highly methylated CRC subgroup (response rate, 35.7% vs 6.3%, P = 0.03; disease control rate, 75% vs 31.3%, P = 0.005; hazard ratio for progression-free survival, 0.27; 95% confidence interval, 0.13-0.57, P < 0.001; overall survival, 0.19; 95% confidence interval, 0.06-0.54, P < 0.001). These results were reproducible in the second cohort. The genome-wide methylation status was a predictive factor of progression-free survival and overall survival independently of RAS mutation status. In conclusion, we found that the genome-wide DNA methylation status is a powerful epigenetic predictor of anti-EGFR treatment in patients with KRAS wild type metastatic colorectal cancer (UMIN000005490). PMID- 26426207 TI - Exploring Expressive Vocabulary Variability in Two-Year-Olds: The Role of Working Memory. AB - PURPOSE: This study explored whether measures of working memory ability contribute to the wide variation in 2-year-olds' expressive vocabulary skills. METHOD: Seventy-nine children (aged 24-30 months) were assessed by using standardized tests of vocabulary and visual cognition, a processing speed measure, and behavioral measures of verbal working memory and phonological short term memory. RESULTS: Strong correlations were observed between phonological short-term memory, verbal working memory, and expressive vocabulary. Speed of spoken word recognition showed a moderate significant correlation with expressive vocabulary. In a multivariate regression model for expressive vocabulary, the most powerful predictor was a measure of phonological short-term memory (accounting for 66% unique variance), followed by verbal working memory (6%), sex (2%), and age (1%). Processing speed did not add significant unique variance. CONCLUSIONS: These findings confirm previous research positing a strong role for phonological short-term memory in early expressive vocabulary acquisition. They also extend previous research in two ways. First, a unique association between verbal working memory and expressive vocabulary in 2-year-olds was observed. Second, processing speed was not a unique predictor of variance in expressive vocabulary when included alongside measures of working memory. PMID- 26426206 TI - Design and preparation of matrine surface-imprinted material and studies on its molecule recognition selectivity. AB - A matrine molecule surface-imprinted material was designed and prepared using an effective surface-imprinting technique developed by our group, and its molecular recognition performance and mechanism were investigated in depth. Monomer glycidyl methacrylate (GMA) was first graft-polymerized on the surfaces of micron sized silica gel particles in surface-initiated graft polymerization manner, obtaining the grafted particles PGMA/SiO(2) with high grafting degree. Subsequently, the ring-opening reaction of the epoxy groups of the grafted macromolecules PGMA with 5-aminosalicylic acid (5-ASA) was carried out, resulting in the functional grafted particle SA-PGMA/SiO(2), on whose surfaces salicylic acid as functional group was chemically bonded. By right of the mutual strong secondary bond forces, electrostatic interaction and hydrogen bonding, SA PGMA/SiO(2) particles produced strong adsorption for matrine. Finally, with this strong adsorption, matrine molecule surface imprinting was carried out on the surfaces of SA-PGMA/SiO(2) particles with ethylene glycol diglycidyl ether as cross-linking agent, resulting in the matrine molecule surface-imprinted material MIP-SAP/SiO(2). The binding characteristic of MIP-SAP/SiO(2) toward matrine was investigated in depth with both batch and column methods and using oxymatrine and cytisine as two contrast alkaloids. The experimental results show that MIP SAP/SiO(2) has special recognition selectivity and excellent binding affinity for matrine. Relative to oxymatrine and cytisine, the selectivity coefficients of MIP SAP/SiO(2) for matrine are 5.66 and 11.17, respectively. PMID- 26426208 TI - Investigating the impact of pain, age, Gross Motor Function Classification System, and sex on health-related quality of life in children with cerebral palsy. AB - AIM: To explore whether health-related quality of life (HRQOL) can be predicted by pain, age, Gross Motor Function Classification System (GMFCS) level, and sex in children with cerebral palsy (CP) and whether different pain etiologies have varying effects on HRQOL. METHODS: Children with CP aged 3 to 19 years and their caregivers were consecutively recruited. Caregivers reported their child's pain (Health Utilities Index 3 [HUI3] pain subset) and HRQOL (DISABKIDS questionnaires). Physicians identified pain etiologies. A multiple linear regression model determined whether pain, GMFCS level, sex, and age predicted HRQOL. An ANOVA evaluated the effects of pain etiologies on HRQOL. RESULTS: Three hundred and forty-four participants were approached and 87% (n=300) participated. Sufficient data were available on 248 (72% of total sample). Sixty-six participants (27%) formed the pain group with HUI3 pain scores of at least 3. The presence of pain and increasing age significantly negatively predicted HRQOL (p<0.001, R(2) =0.141), while GMFCS and sex did not. Musculoskeletal deformity (24%) and hypertonia (18%) were the most frequent pain causes. HRQOL statistically differed depending on the pain etiology (p=0.028) with musculoskeletal deformity showing the lowest mean HRQOL. INTERPRETATION: The presence of pain and increasing age negatively predict HRQOL in CP. musculoskeletal deformity has the greatest negative impact on HRQOL. PMID- 26426209 TI - Protic Ionic Liquids: Evolving Structure-Property Relationships and Expanding Applications. PMID- 26426210 TI - Building intentions with the theory of planned behaviour: a qualitative assessment of salient beliefs about pharmacy value added services in Malaysia. AB - OBJECTIVE: To improve pharmaceutical care delivery in Malaysia, the Ministry of Health (MOH) had introduced the concept of value added services (VAS). Despite its reported convenience and advantages, VAS utilization rate is low in the country. The study aims to explore patients' understanding, beliefs and expectations towards VAS in Malaysia using the theory of planned behaviour (TPB) as the theoretical model. METHODS: A qualitative methodology was used whereby face-to-face interviews were conducted with 12 patients who collected partial medicine supplies from government pharmacies. Participants were recruited using purposive and snowball sampling method in the state of Negeri Sembilan, Malaysia. Interviews were audio-recorded. Verbatim transcription and thematic content analysis were performed on the data. RESULTS: Thematic content analysis yielded five major themes: (i) attitudes towards using VAS, (ii) subjective norms, (iii) perceived behavioural control, (iv) lack of knowledge and understanding of VAS and (v) expectations towards VAS. CONCLUSION: The interviews explored and informed new information about salient beliefs towards pharmacy VAS. The findings suggest that VAS is still in its infancy and a more robust and effective advertising and marketing campaign is needed to boost the adoption rate. Behavioural attitudes, subjective norms and perceived control elements were discussed and serve as important variables of interest in future study. Expectations towards VAS serve as an important guideline to further improve patient-oriented services. PMID- 26426211 TI - OPG, RANKL, and RANK gene polymorphisms and the bone mineral density response to alendronate therapy in postmenopausal Chinese women with osteoporosis or osteopenia. AB - OBJECTIVE: The aim of the study was to explore the association between OPG, RANKL, and RANK gene variations and the bone mineral density (BMD) response to alendronate therapy in postmenopausal Chinese women with osteoporosis or osteopenia. MATERIALS AND METHODS: In the present study, 40 single-nucleotide polymorphisms (SNPs) in the OPG, RANKL, and RANK genes were genotyped in 501 postmenopausal Chinese women with osteoporosis or osteopenia who were given alendronate (70 mg weekly) orally for 1 year. The BMD at the lumbar spine 1-4 (L1 L4), femoral neck, and total hip was measured. RESULTS: A total of 442 patients completed 1 year of alendronate therapy. The rs7239261 SNP of the RANK gene was significantly associated with baseline L1-L4 BMD (P=0.0004) after correction for age and BMI. Participants with the SNP A allele (C/A and A/A) had a higher BMD than those with the C/C genotype (C/A vs. C/C, P=0.001; A/A vs. C/C, P=0.025). Haplotypes AG of rs7239261-rs12969154, GG of rs3826619-rs11877530, and CACG of rs1805034-rs8083511-rs17069895-rs7231887 in the RANK gene were genetic protective factors toward a higher baseline L1-L4 BMD. No association was observed between any SNP or haplotype of the OPG, RANKL, and RANK genes and the response of BMD to alendronate therapy. CONCLUSION: The RANK gene might contribute to genetic variability in L1-L4 BMD in postmenopausal Chinese women with osteoporosis or osteopenia. No evidence of an association between any SNP or haplotype of the OPG, RANKL, and RANK genes and the response of BMD to alendronate therapy was found in postmenopausal Chinese women with osteoporosis or osteopenia. PMID- 26426212 TI - A genetic variant in NRP1 is associated with worse response to ranibizumab treatment in neovascular age-related macular degeneration. AB - OBJECTIVE: The aim of the study was to investigate the role of single-nucleotide polymorphisms (SNPs) located in the neuropilin-1 (NRP1) gene in treatment response to antivascular endothelial growth factor (VEGF) therapy for neovascular age-related macular degeneration (nvAMD). METHODS: Four SNPs in the NRP1 gene (rs2229935, rs2247383, rs2070296, and rs2804495) were genotyped in a study cohort of 377 nvAMD patients who received the loading dose of three monthly ranibizumab injections. Treatment response was assessed as the change in visual acuity after three monthly loading injections compared with baseline. RESULTS: SNP rs2070296 was associated with change in visual acuity after 3 months of treatment. Patients carrying the GA or AA genotypes performed significantly worse than individuals carrying the GG genotype (P=0.01). A cumulative effect of rs2070296 in the NRP1 gene and rs4576072 located in the VEGF receptor 2 (VEGFR2 or KDR) gene, previously associated with treatment response, was observed. Patients carrying two risk alleles performed significantly worse than patients carrying zero or one risk allele (P=0.03), and patients with more than two risk alleles responded even worse to the therapy (P=3*10). The combined effect of these two SNPs on the response was also seen after 6 and 12 months of treatment. CONCLUSION: This study suggests that genetic variation in NRP1, a key molecule in VEGFA-driven neovascularization, influences treatment response to ranibizumab in nvAMD patients. The results of this study may be used to generate prediction models for treatment response, which in the future may help tailor medical care to individual needs. PMID- 26426215 TI - Integrating Tobacco Use Treatment Into Practice: Billing and Documentation. AB - Balancing population-based efforts to modify the social and environmental factors that promote tobacco dependence with efforts to improve the delivery of case based treatments is necessary for realizing maximum reductions in the cost and consequences of the disease. Public health antismoking campaigns following the 1964 Surgeon General's report on the health risks of smoking have changed social norms, prevented initiation among youth, and promoted abstinence among the addicted. However, the rate of progress enjoyed to date is unlikely to continue into the coming decades, given that current annual unassisted cessation rates among prevalent smokers remains fairly low. With more than 1 billion patient interactions annually, there is an enormous unrealized capacity for health-care systems to have an effect on this problem. Clinicians report a perceived lack of reimbursement as a significant barrier to full integration of tobacco dependence into health care. A more complete understanding of the coding and documentation requirements for successful practice in this critically important area is a prerequisite to increasing engagement. This paper presents several case-based scenarios illustrating important practice management issues related to the treatment of tobacco dependence in health care. PMID- 26426216 TI - Association between the diagnosis of atrial fibrillation and aspects of health status: a Danish cross-sectional study. AB - BACKGROUND: Caring for patients living with atrial fibrillation (AF) is expected to be an increasing challenge for the healthcare sector in the future. Inconclusive results on self-reported health-related quality of life and health status in patients living with AF have previously been reported, ranging from being similar to those observed in patients who have sustained and survived a myocardial infarction to not being different from those of healthy subjects. In these studies, gender differences were not taken into account. AIM AND OBJECTIVE: To investigate the association between the diagnosis of atrial fibrillation and self-reported health status. DESIGN: An observational, cross-sectional study was conducted using data from the Danish Diet, Cancer and Health cohort. Information on health status was obtained using the Danish version of the Short Form 36 version 2 questionnaire. The analyses were stratified on gender. In adjusted analysis, we considered potential confounding from comorbidity expressed by the Charlson Comorbidity Index and effect modification by age. ETHICAL APPROVAL: The local ethical committees of Copenhagen and Frederiksberg municipalities (Approval no.: (KF) 01-345/93) approved the study. RESULTS: We included 42 598 participants of whom 873 had a diagnosis of AF and/or atrial flutter. We found a lower adjusted physical component score among AF patients. No systematic differences in the mental component score (MCS) were observed. CONCLUSION: Participants diagnosed with AF report a clinically and statistically significantly lower physical health component score. No systematic differences in the MCS were found when comparing with the remaining participants in the cohort. As healthcare professionals caring for patients living with AF are not always expecting patients living with AF to experience a burden from their disease, the individual patients' experience of their situation, feelings, preferences, symptoms and needs leading to physical limitations should always be articulated. PMID- 26426229 TI - For All Intensive Purposes. PMID- 26426217 TI - Seroprevalence of Babesia microti infection in Canadian blood donors. AB - BACKGROUND: Human babesiosis, caused by the intraerythrocytic protozoan parasite Babesia microti, is primarily transmitted by tick bites and is also transmitted by transfusion. Infections have been identified in U.S. blood donors close to Canadian borders. We aimed to assess the risk of transfusion-transmitted babesiosis in Canada by examining infections in ticks and seroprevalence in blood donors. STUDY DESIGN AND METHODS: Passive surveillance (receipt of ticks submitted by the public) was used to identify regions for tick drag sampling (active surveillance, 2009-2014). All ticks were tested for B. microti using an indirect immunofluorescent antibody assay (Imugen, Inc.). Between July and December 2013, blood donations from selected sites (southern Manitoba, Ontario, Quebec, New Brunswick, and Nova Scotia) near endemic U.S. regions were tested for antibody to B. microti. Donors completed a questionnaire about risk travel and possible tick exposure. RESULTS: Of approximately 12,000 ticks submitted, 14 were B. microti positive (10 in Manitoba, one in Ontario, one in Quebec, two in New Brunswick). From active tick surveillance, six of 361 ticks in Manitoba were positive (1.7%), three of 641 (0.5%) in Quebec, and none elsewhere. There were 26,260 donors at the selected sites of whom 13,993 (53%) were tested. None were positive for antibody to B. microti. In 2013, 47% of donors visited forested areas in Canada, and 41% traveled to the United States. CONCLUSION: The data do not suggest that laboratory-based testing is warranted at this time. However, there are indicators that B. microti may be advancing into Canada and ongoing monitoring of tick populations and donor seroprevalence is indicated. PMID- 26426230 TI - Diagnosis and Management of Subarachnoid Hemorrhage. AB - PURPOSE OF REVIEW: The purpose of this article is to present the epidemiology, clinical presentation, and management of patients with subarachnoid hemorrhage (SAH). SAH is a neurologic emergency that carries high morbidity and mortality. Patients with SAH are at risk for several significant neurologic complications, including hydrocephalus, cerebral edema, delayed cerebral ischemia, rebleeding, seizures, and neuroendocrine abnormalities that lead to impaired body regulation of sodium, water, and glucose. RECENT FINDINGS: The incidence of SAH has remained stable, but mortality of hospitalized patients has significantly declined over the past 3 decades. Many common therapies for SAH have created controversy, and various recent neuroprotective clinical trials have produced negative results. However, the publication of two consensus guidelines by the American Heart Association/American Stroke Association and the Neurocritical Care Society have provided a clarification for what should constitute best practice for patients with SAH. The most important of those recommendations include the following: admission of patients to high-volume centers (defined as more than 35 patients with SAH per year) under the management of a specialized and multidisciplinary team; early identification and management of the bleeding source; evaluation and treatment decision for unsecured aneurysms by a multidisciplinary team made up of cerebrovascular neurosurgeons, endovascular practitioners, and neurointensivists; management of patients in the neurocritical care unit with oral nimodipine, blood pressure control, euvolemia, and frequent monitoring for neurologic and systemic complications; and delayed cerebral ischemia secondary to cerebral vasospasm should be treated with induced hypertension and endovascular therapies once confirmed. SUMMARY: SAH is a devastating neurologic disease. Management of patients with SAH should adhere to currently available treatment guidelines. Several aspects of SAH management remain controversial and need further studies to clarify their role in improving patient outcome. PMID- 26426231 TI - Diagnosis and Management of Spontaneous Intracerebral Hemorrhage. AB - PURPOSE OF REVIEW: This article updates neurologists on recent insights and management strategies of intracerebral hemorrhage (ICH). RECENT FINDINGS: Blood pressure reduction likely improves outcomes in patients with intracerebral hemorrhage, although not by the expected mechanism of reducing hematoma growth. One formulation of prothrombin complex concentrate for reversing severe bleeding associated with warfarin is now approved by the US Food and Drug Administration (FDA), and specific reversal therapies for the novel oral anticoagulants are in development. Neurologic monitoring frequently detects ICH worsening that requires an intervention. Platelet transfusion and pharmacologic platelet activation are promising and often used as part of patient management but have not yet been shown to improve patient outcomes. SUMMARY: Measurable progress continues toward establishing effective therapies to improve outcomes in patients with ICH. Blood pressure reduction and reversal of medications that exacerbate bleeding are likely to improve outcomes. Recommendations for neuromonitoring will help clinicians at the bedside attend to the most important abnormalities and optimize later quality of life. This article reviews standards for diagnosis and severity of ICH, monitoring and treatment of complications in the hospital, available interventions, and the measurement of outcomes. PMID- 26426232 TI - Management of Intracranial Pressure. AB - PURPOSE OF REVIEW: Intracranial pressure (ICP) can be elevated in traumatic brain injury, large artery acute ischemic stroke, intracranial hemorrhage, intracranial neoplasms, and diffuse cerebral disorders such as meningitis, encephalitis, and acute hepatic failure. Raised ICP is also known as intracranial hypertension and is defined as a sustained ICP of greater than 20 mm Hg. RECENT FINDINGS: ICP must be measured through an invasive brain catheter, typically an external ventricular catheter that can drain CSF and measure ICP, or through an intraparenchymal ICP probe. Proper recognition of the clinical signs of elevated ICP is essential for timely diagnosis and treatment to prevent cerebral hypoperfusion and possible brain death. Clinical signs of elevated ICP include headache, papilledema, nausea, and vomiting in the early phases, followed by stupor and coma, pupillary changes, hemiparesis or quadriparesis, posturing and respiratory abnormalities, and eventually cardiopulmonary arrest. SUMMARY: Management of elevated ICP is, in part, dependent on the underlying cause. Medical options for treating elevated ICP include head of bed elevation, IV mannitol, hypertonic saline, transient hyperventilation, barbiturates, and, if ICP remains refractory, sedation, endotracheal intubation, mechanical ventilation, and neuromuscular paralysis. Surgical options include CSF drainage if hydrocephalus is present and decompression of a surgical lesion, such as an intracranial hematoma/large infarct or tumor, if the patient's condition is deemed salvageable. Future research should continue investigating medical and surgical options for the treatment of raised ICP, such as hypothermia, drugs that reduce cerebral edema, and operations aimed at reducing intracranial mass effect. PMID- 26426233 TI - Acute Neuromuscular Respiratory Failure. AB - PURPOSE OF REVIEW: Neurologists working in the hospital are often called to evaluate patients with severe muscle weakness. Some of these patients can develop ventilatory compromise and require admission to the intensive care unit (ICU). This article reviews the general evaluation of neuromuscular respiratory failure, discusses its differential diagnosis, and provides practical advice on the management of its most common causes. RECENT FINDINGS: Determining the cause of acute neuromuscular respiratory failure is crucial because functional prognosis is poor in patients for whom the cause cannot be defined. The differential diagnosis is extensive, but the first step is to discriminate between cases related to a primary neurologic disease (primary neuromuscular respiratory failure) and those provoked by systemic disease, most often critical illness from sepsis and multiorgan failure (secondary neuromuscular respiratory failure). Guillain-Barre syndrome (GBS) and myasthenic crisis are the two most frequent causes of primary neuromuscular respiratory failure. Although they are both autoimmune conditions that benefit from the administration of plasma exchange or IV immunoglobulin (IVIg), they are otherwise very different disorders with unique features and distinct complications. Optimal strategies for mechanical ventilation also differ between these two conditions; while myasthenic crisis is ideally managed with noninvasive bilevel positive airway pressure (BiPAP) ventilation, GBS demands early intubation. SUMMARY: Prompt recognition of neuromuscular respiratory failure can be lifesaving, and identification of its cause has substantial prognostic implications. Adequate management of these patients requires a multidisciplinary team with the neurologist at its center, not only to guide the diagnostic evaluation but often also to prescribe the optimal management. PMID- 26426234 TI - Management of Hemispheric Infarction and Ischemic Swelling. AB - PURPOSE OF REVIEW: This article provides an overview of large territory hemispheric infarction, with an emphasis on recent developments and practical issues related to its evaluation, diagnosis, monitoring, and treatment. Swelling after large infarction results in severe morbidity and often death. Early vigilance for the development of swelling is critical to optimize patient outcome. Comprehensive management is highly dependent on a strong multidisciplinary, collaborative approach. RECENT FINDINGS: Several advances in the last decade have led to an increasingly standardized approach to the patient with significant brain swelling after stroke. In particular, early identification of patients with large stroke at high risk for deterioration, and decompressive craniectomy as an important treatment option, are two significant advances. SUMMARY: Effective management of hemispheric ischemic stroke and swelling requires a team skilled in the neurologic examination of critically ill patients and a broad understanding of the natural history of brain swelling after stroke. PMID- 26426235 TI - Status Epilepticus. AB - PURPOSE OF REVIEW: Status epilepticus, which is simultaneously a neurologic and systemic emergency, often results in significant disability and may be fatal. This article presents a pragmatic approach to the evaluation and management of status epilepticus in adults for the practicing clinician. RECENT FINDINGS: Rapid recognition, treatment respecting a written protocol, and careful attention to potential complications may limit sequelae. Studies aimed at earlier identification of etiologies in cryptogenic status epilepticus and improving the treatment of established status epilepticus are urgently needed to limit the development of refractoriness. SUMMARY: This article reviews the guidelines and up-to-date information on the use of both pharmacologic and nonpharmacologic therapies in status epilepticus and discusses the shifts in our understanding of the balance between the need for aggressive control of seizures and the risks of treatment. This article also presents a suggested approach to the evaluation and management of common types of status epilepticus and explores future directions. PMID- 26426236 TI - Cardiac Arrest and Postanoxic Encephalopathy. AB - PURPOSE OF REVIEW: Neuroprognostication following cardiac arrest is a common and challenging dilemma for neurologists and intensivists, complicated by the use of therapeutic hypothermia and targeted temperature management. Great advances have been made in understanding the mechanisms of disorders of consciousness in hypoxic-ischemic brain injury, and new diagnostic and therapeutic avenues are arising. RECENT FINDINGS: In the era of therapeutic hypothermia and targeted temperature management, traditional clinical signs, electrophysiologic findings, and chemical biomarkers have now become questionable or variable, and the proper time for diagnostic and prognostic testing has become murky. Although the value of absent pupillary and corneal reflexes remains fairly robust, the presence of myoclonic status epilepticus and a motor response of extensor posturing or worse no longer appear to have acceptable false-positive rates. Somatosensory evoked potentials (SSEPs), thought to be the most reliable ancillary test for predicting prognosis, have recently been the subject of several reports showing unexpectedly good outcome in the face of absent cortical responses. The presence or absence of reactivity on EEG appears to be a promising prognostic sign, and aggressive treatment of seizures (and even status epilepticus) may lead to better than expected outcomes. Serum biomarkers that were previously felt to be valid, such as elevated neuron-specific enolase, have been drawn into question owing to multiple reports of patient survival with good outcome despite highly elevated levels. Advanced EEG and neuroimaging techniques, particularly looking at functional connectivity and underlying neuronal pathways, are giving great insights to the underlying mechanisms of disease and potential therapeutic targets. SUMMARY: Predicting neurologic prognosis following cardiac arrest is an evolving field, with new prognostic methods and reevaluation of older techniques holding great promise for advancing our ability to predict outcome and improve patient care. PMID- 26426237 TI - Evaluating the Potential for Recovery of Consciousness in the Intensive Care Unit. AB - PURPOSE OF REVIEW: Evaluating patients in the intensive care unit (ICU) with disorders of consciousness has prognostic implications. When brainstem functions are intact, the neurologist must use ancillary testing to help determine prognosis. This article addresses the challenges of arriving at prognoses in patients with hypoxic-ischemic encephalopathy and traumatic brain injury (TBI) and discusses strategies for dealing with these challenges. This has some relevance to other conditions that are capable of causing irreversible brain damage. RECENT FINDINGS: Although practice parameters formulated by an American Academy of Neurology (AAN) subcommittee in 2006 were reliable for evaluating patients with hypoxic-ischemic encephalopathy who did not receive hypothermia, the advent of hypothermia has shown that some of these prognostic features were unreliable. Some patients with TBI thought to be vegetative have been found to have cognitive responses. These revelations require neurologists to reconsider prognostic strategies. SUMMARY: To arrive at a more accurate prognosis, it is best to employ multiple pieces of evidence and incorporate the most updated information from the literature. In some cases, newer technologies can provide further insights into cortical function in behaviorally unresponsive patients. PMID- 26426238 TI - Determining Brain Death. AB - PURPOSE OF REVIEW: Major complexities exist in the assessment of a patient with a catastrophic neurologic disorder that might have progressed to loss of all brain function. The determination of brain death and initial management of the potential organ donor is one of the major key tasks of the neurologist. This article addresses the potential for errors, mimickers, and uncertainties associated with ancillary tests for determining brain death. RECENT FINDINGS: Major professional neurologic organizations including the American Academy of Neurology have published guidelines for the determination of brain death in both adults and children. Checklists are now available to assist physicians in the assessment of the patient. SUMMARY: The clinical diagnosis of brain death in a patient with a catastrophic brain injury is determined by a comprehensive clinical examination that involves at least 25 individual assessments. It requires excluding confounding factors first (to confirm futility), examining the patient carefully with special attention to signs of brainstem function, and, finally, performing an apnea test. Once a patient is declared brain dead, organ donation may proceed after consent is obtained. PMID- 26426239 TI - Complications of Neurosurgery. AB - PURPOSE OF REVIEW: This article provides an overview of the major neurologic complications of common neurosurgical and endovascular procedures. RECENT FINDINGS: Brain edema, seizures, postoperative hemorrhage, and cerebral ischemia can complicate neurosurgical procedures and produce neurologic decline. The high variability of reporting, types of operations, patient characteristics, and acuity of cases make estimating the incidence and severity of complications difficult. Overall, the complication rate of neurosurgical procedures is approximately 14%, but these are commonly systemic complications (eg, bleeding requiring transfusion, need for mechanical ventilation). In addition to intracranial hemorrhage, ischemia, and seizures after craniotomies, additional characteristic complications include hyperperfusion syndrome and cranial nerve palsies after carotid endarterectomy, cerebrospinal fluid leaks and aseptic meningitis after posterior fossa surgery, and arterial dissections or groin hematomas after endovascular procedures. SUMMARY: Neurologic decline can be caused by a variety of causes in the postoperative period. The indication for surgery, type of surgery, and time of decline is helpful in narrowing the differential diagnosis. Brain edema, elevated intracranial pressure (ICP), seizures, intracranial hemorrhage, ischemic infarction, and cranial nerve palsies are some of the more common complications in patients that neurologists may be asked to evaluate or comanage in the postoperative setting. PMID- 26426240 TI - Ethical Aspects of Organ Donation After Circulatory Death. AB - Neurologists should be familiar with the process and ethical aspects of organ donation. While most neurologists understand the steps involved in organ procurement following brain death, the controversial practice of organ donation after circulatory death (also referred to as non-heart-beating organ donation) is less familiar but increasingly frequent. This article presents a hypothetical case of a patient with a devastating neurologic injury and a poor prognosis for meaningful recovery and discusses the ethical considerations underlying donation after circulatory death, the general procedure of donation after circulatory death, and ethical controversies associated with this practice. PMID- 26426241 TI - Advanced Practice Provider Utilization in the Neurocritical Care Unit. AB - This article discusses the role of advanced practice providers (APPs) in the interprofessional team management of patients with critical neurologic illnesses and how this role has evolved through the years. There is increasing demand for these types of practitioners, formerly termed midlevel providers. Furthermore, the use of APPs appears to have a positive impact on patient satisfaction, reduced costs, and reduced length of stays. PMID- 26426242 TI - Critical Care Coding for Neurologists. AB - Accurate coding is an important function of neurologic practice. This contribution to Continuum is part of an ongoing series that presents helpful coding information along with examples related to the issue topic. Tips for diagnosis coding, Evaluation and Management coding, procedure coding, or a combination are presented, depending on which is most applicable to the subject area of the issue. PMID- 26426247 TI - Patient Management Problem. PMID- 26426250 TI - Next-Generation Sequencing for the Identification of Targetable Molecular Alterations in Cancer. PMID- 26426252 TI - A strategy for reducing neonatal mortality at high altitude using oxygen conditioning. AB - Neonatal mortality increases with altitude. For example, in Peru the incidence of neonatal mortality in the highlands has been shown to be about double that at lower altitudes. An important factor is the low inspired PO2 of newborn babies. Typically, expectant mothers at high altitude will travel to low altitude to have their babies if possible, but often this is not feasible because of economic factors. The procedure described here raises the oxygen concentration in the air of rooms where neonates are being housed and, in effect, this means that both the mother and baby are at a much lower altitude. Oxygen conditioning is similar to air conditioning except that the oxygen concentration of the air is increased rather than the temperature being reduced. The procedure is now used at high altitude in many hotels, dormitories and telescope facilities, and has been shown to be feasible and effective. PMID- 26426251 TI - Cancer-Cell-Specific Nuclear-Targeted Drug Delivery by Dual-Ligand-Modified Mesoporous Silica Nanoparticles. AB - Mesoporous silica nanoparticles are modified with dual targeting ligands, i.e., folic acid and dexamethasone, to construct a cancer-cell-specific nuclear targeted delivery system. The resulting nanocarriers can not only enhance the inhibition efficacy of doxorubicin on Hela cells through active nucleus accumulation but also reduce toxic side effects on noncancer cells though receptor-mediated selective cellular uptake. PMID- 26426254 TI - Palladium-catalyzed three-component reaction of N-tosyl hydrazones, isonitriles and amines leading to amidines. AB - A palladium-catalyzed three-component reaction between N-tosyl hydrazones, aryl isonitriles and amines was developed, leading to amidines in moderate to good yields. This procedure features the rapid construction of amidine frameworks with high diversity and complexity. Ketenimines serve as intermediates, which encounter nucleophilic attack by amines to produce amidines. PMID- 26426253 TI - Proton magnetic resonance spectroscopy and outcome in term neonates with chorioamnionitis. AB - OBJECTIVE: Evaluate brain metabolites, which reflect neuroinflammation, and relate to neurodevelopmental outcomes in healthy term neonates exposed to chorioamnionitis. STUDY DESIGN: Thirty-one healthy term neonates with documented fetal inflammatory response after maternal chorioamnionitis underwent magnetic resonance spectroscopy (MRS), with voxels placed in basal ganglia (BG) and frontal white matter. Bayley III examinations were performed at 12 months of age. RESULT: Infants with below average outcomes did not show the same increase in NAA/Cho ratios postnatally as the group with normal outcomes. Decreased NAA/Cho and increased Lac/Cr in BG correlated with lower motor and cognitive composite scores, respectively, controlling for postnatal age. In males, increased lactate/NAA in BG were associated with lower motor scores. Funisitis severity was associated with decreased NAA/Cho and increased mI/NAA in males. CONCLUSION: In healthy term newborns with chorioamnionitis, MRS ratios shortly after birth may provide evidence of occult neuroinflammation, which may be associated with worse performance on 1-year neurodevelopmental tests. PMID- 26426255 TI - Reprogramming of macrophages--new opportunities for therapeutic targeting. AB - Macrophages are key players of tissue homeostasis and are cells involved in all major human diseases including infections, tumors, western life-style associated diseases and even neurodegenerative diseases. Therefore, specifically targeting macrophages seems to be an attractive therapeutic approach, yet such strategies have not been successfully translated to the clinic. An important hallmark of macrophages is their astounding plasticity and their capacity to integrate microenvironmental signals to perform distinct biological functions. Understanding the cellular programming of macrophages during such events will be a fundamental pre-requisite to develop targeted therapeutic approaches in human diseases. Here, I highlight recent findings of how macrophage activation is regulated and how one can envision much more specific approaches of targeting macrophages. PMID- 26426257 TI - Brassinin Combined with Capsaicin Enhances Apoptotic and Anti-metastatic Effects in PC-3 Human Prostate Cancer Cells. AB - Brassinin (BSN), a type of indole compound derived from cruciferous vegetables, has shown anti-cancer effects in cells and animals. Capsaicin (CAP), an alkaloid derived from the chilli pepper, is also of interest in for its reported efficacy against various malignancies. The objective of our study was to analyze the potential synergistic anti-tumor effects of BSN combined with CAP on prostate cancer PC-3 cells. After treatment with BSN and CAP at various concentrations, the synergistic cytotoxic effect of PC-3 cells was analyzed by MTT method, proliferation, apoptosis, mitochondrial membrane potential, colony formation, and Western blotting. Moreover, the inhibitory effects of BSN and CAP on the constitutive expressions of MMP-9/2, their enzymatic activities, cellular migration, and cell invasion were also investigated. The cytotoxicity was synergistically increased in combination compared with the single drug used; moreover, proliferation, apoptosis, mitochondrial membrane potential, and colony formation were significantly suppressed and anti-apoptotic-, proliferative-, and metastatic-related proteins were clearly abolished in the combination group. Besides, constitutive MMP-9/2 expression, their enzymatic activities, cell migration, and tumor cell invasion were inhibited, and TIMP-1 was up-regulated in the combination group in PC-3 cells. Our results indicate, for the first time, that BSN and CAP in combination exert synergistic anticancer effects in prostate carcinoma. PMID- 26426256 TI - Potassium inhibits nitric oxide and adenosine arteriolar vasodilatation via K(IR) and Na(+)/K(+) ATPase: implications for redundancy in active hyperaemia. AB - Redundancy, in active hyperaemia, where one vasodilator can compensate for another if the first is missing, would require that one vasodilator inhibits the effects of another; therefore, if the first vasodilator is inhibited, its inhibitory influence on the second vasodilator is removed and the second vasodilator exerts a greater vasodilatory effect. We aimed to determine whether vasodilators relevant to skeletal muscle contraction [potassium chloride (KCl), adenosine (ADO) and nitric oxide] inhibit one another and, in addition, to investigate the mechanisms for this interaction. We used the hamster cremaster muscle and intravital microscopy to directly visualize 2A arterioles when exposed to a range of concentrations of one vasodilator [10(-8) to 10(-5) M S-nitroso-N acetyl penicillamine (SNAP), 10(-8) to 10(-5) M ADO, 10 and 20 mM KCl] in the absence and then in the presence of a second vasodilator (10(-7) M ADO, 10(-7) M SNAP, 10 mM KCl). We found that KCl significantly attenuated SNAP-induced vasodilatations by ~65.8% and vasodilatations induced by 10(-8) to 10(-6) M ADO by ~72.8%. Furthermore, we observed that inhibition of KCl vasodilatation, by antagonizing either Na(+)/K(+) ATPase using ouabain or inward rectifying potassium channels using barium chloride, could restore the SNAP-induced vasodilatation by up to ~53.9% and 30.6%, respectively, and also restore the ADO induced vasodilatations by up to ~107% and 76.7%, respectively. Our data show that vasodilators relevant to muscle contraction can interact in a way that alters the effectiveness of other vasodilators. These data suggest that active hyperaemia may be the result of complex interactions between multiple vasodilators via a redundant control paradigm. PMID- 26426258 TI - Neurodegeneration in Autoimmune Optic Neuritis Is Associated with Altered APP Cleavage in Neurons and Up-Regulation of p53. AB - Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS). Histopathological and radiological analysis revealed that neurodegeneration occurs early in the disease course. However, the pathological mechanisms involved in neurodegeneration are poorly understood. Myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in Brown Norway rats (BN-rats) is a well-established animal model, especially of the neurodegenerative aspects of MS. Previous studies in this animal model indicated that loss of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve, occurs in the preclinical phase of the disease and is in part independent of overt histopathological changes of the optic nerve. Therefore, the aim of this study was to identify genes which are involved in neuronal cell loss at different disease stages of EAE. Furthermore, genes that are highly specific for autoimmune-driven neurodegeneration were compared to those regulated in RGCs after optic nerve axotomy at corresponding time points. Using laser capture micro dissection we isolated RNA from unfixed RGCs and performed global transcriptome analysis of retinal neurons. In total, we detected 582 genes sequentially expressed in the preclinical phase and 1150 genes in the clinical manifest EAE (P < 0.05, fold-induction >1.5). Furthermore, using ingenuity pathway analysis (IPA), we identified amyloid precursor protein (APP) as a potential upstream regulator of changes in gene expression in the preclinical EAE but neither in clinical EAE, nor at any time point after optic nerve transection. Therefore, the gene pathway analysis lead to the hypothesis that altered cleavage of APP in neurons in the preclinical phase of EAE leads to the enhanced production of APP intracellular domain (AICD), which in turn acts as a transcriptional regulator and thereby initiates an apoptotic signaling cascade via up-regulation of the target gene p53. PMID- 26426259 TI - TRPM8-Dependent Dynamic Response in a Mathematical Model of Cold Thermoreceptor. AB - Cold-sensitive nerve terminals (CSNTs) encode steady temperatures with regular, rhythmic temperature-dependent firing patterns that range from irregular tonic firing to regular bursting (static response). During abrupt temperature changes, CSNTs show a dynamic response, transiently increasing their firing frequency as temperature decreases and silencing when the temperature increases (dynamic response). To date, mathematical models that simulate the static response are based on two depolarizing/repolarizing pairs of membrane ionic conductance (slow and fast kinetics). However, these models fail to reproduce the dynamic response of CSNTs to rapid changes in temperature and notoriously they lack a specific cold-activated conductance such as the TRPM8 channel. We developed a model that includes TRPM8 as a temperature-dependent conductance with a calcium-dependent desensitization. We show by computer simulations that it appropriately reproduces the dynamic response of CSNTs from mouse cornea, while preserving their static response behavior. In this model, the TRPM8 conductance is essential to display a dynamic response. In agreement with experimental results, TRPM8 is also needed for the ongoing activity in the absence of stimulus (i.e. neutral skin temperature). Free parameters of the model were adjusted by an evolutionary optimization algorithm, allowing us to find different solutions. We present a family of possible parameters that reproduce the behavior of CSNTs under different temperature protocols. The detection of temperature gradients is associated to a homeostatic mechanism supported by the calcium-dependent desensitization. PMID- 26426261 TI - Squaraine based solution processed inverted bulk heterojunction solar cells processed in air. AB - Inverted bulk heterojunction solar cells based on low temperature solution processed squaraine (SQ) and [6,6]-phenyl C71 butyric acid methyl-ester (PC71BM) with varying blend ratios were made in air. An optimized bulk heterojunction device of SQ and PC71BM (with a blend ratio of 1 : 6) showed a power conversion efficiency (PCE) of 2.45% with an incident photon to current conversion efficiency of 65% at 680 nm and a spectral window extending to the NIR region. The devices also showed an enhanced PCE value of 4.12% upon continuous illumination from an AM1.5G light source of intensity 1 Sun. The intensity dependent photocurrent studies showed a monomolecular recombination mechanism in the photovoltaic device performance. The device stored in air showed reasonable stability for a period of one month. PMID- 26426262 TI - Si Donor Incorporation in GaN Nanowires. AB - With increasing interest in GaN based devices, the control and evaluation of doping are becoming more and more important. We have studied the structural and electrical properties of a series of Si-doped GaN nanowires (NWs) grown by molecular beam epitaxy (MBE) with a typical dimension of 2-3 MUm in length and 20 200 nm in radius. In particular, high resolution energy dispersive X-ray spectroscopy (EDX) has illustrated a higher Si incorporation in NWs than that in two-dimensional (2D) layers and Si segregation at the edge of the NW with the highest doping. Moreover, direct transport measurements on single NWs have shown a controlled doping with resistivity from 10(2) to 10(-3) Omega.cm, and a carrier concentration from 10(17) to 10(20) cm(-3). Field effect transistor (FET) measurements combined with finite element simulation by NextNano(3) software have put in evidence the high mobility of carriers in the nonintentionally doped (NID) NWs. PMID- 26426260 TI - Transcriptomic Analysis of Ovaries from Pigs with High And Low Litter Size. AB - Litter size is one of the most important economic traits for pig production as it is directly related to the production efficiency. Litter size is affected by interactions between multiple genes and the environment. While recent studies have identified some genes associated with prolificacy in pigs, transcriptomic studies of specific genes affecting litter size in porcine ovaries are rare. In order to identify candidate genes associated with litter size in swine, we assessed gene expression differences between the ovaries of Yorkshire pigs with extremely high and low litter sizes using the RNA-Seq method. A total of 1 243 differentially expressed genes were identified: 897 genes were upregulated and 346 genes were downregulated in high litter size ovary samples compared with low litter size ovary samples. A large number of these genes related to steroid hormone regulation in animal ovaries, including 59 Gene Ontology terms and 27 Kyoto Encyclopedia of Genes and Genomes pathways involved in steroid biosynthesis and ovarian steroidogenesis. From these differentially expressed genes, we identified a total of 11 genes using a bioinformatics screen that may be associated with high litter size in Yorkshire pigs. These results provide a list of new candidate genes for porcine litter size and prolificacy to be further investigated. PMID- 26426263 TI - Anti-inflammatory role of obestatin in autoimmune myocarditis. AB - Obestatin is a popular endogeneous peptide, known to have an autoimmune regulatory effect on energy metabolism and the gastrointestinal system. Studies regarding the anti-inflammatory effects of obestatin are scarce. The aim of this study was to show the anti-inflammatory effect of obestatin in an experimental model of autoimmune myocarditis in rats. Experimental autoimmune myocarditis was induced in Lewis rats by immunization with subcutaneous administration of porcine cardiac myosin, twice at 7-day intervals. Intraperitoneal pretreatment with obestatin (50 MUg/kg) was started before the induction of myocarditis and continued for 3 weeks. The severity of myocarditis was evidenced by clinical, echocardiographic and histological findings. In addition, by-products of neutrophil activation, lipid peroxidation, inflammatory and anti-inflammatory cytokines were measured in serum. Obestatin significantly ameliorated the clinical and histopathological severity of autoimmune myocarditis. Therapeutic effects of obestatin in myocarditis were associated with reduced lipid peroxidation, suppression of polymorphonuclear leukocyte infiltration and enhancement of glutathione synthesis, inhibition of serum inflammatory and activation of anti-inflammatory cytokines. Histopathologically, the left ventricle was significantly dilated, and its wall thickened, along with widespread lymphocytic and histocytic infiltration. The myocardium was severely infiltrated with relatively large mononuclear cells. These histopathological changes were observed in lesser degrees in obestatin-treated rats. This study demonstrated a novel anti-inflammatory effect of obestatin in an experimental model of autoimmune myocarditis. Consequently, obestatin administration may represent a promising therapeutic approach for myocarditis and dilated cardiomyopathy in the future. PMID- 26426264 TI - A Quinoline Carboxamide Antimalarial Drug Candidate Uniquely Targets Plasmodia at Three Stages of the Parasite Life Cycle. PMID- 26426265 TI - A 15-year retrospective analysis of prognostic factors in childhood bacterial meningitis. AB - AIM: This retrospective chart review aimed to identify factors in childhood bacterial meningitis that predicted disease severity and long-term outcome. METHODS: The study included 112 episodes of microbiologically confirmed bacterial meningitis in children aged three days to 15 years who were admitted to a Singapore hospital from 1998 to 2013. RESULTS: The mortality rate was 6%, and 44% required intensive care unit (ICU) admission. Predictive factors associated with ICU admission included pneumococcal meningitis, with an odds ratio (OR) of 5.2 and 95% confidence interval (CI) of 1.5-18.2, leukopenia (OR 5.6, 95% CI 1.7 17.9) and a cerebrospinal fluid (CSF):serum glucose ratio <0.25 (OR 4.5, 95% CI 1.4-14.4). An initial CSF white blood cell count >1000/mm(3) (OR 0.26, 95% CI 0.086-0.76) was negatively associated with ICU admission. Five years after meningitis, 32% had residual sequelae, and the associated prognostic factors were Haemophilus influenzae type b (Hib) meningitis (OR 29.5, 95% CI 2-429), seizures during their inpatient stay (OR 10.6, 95% CI 1.9-60.2) and septic shock (OR 8.4, 95% CI 1.1-62.1). CONCLUSION: As mortality was low in this bacterial meningitis study, ICU admission was used as a marker of disease severity. These findings underscore the importance of the pneumococcal and Hib meningitis vaccines. PMID- 26426266 TI - A Novel Tau Mutation in Exon 12, p.Q336H, Causes Hereditary Pick Disease. AB - Pick disease (PiD) is a frontotemporal lobar degeneration with distinctive neuronal inclusions (Pick bodies) that are enriched in 3-repeat (3R) tau. Although mostly sporadic, mutations in the tau gene (MAPT) have been reported. We screened 24 cases of neuropathologically confirmed PiD for MAPT mutations and found a novel mutation (c.1008G>C, p.Q336H) in 1 patient. Pathogenicity was confirmed on microtubule assembly and tau filament formation assays. The patient was compared with sporadic PiD and PiD associated with MAPT mutations from a review of the literature. The patient had behavioral changes at 55 years of age, followed by reduced verbal fluency, parkinsonism, and death at 63 years of age. His mother and maternal uncle had similar symptoms. Recombinant tau with p.Q336H mutation formed filaments faster than wild-type tau, especially with 3R tau. It also promoted more microtubule assembly than wild-type tau. We conclude that mutations in MAPT, including p.Q336H, can be associated with clinical, pathologic, and biochemical features that are similar to those in sporadic PiD. The pathomechanism of p.Q336H, and another previously reported variant at the same codon (p.Q336R), seems to be unique to MAPT mutations in that they not only predispose to abnormal tau filament formation but also facilitate microtubule assembly in a 3R tau-dependent manner. PMID- 26426268 TI - Neuronal ADAM10 Promotes Outgrowth of Small-Caliber Myelinated Axons in the Peripheral Nervous System. AB - The regulation of myelination and axonal outgrowth in the peripheral nervous system is controlled by a complex signaling network involving various signaling pathways. Members of the A Disintegrin And Metalloproteinase (ADAM) family are membrane-anchored proteinases with both proteolytic and disintegrin characteristics that modulate the function of signaling molecules. One family member, ADAM17, is known to influence myelination by cleaving and thus regulating one of the key signals, neuregulin-1, which controls peripheral nervous system myelination. A similar function for ADAM10 had been suggested by previous in vitro studies. Here, we assessed whether ADAM10 exerts a similar function in vivo and deleted ADAM10 in a cell type-specific manner in either neurons or Schwann cells. We found that ADAM10 is not required in either Schwann cells or neurons for normal myelination during development or for remyelination after injury. Instead, ADAM10 is required specifically in neurons for the outgrowth of myelinated small-fiber axons in vitro and after injury in vivo. Thus, we report for the first time a neuron-intrinsic function of ADAM10 in axonal regeneration that is distinct from that of the related protein family member ADAM17 and that may have implications for targeting ADAM function in nervous system diseases. PMID- 26426267 TI - Persistent Peripheral Nervous System Damage in Simian Immunodeficiency Virus Infected Macaques Receiving Antiretroviral Therapy. AB - Human immunodeficiency virus (HIV)-induced peripheral neuropathy is the most common neurologic complication associated with HIV infection. In addition to virus-mediated injury of the peripheral nervous system (PNS), treatment of HIV infection with combination antiretroviral therapy (cART) may induce toxic neuropathy as a side effect. Antiretroviral toxic neuropathy is clinically indistinguishable from the sensory neuropathy induced by HIV; in some patients, these 2 processes are likely superimposed. To study these intercurrent PNS disease processes, we first established a simian immunodeficiency virus (SIV)/pigtailed macaque model in which more than 90% of animals developed PNS changes closely resembling those seen in HIV-infected individuals with distal sensory neuropathy. To determine whether cART alters the progression of SIV induced PNS damage, dorsal root ganglia and epidermal nerve fibers were evaluated in SIV-infected macaques after long-term suppressive cART. Although cART effectively suppressed SIV replication and reduced macrophage activation in the dorsal root ganglia, PGP 9.5 immunostaining and measurements of epidermal nerve fibers in the plantar surface of the feet of treated SIV-infected macaques clearly showed that cART did not normalize epidermal nerve fiber density. These findings illustrate that significant PNS damage persists in SIV-infected macaques on suppressive cART. PMID- 26426269 TI - Investigation of a Simple Model for Within-Flock Transmission of Scrapie. AB - Genetic control programs for scrapie in sheep build on solid knowledge of how susceptibility to scrapie is modulated by the prion protein genotype at the level of an individual sheep. In order to satisfactorily analyze the effectivity of control programs at the population level, insight is needed at the flock level, i.e., how the grouping of sheep in flocks affects the population-level transmission risk. In particular, one would like to understand how this risk is affected by between-flock differences in genotype frequency distribution. A first step is to model the scrapie transmission risk within a flock as a function of the flock genotype profile. Here we do so by estimating parameters for a model of within-flock transmission using genotyping data on Dutch flocks affected by scrapie. We show that the data are consistent with a relatively simple transmission model assuming horizontal transmission and homogeneous mixing between animals. The model expresses the basic reproduction number for within flock scrapie as a weighted average of genotype-specific susceptibilities, multiplied by a single overall transmission parameter. The value of the overall transmission parameter may vary between flocks to account for random between flock variation in non-genetic determinants such as management practice. Here we provide an estimate of its mean value and variation for Dutch flocks. PMID- 26426270 TI - The Effect of Deworming on Growth in One-Year-Old Children Living in a Soil Transmitted Helminth-Endemic Area of Peru: A Randomized Controlled Trial. AB - BACKGROUND: Appropriate health and nutrition interventions to prevent long-term adverse effects in children are necessary before two years of age. One such intervention may include population-based deworming, recommended as of 12 months of age by the World Health Organization in soil-transmitted helminth (STH) endemic areas; however, the benefit of deworming has been understudied in early preschool-age children. METHODOLOGY/PRINCIPAL FINDINGS: A randomized, double blind, placebo-controlled trial was conducted to determine the effect of deworming (500 mg single-dose crushed mebendazole tablet) on growth in one-year old children in Iquitos, Peru. Children were enrolled during their routine 12 month growth and development clinic visit and followed up at their 18 and 24 month visits. Children were randomly allocated to: Group 1: deworming at 12 months and placebo at 18 months; Group 2: placebo at 12 months and deworming at 18 months; Group 3: deworming at both 12 and 18 months; or Group 4: placebo at both 12 and 18 months (i.e. control group). The primary outcome was weight gain at the 24-month visit. An intention-to-treat approach was used. A total of 1760 children were enrolled between September 2011 and June 2012. Follow-up of 1563 children (88.8%) was completed by July 2013. STH infection was of low prevalence and predominantly light intensity in the study population. All groups gained between 1.93 and 2.05 kg on average over 12 months; the average difference in weight gain (kg) compared to placebo was: 0.05 (95% CI: -0.05, 0.17) in Group 1; 0.07 (95%CI: -0.17, 0.04) in Group 2; and 0.04 (95%CI: -0.06, 0.14) in Group 3. There was no statistically significant difference in weight gain in any of the deworming intervention groups compared to the control group. CONCLUSIONS: Overall, with one year of follow-up, no effect of deworming on growth could be detected in this population of preschool-age children. Low baseline STH prevalence and intensity and/or access to deworming drugs outside of the trial may have diluted the potential effect of the intervention. Additional research is required to overcome these challenges and to contribute to strengthening the evidence base on deworming. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01314937). PMID- 26426271 TI - Incidence of HIV and Syphilis among Men Who Have Sex with Men (MSM) in Beijing: An Open Cohort Study. AB - BACKGROUND: This study investigated HIV and syphilis incidence among men who have sex with men (MSM) in Beijing, China. METHODS: An open cohort was established from September 2009 to April 2012. Participants were followed up with every three to four months after recruitment and for thirty-one months in total. Chi-square tests were used to compare demographic and behavioral characteristics between participants who were followed up with and those lost to follow up. Univariate and multivariate Cox proportional hazards regression analyses were used to examine demographic and behavioral associations with HIV and syphilis incidence. RESULTS: 69.7% (699/1,003) of the participants finished at least two follow-up surveys during the study period. Variables which corresponded to increased loss to follow-up included younger age, less education, non-identification of homosexual identity, and migrant status. A total of 1,045 person-years (PYs) and 1,016.4 PYs were followed up for HIV and syphilis incidence estimation, respectively. The HIV incidence was 5.9 per 100 PYs and 7.8 per 100 PYs for syphilis. The predictors for the high HIV incidence included unsafe anal sex, sex after drinking alcohol and STI infection. CONCLUSION: HIV incidence increased rapidly within the cohort, but syphilis incidence remained stable and decreased. More research is needed to provide multi-pronged HIV prevention interventions among MSM in order to reduce the increasing burden of HIV and sexually transmitted infections (STIs) in China. PMID- 26426273 TI - Incidence and characterisation of spontaneous coronary artery dissection as a cause of acute coronary syndrome--A single-centre Australian experience. PMID- 26426272 TI - The White-Nose Syndrome Transcriptome: Activation of Anti-fungal Host Responses in Wing Tissue of Hibernating Little Brown Myotis. AB - White-nose syndrome (WNS) in North American bats is caused by an invasive cutaneous infection by the psychrophilic fungus Pseudogymnoascus destructans (Pd). We compared transcriptome-wide changes in gene expression using RNA-Seq on wing skin tissue from hibernating little brown myotis (Myotis lucifugus) with WNS to bats without Pd exposure. We found that WNS caused significant changes in gene expression in hibernating bats including pathways involved in inflammation, wound healing, and metabolism. Local acute inflammatory responses were initiated by fungal invasion. Gene expression was increased for inflammatory cytokines, including interleukins (IL) IL-1beta, IL-6, IL-17C, IL-20, IL-23A, IL-24, and G CSF and chemokines, such as Ccl2 and Ccl20. This pattern of gene expression changes demonstrates that WNS is accompanied by an innate anti-fungal host response similar to that caused by cutaneous Candida albicans infections. However, despite the apparent production of appropriate chemokines, immune cells such as neutrophils and T cells do not appear to be recruited. We observed upregulation of acute inflammatory genes, including prostaglandin G/H synthase 2 (cyclooxygenase-2), that generate eicosanoids and other nociception mediators. We also observed differences in Pd gene expression that suggest host-pathogen interactions that might determine WNS progression. We identified several classes of potential virulence factors that are expressed in Pd during WNS, including secreted proteases that may mediate tissue invasion. These results demonstrate that hibernation does not prevent a local inflammatory response to Pd infection but that recruitment of leukocytes to the site of infection does not occur. The putative virulence factors may provide novel targets for treatment or prevention of WNS. These observations support a dual role for inflammation during WNS; inflammatory responses provide protection but excessive inflammation may contribute to mortality, either by affecting torpor behavior or causing damage upon emergence in the spring. PMID- 26426274 TI - Importance of chronotropic response and left ventricular long-axis function for exercise performance in patients with heart failure and preserved ejection fraction. AB - BACKGROUND: We evaluated the relationship between the degree of chronotropic incompetence and left ventricular (LV) impairment during exercise with severity of exercise intolerance in patients with heart failure and preserved ejection fraction (HFPEF). METHODS: All patients underwent exercise echocardiography during bicycle Ergometer exercise with the acquisition of long-axis tissue Doppler imaging (TDI). Peak heart rates during exercise were also recorded and the percentages of maximal age-predicted heart rate (%MPHR) and heart rate reserve (%HRR) were calculated thereby. Besides, cardiopulmonary exercise testing was performed with peak oxygen consumption (VO2) measuring averaged at the highest 30-second during exercise. RESULTS: Forty HFPEF patients (aged 65+/-9 years; 75% male) were divided into two groups according to the median of peak VO2: patients with peak VO2<16.5 and >=16.5 ml/kg/min, respectively. Patients with lower peak VO2 had decreased peak heart rates, %MPHR, %HRR, stroke volume and cardiac indices (LVSI and LVCI) than those with higher peak VO2 (all p<0.05). The LV long-axis functions (TDI Sm, Em, s' and e') were reduced in patients with lower peak VO2 (all p<0.05). Moreover, peak VO2 correlated with the following parameters: peak heart rates, %MPHR, %HRR, LVSI, LVCI, TDI Sm, Em, s' and e'(all p<0.05). CONCLUSIONS: The degree of blunted chronotropic response and impaired LV long-axis function were more profound in HFPEF patients with poor exercise performance. PMID- 26426275 TI - Microvascular obstruction detected by cardiac MRI after AMI for the prediction of LV remodeling and MACE: A meta-analysis of prospective trials. PMID- 26426276 TI - Cardiac resynchronization therapy in chronic heart failure with moderately reduced left ventricular ejection fraction: Lessons from the Multicenter InSync Randomized Clinical Evaluation MIRACLE EF study. AB - BACKGROUND: The benefits of CRT for symptomatic heart failure (HF) patients with a wide QRS and reduced left ventricular ejection fraction (LVEF<=35%), are well established .Post-hoc subgroup analyses suggest that CRT benefit may extend to patients with LVEF>35%. METHODS: The MIRACLE EF was a prospective, randomized, controlled, double-blinded study to evaluate CRT-P in NYHA II-III HF patients with LBBB and with LVEF of 36%-50% and no previous pacing or ICD. The primary endpoint was a composite of time to first HF event or death. All patients were implanted with a CRT-P and randomized 2:1 to CRT-P ON or CRT-P OFF groups. The minimum follow up time was 24 months. RESULTS: The MIRACLE EF study was stopped for enrollment futility after 13 months and enrolling only 44 patients. The main difficulties in recruiting patients were lack of eligible patients, previous ICD implants, and the reluctance of institutions, patients or physicians to enroll in the study which included a potential 5 year CRT OFF period. CONCLUSION: Despite a careful design, identification and randomization of eligible patients were challenging and a trial to assess morbidity and mortality trial was not feasible. The MIRACLE EF experience illustrates the difficulties of designing a scientifically robust but feasible study to assess potential new indications for implantable devices. Smaller randomized studies with surrogate endpoints may therefore be more reasonable, although the potential impact of such studies on clinical practice, guidelines, and reimbursement remain to be determined. PMID- 26426277 TI - Aerobic exercise improves cardiac autonomic modulation in women with polycystic ovary syndrome. AB - BACKGROUND: This study aimed to evaluate the effects of aerobic exercise on cardiac autonomic modulation in women with polycystic ovary syndrome (PCOS). METHODS: Thirty women with PCOS (25.8+/-4.8 years old; body mass index, BMI>=25 kg/m2) were divided into two groups; exercise group (n=15) and control group (n=15). R-R interval was recorded during 15-min at rest in the supine position. Heart rate variability (HRV) was analyzed by linear (rMSSD, SDNN, LF, HF, LFnu, HFnu, and LF/HF) and nonlinear methods (Shannon entropy, SE; symbolic analyses, 0 V%, 1 V%, 2LV%, and 2UV%) at baseline and after 16 weeks. The multivariate analysis of covariance was used to analyze the effects of exercise on HRV indexes, adjusted for changes in BMI, fasting insulin, and testosterone level. RESULTS: The exercise group increased parasympathetic modulation (rMSSD, HF, HFnu, 2UV%; (p<0.05)) and decreased sympathetic modulation (LF, LFnu, 0 V%; (p<0.05)) independently of changes in BMI, fasting insulin, and testosterone level. Moreover, the exercise group decreased resting HR and systolic blood pressure (p<0.05). All parameters remained unchanged in the control group. CONCLUSIONS: Aerobic exercise increased vagal modulation and decreased sympathetic modulation in women with PCOS. This finding reinforces the recommendations for exercise during the clinical management of these patients. PMID- 26426278 TI - The association of frailty with abnormal ankle-brachial index determinations is related to age: Results from the Atahualpa Project. PMID- 26426279 TI - Profile Changes in the Soil Microbial Community When Desert Becomes Oasis. AB - The conversion of virgin desert into oasis farmland creates two contrasting types of land-cover. During oasis formation with irrigation and fertilizer application, however, the changes in the soil microbial population, which play critical roles in the ecosystem, remain poorly understood. We applied high-throughput pyrosequencing to investigate bacterial and archaeal communities throughout the profile (0-3 m) in an experimental field, where irrigation and fertilization began in 1990 and cropped with winter wheat since then. To assess the effects of cultivation, the following treatments were compared with the virgin desert: CK (no fertilizer), PK, NK, NP, NPK, NPKR, and NPKM (R: straw residue; M: manure fertilizer). Irrigation had a greater impact on the overall microbial community than fertilizer application. The greatest impact occurred in topsoil (0-0.2 m), e.g., Cyanobacteria (25% total abundance) were most abundant in desert soil, while Actinobacteria (26%) were most abundant in oasis soil. The proportions of extremophilic and photosynthetic groups (e.g., Deinococcus-Thermus and Cyanobacteria) decreased, while the proportions of R-strategy (e.g., Gammaproteobacteria including Xanthomonadales), nitrifying (e.g., Nitrospirae), and anaerobic bacteria (e.g., Anaerolineae) increased throughout the oasis profile. Archaea occurred only in oasis soil. The impact of fertilizer application was mainly reflected in the non-dominant communities or finer taxonomic divisions. Oasis formation led to a dramatic shift in microbial community and enhanced soil enzyme activities. The rapidly increased soil moisture and decreased salt caused by irrigation were responsible for this shift. Furthermore, difference in fertilization and crop growth altered the organic carbon contents in the soil, which resulted in differences of microbial communities within oasis. PMID- 26426281 TI - Clarifying the role of Ru in methanol oxidation at Ru(core)@Pt(shell) nanoparticles. AB - The catalytic activity of Rucore@Ptshell nanoparticles (NPs) towards CO oxidation, a strongly adsorbed intermediate that compromises the performance of direct methanol fuel cells, is known to be significantly better than at Pt alone. However, a systematic study aimed at understanding the beneficial effect of Ru on Pt during the methanol oxidation reaction (MOR) has not been carried out as yet. Here, Rucore@Ptshell NPs, having a controlled Ptshell coverage of zero to two monolayers and two different Rucore sizes (2 and 3 nm), were synthesized using the simple polyol method to determine the precise role and impact of Ru on the MOR in 0.5 M H2SO4 + 1 M methanol at RT and 60 degrees C. Because the structure of our Rucore@Ptshell NPs is known with such certainty, we were able to show here that the rate of methanol adsorption/dehydrogenation can be accelerated either by compression of the Ptshell (by making the Rucore larger) when it is less than one monolayer in thickness, or by decreasing the electronic effect of the Rucore on the Ptshell (achieved by adding a second Pt layer to the Ptshell). At low overpotentials, decreasing the Ptshell thickness also helps in increasing the rate of the MOR by enhancing the rate of oxidation of adsorbed CO. Finally, it is shown that the bi-functional effect of Ru on the Ptshell plays only a minor role in the catalysis of the MOR, especially at large particles where CO surface diffusion is facilitated. PMID- 26426280 TI - The Combined Use of Correlative and Mechanistic Species Distribution Models Benefits Low Conservation Status Species. AB - Species can respond to climate change by tracking appropriate environmental conditions in space, resulting in a range shift. Species Distribution Models (SDMs) can help forecast such range shift responses. For few species, both correlative and mechanistic SDMs were built, but allis shad (Alosa alosa), an endangered anadromous fish species, is one of them. The main purpose of this study was to provide a framework for joint analyses of correlative and mechanistic SDMs projections in order to strengthen conservation measures for species of conservation concern. Guidelines for joint representation and subsequent interpretation of models outputs were defined and applied. The present joint analysis was based on the novel mechanistic model GR3D (Global Repositioning Dynamics of Diadromous fish Distribution) which was parameterized on allis shad and then used to predict its future distribution along the European Atlantic coast under different climate change scenarios (RCP 4.5 and RCP 8.5). We then used a correlative SDM for this species to forecast its distribution across the same geographic area and under the same climate change scenarios. First, projections from correlative and mechanistic models provided congruent trends in probability of habitat suitability and population dynamics. This agreement was preferentially interpreted as referring to the species vulnerability to climate change. Climate change could not be accordingly listed as a major threat for allis shad. The congruence in predicted range limits between SDMs projections was the next point of interest. The difference, when noticed, required to deepen our understanding of the niche modelled by each approach. In this respect, the relative position of the northern range limit between the two methods strongly suggested here that a key biological process related to intraspecific variability was potentially lacking in the mechanistic SDM. Based on our knowledge, we hypothesized that local adaptations to cold temperatures deserved more attention in terms of modelling, but further in conservation planning as well. PMID- 26426282 TI - Palagonitization of Basalt Glass in the Flanks of Mid-Ocean Ridges: Implications for the Bioenergetics of Oceanic Intracrustal Ecosystems. AB - When basalt is exposed to oxygenated aqueous solutions, rims of palagonite form along fractures at the expense of glass. We employed electron microprobe and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) analyses of fresh glass and adjacent palagonite crusts to determine the geochemical changes involved in palagonite formation. Samples were retrieved from drill cores taken in the North Pond Area, located on the western flank of the Mid-Atlantic Ridge at 22 degrees 45'N and 46 degrees 05'W. We also analyzed whole rock powders to determine the overall crust-seawater exchange in a young ridge flank. Radioactive elements are enriched in palagonite relative to fresh glass, reaching concentrations where radiolytic production of molecular hydrogen (H2) may be a significant energy source. Based on these results, we hypothesize that microbial ecosystems in ridge flank habitats undergo a transition in the principal energy carrier, fueling carbon fixation from Fe oxidation in very young crust to H2 consumption in older crust. Unless the H2 is swept away by rapid fluid flow (i.e., in young flanks), it may easily accumulate to levels high enough to support chemolithoautotrophic life. In older flanks, crustal sealing and sediment accumulation have slowed down seawater circulation, and the significance of radiolytically produced H2 for catalytic energy supply is expected to increase greatly. Similar habitats on other planetary surfaces are theoretically possible, as accumulation of radiolytically produced hydrogen merely requires the presence of H2O molecules and a porous medium, from which the hydrogen is not lost. PMID- 26426283 TI - Emergence, institutionalization and renewal: Rhythms of adaptive governance in complex social-ecological systems. AB - Adaptive governance provides the capacity for environmental managers and decision makers to confront variable degrees of uncertainty inherent to complex social ecological systems. Current theoretical conceptualizations of adaptive governance represent a series of structures and processes best suited for either adapting or transforming existing environmental governance regimes towards forms flexible enough to confront rapid ecological change. As the number of empirical examples of adaptive governance described in the literature grows, the conceptual basis of adaptive governance remains largely under theorized. We argue that reconnecting adaptive governance with foundational concepts of ecological resilience specifically Panarchy and the adaptive cycle of complex systems-highlights the importance of episodic disturbances and cross-scale interactions in triggering reorganizations in governance. By envisioning the processes of adaptive governance through the lens of Panarchy, scholars and practitioners alike will be better able to identify the emergence of adaptive governance, as well as take advantage of opportunities to institutionalize this type of governance in pursuit of sustainability outcomes. The synergistic analysis of adaptive governance and Panarchy can provide critical insight for analyzing the role of social dynamics during oscillating periods of stability and instability in social-ecological systems. A deeper understanding of the potential for cross-scale interactions to shape adaptive governance regimes may be useful as society faces the challenge of mitigating the impacts of global environmental change. PMID- 26426284 TI - Trends in the incidence of Oral and Pharyngeal Cancer (ICD00-14) in Guilan, North of Iran. AB - AIM: This study sought to assess the incidence of oral and pharyngeal cancer based on ICD-10 in Guilan, Iran, from 2004 to 2009. METHOD: This retrospective study assessed data collected from the Iranian cancer registries and publications. The rate, age-standardized incidence, type, and location of lesions according to ICD-10 were evaluated. Annual percent changes (APC) were estimated. RESULTS: A total of 1533 head and neck cancers were recorded. Of them, 290 cases (185 males and 105 females) were identified with oral and pharyngeal carcinoma (ICD00-14) with a mean age of 58.92 +/- 17.94 years. The most common type of cancer was oral squamous cell carcinoma (n = 156). Cancer of the oropharynx (ICD 06) and lips (ICD00) had high incidence. APC was 1.36%. ASR was 3.5 and 2.04 per 100 000 among males and females, respectively. The mean crude rate was 3.69 per 1 000 000. CONCLUSION: In contrast to the global cancer statistics (ICD 00-14), Guilan showed lower incidence of oral and pharyngeal cancer during the understudy years. Oral squamous cell carcinoma was the most common type of cancer in this region. PMID- 26426285 TI - Clinimetric properties and clinical utility in rehabilitation of postsurgical scar rating scales: a systematic review. AB - The aim of this study was to review and critically assess the most used and clinimetrically sound outcome measures currently available for postsurgical scar assessment in rehabilitation. We performed a systematic review of the Medline and Embase databases to June 2015. All published peer-reviewed studies referring to the development, validation, or clinical use of scales or questionnaires in patients with linear scars were screened. Of 922 articles initially identified in the literature search, 48 full-text articles were retrieved for assessment. Of these, 16 fulfilled the inclusion criteria for data collection. Data were collected pertaining to instrument item domains, validity, reliability, and Rasch analysis. The eight outcome measures identified were as follows: Vancouver Scar Scale, Dermatology Life Quality Index, Manchester Scar Scale, Patient and Observer Scar Assessment Scale, Bock Quality of Life (Bock QoL) questionnaire, Stony Brook Scar Evaluation Scale, Patient-Reported Impact of Scars Measure, and Patient Scar Assessment Questionnaire. Scales were examined for their clinimetric properties, and recommendations for their clinical or research use and selection were made. There is currently no absolute gold standard to be used in rehabilitation for the assessment of postsurgical scars, although the Patient and Observer Scar Assessment Scale and the Patient-Reported Impact of Scars Measure emerged as the most robust scales. PMID- 26426290 TI - DNA barcodes from century-old type specimens using next-generation sequencing. AB - Type specimens have high scientific importance because they provide the only certain connection between the application of a Linnean name and a physical specimen. Many other individuals may have been identified as a particular species, but their linkage to the taxon concept is inferential. Because type specimens are often more than a century old and have experienced conditions unfavourable for DNA preservation, success in sequence recovery has been uncertain. This study addresses this challenge by employing next-generation sequencing (NGS) to recover sequences for the barcode region of the cytochrome c oxidase 1 gene from small amounts of template DNA. DNA quality was first screened in more than 1800 century-old type specimens of Lepidoptera by attempting to recover 164-bp and 94-bp reads via Sanger sequencing. This analysis permitted the assignment of each specimen to one of three DNA quality categories--high (164-bp sequence), medium (94-bp sequence) or low (no sequence). Ten specimens from each category were subsequently analysed via a PCR-based NGS protocol requiring very little template DNA. It recovered sequence information from all specimens with average read lengths ranging from 458 bp to 610 bp for the three DNA categories. By sequencing ten specimens in each NGS run, costs were similar to Sanger analysis. Future increases in the number of specimens processed in each run promise substantial reductions in cost, making it possible to anticipate a future where barcode sequences are available from most type specimens. PMID- 26426291 TI - Comprehensive interactome of Otx2 in the adult mouse neural retina. AB - The Otx2 homeodomain transcription factor exerts multiple functions in specific developmental contexts, probably through the regulation of different sets of genes. Protein partners of Otx2 have been shown to modulate its activity. Therefore, the Otx2 interactome may play a key role in selecting a precise target gene repertoire, hence determining its function in a specific tissue. To address the nature of Otx2 interactome, we generated a new recombinant Otx2(CTAP-tag) mouse line, designed for protein complexes purification. We validated this mouse line by establishing the Otx2 interactome in the adult neural retina. In this tissue, Otx2 is thought to have overlapping function with its paralog Crx. Our analysis revealed that, in contrary to Crx, Otx2 did not develop interactions with proteins that are known to regulate phototransduction genes but showed specific partnership with factors associated with retinal development. The relationship between Otx2 and Crx in the neural retina should therefore be considered as complementarity rather than redundancy. Furthermore, study of the Otx2 interactome revealed strong associations with RNA processing and translation machineries, suggesting unexpected roles for Otx2 in the regulation of selected target genes all along the transcription/translation pathway. The Otx2(CTAP-tag) line, therefore, appears suitable for a systematic approach to Otx2 protein protein interactions. genesis 53:685-694, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26426292 TI - Association of a (TTTA)n microsatellite and a TCT del/ins polymorphisms in the aromatase gene (CYP19) with hip fracture risk in Mexican postmenopausal women. AB - A (TTTA)n polymorphism in the aromatase gene has been studied in relation to bone mineral density (BMD). The low number of TTTA repeats has been associated with low BMD and fracture risk. The aim of this study was to search for associations of TTTA copy number with hip fracture and lumbar spine osteoporosis in Mexican peri and postmenopausal women. The allele with seven repeats was present in the two reported versions, with or without a TCT deletion upstream of the microsatellite (A1 and A2, respectively). After adjustment by confounders, the A1 allele and the A1A1 genotype were significantly associated with an elevated risk of fracture (p = 0.034, OR = 3.2 [95% CI, 1.09-9.41] and p = 0.019, OR = 2.26 [95% CI, 1.14-4.49], respectively) and the A2 allele was associated with protection of hip fracture (p = 0.04, OR = 0.48, [95% CI, 0.22-1.05]) as the A2A2 genotype (p = 0.048, OR = 0.29 [95% CI, 0.06-1.16]). The analysis allowed us to defining the usefulness of the (TTTA)n polymorphism in the aromatase gene as an indicator of hip fracture risk in Mexican population. PMID- 26426293 TI - Mechanisms of fluorescence decays of colloidal CdSe-CdS/ZnS quantum dots unraveled by time-resolved fluorescence measurement. AB - By narrowing the detection bandpass and increasing the signal-to-noise ratio in measuring the time-resolved fluorescence decay spectrum of colloidal CdSe-CdS/ZnS quantum dots (QDs), we show that directly after the photoexcitation, the fluorescence decay spectrum is characterized by a single exponential decay, which represents the energy relaxation of the photogenerated exciton from its initial high-energy state to the ground exciton state. The fluorescence decay spectrum of long decay time is in the form of beta/t(2), where beta is the radiative recombination time of the ground-state exciton and t is the decay time. Our findings provide us with a direct and quantitative link between fluorescence decay measurement data and fundamental photophysics of QD exciton, thereby leading to a novel way of applying colloidal QDs to study microscopic, physical and chemical processes in many fields including biomedicine. PMID- 26426295 TI - Mechanical properties of ProTaper Gold nickel-titanium rotary instruments. AB - AIM: To evaluate and compare the resistance to cyclic fatigue and torsional stress, flexibility and surface microhardness of ProTaper Gold (PTG; Dentsply, Tulsa Dental Specialties, Tulsa, OK, USA) system with ProTaper Universal (PTU; Dentsply Maillefer, Ballaigues, Switzerland). METHODOLOGY: PTG and PTU instruments were rotated in simulated canals and the number of cycles to failure was recorded to assess their cyclic fatigue resistance. Torsional strength was measured using a torsiometer after fixing firmly the apical 3 mm of the instrument. A scanning electron microscope was used to characterize the topographic features of the fracture surfaces of the broken instruments. The instruments were tested for bending resistance using cantilever-bending test. Vickers microhardness was measured on the cross section of instruments with 300 g load and 15 s dwell time. Data were analysed statistically using independent t tests. Statistical significance was set at P < 0.05. RESULTS: PTG instruments had a significantly higher resistance to cyclic fatigue and flexibility than PTU (P < 0.001). The fractured cross-sectional surfaces revealed typical features of cyclic fractures, including crack origins, fatigue zones and overload fast fracture zones. On the other hand, PTU instruments were associated with higher resistance to torsional stress and microhardness than PTG instruments (P < 0.001). After torsional tests, the fractured cross-sectional surfaces revealed skewed dimples near the centre of the fracture surfaces and circular abrasion streaks. CONCLUSIONS: The PTG instrument had improved resistance to cyclic fatigue and flexibility compared with PTU. PTU instruments had improved resistance to torsional stress and microhardness compared with PTG. PMID- 26426294 TI - A kinetic model of municipal sludge degradation during non-catalytic wet oxidation. AB - Wet oxidation is a successful process for the treatment of municipal sludge. In addition, the resulting effluent from wet oxidation is a useful carbon source for subsequent biological nutrient removal processes in wastewater treatment. Owing to limitations with current kinetic models, this study produced a kinetic model which predicts the concentrations of key intermediate components during wet oxidation. The model was regressed from lab-scale experiments and then subsequently validated using data from a wet oxidation pilot plant. The model was shown to be accurate in predicting the concentrations of each component, and produced good results when applied to a plant 500 times larger in size. A statistical study was undertaken to investigate the validity of the regressed model parameters. Finally the usefulness of the model was demonstrated by suggesting optimum operating conditions such that volatile fatty acids were maximised. PMID- 26426296 TI - A High-Throughput Genetic Complementation Assay in Yeast Cells Identified Selective Inhibitors of Sphingosine Kinase 1 Not Found Using a Cell-Free Enzyme Assay. AB - Sphingosine kinase 1 (SphK1) is a lipid kinase that phosphorylates sphingosine to produce the bioactive sphingolipid, sphingosine-1-phosphate (S1P), and therefore represents a potential drug target for a variety of pathological processes such as fibrosis, inflammation, and cancer. We developed two assays compatible with high-throughput screening to identify small-molecule inhibitors of SphK1: a purified component enzyme assay and a genetic complementation assay in yeast cells. The biochemical enzyme assay measures the phosphorylation of sphingosine fluorescein to S1P-fluorescein by recombinant human full-length SphK1 using an immobilized metal affinity for phosphochemicals (IMAP) time-resolved fluorescence resonance energy transfer format. The yeast assay employs an engineered strain of Saccharomyces cerevisiae, in which the human gene encoding SphK1 replaced the yeast ortholog and quantitates cell viability by measuring intracellular adenosine 5'-triphosphate (ATP) using a luciferase-based luminescent readout. In this assay, expression of human SphK1 was toxic, and the resulting yeast cell death was prevented by SphK1 inhibitors. We optimized both assays in a 384-well format and screened ~10(6) compounds selected from the Boehringer Ingelheim library. The biochemical IMAP high-throughput screen identified 5,561 concentration-responsive hits, most of which were ATP competitive and not selective over sphingosine kinase 2 (SphK2). The yeast screen identified 205 concentration-responsive hits, including several distinct compound series that were selective against SphK2 and were not ATP competitive. PMID- 26426298 TI - Risk of gentamicin toxicity in neonates treated for possible severe bacterial infection in low- and middle-income countries: Systematic Review. AB - OBJECTIVES: To assess the risk of gentamicin toxicity and potential number of neonates exposed annually to this risk, through treatment with WHO-recommended first-line antibiotics (gentamicin with penicillin) for the 6.9 million neonates with possible serious bacterial infection (PSBI). METHODS: Systematic literature review and assessment of the evidence using Cochrane and GRADE criteria. Meta analysis was undertaken for pooled estimates where appropriate. RESULTS: Eleven studies (946 neonates) were included (nine randomised controlled trials and two prospective cohort studies). Six trials reported consistently measured ototoxicity outcomes in neonates treated with gentamicin, and the pooled estimate for hearing loss was 3% (95% CI 0-7%). Nephrotoxicity could not be assessed due to variation in case definitions used. Estimates of the number of neonates potentially affected by gentamicin toxicity were not undertaken due to insufficient data. CONCLUSION: Given wider scale-up of outpatient-based and lower level treatment of PSBI, improved data are essential to better assess the risks from neonatal gentamicin treatment without assessment of blood levels, to maximise benefit and reduce harm. PMID- 26426299 TI - Hybrid percutaneous and surgical minimally invasive, thoracoscopy-guided removal of a pacemaker lead subacutely perforating the right ventricle. PMID- 26426300 TI - The predictive value of plasma biomarkers in discharged heart failure patients: role of galectin-3. AB - Over the last years a number of new biomarkers reflecting different aspects of heart failure (HF) pathophysiology have been evaluated in order to improve diagnosis and to better define prognosis of patients. Among these, Galectin 3 (Gal-3) seems particularly promising. It is a soluble beta galactoside-binding lectin produced by activated macrophages which binds and activates the fibroblasts thus leading to the deposition of collagen into the extracellular matrix and to a progressive cardiac fibrosis. Gal-3 plays also an important regulatory role in inflammatory status. Experimental studies have demonstrated that it is involved in cardiac remodeling and that it is one of the main determinants of development and progression of HF. In humans, Gal-3 plasma levels are associated with the onset of HF in apparently healthy patients and have been found being predictors of a worse prognosis in acute (AHF) as well as in chronic heart failure (CHF). Furthermore, Gal-3 serum levels are strongly correlated with renal dysfunction thus suggesting a possible role in better characterizing cardiorenal syndrome. The aim of this review was to revise the available experimental and clinical data concerning the role of Gal-3 as prognostic marker in HF. PMID- 26426301 TI - Identification and quantification of vinpocetine and picamilon in dietary supplements sold in the United States. AB - Vinpocetine and picamilon are drugs prescribed in many countries to treat a variety of cerebrovascular disorders. In the United States, vinpocetine and picamilon have never been approved by the US Food and Drug Administration, but they are both available for sale directly to consumers as dietary supplements. We designed our study to determine the accuracy of supplement labels with regard to the presence and quantity of vinpocetine and picamilon. A validated ultra-high performance liquid chromatography-photodiode-array method was developed for the quantification of vinpocetine and picamilon. The separation was achieved using a reversed phase (C-18) column, photodiode array detection, and water/acetonitrile as the mobile phase. Vinpocetine and picamilon were detected at concentrations as low as 10 and 50 ng/mL, respectively. The presence of vinpocetine and picamilon was confirmed using reference standards. Twenty-three supplements labelled as containing vinpocetine were available for sale at two large supplement retail chains; 17 contained vinpocetine with quantities ranging from 0.3 to 32 mg per recommended daily serving. No vinpocetine was detected in six of the sampled supplements. The supplement label implied that vinpocetine was a constituent of lesser periwinkle in three of the supplements. Of the 31 picamilon supplements available for sale from a variety of retailers: 30 contained picamilon in quantities ranging from 2.7 to 721.5 mg per recommended daily serving. We found that consumers cannot obtain accurate information from supplement labels regarding the presence or quantity of vinpocetine and picamilon. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26426302 TI - Association between Macrophage Migration Inhibitory Factor Gene Variation and Response to Glucocorticoid Treatment in Sudden Sensorineural Hearing Loss. AB - Several lines of evidence suggest the role of the immune system in the pathogenesis of sudden sensorineural hearing loss (SSNHL). Macrophage migration inhibitory factor (MIF) mediates its role in various immune and inflammatory conditions by the regulation of immune reactions. Several studies have confirmed an association between MIF gene polymorphisms and susceptibility to various inflammatory and autoimmune disorders. The aim of this study was to explore the association between the MIF (-173 G/C) polymorphism (rs755622) and SSNHL in an Iranian population. In this case-control association study, SSNHL cases (n = 77) were included. Normal healthy subjects (n = 100) were also recruited from the same region. Genotyping for MIF (-173 G/C) polymorphism was carried out using the polymerase chain reaction-restriction fragment length polymorphism technique. The frequency of the MIF -173 C allele carriers (GC + CC genotype) was significantly elevated in SSNHL patients who responded to glucocorticoid treatment compared with the patients with no response to treatment. These results suggest that the MIF gene polymorphism is associated with a response to glucocorticoid treatment in patients with SSNHL. PMID- 26426303 TI - Highly Conductive Ionic-Liquid Gels Prepared with Orthogonal Double Networks of a Low-Molecular-Weight Gelator and Cross-Linked Polymer. AB - We prepared a heterogeneous double-network (DN) ionogel containing a low molecular-weight gelator network and a polymer network that can exhibit high ionic conductivity and high mechanical strength. An imidazolium-based ionic liquid was first gelated by the molecular self-assembly of a low-molecular-weight gelator (benzenetricarboxamide derivative), and methyl methacrylate was polymerized with a cross-linker to form a cross-linked poly(methyl methacrylate) (PMMA) network within the ionogel. Microscopic observation and calorimetric measurement revealed that the fibrous network of the low-molecular-weight gelator was maintained in the DN ionogel. The PMMA network strengthened the ionogel of the low-molecular-weight gelator and allowed us to handle the ionogel using tweezers. The orthogonal DNs produced ionogels with a broad range of storage elastic moduli. DN ionogels with low PMMA concentrations exhibited high ionic conductivity that was comparable to that of a neat ionic liquid. The present study demonstrates that the ionic conductivities of the DN and single-network, low-molecular-weight gelator or polymer ionogels strongly depended on their storage elastic moduli. PMID- 26426304 TI - Designing the shape evolution of SnSe2 nanosheets and their optoelectronic properties. AB - Layered chalcogenide materials (LCMs) are emerging materials in recent years for their great potential in applications of electronics and optoelectronics. As a member of LCMs, SnSe2, an n-type semiconductor with a band gap of ~1.0 eV, is of great value to explore. In this paper, we develop a facile CVD method, for the first time, to synthesize diverse shaped SnSe2 and square SnSe nanosheets (NSs) on SiO2/Si substrates. To the best of our knowledge, the thickness of as-grown SnSe2 is among the thinnest ones synthesized by CVD methods on various substrates. What's more, photodetectors are fabricated to investigate the optoelectronic properties of SnSe2. The on/off ratio of photoswitches reaches 100 under the illumination of an 800 nm laser. This work will pave a new pathway to synthesize LCM nanostructures, shed light on the shape evolution during the growth process and expand the candidates for high performance optoelectronic devices. PMID- 26426305 TI - Oncologic Outcomes according to the Treatment Strategy in Radiologic Complete Responders after Neoadjuvant Chemoradiation for Rectal Cancer. AB - OBJECTIVE: This study aimed to compare the oncologic outcomes between treatment strategies for rectal cancer [radical surgery, local excision (LE), and the wait and-see approach] in radiologic complete responders after neoadjuvant chemoradiation (nCRT). METHODS: We retrospectively reviewed rectal cancer patients and included 52 radiologic complete responders after nCRT defined as no residual tumor or residual fibrosis and no suspicious metastatic lymph nodes on magnetic resonance imaging (MRI). Clinicopathologic features and oncologic outcomes were compared according to the treatment strategies. RESULTS: The median follow-up period was 41 months (range, 6-80). Twenty-eight patients underwent radical surgery, whereas 16 underwent LE, and 8 were closely monitored without initial surgery. The pathologic complete response rate was 40.9%. Patients who underwent radical surgery showed better prognosis compared to those who underwent LE or wait-and-see (3-year disease-free survival: radical surgery 85.0% vs. LE 62.5%, wait-and-see 75.0%, p = 0.019; 3-year local recurrence-free survival: radical surgery 96.4% vs. LE 67.0%, wait-and-see 75.0%, p = 0.009). After recurrence, patients who underwent salvage surgery showed a relatively good oncologic outcome. CONCLUSION: Pursuing LE or the wait-and-see approach instead of radical surgery in rectal cancer patients undergoing nCRT may bring about a detrimental oncologic outcome if clinical complete response is solely determined by MRI. PMID- 26426306 TI - Robust species taxonomy assignment algorithm for 16S rRNA NGS reads: application to oral carcinoma samples. AB - BACKGROUND: Usefulness of next-generation sequencing (NGS) in assessing bacteria associated with oral squamous cell carcinoma (OSCC) has been undermined by inability to classify reads to the species level. OBJECTIVE: The purpose of this study was to develop a robust algorithm for species-level classification of NGS reads from oral samples and to pilot test it for profiling bacteria within OSCC tissues. METHODS: Bacterial 16S V1-V3 libraries were prepared from three OSCC DNA samples and sequenced using 454's FLX chemistry. High-quality, well-aligned, and non-chimeric reads >=350 bp were classified using a novel, multi-stage algorithm that involves matching reads to reference sequences in revised versions of the Human Oral Microbiome Database (HOMD), HOMD extended (HOMDEXT), and Greengene Gold (GGG) at alignment coverage and percentage identity >=98%, followed by assignment to species level based on top hit reference sequences. Priority was given to hits in HOMD, then HOMDEXT and finally GGG. Unmatched reads were subject to operational taxonomic unit analysis. RESULTS: Nearly, 92.8% of the reads were matched to updated-HOMD 13.2, 1.83% to trusted-HOMDEXT, and 1.36% to modified GGG. Of all matched reads, 99.6% were classified to species level. A total of 228 species-level taxa were identified, representing 11 phyla; the most abundant were Proteobacteria, Bacteroidetes, Firmicutes, Fusobacteria, and Actinobacteria. Thirty-five species-level taxa were detected in all samples. On average, Prevotella oris, Neisseria flava, Neisseria flavescens/subflava, Fusobacterium nucleatum ss polymorphum, Aggregatibacter segnis, Streptococcus mitis, and Fusobacterium periodontium were the most abundant. Bacteroides fragilis, a species rarely isolated from the oral cavity, was detected in two samples. CONCLUSION: This multi-stage algorithm maximizes the fraction of reads classified to the species level while ensuring reliable classification by giving priority to the human, oral reference set. Applying the algorithm to OSCC samples revealed high diversity. In addition to oral taxa, a number of human, non-oral taxa were also identified, some of which are rarely detected in the oral cavity. PMID- 26426307 TI - Mining Novel Allergens from Coconut Pollen Employing Manual De Novo Sequencing and Homology-Driven Proteomics. AB - Coconut pollen, one of the major palm pollen grains is an important constituent among vectors of inhalant allergens in India and a major sensitizer for respiratory allergy in susceptible patients. To gain insight into its allergenic components, pollen proteins were analyzed by two-dimensional electrophoresis, immunoblotted with coconut pollen sensitive patient sera, followed by mass spectrometry of IgE reactive proteins. Coconut being largely unsequenced, a proteomic workflow has been devised that combines the conventional database dependent analysis of tandem mass spectral data and manual de novo sequencing followed by a homology-based search for identifying the allergenic proteins. N terminal acetylation helped to distinguish "b" ions from others, facilitating reliable sequencing. This led to the identification of 12 allergenic proteins. Cluster analysis with individual patient sera recognized vicilin-like protein as a major allergen, which was purified to assess its in vitro allergenicity and then partially sequenced. Other IgE-sensitive spots showed significant homology with well-known allergenic proteins such as 11S globulin, enolase, and isoflavone reductase along with a few which are reported as novel allergens. The allergens identified can be used as potential candidates to develop hypoallergenic vaccines, to design specific immunotherapy trials, and to enrich the repertoire of existing IgE reactive proteins. PMID- 26426308 TI - Spatial predictions at the community level: from current approaches to future frameworks. AB - A fundamental goal of ecological research is to understand and model how processes generate patterns so that if conditions change, changes in the patterns can be predicted. Different approaches have been proposed for modelling species assemblage, but their use to predict spatial patterns of species richness and other community attributes over a range of spatial and temporal scales remains challenging. Different methods emphasize different processes of structuring communities and different goals. In this review, we focus on models that were developed for generating spatially explicit predictions of communities, with a particular focus on species richness, composition, relative abundance and related attributes. We first briefly describe the concepts and theories that span the different drivers of species assembly. A combination of abiotic processes and biotic mechanisms are thought to influence the community assembly process. In this review, we describe four categories of drivers: (i) historical and evolutionary, (ii) environmental, (iii) biotic, and (iv) stochastic. We discuss the different modelling approaches proposed or applied at the community level and examine them from different standpoints, i.e. the theoretical bases, the drivers included, the source data, and the expected outputs, with special emphasis on conservation needs under climate change. We also highlight the most promising novelties, possible shortcomings, and potential extensions of existing methods. Finally, we present new approaches to model and predict species assemblages by reviewing promising 'integrative frameworks' and views that seek to incorporate all drivers of community assembly into a unique modelling workflow. We discuss the strengths and weaknesses of these new solutions and how they may hasten progress in community-level modelling. PMID- 26426309 TI - Digital microfluidics platform for interfacing solid-liquid extraction column with portable capillary electropherograph for analysis of soil amino acids. AB - In this work, the concept of a field-portable analyzer is proposed that operates with milliliter amounts of solvents and samples. The need to develop such an analyzer is not only driven by specific extraterrestrial analysis but also, for example, by forensics applications where the amount of liquid that can be taken to the field is severely limited. The prototype of the proposed analyzer consists of a solid-liquid extractor, the output of which is connected to the micropump, which delivers droplets of extracts to digital microfluidic platform (DMFP). In this way, world-to-chip interfacing is established. Further, the sample droplets are transported to CE capillary inlet port, separated and detected via a contactless conductivity detector. Working buffers and other solvents needed to perform CE analysis are also delivered as droplets to the DMFP and transported through the CE capillary. The performance of the analyzer is demonstrated by analysis of amino acids in sand matrices. The recovery of the spiked amino acids from the inert sand sample was from 34 to 51% with analysis LOD from 0.2 to 0.6 ppm and migration time RSD from 0.2 to 6.0%. PMID- 26426310 TI - Description and Phylogeny of Urostyla grandis wiackowskii subsp. nov. (Ciliophora, Hypotricha) from an Estuarine Mangrove in Brazil. AB - Interphase specimens, aspects of physiological reorganization and divisional morphogenesis were investigated in a strain of a hypotrichous ciliate highly similar to Urostyla grandis Ehrenberg, (type species of Urostyla), collected from a mangrove area in the estuary of the Paraiba do Sul river (Rio de Janeiro, Brazil). The results revealed that albeit interphase specimens match with the known morphologic variability in U. grandis, morphogenetic processes have conspicuous differences. Parental adoral zone is entirely renewed during morphogenesis, and marginal cirri exhibit a unique combination of developmental modes, in which left marginal rows originate from multiple anlagen arising from innermost left marginal cirral row, whereas right marginal ciliature originates from individual within-row anlagen. Based on such characteristics, a new subspecies, namely U. grandis wiackowskii subsp. nov. is proposed, and consequently, U. grandis grandis Ehrenberg, stat. nov. is established. Bayesian and maximum-likelihood analyses of the 18S rDNA unambiguously placed U. grandis wiackowskii as adelphotaxon of a cluster formed by other U. grandis sequences. The implications of such findings to the systematics of Urostyla are discussed. PMID- 26426311 TI - Expanding population edges: theories, traits, and trade-offs. AB - Recent patterns of global change have highlighted the importance of understanding the dynamics and mechanisms of species range shifts and expansions. Unique demographic features, spatial processes, and selective pressures can result in the accumulation and evolution of distinctive phenotypic traits at the leading edges of expansions. We review the characteristics of expanding range margins and highlight possible mechanisms for the appearance of phenotypic differences between individuals at the leading edge and core of the range. The development of life history traits that increase dispersal or reproductive ability is predicted by theory and supported with extensive empirical evidence. Many examples of rapid phenotypic change are associated with trade-offs that may influence the persistence of the trait once expansion ends. Accounting for the effects of edge phenotypes and related trade-offs could be critical for predicting the spread of invasive species and population responses to climate change. PMID- 26426313 TI - Electrochemistry of Nanostructured Layered Transition-Metal Dichalcogenides. PMID- 26426312 TI - The Relationship Between Submental Surface Electromyography and Hyo-Laryngeal Kinematic Measures of Mendelsohn Maneuver Duration. AB - PURPOSE: The Mendelsohn Maneuver (MM) is a commonly prescribed technique that is taught to individuals with dysphagia to improve swallowing ability. Due to cost and safety concerns associated with videofluoroscopy (VFS) use, submental surface electromyography (ssEMG) is commonly used in place of VFS to train the MM in clinical and research settings. However, it is unknown whether ssEMG accurately reflects the prolonged hyo-laryngeal movements required for execution of the MM. The primary goal of this study was to examine the relationship among ssEMG duration, duration of laryngeal vestibule closure, and duration of maximum hyoid elevation during MM performance. METHOD: Participants included healthy adults and patients with dysphagia due to stroke. All performed the MM during synchronous ssEMG and VFS recording. RESULTS: Significant correlations between ssEMG duration and VFS measures of hyo-laryngeal kinematic durations during MM performance ranged from very weak to moderate. None of the correlations in the group of stroke patients reached statistical significance. CONCLUSION: Clinicians and researchers should consider that the MM involves novel hyo-laryngeal kinematics that may be only moderately represented with ssEMG. Thus, there is a risk that these target therapeutic movements are not consistently being trained. PMID- 26426315 TI - Gastric emptying and disease activity in inflammatory bowel disease. AB - BACKGROUND: Gastric emptying (GE) is delayed in a subset of patients with inflammatory bowel disease (IBD). We have shown before that altered release of gastrointestinal hormones may contribute to GE disturbances, but overall effects of disease activity remain unclear. Thus, we aimed to evaluate GE in patients with IBD during active disease and following therapy. DESIGN: A total of 20 healthy subjects (HC) and 26 patients with IBD hospitalized because of an acute episode of their disease (Crohn's disease (CD) n = 13, ulcerative colitis (UC) n = 13) underwent a standardized (13) C-octanoic acid GE breath test (baseline test). Plasma glucose, cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) were measured periodically throughout the test. A total of 16 patients underwent a second GE test after 3-4 months of therapy. RESULTS: At baseline, nine patients with IBD had pathologically delayed GE half-time (T1/2 > 150 min) (P = 0.028 vs. HC). Moreover, T1/2 was significantly longer in the total group of patients with IBD than in HC (129 +/- 12 min vs. 96 +/- 7, P = 0.030). Postprandial GLP-1 responses were elevated in IBD (P = 0.002 vs. HC) and correlated with T1/2 (P = 0.05). Following therapy clinical activity indices and T1/2 were decreased in IBD (P <= 0.01 vs. baseline), and T1/2 no longer differed from HC (P > 0.5). Moreover, GLP-1 plasma levels decreased significantly (P = 0.031). CONCLUSIONS: Higher disease activity in IBD is associated with prolonged GE and increased release of GLP-1. Following effective therapy, GE is accelerated and GLP-1 release decreases significantly. Thus, increased release of GLP-1 from the inflamed mucosa might contribute to GE disturbances in IBD. PMID- 26426316 TI - Pediatric deceased donor renal transplantation: An approach to decision making I. Pediatric kidney allocation in the USA: The old and the new. AB - Renal transplantation is the treatment of choice for children with end-stage renal disease. More than 50% of children receive a deceased donor renal transplant. Marked disparity between the number of children on the renal transplant wait list and the supply has prompted numerous advances to increase supply as well as maximize the utility of donor organs. Allocation of deceased donor kidneys is based on several criteria. The organ allocation system policy is continually evaluated and changed incrementally to optimize allocation. We, in the United States, are in the process of transitioning into a new kidney allocation system to enhance post-transplant survival benefit, increase utilization of donated kidneys, and increase transplant access for biologically disadvantaged candidates. This review will provide a brief overview of the organ sharing system in the United States, compare the "old" and the "new" allocation system, and discuss the considerations for the pediatric nephrologist while accepting a deceased donor kidney for a particular pediatric patient. PMID- 26426314 TI - Treatment of Unexplained Chronic Cough: CHEST Guideline and Expert Panel Report. AB - BACKGROUND: Unexplained chronic cough (UCC) causes significant impairments in quality of life. Effective assessment and treatment approaches are needed for UCC. METHODS: This systematic review of randomized controlled trials (RCTs) asked: What is the efficacy of treatment compared with usual care for cough severity, cough frequency, and cough-related quality of life in patients with UCC? Studies of adults and adolescents aged > 12 years with a chronic cough of > 8 weeks' duration that was unexplained after systematic investigation and treatment were included and assessed for relevance and quality. Based on the systematic review, guideline suggestions were developed and voted on by using the American College of Chest Physicians organization methodology. RESULTS: Eleven RCTs and five systematic reviews were included. The 11 RCTs reported data on 570 participants with chronic cough who received a variety of interventions. Study quality was high in 10 RCTs. The studies used an assortment of descriptors and assessments to identify UCC. Although gabapentin and morphine exhibited positive effects on cough-related quality of life, only gabapentin was supported as a treatment recommendation. Studies of inhaled corticosteroids (ICS) were affected by intervention fidelity bias; when this factor was addressed, ICS were found to be ineffective for UCC. Esomeprazole was ineffective for UCC without features of gastroesophageal acid reflux. Studies addressing nonacid gastroesophageal reflux disease were not identified. A multimodality speech pathology intervention improved cough severity. CONCLUSIONS: The evidence supporting the diagnosis and management of UCC is limited. UCC requires further study to establish agreed terminology and the optimal methods of investigation using established criteria for intervention fidelity. Speech pathology-based cough suppression is suggested as a treatment option for UCC. This guideline presents suggestions for diagnosis and treatment based on the best available evidence and identifies gaps in our knowledge as well as areas for future research. PMID- 26426317 TI - The Implementation and Evaluation of the Patient Admission Prediction Tool: Assessing Its Impact on Decision-Making Strategies and Patient Flow Outcomes in 2 Australian Hospitals. AB - STUDY OBJECTIVES: To evaluate the implementation of a Patient Admission Prediction Tool (PAPT) in terms of patient flow outcomes and decision-making strategies. METHODS: SETTING: The PAPT was implemented in 2 Australian public teaching hospitals during October-December 2010 (hospital A) and October-December 2011 (hospital B). DESIGN: A multisite prospective, comparative (before and after) design was used. Patient flow outcomes measured included access block and hospital occupancy. Daily and weekly data were collected from patient flow reports and routinely collected emergency department information by the site champion and researchers. RESULTS: Daily decision-making strategies ranged from business as usual to use of overcensus beds. Weekly strategies included advanced approval to use of overcensus beds and prebooking nursing staff. These strategies resulted in improved weekend discharges to manage incoming demand for the following week. Following the introduction of the PAPT and workflow guidelines, patient access and hospital occupancy levels could be maintained despite increases in patient presentations (hospital A). CONCLUSIONS: The use of a PAPT, embedded in patient flow management processes and championed by a manager, can benefit bed and staff management. Further research that incorporates wider evaluation of the use of the tool at other sites is warranted. PMID- 26426318 TI - Increasing Efficiency in Evaluation of Chronic Cough: A Multidisciplinary, Collaborative Approach. AB - Chronic cough is the most common reason for medical office visits in the United States. The typical patient has coughed more than 8 years and seen many specialists. This quality improvement project is an ambulatory clinic redesign to deliver efficient, patient-centered care with interspecialty collaboration. Methodology included the Institute for Healthcare Improvement collaborative model focused on Lean/Six Sigma and ADKAR (Awareness, Desire, Knowledge, Ability, Reinforcement) Change Management. Interventions targeted education to referring providers, implementation of software changes, building a collaborative interdepartmental scheduling decision tree, and an interclinic dashboard enhancing communication and decision support. Outcome measures compare group resource utilization, evidenced by the total number of specialist referrals for same indication of chronic cough (International Classification of Diseases, Ninth Revision: 786.2), and length of time to complete evaluation. A retrospective review of 165 medical records yielded 2 groups, "current care" (n = 67) and "intervention" (n = 68). The number of specialist referrals per patient was reduced in the intervention group (M = 1.22, SD = 0.48) compared with the current care group (M = 3.33, SD = 1.02). Length of itinerary was reduced in the intervention group (M = 11.90, SD = 12.13, GM = 6.82) compared with the current care group (M = 126.93, SD = 158.13, GM = 54.8). Multidisciplinary collaboration, communication, coordinating diagnosis, and management of multifactorial conditions, such as chronic cough, are associated with lower costs and decreased utilization of health care resources. PMID- 26426319 TI - Patient Satisfaction in an Outpatient Hand Surgery Office: A Comparison of English- and Spanish-Speaking Patients. AB - BACKGROUND: As health care in the United States transitions from a fee-for service to an outcomes-based environment, patient satisfaction is increasingly incentivized and publicly reported. Despite the continued growth of the Latino population and concomitant rise in the demand for health care, relatively little is known regarding patient satisfaction in Spanish speakers. We sought to compare patient satisfaction with hand surgery office visits between Spanish- and English speaking patients. METHODS: Directly after the office visit, 150 patients (75 English speakers and 75 Spanish speakers) completed a sociodemographic survey, an 11-point ordinal rating of pain intensity, and a survey of satisfaction with the encounter using items derived from the CG-CAHPS (Clinician and Group-Consumer Assessment of Healthcare Providers and Systems) survey. Multivariable regression modeling was used to identify factors associated with patient dissatisfaction. RESULTS: Overall, 79% of Spanish-speaking patients were satisfied with the physician as compared with 91% of English speakers (P = .041). Compared with English-speaking patients, Spanish speakers were less likely to be satisfied with provider listening carefully (91% vs 100%, P = .007) and spending enough time with them (56% vs 93%, P < .001), as well as with waiting times (81% vs 96%, P = .005). There was no difference with regard to provider showing respect, clarity of communication, and explanation of what was done. Younger age and Spanish language were independent predictors of patient dissatisfaction. CONCLUSIONS: Spanish-speaking patients are less satisfied with the care provided in a hand surgery office. In light of the growing diversity of the US population and the fact that patient satisfaction is increasingly tied to reimbursement, additional research might identify potential areas of improvement from both the surgeon (eg, communication strategies, cultural competence) and patient (eg health literacy, expectations) perspectives. PMID- 26426320 TI - Electronic Tracking of Patients in an Outpatient Ophthalmology Clinic to Improve Efficient Flow: A Feasibility Analysis and Benchmarking Study. AB - INTRODUCTION: Real-time location systems (RTLS) and Lean management approaches have been employed to improve patient flow in clinical settings. This study explored the feasibility of using these methodologies in an outpatient resident ophthalmology clinic. METHODS: Patients, providers, and staff in Wilmer Eye Institute General Eye Services Clinic were provided RTLS tags to track their movement throughout the clinic after observational studies modeling flow were conducted. Tracking data guided changes for clinic processes based on Lean management approaches, including reorganization of the reception desk, consolidation of forms, creation of task sheets to improve communication, installation of door flags on examination rooms, and training the staff in service excellence. Tracking was repeated after changes were implemented. A patient satisfaction survey was also conducted prior to and after the changes. RESULTS: After intervention, significant increases were measured in the average time patients spent in the clinic (99.3 minutes vs 112.8 minutes). Significant decreases were seen in the times patients spent with the optometrists (15.4 minutes vs 12.1 minutes), testing (24.7 minutes vs 23.0 minutes), and together with both the attending and the resident (8.3 minutes vs 5.8 minutes). The patient satisfaction survey indicated improvements in patients' perception of the helpfulness/friendliness of the staff, the length of time patients perceived they waited, and overall clinic experience. DISCUSSION: Both RTLS and Lean management approaches may be feasible ways to track and improve patient flow and satisfaction if certain limitations can be overcome. This is the first published report describing these approaches applied to an academic ophthalmology clinic in the United States. PMID- 26426321 TI - Factors Associated With Reintubation in Patients With Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (COPD) increase morbidity, mortality, and health care costs in COPD patients. Patients who require mechanical ventilation and fail extubation often have longer hospital stays and/or increased mortality. Determining predictors to identify patients who might require reintubation could help respiratory care teams manage these patients better. METHODS: We retrospectively reviewed data of COPD patients over a 3-year period. Inclusion criteria were patients with acute exacerbations of COPD, age more than 45 years, and patients on mechanical ventilation. Exclusion criteria were ventilated via tracheostomy, unplanned extubation, and reintubation for reasons other than respiratory failure. RESULTS: This study included 88 patients; 61 patients were successfully extubated, 11 patients were extubated and required reintubation, and 16 patients were not extubated during their intensive care unit stay. There were no differences in demographic or clinical characteristics between the patients with successful extubation and failed extubation. Patients with successful extubation were more likely to have a "good cough" assessment and to not receive any sedatives or analgesics in the 24 hours prior to extubation than patients who failed extubation (P < .05). Multiple variable logistic regression demonstrated that reintubation was significantly associated with sedatives/analgesics given prior to extubation (odds ratio = 8.6; 95% confidence interval, 1.23-60.8). Intensive care unit and hospital lengths of stay, tracheostomy events, and mortality rates were higher in the reintubation group (P < .001). CONCLUSION: Sedative and analgesic drug use prior to extubation was associated with more frequent reintubation in patients with acute exacerbations of COPD. This study suggests that the judicious withdrawal of sedatives prior to extubation may reduce reintubations. PMID- 26426322 TI - A Simulated Level Loading of Supply and Demand for Beds in a Tertiary Care Children's Hospital Reduces Overall Bed Requirements. AB - BACKGROUND: Anticipating throughput and allocating resources effectively in children's hospitals have unique challenges relative to adult inpatient centers. The seasonal and daily variation can be difficult to anticipate in terms of impact and creating plans for adequate preparation. Discrete event simulation methodology can be helpful in determining appropriate allocation of resources and has been increasingly appropriated in health care from industry. METHODS: A representative sample set was abstracted from the Cohen Children's Medical Center census tracking system to describe the present state. A larger data set was used to determine the appropriate level load. The total work performed each hour from 8 AM to 8 PM was evaluated against the level load plan of 11.5%. During the initial hours of the working period when the total work was low, more discharges were added. For each discharge added, an equal quantity of discharges was subtracted from the later hours of the day to bring the total work below 11.5% for each hour. Once the simulated state discharges were determined, a new aggregate bed supply line was created. These values were then added to the original visualization to show improvement. RESULTS: Our analysis suggests that a large part of the discharge/transfer activity and bed demand activity occurs in the pediatric intensive care unit in a roughly 4- to 5-hour window. Our simulation analysis suggests that level loading of this resource-intensive activity period has a potential to reduce bed occupancy, increase bed availability in peak bed demand times, and improve efficiency and throughput throughout the hospital. CONCLUSION: Discrete event simulation can be an effective tool for pediatric inpatient centers to determine appropriate allocation of resources to enhance patient safety and throughput without significant, costly expansion of bed capacity. PMID- 26426323 TI - Collaboratively Improving Diabetes Care in Sweden Using a National Quality Register: Successes and Challenges-A Case Study. AB - BACKGROUND: Since 1996, the Swedish National Diabetes Register (NDR) enabled health care providers to monitor their clinical performance over time and compare it with the national average. All health systems of Swedish county councils report data. By 2014, the NDR included data from 360 000 patients. Comparisons among county councils show significant variations in clinical outcomes and in adherence to evidence-based national guidelines. The purpose of this study was to evaluate whether and how a quality improvement collaborative could influence clinical practice and outcomes. METHODS: Twenty-three diabetes teams from all over Sweden, both primary care units and internal medicine departments, joined a quality improvement collaborative. The project was inspired by the Breakthrough Collaborative Model and lasted for 20 months. Evaluation data were collected from the teams' final reports and the NDR throughout the study period. RESULTS AND CONCLUSION: The teams reported improved patient outcomes significantly compared with the national average for systolic blood pressure and low-density lipoprotein levels. In contrast, glycated hemoglobin A1c levels deteriorated in the whole NDR population. Five themes of changes in practice were tested and implemented. Success factors included improved teamwork, with active use of register data, and testing new ideas and learning from others. PMID- 26426324 TI - How Visual Management for Continuous Improvement Might Guide and Affect Hospital Staff: A Case Study. AB - Visual management (VM) tools such as whiteboards, often employed in Lean thinking applications, are intended to be helpful in improving work processes in different industries including health care. It remains unclear, however, how VM is actually applied in health care Lean interventions and how it might influence the clinical staff. We therefore examined how Lean-inspired VM using whiteboards for continuous improvement efforts related to the hospital staff's work and collaboration. Within a case study design, we combined semistructured interviews, nonparticipant observations, and photography on 2 cardiology wards. The fate of VM differed between the 2 wards; in one, it was well received by the staff and enhanced continuous improvement efforts, whereas in the other ward, it was not perceived to fit in the work flow or to make enough sense in order to be sustained. Visual management may enable the staff and managers to allow communication across time and facilitate teamwork by enabling the inclusion of team members who are not present simultaneously; however, its adoption and value seem contingent on finding a good fit with the local context. A combination of continuous improvement and VM may be helpful in keeping the staff engaged in the change process in the long run. PMID- 26426328 TI - Correlation between Serum Levels of 3,3',5'-Triiodothyronine and Thyroid Hormones Measured by Liquid Chromatography-Tandem Mass Spectrometry and Immunoassay. AB - OBJECTIVE: For measuring serum 3,3',5'-triiodothyronine (rT3) levels, radioimmunoassay (RIA) has traditionally been used owing to the lack of other reliable methods; however, it has recently become difficult to perform. Meanwhile, liquid chromatography-tandem mass spectrometry (LC-MS/MS) has recently been attracting attention as a novel alternative method in clinical chemistry. To the best of our knowledge, there are no studies to date comparing results of the quantification of human serum rT3 between LC-MS/MS and RIA. We therefore examined the feasibility of LC-MS/MS as a novel alternative method for measuring serum rT3, thyroxine (T4), and 3,5,3'-triiodothyronine (T3) levels. METHODS: Assay validation was performed by LC-MS/MS using quality control samples of rT3, T4, and T3 at 4 various concentrations which were prepared from reference compounds. Serum samples of 50 outpatients in our department were quantified both by LC MS/MS and conventional immunoassay for rT3, T4, and T3. Correlation coefficients between the 2 measurement methods were statistically analyzed respectively. RESULTS: Matrix effects were not observed with our method. Intra-day and inter day precisions were less than 10.8% and 9.6% for each analyte at each quality control level, respectively. Intra-day and inter-day accuracies were between 96.2% and 110%, and between 98.3% and 108.6%, respectively. The lower limit of quantification was 0.05 ng/mL. Strong correlations were observed between the 2 measurement methods (correlation coefficient, T4: 0.976, p < 0.001; T3: 0.912, p < 0.001; rT3: 0.928, p < 0.001). CONCLUSIONS: Our LC-MS/MS system requires no manual cleanup operation, and the process after application of a sample is fully automated; furthermore, it was found to be highly sensitive, and superior in both precision and accuracy. The correlation between the 2 methods over a wide range of concentrations was strong. LC-MS/MS is therefore expected to become a useful tool for clinical diagnosis and research. PMID- 26426329 TI - Concurrent Relations between Face Scanning and Language: A Cross-Syndrome Infant Study. AB - Typically developing (TD) infants enhance their learning of spoken language by observing speakers' mouth movements. Given the fact that word learning is seriously delayed in most children with neurodevelopmental disorders, we hypothesized that this delay partly results from differences in visual face scanning, e.g., focusing attention away from the mouth. To test this hypothesis, we used an eye tracker to measure visual attention in 95 infants and toddlers with Down syndrome (DS), fragile X syndrome (FXS), and Williams syndrome (WS), and compared their data to 25 chronological- and mental-age matched 16-month-old TD controls. We presented participants with two talking faces (one on each side of the screen) and a sound (/ga/). One face (the congruent face) mouthed the syllable that the participants could hear (i.e., /ga/), while the other face (the incongruent face) mouthed a different syllable (/ba/) from the one they could hear. As expected, we found that TD children with a relatively large vocabulary made more fixations to the mouth region of the incongruent face than elsewhere. However, toddlers with FXS or WS who had a relatively large receptive vocabulary made more fixations to the eyes (rather than the mouth) of the incongruent face. In DS, by contrast, fixations to the speaker's overall face (rather than to her eyes or mouth) predicted vocabulary size. These findings suggest that, at some point in development, different processes or strategies relating to visual attention are involved in language acquisition in DS, FXS, and WS. This knowledge may help further explain why language is delayed in children with neurodevelopmental disorders. It also raises the possibility that syndrome specific interventions should include an early focus on efficient face-scanning behaviour. PMID- 26426330 TI - Re-Annotator: Annotation Pipeline for Microarray Probe Sequences. AB - Microarray technologies are established approaches for high throughput gene expression, methylation and genotyping analysis. An accurate mapping of the array probes is essential to generate reliable biological findings. However, manufacturers of the microarray platforms typically provide incomplete and outdated annotation tables, which often rely on older genome and transcriptome versions that differ substantially from up-to-date sequence databases. Here, we present the Re-Annotator, a re-annotation pipeline for microarray probe sequences. It is primarily designed for gene expression microarrays but can also be adapted to other types of microarrays. The Re-Annotator uses a custom-built mRNA reference database to identify the positions of gene expression array probe sequences. We applied Re-Annotator to the Illumina Human-HT12 v4 microarray platform and found that about one quarter (25%) of the probes differed from the manufacturer's annotation. In further computational experiments on experimental gene expression data, we compared Re-Annotator to another probe re-annotation tool, ReMOAT, and found that Re-Annotator provided an improved re-annotation of microarray probes. A thorough re-annotation of probe information is crucial to any microarray analysis. The Re-Annotator pipeline is freely available at http://sourceforge.net/projects/reannotator along with re-annotated files for Illumina microarrays HumanHT-12 v3/v4 and MouseRef-8 v2. PMID- 26426332 TI - Facilitators and barriers for electronic social support. AB - BACKGROUND: Nonprofit cancer societies play an important role in providing social support for patients with cancer through nonprofit electronic counselling services (ECS) provided by counselling nurses (CNs) with experience in oncology nursing. To date, there exist only few studies addressing the facilitators and barriers for social support of patients with cancer as reported by CNs. OBJECTIVE: To describe the facilitators and barriers for electronic social support of patients with cancer received from the ECS in the nonprofit cancer societies as reported by CNs. METHODS: Qualitative design with three group interviews was conducted with 10 CNs in three nonprofit cancer societies in southern and western parts of Finland. Interviews were recorded, transcribed verbatim and content analysed inductively. FINDINGS: The facilitators were promotion of the access to ECS, functioning structures of ECS, utilisation of the strengths of an individual CN in ECS, promotion of the life management of patients, patient-centeredness as a basis of ECS and reliability of ECS. The barriers for electronic social support were the unmet paths between ECS and patients, nonfunctioning structures of ECS, inadequacy of mutual communication and lack of shared viewpoints between CNs and patients. CONCLUSIONS: Facilitators and barriers for electronic social support of patients with cancer were related to organisation, individuals and counselling process. The counselling work in ECS as its best promotes the life management of patients with cancer but, alternatively, can lead to conflicts in communication and therefore be a barrier for electronic social support. IMPLICATIONS FOR PRACTICE: To make the nonprofit ECS better known, the cooperation with hospitals is needed to enable social support for patients. To improve communication between CNs and patients, continuous communications skills training and functional working environments are needed. PMID- 26426331 TI - Thermoresponsive release of viable microfiltrated Circulating Tumor Cells (CTCs) for precision medicine applications. AB - Stimulus responsive release of Circulating Tumor Cells (CTCs), with high recovery rates from their capture platform, is highly desirable for off-chip analyses. Here, we present a temperature responsive polymer coating method to achieve both release as well as culture of viable CTCs captured from patient blood samples. PMID- 26426333 TI - Potential Value of Cellulose Synthesis Inhibitors Combined With PHMB in the Treatment of Acanthamoeba Keratitis. AB - PURPOSE: The aim of this study was to improve the cytopathic effect (CPE) of antiamebic agents by combining with cellulose synthesis inhibitor as an encystation inhibitor. METHODS: Cellulose synthesis inhibitors, 2,6 dichlorobenzonitrile (DCB) and isoxaben were used to block encystation of Acanthamoeba during cultivation. Cultured human corneal epithelial (HCE) cells and Acanthamoeba were treated with polyhexamethylene biguanide (PHMB) combined with cellulose synthesis inhibitors to evaluate the CPE as an antiamebic agent. RESULTS: 0.02% PHMB showed a 51.9% CPE on HCE cells within 30 minutes but exhibited significant toxic effects on Acanthamoeba. At a level of 0.00125%, PHMB had no significant CPEs on HCE cells, whereas 100 MUM DCB and 10 MUM isoxaben significantly inhibited the formation of the inner cyst wall of Acanthamoeba during encystation, and Acanthamoeba trophozoites failed to convert into mature cysts. Although a low concentration (0.00125%) of PHMB was used, the novel combinations with 100 MUM DCB or 10 MUM isoxaben had 23.4% or 18.7% additional amebicidal effects on Acanthamoeba. However, 100 MUM DCB and 10 MUM isoxaben had no CPEs on HCE cells. CONCLUSIONS: The combination of cellulose synthesis inhibitors with low concentrations of PHMB reduced the CPE on HCE cells and improved the amebicidal effect on Acanthamoeba by inhibition of encystation. PMID- 26426334 TI - Depressive Symptoms in Patients With Dry Eye Disease: A Case-Control Study Using the Beck Depression Inventory. AB - PURPOSE: To measure depressive symptoms in patients with dry eye disease (DED) and controls using the Beck Depression Inventory (BDI) and to determine the association between depressive and DED symptoms. METHODS: Fifty-three patients with DED and 41 controls were recruited to the study. DED symptoms were assessed using the Symptom Burden Tool and Ocular Surface Disease Index tool. Depressive symptoms were assessed using the BDI. Regression diagnostics were performed to detect outliers. Linear statistical models and polynomial regression were used to determine the relationship between depressive symptoms and DED symptoms. An independent t test was performed to determine differences in BDI scores between cases and controls. Scatter plots were generated and linear regression was used to estimate the association between scores. Logistic regression was used for the DED dichotomous outcome and depression status as exposure. RESULTS: Regression models revealed that the association is linear more than quadratic or cubic. After adjusting for age, sex, race, and psychiatric medication, the regression coefficient between DED symptoms and depressive symptoms among DED cases was 1.22 (95% confidence interval, 0.27-2.18). DED symptom scores and depression scores were statistically significantly different between DED cases and controls. Adjusted logistic regression revealed an odds ratio of 2.79 (95% confidence interval, 0.96-8.12). CONCLUSIONS: This study provides further evidence regarding the association between DED and depression and their symptoms. Prospective studies are needed to understand the mechanisms underlying the association between symptoms of depression and symptoms of DED. PMID- 26426335 TI - Global Consensus on Keratoconus Diagnosis. PMID- 26426336 TI - Graphane versus graphene: a computational investigation of the interaction of nucleobases, aminoacids, heterocycles, small molecules (CO2, H2O, NH3, CH4, H2), metal ions and onium ions. AB - Graphane has emerged as a two-dimensional hydrocarbon with interesting physical properties and potential applications. Understanding the interaction of graphane with various molecules and ions is crucial to appreciate its potential applications. We investigated the interaction of nucleobases, aminoacids, saturated and unsaturated heterocycles, small molecules, metal ions and onium ions with graphane by using density functional theory calculations. The preferred orientations of these molecules and ions on the graphane surface have been analysed. The binding energies of graphane with these molecules have been compared with the corresponding binding energies of graphene. Our results reveal that graphane forms stable complexes with all the molecules and ions yet showing lesser binding affinity when compared to graphene. As an exemption, the preferential strong binding of H2O with graphane than graphene reveals the fact that graphane is more hydrophilic than graphene. Charge transfer between graphane and the molecules and ions have been found to be an important factor in determining the binding strength of the complexes. The effect of the interaction of these molecules and ions on the HOMO-LUMO energy gap of graphane has also been investigated. PMID- 26426337 TI - Genetic Testing for BRCA Mutations Today and Tomorrow-About the ABOUT Study. PMID- 26426339 TI - Hemoglobin oxidation at functional amino acid residues during routine storage of red blood cells. AB - BACKGROUND: Routine storage of red blood cells (RBCs) results in the progressive accumulation of storage lesions. While the clinical relevance of these lesions is still a matter of debate, alterations to RBC morphology and biochemistry, especially in terms of energy and redox homeostasis, are likely to affect RBC physiology and functionality at a minimum. Identification of oxidative modifications that accumulate on key RBC proteins will help bridge the gap between storage induced alterations and post-transfusion RBC viability. STUDY DESIGN AND METHODS: Five AS-3 units were analyzed during routine storage via one dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis-nano-high performance liquid chromatography coupled online with tandem mass spectrometry and advanced database searches. RESULTS: We identified oxidative modifications to functional residues of hemoglobin (Hb) beta chain, including proximal histidine, cysteine beta 94 (counting initiator methionine in the sequence), and histidine 144. Semiquantitative analysis indicates that up to approximately 20% of total Hb could be targeted by these oxidative modifications that are overlooked by standard proteomics approaches using routine database search conditions. Progressive accumulation of oxidized residues in stored RBCs and selective accumulation in vesicles was observed, further substantiating the hypothesis that vesiculation represents a self-protective mechanism in ageing RBCs. CONCLUSION: Several of the oxidized residues identified play well-established roles in heme iron coordination, 2,3-diphosphoglycerate binding, and nitric oxide homeostasis. Further functional and structural studies are necessary to determine possible associations between these modifications and impaired gas transport homeostasis in RBCs from old units. PMID- 26426338 TI - Rad and Rem are non-canonical G-proteins with respect to the regulatory role of guanine nucleotide binding in Ca(V)1.2 channel regulation. AB - Rad and Rem are Ras-like G-proteins linked to diverse cardiovascular functions and pathophysiology. Understanding how Rad and Rem are regulated is important for deepened insights into their pathophysiological roles. As in other Ras-like G proteins, Rad and Rem contain a conserved guanine-nucleotide binding domain (G domain). Canonically, G-domains are key control modules, functioning as nucleotide-regulated switches of G-protein activity. Whether Rad and Rem G domains conform to this canonical paradigm is ambiguous. Here, we used multiple functional measurements in HEK293 cells and cardiomyocytes (Ca(V)1.2 currents, Ca(2+) transients, Ca(V)beta binding) as biosensors to probe the role of the G domain in regulation of Rad and Rem function. We utilized Rad(S105N) and Rem(T94N), which are the cognate mutants to Ras(S17N), a dominant-negative variant of Ras that displays decreased nucleotide binding affinity. In HEK293 cells, over-expression of either Rad(S105N) or Rem(T94N) strongly inhibited reconstituted Ca(V)1.2 currents to the same extent as their wild-type (wt) counterparts, contrasting with reports that Rad(S105N) is functionally inert in HEK293 cells. Adenovirus-mediated expression of either wt Rad or Rad(S105N) in cardiomyocytes dramatically blocked L-type calcium current (I(Ca,L)) and inhibited Ca(2+)-induced Ca(2+) release, contradicting reports that Rad(S105N) acts as a dominant negative in heart. By contrast, Rem(T94N) was significantly less effective than wt Rem at inhibiting I(Ca,L) and Ca(2+) transients in cardiomyocytes. FRET analyses in cardiomyocytes revealed that both Rad(S105N) and Rem(T94N) had moderately reduced binding affinity for Ca(V)betas relative to their wt counterparts. The results indicate Rad and Rem are non-canonical G proteins with respect to the regulatory role of their G-domain in Ca(V)1.2 regulation. PMID- 26426340 TI - Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival? AB - Ipilimumab and tremelimumab are human monoclonal antibodies (Abs) against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival in advanced melanoma patients. Currently, there is no proven association between the BRAFV600 mutation and the disease control rate in response to ipilimumab. This analysis was carried out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The median overall survival, defined from the treatment start date with the anti-CTLA-4. Abs treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62) was 10.12 months (95% CI 6.78-13.2) compared to 8.26 months (95% CI 6.02 19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67). The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference didn't reach statistical significance (p = 0.56). 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with selected BRAF- or MEK inhibitors, 16 patients received anti-CTLA 4 Abs following either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles of treatment. Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs. PMID- 26426341 TI - External Validation of Models for Prediction of Lymph Node Metastasis in Urothelial Carcinoma of the Bladder. AB - PURPOSE: To externally validate models to predict LN metastsis; Karakiewicz nomogram, clinical nodal staging score (cNSS), and pathologic nodal staging score (pNSS) using a different cohort. MATERIALS AND METHODS: Clinicopathologic data from 500 patients who underwent radical cystectomy and pelvic lymphadenectomy were analyzed. The overall predictive values of models were compared with the criteria of overall performance, discrimination, calibration, and clinical usefulness. RESULTS: Presence of pN+ stages was recorded in 117 patients (23.4%). Agreement between clinical and pathologic stage was noted in 174 (34.8%). Based on Nagelkerke's peudo-R2 and brier score, pNSS demonstrated best overall performance. Area under the receiver operating characteristics curve, showed that pNSS had the best discriminatory ability. In all models, calibration was on average correct (calibration-in-the-large coefficient = zero). On decision curve analysis, pNSS performed better than other models across a wide range of threshold probabilities. CONCLUSIONS: When compared to pNSS, current precystectomy models such as the Karakiewicz nomogram and cNSS cannot predict the probability of LN metastases accurately. The findings suggest that the application of pNSS to Asian patients is feasible. PMID- 26426343 TI - Diversity and population structure of northern switchgrass as revealed through exome capture sequencing. AB - Panicum virgatum L. (switchgrass) is a polyploid, perennial grass species that is native to North America, and is being developed as a future biofuel feedstock crop. Switchgrass is present primarily in two ecotypes: a northern upland ecotype, composed of tetraploid and octoploid accessions, and a southern lowland ecotype, composed of primarily tetraploid accessions. We employed high-coverage exome capture sequencing (~2.4 Tb) to genotype 537 individuals from 45 upland and 21 lowland populations. From these data, we identified ~27 million single nucleotide polymorphisms (SNPs), of which 1 590 653 high-confidence SNPs were used in downstream analyses of diversity within and between the populations. From the 66 populations, we identified five primary population groups within the upland and lowland ecotypes, a result that was further supported through genetic distance analysis. We identified conserved, ecotype-restricted, non-synonymous SNPs that are predicted to affect the protein function of CONSTANS (CO) and EARLY HEADING DATE 1 (EHD1), key genes involved in flowering, which may contribute to the phenotypic differences between the two ecotypes. We also identified, relative to the near-reference Kanlow population, 17 228 genes present in more copies than in the reference genome (up-CNVs), 112 630 genes present in fewer copies than in the reference genome (down-CNVs) and 14 430 presence/absence variants (PAVs), affecting a total of 9979 genes, including two upland-specific CNV clusters. In total, 45 719 genes were affected by an SNP, CNV, or PAV across the panel, providing a firm foundation to identify functional variation associated with phenotypic traits of interest for biofuel feedstock production. PMID- 26426342 TI - Predicting Risk of Motor Vehicle Collisions in Patients with Glaucoma: A Longitudinal Study. AB - PURPOSE: To evaluate the ability of longitudinal Useful Field of View (UFOV) and simulated driving measurements to predict future occurrence of motor vehicle collision (MVC) in drivers with glaucoma. DESIGN: Prospective observational cohort study. PARTICIPANTS: 117 drivers with glaucoma followed for an average of 2.1 +/- 0.5 years. METHODS: All subjects had standard automated perimetry (SAP), UFOV, driving simulator, and cognitive assessment obtained at baseline and every 6 months during follow-up. The driving simulator evaluated reaction times to high and low contrast peripheral divided attention stimuli presented while negotiating a winding country road, with central driving task performance assessed as "curve coherence". Drivers with MVC during follow-up were identified from Department of Motor Vehicle records. MAIN OUTCOME MEASURES: Survival models were used to evaluate the ability of driving simulator and UFOV to predict MVC over time, adjusting for potential confounding factors. RESULTS: Mean age at baseline was 64.5 +/- 12.6 years. 11 of 117 (9.4%) drivers had a MVC during follow-up. In the multivariable models, low contrast reaction time was significantly predictive of MVC, with a hazard ratio (HR) of 2.19 per 1 SD slower reaction time (95% CI, 1.30 to 3.69; P = 0.003). UFOV divided attention was also significantly predictive of MVC with a HR of 1.98 per 1 SD worse (95% CI, 1.10 to 3.57; P = 0.022). Global SAP visual field indices in the better or worse eye were not predictive of MVC. The longitudinal model including driving simulator performance was a better predictor of MVC compared to UFOV (R2 = 0.41 vs R2 = 0.18). CONCLUSIONS: Longitudinal divided attention metrics on the UFOV test and during simulated driving were significantly predictive of risk of MVC in glaucoma patients. These findings may help improve the understanding of factors associated with driving impairment related to glaucoma. PMID- 26426344 TI - Integration of High-k Oxide on MoS2 by Using Ozone Pretreatment for High Performance MoS2 Top-Gated Transistor with Thickness-Dependent Carrier Scattering Investigation. AB - A top-gated MoS2 transistor with 6 nm thick HfO2 is fabricated using an ozone pretreatment. The influence to the top-gated mobility brought about by the deposition of HfO2 is studied statistically, for the first time. The top-gated mobility is suppressed by the deposition of HfO2 , and multilayered samples are less susceptible than monolayer ones. PMID- 26426345 TI - Exciton-phonon scattering and nonradiative relaxation of excited carriers in hydrothermally synthesized CdTe quantum dots. AB - Naturally formed CdTe/CdS core/shell quantum dot (QD) structures in the presence of surface stabilizing agents have been synthesized by a hydrothermal method. Size and temperature dependent photoluminescence (PL) spectra have been investigated to understand the exciton-phonon interaction, and radiative and nonradiative relaxation of carriers in these QDs. The PL of these aqueous CdTe QDs (3.0-4.8 nm) has been studied in the temperature range 15-300 K. The strength of the exciton-LO-phonon coupling, as reflected in the Huang-Rhys parameter 'S' is found to increase from 1.13 to 1.51 with the QD size varying from 4.8 to 3.0 nm. The PL linewidth (FWHM) increases with increase in temperature and is found to have a maximum in the case of QDs of 3.0 nm in size, where the exciton acoustic phonon coupling coefficient is enhanced to 51 MUeV K(-1), compared to the bulk value of 0.72 MUeV K(-1). To understand the nonradiative processes, which affect the relaxation of carriers, the integrated PL intensity is observed as a function of temperature. The integrated PL intensity remains constant until 50 K for relatively large QDs (3.9-4.8 nm) beyond which a thermally activated process takes over. Below 150 K, a small activation energy, 45-19 meV, is found to be responsible for the quenching of the PL. Above 150 K, the thermal escape from the dot assisted by scattering with multiple longitudinal optical (LO) phonons is the main mechanism for the fast quenching of the PL. Besides this high temperature quenching, interestingly for relatively smaller size QDs (3.4-3.0 nm), the PL intensity enhances as the temperature increases up to 90-130 K, which is attributed to the emission of carriers from interface/trap states having an activation energy in the range of 6-13 meV. PMID- 26426346 TI - Synthesis of Triborylalkenes from Terminal Alkynes by Iridium-Catalyzed Tandem C H Borylation and Diboration. AB - A two-step reaction to convert terminal alkynes into triborylalkenes is reported. In the first step, the terminal alkyne and pinacolborane (HBpin) are converted into an alkynylboronate, which is catalyzed by an iridium complex supported by a SiNN pincer ligand. In the second step, treatment of the reaction mixture with CO generates a new catalyst which mediates dehydrogenative diboration of alkynylboronate with pinacolborane. The mechanism of the diboration remains unclear but it does not proceed via intermediacy of hydroboration products or via B2 pin2. PMID- 26426347 TI - Resilience factors play an important role in the mental health of parents when children survive acute lymphoblastic leukaemia. AB - AIM: Childhood cancer is a tremendous stressor that requires parents to adapt to new challenges, and research has mainly focused on psychopathology and rarely on a resource-oriented perspective, such as resilience. This study assessed resilience factors among parents of children surviving acute lymphoblastic leukaemia and parents of healthy children. We also explored the association between parental resilience and mental health. METHODS: The study compared 57 parents of 40 children from eight to 15 years of age in remission from acute lymphoblastic leukaemia and 63 parents of 42 healthy children. The Resilience Scale for Adults and the General Health Questionnaire were used to assess parental resilience and mental health. RESULTS: Parents of children surviving acute lymphoblastic leukaemia showed significantly lower levels of resilience than parents of healthy children, but no significant difference was found for mental health. Certain resilience factors were positively associated with mental health, especially for mothers, such as family cohesion, good perception of self and being able to plan their future. CONCLUSION: Resilience factors may help to protect parents' mental health, especially mothers, when their child has survived acute lymphoblastic leukaemia and should be considered in a clinical setting. Further research on resilience factors for fathers is needed. PMID- 26426353 TI - Self-management for people with poorly controlled epilepsy: Participants' views of the UK Self-Management in epILEpsy (SMILE) program. AB - BACKGROUND: Epilepsy is a long-term condition that requires self-management, but currently, there is no well-evaluated epilepsy self-education or self-management intervention in the United Kingdom (UK). AIM: The aim of this study was to examine the views and experiences of the first participants of the Self Management in epILEpsy UK (SMILE UK) program to assist the development of a full trial. METHOD: In-depth semistructured interviews and group discussions were conducted with 10 people with poorly controlled epilepsy to explore their views and experiences of the self-management program. Interviews were audio-recorded, transcribed, and analyzed thematically. RESULTS: All participants viewed the program positively. Three themes emerged: i) peer support was experienced through knowledge sharing, disclosure of experiences, and exchange of contact details; ii) participants felt better equipped to enter discussions with doctors and other health-care professionals about their condition; and iii) participants reported an improvement in their personal life through increased confidence to live with epilepsy and acceptance of their diagnosis. CONCLUSION: A brief group self management intervention increased knowledge and confidence in managing epilepsy. PMID- 26426352 TI - The pharmacokinetic and pharmacodynamic interaction of clopidogrel and cilostazol in relation to CYP2C19 and CYP3A5 genotypes. AB - AIM: The primary objective of the present study was to evaluate the pharmacokinetic and pharmacodynamic interactions between clopidogrel and cilostazol in relation to the CYP2C19 and CYP3A5 genotypes. METHODS: In a randomized, three-way crossover study, 27 healthy subjects were administered clopidogrel (300 mg), cilostazol (100 mg) or clopidogrel + cilostazol orally. Plasma concentrations of clopidogrel, cilostazol and their active metabolites (clopidogrel thiol metabolite, 3,4-dehydrocilostazol and 4"-trans hydroxycilostazol), and adenosine diphosphate-induced platelet aggregation were measured for pharmacokinetic and pharmacodynamic assessment. RESULTS: The area under the plasma concentration-time curve (AUC) of the active thiol metabolite of clopidogrel was highest in the CYP2C19 extensive metabolizers (EM) and lowest in the poor metabolizers (PM). Cilostazol decreased the thiol metabolite AUC by 29% in the CYP3A5*1/*3 genotype [geometric mean ratio (GMR) 0.71; 90% confidence interval (CI) 0.58, 0.86; P = 0.020] but not in the CYP3A5*3/*3 genotype (GMR 0.93; 90% CI 0.80, 1.10; P = 0.446). Known effects of the CYP2C19 and CYP3A5 genotypes on the exposure of cilostazol and its metabolites were observed but there was no significant difference in the AUC of cilostazol and 3,4 dehydrocilostazol between cilostazol and clopidogrel + cilostazol. The inhibition of platelet aggregation from 4 h to 24 h (IPA4-24 ) following the administration of clopidogrel alone was highest in the CYP2C19 EM genotype and lowest in the CYP2C19 PM genotype (59.05 +/- 18.95 vs. 36.74 +/- 13.26, P = 0.023). However, the IPA of the CYP2C19 PM following co-administration of clopidogrel and cilostazol was comparable with that of the CYP2C19 EM and intermediate metabolizers (IM) only in CYP3A5*3/*3 subjects. CONCLUSIONS: The additive antiplatelet effect of cilostazol plus clopidogrel is maximized in subjects with both the CYP2C19 PM and CYP3A5*3/*3 genotypes because of a lack of change of clopidogrel thiol metabolite exposure in CYP3A5*3/*3 as well as the highest cilostazol IPA in CYP2C19 PM and CYP3A5*3/*3 subjects. PMID- 26426354 TI - A TaqMan-Based Multiplex qPCR Assay and DNA Extraction Method for Phylotype IIB Sequevars 1&2 (Select Agent) Strains of Ralstonia solanacearum. AB - Ralstonia solanacearum race 3 biovar 2 strains belonging to phylotype IIB, sequevars 1 and 2 (IIB-1&2) cause brown rot of potato in temperate climates, and are quarantined pathogens in Canada and Europe. Since these strains are not established in the U.S. and because of their potential risk to the potato industry, the U.S. government has listed them as select agents. Cultivated geraniums are also a host and have the potential to spread the pathogen through trade, and its extracts strongly inhibits DNA-based detection methods. We designed four primer and probe sets for an improved qPCR method that targets stable regions of DNA. RsSA1 and RsSA2 recognize IIB-1&2 strains, RsII recognizes the current phylotype II (the newly proposed R. solanacearum species) strains (and a non-plant associated R. mannitolilytica), and Cox1 recognizes eight plant species including major hosts of R. solanacearum such as potato, tomato and cultivated geranium as an internal plant control. We multiplexed the RsSA2 with the RsII and Cox1 sets to provide two layers of detection of a positive IIB-1&2 sample, and to validate plant extracts and qPCR reactions. The TaqMan-based uniplex and multiplex qPCR assays correctly identified 34 IIB-1&2 and 52 phylotype II strains out of 90 R. solanacearum species complex strains. Additionally, the multiplex qPCR assay was validated successfully using 169 artificially inoculated symptomatic and asymptomatic plant samples from multiple plant hosts including geranium. Furthermore, we developed an extraction buffer that allowed for a quick and easy DNA extraction from infected plants including geranium for detection of R. solanacearum by qPCR. Our multiplex qPCR assay, especially when coupled with the quick extraction buffer method, allows for quick, easy and reliable detection and differentiation of the IIB-1&2 strains of R. solanacearum. PMID- 26426355 TI - Nanostructured Carbon Allotropes with Weyl-like Loops and Points. AB - Carbon allotropes are subject of intense investigations for their superb structural, electronic, and chemical properties, but not for topological band properties because of the lack of strong spin-orbit coupling (SOC). Here, we show that conjugated p-orbital interactions, common to most carbon allotropes, can in principle produce a new type of topological band structure, forming the so-called Weyl-like semimetal in the absence of SOC. Taking a structurally stable interpenetrated graphene network (IGN) as example, we show, by first-principles calculations and tight-binding modeling, that its Fermi surface is made of two symmetry-protected Weyl-like loops with linear dispersion along perpendicular directions. These loops are reduced to Weyl-like points upon breaking of the inversion symmetry. Because of the topological properties of these band-structure anomalies, remarkably, at a surface terminated by vacuum there emerges a flat band in the loop case and two Fermi arcs in the point case. These topological carbon materials may also find applications in the fields of catalysts. PMID- 26426358 TI - Health Human Resources Guidelines: Minimum staffing standards for cystic fibrosis health care teams. PMID- 26426357 TI - Ruthenium catalysts for water oxidation involving tetradentate polypyridine-type ligands. AB - A series of Ru(II) complexes that behave as water oxidation catalysts were prepared involving a tetradentate equatorial ligand and two 4-substituted pyridines as the axial ligands. Two of these complexes were derived from 2,9-di (pyrid-2'-yl)-1,10-phenanthroline (dpp) and examine the effect of incorporating electron-donating amino and bulky t-butyl groups on catalytic activity. A third complex replaced the two distal pyridines with N-methylimidazoles that are more electron-donating than the pyridines of dpp and potentially stabilize higher oxidation states of the metal. The tetradentate ligand 2-(pyrid-2'-yl)-6 (1'',10''-phenanthrol-2''-yl)pyridine (bpy-phen), possessing a bonding cavity similar to dpp, was also prepared. The Ru(II) complex of this ligand does not have two rotatable pyridines in the equatorial plane and thus shows different flexibility from the [Ru(dpp)] complexes. All the complexes showed activity towards water oxidation. Investigation of their catalytic behavior and electrochemical properties suggests that they may follow the same catalytic pathway as the prototype [Ru(dpp)pic2](2+) involving a seven-coordinated [Ru(IV)(O)] intermediate. The influence of coordination geometry on catalytic performance is analyzed and discussed. PMID- 26426356 TI - Positron emission tomography quantification of serotonin transporter binding in medication-free bipolar disorder. AB - OBJECTIVES: Bipolar disorder (BD) is associated with abnormalities in the serotonin transporter (5-HTT), but specific in vivo findings have been discrepant. Using positron emission tomography (PET) and [(11)C]DASB, we compared 5-HTT binding between unmedicated depressed BD subjects and healthy volunteers (HVs). EXPERIMENTAL DESIGN: 5-HTT binding in six brain regions was compared between 17 depressed, unmedicated BD subjects and 31 HVs, using the outcome measure of VT/fP (proportional to the total number of available transporters). Alternative outcome measures were examined as well. 47% of BD were BP I; and 65% reported a prior suicide attempt. PRINCIPAL OBSERVATIONS: 5-HTT binding (VT/fP ) did not differ between BD and HV groups considering six brain regions of interest simultaneously (P = 0.24). In contrast, alternative outcome measures (BPF*, BPP*, and BPND*) indicated lower binding in BD compared with HV across these six regions of interest (BPF*: P = 0.047; BPP*: P = 0.032; BPND*: P = 0.031). 5-HTT binding was unrelated to suicide attempt history, depression severity, bipolar subtype, or history of past substance use disorder. CONCLUSIONS: Choice of outcome measure strongly affects comparisons of serotonin transporter binding using PET with [(11)C]DASB. We do not find evidence of abnormal 5-HTT binding in bipolar depression using our primary outcome measure, VT /fP . However, we did observe lower 5-HTT binding in BD with alternative outcome measures that are frequently used with [(11)C]DASB. Relative merits and assumptions of different outcome measures are discussed. Evaluation in larger samples and during different mood states, including remission, is warranted. PMID- 26426359 TI - An adverse reaction in a pediatric sleep laboratory. PMID- 26426361 TI - From Dispersed Microspheres to Interconnected Nanospheres: Carbon-Sandwiched Monolayered MoS2 as High-Performance Anode of Li-Ion Batteries. AB - Hierarchical structured carbon@MoS2 (C@MoS2) microspheres and nanospheres composed of carbon-sandwiched monolayered MoS2 building blocks are synthesized through a facile one-pot polyvinylpyrrolidone (PVP) micelle-assisted hydrothermal route. The dimension and carbon content of C@MoS2 spheres are effectively controlled by singly adjusting the concentration of PVP, which plays the dual functions of soft-template and carbon source. As the anode materials of Li-ion batteries, C@MoS2 nanospheres present considerably higher capacity, better rate behavior and cycling stability than C@MoS2 microspheres. The reasons are attributed to the unique interconnected nanospherical morphology and the internal hierarchical construction of C@MoS2 nanospheres with expanded MoS2/carbon interlayer spacing. PMID- 26426360 TI - Compensatory Effect between Aortic Stiffening and Remodelling during Ageing. AB - The arterial tree exhibits a complex spatio-temporal wave pattern, whose healthy behaviour depends on a subtle balance between mechanical and geometrical properties. Several clinical studies demonstrated that such a balance progressively breaks down during ageing, when the aorta stiffens and remodels by increasing its diameter. These two degenerative processes however, have different impacts on the arterial wave pattern. They both tend to compensate for each other, thus reducing the detrimental effect they would have had if they had arisen individually. This remarkable compensatory mechanism is investigated by a validated multi-scale model, with the aim to elucidate how aortic stiffening and remodelling quantitatively impact the complex interplay between forward and reflected backward waves in the arterial network. We focus on the aorta and on the pressure at the ventricular-aortic interface, which epidemiological studies demonstrate to play a key role in cardiovascular diseases. PMID- 26426362 TI - Toll-like receptors 2, 4, and 9 in primary, metastasized, and recurrent oral tongue squamous cell carcinomas. AB - BACKGROUND: Toll-like receptors (TLRs) are pattern-recognizing proteins involved in innate immunity and they seem to regulate both cancer progression and inhibition. In oral cancer, TLR activation has been linked to invasion. To define the role of TLR-2, TLR-4, and TLR-9 in oral tongue squamous cell carcinoma (OTSCC), we studied their expression in vivo in OTSCC tumor samples, as well as in vitro in cell invasion model. METHODS: We used immunohistochemistry to compare the expression of TLR-2, TLR-4, and TLR-9 in 21 primary Stage I-II OTSCCs, neck metastases, and recurrent tumors. In addition, we used myoma organotypic invasion assay to evaluate the effect of GIT27 (4,5-dihydro-3-phenyl-5 isoxasoleaceticacid) on the invasion of the HSC-3 OTSCC cell line. RESULTS: TLR 2, TLR-4, and TLR-9 were expressed in most tumors. Nuclear TLR-2 expression occurred more often in primary tumors than in neck metastases or recurrent tumors of the neck, whereas nuclear TLR-4 expression and cytoplasmic TLR-9 expression were higher in primary tumors than in local recurrent tumors. GIT27 did not affect the invasion of HSC-3 OTSCC cells, but a myoma organotypic invasion assay revealed that the expression of TLR-2 and TLR-4 was stronger in deeper-invading cells. CONCLUSIONS: TLR-2, TLR-4, and TLR-9 were expressed in primary tumors, neck metastases as well as in recurrent tumors of OTSCC. Thus, these receptors seem to play a role in both the development and progression of tongue carcinoma. These TLRs may also contribute to the invasive potential of OTSCC. PMID- 26426363 TI - Conditioned Medium From Mesenchymal Stem Cells Enhances Early Bone Regeneration After Maxillary Sinus Floor Elevation in Rabbits. AB - PURPOSE: Conditioned medium from stem cells contains growth factors and has a promising prospect for use in regenerative medicine. In this study, the effects of marrow-derived stem cell-conditioned medium (MSC-CM) on bone regeneration after maxillary sinus floor elevation were examined in rabbits. MATERIALS AND METHODS: Rabbit bone marrow-derived stem cells (rMSCs) were cultured with MSC-CM for 48 hours, and their mobilization and proliferation were evaluated. Beta tricalcium phosphate scaffolds were impregnated with MSC-CM and grafted in the rabbit maxillary sinus cavities. At 2, 4, and 8 weeks after transplantation, sections of the newly formed bone were evaluated histologically and by immunohistochemical staining. RESULTS: MSC-CM increased the migration and proliferation of rMSCs and the early bone regeneration in rabbit sinus. Cell proliferation and vascularization were increased at 2 weeks after implantation of grafts impregnated with MSC-CM compared to controls, indicating that MSC-CM is effective at the early phase of bone regeneration. CONCLUSION: MSC-CM is a promising novel therapeutic agent to promote bone regeneration after maxillary sinus floor elevation. PMID- 26426364 TI - Acute hemorrhagic complications are associated with lower coated-platelet levels in non-lacunar brain infarction. AB - BACKGROUND: Coated platelets are procoagulant platelets observed upon dual agonist stimulation with collagen and thrombin. Coated-platelet levels are elevated in patients with non-lacunar ischemic stroke and decreased in patients with spontaneous intracerebral hemorrhage as compared with controls. OBJECTIVE: To investigate whether acute hemorrhagic complications occurring during the initial hospital admission for non-lacunar ischemic stroke are associated with lower coated-platelet levels. PATIENTS/METHODS: Coated-platelet levels were determined in 385 consecutive patients with non-lacunar stroke. Hemorrhagic complications were defined as either intracranial hemorrhage or significant extracranial bleeding (drop in hemoglobin of >= 2 g dL(-1) ). The rate of acute hemorrhagic complication was compared among subjects categorized into tertiles of coated-platelet levels using an exact Cochrane-Armitage trend test. Logistic regression was used to estimate the adjusted odds of hemorrhagic complication associated with coated-platelet levels. RESULTS: Hemorrhagic complications were present in 15 (3.9%) cases. Of these, four had intracranial hemorrhage and 11 had extracranial hemorrhage. The occurrence of hemorrhagic complications differed among the coated-platelet tertiles: 10.2% for the first tertile (coated-platelet levels < 35.5%), 1.5% for the second tertile and 0% for the third tertile (coated platelet levels >= 47.5%, trend test). Logistic regression showed that the odds of hemorrhagic complication in those with levels < 35.5% were 14.59 times the odds for patients with levels >= 35.5% (95% CI: 3.24-65.7). CONCLUSIONS: Lower levels of procoagulant platelets are associated with acute hemorrhagic complications following non-lacunar ischemic stroke. These results suggest a role for coated-platelets in risk/benefit assessment in the early stages of stroke. PMID- 26426370 TI - Unusual bonding modes of perfluorobenzene in its polymeric (dimeric, trimeric and tetrameric) forms: entirely negative fluorine interacting cooperatively with entirely negative fluorine. AB - The F(delta-)...F(delta-) intermolecular synthon was recently observed to be useful for generating a two-dimensional layered supramolecular architecture on the Ag(111) surface (Kawai, et al., ACS Nano, 2015). This was formed when the entirely negative covalently bonded fluorine atoms in phenyleneethynylene(bis(2,3,5,6-tetrafluoro-4-(2,3,4,5,6 pentafluorophenylethynyl)phenyl)-ethyne (BPEPE-F18)) were in close proximity to the same atoms in another BPEPE-F18 molecule. With a view to provide rigorous insights into the physical chemistry of such an intermolecular synthon, we have selected perfluorobenzene (C6F6) as a model compound, and have performed extensive DFT-M06-2X/6-311++G(d,p) investigations on a number of its homomolecular dimers, trimers, and tetramers. Of the twelve (C6F6)2 dimers investigated, a displaced-parallel arrangement with an uncorrected binding energy (DeltaE) of -7.4 kcal mol(-1) was found to be the most stable, and an incorporation of the basis set superposition error (BSSE) has significantly reduced its DeltaE to -4.7 kcal mol(-1). Besides, the DeltaE for a minimum-energy least stable conformation of the same dimer, which involves a single sigmahole( )...sigmahole(-) type F(delta-)...F(delta-) intermolecular bonding interaction, amounts to -0.62 and -0.24 kcal mol(-1) without and with BSSE, respectively. The geometry of another conformation of the dimer, which accompanies a set of three F(delta-)...F(delta-) intermolecular interactions somehow similarly to those observed in the layered supramolecular structure formed by the BPEPE-F18 molecules, lies at a relative energy of 6.5 kcal mol(-1) above the most stable conformation. Passing from the latter dimer to an analogous (C6F6)3 trimer, as well as from the trimer to an analogous (C6F6)4 tetramer, the latter two clusters comprising windmill-type F(delta-)...F(delta-) intermolecular topologies, we have marked a preferential increase in the value of DeltaE from -0.94 (dimer) to -2.76 (trimer) to -4.49 kcal mol(-1) (tetramer), thereby suggesting the presence of cooperative binding. An energy decomposition analysis has revealed that dispersion and polarization are the principal driving forces that bring the C6F6 molecules together in complex configurations. While a reasonable agreement was found between the charge density based topological results of the intermolecular bonding interactions that emerged from the application of Quantum Theory of Atoms in Molecules (QTAIM) and Reduced Density Gradient approaches to all the polymeric compounds, the results of the latter method were found to be too vague especially near the (3, +1) ring critical point regions. QTAIM's source function analysis has suggested that the fully negatively charged fluorine atoms in C6F6 serve as sinks for the F(delta-)...F(delta-) bond formation. PMID- 26426371 TI - Erratum. PMID- 26426372 TI - Exhaled breath analysis, a simple tool to study the pathophysiology of obstructive sleep apnoea. AB - Accelerated airway inflammation may play a crucial role in the pathophysiology of obstructive sleep apnoea (OSA); however this phenomenon has been investigated only in a limited number of studies. The analysis of exhaled breath represents a promising, non-invasive tool to evaluate airway inflammation in this context. The knowledge on exhaled biomarkers in OSA has been growing with an emerging number of methodological studies which help to interpret exhaled breath data. This article not only summarises the results of studies on exhaled breath condensate (EBC) biomarkers, exhaled volatile compounds and exhaled monoxides in OSA, but also aims to critically review methodological limitations and provide some guideline for further research. PMID- 26426374 TI - Nutritional status and dental fluorosis among schoolchildren in communities with different drinking water fluoride concentrations in a central region in Mexico. AB - Poor water quality and under nutrition are important factors affecting the health of many communities in developing countries. The aims of this study were: i) to describe the fluoride water concentration and the hydrogeological conditions in a region of a state located in the central in Mexico ii) to measure the association between undernutrition and dental fluorosis in children living in communities with different drinking water fluoride concentrations in a state located in the central region of Mexico. METHODS: Field work was performed in the region to identify the prevailing groundwater flow characteristics and water wells were sampled to analyze water fluoride concentration. Children were selected from three communities that had different drinking water fluoride concentrations (i.e., 0.56, 0.70 and 1.60 mg/l). Fluoridated salt was available in these communities. The Thylstrup-Fejerskov Index (TFI) was used to assess dental fluorosis. Categories four or higher of this index involve changes in the entire tooth surface (ITF >= 4). The weight and height of the children were measured. The assessment of undernutrition was based on the World Health Organization criteria: children were classified as being at risk of low-height (Height-for-Age Z score < - 1.0 SD) and having low-height (Height-for-Age Z score < - 2.0 SD) for age and sex, the same cutoff points of the Z score were used to classify "risk of low-weight" and" low-weight children". RESULTS: In the region the mineralization of the water captured by the wells is the result of a reaction with volcanic materials. The water fluoride concentration in the region ranged from 0.2 to 1.6 mg/l. A total of 734 schoolchildren participated in the study. The percentage of children in fluorosis categories (ITF >= 4) was 15.9%, 21.1% of the children were at risk of low height-for-age, and 8.0% had low height-for-age. The percentage of children with fluorosis (ITF >= 4) was 6.3%, 9.1% and 31.9% (p ? 0.001) and low high-for-age was 2.9%, 2.5% and 8.4% (p ? 0.001), for the communities with F concentrations of 0.56 mg/l, 0.70 mg/l and 1.6 mg/l, respectively. The logistic regression model showed an association between dental fluorosis (TFI >= 4) and low height-for-age (OR 2.09, p = 0.022) after adjusting for sex, number of teeth erupted, source of drinking water, use of fluoridated toothpaste and tap water fluoride concentration in the community. CONCLUSION: Children with low height-for age were more likely to have dental fluorosis in the TFI categories that affect the entire tooth surface. The results suggest that subpopulations with chronic undernutrition are more susceptible to dental fluorosis. PMID- 26426373 TI - Identification and BAC construction of Han, the first characterized HCMV clinical strain in China. AB - Human cytomegalovirus (HCMV) is the leading infectious cause of birth defects, and may lead to severe or lethal diseases in immunocompromised individuals. Several HCMV strains have been identified and widely applied in research, but no isolate from China has been characterized. In the present study, we isolated, characterized and sequenced the first Chinese HCMV clinical strain Han, and constructed the novel and functional HCMV infectious clone Han-BAC-2311. HCMV Han was isolated from the urine sample of a Chinese infant with multiple developmental disorders. It expresses HCMV specific proteins and contains a representative HCMV genome with minor differences compared to other strains. By homologous recombination using mini-F derived BAC vector pUS-F6, the infectious clone Han-BAC-2311 was constructed containing representative viral genes across the HCMV genome. The insertion site and orientation of BAC sequence were confirmed by restriction enzyme digestion and Southern blotting. The reconstituted recombinant virus HanBAC-2311 expresses typical viral proteins with the same pattern as that of wild-type Han, and also displayed a similar growth kinetics to wild-type Han. The identification of the first clinical HCMV strain in China and the construction of its infectious clone will greatly facilitate the pathogenesis studies and vaccine development in China. PMID- 26426375 TI - MuSIC report III: tumour microcirculation patterns and development of metastasis in long-term follow-up of melanocytic uveal tumours. AB - PURPOSE: To statistically determine differences in microcirculation patterns between nevi and uveal melanomas and the influence of these patterns on metastatic potential in the long-term follow-up of 112 patients with melanocytic uveal tumours. In vivo markers indicating malignancy and metastatic potential have implications for treatment decision. METHODS: Primary diagnosis and work-up included clinical examination, fundus photography, standardized A and B scan echography as well as evaluation of tumour microcirculation patterns via confocal fluorescein and indocyanine green angiography (ICGA). Patient data were collected from the patient files, the tumour registry or personal contact. Statistical analysis was performed with spss 22.0 using chi-square, Fisher's exact test and Kaplan-Meier survival analysis. RESULTS: Forty-three uveal melanocytic lesions remained untreated and were retrospectively classified as benign nevi, whereas 69 lesions were malignant melanomas (T1: 32, T2: 28, T3: 6 and T4: 3). 'Silent' and 'arcs without branching' were found significantly more often in nevi (p = 0.001 and p = 0.010), whereas 'parallel with cross-linking' and 'networks' were significantly more frequent in melanomas (p = 0.022 and p = 0.029). The microcirculation pattern 'parallel with cross-linking' proved significantly more frequent in patients who developed metastases (p = 0.001). CONCLUSIONS: Certain microcirculation patterns may guide us in differentiating uveal nevi from malignant melanomas. A non-invasive prognostic marker can be of great value for borderline lesions in which cytology is less likely taken. 'Parallel with cross linking' did not only indicate malignancy, but it was also associated with later tumour metastasis. PMID- 26426376 TI - Recurrent proliferating trichilemmal cyst of the scalp. AB - Pilar tumors, commonly called trichilemmal cysts, are usually benign in nature, malignant transformation (so called proliferating pilar tumors or proliferating trichilemmal cysts [PTCs]) with high recurrence rates, local invasion and metastases have been described. A 64-year-old women presented to our hospital with a recurrent ulcerated mass lesion of the scalp. Non-contrast-enhanced computed tomography scan of the head was performed. The mass was managed by complete excisional biopsy and the defect closure was achieved by using a full thickness skin graft. Histopathological analysis revealed the characteristic structures of PTC; in addition foci of squamous pearls, squamous cells with pleomorphic nuclei suggestive of cellular atypia and increased typical mitotic activity were also noticed. PTCs are related to high recurrency rates, local invasion and possible metastases. Radical surgical treatment and precise histological analysis are essential in order to achieve a fast and complete healing. Cooperation of the clinician and the pathologist is essential for accurate diagnosis, treatment and follow-up planning. PMID- 26426377 TI - Inflammatory linear verrucous epidermal nevus: an unusual manifestation. PMID- 26426378 TI - Performance of a Branch Chain RNA In Situ Hybridization Assay for the Detection of High-risk Human Papillomavirus in Head and Neck Squamous Cell Carcinoma. AB - High-risk human papillomavirus (HR-HPV) is a major etiologic agent in a subset of head and neck squamous cell carcinomas (HNSCCs), and its recognition has prognostic and predictive implications. The availability of a sensitive and specific test to assess HR-HPV status is limited. We evaluate an RNA in situ hybridization (ISH) method using branch chain technology to detect HR-HPV and compare its results with DNA ISH, p16 immunohistochemistry, and polymerase chain reaction (PCR). Tissue sections from 54 patients were stained with a manual RNA ISH assay (ViewRNA), which detects 14 HR-HPV types, an automated DNA ISH assay, and p16 immunohistochemistry. Most cases (83%, n=45) were also tested on an automated platform for 14 HR-HPV types and 1 limited to HPV 16/18. PCR was performed in all cases and was successful in 93% (n=50). The RNA ISH assay produced results in 96% of the cases with strong signals and was easily interpreted. HR-HPV was detected in more cases (63%, n=34) by RNA ISH than by DNA ISH (39%, n=21). Compared with PCR, both ISH platforms were 94% specific. RNA ISH was more sensitive (91%) than DNA ISH (65%), and RNA ISH correlated more strongly with p16 immunostaining. HPV 16 represented 89% of HR-HPV detected. The cocktail HPV 16/18 platform was concordant with the pooled HR-HPV assay in all expected cases. The automated assay demonstrated high concordance (96%) with the manual version, showed decreased background, and should allow for easy implementation into the workflow of the diagnostic pathology laboratory. PMID- 26426379 TI - Do Clear Cell Papillary Renal Cell Carcinomas Have Malignant Potential? AB - There have been no recurrences or metastases of clear cell papillary renal cell carcinoma (CCPRCC) in 268 reported cases with follow-up in the English-language literature. We identified all our cases of CCPRCC (1990 to 2013), reviewing all cases that preceded the formal designation of the entity. Immunohistochemical stains were performed on 32 cases during their initial workup. In addition, stains for carbonic anhydrase IX and cytokeratin 7 were performed on 2 cases, one with atypical follow-up and the other with a more compact morphology, although not performed initially. An extended panel with AMACR, CD10, and renal cell carcinoma (RCC) was added to the case with atypical follow-up. Fluorescence in situ hybridization for chromosomes 3p, 7, and 17 was performed on the latter case and on another clinically presumed metastatic tumor. In classic cases, immunohistochemical staining was not performed. Fifty-eight patients (31 women; 27 men) with follow-up data were included in our study; 39 cases were from our consult service. The patients' ages ranged from 36 to 83 years. Thirty-five patients had cystic or partially cystic lesions; 6 tumors were multifocal, 3 of which were bilateral. The majority (53 patients; 91.4%) presented with stage pT1 disease (size range, 0.2 to 8 cm), 2 patients presented with pT2 disease (8.5 and 10.3 cm), 1 patient presented with pT3 disease (6.5 cm sarcomatoid RCC focally extending out of the kidney), and pathologic stage was unavailable in 2 cases. Treatment consisted of 29 partial nephrectomies, 26 radical nephrectomies, 2 cryoablations, and 1 cyst ablation. The resection margins were negative in all but one case, with this case disease free after a 26-month period. Two patients had intraoperative tumor disruption and were disease free at 9 and 34 months. Five patients had synchronous ipsilateral renal cell carcinomas (non-CCPRCC). Mean follow-up time was 21 months (range, 1 to 175 mo), with all but 3 patients having no evidence of disease. One patient was presumed to have contralateral disease on the basis of imaging findings and is alive and well 37 months after multiple partial nephrectomies. Metastatic disease to the lung was clinically presumed in 1 patient in whom a higher-grade lesion may have been missed during sampling of the predominantly cystic pT1b tumor and tissue confirmation of the metastases was not obtained. Another case presented with multiple skeletal and pulmonary metastases 8 months after resection of pT3 sarcomatoid CCPRCC. The patient with the sarcomatoid RCC died of multifocal skeletal and pulmonary metastatic disease 13 months after resection of the renal tumor. Our study, the largest to date with follow-up, along with others, suggests that pure CCPRCC is an indolent tumor and should be renamed "clear cell papillary neoplasm of low malignant potential" to reflect their biology. PMID- 26426380 TI - Perineural Invasion is a Strong Prognostic Factor in Colorectal Cancer: A Systematic Review. AB - Perineural invasion (PNI) is a possible route for metastatic spread in various cancer types, including colorectal cancer (CRC). PNI is linked to poor prognosis, but systematic analyses are lacking. This study systematically reviews the frequency and impact of PNI in CRC. A literature search was performed using PubMed database from inception to January 1, 2014. Data were analyzed using Review Manager 5.3. A quality assessment was performed on the basis of modified REMARK criteria. Endpoints were local recurrence (LR), 5-year disease-free survival (5yDFS), 5-year cancer-specific survival (5yCSS), and 5-year overall survival (5yOS). Meta-analysis was performed in terms of risk ratios (RR) and hazard ratios (HR) with 95% confidence interval (95% CI). In this meta-analysis, 58 articles with 22,900 patients were included. PNI was present in 18.2% of tumors. PNI is correlated with increased LR (RR 3.22, 95% CI, 2.33-4.44) and decreased 5yDFS (RR 2.35, 95% CI, 1.66-3.31), 5yCSS (RR 3.61, 95% CI, 2.76-4.72), and 5yOS (RR 2.09, 95% CI, 1.68-2.61). In multivariate analysis PNI remains an independent prognostic factor for 5yDFS, 5yCSS, and 5yOS (HR 2.35, 95% CI, 1.97 3.08; HR 1.91, 95% CI, 1.50-2.42; and HR 1.85, 95% CI, 1.63-2.12, respectively). We confirmed the strong impact of PNI for LR and survival in CRC. The prognostic value of PNI is similar to that of well-established prognostic factors as depth of invasion, differentiation grade, lymph node metastases, and lymphatic and extramural vascular invasion. Therefore, PNI should be one of the factors in the standardized reporting of CRC and might be considered a high-risk feature. PMID- 26426382 TI - Carcinoma of the Uterine Cervix Involving the Genitourinary Tract: A Potential Diagnostic Dilemma. AB - Uterine cervical carcinoma secondarily involving the genitourinary tract is rarely documented histologically. These tumors present a unique diagnostic challenge as they can appear morphologically similar to urothelial carcinoma as well as primary squamous cell carcinoma and primary adenocarcinoma of the bladder. Genitourinary consult cases at the Johns Hopkins Hospital from 1984 to the present were searched for cases in which the differential diagnosis was primary bladder carcinoma versus secondary involvement by cervical carcinoma. We identified 10 cases that met these criteria and evaluated them by immunohistochemistry for p16 and GATA3 and in situ hybridization for human papillomavirus (HPV). Six cases were received with a gynecologic history. Four cases had been misdiagnosed as urothelial carcinoma, and 1 case was favored to be cystitis cystica et glandularis by the submitting institutions. Morphologically, the majority of cases showed basaloid nests of tumor cells infiltrating muscle bundles, with several having foci that mimicked urothelial carcinoma in situ. Six tumors were found to be diffusely positive with p16, 1 tumor was patchy, 1 was weak, and 2 were negative. GATA3 staining was negative in 6 cases, and 4 showed weak to strong positivity. Eight cases were positive for high-risk HPV (6 were positive for HPV 16, and 1 was positive for HPV 18). In the 2 cases that were negative for HPV by in situ hybridization, characteristic morphologic features of HPV-unrelated type of endocervical adenocarcinoma were present. On the basis of our findings we advocate a multifaceted approach, combining morphologic evaluation with ancillary studies including immunohistochemistry and in situ hybridization in the evaluation of genitourinary specimens for secondary involvement by cervical carcinoma. Furthermore, gynecologic clinical history is absolutely critical and most important to the evaluation and diagnosis of these specimens, as these ancillary studies are not completely sensitive or specific. PMID- 26426381 TI - NOTCH1, TP53, and MAP2K1 Mutations in Splenic Diffuse Red Pulp Small B-cell Lymphoma Are Associated With Progressive Disease. AB - Splenic diffuse red pulp small B-cell lymphoma (SDRPL) is considered an indolent neoplasm and its pathogenesis is not well known. We investigated the molecular characteristics of 19 SDRPL patients, 5 of them with progressive disease. IGHV genes were mutated in 9/13 (69%). Cytogenetic and molecular studies identified complex karyotypes in 2 cases, and IGH rearrangements in 3, with PAX5 and potentially TCL1 as partners in each one of them. Copy number arrays showed aberrations in 69% of the tumors, including recurrent losses of 10q23, 14q31-q32, and 17p13 in 3, and 9p21 in 2 cases. Deletion of 7q31.3-q32.3 was present in only 1 case and no trisomies 3 or 18 were detected. NOTCH1 and MAP2K1 were mutated in 2 cases each, whereas BRAF, TP53, and SF3B1 were mutated each in single cases. No mutations were found in NOTCH2 or MYD88. Four of the 5 patients with aggressive disease had mutations in NOTCH1 (2 cases), TP53 (1 case), and MAP2K1 (1 case). The progression-free survival of patients with mutated genes was significantly shorter than in the unmutated (P=0.011). These findings show that SDRPL share some mutated genes but not chromosomal alterations, with other splenic lymphomas, that may confer a more aggressive behavior. PMID- 26426383 TI - Idelalisib-associated Enterocolitis: Clinicopathologic Features and Distinction From Other Enterocolitides. AB - Idelalisib is a highly specific small-molecule phosphoinositide-3-kinase delta inhibitor that was recently approved by the Food and Drug Administration for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. The known side effects of idelalisib include severe diarrhea and colitis. Here we report the histologic findings in idelalisib-associated enterocolitis in 11 patients with chronic lymphocytic leukemia or follicular lymphoma receiving idelalisib over a 5-year period (2011 to 2015) at our institution. All 11 patients were receiving idelalisib and underwent colonoscopy for the evaluation of diarrhea. None of the patients had previously received a stem cell transplant. Histologically, the colon biopsies in all 11 cases showed some degree of apoptosis within crypts, with 5 cases showing moderate to severe apoptosis involving the majority of the crypts with loss of goblet cells. No viral inclusions were seen in any case and immunohistochemical stains for cytomegalovirus performed in 9/11 cases were negative. All cases showed at least focal acute cryptitis, and 8 of these cases showed mild architectural distortion. Increased inflammation within the lamina propria was seen in 7 cases, and increased intraepithelial lymphocytes within crypts was seen in 8 cases; the lymphocytes were mostly T cells with a predominance of CD8 T cells, with the majority expressing the alpha/beta T-cell receptor. Diagnoses of graft-versus host disease, autoimmune enteropathy, infectious enterocolitis, and although thought to be less likely, inflammatory bowel disease were considered in each case. The presence of numerous intraepithelial lymphocytes in addition to severe villous blunting and apoptosis in the small intestinal biopsies from a subset of these patients additionally raised the possibility of autoimmune enteropathy, common variable immunodeficiency, or less likely, celiac disease. Awareness of the histologic features of idelalisib-associated enterocolitis is important to distinguish it from potential mimics, particularly graft-versus-host disease, autoimmune enteropathy, and cytomegalovirus/infectious enterocolitis. PMID- 26426384 TI - Whole Mouse Brain Image Reconstruction from Serial Coronal Sections Using FIJI (ImageJ). AB - Whole-brain reconstruction of the mouse enables comprehensive analysis of the distribution of neurochemical markers, the distribution of anterogradely labeled axonal projections or retrogradely labeled neurons projecting to a specific brain site, or the distribution of neurons displaying activity-related markers in behavioral paradigms. This unit describes a method to produce whole-brain reconstruction image sets from coronal brain sections with up to four fluorescent markers using the freely available image-processing program FIJI (ImageJ). PMID- 26426385 TI - Laser-Mediated Microlesions in Mouse Neocortex to Investigate Neuronal Degeneration and Regeneration. AB - In vivo two-photon (2P) imaging enables neural circuitry to be repeatedly visualized in both normal conditions and following trauma. This protocol describes how laser-mediated neuronal microlesions can be created in the cerebral cortex using an ultrafast laser without causing a significant inflammatory reaction or compromising the blood-brain barrier. Furthermore, directives are provided for the acute and chronic in vivo imaging of the lesion site, as well as for post-hoc analysis of the lesion site in fixed tissue, which can be correlated with the live imaging phase. PMID- 26426388 TI - Squaramide-catalysed asymmetric cascade aza-Michael/Michael addition reaction for the synthesis of chiral trisubstituted pyrrolidines. AB - A bifunctional squaramide catalysed aza-Michael/Michael cascade reaction between nitroalkenes and tosylaminomethyl enones or enoates has been developed. This organocatalytic cascade reaction provides easy access to highly functionalized chiral pyrrolidines with a broad substrate scope, giving the desired products in good yields (up to 99%) with good diastereoselectivities (up to 91 : 9 dr) and excellent enantioselectivities (up to >99% ee) under mild conditions. This protocol provides a straightforward entry to highly functionalized chiral trisubstituted pyrrolidine derivatives from simple starting materials. PMID- 26426387 TI - Implementation of isoniazid preventive therapy in an HIV clinic in Cambodia: high rates of discontinuation when combined with antiretroviral therapy. AB - OBJECTIVE: Data on feasibility and completion rates of isoniazid preventive therapy (IPT) in HIV-infected patient in Asia are limited. Within a hospital based HIV programme in Phnom Penh, Cambodia, we determined the proportion completing IPT and reasons for non-completion. METHODS: Retrospective cohort study using HIV/IPT programme data, including all adults starting IPT (300 mg/day self-administered for 24 weeks) from February 2011 to March 2013. All patients underwent symptom screening and further investigations as indicated. After ruling out tuberculosis (TB), IPT was started, with monthly follow-up visits. As per national guideline, IPT was only prescribed for ART-naive patients. IPT completion was defined as taking IPT for at least 22 of the planned 24 weeks. Stavudine/lamivudine/nevirapine was the preferential first-line ART regimen. RESULTS: Among 445 ART-naive patients starting IPT (median age: 35 years (IQR: 31 43), median CD4 count 354 cells/MUl (IQR 215-545) and 288 (65%) were female), 214 (48%) started ART after a median of 4 weeks (IQR 2-6) on IPT ('concurrent ART'). Overall, 348 (78%) completed IPT. Among individuals with concurrent ART, the completion rate was 73% (157/214). Those without concurrent ART had a higher completion rate (83%; 191/231; P 0.017). The main reason for non-completion with concurrent ART was drug toxicity (mainly hepatotoxicity/rash), occurring in 22% (48/214). Without concurrent ART, the main reason for non-completion was loss to follow-up (16/231; 7%). Fourteen (3%) patients were diagnosed with TB while on IPT, of whom three had a positive TB culture at baseline. An additional 14 TB cases were diagnosed after IPT completion; four were bacteriologically confirmed. CONCLUSION: Although overall completion rates were acceptable, IPT discontinuation due to drug toxicity was common in patients subsequently initiating ART. Future studies should evaluate whether this relates to IPT, ARVs or both, and whether the increased toxicity would justify delaying IPT initiation until stabilisation on ART. PMID- 26426386 TI - Use of Adeno-Associated and Herpes Simplex Viral Vectors for In Vivo Neuronal Expression in Mice. AB - Adeno-associated viruses and the herpes simplex virus are the two most widely used vectors for the in vivo expression of exogenous genes. Advances in the development of these vectors have enabled remarkable temporal and spatial control of gene expression. This unit provides methods for storing, delivering, and verifying expression of adeno-associated and herpes simplex viruses in the adult mouse brain. It also describes important considerations for experiments using in vivo expression of these viral vectors, including serotype and promoter selection, as well as timing of expression. Additional protocols are provided that describe methods for preliminary experiments to determine the appropriate conditions for in vivo delivery. PMID- 26426389 TI - Differential expression of CARMIL-family genes during zebrafish development. AB - CARMILs are a conserved family of large multidomain proteins that regulate and target actin assembly by interacting with actin capping protein (CP). Vertebrates contain three highly conserved CARMIL isoforms encoded by three genes, whereas lower organisms contain only one isoform and gene. In order to investigate the functions of vertebrate CARMILs, we identified and characterized the three CARMIL genes in zebrafish (Danio rerio). We isolated and sequenced complete and partial cDNAs from embryos. The three genes display distinct spatial and temporal expression patterns during development. Sequence and phylogenetic analyses of cDNAs and predicted protein sequences reveal that the three zebrafish genes fall into the three conserved isoform groups previously defined for other vertebrates, which have isoform-specific and overlapping functions in human cultured cells. These results provide new tools and offer insight into understanding the role of the regulation of actin assembly dynamics during embryonic development and tissue morphogenesis. PMID- 26426390 TI - Targeted gene exchange in plant cells mediated by a zinc finger nuclease double cut. AB - Genome modification by homology-directed repair (HDR) is an attractive tool for the controlled genetic manipulation of plants. Here, we report the HDR-mediated gene exchange of expression cassettes in tobacco BY-2 cells using a designed zinc finger nuclease (ZFN). The target contained a 7-kb fragment flanked by two ZFN cutting sites. That fragment was replaced with a 4-kb donor cassette, which integrates gene markers for selection (kanamycin resistance) and for scoring targeting (red fluorescent protein, RFP). Candidates resulting from cassette exchange were identified by molecular analysis of calli generated by transformation via direct DNA delivery. The precision of HDR-mediated donor integration was evaluated by Southern blot analysis, sequencing of the integration locus and analysis of RFP fluorescence by flow cytometry. Screening of 1326 kanamycin-resistant calli yielded 18 HDR events, 16 of which had a perfect cassette exchange at the insert junction and 13 of which produced functional RFP. Our results demonstrate that ZFN-based HDR can be used for high frequency, precise, targeted exchange of fragments of sizes that are commercially relevant in plants. PMID- 26426391 TI - Controlling the Fluorescence Response of PET Sensors via the Metal-Ion pi Contacting Ability of the Fluorophore: Coumarin, a Weaker pi Contacter. AB - The pi-contact hypothesis, that quenching of the fluorescence of complexes of photoinduced electron transfer sensors with heavy diamagnetic metal ions may be caused by pi contacts between the metal ion and the fluorophore of the sensor, is examined with a study of the fluorescent properties of the sensor 4-[[bis(2 pyridinylmethyl)amino]methyl]-6,7-dimethoxy-1-benzopyran-2-one (cdpa) and the structures of its complexes with some metal ions. The coumarin-type fluorophore of cdpa is a weaker pi-contact former than the anthracenyl fluorophore of the analogue adpa (Inorg. Chem. 2014, 53, 9014): only Ag(I), the strongest pi contact former, quenches the fluorescence of cdpa, apart from paramagnetic Cu(II) and Ni(II), which quench fluorescence by a redox mechanism not requiring pi contacts. The structures of [Ag(cdpa)NO3] (1), [Pb(cdpa)(NO3)2] (2), [Zn(cdpa)(NO3)2] (3), [Cd(cdpa)Cl2]2 (4), [Cd(cdpa)2H2O](NO3)2 (5), and [Hg(cdpa)2H2O](NO3)2 (6) are reported. Structure 1 shows that Ag(I) is the only metal ion studied that forms pi contacts with the fluorophore of cdpa in the solid state: Ag...C eta(2) pi contacts of 3.083 and 3.095 A, in line with quenching of the fluorescence of the Ag(I)(cdpa) complex. In contrast, Pb(II), Zn(II), and Cd(II) show chelation enhanced fluorescence in their cdpa complexes, and the structures of 2-4 show that the fluorophore of cdpa in each case forms no pi contacts. By contrast, the adpa complexes of Pb(II) and Cd(II) show pi contacts with its more strongly pi contacting fluorophore (Inorg. Chem. 2014, 53, 9014). The structures of 5 and 6 show bis-complexes of cdpa: the coordination geometries of Cd(II) and Hg(II) are discussed in relation to the number of covalently bound donor atoms present. The preferred hapticity of pi-contacted metal ions is evaluated from the literature structures, suggesting that d(10) metal ions such as Ag(I) and Hg(II), and tetragonally distorted Cu(II) and Pd(II), prefer eta(1) and eta(2) pi contacts, while more ionically bound metal ions such as K(I), Ba(II), and La(III), as well as d(10)s(2) metal ions such as Tl(I), Pb(II), and Bi(III), prefer eta(6) contacts. PMID- 26426392 TI - Behavioral Evolution of Progressive Semantic Aphasia in Comparison with Nonfluent Aphasia. AB - BACKGROUND: Patients with primary progressive aphasia (PPA) usually develop significant behavioral disturbances with progression of the disease. We tested our clinical observation that development of disruptive agitation is more likely in semantic than in nonfluent PPA and examined which clinical variables could be associated with this behavior. METHODS: We retrospectively analyzed neuropsychiatric scores and the need for behavioral treatments in semantic PPA (n = 41) and nonfluent PPA (n = 39) cases and compared first (1-3 years since the onset of symptoms) and last (5-13 years since the onset) evaluations. Clinical variables and laterality of temporal atrophy were associated with symptoms in semantic PPA cases. RESULTS: The semantic PPA group developed more frequent (p = 0.03) and intense agitation (p = 0.0008) and had a greater need for antipsychotic drugs (p = 0.001) than the nonfluent PPA group. Presence of agitation was clearly associated with psychotic symptoms (delusions/hallucinations) but was not associated with gender, age at onset, duration of the disease, or laterality of temporal atrophy. In contrast, nonfluent PPA cases were more frequently depressed and treated with antidepressants (p = 0.0007). There were no differences in anxiety, irritability, apathy, perseverations, hyperorality, or abnormal motor behavior. CONCLUSIONS: Semantic PPA in advanced disease is frequently associated with agitation and psychotic symptoms with fewer mood symptoms, while nonfluent PPA maintains a high prevalence of depression. This implies different treatment and care and support needs for each group. PMID- 26426393 TI - A new method to evaluate the effects of shear on the skin. AB - Currently, pressure ulcer preventive strategies focus mainly on pressure redistribution. Little attention is paid to reduce the harmful effects of shear force, because little is known about pathophysiological aspects of shear-force. Even today, no method to measure the effects of shear-force on the skin is available. Therefore, the aim of this study was to investigate the response to shear-forces in terms of analyzing a noninvasive biomarker and reactive hyperemic parameter measured at the skin of healthy participants. A physical model was developed to produce a combination of pressure and shear or pressure alone on the skin. Ten healthy male participants were included and pressure (3.9 kPa) and a combined loading of pressure and shear (2.4 kPa + 14.5 N) was applied at the volar aspect of the forearms for 15 and 30 minutes. A Sebutape sample was used to collect IL-1alpha and total protein (TP) noninvasively. The reactive hyperemic parameter was derived from a laser Doppler flowmeter. The increase in IL 1alpha/TP-ratio after a combined loading of pressure and shear for 30 minutes of 6.2 +/- 2.5 was significantly higher compared with all other test conditions (p < 0.05). The increase in cutaneous blood cell flux was already significantly higher when a combined loading of pressure and shear was applied for 15 minutes compared with pressure alone. These results shows that the IL-1alpha/TP-ratio and cutaneous blood cell flux can be used as robust measures of the effect of shear force on skin in humans. Therefore, this model can be used to evaluate materials aimed at the reduction of shear. PMID- 26426394 TI - Short-term carbon cycling responses of a mature eucalypt woodland to gradual stepwise enrichment of atmospheric CO2 concentration. AB - Projections of future climate are highly sensitive to uncertainties regarding carbon (C) uptake and storage by terrestrial ecosystems. The Eucalyptus Free-Air CO2 Enrichment (EucFACE) experiment was established to study the effects of elevated atmospheric CO2 concentrations (eCO2 ) on a native mature eucalypt woodland with low fertility soils in southeast Australia. In contrast to other FACE experiments, the concentration of CO2 at EucFACE was increased gradually in steps above ambient (+0, 30, 60, 90, 120, and 150 ppm CO2 above ambient of ~400 ppm), with each step lasting approximately 5 weeks. This provided a unique opportunity to study the short-term (weeks to months) response of C cycle flux components to eCO2 across a range of CO2 concentrations in an intact ecosystem. Soil CO2 efflux (i.e., soil respiration or Rsoil ) increased in response to initial enrichment (e.g., +30 and +60 ppm CO2 ) but did not continue to increase as the CO2 enrichment was stepped up to higher concentrations. Light-saturated photosynthesis of canopy leaves (Asat ) also showed similar stimulation by elevated CO2 at +60 ppm as at +150 ppm CO2 . The lack of significant effects of eCO2 on soil moisture, microbial biomass, or activity suggests that the increase in Rsoil likely reflected increased root and rhizosphere respiration rather than increased microbial decomposition of soil organic matter. This rapid increase in Rsoil suggests that under eCO2, additional photosynthate was produced, transported belowground, and respired. The consequences of this increased belowground activity and whether it is sustained through time in mature ecosystems under eCO2 are a priority for future research. PMID- 26426395 TI - Myosin-Powered Membrane Compartment Drives Cytoplasmic Streaming, Cell Expansion and Plant Development. AB - Using genetic approaches, particle image velocimetry and an inert tracer of cytoplasmic streaming, we have made a mechanistic connection between the motor proteins (myosins XI), cargo transported by these motors (distinct endomembrane compartment defined by membrane-anchored MyoB receptors) and the process of cytoplasmic streaming in plant cells. It is shown that the MyoB compartment in Nicotiana benthamiana is highly dynamic moving with the mean velocity of ~3 MUm/sec. In contrast, Golgi, mitochondria, peroxisomes, carrier vesicles and a cytosol flow tracer share distinct velocity profile with mean velocities of 0.6 1.5 MUm/sec. Dominant negative inhibition of the myosins XI or MyoB receptors using overexpression of the N. benthamiana myosin cargo-binding domain or MyoB myosin-binding domain, respectively, resulted in velocity reduction for not only the MyoB compartment, but also each of the tested organelles, vesicles and cytoplasmic streaming. Furthermore, the extents of this reduction were similar for each of these compartments suggesting that MyoB compartment plays primary role in cytosol dynamics. Using gene knockout analysis in Arabidopsis thaliana, it is demonstrated that inactivation of MyoB1-4 results in reduced velocity of mitochondria implying slower cytoplasmic streaming. It is also shown that myosins XI and MyoB receptors genetically interact to contribute to cell expansion, plant growth, morphogenesis and proper onset of flowering. These results support a model according to which myosin-dependent, MyoB receptor-mediated transport of a specialized membrane compartment that is conserved in all land plants drives cytoplasmic streaming that carries organelles and vesicles and facilitates cell growth and plant development. PMID- 26426396 TI - Microarray Analysis of the Gene Expression Profile and Lipid Metabolism in Fat-1 Transgenic Cattle. AB - Long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) are beneficial for human health. However, humans and mammals are unable to synthesize n-3 PUFAs because they lack the n-3 desaturase gene fat-1 and must therefore obtain this type of fatty acid through their diet. Through the production of fat-1 transgenic animals, it is possible to obtain animal products that are rich in n-3 PUFAs, such as meat and milk. The aim of this study was to analyze the gene expression profile and the mechanism of lipid metabolism in fat-1 transgenic cattle and to accumulate important basic data that are required to obtain more efficient fat-1 transgenic cattle. Transcriptome profiling of fat-1 transgenic and wild-type cattle identified differentially expressed genes that are involved in 90 biological pathways, eight pathways of which were related to lipid metabolism processes 36 genes of which were related to lipid metabolism. This analysis also identified 11 significantly enriched genes that were involved in the peroxisome proliferator-activated receptor signaling pathway. These findings were verified by quantitative polymerase chain reaction. The information obtained in this study indicated that the introduction of an exogenous fat-1 gene into cattle affects the gene expression profile and the process of lipid metabolism in these animals. These results may provide important insights into how an exogenous fat-1 gene synthesizes n-3 PUFAs in transgenic cattle and other mammals. PMID- 26426397 TI - Micro-RNA Binding Site Polymorphisms in the WFS1 Gene Are Risk Factors of Diabetes Mellitus. AB - The absolute or relative lack of insulin is the key factor in the pathogenesis of diabetes mellitus. Although the connection between loss of function mutations of the WFS1 gene and DIDMOAD-syndrome including diabetes mellitus underpins the significance of wolframin in the pathogenesis, exact role of WFS1 polymorphic variants in the development of type 1 and type 2 diabetes has not been discovered yet. In this analysis, 787 patients with diabetes and 900 healthy people participated. Genotyping of the 7 WFS1 SNPs was carried out by TaqMan assays. Association study was performed by chi2-test in combination with correction for multiple testing. For functional analysis, the entire 3' UTR of the WFS1 gene was subcloned in a pMIR-Report plasmid and relative luciferase activities were determined. Linkage disequilibrium analysis showed a generally high LD within the investigated region, however the rs1046322 locus was not in LD with the other SNPs. The two miR-SNPs, rs1046322 and rs9457 showed significant association with T1DM and T2DM, respectively. Haplotype analysis also confirmed the association between the 3' UTR loci and both disease types. In vitro experiments showed that miR-185 reduces the amount of the resulting protein, and rs9457 miRSNP significantly influences the rate of reduction in a luciferase reporter assay. Genetic variants of the WFS1 gene might contribute to the genetic risk of T1DM and T2DM. Furthermore demonstrating the effect of rs9457 in binding of miR-185, we suggest that the optimal level of wolframin protein, potentially influenced by miR-regulation, is crucial in normal beta cell function. PMID- 26426399 TI - A Puzzle in the Carotid Space. Ancient schwannoma. PMID- 26426398 TI - Estimation of apparent binding constant of complexes of selected acyclic nucleoside phosphonates with beta-cyclodextrin by affinity capillary electrophoresis. AB - Affinity capillary electrophoresis (ACE) has been applied to estimation of apparent binding constant of complexes of (R,S)-enantiomers of selected acyclic nucleoside phosphonates (ANPs) with chiral selector beta-cyclodextrin (betaCD) in aqueous alkaline medium. The noncovalent interactions of five pairs of (R,S) enantiomers of ANPs-based antiviral drugs and their derivatives with betaCD were investigated in the background electrolyte (BGE) composed of 35 or 50 mM sodium tetraborate, pH 10.0, and containing variable concentration (0-25 mM) of betaCD. The apparent binding constants of the complexes of (R,S)-enantiomers of ANPs with betaCD were estimated from the dependence of effective electrophoretic mobilities of (R,S)-enantiomers of ANPs (measured simultaneously by ACE at constant reference temperature 25 degrees C inside the capillary) on the concentration of betaCD in the BGE using different nonlinear and linear calculation methodologies. Nonlinear regression analysis provided more precise and accurate values of the binding constants and a higher correlation coefficient as compared to the regression analysis of the three linearized plots of the effective mobility dependence on betaCD concentration in the BGE. The complexes of (R,S)-enantiomers of ANPs with betaCD have been found to be relatively weak - their apparent binding constants determined by the nonlinear regression analysis were in the range 13.3-46.4 L/mol whereas the values from the linearized plots spanned the interval 12.3-55.2 L/mol. PMID- 26426400 TI - Relationship of residency program characteristics with pass rate of the American Board of Internal Medicine certifying exam. AB - OBJECTIVES: To evaluate the relationship between the pass rate of the American Board of Internal Medicine (ABIM) certifying exam and the characteristics of residency programs. METHODS: The study used a retrospective, cross-sectional design with publicly available data from the ABIM and the Fellowship and Residency Electronic Interactive Database. All categorical residency programs with reported pass rates were included. Using univariate and multivariate, linear regression analyses, I analyzed how 69 factors (e.g., location, general information, number of faculty and trainees, work schedule, educational environment) are related to the pass rate. RESULTS: Of 371 programs, only one region had a significantly different pass rate from the other regions; however, as no other characteristics were reported in this region, I excluded program location from further analysis. In the multivariate analysis, pass rate was significantly associated with four program characteristics: ratio of full-time equivalent paid faculty to positions, percentage of osteopathic doctors, formal mentoring program, and on-site child care (OCC). Numerous factors were not associated at all, including minimum exam scores, salary, vacation days, and average hours per week. CONCLUSIONS: As shown through the ratio of full-time equivalent paid faculty to positions and whether there was a formal mentoring program, a highly supervised training experience was strongly associated with the pass rate. In contrast, percentage of osteopathic doctors was inversely related to the pass rate. Programs with OCC significantly outperformed programs without OCC. This study suggested that enhancing supervision of training programs and offering parental support may help attract and produce competitive residents. PMID- 26426401 TI - Gamification in medical education. PMID- 26426402 TI - Non-invasive assessment of liver fibrosis in chronic viral hepatitis. AB - BACKGROUND: Hyaluronic acid (HA), ASAT to Platelet Ratio Index (APRI), ASAT/ALAT ratio, Fibrosis 4 score (FIB4) and FibroScan were studied as non-invasive markers of liver fibrosis (F) in chronic viral hepatitis B (CHB) and C (CHC), in an attempt to avoid the complications of liver puncture biopsy, considered the gold standard in the evaluation of F. The aim of our research was to study whether HA, APRI, ASAT/ALAT ratio, FIB4 and FibroScan are useful non-invasive markers in predicting severe F in Romanian patients. PATIENTS AND METHODS: This was a prospective multicenter transversal and observational study, which included 76 patients with CHB/CHC. The independent effect of studied markers was tested using multiple binary logistic regression. RESULTS: In patients with CHB and CHC, the APRI cut-off value for F4 was 0.70 ng/mL (Se = 77%, Sp = 78%), the FIB4 cut-off value was 2.01 (Se = 77%, Sp = 69%), and the FibroScan cut-off value was 13.15 (Se = 92%, Sp = 88%). For patients with CHB/CHC, there was a significant linear positive correlation between F and HA (r = 0.42, P = 0.001), FibroScan (r = 0.67, P < 0.001), APRI (r = 0.46, P < 0.001) and FIB4 (r = 0.51, P < 0.001). Considering age, sex and body mass index as possible confounding factors or covariates in multivariable logistic modelling, FibroScan was the unique test that able to significantly highlight the presence of F4 score in CHB/CHC patients (P = 0.009) while FIB4 test seems to have a tendency to statistical significance. CONCLUSION: FibroScan, APRI and FIB4 are useful non-invasive tests for the evaluation of F4 in patients with CHB and CHC. PMID- 26426403 TI - Details of Glaucomatous Damage Are Better Seen on OCT En Face Images Than on OCT Retinal Nerve Fiber Layer Thickness Maps. AB - PURPOSE: High-resolution images of glaucomatous damage to the retinal nerve fiber layer (RNFL) were obtained with an adaptive optics-scanning light ophthalmoscope (AO-SLO) and used as a basis for comparisons between en face slab images and thickness maps derived from optical coherence tomography (OCT) scans. METHODS: Wide-field (9 * 12 mm) cube scans were obtained with swept-source OCT (DRI-OCT) from six eyes of six patients. All eyes had a deep defect near fixation as seen on a 10-2 visual field test. Optical coherence tomography en face images, based on the average reflectance intensity, were generated (ATL 3D-Suite) from 52-MUm slabs just below the vitreal border of the inner limiting membrane. The RNFL thickness maps were generated from the same OCT data. Both were compared with the AO-SLO peripapillary images that were previously obtained. RESULTS: On AO-SLO images, three eyes showed small regions of preserved and/or missing RNFL bundles within the affected region. Details in these regions were seen on the OCT en face images but not on the RNFL thickness maps. In addition, in the healthier hemi retinas of two eyes, there were darker, arcuate-shaped regions on en face images that corresponded to abnormalities seen on AO-SLO. These were not seen on RNFL thickness maps. CONCLUSIONS: Details of local glaucomatous damage, missing or easily overlooked on traditional OCT RNFL thickness analysis used in clinical OCT reports, were seen on OCT en face images based on the average reflectance intensity. While more work is needed, it is likely that en face slab imaging has a role in the clinical management of glaucoma. PMID- 26426404 TI - Compartmental Innervation of the Superior Oblique Muscle in Mammals. AB - PURPOSE: Intramuscular innervation of mammalian horizontal rectus extraocular muscles (EOMs) is compartmental. We sought evidence of similar compartmental innervation of the superior oblique (SO) muscle. METHODS: Three fresh bovine orbits and one human orbit were dissected to trace continuity of SO muscle and tendon fibers to the scleral insertions. Whole orbits were also obtained from four humans (two adults, a 17-month-old child, and a 33-week stillborn fetus), two rhesus monkeys, one rabbit, and one cow. Orbits were formalin fixed, embedded whole in paraffin, serially sectioned in the coronal plane at 10-MUm thickness, and stained with Masson trichrome. Extraocular muscle fibers and branches of the trochlear nerve (CN4) were traced in serial sections and reconstructed in three dimensions. RESULTS: In the human, the lateral SO belly is in continuity with tendon fibers inserting more posteriorly on the sclera for infraducting mechanical advantage, while the medial belly is continuous with anteriorly inserting fibers having mechanical advantage for incycloduction. Fibers in the monkey superior SO insert more posteriorly on the sclera to favor infraduction, while the inferior portion inserts more anteriorly to favor incycloduction. In all species, CN4 bifurcates prior to penetrating the SO belly. Each branch innervates a nonoverlapping compartment of EOM fibers, consisting of medial and lateral compartments in humans and monkeys, and superior and inferior compartments in cows and rabbits. CONCLUSIONS: The SO muscle of humans and other mammals is compartmentally innervated in a manner that could permit separate CN4 branches to selectively influence vertical versus torsional action. PMID- 26426405 TI - Pediatric deceased donor renal transplantation: An approach to decision making II. Acceptability of a deceased donor kidney for a child, a snap decision at 3 AM. AB - Allocation of deceased donor kidneys is based on several criteria; however, the final decision to accept or reject the offered kidney is made by the potential recipient's transplant team (surgeon/nephrologist). Several considerations including assessment of the donor quality, the HLA match between the donor and the recipient, several recipient factors, the geographical location of the recipient, and the organ all affect the decision of whether or not to finally accept the organ for a particular recipient. This decision needs to be made quickly, often on the spot. Maximizing the benefit from this scarce resource raises difficult ethical issues. The philosophies of equity and utility are often competing. This article will discuss the several considerations for the pediatric nephrologist while accepting a deceased donor kidney for a particular pediatric patient. PMID- 26426407 TI - MULTIFOCAL RETINAL INFILTRATES WITH PHLEBITIS AND OPTIC NEUROPATHY IN AN HIV POSITIVE PEDIATRIC PATIENT. AB - PURPOSE: To describe an unusual presentation of bilateral HIV-associated multifocal retinal infiltrates with phlebitis and optic neuropathy in a pediatric patient from Zimbabwe, Africa. METHODS: Retrospective case report of a 15-year old boy from Zimbabwe, Africa. RESULTS: The patient was found to have bilateral vitritis, multifocal retinitis with phlebitis, and optic neuropathy in the setting of previously unrecognized HIV infection. Vision improved and the clinical findings resolved after treatment with intravenous corticosteroids and highly active retroviral therapy (HAART). CONCLUSION: The authors describe the occurrence and treatment of bilateral, HIV-associated multifocal retinal infiltrates with phlebitis and HIV-associated optic neuropathy in a pediatric patient from Zimbabwe, Africa. PMID- 26426406 TI - Failure of Ovarian Suppression With Gonadotropin-Releasing Hormone Analogs to Preserve Fertility: An Assessment Based on the Quality of Evidence. PMID- 26426408 TI - SEROUS NEUROSENSORY RETINAL DETACHMENT ASSOCIATED WITH ATYPICAL COGAN SYNDROME: A CASE REPORT. AB - PURPOSE: To present a case of a 71-year-old woman with possible focal choroiditis and secondary serous neurosensory retinal detachment associated with atypical Cogan syndrome. METHODS: Retrospective case report. RESULTS: On initial evaluation, the patient had decreased vision with photopsias and distortion in the affected eye. Her history revealed 3 years of preexisting neurosensory hearing loss and corneal scarring in the affected eye. Examination findings were significant for unilateral interstitial keratitis and focal macular neurosensory retinal detachment. Fluorescein and indocyanine green angiography demonstrated focal macular leakage and staining. Treatment with intravitreal and periocular steroid injections resulted in complete resolution of the subretinal fluid and visual improvement. CONCLUSION: Posterior segment manifestations associated with Cogan syndrome are exceedingly rare. This is the first known case of a serous neurosensory retinal detachment from suspected choroidal inflammation associated with Cogan syndrome. Prompt recognition and treatment with corticosteroids may result in anatomical and functional visual improvement, as in this case. PMID- 26426410 TI - Organocatalytic multicomponent synthesis of polysubstituted pyrroles from 1,2 diones, aldehydes and arylamines. AB - We have developed an organocatalyzed three-component reaction of 1,2-diones, aldehydes and arylamines, which provides an efficient approach to access polysubstituted pyrroles. In the catalysis of 4-methylbenzenesulfonic acid monohydrate, the reactions of a wide range of 1,2-diones, arylamines and aldehydes took place smoothly to generate the corresponding polysubstituted pyrroles in acceptable to good yields under mild reaction conditions. PMID- 26426412 TI - Will the attributes of multiparametric MRI permit the creation of a new approach to therapy? AB - PURPOSE OF REVIEW: To explore the concept that MRI can be used to permit a new approach to therapy of localized prostate cancer. RECENT FINDINGS: With the development of multiparametric MRI, we can characterize cancer within the prostate, in terms of location, volume and radiological phenotype. The use of volume and location to identify candidates for focal ablative therapy is well established.The radiological phenotype of a tumour includes the vascularity and diffusion characteristics of that tumour. These characteristics may help us to develop novel interventions to target particular characteristics of a tumour.The assessment of novel interventions such as sulforaphanes found in broccoli, and common medications used for other diseases such as aspirin and metformin typically use population based studies, or repeat biopsy studies in large groups of men on active surveillance. MRI, with its accurate detection of change in visible tumour over a 6-month period, could allow rapid noninvasive assessment of a novel intervention. SUMMARY: MRI could be used to allow the rapid and efficient assessment of dietary and other interventions to identify candidates for assessment in larger studies and potentially, to identify subgroups of tumours which would be most suited to a given intervention. PMID- 26426413 TI - Continent cutaneous diversion. AB - PURPOSE OF REVIEW: This article updates the recently reported intermediate to long-term results with the most commonly used forms of continent cutaneous urinary diversion, and to discuss approaches to early and late complications. RECENT FINDINGS: Many variations on construction of a continent cutaneous diversion have been described. Results with large series of patients demonstrate acceptable results with all of them, but with a significant revision rate. Long term complication rates and adaptation to robotic approaches have recently been described. SUMMARY: Continent cutaneous diversion is rarely offered in the USA to patients undergoing cystectomy except in a few centers. Most studies have found a high complication rate and need for revision surgery in 10-20% of patients. However, functional results are acceptable and many patients are willing to accept the complications in exchange for avoiding an external appliance. PMID- 26426415 TI - Recent advances in energy transfer in bulk and nanoscale luminescent materials: from spectroscopy to applications. AB - Transfer of energy occurs endlessly in our universe by means of radiation. Compared to energy transfer (ET) in free space, in solid state materials the transfer of energy occurs in a rather confined manner, which is usually mediated by real or virtual particles, including not only photons, but also electrons, phonons, and excitons. In the present review, we discuss the recent advances in optical ET by resonance mediated with photons in solid materials as well as their nanoscale counterparts, with focus on the photoluminescence behavior pertaining to ET between optically active centers, such as rare earth (RE) ions. This review begins with a brief discussion on the classification of optical ET together with an overview of the theoretical formulations and experimental method for the examination of ET. We will then present a comprehensive discussion on the ET in practical systems in which normal photoluminescence, upconversion and quantum cutting resulted from ET involving metal ions, QDs, organic species, 2D materials and plasmonic nanostructures. Diverse ET systems are therefore simply categorized into cases of ion-ion interactions and non-ion interactions. Special attention has been paid to the progress in the manipulation of spatially confined ET in nanostructured systems including core-shell structures, as well as the ET in multiple exciton generation found in QDs and organic molecules, which behave quite similarly to resonance ET between metal ion centers. Afterwards, we will discuss the broad spectrum of applications of ET in the aforementioned systems, including solid state lighting, solar energy utilization, bio-imaging and diagnosis, and sensing. In the closing part, along with a short summary, we discuss further research focus regarding the problems and possible future directions of optical ET in solids. PMID- 26426416 TI - Bridging the gap between interviewer and interviewee: developing an interview guide for individual interviews by means of a focus group. AB - BACKGROUND: In developing an interview guide, pre-existing knowledge about the research topic is essential. In a recent study, we were interested in exploring the experiences of weight changes among women treated for breast cancer using individual interviews. However, to develop an interview guide for the individual interviews that covered relevant thematic and dynamic dimensions, we found existing literature insufficient. Thus, we turned our attention to the benefit of the focus group method. OBJECTIVES: This study aims to discuss how a focus group prior to individual interviews may contribute in developing the thematic dimension and translating the dynamic dimension of an interview guide into everyday language. METHODS: We conducted one focus group interview of five women treated for breast cancer with experiences in weight changes. Data were analysed using content and conversation analysis and discussed with relevant literature on interview guide development. ETHICS: The study is approved by the Danish Data Protection Agency (2008-58-0028) and follows the ethical guidelines for qualitative research. RESULTS: Data generation and analysis resulted in themes for the thematic dimension, as well as three dynamic areas to consider in the individual interviews to bridge the gap between the interviewer and the interviewee. The dynamic areas are as follows: The use of words, images and metaphors - a shield and self-protection, Multiple meanings to explore and Staying close to the everyday language. CONCLUSION: The analysis made us more familiar with the content and meaning of weight changes among breast cancer survivors. Furthermore, it provided images and metaphors, multiple meanings and a sense of the women's everyday language that calls for an open interview frame to be used in subsequent individual interviews. PMID- 26426411 TI - Single-Molecule Sequencing Reveals Estrogen-Regulated Clinically Relevant lncRNAs in Breast Cancer. AB - Estrogen receptor (ER)alpha-positive tumors are commonly treated with ERalpha antagonists or inhibitors of estrogen synthesis, but most tumors develop resistance, and we need to better understand the pathways that underlie the proliferative and tumorigenic role of this estrogen-activated transcription factor. We here present the first single-molecule sequencing of the estradiol induced ERalpha transcriptome in the luminal A-type human breast cancer cell lines MCF7 and T47D. Sequencing libraries were prepared from the polyadenylated RNA fraction after 8 hours of estrogen or vehicle treatment. Single-molecule sequencing was carried out in biological and technical replicates and differentially expressed genes were defined and analyzed for enriched processes. Correlation analysis with clinical expression and survival were performed, and follow-up experiments carried out using time series, chromatin immunoprecipitation and quantitative real-time PCR. We uncovered that ERalpha in addition to regulating approximately 2000 protein-coding genes, also regulated up to 1000 long noncoding RNAs (lncRNAs). Most of these were up-regulated, and 178 lncRNAs were regulated in both cell lines. We demonstrate that Long Intergenic Non-protein Coding RNA 1016 (LINC01016) and LINC00160 are direct transcriptional targets of ERalpha, correlate with ERalpha expression in clinical samples, and show prognostic significance in relation to breast cancer survival. We show that silencing of LINC00160 results in reduced proliferation, demonstrating that lncRNA expression have functional consequences. Our findings suggest that ERalpha regulation of lncRNAs is clinically relevant and that their functions and potential use as biomarkers for endocrine response are important to explore. PMID- 26426409 TI - Behavioral and brain asymmetries in primates: a preliminary evaluation of two evolutionary hypotheses. AB - Contrary to many historical views, recent evidence suggests that species-level behavioral and brain asymmetries are evident in nonhuman species. Here, we briefly present evidence of behavioral, perceptual, cognitive, functional, and neuroanatomical asymmetries in nonhuman primates. In addition, we describe two historical accounts of the evolutionary origins of hemispheric specialization and present data from nonhuman primates that address these specific theories. Specifically, we first discuss the evidence that genes play specific roles in determining left-right differences in anatomical and functional asymmetries in primates. We next consider and present data on the hypothesis that hemispheric specialization evolved as a by-product of increasing brain size relative to the surface area of the corpus callosum in different primate species. Last, we discuss some of the challenges in the study of hemispheric specialization in primates and offer some suggestions on how to advance the field. PMID- 26426417 TI - A knowledge-based molecular screen uncovers a broad-spectrum OsSWEET14 resistance allele to bacterial blight from wild rice. AB - Transcription activator-like (TAL) effectors are type III-delivered transcription factors that enhance the virulence of plant pathogenic Xanthomonas species through the activation of host susceptibility (S) genes. TAL effectors recognize their DNA target(s) via a partially degenerate code, whereby modular repeats in the TAL effector bind to nucleotide sequences in the host promoter. Although this knowledge has greatly facilitated our power to identify new S genes, it can also be easily used to screen plant genomes for variations in TAL effector target sequences and to predict for loss-of-function gene candidates in silico. In a proof-of-principle experiment, we screened a germplasm of 169 rice accessions for polymorphism in the promoter of the major bacterial blight susceptibility S gene OsSWEET14, which encodes a sugar transporter targeted by numerous strains of Xanthomonas oryzae pv. oryzae. We identified a single allele with a deletion of 18 bp overlapping with the binding sites targeted by several TAL effectors known to activate the gene. We show that this allele, which we call xa41(t), confers resistance against half of the tested Xoo strains, representative of various geographic origins and genetic lineages, highlighting the selective pressure on the pathogen to accommodate OsSWEET14 polymorphism, and reciprocally the apparent limited possibilities for the host to create variability at this particular S gene. Analysis of xa41(t) conservation across the Oryza genus enabled us to hypothesize scenarios as to its evolutionary history, prior to and during domestication. Our findings demonstrate that resistance through TAL effector dependent loss of S-gene expression can be greatly fostered upon knowledge-based molecular screening of a large collection of host plants. PMID- 26426418 TI - Behavior of Kinesin Driven Quantum Dots Trapped in a Microtubule Loop. AB - We report the observation of kinesin driven quantum dots (QDs) trapped in a microtubule loop, allowing the investigation of moving QDs for a long time and an unprecedented long distance. The QD conjugates did not depart from our observational field of view, enabling the tracking of specific conjugates for more than 5 min. The unusually long run length and the periodicity caused by the loop track allow comparing and studying the trajectory of the kinesin driven QDs for more than 2 full laps, i.e., about 70 MUm, enabling a statistical analysis of interactions of the same kinesin driven object with the same obstacle. The trajectories were extracted and analyzed from kymographs with a newly developed algorithm. Despite dispersion, several repetitive trajectory patterns can be identified. A method evaluating the similarity is introduced allowing a quantitative comparison between the trajectories. The velocity variations appear strongly correlated to the presence of obstacles. We discuss the reasons making this long continuous travel distances on the loop track possible. PMID- 26426419 TI - Highly-efficient and versatile fluorous-tagged Cu(I)-catalyzed azide-alkyne cycloaddition ligand for preparing bioconjugates. AB - A novel ligand (FBTTBE) for Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) has been developed, which demonstrates not only superior catalytic efficiency but also the ease of removing toxic copper species. FBTTBE has also been successfully applied in the synthesis of radiometal-labeled peptide and antibody without observable transchelation with the non-radioactive Cu(i) catalyst. PMID- 26426420 TI - Core-Cone Structured Monodispersed Mesoporous Silica Nanoparticles with Ultra large Cavity for Protein Delivery. AB - A new type of monodispersed mesoporous silica nanoparticles with a core-cone structure (MSN-CC) has been synthesized. The large cone-shaped pores are formed by silica lamellae closely packed encircling a spherical core, showing a structure similar to the flower dahlia. MSN-CC has a large pore size of 45 nm and a high pore volume of 2.59 cm(3) g(-1). MSN-CC demonstrates a high loading capacity of large proteins and successfully delivers active beta-galactosidase into cells, showing their potential as efficient nanocarriers for the cellular delivery of proteins with large molecular weights. PMID- 26426421 TI - Efficacy of a Community-Based Physical Activity Program KM2H2 for Stroke and Heart Attack Prevention among Senior Hypertensive Patients: A Cluster Randomized Controlled Phase-II Trial. AB - OBJECTIVE: To evaluate the efficacy of the program Keep Moving toward Healthy Heart and Healthy Brain (KM2H2) in encouraging physical activities for the prevention of heart attack and stroke among hypertensive patients enrolled in the Community-Based Hypertension Control Program (CBHCP). DESIGN: Cluster randomized controlled trial with three waves of longitudinal assessments at baseline, 3 and 6 months post intervention. SETTING: Community-based and patient-centered self care for behavioral intervention in urban settings of China. PARTICIPANTS: A total of 450 participants diagnosed with hypertension from 12 community health centers in Wuhan, China were recruited, and were randomly assigned by center to receive either KM2H2 plus standard CBHCP care (6 centers and 232 patients) or the standard care only (6 centers and 218 patients). INTERVENTION: KM2H2 is a behavioral intervention guided by the Transtheoretical Model, the Model of Personalized Medicine and Social Capital Theory. It consists of six intervention sessions and two booster sessions engineered in a progressive manner. The purpose is to motivate and maintain physical activities for the prevention of heart attack and stroke. OUTCOME MEASURES: Heart attack and stroke (clinically diagnosed, primary outcome), blood pressure (measured, secondary outcome), and physical activity (self-report, tertiary outcome) were assessed at the individual level during the baseline, 3- and 6-month post-intervention. RESULTS: Relative to the standard care, receiving KM2H2 was associated with significant reductions in the incidence of heart attack (3.60% vs. 7.03%, p < .05) and stroke (5.11% vs. 9.90%, p<0.05), and moderate reduction in blood pressure (-3.72 mmHg in DBP and 2.92 mmHg in DBP) at 6-month post-intervention; and significant increases in physical activity at 3- (d = 0.53, 95% CI: 0.21, 0.85) and 6-month (d = 0.45, 95% CI: 0.04, 0.85) post-intervention, respectively. CONCLUSION: The program KM2H2 is efficacious to reduce the risk of heart attack and stroke among senior patients who are on anti-hypertensive medication. Findings of this study provide solid data supporting a formal phase-III trial to establish the effectiveness of KM2H2 for use in community settings for prevention. TRIAL REGISTRATION: ISRCTN Register ISRCTN12608966. PMID- 26426422 TI - A Novel C-Terminal CIB2 (Calcium and Integrin Binding Protein 2) Mutation Associated with Non-Syndromic Hearing Loss in a Hispanic Family. AB - Hearing loss is a complex disorder caused by both genetic and environmental factors. Previously, mutations in CIB2 have been identified as a common cause of genetic hearing loss in Pakistani and Turkish populations. Here we report a novel (c.556C>T; p.(Arg186Trp)) transition mutation in the CIB2 gene identified through whole exome sequencing (WES) in a Caribbean Hispanic family with non-syndromic hearing loss. CIB2 belongs to the family of calcium-and integrin-binding (CIB) proteins. The carboxy-termini of CIB proteins are associated with calcium binding and intracellular signaling. The p.(Arg186Trp) mutation is localized within predicted type II PDZ binding ligand at the carboxy terminus. Our ex vivo studies revealed that the mutation did not alter the interactions of CIB2 with Whirlin, nor its targeting to the tips of hair cell stereocilia. However, we found that the mutation disrupts inhibition of ATP-induced Ca2+ responses by CIB2 in a heterologous expression system. Our findings support p.(Arg186Trp) mutation as a cause for hearing loss in this Hispanic family. In addition, it further highlights the necessity of the calcium binding property of CIB2 for normal hearing. PMID- 26426423 TI - Rapamycin Promotes Mouse 4T1 Tumor Metastasis that Can Be Reversed by a Dendritic Cell-Based Vaccine. AB - Suppression of tumor metastasis is a key strategy for successful cancer interventions. Previous studies indicated that rapamycin (sirolimus) may promote tumor regression activity or enhance immune response against tumor targets. However, rapamycin also exhibits immunosuppressant effects and is hence used clinically as an organ transplantation drug. We hypothesized that the immunosuppressive activities of rapamycin might also negatively mediate host immunity, resulting in promotion of tumor metastasis. In this study, the effects of rapamycin and phytochemical shikonin were investigated in vitro and in vivo in a 4T1 mouse mammary tumor model through quantitative assessment of immunogenic cell death (ICD), autophagy, tumor growth and metastasis. Tumor-bearing mice were immunized with test vaccines to monitor their effect on tumor metastasis. We found that intraperitoneal (ip) administration of rapamycin after a tumor resection surgery drastically increased the metastatic activity of 4T1 tumors. Possible correlation of this finding to human cancers was suggested by epidemiological analysis of data from Taiwan's National Health Insurance Research Database (NHIRD). Since our previous studies showed that modified tumor cell lysate (TCL)-pulsed, dendritic cell (DC)-based cancer vaccines can effectively suppress metastasis in mouse tumor models, we assessed whether such vaccines may help offset this rapamycin-promoted metastasis. We observed that shikonin efficiently induced ICD of 4T1 cells in culture, and DC vaccines pulsed with shikonin-treated TCL (SK-TCL-DC) significantly suppressed rapamycin-enhanced metastasis and Treg cell expansion in test mice. In conclusion, rapamycin treatment in mice (and perhaps in humans) promotes metastasis and the effect may be offset by treatment with a DC-based cancer vaccine. PMID- 26426424 TI - Multi-probe relaxation dispersion measurements increase sensitivity to protein dynamics. AB - Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion measurements are a valuable tool for the characterization of structural transitions on the micro millisecond timescale. While the measurement of (15)N relaxation dispersion is now routine, the measurements with alternative nuclei remain limited. Here we report (15)N as well as (1)H R2 relaxation dispersion measurements of the N23PP/S148A "dynamic knockout" mutant of dihydrofolate reductase. The (1)H dispersion measurements are complementary to (15)N data as many additional residues are observed to have dispersive behavior for the (1)H nucleus. Simultaneous fitting of the dispersion profiles for the two nuclei increases the accuracy of exchange parameters determined for individual residues and clustered groups of residues. The different sensitivity of the two nuclei to changes in backbone torsional angles, ring currents, and hydrogen bonding effects provides important insights into the nature of the structural changes that take place during the exchange process. We observe clear evidence of direct and indirect hydrogen bond effects for the (15)N and (1)H chemical shift changes in the active site, modulation of ring current shielding in the CD-loop and backbone torsional changes in a cluster of residues associated with the C-terminus. This work demonstrates the power of combined (1)H and (15)N probes for the study of backbone dynamics on the micro-millisecond timescale though the analysis of chemical shift changes. PMID- 26426425 TI - Supracerebellar infratentorial approach with paramedian expansion for posterior third ventricular and pineal region lesions. AB - BACKGROUND: Surgical treatment for lesions in the posterior third ventricle is technically challenging. Surgical approaches to this area carries a risk of both venous and neural injury, with subsequent morbidity. Several approaches are used to reach the pineal region. The supracerebellar infratentorial approach is the commonly approach used for such lesions. OBJECTIVES: This work describes adding a paramedian expansion to the "classical median supracerebellar infratentorial approach" for posterior third ventricular and pineal region lesions with lateral expansion. This study discusses the results concerning the extent of removal and surgical complications for this procedure. Contralateral paramedian expansion is used for targeting lesions inside the posterior third ventricle extending to the lateral ventricular wall and thalamus. Ipsilateral paramedian expansion was used in resecting collicular lesions. METHODS: The authors operated on patients suffering from lesions in the pineal region using a paramedian expanded SCTT approach between 2007 and 2014. The prone position was used in 25 cases. A typical median suboccipital craniotomy with a paramedian expansion was performed. Ipsilateral expansion of the approach has been used for targeting lesions in the pineal region but outside the posterior third ventricle. Contralateral expansion provides a direct view of the lateral walls of the third ventricle. RESULTS: We encountered 28 cases of different pathologies: fourteen patients suffered from pineal body tumors while twelve had glial tumors, one case of cavernoma. Obstructive hydrocephalus was treated by CSF diversion before tumor surgery. Postoperative complications included ataxia, double vision, and Parinaud's syndrome. CONCLUSION: The merit of the expanded supracerebellar infratentorial approach is adding a unilateral paramedian expansion to the classical approach. This paramedian expansion offers a better lateral and inferior tumor resection. This approach does not add any risk of more postoperative complications or jeopardizing the neurological state than the classical midline approach. PRACTICE AND IMPLICATIONS: The paramedian expansion offers a better lateral and inferior tumor resection and a better view of the contralateral extension within the posterior third ventricle. Collicular lesions are better controlled using this approach by gentle inferior and lateral retraction of the cerebellum. The expanded supracerebellar infratentorial approach allows for working on the lateral tumor extension without jeopardizing the deep venous system. PMID- 26426426 TI - Education and Imaging. Gastrointestinal: Sarcomatoid carcinoma of the colon, a rare and highly aggressive tumor subtype. PMID- 26426427 TI - Remote Control of the Planar Chirality in Peptide-Bound Metallomacrocycles and Dynamic-to-Static Planar Chirality Control Triggered by Solvent-Induced 3(10)-to alpha-Helix Transitions. AB - The dynamic planar chirality in a peptide-bound Ni(II)-salphen-based macrocycle can be remotely controlled. First, a right-handed (P)-3(10)-helix is induced in the dynamic helical oligopeptides by a chiral amino acid residue far from the macrocyclic framework. The induced planar chirality remains dynamic in chloroform and acetonitrile, but is almost completely locked in fluoroalcohols as a result of the solvent-induced transition of the peptide chains from a 3(10)-helix to a wider alpha-helix, which freezes the rotation of the pendant peptide units around the macrocycle. PMID- 26426429 TI - Obesity, low levels of physical activity and smoking present opportunities for primary care asthma interventions: an analysis of baseline data from The Asthma Tools Study. AB - BACKGROUND: Asthma prevalence, severity and outcomes are associated with various patient characteristics and lifestyle choices. AIMS: To identify potentially modifiable factors associated with poor asthma outcomes among US primary care patients. METHODS: Using baseline data from the Asthma Tools Study, we calculated cross-sectional frequencies of activity levels, smoking, secondhand smoke exposure and the presence of obesity, as well as rates of out-of-control asthma and asthma exacerbations. Frequencies were stratified by sex, and into three age groups: 5-11 years, 12-18 years and 19 years and older. Logistic regression was used to identify factors associated with each of the asthma outcomes. RESULTS: In the 901 individuals enrolled in this asthma study, tobacco smoke exposure, obesity, low activity levels, poverty, inadequately controlled asthma and high asthma-related health-care utilisation were common. Across all age groups, obesity was associated with poorer asthma outcomes: either poor asthma control (odds ratio (OR)=2.3, 95% confidence interval (CI) 1.1-4.7 in 5- to 11-year-olds and OR=1.5, 95% CI 1.1-2.2 in adults) or asthma exacerbations (OR 2.9, 95% CI 1.6 5.1 in 12- to 18-year-olds and OR 1.7, 95% CI 1.1-2.5 in adults). Among adults, smoking was associated with both measures of poorer asthma outcomes; inadequate asthma control (OR=2.3, 95% CI 1.5-3.5), and asthma exacerbations (OR 1.7, 95% CI 1.1-2.6), and low physical activity were associated with poor asthma control (OR=1.5, 95% CI 1.1-2.2). CONCLUSIONS: Obesity, low levels of physical activity and smoking are common, and they are associated with poor asthma outcomes in a sample of primary care patients, suggesting important targets for intervention. PMID- 26426430 TI - Correlation of Thermal Stability and Structural Distortion of DNA Interstrand Cross-Links Produced from Oxidized Abasic Sites with Their Selective Formation and Repair. AB - C4'-oxidized (C4-AP) and C5'-oxidized abasic sites (DOB) that are produced following abstraction of a hydrogen atom from the DNA backbone reversibly form cross-links selectively with dA opposite a 3'-adjacent nucleotide, despite the comparable proximity of an opposing dA. A previous report on UvrABC incision of DNA substrates containing stabilized analogues of the ICLs derived from C4-AP and DOB also indicated that the latter is repaired more readily by nucleotide excision repair [Ghosh, S., and Greenberg, M. M. (2014) Biochemistry 53, 5958 5965]. The source for selective cross-link formation was probed by comparing the reactivity of ICL analogues of C4-AP and DOB that mimic the preferred and disfavored cross-links with that of reagents that indirectly detect distortion by reacting with the nucleobases. The disfavored C4-AP and DOB analogues were each more reactive than the corresponding preferred cross-link substrates, suggesting that the latter are more stable, which is consistent with selective ICL formation. In addition, the preferred DOB analogue is more reactive than the respective C4-AP ICL, which is consistent with its more efficient incision by UvrABC. The conclusions drawn from the chemical probing experiments are corroborated by UV melting studies. The preferred ICLs exhibit melting temperatures higher than those of the corresponding disfavored isomers. These studies suggest that oxidized abasic sites form reversible interstrand cross links with dA opposite the 3'-adjacent thymidine because these products are more stable and the thermodynamic preference is reflected in the transition states for their formation. PMID- 26426431 TI - Clinicopathological analysis of programmed cell death 1 and programmed cell death ligand 1 expression in the tumour microenvironments of diffuse large B cell lymphomas. AB - AIMS: To investigate the clinicopathological characteristics of programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) expression in the tumour microenvironments of diffuse large B cell lymphoma (DLBCL). METHODS AND RESULTS: Tumour tissues from 126 DLBCL patients were immunostained for PD-L1 and PD-1. The expression of PD-L1 by tumour cells and/or tumour-infiltrating immune cells (mainly macrophages) was evaluated, and the number of tumour-infiltrating PD-1(+) cells was assessed. PD-L1 expression in tumour cells was observed in 61.1% of DLBCLs, with a weak intensity in 29.4%, moderate intensity in 21.4% and strong intensity in 10.3% of cases. Strong PD-L1 expression in tumour cells was associated significantly with the presence of B symptoms (adjusted P = 0.005) and Epstein-Barr virus (EBV) infection (adjusted P = 0.015), and tended to be higher in activated B cell-like immunophenotype (16.7%) than germinal centre B cell-like immunophenotype (2.5%) (adjusted P = 0.271). DLBCLs with PD-L1 expression in tumour cells/macrophages showed similar clinicopathological characteristics. The quantity of PD-1(+) tumour-infiltrating lymphocytes correlated positively with the level of PD-L1 expression in tumour cells (P = 0.042) or in tumour cells/macrophages (P = 0.03). Increased infiltration of PD-1(+) cells was associated with prolonged progression-free survival (P = 0.005) and overall survival (P = 0.026) in DLBCL patients treated with rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP), whereas PD-L1 expression had no prognostic significance. CONCLUSIONS: PD-L1 and PD-1 were expressed variably in DLBCLs by tumour cells and tumour-infiltrating immune cells and might be potential therapeutic targets using PD-1/PD-L1 blockade. PMID- 26426432 TI - Simultaneous mechanical property and biodegradation improvement of wollastonite bioceramic through magnesium dilute doping. AB - The large-area bone defects in head (including calvarial, orbital, and maxillofacial bone) and segmental bone are attracting increased attention in a wide range of clinical departments. A key requirement for the clinical success of the bioactive ceramics is the match of the mechanical behavior of the implants with the specific bone tissue to be filled. This raises the question as to what design strategy might be the best indicators for the balance between mechanical properties and biological performances. Here we go beyond the traditional approaches that use phase conversion or biphasic hybrid; instead, we achieved a simultaneous enhancement of several mechanical parameters and optimalization of biodegradability by using a dilute doping of Mg in a single-phase wollastonite bioceramic. We show that the wollastonite ceramic can be rationally tuned in phase (alpha or beta), mechanical strength (in compression and bending mode), elastic modulus (18-23GPa), and fracture toughness (>3.2MPam(1/2)) through the usage of Mg dopant introduced at precisely defined dilute concentrations (Mg/Ca molar ratio: 1.2-2.1%). Meanwhile, the dilute Mg-doped wollastonite ceramics are shown to exhibit good bioactivity in vitro in SBF but biodegradation in Tris is inversely proportional to Mg content. Consequently, such new highly bioactive ceramics with appreciable strength and toughness are promising for making specific porous scaffolds for enhancing large segmental bone defect and thin-wall bone defect repair. PMID- 26426433 TI - Gate-Tunable Electron Transport Phenomena in Al-Ge?111?-Al Nanowire Heterostructures. AB - Electrostatically tunable negative differential resistance (NDR) is demonstrated in monolithic metal-semiconductor-metal (Al-Ge-Al) nanowire (NW) heterostructures integrated in back-gated field-effect transistors (FETs). Unambiguous signatures of NDR even at room temperature are attributed to intervalley electron transfer. At yet higher electric fields, impact ionization leads to an exponential increase of the current in the ?111? oriented Ge NW segments. Modulation of the transfer rates, manifested as a large tunability of the peak-to-valley ratio (PVR) and the onset of impact ionization is achieved by the combined influences of electrostatic gating, geometric confinement, and heterojunction shape on hot electron transfer and by electron-electron scattering rates that can be altered by varying the charge carrier concentration in the NW FETs. PMID- 26426434 TI - Necrotizing Enterocolitis Is Not Associated With Sequence Variants in Antioxidant Response Genes in Premature Infants. AB - Reactive oxygen species mediate intestinal injury in necrotizing enterocolitis (NEC), and yet the contribution of antioxidant response (ARE) gene polymorphisms to NEC risk remains unknown. Premature infants recruited in a multicenter study were genotyped for 6 ARE variants. Among 637 infants, 52 had NEC, and 22 developed surgical NEC. Gestational age <28 weeks (P < 0.02) and African American race (P = 0.03) were associated with NEC. The NFE2L2 (rs6721961), SOD2 (rs4880), GSTP1 (rs1695), NQO1 (rs1800566), GCLC (rs17883901), and HMOX1 (rs2071747) variants were not associated with medical or surgical NEC. This study does not support a role for common deleterious ARE variants in NEC. PMID- 26426436 TI - Synthesis and strong photooxidation power of a supramolecular hybrid comprising a polyoxometalate and Ru(II) polypyridyl complex with zinc(II). AB - A novel method for constructing supramolecular hybrids composed of polyoxometalates and photofunctional metal complexes was developed. A Ru(II) complex with phosphonate groups (RuP) strongly interacted with Zn(II) to afford a 2 : 1 trinuclear metal complex ([(RuP)2Zn](3+)). In dimethylsulfoxide, [(RuP)2Zn](3+) strongly interacted with a Keggin-type heteropolyoxometalate (Si WPOM) to form a 1 : 1 hybrid ([(RuP)2Zn]-POM). Irradiation of [(RuP)2Zn]-POM in the presence of diethanolamine caused rapid accumulation of the one-electron reduced hybrid with a quantum yield of 0.99. PMID- 26426435 TI - Altered NMDA receptor function in primary cultures of hippocampal neurons from mice lacking the Homer2 gene. AB - N-Methyl-D-Aspartate (NMDA) receptors are inhibited during acute exposure to ethanol and are involved in changes in neuronal plasticity following repeated ethanol exposure. The postsynaptic scaffolding protein Homer2 can regulate the cell surface expression of NMDA receptors in vivo, and mice with a null mutation of the Homer2 gene exhibit an alcohol-avoiding and -intolerant phenotype that is accompanied by a lack of ethanol-induced glutamate sensitization. Thus, Homer2 deletion may perturb the function or acute ethanol sensitivity of the NMDA receptor. In this study, the function and ethanol sensitivity of glutamate receptors in cultured hippocampal neurons from wild-type (WT) and Homer2 knock out (KO) mice were examined at 7 and 14 days in vitro (DIV) using standard whole cell voltage-clamp electrophysiology. As compared with wild-type controls, NMDA receptor current density was reduced in cultured hippocampal neurons from Homer2 KO mice at 14 DIV, but not at 7 DIV. There were no genotype-dependent changes in whole-cell capacitance or in currents evoked by kainic acid. The GluN2B-selective antagonist ifenprodil inhibited NMDA-evoked currents to a similar extent in both wild-type and Homer2 KO neurons and inhibition was greater at 7 versus 14 DIV. NMDA receptor currents from both WT and KO mice were inhibited by ethanol (10-100 mM) and the degree of inhibition did not differ as a function of genotype. In conclusion, NMDA receptor function, but not ethanol sensitivity, is reduced in hippocampal neurons lacking the Homer2 gene. PMID- 26426439 TI - Mg-Zr Cosubstituted Ta3N5 Photoanode for Lower-Onset-Potential Solar-Driven Photoelectrochemical Water Splitting. AB - In p/n photoelectrochemical (PEC) cell systems, a low onset potential for the photoanode, as well as a high photocurrent, are critical for efficient water splitting. Here, we report a Mg-Zr cosubstituted Ta3N5 (Ta3N5:Mg+Zr) photoanode, designed to provide a more negative onset potential for PEC water splitting. The anodic photocurrent onset on Ta3N5:Mg+Zr was 0.55 V(RHE) under AM 1.5G-simulated sunlight, which represented a negative shift from the ca. 0.8 V(RHE) for pure Ta3N5. This negative shift in the onset potential of PEC water splitting was attributed to the change in the bandgap potential due to partial substitution by the foreign ions Mg(2+) and/or Zr(4+). PMID- 26426440 TI - Small RNA and Degradome Sequencing Reveal Complex Roles of miRNAs and Their Targets in Developing Wheat Grains. AB - Plant microRNAs (miRNAs) have been shown to play critical roles in plant development. In this study, we employed small RNA combined with degradome sequencing to survey development-related miRNAs and their validated targets during wheat grain development. A total of 186 known miRNAs and 37 novel miRNAs were identified in four small RNA libraries. Moreover, a miRNA-like long hairpin locus was first identified to produce 21~22-nt phased siRNAs that act in trans to cleave target mRNAs. A comparison of the miRNAomes revealed that 55 miRNA families were differentially expressed during the grain development. Predicted and validated targets of these development-related miRNAs are involved in different cellular responses and metabolic processes including cell proliferation, auxin signaling, nutrient metabolism and gene expression. This study provides insight into the complex roles of miRNAs and their targets in regulating wheat grain development. PMID- 26426441 TI - Vitamin D deficiency is an independent risk factor for PTDM after kidney transplantation. AB - An association between 25 hydroxyvitamin D [25(OH)D] deficiency and type 2 diabetes was observed in the general population. Such association was not investigated in kidney transplant recipients. We prospectively evaluated 444 patients following primary kidney transplantation between 2000 and 2010. The 25(OH)D level at transplantation was classified into three grades: deficiency (< 10 ng/ml), insufficiency (>= 10 and < 30 ng/ml), and normal range (>= 30 ng/ml). Time to Post-Transplant Diabetes Mellitus (PTDM) was defined according to the day of first prescription of hypoglycemic treatment. The 25(OH)D level at transplantation was deficient in 88 patients, insufficient in 264 patients, and normal in 92 patients. At 1 year post-transplantation, cumulative incidence of PTDM was 13.2%. Cox multivariate analysis indicated that 25(OH)D deficiency (<= 10 ng/ml) at the time of transplantation was an independent risk factor for PTDM within the first year post-transplantation (HR = 2.41, 95% CI 1.01-5.75, P = 0.048), whereas insufficiency tended to increase this risk, although not significantly. 25(OH)D deficiency is a new independent risk factor for PTDM within the first year after kidney transplantation. Our study suggests that 25(OH)D may be a marker of general health in kidney transplant recipients and could alert clinicians for PTDM risk. PMID- 26426442 TI - Management of aripiprazole-induced tardive Pisa syndrome: a case report and literature review. AB - Pisa syndrome (PS) is characterized by an abnormally sustained posture with flexion of the body and head to one side and slight axial rotation of the trunk. PS has been related to the use of neuroleptics and is clinically classified as either an acute or a tardive dystonia. This is the first report describing a case of late-onset PS, occurring in a young patient treated with aripiprazole for 2 years. To establish optimal treatment management, we reviewed the literature on aripiprazole-induced PS and tardive dystonia. In light of current knowledge, we proposed a multistep algorithm to aid in the clinical management of this condition. PMID- 26426443 TI - Use of benzodiazepines in obsessive-compulsive disorder. AB - This study aimed to determine the frequency of benzodiazepine (BDZ) use in a large sample of patients with obsessive-compulsive disorder (OCD) and ascertain the type of BDZ used and the correlates and predictors of BDZ use in OCD. The sample consisted of 955 patients with OCD from a comprehensive, cross-sectional, multicentre study conducted by the Brazilian Research Consortium on Obsessive Compulsive Spectrum Disorders between 2003 and 2009. The rate of BDZ use over time in this OCD sample was 38.4%. Of individuals taking BDZs, 96.7% used them in combination with other medications, usually serotonin reuptake inhibitors. The most commonly used BDZ was clonazepam. Current age, current level of anxiety and number of additional medications for OCD taken over time significantly predicted BDZ use. This is the first study to comprehensively examine BDZ use in OCD patients, demonstrating that it is relatively common, despite recommendations from treatment guidelines. Use of BDZs in combination with several other medications over time and in patients with marked anxiety suggests that OCD patients taking BDZs may be more complex and more difficult to manage. This calls for further research and clarification of the role of BDZs in the treatment of OCD. PMID- 26426450 TI - Do resonance-assisted intramolecular halogen bonds exist without a charge transfer and a sigma-hole? AB - To analyze the properties and mechanisms of six types of intramolecular resonance assisted halogen bonds (Br...O, Cl...O, F...O, Br...O, Cl...S and F...S), we have chosen the five-membered closed ring system X-C1R1=C3R2-C2R3=Y (X = Br, Cl & F; Y = O & S) of unsaturated compounds with the substituents NO2, CH3 and H. A total of 78 structures were investigated by quantum chemical calculations at the MP2/aug-cc-pVTZ level of theory. A molecular electrostatic potential (MESP) map reveals that the cusp point of the sigma-hole was not utilized but the belt point was used for all these intramolecular halogen-bonding interactions, indicating that all are electrostatic interactions. The halogen-bonding angle is below 100 degrees with the strongest interactions. The value of the nucleus-independent chemical shift (NICS (1)) reflects the changes and efficiency of resonance in all structures with a long bond. The presence of all interactions was proved by the bond critical point (BCP) and analyzed through its electron density, Laplacian of electron density and ellipticity parameter. The linear-probability correlation between the difference of the sum of the van der Waals radius and the non covalent bond length (?vdW-L) and the electron density of the BCP was reported. 2D and 3D-NCI (non covalent interactions) plots show that halogen-bonding interactions are a mixed type of interactions with an attractive term. Natural bond orbital (NBO) analysis clearly indicates that the halogen bond lacks charge transfer and orbital overlapping through non-interacting lobes. PMID- 26426444 TI - Cloning and Characterization of 5' Flanking Regulatory Sequences of AhLEC1B Gene from Arachis Hypogaea L. AB - LEAFY COTYLEDON1 (LEC1) is a B subunit of Nuclear Factor Y (NF-YB) transcription factor that mainly accumulates during embryo development. We cloned the 5' flanking regulatory sequence of AhLEC1B gene, a homolog of Arabidopsis LEC1, and analyzed its regulatory elements using online software. To identify the crucial regulatory region, we generated a series of GUS expression frameworks driven by different length promoters with 5' terminal and/or 3' terminal deletion. We further characterized the GUS expression patterns in the transgenic Arabidopsis lines. Our results show that both the 65 bp proximal promoter region and the 52 bp 5' UTR of AhLEC1B contain the key motifs required for the essential promoting activity. Moreover, AhLEC1B is preferentially expressed in the embryo and is co regulated by binding of its upstream genes with both positive and negative corresponding cis-regulatory elements. PMID- 26426451 TI - Does attention redirection contribute to the effectiveness of attention bias modification on social anxiety? AB - Attention bias modification (ABM) is designed to modify threat-related attention bias and thus alleviate anxiety. The current research examined whether consistently directing attention towards targeted goals per se contributes to ABM efficacy. We randomly assigned 68 non-clinical college students with elevated social anxiety to non-valence-specific attend-to-geometrics (AGC), attention modification (AMC), or attention control (ACC) conditions. We assessed subjective, behavioral, and physiological reactivity to a speech task and self reported social anxiety symptoms. After training, participants in the AMC exhibited an attention avoidance from threat, and those in the AGC responded more rapidly toward targeted geometrics. There was a significant pre- to post reduction in subjective speech distress across groups, but behavioral and physiological reactivity to speech, as well as self-report social anxiety symptoms, remained unchanged. These results lead to questions concerning effectiveness of ABM training for reducing social anxiety. Further examination of the current ABM protocol is required. PMID- 26426449 TI - Triptolide enhances the tumoricidal activity of TRAIL against renal cell carcinoma. AB - Renal cell carcinoma (RCC) is resistant to traditional cancer therapies, and metastatic RCC (mRCC) is incurable. The shortcomings in current therapeutic options for patients with mRCC provide the rationale for the development of novel treatment protocols. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has proven to be a potent inducer of tumor cell death in vitro and in vivo, and a number of TRAIL death receptor agonists (recombinant TRAIL or TRAIL death receptor-specific mAb) have been developed and tested clinically. Unfortunately the clinical efficacy of TRAIL has been underwhelming and is likely due to a number of possible mechanisms that render tumors resistant to TRAIL, prompting the search for drugs that increase tumor cell susceptibility to TRAIL. The objective of this study was to determine the effectiveness of combining the diterpene triepoxide triptolide, or its water-soluble prodrug, Minnelide, with TRAIL receptor agonists against RCC in vitro or in vivo, respectively. TRAIL induced apoptotic death of human RCC cells was increased in the presence of triptolide. The triptolide-induced sensitization was accompanied by increased TRAIL-R2 (DR5) and decreased heat shock protein 70 expression. In vivo treatment of mice bearing orthotopic RCC (Renca) tumors showed the combination of Minnelide and agonistic anti-DR5 mAb significantly decreased tumor burden and increased animal survival compared to either therapy alone. Our data suggest triptolide/Minnelide sensitizes RCC cells to TRAIL-induced apoptosis through altered TRAIL death receptor and heat shock protein expression. PMID- 26426452 TI - Adipokinins in pregnancies at risk of preterm delivery. AB - OBJECTIVE: To compare adipokinins between women experiencing preterm labor (PTL) and prior preterm deliveries (PTD). STUDY DESIGN: In this prospective observational cohort, 110 women with a singleton <35 weeks at increased risk of PTD were studied. Serum leptin, adiponectin, and resistin were obtained at three times (23-34 weeks, 35-36 weeks, at delivery) and analyzed via enzyme-linked immunosorbent assay. The adipokinins were compared across time and between PTL (n = 59) and prior PTD (n = 51) groups using generalized estimated equation models. RESULTS: There were no differences in leptin, adiponectin, or resistin levels over the three times between the PTL and PTD groups. There was a trend toward higher leptin levels (p = 0.06 unadjusted analysis, p = 0.09 adjusted analysis) at 23-34 weeks. When stratified by body mass index (BMI), there were differences in leptin (p < 0.001 for BMI < 30; p = 0.77 for BMI >= 30) and adiponectin (p = 0.04 for BMI < 30; p = 0.09 for BMI >= 30), but not in resistin over the three times between the PTL and prior PTD groups. CONCLUSION: There were no significant differences in adipokinins in women with PTL and a prior PTD. The trends toward higher leptin levels at 23-34 weeks in women with PTL may represent a compensatory response and require further evaluation in the study of treatments for PTL. PMID- 26426453 TI - MASCG: Multi-Atlas Segmentation Constrained Graph method for accurate segmentation of hip CT images. AB - This paper addresses the issue of fully automatic segmentation of a hip CT image with the goal to preserve the joint structure for clinical applications in hip disease diagnosis and treatment. For this purpose, we propose a Multi-Atlas Segmentation Constrained Graph (MASCG) method. The MASCG method uses multi-atlas based mesh fusion results to initialize a bone sheetness based multi-label graph cut for an accurate hip CT segmentation which has the inherent advantage of automatic separation of the pelvic region from the bilateral proximal femoral regions. We then introduce a graph cut constrained graph search algorithm to further improve the segmentation accuracy around the bilateral hip joint regions. Taking manual segmentation as the ground truth, we evaluated the present approach on 30 hip CT images (60 hips) with a 15-fold cross validation. When the present approach was compared to manual segmentation, an average surface distance error of 0.30 mm, 0.29 mm, and 0.30 mm was found for the pelvis, the left proximal femur, and the right proximal femur, respectively. A further look at the bilateral hip joint regions demonstrated an average surface distance error of 0.16 mm, 0.21 mm and 0.20 mm for the acetabulum, the left femoral head, and the right femoral head, respectively. PMID- 26426454 TI - Further Examination of the Resetting Zone in Supraventricular Tachycardia. PMID- 26426455 TI - Development of chitosan/poly-gamma-glutamic acid/pluronic/curcumin nanoparticles in chitosan dressings for wound regeneration. AB - The hydrophobic polyphenol curcumin has anti-inflammatory, antimicrobial, and wound-healing properties that warrant its pharmacological consideration. We report a curcumin nanoparticle with a tripolymeric composite that can be used as a delivery device for wound healing. The present composite nanoparticles were prepared with three biocompatible polymers of chitosan, poly-gamma-glutamic acid, and pluronic using a simple ionic gelation technology. Pluronic was used to enhance the solubility of curcumin in chitosan/poly-gamma-glutamic acid nanoparticles, leading to the incorporation of chitosan/poly-gamma-glutamic acid/pluronic/curcumin nanoparticles into chitosan membranes, and reduced inflammation and bacterial infection during wound regeneration. Nanoparticles were of 193.1 +/- 8.9 nm and had a zeta potential of 20.6 +/- 2.4 mV. Moreover, in vitro analyses indicated controlled curcumin release in a simulated skin tissue model. Subsequent in vivo studies show that chitosan wound dressing containing chitosan/poly-gamma-glutamic acid/pluronic/curcumin nanoparticles promoted neocollagen regeneration and tissue reconstruction. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 81-90, 2017. PMID- 26426456 TI - The role of serological titres in the diagnosis of ocular toxoplasmosis. PMID- 26426457 TI - Brief report: Assessing youth well-being in global emergency settings: Early results from the Emergency Developmental Assets Profile. AB - The 13-item Emergency Developmental Assets Profile measures the well-being of children and youth in emergency settings such as refugee camps and armed conflict zones, assessing whether young people are experiencing adequate positive relationships and opportunities, and developing positive values, skills, and self perceptions, despite being in crisis circumstances. The instrument was found to have acceptable and nearly identical internal consistency reliability in 22 administrations in non-emergency samples in 15 countries (.75), and in 4 samples of youth ages 10-18 (n = 1550) in the emergency settings (war refugees and typhoon victims, .74) that are the measure's focus, and evidence of convergent validity. Confirmatory Factor Analysis showed acceptable model fit among those youth in emergency settings. Measures of model fit showed that the Em-DAP has configural and metric invariance across all emergency contexts and scalar invariance across some. The Em-DAP is a promising brief cross-cultural tool for assessing the developmental quality of life as reported by samples of youth in a current humanitarian crisis situation. The results can help to inform international relief program decisions about services and activities to be provided for children, youth, and families in emergency settings. PMID- 26426459 TI - Multidetector computed tomography angiography in the management of transarterial embolization of primary and secondary liver malignancy. AB - BACKGROUND: Endovascular management is the mainstay of therapy for most patients with primary and secondary liver tumors. Radiologist should understand the anatomy of the hepatic vasculature and tumor feeding vessels to ensure successful conduction of the embolization procedure. The aim of this study was to evaluate the accuracy of multidetector computed tomographic angiography (MDCTA) for the evaluation of hepatic arterial anatomy and tumor feeding vessels prior to embolization procedure. METHODS: This study included 42 patients. They were 30 with hepatocellular carcinoma, 6 with colorectal cancer metastases, 3 with intrahepatic cholangiocellular carcinoma, 2 with giant focal nodular hyperplasia and 1 with gallbladder tumor. The findings of MDCTA were compared with the DSA findings, which served as the standard of reference. Sensitivity and specificity of the MDCTA were calculated. RESULTS: MDCTA showed 100% coincidence with the DSA and 100% accuracy in the evaluation of gross hepatic arterial anatomy and its variations. 61 out of the 64 feeders were correctly identified with the MDCTA. False positives and false negatives were 3 each. Accordingly sensitivity and specificity were 95.31%, 97.95% respectively. CONCLUSIONS: MDCT angiography permits accurate assessment of the hepatic vascular anatomy. Although some pathways of tumor irrigation may not be well visible on the computed tomography. These require detailed reevaluation of suspected tumor feeders during embolization procedure. PMID- 26426458 TI - Randomized Trial of Apneic Oxygenation during Endotracheal Intubation of the Critically Ill. AB - RATIONALE: Hypoxemia is common during endotracheal intubation of critically ill patients and may predispose to cardiac arrest and death. Administration of supplemental oxygen during laryngoscopy (apneic oxygenation) may prevent hypoxemia. OBJECTIVES: To determine if apneic oxygenation increases the lowest arterial oxygen saturation experienced by patients undergoing endotracheal intubation in the intensive care unit. METHODS: This was a randomized, open label, pragmatic trial in which 150 adults undergoing endotracheal intubation in a medical intensive care unit were randomized to receive 15 L/min of 100% oxygen via high-flow nasal cannula during laryngoscopy (apneic oxygenation) or no supplemental oxygen during laryngoscopy (usual care). The primary outcome was lowest arterial oxygen saturation between induction and 2 minutes after completion of endotracheal intubation. MEASUREMENTS AND MAIN RESULTS: Median lowest arterial oxygen saturation was 92% with apneic oxygenation versus 90% with usual care (95% confidence interval for the difference, -1.6 to 7.4%; P = 0.16). There was no difference between apneic oxygenation and usual care in incidence of oxygen saturation less than 90% (44.7 vs. 47.2%; P = 0.87), oxygen saturation less than 80% (15.8 vs. 25.0%; P = 0.22), or decrease in oxygen saturation greater than 3% (53.9 vs. 55.6%; P = 0.87). Duration of mechanical ventilation, intensive care unit length of stay, and in-hospital mortality were similar between study groups. CONCLUSIONS: Apneic oxygenation does not seem to increase lowest arterial oxygen saturation during endotracheal intubation of critically ill patients compared with usual care. These findings do not support routine use of apneic oxygenation during endotracheal intubation of critically ill adults. Clinical trial registered with www.clinicaltrials.gov (NCT 02051816). PMID- 26426460 TI - Irritable bowel syndrome in quiescent inflammatory bowel disease: a review. AB - Ongoing troublesome bowel symptoms despite quiescent inflammatory disease are a frequent management challenge when caring for patients with inflammatory bowel disease (IBD). Even when active disease has been excluded the prevalence of residual gastrointestinal symptoms is surprisingly high and the cause often obscure. The presence of a concurrent functional disorder such as irritable bowel syndrome (IBS) is associated with worse quality of life, worse physical functioning, higher prevalence of anxiety and greater health care utilization. Potential etiological mechanisms leading to the development of IBS like symptoms include the development of visceral hypersensitivity following the original inflammatory insult, alteration in cortical processing, dysbiosis and residual subacute inflammation. Therapeutic options for managing IBS in patients with IBD include dietary modification, interventions targeted at correction of visceral sensory dysfunction or cortical processing and modulation of the gut microbiota. As there are few studies specifically examining the treatment of IBS in patients with IBD, the majority of therapeutic interventions are extrapolated from the IBS literature. Given the frequency of residual functional symptoms in IBS, significantly more research is warranted in this field. PMID- 26426461 TI - Cerebral Blood-Flow Regulation During Hemorrhage. AB - Massive uncontrolled blood loss can occur under a variety of conditions including trauma, as a complication of childbirth or surgery, ruptured ulcers, clotting disorders, and hemorrhagic fevers. Across the continuum of hemorrhage, loss of blood volume is a significant challenge to the maintenance of cerebral perfusion. During the initial stages of hemorrhage, reflex mechanisms are activated to protect cerebral perfusion, but persistent blood loss will eventually reduce global cerebral blood flow and the delivery of metabolic substrates, leading to generalized cerebral ischemia, hypoxia, and ultimately, neuronal cell death. Cerebral blood flow is controlled by various regulatory mechanisms, including prevailing arterial pressure, intracranial pressure, arterial blood gases, neural activity, and metabolic demand. Hemorrhage represents a unique physiological stress to the brain, as it influences each of these regulatory mechanisms, resulting in complex interplay that ultimately challenges the ability of the brain to maintain adequate perfusion. Early studies of actual hemorrhage in humans employed blood loss protocols up to 1000 mL, but did not include any measurements of cerebral blood flow. As ethical considerations necessarily constrain the use of human volunteers for massive blood loss studies that induce irreversible shock, most of what is known about cerebral blood-flow responses to hemorrhage has been determined from animal models. Limitations of species differences regarding regulatory mechanisms, anatomy, and the effect of anesthesia, however, must be considered. Advances in monitoring technologies, and a recent renewed interest in understanding cerebral blood-flow regulation in humans, however, is rapidly accelerating knowledge in this field. PMID- 26426463 TI - Gene Targeting in Neuroendocrinology. AB - Research in neuroendocrinology faces particular challenges due to the complex interactions between cells in the hypothalamus, in the pituitary gland and in peripheral tissues. Within the hypothalamus alone, attempting to target a specific neuronal cell type can be problematic due to the heterogeneous nature and level of cellular diversity of hypothalamic nuclei. Because of the inherent complexity of the reproductive axis, the use of animal models and in vivo experiments are often a prerequisite in reproductive neuroendocrinology. The advent of targeted genetic modifications, particularly in mice, has opened new avenues of neuroendocrine research. Within this review, we evaluate various mouse models used in reproductive neuroendocrinology and discuss the different approaches to generate genetically modified mice, along with their inherent advantages and disadvantages. We also discuss a variety of versatile genetic tools with a focus on their potential use in reproductive neuroendocrinology. PMID- 26426464 TI - Metabolism at the Max: How Vertebrate Organisms Respond to Physical Activity. AB - Activity metabolism is supported by phosphorylated reserves (adenosine triphosphate, creatine phosphate), glycolytic, and aerobic metabolism. Because there is no apparent variation between vertebrate groups in phosphorylated reserves or glycolytic potential of skeletal muscle, variation in maximal metabolic rate between major vertebrate groups represents selection operating on aerobic mechanisms. Maximal rates of oxygen consumption in vertebrates are supported by increased conductive and diffusive fluxes of oxygen from the environment to the mitochondria. Maximal CO2 efflux from the mitochondria to the environment must be matched to oxygen flux, or imbalances in pH will occur. Among vertebrates, there are a variety of modes of locomotion and vastly different rates of metabolism supported by a variety of cardiorespiratory architectures. However, interclass comparisons strongly implicate systemic oxygen transport as the rate-limiting step to maximal oxygen consumption for all vertebrate groups. The key evolutionary step that accounts for the approximately 10-fold increase in maximal oxygen flux in endotherms versus ectotherms appears to be maximal heart rate. Other variables such as ventilation, pulmonary/gill, and tissue diffusing capacity, have excess capacity and thus are not limiting to maximal oxygen consumption. During maximal activity, the ratio of ventilation to respiratory system blood flow is remarkably similar among vertebrates, and CO2 extraction efficiency increases while oxygen extraction efficiency decreases, suggesting that the respiratory system provides the largest resistance to maximal CO2 flux. Despite the large variation in modes of activity and rates of metabolism, maximal rates of oxygen and CO2 flux appear to be limited by the cardiovascular and respiratory systems, respectively. PMID- 26426465 TI - Human Physiology in an Aquatic Environment. AB - Water covers over 70% of the earth, has varying depths and temperatures and contains much of the earth's resources. Head-out water immersion (HOWI) or submersion at various depths (diving) in water of thermoneutral (TN) temperature elicits profound cardiorespiratory, endocrine, and renal responses. The translocation of blood into the thorax and elevation of plasma volume by autotransfusion of fluid from cells to the vascular compartment lead to increased cardiac stroke volume and output and there is a hyperperfusion of some tissues. Pulmonary artery and capillary hydrostatic pressures increase causing a decline in vital capacity with the potential for pulmonary edema. Atrial stretch and increased arterial pressure cause reflex autonomic responses which result in endocrine changes that return plasma volume and arterial pressure to preimmersion levels. Plasma volume is regulated via a reflex diuresis and natriuresis. Hydrostatic pressure also leads to elastic loading of the chest, increasing work of breathing, energy cost, and thus blood flow to respiratory muscles. Decreases in water temperature in HOWI do not affect the cardiac output compared to TN; however, they influence heart rate and the distribution of muscle and fat blood flow. The reduced muscle blood flow results in a reduced maximal oxygen consumption. The properties of water determine the mechanical load and the physiological responses during exercise in water (e.g. swimming and water based activities). Increased hydrostatic pressure caused by submersion does not affect stroke volume; however, progressive bradycardia decreases cardiac output. During submersion, compressed gas must be breathed which introduces the potential for oxygen toxicity, narcosis due to nitrogen, and tissue and vascular gas bubbles during decompression and after may cause pain in joints and the nervous system. PMID- 26426466 TI - Aging Effects on Cardiac Progenitor Cell Physiology. AB - Cardiac aging has been confounded by the concept that the heart is a postmitotic organ characterized by a predetermined number of myocytes, which is established at birth and largely preserved throughout life until death of the organ and organism. Based on this premise, the age of cardiac cells should coincide with that of the organism; at any given time, the heart would be composed of a homogeneous population of myocytes of identical age. The discovery that stem cells reside in the heart and generate cardiac cell lineages has imposed a reconsideration of the mechanisms implicated in the manifestations of the aging myopathy. The progressive alterations of terminally differentiated myocytes, and vascular smooth muscle cells and endothelial cells may represent an epiphenomenon dictated by aging effects on cardiac progenitor cells (CPCs). Changes in the properties of CPCs with time may involve loss of self-renewing capacity, increased symmetric division with formation of daughter committed cells, partial depletion of the primitive pool, biased differentiation to the fibroblast fate, impaired ability to migrate, and forced entry into an irreversible quiescent state. Telomere shortening is a major variable of cellular senescence and organ aging, and support the notion that CPCs with critically shortened or dysfunctional telomeres contribute to myocardial aging and chronic heart failure. These defects constitute the critical variables that define the aging myopathy in humans. Importantly, a compartment of functionally competent human CPCs persists in the decompensated heart pointing to stem cell therapy as a novel form of treatment for the aging myopathy. PMID- 26426467 TI - Liver Sinusoidal Endothelial Cells. AB - The liver sinusoidal endothelial cell (LSEC) forms the fenestrated wall of the hepatic sinusoid and functions as a control post regulating and surveying the trafficking of molecules and cells between the liver parenchyma and the blood. The cell acts as a scavenger cell responsible for removal of potential dangerous macromolecules from blood, and is increasingly acknowledged as an important player in liver immunity. This review provides an update of the major functions of the LSEC, including its role in plasma ultrafiltration and regulation of the hepatic microcirculation, scavenger functions, immune functions, and role in liver aging, as well as issues that are either undercommunicated or confusingly dealt with in the literature. These include metabolic functions, including energy metabolic interplay between the LSEC and the hepatocyte, and adequate ways of identifying and distinguishing the cells. PMID- 26426462 TI - Biomechanics of Cardiac Function. AB - The heart pumps blood to maintain circulation and ensure the delivery of oxygenated blood to all the organs of the body. Mechanics play a critical role in governing and regulating heart function under both normal and pathological conditions. Biological processes and mechanical stress are coupled together in regulating myocyte function and extracellular matrix structure thus controlling heart function. Here, we offer a brief introduction to the biomechanics of left ventricular function and then summarize recent progress in the study of the effects of mechanical stress on ventricular wall remodeling and cardiac function as well as the effects of wall mechanical properties on cardiac function in normal and dysfunctional hearts. Various mechanical models to determine wall stress and cardiac function in normal and diseased hearts with both systolic and diastolic dysfunction are discussed. The results of these studies have enhanced our understanding of the biomechanical mechanism in the development and remodeling of normal and dysfunctional hearts. Biomechanics provide a tool to understand the mechanism of left ventricular remodeling in diastolic and systolic dysfunction and guidance in designing and developing new treatments. PMID- 26426468 TI - Glucose Homeostasis and Cardiovascular Alterations in Diabetes. AB - Diabetes mellitus is an increasingly prevalent disease associated with a high morbidity and mortality burden. Many of the adverse outcomes secondary to diabetes occur as a result of the impaired glucose homeostasis and pathophysiological alterations to the cardiovascular system. The purpose of this overview is to broadly discuss many of the changes that occur in the context of diabetes that affect cardiovascular function. Following a brief introduction to the classification and etiologies of the various forms of diabetes, the mechanisms of impaired glucose homeostasis will be covered. Vascular endothelial dysfunction, which has been posited to play a major role in the development of target organ pathology, will be addressed, followed by a discussion of the effects of diabetes on the renal, cardiovascular, and pulmonary systems. PMID- 26426469 TI - Pathophysiology of Myocardial Infarction. AB - Myocardial infarction is defined as sudden ischemic death of myocardial tissue. In the clinical context, myocardial infarction is usually due to thrombotic occlusion of a coronary vessel caused by rupture of a vulnerable plaque. Ischemia induces profound metabolic and ionic perturbations in the affected myocardium and causes rapid depression of systolic function. Prolonged myocardial ischemia activates a "wavefront" of cardiomyocyte death that extends from the subendocardium to the subepicardium. Mitochondrial alterations are prominently involved in apoptosis and necrosis of cardiomyocytes in the infarcted heart. The adult mammalian heart has negligible regenerative capacity, thus the infarcted myocardium heals through formation of a scar. Infarct healing is dependent on an inflammatory cascade, triggered by alarmins released by dying cells. Clearance of dead cells and matrix debris by infiltrating phagocytes activates anti inflammatory pathways leading to suppression of cytokine and chemokine signaling. Activation of the renin-angiotensin-aldosterone system and release of transforming growth factor-beta induce conversion of fibroblasts into myofibroblasts, promoting deposition of extracellular matrix proteins. Infarct healing is intertwined with geometric remodeling of the chamber, characterized by dilation, hypertrophy of viable segments, and progressive dysfunction. This review manuscript describes the molecular signals and cellular effectors implicated in injury, repair, and remodeling of the infarcted heart, the mechanistic basis of the most common complications associated with myocardial infarction, and the pathophysiologic effects of established treatment strategies. Moreover, we discuss the implications of pathophysiological insights in design and implementation of new promising therapeutic approaches for patients with myocardial infarction. PMID- 26426471 TI - Assessment of Cardiac Function--Basic Principles and Approaches. AB - Increased access and ability to visualize the heart has provided a means to measure a myriad of cardiovascular parameters in real or near real time. However, without fundamental knowledge regarding the basis for cardiac contraction and how to evaluate cardiac function in terms of loading conditions and inotropic state, appropriate interpretation of these cardiovascular parameters can be difficult and can lead to misleading conclusions regarding the functional state of the cardiac muscle. Thus, in this series of Comprehensive Physiology, the basic properties of cardiac muscle function, the cardiac cycle, and determinants of pump function will be reviewed. These basic concepts will then be integrated by presenting approaches in which the effects of preload, afterload, and myocardial contractility can be examined. Moreover, the utility of the pressure-volume relation in terms of assessing both myocardial contractility as well as critical aspects of diastolic performance will be presented. Finally, a generalized approach for the assessment and interpretation of cardiac function within the intact cardiovascular system will be presented. PMID- 26426472 TI - Skeletal Muscle Changes in Chronic Cardiac Disease and Failure. AB - Peak exercise performance in healthy man is limited not only by pulmonary or skeletal muscle function but also by cardiac function. Thus, abnormalities in cardiac function will have a major impact on exercise performance. Many cardiac diseases affect exercise performance and indeed for some cardiac conditions such as atherosclerotic heart disease, exercise testing is frequently used not only to measure functional capacity but also to make a diagnosis of heart disease, evaluate the efficacy of treatment, and predict prognosis. Early in the course of cardiac diseases, exercise performance will be minimally affected but with disease progression impairment in exercise capacity will become apparent. Ejection fraction, that is, the percent of blood volume ejected with each cardiac cycle is often used as a measure of cardiac performance but frequently there is a dissociation between the ejection fraction and exercise capacity in patients with heart disease. How abnormalities in cardiac function impacts the muscles, vasculature, and lungs to impact exercise performance will here be reviewed. The focus of this work will be on patients with systolic heart failure as the incidence and prevalence of heart failure is reaching epidemic proportions and heart failure is the end result of many other chronic cardiac diseases. The prognostic role of exercise and benefits of exercise training will also be discussed. PMID- 26426473 TI - Corrigendum. PMID- 26426474 TI - An efficient transformation of furano-hydroxychalcones to furanoflavones via base mediated intramolecular tandem O-arylation and C-O bond cleavage: a new approach for the synthesis of furanoflavones. AB - A new and efficient potassium carbonate mediated intramolecular tandem O arylation followed by C-O bond cleavage of furano-hydroxychalcones is described. The treatment of furano-hydroxychalcones pongamol (1a) and ovalitenone (2a) with potassium carbonate in DMF led to the direct formation of the furanoflavones lanceolatin B (3ab) and pongaglabrone (4ab) in excellent yields. This is the first report on the cyclization of furano-hydroxychalcones via C-O bond cleavage (demethoxylation) to produce furanoflavonoids. PMID- 26426475 TI - Origins of the Stereoselectivity in a Thiourea-Primary Amine-Catalyzed Nazarov Cyclization. AB - The origins of stereoselectivity of the Nazarov reactions of alpha hydroxydivinylketones catalyzed by a vicinal thiourea-primary amine first reported by Tius have been explored with density functional theory. The electrocyclization transition structures in which the thiourea group of the catalyst donates two hydrogen bonds to the keto carbonyl group of the Nazarov reactant and the primary amine accepts a hydrogen bond from the hydroxyl group of the reactant have been modeled. The enantiomeric Nazarov transition structures, which are conventionally described by the absolute sense of conrotation of the dienone termini ("clockwise" or "counterclockwise") in the literature, are nonplanar and adopt helically chiral conformations. The interactions of these helical electrocyclization transition structures with the chiral catalyst are studied in detail. The organocatalyst is found to employ a combination of hydrogen bonding and steric effects to achieve helical recognition of the Nazarov transition state. PMID- 26426476 TI - Consideration of Submandibular (Undescended) Ectopic Parathyroid Glands in Surgery and Localization Studies. PMID- 26426477 TI - Water-like Anomalies and Phase Behavior of a Pair Potential that Stabilizes Diamond. AB - Water, silicon, silica, and other liquids that favor tetrahedral order display thermodynamic, dynamic, and structural anomalies in the pressure range in which they form tetrahedrally coordinated crystals. The tetrahedral order in these liquids is induced by anisotropic hydrogen bonding or covalent interactions, or, in ionic melts, by an appropriate size ratio of the ions. Simple isotropic two length scale models have been extensively used to understand the origin of anomalies in complex liquids. However, single-component isotropic liquids characterized to date generally do not stabilize tetrahedral crystals, and in the few cases that they do, it was found that the liquids do not display anomalies in the region of the tetrahedral crystal. This poses the question of whether it is possible for isotropic pair potentials to display water-like phase behavior and anomalies. In this work, we use molecular dynamics simulations to investigate the phase behavior and the existence and loci of anomalies of a single-component purely repulsive isotropic pair potential that stabilizes diamond in the ground state over a wide range of pressures. We demonstrate that, akin to water, silica, and silicon, the isotropic potential of Marcotte, Stillinger, and Torquato (MST) presents structural, dynamic, and thermodynamic anomalies in the region of stability of the tetrahedral crystal. The regions of anomalies of MST are nested in the T-p plane following the same hierarchy as in silica: the region of diffusional anomalies encloses the region of structural anomalies, which in turn contains the region of thermodynamic anomalies. To our knowledge, MST is the first example of pair potential for which water-like anomalies are associated with the formation of tetrahedral order. PMID- 26426470 TI - Physiological Implications of Myocardial Scar Structure. AB - Once myocardium dies during a heart attack, it is replaced by scar tissue over the course of several weeks. The size, location, composition, structure, and mechanical properties of the healing scar are all critical determinants of the fate of patients who survive the initial infarction. While the central importance of scar structure in determining pump function and remodeling has long been recognized, it has proven remarkably difficult to design therapies that improve heart function or limit remodeling by modifying scar structure. Many exciting new therapies are under development, but predicting their long-term effects requires a detailed understanding of how infarct scar forms, how its properties impact left ventricular function and remodeling, and how changes in scar structure and properties feed back to affect not only heart mechanics but also electrical conduction, reflex hemodynamic compensations, and the ongoing process of scar formation itself. In this article, we outline the scar formation process following a myocardial infarction, discuss interpretation of standard measures of heart function in the setting of a healing infarct, then present implications of infarct scar geometry and structure for both mechanical and electrical function of the heart and summarize experiences to date with therapeutic interventions that aim to modify scar geometry and structure. One important conclusion that emerges from the studies reviewed here is that computational modeling is an essential tool for integrating the wealth of information required to understand this complex system and predict the impact of novel therapies on scar healing, heart function, and remodeling following myocardial infarction. PMID- 26426478 TI - Hypocretin neuron-specific transcriptome profiling identifies the sleep modulator Kcnh4a. AB - Sleep has been conserved throughout evolution; however, the molecular and neuronal mechanisms of sleep are largely unknown. The hypothalamic hypocretin/orexin (Hcrt) neurons regulate sleep?wake states, feeding, stress, and reward. To elucidate the mechanism that enables these various functions and to identify sleep regulators, we combined fluorescence cell sorting and RNA-seq in hcrt:EGFP zebrafish. Dozens of Hcrt-neuron-specific transcripts were identified and comprehensive high-resolution imaging revealed gene-specific localization in all or subsets of Hcrt neurons. Clusters of Hcrt-neuron-specific genes are predicted to be regulated by shared transcription factors. These findings show that Hcrt neurons are heterogeneous and that integrative molecular mechanisms orchestrate their diverse functions. The voltage-gated potassium channel Kcnh4a, which is expressed in all Hcrt neurons, was silenced by the CRISPR-mediated gene inactivation system. The mutant kcnh4a (kcnh4a(-/-)) larvae showed reduced sleep time and consolidation, specifically during the night, suggesting that Kcnh4a regulates sleep. PMID- 26426480 TI - Utilization and Outcomes of BRCA Genetic Testing and Counseling in a National Commercially Insured Population: The ABOUT Study. AB - IMPORTANCE: BRCA genetic testing has substantial public health impact, yet little is known of the real-world experiences of the more than 100 000 Americans undergoing testing annually. OBJECTIVE: To identify factors associated with use of BRCA testing, assess whether delivery of genetic counseling and testing services adheres to professional guidelines, and measure the impact on patient reported outcomes. DESIGN, SETTING, AND PARTICIPANTS: The American BRCA Outcomes and Utilization of Testing (ABOUT) Study analyzed data from a consecutive national series of 11 159 women whose clinicians ordered BRCA testing between December 2011 and December 2012. Aetna mailed recruitment information across the United States to commercial health plan members whose clinicians had ordered BRCA testing. A total of 3874 women (34.7%) completed questionnaires. Deidentified clinician-reported data from all respondents and a random sample of 2613 nonrespondents were also analyzed. MAIN OUTCOMES AND MEASURES: The proportion of eligible participants who met testing criteria and respondents' report of receiving genetic counseling by a genetics clinician and its association with BRCA knowledge, understanding, and satisfaction were assessed. RESULTS: Among 3628 women respondents whose clinicians ordered comprehensive BRCA testing, most were white non-Hispanic (2502 [69.0%]), college educated (2953 [81.4%]), married (2751 [75.8%]), and had higher incomes (2011 [55.4%]). Approximately 16.4% (596) did not meet testing criteria. Mutations were identified in 161 (5.3%) of these women who received comprehensive testing. Only 1334 (36.8%) reported receiving genetic counseling from a genetics clinician prior to testing; the lowest rates (130 [12.3%]) were among patients of obstetrician/gynecologists. The most commonly reported reason for not receiving this clinical service was lack of clinician recommendation. Those who received it demonstrated greater knowledge about BRCA (mean score difference adjusted for demographics and clinician specialty, beta = 0.99 [95% CI, 0.83-1.14]; P < .001) and expressed greater understanding (beta = 0.47 [95% CI, 0.41-0.54]; P < .001) and satisfaction (beta = 2.21 [95% CI, 1.60-2.81]; P < .001). CONCLUSIONS AND RELEVANCE: Despite improved patient knowledge, understanding, and satisfaction among patients who receive genetic counseling provided by a genetics clinician, as well as multiple guidelines emphasizing the importance of genetic counseling, most US women undergoing BRCA genetic testing do not receive this clinical service. Lack of physician recommendation is the most commonly reported reason. These findings demonstrate important gaps in clinical genetics services. Recently mandated coverage of genetic counseling services as a preventive service without patient cost sharing should contribute to improving clinical genetics services and associated outcomes in the future. PMID- 26426482 TI - TWO CASES OF ACUTE ENDOPHTHALMITIS AFTER INTRAVITREAL DEXAMETHASONE IMPLANT INJECTION. AB - PURPOSE: To present two cases of acute endophthalmitis after intravitreal dexamethasone implant injection and discuss the management of intravitreal implant-associated endophthalmitis. METHODS: Two patients, who underwent intravitreal dexamethasone implant injection for macular edema secondary to diabetic retinopathy in one and branch retinal vein occlusion in the other, were admitted with decreased vision, pain, and redness in their treated eyes, 3 days and 5 days after the injection, respectively. The clinical findings of both patients were consistent with acute endophthalmitis. RESULTS: After obtaining aqueous and vitreous samples, the patients were treated with intravitreal antibiotic injection and topical fortified antibiotics. Both patients revealed favorable clinical response and functional vision was recovered. CONCLUSION: Intravitreal dexamethasone implant-associated endophthalmitis is an uncommon and a challenging situation. Intravitreal antibiotics may lead to favorable visual outcomes without the need for a pars plana vitrectomy and implant removal in selected cases. PMID- 26426479 TI - Evolutionary adaptation after crippling cell polarization follows reproducible trajectories. AB - Cells are organized by functional modules, which typically contain components whose removal severely compromises the module's function. Despite their importance, these components are not absolutely conserved between parts of the tree of life, suggesting that cells can evolve to perform the same biological functions with different proteins. We evolved Saccharomyces cerevisiae for 1000 generations without the important polarity gene BEM1. Initially the bem1? lineages rapidly increase in fitness and then slowly reach >90% of the fitness of their BEM1 ancestors at the end of the evolution. Sequencing their genomes and monitoring polarization reveals a common evolutionary trajectory, with a fixed sequence of adaptive mutations, each improving cell polarization by inactivating proteins. Our results show that organisms can be evolutionarily robust to physiologically destructive perturbations and suggest that recovery by gene inactivation can lead to rapid divergence in the parts list for cell biologically important functions. PMID- 26426481 TI - Development of Novel, CNS Penetrant Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1 (mGlu1), Based on an N-(3-Chloro-4-(1,3 dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide Scaffold, That Potentiate Wild Type and Mutant mGlu1 Receptors Found in Schizophrenics. AB - The therapeutic potential of selective mGlu1 activation is vastly unexplored relative to the other group I mGlu receptor, mGlu5; therefore, our lab has focused considerable effort toward developing mGlu1 positive allosteric modulators (PAMs) suitable as in vivo proof of concept tool compounds. Optimization of a series of mGlu1 PAMs based on an N-(3-chloro-4-(1,3 dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide scaffold provided 17e, a potent (mGlu1 EC50 = 31.8 nM) and highly CNS penetrant (brain to plasma ratio (Kp) of 1.02) mGlu1 PAM tool compound, that potentiated not only wild-type human mGlu1 but also mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenic patients. Moreover, both electrophysiological and in vivo studies indicate the mGlu1 ago-PAMs/PAMs do not possess the same epileptiform adverse effect liability as mGlu5 ago-PAMs/PAMs and maintain temporal activity suggesting a broader therapeutic window. PMID- 26426483 TI - Gold-installed biostable nanocomplexes for tumor-targeted siRNA delivery in vivo. AB - The key issues, associated with nanocarriers for small interfering RNAs (siRNAs), are their poor stability and lack of tumor targetability in vivo. To address these issues, we developed gold-installed polyethyleneimine/siRNA complexes with a corona of PEGylated hyaluronic acid. PMID- 26426484 TI - Excitation of Ni nanorod colloids in oscillating magnetic fields: a new approach for nanosensing investigated by TISANE. AB - The response of a colloidal dispersion of Ni nanorods to an oscillating magnetic field was characterized by optical transmission measurements as well as small angle neutron scattering (SANS) experiments using the TISANE (Time-dependent SANS experiments) technique. Exposed to a static magnetic field, the scattering intensity of the rod ensemble could be well described by the cylinder form factor using the geometrical particle parameters (length, diameter, orientation distribution) determined by transmission electronmicroscopy and magnetometry. An oscillation of the field vector resulted in a reorientation of the nanorods and a time-dependency of the scattering intensity due to the shape anisotropy of the rods. Analysis of the SANS data revealed that in the range of low frequencies the orientation distribution of the rods is comparable to the static case. With increasing frequency, the rod oscillation was gradually damped due to an increase of the viscous drag. It could be shown that despite of the increased friction in the high frequency range no observable change of the orientation distribution of the ensemble with respect to its symmetry axis occurs. PMID- 26426485 TI - A modelling approach for MOF-encapsulated metal catalysts and application to n butane oxidation. AB - Metal nanoparticles (NP) encapsulated by metal-organic frameworks (MOFs) are novel composite materials that have shown promise as regioselective catalysts. The regioselectivity in these materials arises from steric constraints imposed by the porous MOF structure, which limit the way molecules approach and interact with the metal surface. Here we introduce a conceptually simple DFT approach to model reactions under such steric constraints. This approach is computationally efficient and accounts for the steric constraints imposed by a MOF pore in a general way. The adsorption of reactants, intermediates, and products associated with oxidation of n-butane to 1-butanol (and 2-butanol) on clean and oxygen covered palladium surfaces is investigated with (and without) the constraints of a pore. Reaction energies are calculated, and we find that the thermodynamic favorability of the intermediate reactions is affected by the presence of steric constraints, oxygen coverage, and the exposed crystal surface of the metal. Based on these results, the Pd(111) surface with 0.25 ML oxygen coverage and steric constraints (which could be provided by a suitable MOF) seems promising to favor the desired sequence of reactions that would lead to the conversion of n-butane to 1-butanol. PMID- 26426486 TI - NanoSIMS analysis of an isotopically labelled organometallic ruthenium(II) drug to probe its distribution and state in vitro. AB - The in vitro inter- and intra-cellular distribution of an isotopically labelled ruthenium(II)-arene (RAPTA) anti-metastatic compound in human ovarian cancer cells was imaged using nano-scale secondary ion mass spectrometry (NanoSIMS). Ultra-high resolution isotopic images of (13)C, (15)N, and Ru indicate that the phosphine ligand remains coordinated to the ruthenium(II) ion whereas the arene detaches. The complex localizes mainly on the membrane or at the interface between cells which correlates with its anti-metastatic effects. PMID- 26426487 TI - Profiling Private Water Systems to Identify Patterns of Waterborne Lead Exposure. AB - Although extensive literature documents corrosion in municipal water systems, only minimal data is available describing corrosion in private water systems (e.g., wells), which serve as a primary source of drinking water for approximately 47 million Americans. This study developed a profiling technique specifically tailored to evaluate lead release in these systems. When applied in an intensive field study of 15 private systems, three patterns of lead release were documented: no elevated lead or lead elevated in the first draw only (Type I), erratic spikes of particulate lead (Type II), and sustained detectable lead concentrations (Type III). While flushing protocols as short as 15-30 s may be sufficient to reduce lead concentrations below 15 MUg/L for Types I and III exposure, flushing may not be an appropriate remediation strategy for Type II exposure. In addition, the sustained detectable lead concentrations observed with Type III exposure likely result from corrosion of components within the well and therefore cannot be reduced with increased flushing. As profiling techniques are labor- and sample-intensive, we discuss recommendations for simpler sampling schemes for initial private system surveys aimed at quantifying lead and protecting public health. PMID- 26426488 TI - Editorial: Lessons From the Classic Scientific Literature. PMID- 26426491 TI - Dielectric shell isolated and graphene shell isolated nanoparticle enhanced Raman spectroscopies and their applications. AB - Surface-enhanced Raman scattering (SERS) is a powerful technique that provides fingerprint vibrational information with ultrahigh sensitivity. However, only a few metals (gold, silver and copper) yield a large SERS effect, and they must be rough at the nanoscale. Shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS) was developed to overcome the long-standing materials and morphological limitations of SERS. It has already been applied in a variety of fields such as materials science, electrochemistry, surface science, catalysis, food safety and the life sciences. Here, the principles and applications of SHINERS are highlighted. To provide an understanding of the plasmonics involved, finite difference time-domain (FDTD) calculations and single nanoparticle SHINERS experiments are reviewed. Next, various shell-isolated nanoparticle (SHIN) types are described. Then a number of applications are discussed. In the first application, SHINERS is used to characterize the adsorption processes of pyridine on Au(hkl) single-crystal electrode surfaces. Then, SHINERS' applicability to food inspection and cultural heritage science is demonstrated by the detection of parathion and fenthion pesticides, and Lauth's violet (thionine dye). Finally, graphene-isolated Au nanoparticles (GIANs) are shown to be effective for multimodal cell imaging, photothermal cancer therapy and photothermally-enhanced chemotherapy. SHINERS is a fast, simple and reliable method, suitable for application to many areas of science and technology. The concept of shell isolation can also be applied to other surface-enhanced spectroscopies such as fluorescence, infrared absorption and sum frequency generation. PMID- 26426492 TI - Fano Resonant Aluminum Nanoclusters for Plasmonic Colorimetric Sensing. AB - Aluminum is an abundant and high-quality material for plasmonics with potential for large-area, low-cost photonic technologies. Here we examine aluminum nanoclusters with plasmonic Fano resonances that can be tuned from the near-UV into the visible region of the spectrum. These nanoclusters can be designed with specific chromaticities in the blue-green region of the spectrum and exhibit a remarkable spectral sensitivity to changes in the local dielectric environment. We show that such structures can be used quite generally for colorimetric localized surface plasmon resonance (LSPR) sensing, where the presence of analytes is detected by directly observable color changes rather than through photodetectors and spectral analyzers. To quantify our results and provide a metric for optimization of such structures for colorimetric LSPR sensing, we introduce a figure of merit based on the color perception ability of the human eye. PMID- 26426499 TI - Selective 2'-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP) for direct, versatile and accurate RNA structure analysis. AB - Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) chemistries exploit small electrophilic reagents that react with 2'-hydroxyl groups to interrogate RNA structure at single-nucleotide resolution. Mutational profiling (MaP) identifies modified residues by using reverse transcriptase to misread a SHAPE-modified nucleotide and then counting the resulting mutations by massively parallel sequencing. The SHAPE-MaP approach measures the structure of large and transcriptome-wide systems as accurately as can be done for simple model RNAs. This protocol describes the experimental steps, implemented over 3 d, that are required to perform SHAPE probing and to construct multiplexed SHAPE-MaP libraries suitable for deep sequencing. Automated processing of MaP sequencing data is accomplished using two software packages. ShapeMapper converts raw sequencing files into mutational profiles, creates SHAPE reactivity plots and provides useful troubleshooting information. SuperFold uses these data to model RNA secondary structures, identify regions with well-defined structures and visualize probable and alternative helices, often in under 1 d. SHAPE-MaP can be used to make nucleotide-resolution biophysical measurements of individual RNA motifs, rare components of complex RNA ensembles and entire transcriptomes. PMID- 26426500 TI - Fabrication of nanopores with ultrashort single-walled carbon nanotubes inserted in a lipid bilayer. AB - We describe a protocol for the insertion of ultrashort single-walled carbon nanotubes (SWCNTs) to form nanopores in a Montal-Mueller lipid bilayer. The SWCNTs are designed to bind to a specific analyte of interest; binding will result in the reduction of current in single-channel recording experiments. The first stage of the PROCEDURE is to cut and separate the SWCNTs. We cut long, purified SWCNTs with sonication in concentrated sulfuric acid/nitric acid (3/1). Isolation of ultrashort SWCNTs is carried out by size-exclusion HPLC separation. The second stage is to insert these short SWCNTs into the lipid bilayer. This step requires a microinjection probe made from a glass capillary. The setup for protein nanopore research can be adopted for the single-channel recording experiments without any special treatment. The obtained current traces are of very high quality, showing stable baselines and little background noise. Example procedures are shown for investigating ion transport and DNA translocation through these SWCNT nanopores. This nanopore has potential applications in molecular sensing, nanopore DNA sequencing and early disease diagnosis. For example, we have selectively detected modified 5-hydroxymethylcytosine in single stranded DNA (ssDNA), which may have implications in screening specific genomic DNA sequences. The protocol takes ~15 d, including SWCNT purification, cutting and separation, as well as the formation of SWCNT nanopores for DNA analyses. PMID- 26426501 TI - Efficient processing and analysis of large-scale light-sheet microscopy data. AB - Light-sheet microscopy is a powerful method for imaging the development and function of complex biological systems at high spatiotemporal resolution and over long time scales. Such experiments typically generate terabytes of multidimensional image data, and thus they demand efficient computational solutions for data management, processing and analysis. We present protocols and software to tackle these steps, focusing on the imaging-based study of animal development. Our protocols facilitate (i) high-speed lossless data compression and content-based multiview image fusion optimized for multicore CPU architectures, reducing image data size 30-500-fold; (ii) automated large-scale cell tracking and segmentation; and (iii) visualization, editing and annotation of multiterabyte image data and cell-lineage reconstructions with tens of millions of data points. These software modules are open source. They provide high data throughput using a single computer workstation and are readily applicable to a wide spectrum of biological model systems. PMID- 26426503 TI - Photoelectrochemical properties of porphyrin dyes with a molecular dipole in the linker. AB - The electronic properties of three porphyrin-bridge-anchor photosensitizers are reported with (1a, 1e, 3a and 3e) or without (2a and 2e) an intramolecular dipole in the bridge. The presence and orientation of the bridge dipole is hypothesized to influence the photovoltaic properties due to variations in the intrinsic dipole at the semiconductor-molecule interface. Electrochemical studies of the porphyrin-bridge-anchor dyes self-assembled on mesoporous nanoparticle ZrO2 films, show that the presence or direction of the bridge dipole does not have an observable effect on the electronic properties of the porphyrin ring. Subsequent photovoltaic measurements of nanostructured TiO2 semiconductor films in dye sensitized solar cells show a reduced photocurrent for photosensitizers 1a and 3a containing a bridge dipole. However, cooperative increased binding of the 1a + 3a co-sensitized device demonstrates that dye packing overrides any differences due to the presence of the small internal dipole. PMID- 26426502 TI - Evidence synthesis in international development: a critique of systematic reviews and a pragmatist alternative. AB - Systematic reviews are an instrument of Evidence-Based Policy designed to produce comprehensive, unbiased, transparent and clear assessments of interventions' effectiveness. From their origins in medical fields, systematic reviews have recently been promoted as offering important advances in a range of applied social science fields, including international development. Drawing on a case study of a systematic review of the effectiveness of community mobilisation as an intervention to tackle HIV/AIDS, this article problematises the use of systematic reviews to summarise complex and context-specific bodies of evidence. Social development interventions, such as 'community mobilisation' often take different forms in different interventions; are made successful by their situation in particular contexts, rather than being successful or unsuccessful universally; and have a rhetorical value that leads to the over-application of positively valued terms (e.g. 'community mobilisation'), invalidating the keyword search process of a systematic review. The article suggests that the policy interest in definitive summary statements of 'the evidence' is at odds with academic assessments that evidence takes multiple, contradictory and complex forms, and with practitioner experience of the variability of practice in context. A pragmatist philosophy of evidence is explored as an alternative. Taking this approach implies expanding the definition of forms of research considered to be 'useful evidence' for evidence-based policy-making; decentralising decisions about 'what works' to allow for the use of local practical wisdom; and prioritising the establishment of good processes for the critical use of evidence, rather than producing context-insensitive summaries of 'the evidence'. PMID- 26426504 TI - Early management of neurologic clubfoot using Ponseti casting with minor posterior release in myelomeningocele: a preliminary report. AB - This study aimed to examine the results of manipulation and serial casting, followed by open Achilles lengthening combined, when necessary, with posterior release in the management of neurologic clubfoot in infants with myelomeningocele. This study was carried out prospectively with a minimum follow up of 2 years on 24 consecutive infants (48 feet) with neurologic insensate feet. Manipulation and serial casting were performed, followed by open tendo Achilles lengthening with/without posterior capsulotomy of the ankle and subtalar joints. The Dimeglio scoring system was used to assess the degree of deformity correction immediately postoperatively and the latest follow-up visits. The mean age of the patients at initial treatment was 5.9 (3-8) weeks. None of the patients was lost to follow-up. For 36 feet, the final range of scores was 5-6 and the deformities were grade II of moderate type. Only for seven of 48 feet the final scores were in the range 10-12, grade III, and severe type. Only three infants (5/48 feet) failed to show any improvement. We thus support this treatment for the management of insensate feet of infants with myelomeningocele soon after birth as most infants responded satisfactorily in terms of deformity correction and achieved plantigrade mobile feet that fit into orthotics. PMID- 26426505 TI - Post-traumatic nonunion of a clavicle fracture in a 9-year-old child. AB - Clavicular fractures account for around 15% of fractures in children. Although nonunion is a recognized complication in adults, post-traumatic nonunion of the clavicle in children is extremely rare. To the best of our knowledge, post traumatic nonunion of the clavicle in a child following repeated clavicular fracture has not yet been published in the English literature. Here, we report a case of a 9-year-old boy who presented with post-traumatic nonunion of his right clavicle following his third fracture after radiologically documented healing of the first two fractures. He underwent open reduction and internal fixation, supplemented with ipsilateral iliac crest bone graft, with resultant healing on follow-up radiographs. PMID- 26426506 TI - Salter-Harris type-IV displaced distal radius fracture in a 5-year-old. AB - Displaced Salter-Harris type-IV fractures are rare in young children and can result in articular incongruity or premature physeal arrest. We describe a 5-year old boy who sustained a displaced left distal radial Salter-Harris type-IV fracture. The patient had normal wrist function and physeal growth at the 3-year postoperative follow-up. Our patient is by far the youngest reported child with a displaced Salter-Harris type-IV fracture of the distal radius. Prompt anatomic reduction and fixation of a displaced distal radial Salter-Harris type-IV fracture can result in excellent short-term wrist motion with maintenance of physeal function. PMID- 26426507 TI - A modified Puddu technique for the treatment of adolescent mild to moderate tibia vara. AB - The aim of this work was to evaluate the results of a modified 'subphyseal' Puddu technique for the treatment of selected cases of the adolescent tibia vara. Twenty-five legs in 18 patients with adolescent tibia vara between January 2008 and February 2012 were included. The mean value of angular correction was 22.24 degrees (range, 18 degrees -25 degrees , SD 2.0 degrees ). All of the osteotomies in this series healed by 8 weeks. There were no postoperative neurologic or vascular complications. At the end of follow-up, no iatrogenic disturbance to the proximal tibial physis was observed, but recurrence was reported in three cases (12%). The modified 'subphyseal' Puddu technique is a reproducible, easy, and convenient technique for the treatment of adolescent tibia vara, provided there is proper case selection. PMID- 26426508 TI - Fixator-augmented flexible intramedullary nailing for osteopenic femoral shaft fractures in children. AB - Children with underlying metabolic bone diseases, such as osteogenesis imperfecta and spastic cerebral palsy, pose a challenge in the treatment of femoral shaft fractures. We performed flexible intramedullary nailing with supplemental monolateral external fixation in a subgroup of such patients. The external fixator assists in controlling angulation and rotation at the fracture site, and avoids the need for supplemental casting with its associated problems such as skin breakdown and difficulty with personal hygiene. We describe the surgical technique, pitfalls, and outcomes in a series of four patients with underlying osteopenia treated with external fixator-augmented flexible nailing for femoral shaft fractures. PMID- 26426509 TI - Mesenchymal stem cells and serelaxin synergistically abrogate established airway fibrosis in an experimental model of chronic allergic airways disease. AB - This study determined if the anti-fibrotic drug, serelaxin (RLN), could augment human bone marrow-derived mesenchymal stem cell (MSC)-mediated reversal of airway remodeling and airway hyperresponsiveness (AHR) associated with chronic allergic airways disease (AAD/asthma). Female Balb/c mice subjected to the 9-week model of ovalbumin (OVA)-induced chronic AAD were either untreated or treated with MSCs alone, RLN alone or both combined from weeks 9-11. Changes in airway inflammation (AI), epithelial thickness, goblet cell metaplasia, transforming growth factor (TGF)-beta1 expression, myofibroblast differentiation, subepithelial and total lung collagen deposition, matrix metalloproteinase (MMP) expression, and AHR were then assessed. MSCs alone modestly reversed OVA-induced subepithelial and total collagen deposition, and increased MMP-9 levels above that induced by OVA alone (all p<0.05 vs OVA group). RLN alone more broadly reversed OVA-induced epithelial thickening, TGF-beta1 expression, myofibroblast differentiation, airway fibrosis and AHR (all p<0.05 vs OVA group). Combination treatment further reversed OVA induced AI and airway/lung fibrosis compared to either treatment alone (all p<0.05 vs either treatment alone), and further increased MMP-9 levels. RLN appeared to enhance the therapeutic effects of MSCs in a chronic disease setting; most likely a consequence of the ability of RLN to limit TGF-beta1-induced matrix synthesis complemented by the MMP-promoting effects of MSCs. PMID- 26426510 TI - Hot Electron-Based Near-Infrared Photodetection Using Bilayer MoS2. AB - Recently, there has been much interest in the extraction of hot electrons generated from surface plasmon decay, as this process can be used to achieve additional bandwidth for both photodetectors and photovoltaics. Hot electrons are typically injected into semiconductors over a Schottky barrier between the metal and semiconductor, enabling generation of photocurrent with below bandgap photon illumination. As a two-dimensional semiconductor single and few layer molybdenum disulfide (MoS2) has been demonstrated to exhibit internal photogain and therefore becomes an attractive hot electron acceptor. Here, we investigate hot electron-based photodetection in a device consisting of bilayer MoS2 integrated with a plasmonic antenna array. We demonstrate sub-bandgap photocurrent originating from the injection of hot electrons into MoS2 as well as photoamplification that yields a photogain of 10(5). The large photogain results in a photoresponsivity of 5.2 A/W at 1070 nm, which is far above similar silicon based hot electron photodetectors in which no photoamplification is present. This technique is expected to have potential use in future ultracompact near-infrared photodetection and optical memory devices. PMID- 26426514 TI - Reliability and validity of the 6-min walk test in adults and seniors with intellectual disabilities. AB - INTRODUCTION: Adults with intellectual disabilities (ID) have significantly lower rates of physical activity and fitness than adults without ID. The 6-min walk test (6 MWT) is an inexpensive and simple way to test mobility and submaximal work capacity. PURPOSE: To evaluate the test-retest reliability and validity of the 6 MWT in adults and seniors with ID and explore factors contributing to the 6 MWT distance (6 MWD). METHODS: 46 participants with mild, moderate and severe ID levels (age=41 +/- 11 years) performed the 6 MWT three times (T1; T2; T3) to determine test-retest reliability. To test validity, peak oxygen uptake (VO2 peak) was measured using a treadmill protocol. To analyze factors contributing to the 6 MWD, sex, height, fat mass % and fat free mass %, ID level, isometric leg strength and relative VO2 peak were also measured. RESULTS: The walking distances for T1, T2 and T3 were 460.3 +/- 76.9; 489.4 +/- 81.2 and 491.4 +/- 77.9 m, respectively. The 6 MWDs between T1-T2 and T1-T3 were significantly different (p<0.001), but T2 and T3 were not different. The intraclass correlation coefficient between T2 and T3 was 0.96 indicating high reliability. Relative VO2 peak and isometric leg strength significantly contributed to the 6 MWD (R(2)=0.55). CONCLUSIONS: The 6 MWT is an easy, inexpensive, reliable and valid test in adults and seniors with ID. Familiarization is necessary to obtain reliable values. Relative VO2 peak and leg strength have significant impact on the distance walked. PMID- 26426516 TI - Investigation of stable germane structures under high-pressure. AB - The evolutionary structure-searching method discovers that the energetically preferred compounds of germane can be synthesized at a pressure of 190 GPa. New structures with the space groups Ama2 and C2/c proposed here contain semimolecular H2 and V-type H3 units, respectively. Electronic structure analysis shows the metallic character and charge transfer from Ge to H. The conductivity of the two structures originates from the electrons around the hydrogen atoms. Further electron-phonon coupling calculations predict that the two phases are superconductors with a high Tc of 47-57 K for Ama2 at 250 GPa and 70-84 K for C2/c at 500 GPa from quasi-harmonic approximation calculations, which may be higher than under actual conditions. PMID- 26426515 TI - Ipsilesional motor-evoked potential absence in pediatric hemiparesis impacts tracking accuracy of the less affected hand. AB - This study analyzed the relationship between electrophysiological responses to transcranial magnetic stimulation (TMS), finger tracking accuracy, and volume of neural substrate in children with congenital hemiparesis. Nineteen participants demonstrating an ipsilesional motor-evoked potential (MEP) were compared with eleven participants showing an absent ipsilesional MEP response. Comparisons of finger tracking accuracy from the affected and less affected hands and ipsilesional/contralesional (I/C) volume ratio for the primary motor cortex (M1) and posterior limb of internal capsule (PLIC) were done using two-sample t-tests. Participants showing an ipsilesional MEP response demonstrated superior tracking performance from the less affected hand (p=0.016) and significantly higher I/C volume ratios for M1 (p=0.028) and PLIC (p=0.005) compared to participants without an ipsilesional MEP response. Group differences in finger tracking accuracy from the affected hand were not significant. These results highlight differentiating factors amongst children with congenital hemiparesis showing contrasting MEP responses: less affected hand performance and preserved M1 and PLIC volume. Along with MEP status, these factors pose important clinical implications in pediatric stroke rehabilitation. These findings may also reflect competitive developmental processes associated with the preservation of affected hand function at the expense of some function in the less affected hand. PMID- 26426517 TI - The accuracy of clinical prediction of prognosis for patients admitted with sepsis to internal medicine departments. AB - INTRODUCTION: Prognosis estimation offered by physicians for patients inflicted by sepsis on their admission to Internal Medicine (IM) departments is considered a challenge. Early prognosis estimation is critical and determines the intensity of treatment offered. The accuracy of prognosis estimation made by physicians has previously been investigated mainly among intensive care physicians and oncologists. OBJECTIVE: To ascertain the accuracy of prognosis prediction made by internists for septic patients on admission to IM departments. METHODS: Physicians were asked to estimate the prognosis of every patient identified to have sepsis on admission. Their intuitive assessment of prognosis was incorporated into the patients' electronic medical record. Survival follow-up was recorded until death or for at least 2 years. Later we compared survival with physicians' prognosis estimations. RESULTS: Prognosis estimation was recorded for 1,073 consecutive septic patients admitted throughout the years 2008-2009 to IM departments. The mean age of patients was 74.7 +/- 16.1 years. A total of 42.4% were suspected to have pneumonia, and 65.4% died during a mean follow-up time of 661.1 +/- 612.3 days. Almost half of the patients classified to have good prognosis survived compared to 14.9% and 4.9% of those with intermediate and bad prognosis estimation, respectively (P < 0.001). CONCLUSION: Internists can discriminate well between septic patients with good, intermediate, and bad prognosis. PMID- 26426518 TI - The Adverse Effects of Motherhood on Substance Use Treatment Program Outcomes Among Adolescent Women. AB - OBJECTIVES: Adolescent mothers have differing risks and responsibilities compared to adolescent women without children that may impact substance use treatment. This study sought to describe characteristics of adolescent women in a substance use treatment program and determine the effect of adolescent motherhood on treatment program outcomes. METHODS: Data were collected from standardized interviews of female adolescents in a case management criminal justice diversion program for substance-using adolescents and adults. Variables included sociodemographic factors (ie, race/ethnicity, age, financial support, education, insurance, marital status, sexual abuse), Diagnostic and Statistical Manual-IV (DSM-IV) substance use disorder diagnoses, and motherhood (ie, childbirth and residence with a child). Treatment program outcome was documented by case workers at the end of the participants' time in the program. Chi-square analyses and analysis of variances determined associations between variables. Logistic regression was used to assess characteristics associated with negative treatment program outcome. RESULTS: Data from 1080 adolescent women aged 16-21 years (mean 19.7 years, SD = 1.16) were analyzed; 403 (37%) were mothers. After controlling for sociodemographic factors and substance use disorder diagnoses, adolescent mothers were less likely to successfully complete the treatment program than nonmothers. Adolescent women with reliance on family or friends for financial support, lower education status, and cannabis and cocaine use disorders had worse treatment program outcomes. CONCLUSIONS: Childbirth and parenting adversely affect substance use treatment outcomes for adolescent women in the criminal justice system. Future research should explore tailored substance use treatments for adolescents with children. Job training and educational support may improve outcomes. PMID- 26426519 TI - Protective effects of taurine on doxorubicin-induced acute hepatotoxicity through suppression of oxidative stress and apoptotic responses. AB - The organ toxicity of doxorubicin (DOX), an anthracycline antineoplastic agent, narrows the therapeutic window despite its clinical usefulness. In the present study, we determined whether taurine protected against DOX-induced hepatic injury, and explored the molecular mechanisms underlying the suppressive effects of taurine in terms of alterations in oxidative stress and apoptotic responses. DOX-induced body weight loss was completely suppressed by taurine treatment. Elevations in the serum activity levels of lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase by DOX were also dose-dependently attenuated by a concurrent treatment with taurine. Superoxide dismutase activity and reduced glutathione content in the liver were decreased following the administration of DOX, whereas these changes were suppressed when 10 mg/kg taurine was given in combination with DOX. Taurine attenuated the increased expression of mRNAs for Fas and Bax after DOX exposure. Furthermore, the formation of cleaved caspase-3 protein in the group given DOX with taurine was lower than that in the group treated with DOX alone. Our results suggest that taurine can protect against DOX-induced acute hepatic damage, the underlying mechanism of which is attributable to the suppression of oxidative stress and apoptotic responses. PMID- 26426520 TI - Comparison of the effectiveness of whole-brain radiotherapy plus temozolomide versus whole-brain radiotherapy in treating brain metastases based on a systematic review of randomized controlled trials. AB - Temozolomide (TMZ) combination with whole-brain radiotherapy (WBRT) has been tested by many randomized controlled trials in the treatment of brain metastases (BMs) in China and other countries. We performed an up-to-date meta-analysis to determine (i) the log odds ratios (LORs) of objective response (ORR) and adverse effects (AEs) for all-grade, and (ii) the T value of mean overall survival in patients with BMs treated with WBRT combined with TMZ versus WBRT alone. PubMed, Chinese National Knowledge Infrastructure, and WanFang Data were searched for articles published up to 28 January 2015. Eligible studies were selected according to the PRISMA statement. ORR, AEs, and 95% confidence intervals were calculated using random-effects models. Eighteen studies were included in our analysis. A total of 1028 participants were enrolled. Summary LORs of ORR were 1.0239 (P<0.0001) on comparing WBRT plus TMZ with WBRT ORR (n=17). The overall mean difference of mean overall survival (n=17) between TMZ plus WBRT and WBRT was 2.2505 weeks (P=0.02185). There was a significant difference between WBRT plus TMZ and WBRT alone with a LOR of AEs for all-grade of (i) 0.923 for gastrointestinal toxicity and (ii) 0.7978 for myelosuppression. Sensitivity analysis and subgroup analysis were also performed. The 18 eligible randomized controlled trials demonstrated that the combination of WBRT and TMZ significantly improves the ORR and is statistically insignificant in prolonging the survival of patients with BMs. In addition, an increase in the incidence of gastrointestinal toxicity and myelosuppression was significant for all-grade. PMID- 26426521 TI - Synthesis and assessment of a maleimide functionalized BF2 azadipyrromethene near infrared fluorochrome. AB - The first water soluble maleimide bearing NIR BF2-azadipyrromethene (NIR-AZA) fluorochrome has been synthesised which is capable of rapid thiol conjugations in water with peptides such as glutathione, the cell penetrating peptide (CPP) C(beta-A)SKKKKTKV-NH2 and a thiol substituted cRGD. NIR fluorescence imaging showed rapid cellular delivery of the CPP conjugate and effective in vivo tumour localization for the cRGD conjugate. PMID- 26426523 TI - Mortality in adult immigrants in the 2000s in Belgium: a test of the 'healthy migrant' and the 'migration-as-rapid-health-transition' hypotheses. AB - OBJECTIVE: Firstly, to map out and compare all-cause and cause-specific mortality patterns by migrant background in Belgium; and secondly, to probe into explanations for the observed patterns, more specifically into the healthy migrant, acculturation and the migration-as-rapid-health-transition theories. METHODS: Data comprise individually linked Belgian census-mortality follow-up data for the period 2001-2011. All official inhabitants aged 25-54 at time of the census were included. To delve into the different explanations, differences in all-cause and chronic- and infectious-disease mortality were estimated using Poisson regression models, adjusted for age, socioeconomic position and urbanicity. RESULTS: First-generation immigrants have lower all-cause and chronic disease mortality than the host population. This mortality advantage wears off with length of stay and is more marked among non-Western than Western first generation immigrants. For example, Western and non-Western male immigrants residing 10 years or more in Belgium have a mortality rate ratio for cardiovascular disease of 0.72 (95% CI 0.66-0.78) and 0.59 (95% CI 0.53-0.66), respectively (vs host population). The pattern of infectious-disease mortality in migrants is slightly different, with rather high mortality rates in first generation sub-Saharan Africans and rather low rates in all other immigrant groups. As for second-generation immigrants, the picture is gloomier, with a mortality disadvantage that disappears after control for socioeconomic position. CONCLUSION: Findings are largely consistent with the healthy-migrant, acculturation and the migration-as-rapid-health-transition theories. The convergence of the mortality profile of second-generation immigrants towards that of the host population with similar socioeconomic position indicates the need for policies simultaneously addressing different areas of deprivation. PMID- 26426522 TI - Restoration of Corticosteroid Sensitivity in Chronic Obstructive Pulmonary Disease by Inhibition of Mammalian Target of Rapamycin. AB - RATIONALE: Corticosteroid resistance is a major barrier to the effective treatment of chronic obstructive pulmonary disease (COPD). Several molecular mechanisms have been proposed, such as activations of the phosphoinositide-3 kinase/Akt pathway and p38 mitogen-activated protein kinase. However, the mechanism for corticosteroid resistance is still not fully elucidated. OBJECTIVES: To investigate the role of mammalian target of rapamycin (mTOR) in corticosteroid sensitivity in COPD. METHODS: The corticosteroid sensitivity of peripheral blood mononuclear cells collected from patients with COPD, smokers, and nonsmoking control subjects, or of human monocytic U937 cells exposed to cigarette smoke extract (CSE), was quantified as the dexamethasone concentration required to achieve 30% inhibition of tumor necrosis factor-alpha-induced CXCL8 production in the presence or absence of the mTOR inhibitor rapamycin. mTOR activity was determined as the phosphorylation of p70 S6 kinase, using Western blotting. MEASUREMENTS AND MAIN RESULTS: mTOR activity was increased in peripheral blood mononuclear cells from patients with COPD, and treatment with rapamycin inhibited this as well as restoring corticosteroid sensitivity. In U937 cells, CSE stimulated mTOR activity and c-Jun expression, but pretreatment with rapamycin inhibited both and also reversed CSE-induced corticosteroid insensitivity. CONCLUSIONS: mTOR inhibition by rapamycin restores corticosteroid sensitivity via inhibition of c-Jun expression, and thus mTOR is a potential novel therapeutic target for COPD. PMID- 26426525 TI - Intestinal amoebiasis in a patient with acute graft-versus-host disease after allogeneic bone marrow transplantation successfully treated by metronidazole. AB - Amoebiasis has rarely been reported in patients undergoing hematopoietic stem cell transplantation, although it is a world-wide infection and extremely common. We present a case of intestinal amoebiasis unexpectedly revealed by colonoscopy after allogeneic bone marrow transplantation from a human leukocyte antigen mismatched unrelated donor for acute myeloid leukemia arising from chronic myelomonocytic leukemia and successfully treated by metronidazole. PMID- 26426524 TI - Objective Assessment and Thematic Categorization of Patient-audible Information in an Emergency Department. AB - OBJECTIVES: The objective was to assess and categorize the understandable components of patient-audible information (e.g., provider conversations) in emergency department (ED) care areas and to initiate a baseline ED soundscape assessment. METHODS: Investigators at an academic referral hospital accessed 21 deidentified transcripts of recordings made with binaural in-ear microphones in patient rooms (n = 10) and spaces adjacent to nurses' stations (n = 11), during ED staff sign-outs as part of an approved quality management process. Transcribed materials were classified by speaker (health care provider, patient/family/friend, or unknown). Using qualitative analysis software and predefined thematic categories, two investigators then independently coded each transcript by word, phrase, clause, and/or sentence for general content, patient information, and HIPAA-defined patient identifiers. Scheduled reviews were used to resolve any data coding discrepancies. RESULTS: Patient room recordings featured a median of 11 (interquartile range [IQR] = 2 to 33) understandable words per minute (wpm) over 16.2 (IQR = 15.1 to 18.4) minutes; nurses' station recordings featured 74 (IQR = 47 to 109) understandable wpm over 17.0 (IQR = 15.4 to 20.3) minutes. Transcript content from patient room recordings was categorized as follows: clinical, 44.8% (IQR = 17.7% to 62.2%); nonclinical, 0.0% (IQR = 0.0% to 0.0%); inappropriate (provider), 0.0% (IQR = 0.0% to 0.0%); and unknown, 6.0% (IQR = 1.7% to 58.2%). Transcript content from nurses' stations was categorized as follows: clinical, 86.0% (IQR = 68.7% to 94.7%); nonclinical, 1.2% (IQR = 0.0% to 19.5%); inappropriate (provider), 0.1% (IQR = 0.0% to 2.3%); and unknown, 1.3% (IQR = 0.0% to 7.1%). Limited patient information was audible on patient room recordings. Audible patient information at nurses' stations was coded as follows (median words per sign-out sample): general patient history, 116 (IQR = 19 to 206); social history, 12 (IQR = 4 to 19); physical examination, 39 (IQR = 19 to 56); imaging results, 0 (IQR = 0 to 21); laboratory results, 7 (IQR = 0 to 22); other results, 0 (IQR = 0 to 3); medical decision-making, 39 (IQR = 10 to 69); management (general), 118 (IQR = 79 to 235); pain management, 4 (IQR = 0 to 53); and disposition, 42 (IQR = 22 to 60). Medians of 0 (IQR = 0 to 0) and 3 (IQR = 1 to 4) patient name identifiers were audible on in-room and nurses' station sign out recordings, respectively. CONCLUSIONS: Sound recordings in an ED setting captured audible and understandable provider discussions that included confidential, protected health information and discernible quantities of nonclinical content. PMID- 26426526 TI - Diversification of sterol methyltransferase enzymes in plants and a role for beta sitosterol in oriented cell plate formation and polarized growth. AB - Phytosterols are classified into C24-ethylsterols and C24-methylsterols according to the different C24-alkylation levels conferred by two types of sterol methyltransferases (SMTs). The first type of SMT (SMT1) is widely conserved, whereas the second type (SMT2) has diverged in charophytes and land plants. The Arabidopsis smt2 smt3 mutant is defective in the SMT2 step, leading to deficiency in C24-ethylsterols while the C24-methylsterol pathway is unchanged. smt2 smt3 plants exhibit severe dwarfism and abnormal development throughout their life cycle, with irregular cell division followed by collapsed cell files. Preprophase bands are occasionally formed in perpendicular directions in adjacent cells, and abnormal phragmoplasts with mislocalized KNOLLE syntaxin and tubulin are observed. Defects in auxin-dependent processes are exemplified by mislocalizations of the PIN2 auxin efflux carrier due to disrupted cell division and failure to distribute PIN2 asymmetrically after cytokinesis. Although endocytosis of PIN2-GFP from the plasma membrane (PM) is apparently unaffected in smt2 smt3, strong inhibition of the endocytic recycling is associated with a remarkable reduction in the level of PIN2-GFP on the PM. Aberrant localization of the cytoplasmic linker associated protein (CLASP) and microtubules is implicated in the disrupted endocytic recycling in smt2 smt3. Exogenous C24-ethylsterols partially recover lateral root development and auxin distribution in smt2 smt3 roots. These results indicate that C24-ethylsterols play a crucial role in division plane determination, directional auxin transport, and polar growth. It is proposed that the divergence of SMT2 genes together with the ability to produce C24-ethylsterols were critical events to achieve polarized growth in the plant lineage. PMID- 26426527 TI - Motor Vehicle Crashes, Medical Outcomes, and Hospital Charges Among Children Aged 1-12 Years - Crash Outcome Data Evaluation System, 11 States, 2005-2008. AB - PROBLEM: Motor vehicle crashes are a leading cause of death among children. Age- and size-appropriate restraint use is an effective way to prevent motor vehicle related injuries and deaths. However, children are not always properly restrained while riding in a motor vehicle, and some are not restrained at all, which increases their risk for injury and death in a crash. REPORTING PERIOD: 2005 2008. DESCRIPTION OF THE SYSTEM: The Crash Outcome Data Evaluation System (CODES) is a multistate program facilitated by the National Highway Traffic Safety Administration to probabilistically link police crash reports and hospital databases for traffic safety analyses. Eleven participating states (Connecticut, Georgia, Kentucky, Maryland, Minnesota, Missouri, Nebraska, New York, Ohio, South Carolina, and Utah) submitted data to CODES during the reporting period. Descriptive analysis was used to describe drivers and child passengers involved in motor vehicle crashes and to summarize crash and medical outcomes. Odds ratios and 95% confidence intervals were used to compare a child passenger's likelihood of sustaining specific types of injuries by restraint status (optimal, suboptimal, or unrestrained) and seating location (front or back seat). Because of data constraints, optimal restraint use was defined as a car seat or booster seat use for children aged 1-7 years and seat belt use for children aged 8-12 years. Suboptimal restraint use was defined as seat belt use for children aged 1 7 years. Unrestrained was defined as no use of car seat, booster seat, or seat belt for children aged 1-12 years. RESULTS: Optimal restraint use in the back seat declined with child's age (1 year: 95.9%, 5 years: 95.4%, 7 years: 94.7%, 8 years: 77.4%, 10 years: 67.5%, 12 years: 54.7%). Child restraint use was associated with driver restraint use; 41.3% of children riding with unrestrained drivers also were unrestrained compared with 2.2% of children riding with restrained drivers. Child restraint use also was associated with impaired driving due to alcohol or drug use; 16.4% children riding with drivers suspected of alcohol or drug use were unrestrained compared with 2.9% of children riding with drivers not suspected of such use. Optimally restrained and suboptimally restrained children were less likely to sustain a traumatic brain injury than unrestrained children. The 90th percentile hospital charges for children aged 4-7 years who were in motor vehicle crashes were $1,630.00 and $1,958.00 for those optimally restrained in a back seat and front seat, respectively; $2,035.91 and $3,696.00 for those suboptimally restrained in a back seat and front seat, respectively; and $9,956.60 and $11,143.85 for those unrestrained in a back seat and front seat, respectively. INTERPRETATION: Proper car seat, booster seat, and seat belt use among children in the back seat prevents injuries and deaths, as well as averts hospital charges. However, the number, severity, and cost of injuries among children in crashes who were not optimally restrained or who were seated in a front seat indicates the need for improvements in proper use of age- and size-appropriate car seats, booster seats, and seat belts in the back seat. PUBLIC HEALTH ACTIONS: Effective interventions for increasing proper child restraint use could be universally implemented by states and communities to prevent motor vehicle-related injuries among children and their resulting costs. PMID- 26426528 TI - Nitrate, nitrite and nitric oxide reductases: from the last universal common ancestor to modern bacterial pathogens. AB - The electrochemical gradient that ensues from the enzymatic activity of cytochromes such as nitrate reductase, nitric oxide reductase, and quinol oxidase contributes to the bioenergetics of the bacterial cell. Reduction of nitrogen oxides by bacterial pathogens can, however, be uncoupled from proton translocation and biosynthesis of ATP or NH4(+), but still linked to quinol and NADH oxidation. Ancestral nitric oxide reductases, as well as cytochrome c oxidases and quinol bo oxidases evolved from the former, are capable of binding and detoxifying nitric oxide to nitrous oxide. The NO-metabolizing activity associated with these cytochromes can be a sizable source of antinitrosative defense in bacteria during their associations with host cells. Nitrosylation of terminal cytochromes arrests respiration, reprograms bacterial metabolism, stimulates antioxidant defenses and alters antibiotic cytotoxicity. Collectively, the bioenergetics and regulation of redox homeostasis that accompanies the utilization of nitrogen oxides and detoxification of nitric oxide by cytochromes of the electron transport chain increases fitness of many Gram-positive and negative pathogens during their associations with invertebrate and vertebrate hosts. PMID- 26426529 TI - Peripheral Nerve Transplantation Combined with Acidic Fibroblast Growth Factor and Chondroitinase Induces Regeneration and Improves Urinary Function in Complete Spinal Cord Transected Adult Mice. AB - The loss of lower urinary tract (LUT) control is a ubiquitous consequence of a complete spinal cord injury, attributed to a lack of regeneration of supraspinal pathways controlling the bladder. Previous work in our lab has utilized a combinatorial therapy of peripheral nerve autografts (PNG), acidic fibroblast growth factor (aFGF), and chondroitinase ABC (ChABC) to treat a complete T8 spinal cord transection in the adult rat, resulting in supraspinal control of bladder function. In the present study we extended these findings by examining the use of the combinatorial PNG+aFGF+ChABC treatment in a T8 transected mouse model, which more closely models human urinary deficits following spinal cord injury. Cystometry analysis and external urethral sphincter electromyograms reveal that treatment with PNG+aFGF+ChABC reduced bladder weight, improved bladder and external urethral sphincter histology, and significantly enhanced LUT function, resulting in more efficient voiding. Treated mice's injured spinal cord also showed a reduction in collagen scaring, and regeneration of serotonergic and tyrosine hydroxylase-positive axons across the lesion and into the distal spinal cord. Regeneration of serotonin axons correlated with LUT recovery. These results suggest that our mouse model of LUT dysfunction recapitulates the results found in the rat model and may be used to further investigate genetic contributions to regeneration failure. PMID- 26426530 TI - The Impact of Misuse and Diversion of Opioid Substitution Treatment Medicines: Evidence Review and Expert Consensus. AB - BACKGROUND/AIMS: Opioid substitution treatment (OST) improves outcomes in opioid dependence. However, controlled drugs used in treatment may be misused or diverted, resulting in negative treatment outcomes. This review defines a framework to assess the impact of misuse and diversion. METHODS: A systematic review of published studies of misuse and diversion of OST medicines was completed; this evidence was paired with expert real-world experience to better understand the impact of misuse and diversion on the individual and on society. RESULTS: Direct impact to the individual includes failure to progress in recovery and negative effects on health (overdose, health risks associated with injecting behaviour). Diversion of OST has impacts on a community that is beyond the intended OST recipient. The direct impact includes risk to others (unsupervised use; unintended exposure of children to diverted medication) and drug-related criminal behavior. The indirect impact includes the economic costs of untreated opioid dependence, crime and loss of productivity. CONCLUSION: While treatment for opioid dependence is essential and must be supported, it is vital to reduce misuse and diversion while ensuring the best possible care. Understanding the impact of OST misuse and diversion is key to defining strategies to address these issues. PMID- 26426531 TI - Efficacy of Procyanidins against In Vivo Cellular Oxidative Damage: A Systematic Review and Meta-Analysis. AB - AIMS: In this study, the efficacy of proanthocyanidins (PCs) against oxidative damage was systematically reviewed to facilitate their use in various applications. METHODS: A meta-analysis was performed by two researchers. Each investigator independently searched electronic databases, including Cochrane, PubMed, Springer, Web of Science, China National Knowledge Infrastructure (CKNI), China Science and Technology Journal Database (CSTJ), and WanFang Data, and analyzed published data from 29 studies on the effects of PCs against oxidative damage. Oxidative stress indexes included superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), and total antioxidative capacity (T-AOC). RESULTS: Compared with the oxidative damage model group, PCs effectively improved the T-AOC, SOD, GSH, GPx, and CAT levels, and reduced the MDA levels; these differences were statistically significant (P < 0.05). In studies that used the gavage method, SOD (95% CI, 2.33 4.00) and GPx (95% CI, 2.10-4.05) were 3.16-fold and 3.08-fold higher in the PC group than in the control group, respectively. In studies that used the feeding method, SOD (95% CI, 0.32-1.74) and GPx (95% CI, -0.31 to 1.65) were 1.03-fold and 0.67-fold higher in the PC group than in the control group, respectively. Statistically significant differences in the effects of PCs (P < 0.00001) were observed between these two methods. MDA estimated from tissue samples (95% CI, 5.82 to -2.60) was 4.32-fold lower in the PC group than in the control group. In contrast, MDA estimated using serum samples (95% CI, -4.07 to -2.06) was 3.06 fold lower in the PC group than in the control group. The effect of PCs on MDA was significantly greater in tissue samples than in serum samples (P = 0.02). CONCLUSION: PCs effectively antagonize oxidative damage and enhance antioxidant capacity. The antagonistic effect may be related to intervention time, intervention method, and the source from which the indexes are estimated. PMID- 26426532 TI - Mapping Above- and Below-Ground Carbon Pools in Boreal Forests: The Case for Airborne Lidar. AB - A large and growing body of evidence has demonstrated that airborne scanning light detection and ranging (lidar) systems can be an effective tool in measuring and monitoring above-ground forest tree biomass. However, the potential of lidar as an all-round tool for assisting in assessment of carbon (C) stocks in soil and non-tree vegetation components of the forest ecosystem has been given much less attention. Here we combine the use airborne small footprint scanning lidar with fine-scale spatial C data relating to vegetation and the soil surface to describe and contrast the size and spatial distribution of C pools within and among multilayered Norway spruce (Picea abies) stands. Predictor variables from lidar derived metrics delivered precise models of above- and below-ground tree C, which comprised the largest C pool in our study stands. We also found evidence that lidar canopy data correlated well with the variation in field layer C stock, consisting mainly of ericaceous dwarf shrubs and herbaceous plants. However, lidar metrics derived directly from understory echoes did not yield significant models. Furthermore, our results indicate that the variation in both the mosses and soil organic layer C stock plots appears less influenced by differences in stand structure properties than topographical gradients. By using topographical models from lidar ground returns we were able to establish a strong correlation between lidar data and the organic layer C stock at a stand level. Increasing the topographical resolution from plot averages (~2000 m2) towards individual grid cells (1 m2) did not yield consistent models. Our study demonstrates a connection between the size and distribution of different forest C pools and models derived from airborne lidar data, providing a foundation for future research concerning the use of lidar for assessing and monitoring boreal forest C. PMID- 26426533 TI - Rheumatoid Arthritis Risk Associated with Periodontitis Exposure: A Nationwide, Population-Based Cohort Study. AB - BACKGROUND: The risk of periodontitis (PD) is increased in the patient group of rheumatoid arthritis (RA). RA and PD also shared some pathological mechanism. The aim of this study is to investigate the risk of RA associated with PD exposure. METHODS AND FINDINGS: This study identified 3 mutually exclusive cohorts using the 1999-2010 Taiwanese National Health Insurance Research Database (NHIRD) to investigate the association between PD and the risk of incident RA. All patients with PD in 2000 were identified from the database of all enrollees as the PD cohort. From the representative database of 1,000,000 enrollees randomly selected in 2010 (LHID2010), individuals without any periodontal disease (PO) during 1999 2010 were selected as the non-PO cohort. Individuals who were not included in the non-PO cohort and received dental scaling (DS) no more than two times per year during 1999-2010 were selected as the DS cohort from LHID2010. Using cox proportional regression analysis, hazard ratios (HRs) with 95% confidence intervals (Cis) were calculated to quantify the association between PD exposure and RA development. In the three-group comparison using the non-PO cohort as reference, we found that the risk of RA was higher in the PD and DS cohorts (HRs, 1.89 and 1.43; 95% CIs, 1.56-2.29 and 1.09-1.87, respectively). For comparisons between two cohorts, the PD cohort had a higher risk of RA than the non-PO and DS cohorts (HRs, 1.91 and 1.35; 95% CIs, 1.57-2.30 and 1.09-1.67, respectively). CONCLUSION: PD was associated with an increased risk of RA development. PMID- 26426534 TI - Hemispheric lateralization in reasoning. AB - A growing body of evidence suggests that reasoning in humans relies on a number of related processes whose neural loci are largely lateralized to one hemisphere or the other. A recent review of this evidence concluded that the patterns of lateralization observed are organized according to two complementary tendencies. The left hemisphere attempts to reduce uncertainty by drawing inferences or creating explanations, even at the cost of ignoring conflicting evidence or generating implausible explanations. Conversely, the right hemisphere aims to reduce conflict by rejecting or refining explanations that are no longer tenable in the face of new evidence. In healthy adults, the hemispheres work together to achieve a balance between certainty and consistency, and a wealth of neuropsychological research supports the notion that upsetting this balance results in various failures in reasoning, including delusions. However, support for this model from the neuroimaging literature is mixed. Here, we examine the evidence for this framework from multiple research domains, including an activation likelihood estimation analysis of functional magnetic resonance imaging studies of reasoning. Our results suggest a need to either revise this model as it applies to healthy adults or to develop better tools for assessing lateralization in these individuals. PMID- 26426535 TI - Analgesic and Anti-Inflammatory Properties of Gelsolin in Acetic Acid Induced Writhing, Tail Immersion and Carrageenan Induced Paw Edema in Mice. AB - Plasma gelsolin levels significantly decline in several disease conditions, since gelsolin gets scavenged when it depolymerizes and caps filamentous actin released in the circulation following tissue injury. It is well established that our body require/implement inflammatory and analgesic responses to protect against cell damage and injury to the tissue. This study was envisaged to examine analgesic and anti-inflammatory activity of exogenous gelsolin (8 mg/mouse) in mice models of pain and acute inflammation. Administration of gelsolin in acetic acid-induced writhing and tail immersion tests not only demonstrated a significant reduction in the number of acetic acid-induced writhing effects, but also exhibited an analgesic activity in tail immersion test in mice as compared to placebo treated mice. Additionally, anti-inflammatory function of gelsolin (8 mg/mouse) compared with anti-inflammatory drug diclofenac sodium (10 mg/kg)] was confirmed in the carrageenan injection induced paw edema where latter was measured by vernier caliper and fluorescent tomography imaging. Interestingly, results showed that plasma gelsolin was capable of reducing severity of inflammation in mice comparable to diclofenac sodium. Analysis of cytokines and histopathological examinations of tissue revealed administration of gelsolin and diclofenac sodium significantly reduced production of pro-inflammatory cytokines, TNF-alpha and IL 6. Additionally, carrageenan groups pretreated with diclofenac sodium or gelsolin showed a marked decrease in edema and infiltration of inflammatory cells in paw tissue. Our study provides evidence that administration of gelsolin can effectively reduce the pain and inflammation in mice model. PMID- 26426536 TI - Ornithine Decarboxylase Activity Is Required for Prostatic Budding in the Developing Mouse Prostate. AB - The prostate is a male accessory sex gland that produces secretions in seminal fluid to facilitate fertilization. Prostate secretory function is dependent on androgens, although the mechanism by which androgens exert their effects is still unclear. Polyamines are small cationic molecules that play pivotal roles in DNA transcription, translation and gene regulation. The rate-limiting enzyme in polyamine biosynthesis is ornithine decarboxylase, which is encoded by the gene Odc1. Ornithine decarboxylase mRNA decreases in the prostate upon castration and increases upon administration of androgens. Furthermore, testosterone administered to castrated male mice restores prostate secretory activity, whereas administering testosterone and the ornithine decarboxylase inhibitor D,L-alpha difluromethylornithine (DFMO) to castrated males does not restore prostate secretory activity, suggesting that polyamines are required for androgens to exert their effects. To date, no one has examined polyamines in prostate development, which is also androgen dependent. In this study, we showed that ornithine decarboxylase protein was expressed in the epithelium of the ventral, dorsolateral and anterior lobes of the adult mouse prostate. Ornithine decarboxylase protein was also expressed in the urogenital sinus (UGS) epithelium of the male and female embryo prior to prostate development, and expression continued in prostatic epithelial buds as they emerged from the UGS. Inhibiting ornithine decarboxylase using DFMO in UGS organ culture blocked the induction of prostatic buds by androgens, and significantly decreased expression of key prostate transcription factor, Nkx3.1, by androgens. DFMO also significantly decreased the expression of developmental regulatory gene Notch1. Other genes implicated in prostatic development including Sox9, Wif1 and Srd5a2 were unaffected by DFMO. Together these results indicate that Odc1 and polyamines are required for androgens to exert their effect in mediating prostatic bud induction, and are required for the expression of a subset of prostatic developmental regulatory genes including Notch1 and Nkx3.1. PMID- 26426538 TI - Social Capital as a Determinant of Pregnant Mother's Place of Delivery: Experience from Kongwa District in Central Tanzania. AB - INTRODUCTION: Maternal ill health contributes highly to the global burden of diseases in countries South of Sahara including Tanzania. Ensuring that all deliveries take place in health facilities and hence attended by skilled health personnel is one of the strategies advocated by global and national policies, including the Millennium Development Goals (MDGs). However, the number of women delivered by skilled health personnel has remained low in sub Saharan Africa despite of a number of interventions. We sought to determine the role of social capital in facilitating health facility delivery. METHODS: We randomly selected 744 households with children aged less than five years from two randomly selected wards in a rural area in Tanzania. Mothers were enquired about place of delivery of the last child. Social capital was assessed using a modified questionnaire with both structural and cognitive aspects of social capital, administered in face-to-face interviews. Principal Component Analysis (PCA) was used to develop asocial capital index measure. Uni-variate and multivariable regression models were run using STATA 12. RESULTS: Majority (85.9%) of the mothers reported to have delivered in a health facility during their last birth. Compared to the lowest social capital quintile, delivering in a health facility increased significantly with increase in social capital level: low (Adjusted Odds Ratio (AOR) = 2.9; Confidence Interval (CI): 1.4-6.1, p = 0.004); moderate (AOR = 5.5, CI: 2.3-13.3, p-value<0.001); high (AOR = 4.7; CI: 1.9-11.6, p-value<0.001) and highest (AOR = 5.6, CI: 2.4-13.4, p-value<0.001) and chi2-test for the trend was significant (chi2 = 17.21, p<0.001). CONCLUSION: Overall, social capital seems to play an important role in enhancing health facility delivery that may lead to improved maternal and child health. Concerted efforts should focus on promoting and supporting effective social capital and in particular cognitive social capital. PMID- 26426539 TI - Shifts in functional traits elevate risk of fire-driven tree dieback in tropical savanna and forest biomes. AB - Numerous predictions indicate rising CO2 will accelerate the expansion of forests into savannas. Although encroaching forests can sequester carbon over the short term, increased fires and drought-fire interactions could offset carbon gains, which may be amplified by the shift toward forest plant communities more susceptible to fire-driven dieback. We quantify how bark thickness determines the ability of individual tree species to tolerate fire and subsequently determine the fire sensitivity of ecosystem carbon across 180 plots in savannas and forests throughout the 2.2-million km(2) Cerrado region in Brazil. We find that not accounting for variation in bark thickness across tree species underestimated carbon losses in forests by ~50%, totaling 0.22 PgC across the Cerrado region. The lower bark thicknesses of plant species in forests decreased fire tolerance to such an extent that a third of carbon gains during forest encroachment may be at risk of dieback if burned. These results illustrate that consideration of trait-based differences in fire tolerance is critical for determining the climate carbon-fire feedback in tropical savanna and forest biomes. PMID- 26426537 TI - Reversal of multidrug resistance by co-delivery of paclitaxel and lonidamine using a TPGS and hyaluronic acid dual-functionalized liposome for cancer treatment. AB - Multidrug resistance (MDR) remains the primary issue in cancer therapy, which is characterized by the overexpressed P-glycoprotein (P-gp)-included efflux pump or the upregulated anti-apoptotic proteins. In this study, a D-alpha-tocopheryl poly (ethylene glycol 1000) succinate (TPGS) and hyaluronic acid (HA) dual functionalized cationic liposome containing a synthetic cationic lipid, 1,5 dioctadecyl-N-histidyl-L-glutamate (HG2C18) was developed for co-delivery of a small-molecule chemotherapeutic drug, paclitaxel (PTX) with a chemosensitizing agent, lonidamine (LND) to treat the MDR cancer. It was demonstrated that the HG2C18 lipid contributes to the endo-lysosomal escape of the liposome following internalization for efficient intracellular delivery. The TPGS component was confirmed able to elevate the intracellular accumulation of PTX by inhibiting the P-gp efflux, and to facilitate the mitochondrial-targeting of the liposome. The intracellularly released LND suppressed the intracellular ATP production by interfering with the mitochondrial function for enhanced P-gp inhibition, and additionally, sensitized the MDR breast cancer (MCF-7/MDR) cells to PTX for promoted induction of apoptosis through a synergistic effect. Functionalized with the outer HA shell, the liposome preferentially accumulated at the tumor site and showed a superior antitumor efficacy in the xenograft MCF-7/MDR tumor mice models. These findings suggest that this dual-functional liposome for co-delivery of a cytotoxic drug and an MDR modulator provides a promising strategy for reversal of MDR in cancer treatment. PMID- 26426540 TI - Plasma Peak and Trough Gentamicin Concentrations in Hospitalized Horses Receiving Intravenously Administered Gentamicin. AB - BACKGROUND: Gentamicin is an aminoglycoside antimicrobial commonly used in horses at 6.6 mg/kg IV once daily. Therapeutic drug monitoring (TDM) can confirm desired peak concentration is reached for common bacterial isolates, and detect toxicosis associated with high trough values. OBJECTIVES: Determine the relationship between gentamicin dose and plasma concentration in hospitalized horses, and identify a starting dose range to achieve peaks > 32 MUg/mL. ANIMALS: Sixty-five horses (2002-2010) receiving once-daily gentamicin with TDM performed (N = 99 sets). METHODS: Retrospective study. Data from hospitalized horses including weight, dose, plasma peak, and trough gentamicin concentration, creatinine concentrations and presence of focal or systemic disease were collected from medical records. Peak concentrations measured 25-35 minutes after administration were included (N = 77). Data were divided into low (<7.7 mg/kg), medium (7.7-9.7 mg/kg) and high (>9.7 mg/kg) dose groups, and were grouped by the horse having focal or systemic disease. RESULTS: Peak concentrations resulting from doses >=7.7 mg/kg were 5.74 MUg/mL (SE 2.1 MUg/mL) greater than peaks from doses <7.7 mg/kg (P = .007). Peak concentrations was 3.6 times more likely to be >32 MUg/mL if dose was >=7.7 mg/kg (P = .04). There were no significant effects of dose on trough or creatinine concentration. At a given dose, horses with focal disease had higher peaks than those with systemic disease (P = .039). CONCLUSIONS AND CLINICAL IMPORTANCE: These data suggest gentamicin dosage should be individually determined in horses using TDM, but support an initial once-daily dose of 7.7-9.7 mg/kg IV to achieve peaks >32 MUg/mL and trough concentrations <2 MUg/mL. Further studies evaluating the safety of doses >6.6 mg/kg are required. PMID- 26426541 TI - Rod-to-Globule Transition of pDNA/PEG-Poly(l-Lysine) Polyplex Micelles Induced by a Collapsed Balance Between DNA Rigidity and PEG Crowdedness. AB - The role of poly(ethylene-glycol) (PEG) in rod-shaped polyplex micelle structures, having a characteristic core of folded plasmid DNA (pDNA) and a shell of tethered PEG chains, is investigated using PEG-detachable polyplex micelles. Rod shapes undergo change to compacted globule shapes by removal of PEG from polyplex micelles prepared from block copolymer with acid-labile linkage between PEG and poly(l-lysine) (PLys) through exposure to acidic milieu. This structural change supports the previous investigation on the rod shapes that PEG shell prevents the DNA structure from being globule shaped as the most favored structure in minimizing surface area. Noteworthy, despite the PEG is continuously depleted, the structural change does not occur in gradual shortening manner but the rod shapes keep their length unchanged and abruptly transform into globule shapes. Analysis of PEG density reveals the transition occurred when tethered PEG of rod shapes has decreased to a critical crowdedness, i.e., discontacted with neighboring PEG, which eventually illuminates another contribution, rigidity of DNA packaged as bundle in the rod shapes, in addition to the steric repulsion of PEG, in sustaining rod shapes. This investigation affirms significant role of PEG and also DNA rigidity as bundle in the formation of rod-shaped structures enduring the quest of compaction of charge-neutralized DNA in the polyplex micelles. PMID- 26426542 TI - Recent applications of CE- and HPLC-MS in the analysis of human fluids. AB - The present review intends to cover the literature on the use of CE-/LC-MS for the analysis of human fluids, from 2010 until present. It has been planned to provide an overview of the most recent practical applications of these techniques to less extensively used human body fluids, including, bronchoalveolar lavage fluid, synovial fluid, nipple aspirate, tear fluid, breast fluid, amniotic fluid, and cerumen. Potential pitfalls related to fluid collection and sample preparation, with particular attention to sample clean-up procedures, and methods of analysis, from the research laboratory to a clinical setting will also be addressed. While being apparent that proteomics/metabolomics represent the most prominent approaches for global identification/quantification of putative biomarkers for a variety of human diseases, evidence is also provided of the suitability of these sophisticated techniques for the detection of heterogeneous components carried by these fluids. PMID- 26426543 TI - Preparation of silicon-modified antimicrobial polyethylene endotracheal tubes. AB - Antimicrobial coating of polyethylene endotracheal tubes (PE ETTs) has proven to be an effective method to prevent endoluminal biofilm formation. A transparent silicon-modified antimicrobial PE ETT was obtained by coating PE with a SiO2 /gamma-methacryloxypropyl trimethoxy silane (KH-570)/methyltriethoxysilane (MTES)/Ag-SiO2 solution prepared by chemically mixing Ag-SiO2 with SiO2 /KH 570/MTES in solution via a dip-coating method, with tetraethyl orthosilicate (TEOS) as the inorganic silicon source, followed by drying. All the films were characterized by various techniques, including the pencil hardness test, infrared spectroscopy, scanning electron microscopy, UV-vis analysis, and inductively coupled plasma mass spectrometry (ICP-MS). The results indicated that the TEOS/KH 570/MTES/Ag-SiO2 (15:6:1:0.6-1.0) films, which exhibited simple in-solution film formation on PE ETTs, had a homogeneous morphology, high transmittance above 87%, high hardness of 5H and strong adhesion to the tubes. The concentration of Ag+ ion dissolved out from the antibacterial coating is very low in ICP-MS results. The antibacterial test results show that the antibacterial coatings have excellent antibacterial property with antibacterial ratio up to 93.5% when Ag SiO2 content is 2.6%. In pyrogen test and hemolytic test, the body temperature of rabbits rise 0.03 degrees c for 3 h after inserting antibacterial PE ETT, and the hemolytic ratio is 0.7512%, which conform to the requirements of biomedical material. The results preliminarily proved that the antibacterial materials could be a good candidate of medical catheter material application or medical device surface coating materials. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 91-98, 2017. PMID- 26426544 TI - Sexual function and depressive symptoms in young women with thyroid autoimmunity and subclinical hypothyroidism. AB - OBJECTIVE: The results of few studies conducted to date suggest an increased prevalence of sexual dysfunction in patients with thyroid disorders. DESIGN: The aim of this study was to compare female sexual function and depressive symptoms between women with autoimmune thyroid disease and with mild thyroid failure. PATIENTS: The study included four groups of young women: euthyroid women with Hashimoto's thyroiditis (Group 1), women with nonautoimmune subclinical hypothyroidism (Group 2), women with autoimmune subclinical hypothyroidism (Group 3) and healthy euthyroid females without thyroid autoimmunity (Group 4). MEASUREMENTS: Beyond measuring serum hormone levels and thyroid antibody titres, all enrolled women completed questionnaires evaluating female sexual function (Female Sexual Function Index - FSFI) and the presence and severity of depressive symptoms (Beck Depression Inventory-Second Edition - BDI-II). RESULTS: The mean total FSFI score was lower in women with autoimmune hypothyroidism than in the remaining groups of women, as well as lower in Groups 1 and 2 than in Group 4. Compared to Group 4, three domains (sexual desire, lubrication and sexual satisfaction) were lower in Group 1, four domains (desire, arousal, lubrication and dyspareunia) in Group 2 and all FSFI domain scores in Group 3. The total BDI II score was higher in Groups 1 and 2 than in Group 4, as well as higher in Group 3 than in the other groups of women. CONCLUSIONS: The obtained results suggest that both thyroid autoimmunity and mild thyroid failure, particularly if they occur together, may negatively affect female sexual function and depressive symptoms. PMID- 26426545 TI - Synthesis of Triazole-Linked Analogues of c-di-GMP and Their Interactions with Diguanylate Cyclase. AB - Cyclic di-GMP (c-di-GMP) is a widespread second messenger that plays a key role in bacterial biofilm formation. The compound's ability to assume multiple conformations allows it to interact with a diverse set of target macromolecules. Here, we analyzed the binding mode of c-di-GMP to the allosteric inhibitory site (I-site) of diguanylate cyclases (DGCs) and compared it to the conformation adopted in the catalytic site of the EAL phosphodiesterases (PDEs). An array of novel molecules has been designed and synthesized by simplifying the native c-di GMP structure and replacing the charged phosphodiester backbone with an isosteric nonhydrolyzable 1,2,3-triazole moiety. We developed the first neutral small molecule able to selectively target DGCs discriminating between the I-site of DGCs and the active site of PDEs; this molecule represents a novel tool for mechanistic studies, particularly on those proteins bearing both DGC and PDE modules, and for future optimization studies to target DGCs in vivo. PMID- 26426546 TI - Enantioselective sp(3) C-H alkylation of gamma-butyrolactam by a chiral Ir(I) catalyst for the synthesis of 4-substituted gamma-amino acids. AB - Ir-catalyzed sp(3) C-H alkylation of gamma-butyrolactam with alkenes was used for the highly enantioselective synthesis of 5-substituted gamma-lactams, which were readily converted into chiral 4-substituted gamma-amino acids. A broad scope of alkenes was amenable as coupling partners, and the alkylated product using acrylate could be transformed into the key intermediate of pyrrolam A synthesis. PMID- 26426547 TI - EDUCATION AND IMAGING. Hepatobiliary and Pancreatic: Elastography assessment in AL hepatic amyloidosis with no fibrosis. PMID- 26426548 TI - Regarding: Diabetic macular ischaemia is associated with narrower retinal arterioles in patients with type 2 diabetes. PMID- 26426549 TI - Editor's message. PMID- 26426550 TI - Urticaria and angioedema: Diagnostic and treatment considerations. AB - Urticaria and angioedema are common-and commonly frustrating-problems for physicians and patients alike. Patients often are in considerable distress with pruritus and uncomfortable lesions. They are frightened about their condition and frustrated when modem medicine cannot pinpoint the cause of the symptoms. Both urticaria and angioedema may be categorized as acute and chronic conditions. The dividing line between acute and chronic forms is relatively arbitrarily set at 6 weeks. A thorough history and physical examination may provide clues to the underlying cause, but in the majority of patients, the cause is rarely identified. One is more likely to discover the cause of acute than of chronic urticaria. A multitude of laboratory tests can be performed, but they often do not provide a diagnosis. It is not appropriate to do a large "screening" battery oflaboratory tests. The dermal mast cells and their mediators playa central role in chronic urticaria. Chronic urticaria may have an autoimmune aspect. Recent evidence reveals that 50% of patients with chronic urticaria have a cutaneous autoimmune disorder mediated by autoantibodies to the high-affinity IgE receptor on mast cells. Biopsy may be necessary and may help with treatment. PMID- 26426551 TI - Contact dermatitis: Evaluation and treatment. AB - Contact dermatitis is a common condition that can be categorized as irritant dermatitis and allergic contact dermatitis. Although each of these conditions may have a similar presentation, allergic contact dermatitis is immunologically mediated, whereas irritant contact dermatitis is not. Contact dermatitis can be acute, subacute, or chronic, and each of these phases may progress into the next. Almost any substance may induce a cutaneous reaction, depending on its concentration, the duration of contact, and the condition of the contacted skin. It is estimated that there are more than 6 million chemicals in the environment; approximately 3000 are potential sensitizers. A careful history may identify the responsible agent. If the contactant is identified and eliminated, the contact dermatitis can be a self-limited, mild condition. H the exposure is not discontinued, a cycle of itching, scratching, and skin disruption occurs, which leads to chronic changes in the skin. The history of presentation, including occupational exposures, and distribution of the rash are important in identifying the offending agent. More severe cases may require more extensive evaluation, possibly including patch testing, to determine the offending agent. This article reviews treatment, including antihistamines, topical and oral steroids, physical measures such as cold water compresses, and the treatment of secondary infection. PMID- 26426552 TI - Skin manifestations of food allergies. AB - The role of dietary factors in chronic skin diseases has been a subject of controversy, but several investigators have shown the effectiveness of elimination diets in the management of some patients with atopic dermatitis. Chronic skin diseases are common, complex, and often difficult to treat; therefore, the physician should consider all possible causes. More people consider themselves to have food allergies than can actually be documented to have an immunologic reaction to foods. Six foods--egg, peanut, cow's milk, soy, fish, and wheat-account for most skin reactions to food in children, with egg, peanut, and cow's milk being most common. Elimination of the offending food can be an effective form of treatment, but it must be done with caution, and while ensuring that the patient maintains adequate nutrition. PMID- 26426553 TI - Skin manifestations of allergic reactions: A 'comparative color atlas'. PMID- 26426554 TI - CME QUIZ. PMID- 26426555 TI - Atopic dermatitis: A clinical review for the primary care physician. AB - Atopic dermatitis is a common disease, causing significant morbidity. The histology and cellular mechanisms suggest that atopic dermatitis is an atopic disease similar to asthma and allergic rhinitis, with helper T type 2 lymphocytes being at least a component of the pathogenesis of the disease. Specific allergies, including food allergies, should be explored and treated. Treatment should be directed at increasing the patient's quality of life. Antihistamines, topical steroids, and lubricants are the keystones of therapy. In severe cases, oral steroids may be necessary but should be used sparingly. Interferon, cyclospocine, phototherapy, and immunosuppressive agents may be necessary in refractory cases. It appears that leukotriene inhibitors may have a future role in therapy. Clinical assessment and follow-up are important, as other atopic diseases such as asthma and allergic nasosinus disease may eventually develop in many of these patients. PMID- 26426556 TI - Comparison of Chest Compressions Metrics Measured Using the Laerdal Skill Reporter and Q-CPR: A Simulation Study. AB - INTRODUCTION: There has been an increased emphasis on the quality of chest compressions as a part of the cardiopulmonary resuscitation (CPR) bundle of care for recent times. During CPR training, chest compression quality parameters can be measured directly from sensors within a manikin or from external devices placed on the manikin chest that use accelerometer-based technology. The aim of this study was to compare external chest compression data from the manikin-based Laerdal Skill Reporter (LSR) and the accelerometer-based Q-CPR technology, incorporated into the Philips MRx defibrillator, during CPR on a single Resusci Anne Simulator manikin. METHODS: Each paramedic (n = 15) performed 2 sessions of 2 minutes of chest compressions, with a 2-minute rest period in between sessions. Both over-the-head and from-the-side positions were used on a single manikin. The quality of chest compressions were concurrently measured using both LSR and Philips MRx Q-CPR accelerometer with audiovisual feedback disabled. RESULTS: There was no significant difference in the measurement of the number of chest compressions performed in 2 minutes, the compression rate, total number of compressions of adequate depth, or the number of compressions exhibiting leaning between the LSR and the Phillips Q-CPR devices. There was a significant difference in measurement of compression depth (P < 0.0001) and duty cycle (P < 0.0001) with the MRx Q-CPR accelerometer demonstrating both lower compression depth and duty cycle compared with LSR. CONCLUSIONS: There was no significant difference in most chest compression quality metrics measured between the LSR and the Phillips Q-CPR devices when measured on a manikin. However, there were significant differences in the measurement of duty cycle and also the depth of compressions between the 2 devices with the Phillips Q-CPR device measuring lower depth of compression and duty cycle compared with the LSR device. PMID- 26426557 TI - Clinical Placement Before or After Simulated Learning Environments?: A Naturalistic Study of Clinical Skills Acquisition Among Early-Stage Paramedicine Students. AB - BACKGROUND: There is conflicting evidence surrounding the merit of clinical placements (CPs) for early-stage health-profession students. Some contend that early-stage CPs facilitate contextualization of a subsequently learned theory. Others argue that training in simulated-learning experiences (SLEs) should occur before CP to ensure that students possess at least basic competency. We sought to investigate both claims. METHODS: First-year paramedicine students (n = 85) undertook 3 days of CP and SLEs as part of course requirements. Students undertook CP either before or after participation in SLEs creating 2 groups (Clin -> Sim/Sim -> Clin). Clinical skills acquisition was measured via direct scenario based clinical assessments with expert observers conducted at 4 intervals during the semester. Perceptions of difficulty of CP and SLE were measured via the National Aeronautics and Space Administration Task Load Index. RESULTS: Students' clinical assessment scores in both groups improved significantly from beginning to end of semester (P < 0.001). However, at semester's end, clinical assessment scores for the Sim -> Clin group were statistically significantly greater than those of the Clin -> Sim group (P = 0.021). Both groups found SLEs more demanding than CP (P < 0.001). However, compared with the Sim -> Clin group, the Clin -> Sim group rated SLE as substantially more time-demanding than CP (P = 0.003). CONCLUSIONS: Differences in temporal demand suggest that the Clin -> Sim students had fewer opportunities to practice clinical skills during CP than the Sim -> Clin students due to a more limited scope of practice. The Sim -> Clin students contextualized SLE within subsequent CP resulting in greater improvement in clinical competency by semester's end in comparison with the Clin -> Sim students who were forced to contextualize skills retrospectively. PMID- 26426558 TI - Use of the Learning Curve-Cumulative Summation Test for Leopold Maneuvers Assessment in a Simulator: A Pilot Study. AB - INTRODUCTION: Simulation enables medical students to practice clinical skills in a safe environment. Graduates in medicine must be able to correctly perform an examination on a pregnant woman using Leopold maneuvers. Learning curves cumulative summation (LC-CUSUM) may help determine when the student has achieved a specific skill. Our objective was to perform the LC-CUSUM test regarding the ability of students to correctly carry out Leopold maneuvers; a pregnancy simulator was used, transferring the results to a clinical setting. METHODS: Five medical students were trained to carry out Leopold maneuvers using the simulator. Each student performed maneuvers for 50 cases of different fetus positions; a LC CUSUM was plotted for each student. Afterward, the students performed the Leopold maneuvers on 5 pregnant women. RESULTS: Of the 5 students, 3 achieved a level of proficiency; the attempts needed for reaching this level were 13, 13, and 37, respectively. The other 2 students did not reach proficiency level. Of the students who became successfully proficient with the simulator, one of them attained a 100% success rate in pregnant patients, whereas the other two had success rates of 80%. The students who did not achieve a level of competency with the simulator had only a 60% success rate with patients. CONCLUSIONS: Because of the differences observed between students in the number of attempts needed for achieving proficiency in Leopold maneuvers, we believe that each student should build his/her own learning curve. Achieving competency in carrying out Leopold maneuvers using the simulator could be transferable to patients. PMID- 26426559 TI - Defining the Simulation Technician Role: Results of a Survey-Based Study. AB - INTRODUCTION: In health care simulation, simulation technicians perform multiple tasks to support various educational offerings. Technician responsibilities and the tasks that accompany them seem to vary between centers. The objectives were to identify the range and frequency of tasks that technicians perform and to determine if there is a correspondence between what technicians do and what they feel their responsibilities should be. We hypothesized that there is a core set of responsibilities and tasks for the technician position regardless of background, experience, and type of simulation center. METHODS: We conducted a prospective, survey-based study of individuals currently functioning in a simulation technician role in a simulation center. This survey was designed internally and piloted within 3 academic simulation centers. Potential respondents were identified through a national mailing list, and the survey was distributed electronically during a 3-week period. RESULTS: A survey request was sent to 280 potential participants, 136 (49%) responded, and 73 met inclusion criteria. Five core tasks were identified as follows: equipment setup and breakdown, programming scenarios into software, operation of software during simulation, audiovisual support for courses, and on-site simulator maintenance. Independent of background before they were hired, technicians felt unprepared for their role once taking the position. Formal training was identified as a need; however, the majority of technicians felt experience over time was the main contributor toward developing knowledge and skills within their role. CONCLUSIONS: This study represents a first step in defining the technician role within simulation-based education and supports the need for the development of a formal job description to allow recruitment, development, and certification. PMID- 26426560 TI - Assessing Procedural Competence: Validity Considerations. AB - STATEMENT: Simulation-based medical education (SBME) offers opportunities for trainees to learn how to perform procedures and to be assessed in a safe environment. However, SBME research studies often lack robust evidence to support the validity of the interpretation of the results obtained from tools used to assess trainees' skills. The purpose of this paper is to describe how a validity framework can be applied when reporting and interpreting the results of a simulation-based assessment of skills related to performing procedures. The authors discuss various sources of validity evidence because they relate to SBME. A case study is presented. PMID- 26426561 TI - Learning Empathy Through Simulation: A Systematic Literature Review. AB - STATEMENT: Simulation is increasingly used as an educational methodology for teaching empathy to preservice health professional students. This systematic review aimed to determine if and how simulation, including games, simulated patients, and role-play, might develop empathy and empathetic behaviors in learners. Eleven databases or clearing houses including MEDLINE, EMBASE, CINAHL, PsychInfo, and ERIC were searched for all articles published from any date until May 2014, using terms relating to (i) preservice health professional students, (ii) simulation, and (iii) empathy. Twenty-seven studies met the inclusion criteria, including 9 randomized controlled trials. A narrative synthesis suggests that simulation may be an appropriate method to teach empathy to preservice health professional students and identifies the value of the learner taking the role of the patient. PMID- 26426562 TI - Local Anesthetic Systemic Toxicity in a Nonoperative Location. PMID- 26426563 TI - Acquiring Insight Into the Cognitive Processes of Clinicians. PMID- 26426564 TI - Eye Tracking to Acquire Insight Into the Cognitive Processes of Clinicians: Is "Looking" the Same as "Seeing"? PMID- 26426565 TI - Association Between Multimodality Neck Treatment and Work and Leisure Impairment: A Disease-Specific Measure to Assess Both Impairment and Rehabilitation After Neck Dissection. AB - IMPORTANCE: This study describes the effect of adjuvant treatment on shoulder related quality of life, leisure activities, and employment for patients undergoing neck dissection for head and neck cancer. OBJECTIVE: To explore the association between treatment outcome and shoulder-related on critical daily life functions such as employment and recreation. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of patients with head and neck cancer at a tertiary care hospital. EXPOSURES: Level V-sparing selective neck dissection or modified radical neck dissection sparing the accessory nerve, with or without radiation therapy and/or chemotherapy. MAIN OUTCOMES AND MEASURES: Patients completed the Neck Dissection Impairment Index (NDII), with scores ranging from 0 to 100 and higher scores indicating better shoulder functioning and shoulder-related quality of life, and underwent objective testing with the Constant-Murley Shoulder Function Test (Constant test) at least 12 months after the completion of all adjuvant treatment. Additional outcome measures related to physical therapy, pain medication use, leisure activity, and employment status. RESULTS: We evaluated 167 patients who underwent 121 selective neck dissections and 46 modified radical neck dissections. The median (range) NDII score was 90 (10-100). Patients with modified radical neck dissection reported lower scores than those with selective neck dissection (85 [10-100] vs. 92 [30-100]; P = .01). Multivariable analysis showed that advanced-stage disease (mean, 77 [range, 25-100] vs. 87 [18-100]; P = .006), radiation therapy (80 [10-100] vs. 88 [50-100]; P = .03), and chemotherapy (77 [30-100] vs. 83 [18-100]; P = .002) were associated with greater shoulder impairment. The NDII and Constant test were well correlated (0.64; P < .001). Change in leisure activity was correlated with greater impairment (median [range] NDII score, 90 [18-100] for patients with no change vs. 53 [10-100] for patients with change, P = .005; Constant score, 85 [12-100] vs. 68 [10-88], P = .004). Patients who remained employed or resumed working had higher median (range) NDII scores (94 [10-100] and 88 [75-100], respectively) than those who limited or stopped working (70 [10-100]), which also correlates with greater shoulder impairment (P < .001). CONCLUSIONS AND RELEVANCE: More aggressive treatment, either in the form of increased surgical dissection, radiation therapy, or chemotherapy, was associated with worse shoulder function and quality of life. The degree of impairment perceived by the patient and measured in objective testing was correlated with leisure activity and employment status. These findings may stimulate further investigation related to optimizing quality of life following neck dissection. PMID- 26426566 TI - Asystole during Pulse Generator Change: Unexpected Failure of Pacemaker Implant Autoinitialization. PMID- 26426567 TI - Mechanism-Based Trapping of the Quinonoid Intermediate by Using the K276R Mutant of PLP-Dependent 3-Aminobenzoate Synthase PctV in the Biosynthesis of Pactamycin. AB - Mutational analysis of the pyridoxal 5'-phosphate (PLP)-dependent enzyme PctV was carried out to elucidate the multi-step reaction mechanism for the formation of 3 aminobenzoate (3-ABA) from 3-dehydroshikimate (3-DSA). Introduction of mutation K276R led to the accumulation of a quinonoid intermediate with an absorption maximum at 580 nm after the reaction of pyridoxamine 5'-phosphate (PMP) with 3 DSA. The chemical structure of this intermediate was supported by X-ray crystallographic analysis of the complex formed between the K276R mutant and the quinonoid intermediate. These results clearly show that a quinonoid intermediate is involved in the formation of 3-ABA. They also indicate that Lys276 (in the active site of PctV) plays multiple roles, including acid/base catalysis during the dehydration reaction of the quinonoid intermediate. PMID- 26426568 TI - Long-term outcome of living kidney donation: Position paper of the European Committee on Organ Transplantation (CD-P-TO), Council of Europe. PMID- 26426569 TI - Room-Temperature Oxidation of Formaldehyde by Layered Manganese Oxide: Effect of Water. AB - Layered manganese oxide, i.e., birnessite was prepared via the reaction of potassium permanganate with ammonium oxalate. The water content in the birnessite was adjusted by drying/calcining the samples at various temperatures (30 degrees C, 100 degrees C, 200 degrees C, 300 degrees C, and 500 degrees C). Thermogravimetry-mass spectroscopy showed three types of water released from birnessite, which can be ascribed to physically adsorbed H2O, interlayer H2O and hydroxyl, respectively. The activity of birnessite for formaldehyde oxidation was positively associated with its water content, i.e., the higher the water content, the better activity it has. In-situ DRIFTS and step scanning XRD analysis indicate that adsorbed formaldehyde, which is promoted by bonded water via hydrogen bonding, is transformed into formate and carbonate with the consumption of hydroxyl and bonded water. Both bonded water and water in air can compensate the consumed hydroxyl groups to sustain the mineralization of formaldehyde at room temperature. In addition, water in air stimulates the desorption of carbonate via water competitive adsorption, and accordingly the birnessite recovers its activity. This investigation elucidated the role of water in oxidizing formaldehyde by layered manganese oxides at room temperature, which may be helpful for the development of more efficient materials. PMID- 26426570 TI - Evidence of cancer-promoting roles for AMPK and related kinases. AB - The discovery that the 5'AMP-activated protein kinase (AMPK) serves to link the tumour suppressors LKB1 and the tuberous sclerosis complex and functions to slow macromolecular synthesis through attenuation of the mechanistic target of rapamycin complex 1 revealed a role for AMPK in tumour suppression. On the other hand, the well-recognized role of AMPK in maintaining ATP homeostasis, through suppression of anabolism and promotion of catabolism, as well as the role of AMPK in neutralizing reactive oxygen species, via maintenance of NADPH-dependent reductive capacity, point to tumour-protective roles in the context of metabolic stress, which is a key feature of many solid tumours. A growing number of studies thus suggest a duality of functions for AMPK that are either pro- or anti-cancer, depending upon context. Importantly, AMPK is composed of three subunits, and multiple isoforms exist for all three, allowing for different permutations to assemble and the potential for specific AMPK complexes to regulate distinct cellular processes. Moreover, certain subunits of the AMPK complex are frequently overexpressed in a spectrum of human cancer types, suggesting an outright oncogenic function for specific AMPK complexes. Adding complexity to this picture, the catalytic AMPK alpha subunits belong to a family of 14 kinases that can all be activated by LKB1 and studies are beginning to reveal a similar duality of roles in cancer for other members of the AMPK-related kinase family. PMID- 26426571 TI - anti-Selective aminofluorination of alkenes with amidines mediated by hypervalent iodine(iii) reagents. AB - anti-Selective aminofluorination of alkenes with amidines was enabled by hypervalent iodine(iii) reagents, affording 4-fluoroalkyl-2-imidazolines. Further reductive ring-opening of the 2-imidazoline moiety could deliver highly functionalized 3-fluoropropane-1,2-diamine derivatives. PMID- 26426572 TI - The use of the Rx spin label in orientation measurement on proteins, by EPR. AB - The bipedal spin label Rx is more restricted in its conformation and dynamics than its monopodal counterpart R1. To systematically investigate the utility of the Rx label, we have attempted to comprehensively survey the attachment of Rx to protein secondary structures. We have examined the formation, structure and dynamics of the spin label in relation to the underlying protein in order to determine feasibility and optimum conditions for distance and orientation measurement by pulsed EPR. The labeled proteins have been studied using molecular dynamics, CW EPR, pulsed EPR distance measurement at X-band and orientation measurement at W-band. The utility of different modes and positions of attachment have been compared and contrasted. PMID- 26426574 TI - Is pholcodine a dangerous cough suppressant? PMID- 26426573 TI - Gonadotropin-Releasing Hormone Agonists for Ovarian Function Preservation in Premenopausal Women Undergoing Chemotherapy for Early-Stage Breast Cancer: A Systematic Review and Meta-analysis. AB - IMPORTANCE: Chemotherapy may result in a detrimental effect on ovarian function and fertility in premenopausal women undergoing treatment for early-stage breast cancer (EBC). To minimize risk of harm to ovarian function and fertility for patients in this setting, careful considerations should be made. Gonadotropin releasing hormone agonists (GnRHa) have been suggested as an alternative to prevent the loss of ovarian function due to exposure to cytotoxic agents, but GnRHa use for ovarian protection in EBC patients is not fully resolved. OBJECTIVE: To determine the effectiveness of GnRHa administered concurrently with chemotherapy for ovarian function preservation. DATA SOURCES: PubMed, SCOPUS, and Cochrane databases were searched for studies published between January 1975 and March 2015. The abstracts of the American Society of Clinical Oncology Annual Meeting between 1995 and 2014 and the San Antonio Breast Cancer Symposium between 2009 and 2014 were searched as well. STUDY SELECTION: Prospective, randomized, clinical trials addressing the role of ovarian suppression with GnRHa in preventing early ovarian dysfunction in premenopausal women undergoing treatment for EBC were selected. DATA EXTRACTION AND SYNTHESIS: Data extraction was performed independently by 2 authors. The methodology and the risk of bias were assessment based on the description of randomization method, withdrawals, and blinding process. MAIN OUTCOMES AND MEASURES: Rate of resumption of regular menses after a minimal follow-up period of 6 months following chemotherapy was used as a surrogate to assess the incidence of ovarian dysfunction. Additional secondary outcomes included hormone levels and number of pregnancies. Risk ratio estimates were calculated based on the number of evaluable patients. Analyses were conducted using a random effect model. RESULTS: Seven studies were included in this analysis, totaling 1047 randomized patients and 856 evaluable patients. The use of GnRHa was associated with a higher rate of recovery of regular menses after 6 months (odds ratio [OR], 2.41; 95% CI, 1.40-4.15; P = .002) and at least 12 months (OR, 1.85; 95% CI, 1.33-2.59; P < .001) following the last chemotherapy cycle. The use of GnRHa was also associated with a higher number of pregnancies (OR, 1.85; 95% CI, 1.02-3.36; P = .04), although this outcome was not uniformly reported and fertility or rate of pregnancy was not the primary outcome in any of the trials. CONCLUSIONS AND RELEVANCE: Gonadotropin-releasing hormone agonists given with chemotherapy was associated with increased rates of recovery of regular menses in this meta-analysis. Evidence was insufficient to assess outcomes related to GnRHa and ovarian function and fertility and needs further investigation. PMID- 26426576 TI - Comparison of efficacy and safety of lateral-to-medial continuous transversus abdominis plane block with thoracic epidural analgesia in patients undergoing abdominal surgery: A randomised, open-label feasibility study. AB - BACKGROUND: We recently described a lateral-to-medial approach for transversus abdominis plane (LM-TAP) block, which may permit preoperative initiation of the block. OBJECTIVE: Our objective was to evaluate the feasibility of continuous LM TAP blocks in clinical practice in comparison with thoracic epidural analgesia (TEA). DESIGN: A randomised, open-label study. SETTING: University Hospital, London Health Sciences Centre, London, Ontario, Canada from July 2008 to August 2012. PATIENTS: Fifty adult patients undergoing open abdominal surgery via laparotomy were allocated randomly to receive preoperative catheter-congruent TEA or ultrasound-guided continuous bilateral LM-TAP block for 72 h postoperatively. Reasons for noninclusion were American Society of Anesthesiologists' physical status more than 4, known allergy to study drugs, chronic pain/opioid dependence, spinal abnormalities or psychiatric illness. INTERVENTIONS: In the TEA group (n = 24), patient-controlled epidural analgesia was maintained using bupivacaine 0.1% with hydromorphone 10 MUg ml-1 after establishment of the initial block. In the LM-TAP group (n = 26), ultrasound-guided LM-TAP catheters were inserted on each side preoperatively after a bolus of 30 ml of ropivacaine 0.5% (20 ml subcostal and 10 ml subumbilical injections on both sides). Analgesia was maintained with an infusion of ropivacaine 0.35% at a rate of 2 to 2.5 ml h-1 through each catheter, along with rescue intravenous patient-controlled analgesia. MAIN OUTCOME MEASURES: The primary outcome was pain score on coughing 24 h after the end of surgery. Secondary outcomes were pain scores from 24 to 72 h, intraoperative and postoperative opioid consumption, time to onset of bowel movement and side effect profiles. RESULTS: Mean [95% confidence interval (95% CI)] pain scores at rest ranged from 1. 7 (0.9 to 2.5) to 2.3 (1.1 to 3.4) in TEA vs. 1.5 (0.7 to 2.2) to 2.2 (1.3 to 3.0) in LM-TAP (P = 0.829). The dynamic pain scores ranged from 2.9 (1.5 to 4.4) to 3.8 (2.8 to 4.8) in TEA vs. 3.3 (2.4 to 4.3) to 3.8 (2.7 to 4.9) in LM-TAP (P = 0.551). The variability in pain scores was lower in the LM-TAP group than in the TEA group in the first 24 h postoperatively. Patient satisfaction and other secondary outcomes were similar. CONCLUSION: Continuous bilateral LM-TAP block can be initiated preoperatively and may provide comparable analgesia to TEA in patients undergoing laparotomy. CLINICAL TRIALS REGISTRY: not registered because registration was not mandatory at the time of starting the trial. PMID- 26426575 TI - The Shamrock lumbar plexus block: A dose-finding study. AB - BACKGROUND: The Shamrock technique is a new method for ultrasound-guided lumbar plexus blockade. Data on the optimal local anaesthetic dose are not available. OBJECTIVE: The objective of this study is to estimate the effective dose of ropivacaine 0.5% for a Shamrock lumbar plexus block. DESIGN: A prospective dose finding study using Dixon's up-and-down sequential method. SETTING: University Hospital Orthopaedic Anaesthesia Unit. INTERVENTION: Shamrock lumbar plexus block performance and block assessment were scheduled preoperatively. Ropivacaine 0.5% was titrated with the Dixon and Massey up-and-down method using a stepwise change of 5 ml in each consecutive patient. Combined blocks of the femoral, the lateral femoral cutaneous and the obturator nerve were prerequisite for a successful lumbar plexus block. PATIENTS: Thirty patients scheduled for lower limb orthopaedic surgery completed the study. MAIN OUTCOME MEASURES: The minimum effective anaesthetic volume of ropivacaine 0.5% (ED50) to achieve a successful Shamrock lumbar plexus block in 50% of the patients. Further analysis of the data was performed with a logistic regression model to calculate ED95 and to estimate the effective doses for a sensory lumbar plexus block not requiring a motor block of the femoral nerve. RESULTS: The Dixon and Massay estimate of the ED50 was 20.4 [95% confidence interval (95% CI) 13.9 to 30.0] ml ropivacaine 0.5%. The logistic regression estimate of the ED95 was 36.0 (95% CI 19.7 to 52.2) ml ropivacaine 0.5%. For a sensory lumbar plexus block, the ED50 was 17.1 (95% CI 12.3 to 21.9) ml and the ED95 was 25.8 (95% CI 18.6 to 33.1) ml. CONCLUSION: A volume of 20.4 ml ropivacaine 0.5% provided a successful Shamrock lumbar plexus block in 50% of the patients. A volume of 36.0 ml would be successful in 95% of the patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01956617. PMID- 26426578 TI - Correction: Registered report: A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. PMID- 26426577 TI - Clonidine versus sufentanil as an adjuvant to ropivacaine in patient-controlled epidural labour analgesia: A randomised double-blind trial. AB - BACKGROUND: Adjuvants to local anaesthetics for epidural labour analgesia are useful if they reduce side-effects or personnel requirements. Epidural clonidine improves analgesia and provides a significant local anaesthetic-sparing effect. OBJECTIVE: To compare the number of rescue doses administered by the anaesthesiologist when clonidine or sufentanil is added to epidural ropivacaine. DESIGN: A randomised double-blind trial. SETTING: Cliniques Universitaires Saint Luc, Universite Catholique de Louvain, Brussels, Belgium, from June 2009 to June 2010. PATIENTS: One hundred and ninety-five women in labour. INTERVENTION: Epidural analgesia initiated with 10 ml ropivacaine 0.1%, women randomised to receive patient-controlled epidural analgesia (5 ml demand bolus, 15 min lockout) with ropivacaine 0.1% and sufentanil 0.25 MUg ml-1 (RS group; n = 65), or ropivacaine 0.1% and clonidine 1.5 MUg ml-1 (RC1.5 group; n = 65) or ropivacaine 0.1% and clonidine 3 MUg ml-1 (RC3 group; n = 65). Rescue analgesia was available as needed - 10 ml ropivacaine 0.1% (numerical rating scale <6/10) or ropivacaine 0.2% (numerical rating scale >=6/10). MAIN OUTCOME: Comparison of the total number of rescue doses. RESULTS: The total number of rescue doses was similar among the groups [median (interquartile range): 1 (0 to 1) in the RC1.5 group, 1 (1 to 2) in the RC3 group and 2 (1 to 2) in the RS group; overall P = 0.056]. However, fewer patients in both the RC1.5 and RC3 groups needed two or more rescue doses (25 and 29% versus 52% in the RS group, P = 0.01). The rate of instrumental delivery was higher in both clonidine groups (13 and 12% versus 0%, P = 0.03). Nausea was significantly less frequent in both the clonidine groups. Satisfaction scores, total ropivacaine consumption, maternal sedation, and hypotension and neonatal outcomes were similar among the groups. CONCLUSION: Compared with sufentanil 0.25 MUg ml-1, addition of clonidine (1.5 to 3 MUg ml-1) to patient-controlled epidural analgesia with ropivacaine 0.1% provided similar labour analgesia and a similar need for anaesthesiologist-administered rescue doses. Clonidine 3 MUg ml-1 did not offer any advantage over clonidine 1.5 MUg ml 1. The instrumentation rate was higher in both the clonidine groups. PMID- 26426579 TI - On spinning plates. PMID- 26426581 TI - Room-temperature, solution-processable organic electron extraction layer for high performance planar heterojunction perovskite solar cells. AB - In this work, we describe a room-temperature, solution-processable organic electron extraction layer (EEL) for high-performance planar heterojunction perovskite solar cells (PHJ PVSCs). This EEL is composed of a bilayered fulleropyrrolidinium iodide (FPI)-polyethyleneimine (PEIE) and PC61BM, which yields a promising power conversion efficiency (PCE) of 15.7% with insignificant hysteresis. We reveal that PC61BM can serve as a surface modifier of FPI-PEIE to simultaneously facilitate the crystallization of perovskite and the charge extraction at FPI-PEIE/CH3NH3PbI3 interface. Furthermore, the FPI-PEIE can also tune the work function of ITO and dope PC61BM to promote the efficient electron transport between ITO and PC61BM. Based on the advantages of room-temperature processability and decent electrical property of FPI-PEIE/PC61BM EEL, a high performance flexible PVSC with a PCE ~10% is eventually demonstrated. This study shows the potential of low-temperature processed organic EEL to replace transition metal oxide-based interlayers for highly printing compatible PVSCs with high-performance. PMID- 26426580 TI - Lack of PRKD2 and PRKD3 kinase domain somatic mutations in PRKD1 wild-type classic polymorphous low-grade adenocarcinomas of the salivary gland. AB - AIMS: Polymorphous low-grade adenocarcinoma (PLGA) is the second most common intra-oral salivary gland malignancy. The vast majority of PLGAs harbour a PRKD1 E710D hot-spot somatic mutation or somatic rearrangements of PRKD1, PRKD2 or PRKD3. Given the kinase domain homology among PRKD1, PRKD2 and PRKD3, we sought to define whether PLGAs lacking PRKD1 somatic mutations or PRKD gene family rearrangements would be driven by somatic mutations affecting the kinase domains of PRKD2 or PRKD3. METHODS AND RESULTS: DNA was extracted from eight microdissected PLGAs lacking PRKD1 somatic mutations or PRKD gene family rearrangements. Samples were thoroughly centrally reviewed, microdissected and subjected to Sanger sequencing of the kinase domains of the PRKD2 and PRKD3 genes. None of the PLGAs lacking PRKD1 somatic mutations or PRKD gene family rearrangements harboured somatic mutations in the kinase domains of the PRKD2 or PRKD3 genes. CONCLUSION: PLGAs lacking PRKD1 somatic mutations or PRKD gene family rearrangements are unlikely to harbour somatic mutations in the kinase domains of PRKD2 or PRKD3. Further studies are warranted to define the driver genetic events in this subgroup of PLGAs. PMID- 26426583 TI - Increased Risk of Post-Trauma Stroke after Traumatic Brain Injury-Induced Acute Respiratory Distress Syndrome. AB - This study determines whether acute respiratory distress syndrome (ARDS) is an independent risk factor for an increased risk of post-traumatic brain injury (TBI) stroke during 3-month, 1-year, and 5-year follow-ups, respectively, after adjusting for other covariates. Clinical data for the analysis were from the National Health Insurance Database 2000, which covered a total of 2121 TBI patients and 101 patients with a diagnosis of TBI complicated with ARDS (TBI ARDS) hospitalized between January 1, 2001 and December 31, 2005. Each patient was tracked for 5 years to record stroke occurrences after discharge from the hospital. The prognostic value of TBI-ARDS was evaluated using a multivariate Cox proportional hazard model. The main outcome found that stroke occurred in nearly 40% of patients with TBI-ARDS, and the hazard ratio for post-TBI stroke increased fourfold during the 5-year follow-up period after adjusting for other covariates. The increased risk of hemorrhagic stroke in the ARDS group was considerably higher than in the TBI-only cohort. This is the first study to report that post traumatic ARDS yielded an approximate fourfold increased risk of stroke in TBI only patients. We suggest intensive and appropriate medical management and intensive follow-up of TBI-ARDS patients during the beginning of the hospital discharge. PMID- 26426582 TI - Prion Protein Does Not Confer Resistance to Hippocampus-Derived Zpl Cells against the Toxic Effects of Cu2+, Mn2+, Zn2+ and Co2+ Not Supporting a General Protective Role for PrP in Transition Metal Induced Toxicity. AB - The interactions of transition metals with the prion protein (PrP) are well documented and characterized, however, there is no consensus on their role in either the physiology of PrP or PrP-related neurodegenerative disorders. PrP has been reported to protect cells from the toxic stimuli of metals. By employing a cell viability assay, we examined the effects of various concentrations of Cu2+, Zn2+, Mn2+, and Co2+ on Zpl (Prnp-/-) and ZW (Prnp+/+) hippocampus-derived mouse neuronal cells. Prnp-/- Zpl cells were more sensitive to all four metals than PrP expressing Zw cells. However, when we introduced PrP or only the empty vector into Zpl cells, we could not discern any protective effect associated with the presence of PrP. This observation was further corroborated when assessing the toxic effect of metals by propidium-iodide staining and fluorescence activated cell sorting analysis. Thus, our results on this mouse cell culture model do not seem to support a strong protective role for PrP against transition metal toxicity and also emphasize the necessity of extreme care when comparing cells derived from PrP knock-out and wild type mice. PMID- 26426584 TI - Earth-abundant NiS co-catalyst modified metal-free mpg-C3N4/CNT nanocomposites for highly efficient visible-light photocatalytic H2 evolution. AB - In the present work, the earth-abundant NiS co-catalyst modified mesoporous graphite-like C3N4 (mpg-C3N4)/CNT nanocomposites were prepared via a two-step strategy: the sol-gel method and the direct precipitation process. The mpg C3N4/CNT/NiS composite photocatalysts were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), UV-vis absorption spectroscopy, photoluminescence spectroscopy (PL), photoelectrochemical (PEC) and electrochemical impedance spectra (EIS) experiments. The photocatalytic H2-production activity over the composite catalysts was also evaluated by using an aqueous solution containing triethanolamine under visible light (lambda>= 420 nm). The results showed that the loading of earth-abundant NiS co-catalysts onto metal-free mpg-C3N4/CNT nanocomposites can remarkably enhance their photocatalytic H2-production activity. The optimal loading amount of NiS on metal-free mpg-C3N4/CNT nanocomposites was about 1 wt%. The as-obtained mpg-C3N4/CNT/1% NiS ternary composite photocatalyst exhibits the best H2-evolution activity with the highest rate of about 521 MUmol g(-1) h(-1) under visible light (lambda>= 420 nm), which is almost 148 times that of a pure mpg-C3N4/CNT sample. The enhanced photocatalytic activity can be mainly attributed to the synergistic effect of effectively promoted separation of photo-generated electron-hole pairs and enhanced H2-evolution kinetics. The co-loading of nanocarbon materials and earth abundant co-catalysts onto metal-free mpg-C3N4 photocatalysts offers great potential for practical applications in photocatalytic H2 evolution under visible light illumination. PMID- 26426585 TI - Controlled DNA Patterning by Chemical Lift-Off Lithography: Matrix Matters. AB - Nucleotide arrays require controlled surface densities and minimal nucleotide substrate interactions to enable highly specific and efficient recognition by corresponding targets. We investigated chemical lift-off lithography with hydroxyl- and oligo(ethylene glycol)-terminated alkanethiol self-assembled monolayers as a means to produce substrates optimized for tethered DNA insertion into post-lift-off regions. Residual alkanethiols in the patterned regions after lift-off lithography enabled the formation of patterned DNA monolayers that favored hybridization with target DNA. Nucleotide densities were tunable by altering surface chemistries and alkanethiol ratios prior to lift-off. Lithography-induced conformational changes in oligo(ethylene glycol)-terminated monolayers hindered nucleotide insertion but could be used to advantage via mixed monolayers or double-lift-off lithography. Compared to thiolated DNA self assembly alone or with alkanethiol backfilling, preparation of functional nucleotide arrays by chemical lift-off lithography enables superior hybridization efficiency and tunability. PMID- 26426586 TI - Application of Genomic Technologies in Clinical Pharmacology Research. AB - Technology is the basis of scientific progress and is an essential component for continued competitiveness in industry. The development of a new drug candidate is a long and expensive process, in which a molecule undergoes several stages of research (both pre-clinical and clinical) before being approved for commercialization. Scientific progress has revolutionized the pharmaceutical industry and reshaped the processes by which new drugs are discovered, investigated, and developed. Currently, the influence of genomic variations in drug metabolism must be better understood to predict an individual's response to a given treatment. Employing genomics tools, an individual's genetic profile may be obtained and used as the basis for prescription of the best treatment option, thus personalizing medicine. In this review, we discuss how current mainstream genomic technologies used in clinical pharmacology research can accelerate the identification of populations that can benefit the most while reducing adverse events. PMID- 26426587 TI - Economic Evaluation of the Use of Drug-Eluting Stents versus Bare-Metal Stents in Adults with Ischemic Cardiomyopathy Requiring Angioplasty. AB - BACKGROUND: The value of drug-eluting stents in preventing cardiovascular events has not been investigated in Mexico. OBJECTIVE: To conduct a cost-effectiveness analysis of early and new-generation drug-eluting stents from the perspective of a healthcare provider. METHODS: We conducted a cost-effectiveness analysis of early and new-generation drug-eluting stents in patients with ischemic cardiomyopathy attending a Cardiology Hospital of the Mexican Social Security Institute. The health endpoint used was major acute cardiovascular events prevented. The effectiveness by stent type was obtained from the literature. A retrospective chart review study was conducted to collect cost data on cardiovascular events including seven cost categories. Average and incremental cost-effectiveness ratios were estimated. Deterministic and probabilistic sensitivity analyses were performed to test the robustness of estimates. RESULTS: Incremental cost-effectiveness ratios in base-case were 28,910 and US$ 35,590 for early and new-generation stents, respectively. In an optimal scenario, incremental-cost effectiveness ratio was 24,776 and US$ 25,262 for early and new stents, respectively. Probabilistic sensitivity analysis suggested that 90% of cases were cost-effective when willingness-to-pay was 58,000 and US$ 66,000 for early and new-generation stents, respectively. CONCLUSIONS: The cost effectiveness ratios of early and new-generation stents were significantly higher than corresponding bare-metal stents. PMID- 26426588 TI - Proton Magnetic Resonance Spectroscopy Changes in Parkinson's Disease With and Without Psychosis. AB - BACKGROUND: Psychosis prevalence in Parkinson's disease is estimated at 8-30%. Proton magnetic resonance spectroscopy measures specific metabolites as markers of cell functioning. OBJECTIVE: To study N-acetyl-aspartate and glutamate levels in the caudate and putamen nuclei in subjects with Parkinson's disease with and without psychosis. METHODS: We included 20 non-demented Parkinson's disease patients with psychosis and 20 Parkinson's disease patients without psychosis matched for age, sex, disease duration, and levodopa equivalent daily dose, all attended at an academic medical center. Proton magnetic resonance spectroscopy scans were performed in a 3T GE whole-body scanner. RESULTS: Decreased glutamate levels scaled to creatine were found in the dorsal caudate (p = 0.005) and putamen (p = 0.007) of the Parkinson's disease psychosis group compared with the without psychosis group. Glutamate plus glutamine levels scaled to creatine and N acetyl-aspartate levels scaled to creatine were also significantly reduced in the dorsal caudate of the Parkinson's disease with psychosis group (p = 0.018 and p = 0.011, respectively). No group differences were found for any of the other metabolites in the two regions of interest. CONCLUSIONS: Our findings suggest that decreased metabolite levels in specific brain areas may be implicated in the development of psychosis in Parkinson's disease. PMID- 26426590 TI - Carotid Intima-Media Thickness, Ankle-Arm Index, and Inflammation Profile in Mexican Patients with Early and Late Onset Type 2 Diabetes. AB - BACKGROUND: Type 2 diabetes is strongly linked to an increased incidence of cardiovascular outcomes. Carotid artery intima-media thickness and ankle-arm index are non-invasive complementary measures as subclinical markers of atherosclerosis. OBJECTIVE: To evaluate the association of carotid intima-media thickness, ankle-arm index, and inflammation profile in Mexican patients with early- and late-onset type 2 diabetes mellitus. MATERIAL AND METHODS: We included 145 subjects at an academic medical center: 77 patients with early-onset (< 40 years of age) and 33 patients with late-onset (>= 40 years) type 2 diabetes mellitus, and 35 healthy volunteers. Clinical history, anthropometrics, blood chemistry, lipids profile, glycosylated hemoglobin A1c, cytokines, and high sensitivity C-reactive protein were determined; carotid and lower limb ultrasound were taken. Groups were compared with ANOVA or Kruskal-Wallis, Student's t or Mann-Whitney U. Spearman or Pearson correlation and logistic regression analysis were used. RESULTS: There were anthropometric and biochemical differences between the three groups. Concentrations of interleukin-1beta, -4 and -6 were significantly higher in patients with late versus early onset diabetes. There were differences in carotid intima-media thickness and ankle-arm index between early and late onset. Age, body mass index, high-density lipoprotein cholesterol, high-sensitivity C-reactive protein, waist circumference, and glycosylated hemoglobin A1c showed direct correlation with carotid intima-media thickness, while ankle-arm index showed inverse correlation with blood pressure, glycosylated hemoglobin A1c, time with disease, age at onset, triglycerides, and fibrinogen. Multivariate analysis showed an association between carotid intima media thickness and disease duration; ankle-arm index with disease duration and high-sensitivity C-reactive protein; while only body mass index associated with end diastolic flow velocity. CONCLUSIONS: Our findings suggest that carotid intima-media thickness and ankle-arm index are associated with inflammation markers and could be included in the evaluation of type 2 diabetes mellitus patients, according to disease onset and duration. There are important differences in interleukin concentrations between early- and late-onset type 2 diabetes mellitus. Additionally, measurement of high-sensitivity C-reactive protein is suggested in patients with abnormal ankle-arm index. PMID- 26426589 TI - Surveillance of Oseltamivir-Resistant Influenza A(H1N1)pdm09 in Guanajuato State, Mexico from 2009 to 2012. AB - BACKGROUND: The influenza A(H1N1)pdm09 virus was first identified in Mexico in April 2009, subsequently spreading worldwide. Soon after the WHO declared a pandemic, a series of cases involving oseltamivir-resistant viruses were described, following concerns about the spread of strains resistant to neuraminidase inhibitors that could hamper control measures. To study the prevalence of oseltamivir-resistant influenza A(H1N1)pdm09, we implemented a surveillance program across the state of Guanajuato, Mexico. METHODS: We collected respiratory samples from patients with confirmed infection with influenza A(H1N1)pdm09 virus between 2009 and 2012 in rural and urban regions in Guanajuato, Mexico. Specimens were screened for the H275Y mutation by Sanger sequencing. RESULTS: A total of 1,192 laboratory confirmed influenza A(H1N1)pdm09 positive samples were processed between 2009 and 2012. Using two endpoint real time polymerase chain reaction, 575 samples were sequenced. Two different clusters, I and II, were identified. The H275Y substitution was found in only one sample from cluster I. CONCLUSIONS: The prevalence of oseltamivir-resistant influenza A(H1N1)pdm09 2009 viruses during the pandemic period and following years was very low in our State. PMID- 26426591 TI - Parecoxib Increases Blood Pressure Through Inhibition of Cyclooxygenase-2 Messenger RNA in an Experimental Model. AB - BACKGROUND: Cyclooxygenase-2 selective inhibitors have been developed to alleviate pain and inflammation; however, the use of a selective cyclooxygenase-2 inhibitor is associated with mild edema, hypertension, and cardiovascular risk. AIM: To evaluate, in an experimental model in normotensive rats, the effect of treatment with parecoxib in comparison with diclofenac and aspirin and L-NAME, a non-selective nitric oxide synthetase, on mean arterial blood pressure, and cyclooxygenase-1 and -2 messenger RNA and protein expression in aortic tissue. METHODS: Rats were treated for seven days with parecoxib (10 mg/kg/day), diclofenac (3.2 mg/kg/day), aspirin (10 mg/kg/day), or L-NAME (10 mg/kg/day). Mean arterial blood pressure was evaluated in rat tail; cyclooxygenase-1 and -2 were evaluated by reverse transcription-polymerase chain reaction and Western blot analysis in aortic tissue. RESULTS: Parecoxib and L-NAME, but not aspirin and diclofenac, increased mean arterial blood pressure by about 50% (p < 0.05) without changes in cardiac frequency. Messenger RNA cyclooxygenase-1 expression in aortic tissue was not modified with any drug (p < 0.05). L-NAME and parecoxib treatment decreased messenger RNA cyclooxygenase-2 and cyclooxygenase-2 (p < 0.05). While cyclooxygenase-1 protein decreased with the three drugs tested but not with L-NAME (p < 0.05), the cyclooxygenase-2 protein decreased only with aspirin and parecoxib (p < 0.05). CONCLUSION: Parecoxib increases the blood pressure of normotensive rats by the suppression of COX-2 gene expression, which apparently induced cardiovascular control. PMID- 26426592 TI - Diagnostic Value of the Morphometric Model and Adjusted Neck Circumference in Adults with Obstructive Sleep Apnea Syndrome. AB - BACKGROUND: Obstructive sleep apnea syndrome is a major public health problem. The morphometric model and the Sleep Apnea Clinical Score are widely used to evaluate adults; however, neither of these tools has been validated in a Mexican population. OBJECTIVE: To determine the diagnostic value of the morphometric model and the Sleep Apnea Clinical Score and compare them with conventional clinical instruments. METHODS: A total of 97 individuals were recruited prospectively. Initial screening excluded 36, of whom nine were subjects without apnea; the remaining 52 were consecutive patients with obstructive sleep apnea syndrome diagnosed by nocturnal polysomnography. Diagnostic values of each test were calculated. RESULTS: Obstructive sleep apnea syndrome patients had significantly higher scores with both instruments than controls: morphometric model: 61.3 (95% CI: 45.5-75.3) vs. 41.0 (95% CI: 35.6-45.6); Sleep Apnea Clinical Score: 45.3 (95% CI: 39.5-40.3) vs. 36 (95% CI: 34.0-36.5), respectively. For severe cases, the best cutoff point for morphometric model was 46, with a sensitivity of 81% (95% CI: 62.5-92.6) and specificity of 46.7% (95% CI: 66.4-100), while for Sleep Apnea Clinical Score it was > 48, with a sensitivity of 61% (95% CI: 46.1-74.2) and specificity of 80.4% (95% CI: 66 90.6). CONCLUSIONS: A morphometric model value of >= 46 or an adjusted neck circumference (Sleep Apnea Clinical Score) > 48 were adequate for diagnosing obstructive sleep apnea syndrome. PMID- 26426593 TI - Albuminuria and Glomerular Filtration Rate in Individuals with Type 1 Diabetes Mellitus: Contribution of Metabolic Syndrome. AB - BACKGROUND: The development of metabolic syndrome has been described in patients with type 1 diabetes mellitus as the disease progresses over time. The purpose of this study is to assess the relationship between metabolic syndrome, albuminuria, and glomerular filtration rate, as well as to determine the prevalence of metabolic syndrome, in a group of Mexican patients with type 1 diabetes mellitus. METHODS: We conducted a cross-sectional study that included patients with type 1 diabetes mellitus who were diagnosed over 10 years ago and who are seen at the Diabetes Intensive Control Clinic of the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran in Mexico City. The presence of metabolic syndrome was determined by using the National Cholesterol Education Program-Adult Treatment Panel III (ATP III) criteria. RESULTS: A total of 81 individuals were studied. The prevalence of metabolic syndrome was 18.5% (n = 15). A higher albuminuria was found in subjects with metabolic syndrome (34.9 mg/24 hours; 8.3-169.3) than in those without metabolic syndrome (9.0 mg/24 hours; 5.0-27.0; p = 0.02). Glomerular filtration rate was lower in patients with metabolic syndrome (95.3 ml/minute; [64.9-107.2] vs. 110.2 ml/minute [88.1-120.3]; p = 0.04). After classifying the population according to the number of metabolic syndrome criteria, a progressive increase in albuminuria and a progressive decrease in glomerular filtration rate were found with each additional metabolic syndrome criterion (p = 0.008 and p = 0.032, respectively). After adjusting for age, time from diagnosis, systolic blood pressure, triglycerides, HDL-cholesterol, and treatment with angiotensin receptor blockers or angiotensin converting enzyme inhibitors, we found that age, time from diagnosis, triglycerides, and HDL cholesterol were independent factors associated with glomerular filtration rate (R2 = 0.286; p < 0.001). CONCLUSIONS: Metabolic syndrome was associated with a higher albuminuria and a reduction in glomerular filtration rate in patients with type 1 diabetes mellitus. Metabolic syndrome was present in 18.5% of this group of Mexican individuals with type 1 diabetes mellitus. PMID- 26426594 TI - Lactic Acidosis Complicating Metformin and Non-Nucleoside Reverse Transcriptase Inhibitor Combination Therapy: A Smoldering Threat in the Post-HAART Era. AB - Dear Editor, The prevalence of type 2 diabetes (DM-2) in HIV-infected patients and the concomitant use of metformin (MTF) and non-nucleoside reverse transcriptase inhibitors (NRTI) is rising. Through inhibition of NADH dehydrogenase and DNA pol-gamma, both drugs hinder oxidative phosphorylation that may lead to lactic acidosis (LA). Among NRTIs, abacavir and tenofovir have the lowest mitochondrial toxicity, with only a few LA cases reported2-4. We describe here a case of MTF-associated LA (MALA) secondary to the interaction with NRTI. PMID- 26426600 TI - TIIA attenuates LPS-induced mouse endometritis by suppressing the NF-kappaB signaling pathway. AB - Endometritis is one of the main diseases that harms the dairy cow industry. Tanshinone IIA (TIIA), a fat-soluble alkaloid isolated from Salviae miltiorrhizae, has been reported to have potent anti-inflammatory properties. However, the anti-inflammatory effects of TIIA on a mouse model of lipopolysaccharide (LPS)-induced endometritis remain to be elucidated. The purpose of the present study was to investigate the effects of TIIA on LPS induced mouse endometritis. TIIA was intraperitoneally injected 1 h before and 12 h after perfusion of LPS into the uterus. A histological examination was then performed, and the concentrations of myeloperoxidase (MPO) and nitric oxide (NO) in the uterine tissue were determined. The levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in a homogenate of the uterus were detected by enzyme-linked immunosorbent assay. The extent of phosphorylation of IkappaBalpha and p65 was detected by Western blotting. TIIA markedly reduced the infiltration of neutrophils, suppressed MPO activity and the concentration of NO, and attenuated the expression of TNF-alpha and IL-1beta. Furthermore, TIIA inhibited the phosphorylation of the nuclear factor-kappa B (NF-kappaB) p65 subunit and the degradation of its inhibitor IkappaBalpha. All the results suggest that TIIA has strong anti-inflammatory effects on LPS-induced mouse endometritis. PMID- 26426601 TI - Monitoring guanine photo-oxidation by enantiomerically resolved Ru(II) dipyridophenazine complexes using inosine-substituted oligonucleotides. AB - The intercalating [Ru(TAP)2(dppz)](2+) complex can photo-oxidise guanine in DNA, although in mixed-sequence DNA it can be difficult to understand the precise mechanism due to uncertainties in where and how the complex is bound. Replacement of guanine with the less oxidisable inosine (I) base can be used to understand the mechanism of electron transfer (ET). Here the ET has been compared for both Lambda- and Delta-enantiomers of [Ru(TAP)2(dppz)](2+) in a set of sequences where guanines in the readily oxidisable GG step in {TCGGCGCCGA}2 have been replaced with I. The ET has been monitored using picosecond and nanosecond transient absorption and picosecond time-resolved IR spectroscopy. In both cases inosine replacement leads to a diminished yield, but the trends are strikingly different for Lambda- and Delta-complexes. PMID- 26426602 TI - Polymorphisms in the interleukin 4, interleukin 4 receptor and interleukin 13 genes and allergic phenotype: A case control study. AB - PURPOSE: Interleukin 4 (IL4), interleukin 4 receptor (IL4R) and interleukin 13 (IL13) play a key role in the pathogenesis of allergy and asthma development. IL4 and IL13 strongly influence bronchial hyperreactivity in response to allergen, airway remodeling, airway inflammation and airway smooth muscle proliferation. Both IL4 and IL13 exert biologic effect via interleukin 4 receptor. The aim of this study was to evaluate the impact of the polymorphisms within interleukin 4 (rs2243250, rs2227284), interleukin 4 receptor alpha chain (rs1805010, rs1805011) and interleukin 13 (rs20541) genes on the incidence of allergic phenotype in Polish pediatric population. MATERIAL/METHODS: We compared 177 asthmatic pediatric patients with 194 healthy children. Five polymorphisms within IL4, IL13 and IL4Ralpha genes were analyzed. Genotypes of four polymorphisms (rs2243250, rs2227284, rs1805011, rs20541) were assigned by TaqMan SNP Genotyping Assays (Applied Biosystems), whereas rs18050100 polymorphism was established using PCR RFLP method. RESULTS: We observed an association of rs1805011 polymorphism of IL4Ralpha gene with allergy (p=0.021), mild asthma (p=0.00005) and atopic dermatitis (p=0.0056). Significant correlation was found between rs20541 in IL-13 gene and the positive skin prick test results (p=0.029), along with rs2243250 polymorphism with clinical atopy (p=0.033) and rs2227284 with total IgE levels (p=0.00047). No associations were found for rs1805010. CONCLUSIONS: Our results indicate that rs1805011 polymorphism of IL4Ralpha gene seems to influence allergy risk, especially mild asthma and atopic dermatitis predisposition in Polish children. Subgroup analysis of three other SNPs revealed possible influence on allergy development. PMID- 26426603 TI - Cost-Effectiveness Analysis on Endoscopic Surveillance Among Western Patients With Barrett's Esophagus for Esophageal Adenocarcinoma Screening. AB - Incidence of esophageal adenocarcinoma (EAC) has risen rapidly over the past decades in Western countries. As a premalignant lesion, Barrett's esophagus (BE) is an established risk factor of EAC. This study estimated the impact of surveillance endoscopy for BE on population's survival upon EAC by a whole population cost-effectiveness analysis among modeled Western population. Possibilities and survival payoffs were retrieved through literature searching based on PubMed database. Patients with BE were classified as adequate surveillance (AS), inadequate surveillance (IAS), and no surveillance groups. Direct cost of endoscopy per person-year was estimated from diagnosis of BE to before diagnosis of EAC in the whole-population model, whereas the payoff was 2 year disease-specific survival rate of EAC. AS for patients with BE had lower cost-effectiveness ratio (CER) than that of IAS group, as well as lower incremental cost-effectiveness ratio (6116 ?/% vs 118,347 ?/%). Prolonging the surveillance years could decrease the yearly cost in whole population and also relevant CERs, despite increased total cost. Increasing the proportion of participants in AS group could improve the survival benefit. The maximal payoff was up to 2-year mortality reduction of 2.7 per 100,000 persons by spending extra ? 1,658,913 per 100,000 person-years. A longer endoscopic surveillance among BE subpopulation plan can reduce yearly budget. Attempt to increase the proportion of AS participants can induce decline in population mortality of EAC, despite extra but acceptable expenditure. However, regarding optimal cost-effectiveness, further studies are still required to identify a high-risk subpopulation out of BE patients for endoscopic surveillance. PMID- 26426604 TI - Isolated Total Rupture of Extraocular Muscles. AB - Total rupture of extraocular muscles is an infrequent clinical finding. Here we conducted this retrospective study to evaluate their causes of injury, clinical features, imaging, surgical management, and final outcomes in cases of isolated extraocular muscle rupture at a tertiary center in China. Thirty-six patients were identified (24 men and 12 women). Mean age was 34 years (range 2-60). The right eye was involved in 21 patients and the left 1 in 15. A sharp object or metal hook was the cause of this lesion in 16 patients, sinus surgery in 14 patients, traffic accident in 3 patients, orbital surgery in 2 patients, and conjunctive tumor surgery in 1 patient. The most commonly involved muscles were medial (18 patients) and inferior rectus muscles (13 patients). The function of the ruptured muscles revealed a scale of -3 to -4 defect of ocular motility and the amount of deviation in primary position varied from 10 to 140 PD (prism diopter). Computerized tomography (CT) confirmed the presence of ruptured muscles. An end-to-end muscle anastomosis was performed and 3 to 5 mm of muscle was resected in 23 patients. When the posterior border of the injured muscle could not be identified (13 patients), a partial tendon transposition was performed, together with recession of the antagonist in most patients, whereas a recession of the antagonist muscle plus a resection of the involved muscle with or without nasal periosteal fixation was performed in the remaining patients. After an average of 16.42 months of follow-up an excellent result was achieved in 23 patients and results of 13 patients were considered as a failure. In most patients, the posterior border of the ruptured muscle can be identified and an early surgery can be performed to restore function. Alternatively, a partial tendon transposition should be performed. When muscular rupture is suspected, an early orbital CT is required to confirm this possibility, which can then verify the necessity for an early surgical intervention. PMID- 26426605 TI - Socioeconomic Disparities in Colorectal Cancer Screening in Korea: A Nationwide Cross-Sectional Study. AB - Colorectal cancer (CRC) is a common cancer worldwide. The incidence and mortality rates of CRC are higher among lower socioeconomic status (SES) populations. We investigated the association between different indicators of SES and CRC screening rates in Korea. The eligible study population included males and females aged 50 to 74 years who participated in a nationwide cross-sectional survey (2010-2012). The "compliance with recommendation" category was applicable to participants who had undergone a fecal occult blood test (FOBT), double contrast barium enema, or colonoscopy within 1, 5, or 10 years, respectively. In total, 6221 subjects (51.4% female, 55.6% aged 50 years) were included in the final analysis. Lower household income was significantly negatively related to compliance with screening recommendations (P for trend < 0.01) and marginally significantly related to noncompliance with recommendations (P for trend = 0.07). Older age and poor self-reported health were associated with the screening rate using the FOBT; male sex, older age, higher household income, having supplemental insurance, family history of cancer, and poor self-reported health were associated with a higher screening rate using colonoscopy. Lower household income was associated with a higher screening rate using the FOBT and with a lower screening rate using colonoscopy. To increase the rate of CRC screening using colonoscopy, efforts should be made toward improving the education and promotion of screening to the low household income target population. PMID- 26426606 TI - Citrus Fruit Intake Substantially Reduces the Risk of Esophageal Cancer: A Meta Analysis of Epidemiologic Studies. AB - Many epidemiologic studies indicate a potential association between fruit and vegetable intake and various cancers. The purpose of this meta-analysis is to investigate the association between citrus fruit intake and esophageal cancer risk. The authors conducted a comprehensive search on PubMed, EMBASE, and the Cochrane Library from inception until July 2014. Studies presenting information about citrus intake and esophageal cancer were analyzed. The authors extracted the categories of citrus intake, study-specific odds ratio or relative risk, and the P value and associated 95% confidence intervals for the highest versus lowest dietary intake of citrus fruit level. The association was quantified using meta analysis of standard errors with a random-effects model. Thirteen case-control studies and 6 cohort studies were eligible for inclusion. Citrus intake may significantly reduce risk of esophageal cancer (summary odds ratio = 0.63; 95% confidence interval = 0.52-0.75; P = 0), without notable publication bias (intercept = -0.79, P = 0.288) and with significant heterogeneity across studies (I = 52%). The results from epidemiologic studies suggest an inverse association between citrus fruit intake and esophageal cancer risk. The significant effect is consistent between case-control and cohort studies. Larger prospective studies with rigorous methodology should be considered to validate the association between citrus fruits and esophageal cancer. PMID- 26426607 TI - Three-Dimensional Reconstruction Modeling of the Spatial Displacement, Extent and Rotational Orientation of Undisplaced Femoral Neck Fractures. AB - The purpose of this study was to employ a new three-dimensional (3D) reconstruction and modeling method to measure displacement of undisplaced femoral neck fractures (Garden stages I and II). We also aimed to evaluate the effectiveness of the Garden classification for determining the displacement of undisplaced femoral neck fractures. A total of 120 consecutive patients with undisplaced femoral neck fractures were enrolled between 2012 and 2014, including 60 within the Garden I group and 60 within the Garden II group. The displacements of the femoral head center (d1) and the lowest point of the fovea capitis femoris (d2) and rotational displacement of the femoral head (alpha) in the 3D model were measured with 3D computed tomography reconstruction and modeling. Five observers, trauma surgeons, were asked to found the centers of the femoral heads and the deepest points of the foveae. The intraobserver and inter-observer agreements were calculated using Fleiss' kappa. The inter-observer and intra-observer kappa values were 0.937 and 0.985, respectively. Current method has good reliability. We discovered that many participants in our study had been misclassified by an anterior-posterior radiograph as having an "incomplete" fracture. In incomplete fracture of Garden stage I group, the average displacements d1 and d2 were 3.69 +/- 1.77 mm and 14.51 +/- 1.91 mm, respectively. The mean alpha was 4.91 degrees +/- 2.49 degrees . For impacted fracture of Garden stage I, significant spatial displacement in the impacted fractures was observed (d1: 6.22 +/- 3.36 mm; d2: 10.30 +/- 5.73 mm; and alpha: 17.83 degrees +/- 10.72 degrees ). Similarly, significant spatial displacement was observed among the Garden stage II group (d1: 7.16 +/- 4.58 mm; d2: 12.95 +/- 8.25 mm; and alpha: 18.77 degrees +/- 9.10 degrees ). There was no significant difference in alpha, d1, and d2 between impacted fracture and Garden stage II groups (P > 0.05). However, significant differences were found between incomplete fracture and Garden stage II groups (P < 0.05). Our findings suggest that 3D reconstruction and modeling may be a better tool for assessing femoral neck fractures than the Garden classification. Undisplaced femoral neck fractures showed variable degrees of displacement and were not undisplaced, stable fractures. Garden classification for undisplaced femoral neck fractures has certain limitations. PMID- 26426608 TI - Radioguided Adrenal Surgery: Access in Complex Situations: Technical Notes. AB - The laparoscopic adrenalectomy is considered as the procedure of choice for the treatment of adrenal hyperplasia and tumor lesions. However, some special situations may limit the use of this method due to the difficulty to locate the gland and perform the lesion excision. We analyze 2 patients of a left adrenal tumor, explaining how they have overcome the difficulties in both situations. The first case was a patient with a history of intra-abdominal surgery and the other patient suffered from severe obesity. We performed with the use of the gamma probe, and the 2 cases, was of great help to access and glandular localization. The help of gamma probe test was achieved in the surgical bed, that removal was complete. The use of the portable gamma probe facilitated the access to the left adrenal gland as well as conducting the glandular excision without delay, despite the difficulties due to the intra abdominal surgery caused by the previous surgery, and in the case of severe obesity. PMID- 26426609 TI - Improved Sepsis Alert With a Telephone Call From the Clinical Microbiology Laboratory: A Clinical Trial. AB - Early sepsis attention is a standard of care in many institutions and the role of different specialists is well recognized. However, the impact of a telephone call from a specialist in Clinical Microbiology upon blood cultures request has not been assessed to the best of our knowledge. We performed telephone calls followed by an interview with physicians and nurses in charge of adult patients (> 18 years old) whose blood cultures had just been received in the Microbiology Laboratory in a tertiary hospital. Patients were randomly classified in 2 different groups: group A (telephone call performed) and group B (no telephone call). At the end of the telephonic intervention, recommendations on the use of microbiology and biochemical tests as well as on the management and antibiotic therapy of sepsis were made if required. We included 300 patients. Of those fulfilling standard criteria of sepsis, 30.3% of the nurses and 50% of the physicians immediately recognized it. Advice to optimize the use of biochemical and microbiological tests was provided in 36% of the cases and to improve antimicrobial therapy in 57.6%. The median number of days of antibiotic use in groups A and B were, respectively, 6 days (IQR: 2-12) vs 9 days (IQR: 4-16) P = 0.008 and the median number of prescribed daily doses of antimicrobials (6 [IQR: 3-17] vs 10 [IQR: 5-22] P = 0.016) were lower in group A. We estimate a reduction, only in the use of antibiotic, of 1.8 million Euros per year. A telephone call with management advice, immediately after the arrival of blood cultures in the Microbiology Laboratory improves the recognition of sepsis and the use of diagnostic resources and reduces antimicrobial consumption and expenses. PMID- 26426610 TI - Omission of Chemotherapy in Early Stage Nasopharyngeal Carcinoma Treated with IMRT: A Paired Cohort Study. AB - The objective of this study was to evaluate the necessity of concurrent chemotherapy in T1-2N1 nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiation therapy (IMRT). The retrospective analysis was conducted using the paired comparison method. We matched cases to controls using the greedy matching algorithm with 1:1 control to case ratio. Controls were matched to cases by factors including age, gender, T stage, and duration of RT. The control group included patients received IMRT alone. In another group, concurrent chemotherapy (DDP 40 mg2/m/w) was administrated to each paired patient. From Jan 2009 to Dec 2011, a total of 86 well-balanced T1-2N1 (2002 UICC staging system) NPC patients were retrospectively analyzed. Half of them (43 patients) received radical IMRT alone and another 43 received concurrent chemotherapy with IMRT (CCRT). Median follow-up is 37.4 months (4.8-66.2 months). All patients received a radiation dose of 66 Gy/30Fx. In the CCRT group, all patients received a cumulative dose of >= 200 mg/m2. The differences of 3-year overall survival (OS), 3-year progression-free survival (PFS), 3-year relapse free survival (RFS), and 3-year metastasis-free survival (MFS) between 2 groups were not significant (P > 0.05). The most frequently increased toxicities related to chemotherapy were mild to moderate leukopenia (P = 0.003) and mild anemia (P = 0.008).Omission of weekly cisplatin chemotherapy resulted in comparable survival outcomes to CCRT in IMRT populations. More data from future randomized trials are warranted to further confirm it. PMID- 26426611 TI - Strong Neck Accumulation of 131I Is a Predictor of Incomplete Low-Dose Radioiodine Remnant Ablation Using Recombinant Human Thyroid-Stimulating Hormone. AB - The purpose of this study was to identify the factors that predict incomplete low dose radioiodine remnant ablation (RRA) with recombinant human thyroid stimulating hormone (rhTSH) and to report the adverse events associated with this treatment. Between 2012 and 2014, 43 consecutive patients with thyroid cancer received low-dose RRA with rhTSH after total thyroidectomy. We retrospectively investigated the adverse events during low-dose RRA and during diagnostic whole body scan (DxWBS) using rhTSH, and analyzed the rate of RRA completion and the associations between RRA completion and various clinical/pathological factors. Complete RRA was seen in 33 (76.7%) patients, and incomplete RRA was observed in 10 (23.3%). Patients with incomplete RRA had stronger neck accumulation of 131I than those with complete RRA (P < 0.001). Adverse events at RRA and DxWBS were seen in 12 and 9 patients, respectively. All events at RRA were grade 1, with one exception (grade 2 vertigo after rhTSH administration). The rate of adverse events at DxWBS was significantly higher in patients with adverse events seen at RRA (risk ratio, 3.778, P = 0.008). Strong neck accumulation of 131I is significant independent predictor of incomplete low-dose RRA. The risk of adverse events at DxWBS was higher in patients who experienced adverse events at RRA than in those who did not. PMID- 26426612 TI - Upregulated Expression of A20 on Monocytes is Associated With Increased Severity of Acute-on-Chronic Hepatitis B Liver Failure: A Case-Control Study. AB - A20 expression is increased in various inflammatory diseases. However, the role of A20 in acute-on-chronic liver failure is unknown. This study was to evaluate A20 expression on monocytes and its associations with the severity of acute-on chronic hepatitis B liver failure (ACHBLF). Thirty-seven patients with ACHBLF, 20 patients with chronic hepatitis B (CHB), and 15 healthy controls (HC) were enrolled in this case-control study. A20-positive monocytes were identified using flow cytometry. Serum levels of interleukin (IL)-10, IL-12p70, and TNF-alpha were determined using bead cytometry. A20 and IL-10 expressions were examined in THP-1 cells stimulated by lipopolysaccharide (LPS). The frequency of A20+ monocytes was significantly increased in patients with ACHBLF compared with HC (median [interquartile range, IQR]: 15.7 [22.8]% vs 2.5 [4.7]%, P < 0.001). Increased monocyte A20 expression was detected during the progression phase (including the mild/moderate and severe grades of ACHBLF) compared with patients in the recovery phase (both P < 0.05), and in the ACHBLF worsening group compared with patients in the improvement group (P < 0.001). LPS treatment upregulated A20 and IL-10 expressions in THP-1 cells. A20 expression on monocytes from patients with ACHBLF was positively correlated with total bilirubin (r = 0.60, P = 0.0001), direct bilirubin (r = 0.63, P < 0.0001), and MELD score (r = 0.43, P = 0.008), and inversely with prothrombin activity (r = -0.33, P = 0.046). IL-10 and TLR4 expression levels in monocytes, and serum levels of IL-10, IL-12p70, and TNF alpha were increased in patients with ACHBLF compared with patients with CHB and HC. Increased A20 expression on monocytes was associated with the severity of ACHBLF. PMID- 26426613 TI - Pro-Inflammatory Cytokines in Nasopharyngeal Aspirate From Hospitalized Children With Respiratory Syncytial Virus Infection With or Without Rhinovirus Bronchiolitis, and Use of the Cytokines as Predictors of Illness Severity. AB - Respiratory syncytial virus (RSV) and human rhinovirus (HRV) respiratory infection in children induce production of inflammatory interleukins (ILs) in the respiratory epithelium. As IL(s) determine the severity of illness, the purpose of this study was to identify the pro-inflammatory IL(s) that could be predictor(s) of clinical severity. One hundred and fifteen patients <2 years old with bronchiolitis due to RSV and /or HRV and 38 controls were selected from a hospital and an outpatient clinic. Clinical data of all patients were recorded. Severity was defined by the number of days with oxygen need. Nasopharyngeal aspirates (NPA) were collected to perform viral diagnosis by quantitative reverse transcription and polymerase chain reaction (qRT-PCR) and to quantify ILs: TNF alpha, IL-10, IL-6, IL-1beta, and IL-8, by flow cytometry. Simple and multiple regression and receiver operating characteristic (ROC) curves were used for statistical analysis. Of the patients selected 60 were single RSV, 28 RSV associated to HRV, and 27 single HRV. All patients (115) showed significantly higher IL levels when compared with controls. Levels of IL-6, IL-1beta, and IL-8 detected in NPA from RSV single and associated to HRV were significantly higher than HRV infected and positively associated with days requiring O2.Levels of IL 6, IL-1beta, and IL-8 detected in NPA from patients infected with RSV only or with both RSV and HRV are increased, and any of those 3 cytokines may have a predictive value for the number of days with need of supplemental oxygen. PMID- 26426614 TI - Serum Fetuin-A Associated With Fatty Liver Index, Early Indicator of Nonalcoholic Fatty Liver Disease: A Strobe-Compliant Article. AB - Increased fetuin-A has been reported in association with type 2 diabetes and other metabolic diseases. However, the large population data concerning fetuin-A and nonalcoholic fatty liver disease (NAFLD) were limited. In this study, we aimed to investigate the association of serum fetuin-A with fatty liver index (FLI), the indicator of NAFLD. A population-based cross-sectional analysis was performed in 5219 middle-aged and elderly participants who were recruited from 2 nearby urban communities in Shanghai, China. Serum fetuin-A concentrations were measured by enzyme-linked immunosorbent assay (ELISA). The fourth quartiles of FLI, alanine aminotransferance (ALT), aspartate aminotransferance (AST), and gamma-glutamyl transpeptadase (GGT) were defined as elevated FLI, ALT, AST, and GGT, respectively. Fetuin-A was positively associated with log-transformed-FLI, ALT, -AST, and -GGT after adjustment for the confounding factors (all P < 0.05). Multivariate logistic regression analysis showed that each one-standard deviation increase in serum fetuin-A (120.1 mg/L) was associated with 12% (95% confidence interval [CI] 1.01-1.25, P = 0.04), 13% (95% CI 1.06-1.21, P < 0.001), and 10% (95% CI 1.03-1.17, P = 0.005) increased risk of elevated FLI, ALT, and AST, respectively. Categorical analysis showed that as compared to the lowest quartile, the highest quartile of serum fetuin-A associated with a 35% (95% CI 0.98-1.86), 50% (95% CI 1.24-1.83), and 33% (95% CI 1.10-1.60) increased risk of elevated FLI, ALT, and AST, respectively. No significant association was found with GGT. In Chinese adults, serum fetuin-A concentrations were significantly associated with elevated FLI, ALT, and AST, the early indicators of NAFLD. PMID- 26426615 TI - Serum Bone Morphogenic Protein-4 Contributes to Discriminating Coronary Artery Disease Severity. AB - Bone morphogenic protein 4 (BMP-4) is a known pro-inflammatory and pro atherogenic cytokine. Here, we investigated whether the serum BMP-4 level predicts coronary artery disease (CAD) severity in humans. We measured serum BMP 4 concentrations in 1044 consecutive patients who underwent elective coronary angiography and percutaneous coronary intervention. CAD severity was estimated by the number of diseased vessels showing >= 50% diameter stenosis. Among males, the serum BMP-4 level was significantly lower in patients with multivessel disease (MVD) compared with those with single-vessel disease (SVD) (16.3 +/- 22.6 vs. 22.0 +/- 28.4 pg/mL, P < 0.01). After adjustment for other cardiovascular risk factors, a high serum BMP-4 level was an independent predictor for a decreased risk of MVD (odds ratio, 0.992; 95% confidence interval [CI], 0.985-0.998; P = .01) and patients in the lower tertile were 1.55-fold more likely to have MVD compared with upper tertile patients. Receiver-operating characteristic curve analysis demonstrated that the serum BMP-4 level had a 54% sensitivity and 54% specificity for predicting MVD (area under the curve [AUC], 56.5%; 95% CI, 51.9 61.0%; P < 0.01). Serum BMP-4 improved the predictive capability of risk factors for MVD (AUC with and without BMP-4: 64.9 and 63.6%, respectively). Considering the likelihood ratio and number of parameters, adding the serum BMP-4 level provided a better-fit model for predicting MVD compared with the model consisting of conventional risk factors (likelihood ratio chi2 = 6.20, P = .01). However, an association between serum BMP-4 and CAD was not observed in females.Serum BMP 4 levels are independently associated with CAD severity and contribute to discriminating CAD severity in males. PMID- 26426616 TI - Ocular Trauma Score in Siderosis Bulbi With Retained Intraocular Foreign Body. AB - The purpose of this study was to investigate the clinical characteristic and visual outcome of siderosis bulbi with retained intraocular foreign body (IOFB) and to validate the predictive value of the Ocular Trauma Score (OTS) in siderosis bulbi. Certain numerical values rendered to the OTS variables at present were summated (Table 1) and converted into 5 OTS categories as performed in the OTS study. The prognostic value of OTS was first assessed in cases of siderosis bulbi resulting from a chemical reaction of retained IOFBs. Twenty-four eyes of 24 patients diagnosed with siderosis bulbi who underwent surgery between 2007 and 2013 at our medical centre were reviewed. Due to patients' ignorance in ocular injuries, delayed presentation by the patient (54.17%) and no history of trauma (16.67%) were the most common cause of siderosis bulbi with IOFB retention. The main symptom of all these patients was impaired vision. The most common complications were cataract (23/24, 95.83%), followed by retinal pigmentary degeneration (15/22, 68.18%), iris heterochromia (14/24, 58.33%), pupillary mydriasis (10/21, 47.62%), secondary glaucoma (6/24, 25.00%), relative afferent pupillary defect (6/24, 25.00%), and retinal detachment (3/24, 12.50%). IOFBs were removed in 22 eyes (91.67%), except 2 enucleated eyes with absolute glaucoma (8.33%). Among all the patients (24 eyes), the best-corrected visual acuity improved in 63.64%, unchanged in 18.18% and deteriorated in 18.18% after surgical intervention. No statistically significant difference was found between the categorical distributions of our patients and those in the OTS study group. Further promotion and education on eye protection are needed to minimize visual loss from siderosis bulbi. The OTS, which was designed to predict visual outcomes of general ocular trauma, may also provide reliable information about the prognosis of siderosis bulbi resulting from a chemical reaction of retained IOFBs. PMID- 26426617 TI - Value of Chromosome 9p21 Polymorphism for Prediction of Cardiovascular Mortality in Han Chinese Without Coronary Lesions: An Observational Study. AB - Variants at chromosome 9p21 are associated with coronary artery disease (CAD). However, the longitudinal effects of 9p21 variants on cardiovascular mortality remain controversial and may depend on whether the patient has CAD. We tested the hypothesis that the single-nucleotide polymorphism (SNP) rs4977574 is associated longitudinally with cardiovascular death in patients without detectable coronary lesions. We enrolled patients who underwent coronary angiography for angina pectoris but had normal angiographic findings. Laboratory analyses and rs4977574 TaqMan genotyping were performed using fasting blood samples collected during hospitalization. Cardiovascular and all-cause mortality rates were acquired from a national database. Among the 679 enrolled subjects with neither myocardial infarction nor an angiographic coronary lesion, 28 (19.0%) of the 147 homozygous GG carriers suffered a cardiovascular death, compared with 63 (11.8%) of the 532 subjects with the AG or AA genotype during the median 12.3 years (interquartile range 8.6-12.7 years) of follow-up. In a recessive model, cardiovascular mortality was significantly higher in subjects with the GG genotype than in those with the other genotypes (hazard ratio, 1.69, 95% confidence interval 1.08 to 2.64; P = 0.021). In this follow-up study, rs4977574, a tag SNP at chromosome 9p21, was shown to be associated with cardiovascular mortality in Taiwanese patients with angina pectoris but no coronary lesions. PMID- 26426618 TI - Association Between Tooth Loss, Body Mass Index, and All-Cause Mortality Among Elderly Patients in Taiwan. AB - To date, the effect of tooth loss on all-cause mortality among elderly patients with a different weight group has not been assessed. This retrospective cohort study evaluated the data obtained from a government-sponsored, annual physical examination program for elderly citizens residing in Taipei City during 2005 to 2007, and follow-up to December 31, 2010. We recruited 55,651 eligible citizens of Taipei City aged >= 65 years, including 29,572 men and 26,079 women, in our study. Their mortality data were ascertained based on the national death files. The number of missing teeth was used as a representative of oral health status. We used multivariate Cox proportional hazards regression analysis to determine the association between tooth loss and all-cause mortality. After adjustment for all confounders, the hazard ratios (HRs) of all-cause mortality in participants with no teeth, 1 to 9 teeth, and 10 to 19 teeth were 1.36 [95% confidence interval (CI): 1.15-1.61], 1.24 (95% CI: 1.08-1.42), and 1.19 (95% CI: 1.09 1.31), respectively, compared with participants with 20 or more teeth. A significant positive correlation of body mass index (BMI) with all-cause mortality was found in underweight and overweight elderly patients and was represented as a U-shaped curve. Subgroup analysis revealed a significant positive correlation in underweight (no teeth: HR = 1.49, 95% CI: 1.21-1.83; 1-9 teeth: HR = 1.23, 95% CI: 1.03-1.47; 10-19 teeth: HR = 1.20, 95% CI: 1.06-1.36) and overweight participants (no teeth: HR = 1.37, 95% CI: 1.05-1.79; 1-9 teeth: HR = 1.27, 95% CI: 1.07-1.52). The number of teeth lost is associated with an increased risk of all-cause mortality, particularly for participants with underweight and overweight. PMID- 26426619 TI - Early Immunoglobulin Therapy and Outcomes in Kawasaki Disease: A Nationwide Cohort Study. AB - Kawasaki disease is the leading cause of acquired heart disease among children in most industrialized countries; however, only few descriptive studies have discussed the pros and cons of early immunoglobulin therapy. This study aimed to see the effect of early immunoglobulin therapy on Kawasaki disease outcomes. Patients who received immunoglobulin therapy for the first time were enrolled. Basic data were analyzed for descriptive epidemiology. If there was no prescription of antipyretics 4 to 12 days before admission, those patients were regarded as early immunoglobulin therapy group. The risk for acute aneurysm, requiring long-term anticoagulant therapy and recurrence rate were compared. Of 5235 patients with first attack of Kawasaki disease, 1156 received early immunoglobulin therapy. The odds ratios for acute aneurysm and needing long-term anticoagulant therapy were 0.99 (95% confidence interval [CI], 0.75-1.29) and 1.06 (95% CI, 0.86-1.31), respectively. The recurrence rate was higher for the early immunoglobulin therapy group, with an adjusted hazard ratio of 1.38 (95% CI, 1.29-1.47). Early immunoglobulin therapy might not be beneficial for the coronary outcomes of children with Kawasaki disease in this observational study. On the contrary, it might be associated with higher recurrence rate. A randomized controlled study comparing early and late intravenous immunoglobulin therapy would have probably brought relevant results. PMID- 26426620 TI - High Agatston Calcium Score of Intracranial Carotid Artery: A Significant Risk Factor for Cognitive Impairment. AB - The effect of intracranial internal carotid artery (ICA) calcification on cognitive impairment is uncertain. Our objective was to investigate whether intracranial ICA calcification is a significant cognitive predictor for cognitive impairment. Global cognition and degrees of intracranial ICA calcification of 579 subjects were assessed with Mini-Mental State Examination (MMSE) and Agatston calcium scoring method, respectively. Other risk factors for cognitive impairment, including age, education level, hypertension, diabetes mellitus, smoking, hyperlipidemia, and body mass index, were documented and analyzed for their associations with cognitive function. In univariate analyses, older age, lower education level, hypertension, diabetes mellitus, and higher intracranial ICA Agatston scores were significantly associated with cognitive impairment. In ordinal logistic regression, only age and total intracranial ICA Agatston score were significant risk factors for cognitive impairment. After adjustment for the other documented risk factors, subjects were 7% (95% CI: 5-10; P < 0.001) and 6% (95% CI: 0-13; P = 0.04) more likely to have lower cognitive category with every year increment of age and every 100-point increment of the total intracranial ICA Agatston score respectively. These results suggest an important role of the intracranial ICA calcification on cognitive impairment. PMID- 26426621 TI - Relationship of Blood Pressure With Mortality and Cardiovascular Events Among Hypertensive Patients aged >= 60 years in Rural Areas of China: A Strobe Compliant Study. AB - The Eighth Joint National Committee (JNC-8) panel recently recommended a systolic blood pressure (BP) threshold of >= 150 mmHg for the initiation of drug therapy and a therapeutic target of <150/90 mmHg in patients >= 60 years of age. However, results from some post-hoc analysis of randomized controlled trials and observational studies did not support these recommendations. In the prospective cohort study, 5006 eligible hypertensive patients aged >= 60 years from rural areas of China were enrolled for the present analysis. The association between the average follow-up BP and outcomes (all-cause and cardiovascular death, incident coronary heart disease [CHD], and stroke), followed by a median of 4.8 years, were evaluated using Cox proportional hazards models adjusting for other potential confounders. The relationship between BP (systolic or diastolic) showed an increased or J-shaped curve association with adverse outcomes. Compared with the reference group of BP <140/90 mmHg, the risk of all-cause death (hazard ratio [HR]: 2.698; 95% confidence interval [CI]: 1.989-3.659), cardiovascular death (HR: 2.702; 95% CI: 1.855-3.935), incident CHD (HR: 3.263; 95% CI: 2.063-5.161), and stroke (HR: 2.334; 95% CI: 1.559-3.945) was still significantly increased in the group with BP of 140-149/<90 mmHg. Older hypertensive patients with BP of 140 149/<90 mmHg were at higher risk of developing adverse outcomes, implying that lenient BP control of 140-149/<90 mmHg, based on the JNC-8 guidelines, may not be appropriate for hypertensive patients aged >= 60 years in rural areas of China. PMID- 26426622 TI - Prevalence and Predictors of Quality of Recovery at Home After Day Surgery. AB - Traditionally, major complications and unanticipated admission/readmission rates were used to assess outcome after day surgery. However, in view of the relative absence of major complications the quality of recovery (QOR) should be considered one of the principal endpoints after day surgery. In our study, the level of QOR is defined by a combination of the Global Surgical Recovery (GSR) Index and the Quality of Life (QOL). The aim of this study was to analyze prevalence and predictors of QOR after day surgery on the fourth postoperative day. Elective patients scheduled for day surgery from November 2008 to April 2010 were enrolled in a prospective cohort study. Outcome parameters were measured by using questionnaire packages at 2 time points: 1 week preoperatively and 4 days postoperatively. Primary outcome parameter is the QOR and is defined as good if the GSR index >80% as well as the postoperative QOL is unchanged or improved as compared with baseline. QOR is defined as poor if both the GSR index <= 80% and if the postoperative QOL is decreased as compared with baseline. QOR is defined as intermediate in all other cases. Three logistic regression analyses were performed to determine predictors for poor QOR after day surgery. A total of 1118 patients were included. A good QOR was noted in 17.3% of patients, an intermediate QOR in 34.8%, and a poor QOR in 47.8% 4 days after day surgery. The best predictor for poor QOR after day surgery was type of surgery. Other predictors were younger age, work status, and longer duration of surgery. A history of previous surgery, expected pain (by the patient) and high long-term surgical fear were significant predictors of poor QOR in only 1 of 3 prediction models. The QOR at home 4 days after day surgery was poor in the majority of patients and showed a significant procedure-specific variation. Patients at risk for poor QOR can be identified during the preoperative period based on type of surgery, age, work status, and the duration of the surgery. PMID- 26426623 TI - Efficacy of Anakinra in Refractory Adult-Onset Still's Disease: Multicenter Study of 41 Patients and Literature Review. AB - Adult-onset Still's disease (AOSD) is often refractory to standard therapy. Anakinra (ANK), an interleukin-1 receptor antagonist, has demonstrated efficacy in single cases and small series of AOSD. We assessed the efficacy of ANK in a series of AOSD patients. Multicenter retrospective open-label study. ANK was used due to lack of efficacy to standard synthetic immunosuppressive drugs and in some cases also to at least 1 biologic agent. Forty-one patients (26 women/15 men) were recruited. They had a mean age of 34.4 +/- 14 years and a median [interquartile range (IQR)] AOSD duration of 3.5 [2-6] years before ANK onset. At that time the most common clinical features were joint manifestations 87.8%, fever 78%, and cutaneous rash 58.5%. ANK yielded rapid and maintained clinical and laboratory improvement. After 1 year of therapy, the frequency of joint and cutaneous manifestations had decreased to 41.5% and to 7.3% respectively, fever from 78% to 14.6%, anemia from 56.1% to 9.8%, and lymphadenopathy from 26.8% to 4.9%. A dramatic improvement of laboratory parameters was also achieved. The median [IQR] prednisone dose was also reduced from 20 [11.3-47.5] mg/day at ANK onset to 5 [0-10] at 12 months. After a median [IQR] follow-up of 16 [5-50] months, the most important side effects were cutaneous manifestations (n = 8), mild leukopenia (n = 3), myopathy (n = 1), and infections (n = 5). ANK is associated with rapid and maintained clinical and laboratory improvement, even in nonresponders to other biologic agents. However, joint manifestations are more refractory than the systemic manifestations. PMID- 26426624 TI - Hyperhomocysteinemia as an Early Predictor of Erectile Dysfunction: International Index of Erectile Function (IIEF) and Penile Doppler Ultrasound Correlation With Plasma Levels of Homocysteine. AB - Erectile dysfunction (ED) is inability to achieve and maintain an erection to permit satisfactory sexual activity. Homocysteine (Hcys) is a sulfur-containing amino acid synthesized from the essential amino acid methionine. Experimental models have elucidated the role of hyperhomocysteinemia (HHcys) as a strong and independent predictor for atherosclerosis progression and impaired cavernosal perfusion. The aim of this study is to investigate the serum levels of Hcys in our cohort of patients with ED, to compare these values with these of control population and to examine Hcys as a predictive marker for those patients who are beginning to complain mild-moderate ED. A total of 431 patients were enrolled in the study. The whole cohort was asked to complete the International Index of Erectile Function (IIEF) questionnaire. The study population was divided in 3 main groups: Group A: 145 patients with no ED serving as a control group; Group B: 145 patients with mild or mild-moderate ED; Group C: 141 patients with moderate or severe ED. Each participant underwent blood analysis. All patients underwent baseline and dynamic penile Doppler ultrasonography. We found in our cohort mean Hcys plasma concentrations significantly higher than the cut-off point in both groups B and C (18.6 +/- 4.7 and 28.38 +/- 7.8, respectively). Mean IIEF score was 27.9 +/- 1.39, 19.5 +/- 2.6, and 11.1 +/- 2.5 for groups A, B, and C, respectively (P < 0.0001). In the penile Doppler ultrasonography studies, a high significant inverse correlation was detected between the mean values of the 10th minute's peak-systolic velocity (PSV) and Hcys levels for the groups B and C. This establishes a dose-dependent association between Hcys and ED. Furthermore, we showed that Hcys was an earlier predictor of ED than Doppler studies, as the Hcys increase was present in patients with mild ED even before abnormal Doppler values. PMID- 26426625 TI - Modalities of Invasive Arterial Pressure Monitoring in Critically Ill Patients: A Prospective Observational Study. AB - Few studies assessed modalities of invasive arterial pressure monitoring (IAPM). We evaluated effects on measured values of various combinations of transducer level, catheter access site, and patient position. Prospective observational study in consecutive adults admitted to a French intensive care unit in 2009 to 2011 and fulfilling our inclusion criteria. Four combinations (B-E) of transducer level, catheter access site, and patient position were compared with a reference combination (A) (A: patient supine with all catheters in the same plane and a single transducer level (M) for zero point reference (Z) aligned on the phlebostatic axis; B: 45 degrees head-of-bed elevation with M and Z aligned on the phlebostatic axis; C: 45 degrees head-of-bed elevation with M aligned on the catheter access site and Z on the phlebostatic axis; D: 45 degrees head-of-bed elevation with M and Z aligned on the catheter access site; and E: 45 degrees head-of-bed elevation with M aligned on the phlebostatic axis and Z on the catheter access site). We included 103 patients, 68 men and 35 women, with a median age of 69 years (interquartile range [IQR], 56-78); at inclusion, 91 (88.3%) received mechanical ventilation, 45 (43.7%) catecholamines, and 66 (64.1%) sedation. The IAPM access site was femoral in 49 (47.6%) and radial in 54 (52.4%) patients, with 62 of 103 (60.2%) catheters on the right side. Measured absolute mean arterial pressure values were significantly higher with 3 study combinations (C-E) than with the reference combination (A). After adjustment, the differences versus A (median, 83 [IQR, 74-92] mm Hg) remained significant for D (median, 91 [IQR, 85-100] mm Hg, P < 0.001) and E (median, 88 [IQR, 77-99] mm Hg, P < 0.001). The difference versus A was not significant for B (median, 85 [IQR, 76-94] mm Hg, P = 0.21) or C (median, 90 [IQR, 84-100] mm Hg, P = 0.006). Several modalities used for zeroing and/or transducer leveling during IAPM may result in statistically and clinically significant overestimation of measured mean arterial pressure values. For patients in the 45 degrees head-of-bed elevation position, aligning the Z on the phlebostatic axis provides values that are not significantly different from those obtained using the reference supine modality. PMID- 26426626 TI - Very Early Lactate Threshold in Healthy Young Men as Related to Oxygen Uptake Kinetics. AB - We assessed the correspondence between the V-slope ventilatory threshold (VT) and the lactate threshold (LT) by using a distinctive slow submaximal ramp protocol to ensure that sufficient data points exist around the threshold. Twenty healthy young men participated. A submaximal test based on a prior maximal test (25 watt/min, medium ramp) was performed with an individual slow-ramp protocol (6-17 watt/min, slow ramp), in which the time to reach the VT workload was estimated to be 10 minutes. The LT was determined visually by detecting a rise above the resting value, without or with log-log transformation (LT1, LT2). The point at which the blood lactate exceeded the minimal difference (LMD) of 2 resting values was also calculated. The VT appeared significantly earlier under the slow-ramp protocol compared to the medium-ramp protocol (from 19.3 +/- 3.9 to 15.0 +/- 4.0 mL/kg/min VO2, P < 0.001). The mean LT1 and LT2 values appeared even earlier than the VT (LT1, P = 0.004; LT2, P = 0.002) (LT1, 11.9; LT2, 13.4; LMD, 17.0; VT, 15.0 mL/kg/min VO2). As the mean % of peak VO2, each occurred at 29.9%, 33.7%, 42.5%, and 37.8%. The VT correlated significantly with LT1, LT2, and LMD (r = 0.61, 0.64, 0.80; P = 0.004, 0.002, <0.001). Mean blood lactate showed a similar trend (1.30, 1.43, 1.81, 1.68 mmol/L, respectively). Furthermore, the DeltaVO2/Delta work rate slope increased (from 10.8 +/- 0.9 to 11.5 +/- 0.9; P = 0.01) with the slow ramp, and the lower LT was associated with the greater increase in slope (LT1, r = -0.47, P = 0.03; LT2, r = -0.59, P = .005), that is, the lower LT was an indication that on the faster medium ramp the slope would decrease. The LMD and VT did not show this relation. Under slow-ramp exercise testing in healthy young men, the VT appeared earlier than under medium-ramp exercise testing. In addition, the LT appeared even earlier (at approximately 30% of peak VO2) than the VT, although they correlated. This very early onset of LT was, however, associated with evidence of reduced oxygen uptake kinetics. PMID- 26426627 TI - Effects of ACEIs Versus ARBs on Proteinuria or Albuminuria in Primary Hypertension: A Meta-Analysis of Randomized Trials. AB - Although angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) belong to a family of therapies that block the renin angiotensin system and are suggested to improve proteinuria/albuminuria, it is unclear which is more effective. To compare the effects of ACEIs and ARBs on proteinuria in primary hypertension by performing a meta-analysis covering randomized controlled trials (RCTs). We systematically searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from January 1990 to November 2014. Eligible studies were RCTs of ACEI therapy versus ARB therapy that reported the albumin excretion rate (AER), albumin (Alb), and urinary albumin excretion (UAE) as outcomes. Seventeen RCTs, including 17,951 patients (without limit of race, age, or sex) with a mean duration of 62.6 weeks, were included. Pooled analysis suggested that ACEIs and ARBs showed no significant differences in AER/Alb/UAE/24-h urine protein/24-h urine total protein in a comparison of 10 trials (SMD 0.09; 95% CI -0.18-0.36; P = 0.52). No significant differences were observed in urinary protein/creatinine ratio (UPCR)/urinary albumin/creatinine ratio (UACR), or albumin/creatinine ratio (ACR) in 7 trials (SMD 0.15; 95% CI 1.88-2.19; P = 0.88). The total outcome of ACEIs and ARBs also showed no significant difference (SMD 0.13; 95% CI -1.03-1.29; P = 0.83). The efficacies of ACEIs and ARBs in controlling blood pressure as a secondary indicator were also similar (SMD -0.50; 95% CI -1.58-0.58; P = 0.37). Based on a meta-analysis of 17 randomized controlled trials including 17,951 patients, we found that ACEIs and ARBs can reduce urine protein levels, improve blood pressure, and were similarly effective in terms of reducing urinary protein excretion. PMID- 26426628 TI - Clinical Analysis of Pulmonary Nocardiosis in Patients With Autoimmune Disease. AB - Nocardiosis is an opportunistic infection that most commonly involves the lung; however, only a few case reports of autoimmune disease complicated by pulmonary nocardiosis exist in the literature. We conducted a retrospective analysis of 24 cases of both autoimmune disease and pulmonary nocardiosis at the Peking Union Medical College Hospital between 1990 and 2012. Fifty-two cases were hospitalized with nocardiosis, 24 of whom had at least 1 autoimmune disease before the diagnosis of pulmonary nocardiosis. The cohort patients consisted of 5 men and 19 women, with a mean age of 44.2 years. All were negative for human immunodeficiency virus. All but 1 patient had received immunosuppressants, including corticosteroids, cyclophosphamide, azathioprine, methotrexate, or hydroxychloroquine. Fever (87.5%), cough (83.3%), and sputum (79.2%) were the most common clinical manifestations. Ten cases were accompanied by subcutaneous nodules and/or cutaneous abscesses, and 4 had brain abscess. Half of them were lymphocytopenic. Thirteen of the 16 cases who underwent lymphocyte subtype analysis had decreased CD4+ T-cell counts. Nineteen cases had decreased serum albumin levels. Nocardia was isolated from sputum (13/24), bronchoalveolar lavage fluid (4/6), lung tissue (5/6), pleural effusions (3/5), skin or cutaneous pus (7/10), and brain tissue (1/1). The most common imaging findings were air-space opacities (83.3%), followed by nodules (62.5%), cavitations (45.8%), and masses (37.5%). Five were administered co-trimoxazole only, and the others were treated with 2 or more antibiotics. All 5 cases with skin abscesses and 2 of the 4 cases with brain abscesses were treated by surgical incision and drainage. None underwent thoracic surgery. Corticosteroid dosages were decreased in all cases, and cytotoxic agents were discontinued in some cases. Twenty-two cases recovered, and 2 died. Pulmonary nocardiosis associated with an underlying autoimmune disease showed a female predominance and presentation at younger age. Immunosuppressant therapy, lymphocytopenia, particularly low CD4+ T-lymphocyte counts, and low serum albumin levels may be disease susceptibility factors. Air space opacities and nodules were the most common chest imaging features, and disseminated nocardiosis with lung and skin involvement was more common among them. Early diagnosis and anti-nocardial antibiotics with modulation of the basic immunosuppressive therapy were important for them. PMID- 26426630 TI - A Retrospective Cohort Study Comparing Stroke Recurrence Rate in Ischemic Stroke Patients With and Without Acupuncture Treatment. AB - Little was known about the effects of acupuncture on stroke recurrence. The aim of this study is to investigate whether ischemic stroke patients receiving acupuncture treatment have a decreased risk of stroke recurrence. A retrospective cohort study of 30,058 newly diagnosed cases of ischemic stroke in 2000 to 2004 was conducted based on the claims of Taiwan National Health Insurance Research Database. The use of acupuncture treatment and stroke recurrence were identified during the follow-up period from 2000 to 2009. This study compared the risk of stroke recurrence between ischemic stroke cohorts with and without acupuncture treatment by calculating adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of acupuncture associated with stroke recurrence in the Cox proportional hazard model. The stroke recurrence rate per 1000 person-years decreased from 71.4 without to 69.9 with acupuncture treatment (P < 0.001). Acupuncture treatment was associated with reduced risk of stroke recurrence (HR 0.88; 95% CI 0.84-0.91). The acupuncture effect was noted in patients with or without medical treatment for stroke prevention but its impact decreased with aging of stroke patients. Compared with stroke patients without acupuncture treatment and medication therapy, the hazard ratios of stroke recurrence for those had medication therapy only, acupuncture only, and both were 0.42 (95% CI 0.38-0.46), 0.50 (95% CI 0.43-0.57), and 0.39 (95% CI 0.35-0.43), respectively. This study raises the possibility that acupuncture might be effective in lowering stroke recurrence rate even in those on medications for stroke prevention. Results suggest the need of prospective sham-controlled and randomized trials to establish the efficacy of acupuncture in preventing stroke. PMID- 26426631 TI - A Cross-Cultural Study on Behaviors When Death Is Approaching in East Asian Countries: What Are the Physician-Perceived Common Beliefs and Practices? AB - The primary aim of this study was to explore common beliefs and practices when death is approaching in East-Asian countries. A cross-sectional survey was performed involving palliative care physicians in Japan, Korea, and Taiwan. Measurement outcomes were physician-perceived frequencies of the following when patient death was approaching: (1) reluctance to take part in end-of-life discussions, (2) role of family members, (3) home death, and (4) circumstances surrounding death. A total of 505, 211, and 207 responses were obtained from Japanese, Korea, and Taiwan physicians, respectively. While 50% of the Japanese physicians reported that they often or very often experienced families as being reluctant to discuss end-of-life issues, the corresponding figures were 59% in Korea and 70% in Taiwan. Two specific reasons to avoid end-of-life discussion, "bad things happen after you say them out loud" and "a bad life is better than a good death" were significantly more frequently observed in Taiwan. Prioritizing the oldest of the family in breaking bad news and having all family members present at the time of death were significantly more frequently observed in Korea and Taiwan. Half of Taiwanese physicians reported they often or very often experienced the patients/family wanted to go back home to die because the soul would not be able to return from the hospital. In all countries, more than 70% of the physicians reported certain family members were expected to care for the patient at home. At the time of death, while no Japanese physicians stated that they often experienced patients wanted a religious person to visit, the corresponding figure in Korean and Taiwan was about 40%. Uncovered expression of emotion was significantly frequently observed in Korean and Taiwan, and 42% of the Japanese physicians reported family members cleaned the dead body of the patient themselves. There seem to be significant intercountry differences in beliefs and practices when death is approaching in East Asian countries. Future studies on direct observations of patients and families are needed. PMID- 26426632 TI - Perioperative Allogenenic Blood Transfusion is Associated With Worse Clinical Outcome for Patients Undergoing Gastric Carcinoma Surgery: A Meta-Analysis. AB - Whether perioperative allogenic blood transfusion (ABT) has adverse effect on patients with gastric carcinoma (GC) surgery or not, that is controversial. Our study evaluated the association between ABT and some clinical outcomes of GC surgery patients. Data of relevant studies were based on PubMed, EMBASE, and the Cochrane Library search. The relative risk (RR) of 5-year survival rates, tumor recurrence, and postoperative complications were performed; subgroup analyses included district, transfusion rates, age, participants, sex, and tumor stage. The study was approved by the ethics committee of the First People's Hospital of Shunde. In total, 9189 participants from 16 studies were included in the meta analysis. The 5-year survival rate was decreased for the GC patients with ABT (RR = 0.74, 95% confidence interval [CI] = 0.69-0.79), the risk of tumor recurrence was significantly higher for ABT patients (RR = 1.82, 95% CI = 1.32-2.51), and postoperative complications increased in ABT patients (RR = 1.36, 95% CI = 1.02 1.81), respectively; in subgroup analyses, 5-year survival rates were not associated with the transfusion rates (chi2 = 0.37, P = 0.54). Transfusion for patients undergoing GC surgery, even low transfusion rates, would reduce the 5 year survival rates, and elevated the risk of tumor recurrence and postoperative complication. PMID- 26426633 TI - Does Helicobacter pylori Eradication Reduce the Risk of Open Angle Glaucoma in Patients With Peptic Ulcer Disease? AB - To investigate whether Helicobacter pylori (H pylori) eradication would influence the risk of primary open angle glaucoma (POAG) in patients with peptic ulcer disease. From the Longitudinal Health Insurance Database 2000, 6061 patients with peptic ulcer and receiving H pylori eradication therapy were recruited. The study cohort was subdivided into early (within 1 year) and late (after 1 year) eradication cohorts. The 24,244 control cohort subjects were those who without peptic ulcer and without receiving H pylori eradication therapy and were frequency-matched with the H pylori eradication cohort by age, sex, and the year of receiving H pylori eradication therapy. The higher incidence of POAG was observed in late H pylori eradication cohort and in early H pylori eradication cohort than in control cohort (1.57, 1.32, and 0.95, per 1000 person-year, respectively). However, overall risk of glaucoma was not significantly higher in the late eradication than in the early eradication (adjusted hazard ratio = 0.85, 95% confidence interval = 0.48-1.53). The POAG incidence was greater in the late H pylori eradication cohort when follow-up duration <= 5 years (1.59, per 1000 person-years). However, when follow-up duration >5 years, the incidence of POAG was greater in the early H pylori eradication cohort (1.68, per 1000 person years). These relationships were not associated with a significantly increased or decreased risk of POAG in multivariable analyses. Either early or late H pylori eradication does not significantly reduce the risk of glaucoma in patients with peptic ulcer disease compared with normal control. PMID- 26426634 TI - Low Expression of LDHB Correlates With Unfavorable Survival in Hepatocellular Carcinoma: Strobe-Compliant Article. AB - Lactate dehydrogenase B (LDHB) is widely expressed in adult somatic tissue and plays important roles in the development of human cancers. However, the association between LDHB expression and the clinicopathological characteristics of hepatocellular carcinoma (HCC) is not well understood. The study was to detect the expression of LDHB in human HCC and investigate the association between its expression and the clinicopathological characteristics of HCC. Immunohistochemistry (IHC) analysis was performed to characterize the expression of LDHB in HCC and matched noncancerous tissues. Kaplan-Meier survival and Cox regression analyses were employed to evaluate the prognosis of 75 HCC patients. The results showed that the expression of LDHB in HCC was significantly lower than that in noncancerous tissues. Moreover, the expression level of the LDHB protein in HCC was correlated with pathological grade (P = 0.037), vascular invasion (P = 0.037), lymph node metastasis (P = 0.016), and tumor-node metastasis (TNM) stage (P = 0.007). Cox regression analysis further revealed that LDHB expression is an independent prognostic factor for disease-free survival (P = 0.045) and overall survival (P = 0.019).These data are the first to indicate that LDHB expression is a valuable prognostic biomarker for HCC and that low LDHB expression suggests unfavorable survival outcomes in HCC patients. PMID- 26426635 TI - Prognostic Value of the Preoperative Neutrophil to Lymphocyte Ratio in Resectable Gastric Cancer. AB - This study aimed to investigate the prognostic value of the preoperative neutrophil to lymphocyte ratio (NLR) in resectable gastric cancer (GC). This was a retrospective review of 1030 patients with resectable GC managed between 2005 and 2011. Patients were stratified into 2 groups, those with a preoperative NLR >3.44 and those with a preoperative NLR <= 3.44. Clinicopathological data affecting patient prognosis were collected prospectively and analyzed. The high NLR (> 3.44) group had a higher proportion of a platelet to lymphocyte ratio > 132, tumor size > 4.8 cm, T4 lesions, metastatic tumors, a ratio of metastatic to examined lymph nodes >0.18, positive resection margins, and presence of vascular or lymphatic invasion than the low NLR (<= 3.44) group. Patients with a high preoperative NLR had significantly lower 3- and 5-year overall survival rates than those with a low preoperative NLR (55.1% vs 71.0% and 47.2% vs 64.1%, respectively; P < 0.001). Preoperative NLR was a prognostic factor for resectable GC in multivariate analysis. More aggressive tumor behavior was observed in patients with resectable GC with a high preoperative NLR than in those with a low preoperative NLR. High preoperative NLR was an independent unfavorable prognostic factor. Measurement of this ratio may serve as a clinically accessible and useful biomarker for patient outcomes. PMID- 26426629 TI - Characteristics and Outcome of Streptococcus pneumoniae Endocarditis in the XXI Century: A Systematic Review of 111 Cases (2000-2013). AB - Streptococcus pneumoniae is an infrequent cause of severe infectious endocarditis (IE). The aim of our study was to describe the epidemiology, clinical and microbiological characteristics, and outcome of a series of cases of S. pneumoniae IE diagnosed in Spain and in a series of cases published since 2000 in the medical literature. We prospectively collected all cases of IE diagnosed in a multicenter cohort of patients from 27 Spanish hospitals (n = 2539). We also performed a systematic review of the literature since 2000 and retrieved all cases with complete clinical data using a pre-established protocol. Predictors of mortality were identified using a logistic regression model. We collected 111 cases of pneumococcal IE: 24 patients from the Spanish cohort and 87 cases from the literature review. Median age was 51 years, and 23 patients (20.7%) were under 15 years. Men accounted for 64% of patients, and infection was community acquired in 96.4% of cases. The most important underlying conditions were liver disease (27.9%) and immunosuppression (10.8%). A predisposing heart condition was present in only 18 patients (16.2%). Pneumococcal IE affected a native valve in 93.7% of patients. Left-sided endocarditis predominated (aortic valve 53.2% and mitral valve 40.5%). The microbiological diagnosis was obtained from blood cultures in 84.7% of cases. In the Spanish cohort, nonsusceptibility to penicillin was detected in 4.2%. The most common clinical manifestations included fever (71.2%), a new heart murmur (55%), pneumonia (45.9%), meningitis (40.5%), and Austrian syndrome (26.1%). Cardiac surgery was performed in 47.7% of patients. The in-hospital mortality rate was 20.7%. The multivariate analysis revealed the independent risk factors for mortality to be meningitis (OR, 4.3; 95% CI, 1.4-12.9; P < 0.01). Valve surgery was protective (OR, 0.1; 95% CI, 0.04 0.4; P < 0.01). Streptococcus pneumoniae IE is a community-acquired disease that mainly affects native aortic valves. Half of the cases in the present study had concomitant pneumonia, and a considerable number developed meningitis. Mortality was high, mainly in patients with central nervous system (CNS) involvement. Surgery was protective. PMID- 26426636 TI - Acoustic Radiation Force Impulse Measurement in Renal Transplantation: A Prospective, Longitudinal Study With Protocol Biopsies. AB - Interstitial fibrosis and tubular atrophy (IF/TA) is a common cause of kidney allograft loss. Several noninvasive techniques developed to assess tissue fibrosis are widely used to examine the liver. However, relatively few studies have investigated the use of elastographic methods to assess transplanted kidneys. The aim of this study was to explore the clinical implications of the acoustic radiation force impulse (ARFI) technique in renal transplant patients. A total of 91 patients who underwent living donor renal transplantation between September 2010 and January 2013 were included in this prospective study. Shear wave velocity (SWV) was measured by ARFI at baseline and predetermined time points (1 week and 6 and 12 months after transplantation). Protocol biopsies were performed at 12 months. Instead of reflecting IF/TA, SWVs were found to be related to time elapsed after transplantation. Mean SWV increased continuously during the first postoperative year (P < 0.001). In addition, mixed model analysis showed no correlation existed between SWV and serum creatinine (r = 0.2426, P = 0.0771). There was also no evidence of a relationship between IF/TA and serum creatinine (odds ratio [OR] = 1.220, P = 0.7648). Furthermore, SWV temporal patterns were dependent on the kidney weight to body weight ratio (KW/BW). In patients with a KW/BW < 3.5 g/kg, mean SWV continuously increased for 12 months, whereas it decreased after 6 months in those with a KW/BW >= 3.5 g/kg.No significant correlation was observed between SWV and IF/TA or renal dysfunction. However, SWV was found to be related to the time after transplantation. Renal hemodynamics influenced by KW/BW might impact SWV values. PMID- 26426638 TI - CT-Guided Percutaneous Step-by-Step Radiofrequency Ablation for the Treatment of Carcinoma in the Caudate Lobe. AB - The location of the caudate lobe and its complex anatomy make caudate lobectomy and radiofrequency ablation (RFA) under ultrasound guidance technically challenging. The objective of the exploratory study was to introduce a novel modality of treatment of lesions in caudate lobe and discuss all details with our experiences to make this novel treatment modality repeatable and educational. The study enrolled 39 patients with liver caudate lobe tumor first diagnosed by computerized tomography (CT) or magnetic resonance imaging (MRI). After consultation of multi-disciplinary team, 7 patients with hepatic caudate lobe lesions were enrolled and accepted CT-guided percutaneous step-by-step RFA treatment. A total of 8 caudate lobe lesions of the 7 patients were treated by RFA in 6 cases and RFA combined with percutaneous ethanol injection (PEI) in 1 case. Median tumor diameter was 29 mm (range, 18-69 mm). A right approach was selected for 6 patients and a dorsal approach for 1 patient. Median operative time was 64 min (range, 59-102 min). Median blood loss was 10 mL (range, 8-16 mL) and mainly due to puncture injury. Median hospitalization time was 4 days (range, 2-5 days). All lesions were completely ablated (8/8; 100%) and no recurrence at the site of previous RFA was observed during median 8 months follow-up (range 3 11 months). No major or life-threatening complications or deaths occurred. In conclusion, percutaneous step-by-step RFA under CT guidance is a novel and effective minimally invasive therapy for hepatic caudate lobe lesions with well repeatability. PMID- 26426639 TI - Comparative Study of Modified Posterior Operation to Treat Kummell's Disease. AB - The present study aimed at examining the curative effect of modified posterior operation on treatment of Kummell's disease. About 30 patients of Kummell's disease with complete image and clinical data treated during June 2004 to July 2013 were conducted with anterior and posterior approaches, respectively. Kyphotic Cobb angle, fractured vertebra wedge angle, and the anterior and posterior heights of fractured vertebra were all measured through x-ray before and after operation, and the pain visual analog scale (VAS) was determined for evaluating the effect of operations. The injury and restoration of neurological function were assessed using Frankel classification. Patients in group A were treated with anterior operation, whereas group B was posterior operation. Postoperatively, VAS score, kyphotic Cobb angle, anterior vertebra height, and pathologic vertebra wedge angle were all significantly improved in patients with Kummell's disease receiving modified posterior operation (group B). Similar results were also observed in patients with anterior operation. The improvement of VAS and correction rate of kyphotic Cobb angle indicated equivalent effects of posterior and anterior operations. Meanwhile, alleviated neurological function damage was observed in 2 groups. Relevant factor analysis illustrated that there was no significant correlation of the severity and improvement rate of pain symptoms with age, medical history, anterior and posterior vertebra heights, kyphotic Cobb angle, and pathological vertebra wedge angle. Compared with traditional anterior approach, modified posterior operation, adopting transpedicular vertebral body grafting combined with vertebral pedicle screw fixation, could produce equivalent effects on kyphosis correction, pain relief, and improvement of neurological function in patients with Kummell's disease. PMID- 26426637 TI - Predictive Value of Ercc1 and Xpd Polymorphisms for Clinical Outcomes of Patients Receiving Neoadjuvant Therapy: A Prisma-Compliant Meta-Analysis. AB - Excision repair cross complementing 1 (ERCC1) and xeroderma pigmentosum group D (XPD) play important roles in the nucleotide excision repair (NER) pathway. The correlation between ERCC1 polymorphisms (rs11615 and rs3212986) and XPD polymorphisms (rs13181 and rs1799793) with the response rate and overall survival of cancer patients who accept neoadjuvant therapy has been extensively investigated. However, the results are inconclusive. In this study, we performed a meta-analysis to determine the strength of this correlation. A comprehensive literature search was conducted in Medline, PubMed, and Embase up to February 2015. A review of all titles and abstracts was performed by 2 of the authors to screen the articles based on the eligibility criteria. Clinical trials, observational studies, and epidemiological studies describing ERCC polymorphisms and neoadjuvant treatment were considered for review. The response rate was analyzed using pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Overall survival was assessed using the hazard ratio (HR) with corresponding 95% confidence intervals. In the present meta-analysis, we demonstrated that the ERCC1 rs3212986 polymorphism was significantly correlated with the response rate of esophageal cancer patients to neoadjuvant therapy (OR = .49, 95% CI = 0.31-0.76, heterogeneity P = 0.480). Furthermore, a considerable correlation was observed between ERCC1 rs11615 and the response rate of esophageal cancer patients to neoadjuvant therapy (OR = 0.228, 95% CI = 0.125 0.418, heterogeneity P = 0.291). No correlation was observed in the meta-analysis of overall survival. The individual studies included in our study differed in their patient selection and therapeutic protocols, which might lead to some bias in the results. These findings indicate that the ERCC1 rs11615 and ERCC1 rs312986 polymorphisms may be candidate pharmacogenomic factors capable of predicting the response rate of esophageal cancer patients who accept neoadjuvant therapy. Further studies are warranted. PMID- 26426640 TI - The Relationship Between Educational Years and Phonemic Verbal Fluency (PVF) and Semantic Verbal Fluency (SVF) Tasks in Spanish Patients Diagnosed With Schizophrenia, Bipolar Disorder, and Psychotic Bipolar Disorder. AB - Semantic and verbal fluency tasks are widely used as a measure of frontal capacities. It has been well described in literature that patients affected by schizophrenic and bipolar disorders present a worse execution in these tasks. Some authors have also noted the importance of educational years. Our objective is to analyze whether the effect of cognitive malfunction caused by apathology is superior to the expected effect of years of education in phonemic verbal fluency (PVF) and semantic verbal fluency (SVF) task execution. A total of 62 individuals took part in this study, out of which 23 were patients with schizophrenic paranoid disorder, 11 suffered from bipolar disorder with psychotic symptomatology, 13 suffered from bipolar disorder without psychotic symptomatology, and 15 participants were nonpathological individuals. All participants were evaluated with the PVF and SVF tests (animals and tools). The performance/execution results were analyzed with a mixed-model ANCOVA, with educational years as a covariable. The effect of education seems to be more determined by PVF FAS tests than by SVF. With PVF FAS tasks, the expected effect of pathology disappears when the covariable EDUCATION is introduced. With SVF tasks, the effect continues to be significant, even though the EDUACTION covariable dims such effect. These results suggest that SVF tests (animals category) are better evaluation tools as they are less dependent on the patients' education than PVF FAS tests. PMID- 26426641 TI - A Method to Prepare a Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) Graft Using Donor Corneas With Narrow Scleral Rims: A Case Report. AB - Donor corneas with narrow scleral rims are often disqualified for Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK), mainly because of fluid leak and low pressure when they are mounted onto an artificial anterior chamber (AAC). This report describes a novel method to tight-lock a donor cornea with a narrow scleral rim so that microkeratome cutting is possible, allowing a DSAEK procedure to be completed. A 50-year-old male suffering from Epstein-Barr virus (EBV) endotheliitis with resulting corneal edema in his left eye was the subject of this study. His best corrected visual acuity (BCVA) was 20/600. The patient underwent a DSAEK procedure; however, the microkeratome cutting of the donor cornea initially failed due to its narrow scleral rim, which caused the balance salt solution (BSS) to leak out of the AAC. A doughnut-shaped cushion was made from a surgical glove, which enabled a tight lock of the cornea to the AAC, enabling the chamber pressure to be raised and the microkeratome cutting to be completed. A subsequent DSAEK procedure was performed uneventfully. Postoperatively, the patient received oral valganciclovir 450 mg b.i.d. to prevent EBV recurrence. The graft remained clear at 5 months post-op, and the patient's BCVA improved to 6/7.5. His endothelial count was 1830, which was ~ 79% of the original value. Inserting a self-made cushion can enable donor corneas with narrow scleral rims to be used in DSAEK procedures and avoids unwanted switching from endothelial keratoplasty to penetrating keratoplasty (PKP). PMID- 26426642 TI - Fructose Malabsorption in Systemic Sclerosis. AB - The deleterious effect of fructose, which is increasingly incorporated in many beverages, dairy products, and processed foods, has been described; fructose malabsorption has thus been reported in up to 2.4% of healthy subjects, leading to digestive clinical symptoms (eg, pain, distension, diarrhea). Because digestive involvement is frequent in patients with systemic sclerosis (SSc), we hypothesized that fructose malabsorption could be responsible for intestinal manifestations in these patients. The aims of this prospective study were to: determine the prevalence of fructose malabsorption, in SSc; predict which SSc patients are at risk of developing fructose malabsorption; and assess the outcome of digestive symptoms in SSc patients after initiation of standardized low fructose diet. Eighty consecutive patients with SSc underwent fructose breath test. All SSc patients also completed a questionnaire on digestive symptoms, and a global symptom score (GSS) was calculated. The prevalence of fructose malabsorption was as high as 40% in SSc patients. We also observed a marked correlation between the presence of fructose malabsorption and: higher values of GSS score of digestive symptoms (P = 0.000004); and absence of delayed gastric emptying (P = 0.007). Furthermore, in SSc patients with fructose malabsorption, the median value of GSS score of digestive symptoms was lower after initiation of standardized low-fructose diet (4 before vs. 1 after; P = 0.0009). Our study underscores that fructose malabsorption often occurs in SSc patients. Our findings are thus relevant for clinical practice, highlighting that fructose breath test is a helpful, noninvasive method by: demonstrating fructose intolerance in patients with SSc; and identifying the group of SSc patients with fructose intolerance who may benefit from low-fructose diet. Interestingly, because the present series also shows that low-fructose diet resulted in a marked decrease of gastrointestinal clinical manifestations in SSc patients with fructose malabsorption, our findings underscore that fructose malabsorption may play a significant role in the onset of gastrointestinal symptoms in these patients. Finally, we suggest that fructose malabsorption may be due to reduced fructose absorption by enterocytes, impaired enteric microbiome, and decreased intestinal permeability. PMID- 26426643 TI - Etiology and Antimicrobial Susceptibility Pattern of Pathogenic Bacteria in Children Subjected to UTI: A Referral Hospital-Based Study in Northwest of Iran. AB - Urinary tract infection (UTI) is 1 of the most common bacterial diseases in children with a considerable resistance to antimicrobials. This 5 years prospective study was carried out to determine the frequency of isolation and antimicrobial resistance patterns of uropathogens among children subjected to urine culture at Tabriz Children Educational-Health Care Center, in the northwest of Iran. Organisms were isolated using standard culture techniques. Frequency of UTI among children examined by urine culture was 3.6%. The isolated bacteria were Escherichia coli (71.4%), followed by Klebsiella spp. (9.6%), Enterococcus spp. (6.4%), Pseudomonas aeruginosa (4.2%), Serratia spp. (4.2%), and Enterobacter spp. (4.2%). E coli resistance levels were 11% for nitrofurantoin, 15% for ciprofloxacin, 25% for nalidixic acid, and 30% to 75% for amikacin, gentamicin, ceftriaxone, ceftizoxime, cefotaxime, and co-trimoxazole. Among the tested antibiotics, ciprofloxacin, showed the highest activity (100%) against Klebsiella and P aeruginosa isolates followed by amikacin, nalidixic acid, and gentamicin. Overall, the highly active antibiotic against Gram-negative and Gram-positive organisms was amikacin and then ciprofloxacin. On the other hand, the empirical initial therapy with co-trimoxazole and third-generation cephalosporins would be inadequate for more cases of UTI in the study area. Moreover, susceptibility testing should be carried out on all clinical isolates, and the empirical antibiotic treatment changed accordingly. PMID- 26426644 TI - Recovery of HPA Axis Function After Successful Gonadotropin-Induced Pregnancy and Delivery in a Woman With Panhypopituitarism: Case Report and Review. AB - Hypopituitarism is defined as the partial or complete defect of anterior pituitary hormone secretion. Patients with hypopituitarism usually need life-long hormone replacement therapy. However, in this case, we report a patient with panhypopituitarism whose hypothalamus-pituitary-adrenal (HPA) axis function was completely recovered after pregnancy and delivery. In this case study, we reported the case management and conducted a review of literature to identify the possible mechanism of pituitary function recovery. The patient who suffered from secondary amenorrhea was found a nonfunctioning pituitary macroadenoma, and the hormone test showed serum cortisol, FT3, FT4, thyrotropic hormone, and prolactin were at normal range. After surgical removal of the tumor which invasion in the sellar region, the patient had panhypopituitarism confirmed by the routine hormone test. Though spontaneous pregnancy is impossible in female patients with panhypopituitarism, the patient was restored fertility by the help of artificial reproductive techniques. After the confirmation of the pregnancy, levothyroixine was increased to 75 MUg daily and readjusted to 150 MUg daily before delivery according to the monthly measurement thyroid function. Hydrocortisone 10 mg daily replaced cortisone acetate; the dose was increased according to the symptoms of morning sickness. A single stress dose of hydrocortisone (200 mg) was used before elective cesarean delivery and was tapered to the dose of 10 mg per day in 1 week. Levothyroixine was reduced to 75 MUg daily after delivery. During follow up, her hypothalamus-pituitary-adrenal (HPA) axis function was completely recovered. The peak serum cortisol level could increase to 19.08 MUg/dL by insulin-induced hypoglycemia. However, growth hormone remained unresponsive to the insulin-tolerance test, and thyroid hormone still needed exogenous supplementation. Hormone replacement therapy needed closely followed by endocrinologist and multidisciplinary cooperation during the pregnancy of patients with hypopituitarism. This case indicates that the pituitary function may partially recover after pregnancy in panhypopituitarism patients. PMID- 26426645 TI - Interface Fluid Syndrome Induced by Uncontrolled Intraocular Pressure Without Triggering Factors After LASIK in a Glaucoma Patient: A Case Report. AB - This study sought to describe a glaucoma patient with interface fluid syndrome (IFS) induced by uncontrolled intraocular pressure (IOP) without triggering factors after laser in situ keratomileusis (LASIK). Case report and review of the literature. A 23-year-old man with open-angle glaucoma underwent bilateral LASIK for myopia in 2009. Two years later, the patient reported sudden vision loss. The IOP in the right eye was not measurable using Goldmann applanation tonometry (GAT), but was determined to be 33.7 mm Hg using a noncontact tonometer. IFS was diagnosed based on the presence of space-occupying interface fluid on anterior segment optical coherence tomography images. After a trabeculectomy was performed, the IOP decreased to 10 mm Hg, and GAT measurement became possible. However, the corneal fold remained visible in the flap interface. Six months later, the IOP in the left eye increased, and a trabeculectomy was performed during the early stages of this increase in IOP. Following this procedure, the IOP decreased, and visual acuity remained stable. In glaucoma cases that involve a prior increase in IOP, IOP can continue to increase during the disease course even if temporary control of IOP has been achieved. If LASIK is performed in such cases, the treatment of glaucoma becomes insufficient because of underestimation of the typical IOP. In fact, the measurement of IOP can become difficult because of high-IOP levels. Therefore, LASIK should not be performed on patients with glaucoma who are at high risk of elevated IOP. PMID- 26426646 TI - Novel Therapy for Primary Canaliculitis: A Pilot Study of Intracanalicular Ophthalmic Corticosteroid/Antibiotic Combination Ointment Infiltration. AB - In patients with primary canaliculitis, conservative medical therapy is associated with a high recurrence rate. Surgical treatments carry a great resolution rate but sometimes can result in the lacrimal pump dysfunction and canalicular scarring. The aim of this study is to introduce a minimally invasive approach, intracanalicular ophthalmic corticosteroid/antibiotic combination ointment infiltration (IOI, intracanalicular ointment infiltration), and to report our preliminary results for treating primary canaliculitis. In this retrospective, interventional case series, 68 consecutive patients with newly developed primary canaliculitis at a major tertiary eye center between January 2012 and January 2015. Thirty-six patients received conservative medical treatment alone (group 1; 36 eyes). Twenty-two patients and 10 medically uncontrolled patients from group 1 underwent IOI therapy (group 2; 32 eyes). Ten patients and 26 recurrent patients from group 1 and group 2 underwent surgery (group 3; 36 eyes). Patients were followed-up for at least 8 weeks. Clinical characteristics and outcomes were analyzed and compared. In this study, patients' age, sex, onset location, and durations of disease among 3 groups showed no significant difference. The resolution rate in group 2 was 72.7% (16/22) for new patients and 68.8% (22/32) for gross patients, respectively, both of which are higher than that of group 1 (22.2%, 10/36) but lower than that of group 3 (100%, 36/36). Of group 3, 2 patients received 2 surgical interventions and resolved finally. Microbiological workup was available in 51 patients. The most common isolates were staphylococcus species (27.9%) and streptococcus species (20%). Canalicular laceration developed in 1 patient during the IOI procedure and 1 patient undergoing surgery. Only 2 had postoperative lacrimal pump dysfunction and 1 had canalicular scarring in group 3. The IOI may be an effective and minimally invasive technique for treating primary canaliculitis and obviate the need for further intensive surgery. PMID- 26426647 TI - The Expanding Burden of Elevated Blood Pressure in China: Evidence From Jiangxi Province, 2007-2010. AB - Elevated blood pressure (BP) as a risk factor accounts for the biggest burden of disease worldwide and in China. This study aimed to estimate attributed mortality and life expectancy (LE) to elevated BP in Jiangxi province between 2007 and 2010. BP and mortality data (2007 and 2010 inclusive) were obtained from the National Chronic Diseases and Risk Factors Surveillance Survey and Disease Surveillance Points system, respectively. Population-attributable fraction used in comparative risk assessment of the Global Burden of Disease study 2010 were followed to quantify the attributed mortality to elevated BP, subsequently life table methods were applied to estimate its effects on LE. Uncertainty analysis was conducted to get 95% uncertainty intervals (95% uncertainty interval [UI]) for each outcome. There are 35,482 (95% UI: 31,389-39,928) and 47,842 (42,323 53,837) deaths in Jiangxi province were caused by elevated BP in 2007 and 2010, respectively. 2.24 (1.87-2.65) years of LE would be gained if all the attributed deaths were eliminated in 2007, and increased to 3.04 (2.52-3.48) in 2010. If the mean value of elevated BP in 2010 was decreased by 5 and 10 mm Hg, 5324 (4710 5991) and 11,422 (10,104-12,853) deaths would be avoided, with 0.41 (0.37-0.48) and 0.85 (0.71-1.09) years of LE gained, respectively. The deaths attributable to elevated BP in Jiangxi province has increased by 35% from 2007 to 2010, with 0.8 years of LE loss, suggesting the necessity to take actions to control BP in Chinese population. PMID- 26426648 TI - Plasma Biomarkers Can Predict Treatment Response in Tuberculosis Patients: A Prospective Observational Study. AB - Despite numerous studies, there has been little progress in the use of biomarkers for predicting treatment response in patients with tuberculosis (TB). Patients with culture-confirmed pulmonary TB between 2010 and 2014 were prospectively recruited. Blood samples were taken upon diagnosis and 2 months after the start of standard anti-TB treatment. A pilot study utilizing measurement of TB-antigen stimulated cytokines was conducted to select potential biomarkers for further testing. Outcome was defined as persistent culture positivity at 2 months into treatment. Of 167 enrolled patients, 26 had persistent culture positivity. RANTES, IL-22, MMP-8, IL-18, MIG, and Granzyme A were selected as potential biomarkers. For predicting persistent culture positivity, receiver-operating characteristics (ROC) analysis showed that initial RANTES (AUC: 0.725 [0.624 0.827]) and 2-month MMP-8 (AUC: 0.632 [0.512-0.713]) had good discriminative ability. Using a logistic regression model, low initial RANTES level (< 440 pg/mL), initial smear positivity, and high 2-month MMP-8 level (> 3000 pg/mL) were associated with persistent culture positivity. Low initial RANTES level and initial smear positivity had a positive predictive value of 60% (12/20) for persistent culture positivity, compared with 4% (3/75) among patients with high RANTES level and smear negativity upon diagnosis. In the 72 patients with either low RANTES/smear negativity or high RANTES/smear positivity upon diagnosis, the 2 month MMP-8 level had a positive and negative predictive value of 24 and 94%, respectively, for 2-month culture status. Aside from an initial sputum smear status, serum RANTES level at diagnosis and MMP-8 level at 2 months of treatment may be used to stratify risk for culture persistence. PMID- 26426649 TI - Effectiveness of Prior Use of Beta-Blockers for Preventing Adverse Influences of Severe Hypoglycemia in Patients With Diabetes: An Observational Study. AB - The study aimed to identify predictors of severe acute hypertension (>= 180/110 mmHg) during severe hypoglycemia and to assess the efficacy of prior use of catecholamine-blocking agents for preventing adverse influences in diabetic patients with severe hypoglycemia. We performed a retrospective study between January 2006 and March 2012 to assess diabetic patients with severe hypoglycemia at a single center in Japan. Severe hypoglycemia was defined as the presence of any hypoglycemic symptoms that required the medical assistance of another person after visiting the emergency room by ambulance. Multivariate logistic regression analysis was performed to identify possible predictors of severe hypertension due to severe hypoglycemia and to assess whether prior use of alpha- or beta-blockers is beneficial for the prevention of severe hypertension in diabetic patients with severe hypoglycemia. Multivariate adjustments were made for age, sex, preexisting hypertension, history of ischemic heart disease, blood glucose level upon arrival, estimated GFR, and prior use of alpha- or beta-blockers. A total of 59,602 patients who visited the emergency room were screened and 352 diabetic patients with severe hypoglycemia were enrolled. Incidences of severe hypertension before and at 3 and 6 hours after the initiation of antihypoglycemic treatment were 21.3%, 6.7%, and 0% in patients with type 1 diabetes (n = 61) and 38.8%, 18.2%, and 8.2% in patients with type 2 diabetes (n = 291), respectively. Aging was positively (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.00 1.03; P = 0.02) and female sex was negatively (OR, 0.50; 95% CI, 0.29-0.86; P = 0.01) associated with occurrence of severe hypertension during severe hypoglycemia. In addition, prior use of beta-blockers was negatively associated with occurrence of severe hypertension during severe hypoglycemia using multivariate logistic regression analysis (OR, 0.31; 95% CI, 0.11-0.83; P = 0.02). None of the patients with prior use of beta-blockers had hypokalemia (<3.0 mEq/L). Prior use of beta-blockers may prevent adverse influences such as severe hypertension and hypokalemia during severe hypoglycemia in diabetic patients. PMID- 26426650 TI - Tumor-Infiltrating Immune Cells Are Associated With Prognosis of Gastric Cancer. AB - Immune cells contribute to determining the prognosis of gastric cancer. However, their exact role is less clear. We determined the prognostic significance of different immune cells in intratumoral tissue (T), stromal tissue (S), and adjacent normal tissue (N) of 166 gastric cancer cases and their interactions, including CD3+, CD4+, CD8, CD57+, CD68+, CD66b+, and Foxp3+ cells, and established an effective prognostic nomogram based on the immune reactions. We found high densities of TCD3+, TCD4+, TCD8+, SCD3+, SCD4+, SCD57+, SCD66b+, and NFoxp3+ cells, as well as high TCD8+/SCD8+ ratio, TCD68+/SCD68+ ratio, TCD3+/TFoxp3+ ratio, TCD4+/TFoxp3+ ratio, TCD8+/TFoxp3+ ratio, SCD3+/SFoxp3+ ratio, and SCD4+/SCD8+ ratio were associated with better survival, whereas high densities of TCD66b+, TFoxp3+, SFoxp3+ and NCD66b+ cells as well as high TCD57+/SCD57+ ratio, TCD66b+/SCD66b+ ratio, SCD8+/SFoxp3+ ratio, and TFoxp3+/NFoxp3+ ratio were associated with significantly worse outcome. Multivariate analysis indicated that tumor size, longitudinal tumor location, N stage, TCD68+/SCD68+ ratio, TCD8+/TFoxp3+ ratio, density of TFoxp3+ cells, and TCD66b+/SCD66b+ ratio were independent prognostic factors, which were all selected into the nomogram. The calibration curve for likelihood of survival demonstrated favorable consistency between predictive value of the nomogram and actual observation. The C-index (0.83, 95% CI: 0.78 to 0.87) of our nomogram for predicting prognosis was significantly higher than that of TNM staging system (0.70). Collectively, high TCD68+/SCD68+ ratio and TCD8+/TFoxp3+ ratio were associated with improved overall survival, whereas high density of TFoxp3+ cells and TCD66b+/SCD66b+ ratio demonstrated poor overall survival, which are promising independent predictors for overall survival in gastric cancer. PMID- 26426651 TI - Comparison of Laparoscopic-Assisted Operations and Laparotomy Operations for the Treatment of Hirschsprung Disease: Evidence From a Meta-Analysis. AB - The purpose of this meta-analysis is to compare the relative merits among laparoscopic-assisted operations and laparotomy operations for patients with Hirschsprung disease. PubMed, Web of Science, and Wanfang databases were searched for the related articles. We analyzed dichotomous variables by estimating odds ratios (ORs) with their 95% confidence intervals (CIs) and continuous variables using the weighted mean difference (WMD) with the 95% CI. The random-effects model (REM) was used to combine the results. The outcome measures included operating time (OT), estimated blood loss (EBL), length of hospital stay (LOHS), mean first bowel movement (MFBM), and number of complications. Sixteen articles were included in the meta-analysis. These studies involved a total of 774 patients, 396 of whom underwent laparoscopic-assisted operations and 378 of whom underwent laparotomy operations. The EBL (WMD = -1.48, 95% CI = -1.82, -1.13), LOHS (WMD = -0.67, 95% CI = -0.86, -0.49), MFBM (WMD = -0.83, 95% CI = -1.05, 0.61), and number of complications (OR = 0.60, 95% CI = 0.40, 0.89) were significantly lower in laparoscopic-assisted operations than in laparotomy operations. The OT (WMD = 0.12, 95% CI = -0.05, 0.28) showed no significant differences between laparoscopic-assisted operations and laparotomy operations. Compared with laparotomy operations, laparoscopic-assisted operations are generally safer and more reliable for patients with Hirschsprung disease. PMID- 26426652 TI - The Risk of Epithelial Ovarian Cancer of Women With Endometriosis May be Varied Greatly if Diagnostic Criteria Are Different: A Nationwide Population-Based Cohort Study. AB - This article aims to test the hypothesis that the risk of epithelial ovarian cancer (EOC) in women with endometriosis might be changed by enrolling different population. A nationwide 14-year historic cohort study using the National Health Insurance Research Database (NHIRD) of Taiwan and the Registry for Catastrophic Illness Patients was conducted. A total of 239,385 women aged between 20 and 51 years, with at least 1 gynecologic visit after 2000, were analyzed. Cases included women with a diagnosed endometriosis, which was established along a spectrum from at least 1 medical record of endometriosis (recalled endometriosis) to tissue-proved ovarian endometriosis (n = X). Controls included women without any diagnosis of endometriosis (n = 239,385 - X). We used Cox regression, and computed hazard ratios (HRs) with 95% confidence intervals (95% CI) to determine the risk of EOC in patients. The EOC incidence rates (IRs, per 10,000 person years) of women with endometriosis ranged from 1.90 in women with recalled endometriosis to 18.70 in women with tissue-proved ovarian endometrioma, compared with those women without any diagnosis of endometriosis (0.77-0.89), contributing to crude HRs ranging from 2.59 (95% CI, 2.09-3.21; P < 0.001) to 24.04 (95% CI, 17.48-33.05; P < 0.001). After adjustment for pelvic inflammatory disease, infertility, Charlson co-morbidity index, and age, adjusted HRs were ranged from the lowest of 1.90 (95% CI, 1.51-2.37; P < 0.001) in recalled endometriosis to the highest of 18.57 (95% CI, 13.37-25.79; P < 0.001) in tissue-proved ovarian endometrioma, which was inversely related to the prevalence rate of endometriosis (from the highest of 30.80% in recalled endometriosis to the lowest of 1.54% in tissue-proved ovarian endometrioma). The risk of EOC in women with endometriosis varied greatly by different criteria used. Women with endometriosis might have a more apparently higher risk than those reported by systematic review and meta analysis. PMID- 26426653 TI - TIPE2 mRNA Level in PBMCs Serves as a Novel Biomarker for Predicting Short-Term Mortality of Acute-on-Chronic Hepatitis B Liver Failure: A Prospective Single Center Study. AB - It remains difficult to accurately predicate short-term mortality of acute-on chronic hepatitis B liver failure (ACHBLF). Tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) is a novel identified negative regulator of immune response and we have previously demonstrated TIPE2 play an essential role in the pathogenesis of ACHBLF. We therefore aimed to evaluate the diagnosis value of TIPE2 mRNA in peripheral blood mononuclear cells (PBMCs) for predicting 3-month mortality of ACHBLF patients. This prospective study consisted of 108 ACHBLF patients from March 2009 to May 2013 as training cohort and 63 ACHBLF patients from June 2013 to December 2014 as validation cohort. Forty-two patients with chronic hepatitis B (CHB) and 22 healthy volunteers were also included as controls. The mRNA level of TIPE2 in PBMCs was determined using quantitative real time polymerase chain reaction. Univariate analysis and Cox proportional hazard regression analysis were performed to identify independent risk factors to 3 month mortality. Area under the receptor operating characteristic curve (AUROC) was performed to assess diagnostic value of TIPE2 mRNA in training and validation cohort. The level of TIPE2 mRNA was significantly higher in ACHBLF patients (median (interquartile): 6.5 [3.7, 9.6]) compared with CHB (2.3 [1.6, 3.7]) and healthy controls (0.4 [0.3, 0.6]; both P < 0.05). Cox proportional hazards regression analyses showed 5 independent risk factors associated with 3-month mortality of ACHBLF: white blood cells (HR = 1.058, 95% CI: 1.023-1.095), spontaneous bacterial peritonitis (HR = 2.541, 95% CI: 1.378-4.686), hepatic encephalopathy (HR = 1.848, 95% CI: 1.028-3.321), model for end-stage liver diseases (MELD) score (HR = 1.062, 95% CI: 1.009-1.118), and TIPE2 mRNA (HR = 1.081, 95% CI: 1.009-1.159). An optimal cut-off point 6.54 of TIPE2 mRNA showed sensitivity of 74.63%, specificity of 90.24%, positive predictive value of 92.5%, and negative predictive value of 67.3% for predicting 3-month mortality in training cohort. Furthermore, TIPE2 mRNA plus MELD performed better than MELD alone for predicting 3-month mortality in training (AUROC, 0.853 vs 0.722, P < 0.05) and validation cohort (AUROC, 0.909 vs 0.717, P < 0.001). TIPE2 mRNA level might be a novel biomarker in predicting 3-month mortality of ACHBLF. Combination of TIPE2 mRNA and MELD would improve the diagnostic value of MELD alone in predicting 3-month mortality of patients with ACHBLF. PMID- 26426654 TI - Lower Serum 25-Hydroxyvitamin D Level is Associated With 3 Types of Autoimmune Thyroid Diseases. AB - Autoimmune thyroid diseases (AITD) are common autoimmune disorders. A few studies have analyzed the association between serum vitamin D levels and AITD, and available data remain inconclusive. The aim of this study was to evaluate the association between serum vitamin D levels and 3 types of AITD, that is Graves' disease (GD), Hashimoto's thyroiditis (HT), and postpartum thyroiditis (PPT). Two independent case-control studies were designed. The first is a cross-sectional case-control study in which we examined the levels of 25(OH)D in patients with newly diagnosed GD or HT and in controls; the second is a nested case-control study in which we compared 25(OH)D levels in 610 women who developed PPT during the follow-up after delivery and those who did not. Compared with the controls, GD patients and HT patients had significantly lower 25(OH)D levels. PPT cases also had a lower serum 25(OH)D concentration than controls. Serum 25(OH)D levels were associated with neither antithyroid peroxidase antibody nor antithyroglobulin antibody in GD and HT. There was no significant relationship between thyroid-stimulating hormone and 25(OH)D levels. Every 5 nmol/L increase in serum 25(OH)D concentrations was associated with a 1.55-, 1.62-, and 1.51-fold reduction in GD, HT, and PPT risk, respectively. We observed a lower serum vitamin D levels in AITD patients compared with controls. The lower the vitamin D level is, not vitamin D deficiency per se, the higher the risk for developing AITD will be. However, vitamin D does not have strong association with the titers of thyroid antibodies or the levels of thyroid hormones. PMID- 26426655 TI - Increased Risk of Chronic Sinusitis in Adults With Gastroesophgeal Reflux Disease: A Nationwide Population-Based Cohort Study. AB - Although gastroesophageal reflux disease (GERD) has been reported to coexist with chronic rhinosinusitis (CRS), it remains controversial whether it increases risk of CRS in adults. This study accesses risk of CRS in adults with newly diagnosed GERD. We identified 15,807 adult patients with newly diagnosed GERD from Taiwan's National Health Insurance Research Database for January 1, 2006 to December 31, 2009. We also randomly selected 47,421 subjects without this disease and matched them with patients by age, sex, index year, and comorbidity to create a control cohort. A Cox proportional hazards model was conducted to estimate the development of CRS, including CRS without nasal polyps and CRS with nasal polyps. Subjects were followed for a median of 2.12 years. In total, CRS developed in 964 (1.52%) of the subjects: 406 patients with GERD (2.57%) and 558 without it (1.18%). After adjustment, those with GERD were found to have a 2.36 times greater risk of CRS (95% confidence interval = 2.08-2.68; P < .001). Risk of this CRS without nasal polyps was higher than the disease with polyps (adjusted hazard ratio: 2.48 vs 1.85). The individuals with GERD in this study were at significantly greater risk of CRS, most often without nasal polyps. PMID- 26426656 TI - Statin Use Reduces Prostate Cancer All-Cause Mortality: A Nationwide Population Based Cohort Study. AB - Studies have suggested that statin use is related to cancer risk and prostate cancer mortality. We conducted a population-based cohort study to determine whether using statins in prostate cancer patients is associated with reduced all cause mortality rates. Data were obtained from the Taiwan National Health Insurance Research Database. The study cohort comprised 5179 patients diagnosed with prostate cancer who used statins for at least 6 months between January 1, 1998 and December 31, 2010. To form a comparison group, each patient was randomly frequency-matched (according to age and index date) with a prostate cancer patient who did not use any type of statin-based drugs during the study period. The study endpoint was mortality. The hazard ratio (HR) and 95% confidence interval (CI) were estimated using Cox regression models. Among prostate cancer patients, statin use was associated with significantly decreased all-cause mortality (adjusted HR = 0.65; 95% CI = 0.60-0.71). This phenomenon was observed among various types of statin, age groups, and treatment methods. Analyzing the defined daily dose of statins indicated that both low- and high-dose groups exhibited significantly decreased death rates compared with nonusers, suggesting a dose-response relationship. The results of this population-based cohort study suggest that using statins reduces all-cause mortality among prostate cancer patients, and a dose-response relationship may exist. PMID- 26426658 TI - Association of Sodium Excretion With Metabolic Syndrome, Insulin Resistance, and Body Fat. AB - Sodium intake was reported to be related to metabolic syndrome (MS). Although a strong association between sodium intake and blood pressure (BP) has been reported, the relationship between sodium intake and other components of MS is unknown. An observational study of 18,146 adults in the Korea National Health and Nutrition Examination Survey IV-V databases (2008-2011) was performed. Estimates of 24-h sodium excretion were made from a single fasting urine sample. A significant positive association was found between sodium excretion and systolic BP and between sodium excretion and diastolic BP in participants with and without hypertension after adjusting for multiple covariates (P < 0.001 for trend). The relationship between triglyceride or glucose levels and sodium excretion was linear (P < 0.005). In both men and women, a positive relationship between sodium excretion and waist circumference and an inverse relationship between sodium excretion and high-density lipoprotein were found (P <= 0.001). Body fat percentage, body fat mass, and insulin level were positively related to sodium excretion (P <= 0.001), and HOMA-IR was significantly associated with sodium excretion (P < 0.05). The risk of MS was elevated 1.279-fold in the second quartile of sodium excretion (95% CI, 1.088-1.504, P = 0.003), 1.479-fold in the third quartile (95% CI, 1.262-1.734; P < 0.001), and 1.929-fold in the highest quartile (95% CI 1.654-2.249, P < .001) compared with the lowest quartile. Sodium intake is significantly associated with all components of MS, body fat, and insulin resistance. Therefore, a high-salt diet is a significant risk factor for MS. PMID- 26426657 TI - Inverse Probability of Treatment Weighting Analysis of Upfront Surgery Versus Neoadjuvant Chemoradiotherapy Followed by Surgery for Pancreatic Adenocarcinoma with Arterial Abutment. AB - Combined arterial resection during pancreatectomy can be a challenging treatment, and outcome would be more favorable if the tumor becomes technically removable from the artery. Neoadjuvant chemoradiotherapy (NACRT) is expected to achieve locoregional control and enable margin-negative resection. To investigate the effects of NACRT in patients with pancreatic adenocarcinoma (PDAC) which were deemed borderline resectable through preoperative imaging due to abutment of the major artery, including the superior mesenteric artery (SMA) or common hepatic artery (CHA), but were still considered to be technically removable. In the current study, comparisons were make between 71 patients who underwent upfront surgery and 21 patients who underwent NACRT followed by surgery in the strategy to preserve the artery, using unmatched and inverse probability of treatment weighting analysis (UMIN000017115). Fifty patients in the upfront surgery group and 18 in the NACRT group underwent curative resection (70% vs 86%, respectively; P = 0.16). The results of the propensity score weighted logistic regressions indicated that the incidences of pathological lymph node metastasis and a pathological positive resection margin were significantly lower in the NACRT group (odds ratio, 0.006; P < 0.001 and odds ratio, 0.007; P < 0.001, respectively). Among the propensity-score matched patients, the estimated 1- and 2-year survival rates in the upfront surgery group were 66.7% and 16.0%, respectively, and those in the NACRT group were 80.0% and 65.2%, respectively. In conclusion, it was suggested that chemoradiotherapy followed by surgery provided clinical benefits in patients with PDACs in contact with the SMA or CHA. PMID- 26426659 TI - Comparison of Efficacy Between Endoscopic Cyclophotocoagulation and Alternative Surgeries in Refractory Glaucoma: A Meta-analysis. AB - Refractory glaucoma refers to uncontrolled intraocular pressure (IOP) despite anti-glaucoma medication and surgical treatment, which remains a challenge to be treated. The objective of this study is to evaluate and statistically compare the clinical efficacy between endoscopic cyclophotocoagulation (ECP) and alternative surgical techniques in the treatment of refractory glaucoma in this article, as a meta-analysis. Data sources are China Biomedical Database (Sinomed, online version), China National Knowledge Infrastructure (CNKI), Cqvip, Wanfang database, and PubMed. The randomized controlled trial (RCT) and case-control study literatures evaluating the clinical efficacy between ECP and other surgical techniques were searched electronically from public databases. The methodology quality of the retrieved articles was evaluated according to the RCT or case control study criteria. The success rate of treatment, intraocular pressure (IOP) and visual acuity were statistically compared. RevMan 5.3 software was used for the meta-analysis. In total, 6 relevant control studies were selected in this study with a total sampling of 429 cases (429 eyes), including 204 eyes in the ECP group and 225 in the non-ECP group. Meta-analysis demonstrated that the clinical efficacy did not significantly differ between 2 groups (P > 0.05). Postoperative IOP was dramatically reduced in both groups. However, it was difficult to evaluate the combined influence of ECP and non-ECP therapies upon IOP reduction. In conclusion, ECP and non-ECP treatment yielded almost equivalent clinical efficacy in treating refractory glaucoma. The IOP-lowering degree, safety, and incidence of complications remain to be further elucidated by RCTs with a larger sample size. PMID- 26426660 TI - Predicting of Venous Thromboembolism for Patients Undergoing Gynecological Surgery. AB - The purpose of this study was to determine the risk stratification of deep venous thrombosis (DVT) in patients undergoing gynecological surgery. A retrospective study was conducted with a cohort of 739 consecutive female patients undergoing gynecological surgery between May 2008 and July 2013 in Beijing Chao-yang hospital. DVT of the leg was detected using complete compression and color Doppler ultrasound. Pulmonary embolism (PE) was diagnosed by computed tomography pulmonary angiogram (CTPA). The overall incidence of DVT was 9.20% (68/739) in this patient population, including 16 (2.17%) symptomatic DVT and 52 (7.04%) silent DVT. A total of 66 (97.06%) DVT events were found within 7 days of surgery and 2 (2.94%) after 1 week. 94.82% thrombi were located in distal vein, and the rest 5.18% located in proximal and distal veins. Among the 68 patients with DVT, 46 patients with suspected PE received CTPA and 21 (45.65%) were confirmed with PE. Six independent factors including varicose vein, bed rest time >= 48 h, length of operation >= 3 h, laparotomy surgery, hypertension, and age >= 50 years significantly increased the incidence of postoperative DVT on multivariate analysis. Patients with none risk factor are at low risk, with 1 or 2 risk factors are at moderate risk, and with >= 3 factors are at high risk of DVT. The incidence of postoperative DVT and PE after gynecological surgery is high in patients with moderate or high-risk level. Noninvasive detection of DVT in 7 days after surgery is necessary because most patients showed no typical symptoms. Appropriate prophylaxis could be performed in patients at moderate or high risk of DVT. PMID- 26426661 TI - Application of Onyx for Renal Arteriovenous Malformation With First Case Report of a Renal Hyperdense Striation Sign: A CARE-Compliant Article. AB - Onyx is an emerging treatment modality for visceral vascular malformations, especially in cases in which delicate nidal penetration of the arteriovenous malformation (AVM) is desired. A computed tomography (CT) image presentation of hyperdense striations along the renal medulla secondary to the tantalum powder has not been previously reported. A 65-year-old woman presented to our institution with intermittent gross hematuria and left flank pain for 10 days. Both CT and conventional angiographies confirmed cirsoid-type renal AVM, which was successfully treated with Onyx. Follow-up CT after treatment revealed presence of hyperdense striations along the renal medulla, which resolved during later image follow-up. Despite its frequent usage in neural intervention, the application of Onyx in visceral AVM is gradually gaining interest, especially in cases in which delicate nidal penetration of the AVM is desired. Renal hyperdense striation sign should be recognized to avoid confusion with embolizer migration, and further studies in patients with renal function impairment may be helpful in understanding its influence of renal function. PMID- 26426662 TI - Risk-Factor Profile and Comorbidities in 2398 Patients With Newly Diagnosed Hypertension From the Abuja Heart Study. AB - Risk factors, comorbidities, and end-organ damage in newly diagnosed hypertension (HT) are poorly described in larger cohorts of urban African patients undergoing epidemiological transition. We therefore decided to characterize a large cohort of hypertensive subjects presenting to a tertiary health center in sub-Saharan Africa. It is an observational cross-sectional study. We prospectively collected detailed clinical, biochemical, electrocardiography, and echocardiography data of all subjects with HT as the primary diagnosis in patients presenting at the Cardiology Unit of the University of Abuja Teaching Hospital over an 8-year period. Of 2398 subjects, 1187 patients (49.4%) were female with a mean age of 51 +/- 12.8 years. Presenting symptoms and signs were most commonly palpitation in 691 (28.8%) followed by dyspnoea on exertion in 541 (22.6%), orthopnea in 532 (22.2%), pedal oedema in 468 (19.5%), paroxysmal nocturnal dyspnoea in 332 (13.8%), whereas only 31 (1.3%) presented with chest pain. Risk factors were obesity in 671 (28%); 523 (21.8%) had total cholesterol >5.2 mmol/L, diabetes mellitus was present in 201 (8.4%) and 187 (7.8%) were smokers. End-organ damage was present in form of echocardiographic left ventricular hypertrophy in 1336 (55.7%) followed by heart failure in 542 (22.6%). Arrhythmias occurred in 110 (4.6%) of cases, cerebrovascular accident in 103 (4.3%), chronic kidney disease in 26 (1.1%), hypertensive encephalopathy in 10 (0.4%), and coronary artery disease in 6 (0.26%). There were marked differences in sex as women were more obese and men presented with more advanced disease. The burden of HT and its complications in this carefully characterized African cohort is quite enormous with more than three-fourth having one form of complication. The need of effective primary and secondary preventive measures to be mapped out to tackle this problem cannot be overemphasized. PMID- 26426663 TI - A Case Report of Gastrointestinal Hemorrhage and Perforation During Apatinib Treatment of Gastric Cancer. AB - Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, which shows good efficacy and safety in clinical trials for chemotherapy-refractory gastric cancer patients. Till now, there is no case report after apatinib came in the market. We presented a 55-year-old Chinese woman with advanced gastric cancer, who received apatinib after failure of second line chemotherapy. On the 19th day of apatinib administration, she suffered from gastrointestinal hemorrhage. Then, her condition rapidly deteriorated to gastrointestinal perforation. Although the patient received timely medical and surgical treatment, she finally died of septic shock. Although apatinib shows exciting efficacy and good tolerance in phase II and III clinical trials, this novel targeted drug should be prescribed carefully and close clinical monitoring is needed when using it. PMID- 26426664 TI - Comparative Treatment Failure Rates of Respiratory Fluoroquinolones or beta Lactam + Macrolide Versus beta-Lactam Alone in the Treatment for Community Acquired Pneumonia in Adult Outpatients: An Analysis of a Nationally Representative Claims Database. AB - No comparative effectiveness study has been conducted for the following 3 antibiotics: respiratory fluoroquinolones, beta-lactam, and beta-lactam + advanced macrolide. To gain insights into the real-world clinical effectiveness of these antibiotics for community-acquired pneumonia in adult outpatients, our study investigated the treatment failure rates in 2 million representative participants from the National Health Informatics Project (NHIP) of Taiwan. A new user cohort design was used to follow NHIP participants from January 2000 until December 2009. Treatment failure was defined by either one of the following events: a second antibiotic prescription, hospitalization due to CAP, an emergency department visit with a diagnosis of CAP, or 30-day nonaccident-related mortality. From 2006 to 2009, we identified 9256 newly diagnosed CAP outpatients, 1602 of whom were prescribed levofloxacin, 2100 were prescribed moxifloxacin, 5049 were prescribed beta-lactam alone, and 505 were prescribed advanced macrolide + beta-lactam. Compared with the beta-lactam-based regimen, the propensity score-matched odds ratio for composite treatment failure was 0.81 (95% CI, 0.67-0.97) for moxifloxacin, 1.10 (95% CI, 0.90-1.35) for levofloxacin, and 0.95 (95% CI, 0.67-1.35) for macrolide +beta-lactam. Moxifloxacin was associated with lower treatment failure rates compared with beta-lactam alone, or levofloxacin in Taiwanese CAP outpatients. However, due to inherent limitations in our claims database, more randomized controlled trials are required before coming to a conclusion on which antibiotic is more effective for Taiwanese CAP outpatients. More population-based comparative effectiveness studies are also encouraged and should be considered as an integral piece of evidence in local CAP treatment guidelines. PMID- 26426665 TI - Steroid Administration is Effective to Prevent Strictures After Endoscopic Esophageal Submucosal Dissection: A Network Meta-Analysis. AB - Esophageal stricture is a severe adverse event after circumferential endoscopic submucosal dissection (ESD). Steroid administration is a new method to prevent stricture formation. We performed a meta-analysis to investigate the efficacy and safety of steroid administration to prevent esophageal stricture after circumferential ESD. PubMed, the Cochrane Library, EMBASE, Chinese Biomedical Database, and Clinicaltrials.gov were searched. Studies on steroid administration + endoscopic balloon dilation (EBD) versus EBD alone for esophageal stricture were included and pooled analyzed in random-effects models. Besides, subgroup analysis and network analysis were performed to define the influence of ESD type and steroid administration method. Twelve studies involving 513 patients were included. Meta-analysis showed that steroid administration significantly achieved a lower stricture rate (risk ratio [RR], 0.40; 95% CI, 0.20-0.81) and less required EBD sessions (mean difference [MD], -4.33; 95% CI, -6.10 to -2.57) than control. Subgroup analysis indicated that steroid was effective after both semi- and complete circumferential ESD. Network meta-analysis showed that compared with oral steroid, local injected steroid had a similar effect to prevent stricture (RR, 1.16; 95% CI, 0.48-2.85), whereas a better effect to reduce required EBD sessions (MD, 7.77; 95%CI, 0.26-15.3). Additional steroid administration is effective to reduce the stricture rate and required EBD sessions. And local injected steroid was superior to oral steroid in EBD reduction, whereas due to the varied method and dose of steroid administration, the finding needs to be clarified in the future. PMID- 26426667 TI - Massive Lumbosacral Subcutaneous Exudate After Surgical Treatment of a Large Lipomyelocele: Case Report and Literature Review. AB - Lipomyelocele is an uncommon type of lipoma that occurs with spina bifida. We present the clinical course and therapeutic process of a female who underwent resection of a lipomyelocele and developed a massive lumbosacral subcutaneous exudate postoperatively. The therapeutic process is described in detail, and a review of the relevant literature on lipomyelocele is presented. A 23-year-old woman presented to our institution complaining of a large lumbosacral subcutaneous mass. She underwent surgical resection of the mass and untethering of the spinal cord under intraoperative neurophysiologic monitoring. A massive lumbosacral subcutaneous exudate developed postoperatively. After excluding cerebrospinal fluid (CSF) leakage, we placed a suction drain. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor of this journal. Because of this, there is no need to conduct special ethic review and the ethical approval is not necessary. Postoperative pathologic examination confirmed the diagnosis of lipomyelocele. Continuation of the negative-pressure drain for 1 week yielded >1000 mL of fluid. The patient recovered well and developed no further subcutaneous exudate. In a patient with massive lumbosacral subcutaneous exudate after surgical treatment of a large lipomyelocele, continuous negative-pressure drainage can be an effective treatment method after excluding CSF leakage. PMID- 26426668 TI - Cyclophilin A in Ruptured Intracranial Aneurysm: A Prognostic Biomarker. AB - Cyclophilin A (CyPA), an oxidative stress-induced factor, was found to play an important role in the aneurysm formation. Our working hypothesis was that the plasma level of CyPA in ruptured intracranial aneurysm could predict the neurological outcome. From 2011 to 2013, a total of 36 patients with ruptured saccular intracranial aneurysm were recruited in our study. Before coil embolization, we draw blood samples at the orifice of a culprit aneurysm and in the remote peripheral vein for measurements of the CyPA levels. We utilized the modified Rankin scale 30 days after aneurysm rupture as the outcome measure. Generalized linear models were used to estimate the adjusted odds ratios of the poor neurological outcome given the presence of high plasma level of CyPA. The aneurysmal and venous CyPA levels were significantly associated with the initial clinical severity (P = 0.004 and 0.03, respectively) and 30-day outcome (P = 0.01 and 0.02, respectively). The aneurysmal CyPA levels modestly correlated with age and high Fisher grade (rho = 0.39 and 0.41; P = 0.02 and 0.01, respectively). The aneurysmal CyPA levels strongly correlated with the venous counterpart (rho = 0.89; P < 0.001). Patients with high levels of aneurysmal CyPA were 15.66 times (95% CI, 1.48-166.24; P = 0.02) more likely to have worse neurological outcome than those with the low levels after adjustment of the age, gender, and the documented confounding factors. High plasma level of CyPA is a significant prognostic biomarker for poor neurological outcome in patients with ruptured intracranial aneurysm. PMID- 26426666 TI - Comparative Effectiveness of First Antiretroviral Regimens in Clinical Practice Using a Causal Approach. AB - The objective of this study was to estimate the cumulative incidences of failure by months 12 (M12) and 24 (M24) for the most prescribed first-line anti retroviral regimens (ART). It is retrospective analysis of a prospectively collected database. All patients who initiated their first ART with the most prescribed regimens between 1st January 2004 and 30th June 2013 in 12 large HIV reference centers in France were included. The outcome was treatment failure- defined by any treatment modification for virological or tolerability reasons- and comparisons between regimens were carried out at M12 and M24. Adjusted and weighted methods via the propensity score (PS) were used to compare the effectiveness of the first antiretroviral regimens. Potential confounders of the treatment-outcome association were used to estimate PS with multinomial logistic regression. Overall, 3128 and 2690 patients were included in the M12 and M24 analyses, respectively. Patients received 5 different regimens (ABC/3TC with ATV/r or DRV/r, TDF/FTC with ATV/r, DRV/r, or EFV). Failure was reported in 25% and 42% at M12 and M24, respectively. Patients who received TDF/FTC/EFV had a significantly higher proportion of failure at M12 by comparison with TDF/FTC with DRV/r (reference), but not at M24. Patients in the 3 other groups had a trend toward a higher proportion of failure at M12 although not statistically significant. No difference was found at M24. Using data from a large prospective cohort, we found that boosted atazanavir and darunavir had comparable effectiveness, whatever the associated NRTIs, whereas efavirenz-based regimens were relatively less performing on the short term. PMID- 26426669 TI - Tibial Tuberosity Avulsion Fracture and Open Proximal Tibial Fracture in an Adult: A Case Report and Literature Review. AB - A displaced tibial tuberosity avulsion fracture associated with an open extra articular proximal tibial diaphyseal fracture is an uncommon fracture pattern. This case report describes the successful management of such a fracture pattern in a 45-year old male using an open reduction and lag screw fixation of the tuberosity with a minimally invasive reduction and plate fixation of the proximal tibial diaphyseal fracture. A literature search was done to determine the expected clinical outcome of this fracture pattern. This is the first reported adult case of an avulsion fractures of the tibial tuberosity associated with an open proximal tibial diaphyseal fracture successfully treated by an anatomical reduction and fixation of the avulsion fracture of the tibial tuberosity combined with minimally invasive percutaneous plate osteosynthesis of the proximal tibial diaphyseal fractures. PMID- 26426670 TI - Hypokalemic Paralysis Complicated by Concurrent Hyperthyroidism and Chronic Alcoholism: A Case Report. AB - Thyrotoxic periodic paralysis (TPP) is characterized by the presence of muscle paralysis, hypokalemia, and hyperthyroidism. We report the case of a young man with paralysis of the lower extremities, severe hypokalemia, and concurrent hyperthyroidism. TPP was suspected; therefore, treatment consisting of judicious potassium (K+) repletion and beta-blocker administration was initiated. However, urinary K+ excretion rate, as well as refractoriness to treatment, was inconsistent with TPP. Chronic alcoholism was considered as an alternative cause of hypokalemia, and serum K+ was restored through vigorous K repletion and the addition of K+ -sparing diuretics. The presence of thyrotoxicosis and hypokalemia does not always indicate a diagnosis of TPP. Exclusion of TPP can be accomplished by immediate evaluation of urinary K+ excretion, acid-base status, and the amount of potassium chloride required to correct hypokalemia at presentation. PMID- 26426671 TI - Strain Lattice Imprinting in Graphene by C60 Intercalation at the Graphene/Cu Interface. AB - Intercalation of C60 molecules at the graphene-substrate interface by annealing leads to amorphous and crystalline structures. A comparison of topography and electronic structure with wrinkles and moire patterns confirms intercalation. The intercalated molecules imprint a local strain/deformation on the graphene layer whose magnitude is controlled by the intermolecular distance. The crystalline intercalated structure exhibits a superlattice peak in the local density of states. This work provides control of local strain in graphene. PMID- 26426675 TI - Enhancement of heat conduction in carbon nanotubes filled with fullerene molecules. AB - Heat conduction in carbon nanopeapods (CNPs), i.e. carbon nanotubes (CNTs) filled with fullerene C60 molecules, is investigated using molecular dynamics simulations. The enhancement mechanisms of CNP thermal conductivity, compared with bare CNTs, are discussed via the local heat flux onto a single atom, the relative contributions of different phonon oscillation frequencies to thermal conductivity and the phonon vibrational density of states. The result shows that filled C60 can increase the CNT thermal conductivity by up to 9.6 times in the temperature range of 100-500 K. The constructive phonon mode couplings between the tube and C60 in a frequency range of 0-20 THz, especially in x-, y-direction transverse acoustic modes and the radial breath mode, are primarily responsible for the increment of thermal conductivity. In addition, filled C60 molecules in CNPs enhance the mass transfer contribution to the total heat flux. This contribution accounts for 22-58% in CNPs, much higher than 12% in CNTs. With the temperature going up, the phonon scattering increases and the contribution from mass transfer to total heat flux decreases. Therefore, the CNP thermal conductivity decreases with rising temperature. This study sheds lights on nanoscale thermal/phonon engineering by utilization of CNTs and C60. PMID- 26426676 TI - Sitagliptin increases acute pancreatitis risk within 2 years of its initiation: A retrospective cohort analysis of the National Health Insurance database in Taiwan. AB - PURPOSE: To evaluate the risk of acute pancreatitis hospitalization with sitagliptin use in patients with type 2 diabetes mellitus (T2DM). METHODS: This retrospective cohort analysis included newly diagnosed T2DM with onset age >=25 years between 1999 and 2010 from the National Health Insurance database. Ever users (n = 89,800) and never users (n = 449,000) of sitagliptin were followed until end of 2011. A time-dependent approach was used to calculate event incidence and estimate hazard ratios adjusted for propensity score. RESULTS: During follow-up, 261 ever users and 5,840 never users were hospitalized for acute pancreatitis (respective incidence, 224.0 and 168.4 per 100,000 person years), with adjusted hazard ratio of 1.59 (95% CI 1.40-1.81). The respective hazard ratio for the first, second, and third tertile of time since starting sitagliptin <9.5, 9.5-21.0, and >21.0 months was 8.10 (6.80-9.65), 1.70 (1.38 2.11), and 0.41 (0.30-0.56); 3.26 (2.67-3.98), 1.86 (1.52-2.27), and 0.76 (0.59 0.98) for cumulative duration <3.7, 3.7-10.3, and >10.3 months; and 3.21 (2.65 3.90), 1.89 (1.54-2.32), and 0.73 (0.57-0.95) for cumulative dose <9,000, 9,000 28,000, and >28,000 mg. CONCLUSIONS: Sitagliptin is associated with a higher risk of acute pancreatitis within the first 2 years of its initiation. The risk diminishes thereafter, probably due to the depletion of susceptible patients. PMID- 26426678 TI - Blue-Black Trachea as a Result of Minocycline-induced Hyperpigmentation. PMID- 26426677 TI - Neuroimmune pharmacological approaches. AB - Intestinal inflammation is a major health problem which impairs the quality of life, impacts mental health and is exacerbated by stress and psychiatric disturbances which, in turn, can affect disease prognosis and response to treatment. Accumulating evidence indicates that the immune system is an important interface between intestinal inflammation and the enteric, sensory, central and autonomic nervous systems. In addition, the neuroimmune interactions originating from the gastrointestinal tract are orchestrated by the gut microbiota. This article reviews some major insights into this complex homeostatic network that have been achieved during the past two years and attempts to put these advances into perspective with novel opportunities of pharmacological intervention. PMID- 26426679 TI - Protecting patients with cardiovascular diseases from catastrophic health expenditure and impoverishment by health finance reform. AB - OBJECTIVES: To compare the incidences of catastrophic health expenditure (CHE) and impoverishment, the risk protection offered by two health financial reforms and to explore factors associated with CHE and impoverishment among patients with cardiovascular diseases (CVDs) in rural Inner Mongolia, China. METHODS: Cross sectional study conducted in 2014 in rural Inner Mongolia, China. Patients with CVDs aged over 18 years residing in the sample areas for at least one year were eligible. The definitions of CHE and impoverishment recommended by WHO were adopted. The protection of CHE and impoverishment was compared between the New Cooperative Medical Scheme (NCMS) alone and NCMS plus National Essential Medicines Scheme (NEMS) using the percentage change of incidences for CHE and impoverishment. Logistic regression was used to explore factors associated with CHE and impoverishment. RESULTS: The incidences of CHE and impoverishment under NCMS plus NEMS were 11.26% and 3.30%, respectively, which were lower than those under NCMS alone. The rates of protection were higher among households with patients with CVDs covered by NCMS plus NEMS (25.68% and 34.65%, respectively). NCMS plus NEMS could protect the poor households more from CHE but not impoverishment. NCMS plus NEMS protected more than one-fourth of households from CHE and more than one-third from impoverishment. CONCLUSION: NCMS plus NEMS was more effective at protecting households with patients with CVDs from CHE and impoverishment than NCMS alone. An integration of NCMS with NEMS should be expanded. However, further strategies to minimise catastrophic health expenditure after this health finance reform are still needed. PMID- 26426680 TI - The Intestinal Microbiome in Bariatric Surgery Patients. AB - With nearly 39% of the worldwide adult population classified as obese, much of the globe is facing a serious public health challenge. Increasing rates of obesity, coupled with the failure of many behavioural and pharmacological interventions, have contributed to a rise in popularity of bariatric surgery as a treatment for obesity. Surgery-mediated weight loss was initially thought to be a direct result of mechanical alterations causing restriction and calorie malabsorption. However, the mounting evidence suggests that indirect factors influence the accumulation and storage of fat in patients that have undergone this procedure. Given the established impact the intestinal microbiota has on adiposity, it is likely that this complex enteric microbial community contributes to surgery-mediated weight loss and maintenance of weight loss postsurgery. In this review, we discuss the physiological and psychological traits exhibited by bariatric surgery candidates that can be influenced by the intestinal microbiota. Additionally, we detail the studies that investigated the impact of bariatric surgery on the intestinal microbiota in humans and mouse models of this procedure. PMID- 26426682 TI - Post-transplant lymphoproliferative disorder of the adrenal gland after allogeneic hematopoietic stem cell transplantation: report of two cases and literature review. AB - Post-transplant lymphoproliferative disorder (PTLD) is one of the life threatening complications after hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT), and it is associated almost exclusively with Epstein-Barr virus (EBV). We herein report 2 cases of EBV-associated PTLD after allogeneic HSCT localized in the adrenal gland. Both patients developed adrenal tumor within 3 months after HSCT and were successfully treated with rituximab or tapering immunosuppressive agents. Both remained alive without recurrence. A literature review revealed 12 reported cases of PTLD involving the adrenal gland, but the adrenal gland was involved as one of the lesions of advanced-stage PTLD after SOT. To the best of our knowledge, this is the first report to show cases of isolated EBV-associated adrenal PTLD after HSCT. PTLD should be recognized as one of the causes of isolated adrenal tumor after HSCT. PMID- 26426683 TI - Disinfection of transvaginal ultrasound probes in a clinical setting: comparative performance of automated and manual reprocessing methods. AB - OBJECTIVES: Transvaginal and intracavitary ultrasound probes are a possible source of cross-contamination with microorganisms and thus a risk to patients' health. Therefore appropriate methods for reprocessing are needed. This study was designed to compare the standard disinfection method for transvaginal ultrasound probes in Germany with an automated disinfection method in a clinical setting. METHODS: This was a prospective randomized controlled clinical study of two groups. In each group, 120 microbial samples were collected from ultrasound transducers before and after disinfection with either an automated method (Trophon EPR(r)) or a manual method (Mikrozid Sensitive(r) wipes). Samples were then analyzed for microbial growth and isolates were identified to species level. RESULTS: Automated disinfection had a statistically significantly higher success rate of 91.4% (106/116) compared with 78.8% (89/113) for manual disinfection (P = 0.009). The risk of contamination was increased by 2.9-fold when disinfection was performed manually (odds ratio, 2.9 (95% CI, 1.3-6.3)). Before disinfection, bacterial contamination was observed on 98.8% of probes. Microbial analysis revealed 36 different species of bacteria, including skin and environmental bacteria as well as pathogenic bacteria such as Staphylococcus aureus, enterobacteriaceae and Pseudomonas spp. CONCLUSIONS: Considering the high number of contaminated probes and bacterial species found, disinfection of the ultrasound probe's body and handle should be performed after each use to decrease the risk of cross-contamination. This study favored automated disinfection owing to its significantly higher efficacy compared with a manual method. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26426681 TI - QseBC, a two-component bacterial adrenergic receptor and global regulator of virulence in Enterobacteriaceae and Pasteurellaceae. AB - The QseBC two-component system (TCS) is associated with quorum sensing and functions as a global regulator of virulence. Based on sequence similarity within the sensor domain and conservation of an acidic motif essential for signal recognition, QseBC is primarily distributed in the Enterobacteriaceae and Pasteurellaceae. In Escherichia coli, QseC responds to autoinducer-3 and/or epinephrine/norepinephrine. Binding of epinephrine/norepinephrine is inhibited by adrenergic antagonists; hence QseC functions as a bacterial adrenergic receptor. Aggregatibacter actinomycetemcomitans QseC is activated by a combination of epinephrine/norepinephrine and iron, whereas only iron activates the Haemophilus influenzae sensor. QseC phosphorylates QseB but there is growing evidence that QseB is activated by non-cognate sensors and regulated by dephosphorylation via QseC. Interestingly, the QseBC signaling cascades and regulons differ significantly. In enterohemorrhagic E. coli, QseC induces expression of a second adrenergic TCS and phosphorylates two non-cognate response regulators, each of which induces specific sets of virulence genes. This signaling pathway integrates with other regulatory mechanisms mediated by transcriptional regulators QseA and QseD and a fucose-sensing TCS and likely controls the level and timing of virulence gene expression. In contrast, A. actinomycetemcomitans QseC signals through QseB to regulate genes involved in anaerobic metabolism and energy production, which may prime cellular metabolism for growth in an anaerobic host niche. QseC represents a novel target for therapeutic intervention and small molecule inhibitors already show promise as broad-spectrum antimicrobials. Further characterization of QseBC signaling may identify additional differences in QseBC function and inform further development of new therapeutics to control microbial infections. PMID- 26426684 TI - Downregulation of the cancer susceptibility protein WRAP53beta in epithelial ovarian cancer leads to defective DNA repair and poor clinical outcome. AB - Alterations in the scaffold protein WRAP53beta have previously been linked to carcinogenesis and, in particular, associated with an increased risk for epithelial ovarian cancer. Here, we investigated the pathogenic impact and prognostic significance of WRAP53beta in connection with epithelial ovarian cancer and examined the underlying mechanisms. We find that reduced expression of WRAP53beta in ovarian tumors correlated with attenuated DNA damage response and poor patient survival. Furthermore, in ovarian cancer cell lines, WRAP53beta was rapidly recruited to DNA double-strand breaks, where it orchestrated the recruitment of repair factors involved in homologous recombination and non homologous end joining, including RNF168, 53BP1, BRCA1 and RAD51. Mechanistically, WRAP53beta accomplishes this by facilitating the necessary ubiquitinylation at DNA breaks. Finally, we demonstrate that loss of WRAP53beta significantly impairs the repair of DNA double-strand breaks, resulting in their accumulation. Our findings establish WRAP53beta as a regulator of homologous recombination and non-homologous end joining repair in ovarian cancer cells, suggesting that loss of this protein contributes to the development and/or progression of ovarian tumors. Moreover, our current observations identify the nuclear levels of WRAP53beta as a promising biomarker for the survival of patients with ovarian cancer. PMID- 26426685 TI - Caspase-8 activation by TRAIL monotherapy predicts responses to IAPi and TRAIL combination treatment in breast cancer cell lines. AB - The discovery of cancer cell-selective tumour necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis generated broad excitement and development of TRAIL receptor agonists (TRA) as potential cancer therapy. Studies demonstrating the synergistic combination effect of SMAC mimetics and TRA further suggested potentially effective treatment in multiple tumour settings. However, predictive biomarkers allowing identification of patients that could respond to treatment are lacking. Here, we described a high throughput combination screen conducted across a panel of 31 breast cancer cell lines in which we observed highly synergistic activity between TRAIL and the inhibitors of apoptosis proteins (IAP) inhibitor (IAPi) AZD5582 in ~30% of cell lines. We detected no difference in the expression levels of the IAPi or TRAIL-targeted proteins or common modulators of the apoptotic pathway between the sensitive and resistant cell lines. Synergistic combination effect of AZD5582 and TRAIL correlated with sensitivity to TRAIL, but not to AZD5582 as a single agent. TRAIL treatment led to significantly greater activity of Caspase-8 in sensitive than in resistant cell lines (P=0.002). The majority (12/14) of AZD5582+TRAIL-resistant cell lines retained a functional cell death pathway, as they were sensitive to AZD5582+TNFalpha combination treatment. This suggested that failure of the TRAIL receptor complex to transduce the death signal to Caspase-8 underlies AZD5582+TRAIL resistance. We developed a 3D spheroid assay and demonstrated its suitability for the ex vivo analysis of the Caspase-8 activity as a predictive biomarker. Altogether, our study demonstrated a link between the functionality of the TRAIL receptor pathway and the synergistic activity of the IAPi+TRA combination treatment. It also provided a rationale for development of the Caspase-8 activity assay as a functional predictive biomarker that could allow better prediction of the response to IAPi+TRA-based therapies than the analysis of expression levels of protein biomarkers. PMID- 26426686 TI - IMP2/p62 induces genomic instability and an aggressive hepatocellular carcinoma phenotype. AB - Hepatocellular carcinoma (HCC) represents the third leading cause of cancer related deaths and commonly develops in inflammatory environments. The IGF2 mRNA binding protein IMP2-2/IGF2BP2-2/p62 was originally identified as an autoantigen in HCC. Aim of this study was to investigate a potential pathophysiological role of p62 in hepatocarcinogenesis. Human HCC tissue showed overexpression of IMP2, which strongly correlated with the fetal markers AFP and DLK1/Pref-1/FA-1 and was particularly elevated in tumors with stem-like features and hypervascularization. Molecular classification of IMP2-overexpressing tumors revealed an aggressive phenotype. Livers of mice overexpressing the IMP2 splice variant p62 highly expressed the stem cell marker DLK1 and secreted DLK1 into the blood. p62 was oncogenic: diethylnitrosamine (DEN)-treated p62 transgenic mice exhibited a higher tumor incidence and multiplicity than wild types. Tumors of transgenics showed a more aggressive and stem-like phenotype and displayed more oncogenic chromosomal aberrations determined with aCGH analysis. DEN-treated p62 transgenic mice exhibited distinct signs of inflammation, such as inflammatory cytokine expression and oxidative stress markers, that is, thiobarbituric acid-reactive substance (TBARS) levels. Reactive oxygen species (ROS) production was elevated in HepG2 cells, which either overexpressed p62 or were treated with DLK1. p62 induced this ROS production by a DLK1-dependent induction and activation of the small Rho-GTPase RAC1, activating NADPH oxidase and being overexpressed in human HCC. Our data indicate that p62/IMP2 promotes hepatocarcinogenesis by an amplification of inflammation. PMID- 26426688 TI - Oncogenic potential of hepatitis B virus encoded proteins. AB - Due to the limited treatment options hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death, and hepatitis B virus (HBV) infection is the major risk factor for development of HCC worldwide. HCC is typically preceded by chronic inflammation, but may also develop in the absence of liver disease on the basis of HBV infection and even when virus replication is controlled by antivirals. In this situation, HBV antigen expression persists and direct oncogenic effects of HBV are integration of the viral DNA into the host genome as well as direct effects of viral proteins. These factors have to be taken into account in order to personalize HCC surveillance in CHB and unravel novel therapeutic approaches. PMID- 26426687 TI - How do persistent infections with hepatitis C virus cause liver cancer? AB - Persistent infection with hepatitis C virus (HCV) is associated with an increased risk of hepatocellular carcinoma (HCC). Cancer typically develops in a setting of chronic hepatic inflammation and advanced fibrosis or cirrhosis, and such tissue represents a pre-neoplastic 'cancer field'. However, not all persistent infections progress to HCC and a combination of viral and host immune factors likely contributes to carcinogenesis. HCV may disrupt cellular pathways involved in detecting and responding to DNA damage, potentially adding to the risk of cancer. Efforts to unravel how HCV promotes HCC are hindered by lack of a robust small animal model, but a better understanding of molecular mechanisms could identify novel biomarkers for early detection and allow for development of improved therapies. PMID- 26426690 TI - Further Insights into the Allan-Herndon-Dudley Syndrome: Clinical and Functional Characterization of a Novel MCT8 Mutation. AB - BACKGROUND: Mutations in the thyroid hormone (TH) transporter MCT8 have been identified as the cause for Allan-Herndon-Dudley Syndrome (AHDS), characterized by severe psychomotor retardation and altered TH serum levels. Here we report a novel MCT8 mutation identified in 4 generations of one family, and its functional characterization. METHODS: Proband and family members were screened for 60 genes involved in X-linked cognitive impairment and the MCT8 mutation was confirmed. Functional consequences of MCT8 mutations were studied by analysis of [125I]TH transport in fibroblasts and transiently transfected JEG3 and COS1 cells, and by subcellular localization of the transporter. RESULTS: The proband and a male cousin demonstrated clinical findings characteristic of AHDS. Serum analysis showed high T3, low rT3, and normal T4 and TSH levels in the proband. A MCT8 mutation (c.869C>T; p.S290F) was identified in the proband, his cousin, and several female carriers. Functional analysis of the S290F mutant showed decreased TH transport, metabolism and protein expression in the three cell types, whereas the S290A mutation had no effect. Interestingly, both uptake and efflux of T3 and T4 was impaired in fibroblasts of the proband, compared to his healthy brother. However, no effect of the S290F mutation was observed on TH efflux from COS1 and JEG3 cells. Immunocytochemistry showed plasma membrane localization of wild-type MCT8 and the S290A and S290F mutants in JEG3 cells. CONCLUSIONS: We describe a novel MCT8 mutation (S290F) in 4 generations of a family with Allan-Herndon Dudley Syndrome. Functional analysis demonstrates loss-of-function of the MCT8 transporter. Furthermore, our results indicate that the function of the S290F mutant is dependent on cell context. Comparison of the S290F and S290A mutants indicates that it is not the loss of Ser but its substitution with Phe, which leads to S290F dysfunction. PMID- 26426691 TI - Thrombin Generation by Fetoscopic Trauma to the Fetal Membranes: An in vivo and in vitro Study. AB - OBJECTIVE: We first aimed to investigate in vivo thrombin generation induced by fetoscopy, and second we used term membrane explants for measurement of thrombin generation, thrombin receptor location and induction of selected matrix metalloproteinases (MMPs) in tissue culture. MATERIALS AND METHODS: In vivo study (37 cases): samples of amniotic fluid were taken at the beginning and end of fetoscopy (mean gestational age 26.7 weeks) and analyzed by ELISA for thrombin antithrombin complexes. In vitro study: fetal membranes were put in culture and punctured for measurement of thrombin generation by calibrated automated thrombography and ELISA. Induction of MMP-9 and MMP-2 was analyzed by zymography. PAR-1 was localized by immunohistochemistry. RESULTS: No significant increase in thrombin-antithrombin was measured in amniotic fluid obtained during fetoscopy. In vitro, thrombin generation induced by needle trauma of membrane cultures is correlated to the amount of plasma. Activity of MMP-9 but not MMP-2 was elevated in cultured membranes but could not be inhibited by a thrombin inhibitor. On histology, the thrombin receptor PAR-1 was located in the chorion and decidua, but not in the amnion. DISCUSSION: Despite the influence of thrombin on punctured fetal membranes in vitro, the role of thrombin in iatrogenic preterm premature rupture of membranes is questionable. PMID- 26426692 TI - Examining the Impact of a Public Health Message on Fish Consumption in Bermuda. AB - BACKGROUND: In 2003 mean cord blood mercury concentrations in pregnant Bermudian women exceeded levels associated with adverse health outcomes in children. The principal mercury source was local fish species. Public health messages were developed suggesting pregnant women reduce consumption of fish species with higher mercury concentrations (e.g. swordfish), substituting species containing lower mercury concentrations, and elevated omega-3 fatty acids (e.g. anchovies). Recent evidence indicates mercury concentrations in Bermuda's pregnant women have fallen five- fold. OBJECTIVES: Assess whether changes in women's fish eating patterns during pregnancy are consistent with the public health messaging. Determine who is making changes to their diet during pregnancy and why. METHODS: Mixed methods study with a cross-sectional survey of 121 pregnant women, including 13 opened-ended interviews. Health system, social vulnerability, public health messaging, and socio-demographic variables were characterized and related to changes in fish consumption during pregnancy. Qualitative data were coded according to nutritional advice messages, comprehension of communication strategies, and sources of information. RESULTS: 95% of women surveyed encountered recommendations about fish consumption during pregnancy. 75% reported modifying fish eating behaviors because of recommendations. Principal sources of information about fish consumption in pregnancy were health care providers and the Internet. 71% of women reported reducing consumption of large fish species with greater mercury levels, but 60% reported reduced consumption of smaller, low mercury fish. No participant mentioned hearing about the benefits of fish consumption. More frequent exposure to public health messages during pregnancy was associated with lower reported consumption. Bermudian born women were less likely to reduce consumption of large fish species during pregnancy. CONCLUSIONS: In Bermuda, public health messages advocating reduced consumption of larger, higher mercury-containing fish species appear effective, but masked the nutritional value message of small fish species, with low mercury concentration. Adjustment is needed to better balance the risk communication. PMID- 26426693 TI - PD98059 Influences Immune Factors and Enhances Opioid Analgesia in Model of Neuropathy. AB - Neuropathic pain treatment remains challenging due to ineffective therapy and resistance to opioid analgesia. Mitogen-activated protein kinase kinase (MAPKK) have been identified as the crucial regulators of pro- and antinociceptive factors. We used PD98059, an inhibitor of the MAPKK family members MEK1/2. The aim of study was to examine the influence of single and/or repeated PD98059 on nociception and opioid effectiveness in neuropathy. Moreover, we examined how PD98059 influences selected members of cellular pathways and cytokines. The PD98059 (2.5 mcg) was intrathecally preemptively administered before chronic constriction injury (CCI), and then once daily for 7 days. Additionally, at day 7 after CCI the PD98059-treated rats received a single injection of opioids. Using Western blot and qRT-PCR techniques in PD98059-treated rats we analyzed the mRNA and/or protein level of p38, ERK1/2, JNK, NF-kappaB, IL-1beta, IL-6, iNOS and IL 10 in the lumbar spinal cord. Our results indicate that PD98059 has an analgesic effects and potentiates morphine and/or buprenorphine analgesia. Parallel we observed that PD98059 inhibit upregulation of the CCI-elevated p38, ERK1/2, JNK and NF-kappaB protein levels. Moreover, PD98059 also prevented increase of pro- (IL-1beta, IL-6, and iNOS) but enhances anti-nociceptive (IL-10) factors. Summing up, PD98059 diminished pain and increased the effectiveness of opioids in neuropathy. The inhibition of MEKs might inactivate a variety of cell signaling pathways that are implicated in nociception. PMID- 26426694 TI - Decreased Yes-Associated Protein-1 (YAP1) Expression in Pediatric Hearts with Ventricular Septal Defects. AB - BACKGROUND: Ventricular septal defects (VSDs) are the most common and simplest type of congenital heart diseases (CHDs). Animal studies have suggested that the downregulation of Yes-associated protein 1 (YAP1) during embryonic development causes VSD-associated CHDs. However, how YAP1 contributes to isolated VSD (iVSD) is unclear. METHODS AND RESULTS: Twenty right atrial specimens were obtained from iVSD patients during routine congenital cardiac surgery and we assessed YAP1 expression in these specimens. For controls, six right atrial specimens were obtained from normal hearts of children without heart disease, three of whom died from cerebral palsy, and three who underwent heart transplants. YAP1 mRNA and protein levels and nuclear localization were significantly reduced in iVSD specimens compared to normal heart specimens. Concomitantly, mRNA levels of YAP1 downstream targets CTGF and AXL were also significantly decreased in iVSD specimens. Although Ki67-positive cardiomyocytes in iVSD specimens were comparable to normal heart specimens, Ki67-positive non-cardiomyocytes were significantly decreased. CONCLUSIONS: YAP1 expression was markedly decreased in hearts of iVSD children. Given the important role of YAP1 during heart development, downregulation of YAP1 expression may contribute to iVSD and affect the proliferation of non-cardiomyocytes. PMID- 26426695 TI - The GSTome Reflects the Chemical Environment of White-Rot Fungi. AB - White-rot fungi possess the unique ability to degrade and mineralize all the different components of wood. In other respects, wood durability, among other factors, is due to the presence of extractives that are potential antimicrobial molecules. To cope with these molecules, wood decay fungi have developed a complex detoxification network including glutathione transferases (GST). The interactions between GSTs from two white-rot fungi, Trametes versicolor and Phanerochaete chrysosporium, and an environmental library of wood extracts have been studied. The results demonstrate that the specificity of these interactions is closely related to the chemical composition of the extracts in accordance with the tree species and their localization inside the wood (sapwood vs heartwood vs knotwood). These data suggest that the fungal GSTome could reflect the chemical environment encountered by these fungi during wood degradation and could be a way to study their adaptation to their way of life. PMID- 26426697 TI - Zinc-cadmium interactions: Impact on wheat physiology and mineral acquisition. AB - Increasing concentration of Cd in soil is of great concern due to risk of its entry into food chain. Zinc (Zn) being antagonist to Cd is an important micronutrient to ameliorate its toxic effects on plants and to limit its entry into food chain. A pot experiment was conducted using Cd contaminated soil (30 mg Cd kg(-1) soil as 3CdSO4 . 8H2O) to investigate the effect of soil and foliar applied Zn on physiological response and Cd concentration in wheat. In soil, Zn was applied at 15 and 30 mg Zn kg(-1) soil as zinc sulfate (ZnSO4 . 7H2O). For foliar applications, 3 and 6 g L(-1) ZnSO4 solution was sprayed on completing eight weeks of growth. Results indicated that Zn application could effectively improve physiological performance and mineral content of wheat grown on Cd contaminated soils. Among different Zn fertilization treatments, foliar application of 3 g L(-1) ZnSO4 solution recorded the maximum soluble proteins and the minimum grain-Cd concentration. Soil application of ZnSO4 or foliar application at 6 g L(-1) did not affect Cd concentration in grains. Zinc application through both the methods significantly increased phosphorus (P), potassium (K) and Zn concentrations in shoots. Concentration of P and K in grains showed positive relationship with that of Zn. In crux, present study suggests that foliar application of Zn at booting stage in a suitable concentration (3 g L(-1) ZnSO4 solution) can effectively ameliorate the adverse effects of Cd and decrease grain-Cd of wheat grown in Cd contaminated soil. PMID- 26426696 TI - Genetic Variation in miR-146a Is Not Associated with Susceptibility to IgA Nephropathy in Adults from a Chinese Han Population. AB - BACKGROUND: MicroRNA 146a (miR-146a) is a 19 to 23 nucleotide long, small non coding RNA with gene regulatory functions that has influence on the pathogenesis of many diseases. A single nucleotide polymorphism (rs2910164 C>G) in pre-miR 146a is correlated with the expression of miR-146a. The aim of this study was to perform an association analysis of rs2910164 with IgA nephropathy in adult patients from a Chinese Han population. METHODS: A total of 145 patients with renal biopsy-proved IgA nephropathy (IgAN) and 179 healthy controls were recruited to the current study. rs2910164 was genotyped by the polymerase chain reaction (PCR) and high-resolution melting methods (HRM). Clinical characteristics and pathology grading of patients with IgAN were recorded at the time of kidney biopsy. RESULT: There were significant differences among the population of patients grouped by different age of onset in a co-dominant model (CG vs. CC vs. GG) (p = 0.033) and a recessive model (CG+CC vs. GG) (p = 0.001). However, no significant difference was observed in the distribution of genotypes between cases and controls (p = 0.144). There was also no significant difference between rs2910164 and patient quantitative traits (all p > 0.003) or different pathology grading (Lee's grading system and tubular atrophy/interstitial fibrosis in the Oxford classification) (all p > 0.05). CONCLUSIONS: There was no association of rs2910164 with susceptibility to IgAN in adults from a Chinese Han population. However, rs2910164 was correlated with the age of onset of IgAN in adult patients. PMID- 26426698 TI - Shifting grassland plant community structure drives positive interactive effects of warming and diversity on aboveground net primary productivity. AB - Ecosystems worldwide are increasingly impacted by multiple drivers of environmental change, including climate warming and loss of biodiversity. We show, using a long-term factorial experiment, that plant diversity loss alters the effects of warming on productivity. Aboveground primary productivity was increased by both high plant diversity and warming, and, in concert, warming (~1.5 degrees C average above and belowground warming over the growing season) and diversity caused a greater than additive increase in aboveground productivity. The aboveground warming effects increased over time, particularly at higher levels of diversity, perhaps because of warming-induced increases in legume and C4 bunch grass abundances, and facilitative feedbacks of these species on productivity. Moreover, higher plant diversity was associated with the amelioration of warming-induced environmental conditions. This led to cooler temperatures, decreased vapor pressure deficit, and increased surface soil moisture in higher diversity communities. Root biomass (0-30 cm) was likewise consistently greater at higher plant diversity and was greater with warming in monocultures and at intermediate diversity, but at high diversity warming had no detectable effect. This may be because warming increased the abundance of legumes, which have lower root : shoot ratios than the other types of plants. In addition, legumes increase soil nitrogen (N) supply, which could make N less limiting to other species and potentially decrease their investment in roots. The negative warming * diversity interaction on root mass led to an overall negative interactive effect of these two global change factors on the sum of above and belowground biomass, and thus likely on total plant carbon stores. In total, plant diversity increased the effect of warming on aboveground net productivity and moderated the effect on root mass. These divergent effects suggest that warming and changes in plant diversity are likely to have both interactive and divergent impacts on various aspects of ecosystem functioning. PMID- 26426699 TI - Host-Guest Interaction-Mediated Construction of Hydrogels and Nanovesicles for Drug Delivery. AB - Hand-in-hand or head-to-head: A novel naphthalimide derivative is successfully designed and synthesized, which can self-assemble to produce hydrogels. When injecting this compound into CB[8] solution, the nanovesicles are obtained with a narrow size distribution. The cytotoxicity assay confirms that doxorubicin-loaded nanocarriers show therapeutic effects to cancer cells. PMID- 26426700 TI - Association between left ventricular mass, androgens, adiposity and insulin resistance in girls with precocious pubarche: a case-control study. AB - OBJECTIVE: Precocious pubarche (PP) has been linked to higher prevalence of metabolic disturbances and polycystic ovary syndrome (PCOS). The aim of the study was to assess echocardiographic parameters in PP girls and to analyse their relationship with androgens and insulin resistance (IR). DESIGN: Case-control study. PATIENTS: Thirty-five PP girls and 35 healthy age-matched controls. MEASUREMENTS: Clinical, hormonal and metabolic profiles, echocardiography, body composition and oral glucose tolerance test. RESULTS: Chronological age (10.04 +/ 2.6 years in PP vs 10.13 +/- 2.56 years in controls, P = 0.227), and pubertal stage at the time of the study were similar between the groups. PP girls had higher free androgen index (FAI) [1.39 (0.48-3.64) vs 1.06 (0.39-1.7), P = 0.005] and QUICKI (0.58 +/- 0.08 vs 0.63 +/- 0.12, P = 0.021). However, HOMA-IR was not significantly different between the groups [2.79 (1.84-4.05) vs 2.15 (1.09-3.23), P = 0.085]. After adjusting for total body fat, left ventricular mass (LVM) was higher in the PP group (97.31 +/- 33.37 vs 81.25 +/- 19.06 g, P = 0.017) as well as A' wave (5.66 +/- 1.34 vs 5.09 +/- 0.98 cm/s, P = 0.025), a measurement of diastolic function. FAI and total body fat were independent predictors of higher LVM and together with HOMA-IR contributed 72% of LVM variability in the PP group. CONCLUSION: In this study with PP girls, greater LVM, associated with higher androgen levels, IR and total body fat, occurred early in pubertal development. PMID- 26426701 TI - Bayes Node Energy Polynomial Distribution to Improve Routing in Wireless Sensor Network. AB - Wireless Sensor Network monitor and control the physical world via large number of small, low-priced sensor nodes. Existing method on Wireless Sensor Network (WSN) presented sensed data communication through continuous data collection resulting in higher delay and energy consumption. To conquer the routing issue and reduce energy drain rate, Bayes Node Energy and Polynomial Distribution (BNEPD) technique is introduced with energy aware routing in the wireless sensor network. The Bayes Node Energy Distribution initially distributes the sensor nodes that detect an object of similar event (i.e., temperature, pressure, flow) into specific regions with the application of Bayes rule. The object detection of similar events is accomplished based on the bayes probabilities and is sent to the sink node resulting in minimizing the energy consumption. Next, the Polynomial Regression Function is applied to the target object of similar events considered for different sensors are combined. They are based on the minimum and maximum value of object events and are transferred to the sink node. Finally, the Poly Distribute algorithm effectively distributes the sensor nodes. The energy efficient routing path for each sensor nodes are created by data aggregation at the sink based on polynomial regression function which reduces the energy drain rate with minimum communication overhead. Experimental performance is evaluated using Dodgers Loop Sensor Data Set from UCI repository. Simulation results show that the proposed distribution algorithm significantly reduce the node energy drain rate and ensure fairness among different users reducing the communication overhead. PMID- 26426702 TI - Amniotic fluid biochemistry in isolated polyhydramnios: a series of 464 cases. AB - OBJECTIVE: To report amniotic fluid biochemistry in a large series of 464 cases of isolated polyhydramnios in order to analyze both the outcome and the benefit of amniotic fluid biochemistry. METHODS: This retrospective cohort (2008-2012) included polyhydramnios cases for which amniotic fluid samples were sent to our laboratory for biochemical analysis (total protein, alpha-fetoprotein and gamma glutamyl transpeptidase) so as to investigate the etiology. A Bartter index and an esophageal atresia index were defined. Final diagnoses were compared between groups to determine the association between these indices and the frequency and type of adverse outcomes. RESULTS: Among 464 cases of polyhydramnios considered isolated at ultrasound examination, severe fetal diseases were diagnosed in 136 (29.3%): 46 (9.9%) chromosomal anomalies, 28 (6%) Bartter syndrome, 23 (4.95%) other genetic syndromes, 22 (4.75%) swallowing disorders and 17 (3.7%) uro nephrological disorders. Amniotic fluid biochemistry identified esophageal atresia with 66.6% (10/15) sensitivity and 100% specificity and Bartter syndrome with 85.7% (24/28) sensitivity and 84.2% specificity. CONCLUSION: Isolated polyhydramnios is associated with a high risk of severe fetal diseases. Molecular cytogenetics and amniotic fluid biochemistry are helpful tools. PMID- 26426703 TI - Biocompatibility and biomechanical analysis of elastic TPU threads as new suture material. AB - High suture tension is one of the causes for many wound-healing problems. Constriction of tissue within the suture loops of nonelastic sutures can lead to cutting of the suture through tissues and necrosis of the tissue within these loops. The use of elastic materials in new suture types could give the material the ability to adapt tension to the tissue requirements and subsequently lead to more vital tissue within its loops. We evaluated the foreign body host response, as indicator of biocompatibility, to a new thermoplastic poly(carbonate) urethane (TPU) synthetic suture material in a rat model compared with standard nonelastic polypropylene (PP) sutures. Tissue samples were collected at 7 and 21 days, and host response was evaluated. Subsequently, suture tension curves of the new elastic sutures for the first 30 min after knotting were recorded in a pig model. The new TPU sutures showed an improved foreign body response when compared with that of PP, with a reduction in the amount of macrophages surrounding the material. Tension experiments showed a superior tension curve for TPU sutures, with a major reduction in peak suture tension when compared with that of standard PP sutures, while still retaining adequate tension after 30 min. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 99-106, 2017. PMID- 26426705 TI - Quantitative Contact Resonance Force Microscopy for Viscoelastic Measurement of Soft Materials at the Solid-Liquid Interface. AB - Viscoelastic property measurements made at the solid-liquid interface are key to characterizing materials for a variety of biological and industrial applications. Further, nanostructured materials require nanoscale measurements. Here, material loss tangents (tan delta) were extracted from confounding liquid effects in nanoscale contact resonance force microscopy (CR-FM), an atomic force microscope based technique for observing mechanical properties of surfaces. Obtaining reliable CR-FM viscoelastic measurements in liquid is complicated by two effects. First, in liquid, spurious signals arise during cantilever excitation. Second, it is challenging to separate changes to cantilever behavior due to the sample from changes due to environmental damping and added mass effects. We overcame these challenges by applying photothermal cantilever excitation in multiple resonance modes and a predictive model for the hydrodynamic effects. We demonstrated quantitative, nanoscale viscoelastic CR-FM measurements of polymers at the solid liquid interface. The technique is demonstrated on a point-by-point basis on polymer samples and while imaging in contact mode on a fixed plant cell wall. Values of tan delta for measurements made in water agreed with the values for measurements in air for some experimental conditions on polystyrene and for all examined conditions on polypropylene. PMID- 26426706 TI - Exploring water as building bricks in enzyme engineering. AB - A novel enzyme engineering strategy for accelerated catalysis based on redesigning a water network through protein backbone deshielding is presented. Fundamental insight into the energetic consequences associated with the design is discussed in the light of experimental results and computer simulations. Using water as biobricks provides unique opportunities when transition state stabilisation is not easily attained by traditional enzyme engineering. PMID- 26426704 TI - Cohort Study of the Success of Controlled Weight Loss Programs for Obese Dogs. AB - BACKGROUND: Most weight loss studies in obese dogs assess rate and percentage of weight loss in the first 2-3 months, rather than the likelihood of successfully reaching target weight. OBJECTIVE: To determine outcome of controlled weight loss programs for obese dogs, and to determine the factors associated with successful completion. ANIMALS: 143 obese dogs undergoing a controlled weight loss program. METHODS: This was a cohort study of obese dogs attending a referral weight management clinic. Dogs were studied during their period of weight loss, and cases classified according to outcome as "completed" (reached target weight), "euthanized" (was euthanized before reaching target weight), or "stopped prematurely" (program stopped early for other reasons). Factors associated with successful completion were assessed using simple and multiple logistic regression. RESULTS: 87/143 dogs (61%) completed their weight loss program, 11 [8%] died or were euthanized, and the remaining 45 [32%] stopped prematurely. Reasons for dogs stopping prematurely included inability to contact owner, refusal to comply with weight management advice, or development of another illness. Successful weight loss was positively associated with a faster rate (P < .001), a longer duration (P < .001), and feeding a dried weight management diet (P = .010), but negatively associated with starting body fat (P < .001), and use of dirlotapide (P = .0046). CONCLUSIONS AND CLINICAL RELEVANCE: Just over half of all obese dogs on a controlled weight loss program reach their target weight. Future studies should better clarify reasons for success in individual cases, and also the role of factors such as activity and behavioral modification. PMID- 26426707 TI - Education and Imaging. Hepatobiliary and Pancreatic: Role of CT angiography in the evaluation of liver involvement in Rendu-Osler-Weber syndrome. PMID- 26426708 TI - Ultrafast Photoinduced Charge Separation Leading to High-Energy Radical Ion-Pairs in Directly Linked Corrole-C60 and Triphenylamine-Corrole-C60 Donor-Acceptor Conjugates. AB - Closely positioned donor-acceptor pairs facilitate electron- and energy-transfer events, relevant to light energy conversion. Here, a triad system TPACor-C60 , possessing a free-base corrole as central unit that linked the energy donor triphenylamine (TPA) at the meso position and an electron acceptor fullerene (C60) at the beta-pyrrole position was newly synthesized, as were the component dyads TPA-Cor and Cor-C60. Spectroscopic, electrochemical, and DFT studies confirmed the molecular integrity and existence of a moderate level of intramolecular interactions between the components. Steady-state fluorescence studies showed efficient energy transfer from (1) TPA* to the corrole and subsequent electron transfer from (1) corrole* to fullerene. Further studies involving femtosecond and nanosecond laser flash photolysis confirmed electron transfer to be the quenching mechanism of corrole emission, in which the electron transfer products, the corrole radical cation (Cor(?+) in Cor-C60 and TPA-Cor(?+) in TPACor-C60) and fullerene radical anion (C60(?-)), could be spectrally characterized. Owing to the close proximity of the donor and acceptor entities in the dyad and triad, the rate of charge separation, kCS , was found to be about 10(11) s(-1), suggesting the occurrence of an ultrafast charge-separation process. Interestingly, although an order of magnitude slower than kCS , the rate of charge recombination, kCR , was also found to be rapid (kCR ~10(10) s(-1)), and both processes followed the solvent polarity trend DMF>benzonitrile>THF>toluene. The charge-separated species relaxed directly to the ground state in polar solvents while in toluene, formation of (3) corrole* was observed, thus implying that the energy of the charge-separated state in a nonpolar solvent is higher than the energy of (3) corrole* being about 1.52 eV. That is, ultrafast formation of a high-energy charge-separated state in toluene has been achieved in these closely spaced corrole-fullerene donor-acceptor conjugates. PMID- 26426709 TI - The Effect of Smoking on Spinal Cord Healing Following Surgical Treatment of Cervical Myelopathy. AB - STUDY DESIGN: Retrospective cohort. OBJECTIVE: The purpose of this study was to compare outcomes of surgical treatment of cervical myelopathy between smokers and nonsmokers as assessed by the Nurick score. SUMMARY OF BACKGROUND DATA: The harmful effects of smoking on healing have been well established. However, the effect of smoking on postoperative outcomes for cervical myelopathy has not been specifically evaluated. METHODS: The medical records of 212 patients who underwent surgery for cervical spondylotic myelopathy were reviewed. Inclusion criteria were the diagnosis of cervical spondylotic myelopathy with a Nurick score, surgical intervention, and at least 2 years of follow-up. The patients were categorized into 2 groups according to smoking status and stratified according to pack years and packs per day. Age at presentation, sex, preoperative and postoperative Nurick score, duration of symptoms preoperatively, duration of follow-up, procedure performed, surgical approach, number of levels fused, diabetes status, cocaine use, ethanol use, preoperative magnetic resonance imaging signal change, and whether the patient belonged to the Veterans Administration (VA) were recorded. Analysis was done using simple linear regression and multiple regression. RESULTS: Univariate analysis demonstrated a postoperative improvement in nonsmokers of 1.53 points on the Nurick scale compared with 0.6 points in smokers (P < 0.001). There is a progressive decrease in improvement as the number of pack years and packs per day increase (P < 0.001). There is a greater improvement in Nurick score with greater (worse) preoperative score but only in patients with fewer than 25 pack years. Smoking status is not associated with preoperative Nurick score. CONCLUSION: Smoking status is associated with poor improvement in Nurick score after surgical treatment of cervical myelopathy. Smoking may have a directly toxic effect on the intrinsic healing capability of the spinal cord, particularly beyond 25 pack years. LEVEL OF EVIDENCE: 3. PMID- 26426710 TI - Safety and Efficacy of Reconstruction of Complex Cervical Spine Pathology Using Pedicle Screws Inserted with Stealth Navigation and 3D Image-Guided (O-Arm) Technology. AB - STUDY DESIGN: Retrospective analysis. OBJECTIVE: To determine safety and efficacy of cervical pedicle screw placement using O-Arm and Stealth Navigation in patients with cervicothoracic spinal deformities and revision subaxial cervical pathology. SUMMARY OF BACKGROUND DATA: Cervical pedicle screws are biomechanically advantageous to other posterior cervical fixation techniques; however, their use is limited by concerns for neurovascular injury. Few clinical reports exist on their placement safety and efficacy using modern navigation systems. METHODS: Adults who had cervical pedicle screws inserted using O-Arm and Stealth Navigation between November 2007 and January 2014 and with a minimum 1 year follow-up were retrospectively studied. Screw insertion safety, surgical complications, need for reoperation, and clinical outcomes [Neck Disability Index, EQ-5D, numeric pain rating scales] were evaluated. RESULTS: 21 patients (female-10; male-11; average age 63 yr [32-83 yr]) met inclusion criteria. Average follow-up was 29.8 months (12-81.6 mo). Reconstruction of C2 and the subaxial cervical spine included 8 primary operations for cervicothoracic kyphosis and 13 revision operations. 121 pedicle screws were placed (C2: 4, C3: 20, C4: 22, C5: 23, C6: 18, C7: 34) using Stealth Navigation. The average number of screws placed per case was 6 (1-12). Greater than 99% of screws were placed safely without neurovascular injury. 1 screw (0.8%) was noted postoperatively to critically breach the medial wall and was associated with an acute C5 nerve root palsy. 2 patients required revisions for postoperative iatrogenic foraminal stenosis and associated C8 radiculopathies. No vascular complications due to aberrant screw placement occurred. There were significant improvements (P < 0.05) in EQ-5D utility scores and neck and arm pain. Neck Disability Index scores decreased on average by 10 points (P = 0.12). CONCLUSION: Placement of cervical pedicle screws using O-Arm/Stealth Navigation in this series was a safe and effective method for posterior stabilization in cervicothoracic deformity and revision operations of the subaxial cervical spine. LEVEL OF EVIDENCE: 4. PMID- 26426711 TI - American Spinal Injury Association Impairment Scale Predicts the Need for Tracheostomy After Cervical Spinal Cord Injury. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: The objective of this study was to evaluate the ability of the American Spinal Injury Association (ASIA) Impairment Scale and neurological level of injury to predict the need for mechanical ventilation as well as tracheostomy. SUMMARY OF BACKGROUND DATA: High-level cervical spinal cord injuries, high Injury Severity Score, and low Glasgow Coma Scale have been shown to predict tracheostomy. METHODS: A total of 383 patients with fractures, dislocations, or ligamentous injury of the cervical spine were included in the study. Charts were reviewed to determine demographics, Injury Severity Score, Glasgow Coma Scale, presence and severity of chest injuries, length of hospital stay, intensive care unit stay, mechanical ventilation time, and mortality. RESULTS: Fifty-nine patients (15.4%) underwent tracheostomy. An ASIA Impairment Scale of A had a specificity of 98.8% and sensitivity of 32.2% for predicting the need for tracheostomy. This yielded a 1.2% false-positive rate. The ASIA Impairment Scale remained the most significant predictor after regression for Injury Severity Score, Glasgow Coma Scale, and Chest Abbreviated Injury Scale. Neurological level of injury was not a significant predictor of tracheostomy. CONCLUSION: An ASIA Impairment Scale of A at any level of injury is a specific predictor of the need for tracheostomy with a low false-positive rate. Given the relatively low risk of early tracheostomy and the potential benefits, an ASIA Impairment Scale of A would be a sensible early criterion to determine the need for tracheostomy. LEVEL OF EVIDENCE: 3. PMID- 26426712 TI - Radiographical and Implant-Related Complications in Adult Spinal Deformity Surgery: Incidence, Patient Risk Factors, and Impact on Health-Related Quality of Life. AB - STUDY DESIGN: A multicenter, prospective review of surgical patients with adult spine deformity. OBJECTIVE: Assessment of the incidence, risk factor, and impact of radiographical and implant-related complications (RIC) on health-related quality of life measures. SUMMARY OF BACKGROUND DATA: This study provides assessment of the incidence of RIC in adult spinal deformity surgery and impact of these complications on need for reoperation. Risk factors for development of RIC are also assessed, as well as the impact of these complications on health related quality of life (HRQOL) outcomes measures. METHODS: A multicenter, prospective database of surgical patients with adult spinal deformity was reviewed. All patients with complete 2-year follow-up were included. HRQOL was measured using the Oswestry Disability Index, General Health Survey (36-Item Short Form Health Survey [SF-36]), and Scoliosis Research Society-22 (SRS-22r) at baseline, 6 weeks, 1 year, and 2 years postoperatively. Univariate testing was performed as appropriate. Multivariate logistic regression modeling was used to determine independent predictors of RIC. Multivariate repeated-measures mixed models were used to examine HRQOL, accounting for confounders. RESULTS: A total of 245 patients met inclusion criteria. The incidence of RIC was 31.7% and 52.6% of those patients required reoperation. Rod breakage accounted for 47% of the implant-related complications, and proximal junctional kyphosis accounted for 54.5% of radiographical complications. Univariate analysis identified the following potential risk factors for RIC: weight, American Society of Anesthesiologists score, revision, stopping the fusion in the lower thoracic spine, worse SRS-Schwab classification modifiers (pelvic tilt++, pelvic incidence minus lumbar lordosis++, sagittal vertical axis++), higher T1 spinopelvic inclination, and higher T1 slope. Independent predictors of RIC as identified on multivariate logistic regression included American Society of Anesthesiologists (odds ratio: 1.75, P = 0.029) and sagittal vertical axis modifier ++ (odds ratio 3.43, P = 0.0001). The RIC and no RIC groups each experienced significant improvement over time, as measured on the Oswestry Disability Index (P = 0.0001), SF-36 (P = 0.0001), and SRS-22r (P = 0.0001). However, the rate of improvement over time was less for patients with RIC (SRS-22r P = 0.043, SF-36 P = 0.0001). CONCLUSION: This study identified that nearly one-third of patients undergoing adult spinal deformity surgery experienced a radiographical or implant-related complication, and that just more than one-half of these patients experiencing complication required a reoperation within 2 years of surgery. These complications significantly affected HRQOL measures. Baseline patient characteristics and parameters of the SRS-Schwab classification can be used to help identify those patients at greater risk. LEVEL OF EVIDENCE: 3. PMID- 26426713 TI - The Incidence of Durotomy and its Clinical and Economic Impact in Primary, Short segment Lumbar Fusion: An Analysis of 17,232 Cases. AB - STUDY DESIGN: Retrospective database analysis. OBJECTIVE: To determine the incidence of durotomy in primary short-segment lumbar fusion and assess its clinical and economic impacts. SUMMARY OF BACKGROUND DATA: The incidence of durotomy during primary lumbar fusion and its economic impact are not well described. METHODS: The Nationwide Inpatient Sample was queried for all primary 1 or 2-level lumbar fusions performed in adults for lumbar spinal stenosis between 2009 and 2011; only elective cases without concurrent diagnoses of vertebral infection, fracture, or tumor were included. chi and t-tests were used as appropriate to compare categorical and continuous variables, respectively. Multivariate regression analysis was performed to identify factors independently associated with incidental durotomy, as well as total hospital charges, costs, and length of stay. RESULTS: Among 17,232 cases, 802 incidental durotomies were identified (rate 4.65%). The multivariate odds of durotomy in the oldest patients (age >= 73) were 2.4 times greater than the odds of durotomy in the youngest patients (age <= 56; P < 0.0001). Durotomy was associated with increased neurological complications and longer hospital stay. Length of stay was a significant driver of cost. The multivariate odds of dural tears in teaching hospitals was significantly higher compared with nonteaching hospitals (odds ratio 1.27; 95% confidence interval, 1.06-1.52; P < 0.005). Durotomy was associated with a $10,885 increase in total hospital charges, and a $3,873 increase in estimated total costs (compared with no durotomy group with P < 0.0001). CONCLUSION: Increasing age is a risk factor for durotomy in primary lumbar fusion. Durotomy is associated with neurological complications, increased length of stay, greater healthcare costs, and is more common in teaching hospitals. Length of stay is an independent driver of cost and complications. LEVEL OF EVIDENCE: 3. PMID- 26426714 TI - Dante and Musculoskeletal Diseases: Anatomy and Pathophysiology of Orthopedic and Spinal Disorders in the Middle Ages. PMID- 26426715 TI - The Reliability and Validity of the Thoracolumbar Injury Classification System in Pediatric Spine Trauma. AB - STUDY DESIGN: The thoracolumbar injury classification system (TLICS) was evaluated in 20 consecutive pediatric spine trauma cases. OBJECTIVE: The purpose of this study was to determine the reliability and validity of the TLICS in pediatric spine trauma. SUMMARY OF BACKGROUND DATA: The TLICS was developed to improve the categorization and management of thoracolumbar trauma. TLICS has been shown to have good reliability and validity in the adult population. METHODS: The clinical and radiographical findings of 20 pediatric thoracolumbar fractures were prospectively presented to 20 surgeons with disparate levels of training and experience with spinal trauma. These injuries were consecutively scored using the TLICS. Cohen unweighted kappa coefficients and Spearman rank order correlation values were calculated for the key parameters (injury morphology, status of posterior ligamentous complex, neurological status, TLICS total score, and proposed management) to assess the inter-rater reliabilities. Five surgeons scored the same cases 3 months later to assess the intra-rater reliability. The actual management of each case was then compared with the treatment recommended by the TLICS algorithm to assess validity. RESULTS: The inter-rater kappa statistics of all subgroups (injury morphology, status of the posterior ligamentous complex, neurological status, TLICS total score, and proposed treatment) were within the range of moderate to substantial reproducibility (0.524-0.958). All subgroups had excellent intra-rater reliability (0.748-1.000). The various indices for validity were calculated (80.3% correct, 0.836 sensitivity, 0.785 specificity, 0.676 positive predictive value, 0.899 negative predictive value). Overall, TLICS demonstrated good validity. CONCLUSION: The TLICS has good reliability and validity when used in the pediatric population. The inter-rater reliability of predicting management and indices for validity are lower than those in adults with thoracolumbar fractures, which is likely due to differences in the way children are treated for certain types of injuries. TLICS can be used to reliably categorize thoracolumbar injuries in the pediatric population; however, modifications may be needed to better guide treatment in this specific patient population. LEVEL OF EVIDENCE: 4. PMID- 26426717 TI - Conjunctival Melanoma-Clinical Pearls Now, Hope for the Future. PMID- 26426718 TI - A Narrow QRS Tachycardia with Unusual Electrophysiological Characteristics: What Is the Mechanism? PMID- 26426723 TI - Microscopic Mechanism of Doping-Induced Kinetically Constrained Crystallization in Phase-Change Materials. AB - A comprehensive microscopic mechanism of doping-induced kinetically constrained crystallization in phase-change materials is provided by investigating structural and dynamical dopant characteristics via ab initio molecular dynamics simulations. The information gained from this study may provide a basis for a fast screening of dopant species for electronic memory devices, or for understanding the general physics involved in the crystallization of doped glasses. PMID- 26426719 TI - Engineering a Constrained Peptidic Scaffold towards Potent and Selective Furin Inhibitors. AB - We report the engineering of the monocyclic sunflower trypsin inhibitor (SFTI 1[1,14]) into a potent furin inhibitor. In a rational approach, we converted the native scaffold of this trypsin-like serine protease inhibitor into a subtilisin like one by substitutions in the canonical and, particularly, in the substrate binding loop. Although the substrate sequence for furin is Arg-X-Arg/Lys-Arg?, the most potent inhibitor had a lysine at position P1. C-terminally truncated versions demonstrated the strongest activity, thus suggesting a lack of interaction between this motif and the surface of furin. This observation was further supported by molecular modeling. With an inhibition constant of 0.49 nm, the engineered peptide H-KRCKKSIPPICF-NH2 is a promising compound for further development of furin inhibitors aimed at controlling the activity of this protease in vitro and in vivo. PMID- 26426729 TI - Atmospheric Deposition of Indium in the Northeastern United States: Flux and Historical Trends. AB - The metal indium is an example of an increasingly important material used in electronics and new energy technologies, whose environmental behavior and toxicity are poorly understood despite increasing evidence of detrimental health impacts and human-induced releases to the environment. In the present work, the history of indium deposition from the atmosphere is reconstructed from its depositional record in an ombrotrophic bog in Massachusetts. A novel freeze coring technique is used to overcome coring difficulties posed by woody roots and peat compressibility, enabling retrieval of relatively undisturbed peat cores dating back more than a century. Results indicate that long-range atmospheric transport is a significant pathway for the transport of indium, with peak concentrations of 69 ppb and peak fluxes of 1.9 ng/cm2/yr. Atmospheric deposition to the bog began increasing in the late 1800s/early 1900s, and peaked in the early 1970s. A comparison of deposition data with industrial production and emissions estimates suggests that both coal combustion and the smelting of lead, zinc, copper, and tin sulfides are sources of indium to the atmosphere in this region. Deposition appears to have decreased considerably since the 1970s, potentially a visible effect of particulate emissions controls instated in North America during that decade. PMID- 26426725 TI - Freestanding Artificial Synapses Based on Laterally Proton-Coupled Transistors on Chitosan Membranes. AB - Freestanding synaptic transistors are fabricated on solution-processed chitosan membranes. A short-term memory to long-term memory transition is observed due to proton-related electrochemical doping under repeated pulse stimulus. Moreover, freestanding artificial synaptic devices with multiple presynaptic inputs are investigated, and spiking logic operation and logic modulation are realized. PMID- 26426730 TI - Effect of friction on the peeling test at zero-degrees. AB - We describe the peeling of an elastomeric strip adhering to a glass plate through van der Waals interactions in the limit of a zero peeling angle. In contrast to classical studies that predict a saturation of the pulling force, in this lap test configuration the force continuously increases, while a sliding front propagates along the tape. The strip eventually detaches from the substrate when the front reaches its end. Although the evolution of the force is reminiscent of recent studies involving a compliant adhesive coupled with a rigid backing, the progression of a front is in contradiction with such a mechanism. To interpret this behavior, we estimate the local shear stress at the interface by monitoring the deformation of the strip. Our results are consistent with a nearly constant friction stress in the sliding zone in agreement with other experimental observations where adhesion and friction are observed. PMID- 26426732 TI - Correction to "Simple, Chemoselective, Catalytic Olefin Isomerization". PMID- 26426731 TI - Sequence and structure-based prediction of fructosyltransferase activity for functional subclassification of fungal GH32 enzymes. AB - Sucrolytic enzymes catalyse sucrose hydrolysis or the synthesis of fructooligosaccharides (FOSs), a prebiotic in human and animal nutrition. FOS synthesis capacity differs between sucrolytic enzymes. Amino-acid-sequence-based classification of FOS synthesizing enzymes would greatly facilitate the in silico identification of novel catalysts, as large amounts of sequence data lie untapped. The development of a bioinformatics tool to rapidly distinguish between high-level FOSs synthesizing predominantly sucrose hydrolysing enzymes from fungal genomic data is presented. Sequence comparison of functionally characterized enzymes displaying low- and high-level FOS synthesis revealed conserved motifs unique to each group. New light is shed on the sequence context of active site residues in three previously identified conserved motifs. We characterized two enzymes predicted to possess low- and high-level FOS synthesis activities based on their conserved motif sequences. FOS data for the enzymes confirmed our successful prediction of their FOS synthesis capacity. Structural comparison of enzymes displaying low- and high-level FOS synthesis identified steric hindrance between nystose and a long loop region present only in low-level FOS synthesizers. This loop is proposed to limit the synthesis of FOS species with higher degrees of polymerization, a phenomenon observed among enzymes displaying low-level FOS synthesis. Conserved sequence motifs surrounding catalytic residues and a distant structural determinant were identifiers of FOS synthesis capacity and allow for functional annotation of sucrolytic enzymes directly from amino acid sequence. The tool presented may also be useful to study the structure-function relationships of beta-fructofuranosidases by identifying mutations present in a group of closely related enzymes displaying similar function. PMID- 26426733 TI - Light emitting diodes based on carbon dots derived from food, beverage, and combustion wastes. AB - One important resource for material synthesis is waste. Utilization of waste as a resource for material synthesis is an environmentally responsible approach that reduces the need for virgin resources and subsequent processing. In this report a method to produce multicolored, luminescent carbon dots (CDs) and subsequent fabrication of light emitting diodes from food, beverage, and combustion wastes, is discussed. Apart from food and beverages, combustion exhaust was also utilized for CDs production. Optical characterization results suggest that CDs from waste food and beverages are more luminescent than those produced from combustion waste. PMID- 26426734 TI - Diversity Oriented Synthesis of Polycyclic Heterocycles through the Condensation of 2-Amino[1,2,4]triazolo[1,5-a]pyrimidines with 1,3-Diketones. AB - The acid-catalyzed condensation between 2-aminosubstituted [1,2,4]triazolo[1,5 a]pyrimidines and their analogues with various saturation of the pyrimidine ring and 1,3-diketones or 1,1,3,3-tetramethoxypropane was evaluated as a new approach for the synthesis of diversely substituted polycyclic derivatives of triazolopyrimidine. The reaction of 4,5,6,7-tetrahydro- or aromatic aminotriazolopyrimidines results in selective formation of the corresponding [1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium salts, and the condensation of substrates containing the 4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine fragment is accompanied by a cascade rearrangement with unusual recyclization of the dihydropyrimidine ring to yield partially hydrogenated [1,2,4]triazolo[1,5-a:4,3 a']dipyrimidin-5-ium or pyrimido[1',2':1,5][1,2,4]triazolo[3,4-b]quinazolin-5-ium salts. The proposed methodology exhibits a wide scope, providing rapid access to polycondensed derivatives of the [1,2,4]triazolo[1,5-a]pyrimidine scaffold. DFT calculations of the Gibbs free energies of possible isomers were performed to rationalize the experimentally observed reactivity and selectivity. PMID- 26426735 TI - Incidences of Unfavorable Events in the Management of Low-Risk Papillary Microcarcinoma of the Thyroid by Active Surveillance Versus Immediate Surgery. AB - BACKGROUND: The incidence of papillary microcarcinoma (PMC) of the thyroid is rapidly increasing globally, making the management of PMC an important clinical issue. Excellent oncological outcomes of active surveillance for low-risk PMC have been reported previously. Here, unfavorable events following active surveillance and surgical treatment for PMC were studied. METHODS: From February 2005 to August 2013, 2153 patients were diagnosed with low-risk PMC. Of these, 1179 patients chose active surveillance and 974 patients chose immediate surgery. The oncological outcomes and the incidences of unfavorable events of these groups were analyzed. RESULTS: In the active surveillance group, 94 patients underwent surgery for various reasons; tumor enlargement and the appearance of novel lymph node metastases were the reasons in 27 (2.3%) and six patients (0.5%), respectively. One of the patients with conversion to surgery had nodal recurrence, and five patients in the immediate surgery group had a recurrence in a cervical node or unresected thyroid lobe. All of these recurrences were successfully treated. None of the patients had distant metastases, and none died of the disease. The immediate surgery group had significantly higher incidences of transient vocal cord paralysis (VCP), transient hypoparathyroidism, and permanent hypoparathyroidism than the active-surveillance group did (4.1% vs. 0.6%, p < 0.0001; 16.7% vs. 2.8%, p < 0.0001; and 1.6% vs. 0.08%, p < 0.0001, respectively). Permanent VCP occurred only in two patients (0.2%) in the immediate surgery group. The proportion of patients on L-thyroxine for supplemental or thyrotropin (TSH)-suppressive purposes was significantly larger in the immediate surgery group than in the active surveillance group (66.1% vs. 20.7%, p < 0.0001). The immediate surgery group had significantly higher incidences of postsurgical hematoma and surgical scar in the neck compared with the active surveillance group (0.5% vs. 0%, p < 0.05; and 8.0% vs. 100%, p < 0.0001, respectively). CONCLUSIONS: The oncological outcomes of the immediate surgery and active surveillance groups were similarly excellent, but the incidences of unfavorable events were definitely higher in the immediate surgery group. Thus, active surveillance is now recommended as the best choice for patients with low-risk PMC. PMID- 26426736 TI - Effect on the Gastrointestinal Absorption of Drugs from Different Classes in the Biopharmaceutics Classification System, When Treating with Liraglutide. AB - Like other GLP-1 receptor agonists used for treatment of type 2 diabetes, liraglutide delays gastric emptying. In this clinical absorption study, the primary objective was to investigate the effect of liraglutide (at steady state) on the rate and/or extent of gastrointestinal (GI) absorption of concomitantly orally taken drugs from three classes of the Biopharmaceutics Classification System (BCS). To provide a general prediction on liraglutide drug-drug absorption interaction, single-dose pharmacokinetics of drugs representing BCS classes II (low solubility-high permeability; atorvastatin 40 mg and griseofulvin 500 mg), III (high solubility-low permeability; lisinopril 20 mg), and IV (low solubility low permeability; digoxin 1 mg) were studied in healthy subjects at steady state of liraglutide 1.8 mg, or placebo, in a two-period crossover design. With liraglutide, the oral drugs atorvastatin, lisinopril, and digoxin showed delayed tmax (by <=2 h) and did not meet the criterion for bioequivalence for Cmax (reduced Cmax by 27-38%); griseofulvin had similar tmax and 37% increased Cmax. Although the prespecified bioequivalence criterion was not met by all drugs, the overall plasma exposure (AUC) of griseofulvin, atorvastatin, lisinopril, and digoxin only exhibited minor changes and was not considered to be of clinical relevance. PMID- 26426737 TI - Moving Toward Economically Sustainable Value-Based Cancer Care in the Academic Setting. PMID- 26426738 TI - Use of broad-spectrum antibiotics in French EDs: different trends for third generation cephalosporins and fluoroquinolones. AB - OBJECTIVES: Third-generation cephalosporins and fluoroquinolones are particularly prone to promoting bacterial resistance. Their use in Emergency Departments (EDs) is poorly known. Our objectives were to assess the use of antibacterial agents in French EDs. METHODS: This study is a retrospective study of antibiotics delivered to the adult units of 11 EDs of French academic centres in 2012, and to six of these EDs between 2009 and 2012. RESULTS: The total antibiotic use was 66.4 defined daily doses (DDD)/1000 ED visits in 2012, and it increased between 2009 and 2012 (yearly estimate, +1.8+/-0.9 DDD/1000 ED visits, P=0.048). The 3GC-FQ class, which grouped third-generation cephalosporins and fluoroquinolones, accounted for 39.2% of the total antibiotic use, and the use of this class of antibiotics was highly variable among EDs (range, 31.6-49.5% of total antibiotic use). The aminopenicillin and beta-lactamase inhibitor/3GC-FQ ratio varied among EDs [median (range), 0.91 (0.52-1.25)]. Between 2009 and 2012, there was a significant decrease in the use of the 3GC-FQ class (yearly estimate, -0.8+/-0.4% of total antibiotic use), antipneumococcal fluoroquinolones (-0.8+/-0.3%) and other fluoroquinolones (-0.9%+/-0.3%), and there was a significant increase in the use of third-generation cephalosporins (+0.7+/-0.3%), aminoglycosides (+0.4+/ 0.1%), imidazole derivatives (+0.4+/-0.1%) and lincosamides (+0.1+/-0.0%). CONCLUSION: Fluoroquinolones and third-generation cephalosporins are widely used in the ED. Their use is highly variable among EDs. Third-generation cephalosporins were increasingly used between 2009 and 2012, whereas the use of fluoroquinolones decreased. Reduced use of cephalosporins in the ED, without increasing fluoroquinolone use, should be aimed at through antibiotic stewardship programs. PMID- 26426739 TI - Epidemiology and aetiology of impaired level of consciousness in prehospital nontrauma patients in an urban setting. AB - BACKGROUND: There is little information on the epidemiology and aetiology of nontraumatic loss of consciousness in patients in the Emergency Department, and this high-risk patient group has been poorly characterized in the prehospital setting as well. The aim of this study was to study the epidemiology and aetiology of nontraumatic impaired level of consciousness among the patients treated by an urban Emergency Medical Service (EMS) system in Finland. METHODS: Data of all emergency calls not related to trauma in an urban EMS system in southern Finland during 2012 were analysed. The inclusion criterion in this study was impaired level of consciousness as identified from the EMS run sheets. Diagnoses made in the receiving facility were cross-checked with the data. RESULTS: During the study period, the EMS was alerted to 22 184 emergency calls. Of these, 306 calls met the inclusion criterion. The included patients could be categorized into four groups: seizures (32%), diabetes (24%), intoxication (17%) and impaired level of consciousness with no other obvious or specific cause (27%). The overall case fatality rate was 8%. CONCLUSION: Of all EMS calls, patients who presented with an impaired level of consciousness represented 1.4% of all patients, but the fatality rate in those who remained with an impaired level of consciousness during the prehospital phase was considerable. Impaired level of consciousness was associated with a multitude of aetiologies, of which seizures were the most common. PMID- 26426740 TI - Catatonia is a systemic medical syndrome. PMID- 26426742 TI - Visual discrimination of dihydroxybenzene isomers based on a nitrogen-doped graphene quantum dot-silver nanoparticle hybrid. AB - A room temperature reducing agent-free strategy for the synthesis of a nitrogen doped graphene quantum dot-silver nanoparticle (N-GQD/AgNP) hybrid was presented. In this strategy, N-GQDs were used as a reducing agent and stabilizer for the formation of the N-GQD/AgNP hybrid, and the formation of the N-GQD/AgNP hybrid may result from the extraordinary reduction properties of N-GQDs, which are attributed to the nature of the surface oxygen-containing functional groups. The N-GQD/AgNP hybrid exhibits good dispersity and outstanding catalytic ability toward the oxidation of catechol (CC) and hydroquinone (HQ) by Ag(+). In the presence of the N-GQD/AgNP hybrid, the reduction of Ag(+) by CC and HQ was improved. CC enhanced the absorbance of the N-GQD/AgNP-Ag(+) system the most, and HQ followed, while resorcinol (RC) had only a little effect on the absorption intensity of the system. Thus, a sensitive and selective colorimetric sensing method based on the N-GQD/AgNP-Ag(+) system was developed for the discrimination of CC, HQ and RC. A good linear relationship was obtained from 0.1 to 15.0 MUM for CC and from 0.3 to 20.0 MUM for HQ. The detection limits of CC and HQ were 0.03 and 0.1 MUM, respectively. In addition, the proposed method also shows a high selectivity for the detection of CC and HQ, and appreciable changes in color of the N-GQD/AgNP-Ag(+) system toward CC, RC and HQ were observed. PMID- 26426741 TI - MYC/BCL6 double-hit lymphoma (DHL): a tumour associated with an aggressive clinical course and poor prognosis. AB - AIMS: Large B cell lymphomas with MYC and BCL6/3q27 rearrangements, designated MYC/BCL6 DHL, are uncommon. Our aim was to better characterize this group of tumours. METHODS AND RESULTS: We studied the clinicopathological features and outcome of 13 patients with MYC/BCL6 DHL and compared this group to a group of 83 MYC/BCL2 DHL patients. There were eight men and five women, with a median age of 63 years. Eleven tumours were classified as diffuse large B cell lymphomas (DLBCL) and two were B cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (BCLU). Immunohistochemical analysis showed that these tumours were positive for BCL6 (100%), BCL2 (eight of 10; 80%) and CD10 (eight of 10; 80%). Nine of 12 (75%) cases had a germinal centre B cell (GCB) immunophenotype; in one case data were incomplete. All patients were treated with chemotherapy. The clinicopathological features of MYC/BCL6 DHL were similar to MYC/BCL2 DHL, except that MYC/BCL6 DHL had a GCB immunophenotype less often. Patients with MYC/BCL6 DHL had a poor overall survival, similar to patients with MYC/BCL2 DHL (P = 0.32). CONCLUSIONS: MYC/BCL6 DHL is an aggressive B cell lymphoma and patients often have an aggressive clinical course and poor prognosis, similar to patients with MYC/BCL2 DHL. PMID- 26426743 TI - Trajectories of alcohol use and consequences in college women with and without depressed mood. AB - College students with depressed mood face heightened risk for experiencing drinking-related negative consequences. However, few studies have examined prospective patterns of alcohol consequences among depressed students. In the present investigation, we assessed how first-year college women's trajectories of heavy episodic drinking (HED) and alcohol consequences differed as a function of depressed mood at college entry. Participants were 233 heavy drinking incoming first-year college females (61% White) at a mid-sized West Coast University. Participants completed an online baseline survey, attended a single brief group intervention session, and completed 1- and 6-month post-intervention follow-up surveys. Depressed mood, alcohol consumption, and alcohol consequences were assessed at each time point. We employed latent growth curve analyses. Females with depressed mood, versus without depressed mood, experienced greater levels of alcohol consequences overall, particularly during transitions to college. However, contrary to hypotheses, participants with depressed mood (vs. without) exhibited significantly steeper declining trends in consequences, controlling for treatment condition, age, race, and ethnicity, and despite stable drinking levels, depressed mood, and use of protective behaviors over time. Potential explanations and suggestions for future research are discussed. PMID- 26426744 TI - Temporal Profile of MicroRNA Expression in Contused Cortex after Traumatic Brain Injury in Mice. AB - MicroRNAs (miRNAs) were recently identified as important regulators of gene expression under a wide range of physiological and pathophysiological conditions. Thus, they may represent a novel class of molecular targets for the management of traumatic brain injury (TBI). In this study, we investigated the temporal profile of miRNA expression during the development of secondary brain damage after experimental TBI. For this purpose, we used a controlled cortical impact model in C57Bl/6 mice (n = 6) to induce a cortical contusion and analyzed miRNA expression in the traumatized cortex by microarray analysis during the development of secondary contusion expansion-i.e., at 1, 6, and 12 h after TBI. Of a total 780 mature miRNA sequences analyzed, 410 were detected in all experimental groups. Of these, 158 miRNAs were significantly upregulated or downregulated in TBI compared with sham-operated animals, and 52 miRNAs increased more than twofold. We validated the upregulation of five of the most differentially expressed miRNAs (miR-21*, miR-144, miR-184, miR-451, miR-2137) and the downregulation of four of the most differentially expressed miRNAs (miR-107, miR-137, miR-190, miR-541) by quantitative polymerase chain reaction (qPCR). miR-2137, the most differentially expressed miRNA after TBI, was further investigated by in situ hybridization and was found to be upregulated in neurons within the traumatic penumbra. This study gives a comprehensive picture of miRNA expression levels during secondary contusion expansion after TBI and may pave the way for the identification of novel targets for the management of brain trauma. PMID- 26426745 TI - Group 13 complexes of dipyridylmethane, a forgotten ligand in coordination chemistry. AB - The reactions of dipyridylmethane (dpma) with group 13 trichlorides were investigated in 1 : 1 and 1 : 2 molar ratios using NMR spectroscopy and X-ray crystallography. With 1 : 1 stoichiometry and Et2O as solvent, reactions employing AlCl3 or GaCl3 gave mixtures of products with the salt [(dpma)2MCl2](+)[MCl4](-) (M = Al, Ga) as the main species. The corresponding reactions in 1 : 2 molar ratio gave similar mixtures but with [(dpma)MCl2](+)[MCl4](-) as the primary product. Pure salts [(dpma)AlCl2](+)[Cl]( ) and [(dpma)AlCl2](+)[AlCl4](-) could be obtained by performing the reactions in CH3CN. In the case of InCl3, a neutral monoadduct (dpma)InCl3 formed regardless of the stoichiometry employed. A neutral adduct (dpma)(BCl3)2 was obtained from the reaction between dpma and BCl3 in Et2O using 1 : 2 stoichiometry. With 1 : 1 molar ratio of reagents, a mixture of products and deprotonation of the methylene bridge in [(dpma)BCl2](+) was observed. The experimental data showed that the structural flexibility of the dpma ligand results in more diverse coordination chemistry with group 13 elements than that observed for bipyridine (bpy), while computational investigations indicated that the investigated metal-ligand interactions are, to a first approximation, independent of the ligand type. Electrochemical and chemical attempts to reduce the cations [(dpma)MCl2](+) showed that, in stark contrast to the chemistry of the related [(bpy)BCl2](+) cation, the neutral radicals [(dpma)MCl2] are extremely unstable. Differences in the redox behaviour of dpma and bpy could be rationalized with the electronic structure of the ligand and that of the methylene bridge in particular. As a whole, the facile reactivity of the methylene bridge in the dpma ligand renders it amenable to further reactivity and functionalization that is not possible in the case of bpy. PMID- 26426746 TI - Holey Graphene as a Weed Barrier for Molecules. AB - We demonstrate the use of "holey" graphene as a mask against molecular adsorption. Prepared porous graphene is transferred onto a Au{111} substrate, annealed, and then exposed to dilute solutions of 1-adamantanethiol. In the pores of the graphene lattice, we find islands of organized, self-assembled molecules. The bare Au in the pores can be regenerated by postdeposition annealing, and new molecules can be self-assembled in the exposed Au region. Graphene can serve as a robust, patternable mask against the deposition of self-assembled monolayers. PMID- 26426747 TI - Plasma Exosomal miRNAs in Persons with and without Alzheimer Disease: Altered Expression and Prospects for Biomarkers. AB - To assess the value of exosomal miRNAs as biomarkers for Alzheimer disease (AD), the expression of microRNAs was measured in a plasma fraction enriched in exosomes by differential centrifugation, using Illumina deep sequencing. Samples from 35 persons with a clinical diagnosis of AD dementia were compared to 35 age and sex matched controls. Although these samples contained less than 0.1 microgram of total RNA, deep sequencing gave reliable and informative results. Twenty miRNAs showed significant differences in the AD group in initial screening (miR-23b-3p, miR-24-3p, miR-29b-3p, miR-125b-5p, miR-138-5p, miR-139-5p, miR-141 3p, miR-150-5p, miR-152-3p, miR-185-5p, miR-338-3p, miR-342-3p, miR-342-5p, miR 548at-5p, miR-659-5p, miR-3065-5p, miR-3613-3p, miR-3916, miR-4772-3p, miR-5001 3p), many of which satisfied additional biological and statistical criteria, and among which a panel of seven miRNAs were highly informative in a machine learning model for predicting AD status of individual samples with 83-89% accuracy. This performance is not due to over-fitting, because a) we used separate samples for training and testing, and b) similar performance was achieved when tested on technical replicate data. Perhaps the most interesting single miRNA was miR-342 3p, which was a) expressed in the AD group at about 60% of control levels, b) highly correlated with several of the other miRNAs that were significantly down regulated in AD, and c) was also reported to be down-regulated in AD in two previous studies. The findings warrant replication and follow-up with a larger cohort of patients and controls who have been carefully characterized in terms of cognitive and imaging data, other biomarkers (e.g., CSF amyloid and tau levels) and risk factors (e.g., apoE4 status), and who are sampled repeatedly over time. Integrating miRNA expression data with other data is likely to provide informative and robust biomarkers in Alzheimer disease. PMID- 26426748 TI - Quantitative-profiling of neurotransmitter abnormalities in the disease progression of experimental diabetic encephalopathy rat. AB - Diabetic encephalopathy (DE) is one of the most prevalent chronic complications of diabetes mellitus (DM), with neither effective prevention nor proven therapeutic regimen. This study aims to uncover the potential dysregulation pattern of the neurotransmitters in a rat model of streptozotocin (STZ)-induced experimental DE. For that purpose, male Sprague-Dawley (SD) rats were treated with a single intraperitoneal injection of STZ. Cognitive performance was detected with the Morris water maze (MWM) test. Serum, cerebrospinal fluid (CSF), and brain tissues were collected to measure the levels of neurotransmitters. Compared with the control rats, the acetylcholine (ACh) levels in serum, CSF, hippocampus, and cortex were all significantly down-regulated as early as 6 weeks in the STZ treatment group. In contrast, the glutamate (Glu) levels were decreased in CSF and the hippocampus, but unaffected in the serum and cortex of STZ-treated rats. As for gamma-aminobutyric acid (GABA), it was down-regulated in serum, but up-regulated in CSF, hippocampus, and the cortex in the STZ-treated group. The mRNA expressions of neurotransmitter-related rate limiting enzymes (including AChE, GAD1, and GAD2) and pro-inflammatory cytokines (including IL 1beta and TNF-alpha) were all increased in the DE rats. Our data suggest that DM induces isoform-dependent and tissue-specific neurotransmitter abnormalities, and that neuroinflammation may underlay the nervous system dysfunction observed in the progression of DE. PMID- 26426757 TI - Ten Simple Rules for Protecting Research Integrity. PMID- 26426758 TI - Imaging the behavior of molecules in biological systems: breaking the 3D speed barrier with 3D multi-resolution microscopy. AB - The overwhelming effort in the development of new microscopy methods has been focused on increasing the spatial and temporal resolution in all three dimensions to enable the measurement of the molecular scale phenomena at the heart of biological processes. However, there exists a significant speed barrier to existing 3D imaging methods, which is associated with the overhead required to image large volumes. This overhead can be overcome to provide nearly unlimited temporal precision by simply focusing on a single molecule or particle via real time 3D single-particle tracking and the newly developed 3D Multi-resolution Microscopy (3D-MM). Here, we investigate the optical and mechanical limits of real-time 3D single-particle tracking in the context of other methods. In particular, we investigate the use of an optical cantilever for position sensitive detection, finding that this method yields system magnifications of over 3000*. We also investigate the ideal PID control parameters and their effect on the power spectrum of simulated trajectories. Taken together, these data suggest that the speed limit in real-time 3D single particle-tracking is a result of slow piezoelectric stage response as opposed to optical sensitivity or PID control. PMID- 26426759 TI - Photohole Induced Corrosion of Titanium Dioxide: Mechanism and Solutions. AB - Titanium dioxide (TiO2) has been extensively investigated as photoanode for water oxidation, as it is believed to be one of the most stable photoanode materials. Yet, we surprisingly found that TiO2 photoanodes (rutile nanowire, anatase nanotube, and P25 nanoparticle film) suffered from substantial photocurrent decay in neutral (Na2SO4) as well as basic (KOH) electrolyte solution. Photoelectrochemical measurements togehter with electron microscopy studies performed on rutile TiO2 nanowire photoanode show that the photocurrent decay is due to photohole induced corrosion, which competes with water oxidation reaction. Further studies reveal that photocurrent decay profile in neutral and basic solutions are fundamentally different. Notably, the structural reconstruction of nanowire surface occurs simultaneously with the corrosion of TiO2 in KOH solution resulting in the formation of an amorphous layer of titanium hydroxide, which slows down the photocorrosion. Based on this discovery, we demonstrate that the photoelectrochemical stability of TiO2 photoanode can be significantly improved by intentionally coating an amorphous layer of titanium hydroxide on the nanowire surface. The pretreated TiO2 photaonode exhibits an excellent photocurrent retention rate of 97% after testing in KOH solution for 72 h, while in comparison the untreated sample lost 10-20% of photocurrent in 12 h under the same measurement conditions. This work provides new insights in understanding of the photoelectrochemical stability of bare TiO2 photoanodes. PMID- 26426761 TI - Staging and therapy for patients with hepatocellular cancer in a defined population from 2000 to 2011 - active palliative treatment improved overall survival. AB - BACKGROUND: Sweden's western region has successively introduced the use of validated non-invasive diagnostic algorithms and treatment allocation for hepatocellular cancer (HCC). The aim was to analyse whether between 2000 and 2011 these changes in strategy had an impact on survival. METHODS: Data concerning diagnosis, survival and treatment for 687 individuals with HCC were retrieved from the regional cancer centre's register and hospital charts. The 12-year period was divided into three four-year cohorts (A-B-C). RESULTS: There was an increase in the crude incidence rate of HCC from 2.7 to 4.2 per 100 000 inhabitants (p < 0.0001) over the period studied. Imaging was increasingly used for diagnosis over the three time periods (1.4%, 7.9% and 29%; p < 0.0001). Alcohol abuse was the most common aetiology for underlying liver disease (42%). The median survival time for all HCC patients improved over time - period A: 3.8 months, period B: 5.1 months and period C: 7.0 months (p = 0.0007). The 209 patients without any underlying liver disease had a worse survival than the 377 with a reported underlying liver disease (p = 0.0001). Active palliative treatment (APT) increased from 17% to 35% during period C (p < 0.0001). For these patients, median survival increased from 8.8 months to 14.2 months. Best supportive care was used less over time. DISCUSSION: Overall survival improved when more patients had APT, mainly trans arterial chemoembolisation (TACE). PMID- 26426760 TI - Emerging roles for the FBXW7 ubiquitin ligase in leukemia and beyond. AB - Protein degradation plays key roles in diverse pathways in cell division, growth and differentiation. Aberrant stabilization of crucial proteins participating in oncogenic pathways is often observed in cancer. The importance of proper protein turnover is exemplified by the SCF(Fbxw7) ubiquitin ligase, which is frequently mutated in human cancer, including T cell acute lymphoblastic leukemia. Recent studies have revealed novel substrates of Fbxw7 and shed light on its role on differentiation of stem cells and expansion of stem-cell-like cells driving tumorigenesis. Detailed understanding of the contribution of the Fbxw7-regulated network of proteins in initiation and progression of cancer will facilitate the identification of candidate intervention targets in human cancer. PMID- 26426762 TI - Skin self-examination behaviors among individuals diagnosed with melanoma. AB - Many melanoma patients do not regularly perform thorough skin self-examinations. We examined the extent to which melanoma patients conduct thorough skin self examination, how they perform skin self-examination, and their related knowledge and self-efficacy. A sample of 176 individuals (61.5% response rate) diagnosed with primary pathologic stage 0-III cutaneous malignant melanoma at a single cancer center completed a written or telephone survey regarding their skin self examination behaviors and associated factors. Almost all participants (98.9%) reported their race as white. Almost three-quarters (71.6%) of participants reported doing an examination in the past 2 months. However, only 14.2% had examined all areas of the body in the past 2 months. Few participants reported always using a full-length mirror (13.4%), hand-held mirror (11.3%), or having someone help (9.2%) when doing an examination. Having a higher level of education, greater knowledge of the ABCDE rule for detecting potential melanoma, higher skin self-examination self-efficacy, being shown how to do skin self examination, and being shown what a suspicious mole would look like were all significantly associated with conducting more thorough skin self-examination. Most melanoma patients do not engage in regular, thorough skin self-examination, and when they do examine their skin they typically do not sufficiently utilize tools and techniques to facilitate a thorough examination and tracking of potentially suspicious moles. Efforts to promote skin self-examination among melanoma patients should focus on increasing knowledge and self-efficacy and providing education about the why, when, and how of conducting self-examination and mole tracking. PMID- 26426763 TI - Computer-assisted melanoma diagnosis: a new integrated system. AB - In dermatology, attempts at synergy between man and machine have mainly been made to improve melanoma diagnosis. The aim of the present study was to test an 'integrated digital dermoscopy analysis' (i-DDA) system with a series of melanocytic lesions that were benign and malignant in nature, and to evaluate its discriminating power with respect to histological diagnosis. In a retrospective study we used an i-DDA system to evaluate a series of 856 excised, clinically atypical pigmented skin lesions (584 benign and 272 malignant). The system evaluated 48 parameters to be studied as possible discriminant variables, grouped into four categories (geometries, colours, textures and islands of colour) integrated with three personal metadata items (sex, age and site of lesion) and presence/absence of three dermoscopic patterns (regression structures, blue-white veil and polymorphic vascular structures). Stepwise multivariate logistic regression of i-DDA data selected nine variables with the highest possible discriminant power. At the end of the stepwise procedure the percentage of cases correctly classified by i-DDA was 89.2% (100% sensitivity and 40.8% specificity). The limitations of the study included those associated with a retrospective design and the 'a priori' exclusion of nonmelanocytic skin lesions. By incorporating numerical digital features with personal data and some dermoscopic patterns into the learning process, the proposed i-DDA improved the performance of assisted melanoma diagnosis, with the advantage that our results can be objectively repeated in any other clinical setting. PMID- 26426764 TI - Integrating first-line treatment options into clinical practice: what's new in advanced melanoma? AB - Melanoma remains a serious form of skin cancer in Europe and worldwide. Localized, early-stage melanomas can usually be treated with surgical excision. However, the prognosis is poorer for patients with advanced disease. Before 2011, treatment for advanced melanoma included palliative surgery and/or radiotherapy, and chemotherapy with or without immunotherapy, such as interleukin-2. As none of these treatments had shown survival benefits in patients with advanced melanoma, European guidelines had recommended that patients be entered into clinical trials. The lack of approved first-line options and varying access to clinical trials meant that European clinicians relied on experimental regimens and chemotherapy-based treatments when no other options were available. Since 2011, ipilimumab, an immuno-oncology therapy, and vemurafenib and dabrafenib, targeted agents that inhibit mutant BRAF, have been approved by the European Medicines Agency for the treatment of advanced melanoma. More recently, the MEK inhibitor, trametinib, received European marketing authorization for use in patients with BRAF mutation-positive advanced melanoma. In 2014, the anti-PD-1 antibody nivolumab was approved as a first-line therapy in Japan. Whereas nivolumab and another anti-PD-1 antibody, pembrolizumab, were approved as second-line therapies in the USA, their recent approval in Europe are for first-line use based on new clinical trial data in this setting. Together these agents are changing clinical practice and making therapeutic decisions more complex. Here, we discuss current and emerging therapeutic options for the first-line treatment of advanced melanoma, and how these therapies can be optimized to provide the best possible outcomes for patients. PMID- 26426765 TI - Decreased expression of class III beta-tubulin is associated with unfavourable prognosis in patients with malignant melanoma. AB - Class III beta-tubulin (TUBB3) has been recognized as being associated with resistance to taxane-based regimens in several cancers. However, little is known about the clinicopathological significance of TUBB3 expression in patients with cutaneous malignant melanoma. The aim of this study was to examine the prognostic significance of TUBB3 expression in cutaneous malignant melanoma. A total of 106 patients with surgically resected cutaneous malignant melanoma were assessed. Tumour sections were immunohistochemically stained for TUBB3, Ki-67 and microvessel density with CD34. TUBB3 was highly expressed in 80% (85/106) of patients. No statistically significant relationship was observed between the high expression of TUBB3 and any variables. On univariate analysis, ulceration, disease stage, TUBB3 and CD34 revealed a significant relationship with overall survival and progression-free survival. Multivariate analysis confirmed that a low TUBB3 expression was an independent prognostic factor for poor prognosis of cutaneous malignant melanoma. The decreased expression of TUBB3 could be a significant marker for predicting unfavourable prognosis in patients with cutaneous malignant melanoma. PMID- 26426766 TI - Interaction of NBD-labelled fatty amines with liquid-ordered membranes: a combined molecular dynamics simulation and fluorescence spectroscopy study. AB - A complete homologous series of fluorescent 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD) labelled fatty amines of varying alkyl chain lengths, NBD-Cn, inserted in 1 palmitoyl, 2-oleoyl-sn-glycero-3-phosphocholine (POPC) or N-palmitoyl sphingomyelin (SpM) bilayers, with 50 mol% and 40 mol% cholesterol (Chol), respectively, was studied using atomistic molecular dynamics simulations. For all amphiphiles in both bilayers, the NBD fluorophore locates at the interface, in a more external position than that previously observed for pure POPC bilayers. This shallower location of the NBD group agrees with the lower fluorescent quantum yield, shorter fluorescence lifetime, and higher ionisation constants (smaller pKa) determined experimentally. The more external location is also consistent with the changes measured in steady-state fluorescence anisotropy from POPC to POPC/Chol (1 : 1) vesicles. Accordingly, the equilibrium location of the NBD group within the various bilayers is mainly dictated by bilayer compositions, and is mostly unaffected by the length of the attached alkyl chain. Similarly to the behaviour observed in POPC bilayers, the longer-chained NBD-Cn amphiphiles show significant mass density near the mixed bilayers' midplanes, and the alkyl chains of the longer derivatives, mainly NBD-C16, penetrate the opposite bilayer leaflet to some extent. However, this effect is quantitatively less pronounced in these ordered bilayers than in POPC. Similarly to POPC bilayers, the effects of these amphiphiles on the structure and dynamics of the host lipid were found to be relatively mild, in comparison with acyl-chain phospholipid analogues. PMID- 26426767 TI - Correction to Fidelity of RNA Polymerase II Transcription: Role of Rpb9 in Error Detection and Proofreading. PMID- 26426768 TI - Affair With Triphasic Waves-Their Striking Presence, Mysterious Significance, and Cryptic Origins: What are They? AB - Triphasic waves, which have been recorded in the EEG of encephalopathy for more than 50 years, remain clearly identifiable but historically purportedly of uncertain significance. Initially described with liver failure and high serum ammonias, they came to be reported in an ever-expanding list of metabolic, toxic, and structural conditions. Often a dynamic finding (in which the occurrence of triphasic waves might increase or decrease with stimulation or arousal of the patient during EEG), there has been increasing insight into their correlation with multiple concurrent conditions, including subcortical white-matter disease, infections and metabolic disturbances, and their prognostic significance. There are sparse data, but there is active controversy into their confusion for, or occurrence in, nonconvulsive status epilepticus. This review and commentary discuss our current understanding of triphasic waves and the newer areas of contention surrounding this mysterious EEG morphology. PMID- 26426769 TI - Day-Night Patterns of Epileptiform Activity in 65 Patients With Long-Term Ambulatory Electrocorticography. AB - PURPOSE: To characterize cyclic day-night patterns of electrocorticographic epileptiform activity (EA) in patients with focal onset seizures. METHODS: Epileptiform events as defined by the physician (also termed more generally as "epileptiform activity" or EA) were recorded in 65 patients with partial onset (also referred to as "focal onset") seizures using the RNS System, which includes a cranially implanted neurostimulator connected to 1 or two 4-contact leads placed at the seizure focus. The neurostimulator is programmed to detect specific patterns of electrocorticographic activity and to provide responsive stimulation. The 24-hour periodicity of detections of EA was analyzed for individual patients and for subgroups of patients according to the type of EA, laterality, lobe of onset, and whether the onset was neocortical or hippocampal. The time of day when peaks in EA occurred was also analyzed. RESULTS: There were robust circadian patterns of detections of EA in most patients, with a primary peak in detections at night and a secondary peak in the late afternoon in some cases. Subset analyses were performed by lobe, region of the brain, and type of cortex (neocortical vs. hippocampal); significant circadian rhythmicity was present in all subsets. CONCLUSIONS: This is the first report of circadian cycles of EA as assessed through chronic ambulatory electrocorticographic recordings in adults with focal onset seizures. Epileptiform activity displayed circadian patterns in the majority of these patients. These findings suggest that epilepsy therapies might be optimized by adjusting the timing of therapy according to each patient's unique circadian pattern of EA. PMID- 26426770 TI - Clinical and Imaging Correlations of Generalized Hypersynchronous Alpha Activity in Human EEG Recordings, During Alertness. AB - PURPOSE: In a considerable percentage of individuals with a detectable alpha rhythm in their EEG, bursts of generalized hypersynchronous alpha activity (GHSAA) may occur, during alertness. The aim of this study was to examine whether appearance of GHSAA, which probably generates from transcortical circuitry, shows any correlation with demographic characteristics, underlying normal or abnormal pathophysiology, or substances in use. METHODS: The authors retrospectively reviewed 441 EEG recordings performed in their laboratory during a 1-year period for presence of GHSAA, concomitantly collecting data that concerned symptoms, diagnosis, imaging, medication, and demographics. Recordings in mental states other than alertness were excluded from the sample. RESULTS: Generalized hypersynchronous alpha activity was found in 22.95% of the study population. Its occurrence was diminished in male gender (P < 0.001), older age (Kendall tau, 0.16; P < 0.0001), and disorders involving structural abnormalities like brain lesions or neurodegeneration (P < 0.02). Dementia, Parkinson disease, and psychoses showed individually a trend towards lower GHSAA presence. CONCLUSIONS: In the sample, the presence of GHSAA was commonly observed in the cohort of patients without abnormalities in their neuroimaging studies. Generalized hypersynchronous alpha activity is a finding of youth and requires a properly functioning cerebral cortex in order to emerge. Female preponderance may signify underlying trangender differences in alpha rhythm generators. These preliminary results indicate that the significance of GHSAA alterations deserves more thorough evaluation in larger groups of patients suffering from a variety of different neuropsychiatric disorders. PMID- 26426771 TI - Author Response: Concerns About Utility and Cost-Effectiveness of Continuous Critical-Care EEG. PMID- 26426772 TI - Author Response: The Timing of Continuous EEG in Critically Ill Patients: Stat? ASAP? Routine? PMID- 26426773 TI - Dengue in the State of Rio Grande do Norte, Brazil, 2010-2012. AB - OBJECTIVE: To present results of virological surveillance and epidemiological aspects of dengue in the State of Rio Grande do Norte, Brazil. METHODS: A total of 1581 cases, reported from 2010 to 2012 at various health centres in the state, were analysed by viral isolation and/or RT-PCR for viral detection and typing. To identify whether different genotypes were circulating in the state during this period, sequencing of the complete E gene for DENV (1485 bp in length) was performed directly from patient serum samples. RESULTS: All four serotypes of dengue virus circulated in Rio Grande do Norte, with the introduction of DENV-4 in the state in 2011. In 2012, DENV-4 represented 100% of positive confirmed cases. 53.97% of cases occurred in Natal. Case numbers peaked in April (21%) and May (23%). Genetic characterisation of circulating strains confirmed the circulation of genotypes V, south-east Asian/American and II, respectively, for DENV-1, DENV-2 and DENV-4. CONCLUSIONS: This work furthers a better understanding of dengue viruses in the State of Rio Grande do Norte. Strengthening control efforts in the region is important considering the impact of dengue. PMID- 26426777 TI - Single-Molecule Spin Switch Based on Voltage-Triggered Distortion of the Coordination Sphere. AB - Here, we report on a new single-molecule-switching concept based on the coordination-sphere-dependent spin state of Fe(II) species. The perpendicular arrangement of two terpyridine (tpy) ligands within heteroleptic complexes is distorted by the applied electric field. Whereas one ligand fixes the complex in the junction, the second one exhibits an intrinsic dipole moment which senses the E field and causes the distortion of the Fe(II) coordination sphere triggering the alteration of its spin state. A series of complexes with different dipole moments have been synthesized and their transport features were investigated via mechanically controlled break-junctions. Statistical analyses support the hypothesized switching mechanism with increasing numbers of junctions displaying voltage-dependent bistabilities upon increasing the Fe(II) complexes' intrinsic dipole moments. A constant threshold value of the E field required for switching corroborates the mechanism. PMID- 26426778 TI - Fetal cerebellar hemorrhage: three cases with postnatal follow-up. PMID- 26426779 TI - Is genomic medicine finally coming of age for the diagnosis of pneumonia? PMID- 26426780 TI - The evidence for long-term benefits of restoration of CFTR function continues to grow. PMID- 26426781 TI - A milestone in the investigation of population-wide effects of vaccines. PMID- 26426782 TI - Bone morphogenetic protein receptor type II and inflammation are bringing old concepts into the new pulmonary arterial hypertension world. PMID- 26426783 TI - Is the kidney yet another potential end-organ casualty of obstructive sleep apnea? PMID- 26426784 TI - Update in Mycobacterium tuberculosis lung disease 2014. PMID- 26426786 TI - Surgical masks reduce airborne spread of Pseudomonas aeruginosa in colonized patients with cystic fibrosis. PMID- 26426787 TI - Risk factors for frequent severe exacerbations in late-onset eosinophilic asthma. PMID- 26426785 TI - An official American Thoracic Society/American College of Chest Physicians policy statement: implementation of low-dose computed tomography lung cancer screening programs in clinical practice. AB - RATIONALE: Annual low-radiation-dose computed tomography (LDCT) screening for lung cancer has been shown to reduce lung cancer mortality among high-risk individuals and is now recommended by multiple organizations. However, LDCT screening is complex, and implementation requires careful planning to ensure benefits outweigh harms. Little guidance has been provided for sites wishing to develop and implement lung cancer screening programs. OBJECTIVES: To promote successful implementation of comprehensive LDCT screening programs that are safe, effective, and sustainable. METHODS: The American Thoracic Society (ATS) and American College of Chest Physicians (ACCP) convened a committee with expertise in lung cancer screening, pulmonary nodule evaluation, and implementation science. The committee reviewed the evidence from systematic reviews, clinical practice guidelines, surveys, and the experience of early-adopting LDCT screening programs and summarized potential strategies to implement LDCT screening programs successfully. MEASUREMENTS AND MAIN RESULTS: We address steps that sites should consider during the main three phases of developing an LDCT screening program: planning, implementation, and maintenance. We present multiple strategies to implement the nine core elements of comprehensive lung cancer screening programs enumerated in a recent ACCP/ATS statement, which will allow sites to select the strategy that best fits with their local context and workflow patterns. Although we do not comment on cost-effectiveness of LDCT screening, we outline the necessary costs associated with starting and sustaining a high-quality LDCT screening program. CONCLUSIONS: Following the strategies delineated in this policy statement may help sites to develop comprehensive LDCT screening programs that are safe and effective. PMID- 26426788 TI - The forgotten era of medical discoveries. PMID- 26426789 TI - The lung immune response to bacteria in chronic obstructive pulmonary disease. PMID- 26426790 TI - Reply: the lung immune response to bacteria in chronic obstructive pulmonary disease. PMID- 26426791 TI - Understanding the anatomic basis for obstructive sleep apnea syndrome in adolescents: how to proceed? PMID- 26426792 TI - Reply: understanding the anatomic basis for obstructive sleep apnea syndrome in adolescents: how to proceed? PMID- 26426793 TI - Continuous positive airway pressure-emergent protracted central apneas with profound oxygen desaturation. PMID- 26426794 TI - What is lung transplantation? PMID- 26426795 TI - IL-2 and IL-15 regulate CD8+ memory T-cell differentiation but are dispensable for protective recall responses. AB - The ability to mount effective secondary responses is a cardinal feature of memory CD8(+) T cells. An understanding of the factors that regulate the generation and recall capacities of memory T cells remains to be ascertained. Several cues indicate that two highly related cytokines, IL-2 and IL-15, share redundant functions in this process. To establish their combined roles in memory CD8(+) T-cell development, maintenance, and secondary responses, we compared the outcome of adoptively transferred IL2Rbeta(+/-) or IL2Rbeta(-/-) CD8(+) T cells after an acute viral infection in mice. Our results demonstrate that both IL-2 and IL-15 signals condition the differentiation of primary and secondary short lived effector cells by altering the transcriptional network governing lineage choices. These two cytokines also regulate the homeostasis of the memory T-cell pool, with effector memory CD8(+) T cells being the most sensitive to these two interleukins. Noticeably, the inability to respond to both cytokines limits the proliferation and survival of primary and secondary effectors cells, whereas it does not preclude potent cytotoxic functions and viral control either initially or upon rechallenge. Globally, these results indicate that lack of IL-2 and IL-15 signaling modulates the CD8(+) T-cell differentiation program but does not impede adequate effector functions. PMID- 26426796 TI - Similar Reduction of Cholesterol-Adjusted Vitamin E Serum Levels in Simple Steatosis and Non-Alcoholic Steatohepatitis. AB - OBJECTIVES: Reduced vitamin E levels have been reported in patients with non alcoholic steatohepatitis (NASH), but no conclusive data on patients with simple steatosis (SS) are available. Aim of this study was to investigate the association between serum vitamin E levels and SS. METHODS: A cohort of 312 patients with cardio-metabolic risk factors was screened for liver steatosis by ultrasonography (US). We reasonably classified as SS patients with US-fatty liver, normal liver function tests (LFTs) and with Cytokeratin 18 <246 mIU/ml. Liver biopsy was performed in 41 patients with US-fatty liver and persistent elevation of LFTs (>6 months). Serum cholesterol-adjusted vitamin E (Vit E/chol) levels were measured. RESULTS: Mean age was 53.9+/-12.5 years and 38.4% were women. Non-alcoholic fatty liver disease (NAFLD) was detected at US in 244 patients; of those 39 had biopsy-proven NASH and 2 borderline NASH. Vit E/chol was reduced in both SS (3.4+/-2.0, P<0.001), and NASH (3.5+/-2.1, P=0.006) compared with non-NAFLD patients (4.8+/-2.0 MUmol/mmol chol). No difference was found between SS and NASH (P=0.785). After excluding patients with NASH, a multivariable logistic regression analysis found that Vit E/chol (odds ratio (OR): 0.716, 95% confidence interval (CI) 0.602-0.851, P<0.001), alanine aminotransferase (ALT, OR: 1.093, 95% CI 1.029-1.161, P=0.004), body mass index (OR: 1.162, 95% CI 1.055-1.279, P=0.002) and metabolic syndrome (OR: 5.725, 95% CI 2.247-14.591, P<0.001) were factors independently associated with the presence of SS. CONCLUSIONS: Reduced vitamin E serum levels are associated with SS, with a similar reduction between patients with SS and NASH, compared with non-NAFLD patients. Our findings suggest that the potential benefit of vitamin E supplementation should be investigated also in patients with SS. PMID- 26426797 TI - Prenatal diagnosis and outcomes of fetal teratomas. AB - PURPOSE: Our aim was to evaluate the diagnostic performance of ultrasonography (US) in the prenatal identification of teratomas and the perinatal outcome of the fetuses with those teratomas. METHODS: In this retrospective case series study, we searched the archives using the keywords "fetal mass" or "fetal tumor" or "fetal teratoma" and "sacrococcygeal teratoma," diagnosed between 2009 and 2014, within the US database of our center. RESULTS: One hundred seven fetuses were prenatally diagnosed as having a cystic or solid mass, tumor, or teratoma. Nineteen of those cases were diagnosed prenatally as having fetal teratoma, but that diagnosis could not be verified in three cases. In one fetus, the prenatal diagnosis could not be confirmed. The sensitivity of US in identifying fetal teratoma was 100% and the false-positive rate, 3.3%. Six pregnancies complicated by a fetal teratoma were terminated. A normal karyotype was identified in all fetuses that underwent karyotyping. Among the nine women who continued their pregnancy, polyhydramnios was identified in four fetuses; although high-output heart failure was also identified in two of those fetuses during prenatal follow up, none developed hydrops. On delivery, nine infants were born alive, but three (33.3%) of them died within the early neonatal period. CONCLUSIONS: US has very high sensitivity and low false-positive rates in identifying fetal teratoma prenatally. The risk of chromosomal abnormalities is very low in fetuses with teratoma, and their prognosis depends on the location and size of the tumor and any associated perinatal complications. PMID- 26426798 TI - A Multiple Regression Approach to Normalization of Spatiotemporal Gait Features. AB - Normalization of gait data is performed to reduce the effects of intersubject variations due to physical characteristics. This study reports a multiple regression normalization approach for spatiotemporal gait data that takes into account intersubject variations in self-selected walking speed and physical properties including age, height, body mass, and sex. Spatiotemporal gait data including stride length, cadence, stance time, double support time, and stride time were obtained from healthy subjects including 782 children, 71 adults, 29 elderly subjects, and 28 elderly Parkinson's disease (PD) patients. Data were normalized using standard dimensionless equations, a detrending method, and a multiple regression approach. After normalization using dimensionless equations and the detrending method, weak to moderate correlations between walking speed, physical properties, and spatiotemporal gait features were observed (0.01 < |r| < 0.88), whereas normalization using the multiple regression method reduced these correlations to weak values (|r| <0.29). Data normalization using dimensionless equations and detrending resulted in significant differences in stride length and double support time of PD patients; however the multiple regression approach revealed significant differences in these features as well as in cadence, stance time, and stride time. The proposed multiple regression normalization may be useful in machine learning, gait classification, and clinical evaluation of pathological gait patterns. PMID- 26426799 TI - Patterns of Sensitization to Inhalant Allergens in Japanese Lower-Grade Schoolchildren and Related Factors. AB - OBJECTIVE: This study clarified sensitization patterns to house dust mite (HDM) and Japanese cedar pollen (JCP) in Japanese lower-grade schoolchildren. We also explored factors associated with allergic sensitization. METHODS: This cross sectional study used a database from the Study on Respiratory Disease and Automobile Exhaust (SORA), a Japanese health study project. The subjects comprised 8,815 pupils aged 6-9 years. We obtained the distribution of HDM- and JCP-specific IgE, respectively, as a marker of sensitization. To determine factors associated with sensitization, we used logistic regression and calculated adjusted odds ratios (AORs) for the relative prevalence of sensitization. The cut off point for specific IgE levels was 0.35 kU/l. RESULTS: Sensitization to HDM and JCP was detected in 51 and 39% of subjects, respectively, occurring more often in boys and at older ages. In addition, AORs of sensitization to HDM/JCP were higher in subjects with a history of bronchitis, parental asthma, parental atopic eczema and parental pollinosis. In contrast, AORs for sensitization were lower in those subjected to maternal passive smoking as well as among boys with pets. AORs of sensitization to JCP alone were lower in those with a history of otitis media, those who had been bottle milk fed, and those who were not the firstborn and who lived near a busy road. CONCLUSION: Sensitization to HDM and JCP was detected in 51 and 39% of lower-grade schoolchildren, respectively. PMID- 26426800 TI - Complete Plastid Genome Sequence of the Brown Alga Undaria pinnatifida. AB - In this study, we fully sequenced the circular plastid genome of a brown alga, Undaria pinnatifida. The genome is 130,383 base pairs (bp) in size; it contains a large single-copy (LSC, 76,598 bp) and a small single-copy region (SSC, 42,977 bp), separated by two inverted repeats (IRa and IRb: 5,404 bp). The genome contains 139 protein-coding, 28 tRNA, and 6 rRNA genes; none of these genes contains introns. Organization and gene contents of the U. pinnatifida plastid genome were similar to those of Saccharina japonica. There is a co-linear relationship between the plastid genome of U. pinnatifida and that of three previously sequenced large brown algal species. Phylogenetic analyses of 43 taxa based on 23 plastid protein-coding genes grouped all plastids into a red or green lineage. In the large brown algae branch, U. pinnatifida and S. japonica formed a sister clade with much closer relationship to Ectocarpus siliculosus than to Fucus vesiculosus. For the first time, the start codon ATT was identified in the plastid genome of large brown algae, in the atpA gene of U. pinnatifida. In addition, we found a gene-length change induced by a 3-bp repetitive DNA in ycf35 and ilvB genes of the U. pinnatifida plastid genome. PMID- 26426801 TI - Site-adapted admixed tree species reduce drought susceptibility of mature European beech. AB - Some forest-related studies on possible effects of climate change conclude that growth potential of European beech (Fagus sylvatica L.) might be impaired by the predicted increase in future serious drought events during the growing season. Other recent research suggests that not only multiyear increment rates but also growth resistance and recovery of beech during, respectively, after dry years may differ between pure and mixed stands. Thus, we combined dendrochronological investigations and wood stable isotope measurements to further investigate the impact of neighborhood diversity on long-term performance, short-term drought response and soil water availability of European beech in three major geographic regions of Germany. During the last four decades, target trees whose competitive neighborhood consisted of co-occurring species exhibited a superior growth performance compared to beeches in pure stands of the same investigation area. This general pattern was also found in exceptional dry years. Although the summer droughts of 1976 and 2003 predominantly caused stronger relative growth declines if target trees were exposed to interspecific competition, with few exceptions they still formed wider annual rings than beeches growing in close-by monocultures. Within the same study region, recovery of standardized beech target tree radial growth was consistently slower in monospecific stands than in the neighborhood of other competitor species. These findings suggest an improved water availability of beech in mixtures what is in line with the results of the stable isotope analysis. Apparently, the magnitude of competitive complementarity determines the growth response of target beech trees in mixtures. Our investigation strongly suggest that the sensitivity of European beech to environmental constrains depends on neighborhood identity. Therefore, the systematic formation of mixed stands tends to be an appropriate silvicultural measure to mitigate the effects of global warming and droughts on growth patterns of Fagus sylvatica. PMID- 26426802 TI - Implementation of Web-Based Respondent Driven Sampling among Men Who Have Sex with Men in Sweden. AB - BACKGROUND: Respondent driven sampling (RDS) was designed to study 'hidden' populations, for which there are no available sampling frame. RDS has been shown to recruit far into social networks of the study population and achieve unbiased estimates when certain assumptions are fulfilled. Web-based respondent driven sampling (WebRDS) has been implemented among MSM in Vietnam and produced a sufficient sample of MSM. In order to see if WebRDS could work in a 'hidden' population in a high-income setting, we performed a WebRDS among MSM in Sweden to study a sensitive topic, sexual risk behaviour for HIV/STI and Internet use. METHODS: A cross-sectional survey was implemented between July 11, 2012 and January 21, 2013 by using a WebRDS software. Men, fifteen years old or above, who reported having ever had sex with another man were included. The web-survey explored sociodemographics, sexual risk behaviour for HIV/STI and Internet use. RESULTS: The WebRDS process created a sample of 123 eligible respondents. The mean age among participants was 32 years old. All respondents reported having had unprotected anal intercourse (UAI) with at least one regular and one casual sex partner during the last 12 months. On average participants reported having had UAI with three casual sexual partners and in total having had seven casual sex partners during the last 12 months. CONCLUSION: The WebRDS produced a sample of Internet-using MSM in Sweden who all reported sexual risk behaviour for HIV/STI during the last 12 months. It holds promise for future online studies among MSM and a possibility to reach MSM at risk for HIV/STI with interventions or information. Some challenges were found including short recruitment chains, and further research need to address how to optimize WebRDS online recruitment methods in high income settings. PMID- 26426803 TI - Trends in Incidence of Stroke and Transition of Stroke Subtypes in Rural Tianjin China: A Population-Based Study from 1992 to 2012. AB - OBJECTIVES: The incidence of ischemic stroke has increased and that of hemorrhagic stroke has decreased in urban China; however, the trends in rural areas are unknown. We aimed to explore the secular trends in incidence and transition of stroke subtypes among rural Chinese. METHODS: This was a population based stroke surveillance through the Tianjin Brain Study. A total of 14,538 residents in a township of Ji County in Tianjin, China participated in the study since 1985. We investigated the age-standardized stroke incidence (sex-specific, type-specific, and age-specific), the annual proportion of change in the incidence of stroke, and the proportion of intracerebral hemorrhage in the periods 1992-1998, 1999-2005, and 2006-2012, because the neuroimaging technique was available since 1992 in this area. RESULTS: The age-standardized incidence per 100,000 person-years increased significantly for both intracerebral hemorrhage (37.8 in 1992-1998, 46.5 in 1999-2005, and 76.5 in 2006-2012) and ischemic stroke (83.9 in 1992-1998, 135.3 in 1999-2005, and 238.0 in 2006-2012). The age-standardized incidence of first-ever stroke increased annually by 4.9% for intracerebral hemorrhage and by 7.3% for ischemic stroke. The greatest increase was observed in men aged 45-64 years for both stroke types (P < 0.001). The proportion of intracerebral hemorrhage was stable overall, increased among men aged 45-64 years, and decreased among men aged >=65 years. The average age of intracerebral hemorrhage in men reduced by 7.5 years from 1992 to 2012. CONCLUSION: The age-standardized incidence of main stroke subtypes increased significantly in rural China over the past 21 years; the overall proportion of intracerebral hemorrhage was stable, but the incidence increased significantly among middle-aged men. These findings imply that it is crucial to control stroke risk factors in middle-aged men for stroke prevention in future decades. PMID- 26426804 TI - The Use of Solitaire AB Stents in Coil Embolization of Wide-Necked Cerebral Aneurysms. AB - BACKGROUND: The Solitaire AB stent is one of many assistant stents used for treating wide-necked cerebral aneurysm, and has been used since 2003. However, large sample studies on its safety and effectiveness are lacking. The objective of this study was to evaluate the effectiveness and safety of the Solitaire AB stent in the coil embolization of wide-necked cerebral aneurysms. METHODS: Retrospective review of the clinical and image data of 116 patients with wide necked cerebral aneurysms who had been enrolled at six interventional neuroradiology centers from February 2010 to February 2014 and had been treated by coil embolization; in total, 120 Solitaire AB stents were used. The degree of aneurysm occlusion was examined using digital subtraction angiography (DSA) immediately after the procedure and during follow-up, and was graded using the modified Raymond classification. We also observed complications to evaluate the safety and effectiveness of this therapy. RESULTS: The 120 Solitaire AB stents (4 mm * 15 mm, four stents; 4 mm * 20 mm, 16 stents; 6 mm * 20 mm, 36 stents; 6 mm * 30 mm, 64 stents) were inserted to treat 120 wide-necked cerebral aneurysms. All stents were inserted successfully. DSA immediately post-surgery revealed 55 cases of complete occlusion, 59 cases of neck remnant, and six cases of aneurysm remnant. Perioperatively, there were four cases of hemorrhage and four cases of stent thrombosis. The follow-up spanned 3-37 months; of 92 patients examined by DSA at the 6-month follow up, 12 had disease recurrence. CONCLUSIONS: The Solitaire AB stent is effective with a good technical success rate and short-term effect for assisting coil embolization of wide-necked cerebral aneurysms. PMID- 26426805 TI - The Association between Insomnia and Insomnia Treatment Side Effects on Health Status, Work Productivity, and Healthcare Resource Use. AB - The aims of this study were (1) to compare health outcomes (i.e., health-related quality of life [HRQoL], productivity at work, and healthcare resource use visits) between those with insomnia and non-insomnia controls, (2) to compare health outcomes between those treated for insomnia and non-insomnia controls, and (3) to assess the prevalence of side effects of insomnia medications and their relationship with health outcomes. Data from the 2013 US (N = 75,000) and 5EU (N = 62,000) National Health and Wellness Survey (NHWS) were used. The NHWS is a patient-reported survey administered to a demographically representative sample of adults. Those who met DSM-V criteria for insomnia and, separately, those treated for insomnia were compared with equivalently sized control groups who were identified using a propensity score matching method. Outcomes included HRQoL (Short Form 36v2), productivity at work (Work Productivity and Activity Impairment-General Health questionnaire), and healthcare resource use visits in the past 6 months and were analyzed using one-way ANOVAs. Among those with treated insomnia, those with and without side effects were compared on health outcomes using general linear models controlling for confounding variables. Patients with insomnia (n = 4147) and treated insomnia (n = 2860) in the 5EU reported significantly worse HRQoL than controls (health utilities: 0.60 vs. 0.74; 0.60 vs. 0.74, respectively), greater overall work impairment (38.74% vs. 14.86%; 39.50% vs. 15.66%), and more physician visits in the past 6 months (9.10 vs. 4.08; 9.58 vs. 4.11). Similar findings were observed in the US. Among those treated for insomnia, 13.56% and 24.55% in the US and 5EU, respectively, were non adherent due to side effects. In the US, non-adherence was associated with significantly worse HRQoL (health utilities: 0.60 vs. 0.64, p <.05) and greater overall work impairment (37.71% vs. 29.08%, p <.05), among other significant differences. These relationships were not significant in the 5EU. A significant burden of insomnia was observed in both the US and 5EU, and the association remained even after treatment. Non-adherence due to side effects was common and, in the case of the US, associated with significantly poorer health outcomes. PMID- 26426806 TI - The Foreign Body Giant Cell Cannot Resorb Bone, But Dissolves Hydroxyapatite Like Osteoclasts. AB - Foreign body multinucleated giant cells (FBGCs) and osteoclasts share several characteristics, like a common myeloid precursor cell, multinuclearity, expression of tartrate-resistant acid phosphatase (TRAcP) and dendritic cell specific transmembrane protein (DC-STAMP). However, there is an important difference: osteoclasts form and reside in the vicinity of bone, while FBGCs form only under pathological conditions or at the surface of foreign materials, like medical implants. Despite similarities, an important distinction between these cell types is that osteoclasts can resorb bone, but it is unknown whether FBGCs are capable of such an activity. To investigate this, we differentiated FBGCs and osteoclasts in vitro from their common CD14+ monocyte precursor cells, using different sets of cytokines. Both cell types were cultured on bovine bone slices and analyzed for typical osteoclast features, such as bone resorption, presence of actin rings, formation of a ruffled border, and characteristic gene expression over time. Additionally, both cell types were cultured on a biomimetic hydroxyapatite coating to discriminate between bone resorption and mineral dissolution independent of organic matrix proteolysis. Both cell types differentiated into multinucleated cells on bone, but FBGCs were larger and had a higher number of nuclei compared to osteoclasts. FBGCs were not able to resorb bone, yet they were able to dissolve the mineral fraction of bone at the surface. Remarkably, FBGCs also expressed actin rings, podosome belts and sealing zones- cytoskeletal organization that is considered to be osteoclast-specific. However, they did not form a ruffled border. At the gene expression level, FBGCs and osteoclasts expressed similar levels of mRNAs that are associated with the dissolution of mineral (e.g., anion exchange protein 2 (AE2), carbonic anhydrase 2 (CAII), chloride channel 7 (CIC7), and vacuolar-type H+-ATPase (v-ATPase)), in contrast the matrix degrading enzyme cathepsin K, which was hardly expressed by FBGCs. Functionally, the latter cells were able to dissolve a biomimetic hydroxyapatite coating in vitro, which was blocked by inhibiting v-ATPase enzyme activity. These results show that FBGCs have the capacity to dissolve the mineral phase of bone, similar to osteoclasts. However, they are not able to digest the matrix fraction of bone, likely due to the lack of a ruffled border and cathepsin K. PMID- 26426810 TI - Insulin resistance and composite indices of femoral neck strength in Asians: the fourth Korea National Health and Nutrition Examination Survey (KNHANES IV). AB - OBJECTIVE: Fracture risk in type 2 diabetes mellitus with insulin resistance is increased, despite relatively preserved bone mineral density (BMD). In this study, we investigated the relationship between insulin resistance and composite indices of femoral neck strength in Koreans. DESIGN: A population-based, cross sectional study from the Korea National Health and Nutrition Examination Survey PARTICIPANTS: About 1243 men and 1433 women MEASUREMENTS: Insulin resistance was evaluated using the homoeostasis model assessment-estimated insulin resistance (HOMA-IR) index. Femoral neck width and axis length were measured from hip dual energy X-ray absorptiometry scans and combined with BMD, weight and height to calculate composite indices of femoral neck strength relative to load: compression (CSI), bending (BSI) and impact strength indices (ISI). RESULTS: HOMA IR showed an inverse relationship with CSI, BSI and ISI in both genders before and after adjusting for confounders (P < 0.001-0.029). CSI was more strongly associated with HOMA-IR than BSI and/or ISI in both genders (P < 0.001-0.013). When men were stratified according to HOMA-IR quartiles, all strength indices decreased as the quartile increased, after adjusting for all potential confounders (P for trend <0.001-0.001), whereas CSI and ISI did in women (P for trend = 0.012 and 0.002, respectively). Fasting insulin levels, but not glucose levels, were negatively associated with all strength indices regardless of confounders (P < 0.001-0.044). CONCLUSIONS: Insulin resistance is associated with low femoral neck strength, particularly against the compressive load. These findings suggest a better approach to evaluate bone health in insulin-resistant individuals. PMID- 26426811 TI - An extended single-index multiplexed 16S rRNA sequencing for microbial community analysis on MiSeq illumina platforms. AB - The primary 16S rRNA sequencing protocol for microbial community analysis using Illumina platforms includes a single-indexing approach that allows pooling of hundreds of samples in each sequencing run. The protocol targets the V4 hypervariable region (HVR) of 16S rRNA using 150 bp paired-end (PE) sequencing. However, the latest improvement in Illumina chemistry has increased the read length up to 600 bp using 300 bp PE sequencing. To take advantage of the longer read length, a dual-indexing approach was previously developed for targeting different HVRs. However, due to simple working protocols, the single-index 150 bp PE approach still continues to be attractive to many researchers. Here, we described an extended single-indexing protocol for 300 bp PE illumina sequencing that targets the V3-V4 HVRs of 16S rRNA. The new primer set led to increased read length and alignment resolution, as well as increased richness and diversity of resulting microbial profile compared to that obtained from150 bp PE protocol for V4 sequencing. The beta-diversity profile also differed qualitatively and quantitatively between the two approaches. Both primer sets had high coverage rates and specificity to detect dominant phyla; however, their coverage rate with regards to the rare biosphere varied. Our data further confirms that the choice of primer is the most deterministic factor in sequencing coverage and specificity. PMID- 26426812 TI - Bioactive glass plus laser phototherapy as promise candidates for dentine hypersensitivity treatment. AB - Treatments for dentine hypersensitivity (DH) may produce positive effects, though do not have lasting results. We investigated the reparative potential of stem cells derived from deciduous teeth (SHEDs) in response to components delivered from substances used in the treatment of the DH, associated or not to laser phototherapy (LPT), to stimulate dentine formation. SHEDs were submitted to substances delivered from a laboratorial P-rich bioactive glass [57SiO2 -26CaO 17P2 O5 (wt %)] or a commercially available desensitizer (Gluma(r) Desensitizer), associated (or not) to LPT (InGAlP diode laser, 660 nm, 0.028 cm2 , 20 mW, 5 J/cm2 , 7 s, contact mode). Biomaterial characterization was performed by X-ray diffraction, scanning electron microscopy and the particle size was evaluated by dynamic light scattering. SHEDs proliferation and differentiation were analyzed by MTT and Alizarin Red staining, respectively. The conditioned media used in these tests were evaluated regarding their pH and the ionic concentration changes due to ions leached from the bioactive glass (BG). BG majority presented a non crystalline solid structure and mixed particle sizes characterized by the agglomeration of nanoparticles. Cultures treated with BG alone or in association to LPT showed improved cell growth in relation to Gluma(r) (p < 0.05). Gluma(r) was cytotoxic in all tested conditions, regardless irradiated or not. BG associated to LPT induced intense mineral matrix formation. In conclusion, BG releases ionic dissolution products able to promote SHEDs differentiation. BG associated to LPT improves SHEDs proliferation and differentiation in vitro, and may be a promise therapeutic approach for the DH treatment. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 107-116, 2017. PMID- 26426814 TI - Assessment of cardiac dyssynchrony by cardiac MR: A comparison of velocity encoding and feature tracking analysis. AB - PURPOSE: To investigate whether cardiac magnetic resonance (cardiac MR)-based feature tracking (FT) may be used for robust and rapid quantification of dyssynchrony by measurement of the septal to lateral delay (SLD). MATERIALS AND METHODS: Healthy volunteers (n = 18) and patients with mechanical dyssynchrony (n = 17) were investigated. Velocity encoding cardiac MR (VENC) and steady-state free precession (SSFP)-cine sequences were acquired in identical horizontal long axis (HLA) positions using a 1.5T MR scanner. Using FT and VENC cardiac MR software, myocardial velocity curves were calculated for the basal segment of the septal and lateral wall. Based on the quantity of dyssynchrony, the patients were classified into three subgroups (minimal, intermediate, extensive). SLD and patient classification were compared and intra- as well as interobserver variability assessed. RESULTS: VENC and FT SLD measurements showed strong correlation (r = 0.94) and good agreement (mean 1.33 msec; limits of agreement [LoA] -2.96 to 5.63). Dyssynchrony subclassification based on FT was identical to VENC in 83% of the cases. While FT correctly classified all healthy subjects, three patients with mechanical dyssynchrony were misclassified. Compared to VENC, FT showed higher intra- and interobserver variability. VENC: intraobserver: mean 2.5 msec, LoA -17.5 to 22.5; interobserver: mean 1.5 msec, LoA -17.2 to 21.9. FT: intraobserver: mean 2.1 msec, LoA 27.6 to 31.8; interobserver: mean 2.4 msec LoA 31.4 to 34.5. CONCLUSION: Cardiac MR-based FT analysis may be used for rapid appraisal of left ventricle cardiac dyssynchrony from SSFP images. However, FT results are less accurate and reproducible compared to VENC-based assessment of SLD. PMID- 26426813 TI - The Association of Endothelin-1 Signaling with Bone Alkaline Phosphatase Expression and Protumorigenic Activities in Canine Osteosarcoma. AB - BACKGROUND: Canine osteosarcoma (OS) is an aggressive sarcoma characterized by pathologic skeletal resorption and pulmonary metastases. A number of negative prognostic factors, including bone alkaline phosphatase, have been identified in dogs with OS, but the underlying biologic factors responsible for such observations have not been thoroughly investigated. Endothelin-1-mediated signaling is active during bone repair, and is responsible for osteoblast migration, survival, proliferation, and bone alkaline phosphatase expression. HYPOTHESIS: The endothelin-1 signaling axis is active in canine OS cells, and this pathway is utilized by malignant osteoblasts for promoting cellular migration, survival, proliferation, and bone alkaline phosphatase activities. ANIMALS: 45 dogs with appendicular OS. METHODS: The expressions of endothelin-1 and endothelin A receptor were studied in OS cell lines and in samples from spontaneously occurring tumors. Activities mediated by endothelin-1 signaling were investigated by characterizing responses in 3 OS cell lines. In 45 dogs with OS, bone alkaline phosphatase concentrations were correlated with primary tumor osteoproductivity. RESULTS: Canine OS cells express endothelin-1 and endothelin A receptor, and this signaling axis mediates OS migration, survival, proliferation, and bone alkaline phosphatase activities. In OS-bearing dogs, circulating bone alkaline phosphatase activities were positively correlated with primary tumor relative bone mineral densities. CONCLUSIONS AND CLINICAL IMPORTANCE: Canine OS cells express endothelin-1 and functional endothelin A receptors, with the potential for a protumorigenic signaling loop. Increases in bone alkaline phosphatase activity are associated with osteoblastic OS lesions, and might be an epiphenomenon of active endothelin-1 signaling or excessive osteoproduction within the localized bone microenvironment. PMID- 26426816 TI - A rapid and selective synthesis of alpha,alpha-fluorohalo esters via fluorohalogenative or difluorinative hydration of ynol ethers. AB - A Selectfluor-mediated fluorohalogenative or difluorinative hydration of ynol ethers is described, giving various alpha,alpha-fluorohalo esters including alpha,alpha-bromofluoro, alpha,alpha-chlorofluoro, alpha,alpha-fluoroiodo, and alpha,alpha-difluoro derivatives in a highly selective manner under very mild reaction conditions. The resultant products can be applied to the facile synthesis of alpha-monofluoro-alpha-amino acids. This reaction represents a new advance in the trifunctionalization of alkynes. PMID- 26426815 TI - Photobiomodulation Mitigates Diabetes-Induced Retinopathy by Direct and Indirect Mechanisms: Evidence from Intervention Studies in Pigmented Mice. AB - OBJECTIVE: Daily application of far-red light from the onset of diabetes mitigated diabetes-induced abnormalities in retinas of albino rats. Here, we test the hypothesis that photobiomodulation (PBM) is effective in diabetic, pigmented mice, even when delayed until weeks after onset of diabetes. Direct and indirect effects of PBM on the retina also were studied. METHODS: Diabetes was induced in C57Bl/6J mice using streptozotocin. Some diabetics were exposed to PBM therapy (4 min/day; 670 nm) daily. In one study, mice were diabetic for 4 weeks before initiation of PBM for an additional 10 weeks. Retinal oxidative stress, inflammation, and retinal function were measured. In some mice, heads were covered with a lead shield during PBM to prevent direct illumination of the eye, or animals were treated with an inhibitor of heme oxygenase-1. In a second study, PBM was initiated immediately after onset of diabetes, and administered daily for 2 months. These mice were examined using manganese-enhanced MRI to assess effects of PBM on transretinal calcium channel function in vivo. RESULTS: PBM intervention improved diabetes-induced changes in superoxide generation, leukostasis, expression of ICAM-1, and visual performance. PBM acted in part remotely from the retina because the beneficial effects were achieved even with the head shielded from the light therapy, and because leukocyte-mediated cytotoxicity of retinal endothelial cells was less in diabetics treated with PBM. SnPP+PBM significantly reduced iNOS expression compared to PBM alone, but significantly exacerbated leukostasis. In study 2, PBM largely mitigated diabetes induced retinal calcium channel dysfunction in all retinal layers. CONCLUSIONS: PBM induces retinal protection against abnormalities induced by diabetes in pigmented animals, and even as an intervention. Beneficial effects on the retina likely are mediated by both direct and indirect mechanisms. PBM is a novel non pharmacologic treatment strategy to inhibit early changes of diabetic retinopathy. PMID- 26426817 TI - Ultrathin unsedated transnasal gastroscopy in monitoring eosinophilic esophagitis. AB - BACKGROUND: Ultrathin unsedated transnasal gastroscopy (UTEG) has a number of advantages applicable to eosinophilic esophagitis (EoE) and has not been evaluated for this condition. AIM: The aim of the study is to determine the feasibility of UTEG in patients with EoE and the acceptability of histological specimens obtained at biopsy. METHOD: All patients with a diagnosis of EoE presenting to the outpatients department of two hospitals (Box Hill Hospital and The Alfred Hospital, Melbourne Australia) were asked to participate in the study. UTEG was performed on consenting individuals. Feasibility was determined by the success of nasal intubaton, patient perception according to post procedural survey, and adequacy of esophageal biopsies was assessed. RESULTS: Ninety-six consecutive patients with EoE were offered UTEG, and 24 agreed to participate in the study. Seventy-four UTEGs were performed over a period of 26 months (September 2012 to December 2014). Nineteen patients had repeat procedures. Successful nasal intubation occurred in 97% (72 of 74 procedures), and 21 of 24 (86%) described high satisfaction with the procedure and minimal discomfort, and would choose UTEG for future procedures. Mean duration was 5 min. Adverse events of epistaxis (three cases) and vomiting of liquid contents during the procedure (two cases) were recorded, cardiorespiratory parameters remaining normal in all patients. All completed procedures produced adequate histological samples. CONCLUSION: In those who decide to undergo UTEG, it is a safe and well-tolerated procedure. PMID- 26426819 TI - Impaired Visual Acuity and Spectacle Ownership of Urban Migrant Children in Eastern China. PMID- 26426818 TI - Exogenous attention facilitates location transfer of perceptual learning. AB - Perceptual skills can be improved through practice on a perceptual task, even in adulthood. Visual perceptual learning is known to be mostly specific to the trained retinal location, which is considered as evidence of neural plasticity in retinotopic early visual cortex. Recent findings demonstrate that transfer of learning to untrained locations can occur under some specific training procedures. Here, we evaluated whether exogenous attention facilitates transfer of perceptual learning to untrained locations, both adjacent to the trained locations (Experiment 1) and distant from them (Experiment 2). The results reveal that attention facilitates transfer of perceptual learning to untrained locations in both experiments, and that this transfer occurs both within and across visual hemifields. These findings show that training with exogenous attention is a powerful regime that is able to overcome the major limitation of location specificity. PMID- 26426822 TI - Interactions between Flavins and Quadruplex Nucleic Acids. AB - Quadruplex nucleic acids are widespread in genomes. They influence processes such as transcription, translation, replication, recombination, and the regulation of gene expression. Several synthetic ligands have been demonstrated to target quadruplex nucleic acids. However, only very few metabolites have been reported to interact with quadruplexes. In principle, an intracellular metabolite that selectively binds to four-stranded sequences could modulate quadruplex formation, stability, and thus functions in a riboswitch (or deoxyriboswitch) manner. Here we report quadruplex interactions with flavin derivatives such as FMN and FAD. The affinities were highest with parallel quadruplexes, with low (14-20 MUm) dissociation constants. Taking into account combined intracellular flavin concentrations of 243 MUm in E. coli, the observed interactions in principle open up the possibility of flavin levels affecting gene expression and other processes by modulating quadruplex formation. PMID- 26426823 TI - Antibody-Modified Reduced Graphene Oxide Films with Extreme Sensitivity to Circulating Tumor Cells. AB - An antibody-modified reduced graphene oxide (rGO) film with unexpected -extreme sensitivity to circulating tumor cells (CTCs) is reported. The antibody--modified rGO films efficiently capture CTCs from billions of blood cells and minimize the background of white blood cells, without complex microfluidic operations. PMID- 26426824 TI - Configurable lipid membrane gradients quantify diffusion, phase separations and binding densities. AB - Single-experiment analysis of phospholipid compositional gradients reveals diffusion coefficients, phase separation parameters, and binding densities as a function of localized lipid mixture. Compositional gradients are formed by directed self assembly where rapid-prototyping techniques (i.e., additive manufacturing or laser-cutting) prescribe lipid geometries that self-spread, heal and mix by diffusion. PMID- 26426825 TI - Chiral modification of platinum: ab initio study of the effect of hydrogen coadsorption on stability and geometry of adsorbed cinchona alkaloids. AB - The cinchona alkaloids cinchonidine and cinchonine belong to the most efficient chiral modifiers for the noble metal-catalyzed enantioselective hydrogenation of C=O and C=C bonds. Under reaction conditions these modifiers are coadsorbed on the noble metal surface with hydrogen. Using density functional theory, we studied the effect of coadsorbed hydrogen on the adsorption mode of cinchonidine and cinchonine on a Pt(111) surface at different hydrogen coverages. The theoretical study indicates that the presence of coadsorbed hydrogen affects both the adsorption geometry as well as the stability of the adsorbed cinchona alkaloids. At all hydrogen coverages the cinchona alkaloids are found to be adsorbed via anchoring of the quinoline moiety. In the absence of hydrogen as well as at low hydrogen coverage the quinoline moiety adsorbs nearly parallel to the surface, whereas at higher hydrogen coverage it becomes tilted. Higher hydrogen coverage as well as partial hydrogenation of the quinoline part of the cinchona alkaloid and hydrogen transfer to the C[double bond, length as m-dash]C double bond at 10, 11 position of the quinuclidine moiety destabilize the adsorbed cinchona alkaloid, whereas hydrogen transfer to the nitrogen atom of the quinoline and the quinuclidine moiety stabilizes the adsorbed molecule. The stability as well as the adsorption geometry of the cinchona alkaloids are affected by the coadsorbed hydrogen and are proposed to influence the efficiency of the enantiodifferentiating ability of the chirally modified platinum surface. PMID- 26426827 TI - Copper- and Silver-Catalyzed Diastereo- and Enantioselective Conjugate Addition Reaction of 1-Pyrroline Esters to Nitroalkenes: Diastereoselectivity Switch by Chiral Metal Complexes. AB - syn-Diastereoselective conjugate addition of 1-pyrroline esters to nitroalkenes in good yields with an excellent enantioselectivity by using CuOAc/Me-FcPHOX catalyst in the presence of pyridine. In contrast, AgOAc/tBu-ThioClickFerrophos catalyzed the anti diastereoselective conjugate addition with a high enantioselectivity without additional base. Thus, the preparation of chiral 1 pyrroline derivatives bearing diverse stereochemistry could be achieved. The diastereoselective reduction of the imine group in the conjugate adduct could afford the 2,5-cis-proline ester derivative. PMID- 26426826 TI - Genetics of murine craniofacial morphology: diallel analysis of the eight founders of the Collaborative Cross. AB - Using eight inbred founder strains of the mouse Collaborative Cross (CC) project and their reciprocal F1 hybrids, we quantified variation in craniofacial morphology across mouse strains, explored genetic contributions to craniofacial variation that distinguish the founder strains, and tested whether specific or summary measures of craniofacial shape display stronger additive genetic contributions. This study thus provides critical information about phenotypic diversity among CC founder strains and about the genetic contributions to this phenotypic diversity, which is relevant to understanding the basis of variation in standard laboratory strains and natural populations. Craniofacial shape was quantified as a series of size-adjusted linear dimensions (RDs) and by principal components (PC) analysis of morphological landmarks captured from computed tomography images from 62 of the 64 reciprocal crosses of the CC founder strains. We first identified aspects of skull morphology that vary between these phenotypically 'normal' founder strains and that are defining characteristics of these strains. We estimated the contributions of additive and various non additive genetic factors to phenotypic variation using diallel analyses of a subset of these strongly differing RDs and the first eight PCs of skull shape variation. We find little difference in the genetic contributions to RD measures and PC scores, suggesting fundamental similarities in the magnitude of genetic contributions to both specific and summary measures of craniofacial phenotypes. Our results indicate that there are stronger additive genetic effects associated with defining phenotypic characteristics of specific founder strains, suggesting these distinguishing measures are good candidates for use in genotype-phenotype association studies of CC mice. Our results add significantly to understanding of genotype-phenotype associations in the skull, which serve as a foundation for modeling the origins of medically and evolutionarily relevant variation. PMID- 26426828 TI - Thyroid Cancer and Nonsteroidal Anti-Inflammatory Drug Use: A Pooled Analysis of Patients Older Than 40 Years of Age. AB - BACKGROUND: Cyclooxygenase (COX-2) has been associated with tumor growth and metastasis in several cancers, including thyroid cancer. For this reason, several investigators have studied COX-2 inhibitors in preclinical models of thyroid cancer and found antineoplastic effects. Thus, the primary aim of this study was to assess if the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of thyroid cancer. A second aim of the study was to determine additional risk or protective factors for thyroid cancer. METHODS: Three large prospective population-based studies (the NIH-AARP Diet and Health Study; the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; and the U.S. Radiologic Technologists Study) were pooled to investigate the association between self-reported frequency of aspirin and nonaspirin NSAID use one year prior to baseline (no use, <= 2/week, >2-6/week, and >= 7/week) and subsequent risk of thyroid cancer. A Cox regression proportional hazard model was used to estimate aggregated hazard ratios (HR) adjusted for cohort, sex, race/ethnicity, weight, smoking status, and alcohol intake. RESULTS: There were 388,577 participants in the pooled cohort, with 481 cases of thyroid cancer. No significant risk reduction was observed with regular use of nonaspirin NSAIDs (HR = 1.14 [confidence interval (CI) 0.84-1.55]), and/or regular use of aspirin (HR = 1.06 [CI 0.82-1.39]). The multivariate regression analysis confirmed as previously reported in the literature that female sex, obesity class I (body mass index [BMI] = 30-34.99 kg/m(2)), and obesity class II (BMI = 35-35.99 kg/m(2)) were independently associated with an increased thyroid cancer risk. Current smoking status and moderate and excessive alcohol use were also confirmed as independent risk factors associated with a reduced thyroid cancer risk. CONCLUSIONS: Neither nonaspirin NSAIDs nor aspirin use is associated with a reduced risk of thyroid cancer. Women and obesity are associated with an increased risk of thyroid cancer, whereas smoking and alcohol use are associated with decreased risk of thyroid cancer. PMID- 26426829 TI - A Chimeric Cetuximab-Functionalized Corona as a Potent Delivery System for Microtubule-Destabilizing Nanocomplexes to Hepatocellular Carcinoma Cells: A Focus on EGFR and Tubulin Intracellular Dynamics. AB - In this study, we have developed microtubule destabilizing agents combretastatin A4 (CA4) or 2-methoxyestradiol (2ME) encapsulated poly(d,l-lactide-co-glycolide) b-poly(ethylene glycol) (PLGA-b-PEG) nanocomplexes for targeted delivery to human hepatocellular carcinoma (HCC) cells. An epidermal growth factor receptor (EGFR) is known to be overexpressed in HCC cells. Therefore, the targeting moiety cetuximab (Cet), an anti-EGFR chimeric monoclonal antibody, is functionalized on the surface of these diblock copolymeric coronas. Cetuximab is associated with the extracellular domain of the EGFR; therefore, the uptake of the cetuximab conjugated nanocomplexes occurred efficiently in EGFR overexpressing HCC cells indicating potent internalization of the complex. The cetuximab targeted-PLGA-b PEG nanocomplexes encapsulating CA4 or 2ME strongly inhibited phospho-EGFR expression, depolymerized microtubules, produced spindle abnormalities, stalled mitosis, and induced apoptosis in Huh7 cells compared to the free drugs, CA4 or 2ME. Further, the combinatorial strategy of targeted nanocomplexes, Cet-PLGA-b PEG-CA4 NP and Cet-PLGA-b-PEG-2ME NP, significantly reduced the migration of Huh7 cells, and markedly enhanced the anticancer effects of the microtubule-targeted drugs in Huh7 cells compared to the free drugs, CA4 or 2ME. The results indicated that EGFR receptor-mediated internalization via cetuximab facilitated enhanced uptake of the nanocomplexes leading to potent anticancer efficacy in Huh7 cells. Cetuximab-functionalized PLGA-b-PEG nanocomplexes possess a strong potential for the targeted delivery of CA4 or 2ME in EGFR overexpressed HCC cells, and the strategy may be useful for selectively targeting microtubules in these cells. PMID- 26426830 TI - Antimicrobials at the End of Life: An Opportunity to Improve Palliative Care and Infection Management. PMID- 26426831 TI - Serum lipid profile changes after successful treatment with electroconvulsive therapy in major depression: A prospective pilot trial. AB - BACKGROUND: Cholesterol is reduced in depressed patients, however, these patients have a higher risk for cardiovascular diseases. Electroconvulsive therapy (ECT) is a highly effective treatment option for specific forms of depression. Like for other non-pharmacological therapies targeting depression such as psychotherapy or sleep deprivation, there is a lack of evidence about the effects on peripheral lipid parameters. Our objective was to study the impact of ECT as a non pharmacological treatment on the peripheral lipid pattern in depressive patients. METHOD: Peripheral lipid profile composition before and after a course of ECT was analysed in 27 non-fasting inpatients at a university psychiatric hospital with DSM-IV major depressive episode. For the impact of ECT treatment on each lipid parameter a multivariate repeated measurement regression analysis was performed and computed separately for every dependent variable. RESULTS: Total Cholesterol and the cholesterol subtypes HDL and LDL were increased after the treatment compared to baseline. Apolipoprotein A1 was also increased after ECT, whereas apolipoprotein B was not. Indices for the prediction of cardiovascular diseases were unchanged after successful treatment by ECT. The reduction of depressive psychopathology negatively correlated with increases of HDL cholesterol and apolipoprotein A1. LIMITATIONS: Subjects received several antidepressants and other psychotropic medication before and during the ECT. CONCLUSIONS: In our preliminary pilot study ECT as a non-pharmacological, effective treatment of depression led to distinct effects on the peripheral lipid pattern. PMID- 26426832 TI - Survival and risk factors related to death in outpatients with cirrhosis treated in a clinic in Southern Brazil. AB - INTRODUCTION: Cirrhosis represents a public health issue that generally evolves and presents serious complications. OBJECTIVES: To assess the outcomes of outpatients with cirrhosis. PATIENTS AND METHODS: We used a retrospective outpatient-based cohort, assessing 527 patients with cirrhosis. Demographic, clinical, and laboratory variables were analyzed, as well as the risk factors related to death, using the Cox proportional-hazard regression model. The Kaplan Meier method was used to analyze survival rates. RESULTS: Patients had a mean age of 52.9+/-9.7 years and were more frequently men (59%), presenting Child-Turcotte Pugh B or C in 43% of the cases in addition to a mean Model for End-Stage Liver Disease score of 12.0+/-4.1. The predominant etiology of liver disease was the hepatitis C virus. The most frequent complications during follow-up were ascites (34%), hepatic encephalopathy (17%), and hepatocellular carcinoma (17%). The survival rate at years 5 and 10 was 73 and 57%, respectively. The main risk factors that were related to death were, in a multivariate analysis, hepatitis C virus etiology, presence of hepatocellular carcinoma, and serum levels of albumin. CONCLUSION: Patients with cirrhosis monitored on an outpatient basis, despite showing a reasonable survival rate, have a worse prognosis when the etiology of liver disease is related to hepatitis C virus and when they have hepatocellular carcinoma or hypoalbuminemia. PMID- 26426833 TI - Gallstones are associated with hidradenitis suppurativa: a population-based and hospital-based cross-sectional study from Denmark. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory dermatological disease that was recently linked to the metabolic syndrome (MetS). MetS has been associated with gallstones, and nonalcoholic fatty liver has been suggested to be the hepatic expression of MetS. OBJECTIVE: The objective of the study was to investigate whether there was an association of HS with gallstones as well as with hepatic dysfunction. PATIENTS AND METHODS: This was a cross sectional study comparing a hospital-based HS group, a population-based HS group, and controls for self-reported gallstone and blood sample verified hepatic dysfunction. Blood samples were analyzed for alanine transaminase, bilirubin, alkaline phosphatase, albumin, thrombocytes, and the international normalized ratio. RESULTS: A total of 32 hospital HS patients, 430 population-based HS patients, and 20 780 non-HS controls were identified. The age-sex-smoking adjusted analysis of gallstones revealed a significant OR of 1.72 (95% CI 1.23 2.42, P=0.0191) and a borderline significant OR of 3.28 (95% CI 1.24-8.74, P=0.0516) for the population HS group and hospital HS group versus controls, respectively. Furthermore, no clinically significant evidence was found with regard to hepatic dysfunction. CONCLUSION: This study demonstrates an association of HS with gallstones, but not with hepatic dysfunction. The association with gallstones may be partly explained by the comorbidity of hypertriglyceridemia and obesity as a part of MetS. PMID- 26426835 TI - Adalimumab as a second-line biological therapy in children with refractory ulcerative colitis. AB - AIM: The role of adalimumab in medically refractory ulcerative colitis (UC) in children remains to be defined. The aim of this study was to describe 11 cases of paediatric patients who received adalimumab as a second-line anti-TNF-alpha treatment for paediatric UC. METHODS: A retrospective review of all patients with UC who received adalimumab between April 2008 and October 2013 at our hospital was conducted. Clinical efficacy and safety were assessed. RESULTS: Eleven patients (three boys, eight girls) with a median age of 13.8 years (5.7-16.6 years) were included. All patients had been previously treated with infliximab. Six patients achieved and maintained clinical remission, with a median duration of treatment of 25 months. One patient was successfully weaned off adalimumab after 26 months of therapy. Treatment was unsuccessful in four out of 11 patients (36%) who underwent colectomy 4-13 months (median 7 months) from the first adalimumab dose. The remaining patient developed extensive rash and was switched to alternative therapy. CONCLUSION: In this case series, our experience shows that there is a role for adalimumab as a combination therapy in a subgroup of children with refractory UC. PMID- 26426836 TI - A multicenter randomized comparison between high-definition white light endoscopy and narrow band imaging for detection of gastric lesions. AB - OBJECTIVE: Narrow band imaging (NBI) is generally considered to be useful for lesion characterization, but not enhanced detection of gastric lesions, because of the dark endoscopic view. We tested whether the new generation of NBI (190-NBI or 290-NBI), which is twice as bright as the previous version, would improve detection of premalignant gastric lesions compared with high-definition white light endoscopy (HD-WLE). PATIENTS AND METHODS: This was a multicenter prospective randomized study involving five tertiary institutions in the Asia Pacific region. A total of 579 patients aged older than 50 years who underwent diagnostic upper gastrointestinal endoscopy were randomized to either HD-WLE or NBI. The outcome measurements were detection of intestinal metaplasia (IM), focal gastric lesions, and gastric cancers. RESULTS: Focal gastric lesions were detected in 83/286 (29%) and 119/293 patients (40.6%) by HD-WLE and by NBI, respectively (P=0.003). IM was detected in 22/286 patients (7.7%) by HD-WLE and in 52/293 patients (17.7%) by NBI (P<0.001). Gastric cancer were found in 7/286 (2.4%) and 3/293 patients (1%) in HD-WLE and NBI groups, respectively (P=0.189). CONCLUSION: NBI increased the detection rate of IM compared with HD-WLE. PMID- 26426834 TI - Diagnosis of bile acid diarrhoea by fasting and postprandial measurements of fibroblast growth factor 19. AB - BACKGROUND: A deficiency in the ileal hormone fibroblast growth factor 19 (FGF19) has been described in patients with bile acid diarrhoea (BAD), but fasting FGF19 levels have insufficient diagnostic power. We assess whether single postprandial sampling of FGF19 has greater discriminative value than fasting FGF19 for detection of BAD and we evaluate the reproducibility of fasting FGF19. MATERIALS AND METHODS: Twenty-six patients consecutively referred to Se homocholic acid retention test (SeHCAT) were included. Serum FGF19 was measured after an overnight fast and again 1 h postprandially and again in the fasting state 1 week later. RESULTS: Nine of 26 patients had SeHCAT less than 10% and fasting FGF19 was lower [median 62 pg/ml, interquartile range (IQR): 47-67] than in the 17 diarrhoea controls with SeHCAT at least 10% (median 103 pg/ml, IQR: 77-135, P=0.006). Postprandial FGF19 in BAD patients (61 pg/ml, IQR: 48-69) was similar to fasting values (P=0.59) and increased insignificantly in diarrhoea controls (137 pg/ml, IQR: 88-182; P=0.25). The difference in postprandial FGF19 between patients with BAD and diarrhoea controls was highly significant (P<0.001). CONCLUSION: The difference in serum FGF19 between groups of patients with BAD and diarrhoea controls is amplified postprandially. Within each group, the difference between fasting and postprandial FGF19 was not statistically significant. Further investigations are warranted on stimulated FGF19 response to elucidate its role in BAD. PMID- 26426837 TI - Self-expandable metal stent placement for malignant duodenal obstruction distal to the bulb. AB - OBJECTIVE: Self-expandable metal stents (SEMS) are widely used for the palliative management of malignant proximal gastroduodenal obstruction because of its low morbidity and mortality rates compared with surgical bypass. However, stent placement for duodenal obstruction beyond the first part of the duodenum is considered technically difficult and is not routinely performed. We report our experience with SEMS placement for these patients. METHODS: Between 2006 and 2015, 51 patients with unresectable or metastatic malignancy underwent SEMS placements under combined endoscopic and fluoroscopic guidance. Eighteen patients had intestinal obstruction distal to the duodenal bulb. Their demographics, technical and clinical outcomes, periprocedural morbidity and mortality, length of hospital stay, further interventions and overall survival were analysed. RESULTS: Out of the 18 cases, nine cases of intestinal obstruction were due to primary malignancy of the pancreas, three due to gastric malignancy, three from other locoregional cancers and three were the result of metastases. In 12 patients, the obstruction involved the second part (D2), in four the third part (D3) and in two the fourth part (D4) of the duodenum. A front-facing therapeutic gastroscope was used to visualize the duodenum before the stricture was crossed under direct vision and fluoroscopic guidance, with a catheter and guidewire, and a through-the-scope SEMS deployed using an 'over-the-wire' technique. Technical success rate was 89%. The mean gastric outlet obstruction scores improved from 0.63 to 2.57 (P<0.0001). Four patients died within 30 days of the procedure, although none of the deaths were procedure related. The median length of postprocedural hospital stay was 4 days and the median overall survival was 58 days. PMID- 26426838 TI - FoxP3-positive T cell lymphoma arising in non-HTLV1 carrier: clinicopathological analysis of 11 cases of PTCL-NOS and 2 cases of mycosis fungoides. AB - AIMS: Forkhead box protein 3-positive (FoxP3(+) ) T cell lymphoma, in the absence of human T cell lymphotrophic virus type 1 (HTLV-1) infection, is rare and its clinicopathological characteristics still remain unclear. The aim of this study was to elucidate its characteristics. METHODS AND RESULTS: We describe here 11 cases of peripheral T cell lymphoma not otherwise specified (PTCL-NOS) and two cases of mycosis fingoides (MF) which were positive for FoxP3. The median age of the 11 PTCL-NOS cases was 65 years (range: 48-80 years), and all the patients were male. Eight patients (80%) showed stages III/IV disease, and six (60%) were categorized as high-intermediate/high-risk groups according to the International Prognostic Index. Two cases of MF were 57- and 59-year-old males. Both cases were categorized as stage IA, according to International Society for Cutaneous Lymphomas/European Organization of Research and Treatment of Cancer (ISCL/EORTC) classification. Immunohistochemically, all the cases were negative for cytotoxic molecule marker, and nine (75%) were alphabeta T cell type. Scattered Epstein Barr virus (EBV)-infected cells were detected in four cases of PTCL-NOS, implying the reactivation of EBV caused by the immunodeficient status of the patients. CONCLUSIONS: FoxP3(+) PTCL-NOS constitute a minor phenotypical subtype with poor prognosis and EBV reactivation in some. Conversely, two cases of MF showed an indolent clinical course which was different from previously reported cutaneous T cell lymphoma (CTCL) cases. PMID- 26426839 TI - Dust in the wind: How climate variables and volcanic dust affect rates of tooth wear in Central American howling monkeys. AB - OBJECTIVES: Two factors have been considered important contributors to tooth wear: dietary abrasives in plant foods themselves and mineral particles adhering to ingested food. Each factor limits the functional life of teeth. Cross population studies of wear rates in a single species living in different habitats may point to the relative contributions of each factor. MATERIALS AND METHODS: We examine macroscopic dental wear in populations of Alouatta palliata (Gray, 1849) from Costa Rica (115 specimens), Panama (19), and Nicaragua (56). The sites differ in mean annual precipitation, with the Panamanian sites receiving more than twice the precipitation of those in Costa Rica or Nicaragua (~3,500 mm vs. ~1,500 mm). Additionally, many of the Nicaraguan specimens were collected downwind of active plinian volcanoes. Molar wear is expressed as the ratio of exposed dentin area to tooth area; premolar wear was scored using a ranking system. RESULTS: Despite substantial variation in environmental variables and the added presence of ash in some environments, molar wear rates do not differ significantly among the populations. Premolar wear, however, is greater in individuals collected downwind from active volcanoes compared with those living in environments that did not experience ash-fall. DISCUSSION: Volcanic ash seems to be an important contributor to anterior tooth wear but less so in molar wear. That wear is not found uniformly across the tooth row may be related to malformation in the premolars due to fluorosis. A surge of fluoride accompanying the volcanic ash may differentially affect the premolars as the molars fully mineralize early in the life of Alouatta. PMID- 26426840 TI - Increasing the thermopower of crown-ether-bridged anthraquinones. AB - We investigate strategies for increasing the thermopower of crown-ether-bridged anthraquinones. The novel design feature of these molecules is the presence of either () crown-ether or () diaza-crown-ether bridges attached to the side of the current-carrying anthraquinone wire. The crown-ether side groups selectively bind alkali-metal cations and when combined with TCNE or TTF dopants, provide a large phase-space for optimising thermoelectric properties. We find that the optimum combination of cations and dopants depends on the temperature range of interest. The thermopowers of both and are negative and at room temperature are optimised by binding with TTF alone, achieving thermpowers of -600 MUV K(-1) and -285 MUV K(-1) respectively. At much lower temperatures, which are relevant to cascade coolers, we find that for , a combination of TTF and Na(+) yields a maximum thermopower of -710 MUV K(-1) at 70 K, whereas a combination of TTF and Li(+) yields a maximum thermopower of -600 MUV K(-1) at 90 K. For , we find that TTF doping yields a maximum thermopower of -800 MUV K(-1) at 90 K, whereas at 50 K, the largest thermopower (of -600 MUV K(-1)) is obtain by a combination TTF and K(+) doping. At room temperature, we obtain power factors of 73 MUW m(-1) K(-2) for (in combination with TTF and Na(+)) and 90 MUW m(-1) K(-2) for (with TTF). These are higher or comparable with reported power factors of other organic materials. PMID- 26426842 TI - The structures of CyMe4-BTBP complexes of americium(iii) and europium(iii) in solvents used in solvent extraction, explaining their separation properties. AB - Separation of trivalent actinoid (An(iii)) and lanthanoid (Ln(iii)) ions is extremely challenging due to their similar ionic radii and chemical properties. Poly-aromatic nitrogen compounds acting as tetradentate chelating ligands to the metal ions in the extraction, have the ability to sufficiently separate An(iii) from Ln(iii). One of these compounds, 6,6'-bis(5,5,8,8-tetramethyl-5,6,7,8 tetrahydro-benzol[1,2,4]triazin-3-yl)[2,2]bipyridine, CyMe4-BTBP, has proven to be resistant towards acidic environments and strong radiation from radioactive decomposition. EXAFS studies of the dicomplexes of CyMe4-BTBP with americium(iii) and europium(iii) in nitrobenzene, cyclohexanone, 1-hexanol, 1-octanol and malonamide (DMDOHEMA) in 1-octanol have been carried out to get a deeper understanding of the parameters responsible for the separation. The predominating complexes independent of solvent used are [Am(CyMe4-BTBP)2(NO3)](2+) and [Eu(CyMe4-BTBP)2](3+), respectively, which are present as outer-sphere ion-pairs with nitrate ions in the studied solvents with low relative permittivity. The presence of a nitrate ion in the first coordination sphere of the americium(iii) complex compensates the charge density of the complex considerably in comparison when only outer-sphere ion-pairs are formed as for the [Eu(CyMe4-BTBP)2](3+) complex. The stability and solubility of a complex in a solvent with low relative permittivity increase with decreasing charge density. The [Am(CyMe4 BTBP)2(NO3)](2+) complex will therefore be increasingly soluble and stabilized over the [Eu(CyMe4-BTBP)2](3+) complex in solvents with decreasing relative permittivity of the solvent. The separation of americium(iii) from europium(iii) with CyMe4-BTBP as extraction agent will increase with decreasing relative permittivity of the solvent, and thereby also with decreasing solubility of CyMe4 BTBP. The choice of solvent is therefore a balance of a high separation factor and sufficient solubility of the CyMe4-BTBP ligand. PMID- 26426848 TI - Synthesis and Evaluation of 5,5'-Bitetralone-Based Chiral Phosphoric Acids. AB - A new type of phosphoric acid bearing a 5,5'-bitetralone scaffold was synthesized from BINOL and was shown to be a highly effective catalyst as illustrated in the asymmetric transfer hydrogenation of 2-phenylquinoline and the Friedel-Crafts reaction of 2,2,2-trifluoroacetophenone. PMID- 26426849 TI - Water Selective Imaging and bSSFP Banding Artifact Correction in Humans and Small Animals at 3T and 7T, Respectively. AB - INTRODUCTION: The purpose of this paper is to develop an easy method to generate both fat signal and banding artifact free 3D balanced Steady State Free Precession (bSSFP) images at high magnetic field. METHODS: In order to suppress fat signal and bSSFP banding artifacts, two or four images were acquired with the excitation frequency of the water-selective binomial radiofrequency pulse set On Resonance or shifted by a maximum of 3/4TR. Mice and human volunteers were imaged at 7 T and 3 T, respectively to perform whole-body and musculoskeletal imaging. "Sum-Of-Square" reconstruction was performed and combined or not with parallel imaging. RESULTS: The frequency selectivity of 1-2-3-2-1 or 1-3-3-1 binomial pulses was preserved after (3/4TR) frequency shifting. Consequently, whole body small animal 3D imaging was performed at 7 T and enabled visualization of small structures within adipose tissue like lymph nodes. In parallel, this method allowed 3D musculoskeletal imaging in humans with high spatial resolution at 3 T. The combination with parallel imaging allowed the acquisition of knee images with ~500 MUm resolution images in less than 2 min. In addition, ankles, full head coverage and legs of volunteers were imaged, demonstrating the possible application of the method also for large FOV. CONCLUSION: In conclusion, this robust method can be applied in small animals and humans at high magnetic fields. The high SNR and tissue contrast obtained in short acquisition times allows to prescribe bSSFP sequence for several preclinical and clinical applications. PMID- 26426851 TI - Glomerular filtration rate measured by iohexol clearance: A comparison of venous samples and capillary blood spots. AB - BACKGROUND: Glomerular filtration rate (GFR) measured by iohexol clearance using venous samples is widely used. Capillary sampling on filter paper is easier to perform, may be less painful and spares the blood volume. The purpose of the study was to validate a blood spot method for measuring GFR in children aged 6 years or younger suffering from chronic kidney disease (CKD). METHODS: We examined 32 children with CKD, median age (range) 3.0 (0.3-6.2) years. Seven venous samples (10, 30/60, 120, 180, 210, 240, 300 min) were collected and GFR based on all samples was calculated for reference. Following injection of iohexol, blood spots were collected at 120, 180, 210 and 240 min and compared to the reference iohexol clearance. RESULTS: Median (range) reference GFR was 65 (6 122) mL/min/1.73 m(2). The 2, 3 and 4-point blood spot GFR were highly correlated to the reference GFR (r = 0.947, 0.945, 0.937). The mean relative bias between 2 point blood spot and reference GFR was 7.2%, and only 2.3% in the patients with reference GFR < 60 mL/min/1.73 m(2). The diagnostic accuracy for 2-point blood spot was: 87.5% and 96.9% within +/- 15% (P15) and +/- 30% (P30) of the reference GFR respectively. In patients with GFR < 60 mL/min/1.73 m(2), both P15 and P30 were 100%. CONCLUSIONS: GFR calculation based on blood spot iohexol measurement is an alternative method to traditional venous iohexol measurement in children. Our study demonstrates strong agreement between the blood spot and the venous GFR with acceptable bias, precision and diagnostic accuracy, especially in patients with GFR < 60 mL/min/1.73 m(2). PMID- 26426850 TI - Evaluation of a newly developed quantitative heart-type fatty acid binding protein assay based on fluorescence immunochromatography using specific monoclonal antibodies. AB - OBJECTIVES: To develop a rapid, sensitive and specific assay for quantification of serum heart-type fatty acid binding protein (H-FABP) based on immunofluorescence of specific monoclonal antibodies. DESIGN AND METHODS: We generated novel H-FABP-directed monoclonal antibodies by cloning of spleen cells of mice immunized with H-FABP. Epitopes were mapped and antigen affinity was assessed by surface plasmon resonance (SPR). The H-FABP specific monoclonal antibodies were coupled to fluorescent beads and sprayed onto a nitrocellulose membrane facilitating quantification of H-FABP by immunofluorescence. Reagent cross-reactivity, interference resistance, accuracy and sensitivity were examined. A total of 103 clinical samples were used to compare the sensitivity and specificity of the new assay to a commercially available Randox kit. RESULTS: This new assay could be finished within 15 min, with sensitivity reaching 1 ng/ml. In a trial of 103 clinical serum samples, the new testing kit results were highly correlated with those from the Randox kit (R(2) = 0.9707). Using the Randox kit as the reference kit, the sensitivity of the new assay was 98.25%, and specificity was 100%. CONCLUSIONS: An immunofluorescence-based H-FABP assay employing novel monoclonal antibodies could rapidly, specifically and sensitively detect H-FABP in serum samples, providing an effective method for rapid clinical assessment of H-FABP index in the clinic. PMID- 26426852 TI - Impact of incorrect filling of citrate blood sampling tubes on thromboelastometry. AB - BACKGROUND: ROTEM((r)) test results can be affected by the citrate to blood ratio in the tested sample. Overfilling or underfilling specimen tubes can change this ratio. OBJECTIVES: The aim of this study was to determine the impact of under- and overfilling citrate test tubes on ROTEM((r)) EXTEM measurements. RESULTS: Overall repeated measures ANOVA demonstrated significant differences of CT (p = 0.004), CFT (p = 0.005), A5 (p = 0.001), A10 (p <0.001), and MCF (p < 0.001). Pairwise comparison revealed that underfilling significantly altered the results of those parameters reflecting functional clot firmness (A5, A10, and MCF), while overfilling led to a prolongation of the CT results only. No differences were observed for alpha angle and maximum lysis. CONCLUSION: Both underfilling and overfilling specimen tubes have significant influence on the results of the ROTEM((r)) EXTEM test, although the small observed bias is likely of limited clinical relevance. However, it seems prudent to limit the maximum allowed difference in filling to less than +/- 10%. All ROTEM((r)) operators should be aware of this pre-analytical variable. PMID- 26426853 TI - Fluorescent glutathione probe based on MnO2-phenol formaldehyde resin nanocomposite. AB - MnO2-phenol formaldehyde resin (MnO2-PFR) nanocomposite is successfully prepared by a simple chemical reduction process. The resultant MnO2-PFR nanocomposite is well characterized. The absorption band of non-fluorescent MnO2 nanosheets overlaps well with the fluorescence emission of PFR nanoparticles. The green fluorescence of PFR in this nanocomposite can be effectively quenched by fluorescence resonance energy transfer from PFR to MnO2. In the presence of glutathione (GSH), the fluorescence of PFR could be recovered due to MnO2 was reduced to Mn(2+) by GSH. The nanocomposite can be use for detecting glutathione in blood serum. PMID- 26426855 TI - Self-reported benefit, sound perception, and quality-of-life in patients with auditory brainstem implants (ABIs). AB - CONCLUSION: The majority of the patients used their auditory brainstem implants (ABIs) all the time, reporting that he/she would make the decision to receive an implant again if the decision were reconsidered. The findings support that the ABI is a valuable treatment in patients with type 2 neurofibromatosis (NF2) and in children with congenital inner ear and nerve anomalies or cochlear ossification. OBJECTIVE: To evaluate the patients who underwent ABI implantation in Uppsala during 1993-2013. This study analyzed patients' implant use, perception of environmental sounds, perceived benefit from the implant, and quality-of-life (QoL). METHOD: The NF2-patients (n = 20) comprised the majority of the patients, and there were a few non-NF2 pediatric patients (n = 4). The exclusion criteria included deceased patients (n = 4) and patients with no hearing sensations from the implant, or those with an inactivated ABI (n = 2). The data were collected from a questionnaire survey. RESULTS: Eleven adult patients and two pediatric patients answered the questionnaires. Eight of the adult patients used their implants 'always'. The two children always used their implants. Hearing problems had the largest negative effect on the QoL. The non users and the users scored equally on the NFTI-QoL. PMID- 26426854 TI - Implications of Heterogeneous Biting Exposure and Animal Hosts on Trypanosomiasis brucei gambiense Transmission and Control. AB - The gambiense form of sleeping sickness is a neglected tropical disease, which is presumed to be anthroponotic. However, the parasite persists in human populations at levels of considerable rarity and as such the existence of animal reservoirs has been posited. Clarifying the impact of animal host reservoirs on the feasibility of interrupting sleeping sickness transmission through interventions is a matter of urgency. We developed a mathematical model allowing for heterogeneous exposure of humans to tsetse, with animal populations that differed in their ability to transmit infections, to investigate the effectiveness of two established techniques, screening and treatment of at-risk populations, and vector control. Importantly, under both assumptions, an integrated approach of human screening and vector control was supported in high transmission areas. However, increasing the intensity of vector control was more likely to eliminate transmission, while increasing the intensity of human screening reduced the time to elimination. Non-human animal hosts played important, but different roles in HAT transmission, depending on whether or not they contributed as reservoirs. If they did not serve as reservoirs, sensitivity analyses suggested their attractiveness may instead function as a sink for tsetse bites. These outcomes highlight the importance of understanding the ecological and environmental context of sleeping sickness in optimizing integrated interventions, particularly for moderate and low transmission intensity settings. PMID- 26426856 TI - Adrenergic beta2-receptor mediates itch hypersensitivity following heterotypic chronic stress in rats. AB - Chronic stress is widely considered to trigger or enhance itch, especially for pruritic dermatitis. However, the molecular mechanisms linking chronic stress and itch are still unknown. The present study aimed to elucidate the role of adrenergic signaling in itch hypersensitivity following heterotypic chronic intermittent stress (HIS) in rats. HIS significantly increased hindlimb scratching, but not forepaw swiping, induced by intradermal injection of 5 hydroxytryptamine (5-HT) in the rat cheek. Coadministration of stress mediators such as norepinephrine or epinephrine dose-dependently increased both 5-HT induced hindlimb scratching and 5-HT-induced forepaw swiping. HIS-induced itch hypersensitivity was attenuated by blockade of sympathetic signaling through guanethidine treatment, and systemic administration of the beta-adrenoceptor antagonist propranolol and the beta2-adrenoceptor antagonist butoxamine, but not on treatment with an alpha-adrenoceptor antagonist phentolamine and a beta1 adrenoceptor antagonist atenolol. Moreover, HIS selectively increased the expression of beta2-adrenoceptors and proinflammatory factors [tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and nerve growth factor (NGF)] in rat skin. The beta-blockers propranolol and butoxamine abolished the upregulation of proinflammatory factors. The beta2-adrenoceptor agonist terbutaline was sufficient to enhance the skin expression of TNF-alpha and IL 1beta and to increase 5-HT-induced scratching in naive rats. Pretreatment with TNF-alpha could increase 5-HT-induced scratching. Together, these results demonstrate that beta2-adrenoceptors mediate itch hypersensitivity following chronic stress by inducing proinflammatory factors, such as TNF-alpha, in the skin. PMID- 26426857 TI - Brain contrasts between migratory and nonmigratory North American lark sparrows (Chondestes grammacus). AB - The impact of evolving migratory behavior on brain organization in birds has been a foundational question in the emerging field of neuroecology. One generalization that seems to be approaching consensus is that migratory species/populations have smaller brain volumes than their nonmigratory comparison groups. The lark sparrow (Chondestes grammacus) is a North American species characterized by migratory and nonmigratory populations. Consistent with what has been observed in other species/population comparisons, we found that, relative to body weight, migratory females from Nebraska have smaller brain volumes than nonmigratory females from Texas. We also carried out an exploratory, higher-order analysis of possible differences in the volumes of a number of telencephalic subdivisions. Although our small sample size precluded statistical verification of any difference, noteworthy was that, although there seemed to be no indication of a difference in the relative hippocampal volume between the two populations, the migratory birds from Nebraska showed a clear trend toward a smaller nidopallium. The importance of higher-resolution, brain subdivisional analyses has been discussed. PMID- 26426858 TI - The influences of reappraisal and suppression instructions on memory for neutral words in negative background. AB - Previous studies have investigated the influences of emotion regulation on memory for emotional stimuli. However, whether and how emotion regulation impacts recognition memory for neutral items in negative background is still unclear. Thus, the present study used event-related potentials and the study-recognition memory task to examine the effects of the two commonly used emotion regulation strategies, cognitive reappraisal and expressive suppression, on recognition memory of neutral words centrally presented on negative pictures. The behavior results showed that, compared with suppression, the reappraisal strategy enhanced the neutral words memory. Moreover, the event-related potential data demonstrated larger FN400 old/new effect indexing familiarity and late positive component old/new effect presenting episodic information recollection for the reappraisal condition relative to view and suppression conditions. These might be due to significant elaboration encouraged by this strategy. PMID- 26426860 TI - Water-Dispersible, Responsive, and Carbonizable Hairy Microporous Polymeric Nanospheres. AB - Multifunctionalization of microporous polymers is highly desirable but remains a significant challenge, considering that the current microporous polymers are generally hydrophobic and nonresponsive to different environmental stimuli and difficult to be carbonized without damage of their well-defined nanomorphology. Herein, we demonstrate a facile and versatile method to fabricate water dispersible, pH/temperature responsive and readily carbonizable hairy microporous polymeric nanospheres based on combination of the hyper-cross-linking chemistry with the surface-initiated atom transfer radical polymerization (SI-ATRP). The hyper-cross-linking creates a highly microporous core, whereas the SI-ATRP provides diverse functionalities by surface grafting of hairy functional blocks. The as-prepared materials present multifunctional properties, including sensitive response to pH/temperature, high adsorption capacity toward adsorbates from aqueous solution, and valuable transformation into well-defined microporous carbon nanospheres because of hybrid of carbonizable core and thermo-decomposable protection shell. We hope this strategy could promote the development of both functional microporous polymers and advanced hairy nanoparticles for multipurpose applications. PMID- 26426859 TI - Tight junction disruption of blood-brain barrier in white matter lesions in chronic hypertensive rats. AB - Tight junctions (TJs) are the most important structure of the blood-brain barrier (BBB). Studies have shown that triggering of white matter lesions (WMLs) may be related to a BBB dysfunction, but rarely have studies observed the progressive changes in TJs longitudinally. In our present study, the ultrastructure of TJs was observed using a transmission electron microscope in Stroke-prone Renalvascular Hypertensive Rats. Western blotting was used to detect TJ-related proteins zonula occludens-1 and occludin. The results showed that in Stroke-prone Renalvascular Hypertensive Rats, the severity of WMLs increased gradually. TJs was destroyed gradually 8 weeks after hypertension. The levels of zonula occludens-1 and occludin also decreased gradually. These data suggested that long term hypertension may contribute toward the gradual disruption of TJs of BBB and induce WMLs in chronic hypertensive rats. PMID- 26426861 TI - Intravenous Delta-9-Tetrahydrocannabinol to Prevent Postoperative Nausea and Vomiting: A Randomized Controlled Trial. AB - BACKGROUND: Evidence suggests that cannabinoids can prevent chemotherapy-induced nausea and vomiting. The use of tetrahydrocannabinol (THC) has also been suggested for the prevention of postoperative nausea and vomiting (PONV), but evidence is very limited and inconclusive. To evaluate the effectiveness of IV THC in the prevention of PONV, we performed this double-blind, randomized, placebo-controlled trial with patient stratification according to the risk of PONV. Our hypothesis was that THC would reduce the relative risk of PONV by 25% compared with placebo. METHODS: With IRB approval and written informed consent, 40 patients at high risk for PONV received either 0.125 mg/kg IV THC or placebo at the end of surgery before emergence from anesthesia. The primary outcome parameter was PONV during the first 24 hours after emergence. Secondary outcome parameters included early and late nausea, emetic episodes and PONV, and side effects such as sedation or psychotropic alterations. RESULTS: The relative risk reduction of overall PONV in the THC group was 12% (95% confidence interval, -37% to 43%), potentially less than the clinically significant 25% relative risk reduction demonstrated by other drugs used for PONV prophylaxis. Calculation of the effect of treatment group on overall PONV by logistic regression adjusted for anesthesia time gave an odds ratio of 0.97 (95% confidence interval, 0.21 to 4.43, P = 0.97). Psychotropic THC side effects were clinically relevant and mainly consisted of sedation and confusion that were not tampered by the effects of anesthesia. The study was discontinued after 40 patients because of the inefficacy of THC against PONV and the finding of clinically unacceptable side effects that would impede the use of THC in the studied setting. CONCLUSIONS: Because of an unacceptable side effect profile and uncertain antiemetic effects, IV THC administered at the end of surgery before emergence from anesthesia cannot be recommended for the prevention of PONV in high-risk patients. PMID- 26426862 TI - A low-cost cementite (Fe3C) nanocrystal@N-doped graphitic carbon electrocatalyst for efficient oxygen reduction. AB - In this work, chitosan whiskers (CWs) were first extracted using low-cost and earth-abundant crab shells as materials by a series of chemical processes, and then assembled into chitosan whisker microspheres (CWMs) via a simple photochemical polymerization approach. Subsequently, a cementite (Fe3C) nanocrystal@N-doped graphitic carbon (Fe3C@NGC) nanocomposite was successfully fabricated by high temperature pyrolysis of CWMs adsorbed with ferric acetylacetonate (Fe(acac)3) at 900 degrees C. It was found that a suitable growth atmosphere generated inside CWMs during high temperature pyrolysis is critically important to form Fe3C nanocrystal cores, concurrently accompanying a structural transformation from chitosan whiskers to mesoporous graphitic carbon shells with natural nitrogen (N) doping properties, resulting in the formation of a core-shell structure Fe3C@NGC nanocomposite. The resulting samples were evaluated as electrocatalysts for oxygen reduction reaction (ORR). In comparison with sole N-doped graphitic carbon without Fe3C nanocrystals obtained by direct pyrolysis of chitosan whisker microspheres at 900 degrees C (CWMs-900), Fe3C@NGC showed significantly improved ORR catalytic activity. The tolerance to fuel cell molecules (e.g., methanol) and the durability of Fe3C@NGC are obviously superior to commercial Pt/C catalysts in alkaline media. The high ORR performance of Fe3C@NGC could be due to its large surface area (313.7 m(2) g(-1)), a synergistic role of Fe3C nanocrystals, N doping in graphitic carbon creating more catalytic active sites, and a porous structure of the nanocomposite facilitating mass transfer to efficiently improve the utilization of these catalytic active sites. PMID- 26426863 TI - Tuberculin reaction and BCG scar: association with infant mortality. AB - OBJECTIVE: To test the hypothesis that having a scar and a positive tuberculin skin test (TST) response after vaccination with Bacille Calmette-Guerin (BCG) is associated with reduced infant mortality. METHODS: We studied cohorts of 2709 normal-birthweight (NBW) and 1102 low-birthweight (LBW) infants in Guinea-Bissau. Children were enrolled in randomised trials between year 2002 and 2008 and received BCG vaccination at birth. BCG scars and TST responses were assessed at 2 and 6 months of age. The infants were followed for mortality to 12 months of age, and survival was analysed using Cox regression. RESULTS: At age 2 months, 88% of NBW children and 91% of LBW children had a BCG scar, and 36% and 17% had a TST response, respectively. The LBW infants had nearly twofold higher mortality (4.5%) than the NBW infants (2.8%) between 2 and 12 months of age. In the LBW cohort, the adjusted mortality rate ratio (MRR) comparing children with a BCG scar with those without was 0.42 (95% CI = 0.19; 0.93). There was a similar tendency for TST positivity: MRR = 0.47 (95% CI = 0.14; 1.54). For LBW children who had both a positive TST reaction and a scar, the MRR was 0.22 (95% CI = 0.05; 0.87). For NBW children, a scar and a positive TST were associated with 20% reductions in mortality, which did not reach statistical significance. CONCLUSION: We confirmed previous observations that having a scar and a TST response after BCG vaccination is associated with lower mortality risk. The possibility of revaccinating scar-negative children should be considered. PMID- 26426864 TI - Rapid Determination of the Specificity Constant of Irreversible Inhibitors (kinact/KI) by Means of an Endpoint Competition Assay. AB - Owing to their covalent target occupancy, irreversible inhibitors require low exposures and offer long duration, and their use thus represents a powerful strategy for achieving pharmacological efficacy. Importantly, the potency metric of irreversible inhibitors is kinact/KI not IC50. A simple approach to measuring kinact/KI was developed that makes use of an irreversible probe for competitive assays run to completion against test compounds. In this system, the kinact/KI value of the test compound is equal to (kinact/KI)probe *[probe]/IC50. The advantages of this method include simplicity, high throughput, and application to all target classes, and it only requires an in-depth kinetic evaluation of the probe. PMID- 26426866 TI - Establishment of a specific cell death induction system in Bombyx mori by a transgene with the conserved apoptotic regulator, mouse Bcl-2-associated X protein (mouse Bax). AB - The induction of apoptosis in vivo is a useful tool for investigating the functions and importance of particular tissues. B-cell leukaemia/lymphoma 2 associated X protein (Bax) functions as a pro-apoptotic factor and induces apoptosis in several organisms. The Bax-mediated apoptotic system is widely conserved from Caenorhabditis elegans to humans. In order to establish a tissue specific cell death system in the domestic silkworm, Bombyx mori, we constructed a transgenic silkworm that overexpressed mouse Bax (mBax) in particular tissues by the Gal4-upstream activation sequence system. We found that the expression of mBax induced specific cell death in the silk gland, fat body and sensory cells. Fragmentation of genomic DNA was observed in the fat body, which expressed mBax, thereby supporting apoptotic cell death in this tissue. Using this system, we also demonstrated that specific cell death in sensory cells attenuated the response to the sex pheromone bombykol. These results show that we successfully established a tissue-specific cell death system in vivo that enabled specific deficiencies in particular tissues. The inducible cell death system may provide useful means for industrial applications of the silkworm and possible utilization for other species. PMID- 26426865 TI - Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum. AB - A challenge in obstetrics is to distinguish pathological symptoms from those associated with normal changes of pregnancy, typified by the need to differentiate whether gestational pruritus of the skin is an early symptom of intrahepatic cholestasis of pregnancy (ICP) or due to benign pruritus gravidarum. ICP is characterized by raised serum bile acids and complicated by spontaneous preterm labor and stillbirth. A biomarker for ICP would be invaluable for early diagnosis and treatment and to enable its differentiation from other maternal diseases. Three progesterone sulfate compounds, whose concentrations have not previously been studied, were newly synthesized and assayed in the serum of three groups of ICP patients and found to be significantly higher in ICP at 9-15 weeks of gestation and prior to symptom onset (group 1 cases/samples: ICP n = 35/80, uncomplicated pregnancy = 29/100), demonstrating that all three progesterone sulfates are prognostic for ICP. Concentrations of progesterone sulfates were associated with itch severity and, in combination with autotaxin, distinguished pregnant women with itch that would subsequently develop ICP from pruritus gravidarum (group 2: ICP n = 41, pruritus gravidarum n = 14). In a third group of first-trimester samples all progesterone sulfates were significantly elevated in serum from low-risk asymptomatic women who subsequently developed ICP (ICP/uncomplicated pregnancy n = 54/51). Finally, we show mechanistically that progesterone sulfates mediate itch by evoking a Tgr5-dependent scratch response in mice. CONCLUSION: Our discovery that sulfated progesterone metabolites are a prognostic indicator for ICP will help predict onset of ICP and distinguish it from benign pruritus gravidarum, enabling targeted obstetric care to a high-risk population. Delineation of a progesterone sulfate-TGR5 pruritus axis identifies a therapeutic target for itch management in ICP. PMID- 26426867 TI - Pneumothorax in a dog caused by necrotizing pneumonia secondary to heatstroke. AB - OBJECTIVE: To describe the clinical course, diagnostic findings, medical and surgical treatments, and outcome in a dog with spontaneous pneumothorax secondary to necrotizing pneumonia thought to be a delayed complication of heatstroke. CASE SUMMARY: A 1.5-year-old Labrador Retriever developed spontaneous pneumothorax 12 days after an episode of exertional heat stroke. Computed tomography was performed and showed bilateral pneumothorax and multifocal pulmonary consolidation, especially at the lung periphery. A median sternotomy was performed, and multifocal, well-demarcated areas of consolidated pulmonary tissue with purple discoloration were identified and resected from the right middle, right caudal, and accessory lung lobes. Histologic examination of the resected pulmonary tissue indicated necrotizing pneumonia, and bacteriologic culture of the tissue resulted in growth of Pseudomonas aeruginosa. Examination of tissue from a pectoral muscle biopsy performed at this time showed necrotizing myopathy. The dog was discharged 7 days after surgery and made a full recovery. NEW OR UNIQUE INFORMATION PROVIDED: This case report describes pneumothorax and multifocal necrotizing pneumonia as a delayed complication of heatstroke, and provides the first description of the computed tomography appearance of histologically confirmed necrotizing pneumonia in a dog. Multifocal necrotizing pneumonia with or without pneumothorax should be considered in dogs that develop respiratory distress following severe systemic illness. PMID- 26426869 TI - News from the pediatric anesthesia societies: the Congenital Cardiac Anesthesia Society. PMID- 26426870 TI - The puzzling aspects of anesthesia and autism spectrum disorder. PMID- 26426871 TI - Why rare diseases are of special interest to pediatric anesthesiologists. PMID- 26426872 TI - Response to Dr A Snoek - 'Useful as a point-of-care algorithm?'. PMID- 26426873 TI - Useful as a point-of-care algorithm? PMID- 26426874 TI - Response to editorial comments by Drs. Williams and Ramamoorthy. PMID- 26426875 TI - Surveys and all--the role of pediatric anesthetic societies. PMID- 26426876 TI - Reply to Engelhardt, Thomas; Wolf, Andy, regarding their comment 'Surveys and all -the role of pediatric anesthetic societies'. PMID- 26426877 TI - Evaluating the efficacy and safety of scalp blocks in nonsyndromic craniosynostosis surgery. PMID- 26426878 TI - Laryngospasm notch pressure ('Larson's maneuver') may have a role in laryngospasm management in children: highlighting a so far unproven technique. PMID- 26426879 TI - Is the supraclavicular approach to the central vein still risky and taboo? PMID- 26426880 TI - Anesthesia and the developing brain: a way forward for clinical research. PMID- 26426881 TI - Globotriaosylceramide inhibits iNKT-cell activation in a CD1d-dependent manner. AB - Globotriaosylceramide (Gb3) is a glycosphingolipid present in cellular membranes that progressively accumulates in Fabry disease. Invariant Natural Killer T (iNKT) cells are a population of lipid-specific T cells that are phenotypically and functionally altered in Fabry disease. The mechanisms responsible for the iNKT-cell alterations in Fabry disease are not well understood. Here, we analyzed the effect of Gb3 on CD1d-mediated iNKT-cell activation in vitro using human cells and in vivo in the mouse model. We found that Gb3 competes with endogenous and exogenous antigens for CD1d binding, thereby reducing the activation of iNKT cells. This effect was exerted by a reduction in the amount of stimulatory CD1d:alpha-GalCer complexes in the presence of Gb3 as demonstrated by using an mAb specific for the complex. We also found that administration of Gb3 delivered to the same APC as alpha-GalCer, induces reduced iNKT-cell activation in vivo. This work highlights the complexity of iNKT-cell activation and the importance of nonantigenic glycosphingolipids in the modulation of this process. PMID- 26426882 TI - Determination of Intermolecular Interactions Using Polarization Compensated Heteronuclear Overhauser Effect of Hyperpolarized Spins. AB - The nuclear Overhauser effect (NOE) has long been used as a selective indicator for intermolecular interactions. Due to relatively small changes of signal intensity, often on the order of several percent, quantitative NOE measurements can be challenging. Hyperpolarization of nuclear spins can dramatically increase the NOE intensity by increasing population differences, but poses its own challenge in quantifying the original polarization level. Here, we demonstrate a method for the accurate measurement of intermolecular heteronuclear cross relaxation rates by simultaneous acquisition of signals from both nuclei. Using this method, we measure cross-relaxation rates between water protons and (19)F of trifluoroacetic acid at concentrations ranging from 23 to 72 mM. A concentration independent value of 2.46 * 10(-4) +/- 1.02 * 10(-5) s(-1) M(-1) is obtained at a temperature of 301 K and validated using a nonhyperpolarized measurement. In a broader context, accurate measurement of heteronuclear cross-relaxation rates may enable the study of intermolecular interactions including those involving macromolecules where (19)F atoms can be introduced as site-selective labels. PMID- 26426883 TI - Multigene panels in prostate cancer risk assessment: a systematic review. AB - PURPOSE: Single-nucleotide polymorphism (SNP) panel tests have been proposed for use in the detection of, and prediction of risk for, prostate cancer and as prognostic indicator in affected men. A systematic review was undertaken to address three research questions to evaluate the analytic validity, clinical validity, clinical utility, and prognostic validity of SNP-based panels. METHODS: Data sources comprised MEDLINE, Cochrane CENTRAL, Cochrane Database of Systematic Reviews, and EMBASE; these were searched from inception to April 2013. The gray literature searches included contact with manufacturers. Eligible studies included English-language studies evaluating commercially available SNP panels. Study selection and risk of bias assessment were undertaken by two independent reviewers. RESULTS: Twenty-one studies met eligibility criteria. All focused on clinical validity and evaluated 18 individual panels with 2 to 35 SNPs. All had poor discriminative ability (overall area under receiver-operator characteristic curves, 58-74%; incremental gain resulting from inclusion of SNP data, 2.5-11%) for predicting risk of prostate cancer and/or distinguishing between aggressive and asymptomatic/latent disease. The risk of bias of the studies, as assessed by the Newcastle Ottawa Scale (NOS) and Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tools, was moderate. CONCLUSION: The evidence on currently available SNP panels is insufficient to assess analytic validity, and at best the panels assessed would add a small and clinically unimportant improvement to factors such as age and family history in risk stratification (clinical validity). No evidence on the clinical utility of current panels is available.Genet Med 18 6, 535-544. PMID- 26426885 TI - Magnetic nanoparticles for biomedical applications. PMID- 26426886 TI - Mild cognitive impairment affects motor control and skill learning. AB - Mild cognitive impairment (MCI) is a transitional phase between normal cognitive aging and dementia. As the world population is aging rapidly, more MCI patients will be identified, posing significant problems to society. Normal aging is associated with cognitive and motor decline, and MCI brings additional impairments. Compared to healthy older adults, MCI patients show poorer motor control in a variety of tasks. Efficient motor control and skill learning are essential for occupational and leisure purposes; degradation of motor behaviors in MCI patients often adversely affects their health and quality of life. In this article, we first define MCI and describe its pathology and neural correlates. After this, we review cognitive changes and motor control and skill learning in normal aging. This section is followed by a discussion of MCI-related degradation of motor behaviors. Finally, we propose that multicomponent interventions targeting both cognitive and motor domains can improve MCI patients' motor functions. Future research directions are also raised. PMID- 26426884 TI - Cesarean delivery is not associated with decreased at-birth fracture rates in osteogenesis imperfecta. AB - PURPOSE: Osteogenesis imperfecta (OI) predisposes to recurrent fractures. Patients with the moderate to severe forms of OI present with antenatal fractures, and the mode of delivery that would be safest for the fetus is not known. METHODS: We conducted systematic analyses of the largest cohort of individuals with OI (n = 540) enrolled to date in the OI Linked Clinical Research Centers. Self-reported at-birth fracture rates were compared among individuals with OI types I, III, and IV. Multivariate analyses utilizing backward elimination logistic regression model building were performed to assess the effect of multiple covariates, including method of delivery, on fracture-related outcomes. RESULTS: When accounting for other covariates, at-birth fracture rates did not differ based on whether delivery was by vaginal route or by cesarean delivery (CD). Increased birth weight conferred higher risk for fractures irrespective of the delivery method. In utero fracture, maternal history of OI, and breech presentation were strong predictors for choosing CD. CONCLUSION: Our study, the largest to analyze the effect of various factors on at-birth fracture rates in OI, shows that CD is not associated with decreased fracture rate. With the limitation that the fracture data were self-reported in this cohort, these results suggest that CD should be performed only for other maternal or fetal indications, not for the sole purpose of fracture prevention in OI.Genet Med 18 6, 570-576. PMID- 26426888 TI - Cannabis - the Israeli perspective. AB - Short overviews are presented on the historical uses of cannabis in the Middle East and on the more recent scientific and medical research on phytocannabinoids and the endocannabinoid system, with emphasis on research contributions from Israel. These are followed by examples of research projects and clinical trials with cannabinoids and by a short report on the regulation of medical marijuana in Israel, which at present is administered to over 22,000 patients. PMID- 26426887 TI - Targeting the endocannabinoid system to treat anxiety-related disorders. AB - The endocannabinoid system plays an important role in the control of emotions, and its dysregulation has been implicated in several psychiatric disorders. The most common self-reported reason for using cannabis is rooted in its ability to reduce feelings of stress, tension, and anxiety. Nevertheless, there are only few studies in controlled clinical settings that confirm that administration of cannabinoids can benefit patients with a post-traumatic stress disorder (PTSD). There are considerable encouraging preclinical data to suggest that endocannabinoid-targeted therapeutics for anxiety disorders should continue. In this review, we will describe data supporting a role for the endocannabinoid system in preventing and treating anxiety-like behavior in animal models and PTSD patients. Cannabinoids have shown beneficial outcomes in rat and mouse models of anxiety and PTSD, but they also may have untoward effects that discourage their chronic usage, including anxiogenic effects. Hence, clinical and preclinical research on the endocannabinoid system should further study the effects of cannabinoids on anxiety and help determine whether the benefits of using exogenous cannabinoids outweigh the risks. In general, this review suggests that targeting the endocannabinoid system represents an attractive and novel approach to the treatment of anxiety-related disorders and, in particular, PTSD. PMID- 26426889 TI - Synthesis of androstanopyridine and pyrimidine compounds as novel activators of the tumor suppressor protein p53. AB - A series of androstane derivatives 2-16 were synthesized from 3beta hydroxyandrostan-17-one derivatives (1a-e). Compounds (1a,b) were treated with ethyl cyanoacetate, cyanoacetamide, or malononitrile and gave the corresponding derivatives 2-7, respectively. Additionally, compounds (1a-e) were condensed with cyanothioacetamide, urea, or guanidine hydrochloride afforded the corresponding derivatives 8-12, which then by Moffat oxidation gave the oxidized derivatives 9, 11 and 13, respectively. Finally, compound (1) condensed with acetyl acetone or ethyl acetoacetate gave cyclohexene derivatives (14a-c) and (15a,b), respectively. Compound 15 was oxidized with a Moffat oxidizing agent and afforded the corresponding oxidized compound 16. The newly synthesized compounds activated the tumor suppressor p53 in cancer cells through inhibition of the p53-specific ubiquitin E3 ligase HDM2. PMID- 26426890 TI - Comparison between B.R.A.H.M.S PCT direct, a new sensitive point-of-care testing device for rapid quantification of procalcitonin in emergency department patients and established reference methods - a prospective multinational trial. AB - BACKGROUND: Procalcitonin (PCT) is increasingly being used for the diagnostic and prognostic work up of patients with suspected infections in the emergency department (ED). Recently, B.R.A.H.M.S PCT direct, the first high sensitive point of-care test (POCT), has been developed for fast PCT measurement on capillary or venous blood samples. METHODS: This is a prospective, international comparison study conducted in three European EDs. Consecutive patients with suspicion of bacterial infection were included. Duplicate determination of PCT was performed in capillary (fingertip) and venous whole blood (EDTA), and compared to the reference method. The diagnostic accuracy was evaluated by correlation and concordance analyses. RESULTS: Three hundred and three patients were included over a 6-month period (60.4% male, median age 65.2 years). The correlation between capillary or venous whole blood and the reference method was excellent: r2=0.96 and 0.97, sensitivity 88.1% and 93.0%, specificity 96.5% and 96.8%, concordance 93% and 95%, respectively at a 0.25 MUg/L threshold. No significant bias was observed (-0.04 and -0.02 for capillary and venous whole blood) although there were 6.8% and 5.1% outliers, respectively. B.R.A.H.M.S PCT direct had a shorter time to result as compared to the reference method (25 vs. 144 min, difference 119 min, 95% CI 110-134 min, p<0.0001). CONCLUSIONS: This study found a high diagnostic accuracy and a faster time to result of B.R.A.H.M.S PCT direct in the ED setting, allowing shortening time to therapy and a more wide-spread use of PCT. PMID- 26426891 TI - Non-fasting plasma glucose concentration in blood donors. PMID- 26426892 TI - Croatian laboratories have a good knowledge of the proper detection and management of hemolyzed, icteric and lipemic samples. AB - BACKGROUND: Endogenous interferences are an important source of biased laboratory results. Hemolysis, lipemia and icteria are the main source of endogenous interference in laboratory medicine. Accreditation according to ISO 15189 improves the overall quality of the laboratory procedures. The aim of our study was i) to assess the level of knowledge of Croatian medical biochemists about the proper detection and management of hemolysis, lipemia and icteria; and ii) to identify possible differences in the level of knowledge respective to the laboratory accreditation status. METHODS: An on-line self-report survey was carried out by the Working Group for Preanalytical Phase of the Croatian Society of Medical Biochemistry and Laboratory Medicine during April to May 2015. Survey included 14 statements (Q1-Q14) about procedures for samples with interferences and participants were asked to assess the degree of agreement with the statement using a 4-point Likert scale. RESULTS: The lowest level of knowledge was observed for statements Q10 (dealing with icteric sample; 40.9% participants agreed with the correct procedure), Q12 (allowable error for interference; 47.2%) and Q11 (dealing with lipemic sample; 60.1%). Almost all participants (97.4%) agreed that laboratories in Croatia should have a harmonized protocol for management of samples with interferences. Participants from accredited laboratories showed higher knowledge of hemolysis detection (p=0.031), rejection of hemolyzed sample (p<0.001), management of icteric samples (p=0.038) and allowable error for interferences (p=0.040). CONCLUSIONS: Croatian laboratories have a good knowledge of the proper detection and management of hemolyzed, icteric and lipemic samples. Accreditation is associated with higher knowledge about management of samples with interferences. PMID- 26426893 TI - Useful measures and models for analytical quality management in medical laboratories. AB - The 2014 Milan Conference "Defining analytical performance goals 15 years after the Stockholm Conference" initiated a new discussion of issues concerning goals for precision, trueness or bias, total analytical error (TAE), and measurement uncertainty (MU). Goal-setting models are critical for analytical quality management, along with error models, quality-assessment models, quality-planning models, as well as comprehensive models for quality management systems. There are also critical underlying issues, such as an emphasis on MU to the possible exclusion of TAE and a corresponding preference for separate precision and bias goals instead of a combined total error goal. This opinion recommends careful consideration of the differences in the concepts of accuracy and traceability and the appropriateness of different measures, particularly TAE as a measure of accuracy and MU as a measure of traceability. TAE is essential to manage quality within a medical laboratory and MU and trueness are essential to achieve comparability of results across laboratories. With this perspective, laboratory scientists can better understand the many measures and models needed for analytical quality management and assess their usefulness for practical applications in medical laboratories. PMID- 26426894 TI - Development of reference intervals for serum alkaline phosphatase among adults in Southern China traced to the new IFCC reference measurement procedure. AB - BACKGROUND: Serum alkaline phosphatase (ALP) plays a critical role in the diagnosis of various diseases, and the establishment of relevant, reliable reference intervals (RI) is key to avoiding misdiagnoses. In 2011, IFCC published the new reference measurement procedure (RMP) for the determination of serum ALP in which one of the main modifications was the measuring temperature of the assay. Here, the new RMP was used to help establish RIs for serum ALP concentrations in healthy Chinese Han. METHODS: Volunteer individuals in Guangdong province, China (n=1622) were screened by questionnaire and laboratory testing for eligibility as a reference. Blood (20 mL) was collected and samples were measured by the Roche Modular system using the new RMP for the serum ALP compatible method. Partitioning of values by gender and/or age was evaluated with a standard normal deviate test after removing outliers. A simple non-parametric method for a two-sided 95% distribution of reference values was calculated. RESULTS: Serum ALP concentrations were obtained from the cohort of eligible reference individuals (n=658). The RI for serum ALP in males age 18-79 years was 48-131 U/L. Females were partitioned into two age groups based on statistical analysis, 18-49 years and 50-79 years, and the RIs derived were 40-106 U/L and 57 159 U/L, respectively. CONCLUSIONS: RIs for serum ALP for Chinese Han individuals in between the ages of 18 and 79 years were determined and required partitioning due to the higher ALP values of females age 50-79 years. PMID- 26426895 TI - Birth season predicts the values of red blood cell distribution width (RDW) in adulthood. AB - BACKGROUND: Recent evidence suggests that red blood cell distribution width (RDW), a simple measure of anisocytosis, may predict the risk of adverse clinical outcomes in both the general population and in patients with severe pathologies. Since it was also shown that the birth season influences the lifetime disease risk, this study was aimed to investigate whether an association may exist between adult RDW values and birth season. METHODS: The study population consisted in healthy Caucasian blood donors aged 18 or older, undergoing routine laboratory testing before regular blood donation. RESULTS: Overall, 6122 healthy blood donors were included in this study (median age 41 years; 1807 women and 4315 men). Age, sex, mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) but not hemoglobin and hematocrit were found to be independent predictors of RDW. When the study population was classified according to birth season, a significant difference was found for RDW values, but not for age, sex, hemoglobin, hematocrit, MCV and MCH. Subjects born in spring exhibited RDW values generally higher compared to those born in other seasons, reaching statistical significance when compared to those born in summer and winter. In particular, subjects born in spring had a 33% (p=0.014) higher probability of displaying increased RDW values in adulthood compared to those with summer birth. CONCLUSIONS: Despite additional studies that are needed to confirm these original findings, the evidence that a significant link exists between birth season and adult anisocytosis provides a plausible explanation for the association between birth season and lifetime disease risk. PMID- 26426896 TI - A robust distribution-free test for genetic association studies of quantitative traits. AB - In association studies of quantitative traits, the association of each genetic marker with the trait of interest is typically tested using the F-test assuming an additive genetic model. In practice, the true model is rarely known, and specifying an incorrect model can lead to a loss of power. For case-control studies, the maximum of test statistics optimal for additive, dominant, and recessive models has been shown to be robust to model misspecification. The approach has later been extended to quantitative traits. However, the existing procedures assume that the trait is normally distributed and may not maintain correct type I error rates and can also have reduced power when the assumption of normality is violated. Here, we introduce a maximum (MAX3) test that is based on ranks and is therefore distribution-free. We examine the behavior of the proposed method using a Monte Carlo simulation with both normal and non-normal data and compare the results to the usual parametric procedures and other nonparametric alternatives. We show that the rank-based maximum test has favorable properties relative to other tests, especially in the case of symmetric distributions with heavy tails. We illustrate the method with data from a real association study of symmetric dimethylarginine (SDMA). PMID- 26426897 TI - Likelihood ratio and score burden tests for detecting disease-associated rare variants. AB - This paper presents two simple rare variant (RV) burden tests based on the likelihood ratio test (LRT) and score statistics. LRT is one of the commonly used tests in practical data analysis, and we show here that there is no reason to ignore it in testing RV associations. With the Bartlett correction, we have numerically shown that the LRT-based test can have a reliable distribution. Our simulation study indicates that if the non-null variants are as common as the null variants, then the LRT and score statistics have comparable performance to the C-alpha test, and if the former is rarer than the null variants, then they outperform the C-alpha test. PMID- 26426898 TI - Plant responses to climatic extremes: within-species variation equals among species variation. AB - Within-species and among-species differences in growth responses to a changing climate have been well documented, yet the relative magnitude of within-species vs. among-species variation has remained largely unexplored. This missing comparison impedes our ability to make general predictions of biodiversity change and to project future species distributions using models. We present a direct comparison of among- versus within-species variation in response to three of the main stresses anticipated with climate change: drought, warming, and frost. Two earlier experiments had experimentally induced (i) summer drought and (ii) spring frost for four common European grass species and their ecotypes from across Europe. To supplement existing data, a third experiment was carried out, to compare variation among species from different functional groups to within species variation. Here, we simulated (iii) winter warming plus frost for four grasses, two nonleguminous, and two leguminous forbs, in addition to eleven European ecotypes of the widespread grass Arrhenatherum elatius. For each experiment, we measured: (i) C/N ratio and biomass, (ii) chlorophyll content and biomass, and (iii) plant greenness, root (15) N uptake, and live and dead tissue mass. Using coefficients of variation (CVs) for each experiment and response parameter, a total of 156 within- vs. among-species comparisons were conducted, comparing within-species variation in each of four species with among-species variation for each seed origin (five countries). Of the six significant differences, within-species CVs were higher than among-species CVs in four cases. Partitioning of variance within each treatment in two of the three experiments showed that within-species variability (ecotypes) could explain an additional 9% of response variation after accounting for the among-species variation. Our observation that within-species variation was generally as high as among-species variation emphasizes the importance of including both within- and among-species variability in ecological theory (e.g., the insurance hypothesis) and for practical applications (e.g., biodiversity conservation). PMID- 26426899 TI - Galactose-alpha-1,3-Galactose Allergy Is Not a Hitherto Unrecognized Cause of Chronic Spontaneous Urticaria. AB - BACKGROUND: Tick bite-induced galactose-alpha-1,3-galactose (alpha-Gal) IgE and subsequent ingestion of red meat may cause delayed severe allergic reactions including urticaria, gastrointestinal symptoms or anaphylaxis. We tested the hypothesis that increased levels of IgE to alpha-Gal due to tick bites and the subsequent ingestion of red meat or meat products may possibly be an un(der)recognized cause of chronic spontaneous urticaria (CSU). METHODS: Levels of IgE to alpha-Gal and total IgE were measured (ImmunoCAP, Phadia AB/Thermo Fisher Scientific) in 83 patients (61 female and 22 male, median age 43 years, range 18-82) from the Department of Dermatology and Allergy, Charite - Universitatsmedizin, Berlin, Germany. All had been clinically diagnosed with moderate-to-severe CSU of a median duration of 2.9 years (range 0.1-50). RESULTS: Eighty of the 83 patients (96%) had undetectable (<0.1 kUA/l) serum levels of IgE against alpha-Gal. The levels in the remaining 3 were all low (0.25, 0.4 and 3.1 kUA/l). In no patient, including those with measurable serum levels of IgE against alpha-Gal, was eating red meat associated with the development of symptoms of urticaria. CONCLUSION: Our results indicate that an allergic response to alpha-Gal is highly unlikely to be a hitherto unrecognized common cause of CSU. PMID- 26426900 TI - Inhibitory Effects of Green Tea and (-)-Epigallocatechin Gallate on Transport by OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K and P-Glycoprotein. AB - Green tea catechins inhibit the function of organic anion transporting polypeptides (OATPs) that mediate the uptake of a diverse group of drugs and endogenous compounds into cells. The present study was aimed at investigating the effect of green tea and its most abundant catechin epigallocatechin gallate (EGCG) on the transport activity of several drug transporters expressed in enterocytes, hepatocytes and renal proximal tubular cells such as OATPs, organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), and P glycoprotein (P-gp). Uptake of the typical substrates metformin for OCTs and MATEs and bromosulphophthalein (BSP) and atorvastatin for OATPs was measured in the absence and presence of a commercially available green tea and EGCG. Transcellular transport of digoxin, a typical substrate of P-gp, was measured over 4 hours in the absence and presence of green tea or EGCG in Caco-2 cell monolayers. OCT1-, OCT2-, MATE1- and MATE2-K-mediated metformin uptake was significantly reduced in the presence of green tea and EGCG (P < 0.05). BSP net uptake by OATP1B1 and OATP1B3 was inhibited by green tea [IC50 2.6% (v/v) and 0.39% (v/v), respectively]. Green tea also inhibited OATP1B1- and OATP1B3 mediated atorvastatin net uptake with IC50 values of 1.9% (v/v) and 1.0% (v/v), respectively. Basolateral to apical transport of digoxin was significantly decreased in the presence of green tea and EGCG. These findings indicate that green tea and EGCG inhibit multiple drug transporters in vitro. Further studies are necessary to investigate the effects of green tea on prototoypical substrates of these transporters in humans, in particular on substrates of hepatic uptake transporters (e.g. statins) as well as on P-glycoprotein substrates. PMID- 26426901 TI - Population Trends of Central European Montane Birds Provide Evidence for Adverse Impacts of Climate Change on High-Altitude Species. AB - Climate change is among the most important global threats to biodiversity and mountain areas are supposed to be under especially high pressure. Although recent modelling studies suggest considerable future range contractions of montane species accompanied with increased extinction risk, data allowing to test actual population consequences of the observed climate changes and identifying traits associated to their adverse impacts are very scarce. To fill this knowledge gap, we estimated long-term population trends of montane birds from 1984 to 2011 in a central European mountain range, the Giant Mountains (Krkonose), where significant warming occurred over this period. We then related the population trends to several species' traits related to the climate change effects. We found that the species breeding in various habitats at higher altitudes had more negative trends than species breeding at lower altitudes. We also found that the species moved upwards as a response to warming climate, and these altitudinal range shifts were associated with more positive population trends at lower altitudes than at higher altitudes. Moreover, long-distance migrants declined more than residents or species migrating for shorter distances. Taken together, these results indicate that the climate change, besides other possible environmental changes, already influences populations of montane birds with particularly adverse impacts on high-altitude species such as water pipit (Anthus spinoletta). It is evident that the alpine species, predicted to undergo serious climatically induced range contractions due to warming climate in the future, already started moving along this trajectory. PMID- 26426903 TI - Causes and Consequences of Schadenfreude and Sympathy: A Developmental Analysis. AB - Moral judgments and moral emotions are a ubiquitous feature of social interactions. Humans decide quickly and intuitively whether an action is morally right or wrong. Schadenfreude and sympathy, as emotional reactions to the misfortunes of others, are prototypical moral emotions. So far, however, little evidence exists concerning children's understanding of schadenfreude. Within three studies, we investigated the experience of schadenfreude and sympathy among N = 364 children of different age groups. We interviewed the children while showing them picture stories. In the picture stories, we varied the behavior of the protagonist prior to a misfortune: (1) whether his behavior had been morally right or wrong, (2) whether the protagonist attained his goal, (3) whether the protagonist was responsible for the misfortune. In addition, in one study we varied (4) the emotional relationship of the interviewed children to the protagonist. Furthermore, we asked the children to decide whether they want to sit next to the protagonist or do him a favor. Results show that children experience sympathy as well as schadenfreude at the age of 4 years. Sympathy is more likely to arise when the protagonists of a story are likable, when these actors typically pursue morally positive goals, and if they are not responsible for their misfortune. In contrast, schadenfreude is more likely when the protagonist is disliked, when actors pursue immoral goals and if they are responsible for their misfortune. In addition, sympathy increases approach (helping behavior, sitting next to the agent and doing favors), whereas schadenfreude increases avoidance tendencies. PMID- 26426902 TI - N-3 Polyunsaturated Fatty Acids (PUFAs) Reverse the Impact of Early-Life Stress on the Gut Microbiota. AB - BACKGROUND: Early life stress is a risk factor for many psychiatric disorders ranging from depression to anxiety. Stress, especially during early life, can induce dysbiosis in the gut microbiota, the key modulators of the bidirectional signalling pathways in the gut-brain axis that underline several neurodevelopmental and psychiatric disorders. Despite their critical role in the development and function of the central nervous system, the effect of n-3 polyunsaturated fatty acids (n-3 PUFAs) on the regulation of gut-microbiota in early-life stress has not been explored. METHODS AND RESULTS: Here, we show that long-term supplementation of eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) (80% EPA, 20% DHA) n-3 PUFAs mixture could restore the disturbed gut microbiota composition of maternally separated (MS) female rats. Sprague-Dawley female rats were subjected to an early-life stress, maternal separation procedure from postnatal days 2 to 12. Non-separated (NS) and MS rats were administered saline, EPA/DHA 0.4 g/kg/day or EPA/DHA 1 g/kg/day, respectively. Analysis of the gut microbiota in adult rats revealed that EPA/DHA changes composition in the MS, and to a lesser extent the NS rats, and was associated with attenuation of the corticosterone response to acute stress. CONCLUSIONS: In conclusion, EPA/DHA intervention alters the gut microbiota composition of both neurodevelopmentally normal and early-life stressed animals. This study offers insights into the interaction between n-3 PUFAs and gut microbes, which may play an important role in advancing our understanding of disorders of mood and cognitive functioning, such as anxiety and depression. PMID- 26426905 TI - A Symposium in Honor of Richard G. Powell, a Long-Time Associate Editor of the Journal of Natural Products. PMID- 26426904 TI - The Effect of Comorbidity on Glycemic Control and Systolic Blood Pressure in Type 2 Diabetes: A Cohort Study with 5 Year Follow-Up in Primary Care. AB - AIMS: To explore the longitudinal effect of chronic comorbid diseases on glycemic control (HbA1C) and systolic blood pressure (SBP) in type 2 diabetes patients. METHODS: In a representative primary care cohort of patients with newly diagnosed type 2 diabetes in The Netherlands (n = 610), we tested differences in the five year trend of HbA1C and SBP according to comorbidity profiles. In a mixed model analysis technique we corrected for relevant covariates. Influence of comorbidity (a chronic disease already present when diabetes was diagnosed) was tested as total number of comorbid diseases, and as presence of specific disease groups, i.e. cardiovascular, mental, and musculoskeletal disease, malignancies, and COPD. In subgroup effect analyses we tested if potential differences were modified by age, sex, socioeconomic status, and BMI. RESULTS: The number of comorbid diseases significantly influenced the SBP trend, with highest values after five years for diabetes patients without comorbidity (p = 0.005). The number of diseases did not influence the HbA1C trend (p = 0.075). Comorbid musculoskeletal disease resulted in lower HbA1C at the time of diabetes diagnosis, but in higher values after five years (p = 0.044). Patients with cardiovascular diseases had sustained elevated levels of SBP (p = 0.014). Effect modification by socioeconomic status was observed in some comorbidity subgroups. CONCLUSIONS: Presence of comorbidity in type 2 diabetes patients affected the long-term course of HbA1C and SBP in this primary care cohort. Numbers and types of comorbidity showed differential effects: not the simple sum of diseases, but specific types of comorbid disease had a negative influence on long-term diabetes control parameters. The complex interactions between comorbidity, diabetes control and effect modifiers require further investigation and may help to personalize treatment goals. PMID- 26426906 TI - Comparison of high-intensity sound and mechanical vibration for cleaning porous titanium cylinders fabricated using selective laser melting. AB - Orthopedic components, such as the acetabular cup in total hip joint replacement, can be fabricated using porous metals, such as titanium, and a number of processes, such as selective laser melting. The issue of how to effectively remove loose powder from the pores (residual powder) of such components has not been addressed in the literature. In this work, we investigated the feasibility of two processes, acoustic cleaning using high-intensity sound inside acoustic horns and mechanical vibration, to remove residual titanium powder from selective laser melting-fabricated cylinders. With acoustic cleaning, the amount of residual powder removed was not influenced by either the fundamental frequency of the horn used (75 vs. 230 Hz) or, for a given horn, the number of soundings (between 1 and 20). With mechanical vibration, the amount of residual powder removed was not influenced by the application time (10 vs. 20 s). Acoustic cleaning was found to be more reliable and effective in removal of residual powder than cleaning with mechanical vibration. It is concluded that acoustic cleaning using high-intensity sound has significant potential for use in the final preparation stages of porous metal orthopedic components. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 117-123, 2017. PMID- 26426907 TI - Understanding the rates of nonpolar organic chemical accumulation into passive samplers deployed in the environment: Guidance for passive sampler deployments. AB - Polymeric passive samplers have become a common method for estimating freely dissolved concentrations in environmental media. However, this approach has not yet been adopted by investigators conducting remedial investigations of contaminated environmental sites. Successful adoption of this sampling methodology relies on an understanding of how passive samplers accumulate chemical mass as well as developing guidance for the design and deployment of passive samplers. Herein, we outline the development of a simple mathematical relationship of the environmental, polymer, and chemical properties that control the uptake rate. This relationship, called a timescale, is then used to illustrate how each property controls the rate of equilibration in samplers deployed in the water or in the sediment. Guidance is also given on how to use the timescales to select an appropriate polymer, deployment time, and suite of performance reference compounds. Integr Environ Assess Manag 2016;12:486-492. (c) 2015 SETAC. PMID- 26426910 TI - Telomere measurement in individuals occupationally exposed to pesticide mixtures in tobacco fields. AB - Occupational exposure to pesticides in tobacco fields causes genetic damage in farmers. The aim of this study was to analyze tobacco farmers chronically exposed to low doses of pesticides and nicotine (present in the tobacco leaves) in relation to absolute telomere length (aTL), and explore the influence of lifestyle characteristics, oxidative stress, and inorganic element levels. DNA was isolated from peripheral blood samples from agricultural workers and non exposed individuals, and aTL was measured by quantitative real time polymerase chain reaction (qPCR) analysis. Oxidative stress (thiobarbituric acid reactive substances [TBARS], which measures oxidative damage to lipids; and toxic equivalent antioxidant capacity [TEAC], which measures total equivalent antioxidant capacity) was evaluated in serum, and inorganic element content was analyzed in whole blood through particle-induced X-ray emission technique. It was found that exposure to pesticides and tobacco smoking had significant effects on aTL. Individuals occupationally exposed to complex mixtures of pesticides in tobacco fields and individuals who smoked had decreased aTL compared with the non exposed group. TBARS and TEAC were significantly elevated in the exposed group. There were no significant differences in inorganic elements. There was no evidence of an influence of age, gender, consumption of alcoholic beverages, or intake of fruits and vegetables on aTL within the groups. In addition, years of work in the tobacco field in the exposed group did not influence any of the variables analyzed. Although further studies were needed, these results suggested differences in telomere maintenance in tobacco farmers compared with the control group, indicating that telomere length may be a good biomarker of occupational exposure. PMID- 26426911 TI - Depression and distress in caregivers of children with brain tumors undergoing treatment: psychosocial factors as moderators. AB - OBJECTIVE: This study's objectives were to examine the effects of depression on the distress of caregivers of children with brain tumors and to identify the factors moderating depression and caregiver distress. METHODS: Participants were 82 caregivers of children with brain tumors undergoing treatment in the National Cancer Center of South Korea. The depression subscale of the Symptom Checklist 90 Revised (SCL-90-R) and the Burden of a Primary Caregiver (BPC) Scale were used to measure participants' depression and caregiver distress, respectively. The Korean version of the Parenting Sense of Competence (K-PSOC) Scale, Family Environmental Scale-Revised (K-FES-R), and the DUKE-UNC Functional Social Support Questionnaire S (DUKE-UNC-FSSQ) were used to assess parental efficacy, family relationships, and perceived social support, respectively. RESULTS: Younger patient age, lower family income, and caregivers' greater number of years of education significantly predicted caregiver distress. Caregivers with depression experienced significantly more distress than those without depression. The interaction of depression with parenting efficacy and social support affected caregiver distress. For highly depressed caregivers, parental efficacy, social support, and family relationships played weaker roles as protective factors against caregiver distress. High parental efficacy and social support were protective factors against distress in caregivers without depression. CONCLUSIONS: A multi dimensional assessment of the psychosocial factors that may affect caregivers of children with brain tumors should precede interventions for distress management. Interventions tailored to individuals' psychosocial factors are needed. PMID- 26426914 TI - Noise masking of White's illusion exposes the weakness of current spatial filtering models of lightness perception. AB - Spatial filtering models are currently a widely accepted mechanistic account of human lightness perception. Their popularity can be ascribed to two reasons: They correctly predict how human observers perceive a variety of lightness illusions, and the processing steps involved in the models bear an apparent resemblance with known physiological mechanisms at early stages of visual processing. Here, we tested the adequacy of these models by probing their response to stimuli that have been modified by adding narrowband noise. Psychophysically, it has been shown that noise in the range of one to five cycles per degree (cpd) can drastically reduce the strength of some lightness phenomena, while noise outside this range has little or no effect on perceived lightness. Choosing White's illusion (White, 1979) as a test case, we replicated and extended the psychophysical results, and found that none of the spatial filtering models tested was able to reproduce the spatial frequency specific effect of narrowband noise. We discuss the reasons for failure for each model individually, but we argue that the failure is indicative of the general inadequacy of this class of spatial filtering models. Given the present evidence we do not believe that spatial filtering models capture the mechanisms that are responsible for producing many of the lightness phenomena observed in human perception. Instead we think that our findings support the idea that low-level contributions to perceived lightness are primarily determined by the luminance contrast at surface boundaries. PMID- 26426912 TI - Claudin-16 Deficiency Impairs Tight Junction Function in Ameloblasts, Leading to Abnormal Enamel Formation. AB - Claudin-16 protein (CLDN16) is a component of tight junctions (TJ) with a restrictive distribution so far demonstrated mainly in the kidney. Here, we demonstrate the expression of CLDN16 also in the tooth germ and show that claudin 16 gene (CLDN16) mutations result in amelogenesis imperfecta (AI) in the 5 studied patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). To investigate the role of CLDN16 in tooth formation, we studied a murine model of FHHNC and showed that CLDN16 deficiency led to altered secretory ameloblast TJ structure, lowering of extracellular pH in the forming enamel matrix, and abnormal enamel matrix protein processing, resulting in an enamel phenotype closely resembling human AI. This study unravels an association of FHHNC owing to CLDN16 mutations with AI, which is directly related to the loss of function of CLDN16 during amelogenesis. Overall, this study indicates for the first time the importance of a TJ protein in tooth formation and underlines the need to establish a specific dental follow-up for these patients. PMID- 26426913 TI - Initiation of Antiretroviral Therapy (ART) at Different Stages of HIV-1 Disease Is Not Associated with the Proportion of Exhausted CD8+ T Cells. AB - CD8+ T cell-restricted immunity is important in the control of HIV-1 infection, but continued immune activation results in CD8+ T cell dysfunction. Early initiation of antiretroviral treatment (ART) and the duration of ART have been associated with immune reconstitution. Here, we evaluated whether restoration of CD8+ T cell function in HIV-1-infected individuals was dependent on early initiation of ART. HIV-specific CD107a, IFNgamma, IL-2, TNFalpha and MIP-1beta expression by CD8+ T cells and the frequency of CD8+ T cells expressing PD-1, 2B4 and CD160 were measured by flow cytometry. The frequency of CD8+ T cells expressing the inhibitory markers PD-1, 2B4 and CD160 was lower in ART-treated individuals compared with ART-naive individuals and similar to the frequency in HIV-uninfected controls. The expression of the three markers was similarly independent of when therapy was initiated. Individuals treated before seroconversion displayed an HIV-specific CD8+ T cell response that included all five functional markers; this was not observed in individuals treated after seroconversion or in ART-naive individuals. In summary, ART appears to restore the total CD8+ T cell population to a less exhausted phenotype, independent of the time point of initiation. However, to preserve multifunctional, HIV-1 specific CD8+ T cells, ART might have to be initiated before seroconversion. PMID- 26426915 TI - Comparison of stimulus rivalry to binocular rivalry with functional magnetic resonance imaging. AB - When incompatible images are presented to each eye, a phenomenon known as binocular rivalry occurs in which the viewer's conscious visual perception alternates between the two images. In stimulus rivalry, similar perceptual alternations between rival images can occur even in the midst of fast image swapping between the eyes. Here, we used functional magnetic resonance imaging to directly compare brain activity underlying the two types of perceptual rivalry. Overall, we found that activity for binocular rivalry was always stronger and more widespread than that for stimulus rivalry-even more so during passive viewing conditions. In particular, the right superior parietal cortex and the right temporoparietal junction were prominently engaged for passive binocular rivalry. While both types of rivalry engaged higher tier visual regions such as the ventral temporal cortex during an active task, activity for stimulus rivalry was comparatively weak in early visual areas V1 to V3, presumably due to a weaker feed-forward signal due to both intraocular and interocular inhibition that may reduce effective contrast. In sum, only binocular rivalry produced perceptually vivid alternations, increased activation of the early visual cortex, and the coordinated engagement of dorsal stream regions, even when a task was not performed. These findings help characterize how stimulus rivalry fits within hierarchical models of binocular rivalry. PMID- 26426916 TI - Invasive Squamous Cell Carcinoma With Clear Cell Change of the Eyelid Arising in a Seborrheic Keratosis. PMID- 26426918 TI - New Tricks for Leukocytes: Memory Where You Least Suspect It. PMID- 26426919 TI - Quantification of mRNA Expression by RT-qPCR. PMID- 26426920 TI - Jean-Francoise Borel and the Origin of the World's First Billion Dollar Molecule. PMID- 26426921 TI - Use of Oxygen Carriers to Promote Islet Engraftment in Extravascular Sites. PMID- 26426922 TI - Living Unrelated Kidney Transplantation: Trust, But Verify! PMID- 26426923 TI - A Primer of Neoclassical (Traditional) and Behavioral Economic Principles for Organ Transplantation: Part 1. PMID- 26426924 TI - Cotransplantation of Polymerized Hemoglobin Reduces beta-Cell Hypoxia and Improves beta-Cell Function in Intramuscular Islet Grafts. AB - BACKGROUND: Muscle is a promising alternative site for islet transplantation that facilitates rapid restoration of islet vascularization. However, the development of fibrosis suggests massive cellular death after transplantation. This study tested the hypothesis that islet graft function is limited by hypoxia-related death early after intramuscular transplantation, but that this can be overcome by cotransplantation of an oxygen carrier, that is, polymerized bovine hemoglobin (PolyHb). METHODS: Two hundred islets were transplanted with or without different doses of PolyHb intramuscularly to nondiabetic C57BL/6 and diabetic C57BL/6 nu/nu mice. beta-cell hypoxia and apoptosis were evaluated by immunohistochemistry after injection of the biochemical marker pimonidazole or by staining for caspase 3, respectively. Blood glucose concentrations were monitored for 30 days after islet transplantation and animals were then subjected to an intravenous glucose tolerance test. RESULTS: Substantial hypoxia was observed in control islet grafts during the first 4 days after transplantation. Cotransplantation of PolyHb resulted in a dose-dependent reduction of beta-cell hypoxia, but beta-cell apoptosis was only reduced by cotransplantation of low-dose PolyHb (0.03 mg/g body weight) due to the inflammatory effects of higher PolyHb concentrations. Cotransplantation of low-dose PolyHb resulted in improved islet graft function 30 days after transplantation in diabetic mice, with a glucose tolerance comparable to transplantation of 50% more islets. CONCLUSION: We conclude that cotransplantation of islets with PolyHb can be used to effectively bridge the critical hypoxic phase immediately after transplantation, improve islet graft function, and reduce the number of islets needed for successful intramuscular transplantation. PMID- 26426925 TI - Response to Kidney Transplantation Threshold in Patients With Hepatitis C: A Decision Analysis Model. PMID- 26426927 TI - Outcomes of Kidney Transplant Recipients From Donation After Circulatory Death Donors Without Preagonal Heparin Administration. PMID- 26426926 TI - Preoperative Assessment of Renal Transplant Ureteric Blood Supply Using Ex Vivo Normothermic Perfusion. PMID- 26426928 TI - Cold Denaturation Unveiled: Molecular Mechanism of the Asymmetric Unfolding of Yeast Frataxin. AB - What is the mechanism that determines the denaturation of proteins at low temperatures, which is, by now, recognized as a fundamental property of all proteins? We present experimental evidence that clarifies the role of specific interactions that favor the entrance of water into the hydrophobic core, a mechanism originally proposed by Privalov but never proved experimentally. By using a combination of molecular dynamics simulation, molecular biology, and biophysics, we identified a cluster of negatively charged residues that represents a preferential gate for the entrance of water molecules into the core. Even single-residue mutations in this cluster, from acidic to neutral residues, affect cold denaturation much more than heat denaturation, suppressing cold denaturation at temperatures above zero degrees. The molecular mechanism of the cold denaturation of yeast frataxin is intrinsically different from that of heat denaturation. PMID- 26426929 TI - Robust Eye Center Localization through Face Alignment and Invariant Isocentric Patterns. AB - The localization of eye centers is a very useful cue for numerous applications like face recognition, facial expression recognition, and the early screening of neurological pathologies. Several methods relying on available light for accurate eye-center localization have been exploited. However, despite the considerable improvements that eye-center localization systems have undergone in recent years, only few of these developments deal with the challenges posed by the profile (non frontal face). In this paper, we first use the explicit shape regression method to obtain the rough location of the eye centers. Because this method extracts global information from the human face, it is robust against any changes in the eye region. We exploit this robustness and utilize it as a constraint. To locate the eye centers accurately, we employ isophote curvature features, the accuracy of which has been demonstrated in a previous study. By applying these features, we obtain a series of eye-center locations which are candidates for the actual position of the eye-center. Among these locations, the estimated locations which minimize the reconstruction error between the two methods mentioned above are taken as the closest approximation for the eye centers locations. Therefore, we combine explicit shape regression and isophote curvature feature analysis to achieve robustness and accuracy, respectively. In practical experiments, we use BioID and FERET datasets to test our approach to obtaining an accurate eye-center location while retaining robustness against changes in scale and pose. In addition, we apply our method to non-frontal faces to test its robustness and accuracy, which are essential in gaze estimation but have seldom been mentioned in previous works. Through extensive experimentation, we show that the proposed method can achieve a significant improvement in accuracy and robustness over state-of-the-art techniques, with our method ranking second in terms of accuracy. According to our implementation on a PC with a Xeon 2.5Ghz CPU, the frame rate of the eye tracking process can achieve 38 Hz. PMID- 26426930 TI - Side-Chain Engineering for Enhancing the Thermal Stability of Polymer Solar Cells. AB - An effective strategy of engineering side chains is proposed for enhancing solar cell-device thermal stability. As the conjugated length of the side chains increases, the morphological stability of the blend film is enhanced. The thermal stability of corresponding devices is consequently improved. PMID- 26426931 TI - Au nanoflower-Ag nanoparticle assembled SERS-active substrates for sensitive MC LR detection. AB - Surface-enhanced Raman scattering (SERS)-active substrates assembled by two types of metallic nanoparticles (NPs) were fabricated. Aptamers driven Au nanoflower (Au NF)-Ag NP core-satellite assemblies exhibited amplified SERS signals and achieved the sensitive detection of microcystin-LR (MC-LR) in Tai lake water with the limit of detection (LOD) of 8.6 +/- 0.4 pM. PMID- 26426932 TI - Short-time dynamics in dispersions with competing short-range attraction and long range repulsion. AB - Dynamic clustering of globular Brownian particles in dispersions exhibiting competing short-range attraction and long-range repulsion (SALR) such as low salinity protein solutions has gained a lot of interest over the past few years. While the structure of the various cluster phases has been intensely explored, little is known about the dynamics of SALR systems. We present the first systematic theoretical study of short-time diffusion and rheological transport properties of two-Yukawa potential SALR systems in the single-particle dominated dispersed-fluid phase, using semi-analytic methods where the salient hydrodynamic interactions are accounted for. We show that the dynamics has unusual features compared to reference systems with pure repulsion or attraction. Results are discussed for the hydrodynamic function characterizing short-time diffusion that reveals an intermediate-range-order (cluster) peak, self-diffusion and sedimentation coefficients, and high-frequency viscosity. As important applications, we discuss the applicability of two generalized Stokes-Einstein relations, and assess the wavenumber range required for the determination of self diffusion in a dynamic scattering experiment. PMID- 26426934 TI - Dynamics of ultrathin gold layers on vitreous silica probed by density functional theory. AB - The structure and properties of Au ultrathin films on hydroxyl-free and hydroxylated silica glass surfaces are investigated using ab initio molecular dynamics simulations. Substantial surface structure dependence of Au agglomeration behavior (solid-state dewetting) is found. On hydroxyl-free surfaces, the Au film virtually undergoes instantaneous agglomeration accompanied by the formation of voids exposing a bare silica glass surface. In contrast, simulated annealing of the Au film on hydroxylated surface models leaves its structure unchanged within the simulation time. This points to a key role of reactive defect sites in the kinetics of solid-state dewetting processes of metals deposited on the glass surface. Such sites are important for initial void nucleation and formation of metal clusters. In addition, our calculations demonstrate the crucial role of the appropriate inclusion of dispersion interactions in density functional theory simulations of metals deposited on glass surfaces. For defective, hydroxyl-free glass surfaces the dispersion correction accounts for 35% of the total adhesion energy. The effect is even more dramatic for hydroxylated glass surfaces, where adhesion energies are almost entirely due to dispersion interactions. The Au adhesion energies of 200 and 160 kJ (mol nm(2))(-1) calculated for hydroxylated glass surfaces are in good agreement with the experimental data. PMID- 26426933 TI - Synthesis, Biological Evaluation, and Molecular Docking of (R)-2-((8-(3 aminopiperidin-1-yl)-3-methyl-7-(3-methylbut-2-en-1-yl)-2,6-dioxo-2,3,6,7 tetrahydro-1H-purin-1-yl)methyl)benzonitrile as Dipeptidyl Peptidase IV Inhibitors. AB - Type 2 diabetes (T2D) is classified as a major metabolic disorder, which has affected approximately 194 million people worldwide. DPP-IV inhibitors as a new therapy have shown several advantages over traditional antidiabetic drugs. Based on the similar binding modes of Alogliptin and Linagliptin, molecular operation was conducted via combining pharmacophore hybridization with structural optimization between the two market drugs and racemic compounds 40 and 43 were reported as DPP-IV inhibitors in our previous studies. But the majority of DPP-IV inhibitors have developed into a small molecule with certain conformation; in this study, we described the synthesis, biological evaluation, and molecular docking of corresponding enantiomers of compounds 40 and 43. The most potent inhibitor is (R)-40 (IC50 = 23.5 nm, F = 74.67%, T1/2 = 4 h), which exhibited moderate antihyperglycemic activity as compared to the standard antidiabetic drug Linagliptin in OGTT. In addition, compound (R)-40 effectively improved the pathological state of DIO mice. Molecular docking studies clarified the favorable binding affinity between compound (R)-40 and DPP-IV active site. Thus, compound (R)-40 would be entitled to further development as a drug candidate on the basis of the suitable pharmacokinetic (PK) and desirable pharmacodynamic (PD) profiles. PMID- 26426935 TI - Expression of amelogenin and effects of cyclosporin A in developing hair follicles in rats. AB - Amelogenin, an enamel matrix protein has been considered to be exclusively expressed by ameloblasts during odontogenesis. However, burgeoning evidence indicates that amelogenin is also expressed in non-mineralizing tissues. Under the hypothesis that amelogenin may be a functional molecule in developing hair follicles which share developmental features with odontogenesis, this study for the first time elucidated the presence and functional changes of amelogenin and its receptors during rat hair follicle development. Amelogenin was specifically localized in the outer epithelial root sheath of hair follicles. Its expression appeared in the deeper portion of hair follicles, i.e. the bulbar and suprabulbar regions rather than the superficial region. Lamp-1, an amelogenin receptor, was localized in either follicular cells or outer epithelial sheath cells, reflecting functional changes during development. The expression of amelogenin splicing variants increased in a time-dependent manner during postnatal development of hair follicles. Amelogenin expression was increased by treatment with cyclosporin A, which is an inducer of anagen in the hair follicle, whereas the level of Lamp 1 and -2 was decreased by cyclosporin A treatment. These results suggest that amelogenin may be a functional molecule involved in the development of the hair follicle rather than an inert hair shaft matrix protein. PMID- 26426936 TI - The Mosaic of Rottlerin. AB - The first total synthesis of rottlerin is described. The methodology allows the development of potential novel protein kinase C delta (PKCdelta) analogues for better treatment of various diseases. Kamalachalcone A and dimeric rottlerin were synthesized in a very practical and economical way using FeCl3 as a catalyst. PMID- 26426937 TI - Modeling Our Way to Better Outcomes. PMID- 26426938 TI - Protein expression in dairy cows with and without subclinical hypocalcaemia. AB - AIM: To determine differences in plasma proteomic profiles between healthy cows and those with subclinical hypocalcaemia within 12 hours after calving, and thereby explore the underlying biological mechanism of subclinical hypocalcaemia in dairy cows. METHODS: Plasma samples were collected within 6 hours of calving from Holstein cows on a farm in Heilongjiang, China; 32 with subclinical hypocalcaemia (plasma calcium concentration 1.38-2.00 mmol/L and no clinical signs) and 59 control cows (plasma calcium concentration 2.10-2.8 mmol/L). Plasma samples were applied to weak cationic exchange protein chips for protein profiling by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF-MS), and the data were analysed using the PBS-IIC system. The amplitude of peaks for the two groups were compared using the Wilcoxon sum rank test, and the mass-to-charge ratio of the peaks that differed was used to identify peptide fragments using the Swiss-Prot protein database. RESULTS: Seven peaks were identified in the subclinical hypocalcaemia group that differed from those of the control group (p<0.001), that represented six unique proteins. Expression of serum albumin, fibrinogen alpha chain, amyloid beta A4 proteins and neurosecretory protein VGF were increased, and expression of apolipoprotein A-II and serum amyloid A proteins were decreased in the subclinical hypocalcaemic cows compared with control cows. CONCLUSION: Use of SELDI-TOF-MS technology can effectively identify differences in plasma protein expression patterns in cows with subclinical hypocalcaemia. Neurosecretory protein VGF and amyloid beta A4 protein might represent useful biomarkers for diagnosis of subclinical hypocalcaemia. PMID- 26426939 TI - Traffic Noise and Adverse Birth Outcomes in Madrid: A Time-series Analysis. PMID- 26426940 TI - Re: The Quasi-cohort Approach in Pharmaco epidemiology: Upgrading the Nested Case control. PMID- 26426941 TI - A New Technique for Evaluating Land-use Regression Models and Their Impact on Health Effect Estimates. AB - BACKGROUND: Leave-one-out cross-validation that fails to account for variable selection does not properly reflect prediction accuracy when the number of training sites is small. The impact on health effect estimates has rarely been studied. The objective of this study was to develop an improved validation procedure for land-use regression models with variable selection and investigate health effect estimates in relation to land-use regression model performance. METHODS: We randomly generated 10 training and test sets for nitrogen dioxide and particulate matter. For each training set, we developed models and evaluated them using a cross-holdout validation approach. Cross-holdout validation develops new models for each evaluation compared with refitting the model without variable selection, as in standard leave-one-out cross-validation. We also implemented holdout validation, which evaluates model predictions using independent test sets. We evaluated the relationship between cross-holdout validation and holdout validation R and estimates of the association between air pollution and forced vital capacity in the Dutch birth cohort. RESULTS: Cross-holdout validation Rs were generally identical to holdout validation Rs, but were notably smaller than leave-one-out cross-validation Rs. Decreases in forced vital capacity in relation to air pollution exposure were larger for land-use regression models that had larger holdout validation and cross-holdout validation Rs rather than leave-one out cross-validation R. CONCLUSION: Cross-holdout validation accurately reflects predictive ability of land-use regression models and is a useful validation approach for small datasets. Land-use regression predictive ability in terms of holdout validation and cross-holdout validation rather than leave-one-out cross validation was associated with the magnitude of health effect estimates in a case study. PMID- 26426942 TI - Air Pollution and Cognitive Development at Age 7 in a Prospective Italian Birth Cohort. AB - BACKGROUND: Early life exposure to air pollution has been linked with cognitive impairment in children, but the results have not been conclusive. We analyzed the association between traffic-related air pollution and cognitive function in a prospective birth cohort in Rome. METHODS: A cohort of 719 newborns was enrolled in 2003-2004 as part of the GASPII project. At age 7 years, 474 children took the Wechsler Intelligence Scale for Children-III to assess their cognitive development in terms of IQ composite scores. Exposure to air pollutants (NO2, PMcoarse, PM2.5, PM2.5 absorbance) at birth was assessed using land use regression models. We also considered variables indicating traffic intensity. The effect of environmental pollution on IQ was evaluated performing a linear regression model for each outcome, adjusting for gender, child age at cognitive test, maternal age at delivery, parental educational level, siblings, socio economic status, maternal smoking during pregnancy, and tester. To account for selection bias at enrollment and during follow-up, the regression models were weighted for the inverse probabilities of participation and follow-up. RESULTS: A 10 MUg/m3 higher NO2 exposure during pregnancy was associated with 1.4 fewer points (95% confidence interval = -2.6, -0.20) of verbal IQ, and 1.4 fewer points (95% confidence interval = -2.7, -0.20) of verbal comprehension IQ. Similar associations were found for traffic intensity in a 100 m buffer around home. Other pollutants showed negative associations with larger confidence intervals. CONCLUSIONS: Consistent with previous evidence, this study suggests an association of exposure to NO2 and traffic intensity with the verbal area of cognitive development.See Video Abstract at http://links.lww.com/EDE/B12. PMID- 26426943 TI - Bias Formulas for Estimating Direct and Indirect Effects When Unmeasured Confounding Is Present. AB - Mediation analysis examines the influence of intermediate factors in the causal pathway between an exposure and an outcome. It yields estimates of the direct effect of the exposure on the outcome and of the indirect effect through the intermediate variable. Both estimates can be biased if the relationship between the mediator and the outcome is confounded. In this article, we study the effect of unmeasured confounding on direct and indirect effect estimates for a continuous mediator and an outcome that may be either binary, count, or continuous. We formulate the effect of the confounder on the intermediate and on the outcome directly in regression models, which makes the formulas intuitive to use by applied users. The formulas are derived under the assumption that the confounder follows a normal distribution. In simulations, the formulas for a linear response model performed well, also as it did when the unmeasured confounder was binary. For a rare binary outcome, the formulas for logistic regression performed well if the unmeasured confounder followed a normal distribution, but for a binary confounder the bias in the direct effect was overcorrected. We applied the formulas to data from a case-control study (Leiden Thrombophilia Study) on risk factors for venous thrombosis. This showed that unmeasured confounding can severely bias the estimates of direct and indirect effects. PMID- 26426944 TI - Occupational Diesel Exposure, Duration of Employment, and Lung Cancer: An Application of the Parametric G-Formula. AB - BACKGROUND: If less healthy workers terminate employment earlier, thus accumulating less exposure, yet remain at greater risk of the health outcome, estimated health effects of cumulative exposure will be biased downward. If exposure also affects termination of employment, then the bias cannot be addressed using conventional methods. We examined these conditions as a prelude to a reanalysis of lung cancer mortality in the Diesel Exhaust in Miners Study. METHODS: We applied an accelerated failure time model to assess the effect of exposures to respirable elemental carbon (a surrogate for diesel) on time to termination of employment among nonmetal miners who ever worked underground (n = 8,307). We then applied the parametric g-formula to assess how possible interventions setting respirable elemental carbon exposure limits would have changed lifetime risk of lung cancer, adjusting for time-varying employment status. RESULTS: Median time to termination was 36% shorter (95% confidence interval = 33%, 39%), per interquartile range width increase in respirable elemental carbon exposure. Lung cancer risk decreased with more stringent interventions, with a risk ratio of 0.8 (95% confidence interval = 0.5, 1.1) comparing a limit of <=25 ug/m respirable elemental carbon to no intervention. The fraction of cases attributable to diesel exposure was 27% in this population. CONCLUSIONS: The g-formula controlled for time-varying confounding by employment status, the signature of healthy worker survivor bias, which was also affected by diesel exposure. It also offers an alternative approach to risk assessment for estimating excess cumulative risk, and the impact of interventions based entirely on an observed population. PMID- 26426945 TI - Unconventional Natural Gas Development and Birth Outcomes in Pennsylvania, USA. AB - BACKGROUND: Unconventional natural gas development has expanded rapidly. In Pennsylvania, the number of producing wells increased from 0 in 2005 to 3,689 in 2013. Few publications have focused on unconventional natural gas development and birth outcomes. METHODS: We performed a retrospective cohort study using electronic health record data on 9,384 mothers linked to 10,946 neonates in the Geisinger Health System from January 2009 to January 2013. We estimated cumulative exposure to unconventional natural gas development activity with an inverse-distance squared model that incorporated distance to the mother's home; dates and durations of well pad development, drilling, and hydraulic fracturing; and production volume during the pregnancy. We used multilevel linear and logistic regression models to examine associations between activity index quartile and term birth weight, preterm birth, low 5-minute Apgar score and small size for gestational age birth, while controlling for potential confounding variables. RESULTS: In adjusted models, there was an association between unconventional natural gas development activity and preterm birth that increased across quartiles, with a fourth quartile odds ratio of 1.4 (95% confidence interval = 1.0, 1.9). There were no associations of activity with Apgar score, small for gestational age birth, or term birth weight (after adjustment for year). In a posthoc analysis, there was an association with physician-recorded high-risk pregnancy identified from the problem list (fourth vs. first quartile, 1.3 [95% confidence interval = 1.1, 1.7]). CONCLUSION: Prenatal residential exposure to unconventional natural gas development activity was associated with two pregnancy outcomes, adding to evidence that unconventional natural gas development may impact health.See Video Abstract at http://links.lww.com/EDE/B14. PMID- 26426946 TI - Prevalence of oesophageal epidermoid metaplasia in 1048 consecutive patients and 58 patients with squamous neoplasms. AB - AIMS: Oesophageal epidermoid metaplasia is defined by a dense granular layer with overlying hyperorthokeratosis, resembling the epidermis of skin. A possible association between epidermoid metaplasia, squamous dysplasia and squamous cell carcinoma has been proposed. The aim of this study was to compare the prevalence of epidermoid metaplasia in patients with oesophageal squamous neoplasms with that in a control cohort. METHODS AND RESULTS: Medical records and slides from 1048 consecutive oesophageal biopsies and resections for any indication and 58 patients with oesophageal squamous neoplasms were reviewed. Two cases (0.19%) of epidermoid metaplasia were identified in the 1048-patient control group. The prevalence of epidermoid metaplasia was significantly higher (P < 0.05) in the 58 patients with oesophageal squamous neoplasms, two of whom (3.5%) had concurrent epidermoid metaplasia (odds ratio 18.1, 95% confidence interval 2.5-131). One case was associated with a verrucous carcinoma and the other with a well differentiated, superficial (pT1), exophytic squamous cell carcinoma. No patients had epidermoid metaplasia in a biopsy prior to the diagnosis of squamous neoplasia. CONCLUSIONS: The increased prevalence of epidermoid metaplasia observed in patients with squamous neoplasms provides some additional support for the proposed association. The hypothesis that epidermoid metaplasia is a precursor to squamous neoplasms remains unproven. PMID- 26426947 TI - Integrating the concept of advanced gynaecological imaging for endometriosis. PMID- 26426948 TI - Re: New Zealand National GDM Guidelines: an alternative view of some good practice points. PMID- 26426949 TI - Oxygen orders differently under graphene: new superstructures on Ir(111). AB - Using scanning tunneling microscopy, the oxygen adsorbate superstructures on bare Ir(111) are identified and compared to the ones formed by intercalation in between graphene and the Ir(111) substrate. For bare Ir(111) we observe O-(2 * 2) and O-(2 * 1) structures, thereby clarifying a persistent uncertainty about the existence of these structures and the role of defects for their stability. For the case of graphene-covered Ir(111), oxygen intercalation superstructures can be imaged through the graphene monolayer by choosing proper tunneling conditions. Depending on the pressure, temperature and duration of O2 exposure as well as on the graphene morphology, O-(2 * 2), O-(?3*?3)-R30 degrees , O-(2 * 1) and O-(2?3 * 2?3)-R30 degrees superstructures with respect to Ir(111) are observed under the graphene cover. Two of these structures, the O-(?3 * ?3)-R30 degrees and the (2?3 * 2?3)-R30 degrees structure are only observed when the graphene layer is on top. Phase coexistence and formation conditions of the intercalation structures between graphene and Ir(111) are analyzed. The experimental results are compared to density functional theory calculations including dispersive forces. The existence of these phases under graphene and their absence on bare Ir(111) are discussed in terms of possible changes in the adsorbate-substrate interaction due to the presence of the graphene cover. PMID- 26426950 TI - Multifunctional polyoxometalates encapsulated in MIL-100(Fe): highly efficient photocatalysts for selective transformation under visible light. AB - H3PMo12O40 molecules have been successfully encapsulated in the cavities of MIL 100(Fe) via a facile hydrothermal method (denoted as HPMo@MIL-100(Fe)). A series of characterization has corroborated the insertion of H3PMo12O40 within the cavities of MIL-100(Fe). The resulting HPMo@MIL-100(Fe) nanocomposites have exhibited much higher photoactivity than the original-MIL-100(Fe) toward the photocatalytic selective oxidation of benzylic alcohols and the reduction of Cr(vi) under visible light irradiation (lambda>= 420 nm). The higher photoactivity of HPMo@MIL-100(Fe) can be attributed to the integrative effect of enhanced light absorption intensity and more efficient separation of photogenerated electron-hole pairs. The host porous structure of MIL-100(Fe) can achieve a uniform composition with H3PMo12O40, which is significantly important for producing highly reactive dispersed H3PMo12O40 molecules and enhancing the photocatalytic activity of HPMo@MIL-100(Fe) nanocomposites. And the immobilized H3PMo12O40 molecules are more convenient for recycling. Importantly, almost no Fe and Mo ions leach from the MIL-100(Fe) during the reaction, which verifies the photostability of the HPMo@MIL-100(Fe). In addition, possible photocatalytic redox reaction mechanisms have been investigated. PMID- 26426954 TI - Assessment of carboxyhemoglobin, hydrogen cyanide and methemoglobin in fire victims: a novel approach. AB - To establish the cause of death, carboxyhemoglobin (COHb), total hemoglobin (tHb), methemoglobin (MetHb), and hydrogen cyanide (HCN) were quantified in the blood of fire victims. We analyzed 32 out of 33 blood samples from forensic autopsy cases in a disastrous polyurethane mattress fire, which caused the deaths of 33 inmates at a prison in Argentina in 2006. The cadaveric blood samples were collected by femoral vein puncture. These samples were analyzed using the IL80 CO oximeter system for tHb, MetHb, and COHb levels and by microdiffusion for HCN and COHb levels. Blood alcohol (ethanol) and drugs were examined by headspace gas chromatography-flame ionization detection (HS-GC-FID) and GC-mass spectrometry (MS), respectively. Polyurethane mattress samples were analyzed according to the California 117 protocol. The saturation of COHb ranged from 10% to 43%, tHb from 2% to 19.7%, MetHb from 0.10% to 35.7%, and HCN from 0.24 to 15mg/L. These HCN values are higher than the lethal levels reported in the literature. Other toxic components routinely measured (ethanol, methanol, aldehydes, and other volatile compounds) gave negative results in the 32 cases. Neither drugs of abuse nor psychotropic drugs were detected. The results indicate that death in the 32 fire victims was probably caused in part by HCN, generated during the extensive polyurethane decomposition stimulated by a rapid increase in temperature. We also considered the influence of oxygen depletion and the formation of other volatile compounds such as NOx in this disaster, as well as pathological evidence demonstrating that heat was not the cause of death in all victims. Furthermore, statistical analysis showed that the percentage values of COHb and MetHb in the blood were not independent variables, with chi(2)=11.12 (theoretical chi(2)=4.09, degrees of freedom=12, and alpha=0.05). However, no correlation was found between HCN and MetHb in the blood of the victims. This is the first report to assess the relationship between COHb and MetHb in forensic blood samples. We further discuss other factors that could lead to a lethal atmosphere generated by the fire and compare the data from this disaster with that of other published fire episodes. PMID- 26426956 TI - Two Enantiomeric Pairs of Meroterpenoids from Rhododendron capitatum. AB - Two enantiomeric pairs of meroterpenoids, (-)- and (+)-rhodonoids A (1a and 1b) and B (2a and 2b), were isolated unprecedentedly from partially racemic mixtures that naturally occurred in Rhododendron capitatum. Their structures were fully determined by spectroscopic data, X-ray crystallography, and electronic circular dichroism analysis. Compounds 1a and 1b are the first examples of meromonoterpenes featuring a unique 6/6/6/4 ring system. Compounds 2a and 2b showed PTP1B inhibitory activity. PMID- 26426957 TI - Needle-free nasal delivery of glucagon for treatment of diabetes-related severe hypoglycemia: toxicology of polypropylene resin used in delivery device. AB - CONTEXT: The intranasal route is a promising route of administration for several emergency rescue drugs including naloxone and glucagon. Glucagon nasal powder (GNP) is a novel, needle-free delivery system for intranasal administration of glucagon for the treatment of severe hypoglycemia, an infrequent but serious complication of insulin use in patients with diabetes. The GNP delivery device is a compact, highly portable, single-use nasal powder dosing device constructed of polypropylene that allows for simple, single-step administration. OBJECTIVE: To evaluate the toxicological profile of the polypropylene resin used in the actuator part of the delivery device that will contact skin and nasal mucosal membranes of the patient, we performed an in vitro cytotoxicity study, a skin sensitization study and an irritation (intracutaneous reactivity) study in animal models. METHODS: Extracts of the actuator of the GNP device were generated from HAM F12 medium with 10% fetal bovine serum, 0.9% sodium chloride (NaCl) or sesame oil. The in vitro cytotoxicity test was performed in cultured L929 mouse fibroblasts. Skin sensitization analysis was performed in 10 guinea pigs according to the Magnusson-Kligman method, using a maximization method with Freund's Complete Adjuvant. Irritation following intracutaneous/intradermal treatment with device extracts (NaCl and sesame oil extractants) was assessed in three New Zealand White rabbits. RESULTS: In vitro cytotoxicity test: Both undiluted and diluted extract showed no toxicity (i.e. no abnormal morphology, cell death or cell lysis) toward L929 fibroblasts (cytotoxicity grade 0). Sensitization test in guinea pigs: Challenge with device extracts did not evoke positive responses in test animals previously induced with device extracts. The net response value represented an incidence rate of 0% and a net dermal irritation score value of 0.00. Irritation (intracutaneous/intradermal) test in New Zealand White rabbits: Device extracts and corresponding vehicle controls caused similar irritation reactions. The difference between the mean scores for the device extracts and the corresponding vehicle controls was less than 1.0. CONCLUSIONS: Extracts of the polypropylene resin of the GNP delivery device are not cytotoxic, do not result in dermal sensitization and do not cause irritation when applied topically or intracutaneously. Given the infrequent use and very short duration of exposure to the nasal mucosa during administration of GNP, the polypropylene resin of the GNP device actuator will likely not cause adverse dermal sensitization effects or irritation effects in humans and can, therefore, be considered for use as a delivery device in clinical trials assessing the efficacy and safety of GNP for the treatment of insulin-using patients experiencing episodes of severe hypoglycemia. PMID- 26426958 TI - Microbial production of scent and flavor compounds. AB - Scents and flavors like those of fresh oranges are no longer limited to just the natural product. Fruit, flower, and essential oil scents have found place in cosmetics, soaps, candles, and food amongst many common household products. With their increasing global demand and difficulty in extractation from the natural source, alternative methods of their production are being sought. One sustainable method is to employ microorganisms for the production of these high value compounds. With the tools of metabolic engineering, microorganisms can be modified to produce compounds such as esters, terpenoids, aldehydes, and methyl ketones. Approaches and challenges for the production of these compounds from microbial hosts are discussed in this review. PMID- 26426959 TI - Food metabolomics: from farm to human. AB - Metabolomics, one of the latest components in the suite of systems biology, has been used to understand the metabolism and physiology of living systems, including microorganisms, plants, animals and humans. Food metabolomics can be defined as the application of metabolomics in food systems, including food resources, food processing and diet for humans. The study of food metabolomics has increased gradually in the recent years, because food systems are directly related to nutrition and human health. This review describes the recent trends and applications of metabolomics to food systems, from farm to human, including food resource production, industrial food processing and food intake by humans. PMID- 26426951 TI - Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome. AB - Polycystic ovary syndrome (PCOS) is a heterogeneous and complex disorder that has both adverse reproductive and metabolic implications for affected women. However, there is generally poor understanding of its etiology. Varying expert-based diagnostic criteria utilize some combination of oligo-ovulation, hyperandrogenism, and the presence of polycystic ovaries. Criteria that require hyperandrogenism tend to identify a more severe reproductive and metabolic phenotype. The phenotype can vary by race and ethnicity, is difficult to define in the perimenarchal and perimenopausal period, and is exacerbated by obesity. The pathophysiology involves abnormal gonadotropin secretion from a reduced hypothalamic feedback response to circulating sex steroids, altered ovarian morphology and functional changes, and disordered insulin action in a variety of target tissues. PCOS clusters in families and both female and male relatives can show stigmata of the syndrome, including metabolic abnormalities. Genome-wide association studies have identified a number of candidate regions, although their role in contributing to PCOS is still largely unknown. PMID- 26426960 TI - Objective measurements of excess skin in post bariatric patients--inter-rater reliability. AB - BACKGROUND: An ability to reliably assess excess skin after massive weight loss using well-described and transferrable methods is important. The aim of this trial was to evaluate inter-rater reliability of ptosis and circumference measurements in patients with excess skin after bariatric surgery. MATERIALS AND METHODS: Twenty-five postbariatric patients were included in the study, and their excess skin was measured 18 months after surgery. A protocol was designed to measure excess skin in a standardised way. To evaluate the inter-rater reliability in the measuring protocol, all patients were measured twice, by a specialist nurse and a specialist physiotherapist. RESULTS: All circumference measurements on different body parts had an ICC > 0.9, indicating high reliability. Furthermore, all breast and abdominal ptosis measurements had high reliability. In contrast, visual evaluation of abdominal ptosis had poor reliability. Measurements of ptoses on different body parts had an ICC > 0.6. There were no systematic differences between the results of the two testers, except for measurements of the buttocks and maximal knee circumference. CONCLUSION: The measuring protocol presented in this study has high reliability and, therefore, represents a useful instrument to provide a consistent and objective assessment of excess skin in the postbariatric patient. PMID- 26426961 TI - Correction: Comparative Analysis of Label-Free and 8-Plex iTRAQ Approach for Quantitative Tissue Proteomic Analysis. PMID- 26426962 TI - Interplay between the virus and the ubiquitin-proteasome system: molecular mechanism of viral pathogenesis. AB - The ubiquitin-proteasome system (UPS) plays a central role in a wide range of fundamental cellular functions by ensuring protein quality control and through maintaining a critical level of important regulatory proteins. Viruses subvert or manipulate this cellular machinery to favor viral propagation and to evade host immune response. The UPS serves as a double-edged sword in viral pathogenesis: on the one hand, the UPS is utilized by many viruses to maintain proper function and level of viral proteins; while on the other hand, the UPS constitutes a host defense mechanism to eliminate viral components. To combat this host anti-viral machinery, viruses have evolved to employ the UPS to degrade or inactivate cellular proteins that limit viral growth. This review will highlight our current knowledge pertaining to the different roles for the UPS in viral pathogenesis. PMID- 26426963 TI - Uncovering Nonconventional and Conventional Hydrogen Bonds in Oligosaccharides through NMR Experiments and Molecular Modeling: Application to Sialyl Lewis-X. AB - We describe the direct NMR detection of a C-H...O nonconventional hydrogen bond (Hbond) and provide experimental and theoretical evidence for conventional Hbonds in the pentasaccharide sialyl Lewis-X (sLe(X)-5) between 5 and 37 degrees C in water. Extensive NMR structural studies together with molecular dynamics simulations offer strong evidence for significant local dynamics in the Le(X) core and for previously undetected conventional Hbonds in rapid equilibrium that modulate structure. These NMR studies also showed temperature-dependent (1)H and (13)C line broadening. The resulting model emerging from this study is more complex than a simple rigid core description of Le(X)-like molecules and improves our understanding of stabilizing interactions in glycans. PMID- 26426964 TI - What approach should we take for the incidental finding of increased 18F-FDG uptake foci in the colon on PET/CT? AB - INTRODUCTION: F-Fluorodeoxyglucose (F-FDG) PET/CT represents an imaging modality that is gaining increasingly more prominence in screening, staging, and therapeutic monitoring of malignant diseases. An incidental focus of uptake in different regions of the body is not an uncommon finding during PET/CT imaging. Patients with incidental gastrointestinal tract findings comprise ~3% of the overall patient group. The aim of the current study was to provide contributory information in relation to the answer on the most appropriate approach in cases with incidental colonic F-FDG uptake. PATIENTS AND METHODS: A retrospective examination was performed on PET/CT results of 5258 patients. Of these, 152 were recommended to undergo colonoscopy because of the presence of suspicious foci and 31 underwent colonoscopy within 60 days with biopsy from all visible lesions. These dates were also examined. RESULTS: Of the 24 patients undergoing colonoscopy with a suspicion of malignancy, five (20.83%) had no pathological findings. Of the 19 (79.17%) cases with a pathological finding in endoscopy, histopathology showed a benign lesion in five (20.83%), premalignant lesion in seven (29.17%), and a malignant lesion in seven (29.17%). Among seven patients undergoing colonoscopy because of a suspicion of inflammatory bowel disease, five were free of pathological signs and two patients with pathological endoscopy findings had nonspecific inflammation as documented by histopathological examination. CONCLUSION: Colonoscopic and histopathological examination of the increased foci of colonic F-FDG uptake incidentally detected at PET/CT seems to be a plausible approach. PMID- 26426965 TI - Methimazole discontinuation before radioiodine therapy in patients with Graves' disease. AB - INTRODUCTION: Although radioiodine therapy (RIT) has been used for the treatment of hyperthyroidism for many decades, there is no consensus on the optimal time of methimazole (MMI) discontinuation before RIT. The aim of this clinical trial is to study the effect of three different time points of MMI discontinuation on response to RIT. METHOD AND PATIENTS: Overall, 151 patients (18-65 years old), with Graves' disease who were taking MMI and referred to I-131 therapy, were consecutively assigned to one of three groups, and MMI was discontinued for 24 48, 48.1-72, and 72.1-168 h in group, 1, 2, and 3, respectively. Radioiodine uptake was measured in all patients and the radioiodine dose was calculated according to the Quimby formula to deliver 7.4 MBq of I-131 per gram of thyroid weight. Response to RIT was assessed at 1, 3, 6, and 12 months after RIT. RESULTS: A total of 102 women and 49 men were included in the study. The mean administered dose of I-131 was 362.9+/-188.7 MBq (9.8+/-5.1 mCi) and the mean time to response for radioiodine was 4.1+/-3.6 months. There was no significant difference between the three groups in age, thyroid weight, anti-TPO level, radioactive iodine uptake level, and radioiodine dose (P>0.1). Response to RIT at 1, 3, 6, and 12 months after administration was also not different between the three groups (P>0.57). CONCLUSION: No difference was found in the response to treatment between patients with MMI discontinuation for 24-48, 48.1-72, and 72.1 96 h before RIT. Shorter discontinuation of MMI before RIT may be preferable in most patients. Video Abstract: http://links.lww.com/NMC/A39. PMID- 26426966 TI - Determinants of diagnostic performance of 18F-FDG PET/CT in patients with fever of unknown origin. AB - OBJECTIVES: There is uncertainty about patient selection and the adequate timing at which fluorine-18 fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) is indicated in the diagnostic work-up of fever of unknown origin (FUO). The aim of this study was to determine the diagnostic performance of F-FDG PET/CT in patients with FUO. METHODS: All consecutive patients who underwent F-FDG PET/CT at the University Hospital Zurich because of FUO between 2006 and 2012 were included in this retrospective, observational study. RESULTS: A total of 76 patients [70% men, median (interquartile range) age 60 (47-67) years] were included. F-FDG PET/CT showed characteristically increased F-FDG activity in 56 patients (74%), leading to confirmation of or change in the suspected cause of FUO in 57 and 17%, respectively. The final diagnosis after F-FDG PET/CT included infection (21%), malignancy (22%), noninfectious inflammatory disease (12%), others (5%), or an unknown cause (40%). The success rate, sensitivity, and specificity of F-FDG PET/CT were 60, 77, and 31%, respectively. Sensitivity was highest in patients with suspected malignancy (100%, 95% confidence interval 79 100%). Diagnostic performance was independent of the investigated variables other than suspected infection as a cause of FUO (odds ratio 0.1, 95% confidence interval 0.01-0.8, P=0.033). CONCLUSION: The diagnostic performance of F-FDG PET/CT was significantly higher in patients with suspected malignancy causing a FUO compared with suspected infection or noninfectious inflammatory disease. However, it was independent of the baseline characteristics and duration of fever. This supports the recommendation to perform F-FDG PET/CT early in the diagnostic work-up of FUO, which may shorten disease duration and lower health costs, particularly when infection or malignancy is suspected. PMID- 26426967 TI - Partial volume correction and image segmentation for accurate measurement of standardized uptake value of grey matter in the brain. AB - OBJECTIVES: Our aim was to explore a novel quantitative method [based upon an MRI based image segmentation that allows actual calculation of grey matter, white matter and cerebrospinal fluid (CSF) volumes] for overcoming the difficulties associated with conventional techniques for measuring actual metabolic activity of the grey matter. METHODS: We included four patients with normal brain MRI and fluorine-18 fluorodeoxyglucose (F-FDG)-PET scans (two women and two men; mean age 46+/-14 years) in this analysis. The time interval between the two scans was 0 180 days. We calculated the volumes of grey matter, white matter and CSF by using a novel segmentation technique applied to the MRI images. We measured the mean standardized uptake value (SUV) representing the whole metabolic activity of the brain from the F-FDG-PET images. We also calculated the white matter SUV from the upper transaxial slices (centrum semiovale) of the F-FDG-PET images. The whole brain volume was calculated by summing up the volumes of the white matter, grey matter and CSF. The global cerebral metabolic activity was calculated by multiplying the mean SUV with total brain volume. The whole brain white matter metabolic activity was calculated by multiplying the mean SUV for the white matter by the white matter volume. The global cerebral metabolic activity only reflects those of the grey matter and the white matter, whereas that of the CSF is zero. We subtracted the global white matter metabolic activity from that of the whole brain, resulting in the global grey matter metabolism alone. We then divided the grey matter global metabolic activity by grey matter volume to accurately calculate the SUV for the grey matter alone. RESULTS: The brain volumes ranged between 1546 and 1924 ml. The mean SUV for total brain was 4.8-7. Total metabolic burden of the brain ranged from 5565 to 9617. The mean SUV for white matter was 2.8-4.1. On the basis of these measurements we generated the grey matter SUV, which ranged from 8.1 to 11.3. CONCLUSION: The accurate metabolic activity of the grey matter can be calculated using the novel segmentation technique that we applied to MRI. By combining these quantitative data with those generated from F-FDG-PET images we were able to calculate the accurate metabolic activity of the grey matter. These types of measurements will be of great value in accurate analysis of the data from patients with neuropsychiatric disorders. PMID- 26426968 TI - A comparison of acoustic radiation force impulse imaging and scintigraphy in the functional evaluation of the major salivary glands. AB - PURPOSE: This study aimed to determine the efficacy of acoustic radiation force impulse (ARFI) imaging for the functional assessment of salivary glands by comparing ARFI with salivary gland scintigraphy. MATERIALS AND METHODS: We prospectively evaluated 60 parotid (P) glands and 60 submandibular (SM) glands of 30 patients using salivary gland scintigraphy and ARFI elastography. The average pixel uptake and the excretion fraction (EF) in the P and SM glands were determined scintigraphically. The degree of stiffness in the P and SM glands at prelemon and postlemon stimulation periods were measured elastographically with ARFI. Changes in the degree of stiffness of the P and SM glands were also calculated with lemon stimulation. The scintigraphic and elastographic parameters were then compared statistically. RESULTS: We found a moderate linear correlation between the excretion function and the changes in the degree of stiffness of the P and SM glands induced by lemon stimulation (P<0.001, r=0.661; P<0.001, r=0.530, respectively). We also found a weak positive correlation between the EF and the degree of stiffness of the P and SM glands in the prelemon stimulation period (P=0.001, r=0.405; P<0.001, r=0.480, respectively). However, we did not find any significant correlation between other scintigraphic and elastographic parameters. CONCLUSION: ARFI imaging may play a role in the determination of the EF of P and SM glands by measuring tissue elasticity changes with lemon stimulation. However, ARFI does not seem to be a suitable substitute for scintigraphy in the evaluation of the parenchymal function of P and SM glands. PMID- 26426970 TI - Development of a conversion program to make SIMIND-generated SPECT data interfile acceptable to Xeleris. AB - The Monte Carlo code SIMIND is used in nuclear medicine for research purposes, and also for testing the validity of various applications. Conversion of a SIMIND generated interfile (header and image data file) is required to process the simulated image data on a Xeleris workstation. Currently there is no conversion program provided with SIMIND to convert its interfile, which is acceptable in any nuclear medicine workstation. Manual editing of the header file is possible with any standard text editor but it is time-consuming (requiring ~1 h) and stressful. To alleviate this, we have developed a conversion program using FreeMat V4.0 (an open source software similar to MATLAB from MathWorks). It takes an average of 0.04404 s to convert a SIMIND SPECT data interfile and make it acceptable to Xeleris. PMID- 26426969 TI - Consistency of metabolic tumor volume of non-small-cell lung cancer primary tumor measured using 18F-FDG PET/CT at two different tracer uptake times. AB - OBJECTIVES: The objective of this study was to test the hypothesis that the metabolic tumor volume (MTV) of primary non-small-cell lung cancer is not sensitive to differences in F-fluorodeoxyglucose (F-FDG) uptake time, and to compare this consistency of MTV measurements with that of standardized uptake value (SUV) and total lesion glycolysis (TLG). METHODS: Under Institutional Review Board approval, 134 consecutive patients with histologically proven non small-cell lung cancer underwent F-FDG PET/computed tomography scanning at about 1 h (early) and 2 h (delayed) after intravenous injection of F-FDG. MTV, SUV, and TLG of the primary tumor were all measured. Student's t-test and Wilcoxon's signed-rank test for paired data were used to compare MTV, SUV, and TLG between the two scans. The intraclass correlation coefficient (ICC) was used to assess agreement in PET parameters between the two scans and between the measurements made by two observers. RESULTS: MTV was not significantly different (P=0.17) between the two scans. However, SUVmax, SUVmean, SUVpeak, and TLG increased significantly from the early to the delayed scans (P<0.0001 for all). The median percentage change between the two scans in MTV (1.65%) was smaller than in SUVmax (11.76%), SUVmean(10.57%), SUVpeak(13.51%), and TLG (14.34%); the ICC of MTV (0.996) was greater than that of SUVmax (0.933), SUVmean (0.952), SUVpeak (0.928), and TLG (0.982). Interobserver agreement between the two radiologists was excellent for MTV, SUV, and TLG on both scans (ICC: 0.934-0.999). CONCLUSION: MTV is not sensitive to common clinical variations in F-FDG uptake time, its consistency is greater than that of SUVmax, SUVmean, SUVpeak, and TLG, and it has excellent interobserver agreement. PMID- 26426972 TI - Enhanced thermoelectric performance of carbon nanotubes at elevated temperature. AB - The electronic and transport properties of the (10, 0) single-walled carbon nanotube are studied by performing first-principles calculations and semi classical Boltzmann theory. It is found that the (10, 0) tube exhibits a considerably large Seebeck coefficient and electrical conductivity which are highly desirable for good thermoelectric materials. Together with the lattice thermal conductivity predicted by non-equilibrium molecular dynamics simulations, the room temperature ZT value of the (10, 0) tube is estimated to be 0.15 for p type carriers. Moreover, the ZT value exhibits strong temperature dependence and can reach to 0.77 at 1000 K. Such a ZT value can be further enhanced to as high as 1.9 by isotopic substitution and chemisorptions of hydrogen on the tube surface. PMID- 26426973 TI - Ca(2+) Interacts with Glu-22 of Abeta(1-42) and Phospholipid Bilayers to Accelerate the Abeta(1-42) Aggregation Below the Critical Micelle Concentration. AB - The amyloid cascade hypothesis links the amyloid-beta (Abeta) peptide aggregation to neuronal cell damage and ultimately the etiology of Alzheimer's disease (AD). Although Abeta aggregation has been known to accelerate at cell membranes, the exact mechanism of Abeta peptide deposition and the involvement of extracellular species are still largely unclear. Using surface plasmon resonance (SPR) and atomic force microscopy (AFM), we demonstrate that Ca(2+) ions, in conjunction with lipid bilayer, lower the threshold concentration for Abeta aggregation (>a few micromolar in vitro) to physiological levels (low nanomolar). Circular dichroism spectroscopy reveals that Ca(2+) ions and the lipid bilayer concertedly accelerate the conformational change or misfolding of Abeta peptides. Molecular dynamics calculation indicates that Ca(2+) is sandwiched between Glu-22 of Abeta and the lipid phosphate group. SPR experiments conducted using an E22G mutant confirmed the strong interaction among Ca(2+), Abeta(1-42), and the phospholipid bilayer. With the C- and N-termini of the Abeta dimer fully exposed for the attachment of additional Abeta molecules, fibrils formed with the Ca(2+)-anchored Abeta nuclei appear to interact with lipid bilayers differently from those preformed in solution. Thus, similar to the role of Ca(2+) in enriching islet amyloid polypeptides in the pancreas of diabetic patients ( Biophys. J. 2013 , 104 , 173 - 184 ) and the "Ca(2+) bridge" in mediating membrane interaction with alpha-synuclein in the Parkinson's disease ( Biochemistry , 2006 , 45 , 10947 - 10956 ), the influence of Ca(2+) on the Abeta adsorption at cell membranes, which leads to neuronal membrane damage in AD, cannot be overlooked. PMID- 26426974 TI - Multimorbidity among registered immigrants in Norway: the role of reason for migration and length of stay. AB - OBJECTIVES: International migration is rapidly increasing worldwide. However, the health status of migrants differs across groups. Information regarding health at arrival and subsequent periodic follow-up in the host country is necessary to develop equitable health care to immigrants. The objective of this study was to determine the impact of the length of stay in Norway and other sociodemographic variables on the prevalence of multimorbidity across immigrant groups (refugees, labour immigrants, family reunification immigrants and education immigrants). METHODS: This is a register-based study merging data from the National Population Register and the Norwegian Health Economics Administration database. Sociodemographic variables and multimorbidity across the immigrant groups were compared using Persons' chi-square test and anova as appropriate. Several binary logistic regression models were conducted. RESULTS: Multimorbidity was significantly lower among labour immigrants (OR (95% CI) 0.23 (0.21-0.26) and 0.45 (0.40-0.50) for men and women, respectively) and education immigrants (OR (95% CI) 0.40 (0.32-0.50) and 0.38 (0.33-0.43)) and higher among refugees (OR (95% CI) 1.67 (1.57-1.78) and 1.83 (1.75-1.92)), compared to family reunification immigrants. For all groups, multimorbidity doubled after a five-year stay in Norway. Effect modifications between multimorbidity and sociodemographic characteristics across the different reasons for migration were observed. CONCLUSIONS: Multimorbidity was highest among refugees at arrival but increased rapidly among labour immigrants, especially females. Health providers need to ensure tailor-made preventive and management strategies that take into account pre-migration and post-migration experiences for immigrants in order to address their needs. PMID- 26426975 TI - Direct and indirect relations between parent-child attachments, peer acceptance, and self-esteem for preschool children. AB - The present study aims to test Bowlby's suggestions concerning relations between the child's attachment quality with parents and subsequently constructed models of self-worth during early childhood. In most research on this question, attachment with mothers is considered in relation to self-worth but the child's attachment with fathers is not. Neither has the peer group been studied as an influence on child self-esteem, in the context of attachment research. This study addresses these relatively unstudied influences on child self-esteem. Attachment security to mother and father was measured by the Attachment Behavior Q-Set at two and half years of age. At five years of age social acceptance was measured using two sociometric techniques, and the self-esteem with the California Child Q Sort. Our analyses indicated that security of the attachment to father and peer acceptance are both unique, significant predictors of the childrens' self-esteem. The security of the attachment to mother was also related to child self-esteem but did not emerge as a uniquely significant predictor. Peer acceptance appeared to moderate of the effect of the security of the attachment to father on the self esteem of children. Our results extend the relatively sparse literature relating early attachments to self-esteem during early childhood. PMID- 26426976 TI - Chiral phosphoric acid catalyzed oxidative kinetic resolution of cyclic secondary amine derivatives including tetrahydroquinolines by hydrogen transfer to imines. AB - A chiral Bronsted acid catalyzed dehydrogenative kinetic resolution of tetrahydroquinoline derivatives, which are representative of cyclic secondary amines, based on their hydrogen transfer to aromatic imines was efficiently achieved with high enantioselectivities. This hydrogen transfer of tetrahydroquinolines to imines was not driven by their aromatization to quinolines. This dehydrogenative kinetic resolution could be also applied to the asymmetric synthesis of various benzofused heterocycles containing secondary amine cores. PMID- 26426977 TI - A Dioxobilin-Type Fluorescent Chlorophyll Catabolite as a Transient Early Intermediate of the Dioxobilin-Branch of Chlorophyll Breakdown in Arabidopsis thaliana. AB - Chlorophyll breakdown in higher plants occurs by the so called "PaO/phyllobilin" path. It generates two major types of phyllobilins, the characteristic 1-formyl 19-oxobilins and the more recently discovered 1,19-dioxobilins. The hypothetical branching point at which the original 1-formyl-19-oxobilins are transformed into 1,19-dioxobilins is still elusive. Here, we clarify this hypothetical crucial transition on the basis of the identification of the first natural 1,19 dioxobilin-type fluorescent chlorophyll catabolite (DFCC). This transient chlorophyll breakdown intermediate was isolated from leaf extracts of Arabidopsis thaliana at an early stage of senescence. The fleetingly existent DFCC was then shown to represent the direct precursor of the major nonfluorescent 1,19 dioxobilin that accumulated in fully senescent leaves. PMID- 26426978 TI - Association between nucleos(t)ide analog and tumor recurrence in hepatitis B virus-related hepatocellular carcinoma after radiofrequency ablation. AB - Radiofrequency ablation (RFA) is the best choice for curative treatment of hepatocellular carcinoma (HCC) cases not suitable for surgical intervention, but efforts should be made to reduce the risk of tumor recurrence. We aimed to investigate the association between nucleos(t)ide analog (NA) therapy for hepatitis B virus (HBV) and the risk of HCC recurrence post-RFA. Using the Taiwan National Health Insurance Research Database between July 1, 2004 and December 31, 2012, we screened 48,807 patients with newly diagnosed HBV-related HCC. We identified 850 patients (200 patients who used NAs for more than 90 days and 650 who never used NA post-RFA) who received RFA as a potentially curative treatment for HCC. Patients in the NA-treated cohort were randomly matched 1:2 with patients in the untreated cohort by age, sex, cirrhosis, and the time period between RFA and initiation of NA therapy. Finally, 133 patients were recruited in the NA-treated group and 266 in the untreated group for analysis. Cumulative incidences of and hazard ratios (HRs) for HCC recurrence were analyzed after adjusting for competing mortality. The HCC recurrence rate of the NA-treated group was significantly lower than that of the untreated group (2-year recurrence rate: 41.8%; 95% confidence interval [CI]: 32.9-50.6 vs. 54.3%; 95% CI: 48.0 60.6; modified log-rank test: P < 0.05). In modified Cox's regression analysis, NA therapy was independently associated with a decreased risk of HCC recurrence (HR, 0.69; 95% CI: 0.50-0.95; P < 0.05). Multivariate stratified analyses verified the association of NA therapy and decreased HCC recurrence in almost all patient subgroups. CONCLUSION: NA therapy was associated with a decreased risk of HCC recurrence among patients with HBV-related HCC post-RFA. PMID- 26426979 TI - Hybrid 'superswarm' leads to rapid divergence and establishment of populations during a biological invasion. AB - Understanding the genetic background of invading species can be crucial information clarifying why they become invasive. Intraspecific genetic admixture among lineages separated in the native ranges may promote the rate and extent of an invasion by substantially increasing standing genetic variation. Here, we examined the genetic relationships among threespine stickleback that recently colonized Switzerland. This invasion results from several distinct genetic lineages that colonized multiple locations and have since undergone range expansions, where they coexist and admix in parts of their range. Using 17 microsatellites genotyped for 634 individuals collected from 17 Swiss and two non Swiss European sites, we reconstruct the invasion of stickleback and investigate the potential and extent of admixture and hybridization among the colonizing lineages from a population genetic perspective. Specifically, we test for an increase in standing genetic variation in populations where multiple lineages coexist. We find strong evidence of massive hybridization early on, followed by what appears to be recent increased genetic isolation and the formation of several new genetically distinguishable populations, consistent with a hybrid 'superswarm'. This massive hybridization and population formation event(s) occurred over approximately 140 years and likely fuelled the successful invasion of a diverse range of habitats. The implications are that multiple colonizations coupled with hybridization can lead to the formation of new stable genetic populations potentially kick-starting speciation and adaptive radiation over a very short timescale. PMID- 26426980 TI - The use of the diaphragmatico-hepatic (DH) views of the abdominal and thoracic focused assessment with sonography for triage (AFAST/TFAST) examinations for the detection of pericardial effusion in 24 dogs (2011-2012). AB - OBJECTIVE: To evaluate the clinical usefulness of the diaphragmatico-hepatic (DH) view of the abdominal and thoracic focused assessment with sonography for triage (AFAST/TFAST) in detecting pericardial effusion (PE) in dogs. DESIGN: Retrospective case series from 2011 to 2012. SETTING: Private practice emergency and critical care hospital. ANIMALS: Twenty-four dogs with PE diagnosed by FAST. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Fifty-two medical records from October 1, 2011 through September 30, 2012 had the terms "PE" within the medical record. Twenty-four dogs were diagnosed with PE by FAST with entries for the DH view. Of the 24 dogs, 7 had abdominal FAST, 6 had thoracic FAST (TFAST), and 11 had both exams performed. PE was noted on the DH view in 20 of 24 (83%) cases. Subjective PE volume assessment ranged from trivial (<5 mm) to severe. Of the 4 cases in which PE was absent via the DH view, PE was seen during the same exam at the TFAST pericardial views (n = 2) or detected on serial exam at the DH view (n = 2). The PE volume that was missed via the DH view was characterized as trivial (<5 mm; n = 1), mild (n = 1), and moderate (n = 2). CONCLUSIONS: The DH view of FAST was found to be clinically helpful for the detection of PE. Veterinarians should make it routine practice and part of FAST training to look into the thorax via the DH view during both abdominal FAST and TFAST exams. PMID- 26426983 TI - Association of serum sodium levels with all-cause and cardiovascular mortality in chronic kidney disease: Results from a prospective observational study. AB - AIMS: The prevalence of hyponatraemia in the outpatient setting has not been thoroughly explored, and little is known about the prognostic implication of dysnatraemia in chronic kidney disease (CKD) patients, in particular accommodating the effect of concurrent medications. METHODS: This is a prospective observational study of non-dialysis-dependent CKD patients managed in a nephrology clinic. Patients enrolled between 2002 and 2012 in the Chronic Renal Insufficiency Standards Implementation Study were assessed. Survival analyses were performed using baseline sodium and 12-month time-averaged sodium, with adjustment for co-morbid diseases, laboratory findings and concurrent medications. RESULTS: At baseline (n = 2093), mean estimated glomerular filtration rate was 32.8 +/- 15.9 ml/min per 1.73 m(2) , median age was 67 (interquartile range 56-75) years and median serum sodium concentration was 140 (138-142) mmol/l. After a follow up of 41 (18-67) months, there were 684 deaths, 174 from cardiovascular causes; 1925 time-averaged sodium values were analysed. In the Cox multivariate adjusted regression, baseline hyponatraemia, but not hypernatraemia, was independently associated with all-cause mortality (hazard ratio (HR) 1.35, 95% confidence interval (CI) 1.02-1.78, P = 0.04, and HR 1.15, 95% CI 0.84-1.57, P = 0.39, respectively). This was similarly the case for time averaged hyponatraemia and hypernatraemia (HR 2.15, 95% CI 1.59-2.91, P < 0.01, and HR 1.47, 95% CI 0.93-2.38, P = 0.10, respectively). However, the association of baseline and time-averaged hyponatraemia with cardiovascular mortality was not significant. CONCLUSION: Hyponatraemia in the ambulatory setting is associated with all-cause but not cardiovascular mortality in CKD, independent of concomitant medications and co-morbidities. PMID- 26426981 TI - Protection from Radiation-Induced Pulmonary Fibrosis by Peripheral Targeting of Cannabinoid Receptor-1. AB - Radiation-induced pulmonary fibrosis (RIF) is a severe complication of thoracic radiotherapy that limits its dose, intensity, and duration. The contribution of the endocannabinoid signaling system in pulmonary fibrogenesis is not known. Using a well-established mouse model of RIF, we assessed the involvement of cannabinoid receptor-1 (CB1) in the onset and progression of pulmonary fibrosis. Female C57BL/6 mice and CB1 knockout mice generated on C57BL/6 background received 20 Gy (2 Gy/min) single-dose thoracic irradiation that resulted in pulmonary fibrosis and animal death within 15 to 18 weeks. Some C57BL/6 animals received the CB1 peripherally restricted antagonist AM6545 at 1 mg/kg intraperitoneally three times per week. Animal survival and parameters of pulmonary inflammation and fibrosis were evaluated. Thoracic irradiation (20 Gy) was associated with marked pulmonary inflammation and fibrosis in mice and high mortality within 15 to 18 weeks after exposure. Genetic deletion or pharmacological inhibition of CB1 receptors with a peripheral CB1 antagonist AM6545 markedly attenuated or delayed the lung inflammation and fibrosis and increased animal survival. Our results show that CB1 signaling plays a key pathological role in the development of radiation-induced pulmonary inflammation and fibrosis, and peripherally restricted CB1 antagonists may represent a novel therapeutic approach against this devastating complication of radiotherapy/irradiation. PMID- 26426984 TI - Barrier function and natural moisturizing factor levels after cumulative exposure to a fruit-derived organic acid and a detergent: different outcomes in atopic and healthy skin and relevance for occupational contact dermatitis in the food industry. AB - BACKGROUND: Fruit-derived organic compounds and detergents are relevant exposure factors for occupational contact dermatitis in the food industry. Although individuals with atopic dermatitis (AD) are at risk for development of occupational contact dermatitis, there have been no controlled studies on the effects of repeated exposure to multiple irritants, relevant for the food industry, in atopic skin. OBJECTIVES: The aim of the study was to investigate the outcomes of repeated exposure to a fruit-derived organic acid and a detergent in AD compared to healthy volunteers. METHODS: The volunteers were exposed to 2.0% acetic acid (AcA) and/or 0.5% sodium lauryl sulfate (SLS) in controlled tandem repeated irritation test. The outcomes were assessed by measurements of erythema, transepidermal water loss (TEWL) and natural moisturizing factor (NMF) levels. RESULTS: In the AD volunteers, repeated AcA exposure led to barrier disruption and significant TEWL increase; no significant differences after the same exposure in the healthy controls were found. Repeated exposure to SLS and the irritant tandems enhanced the reactions and resulted in a significantly higher increase in TEWL in the AD compared to the control group. Cumulative irritant exposure reduced the NMF levels in both groups. CONCLUSIONS: Differences in the severity of irritant-induced barrier impairment in atopic individuals contribute to the risk for occupational contact dermatitis in result of multiple exposures to food derived irritants and detergents. PMID- 26426985 TI - Loss of thermal refugia near equatorial range limits. AB - This study examines the importance of thermal refugia along the majority of the geographical range of a key intertidal species (Patella vulgata Linnaeus, 1758) on the Atlantic coast of Europe. We asked whether differences between sun-exposed and shaded microhabitats were responsible for differences in physiological stress and ecological performance and examined the availability of refugia near equatorial range limits. Thermal differences between sun-exposed and shaded microhabitats are consistently associated with differences in physiological performance, and the frequency of occurrence of high temperatures is most probably limiting the maximum population densities supported at any given place. Topographical complexity provides thermal refugia throughout most of the distribution range, although towards the equatorial edges the magnitude of the amelioration provided by shaded microhabitats is largely reduced. Importantly, the limiting effects of temperature, rather than being related to latitude, seem to be tightly associated with microsite variability, which therefore is likely to have profound effects on the way local populations (and consequently species) respond to climatic changes. PMID- 26426986 TI - Nanoscopic fuel-rich thermobaric formulations: Chemical composition optimization and sustained secondary combustion shock wave modulation. AB - Advanced thermobaric explosives have become one of the urgent requirements when targeting caves, fortified structures, and bunkers. Highly metal-based systems are designed to exploit the secondary combustion resulted from active metal particles; thus sustained overpressure and additional thermal loadings can be achieved. This study, reports on a novel approach for chemical composition optimization using thermochemical calculations in an attempt to achieve the highest explosion power. Shock wave resulted from thermobaric explosives (TBX) was simulated using ANSYS((r)) AUTODYN((r)) 2D hydrocode. Nanoscopic fuel-rich thermobaric charge was prepared by pressing technique; static field test was conducted. Comparative studies of modeled pressure-time histories to practical measurements were conducted. Good agreement between numerical modeling and experimental measurements was observed, particularly in terms of the prediction of wider overpressure profile which is the main characteristics of TBX. The TBX wider overpressure profile was ascribed to the secondary shock wave resulted from fuel combustion. The shock wave duration time and its decay pattern were acceptably predicted. Effective lethal fire-ball duration up to 50ms was achieved and evaluated using image analysis technique. The extended fire-ball duration was correlated to the additional thermal loading due to active metal fuel combustion. The tailored thermobaric charge exhibited an increase in the total impulse by 40 45% compared with reference charge. PMID- 26426987 TI - Enrichment of adenosine using thermally responsive chromatographic materials under friendly pH conditions. AB - A thermally responsive boronate affinity chromatographic material, which showed thermal sensitivity, had been successfully applied for the enrichment and separation of cis-diol-containing compounds, and the capture and release process could be facilitated by adjusting the temperature. However, in this system, the pH of the mobile phase must be higher than 9.8, and alkaline media can lead to the degradation of labile compounds; the use of silica beads also limits its use. In this study, thermally responsive boronate affinity chromatographic material, namely poly(N-isopropylacrylamide-co-N-acryloyl-3-aminophenylboronic acid) grafted silica, was successfully prepared by atom transfer radical polymerization. Its structure was confirmed by IR spectroscopy and the graft ratio was 20.8%, determined by thermogravimetric analysis. Furthermore, the capture/release of adenosine, a cis-diol, was performed from pH 5.0-9.0 and 10-50 degrees C. The elution of adenosine was remarkably retarded at decreased temperatures and adenosine could be captured completely at 10 degrees C at pH values of 5.0-9.0. The enrichment of adenosine could be achieved by simply changing the temperature from 10 to 50 degrees C. Therefore, this material not only improved the stability of the silica, but was also suitable for the capture of oxidation-sensitive biological analytes. Moreover, it could be used for the enrichment of cis-diol-containing compounds in LC with MS. PMID- 26426989 TI - Lipids under stress--a lipidomic approach for the study of mood disorders. AB - The emerging field of lipidomics has identified lipids as key players in disease physiology. Their physicochemical diversity allows precise control of cell structure and signaling events through modulation of membrane properties and trafficking of proteins. As such, lipids are important regulators of brain function and have been implicated in neurodegenerative and mood disorders. Importantly, environmental chronic stress has been associated with anxiety and depression and its exposure in rodents has been extensively used as a model to study these diseases. With the accessibility to modern mass-spectrometry lipidomic platforms, it is now possible to snapshot the extensively interconnected lipid network. Here, we review the fundamentals of lipid biology and outline a framework for the interpretation of lipidomic studies as a new approach to study brain pathophysiology. Thus, lipid profiling provides an exciting avenue for the identification of disease signatures with important implications for diagnosis and treatment of mood disorders. PMID- 26426988 TI - Control of hydroxyapatite coating by self-assembled monolayers on titanium and improvement of osteoblast adhesion. AB - Self-assembly technique was applied to introduce functional groups and form hydroxyl-, amine-, and carboxyl-terminal self-assembled monolayers (SAMs). The SAMs were grafted onto titanium substrates to obtain a molecularly smooth functional surface. Subsequent hydrothermal crystal growth formed homogeneous and crack-free crystalline hydroxyapatite (HA) coatings on these substrates. AFM and XPS were used to characterize the SAM surfaces, and XRD, SEM, and TEM were used to characterize the HA coatings. Results show that highly crystalline, dense, and oriented HA coatings can be formed on the OH-, NH2 -, and COOH-SAM surfaces. The SAM surface with -COOH exhibited stronger nucleating ability than that with -OH and -NH2 . The nucleation and growth processes of HA coatings were effectively controlled by varying reaction time, pH, and temperature. By using this method, highly crystalline, dense, and adherent HA coatings were obtained. In addition, in vitro cell evaluation demonstrated that HA coatings improved cell adhesion as compared with pristine titanium substrate. The proposed method is considerably effective in introducing the HA coatings on titanium surfaces for various biomedical applications and further usage in other industries. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 124-135, 2017. PMID- 26426991 TI - Mindfulness, Self-Compassion, Posttraumatic Stress Disorder Symptoms, and Functional Disability in U.S. Iraq and Afghanistan War Veterans. AB - Mindfulness and self-compassion are overlapping, but distinct constructs that characterize how people relate to emotional distress. Both are associated with posttraumatic stress disorder (PTSD) and may be related to functional disability. Although self-compassion includes mindful awareness of emotional distress, it is a broader construct that also includes being kind and supportive to oneself and viewing suffering as part of the shared human experience--a potentially powerful way of dealing with distressing situations. We examined the association of mindfulness and self-compassion with PTSD symptom severity and functional disability in 115 trauma-exposed U.S. Iraq/Afghanistan war veterans. Mindfulness and self-compassion were each uniquely, negatively associated with PTSD symptom severity. After accounting for mindfulness, self-compassion accounted for unique variance in PTSD symptom severity (f(2) = .25; medium ES). After accounting for PTSD symptom severity, mindfulness and self-compassion were each uniquely negatively associated with functional disability. The combined association of mindfulness and self-compassion with disability over and above PTSD was large (f(2) = .41). After accounting for mindfulness, self-compassion accounted for unique variance in disability (f(2) = .13; small ES). These findings suggest that interventions aimed at increasing mindfulness and self-compassion could potentially decrease functional disability in returning veterans with PTSD symptoms. PMID- 26426992 TI - First description of a sporadic breast cancer in a woman with BRCA1 germline mutation. AB - We describe the case of a woman carrying a germline pathogenic BRCA1 mutation diagnosed with a breast cancer overexpressing HER2. Clinical presentation of the tumor, HER2-positivity, genomic profile and loss of the mutated BRCA1 allele in tumor evidence that BRCA1 is not inactivated in this breast cancer. It represents the first biological demonstration for the existence of a sporadic HER2-positive breast cancer independent from BRCA loss of function in a woman carrier of a deleterious BRCA1 mutation. In a context where targeted therapies based on BRCA loss of function in the tumor are developed, such case could have direct implications. PMID- 26426971 TI - The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study. AB - Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men <=50y, men >50y, women <=50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (>=50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape. PMID- 26426993 TI - Prognosis of patients with esophageal squamous cell carcinoma after esophagectomy using the log odds of positive lymph nodes. AB - To compare the log odds of positive lymph nodes (LODDS) with the number of positive lymph nodes (pN), lymph node ratio (LNR), removed lymph node (RLN) count, and negative lymph node (NLN) count in determining the prognosis of patients with esophageal squamous cell carcinoma (ESCC) after esophagectomy. The records of patients with ESCC who received esophagectomy were retrospectively reviewed. The log-rank test was used to compare curves for overall survival (OS), and Cox regression analysis was performed to identify prognostic factors. The prognostic performance of the different lymph node staging systems were compared using the linear trend chi-square test, likelihood ratio chi-square test, and Akaike information criterion. A total of 589 patients were enrolled. Univariate Cox analysis showed that pN stage, LNR, RLN count, NLN count, and the LODDS were significantly associated with OS (p < 0.05 for all). Multivariate Cox analysis adjusted for significant factors indicated that LODDS was independent risk factor on overall survival (OS), and a higher LODDS was associated with worse OS (hazard ratio = 3.297, 95% confidence interval: 2.684-4.050, p < 0.001). The modified Tumor-LODDS-Metastasis staging system had better discriminatory ability, monotonicity, and homogeneity, and better optimistic prognostic stratification than the Tumor-Node-Metastasis staging system in determining the prognosis of patients with ESCC. The LODDS staging system was superior to other lymph node classifications in determining the prognosis of patients with ESCC after esophagectomy. LODDS may be incorporated into esophageal staging system if these results are eventually confirmed by other studies. PMID- 26426995 TI - Psychometric evaluation of novel measures of partner interfering and supportive behaviors among women with cancer. AB - PURPOSE: The aim of this study was to evaluate the psychometric properties of complementary and novel measures of partner interfering and partner supportive behaviors in cancer care (PIB-C and PSB-C). METHODS: Structured telephone interviews were conducted with 378 women (aged 18-79) in partnered relationships and recruited from the Kentucky Cancer Registry. Psychometric analyses of PIB-C and PSB-C were used to determine scale reliability, and scale construct and predictive validity (correlations with indicators of partner abuse, symptoms of depression, anxiety, and stress after cancer). RESULTS: Cronbach's alpha and split-half calculations indicated excellent internal consistency of the 20-item PIB-C (0.936 and 0.87, respectively) and 12-item PSB-C (0.930 and 0.89). Three thematic clusters for the PIB-C and two for the PSB-C were identified through factor analyses. Regarding construct validity, higher PIB-C and lower PSB-C scores were associated with a measure of psychological impacts from abuse. Predictive validity was suggested through (1) lower PSB-C associated with depression, (2) higher PIB-C associated with anxiety, and (3) higher perceived stress associated with higher PIB-C/lower PSB-C scores. CONCLUSION: Both PIB-C and PSB-C have strong psychometric properties and distinguish partner behaviors more likely to negatively impact women's depression, anxiety, and stress during cancer care/recovery. Use of these measures may assist clinical teams in comprehensively assessing women patients' home environment to best ensure cancer care/recovery. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26426994 TI - Repurposing the anti-malarial drug artesunate as a novel therapeutic agent for metastatic renal cell carcinoma due to its attenuation of tumor growth, metastasis, and angiogenesis. AB - Despite advances in the development of molecularly targeted therapies, metastatic renal cell carcinoma (RCC) is still incurable. Artesunate (ART), a well-known anti-malarial drug with low toxicity, exhibits highly selective anti-tumor actions against various tumors through generation of cytotoxic carbon-centered free radical in the presence of free iron. However, the therapeutic efficacy of ART against metastatic RCC has not yet been fully elucidated. In the analysis on a dataset from The Cancer Genome Atlas (TCGA) (n = 469) and a tissue microarray set from Samsung Medical Center (n = 119) from a cohort of patients with clear cell RCC (ccRCC), up-regulation of transferrin receptor 1 (TfR1), which is a well known predictive marker for ART, was correlated with the presence of distant metastasis and an unfavorable prognosis. Moreover, ART exerted potent selective cytotoxicity against human RCC cell lines (Caki-1, 786-O, and SN12C-GFP-SRLu2) and sensitized these cells to sorafenib in vitro, and the extent of ART cytotoxicity correlated with TfR1 expression. ART-mediated growth inhibition of human RCC cell lines was shown to result from the induction of cell cycle arrest at the G2/M phase and oncosis-like cell death. Furthermore, ART inhibited cell clonogenicity and invasion of human RCC cells and anti-angiogenic effects in vitro in a dose-dependent manner. Consistent with these in vitro data, anti tumor, anti-metastatic and anti-angiogenic effects of ART were also validated in human 786-O xenografts. Taken together, ART is a promising novel candidate for treating human RCC, either alone or in combination with other therapies. PMID- 26426996 TI - c-MYC Copy-Number Gain Is an Independent Prognostic Factor in Patients with Colorectal Cancer. AB - BACKGROUND: The aim of this study was to determine the incidence and clinicopathological significance of c-MYC gene copy-number (GCN) gain in patients with primary colorectal cancer (CRC). METHODS: The c-MYC GCN was investigated in 367 consecutive CRC patients (cohort 1) by using dual-color silver in situ hybridization. Additionally, to evaluate regional heterogeneity, we examined CRC tissue from 3 sites including the primary cancer, distant metastasis, and lymph node metastasis in 152 advanced CRC patients (cohort 2). KRAS exons 2 and 3 were investigated for mutations. RESULTS: In cohort 1, c-MYC gene amplification, defined by a c-MYC:centromere of chromosome 8 ratio >= 2.0, was detected in 31 (8.4%) of 367 patients. A c-MYC GCN gain, defined by >= 4.0 c-MYC copies/nucleus, was found in 63 (17.2%) patients and was associated with poor prognosis (P = 0.015). Multivariate Cox regression analysis showed that the hazard ratio for c MYC GCN gain was 2.35 (95% confidence interval, 1.453-3.802; P < 0.001). In a subgroup of stage II-III CRC patients, c-MYC GCN gain was significantly associated with poor prognosis by univariate (P = 0.034) and multivariate (P = 0.040) analyses. c-MYC protein overexpression was observed in 201 (54.8%) out of 367 patients and weakly correlated with c-MYC GCN gain (rho, 0.211). In cohort 2, the c-MYC genetic status was heterogenous in advanced CRC patients. Discordance between GCN gain in the primary tumor and either distant or lymph-node metastasis was 25.7% and 30.4%, respectively. A similar frequency for c-MYC GCN gain and amplification was observed in CRC patients with both wild-type and mutated KRAS. CONCLUSIONS: c-MYC GCN gain was an independent factor for poor prognosis in consecutive CRC patients and in the stage II-III subgroup. Our findings indicate that the status of c-MYC may be helpful in predicting the patients' outcome and for managing CRC patients. PMID- 26426998 TI - The Long-Run Socio-Economic Consequences of a Large Disaster: The 1995 Earthquake in Kobe. AB - We quantify the 'permanent' socio-economic impacts of the Great Hanshin-Awaji (Kobe) earthquake in 1995 by employing a large-scale panel dataset of 1,719 cities, towns, and wards from Japan over three decades. In order to estimate the counterfactual--i.e., the Kobe economy without the earthquake--we use the synthetic control method. Three important empirical patterns emerge: First, the population size and especially the average income level in Kobe have been lower than the counterfactual level without the earthquake for over fifteen years, indicating a permanent negative effect of the earthquake. Such a negative impact can be found especially in the central areas which are closer to the epicenter. Second, the surrounding areas experienced some positive permanent impacts in spite of short-run negative effects of the earthquake. Much of this is associated with movement of people to East Kobe, and consequent movement of jobs to the metropolitan center of Osaka, that is located immediately to the East of Kobe. Third, the furthest areas in the vicinity of Kobe seem to have been insulated from the large direct and indirect impacts of the earthquake. PMID- 26426997 TI - Genome and Phenotype Microarray Analyses of Rhodococcus sp. BCP1 and Rhodococcus opacus R7: Genetic Determinants and Metabolic Abilities with Environmental Relevance. AB - In this paper comparative genome and phenotype microarray analyses of Rhodococcus sp. BCP1 and Rhodococcus opacus R7 were performed. Rhodococcus sp. BCP1 was selected for its ability to grow on short-chain n-alkanes and R. opacus R7 was isolated for its ability to grow on naphthalene and on o-xylene. Results of genome comparison, including BCP1, R7, along with other Rhodococcus reference strains, showed that at least 30% of the genome of each strain presented unique sequences and only 50% of the predicted proteome was shared. To associate genomic features with metabolic capabilities of BCP1 and R7 strains, hundreds of different growth conditions were tested through Phenotype Microarray, by using Biolog plates and plates manually prepared with additional xenobiotic compounds. Around one-third of the surveyed carbon sources was utilized by both strains although R7 generally showed higher metabolic activity values compared to BCP1. Moreover, R7 showed broader range of nitrogen and sulphur sources. Phenotype Microarray data were combined with genomic analysis to genetically support the metabolic features of the two strains. The genome analysis allowed to identify some gene clusters involved in the metabolism of the main tested xenobiotic compounds. Results show that R7 contains multiple genes for the degradation of a large set of aromatic and PAHs compounds, while a lower variability in terms of genes predicted to be involved in aromatic degradation was found in BCP1. This genetic feature can be related to the strong genetic pressure exerted by the two different environment from which the two strains were isolated. According to this, in the BCP1 genome the smo gene cluster involved in the short-chain n alkanes degradation, is included in one of the unique regions and it is not conserved in the Rhodococcus strains compared in this work. Data obtained underline the great potential of these two Rhodococcus spp. strains for biodegradation and environmental decontamination processes. PMID- 26426999 TI - Multimodal endoscope can quantify wide-field fluorescence detection of Barrett's neoplasia. AB - BACKGROUND AND STUDY AIMS: To demonstrate the clinical use of a multimodal endoscope with a targeted fluorescently labeled peptide for quantitative detection of Barrett's neoplasia. PATIENTS AND METHODS: We studied 50 patients with Barrett's esophagus using a prototype multimodal endoscope with a fluorescently labeled peptide. Co-registered fluorescence and reflectance images were converted to ratios to correct for differences in distance and geometry over the image field of view. The ratio images were segmented using a unique threshold that maximized the variance between high and low intensities to localize regions of high grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). RESULTS: Early neoplasia (HGD and EAC) was identified with 94 % specificity and 96 % positive predictive value at a threshold of 1.49. The mean results for HGD and EAC were significantly greater than those for squamous/Barrett's esophagus and low grade dysplasia by one-way analysis of variance (ANOVA). The receiver operator characteristic curve for detection of early neoplasia had an area under the curve of 0.884. No adverse events associated with the endoscope or peptide were found. CONCLUSION: A multimodal endoscope can quantify fluorescence images from targeted peptides to localize early Barrett's neoplasia. (ClinicalTrials.gov number NCT01630798.). PMID- 26427000 TI - Rarity of adenomatous polyps in ulcerative colitis and its implications for colonic carcinogenesis. AB - BACKGROUND AND STUDY AIMS: Despite ample research on the dysplasia to carcinoma risk in ulcerative colitis, there are scant data on the prevalence of adenomatous polyps in this population. METHODS: The number and histology of all polyps detected at colonoscopies of ulcerative colitis patients aged > 50 during 2006 - 2012 were compared with similarly aged controls undergoing screening colonoscopy. RESULTS: There were 206 patients with ulcerative colitis and 624 controls included in the study (mean age 61.7 +/- 8.7 vs. 60.8 +/- 6.1, respectively; P = 0.15). Adenomatous polyps were detected in only 13/206 colonoscopies for ulcerative colitis compared with 162 /624 controls (6.3 % vs. 25.9 %, respectively; odds ratio [OR] 0.19, 95 % confidence interval [CI] 0.1 - 0.34; P < 0.0001). When also considering all prior colonoscopies performed over 7.7 +/- 4.6 years of follow-up (mean 4.1 +/- 2.9 colonoscopies/patient, range 1 - 15, total 832 colonoscopies), the risk of ever finding an adenoma in ulcerative colitis patients was still significantly lower compared with controls (14.1 % vs. 25.9 %, respectively; OR 0.47, 95 %CI 0.3 - 0.72; P = 0.0005). On multivariable analysis, adenomas were positively associated with advanced age (OR 1.07/year, 95 %CI 1.03 1.1; P < 0.0001) and with increasing body mass index (BMI; OR 1.06/kg/m(2), 95 %CI 1.01 - 1.1; P = 0.01) and negatively associated with having ulcerative colitis (OR 0.15, 95 %CI 0.09 - 0.44; P = 0.0005). Among 115 Crohn's disease patients aged > 50 years, the rate of ever-adenomas in small-bowel Crohn's disease was similar to the controls (P = 0.8) and not influenced by 5 aminosalicylic acid use, whereas patients with colonic Crohn's disease had a significantly lower rate of adenomas compared with the controls (3.9 % vs. 25.9 %; P = 0.002). CONCLUSION: Unlike patients with small-bowel Crohn's disease, patients with ulcerative colitis or with colonic Crohn's disease seldom develop sporadic adenomatous polyps. These data may provide novel clues to a possible role for colonic immune activation in restricting the adenoma to carcinoma sequence while propagating the dysplasia to carcinoma pathway. PMID- 26427001 TI - Efficacy of the endoscopic rendez-vous technique for the reconstruction of complete esophageal disruptions. AB - BACKGROUND AND STUDY AIMS: The rendezvous endoscopic approach, already described, might be an interesting technique in complete esophageal obstructions (CEO). PATIENTS AND METHODS: This retrospective report on nine patients referred because of CEO classified patients into two groups based on length of their esophageal disruption: the long (> 5 cm) group were three patients (esophageal stripping at stent removal [n = 2] and caustic ingestion [n = 1]; two patients having superior esophageal sphincter [SES] destruction); the short (< 5 cm) group were six patients (anastomotic or post-radiotherapy). The procedures were performed under radiographic guidance. RESULTS: All the reconstructions were successful. In four patients, a neo-SES was created, by transillumination (n = 2) or surgery (n = 2). The first dilation was performed by hydrostatic balloon, with additional metal stents (n = 4) and nasogastric tubes (n = 2) used. All the patients were able to eat after the procedure. Two delayed bleeds occurred, which were managed endoscopically. The patients underwent a median of seven dilations (range 3 - 55) over 8 months (2 - 32 months), with dilations ongoing in five patients, but all able to eat normally. CONCLUSION: Endoscopic rendezvous for CEO is safe and effective, even in patients with long disruptions and complete loss of SES. PMID- 26427002 TI - In-class didactic versus self-directed teaching of the probe-based confocal laser endomicroscopy (pCLE) criteria for Barrett's esophagus. AB - BACKGROUND AND AIMS: Optimal teaching methods for disease recognition using probe based confocal laser endomicroscopy (pCLE) have not been developed. Our aim was to compare in-class didactic teaching vs. self-directed teaching of Barrett's neoplasia diagnosis using pCLE. METHODS: This randomized controlled trial was conducted at a tertiary academic center. Study participants with no prior pCLE experience were randomized to in-class didactic (group 1) or self-directed teaching groups (group 2). For group 1, an expert conducted a classroom teaching session using standardized educational material. Participants in group 2 were provided with the same material on an audio PowerPoint. After initial training, all participants graded an initial set of 20 pCLE videos and reviewed correct responses with the expert (group 1) or on audio PowerPoint (group 2). Finally, all participants completed interpretations of a further 40 videos. RESULTS: Eighteen trainees (8 medical students, 10 gastroenterology trainees) participated in the study. Overall diagnostic accuracy for neoplasia prediction by pCLE was 77 % (95 % confidence interval [CI] 74.0 % - 79.2 %); of predictions made with high confidence (53 %), the accuracy was 85 % (95 %CI 81.8 % - 87.8 %). The overall accuracy and interobserver agreement was significantly higher in group 1 than in group 2 for all predictions (80.4 % vs. 73 %; P = 0.005) and for high confidence predictions (90 % vs. 80 %; P < 0.001). Following feedback (after the initial 20 videos), the overall accuracy improved from 73 % to 79 % (P = 0.04), mainly driven by a significant improvement in group 1 (74 % to 84 %; P < 0.01). Accuracy of prediction significantly improved with time in endoscopy training (72 % students, 77 % FY1, 82 % FY2, and 85 % FY3; P = 0.003). CONCLUSION: For novice trainees, in-class didactic teaching enables significantly better recognition of the pCLE features of Barrett's esophagus than self-directed teaching. The in class didactic group had a shorter learning curve and were able to achieve 90 % accuracy for their high confidence predictions. PMID- 26427003 TI - Gastrocnemius muscle architecture and achilles tendon properties influence walking distance in claudicants with peripheral arterial disease. AB - INTRODUCTION: The extent to which gastrocnemius muscle and Achilles tendon properties contribute to the impaired walking endurance of claudicants is not known. METHODS: Ultrasound images quantified muscle architecture of the lateral and medial gastrocnemius (GL and GM) and were combined with dynamometry during plantarflexor contractions to calculate tendon stress, strain, stiffness, the Young modulus, and hysteresis. Key parameters were entered into multiple regression models to explain walking endurance. RESULTS: Worse disease severity was significantly associated with longer fascicle: tendon length ratios (GL R = 0.789 and GM R = -0.828) and increased tendon hysteresis (R = -0.740). Walking endurance could be explained by GL and GM pennation angle, maximum tendon force, tendon hysteresis, and disease severity (R(2) = ~0.6). CONCLUSIONS: Peripheral arterial disease was associated with functionally important changes in muscle and tendon properties, including the usage of stored elastic energy. Interventions known to target these characteristics should be adopted as a means to improve walking endurance. PMID- 26427006 TI - Thermally Driven Large N-Type Voltage Responses from Hybrids of Carbon Nanotubes and Poly(3,4-ethylenedioxythiophene) with Tetrakis(dimethylamino)ethylene. AB - Hybrids of carbon nanotubes (CNTs) and poly(3,4-ethylenedioxythiophene) (PEDOT) treated by tetrakis(dimethylamino)ethylene (TDAE) have large n-type voltages in response to temperature differences. The reduced carrier concentration by TDAE reduction and partially percolated CNT networks embedded in the PEDOT matrix result in high thermopower and low thermal conductivity. The high electron mobility in the CNTs helps to minimally reduce the electrical conductivity of the hybrid, resulting in a large figure-of-merit. PMID- 26427005 TI - De Novo Transcriptome Assembly in Firmiana danxiaensis, a Tree Species Endemic to the Danxia Landform. AB - Many Firmiana species are locally endemic, providing an interesting system for studying adaptation and speciation. Among these species, F. danxiaensis is a tree species endemic to Mount Danxia in Guangdong, China, which is an area known for presenting the Danxia landform. How F. danxiaensis could have adapted to the stressful environment of rocky cliffs covered with barren soils in the Danxia landform is still unknown. In this study, we performed de novo assembly of the transcriptome of F. danxiaensis, obtaining 47,221 unigenes with an N50 value of 987 bp. Homology analysis showed that 32,318 of the unigenes presented hits in the NCBI non-redundant database, and 31,857 exhibited significant matches with the protein database of Theobroma cacao. Gene Ontology (GO) annotation showed that hundreds of unigenes participated in responses to various stresses or nutritional starvation, which may help us to understand the adaptation of F. danxiaensis to Danxia landform. Additionally, we found 263 genes related to responses to Cd, partially explaining the high accumulation of Cd observed in Firmiana species. The EuKaryotic Orthologous Groups (KOG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations revealed many genes playing roles in the biosynthesis of secondary metabolites and environmental adaptation, which may also contribute to the survivor and success of Firmiana species in extreme environments. Based on the obtained transcriptome, we further identified a Firmiana-specific whole-genome duplication event that occurred approximately 20 Mya, which may have provided raw materials for the diversification of Firmiana species. PMID- 26427004 TI - Comparison of Fecal Microbiota in Children with Autism Spectrum Disorders and Neurotypical Siblings in the Simons Simplex Collection. AB - In order to assess potential associations between autism spectrum disorder (ASD) phenotype, functional GI disorders and fecal microbiota, we recruited simplex families, which had only a single ASD proband and neurotypical (NT) siblings, through the Simons Simplex Community at the Interactive Autism Network (SSC@IAN). Fecal samples and metadata related to functional GI disorders and diet were collected from ASD probands and NT siblings of ASD probands (age 7-14). Functional gastrointestinal disorders (FGID) were assessed using the parent completed ROME III questionnaire for pediatric FGIDs, and problem behaviors were assessed using the Child Behavior Check List (CBCL). Targeted quantitative polymerase chain reaction (qPCR) assays were conducted on selected taxa implicated in ASD, including Sutterella spp., Bacteroidetes spp. and Prevotella spp. Illumina sequencing of the V1V2 and the V1V3 regions of the bacterial 16S rRNA genes from fecal DNA was performed to an average depth of 208,000 and 107,000 high-quality reads respectively. Twenty-five of 59 ASD children and 13 of 44 NT siblings met ROME III criteria for at least one FGID. Functional constipation was more prevalent in ASD (17 of 59) compared to NT siblings (6 of 44, P = 0.035). The mean CBCL scores in NT siblings with FGID, ASD children with FGID and ASD without FGID were comparably higher (58-62 vs. 44, P < 0.0001) when compared to NT children without FGID. There was no significant difference in macronutrient intake between ASD and NT siblings. There was no significant difference in ASD severity scores between ASD children with and without FGID. No significant difference in diversity or overall microbial composition was detected between ASD children with NT siblings. Exploratory analysis of the 16S rRNA sequencing data, however, identified several low abundance taxa binned at the genus level that were associated with ASD and/or first order ASD*FGID interactions (FDR <0.1). PMID- 26427007 TI - Iridotomy: a brief history and some physics. PMID- 26427008 TI - Carpe diem. PMID- 26427010 TI - Deducing CO2 motion, adsorption locations and binding strengths in a flexible metal-organic framework without open metal sites. AB - Microporous metal-organic frameworks (MOFs) have high surface areas and porosities, and are well-suited for CO2 capture. MIL-53 features corner-sharing MO4(OH)2 (M = Al, Ga, Cr, etc.) octahedra interconnected by benzenedicarboxylate linkers that form one-dimensional rhombic tunnels, and exhibits an excellent adsorption ability for guest molecules such as CO2. Studying the behavior of adsorbed CO2 in MIL-53 via solid-state NMR (SSNMR) provides rich information on the dynamic motion of guest molecules as well as their binding strengths to the MOF host, and sheds light on the specific guest adsorption mechanisms. Variable temperature (13)C SSNMR spectra of (13)CO2 adsorbed within various forms of MIL 53 are acquired and analyzed. CO2 undergoes a combination of two motions within MIL-53; we report the types of motion present, their rates, and rotational angles. (1)H-(13)C CP SSNMR experiments are used to examine the proximity of (1)H atoms in the MOF to (13)C atoms in CO2 guests. By replacing (1)H with (2)H in MIL 53, the location of the CO2 adsorption site in MIL-53 is experimentally confirmed by (1)H-(13)C CP SSNMR. The binding strength of CO2 within these MIL-53 MOFs follows the order MIL-53-NH2 (Al) > MIL-53-NH2 (Ga) > MIL-53 (Al) > MIL-53 (Ga). PMID- 26427011 TI - Reduced Dentin Matrix Protein Expression in Camurati-Engelmann Disease Transgenic Mouse Model. AB - Overexpression of transforming growth factor-beta1 (TGF-beta1) has been shown to lead to mineralization defects in both the enamel and dentin layers of teeth. A TGFB1 point mutation (H222D), derived from published cases of Camurati-Engelmann disease (CED), has been shown to constitutively activate TGF-beta1, leading to excess bone matrix production. Although CED has been well documented in clinical case reports, there are no published studies on the effect of CED on the dentition. The objective of this study was to determine the dental manifestations of hyperactivated TGF-beta1 signaling using an established mouse model of CED derived TGF-beta1 mutation. Murine dental tissues were studied via radiography, micro-CT, immunohistochemistry, and qRT-PCR. Results showed that initial decreased dental mineralized tissue density is resolved. Proliferation assays of incisor pulp and alveolar bone cell cultures revealed that cells from transgenic animals displayed a reduced rate of growth compared to alveolar bone cultures from wild-type mice. TGF-beta family gene expression analysis indicated significant fold changes in the expression of Alpl, Bmp2-5, Col-1, -2, -4, and 6, Fgf, Mmp, Runx2, Tgfb3, Tfgbr3, and Vdr genes. Assessment of SIBLINGs revealed downregulation of Ibsp, Dmp1, Dspp, Mepe, and Spp1, as well as reduced staining for BMP-2 and VDR in mesenchymal-derived pulp tissue in CED animals. Treatment of dental pulp cells with recombinant human TGF-beta1 resulted in increased SIBLING gene expression. CONCLUSIONS: Our results provide in vivo evidence suggesting that TFG-beta1 mediates expression of important dentin extracellular matrix components secreted by dental pulp, and when unbalanced, may contribute to abnormal dentin disorders. PMID- 26427012 TI - Finite Element Model Analysis of Cephalic Trim on Nasal Tip Stability. AB - IMPORTANCE: Alar rim retraction is the most common unintended consequence of tissue remodeling that results from overresection of the cephalic lateral crural cartilage; however, the complex tissue remodeling process that produces this shape change is not well understood. OBJECTIVES: To simulate how resection of cephalic trim alters the stress distribution within the human nose in response to tip depression (palpation) and to simulate the internal forces generated after cephalic trim that may lead to alar rim retraction cephalically and upward rotation of the nasal tip. DESIGN, SETTING, AND PARTICIPANTS: A multicomponent finite element model was derived from maxillofacial computed tomography with 1-mm axial resolution. The 3-dimensional editing function in the medical imaging software was used to trim the cephalic portion of the lower lateral cartilage to emulate that performed in typical rhinoplasty. Three models were created: a control, a conservative trim, and an aggressive trim. Each simulated model was imported to a software program that performs mechanical simulations, and material properties were assigned. First, nasal tip depression (palpation) was simulated, and the resulting stress distribution was calculated for each model. Second, long term tissue migration was simulated on conservative and aggressive trim models by placing normal and shear force vectors along the caudal and cephalic borders of the tissue defect. RESULTS: The von Mises stress distribution created by a 5-mm tip depression revealed consistent findings among all 3 simulations, with regions of high stress being concentrated to the medial portion of the intermediate crus and the caudal septum. Nasal tip reaction force marginally decreased as more lower lateral cartilage tissue was resected. Conservative and aggressive cephalic trim models produced some degree of alar rim retraction and tip rotation, which increased with the magnitude of the force applied to the region of the tissue defect. CONCLUSIONS AND RELEVANCE: Cephalic trim was performed on a computerized composite model of the human nose to simulate conservative and aggressive trims. Internal forces were applied to each model to emulate the tissue migration that results from decades of wound healing. Our simulations reveal that the degree of tip rotation and alar rim retraction is dependent on the amount of cartilage that was resected owing to cephalic trim. Tip reaction force is marginally reduced with increasing tissue volume resection. LEVEL OF EVIDENCE: NA. PMID- 26427014 TI - Experimental and theoretical photoluminescence studies in nucleic acid assembled gold-upconverting nanoparticle clusters. AB - Combinations of rare earth doped upconverting nanoparticles (UCNPs) and gold nanostructures are sought as nanoscale theranostics due to their ability to convert near infrared (NIR) photons into visible light and heat, respectively. However, because the large NIR absorption cross-section of the gold coupled with their thermo-optical properties can significantly hamper the photoluminescence of UCNPs, methods to optimize the ratio of gold nanostructures to UCNPs must be developed and studied. We demonstrate here nucleic acid assembly methods to conjugate spherical gold nanoparticles (AuNPs) and gold nanostars (AuNSs) to silica-coated UCNPs and probe the effect on photoluminescence. These studies showed that while UCNP fluorescence enhancement was observed from the AuNPs conjugated UCNPs, AuNSs tended to quench fluorescence. However, conjugating lower ratios of AuNSs to UCNPs led to reduced quenching. Simulation studies both confirmed the experimental results and demonstrated that the orientation and distance of the UCNP with respect to the core and arms of the gold nanostructures played a significant role in PL. In addition, the AuNS-UCNP assemblies were able to cause rapid gains in temperature of the surrounding medium enabling their potential use as a photoimaging-photodynamic-photothermal agent. PMID- 26427013 TI - Ternary Dinuclear Copper(II) Complexes of a Reduced Schiff Base Ligand with Diimine Coligands: DNA Binding, Cytotoxic Cell Apoptosis, and Apoptotic Mechanism. AB - A serial of mixed-ligand Cu(II) complexes of the type [Cu(phens)(H2 PDILeu)]H2 O (1-4) containing phens as 2,2'-bipyridyl (bpy, 1), 1,10-phenanthroline (phen, 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 3), and dipyrido[3,2-a:2',3'-c]phenazine (dppz, 4) have been isolated and characterized. The interaction of the complexes with calf-thymus DNA has been explored by physical methods to propose modes of DNA binding of the complexes, which indicate that 4 interacts with DNA more strongly than all of the other complexes through intercalation interaction. Furthermore, cell apoptosis was detected by AnnexinV/PI flow cytometry and TUNEL assay and by Western blotting to detect the protein expression of p53, Bax, and Bcl-2. All the three copper complexes can effectively induce apoptosis of the three human tumor cells, which was accompanied with upregulation of the expression of p53 and Bax, while Bcl-2 decreased. PMID- 26427015 TI - X-ray structure of a Ni(II)-tri-phenoxyl radical complex. AB - The diimino-diphenolato neutral square-planar Ni(ii) complex, NiL2, is readily oxidised with 2 equiv. of Ag[SbF6], to produce an unprecedented octahedral Ni(ii) tris(phenoxyl) radical complex, [Ni(L)3][SbF6]2. This study reveals, for the first time, the X-ray structure of a metal-tri-phenoxyl radical complex. PMID- 26427016 TI - Knockdown of LRP/LR Induces Apoptosis in Breast and Oesophageal Cancer Cells. AB - Cancer is a global burden due to high incidence and mortality rates and is ranked the second most diagnosed disease amongst non-communicable diseases in South Africa. A high expression level of the 37kDa/67kDa laminin receptor (LRP/LR) is one characteristic of cancer cells. This receptor is implicated in the pathogenesis of cancer cells by supporting tumor angiogenesis, metastasis and especially for this study, the evasion of apoptosis. In the current study, the role of LRP/LR on cellular viability of breast MCF-7, MDA-MB 231 and WHCO1 oesophageal cancer cells was investigated. Western blot analysis revealed that total LRP expression levels of MCF-7, MDA-MB 231 and WHCO1 were significantly downregulated by targeting LRP mRNA using siRNA-LAMR1. This knockdown of LRP/LR resulted in a significant decrease of viability in the breast and oesophageal cancer cells as determined by an MTT assay. Transfection of MDA-MB 231 cells with esiRNA-RPSA directed against a different region of the LRP mRNA had similar effects on LRP/LR expression and cell viability compared to siRNA-LAMR1, excluding an off-target effect of siRNA-LAMR1. This reduction in cellular viability is as a consequence of apoptosis induction as indicated by the exposure of the phosphatidylserine protein on the surface of breast MCF-7, MDA-MB 231 and oesophageal WHCO1 cancer cells, respectively, detected by an Annexin-V/FITC assay as well as nuclear morphological changes observed post-staining with Hoechst. These observations indicate that LRP/LR is crucial for the maintenance of cellular viability of breast and oesophageal cancer cells and recommend siRNA technology targeting LRP expression as a possible novel alternative technique for breast and oesophageal cancer treatment. PMID- 26427017 TI - Prevalence and Incidence of Epilepsy Associated with Convulsive Seizures in Rural Bolivia. A Global Campaign against Epilepsy Project. AB - OBJECTIVE: we performed a three-stages door-to-door survey to estimate incidence and prevalence of epilepsy associated with convulsive seizures (EACS) in a rural area of Bolivia. METHODS: the study was carried out in the Cordillera Province, southern-eastern Bolivia. One hundred fourteen rural communities with a total population of 18,907 inhabitants were included in the survey. In order to identify subjects with EACS, trained fieldworkers administered a validated single screening question to the householders (stage I). A second face-to-face questionnaire was administered to each positive subject (stage II) that, in case of positive answer, underwent a complete neurological examination to confirm the diagnosis (stage III). We estimated age and sex specific life-time and active EACS prevalence at the prevalence day (30th June 2010). Incidence risk was evaluated for the 10-year period between January 2000 and December 2010. RESULTS: on prevalence day we identified 136 subjects with EACS, 124 of whom had active epilepsy. The life-time prevalence of EACS was 7.2/1,000 (7.6/1,000 age-adjusted to the world standard population) while the prevalence of active EACS was 6.6/1,000 (6.7/1,000 age-adjusted to the world standard population). Both life time and active prevalence showed a peak (10.3/1,000) in the 15-24 years age group and, overall, were higher among women. During the incidence study period, 105 patients living in the study area had the onset of EACS. The crude incidence risk was 55.4/100,000 (49.5/100,000 age-adjusted to the world standard population). Incidence was slightly but not significantly higher among women (58.9/100,000 versus 51.9/100,000). CONCLUSIONS: the present study demonstrated a considerable burden of EACS in the Bolivian Chaco, showing prevalence and incidence estimates close to those reported for low and middle- income countries and underlying the need of treatment programs. PMID- 26427018 TI - Antimony(III) complexes with 2-amino-4,6-dimethoxypyrimidines: Synthesis, characterization and biological evaluation. AB - Novel pyrimidine compound bearing disulfide bridge, 5,5'-disulfanediylbis(2-amino 4,6-dimetoxypyrimidine) (3) was synthesized by reduction of 2-amino-4,6-dimethoxy 5-thiocyanatopyrimidine for the first time, and its structure was confirmed by X ray crystallographic analysis. Novel binuclear antimony(III) compound of (3), {Sb[5,5'-disulfanediylbis(2-amino-4,6-dimetoxypyrimidine)]Cl3}2 (4) and mononuclear antimony(III) compounds, SbL2Cl3, [L: 2-amino-5-thiol-4,6-dimethoxy pyrimidine (2) and 2-amino-5-(1H-tetrazol-5-ylthio)-4,6-dimethoxypyrimidine (6)] were synthesized and characterized with the help of elemental analysis, molecular conductivity, FT-IR, (1)H-NMR and LC-MS techniques. The geometrical structures optimized by a DFT/B3LYP/LANL2DZ method of the compounds, indicated that monomeric compounds have square pyramidal shape. Both antileishmanial activity against Leishmania tropica promastigote and glutathione reductase inhibitory activity were determined in vitro. The results showed that (3) has the best biological activity. PMID- 26427020 TI - The relationship between chemical concentration and odor activity value explains the inconsistency in making a comprehensive surrogate scent training tool representative of illicit drugs. AB - This report highlights the importance of an individual chemical's odor impact in the olfactory identification of marijuana, cocaine, and heroin. There are small amounts of highly odorous compounds present in headspace of these drugs, with very low odor detection thresholds, that are more likely responsible for contributing to the overall odor of these drugs. Previous reports of the most abundant compounds in headspace can mislead researchers when dealing with whole odor of these drugs. Surrogate scent formulations, therefore, must match the odor impact of key compounds and not just the chemical abundance of compounds. The objective of this study was to compare odorous volatile organic compounds (VOCs) emitted from illicit drug samples of marijuana, cocaine, and heroin to surrogate smell formulations using simultaneous sensory (via human olfaction) and chemical analyses. Use of solid phase microextraction (SPME) allowed VOCs in drug headspace to be extracted and pre-concentrated on site, and analyzed by multidimensional gas chromatography-mass spectrometry-olfactometry (MDGC-MS-O). Use of MDGC-MS-O allowed for further separation of odorous compounds and simultaneous detection by the human nose of the separate odor parts that make up the total aroma of these drugs. The compounds most abundant in headspace were not the most odor impactful when ranked by odor activity values (OAVs) (defined as ratio of concentration to odor detection threshold, ODT). There were no apparent correlations between concentrations and OAVs. A 1g marijuana surrogate lacked in odor active acids, aldehydes, ethers, hydrocarbons, N-containing, and S containing VOCs and was overabundant in odor active alcohols and aromatics compared with real marijuana. A 1g cocaine surrogate was overabundant in odor active alcohols, aldehydes, aromatics, esters, ethers, halogenates, hydrocarbons, ketones and N-containing compounds compared with real. A 1g heroin surrogate should contain less odor active acids, alcohols, aromatics, esters, ketones, and N-containing compounds. Drug quantity, age and adulterants can affect VOC emissions and their odor impact. The concept of odor activity value, then, is useful to researchers without access to more sophisticated instrumentation. Odor activity values can be calculated from published odor detection thresholds. More research is warranted to expand the database, and determine odor detection thresholds for compounds of interest. Additional information could be obtained from establishing ODTs of key odorants for canines. PMID- 26427019 TI - Oral administration of hyaluronan prevents skin dryness and epidermal thickening in ultraviolet irradiated hairless mice. AB - Hyaluronan is a component of the extracellular matrix that plays a role in water retention in tissues. In this study, we orally administered hyaluronans of varying molecular weights (300k and less than 10k) repeatedly to hairless mice exposed to ultraviolet (UV) irradiation and examined their effects on the skin of these mice. UV irradiation induces a marked increase in the epidermal thickness of the dorsal skin and a marked decrease in the skin moisture content; however, orally administered hyaluronan, particularly that with a molecular weight of less than 10k, markedly reversed the increase and decrease in the epidermal thickness and skin moisture content, respectively. Furthermore, on analyzing the mice skin, orally administered hyaluronan with a molecular weight of less than 10k increased the levels of the HAS2 gene expression in the skin. Based on these findings, it is assumed that orally administered hyaluronans, with molecular weight of 300k and less than 10k, reversed UV irradiation-induced skin disturbance. In particular, it was considered that the increase in the skin moisture content by orally administered hyaluronan, with a molecular weight of less than 10k, was related to the effect on skin cells. PMID- 26427021 TI - Differential grandparental investment - the impact of phenotypic resemblance. AB - Differential grandparental investment is mainly explained as a result of paternity uncertainty. Phenotypic resemblance may be interpreted as an indicator of genetically relatedness. Consequently the present study focused on the impact of phenotypic resemblance on grandparental investment, i.e. solicitude, contact frequency and quality of relationship. 213 adults persons between the age 19 and 32 years (x = 25.5; SD = 3.4) were enrolled in the study. Data concerning grandparental investment during childhood were collected retrospectively using a 30 item questionnaire. Grandparental investment patterns differed significantly according grandparent category. In detail maternal grandmothers showed the highest contact frequency and the highest solicitude while - as to be expected - the paternal grandfather exhibited the lowest degree of investment. Grandparental investment was independent of grandparent category mainly influenced by residential distance. Phenotypic resemblance had an impact on grandparental investment independent of residential distance. This was first of all true of paternal grandfathers. An impact of phenotypic resemblance on grandparental investment patters can be assumed. PMID- 26427022 TI - Self-catalytic polymerization of a water-soluble selenium/polypyrrole nanocomposite and its nonlinear optical properties. AB - A facile one-step method for the synthesis of a water-soluble selenium/polypyrrole (Se/PPy) nanocomposite was developed. In the aqueous synthesis process, the pyrrole acted as a reductant for the reduction of H2SeO3, and then the elemental Se formed in situ acted as a catalyst for the polymerization of pyrrole. The characterization results show that the as-obtained composite (Se/PPy) is a spherical (Phi80 nm) product that is made up of amorphous Se particles coated by PPy layers. The formation mechanism and influence factors of the products were discussed, based on a series of experiments. It is proposed that remainder H2SeO3 adsorbed on the PPy chains increased the water-solubility and conductivity of the Se/PPy nanocomposite. Significantly, relying on the synergistic effect of photo-conductive Se nanoparticles and electric-conductive PPy molecules, the Se/PPy nanocomposite possesses a large two-photon absorption (2PA) cross-section and good optical limiting properties, which were demonstrated by the Z-scan technique using a femtosecond laser. We believe that this work should be an interesting strategy for developing polymer composites with excellent optoelectrical properties. PMID- 26427023 TI - Dynamics of Weeds in the Soil Seed Bank: A Hidden Markov Model to Estimate Life History Traits from Standing Plant Time Series. AB - Predicting the population dynamics of annual plants is a challenge due to their hidden seed banks in the field. However, such predictions are highly valuable for determining management strategies, specifically in agricultural landscapes. In agroecosystems, most weed seeds survive during unfavourable seasons and persist for several years in the seed bank. This causes difficulties in making accurate predictions of weed population dynamics and life history traits (LHT). Consequently, it is very difficult to identify management strategies that limit both weed populations and species diversity. In this article, we present a method of assessing weed population dynamics from both standing plant time series data and an unknown seed bank. We use a Hidden Markov Model (HMM) to obtain estimates of over 3,080 botanical records for three major LHT: seed survival in the soil, plant establishment (including post-emergence mortality), and seed production of 18 common weed species. Maximum likelihood and Bayesian approaches were complementarily used to estimate LHT values. The results showed that the LHT provided by the HMM enabled fairly accurate estimates of weed populations in different crops. There was a positive correlation between estimated germination rates and an index of the specialisation to the crop type (IndVal). The relationships between estimated LHTs and that between the estimated LHTs and the ecological characteristics of weeds provided insights into weed strategies. For example, a common strategy to cope with agricultural practices in several weeds was to produce less seeds and increase germination rates. This knowledge, especially of LHT for each type of crop, should provide valuable information for developing sustainable weed management strategies. PMID- 26427024 TI - Prevalence of malaria across Papua New Guinea after initial roll-out of insecticide-treated mosquito nets. AB - OBJECTIVES: To assess the population prevalence of malaria in villages across Papua New Guinea (PNG) following the first roll-out of free long-lasting insecticidal nets (LLIN). METHODS: Between October 2008 and August 2009, a household survey was conducted in 49 random villages in districts covered by the LLIN distribution campaign. The survey extended to 19 villages in sentinel sites that had not yet been covered by the campaign. In each village, 30 households were randomly sampled, household heads were interviewed and capillary blood samples were collected from all consenting household members for microscopic diagnosis of malaria. RESULTS: Malaria prevalence ranged from 0% to 49.7% with a weighted average of 12.1% (95% CI 9.5, 15.3) in the national sample. More people were infected with Plasmodium falciparum (7.0%; 95% CI 5.4, 9.1) than with P. vivax (3.8%; 95% CI 2.4, 5.7) or P. malariae (0.3%; 95% CI 0.1, 0.6). Parasitaemia was strongly age-dependent with a P. falciparum peak at age 5-9 years and a P. vivax peak at age 1-4 years, yet with differences between geographical regions. Individual LLIN use and high community coverage were associated with reduced odds of infection (OR = 0.64 and 0.07, respectively; both P < 0.001). Splenomegaly in children and anaemia were common morbidities attributable to malaria. CONCLUSIONS: Malaria prevalence across PNG is again at levels comparable to the 1970s. The strong association of LLIN use with reduced parasitaemia supports efforts to achieve and maintain high country-wide coverage. P. vivax infections will require special targeted approaches across PNG. PMID- 26427025 TI - Nanoparticles made of pi-conjugated compounds targeted for chemical and biological applications. AB - Semiconducting organic nanoparticles have recently attracted increasing attention in the chemical and biomedical fields. Such nanoparticles are mainly composed of pi-conjugated compounds. They possess the properties of easy synthesis, facile tuning, less toxicity and more biocompatibility relative to the existing inorganic nanoparticles. In addition, they show advantages such as brighter fluorescence, higher photostability and higher biocompatibility, compared with classical fluorescent organic dyes. In this review, we summarize the latest advances in the development of organic nanoparticles made of pi-conjugated compounds, including preparation methods, material design, nanoparticle fabrication and surface functionalization for chemical and biological applications. Especially, we focus on the applications of semiconducting organic nanoparticles in chemical and biological sensing by monitoring the fluorescence signal, as nanocarriers for drug/gene delivery, in photothermal and photodynamic therapy, and in photoacoustic imaging. Finally, the challenges and perspectives for the future development of organic nanoparticles based on pi-conjugated compounds are also discussed. PMID- 26427026 TI - The Synthesis of B2(SIDip)2 and its Reactivity Between the Diboracumulenic and Diborynic Extremes. AB - A new compound with the formula L-B2-L wherein the stabilizing ligand (L) is 1,3 bis[diisopropylphenyl]-4,5-dihydroimidazol-2-ylidene (SIDip) has been synthesized, isolated, and characterized. The pi-acidity of the SIDip ligand, intermediate between the relatively non-acidic IDip (1,3 bis[diisopropylphenyl]imidazol-2-ylidene) ligand and the much more highly acidic CAAC (1-[2,6-diisopropylphenyl]-3,3,5,5-tetramethylpyrrolidin-2-ylidene) ligand, gives rise to a compound with spectroscopic, electrochemical, and structural properties between those of L-B2-L compounds stabilized by CAAC and IDip. Reactions of all three L-B2-L compounds with CO demonstrate the differences caused by their respective ligands, as the pi-acidities of the CAAC and SIDip carbenes enabled the isolation of bis(boraketene) compounds (L(OC)B-B(CO)L), which could not be isolated from reactions with B2(IDip)2. However, only B2(IDip)2 and B2(SIDip)2 could be converted into bicyclic bis(boralactone) compounds. PMID- 26427028 TI - What is your diagnosis? A soft tissue mass in a Black Rat Snake. PMID- 26427029 TI - Rapid changes in genetic architecture of behavioural syndromes following colonization of a novel environment. AB - Behavioural syndromes, that is correlated behaviours, may be a result from adaptive correlational selection, but in a new environmental setting, the trait correlation might act as an evolutionary constraint. However, knowledge about the quantitative genetic basis of behavioural syndromes, and the stability and evolvability of genetic correlations under different ecological conditions, is limited. We investigated the quantitative genetic basis of correlated behaviours in the freshwater isopod Asellus aquaticus. In some Swedish lakes, A. aquaticus has recently colonized a novel habitat and diverged into two ecotypes, presumably due to habitat-specific selection from predation. Using a common garden approach and animal model analyses, we estimated quantitative genetic parameters for behavioural traits and compared the genetic architecture between the ecotypes. We report that the genetic covariance structure of the behavioural traits has been altered in the novel ecotype, demonstrating divergence in behavioural correlations. Thus, our study confirms that genetic correlations behind behaviours can change rapidly in response to novel selective environments. PMID- 26427027 TI - Functional Impact and Evolution of a Novel Human Polymorphic Inversion That Disrupts a Gene and Creates a Fusion Transcript. AB - Despite many years of study into inversions, very little is known about their functional consequences, especially in humans. A common hypothesis is that the selective value of inversions stems in part from their effects on nearby genes, although evidence of this in natural populations is almost nonexistent. Here we present a global analysis of a new 415-kb polymorphic inversion that is among the longest ones found in humans and is the first with clear position effects. This inversion is located in chromosome 19 and has been generated by non-homologous end joining between blocks of transposable elements with low identity. PCR genotyping in 541 individuals from eight different human populations allowed the detection of tag SNPs and inversion genotyping in multiple populations worldwide, showing that the inverted allele is mainly found in East Asia with an average frequency of 4.7%. Interestingly, one of the breakpoints disrupts the transcription factor gene ZNF257, causing a significant reduction in the total expression level of this gene in lymphoblastoid cell lines. RNA-Seq analysis of the effects of this expression change in standard homozygotes and inversion heterozygotes revealed distinct expression patterns that were validated by quantitative RT-PCR. Moreover, we have found a new fusion transcript that is generated exclusively from inverted chromosomes around one of the breakpoints. Finally, by the analysis of the associated nucleotide variation, we have estimated that the inversion was generated ~40,000-50,000 years ago and, while a neutral evolution cannot be ruled out, its current frequencies are more consistent with those expected for a deleterious variant, although no significant association with phenotypic traits has been found so far. PMID- 26427030 TI - Estimating glomerular filtration rate by serum creatinine or/and cystatin C equations: An analysis of multi-centre Chinese subjects. AB - AIM: Various equations based on serum creatinine or/and cystatin C, required further validation in a Chinese population. We compared the performance of six Chinese equations (Mascr, Peiscr, Macys, Fengcys, Mascr-cys and Fengscr-cys) with the CKD-EPI equations in multi-centre Chinese subjects and evaluated their applicability in clinical practice. METHODS: A total of 1522 adult patients from four different hospitals of China were enrolled in the study. (99m) Tc-DTPA renal dynamic imaging was used as the reference GFR (rGFR), and serum creatinine and cystatin C were measured by standardized assays. An optimal score system was implemented in the study. RESULTS: The average rGFR of recruited subjects was 67.30+/-28.89 mL/min per 1.73m(2) . All estimated GFR (eGFR) correlated well with rGFR. In accordance with Bland-Altman analysis, the Fengscr-cys equations achieved optimal overall performance (score 14 vs 0-6), with least bias (median difference, -0.57 mL/min per 1.73m(2) ; median absolute difference, 8.83 mL/min per 1.73m(2) ), best precision (17.99 mL/min per 1.73m(2) ), highest accuracy (percentage of eGFR within 15%, 30% and 50% of the rGFR (P15 , P30 and P50 ; 49.7%, 78.7% and 91.8%, respectively); root-mean-square-error (RMSE, 16.28)). The Fengcys equation, a typical cystatin C based equation, was another well-behaved formula with an impressive performance. The Ma equations performed much poorer than the CKD-EPI equations. Consistent results can be observed in the GFR- /age- and sex-specific subgroups, while none equation yielded ideal accuracy in GFR<60 mL/min per 1.73 m(2) subgroup. CONCLUSION: The Fengscr-cys equation appeared to achieve the best performance for GFR estimation in overall Chinese adult patients. However, further research is warranted to improve the accuracy of available equations in GFR less than 60 mL/min per 1.73 m(2) individuals. PMID- 26427031 TI - Congruent phylogenetic and fossil signatures of mammalian diversification dynamics driven by Tertiary abiotic change. AB - Computational methods for estimating diversification rates from extant species phylogenetic trees have become abundant in evolutionary research. However, little evidence exists about how their outcome compares to a complementary and direct source of information: the fossil record. Furthermore, there is virtually no direct test for the congruence of evolutionary rates based on these two sources. This task is only achievable in clades with both a well-known fossil record and a complete phylogenetic tree. Here, we compare the evolutionary rates of ruminant mammals as estimated from their vast paleontological record--over 1200 species spanning 50 myr--and their living-species phylogeny. Significantly, our results revealed that the ruminant's fossil record and phylogeny reflect congruent evolutionary processes. The concordance is especially strong for the last 25 myr, when living groups became a dominant part of ruminant diversity. We found empirical support for previous hypotheses based on simulations and neontological data: The pattern captured by the tree depends on how clade specific the processes are and which clades are involved. Also, we report fossil evidence for a postradiation speciation slowdown coupled with constant, moderate extinction in the Miocene. The recent deceleration in phylogenetic rates is connected to rapid extinction triggered by recent climatic fluctuations. PMID- 26427032 TI - Dendritic cells revisited in human allergic rhinitis and asthma. AB - The role of dendritic cells (DCs) in airway allergy has been studied for 15 years; recent data has highlighted the cross talk with airway epithelial cells and environmental factors (allergens, virus) during the inception and exacerbation of allergic asthma. Although murine models have provided key information, it remains uncertain to what extent these basic mechanisms take place in human allergic disease, notably with regard to different clinical phenotypes. In the present review, we discuss new evidence regarding mechanisms of DC regulation in the mouse which could be important in human asthma. Finally, after discussing the effects of current therapies on DC biology, we focus on pathways that could represent targets for future therapies. PMID- 26427034 TI - Efficacy of disinfectants against porcine rotavirus in the presence and absence of organic matter. AB - Rotavirus is an enteric pathogen that causes morbidity and mortality in young mammals, including pigs. Outbreaks of rotavirus on commercial farms have a significant economic impact in terms of losses in production. Effective cleaning and disinfection along with good farm management can reduce rotavirus contamination in the environment, and decrease the chance of outbreaks of disease. This study investigated the efficacy of six commercial disinfectants against MS2 bacteriophage and Group A porcine rotavirus, in the presence of high and low levels of organic matter to simulate the farm environment. A phenolic based disinfectant (Bi-OO-cyst) was effective at all levels of organic matter concentrations. Iodophore-based disinfectants did not have a significant virucidal effect against rotavirus under any conditions. For peroxygen compound based disinfectants and glutaraldehyde-based disinfectants, organic matter load made a significant difference in reducing efficacy. This highlights the importance of thorough cleaning with detergent before disinfection to reduce viral contamination on the farm and decrease rotavirus disease incidence in pigs. SIGNIFICANCE AND IMPACT OF THE STUDY: Infection of rotavirus has a negative impact on the health and growth of pigs in production. Given that the virus is transmitted faecal-orally, use of an effective disinfectant on farm, which works even in high organic matter, has the potential to save costs in terms of outbreaks of disease and viral contamination. Here, we test a number of commercial disinfectants of which one a phenolic compound, Bio-OO-cyst, shows effectivity even in high organic matter, implying its use could have a huge impact in reducing viral contamination and preventing losses in production. PMID- 26427033 TI - Sodium stibogluconate and paromomycin for treating visceral leishmaniasis under routine conditions in eastern Sudan. AB - OBJECTIVES: Among patients with primary and relapse visceral leishmaniasis (VL) in eastern Sudan, we determined the proportion eligible for treatment with sodium stibogluconate and paromomycin (SSG/PM) and, of these, their demographic and clinical characteristics; initial treatment outcomes including adverse side effects requiring treatment discontinuation; treatment outcomes by 6 months; and risk factors associated with initial (slow responders) and late treatment failure (relapses and post-kala-azar dermal leishmaniasis, PKDL). METHODS: A retrospective cohort study in Tabarak Allah Hospital, Gedaref Province, eastern Sudan, from July 2011 to January 2014. RESULTS: Of 1252 individuals diagnosed with VL (1151 primary and 101 relapses), 65% were eligible for SSG/PM including 83% children, almost half of them malnourished and anaemic. About 4% of individuals discontinued treatment due to side effects; 0.7% died during treatment. Initial cure was achieved in 93% of 774 primary cases and 77% of 35 relapse cases (P < 0.001). Among the 809 patients eligible for SSG/PM, 218 (27%) were lost to follow-up. Outcomes by six months among the 591 patients with available follow-up data were: definitive cure (n = 506; 86%), relapse (n = 38; 6%), treatment discontinuation (n = 33; 6%), PKDL (n = 7; 1%) and death (n = 7; 1%). Among those completing a full course of SSG/PM, relapses and under-fives were at significantly higher risk of early and late treatment failure, respectively. CONCLUSION: Whether SSG/PM as a first-line regimen is an undeniable progress compared to SSG monotherapy, it excluded a considerable proportion of VL patients due to drug safety concerns. We call for accelerated development of new drugs and treatment regimens to improve VL treatment in Sudan. PMID- 26427035 TI - Improving healthcare worker hand hygiene adherence before patient contact: A multimodal intervention of hand hygiene practice in Three Japanese tertiary care centers. AB - BACKGROUND: Though hand hygiene is an important method of preventing healthcare associated infection, we found suboptimal hand hygiene adherence among healthcare workers in 4 diverse Japanese hospitals (adherence rates of 11%-25%). OBJECTIVE: Our goal was to assess multimodal hand hygiene intervention coupled with a contest to improve hand hygiene adherence. SETTING: A total of 3 to 4 inpatient wards in 3 Japanese hospitals. DESIGN: Pre-post intervention study. INTERVENTION: The intervention was a multimodal hand hygiene intervention recommended by the World Health Organization that was tailored to each facility. The hospital with the highest adherence after the intervention was given $5000 US dollars and a trophy, provided by an American coinvestigator unaffiliated with any of the Japanese hospitals. MEASUREMENT: We tracked hand hygiene adherence rates before patient contact for each unit and hospital and compared these to pre-intervention adherence rates. RESULTS: We observed 2982 postintervention provider-patient encounters in 10 units across 3 hospitals. Hand hygiene adherence rates were improved overall after the intervention (18% pre- to 33% postintervention; P < 0.001), but postintervention adherence rates varied considerably: hospital A + 29%, B + 5%, C + 8%. Hospital A won the contest with 40% adherence after the intervention. CONCLUSIONS: Using a novel contest coupled with a multimodal intervention successfully improved hand hygiene rates among Japanese healthcare workers. Given the overall low rates, however, further improvement is necessary. PMID- 26427036 TI - The effect of a streptococci containing probiotic in periodontal therapy: a randomized controlled trial. AB - AIM: To evaluate the adjunctive effects of a Streptococcus oralis KJ3, Streptococcus uberis KJ2 and Streptococcus rattus JH145 containing probiotic tablet after scaling and root planing (SRP). MATERIALS AND METHODS: Forty-eight periodontitis patients were included in this double-blind, placebo-controlled clinical trial. After root planing, patients used either a placebo or a probiotic tablet twice a day for 12 weeks. The pocket probing depth (primary outcome measure), bleeding on probing and relative attachment levels were measured at baseline, 12 and 24 weeks. At baseline, 4, 8, 12 and 24 weeks, microbiological sampling was performed and plaque and gingival indices were recorded. RESULTS: The primary and secondary outcome measures were significantly (p < 0.05) improved at the 12- and the 24-week evaluation in both groups. However, no significant inter-group differences could be detected at any time point, except from the % of sites with plaque that were significantly lower in the probiotic group than in the control group at the 24-week evaluation. In addition, at the 12-week time point, the salivary Prevotella intermedia counts were significantly lower in the probiotic group. CONCLUSIONS: No differences were detected when comparing the adjunctive use of a placebo or the investigated streptococci containing probiotic tablet after SRP. ClinicalTrials.gov Identifier: NCT02403960. PMID- 26427037 TI - The flavors of plasma cells. PMID- 26427038 TI - Adenosine: a selfish-immunity signal? PMID- 26427039 TI - Sub-apoptotic dosages of pro-oxidant vitamin cocktails sensitize human melanoma cells to NK cell lysis. AB - Alpha-tocopheryl succinate (alphaTOS), vitamin K3 (VK3) and vitamin C (ascorbic acid, AA) were previously shown to synergistically promote different death pathways in carcinoma cells, depending on their concentrations and combinations. Similar effects were observed herein in melanoma cells, although alphaTOS behaved as an antagonist. Interestingly, suboptimal cell death-inducing concentrations (1.5 MUM alphaTOS/20 MUM AA/0.2 MUM VK3) effectively up-regulated activating Natural Killer (NK) cell ligands, including MICA (the stress-signaling ligand of the NKG2D receptor), and/or the ligands of at least one of the natural cytotoxicity receptors (NKp30, NKp44 and NKp46) in 5/6 melanoma cell lines. Only an isolated MICA down-regulation was seen. HLA class I, HLA class II, ULBP1, ULBP2, ULBP3, Nectin-2, and PVR displayed little, if any, change in expression. Ligand up-regulation resulted in improved lysis by polyclonal NK cells armed with the corresponding activating receptors. These results provide the first evidence for concerted induction of cell death by cell-autonomous and extrinsic (immune) mechanisms. Alarming the immune system much below the cell damage threshold may have evolved as a sensitive readout of neoplastic transformation and oxidative stress. Cocktails of vitamin analogues at slightly supra-physiological dosages may find application as mild complements of melanoma treatment, and in chemoprevention. PMID- 26427040 TI - Decoding c-Myc networks of cell cycle and apoptosis regulated genes in a transgenic mouse model of papillary lung adenocarcinomas. AB - The c-Myc gene codes for a basic-helix-loop-helix-leucine zipper transcription factor protein and is reported to be frequently over-expressed in human cancers. Given that c-Myc plays an essential role in neoplastic transformation we wished to define its activity in lung cancer and therefore studied its targeted expression to respiratory epithelium in a transgenic mouse disease model. Using histological well-defined tumors, transcriptome analysis identified novel c-Myc responsive cell cycle and apoptosis genes that were validated as direct c-Myc targets using EMSA, Western blotting, gene reporter and ChIP assays.Through computational analyses c-Myc cooperating transcription factors emerged for repressed and up-regulated genes in cancer samples, namely Klf7, Gata3, Sox18, p53 and Elf5 and Cebpalpha, respectively. Conversely, at promoters of genes regulated in transgenic but non-carcinomatous lung tissue enriched binding sites for c-Myc, Hbp1, Hif1 were observed. Bioinformatic analysis of tumor transcriptomic data revealed regulatory gene networks and highlighted mortalin and moesin as master regulators while gene reporter and ChIP assays in the H1299 lung cancer cell line as well as cross-examination of published ChIP-sequence data of 7 human and 2 mouse cell lines provided strong evidence for the identified genes to be c-Myc targets. The clinical significance of findings was established by evaluating expression of orthologous proteins in human lung cancer. Taken collectively, a molecular circuit for c-Myc-dependent cellular transformation was identified and the network analysis broadened the perspective for molecularly targeted therapies. PMID- 26427041 TI - Comprehensive portrait of recurrent glioblastoma multiforme in molecular and clinical characteristics. AB - Glioblastoma multiforme is the most common primary malignant brain tumor in adults. In addition to poor response to treatment, a high recurrence rate contributes to the poor prognosis. The purpose of this study was to investigate the genetical and clinical characteristics of recurrent glioblastoma. We used whole transcriptome sequencing data to examine the distribution of molecular subtypes and gene signatures in 22 recurrent glioblastoma taken from the Chinese population, and further analyzed biological progression of the tumors, when compared with primary glioblastoma. The proportion of the classical subtype in recurrent ones (22%) was lower than that in primary glioblastoma (36%). The frequency of IDH1 mutations in recurrent glioblastomas was nearly twice that in primary glioblastomas. TP53 mutations were fewer in proneural recurrent glioblastomas (20%) but frequent in classical recurrent glioblastomas (80%). The most common sites of recurrent glioblastomas were the temporal lobe (41%). In patients diagnosed with recurrent glioblastoma multiforme, 64% were younger than 50 years. Gene set enrichment analysis revealed that chromatin fracture, repair, and remodeling genes were enriched in recurrent glioblastoma. Our results highlight the differences in clinical features, molecular subtypes and gene alterations between primary and recurrent glioblastoma and may be helpful for targeted therapy for recurrent glioblastoma. PMID- 26427043 TI - DOT1L: a new therapeutic target for aggressive breast cancer. PMID- 26427042 TI - Targeted therapy for Epstein-Barr virus-associated gastric carcinoma using low dose gemcitabine-induced lytic activation. AB - The constant presence of the viral genome in Epstein-Barr virus (EBV)-associated gastric cancers (EBVaGCs) suggests the applicability of novel EBV-targeted therapies. The antiviral nucleoside drug, ganciclovir (GCV), is effective only in the context of the viral lytic cycle in the presence of EBV-encoded thymidine kinase (TK)/protein kinase (PK) expression. In this study, screening of the Johns Hopkins Drug Library identified gemcitabine as a candidate for combination treatment with GCV. Pharmacological induction of EBV-TK or PK in EBVaGC originated tumor cells were used to study combination treatment with GCV in vitro and in vivo. Gemcitabine was found to be a lytic inducer via activation of the ataxia telangiectasia-mutated (ATM)/p53 genotoxic stress pathway in EBVaGC. Using an EBVaGC mouse model and a [125I] fialuridine (FIAU)-based lytic activation imaging system, we evaluated gemcitabine-induced lytic activation in an in vivo system and confirmed the efficacy of gemcitabine-GCV combination treatment. This viral enzyme-targeted anti-tumor strategy may provide a new therapeutic approach for EBVaGCs. PMID- 26427044 TI - EFTUD2 on innate immunity. PMID- 26427045 TI - The Complete Mitochondrial Genome of Delia antiqua and Its Implications in Dipteran Phylogenetics. AB - Delia antiqua is a major underground agricultural pest widely distributed in Asia, Europe and North America. In this study, we sequenced and annotated the complete mitochondrial genome of this species, which is the first report of complete mitochondrial genome in the family Anthomyiidae. This genome is a double stranded circular molecule with a length of 16,141 bp and an A+T content of 78.5%. It contains 37 genes (13 protein-coding genes, 22 tRNAs and 2 rRNAs) and a non-coding A+T rich region or control region. The mitochondrial genome of Delia antiqua presents a clear bias in nucleotide composition with a positive AT-skew and a negative GC-skew. All of the 13 protein-coding genes use ATN as an initiation codon except for the COI gene that starts with ATCA. Most protein coding genes have complete termination codons but COII and ND5 that have the incomplete termination codon T. This bias is reflected in both codon usage and amino acid composition. The protein-coding genes in the D. antiqua mitochondrial genome prefer to use the codon UUA (Leu). All of the tRNAs have the typical clover-leaf structure, except for tRNASer(AGN) that does not contain the dihydrouridine (DHU) arm like in many other insects. There are 7 mismatches with U-U in the tRNAs. The location and structure of the two rRNAs are conservative and stable when compared with other insects. The control region between 12S rRNA and tRNAIle has the highest A+T content of 93.7% in the D. antiqua mitochondrial genome. The control region includes three kinds of special regions, two highly conserved poly-T stretches, a (TA)n stretch and several G(A)nT structures considered important elements related to replication and transcription. The nucleotide sequences of 13 protein-coding genes are used to construct the phylogenetics of 26 representative Dipteran species. Both maximum likelihood and Bayesian inference analyses suggest a closer relationship of D. antiqua in Anthomyiidae with Calliphoridae, Calliphoridae is a paraphyly, and both Oestroidea and Muscoidea are polyphyletic. PMID- 26427046 TI - Interactive Effects of Temperature and UV Radiation on Photosynthesis of Chlorella Strains from Polar, Temperate and Tropical Environments: Differential Impacts on Damage and Repair. AB - Global warming and ozone depletion, and the resulting increase of ultraviolet radiation (UVR), have far-reaching impacts on biota, especially affecting the algae that form the basis of the food webs in aquatic ecosystems. The aim of the present study was to investigate the interactive effects of temperature and UVR by comparing the photosynthetic responses of similar taxa of Chlorella from Antarctic (Chlorella UMACC 237), temperate (Chlorella vulgaris UMACC 248) and tropical (Chlorella vulgaris UMACC 001) environments. The cultures were exposed to three different treatments: photosynthetically active radiation (PAR; 400-700 nm), PAR plus ultraviolet-A (320-400 nm) radiation (PAR + UV-A) and PAR plus UV-A and ultraviolet-B (280-320 nm) radiation (PAR + UV-A + UV-B) for one hour in incubators set at different temperatures. The Antarctic Chlorella was exposed to 4, 14 and 20 degrees C. The temperate Chlorella was exposed to 11, 18 and 25 degrees C while the tropical Chlorella was exposed to 24, 28 and 30 degrees C. A pulse-amplitude modulated (PAM) fluorometer was used to assess the photosynthetic response of microalgae. Parameters such as the photoadaptive index (Ek) and light harvesting efficiency (alpha) were determined from rapid light curves. The damage (k) and repair (r) rates were calculated from the decrease in PhiPSIIeff over time during exposure response curves where cells were exposed to the various combinations of PAR and UVR, and fitting the data to the Kok model. The results showed that UV-A caused much lower inhibition than UV-B in photosynthesis in all Chlorella isolates. The three isolates of Chlorella from different regions showed different trends in their photosynthesis responses under the combined effects of UVR (PAR + UV-A + UV-B) and temperature. In accordance with the noted strain specific characteristics, we can conclude that the repair (r) mechanisms at higher temperatures were not sufficient to overcome damage caused by UVR in the Antarctic Chlorella strain, suggesting negative effects of global climate change on microalgae inhabiting (circum-) polar regions. For temperate and tropical strains of Chlorella, damage from UVR was independent of temperature but the repair constant increased with increasing temperature, implying an improved ability of these strains to recover from UVR stress under global warming. PMID- 26427047 TI - Reliability of measures of quadriceps muscle function using magnetic stimulation. AB - INTRODUCTION: Magnetic stimulation can be used to assess muscle function by calculating voluntary activation using an interpolated twitch during maximal voluntary contractions (MVCs) and control twitches to potentiated muscle. In this study we assessed the reliability of torque, electromyography (EMG), and voluntary activation variables. METHODS: Fifteen men completed 5 testing sessions (2 familiarization and 3 reliability trials) to assess quadriceps femoris muscle function. Intra- and interday reliability levels of torque and EMG variables were estimated using typical error +/- 90% confidence limits, expressed as percentage [coefficient of variation (CV)] and intraclass correlation coefficient. The smallest worthwhile change was calculated as 0.2 * between-participant standard deviation. RESULTS: Intra- and interday torque variables for MVC were reliable (CV < 4%, ICC 0.98, and CV < 5%, ICC 0.99, respectively). EMG variables were less reliable than torque variables, with CVs ranging from 7% to 18%. CONCLUSION: Magnetic stimulation of the femoral nerve is a reliable method for assessing muscle function. PMID- 26427048 TI - Role of the nucleolus in neurodegenerative diseases with particular reference to the retina: a review. AB - The nucleolus has emerged as a key regulator of cellular growth and the response to stress, in addition to its traditionally understood function in ribosome biogenesis. The association between nucleolar function and neurodegenerative disease is increasingly being explored. There is also recent evidence indicating that the nucleolus may well be crucial in the development of the eye. In this present review, the role of the nucleolus in retinal development as well as in neurodegeneration with an emphasis on the retina is discussed. PMID- 26427049 TI - Acute generalized exanthematous pustulosis induced by Mycoplasma pneumoniae infection. PMID- 26427050 TI - Fluorescence-Guided Surgery of Liver Metastasis in Orthotopic Nude-Mouse Models. AB - We report here the development of fluorescence-guided surgery of liver metastasis. HT29 human colon cancer cells expressing green fluorescent protein (GFP) were initially injected in the spleen of nude mice. Three weeks later, established liver metastases were harvested and implanted on the left lobe of the liver in other nude mice in order to make an orthotopic liver metastasis model. Fourteen mice with a single liver metastasis were randomized into bright-light surgery (BLS) or fluorescence-guided surgery (FGS) groups. Seven mice were treated with BLS, seven were treated with FGS. Three weeks after implantation, the left lobe of the liver with a single metastasis was exposed through a median abdominal incision. BLS was performed under white light. FGS was performed using a hand-held portable fluorescence imaging system (Dino-Lite). Post-surgical residual tumor fluorescence was visualized with the OV100 Small Animal Imaging System. Residual tumor fluorescence after BLS was clearly visualized at high magnification with the OV100. In contrast, residual tumor fluorescence after FGS was not detected even at high magnification with the OV100. These results demonstrate the feasibility of FGS for liver metastasis. PMID- 26427051 TI - A Non-Interventional Naturalistic Study of the Prescription Patterns of Antipsychotics in Patients with Schizophrenia from the Spanish Province of Tarragona. AB - BACKGROUND: The analysis of prescribing patterns in entire catchment areas contributes to global mapping of the use of antipsychotics and may improve treatment outcomes. OBJECTIVE: To determine the pattern of long-term antipsychotic prescription in outpatients with schizophrenia in the province of Tarragona (Catalonia-Spain). METHODS: A naturalistic, observational, retrospective, non-interventional study based on the analysis of registries of computerized medical records from an anonymized database of 1,765 patients with schizophrenia treated between 2011 and 2013. RESULTS: The most used antipsychotic was risperidone, identified in 463 (26.3%) patients, followed by olanzapine in 249 (14.1%), paliperidone in 225 (12.7%), zuclopenthixol in 201 (11.4%), quetiapine in 141 (8%), aripiprazole in 100 (5.7%), and clozapine in 100 (5.7%). Almost 8 out of 10 patients (79.3%) were treated with atypical or second generation antipsychotics. Long-acting injectable (LAI) formulations were used in 44.8% of patients. Antipsychotics were generally prescribed in their recommended doses, with clozapine, ziprasidone, LAI paliperidone, and LAI risperidone being prescribed at the higher end of their therapeutic ranges. Almost 7 out of 10 patients (69.6%) were on antipsychotic polypharmacy, and 81.4% were on psychiatric medications aside from antipsychotics. Being prescribed quetiapine (OR 14.24, 95% CI 4.94-40.97), LAI (OR 9.99, 95% CI 6.45-15.45), psychiatric co medications (OR 4.25, 95% CI 2.72-6.64), and paliperidone (OR 3.13, 95% CI 1.23 7.92) were all associated with an increased likelihood of polypharmacy. Being prescribed risperidone (OR 0.54, 95% CI 0.35-0.83) and older age (OR 0.98, 95% CI 0.97-0.99) were related to a low polypharmacy probability. CONCLUSIONS: Polypharmacy is the most common pattern of antipsychotic use in this region of Spain. Use of atypical antipsychotics is extensive. Most patients receive psychiatric co-medications such as anxiolytics or antidepressants. Polypharmacy is associated with the use of quetiapine or paliperidone, use of a LAI, younger age, and psychiatric co-medication. PMID- 26427052 TI - Heterogeneous Mechanisms of Secondary Resistance and Clonal Selection in Sarcoma during Treatment with Nutlin. AB - Nutlin inhibits TP53-MDM2 interaction and is under investigation in soft-tissue sarcomas (STS) and other malignancies. Molecular mechanisms of secondary resistance to nutlin in STS are unknown. We performed whole-transcriptome sequencing (RNA-seq) on three pretreatment and secondary resistant STS cell lines selected based on their high primary sensitivity to nutlin. Our data identified a subset of cancer gene mutations and ploidy variations that were positively selected following treatment, including TP53 mutations in 2 out of 3 resistant cell lines. Further, secondary resistance to nutlin was associated with deregulation of apoptosis-related genes and marked productive autophagy, the inhibition of which resulted in significant restoration of nutlin-induced cell death. Collectively, our findings argue that secondary resistance to nutlin in STS involved heterogeneous mechanisms resulting from clonal evolution and several biological pathways. Alternative dosing regimens and combination with other targeted agents are needed to achieve successful development of nutlin in the clinical setting. PMID- 26427053 TI - Attenuation of Inflammatory Mediators (TNF-alpha and Nitric Oxide) and Up Regulation of IL-10 by Wild and Domesticated Basidiocarps of Amauroderma rugosum (Blume & T. Nees) Torrend in LPS-Stimulated RAW264.7 Cells. AB - Amauroderma rugosum, commonly known as "Jiazi" in China, is a wild mushroom traditionally used by the Chinese to reduce inflammation, to treat diuretic and upset stomach, and to prevent cancer. It is also used by the indigenous communities in Malaysia to prevent epileptic episodes and incessant crying by babies. The aim of this study was to compare the wild and domesticated basidiocarps of A. rugosum for antioxidant and in vitro anti-inflammatory effects in LPS-stimulated RAW264.7 cells. The wild basidiocarps of A. rugosum were collected from the Belum Forest, Perak, Malaysia and the domesticated basidiocarps of A. rugosum were cultivated in the mushroom house located in the University of Malaya, Kuala Lumpur, Malaysia. Both the wild and domesticated basidiocarps were subjected to ethanolic extraction and the extracts were tested for antioxidant and anti-inflammatory activities. In this study, the crude ethanolic extract of wild (WB) and domesticated (DB) basidiocarps of A. rugosum had comparable total phenolic content and DPPH scavenging activity. However, WB (EC50 = 222.90 MUg/mL) displayed a better ABTS cation radical scavenging activity than DB (EC50 = 469.60 MUg/mL). Both WB and DB were able to scavenge nitric oxide (NO) radical and suppress the NO production in LPS-stimulated RAW264.7 cells and this effect was mediated through the down-regulation of inducible nitric oxide synthase (iNOS) gene. In addition, both WB and DB caused down-regulation of the inflammatory gene TNF-alpha and the up-regulation of the anti-inflammatory gene IL-10. There was no inhibitory effect of WB and DB on nuclear translocation of NF kappaB p65. In conclusion, the wild and domesticated basidiocarps of A. rugosum possessed antioxidant and in vitro anti-inflammatory properties. WB and DB inhibited downstream inflammatory mediators (TNF-alpha and NO) and induced anti inflammatory cytokine IL-10 production. No inhibitory effects shown on upstream nuclear translocation of NF-kappaB p65. WB and DB exhibited antioxidant activity and attenuation of proinflammatory mediators and therefore, A. rugosum may serve as a potential therapeutic agent in the management of inflammation. PMID- 26427055 TI - Accuracy of blood pressure monitors available in high street pharmacies. AB - The aim of this study was to assess the accuracy of automated blood pressure monitors on sale to the UK general public. We conducted static pressure accuracy testing on all compatible (19 out of 22 available) blood pressure monitors available for sale in pharmacies within the city of Oxford, UK, and tested two devices for accuracy in measurement of systolic and diastolic blood pressures in 21 adults. The devices showed good accuracy when measuring static pressure in laboratory bench testing, with the median error per device ranging from -2.2 to +1.2 mmHg; however, the two devices tested performed worse in vivo than in laboratory tests, with median errors as high as 6 mmHg. The monitors showed good accuracy in static pressure testing, with a lack of correlation between monitor price and accuracy. However, higher error rates seen during in-vivo testing of a subset of monitors may indicate that static testing may not be appropriate for routine accuracy assessment of these monitors. PMID- 26427054 TI - Expression of Mitochondrial Cytochrome C Oxidase Chaperone Gene (COX20) Improves Tolerance to Weak Acid and Oxidative Stress during Yeast Fermentation. AB - INTRODUCTION: Saccharomyces cerevisiae is the micro-organism of choice for the conversion of fermentable sugars released by the pre-treatment of lignocellulosic material into bioethanol. Pre-treatment of lignocellulosic material releases acetic acid and previous work identified a cytochrome oxidase chaperone gene (COX20) which was significantly up-regulated in yeast cells in the presence of acetic acid. RESULTS: A Deltacox20 strain was sensitive to the presence of acetic acid compared with the background strain. Overexpressing COX20 using a tetracycline-regulatable expression vector system in a Deltacox20 strain, resulted in tolerance to the presence of acetic acid and tolerance could be ablated with addition of tetracycline. Assays also revealed that overexpression improved tolerance to the presence of hydrogen peroxide-induced oxidative stress. CONCLUSION: This is a study which has utilised tetracycline-regulated protein expression in a fermentation system, which was characterised by improved (or enhanced) tolerance to acetic acid and oxidative stress. PMID- 26427056 TI - Structural and Ultrastructural Analysis of the Cervical Discs of Young and Elderly Humans. AB - Several studies describing the ultrastructure and extracellular matrix (ECM) of intervertebral discs (IVDs) involve animal models and specimens obtained from symptomatic individuals during surgery for degenerative disease or scoliosis, which may not necessarily correlate to changes secondary to normal aging in humans. These changes may also be segment-specific based on different load patterns throughout life. Our objective was to describe the ECM and collagen profile of cervical IVDs in young (G1 - <35 years) and elderly (G2 - >65 years) presumably-asymptomatic individuals. Thirty cervical discs per group were obtained during autopsies of presumably-asymptomatic individuals. IVDs were analyzed with MRI, a morphological grading scale, light microscopy, scanning electron microscopy (SEM) and immunohistochemistry (IHC) for collagen types I, II, III, IV, V, VI, IX and X. Macroscopic degenerative features such as loss of annulus-nucleus distinction and fissures were found in both groups and significantly more severe in G2 as expected. MRI could not detect all morphological changes when compared even with simple morphological inspection. The loose fibrocartilaginous G1 matrix was replaced by a denser ECM in G2 with predominantly cartilaginous characteristics, chondrocyte clusters and absent elastic fibers. SEM demonstrated persistence of an identifiable nucleus and Sharpey-type insertion of cervical annulus fibers even in highly-degenerated G2 specimens. All collagen types were detected in every disc sector except for collagen X, with the largest area stained by collagens II and IV. Collagen detection was significantly decreased in G2: although significant intradiscal differences were rare, changes may occur faster or earlier in the posterior annulus. These results demonstrate an extensive modification of the ECM with maintenance of basic ultrastructural features despite severe macroscopic degeneration. Collagen analysis supports there is not a "pathologic" collagen type and changes are generally similar throughout the disc. Understanding the collagen and ultrastructural substrate of degenerative changes in the human disc is an essential step in planning restorative therapies. PMID- 26427057 TI - Retinoic Acid Receptors Control Spermatogonia Cell-Fate and Induce Expression of the SALL4A Transcription Factor. AB - All-trans retinoic acid (ATRA) is instrumental to male germ cell differentiation, but its mechanism of action remains elusive. To address this question, we have analyzed the phenotypes of mice lacking, in spermatogonia, all rexinoid receptors (RXRA, RXRB and RXRG) or all ATRA receptors (RARA, RARB and RARG). We demonstrate that the combined ablation of RXRA and RXRB in spermatogonia recapitulates the set of defects observed both upon ablation of RAR in spermatogonia. We also show that ATRA activates RAR and RXR bound to a conserved regulatory region to increase expression of the SALL4A transcription factor in spermatogonia. Our results reveal that this major pluripotency gene is a target of ATRA signaling and that RAR/RXR heterodimers are the functional units driving its expression in spermatogonia. They add to the mechanisms through which ATRA promote expression of the KIT tyrosine kinase receptor to trigger a critical step in spermatogonia differentiation. Importantly, they indicate also that meiosis eventually occurs in the absence of a RAR/RXR pathway within germ cells and suggest that instructing this process is either ATRA-independent or requires an ATRA signal originating from Sertoli cells. PMID- 26427059 TI - Zipf's Law: Balancing Signal Usage Cost and Communication Efficiency. AB - We propose a model that explains the reliable emergence of power laws (e.g., Zipf's law) during the development of different human languages. The model incorporates the principle of least effort in communications, minimizing a combination of the information-theoretic communication inefficiency and direct signal cost. We prove a general relationship, for all optimal languages, between the signal cost distribution and the resulting distribution of signals. Zipf's law then emerges for logarithmic signal cost distributions, which is the cost distribution expected for words constructed from letters or phonemes. PMID- 26427058 TI - Postoperative Changes in Aqueous Monocyte Chemotactic Protein-1 Levels and Bleb Morphology after Trabeculectomy vs. Ex-PRESS Shunt Surgery. AB - PURPOSE: To evaluate the postoperative changes in blebs and levels of aqueous monocyte chemotactic protein-1 (MCP-1) after trabeculectomy vs. Ex-PRESS tube shunt surgery. METHODS: Rabbits were subjected to trabeculectomy or Ex-PRESS tube shunt surgery and observed for up to 3 months. Intraocular pressure (IOP) was measured using a rebound tonometer. The MCP-1 level was measured by enzyme-linked immunosorbent assay (ELISA). Bleb morphology was evaluated using photos and anterior-segment optical coherence tomography (OCT). RESULTS: There were no differences in bleb appearance or IOP at any time between the groups. Bleb wall density in the anterior-segment OCT image was significantly lower 1 week after surgery in the Ex-PRESS group than the trabeculectomy group. The MCP-1 level in control eyes was 304.1 +/- 45.2 pg/mL. In the trabeculectomy group, the mean aqueous MCP-1 level was 1444.9, 1914.3, 1899.8, 516.4, 398.3, 427.3, 609.5, 1612.7, 386.2, and 167.9 pg/mL at 3, 6, and 12 h, and 1, 2, 5, 7, 14, 30, and 90 days after surgery, respectively. In the Ex-PRESS group, the corresponding values were 1744.0, 1372.0, 932.5, 711.7, 396.1, 487.3, 799.5, 1327.9, 293.6, and 184.0 pg/mL. There were no significant differences in the aqueous MCP-1 level between the groups at any time point. CONCLUSION: The postoperative changes were similar in the Ex-PRESS and trabeculectomy groups, except for bleb wall density in the anterior-segment OCT image. The postoperative aqueous MCP-1 level had bimodal peaks in both groups. PMID- 26427060 TI - Design, Synthesis and Evaluation of 2,5-Diketopiperazines as Inhibitors of the MDM2-p53 Interaction. AB - The transcription factor p53 is the main tumour suppressor in cells and many cancer types have p53 mutations resulting in a loss of its function. In tumours that retain wild-type p53 function, p53 activity is down-regulated by MDM2 (human murine double minute 2) via a direct protein-protein interaction. We have designed and synthesised two series of 2,5-diketopiperazines as inhibitors of the MDM2-p53 interaction. The first set was designed to directly mimic the alpha helical region of the p53 peptide, containing key residues in the i, i+4 and i+7 positions of a natural alpha-helix. Conformational analysis indicated that 1,3,6 trisubstituted 2,5-diketopiperazines were able to place substituents in the same spatial orientation as an alpha-helix template. The key step of the synthesis involved the cyclisation of substituted dipeptides. The other set of tetrasubstituted 2,5-diketopiperazines were designed based on structure-based docking studies and the Ugi multicomponent reaction was used for the synthesis. This latter set comprised the most potent inhibitors which displayed micromolar IC50-values in a biochemical fluorescence polarisation assay. PMID- 26427061 TI - Histological and Transcriptomic Analysis of Adult Japanese Medaka Sampled Onboard the International Space Station. AB - To understand how humans adapt to the space environment, many experiments can be conducted on astronauts as they work aboard the Space Shuttle or the International Space Station (ISS). We also need animal experiments that can apply to human models and help prevent or solve the health issues we face in space travel. The Japanese medaka (Oryzias latipes) is a suitable model fish for studying space adaptation as evidenced by adults of the species having mated successfully in space during 15 days of flight during the second International Microgravity Laboratory mission in 1994. The eggs laid by the fish developed normally and hatched as juveniles in space. In 2012, another space experiment ("Medaka Osteoclast") was conducted. Six-week-old male and female Japanese medaka (Cab strain osteoblast transgenic fish) were maintained in the Aquatic Habitat system for two months in the ISS. Fish of the same strain and age were used as the ground controls. Six fish were fixed with paraformaldehyde or kept in RNA stabilization reagent (n = 4) and dissected for tissue sampling after being returned to the ground, so that several principal investigators working on the project could share samples. Histology indicated no significant changes except in the ovary. However, the RNA-seq analysis of 5345 genes from six tissues revealed highly tissue-specific space responsiveness after a two-month stay in the ISS. Similar responsiveness was observed among the brain and eye, ovary and testis, and the liver and intestine. Among these six tissues, the intestine showed the highest space response with 10 genes categorized as oxidation-reduction processes (gene ontogeny term GO:0055114), and the expression levels of choriogenin precursor genes were suppressed in the ovary. Eleven genes including klf9, klf13, odc1, hsp70 and hif3a were upregulated in more than four of the tissues examined, thus suggesting common immunoregulatory and stress responses during space adaptation. PMID- 26427062 TI - Fingerspelling as a Novel Gateway into Reading Fluency in Deaf Bilinguals. AB - Studies have shown that American Sign Language (ASL) fluency has a positive impact on deaf individuals' English reading, but the cognitive and cross linguistic mechanisms permitting the mapping of a visual-manual language onto a sound-based language have yet to be elucidated. Fingerspelling, which represents English orthography with 26 distinct hand configurations, is an integral part of ASL and has been suggested to provide deaf bilinguals with important cross linguistic links between sign language and orthography. Using a hierarchical multiple regression analysis, this study examined the relationship of age of ASL exposure, ASL fluency, and fingerspelling skill on reading fluency in deaf college-age bilinguals. After controlling for ASL fluency, fingerspelling skill significantly predicted reading fluency, revealing for the first-time that fingerspelling, above and beyond ASL skills, contributes to reading fluency in deaf bilinguals. We suggest that both fingerspelling--in the visual-manual modality--and reading--in the visual-orthographic modality--are mutually facilitating because they share common underlying cognitive capacities of word decoding accuracy and automaticity of word recognition. The findings provide support for the hypothesis that the development of English reading proficiency may be facilitated through strengthening of the relationship among fingerspelling, sign language, and orthographic decoding en route to reading mastery, and may also reveal optimal approaches for reading instruction for deaf and hard of hearing children. PMID- 26427063 TI - Intrinsic Multi-Scale Dynamic Behaviors of Complex Financial Systems. AB - The empirical mode decomposition is applied to analyze the intrinsic multi-scale dynamic behaviors of complex financial systems. In this approach, the time series of the price returns of each stock is decomposed into a small number of intrinsic mode functions, which represent the price motion from high frequency to low frequency. These intrinsic mode functions are then grouped into three modes, i.e., the fast mode, medium mode and slow mode. The probability distribution of returns and auto-correlation of volatilities for the fast and medium modes exhibit similar behaviors as those of the full time series, i.e., these characteristics are rather robust in multi time scale. However, the cross correlation between individual stocks and the return-volatility correlation are time scale dependent. The structure of business sectors is mainly governed by the fast mode when returns are sampled at a couple of days, while by the medium mode when returns are sampled at dozens of days. More importantly, the leverage and anti-leverage effects are dominated by the medium mode. PMID- 26427066 TI - [Evidence-based practice guidelines for standardized pathological diagnosis of primary liver cancer in China: 2015]. PMID- 26427064 TI - Comparisons of the Effects of Elevated Vapor Pressure Deficit on Gene Expression in Leaves among Two Fast-Wilting and a Slow-Wilting Soybean. AB - Limiting the transpiration rate (TR) of a plant under high vapor pressure deficit (VPD) has the potential to improve crop yield under drought conditions. The effects of elevated VPD on the expression of genes in the leaves of three soybean accessions, Plant Introduction (PI) 416937, PI 471938 and Hutcheson (PI 518664) were investigated because these accessions have contrasting responses to VPD changes. Hutcheson, a fast-wilting soybean, and PI 471938, a slow-wilting soybean, respond to increased VPD with a linear increase in TR. TR of the slow wilting PI 416937 is limited when VPD increases to greater than about 2 kPa. The objective of this study was to identify the response of the transcriptome of these accessions to elevated VPD under well-watered conditions and identify responses that are unique to the slow-wilting accessions. Gene expression analysis in leaves of genotypes PI 471938 and Hutcheson showed that 22 and 1 genes, respectively, were differentially expressed under high VPD. In contrast, there were 944 genes differentially expressed in PI 416937 with the same increase in VPD. The increased alteration of the transcriptome of PI 416937 in response to elevated VPD clearly distinguished it from the other slow-wilting PI 471938 and the fast-wilting Hutcheson. The inventory and analysis of differentially expressed genes in PI 416937 in response to VPD is a foundation for further investigation to extend the current understanding of plant hydraulic conductivity in drought environments. PMID- 26427065 TI - Evaluation of LiF:Mg,Ti (TLD-100) for Intraoperative Electron Radiation Therapy Quality Assurance. AB - BACKGROUND: Purpose of the present work was to investigate thermoluminescent dosimeters (TLDs) response to intraoperative electron radiation therapy (IOERT) beams. In an IOERT treatment, a large single radiation dose is delivered with a high dose-per-pulse electron beam (2-12 cGy/pulse) during surgery. To verify and to record the delivered dose, in vivo dosimetry is a mandatory procedure for quality assurance. The TLDs feature many advantages such as a small detector size and close tissue equivalence that make them attractive for IOERT as in vivo dosimeters. METHODS: LiF:Mg,Ti dosimeters (TLD-100) were irradiated with different IOERT electron beam energies (5, 7 and 9 MeV) and with a 6 MV conventional photon beam. For each energy, the TLDs were irradiated in the dose range of 0-10 Gy in step of 2 Gy. Regression analysis was performed to establish the response variation of thermoluminescent signals with dose and energy. RESULTS: The TLD-100 dose-response curves were obtained. In the dose range of 0 10 Gy, the calibration curve was confirmed to be linear for the conventional photon beam. In the same dose region, the quadratic model performs better than the linear model when high dose-per-pulse electron beams were used (F test; p<0.05). CONCLUSIONS: This study demonstrates that the TLD dose response, for doses <=10 Gy, has a parabolic behavior in high dose-per-pulse electron beams. TLD-100 can be useful detectors for IOERT patient dosimetry if a proper calibration is provided. PMID- 26427067 TI - [Percutaneous transhepatic variceal embolization followed with partial splenic embolization for the acute variceal massive hemorrhage in cirrhosis]. PMID- 26427068 TI - [Clinical study on the risk factors of severe hepatitis with nosocomial fungal infection]. PMID- 26427069 TI - [Evaluation of the safety of granulocyte colony-stimulating factor subcutaneous injection as treatment for HBV-related acute on chronic liver failure]. PMID- 26427070 TI - [Prevalence of nutritional risk factors and malnutrition among inpatients with fever diseases in Tianjin]. PMID- 26427071 TI - [Performance evaluation of the IS1200 domestic chemiluminescence analyzer for detecting hepatitis B virus serum markers]. PMID- 26427072 TI - [A case report of overlapping Rosai-Dorfman disease of the liver and gallbladder combined with hepatocellular adenoma]. PMID- 26427074 TI - [Obstructive sleep apnea hypopnea syndrome and nonalcoholic fatty liver disease]. PMID- 26427073 TI - [Observational research is an important accompaniment to randomized and controlled clinical studies]. PMID- 26427075 TI - [Hepokines in metabolic diseases]. PMID- 26427076 TI - [Progress in the clinical and basic research of liver fibrosis]. PMID- 26427077 TI - [Diagnose the regression of liver fibrosis and cirrhosis]. PMID- 26427078 TI - [Researches on the prevention and treatment of bleeding gastroesophageal varices secondary to portal hypertension in patients with cirrhosis]. PMID- 26427080 TI - [Efficacy and safety of Fuzhenghuayu capsule for treating liver fibrosis in patients with chronic hepatitis B: a meta-analysis]. PMID- 26427079 TI - [Diffraction-enhanced imaging and in-line phase contrast imaging with synchrotron radiation for human intra-hepatic bile duct dilation ex vivo]. PMID- 26427081 TI - [Potential values for diagnosis and assessment of nonalcoholic fatty liver disease staging using Gd+-EOB-DTPA-enhanced MRI]. PMID- 26427082 TI - [Expression and prognostic significance of cyclin kinase subunit 1 in human hepatocellular carcinoma]. PMID- 26427083 TI - [Clinical analysis of Fanconi syndrome induced by adefovir dipivoxil]. PMID- 26427084 TI - [Report of the Sixth Symposium on the Hotspots and Challenges in Research of Antiviral Therapy for Chronic Hepatitis B and Chronic Hepatitis C]. PMID- 26427085 TI - [Rules of lipotoxicity and lipoapoptosis in the pathogenesis of alcoholic fatty liver disease]. PMID- 26427086 TI - [Polymorphisms in the PNPLA3 gene are associated with hepatocellular carcinoma]. PMID- 26427087 TI - [Acquired hepatocerebral degeneration: a rare liver-related neurological disorder]. PMID- 26427088 TI - [Advances in diagnosis and management of adult-onset type II citrullinemia (CTLN2)]. PMID- 26427089 TI - Gertrude H. Lamb, 1918-2015, AHIP, FMLA. PMID- 26427090 TI - Observing the human condition. PMID- 26427091 TI - Better concordance for interphalangeal depth ratio than Schamroth's sign or hyponychial angle for diagnosis of digital clubbing. PMID- 26427092 TI - Patients' perspectives on the delivery of hepatitis B management and care. PMID- 26427093 TI - Developing a care model for hospice and palliative nurses. Reply. PMID- 26427094 TI - [History of Japanese Kampo Medicines Manufacturers]. PMID- 26427095 TI - [History of Inorganic-pharmaceutics in Japan]. PMID- 26427096 TI - [Transition of Psychotropic Drugs in Japanese Pharmacopoeia (JP) (Part 15). Transitions in the Standards and Test Methods of Potassium Bromide in JP I (1886) and JP X VI (2011), and Comparison between the USP and BP]. AB - In mental clinics, bromide agents such as potassium bromide were often once used as therapeutic drugs to treat psychiatric disorders. They were also given as hypnotic, sedative and antiepileptic medicines. However, the appearance of new medicines has resulted in them not being used for these purposes in recent years. Potassium bromide is still continuously listed in today's JP and BP. This suggests that it maintains value as a basic medicine for treating mental disorders in the history of psychotropic medicines. However, regarding the standards and test methods for potassium bromide in the present JP, as a result of a comparison between the USP of the same age, BP and EP, a gap is seen, and this is very regrettable. The exchange of art and scientific information related to medical sciences with foreign countries is becoming more active today. Therefore, scholarly information overseas should be collected and reflected in the standards and test methods for potassium bromide adopted in the JP of Japan. The author believes that the standards and test methods comparable to those at the international level should introduced. On the other hand, potassium bromide was recetnly relisted by USP29 (2006) for the first time in approximately 50 years. Moreover, instrumental analysis was introduced as part of the test methods in BP2013; that is, an epoch-making revision was made in terms of test methods. It is assumed from this that there is a sign of new change regarding the existence of potassium bromide as hypnotic, sedative and antiepileptic medicines, and its utility value. It is believed that the sign of change in view of the utility value and pharmacological evaluation probably arose with the new clinical knowledge that potassium bromide was used to treat a baby seriously ill with myoclony epilepsy, as well as to treat a dog with epilepsy. PMID- 26427097 TI - [Element Analysis of a Chinese Yagen Bearing the Inscription of "Product of the Ming-Zhengde Period" [Property of the Naito Memorial Museum of Pharmaceutical Science and Industry, Gifu] using an X-ray Fluorescence Spectrometer]. AB - Yagen (see text) is an oriental grinder for crude plant medicines. It consists of a disk and navicular mortar. A Chinese yagen with the inscription, "Product of the Ming-Zhengde Period (See text), (1506-1521 A.D.)" has been housed for 40 years in the Naito Memorial Museum of Pharmaceutical Science and Industry (Kakamigahara, Gifu Prefecture, Japan). To identify the district that produced this yagen, the authors analyzed the elements using an X-ray fluorescence spectrometer. The results showed that the blue design and blue Chinese characters on the yagen were enameled with elements of cobalt, manganese, and iron. Therefore, it is believed that the yagen was made in an old porcelain kiln near Zhangzhou in Fujian Province, China. However, as the period of production could not determined in the present study, further research is needed in the future. PMID- 26427098 TI - [Herbological Study on the Medicinal Effects of Roasted Licorice and Honey roasted Licorice]. AB - In China, the crude drug licorice ("kanzo" in Japanese, "gancao" in Chinese) has been used both dried and roasted as the situation demands from ancient times. The meaning of "roasted licorice" is simply roasted and honey-roasted in ancient and modern times, respectively. However, it is not clear medicinal purposes of processed licorice or why licorice processed with honey began to be used. We researched ancient literature and found that the main objective of roasting was to change the property of licorice from cool to warm (i.e., dried licorice had the effect of draining fire), while roasted licorice was used as an energy supplement, having a digestive effect and thus warming the body. Meanwhile, doctors began using honey-roasted licorice to treat throat pain from the Song dynasty, and then at the end of the Qing dynasty, honey-roasted licorice was expected to have the same effects of roasted licorice (i.e., supplementing energy and having a digestive effect). PMID- 26427099 TI - [Tri-phala (Three Myrobalans) as Described in the Second Part of the Bower Manuscript, the Navanitaka]. AB - In India, since ancient times Tri-phala (meaning "three fruits" in Sanskrit) has been considered to be a combination of the following fruits: -Haritaki (Terminalia chebula, Retz.), Amalaka (Embelica officinalis Gaertn), and Vibhitaka (Terminalia belerica Roxb.). These plants are also listed in the Ayurvedic Pharmacopoeia of India. Haritaki and Amalaka have also been used for medicinal purposes since ancient times in Japan under the Japanese names of (see text) (Kariroku) and (see text) (Annmaroku), respectively. Both have been carefully preserved as treasured drugs in the nationally important Shosoin treasure storehouse. This study attempts to clarify the description of Tri-phala in the Navanitaka, which is the second part of the Bower Manuscript (Bower Ms.), and examines the reasons why these plants were combined. This paper begins with a summary description of Tri-phala in the context of traditional Asian medicine, followed by the delineation of drug selection principles in Ayurveda. Tri-phala formulas in the Navanitaka are then examined. The Carakasamhita (CS) treats Tri phala as a purifier and tonic (rasayana), describing it as a formula for rejuvenation and longevity. On the other hand, the Susrutasamhitd (SS) regards Tri-phala as having the efficacy of balancing kapha (phlegm) and pitta (bile), and also as being a medicine to promote excretion and enhance digestive functions for better nutritional intake. It is described to have an effect of curing diseases by keeping the tridhau (theree element) valance. Tri-phala is thus used as an ingredient of laxatives for diseases that result from kapha imbalance and tonic. The Astangahrdayasamhita (AHS) considers Tri-phala to have a particular superiority among cure-all medicines with the power to dispel illness. It controls kapha and overcomes blood diseases. Tri-phala formulas found in the Navanitaka were prescribed for the treatment of abdominal tumors induced by vayu (wind) disorder as well as for coughs caused by pitta and kapha disorder. Tri phala was also administered to facilitate nutrient absorption, regulate bowel function, and promote excretion. Tri-phala thus restores the balance of tridhau by facilitating water distribution in the body. For these reasons, the optimal combination of Tri-phala was then established to adjust kapha for most efficient purification effects. PMID- 26427100 TI - [Twenty-year History and Future Challenges in Transparency Enhancement of Review Process for Approval: Focus on Public Release of Review Reports regarding New Drugs and Medical Devices]. AB - For 20 years, the Ministry of Health, Labour and Welfare (MHLW, formerly Ministry of Health and Welfare (MHW)) has been trying to increase transparency of the review process for approving reports in order to promote the rational use of newly approved drugs and medical devices. The first Summary Basis of Approval (SBA) was published by MHW in 1994. In 1999, evaluation reports were prepared by MHW and the Pharmaceuticals and Medical Devices Evaluation Center to make them available to the public. In 2005, a notice from the Chief Executive of the Pharmaceuticals and Medical Devices Agency (PMDA) made procedures for public release of information on reviewing applications for new drugs. In 2006, 90 review reports of newly approved drugs and eight medical devices were revealed on PMDA websites. The dissemination of information by the United States Food and Drug Administration (FDA) and that of the European Medicines Agency (EMA) were studied and compared with that of the MHLW and PMDA. While common technical documents (CTD) for new drugs and summary technical documents (STED) for new medical devices have been released by PMDA, such documents are not released by the FDA and EMA. The European Public Assessment Report (EAPR) summary for the public is an interesting questionnaire approach that uses the "What," "How" and "Why" format. Finally, future proposals for the next decade are also outlined. PMID- 26427101 TI - [The Original Formulation for Toso-shu (Tusujiu), Created by the 3rd Century Chinese Physician, Hua Tuo]. AB - The original formulation for "Tusujiu," which Japanese people still consume on the morning of January 1st, was created by Hua Tuo, but has not been studied in detail. The book Huatuo Shenyi Bizhuan, found in 1918, describes a concoction, "Biyijiu," that shows great similarity to the current Tusujiu; the ingredients for Biyijiu being rhubarb, atractylodes rhizome, cinnamon bark, platycodon root, zanthoxylum fruit, processed aconite root and smilax rhizome. The procedures for preparing and drinking it are to "pound the ingredients and then put them into a silk bag dyed with madder. During the daytime of the last day of the year, hang the bag in a well to soften the powder. Take the bag out early in the morning of the next day, the first day of the year. Heat the bag in fermented liquor until simmering. Drink the liquid with all family members, doing so while facing east. If one person drinks it, there will be no disease in the family. If the whole family drinks it, there will be no disease in their neighborhood in an area of one square 'li'. In this study, to determine the original formulation for Tusujiu, we examined a number of ancient medical texts from the 3rd to the 13th century that discuss Biyijiu and Tusujiu. As a result, we concluded that "Biyijiu" is likely to be the original formulation developed by Hua Tuo. PMID- 26427102 TI - [Pharmaceutical Regulations in the Japanese Hospitals in 1880s and the Case of a Scholar of Pharmacology in Oita Prefecture]. AB - In the 1870s, various provisions existed regarding pharmacists working at Japanese military hospitals. And in the decade of the 1880s, some hospitals in Tokyo and Oita implemented them. These provisions gave pharmacists the right to challenge doctors' prescriptions and provide patients with medicine-related information. In Oita Prefecture, patients could have their prescriptions filled outside of the hospital. This paper examines the case of one scholar of pharmacology who worked in Oita Medical School Hospital. PMID- 26427103 TI - [Visualization for Traditional Quality Management Techniques--Characterization Method for Spikenard of INUBUSHI SEIYAKU Established in the Edo Period]. AB - INUBUSHI SEIYAKU, a Japanese pharmaceutical company established in 1807, manufactures KEISHIN-TAN. This is an original drug developed by the company, and consists of 14 exotic natural medicines, spikenard, oriental bezoar, musk, agarwood, etc. It has been used for adjusting the autonomic nervous system and physical conditions. We studied the original methods of the traditional quality management techniques handed down within INUBUSHI SEIYAKU in selecting the appropriate spikenard (Nardostachys chinensis) for medicinal use. Currently, spikenards are mainly used as incense rather than medicine. KEISHIN-TAN is a rare case in that the bulk powder of the spikenards is used for pharmaceutical products in Japan. We examined the morphological characteristics and made an analysis of the component of spikenards selected by traditional methods. The raw material of the spikenards was purchased from the Japanese market, and was classified into two categories-superior, fit for medicinal use and defective, to be discarded-by traditional methods of INUBUSHI SEIYAKU. The methods of the characterization of the spikenard by INUBUSHI SEIYAKU were investigated. As a result, only thick spikenard roots over 2.0 cm in length and approximately 0.5 cm in diameter were found to be used, and the total weight of the superior was only 15% of the raw material. By comparing the weights of hexane extracts and GC-MS analyses, the content of calarene--main sedative compound in spikenards--in the superior material was 2.8 times higher than the raw material and 4.3 times higher than the defective material. The ways to devise how to enhance the pharmacological effects of spikenards may be contained in this method. These results revealed the traditional spikenard selection criteria, and may show the indications of using spikenard or its compounds for medicinal purposes. PMID- 26427104 TI - Effect of Aidi injection plus chemotherapy on gastric carcinoma: a Meta-analysis of randomized controlled trials. AB - OBJECTIVE: To conduct a Meta-analysis of studies on the effect of Aidi injection combined with chemotherapy versus chemotherapy alone in the treatment of gastric cancer (GC). METHODS: Nine electronic databases and six gray literature databases were comprehensively searched until April 20, 2013. Two reviewers independently selected and assessed included trials according to the inclusion and exclusion criteria. The risk of bias tool from the Cochrane Handbook version 5.1.0 was used to assess trial quality. All calculations were performed using Review Manager 5.0. RESULTS: Thirty-two studies including 1927 participants met the inclusion criteria, most of which were low quality. Compared with chemotherapy alone, Aidi injection plus the same chemotherapy significantly improved the effective rate [OR = 1.52, 95% CI (1.24, 1.86), P < 0.0001], clinical beneficial rate [OR = 1.77, 95% CI (1.33, 2.36), P < 0.0001], and quality of life [OR = 3.02, 95% CI (2.39, 3.82), P < 0.000 01]. There was a significant improvement in nausea and vomiting incidence [OR = 0.34, 95% CI (0.24, 0.47), P < 0.000 01], diarrhea [OR = 0.47, 95% CI (0.33, 0.69), P < 0.000 01], leukopenia (III-IV) [OR = 0.34, 95% CI (0.23, 0.51), P = 0.05], hemoglobin decrease (III-IV) [OR = 0.42, 95% CI (0.18 1.00), P = 0.05], thrombocytopenia (III-IV) [OR = 0.46, 95% CI (0.22, 0.96), P = 0.04], and damage to liver function [OR = 0.36, 95% CI (0.24, 0.54), P < 0.00001]. CONCLUSION: Aidi injection combined with chemotherapy significantly improved the clinical effect of chemotherapy, reducing the incidence of adverse events. Use of the CONSORT statement for randomized controlled trials is recommended for stricter reporting. PMID- 26427105 TI - Effect of Sancaijiangtang on plasma nitric oxide and endothelin-1 levels in patients with type 2 diabetes mellitus and vascular dementia: a single-blind randomized controlled trial. AB - OBJECTIVE: To observe the effect of Sancaijiangtang powders on plasma nitric oxide and endothelin-1 levels. We sought to identify the common pathological link and mechanism of action for Traditional Chinese medicine in type 2 diabetes mellitus and vascular dementia, and to explicate the material basis for treating the different diseases with the same method in Traditional Chinese Medicine. METHODS: In total, 168 patients with type 2 diabetes mellitus and vascular dementia were enrolled in the study, and randomly divided into two groups by simple randomization. Patients in the treatment group received oral Sancaijiangtang powders with pioglitazone hydrochloride three times daily, while patients in the control group received pioglitazone hydrochloride alone. The treatment course was for 12 weeks. Mini-mental state examinations (Chinese version) and Montreal Cognitive Assessments (Beijing version) were performed, and fasting plasma glucose, fasting insulin, hemoglobin A1c, homeostasis model assessment of insulin resistance, plasma nitric oxide and endothelin-1 levels were measured before and after the treatment. RESULTS: The post-treatment levels for all measurements in both groups were better than pre-treat- ment levels (P < 0.05). The post-treatment levels for all measurements in the treatment group were better than the levels measured in the control group (P < 0.05). CONCLUSION: Type 2 diabetes mellitus and vascular dementia have common pathological mechanisms for insulin resistance and endothelium dysfunction. Sancaijiangtang powders could improve the release of nitric oxide and inhibit the secretion of endothelin-1. Therefore, the material basis exists for treating the different diseases with the same method in Traditional Chinese Medicine. PMID- 26427106 TI - Efficacy of Zhenjingdingzhi decoction in treating insomnia with Qi-deficiency of heart and gallbladder: a randomized, double-blind, controlled trial. AB - OBJECTIVE: To evaluate the clinical efficacy of Zhenjingdingzhi decoction in treating insomnia with Qi-deficiency of heart and gallbladder. METHODS: We conducted a double-blind, randomized, controlled trial involving 100 patients with insomnia of Qi-deficiency of heart and gallbladder. Patients were randomly divided into the treatment group (n = 50) and the control group (n = 50) according to a random number table. The treatment group was given Zhenjingdingzhi decoction, while the control group was treated with Suanzaoren decoction. The pharmacological treatment lasted for 8 weeks. The clinical efficacy was assessed by using Spiegel scale, Pittsburgh sleep quality index (PSQ) and Traditional Chinese Medicine (TCM) syndrome scores. RESULTS: Comparing Spiegel scores between the two groups at 4 and 8 weeks, the differences in curative effect between the two groups were both significant (both P < 0.05). The total effective rate was 46% in the treatment group and 27.7% in the control group at 4 weeks, and 80% and 53.2% at 8 weeks, respectively; After 8 weeks, PSQI scores showed that the total effective rates differed significantly between the two groups (P < 0.01): 84% in the treatment group and 59.6% in the control group; In improving sleep quality and sleep duration, the curative effect of the treatment group was better than that of the control group (P < 0.05). TCM syndrome, especially insomnia and palpitation, was improved better in the treatment group after 8 weeks as compared to that in the control group (P < 0.05). The total effective rate of the two groups was 84% and 66%, respectively. CONCLUSION: Zhenjingdingzhi decoction is effective and safe for the treatment of insomnia with Qi-deficiency of heart and gallbladder, especially for improving sleep quality and sleep duration. PMID- 26427107 TI - Effect of Shoushen granule on arterial elasticity in patients with carotid atherosclerosis: a clinical randomized controlled trial. AB - OBJECTIVE: To investigate the effectiveness of Shoushen granule, Chinese herbal preparation, on carotid artery elasticity in patients with carotid atherosclerosis. METHODS: The total of 156 carotid atherosclerosis patients were randomly divided into the intervention group (83 cases, treated with Shoushen granule) and the control group (73 cases, treated with pravastatin). Brachial ankle pulse wave velocity baPWV) and Ankle-Brachial Pressure Index (ABI) were measured by automated arteriosclerosis detector. The changes of common carotid artery intima-media thickness (IMT) and parameters of the carotid artery elasticity in patients, including stiffness parameter (beta), pressure-strain elastic modulus (Ep), arterial compliance (Ac), augmentation index (AI), and pulse wave velocity (PWV) were detected by Echo-Tracking (ET) technique before and after 24 week treatment. In the meantime, levels of blood lipid, and liver and renal function were measured respectively. RESULTS: After 24 weeks, baPWV, MT and parameters of the carotid artery elasticity (beta, Ep, AI and PWVbeta) were markedly decreased in intervention group compared with those of before treatment (P < 0.01), but the level of Ac was increased significantly (P < 0.01). And there were no significant differences compared with control group on the same period (P > 0.05). CONCLUSION: In this pilot study, it was demonstrated ET technology and automated arteriosclerosis detector could be used to evaluate carotid artery elasticity effectively, and the action of Shoushen granule on carotid atherosclerosis might be related to the regulation of carotid artery elasticity. PMID- 26427108 TI - Impact of classic massage on blood pressure in patients with clinically diagnosed hypertension. AB - OBJECTIVE: To assess the impact of classic massage on the changes in the values of blood pressure in women with previously diagnosed hypertension. METHODS: The study involved a group often women aged 60-68, who had previously been diagnosed with hypertension. Ten sessions of classic massage of the lower limbs were performed on the subjects. The massage sessions were conducted every day over ten consecutive days. Throughout the treatment, the subjects' blood pressure was measured using a manometer with a stethoscope TRO-CARDIO KIT 2 MONO. Their blood pressure was taken 1 min before the massage, as well as 1 min and 5 min after each session. The study took place between March and June 2013 in Szpital Specjalistyczny im. Jedrzeja Sniadeckiego (Jedrzej Sniadecki Specialist Hospital) in Nowy Sacz, at the Department of Internal Diseases. RESULTS: For ten consecutive days, the blood pressure values in the examined women were decreasing, with the exception of the diastolic blood pressure measured 5 min after the massage. CONCLUSION: The drops in blood pressure by several percent, noted in the majority of the female subjects over the time of the study. Classic massage might provide a safe supportive measure in pharmacologic treatment of hypertension. PMID- 26427109 TI - Comparative effect of electroacupuncture and moxibustion on the expression of substance P and vasoactive intestinal peptide in patients with irritable bowel syndrome. AB - OBJECTIVE: To compare the impacts of electroacu puncture (EA) and moxibustion (Mox) on the prima ry gastrointestinal symptoms and the expressions of colonic mucosa-associated neuropeptide substance P (SP) and vasoactive intestinal peptide (VIP) in patients with either diarrhea-predominant or constipation-predominant irritable bowel syndrome (IBS-D and IBS-C, respectively). METHODS: Eighty-five IBS patients were randomly allocated to the EA and Mox groups. Zusanli (ST 36) and Shangjuxu (ST 37) were selected as acupoints for electroacupuncture or warm moxibustion treatment once a day for 14 consecutive days. Before and after the treatment sessions, a Visual Analog Pain Scale and the Bristol Stool Form Scale were used to evaluate gastrointestinal symptoms. There were four dropout cases, leaving 81 participants (41 with IBS-D and 40 with IBS-C) who volunteered to undergo colonoscopy before and after the treatment sessions. During colonoscopy, sigmoid mucosa were collected to detect SP and VIP expression using immunohistochemistry assay. RESULTS: Both EA and Mox treatments were effective at relieving abdominal pain in IBS-D and IBS-C patients. However, Mox was more effective at reducing diarrhea in IBS-D patients, whereas EA was more effective at improving constipation in IBS-C patients. EA and Mox treatments both down regulated the abnormally increased SP and VIP expression in the colonic mucosa, with no significant difference shown between the two treatments. CONCLUSION: Both EA and Mox treatments are effective at ameliorating gastrointestinal symptoms by reducing SP and VIP expression in the colonic mucosa of IBS patients. PMID- 26427110 TI - Gait analysis of patients with knee osteoarthritis before and after Chinese massage treatment. AB - The objective of this study was to evaluate the effectiveness of Chinese massage therapy in patients with knee osteoarthritis (OA) by measuring lower-limb gait parameters. We recruited 20 women with knee OA, who then underwent Chinese massage therapy three times per week for 2 weeks. The patients underwent gait evaluation using a six-camera infrared motion analysis system. They completed Western Ontario and McMaster Universities Osteoarthritis Index questionnaires before and after treatment. We calculated the forward speed, step width, step length, total support time percentage, initial double support time percentage, and single support time percentage. We also measured the angles at the knee, hip, and ankle during the stance phase of walking. The results showed statistically significant mean differences in knee pain relief, alleviation of stiffness, and physical function enhancement after therapy (P < 0.05). The patients gained significantly faster gait speed, greater step width, and increased total support time percentage after the Chinese massage therapy (P < 0.05). There were no significant differences in the range of motion or initial contact angles of the knee, hip, or ankle during the stance phase of walking. We concluded that Chinese massage is a beneficial complementary treatment and an alternative therapy choice for patients with knee OA for short-term pain relief. Chinese massage may improve walking ability for these patients. PMID- 26427111 TI - Effect of Huqian Wan on liver-Yin and kidney-Yin deficiency patterns in patients with knee osteoarthritis. AB - OBJECTIVE: To observe the curative effect of Huqian Wan on liver and kidney-Yin deficiency knee osteoarthritis (KOA). METHODS: One hundred patients were randomly divided, into a treatment (50 patients) and control group (50 patients). In the treatment group, patients orally took the Chinese medicine Huqian Wan. Control group patients orally took Votalin, 75 mg, once a day, for 8 weeks. The visual analog scale (VAS), Western Ontario and McMaster University Osteoarthritis Index (WOMAC), and Medical Outcomes Study Short Form 36-Item Health Survey (SF 36) were used to evaluate the curative effect before treatment and after 8 and 16 weeks of treatment. RESULTS: VAS and WOMAC scores significantly decreased and SF 36 scores significantly increased after treatment in both groups compared with before treatment (P < 0.05). There were significant differences in VAS, WOMAC, and SF 36 score changes between the two groups at week 16 (P < 0.05). There was a significant increase in VAS and WOMAC scores in the control groups (P < 0.05) between weeks 8 and 16, but no significant difference was found in the treatment group (P > 0.05). CONCLUSION: Huqian Wan could effectively improve the clinical symptoms and quality of life in patients with KOA. It could also have a better and longer lasting curative effect without obvious adverse events compared with Votalin. PMID- 26427112 TI - Effect of Dongchongxiacao (Cordyceps) therapy on contrast-induced nephropathy in patients with type 2 diabetes and renal insufficiency undergoing coronary angiography. AB - OBJECTIVE: To study the protective effects of Dongchongxiacao (Cordyceps) (DCXC) on contrast-induced nephropathy (CIN) in patients with type 2 diabetes and renal insufficiency undergoing coronary angiography. METHODS: A total of 120 patients with type 2 diabetes whose estimated glomerular filtration rater (eGFR) was 60 mL/min . 1.73 in2, were divided randomly into three groups, basic treatment group (n = 41), standard DCXC therapy group (n = 39, 2-g corbrin capsules, 3 times/d, 3 days before and after angiography), and intensive DCXC therapy group (n = 40, 3-g corbrin capsules, 3 times/d, 3 days before and after angiography). Serum creatinine (cr) and eGFR were assessed at the time of admission to hospital, and on days 1, 2 and 3 after angiography. Urine neutrophil-gelatinase-associated-lipo calin (NGAL), kidney injury molecule-1 (KIM-1) and interleukin-18 (IL-18) were measured before angiography and at day 1 after angiography for all patients. The primary end point was the prevalence of CIN. The secondary end point was a 25% or greater reduction in eGFR. RESULTS: CIN occurred in 11 of 120 patients (9.17 %). The prevalence of CIN was lower in the DCXC treatment groups than in the basic treatment group (P < 0.05), with a more significant decrease in the prevalence of CIN in the intensive DCXC therapy group (P < 0.01). Compared with the basic treatment group, a lower proportion of patients in the DCXC treatment groups had an eGFR decrease of 25% or greater (P < 0.05); patients with an eGFR decrease of 25% or greater accounted for an even lower proportion in the intensive DCXC therapy group (P < 0.01). Within 1 day of the procedure, urine levels of KIM-1, NGAL and IL-18 in patients in the intensive DCXC therapy group were lower than those in the basic treatment group and standard therapy group (P < 0.05). CONCLUSION: DCXC treatment may protect against CIN in patients with type 2 diabetes and renal insufficiency undergoing coronary angiography, with intensive DCXC therapy being more effective. PMID- 26427113 TI - Effect of traditional Chinese comprehensive therapy on gestation in patients with previously failed in vitro fertilization and embryo transfer. AB - OBJECTIVE: To explore the effect of traditional Chinese comprehensive therapy (TCCT) on promoting gestation in patients with previously failed in vitro fertilization and embryo transfer (IVF-ET) because of kidney deficiency, liver stagnation, and blood stasis (KLB). METHODS: Sixty-seven patients were enrolled in this study and divided into two groups: a trial group with 35 patients and a control group with 32 patients. The trial group was given TCCT for 3 months, then administered IVF-ET or awaited natural pregnancy. The control group was administered IVF--ET without TCCT 3 months after the previous IVF-ET or natural pregnancy attempt. The patterns of KLB were observed both before and after treatment. The natural pregnancy rate of the two groups was calculated after treatment. Differences between the two groups were compared after using IVF-ET treatment again in fertilized egg number and fertilization rate were evaluated. RESULTS: After treatment with TCM comprehensive therapy, seven patients in the treatment group became pregnant, while there were no successful conceptions in the control group. The difference in clinical pregnancy rate in the initial cycle and transfer cycle of IVF were significantly different (P < 0.05). The trial group had a significantly higher conception rate than that of the control group (P < 0.05). CONCLUSION: TCCT can promote the natural pre nancy rate in patients with previously failed IVF-ET. TCCT could increase patients' fertilized egg number, fertilization rate, pregnancy rate, and clinical pregnancy rate after another IVF-ET treatment. PMID- 26427114 TI - Effect of Chaiqinchengqi decoction on inositol requiring enzyme 1alpha in alveolar macrophages of dogs with acute necrotising pancreatitis induced by sodium taurocholate. AB - OBJECTIVE: To investigate the effect of Chaiqinchengqi decoction (CQCQD) on inositol requiring enzyme lalpha (IRElalpha) in alveolar macrophages (AMs) of the dog model of acute necrotising pancreatitis (ANP) induced by sodium taurocholate. METHODS: Fifteen beagle dogs were randomised into a control group, ANP group and CQCQD group (n = 5 per group). ANP was induced by a retrograde duct injection of 50 mg/kg of 5% sodium taurocholate. The dogs in the control group received injections of the same volume of saline as the sodium taurocholate. After the models were induced, the dogs in the CQCQD group were administered 10 mL/kg CQCQD every 2 h for 6 h. Two hours after the last administration of either CQCQD or saline, they were sacrificed by anaesthesia. AMs were collected to determine the IRElalpha and interleukin-1beta (IL-1beta) mRNA and protein expression, and pancreatic tissues were collected for histopathology analysis. RESULTS: Compared with the ANP group, the mRNA and protein expression of IREl a and the protein expression of IL-1beta of AMs in the CQCQD group were significantly down regulated, and the pancreatic histopathology score of the CQCQD group also was lower. There was no significant difference in the mRNA expression of IL-1beta of AMs between the two groups. CONCLUSION: The CQCQD-induced down-regulation of the IL-1beta protein expression may involve the down-regulation of the mRNA and protein expression of IRElalpha in AMs. PMID- 26427115 TI - Ginsenoside Rg3 inhibits colon cancer cell migration by suppressing nuclear factor kappa B activity. AB - OBJECTIVE: To study the mechanism of the inhibitory effect of ginsenoside Rg3 on colon cancer cell migration. METHODS: Transwell migration assays were performed to investigate the inhibitory effect of ginsenoside Rg3 on SW480 cell migration. Electrophoretic mobility shift assays (EMSAs) and dual luciferase reporter assays were used to study the suppression capability of Rg3 on nuclear factor kappa B (NF-kappaB) activity. Western blotting was adopted to determine protein levels. RESULTS: Two-hundred micromolar ginsenoside Rg3 significantly inhibited SW480 cell migration (P < 0.05). EMSA showed that Rg3 suppressed the DNA binding ability of NF-kappaB. Dual luciferase reporter assay showed that Rg3 decreased NF kappaB-regulated gene transcription (P < 0.01). Western blots indicated that Rg3 down-regulated expression of the NF-kappaB-regulated matrix metalloproteinase 9, cyclooxygenase-2 and C-Myc. An NF-kappaB inhibitor, pyrrolidine dithiocarbamate, enhanced the inhibitory effect of Rg3 on SW480 cell migration. CONCLUSION: Ginsenoside Rg3 has a strong antitumor migration capability by suppressing NF kappaB activity and expression of NF-kappaB-regulated gene products. It could be a good adjuvant for colon cancer patients during the course of chemotherapy. PMID- 26427116 TI - Effect of Chaihushugan San on expression of the Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase pathway in the hippocampi of perimenopausal rats induced by immobilization stress. AB - OBJECTIVE: We wished to study the impact of Chaihushugan San (CSS) on the behavior of perimenopausal rats with liver-Qi stagnation (LQS) and to investigate the effect of CSS on signal transduction of the Raf/mitogen-activated protein kinase (MEK)/ extracellular signal-regulated kinase (ERK) cascade in the hippocampi of rats induced by immobilization. METHODS: Twenty 52-week-old female rats were divided into two groups by the random number table method: model control group (MCG) and CSS group (CSSG), with 10 rats in each group. Ten-week old female rats were used as the normal control group (NCG). CSS effects were assessed using rats exposed to immobilization stress by measuring body weight and sucrose consumption, serum hormone levels, and observing performance in the open field test (OFT). Molecular mechanisms were examined by measuring the effect of CSS on expression of Raf1, MEK1/2 and ERK1/2 mRNA in hippocampi using quantitative real-time polymerase chain reaction and by measuring levels of these proteins and related phospho-proteins using Western blotting. RESULTS: Perimenopausal rats with LQS had decreased locomotor activity; reduced sucrose consumption; and increased serum levels of corticotropin releasing hormone (CRH) and corticosterone (CORT). Activation of hippocampal Raf/MEK/ERK cascade was suppressed significantly in the MCG, and activation was increased after 21 days of CSS treatment. CONCLUSION: CSS has significant effects upon relief of the symptoms of LQS in immobilization-induced rats. The mechanism underlying this action might (at least in part) be mediated by reversal of disruption of the Raf/MEK/ERK pathway. PMID- 26427117 TI - Effect of Liuweidihuang pill and Jinkuishenqi pill on inhibition of spontaneous breast carcinoma growth in mice. AB - OBJECTIVE: To investigate the preventing and treating action of Liuweidihuang pill (LP) and Jinkuishenqi pill (JP) on spontaneous breast carcinoma in mice. METHODS: A model of spontaneous breast carcinoma was derived from 11.5-month-old female Kunming breeding mice following the delivery of several litters. The mice were randomly divided into five groups: model control group (C), Liuweidihuang pill high-dose group (LH; 4.6 g . kg(-1) . d(-1)), Liuweidihuang pill low-dose group (LL; 2.3 g . kg(-1) . d(-1)), Jinkuishenqi pill high-dose group (JH; 4.6 g . kg(-1) . d(-1)) and Jinkuishenqi pill low-dose group (JL; 2.3 g . kg(-1) . d( 1)). Cancer tissue volume was measured by water immersion. Histopathology was analyzed by hematoxylin and eosin staining. Vascular endothelial growth factor (VEGF), extracellular signal-regulated kinase (ERK) and cyclin D1 protein expression in cancer tissue was assayed by western blotting. RESULTS: Compared with the control group, cancer tissue volume and weight were lower in the LP and JP groups, and survival time was longer. The expression of VEGF, ERK and Cyclin D1 were inhibited in the LP and JP groups (P < 0.05), and cell differentiation was increased. Tumor weights and volumes and VEGF, ERK and Cyclin D1 expression in LL or LH were significantly lower than in JL and JH (P < 0.01). CONCLUSION: Both LP and JP could restrain cancer growth and promote cancer cell differentiation; moreover, LP was more effective than JP The likely mechanism of action was via inhibition of VEGF, ERK and cyclin D1. PMID- 26427118 TI - Estrogenic effect of the extract of Renshen (Radix Ginseng) on reproductive tissues in immature mice. AB - OBJECTIVE: To evaluate the estrogenic efficacy of Renshen (Radix Ginseng) (GS) on reproductive target tissues in immature mice. METHODS: One hundred and ten female immature Kunming (KM) mice, 21-day-old, were randomly assigned to eleven groups, 10 for each; one served as control group treated with 0.154 mg/kg estradiol valerate (EV, n = 10), the rest were treated respectively with GS intragastrically at a daily dose of 0.5, 1.0, 1.5, 3.0, 6.0, 12.0, 18.0, 24.0 and 30.0 g/kg (n = 10 in per group) for 7 days. The estrous cycle, uterine weight, hormone levels in circulation and histomorphology changes of uterus and vagina were scrupulously examined. The estrogen receptor (ER) alpha and ERbeta expressions in the uterus and vagina were detected by immunohistochemistry and western blotting. RESULTS: Treatment with GS at the dose of 12.0, 18.0 and 24.0 g/kg resulted significant estrogenic activity in the mice, as indicated by advanced and prolonged estrous stage and increased uterine weight (all P < 0.05). GS treatment substantially promoted development of reproductive tisue by thickening the uterine endometrium and increasing vaginal epithelial layers. In addition, treatment with GS induced significant up-regulation of ERalpha and ERbeta expressions in reproductive tissues, and ERalpha up-regulation was stronger than that of ERbeta. GS could raise levels of circulating estrogen, simultaneously decrease levels of luteinizing hormone and follicle-stimulating hormone (all P < 0.001) compared with the control group. CONCLUSION: Our findings suggest that GS had estrogenic effect on reproductive tissues in immature mice by stimulating biosynthesis of estrogen in circulation and up-regulating ERs. PMID- 26427119 TI - Effect of Inonotus Obliquus Polysaccharides on physical fatigue in mice. AB - OBJECTIVE: To evaluate the potential beneficial effects of Inonotus obliquuspolysaccharides (IOP) on the alleviation of physical fatigue in mice. METHODS: Sixty-four male mice were randomly divided into four groups (n = 16 per group). Mice were orally administered IOP for a period of 14 days at 0, 100, 200 and 300 mg/kg/d, and were assigned to the control, IOP-100, IOP-200, and IOP-300 groups, respectively by the random number table method. Mice in the control group received an oral administration of sterile distilled water. A forced swimming test was performed for 8 mice per group at one hour after the last treatment. The other 8 mice in each group swam for 30 min. Blood, liver and muscle samples were taken after resting for 30 min. Levels of blood urea nitrogen and lactate, as well as glycogen contents of the liver and muscle were measured. Morphology of liver was observed by light microscopy. RESULTS: IOP extended the swimming time of mice, and increased the glycogen content of liver and muscle, but decreased blood lactic acid and serum urea nitrogen levels, IOP had no toxic effects on major organs such as the liver as assessed by histopathological examinations. CONCLUSION: IOP might be a potential anti-fatigue pharmacological agent. PMID- 26427120 TI - Survival rate: an indicator of the management of acquired immune deficiency syndrome using Traditional Chinese Medicine. AB - Complementary and alternative medicine, including Traditional Chinese Medicine (TCM), has been used as therapy against acquired immune deficiency syndrome (AIDS) for almost 30 years. Based on evaluation indicators for AIDS treatment using TCM, we discuss why the survival rate (which has been used widely in Western Medicine) should be adopted as a new important indicator of TCM treatment for AIDS. We advise that further prospective or retrospective cohort studies should be carried out to confirm this hypothesis. PMID- 26427121 TI - Epidemiological data on acupuncture and physical and rehabilitation medicine in the European Union. AB - OBJETIVE: To know the prevalence of acupuncturists within physical and rehabilitation medicine specialists in Europe and their characteristics, as well as to analyze the pathologies treated and therapeutic techniques used. METHODS: This is a cross-sectional descriptive study based on a structured and closed questionnaire. The study was carried out from October 2011 to May 2014. RESULTS: A total of 115 specialists from 19 countries completed the questionnaire. The mean characteristics of the physical and rehabilitation medicine (PRM) specialists who are also acupuncturists in Europe were: women (62.6 %); mean age of 47.91 years old; 4.20 years of physical and rehabilitation medicine school and 2.00 years of acupuncture training; 15.03 years of mean time of clinical practice as physical and rehabilitation medicine specialists and 10.42 years of experience as acupuncturists; 35.65 % had a doctorate (PhD) degree, obtained at a mean age of 33.55 years old; working in a public hospital (80%); treating mainly neurological conditions (48.1% ) and using mainly techniques such as kinesiotherapy (11.81%), orthosis (10.40%) and electrotherapy (9.92%). Acupuncture was applied by 32.2% of the participants mainly in musculoskeletal conditions (27.38%). A mean number of more than 20 patients a day were treated by 47.04% of the specialists, being 41.8% of the patients (adults and children). Significant differences were found between the variables, acupuncture and gender (Pearson's correlation Index = 0.007). However, no differences were observed in relation to acupuncture and age, doctorate degree, years of clinical practice and workplace (all with P values > 0.05). CONCLUSION: In the European area, physical and rehabilitation medicine specialists who are also acupuncturists are mainly female, middle-aged, with 15 years of professional experience, PhD holders, working in public hospitals, treating mainly neurological conditions with kinesiotherapy and acupuncture, and treating over 20 patients a day (adults and children) during a 7 h shift. Further epidemiological studies on PRM to provide more information regarding the real situation of this medical specialty and the possibility to open to Chinese traditional medicine techniques such as acupuncture are necessary. PMID- 26427122 TI - [A change in strides may change your life? A new exercise prescription to prevent life-style-related diseases and avoidance of dependence on nursing care]. PMID- 26427123 TI - [From the background to the forefront: The sensor channel related to life and death of cells and constancy of the living systems (3)]. PMID- 26427124 TI - HOW I FELL IN LOVE WITH JAPAN. PMID- 26427125 TI - [Videofluoroscopic Examination of Swallowing Using the AsR Score for Postoperative Swallowing Function in Oral Cancer Patients]. AB - To evaluate the postoperative swallowing function in head and neck cancer patients, videofluoroscopic examination of swallowing (VF) proved useful as a qualitative evaluation, but was complex as a quantitative evaluation. We made use of the AsR score which consisted of a 10-point scale as a quantitative evaluation of VF. To identify the usefulness of the AsR score, 146 patients who had undergone extensive resection and reconstruction with free flaps or pedicle grafts were reviewed. The AsR score of VF for the first time after surgery was defined as "first score", and at the last time in the hospital was defined as "last score". The correlations between the first score and continuity of direct therapy, and between the last score and way of nutrition at the time of discharge were examined. Using the ROC (receiver operator characteristic) analysis and the AUC (area under the curve) the cut-off values of the AsR score were estimated. One hundred and thirty one patients could continue direct therapy after the first time of VF. The first score detected continuity of direct therapy with high accuracy (AUC = 0.946), furthermore using a cut-off of 5, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were about 96.2%, 86.6%, 98.4%, and 72.2%, respectively. At the time of discharge, 138 patients had no limitation of oral intake and 8 patients had a limitation e.g. PEG (n = 7) and a total laryngectomy for preventing aspiration (n = 1). The last score detected oral intake ability with no limitation with high accuracy (AUC = 0.925). Using a cut-off of 6, the sensitivity, specificity, PPV and NPV were about 82.6%, 87.5%, 99.1% and 22.6%, respectively. The AsR score is useful as a quantitative evaluation of postoperative swallowing function in oral cancer patients. PMID- 26427126 TI - [A Retrospective Series of 77 Pediatric Patients with Vertigo at a National Center for Child Health and Development]. AB - The evaluation and management of vertigo in children varies among institutional and medical specialties. The aim of this study was to describe the characteristics of vertigo in children presenting at a national pediatric center. Patients < 16 years old presenting with vertigo to the department of otolaryngology at a national center for child health and development from April 2004 to October 2009 were included (N = 77; 42 males and 35 females; average age, 8.7 +/- 3.4 years) in this study. The most common diagnoses were vestibular migraine (VM; N = 21), benign paroxysmal vertigo (BPV; N =16), unilateral vestibulopathy (N = 12), and psychogenic vertigo (N = 8). Significant differences were observed in the frequency of the diagnoses between children aged older and younger than 7 years: BPV was most common in children < 7 years of age (p < 0.01) and VM was most common in >= 27 years of age (p < 0.05). Because obtaining adequate information from children for making a correct diagnosis is sometimes difficult, acquiring sufficient information from the parents is important. In addition, getting the parents to record the nystagmus during a vertigo attack with a digital camera or cellular phone can be useful because observing the nystagmus recorded on the video is helpful for making a diagnosis. Furthermore, the parents are participating in their child's care by attempting to record the attack, strengthening the relationship between the parents and the child. The incidence of psychogenic vertigo is low (less than 10%). Therefore, although physicians have recently tended to define the disorder as psychogenic when no objective abnormality is found in a patient, making a diagnosis of psychogenic vertigo is not recommended. Because vertigo can sometimes make a child anxious, delivering the correct diagnosis and treatment at the early stage is important for preventing anxiety in affected children. PMID- 26427127 TI - [Intratympanic Steroid Treatment for Severe Idiopathic Sudden Sensorineural Hearing Loss]. AB - Systemic steroid therapy is the only standard drug therapy for severe idiopathic sudden sensorineural hearing loss (ISSHL). We have treated severe ISSHL patients with double combined therapy, intravenous steroids (IVS) and hyperbaric oxygen (HBO). In this study, we retrospectively examined the effects of intratympanic steroids (ITS) by adding it to the double combined therapy. The study subjects were 172 patients with severe ISSHL. Eighty patients (38 men and 42 women) were treated with the double combined IVS and HBO therapy between April, 2007 and July, 2010 (A group: Historical control arm). Ninety-two patients (51 men and 41 women) were treated with triple therapy, combined therapy with IVS and HBO plus ITS, between August, 2010 and October, 2013 (B group: Current protocol arm). Each group was divided into two subgroups; one with a pure-tone average (PTA) between 60 and 89 dB (A1 and B1) and the other with a PTA >= 90 dB. A 1, A2, B1, and B2 sub-groups had 56 (29 men, 27 women), 24 (9 men, 15 women), 64 (36 men, 28 women), and 28 (15 men, 13 women) patients, respectively. All patients were treated within 30 days from the onset. There was a statistically significant difference in hearing improvement between the A2 and B2 groups, whereas no significant difference was observed between the A1 and B1 groups. Furthermore, a significant difference was observed in all frequencies but 2 kHz between at the A2 group and B2 group, but not between the A1 and B1 groups. Multivariate logistic analysis revealed that the treatment method (double vs.. triple combined therapies) had the strongest impact on hearing improvement in the ISSHL patients with a PTA >= 90 dB. These results indicated that the B2 group demonstrated better hearing improvement than the A2 group and suggested that the addition of the ITS could be effective for profound ISSHL patients with a PTA >= 90 dB. PMID- 26427128 TI - [Solitary Fibrous Tumors of the Nasal and Paranasal Sinuses]. AB - Solitary fibrous tumors (SFT) are uncommon neoplasm that arises in most cases from the pleura. SFT has been rarely observed in the head and neck, but SFT of the paranasal sinuses is especially rare, with 39 previously reported cases to date including those reported in this abstract. Herein we describe three cases of SFT in the paranasal sinuses that were successfully treated endoscopically. Two of the three cases involved patients with no previous history of SFT. The lesion of one of the patients was pathologically diagnosed as SFT preoperatively, but the other was diagnosed as an angiogenic tumor without any biopsies. The tumors were completely resected after arterial embolization by a transnasal endoscopic procedure. The third case involved a 43-year old man, who had undergone medial maxillectomy through a lateral rhinotomy incision to resect SFT four years and seven months before. The tumor relapsed intracranially and, therefore, a craniotomy procedure followed by endoscopic skull base surgery was performed. Radiation therapy was performed postoperatively because the recurrent tumor was pathologically identified as malignant SFT, which had been classified benign at the time of the first resection. All three patients are presently alive with no evidence of disease. PMID- 26427129 TI - [Submucosal Partial-turbinectomy (SPT) Preceding an Endoscopic Sinus Surgery (ESS) Procedure]. AB - Preceding a endoscopic sinus surgery (ESS), we have proposed performing a submucosal partial-turbinectomy (SPT) which removes a part of the inferior nasal concha bone attached to maxillary sinus with an antrostomy. By this method, we could not only make a large antrostomy but also obtain good maneuverability by opening the middle nasal meatus in ESS. We performed SPT preceding ESS in 140 cases (261 sides) between January 2012 and June 2014. The stenosis rates of the middle nasal meatus were 14.2% (37 sides from 261 sides) in one month, 7.4% (18 sides from 243 sides) in three months and 3.7% (6 sides from 163 sides) in 6 months after surgery. The closing rates of the antrostomy were 1.5% (4 sides from 261 sides) in one month, 2.9% (7 sides from 243 sides) in three months and 6.7% (11 sides from 163 sides) in 6 months after surgery. We considered that the SPT method would contribute to secure sufficient ventilation routes for wound healing of sinusitis following surgery on the mucous membrane. In addition, the SPT method has merit from the point of deceasing risks of atrophic rhinitis and empty nose syndrome by preserving most of the inferior nasal concha. PMID- 26427130 TI - Vaspin as a Risk Factor of Insulin Resistance in Obstructive Sleep Apnea-Hypopnea Syndrome in an Animal Model. AB - BACKGROUND: In this study, we aimed to establish a chronic intermittent hypoxia model in rats and explore the possible role of vaspin in insulin sensitivity. METHODS: Healthy male Wistar rats were randomly divided into two groups: normal control group (NC) and chronic intermittent hypoxia group (CIH). The NC group was raised under physiological conditions and the CIH group was kept in the plexiglass chamber between 9 am and 5 pm undergoing intermittent hypoxic challenge for 8 hours/day for 8 weeks. Arterial blood pressure of rats (tail cannulation) was measured before and after the study. Fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), fasting insulin (FINS), vaspin, and leptin levels were measured. Vaspin mRNA expression in visceral adipose tissues was measured with Real Time-PCR. The protein levels of vaspin, Akt and phospho-Akt in visceral tissues were determined by Western-blot. RESULTS: At baseline, all the measurements in the CIH and NC groups were comparable. By the end of the experiment, the blood pressure of the CIH group was significantly higher than the NC group. The levels of FPG, FINS, TG, TC, leptin, and vaspin in the CIH group were significantly higher than in NC group. Plasma vaspin levels were correlated with FINS, HOMA-IR, and TG levels. Vaspin expression in both mRNA and protein levels in visceral adipose tissues of the CIH group were clearly higher than the NC group. Phospho-Akt protein level was decreased in visceral adipose tissues of the CIH group compared to the NC group. CONCLUSIONS: In the chronic intermittent hypoxia rat model, the expression of vaspin in visceral adipose tissues and plasma were increased, which were correlated with insulin resistance. PMID- 26427131 TI - Design of Analytical Run Length for Clinical Chemistry Analytes. AB - BACKGROUND: The expected number of unacceptable patient results E (Nu) can be set as a patient-based quality goal. Analytical run length can be designed to limit E (Nu) < 1. METHODS: The new internal quality control (IQC) strategy and length of analytical run for each analyte was applied to routine IQC paralleled with the way before redesign. IQC charts were produced by QC test results to analyze and compare the performance of out-of-control error detection. RESULTS: Optimal analytical run lengths designed by the quality control computer software QCCS 2008 were 39 for albumin, 61 for cholesterol, 900 for triglycerides, 112 for aspartate aminotransferase, 279 for lactate dehydrogenase, 267 for alcaline phospatase, 363 for total bilirubin, 151 for ceatinine, 230 for uric acid, 46 for phosphorus PHOS, 158 for carbon dioxide, and 580 for glucose. After being redesigned, IQC strategies for ALB, CHOL, and PHOS detected more out-of-control error than before and achieved more cost-effectiveness. CONCLUSIONS: Using E (Nu) as a QC performance measure, frequency of QC testing can be objectively designed. Additionally, new QC strategies can help find more problems of testing systems and promote efficiency and cost savings. PMID- 26427132 TI - Age will affect the Growth and Mineralization Ability of the Rat Osteoblast. AB - BACKGROUND: Primary culture of rat osteoblast cells serves as a model in in vitro research of bone metabolism. But most of studies about osteoblast use fetal or newborn rats for cell isolation, including researches about the post-menopausal osteoporosis. This will affect the authenticity and reliability of the results. These differences have been a concern in recent years. So far, little research has focused on adult female rat osteoblasts. METHODS: In this study, a systematic study was done regarding the proliferation, differentiation, and mineralization of adult female rat osteoblasts. RESULTS: The study showed that the age of the host may affect the growth and the mineralization ability of osteoblast. CONCLUSIONS: The result of the study suggests that in vitro studies related to osteoblasts should select the right host and appropriate observation points according to the cell growth characteristics in order to ensure the consistency of the actual changes. PMID- 26427133 TI - The Therapeutic Effects of Thymosin alpha1 Combined with Human Immunoglobulin (Ig) and Bundles on Severe Sepsis: a Retrospective Study. AB - BACKGROUND: To explore the role of human immunoglobulin (Ig) and thymosin alpha1 therapy for severe sepsis through comparison between bundles combined with human immunoglobulin (Ig) and thymosin alpha1 therapy group (A group) and bundles group (B group). METHODS: A total of 526 subjects with severe sepsis in the ICU were divided into two groups: bundles combined with human immunoglobulin (Ig) and thymosin alpha1 therapy (A group) and bundles (B group). The two groups were then divided into two subgroups: one group had a history of underlying disease (A1 group and B1 group) and the other did not (A2 group and B2 group). Data on demographics, underlying diseases, infection site, organ involvement, duration of artificial ventilation, APACHE II and SOFA scores on day-1 and day-14 after ICU admission, and duration of ICU stay, were recorded. The study lasted 28 days. A total of 526 subjects with severe sepsis in the intensive care unit (ICU) of Beijing Chaoyang Hospital (affiliated with Capital Medical University; Beijing, China) from January 2008 to December 2011 were selected. Bundles combined with human immunoglobulin (Ig) and thymosin alpha1 therapy was administrated to 221 patients. 305 patients were treated with bundles. RESULTS: Compared with the B group, the number of days of artificial ventilation was decreased (p < 0.005) and ICU stay shortened (p < 0.001) in the A group. After 14 days of treatment, APACHE II and SOFA scores were decreased (both p < 0.001). Mortality in the A group was decreased by 13.89% (p < 0.005). The survival period in the A group was longer than that of the B group (p < 0.001). CONCLUSIONS: Bundles combined with human immunoglobulin (Ig) and thymosin alpha1 therapy may reduce APACHE II and SOFA scores, shorten the time of artificial ventilation and length of ICU stay, and improve the prognosis of subjects with severe sepsis. PMID- 26427134 TI - The Seroprevalence of Some Pathogen Specific IgM in Children with Acute Respiratory Tract Infections in Guangzhou Region, 2011 - 2012. AB - BACKGROUND: Acute respiratory tract infections (ARTIs) are the leading cause of morbidity and death in children < 5 years worldwide. The aim of this study is to analyze the seroprevalence of nine pathogen specific IgMs in children with ARTIs with respect to gender, age, and seasonality in the Guangzhou region. METHODS: Serum samples were collected from 20160 children with ARTIs admitted to the Guangzhou Women and Children's Medical Center between 2011 and 2012. Serum specific IgM antibodies to nine respiratory pathogens, Mycoplasma pneumonia (MP), Legionella pneumophila (LP), Coxiella burnetii (C. burnetii), Chlamydophila pneumonia (CP), adenovirus (ADV), respiratory syncytial virus (RSV), type A and type B influenza virus (IVA and IVB), and parainfluenza virus (PIV), were detected using immunofluorescence assay. RESULTS: The male-to-female ratio of all patients was 1.9:1. The median age was 3 years and 8 months with a significant difference in seropositivity to respiratory tract pathogens between children from different age groups. Seropositivity was detected in 43.53% of the children with the top three pathogens being MP (33.15%), RSV (10.27%), and ADV (6.63%), followed by IVB (2.63%), LP (2.25%), IVA (1.59%), PIV (1.57%), CP (0.27%), and C. burnetii (0.13%). The prevalence of single, double, and triple seropositivity was 70.20% (6160/8775), 25.22% (2213/8775), and 4.57% (401/8775), respectively. The total IgM seropositivity for any kind of pathogen in the nine kinds of pathogens peaked in winter (46.53%), while the nadir was observed in summer (41.97%). CONCLUSIONS: The top three seroprevalence of nine kinds of pathogen specific IgM was MP, followed by RSV and ADV. The epidemic pathogen specific IgM had a season specific seropositivity distribution. Seroprevalence of the pathogen should be a focus of attention. PMID- 26427135 TI - Frequencies of Six (Five Novel) STR Markers Linked to TUSC3 (MRT7) or NSUN2 (MRT5) Genes Used for Homozygosity Mapping of Recessive Intellectual Disability. AB - BACKGROUND: Non-syndromic autosomal recessive intellectual disability (NS-ARID) is an extremely heterogeneous genetic disorder. Therefore, to investigate these genes, more research is required. One approach to investigate the NS-ARID loci is homozygosity mapping which requires appropriate STR markers within or flanking the gene/s of interest. In this research, we aimed to find novel STRs for two common NS-ARID genes (TUSC3 and NSUN2) and, in addition, to identify allele frequencies of those STR markers. METHODS: The study group included 119 unrelated healthy individuals. STR markers were investigated using the UCSC genome browser web site and SERV software. Genotyping was determined by multiplex PCR. Data were evaluated using Gene Mapper software. Allele frequencies and observed heterozygosity rates were calculated using PowerStatV12. Deviation from Hardy Weinberg equilibrium and expected heterozygosity were assessed using the DNAView software. RESULTS: In total, 56 alleles were detected. According to our research, D8TUSC3SU8.3 and D5NSUN2SU0.5 were the most informative STR markers in MRT7 and MRT5 loci, respectively and showed a high percentage of heterozygosity in Iranian population. The observed range of allele frequencies was from 3.4% to 32.4% and 0.8% to 18.9% for MRT5 and MRT7 loci, respectively. Further, we have evaluated other statistical surveys of these STR markers and discovered that all of the six listed STRs were informative and five meet the Hardy-Weinberg equilibrium for the tester group. CONCLUSIONS: Finding novel STRs, with high allele heterozygosity, is one of the most significant current finding in the present study for the two common NSARID genes. The recognized heterozygosity of these markers make MRT flanking STR markers very efficient to be used in diagnostic medical genetics labs or homozygosity mapping on NS-ARID. PMID- 26427136 TI - Evaluate the Effect of Valproate Monotherapy on the Serum Homocysteine, Folate and Vitamin B12 Levels in Epileptic Children. AB - BACKGROUND: The data regarding Valproate and its influence on serum folate and homocysteine levels are conflicting. The aim of this study was to evaluate whether differences exist in homocysteine, folate, and vitamin B12 levels in children receiving Valproate. METHODS: A total of 55 newly diagnosed epileptic children with ages ranging from 2 to 15 years were enrolled at the start of study but after 3 months follow up, the total sample size finally was only 50 epileptic children. 5 children dropped out of study due to poor follow up. 50 age and gender matched healthy control subjects were also studied on enrollment at the start of study. Serum homocysteine levels were analyzed by enzyme immunoassay method using the kits provided by Axis-Shield Diagnostics Ltd (Dundee DD2 1XA, United Kingdom). Serum folate and serum vitamin B12 were estimated by Competitive Chemiluminescent Enzyme Immunoassay method. RESULTS: The serum homocysteine level in epileptic children was found to be significantly increased after Valproate monotherapy as compared to before therapy. Moreover, a highly significant decrease was observed in the levels of serum folate in epileptic children after Valproate monotherapy as compared to before therapy. But a non significant difference was observed in serum vitamin B12 levels in epileptic children before and after Valproate monotherapy. CONCLUSIONS: Thus, we conclude that there is a significant increase in the levels of homocysteine and a significant decrease in the concentration of serum folate while vitamin B12 decreases non-significantly after Valproate monotherapy. The atherogenic effect of increased serum homocysteine level is well established; the patients under Valproate monotherapy should be monitored for possible atherogenic effects. Considering the above observation and results of children undergoing Valproate monotherapy, these children should be screened for levels of serum homocysteine, folate, and vitamin B12 and treated when their levels are found to be disturbed. PMID- 26427137 TI - Virulence Genes and Antibiotic Susceptibilities of Uropathogenic E. coli Strains. AB - BACKGROUND: The aim of this study is to detect the presence of and possible relation between virulence genes and antibiotic resistance in E. coli strains isolated from patients with acute, uncomplicated urinary tract infections (UTI). METHODS: 62 E. coli strains isolated from patients with acute, uncomplicated urinary tract infections (50 strains isolated from acute uncomplicated cystitis cases (AUC); 12 strains from acute uncomplicated pyelonephritis cases (AUP)) were screened for virulence genes [pap (pyelonephritis-associated pili), sfa/foc (S and F1C fimbriae), afa (afimbrial adhesins), hly (hemolysin), cnf1 (cytotoxic necrotizing factor), aer (aerobactin), PAI (pathogenicity island marker), iroN (catecholate siderophore receptor), ompT (outer membrane protein T), usp (uropathogenic specific protein)] by PCR and for antimicrobial resistance by disk diffusion method according to CLSI criteria. RESULTS: It was found that 56 strains (90.3%) carried at least one virulence gene. The most common virulence genes were ompT (79%), aer (51.6%), PAI (51.6%) and usp (56.5%). 60% of the strains were resistant to at least one antibiotic. The highest resistance rates were against ampicillin (79%) and co-trimoxazole (41.9%). Fifty percent of the E. coli strains (31 strains) were found to be multiple resistant. Eight (12.9%) out of 62 strains were found to be ESBL positive. Statistically significant relationships were found between the absence of usp and AMP - SXT resistance, iroN and OFX - CIP resistance, PAI and SXT resistance, cnf1 and AMP resistance, and a significant relationship was also found between the presence of the afa and OFX resistance. CONCLUSIONS: No difference between E. coli strains isolated from two different clinical presentations was found in terms of virulence genes and antibiotic susceptibility. PMID- 26427138 TI - Molecular Analysis of IGH and Incomplete IGH D-J Clonality Gene Rearrangements in Hodgkin Lymphoma Malignancies. AB - BACKGROUND: We evaluated molecular clonality in immunoglobulin heavy chain (IGH) and incomplete IGH D-J genes for improvement of clinical diagnosis of Hodgkin's lymphoma (HL). We applied BIOMED-2 protocols in HL cases, which were previously approved by clonality detection in non-Hodgkin lymphoma (NHL) cases. METHODS: We investigated 50 consecutive FFPE samples of classical HL (cHL) patients to assess IGH and IGH D-J clonal gene rearrangements by multiplex PCR protocols, which were provided by the European Biomedicine and Health (BIOMED-2) Concerted Action Project BMH4-CT98-3936. RESULTS: In the present study, there was a monoclonality of 86% (43/50) including a clonality of 74% (37/50) for IGH and a clonality of 42% (21/50) in IGHD-J. In addition, a lack of clonality was detected in 14% (7/50) of cases. Frequent gene rearrangements were detected in framework (FR) III (54%) and FRII (20%), whereas no clonality was seen in FRI. Furthermore, a monoclonality of 28% and 14% was detected in the DH(1-6)-JH and DH(see symbol)-JH gene rearrangements, respectively. CONCLUSIONS: The present study suggests that the complete IGH and incomplete IGH D-J clonality gene rearrangement assays using BIOMED-2 protocols could be considered a valuable method for detection of clonal gene rearrangements, especially in HL cases. PMID- 26427139 TI - Differentiation between Transudate and Exudate in Pericardial Effusion has almost no Diagnostic Value in Contemporary Medicine. AB - BACKGROUND: The biochemical analysis of pericardial fluid for differentiating transudate from exudate is often ordered and interpreted according to the criteria extrapolated from pleural effusions. However, the validity of this discrimination when applied to pericardial effusion is under question. METHODS: Patients who underwent pericardiocentesis between January 2004 and February 2014 were identified. Among them, 216 had essential medical records available and constituted the study population. The parameters specifically analyzed were the following: lactate dehydrogenase, total protein and glucose concentrations in both pericardial fluid and serum; pericardial fluid/serum ratios of lactate dehydrogenase and total protein content; and pH and specific gravity of pericardial fluid. RESULTS: Eighty-one percent of pericardial effusions were classified as exudate according to Light's criteria. Both exudate and transudate fluid characteristics were possible for all etiological causes except for tuberculosis in which all were exudates. Although multiple cutoff points for all parameters were tested, significant overlap between different causes persisted (all having an area under the receiver operating characteristic curve of < 0.7). Thus, a reasonable accuracy to differentiate one cause from another could not be achieved. CONCLUSIONS: Although often ordered, the biochemical analysis of pericardial fluid has almost no diagnostic value to distinguish among causes of pericardial effusion in contemporary medicine. PMID- 26427140 TI - Synovial Fluid alpha-MSH Levels are Inversely Correlated with Articular Cartilage Degeneration in Anterior Cruciate Ligament Deficient Knees. AB - BACKGROUND: Secondary osteoarthritis after ligament or meniscus injury generally causes great burdens to patients. Alpha-melanocyte-stimulating hormone (alpha-MSH ), a 13 amino acid neuropeptide produced by intracellular cleavage of the proopiomelanocortin (POMC) hormone, has been proven to suppress inflammation and protect cartilage from damage. The present study was carried out to explore the relationship between synovial fluid alpha-MSH levels and articular cartilage degeneration in patients with anterior cruciate ligament (ACL) deficiency. METHODS: 51 patients with ACL deficiency admitted to our hospital were enrolled. The Noyes score method was used to assess articular cartilage damage arthroscopically. Synovial fluid alpha-MSH levels were examined using a double antibody radioimmunoassay method. Inflammation markers such as IL-6, MMP-3, and degradation biomarker of collagen type II (CTX-II) were also explored by enzyme linked immunosorbent assay (ELISA). RESULTS: The articular cartilage in ACL deficiency patients deteriorated significantly with time after injury (r = 0.673, p < 0.001). Synovial fluid alpha-MSH levels are inversely associated with Noyes scores (r = -0.682, p < 0.001), levels of inflammation markers IL-6 (r = -0.302, p = 0.035), MMP-3 (r = -0.652, p < 0.001) and degradation biomarker CTX-II (r = 0.584, p < 0.001). CONCLUSIONS: Synovial fluid alpha-MSH levels showed an independent and negative correlation with articular cartilage degeneration in patients with knee ACL deficiency. Supplementing with a-MSH may serve as a possible adjuvant therapy for delaying cartilage degeneration after ACL injury. PMID- 26427141 TI - Standardization of a Protocol for Obtaining Platelet Rich Plasma from blood Donors; a Tool for Tissue Regeneration Procedures. AB - BACKGROUND: To develop a protocol for obtaining autologous platelet rich plasma in healthy individuals and to determine the concentration of five major growth factors before platelet activation. This protocol could be integrated into the guidelines of good clinical practice and research in regenerative medicine. METHODS: Platelet rich plasma was isolated by centrifugation from 38 healthy men and 42 women ranging from 18 to 59 years old. The platelet count and quantification of growth factors were analyzed in eighty samples, stratified for age and gender of the donor. Analyses were performed using parametric the t-test or Pearson's analysis for non-parametric distribution. P < 0.05 was considered statistically significant. RESULTS: Our centrifugation protocol allowed us to concentrate basal platelet counts from 1.6 to 4.9 times (mean = 2.8). There was no correlation between platelet concentration and the level of the following growth factors: VEGF-D (r = 0.009, p = 0.4105), VEGF-A (r = 0.0068, p = 0.953), PDGF subunit AA (p = 0.3618; r = 0.1047), PDGF-BB (p = 0.5936; r = 0.6095). In the same way, there was no correlation between donor gender and growth factor concentrations. Only TGF-beta concentration was correlated to platelet concentration (r = 0.3163, p = 0.0175). CONCLUSIONS: The procedure used allowed us to make preparations rich in platelets, low in leukocytes and red blood cells, and sterile. Our results showed biological variations in content of growth factors in PRP. The factors influencing these results should be further studied. PMID- 26427142 TI - The Amount of Phosphorus in the Blood of Heroin Abusers Compared to that of Healthy Subjects. AB - BACKGROUND: The aim of the current retrospective study was to assess any difference in terms of serum phosphate (P) between heroin addicts and healthy subjects. METHODS: Between 2011 and 2012, under the authority of the Greek Organization Against Drugs (OKANA), 30 regular heroin addicts, 22 males and 8 females (Group A) participated at the study. Between 2010 and 2011, 30 healthy individuals, 22 males and 8 females (Group B), presented on an outpatient basis for either fatigue or common flu symptoms without fever at the 424 Military Hospital of Thessaloniki. RESULTS: No significant difference between group A and B, in terms of either age (p = 0.454, Mann-Whitney test) or male/female ratio (p = 0.573, Chi2 test), suggesting a homogeneity for the population of individuals participating in the study. The mean values of serum-P in group A and B were 3.47 +/- 0.65 and 3.35 +/- 0.58, respectively (p = 0.45, Mann Whitney test). CONCLUSIONS: The absence of statistical difference of serum-P between heroin addicts and healthy subjects as shown in our results should be confirmed in further studies. PMID- 26427143 TI - Circulating Double-Stranded DNA in Plasma of Hemodialysis Patients and its Association with Iron Stores. AB - BACKGROUND: Chronic kidney disease (CKD) is characterized by oxidative stress, and most of the adverse effects of CKD are mediated by iron-catalyzed ROS generation. The DNA, in particular, is more susceptible to attack by ROS than other proteins and membrane lipids. Considering the evidence on the relationship between CKD, iron metabolism, and DNA damage, the purpose of this study was to evaluate cell-free DNA in the plasma of HD patients and its association with iron status biomarkers and kidney function. METHODS: Measurements of the circulating cell-free DNA in plasma, iron, ferritin, transferrin and other biochemical parameters were performed in 40 chronic hemodialysis (HD) patients and 40 healthy controls. Blood samples were also collected 1 hour before and 1 hour after the HD session to check whether a single HD session would be able to promote an increase in cell-free DNA in the plasma. RESULTS: Cell-free DNA in plasma was significantly increased in HD patients in comparison with healthy controls (p = 0.0017), and significant correlations were observed between cell-free DNA and GFR and ferritin. Our findings showed that a single HD session was not able to promote an increase in cell-free DNA. It was reported that increased ferritin levels and reduced GFR were associated with higher circulating cell-free DNA. CONCLUSIONS: The HD patients presented increased ceIl-free DNA. In addition, the increase of ferritin levels and the decrease of GFR were associated with DNA damage. We also observed that a single HD session was not able to promote an increase in cell-free DNA. PMID- 26427144 TI - Increased Synovial Fluid YKL-40 Levels are Linked with Symptomatic Severity in Knee Osteoarthritis Patients. AB - BACKGROUND: Elevated serum and synovial fluid (SF) YKL-40 levels have been detected in knee osteoarthritis (OA) patients. The current study was focused on the correlation between YKL-40 levels in serum or SF and symptomatic severity in patients with knee osteoarthritis. METHODS: 144 patients with knee OA and 151 healthy individuals were recruited into this study. Symptomatic severity was determined using Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores from OA patients. Serum and SF levels of YKL-40 were explored by enzyme-linked immunosorbent assay. RESULTS: We found that YKL-40 levels in SF but not serum were independently and positively related to WOMAC pain (r = 0.531, p = 0.001), physical disability (r = 0.380, p = 0.025), and total scores (r = 0.407, p = 0.01) in knee OA patients. CONCLUSIONS: YKL-40 in SF could represent a potential biomarker for assessing the symptomatic severity of OA. PMID- 26427145 TI - Sirt1 and HMGB1 Regulate the AGE-Induced Pro-Inflammatory Cytokines in Human Retinal Cells. AB - BACKGROUND: Advanced glycation end products (AGEs) accumulate in the retinal vascular cells, neurons, and glias of patients with diabetes mellitus and lead to the pathogenesis of diabetic retinopathy (DR). METHODS: In the present study, to elucidate the orchestrated interactions of high mobility group box 1 (HMGB1) and silent mating type information regulation 2 homolog 1 (Sirt 1) in the AGE-induced pro-inflammatory toxicity in retinal epithelial cells, we investigated the role of HMGB1 and Sirt 1 in the AGE-induced pro-inflammatory cytokines and chemokines. RESULTS: It was demonstrated that the expression of TNF-alpha, IL-1beta, IL-6, MCP-1, RANTES and IP-10 was promoted by the AGE-BSA treatment dose-dependently. The treatment with AGE-BSA also significantly promoted the HMGB1 at both mRNA and protein levels, dose-dependently. And in addition, we confirmed that HMGB1 mediated the AGE-induced pro-inflammatory cytokines and chemokines in the AGE treated ARPE-19 cells. Moreover, we found that the Sirt 1 was downregulated by the AGE-BSA treatment at both mRNA and protein levels in the ARPE-19 cells, dose dependently. Our further investigation recognized the regulatory role of Sirt 1 in the AGE-promoted pro-inflammatory cytokines and chemokines. The Sirt 1 inhibitor aggravated, whereas the Sirt 1 activator inhibited, the translocation of HMGB1 and the promotion of AGE-induced IL-1beta and IL-6. CONCLUSIONS: Taken together, we confirmed that AGE-BSA promoted HMGB1 but down regulated Sirt 1 in human retinal cells. Sirt 1 was confirmed to regulate AGE-induced pro inflammatory cytokines and chemokines via inhibiting the nuclear-to-cytoplasmic translocation and release of HMGB1 in retinal ARPE-19 cells. PMID- 26427146 TI - Ciculating miRNA-21 as a Biomarker Predicts Polycystic Ovary Syndrome (PCOS) in Patients. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, hyperinsulinemia, and infertility. In PCOS, abnormal regulation of relevant genes is required for follicular development. By binding to the 3' untranslated region (3'URT), microRNAs (miRNAs) are widely involved in posttranscriptional gene regulation. However, few studies have been conducted on circulating miRNA expression in PCOS. This study aims to describe altered expression of circulating miR-21 in PCOS. METHODS: The expression of serum miRNAs of PCOS patients were explored using the TaqMan Low Density Array followed by individual quantitative reverse transcription polymerase chain reaction assays. The protein level of LATS1 was determined using Western blot. To validate whether miR-21 targeted LATS1, the luciferase assay was applied. RESULTS: In comparison with normal subjects, the circulating level of miRNA-21 was significantly enhanced in PCOS patients. In PCOS patients, the expression levels of MST1/2, LATS1/2, TAZ were much lower than the control subjects. Luciferase reporter assay revealed that LATS1 was a downstream target of miR-21. CONCLUSIONS: In comparison with normal subjects, serum miR-21 is obviously increased in PCOS patients. Through targeting LATS1, miR-21 could prompt PCOS progression and could act as a novel non-invasive biomarker for diagnosis of PCOS. PMID- 26427147 TI - Analysis of the Molecular Evolution of the Mycobacterium Tuberculosis Drug Resistant Gene rpoB in Asia Using a Bayesian Evolutionary Method. AB - BACKGROUND: Tuberculosis (TB) is a serious communicable disease throughout the world. Re-emergence of the TB epidemic is aggravated by the circulation of multidrug-resistant Mycobacterium tuberculosis strains, and more than half of new cases have occurred in Asia. Therefore, it is important to understand the gene mutations underlying the development of rifampicin resistance in Asia. METHODS: In this study, we classified the rifampicin-resistant Mycobacterium tuberculosis (MTB) rpoB data downloaded from Genbank, based on 12 mutation points. The relationship between the mutation sites and regional information was analyzed, after which the mutation dates and mutation trends of the rpoB gene were predicted by the Markov Chain Monte Carlo (MCMC) method. RESULTS: We discovered that the mutation sites of the rpoB gene were disparate in different regions of Asia. The results of this study clearly showed that drug-resistant gene mutations in Asia started to increase in 2000 and peaked in 2006, indicating the relationship between drug resistance and outbreak trends of TB. CONCLUSIONS: From our analysis, it was not difficult to see the relationship between the mutation rates of the rpoB gene and the outbreak of TB. Hence, to some degree, outbreak trends of TB can be predicted through genotyping based on the rpoB gene. PMID- 26427148 TI - Polymorphism of the Fcgamma Receptor II as a Possible Predisposing Factor for Heparin-Induced Thrombocytopenia. AB - BACKGROUND: Heparin-induced thrombocytopenia (HIT) represents a serious complication of heparin treatment. IgG antibodies binding platelet factor 4 (PF4) and heparin trigger the clinical manifestations of HIT. However, only a portion of the antibodies have the ability to activate platelets, and these can be identified by a platelet aggregation test (functional testing). However, this expression has been detected to have a molecular cause, which is a mutation of FcgammaRIIa. The FcgammaRIIa receptor is responsible for the activation of platelets by antibodies in HIT. METHODS: To determine HIT, impedance aggregometry using the Multiplate analyzer (MEA) as heparin-induced aggregation technique and the Technozym HIT IgG ELISA test were used. The MEA method uses sensitization of donor platelets with patient plasma in the presence of heparin at a concentration of 0.5 IU/mL. The results were compared with the ELISA test. Mutation of FcgammaRHa was assessed using the asymmetric real-time PCR method that is based on the reaction with two hybridization probes and melting curve analysis. RESULTS: Examined were 100 patients at a clinically intermediate and higher risk of HIT according to the 4T's score. All samples were examined by the ELISA test and MEA, with positive samples being further confirmed by high-concentration heparin. In the group of patients, 10.0% were positive by MEA as compared with 4% determined by ELISA. The results of genetic analysis of FcgammaRIIa did not provide statistically significant differences between positive patients found by the functional test as well as the ELISA test and seronegative patients. CONCLUSIONS: The genetic mutation FcgammaRIIa is a predisposing factor for manifestation of HIT in the form of thrombocytopenia, but the process of seroconversion apparently needs another inducing factor. Therefore, the examination of mutations can be classified as predisposing factors rather than to confirm the diagnosis of HIT. PMID- 26427149 TI - Association between Common Genetic Variants of alpha2A-, alpha2B-, and alpha2C Adrenergic Receptors and Orthostatic Hypotension. AB - BACKGROUND: The genetic background associated with the dysregulation of orthostatic blood pressure remains poorly understood. The sympathetic nervous system plays a pivotal role in the regulation of blood pressure, as well as in response to positional changes. The essential role of adrenergic receptors in the sympathetic nervous system prompted us to hypothesize that common genetic variants of the alpha2-adrenergic receptor might contribute to the dysregulation of orthostatic blood pressure in general populations. This study is to explore the association between the polymorphisms of the alpha2-adrenergic receptor genes and the occurrence of orthostatic hypotension in Chinese populations. METHODS: The polymorphisms ADRA2A C-1291G (rs1800544), ADRA2B 301-303 I/D (rs28365031), and ADRA2C 322-325 I/D (rs61767072) were genotyped in 317 patients with orthostatic hypotension and 664 age- and gender-matched controls. Logistic regression analyses, adjusted for multiple comparisons, were used to determine the association between the allele/genotype of each ADRA2 gene and the risk of orthostatic hypotension. RESULTS: No significant association was found between the ADRA2A C-1291G, ADRA2B 301-303 I/D, and ADRA2C 322-325 I/D polymorphisms and orthostatic hypotension. CONCLUSIONS: We concluded that the common polymorphisms in the alpha2-adrenergic receptor gene is not associated with orthostatic hypotension risk in Chinese. PMID- 26427150 TI - Inhibition of Autophagy Increases Proliferation Inhibition and Apoptosis Induced by the PI3K/mTOR Inhibitor NVP-BEZ235 in Breast Cancer Cells. AB - BACKGROUND: The phosphoinositide 3 kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) pathway is a complicated intracellular pathway which leads to cell growth and tumor proliferation and plays a significant role in breast cancer. Multiple compounds targeting this pathway are being evaluated in clinical trials. NVP-BEZ235, a novel and orally available dual PI3K/mTOR inhibitor, showed great antitumor effect and provided a therapy strategy in breast cancer. METHODS: In this study, we detect the effect of NVP-BEZ235 on cell viability, apoptosis, and autophagy in a breast cancer cell line. We also test the effect of NVP-BEZ235 on the expression of PI3K/AKT/mTOR pathway proteins p-AKT, p-mTOR, and p-70S6K. RESULTS: The results showed that the PI3K/AKT/mTOR proteins p-AKT, p-mTOR, and p 70S6K were obviously suppressed by NVP-BEZ235. NVP-BEZ235 inhibited cell proliferation and induced apoptosis and autophagy in breast cancer cells. In combination with autophagy inhibitors or autophagy gene knockdown, enhanced growth inhibition and apoptosis was induced by NVP-BEZ235 in MCF-7 cells. CONCLUSIONS: This study provides a novel treatment strategy that PI3K/AKT/mTOR pathway inhibitors in combination with autophagy inhibitors lead to further apoptosis in breast cancer cells. PMID- 26427151 TI - Impact of Systemic Normobaric Short-Term Hypoxia on Pro-Inflammatory and Anti Inflammatory Cytokines in Healthy Volunteers. AB - BACKGROUND: Hypoxia has been shown to induce a microvascular inflammation, affect the cell count of different types of immune cells, and influence cytokine production in blood. In the present study, serum levels of different cytokines were investigated to achieve insights into the effect of hypoxia on the balance of inflammation and anti-inflammation. METHODS: Pro- (IL-8) and anti-inflammatory (IL-10) cytokines were measured in an experiment exposing 12 healthy subjects (35 +/- 9 yr, 176 +/- 7 cm, 73 +/- 16 kg, BMI 23 +/- 4 kg/m2) to systemic, normobaric hypoxia in a hypoxic chamber. In this chamber oxygen was replaced by nitrogen to reach an oxygen content of 9.9% that is equivalent to an altitude of 5500 m during 7 hours. Serum cytokine concentrations were analyzed using ELISA. RESULTS: As expected, a significant decrease in peripheral oxygen saturation accompanied by a significant increase in breathing frequency and heart rate were observed in the subjects during hypoxia compared to baseline (BL). Blood leukocytes increased slightly, but significantly in the course of hypoxia. A statistically significant increase was measured for IL-8 serum level during hypoxia compared to the baseline measurements (BL 12.0 +/- 1.1 pg/mL, hypoxia 16.2 +/- 1.6 pg/mL, p = 0.006). For IL-10 a statistically significant decrease was measured upon hypoxia compared to baseline (BL 11.6 [6.2 - 43.31 pg/mL, hypoxia 8.3 [4.4 - 26.6] pg/mL, p = 0.016). Additionally, a significant inverse correlation was found comparing the anti-inflammatory cytokine IL-10 with the pro-inflammatory cytokine IL-8 (r = -0.69, p < 0.001). CONCLUSIONS: The results of this study demonstrate a hypoxia induced increase in pro- and decrease in anti-inflammatory cytokines reflecting an increased pro-inflammatory status during hypoxia. PMID- 26427152 TI - Fibroblast Growth Factor-23 and Carotid Artery Intima Media Thickness in Chronic Kidney Disease. AB - BACKGROUND: The cause of early-accelerated atherosclerosis development observed in Chronic Kidney Disease (CKD) is not fully understood. The determination of the relationship between the levels of fibroblast growth factor 23 (FGF-23) and the development of endothelial dysfunction, left ventricular hypertrophy, and myocardial infarction lends support to the possibility that FGF-23 plays a role in the development of atherosclerosis in CKD. Only a few studies, however, have been conducted that analyze the relationship between FGF-23 levels in the progression of CKD and the development of atherosclerosis, and these studies have generally been limited to those patients receiving dialysis therapy due to end stage renal disease (ESRD). METHODS: In the present study, carotid artery intima media thicknesses (IMT) were measured ultrasonically as a marker of atherosclerosis in 91 patients with CKD stage 3 - 4 (61 female and 30 male, age between 19 - 65 years, glomerular filtration rate [GFR] 15 - 60 mL/min 1.73 m2, CKD was not related to diabetes mellitus, and without cardiovascular-cerebral disease) in contrast to 36 healthy volunteers (26 female and 10 male, age between 19 - 65 years, GFR > 90 mL/min 1.73 m2, and without any diagnoses of acute or chronic disease), and a possible role of FGF-23 on atherosclerosis was analyzed. RESULTS: Patients were similar to controls with respect to age, gender, smoking status, body mass index, and plasma glucose and lipid profile. On the other hand, IMT measurements (p < 0.00001) and FGF-23 levels (p = 0.00012) were significantly higher in patients than controls. IMT was measured above the subclinical atherosclerosis limit of 0.750 mm in 54% of the patients. Multivariate regression analysis showed that patients' age, high sensitive c-reactive protein (hsCRP), and FGF-23 levels were independent predictors of IMT (p < 0.00001, r = 0.559). Independent of other variables, every 1 MUmol/L increase in FGF-23 levels resulted in 0.444 mm increase of IMT measurements in patients with CKD. CONCLUSIONS: Our findings suggest that monitoring serum FGF-23 may be useful as a non-invasive indicator of subclinical atherosclerosis in patients with chronic kidney disease. PMID- 26427153 TI - Relationship between the Level of Circulating Endothelial Micro-Particles in the Blood and Blood Lipid Content in Uyghur and Han Patients with Acute Coronary Syndrome. AB - BACKGROUND: The aim of this study was to analyze the relationships between the endothelial cell micro-particles (EMPs) blood level and the blood lipid in Uygur and Han patients with acute coronary syndrome (ACS) in order to provide a theoretical basis for the pathogenesis study of ACS. METHODS: 100 ACS patients (50 cases for each ethnic group) were selected as the patient group from January 2012 to August 2013 from the Cardiology Sector of the People's Hospital of the Xinjiang Uygur Autonomous Region, and 100 healthy subjects (50 cases for each ethnic group) were selected as the control group. Blood samples were collected. Flow cytometry was used to detect the EMP levels. An automatic biochemical analyzer was used to detect the levels of the blood lipids and the related indicators. RESULTS: The EMP levels in the patient group of both ethnicities were higher than those in the control group (p < 0.05), although no statistically significant differences were found in the EMP levels between Uygur and Han in the patient groups, nor in the control group (p > 0.05). Multiple linear regression analysis showed significant correlations between the EMP levels and the blood lipid related indexes (p < 0.05), with a degree of correlation of 86.70%. Path analysis indicated that the EMP level was mainly affected by high density lipoprotein cholesterol (HDL-C) (p < 0.05). CONCLUSIONS: The EMP level in the blood of ACS patients is significantly higher than in the control group, and the levels between HDL-C and EMPs are negatively correlated. The pathogenesis of ACS could be associated with the increase of the EMP level in the blood, and HDL-C might affect the level of circulating EMPs. PMID- 26427154 TI - Serum Levels of NTx and TRACP5b in Giant Cell Tumor of Bone and its Clinical Implications. AB - BACKGROUND: To investigate the serum levels of N-terminal telopeptide of type I collagen (NTx) and tartrate-resistant acid phosphatase 5b (TRACP5b) in giant cell tumor of bone (GCT) patients and the clinical implications. METHODS: 56 GCT patients (29 males and 27 females, 15 to 60 years old with a median age of 28.0 years old) with clinicopathological characteristics of GCT were enrolled in the Department of Bone Cancer, the Affiliated Cancer Hospital of Xinjiang Medical University from October 2008 to October 2014. The enzyme-linked immunosorbent assay (ELISA) was used to detect the serum levels of NTx and TRACP5b in the patients. RESULTS: Compared with 21 patients who had a GCT of < 5 cm, the serum levels of NTx and TRACP5b in the 35 patients with a GCT of >= 5 cm were significantly increased (p < 0.05). Compared with those GCT patients who had a grade I tumor, the levels of NTx and TRACP5b in grade II patients were not increased (p > 0.05), but the levels of NTx and TRACP5b were significantly increased in grade III patients (p < 0.05). Moreover, compared with the patients in histologic stage I, the levels of NTx and TRACP5b in stage II GCT patients were not increased (p > 0.05), whereas the levels in grade III patients were significantly increased (p < 0.05). In addition, the location of the tumor had a significant effect on the serum levels of NTx and TRACP5b (p < 0.05). CONCLUSIONS: Our study suggests that serum NTx and TRACP5b are sensitive and simple biomarkers to indicate aberrant bone metabolism in GCT patients, and they may have a clinical significance in GCT diagnosis. Combined examination for both markers helps in the classification of clinicopathological stages of GCT patients and in the prognosis of the disease. PMID- 26427155 TI - High-Sensitivity Cardiac Troponin T in Patients with Acute Myocardial Infarction in Acute Exacerbation of Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: In clinical work, patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) often have high-sensitivity cardiac troponin T (hs-cTnT) levels that surpass the 99th percentile of the normal reference population, a cutoff used to screen patients for acute myocardial infarction (AMI). However, a large proportion of these patients prove not to have AMI and are frequently misdiagnosed and overtreated. We analyzed whether the cutoff value of hs-cTnT for diagnosing AMI in AECOPD patients should be adjusted. METHODS: This was a prospective study of 873 consecutive patients with AECOPD who presented at the emergency department of West China Hospital of Sichuan University from January 2010 to December 2013. Conventional cardiac troponin (cTnT) was measured in patients' blood samples taken at presentation, and values were compared with their final diagnoses. RESULTS: Among patients with a final diagnosis other than AMI, 64.64% had a plasma hs-cTnT concentration above the 99th percentile of a normal reference population (14 ng/L). The median level of hs-cTnT in AECOPD patients without AMI was 16 ng/L. The area under the receiver operating characteristic curve (AUC) of hs-cTnT for diagnosis of AMI was 0.92 (0.85 - 0.99, p < 0.001) with a cutoff value of 60.5 ng/L. CONCLUSIONS: The baseline levels of hs-cTnT were relatively high in AECOPD patients, and the optimal cutoff value of hs-cTnT for AMI diagnosis (60.5 ng/L) was also higher than that for non-AECOPD patients. PMID- 26427156 TI - Reference Interval and Status for Serum Folate and Serum Vitamin B12 in a Norwegian Population. AB - BACKGROUND: Deficiencies of folate and vitamin B12 lead to an elevated serum concentration of homocysteine which has been associated with many diseases including cardiovascular disease. Laboratory algorithms often include initial testing of serum folate and vitamin B12. Reference intervals for these vitamins can vary significantly among populations for which dietary intakes may be different. The aim of this study was to establish reference intervals in a Norwegian population and to assess the folate and vitamin B12 status related to reference intervals. METHODS: Blood samples were taken from 144 healthy volunteers aged 18 - 65 years. A questionnaire provided data of medication, medical history, vitamin supplementation, alcohol consumption, and use of oral contraceptives and others. Serum folate and vitamin B12 concentrations were measured on the Abbott Architect i2000. Reference values were calculated using the bootstrap method. Results of serum folate, vitamin B12, and homocysteine from 1190 individuals from regional primary health care centers were evaluated related to reference values and the proportion of individuals with deficiency was estimated. RESULTS: Mean serum concentrations of folate and vitamin B12 were 11.9 nmol/L and 328 pmol/L, respectively. Men were found to have statistically significant higher vitamin B12 concentrations than women. 95%-reference intervals were calculated to 5.2 - 29.2 nmol/L for folate and 133 - 595 pmol/L for vitamin B12. 1.1% of the study population has serum vitamin B12-concentrations < 133 pmol/L and 3.4% has serum folate concentrations < 5.2 nmoI/L. CONCLUSIONS: The serum reference intervals for folate and vitamin B12 for a healthy, not vitamin supplemented adult population were determined from 144 subjects. The application of these intervals will assist in the evaluation of folate and vitamin status. PMID- 26427157 TI - MicroRNAs as Biomarkers for the Diagnostics of Bladder Cancer: a Meta-Analysis. AB - BACKGROUND: Bladder cancer (BCa) is the fifth most common cancer with significant morbidity and mortality. Recently, numerous studies demonstrated that microRNAs (miRNAs) are emerging as diagnostic biomarkers for BCa. However, the findings in these studies are inconsistent. To systematically assess the potential diagnostic value of miRNAs for BCa, a meta-analysis was performed in this study. METHODS: Relevant literature was researched in PubMed, Embase, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), and WanFang databases up to September 1, 2014. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative LR (NLR), diagnostic odds ratio (DOR), and area under the SROC curve (AUC) value were analyzed by the random-effects model, whose parameters reflected the overall diagnostic performance of miRNAs. RESULTS: Thirty studies from 10 individual publications, including 1019 BCa patients and 690 controls, were included in this meta-analysis. The pooled sensitivity, specificity, PLR, NLR, DOR, and AUC were 0.80 (95% CI: 0.78 - 0.81), 0.74 (95% CI: 0.72 - 0.76), 3.22 (95% CI: 2.68 - 3.87), 0.26 (95% CI: 0.21 - 0.32), 15.20 (95% CI: 10.25 - 22.53) and 0.85, respectively, indicating a moderate diagnostic accuracy for BCa. Moreover, our subgroup analyses showed that analysis of multiple miRNAs (AUC, sensitivity, and specificity of 0.913, 0.86, and 0.80, respectively) yielded a higher diagnostic accuracy than of single miRNAs (AUC, sensitivity, and specificity of 0.84, 0.78, and 0.73, respectively) in BCa diagnosis. In addition, as biomarkers, miRNAs are more suitable for the diagnosis of non-muscle-invasive BCa (NMIBCa) with AUC of 0.84, sensitivity of 0.74, and specificity of 0.77 than muscle-invasive BCa (MIBCa) with AUC of 0.79, sensitivity of 0.73, and specificity of 0.73. CONCLUSIONS: The present meta-analysis suggests that miRNAs are potential novel biomarkers for detection of BCa. However, further validation studies are still needed to confirm our findings. PMID- 26427158 TI - Comparison of the Microarray-Based Assay, the Real-Time PCR Assay, and the Bidirectional Sequencing Method for CYP2C19 Genotyping. AB - BACKGROUND: Cytochrome P450 2C19 (CYP2C19) is a clinically important enzyme that metabolizes a wide variety of drugs. Recently, some new genetic assays designed to identify the CYP2C19 genotype were introduced. METHODS: We compared the abilities of the microarray-based Verigene CYP2C19 Test (Nanosphere, USA) and the AccuPower Real-time PCR CYP (*2,*3,*17) assay (Bioneer, Korea) with the ability of the bidirectional sequencing method for the detection of CYP2C19 genotypes in 78 whole blood samples. RESULTS: Among 78 specimens, 28 were *1/*1, 1 was *1/*17, 27 were *1/*2, 10 were *1/*3, 8 were *2/*2, 1 was *3/*3, and 3 were *2/*3. In the initial test, five samples (6.4%) in the Verigene assay and two samples (2.4%) in the AccuPower assay failed to generate definite results. All retests with both assays generated definitive results. In both assays, the results of CYP2C19 genotyping showed 100% final concordance with those obtained by the direct sequencing method. CONCLUSIONS: These two assays could be useful for the identification of CYP2C19 genotypes in clinical laboratories. PMID- 26427159 TI - [A Prussian in Venice: the botanist Melchior Wieland (1520-1589), pioneer in botanical field research in the Levant]. AB - The Italian physician and botanist Prospero Alpini (1553-1617) is considered as one of the most famous 16th Century Italian botanists having explored the plant species of Egypt and the Near East. Alpinis best-known works as for example De medicina Egyptiorum (Venetijs 1591) or De plantis Aegypti liber (Venetijs 1592), however, wouldn't certainly have been made possible without the influence of his academic teacher, the Prussian physician and botanist Melchior Wieland (ca. 1520 1589), having been applied director of the botanical garden of Padua in 1561. This study is therefore dedicated to the life, academic career, works and reception of this nearly forgotten botanist. PMID- 26427160 TI - [The medical faculty of the Wittenberg University 1502-1817 - the stats of research]. AB - This essay provides an overview of the scientific literature regarding the history of the Faculty of Medicine at the University of Wittenberg, Germany. The University of Wittenberg was the domain, where Martin Luther and Philipp Melanchton worked; in the 16th century it was one of the greatest universities of the Holy Roman Empire. There has been a controversial discussion on the history of the Faculty of Medicine since the mid-19th century. Since the 1980s, it is an accepted and studied field of research on its own. The various publications on the topic can be subdivided into three specific areas: 1. Reformation and medicine, 2. biographic works on professors of medicine, and 3. historical works regarding social and librarian fields of research. The results of those works can be interpreted and merged in view of the Faculty of Medicine. However, for a revalidation of the faculty's role within an European scientific scene further scrutiny of sources is needed. PMID- 26427161 TI - The Historical Discourse on the Etiology of Anorexia Nervosa. Results of a Literature Analysis. PMID- 26427162 TI - Anatomical Modernity in Red Vienna: Textbook for Systematic Anatomy and the Politics of Visual Milieus. PMID- 26427163 TI - [From the history of Roger commentators]. AB - The biblical manuscript A 12, preserved in Duesseldorf's Federal and University Library (Universitaets- und Landesbibliothek Duesseldorf), dates from the mid 13th century. In the course of its scholarly analysis, a piece of parchment was found in the interior board, where a fragment of a surgical text is written on. Judging from the writing, the original manuscript came from southern France (Montpellier) and dates from the late 13th century. Several pas- sages quote "M[agister] W[ilhelmus] de Congenis", but the text bears only a vague resem- blance to Pagel's (1891) and Sudhoff s (1918) editions. Upon the other hand, the author was guided by Roger Frugardi's 'Chirurgia', which presumably gave the structure for Wilhelm's lectures. The edition of the fragmentary text presents a yet unknown example of student notes referring to William of Congenis and illustrates the complex history of Roger commentaries. PMID- 26427164 TI - [An honorable lie: Abderhalden's letter for deletion of Jewish members of the Leopoldina - anticipatory obedience or protective statement?]. AB - In 1938, the president of the German Academy of Scientists Leopoldina, Emil Abderhalden, on his own accord confirmed to the NS-Gauleiter and minister that "to the Academy belong only members who are not Jews" and that the Leopoldina's membership had "already for some time" coincided with contemporary demands. When analysed according to the relevant sources, these exculpatory statements turn out to be intentionally false and, thereby, Abderhalden's only known proven lie, albeit an honourable one since the National Socialist leadership then had no reason to intervene in the Leopoldina's membership affairs. With this letter Abderhalden attempted to suggest that the Leopoldina had always operated in anticipatory obedience--which was not the case in reality. PMID- 26427165 TI - How to Increase Concentration & Focus Using Intention Statements. PMID- 26427166 TI - An Emerging Role for RN's: the RN Primary Care Coordinator. PMID- 26427167 TI - Oklahoma Nurse Practitioners Need Full Practice Authority. PMID- 26427168 TI - Creating a Culture of Innovation. PMID- 26427170 TI - A PHYSICIANS ROLE IN DISMISSING STAFF. PMID- 26427171 TI - FIGHTING BACK. PART 1. Overcome the challenges of independent practice. PMID- 26427173 TI - Improving practice-payer collaboration. PMID- 26427174 TI - PATIENT LANGUAGE BARRIERS: YOU ARE RESPONSIBLE. PMID- 26427175 TI - CLARIFYING INCIDENT-TO BULLING. PMID- 26427176 TI - SETTING UP PATIENT PAYMENT PLANS: WHEN TO USE A THIRD PARTY. PMID- 26427177 TI - Cardiometabolic Syndrome. PMID- 26427179 TI - Suzy. PMID- 26427180 TI - Why physicians must develop a mobile technology strategy. PMID- 26427182 TI - PROTECT YOUR DATA FROM HACKERS IN 5 STEPS. PMID- 26427183 TI - Nuggets of Knowledge and Opportunity. PMID- 26427184 TI - Decreasing Emergency Department Visits and Hospital Admission in the Pediatric Tracheostomy Population. AB - Providing a child with a tracheostomy is often a life saving intervention. However, the impact on the family is frequently life changing. Parents of children with tracheostomies require specialized training in order to provide safe care for their child in the home setting. The purpose of this project was to investigate the outcomes of a parent education program delivered by a nurse practitioner and its impact on patient follow up for children with tracheostomies living at home. This quasi-experimental evidenced based project was based on an intervention group of five parent-child dyads and a control group of 23 parent child dyads. It took place at a local children's hospital. This project compares the number of emergency room visits, inpatient admissions, phone calls and ENT clinic visits between the two groups. A significant increase in the number of phone calls to the clinic was found in the intervention group (p = 0.018). However, there was no significant change in the number of emergency room visits or inpatient admissions in the intervention group. The small number of participants in the intervention group limits the applicability of the results, however clinical significance exists. This study demonstrated that a structured parent education program with scheduled follow up with a nurse practitioner provides a positive impact on the care of the pediatric tracheostomy patient. PMID- 26427186 TI - Diagnostic Considerations of Ultrasound versus Computed Tomography for Pediatric Inflammatory Neck Infections. PMID- 26427185 TI - Children With Sensorineural Hearing Loss And Referral To Early Intervention. AB - OBJECTIVE: Sensorineural hearing loss (SNHL) is identified at a rate of 1-3 per 1,000 newborns in the United States. Timely referral to Early Intervention (EI) services is critical, as early EI referral has been shown to improve outcomes, including speech and language development, social and emotional development, and academic performance. The objective of this study was to determine the rate at which children diagnosed with SNHL at a large tertiary referral center were referred to EI, and, if so, by whom. In addition, we sought to determine the time from the diagnosis of SNHL to the completion of the referral, and what services were received. DESIGN: Prospective observational study METHODS: Data were collected by telephone survey and review of the electronic medical record RESULTS: Children with SNHL were referred to and participated in EI at a high rate. All children in this study (100%) were referred to EI. Most (92%) of the children were referred by 6 months of age, and almost all (98%) participated in EI. CONCLUSION: At our institution, children with SNHL are being consistently referred to EI, meeting the goals of the Early Hearing Detection and Intervention program. Future outcomes research can now be designed to determine whether achieving these benchmark goals improves children's academic performance, expressive and receptive language skills, and development as compared to age matched, normal hearing peers. PMID- 26427187 TI - Case Presentation: Incidental Finding of a Rare Syndrome in 13-Year-Old Girl. PMID- 26427188 TI - A Case Study of Medical and Surgical Management of a Cystic Fibrosis Patient. PMID- 26427190 TI - Commemorating the Anzac nurses. PMID- 26427191 TI - Praise for Christchurch Hospital infection control measures. PMID- 26427192 TI - War memorial honours nurses. PMID- 26427193 TI - Workplace behaviours. PMID- 26427194 TI - HPV immunisation research. PMID- 26427195 TI - The Kaiwhakahaere comments. PMID- 26427196 TI - Celebrations honour caregivers' work. PMID- 26427197 TI - Government to appeal respite carer decision. PMID- 26427198 TI - DHB MECA deal next month. PMID- 26427199 TI - Morale of nurses falling--research. PMID- 26427200 TI - Mental health care 'inequitable'. PMID- 26427201 TI - Nurse appointed to suicide prevention programme. PMID- 26427202 TI - Nurse practitioner heads rural advocacy network. PMID- 26427203 TI - ED waiting time target causing problems. PMID- 26427204 TI - Flu vaccinations now underway. PMID- 26427205 TI - Containing Ebola. Helping nurse and save many patients with the Ebola Virus is a source of much pride for one returning New Zealand nurse. PMID- 26427206 TI - Army nursing service goes to war. PMID- 26427207 TI - Nursing 'our boys' during the Great War. PMID- 26427209 TI - Marking 100 years of military nursing. PMID- 26427208 TI - Making some sense of war. PMID- 26427210 TI - Honouring the Marquette nurses. PMID- 26427211 TI - Electricity in the brain. PMID- 26427212 TI - Pioneering nurse-led clinics enhance patient care. PMID- 26427214 TI - In praise of patient portals. PMID- 26427213 TI - Supporting patients on a life-changing journey. PMID- 26427215 TI - Preserving nursing history. PMID- 26427216 TI - How can unions help achieve effective staffing? PMID- 26427217 TI - Protecting patients with diminished competence. PMID- 26427219 TI - DHB members to consider pay deal. PMID- 26427218 TI - Professionally yours. PMID- 26427220 TI - Responding to member issues. PMID- 26427221 TI - Protecting vulnerable communities. PMID- 26427222 TI - Diabetes: Developing nurse prescribing. PMID- 26427223 TI - Smokefree: Nurse researchers gather in Auckland. PMID- 26427224 TI - Case management's value is finally recognized. What happens now? . AB - In recent years, case management has been recognized as a key in improving healthcare quality and reducing costs, but while hospitals are giving case managers more responsibilities, many administrators are not approving an increase in staff to handle the extra work. Case managers can help their hospital succeed with the Centers for Medicare & Medicaid Services' Value-based Purchasing program, the readmission reduction program, and bundled payments. Case management directors should make sure the hospital's senior leadership understands the roles and responsibilities of case managers and how their interventions can affect outcomes and the bottom line. The number of caseloads depends on the case management model, the responsibilities of case managers, and whether they have assistants or case management extenders who can take over some tasks and allow the licensed staff to work at the top of their licenses. Don't let technology replace communication and patient-centered interactions. PMID- 26427225 TI - There's no magic number for case management caseloads. PMID- 26427226 TI - Case managers just can't do it all alone. PMID- 26427227 TI - Technology is essential today, but there are pitfalls. PMID- 26427228 TI - CASE MANAGEMENT INSIDER. The Top 10 Mistakes You May Be Making In Your Case Management Department! Part 4. AB - We have now completed our review of the top 10 mistakes you may be making in your case management department. I've included tips and strategies for correcting these mistakes if you are facing them in your organization. If you follow these suggestions, you will help to keep your case management practice and your department on track and moving forward! PMID- 26427229 TI - Care management assistants help improve patient flow, care transitions. PMID- 26427230 TI - Community partnerships keep patients safe after discharge. PMID- 26427231 TI - CMS continues its push for quality-based reimbursement. PMID- 26427232 TI - [Hoarding]. AB - Hoarding is a mental disorder having its onset at young age and often worsening with age, manifested as a need of storing up goods to an extent that significantly hampers everyday life. In the light of conducted studies, at least 1 to 2% of the adult population suffers from hoarding. Upon increased compulsive hoarding with aging, problems arise especially for those living alone. Hoarding differs from obsessive-compulsive disorder in its course and treatment response. Treatment of hoarding disorder is based on methods applied in cognitive behavior therapy. PMID- 26427233 TI - [Obesogenic food environment explains most of the obesity epidemic]. AB - The food environment has undergone a considerable chance over the past 30 to 40 years. Availability, variation and low costs increase the consumption of foods. Other changes in the food environment include: increase of the high-energy density foods, increased consumption of sugar-sweetened beverages, large portion sizes, large packages, increased variety, increased visibility of foods, and marketing food to children, all known to augment eating and energy intake. Societies should especially protect children from the obesogenic environment by legislation and other regulations. The main targets should be decreasing the consumption of high-energy density foods and sugar-sweetened beverages and returning the sizes of portions and packages to normal. PMID- 26427234 TI - [Breast lump in a young woman]. AB - While a breast lump in a young woman is almost always benign, the lump may also be caused by breast cancer and rare malignant tumors. Factors increasing the risk of breast cancer, and especially the family history in respect of breast cancer and ovarian cancer should be mapped out from the anamnesis. Clinical examination of both breasts and lymph node regions is carried out in a systematic manner. Benignity of the lump must in all cases be confirmed by imaging and when necessary, by taking a core needle biopsy. Among the benign tumors of the breast, only a small symptomless fibroadenoma confirmed by core needle biopsy does not require an assessment by a surgeon. PMID- 26427235 TI - [Managing aggression and violence associated with psychosis]. AB - Risk for violence in psychosis is associated with the subject's history of early onset antisocial behavior, substance abuse, suicidal ideation, lack of insight, and non-adherence to antipsychotic medication. These risk factors can be managed by effective treatment for psychosis, with the exception of predatory antisocial aggression. Generally, this group of patients is at considerable risk for untreated conditions. There is, however, no pharmacological treatment indicated solely for aggression. Physical violence can often be avoided by alertness and risk monitoring, and by attentive customer service skills. Safety at work is our shared responsibility. PMID- 26427236 TI - [Tick-borne encephalitis in Finland from 2010 to 2012]. AB - The frequency of occurrence of tick-borne encephalitis has increased significantly in Europe and Finland during the past twenty years. There has been a suspicion that the Finnish cases have at least over the last few years been more severe than described in the literature. We analyzed the approximately one hundred cases of tick-borne encephalitis diagnosed in Finland over a three-year period. In two thirds of the patients general physical condition deteriorated clearly, the disease caused permanent disability or the patients required supportive measures in the hospital, such as ventilator therapy. Assessment of the course and severity of the disease would seem to be impossible on the basis of individual symptoms, such as duration of fever. PMID- 26427237 TI - [Respiratory insufficiency due to duplications of the oesophagus]. AB - Duplications of the oesophagus are uncommon congenital malformations with possible occurrence in any part of the gastrointestinal tract. The duplications may be cysts, diverticula or tubular-shaped. Cysts may even occur further away from the gastrointestinal tract, not necessarily having contact with it. I present a patient case, in which a 13-month-old child was brought to the emergency room due to gradually increasing dyspnea. The child made a full recovery after the surgical procedure. PMID- 26427238 TI - "Jeremy Hunt's speech downplayed nurses". PMID- 26427239 TI - Time to be called on unsocial rates. PMID- 26427241 TI - Midwives to be regulated by new system. PMID- 26427240 TI - Health secretary outlines latest move on safe staffing guidance. PMID- 26427242 TI - Race equality rules leave trusts facing 'uncomfortable' truth. PMID- 26427243 TI - New radio series explores state of nurse education. PMID- 26427245 TI - Colchester trust introduces new nursing badge. PMID- 26427244 TI - Rotherham safeguarding review says school nurses overstretched. PMID- 26427246 TI - 'Grave concerns' for hard-won health visitor gains. PMID- 26427247 TI - Nurse-led primary care models could be answer to GP shortage. PMID- 26427248 TI - Nursing team pioneers care home link role. PMID- 26427249 TI - "All staff must know when and how to refer to palliative care". PMID- 26427250 TI - "We need to plan creatively to solve growing healthcare needs". PMID- 26427251 TI - In praise of gerontology. PMID- 26427252 TI - "Nurses must be familiar with acute kidney injury guidelines". PMID- 26427253 TI - Acute kidney injury: prevention and recognition. AB - Acute kidney injury (AKI) is common and often preventable. Nurses should be able to recognise it and respond when it occurs. Through prevention or early detection, nurses can help to reduce morbidity and mortality associated with AKI, improving patients' quality of life and reducing the financial impact of AKI on the NHS. PMID- 26427254 TI - How we are changing mental health nursing. PMID- 26427255 TI - A nurse-led pathway to treat self-harm injuries. AB - Self-harm occurs frequently in psychiatric hospitals and other mental health and outpatient settings. Many patients at the Ayr Clinic are at risk of self-harm and often access the local accident and emergency service for minor injury care. The medical and nursing response to people who repeatedly self-harm, given increasing pressures and dwindling A&E resources, can often be one of impatience, frustration and hostility. A nurse-led pathway was developed by the Ayr Clinic and NHS Ayrshire and Arran to fast-track the assessment and treatment of such injuries and improve health professionals' attitudes towards these patients. This project was winner of the Nursing Times emergency and critical care awrad 2014. PMID- 26427256 TI - Systemic corticosteroids for acute COPD exacerbations. PMID- 26427257 TI - Improving outcomes with online COPD self-care. AB - If self-management was implemented properly, the NHS could save an estimated L235m over the next 10 years. An online self-management system for people with chronic obstructive pulmonary disease allows patients to access information whenever they need it. A comparison of conventional and online approaches to COPD self-management showed the online system is more effective in terms of health status and inhaler technique. PMID- 26427258 TI - Caring for patients with lower limb amputation. AB - In 2014 a National Confidential Enquiry into Patient Outcome and Death report examined the care of people requiring lower limb amputation as a consequence of complications associated with vascular disease or diabetes. It suggests that less than half of patients who undergo surgery receive good care. This article summarises the key findings of the report and the implications for nursing practice. PMID- 26427259 TI - 60 seconds with Liz McCall. PMID- 26427260 TI - Good care is in the blood. PMID- 26427261 TI - Imagining the New NEHA. PMID- 26427262 TI - How Clean Are Hotel Rooms? Part I: Visual Observations vs. Microbiological Contamination. AB - Current evidence of hotel room cleanliness is based on observation rather than empirically based microbial assessment. The purpose of the study described here was to determine if observation provides an accurate indicator of cleanliness. Results demonstrated that visual assessment did not accurately predict microbial contamination. Although testing standards have not yet been established for hotel rooms and will be evaluated in Part II of the authors' study, potential microbial hazards included the sponge and mop (housekeeping cart), toilet, bathroom floor, bathroom sink, and light switch. Hotel managers should increase cleaning in key areas to reduce guest exposure to harmful bacteria. PMID- 26427263 TI - How Clean Are Hotel Rooms? Part II: Examining the Concept of Cleanliness Standards. AB - Hotel room cleanliness is based on observation and not on microbial assessment even though recent reports suggest that infections may be acquired while staying in hotel rooms. Exploratory research in the first part of the authors' study was conducted to determine if contamination of hotel rooms occurs and whether visual assessments are accurate indicators of hotel room cleanliness. Data suggested the presence of microbial contamination that was not reflective of visual assessments. Unfortunately, no standards exist for interpreting microbiological data and other indicators of cleanliness in hotel rooms. The purpose of the second half of the authors' study was to examine cleanliness standards in other industries to see if they might suggest standards in hotels. Results of the authors' study indicate that standards from other related industries do not provide analogous criteria, but do provide suggestions for further research. PMID- 26427264 TI - Prevalence, Knowledge, and Concern About Bed Bugs. AB - Recent research suggests that the resurgence of bed bugs in the U.S. has occurred at an alarming rate. Assumptions have been made that socioeconomic status is not associated with the prevalence of bed bug infestations. Little information is available at the local level, however, about the prevalence of bed bugs in private homes. The authors' pilot study aimed to identify prevalence, knowledge, and concern about bed bugs in one higher income village in Ohio utilizing survey methodology. Responses from 96 individuals who completed the Prevalence, Knowledge, and Concern About Bed Bugs survey were utilized for analysis. The majority of the sample respondents were white and 95% reported that they owned their residence. Only 6% knew someone with bed bugs. Additionally, 52% reported they were somewhat concerned about bed bugs. About 46% reported that they had changed their behavior. For a higher income area, the prevalence was dissimilar to the rate reported in the general public (about 20%). This suggests that bed bugs may be an environmental issue effecting low-income populations disproportionately. Further research is needed in areas of differing socioeconomic levels. PMID- 26427265 TI - Implications of the Fukushima Nuclear Disaster: Man-Made Hazards, Vulnerability Factors, and Risk to Environmental Health. AB - The objective of this article was to examine the environmental health implications of the 2011 Fukushima nuclear disaster from an all-hazards perspective. The authors performed a literature review that included Japanese and international nuclear guidance and policy, scientific papers, and reports on the Chernobyl and Three Mile Island disasters while also considering all-hazards preparedness rubrics in the U.S. The examination of the literature resulted in the following: a) the authors' "All-Hazards Planning Reference Model" that distinguishes three planning categories-Disaster Trigger Event, Man-Made Hazards, and Vulnerability Factors; b) the generalization of their model to other countries; and c) advocacy for environmental health end fate to be considered in planning phases to minimize risk to environmental health. This article discusses inconsistencies in disaster planning and nomenclature existing in the studied materials and international guidance and proposes new opportunity for developing predisaster risk assessment, risk communication, and prevention capacity building. PMID- 26427266 TI - What Is a Diplomate, and What Does It Do? PMID- 26427267 TI - Equipping Environmental Health Workers With Environmental Assessment Tools. PMID- 26427268 TI - A Millennial's Take on CDC's Environmental Public Health Tracking Network. PMID- 26427269 TI - Outraged, Obligated, & Optimistic. PMID- 26427270 TI - Should Substituted Decision-making Be Abolished? PMID- 26427271 TI - Advance Directives in Some Western European Countries: A Legal and Ethical Comparison between Spain, France, England, and Germany. AB - We have studied national laws on advance directives in various Western European countries: Romance-speaking countries (Italy, France, Portugal, and Spain), English-speaking countries (Ireland and the United Kingdom), and German-speaking countries (Austria, Germany, and Switzerland). We distinguish two potentially complementary types of advance medical declaration: the 'living will' and the nomination of a legal proxy. After examining the similarities and differences between countries, we analyse in detail the legislation of four countries (Spain, France, England, and Germany), since the other countries in this survey have similar legal principles and/or a similar political approach. In conclusion, we note that in all the countries examined, advance directives have been seen as an instrument to enable the patient's right to self-determination. Notwithstanding, in Romance-speaking countries, the involvement of physicians in the end-of-life process and risks arising from the execution of advance directives were also considered. PMID- 26427272 TI - Medical Liability: The Current State of Italian Legislation. PMID- 26427273 TI - Use of Force for Medical Purposes--A Danish Perspective. PMID- 26427274 TI - European Court of Human Rights. ECHR 2015/15 Case of Ilievska v. The Former Yugoslav Republic of Macedonia, 7 May 2015, no. 20136/11 (First Section). PMID- 26427275 TI - European Court of Human Rights. ECHR 2015/16 Case of Lambert and Others v. France, 5 June 2015, no. 46043/14 (Grand Chamber). PMID- 26427276 TI - European Court of Justice. ECJ 2015/05, Geoffrey Leger v. Ministre des Affaires sociales, de la Sante et des Droits des femmes, Etablissement francais du sang, 29 April 2015 (c-528/13). PMID- 26427277 TI - [A literature review on the Messerer's fracture]. AB - The characteristic wedge-shaped fracture was first described by Messerer (1880) and Bruns (1884) after performing experiments on long bones. Not much later, Messerer (1885) formulated the forensic significance of the direct bending fracture for the detection of the location and direction of blunt impact trauma. He developed the basic biomechanical theory of the origin of this fracture type, which is therefore called Messerer's fracture in the German-speaking world. In the following decades, the findings concerning the origin, specificity and forensic usability of Messerer's fractures were confirmed and supplemented by experiments and case studies. For forensic examinations, it is important to bear in mind that there are exceptions to the rule according to which the level of the wedge-shaped fracture corresponds exactly to the point of impact. The possibility of "false" or "reversed" wedges must also be considered. Already in the 19th century, authors had pointed out the mechanism of indirect formation of wedge shaped bone fragments. That is why a forensic examination always has to consider the investigation results and medical findings in their entirety. Autopsy of traffic victims is of paramount importance. It must include a thorough examination of clothing, skin, soft tissues and skeletal system using special preparation techniques. The examination of bone injuries in living victims also requires special expertise. If properly applied, valuable results can be obtained by the forensic expert from the wedge-shaped fracture. Until recently, Messerer's fracture was a typical injury sustained by pedestrians hit by vehicles with protruding frontal elements. In modern car production, not only the dimensions of cars have been changed, but the front-end structures have also been modified, e. g. by integrated bumpers. These constructional changes are likely to reduce the frequency of narrow points of impact in collisions. However, further research on the frequency and significance of Messerer's fractures in road traffic accident victims is required. PMID- 26427278 TI - [Reddish discoloration of the vascular intima in charred bodies]. AB - During the autopsy of fire victims, one often sees intensive reddening of the inner vascular layers resembling changes due to putrefaction. To determine the frequency of this phenomenon and the circumstances under which it occurs, in particular the presence of putrescence, signs of vitality and the extent of destruction by the fire, the fire fatalities autopsied at the Institutes of Legal Medicine in Freiburg, Halle and Wurzburg were analyzed. In the concrete study, 259 fire deaths were investigated retrospectively and 21 prospectively. The study material included 191 males and 68 females aged 0 to 93 years. Vital exposure to the fire was found in 70%, perimortal exposure in 23 % and postmortem exposure in 7% of the cases. Red discoloration of the intima of the central vessels was seen in 106 victims (41%). This finding is most likely caused by postmortem heat induced hemolysis, which occurs when the temperature in the body rises above 52 degrees C due to the effect of external heat. Therefore, a reddish discoloration of the intima cannot be regarded as sign of vitality. PMID- 26427279 TI - [Diuretics and their potential effect on breath-alcohol concentration--a case report]. AB - Many objections were raised to breath-alcohol analysis upon its introduction in the field of traffic law enforcement in Germany, but in the meantime this issue has become less relevant in forensic routine work. In the present case, the defending lawyer claimed that the ethanol concentration in the blood and hence in the breath of his client, which was 0.35 mg/l according to the Drager Alcotest 7110(r) Evidential and thus above the legal limit of 0.25 mg/l, had been changed by diuretics taken 4 hours before the breath alcohol test, viz. 10 mg of torasemide, a loop diuretic, and 50 mg of spironolactone, a competitive aldosterone antagonist. According to the literature, the maximum urinary output in healthy subjects within the first 4 hours after 10 mg torasemide was 1450 ml. In patients suffering from heart failure, the urinary volume was reduced by a factor of 2.5-3; after chronic intake of torasemide, water loss did not differ from placebo. Spironolactone, which acts on the distal tubule, has little effect on urinary output. In a publication, the loss of water in excess within 24 hours was 90 ml. Co-administration of 100 mg spironolactone and 20 mg furosemide, which roughly compares to 10 mg torasemide, resulted in a mean urinary volume of 1566 ml within the first 4 hours. In terms of the reported case and provided that no compensatory fluid had been taken, a purely theoretical maximum shift of 0.007 mg/ may occur in the breath-alcohol concentration due to the smaller distribution volume even considering maximum urinary excretion values. On the other hand, already mild levels of dehydration may be associated with negative symptoms affecting driving ability. PMID- 26427280 TI - [Peranal exenteration of the intestine during a homicide]. AB - A 66-year-old female alcoholic was killed in a sexually motivated homicide. After peranal insertion of the hand large parts of the intestine were torn from the mesentery and pulled out through the anus. The findings are discussed and compared with the pertinent literature. PMID- 26427281 TI - [Wrong statement of manner of death after insufficient post-mortem examination]. AB - When death certificates already completed are submitted during forensic post mortem examinations or autopsies, blatant errors are often found, especially with regard to the classification of the manner of death. This is partly attributable to insufficient knowledge of the classification criteria, but also to the fact that the post-mortem examination was not properly performed and even clear signs of unnatural death (e.g. a strangulation mark or sharp force injuries) are overlooked. To avoid such misinterpretations, a thorough reformation of the post mortem examination system and a regular continuing specialized training of the physicians performing post-mortems seem necessary. PMID- 26427282 TI - [Sexual assault during sleep: victim asleep/offender asleep--an update]. AB - The topic of sexual assault during sleep is discussed again on the basis of two case reports and several incidents published in the media. The authors support the assumption of Hohner and Pusche1 (2011). There is evidence that it is indeed possible not to wake up during a sexual assault--even without being under the influence of alcohol, illicit drugs or medication--and that a sexual assault during sleep can pass unnoticed. In such cases the outcome of the criminal trial often depends on the careful assessment of the expert, as the faculty of imagination of those passing judgment varies greatly. Based on new findings regarding sexsomnia, even sexual offenders may use the "sleepwalking defense" in specific cases. PMID- 26427283 TI - REVISED: Accreditation with Follow-up Survey and Preliminary Denial of Accreditation Decision Processes for Organizations Undergoing Resurvey. PMID- 26427284 TI - APPROVED: New Optional Perinatal Care Certification Program. PMID- 26427285 TI - New Speak Up Video Educates Patients on Preparing for Surgery. PMID- 26427286 TI - APPOINTED: Executive Vice President for Division of Healthcare Quality Evaluation. PMID- 26427287 TI - REVISED: Accreditation Decisions for Organizations Undergoing Initial Surveys. PMID- 26427288 TI - [Gram positive multi-drug resistance: what probability and fear?]. AB - Antibiotic resistance in Gram-positive bacteria already has a significant impact on morbidity and mortality. The situation is particularly alarming in the case of methicillin-resistant Staphylococcus aureus and glycopeptide-resistant Enterococcus faecium, which have shown an ability to spread to new ecological niches and to generate new clones with both increased drug resistance and increased virulence. The potential for genetic exchanges between these two species raises the specter of highly resistant and virulent S. aureus strains. PMID- 26427289 TI - [Innovative treatments for multidrug-resistant bacteria]. AB - The spread of multidrug-resistant bacteria has accelerated sharply in the last decade. According to the World Health Organization they are responsible for an estimated 25 000 deaths in Europe each year. In addition, few new antibiotics are under development, raising the spectrum of a return to the "pre-antibiotic era". Non antibiotic antibacterial agents have recently attracted renewed interest. The most promising candidates are: i) phages (bacteria-infecting viruses) have been widely used in Eastern European countries since the 1930s but come up against logistic and regulatory obstacles due to the evolutionary nature of these biologic agents, while convincing clinical data are lacking; ii) bacteriocines are smallantibacterialpeptidesproducedby numerous bacteria; some have a rapid bactericidal effect, good tolerability, and a limited impact on the commensal flora; however, clinical use of bacteriocines is complicated by their fragility, poor penetration, and substantial risk of resistance selection ; iii) antisense oligonucleo tides act by inactivating genes through specific interaction with a complementary DNA or RNA fragment, potentially allowing specific inhibition of selected bacterial virulence factors. However, this therapeutic class may be more suitable for viral or genetic diseases than for multidrug-resistant bacterial infections, owing to the difficulty of delivering them inside bacteria. PMID- 26427290 TI - [Anomalous aortic origin of coronary arteries: a frequent and curable cause of sudden death]. AB - Anomalous aortic origin of coronary arteries is a congenital heart defect in which one coronary artery arises from the opposite sinus (the left coronary artery from the right coronary sinus, or the right coronary artery from the left sinus). The initial segment of the abnormal artery courses between the great arteries and is usually located within the aortic wall. These anomalies are far from rare, affecting 0.1% to 0.3% of the population, and carry a high risk of sudden cardiac death. It is thought that the main mechanism of cardiac death is external compression of the abnormal coronary artery between the great arteries as they expand during strenuous exercise. The risk of sudden death is particularly high in patients with an anomalous left coronary artery or associated anatomic lesions (stenotic intramural segment, slit-like deformation of the ostium), and also in young athletes. A common presentation is sudden unexplained death. The diagnosis can be made by echocardiographic examination. Silent myocardial ischemia must be sought, with stress echocardiography and stress nuclear imaging. Various surgical techniques have been described. Our own technique involves the creation of a neo-ostium in the appropriate sinus. Surgical treatment is relatively safe and provides satisfactory results, most patients having no residual myocardial ischemia under stress. Surgery is recommended for all patients with an anomalous left coronary artery, regardless of symptom status, as well as for symptomatic patients with an anomalous right coronary artery (aborted sudden death, symptoms under stress, myocardial ischemia under stress). Because of the incidence and severity of these anomalies, careful echocardiographic evaluation should be performed routinely, at least in young athletes. PMID- 26427291 TI - [Future of implantable electrical cardiac devices]. AB - Major improvements in implantable electrical cardiac devices have been made during the last two decades, notably with the advent of automatic internal defibrillation (ICD) to prevent sudden arrhythmic death, and cardiac resynchronisation (CRT) to treat the discoordinated failing heart. They now constitute a major therapeutic option and may eventually supersede drug therapy. The coming era will be marked by a technological revolution, with improvements in treatment delivery, safety and efficacy, and an expansion of clinical indications. Leadless technologyfor cardiac pacemakers and defibrillators is already in the pipeline, endovascular leads currently being responsible for most long-term complications (lead failure, infection, vein thrombosis, etc.). Miniaturized pacemakers based on nanotechnology can now be totally implanted inside the right ventricle through the transvenous route, thus eliminating leads, pockets and scarring In the same way, totally subcutaneous ICD systems are now available, although they are currently only capable of delivering shocks, without pacing (including antitachycardia pacing). In CRT optimised delivery is important to improve clinical responses and to reduce the non-response rate (around 30 % with current technology). Endocardial left ventricular pacing could be a solution if it can be achieved at an acceptable risk. Multisite ventricular pacing is an alternative. Besides CRT neuromodulation, especially by vagal stimulation, is another important field of device researchfor heart failure. Preliminary clinical results are encouraging. PMID- 26427292 TI - [Cardiac rehabilitation: physiologic basis, beneficial effects and contraindications]. AB - Cardiac rehabilitation can reduce morbidity and mortality cost-effectively among patients with many types of cardiovascular disease yet is widely underutilized. Rehabilitation is helpful not only for patients who have had myocardial infarction but also for those with stable angina or congestive heart failure and those who have undergone myocardial revascularization, transplantation, or valve surgery. The beneficial effects of rehabilitation include a reduction in mortality from cardiovascular disease, improved exercise tolerance, and fewer cardiac symptoms. This method includes improved risk factor management, more successful smoking cessation, better psychosocial well-being, and an increased likelihood of return to work. Rehabilitation requires a multidisciplinary team focusing on therapeutic education, individually tailored exercise, and optimization of functional status and mental health. Current research trends in this area include the evaluation of new secondary prevention modalities and alternatives such as home-based rehabilitation. PMID- 26427293 TI - [Benefits and indications of rehabilitation for coronary heart diseases]. AB - Cardiac rehabilitation (CR) is an essential element in the treatment of coronary artery disease. It can be conducted on an inpatient or ambulatory basis in cardiac rehabilitation units and includes complementary exercise training and a therapeutic patient education (TPE) program. Rehabilitation can reduce the occurrence of serious cardiac events and provide better control of cardiovascular risk factors. All epidemiological surveys show that this approach is beneficial: multidisciplinary care reduces mortality after myocardial infarction and improves cardiac patients' lifestyles. Rehabilitation centers are the only structures able to conduct 3- to 4-week program of cardiac training and TPE. Unfortunately, the number of patients who participate in such programs is still too low, and cardiac rehabilitation centers are underutilized (32 % in the French cohort of the EUROASPIRE III study and about 15 % of all coronary patients). This situation is regrettable, as all registers and epidemiological surveys have confirmed the capacity of CR to improve exercise tolerance, the ischemic threshold, and secondary prevention. PMID- 26427294 TI - [Cannabis in France, new insights]. AB - France holds the record for cannabis use in Europe, especially among adolescents. This drug of abuse is thus mainly used during a very sensitive period of brain development, education, vehicle driving and development of life projects. In addition, synthetic derivatives of tetrahydrocannabinol (THC), which are more noxious than cannabis itself are now appearing on the market. Traficking and cultivation for personnal use have intensified; products proposed for sale are richer in THC; and some methods of consumption (e-cigarettes, vaporizers, water pipes) increase the supply of THC to the lungs and thence to the body and brain. It is in this context that attempts are being made to legalize this drug of abuse. Other attempts are made to disguise it as a medication. Meanwhile, the list of its psychic as well as physical damages grows longer, with some very severe cases of major injuries. This evolution takes place in spite of numerous warnings expressed by the French Academy of Medicine. Subsequently, it is prompted to carefully and vigorously denounce these events. This will be the aim of this thematic session. PMID- 26427295 TI - [Neurobiology of endocannabinoids and central effects of tetrahydrocannabinol contained in indian hemp]. AB - Tetrahydrocannabinol, the main psychotropic component of Cannabis indica, is an addictive drug with multiple effects including both peripheral and central damages. All these effects are due to interference with endocannabinoidergic transmission. This endocannabinoid system subtly regulates many physiologicalfunctions. This regulation involves various ligands derived from arachidonic acid (anandamide, di-arachidonoylglycerol, virodhamin, noladin ether, N arachidonoyl dopamine, etc.) which stimulate two main types of receptor CB1 in the central nervous system and CB2 in the periphery. CB1 receptors are very numerous and ubiquitous in the brain. They influence various important functions (awakening, attention, delirium, hallucinations, memory, cognition, anxiety, humor stability, motor coordination, brain maturation, etc.). Far from mimicking endocannabinoids, THC caricatures their effects. It affects all brain structures, simultaneously, intensely and durably, inducing down-regulation of CB1 receptors and thereby reducing the effects of their physiological ligands. On account of its exceptional lipophilia, THC accumulates for days and even weeks in the brain. It is not a soft drug but rather a slow drug: its abuse induces long-lasting modifications and deterioration of brain function, potentially leading to various mental and psychiatric disorders. PMID- 26427296 TI - [Tetrahydrocannabinol pharmacokinetics; new synthetic cannabinoids; road safety and cannabis]. AB - Delta-9-tetrahydrocannabinol (THC) is the main psychoactive ingredient of cannabis, a drug which is commonly smoked This paper focuses on the pharmacokinetics of THC. The average THC content in cannabis plant material has risen by a factor offour over the past 20 years, from 4% to 16%. This increase has important implications not only for the pharmacokinetics but also for the pharmacology of THC The mean bioavailability of THC in smoked cannabis is about 25%. In a cigarette containing 3.55% of THC, a peak plasma level of about 160 ng/mL occurs approximately 10 min after inhalation. THC is quickly cleared from plasma in a multiphasic manner and is widely distributed to tissues, leading to its pharmacologic effects. Body fat is a long-term storage site. This particular pharmacokinetic behavior explains the lack of correlation between the THC blood level and clinical effects, contrary to ethanol. The main THC metabolites are 11 OH-THC (the only active metabolite) and THC-COOH, which is eliminated in feces and urine over several weeks. Therefore, abstinence can be established by analyzing THC-COOH in urine, while blood THC analysis is used to confirm recent exposure. Cannabis is the main illicit drug found among vehicle drivers. Various traffic safety studies indicate that recent use of this drug at least doubles the risk of causing an accident, and that simultaneous alcohol consumption multiplies this risk by afactor of 14. Since 2009, synthetic cannabinoids have emerged on the illicit drug market. These substances act on the same CB1 receptors as THC, but with higher afinity. Their pharmacokinetics differs from that of THC, as they are metabolized into multiple derivatives, most of which are more active than THC itself. PMID- 26427297 TI - [Cannabis-induced cognitive and psychiatric disorders]. AB - Several studies have shown that Delta-9-THC the main psychoactive constituent of cannabis, can impair cognitive functions, especially attention, episodic memory, working memory and executive functions. These impairments have been related to the duration, frequency, dose and age at onset of cannabis use. Cognitive deficits may disappear with abstinence, but abnormalities may be long-lasting in subjects who began smoking cannabis before age 15. The lifetime prevalence of cannabis use disorders is about 1% in the general population. The main characteristics of cannabis use disorders are craving, persistent desire or unsuccessful efforts to cut down or control cannabis use, and persistent avoidance of familial, social occupational or recreational activities because of cannabis use. Nine prospective longitudinal studies in the generalpopulation have shown that cannabis use is associated with a two-fold increase in the risk of psychotic disorders, particularly schizophrenia, compared to controls. The risk of psychosis increases in a dose-related fashion. A higher risk of schizophrenia is predicted by earlier onset of cannabis use. The effects of cannabis are exerted primarily through THC interaction with cannabinoid (CB) 1 receptors in the brain. Cannabis exposure may disrupt the last steps of brain maturation, through the endocannabinoid system, thereby increasing the risk of psychosis during adolescence. PMID- 26427298 TI - [Cannabis use among children and adolescents: impacts and consequences]. AB - A health policy for the prevention and treatment of cannabis-related disorders is urgently needed in France, given the high prevalence of cannabis use among children and adolescents. Such a policy will require a better understanding of the endo-cannabinoid system and the impact of exogenous cannabinoids in this fragile population. The brain continues to undergo significant development until the age of about 25 years, and cannabis consumption by young people therefore carries specific risks of dependence (frequency and intensity), and of neuroanatomical, cognitive and emotional damage. This article summarizes the available data and offers a medical view of the risks and consequences of cannabis use by children and adolescents. PMID- 26427300 TI - Family group conferencing in dementia care: an exploration of opportunities and challenges. AB - BACKGROUND: The Family Group Conference (FGC) is an approach to partnership working which brings together service users, their support network and care professionals in a family-led decision making forum. Evidence, though limited, indicates that that FGC can enhance outcomes for service providers and their users. This study aimed to evaluate the impact of the pilot FGC service, delivered to people with dementia and their families, in terms of the experience of care provision by families and care professionals involved in the project. METHODS: Focus group interviews were conducted with families and professionals participating in the pilot intervention. RESULTS: FGC was perceived as having the potential to positively impact service users, their families, service providers and the wider culture of care. However, despite an overall positive evaluation the participants identified a number of challenges related to service implementation. Both the opportunities and challenges identified in this study are discussed in the context of the existing international evidence base. CONCLUSIONS: This study contributes to a better understanding of the applicability of FGC as a strategy to support people with dementia and their families. Although promising in terms of potential outcomes for service users and providers, FGC presents challenges which need to be carefully managed in order to secure maximum benefit to all parties. PMID- 26427299 TI - [Issues surrounding the preservation and subsequent use of transsexual persons' gametes]. AB - Some transsexual persons wish to have their gametes frozen before gender transition, in order to preserve their fertility. This measure should be carried out, in strict compliance with the law, in case of orchidectomy, oophorectomy or hysterectomy However, as hormonal treatments do not irreversibly alter gonadal function, the reproductive capacity of trans-sexual persons can be maintained by avoiding surgical sterilization. There is therefore no obvious medical indication for cryopreserving gametes or germinal tissue in the absence of surgical sterilization. Moreover, the use of such cryopreserved gametes would, in principle, be considered mainly by a same-sex couple, something that French law currently prohibits. Regardless of these legal aspects, the issues surrounding the use of cryopreserved gametes, and its consequences, must not be ignored. If transsexual persons who are already parents may find ways of managing the change in both their personal and parental identity, the use of gametes stored prior to gender transition raises issues of identity whose consequences are difficult to assess, especially for the future child. Cryopreservation of gametes or germinal tissue cannot be undertaken without first considering whether their potential use is in keeping with what is, at present, medically and legally possible. In any case, it is up the physician to decide, on a case by case basis, whether or not to implement cryopreservation, taking into account the situation of the persons who request the procedure and their plans for parenthood. PMID- 26427301 TI - A Comparison of the Use of Glottal Fry in the Spontaneous Speech of Young and Middle-Aged American Women. AB - OBJECTIVES/HYPOTHESIS: To compare vocal fry use in spontaneous speech of young and middle-aged American women. STUDY DESIGN: This is a cross-sectional study. METHODS: Subjects were 40 American women; 20 aged 18-25 years (mean = 22.9 years) and 20 aged 35-50 years (mean = 43.4 years). Participants were asked to describe all the steps involved in making a peanut butter and jelly sandwich and in doing laundry. Acoustical analysis of selected parameters and sentence position of vocal fry occurrences were performed. The acoustic parameters analyzed were mean, minimum and maximum fundamental frequency (F0), glottal fry/minute ratio, and sentence position of glottal fry. RESULTS: Values of minimum fundamental frequency clearly show that there was vocal fry in the participants' spontaneous speech samples. The average minimum F0 was 74.0 Hz (standard deviation [SD] = 5.6) for the younger women and 73.10 Hz (SD = 6.7) for the middle-aged women (P = 0.527). The mean glottal fry for the medial position and for the final position was similar for both groups. The mean glottal fry/minute ratio for young women was 13.8 (SD = 7.0), whereas for middle-aged women was 11.3 (SD = 7.5; P = 0.402). This study showed that all participants had at least one episode of glottal fry in their spontaneous speech sample. CONCLUSIONS: Both groups presented with vocal fry in their spontaneous speech, showing that vocal fry is present in the speech of young and middle-aged women. PMID- 26427302 TI - Three-dimensional ultrasound using the VOCAL technique for estimation of reference values of fetal thigh volume in normally grown Egyptian fetuses from 20 to 41 weeks. AB - OBJECTIVE: To establish the normal reference values for the fetal thigh volume (FTV) of normally grown Egyptian fetuses using three-dimensional (3D) virtual organ computer aided analysis (VOCAL) method. PATIENTS AND METHODS: A total of 334 Egyptian pregnant women carrying a singleton living normally grown fetus between the 20th and the 41st weeks of gestation were enrolled in this cross sectional study. FTV was measured using the 3D VOCAL method with 30 degrees rotation. Estimated fetal weight (EFW) was calculated based on Hadlock formula. RESULTS: FTV correlated strongly with gestational age (r = 0.921, p < 0.001) and EFW (r = 0.891, p < 0.001). For clinical application, a nomogram of growth percentiles of FTV was produced. CONCLUSION: Reference values of FTV between 20th and 41st weeks of gestation in normally grown Egyptian fetuses were provided using the 3D VOCAL method. These data may be helpful to assess fetal growth and to diagnose deviation from normal. PMID- 26427303 TI - Diffuse intestinal ganglioneuromatosis in the adult. PMID- 26427304 TI - Measurement of cardiac index and stroke volume using electrical cardiometry before and after administration of adenosine in a 6-year-old patient with supraventricular tachycardia. AB - We report the case of a 6-year-old boy who developed a supraventricular tachycardia during an upper endoscopy while under general anesthesia. A noninvasive electrical cardiometry device was applied to the patient, and cardiac index and stroke volume were measured before and after the administration of adenosine. Cardiac index fell 41% (P < .0001) after adenosine was given, highlighting the known interdependence between cardiac output and heart rate in the pediatric patient. Stroke volume decreased 9% (P = .0002) after adenosine arrested the tachycardia, lending support to an increasing body of data that suggests that heart rate itself can augment contractility. PMID- 26427305 TI - Length of postanesthetic care unit stay in elderly patients after general anesthesia: a randomized controlled trial comparing desflurane and sevoflurane. AB - OBJECTIVE: The purpose of this study was to compare the length of postanesthetic care unit (PACU) stay and recovery profiles of elderly patients after general anesthesia between sevoflurane and desflurane. DESIGN: Randomized, double-blind, controlled clinical trial. SETTING: Tertiary care hospital, university hospital. PATIENTS: Eighty elderly patients undergoing nonemergency surgery under general anesthesia. INTERVENTION: Patients were randomly allocated into 2 groups: sevoflurane group (n = 38) and desflurane group (n = 42) in a double-blind manner. All of the patients underwent general anesthesia with oral endotracheal intubation using the same induction, muscle relaxants, and narcotics medication. When the operation was finished, the volatile agent was discontinued and muscle relaxation was reversed. MEASUREMENT: The length of PACU stay was recorded as the primary outcome. The recovery profiles (time to open eyes, time to follow to commands, and time to extubation) were assessed. MAIN RESULTS: There was no significance between the groups in age, sex, body mass index, American Society of Anesthesiologists physical status, type of surgery, duration of anesthesia, perioperative use of fentanyl, or blood loss. The length of PACU stay was not significantly different in the patients who recovered from sevoflurane (49.4 +/- 23.1 minutes) or desflurane (50.1 +/- 25.8 minutes) general anesthesia. Desflurane was significantly associated with faster early recovery than sevoflurane measured by time to open eyes (7.5 +/- 3.4 vs 9.6 +/- 4.6 minutes) and time to follow commands (9.0 +/- 3.3 vs 11.2 +/- 5.1 minutes), respectively. CONCLUSION: Desflurane was more associated with a faster early recovery (time to open the eyes and follow commands) than sevoflurane in elderly patients after general anesthesia. However, the length of PACU stay was similar in both groups. PMID- 26427306 TI - Effects of vacuum suctioning and strategic drape tenting on oxygen concentration in a simulated surgical field. AB - STUDY OBJECTIVE: To investigate the isolated and combined effects of vacuum suctioning and strategic drape tenting on oxygen concentration in an experimental setting. DESIGN: Experimental. SETTING: Clinical simulation center of a university-affiliated hospital. PARTICIPANTS: Mannequin simulation of a patient undergoing facial surgery under sedation anesthesia. Supplemental oxygen was delivered via nasal cannula. INTERVENTIONS: Vacuum suctioning and strategic drape tenting. MEASUREMENTS: The experimental trials entailed measuring oxygen concentration around the nasal cannula continuously either in the presence or absence of a standard operating room vacuum suction system and strategic tenting of surgical drapes. The primary outcome was the time required for oxygen concentration to reach 21%. MAIN RESULTS: In the control group (without suction or strategic tenting), a mean time of 180 seconds elapsed until the measured oxygen concentration reached 21% after cessation of oxygen delivery. Use of a vacuum suction device alone (110 seconds; P < .01) or in combination with strategic tenting (110 seconds; P < .01) significantly reduced this time. No significant benefit was seen when tenting was used alone (160 seconds; P < .30). CONCLUSION: Use of a vacuum suction device during surgery will lower local oxygen concentration, and this in turn may decrease the risk of operating room fires. Although strategic tenting of surgical drapes has a theoretical benefit to decreasing the pooling of oxygen around the surgical site, further investigation is necessary before its routine use is recommended. PMID- 26427307 TI - A comparison of ultrasound alone vs ultrasound with nerve stimulation guidance for continuous femoral nerve block in patients undergoing total knee arthroplasty. AB - STUDY OBJECTIVE: To compare analgesic efficacy of ultrasound (US) guidance alone and US guidance combined with nerve stimulation (NS) for continuous femoral nerve block (CFNB) in patients undergoing total knee arthroplasty (TKA). DESIGN: Prospective, randomized double-blind trial. SETTING: Postanesthesia care unit and general ward. PATIENTS: Fifty American Society of Anesthesiologist physical status I to II patients undergoing TKA under spinal anesthesia. INTERVENTIONS: In group A (n = 25), an 18-gauge Tuohy needle was directed at the lower mid-part of the femoral nerve, and a nonstimulating catheter was inserted through the needle under US guidance. In group B (n = 25), an 18-gauge Tuohy needle and stimulating catheter were directed to the lower part of femoral nerve under US guidance, and quadriceps muscle contraction was checked using NS. All patients received a 20-mL loading dose of 0.2% ropivacaine, a continuous infusion of 4 mL/h, and a 4-mL bolus of 0.2% ropivacaine with a lockout time of 60 minutes for patient controlled analgesia. MEASUREMENTS: The primary outcome was resting and exercising pain quality assessed by numeric rating scale. Other outcomes included procedure time for correct catheter placement, block failure rate, patient satisfaction for postoperative pain control, total dose of local anesthetic, additional opioid requirement, and adverse effects postoperatively. MAIN RESULTS: There were no significant differences between groups in resting and exercising numeric rating scale. Procedure times were longer in group B than group A (P < .05). There were no significant differences between groups in block failure rate or other outcomes. CONCLUSIONS: US-guided CFNB was associated with similar analgesic efficacy and block failure rate and reduced procedure time compared to US with NS guidance for CFNB in patients undergoing TKA. PMID- 26427308 TI - Possible missed diagnosis of Ureaplasma spp infection in a case of fatal hyperammonemia after repeat renal transplantation. PMID- 26427309 TI - The impact of watching educational video clips on analogue patients' physiological arousal and information recall. AB - OBJECTIVE: Investigating the influence of watching three educational patient provider interactions on analogue patients' emotional arousal and information recall. METHODS: In 75 analogue patients the emotional arousal was measured with physiological responses (electrodermal activity and heart rate) and self-reported arousal. RESULTS: A moderate increased level of physiological arousal was measured but not too much to inflict emotional distress. Recall of information was within the pursued range. CONCLUSION: Hence, physiological arousal is not expected to hinder the goals we pursue with our online intervention. PRACTICE IMPLICATIONS: Still, developers and researchers should remain attentive to the self-reported (conscious) and hidden (subconscious) emotions evoked by the content of educational video clips presented in self-help interventions. A moderate increased level of arousal is preferred to increase the learning capacity. However, too much arousal may decrease the learning capacity and may cause distress, which should obviously be avoided for ethical reasons. PMID- 26427310 TI - Keep Europe alive. PMID- 26427312 TI - Electrochemical Sensor for Lead Cation Sensitized with a DNA Functionalized Porphyrinic Metal-Organic Framework. AB - An efficient electrochemical sensor was presented for lead cation detection using a DNA functionalized iron-porphyrinic metal-organic framework (GR-5/(Fe-P)n-MOF) as a probe. The newly designed probe showed both the recognition behavior of GR-5 to Pb(2+) with high selectivity and the excellent mimic peroxidase performance of (Fe-P)n-MOF. In the presence of Pb(2+), GR-5 could be specifically cleaved at the ribonucleotide (rA) site, which produced the short (Fe-P)n-MOF-linked oligonucleotide fragment to hybridize with hairpin DNA immobilized on the surface of screen-printed carbon electrode (SPCE). Because of the mimic peroxidase property of (Fe-P)n-MOF, enzymatically amplified electrochemical signal was obtained to offer the sensitive detection of Pb(2+) ranging from 0.05 to 200 nM with a detection limit of 0.034 nM. In addition, benefiting from the Pb(2+) dependent GR-5, the proposed assay could selectively detect Pb(2+) in the presence of other metal ions. The SPCE based electrochemical sensor along with the GR-5/(Fe-P)n-MOF probe exhibited the advantages of low-cost, simple fabrication, high sensitivity and selectivity, providing potential application of on-site and real-time Pb(2+) detection in complex media. PMID- 26427311 TI - Antibacterial and protein-repellent orthodontic cement to combat biofilms and white spot lesions. AB - OBJECTIVES: White spot lesions are the most undesired side-effect of fixed orthodontic treatments. The objectives of this study were to combine nanoparticles of silver (NAg) with 2-methacryloyloxyethyl phosphorylcholine (MPC) to develop a modified resin-modified glass ionomer cement (RMGI) as orthodontic cement with double benefits of antibacterial and protein-repellent capabilities for the first time. METHODS: NAg and MPC were incorporated into a commercial RMGI. Another commercial orthodontic adhesive also served as control. Enamel shear bond strengths (SBS) were determined. Protein adsorption was measured via a micro bicinchoninic acid method. A dental plaque microcosm biofilm model with human saliva as inoculum was tested. Biofilms adherent on the cement samples and planktonic bacteria in the culture medium away from the cement surfaces were both evaluated for bacterial metabolic activity, colony-forming units (CFU), and lactic acid production. RESULTS: Adding 0.1% NAg and 3% MPC to RMGI, and water aging for 30 days, did not adversely affect the SBS, compared to the unmodified RMGI control (p>0.1). The modified RMGI containing 0.1% NAg and 3% MPC achieved the greatest reduction in protein adsorption, bacterial adhesion, CFU, metabolic activity and lactic acid production. The RMGI containing 0.1% NAg and 3% MPC inhibited not only the bacteria on its surface, but also the bacteria away from the surface in the culture medium. CONCLUSIONS: The incorporation of double agents (antibacterial NAg+protein-repellent MPC) into RMGI achieved much stronger inhibition of biofilms than using each agent alone. The novel antibacterial and protein-repellent RMGI with substantially-reduced biofilm acids is promising as an orthodontic cement to combat white spot lesions in enamel. PMID- 26427313 TI - Socio-economic inequalities in tobacco-related diseases in Portugal: an ecological approach. AB - OBJECTIVES: The existence of socio-economic (SE) inequalities in smoking is well demonstrated, but less is known about its consequences. This study measures SE inequalities in the prevalence of tobacco-related diseases (TRD) in Portugal, using a new area-based SE indicator. STUDY DESIGN: Ecological study. METHODS: In patient data were used to identify TRD discharges at all Portuguese NHS hospitals for the year 2011. The definition of TRD incorporates malignant cancers, cardiovascular diseases, cerebrovascular diseases and respiratory diseases. We created an area-based SE indicator on the basis of census data, using factor analyses. The association between the prevalence of TRD and the SE indicators was measured using Generalized Linear Models. The spatial correlation of this indicator was assessed using variograms. RESULTS: Two area-based SE factors were identified at the parish level, reflecting (i) social position (education and occupation); and (ii) deprivation (overcrowding and manual occupations). Upper social-class areas were associated with a lower prevalence of malignant cancers, cardiovascular, and respiratory diseases. CONCLUSION: We found significant inequalities in TRDs across Portuguese parishes using a newly created area-based SE indicator reflecting several SE dimensions. This result emphasizes that inequalities in smoking are reflected in inequalities in health, and should be tackled through equality-oriented area-based tobacco policies. PMID- 26427314 TI - Beyond the Golden Era of public health: charting a path from sanitarianism to ecological public health. AB - The paper considers the long-term trajectory of public health and whether a 'Golden Era' in Public Health might be coming to an end. While successful elements of the 20th century policy approach need still to be applied in the developing world, two significant flaws are now apparent within its core thinking. It assumes that continuing economic growth will generate sufficient wealth to pay for the public health infrastructure and improvement needed in the 21st century when, in reality, externalised costs are spiralling. Secondly, there is evidence of growing mismatch between ecosystems and human progress. While 20th century development has undeniably improved public health, it has also undermined the capacity to maintain life on a sustainable basis and has generated other more negative health consequences. For these and other reasons a rethink about the role, purpose and direction of public health is needed. While health has to be at the heart of any viable notion of progress the dominant policy path offers new versions of the 'health follows wealth' position. The paper posits ecological public health as a radical project to reshape the conditions of existence. Both of these broad paths require different functions and purposes from their institutions, professions and politicians. The paper suggests that eco-systems pressures, including climate change, are already adding to pressure for a change of course. PMID- 26427315 TI - The need to improve implementation and use of lifestyle surveillance systems for planning prevention activities: an analysis of the Italian Regions. AB - OBJECTIVES: To describe the level of use of lifestyle surveillance systems in Italy and to identify predictors of their use by the Italian Regions for planning and monitoring purposes. STUDY DESIGN: Data were extracted from the 19 Regional Prevention Plans (RPPs) and the health promotion and prevention projects included in them developed by the Italian Regions within the National Prevention Plan 2010 2013. METHODS: The 19 RPPs and the 702 projects were appraised using a tool specifically developed for the purpose. Multiple logistic regression was performed to identify predictors of use of surveillance systems in the 359 projects that could use them. RESULTS: The analysis of regional epidemiological contexts does not always rely upon surveillance system data and there were too few projects aimed at the maintenance and the development of these systems. Moreover, fewer than half of projects that could have used surveillance systems for planning and evaluation procedures actually did so, despite the potential value of these data. There was a statistically significant association between Regional Health Care Expenditure (RHCE) and the use of surveillance system data for planning and/or evaluation of the projects (OR 7.81, 95% CI 2.86-21.29). CONCLUSIONS: Use of surveillance systems for regional prevention planning in Italy is not optimal due to late implementation, presence of different data collecting systems and RGDP inequalities. There is a pressing need for full implementation of surveillance systems to allow better definition of the priorities and objectives of public health interventions. PMID- 26427316 TI - Functional characterization of 12 allelic variants of CYP2C8 by assessment of paclitaxel 6alpha-hydroxylation and amodiaquine N-deethylation. AB - Cytochrome P450 2C8 (CYP2C8) is one of the enzymes primarily responsible for the metabolism of many drugs, including paclitaxel and amodiaquine. CYP2C8 genetic variants contribute to interindividual variations in the therapeutic efficacy and toxicity of paclitaxel. Although it is difficult to investigate the enzymatic function of most CYP2C8 variants in vivo, this can be investigated in vitro using recombinant CYP2C8 protein variants. The present study used paclitaxel to evaluate 6alpha-hydroxylase activity and amodiaquine for the N-deethylase activity of wild-type and 11 CYP2C8 variants resulting in amino acid substitutions in vitro. The wild-type and variant CYP2C8 proteins were heterologously expressed in COS-7 cells. Paclitaxel 6alpha-hydroxylation and amodiaquine N-deethylation activities were determined by measuring the concentrations of 6alpha-hydroxypaclitaxel and N-desethylamodiaquine, respectively, and the kinetic parameters were calculated. Compared to the wild type enzyme (CYP2C8.1), CYP2C8.11 and CYP2C8.14 showed little or no activity with either substrate. In addition, the intrinsic clearance values of CYP2C8.8 and CYP2C8.13 for paclitaxel were 68% and 67% that of CYP2C8.1, respectively. In contrast, the CLint values of CYP2C8.2 and CYP2C8.12 were 1.4 and 1.9 times higher than that of CYP2C8.1. These comprehensive findings could inform for further genotype-phenotype studies on interindividual differences in CYP2C8 mediated drug metabolism. PMID- 26427317 TI - Editorial for the Special Issue: Toxins 2015 proceedings. PMID- 26427318 TI - Synergistic effect of artocarpin on antibacterial activity of some antibiotics against methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. AB - CONTEXT: Antibacterial resistance has dramatically increased and resulted in serious health problems worldwide. One appealing strategy to overcome this resistance problem is the use of combinations of antibacterial compounds to increase their potency. OBJECTIVE: The objective of this study is to determine the synergistic effects of artocarpin for ampicillin, norfloxacin, and tetracycline against methicillin-resistant Staphylococcus aureus (MRSA) as well as the Gram-negative bacteria Pseudomonas aeruginosa and Escherichia coli. MATERIALS AND METHODS: A broth microdilution method (1.95-250 ug/mL) was used to determine the minimum inhibitory concentration (MIC) of artocarpin and the antibiotics. Any synergistic effects were evaluated at their own MIC using the checkerboard method and a time-kill assay at 37 degrees C for 24 h. RESULTS AND DISCUSSION: Artocarpin showed antibacterial activity against MRSA and E. coli with an MIC value of 62.5 ug/mL, and against P. aeruginosa with an MIC value of 250 ug/mL. The interaction of artocarpin with all tested antibiotics produced synergistic effects against MRSA with a fractional inhibitory concentration index (FICI) of 0.15-0.37. In addition, a combination of artocarpin and norfloxacin showed a synergistic effect against E. coli with an FICI value of 0.37, while the combinations of artocarpin and tetracycline as well as artocarpin and norfloxacin exhibited synergy interactions against P. aeruginosa with FICI values of 0.24 and 0.37, respectively. Time-kill assays indicated that artocarpin enhanced the antimicrobial activities of tetracycline, ampicillin, and norfloxacin against MRSA as well as Gram-negative bacteria. PMID- 26427319 TI - Quantitative Assessment of Cardiac Function in Fetuses of Women with Maternal Gestational Thyroid Dysfunction Using VVI Echocardiography. AB - BACKGROUND: The study aimed to investigate the clinical value of velocity vector imaging (VVI) in assessing heart function in fetuses of pregnant women with thyroid dysfunction. The inter-observer and intra-observer variability was assessed for all VVI parameters observed. MATERIAL AND METHODS: The participants were enrolled from singleton pregnant women with gestational ages ranging 24+0 to 40+1 weeks who visited the Department of Obstetrics and Gynecology at the Affiliated Hospital of Qingdao University, China, for prenatal care from July 2011 to February 2014. Digital 2-dimensional (2D) dynamic 4-chamber images of the heart were collected. A total of qualified 226 images from 125 fetuses of pregnant women with normal thyroid (control group), 64 fetuses of pregnant women with hypothyroidism (hypothyroidism group), and 37 fetuses of pregnant women with hyperthyroidism (hyperthyroidism group) were interrogated offline using VVI software. The echocardiographic parameters including the myocardium peak systolic velocity (Vs), peak diastolic velocity (Vd), peak systolic strain (S), peak systolic strain rate (SRs), peak diastolic strain rate (SRd) of RV and LV, were obtained from the velocity curves of 2D myocardial motion. The heart rate was measured using a virtual M-mode algorithm built into the software. RESULTS: The study found that the longitudinal Vs and Vd of both ventricles in the control group gradually decreased from basal segments to apical segments and significantly increased over the gestation. S, SRs, and SRd of both ventricles remained stable after middle gestation. Compared with the control group, the hypothyroidism and hyperthyroidism groups exhibited significantly reduced S, SRs, and SRd, even for fetuses at 24-weeks gestation. There were no significant differences in global Vs and global Vd between the control group and the hyperthyroidism or hypothyroidism groups. CONCLUSIONS: The thyroid dysfunction of pregnant women may damage fetal heart function, and VVI could be a sensitive technique to measure the variation of fetal heart function. PMID- 26427320 TI - Speedy standing wave design of size-exclusion simulated moving bed: Solvent consumption and sorbent productivity related to material properties and design parameters. AB - Size-exclusion simulated moving beds (SEC-SMB) have been used for large-scale separations of linear alkanes from branched alkanes. While SEC-SMBs are orders of magnitude more efficient than batch chromatography, they are not widely used. One key barrier is the complexity in design and optimization. A four-zone SEC-SMB for a binary separation has seven material properties and 14 design parameters (two yields, five operating parameters, and seven equipment parameters). Previous optimization studies using numerical methods do not guarantee global optima or explicitly express solvent consumption (D/F) or sorbent productivity (PR) as functions of the material properties and design parameters. The standing wave concept is used to develop analytical expressions for D/F and PR as functions of 14 dimensionless groups, which consist of 21 material and design parameters. The resulting speedy standing wave design (SSWD) solutions are simplified for two limiting cases: diffusion or dispersion controlled. An example of SEC-SMB for insulin purification is used to illustrate how D/F and PR change with the dimensionless groups. The results show that maximum PR for both diffusion and dispersion controlled systems is mainly determined by yields, equipment parameters, material properties, and two key dimensionless groups: (1) the ratio of step time to diffusion time and (2) the ratio of diffusion time to pressure limited convection time. A sharp trade off of D/F and PR occurs when the yield is greater than 99%. The column configuration for maximum PR is analytically related to the diffusivity ratio and the selectivity. To achieve maximum sorbent productivity, one should match step time, diffusion time, and pressure-limited convection time for diffusion controlled systems. For dispersion controlled systems, the axial dispersion time should be about 10 times the step time and about 50 times the pressure-limited convection time. Its value can be estimated from given yields, material properties, and column configuration. Among the material properties, selectivity and particle size have the largest impact on D/F and PR. Particle size and 14 design parameters can be optimized for minimum D/F, maximum PR, or minimum cost on a laptop computer. PMID- 26427321 TI - Gas chromatography with tandem differential mobility spectrometry of fatty acid alkyl esters and the selective detection of methyl linolenate in biodiesels by dual-stage ion filtering. AB - Alkyl esters of fatty acids (FAAEs) with carbon numbers from 8 to 20 formed protonated monomers and proton bound dimers through atmospheric pressure chemical ionization reactions and these gas ions were characterized for their field dependent mobility coefficients using differential mobility spectrometry (DMS). Separation of ion peaks with a vapor modifier was achieved for ions with masses of 317-1033 Da though the differences in these coefficients and the resolution of ion peaks decreased proportionally with increased ion mass. Differences in dispersion curves were sufficient to isolate ions from specific FAAEs in the effluent of a gas chromatograph by dual stage ion filtering using a tandem DMS detector. Methyl linolenate was isolated from nearby eluting methyl oleate, methyl stearate and methyl linoleate within analysis times of 10s without measureable complications from charge suppression in the ion source or leakage in filtering of ions with close proximity of dispersion behavior. PMID- 26427322 TI - Reversed-phase chromatography in extended-nano space for the separation of amino acids. AB - In this work we used reversed-phase chromatography in extended-nano channels to separate amino acids. A hydrophobic surface modification of extended-nano channels was established. A sample mixture of fluorescein and sulforhodamine B (0.5 and 0.05mM respectively) was used for the demonstration of a reversed-phase separation mode. A small amount of sample band (30fL) was injected into the separation channel, and two compounds were successfully separated. The maximum theoretical plate number of sulforhodamine B was 300,000plates/m. Two sets of 3 amino acids (3.75mM each) were separated using 0.01M citrate buffer (pH 5.5) with 0.01M sodium perchlorate and 12 and 25% of acetonitrile as a mobile phase. A successful separation (320,000plates/m with plate height of 3.2MUm for serine) was accomplished. PMID- 26427323 TI - Evaluation of multistep derivatization methods for identification and quantification of oxygenated species in organic aerosol. AB - Two, 3-step methods for derivatizing mono- and multi-functional species with carbonyl (CO), carboxylic acid (-COOH), and alcohol (-OH) moieties were compared and optimized. In Method 1, the CO, -COOH, and -OH moieties were converted (1) to methyloximes (R-CN-OCH3) with O-methylhydroxylamine hydrochloride (MHA), (2) to methyl esters (OC-R-OCH3) with (trimethylsilyl)diazomethane in methanol (TMSD/MeOH), and (3) to trimethylsilyl ethers [R-OSi(CH3)3] with N,O bis(trimethylsilyl)-trifluoroacetamide (BSTFA) containing 1% trimethylchlorosilane (TMCS), respectively. Steps 1 and 3 of both methods were identical; however, in Step 2 of Method 2, -COOH moieties were derivatized with 10% (v/v) boron trifluoride (BF3) in MeOH or n-butanol (n-BuOH). The BF3/MeOH and BF3/n-BuOH were ineffective at converting species with more than 2-OH moieties. Average standard deviations for derivatization of 36 model compounds by the 3 step methods using TMSD/MeOH and BF3/(MeOH) were 7.4 and 14.8%, respectively. Average derivatization efficiencies for Methods 1 and 2 were 88.0 and 114%, respectively. Despite the lower average derivatization efficiency of Method 1, distinct advantages included a greater certainty of derivatization yield for the entire suite of mono- and multi-functional species and fewer processing steps for sequential derivatization. Detection limits for Method 1 using GC*GC-ToF-MS were 0.3-54pgm(-3). Approximately 100 oxygenated organic species were identified and quantified in aerosol filtered from 39m(3) of air in an urban location. Levels of species were 0.013-17ngm(-3) and were nearly all above the Method 1 limit of detection. PMID- 26427324 TI - An improved design of spiral tube assembly for separation of proteins by high speed counter-current chromatography. AB - A new spiral tube assembly was designed to improve the column capacity and partition efficiency for protein separation. This spiral tube assembly has greater column capacity than the original tubing because of an increase in radial grooves from 4 to 12 to accommodate more spiral layers and 12 narrow spots instead of 4 in each circular loop to interrupt the laminar flow that causes sample band broadening. Standard PTFE tubing (1.6mm ID) and the modified flat twisted tubing were used as the separation column. The performances of both assemblies were compared for separating three stable test proteins including cytochrome c, myoglobin, and lysozyme using a two phase aqueous-aqueous solvent system composed of polyethylene glycol 1000 (12.5% w/w) and dibasic potassium phosphate (12.5% w/w). All samples were run at 1, 2, 3, and 5mL/min at both 800rpm and 1000rpm. The separation of these three protein samples produced high stationary phase retentions at 1, 2, and 3mL/min, yet separated efficiently at 5mL/min in 40min. After comparing the separation efficiency in terms of the peak resolutions, theoretical plate numbers, and separation times, it was determined that the flat-twisted tubing was more effective in separating these protein samples. In order to validate the efficacy of this novel assembly, a mixture of five protein samples (cytochrome c, myoglobin, ovalbumin, lysozyme, and hemoglobin) were separated, under the optimal conditions established with these three protein samples, at 1mL/min with a revolution speed of 1000rpm. There were high stationary phase retentions of around 60%, with effective separations, demonstrating the efficiency of the flat-twisted spiral tube assembly. The separation time of 6h was a limitation but can potentially be shortened by improving the strength of the column that will permit an increase in revolution speed and flow rate. This novel spiral separation column will allow rapid and efficient separation of mixtures with high yield of the constituent components. PMID- 26427325 TI - Imidazole-free purification of His3-tagged recombinant proteins using ssDNA aptamer-based affinity chromatography. AB - Immobilized metal ion affinity chromatography (IMAC) is widely used for the purification of many different His6-tagged recombinant proteins. On the one hand, it is a powerful technique but on the other hand it has its disadvantages. In this report, we present the development of a unique ssDNA aptamer for the purification of His3-tagged recombinant proteins. Our study shows that stability of the His3-tag/H3T aptamer complex can be controlled by the sodium ion concentration. Based on this feature, we demonstrate that H3T aptamer resin was successfully employed for the purification of three out of four tested His3 tagged recombinant proteins from an E. coli total protein extract using imidazole free buffers. Finally, we show that the purity of His3-tagged proteins is superior when purified with the help of the H3T aptamer in comparison with Ni-NTA resin. PMID- 26427326 TI - Simultaneous determination of fluoroquinolones in environmental water by liquid chromatography-tandem mass spectrometry with direct injection: A green approach. AB - This work describes an on-line multi-residue method for simultaneous quantification of ciprofloxacin, enrofloxacin, gemifloxacin, moxifloxacin, norfloxacin and ofloxacin in superficial and wastewater samples. For that, an octyl restricted-access media bovine serum albumin column (RAM-BSA C8) was used for sample clean-up, enrichment and analysis with quantitation carried out by tandem mass spectrometry. For water samples volumes of only 500MUL the method provided good selectivity, extraction efficiency, accuracy, and precision with quantification limits in the order of 20-150ngL(-1). Out of the six fluoroquinolones only ciprofloxacin (195ngL(-1)) and norfloxacin (270ngL(-1)) were quantified in an influent sample of the wastewater treatment plant (WWTP) of Sao Carlos (SP, Brazil). None were found in the superficial water samples analyzed. The capability of injecting native sample in an automated mode provides high productivity and represents a greener approach in environmental sample analysis. PMID- 26427327 TI - Characterization of goat colostrum oligosaccharides by nano-liquid chromatography on chip quadrupole time-of-flight mass spectrometry and hydrophilic interaction liquid chromatography-quadrupole mass spectrometry. AB - A detailed qualitative and quantitative characterization of goat colostrum oligosaccharides (GCO) has been carried out for the first time. Defatted and deproteinized colostrum samples, previously treated by size exclusion chromatography (SEC) to remove lactose, were analyzed by nanoflow liquid chromatography-quadrupole-time of flight mass spectrometry (Nano-LC-Chip-Q-TOF MS). Up to 78 oligosaccharides containing hexose, hexosamine, fucose, N acetylneuraminic acid or N-glycolylneuraminic acid monomeric units were identified in the samples, some of them detected for the first time in goat colostra. As a second step, a hydrophilic interaction liquid chromatography coupled to mass spectrometry (HILIC-MS) methodology was developed for the separation and quantitation of the main GCO, both acidic and neutral carbohydrates. Among other experimental chromatographic conditions, mobile phase additives and column temperature were evaluated in terms of retention time, resolution, peak width and symmetry of target carbohydrates. Narrow peaks (wh: 0.2-0.6min) and good symmetry (As: 0.8-1.4) were obtained for GCO using an acetonitrile:water gradient with 0.1% ammonium hydroxide at 40 degrees C. These conditions were selected to quantify the main oligosaccharides in goat colostrum samples. Values ranging from 140 to 315mgL(-1) for neutral oligosaccharides and from 83 to 251mgL(-1) for acidic oligosaccharides were found. The combination of both techniques resulted to be useful to achieve a comprehensive characterization of GCO. PMID- 26427328 TI - Analysis of black pepper volatiles by solid phase microextraction-gas chromatography: A comparison of terpenes profiles with hydrodistillation. AB - Solid phase microextraction (SPME) is widely used in food flavor compounds analysis in majority for profiling volatile compounds. Based on such profiles conclusions are often drawn concerning the percentage composition of volatile compounds in particular food, spices or raw materials. This paper focuses on the usefulness of SPME for the profiling of volatile compounds from spices using black pepper as an example. SPME profiles obtained in different analytical conditions were compared to the profile of pepper volatiles obtained using hydrodistillation in Clevenger apparatus. The profiles of both monoterpenes and sesquiterpenes of black pepper were highly dependent on sample weight (0.1 and 1g samples were tested), and extraction time (durations from 2 to 120min were tested), regardless of the SPME fiber used (PDMS and CAR/PDMS coatings were used). The characteristic phenomenon for extraction from dry ground pepper was the decrease of monoterpenes % share in volatiles with increasing extraction times, whereas at the same time the % contents of sesquiterpenes increased. Addition of water to ground pepper substantially changed extraction kinetics and mutual proportions of mono to sesquiterpenes compared to dry samples by minimizing changes in mono- to sesquiterpenes ratio in different extraction times. Obtained results indicate that SPME can be a fast extraction method for volatiles of black pepper. Short extraction times (2-10min) in conjunction with the fast GC analysis (2.1min) proposed here may offer fast alternative to hydrodistillation allowing black pepper terpenes characterization. PMID- 26427330 TI - Medicinal leech therapy: New life for an ancient treatment. PMID- 26427331 TI - Melioidosis in the non-endemic setting: Not only in diabetic travelers returning from Southeast Asia. PMID- 26427333 TI - Correction: Highly regio- and stereoselective synthesis of alkenylboronic esters by copper-catalyzed boron additions to disubstituted alkynes. AB - Correction for 'Highly regio- and stereoselective synthesis of alkenylboronic esters by copper-catalyzed boron additions to disubstituted alkynes' by Hye Ryung Kim et al., Chem. Commun., 2011, 47, 2943-2945. PMID- 26427332 TI - Self-criticism in therapist training: A grounded theory analysis. AB - OBJECTIVE: The primary objective of this study is to engender an understanding of how therapists-in-training experience and cope with self-criticism in the context of their clinical training and therapy experiences. METHOD: In this study, trainees were interviewed about their experience of self-criticism related to psychotherapy practice and these interviews were subjected to a grounded theory analysis generating a core self-critical process. RESULTS: The analysis highlighted the vulnerability of self-criticism in therapists' training experiences, especially when they related to balancing the "expert" role while maintaining authentic interactions with their clients. The results also described ways in which self-criticism is mitigated by a sense of interpersonal safety and the provision of clinical freedom and flexibility in therapists' training. CONCLUSIONS: The implications for future psychotherapy research and clinical training within clinical training environments are discussed. PMID- 26427329 TI - Small molecule therapeutics targeting F-box proteins in cancer. AB - The ubiquitin proteasome system (UPS) plays vital roles in maintaining protein equilibrium mainly through proteolytic degradation of targeted substrates. The archetypical SCF ubiquitin E3 ligase complex contains a substrate recognition subunit F-box protein that recruits substrates to the catalytic ligase core for its polyubiquitylation and subsequent proteasomal degradation. Several well characterized F-box proteins have been demonstrated that are tightly linked to neoplasia. There is mounting information characterizing F-box protein-substrate interactions with the rationale to develop unique therapeutics for cancer treatment. Here we review that how F-box proteins function in cancer and summarize potential small molecule inhibitors for cancer therapy. PMID- 26427335 TI - Identification of a novel HLA-B*46:01 variant, HLA-B*46:01:20, in a Taiwanese unrelated hematopoietic stem cell donor. AB - One nucleotide replacement at residue 528 of HLA-B*46:01:01 results in a new allele, HLA-B*46:01:20. PMID- 26427334 TI - A common promoter hypomethylation signature in invasive breast, liver and prostate cancer cell lines reveals novel targets involved in cancer invasiveness. AB - Cancer invasion and metastasis is the most morbid aspect of cancer and is governed by different cellular mechanisms than those driving the deregulated growth of tumors. We addressed here the question of whether a common DNA methylation signature of invasion exists in cancer cells from different origins that differentiates invasive from non-invasive cells. We identified a common DNA methylation signature consisting of hyper- and hypomethylation and determined the overlap of differences in DNA methylation with differences in mRNA expression using expression array analyses. A pathway analysis reveals that the hypomethylation signature includes some of the major pathways that were previously implicated in cancer migration and invasion such as TGF beta and ERBB2 triggered pathways. The relevance of these hypomethylation events in human tumors was validated by identification of the signature in several publicly available databases of human tumor transcriptomes. We shortlisted novel invasion promoting candidates and tested the role of four genes in cellular invasiveness from the list C11orf68, G0S2, SHISA2 and TMEM156 in invasiveness using siRNA depletion. Importantly these genes are upregulated in human cancer specimens as determined by immunostaining of human normal and cancer breast, liver and prostate tissue arrays. Since these genes are activated in cancer they constitute a group of targets for specific pharmacological inhibitors of cancer invasiveness. SUMMARY: Our study provides evidence that common DNA hypomethylation signature exists between cancer cells derived from different tissues, pointing to a common mechanism of cancer invasiveness in cancer cells from different origins that could serve as drug targets. PMID- 26427336 TI - Novel Chiral Bifunctional L-Thiazoline-Thiourea Derivatives: Design and Application in Enantioselective Michael Reactions. AB - Several novel chiral bifunctional L-thiazoline-thiourea derivatives were easily synthesized from commercially available L-cysteine in high yield. These catalysts were subsequently applied to the enantioselective Michael addition of acetylacetone to beta-nitrostyrenes. The products with S configuration were obtained in 98% enantiomeric excess (ee) when the L-thiazoline-thiourea derivatives were used. A plausible transition state model is proposed to explain the observed enantioselectivities. PMID- 26427337 TI - Rare k-mer DNA: Identification of sequence motifs and prediction of CpG island and promoter. AB - Empirical analysis on k-mer DNA has been proven as an effective tool in finding unique patterns in DNA sequences which can lead to the discovery of potential sequence motifs. In an extensive study of empirical k-mer DNA on hundreds of organisms, the researchers found unique multi-modal k-mer spectra occur in the genomes of organisms from the tetrapod clade only which includes all mammals. The multi-modality is caused by the formation of the two lowest modes where k-mers under them are referred as the rare k-mers. The suppression of the two lowest modes (or the rare k-mers) can be attributed to the CG dinucleotide inclusions in them. Apart from that, the rare k-mers are selectively distributed in certain genomic features of CpG Island (CGI), promoter, 5' UTR, and exon. We correlated the rare k-mers with hundreds of annotated features using several bioinformatic tools, performed further intrinsic rare k-mer analyses within the correlated features, and modeled the elucidated rare k-mer clustering feature into a classifier to predict the correlated CGI and promoter features. Our correlation results show that rare k-mers are highly associated with several annotated features of CGI, promoter, 5' UTR, and open chromatin regions. Our intrinsic results show that rare k-mers have several unique topological, compositional, and clustering properties in CGI and promoter features. Finally, the performances of our RWC (rare-word clustering) method in predicting the CGI and promoter features are ranked among the top three, in eight of the CGI and promoter evaluations, among eight of the benchmarked datasets. PMID- 26427338 TI - Effect of walking speed on the gait of king penguins: An accelerometric approach. AB - Little is known about non-human bipedal gaits. This is probably due to the fact that most large animals are quadrupedal and that non-human bipedal animals are mostly birds, whose primary form of locomotion is flight. Very little research has been conducted on penguin pedestrian locomotion with the focus instead on their associated high energy expenditure. In animals, tri-axial accelerometers are frequently used to estimate physiological energy cost, as well as to define the behaviour pattern of a species, or the kinematics of swimming. In this study, we showed how an accelerometer-based technique could be used to determine the biomechanical characteristics of pedestrian locomotion. Eight king penguins, which represent the only family of birds to have an upright bipedal gait, were trained to walk on a treadmill. The trunk tri-axial accelerations were recorded while the bird was walking at four different speeds (1.0, 1.2, 1.4 and 1.6km/h), enabling the amplitude of dynamic body acceleration along the three axes (amplitude of DBAx, DBAy and DBAz), stride frequency, waddling and leaning amplitude, as well as the leaning angle to be defined. The magnitude of the measured variables showed a significant increase with increasing speed, apart from the backwards angle of lean, which decreased with increasing speed. The variability of the measured variables also showed a significant increase with speed apart from the DBAz amplitude, the waddling amplitude, and the leaning angle, where no significant effect of the walking speed was found. This paper is the first approach to describe 3D biomechanics with an accelerometer on wild animals, demonstrating the potential of this technique. PMID- 26427339 TI - Liver Contrast-Enhanced Ultrasound Improves Detection of Liver Metastases in Patients with Pancreatic or Periampullary Cancer. AB - The aim of this study is to provide a diagnostic performance evaluation of contrast-enhanced ultrasonography (CEUS) in detecting liver metastases in patients with suspected of pancreatic or periampullary cancer. Computed tomography (CT) is often insufficient for detection of liver metastases, but their presence plays a crucial role in the choice of therapy. Eighty-nine patients with suspected pancreatic or periampullary cancer were included in this prospective study with retrospective analysis. Patients underwent an abdominal CT and CEUS. Fifteen patients had liver metastases. The CT sensitivity was 73.3% (11/15), the specificity 93.2% (69/74), the positive predictive value (PPV) 68.8% (11/16) and the negative predictive value (NPV) 94.6% (69/73). Based on CEUS, the sensitivity was 80% (12/15), specificity 98.6% (73/74), PPV 92.3% (12/13) and NPV 96.1% (73/76). CEUS improved characterization of liver lesions in patients with suspected pancreatic or periampullary cancer compared with CT. CEUS can better detect benign liver lesions and distinguish false-positive or indeterminate CT results. PMID- 26427340 TI - Polypropylene/Polyaniline Nanofiber/Reduced Graphene Oxide Nanocomposite with Enhanced Electrical, Dielectric, and Ferroelectric Properties for a High Energy Density Capacitor. AB - This work demonstrates a ternary nanocomposite system, composed of polypropylene (PP), redoped PANI (r-PANI) nanofibers, and reduced graphene oxides (RGOs), for use in a high energy density capacitor. r-PANI nanofibers were fabricated by the combination methods of chemical oxidation polymerization and secondary doping processes, resulting in higher conductivity (sigma~156 S cm(-1)) than that of the primarily doped PANI nanofibers (sigma~16 S cm(-1)). RGO sheets with high electron mobility and thermal stability can enhance the conductivity of r PANI/RGO (sigma~220 S cm(-1)) and thermal stability of PP matrix. These findings could be extended to combine the advantages of r-PANI nanofibers and RGO sheets for developing an efficient means of preparing PP/r-PANI/RGO nanocomposite. When the r-PANI/RGO cofillers (10 vol %) were added to PP matrix, the resulting PP/r PANI/RGO nanocomposite exhibited high dielectric constant (epsilon'~51.8) with small dielectric loss (epsilon"~9.3*10(-3)). Furthermore, the PP/r-PANI/RGO nanocomposite was used for an energy-harvesting device, which demonstrated high energy density (Ue~12.6 J cm(-3)) and breakdown strength (E~5.86*10(3) kV cm( 1)). PMID- 26427341 TI - Therapeutic education and self-care: Results from the cross-sectional study Diabetes, Attitudes, Wishes and Needs 2 (DAWN2) in Spain. AB - INTRODUCTION: Therapeutic education (TE) has been gradually introduced progressively into diabetes mellitus care programs with the aim of providing patients and their families or caregivers with the necessary skills for the self management of the disease. The Diabetes Attitudes, Wishes and Needs 2 (DAWN2) study helps to clarify what are the unmet needs with regards to self-management and the TE offer available to patients and their families. The objective of this paper is to analyse the results of the DAWN2 study regarding self-care habits and participation in TE activities in Spain. METHODS: The DAWN2 is an observational, cross-national study. In this paper, an analysis was performed on the Spanish sample of diabetic patients (502) and family members (123). RESULTS: Patients report taking their medications as recommended by their doctor an average of 6.4 days/week, and self-monitor their blood glucose an average of 3.4 days/week. The large majority (86%) of patients with diabetes mellitus type 1, 59% of patients with diabetes mellitus type 2, and 21% of family members state to have participated in education activities. CONCLUSIONS: Diabetes educators should reinforce the messages about the benefits of self-care, particularly for patients who are in the early stages of the disease. Likewise, access for family members and people with diabetes mellitus type 2 to TE programs should be improved, and these programs for diabetic patients and their families should be included in the services portfolio of health centres. PMID- 26427342 TI - Chemical contaminants in surficial sediment in Coral and Fish Bays, St. John, U.S. Virgin Islands. AB - Land based sources of pollution have the potential to negatively impact coral reef ecosystems. Many coral systems, including environmentally sensitive marine protected areas, do not have assessments of their chemical contaminant status (magnitude and extent). Without a status assessment, it is impossible to measure change in a system. This study presents surficial sediment data from Coral and Fish Bays (St. John, US Virgin Islands (USVI)). Portions of these bays are included in Virgin Islands National Park, and Virgin Islands Coral Reef National Monument. A suite of analytes (PCBs, PAHs, pesticides, heavy metals, butyltins) was quantified and compared against other regional data and against previously published sediment quality guidelines (SQG). Contamination from toxic contaminants in the system was generally low when compared to other similar studies and potential toxicity thresholds (SQG). Exceptions to this were copper and total chlordane which exceeded the Effects Range Low (ERL) sediment quality guideline, indicating possible sediment toxicity. This assessment will be useful to coastal managers for tracking environmental change, and ensuring that this marine protected area remains relatively free from toxic contamination. PMID- 26427343 TI - Cognitive control during sentence generation. AB - Sentence generation involves selecting the right words out of multiple co activated representations for the right utterance positions. This selection process is hypothesized to involve cognitive control. Previous research has linked cognitive control during language processing to regions within the frontal lobe, including the anterior cingulate cortex (ACC) and left ventrolateral prefrontal cortex (VLPFC). We examined the neural correlates of word and sentence generation to determine whether these cognitive control regions were activated more for sentences than words. We also manipulated the phonological overlap between nouns in the sentence to determine whether cognitive control recruitment increased under phonological competition. Whole-brain analysis revealed increased activation in the ACC and bilateral frontal cortex for sentences over words. Region of interest analysis revealed an effect of phonological competition within the ACC. Psychophysiological interaction (PPI) analysis further showed that functional connectivity within a task-maintenance network increased under phonological competition. These results suggest a role for conflict detection and monitoring during sentence generation, which is consistent with a theoretical framework incorporating domain-general cognitive control processes into language processing. PMID- 26427344 TI - Effects of Maternal Stress During Pregnancy on Birth Outcome and Stress-related Hormones. PMID- 26427346 TI - Stable Co-Catalyst-Free Photocatalytic H2 Evolution From Oxidized Titanium Nitride Nanopowders. AB - A simple strategy is used to thermally oxidize TiN nanopowder (~20 nm) to an anatase phase of a TiO2:Ti(3+):N compound. In contrast to the rutile phase of such a compound, this photocatalyst provides activity for hydrogen evolution under AM1.5 conditions, without the use of any noble metal co-catalyst. Moreover the photocatalyst is active and stable over extended periods of time (tested for 4 months). Importantly, to achieve successful conversion to the active anatase polymorph, sufficiently small starting particles of TiN are needed. The key factor for catalysis is the stabilization of the co-catalytically active Ti(3+) species against oxidation by nitrogen present in the starting material. PMID- 26427347 TI - Identification of a Lead Candidate in the Search for Carbene-Stabilised Homoaromatics. AB - The effect of carbenes as Lewis donor groups on the homoaromaticity of mono- and bicyclic organic molecules is surveyed. The search for viable carbene-stabilised homoaromatics resulted in a large amount of rejected candidates as well as nine promising candidates that are further analysed for their homoaromaticity by using a number of metrics. Of these, five appeared to show modest homoaromaticity, whereas another compound showed a level of homoaromaticity comparable with the homotropylium cation benchmark compound. Isoelectronic analogues and constitutional isomers of the lead compound were investigated, however, none of these showed comparable homoaromaticity. The implications of these calculations on the design of donor-stabilised homoaromatics are discussed. PMID- 26427345 TI - A cell-free expression and purification process for rapid production of protein biologics. AB - Cell-free protein synthesis has emerged as a powerful technology for rapid and efficient protein production. Cell-free methods are also amenable to automation and such systems have been extensively used for high-throughput protein production and screening; however, current fluidic systems are not adequate for manufacturing protein biopharmaceuticals. In this work, we report on the initial development of a fluidic process for rapid end-to-end production of recombinant protein biologics. This process incorporates a bioreactor module that can be used with eukaryotic or prokaryotic lysates that are programmed for combined transcription/translation of an engineered DNA template encoding for specific protein targets. Purification of the cell-free expressed product occurs through a series of protein separation modules that are configurable for process-specific isolation of different proteins. Using this approach, we demonstrate production of two bioactive human protein therapeutics, erythropoietin and granulocyte macrophage colony-stimulating factor, in yeast and bacterial extracts, respectively, each within 24 hours. This process is flexible, scalable and amenable to automation for rapid production at the point-of-need of proteins with significant pharmaceutical, medical, or biotechnological value. PMID- 26427348 TI - NHS commissioning in probation in England - on a wing and a prayer. AB - National guidance in England exhorts Clinical Commissioning Groups [groups of general practices established to organise delivery of National Health Service (NHS) care in their local area (CCGs)] to commission healthcare for those living in the community who are serving non-custodial sentences called 'community orders'. This includes 'approved premises' - accommodation providing enhanced supervision for offenders and individuals on bail who may present a high risk of harm to the public. In this national survey of CCGs in England, we compared the extent to which healthcare services were commissioned for probationers in 2014 with similar data we collected in 2013. A freedom of information (FOI) request was sent to all CCGs (n = 212) and Mental Health Trusts (organisations commissioned to provide health and social care services to individuals with mental health disorders) (n = 53) in England. Mental Health Trusts were included as they were known to fund mental health services for probation as part of their block funding allocations. A small number of basic questions were asked. The response rate was good with 65% of CCGs (n = 137) and 68% (n = 36) of Mental Health Trusts responding. The findings show that the proportion of CCGs commissioning healthcare for probation reduced from 7% to 1%, with 20% of CCGs stating that funding healthcare for this group was the responsibility of the NHS England Area Teams. There was also a reduction in the proportion of Mental Health Trusts funding healthcare for probation but from a much higher baseline, that is from 70% to 61%. The prevalence of mental health disorders in probation is high, so it was of concern that only 12% of Mental Health Trusts provided a service to support approved premises and just 32% provided clinics in probation. The results are discussed within the context of the NHS reforms and the government's plans in England to reform probation. PMID- 26427349 TI - [Effects of satisfaction with leisure time in family carers of elderly dependents]. AB - AIM: To analyse the relationship between satisfaction with leisure time and subjective burden, depression and anxiety in caregivers of dependent elderly relatives. DESIGN: Cross-sectional study. LOCATION: Primary health care (Andalusia, Spain). PARTICIPANTS: A probabilistic sample of 200 primary caregivers of dependent elderly relatives. MAIN MEASUREMENTS: Satisfaction with leisure time, subjective burden, anxiety, depression, and objective burden (functional ability, cognitive impairment and behavioural problems of the care recipient, and dedication to caring of the caregiver). RESULTS: Most of the caregivers were women, daughters of the care recipients, and shared home with them. An inverse statistical association was found between satisfaction with leisure time and subjective burden (r=-0.55, 95%CI: -0.45 to -0.64), anxiety (r= 0.30, 95%CI: -0.17 to -0.41) and depression (r=-0.25, 95%CI: -0.11 to -0.37). These associations remained after controlling for objective burden. CONCLUSIONS: Satisfaction with leisure time may have a protective effect on subjective burden, anxiety and depression, regardless of objective burden. PMID- 26427350 TI - Ginsenoside Rg3 induces FUT4-mediated apoptosis in H. pylori CagA-treated gastric cancer cells by regulating SP1 and HSF1 expressions. AB - Helicobacter pylori (H. pylori) cytotoxin associated antigen A (CagA) plays a significant role in the development of gastric cancer. Ginsenoside Rg3 is a herbal medicine which inhibits cell proliferation and induces apoptosis in various cancer cells. Fucosylation plays important roles in cancer biology as increased fucosylation levels of glycoproteins and glycolipids have been reported in many cancers. Fucosyltransferase IV (FUT4) is an essential enzyme, catalyzes the synthesis of LewisY oligosaccharides and is regulated by specificity protein 1 (SP1) and heat shock factor protein 1 (HSF1) transcription factors. Herein, we studied the mechanism action of Rg3 apoptosis induction in gastric cancer cells. We treated the gastric cancer cells with CagA followed by Rg3, and analyzed their ability to induce apoptosis by evaluating the role of FUT4 as well as SP1 and HSF1 expressions by Western blot, flow cytometry and ELISA. We found that Rg3 significantly induced apoptosis in CagA treated gastric cancer cells, as evidenced by nuclear staining of 4-6-diamidino-2-phenylindole (DAPI) and Annexin V/PI double-labeling. In addition, Rg3 significantly increased the expression of pro-apoptotic proteins and triggered the activation of caspase-3, -8, and -9 and PARP. Moreover, Rg3-induced apoptotic mechanisms indicated that Rg3 inhibited FUT4 expression through SP1 upregulation and HSF1 downregulation. Hence, Rg3 therapy is an effective strategy for gastric cancer treatment. Furthermore SP1 and HSF1 may serve as potential diagnostic and therapeutic targets for gastric cancer. PMID- 26427351 TI - Functional structure and physiological functions of mammalian wild-type HSP60. AB - The Chaperonins comprise a family of molecular chaperones having a double-ring structure and similar sequence homology. These proteins play an essential role in biological reactions that mediate the folding of newly synthesized polypeptides and partially denatured proteins. In the prokaryotic group I chaperonins, structural and reaction cycle analyses of GroEL and its co-chaperone GroES have been performed in detail. While in eukaryotes, there have been limited reports analyzing the group I chaperonin HSP60 and its co-chaperone HSP10. In the present study, we purified the wild type HSP60 from porcine liver and investigated the interaction between HSP60 and HSP10, including conformation and physiological relationships. Based on the results of transmission electron microscopy, native PAGE, and gel filtration column chromatography, the wild type HSP60 displayed a heptameric single-ring structure in the absence of ATP. In contrast, HSP60 formed mainly a "football-type" complex with HSP10 in the presence of ATP and mediated the refolding of denatured substrate protein. The functional conformation cycle of the purified mammalian HSP60 is distinct from the cycle of the prokaryotic GroEL/GroES chaperonin. PMID- 26427352 TI - Glutathione modifies the oxidation products of 2'-deoxyguanosine by singlet molecular oxygen. AB - The oxidation of the free nucleoside 2'-deoxyguanosine (dGuo) by singlet molecular oxygen ((1)O2) has been studied over the three last decades due to the major role of DNA oxidation products in process such as ageing, mutation and carcinogenesis. In the present work we investigated the dGuo oxidation by (1)O2 in the presence of the important low molecular antioxidant, glutathione, in its reduced (GSH) and oxidized (GSSG) forms. There were applied different conditions of concentration, pH, time of incubation, and the use of a [(18)O]-labeled thermolabile endoperoxide naphthalene derivative as a source of [(18)O]-labeled (1)O2. Data was obtained through high performance liquid chromatography (HPLC) and HPLC coupled to micrOTOF Q-II analysis of the main oxidation products: the diastereomers of spiroiminodihydantoin-2'-deoxyribonucleosides (dSp) and 8-oxo 7,8-dihydro-2'-deoxyguanosine (8-oxodGuo). An intriguing result was that 8 oxodGuo levels increased by 100 fold when dGuo was oxidized by (1)O2 in the presence of GSH and by 2 fold in the presence of GSSG, while dSp levels dropped to zero for both conditions. All data from dGuo, 8-oxodGuo and dSp quantification together with the analysis of residual GSH/GSSG content in each sample strongly suggest that glutathione modifies the mechanism of dGuo oxidation by (1)O2 by disfavoring the pathway of dSp formation. PMID- 26427353 TI - Early response as shown by enhancement of transglutaminase 1 expression after cisplatin-induced acute kidney injury. AB - Acute kidney injury (AKI) is caused by drugs and other stimuli, which limits the use of several therapeutic approaches. The AKI mouse model generated by intraperitoneal administration with cisplatin, one of the most widely used anti cancer drugs, is generally applied to study on this disease. Transglutaminases are posttranslational modifying enzymes that catalyze irreversible cross-linking reactions between proteins in several biological events such as skin formation and blood coagulation. In this study, we found an increase in the expression level of transglutaminase (TG1) in the kidney of mice which had been injected with cisplatin and underwent progressive nephrotoxicity. Before the appearance of the tentative symptoms of renal failure, which is apparent by morphological damage in the kidney and increases in blood creatinine levels, both the expression level and activity of TG1 rapidly increased mainly at the proximal tubule. On the other hand, the protein expression level of another major isozyme (TG2) remained mostly unaltered. This investigation will provide a possible basal level biomarker and also information on progression of renal failure from the aspect of the protein-modifying enzyme, transglutaminase. PMID- 26427354 TI - Expression, regulation and functional assessment of the 80 amino acid Small Adipocyte Factor 1 (Smaf1) protein in adipocytes. AB - The gene for Small Adipocyte Factor 1, Smaf1 (also known as adipogenin, ADIG), encodes a ~600 base transcript that is highly upregulated during 3T3-L1 in vitro adipogenesis and markedly enriched in adipose tissues. Based on the lack of an obvious open reading frame in the Smaf1 transcript, it is not known if the Smaf1 gene is protein coding or non-coding RNA. Using a peptide from a putative open reading frame of Smaf1 as antigen, we generated antibodies for western analysis. Our studies prove that Smaf1 encodes an adipose-enriched protein which in western blot analysis migrates at ~10 kDa. Rapid induction of Smaf1 protein occurs during in vitro adipogenesis and its expression in 3T3-L1 adipocytes is positively regulated by insulin and glucose. Moreover, siRNA studies reveal that expression of Smaf1 in adipocytes is wholly dependent on PPARgamma. On the other hand, use of siRNA for Smaf1 to nearly abolish its protein expression in adipocytes revealed that Smaf1 does not have a major role in adipocyte triglyceride accumulation, lipolysis or insulin-stimulated pAkt induction. However, immunolocalization studies using HA-tagged Smaf1 reveal enrichment at adipocyte lipid droplets. Together our findings show that Smaf1 is a novel small protein endogenous to adipocytes and that Smaf1 expression is closely tied to PPARgamma mediated signals and the adipocyte phenotype. PMID- 26427355 TI - China and the United States--Global partners, competitors and collaborators in nanotechnology development. AB - USA and China are two leading countries engaged in nanotechnology research and development. They compete with each other for fruits in this innovative area in a parallel and compatible manner. Understanding the status and developmental prospects of nanotechnology in USA and China is important for policy-makers to decide nanotechnology priorities and funding, and to explore new ways for global cooperation on key issues. We here present the nanoscience and nanomedicine research and the related productivity measured by publications, and patent applications, governmental funding, policies and regulations, institutional translational research, industrial and enterprise growth in nanotechnology related fields across China and USA. The comparison reveals some marked asymmetries of nanotechnology development in China and USA, which may be helpful for future directions to strengthen nanotechnology collaboration for both countries, and for the world as a whole. PMID- 26427356 TI - Shape regulated anticancer activities and systematic toxicities of drug nanocrystals in vivo. AB - In this paper, shape regulated anticancer activities as well as systematic toxicities of hydroxycamptothecin nanorods and nanoparticles (HCPT NRs and NPs) were systematically studied. In vitro and in vivo therapeutic efficacies were evaluated in cancer cells and tumor-bearing mice, indicating that NRs possessed superior antitumor efficacy over NPs at the equivalent dose, while systematic toxicity of the differently shaped nanodrugs assessed in healthy mice, including the maximum tolerated dose, blood analysis and histology examinations and so on, suggested that the NRs also caused higher toxicities than NPs, and also had a long-term toxicity. These results imply that the balance between anticancer efficiency and systematic toxicity of drug nanocrystals should be fully considered in practice, which will provide new concept in the future design of drug nanocrystals for cancer therapy. From the Clinical Editor: Advances in nanotechnology have enabled the design of novel nanosized drugs for the treatment of cancer. One of the interesting findings thus far is the different biological effects seen with different shaped nanoparticles. In this article, the authors investigated and compared the anticancer activities of hydroxycamptothecin nanorods and nanoparticles. The experimental data would provide a better understanding for future drug design. PMID- 26427357 TI - A commentary on "Involvement of activating ERK1/2 trough G protein coupled receptor 30 and estrogen receptor alpha/beta in low doses of bisphenol A promoting growth of Sertoli TM4 cells". PMID- 26427358 TI - Cancer surgery: a vital specialty to prevent premature death. PMID- 26427359 TI - Primacy of surgery in cancer care: a global situation. PMID- 26427360 TI - Cancer surgery: an Indian-Asian perspective. PMID- 26427361 TI - Cancer surgery in Africa: if all you have is a hammer.... PMID- 26427362 TI - The surgeon's role in childhood cancer worldwide. PMID- 26427363 TI - Global cancer surgery: delivering safe, affordable, and timely cancer surgery. AB - Surgery is essential for global cancer care in all resource settings. Of the 15.2 million new cases of cancer in 2015, over 80% of cases will need surgery, some several times. By 2030, we estimate that annually 45 million surgical procedures will be needed worldwide. Yet, less than 25% of patients with cancer worldwide actually get safe, affordable, or timely surgery. This Commission on global cancer surgery, building on Global Surgery 2030, has examined the state of global cancer surgery through an analysis of the burden of surgical disease and breadth of cancer surgery, economics and financing, factors for strengthening surgical systems for cancer with multiple-country studies, the research agenda, and the political factors that frame policy making in this area. We found wide equity and economic gaps in global cancer surgery. Many patients throughout the world do not have access to cancer surgery, and the failure to train more cancer surgeons and strengthen systems could result in as much as US $6.2 trillion in lost cumulative gross domestic product by 2030. Many of the key adjunct treatment modalities for cancer surgery--e.g., pathology and imaging--are also inadequate. Our analysis identified substantial issues, but also highlights solutions and innovations. Issues of access, a paucity of investment in public surgical systems, low investment in research, and training and education gaps are remarkably widespread. Solutions include better regulated public systems, international partnerships, super-centralisation of surgical services, novel surgical clinical trials, and new approaches to improve quality and scale up cancer surgical systems through education and training. Our key messages are directed at many global stakeholders, but the central message is that to deliver safe, affordable, and timely cancer surgery to all, surgery must be at the heart of global and national cancer control planning. PMID- 26427364 TI - Anal Pap Screening for HIV-infected Men Who Have Sex With Men: Practice Improvement. AB - HIV-infected men who have sex with men (MSM) have the highest rates of anal dysplasia and anal cancer when compared to HIV-uninfected MSM and when compared to HIV-infected heterosexual men and women. Despite significantly increasing rates of anal dysplasia and anal cancer in HIV-infected MSM, in many settings, no standard protocol is in place to screen for anal dysplasia in this high-risk group. A practice improvement project was conducted at a primary care health center to educate the HIV health care team about anal Pap screening in an effort to increase provider knowledge and rates of anal Pap screening performed as part of primary comprehensive care for HIV-infected MSM. Increased health care provider knowledge of anal Pap screening within this setting resulted in increased anal Pap screening for HIV-infected MSM. Routine screening leads to improved surveillance and treatment of precancerous lesions, decreasing morbidity and mortality in HIV-infected MSM. PMID- 26427365 TI - Diagnostic accuracy of the rapid urine lipoarabinomannan test for pulmonary tuberculosis among HIV-infected adults in Ghana-findings from the DETECT HIV-TB study. AB - BACKGROUND: Rapid diagnostic tests are urgently needed to mitigate HIV-associated tuberculosis (TB) mortality. We evaluated diagnostic accuracy of the rapid urine lipoarabinomannan (LAM) test for pulmonary TB and assessed the effect of a two sample strategy. METHODS: HIV-infected adults eligible for antiretroviral therapy were prospectively enrolled from Korle-Bu Teaching Hospital in Ghana and followed for minimum 6 months. We applied the LAM test on urine collected as a spot and early morning sample. Diagnostic accuracy was analysed for a microbiological TB reference standard based on sputum culture and Gene Xpert MTB/RIF results and for a composite reference standard including clinical follow-up data. Performance of sputum smear microscopy was included for comparison. RESULTS: Of 469 patients investigated for TB, the LAM test correctly identified 24/55 (44 %) of microbiologically confirmed TB cases. Sensitivity of the LAM test was positively associated with hospitalisation (67 %), Modified Early Warning Score > 4 (57 %) and subsequent death (71 %). LAM test specificity was 95 % increasing to 98 % for the composite reference standard. A two-sample LAM test strategy did not improve test performance. Using concentrated sputum for Ziehl-Neelsen and fluorescence microscopy in combination yielded a sensitivity of 31/55 (56 %) that increased to 35/55 (64 %) when the LAM test was added. Surprisingly, nontuberculous mycobacteria were cultured in 34/469 (7 %) and associated with a positive LAM test (p = 0.008). CONCLUSIONS: LAM test sensitivity was highest in patients with poor prognosis and subsequent death and did not increase with a two-sample strategy. A rigorous sputum microscopy strategy had superior sensitivity, but the simplicity of the LAM test holds operational possibilities as a TB screening method among severely sick patients. PMID- 26427366 TI - A Comparison of transgenic and wild type soybean seeds: analysis of transcriptome profiles using RNA-Seq. AB - BACKGROUND: Soybean (Glycine max) has been bred for thousands of years to produce seeds rich in protein for human and animal consumption, making them an appealing bioreactor for producing valuable recombinant proteins at high levels. However, the effects of expressing recombinant protein at high levels on bean physiology are not well understood. To address this, we investigated whether gene expression within transgenic soybean seed tissue is altered when large amounts of recombinant proteins are being produced and stored exclusively in the seeds. We used RNA-Seq to survey gene expression in three transgenic soybean lines expressing recombinant protein at levels representing up to 1.61 % of total protein in seed tissues. The three lines included: ST77, expressing human thyroglobulin protein (hTG), ST111, expressing human myelin basic protein (hMBP), and 764, expressing a mutant, nontoxic form of a staphylococcal subunit vaccine protein (mSEB). All lines selected for analysis were homozygous and contained a single copy of the transgene. METHODS: Each transgenic soybean seed was screened for transgene presence and recombinant protein expression via PCR and western blotting. Whole seed mRNA was extracted and cDNA libraries constructed for Illumina sequencing. Following alignment to the soybean reference genome, differential gene expression analysis was conducted using edgeR and cufflinks. Functional analysis of differentially expressed genes was carried out using the gene ontology analysis tool AgriGO. RESULTS: The transcriptomes of nine seeds from each transgenic line were sequenced and compared with wild type seeds. Native soybean gene expression was significantly altered in line 764 (mSEB) with more than 3000 genes being upregulated or downregulated. ST77 (hTG) and ST111 (hMBP) had significantly less differences with 52 and 307 differentially expressed genes respectively. Gene ontology enrichment analysis found that the upregulated genes in the 764 line were annotated with functions related to endopeptidase inhibitors and protein synthesis, but suppressed expression of genes annotated to the nuclear pore and to protein transport. No significant gene ontology terms were detected in ST77, and only a few genes involved in photosynthesis and thylakoid functions were downregulated in ST111. Despite these differences, transgenic plants and seeds appeared phenotypically similar to non transgenic controls. There was no correlation between recombinant protein expression level and the quantity of differentially expressed genes detected. CONCLUSIONS: Measurable unscripted gene expression changes were detected in the seed transcriptomes of all three transgenic soybean lines analyzed, with line 764 being substantially altered. Differences detected at the transcript level may be due to T-DNA insert locations, random mutations following transformation or direct effects of the recombinant protein itself, or a combination of these. The physiological consequences of such changes remain unknown. PMID- 26427367 TI - Caffeine differentially alters cortical hemodynamic activity during working memory: a near infrared spectroscopy study. AB - BACKGROUND: Caffeine is a widely used stimulant with potentially beneficial effects on cognition as well as vasoconstrictive properties. In functional magnetic imaging research, caffeine has gained attention as a potential enhancer of the blood oxygenation level-dependent (BOLD) response. In order to clarify changes of oxy- and deoxyhemoglobin (HbO and HbR) induced by caffeine during a cognitive task, we investigated a working memory (WM) paradigm (visual 2-back) using near-infrared spectroscopy (NIRS). RESULTS: Behaviorally, caffeine had no effect on the WM performance but influenced reaction times in the 0-back condition. NIRS data demonstrate caffeine-dependent alterations of the course of the hemodynamic response. The intake of 200 mg caffeine caused a significant decrease of the HbO response between 20 and 40 s after the onset of a 2-back task in the bilateral inferior frontal cortex (IFC). In parallel, the HbR response of the left IFC was significantly increased due to caffeine intake. CONCLUSIONS: In line with previous results, we did not detect an effect of caffeine on most aspects of behavior. Effects of caffeine on brain vasculature were detected as general reduction of HbO. Neuronal effects of caffeine are reflected in an increased concentration of HbR in the left hemisphere when performing a verbal memory task and suggest influences on metabolism. PMID- 26427368 TI - Clinical impact of diabetes mellitus in patients undergoing transcatheter aortic valve replacement. AB - BACKGROUND: Diabetes mellitus (DM) and aortic stenosis (AS) are frequent findings in the elderly population. Data regarding the influence of DM on the outcomes of patients undergoing transcatheter aortic valve replacement (TAVR) due to AS are limited. The aim of this study was to examine the impact of DM on TAVR outcomes. METHODS: We investigated 443 patients with severe AS undergoing TAVR. Subjects were divided into insulin-dependent diabetic mellitus (IDDM) patients (N = 44), non-dependent insulin diabetic mellitus (NIDDM) patients (N = 114) and non diabetics (N = 285) of whom 31 (74%), 86 (79%) and 209 (76%) respectively had trans-femoral TAVR. Peri-procedural complications and outcomes were recorded according to the Valve Academic Research Consortium-2 criteria. RESULTS: Patients with IDDM as well as NIDDM demonstrated similar complication rates compared with non-diabetic patients, except for acute kidney injury (AKI) grade 3 [4 (2%) and 3 (3%) vs. 1 (0.4%) respectively, p = 0.032]. Kaplan-Meier survival analysis showed that DM, regardless of the type of treatment, was not associated with increased 2 years mortality (Log-rank p value 0.44). Multivariate cox regression analysis adjusted for age, gender, coronary artery disease, DM, AKI3, hypertension, chronic renal failure and peripheral vascular disease found that AKI3 was associated with increased risk of 2 years mortality [HR = 7.35, 95% CI 2.16 25.07, p = 0.001] whereas female gender was found as a protective factor [HR = 0.47, 95% CI 0.28-0.8, p = 0.005], and DM was not associated with increased risk. CONCLUSIONS: Following TAVR, DM patients seem to have similar peri-procedural and mid-term outcomes compared with patients without DM, while IDDM patients seem to suffer greater incidence of AKI. Further research in larger cohorts of patients is needed to validate our results. PMID- 26427369 TI - In a context of time: the impact of delay and exposure time on the emergence of memory context effects. AB - Research on context-mediated facilitation of recognition memory distinguishes between the effects of reinstating the exact same context previously associated with a target and a context that is familiar but not directly associated with the target. As both effects are difficult to produce reliably in recognition experiments, attention has turned to measures that may explain inconsistencies, such as the extent to which instructions encourage association between targets and contexts. The aim of the current study was to examine the distinctive and interactive effects of three factors that may lead to variability in context effects (CEs), namely type of instructions given at learning, delay between learning and test, and exposure time for targets and contexts at learning. Using a comprehensive paradigm developed by Vakil and colleagues, with photographs of faces serving as target and context stimuli, both exposure time and delay were shown to be associated with the occurrence of CEs and appeared to interact with one another in determining the nature of these effects. Unlike several previous studies, false alarms did not increase when foils were presented with familiar contexts. Also unexpectedly, the instruction manipulation did not appear to strengthen target-context binding. It may instead have increased attention to contexts at the expense of targets, as suggested by the finding that direct memory for context improved under associative instruction conditions. Overall, the study demonstrates the importance of understanding and controlling various factors that may potentially influence the emergence of both reinstatement and familiarity-based CEs, among them exposure time and learning-to-test delay. PMID- 26427370 TI - What happens when pharmaceuticals meet colloids. AB - Pharmaceuticals (PCs) have been widely detected in natural environment due to agricultural application of reclaimed water, sludge and animal wastes. Their potential risks to various ecosystems and even to human health have caused great concern; however, little was known about their environmental behaviors. Colloids (such as clays, metal oxides, and particulate organics) are kind of substances that are active and widespread in the environment. When PCs meet colloids, their interaction may influence the fate, transport, and toxicity of PCs. This review summarizes the progress of studies on the role of colloids in mediating the environmental behaviors of PCs. Synthesized results showed that colloids can adsorb PCs mainly through ion exchange, complexation and non-electrostatic interactions. During this process the structure of colloids and the stability of PCs may be changed. The adsorbed PCs may have higher risks to induce antibiotic resistance; besides, their transport may also be altered considering they have great chance to move with colloids. Solution conditions (such as pH, ionic strength, and cations) could influence these interactions between PCs and colloids, as they can change the forms of PCs and alter the primary forces between PCs and colloids in the solution. It could be concluded that PCs in natural soils could bind with colloids and then co-transport during the processes of irrigation, leaching, and erosion. Therefore, colloid-PC interactions need to be understood for risk assessment of PCs and the best management practices of various ecosystems (such as agricultural and wetland systems). PMID- 26427371 TI - Biological efficacy and toxic effect of emergency water disinfection process based on advanced oxidation technology. AB - An innovative and removable water treatment system consisted of strong electric field discharge and hydrodynamic cavitation based on advanced oxidation technologies was developed for reactive free radicals producing and waterborne pathogens eliminating in the present study. The biological efficacy and toxic effects of this advanced oxidation system were evaluated during water disinfection treatments. Bench tests were carried out with synthetic microbial contaminated water, as well as source water in rainy season from a reservoir of Dalian city (Liaoning Province, China). Results showed that high inactivation efficiency of Escherichia coli (>5 log) could be obtained for synthetic contaminated water at a low concentration (0.5-0.7 mg L(-1)) of total oxidants in 3-10 s. The numbers of wild total bacteria (108 * 10(3) CFU mL(-1)) and total coliforms (260 * 10(2) MPN 100 mL(-1)) in source water greatly reduced to 50 and 0 CFU mL(-1) respectively after treated by the advanced oxidation system, which meet the microbiological standards of drinking water, and especially that the inactivation efficiency of total coliforms could reach 100%. Meanwhile, source water qualities were greatly improved during the disinfection processes. The values of UV254 in particular were significantly reduced (60-80%) by reactive free radicals. Moreover, the concentrations of possible disinfection by-products (formaldehyde and bromide) in treated water were lower than detection limits, indicating that there was no harmful effect on water after the treatments. These investigations are helpful for the ecotoxicological studies of advanced oxidation system in the treatments of chemical polluted water or waste water. The findings of this work suggest that the developed water treatment system is ideal in the acute phases of emergencies, which also could offer additional advantages over a wide range of applications in water pollution control. PMID- 26427373 TI - Cost-Effectiveness in Hepatic Lobectomy: the Effect of Case Volume on Mortality, Readmission, and Cost of Care. AB - OBJECTIVE(S): Higher-volume centers demonstrate better perioperative outcomes for complex surgical interventions, though resource utilization implications of this hospital-level variation are unclear. We hypothesized that for hepatic lobectomy, higher operative volume correlates with better outcomes and lower costs. METHODS: From 2009 to 2011, 4163 patients undergoing hepatic lobectomy were identified from the University HealthSystems Consortium database. Univariate, multivariate logistic regression, and decision analytic models were constructed to identify differences in hospital utilization and cost. Cost included both index and readmission hospitalizations, when applicable. RESULTS: The annual number of hepatic lobectomies performed by the institutions within the study ranged from 1 to 86. The median age of the 4163 patients was 58 years with a roughly equal gender split (M/F 49 %:51 %) and a racial breakdown which reflected that of the general US population. For all patients, the overall perioperative mortality rate was 2.3 % and the 30-day readmission rate was 13.4 %. Hospitals performing >30 hepatic lobectomies per year had significantly lower mortality and readmission rates than those hospitals performing <=15 lobectomies annually (both p < 0.05). On multivariate analysis, higher severity of illness (odd ratio (OR) 2.13, 95 % confidence interval (CI) [1.48-3.07], p < 0.001), discharge to rehab (OR 1.84, [1.28-2.64], p < 0.001), home with home health care (OR 1.38, [1.08-1.76], p = 0.01), and surgery at a low-volume hospital (OR 1.49, [1.18-1.88], p < 0.001) were significant predictors of readmission. Conversely, surgical intervention at high-volume centers was associated with decreased risk of readmission (OR 0.67, [0.53-0.85], p < 0.001). When both index and readmission costs were considered, per-patient cost at low-volume centers was 21.9 % higher than at high-volume centers ($19,669 vs. $16,137). Sensitivity analyses adjusting for perioperative mortality and readmission at all centers did not significantly change the analysis. CONCLUSIONS: These data, for the first time, demonstrate that hospital volume in hepatic lobectomy is an important, modifiable risk factor for readmission and cost. To optimize resource utilization, patients undergoing complex hepatic surgery should be directed to higher-volume surgical institutions. PMID- 26427372 TI - The role of B-1 cells in inflammation. AB - B-1 lymphocytes exhibit unique phenotypic, ontogenic, and functional characteristics that differ from the conventional B-2 cells. B-1 cells spontaneously secrete germline-like, repertoire-skewed polyreactive natural antibody, which acts as a first line of defense by neutralizing a wide range of pathogens before launching of the adaptive immune response. Immunomodulatory molecules such as interleukin-10, adenosine, granulocyte-macrophage colony stimulating factor, interleukin-3, and interleukin-35 are also produced by B-1 cells in the presence or absence of stimulation, which regulate acute and chronic inflammatory diseases. Considerable progress has been made during the past three decades since the discovery of B-1 cells, which has improved not only our understanding of their phenotypic and ontogenic uniqueness but also their role in various inflammatory diseases including influenza, pneumonia, sepsis, atherosclerosis, inflammatory bowel disease, autoimmunity, obesity and diabetes mellitus. Recent identification of human B-1 cells widens the scope of this field, leading to novel innovations that can be implemented from bench to bedside. Among the vast number of studies on B-1 cells, we have carried out a literature review highlighting current trends in the study of B-1 cell involvement during inflammation, which may result in a paradigm shift toward sustainable therapeutics in various inflammatory diseases. PMID- 26427374 TI - A Tale of Two Cities: Reconsidering Adjuvant Radiation in Pancreatic Cancer Care. AB - Adjuvant chemotherapy plays a critical role in the treatment of resected pancreatic cancer patients. However, the role of adjuvant radiation remains controversial. This study compares survival between resected pancreatic cancer patients who received adjuvant radiation and no adjuvant radiation. Medical records of patients with pancreatic ductal adenocarcinoma who underwent surgical resection from January 2003 through 2013 at medical centers in Boston and Leiden were retrospectively reviewed. Propensity score matching was used to correct for potential selection bias in the allocation of adjuvant chemoradiation versus chemotherapy alone. Three hundred fifty total patients were identified, of whom 138 (39.4%) received adjuvant radiation. On pathological staging, 245 (70.0%) had positive lymph nodes, and these patients gained a significant survival benefit from adjuvant radiation (hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.56-0.99) in the complete cohort. After propensity score matching, adjuvant radiation lost its prognostic significance in the complete cohort. However, after matching, patients who survived longer than 12 months and had positive lymph nodes (n = 108) demonstrated a significant (log-rank p = 0.04) survival benefit from adjuvant radiation. This study, while non-randomized, suggests that adjuvant radiation may be associated with a survival benefit for resected pancreatic cancer patients in specific situations. PMID- 26427376 TI - Low Non-structured Antiretroviral Therapy Interruptions in HIV-Infected Persons Who Inject Drugs Receiving Multidisciplinary Comprehensive HIV Care at an Outpatient Drug Abuse Treatment Center. AB - Continuous HIV treatment is necessary to ensure successful combined antiretroviral therapy (cART). The aim of this study was to evaluate the incidence of patient-initiated non-structured treatment interruptions in HIV infected persons who inject drugs and who received a multidisciplinary comprehensive program, including medical HIV care, drug-dependence treatment and psychosocial support, at a drug outpatient addiction center. Non-structured treatment interruptions were defined as >=30 consecutive days off cART without medical indication. During a median follow-up of 53.8 months, 37/132 (28 %) patients experienced the first non-structured treatment interruptions. The cumulative probability of cART interruption at 5 years was 31.2 % (95 % CI 22.4 40.0). Current drug use injection >=1/day (HR 14.77; 95 % CI 5.90-36.96) and cART naive patients (HR 0.35, 95 % CI 0.14-0.93) were predictive factors for non structured treatment interruptions. HIV care provided at a drug addiction center is a useful strategy to sustain continuous cART, however, drug abstinence is essential for the long-term maintenance of cART. PMID- 26427375 TI - Inferring synthetic lethal interactions from mutual exclusivity of genetic events in cancer. AB - BACKGROUND: Synthetic lethality (SL) refers to the genetic interaction between two or more genes where only their co-alteration (e.g. by mutations, amplifications or deletions) results in cell death. In recent years, SL has emerged as an attractive therapeutic strategy against cancer: by targeting the SL partners of altered genes in cancer cells, these cells can be selectively killed while sparing the normal cells. Consequently, a number of studies have attempted prediction of SL interactions in human, a majority by extrapolating SL interactions inferred through large-scale screens in model organisms. However, these predicted SL interactions either do not hold in human cells or do not include genes that are (frequently) altered in human cancers, and are therefore not attractive in the context of cancer therapy. RESULTS: Here, we develop a computational approach to infer SL interactions directly from frequently altered genes in human cancers. It is based on the observation that pairs of genes that are altered in a (significantly) mutually exclusive manner in cancers are likely to constitute lethal combinations. Using genomic copy-number and gene-expression data from four cancers, breast, prostate, ovarian and uterine (total 3980 samples) from The Cancer Genome Atlas, we identify 718 genes that are frequently amplified or upregulated, and are likely to be synthetic lethal with six key DNA damage response (DDR) genes in these cancers. By comparing with published data on gene essentiality (~16000 genes) from ten DDR-deficient cancer cell lines, we show that our identified genes are enriched among the top quartile of essential genes in these cell lines, implying that our inferred genes are highly likely to be (synthetic) lethal upon knockdown in these cell lines. Among the inferred targets are tousled-like kinase 2 (TLK2) and the deubiquitinating enzyme ubiquitin-specific-processing protease 7 (USP7) whose overexpression correlates with poor survival in cancers. CONCLUSION: Mutual exclusivity between frequently occurring genetic events identifies synthetic lethal combinations in cancers. These identified genes are essential in cell lines, and are potential candidates for targeted cancer therapy. Availability: http://bioinformatics.org.au/tools data/underMutExSL PMID- 26427377 TI - The consequences of the economic crisis in radiology. AB - The effects of the economic crisis have led to complex problems in radiology. The crisis has led to a reduction in the turnover of imaging equipment. This reflects on the quantity and quality of output, an aspect which is worsened by the contraction of the radiology market, late payments on supplies, and competitive procurement of medical goods centralized on a regional or national level. Many local and national institutions have operated with significant reductions of reimbursement for procedures, forcing a reorganization of facilities, manpower, and equipment. The reduction in operating margins of the industry has resulted in a reduction of invested capital for projects of industrial R&D and direct or indirect sponsorship. The quality of care will be affected with less comfortable conditions, reduction of local availability of radiologists, and failure to invest in lower dose equipment to control population medical radiation exposure. The crisis resulted in a reduction in the number of graduates in medicine and scholarships for specialization induced by linear cuts will result in a drastic reduction of radiological specialists. This will favour the development of teleradiology services, with the risk of accelerating the demedicalisation of radiology departments, and isolation of the professionals. MAIN MESSAGES: * The economic crisis has led to reduction in the turnover of imaging equipment. * The economic crisis has led to reductions of reimbursement for procedures. * The economic crisis has led to reductions in operating margins of the industry. * The economic crisis has led to contraction of quantity and quality of output. * The economic crisis resulted in demedicalisation of radiology departments and isolation of professionals. PMID- 26427378 TI - Complete genome sequence of the siphoviral bacteriophage Betaphi-R3177, which lyses an OXA-66-producing carbapenem-resistant Acinetobacter baumannii isolate. AB - In recent years, antimicrobial resistance has become a major medical threat worldwide. Among these threats, the rapid increase in carbapenem-resistant Acinetobacter baumannii (CRAB) is a particularly challenging global issue in the health care setting. In this study, a novel lytic A. baumannii phage, Betaphi R3177, infecting carbapenem-resistant A. baumannii strains was isolated from sewage samples at a hospital. The morphology of the phage as assessed by transmission electron microscopy (TEM) indicated that it belongs to the family Siphoviridae within the order Caudovirales. It has a linear double-stranded DNA genome of 47,575 bp with a G+C content of 39.83%. Eighty open reading frames (ORFs) were predicted; however, only 14 ORFs were annotated as encoding functional proteins, while most of the ORFs encoded hypothetical proteins. Among the total ORFs of the phage genome, no toxin-related genes were detected. A bioinformatics analysis showed that the whole genome sequence of phage Betaphi R3177 exhibited 62% sequence similarity to that of Acinetobacter phage Betaphi B1252, but there was no homology seen with other phages. Physiological characteristics, such as one-step growth properties, pH and temperature stability, and host cell lysis activity showed this phage has high stability and lytic activity against host bacteria and therefore has potential applicability as an antibacterial agent to control pathogens in the hospital environment. PMID- 26427379 TI - Complete nucleotide sequences of two new begomoviruses infecting the wild malvaceous plant Melochia sp. in Brazil. AB - Wild malvaceous plants are hosts for a large number of begomoviruses (genus Begomovirus, family Geminiviridae) in both the Old World and the New World. Here, we report the complete genome sequences of two new begomoviruses from Melochia sp. plants from Brazil. The cloned bipartite genomes, composed of DNA-A and DNA B, showed the typical organization of the New World begomoviruses but they were distantly related to the genomes of other begomoviruses. We propose the names Melochia mosaic virus and Melochia yellow mosaic virus for these begomoviruses. PMID- 26427380 TI - Comparative analysis of transcriptional profiles of retinoic-acid-induced gene I like receptors and interferons in seven tissues from ducks infected with avian Tembusu virus. AB - Avian Tembusu virus (ATV), an emerging virus that mainly infects laying and breeding ducks in China, has caused severe economic loss in duck industry. However, there have been no reports about host innate immune responses during ATV infection and its correlation with clinical signs or pathology. To identify the roles of these immune factors in the innate host response to ATV infection, quantitative real-time PCR (qPCR) was used to analyze the transcriptional profiles on the genes encoding two retinoic-acid-induced gene I (RIG-I)-like receptors (RLRs) and two interferons (INF-alpha and INF-gamma) in seven tissues of an ATV-infected shelduck. After infection with ATV, both RLR genes were significantly upregulated (P < 0.05) in all seven tissues. The peak expression levels of the two RLR genes were observed at 24 hours postinfection (hpi) and were higher in non-lymphoid tissues (liver, lung, kidney, and ovary) than in lymphoid tissues (thymus, spleen and bursa). Although the transcription levels of both IFN genes were also upregulated, they showed different time-dependent expression patterns compared with those of the RLR genes. In addition, the highest mRNA expression of the two IFN genes was observed in the ovary at 6 hpi. This observation suggests that the ovary is the primary target tissue in ATV infection and explains the clinical characteristics of the primary pathological changes in the ovaries of ATV-infected ducks. Our results, for the first time, elucidate the differential and coordinated expression profiles of two RLRs and two IFNs in an ATV-infected shelduck. PMID- 26427382 TI - Erratum to: Healthy Start: Description of a Safety Net for Perinatal Support During Disaster Recovery. PMID- 26427381 TI - Treatment effect, postoperative complications, and their reasons in juvenile thoracic and lumbar spinal tuberculosis surgery. AB - OBJECTIVE: Fifty-four juvenile cases under 18 years of age with thoracic and lumbar spinal tuberculosis underwent focus debridement, deformity correction, bone graft fusion, and internal fixation. The treatment effects, complications, and reasons were analyzed retrospectively. MATERIAL AND METHOD: There were 54 juvenile cases under 18 years of age with thoracolumbar spinal tuberculosis. The average age was 9.2 years old, and the sample comprised 38 males and 16 females. The disease types included 28 thoracic cases, 17 thoracolumbar cases, and 9 lumbar cases. Nerve function was evaluated with the Frankel classification. Thirty-six cases were performed with focus debridement and deformity correction and were supported with allograft or autograft in mesh and fixed with pedicle screws from a posterior approach. Eight cases underwent a combined anterior and posterior surgical approach. Nine cases underwent osteotomy and deformity correction, and one case received focus debridement. The treatment effects, complications, and bone fusions were tracked for an average of 52 months. RESULTS: According to the Frankel classification, paralysis was improved from 3 cases of B, 8 cases of C, 18 cases of D, and 25 cases of E preoperatively. This improvement was found in 3 cases of C, 6 cases of D, and 45 cases of E at a final follow-up postoperatively. No nerve dysfunction was aggravated. VAS was improved from 7.8 +/- 1.7 preoperatively to 3.2 +/- 2.1 at final follow-up postoperatively. ODI was improved from 77.5 +/- 17.3 preoperatively to 28.4 +/- 15.9 at final follow-up postoperatively. Kyphosis Cobb angle improved from 62.2 degrees +/- 3.7 degrees preoperatively to 37 degrees +/- 2.4 degrees at final follow-up postoperatively. Both of these are significant improvements, and all bone grafts were fused. Complications related to the operation occurred in 31.5% (17/54) of cases. Six cases suffered postoperative aggravated kyphosis deformity, eight cases suffered proximal kyphosis deformity, one case suffered pedicle penetration, one case suffered failure of internal devices, and one case suffered recurrence of tuberculosis. CONCLUSION: As long as the treatment plan is fully prepared, the surgical option can achieve a satisfactory curative effect in treating juvenile spinal tuberculosis despite some complications. PMID- 26427383 TI - Significance of Lipolytic Enzymes in Pathogenesis and Treatment of Neglected Diseases. AB - Neglected diseases are infectious diseases that affect poor people of tropical countries. Drug resistance, lower availability of funds and research hinder the opportunities for the development of new drugs. The need for new drugs will persist until pathogens are eradicated. This calls for understanding the disease prognosis to initiate research for new drug targets and thus development of new drugs. As drug development is complex and expensive process, in silico drug development can aid in this regard by reducing time, effort and capital for the quest of a "better drug" for such neglected diseases. Recent knowledge about the genome and proteome has increased enthusiasm for the quest of new drug targets. One such potential target can be lipases which are involved in the lipid metabolism of pathogens. Lipases of pathogens have multitude of functions in many patho-physiological processes including virulence, transmission, life cycle development, modulation of host lipids and host immune responses. Thus the aim of this review is to describe the significance of lipases in the life cycle and pathogenesis of the pathogen and whether they can be used as drug targets. The development of research in this direction has also been brought forward. This may help in finding new drug targets for neglected disease. PMID- 26427384 TI - Multi-output Model with Box-Jenkins Operators of Quadratic Indices for Prediction of Malaria and Cancer Inhibitors Targeting Ubiquitin- Proteasome Pathway (UPP) Proteins. AB - 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 in this 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, the causal 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. PMID- 26427385 TI - Pyrazinamide and Pyrazinoic Acid Derivatives Directed to Mycobacterial Enzymes Against Tuberculosis. AB - Tuberculosis (TB) is an infectious diseases responsible for thousands of deaths worldwide. Due to the use of antimycobacterial drugs, TB prevalence seemed to be controlled, but with the appearance of resistant tuberculosis cases, the concern about the disease had become significant again, as well as the need for new alternatives to TB treatment. Since pyrazinamide (PZA) is part of the firstline agents in TB treatment, several derivatives of this drug were described, besides pyrazinoic acid (POA) derivatives, the active form of PZA. POA has been used mainly to design prodrugs to be activated by mycobacterial esterases, while PZA derivatives should be activated specifically by the nicotinamidase/ pyrazinamidase (PZAse), or other PZAse-independent pathways. The intention of this paper is to discuss the state of art of PZA and POA derivatives and their activity against Mycobacterium tuberculosis and other mycobacteria, besides the therapeutic potential. Focus was given in prodrugs and derivatives directed to mycobacterial enzymes involved in its activation or mechanism of action. PMID- 26427386 TI - Apolipoprotein E Isoforms and AMD. AB - The cholesterol transporting protein apolipoprotein E (ApoE) occurs in three allelic variants in humans unlike in other species. The resulting protein isoforms E2, E3 and E4 exhibit differences in lipid binding, integrating into lipoprotein particles and affinity for lipoprotein receptors. ApoE isoforms confer genetic risk for several diseases of aging including atherosclerosis, Alzheimer's disease, and age-related macular degeneration (AMD). A single E4 allele increases the risk of developing Alzheimer's disease, whereas the E2 allele is protective. Intriguingly, the E4 allele is protective in AMD. Current thinking about different functions of ApoE isoforms comes largely from studies on Alzheimer's disease. These data cannot be directly extrapolated to AMD since the primary cells affected in these diseases (neurons vs. retinal pigment epithelium) are so different. Here, we propose that ApoE serves a fundamentally different purpose in regulating cholesterol homeostasis in the retinal pigment epithelium and this could explain why allelic risk factors are flipped for AMD compared to Alzheimer's disease. PMID- 26427387 TI - Role of Chemokines in Shaping Macrophage Activity in AMD. AB - Age-related macular degeneration (AMD) is a multifactorial disorder that affects millions of individuals worldwide. While the advent of anti-VEGF therapy has allowed for effective treatment of neovascular 'wet' AMD, no treatments are available to mitigate the more prevalent 'dry' forms of the disease. A role for inflammatory processes in the progression of AMD has emerged over a period of many years, particularly the characterisation of leukocyte infiltrates in AMD affected eyes, as well as in animal models. This review focuses on the burgeoning understanding of chemokines in the retina, and their potential role in shaping the recruitment and activation of macrophages in AMD. Understanding the mechanisms which promote macrophage activity in the degenerating retina may be key to controlling the potentially devastating consequences of inflammation in diseases such as AMD. PMID- 26427388 TI - Biology of p62/sequestosome-1 in Age-Related Macular Degeneration (AMD). AB - p62/sequestosome-1 is a multidimensional protein that interacts with many signaling factors, and regulates a variety of cellular functions including inflammation, apoptosis, and autophagy. Our previous work has revealed in the retinal pigment epithelium (RPE) that p62 promotes autophagy and simultaneously enhances an Nrf2-mediated antioxidant response to protect against acute oxidative stress. Several recent studies demonstrated that p62 contributes to NFkB mediated inflammation and inflammasome activation under certain circumstances, raising the question of whether p62 protects against or contributes to tissue injury. Herein, we will review the general characteristics of p62, focusing on its pro- and anti cell survival roles within different physiological/pathological contexts, and discuss the potential of p62 as a therapeutic target for AMD. PMID- 26427389 TI - Gene Structure of the 10q26 Locus: A Clue to Cracking the ARMS2/HTRA1 Riddle? AB - Age-related macular degeneration (AMD) is a sight-threatening disorder of the central retina. Being the leading cause of visual impairment in senior citizens, it represents a major public health issue in developed countries. Genetic studies of AMD identified two major susceptibility loci on chromosomes 1 and 10. The high risk allele of the 10q26 locus encompasses three genes, PLEKHA1, ARMS2, and HTRA1 with high linkage disequilibrium and the individual contribution of the encoded proteins to disease etiology remains controversial. While PLEKHA1 and HTRA1 are highly conserved proteins, ARMS2 is only present in primates and can be detected by using RT-PCR. On the other hand, there is no unequivocal evidence for the existence of the encoded protein. However, it has been reported that risk haplotypes only affect the expression of ARMS2 (but not of HTRA1), making ARMS2 the best candidate for being the genuine AMD gene within this locus. Yet, homozygous carriers of a common haplotype carry a premature stop codon in the ARMS2 gene (R38X) and therefore lack ARMS2, but this variant is not associated with AMD. In this work we aimed at characterizing the diversity of transcripts originating from this locus, in order to find new hints on how to resolve this perplexing paradox. We found chimeric transcripts originating from the PLEKHA1 gene but ending in ARMS2. This finding may give a new explanation as to how variants in this locus contribute to AMD. PMID- 26427390 TI - Conditional Induction of Oxidative Stress in RPE: A Mouse Model of Progressive Retinal Degeneration. AB - An appropriate animal model is essential to screening drugs or designing a treatment strategy for geographic atrophy. Since oxidative stress contributes to the pathological changes of the retinal pigment epithelium (RPE), we are reporting a new mouse AMD model of retinal degeneration by inducing mitochondrial oxidative stress in RPE. Sod2 the gene for manganese superoxide dismutase (MnSOD) was deleted in RPE layer using conditional knockout strategy. Fundus microscopy, SD-OCT and electroretinography were used to monitor retinal structure and function in living animals and microscopy was used to assess pathology post mortem. Tissue specific deletion of Sod2 caused elevated signs of oxidative stress, RPE dysfunction and showed some key features of AMD. Due to induction of oxidative stress, the conditional knockout mice show progressive reduction in ERG responses and thinning of outer nuclear layer (ONL) compared to non-induced littermates. PMID- 26427391 TI - Therapeutic Approaches to Histone Reprogramming in Retinal Degeneration. AB - Recent data have revealed epigenetic derangements and subsequent chromatin remodeling as a potent biologic switch for chronic inflammation and cell survival which are important therapeutic targets in the pathogenesis of several retinal degenerations. Histone deacetylases (HDACs) are a major component of this system and serve as a unique control of the chromatin remodeling process. With a multitude of targeted HDAC inhibitors now available, their use in both basic science and clinical studies has widened substantially. In the field of ocular biology, there are data to suggest that HDAC inhibition may suppress neovascularization and may be a possible treatment for retinitis pigmentosa and dry age-related macular degeneration (AMD). However, the effects of these inhibitors on cell survival and chemokine expression in the chorioretinal tissues remain very unclear. Here, we review the multifaceted biology of HDAC activity and pharmacologic inhibition while offering further insight into the importance of this epigenetic pathway in retinal degenerations. Our laboratory investigations aim to open translational avenues to advance dry AMD therapeutics while exploring the role of acetylation on inflammatory gene expression in the aging and degenerating retina. PMID- 26427392 TI - A Brief Discussion on Lipid Activated Nuclear Receptors and their Potential Role in Regulating Microglia in Age-Related Macular Degeneration (AMD). AB - Age-related macular degeneration (AMD) is the leading cause of legal blindness and visual impairment in individuals over 60 years of age in the Western World. A common morphological denominator in all forms of AMD is the accumulation of microglia within the sub-retinal space, which is believed to be a contributing factor to AMD progression. However, the signaling pathway and molecular players regulating microglial recruitment have not been completely identified. Multiple in-vitro and in-vivo studies, to date, have highlighted the contributions of nuclear receptor ligands in the treatment of inflammation related disorders such as atherosclerosis and Alzheimer's disease. Given that inflammation and the immune response play a vital role in the initiation and progression of AMD, in this brief review we will highlight some of these studies with a particular focus on the lipid activated "adopted orphan" nuclear receptors, the liver x receptors (LXRs) and the peroxisome proliferator-activated receptors (PPARs). The results of these studies strongly support the rationale that treatment with LXR and PPAR ligands may ameliorate microglial activation in the sub-retinal space and ultimately slow down or reverse the progression of AMD. PMID- 26427393 TI - Extracellular Matrix Alterations and Deposit Formation in AMD. AB - Age related macular degeneration (AMD) is the primary cause of vision loss in the western world (Friedman et al., Arch Ophthalmol 122:564-572, 2004). The first clinical indication of AMD is the presence of drusen. However, with age and prior to the formation of drusen, extracellular basal deposits accumulate between the retinal pigment epithelium (RPE) and Bruch's membrane (BrM). Many studies on the molecular composition of the basal deposits and drusen have demonstrated the presence of extracellular matrix (ECM) proteins, complement components and cellular debris. The evidence reviewed here suggests that alteration in RPE cell function might be the primary cause for the accumulation of ECM and cellular debri found in basal deposits. Further studies are obviously needed in order to unravel the specific pathways that lead to abnormal formation of ECM and complement activation. PMID- 26427394 TI - The NLRP3 Inflammasome and its Role in Age-Related Macular Degeneration. AB - Age related macular degeneration (AMD) is the most common cause of blindness among people of 65 years and older in developed countries (Klein and Klein, Invest Ophthalmol Vis Sci 54:7395-7401, 2013). Recent advances in dry AMD research points towards an important role of the inflammatory response in the development of the disease. The presence of inflammatory cells, antibodies, complement factors and pro-inflammatory cytokines in AMD retinas and drusen indicates that the immune system could be an important driving force in dry AMD. The NLRP3 inflammasome has been proposed as an integrator of process associated with AMD and the induction of inflammation. Herein we summarize the most recent studies that attempt to understand the role of the NLRP3 inflammasome in AMD. PMID- 26427395 TI - Oxidative Stress and the Nrf2 Anti-Oxidant Transcription Factor in Age-Related Macular Degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of acquired and irreversible blindness among elderly Americans. Most AMD patients have the dry form of the disease (dAMD) for which reliable therapies are lacking. A major obstacle to the development of effective treatments is a deficit in our understanding of what triggers dAMD onset. This is particularly the case with respect to the events that cause retinal pigment epithelial (RPE) cells to transition from a state of health and homeostasis to one of dysfunction and atrophy. These cells provide critical support to the photoreceptors and their atrophy often precipitates photoreceptor death in dAMD. Chronic oxidative stress is a primary driver of age-dependent, RPE atrophy. Sources of this stress have been identified (e.g., cigarette smoke, photooxidized bisretinoids), but we still do not understand how these stressors damage RPE constituents or what age dependent changes undermine the cytoprotective systems in the RPE. This review focuses on Nrf2, the master antioxidant transcription factor, and its role in the RPE during aging and dAMD onset. PMID- 26427396 TI - Aging Changes in Retinal Microglia and their Relevance to Age-related Retinal Disease. AB - Age-related retinal diseases, such as age-related macular degeneration (AMD) and glaucoma, contain features of chronic retinal inflammation that may promote disease progression. However, the relationship between aging and neuroinflammation is unclear. Microglia are long-lived, resident immune cells of the retina, and mediate local neuroinflammatory reactions. We hypothesize that aging changes in microglia may be causally linked to neuroinflammatory changes underlying age-dependent retinal diseases. Here, we review the evidence for (1) how the retinal microglial phenotype changes with aging, (2) the factors that drive microglial aging in the retina, and (3) aging-related changes in microglial gene expression. We examine how these aspects of microglial aging changes may relate to pathogenic mechanisms of immune dysregulation driving the progression of age-related retinal disease. These relationships can highlight microglial aging as a novel target for the prevention and treatment of retinal disease. PMID- 26427397 TI - VEGF-A and the NLRP3 Inflammasome in Age-Related Macular Degeneration. AB - The pathomechanisms that lead to age-related macular degeneration (AMD) are only partially understood. The NLRP3 inflammasome has been shown to be activated in the retinal pigment epithelium (RPE) in eyes with AMD. However, it is not known whether inflammasome activation is a cause or consequence of pathologic changes in AMD. A roadblock to defining the role of inflammasome activation and pathways that regulate it for AMD has been the lack of a mouse model that forms AMD-like pathologies in an age-dependent manner in which the role of the inflammasome can be investigated using genetic studies. We have recently identified such a mouse model, in which increased VEGF-A levels result in early degenerative changes of the RPE, followed by cardinal features of both nonexudative and neovascular AMD. Importantly, higher VEGF-A levels lead to increased oxidative damage and a sub retinal inflammatory infiltrate that are associated with NLRP3 inflammasome activation in the RPE. Targeting the NLRP3 inflammasome inhibited AMD-like pathologies in these mice. These findings suggest that inhibiting the NLRP3 inflammasome or pathways that regulate it may provide novel therapeutic approaches for the treatment of both forms of AMD. PMID- 26427398 TI - Interrelation Between Oxidative Stress and Complement Activation in Models of Age Related Macular Degeneration. AB - Millions of individuals older than 50-years suffer from age-related macular degeneration (AMD). Associated with this multifactorial disease are polymorphisms of complement factor genes and a main environmental risk factor-oxidative stress. Until now the linkage between these risk factors for AMD has not been fully understood. Recent studies, integrating results on oxidative stress, complement activation, epidemiology and ocular pathology suggested the following sequence in AMD-etiology: initially, chronic oxidative stress results in modification of proteins and lipids in the posterior of the eye; these tissue alterations trigger chronic inflammation, involving the complement system; and finally, invasive immune cells facilitate pathology in the retina. Here, we summarize the results for animal studies which aim to elucidate this molecular interplay of oxidative events and tissue-specific complement activation in the eye. PMID- 26427399 TI - Gene-Diet Interactions in Age-Related Macular Degeneration. AB - Age-related macular degeneration (AMD) is a prevalent blinding disease, accounting for roughly 50 % of blindness in developed nations. Very significant advances have been made in terms of discovering genetic susceptibilities to AMD as well as dietary risk factors. To date, nutritional supplementation is the only available treatment option for the dry form of the disease known to slow progression of AMD. Despite an excellent understanding of genes and nutrition in AMD, there is remarkably little known about gene-diet interactions that may identify efficacious approaches to treat individuals. This review will summarize our current understanding of gene-diet interactions in AMD with a focus on animal models and human epidemiological studies. PMID- 26427400 TI - Challenges in the Development of Therapy for Dry Age-Related Macular Degeneration. AB - Dry age-related macular degeneration (AMD), a multifactorial progressive degenerative disease of the retinal photoreceptors, pigmented epithelium and Bruch's membrane/choroid in central retina, causes visual impairment in millions of elderly people worldwide. The only available therapy for this disease is the over-the-counter (OTC) multi-vitamins plus macular xanthophyll (lutein/zeaxanthin) which attempts to block the damages of oxidative stress and ionizing blue light. Therefore development of dry AMD prescribed treatment is a pressing unmet medical need. However, this effort is currently hindered by many challenges, including an incomplete understanding of the mechanism of pathogenesis that leads to uncertain targets, confounded by not yet validated preclinical models and the difficulty to deliver the drugs to the posterior segment of the eye. Additionally, with slow disease progression and a less than ideal endpoint measurement method, clinical trials are necessarily large, lengthy and expensive. Increased commitment to research and development is an essential foundation for dealing with these problems. Innovations in clinical trials with novel endpoints, nontraditional study designs and the use of surrogate diseases might shorten the study time, reduce the patient sample size and consequently lower the budget for the development of the new therapies for the dry AMD. PMID- 26427401 TI - Nanoceria: a Potential Therapeutic for Dry AMD. AB - Age-related macular degeneration (AMD) is the leading cause of blinding diseases. The "dry" form of AMD is the most common form of AMD. In contrast to the treatable neovascular (wet) AMD, no effective treatment is available for dry AMD. In this review, we summarize the animal models and therapeutic strategies for dry AMD. The novel candidates as potential treatment targets and the potential effectiveness of nanoceria as a treatment of dry AMD are also discussed. PMID- 26427402 TI - beta-amyloidopathy in the Pathogenesis of Age-Related Macular Degeneration in Correlation with Neurodegenerative Diseases. AB - Involvement of new biotechnology and genetic engineering methods to the study of the aging organism allowed to select a group of neurodegenerative diseases (NDD) which have a similar mechanism of pathogenesis including pathological processes of protein aggregation and its deposition in the structures of nerve tissue. The development of eye and brain from one embryonic germ layer, community of ethiopathogenetic and morphological manifestations of age-related macular degeneration (AMD) and Alzheimer's disease (AD), a common pathway of beta-amyloid precursor protein (APP) are associated with the pathological aggregation of fibrillar beta-amyloid (Abeta) protein and the development of beta-amyloidopathy in structural elements of the eye and the brain. The review demonstrates the keynote of AMD and AD pathogenesis is beta-amyloidopathy that is a manifestation of proteinopathy leading to cytotoxicity, neurodegeneration and the development of pathological apoptosis activated by the formation of intracellular Abeta. This view on the problem predetermines the development of new strategies for the creating of ophthalmogeriatric and neuroprotective drugs affecting the pathogenesis and including all stages of Abeta formation and pathological aggregation. PMID- 26427403 TI - Different Mutations in ELOVL4 Affect Very Long Chain Fatty Acid Biosynthesis to Cause Variable Neurological Disorders in Humans. AB - All mammalian cell membranes are characterized by amphipathic lipid molecules that interact with proteins to confer structural and functional properties on the cell. The predominant lipid species are phospholipids, glycolipids, sphingolipids and cholesterol. These lipids contain fatty acids with variable hydrocarbon chain lengths between C14-C40, either saturated or unsaturated, that are derived from diet, synthesized de novo, or elongated from shorter chain fatty acids by fatty acid elongase enzymes. One member of the family of elongases, ELOngation of Very Long chain fatty acids-4 (ELOVL4), mediates the biosynthesis of both saturated and unsaturated very long chain fatty acids (VLC-FA; > C26) in the retina, meibomian gland, brain, skin, and testis. Different mutations in ELOVL4 cause tissue-specific maculopathy and/or neuro-ichthyotic disorders. The goal of this mini-review is to highlight how different mutations in ELOVL4 can cause variable phenotypic disorder, and propose a possible mechanism, based on the role of fatty acids in membranes, which could explain the different phenotypes. PMID- 26427404 TI - Mouse Models of Stargardt 3 Dominant Macular Degeneration. AB - Stargardt type 3 macular degeneration is dependent on a dominant defect in a single gene, ELOVL4 (elongase of very long chain fatty acids 4). The encoded enzyme, ELOVL4, is required for the synthesis of very long chain polyunsaturated fatty acids (VLC-PUFAs), a rare class of > C24 lipids. In vitro expression studies suggest that mutated ELOVL4(STGD3) proteins fold improperly, resulting in ER stress and formation of cytosolic aggresomes of wild type and mutant ELOVL4. Although a number of mouse models have been developed to determine whether photoreceptor cell loss in STGD3 results from depletion of VLC-PUFAs, aggresome dependent cell stress or a combination of these two factors, none of these models adequately recapitulates the disease phenotype in humans. Thus, the precise molecular mechanism by which ELOVL4 mutation causes photoreceptor degeneration in mice and in human patients remains to be characterized. This mini review compares and evaluates current STGD3 mouse models and determines what conclusions can be drawn from past work. PMID- 26427405 TI - Current Progress in Deciphering Importance of VLC-PUFA in the Retina. AB - Stargardt-like macular dystrophy-3 (STGD3) is a juvenile-onset disease caused by mutations in ELOVL4 (elongation of very long fatty acids-4). This gene product catalyzes the elongation of long chain saturated and polyunsaturated fatty acids (LC-FAs and LC-PUFAs) into very long chain FAs and PUFAs (VLC-FAs and VLC-PUFAs). These mutations cause a frame shift in the ELOVL4 transcript, introducing a premature stop codon that results in the translation of a truncated protein that has lost a C-terminus endoplasmic reticulum (ER) retention/retrieval signal. The truncated protein is not targeted to the ER, the site of very long-chain PUFA (VLC-PUFA; 28-40 carbons) synthesis. Expression of the ELOVL4 gene is limited mainly to the brain, testis, skin, and photoreceptor cells of the retina. While the skin and brain contain very long chain saturated fatty acids (VLC-FAs), the other tissues expressing ELOVL4 contain VLC-PUFAs, with sperm and the retina having the highest levels. This review focuses on the current information available concerning the role of VLC-PUFAs in the retina. PMID- 26427406 TI - Malattia Leventinese/Doyne Honeycomb Retinal Dystrophy: Similarities to Age Related Macular Degeneration and Potential Therapies. AB - Fibulin-3 (F3) is a secreted, disulfide-rich glycoprotein which is expressed in a variety of tissues within the body, including the retina. An Arg345Trp (R345W) mutation in F3 was identified as the cause of a rare retinal dystrophy, Malattia Leventinese/Doyne Honeycomb Retinal Dystrophy (ML/DHRD). ML/DHRD shares many phenotypic similarities with age-related macular degeneration (AMD). The most prominent feature of ML/DHRD is the development of radial or honeycomb patterns of drusen which can develop as early as adolescence. Two independent mouse models of ML/DHRD show evidence of complement activation as well as retinal pigment epithelium (RPE) atrophy, strengthening the phenotypic connection with AMD. Because of its similarities with AMD, ML/DHRD is receiving increasing interest as a potential surrogate disease to study the underpinnings of AMD. This mini-review summarizes the current knowledge of F3 and points toward potential therapeutic strategies which directly or indirectly target cellular dysfunction associated with R345W F3. PMID- 26427407 TI - Hsp90 as a Potential Therapeutic Target in Retinal Disease. AB - The molecular chaperone heat shock protein 90 (Hsp90) is a pivotal cellular regulator involved in the folding, activation and assembly of a wide range of proteins. Hsp90 has multiple roles in the retina and the use of different Hsp90 inhibitors has been shown to prevent retinal degeneration in models of retinitis pigmentosa and age-related macular degeneration. Hsp90 is also a potential target in uveal melanoma. Mechanistically, Hsp90 inhibition can evoke a dual response in the retina; stimulating a stress response with molecular chaperone expression. Thereby leading to an improvement in visual function and photoreceptor survival; however, prolonged inhibition can also stimulate the degradation of Hsp90 client proteins potentially deleteriously affect vision. Here, we review the multiple roles of Hsp90 in the retina and the therapeutic potential of Hsp90 as a target. PMID- 26427408 TI - Leber Congenital Amaurosis: Genotypes and Retinal Structure Phenotypes. AB - Leber congenital amaurosis (LCA) patients of 10 known genotypes (n = 24; age range, 3-25 years) were studied clinically and by optical coherence tomography (OCT). Comparisons were made between OCT results across the horizontal meridian (central 60(o)) of the patients. Three patterns were identified. First, there were LCA genotypes with unusual and readily identifiable patterns, such as near normal outer nuclear layer (ONL) across the central retina or severely dysplastic retina. Second, there were genotypes with well-formed foveal architecture but only residual central islands of normal or reduced ONL thickness. Third, some genotypes showed central ONL losses or dysmorphology suggesting early macular disease or foveal maldevelopment. Objective in vivo morphological features could complement other phenotypic characteristics and help guide genetic testing of LCA patients or at least permit a differential diagnosis of genotypes to be made in the clinic. PMID- 26427409 TI - A Chemical Mutagenesis Screen Identifies Mouse Models with ERG Defects. AB - Mouse models provide important resources for many areas of vision research, pertaining to retinal development, retinal function and retinal disease. The Translational Vision Research Models (TVRM) program uses chemical mutagenesis to generate new mouse models for vision research. In this chapter, we report the identification of mouse models for Grm1, Grk1 and Lrit3. Each of these is characterized by a primary defect in the electroretinogram. All are available without restriction to the research community. PMID- 26427410 TI - Ablation of Chop Transiently Enhances Photoreceptor Survival but Does Not Prevent Retinal Degeneration in Transgenic Mice Expressing Human P23H Rhodopsin. AB - RHO (Rod opsin) encodes a G-protein coupled receptor that is expressed exclusively by rod photoreceptors of the retina and forms the essential photopigment, rhodopsin, when coupled with 11-cis-retinal. Many rod opsin disease -mutations cause rod opsin protein misfolding and trigger endoplasmic reticulum (ER) stress, leading to activation of the Unfolded Protein Response (UPR) signal transduction network. Chop is a transcriptional activator that is induced by ER stress and promotes cell death in response to chronic ER stress. Here, we examined the role of Chop in transgenic mice expressing human P23H rhodopsin (hP23H Rho Tg) that undergo retinal degeneration. With the exception of one time point, we found no significant induction of Chop in these animals and no significant change in retinal degeneration by histology and electrophysiology when hP23H Rho Tg animals were bred into a Chop (-/-) background. Our results indicate that Chop does not play a significant causal role during retinal degeneration in these animals. We suggest that other modules of the ER stress induced UPR signaling network may be involved photoreceptor disease induced by P23H rhodopsin. PMID- 26427411 TI - Identification of a Novel Gene on 10q22.1 Causing Autosomal Dominant Retinitis Pigmentosa (adRP). AB - Whole-genome linkage mapping identified a region on chromosome 10q21.3-q22.1 with a maximum LOD score of 3.0 at 0 % recombination in a six-generation family with autosomal dominant retinitis pigmentosa (adRP). All known adRP genes and X-linked RP genes were excluded in the family by a combination of methods. Whole-exome next-generation sequencing revealed a missense mutation in hexokinase 1, HK1 c.2539G > A, p.Glu847Lys, tracking with disease in all affected family members. One severely-affected male is homozygous for this region by linkage analysis and has two copies of the mutation. No other potential mutations were detected in the linkage region nor were any candidates identified elsewhere in the genome. Subsequent testing detected the same mutation in four additional, unrelated adRP families, for a total of five mutations in 404 probands tested (1.2 %). Of the five families, three are from the Acadian population in Louisiana, one is French Canadian and one is Sicilian. Haplotype analysis of the affected chromosome in each family and the homozygous individual revealed a rare, shared haplotype of 450 kb, suggesting an ancient founder mutation. HK1 is a widely-expressed gene, with multiple, abundant retinal transcripts, coding for hexokinase 1. Hexokinase catalyzes phosphorylation of glucose to glusose-6-phospate, the first step in glycolysis. The Glu847Lys mutation is in a highly-conserved site, outside of the active site or known functional sites. PMID- 26427412 TI - FAM161A and TTC8 are Differentially Expressed in Non-Allelelic Early Onset Retinal Degeneration. AB - Ciliary genes FAM161A and TTC8 have been implicated in retinal degeneration (RD) in humans and in dogs. The identification of FAM161A and TTC8 mutations in canine RD is exciting as there is the potential to develop novel large animal models for RD. However, the disease phenotypes in the dog and the roles of abnormal genes in disease pathology have yet to be fully characterized. The present study evaluated the expression patterns of FAM161A and TTC8 during normal retinal development in dogs, and in three non-allelic, early onset canine RD models at critical time points of the disease: RCD1, XLPRA2 and ERD. Both genes were differentially expressed in RCD1 and ERD, but not in XLPRA2. These results add evidence to the hypothesis that (a) mutations in many retinal genes have a cascade effect on the expression of multiple, possibly unrelated genes and (b) a large number and wide range of genes probably contribute to RD in general. PMID- 26427413 TI - Mutations in the Dynein1 Complex are Permissible for Basal Body Migration in Photoreceptors but Alter Rab6 Localization. AB - The photoreceptor outer segment is a specialized primary cilium, and anchoring of the basal body at the apical membrane is required for outer segment formation. We hypothesized that basal body localization and outer segment formation would require the microtubule motor dynein 1 and analyzed the zebrafish cannonball and mike oko mutants, which carry mutations in the heavy chain subunit of cytoplasmic dynein 1 (dync1h1) and the p150(Glued) subunit of Dynactin (dctn1a). The distribution of Rab6, a player in the post-Golgi trafficking of rhodopsin, was also examined. Basal body docking was unaffected in both mutants, but Rab6 expression was reduced. The results suggest that dynein 1 is dispensable for basal body docking but that outer segment defects may be due to defects in post Golgi trafficking. PMID- 26427414 TI - RDS Functional Domains and Dysfunction in Disease. AB - The photoreceptor specific tetraspanin protein retina degeneration slow (RDS) is a critical component of the machinery necessary for the formation of rod and cone outer segments. Over 80 individual pathogenic mutations in RDS have been identified in human patients that lead to a wide variety of retinal degenerative diseases including retinitis pigmentosa, cone-rod dystrophy, and various forms of macular dystrophy. RDS-associated disease is characterized by a high degree of variability in phenotype and penetrance, making analysis of the underlying molecular mechanisms of interest difficult. Here we summarize our modern understanding of RDS functional domains and oligomerization and how disruption of these domains and complexes could contribute to the variety of disease pathologies seen in human patients with RDS mutations. PMID- 26427415 TI - TULP1 Missense Mutations Induces the Endoplasmic Reticulum Unfolded Protein Response Stress Complex (ER-UPR). AB - Mutations in the TULP1 gene are associated with early-onset retinitis pigmentosa (RP); however, the molecular mechanisms related to the deleterious effects of TULP1 mutations remains unknown. Several studies have shown that misfolded proteins secondary to genetic mutations can accumulate within the endoplasmic reticulum (ER), causing activation of the unfolded protein response (UPR) complex followed by cellular apoptosis. We hypothesize that TULP1 mutations produce misfolded protein products that accumulate in the ER and induce cellular apoptosis via the UPR. To test our hypothesis, we first performed three in-silico analyses of TULP1 missense mutations (I459K, R420P and F491L), which predicted misfolded protein products. Subsequently, the three mutant TULP1-GFP constructs and wild-type (wt) TULP1-GFP were transiently transfected into hTERT-RPE-1 cells. Staining of cells using ER tracker followed by confocal microscopy showed wt TULP1 localized predominantly to the cytoplasm and plasma membrane. In contrast, all three mutant TULP1 proteins revealed cytoplasmic punctate staining which co localized with the ER. Furthermore, western blot analysis of cells expressing mutant TULP1 proteins revealed induction of downstream targets of the ER-UPR complex, including BiP/GPR-78, phosphorylated-PERK (Thr980) and CHOP. Our in vitro analyses suggest that mutant TULP1 proteins are misfolded and accumulate within the ER leading to induction of the UPR stress response complex. PMID- 26427416 TI - Understanding Cone Photoreceptor Cell Death in Achromatopsia. AB - Colour vision is only achieved in the presence of healthy and functional cone photoreceptors found in the retina. It is an essential component of human vision and usually the first complaint patients undergoing vision degeneration have is the loss of daylight colour vision. Therefore, an understanding of the biology and basic mechanisms behind cone death under the degenerative state of retinal dystrophies and how the activation of the apoptotic pathway is triggered will provide valuable knowledge. It will also have broader applications for a spectrum of visual disorders and will be critical for future advances in translational research. PMID- 26427417 TI - Geranylgeranylacetone Suppresses N-Methyl-N-nitrosourea-Induced Photoreceptor Cell Loss in Mice. AB - Retinitis pigmentosa is a disease characterized by the loss of photoreceptor cells. The N-methyl-N-nitrosourea (MNU)-induced retinal degeneration model is widely used to study the mechanism of these retinal degenerative disorders because of its selective photoreceptor cell death. As for the cell death mechanism of MNU, calcium-calpain activation and lipid peroxidation processes are involved in the initiation of this cell death. Although such molecular mechanisms of the MNU-induced cell death have been described, the total image of the cell death is still obscure. Heat shock protein 70 (HSP70) has been shown to function as a chaperon molecule to protect cells against environmental and physiological stresses. In this study, we investigated the effect of geranylgeranylacetone (GGA), an accylic polyisoprenoid, on MNU-induced photoreceptor cell loss. HSP70 induction by GGA was effective against MNU-induced photoreceptor cell loss as a result of its ability to prevent HSP70 degradation. The data indicate that GGA may help to suppress the onset and progression of retinitis pigmentosa. PMID- 26427418 TI - My Retina TrackerTM: An On-line International Registry for People Affected with Inherited Orphan Retinal Degenerative Diseases and their Genetic Relatives - A New Resource. AB - My Retina TrackerTM is a new on-line registry for people affected with inherited orphan retinal degenerative diseases, and their unaffected, genetic relatives. Created and supported by the Foundation Fighting Blindness, it is an international resource designed to capture the disease from the perspective of the registry participant and their retinal health care providers. The registry operates under an Institutional Review Board (IRB)-approved protocol and allows sharing of de-identified data with participants, researchers and clinicians. All participants sign an informed consent that includes selecting which data they wish to share. There is no minimum age of participation. Guardians must sign on behalf of minors, and children between the ages of 12 to 17 also sign an informed assent. Participants may compare their disease to others in the registry using graphical interpretations of the aggregate registry data. Researchers and clinicians have two levels of access. The first provides an interface to interrogate all data fields registrants have agreed to share based on their answers in the IRB informed consent. The second provides a route to contact people in the registry who may be eligible for studies or trials, through the Foundation. PMID- 26427419 TI - A Mini-review: Animal Models of GUCY2D Leber Congenital Amaurosis (LCA1). AB - GUCY2D encodes retinal guanylate cylase-1 (retGC1), a protein that plays a pivotal role in the recovery phase of phototransduction. Mutations in GUCY2D are associated with a leading cause of recessive Leber congenital amaurosis (LCA1). Patients present within the first year of life with aberrant or unrecordable electroretinogram (ERG), nystagmus and a relatively normal fundus. Aside from abnormalities in the outer segments of foveal cones and, in some patients, foveal cone loss, LCA1 patients retain normal retinal laminar architecture suggesting they may be good candidates for gene replacement therapy. Several animal models of LCA1, both naturally occurring and engineered, have been characterized and provide valuable tools for translational studies. This mini-review will summarize the phenotypes of these models and describe how each has been instrumental in proof of concept studies to develop a gene replacement therapy for GUCY2D-LCA1. PMID- 26427420 TI - A Comprehensive Review of Mutations in the MERTK Proto-Oncogene. AB - Phagocytosis and elimination of shed aged photoreceptor outer segments (POS) by retinal pigment epithelial cells is crucial for photoreceptor function and survival. Genetic studies on a natural animal model of recessive retinal degeneration allowed the identification of MerTK, the gene encoding the surface receptor required for POS internalization. Following this discovery, screenings of DNA samples from patients have revealed that MERTK mutations cause retinal degenerations in humans. MERTK patients present some of the classical symptoms of retinitis pigmentosa, but it is atypical in that the disease develops very early during childhood and the macula is also involved early on. Therefore, the phenotype ought to be qualified as a rod-cone dystrophy. Recently, MERTK has been implicated in various types of cancers and sclerosis. This review identifies the different MERTK mutations known so far and describes associated pathologies. PMID- 26427421 TI - New Developments in Murine Imaging for Assessing Photoreceptor Degeneration In Vivo. AB - Optical Coherence Tomography (OCT) is a powerful clinical tool that measures near infrared light backscattered from the eye and other tissues. OCT is used for assessing changes in retinal structure, including layer thicknesses, detachments and the presence of drusen in patient populations. Our custom-built OCT system for the mouse eye quantitatively images all layers of the neural retinal, the RPE, Bruchs' membrane and the choroid. Longitudinal assessment of the same retinal region reveals that the relative intensities of retinal layers are highly stable in healthy tissue, but show progressive increases in intensity in a model of retinal degeneration. The observed changes in OCT signal have been correlated with ultrastructural disruptions that were most dramatic in the inner segments and nuclei of the rods. These early changes in photoreceptor structure coincided with activation of retinal microglia, which migrated vertically from the inner to the outer retina to phagocytose photoreceptor cell bodies (Levine et al., Vis Res 102:71-79, 2014). We conclude that quantitative analysis of OCT light scattering signals may be a useful tool for early detection and subcellular localization of cell stress prior to cell death, and for assessing the progression of degenerative disease over time. Future efforts to develop sensitive approaches for monitoring microglial dynamics in vivo may likewise elucidate earlier signs of cellular stress during retinal degeneration. PMID- 26427422 TI - Reliability and Repeatability of Cone Density Measurements in Patients with Congenital Achromatopsia. AB - Adaptive optics scanning light ophthalmoscopy (AOSLO) allows non-invasive assessment of the cone photoreceptor mosaic. Confocal AOSLO imaging of patients with achromatopsia (ACHM) reveals an altered reflectivity of the remaining cone structure, making identification of the cells more challenging than in normal retinas. Recently, a "split-detector" AOSLO imaging method was shown to enable direct visualization of cone inner segments in patients with ACHM. Several studies have demonstrated gene replacement therapy effective in restoring cone function in animal models of ACHM and human trials have on the horizon, making the ability to reliably assess cone structure increasingly important. Here we sought to examine whether absolute estimates of cone density obtained from split detector and confocal AOSLO images differed from one another and whether the inter- and intra-observer reliability is significantly different between these modes. These findings provide an important foundation for evaluating the role of these images as tools to assess the efficacy of future gene therapy trials. PMID- 26427424 TI - Interpretation of Flood-Illuminated Adaptive Optics Images in Subjects with Retinitis Pigmentosa. AB - The purpose of this study was to correlate features on flood-illuminated adaptive optics (AO) images with color fundus, fundus autofluorescence (FAF) and spectral domain optical coherence tomography (SD-OCT) images in patients with retinitis pigmentosa (RP). We imaged 39 subjects diagnosed with RP using the rtx1TM flood illuminated AO camera from Imagine Eyes (Orsay, France). We observed a correlation between hyper-autofluoresence changes on FAF, disruption of the interdigitation zone (IZ) on SD-OCT and loss of reflective cone profiles on AO. Four main patterns of cone-reflectivity were seen on AO: presumed healthy cone mosaics, hypo-reflective blurred cone-like structures, higher frequency disorganized hyper-reflective spots, and lower frequency hypo-reflective spots. These regions were correlated to progressive phases of cone photoreceptor degeneration observed using SD-OCT and FAF. These results help provide interpretation of en face images obtained by flood-illuminated AO in subjects with RP. However, significant ambiguity remains as to what truly constitutes a cone, especially in areas of degeneration. With further refinements in technology, flood illuminated AO imaging has the potential to provide rapid, standardized, longitudinal and lower cost imaging in patients with retinal degeneration. PMID- 26427423 TI - Quantitative Fundus Autofluorescence in Best Vitelliform Macular Dystrophy: RPE Lipofuscin is not Increased in Non-Lesion Areas of Retina. AB - Since the lipofuscin of retinal pigment epithelial (RPE) cells has been implicated in the pathogenesis of Best vitelliform macular dystrophy, we quantified fundus autofluorescence (quantitative fundus autofluorescence, qAF) as an indirect measure of RPE lipofuscin levels. Mean non-lesion qAF was found to be within normal limits for age. By spectral domain optical coherence tomography (SD OCT) vitelliform lesions presented as fluid-filled subretinal detachments containing reflective material. We discuss photoreceptor outer segment debris as the source of the intense fluorescence of these lesions and loss of anion channel functioning as an explanation for the bullous photoreceptor-RPE detachment. Unexplained is the propensity of the disease for central retina. PMID- 26427425 TI - Intra-familial Similarity of Wide-Field Fundus Autofluorescence in Inherited Retinal Dystrophy. AB - To examine the similarity of wide-field fundus autofluorescence (FAF) imaging in inherited retinal dystrophy between siblings and between parents and their children. The subjects included 17 siblings (12 with retinitis pigmentosa and 5 with cone rod dystrophy) and 10 parent-child pairs (8 with retinitis pigmentosa and 2 with cone rod dystrophy). We quantified the similarity of wide-field FAF using image processing techniques of cropping, binarization, superimposition, and subtraction. The estimated similarity of the siblings was compared with that of the parent-child pairs and that of the age-matched unrelated patients. The similarity between siblings was significantly higher that of parent-child pairs or that of age-matched unrelated patients (P = 0.004 and P = 0.049, respectively). Wide-field FAF images were similar between siblings with inherited retinal dystrophy but different between parent-child pairs. This suggests that aging is a confounding factor in genotype-phenotype correlation studies. PMID- 26427426 TI - Wide-Field Fundus Autofluorescence for Retinitis Pigmentosa and Cone/Cone-Rod Dystrophy. AB - Retinitis pigmentosa and cone/cone-rod dystrophy are inherited retinal diseases characterized by the progressive loss of rod and/or cone photoreceptors. To evaluate the status of rod/cone photoreceptors and visual function, visual acuity and visual field tests, electroretinogram, and optical coherence tomography are typically used. In addition to these examinations, fundus autofluorescence (FAF) has recently garnered attention. FAF visualizes the intrinsic fluorescent material in the retina, which is mainly lipofuscin contained within the retinal pigment epithelium. While conventional devices offer limited viewing angles in FAF, the recently developed Optos machine enables recording of wide-field FAF. With wide-field analysis, an association between abnormal FAF areas and visual function was demonstrated in retinitis pigmentosa and cone-rod dystrophy. In addition, the presence of "patchy" hypoautofluorescent areas was found to be correlated with symptom duration. Although physicians should be cautious when interpreting wide-field FAF results because the peripheral parts of the image are magnified significantly, this examination method provides previously unavailable information. PMID- 26427427 TI - The Development of a Cat Model of Retinal Detachment and Re-attachment. AB - We present an optimized surgical technique for feline retinal detachment which allows for natural re-attachment, reduces retinal scarring and vitreal bands, and allows central placement of the detachment in close proximity to the optic nerve. This enables imaging via Optical Coherence Tomography (OCT) and multifocal electroretinography (mfERG) analysis. Ideal detachment conditions involve a lensectomy followed by a three-port pars plana vitrectomy. A 16-20 % retinal detachment is induced by injecting 8 % C3F8 gas into the subretinal space in the central retina with a 42G cannula. The retinal detachment resolves approximately 6 weeks post-surgery. Imaging is enhanced by using a 7.5 and 20 diopter lens for OCT and mfERG fundus imaging, respectively, to compensate for the removed lens. PMID- 26427428 TI - The Role of X-Chromosome Inactivation in Retinal Development and Disease. AB - The expression of X-linked genes is equalized between males and females in mammalian species through X-Chromosome inactivation (XCI). Every cell in a female mammalian embryo randomly chooses one X Chromosome for epigenetic silencing at the 8-16 cell stage, resulting in a Gaussian distribution of XCI ratios with a peak at 50:50. At the tail extremes of this distribution, X-linked recessive mutations can manifest in disease in female carriers if the mutant allele is disproportionately active. The role of XCI skewing, if any, in X-linked retinal disease is still unknown, although many have speculated that such skewing accounts for phenotypic variation in female carriers of X-linked retinitis pigmentosa (XlRP). Some investigators have used clinical findings such as tapetal like reflex, pigmentary changes, and multifocal ERG parameters to approximate XCI patches in the retina. These studies are limited by small cohorts and the relative inaccessibility of retinal tissue for genetic and epigenetic analysis. Although blood has been used as a proxy for other tissues in determining XCI ratios, blood XCI skews with age out of proportion to other tissues and may not accurately reflect retinal XCI ratios. Future investigations in determining retinal XCI ratios and the contribution of XCI to phenotype could potentially impact prognosis for female carriers of X-linked retinal disease. PMID- 26427429 TI - A Non-Canonical Role for beta-Secretase in the Retina. AB - It has long been established that beta-Secretase (BACE) plays a critical role in the formation of amyloid plaques in Alzheimer's Disease patients, but it is only recently that the importance of beta-secretases in retinal pathophysiology has been recognized. BACE expression is elevated in response to stress, and downregulation results in lysosomal abnormalities and mitochondrial changes. Inhibition of BACE can lead to reduced retinal function, retinal thinning, lipofuscin accumulation and vascular dysfunction in mice. Furthermore, BACE inhibition accelerates choroidal neovascularization (CNV) in mice. We propose that BACE plays an important role in retinal homeostasis and that BACE upregulation in response to stress is a protective measure. PMID- 26427430 TI - The Consequences of Hypomorphic RPE65 for Rod and Cone Photoreceptors. AB - RPE65 is essential for both rod- and cone-mediated vision. So far, more than 120 disease-associated mutations have been identified in the human RPE65 gene. Differential clinical manifestations suggested that some patients suffer from null mutations while others retain residual RPE65 activity and some useful vision. To understand the mechanism of retinal degeneration or dysfunction caused by such hypomorphic RPE65 alleles, we generated an Rpe65 (R91W) knock-in mouse (R91W) that expresses a mutant RPE65 protein with reduced function. Data obtained suggested that the R91W mouse is highly suitable to study the impact of RPE65 insufficiency on rod pathophysiology. To study the impact on cones, we combined the R91W with the Nrl (-/-) mouse that develops an all-cone retina. Here we summarize the consequences of hypomorphic RPE65 function (reduced 11-cis-retinal synthesis) for rod and cone pathophysiology. PMID- 26427431 TI - The Rate of Vitamin A Dimerization in Lipofuscinogenesis, Fundus Autofluorescence, Retinal Senescence and Degeneration. AB - One of the earliest events preceding several forms of retinal degeneration is the formation and accumulation of vitamin A dimers in the retinal pigment epithelium (RPE) and underlying Bruch's membrane (BM). Such degenerations include Stargardt disease, Best disease, forms of retinitis pigmentosa, and age-related macular degeneration (AMD). Since their discovery in the 1990's, dimers of vitamin A, have been postulated as chemical triggers driving retinal senescence and degeneration. There is evidence to suggest that the rate at which vitamin A dimerizes and the eye's response to the dimerization products may dictate the retina's lifespan. Here, we present outstanding questions, finding the answers to which may help to elucidate the role of vitamin A dimerization in retinal degeneration. PMID- 26427432 TI - Can Vitamin A be Improved to Prevent Blindness due to Age-Related Macular Degeneration, Stargardt Disease and Other Retinal Dystrophies? AB - We discuss how an imperfect visual cycle results in the formation of vitamin A dimers, thought to be involved in the pathogenesis of various retinal diseases, and summarize how slowing vitamin A dimerization has been a therapeutic target of interest to prevent blindness. To elucidate the molecular mechanism of vitamin A dimerization, an alternative form of vitamin A, one that forms dimers more slowly yet maneuvers effortlessly through the visual cycle, was developed. Such a vitamin A, reinforced with deuterium (C20-D3-vitamin A), can be used as a non disruptive tool to understand the contribution of vitamin A dimers to vision loss. Eventually, C20-D3-vitamin A could become a disease-modifying therapy to slow or stop vision loss associated with dry age-related macular degeneration (AMD), Stargardt disease and retinal diseases marked by such vitamin A dimers. Human clinical trials of C20-D3-vitamin A (ALK-001) are underway. PMID- 26427433 TI - Class I Phosphoinositide 3-Kinase Exerts a Differential Role on Cell Survival and Cell Trafficking in Retina. AB - Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylates the 3'OH of the inositol ring of phosphoinositides. They are responsible for coordinating a diverse range of cell functions including proliferation, cell survival, degranulation, vesicular trafficking, and cell migration. The PI 3-kinases are grouped into three distinct classes: I, II, and III. Class III PI3K has been shown to be involved in intracellular protein trafficking, whereas class I PI3K is known to regulate cell survival following activation of cell surface receptors. However, studies from our laboratory and others have shown that class I PI3K may also be involved in photoreceptor protein trafficking. Therefore, to learn more about the role of class I and class III P13K in trafficking and to understand the impact of the lipid content of trafficking cargo vesicles, we developed a methodology to isolate trafficking vesicles from retinal tissue. PI3K class I and III proteins were enriched in our extracted trafficking vesicle fraction. Moreover, levels of ether phosphatidylethanolamine (PE) and ether phosphatidylcholine (PC) were significantly higher in the trafficking vesicle fraction than in total retina. These two lipid classes have been suggested to be involved with fusion/targeting of trafficking vesicles. PMID- 26427434 TI - Cell Cycle Proteins and Retinal Degeneration: Evidences of New Potential Therapeutic Targets. AB - During different forms of neurodegenerative diseases, including the retinal degeneration, several cell cycle proteins are expressed in the dying neurons from Drosophila to human revealing that these proteins are a hallmark of neuronal degeneration. This is true for animal models of Alzheimer's, and Parkinson's diseases, Amyotrophic Lateral Sclerosis and for Retinitis Pigmentosa as well as for acute injuries such as stroke and light damage. Longitudinal investigation and loss-of-function studies attest that cell cycle proteins participate to the process of cell death although with different impacts, depending on the disease. In the retina, inhibition of cell cycle protein action can result to massive protection. Nonetheless, the dissection of the molecular mechanisms of neuronal cell death is necessary to develop adapted therapeutic tools to efficiently protect photoreceptors as well as other neuron types. PMID- 26427435 TI - Nitric Oxide Synthase Activation as a Trigger of N-methyl-N-nitrosourea-Induced Photoreceptor Cell Death. AB - Retinal degeneration (RD) such as retinitis pigmentosa and age-related macular degeneration are major causes of blindness in adulthood. As one of the model for RD, intraperitoneal injection of N-methyl-N-nitrosourea (MNU) is widely used because of its selective photoreceptor cell death. It has been reported that MNU increases intracellular calcium ions in the retina and induces photoreceptor cell death. Although calcium ion influx triggers the neuronal nitric oxide synthase (nNOS) activation, the role of nNOS on photoreceptor cell death by MNU has not been reported yet. In this study, we investigated the contribution of nNOS on photoreceptor cell death induced by MNU in mice. MNU significantly increased NOS activation at 3 day after treatment. Then, we evaluated the effect of nNOS specific inhibitor, ethyl[4-(trifluoromethyl) phenyl]carbamimidothioate (ETPI) on the MNU-induced photoreceptor cell death. At 3 days, ETPI clearly inhibited the MNU-induced cell death in the ONL. These data indicate that nNOS is a key molecule for pathogenesis of MNU-induced photoreceptor cell death. PMID- 26427436 TI - Molecular Principles for Decoding Homeostasis Disruptions in the Retinal Pigment Epithelium: Significance of Lipid Mediators to Retinal Degenerative Diseases. AB - Dysregulated neuroinflammatory signaling during impending disruption of homeostasis in retinal pigment epithelium (RPE) and photoreceptor cells (PRC) takes place in early stages of retinal degeneration. PRCs avidly retain and display the highest content in the human body of docosahexaenoic acid (DHA; an omega-3 essential fatty acid). Docosanoids are DHA-derived mediators, such as neuroprotectin D1 (NPD1), made on-demand that promote repair, phagocytic clearance, cell survival, and are active participants of effective, well concerted homeostasis restoration. Here we develop the concept that there is a molecular logic that sustains PRC survival and that transcriptional signatures governed by NPD1 in the RPE may be engaged. PMID- 26427437 TI - Aging and Vision. AB - Aging involves defined genetic, biochemical and cellular pathways that regulate lifespan. These pathways are called longevity pathways and they have relevance for many age-related diseases. In the eye, longevity pathways are involved in the major blinding diseases, cataract, glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy. Pharmaceutical targeting of longevity pathways can extend healthy lifespan in laboratory model systems. This offers the possibility of therapeutic interventions to also delay onset or slow the progression of age-related eye diseases. I suggest that retinal degeneration may be viewed as accelerated aging of photoreceptors and that interventions extending healthy lifespan may also slow the pace of photoreceptor loss. PMID- 26427438 TI - The Potential Use of PGC-1alpha and PGC-1beta to Protect the Retina by Stimulating Mitochondrial Repair. AB - Damage to mitochondria is a common mechanism of cell death in inherited neurodegenerative disorders. Therefore, mitochondrial protection and mitochondrial repair are promising strategies to induce retinal neuroprotection. Peroxisome proliferator-activated receptor gamma coactivator-alpha (PGC-1alpha) and beta (PGC-1beta) are transcriptional coactivators that are the main regulators of mitochondrial biogenesis. We propose that PGC-1alpha and PGC-1beta could play a role in regulating retina cell survival, and may be important therapeutic targets to prevent retinal degeneration. PMID- 26427439 TI - Retinal Caveolin-1 Modulates Neuroprotective Signaling. AB - Caveolin-1 (Cav-1), the scaffolding protein of caveolae, is expressed in several retinal cell types and is associated with ocular pathologies. Cav-1 modulates neuroinflammatory/neuroprotective responses to central nervous system injury. We have shown that loss of Cav-1 results in a blunted cytokine response in retinas challenged with inflammatory stimuli. As neuroinflammatory and neuroprotective signaling overlap in their cytokine production and downstream signaling pathways, we hypothesized that loss of Cav-1 may also suppress neuroprotective signaling in the retina. To test this, we subjected mice in which Cav-1 was deleted specifically in the retina to a neurodegenerative insult induced by sodium iodate (NaIO3) and measured STAT3 activation, a measure of neuroprotective signaling. Our results show that Cav-1 ablation blunts STAT3 activation induced by NaIO3. STAT3 activation in response to intravitreal administration of the IL-6 family cytokine, leukemia inhibitory factor (LIF), was not affected by Cav-1 deletion indicating a competent gp130 receptor response. Thus, Cav-1 modulates neuroprotective signaling by regulating the endogenous production of neuroprotective factors. PMID- 26427440 TI - Photoreceptor Neuroprotection: Regulation of Akt Activation Through Serine/Threonine Phosphatases, PHLPP and PHLPPL. AB - Serine/threonine kinase Akt is a downstream effector of insulin receptor/PI3K pathway that is involved in many processes, including providing neuroprotection to stressed rod photoreceptor cells. Akt signaling is known to be regulated by the serine/threonine phosphatases, PHLPP (PH domain and leucine rich repeat protein phosphatase) and PHLPPL (PH domain and leucine rich repeat protein phosphatase-like). We previously reported that both phosphatases are expressed in the retina, as well as in photoreceptor cells. In this study, we examined the PHLPP and PHLPPL phosphatase activities towards non-physiological and physiological substrates. Our results suggest that PHLPP was more active than PHLPPL towards non-physiological substrates, whereas both PHLPP and PHLPP dephosphorylated the physiological substrates of Akt1 and Akt3 with similar efficiencies. Our results also suggest that knockdown of PHLPPL alone does not increase Akt phosphorylation, due to a compensatory increase of PHLPP, which results in the dephosphorylation of Akt. Therefore, PHLPP and PHLPPL regulate Akt activation together when both phosphatases are expressed. PMID- 26427441 TI - The Role of AMPK Pathway in Neuroprotection. AB - Adenosine monophosphate-activated kinase (AMPK) is a highly conserved protein kinase found in all eukaryotic genomes. It exists as heterotrimeric protein consisting of alpha, beta, and gamma subunits. AMPK is activated by elevated levels of adenosine mono-phosphate (AMP), which is produced during conditions of low ATP production and perhaps mitochondrial dysfunction. Activation of AMPK has been shown to regulate a large number of downstream pathways. These will either increase energy production such as increase oxidation of fatty acids and glucose, or decrease energy utilization such as inhibiting synthesis of glycogen, fatty acid synthesis, and protein synthesis. In addition, being a key regulator of physiological energy dynamics, AMPK has been demonstrated to play roles in regulating various cellular processes such as mitochondrial biogenesis (Jager et al. Proc Natl Acad Sci U S A 104:12017-12022, 2007), autophagy (Hyttinen et al. Rejuven Res 14:651-660, 2011) and inflammation and immune responses (Giri et al. 2004). Retinal neurons have a high energy demand but have a poor energy storage capacity. Because of this, it is likely that the AMPK signaling pathway plays an important role in maintaining energy balance, and therefore may be a therapeutic target to prevent or delay retinal degeneration. PMID- 26427443 TI - Near-Infrared Photobiomodulation in Retinal Injury and Disease. AB - Evidence is growing that exposure of tissue to low energy photon irradiation in the far-red (FR) to near-infrared (NIR) range of the spectrum, collectively termed "photobiomodulation" (PBM) can restore the function of damaged mitochondria, upregulate the production of cytoprotective factors and prevent apoptotic cell death. PBM has been applied clinically in the treatment of soft tissue injuries and acceleration of wound healing for more than 40 years. Recent studies have demonstrated that FR/NIR photons penetrate diseased tissues including the retina. The therapeutic effects of PBM have been hypothesized to result from intracellular signaling pathways triggered when FR/NIR photons are absorbed by the mitochondrial photoacceptor molecule, cytochrome c oxidase, culminating in improved mitochondrial energy metabolism, increased cytoprotective factor production and cell survival. Investigations in rodent models of methanol induced ocular toxicity, light damage, retinitis pigmentosa and age-related macular degeneration have demonstrated the PBM attenuates photoreceptor cell death, protects retinal function and exerts anti-inflammatory actions. PMID- 26427442 TI - Tauroursodeoxycholic Acid Protects Retinal Function and Structure in rd1 Mice. AB - We explored the potential protective effects of tauroursodeoxycholic acid (TUDCA) on cone photoreceptor survival in a model of rapid retinal degeneration, the beta Pde6 (rd1) (rd1) mouse model. We injected two strains of rd1 mice (B6.C3-Pde6b (rd1) Hps4(le)/J and C57BL/6J-Pde6b (rd1-2)/J mice) daily from postnatal day (P) 6 to P21 with TUDCA or vehicle. At P21, retinal function was evaluated with light adapted electroretinography (ERG) and retinal structure was observed with plastic or frozen sections. TUDCA treatment partially preserved function and structure in B6.C3-Pde6b (rd1) Hps4(le)/J mice but only partially preserved structure in C57BL/6J-Pde6b (rd1-2)/J mice. Our results suggest a possible intervention for patients undergoing rapid retinal degeneration. PMID- 26427444 TI - Exercise and Cyclic Light Preconditioning Protect Against Light-Induced Retinal Degeneration and Evoke Similar Gene Expression Patterns. AB - To compare patterns of gene expression following preconditioning cyclic light rearing versus preconditioning aerobic exercise. BALB/C mice were preconditioned either by rearing in 800 lx 12:12 h cyclic light for 8 days or by running on treadmills for 9 days, exposed to toxic levels of light to cause light-induced retinal degeneration (LIRD), then sacrificed and retinal tissue harvested. Subsets of mice were maintained for an additional 2 weeks and for assessment of retinal function by electroretinogram (ERG). Both preconditioning protocols partially but significantly preserved retinal function and morphology and induced similar leukemia inhibitory factor (LIF) gene expression pattern. The data demonstrate that exercise preconditioning and cyclic light preconditioning protect photoreceptors against LIRD and evoke a similar pattern of retinal LIF gene expression. It may be that similar stress response pathways mediate the protection provided by the two preconditioning modalities. PMID- 26427445 TI - Small Molecules that Protect Mitochondrial Function from Metabolic Stress Decelerate Loss of Photoreceptor Cells in Murine Retinal Degeneration Models. AB - One feature common to many of the pathways implicated in retinal degeneration is increased metabolic stress leading to impaired mitochondrial function. We found that exposure of cells to calcium ionophores or oxidants as metabolic stressors diminish maximal mitochondrial capacity. A library of 50,000 structurally diverse "drug-like" molecules was screened for protection against loss of calcium-induced loss of mitochondrial capacity in 661W rod-derived cells and C6 glioblastomas. Initial protective hits were then tested for protection against IBMX-induced loss of mitochondrial capacity as measured via respirometry. Molecules that protected mitochondria were then evaluated for protection of rod photoreceptor cells in retinal explants from rd1 mice. Two of the molecules attenuated loss of photoreceptor cells in the rd1 model. In the 661W cells, exposure to calcium ionophore or tert-butylhydroperoxide caused mitochondrial fragmentation that was blocked with the both compounds. Our studies have identified molecules that protect mitochondria and attenuate loss of photoreceptors in models of retinal degeneration suggesting that they could be good leads for development of therapeutic drugs for treatment of a wide variety of retinal dystrophies. PMID- 26427446 TI - Histone Deacetylase: Therapeutic Targets in Retinal Degeneration. AB - Previous studies report that retinitis pigmentosa (RP) patients treated with the histone deacetylase inhibitor (HDACi) valproic acid (VPA) present with improved visual fields and delayed vision loss. However, other studies report poor efficacy and safety of HDACi in other cohorts of retinal degeneration patients. Furthermore, the molecular mechanisms by which HDACi can improve visual function is unknown, albeit HDACi can attenuate pro-apoptotic stimuli and induce expression of neuroprotective factors. Thus, further analysis of HDACi is warranted in pre-clinical models of retinal degeneration including zebrafish. Analysis of HDAC expression in developing zebrafish reveals diverse temporal expression patterns during development and maturation of visual function. PMID- 26427447 TI - Therapeutic Approach of Nanotechnology for Oxidative Stress Induced Ocular Neurodegenerative Diseases. AB - Oxidative stress plays a role in many different forms of neurodegenerative ocular disease. The imbalance between the generation of endogenous reactive oxygen species (ROS) and their corresponding neutralization by endogenous antioxidant defense systems leads to cellular oxidative stress, oxidation of different bio macromolecules, and eventually retinal disease. As a result, the administration of supplemental endogenous antioxidant materials or exogenous ROS scavengers is an interesting therapeutic approach for the treatment of forms of ocular disease associated with oxidative stress. Thus far, different dietary antioxidant supplements have been proven to be clinically reliable and effective, and different antioxidant gene therapy approaches are under investigation. In addition, various metal oxide nanoparticles were shown to be effective in defending against oxidative stress-associated injury. These benefits are due to free radical scavenging properties of the materials arising from non stoichiometric crystal defects and oxygen deficiencies. Here we discuss the application of this approach to the protection of the retina. PMID- 26427448 TI - Transscleral Controlled Delivery of Geranylgeranylaceton Using a Polymeric Device Protects Rat Retina Against Light Injury. AB - We evaluated the effects of a transscleral drug delivery device, consisting of a reservoir and controlled-release cover, which were made of photopolymerized polyethylene glycol dimethacrylate and triethylene glycol dimethacrylate, combined at different ratios. Geranylgeranylacetone (GGA), a heat-shock protein (HSP) inducer, was loaded into the device. The GGA was released from the device under zero-order kinetics. At both 1 week and 4 weeks after device implantation on rat sclera, HSP70 gene and protein expression were up-regulated in the sclera choroid-retinal pigment epithelium fraction of rat eyes treated with the GGA loaded device compared with rat eyes treated with saline-loaded devices or eyes of non-treated rats. Flash electroretinograms were recorded 4 days after white light exposure (8000 lx for 18 h). Electroretinographic amplitudes of the a- and b-waves were preserved significantly in rats treated with GGA-loaded devices compared with rats treated with saline-loaded devices. Histological examination showed that the outer nuclear layer thickness was preserved in rats that had the GGA-loaded device. These results may show that transscleral GGA delivery using our device may offer an alternative method to treat retinal diseases. PMID- 26427449 TI - Targeting the Proteostasis Network in Rhodopsin Retinitis Pigmentosa. AB - Mutations in rhodopsin are one of the most common causes of retinitis pigmentosa (RP). Misfolding of rhodopsin can result in disruptions in cellular protein homeostasis, or proteostasis. There is currently no available treatment for RP. In this review, we discuss the different approaches currently being investigated for treatment of rhodopsin RP, focusing on the potential of manipulation of the proteostasis network as a therapeutic approach to combat retinal degeneration. PMID- 26427451 TI - Tamoxifen-Containing Eye Drops Successfully Trigger Cre-Mediated Recombination in the Entire Eye. AB - Embryonic lethality in mice with targeted gene deletion is a major issue that can be circumvented by using Cre-loxP-based animal models. Various inducible Cre systems are available, e.g. such that are activated following tamoxifen treatment, and allow deletion of a specific target gene at any desired time point during the life span of the animal. In this study, we describe the efficiency of topical tamoxifen administration by eye drops using a Cre- reporter mouse strain (R26R). We report that tamoxifen-responsive CAGGCre-ER (TM) mice show a robust Cre- mediated recombination throughout the entire eye. PMID- 26427450 TI - Gene Therapy for MERTK-Associated Retinal Degenerations. AB - MERTK-associated retinal degenerations are thought to have defects in phagocytosis of shed outer segment membranes by the retinal pigment epithelium (RPE), as do the rodent models of these diseases. We have subretinally injected an RPE-specific AAV2 vector, AAV2-VMD2-hMERTK, to determine whether this would provide long-term photoreceptor rescue in the RCS rat, which it did for up to 6.5 months, the longest time point examined. Moreover, we found phagosomes in the RPE in the rescued regions of RCS retinas soon after the onset of light. The same vector also had a major protective effect in Mertk-null mice, with a concomitant increase in ERG response amplitudes in the vector-injected eyes. These findings suggest that planned clinical trials with this vector will have a favorable outcome. PMID- 26427452 TI - Distinct Expression Patterns of AAV8 Vectors with Broadly Active Promoters from Subretinal Injections of Neonatal Mouse Eyes at Two Different Ages. AB - The retinal expression patterns were analyzed following the injection of serotype 8 adeno-associated virus (AAV8) vectors that utilize two broadly active and commonly used sets of transcription regulatory sequences. These include the human cytomegalovirus (CMV) immediate early (IE) enhancer/promoter and the hybrid CAG element (also known as CAGGS or CBA) composed of a partial human CMV IE enhancer and the chicken beta-actin promoter and intron. Subretinal delivery to postnatal day 0 (P0) or 6 (P6) mouse eyes resulted in efficient labeling of retinal cells, but with very distinct patterns. With P0 delivery, AAV8-CMV-GFP selectively labelled photoreceptors, while AAV8-CAG-GFP efficiently labeled both outer and inner retinal neurons, including photoreceptors, horizontal cells, amacrine cells and retinal ganglion cells. With P6 delivery, both vectors led to efficient labeling of photoreceptors and Muller glia cells, but not of inner retinal neurons. Our results suggest that the cell types that express the genes encoded by subretinally delivered AAV8 vectors are determined by both the timing of the injection and the regulatory sequences. PMID- 26427453 TI - Characterization of Ribozymes Targeting a Congenital Night Blindness Mutation in Rhodopsin Mutation. AB - The G90D mutation in the rhodopsin gene leads to autosomal dominant congenital stationary night blindness (CSNB) in patients. This occurs because the G90D mutant protein cannot efficiently bind chromophore and is constitutively active. To combat this mutation, we designed and characterized two different hammerhead ribozymes to cleave G90D transcript. In vitro testing showed that the G90D1 ribozyme efficiently and specifically cleaved the mutant transcript while G90D2 cleaved both WT and mutant transcript. AAV-mediated delivery of G90D1 under the control of the mouse opsin promoter (MOP500) to G90D transgenic eyes showed that the ribozyme partially retarded the functional degeneration (as measured by electroretinography [ERG]) associated with this mutation. These results suggest that with additional optimization, ribozymes may be a useful part of the gene therapy knockdown strategy for dominant retinal disease. PMID- 26427454 TI - Antisense Oligonucleotide Therapy for Inherited Retinal Dystrophies. AB - Inherited retinal dystrophies (IRDs) are an extremely heterogeneous group of genetic diseases for which currently no effective treatment strategies exist. Over the last decade, significant progress has been made utilizing gene augmentation therapy for a few genetic subtypes of IRD, although several technical challenges so far prevent a broad clinical application of this approach for other forms of IRD. Many of the mutations leading to these retinal diseases affect pre-mRNA splicing of the mutated genes . Antisense oligonucleotide (AON) mediated splice modulation appears to be a powerful approach to correct the consequences of such mutations at the pre-mRNA level , as demonstrated by promising results in clinical trials for several inherited disorders like Duchenne muscular dystrophy, hypercholesterolemia and various types of cancer. In this mini-review, we summarize ongoing pre-clinical research on AON-based therapy for a few genetic subtypes of IRD , speculate on other potential therapeutic targets, and discuss the opportunities and challenges that lie ahead to translate splice modulation therapy for retinal disorders to the clinic. PMID- 26427455 TI - Functional Rescue of Retinal Degeneration-Associated Mutant RPE65 Proteins. AB - More than 100 different mutations in the RPE65 gene are associated with inherited retinal degeneration. Although some missense mutations have been shown to abolish isomerase activity of RPE65, the molecular bases leading to loss of function and retinal degeneration remain incompletely understood. Here we show that several missense mutations resulted in significant decrease in expression level of RPE65 in the human retinal pigment epithelium cells. The 26S proteasome non-ATPase regulatory subunit 13, a newly identified negative regulator of RPE65, mediated degradation of mutant RPE65s, which were misfolded and formed aggregates in the cells. Many mutations, including L22P, T101I, and L408P, were mapped on nonactive sites of RPE65. Enzyme activities of these mutant RPE65s were significantly rescued at low temperature, whereas mutant RPE65s with a distinct active site mutation could not be rescued under the same conditions. 4-phenylbutyrate (PBA) displayed a significant synergistic effect on the low temperature-mediated rescue of the mutant RPE65s. Our results suggest that a low temperature eye mask and PBA, a FDA-approved oral medicine, may provide a promising "protein repair therapy" that can enhance the efficacy of gene therapy for delaying retinal degeneration caused by RPE65 mutations. PMID- 26427456 TI - Evaluation of Ocular Gene Therapy in an Italian Patient Affected by Congenital Leber Amaurosis Type 2 Treated in Both Eyes. AB - Gene therapy clinical trials with gene augmentation therapy for Leber Congenital Amaurosis have shown partial reversal of retinal dysfunction. Most studies described the effect of treatment in a single eye and limited evidence is reported in literature about patients treated in both eyes. In this chapter, we present the findings of a young patient treated in both eyes. Efficacy of the treatment was assessed with Best Corrected Visual Acuity, Goldman Visual Field testing, Esterman computerized binocular visual field and Microperimetric testing. Post-treatment results showed improvement of visual function in both eyes, in particular, a strong amelioration was observed after the first injection, by using conventional monocular tests. Moreover, the treatment in the second eye resulted in a further improvement of binocular visual functionality, as easily detected by computerized binocular visual field. In conclusion, our data suggest that gene therapy can inhibit retinal degeneration and can be safe and effective in restoring visual functionality in young subjects treated in both eyes. Finally, new outcome measurements, in particular binocular computerized visual field parameters, can therefore be useful to quantify overall visual gain in patients undergoing gene therapy in both eyes. PMID- 26427457 TI - Regenerative Medicine: Solution in Sight. AB - The retina, like other central nervous system tissues, has poor regenerative properties in humans. Therefore, diseases that cause retinal cell loss, such as Age-related macular degeneration (AMD), retinitis pigmentosa (RP), Leber congenital amaurosis, Usher syndrome, glaucoma, and diabetic retinopathy, typically result in permanent visual impairment. Stem cell technologies have revolutionized our ability to produce neural cells in abundant supply. Much stem cell research effort is focused on producing the required cell types for cell replacement, or to generate disease-in-a-dish models to elucidate novel disease mechanisms for therapeutic development. Here we review the recent advances in stem cell studies relevant to producing RPE and retinal cells, and highlight future directions. PMID- 26427458 TI - Personalized Medicine: Cell and Gene Therapy Based on Patient-Specific iPSC Derived Retinal Pigment Epithelium Cells. AB - Interest in generating human induced pluripotent stem (iPS) cells for stem cell modeling of diseases has overtaken that of patient-specific human embryonic stem cells due to the ethical, technical, and political concerns associated with the latter. In ophthalmology, researchers are currently using iPS cells to explore various applications, including: (1) modeling of retinal diseases using patient specific iPS cells; (2) autologous transplantation of differentiated retinal cells that undergo gene correction at the iPS cell stage via gene editing tools (e.g., CRISPR/Cas9, TALENs and ZFNs); and (3) autologous transplantation of patient-specific iPS-derived retinal cells treated with gene therapy. In this review, we will discuss the uses of patient-specific iPS cells for differentiating into retinal pigment epithelium (RPE) cells, uncovering disease pathophysiology, and developing new treatments such as gene therapy and cell replacement therapy via autologous transplantation. PMID- 26427459 TI - Human Retinal Pigment Epithelium Stem Cell (RPESC). AB - The retinal pigment epithelium (RPE) is a pigmented cellular monolayer that supports photoreceptor cells located in the overlying neural retina. The RPE is critical for vision and its dysfunction results in numerous pathologies, several with limited available disease-altering strategies. Regeneration of the retina from RPE is robust in lower vertebrates, but is not normally exhibited in mammals. We recently found that a subpopulation of human RPE cells can be stimulated in culture to generate multipotent self-renewing cells-the RPE stem cell (RPESC). RPESC can be expanded to generate RPE progeny that are a potential source for cell replacement therapy. Alternatively, RPESC can produce mesenchymal progeny which serve as a disease model of epiretinal membrane formation. Yet another potential application of RPESCs is activation within the eye to awaken dormant endogenous repair. PMID- 26427460 TI - Embryonic Stem Cell-Derived Microvesicles: Could They be Used for Retinal Regeneration? AB - Mouse embryonic stem cells (mESCs) release into the medium in which they are cultured heterogeneous populations of microvesicles (mESMVs), important components of cell-cell communication, that transfer their contents not only to other stem cells but also to cells of other origins. The purpose of these studies was to demonstrate that ESMVs could be the signals that lead the retinal progenitor Muller cells to de-differentiate and re-entry the cell cycle, followed by differentiation along retinal lineages. Indeed, we found that ESMVs induce these processes and change Muller cells' microenvironment towards a more permissive state for tissue regeneration. PMID- 26427461 TI - Intravitreal Implantation of Genetically Modified Autologous Bone Marrow-Derived Stem Cells for Treating Retinal Disorders. AB - A number of retinal degenerative diseases may be amenable to treatment with continuous intraocular delivery of therapeutic agents that cannot be delivered effectively to the retina via systemic or topical administration. Among these disorders are lysosomal storage diseases resulting from deficiencies in soluble lysosomal enzymes. Most cells, including those of the retina, are able to take up these enzymes and incorporate them in active form into their lysosomes. In theory, therefore, continuous intraocular administration of a normal form of a soluble lysosomal enzyme should be able to cure the molecular defect in the retinas of subjects lacking this enzyme. Experiments were conducted to determine whether genetically modified bone marrow-derived stem cells implanted into the vitreous could be used as -vehicles for continuous delivery of such enzymes to the retina. Bone marrow-derived mesenchymal stem cells (MSCs) from normal mice were implanted into the vitreous of mice undergoing retinal degeneration as a result of a mutation in the PPT1 gene. The implanted cells appeared to survive indefinitely in the vitreous without proliferating or invading the retina. This indicates that intravitreal implantation of MSCs is likely a safe means of long term delivery of proteins synthesized by the implanted cells. Experiments have been initiated to test the efficacy of using genetically modified autologous MSCs to inhibit retinal degeneration in a canine model of neuronal ceroid lipofuscinosis. PMID- 26427462 TI - Gliosis Can Impede Integration Following Photoreceptor Transplantation into the Diseased Retina. AB - Retinal degenerations leading to the loss of photoreceptor (PR) cells are a major cause of vision impairment and untreatable blindness. There are few clinical treatments and none can reverse the loss of vision. With the rapid advances in stem cell biology and techniques in cell transplantation, PR replacement by transplantation represents a broad treatment strategy applicable to many types of degeneration. The number of donor cells that integrate into the recipient retina determines transplantation success, yet the degenerating retinae presents a number of barriers that can impede effective integration. Here, we briefly review recent advances in the field of PR transplantation. We then describe how different aspects of gliosis may impact on cell integration efficiency. PMID- 26427463 TI - Interkinetic Nuclear Migration in the Regenerating Retina. AB - In the adult zebrafish, death of retinal neurons stimulates Muller glia to re enter the cell cycle to produce neuronal progenitor cells (NPCs) that undergo further cell divisions and differentiate to replace lost neurons in the correct spatial locations. Understanding the mechanisms regulating retinal regeneration will ultimately provide avenues to overcome vision loss in human. Recently, the observation of interkinetic nuclear migration (INM) of Muller glia in the regenerating zebrafish retina resulted in the inclusion of an additional complex step to the regeneration process. The pathways regulating INM and its function in the regenerating retina have not been well studied. Here, we summarize the evidence for INM in the regenerating retina and review mechanisms that control INM during neuro-epithelial development in the context of pathways known to be critical during retinal regeneration. PMID- 26427464 TI - Use of a Machine Learning-Based High Content Analysis Approach to Identify Photoreceptor Neurite Promoting Molecules. AB - High content analysis (HCA) has become a leading methodology in phenotypic drug discovery efforts. Typical HCA workflows include imaging cells using an automated microscope and analyzing the data using algorithms designed to quantify one or more specific phenotypes of interest. Due to the richness of high content data, unappreciated phenotypic changes may be discovered in existing image sets using interactive machine-learning based software systems. Primary postnatal day four retinal cells from the photoreceptor (PR) labeled QRX-EGFP reporter mice were isolated, seeded, treated with a set of 234 profiled kinase inhibitors and then cultured for 1 week. The cells were imaged with an Acumen plate-based laser cytometer to determine the number and intensity of GFP-expressing, i.e. PR, cells. Wells displaying intensities and counts above threshold values of interest were re-imaged at a higher resolution with an INCell2000 automated microscope. The images were analyzed with an open source HCA analysis tool, PhenoRipper (Rajaram et al., Nat Methods 9:635-637, 2012), to identify the high GFP-inducing treatments that additionally resulted in diverse phenotypes compared to the vehicle control samples. The pyrimidinopyrimidone kinase inhibitor CHEMBL 1766490, a pan kinase inhibitor whose major known targets are p38alpha and the Src family member lck, was identified as an inducer of photoreceptor neuritogenesis by using the open-source HCA program PhenoRipper. This finding was corroborated using a cell-based method of image analysis that measures quantitative differences in the mean neurite length in GFP expressing cells. Interacting with data using machine learning algorithms may complement traditional HCA approaches by leading to the discovery of small molecule-induced cellular phenotypes in addition to those upon which the investigator is initially focusing. PMID- 26427465 TI - A Novel Approach to Identify Photoreceptor Compartment-Specific Tulp1 Binding Partners. AB - Photoreceptors (PRs) are highly polarized and compartmentalized cells with large amounts of proteins synthesized in the inner segment (IS) and transported to the outer segment (OS) and synaptic terminal. The PR-specific protein, Tulp1, is localized to the IS and synapse and is hypothesized to be involved in protein trafficking. To better understand the molecular processes that regulate protein trafficking in PRs, we aimed to identify compartment-specific Tulp1 binding partners. Serial tangential sectioning of Long Evans rat retinas was utilized to isolate the IS and synaptic PR compartments. Tulp1 binding partners in each of these layers were identified using co-immunoprecipitation (co-IP) with Tulp1 antibodies. The co-IP eluates were separated by SDS-PAGE, trypsinized into peptide fragments, and proteins were identified by liquid chromatography tandem mass spectrometry. In the IS, potential Tulp1-binding partners included cytoskeletal scaffold proteins, protein trafficking molecules, as well as members of the phototransduction cascade. In the synaptic region, the majority of interacting proteins identified were cytoskeletal. A separate subset of proteins were identified in both the IS and synapse including chaperones and family members of the GTPase activating proteins. Tulp1 has two distinct PR compartment specific interactomes. Our results support the hypothesis that Tulp1 is involved in the trafficking of proteins from the IS to the OS and the continuous membrane remodeling and vesicle cycling at the synaptic terminal. PMID- 26427466 TI - Thyroid Hormone Signaling and Cone Photoreceptor Viability. AB - Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and apoptosis. In the retina, TH signaling plays a central role in cone opsin expression. TH signaling inhibits S opsin expression, stimulates M opsin expression, and promotes dorsal-ventral opsin patterning. TH signaling has also been associated with cone photoreceptor viability. Treatment with thyroid hormone triiodothyronine (T3) or induction of high T3 by deleting the hormone inactivating enzyme type 3 iodothyronine deiodinase (DIO3) causes cone death in mice. This effect is reversed by deletion of the TH receptor (TR) gene. Consistent with the T3 treatment effect, suppressing TH signaling preserves cones in mouse models of retinal degeneration. The regulation of cone survival by TH signaling appears to be independent of its regulatory role in cone opsin expression. The mechanism by which TH signaling regulates cone viability remains to be identified. The current understanding of TH signaling regulation in photoreceptor viability suggests that suppressing TH signaling locally in the retina may represent a novel strategy for retinal degeneration management. PMID- 26427467 TI - In-Depth Functional Diagnostics of Mouse Models by Single-Flash and Flicker Electroretinograms without Adapting Background Illumination. AB - Electroretinograms (ERGs) are commonly recorded at the cornea for an assessment of the functional status of the retina in mouse models. Full-field ERGs can be elicited by single-flash as well as flicker light stimulation although in most laboratories flicker ERGs are recorded much less frequently than singleflash ERGs. Whereas conventional single-flash ERGs contain information about layers, i.e., outer and inner retina, flicker ERGs permit functional assessment of the vertical pathways of the retina, i.e., rod system, cone ON-pathway, and cone OFF pathway, when the responses are evoked at a relatively high luminance (0.5 log cd s/m(2)) with varying frequency (from 0.5 to 30 Hz) without any adapting background illumination. Therefore, both types of ERGs complement an in-depth functional characterization of the mouse retina, allowing for a discrimination of an underlying functional pathology. Here, we introduce the systematic interpretation of the single-flash and flicker ERGs by demonstrating several different patterns of functional phenotype in genetic mouse models, in which photoreceptors and/or bipolar cells are primarily or secondarily affected. PMID- 26427468 TI - The Role of Intraflagellar Transport in the Photoreceptor Sensory Cilium. AB - The photoreceptor is a complex specialized cell in which a major component responsible for visual transduction is the photoreceptor sensory cilium (PSC). Building and maintenance of the PSC requires the transport of large proteins along microtubules that extend from the inner segments to the outer segments. A key process, termed intraflagellar transport (IFT), has been recognized as an essential phenomenon for photoreceptor development and maintenance, and exciting new studies have highlighted its importance in retinal and cilia related diseases. This review focuses on the important roles of IFT players, including motor proteins, IFT proteins, and photoreceptor-specific cargos in photoreceptor sensory cilium. In addition, specific IFT components that are involved in inherited human diseases are discussed. PMID- 26427469 TI - Regulation of Retinal Development via the Epigenetic Modification of Histone H3. AB - We are interested in the roles of epigenetic mechanisms in retinal development. By ChIP-qPCR using whole retinal extracts at various developmental stages, we found that the levels of methylation of histones H3K27 and H3K4 and acetylation of histone H3 at specific loci in various genes, which play critical roles in retinal proliferation and differentiation, changed dramatically during retinal development. We next focused on the roles of H3K27 trimethylation in retinal development. Ezh1 and Ezh2 are methyltransferases that act on H3K27, while Jmjd3 and Utx are demethylases. We found that Ezh2 and Jmjd3 were mainly expressed during retinal development, and a loss-of-function of these genes revealed a role for H3K27me3 in the maturation of subsets of bipolar cells. Furthermore, Ezh2 and Jmjd3 regulate H3K27 trimethylation at specific loci within Bhlhb4 and Vsx1, which play critical roles in the differentiation of subsets of bipolar cells. Utx is expressed weakly in retina, and the down-regulation of Utx by sh-RNA in retinal explants suggested that Utx also participates in the maturation of bipolar cells. Ezh1 is expressed weakly in postnatal retina, and the phenotype of Ezh2-knockout retina suggested that Ezh1 plays a role in the methylation of H3K27 in the late phase of retinal differentiation. Taken together, we found that these four genes, which exhibit temporally and spatially unique expression patterns during retinal development, play critical roles in the differentiation of retinal subsets through the regulation of histone H3K27 methylation at critical genetic loci. PMID- 26427470 TI - The Potential Role of Flavins and Retbindin in Retinal Function and Homeostasis. AB - Flavins are highly concentrated in the retina; likely because they are involved as cofactors in energy metabolism and photoreceptors have an extremely high metabolic rate. How this concentration is established is currently unknown, but photoreceptor specific proteins may exist that shuttle flavins to flavoproteins, which may also function in retinal neuron specific processes. It has been suggested due to sequence homology to folate receptors that retbindin could be binding flavins in the retina. Here we present a brief overview of flavins in the retina and initial findings that suggest retbindin may be located in the photoreceptor layer where flavin acquisition from the RPE would occur. PMID- 26427471 TI - Identification of Tyrosine O Sulfated Proteins in Cow Retina and the 661W Cell Line. AB - Lack of tyrosine O Sulfation compromises both rod and cone electroretinographic responses emphasizing the importance of this post-translational modification for vision. To identify tyrosine sulfated proteins in retina, cow retinal lysates were subjected to immunoaffinity purification using an anti-sulfotyrosine antibody. The tyrosine sulfated proteins were eluted from the column using a sulfotyrosine pentapeptide and identified using mass spectrometry. Similarly, tyrosine sulfated proteins secreted by the 661W cell line were identified. Proteins identified were vitronectin, fibronectin, fibulin 2, nidogen, collagen V alpha 2, complement component 3 and C4 and fibrinogen beta. All proteins were subjected to analysis by 'Sulfinator' to determine potential sulfated tyrosines. PMID- 26427472 TI - The Function of Arf-like Proteins ARL2 and ARL3 in Photoreceptors. AB - Arf-like proteins (ARLs) are ubiquitously expressed small G proteins of the RAS superfamily. In photoreceptors, ARL2 and ARL3 participate in the trafficking of lipidated membrane-associated proteins and colocalize in the inner segment with UNC119A and PDEdelta. UNC119A and PDEdelta are acyl- and prenyl-binding proteins, respectively, involved in trafficking of acylated (transducin-alpha subunit, nephrocystin NPHP3) and prenylated proteins (GRK1, PDE6). Germline Arl3 knockout mice do not survive beyond postnatal day 21 and display ciliary defects in multiple organs (kidney, liver and pancreas) as well as retinal degeneration. Conditional knockouts will be necessary to delineate mechanisms of protein transport in retina disease. PMID- 26427473 TI - Characterization of Antibodies to Identify Cellular Expression of Dopamine Receptor 4. AB - The dopamine receptor D4 (DRD4) plays an important role in vision. In order to study the DRD4 expression in vivo, it is important to have antibodies that are specific for DRD4 for both immunoblot and immunohistochemical (IHC) applications. In this study, six antibodies raised against DRD4 peptides were tested in vitro, using transfected mammalian cells, and in vivo, using mouse retinas. Three Santa Cruz (SC) antibodies, D-16, N-20, and R-20, were successful in IHC of transfected DRD4; however, N-20 was the only one effective on immunoblot analysis in DRD4 transfected cells and IHC of mouse retinal sections, while R-20, 2B9, and Antibody Verify AAS63631C were non-specific or below detection. PMID- 26427474 TI - A Possible Role of Neuroglobin in the Retina After Optic Nerve Injury: A Comparative Study of Zebrafish and Mouse Retina. AB - Neuroglobin (Ngb) is a new member of the family of heme proteins and is specifically expressed in neurons of the central and peripheral nervous systems in all vertebrates. In particular, the retina has a 100-fold higher concentration of Ngb than do other nervous tissues. The role of Ngb in the retina is yet to be clarified. Therefore, to understand the functional role of Ngb in the retina after optic nerve injury (ONI), we used two types of retina, from zebrafish and mice, which have permissible and non-permissible capacity for nerve regeneration after ONI, respectively. After ONI, the Ngb protein in zebrafish was upregulated in the amacrine cells within 3 days, whereas in the mouse retina, Ngb was downregulated in the retinal ganglion cells (RGCs) within 3 days. Zebrafish Ngb (z-Ngb) significantly enhanced neurite outgrowth in retinal explant culture. According to these results, we designed an overexpression experiment with the mouse Ngb (m-Ngb) gene in RGC-5 cells (retinal precursor cells). The excess of m Ngb actually rescued RGC-5 cells under hypoxic conditions and significantly enhanced neurite outgrowth in cell culture. These data suggest that mammalian Ngb has positive neuroprotective and neuritogenic effects that induce nerve regeneration after ONI. PMID- 26427475 TI - JNK Inhibition Reduced Retinal Ganglion Cell Death after Ischemia/Reperfusion In Vivo and after Hypoxia In Vitro. AB - Mitogen-activated protein kinases (MAPKs) are key regulators that have been linked to cell survival and death. Among the main classes of MAPKs, c-jun N terminal kinase (JNK) has been shown to mediate cell stress responses associated with apoptosis. In Vitro, hypoxia induced a significant increase in 661W cell death that paralleled increased activity of JNK and c-jun. 661W cells cultured in presence of the inhibitor of JNK (D-JNKi) were less sensitive to hypoxia-induced cell death. In vivo, elevation in intraocular pressure (IOP) in the rat promoted cell death that correlated with modulation of JNK activation. In vivo inhibition of JNK activation with D-JNKi resulted in a significant and sustained decrease in apoptosis in the ganglion cell layer, the inner nuclear layer and the photoreceptor layer. These results highlight the protective effect of D-JNKi in ischemia/reperfusion induced cell death of the retina. PMID- 26427476 TI - Cell Fate of Muller Cells During Photoreceptor Regeneration in an N-Methyl-N nitrosourea-Induced Retinal Degeneration Model of Zebrafish. AB - Zebrafish can regenerate several organs such as the tail fin, heart, central nervous system, and photoreceptors. Very recently, a study has demonstrated the photoreceptor regeneration in the alkylating agent N-methyl-N-nitrosourea (MNU) induced retinal degeneration (RD) zebrafish model, in which whole photoreceptors are lost within a week after MNU treatment and then regenerated within a month. The research has also shown massive proliferation of Muller cells within a week. To address the question of whether proliferating Muller cells are the source of regenerating photoreceptors, which remains unknown in the MNU-induced zebrafish RD model, we employed a BrdU pulse-chase technique to label the proliferating cells within a week after MNU treatment. As a result of the BrdU pulse-chase technique, a number of BrdU(+) cells were observed in the outer nuclear layer as well as the inner nuclear layer. This implies that regenerating photoreceptors are derived from proliferating Muller cells in the zebrafish MNU-induced RD model. PMID- 26427477 TI - Polymodal Sensory Integration in Retinal Ganglion Cells. AB - An animal's ability to perceive the external world is conditioned by its capacity to extract and encode specific features of the visual image. The output of the vertebrate retina is not a simple representation of the 2D visual map generated by photon absorptions in the photoreceptor layer. Rather, spatial, temporal, direction selectivity and color "dimensions" of the original image are distributed in the form of parallel output channels mediated by distinct retinal ganglion cell (RGC) populations. We propose that visual information transmitted to the brain includes additional, light-independent, inputs that reflect the functional states of the retina, anterior eye and the body. These may include the local ion microenvironment, glial metabolism and systemic parameters such as intraocular pressure, temperature and immune activation which act on ion channels that are intrinsic to RGCs. We particularly focus on light-independent mechanical inputs that are associated with physical impact, cell swelling and intraocular pressure as excessive mechanical stimuli lead to the counterintuitive experience of "pressure phosphenes" and/or debilitating blinding disease such as glaucoma and diabetic retinopathy. We point at recently discovered retinal mechanosensitive ion channels as examples through which molecular physiology brings together Greek phenomenology, modern neuroscience and medicine. Thus, RGC output represents a unified picture of the embodied context within which vision takes place. PMID- 26427478 TI - Pigment Epithelium-Derived Factor, a Protective Factor for Photoreceptors in Vivo. AB - Pigment epithelium-derived factor (PEDF) is a natural protein of the retina with demonstrable neurotrophic properties, found in the interphotoreceptor matrix in intimate contact with photoreceptors. This review summarizes the effects of PEDF on photoreceptors in several animal models of retinal degeneration. PMID- 26427479 TI - The mTOR Kinase Inhibitor INK128 Blunts Migration of Cultured Retinal Pigment Epithelial Cells. AB - Retinal pigment epithelium (RPE) cell migration in response to disease has been reported for age-related macular degeneration, proliferative vitreoretinopathy, and proliferative diabetic retinopathy. The complex molecular process of RPE cell migration is regulated in part by growth factors and cytokines, and activation of the PI3/AKT/mTOR signaling pathway. Rapamycin, an allosteric mTOR inhibitor, has been shown to block only one of the primary downstream mTOR effectors, p70 S6 kinase 1, in many cell types. INK128, a selective mTOR ATP binding site competitor, blocks both p70 S6 kinase 1 and a second primary downstream effector, 4E-BP1. We performed scratch assays using differentiated ARPE-19 and primary porcine RPE cells to assess the effect of mTOR inhibition on cell migration. We found that INK128-mediated blocking of both p70 S6 kinase 1 and 4E-BP1 was much more effective at preventing RPE cell migration than rapamycin-mediated inhibition of p70 S6 kinase 1 alone. PMID- 26427480 TI - Live Imaging of LysoTracker-Labelled Phagolysosomes Tracks Diurnal Phagocytosis of Photoreceptor Outer Segment Fragments in Rat RPE Tissue Ex Vivo. AB - Renewal of rod photoreceptor outer segments in the mammalian eye involves synchronized diurnal shedding after light onset of spent distal outer segment fragments (POS) linked to swift clearance of shed POS from the subretinal space by the adjacent retinal pigment epithelium (RPE). Engulfed POS phagosomes in RPE cells mature to acidified phagolysosomes, which accomplish enzymatic degradation of POS macromolecules. Here, we used an acidophilic fluorophore LysoTracker to label acidic organelles in freshly dissected, live rat RPE tissue flat mounts. We observed that all RPE cells imaged contained numerous acidified POS phagolysosomes whose abundance per cell was dramatically increased 2 h after light onset as compared to either 1 h before or 4 h after light onset. Lack of organelles of similar diameter (of 1-2 MUm) in phagocytosis-defective mutant RCS rat RPE confirmed that LysoTracker live imaging detected POS phagolysosomes. Lack of increase in lysosomal membrane protein LAMP-1 in RPE/choroid during the diurnal phagocytic burst suggests that formation of POS phagolysosomes in RPE in situ may not involve extra lysosome membrane biogenesis. Taken together, we report a new imaging approach that directly detects POS phagosome acidification and allows rapid tracking and quantification of POS phagocytosis by live RPE tissue ex situ. PMID- 26427481 TI - Cre Recombinase: You Can't Live with It, and You Can't Live Without It. AB - The development of conditional gene targeting has greatly advanced our knowledge of human retinal diseases, but issues have arisen related to the use of some Cre expressing mouse lines. In this article, we discuss potential problems associated with transgenic Cre expression-induced degeneration and alteration of rod photoreceptors and retinal pigment epithelium (RPE). Our strategy for circumventing RPE degeneration by induced transient Cre expression uses a single intravitreal doxycycline injection in a tetracycline-inducible RPE-specific Cre mouse line, which results in productive Cre-mediated recombination efficiently in the RPE. As constitutive expression of Cre in the RPE alters RPE biology, this inducible Cre/lox system provides an opportunity for conditional gene targeting in the RPE, a tissue that is closely related to photoreceptor degeneration, age related macular degeneration, and diabetic retinopathy. PMID- 26427482 TI - Efficiency of Membrane Protein Expression Following Infection with Recombinant Adenovirus of Polarized Non-Transformed Human Retinal Pigment Epithelial Cells. AB - Transient expression of exogenous proteins facilitates studies of molecular mechanisms and utility for transplantation of retinal pigment epithelial (RPE) cells in culture. Here, we compared expression of the membrane protein beta5 integrin-GFP (beta5-GFP) in two recently established models of differentiated human RPE, adult RPE stem cell-derived RPE and primary fetal RPE, upon infection with recombinant adenovirus or transfection with DNA in liposomes. We varied viral titer and duration of virus incubation and examined beta5-GFP and the tight junction marker ZO-1 in manipulated cells by confocal microscopy. Fewer than 5 % of cells expressed beta5-GFP after liposome-mediated transfection. The percentage of cells with detectable beta5-GFP exceeded 90 % after adenovirus infection for as little as 1 h. Decreasing virus titer two-fold did not alter the fraction of cells expressing beta5-GFP but increased variability of beta5-GFP level among cells. In cells with low expression levels, beta5-GFP localized mostly to the apical plasma membrane like endogenous alphavbeta5 integrin. In cells with high expression levels, beta5-GFP localized to the cytoplasm in addition to the apical surface suggesting accumulation in trafficking compartments. Altogether, adenovirus delivery yields efficient exogenous membrane protein expression of correct polarity in differentiated human RPE cells in culture. PMID- 26427484 TI - Lysosomal Trafficking Regulator (LYST). AB - Regulation of vesicle trafficking to lysosomes and lysosome-related organelles (LROs) as well as regulation of the size of these organelles are critical to maintain their functions. Disruption of the lysosomal trafficking regulator (LYST) results in Chediak-Higashi syndrome (CHS), a rare autosomal recessive disorder characterized by oculocutaneous albinism, prolonged bleeding, severe immunodeficiency, recurrent bacterial infection, neurologic dysfunction and hemophagocytic lympohistiocytosis (HLH). The classic diagnostic feature of the syndrome is enlarged LROs in all cell types, including lysosomes, melanosomes, cytolytic granules and platelet dense bodies. The most striking CHS ocular pathology observed is an enlargement of melanosomes in the retinal pigment epithelium (RPE), which leads to aberrant distribution of eye pigmentation, and results in photophobia and decreased visual acuity. Understanding the molecular function of LYST and identification of its interacting partners may provide therapeutic targets for CHS and other diseases associated with the regulation of LRO size and/or vesicle trafficking, such as asthma, urticaria and Leishmania amazonensis infections. PMID- 26427483 TI - Contribution of Ion Channels in Calcium Signaling Regulating Phagocytosis: MaxiK, Cav1.3 and Bestrophin-1. AB - Mutations in the BEST1 gene lead to a variety of retinal degenerations including Best's vitelliforme macular degeneration. The BEST1 gene product, bestrophin-1, is expressed in the retinal pigment epithelium (RPE). It is likely that mutant bestrophin-1 impairs functions of the RPE which support photoreceptor function and will thus lead to retinal degeneration. However, the RPE function which is influenced by bestrophin-1 is so far not identified. Previously we showed that bestrophin-1 interacts with L-type Ca2+ channels of the CaV1.3 subtype and that the endogenously expressed bestrophin-1 is required for intracellular Ca2+ regulation. A hallmark of Best's disease is the fast lipofuscin accumulation occurring already at young ages. Therefore, we addressed the hypothesis that bestrophin-1 might influence phagocytosis of photoreceptor outer segments (POS) by the RPE. Here, siRNA knock-down of bestrophin-1 expression as well as inhibition of L-type Ca2+ channel activity modulated the POS phagocytosis in vitro. In vivo CaV1.3 expression appeared to be diurnal regulated with a higher expression rate in the afternoon. Compared to wild-type littermates, Ca V 1.3 (-/ ) mice showed a shift in the circadian POS phagocytosis with an increased activity in the afternoon. Thus we suggest that mutant bestrophin-1 leads to an impaired regulation of the POS phagocytosis by the RPE which would explain the fast lipofuscin accumulation in Best patients. PMID- 26427485 TI - Live-Cell Imaging of Phagosome Motility in Primary Mouse RPE Cells. AB - The retinal pigment epithelium (RPE) is a post-mitotic epithelial monolayer situated between the light-sensitive photoreceptors and the choriocapillaris. Given its vital functions for healthy vision, the RPE is a primary target for insults that result in blinding diseases, including age-related macular degeneration (AMD). One such function is the phagocytosis and digestion of shed photoreceptor outer segments. In the present study, we examined the process of trafficking of outer segment disk membranes in live cultures of primary mouse RPE, using high speed spinning disk confocal microscopy. This approach has enabled us to track phagosomes, and determine parameters of their motility, which are important for their efficient degradation. PMID- 26427486 TI - RPE Cell and Sheet Properties in Normal and Diseased Eyes. AB - Previous studies of human retinal pigment epithelium (RPE) morphology found spatial differences in density: a high density of cells in the macula, decreasing peripherally. Because the RPE sheet is not perfectly regular, we anticipate that there will be differences between conditions and when and where damage is most likely to begin. The purpose of this study is to establish relationships among RPE morphometrics in age, cell location, and disease of normal human and AMD eyes that highlight irregularities reflecting damage. Cadaveric eyes from 11 normal and 3 age-related macular degeneration (AMD) human donors ranging from 29 to 82 years of age were used. Borders of RPE cells were identified with phalloidin. RPE segmentation and analysis were conducted with CellProfiler. Exploration of spatial point patterns was conducted using the "spatstat" package of R. In the normal human eye, with increasing age, cell size increased, and cells lost their regular hexagonal shape. Cell density was higher in the macula versus periphery. AMD resulted in greater variability in size and shape of the RPE cell. Spatial point analysis revealed an ordered distribution of cells in normal and high spatial disorder in AMD eyes. Morphometrics of the RPE cell readily discriminate among young vs. old and normal vs. diseased in the human eye. The normal RPE sheet is organized in a regular array of cells, but AMD exhibited strong spatial irregularity. These findings reflect on the robust recovery of the RPE sheet after wounding and the circumstances under which it cannot recover. PMID- 26427487 TI - Valproic Acid Induced Human Retinal Pigment Epithelial Cell Death as Well as its Survival after Hydrogen Peroxide Damage is Mediated by P38 Kinase. AB - Age-related macular degeneration (AMD) is a leading cause of legal blindness in developed countries. Several new drugs are now available to reduce the sight threatening complications of this disease, however, all are useful in only a small fraction of patients and none of them prevents disease development. An understanding of the pathogenesis of the retinal and macular degeneration is the first step in developing preventive and fully effective treatment options for this condition. Lifelong oxidative stress seems to be an etiologic factor. In this study, we used cultured human retinal pigment epithelial cells to study the mechanism of cell death and survival in cells exposed to oxidative stress. Our studies demonstrate that valproic acid (VPA), an epigenetic factor, reduces apoptosis in hRPE cells that were subjected to hydrogen peroxide-induced oxidative injury by alteration in P38 kinase activity. Since VPA has been shown to have therapeutic use in other neuronal diseases, better understanding of the mechanism of this VPA anti-apoptotic activity may enhance its development as a therapeutic agent. PMID- 26427488 TI - Blockade of MerTK Activation by AMPK Inhibits RPE Cell Phagocytosis. AB - Timely removal of shed photoreceptor outer segments by retinal pigment epithelial cells (RPE) plays a key role in biological renewal of these highly peroxidizable structures and in maintenance of retina health. How environmental stress cause RPE cell dysfunction is undefined however. AMP-activated protein kinase (AMPK), a heterotrimer of a catalytic alpha subunit and regulatory beta and gamma subunits, maintains energy homeostasis by limiting energy utilization and/or promoting energy production when energy supply is compromised. Intriguingly, AMPK has been shown to be important in functions of RPE cells. In this mini-review, the role and mechanisms of AMPK in controlling RPE cell phagocytosis are discussed. PMID- 26427489 TI - Modulation of V-ATPase by betaA3/A1-Crystallin in Retinal Pigment Epithelial Cells. AB - We have previously demonstrated that betaA3/A1-crystallin, a member of the beta/gamma-crystallin superfamily, is expressed in the astrocytes and retinal pigment epithelial (RPE) cells of the eye. In order to understand the physiological functions of betaA3/A1-crystallin in RPE cells, we generated conditional knockout (cKO) mice where Cryba1, the gene encoding betaA3/A1 crystallin, is deleted specifically from the RPE using the Cre-loxP system. By utilizing the cKO model, we have shown that this protein is required by RPE cells for proper lysosomal degradation of photoreceptor outer segments (OS) that have been internalized in phagosomes and also for the proper functioning of the autophagy process. We also reported that betaA3/A1-crystallin is trafficked to lysosomes, where it regulates endolysosomal acidification by modulating the activity of the lysosomal V-ATPase complex. Our results show that the V-ATPase activity in cKO RPE is significantly lower than WT RPE. Since, V-ATPase is important for regulating lysosomal pH, we noticed that endolysosomal pH was higher in the cKO cells compared to the WT cells. Increased lysosomal pH in cKO RPE is also associated with reduced Cathepsin D activity. Cathepsin D is a major lysosomal aspartic protease involved in the degradation of the OS and hence we believe that reduced proteolytic activity contributes to impaired degradation of OS in the cKO RPE. Reduced lysosomal activity in the cKO RPE also contributes to the incomplete degradation of the autophagosomes. Our results also suggest that betaA3/A1-crystallin regulates V-ATPase activity by binding to the V0 subunit of the V-ATPase complex. Taken together, these results suggest a novel mechanism by which betaA3/A1-crystallin regulates lysosomal function by modulating the activity of V-ATPase. PMID- 26427490 TI - Proteomic Profiling of Cigarette Smoke Induced Changes in Retinal Pigment Epithelium Cells. AB - Age-related macular degeneration (AMD) is a medical condition usually affecting older adults and resulting in a loss of vision in the macula, the center of the visual field. The dry form of this disease presents with atrophy of the retinal pigment epithelium, resulting in the detachment of the retina and loss of photoreceptors. Cigarette smoke is one main risk factor for dry AMD and increases the risk of developing the disease by three times. In order to understand the influence of cigarette smoke on retinal pigment epithelial cells, cultured human ARPE-19 cells were treated with cigarette smoke extract for 24 h. Using quantitative mass spectrometry more than 3000 proteins were identified and their respective abundances were compared between cigarette smoke-treated and untreated cells. Altogether 1932 proteins were quantified with at least two unique peptides, with 686 proteins found to be significantly differentially abundant with p > 0.05. Of these proteins the abundance of 64 proteins was at least 2-fold down-regulated after cigarette smoke treatment while 120 proteins were 2-fold up regulated. The analysis of associated biological processes revealed an alteration of proteins involved in RNA processing and transport as well as extracellular matrix remodelling in response to cigarette smoke treatment. PMID- 26427491 TI - Reduced Metabolic Capacity in Aged Primary Retinal Pigment Epithelium (RPE) is Correlated with Increased Susceptibility to Oxidative Stress. AB - One of the affected tissues in age-related macular degeneration (AMD) is the retinal pigment epithelium (RPE), a tissue that consists of terminally differentiated cells and that accumulates damage over time. In all tissues, mitochondria (mt), which play an essential role in both cell health (energy) and death (initiator of apoptosis), undergo an aging process through the accumulation of mtDNA damage, changes in mitochondrial dynamics, a reduction in biogenesis, and mitophagy, leading to an overall reduction in mitochondrial energy production and other non-energy-related functions. Here we have compared energy metabolism in primary human RPE cells isolated from aborted fetus or aged donor eyes and grown as stable monolayers. H2O2 treatment resulted in the generation of reactive oxygen species and superoxide, an effect that was significantly augmented by age. Mitochondrial metabolism, as analyzed by Seahorse respirometry, revealed reduced mitochondrial oxygen consumption (ATP production) at baseline and a complete loss of reserve capacity in aged cells. Likewise, glycolysis was blunted in aged cells. Taken together, these studies showed that RPE cells derived from aged donor eyes are more susceptible to oxidative stress, and exhibit a loss in mitochondrial respiratory reserve capacity and a reduction in glycolysis. These data suggest that while old cells may have sufficient energy at rest, they cannot mount a stress response requiring additional ATP and reducing agents. In summary, these data support the hypothesis that mitochondria or energy metabolism is a valid target for therapy in AMD. PMID- 26427492 TI - Cell phone explosion. AB - Cell phone explosions and resultant burn injuries are rarely reported in the scientific literature. We report a case of cell phone explosion that occurred when a young male was listening to music while the mobile was plugged in for charging. PMID- 26427493 TI - Animal models of hepatotoxicity. AB - INTRODUCTION: Liver is the largest and important organ in the body, involved in the metabolism of food and drugs. Liver diseases are potentially life threatening for humans. The etiology of liver disorder varied due to different reasons like autoimmune disorder, viral infection, toxic chemical, and due to changing diet style. Liver injury produces pathological changes like increase level of SGOT, SGPT, TB and generation of free radical radicals. METHODS: A better understanding of primary mechanisms is mandatory for designing of new therapeutic drugs. Therefore, animal models are being developed to mimic human liver diseases. Animal models are being used for several decades to study the pathogenesis of liver disorders and related toxicities. CONCLUSION: In this review, we revealed various animal models with their merits and demerits. Our main focus is to explore all new and traditional animal models under broad classification like non invasive, invasive and genetic models which directly or indirectly produce hepatotoxicity. PMID- 26427494 TI - Dual effects of a lectin from the green seaweed Caulerpa cupressoides var. lycopodium on inflammatory mediators in classical models of inflammation. AB - OBJECTIVE: Wide biotechnological investigations of only a limited number of seaweed lectins have been performed. We previously demonstrated the anti nociceptive and anti-inflammatory effects of a lectin isolated from the green seaweed Caulerpa cupressoides var. lycopodium (CcL). Herein, we further studied the mechanisms of action of CcL. METHODS: Classical acute inflammation models induced by different flogistic agents were used to evaluate the anti-inflammatory action of CcL. CcL was injected locally into the rat paw to verify a possible pro inflammatory outcome. RESULTS: CcL (0.1, 1 or 10 mg/kg; i.v.) reduced the carrageenan-induced rat paw edema and neutrophilic infiltration, which was not altered by either mucin (inhibitor of CcL carbohydrate-binding site) or ZnPP-IX (specific HO-1 inhibitor). Immunohistochemical analyses showed that CcL (1 mg/kg) reduced the expression of the cytokines IL-1beta, TNF-alpha, IL-6 and COX-2. CcL (0.1, 1 or 10 mg/kg) inhibited dextran, and CcL (1 mg/kg) inhibited histamine induced rat paw edema. Both effects were reversed by mucin inhibition. CcL (1 mg/kg) was ineffective for the treatment of serotonin- and bradykinin-induced rat paw edema. When injected via the i.pl. route, CcL (10 mg/kg) elicited rat paw edema involving a wide range of mediators. CONCLUSIONS: The anti-inflammatory action of CcL involves the inhibition of IL-1beta, TNF-alpha, IL-6 and COX-2 expression and histamine H1 receptors. When locally administered, CcL exerts pro inflammatory actions. PMID- 26427496 TI - WHO should commit to eradicating malaria by 2040, says Gates Foundation. PMID- 26427495 TI - Prenatal constriction of the ductus arteriosus following maternal diclofenac medication in the third trimester. AB - We describe a case of a 21-year-old primigravida at 36 weeks' gestation who was admitted to a local hospital because of abdominal pain. She was prescribed a total of six doses of diclofenac 50 mg over 2 days. One day later, there was difficulty registering the fetal heartbeats on cardiotocography. Ultrasound examination revealed a fetus with ascites and pathological flow over the tricuspid valve. The patient was referred to a tertiary centre for fetal medicine. Fetal echocardiography revealed, in addition to ascites and tricuspid regurgitation, a constricted ductus arteriosus, dilated right ventricle and reduced flow in the pulmonary artery. Immediate caesarean section resulted in an excellent neonatal outcome. PMID- 26427497 TI - Multi-class method for biomonitoring of hair samples using gas chromatography mass spectrometry. AB - Currently, non-invasive biomonitoring of human exposure to organic pollutants bases upon the analysis mainly of urine and human breast milk. While mostly persistent organic pollutants are the center of interest, the aim of our study was to develop a method for the determination of different chemical classes of emerging pollutants (organophosphorus flame retardants, plastic additives such as phthalates, bisphenol A, insecticides, antimicrobials, preservatives and musk fragrances) in hair by gas chromatography-mass spectrometry. The preferred sample preparation included hydrolysis of the hair with trifluoroacetic acid in methanol followed by a liquid-liquid extraction using hexane/ethyl acetate. The validated method is characterized by recoveries higher than 77 % for most analytes, relative standard deviations below 16 % and limits of detection between 2 pg mg( 1) (HHCB) and 292 pg mg(-1) (propylparaben) using 50 mg of dry hair. After respective blank corrections, bis-(2-ethylhexyl)phthalate (DEHP) and the musk fragrance HHCB were the predominant compounds determined in all hair samples at concentrations between 32 and 59 ng mg(-1) and 0.8-13 ng mg(-1), respectively. The bactericide triclosan and the insect repellent N,N-diethyl-3-methylbenzamide (DEET) were detected in selected hair samples at 2 and 0.8 ng mg(-1), respectively. PMID- 26427498 TI - Prediction of retention characteristics of heterocyclic compounds. AB - The CORAL software ( http://www.insilico.eu/coral ) was used to build up quantitative structure-property relationships (QSPRs) for the retention characteristics of 93 derivatives of three groups of heterocyclic compounds: 2 phenyl-1,3-benzoxazoles, 4-benzylsulfanylpyridines, and benzoxazines. The QSPRs are one-variable models based on the optimal descriptors calculated from the molecular structure represented by simplified molecular input-line entry systems (SMILES). Each symbol (or two undivided symbols) of SMILES is characterized by correlation weight. The optimal descriptor is the sum of the correlation weights. The numerical data on the correlation weights were calculated with the Monte Carlo method by the manner which provides best correlation between endpoint and optimal descriptor for the calibration set. The predictive ability of the model is checked with the validation set (compounds invisible during building up of the model). The approach has been checked with three random splits into the training, calibration, and validation sets: all models have apparent predictive potential. The mechanistic interpretation of the molecular features extracted from SMILES as the promoters of increase or decrease of examined endpoints is suggested. PMID- 26427499 TI - Separation of peptide fragments of a protein kinase C substrate fused to a beta hairpin by capillary electrophoresis. AB - Synthetic peptides incorporating well-folded beta-hairpin peptides possess advantages in a variety of cell biology applications by virtue of increased resistance to proteolytic degradation. In this study, the WKpG beta-hairpin peptide fused to a protein kinase C (PKC) substrate was synthesized, and capillary-electrophoretic separation conditions for this peptide and its proteolytic fragments were developed. Fragments of WKpG-PKC were generated by enzymatic treatment with trypsin and Pronase E to produce standards for identification of degradation fragments in a cellular lysate. A simple buffer system of 250 mM H3PO4, pH 1.5 enabled separation of WKpG-PKC and its fragments by capillary electrophoresis in less than 16 min. Using a cellular lysate produced from Ba/F3 cells, the beta-hairpin-conjugated substrate and its PKCalpha phosphorylated product could be detected and separated from peptidase-generated fragments produced in a cell lysate. The method has potential application for identification and quantification of WKpG-PKC and its fragments in complex biological systems when the peptide is used as a reporter to assay PKC activity. PMID- 26427500 TI - Analysis of epinephrine, norepinephrine, and dopamine in urine samples of hospital patients by micellar liquid chromatography. AB - An analytical method based on micellar liquid chromatography was developed to determine the concentration of three catecholamines (epinephrine, norepinephrine, and dopamine) in urine. The detection of these compounds in urine can be useful to diagnose several diseases, related to stress and sympathoadrenal system dysfunction, using a non-invasive collection procedure. The sample pretreatment was a simple dilution in a micellar solution, filtration, and direct injection, thus avoiding time-consuming and tedious extraction steps. Therefore, there is no need to use an internal standard. The three catecholamines were eluted using a C18 column and a mobile phase of 0.055 M sodium dodecyl sulfate-1.5% methanol buffered at pH 3.8 running at 1.5 mL/min under isocratic mode in less than 25 min. The detection was performed by amperometry applying a constant potential of +0.5 V. The procedure was validated following the guidelines of the European Medicines Agency in terms of the following: calibration range (0.09-5 MUg/mL), linearity (r(2) > 0.9995), limit of detection (0.02 MUg/mL), within- and between run accuracy (-6.5 to +8.4%) and precision (<10.2%), dilution integrity, matrix effect, robustness (<8.4), and stability. The obtained values were below those required by the guide. The method was rapid, easy-to-handle, eco-friendly, and safe and provides reliable quantitative data, and is thus useful for routine analysis. The procedure was applied to the analysis of epinephrine, norepinephrine, and dopamine in urine samples from patients of a local hospital. PMID- 26427501 TI - New ex-ovo colorectal-cancer models from different SdFFF-sorted tumor-initiating cells. AB - Despite effective treatments, relapse of colorectal cancer (CRC) is frequent, in part caused by the existence of tumor-initiating cells (TICs). Different subtypes of TICs, quiescent and activated, coexist in tumors, defining the tumor aggressiveness and therapeutic response. These subtypes have been sorted by hyperlayer sedimentation field-flow fractionation (SdFFF) from WiDr and HCT116 cell lines. On the basis of a new strategy, including TIC SdFFF sorting, 3D Matrigel amplification, and grafting of corresponding TIC colonies on the chick chorioallantoic membrane (CAM), specific tumor matrices could be obtained. If tumors had similar architectural structure with vascularization by the host system, they had different proliferative indices in agreement with their initial quiescent or activated state. Protein analysis also revealed that tumors obtained from a population enriched for "activated" TICs lost "stemness" properties and became invasive. In contrast, tumors obtained from a population enriched for "quiescent" TICs kept their stemness properties and seemed to be less proliferative and invasive. Then, it was possible to produce different kinds of tumor which could be used as selective supports to study carcinogenesis and therapy sensitivity. PMID- 26427502 TI - Development of a MAb-based immunoassay for the simultaneous determination of O,O diethyl and O,O-dimethyl organophosphorus pesticides in vegetable and fruit samples pretreated with QuEChERS. AB - To develop a broad-specificity immunoassay for organophosphorus pesticides (OPs), a broad-specificity monoclonal antibody (MAb) for OPs against a generic hapten, O,O-diethyl O-(3-carboxyphenyl) phosphorothioate with the carboxy group in the meta position of the benzene ring, was produced. Eight haptens were prepared and covalently attached to ovalbumin (OVA) for use as coating antigens, and the optimum coating antigen was selected. Then, a sensitive and broadly class selective competitive indirect enzyme-linked immunosorbent assay (ciELISA) based on the MAb and the optimum coating antigen (hapten H-OVA, possessing an O,O dimethyl generic structure and linked through a linear spacer arm) was developed and optimized. The MAb developed in this study showed quite different cross reactivity and selectivity compared to previously produced anti-OPs broad specificity MAbs. Specifically, the MAb showed high and uniform sensitivity to seven O,O-diethyl OPs and six O,O-dimethyl OPs. With the optimum ciELISA, the IC50 values of the 13 OPs were determined as 23.1~151.2 ng mL(-1). The average IC50 and coefficient of variation (CV) for the IC50 values of the 13 OPs were 74.6 ng mL(-1) and 33.9%, respectively. For the recovery study, a QuEChERS approach based on dispersive solid-phase extraction (d-SPE) was implemented to decrease the matrix effects of vegetable and fruit samples. The recoveries of six representative OPs from the spiked samples ranged from 89.4 to 135.5%; the CV ranged from 3.5 to 15.7%. The ciELISA was also applied to real samples, followed by confirmation with gas chromatography-tandem mass spectrometry (GC-MS/MS) analysis. The results demonstrated that the ciELISA is suitable for monitoring OP contamination in vegetable and fruit samples. PMID- 26427503 TI - Novel imidazolium-embedded N,N-dimethylaminopropyl-functionalized silica-based stationary phase for hydrophilic interaction/reversed-phase mixed-mode chromatography. AB - A novel imidazolium-embedded N,N-dimethylaminopropyl-functionalized silica-based stationary phase (Sil-ImCl) was prepared and further used for hydrophilic interaction/reversed-phase mixed-mode chromatography. The Sil-ImCl stationary phase was respectively characterized by Fourier transform infrared spectrometry, thermogravimetric analysis, and element analysis. A variety of hydrophilic or hydrophobic compounds were used to evaluate the retention mechanisms of the developed stationary phase, and the effects of buffer salt concentration and pH of mobile phase on the retention of these compounds were also investigated. The developed stationary phase was successfully applied for separation of nucleosides and nucleic acid bases, water-soluble vitamins, phenols, and positional isomers. Moreover, simultaneous separation of polar and nonpolar compounds was also achieved with high resolution, outperforming the commercially available C8 column and amino column. Furthermore, the Sil-ImCl stationary phase has been successfully applied for separation of secondary metabolites of Hansfordia sinuosae. All these results demonstrate that the Sil-ImCl stationary phase might be promising for separation of complex polar and nonpolar compounds with high efficiency, especially in biological industry. PMID- 26427504 TI - Immobilizing affinity proteins to nitrocellulose: a toolbox for paper-based assay developers. AB - To enable enhanced paper-based diagnostics with improved detection capabilities, new methods are needed to immobilize affinity reagents to porous substrates, especially for capture molecules other than IgG. To this end, we have developed and characterized three novel methods for immobilizing protein-based affinity reagents to nitrocellulose membranes. We have demonstrated these methods using recombinant affinity proteins for the influenza surface protein hemagglutinin, leveraging the customizability of these recombinant "flu binders" for the design of features for immobilization. The three approaches shown are: (1) covalent attachment of thiolated affinity protein to an epoxide-functionalized nitrocellulose membrane, (2) attachment of biotinylated affinity protein through a nitrocellulose-binding streptavidin anchor protein, and (3) fusion of affinity protein to a novel nitrocellulose-binding anchor protein for direct coupling and immobilization. We also characterized the use of direct adsorption for the flu binders, as a point of comparison and motivation for these novel methods. Finally, we demonstrated that these novel methods can provide improved performance to an influenza hemagglutinin assay, compared to a traditional antibody-based capture system. Taken together, this work advances the toolkit available for the development of next-generation paper-based diagnostics. PMID- 26427505 TI - A selective biomarker for confirming nitrofurazone residues in crab and shrimp using ultra-performance liquid chromatography-tandem mass spectrometry. AB - Reliably detecting nitrofurazone (NFZ) residues in farmed crab and shrimp was previously hindered by lack of appropriately specific analytical methodology. Parent NFZ rapidly breaks down in meat, and the commonly used side-chain metabolite, semicarbazide (SEM), is non-specific as it occurs naturally in crustacean shell often leading to 'false positive' detections in meat. Using 5 nitro-2-furaldehyde (NF) as marker metabolite, following pre-column derivatization with 2,4-dinitrophenylhydrazine (DNPH), ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis in negative electrospray ionization mode enabled confirmation of NFZ residues in deliberately treated whole crab, crab meat and shrimp meat, with a limit of detection (LOD) and limit of quantification (LOQ) below 1 ng g(-1). Meanwhile, the derivatives of DNPH-NF were synthesized for the first time, purified by preparative liquid chromatography and structure characterized with nuclear magnetic resonance spectroscopy ((1)H-NMR). The purity of derivative was checked by ultra performance liquid chromatography-tunable ultraviolet (UPLC-TUV), and the contents were beyond 99.9%. For comparison purposes, crustacean samples were analysed using both NF and SEM marker metabolites. NFZ treatment was revealed by both NF and SEM marker metabolites, but untreated crab also showed measurable levels of SEM which could potentially be misinterpreted as evidence of illegal NFZ use. PMID- 26427506 TI - Stable isotope tracing: a powerful tool for selenium speciation and metabolic studies in non-hyperaccumulator plants (ryegrass Lolium perenne L.). AB - Selenium is both essential and toxic for mammals; the range between the two roles is narrow and not only dose-dependent but also related to the chemical species present in foodstuff. Unraveling the metabolism of Se in plants as a function of Se source may thus lead to ways to increase efficiency of fertilization procedures in selenium deficient regions. In this study, stable-isotope tracing was applied for the first time in plants to simultaneously monitor the bio incorporation of two inorganic Se species commonly used as foodstuff enrichment sources. Occurrence and speciation of Se coming from different Se sources were investigated in root and leaf extracts of ryegrass (Lolium perenne L.), which had been co-exposed to two labeled Se species ((77)SeIV and (82)SeVI). Although the plant absorbed similar amounts of Se when supplied in the form of selenite or selenate, the results evidenced marked differences in speciation and tissues allocation. Selenite was converted into organic forms incorporated mostly into high molecular weight compounds with limited translocation to leaves, whereas selenate was highly mobile being little assimilated into organic forms. Double spike isotopic tracer methodology makes it possible to compare the metabolism of two species-specific Se sources simultaneously in a single experiment and to analyze Se behavior in not-hyperaccumulator plants, the ICP-MS sensitivity being improved by the use of enriched isotopes. PMID- 26427507 TI - Analysis of gamma-hydroxy butyrate by combining capillary electrophoresis indirect detection and wall dynamic coating: application to dried matrices. AB - gamma-Hydroxybutyric acid (GHB) is a powerful central nervous system depressant, currently used in medicine for the treatment of narcolepsy and alcohol dependence. In recent years, it has gained popularity among illegal club drugs, mainly because of its euphoric effects as well as doping agent and date rape drug. The purpose of the present work was the development of a rapid analytical method for the analysis of GHB in innovative biological matrices, namely dried blood spots (DBSs) and dried urine spots (DUSs). The analytical method is based on capillary zone electrophoresis with indirect UV absorption detection at 210 nm and capillary wall dynamic coating. The background electrolyte is composed of a phosphate buffer containing nicotinic acid (probe for detection) and cetyltrimethylammonium bromide (CTAB, reversal of electroosmosis in wall dynamic coating). The influence of probe and CTAB concentration, together with buffer pH, on migration time and signal response was investigated. Under the optimized conditions, analytical linearity and precision were satisfactory; absolute recovery values were also high (>90 %); the use of dried matrices (DBSs and DUSs) was advantageous as an alternative matrix to classical ones. No interferences were found either from the most common exogenous or from endogenous compounds. This analytical approach can offer a rapid, precise and accurate method for GHB determination in innovative biological samples, which could be important for screening purposes in clinical and forensic toxicology. Graphical Abstract CE method, by combined indirect UV detection and dynamic coating, for GHB determination in DBSs and DUSs. PMID- 26427509 TI - Commentary on: isolation and differentiation potential of human mesenchymal stem cells from adipose tissue harvested by water jet-assisted liposuction. PMID- 26427508 TI - Serum urate gene associations with incident gout, measured in the Framingham Heart Study, are modified by renal disease and not by body mass index. AB - We hypothesized that serum urate-associated SNPs, individually or collectively, interact with BMI and renal disease to contribute to risk of incident gout. We measured the incidence of gout and associated comorbidities using the original and offspring cohorts of the Framingham Heart Study. We used direct and imputed genotypes for eight validated serum urate loci. We fit binomial regression models of gout incidence as a function of the covariates, age, type 2 diabetes, sex, and all main and interaction effects of the eight serum urate SNPs with BMI and renal disease. Models were also fit with a genetic risk score for serum urate levels which corresponds to the sum of risk alleles at the eight SNPs. Model covariates, age (P = 5.95E-06), sex (P = 2.46E-39), diabetes (P = 2.34E-07), BMI (P = 1.14E 11) and the SNPs, rs1967017 (P = 9.54E-03), rs13129697 (P = 4.34E-07), rs2199936 (P = 7.28E-03) and rs675209 (P = 4.84E-02) were all associated with incident gout. No BMI by SNP or BMI by serum urate genetic risk score interactions were statistically significant, but renal disease by rs1106766 was statistically significant (P = 6.12E-03). We demonstrated that minor alleles of rs1106766 (intergenic, INHBC) were negatively associated with the risk of incident gout in subjects without renal disease, but not for individuals with renal disease. These analyses demonstrate that a significant component of the risk of gout may involve complex interplay between genes and environment. PMID- 26427510 TI - The National Mental Health Commission Report: Evidence based or ideologically driven? PMID- 26427511 TI - A record linkage study of antidepressant medication use and weight change in Australian adults. AB - OBJECTIVE: Antidepressant use is widespread. While weight gain is a commonly reported side-effect of antidepressant use and has the potential to affect population health, there is little large-scale population-based evidence on the issue, particularly for long-term use (?12 months). The aim of this study is to investigate the association between antidepressant use and weight change, including whether this relationship varies according to antidepressant class, recency of use, duration of use and dose. METHODS: Annual percentage weight change was calculated from self-reported weight at two time-points from 20,751 participants aged ?45 years from the 45 and Up Study - a population-based cohort study from New South Wales, Australia. Antidepressant use, ascertained from linked pharmaceutical data, from 19 months before baseline until end of follow-up (mean = 3.3 years of follow-up), was categorised as current, past-only, non persistent or non-use. The association between antidepressant use and weight change was modelled using linear and multinomial logistic regressions and according to antidepressant class, recency, duration and dose. RESULTS: Antidepressants were dispensed to 23% of participants (n = 4748) during the study period. Current antidepressant users were significantly more likely to gain >3% of their body weight annually than non-users (adjusted relative risk ratio = 1.19; 95% confidence interval: [1.03, 1.38]); the risk increased with increasing dose among current users (p[trend] = 0.003). Risk of weight gain did not vary significantly according to antidepressant class, recency or duration of use; however, statistical power was limited. No significant associations were found between antidepressant use and weight loss. CONCLUSION: Current antidepressant use was associated with modest but statistically significant annual gains in weight, with similar effects observed across the different classes of antidepressants used. PMID- 26427512 TI - Degradation of miR-21 induces apoptosis and inhibits cell proliferation in human hepatocellular carcinoma. AB - MicroRNAs (miRNAs) are small non-coding RNAs, 18-25 nucleotides long and have an important role in post-transcriptional regulation of gene. Several aspects of cellular activities such as cell growth, proliferation and differentiation are regulated by miRNAs. In many cancers and malignancies, up- or downregulation of different miRNAs has been reported. In human hepatocellular carcinoma (HCC), upregulation of miR-21 has been reported in human in vitro studies. Here, we made an assessment of the effect of miR-21 degradation on viability and apoptosis of HCC cell line (HepG2) using locked nucleic acid (LNA). At different time points (24, 48, 72 h) after LNA-anti-miR-21 transfection, 3-[4,5-dimethylthiazol-2-yl] 2, 5-diphenyl tetrazolium bromide assay and Annexin/propidium iodide staining were performed. The results show that miR-21 degradation can decrease the viability of cells, mainly by induction of apoptosis and necrosis. These findings suggest that degradation of miR-21 could be used as a novel approach in treatment of HCC. PMID- 26427513 TI - Integrated analysis of gene expression and genomic aberration data in osteosarcoma (OS). AB - Cytogenetic analyses have revealed that complex karyotypes with numerous and highly variable genomic aberrations including single-nucleotide polymorphisms (SNPs) and copy number variants (CNVs), are observed in most of the conventional osteosarcomas (OSs). Several genome-wide studies have reported that the dysregulated expression of many genes is correlated with genomic aberrations in OS. We first compared OS gene expression in Gene Expression Omnibus (GEO) data sets and genomic aberrations in International Cancer Genome Consortium (ICGC) database to identify differentially expressed genes (DEGs) associated with SNPs or CNVs in OS. Then the function annotation of SNP- or CNV-associated DEGs was performed in terms of gene ontology analysis, pathway analysis and protein protein interactions (PPIs). Finally, the expression of genes correlated with both SNPs and CNVs were confirmed by quantitative reverse-transcription PCR. Eight publicly available GEO data sets were obtained, and a set of 979 DEGs were identified (472 upregulated and 507 downregulated DEGs). Moreover, we obtained 1039 SNPs mapped in 938 genes, and 583 CNV sites mapped in 2915 genes. Comparing genomic aberrations and DGEs, we found 41 SNP-associated DEGs and 124 CNV associated DEGs, in which 7 DGEs were associated with both SNPs and CNVs, including WWP1, EXT1, LDHB, C8orf59, PLEKHA5, CCT3 and VWF. The result of function annotation showed that ossification, bone development and skeletal system development were the significantly enriched terms of biological processes for DEGs. PPI network analysis showed that CCT3, COPS3 and WWP1 were the significant hub proteins. We conclude that these genes, including CCT3, COPS3 and WWP1 are candidate driver genes of importance in OS tumorigenesis. PMID- 26427515 TI - The professionalization and training of psychologists: The place of clinical wisdom. AB - OBJECTIVE: The current study examines how clinical wisdom develops and how it both is and can be influenced by professional training processes. In this way, the project is studying the intersection of developmental and systemic processes related to clinical wisdom. METHOD: Researchers analyzed the interviews of psychologists practicing in the USA and Canada who were nominated for their clinical wisdom by their peers. These interviews explored how graduate training and professionalization were thought to influence the development of clinical wisdom and were subjected to an adapted grounded theory analysis. RESULTS: The findings described both professional and personal disincentives toward developing wisdom, including the dangers of isolation. Therapists reported concerns about educational systems that rewarded quick answers instead of thoughtful questioning in processes of admittance, training, and accreditation. Findings emphasized the importance of teaching multiple psychotherapy orientations, critical self- and professional-reflection skills, and openly supporting graduate students' curiosities and continued professional engagement. CONCLUSIONS: Recommended principles for training are put forward for the development and evaluation of psychotherapy training programs that aim to foster clinical wisdom. These principles complement training models focused upon clinical competence by helping trainees to develop a foundation for clinical wisdom. PMID- 26427514 TI - Down-regulation of IKKbeta expression in glioma-infiltrating microglia/macrophages is associated with defective inflammatory/immune gene responses in glioblastoma. AB - Glioblastoma (GBM) is an aggressive malignancy associated with profound host immunosuppression. Microglia and macrophages infiltrating GBM acquire the pro tumorigenic, M2 phenotype and support tumor invasion, proliferation, survival, angiogenesis and block immune responses both locally and systematically. Mechanisms responsible for immunological deficits in GBM patients are poorly understood. We analyzed immune/inflammatory gene expression in five datasets of low and high grade gliomas, and performed Gene Ontology and signaling pathway analyses to identify defective transcriptional responses. The expression of many immune/inflammatory response and TLR signaling pathway genes was reduced in high grade gliomas compared to low grade gliomas. In particular, we found the reduced expression of the IKBKB, a gene coding for IKKbeta, which phosphorylates IkappaB proteins and represents a convergence point for most signal transduction pathways leading to NFkappaB activation. The reduced IKBKB expression and IKKbeta levels in GBM tissues were demonstrated by qPCR, Western blotting and immunohistochemistry. The IKKbeta expression was down-regulated in microglia/macrophages infiltrating glioblastoma. NFkappaB activation, prominent in microglia/macrophages infiltrating low grade gliomas, was reduced in microglia/macrophages in glioblastoma tissues. Down-regulation of IKBKB expression and NFkappaB signaling in microglia/macrophages infiltrating glioblastoma correlates with defective expression of immune/inflammatory genes and M2 polarization that may result in the global impairment of anti-tumor immune responses in glioblastoma. PMID- 26427517 TI - Quote ... unquote. PMID- 26427516 TI - Intuition in medical practice: A reflection on Donald Schon's reflective practitioner. AB - In a recent commentary, Dr. Abhishek Biswas asks the question whether physicians should rely on their "gut feeling" when making clinical decisions. Biswas describes a situation where his intuition resulted in an immediate course of action that prompted urgent medical attention for a patient who had "routine" pain. Inspired by the author's account, I would like to further Biswas' discussion and examine its importance using the educational theories of Donald Schon and his concept of the reflective practitioner. Schon argues that technical knowledge alone is not sufficient to solve the complex problems that professionals face on a daily basis and intuition, developed through a reflective practice, is crucial for any professional's practice, especially in a time of greater uncertainty in the workplace. PMID- 26427518 TI - A critical appraisal of the selegiline transdermal system for major depressive disorder. AB - The selegiline transdermal system (STS) is the first antidepressant transdermal medication approved by the US FDA for the treatment of major depressive disorder. Its unique antidepressant delivery system allows for steady release of selegiline over 24 h with minimal fluctuation in drug serum levels. It is able to deliver high enough central nervous system concentrations required for an antidepressant effect without substantially inhibiting Monoamine oxidase-A in the gastrointestinal and hepatic system, thereby reducing the risk of tyramine hypertensive crises especially at the lowest doses. Patient adherence theoretically could be improved due to ease of use and once-daily dosing when compared to oral counterparts' need for multiple daily doses. Clinical trials have established that doses between 6 and 12 mg over 24 h have been effective for major depressive disorder and tolerated among patients. Episodes of hypertensive crisis with STS have been minimally reported thus far. Overall, STS appears to be an effective agent for major depressive disorder when held to regulatory standards and post marketing analyses. This paper reviews the pharmacologic characteristics of STS and results of studies investigating its clinical efficacy and safety. PMID- 26427519 TI - Controlled-release dinoprostone insert versus Foley catheter for labor induction: a meta-analysis. AB - OBJECTIVE: To compare the effectiveness and safety of controlled-release dinoprostone insert with Foley catheter balloon for cervical ripening and labor induction. METHODS: PubMed, Cochrane Central Register of Controlled Trials, Web of Science, and China Knowledge Resource Integrated Database were searched. Only randomized controlled trials comparing controlled-release dinoprostone insert with Foley catheter balloon were included. Risk ratio (RR) or mean difference (MD) with 95% confidence interval (CI) was calculated. RESULTS: Six studies were included with 731 women received dinoprostone insert and 722 Foley catheter. Time from induction to delivery was significantly shortened in dinoprostone insert group compared to Foley catheter group (MD 5.73 h, 95% CI 1.26-10.20). There were no significant differences in vaginal delivery within 24 h (RR 0.75, 95% CI 0.43 1.30) or cesarean section (RR 0.94, 95% CI 0.80-1.12) between two ripening methods. Dinoprostone insert was related with increased rate of excessive uterine contraction (RR 0.07, 95% CI 0.03-0.19), but less oxytocin use (RR 1.86, 95% CI 1.25-2.77) when compared with Foley catheter. CONCLUSIONS: Induction of labor with controlled-release dinoprostone insert seems to be more effective than Foley catheter. However, the former method causes excessive uterine contraction more frequently. PMID- 26427520 TI - Nitrogen-Doped Graphene Quantum Dots as a New Catalyst Accelerating the Coordination Reaction between Cadmium(II) and 5,10,15,20-Tetrakis(1-methyl-4 pyridinio)porphyrin for Cadmium(II) Sensing. AB - Small molecules or metal ions can be employed as catalysts to accelerate metalloporphyrin formation. Herein, we for the first time report the coordination reaction between cadmium(II) and 5,10,15,20-tetrakis(1-methyl-4 pyridinio)porphyrin can be accelerated by nitrogen-doped graphene quantum dots (NGQDs). This catalytic reaction results in the change of the absorption of porphyrins and the fluorescence of NGQDs as a result of the inner filter effect (IFE) of the porphyrins on the assembled NGQDs. Both signals can be used for rapid and sensitive determination of metal ions. The present work promises a novel strategy for constructing sensors for metal ions. PMID- 26427521 TI - Kaurane diterpenes as mitochondrial alterations preventive agents under experimental oxidative stress conditions. AB - CONTEXT: Foliol, linearol, and sidol are the most common diterpenes found in Sideritis L. spp. (Lamiaceae) with a wide range of demonstrated properties including anti-inflammatory, antioxidant, and anti-apoptotic effects. OBJECTIVE: For the first time, the present work was studied for the potential protective role of these kaurane-type diterpenes on mitochondrial oxidative stress induced by H2O2 in the human astrocytoma U373-MG cell line and in the rat adrenal pheochromocytoma PC12 cell line. MATERIALS AND METHODS: Mitochondrial protection was assayed at 5 and 10 uM concentrations for 24 h (for kaurane diterpenes) and H2O2 as oxidative stress inducer (0.1 mM for PC12 cells and 1 mM for U373-MG, for 30 min). ATP concentration was determined by high-performance liquid chromatography (HPLC), and changes in mitochondrial membrane potential, caspase-3 activity as well as in cytosolic and mitochondrial calcium levels were assessed by fluorometric techniques, by using specific fluorescent probes. RESULTS: Pretreatments for 24 h with linearol and sidol, prior to H2O2 exposure, acted as mitochondrial alterations preventive agents by increasing membrane potential (over 40-60% in PC12 cells and over 10-20% in U373-MG), restoring both cytosolic and mitochondrial calcium homeostasis (linearol at 10 uM caused a 3.5-fold decrease in cytosolic calcium concentration in PC12 cells), decreasing caspase-3 activity (over 1.25-1.5-fold for linearol and sidol) and avoiding ATP depletion (linearol increased over 20% ATP level in both cell types). CONCLUSION: Our results suggest that linearol and sidol could provide protective activity by targeting mitochondria in response to the deleterious changes induced by H2O2. PMID- 26427522 TI - Pharmacogenomics in the treatment of lung cancer: an update. AB - Significant advances have been made in the analysis of the human genome in the first decades of the 21st century and understanding of tumor biology has matured greatly. The identification of tumor-associated mutations and the pathways involved has led to the development of targeted anticancer therapies. However, the challenge now in using chemotherapy to treat nonsmall-cell lung cancer is to identify more molecular markers predictive of drug sensitivity and determine the optimal drug sequences in order to tailor treatment to each patient. This approach could permit selection of patients who could benefit most from a specific type of chemotherapy by matching their tumor and individual genetic profile. Nevertheless, this potential has been limited so far by reliance on the single biomarker approach, though this is now on the way to being overcome through whole genome studies. PMID- 26427523 TI - Transferring research from researchers to knowledge users: the importance of relationships and getting them right. PMID- 26427524 TI - The challenge of creating a 'Welsh NHS'. AB - Health policy in the UK has been greatly affected by devolution, with growing divergence in policy and practice across the four UK countries. Since 1999, Wales has created distinctive policies and structures and made some progress in improving health and services, despite obstacles. These include financial and demographic challenges faced elsewhere and others rooted in local attitudes and expectations and in the nature of the Welsh constitutional settlement. PMID- 26427525 TI - An innovative strategy to increase a professional workforce: the fast track initiative for health visitors in England. AB - OBJECTIVES: Fast tracking is one strategy that organizations use to ameliorate workforce shortfalls by attracting new recruits, and accelerating their skills development and experience. In response to the Government's target of rapidly expanding the number of health visitors in England's National Health Service, the fast track initiative was launched to recruit newly qualified (fast track) as well as experienced (standard entry) nurses and midwives onto health visiting programmes. This paper evaluates the fast track initiative, from the perspective of fast track and standard entry students, practice teachers and health visitor managers. METHODS: A mixed methods design was used comprising a questionnaire survey (n = 71 students), semi-structured interviews (n = 37 students), telephone interviews (n = 13 managers) and six focus groups (n = 24 practice teachers). Data were collected between April 2012 and July 2013. Descriptive statistics, t tests and the Pearson Chi-square test were used to analyse the quantitative data. The qualitative data were analysed thematically. RESULTS: Motivations for health visiting as a career choice were similar for fast track and standard entry students, with career progression and interest in health promotion being key motivators. There was consensus that personal qualities and characteristics were more important than experience or qualifications. However, fast track students were significantly less confident about their public health competencies in leadership and management (p < 0.05) and communication (p < 0.02). Practice teachers and managers also reported that fast track students required more intensive supervision particularly at the beginning of the programme. Programme completion including pass rates and academic achievement showed no significant difference by route of entry (p > 0.5). CONCLUSION: Fast tracking offers a useful recruitment strategy in order to expand the health visitor workforce, but longitudinal research is needed to confirm benefits such as retention and career trajectories. PMID- 26427526 TI - A cigar by any other name would taste as sweet. PMID- 26427527 TI - Economic burden from smoking-related diseases in Thailand. AB - OBJECTIVE: To assess economic burden attributable to smoking in Thailand in 2009. METHODS: A prevalence-based, disease-specific cost of illness approach was used to estimate the direct medical costs, indirect medical costs, productivity loss due to premature deaths and absenteeism caused by smoking-related diseases. Direct healthcare costs were obtained from the inpatient and outpatient charge database at the National Health Security Office and the Central Office for Healthcare Information. Indirect healthcare costs were obtained from the Health and Welfare Survey. The household Socioeconomic Survey provided data on income of the population. Costs were estimated for 7 disease groups, namely, lung cancer, chronic obstructive pulmonary disease (COPD), cardiovascular disease (CVD), upper aerodigestive tract cancer, other cancer, other respiratory diseases and other medical conditions. Smoking Attributable Fractions were derived from the 2009 Thai Burden of Disease study. RESULTS: Total economic burden of smoking amounted to 74.88 billion Thai Baht (THB) (95% CI 74.59 to 75.18) (US$2.18, 95% CI US$2.17 to US$2.19 billion). Of this, most of the burden resulted from productivity loss 62.24 billion THB (95% CI 62.05 to 62.44) (US$1.81, 95% CI US$1.81 to US$1.82 billion). Total medical cost was 12.64 billion THB (12.44 to 12.85) (US$0.37, 95% CI US$0.36 to US$0.37 billion). Excluding other medical conditions, the direct healthcare costs were highest for CVD, followed by COPD and other respiratory diseases, respectively. All together, the total cost of smoking accounted for 0.78% (95% CI 0.78% to 0.79%) of the national gross domestic product and about 18.19% (95% CI 18.12% to 18.27%) of total health expenditure. CONCLUSIONS: The total economic loss from smoking-related diseases highlights the significant loss to the society, health sector and the country's economy. Such information is crucial for informing national public health policy, particularly when a conflict arises between the economy and health. PMID- 26427528 TI - Assessing tobacco marketing receptivity among youth: integrating point of sale marketing, cigarette package branding and branded merchandise. AB - BACKGROUND: As countries prohibit tobacco marketing through traditional channels, marketing at point of sale (PoS) and through tobacco packaging is increasingly important for promoting tobacco consumption. OBJECTIVES: Assess the validity of a novel marketing receptivity index that considers frequency of PoS exposures, tobacco brand recall and ownership of branded merchandise. METHODS: Data come from a cross-sectional survey of 3172 secondary school students in Argentina. Questions assessed frequency of going to stores where tobacco is often sold; cued recall of brand names for 3 cigarette packages with brand name removed and ownership of branded merchandise. A four-level marketing receptivity index was derived: low PoS exposure only; high PoS exposure or recall of 1 brand; recall of 2 or more brands; and ownership of branded merchandise. Indicators of marketing receptivity and smoking involvement were regressed on the index, including in adjusted models that controlled for sociodemographics, social influences and sensation seeking. FINDINGS: Among never-smokers, the index had independent positive associations with smoking susceptibility (ie, adjusted OR (AOR)2v1=1.66; AOR3v1=1.64; AOR4v1=2.95), willingness to try a specific brand (ie, AOR2v1=1.45; AOR3v1=2.38; AOR4v1=2.20) and positive smoking expectancies (ie, Badj 2v1=0.09; Badj 3v1=0.18; Badj 4v1=0.34). A more marked dose-response independent association was found with current smoking behaviour (ie, AOR2v1=2.47; AOR3v1=3.16; AOR4v1=3.62). CONCLUSIONS: The marketing receptivity index was associated with important variation in smoking-related perceptions, intentions and behaviour among Argentine adolescents. Future research should determine the predictive validity and generalisability of this measure to other contexts, including the explanatory power gained by integrating cigarette package brand recognition tasks. PMID- 26427529 TI - Histone deacetylase inhibition reduces hypothyroidism-induced neurodevelopmental defects in rats. AB - Thyroid hormone (TH) through its receptor (TRalpha/beta) influences spatio temporal regulation of its target gene repertoire during brain development. Though hypothyroidism in WT rodent models of perinatal hypothyroidism severely impairs neurodevelopment, its effect on TRalpha/beta knockout mice is less severe. An explanation to this paradox is attributed to a possible repressive action of unliganded TRs during development. Since unliganded TRs suppress gene expression through the recruitment of histone deacetylase (HDACs) via co repressor complexes, we tested whether pharmacological inhibition of HDACs may prevent the effects of hypothyroidism on brain development. Using valproate, an HDAC inhibitor, we show that HDAC inhibition significantly blocks the deleterious effects of hypothyroidism on rat cerebellum, evident by recovery of TH target genes like Bdnf, Pcp2 and Mbp as well as improved dendritic structure of cerebellar Purkinje neurons. Together with this, HDAC inhibition also rescues hypothyroidism-induced motor and cognitive defects. This study therefore provides an insight into the role of HDACs in TH insufficiency during neurodevelopment and their inhibition as a possible therapeutics for treatment. PMID- 26427530 TI - What Influences Patient-Therapist Interactions in Musculoskeletal Physical Therapy? Qualitative Systematic Review and Meta-Synthesis. AB - BACKGROUND: Musculoskeletal physical therapy involves both specific and nonspecific effects. Nonspecific variables associated with the patient, therapist, and setting may influence clinical outcomes. Recent quantitative research has shown that nonspecific factors, including patient-therapist interactions, can influence treatment outcomes. It remains unclear, however, what factors influence patient-therapist interaction. PURPOSE: This qualitative systematic review and meta-synthesis investigated patients' and physical therapists' perceptions of factors that influence patient-therapist interactions. DATA SOURCES: Eleven databases were searched independently. STUDY SELECTION: Qualitative studies examining physical therapists' and patients' perceptions of factors that influence patient-therapist interactions in musculoskeletal settings were included. DATA EXTRACTION: Two reviewers independently selected articles, assessed methodological quality using the Critical Appraisal Skills Programme (CASP), and performed the 3 stages of analysis: extraction of findings, grouping of findings (codes), and abstraction of findings. DATA SYNTHESIS: Thirteen studies were included. Four themes were perceived to influence patient-therapist interactions: (1) physical therapist interpersonal and communication skills (ie, presence of skills such as listening, encouragement, confidence, being empathetic and friendly, and nonverbal communication), (2) physical therapist practical skills (ie, physical therapist expertise and level of training, although the ability to provide good education was considered as important only by patients), (3) individualized patient-centered care (ie, individualizing the treatment to the patient and taking patient's opinions into account), and (4) organizational and environmental factors (ie, time and flexibility with care and appointments). LIMITATIONS: Only studies published in English were included. CONCLUSIONS: A mix of interpersonal, clinical, and organizational factors are perceived to influence patient-therapist interactions, although research is needed to identify which of these factors actually influence patient-therapist interactions. Physical therapists' awareness of these factors could enhance patient interactions and treatment outcomes. Mechanisms to best enhance these factors in clinical practice warrant further study. PMID- 26427531 TI - Root resorption of self-ligating and conventional preadjusted brackets in severe anterior crowding Class I patients: a longitudinal retrospective study. AB - BACKGROUND: To test the null hypothesis that there is no difference in the apical root resorption seen after orthodontic treatment with the conventional brackets and the self-ligating brackets. METHODS: Pre-treatment and post-treatment periapical radio-graphs of 70 patients, (35 treated with the Damon3 0.022" bracket and 35 with the 0.022" 3 M bracket) were studied. The long cone paralleling technique was used for all the radio-graphs. Any image distortion between the pre-treatment and post-treatment radio-graph was calculated and compensated for by using the crown length measurements, on the assumption that the crown length remains unaltered during the treatment period. Quantitative measurements of crown and root lengths for the maxillary and the mandibular central and lateral incisors were compared. Means and standard deviations for the percentage root resorption per tooth group were calculated. A paired t-test and non paired t-test analysis was performed to determine whether there was an appliance, treatment time, or initial age effect on the amount of root resorption seen after treatment. RESULT: No statistically significant difference in root resorption between the two appliance systems was found. The patient's degree of root resorption were graded as grade 1 and grade 2 in the self-ligating group which is more than the conventional group. CONCLUSIONS: There was no significant difference in root resorption between self-ligating brackets and conventional brackets in severe crowding incisors subjects. PMID- 26427532 TI - Women's satisfaction with childbirth care in Felege Hiwot Referral Hospital, Bahir Dar city, Northwest Ethiopia, 2014: cross sectional study. AB - BACKGROUND: Globally, each year more than half million women die from pregnancy related causes and an estimated 10 million experience injuries, infections and disease that can cause lifelong suffering attributed to poor quality care. Client satisfaction on health care delivery is an indication of quality care and reported to affect health service utilization. Individuals happy with the care received comply with services and follow up. The aim of this study was to assess women's satisfaction with care during child birth and associated factors. METHODS: Hospital based cross-sectional study was conducted on women delivering their baby in April to May 2014. Systematic sampling procedure was used to select 594 eligible women, and face to face interview technique was used to collect the data. The data were coded, entered into EPI-INFO (3.5.1) and analyzed using SPSS version 20 software package. RESULTS: The findings of this study revealed that the proportion of women satisfied with childbirth care service was 74.9 %. Mothers whose age less than 20, and 20-34 years were less likely to satisfy with the care during child birth compared to mothers whose age was above 35 years (AOR = 0.17, 95 % CI 0.04-0.68, and AOR = 0.13.95 % CI 0.13-0.85). Besides, women who did not attend ANC were more than 3 times likely to satisfy with care compared to women attended ANC (AOR = 3.75, 95 % CI 1.12-12.59). Moreover, who who gave birth for the first time, and two to five times were more than 4 times likely to satisfy compared to women who gave birth for more than 5 times (AOR = 4.68, 95 % CI 1.75-12.54, and AOR = 4.38, 95 % CI 1.91-12.22). CONCLUSION: Only 75 % of women gave birth satisfied with the care they received. Moreover, age of women, antenatal care follow-up and the number of deliveries were important predictors of level of satisfaction. Therefore, the hospital administration and health professionals need to offer patient oriented service to increase level of satisfaction, as it is one of the measures of quality care. PMID- 26427533 TI - A cross sectional study of upper extremity strength ten days after a stroke; relationship between patient-reported and objective measures. AB - BACKGROUND: Reduced upper extremity function early after a stroke is common, and a combination of strength capacity and patient-reported measures contribute to setting realistic goals. The validity of the patient's perception of upper extremity strength in relation to objective strength assessments early after a stroke needs to be clarified. The objective was to investigate the relationship between perceived upper extremity strength and measured hand strength at ten days post-stroke. METHODS: This study of 99 patients with reduced upper extremity function at 3 days post stroke, were consecutively included from a stroke unit to the Stroke Arm Longitudinal Study at the University of Gothenburg, (the SALGOT study). The correlations between two questions from the Stroke Impact Scale (SIS 1a and 1b), and a dynamometer measure of hand strength values (percentage of normative values) were investigated. In order to explain differences between the two types of measurements, the accordance between perceived strength in a dichotomized SIS and objective measures was explored. In SIS 1a and 1b, 1-3 points correspond to reduced strength (<80% or normative strength values). In SIS 1a and 1b, 4-5 points correspond to normal strength (>= 80% of normative strength values). RESULTS: The correlation between the measured strength values and perceived arm strength was rho 0.82 (p = <0.001) and with perceived grip strength rho 0.87 (p = <0.001). Using the dichotomized SIS and the 80% cut-off correctly classified arm strength in 81% and grip strength in 84% of the patients, with a sensitivity of 0.86-0.87, a specificity of 0.62-0.77, positive predicted values of 0.87-0.91 and negative predicated values of 0.64-0.67. DISCUSSION: The discrepancy between assessed strength capacity and self-perceived strength highlights the importance of including self-perceived assessments early after stroke, in order to increase knowledge of a patient's awareness of functioning or lack thereof. CONCLUSIONS: Ten days after stroke in patients without severe cognitive disabilities, this study suggests that despite high correlations between measures, an objective assessment of arm and hand strength does not always reflect the patient's perspective. A combination of self-reported and objective strength assessment is requested to enhance in setting of realistic goals early after stroke. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01115348, May 3, 2010. PMID- 26427535 TI - A 16-year-old with ST elevation myocardial infarction: case report and review of the literature. AB - Chest pain in young adults presents a unique diagnostic challenge, placing young patients at an increased risk to be misdiagnosed, as this patient population typically does not demonstrate the traditional risk factors associated with cardiovascular disease. This study details the case of a 16-year-old male who presented with new-onset chest pain and ST elevation on electrocardiogram. His history was unremarkable for known cardiac risk factors, but laboratory evaluation demonstrated markedly elevated troponins and electrocardiographic findings confirmed ST-segment elevation myocardial infarction. Coronary angiography demonstrated 100% occlusion of the left anterior descending artery, which was managed with percutaneous transluminal coronary angioplasty, thrombectomy, and bare-metal stenting. The patient had an uneventful recovery. This study examines the major causes of ST elevation myocardial infarction in young adults and reviews the major differences between younger and older myocardial infarction populations with emphasis on risk factor profile, pathophysiological mechanisms, clinical presentation, angiographic findings, and prognosis. This review highlights the need for consideration of a wide differential in younger subsets of the population presenting with chest pain and ST elevation. The implementation of current adult management protocols and guidelines for ST elevation myocardial infarction should not be overlooked due to age. Given the potential for premature death and long-term disability with resulting individual and societal consequences, it is crucial to understand the importance of correct diagnostic evaluation in this clinical scenario. PMID- 26427534 TI - Gender differences in the progression of target organ damage in patients with increased insulin resistance: the LOD-DIABETES study. AB - BACKGROUND: The purpose of this study was to analyze the evolution of vascular, cardiac and renal target organ damage (TOD) in patients with increased insulin resistance over a 3.5 year follow-up and to investigate gender difference and factors that influence its progression. METHODS: We performed a prospective observational study involving 112 patients (71 men, 41 women) who were followed for 3.5 years. Measurements included blood pressure, blood glucose, lipids, smoking, body mass index (BMI) and HOMA-Ir Vascular TOD included carotid intima media thickness (IMT), pulse wave velocity (PWV) and ankle/brachial index (ABI). Cardiac TOD included Cornell voltage-duration product and Sokolow. Renal TOD included creatinine, glomerular filtration and albumin/creatinine ratio. RESULTS: The IMT increased in both genders. Each year, the IMT increased 0.005 mm in men and 0.011 in women and the PWV 0.024 and 0.020 m/sec, respectively. The highest increase was in women with type 2 diabetes mellitus, who had an increase in TOD carotid (40%), PWV (24%) and renal TOD (20 %). Multiple regression analysis, after adjusting for age and gender, showed a negative association between duration since diabetes diagnosis and ABI (beta = -0.006; p = 0.017) and between BMI and glomerular filtration (beta = -0.813; p = 0.014). HbA1c was positively associated with PWV (beta = 0.501; p = 0.014). CONCLUSIONS: This study showed that the progression of vascular and renal TOD differs by gender. The increase in vascular and renal TOD was higher in women, especially in diabetic women. The PWV increase showed a positive association with mean HbA1c levels during the follow up. Glomerular filtration was associated with BMI and the ABI was associated with duration since type 2 diabetes mellitus diagnosis. TRIAL REGISTRATION: Clinical Trials.gov Identifier NCT01065155. PMID- 26427536 TI - Brugia RapidTM antibody responses in communities of Indonesia in relation to the results of 'transmission assessment surveys' (TAS) for the lymphatic filariasis elimination program. AB - BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis recommends the transmission assessment survey (TAS) as the preferred methodology for determining whether mass drug administration can be stopped in an endemic area. Because of the limited experience available globally with the use of Brugia RapidTM tests in conducting TAS in Brugia spp. areas, we explored the relationship between the antibody test results and Brugia spp. infection as detected by microfilaremia in different epidemiological settings. METHODS: The study analyzes the Brugia RapidTM antibody responses and microfilaremia in all ages at three study sites in: i) a district which was classified as non-endemic, ii) a district which passed TAS, and iii) a district which failed TAS. Convenience sampling was done in each site, in one to three purposefully selected villages with a goal of 500 samples in each district. RESULTS: A total of 1543 samples were collected from residents in all three study sites. In the site which was classified as non endemic and where MDA had not been conducted, 5 % of study participants were antibody positive, none was positive for microfilaremia, and age-specific antibody prevalence peaked at almost 8 % in the 25-34 year-old age range, with no antibody-positive results found in children under eight years of age. In the site that had passed TAS, 1 % of participants were antibody positive and none was positive for microfilaremia. In the site which failed TAS, 15 % of participants were antibody positive, 0.2 % were microfilaremic, and age-specific antibody prevalence was highest in 6-7 year olds (30 %), but above 8 % in all age levels above 8 years old. CONCLUSIONS: These results from districts which followed the current WHO guidance for mapping, MDA, and implementing TAS, while providing antibody profiles of treated and untreated populations under programmatic settings, support the choice of antibody prevalence in the 6- and 7-year-old age group in TAS for making stopping MDA decisions. Since only one study participant was microfilaremic, no conclusions could be drawn about the relationship between antibodies and microfilaremia and further longitudinal studies are required to understand this relationship. PMID- 26427537 TI - Comprehensive Two-Dimensional Interrogation of the Tricuspid Valve Using Knowledge Derived from Three-Dimensional Echocardiography. AB - BACKGROUND: Accurate identification of tricuspid valve (TV) leaflets by two dimensional (2D) transthoracic echocardiography is difficult because of variability in the intersection between the imaging plane and leaflets. Using information obtained from multiplanar reconstruction (MPR) of three-dimensional (3D) data sets, the investigators sought to define "novel" 2D views that would allow targeted interrogation of TV leaflets using 2D transthoracic echocardiography. METHODS: Images of the TV in the standard 2D views (apical four chamber, right ventricular focused, right ventricular inflow, and parasternal short axis) and 3D data sets were acquired from the same probe position in 106 adults. Three-dimensional MPR was used to determine which leaflet combination was seen in the 2D image: anterior and septal, anterior and posterior, anterior alone, or posterior and septal. Using this analysis, 2D landmarks were identified to define nonstandard TV views tailored to depict specific leaflets. Two dimensional images in these views and 3D data sets were then prospectively collected in 54 additional patients. Three independent readers analyzed these 2D views to determine TV leaflet combinations, and their interpretation was compared with 3D MPR-derived reference. RESULTS: Three-dimensional MPR views made it possible to define six nonstandard 2D views on the basis of anatomic clues and landmarks, which consistently depicted all the aforementioned leaflet combinations. When these six views were prospectively tested, the agreement of TV leaflet identification against 3D MPR was excellent (kappa = 0.88, kappa = 0.93, and kappa = 0.98). CONCLUSION: The nonstandard 2D views defined in this study allow accurate TV leaflet identification and may thus be useful when localization of TV leaflet pathology is clinically important. PMID- 26427538 TI - [Endotracheal intubation using the Airtraq optical laryngoscope when the glottis is off-center of the viewfinder: are the options of optimization exhausted?]. PMID- 26427539 TI - [Pretreatment with remifentanil protects against the reduced-intestinal contractility related to the ischemia and reperfusion injury in rat]. AB - BACKGROUND AND OBJECTIVES: Serious functional and structural alterations of gastrointestinal tract are observed in failure of blood supply, leading to gastrointestinal dismotility. Activation of opioid receptors provides cardioprotective effect against ischemia-reperfusion (I/R) injury. The aim of the present study was to determine whether or not remifentanil could reduce I/R injury of small intestine. METHODS: Male Wistar Albino rats were subjected to mesenteric ischemia (30min) followed by reperfusion (3h). Four groups were designed: sham control; remifentanil alone; I/R control; and remifentanil+I/R. Animals in remifentanil+I/R group were subjected to infusion of remifentanil (2ugkg(-1)min(-1)) for 60min, half of which started before inducing ischemia. Collecting the ileum tissues, evaluation of damage was based on contractile responses to carbachol, levels of lipid peroxidation and neutrophil infiltration, and observation of histopathological features in intestinal tissue. RESULTS: Following reperfusion, a significant decrease in carbachol-induced contractile response, a remarkable increase in both lipid peroxidation and neutrophil infiltration, and a significant injury in mucosa were observed. An average contractile response of remifentanil+I/R group was significantly different from that of the I/R group. Lipid peroxidation and neutrophil infiltration were also significantly suppressed by the treatment. The tissue samples of the I/R group were grade 4 in histopathological evaluation. In remifentanil+I/R group, on the other hand, the mucosal damage was moderate, staging as grade 1. CONCLUSIONS: The pretreatment with remifentanil can attenuate the intestinal I/R injury at a remarkable degree possibly by lowering lipid peroxidation and leukocyte infiltration. PMID- 26427540 TI - Non-steroidal anti-inflammatory drugs and risk of heart failure exacerbation: A systematic review and meta-analysis. AB - BACKGROUND: The association between exacerbation of heart failure (HF) and use of non-steroidal anti-inflammatory drugs (NSAIDs) has long been recognized but the data on this adverse effect are limited. METHODS: To further characterize this possible association, we conducted a systematic review and meta-analysis of observation studies that reported odds ratio, relative risk, hazard ratio or standardized incidence ratio comparing risk of exacerbation of HF in patients with pre-existing HF who took NSAIDs versus non-users. Pooled risk ratios (RR) and 95% confidence intervals for conventional NSAIDs, celecoxib and rofecoxib were calculated using random-effect, generic inverse variance method. RESULTS: Six studies were identified and included in our data analysis. Use of conventional NSAIDs was associated with a significantly higher risk of development of exacerbation of HF with the pooled RR of 1.39 (95% CI 1.20-1.62). Elevated risk was also observed among celecoxib and rofecoxib users (RR 1.34, 95% CI 0.98-1.85 and RR 2.04, 95% CI 1.68-2.48). The pooled RR of rofecoxib was significantly higher than conventional NSAIDs (p=0.02). CONCLUSION: Use of NSAIDs is associated with an increased risk of HF exacerbation among patients with pre existing HF. The excess risk was approximately 40% for conventional NSAIDs and celecoxib. The highest risk was observed among rofecoxib users. PMID- 26427541 TI - Dioxygen activation in the Cu-amyloid beta complex. AB - We investigate, by means of density-functional theory, the binding of dioxygen to Cu(I)-amyloid beta (Abeta), one of the first steps in the oxidation of ascorbate by dioxygen. Cu, Abeta, ascorbate and dioxygen are all present in the synapse during neurodegeneration, when the above species can trigger an irreversible oxidative stress inducing the eventual death of neurons. The binding of dioxygen to Cu(I) is possible and its role in dioxygen activation of Cu ligands and of residues in the first coordination sphere is described in atomic detail. Dioxygen is activated when a micro-environment suitable for a square-planar Cu(2+) coordination is present and a negatively charged group like Asp 1 carboxylate takes part in the Cu coordination anti to O2. PMID- 26427542 TI - Breast cancer prognosis and isolated tumor cell findings in axillary lymph nodes after core needle biopsy and fine needle aspiration cytology: Biopsy method and breast cancer outcome. AB - BACKGROUND: It is unknown whether performing a core needle biopsy (CNB) to diagnose breast cancer increases the incidence of isolated tumor cells (ITC) in the axillary sentinel lymph nodes. METHODS: Patients diagnosed with unilateral invasive pT1 breast cancer (<=2 cm in diameter, n = 1525) at a single center between February 2001 and August 2005 were included in this prospective observational cohort study. The patients were categorized into two groups according to the type of the preoperative breast needle biopsy performed, the CNB and the fine needle aspiration cytology (FNAC) groups, and followed up for a median of 9.5 years after breast surgery. RESULTS: 868 (56.9%) patients had FNAC and 657 (43.2%) CNB. In the subset of patients with no axillary metastases (pN0, n = 1005) 70 patients had ITC, 37 (4.3%) out of the 546 patients in FNAC group and 33 (5.0%) out of the 459 patients in the CNB group (p = 0.798). The type of tumor biopsy did not influence breast cancer-specific survival (p = 0.461) or local recurrence-free survival (p = 0.814) in univariable survival analyses. Overall, survival favored the CNB group in a univariable analysis, but no difference in survival emerged in a multivariable analysis (p = 0.718). CONCLUSIONS: CNB was not associated with a greater incidence of ITC in axillary lymph nodes as compared with FNAC, and did not have an adverse effect on survival outcomes in a patient population treated with modern adjuvant therapies. PMID- 26427543 TI - Sitagliptin and cardiovascular outcomes in diabetic patients with chronic kidney disease after acute myocardial infarction. PMID- 26427544 TI - Risk of major cardiovascular events in patients with hemodialysis or peritoneal dialysis with special reference to stroke. PMID- 26427545 TI - Identification of a conserved neutralizing linear B-cell epitope in the VP1 proteins of duck hepatitis A virus type 1 and 3. AB - Duck virus hepatitis (DVH), mainly caused by duck hepatitis A virus (DHAV), is a severe disease threaten to duck industry and has worldwide distribution. As the major structural protein, the VP1 protein of DHAV is able to induce neutralizing antibody in ducks. In this study, a monoclonal antibody (mAb) 4F8 against the intact DHAV-1 particles was used to identify the possible epitope in the three serotypes of DHAV. The mAb 4F8 had weak neutralizing activities to both DHAV-1 and DHAV-3, and reacted with the conserved linear B-cell epitopes of (75)GEIILT(80) in DHAV-1 VP1 and (75)GEVILT(80) in DHAV-3 VP1 protein, respectively, while not with DHAV-2 VP1. This was the first report about identification of the common conserved neutralizing linear B-cell epitope of DHAV 1 and DHAV-3, which will facilitate understanding of the antigenic structure of VP1 and the serologic diagnosis of DHAV infection. PMID- 26427546 TI - Evaluation of in-vivo measurement errors associated with micro-computed tomography scans by means of the bone surface distance approach. AB - In vivo micro-computed tomography (uCT) scanning is an important tool for longitudinal monitoring of the bone adaptation process in animal models. However, the errors associated with the usage of in vivo uCT measurements for the evaluation of bone adaptations remain unclear. The aim of this study was to evaluate the measurement errors using the bone surface distance approach. The right tibiae of eight 14-week-old C57BL/6 J female mice were consecutively scanned four times in an in vivo uCT scanner using a nominal isotropic image voxel size (10.4 um) and the tibiae were repositioned between each scan. The repeated scan image datasets were aligned to the corresponding baseline (first) scan image dataset using rigid registration and a region of interest was selected in the proximal tibia metaphysis for analysis. The bone surface distances between the repeated and the baseline scan datasets were evaluated. It was found that the average (+/-standard deviation) median and 95th percentile bone surface distances were 3.10 +/- 0.76 um and 9.58 +/- 1.70 um, respectively. This study indicated that there were inevitable errors associated with the in vivo uCT measurements of bone microarchitecture and these errors should be taken into account for a better interpretation of bone adaptations measured with in vivo uCT. PMID- 26427547 TI - Behavioral and physiological changes around estrus events identified using multiple automated monitoring technologies. AB - This study included 2 objectives. The first objective was to describe estrus related changes in parameters automatically recorded by the CowManager SensOor (Agis Automatisering, Harmelen, the Netherlands), DVM bolus (DVM Systems LLC, Greeley, CO), HR Tag (SCR Engineers Ltd., Netanya, Israel), IceQube (IceRobotics Ltd., Edinburgh, UK), and Track a Cow (Animart Inc., Beaver Dam, WI). This objective was accomplished using 35 cows in 3 groups between January and June 2013 at the University of Kentucky Coldstream Dairy. We used a modified Ovsynch with G7G protocol to partially synchronize ovulation, ending after the last PGF2alpha injection (d 0) to allow estrus expression. Visual observation for standing estrus was conducted for four 30-min periods at 0330, 1000, 1430, and 2200h on d 2, 3, 4, and 5. Eighteen of the 35 cows stood to be mounted at least once during the observation period. These cows were used to compare differences between the 6h before and after the first standing event (estrus) and the 2wk preceding that period (nonestrus) for all technology parameters. Differences between estrus and nonestrus were observed for CowManager SensOor minutes feeding per hour, minutes of high ear activity per hour, and minutes ruminating per hour; twice daily DVM bolus reticulorumen temperature; HR Tag neck activity per 2h and minutes ruminating per 2h; IceQube lying bouts per hour, minutes lying per hour, and number of steps per hour; and Track a Cow leg activity per hour and minutes lying per hour. No difference between estrus and nonestrus was observed for CowManager SensOor ear surface temperature per hour. The second objective of this study was to explore the estrus detection potential of machine-learning techniques using automatically collected data. Three machine-learning techniques (random forest, linear discriminant analysis, and neural network) were applied to automatically collected parameter data from the 18 cows observed in standing estrus. Machine learning accuracy for all technologies ranged from 91.0 to 100.0%. When we compared visual observation with progesterone profiles of all 32 cows, we found 65.6% accuracy. Based on these results, machine-learning techniques have potential to be applied to automatically collected technology data for estrus detection. PMID- 26427550 TI - Maternal mortality and severe morbidity in a migration perspective. AB - Among migrants in high-income countries, maternal mortality and severe morbidity generally occur more frequently as compared to host populations. There is marked variation between groups of migrants and host countries, with much elevated risks in some groups and no elevated risk at all in others. Those without a legal resident permit are most vulnerable. A reason for these elevated risks could be a different risk profile in migrants, but risk factors are unevenly distributed and not always present. Another reason is substandard care, which is identified more frequently in migrants, and comprises patient delays, for example, due to a lack of knowledge about the health system in the host country, and health worker delays, often compounded by communication barriers. Improvements in family planning and antenatal services are needed, and audits and confidential enquiries should be extended to include maternal morbidity and ethnic background. This requires scientific and political efforts. PMID- 26427551 TI - Induced pluripotent stem (iPS) cells from human fetal stem cells. AB - Pluripotency defines the ability of stem cells to differentiate into all the lineages of the three germ layers and self-renew indefinitely. Somatic cells can regain the developmental potential of embryonic stem cells following ectopic expression of a set of transcription factors or, in certain circumstances, via modulation of culture conditions and supplementation with small molecule, that is, induced pluripotent stem (iPS) cells. Here, we discuss the use of fetal tissues for reprogramming, focusing in particular on stem cells derived from human amniotic fluid, and the development of chemical reprogramming. We next address the advantages and disadvantages of deriving pluripotent cells from fetal tissues and the potential clinical applications. PMID- 26427548 TI - PatchSurfers: Two methods for local molecular property-based binding ligand prediction. AB - Protein function prediction is an active area of research in computational biology. Function prediction can help biologists make hypotheses for characterization of genes and help interpret biological assays, and thus is a productive area for collaboration between experimental and computational biologists. Among various function prediction methods, predicting binding ligand molecules for a target protein is an important class because ligand binding events for a protein are usually closely intertwined with the proteins' biological function, and also because predicted binding ligands can often be directly tested by biochemical assays. Binding ligand prediction methods can be classified into two types: those which are based on protein-protein (or pocket pocket) comparison, and those that compare a target pocket directly to ligands. Recently, our group proposed two computational binding ligand prediction methods, Patch-Surfer, which is a pocket-pocket comparison method, and PL-PatchSurfer, which compares a pocket to ligand molecules. The two programs apply surface patch based descriptions to calculate similarity or complementarity between molecules. A surface patch is characterized by physicochemical properties such as shape, hydrophobicity, and electrostatic potentials. These properties on the surface are represented using three-dimensional Zernike descriptors (3DZD), which are based on a series expansion of a 3 dimensional function. Utilizing 3DZD for describing the physicochemical properties has two main advantages: (1) rotational invariance and (2) fast comparison. Here, we introduce Patch-Surfer and PL-PatchSurfer with an emphasis on PL-PatchSurfer, which is more recently developed. Illustrative examples of PL-PatchSurfer performance on binding ligand prediction as well as virtual drug screening are also provided. PMID- 26427549 TI - Using magnets and magnetic beads to dissect signaling pathways activated by mechanical tension applied to cells. AB - Cellular tension has implications in normal biology and pathology. Membrane adhesion receptors serve as conduits for mechanotransduction that lead to cellular responses. Ligand-conjugated magnetic beads are a useful tool in the study of how cells sense and respond to tension. Here we detail methods for their use in applying tension to cells and strategies for analyzing the results. We demonstrate the methods by analyzing mechanotransduction through VE-cadherin on endothelial cells using both permanent magnets and magnetic tweezers. PMID- 26427552 TI - Electron transfer activity of a de novo designed copper center in a three-helix bundle fold. AB - In this work, we characterized the intermolecular electron transfer (ET) properties of a de novo designed metallopeptide using laser-flash photolysis. alpha3D-CH3 is three helix bundle peptide that was designed to contain a copper ET site that is found in the beta-barrel fold of native cupredoxins. The ET activity of Cualpha3D-CH3 was determined using five different photosensitizers. By exhibiting a complete depletion of the photo-oxidant and the successive formation of a Cu(II) species at 400 nm, the transient and generated spectra demonstrated an ET transfer reaction between the photo-oxidant and Cu(I)alpha3D CH3. This observation illustrated our success in integrating an ET center within a de novo designed scaffold. From the kinetic traces at 400 nm, first-order and bimolecular rate constants of 10(5) s(-1) and 10(8) M(-1) s(-1) were derived. Moreover, a Marcus equation analysis on the rate versus driving force study produced a reorganization energy of 1.1 eV, demonstrating that the helical fold of alpha3D requires further structural optimization to efficiently perform ET. This article is part of a Special Issue entitled Biodesign for Bioenergetics--the design and engineering of electronic transfer cofactors, proteins and protein networks, edited by Ronald L. Koder and J.L. Ross Anderson. PMID- 26427553 TI - Nasal chitosan microparticles target a zidovudine prodrug to brain HIV sanctuaries. AB - Zidovudine (AZT) is an antiretroviral drug that is a substrate of active efflux transporters (AETs) that extrude the drug from the central nervous system (CNS) and macrophages, which are considered to be sanctuaries of HIV. The conjugation of AZT to ursodeoxycholic acid is known to produce a prodrug (UDCA-AZT) that is able to elude the AET systems, indicating the potential ability of this prodrug to act as a carrier of AZT in the CNS and in macrophages. Here, we demonstrate that UDCA-AZT is able to permeate and remain in murine macrophages with an efficiency twenty times higher than that of AZT. Moreover, we propose the nasal administration of this prodrug in order to induce its uptake into the CNS. Chitosan chloride-based microparticles (CP) were prepared by spray-drying and were characterized with respect to size, morphology, density, water uptake and the dissolution profile of UDCA-AZT. The CP sample was then nasally administered to rats. All in vitro and in vivo measurements were also performed for a CP parent physical mixture. The CP sample was able to increase the dissolution rate of UDCA-AZT and to reduce water uptake with respect to its parent physical mixture, inducing better uptake of UDCA-AZT into the cerebrospinal fluid of rats, where the prodrug can act as an AZT carrier in macrophages. PMID- 26427554 TI - Antiretroviral drugs do not interfere with bryostatin-mediated HIV-1 latency reversal. AB - Although an effective combination of antiretroviral therapy (cART) controls HIV-1 viraemia in infected patients, viral latency established soon after infection hinders HIV-1 eradication. It has been shown that bryostatin-1 (BRY) inhibits HIV infection in vitro and reactivates the latent virus through the protein kinase C NF-kappaB pathway. We determined the in vitro potential effect of BRY in combination with currently used antiretroviral drugs. BRY alone or in combination with maraviroc (MVC)/Atripla (ATP) was tested for its capacity to reactivate latent virus and inhibit new infections. JLTRG-R5 cells and two latent HIV-1 infected cell lines, J89GFP and THP89GFP, were used as latency models. To quantify HIV infection, the reporter cell line TZM-bl was used. We found that BRY reactivates HIV-1 even in combination with MVC or ATP. Antiretroviral combinations with BRY do not interfere with BRY activity (i.e., the reactivation of latently infected cells) or with the antiviral activity of antiretroviral drugs. In addition, BRY-mediated down-modulation of surface CD4 and CXCR4 was not affected when it was used in combination with other antiretrovirals, and no hyperactivation or high-proliferation effects were observed in primary T cells. Moreover, the BRY treatment was able to reactivate HIV-1 in CD4+ T cells from HIV 1-infected patients under cART. Thus, we propose the use of BRY to purge the viral reservoir and recommend its combination with current antiretroviral treatments. PMID- 26427555 TI - Molecular simulations of glycolipids: Towards mammalian cell membrane models. AB - Glycolipids are key components of mammalian cell membranes, influencing a diverse range of cellular functions. For example, a number of receptor tyrosine kinases, including the epidermal growth factor receptor (EGFR), are allosterically regulated by the glycolipid monosialodihexosylganglioside (GM3). Recent advances in molecular dynamics methods, especially the development of coarse-grained models, have enabled simulations of increasingly complex models of cell membranes. We demonstrate these methodological developments via a case study of a coarse-grained model for the ganglioside GM3. This glycolipid is included in simulations of a mixed lipid bilayer model reflecting the compositional complexity of a mammalian cell membrane. The resultant membrane model is used to simulate the interactions of GM3 with the transmembrane domain of the EGFR. PMID- 26427556 TI - Changing in lipid profile induced by the mutation of Foxn1 gene: A lipidomic analysis of Nude mice skin. AB - Nude mice carry a spontaneous mutation affecting the gene Foxn1 mainly expressed in the epidermis. This gene is involved in several skin functions, especially in the proliferation and the differentiation of keratinocytes which are key cells of epithelial barrier. The skin, a protective barrier for the body, is essentially composed of lipids. Taking into account these factors, we conducted a lipidomic study to search for any changes in lipid composition of skin possibly related to Foxn1 mutation. Lipids were extracted from skin biopsies of Nude and BALB/c mice to be analyzed by liquid chromatography coupled to a high resolution mass spectrometer (HRMS). Multivariate and univariate data analyses were carried out to compare lipid extracts. Identification was performed using HRMS data, retention time and mass spectrometry fragmentation study. These results indicate that mutation of Foxn1 leads to significant modifications in the lipidome in Nude mice skin. An increase in cholesterol sulfate, phospholipids, sphingolipids and fatty acids associated with a decrease in glycerolipids suggest that the lipidome in mice skin is regulated by the Foxn1 gene. PMID- 26427557 TI - Kinetics of quadruplex to duplex conversion. AB - The equilibrium between G-quadruplex (G4) and duplex DNA structures is a fundamental question whenever G4 are considered within a genomic context. In this study, we performed a detailed thermodynamic and kinetic analysis of this equilibria using a new fast and high throughput technique for the screening of G4 structures. This assay examines the isothermal stability of G-quadruplexes in the presence of complementary strands monitoring the unwinding process by fluorescence techniques. Unlabelled G4 structures were used in order to avoid any thermodynamic effect that fluorophores could have on the G4 stability. The assay was applied to investigate the effect that flanking sequences can have on the thermodynamic stability of the quadruplex motifs. Interestingly, the presence of adjacent bases to the G4 structure facilitates the recognition of the complementary strand accelerating the G4 unfolding reaction. The simplicity of the systems employed and the use of fluorescence emission allowed the use of high throughput techniques and to monitor the opening reaction in real time in a "pseudo" label-free method. This G4 opening reaction may be easily implemented as a new isothermal assay for the screening of G4 structures, G4 ligands or G4 binding proteins. PMID- 26427558 TI - Initiation of phospholipomannan beta-1,2 mannosylation involves Bmts with redundant activity, influences its cell wall location and regulates beta-glucans homeostasis but is dispensable for Candida albicans systemic infection. AB - Pathogenic and non-pathogenic fungi synthesize glycosphingolipids, which have a crucial role in growth and viability. Glycosphingolipids also contribute to fungal-associated pathogenesis. The opportunistic yeast pathogen Candida albicans synthesizes phospholipomannan (PLM), which is a glycosphingolipid of the mannosylinositol phosphorylceramide family. Through its lipid and glycan moieties, PLM contributes to the initial recognition of the yeast, causing immune system disorder and persistent fungal disease through activation of host signaling pathways. The lipid moiety of PLM activates the deregulation signaling pathway involved in yeast phagocytosis whereas its glycan moiety, composed of beta-1,2 mannosides (beta-Mans), participates to inflammatory processes through a mechanism involving Galectin-3. Biosynthesis of PLM beta-Mans involves two beta 1,2 mannosyltransferases (Bmts) that initiate (Bmt5) and elongate (Bmt6) the glycan chains. After generation of double bmtsDelta mutants, we show that Bmt5 has redundant activity with Bmt2, which can replace Bmt5 in bmt5Delta mutant. We also report that PLM is located in the inner layer of the yeast cell wall. PLM seems to be not essential for systemic infection of the yeast. However, defect of PLM beta-mannosylation increases resistance of C. albicans to inhibitors of beta glucans and chitin synthesis, highlighting a role of PLM in cell wall homeostasis. PMID- 26427559 TI - [Bloodstream infection due to Campylobacter fetus subspecies fetus and skin involvement: A case series of three patients]. AB - INTRODUCTION: Among the species of Campylobacter, C. fetus subspecies fetus is characterized by extra-intestinal manifestations, including bloodstream and cardiovascular infections, occurring preferentially in the context of immunosuppression. The cutaneous lesions are rarely described but may be underestimated. CASE REPORTS: We report on 3 cases of cellulitis with bloodstream infection due to Campylobacter fetus subspecies fetus, without cardiovascular infection in a 72- and 85-year-old women, respectively, and a 79-year-old man. Outcome was successful in all 3 cases after prolonged amoxicillin-clavulanic acid treatment, without relapse. CONCLUSION: C. fetus subspecies fetus is rarely associated with skin and soft tissue infections. Cardiovascular complications may be searched in such context. PMID- 26427560 TI - Influence of remission and its duration on development of early microvascular complications in young adults with type 1 diabetes. AB - INTRODUCTION: Prevalence of partial remission ranges between 20% and 80% in the initial course of type 1 diabetes. In this phase of the disease, a substantial insulin secretion contributes to good metabolic control. The aim of the study was to determine the association between presence of partial remission and occurrence of microangiopathy complications in type 1 diabetes. MATERIAL AND METHODS: Ninety eight consecutive patients with newly diagnosed type 1 diabetes were asked to participate in a cohort study. Partial remission was defined as the time in which all of the following criteria were met: HbA1c below 6.5% (48mmol/mol), daily insulin requirement below 0.3 U/kg body weight and serum Cpeptide concentration above 0.5ng/ml. Patients were divided into those who were in remission at any time during follow-up (remitters) and non-remitters. After 7years of follow-up, the occurrence of microangiopathy complications was analyzed. In statistical analysis, Mann-Whitney test, chi(2) test and Fisher test were used for analysis between groups. We applied a Cox's multivariate regression model and univariate regression method. P<0.05 was considered statistically significant. RESULTS: In univariate logistic regression, a significant association was found between absence of remission and occurrence of at least one microvascular complication. In the Cox proportional hazards regression model that included clinically significant parameters at diagnosis (presence of ketoacidosis, cigarette smoking and HbA1c value) as covariates, absence of remission was associated with occurrence of chronic complications of diabetes at 7years [HR: 3.65 (95% CI 1.23 4.56), p=0.04]. In non-remitters, higher incidence of at least one microvascular complication (46.4% vs. 7.6%), higher incidence of retinopathy (42.8% vs. 5.7%), and neuropathy (21.4% vs. 1.9%) was found. CONCLUSIONS: Occurrence of partial remission of diabetes is associated with a reduced risk of chronic microvascular complications at 7-year follow-up. PMID- 26427561 TI - Evaluation of a supervised multi-modal physical exercise program for prostate cancer survivors in the rehabilitation phase: Rationale and study protocol of the ProCaLife study. AB - BACKGROUND: After treatment for localized prostate cancer, many survivors experience severe physical and psychological/psychosocial impairments, such as urinary incontinence, erectile dysfunction, fatigue, depressive symptoms and decreased physical functioning. Physical activity and exercise can positively influence such side effects and improve quality of life. However, the majority of prostate cancer survivors are not physically active. Thus, supportive interventions, such as supervised exercise programs, are necessary. But particularly in the post-treatment phase, infrastructure and resources are limited and specific exercise recommendations for prostate cancer survivors do not yet exist. METHODS/DESIGN: The ProCaLife study is a quasi-randomized controlled intervention trial evaluating a specific 26-week physical exercise program for prostate cancer survivors in the rehabilitation phase following medical treatment. Participants are assigned to one of two intervention groups (supervised multi-modal physical exercise including or not including further behavior-oriented techniques) or a control group (not receiving any supervised intervention). Exercise sessions are performed twice weekly and contain specific aerobic, strengthening, flexibility, balance, relaxation and pelvic floor/sphincter exercises as well as mixed games. Behavior-oriented techniques include physical activity-related knowledge transfer and barriers management. The primary endpoint quality of life and secondary psychological/psychosocial, urological, physical fitness and physical activity outcomes are assessed at pre intervention, post-intervention and follow-up time points. DISCUSSION/CONCLUSION: By evaluating a specific supervised multi-modal physical exercise program, the ProCaLife study contributes to identify effective forms of physical exercise for prostate cancer survivors in the rehabilitation phase. This is of great importance for establishing specific exercise recommendations which are missing so far. PMID- 26427562 TI - Connect for Health: Design of a clinical-community childhood obesity intervention testing best practices of positive outliers. AB - BACKGROUND: The Connect for Health study is designed to assess whether a novel approach to care delivery that leverages clinical and community resources and addresses socio-contextual factors will improve body mass index (BMI) and family centered, obesity-related outcomes of interest to parents and children. The intervention is informed by clinical, community, parent, and youth stakeholders and incorporates successful strategies and best practices learned from 'positive outlier' families, i.e., those who have succeeded in changing their health behaviors and improve their BMI in the context of adverse built and social environments. DESIGN: Two-arm, randomized controlled trial with measures at baseline and 12 months after randomization. PARTICIPANTS: 2-12 year old children with overweight or obesity (BMI >= 85th percentile) and their parents/guardians recruited from 6 pediatric practices in eastern Massachusetts. INTERVENTION: Children randomized to the intervention arm receive a contextually-tailored intervention delivered by trained health coaches who use advanced geographic information system tools to characterize children's environments and neighborhood resources. Health coaches link families to community-level resources and use multiple support modalities including text messages and virtual visits to support families over a one-year intervention period. The control group receives enhanced pediatric care plus non-tailored health coaching. MAIN OUTCOME MEASURES: Lower age-associated increase in BMI over a 1-year period. The main parent- and child reported outcome is improved health-related quality of life. CONCLUSIONS: The Connect for Health study seeks to support families in leveraging clinical and community resources to improve obesity-related outcomes that are most important to parents and children. PMID- 26427565 TI - Renal Tumour Biopsy--A New Standard of Care? PMID- 26427564 TI - The Surgical Learning Curve for One-stage Anterior Urethroplasty: A Prospective Single-surgeon Study. AB - BACKGROUND: The learning process for one-stage anterior urethroplasty has never been addressed before. OBJECTIVE: To evaluate the surgical learning curve for one stage anterior urethroplasty. DESIGN, SETTING, AND PARTICIPANTS: Data from 641 consecutive patients treated with one-stage urethroplasty for urethral stricture were collected prospectively. All the procedures were performed by a single surgeon between 1994 and 2014. INTERVENTION: One-stage anterior urethroplasty using substitute tissues. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome was treatment failure, defined as any postoperative instrumentation needed including dilation. Surgeon experience was coded as the total number of one-stage urethroplasties performed by the surgeon before the operation. Multivariable Cox regression analysis was used to evaluate the association between surgeon experience and treatment failure. Covariates consisted of age, body mass index, smoking history (no, yes, ex-smoker), diabetes history (no or yes), previous surgical treatments (no or yes), stricture length, and stricture site (bulbar, penile, panurethral). RESULTS AND LIMITATIONS: Overall, 546 patients (85%) were treated with one-stage oral mucosa urethroplasty; penile skin or skin flap was used in 95 patients (15%). Median follow-up among patients who did not experience surgical failure was 69 mo (interquartile range: 35-118). The failure-free survival at 5 yr was 77% (95% confidence interval [CI], 74-81). At multivariable analysis, surgeon experience was significantly associated with a lower probability of treatment failure (hazard ratio per 20 procedures: 0.98; 95% CI, 0.97-0.99; p=0.008). The surgical learning curve appeared lengthened, without reaching a plateau even after 600 procedures. CONCLUSIONS: In this single-surgeon analysis, surgical experience has a significant impact on the probability of treatment success for one-stage urethroplasty. Better results are achieved only after a long learning curve that may not be justifiable for late-career and low volume surgeons. PATIENT SUMMARY: The probability of surgical success after one stage urethroplasty is importantly influenced by surgeon experience. Better results are achieved only after a very long learning process. PMID- 26427563 TI - Impact of increasing physical activity on cognitive functioning in breast cancer survivors: Rationale and study design of Memory & Motion. AB - INTRODUCTION: Many breast cancer survivors experience problems with cognitive functioning that can persist years after treatment. Increasing physical activity has been shown to improve cognitive functioning in healthy and cognitively impaired adults, but has not yet been tested in cancer survivors. The primary aim of this randomized controlled trial is to examine the effects of a 3-month physical activity intervention compared to a waitlist Control arm on neuropsychological outcomes and subjective cognitive concerns in breast cancer survivors. METHODS: Eighty sedentary breast cancer survivors, self-reporting difficulties with cognition, will be randomized into an Exercise arm or Control arm. The Exercise arm includes an activity tracker (i.e., a Fitbit), phone calls, plus tailored and non-tailored email content. The Control arm will receive emails on women's health topics on the same schedule as the Exercise arm. Assessments conducted at baseline and 3 months include: neuropsychological testing, cognitive concerns and other aspects of quality of life, and 7 days of a hip-worn accelerometer. Participants will also provide fasting blood draws to assess brain derived neurotropic factor, Insulin-like growth factor 1, insulin resistance, and C-reactive protein. Primary and secondary outcomes are changes in neuropsychological testing and cognitive concerns. Biomarkers will be examined to further understand the underlying relationship between physical activity and cognition. CONCLUSION: The Memory & Motion study is designed to test whether increasing physical activity can improve cognitive functioning in breast cancer survivors. Results from this study could be used to guide development of interventions to improve cognitive functioning in breast cancer survivors. PMID- 26427566 TI - PI-RADS Prostate Imaging - Reporting and Data System: 2015, Version 2. AB - The Prostate Imaging - Reporting and Data System Version 2 (PI-RADSTM v2) is the product of an international collaboration of the American College of Radiology (ACR), European Society of Uroradiology (ESUR), and AdMetech Foundation. It is designed to promote global standardization and diminish variation in the acquisition, interpretation, and reporting of prostate multiparametric magnetic resonance imaging (mpMRI) examination, and it is based on the best available evidence and expert consensus opinion. It establishes minimum acceptable technical parameters for prostate mpMRI, simplifies and standardizes terminology and content of reports, and provides assessment categories that summarize levels of suspicion or risk of clinically significant prostate cancer that can be used to assist selection of patients for biopsies and management. It is intended to be used in routine clinical practice and also to facilitate data collection and outcome monitoring for research. PMID- 26427567 TI - What is the Contribution of Genetics to Periodontal Risk? AB - This review addresses the multicausal etiology of periodontitis, in which genetic factors play a role. The various proposed causes for periodontitis always work simultaneously, but the relative contribution of each of these varies from case to case. We are still at an early stage to identify the genes involved, in comparison with other chronic diseases. To date, the genetic variations firmly and repeatedly associated with periodontitis in some populations are found within the following genes: ANRIL, COX2, IL1, IL10, DEFB1, whereas many other proposed periodontitis candidate genes have not been firmly proven or replicated. PMID- 26427568 TI - What is the Proper Sample Size for Studies of Periodontal Treatment? AB - Small sample sizes are a common problem in biomedical research, and the periodontal literature is no exception. It is a problem leading to not only reduced statistical power but also an inappropriate statistical inference of a treatment effect. Using statistical methods with an insufficient sample size may give rise to an increased chance of falsely detecting treatment efficacy. This article provides some guidelines to cope with the small sample size problem. The authors discuss adequate sample sizes in several statistical tests and then suggest alternative statistical methods that are valid with a small sample size. PMID- 26427569 TI - Can Chemical Mouthwash Agents Achieve Plaque/Gingivitis Control? AB - Also note that structured abstracts are not allowed per journal style: What is the effect of a mouthwash containing various active chemical ingredients on plaque control and managing gingivitis in adults based on evidence gathered from existing systematic reviews? The summarized evidence suggests that mouthwashes containing chlorhexidine(CHX) and essential oils (EO) had a large effect supported by a strong body of evidence. Also there was strong evidence for a moderate effect of cetylpyridinium chloride(CPC). Evidence suggests that a CHX mouthwash is the first choice, the most reliable alternative is EO. No difference between CHX and EO with respect to gingivitis was observed. PMID- 26427570 TI - Is Photodynamic Therapy an Effective Treatment for Periodontal and Peri-Implant Infections? AB - Antimicrobial photodynamic therapy (PDT) has attracted much attention for the treatment of pathogenic biofilm associated with peridontitis and peri implantitis. However, data from randomized controlled clinical studies (RCTs) are limited and, to some extent, controversial, making it difficult to provide appropriate recommendations. Therefore, the aims of the present study were (a) to provide an overview on the current evidence from RCTs evaluating the potential clinical benefit for the additional use of PDT to subgingival mechanical debridement (ie, scaling and root planing) alone in nonsurgical periodontal therapy; and (b) to provide clinical recommendations for the use of PDT in periodontal practice. PMID- 26427572 TI - Do Mobility and Occlusal Trauma Impact Periodontal Longevity? AB - The impact of tooth mobility and occlusal trauma (OT) on periodontal bone loss and need for therapy has been debated for many years. This paper summarizes the relevant literature reported in three Dental Clinics of North America articles in the late 1990s, and adds newer information from the 2000s. Principle findings indicate that strong evidence of mobility and OT impacting tooth longevity is lacking, but reducing inflammation in the surrounding periodontium remains a critical treatment. Occlusal therapy when mobility is increasing, comfort or function are compromised, or periodontal regeneration procedures are planned should be considered. PMID- 26427571 TI - Is Radiologic Assessment of Alveolar Crest Height Useful to Monitor Periodontal Disease Activity? AB - The mainstay of periodontal assessment is clinical probing. Radiographic assessment provides quantitative information on the status of tooth-supporting bone. This article reviews methods to assess periodontal structures, including basic radiograph acquisition, assessment of alveolar crest levels, and typical patterns of bone loss. Computer technology to objectively assess loss of alveolar crest from radiographs is reviewed. Developments in computer-assisted quantitation of alveolar crest height are described. Although probing measurements continue to be viewed as more practical than radiographic measurements, radiographic assessment can be made quantitative and is likely easier and more precise than probing for routine assessment of periodontal disease activity. PMID- 26427573 TI - Does Treatment of Periodontal Disease Influence Systemic Disease? AB - Periodontal diseases are the most common human diseases globally, with gingivitis affecting up to 90% and periodontitis affecting 50% of adults. Tooth enamel is the only nonshedding tissue in the human body. In the absence of proper oral hygiene measures, microbial biofilm (dental plaque) develops on the teeth to include more than 700 different bacterial species, along with viruses, fungi, archea, and parasites. With time, ecological imbalances promote the growth of selected commensal species that induce host inflammatory pathways resulting in tissue destruction, including ulceration of the periodontal epithelium. PMID- 26427575 TI - Unanswered Questions: Can Bone Lost from Furcations Be Regenerated? AB - Periodontal regeneration-treatment that results in new alveolar bone, cementum, and a functional periodontal ligament-is successful in class II furcation defects. This article examines one aspect of periodontal regeneration-alveolar bone growth in furcation defects-in trying to answer the question, Can bone lost from furcations be regenerated? The best evidence for bone growth is histology but there is limited histologic evidence for bone growth in human furcation defects. There is more evidence from intraoperative measurements for hard tissue growth in treated furcation defects, but the nature of the hard tissue needs to be determined histologically. PMID- 26427574 TI - Should Antibiotics Be Prescribed to Treat Chronic Periodontitis? AB - Although scaling and root planing is a cost-effective approach for initial treatment of chronic periodontitis, it fails to eliminate subgingival pathogens and halt progressive attachment loss in some patients. Adjunctive use of systemic antibiotics immediately after completion of scaling and root planing can enhance the degree of clinical attachment gain and probing depth reduction provided by nonsurgical periodontal treatment. This article discusses the rationale for prescribing adjunctive antibiotics, reviews the evidence for their effectiveness, and outlines practical issues that should be considered before prescribing antibiotics to treat chronic periodontitis. PMID- 26427576 TI - Can Periimplantitis Be Treated? AB - Over the past few decades, dental implants have been found to have high predictability and survival rates because of improvements in knowledge, clinical expertise, and implant designs. As such, dental implants are frequently integrated in the clinical management of fully or partially edentulous patients. It is prudent to realize that despite the high early survival rates, dental implants do have their fair share of long-term esthetic, biological, and mechanical complications. Therefore, this paper aims to review the current evidence on the management of peri-implant diseases in an attempt to answer the following question: Can periimplantitis be treated? PMID- 26427577 TI - Does Gingival Recession Require Surgical Treatment? AB - Gingival recession represents a clinical condition in adults frequently encountered in the general dental practice. Clinicians often face dilemmas of whether or not to treat such a condition surgically. An initial condensed literature search was performed using a combination of gingival recession and surgery controlled terms and keywords. An analysis of the search results highlights the limited understanding of the factors that guide the treatment of gingival recession. Understanding the cause, prognosis, and treatment of gingival recession continues to offer many unanswered questions and challenges in periodontics as we strive to provide the best care possible for our patients. PMID- 26427578 TI - Unanswered Questions in Periodontology. PMID- 26427579 TI - Incidence of Neutropenia With Valproate and Quetiapine Combination Treatment in Subjects With Acquired Brain Injuries. AB - OBJECTIVE: To investigate whether the incidence of neutropenia was higher in subjects who received a combination treatment with valproate and quetiapine than in those who were administered monotherapy. DESIGN: Retrospective cohort study. SETTING: Rehabilitation department of a university hospital. PARTICIPANTS: Patients with acquired brain injuries who had taken valproate for seizures or quetiapine for delirium for >7 days (N=101). Data were extracted from electronic medical records of the hospital. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Incidence of neutropenia (absolute neutrophil count<2000 cells/MUL) was elicited from the weekly complete blood cell records for 71.07+/-43.71 days of observation. The odds ratio for neutropenia development was calculated and adjusted for variables that showed significant differences between patients with or without neutropenia. RESULTS: The incidence of neutropenia was significantly higher in the group receiving the combination treatment than in those receiving the monotherapy (32.26% vs 12.90%, adjusted P=.036), despite a lack of any differences in the daily doses of the medications. Coadministration of quetiapine and valproate was the predictor of neutropenia development when age, body weight, and underlying diseases were adjusted in the logistic regression model (odds ratio=3.749; 95% confidence interval, 1.161-12.099; P=.027). CONCLUSIONS: Administration of quetiapine together with valproate in patients with acquired brain injury could increase the incidence of medication-induced neutropenia. PMID- 26427580 TI - Facing our future. PMID- 26427581 TI - Ramelteon-induced nightmares: A case report. AB - Ramelteon is the only FDA-approved melatonin agonist for treatment of insomnia. It acts on melatonin MT1 and MT2 receptors. We describe a case of a patient who was prescribed ramelteon for insomnia disorder. Shortly after initiation of ramelteon, he described vivid nightmares leading to discontinuation of ramelteon. The nightmares ameliorated with ramelteon discontinuation. Ramelteon is well tolerated with a favorable side-effect profile. No documented cases of nightmares secondary to ramelteon use were found in the literature. The effects of ramelteon on rapid eye movement sleep, the stage of sleep where dreams occur, need to be further explored. PMID- 26427582 TI - Pervasive refusal syndrome: A misnomer for catatonia. PMID- 26427583 TI - Audiograms, gap detection thresholds, and frequency difference limens in cannabinoid receptor 1 knockout mice. AB - The cannabinoid receptor 1 (CB1R) is found at several stages in the auditory pathway, but its role in hearing is unknown. Hearing abilities were measured in CB1R knockout mice and compared to those of wild-type mice. Operant conditioning and the psychophysical Method of Constant Stimuli were used to measure audiograms, gap detection thresholds, and frequency difference limens in trained mice using the same methods and stimuli as in previous experiments. CB1R knockout mice showed deficits at frequencies above 8 kHz in their audiograms relative to wild-type mice. CB1R knockouts showed enhancements for detecting gaps in low-pass noisebursts relative to wild-type mice, but were similar for other noise conditions. Finally, the two groups of mice did not differ in their frequency discrimination abilities as measured by the frequency difference limens task. These experiments suggest that the CB1R is involved in auditory processing and lay the groundwork for future physiological experiments. PMID- 26427584 TI - p11 modulates calcium handling through 5-HT4R pathway in rat ventricular cardiomyocytes. AB - BACKGROUND: The role of the serotonin receptor 4 (5-HT4R) pathway in cardiac excitation-contraction coupling (ECC) remains unclear. In the brain, induction of the calcium (Ca(2+))-binding protein p11 enhances 5-HT4R translocation and signaling and could therefore be considered as a modulator of the 5-HT4R pathway in the myocardium. p11 expression is increased by brain-derived neurotrophic factor (BDNF) or antidepressant drugs (imipramine). Thus, we investigated whether p11 regulates the 5-HT4R pathway in the heart in physiological conditions or under pharmacological induction and the effects on calcium handling. METHODS AND RESULTS: p11 expression was induced in vivo in healthy Wistar rats by imipramine (10 mg/kg/21 days) and in vitro in left ventricular cardiomyocytes exposed to BDNF (50 ng/ml/8h). Cell shortening and real-time Ca(2+) measurements were processed on field-stimulated intact cardiomyocytes with the selective 5-HT4R agonist, prucalopride (1 MUM). Both imipramine and BDNF-induced cardiomyocyte p11 expression unmasked a strong response to prucalopride characterized by an increase of both cell shortening and Ca(2+) transient amplitude compared to basal prucalopride associated with a high propensity to trigger diastolic Ca(2+) events. Healthy rats treated with BDNF (180 ng/day/14 days) exhibited a sustained elevated heart rate following a single injection of prucalopride (0.1 mg/kg) which was not observed prior to treatment. CONCLUSIONS: We have identified a novel role for p11 in 5-HT4R signaling in healthy rat ventricular cardiomyocytes. Increased p11 expression by BDNF and imipramine unraveled a 5-HT4R-mediated modulation of cardiac Ca(2+) handling and ECC associated with deleterious Ca(2+) flux disturbances. Such mechanism could partly explain some cardiac adverse effects induced by antidepressant treatments. PMID- 26427585 TI - Acute liver failure during hepatitis C treatment with sofosbuvir and ledipasvir. PMID- 26427586 TI - Circulatory response to volume expansion and transjugular intrahepatic portosystemic shunt in refractory ascites: Relationship with diastolic dysfunction. AB - BACKGROUND: Cirrhotic cardiomyopathy may lead to heart failure in stressful circumstances, such as after transjugular intrahepatic portosystemic shunt (TIPS) placement. AIM: To examine whether acute volume expansion predicts haemodynamic changes after TIPS and elicits signs of impending heart failure. METHODS: We prospectively evaluated refractory ascites patients (group A) and compensated cirrhotics (group B), who underwent echocardiography, NT-proBNP measurement, and heart catheterization before and after volume load; group A repeated measurements after TIPS. RESULTS: 15 patients in group A (80% male; 54+/-12.4 years) and 8 in group B (100% male; 56+/-6.2 years) were enrolled. Echocardiography disclosed diastolic dysfunction in 30% and 12.5%, respectively. In group A, volume load and TIPS induced a significant increase in right atrial, mean pulmonary, capillary wedge pressure and cardiac index, and a decrease in systemic vascular resistance (respectively, 4.7+/-2.8 vs. 9.9+/-3.6 mmHg; 13.3+/-3.5 vs. 21.9+/-5.9 mmHg; 8.3+/-3.4 vs. 15.4+/-4.7 mmHg; 3.7+/-0.7 vs. 4.6+/-11 t/min/m2; 961+/-278 vs. 767+/-285 dynscm(-5); and 10.1+/-3.3 vs. 14.2+/-3.4 mmHg; 17.5+/-4 vs. 25.2+/-4.2 mmHg; 12.3+/-4 vs. 19.3+/-3.4 mmHg; 3.4+/-0.8 vs. 4.5+/-0.91l t/min/m2; 779+/-62 vs. 596+/-199 dynscm(-5), p<0.001 for all pairs). At 24h, cardiopulmonary pressures returned towards baseline. CONCLUSIONS: Acute volume expansion predicted haemodynamic changes immediately after TIPS. All patients had adequate haemodynamic adaptation to TIPS; none developed signs of heart failure. PMID- 26427587 TI - Reinfusion of highly purified CD133+ bone marrow-derived stem/progenitor cells in patients with end-stage liver disease: A phase I clinical trial. AB - BACKGROUND: Bone marrow stem/progenitor cells seem to be effective in liver regeneration after tissue injury. AIM: To evaluate the feasibility and safety of the mobilization and reinfusion of CD133+ stem/progenitor cells in patients with end-stage liver disease. METHODS: Autologous CD133+ stem/progenitor cells, mobilized with granulocyte-colony stimulating factor, were collected by leukapheresis and reinfused at increasing doses through the hepatic artery starting from 5*10(4)/kg up to 1*10(6)/kg. RESULTS: 16 subjects with Model for End-stage Liver Disease (MELD) score between 17 and 25 were enrolled, 14 mobilized an adequate number of CD133+ stem/progenitor cells and 12 were reinfused. No severe adverse events related to the procedure were reported. MELD score significantly worsened during mobilization in Child Turcotte Pugh-C patients. A significant improvement of liver function was observed 2 months after reinfusion (MELD 19.5 vs. 16; P=0.045). Overall, 5 patients underwent liver transplantation within 12 months from reinfusion and 2 died because of progressive liver failure. CONCLUSIONS: CD133+ stem/progenitor cells reinfusion in patients with end-stage liver disease is feasible and safe. A worsening of liver function was observed during mobilization in Child Turcotte Pugh-C patients. The temporary improvement of MELD score after reinfusion suggests that stem cells therapy may be a "bridge to transplant" approach for these patients. PMID- 26427588 TI - Failure to Improve the Oxygenation Index Is a Useful Predictor of Therapy Failure in Acute Respiratory Distress Syndrome Clinical Trials. AB - OBJECTIVE: Acute respiratory distress syndrome trials powered for mortality require significant resources, limiting the number of evaluable therapies. Validation of intermediate endpoints would enhance the feasibility of testing novel acute respiratory distress syndrome therapies in pilot studies and potentially reduce the frequency of failed large clinical trials. We sought to determine whether a change in the oxygenation index over the first 7 days of acute respiratory distress syndrome could discriminate between therapies likely or unlikely to show benefit in larger clinical trials. DESIGN: A derivation cohort from three acute respiratory distress syndrome studies was used to estimate the 7-day change in oxygenation index. Receiver operating characteristic curves were used to calculate optimal thresholds and predictability of the change in oxygenation index for 28-day mortality and ventilator-free days. The thresholds were then validated in two cohorts. Then, for each individual acute respiratory distress syndrome study, the threshold 7-day oxygenation index change was tested as an outcome measure and compared with mortality and ventilator-free days as reported in the original study. SETTING: Medical ICUs. PATIENTS: Acute respiratory distress syndrome patients. INTERVENTIONS: Various. MEASUREMENTS AND MAIN RESULTS: Change in oxygenation index, 28-day mortality, and ventilator-free days. In the derivation cohort, the mean 7-day oxygenation index improved by 4.2 (+/- 11.7) in 28-day survivors compared with an increase of 2.4 (+/- 11.6) in 28 day nonsurvivors (p < 0.001). The mean 7-day oxygenation index decreased by 5.9 (+/- 8.4) in patients with more than 14 ventilator-free days, compared with a decrease of 1.9 (+/- 12.4) among those with less than 14 ventilator-free days (p = 0.001). The optimal 7-day oxygenation index threshold for predicting mortality was an increase of 1.71 and for predicting less than 14 ventilator-free days, a decrease of 2.34. When used as a surrogate endpoint, the optimal 7-day oxygenation index change closely approximated mortality and ventilator-free day outcomes in three Acute Respiratory Distress Syndrome Network studies used for the derivation cohort and a distinct study used for validation. The change in oxygenation index was a poor predictor of individual patient outcome. CONCLUSIONS: Failure to meet a threshold improvement in the oxygenation index over the first 7 days of therapy can be used to identify therapies unlikely to succeed in subsequent trials powered for mortality and ventilator-free days. By reducing trial time and costs, use of the 7-day oxygenation index change as an intermediate endpoint could increase the number of clinical trials of promising therapies for acute respiratory distress syndrome and reduce the number of large scale trials of therapies unlikely to be of benefit. PMID- 26427589 TI - Systemic Corticosteroids and Transition to Delirium in Critically Ill Patients. AB - OBJECTIVE: Corticosteroids are frequently used in critically ill patients. We investigated whether systemic corticosteroid use increases the probability of transitioning to delirium in a large population of mixed medical-surgical ICU patients. DESIGN: Prospective cohort study. SETTING: A 32-bed medical-surgical ICU at an academic medical center. PATIENTS: Critically ill adults (n = 1,112), admitted to the ICU for more than 24 hours without a condition that could hamper delirium assessment. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Systemic corticosteroid exposure was measured daily and converted to prednisone equivalents (milligrams). Daily mental status was classified as coma, delirium, or an awake without delirium state. Transitions between states were analyzed using a first-order Markov multinomial logistic regression model with 11 different covariables, with the transition from an awake without delirium state to delirium as a primary interest. Among the 1,112 patients, corticosteroids were administered on 35% (3,483/9,867) of the ICU days at a median dose of 50 mg (interquartile range, 25-75 mg) prednisone equivalent. Administration of a corticosteroid, and any increase in the dose of the corticosteroid given on exposure days, was not significantly associated with the transition to delirium (adjusted odds ratio, 1.08; 95% CI, 0.89-1.32 and adjusted odds ratio, 1.00; 95% CI, 0.99-1.01, per 10 mg increase in prednisone equivalent). CONCLUSIONS: In a large population of mixed medical-surgical ICU patients, systemic corticosteroid use was not associated with an increased probability of transitioning to delirium. PMID- 26427590 TI - Long-Term beta-Blocker Therapy Decreases Blood Lactate Concentration in Severely Septic Patients. AB - OBJECTIVES: Measurement of blood lactate concentration in the early management of sepsis is an important step in severity assessment. High blood lactate levels in the early phase of sepsis have classically been thought to be related to tissue hypoxia, but other factors could intervene. We hypothesized that the activation of glycolysis through beta-adrenergic stimulation by endogenous catecholamines plays an important role in lactate production and that long-term beta-blocker therapy could affect the lactate concentration in patients with severe sepsis and septic shock. DESIGN: Retrospective cohort study. SETTING: Emergency department. PATIENTS: Two hundred sixty patients with severe sepsis or septic shock were included. Twenty-five percent were previously treated with beta-blockers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We recorded initial vital signs, the source of infection, mortality at 28 days, blood lactate concentration, and Predisposition Insult Response of Organ failure and Sequential Organ Failure Assessment scores using an electronic database. Blood lactate concentration was significantly lower in patients previously treated with beta blockers (3.9 +/- 2.3 mmol/L vs 5.6 +/- 3.6 mmol/L; p < 0.001). This difference was still significant after controlling for mortality (p < 0.005), for the level of the Predisposition Insult Response of Organ failure (p < 0.05) and Sequential Organ Failure Assessment (p < 0.05) scores, and for the source of infection (p < 0.05). Nearly four times more patients treated with beta-blockers had normal blood lactate levels (p< 0.001). Only two factors were significantly and independently associated with normal blood lactate concentration during severe sepsis and septic shock: survival (p = 0.03) and beta-blocker therapy (p = 0.01). CONCLUSIONS: Long-term beta-blocker therapy decreases blood lactate concentration of severely ill septic patients at presentation. We conclude that the use of blood lactate measurement as a triage tool in the initial assessment of septic patients with beta-blocker therapy may underestimate the severity of the sepsis. PMID- 26427592 TI - Nutritional Status and Mortality in the Critically Ill. AB - OBJECTIVES: The association between nutritional status and mortality in critically ill patients is unclear based on the current literature. To clarify this relation, we analyzed the association between nutrition and mortality in a large population of critically ill patients and hypothesized that mortality would be impacted by nutritional status. DESIGN: Retrospective observational study. SETTING: Single academic medical center. PATIENTS: Six thousand five hundred eighteen adults treated in medical and surgical ICUs between 2004 and 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All cohort patients received a formal, in-person, standardized evaluation by a registered dietitian. The exposure of interest, malnutrition, was categorized as nonspecific malnutrition, protein-energy malnutrition, or well nourished and determined by data related to anthropometric measurements, biochemical indicators, clinical signs of malnutrition, malnutrition risk factors, and metabolic stress. The primary outcome was all-cause 30-day mortality determined by the Social Security Death Master File. Associations between nutrition groups and mortality were estimated by bivariable and multivariable logistic regression models. Adjusted odds ratios were estimated with inclusion of covariate terms thought to plausibly interact with both nutrition status and mortality. We used propensity score matching on baseline characteristics to reduce residual confounding of the nutrition status category assignment. In the cohort, nonspecific malnutrition was present in 56%, protein-energy malnutrition was present in 12%, and 32% were well nourished. The 30-day and 90-day mortality rates for the cohort were 19.1% and 26.6%, respectively. Nutritional status is a significant predictor of 30-day mortality following adjustment for age, gender, race, medical versus surgical patient type, Deyo-Charlson index, acute organ failure, vasopressor use, and sepsis: nonspecific malnutrition 30-day mortality odds ratio, 1.17 (95% CI, 1.01-1.37); protein-energy malnutrition 30-day mortality odds ratio, 2.10 (95% CI, 1.70 2.59), all relative to patients without malnutrition. In the matched cohort, the adjusted odds of 30-day mortality in the group of propensity score-matched patients with protein-energy malnutrition was two-fold greater than that of patients without malnutrition. CONCLUSION: In a large population of critically ill adults, an association exists between nutrition status and mortality. PMID- 26427593 TI - High Level of Endotoxemia Following Out-of-Hospital Cardiac Arrest Is Associated With Severity and Duration of Postcardiac Arrest Shock. AB - OBJECTIVE: To investigate the contribution of endotoxemia to the severity of postcardiac arrest shock. DESIGN: A prospective monocentric study. SETTING: A tertiary hospital in Paris, France. PATIENTS: Patients admitted in our ICU after a successfully resuscitated out-of-hospital cardiac arrest. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Endotoxin measurement was performed in the 12 hours following return of spontaneous circulation using the endotoxin activity assay. Endotoxin level was classified as low (< 0.4 endotoxin activity), intermediate (0.4 to < 0.6 endotoxin activity), or high (>= 0.6 endotoxin activity) according to manufacture guidelines. Severity of shock was assessed by the vasopressor-free days and by the mean daily dose of vasopressor to insure a mean arterial pressure of 65-75 mm Hg. Among 92 patients included in the study, 60 presented a postcardiac arrest shock. Endotoxemia level was higher in patients with postcardiac arrest shock. Among these patients, by multivariate linear regression, high endotoxin class (adjusted estimate -2.0; 95% CI, -3.90 to 0.11), public place of cardiac arrest (adjusted estimate, 1.47; 95% CI, 0.007 to 2.93), and time to return of spontaneous circulation (adjusted estimate -0.08; 95% CI, -0.13 to -0.03) were independently associated with the number of vasopressor-free days. Furthermore, high endotoxin class (adjusted estimate, 97.95; 95% CI, 20.5 to 175.4) and a nonshockable rhythm (adjusted estimate, 59.9; 95% CI, 6.2 to 113.7) were the sole factors independently associated with the mean daily dose of vasopressors. CONCLUSIONS: In patients successfully resuscitated from cardiac arrest with a postcardiac arrest shock, high level of endotoxemia is independently associated with duration of postcardiac arrest shock and the amount of vasopressive drugs. Whether treatment targeting endotoxemia could be beneficial in the management of postcardiac arrest shock needs to be studied in further randomized controlled studies. PMID- 26427595 TI - Special Issue "Proteomics in India": Gazing Forward while Reflecting on the Lessons Learned in Global Proteomics. PMID- 26427594 TI - Predictors of Circulating Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor-Binding Protein-3 in Critical Illness. AB - OBJECTIVE: To characterize predictors of insulin-like growth factor-1 and insulin like growth factor-binding protein-3 in acute critical illness with the hypothesis that acute factors associated with critical illness will more strongly predict circulating insulin-like growth factor-1 and insulin-like growth factor binding protein-3 than chronic clinical or genetic factors. DESIGN: Observational study nested within a large prospective study using multivariable linear regression to model circulating insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 with acute and chronic clinical variables, and genotype from five polymorphisms in insulin-like growth factor pathway genes. SETTING: ICUs from two large academic medical centers. PATIENTS: Five hundred forty-three Caucasian patients with risk factors for acute respiratory distress syndrome and available plasma from early in critical illness. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Total insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 were measured in plasma using IMMULITE assays (Siemens, Malvern, PA). We examined age, gender, body mass index, cirrhosis, and diabetes, as well as Acute Physiology, Age, and Chronic Health Evaluation III score, acute hepatic dysfunction, pneumonia and aspiration, sepsis/septic shock, acute respiratory distress syndrome, and receipt of corticosteroids. Body mass index, cirrhosis, and acute respiratory distress syndrome were strongly associated with insulin-like growth factor-1 and insulin like growth factor-binding protein-3 levels; Acute Physiology, Age, and Chronic Health Evaluation III was strongly associated with insulin-like growth factor-1 levels; and age was strongly associated with insulin-like growth factor-binding protein-3. Five polymorphisms (IGF1: rs1520220, rs35767, rs2946834; IGFBP1: rs4619; IGFBP3: rs2854746) were analyzed for associations with plasma levels. When genotypes were added to models, rs2854746 was significantly associated with plasma insulin-like growth factor-binding protein-3. Genotype explained an additional 2% of variability with an overall adjusted R-square of 0.18. CONCLUSIONS: Despite the acute derangements of critical illness, both acute and chronic health factors significantly influence circulating levels of insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 early in critical illness. rs2854746 is also significantly associated with insulin-like growth factor-binding protein-3 levels in this ICU cohort. Overall, phenotypic and genotypic factors explained only a modest amount of variability in insulin like growth factor-1 and insulin-like growth factor-binding protein-3. Further research is needed to understand how to apply these findings to patient care. PMID- 26427596 TI - The 5-HT(2C) receptor agonist lorcaserin reduces cocaine self-administration, reinstatement of cocaine-seeking and cocaine induced locomotor activity. AB - Lorcaserin (Lorqess, Belviq((r))) is a selective 5-HT(2C) receptor agonist that has received FDA approval for the treatment of obesity. 5-HT(2C) receptor agonists are also efficacious in decreasing multiple aspects of cocaine motivation and reward in preclinical models. This would suggest that lorcaserin is a clinically available therapeutic with the potential to treat cocaine addiction. Here we report the effects of lorcaserin (0.1 mg/kg-1.0 mg/kg) on multiple aspects of cocaine-related behaviours in rats. We find that lorcaserin dose-dependently decreases cocaine self-administration on progressive and fixed ratio schedules of reinforcement. Lorcaserin also reduces reinstatement of cocaine-seeking behaviour in response to priming injections of cocaine and/or reintroduction of cocaine-associated cues. Finally, lorcaserin dose-dependently decreases cocaine-induced hyperlocomotion. Our results, when considered in concert with similar emergent findings in non-human primates, strongly support continued research into the potential of lorcaserin as a clinical treatment for cocaine addiction. PMID- 26427598 TI - Helical computed tomography scanning of the larynx and upper trachea in rabbits. AB - BACKGROUND: Computed tomography (CT) is used to evaluate the human tracheobronchial tree because of its unsurpassed ability to visualize the airway and surrounding structures. To establish an ideal animal model for studying subglottic stenosis, we assessed the size and morphology of the normal rabbit's laryngotracheal airway by helical CT. We measured luminal dimensions at the levels of the arytenoid and cricoid cartilages and the first, third, and eighth tracheal rings. At all levels, the axial slices were used to calculate the maximum anteroposterior (AP) dimension, transverse dimension, and cross-sectional areas. We measured the tracheal length from the cricoid to the third and eighth tracheal rings on sagittal reformation. We assessed the hyoid, thyroid, cricoid, arytenoid, and tracheal rings for the presence of calcific or soft tissue densities. We also addressed the presence or absence of pre-epiglottic and paraglottic fat. RESULTS: The mean AP tracheal dimension +/- standard deviation (SD) was 8.6 +/- 0.5 mm at the arytenoid level, 8.2 +/- 0.7 mm at the cricoid level, and 7.7 +/- 0.2 mm at the first tracheal ring level. The transverse tracheal dimension +/-SD was 5.3 +/- 0.1 mm at the arytenoid level, 5.5 +/- 0.5 mm at the cricoid level, and 6.1 +/- 0.6 mm at the first tracheal ring level. The mean tracheal area +/-SD was 35.7 +/- 2.2 mm(2) at the arytenoid level, 35.8 +/- 5.1 mm(2) at the cricoid level, and 39.2 +/- 4.3 mm(2) at the first tracheal ring level. The tracheal length +/-SD was 10.7 +/- 2.3 mm from the cricoid to the third tracheal ring and 19.1 +/- 1.14 mm to the eighth tracheal ring. There was complete calcification of the hyoid in all rabbits. Only two rabbits showed complete thyroid, arytenoid, or tracheal ring calcification. The remaining airway components were otherwise either uncalcified or partially calcified. The uvula, epiglottis, aryepiglottic fold, vallecula, piriform sinus, true/false vocal cords, and pre-epiglottic/paraglottic fat were not seen in any rabbit. CONCLUSIONS: Helical CT investigation provides good, highly definitive anatomic details of the larynx and trachea in rabbits. Such results may be used in further evaluation of the normal airway and in cases of subglottic stenosis. PMID- 26427597 TI - Deubiquitinating enzyme USP37 regulating oncogenic function of 14-3-3gamma. AB - 14-3-3 is a family of highly conserved protein that is involved in a number of cellular processes. In this study, we identified that the high expression of 14-3 3gamma in various cancer cell lines correlates with the invasiveness of the cancer cells. Overexpression of 14-3-3gamma causes changes to the morphologic characteristics of cell transformation, and promotes cell migration and invasion. The cells overexpressed with 14-3-3gamma have been shown to stimulate foci and tumor formation in SCID-NOD mice in concert with signaling components as reported with the 14-3-3beta. In our previous study, we demonstrated that 14-3-3gamma inhibits apoptotic cell death and mediates the promotion of cell proliferation in immune cell lines. Earlier, binding partners for 14-3-3gamma were defined by screening. We found that USP37, one of deubiquitinating enzymes (DUBs), belongs to this binding partner group. Therefore, we investigated whether 14-3-3gamma mediates proliferation in cancer cells, and 14-3-3gamma by USP37 is responsible for promoting cell proliferation. Importantly, we found that USP37 regulates the stability of ubiquitin-conjugated 14-3-3gamma through its catalytic activity. This result implies that the interactive behavior between USP37 and 14-3-3gamma could be involved in the regulation of 14-3-3gamma degradation. When all these findings are considered together, USP37 is shown to be a specific DUB that prevents 14-3-3gamma degradation, which may contribute to malignant transformation via MAPK signaling pathway, possibly providing a new target for therapeutic objectives of cancer. PMID- 26427599 TI - Contributions of voluntary activation deficits to hand weakness after stroke. AB - BACKGROUND: Hemiparetic stroke survivors often exhibit profound weakness in the digits of the paretic hand, but the relative contribution of potential biomechanical and neurological impairment mechanisms is not known. Establishing sources of impairment would help in guiding treatment. OBJECTIVE: The present study sought to quantify the role of diminished capacity to voluntarily active finger flexor and extensor muscles as one possible neurological mechanism. METHODS: Two groups of stroke survivors with "severe" (N = 9) or "moderate" (N = 9) hand impairment and one group of neurologically intact individuals (N = 9) participated. Subjects were asked to create isometric flexion force and extension force, respectively, with the tip of the middle finger. The maximum voluntary force (MVF) and the maximum stimulated force (MSF) produced by an applied train of electrical current pulses (MSF) were recorded for flexion and extension. Percent voluntary activation (PVA) was computed from MVF and MSF. RESULTS: Significant deficits in both MVF and PVA were observed for stroke subjects compared to control subjects. For example, activation deficits were >80% for extensor digitorum communis (EDC) for the "severe" group. Maximum voluntary force and PVA deficits were greater for EDC than for flexor digitorum superficialis (FDS) for stroke subjects with severe impairment. Maximum voluntary force and PVA correlated significantly for stroke subjects but not for control subjects. CONCLUSIONS: Although extrinsic finger muscles could be successfully recruited electrically, voluntary excitation of these muscles was substantially limited in stroke survivors. Thus, finger weakness after stroke results predominantly from the inability to fully activate the muscle voluntarily. PMID- 26427600 TI - Tremelimumab-associated tumor regression following after initial progression: two case reports. AB - The human IgG2 monoclonal antibody tremelimumab is an immune checkpoint inhibitor that blocks cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). The therapeutic response of anti-CTLA-4 monoclonal antibodies possess unique kinetics, in that antitumor responses are often observed after initial short-term disease progression, in some cases as long as 6-12 months after anti-CTLA-4 treatment initiation. Here, we report two cases: one of bile duct cancer and the other of squamous cell carcinoma of unknown primary, both of which demonstrated initial rapid disease progression followed by dramatic tumor shrinkage after one or two doses of tremelimumab, without any immune-related adverse events. This delayed, yet dramatic antitumor response suggests that tremelimumab may hold promise in the treatment of solid tumors. PMID- 26427601 TI - Asthma symptoms in obese adults: The challenge of achieving asthma control. AB - The association between asthma and obesity is well-described, but not straightforward, and according to current guidelines asthma control is more difficult to achieve in obese patients. The currently available studies evaluating response to pharmacological asthma therapy in obese patients show that these patients have an altered, in general less favorable, response to both reliever and controller medication compared to normal weight patients. However, at present, the limited available evidence precludes evidence-based recommendations. The 'obesity-related asthma' phenotype has different characteristics, including association with atopy and type of airway inflammation, compared to 'classic' asthma. Furthermore, weight loss in patients with this phenotype leads to an improvement in symptoms, lung function, and airway responsiveness, as well as a reduction in medication utilization and hospital admissions. Obese patients, who present with symptoms suggesting a diagnosis of asthma, may have a distinct phenotype or a disease mimicking asthma, likely to have a potentially higher remission rate. And by that, our approach to this group of patients should combine pharmacologic and non-pharmacologic therapies, including exercise, weight loss and dietary interventions, instead of primarily focusing on disease control by stepping up asthma therapy. PMID- 26427602 TI - Risk of adverse pregnancy outcomes stratified for pre-pregnancy body mass index. AB - OBJECTIVE: To estimate the risk of adverse maternal and perinatal outcomes in women with different pre-pregnancy body mass index (BMI). METHODS: We conducted a cohort study with 14 451 singleton pregnancies in 15 medical centers in Beijing between 20 June 2013 and 30 November 2013 using cluster random sampling. We divided participants into four groups based on pre-pregnancy BMI: Group A (underweight): BMI < 18.5 kg/m(2), Group B (normal): 18.5-23.9 kg/m(2), Group C (overweight): 24-27.9 kg/m(2), Group D (obesity): >=28 kg/m(2). We used multivariate analysis to evaluate the association of the risk of adverse pregnancy outcomes and pre-pregnancy BMI. RESULTS: The prevalence of maternal overweight and obesity was 14.82% (2142/14 451) and 4.71% (680/14 451) in the study population, respectively. Higher pre-pregnancy BMI is associated with higher prevalence of gestational diabetes (GDM), macrosomia, Cesarean section (C section), preeclampsia and postpartum hemorrhage. Pre-pregnancy overweight or obesity increases the risk of adverse pregnancy outcomes, regardless of GDM status. CONCLUSIONS: Pre-pregnancy overweight or obesity is associated with increased risk of adverse pregnancy outcomes. Nutrition counseling is recommended before pregnancy in women who have overweight or obesity. PMID- 26427603 TI - The Sojourn from Parenteral to Oral Taxanes using Nanocarrier Systems: A Patent Review. AB - Natural diterpenoid taxanes and their semisynthetic analogues have already made an indelible mark in the chemotherapeutic world for treating various kinds of malignancies. However, due to the absence of any functional groups which could be ionized by pH alteration or which may participate in salt formation, these taxanes, exhibit low solubility. Parenteral administration of taxanes with solubilising agents such as Cremophor EL and Polysorbate 80 results in undesirable side effects like hypersensitivity reactions, myelosuppression and peripheral neuropathy. Nanoengineered drug delivery systems like nanoemulsions, nanocrystals, dendrimers, micelles, selfnanoemulsifying systems, liposomes, solid lipid nanoparticles and biodegradable polymeric nanoparticles, in this regard, tend to surmount these ostensible challenges, when administered orally. The bare taxanes encounter several inadequacies, namely poor aqueous solubility, structural instability in physiological fluids, p-glycoprotein recognition, hepatic first-pass effect, gastrointestinal permeability, and Cytochrome P450 enzymatic metabolism, etc. In addition, nanoscaled oral delivery improves drug encapsulation, thus facilitating diffusion through intestinal epithelium, modification of pharmacokinetic and tissue distribution profile of the drug, eventually resulting in flexibility of dosing schedules, prevention of discomfort of the injection and hospitalization, and improved patient convenience. The current review paper endeavors to provide a bird's eye view on the significant headway made on orally-administered nanosystems of taxanes and their analogues through patent applications published till date since its discovery. PMID- 26427604 TI - Promoting social capital to alleviate loneliness and improve health among older people in Spain. AB - Loneliness is especially frequent among older people in Southern Europe. Furthermore, promoting social capital to tackle loneliness and its health effects is an understudied intervention strategy. Therefore, a complex intervention was piloted in Spain in a pre-post study with a 2-year follow-up. Its aims were to explore the feasibility of the intervention and its short- and long-term effects. It was conducted in one mixed rural-urban and two urban areas of diverse socioeconomic levels from 2011 to 2012. The intervention framework was based on social capital theory applying a behaviour change model and care co-ordination. The intervention comprised: (i) a co-ordinated action aimed at building a network between primary healthcare centres and community assets in the neighbourhood and (ii) a group-based programme, which promoted social capital among lonely older people, especially social support and participation. Older people active in senior centres volunteered as gatekeepers. The main outcome domain was loneliness. Secondary outcome domains were participation, social support, self perceived health, quality of life, depressive symptoms and use of health resources. Pre-post changes were assessed with t-test, Wilcoxon signed-rank test and McNemar's test. Differences between the three time points were assessed with a one-way ANOVA with repeated measures. Social workers and nurses were successfully involved as group leaders, 10 volunteers took part and 38 participants were included. After the intervention, loneliness decreased while social participation and support significantly increased. Furthermore, the number of visits to nurses increased. Exactly 65.8% of the participants built social contacts within the group and 47.4% became engaged in new activities. Two years later, social effects were maintained and depressive symptoms had decreased. Exactly 44.7% of the participants continued to be in contact with at least one person from the group and 39.5% continued participating. The intervention contributes a novel and feasible social capital-based approach for alleviating loneliness among older adults while prompting meaningful changes in their lives. PMID- 26427605 TI - Genetic traceability of cattle using an OpenArray genotyping platform. PMID- 26427606 TI - SCN4A pore mutation pathogenetically contributes to autosomal dominant essential tremor and may increase susceptibility to epilepsy. AB - Essential tremor (ET) is the most prevalent movement disorder, affecting millions of people in the USA. Although a positive family history is one of the most important risk factors for ET, the genetic causes of ET remain unknown. In an attempt to identify genetic causes for ET, we performed whole-exome sequencing analyses in a large Spanish family with ET, in which two patients also developed epilepsy. To further assess pathogenicity, site-directed mutagenesis, mouse and human brain expression analyses, and patch clamp techniques were performed. A disease-segregating mutation (p.Gly1537Ser) in the SCN4A gene was identified. Posterior functional analyses demonstrated that more rapid kinetics at near threshold potentials altered ion selectivity and facilitated the conductance of both potassium and ammonium ions, which could contribute to tremor and increase susceptibility to epilepsy, respectively. In this report, for the first time, we associated the genetic variability of SCN4A with the development of essential tremor, which adds ET to the growing list of neurological channelopathies. PMID- 26427591 TI - Being Overweight Is Associated With Greater Survival in ICU Patients: Results From the Intensive Care Over Nations Audit. AB - OBJECTIVE: To assess the effect of body mass index on ICU outcome and on the development of ICU-acquired infection. DESIGN: A substudy of the Intensive Care Over Nations audit. SETTING: Seven hundred thirty ICUs in 84 countries. PATIENTS: All adult ICU patients admitted between May 8 and 18, 2012, except those admitted for less than 24 hours for routine postoperative monitoring (n = 10,069). In this subanalysis, only patients with complete data on height and weight (measured or estimated) on ICU admission in order to calculate the body mass index were included (n = 8,829). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Underweight was defined as body mass index less than 18.5 kg/m, normal weight as body mass index 18.5-24.9 kg/m, overweight as body mass index 25-29.9 kg/m, obese as body mass index 30-39.9 kg/m, and morbidly obese as body mass index greater than or equal to 40 kg/m. The mean body mass index was 26.4 +/- 6.5 kg/m. The ICU length of stay was similar among categories, but overweight and obese patients had longer hospital lengths of stay than patients with normal body mass index (10 [interquartile range, 5-21] and 11 [5-21] vs 9 [4-19] d; p < 0.01 pairwise). ICU mortality was lower in morbidly obese than in normal body mass index patients (11.2% vs 16.6%; p = 0.015). In-hospital mortality was lower in morbidly obese and overweight patients and higher in underweight patients than in those with normal body mass index. In a multilevel Cox proportional hazard analysis, underweight was independently associated with a higher hazard of 60-day in hospital death (hazard ratio, 1.32; 95% CI, 1.05-1.65; p = 0.018), whereas overweight was associated with a lower hazard (hazard ratio, 0.79; 95% CI, 0.71 0.89; p < 0.001). No body mass index category was associated with an increased hazard of ICU-acquired infection. CONCLUSIONS: In this large cohort of critically ill patients, underweight was independently associated with a higher hazard of 60 day in-hospital death and overweight with a lower hazard. None of the body mass index categories as independently associated with an increased hazard of infection during the ICU stay. PMID- 26427607 TI - Impaired bone remodeling and its correction by combination therapy in a mouse model of mucopolysaccharidosis-I. AB - Mucopolysaccharidosis-I (MPS-I) is a lysosomal storage disease (LSD) caused by inactivating mutations of IDUA, encoding the glycosaminoglycan-degrading enzyme alpha-l-iduronidase. Although MPS-I is associated with skeletal abnormalities, the impact of IDUA deficiency on bone remodeling is poorly defined. Here we report that Idua-deficient mice progressively develop a high bone mass phenotype with pathological lysosomal storage in cells of the osteoblast lineage. Histomorphometric quantification identified shortening of bone-forming units and reduced osteoclast numbers per bone surface. This phenotype was not transferable into wild-type mice by bone marrow transplantation (BMT). In contrast, the high bone mass phenotype of Idua-deficient mice was prevented by BMT from wild-type donors. At the cellular level, BMT did not only normalize defects of Idua deficient osteoblasts and osteocytes but additionally caused increased osteoclastogenesis. Based on clinical observations in an individual with MPS-I, previously subjected to BMT and enzyme replacement therapy (ERT), we treated Idua deficient mice accordingly and found that combining both treatments normalized all histomorphometric parameters of bone remodeling. Our results demonstrate that BMT and ERT profoundly affect skeletal remodeling of Idua-deficient mice, thereby suggesting that individuals with MPS-I should be monitored for their bone remodeling status, before and after treatment, to avoid long-term skeletal complications. PMID- 26427608 TI - Design, Synthesis and in vitro Evaluation of Indolotacrine Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease. AB - Novel indolotacrine analogues were designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease. By using a multitarget directed ligand approach, compounds were designed to act simultaneously as cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors. The compounds were also evaluated for antioxidant, cytotoxic, hepatotoxic, and blood-brain barrier (BBB) permeability properties. Indolotacrine 9 b (9-methoxy-2,3,4,6-tetrahydro-1H indolo[2,3-b]quinolin-11-amine) showed the most promising results in the in vitro assessment; it is a potent inhibitor of acetylcholinesterase (AChE IC50 : 1.5 MUm), butyrylcholinesterase (BChE IC50 : 2.4 MUm) and MAO A (IC50 : 0.49 MUm), and it is also a weak inhibitor of MAO B (IC50 : 53.9 MUm). Although its cytotoxic (IC50 : 5.5+/-0.4 MUm) and hepatotoxic (IC50 : 1.22+/-0.11 MUm) profiles are not as good as those of the standard 7-methoxytacrine (IC50 : 63+/-4 and 11.50+/-0.77 MUm, respectively), the overall improvement in the inhibitory activities and potential to cross the BBB make indolotacrine 9 b a promising lead compound for further development and investigation. PMID- 26427609 TI - Increased levels of MIP-1alpha in CSF and serum of ALS. AB - OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with complicated pathogenesis. No effective diagnostic test and cure exists for the disease at present. We detected the levels of MIP 1alpha in cerebrospinal fluid (CSF) and serum and then further evaluated whether MIP-1alpha levels correlate with the severity and progression of ALS. METHODS: We used ELISAs to detect MIP-1alpha levels from 58 patients with ALS and 45 age- and gender-matched controls. The patients with ALS were also clinically evaluated with the revised ALS functional rating scale (ALSFRS-r). Moreover, we followed up with 40 cases of ALS by way of call or clinic visit 4 years after enrollment in this study. Finally, we assessed the correlations between MIP-1alpha levels and various clinical parameters. RESULTS: We found that the levels of MIP-1alpha in patients with ALS significantly increased compared to controls and they were positively correlated with duration. MIP-1alpha showed negative correlations with disease progression rate and the decrease in ALSFRS-r. Furthermore, the cumulative survival of patients with ALS with high levels of MIP-1alpha exceeded patients with low MIP-1alpha levels. CONCLUSIONS: MIP-1alpha levels increased in both CSF and serum of patients with ALS, and it may be a potential neuroprotective biomarker in ALS. PMID- 26427610 TI - Joint attention behaviours in people with profound intellectual and multiple disabilities: the influence of the context. AB - BACKGROUND: In spite of the profound cognitive and physical problems, people with profound intellectual and multiple disabilities (PIMD) are able to develop joint attention behaviours (JAB) and benefit from positive interactions. AIMS: To investigate which context factors influence the JAB of people with PIMD. METHOD: Based on video recordings of 45 participants, JAB and context factors were analysed. RESULTS: An unstructured interaction situation produced the most responses of a person with PIMD, whereas a structured interaction situation produced the most initiatives. Furthermore, the familiarity of the partner and the familiarity of objects used in the interaction had no influence on the JAB. The sensitivity of the interaction partner was positively related to the presence of JAB. CONCLUSIONS: Interaction partners of people with PIMD should be aware of both the ability of people with PIMD to use JAB and the influence of different context factors on these JAB. PMID- 26427611 TI - Anti-HIV-1 integrase effect of compounds from Aglaia andamanica leaves and molecular docking study with acute toxicity test in mice. AB - CONTEXT: Acquired immunodeficiency syndrome (AIDS) is a serious health problem worldwide. It has been reported that Aglaia andamanica Hiern (Meliaceae) leaves possessed an antiviral effect. Therefore, a search of anti-HIV-1 integrase (HIV-1 IN) agents from A. andamanica is a promising target. OBJECTIVE: The objective of this study is to evaluate anti-HIV-1 IN activity of isolated compounds from A. andamanica using an in vitro assay and molecular docking study as well as testing acute toxicity in mice using the up and down method. MATERIALS AND METHODS: The leaves and compounds (3-100 MUg/mL) from A. andamanica were determined for the anti-HIV-1 IN effect using the multiplate integration assay (MIA) by detection the absorbance of the final product, p-nitrophenol, at 405 nm. The molecular docking with the HIV-1 IN of the active compound N-methyl-trans-4-hydroxy-l proline (10) was also studied. The Swiss albino mice were used for an acute toxicity test. RESULTS AND DISCUSSION: Among the isolated compounds, 10 showed marked anti-HIV-1 IN effect with an IC50 value of 11.8 MUg/mL, whereas other compounds were inactive (IC50 value > 100 MUg/mL). The molecular docking of compound 10 with an HIV-1 IN enzyme was also studied. The result revealed that this compound formed the hydrogen bonding with the Thr66, Asn155, and Lys159 of the HIV-1 IN binding site. The acute toxicity of the A. andamanica extract was not observed at the dose 2000 mg/kg mice. This is the first report of A. andamanica for anti-HIV-1 IN activity. PMID- 26427612 TI - Stereodivergent Dual Catalytic alpha-Allylation of Protected alpha-Amino- and alpha-Hydroxyacetaldehydes. AB - Fully stereodivergent dual-catalytic alpha-allylation of protected alpha-amino- and alpha-hydroxyacetaldehydes is achieved through iridium- and amine-catalyzed substitution of racemic allylic alcohols with chiral enamines generated in situ. The operationally simple method furnishes useful aldehyde building blocks in good yields, more than 99% ee, and with d.r. values greater than 20:1 in some cases. Additionally, the gamma,delta-unsaturated products can be further functionalized in a stereodivergent fashion with high selectivity and with preservation of stereochemical integrity at the Calpha position. PMID- 26427613 TI - Type of LDLR mutation and the pharmacogenetics of familial hypercholesterolemia treatment. AB - Familial hypercholesterolemia (FH) is an autosomal dominant disease mainly caused by mutations in the low-density lipoprotein receptor (LDLR) gene. FH patients present a wide variability regarding response to drugs and they are usually undertreated. Here, we review studies that evaluated the association between the type of LDLR mutation and the response to lipid-lowering therapy. The main findings were that patients with a null LDLR mutation had: higher baseline LDL-C, higher LDL-C after drug therapy, lower proportion of patients within the LDL-C target value and higher frequencies of CVD. Thus, we conclude that FH patients harboring a null mutation have a trend to an increased risk, even if diagnosis is early established and lipid-lowering treatment instituted. It is suggested that these individuals may benefit from the use of newly approved lipid-lowering agents. PMID- 26427614 TI - Creation of the first ultra-low gluten barley (Hordeum vulgare L.) for coeliac and gluten-intolerant populations. AB - Coeliac disease is a well-defined condition that is estimated to affect approximately 1% of the population worldwide. Noncoeliac gluten sensitivity is a condition that is less well defined, but is estimated to affect up to 10% of the population, and is often self-diagnosed. At present, the only remedy for both conditions is a lifelong gluten-free diet. A gluten-free diet is often expensive, high in fat and low in fibre, which in themselves can lead to adverse health outcomes. Thus, there is an opportunity to use novel plant breeding strategies to develop alternative gluten-free grains. In this work, we describe the breeding and characterization of a novel ultra-low gluten (ULG) barley variety in which the hordein (gluten) content was reduced to below 5 ppm. This was achieved using traditional breeding strategies to combine three recessive alleles, which act independently of each other to lower the hordein content in the parental varieties. The grain of the initial variety was shrunken compared to wild-type barleys. We implemented a breeding strategy to improve the grain size to near wild-type levels and demonstrated that the grains can be malted and brewed successfully. The ULG barley has the potential to provide novel healthy foods and beverages for those who require a gluten-free diet. PMID- 26427615 TI - Mesoporous Zirconium Phenylenesiliconate-phosphonate Hybrids with Ordered Lamellar Nanostructures. AB - Novel ordered lamellar mesostructure pZrPS-2 was hydrothermally prepared by using zirconium propoxide and 4-(EtO)2OPC6H4Si(OEt)3 (pPPS-E), which was hydrolyzed to organic building units substituted with both siliconate and phosphonate groups, in the presence of Cn TAB and TMAOH. The pZrPS-2 materials were obtained at a Zr/PPS ratio of 2 or higher and the basal spacing was increased by using a longer chain surfactant (n = 12-18). Removal of the occluded surfactants at 300 degrees C resulted in retention of the lamellar structure with negligible shrinkage of the interlayer distance. Nitrogen adsorption studies revealed the ordered mesoporous nature of pZrPS-2 with a pore diameter of approximately 2 to 3 nm. The lamellar structure is assumed to be composed of layers that include zirconia based crystalline nanodomains and interlayer pillars mainly based on PPS units. Although lamellar structures with the same crystalline phase also formed when no surfactant was added or when the meta isomer of PPS was used, no mesoporous materials were obtained except pZrPS-2. A possible schematic model to elucidate these results is also proposed. PMID- 26427617 TI - Consider obstructive sleep apnea in patients with oropharyngeal vascular malformations. AB - INTRODUCTION: Patients with oropharyngeal vascular malformations with complaints of upper airway obstruction were referred to a sleep specialist to investigate the existence of obstructive sleep apnea (OSA). METHODS: Demography, complaints, localization, and extent of the malformation were noted. The Epworth Sleeping Scale (ESS) and a polysomnography were performed to analyze the existence of OSA. RESULTS: Thirteen patients with vascular malformations in the upper oropharyngeal tract were referred, with a mean age of 49 years (range, 20-77 years). The male: female ratio was 7:6. In 2 patients the ESS was missed, and in the other 11 patients the mean ESS was 11.7 (range, 4-23). After polysomnography, 11 of the 13 patients (85%) were diagnosed with OSA, of whom 7 patients had severe OSA. CONCLUSION: Patients with oropharyngeal vascular malformations with complaints of upper airway obstruction have a high risk of OSA, and should be referred to a sleep specialist. PMID- 26427616 TI - Incidence of pain flare following palliative radiotherapy for symptomatic bone metastases: multicenter prospective observational study. AB - BACKGROUND: Palliative radiotherapy (RT) is an effective treatment for symptomatic bone metastases. Pain flare, a transient worsening of the bone pain after RT, has been described in previous reports with different incidence rates. The aim of the study was to prospectively evaluate the incidence of pain flare following RT for painful bone metastases and evaluate its effects on pain control and functionality of the patients. METHODS: Between June 2010 and June 2014, 204 patients were enrolled in this study and 135 patients with complete data were evaluable. Pain flare was defined as a 2- point increase in worst pain score as compared with baseline with no decrease in analgesic intake or a 25% increase in analgesic intake as compared with baseline with no decrease in worst pain score. All pain medications and worst pain scores were collected before, daily during, and for 10 days after RT. The Brief Pain Inventory (BPI) was filled out on the pretreatment and at the 4 weeks follow-up visit. RESULTS: There were 90 men (66.7%) and 45 women (33.3%). Mean age was 66 years (SD 9.8). The most common primary cancer site was lung in 42 patients (31.1%), followed by prostate in 27 patients (20.0%). Forty-two patients (31.1%) patients received a single fraction of 8 Gy and 83 (61.5%) received 20 Gy in five fractions. The overall pain flare incidence across all centers was 51/135 (37.7%). The majority of pain flares occurred on days 1-5 (88.2%). The mean duration of the pain flare was 3 days (SD: 3). There were no significant relationships between the occurrence of pain flare and collected variables. All BPI items measured four weeks after end of RT showed significant improvement as compared with pretreatment scores (p < 0.001). No significant differences in BPI time trends were found between patients with and without flare pain. CONCLUSION: Pain flare is a common event, occurring in nearly 40% of the patients that receive palliative RT for symptomatic bone metastases. This phenomenon is not a predictor for pain response. PMID- 26427618 TI - Does a large dehiscent implant surface at placement affect the 5-year treatment outcome? An assessment of implants placed to support a maxillary overdenture. AB - The aim of this study was to assess the 5-year clinical and radiographic outcome of implants with a dehiscent surface at implant placement. A total of 26 consecutive patients (mean age 61.6 years; SD 8.0 years) with at least one implant with a dehiscent implant surface of >= two thirds of the implant length on the labial side were included. All implants were placed to support a maxillary overdenture. The implants were placed with adequate primary stability and the dehiscent surface was covered with autologous bone, inorganic bovine bone and a resorbable membrane. Outcome measures were soft tissue conditions, change of radiographic marginal bone level and implant survival. Baseline data (at loading, T0) were compared with 1-year (T1) and 5-year (T5) post loading data. Of the 116 implants, 40 implants had no dehiscence, 16 had a buccal dehiscence < two thirds of the implant length, and 60 implants had a dehiscence >= two thirds. The peri implant tissues were healthy and 5-year marginal bone changes were well within normal limits (-0.4 mm; range: -0.8 to -0.1). One implant was lost during the osseointegration period. Even when implants are placed with a dehiscence >= two thirds of the buccal implant surface, favorable 5-year peri-implant health can be achieved provided these dehiscences are covered with autologous bone, inorganic bone and a resorbable membrane, and there is good initial stability of the implants. PMID- 26427619 TI - Outcomes of microvascular free flap reconstruction for mandibular osteoradionecrosis: A systematic review. AB - INTRODUCTION: Osteoradionecrosis of the mandible is a devastating complication of radiotherapy in patients with head and neck cancer. Many cases present at a late stage, from months to years following completion of radiation therapy. When medical treatment fails, surgery may be required with a variety of free flaps available for microvascular reconstructive techniques. OBJECTIVE: To conduct a systematic review of the literature investigating the outcomes of free flap reconstruction of the jaw in mandibular osteoradionecrosis and determine the failure rates of different flap tissue. METHODS: A systematic literature search was performed using Medline (Ovid) Pubmed and Embase databases and Google Scholar. Primary outcome measures were flap failures and complications, with donor site complications representing the secondary outcome measure. Analysis of pooled outcomes was undertaken for different flaps. RESULTS: 333 articles were identified and 15 articles met the final inclusion criteria, detailing 368 primary free tissue flap transfers. There was a flap failure rate of 9.8%. There were 146 post-operative complications (39.7%), the most common being fistula formation (8.4%), hardware plate exposure (7.1%) and flap wound infections (6.5%). CONCLUSION: The fibula is the workhorse free flap for reconstruction in mandibular osteoradionecrosis. Evidence to date is largely limited with the need for larger powered multi-institutional prospective studies to determine the ideal flap donor tissue and evaluate patient and treatment predictors of free flap outcomes in order to tailor the best patient-based surgical approach for mandibular osteoradionecrosis. PMID- 26427620 TI - Etiology and injury patterns of maxillofacial fractures from the years 2010 to 2013 in Mecklenburg-Western Pomerania, Germany: A retrospective study of 409 patients. AB - OBJECTIVE: The aim of the present study was to illustrate the injury patterns and the etiology of accident victims with maxillofacial fractures in the state of Mecklenburg-Western Pomerania (M-P), Germany. MATERIAL AND METHODS: Between 2010 and 2013, patients with maxillofacial fractures from the Department of Oral and Maxillofacial Surgery at the Helios Kliniken Schwerin, were evaluated with a specially constructed data set in a retrospective analysis. After review of the patient records, a case-related data collection was performed with the pre-set characteristics: age, gender, age group, maxillofacial fracture, and cause of injury. RESULTS: Of 409 patients, 79% (n = 323) were male and 21% (n = 86) were female. A fracture of the zygomaticomaxillary complex was most frequently observed (31%; n = 240). Midface fractures with orbital floor involvement were the most common fracture types (48.4%; n = 137). A significant percentage of the fractures (45.2%; n = 185) were caused by interpersonal violence; 70.8% (n = 131), and thus the majority of the patients who were treated due to a brutal offense, had consumed alcohol. Within this group, men in the age group of 20-29 years were most prevalent (38.7%; n = 125). Etiologically, 25.2% (n = 103) of fractures were caused by a fall. CONCLUSION: The regionalization of data on the distribution, emergence, and localization of maxillofacial fractures in M-P allows not only a national comparison but also an international comparison with areas that are in a similar strong socio-demographic change, as it applies to the East German population. This provides the opportunity to develop the global preventive measures and to apply suitable quality management. PMID- 26427621 TI - Geographic measures of retail food outlets and perceived availability of healthy foods in neighbourhoods. AB - OBJECTIVE: To examine associations between geographic measures of retail food outlets and perceived availability of healthy foods. DESIGN: Cross-sectional. SETTING: A predominantly rural, eight-county region of South Carolina, USA. SUBJECTS: Data from 705 household shoppers were analysed using ordinary least squares regression to examine relationships between geographic measures (presence and distance) of food outlets obtained via a geographic information system and perceived availability of healthy foods (fresh fruits and vegetables and low-fat foods). RESULTS: The presence of a supermarket within an 8.05 km (5-mile) buffer area was significantly associated with perceived availability of healthy foods (beta=1.09, P=0.025) when controlling for all other food outlet types. However, no other derived geographic presence measures were significant predictors of perceived availability of healthy foods. Distances to the nearest supermarket (beta=-0.16, P=0.003), dollar and variety store (beta=-0.15, P=0.005) and fast food restaurant (beta=0.11, P=0.015) were all significantly associated with perceptions of healthy food availability. CONCLUSIONS: Our results suggest that distance to food outlets is a significant predictor of healthy food perceptions, although presence is sensitive to boundary size. Our study contributes to the understanding and improvement of techniques that characterize individuals' food options in their community. PMID- 26427622 TI - An evaluation of a community-based food supplementation for people living with HIV in Ghana: implications for community-based interventions in Ghana. AB - BACKGROUND: Community-based care and support services are limited in sub-Saharan Africa and as a result a high number of people living with HIV (PLHIV) are not getting the required care and support services. The aim of this study was to assess the impact of food supplementation services for PLHIV in Ghana on weight gained and factors associated with weight gained. METHODS: The study employed mixed methods study design involving quantitative and qualitative techniques. These were structured questionnaire administered to 200 PLHIV selected through simple random sampling and a qualitative component consisting of 14 semi structured interviews with purposefully selected stakeholders and eight focus group discussions with the beneficiaries. RESULTS: The analysis of the quantitative data showed on average, beneficiaries had gained weight [mean difference in weight was 2 kg with 95 % CI (1.1, 2.9), P value <0.001]. Multivariate analysis showed that the support group to which the beneficiary belonged was the most important determinant of gaining weight. Through the qualitative interviews, beneficiaries indicated that the anti-retroviral drugs were making them hungry and the food helped to alleviate that effect. Notwithstanding, they indicated that the food was nutritious, made them healthy and strong, contributed to their weight gain and was their main sources of hope at home when they had no money. CONCLUSIONS: A broad strategy of food supplementation for PLHIV should be implemented in different ways for different support groups taking into account the differences between different support groups when planning such an intervention. PMID- 26427623 TI - Role of Dectin-1 in the innate immune response of rat corneal epithelial cells to Aspergillus fumigatus. AB - BACKGROUND: To observe Dectin-1 expression in fungal keratitis on rat models and to determine the role of Dectin-1 in innate immune response to Aspergillus fumigatus. METHODS: Wistar rats were randomly divided into control, fungal keratitis and pretreatment (pretreated with Laminarin) groups. Samples were used for conducting immunohistochemical staining and real-time PCR to observe expression of cytokines like CCL2, CCL3, CXCL1, CXCL2, IL-1beta, TNF-alpha, IL-6, IL-10. RESULTS: After fungal stimulations, all 7 inflammatory factors, except IL 10, increased with different levels. After 4 h of fungal stimulations, IL-1beta, IL-6, CCL2, CXCL1 and CXCL2 of pretreatment groups were significantly (p < 0.05) lower than fungal groups, while the other 3 cytokines had no significant changes. After 8 h of fungal stimulations, IL-6 and CXCL1 of pretreatment groups were still significantly (p < 0.05) lower than fungal groups. DISCUSSION: With progress of fungus stimulation, expression of IL-1beta,CXCL1 ,CXCL2,MCP-1 gradually increased, whilepretreated with Laminarin to block Dectin-1, these expression decreased, indicating that Dectin-1 maypromote immune reaction through them. IL-10 decreased in fungal group because of itsimmunosuppressive effect at 4h, and it began to increase at 8h to suppress Th1 inflammation response inorder to avoid excessive tissue damage. CONCLUSION: Dectin-1 in early period of innate immune responses in rat fungal keratitis might work through IL-1beta, IL-6, CCL2, CXCL1, CXCL2 to recruit neutrophils and macrophages to participate anti-fungal immunity. PMID- 26427626 TI - Electrochemical lithiation-induced polymorphism of anthraquinone derivatives observed by operando X-ray diffraction. AB - The use of organic molecules represents a very attractive and promising alternative for electrical energy storage applications. Quinones, in general, and anthraquinones, in particular, are especially attractive due to their ability to reversibly exchange multiple electrons per formula unit. When used as the active electrode material in a real lithium-ion battery (LIB), crystalline anthraquinone powders reversibly change crystal packing as a function of state-of-charge (redox state), with well-defined voltage plateaus appearing concomitantly with new phases. Operando powder X-ray diffraction (XRD) is a powerful method for screening the structural stability of organic cathode candidates and for understanding electrochemically-induced structural transformations within organic molecular crystals. Herein we explore the electrochemical lithiation-induced polymorphism of anthraquinone (AQ) and three related derivatives. We believe that this analysis can serve as a model for studying organic charge storage within crystalline small-molecule candidates. PMID- 26427625 TI - Development of a framework for genotyping bovine-derived Cryptosporidium parvum, using a multilocus fragment typing tool. AB - BACKGROUND: There is a need for an integrated genotyping approach for C. parvum; no sufficiently discriminatory scheme to date has been fully validated or widely adopted by veterinary or public health researchers. Multilocus fragment typing (MLFT) can provide good differentiation and is relatively quick and cheap to perform. A MLFT tool was assessed in terms of its typeability, specificity, precision (repeatability and reproducibility), accuracy and ability to genotypically discriminate bovine-derived Cryptosporidium parvum. METHODS: With the aim of working towards a consensus, six markers were selected for inclusion based on their successful application in previous studies: MM5, MM18, MM19, TP14, MS1 and MS9. Alleles were assigned according to the fragment sizes of repeat regions amplified, as determined by capillary electrophoresis. In addition, a region of the GP60 gene was amplified and sequenced to determine gp60 subtype and this was added to the allelic profiles of the 6 markers to determine the multilocus genotype (MLG). The MLFT tool was applied to 140 C. parvum samples collected in two cross-sectional studies of UK calves, conducted in Cheshire in 2004 (principally dairy animals) and Aberdeenshire/Caithness in 2011 (beef animals). RESULTS: Typeability was 84 %. The primers did not amplify tested non parvum species frequently detected in cattle. In terms of repeatability, within- and between-run fragment sizes showed little variability. Between laboratories, fragment sizes differed but allele calling was reproducible. The MLFT had good discriminatory ability (Simpson's Index of Diversity, SID, was 0.92), compared to gp60 sequencing alone (SID 0.44). Some markers were more informative than others, with MS1 and MS9 proving monoallelic in tested samples. CONCLUSIONS: Further inter-laboratory trials are now warranted with the inclusion of human-derived C. parvum samples, allowing progress towards an integrated, standardised typing scheme to enable source attribution and to determine the role of livestock in future outbreaks of human C. parvum. PMID- 26427627 TI - The effect of Varenicline on smoking cessation in a group of young asthma patients. AB - BACKGROUND: Tobacco use causes long-term morbidity and mortality. In patients with asthma, the frequency of smokers is high; however, asthmatic smokers experience more pronounced symptoms, accelerated loss of lung function and treatment resistance. Varenicline is an effective drug in smoking cessation, when investigated in COPD patients and general populations. The aim of the present study was to evaluate the effect of Varenicline on tobacco cessation in young asthmatics. METHODS: In a randomized, placebo-controlled, double-blinded trial, 52 asthmatic current smokers (age 19-40) >= 10 cigarettes daily and >=10 packyears (mean 15.6) were recruited to a 12 week treatment period with Varenicline or placebo (1:1) in parallel design. Evaluation of smoking status, asthma symptom score, general health quality score and methacholine challenge were performed at week 0, week 6, week 12 and week 24. RESULTS: In the Varenicline group, at week 12, 69% of the patients quit smoking vs. 36% in the placebo group (p = 0.017, intended-to-treat analysis), but after 24 weeks, a high relapse rate was present (quit rates 19% vs. 16%, NS). After 6 weeks of treatment, significant improvements in airway hyperresponsiveness (AHR) in the Varenicline group was found (from 88% to 58%, p = 0.016), whereas no change was observed in the placebo group. Symptom score and general health quality improved in both the Varenicline and the placebo group. CONCLUSION: We demonstrated that Varenicline can be used with a high probability of success with tobacco cessation in young smokers with asthma, but relapse rate after end of treatment is high. Quitting smoking can improve asthma control. PMID- 26427628 TI - Validation of human small airway measurements using endobronchial optical coherence tomography. AB - BACKGROUND: Small airway remodeling is the cardinal feature underlying chronic airway diseases. There is no modality which identifies small airway pathological changes, which is crucial for early diagnosis, efficacy and prognostic assessment. OBJECTIVE: To evaluate the usefulness of endobronchial optical coherence tomography (EB-OCT) in assessing small airways morphology in vivo. METHODS: Twelve patients with pulmonary nodules scheduled for lung resection underwent spirometry, multi-detector computed tomography (MDCT) and EB-OCT. We measured D(mean) (mean luminal diameter), Ai (inner luminal area), Aw (airway wall area) and Aw% [Aw/(Ai + Aw) * 100%] from the 3rd to 5th generation bronchi of RB9 segment by MDCT. D(mean), Ai, Aw and Aw% from the 3rd to 9th generation bronchi of RB9 segment were measured by EB-OCT and histology. Correlations of these parameters, measured by three different methods, were evaluated. We recruited 4 COPD patients to determine if EB-OCT could identify peripheral airway remodeling. RESULTS: The 4 parameters, measured by CT and EB-OCT, correlated significantly [D(mean) (r = 0.991), Ai (r = 0.997), Aw (r = 0.997), Aw% (r = 0.991), all P < 0.01]. Significant correlation were found for these parameters, measured by histology and EB-OCT, from the 3rd to 5th generation bronchi [D(mean) (r = 0.989), Ai (r = 0.997), Aw (r = 0.999), Aw% (r = 0.988), all P < 0.01], and from the 6th to 9th generation bronchi [D(mean) (r = 0.979), Ai (r = 0.997), Aw (r = 0.994) and Aw% (r = 0.988), all P < 0.01]. Significant small airways morphological abnormalities were observed in COPD patients. CONCLUSIONS: EB-OCT, a minimally invasive imaging modality with high-resolution, is useful and clinically practical for assessing proximal and distal airways of human compared with CT and histology. PMID- 26427629 TI - Does Femoroacetabular Impingement Cause Hip Instability? A Systematic Review. AB - PURPOSE: To determine whether femoroacetabular impingement (FAI) is associated with hip instability. METHODS: A systematic search examining FAI and hip instability was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Clinical and basic science studies were included. Instability had to be documented with either a clinical or imaging examination. Studies were excluded if they did not define diagnostic criteria for FAI, involved prosthetic hips, were not in English, were review articles, or reported Level V evidence (case reports, expert opinion). Rates of FAI morphologic features in patients with documented hip instability were determined. Mechanisms and rates of FAI-induced hip subluxation were examined in basic science studies. RESULTS: The search yielded 1,630 relevant studies. Seven studies (4 clinical and 3 basic science) met inclusion criteria. Four studies investigated an association between FAI and hip instability in 92 patients with an average age of 31 years. Seventy-six patients experienced frank dislocations and 16 experienced posterior subluxation events. The prevalence of FAI was documented in 89 patients with hip instability. The rates of cam and pincer morphologic characteristics were 74% and 64%, respectively. The average lateral center edge angle and prevalence of acetabular retroversion were 30 degrees and 70%, respectively (n = 76 patients). All 3 basic science studies had real-time visualization of FAI-induced hip subluxations. CONCLUSIONS: High rates of FAI morphologic characteristics are present in patients with hip instability. FAI morphologic characteristics may predispose the hip to instability through anatomic conflict caused by pincer or cam lesions (or both) levering the femoral head posteriorly. LEVEL OF EVIDENCE: Level IV, systematic review of Level III, Level IV, and non-clinical studies. PMID- 26427630 TI - Bone-Patellar Tendon-Bone Versus Soft-Tissue Allograft for Anterior Cruciate Ligament Reconstruction: A Systematic Review. AB - PURPOSE: To describe the outcomes of bone-patellar tendon-bone (BPTB) and soft tissue allografts in anterior cruciate ligament (ACL) reconstruction with respect to graft failure risk, physical examination findings, instrumented laxity, and patient-reported outcomes. METHODS: A search of the PubMed, Scopus, CINAHL (Cumulative Index to Nursing and Allied Health Literature) Complete, Cochrane Collaboration, and SPORTDiscus databases was performed. English-language studies with outcome data on primary ACL reconstruction with nonirradiated BPTB and soft tissue allografts were identified. Outcome data included failure risk, physical examination findings, instrumented laxity measurements, and patient-reported outcome scores. RESULTS: Seventeen studies met the inclusion criteria. Of these studies, 11 reported on BPTB allografts exclusively, 5 reported on soft-tissue allografts exclusively, and 1 compared both types. The comparative study showed no difference in failure risk, Lachman grade, pivot-shift grade, instrumented laxity, or overall International Knee Documentation Committee score between the 2 allograft types. Data from all studies yielded a failure risk of 10.3% (95% confidence interval [CI], 4.5% to 18.1%) in the soft-tissue group and 15.2% (95% CI, 11.3% to 19.6%) in the BPTB group. The risk of a Lachman grade greater than 5 mm was 6.4% (95% CI, 1.7% to 13.7%) in the soft-tissue group and 8.6% (95% CI, 6.3% to 11.2%) in the BPTB group. The risk of a grade 2 or 3 pivot shift was 1.4% (95% CI, 0.3% to 3.3%) in the soft-tissue group and 4.1% (95% CI, 1.9% to 7.2%) in the BPTB group. CONCLUSIONS: One comparative study showed no difference in results after ACL reconstruction with nonirradiated BPTB and soft-tissue allografts. Inclusion of case series in the analysis showed qualitatively similar outcomes with the 2 graft types. PMID- 26427631 TI - Systematic Review of Biceps Tenodesis: Arthroscopic Versus Open. AB - PURPOSE: We present a systematic review of the recent literature regarding the use of arthroscopic and open methods of tenodesis for lesions of the long head of the biceps brachii and present an analysis of the subjective and objective outcomes after these 2 procedures. METHODS: PubMed was carefully reviewed for suitable articles relating to biceps tenodesis, both open and arthroscopic. We included studies reporting on the clinical outcomes of these 2 procedures that were of Level I to IV evidence and were published in the English language. The primary clinical outcomes for each study were determined, normalized, and reported as the percentage of good or excellent results versus poor results based on the outcome scores and criteria laid out by the authors in each of the studies. The exclusion criteria included studies in which biceps tenodesis was performed in patients with concomitant rotator cuff repairs, nonhuman studies, and biomechanical studies. RESULTS: A total of 16 studies met our inclusion criteria. Among all studies, a total of 205 arthroscopic tenodesis procedures and a total of 271 open tenodesis procedures were performed. Among the 271 open tenodesis patients, 98% had a good or excellent outcome, with a poor outcome in 5 patients (2%). Among the 205 patients who underwent arthroscopic tenodesis, 98% had a good or excellent outcome, with a poor outcome in 5 patients (2%). CONCLUSIONS: Both open and arthroscopic biceps tenodesis provided satisfactory outcomes in most patients, and there were no identifiable differences in this review. PMID- 26427632 TI - Effect of the Osteotomy Length on the Change of the Posterior Tibial Slope With a Simple Distraction of the Posterior Gap in the Uni- and Biplanar Open-Wedge High Tibial Osteotomy. AB - PURPOSE: To (1) determine the length of the osteotomy at the anterior and posterior cortex, (2) compare between uni- and biplanar osteotomy, and (3) evaluate the relationship between the extent of the osteotomy and change of the posterior tibial slope. METHODS: A prospective comparative study of 24 uniplanar and 30 biplanar osteotomies was performed. To evaluate the length of osteotomy, osteotomy lines of the anterior and posterior cortex were analyzed in the 3 dimensional surface models. For slope measurement, the intramedullary axis of the proximal tibia (slope P), posterior cortical line of the proximal tibia (slope C), and anterior cortical line of the proximal fibula (slope F) were used. An analysis of the changes in the posterior tibial slope was performed independently using a pre- and postoperative lateral plane radiograph. RESULTS: In the uniplanar osteotomy, ratios of the osteotomized length to the total cortical length aligned with the osteotomized plane were larger in the anterior cortex (0.91 in uniplanar v 0.46 in biplanar; P = 0) and posterior cortex (0.97 in uniplanar v 0.79 ratio in biplanar; P = 0). Furthermore, the posterior tibial slope was maintained in both groups and the ratios between the anterior and posterior gap in both groups were 0.57 and 0.63, respectively. The maintenance of the slope was not related to any specific variables. Additionally, these phenomena did not differ between those patients who underwent uni- and those who underwent biplanar osteotomy. CONCLUSIONS: Increase in the posterior tibial slope was prevented with appropriate uni- or biplanar osteotomy with a simple distraction at the most posterior gap. However, in the uniplanar osteotomy, the ratio of the osteotomized length to the total cortical length was larger in both the anterior and posterior cortex. PMID- 26427633 TI - Effects of different spray formulations on the reproductive parameters of engorged Rhipicephalus (Boophilus) microplus females detached from experimentally infested cattle. AB - This present study aimed to evaluate the deleterious effects of some commercially available spray formulations (15% Cypermethrin+25% Chlorpyriphos+1% Citronellal and 8% Cypermethrin+60% Ethion) on the reproductive parameters of engorged Rhipicephalus (Boophilus) microplus females that detached from experimentally infested cattle. The following reproductive parameters of engorged female ticks were analyzed: female weight, egg mass weight, percentage of hatchability, percentage of reduction in oviposition, percentage of reduction in hatchability, reproductive efficiency and percent control/efficacy of formulations for reproductive parameters. Our findings showed that although the strain R. (B.) microplus used in both experiments was thought to be sensitive to the test compounds because of the acaricidal efficacy observed throughout these trials, it was not possible to observe overall deleterious effects on the reproductive parameters of this tick species with both spray formulations. However, the 8% Cypermethrin+60% Ethion showed short-term significant effects on the weight of female ticks between the 14th and 16th days post-treatment and the weight of female and the egg mass weight between the 20th and 22nd days post-treatment. New studies should be conducted to show if these results regarding the reproductive parameters of fully engorged R. (B.) microplus females, combined with the acaricidal efficacy can be sufficient to reduce the number of chemical treatments administered to cattle. PMID- 26427634 TI - Quantitative risk assessment of entry of contagious bovine pleuropneumonia through live cattle imported from northwestern Ethiopia. AB - Contagious bovine pleuropneumonia (CBPP) is a highly contagious bacterial disease of cattle caused by Mycoplasma mycoides subspecies mycoides small colony (SC) bovine biotype (MmmSC). It has been eradicated from many countries; however, the disease persists in many parts of Africa and Asia. CBPP is one of the major trade restricting diseases of cattle in Ethiopia. In this quantitative risk assessment the OIE concept of zoning was adopted to assess the entry of CBPP into an importing country when up to 280,000 live cattle are exported every year from the northwestern proposed disease free zone (DFZ) of Ethiopia. To estimate the level of risk, a six-tiered risk pathway (scenario tree) was developed, evidences collected and equations generated. The probability of occurrence of the hazard at each node was modelled as a probability distribution using Monte Carlo simulation (@RISK software) at 10,000 iterations to account for uncertainty and variability. The uncertainty and variability of data points surrounding the risk estimate were further quantified by sensitivity analysis. In this study a single animal destined for export from the northwestern DFZ of Ethiopia has a CBPP infection probability of 4.76*10(-6) (95% CI=7.25*10(-8) 1.92*10(-5)). The probability that at least one infected animal enters an importing country in one year is 0.53 (90% CI=0.042-0.97). The expected number of CBPP infected animals exported any given year is 1.28 (95% CI=0.021-5.42). According to the risk estimate, an average of 2.73*10(6) animals (90% CI=10,674-5.9*10(6)) must be exported to get the first infected case. By this account it would, on average, take 10.15 years (90% CI=0.24-23.18) for the first infected animal to be included in the consignment. Sensitivity analysis revealed that prevalence and vaccination had the highest impact on the uncertainty and variability of the overall risk. PMID- 26427635 TI - Hyperostotic En Plaque Meningioma Mimicking Fibrous Dysplasia of the Temporal Bone. PMID- 26427636 TI - The Natural History and Management of Petrous Apex Cholesterol Granulomas. AB - OBJECTIVE: To evaluate the clinical and radiographic characteristics of cholesterol granulomas of the petrous apex, as well as the outcomes of operative and conservative management. STUDY DESIGN: Retrospective chart review. SETTING: Two independent tertiary academic referral centers. PATIENTS: Adult and pediatric patients with cholesterol granulomas of the petrous apex were identified from the experience of two separate centers. Patients were included after radiographic diagnosis and clinical evaluation. All patients with less than 6 months of follow up and those with iatrogenic postoperative cholesterol granulomas were excluded. INTERVENTION: Demographic information, presenting symptoms, imaging characteristics, treatment strategies, and outcomes were recorded. MAIN OUTCOME MEASURES: Patients were evaluated on the basis of symptom and radiographic evolution during time, with or without operative intervention. RESULTS: Ninety petrous apex cholesterol granulomas were analyzed (57.8% females, 55.6% right sided). The average age at presentation was 43.1 years (median 42.0, range 8.0 77.0 years). The most common presenting symptom was headache (56.7%), and the average lesion size in the greatest dimension was 2.1 cm (median 1.7, range 0.7 5.0 cm). During a mean follow-up of 46.0 months, no cases of spontaneous rupture or carotid injury occurred. Twenty-three patients (25.6%) ultimately underwent surgical management, most commonly for intractable headache, and only 47.8% of these patients experienced durable symptom improvement by their last postoperative follow-up. CONCLUSION: Many cholesterol granulomas of the petrous apex remain stable during time and can be safely managed with primary observation. Surgery should be reserved for lesions that are causing, or threatening, neurologic dysfunction because of mass effect or erosion of critical structures such as the otic capsule. Cranial neuropathy associated with cholesterol granuloma may improve after operative management; however, symptoms such as headache and dizziness are less likely to benefit from surgery. As a general guideline, in the presence of a radiologically stable cholesterol granuloma in the petrous apex, alternative etiologies for headache and dizziness should be considered and treated before offering surgical intervention. PMID- 26427637 TI - Speech Intelligibility in Noise With a Pinna Effect Imitating Cochlear Implant Processor. AB - OBJECTIVE: To evaluate the speech intelligibility in noise with a new cochlear implant (CI) processor that uses a pinna effect imitating directional microphone system. STUDY DESIGN: Prospective experimental study. SETTING: Tertiary referral center. PATIENTS: Ten experienced, unilateral CI recipients with bilateral severe to-profound hearing loss.Intervention: All participants performed speech in noise tests with the Opus 2 processor (omnidirectional microphone mode only) and the newer Sonnet processor (omnidirectional and directional microphone mode). MAIN OUTCOME MEASURE: The speech reception threshold (SRT) in noise was measured in four spatial settings. The test sentences were always presented from the front. The noise was arriving either from the front (S0N0), the ipsilateral side of the CI (S0NIL), the contralateral side of the CI (S0NCL), or the back (S0N180). RESULTS: The directional mode improved the SRTs by 3.6 dB (p < 0.01), 2.2 dB (p < 0.01), and 1.3 dB (p < 0.05) in the S0N180, S0NIL, and S0NCL situations, when compared with the Sonnet in the omnidirectional mode. There was no statistically significant difference in the S0N0 situation. No differences between the Opus 2 and the Sonnet in the omnidirectional mode were observed. CONCLUSION: Speech intelligibility with the Sonnet system was statistically different to speech recognition with the Opus 2 system suggesting that CI users might profit from the pinna effect imitating directionality mode in noisy environments. PMID- 26427624 TI - Patients with coronary artery disease and diabetes need improved management: a report from the EUROASPIRE IV survey: a registry from the EuroObservational Research Programme of the European Society of Cardiology. AB - BACKGROUND: In order to influence every day clinical practice professional organisations issue management guidelines. Cross-sectional surveys are used to evaluate the implementation of such guidelines. The present survey investigated screening for glucose perturbations in people with coronary artery disease and compared patients with known and newly detected type 2 diabetes with those without diabetes in terms of their life-style and pharmacological risk factor management in relation to contemporary European guidelines. METHODS: A total of 6187 patients (18-80 years) with coronary artery disease and known glycaemic status based on a self reported history of diabetes (previously known diabetes) or the results of an oral glucose tolerance test and HbA1c (no diabetes or newly diagnosed diabetes) were investigated in EUROASPIRE IV including patients in 24 European countries 2012-2013. The patients were interviewed and investigated in order to enable a comparison between their actual risk factor control with that recommended in current European management guidelines and the outcome in previously conducted surveys. RESULTS: A total of 2846 (46%) patients had no diabetes, 1158 (19%) newly diagnosed diabetes and 2183 (35%) previously known diabetes. The combined use of all four cardioprotective drugs in these groups was 53, 55 and 60%, respectively. A blood pressure target of <140/90 mmHg was achieved in 68, 61, 54% and a LDL-cholesterol target of <1.8 mmol/L in 16, 18 and 28%. Patients with newly diagnosed and previously known diabetes reached an HbA1c <7.0% (53 mmol/mol) in 95 and 53% and 11% of those with previously known diabetes had an HbA1c >9.0% (>75 mmol/mol). Of the patients with diabetes 69% reported on low physical activity. The proportion of patients participating in cardiac rehabilitation programmes was low (~40 %) and only 27% of those with diabetes had attended diabetes schools. Compared with data from previous surveys the use of cardioprotective drugs had increased and more patients were achieving the risk factor treatment targets. CONCLUSIONS: Despite advances in patient management there is further potential to improve both the detection and management of patients with diabetes and coronary artery disease. PMID- 26427638 TI - REM sleep Behaviour Disorder. AB - Rapid Eye Movement (REM) sleep Behaviour Disorder (RBD) is a REM sleep parasomnia characterized by loss of the muscle atonia that typically occurs during REM sleep, therefore allowing patients to act out their dreams. RBD manifests itself clinically as a violent behaviour occurring during the night, and is detected at the polysomnography by phasic and/or tonic muscle activity on the electromyography channel. In absence of neurological signs or central nervous system lesions, RBD is defined as idiopathic. Nevertheless, in a large number of cases the development of neurodegenerative diseases in RBD patients has been described, with the duration of the follow-up representing a fundamental aspect. A growing number of clinical, neurophysiologic and neuropsychological studies aimed to detect early markers of neurodegenerative dysfunction in RBD patients. Anyway, the evidence of impaired cortical activity, subtle neurocognitive dysfunction, olfactory and autonomic impairment and neuroimaging brain changes in RBD patients is challenging the concept of an idiopathic form of RBD, supporting the idea of RBD as an early manifestation of a more complex neurodegenerative process. PMID- 26427640 TI - Intertemporal choice in Parkinson's disease and restless legs syndrome. AB - BACKGROUND: Impulse control disorders in Parkinson's disease are a potential consequence of dopaminergic therapy. Impulse control problems might be revealed by intertemporal choice tasks which entail to forgo an immediately available reward in favor of a larger but later reward. The steepness of the discounting curve can be quantified by the parameter k. METHODS: Participants (37 Parkinson patients [13 de novo, 24 medicated], 24 patients with restless legs syndrome, and 22 controls) were offered 54 choices between immediate smaller rewards and delayed larger and the k value was estimated from the participants' responses. Participants had the chance of winning one of their decisions. None of the participants had impulse control disorders. RESULTS: Unmedicated Parkinson patients had a higher discounting rate than controls and medicated patients with restless legs syndrome. The k values of medicated Parkinson patients and patients with restless legs syndrome did not differ from those of controls. No correlation was found between the k value and the dopamine agonist dose. CONCLUSION: Impulsive decision making in patients with Parkinson's disease may occur as part of the disease rather than as a consequence of dopamine agonist therapy. PMID- 26427639 TI - Psychogenic and neural visual-cue response in PD dopamine dysregulation syndrome. AB - INTRODUCTION: Dopamine dysregulation syndrome (DDS) in Parkinson's disease (PD) patients refers to the compulsive use of dopaminergic replacement therapy and has serious psycho-social consequences. Mechanisms underlying DDS are not clear although has been linked to dysfunctional brain reward networks. METHODS: With fMRI, we investigate behavioral and neural response to drug-cues in six PD DDS patients and 12 PD control patients in both the ON and OFF medication state. Behavioral measures of liking, wanting and subjectively 'feeling ON medication' were also collected. RESULTS: Behaviorally, PD DDS patients feel less ON and want their drugs more at baseline compared to PD controls. Following drug-cue exposure, PD DDS patients feel significantly more ON medication, which correlates with significant increases in reward related regions. CONCLUSIONS: The results demonstrate that exposure to drug-cues increases the subjective feeling of being 'ON' medication which corresponds to dysfunctional activation in reward related regions in PD DDS patients. These findings should be extended in future studies. Visual stimuli being sufficient to elicit behavioral response through neuroadaptations could have direct implications to the management of addictive behavior. PMID- 26427641 TI - Reduced early dried blood spot citrulline levels in preterm infants with meconium obstruction of prematurity. AB - BACKGROUND: Citrulline is a non-protein amino acid synthesized in the enterocytes of the small bowel. Recent studies have reported that plasma citrulline levels correlate with functional enterocyte mass. AIMS: This study aimed to determine the normal dried blood spot (DBS) citrulline levels and to determine the existence of a correlation between citrulline levels and meconium obstruction of prematurity (MOP). STUDY DESIGN AND SUBJECTS: A retrospective cohort study was performed involving 285 infants born at less than 32weeks gestation who were admitted to the neonatal intensive care unit between Oct 2009 and Aug 2014. OUTCOME MEASURES: We analyzed the DBS citrulline levels, which are routinely measured via newborn screening at 7days following birth, using liquid chromatography-MS/MS. We investigated the relationship between DBS citrulline levels and clinical parameters such as gestational age (GA), body measurements at birth, gender, or the presence or absence of either necrotizing enterocolitis or MOP. RESULTS: A total of 229 infants with a median GA of 29.6weeks and a median birth weight of 1160g were included. DBS citrulline levels were not associated with GA, body measurements at birth or gender. DBS citrulline levels were significantly decreased when patients presented with MOP (p=0.037). CONCLUSIONS: Early DBS citrulline levels were not associated with either GA or body measurements at birth but were reduced among preterm infants with MOP compared with the control infants. These results may be indicative of abnormal fetal intestinal development and reduced functional enterocyte mass among preterm infants with MOP. PMID- 26427643 TI - Temporal dynamics of visual working memory. AB - The involvement of the human cerebellum in working memory has been well established in the last decade. However, the cerebro-cerebellar network for visual working memory is not as well defined. Our previous fMRI study showed superior and inferior cerebellar activations during a block design visual working memory task, but specific cerebellar contributions to cognitive processes in encoding, maintenance and retrieval have not yet been established. The current study examined cerebellar contributions to each of the components of visual working memory and presence of cerebellar hemispheric laterality was investigated. 40 young adults performed a Sternberg visual working memory task during fMRI scanning using a parametric paradigm. The contrast between high and low memory load during each phase was examined. We found that the most prominent activation was observed in vermal lobule VIIIb and bilateral lobule VI during encoding. Using a quantitative laterality index, we found that left-lateralized activation of lobule VIIIa was present in the encoding phase. In the maintenance phase, there was bilateral lobule VI and right-lateralized lobule VIIb activity. Changes in activation in right lobule VIIIa were present during the retrieval phase. The current results provide evidence that superior and inferior cerebellum contributes to visual working memory, with a tendency for left-lateralized activations in the inferior cerebellum during encoding and right-lateralized lobule VIIb activations during maintenance. The results of the study are in agreement with Baddeley's multi-component working memory model, but also suggest that stored visual representations are additionally supported by maintenance mechanisms that may employ verbal coding. PMID- 26427644 TI - Stratified mixture modeling for segmentation of white-matter lesions in brain MR images. AB - Accurate characterization of white-matter lesions from magnetic resonance (MR) images has increasing importance for diagnosis and management of treatment of certain neurological diseases, and can be performed in an objective and effective way by automated lesion segmentation. This usually involves modeling the whole brain MR intensity distribution, however, capturing various sources of MR intensity variability and lesion heterogeneity results in highly complex whole brain MR intensity models, thus their robust estimation on a large set of MR images presents a huge challenge. We propose a novel approach employing stratified mixture modeling, where the main premise is that the otherwise complex whole-brain model can be reduced to a tractable parametric form in small brain subregions. We show on MR images of multiple sclerosis (MS) patients with different lesion loads that robust estimators enable accurate mixture modeling of MR intensity in small brain subregions even in the presence of lesions. Recombination of the mixture models across strata provided an accurate whole brain MR intensity model. Increasing the number of subregions and, thereby, the model complexity, consistently improved the accuracy of whole-brain MR intensity modeling and segmentation of normal structures. The proposed approach was incorporated into three unsupervised lesion segmentation methods and, compared to original and three other state-of-the-art methods, the proposed modeling approach significantly improved lesion segmentation according to increased Dice similarity indices and lower number of false positives on real MR images of 30 patients with MS. PMID- 26427642 TI - Generative models of the human connectome. AB - The human connectome represents a network map of the brain's wiring diagram and the pattern into which its connections are organized is thought to play an important role in cognitive function. The generative rules that shape the topology of the human connectome remain incompletely understood. Earlier work in model organisms has suggested that wiring rules based on geometric relationships (distance) can account for many but likely not all topological features. Here we systematically explore a family of generative models of the human connectome that yield synthetic networks designed according to different wiring rules combining geometric and a broad range of topological factors. We find that a combination of geometric constraints with a homophilic attachment mechanism can create synthetic networks that closely match many topological characteristics of individual human connectomes, including features that were not included in the optimization of the generative model itself. We use these models to investigate a lifespan dataset and show that, with age, the model parameters undergo progressive changes, suggesting a rebalancing of the generative factors underlying the connectome across the lifespan. PMID- 26427645 TI - Neural structures involved in visual search guidance by reward-enhanced contextual cueing of the target location. AB - Spatial contextual cueing reflects an incidental form of learning that occurs when spatial distractor configurations are repeated in visual search displays. Recently, it was reported that the efficiency of contextual cueing can be modulated by reward. We replicated this behavioral finding and investigated its neural basis with fMRI. Reward value was associated with repeated displays in a learning session. The effect of reward value on context-guided visual search was assessed in a subsequent fMRI session without reward. Structures known to support explicit reward valuation, such as ventral frontomedial cortex and posterior cingulate cortex, were modulated by incidental reward learning. Contextual cueing, leading to more efficient search, went along with decreased activation in the visual search network. Retrosplenial cortex played a special role in that it showed both a main effect of reward and a reward*configuration interaction and may thereby be a central structure for the reward modulation of context-guided visual search. PMID- 26427646 TI - Estimation of the Survival of Patients With Lung Squamous Cell Carcinoma Using Genomic Copy Number Aberrations. AB - BACKGROUND: Estimation of the survival of patients with lung squamous cell carcinoma (SCC) on the basis of histopathology is inadequate. The aim of this study was to identify genomic regions with potential value for estimating the prognosis of these patients. PATIENTS AND METHODS: Depending on their survival time, 100 patients with primary lung SCC were separated into high- or low-risk prognostic groups, and their copy number aberrations (CNAs) were analyzed using array-comparative genomic hybridization (array-CGH). RESULTS: We identified 123 CNA regions that were significantly associated with survival. Among these regions, some have been reported previously (eg, amplifications of 8p12, 3q27.1, and loss of 9p21.3 and 13q34) but others have never been reported. For example, gains of 3q27.1, 5p13.2, and 5p13.3 were found to be associated with a favorable prognosis, but patients harboring gains of 11q23.3, 11q13.1, and 14q32.3, and deletions of 3p21.3 and 9p21.3 tended to have poor survival. Among the 123 CNA regions, 41 were further selected to construct a survival estimation model that could effectively separate SCC patients into high- or low-risk groups with an accuracy of 92%, sensitivity of 90%, and specificity of 94%. The results of the array-CGH were further validated in an independent cohort of 45 formalin-fixed, paraffin-embedded specimens using real-time polymerase chain reaction. CONCLUSION: A number of CNA regions were found to be associated with the survival of SCC patients, and we were able to construct a model to estimate prognosis on the basis of these regions. Assessment of these CNAs could potentially assist in clinical decision-making regarding adjuvant therapy after surgery. PMID- 26427647 TI - Renin-Angiotensin System Inhibitors Might Help to Reduce the Development of Symptomatic Radiation Pneumonitis After Stereotactic Body Radiotherapy for Lung Cancer. AB - INTRODUCTION: The purpose of the present study was to evaluate the role of renin angiotensin system (RAS) inhibitors in preventing symptomatic radiation pneumonitis (RP) after stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: The data from 158 patients with a solitary lung lesion treated with 1 to 3 fractions of SBRT from December 2008 to July 2014 were retrospectively analyzed. The incidence of RP was evaluated according to the Common Toxicity Criteria for Adverse Events, version 4. The use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) was analyzed to assess for possible correlations with the development of grade >= 2 RP. The patient and dosimetric variables were also assessed. RESULTS: After a median follow-up period of 13.8 months (range, 3.2-55.0 months), 22 patients had developed grade >= 2 RP. Patients with peripheral lesions, favorable dosimetric data, and ACEI and/or ARB use had a reduced risk of symptomatic RP. In unadjusted and adjusted multivariate analyses, ACEI and/or ARB intake and the dosimetric variables were statistically significant factors. In a secondary analysis, the use of ACEIs and ARBs among patients with a greater planning target volume and higher dosimetric values correlated with a reduced risk of symptomatic RP. CONCLUSION: The use of a RAS inhibitor was associated with a decreased incidence of symptomatic RP among patients undergoing SBRT for lung lesions. Patients with higher dosimetric values had a reduced risk of grade >= 2 RP with ACEI and ARB use. PMID- 26427648 TI - Potential of carboxymethyl cellulose and gamma-irradiation to maintain quality and control disease of peach fruit. AB - Carboxymethyl cellulose (CMC) coatings alone and in combination with gamma irradiation were tested for maintaining the storage quality and control of post harvest gray and black mold disease of peach. Matured green peaches were CMC coated at levels 0.5-1.0% (w/v) and gamma irradiated at 1.2 kGy. The treated fruit including control was stored under ambient (temperature 25 +/- 2 degrees C, RH 70%) and refrigerated (temperature 3 +/- 1 degrees C, RH 80%) conditions. In fruits treated with individual treatments of 1.0% (w/v) CMC; 1.2 kGy irradiation and combination of 1.0% (w/v) CMC and 1.2 kGy irradiation, no decay was recorded up to 6, 8 and 14 days of ambient storage. Irradiation alone at 1.2 kGy prevented the onset of disease incidence up to 4 days compared to 2 days by 1.0% (w/v) CMC coating following 30 days of refrigeration. Combination of CMC at 1.0% (w/v) and 1.2 kGy irradiation prevented disease incidence of peach up to 7 days during post refrigerated storage at 25 +/- 2 degrees C, RH 70% following 30 days of refrigeration. Above combinatory treatment can be of great potential in facilitating the marketing of the fruit, thereby benefiting the growers. PMID- 26427649 TI - Tensin1 positively regulates RhoA activity through its interaction with DLC1. AB - DLC1 is a RhoGAP-containing tumor suppressor and many of DLC1's functions are absolutely dependent on its RhoGAP activity. Through its RhoGAP domain, DLC1 inhibits the activity of RhoA GTPase, which regulates actin cytoskeleton networks and dis/assembly of focal adhesions. Tensin1 (TNS1) is a focal adhesion molecule that links the actin cytoskeleton to integrins and forms signaling complexes through its multiple binding domains. Here, we report that TNS1 enhances RhoA activity in a DLC1-dependent manner. This is accomplished by binding to DLC1 through TNS1's C2, SH2, and PTB domains. Point mutations at these three sites disrupt TNS1's interaction with DLC1 as well as its effect on RhoA activity. The biological relevance of this TNS1-DLC1-RhoA signaling axis is investigated in TNS1 knockout (KO) cells and mice. Endothelial cells isolated from TNS1 KO mice or those silenced with TNS1 siRNA show significant reduction in proliferation, migration, and tube formation activities. Concomitantly, the RhoA activity is down-regulated in TNS1 KO cells and this reduction is restored by further silencing of DLC1. Furthermore, the angiogenic process is compromised in TNS1 KO mice. These studies demonstrate that TNS1 binds to DLC1 and fine-tunes its RhoGAP activity toward RhoA and that the TNS1-DLC1-RhoA signaling axis is critical in regulating cellular functions that lead to angiogenesis. PMID- 26427650 TI - Amphiregulin lacks an essential role for the bone anabolic action of parathyroid hormone. AB - Although parathyroid hormone (PTH) has long been known to act as a bone anabolic agent when administered intermittently, the exact underlying mechanisms remain largely unknown. Amphiregulin (AREG), a ligand of the epidermal growth factor receptor, has been identified to be a PTH target gene in vitro and in vivo. Here, we used female global AREG knockout (AREG-KO) mice to explore the role of AREG in mediating the bone anabolic effects of PTH. AREG-KO mice were characterized by unchanged distal femoral cancellous bone mass and only subtle decreases in bone mineral density (BMD) and cortical thickness at the femoral midshaft at 3 and 8 months of age, relative to wildtype controls. AREG deficiency was associated with complex changes in the mRNA expression of other EGFR ligands in femoral cancellous bone osteoblasts in situ in 3-week-old mice. To examine the bone anabolic effects of PTH in the absence and presence of AREG, we injected 3-month old AREG-KO females and wildtype control littermates with 80 MUg/kg PTH or vehicle 5 times per week over 4 weeks. Intermittent PTH treatment of AREG-KO mice led to increases in femoral trabecular and cortical BMD, cortical thickness, endocortical and periosteal bone formation, cancellous bone formation rate, and serum osteocalcin, comparable to those observed in wildtype control mice. In conclusion, our data indicate that the bone anabolic effects of PTH do not require AREG, at least in 3-month-old female mice. PMID- 26427651 TI - Developmental exposure to bisphenol A alters expression and DNA methylation of Fkbp5, an important regulator of the stress response. AB - Bisphenol A (BPA), an abundant endocrine disruptor, affects stress-responsiveness and related behaviors in children. In rats, perinatal BPA exposure modifies stress response in pubertal offspring via unknown mechanisms. Here we examined possible epigenetic modifications in the glucocorticoid receptor gene and its regulator Fkbp5 in hypothalamus and hippocampus of exposed offspring. We found increased DNA methylation of Fkbp5 and reduced protein levels in the hippocampus of exposed male rats. Similar effects were obtained in a male hippocampal cell line when exposed to BPA during differentiation. The estrogen receptor (ER) antagonist ICI 182,780 or ERbeta knock-down affected Fkbp5 expression and methylation similarly to BPA. Further, BPA's effect on Fkbp5 was abolished upon knock-down of ERbeta, suggesting a role for this receptor in mediating BPA's effects on Fkbp5. These data demonstrate that developmental BPA exposure modifies Fkbp5 methylation and expression in male rats, which may be related to its impact on stress responsiveness. PMID- 26427653 TI - Genome-wide association studies of human adiposity: Zooming in on synapses. AB - The decade anniversary for genome-wide association studies (GWAS) is approaching, and this experimental approach has commenced a deeper understanding of the genetics underlying complex diseases. In obesity genetics the GIANT (Genetic Investigation of ANthropometric Traits) consortium has played a crucial role, recently with two comprehensive meta-analyses, one focusing on general obesity, analyzing body-mass index (BMI) and the other on fat distribution, focusing on waist-hip ratio adjusted for BMI. With the in silico methods applied in these two studies as the pivot, this review looks into some of the biological knowledge, beginning to emerge from the intricate genomic background behind the genetic determinants of human adiposity. These include synaptic dysfunction, where GWAS pinpoint potential new mechanisms in pathways already known to be linked with obesity. PMID- 26427652 TI - Lxr regulates lipid metabolic and visual perception pathways during zebrafish development. AB - The Liver X Receptors (LXRs) play important roles in multiple metabolic pathways, including fatty acid, cholesterol, carbohydrate and energy metabolism. To expand the knowledge of the functions of LXR signaling during embryonic development, we performed a whole-genome microarray analysis of Lxr target genes in zebrafish larvae treated with either one of the synthetic LXR ligands T0901317 or GW3965. Assessment of the biological processes enriched by differentially expressed genes revealed a prime role for Lxr in regulating lipid metabolic processes, similarly to the function of LXR in mammals. In addition, exposure to the Lxr ligands induced changes in expression of genes in the neural retina and lens of the zebrafish eye, including the photoreceptor guanylate cyclase activators and lens gamma crystallins, suggesting a potential novel role for Lxr in modulating the transcription of genes associated with visual function in zebrafish. The regulation of expression of metabolic genes was phenotypically reflected in an increased absorption of yolk in the zebrafish larvae, and changes in the expression of genes involved in visual perception were associated with morphological alterations in the retina and lens of the developing zebrafish eye. The regulation of expression of both lipid metabolic and eye specific genes was sustained in 1 month old fish. The transcriptional networks demonstrated several conserved effects of LXR activation between zebrafish and mammals, and also identified potential novel functions of Lxr, supporting zebrafish as a promising model for investigating the role of Lxr during development. PMID- 26427654 TI - Influence of organic matters on AsIII oxidation by the microflora of polluted soils. AB - The global AsIII-oxidizing activity of microorganisms in eight surface soils from polluted sites was quantified with and without addition of organic substrates. The organic substances provided differed by their nature: either yeast extract, commonly used in microbiological culture media, or a synthetic mixture of defined organic matters (SMOM) presenting some common features with natural soil organic matter. Correlations were sought between soil characteristics and both the AsIII oxidizing rate constants and their evolution in accordance with inputs of organic substrates. In the absence of added substrate, the global AsIII oxidation rate constant correlated positively with the concentration of intrinsic organic matter in the soil, suggesting that AsIII-oxidizing activity was limited by organic substrate availability in nutrient-poor soils. This limitation was, however, removed by 0.08 g/L of added organic carbon. In most conditions, the AsIII oxidation rate constant decreased as organic carbon input increased from 0.08 to 0.4 g/L. Incubations of polluted soils in aerobic conditions, amended or not with SMOM, resulted in short-term As mobilization in the presence of SMOM and active microorganisms. In contrast, microbial AsIII oxidation seemed to stabilize As when no organic substrate was added. Results suggest that microbial speciation of arsenic driven by nature and concentration of organic matter exerts a major influence on the fate of this toxic element in surface soils. PMID- 26427655 TI - Quality assurance in clinical trials--the role of pathology. AB - In the last two decades, our knowledge about cancer genetics and cancer biology increased exponentially. Deep sequencing now allows rapid and cost-effective analysis of entire cancer genomes. Dysregulation of cell growth, cell survival, tissue homeostasis, and immune surveillance have been recognized as hallmarks of cancer. In parallel, diagnostic surgical pathology has been harmonized and consensus diagnostic criteria for cancer classification have been developed by initiatives of the World Health Organization, the International Agency for Research on Cancer, and the Union for International Cancer Control. Pharmaceutical companies developed novel drugs targeting specific molecules in signaling pathways, which has allowed the development of the concept of precision medicine. Now, we are facing a large number of clinical trials which bring together these advances and will explore efficacy of novel treatment regimens. Assessment of the efficacy of a new drug is often coupled with the simultaneous assessment of the capacity of tissue-based biomarkers to predict response of individual patients (companion diagnostics/precision medicine). Patients with histologically similar tumors might respond differently to the same drug. This review summarizes the diverse roles played by surgical pathologists involved in clinical trials, with a special focus on quality assurance of diagnostic, laboratory, and reporting standards. PMID- 26427656 TI - Potential role of Th17 cells in the pathogenesis of type 2 autoimmune pancreatitis. AB - Th17 cells have been shown to play an important role in the pathogenesis of a variety of autoimmune diseases. The aim of this study was to investigate the potential role of Th17 cells in autoimmune pancreatitis (AIP). Quantitative real time polymerase chain reaction (qRT-PCR) was performed to determine gene expression of the signature cytokines of Th17 cells IL-17A and IL-21 and of the Th17 lineage-specific transcription factor retinoic acid receptor-related orphan receptor C (RORC) in human tissue specimens of AIP, classical chronic pancreatitis (CP), and normal pancreas (NP). Infiltrating immune cells were characterized by immunohistochemistry (IHC). Gene expression of IL-17A, IL-21, and RORC were found to be significantly increased in AIP. Accordingly, the number of Th17 cells was significantly increased in AIP compared to NP or CP. Both gene expression analysis and IHC revealed a clear difference between type 1 and 2 AIP. In the periductal compartment of type 2 AIP, which is characterized by granulocytic epithelial lesions (GELs), the number of infiltrating Th17 cells and neutrophilic granulocytes was significantly increased compared to type 1 AIP. Our data suggest that Th17 cells play a role in the pathogenesis of AIP, in particular of type 2 AIP. Cross-talk between Th17 cells and neutrophilic granulocytes mediated via IL-17A may be a potential mechanism by which neutrophils are recruited to the duct and acinar cells with subsequent destruction, a process that is pathognomonic for type 2 AIP. PMID- 26427657 TI - ROBO1 deletion as a novel germline alteration in breast and colorectal cancer patients. AB - Despite one third of breast (BC) and colorectal cancer (CRC) cases having a hereditary component, only a small proportion can be explained by germline mutations. The aim of this study was to identify potential genomic alterations related to cancer predisposition. Copy number variations (CNVs) were interrogated in 113 unrelated cases fulfilling the criteria for hereditary BC/CRC and presenting non-pathogenic mutations in BRCA1, BRCA2, MLH1, MSH2, TP53, and CHEK2 genes. An identical germline deep intronic deletion of ROBO1 was identified in three index patients using two microarray platforms (Agilent 4x180K and Affymetrix CytoScan HD). The ROBO1 deletion was confirmed by quantitative PCR (qPCR). Six relatives were also evaluated by CytoScan HD Array. Genomic analysis confirmed a co-segregation of the ROBO1 deletion with the occurrence of cancer in two families. Direct sequencing revealed no pathogenic ROBO1 point mutations. Transcriptomic analysis (HTA 2.0, Affymetrix) in two breast carcinomas from a single patient revealed ROBO1 down-expression with no splicing events near the intronic deletion. Deeper in silico analysis showed several enhancer regions and a histone methylation mark in the deleted region. The ROBO1 deletion in a putative transcriptional regulatory region, its down-expression in tumor samples, and the results of the co-segregation analysis revealing the presence of the alteration in affected individuals suggest a pathogenic effect of the ROBO1 in cancer predisposition. PMID- 26427658 TI - The effect of bovine rotavirus and its nonstructural protein 4 on ER stress mediated apoptosis in HeLa and HT-29 cells. AB - Endoplasmic reticulum (ER) plays important roles in multiple cellular processes as well as cell survival and apoptosis. Perturbation of ER functions leads to ER stress and unfolded protein response (UPR). The primary goal of this response is cell survival, but severe ER stress can trigger apoptosis signaling. In tumor cells, chronically activated UPR response provides tumor growth. So, apoptosis induced by the ER stress has been the target for anti-cancer therapy. In this in vitro study, we examined the apoptotic effect associated with ER stress of bovine rotavirus and its nonstructural protein 4 (NSP4) alone in two cancer cell lines. The plasmid pcDNA3.1 encoding NSP4 protein of bovine rotavirus transfected with lipofectamine 2000 into the HeLa and HT-29 cells for protein production. MTT, flow cytometry, and Western blot were used to evaluate the cell viability, apoptosis, and expression level of C/EBP-homologous protein (CHOP) and activated caspase-4. In parallel, the apoptotic effect of the bovine rotavirus associated with ER stress in the infected cells was examined too. The cytotoxic and apoptotic effect of NSP4 protein on the cells were statistically significant compared to the control groups. However, Western blot showed that the expression of the NSP4 protein by recombinant plasmid did not lead to high expression of CHOP and activation of caspase-4. Interestingly, rotavirus not only induced significant apoptosis but also caused an increase in CHOP expression and caspase 4 activation in the infected cells compared to control. As a result, NSP4 protein and bovine rotavirus can be considered a potential novel bio-therapeutic strategy for cancer treatment. PMID- 26427659 TI - Deregulation of miR-93 and miR-143 in human esophageal cancer. AB - Esophageal squamous cell carcinoma (ESCC) is the second and third most common malignancy in Iranian males and females, respectively. Treatment of ESCC is largely ineffective due to lack of detection at early stages of the disease. In recent years, miRNA, a small RNA molecule, has drawn much attention to researchers as a potential biomarker for esophageal cancer. miR-93 and miR-143 are two miRNA molecules reported to be frequently deregulated in various cancers, including prostate, stomach, cervix, and etc. The purpose of this study was to investigate the expression levels of these miRNAs and evaluate their diagnostic and therapeutic potential in esophageal squamous cell carcinoma. In this study, total RNA was extracted from 30 tumor tissues and 30 nontumor tissues of esophageal tumor margins, using RNX-plus solution. After validating the quality and quantity of total RNA, cDNAs of interest were synthesized using microRNA specific cDNA Synthesis Kit. The expression level of miR-93 and miR-143 was evaluated using quantitative real-time PCR with miRNA-specific primers. Finally, the obtained data was analyzed by SPSS ver.20 software and paired t test was performed to observe the significance of difference between groups. The expression level of miR-93 was significantly increased and of miR-143 was significantly decreased in most of the examined tumor tissues, compared to nontumor tissues. Also, our findings did not detect correlation between mir-93 and mir-143 expressions in regard to stage and grade of the samples. These findings suggest that the deregulation of these miRNAs may play an important role in esophageal squamous cell carcinoma. Both miR-93 and miR-143 might be used as potential biomarkers in esophageal squamous cell carcinoma. However, more studies with large population of samples are necessary. PMID- 26427660 TI - Long noncoding RNA PVT1 modulates thyroid cancer cell proliferation by recruiting EZH2 and regulating thyroid-stimulating hormone receptor (TSHR). AB - The purposes of this study were to investigate the potential roles of long noncoding RNA (lncRNA) PVT1 in thyroid cancer cell proliferation and to explore their possible mechanisms. A total of 84 patients who were diagnosed as having thyroid cancer (papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), and anaplastic thyroid carcinoma (ATC)) in Renji Hospital were enrolled in this study. Expressions of lncRNA PVT1 in thyroid cancer tissues and cell lines (IHH-4, FTC-133, and 8505C) were analyzed using RT-polymerase chain reaction (PCR) and western blotting analysis. The effects of lncRNA PVT1 expression on thyroid cancer cell proliferation and cell cycle were analyzed using flow cytometry. Furthermore, the effects of lncRNA expression on thyroid-stimulating hormone receptor (TSHR) expression and polycomb enhancer of zeste homolog 2 (EZH2) were also analyzed using RNA immunoprecipitation (RIP) assay and chromatin immunoprecipitation (ChIP) assay, respectively. Compared to the controls, lncRNA PVT1 was significantly up-regulated in thyroid tissues, as well as in three kinds of tumor cell lines (P < 0.05). Silenced PVT1 significantly inhibited thyroid cell line IHH-4, FTC-133, and 8505C cell proliferation and arrested cell cycle at G0/G1 stage and significantly decreased cyclin D1 and TSHR expressions (P < 0.05). Moreover, lncRNA PVT1 could be enriched by EZH2, and silencing PVT1 resulted in the decreased recruitment of EZH2. This study suggested that lncRNA PVT1 may contribute to tumorigenesis of thyroid cancer through recruiting EZH2 and regulating TSHR expression. PMID- 26427662 TI - RETRACTED ARTICLE: Upregulation of miR-20a and miR-10a expression levels act as potential biomarkers of aggressive progression and poor prognosis in cervical cancer. PMID- 26427661 TI - Synthetic Tet-inducible small hairpin RNAs targeting hTERT or Bcl-2 inhibit malignant phenotypes of bladder cancer T24 and 5637 cells. AB - Small hairpin RNA (shRNA) can inhibit the malignant phenotypes of tumor cell through ribonucleic acid interference (RNAi). However, it is hardly to be regulated and it may induce few phenotypic changes. Here, we build a type of tetracycline (Tet)-inducible vectors which can achieve regulatable expression of shRNA in a time-dependent manner by using synthetic biology approach. In order to prove the effectiveness of this device, we chose hTERT and Bcl-2 as target genes and test the utility of the device on 5637 and T24 cell lines. The experiments show that the Tet-inducible small hairpin RNA can effectively suppress their target genes and generate anti-cancer effects on both 5637 and T24 cell lines. The device we build not only can inhibit proliferation but also can induce apoptosis and suppress migration of the bladder cancer cell lines 5637 and T24. The Tet-inducible small hairpin RNAs may provide a novel strategy for the treatment of human bladder cancer in the future. PMID- 26427663 TI - The diagnostic utility of the triple markers Napsin A, TTF-1, and PAX8 in differentiating between primary and metastatic lung carcinomas. AB - Napsin A and thyroid transcription factor-1 (TTF-1) are useful biomarkers for differentiating lung adenocarcinoma from squamous cell carcinoma and also for differentiating primary lung adenocarcinoma from metastatic lung carcinoma. Pair boxed 8 (PAX8) can help in distinguishing primary lung carcinoma from metastatic carcinomas and help to determine the primary sites of metastatic carcinomas. Immunohistochemistry for Napsin A, TTF-1, and PAX8 were performed on 193 cases of carcinoma: 50 primary lung carcinoma and 143 carcinomas from other sites. Napsin A and TTF-1 were positive in 54, 52 % of lung carcinomas cases, respectively. While in adenocarcinoma cases, their expressions were 86.7 and 83.3 %, respectively. PAX8 was negative in all lung carcinomas. TTF-1 and PAX8 were positive in 93.3 and 96.7 % of thyroid carcinoma cases and in 87.5 and 93.8 % of papillary carcinoma respectively, and both were positive in 100 % of follicular carcinoma. Napsin A was negative in all thyroid carcinomas. Napsin A and PAX8 were positive in 50 and 93.3 % of renal carcinoma cases and in 81.8 and 100 % of papillary carcinoma, 38.5 and 92.3 % of clear cell carcinoma, and 16.7 and 83.3 % of chromophobe carcinoma respectively. TTF-1 was negative in all renal carcinomas. PAX8 was positive in 80 % of ovarian carcinoma cases; 100 and 60 % of serous mucinous carcinomas, respectively. It was also positive in 100 % of endometrial carcinoma. Napsin A and TTF-1 were negative in both ovarian and endometrial carcinomas. Our data demonstrated that combined use of Napsin A, TTF 1, and PAX8 may help in differentiating between primary lung adenocarcinoma and metastatic lung carcinomas. PMID- 26427664 TI - Icaritin activates JNK-dependent mPTP necrosis pathway in colorectal cancer cells. AB - The colorectal cancer (CRC) is one leading contributor of cancer-related mortality worldwide. The search for effective anti-CRC agents is valuable. In the current study, we showed that icaritin (ICT), an active natural ingredient from the Chinese plant Epimedium, potently inhibited proliferation and survival of established (HT-29, HCT-116, DLD-1, and SW-620) and primary (patient-derived) CRC cells. Significantly, ICT mainly induced necrosis, but not apoptosis, in CRC cells. The necrosis inhibitor necrostatin-1 attenuated ICT-mediated cytotoxicity in CRC cells. We showed that ICT treatment in CRC cells induced mitochondrial permeability transition pore (mPTP) opening, which was evidenced by mitochondrial membrane potential (MMP) decrease and mitochondrial adenine nucleotide translocator-1 (ANT-1)-cyclophilin-D (CyPD) association. On the other hand, mPTP blockers, including sanglifehrin A, cyclosporin A, and bongkrekic acid, as well as siRNA-mediated knockdown of mPTP component (CyPD or ANT-1), significantly alleviated ICT-mediated cytotoxicity against CRC cells. We suggested that Jun-N terminal kinase (JNK) activation by ICT mediated mPTP opening and subsequent CRC cell necrosis. JNK pharmacological inhibition, dominant negative mutation, or shRNA downregulation suppressed ICT-induced MMP reduction and subsequent HT-29 cell necrosis. In vivo, oral gavage of ICT dramatically inhibited HT-29 xenograft growth in nude mice. The in vivo activity by ICT was largely attenuated by co administration with the mPTP blocker CsA. Collectively, our results showed that ICT exerts potent inhibitory effect against CRC cells in vitro and in vivo. JNK dependent mPTP necrosis pathway could be key mechanism responsible for ICT's actions. PMID- 26427665 TI - The emerging role of Nemo-like kinase (NLK) in the regulation of cancers. AB - Nemo-like kinase (NLK) is an evolutionarily conserved mitogen-activated protein (MAP) kinase-related kinase that is highly expressed in neural tissues and minimally detected in others. Accumulating evidence demonstrates that NLK exerts a pivotal role in cell proliferation, migration, invasion, and apoptosis via regulation of a variety of transcriptional molecules. The results of recent studies have shown that aberrant expression of NLK is significantly associated with the initiation and progression of various types of human cancers, as well as clinicopathologic features and survival rate. NLK is gradually considered as a potential tumor suppressor or an oncogene depending on the tumor system, and silencing or upregulating of NLK may provide an effective therapeutic approach against tumors. In this review, we will make a summary on the comprehensive roles of NLK in the regulation of various cancers. PMID- 26427666 TI - XPC (A2920C), XPF (T30028C), TP53 (Arg72Pro), and GSTP1 (Ile105Val) polymorphisms in prognosis of cutaneous melanoma. AB - This study aimed to evaluate whether XPC A2920C, XPF T30028C, TP53 Arg72Pro, and GSTP1 Ile105Val polymorphisms alter outcomes of cutaneous melanoma (CM) patients. DNA from 237 CM patients seen at the University of Campinas Teaching Hospital from April 2000 to February 2014 was analyzed by polymerase chain reaction and restriction fragment length polymorphism assays. The prognostic impact of genotypes of polymorphisms on progression-free survival (PFS) and overall survival (OS) of CM patients were examined using the Kaplan-Meier probability estimates and univariate and multivariate Cox regression analyses. At 60 months of follow-up, shorter PFS and OS were seen in patients with XPF CC genotype (48.9 vs. 66.7 %, P = 0.002; 77.9 vs. 83.5 %, P = 0.006, respectively) and XPF CC + TP53 ArgArg (43.6 vs. 65.9 %, P = 0.007; 71.6 vs. 84.8 %, P = 0.006, respectively) compared with those with remaining genotypes (Kaplan-Meier estimates). Patients with XPF CC (hazard ratio (HR) 2.45, P = 0.002; HR 3.77, P = 0.005) and XPF CC + TP53 ArgArg (HR 2.67, P = 0.009; HR 4.04, P = 0.03) genotypes had more chance to present tumor progression in univariate and multivariate analyses, whereas patients with XPF CC (HR 2.78, P = 0.009) and XPF CC + TP53 ArgArg (HR 3.84, P = 0.01) genotypes were under greater risk of progressing to death in univariate analysis, compared with those with the remaining genotypes. The data suggest, for the first time, that inherited abnormalities in DNA repair pathway related to XPF 30028C and TP53 Arg72Pro polymorphisms act as prognostic factors for PFS and OS of CM patients. PMID- 26427667 TI - FGF18 as a potential biomarker in serous and mucinous ovarian tumors. AB - Fibroblast growth factor 18 (FGF18) has been suggested to play important roles in promoting progression of ovarian high-grade serous carcinoma. Our aim was to investigate FGF18 expression in the whole spectrum of serous and mucinous ovarian tumors, highlighting differences in expression within the adenoma-carcinoma sequence and differences between type I and type II tumors. We also aimed to test the prognostic significance of this expression and its relation to microvessel density (MVD). We evaluated the immunohistochemical expression of FGF18 and CD31 in 103 ovarian tumors and statistically analyzed their association with clinicopathological variables and patients' outcome. FGF18 score increased significantly within the adenoma-carcinoma sequence for serous and mucinous tumors. MVD increased significantly only among serous tumors. FGF18 and MVD correlated significantly (overall and among serous tumors only) and were significantly higher in type II than type I tumors. Cox regression models were built. Independent predictors could not be determined due to multicollinearity between the predictors. However, the combination of International Federation of Gynecology and Obstetrics (FIGO) stage, ovarian carcinoma type, and/or FGF18 score achieved the highest predictability of poor prognosis. FGF18 could play a role within the adenoma-carcinoma sequence in type I tumors and might modulate angiogenesis among serous tumors. Our findings further augment the differences between type I and type II tumors. The combination of FIGO stage, ovarian carcinoma type, and/or FGF18 score could predict poor prognosis among ovarian carcinoma patients. Our work identifies FGF18 in ovarian neoplasia as a promising field of research, although evaluation of the performance of the developed models is still needed. PMID- 26427668 TI - A patient as a self-manager of their personal data on health and disease with new technology--challenges for nursing education. AB - Background: Digital technologies have transformed nearly every aspect of our lives. However, for many of us, they have not yet improved the way we receive or participate in our health services and disease care. Hostetter et al. (2014) explore in a new multimedia essay the changes occurring with the arrival of new digital tools, from mobile apps and data-driven software solutions to wearable sensors that transmit information to a patient's team of health care providers. Digitisation will revolutionise health technology to a new extent, as the self measurement, cloud services, teleconsultation and robotics technologies are being used to get health expenditure under control. In the future, robots will dispense drugs, and treatment routines will utilise cloud services (Biesdorf and Niedermann, 2014; Grain and Sharper, 2013). According to the rationale of the Horizon 2020 (European Commission, 2013b) work programme, personalising health and care has been stated to empower citizens and patients to manage their own health and disease, which can result in more cost-effective healthcare systems by enabling the management of chronic diseases outside institutions, improving health outcomes, and by encouraging healthy citizens to remain so. Solutions should be developed and tested with the use of open innovation platforms, such as large-scale demonstrators for health and service innovation. It is a fact that ICT/new health technology and personal health applications are transforming patients' self-management in many ways. A huge amount of personal health application solutions are being offered in the marketplace, which engage in activities that promote health, monitoring the symptoms and signs of illness, and managing the impact of illness (European Commission eHealth Action Plan 2012 2020, 2012). The WHO (2011) has conducted a comprehensive study and published a report on Member States' use of mHealth (mobile Health) as well as the readiness and barriers to its use. The percentage of countries reporting that they had formally evaluated mHealth initiatives was 12%. Seven per cent of developing countries reported conducting a mHealth evaluation. Mobile technologies have already changed, and they will continue to change the lives of millions around the world. In the WHO's report, it was estimated that mHealth can revolutionise health and well-being outcomes if implemented strategically and systematically, thereby providing virtually anyone with a mobile phone with health and well-being expertise and knowledge in real-time. In the research reports (European Commission eHealth Action Plan 2012-2020, 2012; Blake, 2013), it was reported that mobile phones as a tool are cost-effective and wide reaching, while they easily target large samples and hard-to-reach groups. Studies show that eHealth as a way to self-monitor and self-manage as well as supportive interventions for clients offers a good possibility to bridge the gap between inpatient and outpatient care. The mobile phone is especially effective in enhancing the therapist-patient bond so that this does not collapse when the client leaves the therapist's consulting room. Furthermore, eHealth applications can assist the client to cope with everyday situations in an autonomous way while improving the transfer of the abilities acquired by the client in the health care setting to everyday life. The findings of various projects (European Commission eHealth Action Plan 2012-2020, 2012; European Commission, 2012; European Commission, 2013b; Hamalainen, 2013) provide an opportunity for an open discussion regarding the digital health revolution, which will change health care processes and citizens' applications for health promotion and self-care. PMID- 26427669 TI - Narrative competence: A neglected area in undergraduate curricula. PMID- 26427670 TI - Notch2 signaling contributes to cell growth, invasion, and migration in salivary adenoid cystic carcinoma. AB - Many studies have explored whether the Notch signaling pathway has a tumor suppressive or an oncogenic role in various tumors; however, the role of the Notch signaling pathway in salivary adenoid cystic carcinoma (SACC) is still unknown. In this study, we attempt to define the role of Notch2 signaling in cell growth, invasion, and migration in SACC. We compared Notch2 expression in clinical SACC samples with that of normal samples by using immunohistochemical staining. Then, we down-regulated Notch2 expression to observe the effect of Notch2 on proliferation, invasion, migration, and the expression of known target genes of Notch signal pathway. According to our results, Notch2 expression was higher in SACC tissues compared with normal tissues. Knockdown of Notch2 inhibited cell proliferation, invasion, and migration in vitro and down-regulated the expression of HEY2 and CCND1. The results of this study suggest that Notch2 has an essential role in the cell growth, invasion, and migration of SACC. Notch2 may therefore be a potential target gene for the treatment of SACC by interfering with cell growth and metastasis. PMID- 26427672 TI - The beta-Barrel Assembly Machinery Complex. AB - The outer membranes of gram-negative bacteria contain integral membrane proteins, most of which are of beta-barrel structure, and critical for bacterial survival. These beta-barrel proteins rely on the beta-barrel assembly machinery (BAM) complex for their integration into the outer membrane as folded species. The central and essential subunit of the BAM complex, BamA, is a beta-barrel protein conserved in all gram-negative bacteria and also found in eukaryotic organelles derived from bacterial endosymbionts. In Escherichia coli, BamA docks with four peripheral lipoproteins, BamB, BamC, BamD and BamE, partner subunits that add to the function of the BAM complex in outer membrane protein biogenesis. By way of introduction to this volume, we provide an overview of the work that has illuminated the mechanism by which the BAM complex drives beta-barrel assembly. The protocols and methodologies associated with these studies as well as the challenges encountered and their elegant solutions are discussed in subsequent chapters. PMID- 26427671 TI - Brain opioid and nociceptin receptors are involved in regulation of bombesin induced activation of central sympatho-adrenomedullary outflow in the rat. AB - Previously, we reported that central administration of bombesin, a stress-related peptide, elevated plasma levels of catecholamines (noradrenaline and adrenaline) in the rat. The sympatho-adrenomedullary system, which is an important component of stress responses, can be regulated by the central opioid system. In the present study, therefore, we examined the roles of brain opioid receptor subtypes (u, delta, and kappa) and nociceptin receptors, originally identified as opioid like orphan receptors, in the bombesin-induced activation of central sympatho adrenomedullary outflow using anesthetized male Wistar rats. Intracerebroventricularly (i.c.v.) administered bombesin-(1 nmol/animal) induced elevation of plasma catecholamines was significantly potentiated by pretreatment with naloxone (300 and 1000 ug/animal, i.c.v.), a non-selective antagonist for u , delta-, and kappa-opioid receptors. Pretreatment with cyprodime (100 ug/animal, i.c.v.), a selective antagonist for u-opioid receptors, also potentiated the bombesin-induced responses. In contrast, pretreatment with naltrindole (100 ug/animal, i.c.v.) or nor-binaltorphimine (100 ug/animal, i.c.v.), a selective antagonist for delta- or kappa-opioid receptors, significantly reduced the elevation of bombesin-induced catecholamines. In addition, pretreatment with JTC 801 (30 and 100 ug/animal, i.c.v.) or J-113397 (100 ug/animal, i.c.v.), which are selective antagonists for nociceptin receptors, also reduced the bombesin-induced responses. These results suggest that brain u-opioid receptors play a suppressive role and that brain delta-, kappa-opioid, and nociceptin receptors play a facilitative role in the bombesin-induced elevation of plasma catecholamines in the rat. Thus, in the brain, these receptors could play differential roles in regulating the activation of central sympatho-adrenomedullary outflow. PMID- 26427673 TI - Yeast Mitochondria as a Model System to Study the Biogenesis of Bacterial beta Barrel Proteins. AB - Beta-barrel proteins are found in the outer membrane of Gram-negative bacteria, mitochondria, and chloroplasts. The evolutionary conservation in the biogenesis of these proteins allows mitochondria to assemble bacterial beta-barrel proteins in their functional form. In this chapter, we describe exemplarily how the capacity of yeast mitochondria to process the trimeric autotransporter YadA can be used to study the role of bacterial periplasmic chaperones in this process. PMID- 26427674 TI - Experimental Methods for Studying the BAM Complex in Neisseria meningitidis. AB - Neisseria meningitidis is a human pathogen. It is intensively studied for host pathogen interactions and vaccine development. However, its favorable growth properties, genetic accessibility, and small genome size also make it an excellent model organism for studying fundamental biological processes, such as outer membrane biogenesis. Indeed, the first component of the assembly machinery for outer-membrane proteins, the BAM complex, was identified in N. meningitidis. Here, we describe protocols to inactivate chromosomal genes and to express genes from a well-controlled promoter on a plasmid in N. meningitidis. Together, these protocols can be used, for example, to deplete cells from essential components of the BAM complex. We also describe a simple, gel-based assay to assess the proper functioning of the BAM complex in vivo. PMID- 26427675 TI - Heat Modifiability of Outer Membrane Proteins from Gram-Negative Bacteria. AB - beta-barrel membrane proteins are somewhat unique in that their folding states can be monitored using semi-native SDS-PAGE methods to determine if they are folded properly or not. This property, which is commonly referred to as heat modifiability, has been used for many years on both purified protein and on whole cells to monitor folded states of proteins of interest. Additionally, heat modifiability assays have proven indispensable in studying the BAM complex and its role in folding and inserting beta-barrel membrane proteins into the outer membrane. Here, we describe the protocol our lab uses for performing the heat modifiability assay in our studies on outer membrane proteins. PMID- 26427676 TI - The Role of a Destabilized Membrane for OMP Insertion. AB - Here we describe the procedures used in our laboratory for the in vitro investigation of the apparent folding kinetics as well as the folding efficiencies of outer membrane proteins (OMPs). Because microbial OMPs display a change in their gel migration upon folding, the usage of traditional gel electrophoresis is a standard method of folding analysis. Additional aspects of the method we detail herein include the preparation and storage of OMP stocks, the setup procedures for a folding reaction, and the analysis of fraction folded from scanned gel images. PMID- 26427677 TI - Treponema pallidum in Gel Microdroplets: A Method for Topological Analysis of BamA (TP0326) and Localization of Rare Outer Membrane Proteins. AB - The noncultivable spirochete Treponema pallidum subspecies pallidum (T. pallidum) is the etiological agent of venereal syphilis. In contrast to the outer membranes (OMs) of gram-negative bacteria, the OM of T. pallidum lacks lipopolysaccharide, contains a paucity of integral membrane proteins, and is extremely labile. The lability of the T. pallidum OM greatly hinders efforts to localize the bacterium's rare outer membrane proteins (OMPs). To circumvent this problem, we developed the gel microdroplet method in which treponemes are encapsulated in porous agarose beads and then probed with specific antibodies in the absence or presence of low concentrations of the non-ionic detergent Triton X-100. To demonstrate the general utility of this method for surface localization of any T. pallidum antigen, herein we describe a protocol for immunolabeling of encapsulated treponemes using antibodies directed against the beta-barrel and POTRA domains of TP0326, the spirochete's BamA ortholog. PMID- 26427678 TI - Analyzing the Role of Periplasmic Folding Factors in the Biogenesis of OMPs and Members of the Type V Secretion System. AB - The outer membrane (OM) of gram-negative bacteria is highly packed with OM proteins (OMPs) and the trafficking and assembly of OMPs in gram-negative bacteria is a subject of intense research. Structurally, OMPs vary in the number of beta-strands and in the size and complexity of extra-membrane domains, with extreme examples being the members of the type V protein secretion system (T5SS), such as the autotransporter (AT) and intimin/invasin families of secreted proteins, in which a large extracellular "passenger" domain is linked to a beta barrel that inserts in the OM. Despite their structural and functional diversity, OMPs interact in the periplasm with a relatively small set of protein chaperones that facilitate their transport from the inner membrane (IM) to the beta-barrel assembly machinery (BAM complex), preventing aggregation and assisting their folding in various aspects including disulfide bond formation. This chapter is focused on the periplasmic folding factors involved in the biogenesis of integral OMPs and members of T5SS in E. coli, which are used as a model system in this field. Background information on these periplasmic folding factors is provided along with genetic methods to generate conditional mutants that deplete these factors from E. coli and biochemical methods to analyze the folding, surface display, disulfide formation and oligomerization state of OMPs/T5SS in these mutants. PMID- 26427679 TI - An In Vitro Assay for Substrate Translocation by FhaC in Liposomes. AB - The two-partner secretion (TPS) pathway is used by gram-negative bacteria to secrete a large family of virulence exoproteins. Its name is derived from the fact that it involves two proteins, a secreted TpsA protein and a cognate TpsB transporter in the outer membrane. A typical TPS system is represented by the filamentous hemagglutinin FhaB (TpsA protein) and its transporter FhaC (TpsB protein) of Bordetella pertussis. Results from mutational analysis and heterologous expression experiments suggested that FhaC is essential for FhaB translocation across the outer membrane of bacteria. We have devised a cell-free biochemical assay to reconstitute in vitro the translocation of FhaB into reconstituted membrane vesicles. Thereby the clearest evidence has been provided that the single beta-barrel FhaC protein serves as the sole translocator to transport FhaB across the outer membrane. This is the first in vitro assay for protein secretion across the Escherichia coli outer membrane and the detailed protocol described here should be amenable to modifications and application to the analysis of related protein transport events occurring at the outer membranes of gram-negative bacteria. PMID- 26427680 TI - Measuring Cell-Cell Binding Using Flow-Cytometry. AB - Cell-cell adhesion mediates a number of competitive and cooperative microbial interactions. Fluorescence labeling and flow cytometry techniques allow us to observe and measure these interactions rapidly and easily. Here, we describe a method to quantify cell-cell adhesion events between two differentially labeled cell populations. PMID- 26427681 TI - Methods to Characterize Folding and Function of BamA Cross-Link Mutants. AB - The utility of protein engineering, both the mutation and deletion of specific amino acids, to investigate protein structure and function has been demonstrated time and time again, and intermolecular and intramolecular interactions within the BAM complex and its individual components are no exception. Extensive efforts have probed conserved and unique amino acid sequences of the Bam proteins to define their functional roles. This chapter summarizes efforts as applied to the disulfide cross-link mutants of BamA and describes experimental methods used in our studies to determine that lateral opening of the barrel domain is required for function. PMID- 26427682 TI - Small Angle X-ray Scattering (SAXS) Characterization of the POTRA Domains of BamA. AB - BamA is the central component of the BAM complex and contains a C-terminal beta barrel domain embedded in the outer membrane, and a soluble, periplasmic domain, made out of five polypeptide transport associated (POTRA) motifs. Structural characterization of the POTRA domains was carried out by a combination of crystallographic, NMR and solution Small Angle X-ray Scattering (SAXS) approaches. Despite its limited resolution, SAXS is an excellent complement to NMR and crystallography. It is well suited to validate high-resolution models in solution and is particularly useful to characterize flexible systems such as the POTRA domains of BamA. Here we present a protocol for sample preparation and discuss the considerations of SAXS data collection and quality control, which is applicable to most soluble proteins. PMID- 26427683 TI - Assessing the Outer Membrane Insertion and Folding of Multimeric Transmembrane beta-Barrel Proteins. AB - In addition to the cytoplasmic membrane, Gram-negative bacteria have a second lipid bilayer, the outer membrane, which is the de facto barrier between the cell and the extracellular milieu. Virtually all integral proteins of the outer membrane form beta-barrels, which are inserted into the outer membrane by the BAM complex. Some outer membrane proteins, like the porins and trimeric autotransporter adhesins, are multimeric. In the former case, the porin trimer consists of three individual beta-barrels, whereas in the latter, the single autotransporter beta-barrel domain is formed by three separate polypeptides. This chapter reviews methods to investigate the folding and membrane insertion of multimeric OMPs and further explains the use of a BamA depletion strain to study the effects of the BAM complex on multimeric OMPs in E. coli. PMID- 26427684 TI - The Expression, Purification, and Structure Determination of BamA from E. coli. AB - In gram-negative bacteria, assembly of outer membrane proteins requires the multicomponent beta-barrel assembly machinery (BAM) complex, of which BamA is an essential and evolutionarily conserved integral outer membrane protein. To understand how BamA facilitates outer membrane protein biogenesis, it is important to obtain sufficient amounts of purified recombinant BamA protein for in vitro functional analysis and structure determination. In this chapter, we describe the protocol that we used in our laboratory for the cloning, expression, and purification of E. coli BamA and its N-terminal deletion variants for in vitro functional studies and for structure determination of the beta-barrel domain alone (residues 426-810). PMID- 26427685 TI - Expression and Purification of the Individual Bam Components BamB-E. AB - BamB, BamC, BamD, and BamE are lipoproteins that, along with the integral membrane protein BamA, form the beta-barrel assembly machinery (BAM) complex in the outer-membrane of Gram-negative bacteria. Elucidating the roles that these lipoproteins play in the beta-barrel assembly process requires both structural and functional studies that rely on milligram quantities of pure protein. Here, we describe a simple protocol for expressing individual BamB-BamE proteins in Escherichia coli and purifying them by nickel affinity and size-exclusion chromatography. This protocol yields pure proteins in amounts that are sufficient for crystallization trials, in vitro protein-protein interaction studies, NMR, and other biochemical experiments. PMID- 26427686 TI - Structure Determination of the BAM Complex Accessory Lipoproteins BamB-E. AB - Outer membrane protein biogenesis is a fundamental and essential process in all Gram-negative bacteria. The key players conducting this process are organized in the beta-barrel assembly machinery (BAM) complex. This complex has recently attracted a lot of attention due to its importance in cell wall generation, maintenance, and the fascinating yet partially unknown mechanism. The currently best studied example is the BAM complex from E. coli which comprises five proteins, BamA-BamE, two of which, BamA and BamD, are essential for cell survival. Four of the complex proteins, BamB-BamE, are lipoproteins and are attached to the outer membrane via N-terminal lipid anchors. Two of them, BamB and BamD, comprise protein folds known to mediate protein-protein interactions through WD40 and TPR domains, respectively. Structures of BamB to BamE have been determined using X-ray crystallography, NMR and SAXS techniques. Details on protein preparation, crystallization, data acquisition, and determination of structures are given here along with the brief summary of the currently available structural Bam protein repertoire. PMID- 26427687 TI - An In Vitro Assay for Outer Membrane Protein Assembly by the BAM Complex. AB - To elucidate the mechanism of a biochemical process it is often essential to reconstitute the reaction in vitro using the minimal set of factors required to drive the reaction to completion. Here, we describe a method to reconstitute the folding and membrane integration of bacterial outer membrane (OM) proteins that have a characteristic beta-barrel structure. In this method the BAM complex, a heteroligomer that catalyzes the membrane integration of beta-barrel proteins, is first purified and inserted into small lipid vesicles. Denatured OM proteins are then assembled and integrated into the vesicles in the presence of a molecular chaperone called SurA. PMID- 26427688 TI - Identification of BamC on the Surface of E. coli. AB - In order to relate the structural architecture of the BAM complex to its function in outer membrane protein assembly, the arrangement of each component within the complex is vital. This chapter explores the structure and topology of BamC, using a range of biochemical techniques to probe the topology and surface exposure. PMID- 26427689 TI - Construction and Characterization of an E. coli bamD Depletion Strain. AB - The central Bam components BamA and BamD are both essential genes in E. coli, a fact that often confounds genetic analysis using classical methods. The isolation of "depletion strains" in which these genes can be conditionally expressed removes this obstacle and facilitates the in vivo characterization of Bam function. This chapter describes an efficient two-step recombineering method for the construction of such a depletion strain, which contains an arabinose inducible allele of bamD, using the lambda Red system. Additionally, a simple protocol is presented for the depletion of bamD expression in live cells, which is particularly useful for the characterization of mutant alleles of bamD (complementation analysis). In principle, the procedures described can be adapted to produce and characterize depletion strains for any essential gene in E. coli or any other bacterium that is similarly amenable to genome engineering. PMID- 26427690 TI - Expression, Purification, and Screening of BamE, a Component of the BAM Complex, for Structural Characterization. AB - In Gram-negative bacteria, integral outer membrane beta-barrel proteins (OMP) are assembled by the beta-barrel assembly machine complex, or BAM complex. This complex includes the essential components BamA, an OMP composed of a carboxyl terminal beta-barrel domain and five polypeptide transport-associated domains (POTRA), and the lipoprotein BamD. In Escherichia coli, the complex contains an additional three lipoproteins, BamB, C and E required for efficient delivery of OMPs to the outer membrane. Here we provide methods for production, isotope labeling, purification, and functional screening of BamE for research purposes. Purification strategies of both the soluble and wild-type membrane-tethered forms of BamE are described using techniques including osmotic shock, Ni-NTA purification, and size-exclusion chromatography. Functional screening using a simple plate assay is also described which allows screening for defects in outer membrane permeability. PMID- 26427691 TI - Purification and Bicelle Crystallization for Structure Determination of the E. coli Outer Membrane Protein TamA. AB - TamA is an Omp85 protein involved in autotransporter assembly in the outer membrane of Escherichia coli. It comprises a C-terminal 16-stranded transmembrane beta-barrel as well as three periplasmic POTRA domains, and is a challenging target for structure determination. Here, we present a method for crystal structure determination of TamA, including recombinant expression in E. coli, detergent extraction, chromatographic purification, and bicelle crystallization in combination with seeding. As a result, crystals in space group P21212 are obtained, which diffract to 2.3 A resolution. This protocol also serves as a template for structure determination of other outer membrane proteins, in particular of the Omp85 family. PMID- 26427692 TI - Strategies for the Analysis of Bam Recognition Motifs in Outer Membrane Proteins. AB - Well-structured proteins interact with other proteins through surface-surface interactions. In such cases, the residues that form the interacting surface are not necessarily neighboring residues on the level of protein sequence. In contrast, unfolded or partially unfolded proteins can interact with other proteins through defined linear motifs. In the case of the beta-barrel assembly machinery (BAM) in the outer membrane of Gram-negative bacteria, unfolded beta barrel proteins are recognized through a C-terminal linear motif, and are inserted into the membrane. While the exact mechanism of recognition is still under investigation, it has been shown that mutations in the recognition motif can partially or completely abolish membrane insertion. In this chapter, we demonstrate the workflow for motif discovery, motif extraction, and motif visualization on the example of the C-terminal motifs in transmembrane beta barrel proteins. PMID- 26427693 TI - Summary and Future Directions. AB - beta-barrel outer membrane proteins (OMPs) are found in the outer membranes (OMs) of all gram-negative bacteria, yet exactly how they are folded and inserted remains unknown. The last decade has provided a wealth of discovery including the identification of the BAM complex, a multicomponent complex responsible for the biogenesis of all OMPs into the OM. It is anticipated that the next decade will further advance our knowledge of how the BAM complex is able to perform its unique and interesting function. PMID- 26427694 TI - Evaluation of positive surgical margins in patients undergoing robot-assisted and open radical prostatectomy according to preoperative risk groups. AB - OBJECTIVES: Recent studies showed that robot-assisted radical prostatectomy (RARP) represents an oncologically safe procedure in patients with prostate cancer (PCa), where the rate of positive surgical margins (PSMs) might be lower in patients treated with RARP as compared with that of those undergoing the open approach (open RP [ORP]). The aim of this study is to analyze the rate of PSMs according to preoperative risk groups in a large cohort of patients treated with RARP and ORP in a single institution with standardized surgical technique and pathological examination. MATERIALS AND METHODS: We evaluated 6,194 consecutive patients with PCa undergoing either ORP (71.1%) or RARP (28.9%) between 1992 and 2014. Logistic regression analyses were used to test the association between type of surgery and PSMs in each preoperative risk group (low vs. intermediate vs. high) after adjusting for confounders. RESULTS: Overall, 21.6% patients had PSMs. RARP was associated with a lower rate of PSMs in low-risk (11.5 vs. 15.4%, P = 0.01), intermediate-risk (18.9 vs. 23.5%, P = 0.008), and high-risk patients (19.7 vs. 30.1%, P<0.001). In multivariable analyses, after stratification according to risk group categories, no difference in PSMs between RARP and ORP was observed for low-risk (odds ratio [OR] = 0.87, P = 0.46) and intermediate risk patients (OR = 0.84, P = 0.19). Conversely, RARP was associated with lower odds of PSMs in high-risk patients (OR = 0.69, P = 0.04). Similar results were observed when our analyses were repeated after accounting for pathological characteristics, in patients treated between 2006 and 2014 and in a cohort of men treated by high-volume surgeons (all P<= 0.03). CONCLUSIONS: The introduction of RARP at our institution led to a significant reduction in the risk of PSMs in patients with PCa with high-risk disease. PMID- 26427695 TI - Unemployment risk and income change after testicular cancer diagnosis: A population-based study. AB - BACKGROUND: Among patients with cancer, returning to full working may serve as an indicator for return to normal lifestyle following illness, as opposed to unemployment or shifting to part-time work. The aim of the project was to clarify the association between unemployment risk and decreased income at 4 years after the diagnosis of testicular cancer (TC). PARTICIPANTS AND METHODS: A case control in a cohort study includes baseline measurement of people participating in the Israeli Central Bureau of Statistics 1995 National Census, and follow-up until 2011. Cancer incidence, employment status, and income level were ascertained through the Israel Cancer Registry and Tax Authority, respectively. A matched group was sampled from the population in the census. Binary logistic regression analyses were used to assess odds ratios (ORs) for study's outcomes, while controlling for age, ethnicity, education, and socioeconomic and employment status at 2 years before diagnosis. RESULTS: A total of 113 cases of TC and 468 persons in the matched group were included in the study after excluding persons who died during the study period. No association was found between TC and subsequent risk after the 4 years of unemployment (OR = 1.12, 95% CI: 0.65-1.95) or decreased income (OR = 1.41, 95% CI: 0.84-2.36). Predictors of subsequent unemployment were unemployment 2 years before diagnosis (OR = 6.91, 95% CI: 4.39 10.86) and increasing age (OR = 1.03 per year, 95% CI: 1.01-1.06). CONCLUSION: TC survivorship is not associated with subsequent unemployment or decreased income at 4 years after diagnosis. PMID- 26427696 TI - Contemporary role of advanced imaging for bladder cancer staging. AB - Optimized pretreatment staging of bladder urothelial carcinoma is essential in guiding appropriate treatment. This staging process relies heavily on tissue pathology from transurethral resection of bladder tumor as well as imaging for diagnosis of local, regional, nodal, or distant visceral spread. Accurate preoperative staging is critical for appropriate treatment decision making and patient counseling as these are based on the extent of disease involvement, largely classifying the cancer as having local, regional, or distant spread. Currently, the gold standard of transurethral resection of bladder tumor followed by computed tomography imaging with intravenous contrast provides excellent staging specificity in cases of more advanced bladder cancers with suspicion of spread; however, this often under stages patients that can lead to adverse oncologic outcomes in these patients undergoing radical cystectomy. Incorporation of novel imaging modalities including multiparametric magnetic resonance imaging and positron emission tomography imaging have shown promise in improving accuracy of staging for both local and distant disease in patients with bladder urothelial carcinoma. PMID- 26427697 TI - The value of a rapid contrast-enhanced angio-MRI protocol in the detection of head and neck paragangliomas in SDHx mutations carriers: a retrospective study on behalf of the PGL.EVA investigators. AB - OBJECTIVES: To assess the performance of a simplified MRI protocol consisting of a contrast-enhanced three-dimensional MR angiography (CE-MRA) in association with a post-contrast T1-weighted sequence (T1WIV) for the detection of HNPGLs in SDHx mutation carriers. METHODS: This retrospective sub-study is based on the multicenter PGL.EVA cohort, which prospectively enrolled SDHx mutation carriers from 2005 to 2009; 157 index cases or relatives were included. CE-MRA and the T1WIV images were read solely with knowledge of the clinical data but blind to the diagnosis. Sensitivity, specificity and likelihood ratios for the simplified MRI protocol were compared to the full MRI protocol reading results and to the gold standard status obtained through the consensus of an expert committee. RESULTS: The sensitivity and specificity of the readings of the simplified MRI protocol were, respectively, 88.7 % (95 % CI = 78.1-95.3) and 93.7 % (95 % CI = 86.8-97.7) versus 80.7 % (95 % CI = 68.6-89.6) and 94.7 % (95 % CI = 88.1-98.3) for the readings of the full MRI protocol. CONCLUSIONS: The simplified post contrast MRI with shorter duration (5 to 10 minutes) showed no performance difference compared to the lengthy standard full MRI and can be proposed for the detection of head and neck paragangliomas (HNPGLs) in SDHx mutation carriers. KEY POINTS: * Rapid angio-MRI protocol and the usual lengthy protocol show equal diagnostic performance. * The CE-MRA is the key sequence for the detection of HNPGLs. * The T1WIV sequence assists in localizing HNPGLs. PMID- 26427698 TI - Diffusion-weighted magnetic resonance imaging of thymoma: ability of the Apparent Diffusion Coefficient in predicting the World Health Organization (WHO) classification and the Masaoka-Koga staging system and its prognostic significance on disease-free survival. AB - OBJECTIVES: To evaluate the usefulness of diffusion-weighted magnetic resonance for distinguishing thymomas according to WHO and Masaoka-Koga classifications and in predicting disease-free survival (DFS) by using the apparent diffusion coefficient (ADC). METHODS: Forty-one patients were grouped based on WHO (low risk vs. high-risk) and Masaoka-Koga (early vs. advanced) classifications. For prognosis, seven patients with recurrence at follow-up were grouped separately from healthy subjects. Differences on ADC levels between groups were tested using Student-t testing. Logistic regression models and areas under the ROC curve (AUROC) were estimated. RESULTS: Mean ADC values were different between groups of WHO (low-risk = 1.58 +/- 0.20 * 10(-3)mm(2)/sec; high-risk = 1.21 +/- 0.23 * 10( 3)mm(2)/sec; p < 0.0001) and Masaoka-Koga (early = 1.43 +/- 0.26 * 10( 3)mm(2)/sec; advanced = 1.31 +/- 0.31 * 10(-3)mm(2)/sec; p = 0.016) classifications. Mean ADC of type-B3 (1.05 +/- 0.17 * 10(-3)mm(2)/sec) was lower than type-B2 (1.32 +/- 0.20 * 10(-3)mm(2)/sec; p = 0.023). AUROC in discriminating groups was 0.864 for WHO classification (cut-point = 1.309 * 10( 3)mm(2)/sec; accuracy = 78.1 %) and 0.730 for Masaoka-Koga classification (cut point = 1.243 * 10(-3)mm(2)/sec; accuracy = 73.2 %). Logistic regression models and two-way ANOVA were significant for WHO classification (odds ratio[OR] = 0.93, p = 0.007; p < 0.001), but not for Masaoka-Koga classification (OR = 0.98, p = 0.31; p = 0.38). ADC levels were significantly associated with DFS recurrence rate being higher for patients with ADC <= 1.299 * 10(-3)mm(2)/sec (p = 0.001; AUROC, 0.834; accuracy = 78.0 %). CONCLUSIONS: ADC helps to differentiate high risk from low-risk thymomas and discriminates the more aggressive type-B3. Primary tumour ADC is a prognostic indicator of recurrence. KEY POINTS: * DW-MRI is useful in characterizing thymomas and in predicting disease-free survival. * ADC can differentiate low-risk from high-risk thymomas based on different histological composition * The cutoff-ADC-value of 1.309 * 10 (-3) mm (2) /sec is proposed as optimal cut-point for this differentiation * The ADC ability in predicting Masaoka-Koga stage is uncertain and needs further validations * ADC has prognostic value on disease-free survival and helps in stratification of risk. PMID- 26427699 TI - Safety and Clinical Effectiveness of Percutaneous Vertebroplasty in the Elderly (>=80 years). AB - PURPOSE: To evaluate the safety and clinical effectiveness of percutaneous vertebroplasty (PVP) in patients aged 80 and over. METHODS: One hundred and seventy-three patients (127 women, 46 men; mean age = 84.2y) underwent 201 PVP procedures (391 vertebrae) in our institution from June 2008 to March 2012. One hundred and twenty-six patients (73 %) had osteoporotic vertebral compression fractures (VCF), 36 (20.5 %) were treated for tumour lesions, and the remaining 11 (6.5 %) for lesions from another cause. Comorbidities and American Society of Anesthesiologists (ASA) scores were assessed before treatment. Periprocedural and delayed complications were systematically recorded. A qualitative scale was used to evaluate pain relief at 1-month follow-up, ranging from significant pain worsening to marked improvement or disappearance. New fracture occurrence was assessed on follow-up imaging. RESULTS: Forty-five percent of patients had pretreatment ASA class scores >=3. No major complication occurred. Pain was unchanged in 16.9 % of cases, mildly improved in 31.5 %, and disappeared in 47.8 %. We identified 27 (11 %) symptomatic new VCFs in patients with osteoporosis on follow-up imaging. The mean delay in diagnosis of new fractures was 5 +/- 8.7 months. CONCLUSIONS: Even in the elderly, PVP remains a safe and effective technique for pain relief, independently of the underlying disease. KEY POINTS: * Post-PVP pain improvement was observed in 79.3 % of elderly patients. * PVP remains a safe technique in elderly patients. * No decompensation of comorbidity was observed in our series. PMID- 26427700 TI - Protective effect against repeat adverse reactions to iodinated contrast medium: Premedication vs. changing the contrast medium. AB - OBJECTIVES: The purpose of this study was to assess the protective effect of premedication and changing contrast media (CM) against repeat adverse reactions (ARs) to iodinated CM. METHODS: Between January 2006 and September 2014, 771 cases with previous ARs to CM were administered CM. The same CM that had caused ARs previously was administered to 491 cases (220 without premedication [defined as the control group], and 271 with premedication [the premedication alone group]). A different CM from the previous CM was given to 280 cases (58 without premedication [the changing CM alone group], and 222 with premedication [the premedication and changing CM group]). RESULTS: The control group had 61 repeat ARs (27.7%). The premedication alone group had 47 ARs (17.3%, p<0.01). The changing CM alone group had 3 ARs (5.2%, p<0.001). Three ARs (7.9%) were observed in 38 cases changing from one to another low-osmolar nonionic CM. Twenty cases with previous ARs to the high-osmolar CM and to the low-osmolar ionic CM showed no ARs. The premedication and changing CM group had 6 ARs (2.7%, p<0.001). CONCLUSION: Premedication prior to contrast for patients with previous ARs may be protective, however, changing CM was more effective. KEY POINTS: * In patients with previous adverse reactions, changing contrast media is recommended. * Premedication is unnecessary against previous reactions to high-osmolar or ionic CM. * Changing from one to another low-osmolar non-ionic CM may be effective. PMID- 26427702 TI - Adenomyosis: A Clinical Review of a Challenging Gynecologic Condition. AB - Adenomyosis is a heterogenous gynecologic condition. Patients with adenomyosis can have a range of clinical presentations. The most common presentation of adenomyosis is heavy menstrual bleeding and dysmenorrhea; however, patients can also be asymptomatic. Currently, there are no standard diagnostic imaging criteria, and choosing the optimal treatment for patients is challenging. Women with adenomyosis often have other associated gynecologic conditions such as endometriosis or leiomyomas, therefore making the diagnosis and evaluating response to treatment challenging. The objective of this review was to highlight current clinical information regarding the epidemiology, risk factors, pathogenesis, clinical manifestations, diagnosis, imaging findings, and treatment of adenomyosis. Several studies support the theory that adenomyosis results from invasion of the endometrium into the myometrium, causing alterations in the junctional zone. These changes are commonly seen on imaging studies such as transvaginal ultrasound (TVUS) and magnetic resonance imaging (MRI). The second most common theory is that adenomyosis results from embryologic-misplaced pluripotent mullerian remnants. Traditionally, adenomyosis was only diagnosed after hysterectomy; however, studies have shown that a diagnosis can be made with biopsies at hysteroscopy and laparoscopy. Noninvasive imaging can be used to help guide the differential diagnosis. The most common findings on 2-dimensional/3 dimensional TVUS and MRI are reviewed. Two-dimensional TVUS and MRI have a respectable sensitivity and specificity; however, recent studies indicate that 3 dimensional TVUS is superior to 2-dimensional TVUS for the diagnosis of adenomyosis and may allow for the diagnosis of early-stage disease. Management options for adenomyosis, both medical and surgical, are reviewed. Currently, the only definitive management option for patients is hysterectomy. PMID- 26427701 TI - Cholangiocarcinoma: from molecular biology to treatment. AB - Cholangiocarcinoma is a rare tumor originating in the bile ducts, which, according to their anatomical location, is classified as intrahepatic, extrahepatic and hilar. Nevertheless, incidence rates have increased markedly in recent decades. With respect to tumor biology, several genetic alterations correlated with resistance to chemotherapy and radiotherapy have been identified. Here, we highlight changes in KRAS and TP53 genes that are normally associated with a more aggressive phenotype. Also IL-6 and some proteins of the BCL-2 family appear to be involved in the resistance that the cholangiocarcinoma presents toward conventional therapies. With regard to diagnosis, tumor markers most commonly used are CEA and CA 19-9, and although its use isolated appears controversial, their combined value has been increasingly advocated. In imaging terms, various methods are needed, such as abdominal ultrasound, computed tomography and cholangiopancreatography. Regarding therapy, surgical modalities are the only ones that offer chance of cure; however, due to late diagnosis, most patients cannot take advantage of them. Thus, the majority of patients are directed to other therapeutic modalities like chemotherapy, which, in this context, assumes a purely palliative role. Thus, it becomes urgent to investigate new therapeutic options for this highly aggressive type of tumor. PMID- 26427703 TI - Impact of Laparoscopic Surgical Management of Deep Endometriosis on Pregnancy Rate. AB - STUDY OBJECTIVE: To evaluate the impact of laparoscopic excision of lesions on deep endometriosis-related infertility. DESIGN: Retrospective study. SETTING: Endometriosis tertiary referral center (Canadian Task Force II-2). PATIENTS: A group of 115 patients who had undergone laparoscopic surgery for infertility with histologic confirmation of deep endometriosis. INTERVENTIONS: Patient medical records and operative reports were reviewed. Telephone interviews were conducted for long-term follow-up of fertility outcomes. MEASUREMENTS AND MAIN RESULTS: Evaluation of fertility outcome after laparoscopic treatment of deep endometriosis by spontaneous conception and by assisted reproductive technology (ART) correlated with lesion number, size, and location (anterior, posterolateral, pouch of Douglas, and multiple locations). After a mean follow-up of 22 months the overall pregnancy rate was 54.78% (n = 63) with a live-birth rate of 42.6% (n = 49). Among those patients given the chance to conceive spontaneously (n = 70), the overall pregnancy rate was 60% (n = 42): 38.5% (n = 27) spontaneously and 21.4% (n = 15) by ART. The removal of multiple lesions was associated with a higher pregnancy rate after surgery. When comparing isolated lesion size and disease location, there was no difference in pregnancy rate. Furthermore, those patients who underwent surgical eradication of the disease for the first time had a higher pregnancy rate (odds ratio, 4.18). CONCLUSION: This study demonstrates that laparoscopic excision of deep endometriosis enhances pregnancy rate, by both spontaneous conception and ART. First surgical treatment of multiple lesions was associated with higher pregnancy rates, whereas isolated lesions influenced the pregnancy rate irrespective of their location and size. PMID- 26427704 TI - Efficient passage of human pluripotent stem cells on spider silk matrices under xeno-free conditions. AB - Human pluripotent stem cells (hPSCs) hold great promise for applications in regenerative medicine and pharmaceutical development. Such applications require cell culture methods and reagents that are chemically defined, xeno-free, scalable, and low-cost. Herein, we describe non-mechanical passaging of hPSCs on spider silk films under chemically defined and xeno-free conditions. The cells were dissociated into single cells or small aggregates using Accutase or enzyme free dissociation buffer and then passaged to spider silk films, where they expanded in monolayers until they covered the surface. Cells cultured over 10 passages on spider silk film remained karyotypically normal and pluripotent. In conclusion, a novel method for passaging dissociated hPSCs under conditions that are compatible with clinical applications is presented. The method is cost efficient and may be useful for both research and clinical applications. PMID- 26427705 TI - One-day front-loading with four doses of rabeprazole followed by a standard twice daily regimen provides sufficient acid inhibition in extensive metabolizers of CYP2C19. AB - BACKGROUND: Four times daily dosing (qid) with a proton pump inhibitor can cause rapid increase in intragastric pH. We investigated the efficacy of the front loading with rabeprazole 10 mg qid on a subsequent regimen with rabeprazole 10 mg twice daily (bid) for 7 days in extensive metabolizers (EMs) of CYP2C19. METHODS: Five EMs received three different 1-week regimens in a crossover manner as follows: (1) rabeprazole 10 mg bid for 7 days; (2) a front-loading regimen of rabeprazole (rabeprazole 10 mg qid on day 0 and bid on days 1 to 7); and (3) rabeprazole 10 mg qid for 7 days. Five intermediate metabolizers (IMs) and four poor metabolizers (PMs) received rabeprazole 10 mg bid regimen only. Twenty-four hour intragastric pH-monitorings were performed on days 1, 4, and 7. Area under the intragastric pH-time curves (AUCs) from days 1 to 7 was calculated using 24-h median intragastric pHs on days 1, 4, and 7. RESULTS: Twenty-four-hour intragastric pHs in the front-loading group on days 1, 4, and 7 were 5.1, 4.9, and 5.1, respectively. The median AUC with front-loading in EMs (34.4, pH.day) was significantly higher than that in EMs with rabeprazole 10 mg bid (30.74, p = 0.043). No statistically significant differences in median AUCs were noted among front-loading in EMs, rabeprazole 10 mg qid in EMs (37.2), rabeprazole 10 mg bid in IMs (37.3), and PMs (39.4). CONCLUSIONS: The one-day front-loading regimen of rabeprazole 10 mg qid provided sufficient acid inhibition for 7 days, even in CYP2C19 EMs. PMID- 26427706 TI - Luteolin induces caspase-14-mediated terminal differentiation in human epidermal keratinocytes. AB - Recent studies have demonstrated the role of caspase-14 in terminally differentiated keratinocytes, and its expression may decrease the magnitude of tumors in the epidermis. In the present study, we assessed the potential of luteolin (LUT) to elicit the expression of caspase-14 in terminal differentiation of human keratinocytes. The semi-qualitative RT-PCR data revealed a significant level of caspase-14 expression in LUT-treated human immortalized keratinocytes (HaCaT) with respect to untreated cells. The quantitative data (ELISA) further supported the potency of LUT to induce caspase-14 expression at 3.19 ng/ml when compared to 1.29 ng/ml of vitamin D3 (positive control). Further, the enhanced expression of human involucrin gene in LUT-treated HaCaT cells confirmed its ability to drive terminal differentiation in these cells. These preliminary results provide first-hand information about the in vitro potential of LUT to elicit the expression of caspase-14, thereby inducing terminal differentiation in human keratinocytes. PMID- 26427707 TI - Erratum to: Maintenance of bladder urothelia integrity and successful urothelialization of various tissue-engineered mesenchymes in vitro. PMID- 26427708 TI - The primary culture of carp (Cyprinus carpio) macrophages and the verification of its phagocytosis activity. AB - This study establishes the primary culture method for red carp (Cyprinus carpio) macrophages in vitro and lays the foundation for further research in the fish immune system. The healthy adult red carp was chosen, and mechanical separation and cell adherent culture methods were used to isolate the primary macrophages. Compared to the traditional method of Percoll discontinuous density gradient isolation, the protocol we reported here makes cell isolation steps more concise and obtains more healthy cells with high macrophage purity. The cells were uniform in size with a clearly visible nucleus. Trypan blue staining and non radioactive cell proliferation assay were used to detect the cell survival rate. Further, we provide optimum culture conditions which include cell density (1 * 10(7) cells/mL), culture medium (Leibovitz's L-15), pH (7.2-7.4), temperature (26 degrees C), and adherent time (24 h). Macrophages have been identified by nonspecific esterase and Wright-Giemsa staining and have shown to grow very well. In addition, the macrophages have a very strong bactericidal activity against three kinds of bacteria, further verifying good growth conditions and proper function. PMID- 26427709 TI - The Wolbachia WO bacteriophage proteome in the Aedes albopictus C/wStr1 cell line: evidence for lytic activity? AB - Wolbachia pipientis (Rickettsiales), an obligate intracellular alphaproteobacterium in insects, manipulates host reproduction to maximize invasion of uninfected insect populations. Modification of host population structure has potential applications for control of pest species, particularly if Wolbachia can be maintained, manipulated, and genetically engineered in vitro. Although Wolbachia maintains an obligate mutualism with genome stability in nematodes, arthropods can be co-infected with distinct Wolbachia strains, and horizontal gene transfer between strains is potentially mediated by WO phages encoded within Wolbachia genomes. Proteomic analysis of a robust, persistent infection of a mosquito cell line with wStr from the planthopper, Laodelphax striatellus, revealed expression of a full array of WO phage genes, as well as nine of ten non-phage genes that occur between two distinct clusters of WOMelB genes in the genome of wMel, which infects Drosophila melanogaster. These non phage genes encode potential host-adaptive proteins and are expressed in wStr at higher levels than phage structural proteins. A subset of seven of the non-phage genes is flanked by highly conserved non-coding sequences, including a putative promoter element, that are not present in a syntenically arranged array of homologs in plasmids from three tick-associated Rickettsia spp. These studies expand our understanding of wStr in a host cell line derived from the mosquito, Aedes albopictus, and provide a basis for investigating conditions that favor the lytic phase of the WO phage life cycle and recovery of infectious phage particles. PMID- 26427710 TI - Development of primary cell cultures using hemocytes and phagocytic tissue cells of Locusta migratoria: an application for locust immunity studies. AB - Insect cell cultures played central roles in unraveling many insect physiological and immunological processes. Regardless, despite imminent needs, insect cell lines were developed primarily from Dipteran and Lepidopteran orders, leaving many important insects such as Orthopteran locusts under-represented. Besides the lack of cell lines, the slow progress in development of in vitro techniques is attributed to poor communications between different laboratories regarding optimized primary cell cultures. Therefore, we report here about methods developed for primary cell culture of Locusta migratoria hemocyte and phagocytic tissue cells by which we could maintain viable hemocytes in vitro for over 5 d and phagocytic tissue cells for over 12 d. 2-Mercaptoethanol and phenyl-thiourea supplements in Grace's medium together with addition of fetal bovine serum 30 min after cell seeding resulted in a successful setup of the primary cell cultures and a week-long survival of the hemocytes and phagocytic tissue cells in vitro. PMID- 26427711 TI - Anticancer effect of rapamycin on MCF-7 via downregulation of VEGF expression. AB - The importance of mTOR signaling in tumor biology is widely accepted and a number of agents that selectively target mTOR are being developed in cancer therapy. On the other hand, it has been demonstrated that mTOR can act as an angiogenic agent. Thus, we hypothesized that the mTOR inhibitor-induced anticancer effect is affected by expression of a key angiogenic factor, vascular endothelial growth factor (VEGF) and investigated the anticancer effect underlying mTOR using an in vitro assay. The mTOR inhibitor rapamycin dose-dependently reduced the cell viability of the breast cancer cell line, MCF-7, but did not reduce the cell viability of the colon cancer cell line, HT-29. Rapamycin reduced the VEGF expression in the culture medium of MCF-7, while rapamycin did not contribute VEGF expression in the culture medium of HT-29. VEGF stimulated cell viability and VEGF inhibition reduced cell viability of MCF-7, and rapamycin dose dependently restored the cell viability of MCF-7 reduced by rapamycin. These findings suggest that mTOR acts as a direct anticancer agent and that the mTOR inhibitor-induced anticancer effect involved the reduced expression of VEGF in MCF-7. Our results imply that mTOR regulates the expression of VEGF and is involved in breast cancer progression. PMID- 26427712 TI - Staurosporine induces chondrogenesis of chick embryo wing bud mesenchyme in monolayer cultures through canonical and non-canonical TGF-beta pathways. AB - Staurosporine has been known to induce chondrogenesis in monolayer cultures of mesenchymal cells by dissolving actin stress fibers. The aim of this study was to further elucidate how the alteration of actin filaments by staurosporine induces chondrogenesis. Specifically, we examined whether the transforming growth factor (TGF)-beta pathway is implicated. SB505124 strongly suppressed staurosporine induced chondrogenesis without affecting the drug's action on the actin cytoskeleton. Staurosporine increased the phosphorylation of TGF-beta receptor I (TbetaRI) but had no significant effect on the expression levels of TGF-beta1, TGF-beta2, TGF-beta3, TbetaRI, TbetaRII, and TbetaRIII. Phosphorylation of Smad2 and Smad3 was not increased by staurosporine. However, SB505124 almost completely suppressed the phosphorylation of Smad2 and Smad3. In addition, inhibition of Smad3 blocked staurosporine-induced chondrogenesis. Inhibition of Akt, p38 mitogen-activated protein kinase (MAPK), and c-jun N-terminal kinase (JNK) suppressed chondrogenesis induced by staurosporine. Phosphorylation of Akt, p38 MAPK, and JNK was increased by staurosporine. SB505124 reduced the phosphorylation of Akt and p38 MAPK, while it had no effect on the phosphorylation of JNK. The phosphorylation level of extracellular signal regulated kinase (ERK) was not significantly affected by staurosporine. In addition, inhibition of ERK with PD98059 alone did not induce chondrogenesis. Taken together, these results suggest that staurosporine induces chondrogenesis through TGF-beta pathways including canonical Smads and non-canonical Akt and p38 MAPK signaling. PMID- 26427714 TI - Glutaminase 1 is a potential biomarker for chronic post-surgical pain in the rat dorsal spinal cord using differential proteomics. AB - Chronic post-surgical pain (CPSP) is a normal and significant symptom in clinical surgery, such as breast operation, biliary tract operation, cesarean operation, uterectomy and thoracic operation. Severe chronic post-surgical pain could increase post-surgical complications, including myocardial ischemia, respiratory insufficiency, pneumonia and thromboembolism. However, the underlying mechanism is still unknown. Herein, a rat CPSP model was produced via thoracotomy. After surgery, in an initial study, 5 out of 12 rats after surgery showed a significant decrease in mechanical withdrawal threshold and/or increase in the number of acetone-evoked responses, and therefore classified as the CPSP group. The remaining seven animals were classified as non-CPSP. Subsequently, open-chest operation was performed on another 30 rats and divided into CPSP and non-CPSP groups after 21-day observation. Protein expression levels in the dorsal spinal cord tissue were determined by 12.5 % SDS-PAGE. Finally, differently expressed proteins were identified by LC MS/MS and analyzed by MASCOT software, followed by Gene Ontology cluster analysis using PANTHER software. Compared with the non-CPSP group, 24 proteins were only expressed in the CPSP group and another 23 proteins expressed differentially between CPSP and non-CPSP group. Western blot further confirmed that the expression of glutaminase 1 (GLS1) was significantly higher in the CPSP than in the non-CPSP group. This study provided a new strategy to identify the spinal proteins, which may contribute to the development of chronic pain using differential proteomics, and suggested that GLS1 may serve as a potential biomarker for CPSP. PMID- 26427713 TI - In vitro differentiation process of human Wharton's jelly mesenchymal stem cells to male germ cells in the presence of gonadal and non-gonadal conditioned media with retinoic acid. AB - Human umbilical Wharton's jelly-derived mesenchymal stem cells (HWJMSCs) are the best candidate to get plentiful stem cells and differentiate them to germ cells under appropriate conditions to treat infertility. We sought to determine under which conditions HWJMSCs could form male germ cells in vitro. So, HWJMSCs were differentiated to male germ cells under a mixture of bone morphogenetic protein-4 (BMP-4) and testicular and placental culture condition (TCC and PCC) medium followed by retinoic acid for 21 d. In the present study, the HWJMSCs were obtained from Wharton's jelly of umbilical cords of male neonates delivered by cesarean section. At the third passage, mesenchymal stem cell markers and differentiation to osteocytes and adipocytes were investigated. Then, HWJMSCs were induced to differentiate into male germ cells in the presence of BMP-4, all trans retinoic acid, PCC, and TCC for 21 d. The profile of c-Kit, DDX4, Piwil2, and Dazl gene expression was evaluated by qPCR and ICC. Data was analyzed by ANOVA test. After 3 wk of treatment with different reagents, the morphology of these spindle-like cells changed to shiny clusters and germ cell-specific markers in mRNA were upregulated in both TCC + retinoic acid (RA) and BMP-4 + RA. Induction of HWJMSCs with TCC in the presence of RA resulted in significant upregulation (P <= 0.05) of all germ cell-specific genes (c-Kit 2.6795 +/- 0.75, DDX4 4.3188 +/- 1.18, Piwil2 4.9962 +/- 1.55, Dazl 6.1199 +/- 0.78) compared to control and PCC + RA. Our results indicated that TCC and RA are involved in human germ cell development. Moreover, BMP signaling also induced differentiation. Our findings provide a novel effective approach for generation of germ cells in vitro and studying the interaction of germ cells with their niche. Our work represents an essential step toward gaining knowledge of the molecular properties of HWJMSCs in the field of cell therapy. We demonstrated that under a suitable situation, HWJMSCs have the ability to differentiate into germ cells and this provides an excellent pattern to study infertility cause and cure. PMID- 26427716 TI - Direct conversion of astrocytes into neuronal cells by drug cocktail. PMID- 26427718 TI - One-Step Conversion of Methyl Ketones to Acyl Chlorides. AB - Treatment of aromatic and heteroaromatic methyl ketones with sulfur monochloride and catalytic amounts of pyridine in refluxing chlorobenzene leads to the formation of acyl chlorides. Both electron-rich and electron-poor aryl methyl ketones can be used as starting materials. The resulting C1-byproduct depends on the precise reaction conditions chosen. PMID- 26427717 TI - Implication of cell-in-cell structures in the transmission of HIV to epithelial cells. PMID- 26427715 TI - MSX2 mediates entry of human pluripotent stem cells into mesendoderm by simultaneously suppressing SOX2 and activating NODAL signaling. AB - How BMP signaling integrates into and destabilizes the pluripotency circuitry of human pluripotent stem cells (hPSCs) to initiate differentiation into individual germ layers is a long-standing puzzle. Here we report muscle segment homeobox 2 (MSX2), a homeobox transcription factor of msh family, as a direct target gene of BMP signaling and a master mediator of hPSCs' differentiation to mesendoderm. Enforced expression of MSX2 suffices to abolish pluripotency and induce directed mesendoderm differentiation of hPSCs, while MSX2 depletion impairs mesendoderm induction. MSX2 is a direct target gene of the BMP pathway in hPSCs, and can be synergistically activated by Wnt signals via LEF1 during mesendoderm induction. Furthermore, MSX2 destabilizes the pluripotency circuitry through direct binding to the SOX2 promoter and repression of SOX2 transcription, while MSX2 controls mesendoderm lineage commitment by simultaneous suppression of SOX2 and induction of NODAL expression through direct binding and activation of the Nodal promoter. Interestingly, SOX2 can promote the degradation of MSX2 protein, suggesting a mutual antagonism between the two lineage-specifying factors in the control of stem cell fate. Together, our findings reveal crucial new mechanisms of destabilizing pluripotency and directing lineage commitment in hPSCs. PMID- 26427719 TI - Cost and Cost-Effectiveness of Students for Nutrition and eXercise (SNaX). AB - OBJECTIVE: To examine the cost and cost-effectiveness of implementing Students for Nutrition and eXercise (SNaX), a 5-week middle school-based obesity prevention intervention combining school-wide environmental changes, multimedia, encouragement to eat healthy school cafeteria foods, and peer-led education. METHODS: Five intervention and 5 control middle schools (mean enrollment, 1520 students) from the Los Angeles Unified School District participated in a randomized controlled trial of SNaX. Acquisition costs for materials and time and wage data for employees involved in implementing the program were used to estimate fixed and variable costs. Cost-effectiveness was determined using the ratio of variable costs to program efficacy outcomes. RESULTS: The costs of implementing the program over 5 weeks were $5433.26 per school in fixed costs and $2.11 per student in variable costs, equaling a total cost of $8637.17 per school, or $0.23 per student per day. This investment yielded significant increases in the proportion of students served fruit and lunch and a significant decrease in the proportion of students buying snacks. The cost-effectiveness of the program, per student over 5 weeks, was $1.20 per additional fruit served during meals, $8.43 per additional full-priced lunch served, $2.11 per additional reduced-price/free lunch served, and $1.69 per reduction in snacks sold. CONCLUSIONS: SNaX demonstrated the feasibility and cost-effectiveness of a middle school-based obesity-prevention intervention combining school-wide environmental changes, multimedia, encouragement to eat healthy school cafeteria foods, and peer-led education. Its cost is modest and unlikely to be a significant barrier to adoption for many schools considering its implementation. PMID- 26427721 TI - Evaluating the Validity of a Two-stage Sample in a Birth Cohort Established from Administrative Databases. AB - BACKGROUND: When using administrative databases for epidemiologic research, a subsample of subjects can be interviewed, eliciting information on undocumented confounders. This article presents a thorough investigation of the validity of a two-stage sample encompassing an assessment of nonparticipation and quantification of the extent of bias. METHODS: Established through record linkage of administrative databases, the Quebec Birth Cohort on Immunity and Health (n = 81,496) aims to study the association between Bacillus Calmette-Guerin vaccination and asthma. Among 76,623 subjects classified in four Bacillus Calmette-Guerin-asthma strata, a two-stage sampling strategy with a balanced design was used to randomly select individuals for interviews. We compared stratum-specific sociodemographic characteristics and healthcare utilization of stage 2 participants (n = 1,643) with those of eligible nonparticipants (n = 74,980) and nonrespondents (n = 3,157). We used logistic regression to determine whether participation varied across strata according to these characteristics. The effect of nonparticipation was described by the relative odds ratio (ROR = ORparticipants/ORsource population) for the association between sociodemographic characteristics and asthma. RESULTS: Parental age at childbirth, area of residence, family income, and healthcare utilization were comparable between groups. Participants were slightly more likely to be women and have a mother born in Quebec. Participation did not vary across strata by sex, parental birthplace, or material and social deprivation. Estimates were not biased by nonparticipation; most RORs were below one and bias never exceeded 20%. CONCLUSIONS: Our analyses evaluate and provide a detailed demonstration of the validity of a two-stage sample for researchers assembling similar research infrastructures. PMID- 26427722 TI - Re: Ambient Air Pollution and Early Manifestation of Type 1 Diabetes. PMID- 26427720 TI - Transcriptional Regulation of Cytosolic Sulfotransferase 1C2 by Intermediates of the Cholesterol Biosynthetic Pathway in Primary Cultured Rat Hepatocytes. AB - Cytosolic sulfotransferase 1C2 (SULT1C2) is expressed in the kidney, stomach, and liver of rats; however, the mechanisms regulating expression of this enzyme are not known. We evaluated transcriptional regulation of SULT1C2 by mevalonate (MVA) derived intermediates in primary cultured rat hepatocytes using several cholesterol synthesis inhibitors. Blocking production of mevalonate with the 3 hydroxy-3-methylglutaryl-CoA reductase inhibitor pravastatin (30 MUM), reduced SULT1C2 mRNA content by ~40% whereas the squalene synthase inhibitor squalestatin (SQ1, 0.1 MUM), which causes accumulation of nonsterol isoprenoids, increased mRNA content by 4-fold. Treatment with MVA (10 mM) strongly induced SULT1C2 mRNA by 12-fold, and this effect was blocked by inhibiting squalene epoxidase but not by more distal cholesterol inhibitors, indicating the effects of MVA are mediated by postsqualene metabolites. Using rapid amplification of cDNA ends (RACE), we characterized the 5' end of SULT1C2 mRNA and used this information to generate constructs for promoter analysis. SQ1 and MVA increased reporter activity by ~1.6 and 3-fold, respectively, from a construct beginning 49 base pairs (bp) upstream from the longest 5'-RACE product (-3140:-49). Sequence deletions from this construct revealed a hepatocyte nuclear factor 1 (HNF1) element (-2558), and mutation of this element reduced basal (75%) and MVA-induced (30%) reporter activity and attenuated promoter activation following overexpression of HNF1alpha or 1beta. However, the effects of SQ1 were localized to a more proximal promoter region (-281:-49). Collectively, our findings demonstrate that cholesterol biosynthetic intermediates influence SULT1C2 expression in rat primary hepatocytes. Further, HNF1 appears to play an important role in mediating basal and MVA-induced SULT1C2 transcription. PMID- 26427723 TI - Quantifying Protection Against Influenza Virus Infection Measured by Hemagglutination-inhibition Assays in Vaccine Trials. AB - BACKGROUND: Correlations between hemagglutination-inhibition titers (hereafter "titers") and protection against infection have been identified in historical studies. However, limited information is available about the dynamics of how titer influences protection. METHODS: Titers were measured in randomized, placebo controlled vaccine trials in Hong Kong among pediatrics during September 2009 December 2010 and the United States among adults during Oct 2007-April 2008. Intermediate unobserved titers were imputed using three interpolation methods. As participants were recruited at different times leading to varying exposure to infection relative to entry, a modified proportional hazards model was developed to account for staggered entry into the studies and to quantify the correlation of titers with protection against influenza infections, adjusting for waning in titers. The model was fitted using Markov chain Monte Carlo and importance sampling. RESULTS: A titer of 1:40 was associated with a reduced infection risk of 40%-70% relative to a titer of 1:10, depending on the circulating strain; the corresponding protection associated with a titer of 1:80 was 54%-84%. Results were robust across interpolation methods. The trivalent-inactivated vaccine reduced cumulative incidence of influenza B and influenza A(H3N2) infections by six percentage points (pp; 95% credible interval = 2 pp, 10 pp) and 1 pp (95% credible interval = 0.3 pp, 2 pp) respectively, but not for influenza A(H1N1)pdm09. The live-attenuated vaccine showed little efficacy against influenza A(H3N2) infections. CONCLUSIONS: Titers are correlated with protection against influenza infections. The trivalent inactivated vaccine can reduce the risk of influenza A(H3N2) and influenza B infections in the community. PMID- 26427724 TI - Maternal Leisure Time Physical Activity and Infant Birth Size. AB - BACKGROUND: Associations of maternal leisure time physical activity with birth size are inconsistent. Roles of infant sex and maternal prepregnancy body mass index (BMI) in these associations have not been studied. METHODS: Participants (N = 3,310) in the Omega study, a cohort in Washington State (1996-2008), reported leisure time physical activity duration and energy expenditure in the year prepregnancy and in early pregnancy (mean 15 weeks gestation). Regression models estimated mean differences in infant head circumference, birthweight, and ponderal index (birthweight/length) across quartiles of pre- or early-pregnancy leisure time physical activity. We assessed effect modification by infant sex or prepregnancy overweight/obese status (BMI >= 25 kg/m). RESULTS: We observed positive associations between prepregnancy leisure time physical activity and head circumference overall and among male infants. Among males, each quartile increase in prepregnancy physical activity duration was associated with 0.14 cm (95% confidence interval = 0.046, 0.24; trend P = 0.004) greater head circumference. We did not observe associations between leisure time physical activity and birthweight or ponderal index overall. Each quartile increase in pre or early-pregnancy physical activity duration was associated with 17-23 g lower birthweight among female infants and among women with normal prepregnancy BMI. CONCLUSIONS: We observed positive associations between prepregnancy leisure time physical activity and head circumference among male infants, and inverse associations of pre- and early-pregnancy physical activity with birthweight among female infants and women with normal prepregnancy BMI. Future studies should confirm results and elucidate mechanisms of observed associations. PMID- 26427726 TI - European regulation of continuing professional development won't improve quality of care. PMID- 26427725 TI - Interpreting Seroepidemiologic Studies of Influenza in a Context of Nonbracketing Sera. AB - BACKGROUND: In influenza epidemiology, analysis of paired sera collected from people before and after influenza seasons has been used for decades to study the cumulative incidence of influenza virus infections in populations. However, interpretation becomes challenging when sera are collected after the start or before the end of an epidemic, and do not neatly bracket the epidemic. METHODS: Serum samples were collected longitudinally in a community-based study. Most participants provided their first serum after the start of circulation of influenza A(H1N1)pdm09 virus in 2009. We developed a Bayesian hierarchical model to correct for nonbracketing sera and estimate the cumulative incidence of infection from the serological data and surveillance data in Hong Kong. RESULTS: We analyzed 4,843 sera from 2,097 unvaccinated participants in the study, collected from April 2009 to December 2010. After accounting for nonbracketing, we estimated that the cumulative incidence of H1N1pdm09 virus infection was 45% (95% credible interval [CI] = 40%, 49%), 17% (95% CI = 13%, 20%), and 11% (95% CI = 6%, 18%) for children ages 0-18 years, adults 19-50 years, and older adults >50 years, respectively. Including all available data substantially increased precision compared with a simpler analysis based only on sera collected at 6 month intervals in a subset of participants. CONCLUSIONS: We developed a framework for the analysis of antibody titers that accounted for the timing of sera collection with respect to influenza activity and permitted robust estimation of the cumulative incidence of infection during an epidemic. PMID- 26427727 TI - Telomere dynamics in patients with del (5q) MDS before and under treatment with lenalidomide. AB - Myelodysplastic syndrome (MDS) associated with an acquired, isolated deletion of chromosome 5q (del (5q) MDS), represent a clonal disorder of hematopoiesis and a clinically distinct entity of MDS. Treatment of del (5q) MDS with the drug lenalidomide has significantly improved quality of life leading to transfusion independence and complete cytogenetic response rates (CCR) in the majority of patients. Telomeres are located at the end of eukaryotic chromosomes and are linked to replicative history/potential as well as genetic (in) stability of hematopoietic stem cells. Here, we analyzed telomere length (TL) dynamics before and under lenalidomide treatment in the peripheral blood and/or bone marrow of del (5q) patients enrolled in the LEMON-5 study (NCT01081431). Hematopoietic cells from del (5q) MDS patients were characterized by significantly shortened TL compared to age-matched healthy controls. Telomere loss was more accelerated in patients with longer disease duration (>2 years) and more pronounced cytopenias. Sequential analysis under lenalidomide treatment revealed that previously shortened TL in peripheral blood cells was significantly "elongated" towards normal levels within the first six months suggesting a shift from clonal del (5q) cells towards normal hematopoiesis in lenalidomide treated MDS patients. Taken together our findings suggest that the development of the del (5q) clone is associated with accelerated telomere shortening at diagnosis. However, upon induction of CCR and reoccurrence of normal hematopoiesis, the lack of a persistent TL deficit argues against telomere-mediated genetic instability neither as a disease-promoting event of del (5q) MDS nor for lenalidomide mediated development of secondary primary malignancies of the hematopoietic system in responding patients. PMID- 26427728 TI - Comparison of immune manifestations between refractory cytopenia of childhood and aplastic anemia in children: A single-center retrospective study. AB - This retrospective single-center study assessed the incidence and clinical features of immune manifestations of refractory cytopenia of childhood (RCC) and childhood aplastic anemia (AA). We evaluated 72 children with RCC and 123 with AA between February 2008 and March 2013. RCC was associated with autoimmune disease in 4 children, including 1 case each with autoimmune hemolytic anemia, rheumatoid arthritis, systemic lupus erythematosus, and anaphylactoid purpura. No children with AA were diagnosed with autoimmune diseases. Immune abnormalities were common in both RCC and AA; the most significant reductions were in the relative numbers of CD3-CD56+ subsets found in RCC. Despite the many similar immunologic abnormalities in AA and RCC, the rate of autoimmune disease was significantly lower in childhood AA than RCC (p=0.008, chi2=6.976). The relative numbers of natural killer cells were significantly lower in RCC patients than AA patients. By month 6, there was no significant difference in autoimmune manifestations between RCC and AA in relation to the response to immunosuppressive therapy (p=0.907, chi2=0.014). The large overlap of analogous immunologic abnormalities indicates that RCC and childhood AA may share the same pathogenesis. PMID- 26427729 TI - Secondary acute lymphoblastic leukemia is an independent predictor of poor prognosis. AB - Compared to secondary acute myeloid leukemia, secondary acute lymphoblastic leukemia (sALL) is poorly characterized. We utilized data from the Surveillance, Epidemiology, and End Results (SEER) 13 database to further elucidate patient characteristics and prognostic factors in sALL. Cases of adult de novo acute lymphoblastic leukemia (ALL) and sALL in patients with primary breast, rectum, cervix, or ovarian cancers or lymphoma with a latency period of at least 12 months were identified within the SEER 13 database. Survival in sALL and de novo ALL were compared after propensity matching based on age, gender, race, ALL subtype, and year of diagnosis. 4124 cases of de novo ALL and 79 cases of sALL were identified. sALL patients were older at diagnosis (median 62 years vs. 44 years; p<0.01). Overall survival (OS) in sALL was lower than de novo ALL (median 8 months vs. 11 months), 1 year OS: 35% vs. 47% (p=0.05), 2 year OS: 16% vs. 31% (p<0.01), and 5 year OS: 7% vs. 21% (p<0.01). Multivariate analysis revealed sALL as an independent predictor of worsened survival (adjusted HR 1.54; 95% CI 1.16 2.04, p<0.01) after propensity matching. PMID- 26427730 TI - Quantitative PCR for the diagnosis of cutaneous leishmaniasis from formalin-fixed and paraffin-embedded skin sections. AB - The present report describes a real-time PCR-based procedure to reliably determine the quantity of Leishmania amastigotes in relation to the amount of host tissue in histological skin sections from canine and equine cases of cutaneous leishmaniasis. The novel diagnostic Leishmania-PCR has a detection limit of <0.02 amastigotes per MUg tissue, which corresponds well to the detection limit of immunohistochemistry and is far beyond that of conventional histology. Our results emphasise the importance of PCR to complement routine histology of cutaneous leishmaniasis cases, particularly in laboratories in which no immunohistochemical assay is available. PMID- 26427731 TI - Developmental expression of Kir4.1 in astrocytes and oligodendrocytes of rat somatosensory cortex and hippocampus. AB - Kir4.1 is the principal K(+) channel expressed in glial cells. It has been shown that it plays a fundamental role in K(+)-spatial buffering, an astrocyte-specific process where excess extracellular concentration of K(+) ions, generated by synaptic activity, is spatially redistributed to distant sites via astrocytic syncytia. Experimental and clinical evidence suggested that abnormality of Kir4.1 function in the brain is involved in different neurological diseases such as epilepsy, dysmyelination, and Huntington's disease. Although it has been shown that Kir4.1 is expressed predominantly in astrocytes in certain areas of the rat brain and its transcript is present in the rat forebrain as early as embryonic day E14, no information is available concerning the temporal sequence of Kir4.1 protein appearance during embryonic and post-natal development. Aim of this work was to study the expression pattern of Kir4.1 channel in rat somatosensory cortex and hippocampus during development and to examine its cellular localization with the glial and oligodendroglial markers S100-beta, GFAP, and Olig-2. Kir4.1 protein was detected since E20 and a gradual increase of Kir4.1 expression occurred between early postnatal period and adulthood. We showed a gradual shift in Kir4.1 subcellular localization from the soma of astrocytes to distal glial processes. Double immunofluorescence experiments confirmed the cellular localization of Kir4.1 in glial cells. Our data provide the first overview of Kir4.1 developmental expression both in the cortex and hippocampus and support the glial role of Kir4.1 in K(+) spatial buffering. PMID- 26427732 TI - Interaction between Pseudomonas aeruginosa and dermatophyte fungi: Repercussions on the clinical course and microbiological diagnosis of tinea pedis. PMID- 26427733 TI - New Information Technologies in Dermatology Education: Dermaconsulta--a Virtual Patient Tool. PMID- 26427734 TI - Neutrophilic Dermatoses Associated With Autoimmunity. PMID- 26427735 TI - Why Is Mohs Micrographic Surgery Underused in the Treatment of Dermatofibrosarcoma Protuberans in Children? PMID- 26427736 TI - Comment on "Hidradenitis Suppurativa: New Opportunities for an Orphan Skin Disease". PMID- 26427737 TI - Usefulness of Photodynamic Therapy in the Management of Onychomycosis. AB - Onychomycosis, or fungal infection of the nails, is one of the most prevalent fungal diseases in the general population. Treatment is of limited effectiveness, tedious, and must be administered for long periods. Furthermore, systemic antifungal agents are associated with adverse effects. Photodynamic therapy (PDT) may prove to be a viable alternative in the treatment of superficial skin infections, including onychomycosis. We review articles relating to the usefulness of PDT in onychomycosis in both in vitro and in vivo settings and discuss the potential and limitations of various photosensitizing agents. In vivo, methylene blue and 5-aminolevulinic acid have led to cure rates in 80% and 43% of cases, respectively, at 12 months. Finally, based on data in the literature and our own experience, we propose a protocol of 3 PDT sessions, separated by an interval of 1 or 2 weeks, using methyl aminolevulinate 16% as a photosensitizing agent and red light (lambda=630 nm, 37 J.cm(-2)). Each session is preceded by the topical application of urea 40% over several days. Clinical trials are needed to optimize PDT protocols and to identify those patients who will benefit most from this treatment. PMID- 26427738 TI - Aging and Parkinson's disease as functional models of temporal order perception. AB - OBJECTIVE: Our study evaluates how aging and Parkinson's disease (PD) alter temporal order judgment (TOJ). METHOD: Two TOJ experiments were performed with young participants, healthy elderly participants, and PD patients. Two white squares were presented on opposite sides of a screen and participants responded which appeared first. In Experiment 1, it was assessed how accurately each group could judge temporal order at intervals from 0ms to 167ms. Detectability, the capacity of detecting which stimulus appeared first, was measured. In Experiment 2, participants were asked to orient their attention to the hemifield indicated by a cue. The PSS ("point of subjective simultaneity"), where the participant was equally likely to respond that either stimulus appeared first, was measured. RESULTS: In Experiment 1, PD patients had smaller detectability than healthy elderly (p<0.05) and young participants (p<0.001), and healthy elderly participants had smaller detectability than young participants (p<0.001). In Experiment 2, PSS was 29ms for young participants, 121ms for healthy elderly participants, and 283ms for PD patients; differences were statistically significant for comparisons between PD patients and healthy elderly participants (p<0.001), PD patients and young participants (p<0.001), and healthy elderly and young participants (p<0.04). CONCLUSIONS: TOJ is impaired by aging and PD. Our results suggest that dopamine loss increases latency and variability in visual decision making due to a lower signal-to-noise ratio in the visual pathways. PMID- 26427739 TI - Synaesthetic interactions across vision and audition. AB - In everyday life our senses are exposed to a constant influx of sensory signals. The brain binds signals into a coherent percept based on temporal, spatial or semantic correspondences. In addition, synaesthetic correspondences may form important cues for multisensory binding. This study focussed on the synaesthetic correspondences between auditory pitch and visual size. While high pitch has been associated with small objects in static contexts, recent research has surprisingly found that increasing size is linked with rising pitch. The current study presented participants with small/large visual circles/discs together with high/low pitched pure tones in an intersensory selective attention paradigm. Whilst fixating a central cross participants discriminated between small and large visual size in the visual modality or between high and low pitch in the auditory modality. Across a series of five experiments, we observed convergent evidence that participants associated small visual size with low pitch and large visual size with high pitch. In other words, we observed the pitch-size mapping that has previously been observed only for dynamic contexts. We suggest that these contradictory findings may emerge because participants can interpret visual size as an index of permanent object size or distance (e.g. in motion) from the observer. Moreover, the pitch-size mapping may depend not only on relative but also on the absolute levels of pitch and size of the presented stimuli. PMID- 26427740 TI - Measurement of Load Redistribution Properties of Wheelchair Cushions Using a Compliant Cushion Loading Indenter. AB - The aim of this project was to develop and validate a compliant cushion loading indenter (CCLI) capable of evaluating wheelchair cushion performance by measuring internal pressures and deflection. The design of the CCLI consists of 3 subsystems: 1) an internal substructure with medial and lateral protuberances to mimic the load-bearing ischial tuberosities and trochanters, 2) an elastomeric shell to mimic soft tissue and 3) instrumentation to measure internal pressures at both protuberances and deflection of the elastomer at 7 locations. It is parametrically designed so can be scaled larger or smaller to represent different body sizes. To assess the repeatability and sensitivity of measurements, the model was loaded onto two wheelchair cushions, 3" flat foam and Jay3, using two loads, 44kgf and 53kgf, representing the average upper body mass of 70kg and 83kg persons, respectively. The results showed a high precision of pressure and deflection measurement across two different cushions and loads. Under both loads, pressure measurements exhibited a standard error of < 1 mm and <3 mmHg. The standard deviations of deflection values were less than 2.5 mm (0.1 in.). The pressures and absolute deflection differed significantly across load and cushion type indicating sensitivity to change. PMID- 26427741 TI - Automatic Adjustment of Keyboard Settings Can Enhance Typing. AB - We developed and evaluated a software tool for the automatic configuration of Windows keyboard settings. The software is intended to accommodate the needs of people with physical impairments, with a goal of improved productivity and comfort during typing. The prototype software, called AutoIDA, monitors user activity during performance of regular computer tasks and recommends the Sticky Keys and key repeat settings to meet the user's specific needs. The evaluation study included fourteen individuals with upper extremity impairments. AutoIDA recommended changes to the default keyboard settings for 10 of the 14 participants. For these individuals, average typing speed was essentially the same whether users typed with the default keyboard settings (5.5 wpm) or the AutoIDA-recommended settings (5.3 wpm). Average typing errors decreased with use of the recommended settings, from 17.6% to 13.3%, but this was not quite statistically significant (p = .10). On an individual basis, four participants appeared to improve their overall typing performance with AutoIDA-recommended settings. For more specific metrics, AutoIDA prevented about 90% of inadvertent key repeats (with a revised algorithm) and increased the efficiency and accuracy of entering modified (shifted) characters. Participants agreed that software like AutoIDA would be useful to them (average rating 4.1, where 5 = strongly agree). PMID- 26427743 TI - A Low-Cost Audio Prescription Labeling System Using RFID for Thai Visually Impaired People. AB - This research aims to develop a low-cost audio prescription labeling (APL) system for visually-impaired people by using the RFID system. The developed APL system includes the APL machine and APL software. The APL machine is for visually impaired people while APL software allows caregivers to record all important information into the APL machine. The main objective of the development of the APL machine is to reduce costs and size by designing all of the electronic devices to fit into one print circuit board. Also, it is designed so that it is easy to use and can become an electronic aid for daily living. The developed APL software is based on Java and MySQL, both of which can operate on various operating platforms and are easy to develop as commercial software. The developed APL system was first evaluated by 5 experts. The APL system was also evaluated by 50 actual visually-impaired people (30 elders and 20 blind individuals) and 20 caregivers, pharmacists and nurses. After using the APL system, evaluations were carried out, and it can be concluded from the evaluation results that this proposed APL system can be effectively used for helping visually-impaired people in terms of self-medication. PMID- 26427744 TI - Usability of a Low-Cost Head Tracking Computer Access Method following Stroke. AB - Assistive technology devices for computer access can facilitate social reintegration and promote independence for people who have had a stroke. This work describes the exploration of the usefulness and acceptability of a new computer access device called the NouseTM (Nose-as-mouse). The device uses standard webcam and video recognition algorithms to map the movement of the user's nose to a computer cursor, thereby allowing hands-free computer operation. Ten participants receiving in- or outpatient stroke rehabilitation completed a series of standardized and everyday computer tasks using the NouseTM and then completed a device usability questionnaire. Task completion rates were high (90%) for computer activities only in the absence of time constraints. Most of the participants were satisfied with ease of use (70%) and liked using the NouseTM (60%), indicating they could resume most of their usual computer activities apart from word-processing using the device. The findings suggest that hands-free computer access devices like the NouseTM may be an option for people who experience upper motor impairment caused by stroke and are highly motivated to resume personal computing. More research is necessary to further evaluate the effectiveness of this technology, especially in relation to other computer access assistive technology devices. PMID- 26427745 TI - Design of a Braille Learning Application for Visually Impaired Students in Bangladesh. AB - Visually impaired students (VIS) are unable to get visual information, which has made their learning process complicated. This paper discusses the overall situation of VIS in Bangladesh and identifies major challenges that they are facing in getting education. The Braille system is followed to educate blind students in Bangladesh. However, lack of Braille based educational resources and technological solutions have made the learning process lengthy and complicated for VIS. As a developing country, Bangladesh cannot afford for the costly Braille related technological tools for VIS. Therefore, a mobile phone based Braille application, "mBRAILLE", for Android platform is designed to provide an easy Braille learning technology for VIS in Bangladesh. The proposed design is evaluated by experts in assistive technology for students with disabilities, and advanced learners of Braille. The application aims to provide a Bangla and English Braille learning platform for VIS. In this paper, we depict iterative (participatory) design of the application along with a preliminary evaluation with 5 blind subjects, and 1 sighted and 2 blind experts. The results show that the design scored an overall satisfaction level of 4.53 out of 5 by all respondents, indicating that our design is ready for the next step of development. PMID- 26427746 TI - Design and Evaluation of the Kinect-Wheelchair Interface Controlled (KWIC) Smart Wheelchair for Pediatric Powered Mobility Training. AB - BACKGROUND: Children with severe disabilities are sometimes unable to access powered mobility training. Thus, we developed the Kinect-Wheelchair Interface Controlled (KWIC) smart wheelchair trainer that converts a manual wheelchair into a powered wheelchair. The KWIC Trainer uses computer vision to create a virtual tether with adaptive shared-control between the wheelchair and a therapist during training. It also includes a mixed-reality video game system. METHODS: We performed a year-long usability study of the KWIC Trainer at a local clinic, soliciting qualitative and quantitative feedback on the device after extended use. RESULTS: Eight therapists used the KWIC Trainer for over 50 hours with 8 different children. Two of the children obtained their own powered wheelchair as a result of the training. The therapists indicated the device allowed them to provide mobility training for more children than would have been possible with a demo wheelchair, and they found use of the device to be as safe as or safer than conventional training. They viewed the shared control algorithm as counter productive because it made it difficult for the child to discern when he or she was controlling the chair. They were enthusiastic about the video game integration for increasing motivation and engagement during training. They emphasized the need for additional access methods for controlling the device. CONCLUSION: The therapists confirmed that the KWIC Trainer is a useful tool for increasing access to powered mobility training and for engaging children during training sessions. However, some improvements would enhance its applicability for routine clinical use. PMID- 26427747 TI - Rare adverse events due to house dust mite sublingual immunotherapy in pediatric practice: two case reports. AB - Sublingual route, a noninjective way of allergen administration appears to be associated with a lower incidence of severe systemic reactions compared with the subcutaneous route. Local adverse reactions are reported which resolve spontaneously within a few days without need for discontinuation of treatment. Hereby, we report two pediatric cases, one with persistent asthma and the other one with persistent allergic rhinitis. Both were treated by house dust mite sublingual immunotherapy, one of whom developed severe wheezing (grade 2 systemic reaction based on World Allergy Organization subcutaneous systemic reaction grading system) and the other intractable vomiting (grade 3 local reaction based on World Allergy Organization sublingual immunotherapy local adverse events grading system) at the end of the build-up phase which repeated on re administration of the same dose. Both of those two cases completed their 3-year immunotherapy successfully by patient-based adjustment of the highest tolerated dose of the maintenance. PMID- 26427748 TI - Adhesive Nanoparticles as Local Probes of Membrane Curvature. AB - Biological and biomimetic membranes display complex shapes with nonuniform curvature. Because the interaction of adhesive nanoparticles with such membranes depends on the local membrane curvature, different segments of the same membrane can differ in their engulfment behavior. For a single vesicle in contact with many nanoparticles, we predict ten distinct engulfment patterns as well as morphological transitions between these patterns, which are directly accessible to experiment. PMID- 26427749 TI - Transcriptomic Responses During Early Development Following Arsenic Exposure in Western Clawed Frogs, Silurana tropicalis. AB - Arsenic compounds are widespread environmental contaminants and exposure elicits serious health issues, including early developmental anomalies. Depending on the oxidation state, the intermediates of arsenic metabolism interfere with a range of subcellular events, but the fundamental molecular events that lead to speciation-dependent arsenic toxicity are not fully elucidated. This study therefore assesses the impact of arsenic exposure on early development by measuring speciation and gene expression profiles in the developing Western clawed frog (Silurana tropicalis) larvae following the environmental relevant 0.5 and 1 ppm arsenate exposure. Using HPLC-ICP-MS, arsenate, dimethylarsenic acid, arsenobetaine, arsenocholine, and tetramethylarsonium ion were detected. Microarray and pathway analyses were utilized to characterize the comprehensive transcriptomic responses to arsenic exposure. Clustering analysis of expression data showed distinct gene expression patterns in arsenate treated groups when compared with the control. Pathway enrichment revealed common biological themes enriched in both treatments, including cell signal transduction, cell survival, and developmental pathways. Moreover, the 0.5 ppm exposure led to the enrichment of pathways and biological processes involved in arsenic intake or efflux, as well as histone remodeling. These compensatory responses are hypothesized to be responsible for maintaining an in-body arsenic level comparable to control animals. With no appreciable changes observed in malformation and mortality between control and exposed larvae, this is the first study to suggest that the underlying transcriptomic regulations related to signal transduction, cell survival, developmental pathways, and histone remodeling may contribute to maintaining ongoing development while coping with the potential arsenic toxicity in S. tropicalis during early development. PMID- 26427750 TI - Anti-inflammatory strategies in the treatment of schizophrenia. AB - Schizophrenia is a major mental illness with a lifetime prevalence of about 1%. Antipsychotic drugs, with a primary mechanism of action that involves dopamine receptor blockade, are the mainstay in the treatment of the disorder. However, despite optimum antipsychotic treatment, few patients return to pre-morbid levels; the treatment deficit includes refractory positive symptoms, negative symptoms, mood impairments, cognitive impairments, social impairments, and/or a variety of medication-related adverse effects, including extrapyramidal symptoms, metabolic disturbances, hyperprolactinemia, and others. To address these, antipsychotic treatment has been augmented with psychosocial interventions, cognitive rehabilitation, different kinds of electrical and magnetic brain stimulation, and a large range of drugs from the neuropsychiatric as well as, surprise, the general medical pharmacopeia. The pleomorphic pathophysiology of schizophrenia includes abnormalities in immunological and inflammatory pathways, and so it is not surprising that anti-inflammatory drugs have also been trialed as augmentation agents in schizophrenia. This article critically examines the outcomes after augmentation with conventional anti-inflammatory interventions; results from randomized controlled trials do not encourage the use of either aspirin (1000 mg/day) or celecoxib (400 mg/day), both of which have been studied for this indication during the past decade and a half. PMID- 26427752 TI - Erratum to: Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer. PMID- 26427754 TI - Editorial: preventing disease progression in Crohn's--can we shut the stable door before the horse bolts? PMID- 26427753 TI - Self-reported care needs of Dutch homeless people with and without a suspected intellectual disability: a 1.5-year follow-up study. AB - Cognitive impairment is a prevalent problem among the homeless and seems related to more psychosocial problems. However, little is known about the care needs of the subgroup of homeless people with an intellectual disability compared to those without an intellectual disability and how their care needs develop over time. This study explores self-reported care needs within a broad range of life domains among Dutch homeless people with and without a suspected intellectual disability to gain insight into the transition of self-reported care needs from baseline to follow-up in both subgroups. This longitudinal study is part of a cohort study among homeless people who had been accepted for an individual programme plan in four major Dutch cities. The initial cohort consisted of 513 participants who were interviewed in 2011. At 1.5-year follow-up, 336 participants (65.5%) were also interviewed and screened for intellectual disability. Of these participants, 31% (95% CI 26.2-36.1) had a suspected intellectual disability. For both groups, between baseline and follow-up, the number of 'unmet care needs' decreased significantly and the number of 'no care needs' increased significantly, while at follow-up, participants with a suspected intellectual disability reported 'no care needs' on significantly fewer life domains than those without a suspected intellectual disability (mean numbers 16.4 vs. 17.5). Between baseline and follow up, 'met care needs' decreased significantly on housing for both groups, and increased on finances and dental care for participants with a suspected intellectual disability. At follow-up, participants with a suspected intellectual disability more often preferred housing support available by appointment than those without a suspected intellectual disability. These findings suggest that homeless people who had been accepted for an individual programme plan with a suspected intellectual disability have care needs for a longer period of time than those without a suspected intellectual disability. Providing care to homeless people with a suspected intellectual disability might require ongoing care and support, also after exiting homelessness. Support services should take this into account when considering their care provision and planning of services. PMID- 26427755 TI - Letter: infliximab therapy for patients with inflammatory bowel disease--some unanswered questions. PMID- 26427756 TI - Letter: infliximab therapy for patients with inflammatory bowel disease--some unanswered questions. Authors' reply. PMID- 26427757 TI - Corrigendum. AB - In the paper 'Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn's disease' published in Volume 42, Issue 2 (July 2015), an error was found on page 2, column 1 last paragraph-the unit used for the concentration is incorrect. It should be 1-10 MUg/mL instead of 1-10 ng/mL. The sentence should read 'After reaching peak concentrations, vedolizumab serum concentrations fell in a generally biexponential fashion until concentrations reached approximately 1-10 MUg/mL'.The authors apologise for this error. PMID- 26427758 TI - cIAP2 supports viability of mice lacking cIAP1 and XIAP. PMID- 26427759 TI - Response to Heard et al. PMID- 26427760 TI - The inner membrane histidine kinase EnvZ senses osmolality via helix-coil transitions in the cytoplasm. PMID- 26427761 TI - Identification of the Substrate Access Portal of 5-Lipoxygenase. AB - The overproduction of inflammatory lipid mediators derived from arachidonic acid contributes to asthma and cardiovascular diseases, among other pathologies. Consequently, the enzyme that initiates the synthesis of pro-inflammatory leukotrienes, 5-lipoxygenase (5-LOX), is a target for drug design. The crystal structure of 5-LOX revealed a fully encapsulated active site; thus the point of substrate entry is not known. We asked whether a structural motif, a "cork" present in 5-LOX but absent in other mammalian lipoxygenases, might be ejected to allow substrate access. Our results indicate that reduction of cork volume facilitates access to the active site. However, if cork entry into the site is obstructed, enzyme activity is significantly compromised. The results support a model in which the "cork" that shields the active site in the absence of substrate serves as the active site portal, but the "corking" amino acid Phe-177 plays a critical role in providing a fully functional active site. Thus, the more appropriate metaphor for this structural motif is a "twist-and-pour" cap. Additional mutagenesis data are consistent with a role for His-600, deep in the elongated cavity, in positioning the substrate for catalysis. PMID- 26427762 TI - Influence of developmental nicotine exposure on the ventilatory and metabolic response to hyperthermia. AB - To determine whether developmental nicotine exposure (DNE) alters the ventilatory and metabolic response to hyperthermia in neonatal rats (postnatal age 2-4 days), pregnant dams were exposed to nicotine (6 mg kg(-1) of nicotine tartrate daily) or saline with an osmotic mini-pump implanted subdermally on day 5 of gestation. Rat pups (a total of 72 controls and 72 DNE pups) were studied under thermoneutral conditions (chamber temperature 33 degrees C) and during moderate thermal stress (37.5 degrees C). In all pups, core temperature was similar to chamber temperature, with no treatment effects. The rates of pulmonary ventilation (V(I)), O2 consumption (V(O2)) and CO2 production (V(CO2)) did not change with hyperthermia in either control or DNE pups. However, V(I) was lower in DNE pups at both chamber temperatures, whereas the duration of spontaneous apnoeas was longer in DNE pups than in controls at 33 degrees C. The V(I)/V(O2) ratio increased at 37.5 degrees C in control pups, although it did not change in DNE pups. To simulate severe thermal stress, additional pups were studied at 33 degrees C and 43 degrees C. V(I) increased with heating in control pups but not in DNE pups. As heat stress continued, gasping was evoked in both groups, with no effect of DNE on the gasping pattern. Over a 20 min recovery period at 33 degrees C, V(I) returned to baseline in control pups but remained depressed in DNE pups. In addition to altering baseline V(I) and apnoea duration, DNE is associated with subtle but significant alterations in the ventilatory response to hyperthermia in neonatal rats. PMID- 26427763 TI - Role of aberrant IgG glycosylation in the pathogenesis of inflammatory bowel disease. AB - The intestine is one of the most important organs associated with the immune system. It is thought that disruption of intestinal immunity causes inflammatory bowel disease (IBD). Recent advances in immune glycobiology have provided novel insights into many human diseases. For example, studies of glycosylation remodeling in mice have underscored the importance of oligosaccharides in the pathogenesis of IBD. Furthermore, aberrant glycosylation of IgG is a good serum marker of IBD activity. In this review, we examine current understanding of the role of aberrant glycosylation in the pathogenesis of IBD in terms of our original data and recent reports. PMID- 26427764 TI - Teatime Threats. Choking Incidents at the Evening Meal. AB - PURPOSE: To explore caregiver perceptions of the socio-environmental issues around evening meal ('teatime') which influence choking. Mealtime difficulties for people with intellectual disabilities and/or mental illness may be underdiagnosed. Difficulties affect quality of life with social aspects impacting on service-users and caregivers. Reporting of choking incidents has increased locally following widespread training. Analysis of reports showed most incidents were occurring around evening meal. METHODOLOGY: A qualitative study of caregivers witnessing a choking incident was undertaken. Semi-structured interviews explored perceptions of the causes. Data were analysed using thematic analysis. FINDINGS: Thematic analysis elicited individual service user characteristics, and social and contextual factors implicated in choking. The findings will facilitate risk assessment for service-users and inform mealtime practice. Staff familiarity is a key factor. Further research involving service users is indicated to complement these findings. This study widens the focus of recent studies which have considered physical more than socio-environmental aspects of mealtime difficulties. PMID- 26427765 TI - Neuropsychological correlates of Pisa syndrome in patients with Parkinson's disease. AB - BACKGROUND: A complex relationship exists between postural control and cognition in the elderly. Namely, neural mechanisms that are required for the regulation of posture have been variably associated with cognitive dysfunctions. Parkinson's disease (PD) is the second most common neurodegenerative disease among the elderly, and it has been associated with both cognitive and postural abnormalities such as Pisa syndrome (PS). Although its onset has been considered to be multifactorial, the pathophysiological mechanisms underpinning PS are still not fully explained. Until now, no study investigated the possible contribution of cognitive dysfunction to occurrence of PS in PD. PATIENTS AND METHODS: Twenty PD patients with PS and 20 PD patients without PS were enrolled. All patients with PD underwent neuropsychological battery to assess behavioural disturbances, memory, attention, frontal/executive and visuospatial functions. RESULTS: The two groups did not differ on demographic features, age at PD onset and disease duration, whereas they significantly differed on UPDRS-Part III, and levodopa equivalent daily dose (LEDD). MANCOVA with above-mentioned clinical variable as covariates revealed significant differences on tasks tapping verbal long-term memory, and attentional and visuoperceptual abilities between groups. The binary logistic regression revealed that higher LEDD and lower performance on visuospatial task (Benton Judgment of Lines Orientation test) significantly predicted occurrence of PS. CONCLUSION: Our results revealed a significant association of PS with altered attention and visuoperceptual functions in PD, suggesting that the occurrence of PS may be associated with alteration of both frontal-striatal systems and posterior cortical areas. PMID- 26427766 TI - The anti-dermatophyte activity of Commiphora molmol. AB - CONTEXT: Commiphora molmol Engl (Burseraceae) or myrrh has been traditionally used for the treatment of skin fungal infections. OBJECTIVE: This study evaluates the antifungal activity of myrrh ethanol extract and essential oil against skin dermatophytes. MATERIALS AND METHODS: The antifungal evaluations were performed by the food poisoning technique (250 ppm) and micro-broth dilution assay (800 6.25 ug/mL) against Trichophyton rubrum, T. mentagrophytes, Microsporum canis, M. gypseum, and T. verrucosum. The chemical composition of myrrh oil and ethanol extract was analyzed by GC and GC-MS. RESULTS: Furanoeudesma 1,3-diene and menthofuran were the main components of myrrh oil, while 2-tert-butyl-1,4 naphthoquinone, benzenemethanol,3-methoxy-alpha-phenyl, and curzerene were the main components of myrrh ethanol extract. The inhibitory effect of myrrh oil and ethanol extract against dermatophytes were 43.1-61.6% and 12.5-27.5%, respectively. The MIC and MFC values of myrrh oil were 25-100 and 25-200 ug/mL while these amounts for ethanol extract were 25-400 and 25-400 ug/mL, respectively. Therefore, myrrh oil had higher antifungal activity than that of the ethanol extract. Both extracts showed good anti-elastase activity. CONCLUSION: The results of our investigation confirmed the traditional uses of C. molmol as a poultice for the treatment of cutaneous fungal infections. PMID- 26427767 TI - Striking Differences in Properties of Geometric Isomers of [Ir(tpy)(ppy)H](+): Experimental and Computational Studies of their Hydricities, Interaction with CO2, and Photochemistry. AB - We prepared two geometric isomers of [Ir(tpy)(ppy)H](+), previously proposed as a key intermediate in the photochemical reduction of CO2 to CO, and characterized their notably different ground- and excited-state interactions with CO2 and their hydricities using experimental and computational methods. Only one isomer, C trans-[Ir(tpy)(ppy)H](+), reacts with CO2 to generate the formato complex in the ground state, consistent with its calculated hydricity. Under photocatalytic conditions in CH3CN/TEOA, a common reactive C-trans-[Ir(tpy)(ppy)](0) species, irrespective of the starting isomer or monodentate ligand (such as hydride or Cl), reacts with CO2 and produces CO with the same catalytic efficiency. PMID- 26427769 TI - Functional Properties of Soybean and Processed Soy Foods Ingredients. PMID- 26427770 TI - Feasibility of intercostal blood flow measurement by echo-Doppler technique in healthy subjects. AB - Intercostal artery blood flow supplies the external and internal intercostal muscles, which are inspiratory and expiratory muscles. Intercostal blood flow measured by the echo-Doppler (ED) technique has not previously been reported in humans. This study describes the feasibility of this measurement during free and loaded breathing in healthy subjects. Systolic, diastolic and mean blood flows were measured in the eighth dorsal intercostal space during free and loaded breathing using the ED technique. Flows were calculated as the product of the artery intraluminal surface and blood velocity. Ten healthy subjects (42 +/- 13.6 years) were included. Integrated electromyogram (iEMG), arterial pressure, cardiac frequency and breathing pattern were also recorded. Mean blood flows were 3.5 +/- 1.2 ml min-1 at rest, 6 +/- 2.6 ml min-1 while breathing through a combined inspiratory and expiratory resistance and 4.0 +/- 1.3 ml min-1 1 min after unloading. Diastolic blood flow was about one-third the systolic blood flow. The changes in blood flows were consistent with those in iEMG. No change in mean blood flow was observed between inspiration and expiration, suggesting a balance in the perfusion of external and internal muscles during breathing. In conclusion, ED is a feasible technique for non-invasive, real-time measurement of intercostal blood flow in humans. In healthy subjects, mean blood flow appeared tightly matched to iEMG activity. This technique may provide a way to assess the vascular adaptations induced by diseases in which respiratory work is increased or cardiac blood flow altered. PMID- 26427771 TI - User-Friendly Platinum Catalysts for the Highly Stereoselective Hydrosilylation of Alkynes and Alkenes. AB - With a view to addressing the shortcomings of traditional catalysts, a new generation of outstanding N-heterocyclic carbene platinum(0) complexes for the hydrosilylation of unsaturated carbon-carbon bonds is reported. Their discovery and application to the stereoselective addition of various silanes to silylated alkynes, terminal acetylenes, and olefins is presented. Insights into the catalytic cycle and the origin of the stereoselectivity are also discussed. PMID- 26427772 TI - The Development of Faculty in Dental Education. PMID- 26427773 TI - New Dental Accreditation Standard on Critical Thinking: A Call for Learning Models, Outcomes, Assessments. AB - This opinion article applauds the recent introduction of a new dental accreditation standard addressing critical thinking and problem-solving, but expresses a need for additional means for dental schools to demonstrate they are meeting the new standard because articulated outcomes, learning models, and assessments of competence are still being developed. Validated, research-based learning models are needed to define reference points against which schools can design and assess the education they provide to their students. This article presents one possible learning model for this purpose and calls for national experts from within and outside dental education to develop models that will help schools define outcomes and assess performance in educating their students to become practitioners who are effective critical thinkers and problem-solvers. PMID- 26427774 TI - Social Media in the Dental School Environment, Part A: Benefits, Challenges, and Recommendations for Use. AB - Social media consist of powerful tools that impact not only communication but relationships among people, thus posing an inherent challenge to the traditional standards of who we are as dental educators and what we can expect of each other. This article examines how the world of social media has changed dental education. Its goal is to outline the complex issues that social media use presents for academic dental institutions and to examine these issues from personal, professional, and legal perspectives. After providing an update on social media, the article considers the advantages and risks associated with the use of social media at the interpersonal, professional, and institutional levels. Policies and legal issues of which academic dental institutions need to be aware from a compliance perspective are examined, along with considerations and resources needed to develop effective social media policies. The challenge facing dental educators is how to capitalize on the benefits that social media offer, while minimizing risks and complying with the various forms of legal constraint. PMID- 26427775 TI - Social Media in the Dental School Environment, Part B: Curricular Considerations. AB - The goal of this article is to describe the broad curricular constructs surrounding teaching and learning about social media in dental education. This analysis takes into account timing, development, and assessment of the knowledge, skills, attitudes, and behaviors needed to effectively use social media tools as a contemporary dentist. Three developmental stages in a student's path to becoming a competent professional are described: from undergraduate to dental student, from the classroom and preclinical simulation laboratory to the clinical setting, and from dental student to licensed practitioner. Considerations for developing the dental curriculum and suggestions for effective instruction at each stage are offered. In all three stages in the future dentist's evolution, faculty members need to educate students about appropriate professional uses of social media. Faculty members should provide instruction on the beneficial aspects of this communication medium and help students recognize the potential pitfalls associated with its use. The authors provide guidelines for customizing instruction to complement each stage of development, recognizing that careful timing is not only important for optimal learning but can prevent inappropriate use of social media as students are introduced to novel situations. PMID- 26427776 TI - Recruitment of Dental Hygiene Students from Underrepresented Minority Groups: A National Survey of U.S. Dental Hygiene Programs. AB - The aims of this study were to assess how U.S. undergraduate dental hygiene programs recruit students, especially students from underrepresented minority (URM) groups, and how the program directors value recruiting those students, how satisfied they are with their efforts, which practices they use, and which challenges they encounter. Relationships between diversity-related recruitment motivation and satisfaction and the program and recruitment characteristics were also explored. Survey data were collected from 56 of the 287 programs that could be successfully contacted with individual emails to their directors (response rate: 20%). The majority of responding programs recruited students into their programs by using written materials (91%), websites (91%), on-campus events (77%), and high school visits (52%). However, only 20% had written materials and 13% special events for recruiting students from URM groups. While 75% of the responding program directors considered high grade point averages (GPAs) to be a priority and 85% thought high GPAs were important/very important when recruiting students, only 17% considered it a priority to recruit URM students, and only 35% reported thinking it was important/very important to do so. The more of a priority it was to have a diverse student body and the more important the respondents considered it, the more likely they were to have written URM-specific recruitment materials (r=0.34; p<0.05/r=0.39; p<0.01). The more the respondents valued ACT scores, the less likely they were to engage in URM-specific recruitment efforts (r=-0.38; p<0.05/r=-0.34; p<0.05). If the dental hygiene profession is to better reflect the racial/ethnic makeup of the U.S. population, dental hygiene programs' considerations and efforts related to the recruitment of URM students need to be reconsidered. PMID- 26427777 TI - Faculty Development at One Midwestern Dental School: A Program Evaluation. AB - Most dental school faculty members arrive on campus with a wealth of clinical experience but little to no teacher training. For the past two decades, there has been a call for schools to educate their faculty on a wide variety of topics including educational methodology and cutting-edge educational techniques through faculty development programs. Drawing on theories of general program evaluation as well as evaluation specific to educational programming, the aim of this study was to investigate outcomes of the Faculty Development Program at the University of Missouri-Kansas City School of Dentistry between 2007 and 2014. A mixed methods research design gathered quantitative data via email survey sent to all eligible teaching faculty members; it received an overall response rate of 54% (N=51). Qualitative data came from open-ended survey questions and a focus group with seven volunteer faculty participants. The survey data suggested that the stated outcomes of faculty development were being met for all stakeholder groups with varying degrees of success. Focus group results indicated a need for a more formal new faculty orientation and better communication with all about the specific charge of faculty development within the school. Evaluation of faculty development activities in academic dental institutions is a necessary component of the ongoing improvement of dental education. Suggestions for future evaluations include the idea of collaborating with other dental schools to increase sample sizes, which would increase participants' perception of the level of confidentiality and make statistical analyses more robust. PMID- 26427778 TI - Developing Dental Students' Awareness of Health Care Disparities and Desire to Serve Vulnerable Populations Through Service-Learning. AB - Service-learning in dental education helps students integrate knowledge with practice in an underserved community setting. The aim of this study was to explore how a service-learning experience affected a small group of dental students' beliefs about cultural competence, professionalism, career development, desire to practice in a community service setting, and perceptions about access and disparities issues. Prior to beginning their first year of dental school, five first-year dental students at one U.S. dental school participated in a six week service-learning program in which they interned at one of three at-risk settings in order to experience health care delivery there. After the program, 60 reflective writing assignments completed by the participants were analyzed using grounded theory methods; interviews with the students were used to corroborate the findings from that analysis. Seven themes identified in the journal reflections and interview findings showed enhanced awareness of social health care issues and patient differences, as well as a social justice orientation and desire to address disparities. Building on this study, future research should explore the curricular components of service-learning programs to ensure students receive ample opportunity to reflect upon their experiences in order to integrate previously held assumptions with their newfound knowledge. PMID- 26427779 TI - Patients' Perceptions of Dehumanization of Patients in Dental School Settings: Implications for Clinic Management and Curriculum Planning. AB - Although the importance of empathy, rapport, and anxiety/pain awareness in dentist-patient relations has been well documented, these factors continue to be an issue with patients in many dental school clinics. The aim of this study was to develop an in-depth understanding of how patients at an urban, university affiliated medical center and its dental school's clinic experienced oral health care and to generate ideas for improving the dental school's clinical curriculum and management of the clinic. Although patient satisfaction surveys are common, in-depth patient narratives are an underutilized resource for improving dental education. In-depth qualitative interviews were conducted with 20 uninsured or underinsured dental patients at these sites, and the results were analyzed using content analysis. Major phenomena that participants discussed were the importance of empathy and good rapport with their oral health providers and provider awareness of dental pain and anxiety. Many patients also discussed feeling dehumanized during dental visits. Based on their positive and negative experiences, the participants made suggestions for how oral health professionals can successfully engage patients in treatment. PMID- 26427780 TI - Dental Students' Learning Experiences and Preferences Regarding Orofacial Pain: A Cross-Sectional Study. AB - Pain is a global health problem, the effects of which range from diminished quality of life to pain management costs and loss of work and productivity. Pain in the head and neck region is defined as a separate entity: orofacial pain (OFP). However, some graduates from dental schools have reported feeling less competent in their ability to diagnose OFP than in other areas of dentistry. The aims of this study were to assess how students at one U.S. dental school had learned about OFP and to identify the teaching methods and venues they would like to see enhanced in the school's OFP curriculum. A cross-sectional four-question survey was administered to 140 dental students in their third and fourth years; the survey had a response rate of 53%. Most students reported having gained their OFP knowledge mainly in dental school, and 91.9% selected didactic courses as the main teaching method in which they had learned about this topic. Clinical education was the main teaching venue these students said they would like to see enhanced in order to gain more knowledge in most forms of OFP; this result aligned with their learning preferences in general. These findings may help dental schools design their OFP curricula to take account of students' preferences as well as practical limitations regarding availability of clinical experiences. PMID- 26427781 TI - Establishing CAD/CAM in Preclinical Dental Education: Evaluation of a Hands-On Module. AB - The aim of this study was to evaluate a hands-on computer-assisted design/computer-assisted manufacture (CAD/CAM) module in a preclinical dental course in restorative dentistry. A controlled trial was conducted by dividing a class of 56 third-year dental students in Germany into study and control groups; allocation to the two groups depended on student schedules. Prior information about CAD/CAM-based restorations was provided for all students by means of lectures, preparation exercises, and production of gypsum casts of prepared resin teeth. The study group (32 students) then participated in a hands-on CAD/CAM module in small groups, digitizing their casts and designing zirconia frameworks for single crowns. The digitization process was introduced to the control group (24 students) solely by means of a video-supported lecture. To assess the knowledge gained, a 20-question written examination was administered; 48 students took the exam. The results were analyzed with Student's t-tests at a significance level of 0.05. The results on the examination showed a significant difference between the two groups: the mean scores were 16.8 (SD 1.7, range 13-19) for the study group and 12.5 (SD 3, range 4-18) for the control group. After the control group had also experienced the hands-on module, a total of 48 students from both groups completed a questionnaire with 13 rating-scale and three open-ended questions evaluating the module. Those results showed that the module was highly regarded by the students. This study supports the idea that small-group hands-on courses are helpful for instruction in digital restoration design. These students' knowledge gained and satisfaction seemed to justify the time, effort, and equipment needed. PMID- 26427782 TI - Evidence Regarding Teaching and Assessment of Record-Keeping Skills in Training of Dental Students. AB - The aim of this study was to assess the literature on teaching and assessing dental students' record-keeping skills prior to qualification to practice independently as a dentist. A systematic literature review was performed using Ovid MEDLINE and SCOPUS. Keywords used in the search included dental, record, audit, education, and assessment. Electronic search results were screened for publications that targeted undergraduate dental training, related to a record keeping education intervention, and were published in English and available in full text. Six studies met the inclusion and exclusion criteria. Data extraction and quality assessment were performed, and research findings were compared across the included studies. These six articles addressed the techniques used to teach and assess record-keeping skills in a pre-qualification context. The techniques included supervisor audits, peer audits, lectures, tutorials, research assignments, case reports, record-keeping templates, and checklists of required record components. The use of record audit as part of teaching and evaluation dominated these articles; it was used as the assessment method in five of the six studies. All methods of record-keeping training in studies published to date were found effective in improving student record-keeping skills. However, there was insufficient evidence to determine whether certain methods were more effective than others. PMID- 26427784 TI - Evaluation of new bone formation after sinus augmentation with two different methods. AB - The sinus infiltration technique for sinus floor elevation and simultaneous implant placement has been used successfully when a reduced vertical height is available in the posterior maxilla. However, the effect of the quantity of graft material and the volume of the solution used on the volume of new bone formed has not been fully investigated. The aim of this study was to evaluate, both quantitatively and qualitatively, the new bone formation after sinus augmentation using either the lateral sinus lift or sinus infiltration technique and to determine any correlation with the volume of bone grafting material used. Further, the volume of solution used in the sinus infiltration technique was also assessed. Twenty healthy adults (13 women, seven men) were randomized to two groups, each undergoing one of the two techniques. Quantitative aspects and the space lifted in the sinus floor were analyzed using Simplant Pro Crystal software. No correlation was found between the volume of bone created in the sinus floor and the volume of bone grafting material used for the sinus infiltration technique or the lateral sinus lift. A strong correlation was found between the volume of liquid used in the sinus infiltration technique and the new volume created in the sinus floor. PMID- 26427785 TI - Cancer modelling in the NGS era - Part I: Emerging technology and initial modelling. AB - It is today indisputable that great progresses have been made in our molecular understanding of cancer cells, but an effective implementation of such knowledge into dramatic cancer-cures is still belated and yet desperately needed. This review gives a snapshot at where we stand today in this search for cancer understanding and definitive treatments, how far we have progressed and what are the major obstacles we will have to overcome both technologically and for disease modelling. In the first part, promising 3rd/4th Generation Sequencing Technologies will be summarized (particularly IonTorrent and OxfordNanopore technologies). Cancer modelling will be then reviewed from its origin in XIX Century Germany to today's NGS applications for cancer understanding and therapeutic interventions. Developments after Molecular Biology revolution (1953) are discussed as successions of three phases. The first, PH1, labelled "Clonal Outgrowth" (from 1960s to mid 1980s) was characterized by discoveries in cytogenetics (Nowell, Rowley) and viral oncology (Dulbecco, Bishop, Varmus), which demonstrated clonality. Treatments were consequently dominated by a "cytotoxic eradication" strategy with chemotherapeutic agents. In PH2, (from the mid 1980s to our days) the description of cancer as "Gene Networks" led to targeted-gene-therapies (TGTs). TGTs are the focus of Section 3: in view of their apparent failing (Ephemeral Therapies), alternative strategies will be discussed in review part II (particularly cancer immunotherapy, CIT). Additional Pitfalls impinge on the concepts of tumour heterogeneity (inter/intra; ITH). The described pitfalls set the basis for a new phase, PH3, which is called "NGS Era" and will be also discussed with ten emerging cancer models in the Review 2nd part. PMID- 26427787 TI - Yiguanjian decoction and its ingredients inhibit angiogenesis in carbon tetrachloride-induced cirrhosis mice. AB - BACKGROUND: Cirrhosis is associated with angiogenesis and disruption of hepatic vascular architecture. Yiguanjian (YGJ) decoction, a prescription from traditional Chinese medicine, is widely used for treating liver diseases. We studied whether YGJ or its ingredients (iYGJ) had an anti-angiogenic effect and explored possible mechanisms underlying this process. METHODS: Cirrhosis was induced with carbon tetrachloride (CCl4) (ip) in C57BL/6 mice for 6 weeks. From week 4 to week 6, cirrhotic mice were randomly divided into four groups: sorafenib-treated, YGJ-treated and iYGJ-treated mice and placebo. Serum biochemistries, hydroxyproline (Hyp) content and histopathological changes of hepatic tissues were measured as were alpha-smooth muscle actin (alpha-SMA), collagen I, CD31, vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR) 2 and hypoxia-inducible factor (HIF)-1alpha. RESULTS: Both YGJ and iYGJ improved serum biochemistries. Changes of histopathology showed that YGJ and iYGJ reduced hepatic tissue necroinflammatory and collagen fiber deposition in cirrhosis mice. Compared to the CCl4 treated animals, Hyp, alpha-SMA, collagen I, CD31, VEGF, VEGFR, and HIF-1alpha expression decreased in YGJ and iYGJ groups. CONCLUSIONS: YGJ and iYGJ inhibited liver angiogenesis in cirrhotic mice treated with CCl4 by inhibiting the HIF-1alpha/VEGF signaling pathway, suggesting that anti-angiogenic effects of YGJ and iYGJ are associated with improving the hepatic hypoxic microenvironment. PMID- 26427788 TI - Evaluating Nonattachment and Decentering as Possible Mediators of the Link Between Mindfulness and Psychological Distress in a Nonclinical College Sample. AB - Although increasing evidence shows that mindfulness is positively related to mental health, the nature and mechanisms of this relationship are not fully understood. Based on previous research findings and suggestions, the authors of the current study hypothesized that decentering and nonattachment are 2 variables that mediate the relationship between mindfulness and psychological distress. A nonclinical, non-treatment-seeking sample of 308 students and employees from a middle-class, primarily Caucasian university filled out mindfulness, decentering, nonattachment, and mental distress measures online. Mediational analyses failed to support the hypothesis. Results suggest that mindfulness and nonattachment are independent predictors of nonclinical psychological distress and fully explain the effect of decentering on psychological distress. Results should be interpreted with caution and not generalized to clinical issues. A more comprehensive look into the mechanisms of mindfulness, especially with rigorous experimental, longitudinal studies, is warranted. The authors stress the importance of checking alternative, equivalent models in mediation studies. PMID- 26427786 TI - Structural Brain MRI Trait Polygenic Score Prediction of Cognitive Abilities. AB - Structural brain magnetic resonance imaging (MRI) traits share part of their genetic variance with cognitive traits. Here, we use genetic association results from large meta-analytic studies of genome-wide association (GWA) for brain infarcts (BI), white matter hyperintensities, intracranial, hippocampal, and total brain volumes to estimate polygenic scores for these traits in three Scottish samples: Generation Scotland: Scottish Family Health Study (GS:SFHS), and the Lothian Birth Cohorts of 1936 (LBC1936) and 1921 (LBC1921). These five brain MRI trait polygenic scores were then used to: (1) predict corresponding MRI traits in the LBC1936 (numbers ranged 573 to 630 across traits), and (2) predict cognitive traits in all three cohorts (in 8,115-8,250 persons). In the LBC1936, all MRI phenotypic traits were correlated with at least one cognitive measure, and polygenic prediction of MRI traits was observed for intracranial volume. Meta analysis of the correlations between MRI polygenic scores and cognitive traits revealed a significant negative correlation (maximal r = 0.08) between the HV polygenic score and measures of global cognitive ability collected in childhood and in old age in the Lothian Birth Cohorts. The lack of association to a related general cognitive measure when including the GS:SFHS points to either type 1 error or the importance of using prediction samples that closely match the demographics of the GWA samples from which prediction is based. Ideally, these analyses should be repeated in larger samples with data on both MRI and cognition, and using MRI GWA results from even larger meta-analysis studies. PMID- 26427790 TI - Evaluation of Anti-inflammatory and Some Possible Mechanisms of Antinociceptive Effect of Ferula assa foetida Oleo Gum Resin. AB - Asafetida is well known for its medicinal and therapeutic values in Iranian folk medicine. This study was conducted to investigate the antinociceptive and anti inflammatory effects of asafetida. In hot plate test, asafetida exhibited a significant antinociceptive effect at all administered doses and the most effective dose was 10 mg/kg. The highest maximum potent effect was observed 15 minutes after asafetida administration. The antinociceptive effect of asafetida was not reversed by administration of any antagonist used in this study but asafetida showed a remarkable antioxidant and also inhibitory action against lipoxygenase activity. Paw weight was significantly reduced only in treated animals with 2.5 mg/kg asafetida. Results clearly indicate that the asafetida could be a potential source of anti-inflammatory and analgesic agent. These effects may be due to its effective constituents such as monoterpenes, flavonoids and phenolic components that have antioxidant properties and inhibit lipoxygenase activity. PMID- 26427789 TI - Topical use of Matricaria recutita L (Chamomile) Oil in the Treatment of Monosymptomatic Enuresis in Children: A Double-Blind Randomized Controlled Trial. AB - AIM: To evaluate the efficacy of topical use of Matricaria recutita L oil in the treatment of enuresis in children. METHODS: Eighty patients diagnosed as monosymptomatic nocturnal or daytime enuresis were allocated to receive Matricaria recutita L (chamomile) oil or placebo topically for 6 weeks in a double-blind randomized placebo-controlled trial with a parallel design. Patients were evaluated prior to and following 8 weeks of the intervention in terms of frequency of enuresis and any observed adverse events. RESULTS: The mean frequency of enuresis at the first, second, and third 2 weeks was lower in the intervention group compared with the placebo group, and the differences were statistically significant (P < .001, P = .03, and P < .001, respectively). There was no report of any adverse event in the study groups. CONCLUSION: The findings of this study showed that the topical use of (chamomile) oil can decrease the frequency of nocturia in children with monosymptomatic nocturnal or daytime enuresis. PMID- 26427791 TI - Physiopathology of Dementia in Iranian Traditional Medicine. AB - Recently, an article published in this journal by Dr Seifaddini and colleagues. In that article, the authors tried to connect dementia, including Alzheimer's disease, with a condition mentioned in Iranian traditional medical condition, Raoonat and Homgh In this condition, intellectual functions of the brain are disturbed and therefore, learning and decision-making abilities are damaged. This condition is not age limited and affects thinking ability but not memory. On the other hand, there is a condition described in Iranian traditional medicine, which completely matches with Alzheimer's disease. This condition is explained under the title of Nesyan (forgetfulness). Nesyan has 5 subdivisions, one of which is caused by the inclination of the brain normal temperament to more coldness and dryness. By performing animal studies, we have recently shown that this kind of Nesyan is related with Alzheimer's disease. Studies on the traditional recommendations on treatment of this kind of Nesyan can be useful in treatment of Alzheimer's disease. PMID- 26427792 TI - The whole is greater than the sum of the parts: Distributed circuits in visual cognition. PMID- 26427793 TI - Fibronectin Splicing Variants Containing Extra Domain A Promote Atherosclerosis in Mice Through Toll-Like Receptor 4. AB - OBJECTIVE: Cellular fibronectin containing extra domain A (EDA(+)-FN) is abundant in the arteries of patients with atherosclerosis. Several in vitro studies suggest that EDA(+)-FN interacts with Toll-like receptor 4 (TLR4). We tested the hypothesis that EDA(+)-FN exacerbates atherosclerosis through TLR4 in a clinically relevant model of atherosclerosis, the apolipoprotein E-deficient (Apoe(-/-)) mouse. APPROACH AND RESULTS: The extent of atherosclerosis was evaluated in whole aortae and cross sections of the aortic sinus in male and female EDA(-/-)Apoe(-/-) mice (which lack EDA(+)-FN), EDA(fl/fl)Apoe(-/-) mice (which constitutively express EDA(+)-FN), and control Apoe(-/-) mice fed a high fat Western diet for 14 weeks. Irrespective of sex, EDA(fl/fl)Apoe(-/-) mice exhibited a 2-fold increase in atherosclerotic lesions (aorta and aortic sinus) and macrophage content within plaques, whereas EDA(-/-)Apoe(-/-) mice exhibited reduced atherosclerotic lesions (P<0.05 versus Apoe(-/-), n=10-12 mice/group), although cholesterol and triglyceride levels and circulating leukocytes were similar. Genetic ablation of TLR4 partially reversed atherosclerosis exacerbation in EDA(fl/fl)Apoe(-/-) mice (P<0.05) but had no effect on atherosclerotic lesions in EDA(-/-)Apoe(-/-) mice. Purified cellular FN, which contains EDA, potentiated dose-dependent NFkappaB-mediated inflammation (increased phospho-NFkappaB p65/NFkappaB p65, tumor necrosis factor-alpha, and interleukin-1beta) in bone marrow-derived macrophages from EDA(-/-)Apoe(-/-) mice but not from EDA(-/-)TLR4( /-)Apoe(-/-) mice. Finally, using immunohistochemistry, we provide evidence for the first time that EDA(+)-FN colocalizes with macrophage TLR4 in murine aortic lesions and human coronary artery atherosclerotic plaques. CONCLUSIONS: Our findings reveal that TLR4 signaling contributes to EDA(+)-FN-mediated exacerbation of atherosclerosis. We suggest that EDA(+)-FN could be a therapeutic target in atherosclerosis. PMID- 26427794 TI - Therapeutic Inhibition of miR-33 Promotes Fatty Acid Oxidation but Does Not Ameliorate Metabolic Dysfunction in Diet-Induced Obesity. AB - OBJECTIVE: miR-33 has emerged as an important regulator of lipid homeostasis. Inhibition of miR-33 has been demonstrated as protective against atherosclerosis; however, recent studies in mice suggest that miR-33 inhibition may have adverse effects on lipid and insulin metabolism. Given the therapeutic interest in miR-33 inhibitors for treating atherosclerosis, we sought to test whether pharmacologically inhibiting miR-33 at atheroprotective doses affected metabolic parameters in a mouse model of diet-induced obesity. APPROACH AND RESULTS: High fat diet (HFD) feeding in conjunction with treatment of male mice with 10 mg/kg control anti-miR or anti-miR33 inhibitors for 20 weeks promoted equivalent weight gain in all groups. miR-33 inhibitors increased plasma total cholesterol and decreased serum triglycerides compared with control anti-miR, but not compared with PBS-treated mice. Metrics of insulin resistance were not altered in anti miR33-treated mice compared with controls; however, respiratory exchange ratio was decreased in anti-miR33-treated mice. Hepatic expression of miR-33 targets Abca1 and Hadhb were derepressed on miR-33 inhibition. In contrast, protein levels of putative miR-33 target gene SREBP-1 or its downstream targets genes Fasn and Acc were not altered in anti-miR33-treated mice, and hepatic lipid accumulation did not differ between groups. In the adipose tissue, anti-miR33 treatment increased Ampk gene expression and markers of M2 macrophage polarization. CONCLUSIONS: We demonstrate in a mouse model of diet-induced obesity that therapeutic silencing of miR-33 may promote whole-body oxidative metabolism but does not affect metabolic dysregulation. This suggests that pharmacological inhibition of miR-33 at doses known to reduce atherosclerosis may be a safe future therapeutic. PMID- 26427795 TI - Novel CREB3L3 Nonsense Mutation in a Family With Dominant Hypertriglyceridemia. AB - OBJECTIVE: Cyclic AMP responsive element-binding protein 3-like 3 (CREB3L3) is a novel candidate gene for dominant hypertriglyceridemia. To date, only 4 kindred with dominant hypertriglyceridemia have been found to be carriers of 2 nonsense mutations in CREB3L3 gene (245fs and W46X). We investigated a family in which hypertriglyceridemia displayed an autosomal dominant pattern of inheritance. APPROACH AND RESULTS: The proband was a 49-year-old woman with high plasma triglycerides (<=1300 mg/dL; 14.68 mmol/L). Her father had a history of moderate hypertriglyceridemia, and her 51-year-old brother had triglycerides levels as high as 1600 mg/dL (18.06 mmol/L). To identify the causal mutation in this family, we analyzed the candidate genes of recessive and dominant forms of primary hypertriglyceridemia by direct sequencing. The sequencing of CREB3L3 gene led to the discovery of a novel minute frame shift mutation in exon 3 of CREB3L3 gene, predicted to result in the formation of a truncated protein devoid of function (c.359delG-p.K120fsX20). Heterozygosity for the c.359delG mutation resulted in a severe phenotype occurring later in life in the proband and her brother and a good response to diet and a hypotriglyceridemic treatment. The same mutation was detected in a 13-year-old daughter who to date is normotriglyceridemic. CONCLUSIONS: We have identified a novel pathogenic mutation in CREB3L3 gene in a family with dominant hypertriglyceridemia with a variable pattern of penetrance. PMID- 26427797 TI - A soluble cryogenic thermometer with high sensitivity based on excited-state configuration transformations. AB - Cryogenic temperature detection plays an irreplaceable role in exploring nature. Developing high sensitivity, accurate, observable and convenient measurements of cryogenic temperature is not only a challenge but also an opportunity for the thermometer field. The small molecule 9-(9,9-dimethyl-9H-fluoren-3yl)-14-phenyl 9,14-dihydrodibenzo[a,c]phenazine (FIPAC) in 2-methyl-tetrahydrofuran (MeTHF) solution is utilized for the detection of cryogenic temperature with a wide range from 138 K to 343 K. This system possesses significantly high sensitivity at low temperature, which reaches as high as 19.4% K(-1) at 138 K. The temperature dependent ratio of the dual emission intensity can be fitted as a single exponential curve as a function of temperature. This single-exponential curve can be explained by the mechanism that the dual emission feature of FIPAC results from the excited-state configuration transformations upon heating or cooling, which is very different from the previously reported mechanisms. Here, our work gives an overall interpretation for this mechanism. Therefore, application of FIPAC as a cryogenic thermometer is experimentally and theoretically feasible. PMID- 26427796 TI - Epac1 Deficiency Attenuated Vascular Smooth Muscle Cell Migration and Neointimal Formation. AB - OBJECTIVE: Vascular smooth muscle cell (SMC) migration causes neointima, which is related to vascular remodeling after mechanical injury and atherosclerosis development. We previously reported that an exchange protein activated by cAMP (Epac) 1 was upregulated in mouse arterial neointima and promoted SMC migration. In this study, we examined the molecular mechanisms of Epac1-induced SMC migration and the effect of Epac1 deficiency on vascular remodeling in vivo. APPROACH AND RESULTS: Platelet-derived growth factor-BB promoted a 2-fold increase in SMC migration in a primary culture of aortic SMCs obtained from Epac1(+/+) mice (Epac1(+/+)-ASMCs), whereas there was only a 1.2-fold increase in Epac1(-/-)-ASMCs. The degree of platelet-derived growth factor-BB-induced increase in intracellular Ca(2+) was smaller in Fura2-labeled Epac1(-/-)-ASMCs than in Epac1(+/+)-ASMCs. In Epac1(+/+)-ASMCs, an Epac-selective cAMP analog or platelet-derived growth factor-BB increased lamellipodia accompanied by cofilin dephosphorylation, which is induced by Ca(2+) signaling, whereas these effects were rarely observed in Epac1(-/-)-ASMCs. Furthermore, 4 weeks after femoral artery injury, prominent neointima were formed in Epac1(+/+) mice, whereas neointima formation was significantly attenuated in Epac1(-/-) mice in which dephosphorylation of cofilin was inhibited. The chimeric mice generated by bone marrow cell transplantation from Epac1(+/+) into Epac1(-/-) mice and vice versa demonstrated that the genetic background of vascular tissues, including SMCs rather than of bone marrow-derived cells affected Epac1-mediated neointima formation. CONCLUSIONS: These data suggest that Epac1 deficiency attenuates neointima formation through, at least in part, inhibition of SMC migration, in which a decrease in Ca(2+) influx and a suppression of cofilin-mediated lamellipodia formation occur. PMID- 26427798 TI - Predictors of non-adherence to antihypertensive medication in Kinshasa, Democratic Republic of Congo: a cross-sectional study. AB - BACKGROUND: Hypertension remains a public health challenge worldwide. In the Democratic Republic of Congo, its prevalence has increased in the past three decades. Higher prevalence of poor blood pressure control and an increasing number of reported cases of complications due to hypertension have also been observed. It is well established that non-adherence to antihypertensive medication contributes to poor control of blood pressure. The aim of this study is to measure non-adherence to antihypertensive medication and to identify its predictors. METHODS: A cross-sectional study was conducted at Kinshasa Primary Health-care network facilities from October to November 2013. A total of 395 hypertensive patients were included in the study. A structured interview was used to collect data. Adherence to medication was assessed using the Morisky Medication Scale. Covariates were defined according to the framework of the World Health Organization. Logistic regression was used to identify predictors of non adherence. RESULTS: A total of 395 patients participated in this study. The prevalence of non-adherence to antihypertensive medication and blood pressure control was 54.2 % (95 % CI 47.3-61.8) and 15.6 % (95 % CI 12.1-20.0), respectively. Poor knowledge of complications of hypertension (OR = 2.4; 95 % CI 1.4-4.4), unavailability of antihypertensive drugs in the healthcare facilities (OR = 2.8; 95 % CI 1.4-5.5), lack of hypertensive patients education in the healthcare facilities (OR = 1.7; 95 % CI 1.1-2.7), prior experience of medication side effects (OR = 2.2; 95 % CI 1.4-3.3), uncontrolled blood pressure (OR = 2.0; 95 % CI 1.1-3.9), and taking non-prescribed medications (OR = 2.2; 95 % CI 1.2 3.8) were associated with non-adherence to antihypertensive medication. CONCLUSION: This study identified predictors of non-adherence to antihypertensive medication. All predictors identified were modifiable. Interventional studies targeting these predictors for improving adherence are needed. PMID- 26427799 TI - Nutritional epigenetics with a focus on amino acids: implications for the development and treatment of metabolic syndrome. AB - Recent findings from human and animal studies indicate that maternal undernutrition or overnutrition affects covalent modifications of the fetal genome and its associated histones that can be carried forward to subsequent generations. An adverse outcome of maternal malnutrition is the development of metabolic syndrome, which is defined as a cluster of disorders including obesity, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertension and insulin resistance. The transgenerational impacts of maternal nutrition are known as fetal programming, which is mediated by stable and heritable alterations of gene expression through covalent modifications of DNA and histones without changes in DNA sequences (namely, epigenetics). The underlying mechanisms include chromatin remodeling, DNA methylation (occurring at the 5'-position of cytosine residues within CpG dinucleotides), histone modifications (acetylation, methylation, phosphorylation, ubiquitination and sumoylation) and expression and activity of small noncoding RNAs. The enzymes catalyzing these reactions include S adenosylmethionine-dependent DNA and protein methyltransferases, DNA demethylases, histone acetylase (lysine acetyltransferase), general control nonderepressible 5 (GCN5)-related N-acetyltransferase (a superfamily of acetyltransferase) and histone deacetylase. Amino acids (e.g., glycine, histidine, methionine and serine) and vitamins (B6, B12 and folate) play key roles in provision of methyl donors for DNA and protein methylation. Therefore, these nutrients and related metabolic pathways are of interest in dietary treatment of metabolic syndrome. Intervention strategies include targeting epigenetically disturbed metabolic pathways through dietary supplementation with nutrients (particularly functional amino acids and vitamins) to regulate one carbon-unit metabolism, antioxidative reactions and gene expression, as well as protein methylation and acetylation. These mechanism-based approaches may effectively improve health and well-being of affected offspring. PMID- 26427800 TI - A cell-targeted chemotherapeutic nanomedicine strategy for oral squamous cell carcinoma therapy. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) or cancers of oral cavity is one of the most common cancers worldwide with high rate of mortality and morbidity. At present, chemotherapy is one of the most effective treatments; however it often fails to meet the requirements in the clinical therapy. In the present study, we have successfully formulated ligand-decorated cancer-targeted CDDP loaded PLGA-PEG/NR7 nanoparticles and demonstrated the feasibility of using NR7 peptide for targeted delivery, rapid intracellular uptake, and enhanced cytotoxic effect in receptor-overexpressed OSCC cancer cells. RESULTS: Nanosized particles were formed and sustained release patterns were observed for PLGA/NR7 nanoparticles. Significantly higher cellular uptake was observed in HN6 OSCC cancer cells and superior anticancer effects are observed from the optimized targeted nanoparticles. Furthermore, Live/Dead assay showed a higher extent of red fluorescence was observed for the cells exposed with PLGA/NR7 than compared with non-targeted PLGA NP. The presence of the NR7-targeting moiety on the surface of PLGA carriers could allow the specific receptor-mediated internalization, enhanced cellular uptake, and higher cell killing potency. Especially, PLGA/NR7 NP exhibited a superior apoptosis effect in HN6 cancer cells with around ~45 % (early and late apoptotic stage) and ~59 % after 24 and 48 h incubation, respectively. It is apparent that the actively targeted micelles will deliver more anticancer agent to cancer cell than non-targeted one. CONCLUSION: Altogether, our results show the feasibility and promise of a cell-targeted anticancer nanomedicine strategy that can be effective for the treatment of oral squamous cell carcinoma. The present work might be of great importance to the further exploration of the potential application of PLGA/NR7 in the clinically relevant animal models. PMID- 26427801 TI - Prognostic impact of decisions taken by the heart team in patients evaluated for transcatheter aortic valve implantation. AB - OBJECTIVE: To analyze long-term survival and predictors of mortality in patients evaluated for transcatheter aortic valve implantation (TAVI) depending on the decision taken by the heart team. METHODS: All patients with severe aortic stenosis and high surgical risk evaluated for TAVI between June 2008 and June 2012 were included. Patients were grouped according to the therapeutic strategy decided by the heart team. Mean follow-up was 16.6 months (maximum 55.3). RESULTS: A total of 149 patients were evaluated: 79 were accepted for TAVI, 12 had no current indication for valve replacement and were deferred, 13 were redirected to conventional surgery and 45 received medical treatment. The evaluated patients had a mean age of 83.7 years and a mean EuroSCORE of 19.8+/ 12.3. Median survival free from all-cause death was 34.7 months (95% CI 27.1 42.3) in the TAVI group, 47.4 months (95% CI 0-97.4) in the deferred intervention group, not available in the surgery group and 8.2 months (95% CI 5.6-10.9) in the medical treatment group (log-rank p<0.001). After multivariable adjustment, only treatment group remained as an independent predictor of mortality. Considering the TAVI group as the reference category, the adjusted hazard ratio for all-cause death was 0.70 (95% CI 0.24-2.04) for the deferred intervention group, 0.16 (95% CI 0.02-1.19) for the surgery group and 2.47 (95% CI 1.46-4.18) for the medical treatment group. CONCLUSION: The decision taken by the heart team on potential candidates for TAVI has a decisive prognostic significance, as those who are unsuitable for any kind of valve replacement have a significantly higher mortality. PMID- 26427802 TI - Anemia and iron in heart failure--a brief comment. PMID- 26427803 TI - The temperament and character personality profile of the glaucoma patient. AB - BACKGROUND: To determine the temperament and character profile of glaucoma patients. METHODS: A total of 234 patients (104 with primary open angle glaucoma, and 130 control subjects without any ocular disease) were selected for this prospective, cross-sectional study. All the participants underwent a comprehensive ophthalmological examination, including the best corrected visual acuity, intraocular pressure measurement, gonioscopy, and visual field analysis. All the participants were given the Turkish version of the Temperament and Character Inventory (TCI). The TCI is a self-reported evaluate, with 240 true/false items measuring four domains of temperament; harm avoidance (HA), persistence (PS), novelty seeking (NS), reward dependence (RD), and three domains of character; self-transcendence (ST), cooperativeness (C), self-directedness (SD). RESULTS: The glaucoma patients achieved the higher scores than the controls for the HA and SD dimensions (p < 0.001 and p = 0.033). The glaucoma patients scored lower than the controls for the NS, P and ST dimensions (p < 0.001, p < 0.001 and p = 0.002). There were no differences in the RD and C scores between the patients and the controls (p = 0.944 and p = 0.343). There was no correlation between the duration of illness and the TCI dimensions. Disease severity was positively associated with HA (r = 0,220, p = 0,025) and the anticipatory worry (r = 0.227, p = 0.021) dimension. CONCLUSIONS: Glaucoma patients had a different personality profile to healthy individuals. This may affect treatment compliance and is also important when coping with maladaptive patient attitudes. PMID- 26427804 TI - A phantom assessment of achievable contouring concordance across multiple treatment planning systems. AB - In this paper, the highest level of inter- and intra-observer conformity achievable with different treatment planning systems (TPSs), contouring tools, shapes, and sites have been established for metrics including the Dice similarity coefficient (DICE) and Hausdorff Distance. High conformity values, e.g. DICE(Breast_Shape)=0.99+/-0.01, were achieved. Decreasing image resolution decreased contouring conformity. PMID- 26427805 TI - Mature results from a Swedish comparison study of conventional versus accelerated radiotherapy in head and neck squamous cell carcinoma - The ARTSCAN trial. AB - BACKGROUND AND PURPOSE: This report contains the mature five-year data from the Swedish ARTSCAN trial including information on the influence of p16 positivity (p16+) for oropharyngeal cancers. MATERIAL AND METHODS: Patients with previously untreated squamous cell carcinoma without distant metastases of the oral cavity, oropharynx, larynx (except T1-2, N0 glottic cancers) and hypopharynx were included. Patients were randomised between accelerated fractionation (AF) (1.1Gy+2Gy per day, 5days/week for 4.5weeks, total dose 68Gy) and conventional fractionation (CF) (2Gy per day, 5days/week for 7weeks, total dose 68Gy). Human papillomavirus (HPV)-associated p16-expression was assessed retrospectively in tumour tissues from patients with oropharyngeal carcinoma. RESULTS: There was no significant difference in loco-regional control (LRC) between AF and CF (log-rank test p=0.75). LRC at 5years was 65.5% for AF and 64.9% for CF. Overall survival (OS) was similar in both arms (p=0.99). The estimated cancer specific survival (CSS) at 5years was 62.2% (AF) and 63.3% (CF) (p=0.99). 206 specimens were analysed for p16 with 153 specimens (74%) identified as p16+. P16 status did not discriminate for response to AF vs. CF with regard to LRC, OS or CSS. Patients with p16+ tumours had a statistically significant better overall prognosis compared with p16- tumours. CONCLUSION: This update confirms the results of the 2 year report. We failed to identify a positive effect resulting from AF with regards to LRC, OS and CSS. The addition of information on the HPV-associated p16 overexpression did not explain this lack of effect. PMID- 26427807 TI - Is "Good Neurologic Outcome" Following Cardiac Arrest Good Enough? PMID- 26427806 TI - Prognosis of sepsis induced by cecal ligation and puncture in mice improved by anti-Clonorchis Sinensis cyclopholin a antibodies. AB - BACKGROUND: Cyclophilin A (CyPA), a ubiquitously distributed intracellular protein, is thought to be one of the important inflammatory factors and plays a significant role in the development process of sepsis. In the form of cytokine, CyPA deteriorates sepsis by promoting intercellular communication, apoptosis of endothelial cells and chemotactic effect on inflammatory cells. In our previous study, cyclophilin A of Clonorchis sinensis (CsCyPA), a type of excretory secretory antigen, could induce the patients infected with Clonorchis sinensis to produce specific anti-CsCyPA antibodies. In this study, we investigated whether anti-CsCyPA antibodies could cross-react with CyPA and then play a protective role against sepsis, just like other anti-cytokine antagonists. METHODS: The mice model with sepsis was established with cecal ligation and puncture (CLP). Fifty mg/kg purified anti-CsCyPA antibodies were injected via the caudal vein 6 h after the CLP operation, and persistent observation was performed for 72 h. Blood samples and tissues were collected at 6 h, 12 h, 24 h, 48 h and 72 h after CLP. Cytokines in serum were measured by ELISA. Lung and mesentery tissues were stained with hematoxylin-eosin. Endothelial cells (ECs) isolated from murine aorta were co-cultured with CyPA of mice (MuCyPA) and anti-CsCyPAs for 24 h, then, viability was measured by Cell Counting Kit-8. RESULTS: Anti-CsCyPA antibodies could combine with MuCyPA and inhibit its peptidyl prolyl isomerase (PPIase) activity. In the antibodies treatment group, blood coagulation indicators including PT, aPTT, D-dimer and platelet count were obviously more ameliorative, the proinflammary factors like IL-6, TNF-alpha, IL-1beta were significantly lower at 12 h and 24 h after surgery and the viability of ECs was significantly improved compared to those in the control group. Furthermore, the survival rate was elevated, ranging from 10.0 % to 45.0 % compared to the control group. CONCLUSIONS: These antibodies may have a favorable effect on sepsis via inhibition of enzymic activity or protection of endothelial cells. PMID- 26427808 TI - Pediatric Acute Kidney Injury-Deadly Now, Costly Later, and a Public Health Burden. PMID- 26427809 TI - Critical Care Transport: How Do We Measure Up? PMID- 26427810 TI - Under Pressure: Defining Management Goals for Pediatric Traumatic Brain Injury. PMID- 26427811 TI - Pediatric Out-of-Hospital Cardiac Arrest Outcomes: A Case of Male/Female Inequality? PMID- 26427812 TI - Family-Centered Care in the PICU: Where Do We Go From Here? PMID- 26427813 TI - Is It Safe? Are There Limits With Procedural Sedation for Endoscopy in Children? PMID- 26427814 TI - Who Should Perform Critical Procedures on Children Prehospital, and How Often? PMID- 26427815 TI - Early Enteral Nutrition in the PICU: Should We Trust Our Gut? PMID- 26427816 TI - Fluid Resuscitation in Pediatric Sepsis: Lack of Data Versus Lack of Equipoise. PMID- 26427817 TI - A Changing Workforce for the Changing Needs of Critically Ill Children in the United States and Canada. PMID- 26427818 TI - It's About Time .... PMID- 26427819 TI - Standardizing the Postoperative Handover Process in the PICU. PMID- 26427820 TI - The authors reply. PMID- 26427821 TI - Is It Time for Food of the Soul in Pediatric Critical Care? PMID- 26427822 TI - The authors reply. PMID- 26427823 TI - Motivational strategies for returning patients with low back pain to usual activities: A survey of physiotherapists working in Australia. AB - Timely resumption of usual activities is integral to successful functional outcomes in individuals with low back pain (LBP). Little is known about how physiotherapists motivate their patients achieve this. This study examined physiotherapists' knowledge, reported usage and training in a set of 12 motivational strategies. The results of an online cross sectional survey of 170 Australian physiotherapists were compared descriptively, and potential associations between therapist training and strategy use, confidence and perceived effectiveness analysed. Participants considered it extremely important to motivate individuals with LBP to return to usual activities and most commonly reported managing this aspect of treatment exclusively. Active goal setting was the most recognised motivational strategy and transtheoretical based counselling the least recognised. Provision of verbal information and praise/encouragement were reported as the most frequently used strategies. The most common reasons for not using a familiar motivational strategy were time constraints and lack of training. Training in active goal setting was associated with greater use, confidence and perceived effectiveness and was most commonly perceived as moderately effective. Cognitive behavioural therapy was well recognised and training associated with greater use and confidence but not perceived effectiveness. Motivational interviewing was known to approximately half of respondents, consistent with its infancy in LBP and training was not associated with use, confidence or perceived effectiveness. Further research into clearly defined, time efficient and physiotherapy specific motivational interventions for individuals ambivalent to returning to usual activities following an episode of low back pain, may help address the issues identified by the current survey. PMID- 26427824 TI - Osteopathic educators' attitudes towards osteopathic principles and their application in clinical practice: A qualitative inquiry. AB - RATIONALE: The implicit use of overarching osteopathic principles (OP) in clinical practice is a regulatory requirement; agreed definition of what constitutes such principles remains elusive. The profession currently faces questions of identity and relevance in the face of evidence-informed healthcare. OBJECTIVE: This study sought to investigate the opinions and experiences of practising osteopathic educators as to how OP are relevant to clinical practice in isolation and to the profession as a whole. DESIGN: A qualitative approach employing grounded theory to explore the views of current practitioners involved in osteopathic education. SUBJECTS: Nine practising osteopaths were selected for the study using initially purposive then theoretical sampling. METHODOLOGY: Semi structured interviews were used to gather data, audio-recorded, transcribed verbatim and anonymised. Data was analysed and interpreted using a thematic framework approach and conceptually modelled. Triangulation was completed; peer corroboration for high-level themes and participant confirmation for transcript authenticity was obtained. RESULTS: Two polarised concepts emerged: (1) OP benefit the profession and (2) OP limit or jeopardize the profession. These emanated from different perceptions of the identity of osteopathy: (1) osteopathy as a philosophy or (2) osteopathy as a manual therapy with a philosophical background. CONCLUSION: The osteopathic profession faces the danger of being divided on the basis of ideological differences from within. The increasing criticality applied to UK healthcare behoves the osteopathic profession to clarify its aims, guiding 'principles' and underlying values. This could be problematic in light of the divergence of views, leading to a situation of either settling these differences or irrevocably fracturing the profession. PMID- 26427825 TI - Clarifying phylogenetic relationships and the evolutionary history of the bivalve order Arcida (Mollusca: Bivalvia: Pteriomorphia). AB - The systematics of the bivalve order Arcida constitutes an unresolved conundrum in bivalve systematics. The current definition of Arcida encompasses two superfamilies: Limopsoidea, which includes the recent families Philobryidae and Limopsidae, and Arcoidea, which encompasses the families Arcidae, Cucullaeidae, Noetiidae, Glycymerididae and Parallelodontidae. This classification, however, is controversial particularly with respect to the position and taxonomic status of Glycymerididae. Previous molecular phylogenies were limited either by the use of only a single molecular marker or by including only a few limopsoid and glycymeridid taxa. The challenging nature of Arcida taxonomy and the controversial results of some of the previous studies, prompted us to use a broad range of taxa (55 species), three nuclear markers (18S rRNA, 28S rRNA and histone H3) and a wide range of algorithmic approaches. This broad but stringent approach led to a number of results that differ significantly from previous studies. We provide the first molecular evidence that supports the separation of Arcoidea from Limopsoidea, although the exact position of Glycymerididae remains unresolved, and the monophyly of Limopsoidea is algorithm-dependent. In addition, we present the first time-calibrated evolutionary tree of Arcida relationships, indicating a significant increase in the diversification of arcidan lineages at the beginning of the Cretaceous, around 140Ma. The monophyly of Arcida, which has been supported previously, was confirmed in all our analyses. Although relationships among families remain somehow unresolved we found support for the monophyly of most arcidan families, at least under some analytical conditions (i.e., Glycymerididae, Noetiidae, Philobryidae, and Limopsidae). However, Arcidae, and particularly Arcinae, remain a major source of inconsistency in the current system of Arcida classification and are in dire need of taxonomic revision. PMID- 26427826 TI - Inactivation of human pathogenic dermatophytes by non-thermal plasma. AB - Non-thermal plasma (NTP) was tested as an in vitro deactivation method on four human pathogenic dermatophytes belonging to all ecological groups including anthropophilic Trichophyton rubrum and Trichophyton interdigitale, zoophilic Arthroderma benhamiae, and geophilic Microsporum gypseum. The identification of all strains was confirmed by sequencing of ITS rDNA region (internal transcribed spacer region of ribosomal DNA). Dermatophyte spores were suspended in water or inoculated on agar plates and exposed to NTP generated by a positive or negative corona discharge, or cometary discharge. After 15 min of exposure to NTP a significant decrease in the number of surviving spores in water suspensions was observed in all species. Complete spore inactivation and thus decontamination was observed in anthropophilic species after 25 min of exposure. Similarly, a significant decrease in the number of surviving spores was observed after 10-15 min of exposure to NTP on the surface of agar plates with full inhibition after 25 min in all tested species except of M. gypseum. Although the sensitivity of dermatophytes to the action of NTP appears to be lower than that of bacteria and yeast, our results suggest that NTP has the potential to be used as an alternative treatment strategy for dermatophytosis and could be useful for surface decontamination in clinical practice. PMID- 26427827 TI - Flavin mononucleotide (FMN)-based fluorescent protein (FbFP) as reporter for promoter screening in Clostridium cellulolyticum. AB - Conventional methods for screening promoters in anaerobic bacteria are generally based on detection of enzymatic reactions and thus usually complicated or strain specific. Therefore a more efficient and universal method will be valuable. Here, using cellulolytic bacteria Clostridium cellulolyticum H10 as a model, we employed an oxygen-independent flavin-based fluorescent protein (FbFP) derived from Pseudomonas putida as a quantitative reporter for the screening of promoter via monitoring fluorescence intensity. The stability and reliability of FbFP fluorescence were proven by the high correlation (R(2)=0.87) between fluorescence intensity and abundance of FbFP. Moreover, two endogenous promoters with exceptional performance were identified and characterized, including a constitutive promoter p3398 and an inducible promoter p1133. Compared to the existing reporter systems widely used in clostridia, this FbFP-based method is more rapid, intuitive and versatile, and the endogenous promoters reported here should enrich the synthetic biology toolbox for this and related organisms. PMID- 26427828 TI - Usefulness of Pseudocontinuous Arterial Spin-Labeling for the Assessment of Patients with Head and Neck Squamous Cell Carcinoma by Measuring Tumor Blood Flow in the Pretreatment and Early Treatment Period. AB - BACKGROUND AND PURPOSE: For the assessment of the treatment response in non surgical treatment, tumor blood flow provides the functional information of the tumor which is different from the morphological information such as tumor volume. The purpose of this study was to evaluate the diagnostic value of tumor blood flow values obtained by pseudocontinuous arterial spin-labeling in patients with head and neck squamous cell carcinoma. MATERIALS AND METHODS: Forty-one patients with head and neck squamous cell carcinoma were evaluated by using pseudocontinuous arterial spin-labeling. Quantitative tumor blood flow was calculated at the pretreatment and the early treatment periods in all the patients, and the percentage change of tumor blood flow between the two was calculated. At the early treatment period, based on their tumor volume reduction rate, we divided the patients into stable disease and partial response groups for a subgroup analysis. The local control or failure was confirmed either by histopathology or by radiologic evaluation within the follow-up. RESULTS: Pretreatment tumor blood flow in patients in the failure group was significantly lower than that in patients in the local control group. In the subgroup analysis of patients with stable disease, the percentage change of tumor blood flow was significantly larger (due to the tumor blood flow increase from pretreatment value) in the local control group than in the failure group. In addition, in patients with a partial response, the percentage change of tumor blood flow was significantly smaller (due to the tumor blood flow decrease from the pretreatment value) in the local control group than in the failure group. The accuracy for determination of the local control group or the failure group in pretreatment tumor blood flow was 0.83 and that in the combination use of the percentage change of tumor blood flow and tumor volume in the early treatment period was 0.93. CONCLUSIONS: Tumor blood flow obtained by pseudocontinuous arterial spin labeling can be useful for the determination of local control. The combined use of the percentage change of tumor blood flow and tumor volume had particularly high diagnostic accuracy. PMID- 26427829 TI - Posterior Inferior Cerebellar Artery Patency after Flow-Diverting Stent Treatment. AB - BACKGROUND AND PURPOSE: The rate of PICA occlusion after flow-diverting stent placement for vertebral and vertebrobasilar artery aneurysms is not known. The purpose of this study is to determine the medium-term rate of PICA patency and risk factors for occlusion after such aneurysm treatment. MATERIALS AND METHODS: Patients were identified who had vertebral or vertebrobasilar artery aneurysms and who were treated by placing a flow-diverting stent across the PICA ostium. Demographic and procedural factors associated with stent placement were recorded. Patency of the PICA was evaluated immediately after stent placement and on follow up angiography. RESULTS: Thirteen patients with vertebral or vertebrobasilar artery aneurysms were treated in the study period, of whom 4 presented with subarachnoid hemorrhage. The average number of devices that spanned the PICA ostium was 1.77 (range, 1-3), with no immediate PICA occlusions. There were no postoperative strokes in the treated PICA territory, although there was 1 contralateral PICA-territory stroke of unclear etiology without clinical sequelae. In 11 patients with follow-up angiography at a mean of 10.6 months (range, 0.67-27.9 months), the PICA patency rate remained 100%. CONCLUSIONS: Flow diverting stent placement across the PICA ostium in the treatment of vertebral and vertebrobasilar artery aneurysms may not result in immediate or midterm PICA occlusion. PMID- 26427830 TI - Ipilimumab Therapy for Melanoma: A Mimic of Leptomeningeal Metastases. PMID- 26427831 TI - Multimodal Diagnostic Imaging for Hyperacute Stroke. AB - In April 2015, the American Roentgen Ray Society and the American Society of Neuroradiology cosponsored a unique program designed to evaluate the state of the art in the imaging work-up of acute stroke. This topic has grown in importance because of the recent randomized controlled trials demonstrating the clear efficacy of endovascular stroke treatment. The authors, who were participants in that symposium, will highlight the points of emphasis in this article. PMID- 26427832 TI - Diagnostic Accuracy of PET, SPECT, and Arterial Spin-Labeling in Differentiating Tumor Recurrence from Necrosis in Cerebral Metastasis after Stereotactic Radiosurgery. AB - BACKGROUND AND PURPOSE: Radiographic assessment of cerebral metastasis after stereotactic radiosurgery remains a major challenge in neuro-oncology. It is often difficult to distinguish tumor progression from radiation necrosis in this setting using conventional MR imaging. The objective of this study was to compare the diagnostic sensitivity and specificity of different functional imaging modalities for detecting tumor recurrence after stereotactic radiosurgery. MATERIALS AND METHODS: We retrospectively reviewed patients treated between 2007 and 2010 and identified 14 patients with cerebral metastasis who had clinical or radiographic progression following stereotactic radiosurgery and were imaged with arterial spin-labeling, FDG-PET, and thallium SPECT before stereotactic biopsy. Diagnostic accuracy, specificity, sensitivity, positive predictive value, and negative predictive value were calculated for each imaging technique by using the pathologic diagnosis as the criterion standard. RESULTS: Six patients (42%) had tumor progression, while 8 (58%) developed radiation necrosis. FDG-PET and arterial spin-labeling were equally sensitive in detecting tumor progression (83%). However, the specificity of arterial spin-labeling was superior to that of the other modalities (100%, 75%, and 50%, respectively). A combination of modalities did not augment the sensitivity, specificity, positive predictive value, or negative predictive value of arterial spin-labeling. CONCLUSIONS: In our series, arterial spin-labeling positivity was closely associated with the pathologic diagnosis of tumor progression after stereotactic radiosurgery. Validation of this finding in a large series is warranted. PMID- 26427833 TI - On the Use of DSC-MRI for Measuring Vascular Permeability. AB - BACKGROUND AND PURPOSE: Contrast agent extravasation has been shown to confound brain tumor perfusion measurements with DSC-MR imaging, necessitating the use of correction techniques (eg, Weisskoff, Bjornerud). Leakage parameters (K2 and K(a)) postulated to reflect vessel permeability can be extracted from these correction methods; however, the biophysical interpretation of these parameters and their relationship to commonly used MR imaging measures of vascular permeability (eg, contrast agent volume transfer constant, [K(trans)]) remain unclear. Given that vascular density, as assessed by blood volume, and vascular permeability, as reflected by K(trans) (and potentially K2 or K(a)), report on unique and clinically informative vascular characteristics, there is a compelling interest to simultaneously assess these features. MATERIALS AND METHODS: We acquired multiecho DSC-MR imaging data, allowing the simultaneous computation and voxelwise comparison of single- and dual-echo derived measures of K2, K(a) and K(trans) in patients with glioma. This acquisition enabled the investigation of competing T1 and T2* leakage effects and TE dependency on these parameters. RESULTS: K2 and K(a) displayed nonsignificant (P = .150 and P = .060, respectively) voxelwise linear correlations with K(trans), while a significant (P < .001) inverse relationship was observed between K2 and Ka (coefficient of determination [r(2)] = 0.466-0.984). Significantly different (P < .005) mean estimates were found between voxels exhibiting predominately T1 and T2* effects for K2 and K(a). K(trans), however, was observed to be similar between these voxels (0.109 versus 0.092 minutes(-1)). Significant differences (P < .001) in extracellular-extravascular volume fraction (v(e)) (0.285 versus 0.167) were also observed between cohorts. Additionally, K2 and K(a) were found to have a significant quadratic relationship (P = .031 and P = .005, respectively) with v(e). CONCLUSIONS: Estimates of vascular permeability in brain tumors may be simultaneously acquired from multiple-echo DSC-MR imaging via K(trans); however, caution should be used in assuming a similar relationship for K2 and K(a). PMID- 26427834 TI - Postoperative Imaging Findings following Sigmoid Sinus Wall Reconstruction for Pulse Synchronous Tinnitus. AB - BACKGROUND AND PURPOSE: Transmastoid sigmoid sinus wall reconstruction is a surgical technique increasingly used for the treatment of pulsatile tinnitus arising from sigmoid sinus wall anomalies. The imaging appearance of the temporal bone following this procedure has not been well-characterized. The purpose of this study was to evaluate the postoperative imaging appearance in a group of patients who underwent this procedure. MATERIALS AND METHODS: The medical records of 40 consecutive patients who underwent transmastoid sigmoid sinus wall reconstruction were reviewed. Thirteen of 40 patients underwent postoperative imaging. Nineteen CT and 7 MR imaging examinations were assessed for the characteristics of the materials used for reconstruction, the impact of these on the adjacent sigmoid sinus, and complications. RESULTS: Tinnitus resolved in 38 of 40 patients. Nine patients were imaged postoperatively for suspected complications, including dural sinus thrombosis, facial swelling, and wound drainage. Two patients underwent imaging for persistent tinnitus, and 2, for development of tinnitus on the side contralateral to the side of surgery. The materials used for reconstruction (NeuroAlloderm, HydroSet, bone pate) demonstrated characteristic imaging appearances and could be consistently identified. In 5 of 13 patients, there was extrinsic compression of the sigmoid sinus by graft material. Dural sinus thrombosis occurred in 2 patients. CONCLUSIONS: The imaging findings following sigmoid sinus wall repair are characteristic. Graft materials may result in extrinsic compression of the sigmoid sinus, and this finding may be confused with dural venous thrombosis. Awareness of the imaging characteristics of the graft materials used enables this differentiation. PMID- 26427835 TI - Intensity of MRI Gadolinium Enhancement in Cerebral Adrenoleukodystrophy: A Biomarker for Inflammation and Predictor of Outcome following Transplantation in Higher Risk Patients. AB - BACKGROUND AND PURPOSE: Outcomes following hematopoietic stem cell transplantation for higher risk childhood-onset cerebral adrenoleukodystrophy are variable. We explored whether a brain MR imaging gadolinium intensity scoring system improves prediction of neurologic outcome. MATERIALS AND METHODS: We developed a 4-point scale of gadolinium intensity relative to the choroid plexus: 0 = no enhancement; 1 = hypointense; 2 = isointense; 3 = hyperintense. The interobserver concordance of the scale was assessed on 30 randomly chosen studies. Scores were generated for 64 evaluable patients and compared with CSF chitotriosidase levels, a known inflammatory marker correlating with outcomes following transplantation. For 25 evaluable higher risk patients (Loes >=10), the gadolinium intensity score was compared with longer term posttransplantation clinical change. RESULTS: The gadolinium intensity scoring system showed good interobserver reproducibility (kappa = 0.72). Of 64 evaluable boys, the score positively correlated with average concomitant CSF chitotriosidase activity in nanograms/milliliter/hour: 0: 2717, n = 5; 1: 3218, n = 13; 2: 6497, n = 23; and 3: 12,030, n = 23 (P < .01). For 25 evaluable higher risk patients, more intense pretransplantation brain MR imaging gadolinium enhancement predicted greater average loss on the adrenoleukodystrophy neurologic function scale following transplantation: 0/1: adrenoleukodystrophy neurologic function scale score difference = 4.3, n = 7; 2/3: adrenoleukodystrophy neurologic function scale score difference = 10.4, n = 18 (P = .05). CONCLUSIONS: Gadolinium enhancement intensity on brain MR imaging can be scored simply and reproducibly for cerebral adrenoleukodystrophy. The enhancement score significantly correlates with chitotriosidase. In boys with higher risk cerebral disease (Loes >=10), the enhancement score itself predicts neurologic outcome following treatment. Such data may help guide treatment decisions for clinicians and families. PMID- 26427836 TI - Advanced Modeled Iterative Reconstruction in Low-Tube-Voltage Contrast-Enhanced Neck CT: Evaluation of Objective and Subjective Image Quality. AB - BACKGROUND AND PURPOSE: Dose-saving techniques in neck CT cause increased image noise that can be counteracted by iterative reconstruction. Our aim was to evaluate the image quality of advanced modeled iterative reconstruction (ADMIRE) in contrast-enhanced low-tube-voltage neck CT. MATERIALS AND METHODS: Sixty-one patients underwent 90-kV(peak) neck CT by using third-generation 192-section dual source CT. Image series were reconstructed with standard filtered back-projection and ADMIRE strength levels 1, 3, and 5. Attenuation and noise of the sternocleidomastoid muscle, internal jugular vein, submandibular gland, tongue, subscapularis muscle, and cervical fat were measured. Signal-to-noise and contrast-to-noise ratios were calculated. Two radiologists assessed image noise, image contrast, delineation of smaller structures, and overall diagnostic acceptability. Interobserver agreement was calculated. RESULTS: Image noise was significantly reduced by using ADMIRE compared with filtered back-projection with the lowest noise observed in ADMIRE 5 (filtered back-projection, 9.4 +/- 2.4 Hounsfield units [HU]; ADMIRE 1, 8.3 +/- 2.8 HU; ADMIRE 3, 6.7 +/- 2.0 HU; ADMIRE 5, 5.4 +/- 1.7 HU; all, P < .001). Sternocleidomastoid SNR and internal jugular vein-sternocleidomastoid contrast-to-noise ratios were significantly higher for ADMIRE with the best results in ADMIRE 5 (all, P < .001). Subjective image quality and image contrast of ADMIRE 3 and 5 were consistently rated better than those for filtered back-projection and ADMIRE 1 (all, P < .001). Image noise was rated highest for ADMIRE 5 (all, P < .005). Delineation of smaller structures was voted higher in all ADMIRE strength levels compared with filtered back-projection (P < .001). Global interobserver agreement was good (0.75). CONCLUSIONS: Contrast enhanced 90-kVp neck CT is feasible, and ADMIRE 5 shows superior objective image quality compared with filtered back-projection. ADMIRE 3 and 5 show the best subjective image quality. PMID- 26427837 TI - Spine Cryoablation: Pain Palliation and Local Tumor Control for Vertebral Metastases. AB - BACKGROUND AND PURPOSE: Percutaneous cryoablation has emerged as a minimally invasive technique for the management of osseous metastases. The purpose of this study was to assess the safety and effectiveness of percutaneous imaging-guided spine cryoablation for pain palliation and local tumor control for vertebral metastases. MATERIALS AND METHODS: Imaging-guided spine cryoablation was performed in 14 patients (31 tumors) with vertebral metastases refractory to conventional chemoradiation therapy or analgesics, to achieve pain palliation and local tumor control in this retrospective study. Spinal nerve and soft-tissue thermal protection techniques were implemented in all ablations. Patient response was evaluated by a pain numeric rating scale administered before the procedure and 1 week, 1 month, and 3 months after the procedure. Pre- and postprocedural analgesic requirements (expressed as morphine-equivalent dosages) were also analyzed at the same time points. Pre- and postprocedural cross-sectional imaging was evaluated in all patients to assess local control (no radiographic evidence of disease at the treated sites). Complications were monitored. Analysis of the primary end points was undertaken via paired-comparison procedures by using the Wilcoxon signed rank test. RESULTS: Thirty-one tumors were ablated in 14 patients (9 women and 5 men; 20-73 years of age; mean age, 53 years). The most common tumor location was in the lumbar spine (n = 14, 45%), followed by the thoracic spine (n = 8, 26%), sacrum (n = 6, 19%), coccyx (n = 2, 6%), and cervical spine (n = 1, 3%). There were statistically significant decreases in the median numeric rating scale score and analgesic usage at 1-week, 1-month, and 3-month time points (P < .001 for all). Local tumor control was achieved in 96.7% (30/31) of tumors (median follow-up, 10 months). Two patients had transient postprocedural unilateral lower extremity radiculopathy and weakness. CONCLUSIONS: Percutaneous imaging-guided spine cryoablation is a safe and effective treatment for pain palliation and local tumor control for vertebral metastases. PMID- 26427838 TI - Proton Density MRI Increases Detection of Cervical Spinal Cord Multiple Sclerosis Lesions Compared with T2-Weighted Fast Spin-Echo. AB - BACKGROUND AND PURPOSE: There is a paucity of literature that supports the Consortium of Multiple Sclerosis Centers guideline that proton density MR imaging is a core spinal cord sequence. We hypothesized that proton density fast spin echo imaging is superior to T2 fast spin-echo MR imaging for the detection of cervical cord MS lesions. This study compared the detection rate and conspicuity of cervical cord MS lesions on sagittal 1.5T proton density fast spin-echo and T2 fast spin-echo MR imaging. MATERIALS AND METHODS: One hundred consecutive patients with MS imaged with 1.5T sagittal proton density fast spin-echo and T2 fast spin-echo cervical cord MR imaging between September 2012 and October 2013 were retrospectively included. The number of MS lesions detected on each sequence was recorded; conspicuity was assessed quantitatively with the lesion-to-cord contrast ratio and lesion-contrast-to-noise ratio. Statistical analysis was performed by using the Wilcoxon signed rank test. RESULTS: Seventy-eight patients had MS cord lesions detected. Proton density fast spin-echo imaging detected a greater number of lesions (n = 181) compared with T2 fast spin-echo imaging (n = 137, P < .001). Fifteen patients (19%) with abnormal findings on proton density fast spin-echo imaging had normal findings on T2 fast spin-echo imaging; no patient with abnormal T2 fast spin-echo imaging findings had normal proton density fast spin-echo imaging findings. Although proton density fast spin-echo and T2 fast spin-echo imaging had similar lesion-to-cord contrast ratios (proton density fast spin-echo, 0.32 +/- 0.01, versus T2 fast spin-echo, 0.33 +/- 0.01; P = .43), proton density fast spin-echo had greater lesion-contrast-to-noise ratio (proton density fast spin-echo, 82 +/- 3.0, versus T2 fast spin-echo, 64 +/- 2.6; P < .001). CONCLUSIONS: Proton density fast spin-echo imaging is superior to T2 fast spin-echo MR imaging for the detection of cervical cord MS lesions. Proton density fast spin-echo detects cord lesions in patients in whom T2 fast spin-echo findings appear normal. This study forms the evidentiary base for the current Consortium of Multiple Sclerosis Centers guideline that proton density imaging is a core spinal cord sequence. PMID- 26427839 TI - Dynamic Contrast-Enhanced MR Imaging in Head and Neck Cancer: Techniques and Clinical Applications. AB - In the past decade, dynamic contrast-enhanced MR imaging has had an increasing role in assessing the microvascular characteristics of various tumors, including head and neck cancer. Dynamic contrast-enhanced MR imaging allows noninvasive assessment of permeability and blood flow, both important features of tumor hypoxia, which is a marker for treatment resistance for head and neck cancer. Dynamic contrast-enhanced MR imaging has the potential to identify early locoregional recurrence, differentiate metastatic lymph nodes from normal nodes, and predict tumor response to treatment and treatment monitoring in patients with head and neck cancer. Quantitative analysis is in its early stage and standardization and refinement of technique are essential. In this article, we review the techniques of dynamic contrast-enhanced MR imaging data acquisition, analytic methods, current limitations, and clinical applications in head and neck cancer. PMID- 26427840 TI - Proteomics discovery of radioresistant cancer biomarkers for radiotherapy. AB - Radiotherapy (RT) is one of the most important strategies in cancer treatment. Radioresistance is a major challenge to RT and results in locoregional recurrence and metastasis. Thus, there is a great interest in investigating biomarkers to distinguish radiosensitive from radioresistant (RR) cancer patients. The development of proteomic techniques has sparked new searches for novel proteins for cancer biomarker discovery. Modern proteomic techniques allow for a high throughput analysis of samples with the visualization and quantification of thousands of potential protein and peptide markers. The discovery of RR biomarkers can provide a clue for predicting RT response and discover therapeutic targets for developing personalised medicine of individual patients. In the past decade, emerging advanced proteomic technologies have been performed to identify radiation-related biomarkers in human cancers. This review discusses the mass spectrometry (MS)-based proteomic techniques in RR cancer biomarker discovery, summarises RR biomarkers identified in cancers from proteomics-based findings and explores potential values of RR biomarkers for future clinical trials. PMID- 26427841 TI - Identification of novel hereditary cancer genes by whole exome sequencing. AB - Whole exome sequencing (WES) provides a powerful tool for medical genetic research. Several dozens of WES studies involving patients with hereditary cancer syndromes have already been reported. WES led to breakthrough in understanding of the genetic basis of some exceptionally rare syndromes; for example, identification of germ-line SMARCA4 mutations in patients with ovarian hypercalcemic small cell carcinomas indeed explains a noticeable share of familial aggregation of this disease. However, studies on common cancer types turned out to be more difficult. In particular, there is almost a dozen of reports describing WES analysis of breast cancer patients, but none of them yet succeeded to reveal a gene responsible for the significant share of missing heritability. Virtually all components of WES studies require substantial improvement, e.g. technical performance of WES, interpretation of WES results, mode of patient selection, etc. Most of contemporary investigations focus on genes with autosomal dominant mechanism of inheritance; however, recessive and oligogenic models of transmission of cancer susceptibility also need to be considered. It is expected that the list of medically relevant tumor-predisposing genes will be rapidly expanding in the next few years. PMID- 26427842 TI - The effect of preoperative urinary tract infection on postoperative renal function in prenatally diagnosed ureteropelvic junction obstruction: Indications for the timing of pyeloplasty. AB - PURPOSE: We reviewed renal function after pyeloplasty (PP) in cases of prenatally diagnosed ureteropelvic junction obstruction (PDUPJO) to determine the impact of preoperative urinary tract infection (UTI) on the timing of PP. METHODS: We retrospectively reviewed 81 cases of PDUPJO diagnosed between 1998 and 2013. Incidence of UTI was used to divide 37 kidneys requiring PP (3 bilateral) into U( ): UTI<=1; n=25, and U(+): UTI>=2; n=12 to compare age at PP, grade of hydronephrosis (HN) on ultrasonography (US), glomerular filtration rate (GFR) on diethylenetriaminepentacetic acid (DTPA) renography, and uptake on dimercaptosuccinic acid (DMSA) scintigraphy pre/post PP. RESULTS: Age at first UTI and age at PP were similar. HN improved significantly postPP in all cases. Although DTPA and DMSA were similar prePP, improvement postPP was better in U(-) than U(+), but only DMSA in U(-) was statistically significant (15.2%+/-4.0% vs. 20%+/-3.7%; p=0.049). There were no complications or UTI postPP. CONCLUSION: Two or more UTIs would appear to be associated with postPP renal dysfunction in PDUPJO. Thus, PP should be performed after the initial UTI but before the second UTI. PMID- 26427843 TI - Response to Letter to the Editor. PMID- 26427844 TI - Triple-wavelength overlapping resonance Rayleigh scattering method for facile and rapid assay of perfluorooctane sulfonate. AB - In the present study, a novel triple-wavelength overlapping resonance Rayleigh scattering (TWO-RRS) method had been well established to detect perfluorooctane sulfonate (PFOS). We found that crystal violet (CV) could react with PFOS to form 1:1 ion-association complex by electrostatic attraction and hydrophobic effect over a wide pH range (5.0~11.0) in less than 60 s. The complexes would further self-aggregated into nanoparticles [CV-PFOS]n. Based on this phenomenon, not only the absorption and Raman spectra were changed but also the resonance Rayleigh scattering (RRS) intensities were significantly enhanced. And three new RRS peaks located at 327, 492, and 654 nm were clearly observed, respectively. At the same time, it was found that both the enhanced single-wavelength resonance Rayleigh scattering (SW-RRS) and TWO-RRS intensities against the concentration of PFOS showed an excellent correlation. The detection limits for the three single peaks were 27.4 nmol L(-1) (13.7 MUg L(-1), 327 nm), 27.5 nmol L(-1) (13.8 MUg L(-1), 492 nm), and 31.4 nmol L(-1) (15.7 MUg L(-1), 654 nm), and for TWO-RRS method was 5.9 nmol L(-1) (3.0 MUg L(-1)). Moreover, it could be applied to determine PFOS water samples successfully. PMID- 26427845 TI - Assessment of typical natural processes and human activities' impact on the quality of drinking water. AB - This paper provides insight into the quality of groundwater used for public water supply on the territory of Temerin municipality (Vojvodina, Serbia). The following parameters were measured: color, turbidity, pH, KMnO4 consumption, total dissolved solids (TDS), EC, NH4+, Cl-, NO2-, NO3-, Fe, Mn, As, Ca2+, Mg2+, SO4(2-), HCO3-, K+, and Na+. The correlations and ratios among parameters that define the chemical composition were determined aiming to identify main processes that control the formation of the chemical composition of the analyzed waters. Groundwater from three analyzed sources is Na-HCO3 type. Elevated organic matter content, ammonium ion content, and arsene content are characteristic for these waters. The importance of organic matter decay is assumed by positive correlation between organic matter content and TDS, and HCO3- content. There is no evidence that groundwater chemistry is determined by the depth of captured aquifer interval. The main natural processes that control the chemistry of all analyzed water are cation exchange and feldspar weathering. The dominant cause of As concentration in groundwater is the use of mineral fertilizers and of KMnO4 in urban area. The concentration of As and KMnO4 in the observed sources is inversely proportional to the distance from agricultural land and urban area. 2D model of distribution of As and KMnO4 is done, and it is applicable in detecting sources of pollution. By using this model, we can quantify the impact of certain pollutants on unfavorable content of some parameters in groundwater. PMID- 26427846 TI - Enhanced expression of potassium-chloride cotransporter KCC2 in human temporal lobe epilepsy. AB - Synaptic reorganization in the epileptic hippocampus involves altered excitatory and inhibitory transmission besides the rearrangement of dendritic spines, resulting in altered excitability, ion homeostasis, and cell swelling. The potassium-chloride cotransporter-2 (KCC2) is the main chloride extruder in neurons and hence will play a prominent role in determining the polarity of GABAA receptor-mediated chloride currents. In addition, KCC2 also interacts with the actin cytoskeleton which is critical for dendritic spine morphogenesis, and for the maintenance of glutamatergic synapses and cell volume. Using immunocytochemistry, we examined the cellular and subcellular levels of KCC2 in surgically removed hippocampi of temporal lobe epilepsy (TLE) patients and compared them to control human tissue. We also studied the distribution of KCC2 in a pilocarpine mouse model of epilepsy. An overall increase in KCC2-expression was found in epilepsy and confirmed by Western blots. The cellular and subcellular distributions in control mouse and human samples were largely similar; moreover, changes affecting KCC2-expression were also alike in chronic epileptic human and mouse hippocampi. At the subcellular level, we determined the neuronal elements exhibiting enhanced KCC2 expression. In epileptic tissue, staining became more intense in the immunopositive elements detected in control tissue, and profiles with subthreshold expression of KCC2 in control samples became labelled. Positive interneuron somata and dendrites were more numerous in epileptic hippocampi, despite severe interneuron loss. Whether the elevation of KCC2-expression is ultimately a pro- or anticonvulsive change, or both-behaving differently during ictal and interictal states in a context-dependent manner remains to be established. PMID- 26427847 TI - Operative Results and Clinical Features of Chronic Stanford Type B Aortic Dissection: Examination of 234 Patients Over 6 Years. AB - OBJECTIVE/BACKGROUND: Recently, the indications for thoracic endovascular aortic repair (TEVAR) have been expanding, and the applicability of TEVAR for acute type B aortic dissection (TBAD) is proposed with regard to the high mortality of open surgery for chronic TBAD. TEVAR in the acute phase may lead to remodeling of the false lumen (FL), but it is controversial whether it completely resolves the aortic expansion in the chronic phase. In this study, operative results and the relationship between FL status and the time before surgical intervention were retrospectively analyzed. METHODS: From January 2008 to September 2013, 234 patients underwent open surgery for chronic TBAD. Most patients were on left heart bypass. By considering Japanese aortic disease treatment guidelines and the smaller physique of Japanese patients, operative indications were aneurysm >50 mm in diameter or rapid aneurysm enlargement of >5 mm in a 6 month period. RESULTS: In 180 cases, the FL was patent. The mean interval between onset of TBAD and operation was 61 +/- 54 months. There was no significant difference between patients in the patent FL group and those in the thrombosed FL group (p = .44). Mean ratio of FL diameter to maximum aortic diameter (FL/AD) was 0.64 +/- 0.21. There was no correlation between FL and AD before the operation (r = .12). Descending thoracic aortic replacement (DTAR) was performed in 127 cases and thoracic ascending aortic replacement (TAAR) in 107 cases (Crawford type I, n = 9; Crawford type II, n = 65; Crawford type III and IV, n = 22, respectively; Safi type V, n = 11). The overall operative mortality was 6.8%: 3.9% (5/127) for DTAR and 10.3% (11/107) for TAAR. The three year survival was 86.7, and the freedom from re-intervention rate was 97.0%. CONCLUSION: Enlargement of uncomplicated TBAD in the chronic phase was poorly related to FL status and the results of open repair have improved. However, further prospective study is necessary. PMID- 26427848 TI - Linking landscape development intensity within watersheds to methyl-mercury accumulation in river sediments. AB - An indicator of the disturbance of natural systems, the landscape development intensity (LDI) index, was used to assess the potential for land-use within watersheds to influence the production/accumulation of methyl-mercury (MeHg) in river sediments. Sediment samples were collected from locations impacted by well identified land-use types within the Mobile-Alabama River Basin in Southeastern USA. The samples were analyzed for total-Hg (THg) and MeHg concentrations and the obtained values correlated to the calculated LDI indexes of the sampled watersheds to assess the impact of prevalent land use/land cover on MeHg accumulation in sediments. The results show that unlike THg, levels of MeHg found in sediments are impacted by the LDI indexes. Overall, certain combinations of land-use types within a given watershed appear to be more conducive to MeHg accumulation than others, therefore, pointing to the possibility of targeting land-use practices as potential means for reducing MeHg accumulation in sediments, and ultimately, fish contamination. PMID- 26427849 TI - Traumatic Experience and Somatoform Dissociation Among Spirit Possession Practitioners in the Dominican Republic. AB - Recent studies in African contexts have revealed a strong association between spirit possession and severe trauma, with inclusion into a possession cult serving at times a therapeutic function. Research on spirit possession in the Dominican Republic has so far not included quantitative studies of trauma and dissociation. This study evaluated demographic variables, somatoform dissociative symptoms, and potentially traumatizing events in the Dominican Republic with a group of Vodou practitioners that either do or do not experience spirit possession. Inter-group comparisons revealed that in contrast to non-possessed participants (n = 38), those experiencing spirit possession (n = 47) reported greater somatoform dissociation, more problems with sleep, and previous exposure to mortal danger such as assaults, accidents, or diseases. The two groups did not differ significantly in other types of trauma. The best predictor variable for group classification was somatoform dissociation, although those items could also reflect the experience of followers during a possession episode. A factor analysis across variables resulted in three factors: having to take responsibility early on in life and taking on a professional spiritual role; traumatic events and pain; and distress/dissociation. In comparison with the non possessed individuals, the possessed ones did not seem to overall have a remarkably more severe story of trauma and seemed to derive economic gains from possession practice. PMID- 26427850 TI - Phylogenetic analysis of Indian rabies virus isolates targeting the complete glycoprotein gene. AB - Rabies a fatal viral zoonosis is endemic in India. There is no report on phylogenetic study of Indian rabies virus isolates based on the complete G gene. In the present study, a total of 25 rabies positive brain samples collected during 2001-2014 from North India (UP, MP, Delhi, Rajasthan), South India (Kerala and Karnataka) and Gujarat states belonging to six different host species were subjected to G gene amplification by RT-PCR as three overlapping fragments of 881 bp, 991 bp and 618 bp. Phylogenetic analysis revealed that all Indian rabies virus isolates are genetically closely related with Arctic-like 1a lineage viruses. However, two distinct clusters were identified namely, India South and India North. All the Indian rabies isolates had 95.5-100% homology related to geography, but not to host species. Deduced amino acids on comparison revealed two amino acid changes, aa 356 in ECTO; N->K and aa 458; M->I, which were found to distinguish between the India South and India North isolates. PMID- 26427851 TI - Selective Lifelong Destruction of Brain Monoaminergic Nerves Through Perinatal DSP-4 Treatment. AB - N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) is a highly selective neurotoxin for noradrenergic projections originating from the locus coeruleus (LC). The outcome of the systemic DSP-4 treatment of newborn rats is an alteration in postnatal development of the noradrenergic system, involving the permanent denervation of distal noradrenergic projection areas (neocortex, hippocampus, spinal cord), accompanied by noradrenergic hyperinnervation in regions proximal to the LC cell bodies (cerebellum, pons-medulla). DSP-4 is well tolerated by developing rats and does not increase the mortality rate. Permanent noradrenergic denervation in the cerebral cortex and spinal cord is present at all developmental stages, although this effect is more pronounced in rats treated with DSP-4 at an early age, i.e., up to postnatal day 5 (PND 5). Notably, regional hyperinnervation is a hallmark of neonatal DSP-4 treatment, which is not observed after either prenatal or adult DSP-4 application. In contrast to robust biochemical changes in the brain, DSP-4 treatment of newborn rats has a marginal effect on arousal and cognition functions assessed in adulthood, and these processes are critically influenced by the action of the noradrenergic neurotransmitter, norepinephrine (NE). Conversely, neonatal DSP-4 does not significantly affect 5-hydroxytryptamine (serotonin; 5-HT), dopamine (DA), gamma aminobutyric acid (GABA), and histamine levels in brain. However, as a consequence of altering the functional efficacy of 5-HT1A, 5-HT1B, DA, and GABA receptors, these neurotransmitter systems are profoundly affected in adulthood. Thus, the noradrenergic lesion obtained with neonatal DSP-4 treatment represents a unique neurobiological technique for exploring the interplay between various neuronal phenotypes and examining the pathomechanism of neurodevelopmental disorders. PMID- 26427853 TI - Loss of glucocerebrosidase 1 activity causes lysosomal dysfunction and alpha synuclein aggregation. PMID- 26427852 TI - Murine Sca1(+)Lin(-) bone marrow contains an endodermal precursor population that differentiates into hepatocytes. AB - The direct differentiation of hepatocytes from bone marrow cells remains controversial. Several mechanisms, including transdifferentiation and cell fusion, have been proposed for this phenomenon, although direct visualization of the process and the underlying mechanisms have not been reported. In this study, we established an efficient in vitro culture method for differentiation of functioning hepatocytes from murine lineage-negative bone marrow cells. These cells reduced liver damage and incorporated into hepatic parenchyma in two independent hepatic injury models. Our simple and efficient in vitro protocol for endodermal precursor cell survival and expansion enabled us to identify these cells as existing in Sca1(+) subpopulations of lineage-negative bone marrow cells. The endodermal precursor cells followed a sequential developmental pathway that included endodermal cells and hepatocyte precursor cells, which indicates that lineage-negative bone marrow cells contain more diverse multipotent stem cells than considered previously. The presence of equivalent endodermal precursor populations in human bone marrow would facilitate the development of these cells into an effective treatment modality for chronic liver diseases. PMID- 26427855 TI - Erratum to: Streptomyces mangrovi sp. nov., isolated from mangrove forest sediment. PMID- 26427856 TI - Phytomonospora cypria sp. nov., isolated from soil. AB - A Gram-stain positive actinobacterial strain, designated KT1403(T), was isolated from a soil sample, collected from Karpaz, Magusa, Northern Cyprus, and characterised using a polyphasic approach. Morphological characteristics and chemotaxonomic data indicated that the strain belongs to the genus Phytomonospora. The cell wall of the novel strain contained meso-diaminopimelic acid and galactose, glucose and mannose as the major sugars in whole cell hydrolysates. The polar lipids in the cell membrane were identified as diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, an unidentified aminophospholipid and three unidentified glycolipids. The predominant menaquinones were MK-10(H6) and MK-10(H4). The major fatty acids were found to be iso C15:0 , anteiso C15:0 and anteiso C17:0. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain KT1403(T) belongs to the genus Phytomonospora with a sequence similarity of 99.73 % with Phytomonospora endophytica, the type species of the genus. DNA-DNA hybridization further differentiated strain KT1403(T) from its near phylogenetic neighbour, P. endophytica DSM 45386(T) (29.0 +/- 2.2 % DNA relatedness). Therefore, it is proposed that strain KT1403(T) represents a novel species of the genus Phytomonospora, for which the name Phytomonospora cypria sp. nov. is proposed. The type strain is KT1403(T) (=KCTC 29479(T) = DSM 46767(T)). PMID- 26427854 TI - Self-Assembling Peptide Nanofiber Containing Long Motif of Laminin Induces Neural Differentiation, Tubulin Polymerization, and Neurogenesis: In Vitro, Ex Vivo, and In Vivo Studies. AB - Spinal cord injury (SCI) in humans stayed a ruining and healless disorder. Since longer laminin motif (CQAASIKVAV (CQIK)) better mimics conformation of native region in active site than isoleucine-lysine-valine-alanine-valine (IKVAV) and resulted in improved cellular response so, for the first time in this study, CQIK bounded with two glycines spacer and (RADA)4 as a self-assembling peptide nanofiber backbone (-CQIK) was used. The purpose of this study was to investigate the role of -CQIK in neural differentiation of human endometrial-derived stromal cells (hEnSCs) in vitro, tubulin polymerization ex vivo, and assess the supportive effect of this hydrogel in an animal model of chronic SCI. Results disclosed that proton concentration has direct effect on hEnSCs membrane damage but not on neuroblastoma cells. However, cell viability of neuroblastoma encapsulated into -CQIK was higher than hEnSCs at the concentration of 0.125 % v/w. Gene expression data confirmed neurogenesis, TH over-expression, and glial fibrillary acidic protein (GFAP) suppression eventually through alpha6 and beta1 integrin site. However, it revealed higher neurogenesis as compared to bone morrow homing peptides (BMHP). Although, Basso, Beattie, Bresnahan (BBB) score of chronic model of SCI in rat was higher than control and phosphate-buffered saline (PBS) group but significantly was less than BMHP group. However, -CQIK had induced neurite outgrowth and myelination and inhibited astrogliosis. Tubulin polymerization data using UV spectroscopy showed higher degree of polymerization. However, tubulin polymerization was dependent on nanofiber concentration. Based on our results, it might be concluded that peptidic nanofiber containing long motif of laminin holds great promise for spinal cord injury recovery with increment of neurogenesis and astrogliosis decrement. PMID- 26427857 TI - Nocardia arizonensis sp. nov., obtained from human respiratory specimens. AB - In 2008, three clinical isolates (W9405(T), W9409 and W9575) were obtained from bronchial wash or sputum specimens from patients from the state of Arizona and characterised by polyphasic analysis. All three clinical isolates 16S rRNA gene sequences were found to be 100% identical to each other and showed the strains belong in the genus Nocardia. BLASTn searches in the GenBank database of near full-length 16S rRNA gene sequences showed the highest sequence similarities to the type strains of Nocardia takedensis (98.3%, sequence similarity), Nocardia lijiangensis (97.4%), Nocardia harenae (97.4%), and Nocardia xishanensis (97.1%). The DNA-DNA relatedness between isolate W9405(T) and the type strain of N. takedensis is 26.0 +/- 2.4% when measured in silico using genomic DNA sequences. The G+C content of isolate W9405(T) is 68.6 mol%. Chemotaxonomic analyses of the clinical isolates were consistent with their assignment to the genus Nocardia: whole cell hydrolysates contain meso-diaminopimelic acid as the diagnostic diamino acid of peptidoglycan; the whole-cell sugars are arabinose and galactose; the predominant phospholipids include diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylinositol; MK-8-(H4)(omega-cyc) as the major menaquinone; mycolic acids ranging from 38 to 62 carbon atoms; and palmitic acid, tuberculostearic acid, palmitelaidic acid and oleic acid are the major fatty acids. Genus and species specific profiles were obtained following analysis by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectra of the clinical isolates. All isolates were found to be intermediately resistant or resistant to minocycline and resistant to ciprofloxacin but were susceptible to amikacin, imipenem and linezolid. Our polyphasic analysis suggest the three clinical isolates obtained from patients in Arizona represent a novel species of Nocardia for which we propose the name Nocardia arizonensis, with strain W9405(T) (=DSM 45748(T) = CCUG 62754(T) = NBRC 108935(T)) as the type strain. PMID- 26427858 TI - Sphingobium soli sp. nov. isolated from rhizosphere soil of a rose. AB - Strain THG-SQA7(T), a Gram-negative, strictly aerobic, non-motile, rod-shaped bacterium was isolated from rhizosphere soil of a rose in PR China. Strain THG SQA7(T) is closely related to the members of the genus Sphingobium, showing the highest 16S rRNA gene sequence similarities with Sphingobium lactosutens KACC 18100(T) (98.2%) and Sphingobium abikonense KCTC 2864(T) (98.1%). The DNA-DNA relatedness between strain THG-SQA7(T) and S. lactosutens KACC 18100(T) and S. abikonense KCTC 2864(T) was 26.2 +/- 0.9 and 28.3 +/- 1.2%, respectively. Chemotaxonomic data showed that strain THG-SQA7(T) possesses ubiquinone Q-10 as the predominant respiratory quinone, and C(18:1)omega7c, C(16:0), summed feature 3 (C(16:1)omega7c and/or C(16:1)omega6c) and C(14:0) 2OH as the major fatty acids. The major polar lipids were found to be phosphatidylethanolamine, phosphatidylmonomethylethanolamine, phosphatidylglycerol, sphingoglycolipid, diphosphatidylglycerol and phosphatidyldimethylethanolamine. Based on these results, together with phenotypic characterization, a novel species, Sphingobium soli sp. nov. is proposed.with the type strain is THG-SQA7(T) (=CCTCC AB 2015125(T) = KCTC 42607(T)). PMID- 26427859 TI - Breast cancer diagnosis, patterns of care and burden of disease in Queensland, Australia (1998-2004): does being Indigenous make a difference? AB - OBJECTIVES: We compared patterns of care, comorbidity, disability-adjusted life years (DALYs) and survival in Indigenous and non-Indigenous women with breast cancer in Queensland, Australia (1998-2004). METHODS: A cohort study of Indigenous (n = 110) and non-Indigenous women (n = 105), frequency matched on age and remoteness. We used Pearson's Chi-squared analysis to compare proportions, hazard models to assess survival differences and calculated disability-adjusted life years (DALYs). RESULTS: Indigenous women were more likely to be socially disadvantaged (43 vs. 20 %, p < 0.01) have comorbidity (42 vs. 18 % p < 0.01), and have regional spread or distant metastasis (metastasis, 51 vs. 36 %, p = 0.02) than non-Indigenous women; there was no difference in treatment patterns. More Indigenous women died in the follow-up period (p = 0.01). DALY's were 469 and 665 per 100,000 for Indigenous and non-Indigenous women, respectively, with a larger proportion of the burden attributed to premature death among the former (63 vs. 59 %). CONCLUSIONS: Indigenous women with breast cancer received comparable treatment to their non-Indigenous counterparts. The higher proportion of DALYs related to early death in Indigenous women suggests higher fatality with breast cancer in this group. Later stage at diagnosis and higher comorbidity presence among Indigenous women reinforce the need for early detection and improved management of co-existing disease. PMID- 26427860 TI - Educational differentials in cancer mortality and avoidable deaths in Lithuania, 2001-2009: a census-linked study. AB - OBJECTIVES: We investigate relative mortality inequalities by education for detailed cancer sites and provide estimates of deaths which could have been avoided through the elimination of these inequalities. METHODS: A census-linked dataset based on a follow-up of all residents registered in the 2001 census was used for the analysis. Mortality rate ratios were estimated by employing multivariate Poisson regression models for count data. RESULTS: An inverse educational gradient was observed for 11 cancer sites among men and for three cancer sites among women. Substantial shares of these cancer deaths would have been avoided if mortality among less educated groups had been the same as mortality among highly educated groups. CONCLUSIONS: Cancer control plans must consider socioeconomic inequalities and propose ways to improve prevention measures aimed at disadvantaged groups. PMID- 26427861 TI - Support for smoke-free policies in the Cyprus hospitality industry. AB - OBJECTIVES: The present study used attitudinal and behavioural indicators to measure support for smoke-free policies among employers and employees in the hospitality industry in Cyprus. METHODS: A representative sample of 600 participants (95 % response rate) completed anonymous structured questionnaires on demographic variables, smoking status, exposure to second-hand smoke at work and related health beliefs, social norms, and smoke-free policy support. RESULTS: Participants were predominantly males (68.3 %), with a mean age of 40 years (SD = 12.69), and 39.7 % were employers/owners of the hospitality venue. Analysis of variance showed that employers and smokers were less supportive of smoke-free policies, as compared to employees and non-smokers. Linear regression models showed that attitudes towards smoke-free policy were predicted by smoking status, SHS exposure and related health beliefs, and social norm variables. Logistic regression analysis showed that willingness to confront a policy violator was predicted by SHS exposure, perceived prevalence of smoker clients, and smoke-free policy attitudes. CONCLUSIONS: SHS exposure and related health beliefs, and normative factors should be targeted by interventions aiming to promote policy support in the hospitality industry in Cyprus. PMID- 26427863 TI - Charge-Transfer Emission in Organoboron-Based Biphenyls: Effect of Substitution Position and Conformation. AB - A series of organoboron-based biphenyls o,o'-NMe2, o,p'-NMe2, p,p'-NMe2, which contain an electron-donating NMe2 and an electron-accepting BMes2 groups at o,o' , o,p'-, p,p'-positions of biphenyl skeleton, respectively, as well as o,o'-NBn2, which contains more bulky NBn2 rather than NMe2, were fully characterized to explore the effect of structural modification on the intramolecular charge transfer emissions. In addition to significant effect of substitution position on photophysical properties, remarkable influence of conformation was also observed for o,o'-substituted compounds. The emission is substantially blue-shifted as conformation changes from the location of NMe2 and BMes2 at same side of biphenyl axis with a close B...N distance, and thus direct B...N electronic interaction in o,o'-NMe2, to the location of NBn2 and BMes2 on two opposite sides in o,o'-NBn2. And o,o'-NMe2 exhibits the longest emission wavelength, but the shortest absorption wavelength, and thus largest Stokes shift among these four organoboron based biphenyls in both solution and solid state. The theoretical calculations demonstrated that the unique structure of o,o'-NMe2, in which boryl and amino located at the same side of biphenyl axis with close B...N distance and direct B...N electronic interaction, is helpful to stabilize the lowest singly occupied orbital in the exited state. PMID- 26427862 TI - Unemployment, health, and education of HIV-infected males in Germany. AB - OBJECTIVES: The present study on people living with HIV/AIDS (PLWHA) identifies socio-demographic and health-related factors corresponding with their labour market participation. METHODS: The study sample bases on a German observational sub-study of 527 male PLWHA. The present analysis is restricted to male PLWHA in working age. By means of a multivariate regression, we identify factors that contribute to unemployment and job loss. RESULTS: The probability to be unemployed is significantly negatively correlated with age above 40 years and graduation from university and positively correlated with problems with daily activities (frailty) and disease severity (CDC stage C). The probability of employment loss during the 2-year observation period is significantly negatively correlated with the educational level, whereas frailty and hepatitis C (HCV) co infection increase the odds of employment loss. CONCLUSIONS: As problems to manage daily activities and disease progression are associated with unemployment, an effective HIV treatment is an important cornerstone for employment. This is also true for the management of comorbidities, such as HCV co-infection, which also negatively affects employment status in our study. PMID- 26427864 TI - Predicting the mineral composition of ureteral stone using non-contrast computed tomography. AB - We investigated the correlation between computed tomography (CT) density of ureteral stones and their mineral composition. A total of 346 patients who underwent ureteroscopic lithotripsy for calculi all fragments of which were acquired at a single institution from 2009 to 2011 were analyzed. The maximum and mean CT densities were measured preoperatively. A mineral analysis revealed calcium oxalate in 203 (58.7 %), mixed calcium oxalate and calcium phosphate in 78 (23.0 %), calcium phosphate in 18 (5.2 %), uric acid in 8 (2.3 %), struvite in 3 (0.9 %), and cysteine in 5 (1.4 %). The mean Hounsfield units (HUs) of the CT density were 1046 HUs in calcium oxalate, 1101 HUs in mixed calcium oxalate and calcium phosphate, 835 HUs in calcium phosphate, 549 HUs in uric acid, 729 HUs in struvite, and 698 HUs in cystine. The HUs in calcium oxalate were significantly higher than those in uric acid (p < 0.01) and struvite (p < 0.01). Those in monohydrate stones were significantly higher, compared with dehydrate stones (p < 0.05). We analyzed the largest number of stones than each published study to correlate their mineral composition and CT density. Calcium component stones showed significantly higher CT densities than other types. PMID- 26427865 TI - Conditional survival for pediatric and adolescent patients with cancer: Implications for survivorship care. AB - PURPOSE: Few studies have evaluated conditional survival (probability of surviving y years given patients have already survived x years) for pediatric/adolescent patients diagnosed with cancer. To provide more accurate information on ongoing survival, we evaluate conditional survival for pediatric and adolescent patients with cancer. METHODS: The statewide Utah Cancer Registry identified 3344 patients born in Utah diagnosed with cancer at ages 0-21 years, from 1973 to 2009. The Utah Population Database provided demographic information. We estimated five-year conditional survival at diagnosis, and one and three years after diagnosis, by risk factors such as cancer type, sex, diagnosis age and treatment era (1973-1994 vs. 1995-2009). RESULTS: Conditional survival estimates at one (85.1%, 95% CI: 83.7-86.5) and three years (92.9%, 95% CI: 91.8-93.9) after diagnosis were significantly higher than survival at diagnosis (77.2%, 95% CI: 75.6-78.9), although results varied by cancer type and initial prognosis. Diagnosis age affected survival for cancers where age is a risk factor. For example, five-year survival at one year after diagnosis was higher for younger (<= 18 months of age) patients compared to older (>18 months) patients with neuroblastoma (95.4%, 95% CI: 90.9-99.9 vs. 56.8%, 95% CI: 41.8-71.7, p<0.001). Conditional survival improved over time for many cancers. Minimal differences were observed by sex. CONCLUSION: Substantial improvements were observed in conditional survival at one and three years after diagnosis compared with survival at diagnosis. Several risk factors affected these outcomes. Clearer understandings of survival will help in administering effective survivorship care and decreasing prognosis-related anxiety/stress for patients and families. PMID- 26427866 TI - Comparison of pulpal anesthesia and cardiovascular parameters with lidocaine with epinephrine and lidocaine with clonidine after maxillary infiltration in type 2 diabetic volunteers. AB - OBJECTIVES: The pulpal anesthetic and cardiovascular parameters obtained by 2 % lidocaine with epinephrine (LE; 1:80,000) or clonidine (LC; 15 mcg/ml) were studied in diabetes mellitus (DM) type 2 and healthy volunteers (72), after maxillary infiltration anesthesia. MATERIALS AND METHODS: Onset and duration of pulpal anesthesia were measured by electric pulp tester; vasoconstrictive effect of used local anesthetic mixtures by laser Doppler flowmetry (LDF) through pulpal blood flow (PBF); systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were registered by electrocardiogram monitoring. RESULTS: Onset of pulpal anesthesia was shorter for LC than for LE in healthy, while it was not different in diabetic participants; duration of pulpal anesthesia was significantly longer in type 2 diabetic participants, regardless of used anesthetic mixture. Significant reduction of PBF with LE was observed during 45 min in healthy and 60 min in diabetic participants, while with LC such reduction was observed during 45 min in both groups. LE caused a significant increase of SBP in the 5th and 15th minutes in diabetic versus healthy participants, while LC decreased SBP from the 10th to 60th minutes in healthy versus diabetic participants. CONCLUSIONS: DM type 2 influences duration of maxillary infiltration anesthesia obtained with LE and LC, and systolic blood pressure during LE anesthesia. CLINICAL RELEVANCE: The obtained results provide elements for future protocols concerning intraoral local anesthesia in DM type 2 patients. PMID- 26427867 TI - Compliance and persistence with treatment with parathyroid hormone for osteoporosis. A Danish national register-based cohort study. AB - Medical intervention is important in the treatment of osteoporosis, and compliance with medical treatment is essential for an optimal outcome. Based on Danish national registers, we found that compliance with parathyroid hormone (PTH) treatment is high and associated with marital status, working status, and type of PTH treatment. PURPOSE: Compliance and persistence are essential for an optimal outcome during medical treatment of osteoporosis. We aimed to evaluate compliance and persistence with treatment with PTH in daily clinical practice in Danish patients and to describe factors affecting compliance. METHODS: Register based nationwide cohort study on all patients in Denmark initiates PTH or analogue treatment for osteoporosis in 2003-2010 (n = 4281). PTH drugs included were the PTH analogue teriparatide(1-34) and recombinant human PTH (rhPTH(1-84)). Compliance with treatment was calculated by using medication possession ratio (MPR). RESULTS: In the study period, 3702 patients were exclusively treated with teriparatide and 579 were exclusively treated with rhPTH(1-84). We found that for patients persistent with therapy for at least 18 months and with MPR >0.8, 83 % of the patients in the teriparatide group were compliant versus 72 % in the recombinant PTH group (p < 0.01). Being married/cohabiting, still in the labor market, and taking teriparatide were significantly associated with higher compliance, whereas age, gender, level of education, income, alcoholism, and Charlson comorbidity index were not associated with compliance. CONCLUSION: Compliance with PTH treatment overall is high, with teriparatide compliance higher than rhPTH(1-84), in patients persistent to therapy for 18 months. Compliance is associated with marital status, working status, and type of PTH treatment. PMID- 26427868 TI - Down-regulation of uterine LIF expression induced by the hormonal level disorder causes embryo implantation loss after mice exposed to carbon disulfide at peri implantation. AB - Carbon disulfide (CS2) exposure can cause embryo implantation loss but the mechanism remains unclear. Earlier study revealed that the 4th day of gestation (GD4) and GD5 were the most sensitive exposure time on which the number of implanted embryos decreased obviously in mice. Leukemia inhibitory factor (LIF) in maternal uterine tissue is involved in embryo implantation, which is produced by endometrium and Th2 cells that participate in cellular adhesion of maternal fetal interface. We herein investigated the effect of CS2 on the expression of LIF in uterine tissue and its regulatory mechanism in Kunming mice. Exposure was on GD3, GD4, GD5 and GD6, respectively, single administration (631.4 mg/kg), and the indexes were arranged in time series after exposure. The results showed that LIF gene breakage was captured at the 18th hour after exposure by Comet-FISH and the protein and mRNA of LIF in uterine tissue were down-regulated after exposure through the peri-implantation period. In addition, sex steroid hormones, progesterone (P4) and oestrogen (E2) were detected since they can stimulate synthesis of LIF from endometrial cells. Results showed that P4 and E2 in serum were down-regulated at all the endpoints of CS2 exposure groups. These findings suggested that the down-regulated LIF induced by the decreased P4 and E2 after mice exposure to CS2 might be important reasons for implantation disorders. PMID- 26427869 TI - The effect of rat bone marrow derived mesenchymal stem cells transplantation for restoration of olfactory disorder. AB - The purpose of the study was to investigate the effect of bone marrow-derived mesenchymal stem cells (BMSCs) transplantation on olfactory epithelium (OE) of morphologic and functional restoration following neural Sensorineural Disorder in rats. Except the Normal group, twenty-one rats underwent Triton X-100 (TX-100) irrigation to induce degeneration of OE, and then BMSCs and PBS were treated from the both medial canthus to the rear part of the both nasal cavity into the experimental group and then were observed for restoration according to time point. At two and four weeks after transplantation with BMSCs, restoration of OE was observed with olfactory marker protein (OMP) and behavioral test. And we observed the expression of OMP, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). After TX-100 irrigation, the OE almost disappeared in 3 days. At four weeks after transplantation with BMSCs, the thickness and cellular composition of OE was considerably restored to normal group and expression of OMP was markedly increased when compared with PBS group and reduced the searching time in the behavioral test. Furthermore at two weeks after treatment with BMSCs, expression of NGF and BDNF was greatly increased when compared with PBS group. However at four weeks after treatment with BMSCs, expression of NGF and BDNF was slightly decreased. Our results suggest the BMSCs transplantation affect restoration of OE and olfaction, most likely via regulation of the neurotrophic factor expression, especially the expression of NGF and BDNF and has a possibility of a new therapeutic strategy for the treatment of olfactory disorder caused by the degeneration of OE. PMID- 26427870 TI - Therapeutic effects of antibiotic drug tigecycline against cervical squamous cell carcinoma by inhibiting Wnt/beta-catenin signaling. AB - Aberrant activation of the Wnt/beta-catenin signaling pathway is common in human cervical cancers and has great potential therapeutic value. We show that tigecycline, a FDA-approved antibiotic drug, targets cervical squamous cell carcinoma through inhibiting Wnt/beta-catenin signaling pathway. Tigecycline is effective in inducing apoptosis, inhibiting proliferation and anchorage independent colony formation of Hela cells. The inhibitory effects of tigecycline are further enhanced upon combination with paclitaxel, a most commonly used chemotherapeutic drug for cervical cancer. In a cervical xenograft model, tigecycline inhibits tumor growth as a single agent and its combination with paclitaxel significantly inhibits more tumor growth throughout the duration of treatment. We further show that tigecycline decreases level of both cytoplasmic and nuclear beta-catenin and suppressed Wnt/beta-catenin-mediated transcription through increasing levels of Axin 1 in Hela cells. In addition, stabilization or overexpression of beta-catenin using pharmacological and genetic approaches abolished the effects of tigecycline in inhibiting proliferation and inducing apoptosis of Hela cells. Our study suggests that tigecycline is a useful addition to the treatment armamentarium for cervical cancer and targeting Wnt/beta-catenin represents a potential therapeutic strategy in cervical cancer. PMID- 26427873 TI - The N-terminal domains determine cellular localization and functions of the Doa4 and Ubp5 deubiquitinating enzymes. AB - Ubiquitination is involved in numerous cellular regulatory mechanisms including the cell cycle, signal transduction and quality control. Ubiquitin modifies proteins by consecutive actions of ubiquitin-activating/conjugating enzymes. Attachment of ubiquitin is reversible. Deubiquitinating enzymes are responsible for removal of ubiquitin from ubiquitin-protein conjugates. Genome of the yeast Saccharomyces cerevisiae encodes structurally related but functionally distinct enzymes - Doa4 and Ubp5. Doa4 is involved in general ubiquitin-dependent proteolysis and is responsible for deubiquitination of ubiquitin-protein conjugates at the cytoplasmic face of the late endosome. The N-terminal domain targets the enzyme to the endosome membrane after ESCRT-III complex has formed there. By contrast, corresponding region of homologous Ubp5 is critical for its bud neck localization in dividing cells. Conceivably, Ubp5 plays an essential role in cytokinesis. Here we show that Doa4 physically interacts with the ESCRT III component Snf7 and preferentially cleaves Lys63-linked ubiquitin oligomers involved in membrane protein trafficking. We also demonstrate that the unstable regulator of cytokinesis Hof1 accumulates in proteasomal mutants and is required for cellular localization of Ubp5. PMID- 26427872 TI - Maternal diabetes triggers DNA damage and DNA damage response in neurulation stage embryos through oxidative stress. AB - DNA damage and DNA damage response (DDR) in neurulation stage embryos under maternal diabetes conditions are not well understood. The purpose of this study was to investigate whether maternal diabetes and high glucose in vitro induce DNA damage and DDR in the developing embryo through oxidative stress. In vivo experiments were conducted by mating superoxide dismutase 1 (SOD1) transgenic male mice with wild-type (WT) female mice with or without diabetes. Embryonic day 8.75 (E8.75) embryos were tested for the DNA damage markers, phosphorylated histone H2A.X (p-H2A.X) and DDR signaling intermediates, including phosphorylated checkpoint 1 (p-Chk1), phosphorylated checkpoint 2 (p-Chk2), and p53. Levels of the same DNA damage markers and DDR signaling intermediates were also determined in the mouse C17.2 neural stem cell line. Maternal diabetes and high glucose in vitro significantly increased the levels of p-H2A.X. Levels of p-Chk1, p-Chk2, and p53, were elevated under both maternal diabetic and high glucose conditions. SOD1 overexpression blocked maternal diabetes-induced DNA damage and DDR in vivo. Tempol, a SOD1 mimetic, diminished high glucose-induced DNA damage and DDR in vitro. In conclusion, maternal diabetes and high glucose in vitro induce DNA damage and activates DDR through oxidative stress, which may contribute to the pathogenesis of diabetes-associated embryopathy. PMID- 26427871 TI - Stem cell-derived vasculature: A potent and multidimensional technology for basic research, disease modeling, and tissue engineering. AB - Proper blood vessel networks are necessary for constructing and re-constructing tissues, promoting wound healing, and delivering metabolic necessities throughout the body. Conversely, an understanding of vascular dysfunction has provided insight into the pathogenesis and progression of diseases both common and rare. Recent advances in stem cell-based regenerative medicine - including advances in stem cell technologies and related progress in bioscaffold design and complex tissue engineering - have allowed rapid advances in the field of vascular biology, leading in turn to more advanced modeling of vascular pathophysiology and improved engineering of vascularized tissue constructs. In this review we examine recent advances in the field of stem cell-derived vasculature, providing an overview of stem cell technologies as a source for vascular cell types and then focusing on their use in three primary areas: studies of vascular development and angiogenesis, improved disease modeling, and the engineering of vascularized constructs for tissue-level modeling and cell-based therapies. PMID- 26427874 TI - Expression pattern of sonic hedgehog signaling and calcitonin gene-related peptide in the socket healing process after tooth extraction. AB - Sonic Hedgehog (SHH), a neural development inducer, plays a significant role in the bone healing process. Calcitonin gene-related peptide (CGRP), a neuropeptide marker of sensory nerves, has been demonstrated to affect bone formation. The roles of SHH signaling and CGRP-positive sensory nerves in the alveolar bone formation process have been unknown. Here we examined the expression patterns of SHH signaling and CGRP in mouse socket by immunohistochemistry and immunofluorescence analysis. We found that the expression level of SHH peaked at day 3 and was then decreased at 5 days after tooth extraction. CGRP, PTCH1 and GLI2 were each expressed in a similar pattern with their highest expression levels at day 5 and day 7 after tooth extraction. CGRP and GLI2 were co-expressed in some inflammatory cells and bone forming cells. In some areas, CGRP-positive neurons expressed GLI2. In conclusion, SHH may affect alveolar bone healing by interacting with CGRP-positive sensory neurons and thus regulate the socket's healing process after tooth extraction. PMID- 26427875 TI - Ex vivo genome-wide RNAi screening of the Drosophila Toll signaling pathway elicited by a larva-derived tissue extract. AB - Damage-associated molecular patterns (DAMPs), so-called "danger signals," play important roles in host defense and pathophysiology in mammals and insects. In Drosophila, the Toll pathway confers damage responses during bacterial infection and improper cell-fate control. However, the intrinsic ligands and signaling mechanisms that potentiate innate immune responses remain unknown. Here, we demonstrate that a Drosophila larva-derived tissue extract strongly elicits Toll pathway activation via the Toll receptor. Using this extract, we performed ex vivo genome-wide RNAi screening in Drosophila cultured cells, and identified several signaling factors that are required for host defense and antimicrobial peptide expression in Drosophila adults. These results suggest that our larva derived tissue extract contains active ingredients that mediate Toll pathway activation, and the screening data will shed light on the mechanisms of damage related Toll pathway signaling in Drosophila. PMID- 26427876 TI - Caenorhabditis elegans ATAD-3 modulates mitochondrial iron and heme homeostasis. AB - ATAD3 (ATPase family AAA domain-containing protein 3) is a mitochondrial protein, which is essential for cell viability and organismal development. ATAD3 has been implicated in several important cellular processes such as apoptosis regulation, respiratory chain function and steroid hormone biosynthesis. Moreover, altered expression of ATAD3 has been associated with several types of cancer. However, the exact mechanisms underlying ATAD3 effects on cellular metabolism remain largely unclear. Here, we demonstrate that Caenorhabditis elegans ATAD-3 is involved in mitochondrial iron and heme homeostasis. Knockdown of atad-3 caused mitochondrial iron- and heme accumulation. This was paralleled by changes in the expression levels of several iron- and heme-regulatory genes as well as an increased heme uptake. In conclusion, our data indicate a regulatory role of C. elegans ATAD-3 in mitochondrial iron and heme metabolism. PMID- 26427877 TI - Availability of primary care team members can improve teamwork and readiness for change. AB - BACKGROUND: Early experiences of patient-centered medical home implementation indicate that redesigning primary care is an intensive organizational change that is most effectively undertaken by high-functioning interdisciplinary teams. Team effectiveness research indicates that consistent availability of team members and other aspects of team structure can impact teamwork and organizational outcomes. METHODS: We conducted a survey of 766 adult primary care providers and staff in 34 California safety net practices to assess primary care team structure (team size, team member availability, and access to interdisciplinary expertise), teamwork, and readiness for change. We used path models with robust standard errors for clustering of respondents within practices to examine relationships between team member availability and readiness for change. Using path analysis, we examined the extent to which better teamwork mediated relationships between team member availability and readiness for change. RESULTS: We received 628 completed surveys (response rate = 82%). Greater team member availability was associated with greater readiness for change, but the relationship was stronger for staff than for primary care providers. Contrary to our hypothesis, path analyses revealed that the relationship of team member availability and greater readiness for change was only partially mediated (21%) by better teamwork. The direct effect of teamwork on readiness for change is approximately 2.9 times larger than the direct effect of team member availability on greater readiness for change. CONCLUSIONS: Ensuring that members perceive that their teammates are routinely available to them may improve readiness for implementing organizational changes like adopting patient-centered medical home models. Given that better teamwork only partially explained the availability-readiness relationship, additional research to identify the mechanisms through which consistent team member availability increases change readiness could lend insight into how to more effectively support clinicians and staff undergoing complex organizational changes. PMID- 26427878 TI - Oral fungal immunomodulatory protein-Flammulina velutipes has influence on pulmonary inflammatory process and potential treatment for allergic airway disease: A mouse model. AB - BACKGROUND/PURPOSE: House dust mite (HDM) is well known as one of the major indoor allergens that trigger allergic inflammation, especially asthma, and accounts for 85% of all cases. So far, asthma has been thought of as a condition of imbalance between T helper (Th)1 and Th2. Fungal immunomodulatory protein Flammulina velutipes (FIP-fve) has been seemingly demonstrated to modulate the response to Th1 cytokine production. The aim of this study was to investigate if the oral administration of FIP-fve can inhibit HDM-induced asthma inflammation in the mouse model. METHODS: We divided the mice (female BALB/c, 4-6 weeks) into four groups: the prevention group, which consisted of mice sensitized by HDM (intraperitoneally on Day 1, Day 7, and Day 14, and intranasally on Day 14, Day 17, Day 21, Day 24, and Day 27) fed with FIP-fve from Day 1 to Day 14; the treatment group, which comprised mice that received treatment from Day 14 to Day 28; the positive control (PC, sensitized by HDM fed without FIP-fve) group; and the negative control group (NC, nonsensitized). Airway hyperresponsiveness induced by methacholine challenge was determined using whole-body barometric plethysmography. In addition, cytokines were analyzed from bronchoalveolar lavage fluid and serum. Histopathological studies and Liu's staining method in mice lungs were also performed. RESULTS: The results showed that both pre- and posttreated FIP-fve groups had significantly reduced airway hyperresponsiveness compared with the PC group after methacholine challenge. In addition, a significantly decreased level of HDM-specific immunoglobulin E in serum and decreased production of Th2 cytokines in bronchoalveolar lavage fluid and serum were observed in these two FIP-fve fed groups. Moreover, more decreased amounts of infiltrating inflammatory cells were present in the lungs of FIP-fve fed groups than those of the PC group. CONCLUSION: Oral FIP-fve had an anti inflammatory effect on the acute phase of the airway inflammatory process induced by HDM in the mouse model and might have a potentially therapeutic role for allergic airway diseases. PMID- 26427879 TI - DNA adenine methylation modulates pathogenicity of Klebsiella pneumoniae genotype K1. AB - BACKGROUND/PURPOSE: Klebsiella pneumoniae genotype K1 is a highly virulent pathogen that causes liver abscess and metastatic endophthalmitis/meningitis. Whether its pathogenicity is controlled by DNA adenine methylase (Dam), an epigenetic regulator of bacterial virulence gene expression, is yet unknown. We aimed to study the role of DNA adenine methylation in the pathogenicity of K. pneumoniae genotype K1. METHODS: We identified the dam gene in the prototype tissue-invasive strain (NTUH-K2044) of K. pneumoniae genotype K1, using the strain's complete genome sequence in GenBank. We constructed a dam- mutant and compared it with the wild type, in terms of in vitro serum resistance and in vivo BALB/cByl mice inoculation. RESULTS: Loss of Dam activity in the mutant was verified by MboI restriction digestion of the genomic DNA and a 1000-fold increase in spontaneous mutation rate. The dam mutant lost at least 68% of serum resistance when compared with the wild type (survival ratio at 1 hour: 2.6 +/- 0.4 vs. 8.2 +/- 1.9; at 2 hours: 3.9 +/- 1.6 vs. 17.4 +/- 3.6; p values < 0.05). Likewise, virulence to mice decreased by 40-fold in an intraperitoneal injection model [lethal dose, 50% (LD50): 2 * 103 colony-forming units (CFUs) vs. 5 * 101 CFUs] and by sixfold in a gastric ingestion model (LD50: 3 * 104 CFUs vs. 5 * 103 CFUs). Attenuation of the dam mutant was not attributable to its growth rate, which was similar to that of the wild type. CONCLUSION: Our results support the view that DNA adenine methylation plays an important role in modulating the pathogenicity of K. pneumoniae genotype K1. The incomplete attenuation indicates the existence of other regulatory factors. PMID- 26427880 TI - Toxic effect of high concentration of sonochemically synthesized polyvinylpyrrolidone-coated silver nanoparticles on Citrobacter sp. A1 and Enterococcus sp. C1. AB - BACKGROUND/PURPOSE: Currently, silver nanoparticles (AgNPs) have gained importance in various industrial applications. However, their impact upon release into the environment on microorganisms remains unclear. The aim of this study was to analyze the effect of polyvinylpyrrolidone-capped AgNPs synthesized in this laboratory on two bacterial strains isolated from the environment, Gram-negative Citrobacter sp. A1 and Gram-positive Enterococcus sp. C1. METHODS: Polyvinylpyrrolidone-capped AgNPs were synthesized by ultrasound-assisted chemical reduction. Characterization of the AgNPs involved UV-visible spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction, transmission electron microscopy, and energy dispersive X-ray spectroscopy. Citrobacter sp. A1 and Enterococcus sp. C1 were exposed to varying concentrations of AgNPs, and cell viability was determined. Scanning electron microscopy was performed to evaluate the morphological alteration of both species upon exposure to AgNPs at 1000 mg/L. RESULTS: The synthesized AgNPs were spherical in shape, with an average particle size of 15 nm. The AgNPs had different but prominent effects on either Citrobacter sp. A1 or Enterococcus sp. C1. At an AgNP concentration of 1000 mg/L, Citrobacter sp. A1 retained viability for 6 hours, while Enterococcus sp. C1 retained viability only for 3 hours. Citrobacter sp. A1 appeared to be more resistant to AgNPs than Enterococcus sp. C1. The cell wall of both strains was found to be morphologically altered at that concentration. CONCLUSION: Minute and spherical AgNPs significantly affected the viability of the two bacterial strains selected from the environment. Enterococcus sp. C1 was more vulnerable to AgNPs, probably due to its cell wall architecture and the absence of silver resistance-related genes. PMID- 26427881 TI - RNA modification enzymes encoded by the gid operon: Implications in biology and virulence of bacteria. AB - Ribonucleic acid (RNA) molecules consist of numerous chemically modified nucleosides that are highly conserved in eukarya, archeae, and bacteria, while others are unique to each domain of life. In bacteria, hundreds of RNA modification enzymes have been identified and implicated in biological pathways associated with many cell processes. The glucose-inhibited division (gid) operon encodes genes for two RNA modification enzymes named GidA and GidB. Studies have shown GidA is essential for the proper biosynthesis of 5-methylaminomethyl-2 thiouridine (mnm(5)s(2)U) of bacterial transfer RNA (tRNA) with GidB responsible for the methylation of the 16S ribosomal RNA (rRNA). Furthermore, deletion of gidA and gidB has shown to alter numerous bacterial properties like virulence, stress response, morphology, growth, antibiotic susceptibility, and others. In this review, we discuss the present knowledge of the RNA modification enzymes GidA and GidB, and their potential role in the biology and virulence of bacteria. PMID- 26427882 TI - Antibacterial effect of porcine PTX3 against Streptococcus suis type 2 infection. AB - Pentraxin 3 (PTX3), a soluble pattern recognition receptor, plays an important role in innate immunity and has been implicated to be a candidate resistance gene against Streptococcus suis 2 infection. To discover the antibacterial effect of porcine PTX3 against S. suis 2, the 42-kDa PTX3 protein was expressed by Chinese hamster ovary cells (CHO), and an additional eukaryotic expression vector pVAX ptx3 was constructed. The expressed porcine PTX3 mediated a range of antibacterial activities including increasing phagocytic capacity of primary porcine alveolar macrophages (PAM) against S. suis 2 and inhibiting adhesion of S. suis 2 to human epidermoid cancer cells (Hep-2). In mouse model, pre intramuscular injecting with pVAX-ptx3 reduced mortality and reduced bacteria loads in blood, spleen, lung and brain compared with that of control group during 2-12 h following intraperitoneal injection (i.p.) with S. suis 2. Meanwhile, the expressions of IL-6 and IL-8 in blood were increased in pVAX-ptx3 group, whereas no obvious changes about IL-10. In piglet model, bacteria load in blood of pVAX ptx3 group was significantly lower than that of control group after i.p. with S. suis 2, correspondingly, expression of IL-6 and IL-8 were significantly increased in pVAX-ptx3 group. In contrast, white blood cell (WBC) and neutrophil cell (NEU) count of peripheral blood in pVAX-ptx3 group were lower than that of control group. These studies described a novel antibacterial role for porcine PTX3 against S. suis 2 both in vitro and in vivo and suggested that porcine PTX3 may be a potential biological agent against S. suis 2 in pig and be used for the clinical prevention and treatment of streptococcosis caused by S. suis 2. PMID- 26427883 TI - NOX4-dependent Hydrogen peroxide promotes shear stress-induced SHP2 sulfenylation and eNOS activation. AB - Laminar shear stress (LSS) triggers signals that ultimately result in atheroprotection and vasodilatation. Early responses are related to the activation of specific signaling cascades. We investigated the participation of redox-mediated modifications and in particular the role of hydrogen peroxide (H2O2) in the sulfenylation of redox-sensitive phosphatases. Exposure of vascular endothelial cells to short periods of LSS (12 dyn/cm(2)) resulted in the generation of superoxide radical anion as detected by the formation of 2 hydroxyethidium by HPLC and its subsequent conversion to H2O2, which was corroborated by the increase in the fluorescence of the specific peroxide sensor HyPer. By using biotinylated dimedone we detected increased total protein sulfenylation in the bovine proteome, which was dependent on NADPH oxidase 4 (NOX4)-mediated generation of peroxide. Mass spectrometry analysis allowed us to identify the phosphatase SHP2 as a protein susceptible to sulfenylation under LSS. Given the dependence of FAK activity on SHP2 function, we explored the role of FAK under LSS conditions. FAK activation and subsequent endothelial NO synthase (eNOS) phosphorylation were promoted by LSS and both processes were dependent on NOX4, as demonstrated in lung endothelial cells isolated from NOX4 null mice. These results support the idea that LSS elicits redox-sensitive signal transduction responses involving NOX4-dependent generation of hydrogen peroxide, SHP2 sulfenylation, and ulterior FAK-mediated eNOS activation. PMID- 26427884 TI - Methamphetamine oxidative stress, neurotoxicity, and functional deficits are modulated by nuclear factor-E2-related factor 2. AB - Activation of redox-sensitive transcription factors like nuclear factor-E2 related factor 2 (Nrf2) can enhance the transcription of cytoprotective genes during oxidative stress. We investigated whether Nrf2 is activated by methamphetamine (METH) thereby altering neurotoxicity in Nrf2 +/+ and -/- adult mouse brain. A single dose of METH can induce the mRNA levels of Nrf2-regulated antioxidant and cytoprotective proteins in mouse brain. Multiple-day dosing with METH enhanced DNA oxidation and decreased tyrosine hydroxylase and dopamine transporter staining in the striatum, indicating dopaminergic nerve terminal toxicity, which was more severe in -/- mice, as were deficits in motor coordination and olfactory discrimination. These Nrf2-dependent effects were independent of changes in METH metabolism or the induction of hyperthermia. Similarly, METH increased striatal glial fibrillary acidic protein, indicating neurotoxicity. METH neurotoxicity was also observed in the glial cells and in the GABAergic system of the olfactory bulbs and was enhanced in -/- mice, whereas dopaminergic parameters were unaffected. With one-day dosing of METH, there were no differences between +/+ and -/- mice in either basal or METH-enhanced DNA oxidation and neurotoxicity markers. Nrf2-mediated pathways accordingly may protect against the neurodegenerative effects and functional deficits initiated by METH and perhaps other reactive oxygen species-enhancing neurotoxicants, when there is time for transcriptional activation and protein induction. In human users of METH, this mechanism may be essential when differences in drug abuse patterns may alter the induction and duration of Nrf2 activation thereby modulating susceptibility to the neurotoxic effects of METH. PMID- 26427885 TI - Miro1-mediated mitochondrial dysfunction under high nutrient stress is linked to NOD-like receptor 3 (NLRP3)-dependent inflammatory responses in rat pancreatic beta cells. AB - Type 2 Diabetes (T2D) is associated with a state of low-grade inflammation that leads to insulin resistance under sustained high-fat and glucose (HFG) stress. Mitochondria from pancreatic beta cells play an essential role by metabolizing nutrients and generating signals required for both triggering and amplifying pathways of insulin secretion responding to HFG. However, the underlying pathway linking mitochondrial function to initiate and integrate inflammatory responses within the pancreatic beta cells under HFG stress remains poorly defined. Here, we demonstrated that HFG induced Ca(2+)-mediated deleterious effects on mitochondrial rho GTPase 1 (Miro1), a protein allowing mitochondria to move along microtubules to regulate mitochondria dynamics. This redistribution of Miro1 by HFG led to aggravation of proinflammatory responses in rat islets due to damaged mitochondria-producing reactive oxygen species (ROS). In addition, HFG-induced Ca(2+)-mediated increased expression of mitochondrial dynamin-like protein (DLP1) was assembled on the outer membrane of mitochondria to initiate fission events. Higher expression of DLP1 induced mitochondria fragmentation as expected but was not essential for ROS-induced proinflammatory responses, while Miro1-mediated mitochondrial dysfunction induced proinflammatory responses under HFG stress. Combined, we proposed in this study that HFG stress caused mtROS release mainly through Miro1-mediated effects on mitochondria in pancreatic beta cells triggering the NLRP3-dependent proinflammatory responses and, subsequently, damaged insulin secretion. PMID- 26427886 TI - Conditional and indirect effects of age of first exposure on PTSD symptoms. AB - Childhood violence exposure (CVE) in formative developmental years may have potent effects on severity and complexity of post-traumatic stress symptoms (PTSS) in adulthood, yet little research has examined the role of age of first exposure in the context of polyvictimization or gone beyond an examination of direct effects. The current study examines the specific associations between age of first exposure, total CVE, and posttraumatic stress symptoms in adulthood. Further, the conditional and indirect effects of age of first exposure on posttraumatic stress symptoms were examined. We hypothesized that age of first exposure to violence would be associated with higher total violence exposure across childhood, thereby predicting current posttraumatic stress symptom severity (i.e., indirect effect). We also postulated that age of first exposure would affect the relationship between total violence exposure and posttraumatic stress symptoms such that earlier exposure would exacerbate the effects of violence exposure (i.e., conditional effect). Participants included 269 violence exposed adults recruited through MTurk; the mean age of first CVE was 6 years (SD=3.29). Conditional process models indicated that age of first exposure was significantly associated with higher total childhood violence exposure, which in turn, was significantly associated with current posttraumatic stress symptoms in all domains. Further, a conditional effect of age of first exposure was present such that the relationship between total exposure to violence and symptoms of hyperarousal was stronger for those first exposed at earlier ages. Findings provide support suggesting the particular potency of early trauma on regulatory response systems. PMID- 26427887 TI - Community-based surveillance to monitor trends in unaccompanied and separated children in eastern DRC. AB - Children who are separated from their families and usual caregivers in emergencies face a multitude of risks. The humanitarian community lacks methods to systematically capture changes in the frequency and nature of such separations over time. A mobile phone-based community surveillance system was piloted in the Democratic Republic of the Congo. The goal was to identify new cases of unaccompanied and separated children on a weekly basis. Over an 11-week period, community focal points reported 62 cases of separation across 10 communities. The majority of children had been under the care of their parents prior to separation. More than half of the children were unaccompanied, meaning that they were living without an adult relative or customary caregiver. The pilot results suggest that implementing a mobile phone-based surveillance system in a humanitarian setting may be feasible and cost-effective and fills a critical gap in the measurement of separated and unaccompanied children in emergencies. A longer pilot to better understand how the system performs over time is recommended. PMID- 26427888 TI - Speciation, stability, and coagulation mechanisms of hydroxyl aluminum clusters formed by PACl and alum: A critical review. AB - The physicochemical property of coagulant species plays a significant role in the coagulation process. Recent progress on speciation, stability, and coagulation mechanisms of the hydroxyl aluminum clusters formed by PACl and alum has been critically reviewed. The complicated nature on species formation, stability, and transformation of various hydrolyzed aluminum clusters formed by PACl and Alum are discussed. Based on the aspects of spontaneous hydrolysis, forced hydrolysis, and dual-hydrolysis models, the special stability of aluminum clusters that results in various coagulation behaviors is compared with the traditional salts. The coagulation behavior of the hydroxyl aluminum clusters in terms of particle aggregation and restabilization, surface adsorption and coverage, microfloc formation and kinetics, modified DLVO simulation, and finally, the coagulation model is then analyzed in detail. It is indicative that the coagulation mechanism of inorganic coagulants can be understood better with the hydroxyl clusters being tailor-made. PMID- 26427889 TI - Short-term effects of lunch on children's executive cognitive functioning: The randomized crossover Cognition Intervention Study Dortmund PLUS (CogniDo PLUS). AB - OBJECTIVE: Studies indicate that eating lunch impairs some aspects of adults' cognitive functioning. However, the short-term effects of lunch on children's executive functions (EF) have not been examined. The Cognition Intervention Study Dortmund PLUS (CogniDo PLUS) investigated (a) short-term effects of lunch on EF in children and (b) whether the postprandial cortisol increase mediates putative lunch effects on EF performance. METHODS: 5th and 6th grade students of a comprehensive school in Gelsenkirchen (Germany) participated in the randomized crossover intervention study. On Day 1 of the study, Group 1 did not eat lunch,whereas Group 2 received lunch ad libitum. One week later on Day 2 the groups were treated vice versa. At the beginning of the afternoon lessons, the EF parameters task switching,working memory updating and inhibition were tested using a computerized test battery. Saliva samples were used to measure cortisol directly before lunch and again at the beginning of the cognitive assessment. Of the 215 initially recruited children 21 dropped out of the study due to illness or absence on one of the two test days. RESULTS: Lower ratios of false alarms in the working memory updating function were observed when children who ate lunch than for children who had no lunch (8.2% (lunch) versus 9.4% (no lunch), p b 0.01). Parameters of task switching and inhibition did not differ between children who ate lunch compared to children who had no lunch. Stratification according to postprandial cortisol increase showed that the subgroup with a high increase had lower ratios of false alarms after eating lunch, while false alarm values did not change in the group with a low increase. CONCLUSION: In contrast to findings in adults, the results indicate that children's EF are not impaired by lunch under true-to-life conditions. On the contrary, the current study even indicates beneficial effects of lunch intake for the working memory updating. The postprandial cortisol increase in the range observed in our sample does not seem to be related with negative effects on the performance of EF, but even seem to mediate the beneficial effect of lunch on the working memory updating. PMID- 26427890 TI - The clinical characteristics and treatment of cerebral AVM in pregnancy. AB - Cerebral arteriovenous malformation (AVM) in pregnancy is a complex situation and there is no agreement on its hemorrhage risk and treatment. Although studies on bleeding risk of cerebral AVMs in pregnancy are very few and there are different results between them, pregnancy will increase the hemorrhagic risk of AVM, and ruptured cerebral AVM in pregnancy should be treated actively. After intracranial hemorrhage, cerebral angiography should be performed for pregnant women shielded correctly. Cerebral angiography could clearly demonstrate the characteristics of cerebral AVM. The results from the literature show that the radiation dose of endovascular and stereotactic radiotherapy for cerebral AVM in pregnancy is below the safety value and is safe. Unruptured AVM in pregnancy, if there is no bleeding factor, such as no coexisting aneurysm, smooth venous drainage, no venous ectasia, or high risk of treatment, should be observed conservatively. PMID- 26427891 TI - Final infarct volume discriminates outcome in mild strokes. AB - INTRODUCTION: Knowledge of whether final infarct volume (FIV) predicts disability after mild stroke is limited. We sought to determine if FIV could differentiate good versus poor outcome after mild stroke. METHODS: We retrospectively identified 65 patients with mild stroke (National Institutes of Health Stroke Scale<=5) in a multicenter registry of 2453 patients. We evaluated associations between FIV and clinical outcome and evaluated the optimal FIV threshold that discriminated favorable (modified Rankin scale (mRS) 0-1) versus poor (mRS 2-6) outcome. RESULTS: The FIV cut-point of 20 mL differentiated favorable and poor outcomes (area under curve (AUC) 0.73, 95% confidence interval: 0.58-0.88). Favorable outcome was observed in 37/45 (82%) with FIV<20 mL, compared to 5/14 (36%) with FIV>=20 mL (p<0.01). FIV>=20 mL remained strongly associated with poor outcome independent of age, gender, stroke severity, Alberta Stroke Program Early CT Score (ASPECTS), and proximal arterial occlusion. CONCLUSION: In our small sample size, an FIV of 20 mL best differentiated between the likelihood of good versus poor outcome in patients with mild stroke. Further validation of infarct volume as a surrogate marker in mild stroke is warranted. PMID- 26427892 TI - Accuracy of four-dimensional CT angiography in detection and characterisation of arteriovenous malformations and dural arteriovenous fistulas. AB - A retrospective review was made to assess the accuracy of four dimensional CT angiogram (4D-CTA) in diagnosis of arteriovenous malformations (AVM) and dural arteriovenous fistulas (DAVF), with catheter-based digital-subtraction angiogram (DSA) being gold standard. 33 pairs of investigations (DSA and 4D-CTA) were performed primarily for suspicion of AVM/DAVF. Based on blinded reports, sensitivity and specificity for detection of AVM/DAVF were 77% (95% CI: 46-95%) and 100% (95% CI: 83-100%) respectively. Positive predictive value was 100% (95% CI: 69-100%) and negative predictive value 87% (95% CI: 66-97%). 4D-CTA is a practical minimally-invasive technique for evaluating cerebrovascular pathologies. There is good agreement between the findings of 4D-CTA and DSA despite the differences in temporal and spatial resolutions. 4D-CTA may obviate the need for DSA in a subgroup of patients who would otherwise have undergone this invasive investigation, which carries a risk of important complications. PMID- 26427893 TI - Magnetic resonance imaging findings of two sisters with Van der Knaap leukoencephalopathy. AB - Megalencephalic leukoencephalopathy with subcortical cysts, or Van der Knaap leukoencephalopathy, is a rare disease which is characterised by macrocephaly and neurological disorders with autosomal recessive inheritance. Magnetic resonance imaging is very helpful for determining distinctive findings and distinguishing other diseases. We present the radiological findings of two sisters (aged 6 and 10 years) diagnosed with Van der Knaap leukoencephalopathy. PMID- 26427894 TI - Automatic brain matter segmentation of computed tomography images using a statistical model: A tool to gain working time! AB - Brain computed tomography (CT) is useful diagnostic tool for the evaluation of several neurological disorders due to its accuracy, reliability, safety and wide availability. In this field, a potentially interesting research topic is the automatic segmentation and recognition of medical regions of interest (ROIs). Herein, we propose a novel automated method, based on the use of the active appearance model (AAM) for the segmentation of brain matter in CT images to assist radiologists in the evaluation of the images. The method described, that was applied to 54 CT images coming from a sample of outpatients affected by cognitive impairment, enabled us to obtain the generation of a model overlapping with the original image with quite good precision. Since CT neuroimaging is in widespread use for detecting neurological disease, including neurodegenerative conditions, the development of automated tools enabling technicians and physicians to reduce working time and reach a more accurate diagnosis is needed. PMID- 26427895 TI - Imaging of skull base pathologies: Role of advanced magnetic resonance imaging techniques. AB - Imaging plays a vital role in evaluation of skull base pathologies as this region is not directly accessible for clinical evaluation. Computerized tomography (CT) and magnetic resonance imaging (MRI) have played complementary roles in the diagnosis of the various neoplastic and non-neoplastic lesions of the skull base. However, CT and conventional MRI may at times be insufficient to correctly pinpoint the accurate diagnosis. Advanced MRI techniques, though difficult to apply in the skull base region, in conjunction with CT and conventional MRI can however help in improving the diagnostic accuracy. This article aims to highlight the importance of advanced MRI techniques like diffusion-weighted imaging, susceptibility-weighted imaging, perfusion-weighted imaging, and MR spectroscopy in differentiation of various lesions involving the skull base. PMID- 26427896 TI - Contralateral recurrence of tumefactive demyelination. AB - Tumefactive demyelination refers to large focal demyelinating lesions in the brain, which can be mistaken for malignancy. In some patients, these lesions are monophasic with a self-limited course; however, other patients demonstrate recurrent disease with new tumefactive or non-tumefactive lesions, and a subsequent diagnosis of relapsing-remitting multiple sclerosis is not uncommon. Owing to the limited data available in the literature, many questions about the patterns and prognostic significance of recurrent tumefactive lesions remain unanswered. The current case report involves a patient who recovered from tumefactive demyelination and presented two years later with a new recurrent tumefactive lesion in the contralateral brain. PMID- 26427898 TI - Bilateral pallidal hemorrhage in toxoplasmosis update of acute symmetric lesions of deep nuclei. AB - As acute symmetric lesions of deep gray nuclei are often associated with an impaired level of consciousness and neuroimaging by itself cannot distinguish between etiologies, diagnosis may be problematic. Appreciation of the cause of the various neuroimaging patterns in conjunction with the history, examination and laboratory investigations allows for accurate diagnosis in the vast majority of cases. Given the metabolic vulnerability of deep gray nuclei, other than bi thalamic infarction, it follows that toxic-metabolic and hypoxic-ischemic events account for the majority of cases. Nevertheless, the differential diagnosis is broad and diverse. We here describe two cases of bilateral pallidal hemorrhage in AIDS-associated toxoplasmosis, and review conditions recently described with acute symmetric deep gray nuclei lesions on neuroimaging. PMID- 26427897 TI - Neuroimaging evaluation in refractory epilepsy. AB - PURPOSE: To describe the application of neuroimaging analysis, compared to neuropsychological tests and video-electroencephalogram, for the evaluation of refractory epilepsy in a reference centre in Cali, Colombia. METHODS: Between March 2013 and November 2014, 29 patients, 19 men and 10 women, aged 9-65 years and with refractory epilepsy, were assessed by structural and functional magnetic resonance imaging while performing tasks related to language, verbal and non verbal memory. Also, volumetric evaluation was performed. A 1.5 Tesla magnetic resonance imaging scanner was used in all cases. RESULTS: Neuroimaging evaluation identified 13 patients with mesial temporal sclerosis. The remaining patients were classified as: 10 patients with neoplastic masses, two patients with cortical atrophy, two patients with scarring lesions and two patients with non structural aetiology. Among patients with mesial temporal sclerosis, comparison between techniques for lateralising the epileptogenic foci was made; the kappa index between functional magnetic resonance imaging and hippocampi volumetry was kappa=1.00, agreement between neuroimaging and video-electroencephalogram was good (kappa=0.78) and comparison with a neuropsychological test was mild (kappa=0.24). CONCLUSIONS: Neuroimaging studies allow the assessment of functional and structural damage related to epileptogenic lesions and foci, and are helpful to select surgical treatment, conduct intraoperative neuronavigation techniques, predict surgical deficits and evaluate patient recovery. PMID- 26427899 TI - All patients with HIV should get access to drug treatments regardless of CD4 count, says WHO. PMID- 26427901 TI - Women's healthcare: initiatives and challenges. AB - John C Jennings is 2014-2015 President of the American College and Congress of Obstetricians and Gynecologists. He is currently Professor of Obstetrics and Gynecology at Texas Tech University Health Sciences Center and has previously served as Regional Dean of the School of Medicine at TTUHSC Permian Basin. He is a passionate medical educator and during his academic career he has served as division chief, residency program director and department chair. He has authored numerous peer-reviewed and other publications and has been the recipient of multiple teaching awards. Prior to entering academic medicine, he was a busy practicing obstetrician/gynecologist in San Angelo, TX, USA. PMID- 26427902 TI - Gluteal muscle fatty atrophy is not associated with elevated blood metal ions or pseudotumors in patients with a unilateral metal-on-metal hip replacement. AB - BACKGROUND AND PURPOSE: There are no international guidelines to define adverse reaction to metal debris (ARMD). Muscle fatty atrophy has been reported to be common in patients with failing metal-on-metal (MoM) hip replacements. We assessed whether gluteal muscle fatty atrophy is associated with elevated blood metal ion levels and pseudotumors. PATIENTS AND METHODS: 263 consecutive patients with unilateral ASR XL total hip replacement using a posterior approach and with an unoperated contralateral hip were included in the study. All patients had undergone a standard screening program at our institution, including MRI and blood metal ion measurement. Muscle fatty atrophy was graded as being absent, mild, moderate, or severe in each of the gluteal muscles. RESULTS: The prevalence of moderate-to-severe gluteal muscle atrophy was low (12% for gluteus minimus, 10% for gluteus medius, and 2% for gluteus maximus). Muscle atrophy was neither associated with elevated blood metal ion levels (> 5 ppb) nor with the presence of a clear (solid- or mixed-type) pseudotumor seen in MRI. A combination of moderate-to-severe atrophy in MRI, elevated blood metal ion levels, and MRI confirmed mixed or solid pseudotumor was rare. Multivariable regression revealed that "preoperative diagnosis other than osteoarthrosis" was the strongest predictor of the presence of fatty atrophy. INTERPRETATION: Gluteal muscle atrophy may be a clinically significant finding with influence on hip muscle strength in patients with MoM hip replacement. However, our results suggest that gluteal muscle atrophy seen in MRI is not associated with either the presence or severity of ARMD, at least not in patients who have been operated on using the posterior approach. PMID- 26427905 TI - Community pharmacy and emerging public health initiatives in developing Southeast Asian countries: a systematic review. AB - The development of health and healthcare systems in South-East Asia has influenced the practice of community pharmacy. Over the years, community pharmacy in the region has striven to expand services beyond dispensing to encompass more involvement in public health issues. Searches were conducted in Scopus, EMBASE, MEDLINE and PubMed for articles published between January 2000 and December 2014, with 21 studies in five countries meeting the inclusion criteria. The findings showed increasing interest in research into the delivery of pharmacy services and public health initiatives. Overall, the review found that provision of some health services in pharmacies was common; however, most public health initiatives appeared to be poorly implemented, had limited evidence and were not demonstrated to be sustainable across the sector. This indicates that the practice of community pharmacy in the region has not significantly changed over the past 14 years with respect to the scope and quality of pharmacy services provided, and fundamental policy changes are necessary to improve this situation. PMID- 26427904 TI - Orthostatic hypotension: managing a difficult problem. AB - Orthostatic hypotension (OH) leads to a significant number of hospitalizations each year, and is associated with significant morbidity and mortality among affected individuals. Given the increased risk for cardiovascular events and falls, it is important to identify the underlying etiology of OH and to choose appropriate therapeutic agents. OH can be non-neurogenic or neurogenic (arising from a central or peripheral lesion). The initial evaluation includes orthostatic vital signs, complete history and a physical examination. Patients should also be evaluated for concomitant symptoms of post-prandial hypotension and supine hypertension. Non-pharmacologic interventions are the first step for treatment of OH. The appropriate selection of medications can also help with symptomatic relief. This review highlights the pathophysiology, clinical features, diagnostic work-up and treatment of patients with neurogenic OH. PMID- 26427906 TI - Gating by tryptophan 73 exposes a cryptic pocket at the protein-binding interface of the oncogenic eIF4E protein. AB - Targeting protein-protein interacting sites for potential therapeutic applications is a challenge in the development of inhibitors, and this becomes more difficult when these interfaces are relatively planar, as in the eukaryotic translation initiation factor 4E (eIF4E) protein. eIF4E is an oncogene that is overexpressed in numerous forms of cancer, making it a prime target as a therapeutic molecule. We report here the presence of a cryptic pocket at the protein-binding interface of eIF4E, which opens transiently during molecular dynamics simulations of the protein in solvent water and is observed to be stable when solvent water is mixed with benzene molecules. This pocket can also be seen in the ensemble of structures available from the solution-state conformations of eIF4E. The accessibility of the pocket is gated by the side-chain transitions of an evolutionarily conserved tryptophan residue. It is found to be feasible for accommodating clusters of benzene molecules, which signify the plasticity and ligandability of the pocket. We also observe that the newly formed cavity provides a favorable binding environment for interaction of a well-recognized small molecule inhibitor of eIF4E. The occurrence of this transiently accessible cavity highlights the existence of a more pronounced binding groove in a region that has traditionally been considered to be planar. Together, the data suggest that an alternate binding cavity exists on eIF4E and could be exploited for the rational design and development of a new class of lead compounds against the protein. PMID- 26427908 TI - Significantly Enhanced Separation using ZIF-8 Membranes by Partial Conversion of Calcined Layered Double Hydroxide Precursors. AB - Significantly enhanced H2 /CH4 (ca. 80) selectivity was realized by effective suppression of the framework flexibility of a prepared ZIF-8 membrane. Initially a ZnO buffer layer consisting of 20 nm-sized ZnO-nanoparticle aggregates was fabricated by controlled calcination of a ZnAl-NO3 layered double hydroxide membrane. Owing to its high chemical reactivity, the ZnO buffer layer was partially converted into a well-intergrown ZIF-8 membrane with a certain penetration depth upon solvothermal treatment with ligands. Our method may represent a new concept for the design of advanced MOF membranes with high selectivity. PMID- 26427907 TI - Genetic upregulation of BK channel activity normalizes multiple synaptic and circuit defects in a mouse model of fragile X syndrome. AB - KEY POINTS: Single-channel recordings in CA3 pyramidal neurons revealed that large-conductance calcium-activated K(+) (BK) channel open probability was reduced by loss of fragile X mental retardation protein (FMRP) and that FMRP acts on BK channels by modulating the channel's gating kinetics. Fmr1/BKbeta4 double knockout mice were generated to genetically upregulate BK channel activity in the absence of FMRP. Deletion of the BKbeta4 subunit alleviated reduced BK channel open probability via increasing BK channel open frequency, but not through prolonging its open duration. Genetic upregulation of BK channel activity via deletion of BKbeta4 normalized action potential duration, excessive glutamate release and short-term synaptic plasticity during naturalistic stimulus trains in excitatory hippocampal neurons in the absence of FMRP. Genetic upregulation of BK channel activity via deletion of BKbeta4 was sufficient to normalize excessive epileptiform activity in an in vitro model of seizure activity in the hippocampal circuit in the absence of FMRP. Loss of fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS), yet the mechanisms underlying the pathophysiology of FXS are incompletely understood. Recent studies identified important new functions of FMRP in regulating neural excitability and synaptic transmission via both translation-dependent mechanisms and direct interactions of FMRP with a number of ion channels in the axons and presynaptic terminals. Among these presynaptic FMRP functions, FMRP interaction with large-conductance calcium activated K(+) (BK) channels, specifically their auxiliary beta4 subunit, regulates action potential waveform and glutamate release in hippocampal and cortical pyramidal neurons. Given the multitude of ion channels and mechanisms that mediate presynaptic FMRP actions, it remains unclear, however, to what extent FMRP-BK channel interactions contribute to synaptic and circuit defects in FXS. To examine this question, we generated Fmr1/beta4 double knockout (dKO) mice to genetically upregulate BK channel activity in the absence of FMRP and determine its ability to normalize multilevel defects caused by FMRP loss. Single channel analyses revealed that FMRP loss reduced BK channel open probability, and this defect was compensated in dKO mice. Furthermore, dKO mice exhibited normalized action potential duration, glutamate release and short-term dynamics during naturalistic stimulus trains in hippocampal pyramidal neurons. BK channel upregulation was also sufficient to correct excessive seizure susceptibility in an in vitro model of seizure activity in hippocampal slices. Our studies thus suggest that upregulation of BK channel activity normalizes multi-level deficits caused by FMRP loss. PMID- 26427909 TI - Bioactivites of two common polyphenolic compounds: Verbascoside and catechin. AB - CONTEXT: Natural products can present remarkable biological and pharmacological activities. In traditional medicine, plants have been used historically in treating cancer, infections, and other inflammatory conditions. OBJECTIVE: Verbascoside and catechin are widespread polyphenolic plant compounds that could play a role in the anti-inflammatory and health-promoting effects of plants and plant extracts. MATERIALS AND METHODS: This study compares the potential cytotoxic effects of polyphenols verbascoside and catechin (6.25-200 uM) on human peripheral blood mononuclear cells (PBMC) for 48 h and myelomonocytic THP-1 and THP-1 Blue cells for 24 h. The effects of the compounds on immune activation markers such as indoleamine 2,3-dioxygenase (IDO) activity as well as on neopterin formation and nuclear factor-kappaB (NF-kappaB) activation were investigated. Cytotoxicity of the compounds was tested using Cell-Titer Blue assay. RESULTS: Verbascoside exhibited significant suppressive effects in mitogen stimulated PBMC on tryptophan breakdown (>50 uM; IC50 value: 58.6 uM) and the production of neopterin (>6.25 uM; IC50 value: 217 uM). These effects correlated with a decline in cell viability, while THP-1 Blue cells were less sensitive. NF kappaB activity was slightly enhanced at lower concentrations (<50 uM verbascoside) in stimulated cells and at the highest concentration used in unstimulated cells. Catechin had no relevant effects on cell viability and on the tested inflammation markers, except NF-kappaB activation in THP-1 Blue cells. DISCUSSION AND CONCLUSION: The results obtained show that verbascoside and catechin represent effective compounds which interfere with immunobiochemical pathways that are highly relevant for immunosurveillance and competing virus infections. PMID- 26427910 TI - Cerebral hemodynamics in orthostatic intolerance with normal head-up tilt test. AB - OBJECTIVES: Orthostatic hypotension (OH) and postural orthostatic tachycardia syndrome (POTS) are well-known causes of orthostatic intolerance (OI). In addition, there are OI patients who are characterized by the symptoms of OI and lack of abnormal findings in head-up tilt (HUT) test. The aim of this study was to determine the cerebral hemodynamic changes in HUT test of OI patients with normal HUT (OINH). MATERIALS AND METHODS: Two hundred and sixty-one OI patients and 50 healthy controls were enrolled in this study. All subjects underwent transcranial Doppler test while performing the HUT test. Forty-five patients had OH, 33 patients had POTS, and 183 patients had OINH. Blood pressures, heart rate, cerebral blood flow velocities (CBFVs), end-tidal carbon dioxide (ET-PCO2 ), cerebral critical closing pressure (CCP), cerebral perfusion pressure (CPP), and cerebral vascular resistance (CVR) were measured during HUT test. We compared the hemodynamic parameters of OINH with those of OH, POTS, and healthy controls. RESULTS: Reduced CBFVs, CPP, and ET-PCO2 and elevated CCP were observed in the HUT test of all four groups. CVR was reduced in three OI patients. The drops in systolic CBFV, CPP, and CVR of OINH patients were greater than those of healthy controls. The changes in parameters in the HUT test of OINH group were not different from those of OH and POTS groups except prominent decrements of CPP and CVR in OH group. CONCLUSION: Our findings suggest that OINH is true OI sharing the common pathomechanism of OH and POTS. PMID- 26427913 TI - The impact of venous occlusion per se on forearm muscle blood flow: implications for the near-infrared spectroscopy venous occlusion technique. AB - The purpose of this study was to examine the effect of venous occlusion per se on forearm muscle blood flow, as determined by the near-infrared spectroscopy (NIRS) venous occlusion technique (NIRS-VOT). NIRS data were obtained from the flexor digitorum superficialis (FDS) muscle on the dominant arm of 16 young, ostensibly healthy participants (14 men and two women; 30 +/- 6 year; 73 +/- 7 kg). Participants completed a series of five venous occlusion trials while seated at rest, and a series of 12 venous occlusion trials during a reactive hyperaemia induced by 5 min of forearm arterial occlusion. The NIRS-VOT was used to assess FDS muscle blood flow (Qmus), beat-by-beat, over the first four cardiac beats during venous occlusions. Qmus was also reported as a cumulative value, wherein the first two, first three and first four cardiac beats were used to calculate muscle blood flow. We observed that Qmus was highest when calculated over the first cardiac beat during venous occlusions performed at rest and throughout reactive hyperaemia (P<0.05). Moreover, the inclusion of more than one cardiac beat in the calculation of Qmus underestimated muscle blood flows, irrespective of the prevailing level of arterial inflow. These findings support the idea that venous occlusion per se affects the measurement of Qmus via the NIRS-VOT. Accordingly, it is recommended that Qmus is determined over the first cardiac beat when using the NIRS-VOT to assess microvascular blood flow of human forearm muscles. PMID- 26427911 TI - Metal-Free Addition/Head-to-Tail Polymerization of Transient Phosphinoboranes, RPH-BH2: A Route to Poly(alkylphosphinoboranes). AB - Mild thermolysis of Lewis base stabilized phosphinoborane monomers R(1)R(2)P BH2?NMe3 (R(1),R(2)=H, Ph, or tBu/H) at room temperature to 100 degrees C provides a convenient new route to oligo- and polyphosphinoboranes [R(1)R(2)P BH2]n. The polymerization appears to proceed via the addition/head-to-tail polymerization of short-lived free phosphinoborane monomers, R(1)R(2)P-BH2. This method offers access to high molar mass materials, as exemplified by poly(tert butylphosphinoborane), that are currently inaccessible using other routes (e.g. catalytic dehydrocoupling). PMID- 26427912 TI - Direct and Mediating Effects of an Anxiety Sensitivity Intervention on Posttraumatic Stress Disorder Symptoms in Trauma-Exposed Individuals. AB - Anxiety sensitivity (AS), or fear of anxious arousal, is a higher-order cognitive risk-factor for posttraumatic stress disorder (PTSD) composed of lower-order physical, cognitive, and social concerns regarding anxiety symptoms. Brief and effective interventions have been developed targeting AS and its constituent components. However, there is limited evidence as to whether an intervention aimed at targeting AS would result in reductions in PTS symptoms and whether the effects on PTS symptoms would be mediated by reductions in AS. Furthermore, there is no evidence whether these mediation effects would be because of the global or more specific components of AS. The direct and indirect effects of an AS intervention on PTS symptoms were examined in a sample of 82 trauma-exposed individuals (M age = 18.84 years, SD = 1.50) selected based on elevated AS levels (i.e., 1 SD above the mean) and assigned to either a treatment (n = 40) or an active control (n = 42) condition. Results indicated that the intervention led to reductions in Month 1 PTS symptoms, controlling for baseline PTS symptoms. Furthermore, this effect was mediated by changes in global AS and AS social concerns, occurring from intervention to Week 1. These findings provide an initial support for an AS intervention in amelioration of PTS symptoms and demonstrate that it is primarily reductions in the higher-order component of AS contributing to PTS symptom reduction. PMID- 26427915 TI - Evidence of the late lignification of the G-layer in Simarouba tension wood, to assist understanding how non-G-layer species produce tensile stress. AB - To recover verticality after disturbance, angiosperm trees produce 'tension wood' allowing them to bend actively. The driving force of the tension has been shown to take place in the G-layer, a specific unlignified layer of the cell wall observed in most temperate species. However, in tropical rain forests, the G layer is often absent and the mechanism generating the forces to reorient trees remains unclear. A study was carried out on tilted seedlings, saplings and adult Simarouba amara Aubl. trees-a species known to not produce a G-layer. Microscopic observations were done on sections of normal and tension wood after staining or observed under UV light to assess the presence/absence of lignin. We showed that S. amara produces a cell-wall layer with all of the characteristics typical of G layers, but that this G-layer can be observed only as a temporary stage of the cell-wall development because it is masked by a late lignification. Being thin and lignified, tension wood fibres cannot be distinguished from normal wood fibres in the mature wood of adult trees. These observations indicate that the mechanism generating the high tensile stress in tension wood is likely to be the same as that in species with a typical G-layer and also in species where the G layer cannot be observed in mature cells. PMID- 26427914 TI - Cancer-related CD15/FUT4 overexpression decreases benefit to agents targeting EGFR or VEGF acting as a novel RAF-MEK-ERK kinase downstream regulator in metastatic colorectal cancer. AB - BACKGROUND: Cancer-related immune antigens in the tumor microenvironment could represent an obstacle to agents targeting EGFR "cetuximab" or VEGF "bevacizumab" in metastatic colorectal cancer (mCRC) patients. METHODS: Infiltrating immune cells into tumor tissues, cancer-related expression of immune antigens (CD3, CD8, CD68, CD73, MPO, CD15/FUT4) from 102 mCRC patients receiving first-line Cetuximab or Bevacizumab plus chemotherapy were assessed by immunohistochemistry and validated in an independent tissue microarrays of 140 patients. Genome-wide expression profiles from 436 patients and 60 colon cancer cell lines were investigated using bioinformatics analysis. In vitro kinase assays of target genes activated by chemokines or growth factors were performed. RESULTS: Here, we report that cancer-related CD15/FUT4 is overexpressed in most of mCRCs patients (43 %) and associates with lower intratumoral CD3+ and CD8+ T cells, higher systemic inflammation (NLR at diagnosis >5) and poorer outcomes, in terms of response and progression-free survival than those CD15/FUT4-low or negative ones (adjusted hazard ratio (HR) = 2.92; 95 % CI = 1.86-4.41; P < 0.001). Overexpression of CD15/FUT4 is induced through RAF-MEK-ERK kinase cascade, suppressed by MEK inhibitors and exhibits a close connection with constitutive oncogenic signalling pathways that respond to ERBB3 or FGFR4 activation (P < 0.001). CD15/FUT4-high expressing colon cancer cells with primary resistance to cetuximab or bevacizumab are significantly more sensitive to MEK inhibitors than CD15/FUT4-low counterparts. CONCLUSION: Cancer-related CD15/FUT4 overexpression participates in cetuximab or bevacizumab mechanisms of resistance in mCRC patients. CD15/FUT4 as a potential target of the antitumor immune response requires further evaluation in clinical studies. PMID- 26427916 TI - Towards Organized Hybrid Nanomaterials at the Air/Water Interface Based on Liquid Crystal/ZnO Nanocrystals. AB - The ability to self-assemble nanosized ligand-stabilized metal oxide or semiconductor materials offers an intriguing route to engineer nanomaterials with new tailored properties from the disparate components. We describe a novel one pot two-step organometallic approach to prepare ZnO nanocrystals (NCs) coated with deprotonated 4-(dodecyloxy)benzoic acid (i.e., an X-type liquid-crystalline ligand) as a model LC system (termed ZnO-LC1 NCs). Langmuir and Langmuir-Blodgett films of the resulting hybrids are investigated. The observed behavior of the ZnO NCs at the air/water interface is rationalized by invoking a ZnO-interdigitation process mediated by the anchored liquid-crystalline shell. The ordered superstructures form according to mechanism based on a ZnO-interdigitation process mediated by liquid crystals (termed ZIP-LC). The external and directed force applied upon compression at the air/water interface and the packing of the ligands that stabilize the ZnO cores drives the formation of nanorods of ordered internal structure. To study the process in detail, we follow a nontraditional protocol of thin-film investigation. We collect the films from the air/water interface in powder form (ZnO-LC1 LB), resuspend the powder in organic solvents and utilize otherwise unavailable experimental techniques. The structural and physical properties of the resulting superlattices were studied by using electron microscopy, atomic force microscopy, X-ray studies, dynamic light scattering, thermogravimetric analysis, UV/Vis absorption, and photoluminescence spectroscopy. PMID- 26427918 TI - Comparison of people with serious mental illness and general population samples enrolled in lifestyle interventions for weight loss. PMID- 26427917 TI - Improving the understanding of the link between cognition and functional capacity in schizophrenia and bipolar disorder. AB - OBJECTIVE: Deficits in cognitive functioning are related to functional disability in people with serious mental illness. Measures of functional capacity are commonly used as a proxy for functional disabilities for cognitive remediation programs, and robust linear relationships between functional capacity and cognitive deficits are frequently observed. This study aimed to determine whether a curvilinear relationship better approximates the association between cognitive functioning and functional capacity. METHOD: Two independent samples were studied. Study 1: participants with schizophrenia (n=435) and bipolar disorder (n=390) aged 18-83 completed a neuropsychological battery and a performance-based measure of functional capacity. Study 2: 205 participants with schizophrenia (age range=39-72) completed a brief neuropsychological screening battery and a performance-based measure of functional capacity. For both studies, linear and quadratic curve estimations were conducted with cognitive performance predicting functional capacity scores. RESULTS: Significant linear and quadratic trends were observed for both studies. Study 1: in both the schizophrenia and bipolar participants, when cognitive composite z-scores were >0 (indicating normal to above normal performance), cognition was not related to functional capacity. Study 2: when neuropsychological screening battery z-scores were >-1 (indicating low average to average performance), cognition was not related to functional capacity. CONCLUSIONS: These results illustrate that in cognitively normal adults with serious mental illness, the relationship between cognitive function and functional capacity is relatively weak. These findings may aid clinicians and researchers determine who may optimally benefit from cognitive remediation programs, with greater benefits possibly being achieved for individuals with cognitive deficits relative to individuals with normal cognition. PMID- 26427919 TI - Risk of Hospital Readmission Among Infants With Neonatal Abstinence Syndrome. AB - OBJECTIVE: Neonatal abstinence syndrome (NAS) is a postnatal drug withdrawal syndrome that may last for months. Our objective was to determine if infants with NAS are at increased risk for hospital readmission compared with uncomplicated term and late preterm newborns. METHODS: In this longitudinal retrospective cohort study, administrative data were used for all births from 2006 to 2009 in the New York State Inpatient Database. We identified infants with NAS, born late preterm or uncomplicated term, as independent groups using diagnostic codes and determined readmission rates. We fit a multivariable logistic regression model with 30-day readmission after discharge as the outcome and infant characteristics, clinical morbidities, insurance type, and length of birth hospitalization as predictors. RESULTS: From 2006 to 2009 in New York State, 700 613 infants were classified as uncomplicated term, 51 748 were born late preterm, and 1643 infants were diagnosed with NAS. After adjusting for confounders, infants with NAS (odds ratio [OR] 2.49, 95% confidence interval [CI] 1.75-3.55) were more likely than uncomplicated term infants to be readmitted within 30 days of birth hospitalizations. The risk of readmission was similar to late preterm infants (OR 2.26, 95% CI 2.09-2.45). Length of birth hospitalization in days was inversely related to odds of being readmitted within 30 days of birth hospitalization (OR 0.94 95% CI 0.92-0.96). CONCLUSIONS: When compared with uncomplicated term infants, infants diagnosed with NAS were more than twice as likely to be readmitted to the hospital. Future research and state-level policies should investigate means to mitigate risk of hospital readmission for infants with NAS. PMID- 26427920 TI - Clinical Impact of an Antimicrobial Stewardship Program on Pediatric Hospitalist Practice, a 5-Year Retrospective Analysis. AB - BACKGROUND AND OBJECTIVES: Hospitalists increasingly serve as the primary physicians for children hospitalized with infections. Consequently, hospitalists frequently interact with institutional antimicrobial stewardship programs (ASPs). Understanding how these services interact can inform ongoing practice improvement efforts. The objectives of this study were to identify factors associated with ASP recommendations among hospitalist-managed children, and to determine the association of ASP interventions with clinical outcomes for hospitalist-managed patients. METHODS: We retrospectively analyzed ASP reviews of hospitalist patients from a children's hospital from March 2008 to June 2013. Clinical factors associated with an ASP recommendation were determined. Length of stay and 30-day readmission were compared between cases of agreement and disagreement with ASP recommendations. RESULTS: The ASP reviewed 2163 hospitalist patients, resulting in 350 recommendations (16.2% of reviews). Hospitalists agreed with ASP recommendations in 86.9% of cases. The odds of an ASP recommendation decreased during the study period. Ceftriaxone was the most common antibiotic associated with a recommendation (154/350, 44.0%); community-acquired pneumonia was the most common diagnosis (105/350, 30.0%). Antibiotic discontinuation was the most often recommendation; hospitalists most often disagreed with consulting infectious diseases. Disagreement with ASP recommendations was associated with a decreased length of stay of 15.4 (95% confidence interval -33.2 to 1.1) hours but not 30 day readmission prevalence. CONCLUSIONS: Pediatric hospitalists and ASPs can form an effective collaboration that improves antibiotic use while providing safe care. Better characterization of the areas of disagreement between hospitalists and ASPs is needed. Future studies are needed to identify ASP strategies that will be beneficial in other hospitalist settings. PMID- 26427921 TI - Management of Hospitalized Febrile Neonates Without CSF Analysis: A Study of US Pediatric Hospitals. AB - OBJECTIVE: Management of febrile neonates includes obtaining blood, urine, and cerebrospinal fluid (CSF) cultures with hospitalization for empiric parenteral antibiotic therapy. Outcomes and management for neonates were compared based on whether CSF was obtained. METHODS: This multicenter retrospective review of the 2002 to 2012 Pediatric Health Information System database included hospitalized infants aged <=28 days (neonates) admitted to an inpatient ward with a diagnosis code for fever or neonatal fever. Patients admitted to an ICU or with a complex chronic condition diagnosis code were excluded. Neonates were categorized as full septic workup (FSW; charge codes for blood, urine, and CSF culture or cell count) or as partial septic workup (PSW; charge codes for blood and urine cultures only), and their data were compared. RESULTS: Of 27 480 neonates with a diagnosis code for fever, 14 774 underwent the FSW and 3254 had a PSW. Median length of stay was 2 days for both groups, with no significant difference in readmissions, disposition, or parenteral antibiotic administration. Neonates with a PSW had significantly greater odds of having charge codes for additional laboratory testing and imaging, and they were more likely to receive a diagnosis code for sepsis, meningitis, or bronchiolitis. CONCLUSIONS: Neonates with PSW had lengths of stay and readmission rates similar to those with FSW but were more likely to undergo additional laboratory testing and imaging. Future studies including information about clinical severity and test results may provide additional insight into the variation in practice for this patient population. PMID- 26427922 TI - A Brief Inpatient Intervention Using a Short Video to Promote Reduction of Child Tobacco Smoke Exposure. AB - OBJECTIVES: Tobacco smoke exposure (TSE) increases the risk for respiratory related disease and hospitalizations. The hypothesis of this study was that a brief intervention (which included a motivational video) provided to parents and caregivers during their child's hospitalization would be associated with improved knowledge and behavior changes that may reduce the child's TSE. METHODS: Parents and caregivers of children hospitalized for respiratory illnesses with TSE were recruited between June and December 2012. They completed a questionnaire to determine baseline knowledge regarding the health effects of smoke exposure. The intervention included a motivational video, written smoking cessation materials, and referral to the state quitline. The questionnaire was repeated after the intervention; telephone follow-up at 1 and 3 months included knowledge questions and assessed behavior changes. Paired t tests were used to compare preintervention and postintervention knowledge scores. RESULTS: A total of 167 parents/caregivers were enrolled. The mean preintervention knowledge score was high at 5.4 of 6, which improved for 60 parents/caregivers (36%, P < .001) after the intervention and was sustained at follow-up. Follow-up was obtained from 123 (74%) parents/caregivers, and 90% reported behavior changes to reduce TSE. There was a 13% reported quit rate among the 99 parents/caregivers who smoked (95% confidence interval: 7-21). Other behavior changes reported included initiating home and vehicle smoking bans, discussing reduction of the child's smoke exposure, and showing the video to others. Improvement in knowledge after this brief intervention was associated with reported initiation of home and vehicle smoking bans (P < .01). CONCLUSIONS: Parents and caregivers of smoke-exposed children hospitalized for respiratory illnesses had high baseline knowledge of the effects of TSE. A brief intervention that included a motivational video was associated with reported behavior changes in parents/caretakers that decreased second- and third-hand smoke. Improvement of knowledge was associated with institution of home and vehicle smoking bans. PMID- 26427923 TI - Triage of Intermediate-Care Patients in Pediatric Hospitals. AB - BACKGROUND: Hospitalized children have a wide range of acuity and risk of decompensation. The objective of this study was to determine where pediatric patients are triaged when they present to pediatric hospitals needing intense monitoring and nursing care, but do not require invasive monitoring or technology. METHODS: We completed a telephone survey of pediatric hospitals in the United States with at least 2 non-neonatal pediatric wards and at least 50 acute inpatient beds. The survey consisted of a brief scripted portrayal of 6 hypothetical patients who may be admitted to a hospital's general floor, ICU, or an intermediate care unit (IMCU). The scenarios included severe asthma, bronchiolitis, croup, diabetic ketoacidosis, and patients dependent on home ventilation via noninvasive interface or tracheostomy. The hospital bed coordinator or emergency department charge nurse was asked where each hypothetical patient would be admitted in their hospital. RESULTS: A total192 hospitals met inclusion criteria and 164 hospitals (85%) responded. For all of the scenarios, most of the institutions triaged them to the PICU. Twenty-eight (17%) of the responding institutions triaged at least 1 of the patient scenarios to an IMCU. The presence of an IMCU decreased triage to the ICU for all scenarios when comparing hospitals with and without an IMCU (P < .001). CONCLUSIONS: Inpatient triage practices among pediatric hospitals vary widely for patients who require intense nursing or frequent monitoring due to specific acute illnesses or respiratory technologies. Institutions that have an IMCU available are less likely to send these patients to the ICU. PMID- 26427924 TI - Pediatric Post-Acute Hospital Care: Striving for Identity and Value. AB - The landscape of hospital care for children is changing. Hospital clinicians are challenged to provide high-quality care to 2 increasingly complex groups of children: (1) healthy children admitted for high-severity acute illnesses or injury and (2) children admitted with lifelong, and often disabling, chronic conditions. Hospitalizations for both of these groups are becoming more prevalent, lengthy, and costly. In many situations, these children need weeks, or sometimes months, to recover from their illness or injury, with a sustained intensity of daily caregiving needs throughout their recovery period. Pediatric post-acute hospital care is a little-known and underused option in pediatric health care that could substantially help these children stabilize in a less restrictive and less costly environment than acute care hospitals can provide. In this commentary, we (1) propose the need and place for pediatric post-acute care hospitals along the continuum of care, (2) discuss the characteristics of children currently cared for in pediatric post-acute care hospitals, (3) suggest research opportunities and challenges, and (4) present issues related to the cost and value of pediatric post-acute care hospitals. PMID- 26427925 TI - Taking Chances With Strep Throat. PMID- 26427926 TI - Crawling Toward a Diagnosis: Vesicles and Thrombocytopenia in a Neonate. PMID- 26427927 TI - Interferon-beta promotes macrophage foam cell formation by altering both cholesterol influx and efflux mechanisms. AB - Foam cell formation is a crucial event in atherogenesis. While interferon-beta (IFNbeta) is known to promote atherosclerosis in mice, studies on the role of IFNbeta on foam cell formation are minimal and conflicting. We therefore extended these studies using both in vitro and in vivo approaches and examined IFNbeta's function in macrophage foam cell formation. To do so, murine bone marrow-derived macrophages (BMDMs) and human monocyte-derived macrophages were loaded with acLDL overnight, followed by 6h IFNbeta co-treatment. This increased lipid content as measured by Oil red O staining. We next analyzed the lipid uptake pathways of IFNbeta-stimulated BMDMs and observed increased endocytosis of DiI-acLDL as compared to controls. These effects were mediated via SR-A, as its gene expression was increased and inhibition of SR-A with Poly(I) blocked the IFNbeta induced increase in Oil red O staining and DiI-acLDL endocytosis. The IFNbeta induced increase in lipid content was also associated with decreased ApoA1 mediated cholesterol efflux, in response to decreased ABCA1 protein and gene expression. To validate our findings in vivo, LDLR(-/-) mice were put on chow or a high cholesterol diet for 10weeks. 24 and 8h before sacrifice mice were injected with IFNbeta or PBS, after which thioglycollate-elicited peritoneal macrophages were collected and analyzed. In accordance with the in vitro data, IFNbeta increased lipid accumulation. In conclusion, our experimental data support the pro-atherogenic role of IFNbeta, as we show that IFNbeta promotes macrophage foam cell formation by increasing SR-A-mediated cholesterol influx and decreasing ABCA1-mediated efflux mechanisms. PMID- 26427928 TI - Pharmacophore and QSAR Modeling of Neuronal Nitric Oxide Synthase Ligands and Subsequent Validation and In Silico Search for New Scaffolds. AB - Neuronal Nitric Oxide synthase (nNOS) is an attractive challenging target for the treatment of various neurodegenerative disorders. To date, several structure based studies were conducted to search novel selective nNOS inhibitors. OBJECTIVE: Discovery of novel nNOS lead scaffolds through the integration of ligand-based threedimensional (3D) pharmacophore (s) with quantitative structure activity relationship model. METHOD: The pharmacophoric space of ten structurally diverse sets acquired from 145 previously reported nNOS inhibitors was scrutinize to fabricate representative pharmacophores. Afterwards, genetic algorithm together with multiple linear regression analysis was applied to find out an optimal pharmacophoric models and 2D physicochemical descriptors able to produce optimal predictive QSAR equation (r(2) 116 =0.76, F = 353, r(2) LOO = 0.69, r(2) PRESS against 29 external test ligands =0.51). A minimum of three binding modes between ligands and nNOS binding pocket rationalized by the emergence of three pharmacophoric models in the QSAR equation were illustrated. The QSAR-selected pharmacophores were validated by receiver operating characteristic curves analysis and afterward invested as a tool for screening national cancer institute (NCI) database. RESULTS: Low micro molar novel nNOS inhibitors were revealed. CONCLUSION: Two structurally diverse compounds 148 and 153 demonstrated new scaffolds toward the discovery of potent nNOS inhibitors. PMID- 26427929 TI - New Antimycobacterial Leads from Multicomponent Hydrazino-Ugi Reaction. AB - BACKGROUND: Previously, modification of isoniazide- and pyrazinamide-derived pharmacophores via the Ugi multicomponent reaction proved to be an effective strategy to obtain efficacious and non-cytotoxic antimycobacterial leads. OBJECTIVE: To apply the hydrazino-Ugi reaction developed in our group toward modifying these pharmacophores with similar appendages as reported previously; to create hydrolytically more stable compounds which are based on acyl hydrazine, rather than diamide backbone. METHOD: Six hydrazino-Ugi products were synthesized and modified at the reactive nitrogen atom via reductive alkylation. Additionally, by conducting the hydrazino-Ugi reaction in methanol, three methyl ester by-products were obtained and tested alongside the main library. Compounds were screened against M. tuberculosis H37Rv strain and checked for cytotoxicity vs. HEK293 cells. Hydrolytic stability of a model Ugi and one of the newly synthesized hydrazino-Ugi products was compared in rat plasma stability experiments. RESULTS: 6 out of 20 compounds prepared and tested, displayed potent inhibition of M. tuberculosis growth and virtually no cytotoxicity in the testing concentration range. The stability of a sample hydrazino-Ugi product in rat plasma was over 3 times higher compared to that of one of the Ugi products reported earlier. CONCLUSION: Hydrazino-Ugi reaction represents an effective way to modify classical antitubercular chemotypes and generate compounds endowed with specific antimycobacterial activity. These are new, hydrolytically stable leads for the future antitubercular therapy development. PMID- 26427930 TI - QSRR and QSAR Studies of Antitumor Drugs in View of their Biological Activity Prediction. AB - BACKGROUND: The QSRRs and QSARs are relatively new approaches to relate internal chemical structure and particular biological activity. This methodology is based on theory that mechanisms which took place into chromatography column are similar to those that occur in a living organism at the molecular level, for example when compounds penetrate into cells. OBJECTIVE: In this paper, we aim to describe different cytostatic activities of selected anticancer drugs as QSRR and QSAR models, and prove usefulness of connected QSRR and QSAR methodology in different types of studies. METHOD: Chromatographic experiments using gradient RP-HPLC method and different C18 stationary phases were performed. As a result we obtained retention parameter log kw. Moreover, to calculate descriptors, which characterize lipophilicity of analyzed antitumor drugs, DryLab program was utilized. Molecular modeling studies were performed by using HyperChem program. Dragon software was used to calculate structural descriptors, and then selected descriptors were used to build QSRR and QSAR models. Obtained data were analyzed by multiple regression analysis (MLR). RESULTS: Experimental log kw and predicted log kw from QSRR models developed, were further used in QSAR analysis. The goodness of fit was in the range of R2= 0.75 - 0.95, and the predictive performance of the models was Q2 = 0.6 - 0.81. CONCLUSION: Both QSRR and QSAR strategies presented in this paper, allowed predicting HPLC retention parameters and cytotoxic activities of anticancer medicines without the necessity to carry out time-consuming and expensive experimental tests. PMID- 26427931 TI - Monooxime Bispyridinium Reactivators Bearing Xylene Linker Synthesis and In Vitro Evaluation on Model of Organophosphate-Inhibited Acetylcholinesterase. AB - Nine novel mono-oxime reactivators bearing xylene linker were synthesized in an effort to improve previously prepared xylene bisoximes and monocarbamoyl monooximes. The novel compounds were tested in vitro on the model of tabun-, paraoxon-, methylparaoxon- and DFP-inhibited human erythrocyte AChE. Their reactivation ability was compared to pralidoxime, asoxime, obidoxime and two previously prepared xylene linked bisoximes (K107, K108). All compounds showed minimal reactivation of tabun-inhibited AChE at selected concentration scale. This finding was explained by molecular modelling study. Bisoximes obidoxime and K108 resulted as the best reactivators for paraoxon-, methylparaoxon- and DFP inhibited AChE. The loss of nonoxime moiety lead to the loss of reactivation ability within the novel compounds. Though the novel reactivators did not exceed previously known compounds, they confirmed former SAR findings for xylene-linked AChE reactivators. PMID- 26427932 TI - A public mental health approach in humanitarian settings is worthy of consideration, with evidence. PMID- 26427933 TI - Catalytic potential of highly defective (211) surfaces of zinc blende ZnO. AB - Zinc blende (ZB) ZnO has gained increasing research interest due to its favorable properties and its stabilization on the nanoscale. While surface properties are important on the nanoscale, the studies on ZB ZnO surface properties are rare. Here we have performed first principles calculations of the energies and structures of ZB and wurtzite (WZ) ZnO surfaces. Our results indicate that, among the four surfaces parallel to the polar axes, such as (1010) and (1120) of the WZ phase and (110) and (211) of the ZB phase, the polar (211) surface has substantially lower surface vacancy formation energies than the others, which makes ZB ZnO promising for catalytic applications. Our results also imply that the stabilization of ZB ZnO on the nanoscale is due to some mechanisms other than surface energies. PMID- 26427934 TI - Hospital food waste and environmental and economic indicators--A Portuguese case study. AB - This study presents a comprehensive characterization of plate waste (food served but not eaten) at an acute care hospital in Portugal and elaborates on possible waste reduction measures. Even though waste prevention is a priority in Europe, large amounts of food are still being wasted every day, with hospitals giving rise to two to three times more food waste than other foodservice sectors. For this work the plate waste arising at the ward level was audited during 8 weeks, covering almost 8000 meals, using a general hospital as case study. Weighing the food served to patients and that returned after the meal allowed calculating plate waste for the average meal, as well as for individual meal items. Comparison of food waste arising showed that differences exist among wards, with some generating more waste than others. On average each patient throws away 953 g of food each day, representing 35% of the food served. This equates to 8.7 thousand tonnes of food waste being thrown away each year at hospitals across Portugal. These tonnes of food transformed into waste represent economic losses and environmental impacts, being estimated that 16.4 thousand tonnes of CO2 (equivalent) and 35.3 million euros are the annual national indicators in Portugal. This means that 0.5% of the Portuguese National Health budget gets thrown away as food waste. Given the magnitude of the food problem five measures were suggested to reduce food waste, and their potential impact and ease of implementation were discussed. Even though food waste is unavoidable the results obtained in this work highlight the potential financial and environmental savings for Portuguese hospitals, providing a basis to establish future strategies to tackle food waste. PMID- 26427935 TI - Mesophilic and thermophilic anaerobic digestion of the liquid fraction of pressed biowaste for high energy yields recovery. AB - Deep separate collection of the organic fraction of municipal solid waste generates streams with relatively low content of inert material and high biodegradability. This material can be conveniently treated to recovery both energy and material by means of simplified technologies like screw-press and extruder: in this study, the liquid fraction generated from pressed biowaste from kerbside and door-to-door collection was anaerobically digested in both mesophilic and thermophilic conditions while for the solid fraction composting is suggested. Continuous operation results obtained both in mesophilic and thermophilic conditions indicated that the anaerobic digestion of pressed biowaste was viable at all operating conditions tested, with the greatest specific gas production of 0.92m(3)/kgVSfed at an organic loading rate of 4.7kgVS/m(3)d in thermophilic conditions. Based on calculations the authors found that the expected energy recovery is highly positive. The contents of heavy metals and pathogens of fed substrate and effluent digestates were analyzed, and results showed low levels (below End-of-Waste 2014 criteria limits) for both the parameters thus indicating the good quality of digestate and its possible use for agronomic purposes. Therefore, both energy and material were effectively recovered. PMID- 26427936 TI - Evaluation of different end-of-life management alternatives for used natural cork stoppers through life cycle assessment. AB - An important aspect of sustainable development is the implementation of effective and sustainable waste management strategies. The present study focuses on a Life Cycle Assessment (LCA) approach to different waste management strategies for natural cork stoppers, namely incineration at a municipal solid waste incinerator, landfilling in a sanitary landfill, and recycling. In the literature, there are no LCA studies analyzing in detail the end-of-life stage of natural cork stoppers as well as other cork products. In addition, cork is usually treated as wood at the end-of-life stage. Thus, the outcome of this study can provide an important insight into this matter. The results showed that different management alternatives, namely incineration and recycling, could be chosen depending on the impact category considered. The former alternative presented the best environmental results in the impact categories of climate change, ozone depletion and acidification, while the latter for photochemical ozone formation and mineral and fossil resource depletion. The landfilling alternative did not present the best environmental performance in any of the impact categories. However, when the biogenic carbon dioxide emission was assessed for the climate change category, the landfilling alternative was found to be the most effective since most of the biogenic carbon would be permanently stored in the cork products and not emitted into the atmosphere. A sensitivity analysis was performed and the results showed that there are various parameters that can significantly influence the results (e.g., carbon content in cork and decay rate of cork in the landfill). Thus, LCA studies should include a detailed description concerning their assumptions when the end-of-life stage is included in the boundaries since they can influence the results, and furthermore, to facilitate the comparison of different end-of-life scenarios. The present study and the obtained results could be useful for the decision-making process concerning public solid waste policies and industrial strategies. PMID- 26427938 TI - Early Results of Medicare's Bundled Payment Initiative for a 90-Day Total Joint Arthroplasty Episode of Care. AB - BACKGROUND: In 2011 Medicare initiated a Bundled Payment for Care Improvement (BPCI) program with the goal of introducing a payment model that would "lead to higher quality, more coordinated care at a lower cost to Medicare." METHODS: A Model 2 bundled payment initiative for Total Joint Replacement (TJR) was implemented at a large, tertiary, urban academic medical center. The episode of care includes all costs through 90 days following discharge. After one year, data on 721 Medicare primary TJR patients were available for analysis. RESULTS: Average length of stay (LOS) was decreased from 4.27 days to 3.58 days (Median LOS 3 days). Discharges to inpatient facilities decreased from 71% to 44%. Readmissions occurred in 80 patients (11%), which is slightly lower than before implementation. The hospital has seen cost reduction in the inpatient component over baseline. CONCLUSION: Early results from the implementation of a Medicare BPCI Model 2 primary TJR program at this medical center demonstrate cost-savings. LEVEL OF EVIDENCE: IV economic and decision analyses-developing an economic or decision model. PMID- 26427937 TI - Examining influential factors in providers' chronic pain treatment decisions: a comparison of physicians and medical students. AB - BACKGROUND: Chronic pain treatment guidelines are unclear and conflicting, which contributes to inconsistent pain care. In order to improve pain care, it is important to understand the various factors that providers rely on to make treatment decisions. The purpose of this study was to examine factors that reportedly influence providers' chronic pain treatment decisions. A secondary aim was to examine differences across participant training level. METHODS: Eighty five participants (35 medical students, 50 physicians) made treatment decisions for 16 computer-simulated patients with chronic pain. Participants then selected from provided lists the information they used and the information they would have used (had it been available) to make their chronic pain treatment decisions for the patient vignettes. RESULTS: Frequency analyses indicated that most participants reported using patients' pain histories (97.6 %) and pain description (95.3 %) when making treatment decisions, and they would have used information about patients' previous treatments (97.6 %) and average and current pain ratings (96.5 %) had this information been available. Compared to physicians, medical students endorsed more frequently that they would have used patients' employment and/or disability status (p < 0.05). A greater proportion of medical students wanted information on patients' use of illicit drugs and alcohol to make treatment decisions; while a greater proportion of physicians reported using personal experience to inform their decisions. DISCUSSION: This study found providers use patients' information and their own experiences and intuition to make chronic pain treatment decisions. Also, participants of different training levels report using different patient and personal factors to guide their treatment decisions. CONCLUSIONS: These results highlight the complexity of chronic pain care and suggest a need for more chronic pain education aimed at medical students and practicing providers. PMID- 26427939 TI - Tibial Crest Osteotomy in Extensile Knee Exposure-A Modified, Low-Energy, Suture Technique. AB - BACKGROUND: Tibial crest osteotomy is an established extensile knee approach. Complications include mal-union, non-union, and fixation problems.We have designed a technique aimed at reducing complications through the principles of low-energy osteotomy and suture repair. METHODS: We reviewed our clinical and radiological results in 159 consecutive patients 181 osteotomies with a mean age of 66 years, and an average follow up of 22 months. RESULTS: Union occurred in all osteotomies (100%) at a mean period of 11 weeks. Proximal migration averaging 11.5 mm occurred in 6 osteotomies (3%). Crest fragmentation occurred in 11 osteotomies (6%), with all cases resulting in uncomplicated union. No extensor mechanism failure or complications related to the suture material occurred. CONCLUSION: We conclude that this technique results in satisfactory outcomes whilst avoiding hardware-related problems. PMID- 26427940 TI - Hip Resurfacing Implant Orientation Analysis: A Comparison of a Computer-Added Design Technique and Computed Tomography. AB - BACKGROUND: Accurate acetabular component orientation in hip resurfacing is mandatory. The aim of this study is to analyze if interpretation of pelvic radiographs with computer-added design (CAD) software is comparable to computed tomography (CT) in measurement of acetabular anteversion and inclination of a Birmingham Hip Resurfacing (BHR) hip. METHODS: A consecutive series of 49 patients (50 hips) who underwent hip resurfacing arthroplasty between 2005 and 2007 with the BHR system were retrospectively included. The surgical procedure was performed by 1 orthopedic surgeon in the beginning of his learning curve. Computer-added design software was used to measure acetabular component orientation on an anteroposterior pelvic radiograph. These measurements were compared with CT measurements. We calculated the correlation between the CAD software and CT analysis. The degree of underestimation or overestimation was determined, and a Bland-Altman plot was created to visualize the agreement between CAD software and CT results. RESULTS: We analyzed 50 BHR hips with mean inclination of 54.6 degrees and 55.6 degrees and mean anteversion of 24.8 degrees and 13.3 degrees measured by CT and CAD, respectively. Pearson correlation coefficient for inclination was 0.69 (P < .001) and for anteversion 0.81 (P < .001). Computer-added design showed a mean underestimated anteversion of 11.6 degrees (P < .001). There was no significant underestimation or overestimation of inclination with CAD analysis compared to CT measurements. CONCLUSION: The CAD software is useful to assess acetabular inclination in hip resurfacing but underestimates anteversion. PMID- 26427941 TI - Hypoalbuminemia Independently Predicts Surgical Site Infection, Pneumonia, Length of Stay, and Readmission After Total Joint Arthroplasty. AB - This study investigates the association between preoperative hypoalbuminemia, a marker for malnutrition, and complications during the 30 days after total joint arthroplasty. Patients who underwent elective primary total hip and knee arthroplasty as part of the American College of Surgeons National Surgical Quality Improvement Program were identified. Outcomes were compared between patients with and without hypoalbuminemia (serum albumin concentration <3.5 g/dL) with adjustment for patient and procedural factors. A total of 49603 patients were included. In comparison to patients with normal albumin concentration, patients with hypoalbuminemia had a higher risk for surgical site infection, pneumonia, extended length of stay, and readmission. Future efforts should investigate methods of correcting nutritional deficiencies prior to total joint arthroplasty. If successful, such efforts could lead to improvements in short term outcomes for patients. PMID- 26427942 TI - Safe sequencing depth to estimate the intra-host heterogeneity of viruses. AB - Massively parallel sequencing allows efficient determination of genomic sequences and intra-host polymorphisms for viruses. However, the sequencing depth that guarantees safe interpretation of the observed data is unclear. We demonstrated that 10-fold genome coverage may allow safe genome assembly, and 1000-fold coverage is required to obtain reliable polymorphism estimation. PMID- 26427943 TI - The contribution of case study design to supporting research on Clubhouse psychosocial rehabilitation. AB - BACKGROUND: Psychosocial Clubhouses provide recovery-focused psychosocial rehabilitation to people with serious mental illness at over 300 sites in more than 30 countries worldwide. To deliver the services involved, Clubhouses employ a complex mix of theory, programs and relationships, with this complexity presenting a number of challenges to those undertaking Clubhouse research. This paper provides an overview of the usefulness of case study designs for Clubhouse researchers; and suggests ways in which the evaluation of Clubhouse models can be facilitated. RESULTS: The paper begins by providing a brief explanation of the Clubhouse model of psychosocial rehabilitation, and the need for ongoing evaluation of the services delivered. This explanation is followed by an introduction to case study design, with consideration given to the way in which case studies have been used in past Clubhouse research. It is posited that case study design provides a methodological framework that supports the analysis of either quantitative, qualitative or a mixture of both types of data to investigate complex phenomena in their everyday contexts, and thereby support the development of theory. As such, case study approaches to research are well suited to the Clubhouse environment. The paper concludes with recommendations for future Clubhouse researchers who choose to employ a case study design. CONCLUSIONS: While the quality of case study research that explores Clubhouses has been variable in the past, if applied in a diligent manner, case study design has a valuable contribution to make in future Clubhouse research. PMID- 26427945 TI - A Pale Baby With Blue Blood. AB - A previously healthy 9-month-old boy presented to the emergency department with sudden onset of pallor and reduced activity. A detailed history and initial blood tests revealed the diagnosis of oxidant stress-induced hemolysis caused by glucose-6-phosphate dehydrogenase deficiency. However, the child also had a second diagnosis that was revealed with additional testing. This case is described to illustrate the dual diagnosis and management guidelines for both potentially serious conditions. PMID- 26427944 TI - Emergency Department Visits for Gastroenteritis Before and After Rotavirus Vaccine Implementation in 2006. AB - OBJECTIVES: Gastroenteritis (GE) accounts for a significant number of emergency department (ED) visits in children. Several studies since the introduction of a new rotavirus vaccine in 2006 have found decreases in rotavirus illness. We sought to determine in a large multicenter ED database whether there was also a decrease in ED visits in young children for GE. METHODS: DESIGN: Retrospective cohort of ED visits. SETTING: 28 EDs with annual visits between 22,000 and 82,000. POPULATION: Consecutive patients between January 1, 1996, and December 31, 2011. PROTOCOL: We identified GE visits using International Classification of Diseases 9th revision (ICD-9) codes. For each year, less than 5 years, we determined the average daily percent of total ED visits for GE. We calculated the decreases from 2005 to 2011 in the average daily percent GE visits for each year of life and their 95% confidence intervals. RESULTS: There were 7,740,823 total visits in the database, and 811,317 (10.5%) are younger than 5 years. The annual percent of GE visits rose for all years of life from 1999 to 2005 and then decreased from 2005 to 2011. The decreases from 2005 to 2011 were greatest in the earliest years of life ranging from 41% in the first year of life to 15% in the fifth year of life. CONCLUSIONS: We found a decrease in average daily ED visits for GE in each year of life for those younger than 5 years after the introduction of the rotavirus vaccine. This was most pronounced during the earliest years of life. PMID- 26427946 TI - Epiploic Appendagitis: A Rare Cause of Acute Abdominal Pain in Children. Report of a Case and Review of the Pediatric Literature. AB - A 9-year-old boy presented with acute onset of abdominal pain and vomiting. History, physical examination, and initial laboratory testing failed to provide a diagnosis. A computed tomography scan revealed the rare finding of epiploic appendagitis. We review the literature of this rare, but increasingly recognized, condition that mimics appendicitis and needs to be considered in the child with acute abdominal pain. PMID- 26427947 TI - Acute Migraine Management in Children. AB - Migraines are common, incapacitating, and often stress inducing for pediatric patients and parents alike. According to the Agency for Healthcare Research and Quality, more than 1 million Americans seek emergency care every year due to migraines, with increasing frequency among adolescents. The disease can vary in severity and character, often mimicking life-threatening conditions, requiring prompt nuanced recognition by emergency personnel and implementation of an effective treatment strategy. Development of emergency department guidelines for the management of pediatric migraines should be based on up-to-date evidence supporting safe, appropriate therapies for children. PMID- 26427949 TI - ECGs in the ED. PMID- 26427950 TI - Authors' Response to "Parental Cannabis Abuse and Accidental Intoxication in Children: Prevention by Detecting Neglectful Situations and At-Risk Families". PMID- 26427951 TI - The Use of Point-of-Care Ultrasound to Evaluate for Intestinal Foreign Bodies in the Pediatric Emergency Department. AB - We present the use of point-of-care ultrasound to evaluate two patients with examinations concerning for appendicitis who were found to have multiple magnets ingested and subsequent bowel perforations. These cases illustrate the consequences of magnet ingestion as well as the application of point-of-care ultrasound for the identification of intestinal foreign bodies in children. PMID- 26427952 TI - Ultrasonographic assessment of fetal growth in miniature "Shiba" goats (Capra hircus). AB - The aim of the present study was to monitor fetal growth in relation to gestational stage to generate formulae which could be used to estimate fetal age in goats. Eight miniature Shiba goats (Capra hircus) were examined weekly by transrectal and transabdominal ultrasound scanning during the gestation period between Day 21 and 126 days of gestation. For accurate judgment, all fetometric parameters were measured at least three times per one examination for each animal. Quantification of the growth of the fetus allowed the development of a number of predictors of fetal age. Low correlations were associated with measurement of the chest diameter (R(2)=0.869), trunk diameter (R(2)=0.8969), tibia length (R(2)=0.8662) and placentome diameter (R(2)=0.8999). Moderate correlation was assessed by calculation of the length of six successive lumbar vertebrae (R(2)=0.9296), femur length (R(2)=0.9278), heart axis length (R(2)=0.9382 and 0.9589; for the longitudinal and transverse axis, respectively), occipitonasal length (R(2)=0.9527), umbilical cord diameter (R(2)=0.9119) and orbit diameter (R(2)=0.9239). A high correlation was estimated in investigating the length of six successive thoracic vertebrae (R(2)=0.9674), braincase diameter (R(2)=0.9831) and crown rump length (R(2)=0.9848). In conclusion, the intrauterine fetal biometry estimation through ultrasound might be useful to predict the accurate gestational age in miniature goats. PMID- 26427953 TI - Health systems research for policy change: lessons from the implementation of rapid assessment protocols for diabetes in low- and middle-income settings. AB - BACKGROUND: As many challenges exist for access to diabetes care in developing countries, the International Insulin Foundation developed a Rapid Assessment tool and implemented this approach to identify barriers to care and propose concrete recommendations for decision makers. The objective of this paper is to identify the factors that contributed to informing and influencing policymakers with regards to this work. METHODS: A documentary review comprised Stage 1. Stage 2 used an online questionnaire to gain insight from users of the Rapid Assessment results. Based on Stages 1 and 2, Stage 3 comprised in-depth interviews with a total of nine individuals (one individual each from the six participating countries; two individuals from the World Health Organization; one "Global Diabetes Advocate"). Interviews were analyzed based on a list of themes developed from Stage 2. RESULTS: Stage 1 led to the identification of various types of documents referring to the results. The online questionnaire had a response rate of 33%. Respondents directly involved in the assessment had a "Good" or "Very Good" appreciation of most aspects and scored these higher than those not directly involved. From the interviews, formalized methods and close collaboration between the international team and local partners were strengths. Trust and a relationship with local partners were also seen as assets. All stakeholders valued the results and the credibility of the data generated. Local partners felt that more could have been done for dissemination. CONCLUSION: This study shows the importance of specific results from the different assessments. In addressing complex issues having external experts involved was seen as an advantage. The uptake of results was due to the credibility of the research which was influenced by a mix of the people involved, past assessments, trusted local partners, and the use of the results by knowledge brokers, such as the World Health Organization. Through these brokers, others gained ownership of the data. The methods used and the fact that this data was grounded in a local context also reinforced its value. Despite limitations, this study offers a unique perspective where a similar research approach was taken in six countries. PMID- 26427954 TI - Translational assessment of cardiac contractility by echocardiography in the telemetered rat. AB - INTRODUCTION: Cardiac contractility was evaluated using standard inotropic agents in rats. We compared indices of cardiac contractility, i.e. LV dP/dt max from telemetry while simultaneously collecting EF (ejection fraction) and FS (fractional shortening) measures from echocardiography. METHODS: Male Wistar rats were instrumented with telemetry devices for measurements of blood pressure and left ventricular pressure. Milrinone (PDE III inhibitor) and verapamil (L-type calcium channel blocker) at doses of 0, 3, 10, and 30 mg/kg were administered orally using a 4 * 4 Latin square crossover study design. Telemetry data were recorded at predose and continuously for 24h post-dose. Echocardiographic evaluations were conducted once at predose and at 1 and 2h after milrinone or verapamil administration, respectively. During the recording of echocardiograms, telemetry data were collected simultaneously. Blood samples were also collected to confirm plasma drug exposure. RESULTS: As expected, milrinone increased LV dP/dt max, EF and FS while verapamil decreased LV dP/dt max, EF and FS. Linear regression analysis showed a positive correlation between LV dP/dt max and EF or FS (P<0.001) with both test agents. A change in LV dP/dt max of 1000 mmHg/s was found to correspond with a change in EF and FS of 13 and 16%, respectively, in the telemetered rat. DISCUSSION: The correlation between contractility indices assessed by telemetry and echocardiographic methods in rat models has not received much attention to date. Our results with two reference compounds demonstrate that both methods are sensitive to alterations in contractility induced by inotropic agents administered to rats. The high degree of correlation between changes in LV dP/dt max and EF or FS in the rat enables a translational element of clinical relevance following changes in contractility indices when measured with telemetry devices in preclinical studies. PMID- 26427955 TI - Incidence and serotype distribution of invasive group B streptococcal disease in young infants: a multi-country observational study. AB - BACKGROUND: Group B Streptococcus (GBS) is a leading cause of serious infection in very young infants. Robust incidence data from many geographic regions, including Latin America and Asia, are however lacking. METHODS: A multicenter, hospital-based observational study was performed in Panama, Dominican Republic, Hong Kong and Bangladesh. All represented urban, tertiary referral hospitals, except Bangladesh. GBS cases (microbiological isolation from normally sterile sites in infants aged 0-89 days) were collected over 12 months. RESULTS: At 2.35 (95% CI: 1.74-3.18) cases per 1000 live births, the incidence of early onset GBS disease (EOD) was highest in the Dominican Republic, compared with 0.76 (95% CI: 0.41-1.39) in Hong Kong and 0.77 (95% CI: 0.44-1.35) in Panama, while no cases were identified in Bangladesh. Over 90% of EOD cases occurred on the first day of life, with case fatality ratios ranging from 6.7% to 40%, varying by center, age of onset and clinical presentation. Overall, 90% of GBS (EOD and late onset disease) was due to serotypes Ia, Ib and III. CONCLUSIONS: The incidence rate of early onset GBS infection reported in Dominican Republic was not dissimilar from that described in the United States prior to screening and intrapartum antibiotic prophylaxis, while the incidence in Hong Kong was higher than previously reported in the Asian region. The failure to identify GBS cases in Bangladesh highlights a need to better understand the contribution of population, healthcare and surveillance practice to variation in reported incidence. Overall, the identified disease burden and serotype distribution support the need for effective prevention methods in these populations, and the need for community based surveillance studies in rural areas where access to healthcare may be challenging. PMID- 26427956 TI - Identification of chemical constituents of Zanthoxylum heitzii stem bark and their insecticidal activity against the malaria mosquito Anopheles gambiae. AB - BACKGROUND: Zanthoxylum heitzii bark extracts have insecticidal properties and have been reported to be used against malaria in Western Africa. Previously, it has been shown that a hexane extract of the bark is toxic to adult females of the mosquito Anopheles gambiae, a malaria vector. As part of our project on the control of malaria vectors using plant extracts, the phytochemistry of Z. heitzii bark hexane extract has been investigated with the aim to identify the major components with adulticidal and larvicidal effects on An. gambiae. METHODS: Z. heitzii stem bark was extracted with hexane, and the extract was fractionated to isolate major components from the bark, identified by NMR spectroscopy. Isolated compounds were tested for toxicity towards adult female An. gambiae mosquitoes and for larvicidal effects towards An. gambiae. RESULTS: The alkaloid dihydronitidine, the sesquiterpenoid caryophyllene oxide, the amide pellitorine and the lignan sesamin were identified as the major constituents in Z. heitzii bark. Pellitorine was toxic to both adult insects (LD50 50 ng/mg insect) and larvae (LD50 13 MUg/ml). None of the other compounds were toxic to adults, but caryophyllene oxide and sesamin exhibited moderate larvicidal effects (LD50 > 150 MUg/ml). A mixture of the four compounds in the same ratio as in the hexane extract showed higher toxicity (LD50 34 ng/mg insect) towards adult insects than the pure compounds. CONCLUSION: The toxicity of Z. heitzii bark hexane extract to An. gambiae is mostly due to pellitorine, although interactions between pellitorine and other, inactive constituents may enhance the activity of the extract. PMID- 26427957 TI - High-tech image-guided therapy versus low-tech, simple, cheap gynecologic brachytherapy. PMID- 26427958 TI - The fiber-optic imaging and manipulation of neural activity during animal behavior. AB - Recent progress with optogenetic probes for imaging and manipulating neural activity has further increased the relevance of fiber-optic systems for neural circuitry research. Optical fibers, which bi-directionally transmit light between separate sites (even at a distance of several meters), can be used for either optical imaging or manipulating neural activity relevant to behavioral circuitry mechanisms. The method's flexibility and the specifications of the light structure are well suited for following the behavior of freely moving animals. Furthermore, thin optical fibers allow researchers to monitor neural activity from not only the cortical surface but also deep brain regions, including the hippocampus and amygdala. Such regions are difficult to target with two-photon microscopes. Optogenetic manipulation of neural activity with an optical fiber has the advantage of being selective for both cell-types and projections as compared to conventional electrophysiological brain tissue stimulation. It is difficult to extract any data regarding changes in neural activity solely from a fiber-optic manipulation device; however, the readout of data is made possible by combining manipulation with electrophysiological recording, or the simultaneous application of optical imaging and manipulation using a bundle-fiber. The present review introduces recent progress in fiber-optic imaging and manipulation methods, while also discussing fiber-optic system designs that are suitable for a given experimental protocol. PMID- 26427959 TI - Test-retest reliability of the Shape/Texture Identification testTM in people with chronic stroke. AB - OBJECTIVE: To evaluate the test-retest reliability of the Shape/Texture Identification test (STI-testTM) in persons with chronic stroke. DESIGN: A test retest design. SETTING: University hospital outpatient setting. PARTICIPANTS: Forty-five persons (mean age 65 years) with mild to moderate impairments in the arm and hand > 6 months post stroke. INTERVENTIONS: Not applicable. MAIN MEASURE: The STI-testTM was used to assess active touch of the hand. It consists of two subtests: identification of shapes and identification of textures, each in three different sizes. Both hands were assessed twice, one week apart. The reliability of the data was evaluated with weighted Kappa statistics and the Svensson rank invariant method (percentage agreement, systematic and random disagreements). RESULTS: The median total score of the STI-testTM was 5 points (min-max 0-6 points) for the more affected hand and 6 points (min-max 3-6 points) for the less affected hand at both test occasions. The weighted Kappa coefficient was 0.94 for the more affected hand and 0.55 for the less affected hand. The percentage agreement for the more affected hand was 69% for the subtest shapes and 82% for the subtest textures, and for the less affected hand 62% and 91%, respectively. There were no systematic or random disagreements for any of the subtests. CONCLUSION: The STI-testTM is reliable to assess active touch of the hand after stroke. PMID- 26427960 TI - Effects of Whole Body Vibration Exercise associated with Quadriceps Resistance Exercise on functioning and quality of life in patients with knee osteoarthritis: a randomized controlled trial. AB - OBJECTIVE: To determine effects of Whole Body Vibration Exercise (WBVE) associated with quadriceps resistance exercises (QRE) versus QRE only on pain, physical function, biomarkers in serum and urine, activities of daily living (ADL), and quality of life in patients with knee osteoarthitis (OA). DESIGN: Randomized-controlled trial . SETTING: Rehabilitation medicine outpatient department of West China Hospital, Chengdu, Sichuan, People's Republic of China. SUBJECTS: Forty-nine patients were assigned to WBVE+QRE and 50 to QRE . MAIN OUTCOME MEASURES: Primary outcomes included pain assessed with visual analogue scale (VAS), Timed up & go test (TUG), 6-min walk distance test (6MWD), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcomes comprised range of motion, muscular strength, serum COMP and urinary CTX II, Lequesne Index (LI), and SF-36. All outcomes were analyzed with mixed effects regression. RESULTS: Compared with QRE, WBVE+QRE showed significantly greater improvement in VAS at 4weeks ( p=0.03), in VAS ( p<0.01), 6MWD ( p=0.01), WOMAC pain ( p=0.01), and WOMAC physical function ( p=0.02) at 16 weeks, and in all primary outcomes at 24 weeks (all p<0.01). CONCLUSION: Over a six months period, WBVE in combination with QRE was superior to QRE in most outcomes. PMID- 26427961 TI - Toward a model-based cognitive neuroscience of mind wandering. AB - People often "mind wander" during everyday tasks, temporarily losing track of time, place, or current task goals. In laboratory-based tasks, mind wandering is often associated with performance decrements in behavioral variables and changes in neural recordings. Such empirical associations provide descriptive accounts of mind wandering - how it affects ongoing task performance - but fail to provide true explanatory accounts - why it affects task performance. In this perspectives paper, we consider mind wandering as a neural state or process that affects the parameters of quantitative cognitive process models, which in turn affect observed behavioral performance. Our approach thus uses cognitive process models to bridge the explanatory divide between neural and behavioral data. We provide an overview of two general frameworks for developing a model-based cognitive neuroscience of mind wandering. The first approach uses neural data to segment observed performance into a discrete mixture of latent task-related and task unrelated states, and the second regresses single-trial measures of neural activity onto structured trial-by-trial variation in the parameters of cognitive process models. We discuss the relative merits of the two approaches, and the research questions they can answer, and highlight that both approaches allow neural data to provide additional constraint on the parameters of cognitive models, which will lead to a more precise account of the effect of mind wandering on brain and behavior. We conclude by summarizing prospects for mind wandering as conceived within a model-based cognitive neuroscience framework, highlighting the opportunities for its continued study and the benefits that arise from using well developed quantitative techniques to study abstract theoretical constructs. PMID- 26427962 TI - Repetition suppression in transcranial magnetic stimulation-induced motor-evoked potentials is modulated by cortical inhibition. AB - Transcranial magnetic stimulation (TMS) can be applied to modulate cortical phenomena. The modulation effect is dependent on the applied stimulation frequency. Repetition suppression (RS) has been demonstrated in the motor system using TMS with short suprathreshold 1-Hz stimulation trains repeated at long inter-train intervals. RS has been reported to occur in the resting motor-evoked potentials (MEPs) with respect to the first pulse in a train of stimuli. Although this RS in the motor system has been described in previous studies, the neuronal origin of the phenomenon is still poorly understood. The present study evaluated RS in three TMS-induced motor responses; resting and active MEPs as well as corticospinal silent periods (SPs) in order to clarify the mechanism behind TMS induced RS. We studied 10 healthy right-handed subjects using trains of four stimuli with stimulation intensities of 120% of the resting motor threshold (rMT) and 120% of the silent period threshold for an SP duration of 30 ms (SPT30). Inter-trial interval was 20s, with a 1-s inter-stimulus interval within the trains. We confirmed that RS appears in resting MEPs (p < 0.001), whereas active MEPs did not exhibit RS (p > 0.792). SPs, on the contrary, lengthened (p < 0.001) indicating modulation of cortical inhibition. The effects of the two stimulation intensities exhibited a similar trend; however, the SPT30 evoked a more profound inhibitory effect compared to that achieved by rMT. Moreover, the resting MEP amplitudes and SP durations correlated (rho ? -0.674, p < 0.001) and the pre-TMS EMG level did not differ between stimuli in resting MEPs (F = 0.0, p ? 0.999). These results imply that the attenuation of response size seen in resting MEPs might originate from increasing activity of inhibitory GABAergic interneurons which relay the characteristics of SPs. PMID- 26427964 TI - Talking about Death with Children with Incurable Cancer: Perspectives from Parents. AB - OBJECTIVE: To investigate the rationale and consequences associated with a parent's decision to discuss death with a child with incurable cancer. STUDY DESIGN: We present data from a larger retrospective study involving bereaved parents of a child who died of cancer. Parents were asked whether they had discussed the impending death with their child, whether they reflected on this discussion positively, their reasons for not discussing death with their child, and the manner in which the conversation regarding death occurred. The data were analyzed qualitatively using a framework approach. RESULTS: Of the 86 parents of 56 children who answered the questions regarding discussing death with their child, 55 parents of 35 children did not discuss the impending death with their child. The following themes were identified: the parents' inability to discuss the impending death; the parents' desire to protect their child; views regarding talking with children; parents' views of child characteristics; the child's unwillingness to discuss the subject; lack of opportunity to talk; and the child's disability. The parents who did discuss death with their child generally used symbolic and/or religious narratives, or they had brief, direct conversations regarding death. The majority of parents felt positive regarding their decision about whether to talk with their child about his/her impending death. CONCLUSION: Most parents in this study cited several reasons for not discussing death with their child. Our findings highlight the sensitive and complex issues surrounding these conversations, indicating that there may be a role for clinicians in supporting parents. PMID- 26427963 TI - Relations among Adiposity and Insulin Resistance with Flow-Mediated Dilation, Carotid Intima-Media Thickness, and Arterial Stiffness in Children. AB - OBJECTIVE: To determine the associations of adiposity and insulin resistance with measures of vascular structure and function in children. STUDY DESIGN: A cross sectional study included 252 children (age 15.1 +/- 2.4 years; body mass index percentile 68.2 +/- 26.5%; Tanner 2-5). Measurements of body fat percentage were obtained with dual-energy X-ray absorptiometry and visceral adipose tissue (VAT) with computed tomography. Insulin resistance was measured with hyperinsulinemic euglycemic clamp. Vascular measurements for endothelial function (brachial artery flow-mediated dilation [FMD]), vascular structure (carotid intima-media thickness [cIMT]), vascular stiffness (carotid incremental elastic modulus), and pulse wave velocity were analyzed by tertiles of adiposity and insulin resistance. Additional analyses with ANCOVA and linear regression were adjusted for Tanner, sex, race, and family relationship; FMD was also adjusted for baseline artery diameter. RESULTS: FMD was positively associated with high adiposity (body mass index, body fat percentage, and VAT) (P < .01 all). Insulin resistance was not associated with FMD. cIMT was significantly, positively related to obesity, VAT, and insulin resistance (P < .05 all). No differences in carotid incremental elastic modulus and pulse wave velocity were observed in relation to adiposity or insulin resistance. CONCLUSIONS: The findings suggest that adiposity is associated with higher FMD, and insulin resistance and VAT are associated with higher cIMT in children. Further research is needed to clarify the progression of these relations. PMID- 26427965 TI - Non-High-Density Lipoprotein Cholesterol in Children with Diabetes: Proposed Treatment Recommendations Based on Glycemic Control, Body Mass Index, Age, Sex, and Generally Accepted Cut Points. AB - Percentile-based non-high-density lipoprotein cholesterol levels were analyzed by glycemic control, weight, age, and sex of children with type 1 diabetes (n = 26,358). Ten percent of all children and 25% of overweight adolescent girls require both immediate lipid-lowering medication and lifestyle changes to achieve non-high-density lipoprotein cholesterol levels <120 mg/dL and cardiovascular risk reduction. PMID- 26427966 TI - Wimberger Sign in Congenital Syphilis. PMID- 26427967 TI - Stability and complications of miniplates for mandibular reconstruction with a fibular graft: outcomes for 544 patients. AB - Fibular flaps are usually used for the reconstruction of the mandible, but the use of plate systems, including miniplates and reconstruction plates, has recently been debated. We have made a retrospective study of 544 consecutive patients who had fibular grafts with miniplates used for fixation, and also made retrospective measurements of orthopantomographs from 37 patients to assess the stability of the miniplates used in the fibular flaps. When miniplates were used with fibular flaps there were 10.3% (56/544) complications, of which 4.8% (26/544) were loosening of the screws, 2.6% (14/544) fracture of the plate, 1.5% (8/544) exposure of the plate, and 6.4% (35/544) infection. The median (IQR) time at which the complications occurred was 24 (7-48) months. We conclude that loosening of screws is common at the binding interface near the condyle and in the molar region; plates are more likely to fracture near the binding interface in proximity to the molar region; and plates at the chin are the most likely to be exposed. Diabetes and the use of radiotherapy were associated with complications. Our data suggest that miniplates used for mandibular reconstruction are relatively reliable. PMID- 26427968 TI - Evaluation of the efficacy and safety of propranolol, timolol maleate, and the combination of the two, in the treatment of superficial infantile haemangiomas. AB - Our aim was to compare in a prospective study the clinical effects and safety of propranolol given orally, timolol maleate applied locally, and the combination of the two, in the management of superficial infantile haemangiomas. Thirty-nine patients with superficial infantile haemangiomas were randomised into three equal groups of 13 each: the first given timolol maleate applied topically together with propranolol given orally, the second given only propranolol orally, and the third given only timolol maleate topically. Photographs were taken before, and periodically after, starting treatment. A minimum of 50% improvement was considered to be effective. The maximum duration of treatment was planned for 6 months, and the patients were followed up for 3-12 months. The overall rate of clinical effectiveness for the three groups was 11/13, 9/13, and 8/13, respectively. The two drugs together had a shorter effective response time than when they were given separately. There were no serious adverse effects. We therefore conclude that timolol maleate given topically together with propranolol given orally is safe and effective in the treatment of superficial infantile haemangiomas. Compared with simple medication, this method is more rapid, has an appreciable effect, takes a shorter time, and has fewer adverse reactions. It could be used as a first-line treatment, particularly if the lesion is potentially disfiguring or functionally threatening such as large periocular superficial haemangiomas. PMID- 26427969 TI - Prevalence of biphasic response in anaphylaxis due to purposeful administration of allergenic food. PMID- 26427971 TI - Heart Failure and Low Health Literacy: Mitigating This Lethal Combination. PMID- 26427972 TI - Safety First! Using a Checklist for Intrafacility Transport of Adult Intensive Care Patients. AB - BACKGROUND: Adult critical care patients in an academic medical center experienced adverse events during intrafacility transport resulting from lack of preparation. An intervention was needed to help keep patients safe during intrafacility transport. OBJECTIVE: To develop a checklist for transport that is easy to use and effective in preparing patients for transport. METHOD: A checklist was developed and implemented. Elements of the checklist include preparation of the patient before transport, screening of patients for criteria that may place them at higher risk during transport, and a checklist for the procedural site. RESULTS: From May 2011 through July 2014, 2506 transports were conducted. Of these, 97.6% (n = 2445) involved no reported complications. CONCLUSION: This tool is suitable for bedside clinicians to use when preparing patients for transport. PMID- 26427973 TI - Implementation of a Progressive Mobilization Program in a Medical-Surgical Intensive Care Unit. AB - BACKGROUND: Current literature supports implementation of progressive mobility protocols in intensive care units. Education can help nurses overcome barriers to mobility and increase knowledge about the positive effects of mobility. OBJECTIVE: To evaluate the effect of education for a progressive mobilization program for intensive care nurses on knowledge and performance. METHODS: A pretest-posttest evaluation was conducted for 41 nurses, and a chart review was performed before and after implementation of the educational intervention to evaluate changes in knowledge and mobilization. RESULTS: Scores after the educational intervention were significantly higher than scores before the intervention (t = 2.02; P < .001). Overall mobilization (P = .04) and dangling (P = .01) increased significantly after the education. No significant increases occurred in ambulating or getting patients up to a chair. CONCLUSIONS: Mobilization education was effective and increased nurses' knowledge about the benefits of mobility for critically ill patients. The educational program also affected how nurses performed mobility interventions. Although provision of education had positive effects on patients' mobility, leadership and coaching are still important components in implementing change. PMID- 26427974 TI - Overcoming Barriers to Palliative Care Consultation. AB - Palliative care consultations for patients with life-threatening illnesses provide benefits for the patients and their families as well as for the health care team. Patients have better quality of life and live longer but cost the health care system less. Still, many patients are not offered the opportunity to receive a palliative care consultation. Barriers to palliative care consultation for patients in critical care units include misunderstandings about palliative care and not having agreed upon criteria for referral. Critical care nurses can assist in overcoming these barriers. PMID- 26427975 TI - Prenatal Counseling and Care for Single-Ventricle Heart Disease: One Center's Model for Care. AB - Advances in prenatal imaging allow early detection of single-ventricle congenital heart disease, which may enhance prenatal care and maximize care options and decision making. Boston Children's Hospital's Advanced Fetal Care Center and fetal cardiology program provide prenatal counseling and care for single ventricle congenital heart disease. Key points for optimal prenatal counseling and education include explanation of the diagnosis, delivery, the first surgery, cardiac neurodevelopmental issues, feeding and growth issues, quality of life and long-term care, family stressors, and fetal cardiac intervention. Such counseling and education help families make the difficult decisions required in this situation. PMID- 26427976 TI - Critical Care in Critical Access Hospitals. AB - What began as a grant-funded demonstration project, as a means of bridging the gap in rural health care, has developed into a critical access hospital system comprising 1328 facilities across 45 states. A critical access hospital is not just a safety net for health care in a rural community. Such hospitals may also provide specialized services such as same-day surgery, infusion therapy, and intensive care. For hospitals located near the required minimum of 35 miles from a tertiary care center, management of critically ill patients may be a matter of stabilization and transfer. Critical access hospitals in more rural areas are often much farther from tertiary care; some of these hospitals are situated within frontier areas of the United States. This article describes the development of critical access hospitals, provision of care and services, challenges to critical care in critical access hospitals, and suggestions to address gaps in research and collaborative care. PMID- 26427977 TI - The Devil Is in the Details. PMID- 26427978 TI - Use of Bicarbonate in Patients With Metabolic Acidosis. PMID- 26427979 TI - Against All Odds: Preventing Pressure Ulcers in High-Risk Cardiac Surgery Patients. PMID- 26427981 TI - I Am a Critical Care Nurse. PMID- 26427982 TI - Caring for Patients Treated With Therapeutic Hypothermia. AB - Numerous studies have indicated that therapeutic hypothermia can improve neurological outcomes after cardiac arrest. This treatment has redefined care after resuscitation and offers an aggressive intervention that may mitigate postresuscitation syndrome. Caregivers at Lehigh Valley Health Network, Allentown, Pennsylvania, an academic, community Magnet hospital, treated more than 200 patients with therapeutic hypothermia during an 8-year period. An interprofessional team within the hospital developed, implemented, and refined a clinical practice guideline for therapeutic hypothermia. In their experience, beyond a protocol, 5 critical elements of success (interprofessional stakeholders, coordination of care delivery, education, interprofessional case analysis, and participation in a global database) enhanced translation into clinical practice. PMID- 26427983 TI - Tacrolimus use in lupus nephritis: A systematic review and meta-analysis. AB - There is growing interest in the role of tacrolimus as a potential therapeutic agent in SLE. This systematic review and meta-analysis evaluates the evidence for tacrolimus use in the management of lupus nephritis. Thirteen controlled studies were identified (9 suitable for inclusion), using Cochrane database, SCOPUS, Web of Science and OVID (MEDLINE and EMBASE). Data on complete and partial remission rates, proteinuria reduction and adverse events was extracted and analysed using RevMan software. The meta-analysis showed that overall tacrolimus is more effective at inducing complete renal remission than IVCYC (p=0.004), but there is no significant difference compared to MMF (p=0.87). Multi-target TAC+MMF therapy is more effective than IVCYC only when partial remission is included (p=0.0006). Frequency of key adverse effects seems comparable to other agents used in the management of lupus nephritis with fewer gastrointestinal side effects, leukopenia, menstrual disorders, infections and episodes of liver dysfunction reported, but more new onset hypertension and hyperglycaemia. Mortality was lower in the tacrolimus groups, but this was not statistically significant (p=0.15). Tacrolimus may be more effective at reducing proteinuria, but again this was not statistically significant. There are no controlled trials looking at use in pregnancy or juvenile patients, however case reports suggest potential efficacy and safety. In conclusion, in moderately severe lupus nephritis, there is some evidence supporting efficacy of tacrolimus or multi-target TAC+MMF over IVCYC, but no evidence supporting tacrolimus over MMF. Tacrolimus may be more effective at reducing proteinuria, having potential implications for long-term outcome. Key limitations of this study are the lack of long-term outcome data and the lack of high quality, large, blinded controlled trials in multi-ethnic groups. PMID- 26427985 TI - New ideas for glaucoma. PMID- 26427984 TI - Conservative treatment of retinoblastoma: a prospective phase II randomized trial of neoadjuvant chemotherapy followed by local treatments and chemothermotherapy. AB - PurposeIntraocular retinoblastoma treatments often combine chemotherapy and focal treatments. A first prospective protocol of conservative treatments in our institution showed the efficacy of the use of two courses of chemoreduction with etoposide and carboplatin, followed by chemothermotherapy using carboplatin as a single agent and diode laser. In order to decrease the possible long-term toxicity of chemotherapy due to etoposide, a randomized neoadjuvant phase II protocol was conducted using vincristine-carboplatin vs etoposide carboplatin.Patients and methodsThe study was proposed when initial tumor characteristics did not allow front-line local treatments. Patients included in this phase II noncomparative randomized study of neoadjuvant chemotherapy received vincristin-carboplatin (new arm) vs etoposide-carboplatin (our reference arm). They were subsequently treated by local treatments and chemothermotherapy. Primary end point was the need for secondary enucleation or external beam radiotherapy (EBRT) not exceeding 40% at 2 years.ResultsA total of 65 eyes in 55 children were included in the study (May 2004 to August 2009). Of these, 32 eyes (27 children) were treated in the arm etoposide-carboplatin and 33 eyes (28 children) in the arm vincristin-carboplatin. At 2 years after treatment, 23/33 (69.7%) eyes were treated and salvaged without EBRT or enucleation in the arm vincristin-carboplatin and 26/32 (81.2%) in the arm etoposide carboplatin.ConclusionEven if the two treatment arms could be considered as sufficiently active according to the study decision rules, neoadjuvant chemotherapy by two cycles of vincristine-carboplatin followed by chemothermotherapy appear to offer less optimal local control than the etoposide carboplatin combination. PMID- 26427986 TI - Chloroquine retinopathy: pattern of presentation in Ibadan, Sub-Sahara Africa. AB - BackgroundSelf-medication with chloroquine is common in Ibadan, Sub-Sahara Africa. Retinopathy from chloroquine is not uncommon. The aim was to determine the pattern of presentation.MethodologyCases of Chloroquine retinopathy seen at the Retina and Vitreous Unit of the University College Hospital, Ibadan between 2008 and 2014 were reviewed. Information on age, sex, duration of chloroquine use, and visual loss were retrieved. Visual acuity at presentation, anterior, and posterior segment findings were documented. The results were analyzed using proportions and percentages.ResultsFourteen cases were seen during the study period. Mean age was 50.7 years. Male to female ratio was 3.5 : 1. Average duration of visual loss before presentation was 2.7 years. Average duration of self-medication with chloroquine was 5.3 years. Presenting visual acuity showed 2(14%) cases of bilateral blindness(VA<3/60 in both eyes); 5(35.7%) cases of uniocular blindness; three cases of bilateral low vision(VA worse than 6/18 but better than 3/60). Anterior segment examination showed abnormal sluggish pupillary reaction in those with severe affectation. Dilated fundoscopy showed features ranging from mild macular pigmentary changes and bulls eye maculopathy to overt extensive retinal degeneration involving the posterior pole, attenuation of retinal vessels, optic atrophy, and beaten bronze appearance of atrophic maculopathy.ConclusionChloroquine retinopathy is not uncommon in Ibadan, Sub Sahara Africa. Bulls eye maculopathy, extensive retinal, and macular degeneration with optic atrophy are the main presentations. Public health education is imperative. PMID- 26427987 TI - Evaluation the adjunctive use of combined bevacizumab and mitomycinc to trabeculectomy in management of recurrent pediatric glaucoma. AB - PURPOSETO evaluate the efficacy and safety of combined bevacizumab-mitomycin c (MMC) in recurrent cases of pediatric glaucoma.METHODSA prospective non-masked controlled study that included bilateral cases of 12 patients (24 eyes) with recurrent (had previous glaucoma surgery before) pediatric glaucoma. One eye in each patient (12 eyes) was assigned to trabeculectomy operation with combined application of MMC (0.4 mg/ml for 3 min) under and around the scleral flap before trabeculectomy and bevacizumab (avastin) (2.5 mg in 0.2 ml) injected subconjunctivally around the bleb after completing the surgery (group I). The other eye of each patient (12 eyes) was assigned to trabeculectomy operation with application of MMC (0.4 mg/ml for 3 min) only (group II). The mean follow-up period was 13+/-1 months.ResultsThe mean age was 2.16+/-1.5 (range 7 months to 4.1 years). No significant difference in preoperative intraoperative pressure (IOP) was observed between the groups (P>0.05). Recurrent primary congenital glaucoma represents 66.7% of the cases. Other cases included were recurrent aphakic and pseudophakic glaucoma 25% and recurrent post uveitic glaucoma 8.3%. The mean IOP was 12.1+/-4.2, 12.6+/-5.4, and 12.8+/-5.2 mm Hg in group I at 3, 6, and 12 months, respectively, and was 12.8+/-5.3, 13.7+/-6.7 and 15.6+/-5.9 mm Hg in group II at 3, 6, and 12 months, respectively. There was a statistically significant difference in the mean IOP between the studied groups at the 1-year follow-up visit (P<0.05). In addition, group I showed a higher statistically significant difference in absolute and total success (75 and 91.7%, respectively) compared with group II (58.3 and 75%, respectively) (P<0.05). The encountered complications included mild hyphema, which occurred in 8.33% in group 1, wound leakage, which occurred in 8.33% in each group, and shallow anterior chamber (AC), which occurred in 16.7% in each group and was the most common encountered complication in the study. One case of shallow AC in group I led to choroidal effusion (8.33%). One case in group II developed late bleb-related endophthalmitis after 3 months, which resulted in phthisis bulbi (8.33%).ConclusionThe additive effect of subconjunctival bevacizumab to MMC augmented trabeculectomy in the case of recurrent pediatric glaucoma was beneficial in improving the success rate. Better IOP control and prolonging the bleb survivalvia reducing the long-term need of using anti-glaucoma drugs postoperatively without adding complications had also been achieved with this technique. This offers a promising alternative for the treatment of this type of glaucoma. PMID- 26427988 TI - Vision-related quality of life, metamorphopsia, and stereopsis after successful surgery for rhegmatogenous retinal detachment. AB - PurposeTo determine the relationship between vision-related quality of life, metamorphopsia, and stereopsis after successful surgery to correct rhegmatogenous retinal detachment (RRD).Patients and methodsData were obtained from 30 patients with RRD who had scleral buckle surgery or vitrectomy. Age, gender, duration of blurred vision, the best-corrected visual acuity (BCVA), extent of detachment, and the location of retinal tears were measured before surgery. Approximately 1 year after surgery, stereopsis was measured with the Randot stereo test, visual acuity (VA) was measured using a Snell VA acuity measurement at a distance of 5 m and was presented as a linear LogMAR value, metamorphopsia was examined using an M-chart, and vision-related quality of life was determined using the 25-Item National Eye Institute Visual Function Questionnaire (VFQ-25).ResultsAll of the patients achieved anatomical retinal reattachment. There was a significant difference between preoperative BCVA (0.78+/-0.72) and BCVA 1 year postoperatively (0.25+/-0.25) (P<0.05). Twenty-three patients had visual distortion postoperatively, including vertical metamorphopsia (0.53+/-0.52 degrees ), and horizontal metamorphopsia (0.48+/-0.53 degrees ). Twenty patients had no stereopsis. The composite score of VFQ-25 was 76.60 postoperatively. Significant differences in postoperative BCVA, metamorphopsia, and VFQ-25 were found between macula-on and macula-off groups (all P<0.05). There was a negative correlation between VFQ-25 composite score and metamorphopsia (P<0.005); there was no significant correlation between VFQ-25 composite score and BCVA or stereopsis.ConclusionVision-related quality of life correlated with metamorphopsia, but did not correlate with VA or stereopsis. PMID- 26427989 TI - Clinical features of intratarsal keratinous cysts. AB - PURPOSE: Intratarsal keratinous cysts (IKCs) have been frequently misdiagnosed as chalazia or epidermal cysts. We reviewed a series of cases of IKCs to identify clinical features that distinguish IKCs from other eyelid diseases. METHODS: We retrospectively reviewed the medical records of 17 suspected IKC patients between January 2004 and September 2014. RESULTS: Seventeen patients who were clinically suspected to have IKC were enrolled. All patients presented with non-inflamed eyelid nodules fixed to the tarsus. Among them, 12 biopsy specimens were available and 11 patients (91.7%) were diagnosed with IKC, with a pathological finding of stratified squamous cell lining with keratin material. The mean patient age was 55.1 years (31-71). Six patients had a surgical history of incision or incomplete excision of the lesion, followed by recurrence. On eyelid eversion, five patients showed a white-yellow nodule, and three patients had a bluish cystic lesion. The diameter of the nodules ranged from 4 to 10 mm. The intracystic material was a milky white fluid. Ten patients underwent a complete surgical excision including partial tarsectomy and there was no recurrence. CONCLUSIONS: IKC can be distinguished from other intratarsal lesions by a characteristic tarsal nodule fixed to the tarsus. To prevent recurrence, complete excision with partial tarsectomy is needed. PMID- 26427990 TI - Population diversity in Pacific herring of the Puget Sound, USA. AB - Demographic, functional, or habitat diversity can confer stability on populations via portfolio effects (PEs) that integrate across multiple ecological responses and buffer against environmental impacts. The prevalence of these PEs in aquatic organisms is as yet unknown, and can be difficult to quantify; however, understanding mechanisms that stabilize populations in the face of environmental change is a key concern in ecology. Here, we examine PEs in Pacific herring (Clupea pallasii) in Puget Sound (USA) using a 40-year time series of biomass data for 19 distinct spawning population units collected using two survey types. Multivariate auto-regressive state-space models show independent dynamics among spawning subpopulations, suggesting that variation in herring production is partially driven by local effects at spawning grounds or during the earliest life history stages. This independence at the subpopulation level confers a stabilizing effect on the overall Puget Sound spawning stock, with herring being as much as three times more stable in the face of environmental perturbation than a single population unit of the same size. Herring populations within Puget Sound are highly asynchronous but share a common negative growth rate and may be influenced by the Pacific Decadal Oscillation. The biocomplexity in the herring stock shown here demonstrates that preserving spatial and demographic diversity can increase the stability of this herring population and its availability as a resource for consumers. PMID- 26427991 TI - Association between the FTOrs8050136 polymorphism and cancer risk: a meta analysis. AB - A meta-analysis on cancer risk relevant to FTOrs8050136 polymorphism. To investigate the comprehensive effect of FTOrs8050136 polymorphism on cancer risk based on a pooled result. Carcinogenesis is closely related to obesity. Both obesity and cancer share common pathogenic factors such as hereditary susceptibility and environmental predisposition. Recently, several studies had reported that the FTOrs8050136 polymorphism, a genetic variation highly associated with obesity, can be a potential cancer risk factor, while these results were inconsistent. With the help of PubMed, EMBASE, Chinese National Knowledge Infrastructure considerable research was done for potential studies without language restriction. Pooled odds ratio combined with 95 % confidence interval was employed to evaluate the potential correlations, and subgroup analyses were performed based on the cancer types and ethnic populations. There were eight articles comprising 21,810 cases and 85,070 controls met the eligibility criteria. Overall, there was no significant association between the FTOrs8050136 polymorphism and cancer risk (P = 0.163). Subgroup analysis illustrated that no association existed between the FTOrs8050136 polymorphism and cancer risk in Caucasians (P = 0.809), Asians (P = 0.412) and the mixed population (P = 0.093). With regard to cancer types, the result suggested that the FTOrs8050136 polymorphism had no connection with pancreatic cancer (P = 0.089), endometrial cancer (P = 0.353), prostate cancer (P = 0.578), colorectal cancer (P = 0.054) and melanoma (P = 0.357), while the inverse result was obtained in the subgroup of papillary thyroid cancer (P = 0.010). The FTOrs8050136 polymorphism may be not associated with carcinogenesis apart from papillary thyroid cancer, and further studies are needed to investigate the potential correlation. PMID- 26427992 TI - Computational and NMR Spectroscopic Evidence for Stereochemistry-Dependent Conformations of 2,2,6,6-Tetramethylpiperidinyl-Masked 1,2-Diols. AB - 2,2,6,6-Tetramethylpiperidinyl-masked 1,2-diols exhibited stereochemistry dependent hydroxyl proton chemical shifts: ca. 7 ppm for the syn diastereomer and ca. 2 ppm for the anti diastereomer. A computational search for low energy geometries revealed that the syn isomer favors a six-membered ring hydrogen bond to nitrogen and the anti isomer favors a five-membered ring hydrogen bond to oxygen. The computed low energy conformations were found to have a large difference in hydroxyl proton shielding that was reflected in the experimental chemical shift difference. This chemical shift difference was observed in a broad range of solvents, and thus may be useful as a stereochemical probe. The stereochemistry-dependent conformation and chemical shift signature appeared to be due to a syn pentane interaction between the gem-dimethyl groups on the 2,2,6,6-tetramethylpiperidinyl moiety. PMID- 26427993 TI - No Evidence for Association of SCO2 Heterozygosity with High-Grade Myopia or Other Diseases with Possible Mitochondrial Dysfunction. AB - SCO2 mutations cause recessively inherited cytochrome c oxidase deficiency. Recently Tran-Viet et al. proposed that heterozygosity for pathogenic SCO2 variants, including the common E140K variant, causes high-grade myopia. To investigate the association of SCO2 mutations with myopia, ophthalmic examinations were performed on 35 E140K carriers, one homozygous infant, and on a mouse model of Sco2 deficiency. Additionally, a screen for other putative effects of SCO2 heterozygosity was carried out by comparing the prevalence of the common E140K variant in a population of patients with undiagnosed diseases compatible with SCO2-related pathogenesis to that in a general population sample. High-grade myopia was not identified in any of the studied individuals. Of the carriers, 17 were emmetropic, and 18 possessed refractive errors. Additionally, no significant axial elongation indicative of high-grade myopia was found in mice carrying E129K (corresponding to E140K in humans) knock-in mutations. The prevalence of E140K carriers in the symptomatic cohort was evaluated as 1:103 (CI: 0.44-2.09) and did not differ significantly from the population prevalence (1:147, CI: 0.45 1.04).Our study demonstrates that heterozygosity for pathogenic SCO2 variants is not associated with high-grade myopia in either human patients or in mice. PMID- 26427994 TI - Intracranial Pressure Monitoring Demonstrates that Cerebral Edema Is Not Correlated to Hyperammonemia in a Child with Ornithine Transcarbamylase Deficiency. AB - BACKGROUND: Ornithine transcarbamylase deficiency (OTCD) is an inborn error of urea cycle resulting in increased plasma levels of ammonia and glutamine and cerebral edema. However, the underlying mechanism of brain cytotoxicity remains controversial. Our objective is to present an unusual acute hyperammonemic crisis suggesting a key role of brain glutamine to mediate ammonia neurotoxicity and the interest of intracerebral pressure (ICP) monitoring to maintain adequate cerebral perfusion pressure and to prevent neurological damages. PATIENT: A 6-year-old boy with OTCD was admitted for an acute hyperammonemic encephalopathy following viral infection. At admission, he presented vomiting, confusion, lethargy (Glasgow scale 7/15), and bilateral papilledema, suggesting cerebral edema. Plasma ammonia level was slightly increased (194 MUmol/L, rr 25-50 MUmol/L), contrasting with the severity of neurological deterioration and with high levels of glutamine in plasma (1,949 MUmol/L, rr 335-666 MUmol/L) and the brain (10-fold increase on in vivo MR spectroscopy). The patient was placed on neuroprotective treatments and respiratory support. MAIN RESULTS: With a hypercaloric protein-free diet and nitrogen scavenger drugs, plasma levels of ammonia and glutamine rapidly decreased without neurological improvement. Continuous ICP monitoring showed repetitive peaks of pressure up to 60 mmHg in the first four days and was helpful to manage neuroprotective treatments. After several days, the patient progressively recovered without cognitive or motor disability. CONCLUSION: This case report highlights the discrepancy between the severity of neurological impairment, presumably related to high level of brain glutamine, and plasma levels of ammonia or glutamine in a child with acute hyperammonemic encephalopathy related to OTCD. In this situation, continuous ICP monitoring was helpful to manage neuroprotective treatments and prevent brain damages. PMID- 26427995 TI - Developmental plasticity in vision and behavior may help guppies overcome increased turbidity. AB - Increasing turbidity in streams and rivers near human activity is cause for environmental concern, as the ability of aquatic organisms to use visual information declines. To investigate how some organisms might be able to developmentally compensate for increasing turbidity, we reared guppies (Poecilia reticulata) in either clear or turbid water. We assessed the effects of developmental treatments on adult behavior and aspects of the visual system by testing fish from both developmental treatments in turbid and clear water. We found a strong interactive effect of rearing and assay conditions: fish reared in clear water tended to decrease activity in turbid water, whereas fish reared in turbid water tended to increase activity in turbid water. Guppies from all treatments decreased activity when exposed to a predator. To measure plasticity in the visual system, we quantified treatment differences in opsin gene expression of individuals. We detected a shift from mid-wave-sensitive opsins to long wave-sensitive opsins for guppies reared in turbid water. Since long wavelength sensitivity is important in motion detection, this shift likely allows guppies to salvage motion-detecting abilities when visual information is obscured in turbid water. Our results demonstrate the importance of developmental plasticity in responses of organisms to rapidly changing environments. PMID- 26427996 TI - Differential protein expression analysis following olfactory learning in Apis cerana. AB - Studies of olfactory learning in honeybees have helped to elucidate the neurobiological basis of learning and memory. In this study, protein expression changes following olfactory learning in Apis cerana were investigated using isobaric tags for relative and absolute quantification (iTRAQ) technology. A total of 2406 proteins were identified from the trained and untrained groups. Among these proteins, 147 were differentially expressed, with 87 up-regulated and 60 down-regulated in the trained group compared with the untrained group. These results suggest that the differentially expressed proteins may be involved in the regulation of olfactory learning and memory in A. cerana. The iTRAQ data can provide information on the global protein expression patterns associated with olfactory learning, which will facilitate our understanding of the molecular mechanisms of learning and memory of honeybees. PMID- 26427998 TI - Constraints and Benefits of Child Welfare Contracts with Behavioral Health Providers: Conditions that Shape Service Access. AB - This qualitative study examines worker perceptions of how public child welfare agencies' purchase of service contracts with private behavioral health organizations can both facilitate and constrain referral making and children's access to services. Five, 90-min focus groups were conducted with workers (n = 50) from an urban public child welfare agency in the Midwest. Using a modified grounded theory approach, findings suggest that contracts may expedite service linkages, but contract benefits are conditioned upon design and implementation. Results also suggest the critical role of front line workers in carrying out contractual relationships. Implications for research and interventions for enhancing contracting are discussed. PMID- 26427997 TI - Role of serum hepatitis B virus marker quantitation to differentiate natural history phases of HBV infection. AB - PURPOSE: The purpose of this study was to characterize roles of serum hepatitis B virus marker quantitation in differentiation of natural phases of HBV infection. METHODS: A total of 184 chronic hepatitis B (CHB) patients were analyzed retrospectively. Patients were classified into four categories: immune tolerant phase (IT, n = 36), immune clearance phase (IC, n = 81), low-replicative phase (LR, n = 31), and HBeAg-negative hepatitis phase (ENH, n = 36), based on clinical, biochemical, serological, HBV DNA level and histological data. RESULTS: Hepatitis B surface antigen (HBsAg) quantitation in four phases were 4.7 +/- 0.2, 3.8 +/- 0.5, 2.5 +/- 1.2 and 3.4 +/- 0.4 log10 IU/mL, respectively. There were significant differences between IT and IC (p < 0.001) and between LR and ENH phases (p < 0.001). Quantitation of hepatitis B e antigen (HBeAg) in IT and IC phases are 1317.9 +/- 332.9 and 673.4 +/- 562.1 S/CO, respectively (p < 0.001). Hepatitis B core antibody (HBcAb) quantitation in the four groups were 9.48 +/- 3.3, 11.7 +/- 2.8, 11.2 +/- 2.6 and 13.2 +/- 2.9 S/CO, respectively. Area under receiver operating characteristic curve (AUCs) of HBsAg and HBeAg at cutoff values of 4.41 log10 IU/mL and 1118.96 S/CO for differentiation of IT and IC phases are 0.984 and 0.828, with sensitivity 94.4 and 85.2 %, specificity 98.7 and 75 %, respectively. AUCs of HBsAg and HBcAb at cutoff values of 3.4 log10 IU/mL and 10.5 S/CO for differentiation of LR and ENT phases are 0.796 and 0.705, with sensitivity 58.1 and 85.7 %, and specificity 94.4 and 46.2 %, respectively. CONCLUSIONS: HBsAg quantitation has high predictive value and HBeAg quantitation has moderate predictive value for discriminating IT and IC phase. HBsAg and HBcAb quantitations have moderate predictive values for differentiation of LR and ENH phase. PMID- 26427999 TI - What Factors are Associated with Consumer Initiation of Shared Decision Making in Mental Health Visits? AB - Understanding consumer initiation of shared decision making (SDM) is critical to improving SDM in mental health consultations, particularly because providers do not always invite consumer participation in treatment decisions. This study examined the association between consumer initiation of nine elements of SDM as measured by the SDM scale, and measures of consumer illness self-management and the consumer-provider relationship. In 63 mental health visits, three SDM elements were associated with self-management or relationship factors: discussion of consumer goals, treatment alternatives, and pros and cons of a decision. Limitations, implications, and future directions are discussed. PMID- 26428000 TI - [Implementation of a rational standard of hygiene for preparation of operating rooms]. AB - BACKGROUND: The assurance of high standards of care is a major requirement in German hospitals while cost reduction and efficient use of resources are mandatory. These requirements are particularly evident in the high-risk and cost intensive operating theatre field with multiple process steps. The cleaning of operating rooms (OR) between surgical procedures is of major relevance for patient safety and requires time and human resources. The hygiene procedure plan for OR cleaning between operations at the university hospital in Gottingen was revised and optimized according to the plan-do-check-act principle due to not clearly defined specifications of responsibilities, use of resources, prolonged process times and increased staff engagement. METHODS: The current status was evaluated in 2012 as part of the first step "plan". The subsequent step "do" included an expert symposium with external consultants, interdisciplinary consensus conferences with an actualization of the former hygiene procedure plan and the implementation process. All staff members involved were integrated into this management change process. The penetration rate of the training and information measures as well as the acceptance and compliance with the new hygiene procedure plan were reviewed within step "check". The rates of positive swabs and air sampling as well as of postoperative wound infections were analyzed for quality control and no evidence for a reduced effectiveness of the new hygiene plan was found. After the successful implementation of these measures the next improvement cycle ("act") was performed in 2014 which led to a simplification of the hygiene plan by reduction of the number of defined cleaning and disinfection programs for preparation of the OR. RESULTS: The reorganization measures described led to a comprehensive commitment of the hygiene procedure plan by distinct specifications for responsibilities, for the course of action and for the use of resources. Furthermore, a simplification of the plan, a rational staff assignment and reduced process times were accomplished. Finally, potential conflicts due to an insufficient evidence-based knowledge of personnel was reduced. CONCLUSION: This present project description can be used by other hospitals as a guideline for similar changes in management processes. PMID- 26428001 TI - Modulation of ALDH5A1 and SLC22A7 by microRNA hsa-miR-29a-3p in human liver cells. AB - Observed variations in drug responses among patients may result from differences in heritable genetic traits or from alterations in the epigenetic regulation of drug metabolizing enzymes and transporters (DMETs). MicroRNAs (miRNAs), a group of small non-coding RNAs, provide an epigenetic mechanism for fine-tuning the expression of targeted DMET genes by regulating the efficiency of protein translation and by decreasing mRNA stability via enhanced degradation. In the current study we systematically screened 374 important genes encoding DMETs for potential response elements to hsa-miR-29a-3p, a highly abundant miRNA in human liver. RNA electrophoresis mobility shift assays displayed direct interactions between hsa-miR-29a-3p and its cognate targets within the mRNA transcripts for the ABCC6, SLC22A7 and ALDH5A1 genes. The expression of luciferase reporter genes containing the 3'-UTRs of SLC22A7 or ALDH5A1 and the expression of endogenous SLC22A7 and ALDH5A1 were each suppressed by transfection with hsa-miR-29a-3p mimics. Importantly, chemically-induced up-regulation of hsa-miR-29a-3p correlated inversely with the expression of SLC22A7 and ALDH5A1. However, our studies failed to detect suppressive effects of hsa-miR-29a-3p on ABCC6 expression, which might be explained by the notion that the interaction of hsa miR-29a-3p and ABCC6 mRNA was unable to recruit ribonucleoproteins to form a RNA induced silencing complex. PMID- 26428002 TI - Thermodynamics and kinetics of inhibitor binding to human equilibrative nucleoside transporter subtype-1. AB - Many nucleoside transport inhibitors are in clinical use as anti-cancer, vasodilator and cardioprotective drugs. However, little is known about the binding energetics of these inhibitors to nucleoside transporters (NTs) due to their low endogenous expression levels and difficulties in the biophysical characterization of purified protein with ligands. Here, we present kinetics and thermodynamic analyses of inhibitor binding to the human equilibrative nucleoside transporter-1 (hENT1), also known as SLC29A1. Using a radioligand binding assay, we obtained equilibrium binding and kinetic rate constants of well-known NT inhibitors--[(3)H]nitrobenzylmercaptopurine ribonucleoside ([(3)H]NBMPR), dilazep, and dipyridamole--and the native permeant, adenosine, to hENT1. We observed that the equilibrium binding affinities for all inhibitors decreased whereas, the kinetic rate constants increased with increasing temperature. Furthermore, we found that binding is enthalpy driven and thus, an exothermic reaction, implying that the transporter does not discriminate between its inhibitors and substrates thermodynamically. This predominantly enthalpy-driven binding by four chemically distinct ligands suggests that the transporter may not tolerate diversity in the type of interactions that lead to high affinity binding. Consistent with this, the measured activation energy of [(3)H]NBMPR association was relatively large (20 kcal mol(-1)) suggesting a conformational change upon inhibitor binding. For all three inhibitors the enthalpy (DeltaH degrees ) and entropy (DeltaS degrees ) contributions to the reaction energetics were determined by van't Hoff analysis to be roughly similar (25-75% DeltaG degrees ). Gains in enthalpy with increasing polar surface area of inhibitors suggest that the binding is favored by electrostatic or polar interactions between the ligands and the transporter. PMID- 26428003 TI - Mercury Distribution in the Deule River (Northern France) Measured by the Diffusive Gradients in Thin Films Technique and Conventional Methods. AB - The distribution of mercury in surface water and in sediment from Deule River in Northern France was studied by application of conventional sampling methods and by diffusive gradients in thin films technique (DGT). Concentration of total dissolved mercury in surface water was 20.8 +/- 0.8 ng l(-1). The particulate mercury concentration was 6.2 +/- 0.6 ug g(-1). The particulate mercury was accumulated in sediment (9.9 +/- 2.3 mg kg(-1)), and it was transformed by methylating bacteria to methylmercury, mainly in the first 2-cm layer of the sediment. Total dissolved concentration of mercury in sediment pore water obtained by application of centrifugation extraction was 17.6 +/- 4.1 ng l(-1), and it was comparable with total dissolved pore water mercury concentration measured by DGT probe containing Duolite GT-73 resin gel (18.2 +/- 4.3 ng l(-1)), taking the sediment heterogeneity and different principles of the applied methods into account. By application of two DGT probes with different resin gels specific for mercury, it was found that approximately 30% of total dissolved mercury in sediment pore water was present in labile forms easy available for biota. The resolution of mercury DGT depth profiles was 0.5 cm, which allows, unlike conventional techniques, to study the connection of the geochemical cycle of mercury with geochemical cycles of iron and manganese. PMID- 26428004 TI - Sources and Distribution of Trace Elements in Soils Near Coal-Related Industries. AB - The degree of contamination of soil and the potential ecological risks associated with five different coal-burning industries were assessed in Shanxi Province, China. Results showed that the trace element concentrations in soil close to the coal industries were higher than those in the background soils, and the enrichment factors were >1. The potential ecological risk indexes ranged from 99 to 328 for the five coal-related industries. Results also illustrated that the trace elements were transported through the atmosphere. Concentrations of B, Hg, Mo, Pb, Se, Cr, Cu, Ni, V, Zn, and Mn were high in the area around the steel plant. Principal component analysis and redundancy analysis indicated that the sources of Se, Mo, Hg, Cd, As, Cr, B, Ni, and Cu were mainly anthropogenic, whereas Pb, V, Cu, Zn, and Mn were from natural sources. The soil Hg and Se contents were simulated by an artificial neural network model, which showed that Hg and Se in soils were from atmospheric deposits and their spatial distributions were related to the dominant wind direction. The potential ecological risk from Hg was much higher (one order of magnitude) than that from the other trace elements, which highlights the fact that it deserves urgent attention. Control of emissions from the burning of coal and other raw materials (such as iron and phosphate ores) should also be prioritized. PMID- 26428005 TI - Towards an ICF core set for ADHD: a worldwide expert survey on ability and disability. AB - This is the second in a series of four empirical studies designed to develop International Classification of Functioning, Disability and Health (ICF and Children and Youth version, ICF-CY) core sets for attention deficit hyperactivity disorder (ADHD). The objective of this stage was to gather the opinions from international experts on which ability and disability concepts were considered relevant to functioning in ADHD. An email-based survey was carried out amongst international experts in ADHD. Relevant functional ability and disability concepts were extracted from their responses and linked to the ICF/-CY categories by two independent researchers using a standardised linking procedure. 174 experts from 11 different disciplines and 45 different countries completed the survey. Meaningful concepts identified in their responses were linked to 185 ICF/ CY categories. Of these, 83 categories were identified by at least 5 % of the experts and considered the most relevant to ADHD: 30 of these were related to Body functions (most identified: attention functions, 85 %), 30 to Activities and Participation (most identified: school education, 52 %), 20 to Environmental factors (most identified: support from immediate family, 61 %), and 3 to Body structures (most identified: structure of brain, 83 %). Experts also provided their views on particular abilities related to ADHD, naming characteristics such as high-energy levels, flexibility and resiliency. Gender differences in the expression of ADHD identified by experts pertained mainly to females showing more internalising (e.g. anxiety, low self-esteem) and less externalising behaviours (e.g. hyperactivity), leading to a risk of late- and under-diagnosis in females. Results indicate that the impact of ADHD extends beyond the core symptom domains, into all areas of life and across the lifespan. The current study in combination with three additional preparatory studies (comprehensive scoping review, focus groups, clinical study) will provide the scientific basis to define the ADHD ICF/ CY core sets for multi-purpose use in basic and applied research and every day clinical practice. PMID- 26428007 TI - Maternal BCAS2 protects genomic integrity in mouse early embryonic development. AB - Mammalian early embryos maintain accurate genome integrity for proper development within a programmed timeline despite constant assaults on their DNA by replication, DNA demethylation and genetic defects transmitted from germ cells. However, how genome integrity is safeguarded during mammalian early embryonic development remains unclear. BCAS2 (breast carcinoma amplified sequence 2), a core component of the PRP19 complex involved in pre-mRNA splicing, plays an important role in the DNA damage response through the RPA complex, a key regulator in the maintenance of genome integrity. Currently, the physiological role of BCAS2 in mammals is unknown. We now report that BCAS2 responds to endogenous and exogenous DNA damage in mouse zygotes. Maternal depletion of BCAS2 compromises the DNA damage response in early embryos, leading to developmental arrest at the two- to four-cell stage accompanied by the accumulation of damaged DNA and micronuclei. Furthermore, BCAS2 mutants that are unable to bind RPA1 fail in DNA repair during the zygotic stage. In addition, phosphorylated RPA2 cannot localise to the DNA damage sites in mouse zygotes with disrupted maternal BCAS2. These data suggest that BCAS2 might function through the RPA complex during DNA repair in zygotes. Together, our results reveal that maternal BCAS2 maintains the genome integrity of early embryos and is essential for female mouse fertility. PMID- 26428006 TI - Osteogenic capillaries orchestrate growth plate-independent ossification of the malleus. AB - Endochondral ossification is a developmental process by which cartilage is replaced by bone. Terminally differentiated hypertrophic chondrocytes are calcified, vascularized, and removed by chondroclasts before bone matrix is laid down by osteoblasts. In mammals, the malleus is one of three auditory ossicles that transmit vibrations of the tympanic membrane to the inner ear. The malleus is formed from a cartilaginous precursor without growth plate involvement, but little is known about how bones of this type undergo endochondral ossification. Here, we demonstrate that in the processus brevis of the malleus, clusters of osteoblasts surrounding the capillary loop produce bone matrix, causing the volume of the capillary lumen to decrease rapidly in post-weaning mice. Synchrotron X-ray tomographic microscopy revealed a concentric, cylindrical arrangement of osteocyte lacunae along capillaries, indicative of pericapillary bone formation. Moreover, we report that overexpression of Fosl1, which encodes a component of the AP-1 transcription factor complex, in osteoblasts significantly blocked malleal capillary narrowing. These data suggest that osteoblast/endothelial cell interactions control growth plate-free endochondral ossification through 'osteogenic capillaries' in a Fosl1-regulated manner. PMID- 26428009 TI - Intracellular lumen formation in Drosophila proceeds via a novel subcellular compartment. AB - Cellular tubes have diverse morphologies, including multicellular, unicellular and subcellular architectures. Subcellular tubes are found prominently within the vertebrate vasculature, the insect breathing system and the nematode excretory apparatus, but how such tubes form is poorly understood. To characterize the cellular mechanisms of subcellular tube formation, we have refined methods of high pressure freezing/freeze substitution to prepare Drosophila larvae for transmission electron microscopic (TEM) analysis. Using our methods, we have found that subcellular tube formation may proceed through a previously undescribed multimembrane intermediate composed of vesicles bound within a novel subcellular compartment. We have also developed correlative light/TEM procedures to identify labeled cells in TEM-fixed larval samples. Using this technique, we have found that Vacuolar ATPase (V-ATPase) and the V-ATPase regulator Rabconnectin-3 are required for subcellular tube formation, probably in a step resolving the intermediate compartment into a mature lumen. In general, our ultrastructural analysis methods could be useful for a wide range of cellular investigations in Drosophila larvae. PMID- 26428008 TI - Mechano-logical model of C. elegans germ line suggests feedback on the cell cycle. AB - The Caenorhabditis elegans germ line is an outstanding model system in which to study the control of cell division and differentiation. Although many of the molecules that regulate germ cell proliferation and fate decisions have been identified, how these signals interact with cellular dynamics and physical forces within the gonad remains poorly understood. We therefore developed a dynamic, 3D in silico model of the C. elegans germ line, incorporating both the mechanical interactions between cells and the decision-making processes within cells. Our model successfully reproduces key features of the germ line during development and adulthood, including a reasonable ovulation rate, correct sperm count, and appropriate organization of the germ line into stably maintained zones. The model highlights a previously overlooked way in which germ cell pressure may influence gonadogenesis, and also predicts that adult germ cells might be subject to mechanical feedback on the cell cycle akin to contact inhibition. We provide experimental data consistent with the latter hypothesis. Finally, we present cell trajectories and ancestry recorded over the course of a simulation. The novel approaches and software described here link mechanics and cellular decision making, and are applicable to modeling other developmental and stem cell systems. PMID- 26428011 TI - Bone Behavior in Relation to the Depth of the Line of Marginal Cementation of Prostheses on Morse Cone Implants: Radiographic Evaluation in a Dog Model. AB - PURPOSE: This study was aimed at radiographically evaluating the effect of 3 different depths of the cementation line of prosthetic crowns on the bone response around Morse cone implants. MATERIAL AND METHODS: Five dogs underwent extractions of the lower premolars; after 3 months, placement of 30 implants, 3 mm apical to the bone level, was performed. Prefabricated cylinders of alumina, used as abutments, with 3 different transmucosal extension were cemented to the implants with zinc oxide-eugenol cement, determining the depth of the cementation lines (1.5 mm apically, and 0.5 and 2.5 mm coronally, respectively, to the bone level). In the control group, implants and abutments were placed without crowns, therefore, with no cementation line. RESULTS: The results showed no statistically significant differences between the control and test groups regarding the different depths of the cementation line both mesially (P = 0.18) and distally (P = 0.50). CONCLUSION: Different depths of cementation did not affect the behavior of marginal bone, indicating that crowns can be cemented with zinc oxide-eugenol cement at any distance or even at the bone level without disturbing bone healing around Morse cone implants. PMID- 26428010 TI - Opposing Shh and Fgf signals initiate nasotemporal patterning of the zebrafish retina. AB - The earliest known determinants of retinal nasotemporal identity are the transcriptional regulators Foxg1, which is expressed in the prospective nasal optic vesicle, and Foxd1, which is expressed in the prospective temporal optic vesicle. Previous work has shown that, in zebrafish, Fgf signals from the dorsal forebrain and olfactory primordia are required to specify nasal identity in the dorsal, prospective nasal, optic vesicle. Here, we show that Hh signalling from the ventral forebrain is required for specification of temporal identity in the ventral optic vesicle and is sufficient to induce temporal character when activated in the prospective nasal retina. Consequently, the evaginating optic vesicles become partitioned into prospective nasal and temporal domains by the opposing actions of Fgfs and Shh emanating from dorsal and ventral domains of the forebrain primordium. In absence of Fgf activity, foxd1 expression is established irrespective of levels of Hh signalling, indicating that the role of Shh in promoting foxd1 expression is only required in the presence of Fgf activity. Once the spatially complementary expression of foxd1 and foxg1 is established, the boundary between expression domains is maintained by mutual repression between Foxd1 and Foxg1. PMID- 26428012 TI - Effects of Abutment Removal and Reconnection on Inflammatory Cytokine Production Around Dental Implants. AB - OBJECTIVES: The purpose of this study was to examine effects of abutment change on inflammatory cytokine production around implants. MATERIALS AND METHODS: Ten partially edentulous patients with a mean age of 60 years were recruited and divided into 2 groups. External Branemark implants with anodic oxidized surface were installed and submerged in all patients. In the control group, the healing abutments were delivered at the second surgery, and they were removed more than 3 times till the final prosthesis delivery. In the test group, the final abutments were delivered at the second surgery. At different time points during the treatment, periimplant crevicular fluid was collected, and proinflammatory cytokines (interleukin-1beta [IL-1beta] and tumor necrosis factor [TNF]-alpha) were measured with enzyme-linked immunosorbent assay. The bone level was measured on the radiograms and clinical indices were also taken. RESULTS: All implants were osseointegrated. In the test group, IL-1beta level and probing depths were less in test group patients compared with the control group patients, whereas TNF alpha level and bone level were not different between the groups. CONCLUSION: Although TNF-alpha and bone levels were not significantly different, delivering final abutment at the second surgery would induce less inflammation in the tissues around the implant. PMID- 26428013 TI - Erratum to: Optical properties and bandgap evolution of ALD HfSiOxfilms. PMID- 26428014 TI - Characterization and Evaluation of Reverse Osmosis Membranes Modified with Ag2O Nanoparticles to Improve Performance. AB - The objective of this work was to prepare and characterize a new and highly efficient modified membrane by in situ interfacial polymerization on porous polysulfone supports. The process used m-phenylenediamine and trimesoyl chloride in hexane, incorporating silver oxide Ag2O nanoparticles of varied concentrations from 0.001 to 0.1 wt%. Ag2O nanoparticles were prepared at different sizes varying between 20 and 50 nm. The modified membranes were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), atomic force microscopy (AFM), transmission electron microscopy (TEM), and contact angle measurement. The results showed a smooth membrane surface and average surface roughness from 31 to 74 nm. Moreover, hydrophilicity improved and the contact angle decreased to 41 degrees at 0.009 wt% silver oxide. The performances of the developed membranes were investigated by measuring permeate fluxes and salt rejection capability by passing NaCl solutions (2000 ppm) through the membranes at 225 psi. The results showed that the flux increased from 26 to 40.5 L/m(2) h, while the salt rejection was high, at 99 %, with 0.003 wt% Ag2O nanoparticles. PMID- 26428015 TI - Systematic Control of Self-Assembled Au Nanoparticles and Nanostructures Through the Variation of Deposition Amount, Annealing Duration, and Temperature on Si (111). AB - The size, density, and configurations of Au nanoparticles (NPs) can play important roles in controlling the electron mobility, light absorption, and localized surface plasmon resonance, and further in the Au NP-assisted nanostructure fabrications. In this study, we present a systematical investigation on the evolution of Au NPs and nanostructures on Si (111) by controlling the deposition amount (DA), annealing temperature (AT), and dwelling time (DT). Under an identical growth condition, the morphologies of Au NPs and nanostructures drastically evolve when the DA is only slightly varied, based on the Volmer-Weber and coalescence models: i.e. I: mini NPs, II: mid-sized round dome-shaped Au NPs, III: large Au NPs, and IV: coalesced nanostructures. With the AT control, three distinctive ranges are observed: i.e., NP nucleation, Au NPs maturation and melting. The gradual dimensional expansion of Au NPs is always compensated with the density reduction, which is explained with the thermodynamic theory. The DT effect is relatively minor on Au NPs, a sharp contrast to other metallic NPs, which is discussed based on the Ostwald-ripening. PMID- 26428016 TI - Evaluation of High-Performance Curcumin Nanocrystals for Pulmonary Drug Delivery Both In Vitro and In Vivo. AB - This paper focused on formulating high-performance curcumin spray-dried powders for inhalation (curcumin-DPIs) to achieve a high lung concentration. Curcumin DPIs were produced using wet milling combined with the spray drying method. The effects of different milling times on particle size and aerodynamic performance were investigated. The curcumin-DPIs were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), and in vitro dissolution. Furthermore, the in vivo pharmacokinetic behavior and tissue distribution after pulmonary administration were also evaluated. Results showed that the drug dissolution was significantly enhanced by processing into curcumin DPIs. The aerodynamic results indicated that the DPIs displayed a good aerosol performance. The plasma curcumin concentration was obviously enhanced by inhalation, and most of the curcumin-DPIs were deposited in the lung. This study demonstrated that inhalation was an effective way to carry drug to the lung, and curcumin-DPIs were hopeful for lung cancer treatment in the future. PMID- 26428017 TI - Ag2S/CdS/TiO2 Nanotube Array Films with High Photocurrent Density by Spotting Sample Method. AB - Ag2S/CdS/TiO2 hybrid nanotube array films (Ag2S/CdS/TNTs) were prepared by selectively depositing a narrow-gap semiconductor-Ag2S (0.9 eV) quantum dots (QDs)-in the local domain of the CdS/TiO2 nanotube array films by spotting sample method (SSM). The improvement of sunlight absorption ability and photocurrent density of titanium dioxide (TiO2) nanotube array films (TNTs) which were obtained by anodic oxidation method was realized because of modifying semiconductor QDs. The CdS/TNTs, Ag2S/TNTs, and Ag2S/CdS/TNTs fabricated by uniformly depositing the QDs into the TNTs via the successive ionic layer adsorption and reaction (SILAR) method were synthesized, respectively. The X-ray powder diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X-ray photoelectron spectrum (XPS) results demonstrated that the Ag2S/CdS/TNTs prepared by SSM and other films were successfully prepared. In comparison with the four films of TNTs, CdS/TNTs, Ag2S/TNTs, and Ag2S/CdS/TNTs by SILAR, the Ag2S/CdS/TNTs prepared by SSM showed much better absorption capability and the highest photocurrent density in UV-vis range (320~800 nm). The cycles of local deposition have great influence on their photoelectric properties. The photocurrent density of Ag2S/CdS/TNTs by SSM with optimum deposition cycles of 6 was about 37 times that of TNTs without modification, demonstrating their great prospective applications in solar energy utilization fields. PMID- 26428018 TI - A new immunoreactive recombinant protein designated as rBoSA2 from Babesia ovis: Its molecular characterization, subcellular localization and antibody recognition by infected sheep. AB - Ovine babesiosis, caused by the intra-erythrocytic protozoan parasite Babesia ovis, is an infectious and economically important tick-borne disease of sheep. Diagnostic testing is an essential tool used for the control of the disease. In order to identify and characterize the immunoreactive proteins which are useful in serological diagnosis of the disease, a complementary DNA (cDNA) expression library was constructed from B. ovis merozoite mRNA. A cDNA clone designated as BoSA2 was identified by immunoscreening of a cDNA library using immune sheep serum. The sequence of the BoSA2 cDNA had a partial open reading frame of 1156 nucleotides encoding a polypeptide of 384 amino acid residues. Theoretical molecular mass for the mature protein was 43.5 kDa. The sequence of the BoSA2 was inserted into the expression vector pGEX-4T-1 and then expressed in Escherichia coli DH5alpha cells as a glutathione S-transferase (GST)-tagged fusion protein. This recombinant fusion protein (rBoSA2) was purified by GST-affinity chromatography. Immunoreactivity of the rBoSA2 was evaluated by indirect enzyme linked immunosorbent assay (ELISA) using the sera from the animals naturally and experimentally infected with B. ovis. ELISA results demonstrated that this antigen was useful for the diagnosis of ovine babesiosis. The localization of the BoSA2 protein was shown in and on the parasite and in the cytoplasm of the infected erythrocyte by confocal laser microscope. To our knowledge, rBoSA2 is the second immunoreactive recombinant protein of B. ovis until the present. PMID- 26428019 TI - SSRI use during pregnancy. AB - The Society of Maternal and Fetal Medicine recently had a conference on the use of medications during pregnancy, delivery, and breast-feeding. One of the most important topics covered during that 2-day conference was major depression (MDD) and the use of Serotonin Selective Reuptake Inhibitors (SSRIs). This article will review the current state of knowledge about MDD during and immediately after pregnancy and treatment with SSRIs during pregnancy and breast-feeding. PMID- 26428020 TI - FDA drug labeling for pregnancy and lactation drug safety monitoring systems. AB - The product label required by the FDA for every drug approved for marketing in the US is a legal document that originates with the company that wants to market the drug, but it must be approved by the FDA. Despite the recognized limitations of registries, the FDA's new labeling rule, effective from July 1, 2015, has given the data available from post-marketing surveillance priority in the new label. For this information to be maximally useful to both providers and consumers, providers must refer as many exposed consumers as possible to the registries, preferably prior to knowledge of the outcomes of the pregnancies. Consumers need to cooperate with the registries to share their health information with as much detail as possible with the registries. It will take years to accumulate a meaningful quantity of information in many of the registries, but they promise to be our best hope for useful counseling information in the future. PMID- 26428021 TI - Efficacy and Safety of Paclitaxel-Coated Balloon for the Treatment of In-Stent Restenosis in High-Risk Patients. AB - In-stent restenosis (ISR) is a major cause of failure of percutaneous coronary intervention. The efficacy and safety of drug-coated balloon (DCB) in patients with high-risk clinical features are largely unknown. We enrolled 82 consecutive patients at high risk of bleeding with angiographically significant (diameter stenosis >= 50%) ISR of bare metal stent (BMS) or drug-eluting stent (DES), treated with paclitaxel-coated balloon. All patients presented at least one of the following criteria: high bleeding risk, neoplasm, chronic inflammatory disease, and need for noncardiac surgery. Dual antiplatelet therapy was indicated for 4 weeks after the procedure. At angiographic follow-up, overall late lumen loss was 0.24 +/- 0.32 mm, with no significant difference between BMS-ISR and DES ISR (0.25 +/- 0.35 vs 0.22 +/- 0.30 mm, p = 0.714). The Kaplan-Meier estimate for major adverse clinical events-free survival at 3 years was 81.4% (82.3% in BMS ISR vs 79.4% in DES-ISR, log-rank p = 0.866). No stent thrombosis has been recorded. In conclusion, the use of paclitaxel-coated balloon seems to be associated with favorable outcomes after percutaneous coronary intervention for BMS-ISR or DES-ISR in patients with high-risk clinical features and could be considered as a reasonable option in the presence of systemic co-morbidities and contraindications to long-term dual antiplatelet therapy. PMID- 26428023 TI - Obstructive sleep apnea and coronary artery calcium with special emphasis on obesity. PMID- 26428022 TI - Comparison of aortic root anatomy and calcification distribution between Asian and Caucasian patients who underwent transcatheter aortic valve implantation. AB - The current transcatheter aortic valve implantation (TAVI) devices have been designed to fit Caucasian and Latin American aortic root anatomies. We evaluated the racial differences in aortic root anatomy and calcium distribution in patients with aortic stenosis who underwent TAVI. We conducted a multicenter study of 4 centers in Asia and Europe, which includes consecutive patients who underwent TAVI with preprocedural multidetector computed tomography. Quantitative assessment of aortic root dimensions, calcium volume for leaflet, and left ventricular outflow tract were retrospectively performed in a centralized core laboratory. A total of 308 patients (Asian group, n = 202; Caucasian group, n = 106) were analyzed. Compared to Caucasian group, Asian group had smaller annulus area (406.3 +/- 69.8 vs 430.0 +/- 76.8 mm(2); p = 0.007) and left coronary cusp diameter (30.2 +/- 3.2 vs 31.1 +/- 3.4 mm; p = 0.02) and lower height of left coronary artery ostia (12.0 +/- 2.5 vs 13.4 +/- 3.4 mm; p <0.001). Of baseline anatomic characteristics, body height showed the highest correlation with annulus area (Pearson correlation r = 0.64; p <0.001). Co-existence of lower height of left coronary artery ostia (<12 mm) and small diameter of left coronary cusp (<30 mm) were more frequent in Asian group compared with Caucasian group (35.6% vs 20.8%; p = 0.02). In contrast, there were no differences in calcium volumes of leaflet (367.2 +/- 322.5 vs 359.1 +/- 325.7 mm(3); p = 0.84) and left ventricular outflow tract (8.9 +/- 23.4 vs 10.1 +/- 23.8 mm(3); p = 0.66) between 2 groups. In conclusion, judicious consideration will be required to perform TAVI for short patients with lower height of left coronary artery ostia and small sinus of Valsalva. PMID- 26428024 TI - Leg Pain in a Manual Laborer. AB - A man admitted for deep vein thrombosis of his leg is found to have an important unrelated electrocardiographic abnormality. In the second paragraph, either reinsert the comma after V1 in the fifth line or remove the comma after enlargement in the fourth line. PMID- 26428025 TI - Effect of B-type natriuretic peptides on long-term outcomes after transcatheter aortic valve implantation. AB - B-type natriuretic peptide (BNP) levels are elevated in patients with aortic stenosis (AS) and decrease acutely after replacement of the stenotic valve. The long-term prognostic value of BNP after transcatheter aortic valve implantation (TAVI) and the relative prognostic utility of single versus serial peri interventional measurements of BNP and N-terminal prohormone BNP (NT-pro-BNP) are unknown. This study sought to determine the impact of BNP levels on long-term outcomes after TAVI and to compare the utility of BNP versus NT-pro-BNP measured before and after intervention. We analyzed 340 patients with severe AS and baseline pre-TAVI assessment of BNP. In 219 patients, BNP and NT-pro-BNP were measured serially before and after intervention. Clinical outcomes over 2 years were recorded. Patients with high baseline BNP (higher tertile >=591 pg/ml) had increased risk of all-cause mortality (adjusted hazard ratio 3.16, 95% confidence interval 1.84 to 5.42; p <0.001) and cardiovascular death at 2 years (adjusted hazard ratio 3.37, 95% confidence interval 1.78 to 6.39; p <0.001). Outcomes were most unfavorable in patients with persistently high BNP before and after intervention. Comparing the 2 biomarkers, NT-pro-BNP levels measured after TAVI showed the highest prognostic discrimination for 2-year mortality (area under the curve 0.75; p <0.01). Baseline-to-discharge reduction, but not baseline levels of BNP, was related to New York Heart Association functional improvement. In conclusion, high preintervention BNP independently predicts 2-year outcomes after TAVI, particularly when elevated levels persist after the intervention. BNP and NT-pro-BNP and their serial periprocedural changes provide complementary prognostic information for symptomatic improvement and survival. PMID- 26428026 TI - Metabolic Dyslipidemia and Risk of Coronary Heart Disease in 28,318 Adults With Diabetes Mellitus and Low-Density Lipoprotein Cholesterol <100 mg/dl. AB - The risk of future coronary heart disease (CHD) in subjects with diabetes and "metabolic dyslipidemia" (high triglyceride [TGs] and low high-density cholesterol levels) remains a matter of concern. Little is known regarding the risk of CHD for this phenotype with low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dl. We analyzed a diabetes cohort of 28,318 members (aged 30 to 90 years) of Kaiser Permanente Northern California during 2002 to 2011 (192,356 person-years [p-y] follow-up), with LDL-C levels <100 mg/dl and without known CHD. We compared the incidence and hazard ratios (HRs) for CHD events in groups using Cox models: normal high-density lipoprotein (HDL) and TG (reference; n = 7,278, 25.7%); normal HDL and high TG (>= 150 mg/dl; n = 4,484,15.8%); low HDL (<= 50 mg/dl for women and <= 40 mg/dl for men) and normal TG (n = 4,048, 14.3%); low HDL and high TG (metabolic dyslipidemia; n = 12,508, 44%). Patients with metabolic dyslipidemia had the highest age-adjusted CHD events/1,000 p-y (12.7/1,000 p-y and 19.0/1,000 p-y for women and men, respectively). After multivariate adjustment for age, gender, ethnicity, hypertension, smoking, statin use, duration of diabetes, and hemoglobin A1c, we observed an increased CHD risk in women (HR 1.35, 95% confidence interval 1.14 to 1.60) and men (HR 1.62, 95% confidence interval 1.43 to 1.83) with metabolic dyslipidemia compared to those with normal HDL and TG. Even in subjects with an LDL-C <100 mg/dl, presence of metabolic dyslipidemia in adults with diabetes is associated with an increased risk of CHD. In conclusion, effective CHD prevention strategies are needed for adults with diabetes and metabolic dyslipidemia. PMID- 26428027 TI - Impact of hospital volume on outcomes of lower extremity endovascular interventions: the better half? PMID- 26428028 TI - Molecular profiling of estrogen receptor alpha and progesterone receptor transcript variants in endometrial cancer. AB - The human genes coding for estrogen receptor alpha (ERalpha) and progesterone receptor (PR) express multiple receptor splice variants. Some of these receptor variants previously have been shown to exert distinct functions in cancer cells and might therefore differentially affect individual prognosis or therapy response. To examine the role of ERalpha- and PR-isoforms in endometrial cancer, we compared the expression of 19 ERalpha transcripts and 15 PR mRNA isoforms in human endometrium and in endometrioid endometrial cancer. Expression of seven ERalpha splice variants, total PR and of five PR transcript isoforms was found to be significantly decreased in endometrial cancer. In endometrioid G3 tumors, expression of 17 ERalpha and 10 PR splice variants was reduced when compared to normal tissue. Notably, only 13% of G3 tumors did not express any ERalpha variant and only in 25% of G3 samples no PR transcripts were expressed. Seven splice variants were preferentially expressed in G1 and G2 tumors. In G1 tumors, a higher number of different ERalpha and PR splice variants was expressed than in normal endometrium, G2 or G3 tumors. Expression of total PR and of single PR splice variants was found to be positively associated with PTEN. Our results encourage further studies to elucidate to what extent the heterogeneous co expression profiles we found in endometrial cancer patients differentially affect both individual prognosis and therapy response. PMID- 26428031 TI - Differential effects of prandial and non-prandial GLP-1 receptor agonists in type 2 diabetes therapy. AB - In type 2 diabetes mellitus (T2DM), decreased pancreatic beta-cell function and increased insulin resistance contribute to a steady decline in glucose homeostasis. Maintaining levels of glycated hemoglobin <=7.0% is thought to reduce the microvascular and possibly macrovascular complications that result if T2DM is not properly managed. Recent guidelines have recognized the importance of postprandial glucose (PPG) control in reducing cardiovascular risks, and have recommended a more patient-centered approach. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) mimic the action of the endogenous gastrointestinal hormone GLP-1 to activate the insulin response in pancreatic beta cells in a glucose dependent manner. Prandial GLP-1 RAs have a short plasma half-life and are particularly effective at targeting PPG elevations, whereas long-acting non prandial GLP-1 RAs are more effective at reducing fasting plasma glucose. These differences highlight the potential for treatment with these agents to be tailored to the need of individual patients and their glycemic imbalance. All GLP 1 RAs are being evaluated in long-term cardiovascular outcome trials. To date, the only cardiovascular trial that has been completed is the ELIXA trial for lixisenatide, which was found to meet the pre-specified criterion of non inferiority versus placebo in terms of cardiovascular outcomes. PMID- 26428032 TI - Versatile Particle-Based Route to Engineer Vertically Aligned Silicon Nanowire Arrays and Nanoscale Pores. AB - Control over particle self-assembly is a prerequisite for the colloidal templating of lithographical etching masks to define nanostructures. This work integrates and combines for the first time bottom-up and top-down approaches, namely, particle self-assembly at liquid-liquid interfaces and metal-assisted chemical etching, to generate vertically aligned silicon nanowire (VA-SiNW) arrays and, alternatively, arrays of nanoscale pores in a silicon wafer. Of particular importance, and in contrast to current techniques, including conventional colloidal lithography, this approach provides excellent control over the nanowire or pore etching site locations and decouples nanowire or pore diameter and spacing. The spacing between pores or nanowires is tuned by adjusting the specific area of the particles at the liquid-liquid interface before deposition. Hence, the process enables fast and low-cost fabrication of ordered nanostructures in silicon and can be easily scaled up. We demonstrate that the fabricated VA-SiNW arrays can be used as in vitro transfection platforms for transfecting human primary cells. PMID- 26428033 TI - Stimuli-Triggered Activity of Nanoreactors by Biomimetic Engineering Polymer Membranes. AB - The development of advanced stimuli-responsive systems for medicine, catalysis, or technology requires compartmentalized reaction spaces with triggered activity. Only very few stimuli-responsive systems preserve the compartment architecture, and none allows a triggered activity in situ. We present here a biomimetic strategy to molecular transmembrane transport by engineering synthetic membranes equipped with channel proteins so that they are stimuli-responsive. Nanoreactors with triggered activity were designed by simultaneously encapsulating an enzyme inside polymer compartments, and inserting protein "gates" in the membrane. The outer membrane protein F (OmpF) porin was chemically modified with a pH responsive molecular cap to serve as "gate" producing pH-driven molecular flow through the membrane and control the in situ enzymatic activity. This strategy provides complex reaction spaces necessary in "smart" medicine and for biomimetic engineering of artificial cells. PMID- 26428034 TI - Social gradients in health for Pakistani and White British women and infants in two UK birth cohorts. AB - OBJECTIVES: This study aims to examine social gradients in low birth weight (LBW), preterm birth, smoking during pregnancy and maternal health for women and infants of Pakistani origin and White British women and infants in the UK. DESIGN: The sample included women and singleton infants from the Born in Bradford (BiB) study (n = 8181) and the first sweep of the Millennium Cohort Study (MCS) (n = 8980). Social gradients in health for four measures of socioeconomic status (SES): maternal education, means-tested benefits, financial situation, and occupation of the father were analysed in multivariate regression models adjusting for maternal age and parity. RESULTS: For White British mothers and infants in the MCS sample, social gradients in health were observed for at least three out of four measures of SES for each health outcome (p for trend <.01). Similar trends were found for White British mothers and infants in the BiB sample, although these were less likely to be significant. There were few associations between measures of SES and outcomes in the Pakistani samples. The strongest evidence of a social gradient in health for Pakistani women was demonstrated with the self-reported measure of financial situation, in relation to mental health (p for trend <.001 in both cohorts). CONCLUSION: This study describes a lack of social gradients in health for Pakistani women and infants and discusses potential explanations for this finding. PMID- 26428036 TI - Secukinumab (AIN457) for the treatment of psoriasis. AB - Psoriasis is a chronic inflammatory disease with a multifactorial origin that appears in patients with genetic predisposition and is induced by environmental factors, and characterized by alterations in the innate and adaptive immunity. IL 17A is one of the specific cytokines involved in the pathogenesis of psoriasis and its inhibition is highly effective in the treatment of patients with moderate and severe psoriasis. Secukinumab is a monoclonal antibody that specifically binds to IL-17A and inhibits the interaction to its receptor, and it has demonstrated its efficacy and safety in the treatment of psoriasis. Phase II and III clinical trials indicate that > 80% of the patients receiving secukinumab achieve Psoriasis Area Severity Index (PASI) 75 at week 12. In the Phase III efficacy of response and safety of two fixed secukinumab regimens in psoriasis trial, PASI 75 rates were 81.6% with 300 mg secukinumab, 71.6% with 150 mg secukinumab and 4.5% with placebo, and responses were maintained up to 52 weeks in the majority of patients. In the Phase III Full Year Investigative Examination Of Secukinumab versus Etanercept Using Two Dosing Regimens To Determine Efficacy in Psoriasis study, the efficacy of secukinumab was compared to etanercept. The results indicate that both doses of secukinumab (150 and 300 mg) showed superior efficacy compared with etanercept throughout the study; PASI 75 rates at week 12 were 77.1% with 300 mg secukinumab, 67% with 150 mg of secukinumab, 44% with etanercept and 4.9% with placebo. PASI 90 and PASI 100 were 54 and 24% with secukinumab 300 mg and 21 and 4% with etanercept at week 12. At week 52, PASI 90 continued to be higher in the secukinumab group (65%) compared with the etanercept group (33%). Regarding safety, the most common side effects were nasopharyngitis and headache. The rate of infections was higher with secukinumab than placebo. This was especially the case for Candida infections, which were more common in the secukinumab group (4.7% with secukinumab 300 mg and 2.3% with secukinumab 150 mg), but all cases were resolved with conventional treatment. Secukinumab is a well-tolerated treatment that has demonstrated efficacy in treating moderate-to-severe plaque psoriasis. Nevertheless, long-term studies are necessary to confirm Phase II and Phase III data. PMID- 26428035 TI - Influence of Spinal Cord Integrity on Gait Control in Human Spinal Cord Injury. AB - Background Clinical trials in spinal cord injury (SCI) primarily rely on simplified outcome metrics (ie, speed, distance) to obtain a global surrogate for the complex alterations of gait control. However, these assessments lack sufficient sensitivity to identify specific patterns of underlying impairment and to target more specific treatment interventions. Objective To disentangle the differential control of gait patterns following SCI beyond measures of time and distance. Methods The gait of 22 individuals with motor-incomplete SCI and 21 healthy controls was assessed using a high-resolution 3-dimensional motion tracking system and complemented by clinical and electrophysiological evaluations applying unbiased multivariate analysis. Results Motor-incomplete SCI patients showed varying degrees of spinal cord integrity (spinal conductivity) with severe limitations in walking speed and altered gait patterns. Principal component (PC) analysis applied on all the collected data uncovered robust coherence between parameters related to walking speed, distortion of intralimb coordination, and spinal cord integrity, explaining 45% of outcome variance (PC 1). Distinct from the first PC, the modulation of gait-cycle variables (step length, gait-cycle phases, cadence; PC 2) remained normal with respect to regained walking speed, whereas hip and knee ranges of motion were distinctly altered with respect to walking speed (PC 3). Conclusions In motor-incomplete SCI, distinct clusters of discretely controlled gait parameters can be discerned that refine the evaluation of gait impairment beyond outcomes of walking speed and distance. These findings are specifically different from that in other neurological disorders (stroke, Parkinson) and are more discrete at targeting and disentangling the complex effects of interventions to improve walking outcome following motor-incomplete SCI. PMID- 26428037 TI - Behavioural interventions for diabetes yield modest benefits, reviews find. PMID- 26428038 TI - Funding medical education: should we follow a different model to general higher education? Commentary. AB - ISSUE: There has been much recent discussion on the funding of medical education. There has also been much discussion about the funding of higher education more generally. EVIDENCE: The topics of discussion have included the rising costs of education; who should pay; the various potential models of funding; and how best to ensure maximum returns from investment. IMPLICATIONS: Medical education has largely followed the emerging models of funding for higher education. However there are important reasons why the funding models for higher education may not suit medical education. These reasons include the fact that medical education is as important to the public as it is to the learner; the range of funding sources available to medical schools; the strict regulation of medical education; and the fact that the privatisation and commercialisation of higher education may not been in keeping with the social goals of medical schools and the agenda of diversification within the medical student population. PMID- 26428039 TI - Environmental health literacy within the Italian Asbestos Project: experience in Italy and Latin American contexts. Commentary. AB - The adoption of multidisciplinary approaches to foster scientific research in public health and strengthen its impact on society is nowadays unavoidable. Environmental health literacy (EHL) may be defined as the ability to search for, understand, evaluate, and use environmental health information to promote the adoption of informed choices, the reduction of health risks, the improvement of quality of life and the protection of the environment. Both public health and environmental health literacy involve access to and dissemination of scientific information (including research findings), individual and collective decision making and critical thinking. Specific experiences in environmental health literacy have been developed within the Italian National Asbestos Project (Progetto Amianto) in Latin American countries where the use of asbestos is still permitted, and in Italy where a specific effort in EHL has been dedicated to the risks caused by the presence of fluoro-edenite fibers in the town of Biancavilla (Sicily). Taking into account the different geographical and socio-economic contexts, both public health and environmental health literacy were addressed to a wide range of stakeholders, within and outside the health domain. PMID- 26428040 TI - Diabetes: a case study on strengthening health care for people with chronic diseases. Preface. PMID- 26428041 TI - Quality indicators for diabetes prevention programs in health care targeted at people at high risk. AB - OBJECTIVE: Type 2 diabetes can be efficiently prevented by lifestyle intervention provided for people at high diabetes risk. The aim of this paper was to conduct a literature search on existing quality indicators for type 2 diabetes prevention and to collate and present a set of indicators that could be applied in European countries with different health care systems and cultures. METHODS: Scientific and grey literature was searched for relevant studies using electronic databases. We also hand searched previous systematic reviews and reference lists of relevant articles. RESULTS: The only publication identified was the report presenting the results from the IMAGE project. The IMAGE indicators were used as the basis for the proposed indicators. CONCLUSIONS: Publications on quality indicators of diabetes prevention programmes are scarce. The quality indicators presented here are a first step toward the definition of a core set of European indicators to monitor and improve the quality of diabetes prevention. PMID- 26428042 TI - Health promotion interventions in type 2 diabetes. AB - AIM: To present the most common quality criteria in health promotion interventions in type 2 diabetes mellitus (T2DM). METHODS: A systematic literature search was conducted to identify review articles, health technology assessments and policy reports of evaluated health promotion interventions in T2DM. A descriptive analysis of study characteristics and evaluation criteria are presented. RESULTS: Seven studies met the inclusion criteria. The findings indicate that the most common health promotion interventions used in T2DM are initiatives targeting health care professionals. The main ambition of the programs was to increase the collaboration between health care professionals and patients, and between health care centres, program managers and community stakeholders. CONCLUSIONS: This investigation extends our knowledge of the most common health promotion interventions in T2DM and which structure, process and outcome measurements that are reported in such interventions. Future research could usefully explore how the effectiveness of multicomponent and complex interventions may be evaluated and extend the association of these factors into other settings and in relation to other lifestyle related chronic diseases. PMID- 26428043 TI - Education and health professionals training programs for people with type 2 diabetes: a review of quality criteria. AB - OBJECTIVE: To contribute to the development of a set of quality criteria for patient education and health professionals training that could be applied in European countries. METHODS: Literature review quality criteria, pre-selection based on a comparison of the criteria, peer group and expert based selection of the criteria. RESULTS: 14 quality criteria were selected: goals, rationale, target group, setting, scheduling of the education/training sessions, environmental requirements, qualification of the trainers/educators, core components of the educator/trainer's role, curriculum, education methods, education didactics, monitoring of the effectiveness and quality of the program, implementation level and source of funding. DISCUSSION: A set of preliminary quality criteria for patient education and health professionals training was developed, which could be applied in European countries. PMID- 26428044 TI - National Diabetes Plans: can they support changes in health care systems to strengthen diabetes prevention and care? AB - Healthcare systems do not fit well with the "modern" patient, who has a right to autonomy and self-determination. The services that are designed and delivered in policy contexts are not prone to encourage innovation. National Diabetes Plans, defined as "any formal strategy for improving diabetes policy, services and outcomes that encompass structured and integrated or linked activities which are planned and co-ordinated nationally and conducted at the national, regional, and local level", may hold a great potential not only to improve prevention and care for type 2 diabetes, but also for transforming healthcare delivery. Today, changes to adapt healthcare delivery tend to be implemented within existing provider structures, with limited understanding of specific context, structures, processes and potential for change. National Diabetes Plan can be a diagnostic tool for barriers, can be a driver for planning the change, and can help develop capacities and competences that are needed to strengthen healthcare systems to better address health promotion and chronic diseases. PMID- 26428045 TI - Cancer burden trends in Umbria region using a joinpoint regression. AB - INTRODUCTION: The analysis of the epidemiological data on cancer is an important tool to control and evaluate the outcomes of primary and secondary prevention, the effectiveness of health care and, in general, all cancer control activities. MATERIALS AND METHODS: The aim of the this paper is to analyze the cancer mortality in the Umbria region from 1978 to 2009 and incidence from 1994-2008. Sex and site-specific trends for standardized rates were analyzed by "joinpoint regression", using the surveillance epidemiology and end results (SEER) software. RESULTS: Applying the jointpoint analyses by sex and cancer site, to incidence spanning from 1994 to 2008 and mortality from 1978 to 2009 for all sites, both in males and females, a significant joinpoint for mortality was found; moreover the trend shape was similar and the joinpoint years were very close. In males standardized rate significantly increased up to 1989 by 1.23% per year and significantly decreased thereafter by -1.31%; among females the mortality rate increased in average of 0.78% (not significant) per year till 1988 and afterward significantly decreased by -0.92% per year. Incidence rate showed different trends among sexes. In males was practically constant over the period studied (not significant increase 0.14% per year), in females significantly increased by 1.49% per year up to 2001 and afterward slowly decreased (-0.71% n.s. estimated annual percent change - EAPC). CONCLUSIONS: For all sites combined trends for mortality decreased since late '80s, both in males and females; such behaviour is in line with national and European Union data. This work shows that, even compared to health systems that invest more resources, the Umbria public health system achieved good health outcomes. PMID- 26428046 TI - The influence of patients' complexity and general practitioners' characteristics on referrals to outpatient health services in an Italian region. AB - BACKGROUND: Patient referrals to outpatient health services may affect both health outcomes and health expenditures. General practitioners (GP) have a crucial role in driving the use of outpatient services and recognizing factors which affect referrals is important for health managers and planners. OBJECTIVES: We investigated patient- and physician-related determinants of patient referrals in an Italian region. METHODS: This was cross-sectional study based on the individual linkage of administrative databases from the health information system of the Friuli Venezia Giulia region. For each GP of the region, the association of the number of patient referrals to different types of outpatient services with the proportion of patients with chronic conditions, with the number of hospital admissions and drug prescriptions in 2012, and with GP's characteristics was investigated through multilevel multivariable Poisson regression models. RESULTS: Some chronic conditions (e.g., cancer, autoimmune diseases, endocrine diseases, digestive system diseases) were positively associated with the number of referrals, as were hospital admissions and drug prescriptions. Time since GP's graduation was inversely related with referrals. CONCLUSION: Patient complexity and GP's experience affect referral rates. These factors should be considered in case of a reorganization of the general practice structure in Friuli Venezia Giulia. PMID- 26428047 TI - Recent entomological enquiry on mosquito fauna in Circeo National Park. AB - The present study was carried out in Circeo National Park (Lazio region, Central Italy), in order to collect data about mosquito (Diptera, Culicidae) fauna in a protected area for biodiversity. From 2003 to 2004 seasonal surveys allowed to collect and to identify 380 larvae and 713 adult mosquitoes in 6 sites. A total of 15 mosquito species belonging to 6 genera were recorded; the most abundant species were Culex pipens Linnaeus, 1758 known as the main West Nile virus vector, Ochlerotatus detritus (Haliday, 1933) and Culiseta annulata (Dhrank, 1776). Present data show a noteworthy number of other mosquito species, even if less abundant, reflecting the considerable environmental richness. Respect to the past collections of Anophelinae mosquitoes carried out in the same area once affected by malaria, the present research represents the first monitoring of the whole Culicidae Family in Circeo National Park, up to now. This paper reports the collected data as a first base for a future checklist in this protected area. PMID- 26428048 TI - Mechanical qualification of collagen membranes used in dentistry. AB - AIM: The aim of this work is the qualification of commercially available collagen membranes in a comparative manner. The natural origin of collagen makes standardization difficult. Nevertheless, through dimensional and mechanical measures it is possible to mechanically qualify collagen membranes, and compare them. METHODS: Three commercially available collagen membranes used in Guided Bone Regeneration (GBR) and in Guided Tissue Regeneration (GTR) techniques, namely Bio-Gide, Collprotect and Jason, were chosen for the comparison. Quasi static (tensile tests) and time-dependent (stress relaxation test) mechanical tests together with a functional test (tear test) were done to determine the responses of collagen membranes under different loading conditions. RESULTS: The tested membranes exhibited different behaviours, different deformability values and thickness, Jason being the thinnest and Bio-Gide the thickest. Similar differences were also observed in terms of surface density. DISCUSSION: Even though clinical observations were not within the aim of this study, our findings indicate that a better understanding of the correlation between mechanical properties and thickness could lead to a more rational design and use of these membranes in the face of specific clinical cases. PMID- 26428049 TI - Antihypertensive drug use during pregnancy: a population based study. AB - PURPOSE: The study aimed at assessing if the European guideline on the use of antihypertensive drugs (AD) in pregnancy are followed in clinical practice. We also evaluated the association between the use of non-recommended drugs and individual characteristics. METHODS: This study analyzed a cohort of 86 171 singleton deliveries occurring between 2009-2010 in the Lombardy region, Italy. Women with first prescription of AD during pregnancy were considered as incident users. Methyldopa, labetalol and nifedipine were considered as "recommended drugs"; all other AD were considered as "non-recommended". Odds Ratio and 95% confidence intervals were estimated. RESULTS: Among the 1009 patients (1.2%) exposed to AD during pregnancy, 675 (66.9%) were incident users. Among the incident users, 31% received non-recommended drugs; this proportion decreased to 18% among women who started treatment in the third trimester. Women with at least four concomitant diseases had an elevated risk of receiving non-recommended drugs in pregnancy (OR 2.68; 95% CI 1.10-6.73). CONCLUSIONS: Exposure to recommended antihypertensives increased during pregnancy. Nevertheless, a fraction of users that continued or began treatment with non-recommended medications was still present. PMID- 26428050 TI - An ethics for the living world: operation methods of Animal Ethics Committees in Italy. AB - INTRODUCTION AND OBJECTIVES: Coinciding with the recent implementation in Italy of the "Directive 2010/63/EU, regarding the protection of animals used for scientific purposes", the Authors would like to analyse the topic of the introduction of ethical committees for animal experimentation in Italy. This paper furthermore aims to underline some critical aspects concerning the actions taken by Italian institutions to comply with the provisions of EU. RESULTS AND DISCUSSION: The implementation of the recent Italian law (Decreto Legislativo n. 26 on 4 March 2014 Implementation of the Directive 2010/63/EU on the protection of animals used for scientific purposes) leans towards a restrictive interpretation of the European provisions about composition and responsibilities of "Ethical Committee for Animal Experimentation". In the composition of the bodies mentioned, we note a tendency to restrict the composition to few professional figures contemplated by Italian law, without guaranteeing the independence of each committee; also, an absence of hierarchical relationship between a research institution and his committee is apparent. Moreover, a critical aspect is the lack of decision-making powers of these new organisms in terms of ethical evaluation of protocols and research projects. CONCLUSIONS: What EU legislation imposes on the member states is to set up an animal-welfare body (art. 26). This represents a strong incentive for Italy to follow the steps of many other European Countries, where ad hoc ethical committees have been working for a long time. The proper functioning of these bodies may contribute to guarantee the safety and welfare of the animals inside the laboratories, and to balance the protection of animal life and the interests of research. PMID- 26428051 TI - Human papilloma virus (HPV) genotypes prevalence in a region of South Italy (Apulia). AB - INTRODUCTION: Since human papillomavirus (HPV) is the central casual factor in cervical cancer, understanding the epidemiology and geographical area distribution of the most prevalent HPV genotypes constitutes an important step towards development of strategies of prevention. AIM: The aim of this study was to investigate the prevalence of HPV infection and to determine HPV types distribution among 822 HPV positive women and some sexual male partners in Apulia (Italy). METHODS: HPV DNA detection and genotyping was performed by nested-PCR for the L1 region and reverse line blot hybridization allowing the specific detection of 24 HPV genotyping both high risk (HR) and low risk (LR). RESULTS: The most prevalent HPV genotypes were HPV 16 (35%), HPV 31 (16%) HPV 6 (9%), HPV 58 and 66 (7%), followed by HPV 33 (6%), HPV 18 and 56 (4%), HPV 70 and 45 (3%), HPV 53 and 11 (2%). Currently 1.5% of tested specimens remained unclassified. Multiple infections with at last two different high- risk HPV genotypes were observed in 10% of specimens. CONCLUSIONS: This finding adds knowledge to HPV epidemiological investigation, and addresses further studies aimed to consider public health for identifying groups at risk for cervical cancer. PMID- 26428052 TI - Patient satisfaction surveys and care quality: a continuum conundrum. PMID- 26428053 TI - Infectious complications in patients with newly diagnosed multiple myeloma: A complication from the past? AB - Infectious complications are an important risk factor for early mortality in patients with multiple myeloma. However, data about the impact and severity of infections in these patients in the era of new therapies have not been properly analyzed. This review has reviewed the incidence and severity of infections complications and infection-related mortality during induction treatment in patients with newly diagnosed myeloma receiving regimens with new drugs within randomized trials. The results show that infections are still a major cause of morbidity, especially among elderly patients receiving immunomodulatory drugs seen in up to 28% of patients in some trials vs less than 10% among transplant eligible patients. Overall infection-related mortality ranged from 0-7% in transplant-ineligible patients, with no infection-related deaths in the majority of the trials including younger patients. Strategies directed to further reduce these complications and a better knowledge of their impact in patients treated outside clinical trials are needed. PMID- 26428055 TI - Spatio-temporal patterning of arginyl-tRNA protein transferase (ATE) contributes to gametophytic development in a moss. AB - The importance of the arginyl-tRNA protein transferase (ATE), the enzyme mediating post-translation arginylation of proteins in the N-end rule degradation (NERD) pathway of protein stability, was analysed in Physcomitrella patens and compared to its known functions in other eukaryotes. We characterize ATE:GUS reporter lines as well as ATE mutants in P. patens to study the impact and function of arginylation on moss development and physiology. ATE protein abundance is spatially and temporally regulated in P. patens by hormones and light and is highly abundant in meristematic cells. Further, the amount of ATE transcript is regulated during abscisic acid signalling and downstream of auxin signalling. Loss-of-function mutants exhibit defects at various levels, most severely in developing gametophores, in chloroplast starch accumulation and senescence. Thus, arginylation is necessary for moss gametophyte development, in contrast to the situation in flowering plants. Our analysis further substantiates the conservation of the N-end rule pathway components in land plants and highlights lineage-specific features. We introduce moss as a model system to characterize the role of the NERD pathway as an additional layer of complexity in eukaryotic development. PMID- 26428056 TI - A note on bias of measures of explained variation for survival data. AB - Papers evaluating measures of explained variation, or similar indices, almost invariably use independence from censoring as the most important criterion. And they always end up suggesting that some measures meet this criterion, and some do not, most of the time leading to a conclusion that the first is better than the second. As a consequence, users are offered measures that cannot be used with time-dependent covariates and effects, not to mention extensions to repeated events or multi-state models. We explain in this paper that the aforementioned criterion is of no use in studying such measures, because it simply favors those that make an implicit assumption of a model being valid everywhere. Measures not making such an assumption are disqualified, even though they are better in every other respect. We show that if these, allegedly inferior, measures are allowed to make the same assumption, they are easily corrected to satisfy the 'independent from-censoring' criterion. Even better, it is enough to make such an assumption only for the times greater than the last observed failure time tau, which, in contrast with the 'preferred' measures, makes it possible to use all the modeling flexibility up to tau and assume whatever one wants after tau. As a consequence, we claim that some of the measures being preferred as better in the existing reviews are in fact inferior. PMID- 26428057 TI - Sodium tanshinone IIA sulfonate affects Marek's disease virus replication by inhibiting gB expression. AB - CONTEXT: Previous studies demonstrated that sodium tanshinone IIA sulfonate (STS) could inhibit MDV replication in vitro. The mechanism about how STS inhibits MDV replication is still not well understood. OBJECTIVE: In this study, we evaluated the effect of STS on gB gene/protein of Marek's disease virus (MDV). MATERIALS AND METHODS: The concentration of 0.25 mg/ml of STS was used in this study. Meanwhile, 0.25 mg/ml of acyclovir (ACV) was used as a positive control. About 9 11-d-old embryonated specific-pathogen-free (SPF) chicken eggs were used to prepare CEF cells. CEF cells were infected with MDV 2 h, followed by treatment with STS. Real-time PCR and western blot assay were used to measure the gB (UL27) gene/protein expression in STS treatment group at 24, 48, 72, and 96 h post infection. RESULTS: Compared with MDV control, the gB gene copies were significantly decreased in STS and ACV treatment groups at 72 h and 96 h (p < 0.05), both in the DNA and in the mRNA level. Furthermore, the expression of gB protein was also inhibited by STS at 24, 72, and 96 h. DISCUSSION AND CONCLUSION: Our study demonstrated that STS could effectively inhibit the MDV replication by suppressing gB gene/protein expression in cell culture. PMID- 26428058 TI - Successful use of etanercept in a case of toxic epidermal necrolysis induced by rituximab. PMID- 26428059 TI - A Eu(II)-Containing Cryptate as a Redox Sensor in Magnetic Resonance Imaging of Living Tissue. AB - The Eu(II) ion rivals Gd(III) in its ability to enhance contrast in magnetic resonance imaging. However, all reported Eu(II)-based complexes have been studied in vitro largely because the tendency of Eu(II) to oxidize to Eu(III) has been viewed as a major obstacle to in vivo imaging. Herein, we present solid- and solution-phase characterization of a Eu(II)-containing cryptate and the first in vivo use of Eu(II) to provide contrast enhancement. The results indicate that between one and two water molecules are coordinated to the Eu(II) core upon dissolution. We also demonstrate that Eu(II)-based contrast enhancement can be observed for hours in a mouse. PMID- 26428060 TI - Selective hydrogenolysis of raw glycerol to 1,2-propanediol over Cu-ZnO catalysts in fixed-bed reactor. AB - The catalytic properties of Cu-ZnO catalysts for glycerol hydrogenolysis to 1,2 propanediol (1,2-PDO) were tested in a fixed-bed reactor at 250 degrees C and 2.0 MPa H2. The relation between composition, surface properties, and catalytic performance of glycerol hydrogenation of Cu-ZnO catalysts was studied using nitrogen adsorption (BET methods), XRD, H2 temperature-programmed reduction, and N2O chemisorptions. It was found that there was a close link between the surface CuO amount of Cu-ZnO catalyst and the reactivity for glycerol hydrogenation. The Cu-ZnO catalyst (Cu/Zn = 1.86) which had the highest surface Cu amount showed the best catalytic activity for glycerol hydrogenolysis. Furthermore, Cu-ZnO catalyst presented good stability and remarkable catalytic activity for glycerol hydrogenolysis to 1,2-PDO using raw glycerol derived from the fat saponification as feedstock. PMID- 26428061 TI - The link between flowering time and stress tolerance. AB - Evolutionary success in plants is largely dependent on the successful transition from vegetative to reproductive growth. In the lifetime of a plant, flowering is not only an essential part of the reproductive process but also a critical developmental stage that can be vulnerable to environmental stresses. Exposure to stress during this period can cause substantial yield losses in seed-producing plants. However, it is becoming increasingly evident that altering flowering time is an evolutionary strategy adopted by plants to maximize the chances of reproduction under diverse stress conditions, ranging from pathogen infection to heat, salinity, and drought. Here, recent studies that have revealed new insights into how biotic and abiotic stress signals can be integrated into floral pathways are reviewed. A better understanding of how complex environmental variables affect plant phenology is important for future genetic manipulation of crops to increase productivity under the changing climate. PMID- 26428062 TI - Gene networks controlling petal organogenesis. AB - One of the biggest unanswered questions in developmental biology is how growth is controlled. Petals are an excellent organ system for investigating growth control in plants: petals are dispensable, have a simple structure, and are largely refractory to environmental perturbations that can alter their size and shape. In recent studies, a number of genes controlling petal growth have been identified. The overall picture of how such genes function in petal organogenesis is beginning to be elucidated. This review will focus on studies using petals as a model system to explore the underlying gene networks that control organ initiation, growth, and final organ morphology. PMID- 26428063 TI - Founder-cell-specific transcription of the DORNROSCHEN-LIKE promoter and integration of the auxin response. AB - Transcription of the DORNROSCHEN (DRNL) promoter marks lateral-organ founder cells throughout Arabidopsis development, from cotyledons to flowers or floral organs. In the inflorescence apex, DRNL::GFP depicts incipient floral phyllotaxy, and organs in the four floral whorls are differentially prepatterned: the sepals unidirectionally along an abaxial-adaxial axis, the four petals and two lateral stamens in two putative morphogenetic fields, and the medial stamens subsequently in a ring-shaped domain, before two groups of carpel founder cells are specified. The dynamic DRNL transcription pattern is controlled by three enhancer elements, which redundantly and synergistically control qualitative or quantitative aspects of expression, and differentially integrate the auxin response in Arabidopsis inflorescence and floral meristems. The high sequence conservation of all three enhancer elements among the Brassicaceae is striking, which suggests that densely packed cis-regulatory elements are conserved to recruit multiple transcription factors, including auxin response factors, into higher-order enhanceosome complexes. The spatial organization of the enhancers is also conserved, by a microsynteny that extends beyond the Brassicaceae, which relates to enhancer sharing, as the distal element En1 bidirectionally serves DRNL and the upstream At1g24600 gene; the genes are transcribed in opposite directions and possibly comprise a conserved functional chromatin domain. PMID- 26428064 TI - Fluctuation of Arabidopsis seed dormancy with relative humidity and temperature during dry storage. AB - The changes in germination potential of freshly harvested seeds of Arabidopsis thaliana stored in various combinations of temperature and relative humidity were investigated over 63 weeks of storage. Seeds of the wild type Col-0 and of two mutants displaying low and high levels of dormancy, cat2-1 and mtr4-1, respectively, were stored at harvest in 24 different environments including a combination of eight relative humidities, from 1 to 85%, and four temperatures (10, 15, 20, and 25 degrees C). These mutations did not influence behaviour of seeds during storage. Primary dormant seeds did not germinate in darkness at 25 degrees C but acquired the potential to germinate at this temperature within 7 weeks when stored in relative humidities close to 50% across all temperatures. Sorption isotherms and Arrhenius plots demonstrated that the seed moisture content of 0.06 g H2O/g dry weight was a critical value below which dormancy release was associated with reactions of negative activation energy and above which dormancy release increased with temperature. Longer storage times when relative humidity did not exceed 75-85% led to decreased germination at 25 degrees C, corresponding to the induction of secondary dormancy. Dormancy release and induction of secondary dormancy in the dry state were associated with induction or repression of key genes related to abscisic acid and gibberellins biosynthesis and signalling pathways. In high relative humidity, prolonged storage of seeds induced ageing and progressive loss of viability, but this was not related to the initial level of dormancy. PMID- 26428065 TI - Soil water capture trends over 50 years of single-cross maize (Zea mays L.) breeding in the US corn-belt. AB - Breeders have successfully improved maize (Zea mays L.) grain yield for the conditions of the US corn-belt over the past 80 years, with the past 50 years utilizing single-cross hybrids. Long-term improvement for grain yield under water limited conditions has also been reported. Grain yield under water-limited conditions depends on water use, water use efficiency, and harvest index. It has been hypothesized that long-term genetic gain for yield could be due, in part, to increased water capture from the soil. This hypothesis was tested using a set of elite single-cross hybrids that were released by DuPont Pioneer between 1963 and 2009. Eighteen hybrids were grown in the field during 2010 and 2011 growing seasons at Woodland, CA, USA. Crops grew predominantly on stored soil water and drought stress increased as the season progressed. Soil water content was measured to 300cm depth throughout the growing season. Significant water extraction occurred to a depth of 240-300cm and seasonal water use was calculated from the change in soil water over this rooting zone. Grain yield increased significantly with year of commercialization, but no such trend was observed for total water extraction. Therefore, the measured genetic gain for yield for the period represented by this set of hybrids must be related to either increased efficiency of water use or increased carbon partitioning to the grain, rather than increased soil water uptake. PMID- 26428068 TI - Polyfluorides and Neat Fluorine as Host Material in Matrix-Isolation Experiments. AB - The use of neat fluorine in matrix isolation is reported, as well as the formation of polyfluoride monoanions under cryogenic conditions. Purification procedures and spectroscopic data of fluorine are described, and matrix shifts of selected molecules and impurities in solid fluorine are compared to those of common matrix gases (Ar, Kr, N2 , Ne). The reaction of neat fluorine and IR-laser ablated metal atoms to yield fluorides of chromium (CrF5 ), palladium (PdF2 ), gold (AuF5 ), and praseodymium (PrF4 ) has been investigated. The fluorides have been characterized in solid fluorine by IR spectroscopy at 5 K. Also the fluorination of Kr and the photo-dismutation of XeO4 have been studied by using IR spectroscopy in neat fluorine. Formation of the [F5 ](-) ion was obtained by IR-laser ablation of platinum in the presence of fluorine and proven in a Ne matrix at 5 K by two characteristic vibrational bands of [F5 ](-) at $?tilde ?nu $=850.7 and 1805.0 cm(-1) and its photo-behavior. PMID- 26428066 TI - Ethylene negatively regulates transcript abundance of ROP-GAP rheostat-encoding genes and affects apoplastic reactive oxygen species homeostasis in epicarps of cold stored apple fruits. AB - Apple (Malus*domestica Borkh) fruits are stored for long periods of time at low temperatures (1 degrees C) leading to the occurrence of physiological disorders. 'Superficial scald' of Granny Smith apples, an economically important ethylene dependent disorder, was used as a model to study relationships among ethylene action, the regulation of the ROP-GAP rheostat, and maintenance of H2O2 homeostasis in fruits during prolonged cold exposure. The ROP-GAP rheostat is a key module for adaptation to low oxygen in Arabidopsis through Respiratory Burst NADPH Oxidase Homologs (RBOH)-mediated and ROP GTPase-dependent regulation of reactive oxygen species (ROS) homeostasis. Here, it was shown that the transcriptional expression of several components of the apple ROP-GAP machinery, including genes encoding RBOHs, ROPs, and their ancillary proteins ROP-GEFs and ROP-GAPs, is coordinately and negatively regulated by ethylene in conjunction with the progressive impairment of apoplastic H2O2 homeostatic levels. RNA sequencing analyses showed that several components of the known ROP- and ROS associated transcriptional networks are regulated along with the ROP-GAP rheostat in response to ethylene perception. These findings may extend the role of the ROP GAP rheostat beyond hypoxic responses and suggest that it may be a functional regulatory node involved in the integration of ethylene and ROS signalling pathways in abiotic stress. PMID- 26428067 TI - Over-expression of an S-domain receptor-like kinase extracellular domain improves panicle architecture and grain yield in rice. AB - The S-domain receptor kinase (SRK) comprises a highly polymorphic subfamily of receptor-like kinases (RLKs) originally found to be involved in the self incompatibility response in Brassica. Although several members have been identified to play roles in developmental control and disease responses, the correlation between SRKs and yield components in rice is still unclear. The utility of transgenic expression of a dominant negative form of SRK, OsLSK1 (Large spike S-domain receptor like Kinase 1), is reported here for the improvement of grain yield components in rice. OsLSK1 was highly expressed in nodes of rice and is a plasma membrane protein. The expression of OsLSK1 responded to the exogenous application of growth hormones, to abiotic stresses, and its extracellular domain could form homodimers or heterodimers with other related SRKs. Over-expression of a truncated version of OsLSK1 (including the extracellular and transmembrane domain of OsLSK1 without the intracellular kinase domain) increased plant height and improve yield components, including primary branches per panicle and grains per primary branch, resulting in about a 55.8% increase of the total grain yield per plot (10 plants). Transcriptional analysis indicated that several key genes involved in the GA biosynthetic and signalling pathway were up-regulated in transgenic plants. However, full-length cDNA over expression and RNAi of OsLSK1 transgenic plants did not exhibit a detectable visual phenotype and possible reasons for this were discussed. These results indicate that OsLSK1 may act redundantly with its homologues to affect yield traits in rice and manipulation of OsLSK1 by the dominant negative method is a practicable strategy to improve grain yield in rice and other crops. PMID- 26428069 TI - Gender-related patterns and determinants of recent help-seeking for past-year affective, anxiety and substance use disorders: findings from a national epidemiological survey. AB - AIMS: To examine: (1) gender-specific determinants of help-seeking for mental health, including health professional consultation and the use of non-clinical support services and self-management strategies (SS/SM) and; (2) gender differences among individuals with unmet perceived need for care. METHOD: Analyses focused on 689 males and 1075 females aged 16-85 years who met ICD-10 criteria for a past-year affective, anxiety or substance use disorder in an Australian community-representative survey. Two classifications of help-seeking for mental health in the previous year were created: (1) no health professional consultation or SS/SM, or health professional consultation, or SS/SM only, and; (2) no general practitioner (GP) or mental health professional consultation, or GP only consultation, or mental health professional consultation. Between- and within-gender help-seeking patterns were explored using multinomial logistic regression models. Characteristics of males and females with unmet perceived need for care were compared using chi-square tests. RESULTS: Males with mental or substance use disorders had relatively lower odds than females of any health professional consultation (adjusted odds ratio [AOR] = 0.46), use of SS/SM only (AOR = 0.59), and GP only consultation (AOR = 0.29). Notably, males with severe disorders had substantially lower odds than females of any health professional consultation (AOR = 0.29) and GP only consultation (AOR = 0.14). Most correlates of help-seeking were need-related. Many applied to both genders (e.g., severity, disability, psychiatric comorbidity), although some were male-specific (e.g., past-year reaction to a traumatic event) or female-specific (e.g., past-year affective disorder). Certain enabling and predisposing factors increased the probability of health professional consultation for both genders (age 30+ years) or for males (unmarried, single parenthood, reliance on government pension). Males with unmet perceived need for care were more likely to have experienced a substance use disorder and to want medicine or tablets or social intervention, whereas their females peers were more likely to have experienced an anxiety disorder and to want counselling or talking therapy. For both genders, attitudinal/knowledge barriers to receiving the types of help wanted (e.g., not knowing where to get help) were more commonly reported than structural barriers (e.g., cost). CONCLUSIONS: Findings suggest a need to address barriers to help seeking in males with severe disorders, and promote GP consultation. Exploring gender-specific attitudinal/knowledge barriers to receiving help, and the types of help wanted, may assist in designing interventions to increase consultation. Mental health promotion/education efforts could incorporate information about the content and benefits of evidence-based treatments and encourage males to participate in other potentially beneficial actions (e.g., physical activity). PMID- 26428071 TI - Artificial evolution of coumarin dyes for dye sensitized solar cells. AB - The design and discovery of novel molecular structures with optimal properties has been an ongoing effort for materials scientists. This field has in general been dominated by experiment driven trial-and-error approaches that are often expensive and time-consuming. Here, we investigate if a de novo computational design methodology can be applied to the design of coumarin-based dye sensitizers with improved properties for use in Gratzel solar cells. To address the issue of synthetic accessibility of the designed compounds, a fragment-based assembly is employed, wherein the combination of chemical motifs (derived from the existing databases of structures) is carried out with respect to user-adaptable set of rules. Rather than using computationally intensive density functional theory (DFT)/ab initio methods to screen candidate dyes, we employ quantitative structure-property relationship (QSPR) models (calibrated from empirical data) for rapid estimation of the property of interest, which in this case is the product of short circuit current (Jsc) and open circuit voltage (Voc). Since QSPR models have limited validity, pre-determined applicability domain criteria are used to prevent unacceptable extrapolation. DFT analysis of the top-ranked structures provides supporting evidence of their potential for dye sensitized solar cell applications. PMID- 26428072 TI - A comparison of volumetric modulated arc therapy and sliding-window intensity modulated radiotherapy in the treatment of Stage I-II nasal natural killer/T-cell lymphoma. AB - This article is aimed to compare the dosimetric differences between volumetric modulated arc therapy (VMAT) and intensity-modulated radiotherapy (IMRT) for Stage I-II nasal natural killer/T-cell lymphoma (NNKTL). Ten patients with Stage I-II NNKTL treated with IMRT were replanned with VMAT (2 arcs). The prescribed dose of the planning target volume (PTV) was 50Gy in 25 fractions. The VMAT plans with the Anisotropic Analytical Algorithm (Version 8.6.15) were based on an Eclipse treatment planning system; the monitor units (MUs) and treatment time (T) were scored to measure the expected treatment efficiency. All the 10 patients under the study were subject to comparisons regarding the quality of target coverage, the efficiency of delivery, and the exposure of normal adjacent organs at risk (OARs). The study shows that VMAT was associated with a better conformal index (CI) and homogeneity index (HI) (both p < 0.05) but slightly higher dose to OARs than IMRT. The MUs with VMAT (650.80 +/- 24.59) were fewer than with IMRT (1300.10 +/- 57.12) (relative reduction of 49.94%, p = 0.00) when using 2-Gy dose fractions. The treatment time with VMAT (3.20 +/- 0.02 minutes) was shorter than with IMRT (7.38 +/- 0.18 minutes) (relative reduction of 56.64%, p = 0.00). We found that VMAT and IMRT both provide satisfactory target dosimetric coverage and OARs sparing clinically. Likely to deliver a bit higher dose to OARs, VMAT in comparison with IMRT, is still a better choice for treatment of patients with Stage I-II NNKTL, thanks to better dose distribution, fewer MUs, and shorter delivery time. PMID- 26428073 TI - Associations of pancreatic beta-cell function and insulin resistance with microalbuminuria in type 2 diabetes. AB - We investigate the relationships of pancreatic beta-cell function and insulin resistance with microalbuminuria in a cross-sectional study of patients with type 2 diabetes. The study suggests insulin resistance is associated with an increased prevalence of microalbuminuria, while improved pancreatic beta-cell function is linked to decreased rates of microalbuminuria for those patients. PMID- 26428070 TI - Diversity in clinical management and protocols for the treatment of major bleeding trauma patients across European level I Trauma Centres. AB - BACKGROUND: Uncontrolled haemorrhage is still the leading cause of preventable death after trauma and the primary focus of any treatment strategy should be related to early detection and control of blood loss including haemostasis. METHODS: For assessing management practices across six European level I trauma centres with academic interest and research in the field of coagulopathy an online survey was conducted addressing local management practice for bleeding trauma patients including algorithms for detection, management and monitoring coagulation disorders and immediate interventions. Each centre provided their locally applied massive transfusion protocol. RESULTS: All participating trauma centres have developed and implemented a local algorithm and protocol for the bleeding trauma patient. These are uniformly activated by clinical triggers and deactivated once the bleeding has stopped according to clinical assessment in combination with laboratory signs of achieved haemostasis. The severity of coagulopathy and shock is mostly assessed via standard coagulation tests and partially used extended viscoelastic tests. All centres have implemented the immediate use of tranexamic acid. Initial resuscitation is started either pre hospital or after hospital admission by using transfusion packages with pre-fixed universal blood product combinations and ratios following the concept of "damage control resuscitation" at which applied ratios substantially vary. Two centres initially start with transfusion packages but with viscoelastic tests running in parallel to quickly allow a shift towards a viscoelastic test-guided therapy. CONCLUSION: Diversity in the management of bleeding trauma patients such as pre hospital blood administration and routinely performed viscoelastic tests exists even among level I trauma centres. The paucity of consensus among these centres highlights the need for further primary research followed by clinical trials to improve the evidence for sophisticated guidelines and strategies. PMID- 26428074 TI - Increased return of spontaneous circulation at the expense of neurologic outcomes: Is prehospital epinephrine for out-of-hospital cardiac arrest really worth it? AB - INTRODUCTION: Current guidelines for the management of out-of-hospital cardiac arrest (OHCA) recommend the use of prehospital epinephrine by initial responders. This recommendation was initially based on data from animal models of cardiac arrest and minimal human data, but since its inception, more human data regarding prehospital epinephrine in this setting are now available. Although out-of hospital return of spontaneous circulation (ROSC) may be higher with the use of epinephrine, worse neurologic outcomes may be associated with its use. METHODS: A systematic review of the literature was conducted by search of databases including PubMed, Embase, and OVID to identify studies comparing patients with OHCA who had received epinephrine before arrival to the hospital with those who had not. Studies were assessed for quality and bias, and data were abstracted from studies deemed appropriate for inclusion. A meta-analysis was conducted using a Mantel-Haenszel model for dichotomous outcomes. Outcomes studied were prehospital ROSC, survival at 1 month, survival to discharge, and positive neurologic outcome. RESULTS: A total of 14 studies with 655853 patients were included for the meta-analysis. The use of epinephrine for OHCA before arrival to the hospital was associated with a significant increase in ROSC (odds ratio, 2.86; P<.001) and a significant increase in the risk of poor neurologic outcome at the time of discharge (odds ratio 0.51, P=.008). There was no significant difference in survival at 1 month or survival to discharge. CONCLUSION: Use of epinephrine before arrival to the hospital for OHCA does not increase survival to discharge but does make it more likely for those who are discharged to have poor neurologic outcome. There is a need for additional randomized controlled trials. PMID- 26428075 TI - Admission hyperglycemia is associated with poor outcome after emergent coronary bypass grafting surgery. AB - PURPOSE: Hyperglycemia during or after cardiac surgery is a common finding that is associated with poor outcome. Very few data, however, are available regarding a correlation between admission blood glucose and outcomes after coronary artery bypass grafting (CABG). Thus, the goal of the current study was to examine the relationship between admission blood glucose and outcome after emergency CABG surgery. MATERIALS AND METHODS: A retrospective analysis to evaluate whether admission hyperglycemia associated with increased morbidity or mortality was performed in patients after emergency CABG surgery. The records of all the patients undergoing emergency CABG surgery between January 1999 and December 2010 at the University of Virginia Health System were reviewed. Postoperative in hospital mortality and complications were considered as study end points. RESULTS: A total of 240 patients met the final inclusion criteria. Overall mortality was 14.1%. The median admission blood glucose in patients who died 7.4 (interquartile range, 5.9-10.1) mmol/L was significantly higher compared with survivors 6.1 (interquartile range, 5.4-7.2; P<.01). Furthermore, 59% of the patients who died had admission blood glucose levels higher than 6.6 mmol/L, whereas only 35% of the patients who survived had similar blood glucose levels (P=.01). On multivariable analysis, admission blood glucose was identified as an independent risk factor for death after emergency CABG (P=.01; odds ratio, 1.16; 95% confidence interval, 1.04-1.29). Admission blood glucose was further identified as independently associated with increased risk for a composite outcome of death, postoperative renal failure or stroke (P=.01; odds ratio, 1.14; 95% confidence interval, 1.03-1.27). CONCLUSIONS: Our study shows for the first time that admission blood glucose is correlated with increased morbidity and mortality among patients undergoing emergency CABG surgery. PMID- 26428076 TI - Enhanced oral healing following local mesenchymal stromal cell therapy. PMID- 26428077 TI - Link for Injured Kids: A Patient-Centered Program of Psychological First Aid After Trauma. AB - OBJECTIVE: Injury, the most common type of pediatric trauma, can lead to a number of adverse psychosocial outcomes, including posttraumatic stress disorder. Currently, few evidence-based parent programs exist to support children hospitalized after a traumatic injury. Using methods in evaluation and intervention research, we completed a formative research study to develop a new program of psychological first aid, Link for Injured Kids, aimed to educate parents in supporting their children after a severe traumatic injury. METHODS: Using qualitative methods, we held focus groups with parents and pediatric trauma providers of children hospitalized at a Level I Children's Hospital because of an injury in 2012. We asked focus group participants to describe reactions to trauma and review drafts of our intervention materials. RESULTS: Health professionals and caregivers reported a broad spectrum of emotional responses by their children or patients; however, difficulties were experienced during recovery at home and upon returning to school. All parents and health professionals recommended that interventions be offered to parents either in the emergency department or close to discharge among admissions. CONCLUSIONS: Results from this study strongly indicate a need for posttrauma interventions, particularly in rural settings, to support families of children to address the psychosocial outcomes in the aftermath of an injury. Findings presented here describe the process of intervention development that responds to the needs of an affected population. PMID- 26428078 TI - Adverse effects of frailty on social functioning in older adults: Results from the Longitudinal Aging Study Amsterdam. AB - OBJECTIVES: The aim of this study was to examine the association between physical frailty and social functioning among older adults, cross-sectionally and prospectively over 3 years. STUDY DESIGN: The study sample consisted of 1115 older adults aged 65 and over from two waves of the Longitudinal Aging Study Amsterdam, a population based study. MAIN OUTCOME MEASURES: Frailty was measured at T1 (2005/2006) using the criteria of the frailty phenotype, which includes weight loss, weak grip strength, exhaustion, slow gait speed and low physical activity. Social functioning was assessed at T1 and T2 (2008/2009) and included social network size, instrumental support, emotional support, and loneliness. RESULTS: Cross-sectional linear regression analyses adjusted for covariates (age, sex, educational level and number of chronic diseases) showed that pre-frail and frail older adults had a smaller network size and higher levels of loneliness compared to their non-frail peers. Longitudinal linear regression analyses adjusted for covariates and baseline social functioning showed that frailty was associated with an increase in loneliness over 3 years. However, the network size and levels of social support of frail older adults did not further decline over time. CONCLUSIONS: Frailty is associated with poor social functioning, and with an increase in loneliness over time. The social vulnerability of physical frail older adults should be taken into account in the care provision for frail older adults. PMID- 26428079 TI - Regulation of HIPK Proteins by MicroRNAs. AB - INTRODUCTION: The homeodomain-interacting protein kinase (HIPK) family consists of four evolutionarily conserved and highly related nuclear serine/threonine kinases of recent discovery. They interact with homeobox proteins and other transcription factors, as well as transcriptional coactivators or corepressors depending on the cellular context. HIPK proteins are sensors for various extracellular stimuli, which control key cellular functions such as signal transduction to downstream effectors that regulate apoptosis, embryonic development, DNA-damage response, and cellular proliferation. Thus, HIPKs are involved in proliferative diseases such as cancer and fibrosis. mRNA levels and protein stability tightly regulate expression levels of HIPKs. METHODS: Here, we review recent works investigating the regulation of HIPKs expression by microRNAs (miRNAs) that are involved in the control of cell proliferation, sensitivity to chemotherapeutic drugs, epithelial-mesenchymal transition, and glucose-stimulated insulin secretion. CONCLUSION: It appears that HIPK family members, and their related miRNAs, may be considered as novel therapeutic targets for treating cancer, renal fibrosis and type 2 diabetes. PMID- 26428080 TI - Development of Integrative Map of MicroRNA Gene Regulatory Elements. AB - Like many other omics types, miRNomics is the topic of increased research interest. Fast accumulation of diverse biological information generates fragmented and sometimes contradictory results. There is an urgent need for development of protocols for systematic assembling, organization and integration of accumulated genomics data. In the present study we developed a protocol for connecting microRNA (miRNA) interactions into an integrative map of miRNA regulatory elements including: upstream regulators, overlapping genomic elements and downstream targets; miRNA-target interactions (MTIs). Data integration (integromics) in miRNomics enables revealing miRNA regulatory networks, obtaining new knowledge, setting more targeted hypotheses, prioritization of candidate regions, and facilitates biomarker development. PMID- 26428081 TI - Widening access to medicine may improve general practitioner recruitment in deprived and rural communities: survey of GP origins and current place of work. AB - BACKGROUND: Widening access to medicine in the UK is a recalcitrant problem of increasing political importance, with associated strong social justice arguments but without clear evidence of impact on service delivery. Evidence from the United States suggests that widening access may enhance care to underserved communities. Additionally, rural origin has been demonstrated to be the factor most strongly associated with rural practice. However the evidence regarding socio-economic and rural background and subsequent practice locations in the UK has not been explored. The aim of this study was to investigate the association between general practitioners' (GPs) socio-economic and rural background at application to medical school and demographic characteristics of their current practice. METHOD: The study design was a cross-sectional email survey of general practitioners practising in Scotland. Socio-economic status of GPs at application to medical school was assessed using the self-coded National Statistics Socio Economic Classification. UK postcode at application was used to define urban rural location. Current practice deprivation and remoteness was measured using NHS Scotland defined measures based on registered patients' postcodes. RESULTS: A survey was sent to 2050 Scottish GPs with a valid accessible email address, with 801 (41.5 %) responding. GPs whose parents had semi-routine or routine occupations had 4.3 times the odds of working in a deprived practice compared to those with parents from managerial and professional occupations (95 % CI 1.8 10.2, p = 0.001). GPs from remote and rural Scottish backgrounds were more likely to work in remote Scottish practices, as were GPs originating from other UK countries. CONCLUSION: This study showed that childhood background is associated with the population GPs subsequently serve, implying that widening access may positively affect service delivery in addition to any social justice rationale. Longitudinal research is needed to explore this association and the impact of widening access on service delivery more broadly. PMID- 26428083 TI - Ketoacidosis associated with low-carbohydrate diet in a non-diabetic lactating woman: a case report. AB - INTRODUCTION: Non-diabetic ketoacidosis is a rare condition which can be caused by starvation. Lack of glucose can force the body into ketogenesis causing a metabolic acidosis. As previously reported in the literature, ketoacidosis might, on rare occasions, be caused by a diet with low carbohydrate content. However, to the best of our knowledge this is the first reported case in the literature of ketoacidosis, in a non-diabetic patient, associated with a combination of low carbohydrate, high fat diet and lactation. CASE PRESENTATION: A healthy non diabetic, 32-year old white woman started a low carbohydrate, high fat diet when she was breastfeeding her son of 10 months of age. After 10 days she was admitted to our hospital with nausea and vomiting and a serum pH of 7.20 and base excess of -19. Clinical signs and blood samples were compatible with ketoacidosis. She was given fluids intravenously and insulin. No anamnestic or clinical signs of diabetes were found. She recovered quickly and was discharged 3 days later. CONCLUSIONS: Ketogenic diets like low carbohydrate, high fat may induce ketoacidosis. Lactation might further aggravate the condition and can perhaps even be the trigger into ketoacidosis. Health services should be aware of the risks associated with ketogenic diets, and be able to recognize this serious condition when it is presented. PMID- 26428084 TI - An institutional approach to support the conduct and use of health policy and systems research: The Nodal Institute in the Eastern Mediterranean Region. AB - BACKGROUND: The use of health policy and systems research (HPSR) to support decision making in health systems is limited in the Eastern Mediterranean Region (EMR). This is partly due to the lack of effective initiatives to strengthen regional HPSR capacities and promote its use in decision making. This paper offers a structured reflection on the establishment and core functioning of a HPSR Nodal Institute for the EMR with specific focus on the approach used to support the conduct and use of HPSR. It seeks to gain better understanding of the activities conducted by the Nodal Institute, the methods by which the Nodal Institute implemented these activities, and the outcomes of these activities. METHODS: A multi-faceted approach was implemented by the Nodal Institute in collaboration with regional academic/research institutions, Sub-Nodes. The overall approach was a phased one that included the selection of Sub-Nodes, mapping of academic/research institutions in the EMR, stakeholders' meetings, and HPSR capacity building workshops, and culminated with a regional meeting. RESULTS: The mapping of academic/research institutions in the EMR resulted in the identification of 50 institutions, of which only 32 were engaged in HPSR. These institutions have the highest HPSR involvement in information/evidence (84%) and the lowest in human resources for health (34%). Their main HPSR focus areas included quality of healthcare services, patient safety, management of non communicable diseases, and human resources for health. Regional HPSR challenges among these institutions were identified. The validation and ranking questionnaires resulted in the identification of country-specific HPSR priorities according to stakeholders in three countries. From these results, cross-cutting HPSR priorities among the countries related to primary healthcare, non communicable diseases, human resources for health, as well as cross-cutting HPSR priorities among stakeholders and according to stakeholders of the countries, were extracted. CONCLUSION: The Nodal Institute in the EMR is a promising initiative to support the conduct and use of HPSR in health policies. The approach and findings reported in this paper allow for the development of opportunities towards the building of capacity for HPSR in the region and other countries and provide a roadmap for academic/research institutions interested in HPSR in the region. PMID- 26428082 TI - American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple Myeloma. AB - In contrast to the upfront setting in which the role of high-dose therapy with autologous hematopoietic cell transplantation (HCT) as consolidation of a first remission in patients with multiple myeloma (MM) is well established, the role of high-dose therapy with autologous or allogeneic HCT has not been extensively studied in MM patients relapsing after primary therapy. The International Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network, the American Society of Blood and Marrow Transplantation, and the European Society of Blood and Marrow Transplantation convened a meeting of MM experts to: (1) summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy, (2) propose guidelines for the use of salvage HCT in MM, (3) identify knowledge gaps, (4) propose a research agenda, and (5) develop a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: (1) In transplantation-eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high-dose therapy with HCT as part of salvage therapy should be considered standard; (2) High-dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months; (3) High-dose therapy and autologous HCT can be used as a bridging strategy to allogeneic HCT; (4) The role of postsalvage HCT maintenance needs to be explored in the context of well-designed prospective trials that should include new agents, such as monoclonal antibodies, immune-modulating agents, and oral proteasome inhibitors; (5) Autologous HCT consolidation should be explored as a strategy to develop novel conditioning regimens or post-HCT strategies in patients with short (less than 18 months remissions) after primary therapy; and (6) Prospective randomized trials need to be performed to define the role of salvage autologous HCT in patients with MM relapsing after primary therapy comparing it to "best non-HCT" therapy. The expert committee also underscored the importance of collecting enough hematopoietic stem cells to perform 2 transplantations early in the course of the disease. Regarding allogeneic HCT, the expert committee agreed on the following consensus statements: (1) Allogeneic HCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HCT and/or high-risk features (ie, cytogenetics, extramedullary disease, plasma cell leukemia, or high lactate dehydrogenase); (2) Allogeneic HCT should be performed in the context of a clinical trial if possible; (3) The role of postallogeneic HCT maintenance therapy needs to be explored in the context of well-designed prospective trials; and (4) Prospective randomized trials need to be performed to define the role salvage allogeneic HCT in patients with MM relapsing after primary therapy. PMID- 26428085 TI - Molecular detection of vector-borne agents in dogs from ten provinces of China. AB - BACKGROUND: Although many vector-borne agents are potential zoonoses and cause substantial morbidity and mortality in dogs worldwide, there are limited data on these organisms in dogs of China. METHODS: Quantitative PCRs for vector-borne agents were performed to investigate their prevalences in convenience whole blood samples obtained from 1114 dogs from 21 veterinary clinics and a commercial dog breeding facility in ten provinces of China. In addition, the PCRs were performed on 146 Rhipicephalus sanguineus senso lato and 37 Linognathus setosus collected from dogs in the commercial dog breeding facility. RESULTS: DNAs of Babesia gibsoni and B. vogeli (1.2 %), Ehrlichia canis (1.3 %), Hepatozoon canis (1.8 %) and Theileria orientalis (0.1 %) or a closely related organism were detected in the bloods of the dogs studied, and Babesia vogeli (3.4 %) and Ehrlichia canis (4.1 %) in R. sanguineus senso lato. The qPCRs for Anaplasma spp., Dirofilaria immitis and Leishmania spp. were negative for all blood samples, ticks and lice. At least one vector-borne agent was found in dogs from 5 of the 10 provinces investigated in this study. Overall, 4.4 % (49/1117) of the dogs studied were positive for at least one vector-borne agent with the prevalence being highest in the commercial breeding colony (24/97; 24.7 %). CONCLUSIONS: Our study confirms that B. vogeli, B. gibsoni, H. canis, and E. canis occur in China. Also, we present evidence that T. orientalis or a closely related organism can infect dogs. PMID- 26428086 TI - Low case notification rates of childhood tuberculosis in southern Ethiopia. AB - BACKGROUND: Childhood tuberculosis (TB) is a public health concern causing considerable mortality. However, control of childhood TB receives little attention. The control efforts could be inadequate because of challenges associated with difficulties in diagnosing the disease in children. Understanding the burden of the disease among children is important to assess the ongoing transmission of the disease in a community and improving TB control efforts. This study was carried out to assess TB case notification rates (CNRs) and treatment outcomes in children aged less than 15 years over a ten-year period. METHODS: Data were collected from unit TB registers from all health facilities providing TB treatment in the Sidama Zone in Ethiopia. We analysed the CNRs and treatment outcomes by age category, gender, and place of residence. We used logistic regression analysis to identify factors associated with treatment outcomes and to control for confounding. RESULTS: A total of 4,656 cases of children less than 15 years of age were notified as diagnosed and treated for TB, constituting 13% of all notified TB cases in the study area. The mean CNRs per 100,000 children less than 15 years were 30 for all new cases of TB, 28 for rural cases, 67 for urban cases, 28 in boys, and 32 in girls. The proportions of treatment success were 82% for new and 77% for retreatment cases for the entire study period and increased to 93% for new cases in 2012 (X(2) trend, P < 0.001). Children less than five years old had a lower treatment success [adjusted odds ratio (AOR) 0.64 (95% CI, 0.52-0.80)] and higher deaths [AOR 2 (95% CI, 1.27-3.12)]. The proportion of children who died during treatment among children in the less than 2-year-old age group was three times higher than children in the 2 year and above age groups [AOR 3.34 (95% CI, 1.92-5.82)]. CONCLUSION: The CNRs of childhood TB were low in Sidama. Children less than 5 years old had a higher proportion of deaths. Efforts need to be made to improve the diagnosis and treatment of TB among children. PMID- 26428087 TI - Polyhydroxyalkanoates production with Ralstonia eutropha from low quality waste animal fats. AB - Polyhydroxyalkanoates (PHAs) are biodegradable and biocompatible polyesters considered as alternatives to petroleum-based plastics. Ralstonia eutropha is a model organism for PHA production. Utilizing industrially rendered waste animal fats as inexpensive carbon feedstocks for PHA production is demonstrated here. An emulsification strategy, without any mechanical or chemical pre-treatment, was developed to increase the bioavailability of solid, poorly-consumable fats. Wild type R. eutropha strain H16 produced 79-82% (w/w) polyhydroxybutyrate (PHB) per cell dry weight (CDW) when cultivated on various fats. A productivity of 0.3g PHB/(L * h) with a total PHB production of 24 g/L was achieved using tallow as carbon source. Using a recombinant strain of R. eutropha that produces poly(hydroxybutyrate-co-hydroxyhexanoate) [P(HB-co-HHx)], 49-72% (w/w) of PHA per CDW with a HHx content of 16-27 mol% were produced in shaking flask experiments. The recombinant strain was grown on waste animal fat of the lowest quality available at lab fermenter scale, resulting in 45 g/L CDW with 60% (w/w) PHA per CDW and a productivity of 0.4 g PHA/(L * h). The final HHx content of the polymer was 19 mol%. The use of low quality waste animal fats as an inexpensive carbon feedstock exhibits a high potential to accelerate the commercialization of PHAs. PMID- 26428088 TI - Dissecting the functional roles of the conserved NXXE and HXE motifs of the ADP dependent glucokinase from Thermococcus litoralis. AB - The activity of the ADP-dependent glucokinase from Thermococcus litoralis (TlGK) relies on the highly conserved motifs NXXE (i.e. Asn-Xaa-Xaa-Glu) and HXE (i.e. His-Xaa-Glu). Site-directed mutagenesis of residues Glu279 (HXE) and Glu308 (NXXE) leads to enzymes with highly reduced catalytic rates. The replacement of Glu308 by Gln increased the KM for MgADP(-) and was activated by free Mg(2+). On the other hand, HXE mutants did not affect the KM for MgADP(-), were still inhibited by free Mg(2+), and caused a large increase on KM for glucose and an 87 fold weaker binding of glucose onto the non-hydrolysable TlGK.AMP-AlF3 complex. Our findings put forward the fundamental role of the HXE motif in glucose binding during ternary complex formation. PMID- 26428089 TI - The diagnostic utility of scintigraphy in esophageal burn: a rat model. AB - BACKGROUND: Corrosive esophageal injury due to accidental ingestion is a serious clinical problem in children particularly in developing countries. The present study was conducted to evaluate the diagnostic utility of technetium-99m pyrophosphate ((99m)Tc-PYP) scintigraphy in the early stage of esophageal burns by using different concentrations of sodium hydroxide (NaOH) in an experimental rat model. MATERIALS AND METHODS: Twenty-eight male Sprague-Dawley rats, weighing 200-250 g, were used in the study. Esophageal burn model was created in 21 rats by gastrically infusion of various concentrations of NaOH. The rats were divided randomly into three groups: mild-burn group (n = 7) received 15% NaOH, moderate burn group (n = 7) received 30% NaOH and severe-burn group (n = 7) received 45% NaOH. Seven rats were identified as control group and received normal saline. Three hours after burn injury, 1-mCi (99m)Tc-PYP was administered through tail vein. Two hours after (99m)Tc-PYP administration, static imaging with gamma camera was performed. Then, histopathologic assessment of esophageal samples was achieved properly. RESULTS: All NaOH-applied groups (mild, moderate, and severe) showed a significant higher uptake ratio when compared to control group (P < 0.005). NaOH-applied groups displayed important histologic alterations such as mucosal disintegration, edema, inflammation, and stromal damage when compared to control group. Pearson correlation analysis revealed a significant correlation between the (99m)Tc-PYP uptake ratio and histologic score (P < 0.0005). CONCLUSIONS: The scintigraphic imaging may provide advantages in the early stage of esophageal burns in some patients whom endoscopic procedure is contraindicated because of its high risk of complications such as bleeding and perforation. PMID- 26428090 TI - Pulmonary emphysema and tumor microenvironment in primary lung cancer. AB - BACKGROUND: To clarify the relationship between the presence of pulmonary emphysema and tumor microenvironment and their significance for the clinicopathologic aggressiveness of non-small cell lung cancer. METHODS: The subjects included 48 patients with completely resected and pathologically confirmed stage I non-small cell lung cancer. Quantitative computed tomography was used to diagnose pulmonary emphysema, and immunohistochemical staining was performed to evaluate the matrix metalloproteinase (MMP) expression status in the intratumoral stromal cells as well as the microvessel density (MVD). RESULTS: Positive MMP-9 staining in the intratumoral stromal cells was confirmed in 17 (35%) of the 48 tumors. These 17 tumors were associated with a high MVD, frequent lymphovascular invasion, a high proliferative activity, and high postoperative recurrence rate (all, P < 0.05). The majority of the tumors (13 of 17) arose in patients with pulmonary emphysema (P = 0.02). Lung cancers arising from pulmonary emphysema were also associated with a high MVD, proliferative activity, and postoperative recurrence rate (all, P < 0.05). CONCLUSIONS: The MMP-9 expression in intratumoral stromal cells is associated with the clinicopathologic aggressiveness of lung cancer and is predominantly identified in tumors arising in emphysematous lungs. Further studies regarding the biological links between the intratumoral and extratumoral microenvironment will help to explain why lung cancers originating in emphysematous lung tissues are associated with a poor prognosis. PMID- 26428092 TI - Conformation of carboxylated schizophyllan in aqueous solution. AB - Carboxylated schizophyllan (sclerox) samples of different degrees of oxidation were molecularly characterized by size exclusion chromatography equipped with a multi-angle light scattering detector (SEC-MALS) in 0.10 M aqueous NaCl solution. The molar mass distribution obtained by SEC-MALS shows that sclerox of low degree of oxidation is dissolved mainly as the trimer, whereas the trimer and single chain coexist in solution of sclerox of high degree of oxidation. The trimer of sclerox is much more flexible than the fully ordered triple helix of the parent schizophyllan and easily dissociates into single chains upon heating. PMID- 26428091 TI - Exposure to nicotine increases nicotinic acetylcholine receptor density in the reward pathway and binge ethanol consumption in C57BL/6J adolescent female mice. AB - Nearly 80% of adult smokers begin smoking during adolescence. Binge alcohol consumption is also common during adolescence. Past studies report that nicotine and ethanol activate dopamine neurons in the reward pathway and may increase synaptic levels of dopamine in the nucleus accumbens through nicotinic acetylcholine receptor (nAChR) stimulation. Activation of the reward pathway during adolescence through drug use may produce neural alterations affecting subsequent drug consumption. Consequently, the effect of nicotine exposure on binge alcohol consumption was examined along with an assessment of the neurobiological underpinnings that drive adolescent use of these drugs. Adolescent C57BL/6J mice (postnatal days 35-44) were exposed to either water or nicotine (200MUg/ml) for ten days. On the final four days, ethanol intake was examined using the drinking-in-the-dark paradigm. Nicotine-exposed mice consumed significantly more ethanol and displayed higher blood ethanol concentrations than did control mice. Autoradiographic analysis of nAChR density revealed higher epibatidine binding in frontal cortical regions in mice exposed to nicotine and ethanol compared to mice exposed to ethanol only. These data show that nicotine exposure during adolescence increases subsequent binge ethanol consumption, and may affect the number of nAChRs in regions of the brain reward pathway, specifically the frontal cortex. PMID- 26428093 TI - Biophysical properties of carboxymethyl derivatives of mannan and dextran. AB - Mannan from Candida albicans, dextran from Leuconostoc spp. and their carboxymethyl (CM)-derivatives were tested on antioxidant and thrombolytic activities. As antioxidant tests, protection of liposomes against OH radicals and reducing power assay were used. Dextran and mannan protected liposomes in dose dependent manner. Carboxymethylation significantly increased antioxidant properties of both CM-derivatives up to concentration of 10mg/mL, higher concentrations did not change the protection of liposomes. The reducing power of CM-mannan (DS 0.92) was significantly lower (P<0.05) than underivatized mannan. No reductive activity was found for dextran and CM-dextran. All CM-derivatives demonstrated statistically significant increasing activity compared with underivatized polysaccharides. The highest thrombolytic activity was found using CM-mannan (DS 0.92). The clot lysis here amounted to 68.78 +/- 6.52% compared with 0.9% NaCl control (18.3 +/- 6.3%). Three-dimensional surface profiles of mannan, dextran, and their CM-derivatives were compared by atomic force microscopy. PMID- 26428094 TI - Characterization and comparison of polysaccharides from Lycium barbarum in China using saccharide mapping based on PACE and HPTLC. AB - Water-soluble polysaccharides from 51 batches of fruits of L. barbarum (wolfberry) in China were investigated and compared using saccharide mapping, partial acid hydrolysis, single and composite enzymatic digestion, followed by polysaccharide analysis by using carbohydrate gel electrophoresis (PACE) analysis and high performance thin layer chromatography (HPTLC) analysis, respectively. Results showed that multiple PACE and HPTLC fingerprints of partial acid and enzymatic hydrolysates of polysaccharides from L. barbarum in China were similar, respectively. In addition, results indicated that beta-1,3-glucosidic, alpha-1,4 galactosiduronic and alpha-1,5-arabinosidic linkages existed in polysaccharides from L. barbarum collected in China, and the similarity of polysaccharides in L. barbarum collected from different regions of China was pretty high, which are helpful for the improvement of the performance of polysaccharides from L. barbarum in functional/health foods area. Furthermore, polysaccharides from Panax notoginseng, Angelica sinensis, and Astragalus membranaceus var. mongholicus were successfully distinguished from those of L. barbarum based on their PACE fingerprints. These results were beneficial to improve the quality control of polysaccharides from L. barabrum and their products, which suggested that saccharide mapping based on PACE and HPTLC analysis could be a routine approach for quality control of polysaccharides. PMID- 26428095 TI - Effect of post-treatments and concentration of cotton linter cellulose nanocrystals on the properties of agar-based nanocomposite films. AB - Cellulose nanocrystals (CNCs) were prepared by acid hydrolysis of cotton linter pulp fibers and three different purification methods, i.e., without post purification (CNC1), dialyzed against distilled water (CNC2), and neutralized with NaOH (CNC3), and their effect on film properties was evaluated by preparation of agar/CNCs composite films. All the CNCs were rod in shape with diameter of 15-50 nm and length of 210-480 nm. FTIR result indicated that there was no distinctive differences in the chemical structure between CNCs and cotton linter cellulose fiber. No significant relationship was observed between the sulfate content and crystallinity index of CNCs. The CNC3 showed higher thermal stability than the other type of CNCs due to the less adverse effect on the thermal stability of sulfate groups induced by the neutralization with NaOH. The tensile strength (TS) of agar film increased by 15% with incorporation of 5 wt% of CNC3, on the contrary, it decreased by 10% and 15% with incorporation of CNC1 and CNC2, respectively. Other performance properties of agar/CNCs composite films such as optical and water vapor barrier properties showed that the CNC3 was more effective filler than the other CNCs. In the range of concentration of CNC3 tested (1-10 wt%), inclusion of 5 wt% of CNC3 was the maximum concentration for improving or maintaining film properties of the composite films. The neutralization of acid hydrolyzed cellulose using NaOH was simple and convenient for the preparation of CNC and bionanocomposite films. PMID- 26428096 TI - Cationic guar gum orchestrated environmental synthesis for silver nano-bio composite films. AB - This work is meant for environmentally friendly synthesis and functional evaluation of silver nanoparticles in a newer cationic guar biopolymer (GGAA). Assembly of molecules in lower size range (~ 10 nm) was attained in a biopolymer entrapped bottom-up synthesis. Guar gum is a filming biopolymer. Nanoparticles encaged in cationic guar (GGAgnC) were preserved as films for months without any significant effect on particle size, distribution or plasmonic intensity. The new nano-bio-composite and films were characterized fully in FTIR, XRD, SEM and TEM studies. Silver nanoparticles induced surface water repellency remarkably and lowered moisture permeability. GGAgnC film water contact angle was recorded as 115 degrees while, that in case of GGAA was 59 degrees . GGAgnC expressed intense antimicrobial activity when tested against a range of microorganisms. Immobilized silver nanoparticles in GGAA can feasibly be used as filming microbicidals suitable for textiles, packaging and biomedical device applications. PMID- 26428097 TI - Dehydration of an ethanol/water azeotrope through alginate-DNA membranes cross linked with metal ions by pervaporation. AB - To obtain high dehydration membranes for an ethanol/water azeotrope, dried blend membranes prepared from mixtures of sodium alginate (Alg-Na) and sodium deoxyribonucleate (DNA-Na) were cross-linked by immersing in a methanol solution of CaCl2 or MaCl2. In the dehydration of an ethanol/water azeotropic mixture by pervaporation, the effects of immersion time in methanol solution of CaCl2 or MaCl2 on the permeation rate and water/ethanol selectivity through Alg-DNA/Ca(2+) and Alg-DNA/Mg(2+) cross-linked membranes were investigated. Alg-DNA/Mg(2+) cross linked membrane immersed for 12h in methanol solution of MaCl2 exhibited the highest water/ethanol selectivity. This results from depressed swelling of the membranes by formation of a cross-linked structure. However, excess immersion in solution containing cross-linker led to an increase in the hydrophobicity of cross-linked membrane. Therefore, the water/ethanol selectivity of Alg-DNA/Mg(2+) cross-linked membranes with an excess immersion in cross-linking solution was lowered. The relationship between the structure of Alg-DNA/Ca(2+) and Alg DNA/Mg(2+) cross-linked membranes and their permeation and separation characteristics during pervaporation of an ethanol/water azeotropic mixture is discussed in detail. PMID- 26428098 TI - Ionic dextran derivatives for removal of Fastac 10 EC from its aqueous emulsions. AB - Separation studies of Fastac 10 EC from model emulsions by cationic polysaccharides were followed by UV-vis spectroscopy and zeta potential measurements. Floc size measurements at the optimum polycation dose were also carried out using laser diffraction technology. The investigated polyelectrolytes contained various amounts of quaternary ammonium salt groups, N-ethyl(octyl)-N,N dimethyl-2-hydroxypropyl ammonium chloride, attached to a dextran backbone. The effects of polycation dose, its charge density, emulsion pH and pesticide concentration on the flocculation performance were studied. The pesticide removal results (UV-vis spectroscopy) show that the optimum polycation dose decreased with increasing polymer charge density and the emulsion pH and increased with increasing pesticide concentration. The zeta potential values close to zero at the optimum polymer dose point to contribution, mainly, from charge neutralization mechanism for the flocculation process. The flocs size increase with increasing pesticide concentration was also observed. PMID- 26428099 TI - Poly(butylene succinate-co-butylene adipate)/cellulose nanocrystal composites modified with phthalic anhydride. AB - As a kind of biomass nanofiller for polymers, cellulose nanocrystal (CNC) has good mechanical properties and reinforcing capability. To improve the compatibility of poly(butylene succinate-co-butylene adipate) (PBSA)/CNC composites, phthalic anhydride was used as a compatilizer during melt mixing, leading to the significant improvement of the mechanical properties and thermal stability of the composites, which is related to the better dispersion of CNC in the composites. The addition of phthalic anhydride could accelerate the crystallization of PBSA component as evidenced by the curves of isothermal crystallization of the composites, but had little effect on the crystalline polymorphs of PBSA component. The addition of phthalic anhydride could strongly improve the hydrophobicity of the composites. The good mechanical properties, fast crystallization and improved hydrophobicity of PBSA/CNC composites with phthalic anhydride are favor to their practical commercial utilization. PMID- 26428100 TI - Barrier properties of nano silicon carbide designed chitosan nanocomposites. AB - Nano silicon carbide (SiC) designed chitosan nanocomposites were prepared by solution technique. Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) were used for studying structural interaction of nano silicon carbide (SiC) with chitosan. The morphology of chitosan/SiC nanocomposites was investigated by field emission scanning electron microscope (FESEM), and high resolution transmission electron microscope (HRTEM). The thermal stability of chitosan was substantially increased due to incorporation of stable silicon carbide nanopowder. The oxygen permeability of chitosan/SiC nanocomposites was reduced by three folds as compared to the virgin chitosan. The chemical resistance properties of chitosan were enhanced due to the incorporation of nano SiC. The biodegradability was investigated using sludge water. The tensile strength of chitosan/SiC nanocomposites was increased with increasing percentage of SiC. The substantial reduction in oxygen barrier properties in combination with increased thermal stability, tensile strength and chemical resistance properties; the synthesized nanocomposite may be suitable for packaging applications. PMID- 26428101 TI - Immunomodulatory activity on macrophage of a purified polysaccharide extracted from Laminaria japonica. AB - In this work, a novel water-soluble homogeneous polysaccharide (LJP-31) with a molecular mass of 2.24 * 10(6) Da was isolated and purified from Laminaria japonica using DEAE-cellulose and Sephacryl S500 chromatography. Results showed that LJP-31 mainly consists of arabinose, mannose, glucose and galactose in a molar ratio of 1.0:7.8:6.6:0.8. LJP-31 exhibited significant stimulation on macrophages and enhanced the production of NO, TNF-alpha, IL-1beta, IL-6 and IL 10 as well as the up-regulation of their gene expressions. Western blot analysis suggested that LJP-31 has the positive effects on the translocation of NF-kappaB p65 from cytoplasm to nucleus and the phosphorylation of IkappaBalpha, ERK1/2, JNK1/2 and P38 in macrophages. Flow cytometric and confocal laser-scanning microscopy analysis indicated that toll-like receptor 4 (TLR4) was at least one of the recognition receptors of LJP-31 on the plasma membrane of macrophages. Taken together, LJP-31 may exert its immunostimulating potency via TLR4 activation of MAPK and NF-kappaB signaling pathways. PMID- 26428102 TI - pH Effects on solubility, zeta potential, and correlation between antibacterial activity and molecular weight of chitosan. AB - Six chitosans with molecular weights (MWs) of 300, 156, 72.1, 29.2, 7.1, and 3.3 kDa were prepared by cellulase degradation of chitosan (300 kDa) and ultrafiltration techniques. We examined the correlation between activity against Escherichia coli and Staphylococcus aureus and chitosan MW, and provided the underlying explanation. In acidic pH conditions, the chitosan activity increased with increasing MW, irrespective of the temperature and bacteria tested. However, at neutral pH, chitosan activity increased as the MW decreased, and little activity was observed for chitosans with MW >29.2 kDa. At pH 5.0 and 6.0, chitosans exhibited good water solubility and zeta potential (ZP) decreased with the MW, whereas the solubility and ZP of the chitosans decreased with increasing MW at pH 7.0. Particularly, low solubility and negative ZP values were determined for chitosans with MW >29.2 kDa, which may explain the loss of their antibacterial activity at pH 7.0. PMID- 26428103 TI - Investigations of bisacodyl with modified beta-cyclodextrins: Characterization, molecular modeling, and effect of PEG. AB - Bisacodyl inclusion into hydroxypropyl-beta-cyclodextrin and 2,6-di-O-methyl-beta cyclodextrin cavities was experimentally and theoretically investigated, and the effect of PEG 4000 on these inclusions was studied. Isothermal calorimetry titration curves indicated that the binary inclusion processes are enthalpy- and entropy-driven. The solid-state complexes were fully characterized by FT-IR, XRPD, DSC and SEM analyses. FT-IR, (1)H NMR, and ROESY studies provided the most favorable encapsulation modes of binary complexes, and results were further confirmed by molecular docking and molecular dynamics studies. The presence of PEG 4000 slightly enhanced encapsulation efficiency, solubility and dissolution rates of the binary complexes. In vivo studies showed that complexes with CDs markedly accelerated gastrointestinal transit time compared with pure bisacodyl, whereas addition of PEG 4000 showed no further significant improvement of the bioavailability. PMID- 26428104 TI - Effect of the molecular architecture on the thermosensitive properties of chitosan-g-poly(N-vinylcaprolactam). AB - A series of thermoresponsive copolymers based on chitosan-g-poly(N vinylcaprolactam) were synthesized by amidation reaction using 4-(4,6-dimethoxy 1,3,5-triazin-2-yl)-4-methylmorpholinium chloride as coupling reagent. The effect of molecular architecture on the thermoresponsive properties of the graft copolymers solutions was studied by varying the chain length of the grafted poly(N-vinylcaprolactam), PVCL, (in the range from 4 to 26 kDa) and the spacing between grafted chains onto the chitosan backbone. The most interesting characteristic of these copolymers is their solubility in water at temperatures below their lower critical solution temperature (LCST). These solutions presented a LCST between 36 and 44 degrees C, which decreases with the spacing and length of grafted PVCL chains onto the chitosan backbone, in contrast with the limited decrease of the LCST of PVCL above a critical M-n value around 18 kDa. This behavior offers tangible possibilities for the preparation and application of sensitive bioactive formulations and "smart" drug delivery systems. PMID- 26428105 TI - Study of quantitative interactions of potato and corn starch granules with ions in diluted solutions of heavy metal salts. AB - Interactions of potato and corn starch granules with ions in diluted solutions of silver, lead, copper or iron salts were investigated. It was shown experimentally that granules accumulated the cations in amounts depending on the granule structure and water content as well as a type of both metal and counter-ions present in solution. Potato starch retained almost three times more cations compared to corn starch what was proportional to the total phosphorous content in these starches. Quantity of milligrams of cations bound by 1g of starch was inversely correlated with the cation hydration. Ag(+), Pb(2+) and Cu(2+) were connected in stoichiometric amounts of moles to semicrystalline and amorphous parts of the granules. Fe(3+) ions were accumulated in higher than stoichiometric quantities mainly in granule amorphous regions. Metal ions penetrated into granules together with anions except nitrates which remained on surface of potato starch granules. Cations facilitated the starch thermal decomposition in accordance with values of their standard redox potentials. Nitrates supported this process only in the presence of base metal cations. PMID- 26428106 TI - The role of nanocrystalline cellulose on the microstructure of foamed castor-oil polyurethane nanocomposites. AB - Nanocrystalline cellulose (CNC), obtained by sulphuric acid hydrolysis, was used to synthesize polyurethane foams (PUFs) based on a functionalized castor oil polyol and a Methylene diphenyl diisocyanate (MDI). Formulations with varying isocyanate index (FI) and NCO number were prepared. At 0.5 wt.%, SEM's of the fractured surface underlined that the CNC acted both as a nucleation agent and as a particulate surfactant with cell geometries and apparent density changing selectively. The chemical structure of the PUF (FTIR) changed after the incorporation of CNC by a relative change of the amount of urea, urethane and isocyanurate groups. A low NCO number and isocyanate index contributed to the migration of the CNC to the Hard Segment (HS), acting as reinforcement and improving substantially the compressive mechanical properties (Ec and sigmac improvements of 63 and 50%, respectively). For a high NCO number or isocyanate index, the CNC migrated to the Soft Segment (SS), without causing a reinforcement effect. The migration of the CNC was also detected with DSC, TGA and DMA, furtherly supporting the hypothesis that a low NCO number and index contributed both to the formation of a microstructure with a higher content of urethane groups. PMID- 26428107 TI - Interactions between soy protein from water-soluble soy extract and polysaccharides in solutions with polydextrose. AB - This study focuses on the investigation of the interactions between polysaccharides (carrageenan and carboxymethylcellulose--CMC) and soy proteins from the water-soluble soy extract. The influence of pH (2-7) and protein polysaccharide ratio (5:1-40:1) on the interaction between these polyelectrolytes was investigated in aqueous solutions with 10% of polydextrose and without polydextrose. The studied systems were analyzed in terms of pH-solubility profile of protein, zeta-potential, methylene blue-polysaccharide interactions, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and confocal laser scanning microscopy. Although the mixtures of soy extract with both carrageenan and CMC showed dependency on the pH and protein polysaccharide ratio, they did not present the same behavior. Both polysaccharides modified the pH-solubility profile of the soy protein, shifting the pH range in which the coacervate is formed to a lower pH region with the decrease of the soy extract-polysaccharide ratio. The samples also presented detectable differences regarding to zeta-potential, DSC, FTIR and microscopy analyses. The complex formation was also detected even in a pH range where both biopolymers were net-negatively charged. The changes promoted by the presence of polydextrose were mainly detected by blue-polysaccharide interactions measures and confocal microscopy. PMID- 26428108 TI - Application of carboxymethylcellulose hydrogel based silver nanocomposites on cotton fabrics for antibacterial property. AB - In this study, fumaric acid (FA) crosslinked carboxymethylcellulose (CMC) hydrogel (CMCF) based silver nanocomposites were coated on cotton fabric for antibacterial property for the first time. The performance of the nanocomposite treated cotton fabric was tested for different mixing times of hydrogel solution, padding times and concentrations of silver. The cotton fabrics treated with CMC hydrogel based silver nanocomposites demonstrated 99.9% reduction for both Staphylococcus aureus (Sa) and Klebsiella pneumonia (Kp). After one cycle washing processes of treated cotton fabric, there is no significant variation observed in antibacterial activity. From SEM and AFM analyses, silver particles in nano-size, homogenously distributed, were observed. The treated samples were also evaluated by tensile strength, thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR) analysis, fluid absorbency properties, and whiteness index. The treatment of cotton fabric with CMCF hydrogel did not affect the whiteness considerably, but increased the absorbency values of cotton. PMID- 26428109 TI - How copper corrosion can be retarded--New ways investigating a chronic problem for cellulose in paper. AB - To better assess the stabilization effects of chemical treatments on Cu(II) catalyzed cellulose degradation, we developed Cu(II)-containing model rag paper with typical copper corrosion characteristics using e-beam radiation. The paper can be prepared homogeneously and quickly compared to tedious pre-aging methods. Using the Cu(II)-containing model rag paper, the stabilization effects of various chemicals on Cu(II)-catalyzed degradation of cellulose were tested. Benzotriazol was highly effective in retarding the degradation of the Cu(II)-containing model rag paper under hot and humid aging condition, as well as under photo-oxidative stress. Tetrabutylammonium bromide reduced Cu(II)-catalyzed degradation of cellulose, but its efficacy was dependent on the accelerated aging conditions. The results with the alkaline treatments and gelatin treatment suggested that their roles in the degradation mechanisms of cellulose in the presence of Cu(II) differ from those of benzotriazol and tetrabutylammonium bromide. PMID- 26428110 TI - Synthesis of well-dispersed magnetic CoFe2O4 nanoparticles in cellulose aerogels via a facile oxidative co-precipitation method. AB - With the increasing emphasis on green chemistry, it is becoming more important to develop environmentally friendly matrix materials for the synthesis of nanocomposites. Cellulose aerogels with hierarchical micro/nano-scale three dimensional network beneficial to control and guide the growth of nanoparticles, are suitable as a class of ideal green nanoparticles hosts to fabricate multifunctional nanocomposites. Herein, a facile oxidative co-precipitation method was carried out to disperse CoFe2O4 nanoparticles in the cellulose aerogels matrixes, and the cellulose aerogels were prepared from the native wheat straw based on a green NaOH/polyethylene glycol solution. The mean diameter of the well-dispersed CoFe2O4 nanoparticles in the hybrid aerogels is 98.5 nm. Besides, the hybrid aerogels exhibit strong magnetic responsiveness, which could be flexibly actuated by a small magnet. And this feature also makes this class of magnetic aerogels possibly useful as recyclable adsorbents and some magnetic devices. Meanwhile, the mild green preparation method could also be extended to fabricate other miscellaneous cellulose-based nanocomposites. PMID- 26428111 TI - Production of a low molecular weight heparin using recombinant glycuronidase [corrected]. AB - The Delta4,5 unsaturated uronate (4-deoxy-alpha-l-threo-hex-4-eno-pyranosyluronic acid) residue is produced through the depolymerization of heparin, heparosan, and heparan sulfate with heparin lyases. The recovery of unsaturated uronate containing products is necessary to prepare low molecular weight heparin (LMWH) from heparin or heparosan. In this study, the gene of Delta4,5 and Delta4,5(Delta20) unsaturated glycuronidase (EC# 3.2.1.56) from Pedobacter heparinus (formerly Flavobacterium heparinum) was cloned into pMAL-c2x plasmid. Its fusion protein with MBP was expressed in Escherichia coli TB1. After purification, Delta4,5 unsaturated glycuronidase was evaluated. The Delta4,5(Delta20) glycuronidase showed excellent activity on the unsaturated bonds of the different depolymerized products from Hep I, Hep II, and Hep III on heparin, heparosan, and heparan sulfate. PMID- 26428112 TI - Synthesis, characterization, and controlled release of selenium nanoparticles stabilized by chitosan of different molecular weights. AB - Chitosan-stabilized selenium nanoparticles (SeNPs) have been reported, but there is no information on the effect of the chitosan molecular weight on the structure, stability, and selenium release properties of the SeNPs. Herein, we compared the uniform Se(0) spherical nanoparticles prepared through the reduction of seleninic acid with ascorbic acid in the presence of chitosan with different molecular weights (Mws). We found that both low and high molecular weight chitosan-stabilized selenium nanoparticles exhibited core-shell microstructures with a size of about 103 nm after 30 days growing through the "bottom-up approach" and "top-down approach," respectively. Moreover, both chitosan SeNPs processed excellent stability towards pH and enzyme treatment. In contrast, selenium was easily released to different extents from these two chitosan SeNPs upon treatment with different free radicals. This makes these materials potentially useful as oral antioxidant supplements. PMID- 26428113 TI - Gum arabic-curcumin conjugate micelles with enhanced loading for curcumin delivery to hepatocarcinoma cells. AB - Curcumin is conjugated to gum arabic, a highly water soluble polysaccharide to enhance the solubility and stability of curcumin. Conjugation of curcumin to gum arabic is confirmed by (1)H NMR, fluorescence and UV spectroscopy studies. The conjugate self assembles to spherical nano-micelles (270 +/- 5 nm) spontaneously, when dispersed in aqueous medium. Spherical morphology of the self assembled conjugate is evidenced by field emission scanning electron microscopy and transmission electron microscopy. The self assembly of the amphiphilic conjugate into micelle in aqueous medium significantly enhances the solubility (900 fold of that of free curcumin) and stability of curcumin in physiological pH. The anticancer activity of the conjugate micelles is found to be higher in human hepatocellular carcinoma (HepG2) cells than in human breast carcinoma (MCF-7) cells. The conjugate exhibits enhanced accumulation and toxicity in HepG2 cells due to the targeting efficiency of the galactose groups present in gum arabic. PMID- 26428114 TI - A molecular modeling approach to understand the structure and conformation relationship of (GlcpA)Xylan. AB - The structure and conformation relationships of a heteropolysaccharide (GlcpA)Xylan in terms of various molecular weights, Xylp/GlcpA ratio and the distribution of GlcpA along xylan chain were investigated using computer modeling. The adiabatic contour maps of xylobiose, XylpXylp(GlcpA) and (GlcpA)XylpXylp(GlcpA) indicated that the insertion of the side group (GlcpA) influenced the accessible conformational space of xylobiose molecule. RIS Metropolis Monte Carlo method indicated that insertion of GlcpA side chain induced a lowering effect of the calculated chain extension at low GlcpA:Xylp ratio (GlcpA:Xylp = 1:3). The chain, however, became extended when the ratio of GlcpA:Xylp above 2/3. It was also shown that the spatial extension of the polymer chains was dependent on the distribution of side chain: the random distribution demonstrated the most flexible structure compared to block and alternative distribution. The present studies provide a unique insight into the dependence of both side chain ratio and distribution on the stiffness and flexibility of various (GlcpA)Xylan molecules. PMID- 26428115 TI - Coloration of cotton fibers using nano chitosan. AB - A method of coloration of cotton fabrics with nano chitosan is proposed. Nano chitosan were prepared using crab shell chitin nanofibers through alkaline deacetylation process. Average nano fiber diameters of nano chitosan were 18 nm to 35 nm and the lengths were in the range of 0.2-1.3 MUm according to the atomic force microscope study. The degree of deacetylation of the material was found to be 97.3%. The prepared nano chitosan dyed using acid blue 25 (2 anthraquinonesulfonic acid) and used as the coloration agent for cotton fibers. Simple wet immersion method was used to color the cotton fabrics by nano chitosan dispersion followed by acid vapor treatment. Scanning electron microscope and atomic force microscope study of the treated cotton fiber revealed that the nano chitosan were consistently deposited on the cotton fiber surface and transformed in to a thin polymer layer upon the acid vapor treatment. The color strength of the dyed fabrics could be changed by changing the concentration of dyed nano chitosan dispersion. PMID- 26428116 TI - Arsenic(V) sorption using chitosan/Cu(OH)2 and chitosan/CuO composite sorbents. AB - The removal of As(V) ions from aqueous solution was carried out using composite sorbents based on chitosan (as the encapsulating material) and Cu(OH)2 or CuO. The sorbents were characterized using SEM, EDX and Zeta potential analysis. Sorption uptake was highly dependent on pH, temperature, initial As(V) concentration and sorbent dosage (SD): the optimum initial pH for arsenic removal was found close to 4. The sorption isotherm was described by the Langmuir equation. The metal ion can be bound through two different sorption sites: one having a strong affinity for As(V) (probably Cu(OH)2 or CuO) and the other having a lower affinity (probably the encapsulating material). The uptake kinetics was well fitted by the pseudo-second order rate equation. The effect of temperature was also evaluated, verifying the endothermic nature of the sorption process. Arsenic elution was performed using a saline solution (30 g L(-1) NaCl) at pH 12. The recycling of the sorbent was tested, maintaining a removal efficiency and a metal recovery over 95% for five successive sorption/desorption cycles. PMID- 26428117 TI - Enhancement of thermoplastic starch final properties by blending with poly(E caprolactone). AB - Final properties of two thermoplastic corn starch matrices were improved by adding poly(E-caprolactone), PCL, at 2.5, 5, and 10% w/w. One of the thermoplastic starch matrices was processed using water and glycerol as plasticizers (SG) and the other one was plasticized with a mixture of glycerol and sodium alginate (SGA). Blends were suitably processed by melt mixing and further injected. Films obtained by thermo-compression were flexible and easy to handle. Microstructure studies (SEM and FTIR) revealed a nice distribution of PCL within both matrices and also a good starch-PCL compatibility, attributed to the lower polyester concentration. The crystalline character of PCL was the responsible of the increment in the degree of crystallinity of starch matrices, determined by XRD. Moreover, it was demonstrated by TGA that PCL incorporation did not affect the thermal stability of these starch-based materials. In addition, a shift of Tg values of both glycerol and starch-rich phases to lower values was determined by DSC and DMA tests, attributed to the PCL plasticizing action. Besides, PCL blocking effect to visible and UV radiations was evident by the incremented opacity and the UV-barrier capacity of the starch films. Finally, water vapor permeability and water solubility values were reduced by PCL incorporation. PMID- 26428118 TI - Quince seed mucilage magnetic nanocomposites as novel bioadsorbents for efficient removal of cationic dyes from aqueous solutions. AB - This study investigated the potential use of quince seed mucilage (QSM) as alternative bioadsorbents for methylene blue (MB) dye from aqueous solutions. This novel magnetic nanocomposite adsorbent (MNCA) based on QSM was synthesized by in situ formation of magnetic iron oxide nanoparticles into QSM solution. The MNCAs were characterized using FTIR, SEM, TEM, XRD, and VSM. Removal of MB was investigated by batch adsorption technique. The thermodynamic parameters suggest that the dye adsorption process is spontaneous and exothermic in nature. Moreover, the adsorbents showed high selectivity for the adsorption of cationic dyes with regenerated properties. The pseudo-second-order kinetics and Langmuir adsorption isotherm models also provide the best correlation of the experimental data for MB adsorption. The results indicate that the MNCAs can be employed as efficient low cost adsorbents with excellent dye adsorption performance in wastewater treatment process. PMID- 26428119 TI - Physical, antioxidant and structural characterization of blend films based on hsian-tsao gum (HG) and casein (CAS). AB - The effects of hsian-tsao gum (HG) addition on the physical properties, antioxidant activities and structure of casein (CAS) film have been investigated. It has been observed that HG addition provided CAS film with better mechanical properties and resistant to moisture, stronger barrier properties against light and higher antioxidant activities than pure CAS film. Fourier transformation infrared (FTIR) data indicated that hydrogen bonding interactions and Maillard reactions occurred between CAS and HG, giving rise to a more compact structure than CAS film. The results of X-ray diffraction and differential scanning calorimetry (DSC) indicated that CAS and HG were compatible, and addition of HG destroyed the original crystalline domains of CAS film, and the blend films exhibited higher glass transition temperatures than CAS film. Moreover, nuclear magnetic resonance (NMR) analysis showed that HG addition significantly changed the mobility of water molecule in CAS film. Especially, ratio of the high mobility water of CAS/HG films significantly decreased as compared to CAS film. PMID- 26428120 TI - Modification of the cellulosic component of hemp fibers using sulfonic acid derivatives: Surface and thermal characterization. AB - The aim of this study was to characterize the surface, morphological, and thermal properties of hemp fibers treated with two commercially available, inexpensive, and water soluble sulfonic acid derivatives. Specifically, the cellulosic component of the fibers were targeted, because cellulose is not easily removed during chemical treatment. These acids have the potential to selectively transform the surfaces of natural fibers for composite applications. The proposed method proceeds in the absence of conventional organic solvents and high reaction temperatures. Surface chemical composition and signature were measured using gravimetric analysis, X-ray photoelectron spectroscopy (XPS) and Fourier transform infra-red spectroscopy (FTIR). XPS data from the treated hemp fibers were characterized by measuring the reduction in O/C ratio and an increase in abundance of the C-C-O signature. FTIR confirmed the reaction with the emergence of peaks characteristic of disubstituted benzene and amino groups. Grafting of the sulfonic derivatives resulted in lower surface polarity. Thermogravimetric analysis revealed that treated fibers were characterized by lower percent degradation between 200 and 300 degrees C, and a higher initial degradation temperature. PMID- 26428121 TI - Characterization of nanocellulose reinforced semi-interpenetrating polymer network of poly(vinyl alcohol) & polyacrylamide composite films. AB - Semi-interpenetrating polymer network (semi-IPN) of poly(vinyl alcohol)/polyacrylamide was reinforced with various doses of nanocellulose. The different composite films thus prepared were characterized with respect to their mechanical, thermal, morphological and barrier properties. The composite film containing 5 wt.% of nanocellulose showed the highest tensile strength. The semi interpenetrating polymer network of poly(vinyl alcohol)/polyacrylamide; and its various composites with nanocellulose were almost identical in their thermal stability. Each of the composites however exhibited much superior stability with respect to the linear poly(vinyl alcohol) and crosslinked polyacrylamide. The scanning electron microscopy (SEM) and atomic force microscopy (AFM) studies exhibited phase separated morphology where agglomerates of nanocellulose were found to be dispersed in the matrix of the semi-IPN. The moisture vapor transmission rate (MVTR) was the lowest for the film containing 5 wt.% of nanocellulose. PMID- 26428122 TI - Application of Celluclast 1.5L in apple pectin extraction. AB - Pectins were extracted from apple pomace with Celluclast 1.5L at a dose of 25, 50 and 75 MUl per 1g of material. In obtained pectin, the galacturonic acid (GalA) content, the neutral sugars (NS) profile, the degree of methylation (DM) and acetylation (DAc), the molecular mass, protein, ash and polyphenol levels as well as antioxidant and antitumor activity were determined. The lowest dose of enzymatic preparation resulted in the yield of pectin isolation comparable with acidic treatment (15.3%). Application of higher dose caused further, almost 4% increase in polymer recovery. Enzymatically isolated pectin was characterised by larger molecular mass and contained more GalA of higher DM and DAc than polymer extracted with acid. It was also richer in protein and polyphenols, and had different NS profile, which resulted in higher antiradical activity as well as the ability to inhibit the proliferation and invasion of Caco-2 adenocarcinoma cells. PMID- 26428123 TI - Bark derived submicron-sized and nano-sized cellulose fibers: From industrial waste to high performance materials. AB - In this study, the use of bark as a natural source for the production of cellulose nanofibers has been explored for the first time. The fibrillation using bleached and unbleached cellulose fibers from the bark yielded sub-micron scale (<1 MUm) and nanoscale fibers (<100 nm). Previous attempts to break the cross linked lignin barrier to produce fibrillated submicron sized or nano sized cellulose fibers with high lignin content (>20%) have never been possible from any other sources. The maximum elastic modulus value of 15.6 GPa and tensile strength value of 76 MPa were obtained for the films made from fibrillated bark cellulose fibers. The water vapour barrier efficiency for these films is comparable to nanocellulose films from other studies. PMID- 26428124 TI - Robust and biodegradable polymer of cassava starch and modified natural rubber. AB - The application of starch based materials for packaging purposes has attracted significant interest because they are both cheap and renewable resources. The study investigated the preparation and properties of a novel biopolymer sheet produced from a blend of maleated epoxidized natural rubber (MENR) and natural rubber-g-cassava starch (NR-g-CSt). The water resistance, toluene resistance and elongation at break of the polymer blend were enhanced after the addition of the MENR compared to pristine NR-g-CSt. The maximum tensile strength and thermal stability of the NR-g-CSt/MENR blend were found in the 100:50 NR-g-CSt:MENR blend. The novel films demonstrated good biodegradability in soil. PMID- 26428125 TI - Ultrasonic mediated production of carboxymethyl cellulose: Optimization of conditions using response surface methodology. AB - In the present research the optimization of ultrasound-mediated production of carboxymethyl cellulose under microwave irradiation, towards achieving reduction of chemicals, time of reaction and energy was carried out. Cellulose was extracted and treated by environmentally friendly chlorine free bleaching method using hydrogen peroxide. Produced alpha-cellulose was characterized using Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and thermogravimetric/differential thermal analysis (TG/DTA). Response Surface Methodology (RSM) was used to optimize the preparation of carboxymethyl cellulose (CMC). Highest degree of substitution 0.74 was obtained at 240 W ultrasonic power for 37 min followed by etherification at 490 W microwave power for 12 min. Results show that the preparation of CMC from cotton linter using ultrasound and microwave energy can reduce the processing time, chemicals and energy consumption. Additionally, X-ray analysis shows that the ultrasonic energy is able to break cellulose crystals into smaller parts compared to other methods. SEM photographs showed that this treatment is able to remove impurities from raw material. PMID- 26428126 TI - Effects of pH and temperature on colloidal properties and molecular characteristics of Konjac glucomannan. AB - The hydrocolloidal characteristics of Konjac glucomannan (KGM) are important for its application as a thickening and gelling agent for liquid foods. In this study, the rheological behavior and molecular properties such as molar mass, hydrodynamic radius and chain conformation of KGM in water were determined at various pH levels (4.0-10.0) during heating from 20 to 80 degrees C. Acidic and neutral conditions (pH 4.0-7.0) promoted the dispersion of KGM, and alkaline condition at pH 10 favored its aggregation in water, while KGM maintained a random coil conformation in the whole pH range. Associated with the pH effects were changes in the rheological behavior during heating from 20 to 80 degrees C. The significant differences in the colloidal and rheological characteristics were mainly attributed to alteration of intermolecular interaction (attractive or repulsive) rather than deacetylation at various pH levels. Deacetylation occurred in both acidic and alkaline condition. The second virial value was positive in acidic and negative in alkaline condition. The results showed that hydrocolloidal characteristics of KGM in water were significantly affected by pH. PMID- 26428127 TI - alpha,beta-Unsaturated aldehyde of hyaluronan--Synthesis, analysis and applications. AB - Hyaluronic acid (HA) modified with an aldehyde group (HA-CHO or HA-aldehyde) has been extensively used for various biomedical applications. The main advantage of the aldehyde moieties is the ability to react with a wide range of amino compounds under physiological conditions. Reactions of aldehydes with primary amines in water are reversible and equilibrium is thoroughly shifted towards starting aldehyde and amine. This work presents an unique modification of HA: alpha,beta-unsaturated aldehyde of HA (4,5-anhydro-6(GlcNAc)-oxo HA or DeltaHA CHO), which allows the primary amines to be attached to HA more effectively in comparison to the saturated HA-CHO. Higher hydrolytic stability is caused by the conjugation of imine with an adjacent --C=C-- double bond. Two strategies for the preparation of unsaturated HA-aldehyde were developed and chemical structures were studied in details. Cross-linked materials prepared from this precursor are biocompatible and suitable for applications in drug delivery and regenerative medicine. PMID- 26428128 TI - Pharmaceutical grade chondroitin sulfate: Structural analysis and identification of contaminants in different commercial preparations. AB - The aim of the present study was to characterize 16 pharmaceutical grade chondroitin sulfate (CS) samples, concerning the structure and presence of contaminants, in comparison to USP and analytical grade CS. Agarose gel electrophoresis has shown that only 5 samples were >90% CS, while 11 contained less than 15% CS. FACE (fluorophore-assisted carbohydrate electrophoresis) revealed that maltodextrin was the main contaminant in nine of them, and lactose in two. Raman spectroscopy corroborated these results. Concerning the structure of the CS present in the five CS-rich samples, the ratios 4-sulfated:6-sulfated disaccharides varied from 0.9 to 1.7, and their modal molecular weight was 20-29 kDa. Also, they were all contaminated by small amounts of keratan sulfate (<1%). In conclusion, our findings indicate that the composition of CS preparations not always corresponds to the manufacturers' descriptions, and indicate that further characterization should be required for the registry and license of pharmaceutical grade CS. PMID- 26428129 TI - A three-dimensionally chitin nanofiber/carbon nanotube hydrogel network for foldable conductive paper. AB - We reported a highly conductive nanocomposite made with multiwalled carbon nanotubes (MWCNTs) and chitin nanofibers (ChNFs). The MWCNTs were dispersed into ChNFs by the simple process of vacuum-filtration, forming a three-dimensional network structure. In this approach, MWCNT acted as a filler to introduce electron channel paths throughout the ChNF skeleton. And then, a hybrid hydrogel system (20 wt.% NaOH, -18 degrees C) was applied to prepare the ChNF/MWCNT gel film followed with drying process. It is found that the resultant ChNF/MWCNT gel film exposed much more MWCNT areas forming denser structure due to the shrinking of ChNFs after the gelation treatment. Compared with ChNF/MWCNT film, the one treated under hydrogel system (ChNF/MWCNT gel-film) exhibited almost twice higher conductivity (9.3S/cm for 50 wt.% MWCNTs in gel-film; whereas 4.7S/cm for 50 wt.% MWCNTs in film). Moreover, the facile and low-cost of this conductive paper may have great potential in development of foldable electronic devices. PMID- 26428130 TI - Modified hydroxyethyl starch protects cells from oxidative damage. AB - This article describes the synthesis of novel starch-antioxidant conjugates, which show great potential for biomedical applications to protect cells from oxidative damage. These conjugates were synthesized by the modification of a hydroxyethyl starch (molecular weight=200,000g/mol) with various sterically hindered phenols that differ in radical scavenging activity. They possess substantial radical scavenging activity toward a model free radical. It was found that the polymer conjugate conformation depends on the antioxidant structure and degree of substitution. We constructed the complete conformational phase behavior for the polymers with increasing degrees of substitution from small-angle neutron scattering data. It was observed that the conjugate conformation changes are the result of water shifting from a thermodynamically favorable solvent to an unfavorable one, a process that then leads to compaction of the conjugate. We selected the conjugates that possess high substitution degree but still exhibit coil conformation for biological studies. The high efficiency of the conjugates was confirmed by different in vitro (hypotonic hemolysis of erythrocytes/osmotic resistance of erythrocytes and the change of [Ca(2+)]i inside freshly isolated cardiomyocytes) and in vivo (acute hemorrhage/massive blood loss) methods. PMID- 26428131 TI - Agro-industrial residue from starch extraction of Pachyrhizus ahipa as filler of thermoplastic corn starch films. AB - Biocomposites films based on thermoplastic corn starch (TPS) containing 0.5% w/w fibrous residue from Pachyrhizus ahipa starch extraction (PASR) were obtained by melt-mixing and compression molding. PASR is mainly constituted by remaining cell walls and natural fibers, revealed by Scanning Electron Microscopy (SEM). Chemical composition of the residue indicated that fiber and starch were the principal components. Biocomposites thermo-stability was determined by Thermo Gravimetric Analysis. A continuous PASR-TPS interface was observed by SEM, as a result of a good adhesion of the fibrous residue to starch matrix. Likewise, films containing PASR presented fewer superficial cracks than TPS ones, whereas their fracture surfaces were more irregular. Besides, the presence of PASR increased starch films roughness, due to fibers agglomerates. Films reinforced with PASR showed significantly lower water vapor permeability (WVP). In addition, PARS filler increased maximum tensile strength and Young's modulus of TPS films, thus leading to more resistant starch matrixes. PMID- 26428132 TI - Central metabolic pathways of Aureobasidium pullulans CGMCC1234 for pullulan production. AB - With the purpose of understanding the metabolic network of Aureobasidium pullulans, the central metabolic pathways were confirmed by the activities of the key enzymes involved in different pathways. The effect of different iodoacetic acid concentrations on pullulan fermentation was also investigated in this paper. The activities of phosphofructokinases and glucose-6-phosphate dehydrogenase existed in A. pullulans CGMCC1234, whereas 2-keto-3-deoxy-6-phosphogluconate aldolase activity was not detected. We proposed that the central metabolic pathways of A. pullulans CGMCC1234 included EMP and PPP, but no ED. Pullulan production declined fast as the iodoacetic acid increased, while cell growth offered upgrade firstly than descending latter tendency. Compared to the control group, the ratio of ATP/ADP of 0.60 mM iodoacetic acid group was lower at different stages of pullulan fermentation. The findings revealed that low concentration of iodoacetic acid might impel carbon flux flow toward the PPP, but reduce the flux of the EMP. PMID- 26428133 TI - Super water-absorbing new material from chitosan, EDTA and urea. AB - A new, super water-absorbing, material is synthesized by the reaction between chitosan, EDTA and urea and named as CHEDUR. CHEDUR is probably formed through the crosslinking of chitosan molecules (CH) with the EDTA-urea (EDUR) adduct that is formed during the reaction. CHEDUR as well as the other products formed in control reactions are characterized extensively. CHEDUR exhibits a very high water uptake capacity when compared with chitosan, chitosan-EDTA adduct, as well as a commercial diaper material. A systematic study was done to find the optimum composition as well as reaction conditions for maximum water absorbing capacity. CHEDUR can play a vital role in applications that demand the rapid absorption and slow release of water such as agriculture, as a three in one new material for the slow release of urea, water and other metal ions that can be attached through the EDTA component. The other potential advantage of CHEDUR is that it can be expected to degrade in soil based on its chitosan backbone. The new material with rapid and high water uptake could also find potential applications as biodegradable active ingredient of the diaper material. PMID- 26428134 TI - Effects of crosslinking temperature and time on microstructure and stability of cassava starch microspheres. AB - Starch microspheres (SMs) were prepared by a water-in-water emulsion-crosslinking technique at 4 degrees C and 30 degrees C for 1, 6, 12 and 24h; the SMs obtained were analyzed for crosslinking density, morphology, crystalline structure, and stability against temperature, pH, and alpha-amylase hydrolysis. The crosslinking degree at 30 degrees C was considerably higher than that at 4 degrees C. SMs prepared at 4 degrees C for less than 12h incubation had larger size and more porous structure as compared with those prepared at 30 degrees C, but the morphology became comparable (spherical shape with smooth surface and dense structure) after 24h incubation. All SMs samples displayed amorphous structure. Stability tests revealed that the SMs were very stable under acidic and mild basic pH; however, stability against alpha-amylase hydrolysis varied depending on incubation temperature and time. PMID- 26428135 TI - Development of pH sensitive microparticles of Karaya gum: By response surface methodology. AB - The objective of the proposed work was to prepare pH sensitive microparticles (MP) of Karaya gum using distilled water as a solvent by spray drying technique. Different formulations were designed, prepared and evaluated by employing response surface methodology and optimal design of experiment technique using Design Expert((r)) ver 8.0.1 software. SEM photographs showed that MP were roughly spherical in shape and free from cracks. The particle size and encapsulation efficiency for optimized MP was found to be between 3.89 and 6.5 MUm and 81-94% respectively with good flow properties. At the end of the 12th hour the in vitro drug release was found to be 96.9% for the optimized formulation in pH 5.6 phosphate buffer. Low prediction errors were observed for Cmax and AUC0-infinity which demonstrated that the Frusemide IVIVC model was valid. Hence it can be concluded that pH sensitive MP of Karaya gum were effectively prepared by spray drying technique using aqueous solvents and can be used for treating various diseases like chronic hypertension, Ulcerative Colitis and Diverticulitis. PMID- 26428136 TI - Physicochemical and functional performance of pectin extracted by QbD approach from Tamarindus indica L. pulp. AB - The aim of present investigation was to utilize quality by design (QbD) approach for extraction of tamarind pectin (TP) from Tamarindus indica L. pulp employing purity descriptors as indicator. The software generated quadratic equations showed significant effect of polarity index as compared to pulp concentration and boiling temperature on percentage yield and purity characteristics of TP. An insignificant effect on purity descriptors and percentage yield of TP upon replacement of acetone with methanol during predicted vs observed correlation studies (being similar polarity index of 5.1) pointed towards overwhelming influence of solvent polarity. Further, the FTIR-ATR, (1)H NMR, DSC and mass spectroscopy suggested TP was rhamnogalacturonan pectin with no tartaric acid content. TP was found to have significantly higher antioxidant activity as compare to apple pomace pectin, citrus peel pectin and commercial pectin. Overall, the physicochemical properties and antioxidant potential of TP could be utilized as an excipient for food and pharmaceutical industry. PMID- 26428137 TI - A water soluble beta-glucan of an edible mushroom Termitomyces heimii: Structural and biological investigation. AB - A water soluble beta-glucan (PS-I) with an average molecular weight ~ 1.48 * 10(5)Da was isolated from the alkaline extract of an edible mushroom Termitomyces heimii. PS-I contained (1 -> 3)-, (1 -> 6)-, (1 -> 3, 6)-linked and terminal beta d-glucopyranosyl moieties in a ratio of nearly 2:1:1:1. Based on the total hydrolysis, methylation analysis, periodate oxidation, Smith degradation, partial hydrolysis and 1D/2D NMR experiments the structure of the PS-I was elucidated. On the basis of these experiments, the repeating unit of the polysaccharide was found to consist of a backbone chain of two (1 -> 6)-beta-D-glucopyranosyl residues, one of which was branched at O-3 position with the side chain consisting of two (1 -> 3)-beta-D-glucopyranosyl and a terminal beta-D glucopyranosyl residue. Cytotoxic effect of PS-I on human blood lymphocytes at varied concentrations was studied. Moreover, it also exhibited potent antioxidant activities by diminishing the ROS and NO in the nicotine stimulated lymphocytes up to 200 MUg/ml. PMID- 26428138 TI - Synthesis of surfactant-free hydroxypropylcellulose nanogel and its dual responsive properties. AB - Surfactant-free hydroxypropylcellulose (HPC) nanogels were synthesized by using thermo-sensitive HPC as a template to form HPC/PMAA nanoscale complex. The formation mechanism was owing to the interpolymer hydrogen bonding between HPC and PMAA induced phase transition of HPC in aqueous media. The average size of the resulting HPC nanogels ranges from about 98 to 241 nm. It was found that the average size of HPC nanogels changed little with increasing polymerization temperature below 26 degrees C, whereas it greatly increased above 26 degrees C. When the concentration of HPC was increased from 0.1 to 0.9 wt.%, the diameter of nanogels decreased firstly and then increased. Besides, an increasing crosslinker BIS concentration led to a reduced size of HPC nanogels, and the nanogels had the narrowest size distribution when its concentration was 0.1 wt.%. In addition to intrinsic thermo-sensitivity, HPC nanogels also display pH-induced phase transition due to pH-responsive PMAA contained in HPC nanogels. Surfactant free, dual-responsive HPC nanogels would have promising applications in biotechnology and nanomedicine. PMID- 26428139 TI - Carboxymethyl chitosan/clay nanocomposites and their copper complexes: Fabrication and property. AB - To obtain environmentally friendly antifouling agent, an effort was made to intercalate carboxymethyl chitosan into the interlayer of organic montmorillonite to prepare carboxymethyl chitosan/organic montmorillonite nanocomposites and their copper complexes. In comparison, carboxymethyl chitosan-copper complexes were also obtained. Their structures were characterized by X-ray diffaraction, transmittance electron microscopy and Fourier transform infrared, and their thermal behavior and antimicrobial activity were discussed. The results revealed that the interlayer distance of carboxymethyl chitosan/organic montmorillonite nanocomposites enlarged with the increasing mass ratio of carboxymethyl chitosan to organic montmorillonite, when the mass ratio was at 20:1, the layer spacing of carboxymethyl chitosan/organic montmorillonite nanocomposites reached the maximum of 3.68 nm. As compared to other samples, carboxymethyl chitosan/organic montmorillonite-copper nanocomposites showed much higher thermal stability and inhibitory activity against Escherichia coli, the lowest minimum inhibition concentration was only 0.0003125% (w/v). The study provides a new method to find novel antifouling agent. PMID- 26428140 TI - beta-Cyclodextrin associated polymeric systems: Rheology, flow behavior in porous media and enhanced heavy oil recovery performance. AB - This proof of concept research evaluates an approach to improve the enhanced heavy oil recovery performance of conventional polymers. Three associated polymeric systems, based on hydrolyzed polyacrylamide, xanthan gum, and a novel hydrophobic copolymer, were proposed in this work. The results of the theoretically rheology study indicate that these systems offer superior viscoelasticity and pronounced shear-thinning behavior due to the "interlocking effect". As a result of the surfactant collaboration, the dynamic interfacial tension between oil and polymer solution can be reduced by two orders of magnitude. Sandpack flooding tests demonstrated the capacity of the developed systems in mobility control during propagating in porous media, and the adsorption behavior was represented by the thickness of the adsorbed layer. The relationship between microscopic efficiency and capillary number indicated that the associated systems can significantly reduce the residual oil saturation due to the synergistic effect of the mobility reduction and surface activity, and the overall recovery efficiency was raised by 2-20% OOIP compared to the baseline polymers. PMID- 26428141 TI - Antitumor and immunomodulatory activity of a water-soluble polysaccharide from Grifola frondosa. AB - Grifola frondosa has long been known and respected as a medically important fungus. This study investigated the characterization, antitumor and immunomodulatory activity of a polysaccharide named GP11 purified from G. frondosa. The results revealed that GP11 was composed of -> 1)-D-Manp-(6 ->,-> 1) D-Glcp-(4 ->,-> 1)-D-Galp-(6 -> and -> 2,3,6)-D-Glcp-(1 ->, with branches attached at O-2,3 of 1,2,3,6-linked Glcp residues and terminal T-Glcp. GP11 exhibited indirect cytotoxic activity against HepG-2 cells in vitro, and it significantly inhibited the growth of Heps cells in vivo. GP11 increased the relative thymus and spleen weights as well as serum tumor necrosis factor-alpha and interleukin-2 levels. GP11 stimulated tumoricidal activity and the production of nitric oxide (NO), TNF-alpha and interleukin-1beta, and it also stimulated the protein expression of iNOS and mRNA expression of iNOS and TNF-alpha. TLR-4 is a potential receptor for GP11-mediated macrophage activation. The results suggested that the antitumor activity of GP11 may be due to the improvement of immune functions through the TLR-4-mediated up-regulation of NO and TNF-alpha. PMID- 26428142 TI - Inhibition of wheat starch retrogradation by tea derivatives. AB - The effect of four industrial tea derivatives (tea polyphenols [TPS], tea water soluble extracts [TSE], tea polysaccharides [TSS], and green tea powder [GTP]), on the retrogradation of wheat starch was investigated using texture profile analysis (TPA), differential scanning calorimetry (DSC), rapid viscosity analysis (RVA), and the alpha-amylase-iodine method. The addition of the four tea derivatives resulted in decreased hardness and increased cohesiveness of the starch gel as shown by the TPA test. The DSC data demonstrated an increase in the enthalpy change of starch gelatinization and a decrease in the enthalpy change of starch recrystallite dissociation. The RVA results indicated that the peak viscosity, representing the intermolecular forces of wheat starch, was reduced after addition of TPS, TSE, and TSS, respectively, but was increased by GTP. Furthermore, the half crystallization time in the Avrami equation almost doubled after the separate addition of the tea derivatives. PMID- 26428143 TI - Inulin, a flexible oligosaccharide. II: Review of its pharmaceutical applications. AB - Inulin is a flexible oligosaccharide which has been used primarily in food for decades. Recently new applications in the pharmaceutical arena were described. In a previous review (Mensink et al. (2015). Carbohydrate Polymers, 130, 405) we described the physicochemical characteristics of inulin, characteristics which make inulin a highly versatile substance. Here, we review its pharmaceutical applications. Applications of inulin that are addressed are stabilization of proteins, modified drug delivery (dissolution rate enhancement and drug targeting), and lastly physiological and disease-modifying effects of inulin. Further uses of inulin include colon specific drug administration and stabilizing and adjuvating vaccine formulations. Overall, the uses of inulin in the pharmaceutical area are very diverse and research is still continuing, particularly with chemically modified inulins. It is therefore likely that even more applications will be found for this flexible oligosaccharide. PMID- 26428144 TI - Characterization of new natural cellulosic fiber from Lygeum spartum L. AB - Integration of new natural fibers in polymer composites field can contribute to increase the production of natural reinforcements and expand their use into new applications. In the present work, new cellulosic fibers were extracted from Lygeum spartum L. plant using an eco-friendly method. The morphological, physico chemical, thermal and mechanical properties of L. spartum L. fibers were reported for the first time in this paper. The stem anatomy and fiber SEM micrographs showed a strong presence of fiber cells. ATR-FTIR and X-ray analysis proved that these fibers are rich in cellulose content with crystallinity index of 46.19%. The thermogravimetric analysis indicates that the L. spartum fibers are thermally stable until 220 degrees C with apparent activation energy of 68.77 kJ/mol. Young's modulus, tensile strength and strain at failure were determined from the single fiber tensile test as 13.2 GPa, 280 MPa, and 3.7% respectively. PMID- 26428145 TI - Antibacterial activity and in vitro evaluation of the biocompatibility of chitosan-based polysaccharide/polyester membranes. AB - The antibacterial activity and biocompatibility of membranes of poly(3 hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) and chitosan (CS) (PHBV)/CS) were evaluated in this study. Maleic anhydride (MA)-grafted polyhydroxyalkanoate (PHBV g-MA) was evaluated as an alternative to PHBV. Mouse tail skin fibroblasts (FBs) were seeded on two series of these films to assess cytocompatibility. Collagen and cell proliferation analyses indicated that PHBV, PHBV-g-MA and their composite membranes were biocompatible with respect to FB proliferation. However, FB proliferation, collagen production and the percentage of normal cells growing on PHBV/CS membranes were greater than those for PHBV-g-MA/CS membranes. Cell cycle and apoptosis assays by FBs on the PHBV-series membrane samples were not affected by DNA content related to damage; i.e. rapid apoptosis/necrosis was not observed, demonstrating the potential of PHBV/CS or PHBV-g-MA/CS membranes for biomedical material applications. Moreover, CS-based polysaccharide enhanced the Escherichia coli (BCRC 10239) antibacterial activity of the membranes. Membranes of PHBV-g-MA or PHBV containing CS-based polysaccharide had better antibacterial activity. PMID- 26428146 TI - Effect of granule size on the properties of lotus rhizome C-type starch. AB - Lotus rhizome C-type starch was separated into different size fractions. Starch morphologies changed from irregular to elongated, ellipsoid, oval, and spherical with decreasing granule size. The small- and very-small-sized fractions had a centric hilum, and the other size fractions had an eccentric hilum. The different size fractions all showed C-type crystallinity, pseudoplasticity and shear thinning rheological properties. The range of amylose content was 25.6 to 26.6%, that of relative crystallinity was 23.9 to 25.8%, that of swelling power was 29.0 to 31.4 g/g, and that of gelatinization enthalpy was 12.4 to 14.2J/g. The very small-sized fraction had a significantly lower short-range ordered degree and flow behavior index and higher scattering peak intensity, water solubility, gelatinization peak temperature, gelatinization conclusion temperature, consistency coefficient, hydrolysis degrees, and digestion rate than the large sized fraction. Granule size significantly positively influenced short-range ordered structure and swelling power and negatively influenced scattering peak intensity, water solubility, hydrolysis and digestion of starch (p<0.01). PMID- 26428147 TI - Ion-responsive liquid crystals of cellulose nanowhiskers grafted with acrylamide. AB - In order to develop a novel application for cellulose nanowhiskers (CNW) produced from the sulfuric acid hydrolysis of cotton, acrylamide (AM) was grafted onto the CNW. The graft reaction of the acrylamide-grafted CNW (AM-g-CNW) was confirmed by Fourier transform infrared spectroscopy (FTIR) and UV-vis spectroscopy. The carbon and nitrogen contents of the AM-g-CNW were measured by elemental analysis and X-ray photoelectron spectroscopy (XPS). The grafting ratios and average degrees of beta-1,4-linked anhydro-D-glucose unit substitution were measured. The thermochemical properties of the AM-g-CNW were characterized using thermogravimetric analysis (TG). The glass transition temperatures were determined by differential scanning calorimetry (DSC). The degrees of crystallinity were measured by X-ray diffraction (XRD). The liquid crystalline properties of AM-g-CNW were observed by polarizing optical microscopy (POM). AM-g CNW had the best grafting ratio, 12.77%, when the AM/CNW molar ratio was 3, c(K2S2O8)/n(CNW) was 0.15, the reaction temperature was 70 degrees C, and the reaction time was 60 min. The birefringence of AM-g-CNW was responsive to hydroxide ions, which might be useful in applications that benefit from sensitivity towards different ionic species. PMID- 26428148 TI - High-throughput and high-yield fabrication of uniaxially-aligned chitosan-based nanofibers by centrifugal electrospinning. AB - The inability to produce large quantities of nanofibers has been a primary obstacle in advancement and commercialization of electrospinning technologies, especially when aligned nanofibers are desired. Here, we present a high throughput centrifugal electrospinning (HTP-CES) system capable of producing a large number of highly-aligned nanofiber samples with high-yield and tunable diameters. The versatility of the design was revealed when bead-less nanofibers were produced from copolymer chitosan/polycaprolactone (C-PCL) solutions despite variations in polymer blend composition or spinneret needle gauge. Compared to conventional electrospinning techniques, fibers spun with the HTP-CES not only exhibited superior alignment, but also better diameter uniformity. Nanofiber alignment was quantified using Fast Fourier Transform (FFT) analysis. In addition, a concave correlation between the needle diameter and resultant fiber diameter was identified. This system can be easily scaled up for industrial production of highly-aligned nanofibers with tunable diameters that can potentially meet the requirements for various engineering and biomedical applications. PMID- 26428149 TI - Mechanically modified xanthan gum: Rheology and polydispersity aspects. AB - Xanthan gum solutions were treated with high-pressure homogenization (HPH) in order to provide alternative treatments to enzymatic and chemical modification of this carbohydrate. Rheological properties of the treated and control samples were investigated in detail to gain an understanding of functional consequences of physical modification. The molecular structural properties were investigated via Size exclusion chromatography (SEC) coupled with Multi-angle laser light scattering (MALLS) and Circular dichroism (CD). Structured network of xanthan gum solutions was lost gradually depending on the severity of the HPH treatment as evidenced by the observed changes in the viscosity and viscoelasticity of the treated solutions. Reduction in molecular weight and a significant increase in polydispersity of the polymer were the expected causes of these rheological changes. Observed increase in hydrodynamic volume upon HPH treatment was not surprising and attributed to the loss of structured networks. Changes in the rheological and structural characteristics of biopolymer were irreversible and significant recovery was not detected over a period of 11 weeks. PMID- 26428150 TI - Extrusion induced low-order starch matrices: Enzymic hydrolysis and structure. AB - Waxy, normal and highwaymen maize starches were extruded with water as sole plasticizer to achieve low-order starch matrices. Of the three starches, we found that only high-amylose extrudate showed lower digestion rate/extent than starches cooked in excess water. The ordered structure of high-amylose starches in cooked and extruded forms was similar, as judged by NMR, XRD and DSC techniques, but enzyme resistance was much greater for extruded forms. Size exclusion chromatography suggested that longer chains were involved in enzyme resistance. We propose that the local molecular density of packing of amylose chains can control the digestion kinetics rather than just crystallinity, with the principle being that density sufficient to either prevent/limit binding and/or slow down catalysis can be achieved by dense amorphous packing. PMID- 26428151 TI - Development of crosslinked methylcellulose hydrogels for soft tissue augmentation using an ammonium persulfate-ascorbic acid redox system. AB - Hydrogels composed of methylcellulose are candidate materials for soft tissue reconstruction. Although photocrosslinked methylcellulose hydrogels have shown promise for such applications, gels crosslinked using reduction-oxidation (redox) initiators may be more clinically viable. In this study, methylcellulose modified with functional methacrylate groups was polymerized using an ammonium persulfate (APS)-ascorbic acid (AA) redox initiation system to produce injectable hydrogels with tunable properties. By varying macromer concentration from 2% to 4% (w/v), the equilibrium moduli of the hydrogels ranged from 1.47 +/- 0.33 to 5.31 +/- 0.71 kPa, on par with human adipose tissue. Gelation time was found to conform to the ISO standard for injectable materials. Cellulase treatment resulted in complete degradation of the hydrogels within 24h, providing a reversible corrective feature. Co-culture with human dermal fibroblasts confirmed the cytocompatibility of the gels based on DNA measurements and Live/Dead imaging. Taken together, this evidence indicates that APS-AA redox-polymerized methylcellulose hydrogels possess properties beneficial for use as soft tissue fillers. PMID- 26428152 TI - Insights into the nucleation role of cellulose crystals during crystallization of poly(beta-hydroxybutyrate). AB - Cellulose crystals, including microcrystalline cellulose (MCC) and nanocrystalline cellulose (NCC), were used as the fillers to prepare green composites with poly(beta-hydroxybutyrate) (PHB) by melt mixing for crystallization study. The results reveal that the spherulite morphology of PHB and its composites depends highly on the crystallization temperature, evolving from bundle shaped to ring-banded and finally to irregular or zigzag textures with increase of temperature. However, the ring-banded structure is strongly affected by the presence of cellulose crystals, and the average band space decreases evidently with the addition of MCC or NCC. Compared with PHB/MCC composite, PHB/NCC composite shows degraded spherulite structure with smaller band space and higher flocculation level of peak-to-valley height because of stronger unbalanced stresses in this system. Besides, cellulose crystals can act as good heterogeneous nucleating agent to accelerate the crystallization of PHB, which is further confirmed by the polarized optical microscopy observations and the kinetic analyses. PMID- 26428153 TI - Influence of tiopronin, captopril and levamisole therapeutics on the oxidative degradation of hyaluronan. AB - The ability to protect hyaluronic acid (HA) from oxidative degradation by cupric ions and ascorbate (production of (*)OH and peroxy-type radicals) during acute phase joint inflammation has been investigated using the following drugs: tiopronin, captopril, and levamisole. Radical scavenging activity, i.e. the propensity for donation of electrons was assessed for the drugs by ABTS and DPPH assays. The kinetics of HA degradation have been measured in the presence of each drug using rotational viscometry. The results of ABTS and DPPH assays show the highest radical scavenging activity for captopril, followed by tiopronin. For levamisole, no effect was observed. Captopril and tiopronin prevented HA degradation induced by (*)OH radicals in a similar manner, while tiopronin was more effective in scavenging peroxy-type radicals. On the other hand, levamisole was shown to be a pro-oxidant. Recovered HA fragments were characterized using FT IR analysis, the incorporation of a sulphur atom from captopril and tiopronin but not from levamisole into the HA molecule was demonstrated. PMID- 26428154 TI - Complexation of pectin with macro- and microelements. Antianemic activity of Na, Fe and Na, Ca, Fe complexes. AB - New water-soluble pectin complexes with Ca(2+), Mg(2+), Co(2+), Cu(2+), Fe(2+), Mn(2+), Zn(2+) on the basis of pectin biopolymer have been synthesized and successfully tested on white rats. For a starting, we have obtained a sodium pectate to enhance solubility of target complexes as a whole. Shortly afterwards, running the reaction of ligand exchange of Na(+) ions with corresponding s-, d- metal cations we were able to synthesize new pectin complexes. The ranges of s-, d-metals salts concentrations were detected experimentally, in which the selective formation of water-soluble complexes occurred. Antianemic effect of new pectin complexes with Na, Fe and Na, Ca, Fe was investigated on white rats with posthemorrhagic anemia. Under the effect of complexes, the improvement of animals and prevention of erythropoiesis disorders were observed. Antianemic effect of the complexes manifested itself in the doses equivalent to 25% or 50% of the iron daily rate, recommended in the treatment of iron-deficiency anemia with the drugs based on iron sulphate. PMID- 26428155 TI - Isolation and characterization of cellulose nanocrystals from parenchyma and vascular bundle of oil palm trunk (Elaeis guineensis). AB - In this study cellulose nanocrystals were isolated through acid hydrolysis process from parenchyma and vascular bundle of oil palm trunk (Elaeis guineensis). The morphological properties of obtained cellulose nanocrystals were studied by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The microscopy images showed smoother and cleaner surface of parenchyma cellulose nanocrystals when compared to vascular bundle cellulose nanocrystals. The TEM image shows a higher length and diameter for parenchyma cellulose nanocrystals compared to vascular bundle cellulose nanocrystals. The Fourier transform infrared (FTIR) spectra showed changes in functional groups after acid hydrolysis due to removal of lignin, hemicelluloses and other impurities in both type of cellulose nanocrystals. Crystallinity index of cellulose nanocrystals was observed higher for vascular bundle as compared to parenchyma. Thermogravimetric analysis (TGA) was performed to study the thermal stability of cellulose nanocrystals and it was observed higher for parenchyma cellulose nanocrystals compared to vascular bundle. PMID- 26428156 TI - Macro-hydrogels versus nanoparticles by the controlled assembly of polysaccharides. AB - The controlled assembly of oppositely charged chitosan (CS, Mw ~ 33 * 10(3) to 600 * 10(3)g mol(-1)) and dextran sulfate (DS, Mw = 1.3 * 10(6)g mol(-1)) or heparin (HP, Mw = 1.8 * 10(4)g mol(-1)) led either to nanoparticles or macro hydrogels, at room temperature. The control over the electrostatic attractive interactions was achieved using 2 mol L(-1) NaCl in the polyion solutions and subsequent dialysis to let the assembly occur. Macrohydrogels formed with an excess of polyanion. In the presence of an excess of polycation, colloidal gels were exclusively obtained. At salt concentrations lower than 1 mol L(-1), the spontaneous gelation provided macro-hydrogels, whatever the polyion in excess. Rheology measurements showed a similar elastic behaviour for CS-DS and CS-HP hydrogels, though CS-HP hydrogels appeared less cohesive. SAXS experiments revealed an aggregate morphology with internal and surface structure depending on the degree of acetylation (DA) of chitosan. PMID- 26428157 TI - Inclusion complex of erlotinib with sulfobutyl ether-beta-cyclodextrin: Preparation, characterization, in silico, in vitro and in vivo evaluation. AB - The aim of the study was to investigate the impact of erlotinib sulfobutyl ether beta-cyclodextrin complex (ERL-SBE-beta-CD) on ERL dissolution rate and oral bioavailability. Preliminary comparative phase solubility study indicated ERL exhibited maximum solubility in SBE-beta-CD solution. Optimal experimental design confirmed freeze drying of SBE-beta-CD:ERL in 1:1.05 molar ratio as the optimum method. Differential scanning calorimetry (DSC), Fourier transformation infrared spectroscopy (FT-IR), powder X-ray diffractometry (PXRD), proton nuclear magnetic resonance ((1)H NMR) and two-dimensional rotating-frame Overhauser effect spectroscopy (2D ROESY NMR) confirmed the inclusion complexation. The in silico computational study, employed to analyze the comparative interactions of ERL with SBE-beta-CD and beta-CD, indicated ease of ERL-SBE-beta-CD complexation. In vitro dissolution and in vivo bioavailability studies further confirmed the ERL-SBE beta-CD as a valuable approach to enhance ERL oral bioavailability with 3.6-fold increase in relative oral bioavailability with higher Cmax (134.29 +/- 36.51 vs. 42.36 +/- 1.75 MUg/ml) and AUC0-infinity (2103.47 +/- 156.75 vs.580.43 +/- 71.91 MUg/ml h) over the free drug. The complex exhibited 3.2-fold increase in Cmax with 5.4-fold decrease in Tmax (0.5 +/- 0.2 vs. 2.7 +/- 0.8h) in comparison to pure ERL. Thus, ERL-SBE-beta-CD complexation exhibits a potential to enhance oral bioavailability of ERL leading to reduce dose and dose-related side effects. PMID- 26428158 TI - Functional chondroitin sulfate from Enteroctopus dofleini containing a 3-O-sulfo glucuronic acid residue. AB - There are several reports that chondroitin sulfate containing K-type units [GlcA (3S)-GalNAc (4S)] exhibiting similar levels of neurite outgrowth promoting activities as CS having high amounts of B-, D- and E-type disulfated disaccharides. Although CS containing K-type units possess important biological activities, there are only few sources, such as king crab cartilage, squid cartilage or sea cucumber. In this study, CS containing 13.9% of K-type units was found in octopus (Enteroctopus dofleini) cartilage using different substrate specificities of chondroitinases. The 2D NMR spectra showed cross-peaks assigned to protons on sugar ring of GlcA (3S), demonstrating the presence of K-type units in octopus CS. Furthermore, proportion of fucosylated disaccharide units in octopus CS was very low. Octopus CS showed high affinity for growth factors and stimulated neurite outgrowth of hippocampal neurons, similar to the activity of squid CS-E. These results strongly suggest that octopus cartilage is a rich source of CS-K and has important biological activities. PMID- 26428159 TI - Hydrodynamic behavior and dilute solution properties of Ulva fasciata algae polysaccharide. AB - Hydrodynamic behavior and dilute solution properties of Ulva fasciata polysaccharides (UFP) were investigated. Experimental results indicated that the variation of hydrodynamic behavior of UFP was affected by the type and concentration of salts. The specific viscosity of UFP in water increased with its increasing concentration. The slopes of the double logarithmic plots in the dilute and semi-dilute solutions were 0.86 and 1.99, respectively. The molecular conformation could be semi-flexible like. Huggins plots of UFP solutions in the presence of salts including Na(+), K(+), Mg(2+) and Ca(2+) showed that the hydrodynamic behavior of the UFP was strongly affected by the types and strength of salt ion. The stiffness parameter of UFP solution was 0.1149, higher than that of other reported polysaccharides, indicating that it could tolerate high salt concentration. Dynamic rheological results suggested that 0.5% UFP solution was a typical characteristic of polymer solution in the dilute region. This work provided some valuable and fundamental information in understanding the physicochemical properties of UFP solution. PMID- 26428160 TI - Pinhao starch and coat extract as new natural cosmetic ingredients: Topical formulation stability and sensory analysis. AB - The objective of this study was to use pinhao derivatives, starch and coat extract, as new natural ingredients to develop cosmetic formulations. Two types of formulation, gel and emulgel, and their controls were developed. The formulations were characterized by stability studies using thermal stress. The parameters analyzed were resistance to centrifugation, pH, spreadability, rheology, content of phenolic compounds and antioxidant activity. Sensory analysis was also performed to verify the acceptability of the ingredients to potential consumers. The pH was kept the same after heating/freezing cycles for all formulations, and the formulations showed stability by resistance to centrifugation. The formulations did not induce any skin irritation or cutaneous pH alteration. The pinhao starch addition improved spreadability stability and increased viscosity when compared with control formulations. The pinhao coat extract used in these formulations is a good source of phenolic compounds and antioxidant activity. Moreover, sensory analysis indicates that the emulgel formulation is the best vehicle for adding pinhao starch and pinhao coat extract. PMID- 26428161 TI - Chemical isolation and characterization of different cellulose nanofibers from cotton stalks. AB - Recently, cellulose nanofibers (CNFs) have received wide attention in green nanomaterial technologies. Production of CNFs from agricultural residues has many economic and environmental advantages. In this study, four different CNFs were prepared from cotton stalks by different chemical treatments followed by ultrasonication. CNFs were prepared from untreated bleached pulp, sulfuric acid hydrolysis, and TEMPO [(2,2,6,6-tetramethylpiperidin-1-yl) oxy radical]-mediated oxidation process. Physical and chemical properties of the prepared CNFs such as morphological (FE-SEM, AFM), structural (FTIR), and thermal gravimetric analysis (TGA) were investigated. Characterization results clearly showed that the method of preparation results in a significant difference in the structure, thermal stability, shape and dimensions of the produced CNFs. TEMPO-mediated oxidation produced brighter and higher yields (>90%) of CNFs compared to other methods. FE SEM and AFM analysis clearly indicated that, TEMPO-mediated oxidation produced uniform nano-sized fibers with a very small diameter (3-15 nm width) and very small length (10-100 nm). This was the first time uniform and very small nanofibers were produced. PMID- 26428162 TI - Review on complement analysis method and the roles of glycosaminoglycans in the complement system. AB - Complement system is composed of over 30 proteins and it plays important roles in self-defence and inflammation. There are three activation pathways, including classical pathway, alternative pathway and lectin pathway, in complement system, and they are associated with many diseases such as osteoarthritis and age-related macular degeneration. Modulation of the complement system may be a promising strategy in the treatment of related diseases. Glycosaminoglycans are anionic linear polysaccharides without branches. They are one kind of multi-functional macromolecules which have great potential in regulating complement system. This review is organized around two aspects between the introduction of complement system and the interaction of glycosaminoglycans with complement system. Three complement activation pathways and the biological significance were introduced first. Then functional analysis methods were compared to provide a strategy for potential glycosaminoglycans screen. Finally, the roles of glycosaminoglycans played in the complement system were summed up. PMID- 26428163 TI - Preparation of alginate-chitosan fibers with potential biomedical applications. AB - The preparation of alginate-chitosan fibers, through wet spinning technique, as well as the study of their properties as a function of chitosan's molecular weight and retention time in the coagulation bath, is presented and discussed in this work. Scanning electron microscopy (SEM) revealed that the fibers presented irregular and rough surfaces, with a grooved and heavily striated morphology distributed throughout the structure. Dynamic mechanical analysis (DMA) showed that, with the exception of elongation at break, the incorporation of chitosan into the fibers improved their tensile properties. The in vitro release profile of sulfathiazole as a function of chitosan's molecular weight indicated that the fibers are viable carriers of drugs. Kinetic models showed that the release of the model drug is first-order, and the release mechanism is governed by the Korsmeyer-Peppas model. Likewise, fibers loaded with sulfathiazole showed excellent inhibition of Escherichia coli growth after an incubation time of 24h at 37 degrees C. PMID- 26428164 TI - Ionic liquid-mediated technology to produce cellulose nanocrystals directly from wood. AB - We report for the first time the direct extraction of cellulose nanocrystals (CNCs) from wood by means of a 1-ethyl-3-methylimidazolium acetate ([EMIM][OAc]) treatment. A native cellulosic product could be recovered in 44% yield with respect to wood cellulose content. The product was analyzed for morphological (TEM, AFM, XRD), chemical (FTIR, (13)C CP/MAS NMR), thermal (DSC, TGA) and surface properties (Zeta potential, contact angle). These analyses evidenced the presence of partially acetylated (surface DS=0.28) nanocrystals of native cellulose I microstructure, with a crystallinity index of about 75% and aspect ratio of 65. Direct production of CNCs from wood is ascribed to the simultaneous capability of [EMIM][OAc] to (1) dissolve lignin in situ while only swelling cellulose, (2) decrease intermolecular cohesion in wood via acetylation, and (3) to catalyze cellulose hydrolysis. PMID- 26428165 TI - Internal structure and thermo-viscoelastic properties of agar ionogels. AB - Ionic liquids (IL) can alter the physical properties of agar hydrogels. Rheology studies show that gels with wide range of storage moduli (gel strength) G0 values ranging from 1 to 20 KPa could be made in imidazolium based IL solutions where the IL concentration may not exceed 5% (w/v). Gelation and gel melting temperatures (tgel and Tm) could be altered by as much as ~ 10 degrees C. Small angle neutron scattering studies revealed the presence of fibre bundles of agar double helices having typical length of 120 nm that increased to ~ 180 nm under favorable conditions. These structures gain flexibility from the cladding of the agar bundles by IL molecules which in turn caused partial charge neutralization of its surface. Raman spectroscopy revealed differential hydration of these bundles. It was found that IL molecules with longer alkyl chain (more hydrophobic) altered the gel homogeneity, and changed its thermal and mechanical properties significantly. Therefore, customization of agar hydrogels in green solvent medium (IL solutions) widens the scope of its application potential that may include sensing. PMID- 26428166 TI - Optimization of fermentation conditions of pectin production from Aspergillus terreus and its partial characterization. AB - Figures of persimmons for the world's top ten persimmon producing countries are about 4000,000 tons in 2011 and are increasing every year according to FAO statistics. However, there is not any report on pectin production by microbial with persimmon peel as the source. Optimization of fermentation conditions of pectin production from Aspergillus terreus in submerged culture and partial characterization of pectin were carried out in the work. An optimum fermentation condition for pectin production was obtained through a central composite rotatable design in response surface methodology as follows: fermentation time, 30.09 h, temperature, 25.00 degrees C and the initial pH in the fermentation medium, 6.90, respectively and the pectin yield reached the maximal value 0.449 g/g. Persimmon peel pectin had highly methoxylated (62.51%), high galacturonic acid content (82.28%) than citrus pectin, and was classified as the highly methoxylated pectin, the results indicated that persimmon peel had potential good resources for pectin production. The investigation can make it available to utilize persimmon peel to produce high methoxyl pectin for food industry, pharmacy and cosmetic manufacture. PMID- 26428167 TI - Starch/silver nanocomposite: Effect of thermal treatment temperature on the morphology, oxygen and water transport properties. AB - The present work reports a strategy involving the preparation of nanostructured starch based film containing silver nanoparticles (AgNPs) using a completely green chemistry process. The nanocomposite films were prepared by solution cast process. The AgNPs were in situ generated inside the polymer film by thermal treatment at different temperatures (25, 40 and 85 degrees C). The influence of the presence and the amount of reducing agent (glucose) were also investigated. For all nanocomposite films, the AgNPs were spherical with a diameter less than 15 nm. Contrary to the presence of glucose, thermal treatment condition was a key factor for the AgNPs structure. Crystalline AgNPs were obtained only after thermal treatment at 85 degrees C. Improvements of water and oxygen barrier properties near to one decade were observed in this last case and were explained by the formation of crystalline AgNPs associated to the establishment of strong interactions between AgNPs and starch polymer matrix. PMID- 26428168 TI - Facile approach to synthesize chitosan based composite--Characterization and cadmium(II) ion adsorption studies. AB - In this present study, the physicochemical properties, nature and morphology of prepared composite materials involving Activated Eskom fly ash (A-FA) and biopolymer-chitosan (Ch) for two components composite materials were investigated. The nature, morphology, elemental characterizations of these materials were carried out by means of modern analytical methods such as scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray fluorescence (XRF), UV vis spectroscopy (UV-vis), and Fourier transform infrared spectroscopy (FTIR. Other physicochemical characterizations undertaken were carbon, nitrogen and hydrogen (CNH) analysis, and ash content. The precursors and composite materials were then applied to the sorption of cadmium (Cd(2+)) from aqueous water. Maximum Cd(2+) adsorption capacity (Qmax) was recorded to be 87.72 mg/g at pH 8. The adsorption kinetics of the composite materials fitted well with the pseudo second order kinetic model while the adsorption isotherm data could be well described by the Langmuir isotherm model. PMID- 26428169 TI - Delivery of liquorice extract by liposomes and hyalurosomes to protect the skin against oxidative stress injuries. AB - Liquorice extract, obtained by percolation in ethanol of Glycyrrhiza glabra L. roots, was incorporated in liposomes and hyalurosomes, new phospholipid-sodium hyaluronate vesicles, and their protective effect against oxidative stress skin damages was probed. As a comparison, raw glycyrrhizin was also tested. All the vesicles were small in size (<= 100 nm), with a highly negative zeta potential ensuring long-term stability, and able to incorporate a high amount of the extract. In vitro tests showed that the liquorice extract loaded in vesicles was able to scavenge DPPH free radical (80% inhibition) and to protect 3T3 fibroblasts against H2O2-induced oxidative stress, restoring the normal conditions. By contrast, glycyrrhizin showed poor antioxidant activity, and was not able to efficiently counteract the oxidative effect of H2O2. In addition, the incorporation of the liquorice extract into the vesicular systems promoted the proliferation and migration of 3T3 fibroblasts, favouring the closure of the scratched area. In vivo anti-inflammatory tests on mice confirmed the ability of the proposed nanosystems to improve the local efficacy of the extract, favouring the re-epitelization process. PMID- 26428170 TI - Effect of the oxidation treatment on the production of cellulose nanofiber suspensions from Posidonia oceanica: The rheological aspect. AB - Different grades of cellulose nanofibrils (CNF) were prepared from Posidonia oceanica balls and leaves (POB and POL). Pretreatment using 2,2,6,6 tetramethylpiperidine-1-oxyl (TEMPO)-mediated oxidation was performed to facilitate the fibrillation during ultrafine friction grinding process. The ensuing CNF batches were compared in terms of morphology and degree of fibrillation. The rheological properties of the produced CNF suspensions were also analyzed for varying doses of sodium hypochlorite used during the TEMPO- mediated oxidation procedure. The stronger fibrous network structures were formed when increasing the oxidant concentration, which was confirmed by the increase of the storage moduli value. P. oceanica balls were found to undergo stronger fibrillation and, consequently, to form stronger networks, compared to P. oceanica leaves, when using equivalent concentration of the oxidizing agent. PMID- 26428171 TI - Development and characterization of a new hydrogel based on galactomannan and kappa-carrageenan. AB - A new hydrogel based on two natural polysaccharides was prepared in aqueous medium with 1.7% (w/v) galactomannan (from Cassia grandis seeds) and different concentrations of kappa-carrageenan (0.3, 0.4 and 0.5%w/v), CaCl2 (0.0, 0.1 and 0.2M) and pH (5.0, 5.5 and 6.0), using a full factorial design based on rheological parameters. The best formulation was obtained with 1.7% (w/v) galactomannan and 0.5% (w/v) kappa-carrageenan, containing 0.2M CaCl2 at pH 5.0. Nuclear magnetic resonance and scanning electron microscopy where used in order to characterize the hydrogel formulation. A shelf life study was carried out with this formulation along 90 days-period of storage at 4 degrees C, evaluating pH, color, microbial contamination and rheology. This hydrogel showed no significant changes in pH, no microbial contamination and became more translucent along the aging. Analyses by nuclear magnetic resonance and rheology showed a larger organization of the polysaccharides in the hydrogel matrix. The results demonstrated that this hydrogel was stable with possible applications in medical and cosmetic fields. PMID- 26428172 TI - Application of chitosan and its N-heterocyclic derivatives for preconcentration of noble metal ions and their determination using atomic absorption spectrometry. AB - Chitosan and its N-heterocyclic derivatives N-2-(2-pyridyl)ethylchitosan (2-PEC), N-2-(4-pyridyl) ethylchitosan (4-PEC), and N-(5-methyl-4-imidazolyl) methylchitosan (IMC) have been applied in group preconcentration of gold, platinum, and palladium for subsequent determination by atomic absorption spectroscopy (AAS) in solutions with high background concentrations of iron and sodium ions. It has been shown that the sorption mechanism, which was elucidated by XPS, significantly influences the sorption capacity of materials, the efficiency of metal ions elution after preconcentration, and, as a result, the accuracy of metal determination by AAS. We have shown that native chitosan was not suitable for preconcentration of Au(III), if the elution step was used as a part of the analysis scheme. The group preconcentration of Au(III), Pd(II), and Pt(IV) with subsequent quantitative elution using 0.1M HCl/1M thiourea solution was possible only on IMC and 4-PEC. Application of IMC for analysis of the national standard quartz ore sample proved that gold could be accurately determined after preconcentration/elution with the recovery above 80%. PMID- 26428173 TI - Enhancing biocompatibility of some cation selective electrodes using heparin modified bacterial cellulose. AB - Bacterial cellulose (BC) and heparin-modified bacterial cellulose (HBC) were utilized to enhance the biocompatibility of highly thrombogenic PVC-based potassium and calcium membrane electrodes. Three types of membrane electrodes were prepared: (1) conventional PVC electrode (control), (2) PVC-based electrode sandwiched with bacterial cellulose membrane (BC-PVC), and (3) PVC-based electrode sandwiched with heparin-modified bacterial cellulose membrane (HBC PVC). The potentiometric response characteristics of the modified potassium and calcium membrane electrodes (BC-PVC and HBC-PVC) were compared with those of the control PVC-based potassium and calcium selective electrode, respectively. Response characteristics of the modified membrane electrodes were comparable to the control PVC membrane electrode. The platelet adhesion investigations indicated that (BC) and (HBC) layers are less thrombogenic compared to PVC. Therefore, use of BC or HBC would enable the enhancement of the biocompatibility of PVC-based membrane electrodes for potassium and calcium while practically maintaining the overall electrochemical performance of the PVC sensing film. PMID- 26428174 TI - A curcumin activated carboxymethyl cellulose-montmorillonite clay nanocomposite having enhanced curcumin release in aqueous media. AB - A novel curcumin activated carboxymethylcellulose-montmorillonite nanocomposite is reported. A superabsorbent biopolymer; carboxymethyl cellulose (CMC) was used as an emulsifier for curcumin which is a turmeric derived water insoluble polyphenolic compound with antibacterial/anti-cancer properties. Montmorillonite (MMT) nanoclay was incorporated in the formulation as a matrix material which also plays a role in release kinetics. It was observed that water solubility of curcumin in the nanocomposite has significantly increased (60% release within 2h and 30 min in distilled water at pH 5.4) compared to pure curcumin. The prepared curcumin activated carboxymethylcellulose-montmorillonite nanocomposite is suitable as a curcumin carrier having enhanced release and structural properties. PMID- 26428175 TI - Xylan-degrading enzymes from Aspergillus terreus: Physicochemical features and functional studies on hydrolysis of cellulose pulp. AB - Two endo-beta-1,4-xylanases named XylT1 and XylT2, previously purified from Aspergillus terreus, were structurally investigated by fluorescence quenching and characterized with respect to their binding properties with phenolic compounds. Neutral and charged quenchers had access to both enzymes in neutral and alkaline pHs. The greatest access was noted for the negative quencher, possibly due to positive amino acid residues in the vicinity of tryptophan. These tryptophan environments may partially explain the conformational differences and lower binding constants of phenolic compounds for XylT2 than XylT1Phenolic compounds had lower binding constants for XylT2 than XylT1. These results show that xylanases present structural and functional differences, despite belonging to similar families. XylT1 and XylT2 were also evaluated for their ability to hydrolyze cellulose pulp in different stages of bleaching. Both enzymes promoted hydrolysis of cellulose pulps, which was confirmed by the release of total reducing sugars, pentoses and chromophoric material. Analysis of released xylooligosaccharides demonstrated a preferential release of xylobiose. None of xylanases released glucose, showing that they do not hydrolyze the cellulose present in the pulp, making both enzymes excellent choices for bio-bleaching applications. PMID- 26428176 TI - Carbohydrate base co-polymers as an efficient immobilization matrix to enhance lipase activity for potential biocatalytic applications. AB - In the present study, we have synthesized biocompatible hybrid blend of cellulosic polymers of hydroxypropyl-methyl-cellulose (HPMC) and chitosan (CHY) for the immobilization of Candida rugosa lipase (CRL). The immobilized biocatalyst HPMC:CHY:CRL was subjected for characterization such as SEM, TGA, water content analysis, lipase activity, specific activity and protein content analysis. The kinetic parameter study (Rmax/Km) demonstrated improved biocatalytic activity of lipase after immobilization on carbohydrate co-polymers of HPMC:CHY. This biocatalyst was then employed to study practical biocatalytic applications for kinetic resolution which provided 50% conversion and >94% enantiomeric excess of substrate/product (ees/eep). The protocol demonstrated excellent recyclability upto five cycles. Finally, we studied influence of immobilization on cellulosic polymers for substrate, structure and reactivity for kinetic resolution. Hence, we investigated R0 (initial reaction rate), E-value (enantioselectivity) and Ea (activation energy). This study confirms that, lipase immobilized on carbohydrate polymers had 3-4 folds higher biocatalytic activity as compared to crude CRL. PMID- 26428177 TI - Effect of sub- and supercritical water treatments on the physicochemical properties of crab shell chitin and its enzymatic degradation. AB - This study examined the effects of sub- and supercritical water pretreatments on the physicochemical properties of crab shell alpha-chitin and its enzymatic degradation to obtain N,N'-diacetylchitobiose (GlcNAc)2. Following sub- and supercritical water pretreatments, the protein in the crab shell was removed and the residue of crab shell contained alpha-chitin and CaCO3. Prolonged pretreatment led to alpha-chitin decomposition. The reaction of pure alpha-chitin in sub- and supercritical water pretreatments was investigated separately; we observed lower mean molecular weight and weaker hydrogen bonds compared with untreated alpha-chitin. (GlcNAc)2 yields from enzymatic degradation of subcritical (350 degrees C, 7 min) and supercritical water (400 degrees C, 2.5 min) pretreated crab shell were 8% and 6%, compared with 0% without any pretreatment. This study shows that sub- and supercritical water pretreatments of crab shell provide to an alternative method to the use of acid and base for decalcification and deproteinization of crab shell required for (GlcNAc)2 production. PMID- 26428178 TI - Functional, thermal, and antimicrobial properties of soluble soybean polysaccharide biocomposites reinforced by nano TiO2. AB - This study describes a new polysaccharide-based bionanocomposite developed through solvent casting. Different concentrations (i.e., 0%, 1%, 3%, and 5% (w/w)) of nano titanium dioxide (TiO2-N) were incorporated into soluble soybean polysaccharide (SSPS), and the functional properties of the resultant SSPS films were estimated. Incorporation of TiO2-N into the SSPS matrix decreased water vapor permeability from 7.41 to 4.44 * (10(-11)gm(-1) s(-1) Pa(-1)) and oxygen permeability from 202 to 98 (cm(3)MUmm(-2) d(-1) atm(-1)). Moisture content also decreased, the glass transition temperature increased, and the mechanical properties and heat seal strength of the SSPS films improved. SSPS bionanocomposite films showed excellent antimicrobial activity against Escherichia coli and Staphylococcus aureus. In summary, TiO2-N shows potential use as a filler in SSPS-based films for the food and non-food industries. PMID- 26428179 TI - Synthesis and applications of eco-magnetic nano-hydroxyapatite chitosan composite for enhanced fluoride sorption. AB - Adsorption is a significant reaction occurs between adsorbent/water interface for controlling the pollutants in the aqueous environment. In this regard, an eco magnetic biosorbent was prepared by uniform deposition of magnetic Fe3O4 particles on the surface of nano-hydroxyapatite (n-HAp)/chitosan (CS) nanocomposite namely Fe3O4@n-HApCS composite as versatile sorbent for fluoride sorption. The resulting Fe3O4@n-HApCS nanocomposite was characterized by FTIR and SEM with EDAX techniques. The defluoridation capacity (DC) was found to depend on the contact time, pH, co-existing anions, initial fluoride concentration and temperature. The sorption isotherm was investigated by Freundlich, Langmuir and Temkin isotherm models using the batch method. The thermodynamic parameters revealed the feasibility, spontaneity and endothermic nature of fluoride sorption. The results of this research work designated that Fe3O4@n-HApCS composite having the excellent defluoridation capacity than the individual components and interesting to note that the easy magnetic separation of Fe3O4@n HApCS composite from aqueous medium. PMID- 26428180 TI - Cellulosimicrobium cellulans strain E4-5 enzymatic hydrolysis of curdlan for production of (1 -> 3)-linked beta-D-glucan oligosaccharides. AB - In order to find an efficient enzymatic tool for curdlan degradation to produce (1 -> 3)-linked beta-D-glucan oligosaccharides, strain E4-5 (registration number JN089883, Genbank) was isolated from seaside soil. The 16S rRNA gene sequencing classified it as Cellulosimicrobium cellulans. It was the first reported microorganism that succeeded in degrading high-set heated curdlan blocks. The ferments of strain E4-5 also showed good degradation effects on laminaran and alkali-neutralized curdlan. Due to the products with less amount of glucose, it was assumed that endo-1,3-beta-glucanases of strain E4-5 had a greater hydrolyzing effect than exo-1,3-beta-glucanases. This indicated that strain E4-5 was a promising microorganism to hydrolyze (1 -> 3)-linked beta-D-glucan. Moreover, alkali-neutralization pretreatment was effective for promoting a more diversified degree of polymerization (DP) of (1 -> 3)-linked beta-D-glucan oligosaccharides under enzymatic hydrolysis and will pave the way for making full use of curdlan for production of glucan oligosaccharides. PMID- 26428181 TI - Preparation and characterization of novel bionanocomposite based on soluble soybean polysaccharide and halloysite nanoclay. AB - In this research, casting method was used to prepare novel polysaccharide-based bio-nanocomposite films with halloysite nanoclay (HNC). HNC was incorporated into soluble soybean polysaccharide (SSPS) at different concentrations (e.g., 1, 3, and 5%, w/w). Functional properties of SSPS films were evaluated following by ASTM standards. Incorporating HNC to SSPS matrix decreased water vapor permeability from 7.41 * 10(-11) to 3.27 * 10(-11) (gm(-1) s(-1) Pa(-1)) and oxygen permeability from 202 to 84 cm(3)(MUm m(-2) day(-1) atm(-1)). By addition of HNC to SSPS films, glass transition temperature, tensile strength, and heat seal strength was increased and elongation at break was decreased. Uniform and smooth surface morphology revealed by scanning electron microscopy and shows no sign of phase separation among the film constitutes. In summary, HNC has the potential to be a filler in SSPS-based films for use in food and non-food packaging industries. PMID- 26428182 TI - Structural characterization and antioxidant activity of a novel heteropolysaccharide from the submerged fermentation mycelia of Ganoderma capense. AB - A novel heteropolysaccharide (GCPB-2) with a molecular mass of 1.03*10(5)Da was isolated from the submerged fermentation culturing mycelia powder of Lingzhi, Ganoderma capense, by DEAE-52 cellulose, DEAE Sepharose CL-6B, and Sephadex G-75 column chromatography. Its chemical structure was characterized for the first time. The antioxidant activity was evaluated by two antioxidant assay methods. The result of this study introduced G. capense as a possible valuable source that helped to exhibit some antioxidant properties. The homogeneous polysaccharide was composed of xylose and arabinose in the molar ratio of 1:1, and showed a specific optical rotation of [alpha]D(25)=+161 degrees (c 1.0, H2O). Monosaccharide analysis, partial acid hydrolysis, periodic acid oxidation, methylation analysis, gas chromatography-mass spectrometry (GC-MS), Fourier transform-infrared spectroscopy (FT-IR), and nuclear magnetic resonance (NMR) spectroscopy ((1)H, (13)C, HMQC and HMBC) were conducted to elucidate its structure. The backbone of GCPB-2 was composed of (1 -> 4)-linked-beta-D-xylopyranose residues which branched at O-3. The two branches consisted of (1 -> 3)-linked-beta-L arabinopyranose terminated with beta-D-xylopyranose residues, and (1 -> 4)-linked beta-L-arabinopyranose terminated with beta-D-arabinopyranose residues. In the in vitro antioxidant assay, GCPB-2 was found to possess 1-diphenyl-2-picryl-hydrazyl (DPPH) radical-scavenging activity with an EC50 value of 0.379 MUM. The findings of this study indicated that GCPB-2 possesses the hydroxyl radical-scavenging activity, which provided an experimental evidence to support the G. capense as functional foods in some Asian countries. To understand better the bioactivity of GCPB-2, the antioxidant activity should be further investigated to find out its mechanism in future work. PMID- 26428183 TI - Biodegradation of cellulosic and lignocellulosic waste by Pseudoxanthomonas sp R 28. AB - A microbial consortium, designated Con R, was established by successive sub cultivation which can degrade 83% of filter paper after 15 days of incubation over control. Among the 14 bacterial isolates obtained from Con R, only bacterial isolate (R-28) was capable of degrading filter paper. Based on 16S rRNA gene sequence, R-28 was identified as Pseudoxanthomonas sp R-28. After 5 days of incubation, degradation efficiencies of Pseudoxanthomonas sp R-28 on filter paper and pure cellulosic waste were 96% and 95% respectively as compared to control. Pseudoxanthomonas sp R-28 also degraded 60% of non-pretreated rice straw after 7 days as compared to control. The degradation kinetics through a modified logistic model showed high correlation coefficient (R(2)) of 0.965 and 0.665 for cellulosic and rice straw waste degradation respectively. Micro scale structural analysis showed the development of fissures and gaps over time which further supported the degradation potential of Pseudoxanthomonas sp R-28. PMID- 26428184 TI - Gelling process for sodium alginate: New technical approach by using calcium rich micro-spheres. AB - Alginate based materials have become an important class of products in many fields from the pharmaceutical industry to tissue engineering, because of their ability to create stimuli responsive hydrogels. We present a new technical approach for obtaining a controlled gelling process, based on the quantities of Ca(2+) rich alginate micro-beads added as crosslinkers. The gels have been evaluated in light of the amount of Ca(2+) added to the alginate solution, and in light of the different dimensions of the micro-beads, using rheological measurements to assess the variation in the storage modulus (G'), loss modulus (G'') and complex viscosity (eta(*)) as well as swelling and deswelling tests. The methodology was developed to obtain a material with specific characteristics for application in the field of conservation. The material had to be able to create a stable gel after being applied on the artwork surface and to confine the solvent action at the interface during cleaning operations. PMID- 26428185 TI - Tuning Fe3O4 nanoparticle dispersion through pH in PVA/guar gum/electrospun membranes. AB - Polyvinyl Alcohol (PVA)/guar gum (GG) membranes with different loads of paramagnetic iron oxide Fe3O4 nanoparticles were successfully electrospun using both non-alkaline and alkaline stock solutions. The nanoparticle homogeneity distribution was clearly enhanced in fibers obtained from alkaline stock solutions. This is mainly due to the interaction between GG and the metallic ion, which also leads to further dispersion of remained uncoated nanoparticles in the mixture. It was also noticed that GG favors nanoparticle stability in the mixture and contributes to nanoparticle encapsulation. X-ray results showed that all membranes were semi-crystalline. FTIR-ATR spectra showed that Fe-O absorption band intensity improved with increasing nanoparticle load, reaching saturation at 3.5mg/ml Fe3O4 concentration under alkaline conditions. VSM analyses showed that the nanoparticles are paramagnetic and were successfully incorporated by the fibers. In vitro biocompatibility tests using L929 cells indicates adequate levels of cytotoxicity and cell adhesion/proliferation assays for both membranes obtained from non-alkaline and alkaline stock solutions. Therefore, they have potential for biomedical applications as biodegradable wound dressing. PMID- 26428186 TI - Starch based polyurethanes: A critical review updating recent literature. AB - Recent advancements in material science and technology made it obvious that use of renewable feed stock is the need of hour. Polymer industry steadily moved to get rid of its dependence on non-renewable resources. Starch, the second largest occurring biomass (renewable) on this planet provides a cheap and eco-friendly way to form huge variety of materials on blending with other biodegradable polymers. Specific structural versatility design for individual application and tailor-made properties have established the polyurethane (PU) as an important and popular class of synthetic biodegradable polymers. Blending of starch with polyurethane is relatively a developing area in PU chemistry but with lot of attraction for researchers. Herein, various starch based polyurethane materials including blends, grafts, copolymers, composites and nano-composites, as well as the prospects and latest developments are discussed. Additionally, an overview of starch based polymeric materials, including their potential applications are presented. PMID- 26428187 TI - Fabrication and in vitro biological activity of betaTCP-Chitosan-Fucoidan composite for bone tissue engineering. AB - We developed tricalcium phosphate-chitosan-fucoidan biocomposite scaffold (TCP-Ch Fu) by using the freeze-drying technique. The fabricated biocomposite scaffolds were analyzed by spectroscopy and porosity measurement. The biomechanical properties of scaffolds were assessed by compression test and the results suggested that the incorporation of Fucoidan into the biocomposite improves the compression strength of scaffolds. Biomineralization of scaffolds was evaluated by soaking them in simulated body fluid and the results revealed that the addition of Fucoidan into the scaffolds enhanced the formation of apatite layer on the surface of biocomposite after 7 days of immersion. Alamar Blue assay confirmed that the cell viability of human-derived bone marrow stromal cell was superior in the TCP-Ch-Fuscaffold. The addition of Fucoidan to TCP-Ch increased the release of osteocalcin, confirming that it can support osteogenic differentiation of human mesenchymal stromal cells in in vitro culture. Thus, TCP Ch-Fu could be a potential candidate for bone-tissue engineering applications. PMID- 26428188 TI - Identification of a highly sulfated fucoidan from sea cucumber Pearsonothuria graeffei with well-repeated tetrasaccharides units. AB - Sea cucumber fucoidan is a major bioactive component of sea cucumber. The structures of fucoidans have significant influences on their biological activities. The present study clarified the delicate structure of a fucoidan from Pearsonothuria graeffei. Fucoidan was obtained after papain digestion and purified by ion chromatography. The carbohydrate sequence of fucoidan was firstly determined by negative-ion electrospray tandem mass spectrometry (ES-MS) with collision-induced dissociation of the oligosaccharide fragments, which were obtained by mild acid hydrolysis, and completed by NMR for assignment of the anomeric conformation. It was unambiguously identified as a tetrasaccharide repeating unit with a backbone of [ -> 3Fuc (2S, 4S) alpha1 -> 3Fucalpha1-> 3Fuc (4S) alpha1 -> 3Fuc#7 * 10#]n. The glycosidic bonds between the non-sulfated and 2,4-O-disulfated fucose residues were selectively cleaved, and highly ordered oligosaccharide fragments with a tetrasaccharide repeating unit were obtained. The highly 4-O- and 2, 4-di-O-sulfated polysaccharide deserves further developments for Pharmacia use. PMID- 26428189 TI - Timing of Gonadectomy in Patients with Complete Androgen Insensitivity Syndrome Current Recommendations and Future Directions. AB - This review highlights the controversy regarding timing of gonadectomy in patients with complete androgen insensitivity syndrome (CAIS). We will review the published literature regarding frequency of gonadal malignancy and summarize historical findings. Recent research suggests that gonadectomy may be deferred until adulthood due to the low risk of malignancy. An algorithm is also provided to help guide clinicians in management of patients with complete androgen insensitivity syndrome who have deferred gonadectomy. PMID- 26428190 TI - Factors That Affect Perinatal Outcomes of the Second Pregnancy of Adolescents. AB - STUDY OBJECTIVE: We assessed factors that might affect perinatal outcomes in second pregnancies in adolescents. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, MAIN OUTCOME MEASURES: This longitudinal retrospective study was carried out on 66 adolescents who experienced 2 deliveries during their adolescence. Data were collected for the first and second pregnancies. Odds ratios (ORs) and 95% confidence intervals (CIs) for adverse perinatal outcomes in the second pregnancy were calculated using a logistic regression model and SPSS software (version 17.0 for Windows; SPSS Inc, Chicago, IL). A P value < .05 was considered to indicate statistical significance. RESULTS: Body mass index, number of antenatal care visits, weight gain during pregnancy, incidence of anemia, smoking status, gestational week at delivery, cesarean section rate, and birth weight were similar between the first and second pregnancies of these adolescents. Neonatal intensive care unit admission rate, preeclampsia rate, low neonatal birth weight rate, and 5-minute Apgar scores <7 were significantly higher in the first than in the second pregnancy (P < .001). Age of 16 years or younger at the time of first pregnancy (OR = 1.5; 95% CI, 0.9-2.1; P < .01), less than an 18-month interval between births (OR = 1.4; 95% CI, 0.2-1.7; P < .04), presence of gestational complications in the first pregnancy (OR = 1.9; 95% CI, 1.0-3.4; P < .01), and the presence of perinatal complications in the first pregnancy (OR = 1.3; 95% CI, 1.0-1.9; P < .01) were found to be significant indicators for adverse neonatal outcomes in second pregnancies of adolescents. CONCLUSION: We found that the second pregnancies of adolescents were associated with fewer adverse perinatal outcomes than were their first pregnancies. However, some factors regarding the presence of perinatal complications in the first pregnancy, such as maternal age of 16 years or younger at the time of the first pregnancy and interval between first and second pregnancy of less than 18 months, were found to increase the risk of adverse perinatal outcomes for the second births. PMID- 26428191 TI - Vaginal cones or balls to improve pelvic floor muscle performance and urinary continence in women post partum: A quantitative systematic review. AB - OBJECTIVES: the vaginal use of cones or balls aims to increase muscle performance and thereby prevent or treat urinary incontinence. To date, no systematic review has focused on the effectiveness of these devices specifically during the postpartum period. The objectives of this review were: to compare the effectiveness of vaginal cones or balls for improvement of pelvic floor muscle performance and urinary continence in the postpartum period to no treatment, placebo, sham treatment or active controls; to gather information on effect on perineal descent or pelvic organ prolapse, adverse effects and economical aspects. DESIGN: quantitative systematic review. DATA SOURCES: 14 scientific databases (including PubMed and CINAHL) and the world-wide web; experts were contacted for published and unpublished data. REVIEW METHODS: studies had to be randomised/quasi-randomised trials and have female participants up to one year after childbirth. The intervention is compared to no treatment, placebo, sham treatment or active controls. Outcome measures relate to pelvic floor muscle performance or urinary incontinence. Studies were selected, 'risk of bias' assessed, and data extracted by two reviewers independently with inter-reviewer agreement. MAIN FINDINGS: one study met the inclusion criteria; its original data were re-analysed. In an intention-to-treat analysis, compared with the control group, the cone group showed a statistically significant lower rate of urinary incontinence; compared with the exercise group, the prevalence was similar. However, the validity of the analysis is limited. CONCLUSIONS AND IMPLICATIONS: the evidence gained from this systematic review is very limited. The use of cones may be helpful for urinary incontinence after childbirth, but further research is needed. PMID- 26428192 TI - Engineering the lipid layer of lipid-PLGA hybrid nanoparticles for enhanced in vitro cellular uptake and improved stability. AB - Lipid-polymer hybrid nanoparticles (NPs), consisting of a polymeric core and a lipid shell, have been intensively examined as delivery systems for cancer drugs, imaging agents, and vaccines. For applications in vaccine particularly, the hybrid NPs need to be able to protect the enclosed antigens during circulation, easily be up-taken by dendritic cells, and possess good stability for prolonged storage. However, the influence of lipid composition on the performance of hybrid NPs has not been well studied. In this study, we demonstrate that higher concentrations of cholesterol in the lipid layer enable slower and more controlled antigen release from lipid-poly(lactide-co-glycolide) acid (lipid PLGA) NPs in human serum and phosphate buffered saline (PBS). Higher concentrations of cholesterol also promoted in vitro cellular uptake of hybrid NPs, improved the stability of the lipid layer, and protected the integrity of the hybrid structure during long-term storage. However, stabilized hybrid structures of high cholesterol content tended to fuse with each other during storage, resulting in significant size increase and lowered cellular uptake. Additional experiments demonstrated that PEGylation of NPs could effectively minimize fusion-caused size increase after long term storage, leading to improved cellular uptake, although excessive PEGylation will not be beneficial and led to reduced improvement. STATEMENT OF SIGNIFICANCE: This paper reports the engineering of the lipid layer that encloses a polymeric nanoparticle, which can be used as a carrier for drug and vaccine molecules for targeted delivery. We demonstrated that the concentration of cholesterol is critical for the stability and uptake of the hybrid nanoparticles by dendritic cells, a targeted cell for the delivery of immune effector molecules. However, we found that hybrid nanoparticles with high cholesterol concentration tend to fuse during storage resulting in larger particles with decreased cellular uptake. This problem is subsequently solved by PEGylating the hybrid nanoparticles. With increased research and clinical applications of lipid-polymer hybrid nanoparticles in drug and vaccine delivery, this work will significantly impact the design of the hybrid nanoparticles for minimized molecule release during circulation and increased bioavailability of the target molecules. PMID- 26428194 TI - Nasopharyngeal Carriage, Capsular and Molecular Serotyping and Antimicrobial Susceptibility of Streptococcus pneumoniae among Asymptomatic Healthy Children in Egypt. AB - Streptococcus pneumoniae is a major cause of childhood morbidity and mortality worldwide with increasing antimicrobial resistance. 600 randomly chosen asymptomatic healthy children aged 2-60 months attending Alexandria University Children's Hospital were evaluated for prevalence of nasopharyngeal (NP) carriage of S. pneumoniae. Prevalence of NP carriage was 29.2% (n = 175/600) Capsular serotyping was done using Quellung reaction. Vaccine covered serotypes (VST) represented 67.4% while non-vaccine serotypes (NVST) were 32.6%. The most common VST isolated were 19F (24.6%), 6B (14.3%) and 6A (10.9%). Confirmation of serotyping was performed by multiplex PCR which showed 100% concordance with the Quellung reaction. Antimicrobial susceptibility testing showed penicillin non susceptibility of 15% (using non-meningitis penicillin MIC breakpoints) and 55% (using meningitis penicillin MIC breakpoints). Highest resistance was found in sulphamethoxazole-trimethoprim (55%), tetracyclins (49%), erythromycin (40%) and clindamycin (25%). This study revealed the epidemiological importance to evaluate regularly the prevalence, serotypes and the increasing antimicrobial resistance of S. pneumoniae in the community. PMID- 26428193 TI - Surface chemistry regulates valvular interstitial cell differentiation in vitro. AB - The primary driver for valvular calcification is the differentiation of valvular interstitial cells (VICs) into a diseased phenotype. However, the factors leading to the onset of osteoblastic-like VICs (obVICs) and resulting calcification are not fully understood. This study isolates the effect of substrate surface chemistry on in vitro VIC differentiation and calcified tissue formation. Using omega-functionalized alkanethiol self-assembled monolayers (SAMs) on gold [CH3 (hydrophobic), OH (hydrophilic), COOH (COO(-), negative at physiological pH), and NH2 (NH3(+), positive at physiological pH)], we have demonstrated that surface chemistry modulates VIC phenotype and calcified tissue deposition independent of osteoblastic-inducing media additives. Over seven days VICs exhibited surface dependent differences in cell proliferation (COO(-)=NH3(+)>OH>CH3), morphology, and osteoblastic potential. Both NH3(+)and CH3-terminated SAMs promoted calcified tissue formation while COO(-)-terminated SAMs showed no calcification. VICs on NH3(+)-SAMs exhibited the most osteoblastic phenotypic markers through robust nodule formation, up-regulated osteocalcin and alpha-smooth muscle actin expression, and adoption of a round/rhomboid morphology indicative of osteoblastic differentiation. With the slowest proliferation, VICs on CH3-SAMs promoted calcified aggregate formation through cell detachment and increased cell death indicative of dystrophic calcification. Furthermore, induction of calcified tissue deposition on NH3(+) and CH3-SAMs was distinctly different than that of media induced osteoblastic VICs. These results demonstrate that substrate surface chemistry alters VIC behavior and plays an important role in calcified tissue formation. In addition, we have identified two novel methods of calcified VIC induction in vitro. Further study of these environments may yield new models for in vitro testing of therapeutics for calcified valve stenosis, although additional studies need to be conducted to correlate results to in vivo models. STATEMENT OF SIGNIFICANCE: Valvular interstitial cell (VIC) differentiation and aortic valve calcification is associated with increased risk of mortality and onset of other cardiovascular disorders. This research examines effects of in vitro substrate surface chemistry on VIC differentiation and has led to the identification of two materials-based initiation mechanisms of osteoblastic-like calcified tissue formation independent of soluble signaling methods. Such findings are important for their potential to study signaling cascades responsible for valvular heart disease initiation and progression as well providing in vitro disease models for drug development. We have also identified a VIC activating in vitro environment that does not exhibit confluence induced nodule formation with promise for the development of tissue regenerating scaffolds. PMID- 26428195 TI - Use of Nasal Bubble CPAP in Children with Hypoxemic Clinical Pneumonia-Report from a Resource Limited Set-Up. AB - OBJECTIVE: Nasal bubble continuous positive airway pressure (bCPAP) is preferred in developing economies for easy applicability and low cost. Because its use in older children is unexplored, we sought to evaluate its utility in hypoxemic clinical pneumonia. METHODS: Of 330 children (1 month-12 years) with clinical pneumonia enrolled prospectively over 1 year, those with increased work of breathing and/or SpO2 <92% received bCPAP delivered via an underwater 'T' tube through nasal prongs. Proportion requiring intubation despite bCPAP constituted primary outcome. Incidence of complications, duration of bCPAP and emergency stay were secondary outcomes. RESULTS: Oxygen was initiated by nasal prongs (NPO2) in 204 (61.8%), and by bCPAP in 110 (33.3%). Sixteen (4.8%) were intubated at the outset. Fifty-three (25.9%) on NPO2 were shifted to bCPAP for worsening distress and hypoxemia. Only three (1.8%) from bCPAP group required intubation, of which one died. Failure rate and complications were negligent. The median emergency stay was 4 days. CONCLUSIONS: Nasal bCPAP was safe and effective in children with hypoxemic clinical pneumonia. PMID- 26428196 TI - Incidence, Etiology and Risk Factors Associated with Neonatal Healthcare Associated Conjunctivitis: A Prospective Study from a Tertiary Care Hospital in India. AB - INTRODUCTION: Healthcare-associated conjunctivitis (HAC) can lead to serious sequelae including blindness. We conducted a one-year prospective study to determine the epidemiology of neonatal HAC at a tertiary-care hospital in India. METHODS: From the neonates fulfilling a set of predefined inclusion criteria, cases of HAC were diagnosed based on CDC guidelines. Conjunctival swabs, obtained from neonates with suggestive clinical signs, were processed using standard protocols. Twenty-eight potential risk factors were analyzed. RESULTS: We detected 24 cases of HAC among 591 enrolled neonates, with Escherichia coli being the most frequently isolated microorganism. On multivariate analysis, intubation at birth (p = 0.046) and orogastric feeding (p = 0.029) had a statistically significant association with neonatal HAC. Average hospitalization increased from 9.6 to 20.8 days for neonates diagnosed with HAC. CONCLUSION: A standardized case definition and physician awareness of potential serious sequelae would help improve detection rates and timely institution of therapy. Hand hygiene could help control the menace of neonatal HAC. PMID- 26428197 TI - Cell and Molecular Processes in Cancer Metastasis: an AJP-Cell Physiology set of Themed Reviews. PMID- 26428198 TI - In vivo characterization of pancreatic cystic lesions by needle-based confocal laser endomicroscopy (nCLE): proposition of a comprehensive nCLE classification confirmed by an external retrospective evaluation. AB - BACKGROUND AND AIMS: The differential diagnosis of solitary pancreatic cystic lesions is sometimes difficult. Needle-based confocal laser endomicroscopy (nCLE) performed during endoscopic ultrasound-fine-needle aspiration (EUS-FNA) enables real-time imaging of the internal structure of such cysts. Criteria have already been described for serous cystadenoma and intraductal papillary mucinous neoplasm (IPMN). The aims of the study were to determine new nCLE criteria for the diagnosis of pancreatic cystic lesions, to propose a comprehensive nCLE classification for the characterization of those lesions, and to carry out a first external retrospective validation . METHODS: Thirty-three patients with a lone pancreatic cystic lesion were included (CONTACT 1 study). EUS-FNA was combined with nCLE. Diagnosis was based on either pathology result (Group 1, n = 20) or an adjudication committee consensus (Group 2, n = 13). Six investigators, unblinded, studied cases from Group 1 and identified nCLE criteria for mucinous cystic neoplasm (MCN), pseudocyst (PC), and cystic neuroendocrine neoplasm (NEN). Four external reviewers assessed, blinded, the yield and interobserver agreement for the newly identified (MCN, PC) and previously described (IPMN, SC) criteria in a subset of 31 cases. RESULTS: New nCLE criteria were described for MCN (thick gray line), PC (field of bright particles), and cystic NEN (black neoplastic cells clusters with white fibrous areas). These criteria correlated with the histological features of the corresponding lesions. In the retrospective validation, a conclusive nCLE result was obtained for 74 % of the cases (87 % "true" and 13 % "false" with respect to the final diagnosis). On this limited case series, the nCLE criteria showed a trend for high diagnostic specificity (>90 % for mucinous cysts, 100 % for non-mucinous cysts). CONCLUSIONS: Based on this newly completed atlas of interpretation criteria, nCLE could facilitate the diagnosis of pancreatic cystic lesion types. PMID- 26428199 TI - Erratum to: Evaluation of safety profile of thoracoscopic esophagectomy for T1bN0M0 cancer using data from JCOG0502: a prospective multicenter study. PMID- 26428200 TI - Cosmetic outcome of skin adhesives versus transcutaneous sutures in laparoscopic port-site wounds: a prospective randomized controlled trial. AB - BACKGROUND: In an elective laparoscopic surgery, the cosmetic outcome becomes increasingly important. We conducted a study to evaluate the cosmetic outcome 3 months after a laparoscopic procedure and compared skin adhesive (SA) versus transcutaneous suture (TS). METHODS: A randomized, controlled, prospective study was conducted at a single study centre in Hamburg, Germany. Seventy-seven patients undergoing laparoscopic surgery with two lower abdominal port sites met the study requirements. It was decided randomly which port site would be closed with SA. The opposite site was closed with TS. Wounds were assessed after 7-12 days and after 3 months. Cosmetic outcome was measured by a visual analogue scale (VAS) completed by the patient, by the Hollander wound evaluation scale (HWES) and by the judgement of blinded investigators. RESULTS: Seventy-seven subjects were randomized. Complete data from the 3-month follow-up visit were available from 56 patients (72.7 %). The VAS scale ranged from 0 to 100 mm with "0" representing the best possible cosmetic outcome. Median satisfaction was 2 mm in the TS group and 3 mm in the SA group. The mean was high in both groups 4.6 (s = 13.1) versus 3.8 mm (s = 4.6). The outcome was neither clinically nor statistically significant. Cosmetic outcome was assessed by an investigator, and the HWES showed no difference. In regard to complications, no difference was found between SA and TS, either. CONCLUSIONS: In conclusion this study demonstrated that closure of laparoscopic port-site wounds leads to equivalent outcomes whether SAs or TSs are used. Complications are rare in both methods. Thus, SAs seem to be a valid alternative to sutures in laparoscopic surgery. Registration site: www.clinicaltrials.gov . REGISTRATION NUMBER: NCT02179723. PMID- 26428201 TI - Patient comorbidities increase postoperative resource utilization after laparoscopic and open cholecystectomy. AB - BACKGROUND: An understanding of the relationship between patient factors and healthcare resource utilization represents a major point of interest for optimizing clinical care and overall net savings, yet maintaining financial margins for provider revenues. This study aims to review resource utilization after cholecystectomy in order to characterize patient factors associated with increased postoperative ED visits and 30-day readmissions. METHODS: A total of 53,632 open and laparoscopic cholecystectomies were reviewed from July 2009 to December 2010 in a large private payer claims database. ICD-9 and CPT codes were available for each event, as well as basic demographics. Data regarding 30-day postoperative resource utilization metrics (emergency department visits and inpatient hospitalizations) were analyzed and stratified by key patient comorbidities. Differences between subgroups were evaluated with univariate and multivariable methods. RESULTS: Of the 53,632 patients studied, 71.2 % (38,171) were female and 28.8 % (15,461) male. Resource utilization within 30 days of surgery included: 6.6 % (3538) of patients with an ED visit and 7.7 % (4103) with an inpatient hospitalization. The most common comorbidities in the study population were: hypertension, hyperlipidemia, GERD/hiatal hernia, and diabetes mellitus. Patients with heart failure, cirrhosis, and a history of MI or acute ischemic heart disease all had a significant association with postoperative ED visit and the highest likelihood of inpatient hospitalization. Angina, diabetes, and hypertension similarly increased both ED utilization and inpatient readmissions to a lesser but still significant extent. Although patients with GERD/hiatal hernia and sleep apnea had a significant association with ED use, they did not have an increased likelihood of readmission. CONCLUSIONS: Patient comorbidity indexing plays a major role in clinical risk stratification and resource utilization for cholecystectomy. These factors should be considered in bundled reimbursement packages and in the creation of preventive postoperative ambulatory strategies given their role in determining potential resource utilization in the postoperative setting. PMID- 26428202 TI - Simple versus reinforced cruroplasty in patients submitted to concomitant laparoscopic sleeve gastrectomy: prospective evaluation in a bariatric center of excellence. AB - BACKGROUND: Crural closure in addition to laparoscopic sleeve gastrectomy (LSG) represents a valuable option for the synchronous management of morbid obesity and hiatal defects, providing good outcomes in terms of weight loss and gastroesophageal reflux disease (GERD) symptoms control. The aim of this prospective study was to evaluate the safety and effectiveness of the reinforced cruroplasty during LSG compared with a concurrent group of simple cruroplasty. METHODS: The study groups included 96 morbidly obese patients who underwent simultaneous LSG and cruroplasty. Group A: 48 patients with hiatal areal defect <4 cm(2) and normal pillars (simple posterior cruroplasty); group B: 48 patients with hiatal areal defect >4 and <8 cm(2) with weakness of the right pillar (on lay synthetic absorbable mesh-reinforced cruroplasty). Upper GI symptoms were assessed by Roma III standard questionnaire. Endoscopy, imaging, esophageal 24-h pH monitoring and HR manometry were performed in cases of persistent or recurrent symptoms after surgery. RESULTS: Mortality rate was nil. The conversion rate to open was 1 %. Intra-operative diagnosis of hiatal hernia occured in 41 patients (42.7 %). Mesh-related complications were none. Perioperative complications occurred in four patients (4.1 %). After 19- to 21-month follow-up, GERD symptom remission occurred in 89 % of patients. GERD symptoms were detected postoperatively in eight patients: six in group A (five symptomatic and radiological recurrences and one persistent) and two in group B (one persistent and one de novo GERD) (P < 0.05). CONCLUSIONS: The synthetic absorbable mesh offers an effective option for crural repair during LSG with no clinical recurrences at 19 months. The midterm results of this prospective comparative study evaluating two different technical options for cruroplasty confirm that the simultaneous procedures are safe and cruroplasty is effective in mild-to-moderate GERD control . PMID- 26428203 TI - Adverse Selection in the Children's Health Insurance Program. AB - This study investigates whether new enrollees in the Alabama Children's Health Insurance Program have different claims experience from renewing enrollees who do not have a lapse in coverage and from continuing enrollees. The analysis compared health services utilization in the first month of enrollment for new enrollees (who had not been in the program for at least 12 months) with utilization among continuing enrollees. A second analysis compared first-month utilization of those who renew immediately with those who waited at least 2 months to renew. A 2-part model estimated the probability of usage and then the extent of usage conditional on any utilization. Claims data for 826 866 child-years over the period from 1999 to 2012 were used. New enrollees annually constituted a stable 40% share of participants. Among those enrolled in the program, 13.5% renewed on time and 86.5% of enrollees were late to renew their enrollment. In the multivariate 2 part models, controlling for age, gender, race, income eligibility category, and year, new enrollees had overall first-month claims experience that was nearly $29 less than continuing enrollees. This was driven by lower ambulatory use. Late renewals had overall first-month claims experience that was $10 less than immediate renewals. However, controlling for the presence of chronic health conditions, there was no statistically meaningful difference in the first-month claims experience of late and early renewals. Thus, differences in claims experience between new and continuing enrollees and between early and late renewals are small, with greater spending found among continuing and early renewing participants. Higher claims experience by early renewals is attributable to having chronic health conditions. PMID- 26428204 TI - Flare Rate in Patients with Rheumatoid Arthritis in Low Disease Activity or Remission When Tapering or Stopping Synthetic or Biologic DMARD: A Systematic Review. AB - OBJECTIVE: To evaluate the risk of having a disease flare in patients with rheumatoid arthritis (RA) with low disease activity (LDA) or in remission when deescalating (tapering or stopping) disease-modifying antirheumatic drug (DMARD) therapy. METHODS: A search in medical databases including publications from January 1950 to February 2015 was performed. Included were trials and observational studies in adults with RA who were in LDA or remission, evaluating >= 20 patients tapering or stopping DMARD. Flare rates had to have been reported. A metaanalysis was performed on studies deescalating tumor necrosis factor (TNF) blockers. RESULTS: Four studies evaluated synthetic DMARD. Flare rates ranged from 8% at 24 weeks to 63% at 4 months after deescalation. Fifteen studies reported on TNF blockers. Estimated flare rates by metaanalysis on studies tapering or stopping TNF blockers were 0.26 (95% CI 0.17-0.39) and 0.49 (95% CI 0.27-0.73) for good-quality and moderate-quality studies, respectively. Flare rates in 3 studies stopping tocilizumab were 41% after 6 months, 55% at 1 year, and 87% at 1 year. Flare rates in 3 studies deescalating abatacept were 34% at 1 year, 41% at 1 year, and 72% at 6 months. Five studies evaluating radiographic progression in patients deescalating treatment all found limited to no progression. CONCLUSION: Results suggest that more than one-third of patients with RA with LDA or in remission may taper or stop DMARD treatment without experiencing a disease flare within the first year. Dose reduction of TNF blockers results in lower flare rates than stopping and may be noninferior to continuing full dose. Radiological progression after treatment deescalation remains low, but may increase slightly. PMID- 26428206 TI - Concomitant Methotrexate Protects Against Total Knee Arthroplasty in Patients with Rheumatoid Arthritis Treated with Tumor Necrosis Factor Inhibitors. AB - OBJECTIVE: To determine the effects of concomitant methotrexate (MTX) on the incidence of total knee arthroplasty (TKA) resulting from the progression of joint destruction in patients with rheumatoid arthritis (RA) during longterm treatment with tumor necrosis factor (TNF) inhibitors. METHODS: A total of 155 patients with RA (310 knee joints) received TNF inhibitors at our institute between May 1, 2001, and May 31, 2008. A total of 111 symptomatic (tender and/or swollen) knee joints in 68 patients were retrospectively studied over the course of a minimum of 5 years of followup. The median (interquartile range) followup period was 8.1 (7.0-9.3) years. All data were analyzed using the knee joint as the statistical unit of analysis. TKA during treatment with TNF inhibitors was used as the outcome variable in predictive analyses. The cumulative incidence of TKA was compared by concomitant or no MTX use (MTX+/-). RESULTS: There were 79 subjects (71%) who received concomitant MTX. According to Kaplan-Meier estimates, the cumulative incidence of TKA for the MTX+ group was significantly lower than that for the MTX- group (24% vs 45% at 5 yrs, respectively, p = 0.035). Multivariate analysis using the Cox proportional hazards model revealed that concomitant MTX (HR 0.44, 95% CI 0.22-0.89), Larsen grade (HR 2.93, 95% CI 1.94 4.41), and older age at baseline (HR 1.04, 95% CI 1.01-1.08) were independent predictors of TKA. CONCLUSION: Concomitant MTX reduces the incidence of TKA by 56% in patients with RA during longterm treatment with TNF inhibitors. PMID- 26428207 TI - Subclinical Atherosclerosis Is Not Accelerated in Patients with Ankylosing Spondylitis with Low Disease Activity: New Data and Metaanalysis of Published Studies. AB - OBJECTIVE: Chronic inflammatory rheumatic diseases are associated with accelerated atherosclerosis, but data in ankylosing spondylitis (AS) are limited and the relative contribution of inflammation versus classical cardiovascular (CV) risk factors remains a matter of controversy. We addressed this in an original study and a metaanalysis of previous studies. METHODS: Atheromatic plaques in carotid and femoral arteries, carotid hypertrophy [intima-media thickness (IMT), cross-sectional area], and carotid stiffness by ultrasound, as well as aortic stiffness by pulse wave velocity, were examined in consecutive nondiabetic, CV disease (CVD)-free patients with AS. Healthy individuals carefully matched 1:1 with patients for age, sex, smoking habits, hyperlipidemia, and hypertension served as controls. A metaanalysis of original studies that examined subclinical atherosclerosis in patients with AS versus controls with comparable CVD risk factors was also performed. RESULTS: Carotid and femoral atheromatic plaques were slightly less prevalent compared with controls in a contemporary cohort consisting of 67 patients with AS (82% men), aged 47.5 +/- 12.5 years (mean +/- SD), with a median disease duration of 12 years and a Bath AS Disease Activity Index (BASDAI) of 1.8 (interquartile range 0.4-3.6), of whom 66% were receiving anti-tumor necrosis factor (TNF) treatment. Carotid hypertrophy and stiffness, as well as aortic stiffness, were similar between patients and their matched controls. Metaanalysis of all published studies revealed a significantly increased carotid IMT, but not plaque burden, in AS versus controls. Notably, however, increased IMT was not evident in studies involving patients with low disease activity (mean BASDAI < 4) or in those studies that included > 50% of patients treated with anti-TNF. CONCLUSION: Low AS disease activity is not associated with accelerated atherosclerosis. PMID- 26428205 TI - Hydroxychloroquine Blood Levels in Systemic Lupus Erythematosus: Clarifying Dosing Controversies and Improving Adherence. AB - OBJECTIVE: Hydroxychloroquine (HCQ) is used for its effect on systemic lupus erythematosus (SLE) disease activity and longterm benefits. This can be limited by adherence. One way to assess adherence is to measure blood levels. Conflicting data exist regarding blood levels and disease activity. There is disagreement about dosing; rheumatologists recommend weight-based dosing while some other specialists advocate height-based "ideal body weight" dosing. METHODS: Patients were prescribed HCQ not exceeding 6.5 mg/kg (max 400 mg/day). In hemodialysis, the dose was 200 mg after each session, and in renal insufficiency it was 200 mg/day. Levels were measured at each visit with a therapeutic range of 500-2000 ng/ml. Patients were divided according to baseline blood level. To assess the effect of measurement and counseling on adherence, we compared the proportion of patients with a level of 500 ng/ml or higher based on the number of prior assessments. RESULTS: The proportion of patients with HCQ levels in the therapeutic range differed significantly by age, sex, and Vitamin D level. There was a trend toward lower levels with renal failure. Blood levels were similar regardless of height and ideal body weight. Comparing those with undetectable, subtherapeutic, and therapeutic levels, disease activity decreased (SLE Disease Activity Index 2.92, 2.36, and 2.20, p = 0.04 for trend). At first, 56% were therapeutic, and by the third measurement this increased to 80% (p <= 0.0001). CONCLUSION: There was a trend toward higher disease activity with lower HCQ levels. Renal failure dosing led to suboptimum levels. We show that weight-based dosing (max 400 mg daily) is appropriate and that height does not appear to influence levels. Measurement, counseling, and repeated testing can increase adherence rates. PMID- 26428208 TI - Fragility Fractures in Patients with Rheumatoid Arthritis and Osteoarthritis Compared with the General Population. AB - OBJECTIVE: To determine the rate ratios of hip and distal radius fractures in patients with rheumatoid arthritis (RA), hip osteoarthritis (OA), and knee OA. METHODS: Cohort study using healthcare data (1998-2012) covering the entire population of the Skane region of Sweden. RESULTS: We found an increased rate of hip fracture in both female [standardized fracture rate ratio (SFR) 1.54, 95% CI 1.40-1.70] and male patients with RA (SFR 1.81, 95% CI 1.51-2.17). The hip fracture rate in female OA was reduced by 10-20%, and trochanteric fracture tended to have a higher rate ratio compared with the cervical. CONCLUSION: The 50 80% increased rate of hip fracture adds to the total burden of RA while the shifted distribution of cervical/trochanteric fractures in OA is in support of subchondral bone alterations. PMID- 26428209 TI - Effect of Urate Lowering Therapy on Renal Disease Progression in Hyperuricemic Patients with Chronic Kidney Disease. AB - OBJECTIVE: To determine whether urate lowering therapy (ULT) could delay renal disease progression in hyperuricemic patients with chronic kidney disease (CKD). METHODS: We performed a retrospective review of hyperuricemic patients with stage 3 CKD followed from September 2005 to July 2014 in Dongguk University Ilsan Hospital, Goyang, Korea. A total of 158 eligible patients were identified and 65 of them were treated with ULT in addition to the usual CKD management. We divided the patients according to the use of ULT and compared the estimated glomerular filtration rate (eGFR) change from baseline value and the proportion of renal disease progression (decline of eGFR > 30% of the baseline value, initiation of dialysis or eGFR < 15 ml/min/1.73m(2)) at the time of last followup. Risk factors for renal disease progression were identified by logistic regression analysis. RESULTS: After a median followup of 118.5 weeks (minimum 25, maximum 465), the ULT group showed better outcomes compared to the non-ULT group in terms of eGFR change from baseline (-1.19 +/- 12.07 vs -7.37 +/- 11.17 ml/min/1.73 m(2), p = 0.001) and the proportion of renal disease progression (12.3% vs 27.9%, p = 0.01). Goal-directed ULT showed better clinical outcomes compared to maintaining the initial ULT dose. Actual (area under the SUA-time curve adjusted by total observation time period) serum uric acid was significantly associated with the risk of renal disease progression (p for trend = 0.04) and actual serum uric acid level < 7 mg/dl reduced the risk of renal disease progression by 69.4%. CONCLUSION: ULT significantly delayed renal disease progression in hyperuricemic patients with CKD. Goal-directed ULT seems to be better than continuing the initial ULT prescription. PMID- 26428210 TI - Synthesis of a-Alkylated Ketones via Tandem Acceptorless Dehydrogenation/a Alkylation from Secondary and Primary Alcohols Catalyzed by Metal-Ligand Bifunctional Iridium Complex [Cp*Ir(2,2'-bpyO)(H2O)]. AB - A new strategy for the synthesis of alpha-alkylated ketones via tandem acceptorless dehydrogenation/alpha-alkylation from secondary and primary alcohols was proposed and accomplished. In the presence of metal-ligand bifunctional iridium complex [Cp*Ir(2,2'-bpyO)(H2O)], various desirable products were obtained in high yields. Compared with previous methods for the direct dehydrogenative coupling of secondary alcohols with primary alcohols to alpha-alkylated ketones, this protocol has obvious advantages including complete selectivity for alpha alkylated ketones and more environmentally benign conditions. Notably, the study also exhibited the potential to develop tandem reactions catalyzed using a metal ligand bifunctional iridium complex. PMID- 26428211 TI - Risk of ectopic pregnancy is linked to endometrial thickness in a retrospective cohort study of 8120 assisted reproduction technology cycles. AB - STUDY QUESTION: Is endometrial combined thickness (ECT) measured prior to embryo transfer (ET) associated with ectopic pregnancy (EP)? SUMMARY ANSWER: Following IVF, the risk of EP is 4-fold increased in women with an ECT of <9 mm compared with women with an ECT of >12 mm. WHAT IS KNOWN ALREADY: Known risk factors for EP include tubal damage, maternal cigarette smoking and endometriosis. EP is also more common following IVF but the underlying causes for this remain unclear. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study restricted to all IVF cycles leading to a pregnancy (betahCG > 50 IU/l) between January 2006 and December 2014. A total of 6465 patients achieved a pregnancy in 8120 cycles. Cycles using preimplantation genetic screening or donor oocytes were excluded. PARTICIPANTS/MATERIALS, SETTING, METHODS: This cohort consists of 6465 patients achieving a pregnancy in 6920 stimulated cycles with fresh embryo transfers (STIM ET) and 1200 hormone replacement therapy frozen embryo transfers (HRT-FET) cycles at a private IVF unit (Monash IVF, Melbourne, Australia). ECT was the primary independent variable of interest; the primary outcome was a diagnosis of EP. The dataset was analysed using binary logistic general estimating equations (SPSS v22.0) to calculate odds ratio (OR) for EP adjusted for known confounders (aOR). There was no loss to follow-up in the dataset. MAIN RESULTS AND THE ROLE OF CHANCE: The study groups did not differ significantly prior to IVF treatment. After adjusting for confounders, ECT remained statistically significant as an independent risk factor for EP. Compared with women with an ECT of <9 mm, women with an ECT of 9-12 mm had an aOR of 0.44 (95% CI 0.29-0.69, P < 0.01) and women with an ECT > 12 mm had an aOR of 0.27 (95% CI 0.10-0.77, P = 0.01). These differences remained statistically significant after performing a sensitivity analysis excluding HRT-FET, smokers and patients with tubal infertility. LIMITATIONS, REASONS FOR CAUTION: The study design is retrospective, and it is possible that not all confounders have been accounted for. Measurement of ECT was performed by highly trained sonographers, but some inconsistency between individuals may be present. WIDER IMPLICATIONS OF THE FINDINGS: Our group has previously demonstrated an increased risk of placenta praevia with increased ECT. These new findings suggest that the directionality of the uterine peristalsis waves matters more than their frequency or amplitude. Combining the data from both studies we now hypothesize that increased ECT is a marker for increased fundus-to-cervix uterine peristalsis, explaining both the increased placenta praevia risk and the lower EP risk. Further prospective studies are required to confirm these observations. PMID- 26428212 TI - Spermatogenesis in tumor-bearing testes in germ cell testicular cancer patients. AB - STUDY QUESTION: What are the factors that might indicate a greater likelihood of success in oncologic testicular sperm extraction (onco-TESE)? SUMMARY ANSWER: Smaller tumor diameter and greater noncancerous testicular tissue width (NCTW) are positive predictors of spermatogenesis in patients with testicular germ cell tumors (TGCTs). WHAT IS KNOWN ALREADY: Onco-TESE is a key modality for fertility preservation in cases of inadequate pretreatment sperm collection and azoospermic men with testicular cancer. TGCTs are known to reduce sperm quality such that ~ 10% of these patients are azoospermic, making surgical TESE at the same time as orchiectomy their only means of fertility preservation. STUDY DESIGN, SIZE, DURATION: This study is a retrospective analysis performed in a single university hospital from 2002 to 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were 102 male patients (104 testes) who underwent inguinal orchiectomy and were diagnosed with a germinoma. In each specimen, the Johnsen Score Count (JSC) in seminiferous tubules at each established distance from the tumor margin (1, 2.5, 5, 7.5, 10 and 12.5 mm) was determined. We analyzed the relations between age, tumor histopathologic type, tumor size (maximum diameter), distance from the tumor, non-tumor tissue width and JSC. MAIN RESULTS AND THE ROLE OF CHANCE: The 104 specimens consisted of 78 seminomas and 26 non seminomatous TGCTs. The mean +/- SD JSC was 4.7 +/- 2.4 in seminomas and 3.9 +/- 2.5 in non-seminomatous germ cell tumors, with no significant difference between the two subtypes. Single regression analysis showed that tumor diameter was significantly negatively correlated with spermatogenesis (RC = -0.422, P < 0.001). Multiple linear regression analysis also showed that tumor diameter had a negative influence on spermatogenesis (RC = -0.437, P < 0.001). The greater the distance the seminiferous tubules from the tumor, the better the preservation of spermatogenesis. Mature spermatozoa were identified in 93.0% of patients with a NCTW >= 7.5 mm and in 41.3% of those with NCTW < 7.5 mm (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Study data were obtained retrospectively, which might have affected the quality of data. We were unable to compare spermatogenesis determined using preoperative seminograms with that determined histopathologically. It was not possible to evaluate spermatogenesis in the total volume of noncancerous testicular tissue. WIDER IMPLICATIONS OF THE FINDINGS: When Onco-TESE is conducted at sites distant from tumors, the rate of sperm extraction is high and contamination by tumor cells can be prevented. By measuring non-testicular cancerous margin before the operation, the possibility of sperm extraction can be predicted and biopsy of the contralateral testis can be considered based on the results. PMID- 26428214 TI - Introduction to the special issue on chemical glycobiology: all the aspects are important. PMID- 26428213 TI - Linked data research: a valuable tool in the ART field. PMID- 26428215 TI - Sudden occurrence of Roth spots and retinal hemorrhages following endoscopic adhesiolysis: an SD-OCT evaluation. AB - PURPOSE: To document the occurrence of Roth spots and retinal hemorrhages by spectral-domain optical coherence tomography (SD-OCT) following endoscopic adhesiolysis for failed back surgery syndrome. METHODS: Case report. RESULTS: A 47-year-old patient noted progressive and bilateral visual loss immediately after epidural endoscopy and endoscopic adhesiolysis. Funduscopic examination showed multiple Roth spots and retinal hemorrhages at the posterior pole and the retinal midperiphery in both eyes. Spectral-domain optical coherence tomography demonstrated that Roth spots involved the inner retina, while dot hemorrhages involved the outer retina. Most retinal hemorrhages and Roth spots resolved over 6 weeks, with complete functional recovery in both eyes. However, SD-OCT revealed multiple areas of disruption of the outer retinal layers in the left eye. CONCLUSIONS: Roth spots and retinal hemorrhages can occur after endoscopic spinal surgery. Although hemorrhages resolve quickly over few weeks, SD-OCT can demonstrate that retinal damage might persist, especially in the outer retina. This finding may explain cases of incomplete recovery of visual function after complicated endoscopic adhesiolysis. PMID- 26428216 TI - Atlas OCT: angiography in AMD: comparison with multimodal imaging. PMID- 26428217 TI - Choroidal thickness in diabetic retinopathy in relation to long-term systemic treatments for diabetes mellitus. AB - PURPOSE: To measure central choroidal thickness (CCT) in patients with diabetic retinopathy (DR) and analyze the correlation with clinical backgrounds regarding medications for diabetes mellitus (DM). METHODS: We retrospectively identified 86 patients with DR (172 eyes) and 43 healthy subjects (57 eyes) who underwent spectral-domain optical coherence tomography. Among the 86 patients with DM who had received no intraocular treatments, 61 were diabetic patients who had continuously received systemic treatments for DM (under treatment group). Twenty five were patients who had discontinued the treatments or had not received any treatment for DM until this study started (no treatment group). RESULTS: The results of CCT acquired by 2 masked raters showed a significant correlation coefficient (r = 0.98), indicating high reproducibility in this study. No correlation of CCT was noted between normal (272 +/- 71 um) and DM eyes (264 +/- 77 um), the presence of diabetic macular edema, or CCT and the severity of DR in the patients examined. Interestingly, there was a significant decrease in CCT (175 +/- 42 um) in eyes with mild/moderate nonproliferative DR (NPDR) in the no treatment group (p<0.05), whereas CCT was prominently thicker in eyes with severe NPDR (354 +/- 76 um) and proliferative DR (286 +/- 74 um) than in eyes without DR. CONCLUSIONS: This study demonstrated that CCT was significantly decreased in the presence of mild/moderate NPDR in the no treatment group, suggesting that a continuously high blood sugar state caused by insufficient treatments for DM may facilitate vascular damage in the choroid in the early stage of DR. PMID- 26428218 TI - Enhanced depth imaging optical coherence tomography in adult-onset foveomacular vitelliform dystrophy. AB - PURPOSE: To compare mean choroidal thickness in patients with adult-onset foveomacular vitelliform dystrophy (AOFVD) and healthy subjects, to analyze patients with AOFVD in order to evaluate choroidal thickness disease-related changes, also in relation to the different stages of AOFVD disease and to the retinal pigment epithelium (RPE) features, and to correlate mean choroidal thickness with age in both groups. METHODS: In this prospective observational cross-sectional study, a total of 63 eyes of 51 consecutive subjects were examined, consisting of a control group (n = 28 eyes) and the AOFVD group (n = 35 eyes). A complete ophthalmologic examination, fundus autofluorescence, and spectral-domain optical coherence tomography were performed in all patients. RESULTS: Mean subfoveal choroidal thickness was 214.78 +/- 62.35 um in healthy subjects and 222.31 +/- 73.29 um in the AOFVD group (p = 0.33). In the vitelliruptive group, the mean choroidal thickness was significantly thicker than in the control group at each choroidal location. Mean choroidal thickness was significantly increased in the pseudohypopyon stage when compared to the vitelliform one (+66.34 um, p = 0.02). Eyes with subretinal fluid (SRF) showed significantly thicker choroid when compared with those without SRF. No significant correlations were found between age and choroidal thickness in the study group. CONCLUSIONS: The study of the choroid in patients with AOFVD suggested a possible role in the pathologic changes during the different stages of disease, and could help us to evaluate progression of the disease. Greater choroidal thickness associated with SRF and RPE bumps are signs of RPE alterations and could be related to evolution of the AOFVD lesion to a different stage. PMID- 26428219 TI - Study of spectral-domain optical coherence tomography in children: normal values and influence of age, sex, and refractive status. AB - PURPOSE: To establish normal values for retinal nerve fiber layer (RNFL), macular thickness, and macular volume in children using spectral-domain optical coherence tomography (OCT). METHODS: A descriptive cross-sectional study was performed in healthy children between 3 and 14 years of age. Each child underwent a comprehensive ophthalmic examination that included 3 OCT scans with Spectralis (Heidelberg Engineering, Heidelberg, Germany). All measurements were performed by the same operator, and one eye was randomly selected. The influence of age, sex, and refraction on OCT measurements was analyzed. RESULTS: The sample consisted of 162 Caucasian subjects, mean age 8.1 +/- 3.03 years. The spherical equivalent was 0.03 +/- 0.19 D (range +/-4 D, astigmatism <1 D). The average values were 263.69 +/- 4.54 um for central macular thickness, 0.21 +/- 0.01 mm3 for central macular volume, and 100.45 +/- 1.98 um for RNFL. A significant correlation between RNFL and spherical equivalent was found for the nasal (p = 0.001), inferior (p = 0.009), and inferior nasal (p = 0.005) sectors. No differences were found with regard to sex (p>0.05). However, central macular thickness and central macular volume were correlated with age (p = 0.027, p = 0.02). CONCLUSIONS: This study provides reference values for macular thickness, macular volume, and RNFL in healthy children. PMID- 26428220 TI - Intraocular surgery with melphalan irrigation for vitreous hemorrhage in an only eye with retinoblastoma. AB - PURPOSE: To illustrate the successful outcome of pars plana vitrectomy (PPV) with melphalan irrigation for vitreous hemorrhage (VH) with suspected viable retinoblastoma. Despite the high risk of intraocular surgery, it was performed to preserve the only potentially seeing eye with treated retinoblastoma. METHODS: Vitreous hemorrhage occurred in the only eye of a 4-year-old boy after treatment for recurrent multifocal group C retinoblastoma with systemic chemotherapy (carboplatin, etoposide, and cyclophosphamide; and vincristine, cyclophosphamide, and doxorubicin), ruthenium brachytherapy with plaque repositioning, cryotherapy, and external radiotherapy. The VH developed 8 months after repeated brachytherapy with subsequent intravitreal melphalan chemotherapy. The patient's parents refused to remove the eye. The fellow eye was enucleated earlier because of VH and secondary glaucoma, without histologic signs of a viable tumor. Pars plana lensectomy, 25-G vitrectomy with melphalan irrigation (5 MUg/mL), and silicone oil tamponade were performed. RESULTS: No ophthalmoscopic or morphologic signs of a viable tumor were detected. Four months later, the silicone oil was removed. Visual acuity was 20/200 with aphakic correction. Follow-up for 34 months revealed no signs of tumor recurrence or dissemination. CONCLUSIONS: Despite the high risk of intraocular surgery, the need to preserve the only potentially seeing eye with treated retinoblastoma may require PPV. Thus, in unclear cases of VH with suspected viable tumor, PPV with intraocular melphalan irrigation, with caution, may be a reasonable procedure. PMID- 26428222 TI - Intravitreal injection of recombinant tissue plasminogen activator in submacular hemorrhage: case series. AB - PURPOSE: To report the safety and efficacy of intravitreal recombinant tissue plasminogen activator (rtPA) with gas for managing submacular hemorrhage. METHODS: Patients with submacular hemorrhage centered in or close to the fovea underwent hemorrhage displacement with intravitreal injection of rtPA (50 MUg/0.05 mL) followed by gas injection (0.3 mL SF6). Anatomic and visual outcomes are described. RESULTS: Exudative age-related macular degeneration (AMD) (n = 4) and blunt trauma (n = 2) were the etiologies of submacular hemorrhage in this sample. Intravitreal injection of rtPA decreased the extent of submacular hemorrhage in all eyes, with complete hemorrhage displacement in 2 and partial displacement in 4. Visual acuity remained stable (n = 4) or improved (n = 2) after the procedure. Improvements in anatomic and visual outcomes were less evident in exudative AMD cases, which also had longer hemorrhage duration. Recurrence occurred only in 1 eye. No evident rtPA-associated retinal toxicity was observed. CONCLUSIONS: Untreated submacular hemorrhage has poor visual prognosis. Our results suggest that rtPA injection is a minimally invasive, simple, inexpensive procedure with few related complications. Cost-benefit of this injection seems acceptable. PMID- 26428221 TI - Receiver operating characteristic curve to predict anti-VEGF resistance in retinal vein occlusions and efficacy of Ozurdex. AB - PURPOSE: Current treatment paradigms for macular edema associated with retinal vein occlusions (RVO) often involve initial treatment with anti-vascular endothelial growth factor (VEGF) agents, then switching to intravitreal dexamethasone implant (IDI; Ozurdex, Allergan, Parsippany, NJ) for poor responders. However, many patients undergo multiple injections prior to being declared a nonresponder. We devised a method for prediction of poor anti-VEGF response after one injection, and show that these patients subsequently respond well to IDI. METHODS: This study is a retrospective consecutive interventional case series of patients with RVO receiving anti-VEGF agents that were switched to IDI. Patients were categorized as nonresponders to anti-VEGF agents (edema did not improve) or responders (edema improved, but switched to IDI for longer treatment duration). Receiver operating characteristics (ROC) curve analysis was used to determine cutoffs of reduction in central retinal thickness (CRT) to predict poor response to anti-VEGF treatment. RESULTS: Twenty-three patients met inclusion criteria. There were 14 nonresponders and 9 responders. The ROC curve analysis found that the maximal sensitivity and specificity in correctly identifying responders to anti-VEGF therapy was those with >25% reduction in CRT 1 month after 1 anti-VEGF treatment (sensitivity 0.89, specificity 0.79, area under the curve 0.93). After IDI placement, anti-VEGF nonresponders showed significant improvement in visual acuity (VA) (p = 0.02) and CRT (p = 0.01). CONCLUSIONS: In patients with macular edema secondary to RVOs, a reduction in CRT by <=25%, 1 month after 1 anti-VEGF injection, is predictive of poor response to anti-VEGF treatment. These patients may benefit from earlier conversion to IDI treatment, which in our study, resulted in improved VA and CRT. PMID- 26428223 TI - Angiotensin-(1-7) enhances the effects of angiotensin II on the cardiac sympathetic afferent reflex and sympathetic activity in rostral ventrolateral medulla in renovascular hypertensive rats. AB - Excessive sympathetic activity propels the pathogenesis and progression of organ damage in hypertension. Enhanced cardiac sympathetic afferent reflex (CSAR) is involved in sympathetic activation in hypertension. Given the important role of the renin-angiotensin (Ang) system in regulating sympathetic outflow and cardiovascular activity, the present study aimed to investigate the roles of Ang (1-7) in Ang II-induced CSAR and the sympathetic activation responses in the rostral ventrolateral medulla (RVLM) of hypertensive rats. The two-kidney one clip (2K1C) method was used to induce renovascular hypertension. Responses of renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) to epicardial application of capsaicin were used to evaluate the CSAR in sinoaortic denervated and cervical-vagotomized rats with anesthesia. Both Ang II and Ang-(1 7) in the RVLM caused greater increases in RSNA and MAP in 2K1C rats than in sham operated (sham) rats and enhanced CSAR independently. RVLM pretreatment with Ang (1-7) dose dependently augmented the effects of Ang II on RSNA, MAP, and CSAR in 2K1C rats. Mas receptor antagonist A-779 in the RVLM exhibited more powerful inhibitory effects on RSNA, MAP, and CSAR than the Ang II type 1 (AT1) receptor antagonist losartan. The expression of both the AT1 receptor and Mas receptor proteins in the RVLM increased, but neither the Ang II nor Ang-(1-7) levels in the RVLM changed significantly in the 2K1C rats compared with the sham rats. These results indicate that Ang-(1-7) in the RVLM enhances the CSAR and sympathetic output not only by itself but also through enhancing the effects of Ang II in renovascular hypertensive rats. Both endogenous Ang-(1-7) and Ang II in the RVLM contribute to the enhanced CSAR and sympathetic activation in renovascular hypertension. PMID- 26428224 TI - Use of gastrografin in the management of worm-induced small bowel obstruction in children. AB - OBJECTIVE: Ascaris-induced small bowel obstruction (SBO) is a common sequel of Ascaris lumbricoides (AL) infestation. Most cases respond to conservative treatment practiced in different centers worldwide. We conceived a prospective randomized trial to compare the conservative treatment with gastrografin administered in addition to the conservative treatment. STUDY DESIGN: This prospective randomized study was conducted between January 2011 and June 2014 at Department of Paediatric and Neonatal Surgery, a tertiary-care hospital. Patients were divided into two groups, one group received conservative treatment and the other received gastrografin in addition to conservative treatment. Forty patients having uncomplicated AL-induced SBO were included in each group. Gastrografin was administered through nasogastric tube and serial clinical and radiological monitoring was performed. The duration of hospital stay, time between admission and first oral feed, passage of worms/flatus were compared in the two groups. Student's t test was used for comparing these variables. RESULTS: Average time for passage of flatus or worms and resolution of abdominal signs and was shorter in gastrografin group as compared to the conservative group. This difference was found to be statistically significant. The average duration of hospital stay in gastrografin group was 25.20 +/- 8.01 h whereas it was 61.12 +/- 14.64 h in the conservative group (P < 0.001). The difference in the operation rate was statistically insignificant (2 in gastrografin group and 3 in the conservative group).No serious adverse reaction was noted after gastrografin administration. CONCLUSION: Use of gastrografin resulted in faster relief of signs and symptoms of AL-induced SBO, early passage of worms/flatus and return to oral feeds. However, the role of gastrografin role in reducing the likelihood of laparotomy remains inconclusive. Adverse effects of gastrografin can be prevented if it is used in well-hydrated patients. PMID- 26428225 TI - The Primacy of the Social and Sociogenesis. AB - It has become a truism to state that cultural characteristics (knowledge, identity, practices) are "socially constructed." However, critics point out that the social overwhelmingly is understood as a context-a trivial sense of the social-and that the real social nature of human practices tends not to be shown. The Russian social psychologist L. S. Vygotsky assumes in his late work a primacy of the social such that all higher psychological functions are social relations between people before they are functions. As a result, human development occurs in and as sociogenesis. Grounded in an ethnomethodological take on the social, the purpose of this article is to articulate and develop this unrecognized and unheeded, radical aspect of the late Vygotskian theory, thereby going beyond wrote and may have intended. PMID- 26428227 TI - [Impact of anastomotic leakage on long-term survival in mid-to-low rectal cancer]. AB - BACKGROUND: The occurrence of anastomotic leakage (AL) after sphincter preserving anterior rectal resection in patients with rectal cancer is associated with increased morbidity and mortality. The impact of AL on long-term survival has, however, still not been sufficiently investigated and is currently the subject of controversial discussion. OBJECTIVES: The aim of this study was to investigate the impact of AL on long-term survival in patients with Union of International Cancer Control (UICC) (y)0-III stage mid-to-low rectal cancer who underwent sphincter preserving rectal resection. MATERIAL AND METHODS: A total of 108 patients with a mid-to-low rectal cancer (UICC stage (y)0-III) who underwent sphincter preserving surgery between January 2003 and October 2010 were identified within the institutional prospective colorectal cancer database. The impact of AL on 5-year overall (OS), cancer specific (CSS) and relapse-free survival (RFS) was investigated. RESULTS: The overall leakage rate was 17.6 % (grade A 4.6 %, grade B 4.6 % and grade C 8.3 %). After a median follow-up of 70 months (range 24-123 months), patients with an anastomotic leakage had a significantly decreased 5-year OS (63.6 % versus 87.8 %, p = 0.02), CSS (72.2 % versus 93.5 %, p = 0.02) and RFS rate (61.1 % versus 84.2 %, p = 0.01). In univariable Cox regression analysis AL was associated with an unfavorable OS (hazard ratio HR 3.05, 95 % CI: 1.11-8.39, p = 0.03), CSS (HR 4.21, 95 % CI: 1.13 15.70, p = 0.03) and RFS (HR 3.02, 95 % CI: 1.20-7.58, p = 0.02). CONCLUSION: In the study cohort anastomotic leakage after sphincter preserving anterior resection in patients with mid-to-low rectal cancer was associated with a significantly unfavorable impact on overall and oncological survival. PMID- 26428228 TI - [Laparoscopic liver resection for hepatocellular carcinoma]. PMID- 26428226 TI - iPSC-based drug screening for Huntington's disease. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, caused by an expansion of the CAG repeat in exon 1 of the huntingtin gene. The disease generally manifests in middle age with both physical and mental symptoms. There are no effective treatments or cures and death usually occurs 10-20 years after initial symptoms. Since the original identification of the Huntington disease associated gene, in 1993, a variety of models have been created and used to advance our understanding of HD. The most recent advances have utilized stem cell models derived from HD-patient induced pluripotent stem cells (iPSCs) offering a variety of screening and model options that were not previously available. The discovery and advancement of technology to make human iPSCs has allowed for a more thorough characterization of human HD on a cellular and developmental level. The interaction between the genome editing and the stem cell fields promises to further expand the variety of HD cellular models available for researchers. In this review, we will discuss the history of Huntington's disease models, common screening assays, currently available models and future directions for modeling HD using iPSCs-derived from HD patients. This article is part of a Special Issue entitled SI: PSC and the brain. PMID- 26428229 TI - [KRAS mutations and survival after resection of colorectal liver metastases]. PMID- 26428230 TI - Characteristics of Transmitted Drug-Resistant HIV-1 in Recently Infected Treatment-Naive Patients in Japan. AB - OBJECTIVES: Progress in antiretroviral treatment has led to fewer virological failure cases, but 10%-20% of treatment-naive HIV/AIDS cases are reported to harbor drug-resistant strains, suggesting transmission of drug-resistant HIV. We aimed to determine the trend in prevalence of transmitted drug-resistant (TDR) HIV in Japan, particularly in recently infected patients. METHODS: Drug resistance test was performed on 3904 HIV-1-infected cases newly diagnosed between 2007 and 2012. The number of cases infected within 6 months [recent seroconverters (RS)] was estimated by BED assay of 2700 plasma samples. Characteristics of RS cases were further analyzed. RESULTS: The overall prevalence of TDR was 9.1%, ranging from 7.3% in 2008% to 12.5% in 2010. Among 1403 subtype B/E/D cases with >50 CD4 T cell counts and >1000 HIV copies per milliliter, 468 (33.4%) were estimated to be RS. The prevalence of RS was significantly higher among cases who were male, Japanese, and men who have sex with men. The prevalence of TDR did not differ significantly between recent and long-term seroconverters (8.5% vs. 9.2%, respectively, P = 0.68). Common mutations in both groups were M46I/L and T215 revertants. Furthermore, sequences with these mutations, K103N and D30N/N88D formed clusters on phylogenetic trees. CONCLUSION: Our study clarified an increase in prevalence of TDR in Japan from 2007 to 2012. The phylogenetic clustering of cases with M46I/L or T215 revertants suggests that HIV with these mutations have become circulating strains. Furthermore, detailed analyses showed that Japanese men who have sex with men are more aware of their risk of HIV infection. PMID- 26428231 TI - Incorporating Acute HIV Screening into Routine HIV Testing at Sexually Transmitted Infection Clinics, and HIV Testing and Counseling Centers in Lilongwe, Malawi. AB - BACKGROUND AND OBJECTIVES: Integrating acute HIV-infection (AHI) testing into clinical settings is critical to prevent transmission, and realize potential treatment-as-prevention benefits. We evaluated acceptability of AHI testing and compared AHI prevalence at sexually transmitted infection (STI) clinics and HIV testing and counseling (HTC) clinics in Lilongwe, Malawi. METHODS: We conducted HIV RNA testing for HIV-seronegative patients visiting STI and HTC clinics. AHI was defined as positive RNA and negative/discordant rapid antibody tests. We evaluated demographic, behavioral, and transmission-risk differences between STI and HTC patients and assessed performance of a risk-score for targeted screening. RESULTS: Nearly two-thirds (62.8%, 9280/14,755) of eligible patients consented to AHI testing. We identified 59 persons with AHI (prevalence = 0.64%)-a 0.9% case identification increase. Prevalence was higher at STI [1.03% (44/4255)] than at HTC clinics [0.3% (15/5025), P < 0.01], accounting for 2.3% of new diagnoses vs 0.3% at HTC clinic. Median viral load (VL) was 758,050 copies per milliliter; 25% (15/59) had VL >= 10,000,000 copies per milliliter. Median VL was higher at STI (1,000,000 copies/mL) compared with HTC (153,125 copies/mL, P = 0.2). Among persons with AHI, those tested at STI clinics were more likely to report genital sores compared with those tested at HTC clinics (54.6% vs 6.7%, P < 0.01). The risk score algorithm performed well in identifying persons with AHI at HTC clinics (sensitivity = 73%, specificity = 89%). CONCLUSIONS: The majority of patients consented to AHI testing. AHI prevalence was substantially higher in STI clinics than HTC clinics. Remarkably high VLs and concomitant genital scores demonstrate the potential for transmission. Universal AHI screening at STI clinics, and targeted screening at HTC centers, should be considered. PMID- 26428232 TI - Constructing a synthetic constitutive metabolic pathway in Escherichia coli for (R, R)-2,3-butanediol production. AB - Many microorganisms could naturally produce (R, R)-2,3-butanediol ((R, R)-2,3 BD), which has unique applications due to its special chiral group and spatial configuration. But the low enantio-purity of the product hindered the development of large-scale production. In this work, a synthetic constitutive metabolic pathway for enantiomerically pure (R, R)-2,3-BD biosynthesis was constructed in Escherichia coli with vector pUC6S, which does not contain any lac sequences. The expression of this artificial constructed gene cluster was optimized by using two different strength of promoters (AlperPLTet01 (P01) and AlperBB (PBB)). The strength of P01 is twice stronger than PBB. The fermentation results suggested that the yield of (R, R)-2,3-BD was higher when using the stronger promoter. Compared with the wild type, the recombinant strain E. coli YJ2 produced a small amount of acetic acid and showed higher glucose consumption rate and higher cell density, which indicated a protection against acetic acid inhibition. In order to further increase the (R, R)-2,3-BD production by reducing the accumulation of its precursor acetoin, the synthetic operon was reconstructed by adding the strong promoter P01 in front of the gene ydjL coding for the enzyme of (R, R)-2,3-BD dehydrogenase which catalyzes the conversion of acetoin to (R, R)-2,3-BD. The engineered strain E. coli YJ3 showed a 20 % decrease in acetoin production compared with that of E. coli YJ2. After optimization the fermentation conditions, 30.5 g/L of (R, R)-2,3-BD and 3.2 g/L of acetoin were produced from 80 g/L of glucose within 18 h, with an enantio-purity over 99 %. PMID- 26428233 TI - Bioaugmentation of anaerobic sludge digestion with iron-reducing bacteria: process and microbial responses to variations in hydraulic retention time. AB - Although anaerobic digestion (AD) is a widely used option to manage waste activated sludge (WAS), there are some drawbacks related to its slow reaction rate and low energy productivity. This study examined an anaerobic WAS digester, augmented with an iron-reducing microbial consortium, relative to changes in microbial community structure and process performance at decreasing hydraulic retention times (HRTs) of 20 to 10 days. The enhanced methanation performance (approximately 40 % increase in methane yield) by the bioaugmentation was sustained until the HRT was decreased to 12.5 days, under Fe(3+)-rich conditions (ferric oxyhydroxide, 20 mM Fe). Enhanced iron-reducing activity was evidenced by the increased Fe(2+) to total Fe ratio maintained above 50 % during the stable operational phases. A further decrease in HRT to 10 days resulted in a significant performance deterioration, along with a drop in the Fe(2+) to total Fe ratio to <35 %, after four turnovers of operation. Prevailing existence of putative iron-reducing bacteria (IRBs) was identified by denaturing gradient gel electrophoresis (DGGE), with Spirochaetaceae- and Thauera-related organisms being dominant members, and clear dominance shifts among them with respect to decrease in HRT were observed. Lowering HRT led to evident shifts in bacterial community structure likely associated with washout of IRBs, leading to decreases in iron respiration activity and AD performance at a lower HRT. The bacterial community structure shifted dynamically over phases, and the community transitions correlated well with the changes in process performance. Overall, the combined biostimulation and bioaugmentation investigated in this study proved effective for enhanced methane recovery from anaerobic WAS digestion, which suggests an interesting potential for high-rate AD. PMID- 26428234 TI - Mutagenesis of conserved active site residues of dihydrolipoamide succinyltransferase enhances the accumulation of alpha-ketoglutarate in Yarrowia lipolytica. AB - alpha-Ketoglutarate (alpha-KG) is an important intermediate in the tricarboxylic acid cycle and has broad applications. The mitochondrial ketoglutarate dehydrogenase (KGDH) complex catalyzes the oxidation of alpha-KG to succinyl-CoA. Disruption of KGDH, which may enhance the accumulation of alpha-KG theoretically, was found to be lethal to obligate aerobic cells. In this study, individual overexpression of dihydrolipoamide succinyltransferase (DLST), which serves as the inner core of KGDH, decreased overall activity of the enzyme complex. Furthermore, two conserved active site residues of DLST, His419, and Asp423 were identified. In order to determine whether these residues are engaged in enzyme reaction or not, these two conserved residues were individually mutated. Analysis of the kinetic parameters of the enzyme variants provided evidence that the catalytic reaction of DLST depended on residues His419 and Asp423. Overexpression of mutated DLST not only impaired balanced assembly of KGDH, but also disrupted the catalytic integrity of the enzyme complex. Replacement of the Asp423 residue by glutamate increased extracellular alpha-KG by 40 % to 50 g L(-1) in mutant strain. These observations uncovered catalytic roles of two conserved active site residues of DLST and provided clues for effective metabolic strategies for rational carbon flux control for the enhanced production of alpha-KG and related bioproducts. PMID- 26428235 TI - Targeting c-kit receptor in neuroblastomas and colorectal cancers using stem cell factor (SCF)-based recombinant bacterial toxins. AB - Autocrine activation of c-kit (KIT receptor tyrosine kinase) has been postulated to be a potent oncogenic driver in small cell lung cancer, neuroblastoma (NB), and poorly differentiated colorectal carcinoma (CRC). Although targeted therapy involving tyrosine kinase inhibitors (TKIs) such as imatinib mesylate is highly effective for gastrointestinal stromal tumor carrying V560G c-kit mutation, it does not show much potential for targeting wild-type KIT (WT-KIT). Our study demonstrates the role of stem cell factor (SCF)-based toxin conjugates for targeting WT-KIT-overexpressing malignancies such as NBs and CRCs. We constructed SCF-based recombinant bacterial toxins by genetically fusing mutated form of natural ligand SCF to receptor binding deficient forms of Diphtheria toxin (DT) or Pseudomonas exotoxin A (ETA') and evaluated their efficacy in vitro. Efficient targeting was achieved in all receptor-positive neuroblastoma (IMR-32 and SHSY5Y) and colon cancer cell lines (COLO 320DM, HCT 116, and DLD-1) but not in receptor negative breast carcinoma cell line (MCF-7) thereby proving specificity. While dose- and time-dependent cytotoxicity was observed in both neuroblastoma cell lines, COLO 320DM and HCT 116 cells, only an anti-proliferative effect was observed in DLD-1 cells. We prove that these novel targeting agents have promising potential as KIT receptor tyrosine kinase targeting system. PMID- 26428236 TI - Production of halophilic proteins using Haloferax volcanii H1895 in a stirred tank bioreactor. AB - The success of biotechnological processes is based on the availability of efficient and highly specific biocatalysts, which can satisfy industrial demands. Extreme and remote environments like the deep brine pools of the Red Sea represent highly interesting habitats for the discovery of novel halophilic and thermophilic enzymes. Haloferax volcanii constitutes a suitable expression system for halophilic enzymes obtained from such brine pools. We developed a batch process for the cultivation of H. volcanii H1895 in controlled stirred-tank bioreactors utilising knockouts of components of the flagella assembly system. The standard medium Hv-YPC was supplemented to reach a higher cell density. Without protein expression, cell dry weight reaches 10 g L(-1). Two halophilic alcohol dehydrogenases were expressed under the control of the tryptophanase promoter p.tna with 16.8 and 3.2 mg gCDW (-1), respectively, at a maximum cell dry weight of 6.5 g L(-1). Protein expression was induced by the addition of L tryptophan. Investigation of various expression strategies leads to an optimised two-step induction protocol introducing 6 mM L-tryptophan at an OD650 of 0.4 followed by incubation for 16 h and a second induction step with 3 mM L tryptophan followed by a final incubation time of 4 h. Compared with the uncontrolled shaker-flask cultivations used until date, dry cell mass concentrations were improved by a factor of more than 5 and cell-specific enzyme activities showed an up to 28-fold increased yield of the heterologous proteins. PMID- 26428237 TI - Unveiling PHA-storing populations using molecular methods. AB - Enrichment of mixed microbial cultures (MMCs) in polyhydroxyalkanoate (PHA) storing microorganisms must take place to develop a successful PHA production process. Moreover, throughout the operational period of a MMC system, the population needs to be checked in order to understand the changes in the performance that eventually occurred. For these reasons, it is necessary to monitor the population evolution, in order to identify the different groups of microorganisms and relate them with the storage capacity and kinetics of the MMC. Regarding this particular process, several culture-independent molecular techniques were already applied, with the use of hybridization techniques such fluorescence in situ hybridization and also PCR-based methods like denaturing gradient gel electrophoresis, terminal restriction fragment length polymorphism, pyrosequencing, and quantitative PCR standing out. This review intends, thus, to look at the molecular methods currently applied in monitoring the PHA-storing population evolution and how they can be combined with the evolutionary engineering step in order to optimize the overall process. PMID- 26428238 TI - Biogas desulfurization using autotrophic denitrification process. AB - The aim of this study was to evaluate the performance of an autotrophic denitrification process for desulfurization of biogas produced from a chicken manure digester. A laboratory scale upflow fixed bed reactor (UFBR) was operated for 105 days and fed with sodium sulfide or H2S scrubbed from the biogas and nitrate as electron donor and acceptor, respectively. The S/N ratio (2.5 mol/mol) of the feed solution was kept constant throughout the study. When the UFBR was fed with sodium sulfide solution with an influent pH of 7.7, about 95 % sulfide and 90 % nitrate removal efficiencies were achieved. However, the inlet of the UFBR was clogged several times due to the accumulation of biologically produced elemental sulfur particles and the clogging resulted in operational problems. When the UFBR was fed with the H2S absorbed from the biogas and operated with an influent pH of 8-9, around 98 % sulfide and 97 % nitrate removal efficiencies were obtained. In this way, above 95 % of the H2S in the biogas was removed as elemental sulfur and the reactor effluent was reused as scrubbing liquid without any clogging problem. PMID- 26428239 TI - Trophic regulation of autoaggregation in Pseudomonas taiwanensis VLB120. AB - Five mutants of Pseudomonas taiwanensis VLB120DeltaCeGFP showed significant autoaggregation when growing on defined carbohydrates or gluconate, while they grew as suspended cells on complex medium and on organic acids like citrate and succinate. Surprisingly, the respective mutations affected very different genes, although all five strains exhibited the same behaviour of aggregate formation. To elucidate the mechanism of the aggregative behaviour, the microbial adhesion to hydrocarbons (MATH) assay and contact angle measurements were performed that pointed to an increased cell surface hydrophobicity. Moreover, investigations of the outer layer of the cell membrane revealed a reduced amount of O-specific polysaccharides in the lipopolysaccharide of the mutant cells. To determine the regulation of the aggregation, reverse transcription quantitative real-time PCR was performed and, irrespective of the mutation, the transcription of a gene encoding a putative phosphodiesterase, which is degrading the global second messenger cyclic diguanylate, was decreased or even deactivated in all mutants. In summary, it appears that the trophic autoaggregation was regulated via cyclic diguanylate and a link between the cellular cyclic diguanylate concentration and the lipopolysaccharide composition of P. taiwanensis VLB120DeltaCeGFP is suggested. PMID- 26428240 TI - Enzymatic processing of protein-based fibers. AB - Wool and silk are major protein fiber materials used by the textile industry. Fiber protein structure-function relationships are briefly described here, and the major enzymatic processing routes for textiles and other novel applications are deeply reviewed. Fiber biomodification is described here with various classes of enzymes such as protease, transglutaminase, tyrosinase, and laccase. It is expected that the reader will get a perspective on the research done as a basis for new applications in other areas such as cosmetics and pharma. PMID- 26428241 TI - Contrasting microbial community composition and function perspective in sections of a full-scale coking wastewater treatment system. AB - To characterize the microbial community of the coking wastewater (CWW) treatment system and to study the effects of CWW characteristics and operational parameters on microbial communities, active sludge samples were collected from a full-scale CWW treatment plant using three-phase fluidized bed biological reactors. High throughput MiSeq sequencing was used to examine the 16S rRNA genes of microbiology, revealing a distinct microbial composition among the active sludge samples of three sequential bioreactors. Pseudomonas, Comamonas, and Thiobacillus related sequences dominated in the anaerobic bioreactor A, aerobic bioreactor O1, and aerobic bioreactor O2 active sludge with relative abundance of 72.59, 56.75, and 27.82 %, respectively. The physico-chemical characteristics of CWW were analyzed by standard methods and operational parameters were recorded to examine their effects on the microbial communities. The redundancy analysis (RDA) results showed that the bacterial communities of bioreactors A, O1, and O2 correlated strongly with cyanides, phenols, and ammonia, respectively. These results expand the knowledge about the biodiversity and population dynamics of microorganisms and discerned the relationships between bacterial communities and environmental variables in the biological treatment processes in the full-scale CWW treatment system. PMID- 26428242 TI - Tryptophan promotes morphological and physiological differentiation in Streptomyces coelicolor. AB - The molecular mechanisms regulating tryptophan biosynthesis in actinomycetes are poorly understood; similarly, the possible roles of tryptophan in the differentiation program of microorganism life-cycle are still underexplored. To unveil the possible regulatory effect of this amino acid on gene expression, an integrated study based on quantitative teverse transcription-PCR (qRT-PCR) and proteomic approaches was performed on the actinomycete model Streptomyces coelicolor. Comparative analyses on the microorganism growth in a minimal medium with or without tryptophan supplementation showed that biosynthetic trp gene expression in S. coelicolor is not subjected to a negative regulation by the presence of the end product. Conversely, tryptophan specifically induces the transcription of trp genes present in the biosynthetic gene cluster of the calcium-dependent antibiotic (CDA), a lipopeptide containing D- and L-tryptophan residues. In addition, tryptophan stimulates the transcription of the CDA gene cluster regulator cdaR and, coherently, CDA production. Surprisingly, tryptophan also promotes the production of actinorhodin, another antibiotic that does not contain this amino acid in its structure. Combined 2D-DIGE and nano liquid chromatography electrospray linear ion trap tandem mass spectrometry (LC-ESI-LIT MS/MS) analyses revealed that tryptophan exerts a growth-stage-dependent global effect on S. coelicolor proteome, stimulating anabolic pathways and promoting the accumulation of key factors associated with morphological and physiological differentiation at the late growth stages. Phenotypic observations by scanning electron microscopy and spore production assays demonstrated an increased sporulation in the presence of tryptophan. Transcriptional analysis of catabolic genes kynA and kynB suggested that the actinomycete also uses tryptophan as a carbon and nitrogen source. In conclusion, this study originally provides the molecular basis underlying the stimulatory effect of tryptophan on the production of antibiotics and morphological development program of this actinomycete. PMID- 26428243 TI - Characterization of a unique Caulobacter crescentus aldose-aldose oxidoreductase having dual activities. AB - We describe here the characterization of a novel enzyme called aldose-aldose oxidoreductase (Cc AAOR; EC 1.1.99) from Caulobacter crescentus. The Cc AAOR exists in solution as a dimer, belongs to the Gfo/Idh/MocA family and shows homology with the glucose-fructose oxidoreductase from Zymomonas mobilis. However, unlike other known members of this protein family, Cc AAOR is specific for aldose sugars and can be in the same catalytic cycle both oxidise and reduce a panel of monosaccharides at the C1 position, producing in each case the corresponding aldonolactone and alditol, respectively. Cc AAOR contains a tightly bound nicotinamide cofactor, which is regenerated in this oxidation-reduction cycle. The highest oxidation activity was detected on D-glucose but significant activity was also observed on D-xylose, L-arabinose and D-galactose, revealing that both hexose and pentose sugars are accepted as substrates by Cc AAOR. The configuration at the C2 and C3 positions of the saccharides was shown to be especially important for the substrate binding. Interestingly, besides monosaccharides, Cc AAOR can also oxidise a range of 1,4-linked oligosaccharides having aldose unit at the reducing end, such as lactose, malto- and cello oligosaccharides as well as xylotetraose. (1)H NMR used to monitor the oxidation and reduction reaction simultaneously, demonstrated that although D-glucose has the highest affinity and is also oxidised most efficiently by Cc AAOR, the reduction of D-glucose is clearly not as efficient. For the overall reaction catalysed by Cc AAOR, the L-arabinose, D-xylose and D-galactose were the most potent substrates. PMID- 26428244 TI - Inoculum pre-treatment affects the fermentative activity of hydrogen-producing communities in the presence of 5-hydroxymethylfurfural. AB - To enhance the productivity of mixed microbial cultures for fermentative bio hydrogen production, chemical-physical pre-treatments of the original seed are needed to suppress the activity of hydrogen (H2)-consuming microbes. This approach might influence negatively the composition and diversity of the hydrogen producing community with consequences on the functional stability of the H2 producing systems in case of perturbations. In this study, we aimed at investigating the effect of different types of pre-treatment on the performance of hydrogen production systems in the presence of an inhibitor, such as 5 hydroxymethylfurfural (HMF). The efficiency and the microbial community structure of batch reactors amended with HMF and inoculated with non-pretreated and pretreated (acid, heat shock, and aeration) anaerobic sludge were evaluated and compared with control systems. The type of pre-treatments influenced the microbial community assembly and activity in inhibited systems, with significant effect on the performance. Cumulative H2 production tests showed that the pre aerated systems (control and HMF inhibited) were the most efficient, while the difference of the lag phase of the pre-acidified control and HMF-added test was negligible. Analyses of the structure of the enriched microbial community in the systems through PCR-denaturing gradient gel electrophoresis (DGGE) followed by band sequencing revealed that the differences in performance were mostly related to shifts in the metabolic pathways rather than in the predominant species. In conclusion, the findings suggest that the use of specific inoculum pre-treatment could contribute to regulate the metabolic activity of the fermentative H2 producing bacteria in order to enhance the bio-energy production. PMID- 26428245 TI - Receptor Dissociation and B-Cell Activation. AB - The B-cell antigen receptor (BCR) is one of the most abundant receptors on the surface of B cells with roughly 100,000-200,000 copies per cell. Signaling through the BCR is crucial for the activation and differentiation of B cells. Unlike other receptors, the BCR can be activated by a large set of structurally different ligands, but the molecular mechanism of BCR activation is still a matter of controversy. Although dominant for a long time, the cross-link model (CLM) of BCR activation is not supported by recent studies of the nanoscale organization of the BCR on the surface of resting B cells. In contrast to the prediction of CLM, the numerous BCR complexes on these cells are not randomly distributed monomers but rather form oligomers which reside within membrane confinements. This finding is more in line with the dissociation activation model (DAM), wherein B-cell activation is accompanied by an opening of the auto inhibited BCR oligomers instead of a cross-linking of the BCR monomers. In this review, we discuss in detail the new findings and their implications for BCR signaling. PMID- 26428246 TI - Penetration of Treosulfan and its Active Monoepoxide Transformation Product into Central Nervous System of Juvenile and Young Adult Rats. AB - Treosulfan (TREO) is currently investigated as an alternative treatment of busulfan in conditioning before hematopoietic stem cell transplantation. The knowledge of the blood-brain barrier penetration of the drug is still scarce. In this paper, penetration of TREO and its active monoepoxide (S,S-EBDM) and diepoxide (S,S-DEB) into the CNS was studied in juvenile (JR) and young adult rats (YAR) for the first time. CD rats of both sexes (n = 96) received an intravenous dose of TREO 500 mg/kg b.wt. Concentrations of TREO, S,S-EBDM, and S,S-DEB in rat plasma, brain, and cerebrospinal fluid (CSF, in YAR only) were determined by validated bioanalytical methods. Pharmacokinetic calculations were performed in WinNonlin using a noncompartmental analysis and statistical evaluation was done in Statistica software. In male JR, female JR, male YAR, and female YAR, the brain/plasma area under the curve (AUC) ratio for unbound TREO was 0.14, 0.17, 0.10, and 0.07 and for unbound S,S-EBDM, it was 0.52, 0.48, 0.28, and 0.22, respectively. The CSF/plasma AUC ratio in male and female YAR was 0.12 and 0.11 for TREO and 0.66 and 0.64 for S,S-EBDM, respectively. Elimination rate constants of TREO and S,S-EBDM in all the matrices were sex-independent with a tendency to be lower in the JR. No quantifiable levels of S,S-DEB were found in the studied samples. TREO and S,S-EBDM demonstrated poor and sex-independent penetration into CNS. However, the brain exposure was greater in juvenile rats, so very young children might potentially be more susceptible to high-dose TREO related CNS exposure than young adults. PMID- 26428247 TI - Two-component regulatory systems: The moment of truth. PMID- 26428248 TI - The Tunisian oasis ecosystem is a source of antagonistic Bacillus spp. producing diverse antifungal lipopeptides. AB - The use of microbial products has become a promising alternative approach to controlling plant diseases caused by phytopathogenic fungi. Bacteria isolated from the date palm tree rhizosphere of the Tunisian oasis ecosystem could provide new biocontrol microorganisms adapted to extreme conditions, such as drought, salinity and high temperature. The aim of this study was to screen bacteria isolated from the rhizosphere of the date palm tree for their ability to inhibit phytopathogenic fungi, and to identify molecules responsible for their antifungal activity. Screening for antifungal activity was performed on twenty-eight isolates. Five antagonistic isolates were selected and identified as different species of Bacillus using phenotypical methods and a molecular approach. The five antagonistic Bacillus isolated showed tolerance to abiotic stresses (high temperature, salinity, drought). Their ability to produce lipopeptides was investigated using a combination of two techniques: PCR amplification and MALDI ToF mass spectrometry. Analyses revealed that the antagonistic isolates produced a high diversity of lipopeptides that belonged to surfactin, fengycin, iturin and kurstakin families. Their antagonistic activity, related to their capacity for producing diverse antifungal lipopeptides and their tolerance to abiotic stresses, highlighted Bacillus strains isolated from the rhizosphere of the date palm tree as potential biocontrol agents for combatting plant diseases in extreme environments. PMID- 26428249 TI - Long-term Safety and Efficacy of Tapentadol Extended Release Following up to 2 Years of Treatment in Patients With Moderate to Severe, Chronic Pain: Results of an Open-label Extension Trial. AB - PURPOSE: Tapentadol extended release (ER) has demonstrated efficacy and safety for the management of moderate to severe, chronic pain in adults. This study evaluated the long-term safety and tolerability of tapentadol ER in patients with chronic osteoarthritis or low back pain. METHODS: Patients were enrolled in this 1-year, open-label extension study after completing one of two 15-week, placebo controlled studies of tapentadol ER and oxycodone controlled release (CR) for osteoarthritis knee pain (NCT00421928) or low back pain (NCT00449176), a 7-week crossover study between tapentadol immediate release and tapentadol ER for low back pain (NCT00594516), or a 1-year safety study of tapentadol ER and oxycodone CR for osteoarthritis or low back pain (NCT00361504). After titrating the drug to an optimal dose, patients received tapentadol ER (100-250 mg BID) for up to 1 year (after finishing treatment in the preceding studies); patients who were previously treated with tapentadol ER in the 1-year safety study received tapentadol ER continuously for up to 2 years in total. FINDINGS: Of the 1,154 patients in the safety population, 82.7% were aged >65 years and 57.9% were female; 50.1% had mild baseline pain intensity. Mean (SD) pain intensity scores (11-point numerical rating scale) were 3.9 (2.38) at baseline (end of preceding study) and 3.7 (2.42) at end point, indicating that pain relief was maintained during the extension study. Improvements in measures of quality of life (eg, EuroQol-5 Dimension and the 36-item Short Form Health Survey [SF-36]) health status questionnaires) achieved during the preceding studies were maintained during the open-label extension study. Tapentadol ER was associated with a safety and tolerability profile comparable to that observed in the preceding studies. The most common treatment-emergent adverse events (incidence >=10%; n = 1154) were headache (13.1%), nausea (11.8%), and constipation (11.1%). Similar efficacy and tolerability results were shown for patients who received up to 2 years of tapentadol ER treatment. IMPLICATIONS: Pain relief and improvements in quality of life achieved during the preceding studies were maintained throughout this extension study, during which tapentadol ER was well tolerated for the long-term treatment of chronic osteoarthritis or low back pain over up to 2 years of treatment. (ClinicalTrials.gov identifier: NCT00487435.). PMID- 26428250 TI - Gastroesophageal Reflux Disease and Sleeve Gastrectomy. AB - Gastroesophageal reflux disease (GERD) and/or hiatus hernia (HH) are one of the most common disorders of the upper gastrointestinal tract. Despite the positive effect of sleeve gastrectomy (SG) regarding weight loss and improvement in obesity co-morbidities, there are concerns about the development of de novo gastroesophageal reflux disease or worsening the existing GERD after this bariatric operation. Furthermore, controversy exists on the consequences of SG in lower esophageal sphincter function and about the ideal procedure when a hiatus hernia is preoperatively diagnosed or discovered during the laparoscopic SG. This review systematically investigates the incidence, the pathophysiology of GERD and/or HH in morbidly obese individuals before and after SG, and the treatment options for concomitant HH repair during laparoscopic sleeve gastrectomy. PMID- 26428251 TI - Early Weight Loss as a Predictor of 2-Year Weight Loss and Resolution of Comorbidities After Sleeve Gastrectomy. AB - BACKGROUND: The objective of this study was to investigate whether early postoperative weight loss predicts weight loss 1 and 2 years after laparoscopic sleeve gastrectomy (LSG) and to determine its effect on the resolution of comorbidities. METHODS: This was a prospective study of patients who underwent LSG at Jordan University Hospital from February 2009 to January 2014. RESULTS: One hundred ninety patients (mean age 34.0 +/- 10.8 years; mean preoperative body mass index 46.2 +/- 7.7 kg/m(2)) were included in the study. Of these, 146 were followed for 1 year and 73 were followed for 2 years. Thirty patients (20.5 %) had hypertension, 23 (15.8 %) had diabetes, 78 (53.4 %) had hyperlipidemia, 30 (20.5 %) had obstructive sleep apnea, and 50 (34.2 %) had more than one comorbidity. The percentage of excess weight loss (%EWL) was 22.7 +/- 8.1, 75.1 +/- 22.8, and 72.6 +/- 17.5 at 1, 12, and 24 months, respectively. Fifty-five patients (37.7 %) had a 1-year %EWL of >=80 %, and 29 (39.7 %) had a 2-year %EWL of >=80 %. Linear regression analysis showed a strong correlation between 1-month %EWL and %EWL at 1 year (r (2) = 0.23, p < 0.001) and 2 years (r (2) = 0.28, p < 0.001). Resolution of comorbidities was associated with higher %EWL achieved at 1 year, but early postoperative weight loss did not have a significant effect on comorbidity resolution. CONCLUSIONS: Early postoperative weight loss can be used to identify and target poor responders. PMID- 26428252 TI - Association Between Bariatric Surgery and Bone Metabolism. PMID- 26428253 TI - Marriage and Weight Loss Surgery: a Narrative Review of Patient and Spousal Outcomes. AB - Long-term weight maintenance following weight loss surgery (WLS) may be challenging for patients without supportive spouses. The health behaviors and relationship quality of spouses pre- and post-WLS have rarely been explored, leaving providers with little guidance on how to engage spouses in treatment. The purpose of this review is to synthesize the empirical research on relationship factors and WLS among married couples. The identified articles (N = 13) reported that the amount of weight lost post-WLS tended to be lower for married patients, couples' relationship quality tended to decline from pre- to post-WLS, and sexual contact increased post-WLS. Future research should explore how the relationship factors and quality of couples may influence patients' WLS outcomes over time to identify ways that interventions can enhance the couple's relationship and health. PMID- 26428254 TI - Routine Liver Biopsy During Bariatric Surgery: an Analysis of Evidence Base. AB - Non-alcoholic fatty liver disease and non-alcoholic steato-hepatitis are common in patients undergoing bariatric surgery. Non-alcoholic steato-hepatitis can progress to cirrhosis of the liver and hepatocellular carcinoma. Non-invasive methods of diagnosing non-alcoholic steato-hepatitis are not as accurate as liver biopsy, and bariatric surgery presents a unique opportunity to carry out a simultaneous liver biopsy. Routine liver biopsy can help early and accurate diagnosis of obesity-associated liver conditions. This has led some surgeons to argue for routine liver biopsy at the time of bariatric surgery. However, most bariatric surgeons remain unconvinced and liver biopsy is currently not routine practice with bariatric surgery. This review examines published scientific literature to ascertain the usefulness of routine liver biopsy at the time of bariatric surgery. PMID- 26428255 TI - Wolbachia spread dynamics in stochastic environments. AB - Dengue fever is a mosquito-borne viral disease with 100 million people infected annually. A novel strategy for dengue control uses the bacterium Wolbachia to invade dengue vector Aedes mosquitoes. As the impact of environmental heterogeneity on Wolbachia spread dynamics in natural areas has been rarely quantified, we develop a model of differential equations for which the environmental conditions switch randomly between two regimes. We find some striking phenomena that random regime transitions could drive Wolbachia to extinction from certain initial states confirmed Wolbachia fixation in homogeneous environments, and mosquito releasing facilitates Wolbachia invasion more effectively when the regimes transit frequently. By superimposing the phase spaces of the ODE systems defined in each regime, we identify the threshold curves below which Wolbachia invades the whole population, which extends the theory of threshold infection frequency to stochastic environments. PMID- 26428257 TI - Modeling spatial trajectories in dynamics testing using basis splines: application to tracking human volunteers in low-speed frontal impacts. AB - Designing motor vehicle safety systems requires knowledge of whole body kinematics during dynamic loading for occupants of varying size and age, often obtained from sled tests with postmortem human subjects and human volunteers. Recently, we reported pediatric and adult responses in low-speed (<4 g) automotive-like impacts, noting reductions in maximum excursion with increasing age. Since the time-based trajectory shape is also relevant for restraint design, this study quantified the time-series trajectories using basis splines and developed a statistical model for predicting trajectories as a function of body dimension or age. Previously collected trajectories of the head, spine, and pelvis were modeled using cubic basis splines with eight control points. A principal component analysis was conducted on the control points and related to erect seated height using a linear regression model. The resulting statistical model quantified how trajectories became shorter and flatter with increasing body size, corresponding to the validation data-set. Trajectories were then predicted for erect seated heights corresponding to pediatric and adult anthropomorphic test devices (ATDs), thus generating performance criteria for the ATDs based on human response. This statistical model can be used to predict trajectories for a subject of specified anthropometry and utilized in subject-specific computational models of occupant response. PMID- 26428258 TI - A flavonoid compound from Chrysosplenium nudicaule inhibits growth and induces apoptosis of the human stomach cancer cell line SGC-7901. AB - CONTEXT: Gastric cancer remains highly prevalent, but treatment options are limited. Natural products have proved to be a rich source of anticancer drugs. Chrysosplenium nudicaule Ledeb. (Saxifragaceae) is a perennial herb that grows in the highlands of China. It has been used as a traditional Chinese medicine to treat digestive diseases for hundreds of years. Recent studies revealed that this herb had anticancer activity, and the flavonoids were speculated to be the effective components. 6,7,3'-Trimethoxy-3,5,4'-trihydroxy flavone (TTF) and 5,4' dihydroxy-3,6,3'trimethoxy-flavone-7-O-beta-d-glucoside (DTFG) are flavonoid compounds isolated from Chrysosplenium nudicaule. OBJECTIVE: This study examined the effect of TTF and DTFG on SGC-7901 human stomach cancer cell in vitro to determine the anticancer and induction of apoptosis properties of TTF. MATERIALS AND METHODS: The proliferation of cells treated with 32, 16, 8, 4, and 2 MUg/mL of TTF or DTFG for 24, 48, and 72 h was assessed by the MTT assay. After being treated with TTF, the apoptosis of SGC-7901 cells was assessed by acridine orange staining, ultrastructure, electrophoresis of DNA fragmentation, and flow cytometry. RESULTS: Results indicated that TTF inhibited the growth of cancer cells with an IC50 value of 8.33 MUg/mL after 72 h incubation. However, DTFG showed no inhibitory effect on the growth of the cancer cell. Further studies on TTF also confirmed that it was able to induce apoptosis of SGC-7901 cells at a concentration as low as 4 MUg/mL. DISCUSSION AND CONCLUSION: The apoptotic effect of TTF makes it a promising candidate for future chemotherapeutic application in treating stomach cancer. PMID- 26428259 TI - ZnO/CoO and ZnCo2O4 Hierarchical Bipyramid Nanoframes: Morphology Control, Formation Mechanism, and Their Lithium Storage Properties. AB - Mastery over the structure of nanoscale materials can effectively tailor and regulate their electrochemical properties, enabling improvement in both rate capability and cycling stability. We report the shape-controlled synthesis of novel mesoporous bicomponent-active ZnO/CoO hierarchical multilayered bipyramid nanoframes (HMBNFs). The as-synthesized micro/nanocrystals look like multilayered bipyramids and consist of a series of structural units with similar frames and uniform sheet branches. The use of an appropriate straight-chain monoalcohol was observed to be critical for the formation of HMBNFs. In addition, the structure of HMBNFs could be preserved only in a limited range of the precursor ratio. An extremely fast crystal growth process and an unusual transverse crystallization of the ZnCo-carbonate HMBNFs were newly discovered and proposed. By calcination of ZnCo-carbonate HMBNFs at the atmosphere of nitrogen and air, ZnO/CoO and ZnCo2O4 HMBNFs were obtained, respectively. Compared to the ZnCo2O4 HMBNFs, the ZnO/CoO HMBNFs with a uniform distribution of nanocrystal ZnO and CoO subunits exhibited enhanced electrochemical activity, including greater rate capability and longer cycling performance, when evaluated as an anode material for Li-ion batteries. The superior electrochemical performance of the ZnO/CoO HMBNFs is attributed to the unique nanostructure, bicomponent active synergy, and uniform distribution of ZnO and CoO phases at the nanoscale. PMID- 26428260 TI - Is the fibrotic parietal thickening a reliable parameter for diagnosing previous asymptomatic deep vein thrombosis? AB - AIM: Research of a starting point to debate about the possibility of identifying a unique sign of previous DVT. MATERIAL OF STUDY: A retrospective study involving 202 outpatients with venous insufficiency of the lower limbs (CEAP classes C 4/6), classified according to the affected venous district. Patients positive for deep vein thrombosis (DVT) were subjected to Compression Ultra Sound test (CUS test) with measurement of the wall thickness at the point of formation of the thrombus and at fixed points of common femoral and popliteal veins used also in the patients with negative history of DVT RESULTS: Among total group, only 19 patients (9.40%) had an history of DVT. No one of them had a superficial incontinence. The measurement of wall thickness in positive DVT history patients (group A) resulted in an average value of 1.10 mm (s.d=0.06), while the average value obtained in negative DVT history (group B) was 0.55 mm (s.d.= 0.20). However, in 13 patients wall thickness was > 1mm (mean: 1.04 mm). The difference between the averages of group A and B was statistically significant (p <0.05). DISCUSSION: In all positive DVT history patients and in 13 ones with negative history we found an increase in wall thickness, with a value > 1 mm. Can the wall thickening more than 1 mm be considered an indicator of previous DVT? Can it be considered a "marker" for thrombophilia status? CONCLUSIONS: The usefulness of a sign of previous DVT (even if asymptomatic), detected during a routine Doppler ultrasound check of lower limbs, could be a warning bell to investigate thrombophilia status. KEY WORDS: Chronic Venous Insufficiency, Duplex ultrasound, Hypercoagulability, Post-thrombotic Syndrome, Venous Thromboembolism. PMID- 26428261 TI - Zoonotic transmission of rotavirus: surveillance and control. AB - Group A rotavirus (Rotavirus A, RVA) is the main cause of acute dehydrating diarrhea in humans and numerous animal species. RVA shows vast diversity and a variety of human strains share genetic and antigenic features with animal origin RVA strains. This finding suggests that interspecies transmission is an important mechanism of rotavirus evolution and contributes to the diversity of human RVA strains. RVA is responsible for half a million deaths and several million hospitalizations worldwide. Globally, two rotavirus vaccines are available for routine use in infants. These vaccines show a great efficacy profile and induce protective immunity against various rotavirus strains. However, little is known about the long-term evolution and epidemiology of RVA strains under selective pressure related to vaccine use. Continuous strain surveillance in the post vaccine licensure era is needed to help better understand mechanisms that may affect vaccine effectiveness. PMID- 26428262 TI - The application of human phase 0 microdosing trials: A systematic review and perspectives. AB - A decreasing number of new therapeutic drugs reaching the clinic has led to the publication of regulatory guidelines on human microdosing trials by the European Medicines Agency in 2004 and the US Food and Drug Administration in 2006. Microdosing trials are defined by the administration of 1/100th of the therapeutic dose and designed to investigate basic drug properties. This review investigates the current application of phase 0 trials in medical research. Thirty-three studies found in PubMed and EMBASE were systematically reviewed for aim and analytical method. Pharmacokinetic studies have been a major focus of phase 0 trials, but drug distribution, drug-drug interactions, imaging and pharmacogenomics have also been investigated. Common analytical methods were tandem mass liquid chromatography, accelerator mass spectrometry and positron emission tomography. New ongoing trials are investigating the pharmacodynamics and chemoresistance of marketed drugs, suggesting that the application of phase 0 trials is still evolving. PMID- 26428267 TI - Inhaled sildenafil nanocomposites: lung accumulation and pulmonary pharmacokinetics. AB - CONTEXT: Administration of sildenafil citrate (SC) is considered as a strategy in the treatment of pulmonary hypertension. OBJECTIVE: This study reports production of the inhalable microparticles containing SC-loaded poly(lactide-co-glycolic acid)-nanoparticles. METHODS: SC-nanoparticles were prepared by the double emulsion solvent evaporation method. Next, free SC and SC-loaded nanoparticles were spray dried in the presence of appropriate excipients (lactose, maltose and trehalose). Physicochemical properties and aerodynamic behavior of prepared powders were evaluated. In addition, drug accumulation from selected formulations in the rat lung tissue was compared with oral and IV administration. RESULTS: Size and fine particle fraction of selected nanocomposites and free SC microparticles were 7 and 4.5 um, and 60.2% and 68.2%, respectively. Following oral and IV administration, the drug was not detectable in the lung after 4 and 6 h, respectively, but in SC-loaded nanoparticles, the drug was detectable in the lung even after 12 h of inhalation. Respirable particles containing free SC provided high concentration at first that was detectable up to 6 after insufflation. CONCLUSION: In vivo study demonstrated that pulmonary administration of sildenafil and sildenafil nanoparticles produced longer half life and higher concentration of the drug in the lung tissue as compared to oral and IV administration. So, these formulations could be more effective than oral and IV administration of this drug. PMID- 26428268 TI - Emergence of new virulent populations of apple scab from nonagricultural disease reservoirs. AB - Plant pathogens adapt readily to new crop varieties in agrosystems, and it is crucial to understand the factors underlying the epidemic spread of new virulent strains if we are to develop more efficient strategies to control them. In this study we used multilocus microsatellite typing, molecular epidemiology tools and a large collection of isolates from cultivated, wild and ornamental apples to investigate the origin of new virulent populations of Venturia inaequalis, an ascomycete fungus causing apple scab on varieties carrying the Rvi6 resistance gene. We demonstrated a common origin at the European scale of populations infecting apples (Malus * domestica) carrying the Rvi6 resistance and Malus floribunda, the progenitor of the Rvi6 resistance. Demographic modeling indicated that the Rvi6-virulent lineage separated several thousands of years ago from populations infecting non-Rvi6 hosts, without detectable gene flow between the two lineages. These findings show that 'breakdowns' of plant resistance genes can be caused by the selection and migration of virulent genotypes from standing genetic variation maintained in environmental disease reservoirs, here ornamental crabapples. This work stresses the need to take better account of pathogen diversity in resistance screenings of breeding lines and in resistance deployment strategies, in order to enhance sustainable disease management. PMID- 26428269 TI - Quality of life among patients with rosacea: an investigation of patients in China using two structured questionnaires. PMID- 26428271 TI - Cytotoxicity, Antioxidant and Apoptosis Studies of Quercetin-3-O Glucoside and 4 (beta-D-Glucopyranosyl-1->4-alpha-L-Rhamnopyranosyloxy)-Benzyl Isothiocyanate from Moringa oleifera. AB - Moringa oleifera, from the family Moringaceae, is used as a source of vegetable and herbal medicine and in the treatment of various cancers in many African countries, including Kenya. The present study involved the phytochemical analyses of the crude extracts of M.oleifera and biological activities (antioxidant, cytotoxicity and induction of apoptosis in-vitro) of selected isolated compounds. The compounds isolated from the leaves and seeds of the plant were quercetin-3-O glucoside (1), 4-(beta-D-glucopyranosyl-1->4-alpha-L-rhamnopyranosyloxy)-benzyl isothiocyanate (2), lutein (3), and sitosterol (4). Antioxidant activity of compound 1 was significant when compared to that of the control, while compound 2 showed moderate activity. The cytotoxicity of compounds 1 and 2 were tested in three cell lines, viz. liver hepatocellular carcinoma (HepG2), colon carcinoma (Caco-2) and a non-cancer cell line Human Embryonic Kidney (HEK293), using the MTT cell viability assay and compared against a standard anticancer drug, 5 fluorouracil. Apoptosis studies were carried out using the acridine orange/ethidium bromide dual staining method. The isolated compounds showed selective in vitro cytotoxic and apoptotic activity against human cancer and non cancer cell lines, respectively. Compound 1 showed significant cytotoxicity against the Caco-2 cell line with an IC50 of 79 MUg mL(-1) and moderate cytotoxicity against the HepG2 cell line with an IC50 of 150 MUg mL(-1), while compound 2 showed significant cytotoxicity against the Caco- 2 and HepG2 cell lines with an IC50 of 45 MUg mL(-1) and 60 MUg mL(-1), respectively. Comparatively both compounds showed much lower cytotoxicity against the HEK293 cell line with IC50 values of 186 MUg mL(-1) and 224 MUg mL(-1), respectively. PMID- 26428272 TI - Chemoselective Alkene Hydrosilylation Catalyzed by Nickel Pincer Complexes. AB - Chemoselective hydrosilylation of functionalized alkenes is difficult to achieve using base-metal catalysts. Reported herein is that well-defined bis(amino)amide nickel pincer complexes are efficient catalysts for anti-Markovnikov hydrosilylation of terminal alkenes with turnover frequencies of up to 83,000 per hour and turnover numbers of up to 10,000. Alkenes containing amino, ester, amido, ketone, and formyl groups are selectively hydrosilylated. A slight modification of reaction conditions allows tandem isomerization/hydrosilylation reactions of internal alkenes using these nickel catalysts. PMID- 26428273 TI - Identification of a characteristic antioxidant, anthrasesamone F, in black sesame seeds and its accumulation at different seed developmental stages. AB - Assay-guided fractionation of the methanol extract from black seeds of sesame (Sesamum indicum L.) led to the isolation of an active compound that had a 1,1 diphenyl-2-picrylhydrazyl radical scavenging activity. This antioxidant was confirmed to be anthrasesamone F, an anthraquinone derivative previously isolated from different black sesame seeds and biogenetically related to other anthrasesamones in sesame roots. The radical scavenging assay showed that anthrasesamone F had more potent activity than Trolox. The content of anthrasesamone F in different parts and at different developmental stages of black sesame seeds was investigated to clarify the accumulation pattern of this antioxidant in the black seeds. Anthrasesamone F was localized in the seed coat of black seeds and accumulated after the seed coat color changed to black. The content of anthrasesamone F increased gradually with seed maturation and drastically on air-drying, the final stage in sesame cultivation. PMID- 26428274 TI - A Longitudinal (6-week) 3T (1)H-MRS Study on the Effects of Lithium Treatment on Anterior Cingulate Cortex Metabolites in Bipolar Depression. AB - The anterior cingulate cortex (ACC) is a key area in mood regulation. To date, no longitudinal study has specifically evaluated lithium's effects on ACC metabolites using (1)H-MRS, as well as its association with clinical improvement in bipolar depression. This (1)H-MRS (TE=35ms) study evaluated 24 drug-free BD patients during depressive episodes and after lithium treatment at therapeutic levels. Brain metabolite levels (N-acetyl aspartate (NAA), creatine (tCr), choline, myo-inositol, and glutamate levels) were measured in the ACC at baseline (week 0) and after lithium monotherapy (week 6). The present investigation showed that ACC glutamate (Glu/tCr) and glutamate+glutamine (Glx/tCr) significantly increased after six weeks of lithium therapy. Regarding the association with clinical improvement, remitters showed an increase in myoinositol levels (mI/tCr) after lithium treatment compared to non-remitters. The present findings reinforce a role for ACC glutamate-glutamine cycling and myoinositol pathway as key targets for lithium's therapeutic effects in BD. PMID- 26428275 TI - Facile Synthesis of Trisubstituted Carbazoles by Acid-Catalyzed Ring-Opening Annulation of 2-Amidodihydrofurans with Indoles. AB - A mild and convenient synthesis of carbazoles by TfOTMS (trimethylsilyl trifluoromethanesulfonate)-catalyzed ring-opening annulation of 2 amidodihydrofurans is presented with a high degree of chemoselectivity and regioselectivity. This procedure was also scaled up to a gram-scale synthesis. The reaction could involve an iminonium intermediate through a series of C-O, C-N bond cleavages, C-C bond formations, and a 1,2-migration process. PMID- 26428276 TI - Differences in gluten metabolism among healthy volunteers, coeliac disease patients and first-degree relatives. AB - Coeliac disease (CD) is an immune-mediated enteropathy resulting from exposure to gluten in genetically predisposed individuals. Gluten proteins are partially digested by human proteases generating immunogenic peptides that cause inflammation in patients carrying HLA-DQ2 and DQ8 genes. Although intestinal dysbiosis has been associated with patients with CD, bacterial metabolism of gluten has not been studied in depth thus far. The aim of this study was to analyse the metabolic activity of intestinal bacteria associated with gluten intake in healthy individuals, CD patients and first-degree relatives of CD patients. Faecal samples belonging to twenty-two untreated CD patients, twenty treated CD patients, sixteen healthy volunteers on normal diet, eleven healthy volunteers on gluten-free diet (GFD), seventy-one relatives of CD patients on normal diet and sixty-nine relatives on GFD were tested for several proteolytic activities, cultivable bacteria involved in gluten metabolism, SCFA and the amount of gluten in faeces. We detected faecal peptidasic activity against the gluten-derived peptide 33-mer. CD patients showed differences in faecal glutenasic activity (FGA), faecal tryptic activity (FTA), SCFA and faecal gluten content with respect to healthy volunteers. Alterations in specific bacterial groups metabolising gluten such as Clostridium or Lactobacillus were reported in CD patients. Relatives showed similar parameters to CD patients (SCFA) and healthy volunteers (FTA and FGA). Our data support the fact that commensal microbial activity is an important factor in the metabolism of gluten proteins and that this activity is altered in CD patients. PMID- 26428279 TI - Synthesis of magnetic mesoporous titania colloidal crystals through evaporation induced self-assembly in emulsion as effective and recyclable photocatalysts. AB - This study illustrates the directed self-assembly of mesoporous TiO2 with magnetic properties due to its colloidal crystal structure with Fe3O4. The Fe3O4 nanoparticles were synthesized using co-precipitation techniques to a size of 28.2 nm and a magnetic saturation of 66.9 emu g(-1). Meanwhile, mesoporous titania nanoparticles (MTNs) with a particle diameter of 373 nm, a specific surface area of 236.3 m(2) g(-1), and a pore size of 2.8 nm were prepared by controlling the rate of hydrolysis. Magnetic colloidal crystals (a diameter of 10.2 MUm) were formed by the aggregation of Fe3O4 and MTNs caused by the interface phenomena during solvent evaporation in emulsion. Even the anatase octahedrite produced from the colloidal crystal after a hydrothermal reaction retained a magnetic saturation of 2.8 emu g(-1). This study also investigates the photodegradation activity of our synthesized material as a photocatalyst, while utilizing its capability for magnetic separation to prove its usefulness in catalyst recycling. PMID- 26428278 TI - Impact of palm date consumption on microbiota growth and large intestinal health: a randomised, controlled, cross-over, human intervention study. AB - The reported inverse association between the intake of plant-based foods and a reduction in the prevalence of colorectal cancer may be partly mediated by interactions between insoluble fibre and (poly)phenols and the intestinal microbiota. In the present study, we assessed the impact of palm date consumption, rich in both polyphenols and fibre, on the growth of colonic microbiota and markers of colon cancer risk in a randomised, controlled, cross over human intervention study. A total of twenty-two healthy human volunteers were randomly assigned to either a control group (maltodextrin-dextrose, 37.1 g) or an intervention group (seven dates, approximately 50 g). Each arm was of 21 d duration and was separated by a 14-d washout period in a cross-over manner. Changes in the growth of microbiota were assessed by fluorescence in situ hybridisation analysis, whereas SCFA levels were assessed using HPLC. Further, ammonia concentrations, faecal water genotoxicity and anti-proliferation ability were also assessed using different assays, which included cell work and the Comet assay. Accordingly, dietary intakes, anthropometric measurements and bowel movement assessment were also carried out. Although the consumption of dates did not induce significant changes in the growth of select bacterial groups or SCFA, there were significant increases in bowel movements and stool frequency (P<0.01; n 21) and significant reductions in stool ammonia concentration (P<0.05; n 21) after consumption of dates, relative to baseline. Furthermore, date fruit intake significantly reduced genotoxicity in human faecal water relative to control (P<0.01; n 21). Our data indicate that consumption of date fruit may reduce colon cancer risk without inducing changes in the microbiota. PMID- 26428277 TI - Probiotic strain Lactobacillus plantarum 299v increases iron absorption from an iron-supplemented fruit drink: a double-isotope cross-over single-blind study in women of reproductive age. AB - Iron deficiency is common, especially among young women. Adding probiotics to foods could be one way to increase iron absorption. The aim of this study was to test the hypothesis that non-haem iron absorption from a fruit drink is improved by adding Lactobacillus plantarum 299v (Lp299v). Iron absorption was studied in healthy women of reproductive age using a single-blind cross-over design in two trials applying the double-isotope (55Fe and 59Fe) technique. In Trial 1, iron absorption from a fruit drink containing 109 colony-forming units (CFU) Lp299v was compared with that from a control drink without Lp299v. Trial 2 had the same design but 1010 CFU were used. The test and control drinks contained approximately 5 mg of iron as ferrous lactate and were labelled with 59Fe (B) and 55Fe (A), respectively, and consumed on 4 consecutive days in the order AABB. Retention of the isotopes was measured with whole-body counting and in blood. Mean iron absorption from the drink containing 109 CFU Lp299v (28.6(sd 12.5) %) was significantly higher than from the control drink (18.5(sd 5.8) %), n 10, P<0.028). The fruit drink with 1010 CFU Lp299v gave a mean iron absorption of 29.1(sd 17.0) %, whereas the control drink gave an absorption of (20.1(sd 6.4) %) (n 11, P<0.080). The difference in iron absorption between the 109 CFU Lp299v and the 1010 CFU Lp299v drinks was not significant (P=0.941). In conclusion, intake of probiotics can increase iron absorption by approximately 50 % from a fruit drink having an already relatively high iron bioavailability. PMID- 26428280 TI - Significantly increased PELP1 protein expression in primary and metastatic triple negative breast carcinoma: comparison with GATA3 expression and PELP1's potential role in triple-negative breast carcinoma. AB - PELP1 is a novel coregulator of nuclear hormone receptors and is implicated in playing a role in driving breast cancer and enhancing metastatic potential. The PELP1 protein expression and potential role of PELP1 in triple-negative breast carcinoma (TNBC) have not been well characterized. We investigated PELP1 expression by immunohistochemistry in primary and metastatic triple-negative tumors in human tissues and compared its expression with GATA-binding protein 3 (GATA3), a novel diagnostic marker for TNBC. We examined the expression of PELP1 and GATA3 in 70 primary TNBC cases and found that PELP1 had a significantly higher frequency of expression compared to GATA3 (96% versus 46%; P < .0001). The mean extent score of expression of PELP1 was also significantly higher than GATA3's expression (3.87 +/- 0.07 versus 0.91 +/- 0.15; P < .0001). PELP1 had stronger staining intensity than GATA3. Furthermore, PELP1 immunoreactivity was consistently maintained in paired primary and metastatic TNBC cases (100%). The frequency of PELP1 expression (100%) in metastatic triple-negative tumors was higher than that of GATA3 (40%) in the same tumors (P < .0001). These findings indicate that PELP1 is a much more sensitive marker than GATA3 for TNBCs. PELP1 may have diagnostic utility for metastatic TNBC in appropriate settings, such as history of primary TNBC in cases where the primary is negative for GATA3, mammaglobin, and GCDFP-15. The diffuse and strong nuclear immunoreactivity of PELP1 in most cases suggests that PELP1 may be a molecular target for the treatment of TNBC. We hope that this study will provide insights into the role of PELP1 in TNBC. PMID- 26428281 TI - The effects of prophylactic bolus phenylephrine on hypotension during low-dose spinal anesthesia for cesarean section. AB - BACKGROUND: Continuously infused phenylephrine is frequently used to reduce the incidence of hypotension in women undergoing cesarean section under spinal anesthesia, but less is known about the prophylactic bolus method. We evaluated three prophylactic bolus doses of phenylephrine during low-dose spinal anesthesia for cesarean section. METHODS: One-hundred-and-eighty-four patients were randomized to receive 0.9% saline 2mL (Control Group) or phenylephrine 1.0MUg/kg (PHE1 Group), 1.5MUg/kg (PHE1.5 Group), or 2.0MUg/kg (PHE2 Group) immediately after induction of combined spinal-epidural anesthesia. Maternal blood pressure and heart rate were recorded at 1-min intervals until delivery. Hypotension, defined as systolic blood pressure <80% of baseline, was treated with rescue doses of phenylephrine 100MUg at 1-min intervals until hypotension resolved. The incidence of nausea, vomiting, bradycardia, and hypertension, as well as Apgar scores and umbilical blood gases, were recorded. RESULTS: The incidence of hypotension was 71.7% (33/46) in the Control Group, 68.9% (31/45) in the PHE1 Group, 37.0% (17/46) in the PHE1.5 Group and 45.7% (21/46) in the PHE2 Group (P=0.001). The total rescue dose of phenylephrine was greater in the Control Group than those in the PHE1.5 Group (P<0.05) and PHE2 Group (P<0.05). The incidence of hypertension increased as the dose of prophylactic phenylephrine increased (P<0.001) and was highest in the PHE2 group (37%). Other variables did not differ among the four groups. CONCLUSIONS: Under the conditions of this study, prophylactic bolus injection of phenylephrine 1.5MUg/kg was a suitable alternative method for reducing the incidence of hypotension during low-dose spinal anesthesia for cesarean section. PMID- 26428282 TI - On the Way to Speciation: Shedding Light on the Karstic Phylogeography of the Microendemic Cave Beetle Aphaenops cerberus in the Pyrenees. AB - The highly modified morphology and ecological features of cave-dwelling organisms are a strong obstacle to dispersion. Hence, they represent ideal models for the study of historical biogeography at both large and fine timescales. Here, we study the phylogeography of Aphaenops cerberus, an endemic hypogean ground beetle with a fragmented distribution in the French Northern Pyrenees. We extracted 75 exemplars of 17 populations of A. cerberus and sequenced one mitochondrial and one nuclear marker to assess the geographic structuration as well as the recent biogeographic history of this species. We used Bayesian Inference and Maximum Likelihood to reconstruct the relationships among most of the extant populations of this species across its distributional range. We inferred divergence time estimates using carabid substitution rates and reconstructed haplotype networks to investigate the recent biogeographic history of this lineage. We recover a strong geographic structuration of the populations across the mountain range. The strong impact of geology on the structure of the populations is evidenced although geological continuity does not systematically lead to continual gene flow. The origin of the species is dated from the Early Pleistocene and the dispersal predates the main Last Glacial Maximum. Our results indicate broad similitudes between islands and karsts, which make cave organisms an excellent model for the study of evolution mechanisms. PMID- 26428283 TI - Retrospective analysis of pharmacist interventions in an ambulatory palliative care practice. AB - BACKGROUND: We have previously reported the development of an outpatient palliative care practice under pharmacist-physician collaboration. The Doris A. Howell Service at the University of California, San Diego Moores Cancer Center includes two pharmacists who participate in a transdisciplinary clinic and provide follow-up care to patients. OBJECTIVE: This study evaluated pharmacist interventions and patient outcomes of a pharmacist-led outpatient palliative care practice. METHODS: This was a retrospective data analysis conducted at a single, academic, comprehensive cancer center. New (first visit) patient consultations were referred by an oncologist or hematologist to an outpatient palliative care practice. A pharmacist evaluated the patient at the first visit and at follow-up (second, third, and fourth visits). Medication problems identified, medication changes made, and changes in pain scores were assessed. RESULTS: Eighty-four new and 135 follow-up patient visits with the pharmacist occurred from March 2011 to March 2012. All new patients (n = 80) were mostly women (n = 44), had localized disease (n = 42), a gastrointestinal cancer type (n = 21), and were on a long acting (n = 61) and short-acting (n = 70) opioid. A lack of medication efficacy was the most common problem for symptoms of pain, constipation, and nausea/vomiting that was identified by the pharmacist at all visits. A change in pain medication dose and initiation of a new medication for constipation and nausea/vomiting were the most common interventions by the pharmacist. A statistically significant change in pain score was observed for the third visit, but not for the second and fourth visits. CONCLUSIONS: A pharmacist-led outpatient palliative care practice identified medication problems for management of pain, constipation, and nausea/vomiting. Medication changes involved a change in dose and/or initiating a new medication. Trends were observed in improvement and stabilization of pain over subsequent clinic visits. PMID- 26428284 TI - Compatibility of epirubicin-loaded DC beadTM with different non-ionic contrast media. AB - PURPOSE: The aim of this study was to determine the compatibility of epirubicin loaded DC beadTM with different non-ionic contrast media over a period of seven days when stored light protected under refrigerated conditions. METHODS: DC beadTM (2 ml) (Biocompatibles UK Ltd) of the bead size 70-150 um ( = DC bead M1) or bead size 100-300 um were loaded with 75 mg epirubicin powder formulation (Farmorubicin(r) dissolved in 3 ml water for injection to a concentration of 25 mg/ml) or 76 mg epirubicin injection solution (Epimedac(r) 2 mg/ml) within 2 h or 6 h, respectively. After removal of the excess solution, the epirubicin-loaded beads were mixed in polypropylene syringes with an equal volume (~1.5 ml) of contrast media, i.e. AccupaqueTM 300 (Nycomed Inc.), Imeron(r) 300 (Bracco S.p.A), Ultravist(r) 300 (Bayer Pharma AG), VisipaqueTM 320 (GE Healthcare) and agitated in a controlled manner to get a homogenous suspension. Syringes with loaded beads in contrast media were stored protected from light under refrigeration (2-8C). Compatibility was determined by measuring epirubicin concentrations in the suspensions in triplicate on day 0, 1, and 7. A reversed phase high-performance liquid chromatography assay with ultraviolet detection was utilized to analyze the concentration and purity of epirubicin. RESULTS: Mixing of epirubicin-loaded beads with different non-ionic contrast media released 0.1 0.5% of epirubicin over a period of 24 h, irrespectively, of the DC beadTM size or type of contrast media. No further elution or degradation was observed after seven days when the admixtures were stored protected from light under refrigeration. CONCLUSION: Compatibility of epirubicin-loaded DC beadTM with an equal volume of different contrast media in polypropylene syringes is given over a period of seven days. Due to a maximum elution of 0.1-0.5% of epirubicin from loaded DC beadTM, admixtures with contrast media can be prepared in advance in centralized cytotoxic preparation units. Microbiological aspects have to be considered when determining the expiration date of the product. PMID- 26428286 TI - Increased appropriateness of customized alert acknowledgement reasons for overridden medication alerts in a computerized provider order entry system. AB - OBJECTIVE: Computerized provider order entry systems commonly contain alerting mechanisms for patient allergies, incorrect doses, or drug-drug interactions when ordering medications. Providers have the option to override (bypass) these alerts and continue with the order unchanged. This study examines the effect of customizing medication alert override options on the appropriateness of override selection related to patient allergies, drug dosing, and drug-drug interactions when ordering medications in an electronic medical record. MATERIALS AND METHODS: In this prospective, randomized crossover study, providers were randomized into cohorts that required a reason for overriding a medication alert from a customized or non-customized list of override reasons and/or by free-text entry. The primary outcome was to compare override responses that appropriately correlate with the alert type between the customized and non-customized configurations. The appropriateness of a subset of free-text responses that represented an affirmative and active acknowledgement of the alert without further explanation was classified as "indeterminate." Results were analyzed in three different ways by classifying indeterminate answers as either appropriate, inappropriate, or excluded entirely. Secondary outcomes included the appropriateness of override reasons when comparing cohorts and individual providers, reason selection based on order within the override list, and the determination of the frequency of free-text use, nonsensical responses, and multiple selection responses. RESULTS: Twenty-two clinicians were randomized into 2 cohorts and a total of 1829 alerts with a required response were generated during the study period. The customized configuration had a higher rate of appropriateness when compared to the non-customized configuration regardless of how indeterminate responses were classified (p<0.001). When comparing cohorts, appropriateness was significantly higher in the customized configuration regardless of the classification of indeterminate responses (p<0.001) with one exception: when indeterminate responses were considered inappropriate for the cohort of providers that were first exposed to the non-customized list (p=0.103). Free-text use was higher in the customized configuration overall (p<0.001), and there was no difference in nonsensical response between configurations (p=0.39). CONCLUSION: There is a benefit realized by using a customized list for medication override reasons. Poor application design or configuration can negatively affect provider behavior when responding to important medication alerts. PMID- 26428285 TI - Italian guidelines for the management and treatment of neonatal cholestasis. AB - Hyperbilirubinemia is a frequent condition affecting newborns during the first two weeks of life and when it lasts more than 14 days it is defined as prolonged jaundice. This condition requires differential diagnosis between the usually benign unconjugated hyperbilirubinemia and the pathological conjugated hyperbilirubinemia, that is mainly due to neonatal cholestasis. It is important that the diagnosis of neonatal cholestasis be well-timed to optimize its management, prevent worsening of the patient's outcome, and to avoid premature, painful, expensive, and useless tests. Unfortunately, this does not always occur and, therefore, the Task Force on Hyperbilirubinemia of the Italian Society of Neonatology presents these shared Italian guidelines for the management and treatment of neonatal cholestasis whose overall aim is to provide a useful tool for its assessment for neonatologists and family pediatricians. PMID- 26428287 TI - Combination of gaps in noise detection and visual analog scale for measuring tinnitus components in patients treated with repetitive transcranial magnetic stimulation. AB - OBJECTIVES: We aimed to evaluate gaps in noise (GIN) detection and visual analog scale (VAS) for measuring perceived tinnitus loudness and annoyance caused thereby. We quantified the outcomes and effectiveness of repetitive transcranial magnetic stimulation (rTMS) on chronic tinnitus. METHODS: Fourteen tinnitus patients with normal hearing underwent a 10 day course of active 1-Hz rTMS to the left region of the temporoparietal cortex. GIN (in which the matched pitch and loudness of tinnitus was used to determine the frequency and intensity of background noise) and VAS was used to assess tinnitus loudness and the extent of annoyance caused thereby. Both ten patients with tinnitus who underwent left temporoparietal sham stimulation and fifteen volunteers with normal hearing without tinnitus participated with GIN detection as a control. Correlations between VAS scores and GIN detection were determined via Spearman's correlation analysis. RESULTS: The mean GIN thresholds of tinnitus-affected (5.87 ms) ears and the ears of control subjects (4.85 ms) differed significantly. In the tinnitus group, 42.8% (6/14) patients experienced significant reductions in tinnitus annoyance, as assessed by VAS. 71.4% (10/14) patients experienced significant reductions in tinnitus loudness, as evidenced by GIN evaluation. Three tinnitus subjects (21.4%) achieved 30% decrease of the threshold of GIN detection. There was no significant change in GIN detection and VAS scores after sham stimulation. A significant positive correlation was evident between GIN data and VAS scores (r=0.84, p<0.001). CONCLUSIONS: Gaps in noise detection, combined with VAS scores, affords a promising sensitive method by which to evaluate tinnitus loudness and annoyance. Low frequency rTMS significantly decreased tinnitus after the active, but not the sham, treatment. PMID- 26428288 TI - Pseudoknots in RNA folding landscapes. AB - MOTIVATION: The function of an RNA molecule is not only linked to its native structure, which is usually taken to be the ground state of its folding landscape, but also in many cases crucially depends on the details of the folding pathways such as stable folding intermediates or the timing of the folding process itself. To model and understand these processes, it is necessary to go beyond ground state structures. The study of rugged RNA folding landscapes holds the key to answer these questions. Efficient coarse-graining methods are required to reduce the intractably vast energy landscapes into condensed representations such as barrier trees or basin hopping graphs : BHG) that convey an approximate but comprehensive picture of the folding kinetics. So far, exact and heuristic coarse-graining methods have been mostly restricted to the pseudoknot-free secondary structures. Pseudoknots, which are common motifs and have been repeatedly hypothesized to play an important role in guiding folding trajectories, were usually excluded. RESULTS: We generalize the BHG framework to include pseudoknotted RNA structures and systematically study the differences in predicted folding behavior depending on whether pseudoknotted structures are allowed to occur as folding intermediates or not. We observe that RNAs with pseudoknotted ground state structures tend to have more pseudoknotted folding intermediates than RNAs with pseudoknot-free ground state structures. The occurrence and influence of pseudoknotted intermediates on the folding pathway, however, appear to depend very strongly on the individual RNAs so that no general rule can be inferred. AVAILABILITY AND IMPLEMENTATION: The algorithms described here are implemented in C++ as standalone programs. Its source code and Supplemental material can be freely downloaded from http://www.tbi.univie.ac.at/bhg.html. CONTACT: qin@bioinf.uni-leipzig.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26428289 TI - Generalized empirical Bayesian methods for discovery of differential data in high throughput biology. AB - MOTIVATION: High-throughput data are now commonplace in biological research. Rapidly changing technologies and application mean that novel methods for detecting differential behaviour that account for a 'large P, small n' setting are required at an increasing rate. The development of such methods is, in general, being done on an ad hoc basis, requiring further development cycles and a lack of standardization between analyses. RESULTS: We present here a generalized method for identifying differential behaviour within high-throughput biological data through empirical Bayesian methods. This approach is based on our baySeq algorithm for identification of differential expression in RNA-seq data based on a negative binomial distribution, and in paired data based on a beta binomial distribution. Here we show how the same empirical Bayesian approach can be applied to any parametric distribution, removing the need for lengthy development of novel methods for differently distributed data. Comparisons with existing methods developed to address specific problems in high-throughput biological data show that these generic methods can achieve equivalent or better performance. A number of enhancements to the basic algorithm are also presented to increase flexibility and reduce computational costs. AVAILABILITY AND IMPLEMENTATION: The methods are implemented in the R baySeq (v2) package, available on Bioconductor http://www.bioconductor.org/packages/release/bioc/html/baySeq.html. CONTACT: tjh48@cam.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26428290 TI - cl-dash: rapid configuration and deployment of Hadoop clusters for bioinformatics research in the cloud. AB - : One of the solutions proposed for addressing the challenge of the overwhelming abundance of genomic sequence and other biological data is the use of the Hadoop computing framework. Appropriate tools are needed to set up computational environments that facilitate research of novel bioinformatics methodology using Hadoop. Here, we present cl-dash, a complete starter kit for setting up such an environment. Configuring and deploying new Hadoop clusters can be done in minutes. Use of Amazon Web Services ensures no initial investment and minimal operation costs. Two sample bioinformatics applications help the researcher understand and learn the principles of implementing an algorithm using the MapReduce programming pattern. AVAILABILITY AND IMPLEMENTATION: Source code is available at https://bitbucket.org/booz-allen-sci-comp-team/cl-dash.git. CONTACT: hodor_paul@bah.com. PMID- 26428291 TI - ALP & FALP: C++ libraries for pairwise local alignment E-values. AB - MOTIVATION: Pairwise local alignment is an indispensable tool for molecular biologists. In real time (i.e. in about 1 s), ALP (Ascending Ladder Program) calculates the E-values for protein-protein or DNA-DNA local alignments of random sequences, for arbitrary substitution score matrix, gap costs and letter abundances; and FALP (Frameshift Ascending Ladder Program) performs a similar task, although more slowly, for frameshifting DNA-protein alignments. AVAILABILITY AND IMPLEMENTATION: To permit other C++ programmers to implement the computational efficiencies in ALP and FALP directly within their own programs, C++ source codes are available in the public domain at http://go.usa.gov/3GTSW under 'ALP' and 'FALP', along with the standalone programs ALP and FALP. CONTACT: spouge@nih.gov SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26428292 TI - Qualimap 2: advanced multi-sample quality control for high-throughput sequencing data. AB - MOTIVATION: Detection of random errors and systematic biases is a crucial step of a robust pipeline for processing high-throughput sequencing (HTS) data. Bioinformatics software tools capable of performing this task are available, either for general analysis of HTS data or targeted to a specific sequencing technology. However, most of the existing QC instruments only allow processing of one sample at a time. RESULTS: Qualimap 2 represents a next step in the QC analysis of HTS data. Along with comprehensive single-sample analysis of alignment data, it includes new modes that allow simultaneous processing and comparison of multiple samples. As with the first version, the new features are available via both graphical and command line interface. Additionally, it includes a large number of improvements proposed by the user community. AVAILABILITY AND IMPLEMENTATION: The implementation of the software along with documentation is freely available at http://www.qualimap.org. CONTACT: meyer@mpiib-berlin.mpg.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26428293 TI - JEPEGMIX: gene-level joint analysis of functional SNPs in cosmopolitan cohorts. AB - MOTIVATION: To increase detection power, gene level analysis methods are used to aggregate weak signals. To greatly increase computational efficiency, most methods use as input summary statistics from genome-wide association studies (GWAS). Subsequently, gene statistics are constructed using linkage disequilibrium (LD) patterns from a relevant reference panel. However, all methods, including our own Joint Effect on Phenotype of eQTL/functional single nucleotide polymorphisms (SNPs) associated with a Gene (JEPEG), assume homogeneous panels, e.g. European. However, this renders these tools unsuitable for the analysis of large cosmopolitan cohorts. RESULTS: We propose a JEPEG extension, JEPEGMIX, which similar to one of our software tools, Direct Imputation of summary STatistics of unmeasured SNPs from MIXed ethnicity cohorts, is capable of estimating accurate LD patterns for cosmopolitan cohorts. JEPEGMIX uses this accurate LD estimates to (i) impute the summary statistics at unmeasured functional variants and (ii) test for the joint effect of all measured and imputed functional variants which are associated with a gene. We illustrate the performance of our tool by analyzing the GWAS meta-analysis summary statistics from the multi-ethnic Psychiatric Genomics Consortium Schizophrenia stage 2 cohort. This practical application supports the immune system being one of the main drivers of the process leading to schizophrenia. AVAILABILITY AND IMPLEMENTATION: Software, annotation database and examples are available at http://dleelab.github.io/jepegmix/. CONTACT: donghyung.lee@vcuhealth.org SUPPLEMENTARY INFORMATION: Supplementary material is available at Bioinformatics online. PMID- 26428294 TI - Cell line name recognition in support of the identification of synthetic lethality in cancer from text. AB - MOTIVATION: The recognition and normalization of cell line names in text is an important task in biomedical text mining research, facilitating for instance the identification of synthetically lethal genes from the literature. While several tools have previously been developed to address cell line recognition, it is unclear whether available systems can perform sufficiently well in realistic and broad-coverage applications such as extracting synthetically lethal genes from the cancer literature. In this study, we revisit the cell line name recognition task, evaluating both available systems and newly introduced methods on various resources to obtain a reliable tagger not tied to any specific subdomain. In support of this task, we introduce two text collections manually annotated for cell line names: the broad-coverage corpus Gellus and CLL, a focused target domain corpus. RESULTS: We find that the best performance is achieved using NERsuite, a machine learning system based on Conditional Random Fields, trained on the Gellus corpus and supported with a dictionary of cell line names. The system achieves an F-score of 88.46% on the test set of Gellus and 85.98% on the independently annotated CLL corpus. It was further applied at large scale to 24 302 102 unannotated articles, resulting in the identification of 5 181 342 cell line mentions, normalized to 11 755 unique cell line database identifiers. AVAILABILITY AND IMPLEMENTATION: The manually annotated datasets, the cell line dictionary, derived corpora, NERsuite models and the results of the large-scale run on unannotated texts are available under open licenses at http://turkunlp.github.io/Cell-line-recognition/. CONTACT: sukaew@utu.fi. PMID- 26428295 TI - Mutational and network level mechanisms underlying resistance to anti-cancer kinase inhibitors. AB - Tyrosine-specific and other protein kinases are embedded in signaling networks critical for progression of tumors of all types. Hence, kinase inhibitors have nucleated a major arm of personalized cancer therapy. Unfortunately, almost all kinase inhibitors evoke resistance within a year or two, due to secondary mutations, and other alterations within the targeted kinase, or due to emergence of feedback regulatory loops that compensate for extinguished kinases. We review clinically approved kinase inhibitors and the emergence of resistance in leukemia, melanoma, lung and breast tumors, and draw parallel lines in terms of secondary mutations and compensatory mechanisms. Currently emerging are pharmacological strategies able to circumvent resistance and re-sensitize patients to therapeutic treatments. They include second and third generation inhibitors that overcome new mutations, novel drug combinations that simultaneously block the primary oncogenic pathway and compensatory routes, as well as monoclonal antibodies. Deeper understanding of biological signaling networks and their responses to perturbations will aid in the development of effective therapies for patients with cancer. PMID- 26428297 TI - Gliding motility in apicomplexan parasites. AB - Apicomplexan parasites, including Plasmodium and Toxoplasma, employ a unique form of substrate-dependent locomotion known as gliding motility. In these obligate, intracellular parasites, gliding motility is used for migration through the tissues and cells of the host, for active penetration of the host cell, and, at times, for proactive egress from the host. Gliding motility is powered by an actin-myosin based motor apparatus, known as the glideosome, which is situated within the elaborate cortical domain of the parasite. In this system, myosin is anchored to an internal membrane complex and drives the rearward translocation of actin-associated cell surface adhesins, thus leading to forward movement of the parasite. This review outlines our current understanding of glideosome architecture and the molecular basis of parasite motility. PMID- 26428296 TI - Metabolic fibroblast growth factors (FGFs): Mediators of energy homeostasis. AB - The metabolic fibroblast growth factors (FGFs), FGF1, FGF15/19, and FGF21 differ from classic FGFs in that they modulate energy homeostasis in response to fluctuating nutrient availability. These unique mediators of metabolism regulate a number of physiological processes which contribute to their potent pharmacological properties. Administration of pharmacological doses of these FGFs causes weight loss, increases energy expenditure, and improves carbohydrate and lipid metabolism in obese animal models. However, many questions remain regarding the precise molecular and physiological mechanisms governing the effects of individual metabolic FGFs. Here we review the metabolic actions of FGF1, FGF15/19, and FGF21 while providing insights into their pharmacological effects by examining known biological functions. PMID- 26428298 TI - Maternal and reproductive health financing in Burundi: public-sector contribution levels and trends from 2010 to 2012. AB - BACKGROUND: An understanding of public financial flows to reproductive health (RH) at the country level is key to assessing the extent to which they correspond to political commitments. This is especially relevant for low-income countries facing important challenges in the area of RH. To this end, the present study analyzes public expenditure levels and trends with regards to RH in Burundi between the years 2010 to 2012, looking specifically at financing agents, health providers, and health functions. METHODS: The analysis was performed using standard RH sub-account methodology. Information regarding public expenditures was gathered from national budgets, the Burundi Ministry of Public Health information system, and from other relevant public institutions. RESULTS: Public RH expenditures in Burundi accounted for $41.163 million international dollars in 2012, which represents an increase of 16 % from 2010. In 2012, this sum represented 0.57 % of the national GDP. The share of total public health spending allocated to RH increased from 15 % in 2010 to 19 % in 2012. In terms of public agents involved in RH financing, the Ministry of Public Health proved to play the most important role. Half of all public RH spending went to primary health care clinics, while more than 70 % of this money was used for maternal health; average public RH spending per woman of childbearing age stagnated during the study period. CONCLUSIONS: The flow patterns and levels of public funds to RH in Burundi suggest that RH funding correctly reflects governmental priorities for the period between 2010 and 2012. In a context of general shrinking donor commitment, local governments have come to play a key role in ensuring the efficient use of available resources and the mobilizing of additional domestic funding. A strong and transparent financial tracking system is key to carrying out this role and making progress towards the MDG Goals and development beyond 2015. PMID- 26428299 TI - Improving Properties of Recombinant SsoPox by Site-Specific Pegylation. AB - SsoPox, a ~35 kDa enzyme from Sulfolobus solfataricus, can hydrolyze and inactivate a variety of organophosphate (OP)-compounds. The enzyme is a potential candidate for the development of prophylactic and therapeutic agent against OP poisoning in humans. However, the therapeutic use of recombinant SsoPox suffers from certain limitations associated with the use of recombinant protein pharmaceuticals. Some of these limitations could be overcome by conjugating SsoPox enzyme with polyethylene glycol (PEG). In this study, we report generation and in vitro characterization of N-terminal mono-PEGylated rSsoPox(2p) (a variant of rSsoPox(wt) having enhanced OP-hydrolyzing activity). The enzyme was PEGylated with mPEG-propionaldehyde and the PEGylated protein was isolated using ion exchange chromatography. Compared with the unmodified enzyme, mono-PEGylation of rSsoPox results in improvement in the thermostability and protease resistance of the enzyme. PEGylated rSsoPox(2p) can be developed as a candidate for the prevention / treatment of OP-poisoning. PMID- 26428300 TI - Amyloid-like Fibril Formation by Trypsin in Aqueous Ethanol. Inhibition of Fibrillation by PEG. AB - The formation of amyloid-like fibrils was studied by using the well-known serine protease trypsin as a model protein in the presence of ethanol as organic solvent. Trypsin forms amyloid-like fibrils in aqueous ethanol at pH = 7.0. The dye Congo red (CR) was used to detect the presence of amyloid-like fibrils in the samples. The binding of CR to fibrils led to an increase in absorption intensity and a red shift in the absorption band of CR. Thioflavin T (ThT) and 8-anilino-1- naphthalenesulfonic acid (ANS) binding assays were employed to characterize amyloid-like fibril formation. The ThT binding assay revealed that the protein exhibited maximum aggregation in 60% (v/v) ethanol after incubation for 24 h at 24 (o)C. The ANS binding results indicated that the hydrophobic residues were more exposed to the solvent in the aggregated form of the protein. The effects of polyethylene glycol (PEG) on the formation of amyloid-like fibrils was studied in vitro. The aggregation of trypsin was followed via the kinetics of aggregation, the far-UV circular dichroism (CD) and transmission electron microscopy (TEM) in the presence and absence of PEG. The CD measurements indicated that the protein aggregates have a cross-beta structure in 60% ethanol. TEM revealed that trypsin forms fibrils with a thread-like structure. The inhibitory effect of PEG on the aggregation of trypsin increased with rising PEG concentration. PEG therefore inhibits the formation of amyloid-like fibrils of trypsin in aqueous ethanol. PMID- 26428301 TI - NatHER: protocol for systematic evaluation of trends in survival among patients with HER2-positive advanced breast cancer. AB - BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) is an aggressive form of breast cancer and is historically associated with poor outcomes compared with HER2-negative MBC. Since 1998, four drugs have been globally approved for the targeted treatment of HER2-positive MBC. Additional advances in patient care-such as improved breast cancer screening, HER2 testing, and supportive care-have also occurred. The objective of this systematic review and meta-analysis is to determine whether there has been a cumulative change in survival over time in patients with HER2-positive advanced breast cancer based on results from interventional clinical trials (ICTs) and observational studies and to compare outcomes across these types of studies. METHODS/DESIGN: A systematic search of Medline, EMBASE, and the Cochrane Central Register of Controlled Trials will be performed. Two investigators will independently assess each abstract for inclusion. English language reports of ICTs and observational studies that include patients with HER2-positive advanced breast cancer from 1987 onwards will be considered. The primary outcome of interest is overall survival; secondary outcomes include progression-free survival and safety. Data on clinical outcomes, as well as on study design, study population, treatment/intervention, methodological quality, and outcomes, will be extracted using a structured codebook developed by the authors for this study. Standard and cumulative random effects meta-analysis will be performed to derive pooled risk estimates, both overall and by study design, controlling for covariates such as aggregate demographic and clinical characteristics of patients, treatment/intervention, and study characteristics. Heterogeneity of studies will be evaluated using the I(2) statistic. Differences in risk estimates by quality characteristics will be performed using meta-regression. DISCUSSION: This study will evaluate current and evolving trends in survival associated with HER2-positive advanced breast cancer over nearly 30 years and will build upon prior, less comprehensive, systematic analyses. This information is important to patients, healthcare providers, and researchers, particularly in the advanced disease setting, in which new therapies have been recently approved. Including observational studies allows us to evaluate real-world effectiveness; useful information will be gained by comparing findings from observational studies with those from ICTs. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014014345. PMID- 26428303 TI - A determinant of disease symptom severity is located in RNA2 of broad bean wilt virus 2. AB - Broad bean wilt virus 2 (BBWV2), which belongs to the genus Fabavirus, is a destructive pathogen of many economically important horticultural and ornamental crops. In this study, we constructed infectious full-length cDNA clones of two distinct isolates of BBWV2 under control of the cauliflower mosaic virus 35S promoter. BBWV2-PAP1 isolated from paprika (Capsicum annuum var. gulosum) induces severe disease symptoms in various pepper varieties, whereas BBWV2-RP1 isolated from red pepper (Capsicum annuum L.) causes mild symptoms. Agrobacterium-mediated inoculation of the infectious cDNA clones of BBWV2-PAP1 and RP1 resulted in the same symptoms as the original virus isolates. The infectious cDNA clones of BBWV2 PAP1 and RP1 were used to examine the symptoms induced by pseudorecombinants between the two isolates to localize in which of the two genomic RNAs are the symptom severity determinants in BBWV2. The pseudorecombinant of RP1-RNA1 and PAP1-RNA2 induced severe symptoms, similar to those caused by the parental isolate PAP1, whereas the pseudorecombinant of PAP1-RNA1 and RP1-RNA2 induced mild symptoms, similar to those caused by the parental isolate RP1. Our results suggest that BBWV2 RNA2 contains a symptom determinant(s) capable of enhancing symptom severity. PMID- 26428302 TI - The NESH/Abi-3-based WAVE2 complex is functionally distinct from the Abi-1-based WAVE2 complex. AB - BACKGROUND: Abl interactor (Abi) family proteins play significant roles in actin cytoskeleton organization through participation in the WAVE complex. Mammals possess three Abi proteins: Abi-1, Abi-2, and NESH/Abi-3. Abi-1 and Abi-2 were originally identified as Abl tyrosine kinase-binding proteins. It has been disclosed that Abi-1 acts as a bridge between c-Abl and WAVE2, and c-Abl-mediated WAVE2 phosphorylation promotes actin remodeling. We showed previously that NESH/Abi-3 is present in the WAVE2 complex, but neither binds to c-Abl nor promotes c-Abl-mediated phosphorylation of WAVE2. RESULTS: In this study, we characterized NESH/Abi-3 in more detail, and compared its properties with those of Abi-1 and Abi-2. NESH/Abi-3 was ectopically expressed in NIH3T3 cells, in which Abi-1, but not NESH/Abi-3, is expressed. The expression of NESH/Abi-3 caused degradation of endogenous Abi-1, which led to the formation of a NESH/Abi 3-based WAVE2 complex. When these cells were plated on fibronectin-coated dishes, the translocation of WAVE2 to the plasma membrane was significantly reduced and the formation of peripheral lamellipodial structures was disturbed, suggesting that the NESH/Abi-3-based WAVE2 complex was unable to help produce lamellipodial protrusions. Next, Abi-1, Abi-2, or NESH/Abi-3 was expressed in v-src-transformed NIH3T3 cells. Only in NESH/Abi-3-expressed cells did treatment with an Abl kinase inhibitor, imatinib mesylate, or siRNA-mediated knockdown of c-Abl promote the formation of invadopodia, which are ventral membrane protrusions with extracellular matrix degradation activity. Structural studies showed that a linker region between the proline-rich regions and the Src homology 3 (SH3) domain of Abi-1 is crucial for its interaction with c-Abl and c-Abl-mediated phosphorylation of WAVE2. CONCLUSIONS: The NESH/Abi-3-based WAVE2 complex is functionally distinct from the Abi-1-based one, and NESH/Abi-3 may be involved in the formation of ventral protrusions under certain conditions. PMID- 26428304 TI - The phosphoprotein genes of measles viruses from subacute sclerosing panencephalitis cases encode functional as well as non-functional proteins and display reduced editing. AB - Products expressed from the second (P/V/C) gene are important in replication and abrogating innate immune responses during acute measles virus (MV) infection. Thirteen clone sets were derived from the P/V/C genes of measles virus (MV) RNA extracted from brains of a unique collection of seven cases of subacute sclerosing panencephalitis (SSPE) caused by persistent MV in the central nervous system (CNS). Whether these functions are fully maintained when MV replicates in the CNS has not been previously determined. Co-transcriptional editing of the P mRNAs by non-template insertion of guanine (G) nucleotides, which generates mRNAs encoding the viral V protein, occurs much less frequently (9%) in the SSPE derived samples than during the acute infection (30-50%). Thus it is likely that less V protein, which is involved in combatting the innate immune response, is produced. The P genes in MV from SSPE cases were not altered by biased hypermutation but exhibited a high degree of variation within each case. Most but not all SSPE derived phospho-(P) proteins were functional in mini genome replication/transcription assays. An eight amino acid truncation of the carboxyl terminus made the P protein non-functional while the insertion of an additional glycine residue by insertion of G nucleotides at the editing site had no effect on protein function. PMID- 26428305 TI - Comparison of reproductive outcome in oligozoospermic men with high sperm DNA fragmentation undergoing intracytoplasmic sperm injection with ejaculated and testicular sperm. AB - OBJECTIVE: To investigate the effectiveness of intracytoplasmic sperm injection (ICSI) using testicular sperm as a strategy to overcome infertility in men with high sperm DNA fragmentation (SDF). DESIGN: Prospective, observational, cohort study. SETTING: Private IVF centers. PATIENT(S): A total of 147 couples undergoing IVF-ICSI and day 3 fresh ETs whose male partner has oligozoospermia and high SDF. INTERVENTION(S): Sperm injections were carried out with ejaculated sperm (EJA-ICSI) or testicular sperm (TESTI-ICSI) retrieved by either testicular sperm extraction (TESE) or testicular sperm aspiration (TESA). SDF levels were reassessed on the day of oocyte retrieval in both ejaculated and testicular specimens. MAIN OUTCOME MEASURE(S): Percentage of testicular and ejaculated spermatozoa containing fragmented DNA (%DFI) and clinical pregnancy, miscarriage, and live-birth rates. RESULT(S): The %DFI in testicular sperm was 8.3%, compared with 40.7% in ejaculated sperm. For the TESTI-ICSI group versus the EJA-ICSI group, respectively, the clinical pregnancy rate was 51.9% and 40.2%, the miscarriage rate was 10.0% and 34.3%, and the live-birth rate was 46.7% and 26.4%. CONCLUSION(S): ICSI outcomes were significantly better in the group of men who had testicular sperm used for ICSI compared with those with ejaculated sperm. SDF was significantly lower in testicular specimens compared with ejaculated counterparts. Our results suggest that TESTI-ICSI is an effective option to overcome infertility when applied to selected men with oligozoospermia and high ejaculated SDF levels. PMID- 26428306 TI - Results of centralized Asherman surgery, 2003-2013. AB - OBJECTIVE: To study the success rate of hysteroscopic adhesiolysis and the spontaneous recurrence rate of intrauterine adhesions (IUAs) in patients with Asherman syndrome. DESIGN: Cohort study. SETTING: University-affiliated hospitals. PATIENT(S): A total of 638 women with Asherman syndrome were included, all diagnosed using hysteroscopy, and operated on between 2003 and 2013. INTERVENTION(S): Hysteroscopic adhesiolysis. MAIN OUTCOME MEASURE(S): Hysteroscopic adhesiolysis was classified as successful if a normalization of menstrual blood flow occurred, along with a restored, healthy, cavity anatomy, free of adhesions, with hysteroscopic visualization of >= 1 tubal ostium. Recurrences of adhesions were diagnosed using hysteroscopy after an initial successful procedure. RESULT(S): A first-trimester procedure preceded Asherman syndrome in 371 women (58.2%) and caused adhesions of grades 1-2A. In 243 (38.1%) women, a postpartum procedure caused IUAs of grades 3-5. The procedure was successful in 606 women (95%), and restoration of menstrual blood flow occurred in 97.8%; IUAs spontaneously recurred in 174 (27.3%) of these cases. High grades of adhesions were predictive of a higher chance of spontaneous recurrence of adhesions. CONCLUSION(S): In 95% of women with Asherman syndrome, a healthy uterine cavity was restored with hysteroscopic adhesiolysis, in 1-3 attempts, with a 28.7% recurrence rate of spontaneous IUAs. PMID- 26428307 TI - Prostatic relapse of an undifferentiated teratoma 24 years after orchidectomy. AB - BACKGROUND: Non-seminomatous germ cell tumours make up about 40 % of all germ cell tumours, which in turn are the most common tumours in men aged 15-44 years. Low risk stage I non-seminomatous germ cell tumours, which are confined to the testes, are commonly treated by orchiectomy and surveillance. Up to 20 % of patients with this diagnosis relapse, usually within 1-2 years of follow up, but very rarely after more than 5 years. The most common sites of relapse are the retroperitoneal lymph nodes, the mediastinum, and the lungs. We describe a case of relapse in the prostate over 20 years after initial diagnosis, which has not been described in the literature so far. CASE PRESENTATION: This report presents a 49-year-old white British man with relapsed testicular non-seminomatous germ cell tumour 22 years after initial treatment with orchidectomy only. He relapsed with a prostatic mass, haematospermia and back pain. His prostate specific antigen levels were within normal range. Alpha feto-protein and lactate dehydrogenase levels were elevated, and his human chorionic gonadotrophin levels were normal. A biopsy confirmed undifferentiated malignant tumour, shown immunohistochemically to be a yolk sac tumour. The patient was initially treated with bleomycin, etoposide and cisplatin chemotherapy, but developed bleomycin related pulmonary side effects after two cycles. His treatment was changed and he completed four cycles of chemotherapy by receiving two cycles of etoposide, ifosfamide, and cisplatin. Post treatment blood tumour markers were normal, but a follow up computed tomography showed a mass in the base of the prostate, the trigone and the left distal ureter which was surgically resected. The histology from the surgical resection was of necrotic tissue. The patient is now in follow up at 3 years after treatment with no evidence of residual disease on computed tomography. His Alpha feto-protein, beta human chorionic gonadotrophin and lactate dehydrogenase levels are normal. CONCLUSIONS: Very late relapse in stage I non-seminomatous germ cell tumours is extremely rare and the prostate is a highly unusual site of relapsed disease. For diagnosis of late relapse, this case confirms the value of serum biomarkers in germ cell tumours, in particular non seminomatous germ cell tumours. PMID- 26428308 TI - LRP1B deletion is associated with poor outcome for glioblastoma patients. AB - INTRODUCTION: Deletion of the tumor suppressor gene LRP1B has been reported in glioblastoma, the most aggressive primary brain tumor in adults. Our objective was to analyze frequency and prognostic impact of LRP1B deletion and expression levels. METHODS: We retrospectively included all the primary IDH1/2 wild-type GBM patients with available clinical follow-up, DNA and RNA from our database. Deletions were analyzed by SNP-array. LRP1B mRNA expression was analyzed by reverse transcription quantitative polymerase chain reaction. RESULTS: 178 patients were included with a median age of 62.36 years. LRP1B deletions were observed for 10.1% of patients (complete: 2.8%, partial: 7.3%). LRP1B deletions were associated with poor progression-free survival (PFS) (p=0.004) and overall survival (OS) (p=0.001). By multivariate analysis, LRP1B deletions remained significant for both PFS (p=0.003, hazard ratio (HR): 2.261) and OS (p=0.001, HR: 2.609). LRP1B was down expressed with a mean relative expression of 46% comparatively to normal tissue. No association between LRP1B mRNA and patient outcome was observed. No correlation was found between the deletions and the mRNA down-expression. These results were validated using GBM TCGA data. CONCLUSION: LRP1B presents with frequent molecular alterations which impact patient outcome, highlighting the potential interest of this gene for glioblastoma patients. PMID- 26428309 TI - Scales for hyperkinetic disorders: A systematic review. AB - Hyperkinetic movement disorders represent a heterogeneous group of disorders in which involuntary movements are the prevalent clinical symptoms. The five main categories of hyperkinetic disorders are tremor, dystonia, tics,myoclonus and drug-induced dyskinesia.The severity of hyperkinetic disorders is assessed by all clinicians when they examine a patient; quantifying the severity also provides a means of studying the natural history of a given disorder and the possible effect of new therapeutic interventions. This means that good rating instruments are required in both everyday practice and experimental settings. Unfortunately, the clinical evaluation of these disorders is complicated by the inherent nature and variability over time of involuntary movements. A number of scales have been proposed over the years to study the various hyperkinetic disorders. The aim of this review is to systematically identify all the clinical scales that have been proposed and to classify them according to the criteria developed by the Movement Disorder Society (MDS) task force for rating scales in Parkinson's disease.On the basis of this methodology, a scale may be defined as 'Recommended', 'Suggested' or 'Listed' in decreasing order of value.We found that, although numerous scales aimed at assessing hyperkinetic disorders have been published, their variability in terms of clinimetric properties, availability and effort required to administer them is high. In this evaluation, we identified scales defined as 'Recommended' for the assessment of all forms of hyperkinetic disorders. The situation highlighted by our analysis varies considerably, with several 'Recommended' scales being available for some conditions such as tics or dystonia, but only one being available for myoclonus. This gap needs to be filled by the scientific community through both the development of new clinical tools and there finement of existing ones. PMID- 26428310 TI - The characteristics of camptocormia in patients with Parkinson's disease: A large cross-sectional multicenter study in Japan. AB - PURPOSE: The goal of the present study was to clarify the clinical characteristics and laboratory results of parkinsonian symptoms among patients with and without camptocormia. METHODS: Seventy-eight Parkinson's disease (PD) patients with camptocormia and 78 PD patients without camptocormia underwent a neurological examination, a blood test, and spinal magnetic resonance imaging (MRI). PD with camptocormia group and PD with non-camptocormia group were matched on age, age at PD onset, and sex. PRINCIPAL RESULTS: Camptocormia group had significantly higher prevalence of compression fractures, more severe parkinsonian symptoms, and a greater incidence of dementia than those without camptocormia. Serum creatine kinase levels in camptocormia group significantly elevated compared with non-camptocormia group. There were higher prevalence of abnormal findings in spine MRI including compression fractures and paravertebral muscle changes in camptocormia group compared with non-camptocormia group. MAJOR CONCLUSIONS: Camptocormia is associated with a greater prevalence of compression fractures and associated with greater UPDRS part II, part III score, axial score, and lower MMSE in this cross-sectional study. Thus, it can be concluded that camptocormia in PD is predominantly myopathic. PMID- 26428311 TI - Palmaris brevis spasm: Identified by high resolution ultrasound and treated by botulinum toxin. PMID- 26428312 TI - Endothelial nitric oxide synthase: From biochemistry and gene structure to clinical implications of NOS3 polymorphisms. AB - Nitric oxide (NO) is an important vasodilator with a well-established role in cardiovascular homeostasis. While mediator is synthesized from L-arginine by neuronal, endothelial, and inducible nitric oxide synthases (NOS1,NOS3 and NOS2 respectively), NOS3 is the most important isoform for NO formation in the cardiovascular system. NOS3 is a dimeric enzyme whose expression and activity are regulated at transcriptional, posttranscriptional,and posttranslational levels. The NOS3 gene, which encodes NOS3, exhibits a number of polymorphic sites including single nucleotide polymorphisms (SNPs), variable number of tandem repeats (VNTRs), microsatellites, and insertions/deletions. Some NOS3 polymorphisms show functional effects on NOS3 expression or activity, thereby affecting NO formation. Interestingly, many studies have evaluated the effects of functional NOS3 polymorphisms on disease susceptibility and drug responses. Moreover, some studies have investigated how NOS3 haplotypes may impact endogenous NO formation and disease susceptibility. In this article,we carried out a comprehensive review to provide a basic understanding of biochemical mechanisms involved in NOS3 regulation and how genetic variations in NOS3 may translate into relevant clinical and pharmacogenetic implications. PMID- 26428313 TI - Reference gene selection for quantitative gene expression studies during biological invasions: A test on multiple genes and tissues in a model ascidian Ciona savignyi. AB - As invasive species have successfully colonized a wide range of dramatically different local environments, they offer a good opportunity to study interactions between species and rapidly changing environments. Gene expression represents one of the primary and crucial mechanisms for rapid adaptation to local environments. Here, we aim to select reference genes for quantitative gene expression analysis based on quantitative Real-Time PCR (qRT-PCR) for a model invasive ascidian, Ciona savignyi. We analyzed the stability of ten candidate reference genes in three tissues (siphon, pharynx and intestine) under two key environmental stresses (temperature and salinity) in the marine realm based on three programs (geNorm, NormFinder and delta Ct method). Our results demonstrated only minor difference for stability rankings among the three methods. The use of different single reference gene might influence the data interpretation, while multiple reference genes could minimize possible errors. Therefore, reference gene combinations were recommended for different tissues - the optimal reference gene combination for siphon was RPS15 and RPL17 under temperature stress, and RPL17, UBQ and TubA under salinity treatment; for pharynx, TubB, TubA and RPL17 were the most stable genes under temperature stress, while TubB, TubA and UBQ were the best under salinity stress; for intestine, UBQ, RPS15 and RPL17 were the most reliable reference genes under both treatments. Our results suggest that the necessity of selection and test of reference genes for different tissues under varying environmental stresses. The results obtained here are expected to reveal mechanisms of gene expression-mediated invasion success using C. savignyi as a model species. PMID- 26428314 TI - Problem Management Plus (PM+) for common mental disorders in a humanitarian setting in Pakistan; study protocol for a randomised controlled trial (RCT). AB - BACKGROUND: In humanitarian settings common mental disorders (depression, anxiety disorders, posttraumatic stress disorder) are highly prevalent. The World Health Organization (WHO) has developed Problem Management Plus (PM+), a 5-session, individual psychological intervention program, delivered by paraprofessionals that addresses common mental disorders in people in communities affected by adversity. The objectives of this study are to test effectiveness and cost effectiveness of the locally adapted PM+ compared to Treatment as usual (TAU) in Peshawar District, Pakistan. METHODS: A randomised controlled trial will be conducted in 346 primary care attendees in 3 health care centres in Peshawar District, Pakistan. After informed consent, primary care attendees with high levels of psychological distress according to the General Health Questionnaire-12 (GHQ-12) and functional impairment (WHO Disability Assessment Schedule 2.0 (WHODAS)) will be assigned to PM+ (n = 173) or TAU (n = 173). At baseline, 1 week and 3 months following PM+, independent assessors will assess psychological distress with the Hospital Anxiety and Depression Scale (HADS), and functional disability with the WHODAS. Secondary outcomes are posttraumatic stress disorder (PTSD) symptoms, and client-perceived priority problems. Further, cost effectiveness will be assessed using the Service Receipt Inventory (SRI). DISCUSSION: If proven effective, PM+ will be rolled out to other areas for further adaptation and testing in diverse humanitarian settings. TRIAL REGISTRATION: ACTRN12614001235695. Registered 26 November 2014. Australian New Zealand Clinical Trials Registry. PMID- 26428315 TI - Mechanisms underpinning the peak knee flexion moment increase over 2-years following arthroscopic partial meniscectomy. AB - BACKGROUND: Knee osteoarthritis is common in people who have undergone partial meniscectomy, and a higher external knee flexion moment during gait may be a potential contributor. Although the peak external knee flexion moment has been shown to increase from 3 months to 2 years following partial meniscectomy, mechanisms underpinning the increase in the peak knee flexion moment are unknown. METHODS: Sixty-six participants with partial meniscectomy completed three dimensional gait (normal and fast pace) and quadriceps strength assessment at baseline (3 months following partial meniscectomy) and again 2 years later. Variables included external knee flexion moment, vertical ground reaction force, knee flexion kinematics, and quadriceps peak torque. FINDINGS: For normal pace walking, the main significant predictors of change in peak knee flexion moment were an increase in peak vertical ground reaction force (R(2)=0.55), mostly due to an increase in walking speed, and increase in peak knee flexion angle (R(2)=0.19). For fast pace walking, the main significant predictors of change in peak knee flexion moment were an in increase in peak vertical ground reaction force (R(2)=0.51) and increase in knee flexion angle at initial contact (R(2)=0.17). Change in peak vertical force was mostly due to an increase in walking speed. INTERPRETATION: Findings suggest that increases in vertical ground reaction force and peak knee flexion angle during stance are predominant contributors to the 2-year change in peak knee flexion moment. Future studies are necessary to refine our understanding of joint loading and its determinants following meniscectomy. PMID- 26428316 TI - A survey of DICER1 hotspot mutations in ovarian and testicular sex cord-stromal tumors. AB - Sertoli-Leydig cell tumors are characterized by the presence of somatic DICER1 hotspot mutations. In this study, we sought to define the association between DICER1 hotspot mutations and different morphologic subtypes of ovarian Sertoli Leydig cell tumors. Furthermore, we aimed to assess whether DICER1 hotspot mutations occur in other ovarian sex cord-stromal tumors, testicular sex cord stromal tumors, or other female genital tract tumors with rhabdomyosarcomatous differentiation. We subjected a series of ovarian Sertoli-Leydig cell tumors (n=32), Sertoli cell tumors (n=5) and gynandroblastomas (n=5), testicular sex cord-stromal tumors (n=15) and a diverse group of female genital tract tumors with rhabdomyosarcomatous morphology (n=10) to DICER1 hotspot mutation analysis using Sanger sequencing. We also tested two gynandroblastomas for the presence of FOXL2 hotspot mutations (p.C134W; c.402C>G). Twenty of 32 (63%) Sertoli-Leydig cell tumors harbored a DICER1 hotspot mutation, of which 80% had the p.E1705K mutation. No association was found between DICER1 mutation status and the presence of heterologous or retiform differentiation in Sertoli-Leydig cell tumors. DICER1 mutations were found at similar frequencies in gynandroblastoma (2/5; 40%) and ovarian Sertoli cell tumors (5/8; 63%; P>0.1), and all mutated tumors harbored a p.E1705K mutation. DICER1 hotspot mutations were also identified in a single cervical rhabdomyosarcoma and in the rhabdomyosarcomatous component of a uterine carcinosarcoma. No DICER1 mutations were detected in testicular sex cord-stromal tumors. Two DICER1 wild-type gynandroblastomas harbored a p.C134W FOXL2 hotspot mutation in both tumor components. In this study we confirmed that DICER1 hotspot mutations occur in over half of ovarian Sertoli Leydig cell tumors, and are unrelated to tumor differentiation. We also widened the spectrum of ovarian sex cord-stromal tumors with sertoliform differentiation, in which DICER1 mutations are known to occur, to include Sertoli cell tumors and gynandroblastomas. Our results suggest that DICER1 mutations may not have a role in testicular sex cord-stromal tumorigenesis. PMID- 26428317 TI - Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas. AB - According to cytogenetic aberrations, sarcomas can be categorized as complex or simple karyotype tumors. Alternative lengthening of telomeres is a telomere maintenance mechanism common in sarcomas. Recently, this mechanism was found to be associated with loss of either alpha-thalassemia/mental retardation syndrome X linked (ATRX) or death domain-associated (DAXX) protein. We previously reported that alternative lengthening of telomeres and loss of ATRX expression were common in leiomyosarcoma, angiosarcoma, pleomorphic liposarcoma, and dedifferentiated liposarcoma. In the present study, we screened an additional 245 sarcomas of other types to determine the prevalence of alternative lengthening of telomeres, loss of ATRX/DAXX expression, and their relationship. Undifferentiated pleomorphic sarcomas were frequently alternative lengthening of telomeres positive (65%) and loss of ATRX was seen in approximately half of the alternative lengthening of telomeres-positive tumors. Nineteen of 25 myxofibrosarcomas were alternative lengthening of telomeres-positive, but only one was ATRX deficient. Three of 15 radiation-associated sarcomas were alternative lengthening of telomeres positive, but none of them was ATRX deficient. Alternative lengthening of telomeres and/or loss of ATRX were uncommon in malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, and embryonal rhabdomyosarcomas. By contrast, none of the 71 gene fusion-associated sarcomas was ATRX deficient or alternative lengthening of telomeres positive. All tumors exhibited preserved DAXX expression. Combining our previous studies and this study, a total of 384 sarcomas with complex karyotypes were examined, 83 of which were ATRX deficient (22%). By telomere-specific fluorescence in situ hybridization, 45% (138/308) were alternative lengthening of telomeres positive, 55% (76/138) of which were ATRX deficient. Loss of ATRX was highly associated with alternative lengthening of telomeres (P<0.001). We conclude that alternative lengthening of telomeres is a frequent telomere-maintenance mechanism in cytogenetically complex sarcomas. Loss of ATRX is highly associated with this feature. PMID- 26428318 TI - Mitochondrial DNA mutations distinguish bilateral multifocal renal oncocytomas from familial Birt-Hogg-Dube tumors. AB - Oncocytomas are mostly benign tumors characterized by accumulation of defective mitochondria, and in sporadic cases, are associated with disruptive mitochondrial DNA (mtDNA) mutations. However, the role mtDNA mutations have in renal tumors of Birt-Hogg-Dube (BHD) patients and other renal oncocytomas with an apparent genetic component has not been investigated to date. Here we characterize the mitochondrial genome in different renal tumors and investigate the possibility of employing mtDNA sequencing analyses of biopsy specimens to aid in the differential diagnosis of oncocytomas. The entire mitochondrial genome was sequenced in 25 samples of bilateral and multifocal (BMF) renal oncocytomas, 30 renal tumors from BHD patients and 36 non-oncocytic renal tumors of different histologies as well as in biopsy samples of kidney tumors. mtDNA sequencing in BMF oncocytomas revealed that all tumors carry disruptive mutations, which impair the assembly of the NADH-ubiquinone oxidoreductase. Multiple tumors from a given BMF oncocytoma patient mainly harbor the same somatic mutation and the kidneys of these patients display diffuse oncocytosis. In contrast, renal oncocytomas of patients with BHD syndrome and renal tumors with different histologies do not show disruptive mtDNA mutations. Moreover, we demonstrate that it is feasible to amplify and sequence the entire mtDNA in biopsy specimens, and that these sequences are representative of the tumor DNA. These results show that pathogenic mtDNA mutations affecting complex I of the respiratory chain are strongly correlated with the oncocytoma phenotype in non-BHD-related renal tumors and that mtDNA sequences from biopsies are predictive of the tumor genotype. This work supports a role for mtDNA mutations in respiratory chain complexes as diagnostic markers for renal oncocytomas. PMID- 26428319 TI - Combined Hydroxyurea and Verapamil in the Clinical Treatment of Refractory Meningioma: Human and Orthotopic Xenograft Studies. AB - OBJECTIVE: Previous in vitro and in vivo results suggested that hydroxyurea (HU) and verapamil could suppress meningioma growth individually and synergistically. We evaluated the clinical efficacy and safety of this approach for the treatment of refractory recurrent/progressive meningiomas and expanded our studies in a xenograft orthotopic mouse model. METHODS: Six women and 1 man, aged 26-76 years (median, 56 years), with magnetic resonance imaging-proven progression of >= 25% in cross-sectional area of recurrent meningioma (2 World Health Organization grade I, 5 grade II) within the preceding 6 months received HU 1000 or 1500 mg/day (20 mg/kg/day, twice daily) as well as verapamil sustained-release tablets with dose escalation every 2 weeks (120-240 mg/day). They underwent magnetic resonance imaging every 3 months during therapy. To augment the clinical trial results, we performed mouse orthotopic xenograft experiments using similar dosing to test tumor growth, vascularity, and drug bioavailability. RESULTS: After a mean of 8.1 cycles of treatment, the patients demonstrated no significant radiographic responses during mean follow-up of 14.5 +/- 4.8 months. Median progression-free survival (PFS) was 8.0 months, and 6-month PFS was 85%. Side effects occurred in 6 (86%) patients. Xenograft studies showed no effect of individual or combined treatments on meningioma growth. Neither HU nor verapamil was detectable in mouse brain tumor tissue despite adequate serum levels within therapeutic ranges. CONCLUSIONS: Our results showed no effect of HU or verapamil on tumor recurrence, PFS, and in vivo tumor burden reduction. Drug delivery to the tumor may be a major limitation. PMID- 26428320 TI - Intradural Spinal Arachnoid Cyst: A Long-Term Postlaminectomy Complication: A Case Report and Review of the Literature. AB - BACKGROUND: Spinal arachnoid cysts are a rare cause of spinal cord compression. Intradural arachnoid cysts are rarer than extradural arachnoid cysts. Spinal arachnoid cysts are mostly congenital in origin. Arachnoid cysts due to trauma, lumbar puncture, or surgery are rarely reported. Most arachnoid cysts are located posterior to the spinal cord in the thoracic regions. The ideal treatment is laminectomy or laminoplasty with puncture, marsupialization, or excision. But the development of a cervico-thoracic spinal intradural extramedullary arachnoid cyst anteriorly located 28 years after laminectomy is a recognizable complication of laminectomy. CASE DESCRIPTION: We report here a case of a 45-year-old man who underwent C6-T1 laminectomy at the age of 17 years for cervical intervertebral disc prolapse (C6/7, C7/T1) and compressive myelopathy. Twenty-eight years after laminectomy, he developed spastic quadriparesis and was diagnosed with a spinal intradural extramedullary anterior arachnoid cyst at the laminectomy site with compressive myelopathy. CONCLUSIONS: So, although laminectomy with excision is usually practiced to treat spinal arachnoid cysts, laminectomy itself is a cause of development of intradural arachnoid cysts. PMID- 26428321 TI - Near-Complete Resolution of Clinical and Radiographic Findings After Endovascular Embolization of a Giant Serpentine A1 Aneurysm. AB - BACKGROUND: Giant serpentine aneurysms are complex intracranial lesions, associated with a poor prognosis if left untreated. Treatment usually involves surgical trapping of the aneurysm with arterio-arterial anastomosis; however, recent endovascular management has been implemented for the management of such aneurysms. CASE DESCRIPTION: We report the unique case of a 71-year-old woman who presented with visual deficits due to the mass effect of a giant serpentine aneurysm arising from the A1 segment of the anterior cerebral artery. Because of its location proximal to a widely patent anterior communicating artery, angiographic cure was achieved with sacrifice of the A1 segment. Clinical and radiographic follow-up demonstrated resolution of the presenting symptoms and near-complete obliteration of the aneurysm. CONCLUSIONS: Thrombosed giant serpentine aneurysms can show dramatic resolution of mass effect with endovascular treatment. PMID- 26428322 TI - Predictors of Shunt-Dependent Hydrocephalus Following Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: Shunt-dependent hydrocephalus is a common complication of aneurysmal subarachnoid hemorrhage (aSAH). There is a need to identify patients who require ventriculoperitoneal shunt (VPS) insertion so that any modifiable risk factors can be addressed early after aSAH. METHODS: Exploratory analysis was performed on 413 patients enrolled in CONSCIOUS-1, a prospective randomized controlled trial of patients with aSAH treated with clazosentan. The association between clinical and neuroimaging covariates and VPS placement was first determined by univariate analysis. Covariates with P < 0.15 on univariate analysis were then analyzed in a multivariate logistic regression model. Receiver operating characteristic curve analysis was used to define optimal predictive thresholds. The published literature was reviewed to determine the overall rate of VPS insertion after aSAH. RESULTS: Overall, 17.2% (71/413) of patients required VPS insertion. Multivariate analysis demonstrated that insertion of an external ventricular drain (odds ratio, 6.21; 95% confidence interval, 2.51-16.91) and increasing volume of cerebrospinal fluid (CSF) drainage per day (odds ratio, 1.004; 95% confidence interval, 1.000-1.009) were associated with VPS insertion. Receiver operating characteristic curve analysis revealed an optimal daily CSF output threshold of 78 mL was predictive of VPS insertion. Among 41,789 patients with aSAH from 66 published studies, the overall VPS insertion rate was 12.7%. CONCLUSIONS: The presence of an external ventricular drain and increased daily CSF output (above 78 mL/day) seems to be predictive of subsequent VPS insertion after aSAH. Although we could not identify modifiable risk factors for needing a VPS, nevertheless, these findings identify patients at greatest risk of VPS placement and inform treatment decisions as well as patient expectations. PMID- 26428323 TI - Neuroprotective Effects of Thymoquinone on the Hippocampus in a Rat Model of Traumatic Brain Injury. AB - BACKGROUND: Traumatic brain injury is a leading cause of morbidity and mortality worldwide. We evaluated the neuroprotective effects of thymoquinone (TQ) in a rat model of traumatic brain injury by using biochemical and histopathologic methods for the first time. MATERIALS AND METHODS: Twenty-four rats were divided into sham (n = 8), trauma (n = 8), and TQ-treated (n = 8) groups. A moderate degree of head trauma was induced with the use of Feeney's falling weight technique, and TQ (5 mg/kg/day) was administered to the TQ-treated group for 7 days. All animals were killed after cardiac perfusion. Brain tissues were extracted immediately after perfusion without damaging the tissues. Biochemical procedures were performed with the serum, and a histopathologic evaluation was performed on the brain tissues. Biochemical experiments included malondialdehyde (MDA), reduced and oxidized coenzyme Q10 analysis, DNA isolation and hydroylazation, and glutathione peroxidase, and superoxide dismutase analyses. RESULTS: Neuron density in contralateral hippocampal regions (CA1, CA2-3, and CA4) 7 days after the trauma decreased significantly in the trauma and TQ-treated groups, compared with that in the control group. Neuron densities in contralateral hippocampal regions (CA1, CA2-3, and CA4) were greater in the TQ-treated group than in the trauma group. TQ did not increase superoxide dismutase or glutathione peroxidase antioxidant levels. However, TQ decreased the MDA levels. CONCLUSIONS: These results indicate that TQ has a healing effect on neural cells after head injury and this effect is mediated by decreasing MDA levels in the nuclei and mitochondrial membrane of neurons. PMID- 26428324 TI - A 5-Year Retrospective Analysis of Exposure to Ionizing Radiation by Neurosurgery Residents in the Modern Era. AB - BACKGROUND: The potential for radiation exposure during neurosurgical training has increased dramatically in the last decade. Incorporation of instrumented and minimally invasive spinal surgery and neuroendovascular procedures into the curriculum has led to increased potential for exposure to ionizing radiation. Contemporary neurosurgery residents' exposure to radiation has not been previously reported. OBJECTIVE: To determine neurosurgery residents' exposure to radiation over the course of 7 years of training. METHODS: Retrospective analysis of a prospectively maintained radiation database from July 2009 to July 2014 for all neurosurgery residents based on radiation dosimetry data. Standard radiation safety precautions were used (e.g., lead gowns or aprons), although compliance was not specifically monitored. RESULTS: Thirty-eight neurosurgery residents were monitored from 2009 to 2014. Radiation exposure data were available for 34 residents for the final analysis. A total of 20,541 days of radiation monitoring data were available. The mean deep dose equivalent over this period was 0.67 +/- 0.75 mrem per resident/day. The calculated maximum cumulative exposure during the course of residency training was 12.15 +/- 13.50 mSv, approximately equivalent to 6 computed tomography head scans. CONCLUSIONS: To our knowledge, this study is the first to quantify radiation exposure for neurosurgery residents in the current era of training. From this work, efforts may be initiated to increase awareness and safety with regard to radiation exposure. Although the total dose is not high, a better understanding of the impact of radiation exposure on practitioners may help to drive institutional policies to reduce occupational exposure. PMID- 26428325 TI - Experimental Evaluation of the Developmental Mechanism Underlying Fractures at the Adjacent Segment. AB - BACKGROUND: Compression fractures at adjacent mobile segments have been reported as adjacent segment disease under trauma in several studies. In this study, the occurrence of fractures at the adjacent segment was evaluated experimentally under trauma. METHODS: Static testing of different fixation systems was performed to show their biomechanical performances. The ovine vertebrae fixed with rigid, dynamic, and semirigid systems were used as test samples. The stiffness values of the systems were obtained by testing the vertebrectomy models under compression bending, lateral bending, and torsion tests. In addition, their effects on the adjacent segments were experimentally evaluated within a drop mechanism. A free fall drop mechanism was designed and manufactured. Next, 3.5-kg, 5-kg, and 7-kg weights were released from 1 m above the test samples to generate compression fractures. The occurrence of compression fractures was observed with the use of radiograph of test samples, which were obtained before and after the drop test. RESULTS: Dynamic and semirigid systems have advantages compared with rigid systems as the result of their lower stiffness values. Radiographs showed that epiphysis fractures occurred at fixed and adjacent mobile segments, which were fixed with semirigid fixation. In addition, dynamic fixation well preserved the fixed and adjacent mobile segments under trauma. CONCLUSIONS: The dynamic system with a polyetheretherketone rod can better preserve both adjacent and fixed segments. However, because of the cantilever beam effect, the semirigid system exhibits a great disadvantage. PMID- 26428326 TI - Outcome of Surgery for Idiopathic Normal Pressure Hydrocephalus: Role of Preoperative Static and Pulsatile Intracranial Pressure. AB - OBJECTIVES: To examine the outcome of surgery for idiopathic normal-pressure hydrocephalus (iNPH) and how outcome relates to the preoperative static and pulsatile intracranial pressure (ICP). METHODS: An observational cohort study included all patients with iNPH managed at our department during the years 2002 2012 in whom overnight ICP monitoring was part of the preoperative work-up. Clinical data were retrieved from a quality registry and ICP scores from a pressure database. RESULTS: The study included 472 patients, 316 in the surgery group and 156 in the nonsurgery group. Among those treated surgically, 278 (90%) showed clinical improvement (Responders) whereas 32 (10%) had no improvement (Nonresponders). Among Responders, only about one third reached the best clinical scores; moreover, the difference in clinical score between Responders and Nonresponders declined with time after surgery, particularly after 3-4 years. The surgery was accompanied by acute intracranial hematomas in 11 patients (3.5%), of whom 4 (1.3%) died. Survival (age at death) was significantly greater among the Responders than in Nonresponders. Although the static ICP was normal in all patients, the pulsatile ICP was significantly greater in Responders than in Non responders. CONCLUSIONS: The pulsatile ICP was greater in shunt Responders than Nonresponders. Although the clinical improvement declined over time and the majority did not experience complete relief of symptoms, shunt Responders lived significantly longer than Nonresponders. The present observations suggest that the current surgical treatment regimens for iNPH (primarily shunt surgery) address only some aspects of the disease process, in particular the aspect of brain water disturbance. PMID- 26428327 TI - Carotid Artery Stenosis in the Setting of Transcatheter Aortic Valve Replacement: Clinical and Technical Considerations of Carotid Stenting. AB - OBJECTIVE: No consensus exists regarding the safety and efficacy of treatment of carotid stenosis before transcatheter aortic valve replacement (TAVR). Our objective was to review our series of patients treated for carotid stenosis with stenting in the setting of severe aortic valve disease and TAVR to evaluate its safety and efficacy. METHODS: We reviewed patients who underwent carotid stenting in the setting of preoperative work-up or after TAVR from August 2012 through January 2015. Perioperative patient outcomes were collected to assess the safety and efficacy of carotid stenting. RESULTS: Five patients (4 men, 1 woman; median age, 83 years; range, 72-88 years) underwent successful carotid stenting before (median, 30 days before; range, 2 days-3 months) TAVR. The median extent of carotid stenosis was 80% (range, 75%-90%), but the diagnoses were incidental and all patients were asymptomatic. One patient suffered acute systolic heart failure during stenting requiring emergent balloon aortic valvuloplasty and vasopressor therapy. Median intensive care unit stay was 1 day (range, 1-16 days) for all patients, and 1 day for patients treated electively. The median hospital stay was 1 day (range, 1-16 days) for all patients, and 1 day for patients treated electively. All patients were discharged home. None suffered immediate or delayed neurological complications. CONCLUSIONS: We successfully performed carotid stenting in 5 patients before TAVR for severe aortic pathology. These patients require intensive care and careful monitoring. Larger prospective studies are needed to determine whether carotid stenting in the setting of TAVR can provide long-term neurological benefits. PMID- 26428328 TI - Technical Advances in Aneurysm Surgery: Continuous Evolution and Patient Selection Are the Key for Better Outcomes. PMID- 26428329 TI - Screening for the metabolic side effects of antipsychotic medication: findings of a 6-year quality improvement programme in the UK. AB - OBJECTIVES: To increase the frequency and quality of screening for the metabolic syndrome in people prescribed continuing antipsychotic medication. DESIGN: An audit-based, quality improvement programme (QIP) with customised feedback to participating mental health services after each audit, including benchmarked data on their relative and absolute performance against an evidence-based practice standard and the provision of bespoke change interventions. SETTING: Adult, assertive outreach, community psychiatric services in the UK. PARTICIPANTS: 6 audits were conducted between 2006 and 2012. 21 mental health Trusts participated in the baseline audit in 2006, submitting data on screening for 1966 patients, while 32 Trusts participated in the 2012 audit, submitting data on 1591 patients. RESULTS: Over the 6 years of the programme, there was a statistically significant increase in the proportion of patients for whom measures for all 4 aspects of the metabolic syndrome had been documented in the clinical records in the previous year, from just over 1 in 10 patients in 2006 to just over 1 in 3 by 2012. The proportion of patients with no evidence of any screening fell from almost 1/2 to 1 in 7 patients over the same period. CONCLUSIONS: The findings suggest that audit-based QIPs can help improve clinical practice in relation to physical healthcare screening. Nevertheless, they also reveal that only a minority of community psychiatric patients prescribed antipsychotic medication is screened for the metabolic syndrome in accordance with best practice recommendations, and therefore potentially remediable causes of poor physical health remain undetected and untreated. PMID- 26428330 TI - Minimally important difference estimates and methods: a protocol. AB - INTRODUCTION: Patient-reported outcomes (PROs) are often the outcomes of greatest importance to patients. The minimally important difference (MID) provides a measure of the smallest change in the PRO that patients perceive as important. An anchor-based approach is the most appropriate method for MID determination. No study or database currently exists that provides all anchor-based MIDs associated with PRO instruments; nor are there any accepted standards for appraising the credibility of MID estimates. Our objectives are to complete a systematic survey of the literature to collect and characterise published anchor-based MIDs associated with PRO instruments used in evaluating the effects of interventions on chronic medical and psychiatric conditions and to assess their credibility. METHODS AND ANALYSIS: We will search MEDLINE, EMBASE and PsycINFO (1989 to present) to identify studies addressing methods to estimate anchor-based MIDs of target PRO instruments or reporting empirical ascertainment of anchor-based MIDs. Teams of two reviewers will screen titles and abstracts, review full texts of citations, and extract relevant data. On the basis of findings from studies addressing methods to estimate anchor-based MIDs, we will summarise the available methods and develop an instrument addressing the credibility of empirically ascertained MIDs. We will evaluate the credibility of all studies reporting on the empirical ascertainment of anchor-based MIDs using the credibility instrument, and assess the instrument's inter-rater reliability. We will separately present reports for adult and paediatric populations. ETHICS AND DISSEMINATION: No research ethics approval was required as we will be using aggregate data from published studies. Our work will summarise anchor-based methods available to establish MIDs, provide an instrument to assess the credibility of available MIDs, determine the reliability of that instrument, and provide a comprehensive compendium of published anchor-based MIDs associated with PRO instruments which will help improve the interpretability of outcome effects in systematic reviews and practice guidelines. PMID- 26428331 TI - General practitioners' attitudes towards the management of dental conditions and use of antibiotics in these consultations: a qualitative study. AB - OBJECTIVES: This study aimed to produce an account of the attitudes of general practitioners (GPs) towards the management of dental conditions in general practice, and sought to explore how GPs use antibiotics in the treatment of dental problems. DESIGN: Qualitative study employing semistructured telephone interviews and thematic analysis. PARTICIPANTS: 17 purposively sampled GPs working in Wales, of which 9 were male. The median number of years since graduation was 21. Maximum variation sampling techniques were used to ensure participants represented different Rural-Urban localities, worked in communities with varying levels of deprivation, and had differing lengths of practising career. RESULTS: Most GPs reported regularly managing dental problems, with more socioeconomically deprived patients being particularly prone to consult. Participants recognised that dental problems are not optimally managed in general practice, but had sympathy with patients experiencing dental pain who reported difficulty obtaining an emergency dental consultation. Many GPs considered antibiotics an acceptable first-line treatment for acute dental problems and reported that patients often attended expecting to receive antibiotics. GPs who reported that their usual practice was to prescribe antibiotics were more likely to prioritise patients' immediate needs, whereas clinicians who reported rarely prescribing often did so to encourage patients to consult a dental professional. CONCLUSIONS: The presentation of patients with dental problems presents challenges to GPs who report concerns about their ability to manage such conditions. Despite this, many reported frequently prescribing antibiotics for patients with dental conditions. This may contribute to both patient morbidity and the emergence of antimicrobial resistance. This research has identified the need for quantitative data on general practice consultations for dental problems and qualitative research exploring patient perspectives on reasons for consulting. The findings of these studies will inform the design of an intervention to support patients in accessing appropriate care when experiencing dental problems. PMID- 26428332 TI - The UK Out of Hospital Cardiac Arrest Outcome (OHCAO) project. AB - INTRODUCTION: Reducing premature death is a key priority for the UK National Health Service (NHS). NHS Ambulance services treat approximately 30 000 cases of suspected cardiac arrest each year but survival rates vary. The British Heart Foundation and Resuscitation Council (UK) have funded a structured research programme--the Out of Hospital Cardiac Arrest Outcomes (OHCAO) programme. The aim of the project is to establish the epidemiology and outcome of OHCA, explore sources of variation in outcome and establish the feasibility of setting up a national OHCA registry. METHODS AND ANALYSIS: This is a prospective observational study set in UK NHS Ambulance Services. The target population will be adults and children sustaining an OHCA who are attended by an NHS ambulance emergency response and where resuscitation is attempted. The data collected will be characterised broadly as system characteristics, emergency medical services (EMS) dispatch characteristics, patient characteristics and EMS process variables. The main outcome variables of interest will be return of spontaneous circulation and medium-long-term survival (30 days to 10-year survival). ETHICS AND DISSEMINATION: Ethics committee permissions were gained and the study also has received approval from the Confidentiality Advisory Group Ethics and Confidentiality committee which provides authorisation to lawfully hold identifiable data on patients without their consent. To identify the key characteristics contributing to better outcomes in some ambulance services, reliable and reproducible systems need to be established for collecting data on OHCA in the UK. Reports generated from the registry will focus on data completeness, timeliness and quality. Subsequent reports will summarise demographic, patient, process and outcome variables with aim of improving patient care through focus quality improvement initiatives. PMID- 26428334 TI - An unusual presentation of acute Q fever. PMID- 26428333 TI - Effectiveness of multicomponent interventions in primary healthcare settings to promote continuous smoking cessation in adults: a systematic review. AB - OBJECTIVE: The objective of the present review is to evaluate multicomponent/complex primary care (PC) interventions for their effectiveness in continuous smoking abstinence by adult smokers. DESIGN: A systematic review of randomised and non-randomised controlled trials was undertaken. ELIGIBILITY CRITERIA FOR INCLUDED STUDIES: Selected studies met the following criteria: evaluated effects of a multicomponent/complex intervention (with 2 or more intervention components) in achieving at least 6-month abstinence in adult smokers who visited a PC, biochemical confirmation of abstinence, intention-to treat analysis and results published in English/Spanish. METHODS: We followed PRISMA statement to report the review. We searched the following data sources: MEDLINE, Web of Science, Scopus (from inception to February 2014), 3 key journals and a tobacco research bulletin. The Scottish Intercollegiate Guidelines Network checklists were used to evaluate methodological quality. Data selection, evaluation and extraction were done independently, using a paired review approach. Owing to the heterogeneity of interventions in the studies included, a meta-analysis was not conducted. RESULTS: Of 1147 references identified, 9 studies were selected (10,204 participants, up to 48 months of follow-up, acceptable methodological quality). Methodologies used were mainly individual or group sessions, telephone conversations, brochures or quit-smoking kits, medications and economic incentives for doctors and no-cost medications for smokers. Complex interventions achieved long-term continuous abstinence ranging from 7% to 40%. Behavioural interventions were effective and had a dose-response effect. Both nicotine replacement and bupropion therapy were safe and effective, with no observed differences. CONCLUSIONS: Multicomponent/complex interventions in PC are effective and safe, appearing to achieve greater long-term continuous smoking cessation than usual care and counselling alone. Selected studies were heterogeneous and some had significant losses to follow-up. Our results show that smoking interventions should include more than one component and a strong follow up of the patient to maximise results. PMID- 26428336 TI - Researching and preventing diagnostic errors: chasing patient safety from a different angle. PMID- 26428335 TI - Clinical development of cancer therapeutics that target metabolism. AB - Glucose and glutamine metabolism in cancer cells are markedly elevated relative to non-transformed normal cells. This metabolic reprogramming enables the production of adenosine triphosphate and the anabolic precursors needed for survival, growth and motility. The recent observations that mutant oncogenic proteins and the loss of tumor suppressors activate key metabolic enzymes suggest that selective inhibition of these enzymes may yield effective cancer therapeutics with acceptable toxicities. In support of this concept, pre-clinical studies of small molecule antagonists of several metabolic enzymes in tumor bearing mice have demonstrated reasonable therapeutic indices. We will review the rationale for targeting metabolic enzymes as a strategy to treat cancer and will detail the results of several recent clinical trials of metabolic inhibitors in advanced cancer patients. PMID- 26428337 TI - The ethical dilemma posed by unmonitored new anticoagulants. PMID- 26428338 TI - Unusual cause of pleural effusion: ovarian hyperstimulation syndrome. PMID- 26428339 TI - Diffuse iris nevus. PMID- 26428341 TI - You Want to Publish in the Journal of Professional Nursing: Here Are Some Strategies for Success. PMID- 26428342 TI - The Development of a Clinical Nurse Scholar in Baccalaureate Education. AB - The purpose of this national study was to explore the vision of chief academic officers for baccalaureate nursing education. We invited chief academic nursing officers, randomly selected from a representative sample of accredited baccalaureate nursing programs to participate in the study. Audiotaped interviews were conducted in focus groups at professional meetings or by telephone and were transcribed verbatim. Data collection continued until thematic saturation was reached (N = 29). Analysis of the findings revealed themes that described future vision for baccalaureate education that provides guidance to faculty as they develop curriculum. An overarching theme "We are all Stewards of the Profession" and three supporting themes emerged: "Learning Pathways are Varied," "Faculty Need to Grow," and "New Pedagogies Need to Focus on the Development of 'Who I Am' as a Clinical Scholar." Findings point to a future where diverse learning pathways are integrated throughout the curriculum. The curriculum of tomorrow will place greater emphasis on the development of professional identity as a nurse and calls for expanded stewardship for nursing education. Deans recommended that investing time and resources into well-designed faculty development programs will help all faculty, regardless of appointment, to adapt to changing student needs and rapidly evolving practice environments. PMID- 26428343 TI - Collaboration Among DNP- and PhD-Prepared Nurses: Opportunity to Drive Positive Change. AB - Because of the rapidly changing environment of doctoral education, collaborative relationships between doctor of nursing practice and doctor of philosophy prepared nurses continue to evolve. Although there are few currently reportable outcomes, examples are given of collaborative efforts highlighting scholarship, education, practice, and research. In accordance with the Institute Of Medicine recommendations and building upon work done by the American Association of Colleges of Nursing, this article describes opportunities for expanding collaboration among doctoral-prepared nurses. Collaboration facilitates a timely translation of research into practice, enhances educational opportunities, drives positive change, and improves health outcomes. PMID- 26428344 TI - Community-Academic Partnerships: Developing a Service-Learning Framework. AB - Academic partnerships with hospitals and health care agencies for authentic clinical learning have become a major focus of schools of nursing and professional nursing organizations. Formal academic partnerships in community settings are less common despite evolving models of care delivery outside of inpatient settings. Community-Academic partnerships are commonly developed as a means to engage nursing students in service-learning experiences with an emphasis on student outcomes. The benefit of service-learning projects on community partners and populations receiving the service is largely unknown primarily due to the lack of structure for identifying and measuring outcomes specific to service-learning. Nursing students and their faculty engaged in service-learning have a unique opportunity to collaborate with community partners to evaluate benefits of service-learning projects on those receiving the service. This article describes the development of a service-learning framework as a first step toward successful measurement of the benefits of undergraduate nursing students' service-learning projects on community agencies and the people they serve through a collaborative community-academic partnership. PMID- 26428345 TI - Joining Forces: Enriching RN-to-BSN Education With Veteran-Centered Experiences. AB - This article highlights the commitment of the American Association of Colleges of Nursing to engage nursing schools to support the Joining Forces initiative by enhancing the education and preparation of the nation's nurses to care for veterans, service members, and their families. The progress toward meeting the Joining Forces pledge and integrating veteran-centered learning in an on-line registered nurse-to-bachelor of science in nursing program is described. PMID- 26428346 TI - Are Virtual Classrooms Colorblind? AB - E-learning, increasingly employed in nursing education, has been embraced as a means to enhance options for all students, particularly those with limited educational opportunities. Although a desire to increase access for underserved students is often cited, disparities in availability, usage, and quality of e learning persist among diverse households and student populations when compared to the general population. In this article, these issues will be examined along with reflection on the extent to which culture has been integrated into on-line design and instruction. Historical and cultural aspects, circumscribing virtual classrooms, are discussed using African Americans as an exemplar. The imperative to harness the democratizing potential of this educational format is underscored. In this article, culture will be examined in light of the significant growth in on-line nursing education over the past several decades. PMID- 26428347 TI - Mental Snapshots: Creating an Organized Plan for Health Assessment. AB - Beginning nursing students enter a rapidly moving and changing health care climate. Multiple stimulations can frighten and overwhelm the student's ability to find order of essential patient information. Students need to know how to collect, process, and manage important health data accurately and efficiently in the clinical setting. An integrative method for teaching nursing students to walk into the patient's room and construct a patterned sequence of focused assessments assists students in creating an organized plan for health assessment. The Mental Snapshots Method includes three components for health assessment: (a) sequential assessment steps of the patient; (b) color-coded visual images of the patient representing a bodily condition; and (c) focused assessment questions of primary health complaint(s) with a plan for nursing care. This mental snapshots strategy employs an information processing model of sensory, memory, and motor functioning, which enable students to maintain patient quality and safety. PMID- 26428348 TI - The Effect of a Self-Reflection and Insight Program on the Nursing Competence of Nursing Students: A Longitudinal Study. AB - Nurses have to solve complex problems for their patients and their families, and as such, nursing care capability has become a focus of attention. The aim of this longitudinal study was to develop a self-reflection practice exercise program for nursing students to be used during clinical practice and to evaluate the effects of this program empirically and longitudinally on change in students' clinical competence, self-reflection, stress, and perceived teaching quality. An additional aim was to determine the predictors important to nursing competence. We sampled 260 nursing students from a total of 377 practicum students to participate in this study. A total of 245 students nurse completed 4 questionnaires, Holistic Nursing Competence Scale, Self-Reflection and Insight Scale, Perceived Stress Scale, and Clinical Teaching Quality Scale, at 2, 4, and 6 months after clinical practice experience. Generalized estimating equation models were used to examine the change in scores on each of the questionnaires. The findings showed that, at 6 months after clinical practice, nursing competence was significantly higher than at 2 and 4 months, was positively related to self reflection and insight, and was negatively related to practice stress. Nursing students' competence at each time period was positively related to clinical teachers' instructional quality at 4 and 6 months. These results indicate that a clinical practice program with self-reflection learning exercise improves nursing students' clinical competence and that nursing students' self-reflection and perceived practice stress affect their nursing competence. Nursing core competencies are enhanced with a self-reflection program, which helps nursing students to improve self-awareness and decrease stress that may interfere with learning. Further, clinical practice experience, self-reflection and insight, and practice stress are predictors of nursing students' clinical competence. PMID- 26428349 TI - Evaluation of World Health Organization Multi-Professional Patient Safety Curriculum Topics in Nursing Education: Pre-test, post-test, none-experimental study. AB - The Multi-professional Patient Safety Curriculum Guide was launched by the World Health Organization to develop a patient safety-friendly curriculum in health education. The aim of this study was to evaluate the impact of teaching related to two topics from the Patient Safety Curriculum Guide on student nurses' knowledge and attitudes toward patient safety. A pretest, posttest, nonexperimental design was used. Patient safety education questionnaires were distributed to a convenience sample of 181 nursing students before the intervention, and 141 questionnaires after the intervention in one university in the East of England. The intervention consisted of two face-to-face lectures and one facilitated group work discussion. Seventy-one responses from pre- and posttest stages were matched. Paired t test, McNemar's test, and frequency measures were used for data analysis. The findings suggest that there are statistically significant differences in the subscales of the error and patient safety and personal influence over safety. The differences in the students' answers on patient safety knowledge before and after the interventions were not statistically significant. Although the student nurses highly commended the teaching delivered in this study, the use of experimental design in future curriculum evaluation may provide a more complementary insight to the findings of this study. PMID- 26428350 TI - The Stressors and Coping Strategies of Older Adults With Persistent Atrial Fibrillation Prior to and Following Direct Current Cardioversion. AB - OBJECTIVE: The purpose of this study was to explore the stressors and coping strategies of older adults with persistent atrial fibrillation (AF) before and after direct current cardioversion. METHOD: The study used a qualitative descriptive design. Sixteen patients were recruited through an AF clinic to participate in individual interviews prior to the cardioversion and at 6 and 12 weeks post procedure. RESULTS: Pre-cardioversion, older adults experienced symptom and health care-related stressors superimposed on existing non-AF stressors. They used a range of emotion and problem-focused coping. Non-AF stressors increased post procedure at the same time that participants perceived less need for coping strategies with a return to regular rhythm. DISCUSSION: There was a shift from AF to non-AF related stressors following the cardioversion but a decrease in coping strategies. Older adults with AF should be encouraged to maintain use of coping strategies to manage ongoing stress and reduce the risk of AF recurrence. PMID- 26428351 TI - Transcranial Magnetic Stimulation for Bipolar Disorder with Catatonic Stupor: A Case Report. PMID- 26428353 TI - Nutritional Impact of a Gluten-Free Casein-Free Diet in Children with Autism Spectrum Disorder. AB - We compared anthropometric values, nutrient intake, the Healthy Eating Index and food variety in children with autism spectrum disorder (ASD), 20 on a gluten-free casein-free (GFCF) diet and 85 on a regular diet in Valencia (Spain) using 3-days food diaries. Those on the GFCF diet had a lower weight, body mass index, and total energy, pantothenic acid, calcium, phosphorus and sodium intake, but a higher intake of fiber, legumes, and vegetables. Further, the GFCF diet group had a better quality of fat intake, but needed supplementation with vitamin D. Randomized controlled trials are required to explore long-term effects of this diet on anthropometric and nutritional status (the focus of our study), but also behavioral symptoms, in children with ASD. PMID- 26428352 TI - Brexpiprazole Alters Monoaminergic Systems following Repeated Administration: an in Vivo Electrophysiological Study. AB - BACKGROUND: Brexpiprazole was recently approved as adjunctive therapy for depression and treatment of schizophrenia in adults. To complement results from a previous study in which its acute effects were characterized, the present study assessed the effect of repeated brexpiprazole administration on monoaminergic systems. METHODS: Brexpiprazole (1mg/kg, subcutaneous) or vehicle was administered once daily for 2 and 14 days. Single-unit electrophysiological recordings from noradrenaline neurons in the locus coeruleus, serotonin neurons in the dorsal raphe nucleus, dopaminergic neurons in the ventral tegmental area, and pyramidal neurons in the hippocampus CA3 region were obtained in adult male Sprague-Dawley rats under chloral hydrate anesthesia within 4 hours after final dosing. RESULTS: Brexpiprazole blunted D2 autoreceptor responsiveness, while firing activity of ventral tegmental area dopaminergic neurons remained unaltered. Brexpiprazole increased the firing rate of locus coeruleus noradrenaline neurons and increased noradrenaline tone on alpha2-adrenergic receptors in the hippocampus. Administration of brexpiprazole for 2 but not 14 days increased the firing rate of serotonin neurons in the dorsal raphe nucleus. In the hippocampus, serotonin1A receptor blockade significantly disinhibited pyramidal neurons after 2- and 14-day brexpiprazole administration. In contrast, no significant disinhibition occurred after 24-hour washout or acute brexpiprazole. CONCLUSIONS: Repeated brexpiprazole administration resulted in a marked occupancy of D2 autoreceptors, while discharge activity of ventral tegmental area dopaminergic neurons remained unaltered. Brexpiprazole enhanced serotonergic and noradrenergic tone in the hippocampus, effects common to antidepressant agents. Together, these results provide further insight in the neural mechanisms by which brexpiprazole exerts antidepressant and antipsychotic effects. PMID- 26428354 TI - Long-Term Outcomes in Children Diagnosed with Autism Spectrum Disorders in India. AB - We investigated long-term outcomes in children with diagnosis of autism spectrum disorders based on Childhood Autism Rating Scale (CARS score). Information about outcomes such as speech, friendships and activities of daily living (ADLs) was collected through telephone-based interviews. Gilliam Autism Rating Scale-2 and Vineland Social Maturity Scale were used to assess level of functioning at follow up. Parents of 80 [67 males, mean age 12 (3) years] children participated in the interview, 23 attended follow-up assessment. Sixty-four (80%) were verbal, 34 (42.5%) had need-based speech, 20 (25%) had friends and 37 (46%) had achieved age appropriate ADLs. Median total follow-up period was 10 years. Lower disease severity, parent participation and higher maternal education were associated with better outcomes. PMID- 26428355 TI - 4-PBA prevents pressure overload-induced myocardial hypertrophy and interstitial fibrosis by attenuating endoplasmic reticulum stress. AB - Our previous study indicated that attenuation of endoplasmic reticulum (ER) stress by administration of 4-phenylbutyric acid (4-PBA) could prevent cardiac rupture and remodeling in a mouse model of myocardial infarction (MI). However, whether 4-PBA is protective in hypertrophic heart disease is unclear. Thus, we tested the therapeutic effect of 4-PBA on pressure-overload induced myocardial hypertrophy. Transverse aortic constriction (TAC) was used to create myocardial hypertrophy in C57BL/6 male mice for 4 weeks. Immediately after surgery, the mice were administrated either 4-PBA (20 mg/kg/day) or 0.9% NaCl by intraperitoneal injection. At the end of 4 weeks, the mice underwent high-resolution echocardiographic imaging. Our results showed that both the left ventricular posterior wall thickness at end systole (LVPWs) and diastole (LVPWd) were increased in the TAC group, compared to control. 4-PBA administration attenuated hypertrophy and decreased the heart weight over body weight ratio. Masson's trichrome staining showed that myocardial interstitial fibrosis and collagen deposition were also decreased by 4-PBA. We next detected the ER stress response in the heart tissues of TAC mice in different time points. Western blotting showed that the expression of ER stress marker, GRP78, CHOP and phosphor-PERK, were persistently increased 4 weeks after TAC. The treatment of 4-PBA inhibited the expression of ER stress markers. We also demonstrated that the 4-PBA at 20 mg/kg/day had no effect on histone 3 deacetylation inhibition, while attenuating ER stress and TAC-induced hypertrophy. These findings suggest that 4-PBA may be a therapeutic strategy to consider in preventing pressure-overload induced myocardial hypertrophy and interstitial fibrosis by selectively attenuating ER stress. PMID- 26428356 TI - Chemical characteristics for optimizing CYP2E1 inhibition. AB - Cytochrome P450 2E1 (CYP2E1) expression and activity in the liver is associated with the degree of liver damage in patients with alcoholic steatohepatitis (ASH) as well as non-alcoholic steatohepatitis (NASH). CYP2E1 is known to generate reactive oxygen species, which leads to oxidative stress, one of the hallmarks of both diseases. Apart from ROS, toxic metabolites can be formed by CYP2E1 metabolism, further potentiating liver injury. Therefore, CYP2E1 is implicated in the pathogenesis of ASH and NASH. The aim of this study was to determine the chemical characteristics of compounds that are important to inhibit CYP2E1. To this end, structurally related analogs that differed in their lipophilic, steric and electronic properties were tested. In addition, homologues series of aliphatic primary alcohols, secondary alcohols, aldehydes, ketones and carboxylic acids were tested. It was found that inhibition of the CYP2E1 activity is primarily governed by lipophilicity. The optimal log D7.4 (octanol/water distribution coefficient at pH 7.4) value for inhibition of CYP2E1 was approximately 2.4. In the carboxylic acids series the interaction of the carboxylate group with polar residues lining the CYP2E1 active site also has to be considered. This study sketches the basic prerequisites in the search for inhibitors of CYP2E1, which would strengthen our therapeutic armamentarium against CYP2E1 associated diseases, such as ASH and NASH. PMID- 26428357 TI - Pharmacokinetics of Glycopyrronium Following Repeated Once-Daily Inhalation in Healthy Chinese Subjects. AB - BACKGROUND AND OBJECTIVES: Glycopyrronium is a once-daily long-acting muscarinic antagonist for the maintenance treatment of patients with chronic obstructive pulmonary disease. This study assessed the pharmacokinetics of inhaled glycopyrronium 50 ug once-daily for 14 days in healthy Chinese subjects. METHODS: In this open-label study, 12 Chinese healthy subjects (six males and six females; mean age 23.1 years [range 18-26 years]) were enrolled and completed the study. Glycopyrronium in plasma was determined using validated liquid chromatography mass spectrometry method with a lower limit of quantification of 1.5 pg/mL. Plasma pharmacokinetic parameters were determined on Day 1 after first dose and on Day 14 (steady state) after last dose using non-compartmental analysis. Trough pharmacokinetic samples (Days 5, 7, 10 and 12) were collected. Safety was also assessed. RESULTS: Glycopyrronium was rapidly absorbed into the systemic circulation after inhalation and its plasma concentrations decreased rapidly thereafter. Median time to reach maximum concentration (T max) was reached within 5 min after inhalation on both Days 1 and 14. Accumulation in the systemic exposure to glycopyrronium was observed from the time of first dose administration on Day 1 up to Day 14 and the observed accumulation ratio (R acc) values of area under the plasma drug concentration-time curve [AUC] from time 0 to 24 h post-dose (AUC0-24h) and maximum plasma drug concentration (C max) (Day 14/Day 1) were 2.77 and 1.59, respectively. The elimination half-life (T 1/2) was not reported. Mean effective half-life (T 1/2,acc) was 37.7 h. Pharmacokinetic steady state was reached after 5 days of daily dosing. One subject experienced dry mouth; otherwise glycopyrronium was well tolerated. CONCLUSIONS: Comparison of systemic exposure to glycopyrronium in Chinese versus the non-Chinese population did not indicate clinically relevant ethnic differences. Multiple inhaled doses of glycopyrronium were safe and well tolerated. PMID- 26428358 TI - Convection-enhanced delivery of an anti-miR is well-tolerated, preserves anti-miR stability and causes efficient target de-repression: a proof of concept. AB - Over-expressed microRNAs (miRs) are promising new targets in glioblastoma (GBM) therapy. Inhibition of over-expressed miRs has been shown to diminish GBM proliferation, invasion and angiogenesis, indicating a significant therapeutic potential. However, the methods utilized for miR inhibition have had low translational potential. In clinical trials convection-enhanced delivery (CED) has been applied for local delivery of compounds in the brain. The aim of this study was to determine if safe and efficient miR inhibition was possible by CED of an anti-miR. We used a highly invasive GBM orthotopic xenograft model and targeted a well-validated miR, let-7a, with a 2'-O-methoxyethyl anti-miR with a combined phosphodiester/phosphorothioate backbone to establish an initial proof of concept. In vitro, anti-let-7a was delivered unassisted to the patient-derived T87 glioblastoma spheroid culture. In vivo, anti-let-7a or saline were administered by CED into orthotopic T87-derived tumors. After 1 month of infusion, tumors were removed and tumor mRNA levels of the target-gene High mobility group AT-hook 2 (HMGA2) were determined. In vitro, 5 days inhibition was superior to 1 day at de-repressing the let-7a target HMGA2 and the inhibition was stable for 24 h. In vivo, anti-miR integrity was preserved in the pumps and no animals showed signs of severe adverse effects attributable to the anti-miR treatment. HMGA2 tumor level was significantly de-repressed in the anti-miR treated animals. The results showed-as an initial proof of concept-that miRs can be efficiently inhibited using CED delivery of anti-miR. The next step is to apply CED for anti-miR delivery focusing on key oncogenic miRs. PMID- 26428359 TI - Adapting Screening, Brief Intervention, and Referral to Treatment for Alcohol and Drugs to Culturally Diverse Clinical Populations. AB - OBJECTIVES: To review the literature on the screening, brief intervention, and referral to treatment (SBIRT) approach to alcohol and drug use with racial and ethnic subgroups in the United States and to develop recommendations for culturally competent SBIRT practice. METHODS: Articles reporting on the use of SBIRT components (screening, brief intervention, referral to treatment) for alcohol and drug use were identified through a comprehensive literature search of PubMed from 1995 to 2015. RESULTS: A synthesis of the published literature on racial and ethnic considerations regarding SBIRT components (including motivational interviewing techniques) was created using evidence-based findings. Recommendations on culturally competent use of SBIRT with specific ethnic groups are also described. CONCLUSIONS: On the basis of the literature reviewed, SBIRT offers a useful set of tools to help reduce risky or problematic substance use. Special attention to validated screeners, appropriate use of language/literacy, trust building, and incorporation of patient and community health care preferences may enhance SBIRT acceptability and effectiveness. PRACTICE IMPLICATIONS: Providers should consider the implications of previous research when adapting SBIRT for diverse populations, and use validated screening and brief intervention methods. The accompanying case illustration provides additional information relevant to clinical practice. PMID- 26428360 TI - Cultural Adaptation of Screening, Brief Intervention and Referral to Treatment Using Motivational Interviewing. AB - This clinical case presentation and discussion illustrates a culturally adapted alcohol and drug use intervention using the Screening, Brief Intervention, and Referral to Treatment (SBIRT) approach, incorporating motivational interviewing skills. This case conference serves to complement the accompanying review article on SBIRT with diverse cultural groups, placing information from the review in the context of a typical clinical setting. In this example, SBIRT is provided in a primary care clinic to a Latino patient who reports hazardous drinking, depression, chronic pain and use of prescription opioids. PMID- 26428363 TI - Interstitial cells of Cajal increased in patients with rectal prolapse. PMID- 26428361 TI - Correlates of Opioid Use in Adults With Self-Reported Drug Use Recruited From Public Safety-Net Primary Care Clinics. AB - OBJECTIVES: The purpose of this study was to compare demographic, clinical, and survival characteristics of drug-using safety-net primary care patients who used or did not use opioids, and to examine treatment implications of our findings. METHODS: The sample consisted of 868 adults who reported illicit drug use in the 90 days before study enrollment, 396 (45.6%) of whom were opioid users. RESULTS: Multiple measures indicated that, as a group, opioid users were less physically and psychiatrically healthy than drug users who did not endorse using opioids, and were heavy users of medical services (eg, emergency departments, inpatient hospitals, and outpatient medical) at considerable public expense. After adjusting for age, they were 2.61 (confidence interval, 1.48-4.61) times more likely to die in the 1 to 5 years after study enrollment and more likely to die from accidental poisoning than nonopioid users. Subgroup analyses suggested patients using any nonprescribed opioids had more serious drug problems including more intravenous drug use and greater HIV risk than patients using opioids only as prescribed. CONCLUSIONS: Use of opioids adds a dimension of severity over and above illicit drug use as it presents in the primary care setting. Opioid users may benefit from psychiatric and addiction care integrated into their primary care setting, naloxone overdose prevention kits, and prevention efforts such as clean needle exchanges. Addiction or primary care providers are in a key position to facilitate change among such patients, especially the third or more opioid users having a goal of abstinence from drugs. PMID- 26428364 TI - Practical problems of measuring depth of submucosal invasion in T1 colorectal carcinomas. AB - PURPOSE: Submucosal invasion depth (SID) in colorectal carcinoma (CRC) is an important factor in estimating risk of lymph node metastasis, but can be difficult to measure, leading to inadequate or over-extensive treatment. Here, we aimed to clarify the practical aspects of measuring SID in T1 CRC. METHODS: We investigated 568 T1 CRCs that were resected surgically at our hospital from April 2001 to December 2013, and relationships between SID and clinicopathological factors, including the means of measurement, lesion morphology, and lymph node metastasis. RESULTS: Of these 568 lesions, the SID was >=1000 MUm in 508 lesions. SIDs for lesions measured from the surface layer were all >=1000 MUm. Although lesions with SIDs >=1000 MUm were associated with significantly higher levels of unfavorable histologic types and lymphovascular infiltration than shallower lesions, a depth of >=1000 MUm was not a significant risk factor for lymph node metastasis (LNM) (6.7 vs. 9.8 %; P = 0.64), and no lesions for which the sole pathological factor was SID >=1000 MUm had lymph node metastasis. Protruded lesions showed deeper SIDs than other types. CONCLUSIONS: Although we found several problems of measuring SID in this study, we also found, surprisingly, that SID is not a risk factor for lymph node metastasis, and its measurement is not needed to estimate the risk of lymph node metastasis. PMID- 26428365 TI - Proximal humeral osteoarticular allografts: technique, pearls and pitfalls, outcomes. AB - Allograft transplantation is a biologic reconstruction option for massive bone defects after resection of bone sarcomas. This type of reconstruction not only restores bone stock but it also allows us to reconstruct the joint anatomically. These factors are a major concern, especially in a young and active population.We are describing indications, surgical techniques, pearls and pitfalls, and outcomes of proximal humeral osteoarticular allografts, done at present time in our institution.We found that allograft fractures and articular complications, as epiphyseal resorption and subchondral fracture, are the main complications observed in proximal humerus osteoarticular allograft reconstructions. Nevertheless, only fractures need a reconstruction revision. Joint complications may adversely affect the limb function, but for this reason, an allograft revision is rarely performed. PMID- 26428366 TI - Response to: Practice of first aid in burn related injuries in a developing country. AB - Traditional remedies for burns first aid are rarely compliant with current best practice. Greater Manchester is one of the most ethnically diverse regions in the UK. Our burns centre has noted the prevalent use of traditional remedies over recognised first aid prior to presentation. We review traditional burns remedies and highlight the importance of burns first aid education that is accessible to migrant communities. PMID- 26428367 TI - Antitumor activity of ginseng sapogenins, 25-OH-PPD and 25-OCH3-PPD, on gastric cancer cells. AB - OBJECTIVES: 25-Hydroxyprotopanaxadiol (25-OH-PPD) and 25-methoxylprotopanaxadiol (25-OCH3-PPD), two ginseng sapogenins, have potent antitumor activity and their effects on gastric cancer (BGC-823, SGC-7901, MKN-28) cells and a gastric mucosa (GES-1) cell line are reported. RESULTS: Both compounds significantly inhibited the growth of gastric cancer cells, while having lesser inhibitory effects on GES 1 cells by MTT assay. A mechanistic study revealed that the two ginseng sapogenins could induce apoptosis in BGC-823 cells by morphological observation, DNA fragmentation, flow cytometry and western blot analysis. Besides, the apoptosis was inhibited by Ac-DEVD-CHO, a caspase 3 inhibitor, which was confirmed by cell viability analysis. CONCLUSIONS: These results indicate that 25 OH-PPD and 25-OCH3-PPD have potential to be promising agents for the treatment of gastric cancer. PMID- 26428368 TI - Increased production of plumbagin in Plumbago indica root cultures by biotic and abiotic elicitors. AB - OBJECTIVES: To evaluate the effects of 12 biotic and abiotic elicitors for increasing the production of plumbagin in Plumbago indica root cultures. RESULTS: Most elicitors showed minimal effects on the root dry weight, except for 250 mg chitosan l(-1) and 10 mM L-alanine that markedly decreased root biomass by about 40 % compared to the untreated root cultures (5 g l(-1)). Treatments with 100 uM AgNO3 significantly increased intracellular plumbagin production by up to 7.6 mg g(-1) DW that was 4-fold more than the untreated root cultures (1.9 mg g(-1) DW). In contrast, treatments with 150 mg chitosan l(-1), 5 mM L-alanine, and 50 uM 1 naphthol significantly enhanced the extracellular secretion of plumbagin by up to 10.6, 6.9, and 5.7 mg g(-1) DW, respectively, and increased the overall production of plumbagin by up to 12.5, 12.5, and 9.4 mg g(-1) DW, respectively. CONCLUSIONS: Chitosan (150 mg l(-1)), L-alanine (5 mM), and 1-naphthol (50 uM) were the best elicitors to enhance plumbagin production in P. indica root cultures. PMID- 26428369 TI - Lung injury caused by greenstick fracture of the scapular body in a 6-year-old boy. AB - Complications caused by a scapular body fracture are rare, and usually occur due to concomitant injuries or nonunion. Intrathoracic displacement of a fractured scapula has only been described in two reports involving adolescents. In this report, we describe a 6-year-old boy with a parenchymal lung injury caused by a greenstick fracture fragment of the scapular body after being struck by a dump truck. Three-dimensional CT (3D CT) scan showed an incomplete fractured fragment impaling the left lung parenchyma resulting in pneumothorax, parenchymal contusion, and pneumatocele in the left upper lobe. The patient underwent emergency open reduction of the scapular fracture and chest tube insertion. A rare subtype of scapular fracture with resultant fragment rotation and intrathoracic penetration can injure the lung parenchyma. To the best of our knowledge, lung injury caused by incomplete fracture of the scapula in patients younger than 10 years has not been reported previously. PMID- 26428370 TI - EBNA1. AB - Epstein-Barr nuclear antigen 1 (EBNA1) plays multiple important roles in EBV latent infection and has also been shown to impact EBV lytic infection. EBNA1 is required for the stable persistence of the EBV genomes in latent infection and activates the expression of other EBV latency genes through interactions with specific DNA sequences in the viral episomes. EBNA1 also interacts with several cellular proteins to modulate the activities of multiple cellular pathways important for viral persistence and cell survival. These cellular effects are also implicated in oncogenesis, suggesting a direct role of EBNA1 in the development of EBV-associated tumors. PMID- 26428371 TI - EBNA2 and Its Coactivator EBNA-LP. AB - While all herpesviruses can switch between lytic and latent life cycle, which are both driven by specific transcription programs, a unique feature of latent EBV infection is the expression of several distinct and well-defined viral latent transcription programs called latency I, II, and III. Growth transformation of B cells by EBV in vitro is based on the concerted action of Epstein-Barr virus nuclear antigens (EBNAs) and latent membrane proteins(LMPs). EBV growth transformed B-cells express a viral transcriptional program, termed latency III, which is characterized by the coexpression of EBNA2 and EBNA-LP with EBNA1, EBNA3A, -3B, and -3C as well as LMP1, LMP2A, and LMP2B. The focus of this review will be to discuss the current understanding of how two of these proteins, EBNA2 and EBNA-LP, contribute to EBV-mediated B-cell growth transformation. PMID- 26428372 TI - The EBNA3 Family: Two Oncoproteins and a Tumour Suppressor that Are Central to the Biology of EBV in B Cells. AB - Epstein-Barr virus nuclear antigens EBNA3A , EBNA3B and EBNA3C are a family of three large latency-associated proteins expressed in B cells induced to proliferate by the virus. Together with the other nuclear antigens (EBNA-LP, EBNA2 and EBNA1), they are expressed from a polycistronic transcription unit that is probably unique to B cells. However, compared with the other EBNAs, hitherto the EBNA3 proteins were relatively neglected and their roles in EBV biology rather poorly understood. In recent years, powerful new technologies have been used to show that these proteins are central to the latency of EBV in B cells, playing major roles in reprogramming the expression of host genes affecting cell proliferation, survival, differentiation and immune surveillance. This indicates that the EBNA3s are critical in EBV persistence in the B cell system and in modulating B cell lymphomagenesis. EBNA3A and EBNA3C are necessary for the efficient proliferation of EBV-infected B cells because they target important tumour suppressor pathways--so operationally they are considered oncoproteins. In contrast, it is emerging that EBNA3B restrains the oncogenic capacity of EBV, so it can be considered a tumour suppressor--to our knowledge the first to be described in a tumour virus. Here, we provide a general overview of the EBNA3 genes and proteins. In particular, we describe recent research that has highlighted the complexity of their functional interactions with each other, with specific sites on the human genome and with the molecular machinery that controls transcription and epigenetic states of diverse host genes. PMID- 26428373 TI - The Latent Membrane Protein 1 (LMP1). AB - Almost exactly twenty years after the discovery of Epstein-Barr virus (EBV), the latent membrane protein 1 (LMP1) entered the EBV stage, and soon thereafter, it was recognized as the primary transforming gene product of the virus. LMP1 is expressed in most EBV-associated lymphoproliferative diseases and malignancies, and it critically contributes to pathogenesis and disease phenotypes. Thirty years of LMP1 research revealed its high potential as a deregulator of cellular signal transduction pathways leading to target cell proliferation and the simultaneous subversion of cell death programs. However, LMP1 has multiple roles beyond cell transformation and immortalization, ranging from cytokine and chemokine induction, immune modulation, the global alteration of gene and microRNA expression patterns to the regulation of tumor angiogenesis, cell-cell contact, cell migration, and invasive growth of tumor cells. By acting like a constitutively active receptor, LMP1 recruits cellular signaling molecules associated with tumor necrosis factor receptors such as tumor necrosis factor receptor-associated factor (TRAF) proteins and TRADD to mimic signals of the costimulatory CD40 receptor in the EBV-infected B lymphocyte. LMP1 activates NF kappaB, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3-K), IRF7, and STAT pathways. Here, we review LMP1's molecular and biological functions, highlighting the interface between LMP1 and the cellular signal transduction network as an important factor of virus-host interaction and a potential therapeutic target. PMID- 26428374 TI - Latent Membrane Protein 2 (LMP2). AB - LMP2A is an EBV-encoded protein with three domains: (a) an N-terminal cytoplasmic domain, which has PY motifs that bind to WW domain-containing E3 ubiquitin ligases and an ITAM that binds to SH2 domain-containing proteins, (b) a transmembrane domain with 12 transmembrane segments that localizes LMP2A in cellular membranes, and (c) a 27-amino acid C-terminal domain which mediates homodimerization and heterodimerization of LMP2 protein isoforms. The most prominent two isoforms of the protein are LMP2A and LMP2B. The LMP2B isoform lacks the 19-amino acid N-terminal domain found in LMP2A, which modulates cellular signaling resulting in a baseline activation of B cells and degradation of cellular kinases leading to the downregulation of normal B cell signaling pathways. These two seemingly contradictory processes allow EBV to establish and maintain latency. LMP2 is expressed in many EBV-associated malignancies. While its antigenic properties may be useful in developing LMP2-specific immunity, the LMP2A N-terminal motifs also provide a basis to target LMP2A-modulated cellular kinases for the development of treatment strategies. PMID- 26428376 TI - Viral Entry. AB - Epstein-Barr virus primarily, though not exclusively, infects B cells and epithelial cells. Many of the virus and cell proteins that are involved in entry into these two cell types in vitro have been identified, and their roles in attachment and fusion are being explored. This chapter discusses what is known about entry at the cellular level in vitro and describes what little is known about the process in vivo. It highlights some of the questions that still need to be addressed and considers some models that need further testing. PMID- 26428377 TI - Epstein-Barr Virus Lytic Cycle Reactivation. AB - Epstein-Barr virus, which mainly infects B cells and epithelial cells, has two modes of infection: latent and lytic. Epstein-Barr virus infection is predominantly latent; however, lytic infection is detected in healthy seropositive individuals and becomes more prominent in certain pathological conditions. Lytic infection is divided into several stages: early gene expression, DNA replication, late gene expression, assembly, and egress. This chapter summarizes the most recent progress made toward understanding the molecular mechanisms that regulate the different lytic stages leading to production of viral progeny. In addition, the chapter highlights the potential role of lytic infection in disease development and current attempts to purposely induce lytic infection as a therapeutic approach. PMID- 26428378 TI - Innate Immune Recognition of EBV. AB - The ability of Epstein-Barr virus (EBV) to establish latency despite specific immune responses and to successfully persist lifelong in the human host shows that EBV has developed powerful strategies and mechanisms to exploit, evade, abolish, or downsize otherwise effective immune responses to ensure its own survival. This chapter focuses on current knowledge on innate immune responses against EBV and its evasion strategies for own benefit and summarizes the questions that remain to be tackled. Innate immune reactions against EBV originate both from the main target cells of EBV and from nontarget cells, which are elements of the innate immune system. Thus, we structured our review accordingly but with a particular focus on the innate recognition of EBV in its two stages in its life cycle, latent state and lytic replication. Specifically, we discuss (I) innate sensing and resulting innate immune responses against EBV by its main target cells, focusing on (i) EBV transmission between epithelial cells and B cells and their life cycle stages; and (ii) elements of innate immunity in EBV's target cells. Further, we debate (II) the innate recognition and resulting innate immune responses against EBV by cells other than the main target cells, focusing on (iii) myeloid cells: dendritic cells, monocytes, macrophages, and neutrophil granulocytes; and (iv) natural killer cells. Finally, we address (III) how EBV counteracts or exploits innate immunity in its latent and lytic life cycle stages, concentrating on (v) TLRs; (vi) EBERs; and (vii) microRNAs. PMID- 26428375 TI - EBV Noncoding RNAs. AB - EBV expresses a number of viral noncoding RNAs (ncRNAs) during latent infection, many of which have known regulatory functions and can post-transcriptionally regulate viral and/or cellular gene expression. With recent advances in RNA sequencing technologies, the list of identified EBV ncRNAs continues to grow. EBV encoded RNAs (EBERs) , the BamHI-A rightward transcripts (BARTs) , a small nucleolar RNA (snoRNA) , and viral microRNAs (miRNAs) are all expressed during EBV infection in a variety of cell types and tumors. Recently, additional novel EBV ncRNAs have been identified. Viral miRNAs, in particular, have been under extensive investigation since their initial identification over ten years ago. High-throughput studies to capture miRNA targets have revealed a number of miRNA regulated viral and cellular transcripts that tie into important biological networks. Functions for many EBV ncRNAs are still unknown; however, roles for many EBV miRNAs in latency and in tumorigenesis have begun to emerge. Ongoing mechanistic studies to elucidate the functions of EBV ncRNAs should unravel additional roles for ncRNAs in the viral life cycle. In this chapter, we will discuss our current knowledge of the types of ncRNAs expressed by EBV, their potential roles in viral latency, and their potential involvement in viral pathogenesis. PMID- 26428379 TI - Epstein-Barr Virus-Specific Humoral Immune Responses in Health and Disease. AB - Epstein-Barr virus (EBV) is widely distributed in the world and associated with a still increasing number of acute, chronic, malignant and autoimmune disease syndromes. Humoral immune responses to EBV have been studied for diagnostic, pathogenic and protective (vaccine) purposes. These studies use a range of methodologies, from cell-based immunofluorescence testing to antibody-diversity analysis using immunoblot and epitope analysis using recombinant or synthetic peptide-scanning. First, the individual EBV antigen complexes (VCA , MA, EA(D), EA(R) and EBNA) are defined at cellular and molecular levels, providing a historic overview. The characteristic antibody responses to these complexes in health and disease are described, and differences are highlighted by clinical examples. Options for EBV vaccination are briefly addressed. For a selected number of immunodominant proteins, in particular EBNA1, the interaction with human antibodies is further detailed at the epitope level, revealing interesting insights for structure, function and immunological aspects, not considered previously. Humoral immune responses against EBV-encoded tumour antigens LMP1, LMP2 and BARF1 are addressed, which provide novel options for targeted immunotherapy. Finally, some considerations on EBV-linked autoimmune diseases are given, and mechanisms of antigen mimicry are briefly discussed. Further analysis of humoral immune responses against EBV in health and disease in carefully selected patient cohorts will open new options for understanding pathogenesis of individual EBV-linked diseases and developing targeted diagnostic and therapeutic approaches. PMID- 26428380 TI - T-Cell Responses to EBV. AB - Epstein-Barr virus (EBV) is arguably one of the most successful pathogens of humans, persistently infecting over ninety percent of the world's population. Despite this high frequency of carriage, the virus causes apparently few adverse effects in the vast majority of infected individuals. Nevertheless, the potent growth transforming ability of EBV means the virus has the potential to cause malignancies in infected individuals. Indeed, EBV is thought to cause 1% of human malignancies, equating to 200,000 malignancies each year. A clear factor as to why virus-induced disease is relatively infrequent in healthy infected individuals is the presence of a potent immune response to EBV, in particular, that mediated by T cells. Thus, patient groups with immunodeficiencies or whose cellular immune response is suppressed have much higher frequencies of EBV induced disease and, in at least some cases, these diseases can be controlled by restoration of the T-cell compartment. In this chapter, we will primarily review the role the alphabeta subset of T cells in the control of EBV in healthy and diseased individuals. PMID- 26428381 TI - Immune Evasion by Epstein-Barr Virus. AB - Epstein-Bar virus (EBV) is widespread within the human population with over 90% of adults being infected. In response to primary EBV infection, the host mounts an antiviral immune response comprising both innate and adaptive effector functions. Although the immune system can control EBV infection to a large extent, the virus is not cleared. Instead, EBV establishes a latent infection in B lymphocytes characterized by limited viral gene expression. For the production of new viral progeny, EBV reactivates from these latently infected cells. During the productive phase of infection, a repertoire of over 80 EBV gene products is expressed, presenting a vast number of viral antigens to the primed immune system. In particular the EBV-specific CD4+ and CD8+ memory T lymphocytes can respond within hours, potentially destroying the virus-producing cells before viral replication is completed and viral particles have been released. Preceding the adaptive immune response, potent innate immune mechanisms provide a first line of defense during primary and recurrent infections. In spite of this broad range of antiviral immune effector mechanisms, EBV persists for life and continues to replicate. Studies performed over the past decades have revealed a wide array of viral gene products interfering with both innate and adaptive immunity. These include EBV-encoded proteins as well as small noncoding RNAs with immune-evasive properties. The current review presents an overview of the evasion strategies that are employed by EBV to facilitate immune escape during latency and productive infection. These evasion mechanisms may also compromise the elimination of EBV-transformed cells, and thus contribute to malignancies associated with EBV infection. PMID- 26428382 TI - Non-human Primate Lymphocryptoviruses: Past, Present, and Future. AB - Epstein-Barr virus (EBV) orthologues from non-human primates (NHPs) have been studied for nearly as long as EBV itself. Cross-reactive sera and DNA hybridization studies provided the first glimpses of the closely related herpesviruses that belonged to the same gamma-1 herpesvirus, or lymphocryptovirus, genus, as EBV. Over the years, detailed molecular and sequence analyses of LCVs that infect humans and other NHPs revealed similar colinear genome structures and homologous viral proteins expressed during latent and lytic infection. Despite these similarities, experimental infection of NHPs with EBV did not result in acute symptoms or persistent infection as observed in humans, suggesting some degree of host species restriction. Genome sequencing and a molecular clone of an LCV isolate from naturally infected rhesus macaques combined with domestic colonies of LCV-naive rhesus macaques have opened the door to a unique experimental animal model that accurately reproduces the normal transmission, acute viremia, lifelong persistence, and immune responses found in EBV-infected humans. This chapter will summarize the advances made over the last 50 years in our understanding of LCVs that naturally infect both Old and New World NHPs, the recent, groundbreaking developments in the use of rhesus macaques as an animal model for EBV infection, and how NHP LCVs and the rhLCV animal model can advance future EBV research and the development of an EBV vaccine. PMID- 26428383 TI - EBV Infection of Mice with Reconstituted Human Immune System Components. AB - Epstein-Barr virus (EBV) was discovered 50 years ago as the first candidate human tumor virus. Since then, we have realized that this human gamma-herpesvirus establishes persistent infection in the majority of adult humans, but fortunately causes EBV-associated diseases only in few individuals. This is an incredible success story of the human immune system, which controls EBV infection and its transforming capacity for decades. A better understanding of this immune control would not only benefit patients with EBV-associated malignancies, but could also provide clues how to establish such a potent, mostly cell-mediated immune control against other pathogens and tumors. However, the functional relevance of EBV specific immune responses can only be addressed in vivo, and mice with reconstituted human immune system components (huMice) constitute a small animal model to interrogate the protective value of immune compartments during EBV infection, but also might provide a platform to test EBV-specific vaccines. This chapter will summarize the insights into EBV immunobiology that have already been gained in these models and provide an outlook into promising future avenues to develop this in vivo model of EBV infection and human immune responses further. PMID- 26428385 TI - The Development of Prophylactic and Therapeutic EBV Vaccines. AB - Over the last century, the development of effective vaccine approaches to treat a number of viral infections has provided the impetus for the continual development of vaccine platforms for other viral infections, including Epstein-Barr virus (EBV). The clinical manifestations associated with EBV infection occur either following primary infection, such as infectious mononucleosis, or following an extended period of latency, primarily the EBV-associated malignancies and potentially including a number of autoimmune disorders, such as multiple sclerosis. As a consequence, two independent vaccine approaches are under development to prevent or control EBV-associated diseases. The first approach, which has been widely successful against other viral infections, is aimed at inducing a viral neutralisation antibody response to prevent primary infection. The second approach focuses upon the induction of cell-mediated immunity to control latent infected cells in persistently infected individuals. Early clinical studies have offered some insight into the potential efficacy of both of these approaches. PMID- 26428386 TI - The Biology and Clinical Utility of EBV Monitoring in Blood. AB - Epstein-Barr virus (EBV) DNA in blood can be quantified in peripheral blood mononuclear cells, in circulating cell-free (CCF) DNA specimens, or in whole blood. CCF viral DNA may be actively released or extruded from viable cells, packaged in virions or passively shed from cells during apoptosis or necrosis. In infectious mononucleosis, viral DNA is detected in each of these kinds of specimens, although it is only transiently detected in CCF specimens. In nasopharyngeal carcinoma, CCF EBV DNA is an established tumor marker. In EBV associated Hodgkin lymphoma and in EBV-associated extranodal NK-/T-cell lymphoma, there is growing evidence for the utility of CCF DNA as a tumor marker. PMID- 26428384 TI - Adoptive T-Cell Immunotherapy. AB - Epstein-Barr virus (EBV) is associated with a range of malignancies involving B cells, T cells, natural killer (NK) cells, epithelial cells, and smooth muscle. All of these are associated with the latent life cycles of EBV, but the pattern of latency-associated viral antigens expressed in tumor cells depends on the type of tumor. EBV-specific T cells (EBVSTs) have been explored as prophylaxis and therapy for EBV-associated malignancies for more than two decades. EBVSTs have been most successful as prophylaxis and therapy for post-transplant lymphoproliferative disease (PTLD) , which expresses the full array of latent EBV antigens (type 3 latency), in hematopoietic stem-cell transplant (HSCT) recipients. While less effective, clinical studies have also demonstrated their therapeutic potential for PTLD post-solid organ transplant and for EBV-associated malignancies such as Hodgkin's lymphoma, non-Hodgkin's lymphoma, and nasopharyngeal carcinoma (NPC) that express a limited array of latent EBV antigens (type 2 latency). Several approaches are actively being pursued to improve the antitumor activity of EBVSTs including activation and expansion of T cells specific for the EBV antigens expressed in type 2 latency, genetic approaches to render EBVSTs resistant to the immunosuppressive tumor environment, and combination approaches with other immune-modulating modalities. Given the recent advances and renewed interest in cell therapy, we hope that EBVSTs will become an integral part of our treatment armamentarium against EBV-positive malignancies in the near-future. PMID- 26428387 TI - Female plastic surgery patients prefer mirror-reversed photographs of themselves: A prospective study. AB - INTRODUCTION: The use of a patient's image in plastic surgery is common today. Thus, plastic surgeons should master the use of the image and be aware of the implications of the patients' perception of themselves. The mere-exposure effect is a psychological phenomenon in which a person tends to rate things more positively merely because (s)he is familiar with them. Faces are asymmetric, so faces in photos are different from those observed in mirrors. The main objective of this study was to assess whether patients within a plastic surgery population, particularly those undergoing facial aesthetic surgery, preferred standard photographs or mirror-reversed photographs of themselves. METHOD: A prospective study was conducted in a plastic surgery department, which included women who were admitted to the hospital the day before their procedures. The patients were separated into the following two groups: Group 1 was composed of patients who were undergoing facial aesthetic surgeries, and Group 2 consisted of other patients who presented to the plastic surgery department for surgery. The patients were required to rate their appreciation of their own faces and to choose between standard and mirror-reversed photos of themselves. RESULTS: A total of 214 patients participated. The median age was 47.9 years (interquartile range (IQR): 36.4-60.6), and the median face appreciation was 5 (IQR: 5-7). The preference for the mirror-reversed photograph was significantly different from chance (p < 0.001, binomial (214, 156, 0.5)); 73% of the patients preferred the mirror-reversed photographs. The proportions of patients who preferred the mirror reversed photograph differed significantly (p = 0.047) between Groups 1 (84%) and 2 (70%). CONCLUSION: Plastic surgery patients have a significant preference for mirror-reversed photographs of themselves over standard photographs. This preference is even more pronounced among patients who are undergoing facial aesthetic surgery. LEVEL OF EVIDENCE: III. PMID- 26428388 TI - Hydroxyproline metabolism in a mouse model of Primary Hyperoxaluria Type 3. AB - Primary Hyperoxaluria Type 3 is a recently discovered form of this autosomal recessive disease that results from mutations in the gene coding for 4-hydroxy-2 oxoglutarate aldolase (HOGA1). This enzyme is one of the 2 unique enzymes in the hydroxyproline catabolism pathway. Affected individuals have increased urinary excretions of oxalate, 4-hydroxy-L-glutamate (4-OH-Glu), 4-hydroxy-2-oxoglutarate (HOG), and 2,4-dihydroxyglutarate (DHG). While 4-OH-Glu and HOG are precursor substrates of HOGA1 and increases in their concentrations are expected, how DHG is formed and how HOG to oxalate are unclear. To resolve these important questions and to provide insight into possible therapeutic avenues for treating this disease, an animal model of the disease would be invaluable. We have developed a mouse model of this disease which has null mutations in the Hoga1 gene and have characterized its phenotype. It shares many characteristics of the human disease, particularly when challenged by the inclusion of hydroxyproline in the diet. An increased oxalate excretion is not observed in the KO mice which may be consistent with the recent recognition that only a small fraction of the individuals with the genotype for HOGA deficiency develop PH. PMID- 26428389 TI - Optimization of microwave-assisted extraction conditions for preparing lignan rich extract from Saraca asoca bark using Box-Behnken design. AB - CONTEXT: Lyoniside is the major constituent of Saraca asoca Linn. (Caesalpiniaceae) bark. There is an immediate need to develop an efficient method to isolate its chemical constituents, since it is a therapeutically important plant. OBJECTIVE: A rapid extraction method for lyoniside based on microwave assisted extraction of S. asoca bark was developed and optimized using response surface methodology (RSM). MATERIALS AND METHODS: Lyoniside was analyzed and quantified by high-performance liquid chromatography coupled with ultraviolet detection (HPLC-UV). The extraction solvent ratio (%), material solvent ratio (g/ml) and extraction time (min) were optimized using Box-Behnken design (BBD) to obtain the highest extraction efficiency. The optimal conditions were the use of 1:30 material solvent ratio with 70:30 mixture of methanol:water for 10 min duration. RESULTS: The optimized microwave-assisted extraction yielded 9.4 mg/g of lyoniside content in comparison to reflux extraction under identical conditions which yielded 4.2 mg/g of lyoniside content. Under optimum conditions, the experimental values agreed closely with the predicted values. The analysis of variance (ANOVA) indicated a high goodness-of-fit model and the success of the RSM method for optimizing lyoniside extraction from the bark of S. asoca. DISCUSSION: All the three variables significantly affected the lyoniside content. Increased polarity of solvent medium enhances the lyoniside yield. CONCLUSION: The present study shows the applicability of microwave-assisted extraction in extraction of lyoniside from S. asoca bark. PMID- 26428390 TI - Structural basis for pore-forming mechanism of staphylococcal alpha-hemolysin. AB - Staphylococcal alpha-hemolysin (alpha-HL) is a beta-barrel pore-forming toxin (PFT) expressed by Staphylococcus aureus. alpha-HL is secreted as a water-soluble monomeric protein, which binds to target membranes and forms membrane-inserted heptameric pores. To explore the pore-forming mechanism of alpha-HL in detail, we determined the crystal structure of the alpha-HL monomer and prepore using H35A mutant and W179A/R200A mutant, respectively. Although the overall structure of the monomer was similar to that of other staphylococcal PFTs, a marked difference was observed in the N-terminal amino latch, which bent toward the prestem. Moreover, the prestem was fastened by the cap domain with a key hydrogen bond between Asp45 and Tyr118. Prepore structure showed that the transmembrane region is roughly formed with flexibility, although the upper half of the beta-barrel is formed appropriately. Structure comparison among monomer, prepore and pore revealed a series of motions, in which the N-terminal amino latch released upon oligomerization destroys its own key hydrogen bond between Asp45-Tyr118. This action initiated the protrusion of the prestem. Y118F mutant and the N-terminal truncated mutant markedly decreased in the hemolytic activity, indicating the importance of the key hydrogen bond and the N-terminal amino latch on the pore formation. Based on these observations, we proposed a dynamic molecular mechanism of pore formation for alpha-HL. PMID- 26428391 TI - Antimycoplasmic activity and seasonal variation of essential oil of Eugenia hiemalis Cambess. (Myrtaceae). AB - The purpose of this work was to study the chemical composition and antimycoplasmic and anticholinesterase activities of the essential oil of Eugenia hiemalis leaves collected throughout the year. A total of 42 compounds were identified by CG, and are present in almost every seasons. Sesquiterpenes were dominant (86.01-91.48%), and non-functionalised sesquiterpenes comprised the major fraction, which increased in the summer; monoterpenes were not identified. The major components were spathulenol (5.36-16.06%), delta-cadinene (7.50 15.93%), bicyclogermacrene (5.70-14.24%) and beta-caryophyllene (4.80-9.43%). The highest oil yield was obtained in summer and autumn. Essential oils presented activity against three evaluated Mycoplasma strains, but no activity was observed in the anticholinesterase assay. PMID- 26428392 TI - Therapeutic potential of anti-CD137 (4-1BB) monoclonal antibodies. AB - INTRODUCTION: 4-1BB (CD137) is an important T-cell stimulating molecule. The 4 1BB mAb or its variants have shown remarkable therapeutic activity against autoimmunity, viral infections, and cancer. Antibodies to 4-1BB have recently entered clinical trials for the treatment of cancer with favorable toxicity profile. In this article, we present a review documenting the efficacy and pitfalls of 4-1BB therapy. AREAS COVERED: An extensive literature search has been made on 4-1BB, spanning two decades, and a comprehensive report is presented here highlighting the origins, biological effects, therapeutic potential, and mechanistic basis of targeting 4-1BB as well as the side effects associated with such therapy. EXPERT OPINION: Research so far indicates that 4-1BB is highly protective against various pathological conditions including cancer. However, a few important side effects of 4-1BB therapy such as liver toxicity, thrombocytopenia, anemia, and suppressive effects on certain immune competent cells should be taken into consideration before it is used for human therapy. PMID- 26428393 TI - Microfluidic Mobility Shift Profiling of Lysine Acetyltransferases Enables Screening and Mechanistic Analysis of Cellular Acetylation Inhibitors. AB - Lysine acetyltransferases (KATs) are critical regulators of signaling in many diseases, including cancer. A major challenge in establishing the targetable functions of KATs in disease is a lack of well-characterized, cell-active KAT inhibitors. To confront this challenge, here we report a microfluidic mobility shift platform for the discovery and characterization of small molecule KAT inhibitors. Novel fluorescent peptide substrates were developed for four well known KAT enzymes (p300, Crebbp, Morf, and Gcn5). Enzyme-catalyzed acetylation alters the electrophoretic mobility of these peptides in a microfluidic chip, allowing facile and direct monitoring of KAT activity. A pilot screen was used to demonstrate the utility of microfluidic mobility shift profiling to identify known and novel modulators of KAT activity. Real-time kinetic monitoring of KAT activity revealed that garcinol, a natural product KAT inhibitor used in cellular studies, exhibits time-dependent and detergent-sensitive inhibition, consistent with an aggregation-based mechanism. In contrast, the cell-permeable bisubstrate inhibitor Tat-CoA exhibited potent and time-independent KAT inhibition, highlighting its potential utility as a cellular inhibitor of KAT activity. These studies define microfluidic mobility shift profiling as a powerful platform for the discovery and characterization of small molecule inhibitors of KAT activity, and provide mechanistic insights potentially important for the application of KAT inhibitors in cellular contexts. PMID- 26428395 TI - [Scalp folliculitis: Dissequans or decalvans?]. PMID- 26428396 TI - The impact of having both cancer and diabetes on patient-reported outcomes: a systematic review and directions for future research. AB - PURPOSE: This systematic review aims to summarize the current literature regarding potential effects of having both cancer and diabetes on patient reported outcomes (PROs) and to provide directions for future research. METHODS: MEDLINE, The Cochrane Library, CINAHL, and PsycINFO were searched from inception to January 2015. All English peer-reviewed studies that included patients with both cancer and diabetes and assessed PROs were included. All included studies were independently assessed on methodological quality by two investigators. RESULTS: Of the 3553 identified studies, 10 studies were included and all were considered of high (40%) or adequate (60%) methodological quality. Eight of the 10 studies focused on health-related quality of life (HRQoL), functioning, or symptoms and 2 studies assessed diabetes self-management. Overall, HRQoL and functioning was lower, and symptoms were higher among patients with both cancer and diabetes as compared to having cancer or diabetes alone. Furthermore, one study reported that diabetes self-management was impaired after chemotherapy. CONCLUSIONS: Having both cancer and diabetes resulted in worse PROs compared to having either one of the diseases, however, the considerable heterogeneity of the included studies hampered strong conclusions. Future studies are needed as this research area is largely neglected. As the majority of the included studies focused on HRQoL, future research should address the impact of both diseases on other PROs such as depression, patient empowerment and self-management. IMPLICATIONS FOR CANCER SURVIVOR: Having both cancer and diabetes might result in worse PROs, however, more research is needed as current evidence is scarce. PMID- 26428398 TI - Incommensurate modulation and thermal expansion of Sr3B(2 + x)Si(1 - x)O(8 - x/2) solid solutions. AB - Crystal structures of Sr3B(2 + x)Si(1 - x)O(8 - x/2) solid solutions with nominal compositions x = 0.28, 0.53, 0.78 in the Sr3B2SiO8-Sr2B2O5 section of the SrO B2O3-SiO2 system are refined using single-crystal X-ray diffraction data. Incommensurate structure modulations are mainly associated with various orientations of corner-sharing (B,Si)-polyhedra. Preference is given to the (3 + 2)-dimensional symmetry group Pnma(0betagamma)000(0betagamma)000 for a single crystal compared with an alternate model of a twin formed by monoclinic components, each of them corresponding to the (3 + 1)-dimensional symmetry group P2(1)/n(0betagamma). Single-phase polycrystalline samples of solid solutions are investigated by high-temperature X-ray powder diffraction in air. Orientation preferences of the BO3 units lead to a strong anisotropy of thermal expansion. Negative expansion is observed along the a axis over the temperature range 303 753 K. Anisotropy decreases both on heating and decreasing of the boron content. PMID- 26428399 TI - Two-dimensional zeolite-like network in the new caesium copper aluminate Cs2CuAl4O8. AB - Monoclinic dicaesium copper tetraaluminate, Cs2CuAl4O8, space group P2(1)/c, a = 8.4551 (7), b = 10.012 (1), c = 17.073 (2) A, beta = 101.643 (9) degrees , Z = 6, was obtained by high-temperature crystallization from a phosphate flux. Its microporous crystal structure presents the first example of double layers built from [AlO4] tetrahedra combined in 4-, 6- and 8-rings, topologically similar to those found in the ATT-type zeolites and isostructural minerals armstrongite, davanite and dalyite. These layers show a rare arrangement of three [AlO4] tetrahedra sharing one oxygen vertex. The aluminate slabs are further linked by chains of edge-sharing [CuO4] square planes to form a mixed anionic three dimensional framework with Cs(+) cations in channels and cavities. An unusually short Cu...Cs distance of 3.166 A is ascribed to the strong Jahn-Teller effect of Cu(2+). The magnetic subsystem demonstrates properties of an alternating antiferromagnetic chain with a gap in the spectrum of magnetic excitations. PMID- 26428397 TI - Novel JAZ co-operativity and unexpected JA dynamics underpin Arabidopsis defence responses to Pseudomonas syringae infection. AB - Pathogens target phytohormone signalling pathways to promote disease. Plants deploy salicylic acid (SA)-mediated defences against biotrophs. Pathogens antagonize SA immunity by activating jasmonate signalling, for example Pseudomonas syringae pv. tomato DC3000 produces coronatine (COR), a jasmonic acid (JA) mimic. This study found unexpected dynamics between SA, JA and COR and co operation between JAZ jasmonate repressor proteins during DC3000 infection. We used a systems-based approach involving targeted hormone profiling, high-temporal resolution micro-array analysis, reverse genetics and mRNA-seq. Unexpectedly, foliar JA did not accumulate until late in the infection process and was higher in leaves challenged with COR-deficient P. syringae or in the more resistant JA receptor mutant coi1. JAZ regulation was complex and COR alone was insufficient to sustainably induce JAZs. JAZs contribute to early basal and subsequent secondary plant defence responses. We showed that JAZ5 and JAZ10 specifically co operate to restrict COR cytotoxicity and pathogen growth through a complex transcriptional reprogramming that does not involve the basic helix-loop-helix transcription factors MYC2 and related MYC3 and MYC4 previously shown to restrict pathogen growth. mRNA-seq predicts compromised SA signalling in a jaz5/10 mutant and rapid suppression of JA-related components on bacterial infection. PMID- 26428400 TI - Classification of ABO3 perovskite solids: a machine learning study. AB - We explored the use of machine learning methods for classifying whether a particular ABO3 chemistry forms a perovskite or non-perovskite structured solid. Starting with three sets of feature pairs (the tolerance and octahedral factors, the A and B ionic radii relative to the radius of O, and the bond valence distances between the A and B ions from the O atoms), we used machine learning to create a hyper-dimensional partial dependency structure plot using all three feature pairs or any two of them. Doing so increased the accuracy of our predictions by 2-3 percentage points over using any one pair. We also included the Mendeleev numbers of the A and B atoms to this set of feature pairs. Doing this and using the capabilities of our machine learning algorithm, the gradient tree boosting classifier, enabled us to generate a new type of structure plot that has the simplicity of one based on using just the Mendeleev numbers, but with the added advantages of having a higher accuracy and providing a measure of likelihood of the predicted structure. PMID- 26428401 TI - Fluorite-related one-dimensional units in natural bismuth oxysulfates: the crystal structures of Bi14O16(SO4)5 and Bi30O33(SO4)9(AsO4)2. AB - The crystal structures of two new natural Bi oxysulfates with the formula Bi14O16(SO4)5 [labelled new phase I; monoclinic, space group C2, a = 21.658 (4), b = 5.6648 (9), c = 15.092 (3) A, beta = 119.433 (11) degrees and Z = 2] and Bi30O33(SO4)9(AsO4)2 [labelled new phase II; triclinic, space group P1, a = 5.670 (3), b = 13.9408 (9), c = 22.7908 (18) A, alpha = 80.903 (5), beta = 82.854 (14), gamma = 78.27 (2) degrees and Z = 1] from the high-temperature fumarole deposit of the La Fossa crater at Vulcano (Aeolian Islands, Italy) are reported. The structures are built up by a combination of fluorite-related Bi-O units and isolated (SO4)(2-) tetrahedra (new phase I) or both (SO4)(2-) and (AsO4)(3-) tetrahedra (new phase II). Owing to the effect of stereoactive lone pairs of Bi(3+), Bi-O units in both the structures can be suitably described in terms of oxo-centered OBi4 tetrahedra. The structure of Bi14O16(SO4)5 is based upon one dimensional [O16Bi14](10+) ribbons formed by six chains of edge-sharing OBi4 tetrahedra extending along [010]. In the structure of Bi30O33(SO4)9(AsO4)2 the same ribbon type coexists with another one-dimensional ribbon formed by seven chains of edge-sharing OBi4 tetrahedra and with the composition [O17Bi16](14+). Ribbons of the same type are joined by (SO4)(2-) and (AsO4)(3-) tetrahedra along [010] - if a reduced triclinic unit-cell setting is considered - so forming two different (001) slabs which alternate to each other along [001] and are joined by additional (SO4)(2-) tetrahedra. New phase I represents the natural analogues of synthetic Bi14O16(SO4)5, but with an ordered structure model. PMID- 26428402 TI - Twinning of three Fe-PNP pincer complexes interpreted according to order-disorder (OD) theory. AB - The systematic twinning of three 2,6-diaminopyridine-based Fe-PNP complexes is interpreted using order-disorder (OD) theory. The monoclinic [Fe(0)(PNP(Et) (i)Pr)(CO)2] [P112(1)/b, Z' = 4] possesses pseudo-orthorhombic metrics and crystallizes as a reflection twin by pseudo-merohedry with the twin plane (100). The structure is made up of layers with idealized p2(1)a(b) symmetry. The a glide planes of adjacent layers do not overlap, leading to OD polytypism. trans [Fe(II)(PNP-Et)Br2(CO)] [P2(1)/n, Z' = 1] is systematically twinned via twofold rotation about [001]. It is made up of OD layers with idealized p2(1)2(1)(2) symmetry. OD polytypism is caused by the twofold rotation axes of adjacent layers which do not overlap. [Fe(II)(kappa(2)P,N-PNP-(i)Pr,TAD)Cl2].THF [P1, Z^{?prime} = 2] is systematically twinned via a twofold rotation about [010]. It is made up of layers with idealized p121(1) symmetry. OD polytypism is caused by screw rotations relating adjacent layers with an intrinsic translation along a fourth of a primitive lattice vector. In all three structures the twin individuals are a polytype with a maximum degree of order (MDO) and at the twin interface is located a fragment of the second MDO polytype. PMID- 26428403 TI - Crystalline state photochromism of 3-furylfulgides: impact of size and bond flexibility of the non-aromatic alkylidene group. AB - 3-Furylfulgides are photochromic compounds showing high thermal stability in their closed forms. However, their photochromic properties in the solid state should be improved further to fabricate molecular devices. Understanding how the size and the flexibility of the non-aromatic alkylidene moiety alter the crystalline state photochromic properties is also important here, as the alkylidene group is directly involved in the photochromic ring closing and opening reactions. The synthesis of four 3-furylfulgides composed of different alkylidene groups (rigid isopropyl, flexible 2-butyl, rigid cyclopentyl and flexible cyclohexyl), their crystal structures and structure-photochromic property correlation in the crystalline state are reported here. Crystallographic data along with reaction cavity volumes calculated using the program CAVITY [Ohashi et al. (1981), J. Am. Chem. Soc. 103, 5805-5812] disclosed that fulgides with flexible groups at the ring closing site have more free volume around the reactive area in the crystal lattice, which can provide more space for the atomic movements in the reaction and flexibility can reduce the strain built up in the closed C-isomers by making conformations. According to UV-vis spectroscopic data, a higher yield of C-isomers and a better fatigue resistance were obtained for the 3-furylfulgide with the largest and flexible cyclohexyl group showing greater photochromic properties in the crystalline state than the fulgide containing the smallest and rigid isopropyl group. PMID- 26428404 TI - Combined analysis of chemical bonding in a Cu(II) dimer using QTAIM, Voronoi tessellation and Hirshfeld surface approaches. AB - Interaction of 1-(1H-pyrazol-5-yl)ethanone oxime (H2PzOx) with copper(II) chloride in the presence of pyridine afforded a binuclear discrete [Cu2(HPzOx)2Cl2py2] complex, which was characterized by Fourier transform-IR and electron paramagnetic resonance (EPR) spectra, magnetochemistry and high resolution X-ray diffraction experiments. Multipole refinement of X-ray diffraction data and density-functional theory (DFT) calculations of an isolated molecule allowed charge and spin distributions to be obtained for this compound. Magnetochemistry data, EPR spectra and DFT calculations of an isolated molecule show antiferromagnetic coupling between copper(II) ions. The spin distribution suggests an exchange pathway via the bridging pyrazole ring in the equatorial plane of the CuN4Cl coordination polyhedron, thus providing support for the classical superexchange mechanism; the calculated value of the magnetic coupling constant -2J is equal to 220 cm(-1), which compares well with the experimental value of 203 +/- 2 cm(-1). Chemical connectivity was derived by Bader's 'quantum theory of atoms in molecules' and compared with Voronoi tessellation and Hirshfeld surface representations of crystal space. All methodologies gave a similar qualitative and semi-quantitative description of intra- and intermolecular connectivity. PMID- 26428405 TI - At last! The single-crystal X-ray structure of a naturally occurring sample of the ilmenite-type oxide FeCrO3. AB - A natural single crystal of the ferrimagnetic oxide FeCrO3, which was found in an opencast mine situated in the San Luis Potosi State in Mexico, has been characterized in order to elucidate some outstanding issues about the actual structure of this material. The single-crystal X-ray analysis unambiguously shows that transition metal cations are segregated in alternating layers normal to the threefold crystallographic axis, affording a structure isomorphous to that of ilmenite (FeTiO3), in the space group R3. The possible occurrence of cation antisite and vacancy defects is below the limit of detection available from X-ray data. Structural and magnetic results are in agreement with the coherent slow intergrowth of magnetic phases provided by the two antiferromagnetic corundum type parent oxides Fe2O3 (hematite) and Cr2O3 (eskolaite). Our results are consistent with the most recent density functional theory (DFT) studies carried out on digital FeCrO3 [Sadat Nabi & Pentcheva (2011). Phys. Rev. B, 83, 214424], and suggest that synthetic samples of FeCrO3 might present a cation distribution different to that of the ilmenite structural type. PMID- 26428406 TI - Comprehensive derivation of bond-valence parameters for ion pairs involving oxygen. AB - Published two-body bond-valence parameters for cation-oxygen bonds have been evaluated via the root mean-square deviation (RMSD) from the valence-sum rule for 128 cations, using 180,194 filtered bond lengths from 31,489 coordination polyhedra. Values of the RMSD range from 0.033-2.451 v.u. (1.1-40.9% per unit of charge) with a weighted mean of 0.174 v.u. (7.34% per unit of charge). The set of best published parameters has been determined for 128 ions and used as a benchmark for the determination of new bond-valence parameters in this paper. Two common methods for the derivation of bond-valence parameters have been evaluated: (1) fixing B and solving for R(o); (2) the graphical method. On a subset of 90 ions observed in more than one coordination, fixing B at 0.37 A leads to a mean weighted-RMSD of 0.139 v.u. (6.7% per unit of charge), while graphical derivation gives 0.161 v.u. (8.0% per unit of charge). The advantages and disadvantages of these (and other) methods of derivation have been considered, leading to the conclusion that current methods of derivation of bond-valence parameters are not satisfactory. A new method of derivation is introduced, the GRG (generalized reduced gradient) method, which leads to a mean weighted-RMSD of 0.128 v.u. (6.1% per unit of charge) over the same sample of 90 multiple-coordination ions. The evaluation of 19 two-parameter equations and 7 three-parameter equations to model the bond-valence-bond-length relation indicates that: (1) many equations can adequately describe the relation; (2) a plateau has been reached in the fit for two-parameter equations; (3) the equation of Brown & Altermatt (1985) is sufficiently good that use of any of the other equations tested is not warranted. Improved bond-valence parameters have been derived for 135 ions for the equation of Brown & Altermatt (1985) in terms of both the cation and anion bond-valence sums using the GRG method and our complete data set. PMID- 26428408 TI - In vitro toxicity assay of cisplatin on mouse acute lymphoblastic leukaemia and spermatogonial stem cells. AB - Testicular cancer is the most common cancer affecting men in reproductive age, and cisplatin is one of the major helpful chemotherapeutic agents for treatment of this cancer. In addition, exposure of testes cancer cells to cisplatin could potentially eliminate tumour cells from germ cells in patients. The aim of this study was to evaluate the effect of cisplatin on viability of mouse acute lymphoblastic leukaemia cell line (EL-4) and neonatal mouse spermatogonial cells in vitro. In this study, the isolated spermatogonial stem cells (SSC) and EL-4 were divided into six groups including control (received medium), sham (received DMSO in medium) and experimental groups which received different doses of cisplatin (0.5, 5, 10 and 15 MUg ml(-1) ). Cells viability was evaluated with MTT assay. The identity of the cultured cells was confirmed by the expression of specific markers. Our finding showed that viability of both SSC and EL-4 cells was reduced with the dose of 15 MUg/ml when compared to the control group (P <= 0.05). Also, the differences between the IC50 in doses 10 and 15 MUg/ml at different time were significant (P <= 0.05). The number of TUNEL-positive cells was increased, and the BAX and caspase-3 expressions were upregulated in EL4 cells for group that received an effective dose of cisplatin). In conclusion, despite the dramatic effects of cisplatin on both cells, spermatogonial stem cells could form colony in culture. PMID- 26428409 TI - Efficacy and effects of palifermin for the treatment of oral mucositis in patients affected by acute lymphoblastic leukemia. AB - This randomized-controlled trial studied the efficacy of palifermin, administered as a dose during hematopoietic stem cell transplant (HSCT) therapy, as primary prophylaxis on pediatric patients with acute lymphoblastic leukemia in order to reduce oral mucositis (OM). Patients in the palifermin group were randomly assigned to receive palifermin, 60 MUg/kg, intravenously as a single dose 3 days before and 0, +1, and +2 post autologous HSCT infusion. The patients in the control group received only a placebo treatment. OM-related assessments were the WHO oral-toxicity scale and the patient-reported outcomes. There was a statistically significant reduction in the incidence of OM grade 3 and 4 in the palifermin group compared to the control group. There was also a reduction in the degree of severity of OM in the palifermin group (1.65 grade respect to 2.33 in the control group). Palifermin could prevent the recurrence of severe OM and improve the quality of life in patients with acute lymphoblastic leukemia (ALL). PMID- 26428411 TI - A systematic review of outcome measures used in clinical trials of treatment interventions following traumatic dental injuries. AB - BACKGROUND: Traumatic dental injuries (TDI) are common, and appropriate treatment will maximize the chances of maintaining teeth in function while safeguarding their longevity and aesthetics. Subjectively, it appears that outcome measures used in studies investigating TDI are numerous and diverse. OBJECTIVES: To undertake a systematic review of the outcomes used in clinical trials of treatment interventions following TDI. DATA SOURCES: The MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and EMBASE databases were searched up to June 2014. Reference lists of eligible studies were cross-checked to identify additional studies and strategies to identify grey literature and ongoing trials were employed. STUDY SELECTION: Two authors independently assessed studies for inclusion and undertook data extraction. The study designs included were as follows: systematic reviews with/without meta-analyses, randomized and pseudo-randomized controlled trials and controlled clinical trials. There were no language restrictions. RESULTS: Ten studies confined to two types of TDI were included: avulsion (5) and non-vital immature permanent incisor teeth (5). The outcomes reported predominantly concentrated on injury activity and the physical consequence of injury. There was little consistency between studies for the length of follow up, the time points at which outcomes were evaluated or the methods used to measure them. CONCLUSIONS: There is significant heterogeneity in outcomes reported for TDI in the literature. These findings preclude meaningful meta-analysis between studies. Future clinical studies need to consider collecting a more consistent and wider range of outcomes, which should include one or more from each of the following domains: health resources utilisation, adverse effects and quality of life and family outcome. There is a clear need for the development of a Core Outcome Set for TDI using robust and established methodology, thus optimizing the value of future research. PMID- 26428410 TI - Prevalence of Cognitive Impairment and Dementia in Malays - Epidemiology of Dementia in Singapore Study. AB - OBJECTIVE: To study the prevalence of cognitive impairment and dementia in communitydwelling Malays from Singapore; and to examine differences in prevalence among Chinese and Malays. METHODS: Subjects (>= 60 years) - drawn from the Malay component of the on-going multiethnic Epidemiology of Dementia in Singapore study - were screened using locally validated Abbreviated Mental Test and Progressive Forgetfulness Questionnaire. Subsequently, screen-positive participants underwent detailed neuropsychological assessments and neuroimaging. Cognitive impairment no dementia (CIND) and dementia were diagnosed based on accepted criteria. RESULTS: A total of 966 Malay subjects were included, of whom 102 had CIND-mild, 135 CINDmoderate, and 27 dementia. The overall age-standardized prevalence of any cognitive impairment was 25.5%, including 2% of dementia. The prevalence of any cognitive impairment increased with age from 14.9% in those aged 60-64 years to 40.2% in age >=80 years. Women had a higher prevalence of CIND and dementia than men. Compared to previously published data from EDIS on Chinese, Malay were nearly twice more likely to have any cognitive impairment (Odds ratios adjusted for age, demographic and cardiovascular risk factors, and ApoEepsilon4 carrier: 2.03, 95% confidence interval: 1.48-2.77). CONCLUSION: Among elderly Malays, the overall prevalence of any cognitive impairment was 25.5%. Even with a similar protocol of recruitment and assessment and adjusting for known risk factors, the prevalence of cognitive impairment was higher in Malays compared to Chinese. Further research is needed to unravel other factors that may underlie these ethnic differences in the occurrence of cognitive impairment. PMID- 26428412 TI - Sequestration and speciation of Eu(iii) on gamma alumina: role of temperature and contact order. AB - The speciation, migration and transport of radionuclides in the environment are significantly influenced by their interactions with the natural minerals and humic substances therein. In view of this, the effect of temperature and contact order on the sorption behaviors of trivalent Eu(iii) in the gamma-Al2O3/Eu(iii) and gamma-Al2O3/HA/Eu(iii) systems was studied using batch experiments and the extended X-ray absorption fine structure spectroscopy (EXAFS) technique. The endothermic sorption behavior of Eu(iii) in the gamma-Al2O3/Eu(iii) systems was induced by the hydrolysis reaction of Eu(iii) in solution and the complexation of Eu(iii) with the gamma-Al2O3 surface sites. The endothermic sorption of Eu(iii) in the gamma-Al2O3/HA/Eu(iii) systems was attributed to the endothermic binding of HA on gamma-Al2O3 and the endothermic complexation between Eu(iii) and HA. EXAFS analysis suggested the formation of type B ternary complexes and their thermodynamic stability improves with rising temperature. The different sorption percentages under various contact orders were closely related to the binding mode of Eu(iii) on the exposed gamma-Al2O3 surfaces or the gamma-Al2O3/HA colloids. The findings obtained herein are important to evaluate the security of the radioactive waste repository and predict the fate of trivalent actinides (e.g., Am(iii), Cm(iii), Pu(iii), etc.) near the geological repository. PMID- 26428413 TI - Total Synthesis of Codeine. AB - In this paper, a new strategy towards the synthesis of codeine and morphine is reported. This new approach features a cascade cyclization to construct the dihydrofuran ring, and an intramolecular palladium catalyzed C-H olefination of unactivated aliphatic alkene to install the morphinan ring system. PMID- 26428414 TI - Liver regeneration after splenectomy in patients with liver cirrhosis. AB - AIM: Splenectomy is a well-known procedure to improve thrombocytopenia and liver function in patients with liver cirrhosis (LC). However, the effect of splenectomy on liver regeneration remains unclear. The aim of this study is to investigate the effect of splenectomy on liver regeneration. METHODS: Twenty patients with LC who underwent splenectomy were included in this study. Liver and splenic volumes were measured by a 3-D simulation imaging system. Liver volume (LV) and clinicopathological data were compared before and 6 months after splenectomy. Thereafter, patients were divided into two groups: the elevated LV group and the reduced LV group. Patient characteristics were compared between the two groups. RESULTS: Postoperative LV was increased in 14 patients compared with the preoperative state. Thrombocytopenia, leukopenia, total bilirubin and prothrombin time were improved after splenectomy. In the elevated LV group, four patients exhibited improved Child-Pugh grades after splenectomy, whereas no patients demonstrated improvement in the reduced LV group. The elevated LV group exhibited high albumin level, good indocyanine green retention rate at 15 min and large splenic volume compared with the same measurements in the decreased group. Patients with larger spleen volumes and higher albumin values before splenectomy showed increased rates of LV after splenectomy. CONCLUSION: Splenectomy for patients with LC improved pancytopenia and liver function. Especially, in patients with large spleen and high albumin levels, considerable increases in LV and improved liver function were observed. PMID- 26428415 TI - Clean intermittent self-catheterization does not appear to be effective in the prevention of urethral stricture recurrence. AB - OBJECTIVE: The aim of this study was to assess the effect of clean intermittent self-catheterization (CISC) on stricture recurrence. MATERIALS AND METHODS: The incidence of stricture recurrence was assessed retrospectively in a group of 126 new patients treated endoscopically for urethral stricture in a general urological setting between 1994 and 2001, of whom 31 performed twice-weekly CISC and 95 did not. Stricture recurrence was defined as recurrent symptomatic stricture requiring further operative intervention following initial intervention. The mean follow-up available was 25 months (range 1-132 months). RESULTS: Of the 126 patients assessed, 60 (47.6%) developed recurrent stricture and required an average of 3.13 endoscopic retreatments each during the follow-up period. There was no significant difference (chi-squared p = 0.46) between the number of stricture recurrences in those performing CISC (13-41.9%) and those not performing CISC (47-49.5%). CONCLUSION: CISC does not appear to prevent medium term stricture recurrence. PMID- 26428416 TI - The impact of oral anticoagulation on time to surgery in patients hospitalized with hip fracture. AB - INTRODUCTION: Current clinical guidelines recommend expedited repair of hip fracture to reduce morbidity and mortality. A significant number of hip fracture patients have concomitant cardiovascular disease requiring anticoagulation. Vitamin K antagonists (VKAs), which have been traditionally used, might be associated with an increased time to surgery (TTS) and it remains unknown what effect direct oral anticoagulants (DOACs) have on this metric. Our objective is to determine how anticoagulation with a VKA or DOAC affects TTS. MATERIALS AND METHODS: This is a case control study comparing TTS in consecutively admitted hip fracture patients receiving either a DOAC or VKA with age- and gender-matched controls between January 1, 2010 and March 24, 2014. The primary end point is TTS, which is defined as the time elapsed from admission to surgery. Secondary end points include the rate of stroke, death, bleeding and VTE during admission. RESULTS: Of 2258 patients, 233 were on a VKA while 27 were on a DOAC. Median TTS seems to be longer in patients receiving a DOAC or a VKA when compared to controls. (40 h vs. 26.2h). The DOAC group tended to have longer median TTS when compared to the VKA groups (66.9h vs. 39.4h) There was no difference in the rate of stroke, death, bleeding and VTE during admission. CONCLUSIONS: Patients on anticoagulation prior to admission for hip fracture experienced longer delays in surgery when compared to patients not receiving anticoagulation. Patients on a DOAC experienced the longest surgical delay. PMID- 26428417 TI - Paradigm lost: Reflections on grandparents. PMID- 26428418 TI - The child with short stature. PMID- 26428419 TI - ASCIA guidelines for prevention of anaphylaxis in schools, pre-schools and childcare: 2015 update. AB - The aim of these guidelines is to assist staff in school and childcare settings to plan and implement appropriate risk minimisation strategies, taking into consideration the needs of the allergic child, the likely effectiveness of measures and the practicality of implementation. Although these guidelines include risk minimisation strategies for allergic reactions to insect stings or bites, latex and medication, the major focus relates to food allergy. This is due to the higher relative prevalence of food allergy in childhood (compared with other allergic triggers) and the higher likelihood of accidental exposure in these settings. Care of the allergic child in the school, pre-school or childcare settings requires accurate information obtained from parents and carers, staff training in the recognition and management of acute allergic reactions, planning for unexpected reactions (including in those not previously identified as being at risk), age appropriate education of children with severe allergies and their peers, and implementation of practical strategies to reduce the risk of accidental exposure to known allergic triggers. Strategy development also needs to take into account local or regional established legislative or procedural guidelines and the possibility that the first episode of anaphylaxis may occur outside the home. Food bans are not recommended as the primary risk minimisation strategy due to difficulties in implementation and lack of proven effectiveness. PMID- 26428420 TI - Retinopathy of prematurity: New Zealand recommendations for case detection and treatment. PMID- 26428421 TI - Is day surgery failing our children? PMID- 26428422 TI - Psychological interventions for parents of children and adolescents with chronic illness. PMID- 26428423 TI - Medecins Sans Frontieres paediatrician profile. PMID- 26428424 TI - A baby with an oral surprise. PMID- 26428425 TI - Multicoloured papules on the neck. PMID- 26428432 TI - Academy of Paediatrics. PMID- 26428433 TI - Early screening of autism: Is age a confounding factor when screening for autism? PMID- 26428434 TI - Early screening of autism: Is age a confounding factor when screening for autism? PMID- 26428435 TI - CXCL14, CXCR7 expression and CXCR4 splice variant ratio associate with survival and metastases in Ewing sarcoma patients. AB - PURPOSE: Ewing sarcoma (EWS) is the second most common sarcoma of bone in children and young adults. Patients with disseminated disease at diagnosis or early relapse have a poor prognosis. Our goal was to identify novel predictive biomarkers for these patients, focusing on chemokines, specifically genes involved in the CXCR4-pathway because of their established role in metastasis and tumour growth. METHODS: Total RNA isolated from therapy-naive tumour samples (n=18; panel I) and cell lines (n=21) was used to study expression of CXCR4 pathway related genes and CXCR4 splice variants (CXCR4-2: Small and CXCR4-1: Large) by RT-Q-PCR. Expression levels were correlated to overall survival (OS) and event free survival (EFS). Study results were validated in an independent series of 26 tumour samples (panel II) from therapy-naive tumour samples. RESULTS: CXCL12, CXCR4, CXCR7 and CXCL14 were expressed and high CXCR7 and CXCL14 expression showed a positive correlation with EFS and OS and a negative correlation with metastasis development. Both splice variants CXCR4 were expressed in cell lines and tumour samples and CXCR4-1/CXCR4-2 ratio was significantly higher in tumour samples compared to cell lines and correlated with an improved EFS and OS. The results from the test panel were validated in an independent sample panel. CONCLUSIONS: We identified a set of genes involved in CXCR4 signalling that may be used as a marker to predict survival and metastasis development in Ewing sarcoma. PMID- 26428436 TI - Unmet medical needs for chronic spontaneous urticaria patients: highlighting the real-life clinical practice in Taiwan. AB - BACKGROUND: Treatment guidelines for chronic spontaneous/idiopathic urticaria (CSU) are available; however, only 50% of patients are well controlled with approved doses of H1-antihistamines, and certain patients remain symptomatic despite receiving up to 4* the approved dose of H1-antihistamines plus H2 antihistamines and/or leucotriene-receptor antagonists. OBJECTIVES: To highlight real-life clinical practice in Taiwan and to understand the unmet medical needs of CSU patients. METHODS: A nationwide cross-sectional, observational survey of 50 dermatologists and 200 CSU patients was conducted between June 2013 and November 2013. Face-to-face interviews of dermatologists and online interviews of CSU patients were conducted independently. RESULTS: Dermatologists reported that dermographism and blood tests were the most commonly used diagnostic methods to confirm the diagnosis. The key driving factor for most clinic-based dermatologists (70%) in choosing a treatment was 'response to my medicines', and most preferred H1-antihistamines and steroids for treating CSU patients, whereas most hospital-based dermatologists (85%) gave higher priority to 'severity and impact of the conditions'. Patients were reported to have high psychological pressures and significant impact of CSU on their daily activity. In addition, CSU patients were not satisfied with their current treatment and 69% of patients switched their first-consulted physician. Furthermore, lack of information and concerns about side-effects were major factors which held back patients from seeking Western treatment. CONCLUSIONS: There is an unmet medical need of CSU patients in Taiwan highlighting gaps among guidelines, real-life clinical practice, patients' perceptions and patients' knowledge of their disease. PMID- 26428438 TI - Efficient and Accurate Identification of Platinum-Group Minerals by a Combination of Mineral Liberation and Electron Probe Microanalysis with a New Approach to the Offline Overlap Correction of Platinum-Group Element Concentrations. AB - Identification and accurate characterization of platinum-group minerals (PGMs) is usually a very cumbersome procedure due to their small grain size (typically below 10 um) and inconspicuous appearance under reflected light. A novel strategy for finding PGMs and quantifying their composition was developed. It combines a mineral liberation analyzer (MLA), a point logging system, and electron probe microanalysis (EPMA). As a first step, the PGMs are identified using the MLA. Grains identified as PGMs are then marked and coordinates recorded and transferred to the EPMA. Case studies illustrate that the combination of MLA, point logging, and EPMA results in the identification of a significantly higher number of PGM grains than reflected light microscopy. Analysis of PGMs by EPMA requires considerable effort due to the often significant overlaps between the X ray spectra of almost all platinum-group and associated elements. X-ray lines suitable for quantitative analysis need to be carefully selected. As peak overlaps cannot be avoided completely, an offline overlap correction based on weight proportions has been developed. Results obtained with the procedure proposed in this study attain acceptable totals and atomic proportions, indicating that the applied corrections are appropriate. PMID- 26428437 TI - A goose-type lysozyme from ostrich (Struthio camelus) egg white: multiple roles of His101 in its enzymatic reaction. AB - A goose-type lysozyme from ostrich egg white (OEL) was produced by Escherichia coli expression system, and the role of His101 of OEL in the enzymatic reaction was investigated by NMR spectroscopy, thermal unfolding, and theoretical modeling of the enzymatic hydrolysis of hexa-N-acetylchitohexaose, (GlcNAc)6. Although the binding of tri-N-acetylchitotriose, (GlcNAc)3, to OEL perturbed several backbone resonances in the (1)H-(15)N HSQC spectrum, the chemical shift of the backbone resonance of His101 was not significantly affected. However, apparent pKa values of His101 and Lys102 determined from the pH titration curves of the backbone chemical shifts were markedly shifted by (GlcNAc)3 binding. Thermal unfolding experiments and modeling study of (GlcNAc)6 hydrolysis using a His101-mutated OEL (H101A-OEL) revealed that the His101 mutation affected not only sugar residue affinities at subsites -3 and -2 but also the rate constant for bond cleavage. His101 appears to play multiple roles in the substrate binding and the catalytic reaction. PMID- 26428439 TI - Identification of Organic Binders in Ancient Chinese Paintings by Immunological Techniques. AB - The identification and localization of organic binders in artworks are big challenges in archaeology and conservation science. Immunological techniques, such as enzyme-linked immunosorbent assay (ELISA) and immunofluorescence microscopy (IFM) have the potential to become powerful tools for the analysis of organic materials in ancient samples. In this study, ELISA and IFM techniques were combined to identify chicken ovalbumin, glue from several mammalian species, bovine milk, and fish glue in ancient Chinese painting samples. As binders, egg ovalbumin was found in two painting samples and animal glue was found in three samples, which were dated from the 4th to 8th centuries. The results clearly demonstrate that ELISA and IFM can be used to validate results from ancient samples. PMID- 26428440 TI - Interferometric Diffraction from Amorphous Double Films. AB - We explore the interference fringes that arise in diffraction patterns from double-layer amorphous samples where there is a substantial separation, up to about a micron, between two overlapping thin films. This interferometric diffraction geometry, where both waves have interacted with the specimen, reveals phase gradients within microdiffraction patterns. The rapid fading of the observed fringes as the magnitude of the diffraction vector increases confirms that displacement decoherence is strong in high-energy electron scattering from amorphous samples. The fading of fringes with increasing layer separation indicates an effective illumination coherence length of about 225 nm, which is consistent with the value of 270 nm expected for the heated Schottky field emitter source. A small reduction in measured coherence length is expected because of the additional energy spread induced in the beam after it passes through the first layer. PMID- 26428441 TI - Which hospitalisations are ambulatory care-sensitive, to what degree, and how could the rates be reduced? Results of a group consensus study in Germany. AB - BACKGROUND: Much has been written lately regarding hospitalisations for ambulatory care-sensitive conditions (ACSH) and their strengths and weaknesses as a quality management indicator. The idea underlying ambulatory care-sensitive conditions (ACSC) is that effective treatment of acute conditions, good management of chronic illnesses and immunisation against infectious diseases can reduce the risk of a specified set of hospitalisations. METHODS: The present paper applies group consensus methods to synthesise available evidence with expert opinion, thus identifying relevant ACSC. It contributes to the literature by evaluating the degree of preventability of ACSH and surveying the medical and systemic changes needed to increase quality for each diagnosis group. Forty physicians proportionally selected from all medical disciplines relevant to the treatment of ACSC participated in the three round Delphi survey. The setting of the study is Germany. RESULTS: The proposed core list is a subset of 22 ACSC diagnosis groups, covering 90% of all consented ACSH and conditions with a higher than 85% estimated degree of preventability. Of all 18.6 million German hospital cases in the year 2012, the panelists considered 5.04 million hospitalisations (27%) to be sensitive to ambulatory care, of which 3.72 (20%) were estimated to be actually preventable. If only emergencies are considered, the ACSH share reduces to less than 8%. The geographic distribution of ACSH indicates significant regional variation with particularly high rates and potential for improvement in the North Rhine region, in Thuringia, Saxony-Anhalt, northern and eastern Bavaria and the Saarland. The average degree of preventability was 75% across all diagnosis groups. By far the most often mentioned strategy for reducing ACSH was 'improving continuous care'. CONCLUSION: There are several good reasons why process indicators prevail in the assessment of ambulatory care. ACSH rates can however provide a more complete picture by adding useful information related to the overall patient outcome. The results of our analysis should be used to encourage debate and as a basis for further confirmatory work. PMID- 26428442 TI - Physical employment standards for U.K. fire and rescue service personnel. AB - BACKGROUND: Evidence-based physical employment standards are vital for recruiting, training and maintaining the operational effectiveness of personnel in physically demanding occupations. AIMS: (i) Develop criterion tests for in service physical assessment, which simulate the role-related physical demands of UK fire and rescue service (UK FRS) personnel. (ii) Develop practical physical selection tests for FRS applicants. (iii) Evaluate the validity of the selection tests to predict criterion test performance. METHODS: Stage 1: we conducted a physical demands analysis involving seven workshops and an expert panel to document the key physical tasks required of UK FRS personnel and to develop 'criterion' and 'selection' tests. Stage 2: we measured the performance of 137 trainee and 50 trained UK FRS personnel on selection, criterion and 'field' measures of aerobic power, strength and body size. Statistical models were developed to predict criterion test performance. Stage 3: matter experts derived minimum performance standards. RESULTS: We developed single person simulations of the key physical tasks required of UK FRS personnel as criterion and selection tests (rural fire, domestic fire, ladder lift, ladder extension, ladder climb, pump assembly, enclosed space search). Selection tests were marginally stronger predictors of criterion test performance (r = 0.88-0.94, 95% Limits of Agreement [LoA] 7.6-14.0%) than field test scores (r = 0.84-0.94, 95% LoA 8.0-19.8%) and offered greater face and content validity and more practical implementation. CONCLUSIONS: This study outlines the development of role-related, gender-free physical employment tests for the UK FRS, which conform to equal opportunities law. PMID- 26428443 TI - Coping patterns in special school staff: demographic and organizational factors. AB - BACKGROUND: Teachers' mental health is commonly discussed in organizational health studies, but studies in special schools are rare. Work-related coping and experience patterns (WCEPs) have been shown to be associated with mental health and intentions to leave. The influence of organizational factors on coping patterns has not been examined. AIMS: To assess the distribution of WCEPs in special school staff and to identify potential influencing factors. METHODS: We surveyed a sample of teachers and educational staff in 13 German special schools using the WCEP questionnaire and COPSOQ (Copenhagen Psychosocial Questionnaire). RESULTS: Of 245 teachers and 417 educational staff contacted, 114 teachers (47%) and 252 educational staff (60%) responded, an overall response rate of 55% (366/662). Coping patterns of special school staff were classified as unambitious (30%), excessively ambitious (7%), resigned (17%), healthy-ambitious (12%) or unclassifiable (34%). Furthermore we found several significant relations with demographic and organizational factors. For example, the resigned pattern is associated with age [Exp(B) 1.12; 95% CI 1.05-1.19], emotional demands [Exp(B) 1.07; 95% CI 1.01-1.12], work-family conflict [Exp(B) 1.07; 95% CI 1.03-1.10] and bullying [Exp(B) 1.04; 95% CI 1.00-1.08]. CONCLUSIONS: Since emotional and social factors are associated with risky (excessively ambitious or resigned) and unambitious coping patterns in special school teachers and educational staff, interventions should focus on them. Further research could explore causal relations and observe the development of coping styles over time. PMID- 26428444 TI - Outcome of hemiplegic cerebral palsy born at term depends on its etiology. AB - OBJECTIVES: To elucidate the etiology and its relationship to the outcomes of hemiplegic cerebral palsy (HCP). PARTICIPANTS AND METHODS: MR images and outcomes of 156 children with HCP born at term and older than three years were investigated in two major centers for cerebral palsy in Japan. Etiologies were classified into perinatal ischemic stroke (PIS), cerebral dysgenesis (CD), and others. PIS was divided into periventricular venous infarction (PVI) and two types of arterial infarction; middle cerebral artery infarction (MCAI) and deep gray matter infarction (DGMI). Initial signs and the time of presentation were investigated among the three types of PIS. As functional outcomes, laterality of paresis, age at initial walk, affected hand's function, intellectual development, and occurrence of epilepsy were compared among all the four types. RESULTS: ETIOLOGY: PIS was found in 106 children (68%), while CD accounted for 28 (18%). Among PIS, venous infarction was more common than arterial infarction (62:44). OUTCOMES: PVI revealed later presentation of motor asymmetry and more involvement of lower extremity as the initial sign among PIS groups. Only MCAI showed right side predominance in laterality of paresis. DGMI related to better intellectual development and PVI showed lower occurrence of epilepsy, while there was no significant difference in affected hand's function among the four groups. PIS groups showed significantly earlier attainment of independent walk, better intellectual development, and lower occurrence of epilepsy than CD. CONCLUSIONS: PVI was the most common cause of HCP born at term, and the etiology closely related to the initial signs of hemiplegia and overall outcomes. PMID- 26428445 TI - Positive Affect and Health Behaviors Across 5 Years in Patients With Coronary Heart Disease: The Heart and Soul Study. AB - OBJECTIVES: Positive psychological states are linked to superior health and longevity, possibly due to behavioral factors. We evaluated cross-sectional and 5 year associations between positive affect and health behaviors in patients with coronary heart disease (CHD). METHODS: Outpatients with CHD reported positive affect, physical activity, sleep quality, medication adherence, cigarette smoking, and alcohol use at baseline (n = 1022) and 5 years later (n = 662). Covariates in regression analyses included demographics, cardiac disease severity, and depressive symptoms. RESULTS: At baseline, higher positive affect (per 1 standard deviation) was associated with better health behaviors: physical activity (odds ratio [OR] = 1.52, 95% 95% confidence interval [CI] = 1.30-1.77, p < .001), sleep quality (OR = 1.24, 95% CI = 1.04-1.48, p = .015), medication adherence (OR = 1.46, 95% CI = 1.12-1.90, p = .005), and nonsmoking (OR = 1.29, 95% CI = 1.06-1.57, p = .012), but was unrelated to alcohol use. Baseline positive affect did not predict health behaviors at follow-up, accounting for baseline behaviors. However, increases in positive affect across 5 years co occurred with improvements in physical activity (B = 0.023, standard error [SE] = 0.008, p = .002), sleep quality (B = 0.011, SE = 0.005, p = .039), and medication adherence (B = 0.014, SE = 0.004, p < .001), but not smoking status (OR = 1.07, 95% CI = 0.73-1.55, p = .74). CONCLUSIONS: Positive affect was associated with health behaviors among patients with CHD. Efforts to sustain or enhance positive affect may be promising for promoting better health behaviors. PMID- 26428446 TI - The Intestinal Microbiota in Acute Anorexia Nervosa and During Renourishment: Relationship to Depression, Anxiety, and Eating Disorder Psychopathology. AB - OBJECTIVE: The relevance of the microbe-gut-brain axis to psychopathology is of interest in anorexia nervosa (AN), as the intestinal microbiota plays a critical role in metabolic function and weight regulation. METHODS: We characterized the composition and diversity of the intestinal microbiota in AN, using stool samples collected at inpatient admission (T1; n = 16) and discharge (T2; n = 10). At T1, participants completed the Beck Depression and Anxiety Inventories and the Eating Disorder Examination-Questionnaire. Patients with AN were compared with healthy individuals who participated in a previous study (healthy comparison group; HCG). Genomic DNA was isolated from stool samples, and bacterial composition was characterized by 454 pyrosequencing of the 16S rRNA gene. Sequencing results were processed by the Quantitative Insights Into Microbial Ecology pipeline. We compared T1 versus T2 samples, samples from both points were compared with HCG (n = 12), and associations between psychopathology and T1 samples were explored. RESULTS: In patients with AN, significant changes emerged between T1 and T2 in taxa abundance and beta (between-sample) diversity. Patients with AN had significantly lower alpha (within-sample) diversity than did HCG at both T1 (p = .0001) and T2 (p = .016), and differences in taxa abundance were found between AN patients and HCG. Levels of depression, anxiety, and eating disorder psychopathology at T1 were associated with composition and diversity of the intestinal microbiota. CONCLUSIONS: We provide evidence of an intestinal dysbiosis in AN and an association between mood and the enteric microbiota in this patient population. Future directions include mechanistic investigations of the microbe-gut-brain axis in animal models and association of microbial measures with metabolic changes and recovery indices. PMID- 26428447 TI - Myoclonus in the critically ill: Diagnosis, management, and clinical impact. AB - Myoclonus is the second most common involuntary non-epileptic movement in intensive care units following tremor-like gestures. Although there are several types of myoclonus, they remain underappreciated, and their diagnostic and prognostic associations are largely ignored. This review discusses clinical, electrophysiological, neuroanatomical, and neuroimaging characteristics of different types of myoclonus in critically ill adults along with their prognostic impact and treatment options. Myoclonus is characterized by a sudden, brief, and sometimes repetitive muscle contraction of body parts, or a brief and sudden cessation of tonic muscle innervation followed by a rapid recovery of tonus. Myoclonus can resemble physiologic and other pathologic involuntary movements. Neurologic injuries, anesthetics, and muscle relaxants interfere with the typical appearance of myoclonus. Identifying "real myoclonus" and determining the neuroanatomical origin are important, as treatment responses depend on the involved neuroanatomical structures. The identification of the type of myoclonus, the involved neuroanatomical structures, and the associated illnesses is essential to direct treatment. In conclusion, the combined clinical, electrophysiological, and neuroradiological examination reliably uncovers the neuroanatomical sources and the pathophysiology of myoclonus. Recognizing cortical myoclonus is critical, as it is treatable and may progress to generalized convulsive seizures or status epilepticus. PMID- 26428448 TI - Echocardiography for adult patients supported with extracorporeal membrane oxygenation. AB - Venoarterial (VA) and venovenous (VV) extracorporeal membrane oxygenation (ECMO) support is increasingly being used in recent years in the adult population. Owing to the underlying disease precipitating severe respiratory or cardiac failure, echocardiography plays an important role in the management of these patients. Nevertheless, there are currently no guidelines on the use of echocardiography in the setting of ECMO support. This review describes the current state of application of echocardiography for patients supported with both VA and VV ECMO. PMID- 26428449 TI - Lysate of engineered Escherichia coli supports high-level conversion of glucose to 2,3-butanediol. AB - Cell-free metabolic engineering (CFME) is emerging as a powerful approach for the production of target molecules and pathway debugging. Unfortunately, high cofactor costs, limited cofactor and energy regeneration, and low volumetric productivities hamper the widespread use and practical implementation of CFME technology. To address these challenges, we have developed a cell-free system that harnesses ensembles of catalytic proteins prepared from crude lysates, or extracts, of cells to fuel highly active heterologous metabolic conversions. As a model pathway, we selected conversion of glucose to 2,3-butanediol (2,3-BD), a medium level commodity chemical with many industrial applications. Specifically, we engineered a single strain of Escherichia coli to express three pathway enzymes necessary to make meso-2,3-BD (m2,3-BD). We then demonstrated that lysates from this strain, with addition of glucose and catalytic amounts of cofactors NAD+ and ATP, can produce m2,3-BD. Endogenous glycolytic enzymes convert glucose to pyruvate, the starting intermediate for m2,3-BD synthesis. Strikingly, with no strain optimization, we observed a maximal synthesis rate of m2,3-BD of 11.3 +/- 0.1 g/L/h with a theoretical yield of 71% (0.36 g m2,3-BD/g glucose) in batch reactions. Titers reached 82 +/- 8 g/L m2,3-BD in a 30 h fed batch reaction. Our results highlight the ability for high-level co-factor regeneration in cell-free lysates. Further, they suggest exciting opportunities to use lysate-based systems to rapidly prototype metabolic pathways and carry out molecular transformations when bioconversion yields (g product/L), productivities (g product/L/h), or cellular toxicity limit commercial feasibility of whole-cell fermentation. PMID- 26428451 TI - Whole organism blood stage vaccines against malaria. AB - Despite a century of research focused on the development and implementation of effective control strategies, infection with the malaria parasite continues to result in significant morbidity and mortality worldwide. An effective malaria vaccine is considered by many to be the definitive solution. Yet, after decades of research, we are still without a vaccine that is capable of inducing robust, long lasting protection in naturally exposed individuals. Extensive sub-unit vaccine development focused on the blood stage of the malaria parasite has thus far yielded disappointing results. There is now a renewed focus on whole parasite vaccine strategies, particularly as they may overcome some of the inherent weaknesses deemed to be associated with the sub-unit approach. This review discusses the whole parasite vaccine strategy focusing on the blood stage of the malaria parasite, with an emphasis on recent advances and challenges in the development of killed and live attenuated vaccines. PMID- 26428452 TI - Promoting Tdap immunization in pregnancy: Associations between maternal perceptions and vaccination rates. AB - OBJECTIVE: Tdap vaccine uptake among US pregnant women is low despite current recommendations. This study evaluated if a Tdap vaccine information statement (VIS) affected overall perception, vaccination intention, and components of a health behavior model associated with Tdap vaccination rates. METHODS: A randomized, prospective study was conducted among pregnant women receiving care at two women's clinics in May-August 2014. Verbally consented participants were randomized to receive either the standard CDC Tdap VIS (sVIS) or a modified version (mVIS) before completing the first multi-part survey (T1). After T1, participants read their assigned VIS then completed the second part (T2). A 2015 chart review identified vaccinated participants. A health behavior model was hypothesized using the Reasoned Action Approach and Health Belief Model. Logistic regression, path analysis, and chi-square tests were used in the analysis. RESULTS: 279 surveys were analyzed. Average age of the participants was 26.4 years (SD=5.7) with average gestational age of 25.9 weeks (SD=9.2). 13% self reported receiving Tdap vaccine prior to the survey. Overall perception scores significantly increased (3.1-3.4, p<0.001) after VIS review. A chart review showed that 131 (47%) received the vaccine post study. There was no significant difference in vaccination rates between the sVIS and mVIS groups (45% vs. 49%). Perceived benefits (B=0.315) and self-efficacy (B=0.197) were positively associated with the overall perception (T1), while perceived barriers (B=-0.191) were negatively associated with the overall perception (T1). Social norms (B=0.230), self-efficacy (B=0.213), and perceived benefits (B=0.117) were positively associated with vaccination intention (T1). The vaccination intention (T2) was positively associated with participants' decision to receive Tdap vaccine (B=0.223). CONCLUSION: A VIS improved overall perception of the Tdap vaccine. Vaccination intention was a predictor of Tdap vaccination. It is crucial to provide information about immunization benefits to promote maternal Tdap vaccination. PMID- 26428450 TI - Impact of the learning curve on procedural results and acute outcome after percutaneous coronary interventions with everolimus-eluting bioresorbable scaffolds in an all-comers population. AB - BACKGROUND/PURPOSE: The implantation of bioresorbable scaffolds (BVSs) is an emerging technique in the treatment of coronary lesions and implantation of BVSs is different than that of metallic drug-eluting stents, however, due to different mechanical properties. This investigation focused on procedural and mid-term results and was designed to evaluate whether there is evidence of a learning curve with BVSs and how it might influence the clinical outcome. METHODS/MATERIALS: In an all-comers registry, the first 100 consecutive patients were compared with the second 100 patients. Target parameters were major adverse cardiac events (MACEs), including cardiac death, any myocardial infarction, and percutaneous or surgical target lesion revascularization (TLR). Target vessel failure (TVF) comprised cardiac death, target vessel myocardial infarction, and percutaneous or surgical target vessel revascularization (TVR). RESULTS: Baseline characteristics were not significantly different. Post-dilatation was used significantly more often in the second group (23.8% vs. 50.5%, p<0.05) as was intravascular imaging (9% vs. 19%, p<0.05). In-hospital MACEs (2.0% for both groups) and median duration of hospital stay (4 (2-6)days) did not differ significantly. During a follow-up of 210 (155-369) or 200 (176-286)days (p=n.s.) for the first and second groups, respectively, MACE (11.2% vs. 1.1%, p<0.01), TVF (10.1% vs. 1.1%, p<0.01), and TVR (9.9% vs. 1.1%, p<0.05) rates were significantly lower in the second group. CONCLUSION: There is evidence of a learning curve. Post-dilatation is most probably associated with an improved clinical result and intravascular imaging might be useful for further improvement. PMID- 26428453 TI - Development of vaccines for Plasmodium vivax malaria. AB - Plasmodium vivax continues to cause significant morbidity outside Africa with more than 50% of malaria cases in many parts of South and South-east Asia, Pacific islands, Central and South America being attributed to P. vivax infections. The unique biology of P. vivax, including its ability to form latent hypnozoites that emerge months to years later to cause blood stage infections, early appearance of gametocytes before clinical symptoms are apparent and a shorter development cycle in the vector makes elimination of P. vivax using standard control tools difficult. The availability of an effective vaccine that provides protection and prevents transmission would be a valuable tool in efforts to eliminate P. vivax. Here, we review the latest developments related to P. vivax malaria vaccines and discuss the challenges as well as directions toward the goal of developing highly efficacious vaccines against P. vivax malaria. PMID- 26428454 TI - A study of different buffers to maximize viability of an oral Shigella vaccine. AB - Live, whole cell killed and subunit vaccines are being developed for diarrheal diseases caused by V. cholerae, Shigella species, ETEC, and Campylobacter. Some of these vaccines can be administered orally since this route best mimics natural infection. Live vaccines administered orally have to be protected from the harsh acidic gastric environment. Milk and bicarbonate solutions have been administered to neutralize the stomach acid. For many Shigella vaccine trials, 100-120 ml of a bicarbonate solution is ingested followed by the live vaccine candidate, which is delivered in 30 ml of bicarbonate, water or saline. It is not clear if maximum bacterial viability is achieved under these conditions. Also, volumes of neutralizing buffer that are optimal for adults may be unsuitable for children and infants. To address these questions, we performed studies to determine the viability and stability of a Shigella sonnei vaccine candidate, WRSS1, in a mixture of different volumes of five different buffer solutions added to hydrochloric acid to simulate gastric acidity. Among the buffers tested, bicarbonate solution, rotavirus buffer and CeraVacx were better at neutralizing acid and maintaining the viability of WRSS1. Also, a much smaller volume of the neutralizing buffer was sufficient to counteract stomach acid while maintaining bacterial viability. PMID- 26428455 TI - Optimal attenuation of a PR8-derived mouse pathogenic H5N1 recombinant virus for testing antigenicity and protective efficacy in mice. AB - The PR8-based reverse genetics vector system is widely used to generate commercial vaccine strains, but the pathogenicity of PR8-derived recombinant viruses in mice hinders further immunological studies. In the present study, we generated PR8-derived H5N1 recombinant viruses, in which haemagglutinin (HA) and neuraminidase (NA) originated from a mouse-pathogenic H5N1 low pathogenic avian influenza virus (LPAIV), and the non-structural proteins (NS) and polymerase basic protein 2 (PB2) originated from different H9N2 LPAIVs. In contrast to the control H5N1 recombinant virus, harboring six internal genes from PR8, the NS and PB2 recombinant viruses did not cause body weight loss in mice. However, the NS recombinant virus replicated in the lungs of mice. It was more immunogenic than the PB2 recombinant virus to protect efficiently against a lethal challenge of a H5N1 highly pathogenic AIV with 89 and 88% amino acid identity in HA and NA, respectively. Therefore, the NS gene may be useful for generating nonpathogenic and immunogenic PR8-derived recombinant viruses for studies of antigenicity and protective efficacy in mice. PMID- 26428456 TI - Novel pseudorabies virus variant with defects in TK, gE and gI protects growing pigs against lethal challenge. AB - One of the distinct features of the emerging Chinese pseudorabies virus (PRV) variant is its ability to cause severe neurological signs and high mortality in growing pigs in Bartha-K61-vaccinated pig farms. Either single- or multiple-gene deleted live vaccine candidates have been developed; however, none was evaluated thoroughly in growing pigs. Here, we generated rSMXDeltagI/gEDeltaTK, an attenuated PRV variant with defects in TK, gI and gE genes. The growth kinetics of the attenuated virus was similar to the wild type (wt) strain. It was safe for 1-day-old piglets. Twenty one-day-old weaned pigs were immunized intramuscularly either with 10(6.0) TCID50 of rSMXDeltagI/gEDeltaTK or one dose of commercial Bartha-K61 vaccine, or with DMEM, and were challenged intranasally with 10(7.0) TCID50 wt virus at 28 days post vaccination. rSMXDeltagI/gEDeltaTK elicited higher level neutralization antibody against both PRV variant SMX and Bartha-K61 strain, while Bartha-K61 vaccine elicited lower neutralization activity of antibody against SMX. After challenge, all pigs in rSMXDeltagI/gEDeltaTK group survived without any clinical signs, while unvaccinated group showed 100% mortality, and Bartha-K61 group showed severe respiratory symptoms and 3 out of 5 pigs exhibited severe neurological signs. Pigs in rSMXDeltagI/gEDeltaTK group gained significantly higher body weight and diminished viral excretion titer and period, compared with Bartha-K61 group. Furthermore, the safety and efficacy of rSMXDeltagI/gEDeltaTK was also evaluated in sheep and compared with local vaccine in growing pigs. These data suggest that the attenuated strain rSMXDeltagI/gEDeltaTK is a promising live marker vaccine candidate for PR control in the context of emerging PRV variants. PMID- 26428457 TI - Hit-and-run, hit-and-stay, and commensal bacteria present different peptide content when viewed from the perspective of the T cell. AB - Different types of bacteria face different pressures from the immune system, with those that persist ("hit-and-stay") potentially having to adapt more in order to escape than those prone to short-lived infection ("hit-and-run"), and with commensal bacteria potentially different from both due to additional physical mechanisms for avoiding immune detection. The Janus Immunogenicity Score (JIS) was recently developed to assess the likelihood of T cell recognition of an antigen, using an analysis that considers both binding of a peptide within the antigen by major histocompatability complex (MHC) and recognition of the peptide:MHC complex by cognate T cell receptor (TCR). This score was shown to be predictive of T effector vs. T regulatory or null responses in experimental data, as well as to distinguish viruses representative of the hit-and-stay vs. hit-and run phenotypes. Here, JIS-based analyses were conducted in order to characterize the extent to which the pressure to avoid T cell recognition is manifested in genomic differences among representative hit-and-run, hit-and-stay, and commensal bacteria. Overall, extracellular proteins were found to have different JIS profiles from cytoplasmic ones. Contrasting the bacterial groups, extracellular proteins were shown to be quite different across the groups, much more so than intracellular proteins. The differences were evident even at the level of corresponding peptides in homologous protein pairs from hit-and-run and hit-and stay bacteria. The multi-level analysis of patterns of immunogenicity across different groups of bacteria provides a new way to approach questions of bacterial immune camouflage or escape, as well as to approach the selection and optimization of candidates for vaccine design. PMID- 26428459 TI - Assessing the relationship between neighborhood factors and diabetes related health outcomes and self-care behaviors. AB - BACKGROUND: Studies have shown that community and neighborhood characteristics can impact health outcomes of those with chronic illness, including T2DM. Factors, such as crime, violence, and lack of resources have been shown to be barriers to optimal health outcomes in diabetes. Thus, the objective of this study is to assess the effects of neighborhood factors on diabetes-related health outcomes and self-care behaviors. METHODS: Adult patients (N = 615) with type 2 diabetes mellitus (T2DM) were recruited from an academic medical center and a Veterans Affairs medical center in the southeastern United States. Validated scales and indices were used to assess neighborhood factors and diabetes-related self-care behaviors. The most recent HbA1c, blood pressure, and LDL cholesterol were abstracted from each patients' electronic medical record. RESULTS: In the fully adjusted model, significant associations were between neighborhood aesthetics and diabetes knowledge (beta = 0.141) and general diet (beta = 0.093); neighborhood comparison and diabetes knowledge (beta = 0.452); neighborhood activities and general diet (beta = -0.072), exercise (beta = 0.104), and foot care (beta = -0.114); food insecurity and medication adherence (beta = -0.147), general diet (beta = -0.125), and blood sugar testing (beta = 0.172); and social support and medication adherence (beta = 0.009), foot care (beta = 0.010), and general diet (beta = 0.016). Significant associations were also found between neighborhood violence and LDL Cholesterol (beta = 4.04), walking environment and exercise (beta = -0.040), and social cohesion and HbA1c (beta = -0.086). DISCUSSION: We found that neighborhood violence, aesthetics, walking environment, activities, food insecurity, neighborhood comparison, social cohesion and social support have statistically significant associations with self care behaviors and outcomes to varying degrees. However, the key neighborhood factors that had independent associations with multiple self-care behaviors and outcomes were food insecurity, neighborhood activities and social support. CONCLUSION: This study suggests that food insecurity, neighborhood activities, aesthetics, and social support may be important targets for interventions in individuals with T2DM. PMID- 26428458 TI - Large screen approaches to identify novel malaria vaccine candidates. AB - Until recently, malaria vaccine development efforts have focused almost exclusively on a handful of well characterized Plasmodium falciparum antigens. Despite dedicated work by many researchers on different continents spanning more than half a century, a successful malaria vaccine remains elusive. Sequencing of the P. falciparum genome has revealed more than five thousand genes, providing the foundation for systematic approaches to discover candidate vaccine antigens. We are taking advantage of this wealth of information to discover new antigens that may be more effective vaccine targets. Herein, we describe different approaches to large-scale screening of the P. falciparum genome to identify targets of either antibody responses or T cell responses using human specimens collected in Controlled Human Malaria Infections (CHMI) or under conditions of natural exposure in the field. These genome, proteome and transcriptome based approaches offer enormous potential for the development of an efficacious malaria vaccine. PMID- 26428460 TI - Coronary risk in relation to genetic variation in MEOX2 and TCF15 in a Flemish population. AB - BACKGROUND: In mice MEOX2/TCF15 heterodimers are highly expressed in heart endothelial cells and are involved in the transcriptional regulation of lipid transport. In a general population, we investigated whether genetic variation in these genes predicted coronary heart disease (CHD). RESULTS: In 2027 participants randomly recruited from a Flemish population (51.0 % women; mean age 43.6 years), we genotyped six SNPs in MEOX2 and four in TCF15. Over 15.2 years (median), CHD, myocardial infarction, coronary revascularisation and ischaemic cardiomyopathy occurred in 106, 53, 78 and 22 participants. For SNPs, we contrasted CHD risk in minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers (variant) vs. non-carriers. In multivariable-adjusted analyses with correction for multiple testing, CHD risk was associated with MEOX2 SNPs (P <= 0.049), but not with TCF15 SNPs (P >= 0.29). The MEOX2 GTCCGC haplotype (frequency 16.5 %) was associated with the sex- and age-standardised CHD incidence (5.26 vs. 3.03 events per 1000 person-years; P = 0.036); the multivariable-adjusted hazard ratio [HR] of CHD was 1.78 (95 % confidence interval, 1.25-2.56; P = 0.0054). For myocardial infarction, coronary revascularisation, and ischaemic cardiomyopathy, the corresponding HRs were 1.96 (1.16-3.31), 1.87 (1.20-2.91) and 3.16 (1.41-7.09), respectively. The MEOX2 GTCCGC haplotype significantly improved the prediction of CHD over and beyond traditional risk factors and was associated with similar population-attributable risk as smoking (18.7 % vs. 16.2 %). CONCLUSIONS: Genetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms. PMID- 26428461 TI - A stapled peptide antagonist of MDM2 carried by polymeric micelles sensitizes glioblastoma to temozolomide treatment through p53 activation. AB - Antagonizing MDM2 and MDMX to activate the tumor suppressor protein p53 is an attractive therapeutic paradigm for the treatment of glioblastoma multiforme (GBM). However, challenges remain with respect to the poor ability of p53 activators to efficiently cross the blood-brain barrier and/or blood-brain tumor barrier and to specifically target tumor cells. To circumvent these problems, we developed a cyclic RGD peptide-conjugated poly(ethylene glycol)-co-poly(lactic acid) polymeric micelle (RGD-M) that carried a stapled peptide antagonist of both MDM2 and MDMX (sPMI). The peptide-carrying micelle RGD-M/sPMI was prepared via film-hydration method with high encapsulation efficiency and loading capacity as well as ideal size distribution. Micelle encapsulation dramatically increased the solubility of sPMI, thus alleviating its serum sequestration. In vitro studies showed that RGD-M/sPMI efficiently inhibited the proliferation of glioma cells in the presence of serum by activating the p53 signaling pathway. Further, RGD M/sPMI exerted potent tumor growth inhibitory activity against human glioblastoma in nude mouse xenograft models. Importantly, the combination of RGD-M/sPMI and temozolomide--a standard chemotherapy drug for GBM increased antitumor efficacy against glioblastoma in experimental animals. Our results validate a combination therapy using p53 activators with temozolomide as a more effective treatment for GBM. PMID- 26428462 TI - Liposome-based glioma targeted drug delivery enabled by stable peptide ligands. AB - The treatment of glioma is one of the most challenging tasks in clinic. As an intracranial tumor, glioma exhibits many distinctive characteristics from other tumors. In particular, various barriers including enzymatic barriers in the blood and brain capillary endothelial cells, blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) rigorously prevent drug and drug delivery systems from reaching the tumor site. To tackle this dilemma, we developed a liposomal formulation to circumvent multiple-barriers by modifying the liposome surface with proteolytically stable peptides, (D)CDX and c(RGDyK). (D)CDX is a D-peptide ligand of nicotine acetylcholine receptors (nAChRs) on the BBB, and c(RGDyK) is a ligand of integrin highly expressed on the BBTB and glioma cells. Lysosomal compartments of brain capillary endothelial cells are implicated in the transcytosis of those liposomes. However, both peptide ligands displayed exceptional stability in lysosomal homogenate, ensuring that intact ligands could exert subsequent exocytosis from brain capillary endothelial cells and glioma targeting. In the cellular uptake studies, dually labeled liposomes could target both brain capillary endothelial cells and tumor cells, effectively traversing the BBB and BBTB monolayers, overcoming enzymatic barrier and targeting three dimensional tumor spheroids. Its targeting ability to intracranial glioma was further verified in vivo by ex vivo imaging and histological studies. As a result, doxorubicin liposomes modified with both (D)CDX and c(RGDyK) presented better anti-glioma effect with prolonged median survival of nude mice bearing glioma than did unmodified liposomes and liposomes modified with individual peptide ligand. In conclusion, the liposome suggested in the present study could effectively overcome multi-barriers and accomplish glioma targeted drug delivery, validating its potential value in improving the therapeutic efficacy of doxorubicin for glioma. PMID- 26428463 TI - Reply: To PMID 25823770. PMID- 26428464 TI - White light endoscopy versus chromoendoscopy for the detection of dysplasia during inflammatory bowel disease surveillance with colonoscopy. PMID- 26428465 TI - Defining the relationship between clinical and biochemical disease activity indices and perceived stress in inflammatory bowel disease. PMID- 26428466 TI - Reply: To PMID 26077178. PMID- 26428467 TI - Effects of education to facilitate knowledge about chronic pain for adults: a systematic review with meta-analysis. AB - BACKGROUND: Chronic pain can contribute to disability, depression, anxiety, sleep disturbances, poor quality of life and increased health care costs, with close to 20 % of the adult population in Europe reporting chronic pain. To empower the person to self-manage, it is advocated that education and training about the nature of pain and its effects and how to live with pain is provided. The objective of this review is to determine the level of evidence for education to facilitate knowledge about chronic pain, delivered as a stand-alone intervention for adults, to reduce pain and disability. METHODS: We identified randomised controlled trials of educational intervention for chronic pain by searching CENTRAL, MEDLINE, EMBASE and ongoing trials registries (inception to December 2013). Main inclusion criteria were (1) pain >3 months; (2) study design that allowed isolation of effects of education and (3) measures of pain or disability. Two reviewers independently screened and appraised each study. RESULTS: Nine studies were analysed. Pooled data from five studies, where the comparator group was usual care, showed no improvement in pain or disability. In the other four studies, comparing different types of education, there was no evidence for an improvement in pain; although, there was evidence (from one study) of a decrease in disability with a particular form of education-pain neurophysiology education (PNE). Post-hoc analysis of psychosocial outcomes reported in the studies showed evidence of a reduction in catastrophising and an increase of knowledge about pain following PNE. CONCLUSIONS: The evidence base is limited by the small numbers of studies, their relatively small sample sizes, and the diversity in types of education studied. From that limited evidence, the only support for this type of education is for PNE, though it is insufficiently strong to recommend conclusively that PNE should be delivered as a stand-alone intervention. It therefore remains sensible to recommend that education be delivered in conjunction with other pain management approaches as we cannot confidently conclude that education alone is effective in reducing pain intensity or related disability in chronic pain in adults. PMID- 26428470 TI - An interview with David Sackett, 2014-2015. PMID- 26428468 TI - Saturation pulse design for quantitative myocardial T1 mapping. AB - BACKGROUND: Quantitative saturation-recovery based T1 mapping sequences are less sensitive to systematic errors than the Modified Look-Locker Inversion recovery (MOLLI) technique but require high performance saturation pulses. We propose to optimize adiabatic and pulse train saturation pulses for quantitative T1 mapping to have <1 % absolute residual longitudinal magnetization (|MZ/M0|) over ranges of B0 and [Formula: see text] (B1 scale factor) inhomogeneity found at 1.5 T and 3 T. METHODS: Design parameters for an adiabatic BIR4-90 pulse were optimized for improved performance within 1.5 T B0 (+/-120 Hz) and [Formula: see text] (0.7 1.0) ranges. Flip angles in hard pulse trains of 3-6 pulses were optimized for 1.5 T and 3 T, with consideration of T1 values, field inhomogeneities (B0 = +/ 240 Hz and [Formula: see text]=0.4-1.2 at 3 T), and maximum achievable B1 field strength. Residual MZ/M0 was simulated and measured experimentally for current standard and optimized saturation pulses in phantoms and in-vivo human studies. T1 maps were acquired at 3 T in human subjects and a swine using a SAturation recovery single-SHot Acquisition (SASHA) technique with a standard 90 degrees -90 degrees -90 degrees and an optimized 6-pulse train. RESULTS: Measured residual MZ/M0 in phantoms had excellent agreement with simulations over a wide range of B0 and [Formula: see text]. The optimized BIR4-90 reduced the maximum residual |MZ/M0| to <1 %, a 5.8* reduction compared to a reference BIR4-90. An optimized 3 pulse train achieved a maximum residual |MZ/M0| <1 % for the 1.5 T optimization range compared to 11.3 % for a standard 90 degrees -90 degrees -90 degrees pulse train, while a 6-pulse train met this target for the wider 3 T ranges of B0 and [Formula: see text]. The 6-pulse train demonstrated more uniform saturation across both the myocardium and entire field of view than other saturation pulses in human studies. T1 maps were more spatially homogeneous with 6-pulse train SASHA than the reference 90 degrees -90 degrees -90 degrees SASHA in both human and animal studies. CONCLUSIONS: Adiabatic and pulse train saturation pulses optimized for different constraints found at 1.5 T and 3 T achieved <1 % residual |MZ/M0| in phantom experiments, enabling greater accuracy in quantitative saturation recovery T1 imaging. PMID- 26428471 TI - Atmospheric polycyclic aromatic hydrocarbons in the urban environment: Occurrence, toxicity and source apportionment. AB - Polycyclic Aromatic Hydrocarbons (PAHs) represent a major class of toxic pollutants because of their carcinogenic and mutagenic characteristics. People living in urban areas are regularly exposed to PAHs because of abundance of their emission sources. Within this context, this study aimed to: (i) identify and quantify the levels of ambient PAHs in an urban environment; (ii) evaluate their toxicity; and (iii) identify their sources as well as the contribution of specific sources to measured concentrations. Sixteen PAHs were identified and quantified in air samples collected from Brisbane. Principal Component Analysis - Absolute Principal Component Scores (PCA-APCS) was used in order to conduct source apportionment of the measured PAHs. Vehicular emissions, natural gas combustion, petrol emissions and evaporative/unburned fuel were the sources identified; contributing 56%, 21%, 15% and 8% of the total PAHs emissions, respectively, all of which need to be considered for any pollution control measures implemented in urban areas. PMID- 26428472 TI - The Vanderbilt Head and Neck Symptom Survey Brazilian Portuguese version 2.0 (VHNSS 2.0): psychometric properties for patients with head and neck cancer who have undergone radiotherapy. AB - BACKGROUND: Patients who undergo radiotherapy to treat head and neck cancer can present with several symptoms, including oral ones. The symptoms are usually assessed using instruments to evaluate quality of life. However, these instruments do not really assess oral health outcomes and their functional implications. The VHNSS 2.0 instrument was developed to be used with head and neck cancer patients, and has recently been translated and culturally adapted to be used in Brazil. The purpose of the study was to evaluate the psychometric properties of the VHNSS 2.0 Brazilian Portuguese version. METHODS: Three assessment instruments, the Brazilian Portuguese versions of EORTC QLQ-C30, EORTC H&N 35 and VHNSS 2.0, were answered by 241 head and neck cancer patients, of whom 47 were submitted to the test retest in 5-16 days. The construct validity was assessed through convergent validation (assuming correlations between VHNSS 2.0 and EORTC), and known group analysis (radiotherapy time, site of tumor, staging and surgery). Reliability was evaluated by means of Cronbach's alpha and test retest using the intraclass correlation coefficient. RESULTS: 241 head and neck cancer patients, median age 58.8, were included in this study. Hypothesized correlations were confirmed, the comparison among the groups showed differences in most of the domains. Reliability for the domains of swallowing solids, dry mouth, mouth pain, mucus, voice, pain and taste/smell presented Cronbach's alpha values from 0.858 to 0.735 and for the domains of nutrition, swallowing liquids and teeth, 0.618, 0.620 and 0.670 respectively. The test-retest reliability, for the domains of the VHNSS 2.0, measured using intraclass correlation coefficient, ranged from 0.372 to 0.854. CONCLUSION: The VHNSS 2.0 Brazilian Portuguese version presented good results for the convergent validation and known-group analyses. It also showed reliability for the Cronbach's alpha and test retest for most domains. PMID- 26428474 TI - Systematic donor selection review process improves cardiac transplant volumes and outcomes. AB - BACKGROUND: Heart transplant remains the definitive therapy for advanced heart failure patients but is limited by organ availability. We identified a large number of donor hearts from our organ procurement organization (OPO) being exported to other regions. METHODS: We engaged a multidisciplinary team including transplant surgeons, cardiologists, and our OPO colleagues to identify opportunities to improve our center-specific organ utilization rate. We performed a retrospective analysis of donor offers before and after institution of a novel review process. RESULTS: Each donor offer made to our program was reviewed on a monthly basis from July 2013 to June 2014 and compared with the previous year. This review process resulted in a transplant utilization rate of 28% for period 1 versus 49% for period 2 (P = .007). Limiting the analysis to offers from our local OPO changed our utilization rate from 46% to 75% (P = .02). Transplant volume increased from 22 to 35 between the 2 study periods. Thirty-day and 1-year mortality were unchanged over the 2 periods. A total of 58 hearts were refused by our center and transplanted at other centers. During period 1, the 30-day and 1 year survival rates for recipients of those organs were 98% and 90%, respectively, comparable with our historical survival data. CONCLUSIONS: The simple process of systematically reviewing donor turndown events as a group tended to reduce variability, increase confidence in expanded criteria for donors, and resulted in improved donor organ utilization and transplant volumes. PMID- 26428473 TI - Use of human fibrinogen concentrate during proximal aortic reconstruction with deep hypothermic circulatory arrest. AB - OBJECTIVE: Human fibrinogen concentrate (HFC) is approved by the Food and Drug Administration for use at 70 mg/kg to treat congenital afibrinogenemia. We sought to determine whether this dose of HFC increases fibrinogen levels in the setting of high-risk bleeding associated with aortic reconstruction and deep hypothermic circulatory arrest (DHCA). METHODS: This was a prospective, pilot, off-label study in which 22 patients undergoing elective proximal aortic reconstruction with DHCA were administered 70 mg/kg HFC upon separation from cardiopulmonary bypass (CPB). Fibrinogen levels were measured at baseline, just before, and 10 minutes after HFC administration, on skin closure, and the day after surgery. The primary study outcome was the difference in fibrinogen level immediately after separation from CPB, when HFC was administered, and the fibrinogen level 10 minutes following HFC administration. Additionally, postoperative thromboembolic events were assessed as a safety analysis. RESULTS: The mean baseline fibrinogen level was 317 +/- 49 mg/dL and fell to 235 +/- 39 mg/dL just before separation from CPB. After HFC administration, the fibrinogen level rose to 331 +/- 41 mg/dL (P < .001) and averaged 372 +/- 45 mg/dL the next day. No postoperative thromboembolic complications occurred. CONCLUSIONS: Administration of 70 mg/kg HFC upon separation from CPB raises fibrinogen levels by approximately 100 mg/dL without an apparent increase in thrombotic complications during proximal aortic reconstruction with DHCA. Further prospective study in a larger cohort of patients will be needed to definitively determine the safety and evaluate the efficacy of HFC as a hemostatic adjunct during these procedures. PMID- 26428475 TI - Utility of Allergy Testing in Patients with Chronic Laryngopharyngeal Symptoms: Is It Allergic Laryngitis? AB - OBJECTIVE: To determine the utility of allergy evaluation in patients with chronic refractory laryngeal symptoms. STUDY DESIGN: Case series with chart review. SETTING: Tertiary academic medical center. SUBJECTS: All patients who underwent in vitro allergy testing at a single institution from 2006 to 2010, for a total of 998 patients. METHODS: Charts of patients who underwent in vitro allergy testing were identified. The charts were reviewed for the primary indication for allergy testing, as categorized into rhinitis complaints, chronic sinusitis, otitis media, and refractory laryngeal symptoms (globus, cough, throat clearing, increased secretions, and hoarseness). Results of allergy tests and comorbid conditions were analyzed and compared among groups. RESULTS: The positive yield of allergy testing in patients with primary laryngeal indications was 51.8%, 63.3% for rhinitis, 60.9% for sinusitis, and 33.3% for otitis media. The odds ratio of having a positive test was not statistically different for patients with laryngeal symptoms, rhinitis, or sinusitis. Patients with chronic laryngeal symptoms and positive allergy testing were most often sensitized to dust mites (63%) and least often sensitized to molds (1.3%). CONCLUSIONS: Allergy testing in patients with chronic laryngeal symptoms yields positive results in equivalent proportion to patients with other common presenting symptoms. Dust mites sensitization is the most common sensitization in patients with allergic laryngitis. PMID- 26428477 TI - Application of 3-dimensional Modeling to Plan Totally Endoscopic Per-Meatal Drainage of Petrous Apex Cholesterol Granuloma. PMID- 26428476 TI - Sensitivity, Specificity, and Posttest Probability of Parotid Fine-Needle Aspiration: A Systematic Review and Meta-analysis. AB - OBJECTIVES: (1) To analyze the sensitivity and specificity of fine-needle aspiration (FNA) in distinguishing benign from malignant parotid disease. (2) To determine the anticipated posttest probability of malignancy and probability of nondiagnostic and indeterminate cytology with parotid FNA. DATA SOURCES: Independently corroborated computerized searches of PubMed, Embase, and Cochrane Central Register were performed. These were supplemented with manual searches and input from content experts. REVIEW METHODS: Inclusion/exclusion criteria specified diagnosis of parotid mass, intervention with both FNA and surgical excision, and enumeration of both cytologic and surgical histopathologic results. The primary outcomes were sensitivity, specificity, and posttest probability of malignancy. Heterogeneity was evaluated with the I(2) statistic. Meta-analysis was performed via a 2-level mixed logistic regression model. Bayesian nomograms were plotted via pooled likelihood ratios. RESULTS: The systematic review yielded 70 criterion-meeting studies, 63 of which contained data that allowed for computation of numerical outcomes (n = 5647 patients; level 2a) and consideration of meta-analysis. Subgroup analyses were performed in studies that were prospective, involved consecutive patients, described the FNA technique utilized, and used ultrasound guidance. The I(2) point estimate was >70% for all analyses, except within prospectively obtained and ultrasound-guided results. Among the prospective subgroup, the pooled analysis demonstrated a sensitivity of 0.882 (95% confidence interval [95% CI], 0.509-0.982) and a specificity of 0.995 (95% CI, 0.960-0.999). The probabilities of nondiagnostic and indeterminate cytology were 0.053 (95% CI, 0.030-0.075) and 0.147 (95% CI, 0.106-0.188), respectively. CONCLUSION: FNA has moderate sensitivity and high specificity in differentiating malignant from benign parotid lesions. Considerable heterogeneity is present among studies. PMID- 26428478 TI - Do everyday problems of people with chronic illness interfere with their disease management? AB - BACKGROUND: Being chronically ill is a continuous process of balancing the demands of the illness and the demands of everyday life. Understanding how everyday life affects self-management might help to provide better professional support. However, little attention has been paid to the influence of everyday life on self-management. The purpose of this study is to examine to what extent problems in everyday life interfere with the self-management behaviour of people with chronic illness, i.e. their ability to manage their illness. METHODS: To estimate the effects of having everyday problems on self-management, cross sectional linear regression analyses with propensity score matching were conducted. Data was used from 1731 patients with chronic disease(s) who participated in a nationwide Dutch panel-study. RESULTS: One third of people with chronic illness encounter basic (e.g. financial, housing, employment) or social (e.g. partner, children, sexual or leisure) problems in their daily life. Younger people, people with poor health and people with physical limitations are more likely to have everyday problems. Experiencing basic problems is related to less active coping behaviour, while experiencing social problems is related to lower levels of symptom management and less active coping behaviour. DISCUSSION: The extent of everyday problems interfering with self-management of people with chronic illness depends on the type of everyday problems encountered, as well as on the type of self-management activities at stake. CONCLUSIONS: Healthcare providers should pay attention to the life context of people with chronic illness during consultations, as patients' ability to manage their illness is related to it. PMID- 26428479 TI - Electronic cigarettes: scarce data and divergent legislations. The need for evidence-based health policies and research funding. PMID- 26428480 TI - Investigating the effect of banning non-reduced ignition propensity cigarettes on fatal residential fires in Sweden. AB - BACKGROUND: Annually, 100 people die as a result of residential fires in Sweden and almost a third of the fatal fires are known to be caused by smoking. In an attempt to reduce the occurrence of these events, reduced ignition propensity (RIP) cigarettes have been developed. They are designed to reduce the risk of fire by preventing the cigarette from burning through the full length when left unattended. In November 2011, a ban was introduced, forbidding the production and sale of all non-RIP cigarettes in all member states of the European Union, including Sweden. METHODS: Monthly data on all recorded residential fires and associated fatalities in Sweden from January 2000 to December 2013 were analyzed using an interrupted time series design. The effect of the intervention [in relative risk (RR)] was quantified using generalised additive models for location, shape and scale. RESULTS: There were no statistically significant intervention effects on residential fires (RR 0.95 [95% CI: 0.89-1.01]), fatal residential fires (RR 0.99 [95% CI: 0.80-1.23]), residential fires where smoking was a known cause (RR 1.10 [95% CI: 0.95-1.28]) or fatal residential fires where smoking was a known cause (RR 0.92 [95% CI: 0.63-1.35]). CONCLUSION: No evidence of an effect of the ban on all non-RIP cigarettes on the risk of residential fires in Sweden was found. The results may not be generalisable to other countries. PMID- 26428481 TI - Factors associated with the prevalence of adolescent binge drinking in the urban areas of Greater Manchester. AB - Background: Binge drinking in adolescents is a serious problem that has been recognised for over a generation. On average 61% of students in the European region had consumed alcohol in the last 30 days and 43% had participated in binge drinking in the same period. This article investigates the prevalence of adolescent binge drinking and the factors associated with this prevalence in urban areas of Greater Manchester. Methods: Data were obtained from the youth survey of the European Urban Health Indicator System 2 project. Study participants were school students aged 14-16 from the urban areas of Greater Manchester. The main outcome measures were adolescent binge drinking prevalence in Greater Manchester and the socio-demographic factors influencing it. Results: Greater Manchester had an adolescent binge drinking prevalence of 49.8%. Individual factors associated with increased prevalence of binge drinking were: age, substance use, school performance and early initiation of drinking (all significant at chi2, P < 0.05). Peer factors associated with increased prevalence of binge drinking were spending evenings with friends, keeping in touch with friends, having a good relationship with peers and self-reported bullying behaviours (all significant at chi2, P < 0.05). Family support lowered the prevalence of adolescent binge drinking. Conduct problems, family affluence and perceived local crime increased the prevalence of adolescent binge drinking. Conclusions: Binge drinking is highly prevalent in Greater Manchester adolescents. Various individual, peer-related, family-related and community related factors were associated with this problem. Any attempt to tackle the prevalence of adolescent binge drinking must take into account all of these factors. PMID- 26428483 TI - Developing a spinal cord injury research strategy. PMID- 26428482 TI - Added effect of heat wave on mortality in Seoul, Korea. AB - A heat wave could increase mortality owing to high temperature. However, little is known about the added (duration) effect of heat wave from the prolonged period of high temperature on mortality and different effect sizes depending on the definition of heat waves and models. A distributed lag non-linear model with a quasi-Poisson distribution was used to evaluate the added effect of heat wave on mortality after adjusting for long-term and intra-seasonal trends and apparent temperature. We evaluated the cumulative relative risk of the added wave effect on mortality on lag days 0-30. The models were constructed using nine definitions of heat wave and two relationships (cubic spline and linear threshold model) between temperature and mortality to leave out the high temperature effect. Further, we performed sensitivity analysis to evaluate the changes in the effect of heat wave on mortality according to the different degrees of freedom for time trend and cubic spline of temperature. We found that heat wave had the added effect from the prolonged period of high temperature on mortality and it was considerable in the aspect of cumulative risk because of the lagged influence. When heat wave was defined with a threshold of 98th percentile temperature and >=2, 3, and 4 consecutive days, mortality increased by 14.8 % (7.5-22.6, 95 % confidence interval (CI)), 18.1 % (10.8-26.0, 95 % CI), 18.1 % (10.7-25.9, 95 % CI), respectively, in cubic spline model. When it came to the definitions of 90th and 95th percentile, the risk increase in mortality declined to 3.7-5.8 % and 8.6 11.3 %, respectively. This effect was robust to the flexibility of the model for temperature and time trend, while the definitions of a heat wave were critical in estimating its relationship with mortality. This finding could help deepen our understanding and quantifying of the relationship between heat wave and mortality and select an appropriate definition of heat wave and temperature model in the future studies. PMID- 26428484 TI - The Evolution of MALDI-TOF Mass Spectrometry toward Ultra-High-Throughput Screening: 1536-Well Format and Beyond. AB - Mass spectrometry (MS) offers a label-free, direct-detection method, in contrast to fluorescent or colorimetric methodologies. Over recent years, solid-phase extraction-based techniques, such as the Agilent RapidFire system, have emerged that are capable of analyzing samples in <10 s. While dramatically faster than liquid chromatography-coupled MS, an analysis time of 8-10 s is still considered relatively slow for full-diversity high-throughput screening (HTS). Matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) offers an alternative for high-throughput MS detection. However, sample preparation and deposition onto the MALDI target, as well as interference from matrix ions, have been considered limitations for the use of MALDI for screening assays. Here we describe the development and validation of assays for both small molecule and peptide analytes using MALDI-TOF coupled with nanoliter liquid handling. Using the JMJD2c histone demethylase and acetylcholinesterase as model systems, we have generated robust data in a 1536 format and also increased sample deposition to 6144 samples per target. Using these methods, we demonstrate that this technology can deliver fast sample analysis time with low sample volume, and data comparable to that of current RapidFire assays. PMID- 26428485 TI - Reliability of Ultrasound Imaging Measures of Transverse Abdominis and Lumbar Multifidus in Various Positions. AB - OBJECTIVE: To determine the reliability of measurement of muscle activation via ultrasound imaging measures of the transverse abdominis (TrA) and lumbar multifidus (LM) in tabletop, seated, standing, and walking conditions. DESIGN: Descriptive laboratory study. SETTING: University research laboratory. PARTICIPANTS: Sixteen healthy participants (age, 20.4 +/- 1.8 years; height, 167.7 +/- 9.0 cm; mass, 65.1 +/- 10.8 kg). INTERVENTIONS: None. MAIN OUTCOME MEASUREMENTS: The activation ratio (AR) of TrA and LM and preferential activation ratio of TrA in tabletop, seated, standing, and walking positions were assessed by the same examiner during 2 ultrasound imaging sessions 24-72 hours apart. Statistical analysis included determination of intraclass correlation coefficients (ICCs) using analysis of variance for each muscle and position between sessions. RESULTS: Excellent reliability was found in TrA AR between sessions for healthy participants in the tabletop position (ICC3,k = 0.903), and acceptable to excellent reliability was found in seated (ICC3,k = 0.613), standing (ICC3,k = 0.553), and walking (ICC3,k = 0.737) positions. LM AR was fair in the tabletop position for these participants (ICC3,k = 0.264). The preferential activation ratio for healthy participants was substantially reliable in tabletop and seated positions (ICC3,k = 0.668, 0.684) and showed fair reliability for walking (ICC3,k = 0.455). CONCLUSIONS: Ultrasound imaging is a reliable method of measuring muscle thickness across multiple positions in healthy persons. This measure may be used to compare abdominal muscle thickness across populations or after interventions. LM AR was only found to be reliable in the tabletop position. PMID- 26428486 TI - A Phase II Trial of Fludarabine/Melphalan 100 Conditioning Therapy Followed by Allogeneic Hematopoietic Cell Transplantation for Patients With Lymphoma. AB - BACKGROUND: Conditioning therapy with fludarabine and melphalan 140 mg/m(2) has been widely used before allogeneic hematopoietic cell transplantation (HCT) for lymphoma. A lower dose of melphalan might result in lower mortality and morbidity without compromising engraftment. PATIENTS AND METHODS: In our phase II trial, we investigated a conditioning regimen of fludarabine (30 mg/m(2)/day for 5 days on days -6 to -2) and melphalan (100 mg/m(2) on day -2). Antithymocyte globulin was added to fludarabine and melphalan for unrelated or mismatched familial donor HCT. The present study included 26 patients with lymphoma (B-cell in 10, T-cell in 11, and natural killer/T-cell lymphoma in 2). RESULTS: An objective tumor response after HCT was observed in 18 patients (75.0%; complete in 14 and partial in 4). Acute and chronic graft-versus-host disease (GVHD) occurred in 23.1% and 55.0% of the assessable patients, respectively. The 5-year overall survival, nonrelapse mortality, progression-free survival, and event-free survival rate was 40.4%, 21.6%, 39.2%, and 30.8%, respectively. Donor lymphocyte infusions were given to 3 patients who had developed a relapse or progression after HCT, and 2 of whom had a showed partial response. Patients with severe chronic GVHD had greater overall survival than those with no, mild, or moderate chronic GVHD. CONCLUSION: Conditioning therapy with a lower dose of melphalan, combined with fludarabine, appears to be promising in allogeneic HCT for lymphoma. The Clinicaltrials.gov identification number for the present study is NCT00772811. PMID- 26428487 TI - Images of the human placenta. PMID- 26428488 TI - Functional imaging of the human placenta with magnetic resonance. AB - Abnormal placentation is responsible for most failures in pregnancy; however, an understanding of placental functions remains largely concealed from noninvasive, in vivo investigations. Magnetic resonance imaging (MRI) is safe in pregnancy for magnetic fields of up to 3 Tesla and is being used increasingly to improve the accuracy of prenatal imaging. Functional MRI (fMRI) of the placenta has not yet been validated in a clinical setting, and most data are derived from animal studies. FMRI could be used to further explore placental functions that are related to vascularization, oxygenation, and metabolism in human pregnancies by the use of various enhancement processes. Dynamic contrast-enhanced MRI is best able to quantify placental perfusion, permeability, and blood volume fractions. However, the transplacental passage of Gadolinium-based contrast agents represents a significant safety concern for this procedure in humans. There are alternative contrast agents that may be safer in pregnancy or that do not cross the placenta. Arterial spin labeling MRI relies on magnetically labeled water to quantify the blood flows within the placenta. A disadvantage of this technique is a poorer signal-to-noise ratio. Based on arterial spin labeling, placental perfusion in normal pregnancy is 176 +/- 91 mL * min(-1) * 100 g(-1) and decreases in cases with intrauterine growth restriction. Blood oxygen level dependent and oxygen-enhanced MRIs do not assess perfusion but measure the response of the placenta to changes in oxygen levels with the use of hemoglobin as an endogenous contrast agent. Diffusion-weighted imaging and intravoxel incoherent motion MRI do not require exogenous contrast agents, instead they use the movement of water molecules within tissues. The apparent diffusion coefficient and perfusion fraction are significantly lower in placentas of growth restricted fetuses when compared with normal pregnancies. Magnetic resonance spectroscopy has the ability to extract information regarding metabolites from the placenta noninvasively and in vivo. There are marked differences in all 3 metabolites N-acetyl aspartate/choline levels, inositol/choline ratio between small, and adequately grown fetuses. Current research is focused on the ability of each fMRI technique to make a timely diagnosis of abnormal placentation that would allow for appropriate planning of follow-up examinations and optimal scheduling of delivery. These research programs will benefit from the use of well defined sequences, standardized imaging protocols, and robust computational methods. PMID- 26428490 TI - How the placenta affects your life, from womb to tomb. PMID- 26428489 TI - Why is placentation abnormal in preeclampsia? AB - The causes of preeclampsia remain one of the great medical mysteries of our time. This syndrome is thought to occur in 2 stages with abnormal placentation leading to a maternal inflammatory response. Specific regions of the placenta have distinct pathologic features. During normal pregnancy, cytotrophoblasts emigrate from the chorionic villi and invade the uterus, reaching the inner third of the myometrium. This unusual process is made even more exceptional by the fact that the placental cells are hemiallogeneic, coexpressing maternal and paternal genomes. Within the uterine wall, cytotrophoblasts deeply invade the spiral arteries. Cytotrophoblasts migrate up these vessels and replace, in a retrograde fashion, the maternal endothelial lining. They also insert themselves among the smooth muscle cells that form the tunica media. As a result, the spiral arteries attain the physiologic properties that are required to perfuse the placenta adequately. In comparison, invasion of the venous side of the uterine circulation is minimal, sufficient to enable venous return. In preeclampsia, cytotrophoblast invasion of the interstitial uterine compartment is frequently shallow, although not consistently so. In many locations, spiral artery invasion is incomplete. There are many fewer endovascular cytotrophoblasts, and some vessels retain portions of their endothelial lining with relatively intact muscular coats, although others are not modified. Work from our group showed that these defects mirror deficits in the differentiation program that enables cytotrophoblast invasion of the uterine wall. During normal pregnancy, invasion is accompanied by the down-regulation of epithelial-like molecules that are indicative of their ectodermal origin and up-regulation of numerous receptors and ligands that typically are expressed by endothelial or vascular smooth muscle cells. For example, the expression of epithelial-cadherin (the cell-cell adhesion molecule that many ectodermal derivatives use to adhere to one another) becomes nearly undetectable, replaced by vascular-endothelial cadherin, which serves the same purpose in blood vessels. Invading cytotrophoblasts also modulate vascular endothelial growth factor ligands and receptors, at some point in the differentiation process expressing every (mammalian) family member. Molecules in this family play crucial roles in vascular and trophoblast biology, including the prevention of apoptosis. In preeclampsia, this process of vascular mimicry is incomplete, which we theorize hinders the cells interactions with spiral arterioles. What causes these aberrations? Given what is known from animal models and human risk factors, reduced placental perfusion and/or certain disease states (metabolic, immune and cardiovascular) lie upstream. Recent evidence suggests the surprising conclusion that isolation and culture of cytotrophoblasts from the placentas of pregnancies complicated by preeclampsia enables normalization of their gene expression. The affected molecules include SEMA3B, which down regulates vascular endothelial growth factor signaling through the PI3K/AKT and GSK3 pathways. Thus, some aspects of the aberrant differentiation of cytotrophoblasts within the uterine wall that is observed in situ may be reversible. The next challenge is asking what the instigating causes are. There is added urgency to finding the answers, because these pathways could be valuable therapeutic targets for reversing abnormal placental function in patients. PMID- 26428492 TI - Trophoblast-microbiome interaction: a new paradigm on immune regulation. AB - The immunologic paradigm of pregnancy led to the conceptualization of pregnancy as an organ transplant that requires, for its success, suppression of the maternal immune system. Growing scientific evidence suggests that in many ways the placenta functions as a tumor rather than a transplant and the immune regulation of the maternal-fetal interface is the result of the coordinated interaction between all its cellular components, including bacteria. Examining the role of microbiota in reproduction is in its infancy, but there is growing literature that supports its relevance. We discuss a potential normal function of bacteria in the establishment of immune tolerance and compelling evidence that a viral infection might be the underlying cause of perturbation of homeostasis. There is compelling evidence that many infectious diseases of human beings are caused by >1 microorganism and are defined as polymicrobial infections. We propose that pregnancy complications, such as preterm birth, are the result of polymicrobial infections. We examine the potential cellular and molecular mechanisms by which a viral infection of the placenta might disrupt the normal interaction between the cellular component of the implantation site and bacteria. As we better understand the normal homeostasis among the maternal immune system, placenta, and commensal, we will be able to elucidate pathogenic conditions and design better approaches to treat pregnancy complications associated with infection. PMID- 26428491 TI - Role of the fetoplacental endothelium in fetal growth restriction with abnormal umbilical artery Doppler velocimetry. AB - Growth-restricted fetuses with absent or reversed end-diastolic velocities in the umbilical artery are at substantially increased risk for adverse perinatal and long-term outcome, even in comparison to growth-restricted fetuses with preserved end-diastolic velocities. Translational studies show that this Doppler velocimetry correlates with fetoplacental blood flow, with absent or reversed end diastolic velocities signifying abnormally elevated resistance within the placental vasculature. The fetoplacental vasculature is unique in that it is not subject to autonomic regulation, unlike other vascular beds. Instead, humoral mediators, many of which are synthesized by local endothelial cells, regulate placental vascular resistance. Existing data demonstrate that in growth restricted pregnancies complicated by absent or reversed umbilical artery end diastolic velocities, an imbalance in production of these vasoactive substances occurs, favoring vasoconstriction. Morphologically, placentas from these pregnancies also demonstrate impaired angiogenesis, whereby vessels within the terminal villi are sparsely branched, abnormally thin, and elongated. This structural deviation from normal placental angiogenesis restricts blood flow and further contributes to elevated fetoplacental vascular resistance. Although considerable work has been done in the field of fetoplacental vascular development and function, much remains unknown about the mechanisms underlying impaired development and function of the human fetoplacental vasculature, especially in the context of severe fetal growth restriction with absent or reversed umbilical artery end-diastolic velocities. Fetoplacental endothelial cells are key regulators of angiogenesis and vasomotor tone. A thorough understanding of their role in placental vascular biology carries the significant potential of discovering clinically relevant and innovative approaches to prevention and treatment of fetal growth restriction with compromised umbilical artery end-diastolic velocities. PMID- 26428493 TI - Placental transcriptome in development and pathology: expression, function, and methods of analysis. AB - The placenta is the essential organ of mammalian pregnancy and errors in its development and function are associated with a wide range of human pathologies of pregnancy. Genome sequencing has led to methods for investigation of the transcriptome (all expressed RNA species) using microarrays and next-generation sequencing, and implementation of these techniques has identified many novel species of RNA including: micro-RNA, long noncoding RNA, and circular RNA. These species can physically interact with both each other and regulatory proteins to modify gene expression and messenger RNA to protein translation. Transcriptome analysis is actively used to investigate placental development and dysfunction in pathologies ranging from preeclampsia and fetal growth restriction to preterm labor. Genome-wide gene expression analysis is also being applied to identify prognostic and diagnostic biomarkers of these disorders. In this comprehensive review we summarize transcriptome biology, methods of isolation and analysis, application to placental development and pathology, and use in diagnostic analysis in maternal blood. Key information for analysis methods is organized into quick reference tables where current analysis techniques and tools are cited and compared. We have created this review as a practical guide and starting reference for those interested in beginning an investigation into the transcriptome of the placenta. PMID- 26428494 TI - The placenta is the center of the chronic disease universe. PMID- 26428495 TI - Genomic imprinting in the human placenta. AB - With the launch of the National Institute of Child Health and Human Development/National Institutes of Health Human Placenta Project, the anticipation is that this often-overlooked organ will be the subject of much intense research. Compared with somatic tissues, the cells of the placenta have a unique epigenetic profile that dictates its transcription patterns, which when disturbed may be associated with adverse pregnancy outcomes. One major class of genes that is dependent on strict epigenetic regulation in the placenta is subject to genomic imprinting, the parent-of-origin-dependent monoallelic gene expression. This review discusses the differences in allelic expression and epigenetic profiles of imprinted genes that are identified between different species, which reflect the continuous evolutionary adaption of this form of epigenetic regulation. These observations divulge that placenta-specific imprinted gene that is reliant on repressive histone signatures in mice are unlikely to be imprinted in humans, whereas intense methylation profiling in humans has uncovered numerous maternally methylated regions that are restricted to the placenta that are not conserved in mice. Imprinting has been proposed to be a mechanism that regulates parental resource allocation and ultimately can influence fetal growth, with the placenta being the key in this process. Furthermore, I discuss the developmental dynamics of both classic and transient placenta-specific imprinting and examine the evidence for an involvement of these genes in intrauterine growth restriction and placenta-associated complications. Finally, I focus on examples of genes that are regulated aberrantly in complicated pregnancies, emphasizing their application as pregnancy-related disease biomarkers to aid the diagnosis of at-risk pregnancies early in gestation. PMID- 26428497 TI - Placental exosomes in normal and complicated pregnancy. AB - While there is considerable contemporary interest in elucidating the role of placenta-derived extracellular vesicles in normal and complicated pregnancies and their utility as biomarkers and therapeutic interventions, progress in the field is hindered by a lack of standardized extracellular vesicle taxonomy and isolation protocols. The term "extracellular vesicle" is nonspecific and refers to all membrane-bound vesicles from nanometer to micrometer diameters and of different biogenic origins. To meaningfully ascribe biological function and/or diagnostic and therapeutic utility to extracellular vesicles, and in particular exosomes, greater specificity and vesicle characterization is required. The current literature relating to exosome biology must be interpreted in this context. Exosomes are a subtype of extracellular vesicle that are specifically defined by an endosomal biogenesis and particle size (40-120 nm) and density (1.13-1.19 g/mL(-1)). Exosomes are specifically package with signaling molecules (including protein, messenger RNA, microRNA, and noncoding RNA) and are released by exocytosis into biofluid compartments. Exosomes regulate the activity of both proximal and distal target cells, including translational activity, angiogenesis, proliferation, metabolism, and apoptosis. As such, exosomal signaling represents an integral pathway mediating intercellular communication. During pregnancy, the placenta releases exosomes into the maternal circulation from as early as 6 weeks of gestation. Release is regulated by factors that include both oxygen tension and glucose concentration and correlates with placental mass and perfusion. The concentration of placenta-derived exosomes in maternal plasma increases progressively during gestation. Exosomes isolated from maternal plasma are bioactive in vitro and are incorporated into target cells by endocytosis. While the functional significance of placental exosomes in pregnancy remains to be fully elucidated, available data support a role in normal placental development and maternal immunotolerance. Similarly, the role of exosomes in the etiology and progression of complications of pregnancy remains in a formative stage. Changes in the release of placenta- and nonplacenta-derived exosomes, their concentration in maternal plasma, composition, and bioactivity have been reported in association with pregnancies complicated by gestational diabetes and preeclampsia. The data, however, are confounded by the use of different isolation methodologies and vesicle subpopulations. The application of specific and well characterized isolation methodologies is requisite to resolving the precise role of exosomes in complications of pregnancies and their ultimate clinical utility. PMID- 26428498 TI - Epigenetic regulation of human placental function and pregnancy outcome: considerations for causal inference. AB - Epigenetic mechanisms, often defined as regulating gene activity independently of underlying DNA sequence, are crucial for healthy development. The sum total of epigenetic marks within a cell or tissue (the epigenome) is sensitive to environmental influence, and disruption of the epigenome in utero has been associated with adverse pregnancy outcomes. Not surprisingly, given its multifaceted functions and important role in regulating pregnancy outcome, the placenta shows unique epigenetic features. Interestingly however, many of these are only otherwise seen in human malignancy (the pseudomalignant placental epigenome). Epigenetic variation in the placenta is now emerging as a candidate mediator of environmental influence on placental functioning and a key regulator of pregnancy outcome. However, replication of findings is generally lacking, most likely due to small sample sizes and a lack of standardization of analytical approaches. Defining DNA methylation "signatures" in the placenta associated with maternal and fetal outcomes offers tremendous potential to improve pregnancy outcomes, but care must be taken in interpretation of findings. Future placental epigenetic research would do well to address the issues present in epigenetic epidemiology more generally, including careful consideration of sample size, potentially confounding factors, issues of tissue heterogeneity, reverse causation, and the role of genetics in modulating epigenetic profile. The importance of animal or in vitro models in establishing a functional role of epigenetic variation identified in human beings, which is key to establishing causation, should not be underestimated. PMID- 26428496 TI - MicroRNAs in placental health and disease. AB - MicroRNAs (miRNAs) constitute a large family of small noncoding RNAs that are encoded by the genomes of most organisms. They regulate gene expression through posttranscriptional mechanisms to attenuate protein output in various genetic networks. The discovery of miRNAs has transformed our understanding of gene regulation and sparked intense efforts intended to harness their potential as diagnostic markers and therapeutic tools. Over the last decade, a flurry of studies has shed light on placental miRNAs but has also raised many questions regarding the scope of their biologic action. Moreover, the recognition that miRNAs of placental origin are released continually in the maternal circulation throughout pregnancy suggested that circulating miRNAs might serve as biomarkers for placental function during pregnancy. Although this generated much enthusiasm, recently recognized challenges have delayed the application of miRNA-based biomarkers and therapeutics in clinical practice. In this review, we summarize key findings in the field and discuss current knowledge related to miRNAs in the context of placental biology. PMID- 26428499 TI - Noninvasive nucleic acid-based approaches to monitor placental health and predict pregnancy-related complications. AB - During pregnancy, the placenta releases a variety of nucleic acids (including deoxyribonucleic acid, messenger ribonucleic acid, or microribonucleic acids) either as a result of cell turnover or as an active messaging system between the placenta and cells in the maternal body. The profile of released nucleic acids changes with the gestational age and has been associated with maternal and fetal parameters. It also can directly reflect pathological changes in the placenta. Nucleic acids may therefore provide a rich source of novel biomarkers for the prediction of pregnancy complications. However, their utility in the clinical setting depends, first, on overcoming some technical considerations in their quantification, and, second, on developing a better understanding of the factors that influence their function and abundance. PMID- 26428500 TI - Classification of placental lesions. AB - Placental pathology can be useful in a variety of ways including immediate diagnosis of important conditions affecting the mother or infant, identifying conditions that are likely to recur in subsequent pregnancies, separating clinical syndromes into distinct pathological phenotypes for further investigation, and uncovering the underlying cause of unexpected adverse outcomes. Classification of placental lesions has evolved from being a purely descriptive exercise through a stage in which the major pathophysiological processes such as disorders of maternal implantation and the amniotic fluid infection syndrome were first described to a recently proposed comprehensive classification system that includes all of the major maternal and fetal vascular and infectious and idiopathic/immune inflammatory processes (Amsterdam Placental Workshop Group). Implementation of this unified system with reproducible grading and staging should help establish evidence-based recommendations for placental submission and facilitate progress in studying the pathogenesis, diagnosis, and treatment of obstetric disorders with an underlying placental etiology. PMID- 26428502 TI - The human placenta project: it's time for real time. PMID- 26428504 TI - What is the placenta? AB - Discarded at birth, the placenta is a highly complex and fascinating organ. During the course of a pregnancy, it acts as the lungs, gut, kidneys, and liver of the fetus. The placenta also has major endocrine actions that modulate maternal physiology and metabolism and provides a safe and protective milieu in which the fetus can develop. The human placenta undergoes dramatic transformations in form and function between the first trimester, when organogenesis occurs, and the remainder of pregnancy that reflect evolutionary responses to changing oxygen concentrations in the earth's atmosphere. Recent research indicates a more interactive dialogue between the placenta and the maternal tissues than previously recognized. The endometrial glands provide histotrophic support during the first weeks of pregnancy, and the placenta appears able to stimulate its own development by up-regulating gland activity in response to endocrine signals. Extravillous trophoblast cells migrate from the placenta into the uterine wall, in which they interact with cells of the maternal innate immune system. These interactions have a physiological, rather than a classical immunological, outcome and most probably mediate remodeling of the uterine spiral arteries that supply the placenta. Furthermore, deportation of aggregates of transcriptionally active trophoblast nuclei, and the release of exosomes carrying microribonucleic acids challenge our perceptions of fetal maternal signaling and where the placental interface actually lies. Here we reconsider definitions of the placenta in the light of these recent advances. PMID- 26428505 TI - Using ultrasound in the clinical management of placental implantation abnormalities. AB - Placental implantation abnormalities, including placenta previa, placenta accreta, vasa previa, and velamentous cord insertion, can have catastrophic consequences for both mother and fetus, especially as pregnancy progresses to term. In these situations, current recommendations for management usually call for an indicated preterm delivery even in asymptomatic patients. However, the recommended gestational age(s) for delivery in asymptomatic patients are empirically determined without consideration of the recent literature regarding the usefulness of specific ultrasound findings to help individualize management. The purpose of this article is to propose literature-supported guidelines to the current opinion-based management of asymptomatic patients with placental implantation abnormalities based on relevant and specific ultrasound findings such as cervical length, distance between the internal cervical os and placenta, and placental edge thickness. PMID- 26428506 TI - Placental implantation abnormalities and risk of preterm delivery: a systematic review and metaanalysis. AB - We sought to evaluate the extent of the association between placental implantation abnormalities (PIA) and preterm delivery in singleton gestations. We conducted a systematic review of English-language articles published from 1980 onward using PubMed, MEDLINE, EMBASE, CINAHL, LILACS, and Google Scholar, and by identifying studies cited in the references of published articles. Search terms were PIA defined as >= 1 of the following: placenta previa, placenta accreta, vasa previa, and velamentous cord insertion. Observational and experimental studies were included for review if data were available regarding any of the aforementioned PIA and regarding gestational age at delivery or preterm delivery. Case reports and case series were excluded. Studies were reviewed and data extracted. The primary outcome was gestational age at delivery or preterm delivery <37 weeks' gestation. Secondary outcomes included birthweight, 1- and 5 minute Apgar scores, neonatal intensive care unit (NICU) admission, neonatal and perinatal death, and small for gestational age. Of the 1421 studies identified, 79 met the defined criteria; 56 studies were descriptive and 23 were comparative. Based on the descriptive studies, the preterm delivery rates for low lying/marginal placenta, placenta previa, placenta accreta, vasa previa, and velamentous cord insertion were 26.9%, 43.5%, 57.7%, 81.9%, and 37.5%, respectively. Based on the comparative studies using controls, there was decreased pregnancy duration for every PIA; more specifically, there was an increased risk for preterm delivery in patients with placenta previa (risk ratio [RR], 5.32; 95% confidence interval [CI], 4.39-6.45), vasa previa (RR, 3.36; 95% CI, 2.76-4.09), and velamentous cord insertion (RR, 1.95; 95% CI, 1.67-2.28). Risks of NICU admissions (RR, 4.09; 95% CI, 2.80-5.97), neonatal death (RR, 5.44; 95% CI, 3.03-9.78), and perinatal death (RR, 3.01; 95% CI, 1.41-6.43) were higher with placenta previa. Perinatal risks were also higher in patients with vasa previa (perinatal death rate RR, 4.52; 95% CI, 2.77-7.39) and velamentous cord insertion (NICU admissions [RR, 1.76; 95% CI, 1.68-1.84], small for gestational age [RR, 1.69; 95% CI, 1.56-1.82], and perinatal death [RR, 2.15; 95% CI, 1.84 2.52]). In singleton gestations, there is a strong association between PIA and preterm delivery resulting in significant perinatal morbidity and mortality. PMID- 26428507 TI - Preeclampsia, biomarkers, syncytiotrophoblast stress, and placental capacity. AB - The maternal syndrome of preeclampsia is mediated by dysfunctional syncytiotrophoblast (STB). When this is stressed by uteroplacental malperfusion, its signaling to the mother changes, as part of a highly coordinated stress response. The STB signals are both proinflammatory and dysangiogenic such that the preeclamptic mother has a stronger vascular inflammatory response than normal, with an antiangiogenic bias. Angiogenic factors have limitations as preeclampsia biomarkers, especially for prediction and diagnosis of preeclampsia at term. However, if they are recognized as markers of STB stress, their physiological changes at term demonstrate that STB stress develops in all pregnancies. The biomarkers reveal that the duration of pregnancies is restricted by placental capacity, such that there is increasing placental dysfunction, at and beyond term. This capacity includes limitations imposed by the size of the uterus, the capacity of the uteroplacental circulation and, possibly, the supply of villous progenitor trophoblast cells. Limited placental capacity explains the increasing risks of postmaturity, including preeclampsia. Early-onset preeclampsia is predictable because STB stress and changes in its biomarkers are intrinsic to poor placentation, an early pregnancy pathology. Prediction of preeclampsia at term is not good because there is no early STB pathology. Moreover, biomarkers cannot accurately diagnose term preeclampsia against a background of universal STB dysfunction, which may or may not be clinically revealed before spontaneous or induced delivery. In this sense, postterm pregnancy is, at best, a pseudonormal state. However, the markers may prove useful in screening for women with more severe problems of postmaturity. PMID- 26428503 TI - Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance. AB - Chronic inflammatory lesions of the placenta are characterized by the infiltration of the organ by lymphocytes, plasma cells, and/or macrophages and may result from infections (viral, bacterial, parasitic) or be of immune origin (maternal anti-fetal rejection). The 3 major lesions are villitis (when the inflammatory process affects the villous tree), chronic chorioamnionitis (which affects the chorioamniotic membranes), and chronic deciduitis (which involves the decidua basalis). Maternal cellular infiltration is a common feature of the lesions. Villitis of unknown etiology (VUE) is a destructive villous inflammatory lesion that is characterized by the infiltration of maternal T cells (CD8+ cytotoxic T cells) into chorionic villi. Migration of maternal T cells into the villi is driven by the production of T-cell chemokines in the affected villi. Activation of macrophages in the villi has been implicated in the destruction of the villous architecture. VUE has been reported in association with preterm and term fetal growth restriction, preeclampsia, fetal death, and preterm labor. Infants whose placentas have VUE are at risk for death and abnormal neurodevelopmental outcome at the age of 2 years. Chronic chorioamnionitis is the most common lesion in late spontaneous preterm birth and is characterized by the infiltration of maternal CD8+ T cells into the chorioamniotic membranes. These cytotoxic T cells can induce trophoblast apoptosis and damage the fetal membranes. The lesion frequently is accompanied by VUE. Chronic deciduitis consists of the presence of lymphocytes or plasma cells in the basal plate of the placenta. This lesion is more common in pregnancies that result from egg donation and has been reported in a subset of patients with premature labor. Chronic placental inflammatory lesions can be due to maternal anti-fetal rejection, a process associated with the development of a novel form of fetal systemic inflammatory response. The syndrome is characterized by an elevation of the fetal plasma T-cell chemokine. The evidence that maternal anti-fetal rejection underlies the pathogenesis of many chronic inflammatory lesions of the placenta is reviewed. This article includes figures and histologic examples of all chronic inflammatory lesions of the placenta. PMID- 26428501 TI - Acute chorioamnionitis and funisitis: definition, pathologic features, and clinical significance. AB - Acute inflammatory lesions of the placenta consist of diffuse infiltration of neutrophils at different sites in the organ. These lesions include acute chorioamnionitis, funisitis, and chorionic vasculitis and represent a host response (maternal or fetal) to a chemotactic gradient in the amniotic cavity. While acute chorioamnionitis is evidence of a maternal host response, funisitis and chorionic vasculitis represent fetal inflammatory responses. Intraamniotic infection generally has been considered to be the cause of acute chorioamnionitis and funisitis; however, recent evidence indicates that "sterile" intraamniotic inflammation, which occurs in the absence of demonstrable microorganisms induced by "danger signals," is frequently associated with these lesions. In the context of intraamniotic infection, chemokines (such as interleukin-8 and granulocyte chemotactic protein) establish a gradient that favors the migration of neutrophils from the maternal or fetal circulation into the chorioamniotic membranes or umbilical cord, respectively. Danger signals that are released during the course of cellular stress or cell death can also induce the release of neutrophil chemokines. The prevalence of chorioamnionitis is a function of gestational age at birth, and present in 3-5% of term placentas and in 94% of placentas delivered at 21-24 weeks of gestation. The frequency is higher in patients with spontaneous labor, preterm labor, clinical chorioamnionitis (preterm or term), or ruptured membranes. Funisitis and chorionic vasculitis are the hallmarks of the fetal inflammatory response syndrome, a condition characterized by an elevation in the fetal plasma concentration of interleukin-6, and associated with the impending onset of preterm labor, a higher rate of neonatal morbidity (after adjustment for gestational age), and multiorgan fetal involvement. This syndrome is the counterpart of the systemic inflammatory response syndrome in adults: a risk factor for short- and long-term complications (ie, sterile inflammation in fetuses, neonatal sepsis, bronchopulmonary dysplasia, periventricular leukomalacia, and cerebral palsy). This article reviews the definition, pathogenesis, grading and staging, and clinical significance of the most common lesions in placental disease. Illustrations of the lesions and diagrams of the mechanisms of disease are provided. PMID- 26428508 TI - Anomalies of the placenta and umbilical cord in twin gestations. AB - The frequency of twin gestations has increased over the last few decades, mainly due to maternal age at childbearing, and the use of assisted reproductive technologies. Twins are at higher risk of aneuploidy, structural anomalies, and placental abnormalities. Some of the placental and umbilical cord abnormalities found in twin gestations are nonspecific and can be found in singleton gestations (ie, placenta previa, placental abruption, single umbilical artery, velamentous cord insertion, vasa previa, etc). However, other anomalies are unique to twin gestations, and are mainly associated with monochorionic twins-these include intraplacental anastomosis and cord entanglement. Most of these conditions can be diagnosed with ultrasound. An accurate and early diagnosis is important in the management of twin gestations. Determination of chorionicity, amnionicity, and the identification of placental anomalies are key issues for the adequate management of twin pregnancies. Pathologic placental examination after delivery can help in assessing the presence of placental and umbilical cord abnormalities, as well as providing information about chorionicity and gaining insight into the potential mechanisms of disease affecting twin gestations. PMID- 26428509 TI - Emergency percutaneous, bicaval double-lumen, ECMO cannulation in neonates and infants: insights from three consecutive cases. AB - BACKGROUND: Veno-venous extracorporeal membrane oxygenation (ECMO) is probably the preferable configuration to assist children with respiratory failure who do not respond to maximized conventional therapies. The single-vessel, double-lumen approach through the internal jugular vein is extremely advantageous, especially in infants, where femoral access presents limitations related to the small dimensions of the veins. In case of emergencies, ECMO might need to be started at the bedside, without the availability of fluoroscopic guidance. To our knowledge, a completely percutaneous approach has not been reported before in children younger than 1 year and weighing less than 5 kg. METHODS: We describe 3 cases of emergency bedside, percutaneous, bicaval double-lumen cannulation under real-time transthoracic ultrasound control in 2 neonates and 1 infant. RESULTS: In our experience, this approach proved to be safe, effective and time saving, while minimizing bleeding from the cannula insertion site. Cannulation times, from decision making to the beginning of ECMO flow, were 30, 28, 25 minutes respectively, from patient 1 to 3. We do not report any cannula-related injury to vessels and heart structures. CONCLUSIONS: Our preliminary data suggest that, with the described precautions, percutaneous, echo-guided, bicaval double-lumen cannulation in neonates and infants could be effective and free from major complications. Further evaluation should be warranted in the neonatal population. PMID- 26428510 TI - A Comparison of Techniques for Optimal Performance of Bronchoalveolar Lavage. AB - BACKGROUND: Bronchoalveolar lavage (BAL) is a commonly used diagnostic and research tool. Currently, there is limited evidence regarding standardizing this technique. The type of suction method and number of aliquots used as well as the anatomic lung segment sampled are not standardized nor well studied. Our primary aim was to compare the quantity and quality of BAL specimens using 2 suction methods, hand-held syringe versus wall suction. Our secondary aim was to assess which anatomic lung segment yields the greatest BAL results and how many aliquots are required. METHODS: A prospective clinical study was performed in patients undergoing bronchoscopies using hand-held syringe or wall suction. On the basis of radiologic findings, 100 mL (with 4 aliquots) of normal saline was instilled and the percentage volume return calculated. RESULTS: Sixy-six patients were enrolled. Thirty-three patients received hand-held syringe and 33 using wall suction. There was no significant difference in the percentage volume returned, or the adequacy of fluid between these suction methods. When comparing volumes of return from different lobes, greater returns were demonstrated from the right middle lobe (P=0.002). In addition, with each sequential aliquot instilled, the return of fluid was increased significantly (P<0.001). CONCLUSIONS: No significant difference was observed between hand-held syringe and wall suction in terms of volumes returned and microbiological or diagnostic yield. Performance of BAL in the right middle lobe is associated with increased return and should be preferentially used when performing a nontargeted BAL in patients with diffuse computed tomography chest changes. PMID- 26428511 TI - Wingless mediated apoptosis: How cone cells direct the death of peripheral ommatidia in the developing Drosophila eye. AB - Morphogen gradients play pervasive roles in development, and understanding how they are established and decoded is a major goal of contemporary developmental biology. Here we examine how a Wingless (Wg) morphogen gradient patterns the peripheral specialization of the fly eye. The outermost specialization is the pigment rim; a thick band of pigment cells that circumscribes the eye and optically insulates the sides of the retina. It results from the coalescence of pigment cells that survive the death of the outermost row of developing ommatidia. We investigate here how the Wg target genes expressed in the moribund ommatidia direct the intercellular signaling, the morphogenetic movements, and ultimately the ommatidial death. A salient feature of this process is the secondary expression of the Wg morphogen elicited in the ommatidia by the primary Wg signal. We find that neither the primary nor secondary sources of Wg alone are able to promote ommatidial death, but together they suffice to drive the apoptosis. This represents an unusual gradient read-out process in which a morphogen induces its own expression in its target cells to generate a concentration spike required to push the local cellular responses to the next threshold response. PMID- 26428512 TI - Introduction to the special issue: Data Part 2: Experimental Data. PMID- 26428513 TI - TAS-102, a novel antitumor agent: a review of the mechanism of action. AB - Inhibition of nucleoside metabolism is an important principle in cancer therapy as evidenced by the role of fluoropyrimidines, such as 5-fluorouracil (5-FU), and antifolates in the treatment of many cancers. TAS-102 is an oral combination therapy consisting of trifluridine (FTD), a thymidine-based nucleoside analog, plus tipiracil hydrochloride (TPI), a novel thymidine phosphorylase inhibitor that improves the bioavailability of FTD. TAS-102 has demonstrated efficacy in 5 FU-refractory patients based on a different mechanism of action and has been approved for the treatment of metastatic colorectal cancer in Japan. This review describes the mechanism of action of TAS-102, highlighting key differences between TAS-102 and 5-FU-based therapies. While both FTD and 5-FU inhibit thymidylate synthase (TS), a central enzyme in DNA synthesis, sufficient TS inhibition by FTD requires continuous infusion; therefore, it is not considered a clinically relevant mechanism with oral dosing. Instead, the primary cytotoxic mechanism with twice-daily oral dosing, the schedule used in TAS-102 clinical development, is DNA incorporation. FTD incorporation into DNA induces DNA dysfunction, including DNA strand breaks. Uracil-based analogs such as 5-FU may also be incorporated into DNA; however, they are immediately cleaved off by uracil-DNA glycosylases, reducing their ability to damage DNA. Moreover, the TPI component may enhance the durability of response to FTD. With its distinct mechanism of action and metabolism, TAS-102 is a promising treatment option for patients resistant to or intolerant of 5-FU-based fluoropyrimidines. PMID- 26428515 TI - On the Plausibility of Pseudosugar Formation in Cometary Ices and Oxygen-rich Tholins. AB - We revisit herein the formation and structure of dihydroxy dioxanes, which can be obtained from prebiotically available precursors and can be regarded as primeval sugar surrogates. Previous studies dealing with the heterogeneous composition of interstellar bodies point to the existence of significant amounts of small polyalcohols along with oxygen-containing oligomers. Even though such derivatives did not give rise to nucleosides and oligonucleotides, nor they were incorporated into subsequent metabolic routes, molecular chimeras based on sugar-like species could be opportunistic scaffolds in pre-evolutionary scenarios. We could figure out that pseudosugars, assembled by hemiacetalic bonds from available precursors in both interstellar and terrestrial scenarios, were presumably more abundant than thought. Moreover, these species share some key features with naturally occurring sugar rings, such as anomeric preferences, coordinating ability, and the prevalent occurrence of racemic compounds. PMID- 26428516 TI - Interventional ASD II closure in the presence of an abnormally localized left main coronary artery. PMID- 26428514 TI - Cell-free mitochondrial DNA in CSF is associated with early viral rebound, inflammation, and severity of neurocognitive deficits in HIV infection. AB - Cell-free mitochondiral DNA (mtDNA) is an immunogenic molecule associated with many inflammatory conditions. We evaluated the relationship between cell-free mtDNA in cerebrospinal fluid (CSF) and neurocognitive performance and inflammation during HIV infection. In a cross-sectional analysis, we evaluated the association of mtDNA levels with clinical assessments, inflammatory markers, and neurocognitive performance in 28 HIV-infected individuals. In CSF, we measured mtDNA levels by droplet digital PCR, and soluble CD14 and CD163, neurofilament light, and neopterin by ELISA. In blood and CSF, we measured soluble IP-10, MCP-1, TNF-alpha, and IL-6 by ELISA, and intracellular expression of IL-2, IFN-gamma, and TNF-alpha in CD4(+) and CD8(+) T cells by flow cytometry. We also evaluated the relationship between CSF pleocytosis and mtDNA longitudinally in another set of five individuals participating in an antiretroviral treatment (ART) interruption study. Cell-free CSF mtDNA levels strongly correlated with neurocognitive performance among individuals with neurocognitive impairment (NCI) (r = 0.77, p = 0.001). CSF mtDNA also correlated with levels of IP-10 in CSF (r = 0.70, p = 0.007) and MCP-1 in blood plasma (r = 0.66, p = 0.01) in individuals with NCI. There were no significant associations between inflammatory markers and mtDNA in subjects without NCI, and levels of mtDNA did not differ between subjects with and without NCI. MtDNA levels preceded pleocytosis and HIV RNA following ART interruption. Cell-free mtDNA in CSF was strongly associated with the severity of neurocognitive dysfunction and inflammation only in individuals with NCI. Our findings suggest that within a subset of subjects cell-free CSF mtDNA is associated with inflammation and degree of NCI. PMID- 26428517 TI - Dissolution Similarity Requirements: How Similar or Dissimilar Are the Global Regulatory Expectations? AB - The objective of this article is to compare and contrast the international expectations associated with the model-independent similarity factor approach to comparing dissolution profiles. This comparison highlights globally divergent regulatory requirements to meet local dissolution similarity requirements. In effect, experiments customized to meet the current international regulatory expectations for dissolution and drug release unnecessarily increase manufacturing costs, hinder science and risk-based approaches, increase collective regulatory burden, reduce continuous improvement and innovation, and potentially delay patient access to urgently needed medication. Comparative assessment of regulatory differences in applying dissolution to demonstrate product similarity is crucial to reduce non-scientifically justified experiments and foster collaborative harmonization among global regulatory health authorities and the pharmaceutical industry. PMID- 26428519 TI - Novel dysfunctional variant in ABCG2 as a cause of severe tophaceous gout: biochemical, molecular genetics and functional analysis. PMID- 26428520 TI - Hydroxychloroquine-related retinal toxicity. AB - HCQ is widely used for the treatment of rheumatic diseases, particularly lupus and RA. It is generally well tolerated, but retinopathy is a concern. Retinopathy is rare, but is sight threatening, generally irreversible and may progress even after cessation of therapy. Damage may be subclinical. Although a number of risk factors have been proposed (such as duration of therapy and cumulative dose), the many exceptions (e.g. retinopathy on low-dose HCQ, or no retinopathy after a very large cumulative dose of HCQ) highlight our limited understanding of the disease process. Novel technologies such as optical coherence tomography (OCT), fundus autofluorescence (FAF) and multifocal electroretinogram (mfERG) may provide the earliest structural and functional evidence of toxicity in these stages. Along with the well-established technique of central visual field testing (10-2 visual fields), these modalities are increasingly being used as part of screening programmes. The ideal single test with high sensitivity and high specificity for HCQ retinopathy has still not been achieved. Screening for HCQ retinopathy remains an area of considerable debate, including issues of when, who and how to screen. Commonly accepted risk factors include receiving >6.5 mg/kg/day or a cumulative dose of >1000 g of HCQ, being on treatment for >5 years, having renal or liver dysfunction, having pre-existing retinopathy and being elderly. HCQ continues to be a valuable drug in treating rheumatic disease, but clinicians need to be aware of the associated risks and to have arrangements in place that would enable early detection of toxicity. PMID- 26428518 TI - Post-diagnosis adiposity and survival among breast cancer patients: influence of breast cancer subtype. AB - PURPOSE: Adiposity has been linked with increased breast cancer risk and mortality. It is established that etiologic associations for adiposity vary by tumor subtype, but the influence of adiposity on subtype-specific survival is unknown. METHODS: Study participants were 1,109 invasive breast cancer participants in the population-based Carolina Breast Cancer Study, diagnosed between 1993 and 2001, and with tissue blocks available for immunohistochemical subtyping. General and central adiposities were assessed by body mass index (BMI) and waist-to-hip ratio (WHR), respectively, based on in-person measurements after diagnosis. Vital status as of 2011 was determined using the National Death Index (median follow-up = 13.5 years). Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer (BC)-specific and all-cause mortalities. RESULTS: Among all patients, high WHR (>=0.84), but not BMI, was associated with all-cause mortality (adjusted HR 1.50, 95% CI 1.11-2.05, <0.77 as reference). No significant association between adiposity and BC-specific mortality was detected, although there was a suggestion of increased mortality risk among high-BMI (>=30 kg/m(2)) patients with basal like tumors (adjusted HR 2.44, 95% CI 0.97-6.12, <25 kg/m(2) as reference). Quantitative differences in all-cause mortality were observed by subtype, with BMI associated with basal-like mortality and WHR associated with luminal mortality. The associations were attenuated by tumor characteristics. CONCLUSIONS: Our study confirms the association of adiposity and unfavorable overall survival in breast cancer patients and suggests that this association may vary by intrinsic subtype and adiposity measure. PMID- 26428521 TI - [Screening and prevention of diabetes]. AB - A valid and efficient screening for individual diabetes risk is a highly welcomed tool in primary care and specialist medical practice. It is needed to detect early stages of diabetes risk and prediabetes and to start interventions that have the aim to prevent diabetes and also other chronic diseases from developing. The oral glucose tolerance test is the gold standard, but it is difficult to perform in an evidence-based manner in primary care. Furthermore, measuring fasting and 2-h postprandial glucose values detects only late stages of the pathophysiological development of type 2 diabetes. Interestingly, the 1-h glucose value is highly predictive of future diabetes risk, but is rarely used in primary care. Therefore, risk scores are commonly used to evaluate diabetes risk, but unfortunately, they generally do not mirror the relevance of increased risk due to the person's own lifestyle. Measuring waist circumference is another possibility, because the waist is directly associated with the amount of visceral fat, which again directly correlates with the pathophysiology of diabetes development. A further possibility is the EZSCANTM technology. The EZSCANTM is based on reverse iontophoresis, a new technology to detect very early forms of peripheral neuropathies, which are commonly associated with early diabetes risk stages. It is important to perform diabetes screening in a targeted manner, in both medical and paramedical environments, and it is mandatory to add targeted interventions, based on the screening evaluated diabetes risk. PMID- 26428525 TI - [Bridging in patients with atrial fibrillation]. PMID- 26428526 TI - [Erratum to: The most frequent electrolyte disorders in the emergency department. What must be done immediately?]. PMID- 26428527 TI - Use of communication technologies by people with type 1 diabetes in the social networking era. A chance for improvement. AB - AIMS: To evaluate the health-related use of Web 2.0 tools by patients with type 1 diabetes. METHODS: Cross-sectional survey assessing views and usage of the Internet, Apps and Web 2.0. RESULTS: Number of participants: 289 (age 42.8+/-13.5 years; diabetes duration 18.4+/-12.2 years; 58.7% males; 39% with an upper secondary or higher education level). Web 2.0 usage for health purposes was low with 19.6% and 14% of Web 2.0 members (147; 50.9%) having health-related contacts and posting health comments. Health-related Apps were used by 35.4% of Smartphone owners (161; 55.7%). 75.3% patients would share information online with professionals, preferably through e-mail (78.7%) rather than Facebook (47.7%). 141 (66.5%) of those willing to share information would participate in a professional-moderated Facebook group. CONCLUSIONS: Web 2.0 and Apps usage for health purposes is low. The difference between the use of Web 2.0 networks and the willingness to participate in professional-moderated Web 2.0 groups points to the need of a higher implication of health professionals in promoting Web 2.0 technologies if these are to be adopted in a clinical setting. Currently, e-mail is the tool to be considered when aiming to increase online communication with patients with type 1 diabetes. PMID- 26428528 TI - Crataegus songarica methanolic extract accelerates enzymatic status in kidney and heart tissue damage in albino rats and its in vitro cytotoxic activity. AB - CONTEXT: Crataegus songarica K. Koch (Rosaceae) has been used in folk medicine to treat various diseases. OBJECTIVE: This study evaluates the effect of C. songarica methanol extract on the kidney and heart tissue damage of albino rats, and to determine cytotoxic activity of various extracts of songarica on various human cancer cell lines. MATERIALS AND METHODS: Rats were divided into six groups, Group I received water only; Group II received CCl4 (1 mL/kg b wt) intraperitoneal; C. songarica extract (at doses of 100, 200 and 300 mg/kg b wt) orally for 15 days. Cytotoxic activity was determined by SRB method using MCF-7, HeLa, HepG2, SF-295, SW480 and IMR-32 cell lines. RESULTS: Compared with CCl4 group, administration of C. songarica extract at the dose of 300 mg/kg b wt, significantly decreases serum creatinine (59.74%), urea (40.23%) and cholesterol (54 mg/dL), MDA (0.007 nmol/mg protein) in kidney and (0.025 nmol/mg protein) in heart tissue, along with evaluation of GSH (209.79 +/- 54.6), GR (111.45 +/- 2.84), GPx (94.01 +/- 14.80), GST (201.71) in kidney tissue and GSH (51.47 +/- 1.47), GR (45.42 +/- 6.69), GPx (77.19 +/- 10.94), GST (49.89) in heart tissue. In addition, methanol, ethanol and ethyl acetate extracts exhibited potent anticancer activity on six cancer cell lines with IC50 values ranging from 28.57 to 85.106 ug/mL. DISCUSSION AND CONCLUSION: Crataegus songarica methanol extract has a potential antioxidant effect as it protects the kidney and heart tissue against CCl4-induced toxicity, prevents DNA damage and showed strong anticancer activity. PMID- 26428529 TI - Qualitative interpretation of PET scans using a Likert scale to assess neck node response to radiotherapy in head and neck cancer. AB - PURPOSE: The aim of this study was to determine whether PET scans after radiotherapy (RT), visually interpreted as equivocal regarding metabolic neck node response can be used to accurately categorize patients as responders or nonresponders using a Likert scale and/or maximum standardized uptake value (SUVmax). Other aims were to determine the performance of different methods for assessing post-RT PET scans (visual inspection, a Likert scale and SUVmax) and to establish whether any method is superior in predicting regional control (RC) and overall survival (OS). METHODS: In 105 patients with neck node-positive head and neck cancer, the neck node response was evaluated by FDG PET/CT 6 weeks after RT. The scans were clinically assessed by visual inspection and, for the purposes of this analysis, re-evaluated using the Deauville criteria, a five-point Likert scale previously used in lymphoma studies. In addition, SUVmax was determined. RESULTS: All assessment methods were able to significantly predict RC but not OS. The methods were also able to significantly predict remission of tumour after completion of RT. Of the 105 PET scans, 19 were judged as equivocal on visual inspection. The Likert scale was preferable to SUVmax for grouping patients as responders or nonresponders. CONCLUSION: All methods (visual inspection, SUVmax and the Likert scale) identified responders and nonresponders and predicted RC. A Likert scale is a promising tool to reduce to a minimum the problem of PET scans judged as equivocal. Consensus regarding qualitative assessment would facilitate PET reporting in clinical practice. PMID- 26428530 TI - Periodic model of an LTA framework. AB - Zeolites are a group of microporous aluminosilicate frameworks with numerous applications in, for example, catalysis and ion-exchange and sorption processes. One of the most important tools for analyzing the properties of zeolite structures is vibrational spectroscopy. However, the complexity of these structures often leads to difficulties when attempting to interpret the resulting spectra, so an additional complementary tool is required: computational methods. The aim of this study was to formulate a simplified periodic model of an LTA framework containing alkali metal cations (either Li(+), Na(+), K(+), Rb(+), or Cs(+)) and to perform a set of ab initio calculations aimed at assessing the influence of these cations on the properties of the vibrational spectra of the LTA framework. Additionally, chemical bonding was analyzed by means of electron density topology analysis. Results obtained were compared with experimental spectra for alkali metal forms of zeolite A. It was found that the vibrational spectra obtained using the proposed model agree well with the corresponding experimentally derived spectra, meaning that the model can be used to analyze real spectra in detail. PMID- 26428531 TI - Does glimepiride alter the pharmacokinetics of sildenafil citrate in diabetic nephropathy animals: investigating mechanism of interaction by molecular modeling studies. AB - The present study evaluates possible drug interactions between glimepiride (GLIM) and sildenafil citrate (SIL) in streptozotocin (STZ)-induced diabetic nephropathic (DN) animals and also postulates the possible mechanism of interaction based on molecular modeling studies. Diabetic nephropathy was induced by single dose of STZ (60 mg kg(-1), i.p.) and was confirmed by assessing blood and urine biochemical parameters 28 days after induction. Selected DN animals were used to explore the drug interaction between GLIM (0.5 mg kg(-1), p.o.) and SIL (2.5 mg kg(-1), p.o.) on the 29th and 70th day of the protocol. Possible drug interaction was assessed by evaluating the plasma drug concentration using HPLC UV and changes in biochemical parameters in blood and urine were also determined. The mechanism of the interaction was postulated from the results of a molecular modeling study using the Maestro module of Schrodinger software. DN was confirmed as there was significant alteration in blood and urine biochemical parameters in STZ-treated groups. The concentration of SIL increased significantly (P < 0.001) in rat plasma when co-administered with GLIM on the 70th day of the protocol. Molecular modeling revealed important interactions with rat serum albumin and CYP2C9. GLIM has a strong hydrophobic interaction with binding site residues of rat serum albumin compared to SIL, whereas for CYP2C9, GLIM forms a stronger hydrogen bond than SIL with polar contacts and hydrophobic interactions. The present study concludes that bioavailability of SIL increases when co administered chronically with GLIM in the management of DN animals, and the mechanism is supported by molecular modeling studies. PMID- 26428532 TI - Roles of the NMDA Receptor and EAAC1 Transporter in the Modulation of Extracellular Glutamate by Low and High Affinity AMPA Receptors in the Cerebellum in Vivo: Differential Alteration in Chronic Hyperammonemia. AB - The roles of high- and low-affinity AMPA receptors in modulating extracellular glutamate in the cerebellum remain unclear. Altered glutamatergic neurotransmission is involved in neurological alterations in hyperammonemia, which differently affects high- and low-affinity AMPA receptors. The aims were to assess by in vivo microdialysis (a) the effects of high- and low-affinity AMPA receptor activation on extracellular glutamate in the cerebellum; (b) whether chronic hyperammonemia alters extracellular glutamate modulation by high- and/or low-affinity AMPA receptors; and (c) the contribution of NMDA receptors and EAAC1 transporter to AMPA-induced changes in extracellular glutamate. In control rats, high affinity receptor activation does not affect extracellular glutamate but increases glutamate if NMDA receptors are blocked. Low affinity AMPA receptor activation increases transiently extracellular glutamate followed by reduction below basal levels and return to basal values. The reduction is associated with transient increased membrane expression of EAAC1 and is prevented by blocking NMDA receptors. Blocking NMDA receptors with MK-801 induces a transient increase in extracellular glutamate which is associated with reduced membrane expression of EAAC1 followed by increased membrane expression of the glutamate transporter GLT-1. Chronic hyperammonemia does not affect responses to activation of low affinity AMPA receptors. Activation of high affinity AMPA receptors increases extracellular glutamate in hyperammonemic rats by an NMDA receptor-dependent mechanism. In conclusion, these results show that there is a tightly controlled interplay between AMPA and NMDA receptors and an EAAC1 transporter in controlling extracellular glutamate. Hyperammonemia alters high- but not low-affinity AMPA receptors. PMID- 26428533 TI - Probing the kinetic landscape of Hox transcription factor-DNA binding in live cells by massively parallel Fluorescence Correlation Spectroscopy. AB - Hox genes encode transcription factors that control the formation of body structures, segment-specifically along the anterior-posterior axis of metazoans. Hox transcription factors bind nuclear DNA pervasively and regulate a plethora of target genes, deploying various molecular mechanisms that depend on the developmental and cellular context. To analyze quantitatively the dynamics of their DNA-binding behavior we have used confocal laser scanning microscopy (CLSM), single-point fluorescence correlation spectroscopy (FCS), fluorescence cross-correlation spectroscopy (FCCS) and bimolecular fluorescence complementation (BiFC). We show that the Hox transcription factor Sex combs reduced (Scr) forms dimers that strongly associate with its specific fork head binding site (fkh250) in live salivary gland cell nuclei. In contrast, dimers of a constitutively inactive, phospho-mimicking variant of Scr show weak, non specific DNA-binding. Our studies reveal that nuclear dynamics of Scr is complex, exhibiting a changing landscape of interactions that is difficult to characterize by probing one point at a time. Therefore, we also provide mechanistic evidence using massively parallel FCS (mpFCS). We found that Scr dimers are predominantly formed on the DNA and are equally abundant at the chromosomes and an introduced multimeric fkh250 binding-site, indicating different mobilities, presumably reflecting transient binding with different affinities on the DNA. Our proof-of principle results emphasize the advantages of mpFCS for quantitative characterization of fast dynamic processes in live cells. PMID- 26428534 TI - Mitochondrial implications in bulbospinal muscular atrophy (Kennedy disease). AB - There is increasing evidence that mitochondrial functions are secondarily disturbed in bulbospinal muscular atrophy (BSMA). This review focuses on the relation between BSMA and the effect of the expanded polyglutamine (poly-Q) androgen receptor (AR) on mitochondrial functions. Mitochondrial functions in bulbospinal muscular atrophy (SBMA) are affected on the molecular, clinical, and therapeutic level. On the molecular level there is down-regulation of various nuclear-DNA-encoded mitochondrial proteins by mutant androgen receptor (mAR), colocalization of the mAR with various mitochondrial proteins, association of mAR aggregates with mitochondria resulting in abnormal distribution of mitochondria, mtDNA depletion or multiple mtDNA deletions, mitochondrial membrane depolarization, increase in reactive oxidative species, and activation of the mitochondrial caspase pathway. On the clinical level various mitochondrial disorders mimic SBMA, and on the therapeutic level pioglitazone expresses PPAR gamma, cyclosporine-A restores mitochondrial membrane potentials, coenzyme-Q and idebenone reduce oxidative stress, and geldanamycin up-regulates protective mitochondrial heat shock proteins. In conclusion, in BSMA mitochondrial dysfunction results from various interactions of elongated poly-Q AR with mitochondria, mitochondrial proteins, nuclear or mitochondrial DNA, causing oxidative stress, decreased mitochondrial membrane potential, or activation of the mitochondrial caspase pathway. Additionally, mitochondrial disease may mimic BSMA and therapeutic approaches may depend on modifications of mitochondrial pathways. PMID- 26428535 TI - Mathematics and biology: The ultimate interface? PMID- 26428536 TI - Editorial. AB - Preparing this ambitious Special Issue has challenged everyone involved: authors, reviewers, and guest editors. The editors solicited contributions from many leading figures in a broad array of scientific and philosophical disciplines, with emphasis on phenomenological approaches to philosophy (see Section I). The motivating force was the conviction that if we could find a viable bridge for the gap between the "two cultures"(1) of science and philosophy, fundamental problems in each camp could be addressed more fruitfully than ever before and a new kind of science be born. We believe the unprecedented cross-fertilization of ideas from this initiative may furnish seeds from which that new, better integrated, and more effective approach to science may arise. This Special Issue consists of forty papers. For each one, multiple reviewers were solicited, with at least one reviewer from each "culture" (a scientist and a philosopher). In many cases, several rounds of revision were carried out. Needless to say, this required great patience and dedication of all participants. The editors gratefully acknowledge the contributions of our authors, and of our anonymous reviewers, who worked long and hard on the papers we sent them with no compensation for their efforts. We also wish to thank the Elsevier editorial and production team for the support they gave us in bringing this project to fruition. We would now like to offer a synoptic overview of the Special Issue, proceeding section by section and paper by paper. Our hope is that the reader will find this unique effort to marry science and philosophy both meaningful and enjoyable. PMID- 26428537 TI - Ruthenium(II) p-cymene complex bearing 2,2'-dipyridylamine targets caspase 3 deficient MCF-7 breast cancer cells without disruption of antitumor immune response. AB - [Ru(eta(6)-p-cym)Cl{dpa(CH2)4COOEt}][PF6] (cym=cymene; dpa=2,2'-dipyridylamine; complex 2) was prepared and characterized by elemental analysis, IR and multinuclear NMR spectroscopy, as well as ESI-MS and X-ray structural analysis. The structural analog without a side chain [Ru(eta(6)-p-cym)Cl(dpa)][PF6] (1) as well as 2 were investigated in vitro against 518A2, SW480, 8505C, A253 and MCF-7 cell lines. Complex 1 is active against all investigated tumor cell lines while the activity of compound 2 is limited only to caspase 3 deficient MCF-7 breast cancer cells, however, both are less active than cisplatin. As CD4(+)Th cells are necessary to trigger all the immune effector mechanisms required to eliminate tumor cells, besides testing the in vitro antitumor activity of 1 and 2, the effect of ruthenium(II) complexes on the cells of the adaptive immune system have also been evaluated. Importantly, complex 1 applied in concentrations which were effective against tumor cells did not affect immune cell viability, nor did exert a general immunosuppressive effect on cytokine production. Thus, beneficial characteristics of 1 might contribute to the overall therapeutic properties of the complex. PMID- 26428539 TI - Population Screening and Prevention Strategies for Thalassemias and other Hemoglobinopathies of Eastern India: Experience of 18,166 cases. AB - We evaluated population screening programs (1999-2011), conducted by the Thalassaemia Foundation, Kolkata, India, for the first time in Eastern India in different districts of West Bengal, for prevention of thalassemia comprising screening of heterozygotes and beta-thalassemia intermedia (beta-TI) cases [beta(+), beta(++), beta(0)/beta(+), beta(E)/beta(E) (codon 26 or HBB: c.79G > A), Hb-E-beta-thalassemia (Hb E-beta-thal)]. Among 18,166 cases, we found 2092 heterozygotes and 2245 beta-TI individuals (who had no information about their disorders). Results were evaluated with standard hematological analyses including erythrocyte indices, hemoglobin (Hb) typing and quantification. Participants were divided into five groups (children, pre-marriage cases, pre-pregnancy cases, affected family members, pregnant women). The objectives of this evaluation were to fix cut-off values of red blood cells (RBCs), mean corpuscular volume (MCV), mean corpuscular Hb (MCH), red blood cell distribution width (RDW) and Hb A2, as the standard World Health Organization (WHO) guidelines were not strictly followed in mass-scale screening programs. We have observed many dilemmas in considering the status of the thalassemia subject, due to presence of some other clinical conditions such as iron deficiency anemia, alpha-thalassemia (alpha thal), delta-thalassemia (delta-thal), clinically silent Hb variants, and some cases of non hemoglobinopathies (such as pregnancy) along with thalassemia. The MCV values varied greatly in different conditions of hemoglobinopathies, whereas MCH provided a more stable measurement. We found an MCH value of <27.0 pg is a suitable cut-off point for screening in this population. Participants with an MCH of <27.0 pg should be investigated further to confirm or exclude a diagnosis of beta-thal trait. PMID- 26428540 TI - Occlusal traits in children with neurofibromatosis type 1. AB - OBJECTIVES: Literature is poor of data about the occlusion in children affected by neurofibromatosis type 1 (NF1). This case-control study investigated the occlusal traits in a group of children with NF1. SETTING AND SAMPLE POPULATION: A hundred and fifteen children with NF1 were enrolled; non-NF1 controls were sequentially selected among subjects referred to the Pediatric Dentistry Department. MATERIAL AND METHODS: All patients underwent a clinical dental examination and a panoramic radiography. The following orthodontic variables were considered: molar relationship, overjet, overbite, cross-bite, scissor bite, and crowding/spacing. RESULTS: Class III molar relationship resulted significantly (p = 0.01) more common in children with NF1 than in the control group as well as the unilateral posterior cross-bite (p = 0.0017). Forty-three children with NF1 (37.3%) showed radiographic abnormalities; in one case, a plexiform neurofibroma was detected. CONCLUSIONS: An early orthodontic evaluation might be planned in the management of children with NF1 to prevent or decrease the need for extensive orthodontic interventions. PMID- 26428538 TI - On scattered waves and lipid domains: detecting membrane rafts with X-rays and neutrons. AB - In order to understand the biological role of lipids in cell membranes, it is necessary to determine the mesoscopic structure of well-defined model membrane systems. Neutron and X-ray scattering are non-invasive, probe-free techniques that have been used extensively in such systems to probe length scales ranging from angstroms to microns, and dynamics occurring over picosecond to millisecond time scales. Recent developments in the area of phase separated lipid systems mimicking membrane rafts will be presented, and the underlying concepts of the different scattering techniques used to study them will be discussed in detail. PMID- 26428541 TI - Disparities in conditional net survival among non-Hodgkin lymphoma survivors: a population-based analysis. AB - We evaluated the association of baseline prognostic factors with conditional net survival among survivors of six subtypes non-Hodgkin lymphoma using the SEER program data from 2000-2012. Among 2-year survivors, further prognosis markedly improved in Burkitt's (BL) and diffuse large B-cell lymphoma (DLBCL), and became the same as for follicular lymphoma (5-year net survival >= 85%). Mantle cell lymphoma (MCL) demonstrated the worst prognosis of all studied histologies up to 5 years of survivorship. Age and stage lost prognostic significance in BL within 2 years from diagnosis. Racial disparities in net survival disappeared within 2 years for all subtypes, except in chronic lymphocytic leukemia, where black patients had persistently worse prognosis, and in MCL, where they had unexpectedly better prognosis than other races after 2 years. Many baseline factors may lose their initial prognostic value for lymphoma survivors, which should be considered when counseling patients about their prognosis and long-term surveillance. PMID- 26428546 TI - Towards witnessing quantum effects in complex molecules. AB - Whether many-body objects like organic molecules can exhibit full quantum behaviour, including entanglement, is an open fundamental question. We present a generic theoretical protocol for entangling two organic molecules, such as dibenzoterrylene in anthracene. The availability of organic dye molecules with two-level energy structures characterised by sharp and intense emission lines are characteristics that position them favourably as candidates for quantum information processing technologies involving single-photons. Quantum entanglement can in principle be generated between several organic molecules by carefully interfering their photoluminescence spectra. Major milestones have been achieved in the last 10 years showcasing entanglement in diverse systems including ions, cold atoms, superconductors, photons, quantum dots and NV-centres in diamond, but not yet in molecules. PMID- 26428547 TI - Erratum to: Vertical scapular osteotomy in congenital high scapula. PMID- 26428548 TI - Postharvest Biological Control of Colletotrichum acutatum on Apple by Bacillus subtilis HM1 and the Structural Identification of Antagonists. AB - Bacillus subtilis HM1 was isolated from the rhizosphere region of halophytes for its antifungal activity against Colletotrichum acutatum, the causative agent of anthracnose. Treatment of postharvest apples with the cell culture or with a cell free culture supernatant reduced disease severity 80.7% and 69.4%, respectively. Both treatments also exhibited antifungal activity against various phytopathogenic fungi in vitro. The antifungal substances were purified and analyzed by acid precipitation, gel filtration, high-performance liquid chromatography, and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Three compounds were identified as fengycin, iturin, and surfactin. The MALDI-TOF/ TOF mass spectrum revealed the presence of cyclized fengycin homologs A and B, which were distinguishable on the basis of the presence of either alanine or valine, respectively, at position 6 of the peptide sequence. In addition, the cyclized structure of fengycin was shown to play a critical role in antifungal activity. PMID- 26428550 TI - The Lag of the Proliferative Aging Clock Underlies the Lifespan-Extending Effect of Calorie Restriction. AB - BACKGROUND: The nature of the life-extending effect of calorie restriction (CR) is an unsolved problem in biology since 30 years of the last century. Furthermore, many different factors that cause analogous life-extending effect, so called CR-mimetic factors, have been found. They increase the lifespan of different animal species (repeatedly in invertebrates) and therefore remain in the forefront of anti-aging researches. The aims of this paper is to find an overarching solution for the nature of CR and all CR-mimetic factors and to analyze the consequences following this phenomenon. METHODS: The analysis of empirical scientific data, which concern aging process and boundary areas from the point of view of the bioenergetics theory of aging. RESULTS: "Anything that affects a living system that slows (accelerates) the rate of cell division entails extending (reducing) life duration" is this overarching solution. CR is one of such factors that cause a retardation in the rate of cell divisions due to the shortage in 'construction materials' necessary for doubling cell mass during reduplication. This put a brake on realization of the aging program. To draw this conclusion, a new concept of the proliferative aging clock based on bioenergetics theory of aging was put forward. This clock governs the rate of the aging process via programmed, proliferative dependent and stepwise bioenergetics decline. CONCLUSION: The mechanism of the life-extending effect of CR and CR-mimetic factors is not related to that of natural aging, therefore this unable to be the basis for elaboration of radical remedy for senescence. However, both the CR and some of CR-mimetic factors can undoubtedly lead to human life extension: our organism differs from that of the other mammals only slightly. It is the wellbeing and vulnerability of such extended life that are under consideration. To achieve a healthy and unlimited life it is necessary to reprogram gene expression so that cell bioenergetics levels either remain at a previous level after cell division, which will stop aging, or else grow, which will result in organism rejuvenation. PMID- 26428549 TI - Variation in serotonin neurotransmission genes affects neural activation during response inhibition in adolescents and young adults with ADHD and healthy controls. AB - OBJECTIVES: Deficits in response inhibition have been associated with attention deficit/hyperactivity disorder (ADHD). Given the role of serotonin in ADHD and impulsivity, we postulated that genetic variants within the serotonin pathway might influence response inhibition. METHODS: We measured neural activation during stop-signal task performance in adolescents with ADHD (N = 185), their unaffected siblings (N = 111), and healthy controls (N = 124), and investigated the relationship of two serotonin gene polymorphisms (the rs6296 SNP of the HTR1B gene and HTTLPR variants of the 5-HTT gene) with the neural correlates of response inhibition. RESULTS: The whole-brain analyses demonstrated large scale neural activation differences in the inferior and medial frontal and temporal/parietal regions of the response inhibition network between the different variants of both the HTR1B and 5HTT genes. Activation in these regions was significantly associated with stop-task performance, but not with ADHD diagnosis or severity. No associations were found between HTR1B and 5HTT variants and ADHD or ADHD-related neural activation. CONCLUSIONS: These results provide novel evidence that serotonin may play an important role in the neurobiology of response inhibition. Although response inhibition is strongly linked to ADHD, serotonin linked genetic variants associated with response inhibition and its neural correlates do not explain variance of the ADHD phenotype. PMID- 26428551 TI - Looking forward and looking back: the balancing act in new drug user designs for pharmacoepidemiological research. PMID- 26428552 TI - Editorial: The pre-history of Chaos-An Interdisciplinary Journal of Nonlinear Science. PMID- 26428553 TI - Introduction to Focus Issue: The 25th Anniversary of Chaos: Perspectives on Nonlinear Science-Past, Present, and Future. PMID- 26428554 TI - Quantum and wave dynamical chaos in superconducting microwave billiards. AB - Experiments with superconducting microwave cavities have been performed in our laboratory for more than two decades. The purpose of the present article is to recapitulate some of the highlights achieved. We briefly review (i) results obtained with flat, cylindrical microwave resonators, so-called microwave billiards, concerning the universal fluctuation properties of the eigenvalues of classically chaotic systems with no, a threefold and a broken symmetry; (ii) summarize our findings concerning the wave-dynamical chaos in three-dimensional microwave cavities; (iii) present a new approach for the understanding of the phenomenon of dynamical tunneling which was developed on the basis of experiments that were performed recently with unprecedented precision, and finally, (iv) give an insight into an ongoing project, where we investigate universal properties of (artificial) graphene with superconducting microwave photonic crystals that are enclosed in a microwave resonator, i.e., so-called Dirac billiards. PMID- 26428555 TI - Thirty years of turnstiles and transport. AB - To characterize transport in a deterministic dynamical system is to compute exit time distributions from regions or transition time distributions between regions in phase space. This paper surveys the considerable progress on this problem over the past thirty years. Primary measures of transport for volume-preserving maps include the exiting and incoming fluxes to a region. For area-preserving maps, transport is impeded by curves formed from invariant manifolds that form partial barriers, e.g., stable and unstable manifolds bounding a resonance zone or cantori, the remnants of destroyed invariant tori. When the map is exact volume preserving, a Lagrangian differential form can be used to reduce the computation of fluxes to finding a difference between the actions of certain key orbits, such as homoclinic orbits to a saddle or to a cantorus. Given a partition of phase space into regions bounded by partial barriers, a Markov tree model of transport explains key observations, such as the algebraic decay of exit and recurrence distributions. PMID- 26428556 TI - Dynamical disease: Challenges for nonlinear dynamics and medicine. AB - Dynamical disease refers to illnesses that are associated with striking changes in the dynamics of some bodily function. There is a large literature in mathematics and physics which proposes mathematical models for the physiological systems and carries out analyses of the properties of these models using nonlinear dynamics concepts involving analyses of the stability and bifurcations of attractors. This paper discusses how these concepts can be applied to medicine. PMID- 26428557 TI - Invariant manifolds and global bifurcations. AB - Invariant manifolds are key objects in describing how trajectories partition the phase spaces of a dynamical system. Examples include stable, unstable, and center manifolds of equilibria and periodic orbits, quasiperiodic invariant tori, and slow manifolds of systems with multiple timescales. Changes in these objects and their intersections with variation of system parameters give rise to global bifurcations. Bifurcation manifolds in the parameter spaces of multi-parameter families of dynamical systems also play a prominent role in dynamical systems theory. Much progress has been made in developing theory and computational methods for invariant manifolds during the past 25 years. This article highlights some of these achievements and remaining open problems. PMID- 26428558 TI - Chaos, patterns, coherent structures, and turbulence: Reflections on nonlinear science. AB - The paradigms of nonlinear science were succinctly articulated over 25 years ago as deterministic chaos, pattern formation, coherent structures, and adaptation/evolution/learning. For chaos, the main unifying concept was universal routes to chaos in general nonlinear dynamical systems, built upon a framework of bifurcation theory. Pattern formation focused on spatially extended nonlinear systems, taking advantage of symmetry properties to develop highly quantitative amplitude equations of the Ginzburg-Landau type to describe early nonlinear phenomena in the vicinity of critical points. Solitons, mathematically precise localized nonlinear wave states, were generalized to a larger and less precise class of coherent structures such as, for example, concentrated regions of vorticity from laboratory wake flows to the Jovian Great Red Spot. The combination of these three ideas was hoped to provide the tools and concepts for the understanding and characterization of the strongly nonlinear problem of fluid turbulence. Although this early promise has been largely unfulfilled, steady progress has been made using the approaches of nonlinear science. I provide a series of examples of bifurcations and chaos, of one-dimensional and two dimensional pattern formation, and of turbulence to illustrate both the progress and limitations of the nonlinear science approach. As experimental and computational methods continue to improve, the promise of nonlinear science to elucidate fluid turbulence continues to advance in a steady manner, indicative of the grand challenge nature of strongly nonlinear multi-scale dynamical systems. PMID- 26428559 TI - Cycles, randomness, and transport from chaotic dynamics to stochastic processes. AB - An overview of advances at the frontier between dynamical systems theory and nonequilibrium statistical mechanics is given. Sensitivity to initial conditions is a mechanism at the origin of dynamical randomness-alias temporal disorder-in deterministic dynamical systems. In spatially extended systems, sustaining transport processes, such as diffusion, relationships can be established between the characteristic quantities of dynamical chaos and the transport coefficients, bringing new insight into the second law of thermodynamics. With methods from dynamical systems theory, the microscopic time-reversal symmetry can be shown to be broken at the statistical level of description in nonequilibrium systems. In this way, the thermodynamic entropy production turns out to be related to temporal disorder and its time asymmetry away from equilibrium. PMID- 26428560 TI - Self-organization of pulsing and bursting in a CO2 laser with opto-electronic feedback. AB - We report a detailed investigation of the stability of a CO2 laser with feedback as described by a six-dimensional rate-equations model which provides satisfactory agreement between numerical and experimental results. We focus on experimentally accessible parameters, like bias voltage, feedback gain, and the bandwidth of the feedback loop. The impact of decay rates and parameters controlling cavity losses are also investigated as well as control planes which imply changes of the laser physical medium. For several parameter combinations, we report stability diagrams detailing how laser spiking and bursting is organized over extended intervals. Laser pulsations are shown to emerge organized in several hitherto unseen regular and irregular phases and to exhibit a much richer and complex range of behaviors than described thus far. A significant observation is that qualitatively similar organization of laser spiking and bursting can be obtained by tuning rather distinct control parameters, suggesting the existence of unexpected symmetries in the laser control space. PMID- 26428561 TI - From globally coupled maps to complex-systems biology. AB - Studies of globally coupled maps, introduced as a network of chaotic dynamics, are briefly reviewed with an emphasis on novel concepts therein, which are universal in high-dimensional dynamical systems. They include clustering of synchronized oscillations, hierarchical clustering, chimera of synchronization and desynchronization, partition complexity, prevalence of Milnor attractors, chaotic itinerancy, and collective chaos. The degrees of freedom necessary for high dimensionality are proposed to equal the number in which the combinatorial exceeds the exponential. Future analysis of high-dimensional dynamical systems with regard to complex-systems biology is briefly discussed. PMID- 26428562 TI - Complex network based techniques to identify extreme events and (sudden) transitions in spatio-temporal systems. AB - We present here two promising techniques for the application of the complex network approach to continuous spatio-temporal systems that have been developed in the last decade and show large potential for future application and development of complex systems analysis. First, we discuss the transforming of a time series from such systems to a complex network. The natural approach is to calculate the recurrence matrix and interpret such as the adjacency matrix of an associated complex network, called recurrence network. Using complex network measures, such as transitivity coefficient, we demonstrate that this approach is very efficient for identifying qualitative transitions in observational data, e.g., when analyzing paleoclimate regime transitions. Second, we demonstrate the use of directed spatial networks constructed from spatio-temporal measurements of such systems that can be derived from the synchronized-in-time occurrence of extreme events in different spatial regions. Although there are many possibilities to investigate such spatial networks, we present here the new measure of network divergence and how it can be used to develop a prediction scheme of extreme rainfall events. PMID- 26428563 TI - Nonlinear time-series analysis revisited. AB - In 1980 and 1981, two pioneering papers laid the foundation for what became known as nonlinear time-series analysis: the analysis of observed data-typically univariate-via dynamical systems theory. Based on the concept of state-space reconstruction, this set of methods allows us to compute characteristic quantities such as Lyapunov exponents and fractal dimensions, to predict the future course of the time series, and even to reconstruct the equations of motion in some cases. In practice, however, there are a number of issues that restrict the power of this approach: whether the signal accurately and thoroughly samples the dynamics, for instance, and whether it contains noise. Moreover, the numerical algorithms that we use to instantiate these ideas are not perfect; they involve approximations, scale parameters, and finite-precision arithmetic, among other things. Even so, nonlinear time-series analysis has been used to great advantage on thousands of real and synthetic data sets from a wide variety of systems ranging from roulette wheels to lasers to the human heart. Even in cases where the data do not meet the mathematical or algorithmic requirements to assure full topological conjugacy, the results of nonlinear time-series analysis can be helpful in understanding, characterizing, and predicting dynamical systems. PMID- 26428564 TI - Synchronization of chaotic systems. AB - We review some of the history and early work in the area of synchronization in chaotic systems. We start with our own discovery of the phenomenon, but go on to establish the historical timeline of this topic back to the earliest known paper. The topic of synchronization of chaotic systems has always been intriguing, since chaotic systems are known to resist synchronization because of their positive Lyapunov exponents. The convergence of the two systems to identical trajectories is a surprise. We show how people originally thought about this process and how the concept of synchronization changed over the years to a more geometric view using synchronization manifolds. We also show that building synchronizing systems leads naturally to engineering more complex systems whose constituents are chaotic, but which can be tuned to output various chaotic signals. We finally end up at a topic that is still in very active exploration today and that is synchronization of dynamical systems in networks of oscillators. PMID- 26428565 TI - Recent advances in symmetric and network dynamics. AB - We summarize some of the main results discovered over the past three decades concerning symmetric dynamical systems and networks of dynamical systems, with a focus on pattern formation. In both of these contexts, extra constraints on the dynamical system are imposed, and the generic phenomena can change. The main areas discussed are time-periodic states, mode interactions, and non-compact symmetry groups such as the Euclidean group. We consider both dynamics and bifurcations. We summarize applications of these ideas to pattern formation in a variety of physical and biological systems, and explain how the methods were motivated by transferring to new contexts Rene Thom's general viewpoint, one version of which became known as "catastrophe theory." We emphasize the role of symmetry-breaking in the creation of patterns. Topics include equivariant Hopf bifurcation, which gives conditions for a periodic state to bifurcate from an equilibrium, and the H/K theorem, which classifies the pairs of setwise and pointwise symmetries of periodic states in equivariant dynamics. We discuss mode interactions, which organize multiple bifurcations into a single degenerate bifurcation, and systems with non-compact symmetry groups, where new technical issues arise. We transfer many of the ideas to the context of networks of coupled dynamical systems, and interpret synchrony and phase relations in network dynamics as a type of pattern, in which space is discretized into finitely many nodes, while time remains continuous. We also describe a variety of applications including animal locomotion, Couette-Taylor flow, flames, the Belousov Zhabotinskii reaction, binocular rivalry, and a nonlinear filter based on anomalous growth rates for the amplitude of periodic oscillations in a feed forward network. PMID- 26428566 TI - From chemical systems to systems chemistry: Patterns in space and time. AB - We present a brief, idiosyncratic overview of the past quarter century of progress in nonlinear chemical dynamics and discuss what we view as the most exciting recent developments and some challenges and likely areas of progress in the next 25 years. PMID- 26428567 TI - Some new surprises in chaos. AB - "Chaos is found in greatest abundance wherever order is being sought.It always defeats order, because it is better organized"Terry PratchettA brief review is presented of some recent findings in the theory of chaotic dynamics. We also prove a statement that could be naturally considered as a dual one to the Poincare theorem on recurrences. Numerical results demonstrate that some parts of the phase space of chaotic systems are more likely to be visited earlier than other parts. A new class of chaotic focusing billiards is discussed that clearly violates the main condition considered to be necessary for chaos in focusing billiards. PMID- 26428568 TI - Exploiting chaos for applications. AB - We discuss how understanding the nature of chaotic dynamics allows us to control these systems. A controlled chaotic system can then serve as a versatile pattern generator that can be used for a range of application. Specifically, we will discuss the application of controlled chaos to the design of novel computational paradigms. Thus, we present an illustrative research arc, starting with ideas of control, based on the general understanding of chaos, moving over to applications that influence the course of building better devices. PMID- 26428569 TI - Dynamics of globally coupled oscillators: Progress and perspectives. AB - In this paper, we discuss recent progress in research of ensembles of mean field coupled oscillators. Without an ambition to present a comprehensive review, we outline most interesting from our viewpoint results and surprises, as well as interrelations between different approaches. PMID- 26428570 TI - Lagrangian based methods for coherent structure detection. AB - There has been a proliferation in the development of Lagrangian analytical methods for detecting coherent structures in fluid flow transport, yielding a variety of qualitatively different approaches. We present a review of four approaches and demonstrate the utility of these methods via their application to the same sample analytic model, the canonical double-gyre flow, highlighting the pros and cons of each approach. Two of the methods, the geometric and probabilistic approaches, are well established and require velocity field data over the time interval of interest to identify particularly important material lines and surfaces, and influential regions, respectively. The other two approaches, implementing tools from cluster and braid theory, seek coherent structures based on limited trajectory data, attempting to partition the flow transport into distinct regions. All four of these approaches share the common trait that they are objective methods, meaning that their results do not depend on the frame of reference used. For each method, we also present a number of example applications ranging from blood flow and chemical reactions to ocean and atmospheric flows. PMID- 26428571 TI - Defining chaos. AB - In this paper, we propose, discuss, and illustrate a computationally feasible definition of chaos which can be applied very generally to situations that are commonly encountered, including attractors, repellers, and non-periodically forced systems. This definition is based on an entropy-like quantity, which we call "expansion entropy," and we define chaos as occurring when this quantity is positive. We relate and compare expansion entropy to the well-known concept of topological entropy to which it is equivalent under appropriate conditions. We also present example illustrations, discuss computational implementations, and point out issues arising from attempts at giving definitions of chaos that are not entropy-based. PMID- 26428572 TI - The joy of transient chaos. AB - We intend to show that transient chaos is a very appealing, but still not widely appreciated, subfield of nonlinear dynamics. Besides flashing its basic properties and giving a brief overview of the many applications, a few recent transient-chaos-related subjects are introduced in some detail. These include the dynamics of decision making, dispersion, and sedimentation of volcanic ash, doubly transient chaos of undriven autonomous mechanical systems, and a dynamical systems approach to energy absorption or explosion. PMID- 26428573 TI - Beyond the KdV: Post-explosion development. AB - Several threads of the last 25 years' developments in nonlinear wave theory that stem from the classical Korteweg-de Vries (KdV) equation are surveyed. The focus is on various generalizations of the KdV equation which include higher-order nonlinearity, large-scale dispersion, and a non-local integral dispersion. We also discuss how relatively simple models can capture strongly nonlinear dynamics and how various modifications of the KdV equation lead to qualitatively new, non trivial solutions and regimes of evolution observable in the laboratory and in nature. As the main physical example, we choose internal gravity waves in the ocean for which all these models are applicable and have genuine importance. We also briefly outline the authors' view of the future development of the chosen lines of nonlinear wave theory. PMID- 26428575 TI - Granular chaos and mixing: Whirled in a grain of sand. AB - In this paper, we overview examples of chaos in granular flows. We begin by reviewing several remarkable behaviors that have intrigued researchers over the past few decades, and we then focus on three areas in which chaos plays an intrinsic role in granular behavior. First, we discuss pattern formation in vibrated beds, which we show is a direct result of chaotic scattering combined with dynamical dissipation. Next, we consider stick-slip motion, which involves chaotic scattering on the micro-scale, and which results in complex and as yet unexplained peculiarities on the macro-scale. Finally, we examine granular mixing, which we show combines micro-scale chaotic scattering and macro-scale stick-slip motion into behaviors that are well described by dynamical systems tools, such as iterative mappings. PMID- 26428574 TI - Networkcontrology. AB - An increasing number of complex systems are now modeled as networks of coupled dynamical entities. Nonlinearity and high-dimensionality are hallmarks of the dynamics of such networks but have generally been regarded as obstacles to control. Here, I discuss recent advances on mathematical and computational approaches to control high-dimensional nonlinear network dynamics under general constraints on the admissible interventions. I also discuss the potential of network control to address pressing scientific problems in various disciplines. PMID- 26428576 TI - Advanced treatment of biologically pretreated coal gasification wastewater by a novel integration of three-dimensional catalytic electro-Fenton and membrane bioreactor. AB - Laboratorial scale experiments were conducted to investigate a novel system three dimensional catalytic electro-Fenton (3DCEF, catalyst of sewage sludge based activated carbon which loaded Fe3O4) integrating with membrane bioreactor (3DCEF MBR) on advanced treatment of biologically pretreated coal gasification wastewater. The results indicated that 3DCEF-MBR represented high efficiencies in eliminating COD and total organic carbon, giving the maximum removal efficiencies of 80% and 75%, respectively. The integrated 3DCEF-MBR system significantly reduced the transmembrane pressure, giving 35% lower than conventional MBR after 30 days operation. The enhanced hydroxyl radical oxidation and bacteria self repair function were the mechanisms for 3DCEF-MBR performance. Therefore, the integrated 3DCEF-MBR was expected to be the promising technology for advanced treatment in engineering applications. PMID- 26428577 TI - Reflectance confocal microscopy features of acral lentiginous melanoma: a comparative study with acral nevi. AB - BACKGROUND: Acral lentiginous melanoma (ALM) can be difficult to differentiate from acral nevus. Reflectance confocal microscopy (RCM) is widely used for the diagnosis of melanocytic tumours, but the RCM features of ALM and acral nevus have not been described yet. OBJECTIVE: To determine the RCM features of ALM and acral nevus, and their correlation with clinical and histological characteristics. METHODS: Retrospective study of 17 cases of ALM and 26 acral nevi. RESULTS: Pagetoid cells were present in all ALMs with a visible epidermis and in three nevi. A proliferation of atypical melanocytes at the dermal epidermal junction (DEJ) and/or in the dermis was visible in nine ALMs but not in nevi. The histopathological examination of initial skin biopsies was unable to diagnose ALM in four cases, differing from RCM that could identify malignant tumour cells by exploring the whole lesions. CONCLUSION: Reflectance confocal microscopy can help in the differentiation of ALM and acral nevus, and to guide the biopsy. PMID- 26428578 TI - Exploring the roles of basal transcription factor 3 in eukaryotic growth and development. AB - Basal transcription factor 3 (BTF3) has been reported to play a significant part in the transcriptional regulation linking with eukaryotes growth and development. Alteration in the BTF3 gene expression patterns or variation in their activities adds to the explanation of different signaling pathways and regulatory networks. Moreover, BTF3s often respond to numerous stresses, and subsequently they are involved in regulation of various mechanisms. BTF3 proteins also function through protein-protein contact, which can assist us to identify the multifaceted processes of signaling and transcriptional regulation controlled by BTF3 proteins. In this review, we discuss current advances made in starting to explore the roles of BTF3 transcription factors in eukaryotes especially in plant growth and development. PMID- 26428580 TI - Developing the Evidence Base for Interventions for International Child Health. PMID- 26428579 TI - Nicotine inhibits hippocampal and striatal acetylcholinesterase activities, and demonstrates dual action on adult neuronal proliferation and maturation. AB - AIM: The present study investigated the effects of nicotine on acetylcholinesterase (AChE) activities in the hippocampus and striatum; and on immunoreactivity of certain neurogenic markers in the dentate gyrus (DG) of the hippocampus. METHODS: Male rats were given daily subcutaneous injections of nicotine at doses of 0.25, 2 or 4mg/kg body weight for 28 days. Animals were euthanized by cervical dislocation at the end of administration. Brains were excised and processed for histochemical demonstration of AChE and immunohistochemical studies of Ki67, GFAP and NSE. RESULTS: There was significant decrease (P<0.001) in AChE positive cells in the hippocampus and striatum following 2 and 4mg/kg nicotine but not at 0.25mg/kg. Nicotine treatment at 0.25 and 4mg/kg significantly decrease (P<0.05) immunoreactivity of Ki67 and NSE in DG. Contrastingly, 2mg/kg nicotine did not alter Ki67 immunoreactivity but rather significantly increased (P<0.05) NSE immunoreactivity in DG compared to control. CONCLUSION: This study suggests that nicotine may inhibit AChE activities in the brain, thereby having a direct or indirect influence on prevention of central acetylcholine degradation, as well as either improve or retard maturation adult born neurons in DG, at different doses. PMID- 26428581 TI - Non-typhoidal Salmonella infections in HIV-positive adults. AB - Non-typhoidal salmonellae are important pathogens causing bacteraemia, especially in immunocompromised patients, but there are limited data explicitly describing the clinical characteristics and outcome in these individuals. Recurrent invasive salmonellosis has been recognised as an AIDS-defining condition in HIV-positive patients since the 1980s. Salmonella meningitis is an infrequent complication of Salmonella sepsis, accounting for 0.8-6% of all cases of bacterial meningitis, and is associated with a high mortality rate. PMID- 26428582 TI - Indications for the use of bronchial thermoplasty in severe asthma. AB - Approximately 5% of the ~3 million asthmatics in South Africa have severe asthma that is associated with substantial morbidity, cost, absenteeism, preventable mortality, and the requirement for costly chronic medication that may be associated with significant adverse events. There is an unmet need for alternative safer and more effective interventions for severe asthma. A recently introduced option, bronchial thermoplasty (BT), imparts radiofrequency-generated heat energy to the airways to cause regression of airway smooth muscle. The effectiveness of this technique has been confirmed in randomised control trials and is now endorsed by several international guidelines, including the Global Initiative for Asthma (GINA) guideline, the British Asthma Guideline, and the UK National Institute of Clinical Excellence (NICE) guideline. We recommend BT as a potential therapeutic intervention for severe uncontrolled asthma, provided that it is performed by an experienced pulmonologist at an accredited centre and done within the broader context of appropriate management of the disease by doctors experienced in treating difficult-to-control asthma. PMID- 26428583 TI - Recommendations for the use of endoscopic lung volume reduction in South Africa: Role in the treatment of emphysema. AB - Emphysema is a very common cause of morbidity and mortality in South Africa (SA). Therapeutic options in severe emphysema are limited. Endoscopic lung volume reduction (ELVR) is increasingly being used internationally for the treatment of advanced emphysema in a subset of patients with advanced disease, aiming to obtain the same functional advantages as surgical lung volume reduction while reducing risks and costs. In addition to endobronchial valves, ELVR using endobronchial coils is now available in SA. The high cost of these interventions underscores the need for careful patient selection to best identify those who may or may not benefit from ELVR-related procedures. The Assembly on Interventional Pulmonology of the South African Thoracic Society appointed a committee comprising both local and international experts to extensively review all relevant evidence and provide advice on the use of ELVR in SA based on published evidence, expert opinion and local access to the various devices. PMID- 26428584 TI - Impact of transthoracic echocardiography at district hospital level. AB - BACKGROUND: The use of and demand for echocardiography (ECHO) has increased worldwide. In developed countries, this has not translated into improved access outside tertiary centres. Previous studies have favoured the appropriate use of ECHO over its clinical impact, limiting generalisability to resource-constrained settings. OBJECTIVES: To assess the impact of an ECHO service at district hospital level in Cape Town, South Africa. METHODS: A prospective, cross sectional study was performed. A total of 210 consecutive patients, referred to the ECHO clinic over a 5-month period, were recruited. Transthoracic ECHO was evaluated in terms of its indication, new information provided, correlation with the referring doctor's diagnosis and subsequent management plan. Impact included the escalation and de-escalation of treatment, as well as usefulness without a change in management. RESULTS: The results show that 83.8% of the patients' management was impacted on by echocardiography. Valvular lesions were the main indication. The most frequent contribution was information provided towards the diagnosis of heart failure and assessment after myocardial infarction. Of the echocardiograms, 56.2% confirmed the referring doctor's diagnosis, yet were still associated with a significant impact. The rational prescription of medication had the major impetus, followed by de-escalation of therapy and screening patients to determine referral to a tertiary facility. CONCLUSION: ECHO has a positive impact on patient management outside tertiary settings, where the definition of impact appears to be different. The value of a normal study, screening prior to upstream referral and usefulness irrespective of change have been established. This should alert policy makers against restriction of access to ECHO and promote training of personnel in its use. PMID- 26428585 TI - The wrong and wounding road: Paediatric polytrauma admitted to a level 1 trauma intensive care unit over a 5-year period. AB - BACKGROUND: Injury in childhood is a major cause of potentially preventable morbidity and mortality. In order to implement effective preventive strategies, epidemiological data on mechanisms of injury and outcome are essential. OBJECTIVES: To assess the causation, severity of injury, morbidity and mortality of paediatric trauma admitted to a level 1 trauma intensive care unit (TICU). METHODS: Children were defined as being <16 years of age. The study covered the 5 year period January 2008-December 2012. Eligible patients were identified from a prospective database maintained in the level 1 TICU at Inkosi Albert Luthuli Central Hospital, Durban, South Africa. Data extracted were referral source, mechanism of injury, age and gender distribution, injury severity score (ISS), anatomical distribution of injury and mortality. RESULTS: A total of 181 patients admitted during the study period accounted for 15.9% of all admissions. There were 84 females (46.4%) and 97 males (53.6%), with a median age of 7 years (interquartile range (IQR) 4-10). Sources of admission were directly from the scene in 38 cases (21.0%), from a primary healthcare facility in 47 (26.0%), from a regional hospital in 56 (31.0%) and from a tertiary facility in 40 (22.0%). Mortality rates according to location of transfer were regional hospital 8 deaths (30.8%), tertiary facility 7 (26.9%), primary health clinic 7 (26.9%), and from the scene 4 (15.4%). Mechanisms of injury were pedestrian-motor vehicle collision (PMVC) in 105 cases (58.0%), motor vehicle passenger in 38 (21.0%), non-vehicular blunt trauma in 18 (10.0%), gunshot wounds (GSWs) in 12 (6.6%), stab wounds in 6 (3.3%), bull goring in 1 (0.5%) and bicycle accident 1 (0.5%). The median ISS for all admissions was 25 (IQR 16-38). ISSs were >25 in 98 patients (54.1%), 16-25 in 51 (28.2%), 9-15 in 9 (4.9%) and <9 in 13 (7.2%); 61.9% of patients had head injuries, 48.1% injuries to the extremities, 41.4% abdominal trauma, 40.3% thoracic trauma, 20.4% external soft-tissue trauma, 9.9% cervical injury and 9.4% facial trauma. There were 26 deaths (14.4%), of which PMVCs accounted for 16 (61.5%), motor vehicle passengers for 7 (26.9%), blunt trauma for 2 (7.7%) and GSWs for 1 (3.8%). The majority of deaths (92%) were of patients with an ISS>25. Of the 26 patients who died, 88.4% had a head injury, 46.2% an extremity injury, 38.5% an external injury, 34.6% abdominal or chest injuries, 19.2% neck injury and 11.5% facial injury. CONCLUSIONS: Motor vehicle-related injuries, especially PMVCs, dominate severe paediatric trauma and there is an urgent need for more road traffic education and stringent measures to decrease the incidence and associated morbidity and mortality. PMID- 26428586 TI - Interpersonal violence as a major contributor towards the skewed burden of trauma in KwaZulu-Natal, South Africa. AB - BACKGROUND: Trauma is one of the foremost causes of death worldwide, but there is a paucity of data on demographics and injury patterns in developing countries. OBJECTIVES: To quantify and describe the major trauma burden at a regional hospital in KwaZulu-Natal (KZN), South Africa (SA), over a 5-year period. METHODS: Ngwelezane Hospital is a large regional hospital in northern KZN. A database is maintained of all major trauma patients admitted to the Emergency Department (ED) resuscitation unit. Statistical analysis was performed to quantify the burden of trauma and analyse trends in these data. RESULTS: Over a 5 year period, 3 735 major trauma patients were admitted to the ED resuscitation unit. Analysis showed a male predominance, with a mean patient age of 28.6 years. An average of 62 patients per month were admitted, the rate peaking over the holiday seasons. Trauma secondary to interpersonal violence (IPV) predominated. A disproportionately high level of pedestrian-motor vehicle collisions (PMVCs) in relation to total road traffic collisions was noted. Blunt force trauma secondary to motor vehicle collisions was the leading cause of death, while blunt force trauma secondary to PMVC s carried the highest mortality rate. CONCLUSION: This study highlights the high incidences of both IPV and PMVCs typical of trauma in an SA setting. The demographics and injury patterns noted may be used to drive public health interventions to address this burden of trauma. PMID- 26428587 TI - The epidemiology of major incidents in the Western Cape Province, South Africa. AB - BACKGROUND: Major incidents put pressure on any health system. There are currently no studies describing the epidemiology of major incidents in South Africa (SA). The lack of data makes planning for major incidents and exercising of major incident plans difficult. OBJECTIVE: To describe the epidemiology of major incidents in the Western Cape Province, SA. METHODS: A retrospective analysis of the Western Cape Major Incident database was conducted for the period 1 December 2008-30 June 2014. Variables collected related to patient demographics and incident details. Summary statistics were used to describe all variables. RESULTS: Seven hundred and seventy-seven major incidents were reviewed (median n=11 per month). Most major incidents occurred in the City of Cape Town (57.8%, n=449), but the Central Karoo district had the highest incidence (11.97/10 000 population). Transport-related incidents occurred most frequently (94.0%, n=730). Minibus taxis were involved in 312 major incidents (40.2%). There was no significant difference between times of day when incidents occurred. A total of 8,732 patients were injured (median n=8 per incident); ten incidents involved 50 or more victims. Most patients were adults (80.0%, n=6 986) and male (51.0%, n=4,455). Of 8,440 patients, 630 (7.5%) were severely injured. More than half of the patients sustained minor injuries (54.6%, n=4,605). CONCLUSION: Major incidents occurred more often than would have been expected compared with other countries, with road traffic crashes the biggest contributor. A national database will provide a better perspective of the burden of major incidents. PMID- 26428588 TI - Epidemiology of acute spinal cord injuries in the Groote Schuur Hospital Acute Spinal Cord Injury (GSH ASCI) Unit, Cape Town, South Africa, over the past 11 years. AB - BACKGROUND: Spinal cord injury (SCI) is devastating to both patient and society, with acute management and ongoing care being extremely expensive. Few epidemiological data are available on SCIs in South Africa (SA). OBJECTIVES: To identify the epidemiological profile of SCI patients at Groote Schuur Hospital (GSH), Cape Town, SA, and identify seasonal trends and peak periods. As the majority of the injuries are preventable, these data are important to develop prevention strategies. METHODS: A retrospective review of prospectively collected data was conducted on all patients admitted to the Acute Spinal Cord Injury (ASCI) Unit at GSH from 1 April 2003 to 31 March 2014. All cases registered on a prospectively maintained database were included in the study. RESULTS: The total number of patients admitted to the ASCI Unit was 2,042, with an average of 185 admissions per year. The male/female ratio was 5.25:1. The 21-30-year-old age category was the largest, comprising 33.5% of the patients. The most prevalent cause of injury was motor vehicle accidents (44.6%), followed by violence-related injuries (27.2%). Thirty-two point two per cent of patients needed ventilatory support, and 91.5% of mechanically ventilated patients were successfully weaned. December was the busiest month in the unit. In patients in whom neurological deficit was incomplete, the average motor function improvement was 16.0%. CONCLUSIONS: Data capturing and analysis of SCIs should be encouraged in SA to guide management and prevention strategies, and to optimise outcomes. This study establishes the ASCI Unit at GSH to be one of the key role players in acute SCI management in SA. PMID- 26428589 TI - Meeting national response time targets for priority 1 incidents in an urban emergency medical services system in South Africa: More ambulances won't help. AB - BACKGROUND: Response time is viewed as a key performance indicator in most emergency medical services (EMS) systems. OBJECTIVE: To determine the effect of increased emergency vehicle numbers on response time performance for priority 1 incidents in an urban EMS system in Cape Town, South Africa, using discrete-event computer simulation. METHOD: A simulation model was created, based on input data from part of the EMS operations. Two different versions of the model were used, one with primary response vehicles and ambulances and one with only ambulances. In both cases the models were run in seven different scenarios. The first scenario used the actual number of emergency vehicles in the real system, and in each subsequent scenario vehicle numbers were increased by adding the baseline number to the cumulative total. RESULTS: The model using only ambulances had shorter response times and a greater number of responses meeting national response time targets than models using primary response vehicles and ambulances. In both cases an improvement in response times and the number of responses meeting national response time targets was observed with the first incremental addition of vehicles. After this the improvements rapidly diminished and eventually became negligible with each successive increase in vehicle numbers. The national response time target for urban areas was never met, even with a seven-fold increase in vehicle numbers. CONCLUSION: The addition of emergency vehicles to an urban EMS system improves response times in priority 1 incidents, but alone is not capable of the magnitude of response time improvement needed to meet the national response time targets. PMID- 26428590 TI - The appropriateness of emergency medical service responses in the eThekwini district of KwaZulu-Natal, South Africa. AB - INTRODUCTION: Emergency medical services (EMS) are sometimes required to respond to cases that are later found not to be emergencies, resulting in high levels of inappropriate responses. This study evaluated the extent to which this occurs. METHODS: All cases dispatched over 72 hours by the eThekwini EMS in Durban, South Africa, were prospectively enrolled in a quantitative descriptive study. Vehicle control forms containing dispatch data were matched and compared with patient report forms containing epidemiological and clinical data to describe the nature and extent of inappropriate responses based on patient need. Data were subjected to simple descriptive analysis, correlations and chi2 testing. RESULTS: A total of 1 385 cases met the study inclusion criteria. Marked variations existed between dispatch and on-scene priority settings, most notably in the highest priority 'red-code' category, which constituted >56% of cases dispatched yet accounted for <2% at the scene (p<0.001). Conversely, >80% of 'red-code' dispatches required a lower priority response. When comparing resource allocation according to patient interventional needs, >58% of cases required either no intervention or transport only and almost 36% required basic life support intervention only (p<0.001). Moreover, <12% of advanced life support dispatches were for patients found to be 'red code' at the scene. CONCLUSION: There is a significant mismatch between the dispatch of EMS resources and actual patient need in the eThekwini district, with significantly high levels of inappropriate emergency responses. PMID- 26428591 TI - A 10-year review of fatal community assault cases at a regional forensic pathology facility in Cape Town, South Africa. AB - BACKGROUND: An increase in autopsied community assault (CA) fatalities was observed at the Tygerberg Forensic Pathology Services (FPS), Cape Town, South Africa (SA). There is a paucity of information on the incidence and prevalence of these cases in SA. OBJECTIVES: To determine the patterns and trends of injuries sustained in so-called CA fatalities. METHODS: A retrospective and descriptive study was conducted. Fatal CA cases admitted to the Tygerberg FPS over the 10 year period 1 January 2003-31 December 2012 were reviewed. Data were collected from autopsy/postmortem reports, contemporaneous notes, attached hospital records, the South African Police Services (SAPS) 180 form (completed by the SAPS representative) and other FPS documentation. RESULTS: A total of 424 cases of fatal CA were seen during the study period, with an annual increase between 2003 and 2007 and a second peak in 2012. The cause of death in most cases was multiple injuries (42.0%), with blunt-force trauma being the basis of most injuries sustained. The area with the greatest burden of injury was the township of Mfuleni (73 CA deaths per 100,000 population). There was a predominance of males, with only one female fatality recorded. CONCLUSION: Adequate policing in prevalent areas is essential to address unnecessary loss of life and the burden imposed by these cases on the criminal justice system and healthcare services. PMID- 26428592 TI - A review of primary and secondary burn services in the Western Cape, South Africa. AB - BACKGROUND: In 2011, the Department of Health of the Western Cape Province, South Africa, requested a review of current burn services in the province, with a view to formulating a more efficient and cost-effective service. This article considers the findings of the review and presents strategies to improve delivery of appropriate burn care at primary and secondary levels. METHODS: Surveys were conducted at eight rural and urban hospitals, two outreach workshops on burn care, four regional hospitals and at least 60 clinics in Cape Town and in the Western Cape as far as Ladismith. A survey on community management of paediatric burns was also included in the study. RESULTS: The incidence of burns was highest in the winter months, more than half of those affected were children, and the majority of burns were scalds from hot liquids. Most burn injuries managed at primary level were minor, with 75% of patients treated by nurse practitioners and discharged. The four regional secondary hospitals managed the majority of moderate to severe burns. There is room for improvement in terms of treatment facilities and consumables at all levels, regional hospitals being particularly restricted in terms of outdated equipment, a shortage of intensive care unit beds, and difficulties in transferring patients with major burns to a burns unit when indicated. CONCLUSION: The community management of paediatric burns was satisfactory, although considerable delays in transfer and insufficient pain control hampered appropriate care. A great need for ongoing education at all levels was identified. Ten strategies are presented that could, if implemented, lead to tangible improvements in the management of burn patients at primary and secondary levels in the Western Cape. PMID- 26428593 TI - Self-expanding metal stent placement for oesophageal cancer without fluoroscopy is safe and effective. AB - BACKGROUND: Self-expanding metal stents (SEMS) are widely used to palliate patients with oesophageal cancer. Placement is usually done under endoscopic and fluoroscopic guidance. We have developed an exclusively endoscopic technique to deploy these stents. This article documents the technique and periprocedural experience. PATIENTS AND METHODS: All patients who had SEMS placement for oesophageal cancer at Grey's Hospital, Pietermaritzburg, South Africa, over a 5 year period (2007-2011) were reviewed. Stenting was performed without radiological guidance using the technique documented in this article. At endoscopy, the oesophageal lesion was identified, dilated over a guidewire if necessary, and a partially covered stent was passed over the wire and positioned and deployed under direct vision. Data were captured from completed procedure forms and included demographics, tumour length, the presence of fistulas, stent size and immediate complications. RESULTS: A total of 480 SEMS were inserted, involving 453 patients, of whom 43 required repeat stenting. There were 185 female patients (40.8%) and 268 male patients (59.2%). The mean age was 60 years (range 38 - 101). There were 432 black patients (95.4%), 15 white patients (3.3%) and 6 Indian patients (1.3%). The reasons for palliative stenting were distributed as follows: age>70 years n=95 patients, tumour>8 cm n=142, tracheo oesophageal fistula (TOF) n=29, and unspecified n=170. One patient refused surgery, and one stent was placed for a post-oesophagectomy leak. Repeat stenting was for stent migration (n=15), tumour overgrowth (n=26) and a blocked stent and a stricture (n=1 each). Complications were recorded in six cases (1.3%): iatrogenic TOF (n=2), false tracts (n=3) and perforation (n=1). All six were nevertheless successfully stented. There was no periprocedural mortality. CONCLUSION: The endoscopic placement technique described is a viable and safe option with a low periprocedural complication rate. It is of particular use in situations of restricted access to fluoroscopic guidance. PMID- 26428594 TI - Pulmonary tuberculosis in a South African regional emergency centre: Can infection control be improved to lower the risk of nosocomial transmission? AB - BACKGROUND: George Regional Hospital (GRH) is a 272-bed regional referral hospital for the Eden and Central Karoo districts, Western Cape Province, South Africa. The perception among emergency centre (EC) staff is that a high burden of tuberculosis (TB) is being diagnosed and that infection control procedures are currently lacking, leading to a high risk of nosocomial transmission. OBJECTIVES: To establish the burden of pulmonary TB (PTB) presenting to GRH via the EC and audit current infection prevention and control practices, to quantify the risk of transmission of PTB in the EC and to establish whether infection control measures are inadequate. METHODS: An audit of infection control based on the Centers for Disease Control audit tool for TB, analysis of results, and implementation of new infection control measures including a new standard operating procedure based on a set of triage criteria. RESULTS: Implementation of new triage criteria and a standard operating procedure led to the longest length of stay of a patient with suspected TB in the EC being reduced by 40% (from 142 hours to 84 hours). The average time between seeing a doctor and leaving the EC for patients with suspected TB was reduced by 20% (from 20 hours 40 minutes to 16 hours 45 minutes). CONCLUSION: Simple measures implemented in the EC led to a significant reduction in the time patients with suspected or confirmed TB spent in the EC. This should lead to a reduced risk of nosocomial transmission of TB to both staff and patients. PMID- 26428595 TI - Prevalence of breast tuberculosis: Retrospective analysis of 65 patients attending a tertiary hospital in Durban, South Africa. AB - BACKGROUND: Breast tuberculosis (BTB) is uncommon, but not rare. Knowledge of the ways in which it can present can prevent unnecessary invasive procedures and delay in diagnosis. OBJECTIVES: To describe the clinical and radiological findings in patients with BTB, including evaluation of current treatment methods. METHODS: We retrospectively analysed 65 patients diagnosed with BTB at Addington and King Edward VIII hospitals, Durban, South Africa, between 2000 and 2013. Demographic, clinical and radiological findings and treatment outcomes were noted. RESULTS: A total of 11,092 patients underwent breast investigations between 2009 and 2013, with a prevalence of BTB for the period of 0.3% (30 patients). Of the 65 patients diagnosed between 2000 and 2013, 64 were female (98.5%) and one was male (1.5%). The age range was 23-69 years (mean 38.5). The most common mammographic pattern was density (39.4%) and the least common a mass (6.1%). Isolated axillary lymphadenitis was found in 12.1%. Abscess was the commonest ultrasound pattern (39.0%). Of the 47 patients with a known history of pulmonary tuberculosis (TB), 68.1% (n=32) did not have radiological evidence of previous or concurrent pulmonary TB, nor was there evidence of TB elsewhere. Of 47 patients with known HIV status, 34 were HIV-positive. Fine-needle aspiration cytology had sensitivity of only 28% compared with 94% for histology. Of those treated, 72.7% obtained full resolution following 9 months of TB treatment; 25.0% did not complete treatment, and 2.3% (n=1) died while on treatment. Follow-up data on relapse rates after treatment completion and disease resolution are scanty. CONCLUSION: Understanding and being aware of the various presentations of BTB make it possible to treat most patients successfully. PMID- 26428596 TI - Prenatal BoBsTM in the cytogenetic analysis of products of spontaneous miscarriage. AB - BACKGROUND: Fifty percent of spontaneous miscarriages (SMs) are attributed to chromosomal abnormalities. Cytogenetic analysis is an important tool for patient counselling and assessment of the risk of recurrence in future pregnancies. Conventional karyotyping has been the gold standard for chromosomal investigation of products of conception (POC), but it has limitations due to sample maceration, culture failure and maternal cell contamination. Molecular cytogenetic approaches have therefore been developed and found valuable in the cytogenetic investigation of these samples. The Prenatal BoBsTM and KaryoLite BoBsTM, based on the newly developed BACs-on-BeadsTM technology, have been described as reliable tests for rapid detection of aneuploidies in prenatal and POC samples, respectively. OBJECTIVE: To describe our clinical experience of routine screening of POC samples with Prenatal BoBsTM, the test used by our laboratory in France. METHODS: Seventeen samples collected at the University Hospital of Sidi Bel Abbes (Western Algeria) and a further 60 from the University Hospital of Clermont-Ferrand (France) were analysed (19 chorionic villi from products of curettage, 12 placentas, 9 amniotic cells and 37 biopsy specimens). All were screened for the frequent aneuploidies (chromosomes 13, 18, 21, X and Y) in addition to nine microdeletion/microduplication syndrome regions by Prenatal BoBsTM. Standard karyotyping was performed on 51 samples, but failed in 38 cases. RESULTS: Prenatal BoBsTM identified one trisomy 21 and one deletion of 17p13.3. Furthermore, it provided a conclusive result in cases of culture failure (n=38) and in samples with macerated tissue (n=19). The overall failure rate was 11.4%. CONCLUSIONS: Prenatal BoBsTM is a promising technology that represents a fast, sensitive and robust alternative to routine screening for chromosomal abnormality in products of SM. Furthermore, it overcomes the limitations of conventional karyotyping and current molecular cytogenetic techniques. PMID- 26428597 TI - Geography should be taught at medical school. PMID- 26428598 TI - Compressed sensing of ECG signal for wireless system with new fast iterative method. AB - Recent experiments in wireless body area network (WBAN) show that compressive sensing (CS) is a promising tool to compress the Electrocardiogram signal ECG signal. The performance of CS is based on algorithms use to reconstruct exactly or approximately the original signal. In this paper, we present two methods work with absence and presence of noise, these methods are Least Support Orthogonal Matching Pursuit (LS-OMP) and Least Support Denoising-Orthogonal Matching Pursuit (LSD-OMP). The algorithms achieve correct support recovery without requiring sparsity knowledge. We derive an improved restricted isometry property (RIP) based conditions over the best known results. The basic procedures are done by observational and analytical of a different Electrocardiogram signal downloaded them from PhysioBankATM. Experimental results show that significant performance in term of reconstruction quality and compression rate can be obtained by these two new proposed algorithms, and help the specialist gathering the necessary information from the patient in less time if we use Magnetic Resonance Imaging (MRI) application, or reconstructed the patient data after sending it through the network. PMID- 26428599 TI - MioLab, a rat cardiac contractile force simulator: Applications to teaching cardiac cell physiology and biophysics. AB - INTRODUCTION: Understanding the basic concepts of physiology and biophysics of cardiac cells can be improved by virtual experiments that illustrate the complex excitation-contraction coupling process in cardiac cells. The aim of this study is to propose a rat cardiac myocyte simulator, with which calcium dynamics in excitation-contraction coupling of an isolated cell can be observed. This model has been used in the course "Mathematical Modeling and Simulation of Biological Systems". In this paper we present the didactic utility of the simulator MioLab((r)). METHODS: The simulator enables virtual experiments that can help studying inhibitors and activators in the sarcoplasmic reticulum sodium-calcium exchanger, thus corroborating a better understanding of the effects of medications, which are used to treat arrhythmias, on these compartments. The graphical interfaces were developed not only to facilitate the use of the simulator, but also to promote a constructive learning on the subject, since there are animations and videos for each stage of the simulation. The effectiveness of the simulator was tested by a group of graduate students. RESULTS: Some examples of simulations were presented in order to describe the overall structure of the simulator. Part of these virtual experiments became an activity for Biomedical Engineering graduate students, who evaluated the simulator based on its didactic quality. As a result, students answered a questionnaire on the usability and functionality of the simulator as a teaching tool. All students performed the proposed activities and classified the simulator as an optimal or good learning tool. In their written questions, students indicated as negative characteristics some problems with visualizing graphs; as positive characteristics, they indicated the simulator's didactic function, especially tutorials and videos on the topic of this study. CONCLUSIONS: The results show that the simulator complements the study of the physiology and biophysics of the cardiac cell. PMID- 26428600 TI - Congenital Mirror Movements in a 7-Year-Old Boy. PMID- 26428601 TI - [Solitary tuberculous lesion of the right frontal lobe mimicking a malignant tumor]. PMID- 26428602 TI - Update on the epidemiology, diagnosis, and treatment of leprosy. AB - Leprosy is an infectious disease that has now been reported for more than 2000 years. The leprosy elimination goal set by the World Health Organization (WHO), i.e. a global prevalence rate <1 patient per 10,000 population, was achieved in the year 2000, but more than 200,000 new case patients are still reported each year, particularly in India, Brazil, and Indonesia. Leprosy is a specific infection: (i) it is a chronic infection primarily affecting the skin and peripheral nerves, (ii) Mycobacterium leprae is one of the last bacterial species of medical interest that cannot be cultured in vitro (mainly because of its reductive genome evolution), and (iii) transmission and pathophysiological data is still limited. The various presentations of the disease (Ridley-Jopling and WHO classifications) are correlated with the patient's immune response, bacillary load, and by the delay before diagnosis. Multidrug therapy (dapsone, rifampicin, with or without clofazimine) has been recommended since 1982 as the standard treatment of leprosy; 6 months for patients presenting with paucibacillary leprosy and 12 months for patients presenting with multibacillary leprosy. The worldwide use of leprosy drugs started in the 1980s and their free access since 1995 contributed to the drastic decline in the number of new case patients. Resistant strains are however emerging despite the use of multidrug therapy; identifying and monitoring resistance is still necessary. PMID- 26428603 TI - Biodegradation and detoxification of textile dye Disperse Red 54 by Brevibacillus laterosporus and determination of its metabolic fate. AB - Bioremediation is one of the milestones achieved by the biotechnological innovations. It is generating superior results in waste management such as removal of textile dyes, which are considered xenobiotic compounds and recalcitrant to biodegradation. In the present bioremedial approach, Brevibacillus laterosporus was used as an effective microbial tool to decolorize disperse dye Disperse Red 54 (DR54). Under optimized conditions (pH 7, 40 degrees C), B. laterosporus led to 100% decolorization of DR54 (at 50 mg L(-1)) within 48 h. Yeast extract and peptone, supplemented in medium enhanced the decolorization efficiency of the bacterium. During the decolorization process, activities of enzymes responsible for decolorization, such as tyrosinase, veratryl alcohol oxidase and NADH--DCIP reductase were induced by 1.32-, 1.51- and 4.37-fold, respectively. The completely different chromatographic/spectroscopic spectrum of metabolites obtained after decolorization confirmed the biodegradation of DR54 as showed by High pressure liquid chromatography, High pressure thin layer chromatography and Fourier transform infrared spectroscopy. Gas chromatography Mass spectroscopy studies suggested the parent dye was biodegraded into simple final product, N-(1lambda(3)-chlorinin-2-yl)acetamide. Phytotoxicity study suggested that the metabolites obtained after biodegradation of DR54 were non toxic as compared to the untreated dye signifying the detoxification of the DR54 by B. laterosporus. PMID- 26428604 TI - DISTINGUISHING POLYPOIDAL CHOROIDAL VASCULOPATHY FROM TYPICAL NEOVASCULAR AGE RELATED MACULAR DEGENERATION BASED ON SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY. AB - PURPOSE: To investigate the sensitivity and specificity of spectral domain optical coherence tomography in distinguishing polypoidal choroidal vasculopathy (PCV) from typical neovascular age-related macular degeneration (nAMD). METHODS: One hundred and eighty-eight eyes in 156 patients with active PCV or typical nAMD were enrolled prospectively. Three spectral domain optical coherence tomography manifestations, pigment epithelium detachment, double-layer sign, and thumb-like polyps were estimated in all the eyes. A diagnostic test to differentiate PCV from nAMD based on spectral domain optical coherence tomography was performed. Furthermore, the sensitivity and specificity was validated in a retrospective series of patients. RESULTS: Pigment epithelium detachment, double-layer sign, and thumb-like polyps were more common in PCV eyes than in nAMD eyes. When the cutoff point was set as at least 2 positive signs out of 3 in the diagnostic test, the sensitivity was 89.4% and specificity was 85.3%. The results of the validation test further confirmed the strategy, with satisfying sensitivity (87.5%) and specificity (86.2%). CONCLUSION: Spectral domain optical coherence tomography is sensitive and specific in distinguishing PCV from nAMD. From these results, the presence of at least two out three signs (pigment epithelium detachment, double-layer sign, and thumb-like polyps) indicates a positive test and is therefore suggested to be the screening strategy for PCV. PMID- 26428605 TI - SURGICAL OUTCOME OF LATE IN-THE-BAG INTRAOCULAR LENS DISLOCATION TREATED WITH PARS PLANA VITRECTOMY. AB - PURPOSE: To present the visual outcome and postoperative complications of pars plana vitrectomy and intraocular lenses (IOL) removal with or without IOL exchange of late in-the-bag IOL dislocation after uneventful cataract surgery. METHODS: Retrospective analysis of a consecutive series of 83 eyes with late in the-bag dislocated IOL treated with pars plana vitrectomy and anterior chamber IOL (25 eyes), transscleral suture-fixated posterior chamber IOL (38 eyes), or aphakia (20 eyes). RESULTS: High myopia was the major predisposing factor (40%). The interval between cataract surgery and the dislocation was 10.9 years. The complication rate after the second surgery was 43%; being transient hypotony (19%) and hypertension (15%) the most frequent. Postoperative best-corrected visual acuity improvement was statistically significant (P < 0.001), with a mean of 3 Snellen lines. This improvement was also significant in 2 subgroups, patients with sutured posterior chamber IOL (20/80-20/40; P < 0.001) and in patients with anterior chamber IOL (20/125-20/40; P < 0.001). However, best corrected visual acuity did not improve in aphakic patients (20/63-20/63; P = 0.13). Postoperative astigmatism increased significantly (P < 0.001), with a mean of -1 D. Mean follow-up was 24 months. CONCLUSION: The major predisposing factor for late in-the-bag IOL dislocation is myopia. Despite a complication rate of 43%, mostly minor and transient, IOL exchange surgery is an effective procedure with a good visual outcome (mean 3 Snellen lines improvement). There were no statistically significant differences in the final best-corrected visual acuity or complication rate between anterior chamber IOL and sutured posterior chamber IOL, thus, both surgical techniques may be considered to treat this condition. PMID- 26428606 TI - SOCIETAL COSTS ASSOCIATED WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION IN THE UNITED STATES. AB - PURPOSE: The purpose of this study was to use a cross-sectional prevalence-based health care economic survey to ascertain the annual, incremental, societal ophthalmic costs associated with neovascular age-related macular degeneration. METHODS: Consecutive patients (n = 200) with neovascular age-related macular degeneration were studied. A Control Cohort included patients with good (20/20 20/25) vision, while Study Cohort vision levels included Subcohort 1: 20/30 to 20/50, Subcohort 2: 20/60 to 20/100, Subcohort 3: 20/200 to 20/400, and Subcohort 4: 20/800 to no light perception. An interviewer-administered, standardized, written survey assessed 1) direct ophthalmic medical, 2) direct nonophthalmic medical, 3) direct nonmedical, and 4) indirect medical costs accrued due solely to neovascular age-related macular degeneration. RESULTS: The mean annual societal cost for the Control Cohort was $6,116 and for the Study Cohort averaged $39,910 (P < 0.001). Study Subcohort 1 costs averaged $20,339, while Subcohort 4 costs averaged $82,984. Direct ophthalmic medical costs comprised 17.9% of Study Cohort societal ophthalmic costs, versus 74.1% of Control Cohort societal ophthalmic costs (P < 0.001) and 10.4% of 20/800 to no light perception subcohort costs. Direct nonmedical costs, primarily caregiver, comprised 67.1% of Study Cohort societal ophthalmic costs, versus 21.3% ($1,302/$6,116) of Control Cohort costs (P < 0.001) and 74.1% of 20/800 to no light perception subcohort costs. CONCLUSION: Total societal ophthalmic costs associated with neovascular age related macular degeneration dramatically increase as vision in the better-seeing eye decreases. PMID- 26428607 TI - IMAGE ARTIFACTS IN OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. AB - PURPOSE: To describe image artifacts of optical coherence tomography (OCT) angiography and their underlying causative mechanisms. To establish a common vocabulary for the artifacts observed. METHODS: The methods by which OCT angiography images are acquired, generated, and displayed are reviewed as are the mechanisms by which each or all of these methods can produce extraneous image information. A common set of terminology is proposed and used. RESULTS: Optical coherence tomography angiography uses motion contrast to image blood flow and thereby images the vasculature without the need for a contrast agent. Artifacts are very common and can arise from the OCT image acquisition, intrinsic characteristics of the eye, eye motion, image processing, and display strategies. Optical coherence tomography image acquisition for angiography takes more time than simple structural scans and necessitates trade-offs in flow resolution, scan quality, and speed. An important set of artifacts are projection artifacts in which images of blood vessels seem at erroneous locations. Image processing used for OCT angiography can alter vascular appearance through segmentation defects, and because of image display strategies can give false impressions of the density and location of vessels. Eye motion leads to discontinuities in displayed data. Optical coherence tomography angiography artifacts can be detected by interactive evaluation of the images. CONCLUSION: Image artifacts are common and can lead to incorrect interpretations of OCT angiography images. Because of the quantity of data available and the potential for artifacts, physician interaction in viewing the image data will be required, much like what happens in modern radiology practice. PMID- 26428608 TI - VOLUME-RENDERED ANGIOGRAPHIC AND STRUCTURAL OPTICAL COHERENCE TOMOGRAPHY. AB - PURPOSE: To demonstrate combined and integrated volume rendering of the retinal vasculature and selected structural abnormalities information derived from optical coherence tomography. METHODS: The eyes were scanned using optical coherence tomography using split-spectrum amplitude-decorrelation techniques to derive flow information. Various sublayers could be color coded as needed. The corresponding structural optical coherence tomography information was segmented for salient anatomic structures of interest, such as areas of edema fluid or intraretinal lipid deposits. The angiographic and structural data were integrated on a plane-by-plane basis and used to create volume-rendered images. The combined volume-rendered angiographic and structural optical coherence tomography data could be rotated about three different axes for evaluation. RESULTS: Representative images from the eyes with diabetic macular edema, Type 1 macular telangiectasis, choroidal neovascularization, and retinal veno-occlusive disease are shown. The interrelationships between areas of cystoid fluid accumulation or intraretinal lipid accumulation could be visualized. CONCLUSION: Although structural and angiographic findings are typically shown in isolation, they can be integrated into a merged data set that is amenable to volume rendering. Using this new technique will allow investigation into the interrelationships between vascular and structural abnormalities of the retina and choroid. PMID- 26428609 TI - An Effective and Well Tolerated Strategy of Bladder Preservation Therapy in Cisplatin-Ineligible Patients With Muscle-Invasive Bladder Cancer. AB - To investigate bladder preservation therapy with a well tolerated strategy, 30 patients with bladder cancer underwent concomitant chemoradiotherapy with weekly carboplatin. The 2-year overall survival was 75% for all patients, 43% and 95% for patients without adjuvant chemotherapy or with adjuvant chemotherapy separately. This strategy was well tolerated with 7% of Grade 3/4 late bladder toxicity. BACKGROUND: The purpose of this study was to determine the feasibility and clinical effectiveness of concurrent weekly carboplatin chemotherapy in conjunction with definite radiation with or without adjuvant chemotherapy in the treatment of muscle-invasive bladder cancer. PATIENTS AND METHODS: Between April 2010 and December 2013, 30 patients with muscle-invasive bladder cancer were evaluated retrospectively in this study. Concurrent chemoradiotherapy (CCRT) with weekly carboplatin was initiated. CCRT was followed by 2 courses of carboplatin and gemcitabine limited to patients with Eastern Cooperative Oncology Group performance status < 3 and age < 80 years. RESULTS: Thirty patients were treated and all completed the CCRT protocol. Seven of 8 patients (88%) achieved a pathological complete response (pCR) with CCRT alone, and 18 of 22 patients (82%) treated with CCRT followed by adjuvant chemotherapy had a pCR. The median follow up was 23.2 (range, 8.3-40.7) months. The median progression-free survival was 15.9 months for the CCRT group, and not sufficient to evaluate CCRT followed by adjuvant chemotherapy. The median overall survival with CCRT was 18.8 months, and had not yet been reached for CCRT with adjuvant chemotherapy. The protocol was well tolerated for adverse events. CONCLUSION: Our study has shown that concomitant chemotherapy using weekly carboplatin in the management of muscle invasive bladder cancer is feasible and well tolerated, even in older patients. Additional adjuvant chemotherapy with 2 cycles of carboplatin and gemcitabine should be encouraged in physically fit patients. These results provide a basis for randomized studies to compare this approach with conventional therapy for patients who wish to preserve the bladder. PMID- 26428610 TI - Clinical Disparities for Minorities and Foreign-Born Men With Undescended Versus Descended Testicular Germ Cell Tumors. AB - BACKGROUND: Few reports have been published regarding the outcomes of patients who develop an undescended testicular malignancy (UTM). Our objective was to analyze the sociodemographic and survival outcomes of patients with UTM and those of with descended testicular malignancy (DTM). PATIENTS AND METHODS: All 17 registries constituting the Surveillance, Epidemiology, and End Results (SEER) database were analyzed from 1988 to 2008. Patients with a descended or undescended testis and a diagnosis of nonseminomatous or seminomatous testicular cancer were identified. Descriptive statistical data and multivariate analysis were used to identify the predictors of a UTM diagnosis. The primary outcomes were overall and disease-specific survival. RESULTS: The study cohort included 10,159 men (95.3%) with DTM and 496 (4.7%) with UTM. Patients with UTM were more likely to be older, married, and a minority or foreign born and to have seminoma, a higher rate of node positivity, and a higher SEER stage compared with patients with DTM. The median survival time for patients with UTM was longer than that for patients with to DTM (83.1 vs. 72.5 months; P = .0001), although no difference was found in cancer-specific mortality (P = .34). CONCLUSION: Patients with UTM are more likely to be a minority or foreign born, highlighting a previously unrecognized healthcare disparity that might represent a lack of diagnosis and access to care. PMID- 26428611 TI - Decompression of Odontogenic Cystic Lesions: Past, Present, and Future. AB - Tumors and cystic lesions of the jawbones have been described since the late 1600s and it took another 200 years for classification systems to appear in the medical, surgical, and dental literatures. In the late 1800s, Carl Partsch introduced cystostomy, a method by which the cyst is converted into a pouch by suturing its lining to the mucosa of the oral cavity. The purpose of this article is to analyze the history, present, and future of cystic conditions of the jaws and decompression, a modality of treatment that during the past few years has regained the attention of oral and maxillofacial surgeons and pathologists owing to its relative simplicity and effectiveness compared with other conservative options. PMID- 26428612 TI - Evaluation of Bone Healing After Osteotomies Prepared With Er:YAG Laser in Contact and Noncontact Modes and Piezosurgery--An Animal Study. AB - PURPOSE: To analyze the healing of bone tissue treated with Er:YAG laser contact and noncontact modes of and piezosurgery in a rat model using triangular laser profilometry. MATERIALS AND METHODS: Twenty-four 10-week-old adult male Wistar rats were used in the study. Three osteotomies on the medial part of tibia were performed in each animal, 1 in the right tibia and 2 in the left tibia. The osteotomies were performed with a piezoelectric device set at maximal power and the Er:YAG laser in contact mode (power, 7.5 W; pulse energy, 375 mJ; repetition rate, 20 Hz; MSP mode) and noncontact mode (power, 7.5 W; pulse energy, 750 mJ; repetition rate, 10 Hz; QSP mode) with a novel type of circular, digitally controlled handpiece (x-Runner). After surgery, 6 animals were immediately euthanized (group 1), and the others were euthanized after 1 week (group 2, n = 6), 2 weeks (group 3, n = 6), and 3 weeks (group 4, n = 6). Bone healing after osteotomy was analyzed using a 3-dimensional laser scanning technique (ie, laser triangulation profilometry). RESULTS: The volume reduction rates are similar for all 3 techniques (0.2 to 0.25 mm(3) per week). Greater volume reduction of 0.25 mm3 per week was observed for the Er:YAG laser in noncontact mode (x-Runner). After 3 weeks, almost complete healing of the prepared osteotomy was observed. CONCLUSION: Within the limitations of this study, the osteotomies performed by the Er:YAG laser in digitally controlled noncontact mode healed the fastest. PMID- 26428613 TI - A Comparison of Torque Forces Used to Apply Intermaxillary Fixation Screws. AB - PURPOSE: When establishing intermaxillary fixation (IMF) using bone screws, fracture of a screw is a potential complication. This study was conducted to investigate the forces that arise at bone screw insertion and to determine safety margins between torque for manually tightened insertion and torque until breakage for 3 different IMF screw systems, which could ultimately favor the use of 1 IMF screw system based on decreased risk of complications. MATERIALS AND METHODS: IMF screws were placed into porcine mandibles by 3 oral and maxillofacial surgeons. The porcine mandibles were evaluated for cortical thickness and suitable insertion sites by cone-beam computed tomography. Measurements of torque until failure were performed on predrilled aluminum plates by the primary author. A digital torque screwdriver measured 180 data points per second as continuous data and recorded the measurements. RESULTS: Measurements indicated clear differences in torsion forces between manually tightened insertions and torque until breakage for all 3 IMF screw systems. No statistical difference in safety margins was found among the IMF screw systems. CONCLUSIONS: Because no statistical differences in safety margins were found among the IMF screw systems, this study indicates that IMF screw selection should be based on other clinical factors, such as ease of use or economic factors. Future prospective studies are necessary to fully determine evidence-based criteria for IMF screw selection. PMID- 26428614 TI - Severity of Soft Tissue Injury Within the Temporomandibular Joint Following Condylar Fracture as Seen on Magnetic Resonance Imaging and Its Impact on Outcome of Functional Management. AB - PURPOSE: This study aimed to quantify articular soft tissue injury in condylar fractures based on magnetic resonance imaging (MRI) findings and investigate the impact of severity of articular soft tissue injury on the development of postoperative complications after functional reduction of a condylar fracture. PATIENTS AND METHODS: Fifty-four patients 18 to 60 years old with unilateral undisplaced, deviated, or displaced condylar fractures were included in this prospective study. Articular soft tissue within the temporomandibular joint (TMJ) was evaluated using MRI within 7 days after the condylar fracture. Based on MRI findings, such injuries were classified as grade I (hemarthrosis only), grade II (hemarthrosis and disc displacement), grade III (hemarthrosis, disc displacement, and capsular tear), or grade IV (disc perforation in association with grade I, II, or III). All condylar fractures were treated conservatively using a standardized functional reduction method and patients were followed for 1 year. RESULTS: In 37 of 54 TMJs, MRI diagnosis of disc displacement was established, and capsular tear was observed in 12 joints and hemarthrosis was present in 42 joints. Disc perforation was present in only 5 cases. Patients with hemarthrosis alone (grade I) had the best outcome after functional reduction, whereas patients with hemarthrosis and disc displacement (grade II) had comparatively poorer results. Fifty percent of patients with grade II injury and 66.6% of patients with associated capsular tear (grade III) had limited mouth opening and restricted movement at the end of the follow-up period. One hundred percent of patients with disc perforation (grade IV) had restricted joint movement and joint noise. CONCLUSION: Results suggest that serious injury to the articular disc and capsule of the TMJ is a major contributing factor toward the development of complications after closed reduction of a condylar fracture. PMID- 26428616 TI - The role of Amh signaling in teleost fish--Multiple functions not restricted to the gonads. AB - This review summarizes the important role of Anti-Mullerian hormone (Amh) during gonad development in fishes. This Tgfbeta-domain bearing hormone was named after one of its known functions, the induction of the regression of Mullerian ducts in male mammalian embryos. Later in development it is involved in male and female gonad differentiation and extragonadal expression has been reported in mammals as well. Teleosts lack Mullerian ducts, but they have amh orthologous genes. amh expression is reported from 21 fish species and possible regulatory interactions with further factors like sex steroids and gonadotropic hormones are discussed. The gonadotropin Fsh inhibits amh expression in all fish species studied. Sex steroids show no consistent influence on amh expression. Amh is produced in male Sertoli cells and female granulosa cells and inhibits germ cell proliferation and differentiation as well as steroidogenesis in both sexes. Therefore, Amh might be a central player in gonad development and a target of gonadotropic Fsh. Furthermore, there is evidence that an Amh-type II receptor is involved in germ cell regulation. Amh and its corresponding type II receptor are also present in brain and pituitary, at least in some teleosts, indicating additional roles of Amh effects in the brain-pituitary-gonadal axis. Unraveling Amh signaling is important in stem cell research and for reproduction as well as for aquaculture and in environmental science. PMID- 26428615 TI - Six-month quality-of-life and functional status of acute respiratory distress syndrome survivors compared to patients at risk: a population-based study. AB - INTRODUCTION: The long-term attributable burden related to acute respiratory distress syndrome (ARDS) is not fully investigated. The aim of this study is to evaluate the quality of life (QOL) and functional status at 6 months after hospitalization in patients at risk for ARDS who did and did not develop the syndrome. METHOD: This is a population-based prospective cohort study of adult patients from Olmsted County, Minnesota, with or at risk for ARDS hospitalized from October 2008 to July 2011. The primary outcomes were changes in QOL and functional status, measured through 12-Item Short Form Survey (SF-12) and Barthel Index (BI) respectively, from baseline to 6 months, compared between survivors who did and did not develop ARDS. RESULTS: Of 410 patients with or at risk for ARDS, 98 had baseline surveys collected and 67 responded to a 6-month survey (26 ARDS, 41 non-ARDS). Both ARDS and non-ARDS groups had lower physical component of SF-12 at baseline compared to general population (P < 0.001 for both). ARDS patients had poorer baseline functional status compared to non-ARDS (mean BI 80 +/- 25 vs. 88 +/- 22, P = 0.03). No significant differences were observed for the change between 6 months and baseline BI (delta 2.3 for ARDS vs. 2.0 for non-ARDS, P = 0.5), or mental (delta 2.7 vs. 2.4, P = 0.9) or physical (delta -3 vs. -3.3, P = 0.9) component of SF-12 between survivors with and without ARDS. CONCLUSION: In this population-based study, decreased QOL and functional status 6 months after hospitalization were largely explained by baseline condition, with similar recovery in survivors who did and did not develop ARDS. PMID- 26428617 TI - Extracellular signaling molecules to promote fracture healing and bone regeneration. AB - To date, the delivery of signaling molecules for bone regeneration has focused primarily on factors that directly affect the bone formation pathways (osteoinduction) or that serve to increase the number of bone forming progenitor cells. The first commercialized growth factors approved for bone regeneration, Bone Morphogenetic Protein 2 and 7 (BMP2 and BMP7), are direct inducers of osteoblast differentiation. As well, newer generations of potential therapeutics that target the Wnt signaling pathway are also direct osteoinducers. On the other hand, some signaling molecules may play a role as mitogens and serve to increase the number of bone producing cells or may increase vascularization. This is true for factors such as Platelet Derived Growth Factor (PDGF) or Fibroblast Growth Factor (FGF). Vascular Endothelial Growth Factor (VEGF) likely has a special role. Not only does it induce new blood vessel formation, it also has direct effects on osteoblasts through endothelial cell-based BMP production. In addition to these pathways that classically have targeted bone production, there are also opportunities to target other aspects of the bone healing process such as inflammation, vascularization, and cell ingress to the fracture site. Bone regeneration is highly complex with defined, yet overlapping stages of healing. We will review established and novel extracellular signaling factors associated with various stages of fracture healing that could be targeted to promote enhanced bone regeneration. Importantly, multiple potential cell and tissues could be targeted to enhance healing in addition to focusing solely on osteoinductive therapeutics. PMID- 26428618 TI - In vitro cardiac tissue models: Current status and future prospects. AB - Cardiovascular disease is the leading cause of death worldwide. Achieving the next phase of potential treatment strategies and better prognostic tools will require a concerted effort from interdisciplinary fields. Biomaterials-based cardiac tissue models are revolutionizing the area of preclinical research and translational applications. The goal of in vitro cardiac tissue modeling is to create physiological functional models of the human myocardium, which is a difficult task due to the complex structure and function of the human heart. This review describes the advances made in area of in vitro cardiac models using biomaterials and bioinspired platforms. The field has progressed extensively in the past decade, and we envision its applications in the areas of drug screening, disease modeling, and precision medicine. PMID- 26428620 TI - Race/ethnicity, and Americans' perceptions and experiences of over- and under-use of care: a cross-sectional study. AB - BACKGROUND: Despite widespread documentation of racial/ethnic disparities in care (predominantly under-use of needed care), differences in population-wide attitudes or experiences about under- or overuse (care where harms may outweigh potential benefits) of care are not well understood. We examined whether race/ethnicity is associated with perceptions or experiences of overuse or underuse. METHODS: We conducted secondary analysis of a cross-sectional national telephone survey of nationally representative sample of 1238 American adults; 57.9 % female, 75.4 % Non-Hispanic White, 11.8 % Non-Hispanic Black, 10.1 % Hispanic. The main outcome measures are general perceptions and personal experiences of overuse and underuse, including cost-related dimensions of each. RESULTS: Bivariate results indicated that respondents of minority race/ethnicity generally viewed both overuse and underuse as bigger problems than did Whites, and reported more personal experiences of each. After adjustment, Hispanics were less likely than Whites to report personal experiences of overuse (odds ratio [OR] [95 % CI], 0.44 [0.23 to 0.86]), while Blacks and Others were more likely to report cost-related overuse (ORs [95 % CIs], 4.16 [2.30 to 7.51]; 3.55 [1.52 to 8.28], respectively). Non-Hispanic Others more often reported doctors' protection from overuse (OR [95 % CI], 3.69 [1.75 to 7.78]). General concerns with underuse were more frequent among Blacks and Hispanics (ORs [95 % CIs], 3.07 [1.72 to 5.54]; 2.12 [1.24 to 3.61] respectively), while Others reported significantly fewer concerns (OR [95 % CI], 0.43 [0.23 to 0.80]). CONCLUSIONS: Over- and underuse of medical care are important problems for many Americans, and experiences vary by race/ethnicity. Clinician communication and educational campaigns about appropriateness of care may need tailoring for varying population groups. PMID- 26428619 TI - Engineered heart tissues and induced pluripotent stem cells: Macro- and microstructures for disease modeling, drug screening, and translational studies. AB - Engineered heart tissue has emerged as a personalized platform for drug screening. With the advent of induced pluripotent stem cell (iPSC) technology, patient-specific stem cells can be developed and expanded into an indefinite source of cells. Subsequent developments in cardiovascular biology have led to efficient differentiation of cardiomyocytes, the force-producing cells of the heart. iPSC-derived cardiomyocytes (iPSC-CMs) have provided potentially limitless quantities of well-characterized, healthy, and disease-specific CMs, which in turn has enabled and driven the generation and scale-up of human physiological and disease-relevant engineered heart tissues. The combined technologies of engineered heart tissue and iPSC-CMs are being used to study diseases and to test drugs, and in the process, have advanced the field of cardiovascular tissue engineering into the field of precision medicine. In this review, we will discuss current developments in engineered heart tissue, including iPSC-CMs as a novel cell source. We examine new research directions that have improved the function of engineered heart tissue by using mechanical or electrical conditioning or the incorporation of non-cardiomyocyte stromal cells. Finally, we discuss how engineered heart tissue can evolve into a powerful tool for therapeutic drug testing. PMID- 26428621 TI - Protein supplementation does not alter intramuscular anabolic signaling or endocrine response after resistance exercise in trained men. AB - The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway appears to be the primary regulator of muscle protein synthesis. A variety of stimuli including resistance exercise, amino acids, and hormonal signals activate mTORC1 signaling. The purpose of this study was to investigate the effect of a protein supplement on mTORC1 signaling following a resistance exercise protocol designed to promote elevations in circulating hormone concentrations. We hypothesized that the protein supplement would augment the intramuscular anabolic signaling response. Ten resistance-trained men (age, 24.7 +/- 3.4 years; weight, 90.1 +/- 11.3 kg; height, 176.0 +/- 4.9 cm) received either a placebo or a supplement containing 20 g protein, 6 g carbohydrates, and 1 g fat after high-volume, short-rest lower-body resistance exercise. Blood samples were obtained at baseline, immediately, 30 minutes, 1 hour, 2 hours, and 5 hours after exercise. Fine-needle muscle biopsies were completed at baseline, 1 hour, and 5 hours after exercise. Myoglobin, lactate dehydrogenase, and lactate concentrations were significantly elevated after resistance exercise (P < .0001); however, no differences were observed between trials. Resistance exercise also elicited a significant insulin, growth hormone, and cortisol response (P < .01); however, no differences were observed between trials for insulin-like growth factor-1, insulin, testosterone, growth hormone, or cortisol. Intramuscular anabolic signaling analysis revealed significant elevations in RPS6 phosphorylation after resistance exercise (P = .001); however, no differences were observed between trials for signaling proteins including Akt, mTOR, p70S6k, and RPS6. The endocrine response and phosphorylation status of signaling proteins within the mTORC1 pathway did not appear to be altered by ingestion of supplement after resistance exercise in resistance-trained men. PMID- 26428622 TI - Neonatal thyroid-stimulating hormone level is influenced by neonatal, maternal, and pregnancy factors. AB - The percentage of newborns with a neonatal whole blood thyroid-stimulating hormone (TSH) greater than 5 mIU/L has been used as an indicator of iodine deficiency at the population level. However, TSH levels in newborns may be influenced by many factors other than iodine status. The objective of this study was to identify neonatal, maternal, and pregnancy-related determinants of neonatal TSH levels in a retrospective cohort study. The study sample included 313 Belgian mothers and their 4- to 5-year-old children. The children had a neonatal TSH concentration between 0 and 15 mIU/L at neonatal screening, and blood samples were collected 3 to 5 days after birth. Children with suspected congenital hypothyroidism (neonatal TSH level >15 mIU/L), prematurely born (i.e., <37 weeks), or with a low birth weight (i.e., <2500 g) were excluded. Information about maternal and birth-related determinants was collected from the neonatal screening center via a self-administered questionnaire filled in by the mother together with the child's health booklet. Higher TSH levels were found in spring and winter compared to summer and autumn (P = .011). Higher TSH levels were associated with lifetime smoking behavior (up to child birth) in the mother (P = .005), lower weight gain during pregnancy (P = .014), and longer pregnancies (P = .003). This study showed that several neonatal, maternal, and pregnancy-related determinants are influencing neonatal TSH level. PMID- 26428624 TI - Variability of sedimentary organic carbon in patchy seagrass landscapes. AB - Seagrass ecosystems, considered among the most efficient carbon sinks worldwide, encompass a wide variety of spatial configurations in the coastal landscape. Here we evaluated the influence of the spatial configuration of seagrass meadows at small scales (metres) on carbon storage in seagrass sediments. We intensively sampled carbon stocks and other geochemical properties (delta(13)C, particle size, depositional fluxes) across seagrass-sand edges in a Zostera muelleri patchy seagrass landscape. Carbon stocks were significantly higher (ca. 20%) inside seagrass patches than at seagrass-sand edges and bare sediments. Deposition was similar among all positions and most of the carbon was from allochthonous sources. Patch level attributes (e.g. edge distance) represent important determinants of the spatial heterogeneity of carbon stocks within seagrass ecosystems. Our findings indicate that carbon stocks of seagrass areas have likely been overestimated by not considering the influence of meadow landscapes, and have important relevance for the design of seagrass carbon stock assessments. PMID- 26428623 TI - Probiotic and anti-inflammatory attributes of an isolate Lactobacillus helveticus NS8 from Mongolian fermented koumiss. AB - BACKGROUND: Koumiss is a traditionally fermented mare's milk described with health-promoting potentials for decades. However, only a few studies focused on the probiotic strains isolated from koumiss. In this study, we collected koumiss samples from Inner Mongolian pasturing area of China and selected a promising strain of Lactobacillus helveticus, isolate NS8, based on the survival abilities in gastrointestinal tract (GIT) and adhesion to intestinal endothelial cells in vitro. As the ability to positively modulate host immune response is a feature of increasing importance in measuring the probiotic potential of a bacterial strain, our study mainly focus on the immunomodulatory properties of L. helveticus NS8 by using in vivo and ex vivo analyses. RESULTS: L. helveticus NS8 was identified by molecular-typing methods, both at genus and species levels. As a typical food niche-specific bacteria, NS8 showed a moderate survival ability in GIT environment in vitro. However, an excellent binding capacity to the human intestinal epithelial cells, along with significant autoaggregation and cell surface hydrophobicity was observed. Additionally, the presence of S-layer protein was responsible for the cell surface properties of this strain. NS8 was found to be rather protective against TNBS (2,4,6-trinitrobenzene sulfonic acid) induced murine colitis. In the meantime, co-culture with NS8 induced an increased level of secretion of anti-inflammatory cytokine IL-10 in peripheral blood mono nuclear cells (PBMCs). Furthermore, NS8 was also able to diminish the proinflammatory effects of lipopolysaccharide (LPS) in mouse macrophage cell line RAW264.7 by inducing higher levels of IL-10. Specially, adding of the purified S layer protein didn't influence the production of IL-10. The specific ligand-host receptor interactions on the NS8 specific immune responses need to be learned further. CONCLUSION: In summary, L. helveticus NS8 exhibited good probiotic and particularly immunomodulatory properties, with a potential for development of functional food commercially or therapeutic adjuvant for inflammatory diseases. PMID- 26428625 TI - Persistent organic pesticide residues in sediments of Vasai Creek near Mumbai: Assessment of sources and potential ecological risk. AB - Thirteen persistent organic pesticides were investigated in the sediments of Vasai Creek near Mumbai to evaluate their pollution levels and potential risks. It was observed that SigmaOCPs level was in the range of 597-1538ng/g dw, with an average value of 1115.25ng/g dw. The level of SigmaOPPs was in the range of 492 1034ng/g dw, with an average value of 798.15ng/g dw. The values o,p'-DDT/p,p'-DDT ratio gives an indication of use of technical DDT as the prime source of DDT, while the alpha/gamma-BHC ratio indicate that BHCs in study area might have been received from fresh lindane. The results of an ecological risk assessment showed that sediment bound organic pesticides are of more ecotoxicological concern as they might create adverse ecological risk to the marine breeding habitats. These pesticides residues may get remobilize and released to overlying waters creating adverse effects on terrestrial and aquatic organisms. PMID- 26428626 TI - Prevalence, trends, patterns and associations of analgesic use in Germany. AB - BACKGROUND: Despite the public health relevance of analgesic use, large-scale studies on this topic in Germany are lacking. This study describes the prevalence, trends, associations and patterns of use of prescription and over-the counter (OTC) analgesics, focusing on five of the most common agents: aspirin, diclofenac, ibuprofen, naproxen and paracetamol. METHODS: Data from two representative population-based surveys: The German National Health Interview and Examination Survey 1998 (GNHIES98 n = 7099) and the German Health Interview and Examination Survey for Adults 2008-2011 (DEGS1 n = 7091) was investigated. Information on all medicines consumed in the previous 7 days was collected via computer-assisted personal interviews with adults aged 18-79 years. Associations between analgesic use and socio-demographic and health-behaviour factors were analysed using logistic regression models. RESULTS: Analgesic use has increased over the last decade from 19 to 21%. This was exclusively due to the rise in OTC analgesic use from 10.0 to 12.2%. Prescribed analgesic use remained constant (7.9%). Findings from DEGS1 indicate that ibuprofen is the most commonly used analgesic followed by aspirin and paracetamol. OTC analgesic use is higher among women and smokers, but lower among older adults (65-79 years). Prescribed analgesics use is higher among women, older adults, smokers and obese adults with medium or high socio- economic status. Adults performing more than 2 h/week of physical exercise use fewer analgesics. DISCUSSION: Among the adult population of Germany, the prevalence of OTC analgesic use has significantly increased over the last decade. We found differences between adults consuming OTC and prescribed analgesics (or both) concerning their health behaviour and health conditions. International direct comparison between prevalence rates of analgesic use was limited due to varying availability of analgesics between countries and to methodological differences. CONCLUSIONS: About one in five community dwelling adults aged 18-79 years in Germany use analgesics in a given week. Considering the potential harms of analgesic use, monitoring of prevalence, patterns and determinants of use at the population level are important steps to inform disease prevention and health promotion policies. PMID- 26428627 TI - Validation of high temporal resolution spiral phase velocity mapping of temporal patterns of left and right coronary artery blood flow against Doppler guidewire. AB - BACKGROUND: Temporal patterns of coronary blood flow velocity can provide important information on disease state and are currently assessed invasively using a Doppler guidewire. A non-invasive alternative would be beneficial as it would allow study of a wider patient population and serial scanning. METHODS: A retrospectively-gated breath-hold spiral phase velocity mapping sequence (TR 19 ms) was developed at 3 Tesla. Velocity maps were acquired in 8 proximal right and 15 proximal left coronary arteries of 18 subjects who had previously had a Doppler guidewire study at the time of coronary angiography. Cardiovascular magnetic resonance (CMR) velocity-time curves were processed semi-automatically and compared with corresponding invasive Doppler data. RESULTS: When corrected for differences in heart rate between the two studies, CMR mean velocity through the cardiac cycle, peak systolic velocity (PSV) and peak diastolic velocity (PDV) were approximately 40 % of the peak Doppler values with a moderate - good linear relationship between the two techniques (R(2): 0.57, 0.64 and 0.79 respectively). CMR values of PDV/PSV showed a strong linear relationship with Doppler values with a slope close to unity (0.89 and 0.90 for right and left arteries respectively). In individual vessels, plots of CMR velocities at all cardiac phases against corresponding Doppler velocities showed a consistent linear relationship between the two with high R(2) values (mean +/-SD: 0.79 +/-.13). CONCLUSIONS: High temporal resolution breath-hold spiral phase velocity mapping underestimates absolute values of coronary flow velocity but allows accurate assessment of the temporal patterns of blood flow. PMID- 26428628 TI - PSR: polymorphic SSR retrieval. AB - BACKGROUND: With the advent of high-throughput sequencing technologies large scale identification of microsatellites became affordable and was especially directed to non-model species. By contrast, few efforts have been published toward the automatic identification of polymorphic microsatellites by exploiting sequence redundancy. Few tools for genotyping microsatellite repeats have been implemented so far that are able to manage huge amount of sequence data and handle the SAM/BAM file format. Most of them have been developed for and tested on human or model organisms with high quality reference genomes. RESULTS: In this note we describe polymorphic SSR retrieval (PSR), a read counter and simple sequence repeat (SSR) length polymorphism detection tool. It is written in Perl and was developed to identify length polymorphisms in perfect microsatellites exploiting next generation sequencing (NGS) data. PSR has been developed bearing in mind plant non-model species for which de novo transcriptome assembly is generally the first sequence resource available to be used for SSR-mining. PSR is divided into two modules: the read-counting module (PSR_read_retrieval) identifies all the reads that cover the full-length of perfect microsatellites; the comparative module (PSR_poly_finder) detects both heterozygous and homozygous alleles at each microsatellite locus across all genotypes under investigation. Two threshold values to call a length polymorphism and reduce the number of false positives can be defined by the user: the minimum number of reads overlapping the repetitive stretch and the minimum read depth. The first parameter determines if the microsatellite-containing sequence must be processed or not, while the second one is decisive for the identification of minor alleles. PSR was tested on two different case studies. The first study aims at the identification of polymorphic SSRs in a set of de novo assembled transcripts defined by RNA-sequencing of two different plant genotypes. The second research activity aims to investigate sequence variations within a collection of newly sequenced chloroplast genomes. In both the cases PSR results are in agreement with those obtained by capillary gel separation. CONCLUSION: PSR has been specifically developed from the need to automate the gene-based and genome-wide identification of polymorphic microsatellites from NGS data. It overcomes the limits related to the existing and time-consuming efforts based on tools developed in the pre-NGS era. PMID- 26428630 TI - A measurement system analysis with design of experiments: Investigation of the adhesion performance of a pressure sensitive adhesive with the probe tack test. AB - The tack of a pressure sensitive adhesive (PSA) is not an inherent material property and strongly depends on the measurement conditions. Following the concept of a measurement system analysis (MSA), influencing factors of the probe tack test were investigated by a design of experiments (DoE) approach. A response surface design with 38 runs was built to evaluate the influence of detachment speed, dwell time, contact force, adhesive film thickness and API content on tack, determined as the maximum of the stress strain curve (sigmamax). It could be shown that all investigated factors have a significant effect on the response and that the DoE approach allowed to detect two-factorial interactions between the dwell time, the contact force, the adhesive film thickness and the API content. Surprisingly, it was found that tack increases with decreasing and not with increasing adhesive film thickness. PMID- 26428629 TI - Development of chitosan nanoparticles as drug delivery system for a prototype capsid inhibitor. AB - Oral delivery of biopharmaceutics drug disposition classification system (BDDCS) Class II or IV drugs with poor aqueous solubility and poor enzymatic and/or metabolic stability is very challenging. Bay41-4109, a member of the heteroaryldihydropyrimidine (HAP) family, inhibits HBV replication by destabilizing capsid assembly. It pertains to class II of the BDDCS which has a practically insoluble solubility which is 38 MUg/mL (LYSA) and the oral delivery resulted in low bioavailability. The purpose of the current research work was to develop and evaluate Bay41-4109 loaded chitosan nanoparticles to increase the solubility and bioavailability for treatment of HBV. The Bay41-4109 nanoparticles were prepared by gelation of chitosan with tripolyphosphate (TPP) through ionic cross-linking. A three-factor three-level central composite design (CCD) was introduced to perform the experiments. A quadratic polynomial model was generated to predict and evaluate the independent variables with respect to the dependent variables. Bay41-4109 was encapsulated in the chitosan nanoparticles were demonstrated by PLM, FTIR, DSC, XRD and TEM etc. The in vivo results suggest that Bay41-4109 nanoparticles have better bioavailability and would be a promising approach for oral delivery of Bay41-4109 for the treatment of HBV. PMID- 26428631 TI - Evaluation of a biodegradable microparticulate polymer as a carrier for Burkholderia pseudomallei subunit vaccines in a mouse model of melioidosis. AB - Melioidosis, a potentially lethal disease of humans and animals, is caused by the soil-dwelling bacterium Burkholderia pseudomallei. Due to B. pseudomallei's classification as a Tier 1 Select Agent, there is substantial interest in the development of an effective vaccine. Yet, despite decades of research, no effective target, adjuvant or delivery vehicle capable of inducing protective immunity against B. pseudomallei infection has been identified. We propose a microparticulate delivery vehicle comprised of the novel polymer acetalated dextran (Ac-DEX). Ac-DEX is an acid-sensitive biodegradable carrier that can be fabricated into microparticles (MPs) that are relatively stable at pH 7.4, but rapidly degrade after phagocytosis by antigen presenting cells where the pH can drop to 5.0. As compared to other biomaterials, this acid sensitivity has been shown to enhance cross presentation of subunit antigens. To evaluate this platform as a delivery system for a melioidosis vaccine, BALB/c mice were vaccinated with Ac-DEX MPs separately encapsulating B. pseudomallei whole cell lysate and the toll-like receptor (TLR) 7/8 agonist resiquimod. This vaccine elicited a robust antibody response that included both Th1 and Th2 immunity. Following lethal intraperitoneal challenge with B. pseudomallei 1026b, vaccinated mice demonstrated a significant delay to time of death compared to untreated mice. The formulation, however, demonstrated incomplete protection indicating that lysate protein offers limited value as an antigen. Nevertheless, our Ac-DEX MPs may offer an effective delivery vehicle for a subunit B. psuedomallei vaccine. PMID- 26428632 TI - Development of multifunctional lipid nanocapsules for the co-delivery of paclitaxel and CpG-ODN in the treatment of glioblastoma. AB - In this work, multifunctional lipid nanocapsules (M-LNC) were designed to combine the activity of the cytotoxic drug paclitaxel (PTX) with the immunostimulant CpG. This nanosystem, consisting of modified lipid nanocapsules coated with a cationic polymeric shell composed of chitosan (CS), was able to allocate the hydrophobic drug PTX in the inner oily core, and to associate onto the surface the genetic material CpG. The CS-coated LNC (CS-LNC), showed a narrow size distribution with an average size of 70 nm and a positive zeta potential (+25 mV). They encapsulated PTX in a high amount (98%), and, due to the cationic surface charge, were able to adsorb CpG without losing stability. As a preliminary in vitro study, the apoptotic effect on GL261 glioma cells was investigated. The drug loaded CS-LNC exhibited the ability to interact with glioma cells and induce an important apoptotic effect in comparison with blank systems. Finally, the M-LNC made of CS-LNC loaded with both CpG and PTX were tested in vivo, injected via convention enhanced delivery (CED) in GL261-glioma-bearing mice. The results showed that the overall survival of mice treated with the M-LNC was significantly increased in comparison with the control, Taxol((r)), or the separated injection of PTX-loaded LNC and CpG. This effect was also confirmed by magnetic resonance imaging (MRI) which revealed the reduction of tumor growth in the animals treated with CpG and PTX-loaded M-LNC. All these findings suggested that the developed M LNC could potentiate both CpG immunopotency and PTX antitumor activity by enhancing its delivery into the tumor microenvironment. PMID- 26428633 TI - An investigation into the influence of drug-polymer interactions on the miscibility, processability and structure of polyvinylpyrrolidone-based hot melt extrusion formulations. AB - While hot melt extrusion is now established within the pharmaceutical industry, the prediction of miscibility, processability and structural stability remains a pertinent issue, including the issue of whether molecular interaction is necessary for suitable performance. Here we integrate the use of theoretical and experimental drug-polymer interaction assessment with determination of processability and structure of dispersions in two polyvinylpyrrolidone-based polymers (PVP and PVP vinyl acetate, PVPVA). Caffeine and paracetamol were chosen as model drugs on the basis of their differing hydrogen bonding potential with PVP. Solubility parameter and interaction parameter calculations predicted a greater miscibility for paracetamol, while ATR-FTIR confirmed the hydrogen bonding propensity of the paracetamol with both polymers, with little interaction detected for caffeine. PVP was found to exhibit greater interaction and miscibility with paracetamol than did PVPVA. It was noted that lower processing temperatures (circa 40 degrees C below the Tg of the polymer alone and Tm of the crystalline drug) and higher drug loadings with associated molecular dispersion up to 50% w/w were possible for the paracetamol dispersions, although molecular dispersion with the non-interactive caffeine was noted at loadings up to 20% w./w. A lower processing temperature was also noted for caffeine-loaded systems despite the absence of detectable interactions. The study has therefore indicated that theoretical and experimental detection of miscibility and drug-polymer interactions may lead to insights into product processing and extrudate structure, with direct molecular interaction representing a helpful but not essential aspect of drug-polymer combination prediction. PMID- 26428634 TI - Using simple technology to prompt multistep tasks in the home for people with dementia: An exploratory study comparing prompting formats. AB - Objectives To investigate the relative effectiveness of different prompts for people with dementia during multistep tasks in the home, to inform prompting technology design. Methods Nine pairs of participants (one with dementia and a partner or relative) participated at home. The participants with mild to moderate dementia (5M/4F, aged 73-86 years) functioned at the Planned or Exploratory levels of the Pool Activity Level instrument. A touchscreen computer displayed different prompts during two set tasks: "card-and-envelope" and "CD player." The trials were scored to establish the relative effectiveness of the prompts. Individual tasks were also explored. Results Text and audio prompts were each more effective than video or picture prompts for a card-and-envelope task, but this was not seen in a CD player task. The differences may be related to the type of actions within the tasks; the card-and-envelope actions were easier to convey verbally; the CD player actions lent themselves to visual prompts. Conclusions Designers of technology-based prompts for people with dementia should consider that the effectiveness of different prompts is likely to be task dependent. Familiar, unambiguous language can increase the success of tailored prompts. There are significant practical challenges associated with choosing and deconstructing everyday tasks at home. PMID- 26428635 TI - Understanding the determinants of under-five child mortality in Uganda including the estimation of unobserved household and community effects using both frequentist and Bayesian survival analysis approaches. AB - BACKGROUND: Infant and child mortality rates are among the health indicators of importance in a given community or country. It is the fourth millennium development goal that by 2015, all the United Nations member countries are expected to have reduced their infant and child mortality rates by two-thirds. Uganda is one of those countries in Sub-Saharan Africa with high infant and child mortality rates, therefore it is important to use sound statistical methods to determine which factors are strongly associated with child mortality which in turn will help inform the design of intervention strategies METHODS: The Uganda Demographic Health Survey (UDHS) funded by USAID, UNFPA, UNICEF, Irish Aid and the United Kingdom government provides a data set which is rich in information on child mortality or survival. Survival analysis techniques are among the well developed methods in Statistics for analysing time to event data. These methods were adopted in this paper to examine factors affecting under-five child mortality rates (UMR) in Uganda using the UDHS data for 2011 in R and STATA software. RESULTS: Results obtained by fitting the Cox-proportional hazard model with frailty effects and drawing inference using both the frequentists and Bayesian approaches at 5 % significance level, show evidence of the existence of unobserved heterogeneity at the household level but there was not enough evidence to conclude the existence of unobserved heterogeneity at the community level. Sex of the household head, sex of the child and number of births in the past one year were found to be significant. The results further suggest that over the period of 1990-2015, Uganda reduced its UMR by 52 % . CONCLUSION: Uganda has not achieved the MDG4 target but the 52 % reduction in the UMR is a move in the positive direction. Demographic factors (sex of the household head) and Biological determinants (sex of the child and number of births in the past one year) are strongly associated with high UMR. Heterogeneity or unobserved covariates were found to be significant at the household but insignificant at the community level. PMID- 26428637 TI - Benign Prostatic Hyperplasia - An economic assessment of fixed combination therapy based on a literature review. AB - FederAnziani Senior Italia and SIU - Italian Society of Urology - have decided to work together to draft a document focussing on Benign Prostatic Hyperplasia (BPH), and to stress the importance of adherence with pharmacological treatment in this setting, from both a scientific and a patient standpoint. Starting from a literature search, the two associations analysed to what extent an increase in treatment adherence amongst these patients influences hospital savings and to what extent therapy persistence levels are affected by monotherapy rather than free drug combinations. These estimates were performed only on patients taking medicinal products belonging to the 5 alpha-reductase inhibitors (5ARI) class that, although not indispensable, are the compounds that bring the greatest benefits, especially in the elderly and for which we know that every additional 30 days of therapy reduced the likelihood of acute urinary retention (AUR) and surgery by 14% and 11% respectively *. The results show that the use of fixed combination therapy would involve an increase in persistence due to the lower rate of patients abandoning treatment over time. Each 30 day-increment of 5ARI therapy, i.e. for an expenditure of 10.6 million euros extra per year for 5ARI medication, savings of approximately 24.3 million euros in hospital costs could be achieved. PMID- 26428636 TI - Increased IGF-IEc expression and mechano-growth factor production in intestinal muscle of fibrostenotic Crohn's disease and smooth muscle hypertrophy. AB - The igf1 gene is alternatively spliced as IGF-IEa and IGF-IEc variants in humans. In fibrostenotic Crohn's disease, the fibrogenic cytokine TGF-beta1 induces IGF IEa expression and IGF-I production in intestinal smooth muscle and results in muscle hyperplasia and collagen I production that contribute to stricture formation. Mechano-growth factor (MGF) derived from IGF-IEc induces skeletal and cardiac muscle hypertrophy following stress. We hypothesized that increased IGF IEc expression and MGF production mediated smooth muscle hypertrophy also characteristic of fibrostenotic Crohn's disease. IGF-IEc transcripts and MGF protein were increased in muscle cells isolated from fibrostenotic intestine under regulation by endogenous TGF-beta1. Erk5 and MEF2C were phosphorylated in vivo in fibrostenotic muscle; both were phosphorylated and colocalized to nucleus in response to synthetic MGF in vitro. Smooth muscle-specific protein expression of alpha-smooth muscle actin, gamma-smooth muscle actin, and smoothelin was increased in affected intestine. Erk5 inhibition or MEF2C siRNA blocked smooth muscle-specific gene expression and hypertrophy induced by synthetic MGF. Conditioned media of cultured fibrostenotic muscle induced muscle hypertrophy that was inhibited by immunoneutralization of endogenous MGF or pro-IGF-IEc. The results indicate that TGF-beta1-dependent IGF-IEc expression and MGF production in patients with fibrostenotic Crohn's disease regulates smooth muscle cell hypertrophy a critical factor that contributes to intestinal stricture formation. PMID- 26428638 TI - Improvement of seminal quality and sexual function of men with oligoasthenoteratozoospermia syndrome following supplementation with L-arginine and Pycnogenol(r). AB - We evaluated the effectiveness of antioxidant co-supplementation therapy using Larginine and Pycnogenol((r)) in Japanese men with oligoasthenozoospermia and mild erectile dysfunction (ED). A total of forty-seven adult males with oligoasthenoteratozoospermia syndrome (OAT) were eligible for enrollment. The effectiveness of supplementation with a combination of L-arginine 690 mg and French maritime pine bark extract (Pycnogenol((r))) 60mg for OAT and ED was investigated. The sperm concentration was enhanced significantly after treatment 2 and 4 months (11.79 +/- 9.86 to 21.22 +/- 28.17 and 20.15 +/- 23.99 * 106/ml). Significant improvements in the International Index of Erectile Function (IIEF) were observed in the total score of IIEF (57.69 +/- 11.04 to 59.43 +/- 12.57) and domain of Orgasmic Function (9.01 +/- 1.92 to 9.34 +/- 1.66) after 4 months of treatment. L-arginine acts to increase the production of nitric oxide and Pycnogenol((r)) activates the endothelial nitric oxide synthase and it is a potent antioxidant and inhibitor of inducible nitric oxide synthase. This study suggests that the combination of Pycnogenol((r)) and L-arginine (Edicare((r))) is helpful for infertile men to ameliorate simultaneously quality of sperms as well as erectile functions. PMID- 26428639 TI - The relationship between serum hormone levels (follicle-stimulating hormone, luteinizing hormone, total testosterone) and semen parameters. AB - OBJECTIVE: The aim of this study was to investigate the effect of serum gonadotropin and total testosterone levels on semen parameters. MATERIALS AND METHODS: Three hundred and eighty-two patients that applied to a male infertility polyclinic were included in our study. Serum gonadotropin and total testosterone levels and semen parameters of the patients were analyzed during the first visit to the clinic. The reference FSH value was 1.5-12.4 mIU/mL, that of LH was 1.7 8.6 mIU/mL and the reference value for total testosterone was 249-836 ng/dL. RESULTS: While there was no statistically significant difference between the patients with low gonadotropin levels and the controls regarding any of the semen parameters (p > 0.05), there was a strong statistically significant difference between the patients with high gonadotropin levels and the controls regarding sperm concentration (p = 0.000), total motility (p = 0.000), progressive motility (p = 0.000), and morphology (p = 0.000). There was a strong statistically significant difference between the patients with low testosterone levels and the controls regarding total motility (p = 0.012) and progressive motility (p = 0.010), and a weak statistically significant difference in morphology (p = 0.042). There was no statistically significant difference in semen volume or sperm concentration (p > 0.05). There was no statistically significant difference in any of the semen parameters between the patients with high testosterone levels and the controls (p > 0.05). CONCLUSIONS: Our findings especially regarding LH and T levels are not in agreement with previous reports. In this regard, there is a need for larger-scale and randomized trials to resolve this discrepancy. PMID- 26428641 TI - PDE-5 inhibitors in monotherapy versus combination therapy in a sample of 1200 patients with erectile dysfunction. AB - OBJECTIVES: To compare the effectiveness in the treatment of erectile dysfunction when using PDE-5 inhibitors (PDE5i), alprostadil (PG-E1) and testosterone (TES) in monotherapy or combination therapy. MATERIAL AND METHODS: Observational multicentre retrospective study of men diagnosed and treated for ED between January 2008 and January 2014. Age, social and employment situation, pathological medical history, risk factors, usual treatments, IIEF-5 at the first consultation and at first and each 6 months follow-ups, physical examination, calculated total and free testosterone and received treatment were analysed. Descriptive statistics, one-way ANOVA analysis, Chi2 for qualitative data, t-test, Fisher's exact test and Pearson's correlation coefficient were used; p < 0.05 is considered significant. RESULTS: Average age was 58.61 years, SD5.02, average follow- up time 48.21 months, SD 6.21, range 6-174 months. Out of the patients 76.12% were married, 9.81% divorced/separated, 10.04% single, 4.03% widowed; 85.14% of the total in stable partnership but 66.16% were not accompanied by their partners. In total 844 patients received monotherapy (597 PDE5i; 62 PG-E1; 36 TES; 27 penile prosthesis; 121 psychotherapy/alternative therapies) and 357 combination therapy (167 PDE5i+TES; 124 PDE5i+PGE1; 66 PG-E1+TES). There was a homogeneous distribution between risk factors and medical history groups. Satisfactory response according to IIEF-5 was achieved for 72.33% of patients on PDE5i monotherapy, 46.65% of patients on PDE5i+PG-E1 combination therapy and 83.41% of patients on PDE5i+TES. CONCLUSIONS: The best therapeutic success for ED in this series was achieved through a combination of testosterone+PDE-5 inhibitors without increasing morbidity and maintaining the response over time. Larger studies with longer follow-up will corroborate these findings. PMID- 26428640 TI - The histology and the proapoptotic control in the ipsilateral and the contralateral testes following unilateral vasectomy. AB - OBJECTIVE: The aim of this study was to enlighten both the testicular histology and the genetic aspects of the apoptotic process. Thus an experimental study was designed with a model of unilateral vasectomy. METHODS: Twenty-two adult male rats were used and 4 main groups were formed. The first (A), the second (B), the third (C), and the fourth group (D) consisted of 4, 4, 4 and 10 rats respectively. Rats in group A had sham operation while rats in other groups (B, C, D) underwent left vasectomy operation including binding of ductus deferens with a 3/0 silk and cutting a minimum of 1 cm part while preserving the vascular structure under 9x magnification. Rats undergoing unilateral vasectomy were sacrificed at the 1(st), 2(nd) and 8(th) weeks and their testicular structure and proapoptotic gene proteins were compared with that of the control group undergoing sham operation. RESULTS: We found that vasectomy gradually caused destruction and both ipsilateral and contralateral testicles were affected showing initial apoptosis. CONCLUSION: The procedure causes destruction in the testicular structure by causing bilateral intratubular germ cell necrosis, unilateral obstruction, increase in the tubular pressure and processes that are aggravated by some probable autoimmune reactions. PMID- 26428642 TI - Once-a-day Tadalafil administration improves the spermogram parameters in fertile patients. AB - OBJECTIVES: We explored the safety of Tadalafil once-daily treatment for 12 week and its effects on semen quality in a clinical subpopulation of men with psychogenic erectile dysfunction (ED). PATIENTS AND METHODS: Twenty-seven men, between 19 and 35 years, unaware of their fertility status, suffering from psychogenic ED were enrolled. The examination of the seminal fluid was performed twice before administration of Tadalafil and twice after three months of continuous daily administration of Tadalafil 5 mg. The volume of the seminal fluid, the concentration of sperm, the concentration of sperm with type "a+b" motility, the concentration of sperm with type "a" motility, the concentration of normal sperm were taken into consideration. The results before treatment with Tadalafil (T0) and after 3 months of treatment (T3m) were compared. RESULTS: The administration of once-daily Tadalafil 5mg, brings to an average increase of the total number of sperm cells, both total and fast motility (type a) and the percentage of nemasperms, and to an average increase of semen volume of only 0.41 ml. These quantitative and qualitative improvements of the seminal fluid resulted statistically significant as regard motility, nemasperm percentage and seminal fluid volume. No unespected safety findings were observed. CONCLUSIONS: Tadalafil administration improves the quality of sperm cells and seminal fluid: in particular motility, percentage of nemasperms and volume of seminal fluid. We emphasize the safety of the once-daily treatment with tadalafil 5mg and the positive effects on spermatogenesis. PMID- 26428643 TI - Sexual activity and the risk of prostate cancer: Review article. AB - INTRODUCTION: Sexual activity can affect prostate cancer pathogenesis in a variety of ways; including the proposed high androgen status, risk of sexually transmitted infections and the potential effect of retained carcinogens within the prostatic cells. METHODS: PubMed review of all publications concerning sexual activity and the risk of prostate cancer was done by two researchers. RESULTS: Few publications could be detected and data were classified as a prostate cancer risk in association with either heterosexual or homosexual activities. CONCLUSION: Frequent ejaculation seems to be protective from the development of prostate cancer. Multiple sexual partners may be protective from prostate cancer, excluding the risk of sexually transmitted infections. Homosexual men are at a greater risk for the diagnosis of prostate cancer. PMID- 26428644 TI - 500 penile prostheses implanted by a surgeon in Italy in the last 30 years. AB - OBJECTIVES: The aim of our study was to report our experience with patients affected by Erectile Dysfunction (ED) and undergoing penile prosthetic implantation (PPI) in a single center by a single surgeon. MATERIAL AND METHODS: We retrospectively evaluated the clinical outcome of 500 patients (mean age: 51.5 years, range: 20-86 years) affected by ED and referred to our private andrological center from January 1984 to December 2013 who underwent penile prosthesis implantation, including the reported level of patient satisfaction. RESULTS: 182 silicone, 180 malleable, 18 monocomponent hydraulic and 120 multicomponents hydraulic prostheses were implanted by the same experienced surgeon. All patients were hospitalized for the procedure. All patients were evaluated immediately, 1 month (496 patients) and, for the great majority, every year after implantation. One hundred twenty five patients were lost to follow-up. Twenty two patients underwent revision surgery for complications in the postoperative period. The most serious postoperative complications were mechanical problems (45 patients, 9.0%) and infection (15 patients, 3%). Forty two (8.4%) prostheses were explanted. Overall, 80% (400/500) of patients were able to have sexual intercourse and were fully satisfied with the results. CONCLUSIONS: In our experience prosthetic surgery should be considered a good solution for men affected by ED and not responsive to other therapeutic solutions. Prosthetic surgery can be performed not only in large public hospitals but also in smaller private facilities. PMID- 26428645 TI - Androgen deprivation therapy (castration therapy) and pedophilia: What's new. AB - Andrology is a constantly evolving discipline, embracing social problems like pedophilia and its pharmacological treatment. With regard to chemical castration, the andrologist may perform an important role as part of a team of specialists. At present, no knowledge is available regarding hormonal, chromosomal or genetic alterations involved in pedophilia. International legislation primarily aims to defend childhood, but does not provide for compulsory treatment. We reviewed international literature that, at present, only comprises a few reports on research concerning androgen deprivation. Most of these refer to the use of leuprolide acetate, rather than medroxyprogesterone and cyproterone acetate, which present a larger number of side effects. Current opinions on chemical castration for pedophilia are discordant. Some surveys confirm that therapy reduces sexual thoughts and fantasies, especially in recidivism. On the other hand, some authors report that chemical castration does not modify the pedophile's personality. In our opinion, once existing legislation has changed, andrologists could play a significant role in the selection of patients to receive androgen deprivation therapy, due in part to their knowledge about its action and side effects. PMID- 26428646 TI - Stone size and quality of life: A critical evaluation after extracorporeal shock wave lithotripsy. AB - OBJECTIVES: To evaluate the quality of life (QoL) of the patients after extracorporeal shockwave lithotripsy (ESWL) on a treated stone size related basis. METHODS: 90 patients undergoing ESWL for kidney stones were divided into three groups; Group 1 (n: 30, <= 10 mm), Group 2 (n: 28, 11 mm- <= 20 mm) and Group 3 (n: 32, 20- 25 mm). During 3- months follow-up, outcome of the procedure, number of cases with emergency department visits, analgesic required, re tretatment rates, additional procedures and the changes in the QoL were evaluated. RESULTS: the number of emergency department visits and mean analgesic need; re-treatment rates and additional procedures were significantly higher in Group 3. Evaluation of the QoL scores in three groups showed that cases with larger stone still had lower scores during 3-month evaluation. CONCLUSIONS: Stone size could help us to predict the possible impact of ESWL on the QoL and depending on the size of the stone treated, a well planned indication and effective management possibly by an experienced urologist could limit the changes in the QoL of the patients. PMID- 26428648 TI - Clinical significance of prostatic-urethral angulation on the treatment outcome of patients with symptomatic benign prostatic hyperplasia treated with tamsulosin hydrochloride. AB - OBJECTIVES: To evaluate the impact of the prostatic-urethral angulation (PUA) on the treatment efficacy of selective alpha-1A receptor blocker in male patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH). MATERIALS AND METHODS: A total of 80 patients with LUTS/BPH and with mean age 53.3 +/- 6.3 (range 47-70) were included in our prospective comparative study. The patients were classified into 2 groups as a consecutive cases 40 in each one depending on the PUA either <= 35 degrees (group A) or > 35 degrees (group B). PUA and different prostatic parameters were measured using transrectal ultrasound. Prostate-specific antigen (PSA), the International Prostate Symptom Score and quality of life score (IPSS/QoL score), maximum flow rate (Qmax), and postvoid residual (PVR) volume were compared between the groups. The clinical significance of PUA was evaluated after 8 weeks of medical treatment with tamsulosin hydrochloride 0.4 mg daily. RESULTS: Baseline evaluation (pre treatment) for both groups were comparable to each other with no clinically significant difference regarding age, PSA, IPSS/QoL score, Q(max) and PVR volume (P-value > 0.05). Comparison of parameters after 8 weeks showed that tamsulosin hydrochloride improved the total IPSS and all subscores (P < 0.001), QoL (P = 0.001), Q(max) (P = 0.002), and PVR (P = 0.04) in group A (Table 1). CONCLUSION: Tamsulosin hydrochloride appears to be less effective in improving IPSS/Qol score, Qmax and PVR in patients with lager PUA. The PUA might be a predictor for the treatment efficacy of alpha-blockers and more studies are warranted in the future before the final conclusion. PMID- 26428647 TI - A two staged treatment procedure for the difficult to treat bladder neck contractures with concomitant incontinence. In the search of a solution to a complex problem. AB - OBJECTIVE: To examine the efficacy of a two staged treating strategy with the use of a non-permanent urethral ALLIUM((r)) stent for the management of recurrent bladder neck stenosis and subsequently the use of an artificial sphincter AUS800((r)) by AMS for the management of the incontinence. MATERIALS AND METHODS: We progressively identified patients eligible for the study creating a population of cases with recurrent bladder neck stenosis and concomitant incontinence occurring after the last intervention for the stenosis. Efficacy for the treatment of the stenosis was defined as no recurrence both prior and post to the sphincter placement and efficacy for the treatment of the incontinence was defined as continence (0-1pads) after the sphincter placement. RESULTS AND LIMITATIONS: 14 white males with a mean age of 66.21, ranging from 59 to 73 years consisted the population of the study. All patients had severe stress incontinence following the last transurethral resection. The efficacy of the treatment of the bladder neck stenosis was 93% (13/14) while the efficacy for the treatment of the incontinence was 100%. A single patient had a recurrent bladder neck stenosis after the artificial sphincter placement and was treated with transurethral resection using a long pediatric 13 F resectoscope at 12 months. Our limitations is the absence of a control group and the small number of patients enrolled, with a relatively short time of follow up. CONCLUSIONS: In our series we propose the use of a non-permanent urethral ALLIUM((r)) stent for 6 months in order to control the growth of fibrotic scar tissue, a further 6 months follow up for recurrence, and then placement of an artificial sphincter. The results are very promising both on stabilizing the vesicourethral stenosis, and on patient safety and tolerability. PMID- 26428649 TI - Urinary incontinence: Clinical observation on 30 patients undergoing treatment with F.R.E.M.S (Frequency Rhythmic Electrical Modulation System). AB - AIM OF THE STUDY: Urge incontinence is considered to be a dysfunctional pathology of social interest due to the psychological and relational implications of such disability, the elevated number of affected patients and the consequent treatment costs. We propose an innovative non-pharmacological and non-invasive care methodology: Frequency rhythmic electrical modulation system (F.R.E.M.S.) therapy (FT), based on the administration of electric fields of monophasic pulsed, negative, asymmetric current, generated by a neurostimulator with the characteristics of low variable frequency, high voltage and very low impulse duration. MATERIAL AND METHODS: 30 patients were studied with urodynamic evaluation and radiological diagnostic techniques, and underwent 2 cycles of 15 days therapy, with a 12 months follow-up. RESULTS: In 93% of cases, we obtained a positive result, with either disappearance or improvement of symptoms. CONCLUSION: Although the Authors believe that clinical results deserve further neurohistological and immunohistochemical studies, in order to define the anathomophysiological and biochemical changes induced by FT, they propose it as a possible alternative to traditional pharmacological therapy and electrical stimulation. PMID- 26428651 TI - Late-onset secondary nocturnal enuresis in adolescents associated with post traumatic stress disorder developed after a traffic accident. AB - Secondary nocturnal enuresis is generally seen between 5 and 7 years of age and it is rarely encountered when compared with the primary incontinence. Patients with suggested diagnosis of secondary nocturnal enuresis should be examined for neurological and spinal anomalies and diabetes mellitus, diabetes insipidus, renal failure and urinary tract infection should be ruled out in differential diagnosis (1-3). Herein, we are presenting case reports of adolescent patients with secondary nocturnal enuresis refractory to medical therapy and developed after in-vehicle and extravehicular accidents. PMID- 26428650 TI - A new ultrasound and clinical classification for management of prostatic abscess. AB - OBJECTIVES: In literature, most of the published data regarding prostatic abscess (PA) are case reports, whereas there is no standardization of the diagnostic and therapeutic routines. The purpose of this study is a new classification of ultrasound imaging of PA with clinical features correlation. MATERIAL AND METHODS: We retrospectively analysed the ultrasound database archives and performed a MEDLINE(r) research of the peer reviewed literature on diagnosis and case reports of PA using the terms "prostate and abscess". RESULTS: PA can be classified into five Types: Type I - PA is present focally in a prostate lobe (<= 10 mm). Type II - PA is present in a prostate lobe (> 10 mm) and/or partially overcrosses the border of the midline prostatic glandular. Type III - PA is present in both glandular lobes form of multifocal areas (<= 10 mm). Type IV - PA is present in both glandular lobes form of multifocal areas (> 10 mm). Type V - PA involving intra or extraprostatic structures (bladder, urethra, seminal vesicles and prostatic capsule). The different ultrasound imaging and diagnostic criteria are listed for each type and subtype. CONCLUSIONS: The sonographic pattern of PA is usually characteristic and easily differentiated from other glandular lesions. The purpose of the study was to associate the use of TRUS to a clinical standardized classification in order to facilitate PA diagnosis and localization directing the clinician treatment to the correct management and adequate therapeutic treatment. PMID- 26428652 TI - 10-year survival of a patient with metastatic prostate cancer: Case report and literature review. AB - Prostate cancer is the most common malignancy in men. The 5-year relative survival for all stages combined is 98.8%. Patients diagnosed with metastatic prostate cancer have median survival from 2 to 3 years. We describe a case of 64 year old man who clinically presented with inguinal lymphadenopathy. Because of elevated PSA levels biopsy of prostate was done and adenocarcinoma was diagnosed. Biopsy of inguinal lymph nodes confirmed the diagnosis of prostate cancer. Hormonal treatment was started and at the most recent follow-up, 10 years later, the patient is asymptomatic with no clinical signs of disseminated disease. PMID- 26428653 TI - Treatment of urethral strictures with balloon dilation: A forgotten tale. AB - Urethral stricture is a common condition that can lead to serious complications such as urinary infections and renal insufficiency secondary to urinary retention. Treatment options include catheterization and dilation, urethroplasty and endoscopic internal urethrotomy as well. Although treatment option depends on the type, length and aetiology of stricture, the choice can be influenced to varying degrees by the simplicity of the method, the preferences of the patient the available accoutrements and the patient health condition. Both urethroplasty and endoscopic internal urethrotomy require anaesthesia and thus are not suitable for many elder and unfit for surgical treatment patients. On the other hand, dilations are easy to perform in every day clinical practice however they have been associated with iatrogenic urethral trauma. In contrast, balloon dilation under vision dilates by radial application of forces against the stricture, avoiding the potentially shearing forces associated with sequential rigid dilation. Since it reduces the possibility of an iatrogenic urethral trauma and the subsequent spongiofibrosis may lead into improved therapeutic outcomes. In this report we describe a technique for the treatment of urethral strictures with balloon dilation in elder and unfit for surgical treatment patients. PMID- 26428654 TI - Contralateral tumor seeding of renal cell carcinoma mimicking late metastasis of liver after laparoscopic nephrectomy: A case report with review of the literature. AB - Laparoscopic surgery has been increasingly used every day in the management of urologic malignancies. Even though it seems as a minimally invasive surgery, during these interventions tumor seeding, as seen in open surgery, confronts us as a rarely seen serious risk. Herein, we have reported a case who demonstrated peritoneal tumor implantation at 12 month postoperative follow up after laparoscopic radical nephrectomy (LRN) performed for Furhman grade 1 (T2N0M0) renal cell cancer. PMID- 26428656 TI - Sex-related penile fracture with complete urethral rupture: A case report and review of the literature. AB - OBJECTIVE: To present the management of a patient with partial disruption of both cavernosal bodies and complete urethral rupture and to propose a non-systematic review of literature about complete urethral rupture. MATERIAL AND METHOD - CASE REPORT: A 46 years old man presented to our emergency department after a blunt injury of the penis during sexual intercourse. On physical examination there was subcutaneous hematoma extending over the proximal penile shaft with a dorsal-left sided deviation of the penis and urethral bleeding. Ultrasound investigation showed an hematoma in the ventral shaft of the penis with a discontinuity of the tunica albuginea of the right cavernosal corporum. The patient underwent immediate emergency surgery consisted on evacuation of the hematoma, reparation the partial defect of both two cavernosal bodies and end to end suture of the urethra that resulted completely disrupted. RESULTS: The urethral catheter was removed at the 12-th postoperative day without voiding symptoms after a retrograde urethrography. 6 months postoperatively the patients was evaluated with uroflowmetry demonstrating a max flow rate of 22 ml/s and optimal functional outcomes evaluated with validated questionnaires. 8 months after surgery the patients was evaluated by dynamic magnetic resonance (MRI) of the penis showing only a little curvature on the left side of the penile shaft. CONCLUSION: Penile fracture is an extremely uncommon urologic injury with approximately 1331 reported cases in the literature till the years 2001. To best of our knowledge from 2001 up today, 1839 more cases have been reported, only in 159 of them anterior urethral rupture was associated and in only 22 cases a complete urethral rupture was described. In our opinion, in order to prevent long term complications, in case of clinical suspicion of penile fracture, especially if it is associated to urethral disruption, emergency surgery should be the first choice of treatment. PMID- 26428655 TI - Distal corpus cavernosum fibrosis and erectile dysfunction secondary to non ischaemic priapism. AB - Non-ischaemic priapism is a rare type of priapism and is associated with penile or perineal trauma. The absence of ischaemia should theoretically prevent smooth muscle necrosis and corporal fibrosis which occurs in ischaemic priapism. The aim of this study was to first report a patient series with non-ischaemic priapism that developed distal corpus cavernosum fibrosis and erectile dysfunction. Over a 5 year period, a cohort of 6 patients diagnosed with non-ischaemic priapism presented to a single centre. The diagnosis was based on a clinical history, penile examination with confirmation using a combination of cavernosal blood gas analysis, colour duplex ultrasonography of the penis and angiography. Patients were followed up in clinic at regular intervals with clinical examination and repeat imaging. Following a median follow up of 4 weeks (range 2-12) the patients reported either the development of erectile dysfunction with distal penile flaccidity. Five patients required the use of PDE-5 inhibitors to achieve full tumescence. The remaining patient eventually underwent insertion of a penile prosthesis due to the failure of pharmacotherapies. Based on these findings we suggest that superselective embolisation of non-ischaemic priapism cases occasionally should be performed after a shorter period of conservative treatment. PMID- 26428658 TI - The Radiology of Osteoporotic Vertebral Fractures Redux. AB - When a low-energy fracture occurs, then osteoporosis has progressed to the point of bony structural failure. Because vertebral fractures are the commonest type of osteoporotic fracture, the correct identification of them becomes important for diagnosis, risk estimation, and management. However, there are no uniformly agreed criteria for their diagnosis. The purpose of this review was to examine the diagnostic radiological strategies available and suggest a coherent approach to diagnosis. Diagnosis had come to focus on comparative changes in vertebral dimensions. However, it has become apparent that mild reductions in vertebral height are of uncertain implication. The importance of structural damage in diagnosis has become recognized in parallel. Relative reductions in vertebral height may not be a necessary nor sufficient criterion by which to diagnose a fracture. PMID- 26428657 TI - Parathyroid hormone 1 receptor is essential to induce FGF23 production and maintain systemic mineral ion homeostasis. AB - Parathyroid-hormone-type 1 receptor (PTH1R) is extensively expressed in key regulatory organs for systemic mineral ion homeostasis, including kidney and bone. We investigated the bone-specific functions of PTH1R in modulating mineral ion homeostasis by generating a novel mouse model in which PTH1R is ablated in the limb mesenchyme using Prx1Cre transgenic mice. Such ablation decreased FGF23 protein and serum levels by 50%, despite normal Fgf23 mRNA levels in long bones. Circulating calcium and PTH levels were unchanged, but inorganic phosphate and 1,25(OH)2D3 levels were significantly decreased and accompanied by elevated urinary calcium and phosphate wasting. Key renal genes for balancing mineral ion homeostasis, calbindinD28k, Klotho, and Napi2a were suppressed by 30-40%. Intermittent hPTH(1-34) injections increased Fgf23 mRNA (7.3-fold), Nurr1 mRNA (3.1-fold), and serum intact-FGF23 (1.6-fold) in controls, but failed to induce Fgf23, Nurr1 mRNA, or intact FGF23 production in mutants. Moreover, a significant elevation in serum C-terminal-FGF23 levels (4-fold) was detected in both genotypes. PTH markedly downregulated Galnt3 expression (2.7-fold) in controls but not in mutants. These results demonstrate the pivotal role of PTH1R in long bones to regulate systemic mineral ion homeostasis and the direct induction of FGF23 by PTH1R signaling. PMID- 26428659 TI - A new algorithm to improve assessment of cortical bone geometry in pQCT. AB - High-resolution peripheral quantitative computed tomography (HR-pQCT) is now considered the leading imaging modality in bone research. However, access to HR pQCT is limited and image acquisition is mainly constrained only for the distal third of appendicular bones. Hence, the conventional pQCT is still commonly used despite inaccurate threshold-based segmentation of cortical bone that can compromise the assessment of whole bone strength. Therefore, this study addressed whether the use of an advanced image processing algorithm, called OBS, can enhance the cortical bone analysis in pQCT images and provide similar information to HR-pQCT when the same volumes of interest are analyzed. Using pQCT images of European Forearm Phantom (EFP), and pQCT and HR-pQCT images of the distal tibia from 15 cadavers, we compared the results from the OBS algorithm with those obtained from common pQCT analyses, HR-pQCT manual analysis (considered as a gold standard) and common HR-pQCT analysis dual threshold technique.We found that the use of OBS segmentation method for pQCT image analysis of EFP data did not result in any improvement but reached similar performance in cortical bone delineation as did HR-pQCT image analyses. The assessments of cortical cross-sectional bone area and thickness by OBS algorithm were overestimated by less than 4% while area moments of inertia were overestimated by ~5-10%, depending on reference HR-pQCT analysis method. In conclusion, this study showed that the OBS algorithm performed reasonably well and it offers a promising practical tool to enhance the assessment of cortical bone geometry in pQCT. PMID- 26428660 TI - Radiofrequency ablation plus chemoembolization versus radiofrequency ablation alone for hepatocellular carcinoma: A systematic review and meta-analysis. AB - BACKGROUND: To determine whether the use of radiofrequency ablation (RFA) plus transcatheter arterial chemoembolization (TACE) is more effective than the use of RFA alone for patients with hepatocellular carcinoma (HCC). METHODS: A computer based search was performed. Randomised trials comparing RFA plus TACE and RFA alone for treatment of HCC were included in this meta-analysis. The outcome of interest for our analysis was survival (recurrence-free survival and overall survival). RESULTS: Eight trials with 648 patients were eligible for this meta analysis. Our pooled results suggest that RFA plus TACE is associated with a significant advantage in recurrence-free survival (RFS) (HR=0.58; 95% CI=0.42 0.80, P=0.001), and overall survival (OS) (HR=0.60; 95% CI=0.47-0.76, P<0.001). CONCLUSION: TACE combined with RFA was more effective than RFA alone, especially for treatment for intermediate and large-size hepatic tumours or younger patients with HCC. PMID- 26428662 TI - Survey of Neurological Disorders in Children Aged 9-15 Years in Northern India. AB - The prevalence of neurological disorders in resource-poor settings, although likely to be high, is largely unexplored. The prevalence and risk factors for neurological disorders, including epilepsy and intellectual, motor, vision, and hearing deficits, in children aged 9 to 15 years in the community were investigated. A new instrument was developed, validated, and used in a 2-stage community survey for neurological disorders in Lucknow, India. Screen-positives and random proportion of screen-negatives were validated using predefined criteria. Prevalence of different neurological disorders was calculated by weighted proportions. Of 6431 children screened, 221 were positive. A total of 214 screen-positives and 251 screen-negatives were validated. Prevalence of neurological disorders was 31.3 per 1000 children of this age group (weighted 95% confidence interval = 16.5, 46.4). The final model for risk factors included age, mud house, delayed cry at birth, and previous head injury. The prevalence of neurological disorders is high in this region. Predictors of neurological disorders are largely modifiable. PMID- 26428663 TI - The Val142Ile transthyretin cardiac amyloidosis: not only an Afro-American pathogenic variant? A single-centre Italian experience. AB - Transthyterin amyloidosis is a life-threatening disorder caused by the deposition of hepatocyte-derived transthyretin (TTR) amyloid in various tissues and organs. The most common worldwide pathogenic variant with almost exclusive cardiac involvement is Val142Ile with an allele frequency of 3.5% in U.S. African American population, but supposed extremely rare, with only sporadic cases in Caucasian patients. Unexpectedly, in our amyloidosis referral centre, we identified five patients (15.1% of all TTRm diagnosed patients, three families, two singleton) with Val142Ile variant belonging to unrelated families of Caucasian origin. Molecular study was performed in a total of 10 individuals of which three were Italian families (three affected individuals and five unaffected individuals) and two were singleton (one Italian patient and one patient from Argentine with Spanish ancestry). Sequence analysis of TTR gene revealed the presence of the heterozygous Val142Ile in the five affected patients and in five asymptomatic individuals. All probands underwent, at diagnosis, a complete clinical, echocardiographic and biohumoral evaluation. To the best of our knowledge, we describe the larger report of Caucasian patients with Val142Ile cardiomyopathy. All patients at diagnosis showed symptoms of heart failure with increased thickness of left ventricular walls and systo-diastolic left ventricular dysfunction. They also showed increased plasma values of NT-proBNP and troponin I. Our data confirm that Caucasian patients with the Val142Ile pathogenic variant have phenotypic manifestations similar to that of African American one. Moreover, our data clearly show that Val142Ile pathogenic variant is not only an African-American mutation but could be also an underestimated Caucasian variant. PMID- 26428661 TI - Gastric cancer stem cells: evidence, potential markers, and clinical implications. AB - Gastric cancer is a significant global health problem. It is the fifth most common cancer and third leading cause of cancer-related death worldwide (Torre et al. in CA Cancer J Clin 65(2):87-108, 2015). Despite advances in treatment, overall prognosis remains poor, due to tumour relapse and metastasis. There is an urgent need for novel therapeutic approaches to improve clinical outcomes in gastric cancer. The cancer stem cell (CSC) model has been proposed to explain the high rate of relapse and subsequent resistance of cancer to current systemic treatments (Vermeulen et al. in Lancet Oncol 13(2):e83-e89, 2012). CSCs have been identified in many solid malignancies, including gastric cancer, and have significant clinical implications, as targeting the CSC population may be essential in preventing the recurrence and spread of a tumour (Dewi et al. in J Gastroenterol 46(10):1145-1157, 2011). This review seeks to summarise the current evidence for CSC in gastric cancer, with an emphasis on candidate CSC markers, clinical implications, and potential therapeutic approaches. PMID- 26428664 TI - The small chemical enzyme inhibitor 5-phenylnicotinic acid/CD13 inhibits cell migration and invasion of tartrate-resistant acid phosphatase/ACP5-overexpressing MDA-MB-231 breast cancer cells. AB - Tartrate-resistant acid phosphatase (TRAP/ACP5/uteroferrin/purple acid phosphatase/PP5) has received considerable attention as a newly discovered proinvasion metastasis driver associated with different malignancies. This renders TRAP an interesting target for novel anti-cancer therapy approaches. TRAP exists as two isoforms, 5a and 5b, where the 5a isoform represents an enzymatically less active monomeric precursor to the more enzymatically active 5b isoform generated by proteolytic excision of a repressive loop domain. Recently, three novel lead compounds were identified by fragment-based screening and demonstrated to be efficient TRAP enzyme inhibitors in vitro. We conclude that one of the three compounds i.e. 5-phenylnicotinic acid (CD13) was efficient as a TRAP inhibitor with Kic values in the low micromolar range towards the TRAP 5b isoform, but was not able to inhibit the TRAP 5a isoform. Structure-based docking revealed similar interactions of CD13 with the active site in both TRAP isoforms. In stably TRAP-overexpressing MDA-MB-231 breast cancer cells, CD13 inhibited intracellular TRAP activity and showed no cytotoxicity at 200 uM. Furthermore, CD13 selectively blocked the TRAP 5b isoform compared to the TRAP 5a in cultured cells, indicating the usefulness of CD13 for assessing the different biological functions of the two TRAP isoforms 5a and 5b in cell systems. Moreover, inhibition of cell migration and invasion of stably TRAP-overexpressing MDA-MB 231 by CD13 was observed. These data establish a proof of principle that a small chemical inhibitor of the TRAP enzyme can block TRAP-dependent functions in cancer cells. PMID- 26428665 TI - HSPA12B regulates SSeCKS-mediated astrocyte inflammatory activation in neuroinflammation. AB - Reactive astrocytosis has been considered either beneficial or detrimental effection in neuroinflammatory disease. HSPA12B, a new member belongs to the 70 kDa family of heat shock proteins (HSP70) which could modulate inflammatory response, also shows an connection with the astrocyte activation. Recently, it was reported that Src-Suppressed-C Kinase Substrate (SSeCKS) was detected in heat shock protein A12B (HSPA12B) interacting proteins using a yeast 2-hybrid system. SSeCKS, a major Lipopolysaccharide (LPS) response protein, has been involved in regulating astrocyte activation via production of proinflammatory factor in CNS inflammation. In this study, we found HSPA12B might regulate the expression and activity of SSeCKS to promote astrocyte inflammatory activation and release of inflammatory mediators, such as TNF-alpha and IL-1beta in spinal cord primary astroglial cultures exposed to LPS treatment. The promoting mechanism of interaction between HSPA12B and SSeCKS on LPS-induced astrocyte activation was mediated via the activation of JNK and p38 signaling pathways but not ERK1/2 MAPK signaling pathway. HSPA12B binded to SSeCKS via its both N terminus consisted of amino acids 1-330 and C terminus consisted of amino acids 1278-1596. And, in vivo, we confirmed the interaction between HSPA12B and SSeCKS of astrocyte activation in the pathogenesis of EAE. The regulatory mechanisms of HSPA12B SSeCKS interaction may possibly be the key therapeutic strategy of neuroinflammatory disease. PMID- 26428667 TI - Dynamic risk control by human nucleus accumbens. AB - Real-world decisions about reward often involve a complex counterbalance of risk and value. Although the nucleus accumbens has been implicated in the underlying neural substrate, its criticality to human behaviour remains an open question, best addressed with interventional methodology that probes the behavioural consequences of focal neural modulation. Combining a psychometric index of risky decision-making with transient electrical modulation of the nucleus accumbens, here we reveal profound, highly dynamic alteration of the relation between probability of reward and choice during therapeutic deep brain stimulation in four patients with treatment-resistant psychiatric disease. Short-lived phasic electrical stimulation of the region of the nucleus accumbens dynamically altered risk behaviour, transiently shifting the psychometric function towards more risky decisions only for the duration of stimulation. A critical, on-line role of human nucleus accumbens in dynamic risk control is thereby established. PMID- 26428666 TI - Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings. AB - We recently demonstrated that the frequencies of biomarker groups defined by the presence or absence of both amyloidosis (A+) and neurodegeneration (N+) changed dramatically by age in cognitively non-impaired subjects. Our present objectives were to assess the consequences of defining neurodegeneration in five different ways on the frequency of subjects classified as N+, on the demographic associations with N+, and on amyloidosis and neurodegeneration (A/N) biomarker group frequencies by age. This was a largely cross-sectional observational study of 1331 cognitively non-impaired subjects aged 50-89 drawn from a population based study of cognitive ageing. We assessed demographic associations with N+, and A/N biomarker group frequencies by age where A+ was defined by amyloid PET and N+ was defined in five different ways: (i) abnormal adjusted hippocampal volume alone; (ii) abnormal Alzheimer's disease signature cortical thickness alone; (iii) abnormal fluorodeoxyglucose positron emission tomography alone; (iv) abnormal adjusted hippocampal volume or abnormal fluorodeoxyglucose positron emission tomography; and (v) abnormal Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography. For each N+ definition, participants were assigned to one of four biomarker groups; A-N-, A+N-, A-N+, or A+N+. The three continuous individual neurodegeneration measures were moderately correlated (rs = 0.42 to 0.54) but when classified as normal or abnormal had only weak agreement (kappa = 0.20 to 0.29). The adjusted hippocampal volume alone definition classified the fewest subjects as N+ while the Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography definition classified the most as N+. Across all N+ definitions, N+ subjects tended to be older, more often male and APOE4 carriers, and performed less well on functional status and learning and memory than N- subjects. For all definitions of neurodegeneration, (i) the frequency of A-N- was 100% at age 50 and declined monotonically thereafter; (ii) the frequency of A+N- increased from age 50 to a maximum in the mid-70s and declined thereafter; and3 (iii) the frequency of A-N+ (suspected non-Alzheimer's pathophysiology) and of A+N+ increased monotonically beginning in the mid-50s and mid-60s, respectively. Overall, different neurodegeneration measures provide similar but not completely redundant information. Despite quantitative differences, the overall qualitative pattern of the A-N-, A+N-, A-N+, and A+N+ biomarker group frequency curves by age were similar across the five different definitions of neurodegeneration. We conclude that grouping subjects by amyloidosis and neurodegeneration status (normal/abnormal) is robust to different imaging definitions of neurodegeneration and thus is a useful way for investigators throughout the field to communicate in a common classification framework. PMID- 26428668 TI - Depression and Psychosocial Risk Factors among Community-Dwelling Older Adults in Singapore. AB - Depression is the most common mental and emotional disorder that emerges in the late stages of life. It is closely associated with poor health, disability, mortality, and suicide. The study examines the risk factors of depression in late life, especially the psychosocial factors, among a sample comprising 162 community-dwelling Singaporean adults aged 65 years and above. An interview-based structured survey was conducted in multiple senior activity centers located in different parts of Singapore. Results from the hierarchical regression analysis show that 32.9% of the variance in geriatric depression can be explained by the three psychosocial factors, among which loneliness, perceived social support, and the emotional regulation component of resilience are significantly associated with depression in older adults. Large-scale studies should be conducted to confirm the findings of the present study, and to further examine the predictive effects of these psychosocial factors on depression among older adults. PMID- 26428669 TI - A continuous mapping between space and valence with left- and right-handers. AB - In this research, we examined whether emotional valence could correspond to a continuous lateral bias in space, according to a mental metaphor that establishes the mapping between a concrete domain (space) and an abstract one (valence). Because acting with one's dominant hand is associated with fluency and positive valence (the bodily specificity hypothesis, or BSH), we asked strong right- and left-handers to perform two spatial location tasks using emotional faces with seven levels of valence. We hypothesized and showed through two studies that, according to the BSH, extreme valenced stimuli (as compared to moderate and weak ones) would be located more at the extremity of a horizontal line, according to the correspondences between handedness and the different valences of the stimuli. This research establishes that spatial and continuous mapping of emotions was obtained while controlling for motivational direction. PMID- 26428671 TI - Liposome Formation Using a Coaxial Turbulent Jet in Co-Flow. AB - PURPOSE: Liposomes are robust drug delivery systems that have been developed into FDA-approved drug products for several pharmaceutical indications. Direct control in producing liposomes of a particular particle size and particle size distribution is extremely important since liposome size may impact cellular uptake and biodistribution. METHODS: A device consisting of an injection-port was fabricated to form a coaxial turbulent jet in co-flow that produces liposomes via the ethanol injection method. By altering the injection-port dimensions and flow rates, a fluid flow profile (i.e., flow velocity ratio vs. Reynolds number) was plotted and associated with the polydispersity index of liposomes. RESULTS: Certain flow conditions produced unilamellar, monodispersed liposomes and the mean particle size was controllable from 25 up to >465 nm. The mean liposome size is highly dependent on the Reynolds number of the mixed ethanol/aqueous phase and independent of the flow velocity ratio. CONCLUSIONS: The significance of this work is that the Reynolds number is predictive of the liposome particle size, independent of the injection-port dimensions. In addition, a new model describing liposome formation is outlined. The significance of the model is that it relates fluid dynamic properties and lipid-molecule physical properties to the final liposome size. PMID- 26428670 TI - What a car does to your perception: Distance evaluations differ from within and outside of a car. AB - Almost a century ago it was first suggested that cars can be interpreted as tools, but consequences of this assumption were never tested. Research on hand held tools that are used to manipulate objects in the environment suggests that perception of near space is extended by using tools. Literature on environment perception finds perception of far space to be modulated by the observer's potential to act in the environment. Here we argue that a car increases the action potential and modulates perception of far space in a way similar to how hand-held tools modulate perception of near space. Five distances (4 to 20 meters) were estimated by pedestrians and drivers before and after driving/walking. Drivers underestimated all distances to a larger percentage than did pedestrians. Underestimation was even stronger after driving. We conclude that cars modulate the perception of far distances because they modulate the driver's perception, like a tool typically does, and change the perceived action potential. PMID- 26428672 TI - Understanding the cholesterol metabolism-perturbing effects of docosahexaenoic acid by gas chromatography-mass spectrometry targeted metabonomic profiling. AB - PURPOSE: Over the past few decades, docosahexaenoic acid (DHA) has gained special attention for management of cholesterol-associated metabolic disorders and neurodegenerative diseases such as Alzheimer's disease (AD) owing to its neuroprotective, anti-inflammatory and hypolipidemic properties. Several epidemiological studies have reported the effect of DHA in reducing the risk of developing AD by lowering cholesterol. Hypercholesterolemia is a pro amyloidogenic factor influencing the enzymatic processing of amyloid-beta precursor protein (AbetaPP) to toxic beta-amyloid. However, the mechanism by which DHA modulates the cholesterol pathway has not been established. Thus, the objective of this study was to investigate the mechanism of regulation of cholesterol metabolism by DHA in an AbetaPP695 overexpressing AD cell model. METHODS: A gas chromatography/mass spectrometry method was developed and validated for the targeted profiling of 11 cholesterol metabolites in DHA-treated Chinese hamster ovary wild-type (CHO-wt) and AbetaPP695 overexpressing (CHO AbetaPP695) cells. The differential metabolite profiles between DHA- and vehicle treated groups were further analyzed using fold change values of the ratio of concentration of metabolites in CHO-AbetaPP695 to CHO-wt cells. Effect of DHA on key rate-limiting enzymatic activities within the cholesterol pathway was established using biochemical assays. RESULTS: Our results showed that DHA reduced the levels of key cholesterol anabolites and catabolites in CHO AbetaPP695 cells as compared to CHO-wt cells. Further enzymatic studies revealed that the cholesterol-lowering effect of DHA was mediated by regulating HMG-CoA reductase and squalene epoxidase enzyme activities. CONCLUSION: We demonstrate for the first time the dual effects of DHA in inhibiting HMG-CoA reductase and squalene epoxidase and modulating the sterol biosynthesis axis of the cholesterol pathway in AbetaPP695 overexpressing AD. Our novel findings underscore the potential of DHA as a multi-target hypocholesterolemic agent for the prophylaxis of AD and other cholesterol-associated diseases. PMID- 26428674 TI - Regional right ventricular dysfunction in acute pulmonary embolism: relationship with clot burden and biomarker profile. AB - Regional right ventricular (RV) dysfunction (RRVD) is an echocardiographic feature in acute pulmonary embolism (PE), primarily reported in patients with moderate-to-severe RV dysfunction. This study investigated the clinical importance of RRVD by assessing its relationship with clot burden and biomarkers. We identified consecutive patients admitted to the emergency department between 1999 and 2014 who underwent computed tomographic angiography, echocardiography, and biomarker testing (troponin and NT-proBNP) for suspected acute PE. RRVD was defined as normal excursion of the apex contrasting with hypokinesis of the mid free wall segment. RV assessment included measurements of ventricular dimensions, fractional area change, free-wall longitudinal strain and tricuspid annular plane systolic excursion. Clot burden was assessed using the modified Miller score. Of 82 patients identified, 51 had acute PE (mean age 66 +/- 17 years, 43% male). No patient had RV myocardial infarction. RRVD was present in 41% of PEs and absent in all patients without PE. Among patients with PE, 86% of patients with RRVD had central or multi-lobar PE. Patients with RRVD had higher prevalence of moderate to-severe RV dilation (81 vs. 30%, p < 0.01) and dysfunction (86 vs. 23%, p < 0.01). There was a strong trend for higher troponin level in PE patients with RRVD (38 vs. 13% in PE patients without RRVD, p = 0.08), while there was no significant difference for NT-proBNP (67 vs. 73%, p = 0.88). RRVD showed good concordance between readers (87%). RRVD is associated with an increased clot burden in acute PE and is more prevalent among patients with moderate-to-severe RV enlargement and dysfunction. PMID- 26428673 TI - Resveratrol attenuates norepinephrine-induced ovarian cancer invasiveness through downregulating hTERT expression. AB - Stress hormone norepinephrine (NE) has been associated with acquisition of cancer progression, and naturally occurring phytoalexin resveratrol (REV) has been known to suppress cancer growth and progression. In the present study, we determine the effect of REV on NE-induced ovarian cancer invasiveness. Pretreatment of REV significantly inhibited NE-induced ovarian cancer cell epithelial-to-mesenchymal transition with concomitant recovery of E-cadherin expression. In addition, our data showed that REV downregulates NE-induced human telomerase reverse transcriptase (hTERT) expression through inhibiting Src phosphorylation and HIF 1alpha expression. Further, REV reduced NE-induced Slug expression and subsequent ovarian cancer invasion. More importantly, combined treatment of REV with a pharmacological inhibitor of beta adrenergic receptor significantly attenuated NE induced ovarian cancer invasion compared to single treatment. Therefore, we demonstrate interference of a Src and HIF-1alpha/hTERT/Slug signaling cascade by REV, providing potential therapeutic targets and inhibition of ovarian cancer. PMID- 26428675 TI - Bioimpedance analysis versus lung ultrasonography for optimal risk prediction in hemodialysis patients. AB - Fluid overload is associated with adverse outcomes in hemodialysis (HD) patients. Two bedside methods are increasingly utilized to evaluate objectively fluid status-bioimpedance and lung ultrasonography, but there is no available direct, head-to-head comparison of their prognostic significance. Importantly, their predictive abilities have never been tested in a HD population, alongside those of a classic model that also incorporates established echocardiographic parameters of increased mortality risk. Between 26 May 2011 and 26 October 2012, we included in the study 173 patients undergoing chronic HD treatment for at least 3 months in a single dialysis unit. Relative fluid overload (RFO) and B lines score (BLS) were used as candidate predictors. From Cox survival analysis we evaluated the increase in the predictive abilities for all-cause mortality of adding continuous RFO or BLS to a model including conventional predictors . 31 patients (17.9 %) died during a median follow-up of 21.3 (interquartile range 19.9-30.3) months. All Cox models showed good calibration. The C statistic for the all-cause mortality prediction increased significantly when the RFO was included into the baseline model (DeltaC statistics 0.058 95 %CI = 0.003-0.114), but not when the BLS was included into the baseline model. Only the model that incorporated RFO showed significantly better risk reclassification abilities than the baseline model (IDI = 3.6 % and continuous NRI = 24.8 %). Fluid overload, as assessed by bioimpedance, and not by lung ultrasonography, improves risk prediction for death, beyond classical and echocardiographic-based risk prediction scores/parameters. PMID- 26428676 TI - Relationship between left ventricular mass and coronary artery disease in young adults: a single-center study using cardiac computed tomography. AB - We evaluated the relationship between coronary artery disease (CAD) and left ventricular mass (LVM) as measured by cardiac computed tomography (CT) in young adults <=40 years of age. We retrospectively enrolled 490 consecutive individuals (383 males; mean age, 35.2 +/- 4.4 years) who underwent cardiac CT. CAD was defined by the presence of any plaque detected by coronary CT angiography. Left ventricular (LV) function, including LVM, was automatically measured by a dedicated workstation. LVM and LVM index (LVMi) in patients with CT-detected CAD were compared to those of patients without CT-detected CAD. Logistic regression analysis was used to evaluate the relationship between cardiovascular risk factors and CAD. Fifty-five individuals had CT-detected CAD (11.2 %, 53 males). LVM measured by cardiac CT was 126.9 +/- 30.0 g for males and 93.6 +/- 20.9 g for females. LVM was higher (117.8 +/- 30.8 vs. 133.6 +/- 33.1 g, P < 0.001) in patients with CT-detected CAD compared with patients without CT-detected CAD. Obesity, hypertension, smoking, hypercholesterolemia, LVM and LVMi were predictors of CT-detected CAD. Body mass index (r = 0.237, P < 0.001) and systolic blood pressure (r = 0.281, P < 0.001) were positively correlated with LVM. In the multivariate analysis, LVM [odds ratio (OR) = 1.016] and LVMi (OR = 1.026) remained independent predictors of CAD. LVM and LVMi in patients with CT detected CAD were higher than that of patients without CT-detected CAD. LVM and LVMi measured by cardiac CT were independent predictors of CAD. PMID- 26428677 TI - Real-time in vivo imaging reveals the ability of neutrophils to remove Cryptococcus neoformans directly from the brain vasculature. AB - Although neutrophils are typically the first immune cells attracted to an infection site, little is known about how neutrophils dynamically interact with invading pathogens in vivo. Here, with the use of intravital microscopy, we demonstrate that neutrophils migrate to the arrested Cryptococcus neoformans, a leading agent to cause meningoencephalitis, in the brain microvasculature. Following interactions with C. neoformans, neutrophils were seen to internalize the organism and then circulate back into the bloodstream, resulting in a direct removal of the organism from the endothelial surface before its transmigration into the brain parenchyma. C. neoformans infection led to enhanced expression of adhesion molecules macrophage 1 antigen on neutrophils and ICAM-1 on brain endothelial cells. Depletion of neutrophils enhanced the brain fungal burden. Complement C3 was critically involved in the recognition of C. neoformans by neutrophils and subsequent clearance of the organism from the brain. Together, our finding of the direct removal of C. neoformans by neutrophils from its arrested site may represent a novel mechanism of host defense in the brain, in addition to the known, direct killing of microorganisms at the infection sites. These data are the first to characterize directly the dynamic interactions of leukocytes with a microbe in the brain of a living animal. PMID- 26428678 TI - gammadelta T cells protect against LPS-induced lung injury. AB - gammadelta T lymphocytes are a unique T cell population with important anti inflammatory capabilities. Their role in acute lung injury, however, is poorly understood but may provide significant insight into lung-protective mechanisms occurring after injury. In a murine model of lung injury, wild-type C57BL/6 and TCRdelta(-/-) mice were exposed to Escherichia coli LPS, followed by analysis of gammadelta T cell and macrophage subsets. In the absence of gammadelta T cells, TCRdelta(-/-) mice developed increased inflammation and alveolar-capillary leak compared with wild-type C57BL/6 mice after LPS exposure that correlated with expansion of distinct macrophage populations. Classically activated M1 macrophages were increased in the lung of TCRdelta(-/-) mice at d 1, 4, and 7 after LPS exposure that peaked at d 4 and persisted at d 7 compared with wild type animals. In response to LPS, Vgamma1 and Vgamma7 gammadelta T cells were expanded in the lung and expressed IL-4. Coculture experiments showed decreased expression of TNF-alpha by resident alveolar macrophages in the presence of gammadelta T cells that was reversed in the presence of an anti-IL-4-blocking antibody. Treatment of mice with rIL4 resulted in reduced numbers of M1 macrophages, inflammation, and alveolar-capillary leak. Therefore, one mechanism by which Vgamma1 and Vgamma7 gammadelta T cells protect against LPS-induced lung injury is through IL-4 expression, which decreases TNF-alpha production by resident alveolar macrophages, thus reducing accumulation of M1 macrophages, inflammation, and alveolar-capillary leak. PMID- 26428679 TI - Characterization of lung infection-induced TCRgammadelta T cell phenotypes by CyTOF mass cytometry. AB - T cell receptor gammadelta cells are known to be the primary effector T cells involved in the response to bacterial infections, yet their phenotypic characteristics are not as well established as other T cell subsets. In this study, we used cytometry by time-of-flight mass cytometry to better characterize the phenotypic response of T cell receptor gammadelta cells to Streptococcus pneumoniae lung infection. Mice were infected, and cells from lung washouts, spleen, and lymph nodes were stained to detect cell-surface, intracellular, and signaling markers. We observed that infection caused a significant increase in T cell receptor gammadelta cells, which expressed high interferon-gamma and interleukin-17A levels. Profiling T cell receptor gammadelta cells by cytometry by time-of-flight revealed that activated gammadelta T cells uniquely coexpressed cell-surface Gr-1, cluster of differentiation 14, and cluster of differentiation 274 (programmed death-ligand 1). Further classification of Gr-1 expression patterns on T cell receptor gammadelta cells demonstrated that Gr-1(+) T cell receptor gammadelta cells were the primary source of interferon-gamma, whereas Gr 1(-) cells mostly expressed interleukin-17A. Gr-1(+) T cell receptor gammadelta cells also showed higher zeta-chain-associated protein kinase 70, p38, and 4eBP1 signaling in response to infection as compared with Gr-1(-) T cell receptor gammadelta cells. Taken together, Gr-1 expression patterns on gammadelta T cells in the lung provide a robust marker to differentiate interferon-gamma- and interleukin-17A-producing subsets involved in the early immune response to bacterial pneumonia. PMID- 26428680 TI - Cochlear implant in a patient with neurofibromatosis type 2 undergoing radiotherapy. PMID- 26428681 TI - Anti-endotoxin effects of terpenoids fraction from Hygrophila auriculata in lipopolysaccharide-induced septic shock in rats. AB - CONTEXT: Hygrophila auriculata (K. Schum) Heine (Acanthaceae) has been traditionally used for the treatment of various ailments such as inflammation, rheumatism, jaundice and malaria. OBJECTIVE: The present study aims to separate terpenoid fraction (TF) from alcohol (70%) extract of the whole plant of Hygrophila auriculata and assess its anti-inflammatory activity. MATERIALS AND METHODS: HPTLC analysis of TF was performed for the estimation of lupeol. Edema was induced in Wistar albino rats by subplanter injection of 0.1 ml of 1% (w/v) carrageenan into the right hind paw after 1 h of TF administration (100 and 200 mg/kg oral). Septic shock was induced by intraperitoneal administration of LPS (100 MUg/kg) in rats and interleukins (IL-1beta and IL-6), tumor necrosis factor (TNF-alpha), superoxide dismutase (SOD), lipid peroxidation (LPO), and nitric oxide (NO) were measured in serum. AutoDock 4.2 was used for molecular docking. RESULTS: Administration of TF significantly (p < 0.005) restored the serum levels of cytokines, LPO (7.77 +/- 0.034 versus 4.59 +/- 0.059 nmole of TBARS), NO (9.72 +/- 0.18 versus 4.15 +/- 0.23 umol nitrite/mg of wet tissue), and SOD (4.89 +/- 0.036 versus 7.83 +/- 0.033 Unit/mg protein) compared with the LPS-challenged rats. Analysis of in silico results revealed that TNF-alpha is the most appropriate target in eliciting anti-inflammatory activity. CONCLUSION: The present findings suggest that TF of Hygrophila auriculata possesses great promise as an anti-inflammatory agent which may be due to its antioxidant effect. Molecular docking results could be exploited for lead optimization and development of suitable treatment of inflammatory disorders. PMID- 26428685 TI - The ability of 18F-choline PET/CT to identify local recurrence of prostate cancer. AB - PURPOSE: To determine when 18F-choline PET/CT can truly identify local recurrence of prostate cancer. METHODS: 1031 patients from 3 European centers underwent (18)F-choline PET/CT (FCH PET/CT) for recurrent disease; 131 subjects (12.7%) showed a positive FCH uptake in the prostatic gland or prostatic fossa. Median age was 72 years (range 48-87 years), and the median PSA level at the time of FCH PET/CT scan was 4.41 ng/mL (0.22-18.13 ng/mL). 45 patients (34.4%) had a Gleason score (GS) >7, and the residual subjects had a GS <= 7. The assessment of true or false-positive FCH PET/CT findings was made by magnetic resonance imaging (n = 34) and/or biopsy in 75/131 cases. A chi (2) test and a Z Kolmogorov-Smirnov test were used to assess the correlation between clinical variables (age, PSA, GS, type of therapy) and FCH PET/CT findings. RESULTS: FCH PET/CT resulted truly positive (TP) for recurrent disease in the prostatic gland/fossa in 59/75 patients (79%) and falsely positive (FP) in 16 subjects (21%). The median value of PSA at the time of FCH PET/CT scan was higher in TP as compared to FP, although not statistically significant (4.76 vs. 3.04 ng/mL p > 0.05). Similarly, median age, GS categories, and the type of therapy were similar between the two groups (p > 0.05). However, when matching GS categories and PSA values, we found that the number of patients with TP findings were higher in the case of a PSA > 2 ng/mL, independently from the GS (ranging between 74% and 92%). Conversely, FP rate ranged between 50% and 65% in patients with a PSA <= 2 ng/mL, especially in the case of GS <= 7, whereas FP was around 25% in those with a GS >7 and PSA > 2 ng/mL. CONCLUSIONS: FCH PET/CT has a limited role in evaluation of prostatic gland/fossa recurrence, due to the physiological biodistribution of the radiopharmaceutical agent. However, in 70-90% of patients with a PSA >2 ng/mL, independently from GS, a focal FCH uptake is compatible with a true local recurrence. PMID- 26428686 TI - Chronobiology and Pharmacologic Modulation of the Renin-Angiotensin-Aldosterone System in Dogs: What Have We Learned? AB - Congestive heart failure (CHF) is a primary cause of morbidity and mortality with an increasing prevalence in human and canine populations. Recognition of the role of renin-angiotensin-aldosterone system (RAAS) overactivation in the pathophysiology of CHF has led to significant medical advances. By decreasing systemic vascular resistance and angiotensin II (AII) production, angiotensin converting enzyme (ACE) inhibitors such as benazepril improve cardiac hemodynamics and reduce mortality in human and dog CHF patients. Although several experiments have pointed out that efficacy of ACE inhibitors depends on the time of administration, little attention is paid to the optimum time of dosing of these medications. A thorough characterization of the chronobiology of the renin cascade has the potential to streamline the therapeutic management of RAAS related diseases and to help determining the optimal time of drug administration that maximizes efficacy of ACE inhibitors, while minimizing the occurrence of adverse effects. We have developed an integrated pharmacokinetic-pharmacodynamic model that adequately captures the disposition kinetics of the paradigm drug benazeprilat, as well as the time-varying changes of systemic renin-angiotensin aldosterone biomarkers, without and with ACE inhibition therapy. Based on these chronobiological investigations, the optimal efficacy of ACE inhibitors is expected with bedtime dosing. The data further show that benazepril influences the dynamics of the renin-angiotensin-aldosterone cascade, resulting in a profound decrease in AII and aldosterone (ALD), while increasing renin activity for about 24 h. From the results of recent investigations in human, it is hypothesized that reduction of AII and ALD is one of the drivers of increased survival and improved quality of life in dogs receiving ACE inhibitors. To support and consolidate this hypothesis, additional efforts should be directed toward the collection of circulating RAAS peptides in spontaneous cases of canine CHF. If such a link could be established, profiling of these biomarkers could support determination of the severity of heart failure, complement clinical and echocardiographic findings, and be used for therapeutic drug monitoring purposes. PMID- 26428688 TI - Magnetic Transitions in Iron Porphyrin Halides by Inelastic Neutron Scattering and Ab Initio Studies of Zero-Field Splittings. AB - Zero-field splitting (ZFS) parameters of nondeuterated metalloporphyrins [Fe(TPP)X] (X = F, Br, I; H2TPP = tetraphenylporphyrin) have been directly determined by inelastic neutron scattering (INS). The ZFS values are D = 4.49(9) cm-1 for tetragonal polycrystalline [Fe(TPP)F], and D = 8.8(2) cm-1, E = 0.1(2) cm-1 and D = 13.4(6) cm-1, E = 0.3(6) cm-1 for monoclinic polycrystalline [Fe(TPP)Br] and [Fe(TPP)I], respectively. Along with our recent report of the ZFS value of D = 6.33(8) cm-1 for tetragonal polycrystalline [Fe(TPP)Cl], these data provide a rare, complete determination of ZFS parameters in a metalloporphyrin halide series. The electronic structure of [Fe(TPP)X] (X = F, Cl, Br, I) has been studied by multireference ab initio methods: the complete active space self consistent field (CASSCF) and the N-electron valence perturbation theory (NEVPT2) with the aim of exploring the origin of the large and positive zero-field splitting D of the 6A1 ground state. D was calculated from wave functions of the electronic multiplets spanned by the d5 configuration of Fe(III) along with spin orbit coupling accounted for by quasi degenerate perturbation theory. Results reproduce trends of D from inelastic neutron scattering data increasing in the order from F, Cl, Br, to I. A mapping of energy eigenvalues and eigenfunctions of the S = 3/2 excited states on ligand field theory was used to characterize the sigma- and pi-antibonding effects decreasing from F to I. This is in agreement with similar results deduced from ab initio calculations on CrX63- complexes and also with the spectrochemical series showing a decrease of the ligand field in the same directions. A correlation is found between the increase of D and decrease of the pi- and sigma-antibonding energies e(lambda)(X) (lambda = sigma, pi) in the series from X = F to I. Analysis of this correlation using second order perturbation theory expressions in terms of angular overlap parameters rationalizes the experimentally deduced trend. D parameters from CASSCF and NEVPT2 results have been calibrated against those from the INS data, yielding a predictive power of these approaches. Methods to improve the quantitative agreement between ab initio calculated and experimental D and spectroscopic transitions for high-spin Fe(III) complexes are proposed. PMID- 26428689 TI - Endoscopic Management of Esophageal Anastomotic Leaks After Surgery for Malignant Disease. AB - BACKGROUND: Esophageal anastomotic leaks after cancer surgery remain a major cause of morbidity and mortality. Endoscopic interventions, including covered metal stents (cSEMS), clips, and direct percutaneous endoscopic jejunostomy (dPEJ) tubes are increasingly used despite limited published data regarding their utility in this setting. This study aimed to determine the efficacy and safety of a multimodality endoscopic approach to anastomotic leak management after operation for esophageal or gastric cancer. METHODS: We performed a retrospective review of prospectively maintained databases of gastric and esophageal operations at our hospital between January 2003 and December 2012. Included patients had an operation for esophageal or gastric cancer, demonstrated evidence of an anastomotic leak at the esophageal anastomosis, and underwent attempted endoscopic therapy. Healing was defined as clinical and radiographic leak resolution. RESULTS: Forty-nine patients with leaks underwent endoscopic management. Of the 49 patients, 31 (63%) received cSEMS, 40 (82%) had dPEJ tubes inserted, and 3 (6%) received clips. Twenty-three (47%) patients underwent a combined approach. Overall, 88% of patients achieved healing in a median of 83 days. Twenty-two of 23 patients (96%) who underwent a multimodality endoscopic approach healed. Only 1 patient had a major complication associated with stent erosion into the pulmonary artery, which was successfully treated with operative repair. CONCLUSIONS: Esophageal anastomotic leaks after esophageal and gastric cancer operations can be managed successfully and safely with endoscopic therapy. Combining cSEMS for leak control and dPEJ tube placement for nutritional support was highly effective in achieving healing, without the need for surgical repair. PMID- 26428690 TI - Nodal Upstaging During Lung Cancer Resection Is Associated With Surgical Approach. AB - BACKGROUND: Recent reports indicate that thoracoscopic lobectomy for lung cancer may be associated with lower rates of surgical upstaging. We queried a statewide cancer registry for differences in upstaging rates and survival by surgical approach. METHODS: The Kentucky Cancer Registry (KCR) collects data, including centralized pathology reporting, on cancer patients treated statewide. We performed a retrospective review from 2010 to 2012 to examine clinical and pathologic stage. We assessed rates of upstaging and whether the surgical approach, thoracotomy (THOR) versus minimally invasive techniques (video-assisted thoracic surgery; VATS), had an impact on final pathologic stage and survival. RESULTS: The KCR database from 2010 to 2012 contained information on 2830 lung cancer cases, 1964 having THOR procedure and 500 having VATS resections. Preoperatively, 36.4% of THOR were clinically stage 1a versus 47.4% VATS (p = 0.0002). Of these, final pathologic stage remained stage 1a in 30.5% of THOR procedures and 38.0% of VATS (p = 0.0002). The overall nodal upstaging rate for THOR was 9.9% and 4.8% for VATS (p = 0.002). Decreased nodal upstaging was found with VATS, independent of tumor size and extent of resection (odds ratio 0.6, 95% confidence interval [CI]: 0.387 to 0.985, p = 0.04). However, improved survival was found with VATS compared with THOR (hazard ratio 0.733, 95% CI: 0.592 to 0.907, p = 0.0042). CONCLUSIONS: Consistent with other reports, we report a lower upstaging rate with VATS. Nevertheless, there is a survival advantage in VATS patients. Although selection bias may play a role in these observed differences, the improved quality of life measures associated with VATS may explain survival improvement despite lower surgical upstaging. PMID- 26428691 TI - Anomalous Aortic Origin of a Coronary Artery: Surgical Repair With Anatomic- and Function-Based Follow-Up. AB - BACKGROUND: Anomalous aortic origin of the coronary artery (AAOCA) with an interarterial (IAC) course is an uncommon congenital anomaly. Surgical indications and repair techniques have evolved. We have managed 259 adult patients with AAOCA over 40 years. Our management strategy includes anatomic- and function-based surveillance to select surgical candidates. We reviewed our surgical cohort and analyzed anatomic and functional outcomes. METHODS: We queried our heart center databases to obtain the names of all patients with AAOCA managed at our institution between 1974 and 2014. We performed a retrospective chart review. RESULTS: Two hundred fifty-nine patients were managed for AAOCA. Sixty-one underwent surgical intervention. Twenty-six with associated coronary atherosclerosis were excluded. Thirty-one who underwent surgical repair were analyzed. Mean age was 42.5 +/- 2.7 years. Twenty-four patients (77.4%) had right AAOCA. Six (19.4%) had left AAOCA. One (3.2%) had bilateral coronary anomalies. Repair techniques included 21 unroofing procedures (67.7%), 6 translocations (19.4%), and 4 coronary artery bypass grafting (CABG) procedures (12.9%). Mean follow-up was 3.8 +/- 0.8 years. Thirteen patients underwent follow-up anatomic testing with computed tomography. Twelve of these patients had widely patent coronary arteries, and 1 patient had mild coronary artery stenosis. Seventeen patients underwent functional testing. Fifteen of these patients had no evidence of ischemia. One patient had reversible ischemia after CABG, and 1 had subclinical ischemia after unroofing. There was 1 late mortality from endocarditis. CONCLUSIONS: Our multidisciplinary program uses a treatment algorithm to select patients with AAOCA for surgical intervention. Only a small subset requires an operation, and we favor unroofing and translocation techniques. With this paradigm, outcomes are excellent, as validated with anatomic- and function-based testing. PMID- 26428693 TI - Kommerell Diverticulum Should Be Removed in Children With Vascular Ring and Aberrant Left Subclavian Artery. AB - BACKGROUND: Right aortic arch with aberrant left subclavian artery is the most frequent cause of vascular ring. Ligamentum arteriosus division opens the ring but leaves the Kommerell diverticulum in place, with a risk of residual compression, aneurysmal dilation, dissection, or even rupture. A procedure consisting of translocation of the aberrant left subclavian artery to the left carotid artery with removal of the Kommerell diverticulum and division of the ligamentum is currently advocated. METHODS: Between September /2009 and August 2011, 12 consecutive patients underwent the foregoing procedure. Clinical findings, surgical procedure, complications, histopathologic findings, and follow up data were retrospectively analyzed. RESULTS: Mean age at the time of operation was 7.7 years (median, 4.3 years, range, 0.9 to 18.9 years), and mean weight was 26 kg (median, 18 kg; range, 8.4 to 59 kg). All patients had symptoms. Computed tomography scan or magnetic resonance imaging, or both, had confirmed the diagnosis in all patients. Postoperative events, all transient, included chylothorax (1 patient), phrenic palsy (1 patient), pneumonia (1 patient), and the need for prolonged chest drainage (3 patients). Mean follow-up reached 19 months (median, 13 months; range, 12 to 41 months). Mild residual respiratory symptoms were noted in 3 patients. Echo-Doppler analysis showed a patent left subclavian-to-carotid artery anastomosis. Histopathologic analysis of the resected diverticulum (n = 6) showed cystic medial necrosis in four diverticula (focal in one). CONCLUSIONS: Translocation of the aberrant left subclavian artery with diverticulum resection and ligamentum division is an efficient procedure for symptom relief. Profound wall abnormalities such as medial necrosis in at least 50% of the analyzed diverticula encourage us to maintain this strategy, to reduce the risk of aneurysm formation and dissection. PMID- 26428692 TI - Coxiella burnetii Endocarditis and Aortic Vascular Graft Infection: An Underrecognized Disease. AB - BACKGROUND: Q fever is considered endemic worldwide, and endocarditis, or aortic vascular infection, or both caused by Coxiella burnetii can be a fatal disease. The importance of surgical intervention has not yet been defined. We performed a descriptive retrospective study to assess indications for surgical treatment, timing of treatment, and outcome. METHODS: We studied all patients from the cardiac surgery department of a large tertiary hospital who underwent valve surgical procedure due to endocarditis or aortic surgical procedure due to graft infection. RESULTS: Throughout a 10-year period, we performed a total of 171 procedures due to valve endocarditis and/or vascular infection. In 16 patients (9.36%) Coxiella burnetii infection was diagnosed. Ten patients had previous cardiac surgical procedures, 3 had previous aortic surgical procedures, 2 had preexisting valvular disease, and 1 patient had no previous valve disorder. All patients received prolonged oral-specific antibiotic therapy under serologic guidance. In 9 patients antibiotic treatment (doxycycline and hydroxychloroquine) was started before the surgical procedure (12.4 +/- 37.5 days), and in 7 patients after the surgical procedure (5.1 +/- 13.5 days). We observed one in-hospital death (6.25%) and no long-term mortality. The mean follow-up period was 50.5 +/- 34.7 months (range, 2 to 104 months). CONCLUSIONS: In this series surgical treatment yielded good results for both Q fever endocarditis and vascular graft infection. No association was found between timing of the surgical procedure and patients' outcomes. PMID- 26428696 TI - Crystallization and arrest mechanisms of model colloids. AB - We performed dynamic simulations of spheres with short-range attractive interactions for many values of interaction strength and range. Fast crystallization occurs in a localized region of this parameter space, but the character of crystallization pathways is not uniform within this region. Pathways range from one-step, in which a crystal nucleates directly from a gas, to two step, in which substantial liquid-like clusters form and only subsequently become crystalline. Crystallization can fail because of slow nucleation from either gas or liquid, or because of dynamic arrest caused by strong interactions. Arrested states are characterized by the formation of networks of face-sharing tetrahedra that can be detected by a local common neighbor analysis. PMID- 26428694 TI - Influenza A virus preferentially snatches noncoding RNA caps. AB - Influenza A virus (IAV) lacks the enzyme for adding 5' caps to its RNAs and snatches the 5' ends of host capped RNAs to prime transcription. Neither the preference of the host RNA sequences snatched nor the effect of cap-snatching on host processes is completely defined. Previous studies of influenza cap-snatching used poly(A)-selected RNAs from infected cells or relied on annotated host genes to define the snatched host RNAs, and thus lack details on many noncoding host RNAs including snRNAs, snoRNAs, and promoter-associated capped small (cs)RNAs, which are made by "paused" Pol II during transcription initiation. In this study, we used a nonbiased technique, CapSeq, to identify host and viral-capped RNAs including nonpolyadenylated RNAs in the same samples, and investigated the substrate-product correlation between the host RNAs and the viral RNAs. We demonstrated that noncoding host RNAs, particularly U1 and U2, are the preferred cap-snatching source over mRNAs or pre-mRNAs. We also found that csRNAs are highly snatched by IAV. Because the functions of csRNAs remain mostly unknown, especially in somatic cells, our finding reveals that csRNAs at least play roles in the process of IAV infection. Our findings support a model where nascent RNAs including csRNAs are the preferred targets for cap-snatching by IAV and raise questions about how IAV might use snatching preferences to modulate host-mRNA splicing and transcription. PMID- 26428695 TI - A conserved charged single alpha-helix with a putative steric role in paraspeckle formation. AB - Paraspeckles are subnuclear particles involved in the regulation of mRNA expression. They are formed by the association of DBHS family proteins and the NEAT1 long noncoding RNA. Here, we show that a recently identified structural motif, the charged single alpha-helix, is largely conserved in the DBHS family. Based on the available structural data and a previously suggested multimerization scheme of DBHS proteins, we built a structural model of a (PSPC1/NONO)(n) multimer that might have relevance in paraspeckle formation. Our model contains an extended coiled-coil region that is followed by and partially overlaps with the predicted charged single alpha-helix. We suggest that the charged single alpha-helix can act as an elastic ruler governing the exact positioning of the dimeric core structures relative to each other during paraspeckle assembly along the NEAT1 noncoding RNA. PMID- 26428698 TI - Soluble beta-(1,3)-glucans enhance LPS-induced response in the monocyte activation test, but inhibit LPS-mediated febrile response in rabbits: Implications for pyrogenicity tests. AB - In the present study, we aimed to determine the influence of beta-(1,3)-d-glucans on the LPS-induced pro-inflammatory cytokine response in the Monocyte Activation Test (MAT) for pyrogens, and on the LPS-induced febrile response in the Rabbit Pyrogen Test (RPT), thus evaluating the resulting effect in the outcome of each test. It was found that beta-(1,3)-d-glucans elicited the production of pro inflammatory cytokines IL-1beta, IL-6 and TNF-alpha, also known as endogenous pyrogens, but not enough to classify them as pyrogenic according to MAT. The same beta-(1,3)-d-glucans samples were non-pyrogenic by RPT. However, beta-(1,3)-d glucans significantly enhanced the LPS-induced pro-inflammatory cytokines response in MAT, insomuch that samples containing non-pyrogenic concentrations of LPS become pyrogenic. On the other hand, beta-(1,3)-d-glucans had no effect on sub-pyrogenic LPS doses in the RPT, but surprisingly, inhibited the LPS-induced febrile response of pyrogenic LPS concentrations. Thus, while beta-(1,3)-d glucans could mask the LPS pyrogenic activity in the RPT, they exerted an overstimulation of pro-inflammatory cytokines in the MAT. Hence, MAT provides higher safety since it evidences an unwanted biological response, which is not completely controlled and is overlooked by the RPT. PMID- 26428697 TI - Cutaneous biocompatible rutin-loaded gelatin-based nanoparticles increase the SPF of the association of UVA and UVB filters. AB - The encapsulation of natural ingredients, such as rutin, can offer improvements in sun protection effectiveness. This strategy can provide enhanced flavonoid content and produces an improved bioactive compound with new physical and functional characteristics. As an alternative to common synthetic-based sunscreens, rutin-entrapped gelatin nanoparticles (GNPs) were designed and associated with ethylhexyl dimethyl PABA (EHDP), ethylhexyl methoxycinnamate (EHMC) and methoxydibenzoylmethane (BMDBM) in sunscreen formulations. The purpose of this study was to develop rutin-loaded gelatin nanoparticles and characterize their physicochemical, thermal, functional and safety properties. Rutin-loaded gelatin nanoparticles increased antioxidant activity by 74% relative to free rutin (FR) solution. Also, this new ingredient upgraded the Sun Protection Factor (SPF) by 48%, indicating its potential as a raw material for bioactive sunscreens. The safety profile indicated that GNPs and glutaraldehyde (GTA) decreased HaCaT cell viability in a concentration/time-dependent manner. However, both blank nanoparticles (B-NC) and rutin-loaded nanoparticles (R-NC) had good performance on skin compatibility tests. These results functionally characterized rutin-loaded nanoparticles as a safe SPF enhancer in sunscreens, especially in association with UV filters. PMID- 26428699 TI - Unfriendly Filter: An Unusual Cause of Hydronephrosis and Hematuria. AB - A 67-year-old woman was referred to the urology clinic for abdominal pain and hematuria. Urine analysis showed microscopic hematuria. Computed tomography urogram revealed a misplaced inferior vena cava (IVC) filter in the right gonadal vein causing right hydronephrosis. Retrograde pyelography revealed a 3-cm ureteral narrowing at the level of the IVC filter. A double-J ureteral stent was placed in the right ureter prior to exploratory laparotomy, which revealed partial erosion of the IVC filter into the right ureter and a thrombosed right ovary. The patient underwent a right oophorectomy and removal of the misplaced IVC filter. Her postoperative course was uncomplicated. PMID- 26428700 TI - Tunical Outer Layer Plays an Essential Role in Penile Veno-occlusive Mechanism Evidenced from Electrocautery Effects to the Corpora Cavernosa in Defrosted Human Cadavers. AB - OBJECTIVE: To determine the exact anatomical structure for establishing penile veno-occlusive function, we sought to conduct a hemodynamic study on defrosted human cadavers. MATERIALS AND METHODS: Thirteen penises were used for this experiment, and 11 intact penises were allocated into the electrocautery group (EG, n = 6) and the ligation group (LG, n = 5). A circumcision was made on the penis to access the veins. Two #19 scalp needles were fixed in the 3 and 9 o'clock positions in the distal penis for colloid infusion and intracavernous pressure (ICP) monitoring, respectively. For the EG, the deep dorsal vein and cavernosal vein trunks were freed for 3-5 cm where at least 3 emissary veins were identified via opening Buck's fascia; these veins underwent electrocautery at 45 watts, while the ICP was maintained at 0, 50, 75, 100, 125, and 150 mmHg, respectively. For control, venous ligation was made but at the ICP of 150 mmHg. A tissue block including the emissary vein was then obtained for histological analysis. RESULTS: Except all in the EG and those whose ICP exceed 125 mmHg in the EG, the sinusoids of the corpora cavernosa sustained varied fulgurated fibrosis in every specimen and the severity appeared reversely commensurate with the ICP regarding sinusoidal clumping and darkish bands (P <.02 and .01 respectively). CONCLUSION: We conclude that the tunica albuginea can prevent the electrocautery damage to intracavernous sinusoids once the ICP reached a level corresponding to a rigid erection. The outer tunica plays an essential role in fulfilling the veno-occlusive mechanism. PMID- 26428701 TI - Adherence to NICE guidance on glucagon-like peptide-1 receptor agonists among patients with type 2 diabetes mellitus: an evaluation using the Clinical Practice Research Datalink. AB - AIMS: To assess adherence to the UK's National Institute for Health and Care Excellence (NICE) guidelines for initiating and continuing glucagon-like peptide 1 (GLP-1) receptor agonists in patients with type 2 diabetes (T2DM). RESEARCH DESIGN AND METHODS: A retrospective cohort study of 7133 primary care patients >=40 years with a first prescription for a GLP-1 receptor agonist following publication of NICE guideline/guidance. Patient characteristics and levels of clinical monitoring were assessed using descriptive analyses. MAIN OUTCOME MEASURES: Main outcomes were the proportion of patients initiating GLP-1 receptor agonists as part of NICE-recommended dual- or triple-therapy regimens; the proportions meeting NICE triple therapy initiation criteria (glycosylated hemoglobin [HbA1c] >=7.5% and body mass index [BMI] >=35 kg/m(2)) and the proportions continuing GLP-1 receptor agonist at 6 months according to NICE recommendations. RESULTS: Mean age at initiating GLP-1 receptor agonists was 58.2 years (SD 9.4), BMI 38.4 kg/m(2) (SD 6.8) and HbA1c 9.2% (SD 3.2%). Overall, only 25% of patients initiated GLP-1 receptor agonists as part of a NICE-recommended regimen. Of patients initiated on a recommended triple-therapy regimen, 50% (646/1284) fulfilled both NICE HbA1c and BMI initiation criteria. Approximately 18% (32/174) of patients continuing NICE-recommended dual therapy at 6 months achieved a 1% reduction in HbA1c and 6.4% (33/515) continuing with NICE recommended triple therapy achieved NICE's target reductions for both HbA1c and body weight. About 8% of patients continuing exenatide as triple therapy (N = 243) achieved both targets. CONCLUSIONS: Adherence to NICE guidance for initiating and continuing GLP-1 receptor agonists is low. However, lack of data on ethnicity (for assessing NICE's BMI criteria) and on contraindications and/or hypersensitivity to other diabetes medication in the treatment pathway have limited our ability to fully assess adherence to GLP-1 prescribing. Further research is warranted to better understand general practitioners' prescribing decisions given the cost of prescribing GLP-1 receptor agonists. PMID- 26428702 TI - Combination therapies for MDS and AML: Does one plus one equal one? PMID- 26428703 TI - Decision for disclosure: The experiences of Iranian infertile couples undergoing assisted reproductive donation procedures. AB - Controversy surrounding disclosure among the recipients of assisted reproductive donation procedures is escalating worldwide, but little research has been conducted in this topic. The purpose of this qualitative study was to explore the experiences of infertile couples undergoing assisted reproductive donation procedures. In this exploratory qualitative study, 32 patients (nine couples and 14 women) who were candidates to use donor eggs, donor embryos or surrogacy, and 5 members of infertility treatment team including gynaecologists, midwives and psychologist (total 37) were purposively selected from the Montaserieh Infertility Research Centre at Mashhad, Iran in 2012 and interviewed using a semi structured in-depth method. Data were analysed using conventional qualitative content analysis with MAXqda software. One overarching theme, entitled 'experiencing uncertainty surrounding the disclosure to others' was identified from the data. This theme contained two subthemes including 'Couples' decisions to not disclose to others' and 'Couples' decisions to disclose to others'. Five categories formed the first subtheme, and the second subtheme emerged from four categories which are discussed in this paper. The main reason for secrecy was concern over societal negative views about assisted reproductive donation procedures. This worry deprived the couples from support from family and friends and as a result requires them to tolerate psychological pressure when using such procedures. PMID- 26428711 TI - Genome-wide association analyses reveal complex genetic architecture underlying natural variation for flowering time in canola. AB - Optimum flowering time is the key to maximize canola production in order to meet global demand of vegetable oil, biodiesel and canola-meal. We reveal extensive variation in flowering time across diverse genotypes of canola under field, glasshouse and controlled environmental conditions. We conduct a genome-wide association study and identify 69 single nucleotide polymorphism (SNP) markers associated with flowering time, which are repeatedly detected across experiments. Several associated SNPs occur in clusters across the canola genome; seven of them were detected within 20 Kb regions of a priori candidate genes; FLOWERING LOCUS T, FRUITFUL, FLOWERING LOCUS C, CONSTANS, FRIGIDA, PHYTOCHROME B and an additional five SNPs were localized within 14 Kb of a previously identified quantitative trait loci for flowering time. Expression analyses showed that among FLC paralogs, BnFLC.A2 accounts for ~23% of natural variation in diverse accessions. Genome-wide association analysis for FLC expression levels mapped not only BnFLC.C2 but also other loci that contribute to variation in FLC expression. In addition to revealing the complex genetic architecture of flowering time variation, we demonstrate that the identified SNPs can be modelled to predict flowering time in diverse canola germplasm accurately and hence are suitable for genomic selection of adaptative traits in canola improvement programmes. PMID- 26428712 TI - Evaluation of a web-based educational programme on changes in frequency of nurses' interventions to help smokers quit and reduce second-hand smoke exposure in China. AB - AIMS: To evaluate a web-based educational smoking cessation programme on changes in the frequency of hospital-based nurses' self-reported interventions to help smokers quit using the 5 As (i.e. Ask, Advise, Assess, Assist, Arrange), to reduce exposure to second-hand smoke and to change attitudes about nurses' involvement in tobacco control. BACKGROUND: Few nurses in China support smokers' quit attempts using evidence-based smoking cessation interventions based on the 5 As. Limited knowledge is a barrier to intervention. Web-based tobacco cessation programs have the potential to reach a large population of nurses. DESIGN: A prospective single-group design with pre-, 3- and 6-month follow-up after the educational programme evaluated the feasibility of conducting web-based educational programs in two cities in China in 2012-2013. METHODS: Frequency of interventions was assessed using a valid and reliable web-based survey with a convenience sample of nurses from eight hospitals in Beijing and Hefei, China. Generalized linear models, adjusting for age, clinical setting, education and site were used to determine changes in the consistent (usually/always) use of the 5 As from baseline to 3 and to 6 months. RESULTS: Nurses (N = 1386) had baseline and/or 3- and 6-month data. At 6 months, nurses were significantly more likely to Assess, Assist and Arrange for smoking cessation and recommend smoke-free home environments. There was significant improvement in attitudes about tobacco control. CONCLUSIONS: Nurses receiving web-based smoking cessation education significantly increased self-reports of frequency of providing interventions to patients who smoke, including recommending smoke-free home environments to support quit attempts. PMID- 26428713 TI - Re: Risk of ultrasound-detected neonatal brain abnormalities in intrauterine growth-restricted fetuses born between 28 and 34 weeks' gestation: relationship with gestational age at birth and fetal Doppler parameters. R. Cruz-Martinez, V. Tenorio, N. Padilla, F. Crispi, F. Figueras and E. Gratacos. Ultrasound Obstet Gynecol 2015; 46: 452-459. PMID- 26428714 TI - Re: Early prediction and aspirin for prevention of pre-eclampsia (EPAPP) study: a randomized controlled trial. A. O. Odibo, K. R. Goetzinger, L. Odibo and M. G. Tuuli. Ultrasound Obstet Gynecol 2015; 46: 414-418. PMID- 26428715 TI - Reply. PMID- 26428716 TI - Re: Are fetuses that fail to achieve their growth potential at increased risk of intrapartum compromise? PMID- 26428717 TI - Ultrafast charge transfer dynamics in supramolecular Pt(II) donor-bridge-acceptor assemblies: the effect of vibronic coupling. AB - Thanks to major advances in laser technologies, recent investigations of the ultrafast coupling of nuclear and electronic degrees of freedom (vibronic coupling) have revealed that such coupling plays a crucial role in a wide range of photoinduced reactions in condensed phase supramolecular systems. This paper investigates several new donor-bridge-acceptor charge-transfer molecular assemblies built on a trans-Pt(II) acetylide core. We also investigate how targeted vibrational excitation with low-energy IR light post electronic excitation can perturb vibronic coupling and affect the efficiency of electron transfer (ET) in solution phase. We compare and contrast properties of a range of donor-bridge-acceptor Pt(II) trans-acetylide assemblies, where IR excitation of bridge vibrations during UV-initiated charge separation in some cases alters the yields of light-induced product states. We show that branching to multiple product states from a transition state with appropriate energetics is the most rigid condition for the type of vibronic control we demonstrate in our study. PMID- 26428718 TI - A Calaxin Gene in the Pacific Oyster Crassostrea gigasand Its Potential Roles in Cilia. AB - calaxin is a newly identified calcium sensor gene that modulates the movement of flagella (and possibly cilia). It was first identified from the ascidian Ciona intestinalis, and its orthologs have been observed in a wide range of animals and choanoflagellates. However, no calaxin-ortholog in a Lophotrochozoa species has been reported so far. This leaves open the question of whether the modulation of ciliary motility by calaxin is conserved among animals. We report a calaxin gene from the Pacific oyster Crassostrea gigas. This gene, termed cgi-calaxin, possesses three conserved EF-hand motifs as its orthologs from chordates. A phylogenetic analysis confirmed its orthology. Expression analysis revealed high expression in typical ciliated tissues such as gill and hepatopancreas. The spatiotemporal expression of the gene during early development was investigated using whole mount in situ hybridization. The results revealed that cgi-calaxin mRNA was aggregated in ciliated tissues of early larvae such as prototroch and velum. Immunofluorescence experiment further certified the ciliary localization of Cgi-Calaxin protein in D-veligers. We prepared the recombinant protein of cgi calaxin and proved it had the capacity to bind to calcium. These results support the conserved roles of cgi-calaxin as a calcium sensor in ciliated cells and enrich the current knowledge on regulatory mechanisms of molluscan cilia. Moreover, we found the gene to be expressed in poorly ciliated tissues, such as adductor muscle, indicating possible roles in non-ciliated cells, which merits further investigation. PMID- 26428719 TI - Population Genetic Structure and Species Status of Asiatic Toads (Bufo gargarizans) in Western China. AB - We investigated the population genetic structure of Asiatic toads (Bufo gargarizans) from the mountains of western China to determine their species status, using genotypic data of ten microsatellite DNA loci and DNA sequences from one mitochondrial gene. A total of 197 samples from eight sites were examined, which cover a large range of elevations (559-3457 m), as well as all three traditionally defined species (or subspecies). AMOVA did not reveal any particularly large among-groups structure, whether the sites were grouped by drainage, elevation, region, or species (subspecies). Individual assignment tests placed all samples into two genetic clusters, which largely corresponded to their geographic locations. An isolation-by-distance pattern was also detected when an outlier population (site 3) was excluded. Furthermore, a mitochondrial gene tree revealed deep divergence among haplotypes, sometimes within the same site. The clade patterns were partially associated with geographic distribution but had no resemblance to the traditional 2- or 3-species classification. Overall, these toad populations harbor a large amount of genetic diversity and have very high population differentiation, but taken together the evidence suggests that all populations belong to a single species. Our results are consistent with most previous molecular studies, and we recommend using Bufo gargarizans to represent all Asiatic toad populations from western China without subspecies division. PMID- 26428721 TI - Sexual Dimorphisms of Appendicular Musculoskeletal Morphology Related to Social Display in Cuban Anolis Lizards. AB - In Anolis lizards, sexual dimorphism has been reported in morphological and ecological traits. Males show larger body size and longer limbs related to territorial combat and courtship display with the dewlap. Although functional anatomical traits are closely related to locomotor behaviors, differences between sexes in musculoskeletal traits on limbs remain unclear. We explored the relationships among sexual dimorphisms in musculoskeletal morphology, habitat, and locomotor traits in Anolis lizards. Specifically, we examined appendicular musculoskeletal morphology in three species of Cuban Anolis by measuring muscle mass and lengths of moment arms. Through comparisons of crossing locomotion, we found that the runner species possessed larger extensors in hindlimbs, which are advantageous for running, whereas the masses of the humeral and femoral retractors were larger in climber species, allowing these lizards to hold up their bodies and occupy tree substrates. Comparisons between the sexes showed different trends among the three species. Males of A. porcatus, which inhabit narrow branches or leaves, had stronger elbow extensors that maintain the display posture. In contrast, males of A. sagrei, which occupy broad surfaces, did not show sexual differences that affected social display. Moreover, A. bartschi indicated sexual differences despite the absence of dewlapping behavior. Our findings suggest that both sexes show fundamentally similar relationships between muscular morphology and locomotor habits to adapt arboreal or terrestrial substrates, and yet sexual dimorphism in forelimb muscles may additionally affected by male specific display with the dewlap. PMID- 26428720 TI - An Anomalous Hatchery-Reared Biwa Rock Catfish, Silurus lithophilus (Teleostei: Siluridae),with an Adipose Fin-Like Projection. AB - An anomalous individual with an adipose fin-like projection was discovered during seedling production of Biwa rock catfish, Silurus lithophilus (Teleostei: Siluridae). The external shape of the projection resembled an adipose fin, but soft rays were clearly observed within it. The projection was proximally supported by a series of pterygiophores and by 14 soft rays. The projection can be explained as: I, homologous with a primitive adipose fin, which occurred as a result of localized ontogenetic reversion; II, an extra fin that occurred as a result of abnormal expression of a regeneration mechanism; III, a remnant of a dorsal fin and/or a second dorsal fin; and IV, an inversion phenomenon of the polarity in the formation process of the anal fin. PMID- 26428722 TI - Tolerance to Elevated Temperature and Ocean Acidification of the Larvae of the Solitary Corals Fungia fungites (Linnaues, 1758) and Lithophyllon repanda (Dana, 1846). AB - Increase in atmospheric CO2is the main driver of global climate change and is projected to elevate sea surface temperature by at least 2 degrees C and to decrease oceanic pH by 0.3 to 0.4 units by the end of the century. These factors seriously threaten coral reef ecosystems worldwide. In Okinawa, solitary corals are an important feature of the coral community structure. While previous studies on the effects of ocean warming (OW), ocean acidification (OA) and its combination on larval survival focused on colonial coral species, the present study assessed the effect of high temperature on larvae from solitary corals. In this study, we examined the influence of OW (control = 28 degrees C; control +3 = 31 degrees C; control + 6 = 34 degrees C) and OA (control, pCO2= 400 to 500 MUatm; medium, pCO2= 1000 to 1300 MUatm; high, pCO2= 1700 to 2200 MUatm) on the larval survival of two solitary corals, Fungia fungites and Lithophyllon repanda for eight days. Results showed that F. fungites was neither affected by OW, OA, nor its combination. Similarly, survival of L. repanda was not affected by OA however it was significantly affected by temperature. Temperature tolerance varies between species; L. repanda (+3 degrees C above ambient) has lower tolerance than F. fungites (+6 degrees C above ambient). This observation suggests that fungiid larvae had higher tolerance to elevated temperature stress relative to other scleractinian corals. With the projected increase in OW and OA in the future, fungiidsmay retain good potential to widely disperse and successfully recruit to natal and other neighbouring reefs. PMID- 26428723 TI - Gonadal Morphology, Histology, and Endocrinological Characteristics of Immature Female Whale Sharks, Rhincodon typus. AB - Captive breeding of whale sharks is one of the great challenges for aquariums. However, there is limited information available related to reproductive physiology due to the difficulty of sampling and long-term observation. In the present report, we provide information on the reproductive physiology of female whale sharks, which were incidentally captured as bycatch in a set-net off the coast of Okinawa, Japan. Total lengths of three captured female whale sharks were 403, 665, and 761 cm, respectively, at the time of their death. Collected paired ovaries differed in size between right and left. However, it seems not to determine which side of ovary becomes developed. Histological observations revealed that oocytes surrounded by follicle cell layers localized in the developed ovary, and most developed oocytes exhibited yolk vesicle stage. Additionally, in the largest specimen, there were low levels of three steroid hormones (Testosterone, Dihydrotestosterone, and Estradiol-17beta) that did not show seasonal variation. The present results indicate that even the whale shark over 7 m in TL are still histologically and endocrinologically immature. We expect that the present data will provide fundamental information related to reproductive physiology of female whale sharks, and will contribute to protection activities and increased success in captive breeding of whale sharks. PMID- 26428724 TI - Androgenic Gland Implantation Induces Partial Masculinization in Marmorkrebs Procambarus fallax f. virginalis. AB - The androgenic gland in malacostracan crustacean species produces and secretes androgenic gland hormone, which is responsible for male sexual differentiation, such as the induction and development of male sexual traits, and in turn the suppression of female sexual traits. Marmorkrebs, Procambarus fallax forma virginalis, which was identified as the first parthenogenetic species in decapod crustaceans, produces only female offspring. In this study, in order to reveal whether the Marmorkrebs crayfish is sensitive to androgenic gland hormone, we transplanted an androgenic gland from a related congener, P. clarkii, to P. fallax f. virginalis. In androgenic gland-implanted specimens, partial masculinization was confirmed: the masculinization of several external sexual characteristics (i.e., thickening of the first and second pleopods; formation of reverse spines on the third and fourth pereopods) was detected, whereas that of internal sexual characteristics (e.g., the formation of ovotestes and male gonoducts) was not. Our results imply that P. fallaxf. virginalis still has sensitivity to the androgenic gland hormone and, at least partly, the hormone should be able to induce male characteristics, even in parthenogenetic Marmorkrebs. PMID- 26428725 TI - A Flatworm from the Genus Waminoa (Acoela: Convolutidae) Associated with Bleached Corals in Western Australia. AB - A flatworm isolated from bleached colonies of the coral Coscinaraea marshae at Rottnest Island, Western Australia, is described using a combination of morphological and molecular systematics. This flatworm shares morphological features characteristic of the genus Waminoa (Acoelomorpha: Acoela), including the presence of two algal symbionts, but appears to have genital regions different from those of other described species of Waminoa. The design of new oligonucleotide primers enabled the amplification of partial 18S rDNA of the Rottnest Island acoel specimens, and phylogenetic analysis positioned them within Waminoa, confirming their placement in the genus. Furthermore, Waminoa specimens from Rottnest Island grouped into a sister clade to Waminoa brickneri, indicating that the morphological and genetic differences observed are most likely intraspecific and due to geographic variation. As such, we name these Rottnest Island specimens W. cf. brickneri, but highlight that key differences warrant further exploration before assignment to this species can be confirmed. This is the first acoel flatworm described from Western Australia and contributes to our understanding of the diversity and evolutionary relationship of the Acoela. PMID- 26428726 TI - A New Species of Meristogenys (Anura: Ranidae) from Sarawak, Borneo. AB - A cryptic Bornean torrent frog of the genus Meristogenys, which is divergent genetically and morphologically from all known congeners, is described from mountain streams of western Sarawak, East Malaysia (Borneo). The species occurs sympatrically with the type species of the genus, M. jerboa, but apparently differs from it in adult coloration and larval morphology, such as keratodont formulae and glands in tail fins. Females of the new species possess much larger and fewer eggs than in sympatric M. jerboa, suggesting significantly different reproductive traits between these species. A key to larvae of known species of the genus is provided. PMID- 26428727 TI - Cribrilina mutabilis n. sp., an Eelgrass-Associated Bryozoan (Gymnolaemata: Cheilostomata) with Large Variationin Zooid Morphology Related to Life History. AB - We describe the cribrimorph cheilostome bryozoan Cribrilina mutabilis n. sp., which we detected as an epibiont on eelgrass (Zostera marina) at Akkeshi, Hokkaido, northern Japan. This species shows three distinct zooid types during summer: the R (rib), I (intermediate), and S (shield) types. Evidence indicates that zooids commit to development as a given type, rather than transform from one type to another with age. Differences in the frontal spinocyst among the types appear to be mediated by a simple developmental mechanism, acceleration or retardation in the production of lateral costal fusions as the costae elongate during ontogeny. Colonies of all three types were identical, or nearly so, in partial nucleotide sequences of the mitochondrial COI gene (555-631 bp), suggesting that they represent a single species. Zooid types varied temporally in overall frequency in the population: colonies contained nearly exclusively R-type zooids in mid-June; predominantly I-type, or both R- and I-type, zooids in mid July; and I-type, S-type, or both I- and S-type zooids (interspersed or in discrete bands) in mid- to late August. Reproduction occurred throughout the season, but peaked in July, with only R- and I-type zooids reproducing. Reproductive zooids bear a vestigial compound (tripartite) ooecium and brood internally; S-type zooids, first appearing in August, were non-reproductive, which suggests that they may serve as an overwintering stage. As this species is easily accessible, common, and simple in form, it is potentially useful as a model system for studying polyphenism at multiple levels (zooid, colony, and population) in the context of life-history adaptations. PMID- 26428728 TI - Adalimumab for refractory pulmonary sarcoidosis. AB - BACKGROUND: Ireland has one of the highest prevalence of sarcoidosis globally. Currently anti-TNF treatment in sarcoidosis is considered on a case-by-case basis particularly in patients who have a sub-optimal response to corticosteroid therapy. AIMS: We report our experience of Adalimumab in a series of refractory pulmonary sarcoidosis and discuss implications for treatment. CONCLUSION: Symptomatic improvement was found in all patients as well as stabilisation or improvement in DLCO sb. Improvements in pulmonary function tests correlated well to radiological stage and length of disease. PMID- 26428729 TI - In vitro and in silico comparative evaluation of anti-Acinetobacter baumannii peptides. AB - To control the infection caused by a multi-drug resistant bacterial pathogen, Acinetobacter baumannii, antimicrobial peptides (AMPs) are being considered as a viable option because of their broad range of antimicrobial activity and non specific mode of action. However, high cost of synthesis of AMPs has led to the development of several computational tools to predict the biological and physicochemical properties of AMPs. In the present study, a comparative analysis has been done between in vitro activity of seven anti-Acinetobacter alpha-helical peptides with in silico prediction tools for studying antimicrobial related properties of AMPs. Database of Antimicrobial Activity and Structure of Peptides (DBAASP) and two algorithms, Support Vector Machine (SVM) and Random Forest (RF) of another server, Collection of Antimicrobial Peptides (CAMP) were compared with in vitro results of AMP/non-AMP nature of anti-Acinetobacter peptides. The results of the influence of biophysical properties of peptides on their antimicrobial activity suggested that amphipathicity is more important than spatial arrangement and charge of alpha-helical peptides. No correlation was observed between the MIC50 values and the hydropathy of AMPs. Based on the present study, it is suggested that with further refinements in the available servers/algorithms for correctly predicting the antimicrobial nature of the peptides, in silico tools can be used to assist the development of new antimicrobial agents. PMID- 26428730 TI - Comparison of the Virulence-Associated Phenotypes of Five Species of Acinetobacter baumannii Complex. AB - In this study, we compared the virulence-associated factors of Acinetobacter baumannii complex species. Sixty-three isolates of five A. baumannii complex species, including 19 A. baumannii, 15 A. nosocomialis, 13 A. seifertii, 13 A. pittii, and 3 A. calcoaceticus isolates, were included in this study. For all isolates, biofilm formation, A549 cell adherence, resistance to normal human serum, and motility were evaluated. A. baumannii complex isolates showed diversity in biofilm formation, A549 cell adherence, and serum resistance, and no strong positive relationships among these virulence characteristics. However, A. seifertii showed relatively consistent virulence-associated phenotypes. In addition, A. baumannii clone ST110 exhibited consistently high virulence associated phenotypes. Motility was observed in seven isolates, and all four A. baumannii ST110 isolates showed twitching motility. Although some inconsistencies in virulence-associated phenotypes were seen, high virulence characteristics were observed in A. seifertii, which has been mainly reported in Korea and shows high rates of colistin resistance. PMID- 26428731 TI - Cloning, Purification, and Characterization of a Heterodimeric beta-Galactosidase from Lactobacillus kefiranofaciens ZW3. AB - Lactobacillus kefiranofaciens ZW3 was obtained from kefir grains, which have high lactose hydrolytic activity. In this study, a heterodimeric LacLM-type beta galactosidase gene (lacLM) from ZW3 was isolated, which was composed of two overlapping genes, lacL (1,884 bp) and lacM (960 bp) encoding large and small subunits with calculated molecular masses of 73,620 and 35,682 Da, respectively. LacLM, LacL, and LacM were expressed in Escherichia coli BL21(DE3) and these recombinant proteins were purified and characterized. The results showed that, compared with the recombinant holoenzyme, the recombinant large subunit exhibits obviously lower thermostability and hydrolytic activity. Moreover, the optimal temperature and pH of the holoenzyme and large subunit are 60 degrees C and 7.0, and 50 degrees C and 8.0, respectively. However, the recombinant small subunit alone has no activity. Interestingly, the activity and thermostability of the large subunit were greatly improved after mixing it with the recombinant small subunit. Therefore, the results suggest that the small subunit might play an important role in maintaining the stability of the structure of the catalytic center located in the large subunit. PMID- 26428733 TI - Analysis of Bacterial Diversity and Communities Associated with Tricholoma matsutake Fruiting Bodies by Barcoded Pyrosequencing in Sichuan Province, Southwest China. AB - Endophytes play an important role in the growth and development of the host. However, the study of endophytes is mostly focused on plants, and reports on bacteria associated with fungi are relatively rare. We studied the bacteria associated with fruiting bodies of Tricholoma matsutake picked from seven main T. matsutake-producing areas in Sichuan, China, by barcoded pyrosequencing. About 8,272 reads were obtained per sample, representing 40 phyla, 103 classes, and 495 genera of bacteria and archaea, and 361-797 operational taxonomic units were observed at a 97% similarity level. The bacterial community was always both more abundant and more diverse than the archaeal community. UniFrac analysis showed there were some difference of bacterial communities among the samples sites. Three bacterial phyla, Proteobacteria, Bacteroidetes, and Firmicutes, were dominant in all samples. Correlation analysis showed there was a significant correlation between some soil properties and bacterial community associated with T. matsutake. This study demonstrated that the bacteria associated with T. matsutake fruiting bodies were diversified. Among these bacteria, we may find some strains that can promote the growth of T. matsutake. PMID- 26428734 TI - Clinical Evidence of Effects of Lactobacillus plantarum HY7714 on Skin Aging: A Randomized, Double Blind, Placebo-Controlled Study. AB - The beneficial effects of probiotics are now widely reported, although there are only a few studies on their anti-aging effects. We have found that Lactobacillus plantarum HY7714 (HY7714) improves skin hydration and has anti-photoaging effects, and in the present study, we have further evaluated the anti-aging effect of HY7714 via a randomized, double blind, placebo-controlled clinical trial. The trial included 110 volunteers aged 41 and 59 years who have dry skin and wrinkles. Participants took 1 * 10(10) CFU/day of HY7714 (probiotic group) or a placebo (placebo group) for 12 weeks. Skin hydration, wrinkles, skin gloss, and skin elasticity were measured every 4 weeks during the study period. There were significant increases in the skin water content in the face (p < 0.01) and hands (p < 0.05) at week 12 in the probiotic group. Transepidermal water loss decreased significantly in both groups at weeks 4, 8, and 12 (p < 0.001 compared with baseline), and was suppressed to a greater extent in the face and forearm in the probiotic group at week 12. Volunteers in the probiotic group had a significant reduction in wrinkle depth at week 12, and skin gloss was also significantly improved by week 12. Finally, skin elasticity in the probiotic group improved by 13.17% (p < 0.05 vs. controls) after 4 weeks and by 21.73% (p < 0.01 vs. controls) after 12 weeks. These findings are preliminary confirmation of the anti aging benefit to the skin of L. plantarum HY7714 as a nutricosmetic agent. PMID- 26428735 TI - Tracking Study About Adenovirus 36 Infection: Increase of Adiposity. AB - This study investigated the cross-sectional and longitudinal association between adenovirus 36 (Ad36) and obesity in 79 Korean adolescent boys over 1 year. We analyzed the changes in body composition and metabolic risk factors according to the presence of Ad36 antibodies. Ad36 antibodies in serum were detected using the constant virus-decreasing serum method. We found that the fat percentage and fasting insulin in the Ad36-seropositive group were greater than the Ad36 seronegative group. These results suggest that Ad36 infection is associated with an increase of adiposity, and the experience of Ad36 infection may affect the future fat gain of adolescents. PMID- 26428736 TI - [Organization of collaborative deliberation for limiting or withholding treatments in children]. AB - In 2005, the French law on patients' rights at the end of life required that decisions to withdraw or withhold life-sustaining treatments be made and carried out by the physician in charge of the patient, after obtaining advice from an independent consulting colleague and the caregiving team. The purpose of this study was to identify theoretical and practical obstacles to this collaborative deliberation and to propose practical guidelines to organize it. PMID- 26428737 TI - [Exocrine pancreatic insufficiency and Turner syndrome: a pediatric case report]. PMID- 26428732 TI - Cell-Based Assay Design for High-Content Screening of Drug Candidates. AB - To reduce attrition in drug development, it is crucial to consider the development and implementation of translational phenotypic assays as well as decipher diverse molecular mechanisms of action for new molecular entities. High throughput fluorescence and confocal microscopes with advanced analysis software have simplified the simultaneous identification and quantification of various cellular processes through what is now referred to as highcontent screening (HCS). HCS permits automated identification of modifiers of accessible and biologically relevant targets and can thus be used to detect gene interactions or identify toxic pathways of drug candidates to improve drug discovery and development processes. In this review, we summarize several HCS-compatible, biochemical, and molecular biology-driven assays, including immunohistochemistry, RNAi, reporter gene assay, CRISPR-Cas9 system, and protein-protein interactions to assess a variety of cellular processes, including proliferation, morphological changes, protein expression, localization, post-translational modifications, and protein-protein interactions. These cell-based assay methods can be applied to not only 2D cell culture but also 3D cell culture systems in a high-throughput manner. PMID- 26428738 TI - Methylene blue treatment for resistant shock following renal transplantation. AB - We report a case of a 19-year-old female with a history of hyperoxaluria type 1 and renal failure. The patient presented for a second renal transplantation 17 years after her first combined liver and kidney transplantation. Postoperative shock was highly resistant to fluids and required massive pharmacologic hemodynamic support. Vasoplegic shock was the presumed diagnosis, and methylene blue was utilized as a rescue therapy, with a rapid hemodynamic response and no apparent side effects. PMID- 26428739 TI - Experimental manipulation of floral scent bouquets restructures flower-visitor interactions in the field. AB - A common structural feature of natural communities is the non-random distribution of pairwise interactions between organisms of different trophic levels. For plant animal interactions, it is predicted that both stochastic processes and functional plant traits that facilitate or prevent interactions are responsible for these patterns. However, unbiased manipulative field experiments that rigorously test the effects of individual traits on community structure are lacking. We address this gap by manipulating floral scent bouquets in the field. Manipulation of floral scent bouquets led to quantitative as well as qualitative restructuring of flower-visitor networks, making them more generalized. Olfactometer trials confirmed both positive and negative responses to scent bouquets. Our results clearly show that the distribution of insect visitors to the two abundant study plant species reflects the insects' species-specific preferences for floral scents, rather than for visual or morphological floral traits. Thus, floral scents may be of major importance in partitioning flower visitor interactions. Integrating experimental manipulations of plant traits with field observations of interaction patterns thus represents a promising approach for revealing the processes that structure species assemblages in natural communities. PMID- 26428740 TI - Angiopoietin-2 is a negative prognostic marker in small cell lung cancer. AB - BACKGROUND: Small cell lung cancer (SCLC) is a highly lethal disease due to its chemorefractory nature after initial treatment. Angiogenesis plays an important role in tumor growth, metastasis and chemoresistance. We hypothesized that angiogenesis could predict chemoresistance in SCLC patients and be potentially a therapeutic target in this disease. METHODS: Serum samples from forty-three SCLC patients were prospectively obtained at diagnosis, response evaluation and progression. Angiogenesis-related cytokines (Angiopoietin-2, VEGF-A, C and D) were simultaneously quantified by Luminex Technology. Clinical data were prospectively recorder. RESULTS: Significantly higher concentration of angiogenesis-related cytokines were found in SCLC patients at diagnosis compared to healthy volunteers. High baseline serum concentration of Angiopoietin-2 (sAngiopoietin-2) were associated with a worse overall survival (p=0.006) and remained independently associated with survival in the multivariate analysis (p=0.008). In addition, sAngiopoietin-2 significantly increased at progression when compared to baseline. CONCLUSION: These data provide novel evidence on a role of sAngiopoietin-2 in the adverse clinical behavior of SCLC and could be a potential therapeutic target in this disease. PMID- 26428741 TI - The bronchiolitis season is upon us--recommendations for the management and prevention of acute viral bronchiolitis. AB - Despite being so common, bronchiolitis remains poorly diagnosed and managed. This article is intended as an update on issues pertaining to this condition. PMID- 26428742 TI - Doctor-assisted suicide: What is the present legal position in South Africa? AB - In the recent case of Stransham-Ford v. the Minister of Justice and Correctional Services, the North Gauteng High Court held that a terminally ill patient who was experiencing intractable suffering was entitled to commit suicide with the assistance of his doctor and that the doctor's conduct would not be unlawful. The court was careful to state that it was not making a general rule about doctor assisted suicide. The latter should be left to the Parliament, the Constitutional Court and 'future courts'. The judge dealt specifically with the facts of the case at hand. In order to understand the basis of the decision it is necessary to consider: (i) the facts of the case; (ii) the question of causation; (iii) the paradox of 'passive' and 'active' euthanasia; (iv) the test for unlawfulness in euthanasia cases; and (v) the meaning of doctor-assisted suicide. It is also necessary to clarify the present legal position regarding doctor-assisted suicide. PMID- 26428743 TI - The importance of identified cause-of-death information being available for public health surveillance, actions and research. AB - An amendment to the South African Births and Deaths Registration Act has compromised efforts to strengthen local mortality surveillance to provide statistics for small areas and enable data linkage to provide information for public health actions. Internationally it has been recognised that a careful balance needs to be kept between protecting individual patient confidentiality and enabling effective public health intelligence to guide patient care and service delivery and prevent harmful exposures. This article describes the public health benefits of a local mortality surveillance system in the Western Cape Province, South Africa (SA), as well as its potential for improving the quality of vital statistics data with integration into the national civil registration and vital statistics system. It also identifies other important uses for identifiable cause-of-death data in SA that have been compromised by this legislation. PMID- 26428744 TI - Social franchising primary healthcare clinics--a model for South African National Health Insurance? AB - This article describes the first government social franchise initiative in the world to deliver a 'brand' of quality primary healthcare (PHC) clinic services. Quality and standards of care are not uniformly and reliably delivered across government PHC clinics in North West Province, South Africa, despite government support, numerous policies, guidelines and in-service training sessions provided to staff. Currently the strongest predictor of good-quality service is the skill and dedication of the facility manager. A project utilising the social franchising business model, harvesting best practices, has been implemented with the aim of developing a system to ensure reliably excellent healthcare service provision in every facility in North West. The services of social franchising consultants have been procured to develop the business model to drive this initiative. Best practices have been benchmarked, and policies, guidelines and clinic support systems have been reviewed, evaluated and assessed, and incorporated into the business plan. A pilot clinic has been selected to refine and develop a working social franchise model. This will then be replicated in one clinic to confirm proof of concept before further scale-up. The social franchise business model can provide solutions to a reliable and recognisable 'brand' of quality universal coverage of healthcare services. PMID- 26428745 TI - The state of South African internships: A national survey against HPCSA guidelines. AB - BACKGROUND: Medical internship is designed to bridge the gap between the theoretical knowledge learned as a student and the skills required as a competent medical practitioner. In South Africa (SA) it is a 2-year structured programme incorporating experience in key domains of medicine selected by the Health Professions Council of South Africa (HPCSA). HPCSA guidelines state that the clinical experience should include teaching, supervision and competency in selected logbook procedures. After concerns were raised over some accredited intern facilities, we investigated whether these guidelines were being met for interns across SA. METHODS: An electronic survey was sent to 150 SA doctors who had completed their internship between 2010 and 2013. The questions covered supervision, workload and rest, teaching and perception of patient safety. All responses were anonymous and there was opportunity to comment at the end of each question. RESULTS: The respondents (n=90) included graduates from all eight SA medical schools. Supervision was ranked as the aspect of internship that respondents would change the most, with 33.0% performing an interventional procedure for the first time without supervision and 25.6% experiencing an adverse event where senior help was not available. More than half the interns had an entire shift supervised by a medical officer with less than 3 years' clinical training in that specialty. CONCLUSIONS: This survey identified deficiencies of supervision as directed by the HPCSA. It also highlighted difficulties with workload and teaching opportunities. A significant proportion of interns did not feel that patients were safe under their care. A national annual HPCSA survey would highlight hospitals where closer investigation may be required. PMID- 26428746 TI - A South African family with oculopharyngeal muscular dystrophy: Clinical and molecular genetic characteristics. AB - Autosomal dominantly inherited oculopharyngeal muscular dystrophy (OPMD) is caused by a trinucleotide repeat expansion in exon 1 of the polyadenylate binding protein nuclear 1 (PABPN1) gene on chromosome 14q. A large family with OPMD was recently identified in Pretoria, South Africa (SA). Molecular studies revealed a (GCG)11(GCA)3GCG or (GCN)15 mutant allele. The (GCN)15 mutation detected in this family has been described previously in families from Uruguay and Mexico as a founder effect. To our knowledge, this is the first report of an SA Afrikaner family with molecularly confirmed OPMD. The proband, a 64-year-old woman, presented to the neurology outpatient department at Steve Biko Academic Hospital, Pretoria. A sibship of 18 individuals was identified, of whom eight had OPMD. Four patients were interviewed and examined clinically, and electromyographic studies were performed. Molecular analysis of the PABPN1 gene was performed by polymerase chain reaction amplification and direct sequencing of exon 1 in three of the patients. Patients presented with ptosis, external ophthalmoplegia, dysphagia, dysarthria and mild proximal weakness. High foot arches and absent ankle reflexes raised the possibility of peripheral neuropathy, but electromyography showed only mildly low sensory amplitudes, and myopathic units in two patients. PMID- 26428747 TI - Understanding the genetic diversity of South Africa's peoples. PMID- 26428748 TI - Genomics in medicine: From promise to practice. PMID- 26428749 TI - Impact of fibrinolytics on the outcome of empyema in South African children. AB - BACKGROUND: Childhood pneumonia is common in all countries, and empyema is one of the commonest complications. The role of routine intrapleural fibrinolytics in the management of childhood empyema is not well established in low- and middle income countries. METHODS: We did a prospective observational study of children sequentially hospitalised with empyema between December 2006 and December 2011 in South Africa (SA). Intrapleural tissue plasminogen activator (TPA), administered according to a standard protocol, was introduced in September 2009. Outcomes in children treated with TPA after 2009 were compared with the historical cohort not treated with TPA who met the treatment criteria. RESULTS: One hundred and forty two children with empyema, median age 17 months (interquartile range 8-43), were admitted during the study period. Excluding children who did not have a chest tube inserted and those in whom fibrinolysis was contraindicated, there were 99 patients, 52 of whom received fibrinolytics. Clinical characteristics and empyema aetiology were similar in those who received fibrinolysis and those who did not. Eighteen children (38.3%) not treated with TPA required surgery v. 5 (9.6%) treated with TPA (relative risk 0.25; 95% confidence interval 0.1-0.6). The median duration of hospitalisation was similar in both groups. Complications occurred rarely and with a similar incidence in both groups. In-hospital mortality was low, with two deaths in each group. CONCLUSION: Intrapleural TPA resulted in a four-fold reduction in surgery. Fibrinolytics should be used for management of empyema in children in SA. PMID- 26428750 TI - The impact of highly active antiretroviral therapy on the burden of bacterial lower respiratory tract infections in children. AB - BACKGROUND: Respiratory diseases are common and associated with significant morbidity and mortality in children. OBJECTIVE: To evaluate the prevalence and outcome of bacterial lower respiratory tract infections (LRTIs) in HIV-infected and uninfected children at a primary level hospital. METHODS: A cross-sectional descriptive study of children aged 6 months-18 years was conducted. Recruitment included HIV-positive children who had been on highly active antiretroviral therapy (HAART) for at least 6 months. A comparator group of HIV-negative children admitted with bacterial pneumonia was included. Laboratory data collected included CD4+ T-cell counts, HIV viral load and C-reactive protein (CRP). Data collected in both groups included demographic data, immunisation status, zinc supplementation, previous LRTIs, environmental exposures and treatment. RESULTS: Fifty-nine HIV-infected and 20 uninfected children were enrolled. The HIV-positive children were older, with a mean age of 107.2 (standard deviation 50.0) months v. 12.0 (5.8) months (p<0.005). The HIV-infected group had a mean CD4 percentage of 31.5%, and had had an average of 3.9 visits for bacterial LRTIs. All were treated with amoxicillin with no complications. In the HIV-uninfected group, cough and rapid breathing were the most common presenting symptoms, and the mean CRP level was 463.0 mg/L. The mean hospital stay was 4 days. CONCLUSION: HAART is effective in reducing the burden of LRTIs in HIV-positive children, even when the diagnosis is delayed. Cough and fast breathing are still the most reliable presenting symptoms of pneumonia. The majority of children still respond to amoxicillin as first-line therapy, with low complication rates. PMID- 26428751 TI - Identification of a mutation in the ubiquitin-fold modifier 1-specific peptidase 2 gene, UFSP2, in an extended South African family with Beukes hip dysplasia. AB - BACKGROUND: Beukes hip dysplasia (BHD) is an autosomal dominant disorder of variable penetrance that was originally identified in a large South African family of European origin. BHD is characterised by bilateral dysmorphism of the proximal femur, which results in severe degenerative osteoarthropathy. Previous studies mapped the disorder to a 3.34 Mb region on chromosome 4q35. OBJECTIVE: To fine-map the BHD locus and identify the disease-causing mutation by direct sequencing. RESULTS: The linked BHD allele was refined to 1.33 Mb, reducing the number of candidate genes from 25 to 16. Analysis of protein coding and invariant splice-site sequences in three distantly related individuals identified a single candidate disease-causing variant c.868T>C within exon 8 of the ubiquitin-fold modifier 1 (Ufm1)-specific peptidase 2 gene, UFSP2. The presence of this unique mutation was confirmed in all 17 affected members of the BHD family who were genotyped. The mutation segregated with the BHD phenotype in the extended family with a two-point (single marker) LOD score of 10.4 (theta=0.0 and 80% penetrance). The mutation predicts the substitution of a highly conserved amino acid, p.Tyr290His, in the encoded protein. In vitro functional assays performed using purified recombinant wild-type and mutant UFSP2 protein demonstrated that the BHD mutation abolishes UFSP2-mediated C-terminal cleavage of its substrate, Ufm1. CONCLUSION: We report a unique UFSP2 mutation that segregates with the BHD phenotype. The predicted amino acid substitution inactivates UFSP2 proteolytic function, thus implicating the ubiquitin-fold modifier 1 cascade in this form of severe hip osteoarthropathy. The facile polymerase chain reaction-based assay we describe could be used to confirm the diagnosis of BHD, or for presymptomatic testing of members of the extended BHD family. PMID- 26428753 TI - Prevalence of Blomia tropicalis allergy in two regions of South Africa. AB - BACKGROUND: Asthma and allergic rhinitis affect 15% and 38% of South African (SA) children, respectively. The housedust mite (HDM) is the most significant indoor aeroallergen. Typical HDM species include Dermatophagoides pteronyssinus, D. farinae and Blomia tropicalis. Conventional skin-prick testing (SPT) panels only test for Dermatophagoides. B. tropicalis has been described in the tropical and subtropical regions, but is not routinely tested for in SA. OBJECTIVE: To ascertain the significance of B. tropicalis as an aeroallergen in northern coastal KwaZulu-Natal Province (KZN), a tropical environment, and in Johannesburg in the highveld, where the climate is milder and less humid. METHODS: Children aged 1-18 years with features of allergic rhinitis and/or asthma were recruited over a 6-month period from Alberlito Hospital in northern KZN and the Clinton Clinic in Johannesburg. SPTs included Dermatophagoides and B. tropicalis. Sensitisation was defined as a wheal 3 mm greater than the negative control. RESULTS: Eighty-five subjects were included, 50 in northern KZN and 35 in the Johannesburg arm; 52% of subjects in northern KZN and 3% in Johannesburg were sensitised to B. tropicalis, with a significant difference between these centres (p<0.05). Of the 52% sensitised to B. tropicalis in northern KZN, half were sensitised only to B. tropicalis. CONCLUSION: There is a high prevalence of B. tropicalis allergy in the tropical northern KZN region and a much lower prevalence in the Johannesburg region. Routine testing for B. tropicalis allergy should be employed in northern KZN. PMID- 26428752 TI - Impact of an educational intervention and clinical performance dashboard on neonatal bloodstream infections. AB - BACKGROUND: Blood cultures are the most direct method of detecting bacteraemia. Reducing contamination rates improves the specificity and positive predictive value of the blood culture. Clinical performance dashboards have been shown to be powerful tools in improving patient care and outcomes. OBJECTIVES: To determine whether prospective surveillance of bloodstream infections (BSIs), introduction of an educational intervention and the use of a clinical performance dashboard could reduce BSIs and blood culture contamination rates in a neonatal nursery. METHODS: We compared two time periods, before and after an intervention. Blood culture data were extracted from the local microbiology laboratory database. The educational intervention included the establishment of hand-washing protocols, blood culture techniques and video tools. A clinical performance dashboard was developed to demonstrate the monthly positive blood culture and contamination rates, and this was highlighted and referred to weekly at the unit staff meeting. RESULTS: Before the intervention, 1 460 blood cultures were taken; 206 (14.1%) were positive, of which 104 (7.1% of the total) were contaminants. In the period following the intervention, 1 282 blood cultures were taken; 131 (10.2%) were positive, of which 42 (3.3% of the total) were contaminants. The number of positive blood cultures and contamination rates after the intervention were both statistically significantly reduced (p=0.002 and p<0.001, respectively). CONCLUSION: This study demonstrates that adopting a relatively simple educational tool, making use of a clinical performance dashboard indicator and benchmarking practice can significantly reduce the level of neonatal sepsis while also reducing contaminated blood cultures. PMID- 26428754 TI - Nodular thyroid disease and thyroid malignancy: Experience at Polokwane Mankweng Hospital Complex, Limpopo Province, South Africa. AB - BACKGROUND: Nodular thyroid disease is common throughout the world. Numbers of patients with goitre are increasing worldwide, as also noted in Limpopo Province, South Africa (SA). Globally, thyroid nodules have been reported in 4-7% of the population on neck palpation and in 30-50% by ultrasonography. OBJECTIVES: To review the profile of thyroid disease in patients with goitre presenting to the Department of Surgery at Polokwane Mankweng Hospital Complex (PMHC), Limpopo, SA, to characterise the pattern of malignancy in patients with goitre, and to determine the most common thyroid cancer. METHOD: A 6-year retrospective study (2003-2008) of all patients with thyroid nodules who underwent thyroid surgery at PMHC. RESULTS: The study group included 90 patients (mean age 45 years, range 4 80). The male-to-female ratio was 1:17 (5 men, 85 women). Of these patients, 80 (89.9%) had benign lesions, of which 52 (57.8% of the total) were adenomas, 25 (27.8%) multinodular goitres (MNGs), 2 (2.2%) hyperplastic nodules and 1 (1.1%) Hashimoto's thyroiditis. Ten patients (11.1%) had malignant lesions (7 follicular carcinomas and 3 papillary carcinomas), of which 2 were found in MNGs. CONCLUSIONS: Adenoma and MNG were the predominant non-malignant conditions (85.6%). The prevalence of thyroid cancer in our study was 11.1%, and of all 90 patients, 7.8% had follicular carcinoma. The risk of malignancy in MNG was 8.9%. Rates of thyroid nodules and carcinoma were highest in women aged 41-60 years. We advocate that total thyroidectomy be considered for MNG, because MNG can harbour incidental carcinoma. PMID- 26428755 TI - Household fuel use and child respiratory ill health in two towns in Mpumalanga, South Africa. AB - BACKGROUND: This cross-sectional study examined respiratory health outcomes and associated risk factors in children living in a part of South Africa characterised by high levels of air pollution. METHODS: A questionnaire was used to collect self-reported respiratory health and risk factor data from the parents/guardians of children between the ages of 9 and 11 years attending primary schools in the study area. Six government schools were selected based on their location, class size and willingness to participate. Univariate and bivariate analyses as well as logistic regression analysis were performed on the data, using a p-value of 0.25 and biological plausibility. RESULTS: The overall prevalence of respiratory ill-health symptoms was 34.1%. The prevalence of respiratory ill-health conditions was significantly elevated among children from households using non-electrical fuels v. electricity for cooking (43.9% v. 31.6%; adjusted p-value 0.005). The same was noted among those using non-electrical fuels for heating (37.8% v. 29.0%). CONCLUSION: The elevated prevalence of some respiratory health outcomes among schoolchildren, especially in conjunction with domestic fossil fuel burning, is of concern. The data collected in this study may be used to complement or form a basis for future policy regarding indoor or ambient air quality in the area. PMID- 26428756 TI - Maternal near miss and maternal death in the Pretoria Academic Complex, South Africa: A population-based study. AB - BACKGROUND: In order to reduce maternal mortality in South Africa (SA), it is important to understand the process of obstetric care, identify weaknesses within the system, and implement interventions for improving care. OBJECTIVE: To determine the spectrum of maternal morbidity and mortality in the Pretoria Academic Complex (PAC), SA. METHODS: A descriptive population-based study that included all women delivering in the PAC. The World Health Organization definition, criteria and indicators of near miss and maternal death were used to identify women with severe complications in pregnancy. RESULTS: Between 1 August 2013 and 31 July 2014, there were 26,614 deliveries in the PAC. The institutional maternal mortality ratio was 71.4/100,000 live births. The HIV infection rate was 19.9%, and 2.7% of women had unknown HIV status. Of the women, 1120 (4.2%) developed potentially life-threatening conditions and 136 (0.5%) life-threatening conditions. The mortality index was 14.0% overall, 30.0% for non-pregnancy related infections, 2.0% for obstetric haemorrhage and 13.6% for hypertension. Of the women with life-threatening conditions, 39.3% were referred from the primary level of care. Vascular, uterine and coagulation dysfunctions were the most frequent organ dysfunctions in women with life-threatening conditions. The perinatal mortality rate was 26.9/1000 births overall, 23.1/1000 for women with non-life-threatening conditions, and 198.0/1000 for women with life-threatening conditions. CONCLUSION: About one in 20 pregnant women in the PAC had a potentially life-threatening condition; 39.3% of women presented to a primary level facility as an acute emergency and had to be transferred for tertiary care. All healthcare professionals involved in maternity care must have knowledge and skills that equip them to manage obstetric emergencies. Review of the basic antenatal care protocol may be necessary. PMID- 26428757 TI - Intracranial suppuration: Review of an 8-year experience at Umtata General Hospital and Nelson Mandela Academic Hospital, Eastern Cape, South Africa. AB - BACKGROUND: Intracranial suppuration (ICS) is a life-threatening condition caused by various disease processes and consisting of brain abscess and extradural and subdural empyema. The major causes have changed over the decades. To the author's knowledge, the incidence of ICS in South Africa (SA) has not been established. OBJECTIVE: To determine the incidence of ICS, overall and according to age and gender, and to identify the source and distribution of ICS. METHOD: The archive of the radiology departments at Umtata General Hospital and Nelson Mandela Academic Hospital in the Transkei region, Eastern Cape Province, SA, was searched retrospectively for computed tomography (CT) reports of patients diagnosed with ICS. Cases in which the CT images, patients' clinical information and CT reports were available for an uninterrupted period of at least 1 year were included. RESULTS: Five time frames were established, encompassing 8 years of data. The first time frame established an incidence of ICS of 1/100,000/year for the Transkei region. All the time frames were utilised to determine the incidence according to gender and age, and the source and distribution of ICS. The incidence of ICS was higher among males than females, and highest in the age groups 0-10 and 11-20 years. A seasonal variation in the incidence of sinusitis- and meningitis-related ICS was noted. Numbers of cases declined during the last 3 years of the study period. CONCLUSION: Sinusitis, head trauma, ear infection and meningitis were the major sources of ICS. A pulmonary source was not a major feature. In the last 4 years, trauma became the commonest source of ICS. A steady decline in ear infection- and meningitis-related ICS was noted. PMID- 26428759 TI - Evaluation of the diagnostic accuracy of the HemoCue device for detecting anaemia in healthy school-aged children in KwaZulu-Natal, South Africa. AB - BACKGROUND: The prevalence of anaemia in school-aged children is reported to be high (>10%), yet neither the onset of anaemia nor the disease causing it is easily established. Any form of anaemia, even if mild, can compromise children's health and survival. This study was conducted to generate data to support or reject use of the HemoCue device as a potential point-of-care method for haemoglobin (Hb) assessment in field and primary healthcare settings. OBJECTIVE: To assess the validity of the HemoCue in relation to the gold-standard laboratory method. METHODS: A cross-sectional study of children aged 6-8 years, analysing the diagnostic accuracy of the HemoCue in determining Hb levels in venous blood. Agreement between the HemoCue and laboratory techniques was evaluated using the Bland-Altman plot. The intra-class correlation coefficient was used to assess within-subject variability of measured Hb. RESULTS: A trend of underestimation of Hb values was noted. The mean Hb with the HemoCue was 11.70 g/dL and that with the laboratory method 12.19 g/dL. The mean difference between the two methods was 0.49 g/dL, with a standard deviation of 0.77 g/dL (95% confidence interval -0.59- 0.38). Discrepancies>1 g/dL were identified in 14.1% of cases. Bias increased with increasing Hb values. CONCLUSION: The HemoCue was found to be comparable to the standard laboratory method for determining Hb concentrations in school-aged children. Its usefulness for screening healthy children was demonstrated, although a full blood count is recommended if anaemia or iron deficiency is suspected. PMID- 26428758 TI - Observed full blood count and lymphocyte subset values in a cohort of clinically healthy South African children from a semi-informal settlement in Cape Town. AB - BACKGROUND: The paediatric full blood count and lymphocyte subset reference intervals used by the National Health Laboratory Service (NHLS), South Africa (SA), are taken from two international reference interval publications. Differences in reference intervals suggest that international data sets may not be appropriate for use in SA. OBJECTIVE: To study immunohaematological values of a group of clinically healthy children from an informal settlement in Cape Town, SA, to assess whether international paediatric reference intervals used by the NHLS are appropriate. METHODS: A cross-sectional study of 207 female and 174 male HIV-uninfected children living in an informal settlement in Cape Town was performed. Full blood counts, automated differential counts and lymphocyte subset analysis were done using internationally accepted technologies. Data were categorised by age and reference intervals compiled using medians and 95% confidence intervals (CIs). Gender comparisons were calculated by non-parametric tests. RESULTS: Although median and 95% CI values differed slightly, physiological trends for red cell, platelet, white blood cell differential and lymphocyte subsets were similar to international reference intervals currently in use at the NHLS. Benign ethnic neutropenia was not a significant finding, and gender-specific intervals were not necessary until 12 years of age. Lower overall median values for haemoglobin and haematocrit, and higher median values for mean cell volume and red cell distribution width, were noted. Assessment of haemoglobin, red cell distribution width and calculated Mentzer ratios suggested underlying iron deficiency in 14.2% of participants. CONCLUSION: Paediatric immunohaematological reference intervals observed in this study are similar to, and support continued use of, international paediatric reference intervals. Underlying iron and related nutritional deficiencies may be contributing to lower haemoglobin levels noted in local children. A larger nationwide study, including all ethnic groups, is recommended. PMID- 26428760 TI - Use of EMLA cream as a topical anaesthetic before venepuncture procedures in field surveys: A practice that helps children, parents and health professionals. AB - BACKGROUND: Topical analgesia is becoming essential as the number of invasive screening procedures involving children rises steadily. Little is known about the frequency of these procedures, or about interventions to ease the pain. METHODS: We investigated the use of EMLA cream in 184 school-aged children in KwaZulu Natal Province, South Africa. Another group of 20 children did not receive any local analgesia and was assessed as a control. Anticipatory anxiety, pain, adverse reactions and ease of procedure were assessed using a subjective visual analogue scale (VAS) pain score generated by the researcher and obtained from each child immediately after the procedure. RESULTS: The use of EMLA cream resulted in reduced pain and distress. The pain-relieving influence of EMLA was good (91.3% analgesic effect). Participants who received EMLA cream reported significantly lower VAS pain scores (p=0.001). Pain scores generated by the researcher were also significantly lower in the EMLA group than in the control group (p=0.000). No adverse reactions were observed, and the children could continue with other research activities during the application time and after the procedure. Parent or caregiver scores were in favour of EMLA cream. CONCLUSION: EMLA cream was safe and effective for alleviating the pain associated with venepuncture in a fieldwork setting. We therefore believe that it merits a place in the routine premedication of children before phlebotomy and cannulation procedures in clinical settings, research studies and field surveys. Further research is recommended to assess whether EMLA cream can be used for immunisations. PMID- 26428761 TI - The Cochrane Corner in the SAMJ: Summaries of Cochrane systematic reviews for evidence-informed practice. PMID- 26428762 TI - Anger and Afrophobia in South Africa: What is a health practitioner to do? PMID- 26428763 TI - Modeling of thermoacoustic systems using the nonlinear frequency domain method. AB - When modeling thermoacoustic (TA) devices at high amplitude, nonlinear effects such as time-average mass flows, and the generation of higher harmonics can no longer be neglected. Thus far, modeling these effects in TA devices required a generally computationally costly time integration of the nonlinear governing equations. In this paper, a fast one-dimensional nonlinear model for TA devices is presented, which omits this costly time integration by directly solving the periodic steady state. The model is defined in the frequency domain, which eases the implementation of phase delays due to viscous resistance and thermoacoustic heat exchange. As a demonstration, the model is used to solve an experimental standing wave thermoacoustic engine. The obtained results agree with experimental results, as well as with results from a nonlinear time domain model from the literature. The low computational cost of this model opens the possibility to do optimization studies using a nonlinear TA model. PMID- 26428764 TI - Sources of variability in consonant perception of normal-hearing listeners. AB - Responses obtained in consonant perception experiments typically show a large variability across stimuli of the same phonetic identity. The present study investigated the influence of different potential sources of this response variability. It was distinguished between source-induced variability, referring to perceptual differences caused by acoustical differences in the speech tokens and/or the masking noise tokens, and receiver-related variability, referring to perceptual differences caused by within- and across-listener uncertainty. Consonant-vowel combinations consisting of 15 consonants followed by the vowel /i/ were spoken by two talkers and presented to eight normal-hearing listeners both in quiet and in white noise at six different signal-to-noise ratios. The obtained responses were analyzed with respect to the different sources of variability using a measure of the perceptual distance between responses. The speech-induced variability across and within talkers and the across-listener variability were substantial and of similar magnitude. The noise-induced variability, obtained with time-shifted realizations of the same random process, was smaller but significantly larger than the amount of within-listener variability, which represented the smallest effect. The results have implications for the design of consonant perception experiments and provide constraints for future models of consonant perception. PMID- 26428765 TI - Environmentally adaptive processing for shallow ocean applications: A sequential Bayesian approach. AB - The shallow ocean is a changing environment primarily due to temperature variations in its upper layers directly affecting sound propagation throughout. The need to develop processors capable of tracking these changes implies a stochastic as well as an environmentally adaptive design. Bayesian techniques have evolved to enable a class of processors capable of performing in such an uncertain, nonstationary (varying statistics), non-Gaussian, variable shallow ocean environment. A solution to this problem is addressed by developing a sequential Bayesian processor capable of providing a joint solution to the modal function tracking and environmental adaptivity problem. Here, the focus is on the development of both a particle filter and an unscented Kalman filter capable of providing reasonable performance for this problem. These processors are applied to hydrophone measurements obtained from a vertical array. The adaptivity problem is attacked by allowing the modal coefficients and/or wavenumbers to be jointly estimated from the noisy measurement data along with tracking of the modal functions while simultaneously enhancing the noisy pressure-field measurements. PMID- 26428766 TI - Modeling photoacoustic cavitation nucleation and bubble dynamics with modified classical nucleation theory. AB - Photoacoustic cavitation (PAC) is the formation of bubbles in liquids using a focused laser and a pre-established ultrasound synchronously. The decreased threshold of each modality and the precise location of cavitation determined by the focused laser are both significant in the targeted theranostics. In this study, PAC nucleation was described using the modified classical nucleation theory by Kashchiev's scaling function. A two-stage model of the PAC bubble dynamics was presented based on the two different bubble behaviors. It was clarified that both negative acoustic pressure and laser-induced temperature rise, resulting in the decrease in critical radius and the increase in nucleation rate, and thereby contribute to the increase in nucleation probability in the confocal region. Ultrasound determined the whole PAC bubble dynamics with temperature-dependent parameters, while the laser mainly contributed to its initial conditions. Moreover, the effects of certain parameters on PAC were further discussed, including the relative acoustic phase when a laser is introduced (phi), laser pulse duration (tau(L)), laser focus radius (R(f)), and ultrasound amplitude (P(A)). The model would be helpful in understanding the PAC process and further in introducing PAC to potential targeted theranostics. PMID- 26428768 TI - Enhancing listener strategies using a payoff matrix in speech-on-speech masking experiments. AB - Speech recognition was measured as a function of the target-to-masker ratio (TMR) with syntactically similar speech maskers. In the first experiment, listeners were instructed to report keywords from the target sentence. Data averaged across listeners showed a plateau in performance below 0 dB TMR when masker and target sentences were from the same talker. In this experiment, some listeners tended to report the target words at all TMRs in accordance with the instructions, while others reported keywords from the louder of the sentences, contrary to the instructions. In the second experiment, stimuli were the same as in the first experiment, but listeners were also instructed to avoid reporting the masker keywords, and a payoff matrix penalizing masker keywords and rewarding target keywords was used. In this experiment, listeners reduced the number of reported masker keywords, and increased the number of reported target keywords overall, and the average data showed a local minimum at 0 dB TMR with same-talker maskers. The best overall performance with a same-talker masker was obtained with a level difference of 9 dB, where listeners achieved near perfect performance when the target was louder, and at least 80% correct performance when the target was the quieter of the two sentences. PMID- 26428769 TI - The acoustic structure of male giant panda bleats varies according to intersexual context. AB - Although the acoustic structure of mammal vocal signals often varies according to the social context of emission, relatively few mammal studies have examined acoustic variation during intersexual advertisement. In the current study male giant panda bleats were recorded during the breeding season in three behavioural contexts: vocalising alone, during vocal interactions with females outside of peak oestrus, and during vocal interactions with peak-oestrous females. Male bleats produced during vocal interactions with peak-oestrous females were longer in duration and had higher mean fundamental frequency than those produced when males were either involved in a vocal interaction with a female outside of peak oestrus or vocalising alone. In addition, males produced bleats with higher rates of fundamental frequency modulation when they were vocalising alone than when they were interacting with females. These results show that acoustic features of male giant panda bleats have the potential to signal the caller's motivational state, and suggest that males increase the rate of fundamental frequency modulation in bleats when they are alone to maximally broadcast their quality and promote close-range contact with receptive females during the breeding season. PMID- 26428770 TI - Near-field sound radiation of fan tones from an installed turbofan aero-engine. AB - The development of a distributed source model to predict fan tone noise levels of an installed turbofan aero-engine is reported. The key objective is to examine a canonical problem: how to predict the pressure field due to a distributed source located near an infinite, rigid cylinder. This canonical problem is a simple representation of an installed turbofan, where the distributed source is based on the pressure pattern generated by a spinning duct mode, and the rigid cylinder represents an aircraft fuselage. The radiation of fan tones can be modelled in terms of spinning modes. In this analysis, based on duct modes, theoretical expressions for the near-field acoustic pressures on the cylinder, or at the same locations without the cylinder, have been formulated. Simulations of the near field acoustic pressures are compared against measurements obtained from a fan rig test. Also, the installation effect is quantified by calculating the difference in the sound pressure levels with and without the adjacent cylindrical fuselage. Results are shown for the blade passing frequency fan tone radiated at a supersonic fan operating condition. PMID- 26428771 TI - Waveform modeling and inversion of ambient noise cross-correlation functions in a coastal ocean environment. AB - Theoretical studies have shown that cross-correlation functions (CFs) of time series of ambient noise measured at two locations yield approximations to the Green's functions (GFs) that describe propagation between those locations. Specifically, CFs are estimates of weighted GFs. In this paper, it is demonstrated that measured CFs in the 20-70 Hz band can be accurately modeled as weighted GFs using ambient noise data collected in the Florida Straits at ~100 m depth with horizontal separations of 5 and 10 km. Two weighting functions are employed. These account for (1) the dipole radiation pattern produced by a near surface source, and (2) coherence loss of surface-reflecting energy in time averaged CFs resulting from tidal fluctuations. After describing the relationship between CFs and GFs, the inverse problem is considered and is shown to result in an environmental model for which agreement between computed and simulated CFs is good. PMID- 26428772 TI - Effect of horizontal wave barriers on ground vibration propagation. AB - The aim of this article is to introduce a method to mitigate ground surface vibration through a flexural plate coupled to the ground and acting as a horizontal wave barrier. Using the thin plate hypothesis, two flexural plates are coupled to the ground, the first plate being the excited plate and the second plate the horizontal wave barrier. For instance, the first plate may represent a slab track and be excited by the tramway wheels. A solution to the problem can be found using a spatial two-dimensional Fourier transform of the elastodynamics equation for the ground and a modal decomposition for the flexural plate vibration. The authors show that vibration is substantially mitigated by the horizontal wave barrier and depends on its thickness and width. When the top surface wavelength becomes smaller than twice the plate width, the horizontal wave barrier acts as a wave barrier in the frequency range of interest, i.e., from 20 Hz. PMID- 26428773 TI - Echolocation signals of free-ranging Indo-Pacific humpback dolphins (Sousa chinensis) in Sanniang Bay, China. AB - While the low-frequency communication sounds of Indo-Pacific humpback dolphins (Sousa chinensis) have been reported in a number of papers, the high-frequency echolocation signals of Sousa chinensis, especially those living in the wild, have been less studied. In the current study, echolocation signals of humpback dolphins were recorded in Sanniang Bay, Guangxi Province, China, using a cross type hydrophone array with five elements. In total, 77 candidate on-axis clicks from 77 scans were selected for analysis. The results showed that the varied peak to-peak source levels ranged from 177.1 to 207.3 dB, with an average of 187.7 dB re: 1 MUPa. The mean peak frequency was 109.0 kHz with a -3-dB bandwidth of 50.3 kHz and 95% energy duration of 22 MUs. The -3-dB bandwidth was much broader than the root mean square bandwidth and exhibited a bimodal distribution. The center frequency exhibited a positive relationship with the peak-to-peak source level. The clicks of the wild Indo-Pacific humpback dolphins were short-duration, broadband, ultrasonic pulses, similar to those produced by other whistling dolphins of similar body size. However, the click source levels of the Indo Pacific humpback dolphin appear to be lower than those of other whistling dolphins. PMID- 26428774 TI - Entropy rate defined by internal wave scattering in long-range propagation. AB - The reduction of information capacity of the ocean sound channel due to scattering by internal waves is a potential problem for acoustic communication, navigation, and remote sensing over long ranges. In spite of recent progress in research on acoustic signal scattering by random internal waves and the fact that random internal waves are ubiquitous in the world oceans, there is no clear understanding of how these waves influence data communication performance. The entropy decrease resulting from scattering by internal waves is an important measure of information loss. Here a rigorous calculation of the entropy is carried out using second moment transport theory equations with random sound speed perturbations obeying the Garrett-Munk internal-wave model. It is shown that full-wave rate of entropy is of the same order of magnitude as the Kolmogorov-Sinai entropy and Lyapunov exponents for the relevant ray trajectories. The correspondence between full-wave and ray entropies suggests a correspondence between full-wave scattering and ray chaos near statistical saturation. The relatively small level of entropy rate during propagation through the random internal-wave field shows that scattering by internal waves is likely not an essential limitation for data rate and channel capacity. PMID- 26428775 TI - Reconstruction of specular reflectors by iterative image source localization. AB - A method is presented to reconstruct the geometry of specular reflectors with an ultrasonic array based on the image source principle. The ultrasonic beam is focused at a point in space emulating a point source within the medium. The transmitted wave interacts with the specular reflector and propagates back to the array as if it were generated by an image source. The reflected wave is analyzed with a sound source localization algorithm to estimate the image source location, and the reflector geometry is extracted using the mirror equation for spherical reflectors. The method is validated experimentally and its accuracy is studied. Under ideal conditions the method provides an accurate reconstruction of the position, orientation, and radius of curvature of specular reflectors, with errors Deltar < 0.2 mm, Deltaalpha < 3 degrees , and DeltaR/R0 < 0.2, respectively. The method performs very well in the presence of high levels of thermal and speckle noise, with no degradation of the reconstruction as long as SNR(th) > -3 dB (signal-to-thermal-noise ratio) and SNR(sp) > 7 dB (signal-to speckle-noise ratio). An iterative scheme based on the proposed method is presented to reconstruct the geometry of arbitrary reflectors by subdividing the reflector boundary into smaller segments. The iterative scheme is demonstrated both numerically and experimentally. PMID- 26428776 TI - Description and seasonal detection of two potential whale calls recorded in the Indian Ocean. AB - Unidentified acoustic signals are recorded by hydrophones placed in the world's oceans. Some of these sounds are suspected to originate from marine mammals. In this study, two acoustic signals recorded by two arrays at Diego Garcia in the northern Indian Ocean are described. Data were available between January 2002 and December 2003. Signals were detected manually using long-term spectral average plots. Time and frequency measurements were taken from a sample of both signals. The first unidentified signal [Diego Garcia Downsweep (DGD)] consisted of two main components. The mean frequency range of the entire signal was 19.3-45.0 Hz, with a mean duration of 36.5 s (n = 22). Detections of DGD at the northern array peaked in the austral summer, though detections at the southern array peaked during winter and spring. The second unidentified signal [Diego Garcia Croak (DGC)] consisted of one component with a mean frequency range of 16.9-49.6 Hz. The mean duration of the signal was 13.1 s (n = 10). Detections of DGC did not follow a clear seasonal pattern. These signals followed characteristics of biological sources, suggesting that they could be whale calls. Fin whale calls and possible blue whales D-calls were also identified in the data. PMID- 26428777 TI - Time-varying feedback matrices in feedback delay networks and their application in artificial reverberation. AB - This paper introduces a time-variant reverberation algorithm as an extension of the feedback delay network (FDN). By modulating the feedback matrix nearly continuously over time, a complex pattern of concurrent amplitude modulations of the feedback paths evolves. Due to its complexity, the modulation produces less likely perceivable artifacts and the time-variation helps to increase the liveliness of the reverberation tail. A listening test, which has been conducted, confirms that the perceived quality of the reverberation tail can be enhanced by the feedback matrix modulation. In contrast to the prior art time-varying allpass FDNs, it is shown that unitary feedback matrix modulation is guaranteed to be stable. Analytical constraints on the pole locations of the FDN help to describe the modulation effect in depth. Further, techniques and conditions for continuous feedback matrix modulation are presented. PMID- 26428778 TI - Estimating nonnegative matrix model activations with deep neural networks to increase perceptual speech quality. AB - As a means of speech separation, time-frequency masking applies a gain function to the time-frequency representation of noisy speech. On the other hand, nonnegative matrix factorization (NMF) addresses separation by linearly combining basis vectors from speech and noise models to approximate noisy speech. This paper presents an approach for improving the perceptual quality of speech separated from background noise at low signal-to-noise ratios. An ideal ratio mask is estimated, which separates speech from noise with reasonable sound quality. A deep neural network then approximates clean speech by estimating activation weights from the ratio-masked speech, where the weights linearly combine elements from a NMF speech model. Systematic comparisons using objective metrics, including the perceptual evaluation of speech quality, show that the proposed algorithm achieves higher speech quality than related masking and NMF methods. In addition, a listening test was performed and its results show that the output of the proposed algorithm is preferred over the comparison systems in terms of speech quality. PMID- 26428779 TI - Age and hearing loss and the use of acoustic cues in fricative categorization. AB - This study examined the use of fricative noise information and coarticulatory cues for categorization of word-final fricatives [s] and [f] by younger and older Dutch listeners alike. Particularly, the effect of information loss in the higher frequencies on the use of these two cues for fricative categorization was investigated. If information in the higher frequencies is less strongly available, fricative identification may be impaired or listeners may learn to focus more on coarticulatory information. The present study investigates this second possibility. Phonetic categorization results showed that both younger and older Dutch listeners use the primary cue fricative noise and the secondary cue coarticulatory information to distinguish word-final [f] from [s]. Individual hearing sensitivity in the older listeners modified the use of fricative noise information, but did not modify the use of coarticulatory information. When high frequency information was filtered out from the speech signal, fricative noise could no longer be used by the younger and older adults. Crucially, they also did not learn to rely more on coarticulatory information as a compensatory cue for fricative categorization. This suggests that listeners do not readily show compensatory use of this secondary cue to fricative identity when fricative categorization becomes difficult. PMID- 26428780 TI - Temporal effects in priming of masked and degraded speech. AB - When listeners know the content of the message they are about to hear, the clarity of distorted or partially masked speech increases dramatically. The current experiments investigated this priming phenomenon quantitatively using a same-different task where a typed caption and auditory message either matched exactly or differed by one key word. Four conditions were tested with groups of normal-hearing listeners: (a) natural speech presented in two-talker babble in a non-spatial configuration, (b) same as (a) but with the masker time reversed, (c) same as (a) but with target-masker spatial separation, and (d) vocoded sentences presented in speech-spectrum noise. The primary manipulation was the timing of the caption relative to the auditory message, which varied in 20 steps with a resolution of 200 ms. Across all four conditions, optimal performance was achieved when the initiation of the text preceded the acoustic speech signal by at least 400 ms, driven mostly by a low number of "different" responses to Same stimuli. Performance was slightly poorer with simultaneous delivery and much poorer when the auditory signal preceded the caption. Because priming may be used to facilitate perceptual learning, identifying optimal temporal conditions for priming could help determine the best conditions for auditory training. PMID- 26428782 TI - Tissue physical property of the harbor porpoise Phocoena phocoena for investigation of the sound emission process. AB - The process by which sound is propagated in the head of a toothed whale is still a subject of discussion. Investigating the distribution of acoustic impedance calculated by density and Young's modulus is effective for quantitative comprehension because acoustic impedance determines the reflection coefficient of a sound wave. However, the sound propagation process of the toothed whale has been mainly examined by either anatomical techniques or the measurement of density or sound velocity. In the current study, the acoustic impedance of head tissue of harbor porpoise was measured. Results of this study should be a helpful information for further discussion about the relationship between the structure of sound-producing organ and clicks property. PMID- 26428783 TI - Development and validation of a combined phased acoustical radiosity and image source model for predicting sound fields in rooms. AB - A model, combining acoustical radiosity and the image source method, including phase shifts on reflection, has been developed. The model is denoted Phased Acoustical Radiosity and Image Source Method (PARISM), and it has been developed in order to be able to model both specular and diffuse reflections with complex valued and angle-dependent boundary conditions. This paper mainly describes the combination of the two models and the implementation of the angle-dependent boundary conditions. It furthermore describes how a pressure impulse response is obtained from the energy-based acoustical radiosity by regarding the model as being stochastic. Three methods of implementation are proposed and investigated, and finally, recommendations are made for their use. Validation of the image source method is done by comparison with finite element simulations of a rectangular room with a porous absorber ceiling. Results from the full model are compared with results from other simulation tools and with measurements. The comparisons of the full model are done for real-valued and angle-independent surface properties. The proposed model agrees well with both the measured results and the alternative theories, and furthermore shows a more realistic spatial variation than energy-based methods due to the fact that interference is considered. PMID- 26428785 TI - Dependency of resonance frequencies and effective coupling coefficients of piezoceramic rectangular bars and plates on aspect ratio. AB - The resonance frequencies and effective coupling coefficients of piezoceramic rectangular plates polarized through their width and transversely polarized bars are presented as functions of their lateral aspect ratios. The results are obtained by employing the coupled vibration analysis technique that was previously illustrated for rectangular plates polarized through the thickness [J. Acoust. Soc. Am. 126(6), 2983-2990 (2009)]. The results of calculations show good agreement with experimental data. Conclusions are made on preferable values of the aspect ratios in terms of the effective coupling coefficients. PMID- 26428784 TI - Dual-carrier processing to convey temporal fine structure cues: Implications for cochlear implants. AB - Speech intelligibility in noise can be degraded by using vocoder processing to alter the temporal fine structure (TFS). Here it is argued that this degradation is not attributable to the loss of speech information potentially present in the TFS. Instead it is proposed that the degradation results from the loss of sound source segregation information when two or more carriers (i.e., TFS) are substituted with only one as a consequence of vocoder processing. To demonstrate this segregation role, vocoder processing involving two carriers, one for the target and one for the background, was implemented. Because this approach does not preserve the speech TFS, it may be assumed that any improvement in intelligibility can only be a consequence of the preserved carrier duality and associated segregation cues. Three experiments were conducted using this "dual carrier" approach. All experiments showed substantial sentence intelligibility in noise improvements compared to traditional single-carrier conditions. In several conditions, the improvement was so substantial that intelligibility approximated that for unprocessed speech in noise. A foreseeable and potentially promising implication for the dual-carrier approach involves implementation into cochlear implant speech processors, where it may provide the TFS cues necessary to segregate speech from noise. PMID- 26428786 TI - Objective and perceptual assessment of the scattered sound field in a simulated concert hall. AB - Acoustic scattering audibility thresholds are needed for the efficient design of performance spaces and to increase the accuracy of geometric room acoustic models. This paper focuses on the evaluation of the perceptual thresholds of the scattering coefficient through listening tests in simulated concert halls. It also deals with an investigation on the sensitivity of room acoustic parameters to scattering coefficients. A rectangular concert hall has been simulated with three prediction models, in which scattering coefficients of 0.1, 0.3, 0.5, 0.6, 0.7, and 0.9 were applied to the ceiling and walls in six different configurations. The analysis was performed comparing the results of the three alternative forced choice listening tests and considering the objective parameters T30, early decay time (EDT), C80, and G. An increase in EDT and a decrease in C80 have been observed for increasing scattering coefficient values for all three types of software, while no similar trend was observed for the other parameters. The perceptual evaluation has shown that differences of ~0.4, relative to an anchor value of 0.9 of the scattering coefficient, were perceived in the listening test conducted with one of the three kinds of software, while no clear differences in auralizations were perceived with the other two kinds. PMID- 26428787 TI - On the acoustoelasticity of polycrystalline materials. AB - A linear relation between the strains and stresses of a crystallite within a polycrystal is used to homogenize the polycrystal's elastic properties. The homogenization parallels the self-consistent method that is used for estimating the polycrystal's linear elastic properties. Acoustoelasticity for a macroscopically isotropic polycrystal is then formulated using a homogenized constitutive equation with initial stress. Simple expressions are given for the phase velocities and polarization directions for a uniaxially stressed polycrystal. The present model is compared with the model of Man and Paroni [J. Elast. 45, 91-116 (1996)]. Strong anisotropy of the crystallite elastic constants causes the present model to differ noticeably from the model of Man and Paroni. PMID- 26428788 TI - The effect of stimulus bandwidth on binaural loudness summation. AB - Binaural loudness summation is an important property of the human auditory system. This paper presents an experimental investigation of how binaural loudness summation varies with stimulus bandwidth. Loudness matches were obtained between dichotic stimuli, with interaural level differences (ILDs) of 2-12 dB, and diotic stimuli. The stimuli were noise bands with seven center frequencies and four bandwidths. Results showed that the loudness of dichotic stimuli increased nonlinearly with ILD, the increase being slightly less with broader bandwidths. There was a bandwidth-dependent difference between the listening tests results and the predictions of Moore and Glasberg's [(2007) J. Acoust. Soc. Am. 121, 1604-1612] loudness model. The size of the difference was, however, small. A characteristic function was derived describing how overall loudness depends on stimulus bandwidth and ILD. PMID- 26428789 TI - Acoustic holography as a metrological tool for characterizing medical ultrasound sources and fields. AB - Acoustic holography is a powerful technique for characterizing ultrasound sources and the fields they radiate, with the ability to quantify source vibrations and reduce the number of required measurements. These capabilities are increasingly appealing for meeting measurement standards in medical ultrasound; however, associated uncertainties have not been investigated systematically. Here errors associated with holographic representations of a linear, continuous-wave ultrasound field are studied. To facilitate the analysis, error metrics are defined explicitly, and a detailed description of a holography formulation based on the Rayleigh integral is provided. Errors are evaluated both for simulations of a typical therapeutic ultrasound source and for physical experiments with three different ultrasound sources. Simulated experiments explore sampling errors introduced by the use of a finite number of measurements, geometric uncertainties in the actual positions of acquired measurements, and uncertainties in the properties of the propagation medium. Results demonstrate the theoretical feasibility of keeping errors less than about 1%. Typical errors in physical experiments were somewhat larger, on the order of a few percent; comparison with simulations provides specific guidelines for improving the experimental implementation to reduce these errors. Overall, results suggest that holography can be implemented successfully as a metrological tool with small, quantifiable errors. PMID- 26428790 TI - The influence of proscenium boxes on acoustic response in historical opera halls. AB - In some historical opera halls there are boxes located around the proscenium, commonly called proscenium or "director" boxes. These boxes have a certain influence on the initial part of the impulse response of an opera hall on the singer-auditorium, singer-singer, and singer-orchestra pit paths. During the reconstruction of the Ljubljana opera hall, measurement of a scaled model was performed to quantify the influence of proscenium boxes on the hall's impulse response. Some variation in box configuration on the acoustic response was also tested. This paper describes the results of this research. PMID- 26428791 TI - Difference in electrodynamic transduction between speaker and alternator in thermoacoustic applications. AB - Conventional reciprocating pistons, normally found in thermoacoustic engines, tend to introduce complex impedance characteristics, including acoustic, mechanical, and electrical portions. System behavior and performance usually rely on proper tuning processes and selection of an optimal point of operation, affected substantially by complementary hardware, typically adjusted for the specific application. The present study proposes an alternative perspective on the alternator behavior, by considering the relative motion between gas and piston during the engine mode of operation. Direct analytical derivation of the velocity distribution inside a tight seal gap and the associated impedance is employed to estimate the electro-acoustic conversion efficiency, thus indicating how to improve the system performance. The influence of acoustic phase, gap dimensions, and working conditions is examined, suggesting the need to develop tighter and longer seal gaps, having increased impedance, to allow optimization for use in upcoming sustainable power generation solutions and smart grids. PMID- 26428792 TI - Computing interaural differences through finite element modeling of idealized human heads. AB - Acoustical interaural differences were computed for a succession of idealized shapes approximating the human head-related anatomy: sphere, ellipsoid, and ellipsoid with neck and torso. Calculations were done as a function of frequency (100-2500 Hz) and for source azimuths from 10 to 90 degrees using finite element models. The computations were compared to free-field measurements made with a manikin. Compared to a spherical head, the ellipsoid produced greater large-scale variation with frequency in both interaural time differences and interaural level differences, resulting in better agreement with the measurements. Adding a torso, represented either as a large plate or as a rectangular box below the neck, further improved the agreement by adding smaller-scale frequency variation. The comparisons permitted conjectures about the relationship between details of interaural differences and gross features of the human anatomy, such as the height of the head, and length of the neck. PMID- 26428794 TI - Nonuniform piezoelectric circular plate flexural transducers with underwater applications. AB - An analytical treatment is presented for circular flexural plate transducers that have nonuniform electromechanically active-passive mechanical systems with particular interest in underwater applications. The analysis is made using the energy method that was previously applied to calculating parameters of uniform fully active (bimorph) circular plate transducers [B. S. Aronov, J. Acoust. Soc. Am. 118(2), 627-637 (2005)]. It is shown that the vibration mode shapes remain sufficiently similar to those for uniform plates for a large range of relative dimensions of active and passive laminates of radially nonuniform mechanical systems, and they may be used for calculating transducer parameters. Therefore the transducers can be considered as having a single degree of freedom, and their operational characteristics can be determined using the same technique as previously used for uniform plates. Dependences of the resonance frequencies, effective coupling coefficients, and parameters of the equivalent electromechanical circuit on relative dimensions of active and passive laminates for several combinations of the active and passive materials are presented and compared with those parameters of uniform plates having the same overall dimensions. The results of experimental verification are in good agreement with theoretical predictions. PMID- 26428793 TI - Memory disruption by irrelevant noise-vocoded speech: Effects of native language and the number of frequency bands. AB - To investigate the mechanisms by which unattended speech impairs short-term memory performance, speech samples were systematically degraded by means of a noise vocoder. For experiment 1, recordings of German and Japanese sentences were passed through a filter bank dividing the spectrum between 50 and 7000 Hz into 20 critical-band channels or combinations of those, yielding 20, 4, 2, or just 1 channel(s) of noise-vocoded speech. Listening tests conducted with native speakers of both languages showed a monotonic decrease in speech intelligibility as the number of frequency channels was reduced. For experiment 2, 40 native German and 40 native Japanese participants were exposed to speech processed in the same manner while trying to memorize visually presented sequences of digits in the correct order. Half of each sample received the German, the other half received the Japanese speech samples. The results show large irrelevant-speech effects increasing in magnitude with the number of frequency channels. The effects are slightly larger when subjects are exposed to their own native language. The results are neither predicted very well by the speech transmission index, nor by psychoacoustical fluctuation strength, most likely, since both metrics fail to disentangle amplitude and frequency modulations in the signals. PMID- 26428796 TI - Characterization of the complexity in short oscillating time series: An application to seismic airgun detonations. AB - Extracting frequency-derived parameters allows for the identification and characterization of acoustic events, such as those obtained in passive acoustic monitoring applications. Situations where it is difficult to achieve the desired frequency resolution to distinguish between similar events occur, for example, in short time oscillating events. One feasible approach to make discrimination among such events is by measuring the complexity or the presence of non-linearities in a time series. Available techniques include the delay vector variance (DVV) and recurrence plot (RP) analysis, which have been used independently for statistical testing, however, the similarities between these two techniques have so far been overlooked. This work suggests a method that combines the DVV method with the recurrence quantification analysis parameters of the RP graphs for the characterization of short oscillating events. In order to establish the confidence intervals, a variant of the pseudo-periodic surrogate algorithm is proposed. This allows one to eliminate the fine details that may indicate the presence of non-linear dynamics, without having to add a large amount of noise, while preserving more efficiently the phase-space shape. The algorithm is verified on both synthetic and real world time series. PMID- 26428795 TI - A modified sequential algebraic algorithm applied to identify rough acoustic impedance profiles in slender structures. AB - This paper develops and examines a modified technique for identifying damage in slender structures. An algorithm, called modified sequential algebraic algorithm, is presented to solve the longitudinal acoustic wave propagation problem in inhomogeneous media. This method accurately predicts the echo generated by the inhomogeneities when the acoustic impedance variation profile in the damaged part of the structure is non-smooth. For these cases, the available algorithms fail to provide the actual regressive wave component. In the following, a stochastic optimization scheme, the differential evolution method, is applied to solve the inverse problem. Numerical examples with smooth and non-smooth impedance profiles are considered. It is shown that, for smooth profiles, both the available techniques and the modified algorithm succeed in identifying the actual damage. Nevertheless, in situations where a rough profile is to be reconstructed, only the modified algorithm succeeds. The technique is found to be robust with respect to additive noise in the signals. PMID- 26428798 TI - An integral equation method for calculating sound field diffracted by a rigid barrier on an impedance ground. AB - This paper proposes a different method for calculating a sound field diffracted by a rigid barrier based on the integral equation method, where a virtual boundary is assumed above the rigid barrier to divide the whole space into two subspaces. Based on the Kirchhoff-Helmholtz equation, the sound field in each subspace is determined with the source inside and the boundary conditions on the surface, and then the diffracted sound field is obtained by using the continuation conditions on the virtual boundary. Simulations are carried out to verify the feasibility of the proposed method. Compared to the MacDonald method and other existing methods, the proposed method is a rigorous solution for whole space and is also much easier to understand. PMID- 26428800 TI - Acoustic analysis of the frequency-dependent coupling between the frog's ears. AB - The ears of anurans are coupled through the Eustachian tubes and mouth cavity. The degree of coupling varies with frequency showing a bandpass characteristic, but the characteristics differ between empirically measured data based on auditory nerve responses and tympanic membrane vibration. In the present study, the coupling was modeled acoustically as a tube connected with a side branch. This tube corresponds to the Eustachian tubes, whereas the side branch corresponds to the mouth cavity and nares. The analysis accounts for the frequency dependency shown by the empirical data and reconciles the differences observed between the coupling as measured by tympanic membrane vibration and auditory nerve responses. PMID- 26428799 TI - Individual and sex distinctiveness in bark calls of domestic chinchillas elicited in a distress context. AB - Animals obtain information about their social environment by means of communication signals, which provide relevant subtle cues for individual recognition. An important requisite for this process is the existence of larger between- than within-emitter signal variation. Acoustic signals are complex traits susceptible of variation in their spectral and temporal components, implying that signal distinctiveness can result from differences in single or various acoustic components. In this study, domestic chinchillas were induced to vocalize in a distress context to describe the acoustic characteristics of the bark calls, and to determine features that denote the potential value of this vocalization for individual and/or sexual recognition. The results demonstrate that the variation in spectral and temporal components of the bark calls of chinchillas elicited under a distress context is larger between than within individuals, suggesting the potential of these signals for distinctiveness between individual signalers, although the potential of this call type for sex distinctiveness is quite limited. These results combined with previous studies on auditory capabilities of chinchillas contribute to position this rodent as a valuable model species for studying auditory-vocal interactions. PMID- 26428801 TI - Acousto-optic effect compensation for optical determination of the normal velocity distribution associated with acoustic transducer radiation. AB - The acousto-optic effect, in which an acoustic wave causes variations in the optical index of refraction, imposes a fundamental limitation on the determination of the normal velocity, or normal displacement, distribution on the surface of an acoustic transducer or optically reflecting pellicle by a scanning heterodyne, or homodyne, laser interferometer. A general method of compensation is developed for a pulsed harmonic pressure field, transmitted by an acoustic transducer, in which the laser beam can transit the transducer nearfield. By representing the pressure field by the Rayleigh integral, the basic equation for the unknown normal velocity on the surface of the transducer or pellicle is transformed into a Fredholm equation of the second kind. A numerical solution is immediate when the scanned points on the surface correspond to those of the surface area discretization. Compensation is also made for oblique angles of incidence by the scanning laser beam. The present compensation method neglects edge waves, or those due to boundary diffraction, as well as effects due to baffles, if present. By allowing measurement in the nearfield of the radiating transducer, the method can enable quantification of edge-wave and baffle effects on transducer radiation. A verification experiment has been designed. PMID- 26428803 TI - An algorithm to increase speech intelligibility for hearing-impaired listeners in novel segments of the same noise type. AB - Machine learning algorithms to segregate speech from background noise hold considerable promise for alleviating limitations associated with hearing impairment. One of the most important considerations for implementing these algorithms into devices such as hearing aids and cochlear implants involves their ability to generalize to conditions not employed during the training stage. A major challenge involves the generalization to novel noise segments. In the current study, sentences were segregated from multi-talker babble and from cafeteria noise using an algorithm that employs deep neural networks to estimate the ideal ratio mask. Importantly, the algorithm was trained on segments of noise and tested using entirely novel segments of the same nonstationary noise type. Substantial sentence-intelligibility benefit was observed for hearing-impaired listeners in both noise types, despite the use of unseen noise segments during the test stage. Interestingly, normal-hearing listeners displayed benefit in babble but not in cafeteria noise. This result highlights the importance of evaluating these algorithms not only in human subjects, but in members of the actual target population. PMID- 26428802 TI - Functional modeling of the human auditory brainstem response to broadband stimulation. AB - Population responses such as the auditory brainstem response (ABR) are commonly used for hearing screening, but the relationship between single-unit physiology and scalp-recorded population responses are not well understood. Computational models that integrate physiologically realistic models of single-unit auditory nerve (AN), cochlear nucleus (CN) and inferior colliculus (IC) cells with models of broadband peripheral excitation can be used to simulate ABRs and thereby link detailed knowledge of animal physiology to human applications. Existing functional ABR models fail to capture the empirically observed 1.2-2 ms ABR wave V latency-vs-intensity decrease that is thought to arise from level-dependent changes in cochlear excitation and firing synchrony across different tonotopic sections. This paper proposes an approach where level-dependent cochlear excitation patterns, which reflect human cochlear filter tuning parameters, drive AN fibers to yield realistic level-dependent properties of the ABR wave-V. The number of free model parameters is minimal, producing a model in which various sources of hearing-impairment can easily be simulated on an individualized and frequency-dependent basis. The model fits latency-vs-intensity functions observed in human ABRs and otoacoustic emissions while maintaining rate-level and threshold characteristics of single-unit AN fibers. The simulations help to reveal which tonotopic regions dominate ABR waveform peaks at different stimulus intensities. PMID- 26428805 TI - Source depth estimation based on synthetic aperture beamfoming for a moving source. AB - A continuous wave signal received on a single hydrophone from a moving source is beamformed using the synthetic aperture created by the source, where the signal at each range is steered by a range-dependent phase, relative to the starting point. The range increment (aperture) is determined based on the Doppler shift estimated from the data, knowing the original signal frequency. Given a sufficient signal-to-noise ratio, the source depth can be estimated from the beam output, assuming knowledge of the mode depth functions based on the nominal sound speed and bottom profile in the area. The method is illustrated with simulated data and at-sea data. For real data, the signal phase contains a random, incoherent component caused by the (random) source motion and media fluctuations in addition to the deterministic range-dependent component due to source range change. A phase locked loop is introduced to remove the random component assuming that the random component fluctuates faster with time than the range-dependent phase. When a vertical array of receivers are available covering the depth span of interest, the beam output can be used directly to estimate the source depth. In this case, no knowledge of the acoustic environment is needed. PMID- 26428804 TI - Vowel identification in temporal-modulated noise for native and non-native listeners: Effect of language experience. AB - A previous study found that English vowel identification in babble was significantly different between Chinese-native listeners in China and in the U.S. One possible explanation is that native English experiences might change Chinese native listeners' ability to take advantage of the temporal modulation in noise for their English vowel perception. As a follow-up, the current study explored whether there was a difference between the two groups of Chinese listeners in using temporal gaps in noise for English vowel identification. Vowel identification in temporally modulated noise and a temporal modulation transfer function (TMTF) was measured for American-English-native listeners (EN), Chinese native listeners in the U.S. (CNU), and Chinese-native listeners in China (CNC). The results revealed that TMTFs were similar across the three groups, indicating that psychophysical temporal processing was independent of listeners' language backgrounds. However, for vowel identification in noise, EN and CNU listeners showed significantly greater masking release from the temporal modulation of noise than CNC listeners at low signal-to-noise ratios (e.g., -12 dB). Altogether, native English experiences may change the use of temporal cues in noise for English vowel identification for Chinese-native listeners. PMID- 26428806 TI - Fundamental-frequency discrimination using noise-band-vocoded harmonic complexes in older listeners with normal hearing. AB - Voice-pitch cues provide detailed information about a talker that help a listener to understand speech in complex environments. Temporal-envelope based voice-pitch coding is important for listeners with hearing impairment, especially listeners with cochlear implants, as spectral resolution is not sufficient to provide a spectrally based voice-pitch cue. The effect of aging on the ability to glean voice-pitch information using temporal envelope cues is not completely understood. The current study measured fundamental frequency (f0) discrimination limens in normal-hearing younger and older adults while listening to noise-band vocoded harmonic complexes with varying numbers of spectral channels. Age-related disparities in performance were apparent across all conditions, independent of spectral degradation and/or fundamental frequency. The findings have important implications for older listeners with normal hearing and hearing loss, who may be inherently limited in their ability to perceive f0 cues due to senescent decline in auditory function. PMID- 26428808 TI - Noise-induced hearing loss in marine mammals: A review of temporary threshold shift studies from 1996 to 2015. AB - One of the most widely recognized effects of intense noise exposure is a noise induced threshold shift-an elevation of hearing thresholds following cessation of the noise. Over the past twenty years, as concerns over the potential effects of human-generated noise on marine mammals have increased, a number of studies have been conducted to investigate noise-induced threshold shift phenomena in marine mammals. The experiments have focused on measuring temporary threshold shift (TTS)-a noise-induced threshold shift that fully recovers over time-in marine mammals exposed to intense tones, band-limited noise, and underwater impulses with various sound pressure levels, frequencies, durations, and temporal patterns. In this review, the methods employed by the groups conducting marine mammal TTS experiments are described and the relationships between the experimental conditions, the noise exposure parameters, and the observed TTS are summarized. An attempt has been made to synthesize the major findings across experiments to provide the current state of knowledge for the effects of noise on marine mammal hearing. PMID- 26428809 TI - Benefits and applications of laser-induced sparks in real scale model measurements. AB - The characteristics of using a laser-induced spark as a monopole source in scale model measurements were assessed by comparison with an electric spark and a miniature spherical loudspeaker. Room impulse responses of first order directivity sources were synthesized off-line using six spatially distributed sparks. The source steering direction was scanned across the horizontal and vertical plane to assess the origin of early reflections. The results confirm that the characteristics of the laser-induced spark outperform those of typical sources. Its monopole characteristics enable the authors to synthesize room responses of directional sources, e.g., to obtain directional information about reflections inside scale models. PMID- 26428807 TI - Killer whale (Orcinus orca) whistles from the western South Atlantic Ocean include high frequency signals. AB - Acoustic parameters of killer whale (Orcinus orca) whistles were described for the western South Atlantic Ocean and highlight the occurrence of high frequency whistles. Killer whale signals were recorded on December of 2012, when a pod of four individuals was observed harassing a group of sperm whales. The high frequency whistles were highly stereotyped and were modulated mostly at ultrasonic frequencies. Compared to other contour types, the high frequency whistles are characterized by higher bandwidths, shorter durations, fewer harmonics, and higher sweep rates. The results add to the knowledge of vocal behavior of this species. PMID- 26428810 TI - High sentence predictability increases the fluctuating masker benefit. AB - This study examined the effects of sentence predictability and masker modulation type on the fluctuating masker benefit (FMB), the improvement in speech reception thresholds resulting from fluctuations imposed on a steady-state masker. Square wave modulations resulted in a larger FMB than sinusoidal ones. FMBs were also larger for high compared to low-predictability sentences, indicating that high sentence predictability increases the benefits from glimpses of the target speech in the dips of the fluctuating masker. In addition, sentence predictability appears to have a greater effect on sentence intelligibility when the masker is fluctuating than when it is steady-state. PMID- 26428811 TI - Validation of a simple response-time measure of listening effort. AB - This study compares two response-time measures of listening effort that can be combined with a clinical speech test for a more comprehensive evaluation of total listening experience; verbal response times to auditory stimuli (RT(aud)) and response times to a visual task (RTs(vis)) in a dual-task paradigm. The listening task was presented in five masker conditions; no noise, and two types of noise at two fixed intelligibility levels. Both the RTs(aud) and RTs(vis) showed effects of noise. However, only RTs(aud) showed an effect of intelligibility. Because of its simplicity in implementation, RTs(aud) may be a useful effort measure for clinical applications. PMID- 26428812 TI - Methods to calibrate the absolute receive sensitivity of single-element, focused transducers. AB - Absolute pressure measurements of acoustic emissions by single-element, focused passive cavitation detectors would be facilitated by improved wideband receive calibration techniques. Here, calibration methods were developed to characterize the absolute, frequency-dependent receive sensitivity of a spherically focused, single-element transducer using pulse-echo and pitch-catch techniques. Validation of these calibration methods on a focused receiver were made by generating a pulse from a small diameter source at the focus of the transducer and comparing the absolute pressure measured by a calibrated hydrophone to that of the focused transducer using the receive sensitivities determined here. PMID- 26428813 TI - Acquisition of speech rhythm in first language. AB - Analysis of English rhythm in speech produced by children and adults revealed that speech rhythm becomes increasingly more stress-timed as language acquisition progresses. Children reach the adult-like target by 11 to 12 years. The employed speech elicitation paradigm ensured that the sentences produced by adults and children at different ages were comparable in terms of lexical content, segmental composition, and phonotactic complexity. Detected differences between child and adult rhythm and between rhythm in child speech at various ages cannot be attributed to acquisition of phonotactic language features or vocabulary, and indicate the development of language-specific phonetic timing in the course of acquisition. PMID- 26428814 TI - Across-frequency processing of modulation phase differences in hearing-impaired listeners. AB - Two experiments tested the influence of hearing impairment (HI) on representing across-frequency temporal coherence. In one experiment, HI listeners demonstrated similar abilities to normal-hearing listeners in detecting across-frequency differences in modulation phase. In another, spectral-shape discrimination was detrimentally affected by modulation phase disparities imposed on spectral components. Spectral-shape discrimination by HI listeners was less influenced by the disparities, suggesting that hearing loss alters the representation of envelope phase. Results suggest that multiple approaches may be necessary to determine alterations associated with hearing loss-detection tasks may not be sufficient to elucidate distortions to temporal envelope associated with hearing loss. PMID- 26428815 TI - Relating movement recurrence and expressive timing patterns in music performances. AB - In this study the movement patterns of ten expert musicians are quantitatively related to expressive timing patterns and the music structure during performances. The hypothesis is that ancillary gestures recurrently employed are closely related to expressive intentions, and that the expressive content imposed in key musical passages is thus reflected in the patterns of gestural recurrence. A movement and an audio analysis of 30 clarinet performances of a Brahms' excerpt are compared. Results show direct correlations between the recurrence pattern of clarinetists' ancillary movements and expressive bar duration manipulations employed by them, associated with melodic phrasing and harmonic transitions. PMID- 26428816 TI - Broadband sound blocking in phononic crystals with rotationally symmetric inclusions. AB - This paper investigates the feasibility of broadband sound blocking with rotationally symmetric extensible inclusions introduced in phononic crystals. By varying the size of four equally shaped inclusions gradually, the phononic crystal experiences remarkable changes in its band-stop properties, such as shifting/widening of multiple Bragg bandgaps and evolution to resonance gaps. Necessary extensions of the inclusions to block sound effectively can be determined for given incident frequencies by evaluating power transmission characteristics. By arraying finite dissimilar unit cells, the resulting phononic crystal exhibits broadband sound blocking from combinational effects of multiple Bragg scattering and local resonances even with small-numbered cells. PMID- 26428817 TI - Speaking rate consistency in native and non-native speakers of English. AB - Non-native speech differs from native speech in multiple ways. Previous research has described segmental and suprasegmental differences between native and non native speech in terms of group averages. For example, average speaking rate for non-natives is slower than for natives. However, it is unknown whether non-native speech is also more variable than native speech. This study introduces a method of comparing rate change across utterances, demonstrating that non-native speaking rate is more variable than native speech. These results suggest that future work examining non-native speech perception and production should investigate both mean differences and variability in the signal. PMID- 26428818 TI - Improved speech inversion using general regression neural network. AB - The problem of nonlinear acoustic to articulatory inversion mapping is investigated in the feature space using two models, the deep belief network (DBN) which is the state-of-the-art, and the general regression neural network (GRNN). The task is to estimate a set of articulatory features for improved speech recognition. Experiments with MOCHA-TIMIT and MNGU0 databases reveal that, for speech inversion, GRNN yields a lower root-mean-square error and a higher correlation than DBN. It is also shown that conjunction of acoustic and GRNN estimated articulatory features yields state-of-the-art accuracy in broad class phonetic classification and phoneme recognition using less computational power. PMID- 26428819 TI - An electronically tunable duct silencer using dielectric elastomer actuators. AB - A duct silencer with tunable acoustic characteristics is presented in this paper. Dielectric elastomer, a smart material with lightweight, high elastic energy density and large deformation under high direct current/alternating current voltages, was used to fabricate this duct silencer. The acoustic performances and tunable mechanisms of this duct silencer were experimentally investigated. It was found that all the resonance peaks of this duct silencer could be adjusted using external control signals without any additional mechanical part. The physics of the tunable mechanism is further discussed based on the electro-mechanical interactions using finite element analysis. The present promising results also provide insight into the appropriateness of the duct silencer for possible use as next generation acoustic treatment device to replace the traditional acoustic treatment. PMID- 26428820 TI - A theoretical relation between the celerity and trace velocity of infrasonic phases. AB - This paper presents a relationship between the celerity and trace velocity of infrasound signals propagating in a stratified, windy atmosphere. Despite their importance, known celerity values have only been determined empirically. An infrasonic phase (I-phase) diagram is developed which is useful in identifying different I-phases. Such an I-phase diagram allows for the prediction of the range of values of the celerity and trace velocity for each I-phase. The phase diagram can easily be extended to underwater acoustic and acoustic-gravity waves. An I-phase diagram is compared with data obtained from a ground-truth event where qualitative agreement is obtained. PMID- 26428821 TI - A model for the temporal evolution of the spatial coherence in decaying reverberant sound fields. AB - Reverberant sound fields are often modeled as isotropic. However, it has been observed that spatial properties change during the decay of the sound field energy, due to non-isotropic attenuation in non-ideal rooms. In this letter, a model for the spatial coherence between two sensors in a decaying reverberant sound field is developed for rectangular rooms. The modeled coherence function depends on room dimensions, surface reflectivity, and orientation of the sensor pair, but is independent of the position of source and sensors in the room. The model includes the spherically isotropic (diffuse) and cylindrically isotropic sound field models as special cases. PMID- 26428822 TI - Subwavelength acoustic metamaterial panels for underwater noise isolation. AB - Acoustically thin metamaterial underwater noise isolation panels have been developed that provide as much as 16 dB of noise isolation for a panel with a thickness just 160th of the wavelength in the host medium (fresh water) at 2.5 kHz. The panels are composed of thin layers of neoprene rubber and polyoxymethylene containing air-filled voids. The level of isolation provided by the panels is shown to correlate positively with the volume fraction of air voids within the panel. PMID- 26428823 TI - Distinct effects of moisture and air contents on acoustic properties of sandy soil. AB - Knowledge of distinct effects of moisture content and air volume on acoustic properties of soil is sought to predict the influence of human activities such as cultivation on acoustic propagation outdoors. This work used an impedance tube with the two-thickness method to investigate such effects. For a constant moisture weight percentage, the magnitude of the characteristic impedance became smaller and the absorption coefficient became higher with increase of the air space ratio. For a constant air space ratio, the absorption coefficient became larger and the magnitude of the propagation constant became smaller with increasing moisture weight percentage. PMID- 26428824 TI - Uncertainty of decibel levels. AB - The mean sound exposure level from a source is routinely estimated by the mean of the observed sound exposures from repeated measurements. A formula for the standard uncertainty based on the Guide to the expression of Uncertainty in Measurement (GUM) is derived. An alternative formula is derived for the case where the GUM method fails. The formulas are applied on several examples, and compared with a Monte Carlo calculation of the standard uncertainty. The recommended formula can be seen simply as a convenient translation of the uncertainty on an energy scale into the decibel level scale, but with a theoretical foundation. PMID- 26428825 TI - A biomimetic coupled circuit based microphone array for sound source localization. AB - An equivalent analog circuit is designed to mimic the coupled ears of the fly Ormia ochracea for sound source localization. This coupled circuit receives two signals with tiny phase difference from a space closed two-microphone array, and produces two signals with obvious intensity difference. The response sensitivity can be adjusted through the coupled circuit parameters. The directional characteristics of the coupled circuit have been demonstrated in the experiment. The miniature microphone array can localize the sound source with low computational burden by using the intensity difference. This system has significant advantages in various applications where the array size is limited. PMID- 26428826 TI - Echolocation of insects using intermittent frequency-modulated sounds. AB - Using echolocation influenced by Doppler shift, bats can capture flying insects in real three-dimensional space. On the basis of this principle, a model that estimates object locations using frequency modulated (FM) sound was proposed. However, no investigation was conducted to verify whether the model can localize flying insects from their echoes. This study applied the model to estimate the range and direction of flying insects by extracting temporal changes from the time-frequency pattern and interaural range difference, respectively. The results obtained confirm that a living insect's position can be estimated using this model with echoes measured while emitting intermittent FM sounds. PMID- 26428827 TI - Parameterization of the three-dimensional room transfer function in horizontal plane. AB - This letter proposes an efficient parameterization of the three-dimensional room transfer function (RTF) which is robust for the position variations of source and receiver in respective horizontal planes. Based on azimuth harmonic analysis, the proposed method exploits the underlying properties of the associated Legendre functions to remove a portion of the spherical harmonic coefficients of RTF which have no contribution in the horizontal plane. This reduction leads to a flexible measuring-point structure consisting of practical concentric circular arrays to extract horizontal plane RTF coefficients. The accuracy of the above parameterization is verified through numerical simulations. PMID- 26428828 TI - Empirical estimation of peak pressure level from sound exposure level. Part II: Offshore impact pile driving noise. AB - Numerical models of underwater sound propagation predict the energy of impulsive signals and its decay with range with a better accuracy than the peak pressure. A semi-empirical formula is suggested to predict the peak pressure of man-made impulsive signals based on numerical predictions of their energy. The approach discussed by Galindo-Romero, Lippert, and Gavrilov [J. Acoust. Soc. Am. 138, in press (2015)] for airgun signals is modified to predict the peak pressure from offshore pile driving, which accounts for impact and pile parameters. It is shown that using the modified empirical formula provides more accurate predictions of the peak pressure than direct numerical simulations of the signal waveform. PMID- 26428829 TI - Forward scattering detection of a submerged moving target based on adaptive filtering technique. AB - Forward scattered waves are always overwhelmed by severely intense direct blasts when a submerged target crosses the source-receiver line. A processing scheme called direct blast suppression based on adaptive filtering (DBS-AF) is proposed to suppress such blasts. A verification experiment was conducted in a lake with a vertical hydrophone array and 10 kHz CW impulses. Processing results show that the direct blast is suppressed in a single channel, and an intruding target is identified by the lobes in the detection curve. The detection performance is improved by adopting a time-delay beam-former on the array as a pre-processing technique. PMID- 26428830 TI - Passive acoustic observations of tide height in the Iroise Sea using ambient noise. AB - Considering a broadband motionless source in a waveguide with a depth that varies with time, the time-frequency representation of the acoustic intensity shows a striation pattern than can be explained using the depth-frequency waveguide invariant. This phenomenon is used here to describe acoustic data recorded in the Iroise Sea, where intense tides occur. The originality of this study is that the acoustic data consist of only ambient noise. The best hypothesis is that these striations are created by distant marine traffic in the Bay of Brest, and the results suggest that tide height can be monitored using long-term passive acoustics. PMID- 26428831 TI - Outdoor measurements of spherical acoustic shock decay. AB - Prior anechoic measurements of a small acetylene-oxygen balloon explosion were used to study spherical weak-shock decay over short ranges [Muhlestein et al., J. Acoust. Soc. Am. 131, 2422-2430 (2012)]. Here, longer-range measurements conducted at the Bonneville Salt Flats with a larger balloon are described. Waveform and spectral characteristics and comparisons of the peak pressure decay with an analytical weak-shock model are presented. Weak shocks persist to at least 305 m, with an amplitude decay that is predicted reasonably well using the model. Deviations are discussed in the context of atmospheric effects and nonlinear ground reflections. PMID- 26428833 TI - Spectral density affects the intelligibility of tone-vocoded speech: Implications for cochlear implant simulations. AB - For small numbers of channels, tone vocoders using low envelope cutoff frequencies are less intelligible than noise vocoders, even though the noise carriers introduce random fluctuations into the crucial envelope information. Here it is shown that using tone carriers with a denser spectrum improves performance considerably over typical tone vocoders, at least equaling, and often surpassing, the performance possible with noise vocoders. In short, the spectral sparseness of tone vocoded sounds for low channel numbers, separate from the degradations introduced by using only a small number of channels, is an important limitation on the intelligibility of tone-vocoded speech. PMID- 26428832 TI - Toddlers' comprehension of degraded signals: Noise-vocoded versus sine-wave analogs. AB - Recent findings suggest that development changes the ability to comprehend degraded speech. Preschool children showed greater difficulties perceiving noise vocoded speech (a signal that integrates amplitude over broad frequency bands) than sine-wave speech (which maintains the spectral peaks without the spectrum envelope). In contrast, 27-month-old children in the present study could recognize speech with either type of degradation and performed slightly better with eight-channel vocoded speech than with sine-wave speech. This suggests that children's identification performance depends critically on the degree of degradation and that their success in recognizing unfamiliar speech encodings is encouraging overall. PMID- 26428834 TI - Influence of language experience on digit recognition by English and Chinese listeners. AB - Digit recognition was measured in quiet and in two noise conditions by English native (EN) and Chinese-native (CN) listeners. EN listeners were tested using English digits and CN listeners were tested using both English and Chinese digits. In quiet, forward digit span recall worsened for both groups as the number of digits was increased. Significant effects of language experience were observed with five or more digits. Language experience had a significant effect on digit recognition in babble but not in steady noise. These results suggest that understanding of a nonnative language can be influenced by both cognitive load and listening environment. PMID- 26428835 TI - Cross-coherent vector sensor processing for spatially distributed glider networks. AB - Autonomous underwater gliders fitted with vector sensors can be used as a spatially distributed sensor array to passively locate underwater sources. However, to date, the positional accuracy required for robust array processing (especially coherent processing) is not achievable using dead-reckoning while the gliders remain submerged. To obtain such accuracy, the gliders can be temporarily surfaced to allow for global positioning system contact, but the acoustically active sea surface introduces locally additional sensor noise. This letter demonstrates that cross-coherent array processing, which inherently mitigates the effects of local noise, outperforms traditional incoherent processing source localization methods for this spatially distributed vector sensor network. PMID- 26428836 TI - Ultrasonic guided waves in elliptical annular cylinders. AB - This paper studies the influence of cross-section ovalness or ellipticity on lower order axisymmetric guided wave modes in thin pipes. The second longitudinal mode L(0,2) and the fundamental torsional mode T(0,1) are studied, as these are of interest to current pipe inspection. The semi-analytical finite element (FE) method is mainly used, with three-dimensional FE simulations for visualization and cross-validation of results. The studies reveal that even a small degree of ovalness can affect mode shapes and velocities. The effect is more pronounced on the L(0,2) mode than on T(0,1) and this may be important for practical inspection applications. PMID- 26428837 TI - Sternal vibrations during head-out immersion: A preliminary demonstration of underwater wearable ballistocardiography. AB - Ballistocardiography (BCG) measures vibrations of the body caused by ejection of blood from the heart, and the root mean square (RMS) of BCG measured with a weighing scale trends with cardiac output. However, BCG underwater has not been studied. Head-to-foot BCG signals were recorded with an accelerometer on the sternum of three human subjects. The heartbeats were clearly visible in the signals recorded underwater, and the resting change in RMS BCG was +360 MUg (+36%) from air to cold water immersion (27.8 degrees C) while standing. This is within the 32%-62% increase in cardiac output observed in previous head-out immersion studies. PMID- 26428838 TI - Melodic contour identification and sentence recognition using sung speech. AB - For bimodal cochlear implant users, acoustic and electric hearing has been shown to contribute differently to speech and music perception. However, differences in test paradigms and stimuli in speech and music testing can make it difficult to assess the relative contributions of each device. To address these concerns, the Sung Speech Corpus (SSC) was created. The SSC contains 50 monosyllable words sung over an octave range and can be used to test both speech and music perception using the same stimuli. Here SSC data are presented with normal hearing listeners and any advantage of musicianship is examined. PMID- 26428839 TI - Modified spectral tilt affects infants' native-language discrimination of approximants and vowels. AB - This study's aim was to determine if 6- and 9-month-old infants discriminate approximants and vowels when the spectral shape is modified to emphasize high- or low-frequency information. Infants were presented with /r/-/l/ and /o/-/a/ in three conditions: (a) unmodified; (b) -6 dB/octave tilt; and (c) +6 dB/octave tilt. Six-month-olds discriminated /o/-/a/ in conditions (a) and (b), and /r/-/l/ in conditions (a) and (c), but 9-month-olds only discriminated when unmodified. The results reflect native-language attunement. Six-month-olds discriminate spectrally modified sounds that emphasize relevant cues, but by 9 months, infants are sensitive to the native spectral profiles of speech. PMID- 26428840 TI - Response to Letter to the Editor regarding "Systematic review of flexion/extension radiography of the cervical spine in trauma patients". PMID- 26428841 TI - Pilot study of ultrasound parotid imaging reporting and data system (PIRADS): Inter-observer agreement. AB - AIM: To establish proposal ultrasound parotid imaging reporting and data system (PIRADS) for classification and prediction of malignancy of parotid lesions and to assess the inter-observer agreement of this system. SUBJECTS AND METHODS: Retrospective analysis of ultrasound and power Duplex images of 142 patients with parotid lesions by two reviewers. Parotid focal lesions were classified into nine patterns and then categorized into five groups: PIRADS 1, definitively benign; PIRADS 2, probably benign; PIRADS 3, indeterminate; PIRADS 4, probably malignant; and PIRADS 5, highly suggestive malignant. THE RESULTS: There was excellent interobserver agreement of both reviewers for patterns and PIRADS (K=0.84, P=0.001) with 92% percent agreement. There was excellent agreement of PIRADS 1 (K=1.00, P=0.001), PIRADS 2 (K=0.97, P=0.001), PIRADS 3 (K=0.86, P=0.001) and PIRADS 5 (K=0.88, P=0.001) and good agreement of PIRADS 4 (K=0.67, P=0.001). The Odds ratio of PIRADS 3, 4 and 5 were 1.36 (95% CI=0.39-4.55), 7.11 (95% CI=3.02 11.15) and 8.27 (95% CI=3.49-10.27) respectively. The accuracy was 92% and 90%, sensitivity was 79% and 65%, specificity was 94% and 96% of PIRADS of both reviewers respectively. CONCLUSION: The proposed PIRADS is a reliable non invasive imaging modality that can be used for categorizing parotid lesions and prediction of malignancy. PMID- 26428842 TI - Volume perfusion computed tomography (VPCT)-based evaluation of response to TACE using two different sized drug eluting beads in patients with nonresectable hepatocellular carcinoma: Impact on tumor and liver parenchymal vascularisation. AB - OBJECTIVE: Response monitoring of transarterial chemoembolization (TACE) with the help of volume perfusion computed tomography (VPCT) at day one post-TACE and analysis of TACE-impact on tumor and uninvolved liver parenchymal perfusion by using different particles sizes and epirubicin dose. MATERIALS AND METHODS: Institutional review board approved this prospective study. VPCT was performed in the baseline, post-interventional (FU1; 24 h post-TACE) and at follow-up (FU2; median, 81 days) in 45 consecutive patients. 100-300 MUm (n=17) and 300-500 MUm (n=28) drug eluting beads (DEB) using an epirubicin dose of (<=25 vs. >25) were administered. VPCT was performed for 40-s using 80 kV, 100/120 mAs, 64*0.6 mm collimation, 26 consecutive measurements, IV injection (50 ml iodinated contrast), flow rate (5 ml/s). Blood flow (BF), blood volume (BV) and k-trans were registered as average and max values in the tumor. Arterial liver perfusion (ALP), portal-venous perfusion (PVP) and the hepatic perfusion index (HPI) were registered both in tumor and non-involved liver parenchyma. Response to TACE was classified by VPCT as complete (CR), partial (PR) or no response (NR). RESULTS: A significant reduction of viable tumor tissue was found in all patients between baseline and FU1 (p<0.001) being independent on particle size and epirubicin dose (p>0.05). PPV/NPV/sensitivity/specificity of post-interventional VPCT (FU1) results for prediction of the mid-term tumor course (FU2) were 100%/70%/76%/100%. There was generally a significant increase of the ALP between baseline and FU1 in the liver parenchyma coupled by a significant subsequent decrease (normalization) of ALP and HPI between FU1 and FU2. CONCLUSION: VPCT accurately measures impact of TACE on liver tumor and hepatic parenchymal perfusion. The former proved not to be significantly dependent on particle size and epirubicin dose. There was no persistent perfusion deficit in the liver after TACE. PMID- 26428844 TI - Importance of recognizing sleep health disparities and implementing innovative interventions to reduce these disparities. PMID- 26428843 TI - Disparities and genetic risk factors in obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is an increasingly prevalent condition. A growing body of literature supports substantial racial disparities in the prevalence, risk factors, presentation, diagnosis, and treatment of this disease. Craniofacial structure among Asians appears to confer an elevated risk of OSA despite lower rates of obesity. Among African Americans, Native Americans, and Hispanics, OSA prevalence is increased, likely due in part to obesity. The burden of symptoms, particularly excessive daytime sleepiness, is higher among African Americans, although Hispanics more often report snoring. Limited data suggest that African Americans may be more susceptible to hypertension in the setting of OSA. While differences in genetic risk factors may explain disparities in OSA burden, no definitive genetic differences have yet been identified. In addition to disparities in OSA development, disparities in OSA diagnosis and treatment have also been identified. Increased severity of disease at diagnosis among African Americans suggests a delay in diagnosis. Treatment outcomes are also suboptimal among African Americans. In children, tonsillectomy is less likely to cure OSA and more commonly associated with complications in this group. Among adults, adherence to continuous positive airway pressure (CPAP) is substantially lower in African Americans. The reasons for these disparities, particularly in outcomes, are not well understood and should be a research priority. PMID- 26428846 TI - Incidence and predisposing factors for the development of disturbed glucose metabolism and DIabetes mellitus AFter Intensive Care admission: the DIAFIC study. AB - INTRODUCTION: Elevated blood glucose levels during intensive care unit (ICU) stay, so-called stress hyperglycaemia (SH), is a common finding. Its relation with a future diabetes risk is unclear. Our objective was to determine the incidence of disturbed glucose metabolism (DGM) post ICU admission and to identify predictors for future diabetes risk with a focus on stress hyperglycaemia. METHODS: This single center prospective cohort trial (DIAFIC trial) had a study period between September 2011 and March 2013, with follow-up until December 2013. The setting was a mixed medical/surgical ICU in a tertiary teaching hospital in Belgium. 338 patients without known diabetes mellitus were included for analysis. We assessed the level of glucose metabolism disturbance (as diagnosed with a 75 g oral glucose tolerance test (OGTT) and/or HbA1c level) eight months after ICU admission, and investigated possible predictors including stress hyperglycaemia. RESULTS: In total 246 patients (73 %) experienced stress hyperglycaemia during the ICU stay. Eight months post-ICU admission, 119 (35 %) subjects had a disturbed glucose metabolism, including 24 (7 %) patients who were diagnosed with diabetes mellitus. A disturbed glucose metabolism tended to be more prevalent in subjects who experienced stress hyperglycaemia during ICU stay as compared to those without stress hyperglycaemia (38 % vs. 28 %, P = 0.065). HbA1c on admission correlated with the degree of stress hyperglycaemia. A diabetes risk score (FINDRISC) (11.0 versus 9.5, P = 0.001), the SAPS3 score (median of 42 in both groups, P = 0.003) and daily caloric intake during ICU stay (197 vs. 222, P = 0.011) were independently associated with a disturbed glucose metabolism. CONCLUSIONS: Stress hyperglycaemia is frequent in non-diabetic patients and predicts a tendency towards disturbances in glucose metabolism and diabetes mellitus. Clinically relevant predictors of elevated risk included a high FINDRISC score and a high SAPS3 score. These predictors can provide an efficient, quick and inexpensive way to identify patients at risk for a disturbed glucose metabolism or diabetes, and could facilitate prevention and early treatment. TRIAL REGISTRATION: At ClinicalTrials.gov NCT02180555 . Registered 1 July, 2014. PMID- 26428847 TI - Increased Tim-3 expression in peripheral NK cells predicts a poorer prognosis and Tim-3 blockade improves NK cell-mediated cytotoxicity in human lung adenocarcinoma. AB - T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) has been shown to play an important role in mediating NK-cell function in human diseases. However, the relationship between Tim-3 expression in natural killer (NK) cells and human lung adenocarcinoma remains unclear. We therefore investigated the expression of Tim-3 in NK cells and explored the effect of Tim-3 blockade on NK cell-mediated activity in human lung adenocarcinoma. Upregulated expression of Tim-3 on CD3-CD56+ cells (P<0.05) and CD3-CD56(dim) cells (P<0.05) of patients with lung adenocarcinoma was detected by flow cytometry. Moreover, Tim-3 expression in CD3-CD56+ NK cells was higher in patients with lung adenocarcinoma with lymph node metastasis (LNM) (P<0.05) or with tumor stage T3-T4 (P<0.05). Tim 3 expression in CD56(dim) NK-cell subset was higher in patients with tumor size >=3cm (P<0.05), or LNM (P<0.05) or with tumor stage T3-T4 (P<0.05). Further analysis showed that higher expressions of Tim-3 on both CD3-CD56+ NK cells and CD56(dim) NK-cell subset were independently correlated with shorter overall survival of patients with lung adenocarcinoma (log-rank test, P=0.0418, 0.0406, respectively). Importantly, blockade of Tim-3 signaling with anti-Tim-3 antibodies resulted in the increased cytotoxicity and IFN-gamma production of peripheral NK cells from patients with lung adenocarcinoma. Our data indicate that Tim-3 expression in NK cells can function as a prognostic biomarker in human lung adenocarcinoma and support that Tim-3 could be a new target for an immunotherapeutic strategy. PMID- 26428845 TI - Cellular Therapies in Trauma and Critical Care Medicine: Forging New Frontiers. AB - Trauma is a leading cause of death in both military and civilian populations worldwide. Although medical advances have improved the overall morbidity and mortality often associated with trauma, additional research and innovative advancements in therapeutic interventions are needed to optimize patient outcomes. Cell-based therapies present a novel opportunity to improve trauma and critical care at both the acute and chronic phases that often follow injury. Although this field is still in its infancy, animal and human studies suggest that stem cells may hold great promise for the treatment of brain and spinal cord injuries, organ injuries, and extremity injuries such as those caused by orthopedic trauma, burns, and critical limb ischemia. However, barriers in the translation of cell therapies that include regulatory obstacles, challenges in manufacturing and clinical trial design, and a lack of funding are critical areas in need of development. In 2015, the Department of Defense Combat Casualty Care Research Program held a joint military-civilian meeting as part of its effort to inform the research community about this field and allow for effective planning and programmatic decisions regarding research and development. The objective of this article is to provide a "state of the science" review regarding cellular therapies in trauma and critical care, and to provide a foundation from which the potential of this emerging field can be harnessed to mitigate outcomes in critically ill trauma patients. PMID- 26428848 TI - Anti-inflammatory activities of phospholipase C inhibitor U73122: Inhibition of monocyte-to-macrophage transformation and LPS-induced pro-inflammatory cytokine expression. AB - A wide range of biological processes are controlled by phospholipase C (PLC)/Ca(2+) signaling, which could be blocked by PLC-specific inhibitor U73122. Whether inhibition of PLC with chemical inhibitor U73122 affects the inflammatory response in monocytes/macrophages is currently unknown. In this study, we demonstrated that U73122 inhibited PMA-induced in vitro differentiation of human promonocytic U937 cells into macrophages as reflected by the reduction of cell adherence and the decreased expression of macrophage specific marker CD163. It is possible that U73122 blocked PMA-induced adhesion of U937 cells partially by down regulation and inactivation of both Pyk2 and paxillin signaling. Furthermore, the expression of LPS-induced pro-inflammatory cytokines TNF-alpha and IL-1beta was significantly blocked by U73122 in both dU937 cells and mouse primary peritoneal macrophages. These results suggest that PLC is involved in the sophisticated inflammatory response by monocytes/macrophages, and thereby chemical antagonists of PLC may be potential agents for the suppression of inflammatory response. PMID- 26428849 TI - Inhibitory effect of brazilin on osteoclast differentiation and its mechanism of action. AB - Brazilin isolated from Caesalpinia sappan has long been known as a natural red pigment. Our study evaluated the inhibitory effect of brazilin on osteoclast differentiation and investigated its mechanism of action. Our results demonstrated that brazilin inhibited receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclast differentiation in RAW264.7 cells in a dose dependent manner, without any evidence of cytotoxicity. The mRNA expression of tartrate-resistant acid phosphatase (TRAP), nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), matrix metalloproteinase 9 (MMP-9), and cathepsin K in RANKL-treated RAW264.7 cells was inhibited by brazilin treatment. Brazilin also decreased RANKL-induced expression of inflammatory mediator genes such as inducible nitric oxide synthase, iNOS; cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 and inhibited extracellular signal regulated kinases (ERK) and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kappaB) p65 phosphorylation in RANKL-stimulated RAW264.7 cells. A lipopolysaccharide (LPS)-induced osteoporosis study was also performed to assess the effects of brazilin in vivo. Micro-computed tomography (CT) analysis of the femurs showed that LPS treatment causes bone loss in mice, but it was significantly attenuated after co-treatment with brazilin (100mg/kg). Therefore, brazilin may have therapeutic potential in preventing bone loss. PMID- 26428850 TI - Intravenous immunoglobulin treatment in a HIV-1 positive patient with Guillain Barre syndrome. AB - We report the case of an HIV-1 positive patient with primary demyelinating neuropathy (Guillain-Barre syndrome); after intravenous immunoglobulin treatment (IVIG), he presented with an increase in CD4 and CD8 cell counts and a decrease in plasma viral load. Currently, there is little reported research regarding IVIG treatment in adults with HIV-1. The present report brings further evidence regarding the possible benefit of IVIG in HIV-1 infected patients, providing a novel perspective on treatment. PMID- 26428851 TI - HSPA12B attenuates acute lung injury during endotoxemia in mice. AB - Acute lung injury (ALI) is a critical manifestation of sepsis/septic shock. Heat shock protein A12B (HSPA12B), an endothelial cell-expressed heat shock protein, shows a negative regulation of lipopolysaccharide (LPS)-induced inflammation in myocardium and endothelial cells. However, it is unclear whether HSPA12B exerts protective effects against ALI during sepsis/septic shock. In this study, we treated HSPA12B transgenic mice (Tg) and wild type littermates (WT) with LPS for 6h to induce endotoxemia. LPS treatment significantly caused pulmonary injuries as evidenced by microarchitecture destruction, vascular leakage and neutrophil recruitment in lungs of WT mice. However, the LPS-induced pulmonary injuries were significantly attenuated in Tg mice. Moreover, the LPS-induced activation of extracellular signal-regulated kinases (ERKs) and upregulation of intercellular adhesion molecule-1 (ICAM-1) and Cyclooxygenase-2 (Cox-2) were inhibited in Tg lungs compared with that in WT mice. Additionally, Tg lungs showed a significant lower level of vascular endothelial growth factor (VEGF) compared with WT mice. Our results demonstrate a pulmonary protective effect of HSPA12B against endotoxin challenge, which indicates management of HSPA12B expression could serve as a potential therapeutic target for ALI during sepsis/septic shock. PMID- 26428852 TI - The design and initial patient evaluation of an integrated care pathway for faecal incontinence: a qualitative study. AB - BACKGROUND: Faecal incontinence is a common, distressing and debilitating condition which remains largely hidden, leading to social isolation and loss of confidence. Patients with faecal incontinence experience delays in accessing appropriate treatment services due to embarrassment and lack of enquiry from primary care health professionals. Despite the publication of three government documents related to continence services in the last decade, these services are still fragmented with asynchronous delivery and poor inter-professional integration. The aim of the study was to describe a novel integrated care pathway for the management of faecal incontinence and examine the experiences of patients with faecal incontinence in relation to this pathway. METHODS: A focus group (eight participants) and narrative, qualitative individual interviews (five participants) were used to explore the views of patients with faecal incontinence, relating to access and quality of incontinence services and the new integrated care pathway. Emerging themes were identified from the transcribed focus group and interviews via the thematic analysis method. RESULTS: The concept of an integrated care pathway is attractive for increasing accessibility, streamlining of the patient pathway and providing a dedicated service for the management of faecal incontinence. Patients' initial experiences of the pathway are positive. DISCUSSION: A new ICP was developed and the initial patient evaluation of it was positive. Service users made various suggestions how the FI pathway could have been improved. The issues that patients were most concerned about were access to continence services, GP awareness of continence services and prompt, effective management of their condition. This service was set up within the pelvic floor dysfunction unit with BFNS and an integrated community continence team. The authors are aware that this is not a standard service setup across the country. The fact that it may be uncomfortable for patients to talk about their condition may have led to potential bias when discussing their beliefs or experiences. As with most qualitative studies, our aim was to identify a range of experiences rather than define our participant sample as being representative. Our participant sample was diverse in the key characteristics but a longitudinal study may reveal further important aspects of an ICP for FI. CONCLUSIONS: An integrated care pathway for faecal incontinence appears to have potential to address the long-standing service delivery issues that have blighted continence services historically. PMID- 26428853 TI - Genome-wide analysis of tandem repeats in Tribolium castaneum genome reveals abundant and highly dynamic tandem repeat families with satellite DNA features in euchromatic chromosomal arms. AB - Although satellite DNAs are well-explored components of heterochromatin and centromeres, little is known about emergence, dispersal and possible impact of comparably structured tandem repeats (TRs) on the genome-wide scale. Our bioinformatics analysis of assembled Tribolium castaneum genome disclosed significant contribution of TRs in euchromatic chromosomal arms and clear predominance of satellite DNA-typical 170 bp monomers in arrays of >=5 repeats. By applying different experimental approaches, we revealed that the nine most prominent TR families Cast1-Cast9 extracted from the assembly comprise ~4.3% of the entire genome and reside almost exclusively in euchromatic regions. Among them, seven families that build ~3.9% of the genome are based on ~170 and ~340 bp long monomers. Results of phylogenetic analyses of 2500 monomers originating from these families show high-sequence dynamics, evident by extensive exchanges between arrays on non-homologous chromosomes. In addition, our analysis shows that concerted evolution acts more efficiently on longer than on shorter arrays. Efficient genome-wide distribution of nine TR families implies the role of transposition only in expansion of the most dispersed family, and involvement of other mechanisms is anticipated. Despite similarities in sequence features, FISH experiments indicate high-level compartmentalization of centromeric and euchromatic tandem repeats. PMID- 26428855 TI - Coxiella-like endosymbiont associated to the "Anatolian brown tick" Rhipicephalus bursa in Southern Italy. AB - Several different ticks have been reported to harbor microbes related to Coxiella burnetii, the agent of the Q fever. Rhipicephalus bursa is an important vector of tick-borne diseases in livestock in Mediterranean area; it is also abundant in ovi-caprine farms with C. burnetii infection, in Southern Italy. 60 females of Rh. bursa (15 pools) and 40 their eggs (2 pools) were screened for C. burnetii by a conventional PCR targeting the insertion sequence IS1111 and by Loop mediated isothermal amplification assay (LAMP) targeting com1 gene. One of 15 tick pools (1/15) and both egg pools (2/2) were found positive by LAMP assay and negative by PCR targeting IS1111 gene. 16S rRNA gene was amplified by PCR from the LAMP positive pools, amplicons were sequenced and found 95% similar to the corresponding sequences from C. burnetii. This let us to hypothesize the presence of a new Coxiella-like endosymbiont associated with Rh. bursa which could be vertically transmitted, described here for the first time. The lack of detection of IS1111 in Coxiella endosymbiont of Rh. bursa could be related to the possible absence of the Pathogenicity island of C. burnetii, to which IS1111s are associated. PMID- 26428856 TI - Waddlia chondrophila and Chlamydia trachomatis antibodies in screening infertile women for tubal pathology. AB - Since Waddlia chondrophila is closely related to Chlamydia trachomatis, we hypothesise that W. chondrophila may also be associated with tubal factor infertility (TFI) in women, a major complication of chronic C. trachomatis infection. Five hundred twenty serum samples were tested for anti-Waddlia antibodies by ELISA. Among the 520 investigated women, a total number of 142 (27.3%) has had laparoscopic diagnosis performed, and were either classified TFI positive or negative. Presence of high titres of W. chondrophila antibodies was linked to TFI (p < 0.0001; OR: 7.5; 95% CI: 3.3-17). Moreover, antibody positivity to both W. chondrophila and C. trachomatis-MOMP was strongly associated with TFI (p < 0.0001; OR: 21; 95% CI: 3.8-12E1). This association was much stronger than the statistical association of C. trachomatis-MOMP antibodies only (p < 0.0001; OR: 7.1; 95% CI: 3.7-14), suggesting that co-infection with W. chondrophila and C. trachomatis may lead to more severe reproductive sequelae and immune responses than single infection with either Chlamydiales members. PMID- 26428858 TI - Nuclear Magnetic Resonance (NMR) as a tool for the study of the metabolism of Rickettsia slovaca. AB - Rickettsial infections are caused by intracellular bacteria. They do not grow in standard culture media so there are limitations in routine practice to study their metabolism. Nuclear Magnetic Resonance (NMR) spectroscopy is used for identification of metabolites in biological samples. Vero cells infected with Rickettsia slovaca as well as uninfected cells were monitored by (1)H NMR showing the presence of ethanol and lactic acid. As no differences were observed, labeled compounds were added into cultures. When D-[1-13C]glucose was monitored by (13)C NMR no differences among infected and uninfected cells were observed in metabolic profiles. Glucose was transformed into ethanol in all cultures. Monitored experiments carried out with [2-13C]glycine showed differences between infected and uninfected cell cultures spectra. Glycine was partially transformed into serine, but the amount of the serine formed was larger in those infected. Moreover, L-[2-13C]leucine, L-[1-13C]isoleucine and L-[15N]tyrosine were evaluated. No differences among infected and uninfected cells were observed in the metabolic profiles when tyrosine and leucine were monitored. The amino acid L [1-13C]isoleucine exhibited different metabolism in presence of the R. slovaca, showing a promising behavior as biomarker. In this work we focused on finding one or more compounds that could be metabolized specifically by R. slovaca and could be used as an indicator of its activity. PMID- 26428857 TI - Anaplasma phagocytophilum infection in moose (Alces alces) in Norway. AB - Anaplasma phagocytophilum is a tick-borne bacterium that infects a wide range of animal species. The aim of our study was to investigate the prevalence of A. phagocytophilum in Norwegian moose Alces alces and to characterize the bacteria by sequencing of partial msp4 and 16S rRNA genes. Hunters collected spleen samples from 99 moose of different ages during 2013 and 2014 in two areas: Aust Agder County (n = 70) where Ixodes ricinus ticks are abundant and Oppland County (n = 29) where ticks were either absent, or abundance very low. A. phagocytophilum was detected only in moose from the I. ricinus - abundant area. The overall prevalence of infection according to 16S rRNA and msp4 gene-based PCR was 41.4% and 31.4% respectively. Sequence analysis of the partial 16S rRNA and msp4 gene revealed two and eight different sequence types respectively. Four of eight msp4 sequence types determined in this study were unique, while others were identical to sequences derived from other ruminants and ticks. The present study indicates that moose could be a potential wildlife reservoir of A. phagocytophilum in Norway. PMID- 26428859 TI - Isolation and maintenance of Rickettsia raoultii in a Rhipicephalus sanguineus tick cell line. AB - Rickettsia raoultii, a member of the spotted fever group rickettsiae, has been implicated in cases of DEBONEL/TIBOLA/SENLAT, and has been detected in Dermacentor spp. and Rhipicephalus pumilio ticks by PCR. R. raoultii has been isolated in mammalian and tick cell lines. This study aimed to isolate R. raoultii from Spanish Dermacentor marginatus in tick cell lines. A single adult D. marginatus collected from vegetation in La Rioja (Northen Spain) in October 2012 was surface-sterilised, triturated and aliquots of the homogenate were inoculated into a panel of tick cell lines derived from embryonic Rhipicephalus sanguineus, Rhipicephalus evertsi and Ixodes ricinus. Cultures were maintained at 28 degrees C with weekly medium changes and checked by Gimenez stain for Rickettsia-like intracellular organisms. After 50 days of incubation, intracellular Rickettsia-like organisms were observed in the R. sanguineus cell line RML-RSE using Gimenez stain. PCR assays and sequencing of fragments of 16S RNA, ompB and ompA genes in DNA extracted from the culture suspension showed 100% identity with R. raoultii. Growth of intracellular microorganisms was not observed in preparations of the other tick cell lines. In conclusion, the tick cell line RML-RSE is a useful system for the isolation and maintenance of R. raoultii. PMID- 26428860 TI - Up-regulation of Hsp72 and keratin16 mediates wound healing in streptozotocin diabetic rats. AB - BACKGROUND: Impaired wound healing is a complication of diabetes and a serious problem in clinical practice. We previously found that whey protein (WP) was able to regulate wound healing normally in streptozotocin (STZ)-diabetic models. This subsequent study was designed to assess the effect of WP on heat shock protein-72 (Hsp72) and keratin16 (Krt16) expression during wound healing in diabetic rats. METHODS: WP at a dosage of 100 mg/kg of body weight was orally administered daily to wounded normal and STZ-diabetic rats for 8 days. RESULTS: At day 4, the WP treated diabetic wound was significantly reduced compared to that in the corresponding control. Diabetic wounded rats developed severe inflammatory infiltration and moderate capillary dilatation and regeneration. Treated rats had mild necrotic formation, moderate infiltration, moderate to severe capillary dilatation and regeneration, in addition to moderate epidermal formation. Hsp72 and Krt16 densities showed low and dense activity in diabetic wounded and diabetic wounded treated groups, respectively. At day 8, WP-treatment of diabetic wounded animals revealed great amelioration with complete recovery and closure of the wound. Reactivity of Hsp72 and Krt16 was reversed, showing dense and low, or medium and low, activity in the diabetic wounded and diabetic wounded treated groups, respectively. Hsp72 expression in the pancreas was found to show dense reactivity with WP-treated diabetic wound rats. CONCLUSION: This data provides evidence for the potential impact of WP in the up-regulation of Hsp72 and Krt16 in T1D, resulting in an improved wound healing process in diabetic models. PMID- 26428862 TI - Sensory impact of lowering sugar content in orange nectars to design healthier, low-sugar industrialized beverages. AB - The presence of added sugars (AS) in the diet is associated with increased risk of obesity and other chronic diseases. We assessed sensory impact of lowering AS in orange nectar, aiming at new WHO sugar guideline. Ideal sweetness by just about-right (JAR) tests (60 consumers), difference and rejection thresholds (36 and 35 assessors), and acceptance and sensory profile by Check-all-that-apply (CATA) tests (100 consumers) were performed. JAR test comprised six concentrations of AS from 12% down to 4.5%. Thresholds tests comprised orange nectars at reference sugar concentration (10%) and at lower sugar levels. Acceptance and CATA tests compared reference, ideal sweetness and thresholds concentrations. There were two groups of consumers; one with ideal sweetness lower at 5.5% AS and another with ideal sweetness at standard 10.5% AS. The average ideal sweetness among all consumers was 7.3% AS. The difference threshold from the reference at 10.5% AS was at 8.5% AS and the rejection threshold was 7.2%. Overall acceptance of nectar with 8.5% and 7.2% AS was similar to reference and higher than acceptance of nectar with 5.5%. However, after cluster analysis, nectars with 5.5% AS did not differ from nectars with 8.5% or 7.2% AS, suggesting the possibility of a gradual reduction until 5.5% in the long term. Lowering AS to 7.2% or 5.5% caused significant changes in viscosity, sweet odor, bitterness and sweetness in comparison to the reference concentration. Lowering sugar from 10% to 8.5% did not affect acceptance or sensory attributes, and could be indicated for a first reduction. Results indicate that a gradual reduction to 7.2% and 5.5% would be feasible. Reductions can remove 3150-9450 tons of sugar per year from the Brazilian diet resulting in healthier beverages. PMID- 26428861 TI - Feeding on resistant rice leads to enhanced expression of defender against apoptotic cell death (OoDAD1) in the Asian rice gall midge. AB - BACKGROUND: The Asian rice gall midge (Orseolia oryzae) is a destructive insect pest of rice. Gall midge infestation in rice triggers either compatible or incompatible interactions leading to survival or mortality of the feeding maggots, respectively. In incompatible interactions, generation of plant allelochemicals/defense molecules and/or inability of the maggots to continue feeding on the host initiate(s) apoptosis within the maggots. Unraveling these molecular events, triggered within the maggots as a response to feeding on resistant hosts, will enable us to obtain a better understanding of host resistance. The present study points towards the likely involvement of a defender against apoptotic cell death gene (DAD1) in the insect in response to the host defense. RESULTS: The cDNA coding for the DAD1 orthologue in the rice gall midge (OoDAD1) consisted of 339 nucleotides with one intron of 85 bp and two exons of 208 and 131 nucleotides. The deduced amino acid sequence of OoDAD1 showed a high degree of homology (94.6%) with DAD1 orthologue from the Hessian fly (Mayetiola destructor)--a major dipteran pest of wheat. Southern hybridization analysis indicated that OoDAD1 was present as a single copy in the genomes of the Asian rice gall midge biotypes (GMB) 1, 4 and 4 M. In the interactions involving GMB4 with Jaya (susceptible rice host) the expression level of OoDAD1 in feeding maggots gradually increased to 3-fold at 96 hai (hours after infestation) and peaked to 3.5-fold at 96 hai when compared to that at 24 hai. In contrast, expression in maggots feeding on RP2068 (resistant host) showed a steep increase of more than 8-fold at 24 hai and this level was sustained at 48, 72 and 96 hai when compared with the level in maggots feeding on Jaya at 24 hai. Recombinant OoDAD1, expressed in E. coli cells, when injected into rice seedlings induced a hypersensitive response (HR) in the resistant rice host, RP2068, but not in the susceptible rice variety, Jaya. CONCLUSIONS: The results indicate that the expression of OoDAD1 is triggered in the feeding maggots probably due to the host resistance response and therefore, is likely an important molecule in the initial stages of the interaction between the midge and its rice host. PMID- 26428863 TI - Cognitive functions of intracellular mechanisms for contextual amplification. AB - Evidence for the hypothesis that input to the apical tufts of neocortical pyramidal cells plays a central role in cognition by amplifying their responses to feedforward input is reviewed. Apical tufts are electrically remote from the soma, and their inputs come from diverse sources including direct feedback from higher cortical regions, indirect feedback via the thalamus, and long-range lateral connections both within and between cortical regions. This suggests that input to tuft dendrites may amplify the cell's response to basal inputs that they receive via layer 4 and which have synapses closer to the soma. ERP data supporting this inference is noted. Intracellular studies of apical amplification (AA) and of disamplification by inhibitory interneurons targeted only at tufts are reviewed. Cognitive processes that have been related to them by computational, electrophysiological, and psychopathological studies are then outlined. These processes include: figure-ground segregation and Gestalt grouping; contextual disambiguation in perception and sentence comprehension; priming; winner-take-all competition; attention and working memory; setting the level of consciousness; cognitive control; and learning. It is argued that theories in cognitive neuroscience should not assume that all neurons function as integrate-and-fire point processors, but should use the capabilities of cells with distinct sites of integration for driving and modulatory inputs. Potentially 'unifying' theories that depend upon these capabilities are reviewed. It is concluded that evolution of the primitives of AA and disamplification in neocortex may have extended cognitive capabilities beyond those built from the long-established primitives of excitation, inhibition, and disinhibition. PMID- 26428864 TI - VIIIth nerve cavernous hemangioma mimicking a stage 1 acoustic schwannoma. AB - OBJECTIVE: To report a case of VIIIth nerve cavernous hemangioma, a very rare differential diagnosis among the various pathologies presenting as small enhancing entities into the internal auditory canal. It is one of the most challenging when imaging is not able to differentiate it from an intrameatal vestibular schwannoma. METHODS AND RESULTS: We report a cavernous hemangioma extruding from the internal auditory canal, diagnosed after a left translabyrinthine resection in a 45-year-old man complaining of profound sensorineural hearing loss, with no facial paresis or dizziness. The preoperative differential diagnosis of a vestibular schwannoma was impossible, due to the absence of calcifications that usually characterize temporal bone hemangiomas. Clinical presentation, radiological features and treatment considerations are discussed along with up-to-date review of pertinent literature. CONCLUSIONS: When considering an apparent small intra-auditory canal schwannoma, otoneurologists should be aware of the rare possibility of a cavernous hemangioma. Early diagnosis and surgical treatment may improve the functional outcome, possibly preserving neural integrity. PMID- 26428865 TI - On heart migration of the peritoneal catheter. PMID- 26428866 TI - Accumulation of free amino acids during exposure to drought in three springtail species. AB - Springtails are closely related to insects, but they differ from these with respect to water balance, in particular because springtails are small and have high integumental permeability to water. Here we report a series of experiments addressing the dynamics of osmoregulation, water content and accumulation of free amino acids (FAAs) in three springtail species during exposure to a gradually increasing environmental desiccation simulating conditions in drought exposed soil. Folsomia candida and Protaphorura fimata (both living in the deeper soil layers; euedaphic species) were active throughout the 3week exposure, with the developing drought regime ending at -3.56MPa (the soil water activity at the permanent wilting point of plants is -1.5MPa) and remained hyperosmotic (having an body fluid osmolality higher than the corresponding environment) to their surrounding air. Sinella curviseta (living in upper soil/litter layers; hemiedaphic species) also survived this exposure, but remained hypoosmotic throughout (i.e. with lower osmolality than the environment). The body content of most FAAs increased in response to drought in all three species. Alanine, proline and arginine were the most significantly upregulated FAAs. By combining our results with data in the literature, we could account for 82% of the observed osmolality at -3.56MPa in F. candida and 92% in P. fimata. The osmolality of S. curviseta was only slightly increased under drought, but here FAAs were considerably more important as osmolytes than in the two other species. We propose that FAAs probably have general importance in drought tolerance of springtails. PMID- 26428867 TI - Isolation and anti-microbial susceptibility pattern of group B Streptococcus among pregnant women attending antenatal clinics in Ayder Referral Hospital and Mekelle Health Center, Mekelle, Northern Ethiopia. AB - BACKGROUND: Vaginal colonization with group B Streptococcus (GBS) is the predominant risk factor for the development of invasive neonatal GBS diseases and puts newborns at increased risk for morbidity and mortality. This study is aimed to determine the colonization rate and antimicrobial susceptibility pattern of group B Streptococcus among pregnant women. METHODS: Hospital based cross sectional study was conducted from August to December 2014 at selected health facilities. A total of 139 antenatal clinics attendees, proportionally allocated, were recruited consecutively. Socio-demographic and clinical factors were collected using a structured questionnaire. Vaginal swabs were collected and cultured on Todd Hewitt broth and in 5 % sheep blood agar. Antimicrobial susceptibility test was done using Kirby-Bauer disk diffusion test. Statistical analysis was performed using Pearson's Chi square test. RESULTS: Among the 139, 19 (13.7 %) were positive for GBS. All the GBS isolates were susceptible (100 %) to penicillin G, vancomycin, ampicillin, erythromycin and gentamicin. Two of the GBS isolates showed multidrug resistance against norfloxacin and ciprofloxacin. No statistically significant difference was observed for GBS colonization with any independent variables. CONCLUSION: Vaginal colonization of GBS for the present study put emphasis on further investigation and accomplishment of routine GBS screening practices. The recovery of resistant strains to antimicrobial agents recommended in cases of penicillin allergic mothers indicates the importance of susceptibility test. PMID- 26428868 TI - Diffuse and multifocal nephrogenic adenoma with Familial Mediterranean Fever: a case report with molecular study. AB - Nephrogenic adenoma, also referred to nephrogenic metaplasia, is a benign proliferative lesion of urothelium, usually associated with chronic physical stimuli or inflammation. Familial Mediterranean fever is an inherited autosomal recessive disease characterized by recurrent short episodes of fever. The site of mutation is found in MEFV gene which controls inflammatory responses. We have experienced a case of nephrogenic adenoma in a 16-year-old girl with Familial Mediterranean Fever, showing proliferative lesions diffusely in the urinary bladder and multifocally in the other parts of urinary tract. These lesions disappeared after colchicine treatment. We searched for MEFV gene mutation using the specimen from the resected urinary bladder and detected heterozygous mutation of E148Q. There is a possibility that control of inflammation caused by the surgery for vesicoureteral reflux in the local site didn't work well on the background of heterozygous mutation of MEFV gene, and as a result, nephrogenic adenoma appeared. This is the first report of a combination of two rare diseases. We have to be aware that nephrogenic adenoma can occur in association with Familial Mediterranean Fever, and the former condition should be taken into consideration when rendering a correct pathological diagnosis. PMID- 26428869 TI - Discovery of dihydroquinazolinone derivatives as potent, selective, and CNS penetrant M(1) and M(4) muscarinic acetylcholine receptors agonists. AB - We designed and synthesized a series of dihydroquinazolinone derivatives as selective M1 and M4 muscarinic acetylcholine receptors agonists. Introduction of the N-carbethoxy piperidine unit into a HTS hit compound followed by optimization of the amine linker and the carbamoyl moiety led to the identification of compound 1 as a potential candidate. The identified compound 1 showed high selectivity for M1 and M4 muscarinic acetylcholine receptors with M4 partial agonistic activity. In addition, compound 1 showed good brain penetration and reversed methamphetamine-induced hyperlocomotion in rats (ED50=3.0 mg/kg, sc). PMID- 26428870 TI - Rethinking the old antiviral drug moroxydine: Discovery of novel analogues as anti-hepatitis C virus (HCV) agents. AB - The discovery of a novel class of HCV inhibitors is described. The new amidinourea compounds were designed as isosteric analogues of the antiviral drug moroxydine. The two derivatives 11g and 11h showed excellent HCV inhibition activity and viability and proved to inhibit a step(s) of the RNA replication. The new compounds have been synthesized in only three synthetic steps from cheap building blocks and in high yields, thus turning to be promising drug candidates in the development of cheaper HCV treatments. PMID- 26428871 TI - Discovery and structure-activity analysis of 4-((5-nitropyrimidin-4 yl)amino)benzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors. AB - Despite a potential application of PRMT1 inhibitors in cancer treatment, very few of PRMT1 inhibitors have been reported. To obtain novel potent PRMT1 inhibitors, structure optimizations towards a hit compound, 4-((6-chloro-5-nitropyrimidin-4 yl)amino)benzimidamide, were carried out. A series of 4-((5-nitropyrimidin-4 yl)amino)benzimidamide derivatives were synthesized. Structure-activity relationship analysis led to the discovery of a number of PRMT1 inhibitors. The most potent compound corresponds to compound 6d, which showed an IC50 value of 2.0 MUM against PRMT1. This compound also displayed a considerable anti proliferative activity against three tumor cell lines, DLD-1, T24 and SH-SY-5Y, with IC50 values of 4.4 MUM, 13.1 MUM and 11.4 MUM, respectively. PMID- 26428872 TI - Design, synthesis, and biological evaluation of oxindole derivatives as antidepressive agents. AB - The 3-substituted oxindole derivatives were designed, synthesized, and evaluated for antidepressant activity by employing forced swimming test, tail suspension test, and MAO-A inhibition assay. Results of biological studies revealed that the majority of compounds exhibited potent to moderately potent activity and among them, 12 displayed potency comparable to that of the imipramine with %DID of 37.95 and 44.84 in the FST and TST, respectively. At the same time, imipramine showed %DID of 43.62 and 50.64 in the FST and TST, correspondingly. In the MAO-A inhibition assay, 12 showed an IC50 of 18.27 MUmol, whereas the reference drug moclobemide displayed an IC50 of 13.1 MUmol. The SAR study disclosed that the presence of bromo atom at the phenyl/furanyl or thienyl moiety in the oxindole derivatives was critical for the antidepressant activity. PMID- 26428873 TI - Identification of a molecular target of kurahyne, an apoptosis-inducing lipopeptide from marine cyanobacterial assemblages. AB - In 2014, we isolated kurahyne, an acetylene-containing lipopeptide, from a marine cyanobacterial assemblage of Lyngbya sp. Kurahyne exhibited growth-inhibitory activity against human cancer cells, and induced apoptosis in HeLa cells. However, its mode of action is not yet clear. To elucidate its mode of action, we carried out several cell-based assays, and identified the intracellular target molecule of kurahyne as sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA). In addition, we found that kurahyne inhibited the differentiation of macrophages into osteoclasts. PMID- 26428874 TI - Exploring clotrimazole-based pharmacophore: 3D-QSAR studies and synthesis of novel antiplasmodial agents. AB - We report herein the generation and validation of a 3D-QSAR model based on a set of antimalarials previously described by us and characterized by a clotrimazole based pharmacophore. A novel series of derivatives was synthesized and showed activity against Plasmodium falciparum chloroquine-sensitive (CQ-S) and chloroquine-resistant (CQ-R) strains. Gratifyingly, compounds 35a-c showed interesting activity against P. falciparum CQ-R strains with improved predicted physico-chemical properties. PMID- 26428875 TI - Palmoplantar eczema as initial sign of mycosis fungoides. PMID- 26428876 TI - Initiating technical refinements in high-level golfers: Evidence for contradictory procedures. AB - When developing motor skills there are several outcomes available to an athlete depending on their skill status and needs. Whereas the skill acquisition and performance literature is abundant, an under-researched outcome relates to the refinement of already acquired and well-established skills. Contrary to current recommendations for athletes to employ an external focus of attention and a representative practice design, Carson and Collins' (2011) [Refining and regaining skills in fixation/diversification stage performers: The Five-A Model. International Review of Sport and Exercise Psychology, 4, 146-167. doi: 10.1080/1750984x.2011.613682 ] Five-A Model requires an initial narrowed internal focus on the technical aspect needing refinement: the implication being that environments which limit external sources of information would be beneficial to achieving this task. Therefore, the purpose of this paper was to (1) provide a literature-based explanation for why techniques counter to current recommendations may be (temporarily) appropriate within the skill refinement process and (2) provide empirical evidence for such efficacy. Kinematic data and self-perception reports are provided from high-level golfers attempting to consciously initiate technical refinements while executing shots onto a driving range and into a close proximity net (i.e. with limited knowledge of results). It was hypothesised that greater control over intended refinements would occur when environmental stimuli were reduced in the most unrepresentative practice condition (i.e. hitting into a net). Results confirmed this, as evidenced by reduced intra-individual movement variability for all participants' individual refinements, despite little or no difference in mental effort reported. This research offers coaches guidance when working with performers who may find conscious recall difficult during the skill refinement process. PMID- 26428877 TI - Admissibility analysis for discrete-time singular systems with randomly occurring uncertainties via delay-divisioning approach. AB - This paper deals with the problem of admissibility analysis for discrete-time singular system with time-delays. The uncertainties occurring in the system parameters are assumed to be random. By constructing Lyapunov functional, sufficient delay-dependent stochastic admissibility conditions are established via delay divisioning approach in terms of linear matrix inequalities (LMIs), which can be easily checked by utilizing the numerically efficient Matlab LMI toolbox. Numerical examples and their simulation results are given to illustrate the effectiveness of the obtained theoretical results. PMID- 26428878 TI - Fault tolerant control based on interval type-2 fuzzy sliding mode controller for coaxial trirotor aircraft. AB - In this paper, a robust controller for a Six Degrees of Freedom (6 DOF) coaxial trirotor helicopter control is proposed in presence of defects in the system. A control strategy based on the coupling of the interval type-2 fuzzy logic control and sliding mode control technique are used to design a controller. The main purpose of this work is to eliminate the chattering phenomenon and guaranteeing the stability and the robustness of the system. In order to achieve this goal, interval type-2 fuzzy logic control has been used to generate the discontinuous control signal. The simulation results have shown that the proposed control strategy can greatly alleviate the chattering effect, and perform good reference tracking in presence of defects in the system. PMID- 26428879 TI - Delayed Stenosis in the Intracranial Vessels following Endovascular Treatment for Acute Stroke. AB - PURPOSE: To evaluate delayed stenosis of the vessels after endovascular thrombectomy using magnetic resonance (MR) angiography. MATERIALS AND METHODS: Of 82 consecutive patients who underwent successful endovascular treatment for acute intracranial large vessel occlusion between October 2010 and October 2014 at a single institution, 57 patients for whom 3-month radiologic follow-up examinations using MR angiography were available were included in the analysis. MR angiography images were assessed to detect delayed stenosis, which was defined as a decrease in the diameter of treated vessels > 50% compared with MR angiography images obtained 24 hours after endovascular treatment. RESULTS: MR angiography images obtained 3 months after endovascular treatment revealed delayed stenosis of treated vessels in five (8.8%) of 57 patients. All cases of delayed stenosis were asymptomatic and occurred in the middle cerebral artery (MCA). Further serial radiologic follow-up showed gradual improvement of all delayed stenosis over 12 months. CONCLUSIONS: Endovascular treatment poses a risk of delayed stenosis of treated vessels, especially in the MCA. MR angiography is a useful modality in long-term follow-up to evaluate delayed stenosis after endovascular treatment. PMID- 26428880 TI - Comparative Analysis of Prostate Volume as a Predictor of Outcome in Prostate Artery Embolization. AB - PURPOSE: To determine the role of prostate volume as a predictor of outcome after prostatic artery embolization (PAE). MATERIALS AND METHODS: From January 2012 to September 2014, 78 consecutive patients undergoing PAE were evaluated at baseline and 1, 3, and 6 months. Analysis was performed comparing prostate volume groups (group 1, < 50 cm3; group 2, 50-80 cm(3); group 3, > 80 cm3) at baseline and follow-up to assess for differences in outcomes of American Urological Association (AUA) symptom index, quality of life (QOL)-related symptoms, and International Index of Erectile Function (IIEF). RESULTS: Mean baseline prostate volumes were 37.5 cm(3) in group 1 (n = 16), 65.7 cm3 in group 2 (n = 26), and 139.4 cm3 in group 3 (n = 36). There were no significant differences in baseline age, AUA symptom index, QOL, or IIEF between groups. Bilateral embolization was successful in 75 of 78 patients (96%). Two patients underwent unilateral embolization, and treatment failed in one patient as a result of bilateral atherosclerotic occlusion. A significant reduction in AUA symptom index was achieved within groups from baseline to 1, 3, and 6 months (n = 77): in group 1, from 27.2 to 14.0, 12.9, and 15.9, respectively (P = .002); in group 2, from 25.6 to 17.1, 16.3, and 13.5, respectively (P < .0001); and in group 3, from 26.5 to 15.2, 12.5, and 13.6, respectively (P < .0001). There was also a significant improvement in QOL. Comparative analysis demonstrated no statistically significant differences in AUA symptom index, QOL, or IIEF between groups. Two minor complications occurred: groin hematoma and a urinary tract infection. CONCLUSIONS: PAE offers similar clinical benefits to patients with differing gland sizes and may offer a reasonable alternative for poor candidates for urologic surgery. PMID- 26428881 TI - Histochemical detection of acetogenins and storage molecules in the endosperm of Annona macroprophyllata Donn Sm. seeds. AB - Acetogenins (ACGs) are bioactive compounds with cytotoxic properties in different cell lines. They are antitumoural, antiparasitic, antimalarial, insecticidal, antimicrobial, antifungal and antibacterial. These secondary metabolites function in plant defence and are found in specific organelles and specific cells, thereby preventing toxicity to the plant itself and permitting site-specific defence. The aim of this work was to histochemically determine the in situ localisation of ACGs in the endosperm of Annona macroprophyllata seeds using Kedde's reagent. Additionally, the colocalisation of ACGs with other storage molecules was analysed. The seeds were analysed after 6 and 10 days of imbibition, when 1 or 2 cm of the radicle had emerged and metabolism was fully established. The seeds were then transversally cut in half at the midline and processed using different histological and histochemical techniques. Positive reactions with Kedde's reagent were only observed in fresh, unfixed sections that were preserved in water, and staining was found only in the large cells (the idioblasts) at the periphery of the endosperm. The ACGs' positive reaction with Sudan III corroborated their lipid nature. Paraffin sections stained with Naphthol Blue Black showed reactions in the endosperm parenchyma cells and stained the proteoplasts blue, indicating that they might correspond to storage sites for albumin-like proteins. Lugol's iodine, which is similar in chemical composition to Wagner's reagent, caused a golden brown reaction product in the cytoplasm of the idioblasts, which may indicate the presence of alkaloids. Based on these results, we propose that Kedde's reagent is an appropriate histochemical stain for detecting ACGs in situ in idioblasts and that idioblasts store ACGs and probably alkaloids. ACGs that are located in idioblasts found in restricted, peripheral areas of the endosperm could serve as a barrier that protects the seeds against insects and pathogen attack. PMID- 26428882 TI - Apoptosis activation in human carious dentin. An immunohistochemical study. AB - The exact mechanisms and enzymes involved in caries progression are largely unclear. Apoptosis plays a key role in dentin remodelling related to damage repair; however, it is unclear whether apoptosis in decayed teeth is activated through the extrinsic or the intrinsic pathway. This ex vivo immunohistochemical study explored the localization of TRAIL, DR5, Bcl-2 and Bax, the main proteins involved in apoptosis, in teeth with advanced caries. To evaluate TRAIL, DR5, Bcl 2 and Bax immunoexpressions twelve permanent carious premolars were embedded in paraffin and processed for immunohistochemistry. The results showed that TRAIL and DR5 were overexpressed in dentin and in pulp vessels and mononuclear cells; strong Bax immunostaining was detected in dilated dentinal tubules close to the lesion, and Bcl-2 staining was weak in some dentin areas under the cavity or altogether absent. These findings suggest that both apoptosis pathways are activated in dental caries. Further studies are required to gain insights into its biomolecular mechanisms. PMID- 26428854 TI - Time-series metagenomic analysis reveals robustness of soil microbiome against chemical disturbance. AB - Soil microbial communities have great potential for bioremediation of recalcitrant aromatic compounds. However, it is unclear which taxa and genes in the communities, and how they contribute to the bioremediation in the polluted soils. To get clues about this fundamental question here, time-course (up to 24 weeks) metagenomic analysis of microbial community in a closed soil microcosm artificially polluted with four aromatic compounds, including phenanthrene, was conducted to investigate the changes in the community structures and gene pools. The pollution led to drastic changes in the community structures and the gene sets for pollutant degradation. Complete degradation of phenanthrene was strongly suggested to occur by the syntrophic metabolism by Mycobacterium and the most proliferating genus, Burkholderia. The community structure at Week 24 (~12 weeks after disappearance of the pollutants) returned to the structure similar to that before pollution. Our time-course metagenomic analysis of phage genes strongly suggested the involvement of the 'kill-the-winner' phenomenon (i.e. phage predation of Burkholderia cells) for the returning of the microbial community structure. The pollution resulted in a decrease in taxonomic diversity and a drastic increase in diversity of gene pools in the communities, showing the functional redundancy and robustness of the communities against chemical disturbance. PMID- 26428883 TI - Sox9 expression in canine epithelial skin tumors. AB - Sox9 is a master regulatory gene involved in developmental processes, stem cells maintenance and tumorigenesis. This gene is expressed in healthy skin but even in several skin neoplasms, where its expression patterns often resembles those of the developing hair follicle. In this study, samples from eleven different types of canine skin neoplasms (squamous papilloma, squamous cell carcinoma, infundibular keratinizing acanthoma, inferior tricholemmoma, isthmic tricholemmoma, trichoblastoma, trichoepitelioma, malignant trichoepitelioma, pilomatricoma, subungual keratoacanthoma, subungual squamous cell carcinoma) were immunohistochemically stained and evaluated for Sox9 with the aim to correlate tumor phenotype with molecular characteristics that may help to better define tumor development, contribute to its diagnosis and clinical management. Keratoacanthoma excluded, all the skin neoplasms examined showed a variable positivity to Sox9, especially in the basal layers, but with major intensity in neoplasms developing from the bulge region of the hair follicle, as trichoblastoma. According to our results, Sox9 could be employed as a stem cell marker to better assess the role of stem cells in canine epidermal and follicular tumors. PMID- 26428884 TI - Enhancement of immunohistochemical detection of Salmonella in tissues of experimentally infected pigs. AB - Salmonella Typhimurium is one of the main pathogens compromising porcine and human health as well as food safety, because it is a prevailing source of foodborne infections due to contaminated pork. A prominent problem in the management of this bacteriosis is the number of subclinically infected carrier pigs. As very little is known concerning the mechanisms allowing Salmonella to persist in pigs, the objective of this study was to develop an immunohistochemical approach for the detection of salmonellae in tissue of pigs experimentally infected with Salmonella Typhimurium. Samples were obtained from a challenge trial in which piglets of the German Landrace were intragastrically infected with Salmonella enterica serovar Typhimurium DT104 (1.4-2.1x1010 CFU). Piglets were sacrificed on days 2 and 28 post infection. Tissue samples of jejunum, ileum, colon, ileocecal mesenteric lymph nodes (Lnn. ileocolici), and tonsils (Tonsilla veli palatini) were fixed in Zamboni's fixative and paraffin embedded. Different immunohistochemical staining protocols were evaluated. Salmonella was detected in varying amounts in the tissues. Brown iron-containing pigments in the lymph nodes interfered with the identification of Salmonella if DAB was used as a staining reagent. Detergents like Triton X-100 or Saponin enhanced the sensitivity. It seems advisable not to use a detection system with brown staining for bacteria in an experimental setup involving intestinal damage including haemorrhage. The use of detergents appears to result in a higher sensitivity in the immunohistochemical detection of salmonellae. PMID- 26428885 TI - Heterogeneous vesicles in mucous epithelial cells of posterior esophagus of Chinese giant salamander (Andrias davidianus). AB - The Chinese giant salamander belongs to an old lineage of salamanders and endangered species. Many studies of breeding and disease regarding this amphibian had been implemented. However, the studies on the ultrastructure of this amphibian are rare. In this work, we provide a histological and ultrastructural investigation on posterior esophagus of Chinese giant salamander. The sections of amphibian esophagus were stained by hematoxylin & eosin (H&E). Moreover, the esophageal epithelium was observed by transmission electron microscopy (TEM). The results showed that esophageal epithelium was a single layer epithelium, which consisted of mucous cells and columnar cells. The esophageal glands were present in submucosa. The columnar cells were ciliated. According to the diverging ultrastructure of mucous vesicles, three types of mucous cells could be identified in the esophageal mucosa: i) electron-lucent vesicles mucous cell (ELV MC); ii) electron-dense vesicles mucous cell (EDV-MC); and iii) mixed vesicles mucous cell (MV-MC). PMID- 26428886 TI - Testicular expression of NGF, TrkA and p75 during seasonal spermatogenesis of the wild ground squirrel (Citellus dauricus Brandt). AB - The nerve growth factor (NGF) not only has an essential effect on the nervous system, but also plays an important role in a variety of non-neuronal systems, such as the reproductive system. The aim of this study was to investigate the seasonal changes in expression of NGF and its receptors (TrkA and p75) in testes of the wild ground squirrel during the breeding and nonbreeding seasons. Immunolocalization for NGF was detected mainly in Leydig cells and Sertoli cells in testes of the breeding and nonbreeding seasons. The immunoreactivity of TrkA was highest in the elongated spermatids, whereas p75 in spermatogonia and spermatocytes in testes of the breeding season. In the nonbreeding season testes, TrkA showed positive immunostainings in Leydig cells, spermatogonia and primary spermatocytes, while p75 showed positive signals in spermatogonia and primary spermatocytes. Consistent with the immunohistochemical results, the mean mRNA and protein level of NGF and TrkA were higher in the testes of the breeding season, and then decreased to a relatively low level in the nonbreeding season. In addition, the concentration of plasma gonadotropins and testosterone were assayed by radioimmunoassay (RIA), and the results showed a significant seasonal change between the breeding and nonbreeding seasons. To conclude, these results of this study provide the first evidence on the potential involvement of NGF and its receptor, TrkA and p75 in the seasonal spermatogenesis and testicular function change of the wild ground squirrel. PMID- 26428887 TI - Immunohistochemical demonstration of specific antigens in the human brain fixed in zinc-ethanol-formaldehyde. AB - Tissue fixation is critical for immunohistochemistry. Recently, we developed a zinc-ethanol-formalin fixative (ZEF), and the present study was aimed to assess the applicability of the ZEF for the human brain histology and immunohistochemistry and to evaluate the detectability of different antigens in the human brain fixed with ZEF. In total, 11 antigens were tested, including NeuN, neuron-specific enolase, GFAP, Iba-1, calbindin, calretinin, choline acetyltransferase, glutamic acid decarboxylase (GAD65), tyrosine hydroxylase, synaptophysin, and alpha-tubulin. The obtained data show that: i) the ZEF has potential for use in general histological practice, where detailed characterization of human brain morphology is needed; ii) the antigens tested are well-preserved in the human brain specimens fixed in the ZEF. PMID- 26428888 TI - Immunohistochemical and ultrastructural study of the lamellae of oocytes in atretic follicles in relation to different processes of cell death. AB - Atresia is the process through which non-selectable oocytes are eliminated; it involves apoptosis and/or autophagy. This study used immunohistochemical and ultrastructural techniques to characterize the lamellae present in the cytoplasm of oocytes in follicles in the process of atresia in prepubertal and adult Wistar rats. The results indicate that the lamellae are positive to tubulin and myosin immunodetection under light and electron microscopy. Labeling is greater with anti-tubulin and lesser with anti-myosin. Our observations indicate that lamellae are present in oocytes at the initial antral stage in prepubertal rats; that is, from day 14 post-birth to adult age. We were able to determine that the increase in altered lamellae principally occurs in the apoptotic cells rather than in the autophagic cells. PMID- 26428889 TI - Three-dimensional apoptotic nuclear behavior analyzed by means of Field Emission in Lens Scanning Electron Microscope. AB - Apoptosis is an essential biological function required during embryogenesis, tissue homeostasis, organ development and immune system regulation. It is an active cell death pathway involved in a variety of pathological conditions. During this process cytoskeletal proteins appear damaged and undergo an enzymatic disassembling, leading to formation of apoptotic features. This study was designed to examine the three-dimensional chromatin behavior and cytoskeleton involvement, in particular actin re-modeling. HL-60 cells, exposed to hyperthermia, a known apoptotic trigger, were examined by means of a Field Emission in Lens Scanning Electron Microscope (FEISEM). Ultrastructural observations revealed in treated cells the presence of apoptotic patterns after hyperthermia trigger. In particular, three-dimensional apoptotic chromatin rearrangements appeared involving the translocation of filamentous actin from cytoplasm to the nucleus. FEISEM immunogold techniques showed actin labeling and its precise three-dimensional localization in the diffuse chromatin, well separated from the condensed one. The actin presence in dispersed chromatin inside the apoptotic nucleus can be considered an important feature, indispensable to permit the apoptotic machinery evolution. PMID- 26428890 TI - Immunohistochemical localization of periostin in human gingiva. AB - The periostin is a matricellular protein expressed in collagen-rich tissues including some dental and periodontal tissues where it is regulated by mechanical forces, growth factors and cytokines. Interestingly the expression of this protein has been found modified in different gingival pathologies although the expression of periostin in normal human gingiva was never investigated. Here we used Western blot and double immunofluorescence coupled to laser-confocal microscopy to investigated the occurrence and distribution of periostin in different segments of the human gingival in healthy subjects. By Western blot a protein band with an estimated molecular mass of 94 kDa was observed. Periostin was localized at the epithelial-connective tissue junction, or among the fibers of the periodontal ligament, and never co-localized with cytokeratin or vimentin thus suggesting it is an extracellular protein. These results demonstrate the occurrence of periostin in adult human gingiva; its localization suggests a role in the bidirectional interactions between the connective tissue and the epithelial cells, and therefore in the physiopathological conditions in which these interactions are altered. PMID- 26428891 TI - An in situ hybridization study of perlecan, DMP1, and MEPE in developing condylar cartilage of the fetal mouse mandible and limb bud cartilage. AB - The main purpose of this in situ hybridization study was to investigate mRNA expression of three bone/cartilage matrix components (perlecan, DMP1, and MEPE) in developing primary (tibial) and secondary (condylar) cartilage. Perlecan mRNA expression was first detected in newly formed chondrocytes in tibial cartilage at E13.0, but this expression decreased in hypertrophic chondrocytes at E14.0. In contrast, at E15.0, perlecan mRNA was first detected in the newly formed chondrocytes of condylar cartilage; these chondrocytes had characteristics of hypertrophic chondrocytes, which confirmed the previous observation that progenitor cells of developing secondary cartilage rapidly differentiate into hypertrophic chondrocytes. DMP1 mRNA was detected in many chondrocytes within the lower hypertrophic cell zone in tibial cartilage at E14.0. In contrast, DMP1 mRNA expression was only transiently detected in a few chondrocytes of condylar cartilage at E15.0. Thus, DMP1 may be less important in the developing condylar cartilage than in the tibial cartilage. Another purpose of this study was to test the hypothesis that MEPE may be a useful marker molecule for cartilage. MEPE mRNA was not detected in any chondrocytes in either tibial or condylar cartilage; however, MEPE immunoreactivity was detected throughout the cartilage matrix. Western immunoblot analysis demonstrated that MEPE antibody recognized two bands, one of 67 kDa and another of 59 kDa, in cartilage-derived samples. Thus MEPE protein may gradually accumulate in the cartilage, even though mRNA expression levels were below the limits of detection of in situ hybridization. Ultimately, we could not designate MEPE as a marker molecule for cartilage, and would modify our original hypothesis. PMID- 26428892 TI - Elevation of pivaloylcarnitine by sivelestat sodium in two children. AB - BACKGROUND: Sivelestat sodium (sivelestat), a neutrophil elastase inhibitor, is used to treat acute respiratory distress syndrome (ARDS). We report two cases that developed elevated C5-acylcarnitine (C5-AC) levels following treatment with sivelestat. Case 1 was a 14-day-old female infant born at 25 weeks and 1 day of gestation who was treated with sivelestat for the prophylaxis of Wilson-Mikity syndrome soon after birth. Isovaleric acidemia (IVA) was suspected based on a newborn screening using tandem mass spectrometry (MS/MS). Her C5-AC level was elevated to 4.49 MUM (cut-off, <1.0) after treatment with sivelestat. Case 2 was a 4-year-old female with pneumocystis pneumonia that developed during chemotherapy for disseminated medulloblastoma. Sivelestat was given for the complication of ARDS. Her C5-AC level increased (1.09 MUM) after eight days of treatment with sivelestat. RESULTS: In both cases, IVA was ruled out because isovalerylglycine was not observed in the urinary organic acid analysis. Case 1 was associated with carnitine deficiency (C0 9.16 MUM; reference value, 10-60). Liquid chromatography-MS/MS confirmed elevated pivaloylcarnitine (PVC) in both cases. DISCUSSION: Similar to antibiotics containing pivalic acid (PVA), sivelestat contains PVA, which has the potential to cause secondary carnitine deficiency. In addition, elevated PVC can lead to false positive findings of IVA in newborns screened using MS/MS. PMID- 26428893 TI - In vivo delivery and long-term tissue retention of nano-encapsulated sirolimus using a novel porous balloon angioplasty system. AB - AIMS: Among antirestenotic compounds, sirolimus displays a superior safety profile compared to paclitaxel, but its pharmacokinetic properties make it a challenging therapeutic candidate for single-time delivery. Herein we evaluate the feasibility of delivery, long-term retention and vascular effects of sirolimus nanoparticles delivered through a novel porous angioplasty balloon in normal porcine arteries and in a swine model of in-stent restenosis (ISR). METHODS AND RESULTS: Sirolimus nanoparticle formulation was delivered via porous balloon angioplasty to 753 coronary artery segments for pharmacokinetic studies and 26 segments for biological effect of sirolimus delivery in different clinical scenarios (de novo [n=8], ISR [n=6] and following stent implantation [n=12]). Sirolimus coronary artery concentrations were above the target therapeutic level of 1 ng/mg after 26 days, and were >100-fold higher in coronary artery treatment sites than in distal myocardium and remote tissues at all time points. At 28 days, reduction in percent stenosis in formulation-treated sites compared to balloon angioplasty treatment was noted in all three clinical scenarios, with the largest effect seen in the de novo study. CONCLUSIONS: Local coronary delivery of sirolimus nanoparticles in the porcine model using a novel porous balloon delivery system achieved therapeutic long-term intra-arterial drug levels without significant systemic residual exposure. PMID- 26428894 TI - Associations between parental rules, style of communication and children's screen time. AB - BACKGROUND: Research suggests an inverse association between parental rules and screen time in pre-adolescents, and that parents' style of communication with their children is related to the children's time spent watching TV. The aims of this study were to examine associations of parental rules and parental style of communication with children's screen time and perceived excessive screen time in five European countries. METHODS: UP4FUN was a multi-centre, cluster randomised controlled trial with pre- and post-test measurements in each of five countries; Belgium, Germany, Greece, Hungary and Norway. Questionnaires were completed by the children at school and the parent questionnaire was brought home. Three structural equation models were tested based on measures of screen time and parental style of communication from the pre-test questionnaires. DISCUSSION: Of the 152 schools invited, 62 (41 %) schools agreed to participate. In total 3325 children (average age 11.2 years and 51 % girls) and 3038 parents (81 % mothers) completed the pre-test questionnaire. The average TV/DVD times across the countries were between 1.5 and 1.8 h/day, while less time was used for computer/games console (0.9-1.4 h/day). The children's perceived parental style of communication was quite consistent for TV/DVD and computer/games console. The presence of rules was significantly associated with less time watching TV/DVD and use of computer/games console time. Moreover, the use of an autonomy-supportive style was negatively related to both time watching TV/DVD and use of computer/games console time. The use of a controlling style was related positively to perceived excessive time used on TV/DVD and excessive time used on computer/games console. With a few exceptions, results were similar across the five countries. CONCLUSIONS: This study suggests that an autonomy-supportive style of communicating rules for TV/DVD or computer/ games console use is negatively related to children's time watching TV/DVD and use of computer/games console time. In contrast, a controlling style is associated with more screen time and with more perceived excessive screen time in particular. Longitudinal research is needed to further examine effects of parental style of communication on children's screen time as well as possible reciprocal effects. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number Register, registration number: ISRCTN34562078 . Date applied29/07/2011, Date assigned11/10/2011. PMID- 26428895 TI - Taurodontism in patients with nonsyndromic cleft lip and palate in a Brazilian population: a case control evaluation with panoramic radiographs. AB - OBJECTIVES: The purpose of this study was to evaluate the prevalence of taurodontism in patients with nonsyndromic cleft lip and palate (NSCLP) within a Brazilian population. STUDY DESIGN: The study was designed as an epidemiologic case-control single-center study. Three hundred eighty-eight patients were included: 88 had NSCLP, and 300 comprised the control group. The first and second permanent mandibular molars were included in this study. By using panoramic radiographs, taurodontism was categorized as mesotaurodontism, hypotaurodontism, and hypertaurodontism. RESULTS: Seventy patients (23.3%) from the control group and 36 patients (40.9%) from the case group presented taurodontism (P < .001). In the control group, 108 (9%) teeth showed taurodontism, whereas in the case group with cleft lip and palate (CLP), 64 (18.2%) teeth showed dental anomalies (P < .001). In both groups, most taurodontic teeth presented hypotaurodontism, followed by mesotaurodontism, while hypertaurodontism was found in only two teeth. The probability of taurodontism in patients with cleft lip (CL) was 2.36 (P = .010) times higher compared with those with CLP, whereas the occurrence of taurodontism in patients with cleft palate (CP) was 3.15 (P = .002) times greater than in patients with CLP. CONCLUSIONS: The results from this study indicate a close relationship between taurodontism and NSCLP and the possibility of different cleft subphenotypes. PMID- 26428896 TI - Long-term outcome of transendoscopic oesophageal mass ablation in dogs with Spirocerca lupi-associated oesophageal sarcoma. AB - Oesophageal sarcoma is a potential sequel of Spirocerca lupi infection. Oesophageal mass excision can be performed by open chest surgery. The objectives of this observational study were to evaluate the feasibility, short-term morbidity and long-term outcome of transendoscopic oesophageal mass ablation in dogs with spirocercosis-associated oesophageal neoplasia. A 9 mm video-endoscope and laser or electrocauterisation were used to debulk the oesophageal mass. Long term follow-up was done by telephonic interviews. Fifteen dogs were included. The median tumour size was 5 cm (range 3.5-9). The median procedure time was 75 minutes (range 35-165) and was deemed successful in 12/15 dogs (80 per cent). Recovery was uneventful in all dogs. Immediate complications included oesophageal damage (two dogs) oesophageal perforation (one dog) and a focal thermal damage (one dog). The median hospitalisation time of all dogs was less than one day, with all but two discharged on the procedure day. The median survival time, available in nine dogs that were followed, was 202 days (range 51-691). Four of these dogs (44 per cent) survived more than six months, of which three survived more than one year. In conclusion, transendoscopic oesophageal mass ablation might be considered an alternative, palliative procedure for open-chest oesophageal surgery. It has comparable long-term survival, lower morbidity, short hospitalisation time and relatively low cost. PMID- 26428897 TI - Chlamydiae in corvids. PMID- 26428898 TI - Clostridium perfringens type-D enterotoxaemia in cattle: the diagnostic significance of intestinal epsilon toxin. AB - The aims of this study were to describe 42 cases of Clostridium perfringens type D enterotoxaemia in cattle seen between 2003 and 2014 and to determine the diagnostic value of detecting epsilon toxin in bovine intestinal content. All cases in the series had histological brain changes considered pathognomonic for C. perfringens type-D enterotoxaemia in sheep and goats and the epsilon toxin of C. perfringens was concurrently detected in the intestinal contents of 15 (36 per cent) cases. The data from the case series indicate that intestinal epsilon toxin has a sensitivity of 56 per cent compared with histology of the brain for diagnosis of bovine C. perfringens type-D enterotoxaemia. The diagnostic specificity of detecting epsilon toxin in bovine intestinal content was investigated by screening intestinal contents of 60 bovine carcases submitted for postmortem examination. Epsilon toxin was detected in 11 (18 per cent) carcases but no pathognomonic histological brain change was found in any. The specificity of intestinal epsilon toxin was estimated to be 80.4 per cent. These studies demonstrate that for a definitive diagnosis of C. perfringens type-D enterotoxaemia in cattle histological examination of the brain is essential as the presence of epsilon toxin in the intestinal contents alone is neither sensitive nor specific enough. PMID- 26428899 TI - Relationship of Sit-to-Stand Lower-Body Power With Functional Fitness Measures Among Older Adults With and Without Sarcopenia. AB - BACKGROUND AND PURPOSE: When evaluating health in older adults, batteries of tests are typically utilized to assess functional fitness. Unfortunately, physician's visits are time-sensitive, and it may be important to develop faster methods to assess functional fitness that can be utilized in professional or clinical settings. Therefore, the purpose of this investigation was to examine the relationship of sit-to-stand (STS) power generated through the STS task with previously established measures of functional fitness, specifically strength, endurance, speed, agility, and flexibility in older adults with and without sarcopenia. METHODS: This study consisted of 57 community-dwelling older adults (n = 16 males; n = 41 females). Functional fitness was assessed using the Short Physical Performance Battery (SPPB), Senior Fitness Test, handgrip, gait speed (habitual and maximal), balance, and STS power generated via the Tendo Weightlifting Analyzer. On the basis of data distribution, second-degree polynomial (quadratic) curvilinear models (lines of best fit) were applied for the relationships of 5-time STS time with average and peak power. Zero-order correlations were evaluated between STS power and all other functional fitness measures. Older adults with sarcopenia were also identified (n = 15), and relationships were reevaluated within this subset. RESULTS: STS power (average and peak) was significantly (P <= .01) correlated with physical performance measured via previously established assessments. For average power, this was observed during the senior fitness test (6-minute walk [r = 0.39], 8-ft up-and-go [r = -0.46], arm curl [r = 0.46], and chair stand [r = 0.55]), SPPB (5-time STS time [r = -0.63] and 8-ft walk [r = -0.32]), and other independent functional fitness measures (grip strength [r = 0.65] and maximal gait speed [r = -0.31]). Similar results were observed for peak power during the senior fitness test (6 minute walk [r = 0.39], 8-ft up-and-go [r = -0.46], arm curl [r = 0.45], chair stand [r = 0.52], and sit-and-reach [r = -0.27]), SPPB (5-time STS time [r = 0.60] and 8-ft walk [r = -0.33]), and other independent functional fitness measures (grip strength [r = 0.70] and maximal gait speed [r = -0.32]). Within the sarcopenic subset, for average and peak power, respectively, significant relationships were still retained for handgrip strength (r = 0.57 and r = 0.57), 6-minute walk (r = 0.55 and r = 0.61), chair stand (r = 0.76 and r = 0.81), and 5 time STS time (r = -0.76 and r = -0.80) tests. DISCUSSION/CONCLUSIONS: STS power generated via the STS task significantly relates to commonly administered functional fitness measures. These relationships also appear to exist when evaluating these relationships in older adults with sarcopenia. STS power may be utilized as an independent measure of functional fitness that is feasible to incorporate in clinical settings where time and space are often limiting factors. PMID- 26428900 TI - Comparative Analysis of High-Velocity Versus Low-Velocity Exercise on Outcomes After Total Knee Arthroplasty: A Randomized Clinical Trial. AB - BACKGROUND AND PURPOSE: High-velocity (HV) exercise is defined as performing a concentric muscle contraction as fast as possible, or in 1 second or less. Low velocity (LV) exercise is defined as using 2 seconds to complete the contraction. A comparison of HV to LV exercise performed by community dwelling older adults indicates that HV exercise produces greater gains in power and scores for the 8 ft up-and-go, 30-seond chair stand, and continuous scale physical function performance tests. The effectiveness of HV strengthening exercises has not been identified for individuals who undergo total knee arthroplasty (TKA). The purpose of this research study was to compare the effects of a 6-week exercise program, using either LV or HV contractions, on functional performance, gait, and pain of individuals who have undergone TKA. METHODS: Adults aged 60 to 89 years with a mean (standard deviation) age of 71.2 (6.8) years who underwent TKA an average of 15 days prior were randomly assigned to an HV exercise (n = 19) or LV exercise (n = 19) training group. The training program lasted for 12 sessions, over 6 to 7 weeks. The primary outcome was functional performance rated with the 6-Minute Walk Test. Secondary measures were the stair climb test, Timed Up and Go test, gait velocity, gait deviations measured with the Gait Abnormality Rating Scale, and pain via a visual analog scale. A 2*2 mixed model analysis of variance (group * time) was used for all outcomes. Comparison between LV and HV groups for posttest gait velocity and Gait Abnormality Rating Scale used independent t test and Mann-Whitney U test, respectively. RESULTS: At baseline no differences between groups were noted for sex, age, and height. The LV group weighed more and had more comorbid conditions. Spearman's rho demonstrated that the greater comorbidities of the LV group correlated with a slower stair climb test at baseline. At posttest both groups exhibited significantly improved scores for all outcome measurements except the visual analog scale for pain. The HV group, but not the LV group, reported a significant decrease in pain at the end of the 6 week training program. CONCLUSIONS: Both HV and LV progressive exercises equally improve functional performance. Only the HV group reported significantly decreased pain at posttest. PMID- 26428901 TI - Accelerometer-Based Monitoring of Upper Limb Movement in Older Adults With Acute and Subacute Stroke. AB - BACKGROUND AND PURPOSE: Use of the affected extremity during daily life is important if disuse atrophy is to be prevented after stroke. This study examined whether objectively measured real-world upper limb movement is associated with the amount of use of the affected upper limb, as assessed by a standardized assessment tool in older adults with acute or subacute stroke. This study also examined whether the real-world upper limb movement is associated with the extent of impairment of upper and lower extremities. METHODS: The participants were 19 older adults with hemiparesis from acute or subacute stroke [17 (7) days after the stroke]. All the participants wore 3 accelerometers-1 on each wrist (bilateral accelerometry) and 1 on the waist-throughout a 24-hour period. They were interviewed about use of their upper limb in the real-world setting using a Motor Activity Log. Functions of the affected upper limb or upper and lower limbs were assessed using the National Institute of Health Stroke Scale, the Brunnstrom Recovery Stage (BRS), the Simple Test for Evaluating Hand Function, and the Functional Independence Measure tests. RESULTS AND DISCUSSION: Movement counts measured with the wrist accelerometer on the affected upper limb (unilateral accelerometry) over 24 hours and during the 12-hour daytime period (08:00 to 20:00) were significantly correlated with scores for affected upper limb use (the Motor Activity Log) and functions (the upper extremity BRS and the affected side Simple Test for Evaluating Hand Function), upper and lower extremity functions (the National Institute of Health Stroke Scale, the lower extremity BRS, and the motor Functional Independence Measure), and step counts measured over the same period. To estimate the affected upper limb use or disuse, we subtracted the movement counts of the unaffected upper limb from those of the affected upper limb. As a result, the subtracted counts over 24 hours and during the 12-hour daytime period were only related to scores for affected upper limb use and functions. CONCLUSIONS: Bilateral accelerometry for monitoring upper limb movements in a real-world setting might be useful to clinicians for objective assessment of affected upper limb use or disuse and function among older adults with hemiparesis from acute or subacute stroke. PMID- 26428902 TI - Test-Retest Reliability and Minimal Detectable Change for the 10-Meter Walk Test in Older Adults With Parkinson's disease. AB - BACKGROUND AND PURPOSE: Measurement of gait performance in individuals with Parkinson's disease (PD) can be challenging because of the daily fluctuations in performance and the progressive nature of the condition. The 10-Meter Walk Test (10MWT) is commonly used to measure gait speed of individuals with gait limitations. Existing research on the 10MWT in individuals with PD controls for many variables inherent to this condition, rendering the results of this test in settings where these variables are not controlled questionable. The purpose of this study was to estimate under commonly encountered clinical conditions the test-retest reliability and the minimal detectable change (MDC) of gait speed and step frequency determined during the 10MWT in individuals with PD. METHODS: The 10MWT was administered by 2 testers, on 35 participants, across 2 sessions, separated by 5 to 14 days. Gait speed was measured using a hand-held stopwatch, and step frequency was assessed through visual observation. Test-retest reliability was calculated using the intraclass correlation coefficient (ICC) and the MDC was calculated using the standard error of measurement (SEM). RESULTS AND DISCUSSION: Comfortable and fast gait speeds demonstrated excellent reliability between sessions (ICC = 0.92 and 0.96, respectively). The corresponding MDCs were 0.22 and 0.23 m/s, respectively. The test-retest reliability for step frequency was moderate for comfortable gait speed and good for fast gait speeds (ICC = 0.73 and 0.82, respectively). The corresponding MDCs were 15.1 and 17.4 steps per minute for comfortable and fast step frequency, respectively. CONCLUSIONS: Under both comfortable and fast conditions, measurements of gait speed and step frequency during the 10MWT are reliable between sessions in individuals with PD. PMID- 26428903 TI - High-Velocity Quadriceps Exercises Compared to Slow-Velocity Quadriceps Exercises Following Total Knee Arthroplasty: A Randomized Clinical Study. AB - BACKGROUND AND PURPOSE: Despite improvement in pain and perceived function in older adults following total knee arthroplasty (TKA), objective outcome measures of muscular impairment and ambulatory function demonstrate significant deficits. Evidence suggests that quadriceps power may play a greater role in ambulatory function than measures of strength alone following TKA. The purpose of this study was to compare the effect of high-velocity (HV) quadriceps exercises with that of slow-velocity (SV) quadriceps exercises on functional outcomes and quadriceps power following TKA. METHODS: This study was a randomized clinical study conducted in an outpatient physical therapy clinic. Twenty-one participants who were 4 to 6 weeks post unilateral TKA were randomly assigned to an HV or SV group. Participants performed an evidence-based standardized progressive resistance exercise program in addition to HV quadriceps exercises or SV quadriceps exercises. Participants attended 2 sessions per week for 8 weeks. Before and after the 8-week exercise intervention, participants completed a functional questionnaire, health survey, functional testing, and underwent quadriceps strength and power testing. RESULTS: Both groups demonstrated improvements in ambulatory outcome measures, strength, speed, and power. The HV group demonstrated significantly greater improvements in distance walked and quadriceps strength than the SV group. LIMITATIONS: These data should be considered preliminary because of a small sample size. CONCLUSION: HV quadriceps exercises may be an effective rehabilitation strategy in conjunction with a standardized progressive resistance exercise program beginning 4 to 6 weeks after TKA. PMID- 26428904 TI - Long term study of deoxyribozyme administration to XT-1 mRNA promotes corticospinal tract regeneration and improves behavioral outcome after spinal cord injury. AB - Spinal cord injury (SCI) affects approximately 3 million people around the world, who are desperately awaiting treatment. The pressing need for the development of therapeutics has spurred medical research for decades. To respond to this pressing need, our group developed a potential therapeutic to reduce the presence of proteoglycans at the injury site after acutely traumatizing the spinal cord of rats. With the aid of a DNA enzyme against the mRNA of xylosyltransferase-1 (DNAXT-1as) we adjourn the glycosylation and prevent the assembly of the proteoglycan core protein into the extracellular matrix. Hence, endogenous repair is strengthened due to the allocation of a more growth permissive environment around the lesion site. Here, we present data on a long term study of animals with a dorsal hemisection treated with DNAXT-1as, DNAXT-1mb (control DNA enzyme) or PBS via osmotic minipumps. After successful digestion of the XT-1 mRNA shown by qPCR we observed an overall behavioral improvement of DNAXT-1as treated rats at 8, 10 and 14 weeks after insult to the spine compared to the control animals. This is accompanied by the growth of the cortical spinal tract (CST) in DNAXT-1as treated animals after a 19 week survival period. Furthermore, after evaluating the lesion size tissue-protective effects in the DNAXT-1as treated animals compared to DNAXT-1mb and PBS treated rats are revealed. The results yield new insights into the regeneration processes and provide confirmation to involve DNA enzyme administration in future therapeutic strategies to medicate SCI. PMID- 26428905 TI - Reduced vesicular monoamine transport disrupts serotonin signaling but does not cause serotonergic degeneration. AB - We previously demonstrated that mice with reduced expression of the vesicular monoamine transporter 2 (VMAT2 LO) undergo age-related degeneration of the catecholamine-producing neurons of the substantia nigra pars compacta and locus ceruleus and exhibit motor disturbances and depressive-like behavior. In this work, we investigated the effects of reduced vesicular transport on the function and viability of serotonin neurons in these mice. Adult (4-6 months of age), VMAT2 LO mice exhibit dramatically reduced (90%) serotonin release capacity, as measured by fast scan cyclic voltammetry. We observed changes in serotonin receptor responsivity in in vivo pharmacological assays. Aged (months) VMAT2 LO mice exhibited abolished 5-HT1A autoreceptor sensitivity, as determined by 8-OH DPAT (0.1 mg/kg) induction of hypothermia. When challenged with the 5HT2 agonist, 2,5-dimethoxy-4-iodoamphetamine (1 mg/kg), VMAT2 LO mice exhibited a marked increase (50%) in head twitch responses. We observed sparing of serotonergic terminals in aged mice (18-24 months) throughout the forebrain by SERT immunohistochemistry and [(3)H]-paroxetine binding in striatal homogenates of aged VMAT2 LO mice. In contrast to their loss of catecholamine neurons of the substantia nigra and locus ceruleus, aged VMAT2 LO mice do not exhibit a change in the number of serotonergic (TPH2+) neurons within the dorsal raphe, as measured by unbiased stereology at 26-30 months. Collectively, these data indicate that reduced vesicular monoamine transport significantly disrupts serotonergic signaling, but does not drive degeneration of serotonin neurons. PMID- 26428906 TI - Cognitive impairments may mimic delusions. AB - Delusions are often recognized as key to the concept of psychosis. What is delusion is one of the basic questions of psychopathology. The common denominator of definitions of delusions is the divergence between the strong conviction in the delusional belief and superior evidences to the contrary which are continually ignored. An implicit, sustainably unspoken assumption is that the person with delusional belief has cognitive capacities to process the (counter )arguments relevant to their delusion. However, individual's cognitive capacities are not being emphasized when delusions are evaluated. Moreover, the impact of cognitive decline on formation of delusions is neglected, both in theory and practice. We elaborate that cognitive deficits may facilitate, oppose, or mimic delusions. We focus on the last, which can lead to diagnosing as delusion what could be explained by cognitive decline and better called pseudo-delusion. The risk is significant when cognition is impaired, as in demented people; an issue which has not yet been debated. True delusions are incompatible with person's cognitive capacities, i.e., if we take into account person's cognitive status, we still cannot understand how the person holds the strange belief with an extraordinary conviction. Pseudo-delusions would be beliefs, thoughts or judgments that at first seem delusional (they are false, subculturally atypical beliefs that are strongly maintained in the face of counterargument), but lose the essence of delusions after we take cognitive impairment into account. Pseudo delusions could actually be explained or understood by person's cognitive impairments, they "fit into" them. The reported reality-based contents of delusions in the elderly, poor response to antipsychotics and lack of association with early or family history of psychiatric disorders could in part be accounted for by the bias of misdiagnosing the cognitive impairment as the delusion. Not recognizing that the cognitive impairment underlies formation of pseudo-delusions and misdiagnosing it as delusions may lead to focusing on antipsychotic treatment, instead on treatment of the underlying cognitive deficit. PMID- 26428907 TI - Age-related differences on low back pain and postural control during one-leg stance: a case-control study. AB - BACKGROUND AND PURPOSE: The prevalence of chronic low back pain (CLBP) is higher in older than in younger adults and is associated with poor postural control and falls. The objective of this study was to compare the postural control of younger and older subjects with and without CLBP during a one-leg stance. METHODS: Twenty subjects with and 20 subjects without nonspecific CLBP participated in the study. Each group contained 10 younger (50% males; mean age: 31 years) and 10 older adults (50% males; mean age 71 years). The subjects performed three 30-s trials of a one-leg stance on a force platform. Balance parameters were computed to quantify postural control, including center of pressure (COP) area, mean velocity, and mean frequency in the anteroposterior and mediolateral directions. RESULTS: Participants with CLBP presented significantly poorer balance (P < 0.05) than participants without CLBP. The effect size was large for younger adults (d = 1.44) and small for older adults (d = 0.40). Older adults with CLBP presented poorer balance than younger adults with CLBP (large effect size, d = 1.24). CONCLUSIONS: The findings indicate that CLBP affects the balance of both younger and older adults, and that the age-related changes also affect balance and modify the magnitude of CLBP effects on balance. PMID- 26428908 TI - Fracture Rates and Lifetime Estimations of CAD/CAM All-ceramic Restorations. AB - The gathering of clinical data on fractures of dental restorations through prospective clinical trials is a labor- and time-consuming enterprise. Here, we propose an unconventional approach for collecting large datasets, from which clinical information on indirect restorations can be retrospectively analyzed. The authors accessed the database of an industry-scale machining center in Germany and obtained information on 34,911 computer-aided design (CAD)/computer aided manufacturing (CAM) all-ceramic posterior restorations. The fractures of bridges, crowns, onlays, and inlays fabricated from different all-ceramic systems over a period of 3.5 y were reported by dentists and entered in the database. Survival analyses and estimations of future life revealed differences in performance among ZrO2-based restorations and lithium disilicate and leucite reinforced glass-ceramics. PMID- 26428909 TI - Two-dimensional motion of Brownian swimmers in linear flows. AB - The motion of viruses and bacteria and even synthetic microswimmers can be affected by thermal fluctuations and by external flows. In this work, we study the effect of linear external flows and thermal fluctuations on the diffusion of those swimmers modeled as spherical active (self-propelled) particles moving in two dimensions. General formulae for their mean-square displacement under a general linear flow are presented. We also provide, at short and long times, explicit expressions for the mean-square displacement of a swimmer immersed in three canonical flows, namely, solid-body rotation, shear and extensional flows. These expressions can now be used to estimate the effect of external flows on the displacement of Brownian microswimmers. Finally, our theoretical results are validated by using Brownian dynamics simulations. PMID- 26428910 TI - psiTurk: An open-source framework for conducting replicable behavioral experiments online. AB - Online data collection has begun to revolutionize the behavioral sciences. However, conducting carefully controlled behavioral experiments online introduces a number of new of technical and scientific challenges. The project described in this paper, psiTurk, is an open-source platform which helps researchers develop experiment designs which can be conducted over the Internet. The tool primarily interfaces with Amazon's Mechanical Turk, a popular crowd-sourcing labor market. This paper describes the basic architecture of the system and introduces new users to the overall goals. psiTurk aims to reduce the technical hurdles for researchers developing online experiments while improving the transparency and collaborative nature of the behavioral sciences. PMID- 26428911 TI - Erratum to: Characterization of the Nencki Affective Picture System by discrete emotional categories (NAPS BE). PMID- 26428912 TI - The what, why, and how of born-open data. AB - Although many researchers agree that scientific data should be open to scrutiny to ferret out poor analyses and outright fraud, most raw data sets are not available on demand. There are many reasons researchers do not open their data, and one is technical. It is often time consuming to prepare and archive data. In response, my laboratory has automated the process such that our data are archived the night they are created without any human approval or action. All data are versioned, logged, time stamped, and uploaded including aborted runs and data from pilot subjects. The archive is GitHub, github.com, the world's largest collection of open-source materials. Data archived in this manner are called born open. In this paper, I discuss the benefits of born-open data and provide a brief technical overview of the process. I also address some of the common concerns about opening data before publication. PMID- 26428913 TI - The revised NEUROGES-ELAN system: An objective and reliable interdisciplinary analysis tool for nonverbal behavior and gesture. AB - As visual media spread to all domains of public and scientific life, nonverbal behavior is taking its place as an important form of communication alongside the written and spoken word. An objective and reliable method of analysis for hand movement behavior and gesture is therefore currently required in various scientific disciplines, including psychology, medicine, linguistics, anthropology, sociology, and computer science. However, no adequate common methodological standards have been developed thus far. Many behavioral gesture coding systems lack objectivity and reliability, and automated methods that register specific movement parameters often fail to show validity with regard to psychological and social functions. To address these deficits, we have combined two methods, an elaborated behavioral coding system and an annotation tool for video and audio data. The NEUROGES-ELAN system is an effective and user-friendly research tool for the analysis of hand movement behavior, including gesture, self touch, shifts, and actions. Since its first publication in 2009 in Behavior Research Methods, the tool has been used in interdisciplinary research projects to analyze a total of 467 individuals from different cultures, including subjects with mental disease and brain damage. Partly on the basis of new insights from these studies, the system has been revised methodologically and conceptually. The article presents the revised version of the system, including a detailed study of reliability. The improved reproducibility of the revised version makes NEUROGES ELAN a suitable system for basic empirical research into the relation between hand movement behavior and gesture and cognitive, emotional, and interactive processes and for the development of automated movement behavior recognition methods. PMID- 26428914 TI - Daily television viewing time and associated risk of obesity among U.S. preschool aged children: An analysis of NHANES 2009-2012. PMID- 26428916 TI - Gene expression profiling of DMU-212-induced apoptosis and anti-angiogenesis in vascular endothelial cells. AB - CONTEXT: trans-3,4,5,4'-Tetramethoxystilbene (DMU-212), an derivative of resveratrol, shows strong antiproliferative activities against many cancer cells. In our previous study, we demonstrated that DMU-212 possesses potent proapoptosis and antiangiogenesis effects on vascular endothelial cells (VECs), which made it a promising agent for the treatment of angiogenesis-related diseases. OBJECTIVE: We studied the gene expression profile of DMU-212-treated VECs to gain further insight into the mechanisms by which DMU-212 exerts its potent pro-apoptosis and antiangiogenesis effects. MATERIALS AND METHODS: The potential changes in the gene expression of VECs incubated with DMU-212 were identified and analyzed using the Affymetrix HG-U133 Plus 1.0 array. In addition, the gene expression profile was validated by quantitative real-time PCR (qRT-PCR) analysis for seven of those altered genes. RESULTS AND CONCLUSION: DMU-212 was found to regulate a diverse range of genes, including cytokines (IL8, selectin E, MPZL2, EGR1, CCL20, ITGB8, CXCL1, VCAM1, KITLG, and AREG), transport proteins (TRPC4, SLC41A2, SLC17A5, and CREB5), metabolism (CYP1B1, CYP1A1, PDK4, CSNK1G1, MVK, TCEB3C, and CDKN3), enzymes (RAB23, SPHK1, CHSY3, PLAU, PLA2G4C, and MMP10), and genes involved in signal transduction (TMEM217, DUSP8, and SPRY4), chromosome organization (HIST1H2BH and GEM), cell migration and angiogenesis (ERRFI1, HBEGF, and NEDD9), and apoptosis (TNFSF15, TNFRSF9, CD274, BCL2L11, BIRC3, TNFAIP3, and TIFA), as well as other genes with unknown function (PGM5P2, SNORD1142, LOC151760, KRTAP5 2, C1orf110, SNORA14A, MIR31, C2CD4B, SCARNA4, C2orf66, SC4MOL, LOC644714, and LOC283392). This is the first application of microarray technique to investigate and analyze the profile of genes regulated by DMU-212 in VECs. Our results lead to an increased understanding of the signaling pathways involved in DMU-212 induced apoptosis and antiangiogenesis. PMID- 26428915 TI - Analysis of knockout mutants reveals non-redundant functions of poly(ADP ribose)polymerase isoforms in Arabidopsis. AB - The enzyme poly(ADP-ribose)polymerase (PARP) has a dual function being involved both in the poly(ADP-ribosyl)ation and being a constituent of the NAD(+) salvage pathway. To date most studies, both in plant and non-plant systems, have focused on the signaling role of PARP in poly(ADP-ribosyl)ation rather than any role that can be ascribed to its metabolic function. In order to address this question we here used a combination of expression, transcript and protein localization studies of all three PARP isoforms of Arabidopsis alongside physiological analysis of the corresponding mutants. Our analyses indicated that whilst all isoforms of PARP were localized to the nucleus they are also present in non nuclear locations with parp1 and parp3 also localised in the cytosol, and parp2 also present in the mitochondria. We next isolated and characterized insertional knockout mutants of all three isoforms confirming a complete knockout in the full length transcript levels of the target genes as well as a reduced total leaf NAD hydrolase activity in the two isoforms (PARP1, PARP2) that are highly expressed in leaves. Physiological evaluation of the mutant lines revealed that they displayed distinctive metabolic and root growth characteristics albeit unaltered leaf morphology under optimal growth conditions. We therefore conclude that the PARP isoforms play non-redundant non-nuclear metabolic roles and that their function is highly important in rapidly growing tissues such as the shoot apical meristem, roots and seeds. PMID- 26428917 TI - Sphingomonas parvus sp. nov. isolated from a ginseng-cultivated soil. AB - Strain GP20-2(T) was isolated from a soil cultivated with ginseng in Korea. The 16S rRNA gene sequence of this strain showed the highest sequence similarity with Sphingomonas daechungensis CH15-11(T) (96.7%) and Sphingomonas sediminicola Dae 20(T) (96.2%) among the type strains. The strain GP20-2(T) was a strictly aerobic, Gram-negative, non-motile, rod-shaped bacterium that formed very tiny colonies, less than 0.3 mm in diameter after 10 days on R2A agar. The strain grew at 10-35-C (optimum, 35-C), at a pH of 5.0-8.0 (optimum, pH 6.0), and in the absence of NaCl. The DNA G+C content of strain GP20-2(T) was 67.2 mol%. It contained ubiquinone Q-10 as the major isoprenoid quinone, and summed feature 8 (C18:1omega6c and/or C18:1omega7c, 49.8%) and C16:0 (17.0%) as the major fatty acids. On the basis of evidence from our polyphasic taxonomic study, we concluded that strain GP20-2(T) should be classified as a novel species of the genus Sphingomonas, for which the name Sphingomonas parvus sp. nov. is proposed. The type strain is GP20-2(T) (=KACC 12865(T) =DSM 100456(T)). PMID- 26428918 TI - Illumina-based analysis of bacterial diversity related to halophytes Salicornia europaea and Sueada aralocaspica. AB - We used Illumina-based 16S rRNA V3 amplicon pyrosequencing to investigate the community structure of soil bacteria from the rhizosphere surrounding Salicornia europaea, and endophytic bacteria living in Salicornia europaea plants and Sueada aralocaspica seeds growing at the Fukang Desert Ecosystem Observation and Experimental Station (FDEOES) in Xinjiang Province, China, using an Illumina genome analyzer. A total of 89.23 M effective sequences of the 16S rRNA gene V3 region were obtained from the two halophyte species. These sequences revealed a number of operational taxonomic units (OTUs) in the halophytes. There were between 22-2,206 OTUs in the halophyte plant sample, at the 3% cutoff level, and a sequencing depth of 30,000 sequences. We identified 25 different phyla, 39 classes and 141 genera from the resulting 134,435 sequences. The most dominant phylum in all the samples was Proteobacteria (41.61%-99.26%; average, 43.30%). The other large phyla were Firmicutes (0%- 7.19%; average, 1.15%), Bacteroidetes (0%-1.64%; average, 0.44%) and Actinobacteria (0%-0.46%; average, 0.24%). This result suggested that the diversity of bacteria is abundant in the rhizosphere soil, while the diversity of bacteria was poor within Salicornia europaea plant samples. To the extent of our knowledge, this study is the first to characterize and compare the endophytic bacteria found within different halophytic plant species roots using PCR-based Illumina pyrosequencing method. PMID- 26428919 TI - Performance of PCR-reverse blot hybridization assay for detection of rifampicin resistant Mycobacterium leprae. AB - Drug resistance in Mycobacterium leprae is a significant problem in countries where leprosy is endemic. A sensitive, specific, and high-throughput reverse blot hybridization assay (REBA) for the detection of genotypic resistance to rifampicin (RIF) was designed and evaluated. It has been shown that resistance to RIF in M. leprae involves mutations in the rpoB gene encoding the -subunit of the RNA polymerase. The PCR-REBA simultaneously detects both 6 wild-type regions and 5 different mutations (507 AGC, 513 GTG, 516 TAT, 531 ATG, and 531 TTC) including the most prevalent mutations at positions 507 and 531. Thirty-one clinical isolates provided by Korea Institute of Hansen-s Disease were analyzed by PCR REBA with RIF resistance of rpoB gene. As a result, missense mutations at codons 507 AGC and 531 ATG with 2-nucleotide substitutions were found in one sample, and a missense mutation at codon 516 TAT and DeltaWT6 (deletion of 530-534) was found in another sample. These cases were confirmed by DNA sequence analysis. This rapid, simple, and highly sensitive assay provides a practical alternative to sequencing for genotypic evaluation of RIF resistance in M. leprae. PMID- 26428920 TI - Antifungal activity of violacein purified from a novel strain of Chromobacterium sp. NIIST (MTCC 5522). AB - A novel strain of Chromobacterium sp. NIIST (MTCC 5522) producing high level of purple blue bioactive compound violacein was isolated from clay mine acidic sediment. During 24 h aerobic incubation in modified Luria Bertani medium, around 0.6 g crude violacein was produced per gram of dry weight biomass. An inexpensive method for preparing crystalline, pure violacein from crude pigment was developed (12.8 mg violacein/L) and the pure compound was characterized by different spectrometric methods. The violacein prepared was found effective against a number of plant and human pathogenic fungi and yeast species such as Cryptococcus gastricus, Trichophyton rubrum, Fusarium oxysporum, Rhizoctonia solani, Aspergillus flavus, Penicillium expansum, and Candida albicans. The best activity was recorded against Trichophyton rubrum (2 -g/ml), a human pathogen responsible for causing athlete-s foot infection. This is the first report of antifungal activity of purified violacein against pathogenic fungi and yeast. PMID- 26428921 TI - Relationships between the use of Embden Meyerhof pathway (EMP) or Phosphoketolase pathway (PKP) and lactate production capabilities of diverse Lactobacillus reuteri strains. AB - The aims of this study is to compare the growth and glucose metabolism of three Lactobacillus reuteri strains (i.e. DSM 20016, DSM 17938, and ATCC 53608) which are lactic acid bacteria of interest used for diverse applications such as probiotics implying the production of biomass, or for the production of valuable chemicals (3-hydroxypropionaldehyde, 3-hydroxypropionic acid, 1,3-propanediol). However, the physiological diversity inside the species, even for basic metabolisms, like its capacity of acidification or glucose metabolism, has not been studied yet. In the present work, the growth and metabolism of three strains representative of the species diversity have been studied in batch mode. The strains were compared through characterization of growth kinetics and evaluation of acidification kinetics, substrate consumption and product formation. The results showed significant differences between the three strains which may be explained, at least in part, by variations in the distribution of carbon source between two glycolytic pathways during the bacterial growth: the phosphoketolase or heterolactic pathway (PKP) and the Embden-Meyerhof pathway (EMP). It was also shown that, in the context of obtaining a large amount of biomass, DSM 20016 and DSM 17938 strains were the most effective in terms of growth kinetics. The DSM 17938 strain, which shows the more significant metabolic shift from EMP to PKP when the pH decreases, is more effective for lactate production. PMID- 26428922 TI - Structural basis for the ATP-independent proteolytic activity of LonB proteases and reclassification of their AAA+ modules. AB - Lon proteases degrade defective or denature proteins as well as some folded proteins for the control of cellular protein quality. There are two types of Lon proteases, LonA and LonB. Each consists of two functional components: a protease component and an ATPase associated with various cellular activities (AAA+ module). Here, we report the 2.03 -resolution crystal structure of the isolated AAA+ module (iAAA+ module) of LonB from Thermococcus onnurineus NA1 (TonLonB). The iAAA+ module, having no bound nucleotide, adopts a conformation virtually identical to the ADP-bound conformation of AAA+ modules in the hexameric structure of TonLonB; this provides insights into the ATP-independent proteolytic activity observed in a LonB protease. Structural comparison of AAA+ modules between LonA and LonB revealed that the AAA+ modules of Lon proteases are separated into two distinct clades depending on their structural features. The AAA+ module of LonB belongs to the -H2 & Ins1 insert clade (HINS clade)- defined for the first time in this study, while the AAA+ module of LonA is a member of the HCLR clade. PMID- 26428923 TI - Regulation of HBV-specific CD8(+) T cell-mediated inflammation is diversified in different clinical presentations of HBV infection. AB - Chronic HBV infection is the leading cause of liver cirrhosis and hepatic cancer, but the individual responses toward HBV infection are highly variable, ranging from asymptomatic to chronic active hepatitis B inflammation. In this study, we hypothesized that the different individual responses to HBV infection was associated with differences in HBV-specific CD8(+) T cell-mediated inflammation and cytotoxicity. Blood samples were collected from subjects with asymptomatic HBV-infection, subjects undergoing active chronic HBV flares (active CHB), and subjects with HBV-infected hepatocellular carcinoma (HBV-HCC). By tetramer staining, we found that all three groups had similar frequencies of HBVspecific CD8(+) T cells. However, after HBV peptide stimulation, the HBV-specific CD8(+) T cells in asymptomatic subjects had significantly stronger interferon gamma (IFN gamma), tumor necrosis factor alpha (TNF-alpha), and CD107a expression than those in active CHB and HBV-HCC patients. Examination of surface marker expression revealed that the PD-1(-)Tim-3(-) double-negative cell population was the main contributor to HBV-specific inflammation. In active CHB patients and HBV-HCC patients, however, the frequencies of activated PD-1(-)Tim-3(-) cells were significantly reduced. Moreover, the serum HBV DNA titer was not correlated with the frequencies of HBV-specific CD8(+) T cells but was inversely correlated with the frequencies of IFN-g-expressing and CD107a-express cells in response to HBV stimulation. Together, our data demonstrated that the status of HBVspecific CD8(+) T cell exhaustion was associated with different clinical outcomes of chronic HBV infection. PMID- 26428924 TI - The hrp pathogenicity island of Pseudomonas syringae pv. tomato DC3000 is induced by plant phenolic acids. AB - Plants produce a wide array of antimicrobial compounds, such as phenolic compounds, to combat microbial pathogens. The hrp PAI is one of the major virulence factors in the plant pathogen, Pseudomonas syringae. A major role of hrp PAI is to disable the plant defense system during bacterial invasion. We examined the influence of phenolic compounds on hrp PAI gene expression at low and high concentrations. There was approximately 2.5 times more hrpA and hrpZ mRNA in PtoDC3000 that was grown in minimal media (MM) supplemented with 10 -M of ortho-coumaric acid than in PtoDC3000 grown in MM alone. On the other hand, a significantly lower amount of hrpA mRNA was observed in bacteria grown in MM supplemented with a high concentration of phenolic compounds. To determine the regulation pathway for hrp PAI gene expression, we performed qRTPCR using gacS, gacA, and hrpS deletion mutants. PMID- 26428926 TI - Erratum to: Identification of the Vibrio vulnificus htpG gene and its influence on cold shock recovery. PMID- 26428925 TI - Characterization of the rapamycin-inducible EBV LMP1 activation system. AB - Epstein-Barr virus (EBV) latent infection membrane protein 1 (LMP1) is required for EBV-mediated B lymphocyte transformation into proliferating lymphoblastoid cell lines (LCL). LMP1 oligomerizes spontaneously in membrane lipid rafts via its transmembrane domain and constitutively activates signal transduction pathways, including NF-kappaB, p38 Mitogen-Activated Protein Kinase (MAPK), and c-Jun N terminal Kinase (JNK). Since LMP1 mimics the tumor necrosis factor receptor (TNFR), CD40, it may be effectively utilized to study the effects of constitutive activation of signal transduction pathways on cellular physiology. On the other hand, LMP1 presents a disadvantage in terms of determining the sequential events and factors involved in signaling pathways. A CD40-LMP1 chimeric molecule has been generated to overcome this limitation but does not represent the authentic and physiological nature of LMP1. In the current study, a ligand-dependent activation system for LMP1 using rapamycin-inducible dimerization was generated to delineate the LMP1 signaling pathway. PMID- 26428927 TI - Platelet Larger Cell Ratio and High-on Treatment Platelet Reactivity During Dual Antiplatelet Therapy. AB - BACKGROUND: Low response to antiplatelet agents has been associated to an increased risk of thrombotic complications and recurrent ischemic events. Platelet size has been proposed as a potential marker of platelet reactivity. Therefore, the aim of the present study was to evaluate the impact of platelet Larger Cell Ratio (p-LCR) on platelet aggregation and the prevalence of residual high-on treatment platelet reactivity (HRPR) in patients receiving dual antiplatelet therapy (DAPT) after a recent acute coronary syndrome or coronary revascularization. METHODS: Patients treated with DAPT (ASA and clopidogrel or ticagrelor) were scheduled for platelet function assessment at 30-90 days post discharge. HRPR was considered for ASPI test >862 AU*min (for ASA) or ADP test values >=417 AU*min (for ADP-antagonists) using impedance aggregometry. RESULTS: Our population consisted of 530 patients receiving DAPT, who were divided in tertiles according to values of p-LCR (< 27.6; 27.6-34.7; >=34.7 l). p-LCR was related with use of beta-blockers (p = 0.02) and statins (p = 0.002), and inversely with acute presentation (p = 0.05). Higher platelet count (p < 0.001) and haemoglobin levels (p = 0.001) were observed in higher p-LCR tertiles. The prevalence of HRPR for ASA was low and not significantly different across tertiles of p-LCR (1.1 vs 1.1 vs 1.7%, p = 0.66; adjusted OR[95%CI] = 1.68[0.66 4.29], p = 0.27). Moreover, p-LCR did not influence the occurrence of HRPR for ADP-antagonists (24.4% vs 20.9% vs 25.6 %%, p = 0.80, adjusted OR[95%CI] = 0.88[0.67-1.17], p = 0.38) and similar results were obtained when considering separately patients receiving clopidogrel (adjusted OR[95%CI] = 1.21[0.86-1.69], p = 0.29) or ticagrelor (adjusted OR[95%CI] = 1.17[0.69-2], p = 0.56). CONCLUSION: In patients receiving DAPT for coronary artery disease, p-LCR does not impact platelet reactivity. Larger platelets did not influence the prevalence of high-on treatment platelet reactivity with the antiplatelet agents ASA, clopidogrel or ticagrelor. PMID- 26428928 TI - Rapid Microwave-Assisted Solvothermal Synthesis of Non-Olivine Cmcm Polymorphs of LiMPO4 (M = Mn, Fe, Co, and Ni) at Low Temperature and Pressure. AB - Lithium transition-metal phosphates, LiMPO4 (M = Mn, Fe, Co, and Ni), have attracted significant research interest over the past two decades as an important class of lithium ion battery cathode materials. However, almost all of the investigations thus far have focused on the olivine polymorph that exists in the orthorhombic Pnma space group. In this study, a distinct orthorhombic but non olivine polymorph of LiMPO4, described by a Cmcm space group symmetry, has been synthesized with M = Mn, Fe, Co, and Ni. Of these, LiMnPO4 in the Cmcm space group is reported for the first time. A rapid microwave-assisted solvothermal (MW ST) heating process with tetraethylene glycol (TEG) as the solvent and transition metal oxalates as precursors facilitates the synthesis of these materials. The peak reaction temperatures and pressures were below 300 degrees C and 30 bar, respectively, which are several orders of magnitude lower than those of the previously reported high-pressure (gigapascals) method. X-ray diffraction (XRD) confirms the crystal structure with the Cmcm space group, and scanning electron micrographs indicate a submicrometer thin platelet-like morphology. The synthesis process conditions have been optimized to obtain impurity-free samples with the correct stoichiometry, as characterized by XRD and inductively coupled plasma optical emission spectroscopy (ICP-OES). Upon heat treatment to higher temperatures, an irreversible transformation of the metastable Cmcm polymorphs into olivine is observed by XRD and Fourier transform infrared spectroscopy. Although the electrochemical activity of these polymorphs as lithium ion cathodes turns out to be poor, the facile synthesis under mild conditions has permitted easy access to these materials in a nanomorphology, some of which were not even possible before. PMID- 26428929 TI - Connectivity mapping uncovers small molecules that modulate neurodegeneration in Huntington's disease models. AB - Huntington's disease (HD) is a genetic disease caused by a CAG trinucleotide repeat expansion encoding a polyglutamine tract in the huntingtin (HTT) protein, ultimately leading to neuronal loss and consequent cognitive decline and death. As no treatments for HD currently exist, several chemical screens have been performed using cell-based models of mutant HTT toxicity. These screens measured single disease-related endpoints, such as cell death, but had low 'hit rates' and limited dimensionality for therapeutic detection. Here, we have employed gene expression microarray analysis of HD samples--a snapshot of the expression of 25,000 genes--to define a gene expression signature for HD from publically available data. We used this information to mine a database for chemicals positively and negatively correlated to the HD gene expression signature using the Connectivity Map, a tool for comparing large sets of gene expression patterns. Chemicals with negatively correlated expression profiles were highly enriched for protective characteristics against mutant HTT fragment toxicity in in vitro and in vivo models. This study demonstrates the potential of using gene expression to mine chemical activity, guide chemical screening, and detect potential novel therapeutic compounds. KEY MESSAGES: Single-endpoint chemical screens have low therapeutic discovery hit-rates. In the context of HD, we guided a chemical screen using gene expression data. The resulting chemicals were highly enriched for suppressors of mutant HTT fragment toxicity. This study provides a proof of concept for wider usage in all chemical screening. PMID- 26428931 TI - Laser epilation prior to pilonidal sinus surgery. PMID- 26428930 TI - Haptoglobin promoter polymorphism rs5472 as a prognostic biomarker for peptide vaccine efficacy in castration-resistant prostate cancer patients. AB - Personalized peptide vaccination (PPV) is an attractive approach to cancer immunotherapy with strong immune-boosting effects conferring significant clinical benefit. However, as with most therapeutic agents, there is a difference in clinical efficacy among patients receiving PPV. Therefore, a useful biomarker is urgently needed for prognosticating clinical outcomes to preselect patients who would benefit the most from PPV. In this retrospective study, to detect a molecular prognosticator of clinical outcomes for PPV, we analyzed whole-genome gene expression profiles of peripheral blood mononuclear cells (PBMCs) in castration-resistant prostate cancer (CRPC) patients before administration of PPV. Cox regression analysis revealed that mRNA expression of myeloperoxidase, haptoglobin, and neutrophil elastase was significantly associated with overall survival (OS) among vaccinated CRPC patients (adjusted P < 0.01). By promoter sequence analysis of these three genes, we found that rs5472 of haptoglobin (HP), an acute-phase plasma glycoprotein, was strongly correlated to OS of vaccinated CRPC patients (P = 0.0047, hazard ratio 0.47; 95 % confidence interval 0.28 0.80). Furthermore, both HP mRNA expression in PBMCs and protein level in plasma of CRPC patients before administration of PPV exhibited rs5472 dependence (P < 0.001 for mRNA expression and P < 0.05 for protein level). Our findings suggest that rs5472 may play an important role in the immune response to PPV via regulation of HP. Thus, we concluded that rs5472 is a potential prognostic biomarker for PPV. PMID- 26428932 TI - Integrated cooling-vacuum-assisted 1540-nm erbium:glass laser is effective in treating mild-to-moderate acne vulgaris. AB - Acne treatment by a mid-infrared laser may be unsatisfactory due to deeply situated acne-affected sebaceous glands which serve as its target. Skin manipulation by vacuum and contact cooling may improve laser-skin interaction, reduce pain sensation, and increase overall safety and efficacy. To evaluate the safety and efficacy of acne treatment using an integrated cooling-vacuum-assisted 1540-nm erbium:glass laser, a prospective interventional study was conducted. It included 12 patients (seven men and five women) suffering from mild-to-moderate acne vulgaris. The device utilizes a mid-infrared 1540-nm laser (Alma Lasers Ltd. Caesarea, Israel), which is integrated with combined cooling-vacuum-assisted technology. An acne lesion is initially manipulated upon contact by a vacuum cooling-assisted tip, followed by three to four stacked laser pulses (500-600 mJ, 4 mm spot size, and frequency of 2 Hz). Patients underwent four to six treatment sessions with a 2-week interval and were followed-up 1 and 3 months after the last treatment. Clinical photographs were taken by high-resolution digital camera before and after treatment. Clinical evaluation was performed by two independent dermatologists, and results were graded on a scale of 0 (exacerbation) to 4 (76 100 % improvement). Patients' and physicians' satisfaction was also recorded. Pain perception and adverse effects were evaluated as well. All patients demonstrated a moderate to significant improvement (average score of 3.6 and 2.0 within 1 and 3 months, respectively, following last treatment session). No side effects, besides a transient erythema, were observed. Cooling-vacuum-assisted 1540-nm laser is safe and effective for the treatment of acne vulgaris. PMID- 26428934 TI - Once Daily Self-Monitoring of Blood Glucose (SMBG) Improves Glycemic Control in Oral Hypoglycemic Agents (OHA)-Treated Diabetes: SMBG-OHA Follow-Up Study. AB - BACKGROUND: The aim of this study was to compare glycemic control between SMBG continued and -discontinued subjects with type 2 diabetes in the SMBG-OHA study. METHOD: Of the 96 subjects from the SMBG-OHA study, 59 were recruited for the 24 week, comparison follow-up study. The study outcomes were the differences in change in HbA1c levels at 24 weeks between the 2 groups, and change in SMBG frequency in SMBG-continued subjects. RESULTS: Although health insurance does not cover the cost of SMBG, 22.0% of subjects continued SMBG of their own will after the SMBG-OHA study was completed. HbA1c levels were maintained from 6.81 +/- 0.55% to 6.64 +/- 0.53% in SMBG-continued subjects. Conversely, HbA1c levels were increased from 7.18 +/- 0.63% to 7.48 +/- 0.84% in SMBG-discontinued subjects. HbA1c levels were significantly different by 0.83 +/- 0.25% (95% CI: -1.33 to 0.36). The difference in change in HbA1c between the groups was -0.46% (95% CI: 0.78 to -0.15). SMBG frequency was decreased from 2.02 +/- 1.06 to 1.53 +/- 0.86 times a day. CONCLUSIONS: HbA1c levels were maintained in SMBG-continued subjects but increased in SMBG-discontinued subjects. The study implied that almost once daily SMBG is helpful to maintain glycemic control in non-insulin-treated type 2 diabetes. PMID- 26428935 TI - Accuracy Evaluation of an Integrated Blood Glucose Monitoring System With Improved Test Cassettes Following ISO 15197:2013. PMID- 26428933 TI - Exercise and the Development of the Artificial Pancreas: One of the More Difficult Series of Hurdles. AB - Regular physical activity (PA) promotes numerous health benefits for people living with type 1 diabetes (T1D). However, PA also complicates blood glucose control. Factors affecting blood glucose fluctuations during PA include activity type, intensity and duration as well as the amount of insulin and food in the body at the time of the activity. To maintain equilibrium with blood glucose concentrations during PA, the rate of glucose appearance (Ra) to disappearance (Rd) in the bloodstream must be balanced. In nondiabetics, there is a rise in glucagon and a reduction in insulin release at the onset of mild to moderate aerobic PA. During intense aerobic -anaerobic work, insulin release first decreases and then rises rapidly in early recovery to offset a more dramatic increase in counterregulatory hormones and metabolites. An "exercise smart" artificial pancreas (AP) must be capable of sensing glucose and perhaps other physiological responses to various types and intensities of PA. The emergence of this new technology may benefit active persons with T1D who are prone to hypo and hyperglycemia. PMID- 26428936 TI - Analytical and Biological Characterization of a Noninnovator Insulin Glargine and the Originator Drug Product. PMID- 26428937 TI - Changes in dynamics of the glass-forming pharmaceutical nifedipine in binary mixtures with octaacetylmaltose. AB - Some molecular glass-formers can crystallize in the glassy state, some of which are van der Waals molecules and some are pharmaceuticals. The molecular mechanism responsible for this glass-to-crystal mode of crystallization is of interest to the glass transition research community as well as to the pharmaceutical industry because the effect is detrimental to stability of amorphous form of the drugs stored below the glass transition temperature. Two prominent models have been proposed for the molecular mechanism. In the homogeneous nucleation-based crystallization model, the molecular mechanism is the secondary relaxation, and the other model assumes that the molecular process responsible for crystal growth in the glassy state is from the local molecular motions. Crystal growth requires motion of the entire molecule, and in the glassy state the only such local molecular motion is engendered by the secondary relaxation of the Johari Goldstein (JG) kind. While the JG secondary relaxation is the crux in the two models of glass-to-crystal growth, it has not been found in the glassy state of the pharmaceuticals studied so far. The examples include 5-methyl-2-[(2 nitrophenyl)amino]-3-thiophenecarbonitrile (ROY), indomethacin (IMC) and nifedipine (NIF). In the absence of any evidence of the JG secondary relaxation, the conundrum is that the two models of glass-to-crystal growth cannot be validated. It turns out these pharmaceuticals all have structural alpha relaxations with narrow frequency dispersion. Empirically, glass-formers with narrow alpha-dispersion have JG secondary relaxation with weak relaxation strength, not well separated from the alpha-relaxation, and hence cannot be resolved. Theoretically, the narrow width of the alpha-dispersion is due to weak intermolecular coupling. In this article we enhance the intermolecular coupling of NIF by mixing with octaacetylmaltose to enhance the intermolecular coupling of NIF. In this way we have successfully resolved the JG secondary relaxation in the dielectric loss spectra of the NIF component in the glassy state, and validated the two models of glass-to-crystal growth. PMID- 26428938 TI - Fatty acids for controlled release applications: A comparison between prilling and solid lipid extrusion as manufacturing techniques. AB - The aim of the present study was to evaluate the solid state characteristics, drug release and stability of fatty acid-based formulations after processing via prilling and solid lipid extrusion. Myristic acid (MA), stearic acid (SA) and behenic acid (BA) were used as matrix formers combined with metoprolol tartrate (MPT) as model drug. The prilling process allowed complete dissolution of MPT in the molten fatty acid phase, generating semi-crystalline MPT and the formation of hydrogen bonds between drug and fatty acids in the solid prills. In contrast, as solid lipid extrusion (SLE) induced only limited melting of the fatty acids, molecular interaction with the drug was inhibited, yielding crystalline MPT. Although the addition of a low melting fatty acid allowed more MPT/fatty acid interaction during extrusion, crystalline MPT was detected after processing. Mathematical modeling revealed that the extrudates exhibited a higher apparent drug/water mobility than prills of the same composition, probably due to differences in the inner systems' structure. Irrespective of the processing method, mixed fatty acid systems (e.g. MA/BA) exhibited a lower matrix porosity, resulting in a slower drug release rate. Solid state analysis of these systems indicated that the crystalline structure of the fatty acids was maintained after SLE, while prilling generated a reduced MA crystallinity. Binary MPT/fatty acid systems processed via extrusion showed better stability during storage at 40 degrees C than the corresponding prills. Although mixed fatty acid systems were stable at 25 degrees C, stability problems were encountered during storage at 40 degrees C: a faster release was obtained from the prills, whereas drug release from the extrudates was slower. PMID- 26428939 TI - Selection of a mobilization regimen for multiple myeloma based on the response to induction therapy: granulocyte-colony stimulating factor (G-CSF) alone versus high-dose cyclophosphamide plus G-CSF. AB - To evaluate the feasibility of selecting a mobilization regimen based on the response to induction therapy, we retrospectively analyzed 179 multiple myeloma patients who underwent stem cell mobilization. In comparison with patients who achieved at least a very good partial response (VGPR) to induction therapy and received granulocyte-colony stimulating factor (G-CSF) alone and patients who did not achieve a VGPR and received cyclophosphamide (CY) + G-CSF, treatment-related toxicity was greater and neutrophil engraftment was slower in the CY than the G CSF group. The rate of requisite mobilization (>= 2.0 * 10(6)/kg) was similar in both groups. Overall and progression-free survival was not different between patients in the G-CSF group and patients who achieved at least VGPR and received CY + G-CSF. In conclusion, response-adapted selection of a mobilization regimen is appropriate. G-CSF alone should be the preferred treatment for patients who achieved at least a VGPR to induction therapy. PMID- 26428940 TI - Sentinel nodes in vulvar cancer: Long-term follow-up of the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V) I. AB - OBJECTIVE: In 2008 GROINSS-V-I, the largest validation trial on the sentinel node (SN) procedure in vulvar cancer, showed that application of the SN-procedure in patients with early-stage vulvar cancer is safe. The current study aimed to evaluate long-term follow-up of these patients regarding recurrences and survival. METHODS: From 2000 until 2006 GROINSS-V-I included 377 patients with unifocal squamous cell carcinoma of the vulva (T1, <4 cm), who underwent the SN procedure. Only in case of SN metastases an inguinofemoral lymphadenectomy was performed. For the present study follow-up was completed until March 2015. RESULTS: Themedian follow-up was 105 months (range 0-179). The overall local recurrence ratewas 27.2% at 5 years and 39.5% at 10 years after primary treatment, while for SN-negative patients 24.6% and 36.4%, and for SN-positive patients 33.2% and 46.4% respectively (p = 0.03). In 39/253 SN-negative patients (15.4%) an inguinofemoral lymphadenectomy was performed, because of a local recurrence. Isolated groin recurrence rate was 2.5% for SN-negative patients and 8.0% for SN-positive patients at 5 years. Disease-specific 10-year survival was 91% for SN-negative patients compared to 65% for SN-positive patients (p b .0001). For all patients, 10-year disease-specific survival decreased from 90% for patients without to 69% for patients with a local recurrence (p b .0001). PMID- 26428941 TI - Prognostic factors of oncological and reproductive outcomes in fertility-sparing treatment of complex atypical hyperplasia and low-grade endometrial cancer using oral progestin in Chinese patients. AB - OBJECTIVE: To evaluate the efficacy and fertility outcomes of progestin treatment for complex atypical hyperplasia (CAH)/grade I endometrial cancer (G1EC) in Chinese patients (<=40years old). METHODS: Women <=40years old who were treated with progestin for CAH or G1EC were identified from 9 provinces of China. The time to achieve complete response (CR) and the time from CR to recurrence or pregnancy were censored for patients without events and were analyzed for associations between patient and treatment characteristics. RESULTS: Thirty-two patients were included: 13 with CAH and 19 with G1EC. Nine patients exhibited elevated serum HbA1C before treatment. After a mean follow-up of 32.5months, the CR rate was 84.4%. Patients who exhibited elevated HbA1C were more likely to experience CR, while those with polycystic ovarian syndrome (PCOS) exhibited the opposite outcome (p=0.01, 0.03). Nine of 21 patients experienced clinical pregnancies. Eight patients underwent assisted reproductive technology (ART). Five patients had newborn infants. Patients undergoing ART were more likely to become pregnant (p=0.04). CONCLUSION: Oral progestin is an effective fertility sparing treatment for women with CAH/G1EC in China. Patients with elevated HbA1C receiving both metformin and progestin were more likely to achieve CR, whereas those with PCOS were not. ART is a good choice for clinical pregnancy after treatment. PMID- 26428943 TI - Poly(N-isopropylacrylamide)-clay based hydrogels controlled by the initiating conditions: evolution of structure and gel formation. AB - The formation of the hydrogel poly(N-isopropylacrylamide)-clay (LAPONITE(r)) by redox polymerization was investigated, and the main factors governing the gel build-up were determined. The significant effect of the redox initiating system ammonium peroxodisulfate (APS) and tetramethylethylenediamine (TEMED) on gel formation and structure was established, making it possible to control the structure of the gel. Moreover, the pre-reaction stage involving the quality of the clay exfoliation in an aqueous suspension and the interaction of reaction components with the clay play a role in controlling the polymerization and gel structure. The molecular and phase structure evolution during polymerization was followed in situ by the following independent techniques: Fourier transform infrared spectroscopy (FTIR), chemorheology, small-angle X-ray scattering (SAXS) and ultraviolet-visible spectroscopy (UV/Vis). The combination of these methods enabled us to describe in detail particular progress stages during the gel formation and determine the correlation of the corresponding processes on a time and conversion scale. The mechanism of gel formation was refined based on these experimental results. PMID- 26428942 TI - A randomized controlled trial comparing four versus six courses of adjuvant platinum-based chemotherapy in locally advanced cervical cancer patients previously treated with neo-adjuvant chemotherapy plus radical surgery. AB - OBJECTIVES. The aim of this study was to compare 4 versus 6 courses of adjuvant chemotherapy after neoadjuvant chemotherapy plus radical surgery in terms of overall survival (OS), disease-free survival (DFS), recurrence rate and toxicity profile. METHODS. We randomly assigned 200 patients with IB2-IIB cervical cancer to receive 4 (Group A) or 6 (Group B) courses of cisplatin 100 mg/mq and paclitaxel 175 mg/mq every 21 days. RESULTS. At 4-years follow-up, the comparison of recurrence rate (p = 1; RR = 1.005; 95% CI = 0.87 to 1.161), OS (p = 0.906) and DFS (p = 0.825) did not show statistically significant differences between the two groups. Data analysis showed statistically significant differences between the two groups in term of episodes of leukopenia (p = 0.0072; RR = 1.513; 95% CI = 1.127-2.03), anemia (p = 0.048; RR = 1.188; CI = 1.012-1.395) and febrile neutropenia (p = 0.042; RR = 1.119; 95% CI = 1.014-1.235), in favor of Group A. As regards non-hematological toxicities, there were no statistically significant differences in terms of gastrointestinal symptoms (p = 0.49; RR = 1.046; CI = 0.948-1.153. On the contrary, there was a statistically significant difference regarding neurological symptoms (p=0.014; RR=1.208; CI=1.046-1.395), that were less frequent in Group A (13%) than in Group B (28%). CONCLUSIONS. Adjuvant treatment with 4 or 6 courses of platinum-based chemotherapy showed similar results in terms of OS and DSF, with a favorable toxicity profile in favor of the first regimen. PMID- 26428944 TI - Cost and co-morbidities associated with hypoglycemic inpatients in Belgium. AB - BACKGROUND AND OBJECTIVES: Little is known about the economic burden of hypoglycemia in Belgium, or its related co-morbidities. This study aimed at estimating the cost and length of stay associated with hypoglycemia-related hospitalizations in diabetic patients in Belgium and the association between hypoglycemia and in-hospital all-cause mortality, incidence of traumatic fractures, depression, and cardiovascular diseases (myocardial infarction or unstable angina), using retrospective data from 2011. METHODS: Patient data were retrieved from the IMS Hospital Disease Database, including longitudinal (per calendar year) information on diagnoses, procedures, and drugs prescribed in ~20% of all Belgian hospital beds. The eligible population included all adult (<19 year) diabetic (both types) patients, further split between those with/without a history of hypoglycemia-related hospitalizations. Diabetes, hypoglycemia, and co morbidities of interest were identified based on International Classification of Diseases and Related Health Problems Version 9 (ICD-9) diagnosis codes. All costs were extrapolated to 2014 using progression in hospitalization costs since 2001. RESULTS: A total of 43,410 diabetes-related hospitalizations were retrieved, corresponding to 30,710 distinct patients. The average hospitalization cost was ?10,258 when hypoglycemia was documented (n = 2625), vs ?7173 in other diabetic hospitalized patients (n = 40,785). When controlling for age and sex, a higher mortality risk (OR = 1.59; p-value <0.001), a higher incidence of traumatic fractures (OR = 1.25; p-value = 0.009), and a higher probability of depression related hospitalizations (OR = 1.90; p-value <0.001) were observed in hypoglycemic patients. A similar risk of cardiovascular event was observed in both groups, but hypoglycemic patients were more at risk of experiencing multiple events. CONCLUSION: Hospitalizations for hypoglycemia are expensive and associated with an increased risk of depression and traumatic fractures as well as increased in-hospital mortality. Interventions that can help reduce the risk of hypoglycemia, and consequently the burden on hospitals and society, without compromising glycemic control, will help to further improve diabetes management. PMID- 26428945 TI - Dupilumab for the treatment of atopic dermatitis: A clinical trial review. AB - INTRODUCTION: Current treatment options for moderate-to-severe atopic dermatitis (AD) are limited and have potentially dangerous side effects. Dupilumab is a novel monoclonal antibody that was recently studied in adult patients with moderate-to-severe AD. Dupilumab inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling and was previously found to be effective in asthma. Considering that both AD and asthma are Th2 cell-mediated inflammatory processes, it is reasonable to suspect that dupilumab would be beneficial in AD.' AREAS COVERED: This article is a review of the one major clinical trial that assessed the efficacy of dupilumab in patients with AD. Its goal is to provide a comparison to the current modalities for the treatment of AD and expert insight regarding future studies. EXPERT OPINION: The results of this study are a significant therapeutic advancement. Dupilumab was shown to provide a mean percent change in Eczema Area and Severity Index score of -74% +/- 3.6, in addition to, statistically and clinically significant reductions the severity, symptomatology, and morbidity associated with AD. However, the small sample size makes it difficult to assess the magnitude of this effect. As a result, dupilumab will likely be reserved for cases of severe AD unresponsive to traditional modalities. PMID- 26428946 TI - Automated solvent system screening for the preparative countercurrent chromatography of pharmaceutical discovery compounds. AB - A fully automated countercurrent chromatography system has been constructed to rapidly screen the commonly used heptane/ethyl acetate/methanol/water solvent system series and translate the results to preparative scale separations. The system utilizes "on-demand" preparation of the heptane/ethyl acetate/methanol/water solvent system upper and lower phases. Elution-extrusion countercurrent chromatography was combined with non-dynamic equilibrium injection reducing the screening time for each heptane/ethyl acetate/methanol/water system to 17 min. The result enabled solvent system development to be reduced to under 2 h. The countercurrent chromatography system was interfaced with a mass spectrometer to allow selective detection of target components in crude medicinal chemistry reaction mixtures. Mass-directed preparative countercurrent chromatography purification was demonstrated for the first time using a synthetic tetrazole epoxide derived from a routine medicinal chemistry support workflow. PMID- 26428947 TI - Effect of an educational intervention on parental readiness for premature infant discharge from the neonatal intensive care units. AB - AIM: To examine the effect of an educational intervention on parental readiness for premature infant discharge from neonatal intensive care units. BACKGROUND: Low readiness for discharge can result in negative healthcare outcomes for infants and their parents. However, few studies have examined the effect of discharge education programmes on parental readiness for premature infant discharge in Chinese critical care settings. DESIGN: A quasi-experimental study. METHODS: Between October 2011-March 2012, 154 parents of premature infants were recruited from neonatal intensive care units of two tertiary hospitals in Central China. These parents were assigned to either the intervention or control group based on their entry order. Parents in the intervention group received two sessions of 60-minute discharge education along with hospital routine care; parents in the control group only received hospital routine care. Parental readiness for discharge and quality of discharge education were assessed on the day of infant discharge from neonatal intensive care units. Independent samples t test and linear regression were used to analyse the data. RESULTS: Parental readiness for premature infant discharge was in the moderate level. Independent samples t-test showed that both mean scores of parental discharge readiness and discharge teaching quality from the intervention group were significantly higher than those in the control group. Linear regression analysis showed that discharge teaching quality explained 39.7% of the variance in parental readiness for premature infant discharge. CONCLUSION: Discharge education can improve parental readiness for premature infant discharge. Quality of discharge teaching can significantly predict parental readiness for premature infant discharge. PMID- 26428948 TI - Measuring depression in prostate cancer patients: does the scale used make a difference? AB - This study investigated differences in the scores, relative severity and major depressive disorder (MDD) and subsyndromal depression status from three standardised self-report scales for depression in prostate cancer (PCa) patients. The Hospital Anxiety and Depression Scale Depression subscale (HADS-D), the Self rating Depression Scale (SDS) and the Patient Health Questionnaire (PHQ-9) for depression were administered to a sample of 138 PCa patients via mail-out self reports in Queensland, Australia during May 2014. Despite significant correlations between the total scores from the three scales, severity classification differed across the three scales and there was evidence of considerable underestimation of depression by the HADS-D compared to the PHQ-9, and a similar tendency for the SDS. When patients were classified as fulfilling the criteria for Subsyndromal Depression on the PHQ-9, there were statistically significant differences in the proportion of patients who met those criteria using the HADS-D and the SDS, with large underestimation also present for these two scales. Scale construction and depression items included can produce different results across scales, making inter-study comparisons difficult. Implications for research and clinical practice are described. PMID- 26428950 TI - Kilo-scale droplet generation in three-dimensional monolithic elastomer device (3D MED). AB - Droplet-based microfluidics has led to transformational new approaches in diverse areas including materials synthesis and high-throughput biological assays. However, the translation of droplet microfluidics technology into commercial applications requires scale-up of droplet generation from the laboratory (<10 mL h(-1)) to the industrial (>1 L h(-1)) scale. To address this challenge, we develop a three-dimensional monolithic elastomer device (3D MED) for mass production of monodisperse emulsion droplets. Using double-sided imprinting, 3D microchannels are formed in a single elastomer piece that has 1000 parallel flow focusing generators (k-FFGs). Compared to previous work that parallelizes droplet generation, the 3D MED eliminates the needs for alignment and bonding of multiple pieces and thus makes it possible to achieve the high flow rates and pressure necessary for the kilo-scale generation of droplets. Using this approach, we demonstrate mass production of water-in-oil (W/O) emulsion droplets at production rates as high as 1.5 L h(-1) (>30 billion 45 MUm diameter droplets per hour), with a coefficient of variation of droplet diameter of only 6.6%. Because of the simplicity, robustness, and manufacturability of our 3D MED architecture, it is well suited to bridge the gap between the continuously growing library of promising microfluidic technologies to generate microparticles that have been demonstrated in laboratory settings and their successful application in industry. PMID- 26428949 TI - Murine allergic rhinitis and nasal Th2 activation are mediated via TSLP- and IL 33-signaling pathways. AB - Thymic stromal lymphopoietin (TSLP) and IL-33 are epithelium-derived proallergic cytokines that contribute to allergic diseases. Although the involvement of TSLP in allergic rhinitis (AR) is suggested, the exact role of TSLP in AR is poorly understood. Furthermore, the relative contribution of TSLP and IL-33 in nasal allergic responses has not been described. In this study, we examined the roles of TSLP and IL-33 in AR by analyzing acute and chronic AR models. Acute AR mice were intraperitoneally immunized with ragweed, then intranasally challenged with ragweed pollen for four consecutive days. Chronic AR mice were nasally administrated ragweed pollen on consecutive days for 3 weeks. In both models, TSLP receptor (TSLPR)-deficient mice showed defective sneezing responses and reduced serum ragweed-specific IgE levels compared with wild-type (WT) mice. Analyses of bone-marrow chimeric mice demonstrated that hematopoietic cells were responsible for defective sneezing in TSLPR-deficient mice. In addition, FcepsilonRI(+)-cell-specific TSLPR-deficient mice showed partial but significant reduction in sneezing responses. Of note, Th2 activation and nasal eosinophilia were comparable between WT and TSLPR-deficient mice. ST2- and IL-33-deficient mice showed defective Th2 activation and nasal eosinophilia to acute, but not chronic, ragweed exposure. TSLPR and ST2 double-deficient mice showed defective Th2 activation and nasal eosinophilia even after chronic ragweed exposure. These results demonstrate that TSLPR signaling is critical for the early phase response of AR by controlling the IgE-mast-cell/basophil pathway. The IL-33/ST2 pathway is central to nasal Th2 activation during acute allergen exposure, but both TSLPR and ST2 contribute to Th2 responses in chronically allergen-exposed mice. PMID- 26428951 TI - Memory, Decision-Making, and the Ventromedial Prefrontal Cortex (vmPFC): The Roles of Subcallosal and Posterior Orbitofrontal Cortices in Monitoring and Control Processes. AB - The ventromedial prefrontal cortex (vmPFC) prominently and separately features in neurobiological models of decision-making (e.g., value-encoding) and of memory (e.g., automatic veracity-monitoring). Recent decision-making models propose value judgments that inherently comprise of second-order confidence estimates. These demonstrate quadratic relationships with first-order judgments and are automatically encoded in vmPFC activity. Memory studies use Quantity-Accuracy Profiles to capture similar first-order and second-order meta-mnemonic processes, suggesting convergence across domains. Patients with PFC damage answered general knowledge questionnaires under 2 conditions. During forced report, they chose an answer and rated the probability of it being correct (first-order "monitoring"). During free report, they could choose to volunteer or withhold their previous answers (second-order "control") to maximize performance. We found quadratic relationships between first-order and second-order meta-mnemonic processes; voxel based lesion-symptom mapping demonstrated that vmPFC damage diminished that relationship. Furthermore, damage to subcallosal vmPFC was specifically associated with impaired monitoring and additional damage to posterior orbitofrontal cortex led to deficient control. In decision-making, these regions typically support valuation and choice, respectively. Persistent spontaneous confabulation (false memory production) confirmed the clinical relevance of these dissociations. Compared with patients with no confabulation history, patients who currently confabulate were impaired on both monitoring and control, whereas former confabulators demonstrated impaired monitoring but intact control. PMID- 26428952 TI - Developmental Expression Patterns of KCC2 and Functionally Associated Molecules in the Human Brain. AB - Work on rodents demonstrated that steep upregulation of KCC2, a neuron-specific Cl- extruder of cation-chloride cotransporter (CCC) family, commences in supraspinal structures at around birth, leading to establishment of hyperpolarizing GABAergic responses. We describe spatiotemporal expression profiles of the entire CCC family in human brain. KCC2 mRNA was observed already at 10th postconceptional week (PCW) in amygdala, cerebellum, and thalamus. KCC2 immunoreactive (KCC2-ir) neurons were abundant in subplate at 18 PCW. By 25 PCW, numerous subplate and cortical plate neurons became KCC2-ir. The mRNA expression profiles of alpha- and beta-isoforms of Na-K ATPase, which fuels cation-chloride cotransport, as well of tropomyosin receptor kinase B (TrkB), which promotes developmental upregulation of KCC2, were consistent with data from studies on rodents about their interactions with KCC2. Thus, in human brain, expression of KCC2 and its functionally associated proteins begins in early fetal period. Our work facilitates translation of results on CCC functions from animal studies to human and refutes the view that poor efficacy of anticonvulsants in the term human neonate is attributable to the lack of KCC2. We propose that perinatally low threshold for activation of Ca2+-dependent protease calpain renders neonates susceptible to downregulation of KCC2 by traumatic events, such as perinatal hypoxia ischemia. PMID- 26428953 TI - Comments on "Some Challenges with Statistical Inference in Adaptive Designs" by Hung, Wang, and Yang. PMID- 26428954 TI - The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. AB - BACKGROUND: Atopic dermatitis (AD) shows very high prevalence in Asia, with a large unmet need for effective therapeutics. Direct comparisons between European American (EA) and Asian patients with AD are unavailable, but earlier blood studies detected increased IL-17(+)-producing cell counts in Asian patients with AD. OBJECTIVE: We sought to characterize the Asian AD skin phenotype and compare it with the EA AD skin phenotype. METHODS: We performed genomic profiling (real time PCR) and immunohistochemistry on lesional and nonlesional biopsy specimens from 52 patients with AD (25 EAs and 27 Asians), 10 patients with psoriasis (all EAs), and 27 healthy subjects (12 EAs and 15 Asians). RESULTS: Although disease severity/SCORAD scores were similar between the AD groups (58.0 vs 56.7, P = .77), greater acanthosis, higher Ki67 counts, and frequent parakeratosis were characteristics of lesional epidermis from Asian patients with AD (P < .05). Most (24/27) Asian patients had high IgE levels. A principal component analysis using real-time PCR data clustered the Asian AD phenotype between the EA AD and psoriasis phenotypes. TH2 skewing characterized both Asian and EA patients with AD but not patients with psoriasis. Significantly higher TH17 and TH22 (IL17A, IL19, and S100A12 in lesional and IL-22 in nonlesional skin; P < .05) and lower TH1/interferon (CXCL9, CXCL10, MX1, and IFNG in nonlesional skin; P < .05) gene induction typified AD skin in Asian patients. CONCLUSION: The Asian AD phenotype presents (even in the presence of increased IgE levels) a blended phenotype between that of EA patients with AD and those with psoriasis, including increased hyperplasia, parakeratosis, higher TH17 activation, and a strong TH2 component. The relative pathogenic contributions of the TH17 and TH2 axes in creating the Asian AD phenotype need to be tested in future clinical trials with appropriate targeted therapeutics. PMID- 26428955 TI - Analysis of cross-reactivity among radiocontrast media in 97 hypersensitivity reactions. PMID- 26428956 TI - Sparse deconvolution of higher order tensor for fiber orientation distribution estimation. AB - PURPOSE: Higher order tensor (HOT) imaging approaches based on the spherical deconvolution framework have attracted much interest for their effectiveness in estimating fiber orientation distribution (FOD). However, sparse regularization techniques are still needed to obtain stable FOD in solving the deconvolution problem, particularly in very high orders. Our goal is to adequately characterize the actual sparsity lying in the FOD domain to develop accurate estimation approach for fiber orientation in HOT framework. MATERIALS AND METHODS: We propose a sparse HOT regularization model by enforcing the sparse constraint directly on the representation of FOD instead of imposing it on coefficients of basis function. Then, we incorporate both the stabilizing effect of the l2 penalty and the sparsity encouraging effect of the l1 penalty in the sparse model to adequately characterize the actual sparsity lying in the FOD domain. Furthermore, a weighted regularization scheme is developed to iteratively solve the deconvolution problem. The deconvolution technique is compared against existing methods using l2 or l1 regularizer and tested on synthetic data and real human brain. RESULTS: Experiments were conducted on synthetic data and real human brain data. The synthetic experimental results indicate that crossing fibers are more easily detected and the angular resolution limit is improved by our method by approximately 20 degrees -30 degrees compared to existing HOT method. The detection accuracy is considerably improved compared with that of spherical deconvolution approaches using the l2 regularizer and the reweighted l1 scheme. CONCLUSIONS: Results of testing the deconvolution technique demonstrate that it allows HOTs to obtain increasingly clean and sharp FOD, which in turn significantly increases the angular resolution of current HOT methods. With sparsity on FOD domain, this method efficiently improves the ability of HOT in resolving crossing fibers. PMID- 26428957 TI - Bioavailable vitamin D levels are reduced and correlate with bone mineral density and markers of mineral metabolism in adults with nephrotic syndrome. AB - AIM: Blood levels of 25-hydroxyvitamin D [25(OH) D] are reduced in patients with nephrotic syndrome (NS). The lowering is thought to be due to urinary loss of vitamin D binding protein (DBP). A link between vitamin D deficiency and bone disease or markers of mineral metabolism has not yet been shown in NS. We hypothesized that alterations in bioavailable vitamin D levels might be linked to these abnormalities in NS. METHODS: We measured circulating levels of 25(OH)D, 1,25-dihydroxyvitamin D [1,25(OH)2 D], DBP, serum albumin and intact parathyroid hormone (iPTH) in 106 adults with sporadic idiopathic NS and 40 healthy controls. Bioavailable vitamin D was calculated from previously validated formulae. Bone mineral density (BMD) was measured at left hip (neck of femur) by DEXA. RESULTS: Compared to healthy controls, total and bioavailable 25(OH)D levels were significantly reduced in patients with NS as compared to healthy controls. Among the nephrotic patients, BMD was positively correlated with bioavailable 25(OH)D (r = 0.358; P = 0.0002) but not with total 25(OH)D (r = 0.174; P = 0.079). Total 1,25(OH)2 D and bioavailable 1,25(OH)2 D did not correlate with BMD (r = 0.131; P = 0.206 and r = 0.107, P = 0.295). Bioavailable 25(OH)D levels showed a strong inverse correlation with iPTH on univariate (r = -0.457; P < 0.0001) and multivariate (beta=-0.453, P < 0.0001) analyses. CONCLUSIONS: We conclude that bioavailable 25(OH)D is a better measure of vitamin D status with respect of BMD and mineral metabolism in patients of nephrotic syndrome. PMID- 26428959 TI - Risk factors for meticillin-resistant Staphylococcus aureus colonization in dialysis patients: a meta-analysis. AB - BACKGROUND: Patients on dialysis are particularly vulnerable to meticillin resistant Staphylococcus aureus (MRSA) infections and MRSA colonization is associated with increased risk for severe infections in this population. AIM: Determination of risk factors for MRSA colonization among dialysis patients. METHODS: This is a systematic review and meta-analysis of studies reporting risk factors of MRSA colonization. We performed a PubMed and EMBASE literature search to identify all studies on risk factors for MRSA colonization among patients undergoing dialysis treatment. Previous hospitalization, type of dialysis access, comorbid conditions, dialysis vintage, gender, length of time on dialysis, and previous antibiotic use were extracted and assessed for possible association with MRSA colonization in this population. FINDINGS: Ten out of 8252 articles, presenting data on 2364 dialysis patients, were included. We found that hospitalization within the previous 12 months [odds ratio (OR): 1.93; 95% confidence interval (CI): 1.04-3.58] and the use of temporary dialysis access (relative risk: 1.66; 95% CI: 1.06-2.60) were associated with a significantly higher risk of MRSA colonization. MRSA carriage was associated with lower serum albumin levels compared to non-carriage (OR: 0.8; 95% CI: 0.68-0.95) and was higher among patients with chronic lung disease (OR: 2.16; 95% CI: 1.04-4.51). There were no data on patients undergoing peritoneal dialysis. CONCLUSION: Active surveillance approaches, including potential decolonization strategies, are suggested to focus on these subgroups of haemodialysis patients with hospitalization within the previous year, temporary dialysis access, lower serum albumin levels, and chronic lung disease comorbidity. PMID- 26428958 TI - Primary and Secondary HIV Prevention Among Persons with Severe Mental Illness: Recent Findings. AB - Persons with severe mental illness (SMI) have been disproportionately affected by the HIV epidemic, with higher rates of HIV prevalence and morbidity than the general population. Recent research has advanced our understanding of the complex factors that influence primary and secondary HIV prevention for those with SMI. Sex risk in this population is associated with socioeconomic factors (e.g., low income, history of verbal violence) and other health risk behaviors (e.g., substance use, no prior HIV testing). Several interventions are effective at reducing risk behavior, and reviews highlight the need for more well-controlled studies that assess long-term outcomes. Recent research has elucidated barriers that interfere with HIV treatment for SMI populations, including individual (e.g., apathy, substance use), social (e.g., stigma), and system factors (e.g., transportation, clinic wait times). Interventions that coordinate HIV care for individuals with SMI show promise as cost-effective methods for improving medication adherence and quality of life. PMID- 26428960 TI - Written versus verbal information for patients' education on healthcare associated infections: a cross-sectional study. AB - In 2008, Piedmont region, Italy, recommended delivering written information on healthcare-associated infection (HCAI) to every patient admitted to hospitals. We interviewed 363 patients admitted to five hospitals to evaluate whether patients who received written information were more informed about HCAI than the other patients. We found no statistically significant difference between the two groups. We did observe that knowledge of HCAI was significantly lower among women and significantly higher among patients with higher education and those admitted to a surgical ward. PMID- 26428961 TI - Ebola: Lessons learned. PMID- 26428962 TI - Nososcomial transmission of viral haemorrhagic fever in South Africa. AB - Recent events in West Africa have highlighted the potential for the viral haemorrhagic fevers (VHFs) to cause considerable mortality and morbidity among heathcare workers. However, this is not a new threat as, although the risk is currently increased, it has always been present. In South Africa (SA) the only endemic haemorrhagic fever is Crimean-Congo haemorrhagic fever, transmitted by the Hyalomma tick, which is ubiquitous in cattle farming areas. Johannesburg, the commercial and transport hub of SA, is unusual in that all cases of VHF seen there are imported, either from rural areas in SA or from countries to the north. Johannesburg functions as the gateway to and from the rest of Africa, and as a destination for more affluent residents of neighbouring countries seeking medical attention. Numerous outbreaks of nosocomial infection have occurred in SA, and these are described in the form of brief case reports. PMID- 26428963 TI - Subacute sclerosing panencephalitis in South African children following the measles outbreak between 2009 and 2011. AB - Between 2009 and 2011, there was an outbreak of measles throughout South Africa (SA). The largest age category infected was children<5 years of age. In 2014, four patients, with a median age of 4 years and 5 months (range 4 years 3 months 4.5 years), three males and one female, presented with subacute sclerosing panencephalitis (SSPE). All were infected with measles during the period of the 2009-2011 outbreak in early infancy, at a time when their immune systems were immature and before they were vaccinated against the measles virus. One patient was immunocompromised, with vertically acquired HIV infection. All the children presented with cognitive and behavioural decline, abnormal movements and medically intractable myoclonic and atonic seizures. Outcome was poor in all and no reversibility was evident with standard therapeutic interventions. Optimal seizure control with carbamazepine is reported in patients with SSPE. Three of our patients who received carbamazepine experienced improved seizure control, but their neuroregression continued. Since submission of this case series, patient 1 (see Table 1) has died, and a further child has presented with the same clinical phenotype as described. On the basis of this clustering of patients in the Western Cape Province, SA, it is important to screen children admitted with acute cognitive decline and intractable seizures for SSPE, especially those who were infants during the measles outbreak. PMID- 26428964 TI - A human perspective on body donation: A case study from a psychosocial perspective. AB - Using a case study of how a son consented to his mother becoming a body donor, the factors that may have contributed to that decision are outlined. Social and psychological considerations about body donation in general are presented. These are followed by suggestions for organisational improvements for healthcare facilities and medical schools, including ease of access to accurate information for both medical professionals and members of the public. Finally, it is recommended that medical school staff dealing with potential donors and their families should be trained to communicate empathically and with compassion. PMID- 26428965 TI - Endoscopic lung volume reduction in severe emphysema. AB - Therapeutic options in severe emphysema are limited. Endoscopic lung volume reduction (ELVR) refers to bronchoscopically inducing volume loss to improve pulmonary mechanics and compliance, thereby reducing the work of breathing. Globally, this technique is increasingly used as treatment for advanced emphysema with the aim of obtaining similar functional advantages to surgical lung volume reduction, while reducing risks and costs. There is a growing body of evidence that certain well-defined subgroups of patients with advanced emphysema benefit from ELVR, provided that a systematic approach is followed and selection criteria are met. In addition to endobronchial valves, ELVR using endobronchial coils is now available in South Africa. The high cost of these interventions underscores the need for careful patient selection to best identify those likely to benefit from such procedures. PMID- 26428966 TI - Implementation of electronic scripts in South Africa. AB - The legal framework in South Africa (SA) provides for strict requirements regarding prescriptions. However, pharmacists are still confronted daily with illegible handwritten scripts, increasing the risk of medication errors. E prescribing is being implemented in SA to overcome these disadvantages. The general regulations made in terms of the Medicines and Related Substances Act as well as the Electronic Communications and Transactions Act must be read conjointly for the purposes of understanding the legal framework of electronic prescriptions in SA. PMID- 26428967 TI - Recommendations for the use of bronchial thermoplasty in the management of severe asthma. AB - There are approximately 3 million asthma suffers in South Africa, and the national death rate is ranked as one of the highest in the world. Approximately 5% have severe asthma (uncontrolled despite being adherent on maximal and optimised therapy). Such uncontrolled asthma is associated with high healthcare expenditure and may require treatment with anti-IgE and/or systemic corticosteroids, in addition to inhaler therapy and oral agents. These treatments may be costly, and those such as oral corticosteroids may have potential serious adverse events. There is therefore a need for more effective, affordable and safe therapies for asthma. A new modality of treatment, bronchial thermoplasty (BT), has recently been developed and approved for the treatment of severe asthma. BT involves delivering radio frequency-generated thermal energy to the airways, with the goal of reducing airway-specific smooth-muscle mass. Several clinical studies have confirmed that BT is effective and safe, that it improves control and quality of life in patients whose asthma remains severe despite optimal medical therapy, and that the beneficial effects are sustained for at least 5 years. We provide recommendations for the management of severe asthma, with an emphasis on the role of BT, and endorse the use of BT in patients with severe persistent asthma who remain uncontrolled despite optimal medical therapy as outlined in steps 4 and 5 of the British Thoracic Society (BTS)/Scottish Intercollegiate Guidelines Network (SIGN), UK National Institute of Clinical Excellence (NICE) and Global Initiative for Asthma (GINA) guidelines. We outline the context in which BT should be used, how it works and associated potential adverse events and contraindications, and also review unanswered questions and controversies. PMID- 26428968 TI - Recommendations for the anticoagulation of pregnant patients with mechanical heart valves. AB - BACKGROUND: The management of pregnant patients with mechanical heart valves remains challenging because there are no large randomised studies to provide guidelines for effective anticoagulant therapy. Both vitamin K antagonists and heparins may be associated with maternal and foetal adverse events. METHOD: The Southern African Society of Thrombosis and Haemostasis reviewed available literature and comprehensive evidence-based guidelines for the anticoagulation of pregnant patients with mechanical heart valves. A draft document was produced and revised by consensus agreement. The guidelines were adjudicated by independent international experts to avoid local bias. RESULTS AND CONCLUSION: We present concise, practical guidelines for the clinical management of pregnant patients with mechanical heart valves. Recommendations reflect current best practice which will hopefully lead to improved anticoagulation practice in this select group of high risk patients. PMID- 26428969 TI - National Health Insurance in South Africa: Relevance of a national priority setting agency. PMID- 26428970 TI - Reforming South Africa's procedures for granting patents to improve medicine access. PMID- 26428971 TI - South African Guidelines Excellence (SAGE): Clinical practice guidelines--quality and credibility. PMID- 26428972 TI - Gender and sexual diversity--changing paradigms in an ever-changing world. PMID- 26428973 TI - Viral haemorrhagic fevers in South Africa. AB - Viral haemorrhagic fevers (VHFs) include a diverse array of diseases caused by a broad range of viruses transmitted from various animal hosts and originating from almost all the continents in the world. These are potentially fatal and highly transmissible diseases without specific treatments or prophylactic vaccines. As has been demonstrated during the Ebola virus disease outbreak in West Africa, the consequences of VHFs are not limited to specific countries - they may become epidemic, and may have considerable economic impact and disrupt local public health and social service structures. Intensive public health intervention is necessary to contain these diseases. Here we provide a concise overview of the VHFs that are of current public health importance to South Africa. PMID- 26428974 TI - Antimicrobial resistance of bacteria isolated from patients with bloodstream infections at a tertiary care hospital in the Democratic Republic of the Congo. AB - BACKGROUND: Bloodstream infection (BSI) is a life-threatening condition that requires rapid antimicrobial treatment. METHODS: We determined the prevalence of bacterial isolates associated with BSI at Bukavu General Hospital (BGH), South Kivu Province, Democratic Republic of the Congo, and their patterns of susceptibility to antimicrobial drugs, from February 2013 to January 2014. RESULTS: We cultured 112 clinically relevant isolates from 320 blood cultures. Of these isolates, 104 (92.9%) were Gram-negative bacteria (GNB), with 103 bacilli (92.0%) and one coccus (0.9%). Among GNB, Escherichia coli (51.9%), Klebsiella spp. (20.2%), Enterobacter spp. (6.7%), Shigella spp. (5.8%) and Salmonella spp. (4.8%) were the most frequent agents causing BSIs. Other GNB isolates included Proteus spp., Citrobacter spp. and Pseudomonas aeruginosa (both 2.9%), and Acinetobacter spp. and Neisseria spp. (both 0.9%). High rates of resistance to co trimoxazole (100%), erythromycin (100%) and ampicillin (66.7-100%) and moderate to high resistance to ciprofloxacin, ceftazidime, ceftriaxone, cefuroxime and cefepime were observed among GNB. Furthermore, there were high rates of multidrug resistance and of extended-spectrum beta-lactamase (ESBL) production phenotype among Enterobacteriaceae. Gram-positive bacteria included three Staphylococcus aureus isolates (2.7%), four oxacillin-resistant coagulase-negative staphylococci (CoNS) isolates (3.6%) and one Streptococcus pneumoniae (0.9%). No oxacillin resistant S. aureus was isolated. Among clinically relevant staphylococci, susceptibility to co-trimoxazole and ampicillin was low (0-25%). In addition, 58 contaminant CoNS were isolated from blood cultures, and the calculated ratio of contaminants to pathogens in blood cultures was 1:2. CONCLUSIONS: Multidrug resistant and ESBL-producing GNB are the leading cause of BSI at BGH. PMID- 26428975 TI - The role of point-of-care blood testing for ketones in the diagnosis of diabetic ketoacidosis. AB - BACKGROUND: Urine dipstick testing for ketones is widely used when diabetic ketoacidosis (DKA) is suspected in patients with hyperglycaemia. If urinary ketones are positive, patients are referred for further management--often inappropriately, as the test is a poor surrogate for plasma ketones. Plasma beta hydroxybutyrate (beta-OHB) levels>3 mmol/L are diagnostic of DKA, while levels<1 mmol/L are insignificant. OBJECTIVES: To evaluate a hand-held electrochemical (point-of-care testing; POCT) ketone monitor and compare it with the gold standard manual enzymatic method (MEM) for detection of plasma ketones. METHODS: In a prospective and comparative study, we evaluated the measurement of beta-OHB by means of POCT and the MEM in 61 consecutive samples from patients with suspected DKA at Tygerberg and Karl Bremer hospitals, Cape Town, South Africa. Capillary (for POCT) and plasma samples (for the MEM) were obtained simultaneously and compared for accuracy. Precision was assessed with control samples. RESULTS: The POCT method was precise (coefficient of variation <4.5%), and there was a good correlation between the two methods (r=0.95). Regression analysis showed a proportional bias, with POCT reading higher than the MEM. However, when assessed at the relevant medical decision limits (beta-OHB>3 mmol/L and <1 mmol/L), the total allowable error (bias+imprecision) was not exceeded. Patients will therefore still be classified correctly. The POCT method had a sensitivity of 100% and specificity of 89% for DKA (beta-OHB>3 mmol/L), while at levels<1 mmol/L sensitivity was 100% and specificity 87.5%. CONCLUSION: The POCT device provides an accurate and precise result and can be used as an alternative to the MEM in the diagnosis of DKA. PMID- 26428976 TI - Reproductive knowledge and use of contraception among women with diabetes. AB - BACKGROUND: Poorly controlled diabetes is associated with poor maternal and fetal outcomes, yet many women become pregnant before establishing control. Reducing unintended pregnancies is a vital step towards improving perinatal and maternal morbidity and mortality. OBJECTIVES: To assess the reproductive knowledge and use of contraception in women of reproductive age attending diabetes outpatient clinics. METHODS: A prospective descriptive study was conducted of women known to have diabetes, aged 18 - 45 years, attending the diabetic clinics at Groote Schuur Hospital or the local community health centres in Cape Town, South Africa. A questionnaire consisting of social, demographic and family details as well as contraceptive use and knowledge was administered. RESULTS: Some common themes emerged, namely that 44.2% of the women with previous pregnancies had had unintended pregnancies, and that this was more common among single (58.8%) and younger women. Women with type 1 diabetes had better knowledge than those with type 2 diabetes of how pregnancy affects diabetes, but better knowledge did not translate to better contraception use. Despite the fact that 102 participants (88.7%) attended diabetes clinics two or more times a year, knowledge of pregnancy- and reproductive health-related complications was limited, and only 30 participants (26.1%) had received advice on contraception at these clinics. CONCLUSION: Knowledge about the impact of diabetes on pregnancy and that of pregnancy on diabetes was suboptimal. We recommend that reproductive health services be included at the routine diabetes clinic visit. PMID- 26428977 TI - Time to implement 9-month infant HIV testing in South Africa. AB - BACKGROUND: South Africa (SA) is likely to meet the National Strategic Plan target of <2% mother-to-child HIV transmission at 6 weeks of age in 2015. Children infected with HIV after 6 weeks often remain undiagnosed because of poor implementation of post-weaning and final outcome 18-month HIV testing. The World Health Organization recommends a screening HIV rapid test (HRT) in HIV-exposed infants at the 9-month immunisation visit to exclude postnatal infection, with a confirmatory HIV polymerase chain reaction (PCR) test if the HRT is positive. OBJECTIVE: To evaluate the impact of substituting this recommendation for the post-weaning HIV testing recommended by SA guidelines. METHODS: Rates of seroreversion and probability of infection at 9 months of age were applied to a theoretical population of 100 HIV-exposed infants, uninfected at birth and breastfed for 1 year with antiretroviral prophylaxis. Nine scenarios were developed and the number of HIV PCRs saved compared with current guidelines was calculated. RESULTS: Nine-month testing using the HRT reduced the number of follow-up PCR tests done in all scenarios by >50%, with differences ranging from 51% to 59% and 81% to 89% for low and high seroreversion rates, respectively. CONCLUSIONS: Nine-month testing using HRT would increase identification and early treatment of HIV-infected infants, improve monitoring of postnatal transmission rates, and reduce the number of HIV PCR tests done with resultant cost saving. Training of healthcare workers implementing HRT would be required. Ongoing efforts to improve implementation and monitoring of testing at 9 and 18 months will be essential. PMID- 26428978 TI - Pharmacological treatment of painful HIV-associated sensory neuropathy. AB - BACKGROUND: HIV-associated sensory neuropathy (HIV-SN) is a common and frequently painful complication of HIV infection and its treatment. However, few data exist describing the frequency, type and dosage of pain medications patients are receiving in the clinic setting to manage the painful symptoms of HIV-SN. OBJECTIVE: To report on analgesic prescription for painful HIV-SN and factors influencing that prescription in adults on combination antiretroviral therapy. METHODS: Using validated case ascertainment criteria to identify patients with painful HIV-SN, we recruited 130 HIV-positive patients with painful HIV-SN at Chris Hani Baragwanath Hospital, Johannesburg, South Africa. Demographic and clinical data (including current analgesic use) were collected on direct questioning of the patients and review of the medical files. RESULTS: We found significant associations, of moderate effect size, between higher pain intensity and lower CD4 T-cell counts with prescription of analgesic therapy. Factors previously identified as predicting analgesic treatment in HIV-positive individuals (age, gender, level of education) were not associated with analgesic use here. Consistent with national guidelines, amitriptyline was the most commonly used agent, either alone or in combination therapy. Importantly, we also found that despite the relatively high analgesic treatment rate in this setting, the majority of patients described their current level of HIV-SN pain as moderate or severe. CONCLUSION: Our findings highlight the urgent need for both better analgesic options for HIV-SN pain treatment and ongoing training and support of clinicians managing this common and debilitating condition. PMID- 26428979 TI - Bone marrow aspirate microscopy v. bone marrow trephine biopsy microscopy for detection of Mycobacterium tuberculosis infection. AB - BACKGROUND: Tuberculosis (TB) remains a global health problem. According to the 2013 Global Report on Tuberculosis, 8.6 million people developed TB in 2012 and 1.3 million died from the disease. An estimated 13% of people who developed TB in 2012 were HIV-positive, and 75% of these lived in Africa. While pulmonary TB is the commonest form of Mycobacterium tuberculosis infection, extrapulmonary TB is increasingly being detected in HIV-positive patients. Definitive diagnosis of disseminated TB is a challenge owing to atypical presentations and diagnostic difficulties (negative chest radiograph and sputum microscopy and culture). A rapid diagnosis of disseminated TB is desirable, as early initiation of treatment can reduce mortality. Although TB culture is the gold standard for diagnosis of TB, it has a long turnaround time (up to 6 weeks). OBJECTIVES: To identify a potentially faster and more effective diagnostic strategy for disseminated TB. METHODS: A retrospective 18-month review, conducted at a tertiary hospital, comparing histological findings of an auramine O-stained bone marrow aspiration (BMA) smear and a bone marrow trephine (BMT) biopsy specimen with the gold standard of TB culture. RESULTS: Microscopic examination of BMA smears and BMT biopsy specimens offers a rapid diagnostic strategy, with results available on the same day for the former and within 4 days for the latter. BMT histological examination had a significantly higher detection rate than BMA auramine O staining compared with TB culture. CONCLUSION: We recommend that BMT biopsies remain an essential part of the diagnostic work-up for disseminated TB. PMID- 26428980 TI - Codeine misuse and dependence in South Africa--learning from substance abuse treatment admissions. AB - BACKGROUND: Misuse of prescription and over-the-counter codeine-containing products is a global public health issue. OBJECTIVES: To investigate the extent of treatment demand related to the misuse of codeine or codeine dependence in South Africa (SA) and the profile of patients seeking treatment, so as to understand the nature and extent of the problem. METHOD: Data were collected from centres participating in the South African Community Epidemiology Network on Drug Use in 2014. A total of 17 260 admissions were recorded. RESULTS: There were 435 recorded treatment admissions for codeine misuse or dependence as a primary or secondary substance of abuse (2.5% of all admissions). Of treatment admissions, 137 (0.8%) involved codeine as the primary substance of abuse; 74.9% of patients were males, with an even spread across population groups. Ages ranged from 11 to 70 years, with the highest proportion aged 20 - 29 years; >40% were referred by self, family and/or friends, and 26.7% by health professionals; and 36.8% had received treatment previously. The majority reported misuse of tablets/capsules, with 17.6% reporting misuse of syrups. Oral use comprised 96.6% and daily use 63.1%. CONCLUSIONS: Data from treatment admissions related to codeine misuse and dependence are informative, but provide an incomplete picture of the nature and extent of codeine-related problems in SA. Other data sources must be considered before further regulatory/policy changes regarding codeine are implemented. PMID- 26428981 TI - Affordable moisturisers are effective in atopic eczema: A randomised controlled trial. AB - BACKGROUND: Many patients depend on moisturisers issued by public health services in the management of atopic dermatitis (AD). METHODS: In a randomised controlled trial of patients with mild to moderate AD, aged 1-12 years, study 1 compared aqueous cream v. liquid paraffin (fragrance-free baby oil) as a soap substitute, all patients using emulsifying ointment as moisturiser, and study 2 compared four moisturisers, emulsifying ointment, cetomacrogol, white petroleum jelly and glycerine/petroleum (proportion 1:2; 'the 1:2 moisturiser'), all using fragrance free baby oil as soap substitute. Assessments were one quality of life and three AD severity scores, at baseline and weeks 4, 8 and 12. Differences were compared using repeated measures of analysis of variance. RESULTS: In both studies (120 children randomised, 20 in each group of the two trials) disease severity scores declined with time. The only significant difference was in one AD severity score (SCORing Atopic Dermatitis) in study 1, both at baseline and over time (p=0.042 and p=0.022). The groups did not differ with regard to topical steroid use or side-effects. Itching from baby oil applied as soap was reported by four patients in the two studies, the petroleum jelly group had more dropouts than the 1:2 moisturiser group, although this was not statistically significant, and 110 patients (91.7%) completed the trial. CONCLUSIONS: The small sample limits generalisability, but the duration was longer than in most AD moisturiser studies. Fragrance-free baby oil is an effective soap substitute that may be better tolerated (if irritation occurs) as a bath additive. The home-made 1:2 moisturiser may be preferable to white petroleum jelly, but both are equivalent to cetomacrogol and emulsifying ointment. Use of accessible moisturisers could reduce the cost of managing mild to moderate AD. PMID- 26428988 TI - Communication: Spectroscopic observation of the O-bonded T-shaped isomer of the CO-CO2 dimer and two of its intermolecular frequencies. AB - Infrared spectra in the carbon monoxide CO stretch region (~2150 cm(-1)) are assigned to the previously unobserved O-bonded form of the CO2-CO dimer ("isomer 2"), which has a planar T-shaped structure like that of the previously observed C bonded form ("isomer 1"), but with the CO rotated by 180 degrees . The effective center of mass intermolecular distances are 3.58 A for isomer 2 as compared to 3.91 A for isomer 1. In addition to the fundamental band, two combination bands are observed for isomer 2, yielding values for two intermolecular vibrational modes: 14.19 cm(-1) for the in-plane CO bend and 22.68 cm(-1) for the out-of plane bend. PMID- 26428987 TI - Core diameter of bone marrow aspiration devices influences cell density of bone marrow aspirate in patients with severe peripheral artery disease. AB - BACKGROUND AIMS: Bone marrow (BM) transplantations are an accepted therapeutic strategy for hematologic conditions. In the past decades, interest for BM-derived cell therapy has extended toward the field of regenerative medicine. Irrespective of the treatment strategy, its success depends on the amount of cells available for transplantation. Both patient and procedural factors have been shown to influence the cell density of the BM aspirate. In the present study, the influence of core diameter of the BM aspiration device on cell density of the BM aspirate is studied. METHODS: BM harvesting procedures performed in a clinical trial investigating the effect of BM cell therapy in patients with severe peripheral artery disease were retrospectively studied (clinicaltrials.gov NCT00371371). Patients underwent BM harvesting through the use of either a 15 gauge (n = 85) or an 8-gauge (n = 75) needle. The numbers of harvested white blood cells (WBC) and CD34(+) hematopoietic cells (HPC) were quantified. RESULTS: The amount of WBC per milliliter of BM aspirate was significantly higher when the 8-gauge needle (27.8 * 10(6) WBC/mL [95%CI 25.4-30.5 * 10(6)]) was used compared with the smaller 15-gauge core needle (20.1 * 10(6) WBC/mL [95% confidence interval (CI), 18.7-21.7 * 10(6)], P < 0.001). For the amount of CD34(+) HPC, a similar pattern was observed (185 * 10(3) HPC/mL [95% CI, 161-213 * 10(3)]; 114 * 10(3) HPC/mL [95% CI, 96-134 * 10(3)]; P < 0.001). CONCLUSIONS: The application of a BM aspiration device with a larger core diameter is associated with an increased cell density of the BM aspiration product in patients with severe peripheral artery disease. PMID- 26428989 TI - Communication: Broadband and ultrasensitive femtosecond time-resolved circular dichroism spectroscopy. AB - We report the development of broadband and sensitive time-resolved circular dichroism (TRCD) spectroscopy by exploiting optical heterodyne detection. Using this method, transient CD signals of submillidegree level can be detected over the spectral range of 415-730 nm. We also demonstrate that the broadband measurement with the aid of singular value decomposition enables the discrimination of genuine TRCD signals from artificial optical-anisotropy, such as linear birefringence and linear dichroism, induced by photoexcitation. PMID- 26428991 TI - Directed HK propagator. AB - We offer a more formal justification for the successes of our recently communicated "directed Heller-Herman-Kluk-Kay" (DHK) time propagator by examining its performance in one-dimensional bound systems which exhibit at least quasi periodic motion. DHK is distinguished by its single one-dimensional integral--a vast simplification over the usual 2N-dimensional integral in full Heller-Herman Kluk-Kay (for an N-dimensional system). We find that DHK accurately captures particular coherent state autocorrelations when its single integral is chosen to lie along these states' fastest growing manifold, as long as it is not perpendicular to their action gradient. Moreover, the larger the action gradient, the better DHK will perform. We numerically examine DHK's accuracy in a one dimensional quartic oscillator and illustrate that these conditions are frequently satisfied such that the method performs well. This lends some explanation for why DHK frequently seems to work so well and suggests that it may be applicable to systems exhibiting quite strong anharmonicity. PMID- 26428990 TI - Memetic algorithms for ligand expulsion from protein cavities. AB - Ligand diffusion through a protein interior is a fundamental process governing biological signaling and enzymatic catalysis. A complex topology of channels in proteins leads often to difficulties in modeling ligand escape pathways by classical molecular dynamics simulations. In this paper, two novel memetic methods for searching the exit paths and cavity space exploration are proposed: Memory Enhanced Random Acceleration (MERA) Molecular Dynamics (MD) and Immune Algorithm (IA). In MERA, a pheromone concept is introduced to optimize an expulsion force. In IA, hybrid learning protocols are exploited to predict ligand exit paths. They are tested on three protein channels with increasing complexity: M2 muscarinic G-protein-coupled receptor, enzyme nitrile hydratase, and heme protein cytochrome P450cam. In these cases, the memetic methods outperform simulated annealing and random acceleration molecular dynamics. The proposed algorithms are general and appropriate in all problems where an accelerated transport of an object through a network of channels is studied. PMID- 26428992 TI - Construction of exchange-correlation functionals through interpolation between the non-interacting and the strong-correlation limit. AB - Drawing on the adiabatic connection of density functional theory, exchange correlation functionals of Kohn-Sham density functional theory are constructed which interpolate between the extreme limits of the electron-electron interaction strength. The first limit is the non-interacting one, where there is only exchange. The second limit is the strong correlated one, characterized as the minimum of the electron-electron repulsion energy. The exchange-correlation energy in the strong-correlation limit is approximated through a model for the exchange-correlation hole that is referred to as nonlocal-radius model [L. O. Wagner and P. Gori-Giorgi, Phys. Rev. A 90, 052512 (2014)]. Using the non interacting and strong-correlated extremes, various interpolation schemes are presented that yield new approximations to the adiabatic connection and thus to the exchange-correlation energy. Some of them rely on empiricism while others do not. Several of the proposed approximations yield the exact exchange-correlation energy for one-electron systems where local and semi-local approximations often fail badly. Other proposed approximations generalize existing global hybrids by using a fraction of the exchange-correlation energy in the strong-correlation limit to replace an equal fraction of the semi-local approximation to the exchange-correlation energy in the strong-correlation limit. The performance of the proposed approximations is evaluated for molecular atomization energies, total atomic energies, and ionization potentials. PMID- 26428993 TI - An enhanced version of the heat exchange algorithm with excellent energy conservation properties. AB - We propose a new algorithm for non-equilibrium molecular dynamics simulations of thermal gradients. The algorithm is an extension of the heat exchange algorithm developed by Hafskjold et al. [Mol. Phys. 80, 1389 (1993); 81, 251 (1994)], in which a certain amount of heat is added to one region and removed from another by rescaling velocities appropriately. Since the amount of added and removed heat is the same and the dynamics between velocity rescaling steps is Hamiltonian, the heat exchange algorithm is expected to conserve the energy. However, it has been reported previously that the original version of the heat exchange algorithm exhibits a pronounced drift in the total energy, the exact cause of which remained hitherto unclear. Here, we show that the energy drift is due to the truncation error arising from the operator splitting and suggest an additional coordinate integration step as a remedy. The new algorithm retains all the advantages of the original one whilst exhibiting excellent energy conservation as illustrated for a Lennard-Jones liquid and SPC/E water. PMID- 26428994 TI - Conformational sampling enhancement of replica exchange molecular dynamics simulations using swarm particle intelligence. AB - In this paper, we present a new method based on swarm particle social intelligence for use in replica exchange molecular dynamics simulations. In this method, the replicas (representing the different system configurations) are allowed communicating with each other through the individual and social knowledge, in additional to considering them as a collection of real particles interacting through the Newtonian forces. The new method is based on the modification of the equations of motion in such way that the replicas are driven towards the global energy minimum. The method was tested for the Lennard-Jones clusters of N = 4, 5, and 6 atoms. Our results showed that the new method is more efficient than the conventional replica exchange method under the same practical conditions. In particular, the new method performed better on optimizing the distribution of the replicas among the thermostats with time and, in addition, ergodic convergence is observed to be faster. We also introduce a weighted histogram analysis method allowing analyzing the data from simulations by combining data from all of the replicas and rigorously removing the inserted bias. PMID- 26428995 TI - An EQT-based cDFT approach for a confined Lennard-Jones fluid mixture. AB - Empirical potential-based quasi-continuum theory (EQT) provides a route to incorporate atomistic detail into continuum framework such as the Nernst-Planck equation. EQT can also be used to construct a grand potential functional for classical density functional theory (cDFT). The combination of EQT and cDFT provides a simple and fast approach to predict the inhomogeneous density, potential profiles, and thermodynamic properties of confined fluids. We extend the EQT-cDFT approach to confined fluid mixtures and demonstrate it by simulating a mixture of methane and hydrogen inside slit-like channels of graphene. We show that the EQT-cDFT predictions for the structure of the confined fluid mixture compare well with the molecular dynamics simulation results. In addition, our results show that graphene slit nanopores exhibit a selective adsorption of methane over hydrogen. PMID- 26428996 TI - Adapting algebraic diagrammatic construction schemes for the polarization propagator to problems with multi-reference electronic ground states exploiting the spin-flip ansatz. AB - For the investigation of molecular systems with electronic ground states exhibiting multi-reference character, a spin-flip (SF) version of the algebraic diagrammatic construction (ADC) scheme for the polarization propagator up to third order perturbation theory (SF-ADC(3)) is derived via the intermediate state representation and implemented into our existing ADC computer program adcman. The accuracy of these new SF-ADC(n) approaches is tested on typical situations, in which the ground state acquires multi-reference character, like bond breaking of H2 and HF, the torsional motion of ethylene, and the excited states of rectangular and square-planar cyclobutadiene. Overall, the results of SF-ADC(n) reveal an accurate description of these systems in comparison with standard multi reference methods. Thus, the spin-flip versions of ADC are easy-to-use methods for the calculation of "few-reference" systems, which possess a stable single reference triplet ground state. PMID- 26428997 TI - Analytical optimal pulse shapes obtained with the aid of genetic algorithms. AB - We propose a methodology to design optimal pulses for achieving quantum optimal control on molecular systems. Our approach constrains pulse shapes to linear combinations of a fixed number of experimentally relevant pulse functions. Quantum optimal control is obtained by maximizing a multi-target fitness function using genetic algorithms. As a first application of the methodology, we generated an optimal pulse that successfully maximized the yield on a selected dissociation channel of a diatomic molecule. Our pulse is obtained as a linear combination of linearly chirped pulse functions. Data recorded along the evolution of the genetic algorithm contained important information regarding the interplay between radiative and diabatic processes. We performed a principal component analysis on these data to retrieve the most relevant processes along the optimal path. Our proposed methodology could be useful for performing quantum optimal control on more complex systems by employing a wider variety of pulse shape functions. PMID- 26428998 TI - Grand canonical Monte Carlo using solvent repacking: Application to phase behavior of hard disk mixtures. AB - A new "solvent repacking Monte Carlo" strategy for performing grand canonical ensemble simulations in condensed phases is introduced and applied to the study of hard-disk systems. The strategy is based on the configuration-bias approach, but uses an auxiliary biasing potential to improve the efficiency of packing multiple solvent particles in the cavity formed by removing one large solute. The method has been applied to study the coexistence of ordered and isotropic phases in three binary mixtures of hard disks with a small mole fraction (xL < 0.02) of the larger "solute" component. A chemical potential of 12.81 +/- 0.01 kBT was found to correspond to the freezing transition of the pure hard disk "solvent." Simulations permitted the study of partitioning of large disks between ordered and isotropic phases, which showed a distinct non-monotonic dependence on size; the isotropic phase was enriched approximately 10-fold, 20-fold, and 5-fold over the coexisting ordered phases at diameter ratios d = 1.4, 2.5, and 3, respectively. Mixing of large and small disks within both phases near coexistence was strongly non-ideal in spite of the dilution. Structures of systems near coexistence were analyzed to determine correlations between large disks' positions within each phase, the orientational correlation length of small disks within the fluid phases, and the nature of translational order in the ordered phase. The analyses indicate that the ordered phase coexists with an isotropic phase resembling a nanoemulsion of ordered domains of small disks, with large disks enriched at the disordered domain interfaces. PMID- 26428999 TI - DGDFT: A massively parallel method for large scale density functional theory calculations. AB - We describe a massively parallel implementation of the recently developed discontinuous Galerkin density functional theory (DGDFT) method, for efficient large-scale Kohn-Sham DFT based electronic structure calculations. The DGDFT method uses adaptive local basis (ALB) functions generated on-the-fly during the self-consistent field iteration to represent the solution to the Kohn-Sham equations. The use of the ALB set provides a systematic way to improve the accuracy of the approximation. By using the pole expansion and selected inversion technique to compute electron density, energy, and atomic forces, we can make the computational complexity of DGDFT scale at most quadratically with respect to the number of electrons for both insulating and metallic systems. We show that for the two-dimensional (2D) phosphorene systems studied here, using 37 basis functions per atom allows us to reach an accuracy level of 1.3 * 10(-4) Hartree/atom in terms of the error of energy and 6.2 * 10(-4) Hartree/bohr in terms of the error of atomic force, respectively. DGDFT can achieve 80% parallel efficiency on 128,000 high performance computing cores when it is used to study the electronic structure of 2D phosphorene systems with 3500-14 000 atoms. This high parallel efficiency results from a two-level parallelization scheme that we will describe in detail. PMID- 26429000 TI - Relaxation mode analysis and Markov state relaxation mode analysis for chignolin in aqueous solution near a transition temperature. AB - It is important to extract reaction coordinates or order parameters from protein simulations in order to investigate the local minimum-energy states and the transitions between them. The most popular method to obtain such data is principal component analysis, which extracts modes of large conformational fluctuations around an average structure. We recently applied relaxation mode analysis for protein systems, which approximately estimates the slow relaxation modes and times from a simulation and enables investigations of the dynamic properties underlying the structural fluctuations of proteins. In this study, we apply this relaxation mode analysis to extract reaction coordinates for a system in which there are large conformational changes such as those commonly observed in protein folding/unfolding. We performed a 750-ns simulation of chignolin protein near its folding transition temperature and observed many transitions between the most stable, misfolded, intermediate, and unfolded states. We then applied principal component analysis and relaxation mode analysis to the system. In the relaxation mode analysis, we could automatically extract good reaction coordinates. The free-energy surfaces provide a clearer understanding of the transitions not only between local minimum-energy states but also between the folded and unfolded states, even though the simulation involved large conformational changes. Moreover, we propose a new analysis method called Markov state relaxation mode analysis. We applied the new method to states with slow relaxation, which are defined by the free-energy surface obtained in the relaxation mode analysis. Finally, the relaxation times of the states obtained with a simple Markov state model and the proposed Markov state relaxation mode analysis are compared and discussed. PMID- 26429001 TI - Direct assignment of molecular vibrations via normal mode analysis of the neutron dynamic pair distribution function technique. AB - For over a century, vibrational spectroscopy has enhanced the study of materials. Yet, assignment of particular molecular motions to vibrational excitations has relied on indirect methods. Here, we demonstrate that applying group theoretical methods to the dynamic pair distribution function analysis of neutron scattering data provides direct access to the individual atomic displacements responsible for these excitations. Applied to the molecule-based frustrated magnet with a potential magnetic valence-bond state, LiZn2Mo3O8, this approach allows direct assignment of the constrained rotational mode of Mo3O13 clusters and internal modes of MoO6 polyhedra. We anticipate that coupling this well known data analysis technique with dynamic pair distribution function analysis will have broad application in connecting structural dynamics to physical properties in a wide range of molecular and solid state systems. PMID- 26429002 TI - Elucidation of reactive wavepackets by two-dimensional resonance Raman spectroscopy. AB - Traditional second-order kinetic theories fail to describe sub-picosecond photochemical reactions when solvation and vibrational dephasing undermine the assumption of equilibrium initial conditions. Four-wave mixing spectroscopies may reveal insights into such non-equilibrium processes but are limited by the single "population time" available in these types of experiments. Here, we use two dimensional resonance Raman (2DRR) spectroscopy to expose correlations between coherent nuclear motions of the reactant and product in the photodissociation reaction of triiodide. It is shown that the transition of a nuclear wavepacket from the reactant (triiodide) to product (diiodide) states gives rise to a unique pattern of 2DRR resonances. Peaks associated with this coherent reaction mechanism are readily assigned, because they are isolated in particular quadrants of the 2DRR spectrum. A theoretical model in which the chemical reaction is treated as a vibronic coherence transfer transition from triiodide to diiodide reproduces the patterns of 2DRR resonances detected in experiments. These signal components reveal correlation between the nonequilibrium geometry of triiodide and the vibrational coherence frequency of diiodide. The 2DRR signatures of coherent reaction mechanisms established in this work may generalize to studies of ultrafast energy and charge transfer processes. PMID- 26429003 TI - A method for the direct measurement of electronic site populations in a molecular aggregate using two-dimensional electronic-vibrational spectroscopy. AB - Two dimensional electronic spectroscopy has proved to be a valuable experimental technique to reveal electronic excitation dynamics in photosynthetic pigment protein complexes, nanoscale semiconductors, organic photovoltaic materials, and many other types of systems. It does not, however, provide direct information concerning the spatial structure and dynamics of excitons. 2D infrared spectroscopy has become a widely used tool for studying structural dynamics but is incapable of directly providing information concerning electronic excited states. 2D electronic-vibrational (2DEV) spectroscopy provides a link between these domains, directly connecting the electronic excitation with the vibrational structure of the system under study. In this work, we derive response functions for the 2DEV spectrum of a molecular dimer and propose a method by which 2DEV spectra could be used to directly measure the electronic site populations as a function of time following the initial electronic excitation. We present results from the response function simulations which show that our proposed approach is substantially valid. This method provides, to our knowledge, the first direct experimental method for measuring the electronic excited state dynamics in the spatial domain, on the molecular scale. PMID- 26429004 TI - Spectral reconstruction analysis for enhancing signal-to-noise in time-resolved spectroscopies. AB - We demonstrate a new spectral analysis for the enhancement of the signal-to-noise ratio (SNR) in time-resolved spectroscopies. Unlike the simple linear average which produces a single representative spectrum with enhanced SNR, this Spectral Reconstruction analysis (SRa) improves the SNR (by a factor of ca. 0.6?n) for all n experimentally recorded time-resolved spectra. SRa operates by eliminating noise in the temporal domain, thereby attenuating noise in the spectral domain, as follows: Temporal profiles at each measured frequency are fit to a generic mathematical function that best represents the temporal evolution; spectra at each time are then reconstructed with data points from the fitted profiles. The SRa method is validated with simulated control spectral data sets. Finally, we apply SRa to two distinct experimentally measured sets of time-resolved IR emission spectra: (1) UV photolysis of carbonyl cyanide and (2) UV photolysis of vinyl cyanide. PMID- 26429005 TI - Hyper-Rayleigh scattering in centrosymmetric systems. AB - Hyper-Rayleigh scattering (HRS) is an incoherent mechanism for optical second harmonic generation. The frequency-doubled light that emerges from this mechanism is not emitted in a laser-like manner, in the forward direction; it is scattered in all directions. The underlying theory for this effect involves terms that are quadratic in the incident field and involves an even-order optical susceptibility (for a molecule, its associated hyperpolarizability). In consequence, HRS is often regarded as formally forbidden in centrosymmetric media. However, for the fundamental three-photon interaction, theory based on the standard electric dipole approximation, representable as E1(3), does not account for all experimental observations. The relevant results emerge upon extending the theory to include E1(2)M1 and E1(2)E2 contributions, incorporating one magnetic dipolar or electric quadrupolar interaction, respectively, to a consistent level of multipolar expansion. Both additional interactions require the deployment of higher orders in the multipole expansion, with the E1(2)E2 interaction analogous in rank and parity to a four-wave susceptibility. To elicit the correct form of response from fluid or disordered media invites a tensor representation which does not oversimplify the molecular components, yet which can produce results to facilitate the interpretation of experimental observations. The detailed derivation in this work leads to results which are summarized for the following: perpendicular detection of polarization components both parallel and perpendicular to the pump radiation, leading to distinct polarization ratio results, as well as a reversal ratio for forward scattered circular polarizations. The results provide a route to handling data with direct physical interpretation, to enable the more sophisticated design of molecules with sought nonlinear optical properties. PMID- 26429006 TI - Dissociation energies of Ag-RG (RG = Ar, Kr, Xe) and AgO molecules from velocity map imaging studies. AB - The near ultraviolet photodissociation dynamics of silver atom-rare gas dimers have been studied by velocity map imaging. Ag-RG (RG = Ar, Kr, Xe) species generated by laser ablation are excited in the region of the C ((2)Sigma(+))<-X ((2)Sigma(+)) continuum leading to direct, near-threshold dissociation generating Ag* ((2)P3/2) + RG ((1)S0) products. Images recorded at excitation wavelengths throughout the C ((2)Sigma(+))<-X ((2)Sigma(+)) continuum, coupled with known atomic energy levels, permit determination of the ground X ((2)Sigma(+)) state dissociation energies of 85.9 +/- 23.4 cm(-1) (Ag-Ar), 149.3 +/- 22.4 cm(-1) (Ag Kr), and 256.3 +/- 16.0 cm(-1) (Ag-Xe). Three additional photolysis processes, each yielding Ag atom photoproducts, are observed in the same spectral region. Two of these are markedly enhanced in intensity upon seeding the molecular beam with nitrous oxide, and are assigned to photodissociation of AgO at the two photon level. These features yield an improved ground state dissociation energy for AgO of 15 965 +/- 81 cm(-1), which is in good agreement with high level calculations. The third process results in Ag atom fragments whose kinetic energy shows anomalously weak photon energy dependence and is assigned tentatively to dissociative ionization of the silver dimer Ag2. PMID- 26429007 TI - The structure of the O2-N2O complex. AB - We have investigated the lowest energy structures and interaction energies of the oxygen nitrous oxide complex (O2-N2O) using explicitly correlated coupled cluster theory. We find that the intermolecular potential energy surface of O2-N2O is very flat, with two minima of comparable energy separated by a low energy first order saddle point. Our results are able to conclusively distinguish between the two sets of experimental geometric parameters for O2-N2O that were previously determined from rotationally resolved infrared spectra. The global minimum structure of O2-N2O is therefore found to be planar with a distorted slipped parallel structure. Finally, we show that the very flat potential energy surface of O2-N2O is problematic when evaluating vibrational frequencies with a numerical Hessian and that consideration should be given as to whether results might change if the step-size is varied. PMID- 26429008 TI - Quantum free energy landscapes from ab initio path integral metadynamics: Double proton transfer in the formic acid dimer is concerted but not correlated. AB - With the goal of computing quantum free energy landscapes of reactive (bio)chemical systems in multi-dimensional space, we combine the metadynamics technique for sampling potential energy surfaces with the ab initio path integral approach to treating nuclear quantum motion. This unified method is applied to the double proton transfer process in the formic acid dimer (FAD), in order to study the nuclear quantum effects at finite temperatures without imposing a one dimensional reaction coordinate or reducing the dimensionality. Importantly, the ab initio path integral metadynamics technique allows one to treat the hydrogen bonds and concomitant proton transfers in FAD strictly independently and thus provides direct access to the much discussed issue of whether the double proton transfer proceeds via a stepwise or concerted mechanism. The quantum free energy landscape we compute for this H-bonded molecular complex reveals that the two protons move in a concerted fashion from initial to product state, yet world-line analysis of the quantum correlations demonstrates that the protons are as quantum uncorrelated at the transition state as they are when close to the equilibrium structure. PMID- 26429009 TI - Metal-ligand delocalization and spin density in the CuCl2 and [CuCl4](2-) molecules: Some insights from wave function theory. AB - The aim of this paper is to unravel the physical phenomena involved in the calculation of the spin density of the CuCl2 and [CuCl4](2-) systems using wave function methods. Various types of wave functions are used here, both variational and perturbative, to analyse the effects impacting the spin density. It is found that the spin density on the chlorine ligands strongly depends on the mixing between two types of valence bond structures. It is demonstrated that the main difficulties found in most of the previous studies based on wave function methods come from the fact that each valence bond structure requires a different set of molecular orbitals and that using a unique set of molecular orbitals in a variational procedure leads to the removal of one of them from the wave function. Starting from these results, a method to compute the spin density at a reasonable computational cost is proposed. PMID- 26429010 TI - Interatomic scattering in energy dependent photoelectron spectra of Ar clusters. AB - Soft X-ray photoelectron spectra of Ar 2p levels of atomic argon and argon clusters are recorded over an extended range of photon energies. The Ar 2p intensity ratios between atomic argon and clusters' surface and bulk components reveal oscillations similar to photoelectron extended X-ray absorption fine structure signal (PEXAFS). We demonstrate here that this technique allows us to analyze separately the PEXAFS signals from surface and bulk sites of free standing, neutral clusters, revealing a bond contraction at the surface. PMID- 26429011 TI - Observation and deperturbation of near-dissociation ro-vibrational structure of the Cs2 state 0u(+) (A(1)Sigmau(+)~b(3)Pi0+u) at the asymptote 6S1/2 + 6P1/2. AB - New ro-vibrational structures of cold Cs2 in the 0u(+) state near the asymptote 6S1/2 + 6P1/2 are resolved. The variation of the rotational constants shows that the related energy spectra are strongly perturbed. An analysis of new data along with the empirical and theoretical information available from other sources is performed. For this purpose the model of spin-orbit coupling of the Hund's case (a) states A(1)Sigmau(+)~b(3)Piu proposed by Bai et al. [Phys. Rev. A 83, 032514 (2011)] is extrapolated to the dissociation limit, and the parameters of the extrapolation are fitted from the near-dissociation experimental data. PMID- 26429012 TI - How large are nonadiabatic effects in atomic and diatomic systems? AB - With recent developments in simulating nonadiabatic systems to high accuracy, it has become possible to determine how much energy is attributed to nuclear quantum effects beyond zero-point energy. In this work, we calculate the non-relativistic ground-state energies of atomic and molecular systems without the Born Oppenheimer approximation. For this purpose, we utilize the fixed-node diffusion Monte Carlo method, in which the nodes depend on both the electronic and ionic positions. We report ground-state energies for all systems studied, ionization energies for the first-row atoms and atomization energies for the first-row hydrides. We find the ionization energies of the atoms to be nearly independent of the Born-Oppenheimer approximation, within the accuracy of our results. The atomization energies of molecular systems, however, show small effects of the nonadiabatic coupling between electrons and nuclei. PMID- 26429013 TI - Photodissociation spectroscopy of the dysprosium monochloride molecular ion. AB - We have performed a combined experimental and theoretical study of the photodissociation cross section of the molecular ion DyCl(+). The photodissociation cross section for the photon energy range 35,500 cm(-1) to 47,500 cm(-1) is measured using an integrated ion trap and time-of-flight mass spectrometer; we observe a broad, asymmetric profile that is peaked near 43,000 cm(-1). The theoretical cross section is determined from electronic potentials and transition dipole moments calculated using the relativistic configuration interaction valence-bond and coupled-cluster methods. The electronic structure of DyCl(+) is extremely complex due to the presence of multiple open electronic shells, including the 4f(10) configuration. The molecule has nine attractive potentials with ionically bonded electrons and 99 repulsive potentials dissociating to a ground state Dy(+) ion and Cl atom. We explain the lack of symmetry in the cross section as due to multiple contributions from one-electron dominated transitions between the vibrational ground state and several resolved repulsive excited states. PMID- 26429014 TI - Structure, stability, and superconductivity of new Xe-H compounds under high pressure. AB - Application of high pressure can substantially enhance the chemical reactivity of xenon and has recently extended the Xe-compounds to unexpected elements such as Fe and H. Using unbiased structure searching techniques combined with first principles calculations, we predict novel compounds of stable XeH2 and XeH4, and metastable XeH, XeH3, XeH5, XeH6, XeH7, and XeH8 under high pressure. Rather than van der Waals complexes, these are weakly covalent or ionic compounds stabilized by a pressure-induced increase in charge transfer from Xe to H atoms. The calculated electronic structures with hybrid exchange-correlation functionals reveal that only XeH and XeH2 are metalized under 300 GPa. For the metallic XeH and XeH2 at certain pressures, the superconducting critical temperatures are finally studied, by using Allen-Dynes modified McMillan equation combined with the calculated electron-phonon coupling parameter. PMID- 26429015 TI - Microwave spectra and structure of the cyclopropanecarboxylic acid-formic acid dimer. AB - The rotational spectrum of the cyclopropanecarboxylic acid-formic acid doubly hydrogen bonded dimer has been measured in the 4-11 GHz region using a Flygare Balle type pulsed-beam Fourier transform microwave spectrometer. Rotational transitions were measured for the parent, four unique singly substituted (13)C isotopologues, and a singly deuterated isotopologue. Splittings due to a possible concerted double proton tunneling motion were not observed. Rotational constants (A, B, and C) and centrifugal distortion constants (DJ and DJK) were determined from the measured transitions for the dimer. The values of the rotational (in MHz) and centrifugal distortion constants (in kHz) for the parent isotopologue are A = 4045.4193(16), B = 740.583 80(14), C = 658.567 60(23), DJ = 0.0499(16), and DJK = 0.108(14). A partial gas phase structure of the dimer was derived from the rotational constants of the measured isotopologues, previous structural work on each monomer units and results of the calculations. PMID- 26429016 TI - High reactivity of nanosized niobium oxide cluster cations in methane activation: A comparison with vanadium oxides. AB - The reactions between methane and niobium oxide cluster cations were studied and compared to those employing vanadium oxides. Hydrogen atom abstraction (HAA) reactions were identified over stoichiometric (Nb2O5)N(+) clusters for N as large as 14 with a time-of-flight mass spectrometer. The reactivity of (Nb2O5)N(+) clusters decreases as the N increases, and it is higher than that of (V 2O5)N(+) for N >= 4. Theoretical studies were conducted on (Nb2O5)N(+) (N = 2-6) by density functional calculations. HAA reactions on these clusters are all favorable thermodynamically and kinetically. The difference of the reactivity with respect to the cluster size and metal type (Nb vs V) was attributed to thermodynamics, kinetics, the electron capture ability, and the distribution of the unpaired spin density. Nanosized Nb oxide clusters show higher HAA reactivity than V oxides, indicating that niobia may serve as promising catalysts for practical methane conversion. PMID- 26429017 TI - Line mixing in parallel and perpendicular bands of CO2: A further test of the refined Robert-Bonamy formalism. AB - Starting from the refined Robert-Bonamy formalism [Q. Ma, C. Boulet, and R. H. Tipping, J. Chem. Phys. 139, 034305 (2013)], we propose here an extension of line mixing studies to infrared absorptions of linear polyatomic molecules having stretching and bending modes. The present formalism does not neglect the internal degrees of freedom of the perturbing molecules, contrary to the energy corrected sudden (ECS) modelling, and enables one to calculate the whole relaxation matrix starting from the potential energy surface. Meanwhile, similar to the ECS modelling, the present formalism properly accounts for roles played by all the internal angular momenta in the coupling process, including the vibrational angular momentum. The formalism has been applied to the important case of CO2 broadened by N2. Applications to two kinds of vibrational bands (Sigma -> Sigma and Sigma -> Pi) have shown that the present results are in good agreement with both experimental data and results derived from the ECS model. PMID- 26429018 TI - Nucleation of liquid droplets and voids in a stretched Lennard-Jones fcc crystal. AB - The method of molecular dynamics simulation has been used to investigate the phase decay of a metastable Lennard-Jones face-centered cubic crystal at positive and negative pressures. It is shown that at high degrees of metastability, crystal decay proceeds through the spontaneous formation and growth of new-phase nuclei. It has been found that there exists a certain boundary temperature. Below this temperature, the crystal phase disintegrates as the result of formation of voids, and above, as a result of formation of liquid droplets. The boundary temperature corresponds to the temperature of cessation of a crystal-liquid phase equilibrium when the melting line comes in contact with the spinodal of the stretched liquid. The results of the simulations are interpreted in the framework of classical nucleation theory. The thermodynamics of phase transitions in solids has been examined with allowance for the elastic energy of stresses arising owing to the difference in the densities of the initial and the forming phases. As a result of the action of elastic forces, at negative pressures, the boundary of the limiting superheating (stretching) of a crystal approaches the spinodal, on which the isothermal bulk modulus of dilatation becomes equal to zero. At the boundary of the limiting superheating (stretching), the shape of liquid droplets and voids is close to the spherical one. PMID- 26429019 TI - Pressure in the Landau-Ginzburg functional: Pascal's law, nucleation in fluid mixtures, a meanfield theory of amphiphilic action, and interface wetting in glassy liquids. AB - We set up the problem of finding the transition state for phase nucleation in multi-component fluid mixtures, within the Landau-Ginzburg density functional. We establish an expression for the coordinate-dependent local pressure that applies to mixtures, arbitrary geometries, and certain non-equilibrium configurations. The expression allows one to explicitly evaluate the pressure in spherical geometry, a la van der Waals. Pascal's law is recovered within the Landau Ginzburg density functional theory, formally analogously to how conservation of energy is recovered in the Lagrangian formulation of mechanics. We establish proper boundary conditions for certain singular functional forms of the bulk free energy density that allow one to obtain droplet solutions with thick walls in essentially closed form. The hydrodynamic modes responsible for mixing near the interface are explicitly identified in the treatment; the composition at the interface is found to depend only weakly on the droplet size. Next we develop a Landau-Ginzburg treatment of the effects of amphiphiles on the surface tension; the amphiphilic action is seen as a violation of Pascal's law. We explicitly obtain the binding potential for the detergent at the interface and the dependence of the down-renormalization of the surface tension on the activity of the detergent. Finally, we argue that the renormalization of the activation barrier for escape from long-lived structures in glassy liquids can be viewed as an action of uniformly seeded, randomly oriented amphiphilic molecules on the interface separating two dissimilar aperiodic structures. This renormalization is also considered as a "wetting" of the interface. The resulting conclusions are consistent with the random first order transition theory. PMID- 26429020 TI - Fluid-solid transition in simple systems using density functional theory. AB - A free energy functional for a crystal which contains both the symmetry-conserved and symmetry-broken parts of the direct pair correlation function has been used to investigate the fluid-solid transition in systems interacting via purely repulsive Weeks-Chandler-Anderson Lennard-Jones potential and the full Lennard Jones potential. The results found for freezing parameters for the fluid-face centred cubic crystal transition are in very good agreement with simulation results. It is shown that although the contribution made by the symmetry broken part to the grand thermodynamic potential at the freezing point is small compared to that of the symmetry conserving part, its role is crucial in stabilizing the crystalline structure and on values of the freezing parameters. PMID- 26429021 TI - Ludwig-Soret effect of aqueous solutions of ethylene glycol oligomers, crown ethers, and glycerol: Temperature, molecular weight, and hydrogen bond effect. AB - The thermal diffusion, also called the Ludwig-Soret effect, of aqueous solutions of ethylene glycol oligomers, crown ethers, and glycerol is investigated as a function of temperature by thermal diffusion forced Rayleigh scattering. The Soret coefficient, ST, and the thermal diffusion coefficient, DT, show a linear temperature dependence for all studied compounds in the investigated temperature range. The magnitudes and the slopes of ST and DT vary with the chemical structure of the solute molecules. All studied molecules contain ether and/or hydroxyl groups, which can act as acceptor or donor to form hydrogen bonds, respectively. By introducing the number of donor and acceptor sites of each solute molecule, we can express their hydrogen bond capability. ST and DT can be described by an empirical equation depending on the difference of donor minus acceptor sites and the molecular weight of the solute molecule. PMID- 26429022 TI - Separation of experimental 2D IR frequency-frequency correlation functions into structural and reorientation-induced contributions. AB - A vibrational transition frequency can couple to its environment through a directional vector interaction. In such cases, reorientation of the vibrational transition dipole (molecular orientational relaxation) and its frequency fluctuations can be strongly coupled. It was recently shown [Kramer et al., J. Chem. Phys. 142, 184505 (2015)] that differing frequency-frequency correlation function (FFCF) decays, due to reorientation-induced spectral diffusion (RISD), are observed with different two-dimensional infrared polarization configurations when such strong coupling is present. The FFC functional forms were derived for the situation in which all spectral diffusion is due to reorientational motion. We extend the previous theory to include vibrational frequency evolution (spectral diffusion) caused by structural fluctuations of the medium. Model systems with diffusive reorientation and several regimes of structural spectral diffusion rates are analyzed for first order Stark effect interactions. Additionally, the transition dipole reorientational motion in complex environments is frequently not completely diffusive. Several periods of restricted angular motion (wobbling-in-a-cone) may precede the final diffusive orientational randomization. The polarization-weighted FFCF decays are presented in this case of restricted transition dipole wobbling. With these extensions to the polarization-dependent FFCF expressions, the structural spectral diffusion dynamics of methanol in the room temperature ionic liquid 1-hexyl-3 methylimidazolium hexafluorophosphate can be separated quantitatively from RISD using the experimental center line slope data. In addition, prior results on the spectral diffusion of water, methanol, and ethanol in 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide are re-examined to elucidate the influence of reorientation on the data, which were interpreted in terms of structural fluctuations. PMID- 26429023 TI - Molecular simulation of homogeneous nucleation of crystals of an ionic liquid from the melt. AB - The homogeneous nucleation of crystals of the ionic liquid [dmim(+)][Cl(-)] from its supercooled liquid phase in the bulk (P = 1 bar, T = 340 K, representing a supercooling of 58 K) was studied using molecular simulations. The string method in collective variables [Maragliano et al., J. Chem. Phys. 125, 024106 (2006)] was used in combination with Markovian milestoning with Voronoi tessellations [Maragliano et al., J. Chem. Theory Comput. 5, 2589-2594 (2009)] and order parameters for molecular crystals [E. E. Santiso and B. L. Trout, J. Chem. Phys. 134, 064109 (2011)] to sketch a minimum free energy path connecting the supercooled liquid and the monoclinic crystal phases, and to determine the free energy and the rates involved in the homogeneous nucleation process. The physical significance of the configurations found along this minimum free energy path is discussed with the help of calculations based on classical nucleation theory and with additional simulation results obtained for a larger system. Our results indicate that, at a supercooling of 58 K, the liquid has to overcome a free energy barrier of the order of 60 kcal/mol and to form a critical nucleus with an average size of about 3.6 nm, before it reaches the thermodynamically stable crystal phase. A simulated homogeneous nucleation rate of 5.0 * 10(10) cm(-3) s( 1) was obtained for our system, which is in reasonable agreement with experimental and simulation rates for homogeneous nucleation of ice at similar degrees of supercooling. This study represents our first step in a series of studies aimed at understanding the nucleation and growth of crystals of organic salts near surfaces and inside nanopores. PMID- 26429024 TI - Molecular dynamics simulations of the structure and single-particle dynamics of mixtures of divalent salts and ionic liquids. AB - We report a molecular dynamics study of the structure and single-particle dynamics of mixtures of a protic (ethylammonium nitrate) and an aprotic (1-butyl 3-methylimidazolium hexaflurophosphate [BMIM][PF6]) room-temperature ionic liquids doped with magnesium and calcium salts with a common anion at 298.15 K and 1 atm. The solvation of these divalent cations in dense ionic environments is analyzed by means of apparent molar volumes of the mixtures, radial distribution functions, and coordination numbers. For the protic mixtures, the effect of salt concentration on the network of hydrogen bonds is also considered. Moreover, single-particle dynamics of the salt cations is studied by means of their velocity autocorrelation functions and vibrational densities of states, explicitly analyzing the influence of salt concentration, and cation charge and mass on these magnitudes. The effect of the valency of the salt cation on these properties is considered comparing the results with those for the corresponding mixtures with lithium salts. We found that the main structural and dynamic features of the local solvation of divalent cations in ionic liquids are similar to those of monovalent salts, with cations being localized in the polar nanoregions of the bulk mixture coordinated in monodentate and bidentate coordination modes by the [NO3](-) and [PF6](-) anions. However, stronger electrostatic correlations of these polar nanoregions than in mixtures with salts with monovalent cations are found. The vibrational modes of the ionic liquid (IL) are seen to be scarcely affected by the addition of the salt, and the effect of mass and charge on the vibrational densities of states of the dissolved cations is reported. Cation mass is seen to exert a deeper influence than charge on the low-frequency vibrational spectra, giving a red shift of the vibrational modes and a virtual suppression of the higher energy vibrational modes for the heavier Ca(2+) cations. No qualitative difference with monovalent cations was found in what solvation is concerned, which suggests that no enhanced reduction of the mobility of these cations and their complexes in ILs respective to those of monovalent cations is to be expected. PMID- 26429025 TI - A first-principle calculation of the XANES spectrum of Cu(2+) in water. AB - The progress in high performance computing we are witnessing today offers the possibility of accurate electron density calculations of systems in realistic physico-chemical conditions. In this paper, we present a strategy aimed at performing a first-principle computation of the low energy part of the X-ray Absorption Spectroscopy (XAS) spectrum based on the density functional theory calculation of the electronic potential. To test its effectiveness, we apply the method to the computation of the X-ray absorption near edge structure part of the XAS spectrum in the paradigmatic, but simple case of Cu(2+) in water. In order to keep into account the effect of the metal site structure fluctuations in determining the experimental signal, the theoretical spectrum is evaluated as the average over the computed spectra of a statistically significant number of simulated metal site configurations. The comparison of experimental data with theoretical calculations suggests that Cu(2+) lives preferentially in a square pyramidal geometry. The remarkable success of this approach in the interpretation of XAS data makes us optimistic about the possibility of extending the computational strategy we have outlined to the more interesting case of molecules of biological relevance bound to transition metal ions. PMID- 26429026 TI - Double-walled carbon nanotube array for CO2 and SO2 adsorption. AB - Grand-canonical Monte Carlo simulations and adsorption experiments are combined to find the optimized carbon nanotube (CNT) arrays for gas adsorption at low pressures and 303 K. Bundles of 3D aligned double-walled carbon nanotube (DWCNT) with inner diameter of 8 nm and different intertube distances were made experimentally. The experimental results show that decreasing intertube distance leads to a significant enhancement in carbon-dioxide (CO2) adsorption capacity at 1 bar. The molecular simulation study on CO2 adsorption onto bundles of 3D aligned DWCNT with inner diameters of 1, 3, and 8 nm and intertube distance of 0 15 nm shows that the intertube distance plays a more important role than the CNT diameter. The simulation results show that decreasing the intertube distance up to 1 nm increases the excess adsorption generally in all the studied systems at pressures 0 < p < 14 bars (the increase can be up to ~40% depending on the system and pressure). This is in agreement with the experimental result. Further reduction in intertube distance leads to a decrease in the excess adsorption in the pressure range 9 < p < 14 bars. However, at lower pressure, 0 < p < 9 bars, intertube distance of 0.5 nm is found to have the highest excess adsorption. This result is indifferent to tube diameter. Furthermore, molecular simulations are conducted to obtain the optimal parameters, for the DWCNT bundle, for SO2 adsorption, which are similar to those observed for CO2 in the pressure range 0 < p < 3 bars. PMID- 26429027 TI - Toward ab initio molecular dynamics modeling for sum-frequency generation spectra; an efficient algorithm based on surface-specific velocity-velocity correlation function. AB - Interfacial water structures have been studied intensively by probing the O-H stretch mode of water molecules using sum-frequency generation (SFG) spectroscopy. This surface-specific technique is finding increasingly widespread use, and accordingly, computational approaches to calculate SFG spectra using molecular dynamics (MD) trajectories of interfacial water molecules have been developed and employed to correlate specific spectral signatures with distinct interfacial water structures. Such simulations typically require relatively long (several nanoseconds) MD trajectories to allow reliable calculation of the SFG response functions through the dipole moment-polarizability time correlation function. These long trajectories limit the use of computationally expensive MD techniques such as ab initio MD and centroid MD simulations. Here, we present an efficient algorithm determining the SFG response from the surface-specific velocity-velocity correlation function (ssVVCF). This ssVVCF formalism allows us to calculate SFG spectra using a MD trajectory of only ~100 ps, resulting in the substantial reduction of the computational costs, by almost an order of magnitude. We demonstrate that the O-H stretch SFG spectra at the water-air interface calculated by using the ssVVCF formalism well reproduce those calculated by using the dipole moment-polarizability time correlation function. Furthermore, we applied this ssVVCF technique for computing the SFG spectra from the ab initio MD trajectories with various density functionals. We report that the SFG responses computed from both ab initio MD simulations and MD simulations with an ab initio based force field model do not show a positive feature in its imaginary component at 3100 cm(-1). PMID- 26429028 TI - Quantum dynamics of hydrogen atoms on graphene. I. System-bath modeling. AB - An accurate system-bath model to investigate the quantum dynamics of hydrogen atoms chemisorbed on graphene is presented. The system comprises a hydrogen atom and the carbon atom from graphene that forms the covalent bond, and it is described by a previously developed 4D potential energy surface based on density functional theory ab initio data. The bath describes the rest of the carbon lattice and is obtained from an empirical force field through inversion of a classical equilibrium correlation function describing the hydrogen motion. By construction, model building easily accommodates improvements coming from the use of higher level electronic structure theory for the system. Further, it is well suited to a determination of the system-environment coupling by means of ab initio molecular dynamics. This paper details the system-bath modeling and shows its application to the quantum dynamics of vibrational relaxation of a chemisorbed hydrogen atom, which is here investigated at T = 0 K with the help of the multi-configuration time-dependent Hartree method. Paper II deals with the sticking dynamics. PMID- 26429029 TI - Quantum dynamics of hydrogen atoms on graphene. II. Sticking. AB - Following our recent system-bath modeling of the interaction between a hydrogen atom and a graphene surface [Bonfanti et al., J. Chem. Phys. 143, 124703 (2015)], we present the results of converged quantum scattering calculations on the activated sticking dynamics. The focus of this study is the collinear scattering on a surface at zero temperature, which is treated with high-dimensional wavepacket propagations with the multi-configuration time-dependent Hartree method. At low collision energies, barrier-crossing dominates the sticking and any projectile that overcomes the barrier gets trapped in the chemisorption well. However, at high collision energies, energy transfer to the surface is a limiting factor, and fast H atoms hardly dissipate their excess energy and stick on the surface. As a consequence, the sticking coefficient is maximum (~0.65) at an energy which is about one and half larger than the barrier height. Comparison of the results with classical and quasi-classical calculations shows that quantum fluctuations of the lattice play a primary role in the dynamics. A simple impulsive model describing the collision of a classical projectile with a quantum surface is developed which reproduces the quantum results remarkably well for all but the lowest energies, thereby capturing the essential physics of the activated sticking dynamics investigated. PMID- 26429030 TI - Vibrational dynamics and band structure of methyl-terminated Ge(111). AB - A combined synthesis, experiment, and theory approach, using elastic and inelastic helium atom scattering along with ab initio density functional perturbation theory, has been used to investigate the vibrational dynamics and band structure of a recently synthesized organic-functionalized semiconductor interface. Specifically, the thermal properties and lattice dynamics of the underlying Ge(111) semiconductor crystal in the presence of a commensurate (1 * 1) methyl adlayer were defined for atomically flat methylated Ge(111) surfaces. The mean-square atomic displacements were evaluated by analysis of the thermal attenuation of the elastic He diffraction intensities using the Debye-Waller model, revealing an interface with hybrid characteristics. The methyl adlayer vibrational modes are coupled with the Ge(111) substrate, resulting in significantly softer in-plane motion relative to rigid motion in the surface normal. Inelastic helium time-of-flight measurements revealed the excitations of the Rayleigh wave across the surface Brillouin zone, and such measurements were in agreement with the dispersion curves that were produced using density functional perturbation theory. The dispersion relations for H-Ge(111) indicated that a deviation in energy and lineshape for the Rayleigh wave was present along the nearest-neighbor direction. The effects of mass loading, as determined by calculations for CD3-Ge(111), as well as by force constants, were less significant than the hybridization between the Rayleigh wave and methyl adlayer librations. The presence of mutually similar hybridization effects for CH3 Ge(111) and CH3-Si(111) surfaces extends the understanding of the relationship between the vibrational dynamics and the band structure of various semiconductor surfaces that have been functionalized with organic overlayers. PMID- 26429031 TI - Sustained magnetization oscillations in polyaniline-Fe3O4 nanocomposites. AB - We report experiments with polyaniline-Fe3O4 (PANI-Fe3O4) nanocomposites synthesized under several different conditions. With a reaction carried out at room temperature and assisted by intense ultra-violet (UV) irradiation, we observe sustained oscillations in the magnetization with a period of about 25 min. The oscillations are interpreted as the result of an oscillatory chemical reaction in which part of the Fe(+2) ions of magnetite, Fe3O4, are oxidized by the UV irradiation to form Fe(+3) so that a fraction of the magnetite content transforms into maghemite, gamma-Fe2O3. Then, Fe(+3) ions at the nanoparticle surfaces are reduced and transformed back into Fe(+2), when acting as an oxidizing agent for polyaniline in the polymerization process. Since maghemite has smaller magnetization than magnetite, the oscillating chemical reaction results in the oscillatory magnetization. The observations are interpreted with the Lotka-Volterra nonlinear coupled equations with parameters that can be adjusted to fit very well the experimental data. PMID- 26429032 TI - Accurate determination of complex chi(2) spectrum of the air/water interface. AB - Discussion on the structure of the water surface relies on accurate determination of the chi(2) spectrum. For obtaining accurate chi(2) spectrum of the air/water interface in the OH stretch region, we performed heterodyne-detected vibrational sum-frequency generation measurements with a high phase accuracy, and also examined the validity of the phase and amplitude calibration using different non resonant materials. In contrast to the previous reports, it was concluded that the imaginary part of the chi(2) spectrum of the air/water interface does not exhibit noticeable positive resonance in the low frequency region within the experimental error. This result urges us to reconsider the structure of the air/water interface based on the accurate chi(2) spectrum. PMID- 26429033 TI - An accurate full-dimensional potential energy surface for H-Au(111): Importance of nonadiabatic electronic excitation in energy transfer and adsorption. AB - We have constructed a potential energy surface (PES) for H-atoms interacting with fcc Au(111) based on fitting the analytic form of the energy from Effective Medium Theory (EMT) to ab initio energy values calculated with density functional theory. The fit used input from configurations of the H-Au system with Au atoms at their lattice positions as well as configurations with the Au atoms displaced from their lattice positions. It reproduces the energy, in full dimension, not only for the configurations used as input but also for a large number of additional configurations derived from ab initio molecular dynamics (AIMD) trajectories at finite temperature. Adiabatic molecular dynamics simulations on this PES reproduce the energy loss behavior of AIMD. EMT also provides expressions for the embedding electron density, which enabled us to develop a self-consistent approach to simulate nonadiabatic electron-hole pair excitation and their effect on the motion of the incident H-atoms. For H atoms with an energy of 2.7 eV colliding with Au, electron-hole pair excitation is by far the most important energy loss pathway, giving an average energy loss ~3 times that of the adiabatic case. This increased energy loss enhances the probability of the H-atom remaining on or in the Au slab by a factor of 2. The most likely outcome for H-atoms that are not scattered also depends prodigiously on the energy transfer mechanism; for the nonadiabatic case, more than 50% of the H-atoms which do not scatter are adsorbed on the surface, while for the adiabatic case more than 50% pass entirely through the 4 layer simulation slab. PMID- 26429034 TI - Probing protein orientation near charged nanosurfaces for simulation-assisted biosensor design. AB - Protein-surface interactions are ubiquitous in biological processes and bioengineering, yet are not fully understood. In biosensors, a key factor determining the sensitivity and thus the performance of the device is the orientation of the ligand molecules on the bioactive device surface. Adsorption studies thus seek to determine how orientation can be influenced by surface preparation, varying surface charge, and ambient salt concentration. In this work, protein orientation near charged nanosurfaces is obtained under electrostatic effects using the Poisson-Boltzmann equation, in an implicit solvent model. Sampling the free energy for protein G B1 D4' at a range of tilt and rotation angles with respect to the charged surface, we calculated the probability of the protein orientations and observed a dipolar behavior. This result is consistent with published experimental studies and combined Monte Carlo and molecular dynamics simulations using this small protein, validating our method. More relevant to biosensor technology, antibodies such as immunoglobulin G are still a formidable challenge to molecular simulation, due to their large size. With the Poisson-Boltzmann model, we obtained the probability distribution of orientations for the iso-type IgG2a at varying surface charge and salt concentration. This iso-type was not found to have a preferred orientation in previous studies, unlike the iso-type IgG1 whose larger dipole moment was assumed to make it easier to control. Our results show that the preferred orientation of IgG2a can be favorable for biosensing with positive charge on the surface of 0.05 C/m(2) or higher and 37 mM salt concentration. The results also show that local interactions dominate over dipole moment for this protein. Improving immunoassay sensitivity may thus be assisted by numerical studies using our method (and open source code), guiding changes to fabrication protocols or protein engineering of ligand molecules to obtain more favorable orientations. PMID- 26429035 TI - Rayleigh-type parametric chemical oscillation. AB - We consider a nonlinear chemical dynamical system of two phase space variables in a stable steady state. When the system is driven by a time-dependent sinusoidal forcing of a suitable scaling parameter at a frequency twice the output frequency and the strength of perturbation exceeds a threshold, the system undergoes sustained Rayleigh-type periodic oscillation, wellknown for parametric oscillation in pipe organs and distinct from the usual forced quasiperiodic oscillation of a damped nonlinear system where the system is oscillatory even in absence of any external forcing. Our theoretical analysis of the parametric chemical oscillation is corroborated by full numerical simulation of two well known models of chemical dynamics, chlorite-iodine-malonic acid and iodine-clock reactions. PMID- 26429036 TI - Relaxation times and modes of disturbed aggregate distribution in micellar solutions with fusion and fission of micelles. AB - We have performed direct numerical calculations of the kinetics of relaxation in the system of surfactant spherical micelles under joint action of the molecular mechanism with capture and emission of individual surfactant molecules by molecular aggregates and the mechanism of fusion and fission of the aggregates. As a basis, we have taken the difference equations of aggregation and fragmentation in the form of the generalized kinetic Smoluchowski equations for aggregate concentrations. The calculations have been made with using the droplet model of molecular surfactant aggregates and two modified Smoluchowski models for the coefficients of aggregate-monomer and aggregate-aggregate fusions which take into account the effects of the aggregate size and presence of hydrophobic spots on the aggregate surface. A full set of relaxation times and corresponding relaxation modes for nonequilibrium aggregate distribution in the aggregation number has been found. The dependencies of these relaxation times and modes on the total concentration of surfactant in the solution and the special parameter controlling the probability of fusion in collisions of micelles with other micelles have been studied. PMID- 26429037 TI - Persistent draining crossover in DNA and other semi-flexible polymers: Evidence from hydrodynamic models and extensive measurements on DNA solutions. AB - Although the scaling theory of polymer solutions has had many successes, this type of argument is deficient when applied to hydrodynamic solution properties. Since the foundation of polymer science, it has been appreciated that measurements of polymer size from diffusivity, sedimentation, and solution viscosity reflect a convolution of effects relating to polymer geometry and the strength of the hydrodynamic interactions within the polymer coil, i.e., "draining." Specifically, when polymers are expanded either by self-excluded volume interactions or inherent chain stiffness, the hydrodynamic interactions within the coil become weaker. This means there is no general relationship between static and hydrodynamic size measurements, e.g., the radius of gyration and the hydrodynamic radius. We study this problem by examining the hydrodynamic properties of duplex DNA in solution over a wide range of molecular masses both by hydrodynamic modeling using a numerical path-integration method and by comparing with extensive experimental observations. We also considered how excluded volume interactions influence the solution properties of DNA and confirm that excluded volume interactions are rather weak in duplex DNA in solution so that the simple worm-like chain model without excluded volume gives a good leading-order description of DNA for molar masses up to 10(7) or 10(8) g/mol or contour lengths between 5 MUm and 50 MUm. Since draining must also depend on the detailed chain monomer structure, future work aiming to characterize polymers in solution through hydrodynamic measurements will have to more carefully consider the relation between chain molecular structure and hydrodynamic solution properties. In particular, scaling theory is inadequate for quantitative polymer characterization. PMID- 26429038 TI - Dynamics of flexible fibers in shear flow. AB - Dynamics of flexible non-Brownian fibers in shear flow at low-Reynolds-number are analyzed numerically for a wide range of the ratios A of the fiber bending force to the viscous drag force. Initially, the fibers are aligned with the flow, and later they move in the plane perpendicular to the flow vorticity. A surprisingly rich spectrum of different modes is observed when the value of A is systematically changed, with sharp transitions between coiled and straightening out modes, period-doubling bifurcations from periodic to migrating solutions, irregular dynamics, and chaos. PMID- 26429039 TI - Solvent controlled ion association in structured copolymers: Molecular dynamics simulations in dilute solutions. AB - Tailoring the nature of individual segments within ion containing block co polymers is one critical design tool to achieve desired properties. The local structure including the size and distribution of the ionic blocks, as well as the long range correlations, are crucial for their transport ability. Here, we present molecular dynamics simulations on the effects of varying the concentrations of the ionizable groups on the conformations of pentablock ionomer that consist of a center block of ionic sulfonated styrene tethered to polyethylene and terminated by a bulky substituted styrene in dilute solutions. Sulfonation fractions f (0 <= f <= 0.55), spanning the range from ionomer to polyelectrolytes, were studied. Results for the equilibrium conformation of the chains in water and a 1:1 mixture of cyclohexane and heptane are compared to that in implicit poor solvents with dielectric constants epsilon = 1.0 and 77.73. In water, the pentablock collapses with the sulfonated groups on the outer surface. As f increases, the ionic, center block increasingly segregates from the hydrophobic regions. In the 1:1 mixture of cyclohexane and heptane, the flexible blocks swell, while the center ionic block collapses for f > 0. For f = 0, all blocks swell. In both implicit poor solvents, the pentablock collapses into a nearly spherical shape for all f. The sodium counterions disperse widely throughout the simulation cell for both water and epsilon = 77.73, whereas for epsilon = 1.0 and mixture of cyclohexane and heptane, the counterions largely condense onto the collapsed pentablock. PMID- 26429040 TI - Perturbation theory for multicomponent fluids based on structural properties of hard-sphere chain mixtures. AB - An analytical expression for the Laplace transform of the radial distribution function of a mixture of hard-sphere chains of arbitrary segment size and chain length is used to rigorously formulate the first-order Barker-Henderson perturbation theory for the contribution of the segment-segment dispersive interactions into thermodynamics of the Lennard-Jones chain mixtures. Based on this approximation, a simple variant of the statistical associating fluid theory is proposed and used to predict properties of several mixtures of chains of different lengths and segment sizes. The theory treats the dispersive interactions more rigorously than the conventional theories and provides means for more accurate description of dispersive interactions in the mixtures of highly asymmetric components. PMID- 26429041 TI - Unraveling the luminescence signatures of chemical defects in polyethylene. AB - Chemical defects in polyethylene (PE) can deleteriously downgrade its electrical properties and performance. Although these defects usually leave spectroscopic signatures in terms of characteristic luminescence peaks, it is nontrivial to make unambiguous assignments of the peaks to specific defect types. In this work, we go beyond traditional density functional theory calculations to determine intra-defect state transition and charge recombination process derived emission and absorption energies in PE. By calculating the total energy differences of the neutral defect at excited and ground states, the emission energies from intra defect state transition are obtained, reasonably explaining the photoluminescence peaks in PE. In order to study the luminescence emitted in charge recombination processes, we characterize PE defect levels in terms of thermodynamic and optical charge transition levels that involve total energy calculations of neutral and charged defects. Calculations are performed at several levels of theory including those involving (semi)local and hybrid electron exchange-correlation functionals, and many-body perturbation theory. With these critical elements, the emission energies are computed and further used to clarify and confirm the origins of the observed electroluminescence and thermoluminescence peaks. PMID- 26429042 TI - beta-sheet-like formation during the mechanical unfolding of prion protein. AB - Single molecule experiments and simulations have been widely used to characterize the unfolding and folding pathways of different proteins. However, with few exceptions, these tools have not been applied to study prion protein, PrP(C), whose misfolded form PrP(Sc) can induce a group of fatal neurodegenerative diseases. Here, we apply novel atomistic modeling based on potential energy surface exploration to study the constant force unfolding of human PrP at time scales inaccessible with standard molecular dynamics. We demonstrate for forces around 100 pN, prion forms a stable, three-stranded beta-sheet-like intermediate configuration containing residues 155-214 with a lifetime exceeding hundreds of nanoseconds. A mutant without the disulfide bridge shows lower stability during the unfolding process but still forms the three-stranded structure. The simulations thus not only show the atomistic details of the mechanically induced structural conversion from the native alpha-helical structure to the beta-rich like form but also lend support to the structural theory that there is a core of the recombinant PrP amyloid, a misfolded form reported to induce transmissible disease, mapping to C-terminal residues ~160-220. PMID- 26429043 TI - On the physics of thermal-stability changes upon mutations of a protein. AB - It is of great interest from both scientific and practical viewpoints to theoretically predict the thermal-stability changes upon mutations of a protein. However, such a prediction is an intricate task. Up to now, significantly many approaches for the prediction have been reported in the literature. They always include parameters which are adjusted so that the prediction results can be best fitted to the experimental data for a sufficiently large set of proteins and mutations. The inclusion is necessitated to achieve satisfactorily high prediction performance. A problem is that the resulting values of the parameters are often physically meaningless, and the physicochemical factors governing the thermal-stability changes upon mutations are rather ambiguous. Here, we develop a new measure of the thermal stability. Protein folding is accompanied by a large gain of water entropy (the entropic excluded-volume (EV) effect), loss of protein conformational entropy, and increase in enthalpy. The enthalpy increase originates primarily from the following: The energy increase due to the break of protein-water hydrogen bonds (HBs) upon folding cannot completely be cancelled out by the energy decrease brought by the formation of protein intramolecular HBs. We develop the measure on the basis of only these three factors and apply it to the prediction of the thermal-stability changes upon mutations. As a consequence, an approach toward the prediction is obtained. It is distinguished from the previously reported approaches in the following respects: The parameters adjusted in the manner mentioned above are not employed at all, and the entropic EV effect, which is ascribed to the translational displacement of water molecules coexisting with the protein in the system, is fully taken into account using a molecular model for water. Our approach is compared with one of the most popular approaches, FOLD-X, in terms of the prediction performance not only for single mutations but also for double, triple, and higher-fold (up to sevenfold) mutations. It is shown that on the whole our approach and FOLD-X exhibit almost the same performance despite that the latter uses the adjusting parameters. For multiple mutations, however, our approach is far superior to FOLD-X. Five multiple mutations for staphylococcal nuclease lead to highly enhanced stabilities, but we find that this high enhancement arises from the entropic EV effect. The neglect of this effect in FOLD-X is a principal reason for its ill success. A conclusion is that the three factors mentioned above play essential roles in elucidating the thermal-stability changes upon mutations. PMID- 26429044 TI - Ionic liquid induced dehydration and domain closure in lysozyme: FCS and MD simulation. AB - Effect of a room temperature ionic liquid (RTIL, [pmim][Br]) on the structure and dynamics of the protein, lysozyme, is investigated by fluorescence correlation spectroscopy (FCS) and molecular dynamic (MD) simulation. The FCS data indicate that addition of the RTIL ([pmim][Br]) leads to reduction in size and faster conformational dynamics of the protein. The hydrodynamic radius (rH) of lysozyme decreases from 18 A in 0 M [pmim][Br] to 11 A in 1.5 M [pmim][Br] while the conformational relaxation time decreases from 65 MUs to 5 MUs. Molecular origin of the collapse (size reduction) of lysozyme in aqueous RTIL is analyzed by MD simulation. The radial distribution function of water, RTIL cation, and RTIL anion from protein clearly indicates that addition of RTIL causes replacement of interfacial water by RTIL cation ([pmim](+)) from the first solvation layer of the protein providing a comparatively dehydrated environment. This preferential solvation of the protein by the RTIL cation extends up to ~30 A from the protein surface giving rise to a nanoscopic cage of overall radius 42 A. In the nanoscopic cage of the RTIL (42 A), volume fraction of the protein (radius 12 A) is only about 2%. RTIL anion does not show any preferential solvation near protein surface. Comparison of effective radius obtained from simulation and from FCS data suggests that the "dry" protein (radius 12 A) alone diffuses in a nanoscopic cage of RTIL (radius 42 A). MD simulation further reveals a decrease in distance ("domain closure") between the two domains (alpha and beta) of the protein leading to a more compact structure compared to that in the native state. PMID- 26429045 TI - Publisher's Note: "Anisotropic time-resolved solution X-ray scattering patterns from explicit-solvent molecular dynamics" [J. Chem. Phys. 143, 104108 (2015)]. PMID- 26429046 TI - Publisher's Note: "Assignment of the vibrations of the S0, S1, and D0(+) states of perhydrogenated and perdeuterated isotopologues of chlorobenzene" [J. Chem. Phys. 143, 104312 (2015)]. PMID- 26429047 TI - Erratum: "Stochastic many-body perturbation theory for anharmonic molecular vibrations" [J. Chem. Phys. 141, 084105 (2014)]. PMID- 26429048 TI - Erratum: "Stochastic algorithm for size-extensive vibrational self-consistent field methods on fully anharmonic potential energy surfaces" [J. Chem. Phys. 141, 244111 (2014)]. PMID- 26429049 TI - Laparoscopy Combined With Transanal Endoscopic Microsurgery for Rectal Cancer: A Prospective, Single-blinded, Randomized Clinical Trial. AB - OBJECTIVE: To evaluate the efficacy of laparoscopy combined with transanal endoscopic microsurgery (TEM) in the treatment of rectal cancer. METHODS: A total of 60 rectal cancer patients who underwent radical resection from December 2009 to December 2013 were enrolled in this study. All patients were randomly divided to receive either laparoscopic surgery (LA group) or laparoscopy combined with TEM (LT group). Demographics including age and sex, and tumor characteristics including tumor size, distance from anal verge, and preoperative staging were all recorded. The operation time, hospital stay, cases with intraoperative blood transfusion, the number of resected lymph node, postoperative out-of-bed activity, passage of gas by anus, fasting time, and postoperative complications were assessed. RESULTS: Compared with the LA group, patients in the LT group had shorter operation time (118.5+/-22.0 vs. 138.1+/-23.8 min, P=0.002), earlier out of-bed activity (60.4+/-19.2 vs. 83.6+/-9.6 h, P=0.001) and passage of gas by anus (81.4+/-5.4 vs. 86.2+/-8.7 h, P=0.013), and shorter hospital stay (8.0+/-2.8 vs. 11.0+/-3.5 d, P=0.001). Patients were followed up for a median time of 28 months (range, 3 to 48 mo). No local recurrence and distant metastasis occurred in all cases. CONCLUSIONS: Laparoscopy combined with TEM is a feasible and effective treatment for radical excision of middle-upper rectal cancer due to the advantages of lower morbidity and earlier recovery. PMID- 26429050 TI - Evaluation and Comparison of the Early Outcomes of Open and Laparoscopic Surgery of Liver Hydatid Cyst. AB - BACKGROUND AND AIM: Surgery is the mainstay for treatment of liver hydatid cyst. Different surgical procedures have been suggested, but it is important to select the most appropriate treatment to obtain the best results with the lowest rate of recurrence and minimal morbidity and mortality. The aim of this study was to evaluate the early outcomes of open and laparoscopic surgery of hydatidosis. MATERIALS AND METHODS: In this study, 75 patients with uncomplicated liver hydatid cyst were assigned prospectively to either groups of laparoscopic surgery (37, 50.68%) or open procedure (36, 49.32%) during the period of 2007 to 2012. Conversion to open surgery was required in 2 patients (2.67%), who were excluded from the study. Patients were followed for about 17.86+/-17.64 months. RESULTS: Participants included 73 patients: 49 (67.12%) female and 24 (32.88%) male patients, with the mean age of 38.97+/-16.48 years. There was no statistically significant difference between the 2 groups with regard to the sex, the occupation, and the mean diameter of the cysts. Bilious staining of the cyst content was observed in 23 (35.94%) patients during surgery, and a maximum diameter of 91 mm was considered as a cut point for predicting postoperative fistula with 69.2% sensitivity and 41.1% specificity. The mean duration of operation, postoperative pain, the hospitalization time, and the time to return to work were significantly lower in the laparoscopic group. Postoperative biliary fistula, cyst cavity infection, and wound infection were not different between the 2 groups. CONCLUSIONS: Laparoscopic surgery seems to be effective and safe, with low morbidity rates for uncomplicated cysts in accessible segments of the liver. PMID- 26429051 TI - Per-Oral Endoscopic Myotomy (POEM) After Previous Laparoscopic Heller Myotomy Is Feasible and Safe in a Porcine Model. AB - PURPOSE: We sought to evaluate the feasibility, safety, and difficulty of performing the per-oral endoscopic myotomy (POEM) procedure in the setting of a prior Heller myotomy using a survival porcine model. METHODS: Four pigs underwent laparoscopic Heller myotomy with Dor partial anterior fundoplication followed by the POEM performed 4 weeks later. Two additional pigs served as controls, undergoing only the POEM. RESULTS: All procedures were completed without complications. The revisional POEM was not significantly more difficult than POEM controls based on procedure time, POEM procedure components, or procedure difficulty scores. Revisional POEM had a longer mean operative time when compared with Heller myotomy (126.0 vs. 83.8 min; P<0.01) but had a lower total difficulty score (28.6 vs. 52.1; P?0.01). CONCLUSIONS: A POEM after previous Heller myotomy is safe and feasible in the porcine model and has potential as an option for patients suffering from recurrent or persistent symptoms after failed surgical myotomy. PMID- 26429052 TI - The Survival and Complication Rates of Laparoscopic Versus Open Catheter Placement in Peritoneal Dialysis Patients: A Meta-Analysis. AB - The objective of this meta-analysis was to compare the outcomes of laparoscopic insertion method with a conventional open surgery. A systematical search was conducted in PubMed, Embase, and the Cochrane Library up to June 2014. Relative risks (RRs) and their 95% confidence intervals (CIs) were used as estimates. Four randomized-controlled trials and 10 cohort studies involving 2323 patients were identified. The pooled results showed that laparoscopic insertion technique significantly prolonged the 1-year survival (RR=1.23; 95% CI, 1.12-1.35) and 2 year survival (RR=1.36; 95% CI, 1.16-1.60). Meanwhile, laparoscopic insertion significantly decreased the probability of surgical intervention or catheter revision (RR=0.32; 95% CI, 0.15-0.69) and risk of migration (RR=0.31; 95% CI, 0.18-0.53) and obstruction (RR=0.43; 95% CI, 0.28-0.66). Thus, laparoscopic catheter placement may be superior to open surgery in peritoneal dialysis catheter placement. PMID- 26429053 TI - Open Surgery Against Laparoscopic Surgery for Mid-Rectal or Low-Rectal Cancer of Male Patients: Better Postoperative Genital Function of Laparoscopic Surgery. AB - PURPOSE: To evaluate retrospectively the postoperative genital function, the local recurrence, and the survival rate impacted by laparoscopic or open surgery for rectal cancer (RC) in male patients. METHODS: A total of 398 male RC patients after laparoscopic or open total mesorectal excision (TME) of rectomy (205 patients in the TME with laparoscopy group, and 193 patients in the control group) were included in our study, between October 1997 and December 2013. Postoperative genital function, local recurrence, and the 5-year survival rate were analyzed, retrospectively. RESULTS: The rate of erection dysfunction was lower in the laparoscopic group (60.0%) than in the open group (82.4%, P<0.05); the rate of ejaculation dysfunction in the laparoscopic group (56.6%) was also lower than in the open group (82.4%, P<0.05). No significant difference was found regarding the local recurrence (P=0.87) and the survival rate (P=0.17). Interestingly, for patients with preoperative obstruction, the survival rate was lower in the laparoscopy group compared with the control group (P=0.002). CONCLUSIONS: Laparoscopic surgery should be recommended for mid-RC or low-RC patients to preserve the postoperative genital function. However, for patients with preoperative obstruction, laparoscopy surgery was not recommended. PMID- 26429054 TI - Surgical Residents are Excluded From Robot-assisted Surgery. AB - PURPOSE: Implementation of a robotic system may influence surgical training. The aim was to report the charge of the operating surgeon and the bedside assistant at robot-assisted procedures in urology, gynecology, and colorectal surgery. MATERIALS AND METHODS: A review of hospital charts from surgical procedures during a 1-year period from October 2013 to October 2014. All robot-assisted urologic, gynecologic, and colorectal procedures were identified. Charge of both operating surgeon in the console and bedside assistant were registered. RESULTS: A total of 774 robot-assisted procedures were performed. In 10 (1.3%) of these procedures, a resident attended as bedside assistant and never as operating surgeon in the console. CONCLUSIONS: Our results demonstrate a severe problem with surgical education. Robot-assisted surgery is increasingly used; however, robotic surgical training during residency is almost nonexisting. PMID- 26429055 TI - An 8-Year Experience With Endoscopic Management of Eroded Gastric Bands. AB - BACKGROUND/AIMS: We review our 8-year experience with endoscopic removal of eroded gastric bands. MATERIALS AND METHODS: From 2006 to 2014, 25 patients were diagnosed with band erosion. Clinical data concerning the endoscopic procedure were recorded prospectively and reviewed retrospectively. To remove the migrated band, we used an endoscopic approach with a Gastric Band Cutter (GBC). RESULTS: The median time interval from the initial gastric band placement to the diagnosis of band erosion was 41 (18 to 67) months. Upper abdominal pain was the most common symptom (40%). In 24 of the 25 patients, we used the GBC to remove the band endoscopically. It was able to cut the band successfully in all cases except 1, where twisting of the cutting wire required conversion from endoscopy to laparotomy. In 2 cases, the band, after being cut, was locked in the gastric wall and required laparotomic removal. In 1 patient, we had to perform a surgery for intragastric penetration of the connecting tube broken close to the band. Our success rate was 88% in the single session, with no complications. CONCLUSIONS: Endoscopic removal of a migrated band with the GBC seems to be an effective and safe method for band erosion. PMID- 26429056 TI - Laparoscopic Versus Open Resection for Liver Cavernous Hemangioma: A Single Center of 2-Year Experience. AB - OBJECTIVE: To evaluate the feasibility and safety of laparoscopic versus open resection for liver cavernous hemangioma (LCH). MATERIALS AND METHODS: A total of 131 patients suffering from LCH operated in our department between January 2013 and December 2014 were divided into 2 groups: 31 for laparoscopic liver resection (LR) and 100 for open liver resection (OR). RESULTS: Age, sex, presence or absence of chronic liver disease, tumor size, tumor location, type of resection, estimated intraoperative blood loss, operative time, length of postoperative hospital stay, morbidity, and mortality were equivalent between the 2 groups. There were no significant differences in estimated intraoperative blood loss between the LR and OR groups. The operation time of the LR group was longer than the OR group and the hospitalization expenses less than the OR group. However, the time of postoperative hospital stay and time of oral intake were shorter in the LR group than the OR group. The tumor of the LR group was smaller than the OR group. In liver function, alanine aminotransferase after operation of the LR group was lower than the OR group, the same as aspartate transaminase after operation. But there were no significant differences in total bilirubin after operation. CONCLUSIONS: Laparoscopic resection for LCH is a safe and feasible procedure as OR. PMID- 26429057 TI - Case-matched Comparison of Robotic Versus Laparoscopic Colorectal Surgery: Initial Institutional Experience. AB - Robotic colorectal surgery is an emerging technique. In this study, we aimed to compare outcomes of robotic colorectal operations to laparoscopy. Patients undergoing robotic colorectal surgery between November 2010 and July 2013 were case matched to laparoscopic counterparts based on diagnosis and operation type. Perioperative and short-term postoperative outcomes were compared. There were 57 patients who underwent robotic colorectal surgery. American Society of Anaesthesiologists score was higher in patients who underwent robotic surgery (2 vs. 3, P=0.01). Blood loss (200 vs. 300 mL, P=0.27) and conversion rate to open surgery (6 vs. 5, P=0.75) were similar between the groups. Operating time was longer in robotic surgery (172 vs. 267 min, P<0.0001). Time to first bowel movement (3 vs. 3 d, P=0.38), hospital stay (5 vs. 6 d, P=0.22), and postoperative complications were comparable between the groups. In the early learning curve period, robotic colorectal surgery shows similar short-term outcomes with longer operating time compared with conventional laparoscopy. PMID- 26429058 TI - Laparoscopic Bile Duct Clearance Without Choledochoscopy. AB - BACKGROUND: Laparoscopic common bile duct exploration (LCBDE) has been proven to be a safe, efficient, and cost-effective option for the management of common bile duct (CBD) stones. There are two guiding methods during LCBDE: fluoroscopic or choledochoscopic. Most surgeons prefer the use of flexible choledochoscopy at LCBDE, but it is a fragile, delicate, and expensive instrument. The aim of this work was to report our experience in fluoroscopically guided LCBDE. PATIENTS AND METHODS: A retrospective review of all patients who underwent LCBDE in the Mansoura Gastroenterology surgical center between March 2007 and September 2014 was performed. Patients with gallstones and concomitant CBD stones were included. After the initial assessment, all patients fulfilling the criteria of enrollment underwent magnetic resonance cholangiopancreatography, and only patients with magnetic resonance cholangiopancreatography or endoscopic retrograde cholangiopancreatography evidence of CBD stones were included. Choledochoscopy was not used in any patient, and we depended on fluoroscopic guidance for CBD stone retrieval in all LCBDE. RESULTS: A total of 290 patients were assessed for LCBDE: 76 patients were excluded; 11 patients were not completed laparoscopically due to negative intraoperative cholangiography (n=7) and conversion to laparotomy (n=4); the remaining 203 patients were analyzed. LCBDE failed in 16 of the 203 (7.9%) cases, with a success rate of 92.1%. The median operative time was 79 minutes, and the median hospital stay was 2.4 days. Complications were bile leakage (n=4), mild pancreatitis (n=2), wound infection (n=2), port hernia (n=1), and internal hemorrhage (n=1). CONCLUSIONS: Compared with published studies using choledochoscopy at LCBDE, we found comparable results in terms of the success/failure rate, the morbidity and mortality, the operative time, and the length of hospital stay. LCBDE under fluoroscopic guidance may be as safe and efficient as with choledochoscopic guidance. PMID- 26429059 TI - Retrospective Evaluation of Laparoscopic Versus Open Hartmann's Reversal: A Single-Institution Experience. AB - PURPOSE: Restoration of intestinal continuity after Hartmann's procedure has significant associated morbidity. There has been a trend toward increasing utilization of laparoscopy in colorectal surgery, with improvements in short-term outcomes. This study evaluates our experience with laparoscopic Hartmann's procedure reversal. METHODS: All patients who underwent laparoscopic and open reversal of Hartmann's procedure between 2007 and 2010 were reviewed. Demographics, length of stay, postoperative morbidity, and mortality were compared between the 2 groups. RESULTS: Nineteen patients underwent laparoscopic Hartmann's reversal and 62 underwent open reversal. There were no statistically significant differences in demographics, comorbidities, mean operative times, blood loss, reoperation, and readmission rates between the groups. The laparoscopic group had a shorter length of hospitalization (5.7 vs. 7.9 d, P<0.01). CONCLUSIONS: Laparoscopic reversal of Hartmann's pouch is a safe and feasible alternative to the open reversal technique. Patients who undergo the laparoscopic technique have a shorter length of hospital stay. PMID- 26429060 TI - Robot-assisted Laparoscopic Fenestration of Giant Hepatic Cysts. AB - BACKGROUND: Traditionally, nonparasitic hepatic cysts are marsupialized using laparotomy. In the last 2 decades, laparoscopic fenestration has become the preferred treatment for hepatic cysts. However, this technique is limited by 2 dimensional view and the limited mobility of straight laparoscopic instruments. These limitations may be overcome by the use of a robotic system. We describe laparoscopic fenestration of giant hepatic cysts using the da Vinci Si robotic system with the use of the Endowrist One Vessel Sealer. METHODS: Our first patient is a 32-year-old female with a solitary hepatic cyst. The second patient is a 51-year-old female with polycystic liver disease. RESULTS: We performed robot-assisted laparoscopic cyst fenestration with good clinical outcome. No intraoperative complications occurred and patients recovered rapidly. CONCLUSION: These data show that the da Vinci Si robotic system is eminently suited for the laparoscopic fenestration of large hepatic cysts and that this procedure is associated with rapid recovery. PMID- 26429061 TI - Single-Incision Laparoscopic Nontraumatic Left Lateral Diaphragmatic Hernia Repair. AB - Diaphragmatic hernia is a quite uncommon disease, being congenital or posttraumatic. Its diagnosis is frequently accidental. Surgical treatment can be performed through the abdomen as well as through the chest. Laparoscopy and thoracoscopy offer a surgical benefit because of reduced wall trauma and added advantages of minimally invasive surgery. Besides the improved cosmetic result, transumbilical single-incision laparoscopy can add other advantages to minimally invasive surgery like reduced postoperative pain, shorter hospital stay, and improved patient's comfort. The authors describe the technique of transumbilical single-incision laparoscopic suture and mesh reinforcement for a nontraumatic left lateral diaphragmatic hernia, discovered accidentally in a 45-year-old male. PMID- 26429063 TI - Transcription coupled nucleotide excision repair in the yeast Saccharomyces cerevisiae: The ambiguous role of Rad26. AB - Transcription coupled nucleotide excision repair (TC-NER) is believed to be triggered by an RNA polymerase stalled at a lesion in the transcribed strand of actively transcribed genes. Rad26, a DNA-dependent ATPase in the family of SWI2/SNF2 chromatin remodeling proteins, plays an important role in TC-NER in Saccharomyces cerevisiae. However, Rad26 is not solely responsible for TC-NER and Rpb9, a nonessential subunit of RNA polymerase II (RNAP II), is largely responsible for Rad26-independent TC-NER. The Rad26-dependent and Rpb9-dependent TC-NER have different efficiencies in genes with different transcription levels and in different regions of a gene. Rad26 becomes entirely or partially dispensable for TC-NER in the absence of Rpb4, another nonessential subunit of RNAP II, or a number of transcription elongation factors (Spt4, Spt5 and the RNAP II associated factor complex). Rad26 may not be a true transcription-repair coupling factor that recruits the repair machinery to the damaged sites where RNAP II stalls. Rather, Rad26 may facilitate TC-NER indirectly, by antagonizing the action of TC-NER repressors that normally promote transcription elongation. The underlying mechanism of how Rad26 functions in TC-NER remains to be elucidated. PMID- 26429062 TI - Transformation of enriched mammary cell populations with polyomavirus middle T antigen influences tumor subtype and metastatic potential. AB - INTRODUCTION: Breast cancer exhibits significant molecular, histological, and pathological diversity. Factors that impact this heterogeneity are poorly understood; however, transformation of distinct normal cell populations of the breast may generate different tumor phenotypes. Our previous study demonstrated that the polyomavirus middle T antigen (PyMT) oncogene can establish diverse tumor subtypes when broadly expressed within mouse mammary epithelial cells. In the present study, we assessed the molecular, histological, and metastatic outcomes in distinct mammary cell populations transformed with the PyMT gene. METHODS: Isolated mouse mammary epithelial cells were transduced with a lentivirus encoding PyMT during an overnight infection and then sorted into hormone receptor-positive luminal (CD133+), hormone receptor-negative luminal (CD133-), basal, and stem cell populations using the cell surface markers CD24, CD49f, and CD133. Each population was subsequently transplanted into syngeneic cleared mouse mammary fat pads to generate tumors. Tumors were classified by histology, estrogen receptor status, molecular subtype, and metastatic potential to investigate whether transformation of different enriched populations affects tumor phenotype. RESULTS: Although enriched mammary epithelial cell populations showed no difference in either the ability to form tumors or tumor latency, differences in prevalence of solid adenocarcinomas and squamous, papillary, and sebaceous-like tumors were observed. In particular, squamous metaplasia was observed more frequently in tumors derived from basal and stem cells than in luminal cells. Interestingly, both molecularly basal and luminal tumors developed from luminal CD133+, basal, and stem cell populations; however, luminal CD133- cells gave rise exclusively to molecularly basal tumors. Tumors arising from the luminal CD133-, basal, and stem cell populations were highly metastatic; however, luminal CD133+ cells generated tumors that were significantly less metastatic, possibly due to an inability of these tumor cells to escape the primary tumor site. CONCLUSIONS: Expression of PyMT within different mammary cell populations influences tumor histology, molecular subtype, and metastatic potential. The data demonstrate that luminal CD133+ cells give rise to less metastatic tumors, luminal CD133- cells preferentially establish basal tumors, and the cell of origin for squamous metaplasia likely resides in the basal and stem cell populations. PMID- 26429065 TI - Nucleosome positioning, nucleotide excision repair and photoreactivation in Saccharomyces cerevisiae. AB - The position of nucleosomes on DNA participates in gene regulation and DNA replication. Nucleosomes can be repressors by limiting access of factors to regulatory sequences, or activators by facilitating binding of factors to exposed DNA sequences on the surface of the core histones. The formation of UV induced DNA lesions, like cyclobutane pyrimidine dimers (CPDs), is modulated by DNA bending around the core histones. Since CPDs are removed by nucleotide excision repair (NER) and photolyase repair, it is of paramount importance to understand how DNA damage and repair are tempered by the position of nucleosomes. In vitro, nucleosomes inhibit NER and photolyase repair. In vivo, nucleosomes slow down NER and considerably obstruct photoreactivation of CPDs. However, over-expression of photolyase allows repair of nucleosomal DNA in a second time scale. It is proposed that the intrinsic abilities of nucleosomes to move and transiently unwrap could facilitate damage recognition and repair in nucleosomal DNA. PMID- 26429064 TI - Chromatin dynamics after DNA damage: The legacy of the access-repair-restore model. AB - Eukaryotic genomes are packaged into chromatin, which is the physiological substrate for all DNA transactions, including DNA damage and repair. Chromatin organization imposes major constraints on DNA damage repair and thus undergoes critical rearrangements during the repair process. These rearrangements have been integrated into the "access-repair-restore" (ARR) model, which provides a molecular framework for chromatin dynamics in response to DNA damage. Here, we take a historical perspective on the elaboration of this model and describe the molecular players involved in damaged chromatin reorganization in human cells. In particular, we present our current knowledge of chromatin assembly coupled to DNA damage repair, focusing on the role of histone variants and their dedicated chaperones. Finally, we discuss the impact of chromatin rearrangements after DNA damage on chromatin function and epigenome maintenance. PMID- 26429066 TI - Health and dietary traits of organic food consumers: results from the NutriNet Sante study. AB - The dietary and health traits of organic food (OF) consumers have not been comprehensively described. The aim of this study was to identify factors associated with OF consumption. Data were collected from 54 283 participants from the NutriNet-Sante cohort using self-administered web-based questionnaires. Occasional organic food consumers and regular organic food consumers (ROFC) were compared with non-organic food consumers (NOFC) using logistical regression providing an OR and 95 % CI. Adherence to the French food-based guidelines and interactions between nutritional knowledge and OF consumption in adherence to dietary guidelines were investigated. Medical history was also assessed in relation to OF consumption. Compared with NOFC, ROFC were more likely to be vegetarian (OR 9.93; 95 % CI 7.42, 13.29 in women; OR 13.07; CI 7.00, 24.41 in men) and were less likely to be aware of nutritional guidelines regarding meat consumption (OR 0.37; CI 0.34, 0.40 in women; OR 0.41; CI 0.36, 0.47 in men). Compared with NOFC, ROFC had a lower risk of type II diabetes, hypertension and CVD; however, this effect was only significant for men. In contrast, organic consumers were more likely to report food allergies. Consuming OF appeared to affect the relationship between nutritional knowledge and adequate intake of meat/poultry/seafood/eggs and starchy food among both sexes. Our study provides new insights into the diet- and health-related behaviours of OF consumers in a large sample of participants residing in France. This should be taken into account in future studies investigating relationships between health and OF consumption. PMID- 26429067 TI - Voltage-gated calcium channel blockers deregulate macroautophagy in cardiomyocytes. AB - Voltage-gated calcium channel blockers are widely used for the management of cardiovascular diseases, however little is known about their effects on cardiac cells in vitro. We challenged neonatal ventricular cardiomyocytes (CMs) with therapeutic L-type and T-type Ca(2+) channel blockers (nifedipine and mibefradil, respectively), and measured their effects on cell stress and survival, using fluorescent microscopy, Q-PCR and Western blot. Both nifedipine and mibefradil induced a low-level and partially transient up-regulation of three key mediators of the Unfolded Protein Response (UPR), indicative of endoplasmic (ER) reticulum stress. Furthermore, nifedipine triggered the activation of macroautophagy, as evidenced by increased lipidation of microtubule-associated protein 1 light chain 3 (LC3), decreased levels of polyubiquitin-binding protein p62/SQSTM1 and ubiquitinated protein aggregates, that was followed by cell death. In contrast, mibefradil inhibited CMs constitutive macroautophagy and did not promote cell death. The siRNA-mediated gene silencing approach confirmed the pharmacological findings for T-type channels. We conclude that L-type and T-type Ca(2+) channel blockers induce ER stress, which is divergently transduced into macroautophagy induction and inhibition, respectively, with relevance for cell viability. Our work identifies VGCCs as novel regulators of autophagy in the heart muscle and provides new insights into the effects of VGCC blockers on CMs homeostasis, that may underlie both noxious and cardioprotective effects. PMID- 26429069 TI - Targeting the Hippo Pathway for Anti-cancer Therapies. AB - The Hippo signaling pathway is critical in regulating tissue homeostasis, organ size, and tumorigenesis. YAP and TAZ, two major effectors of the Hippo pathway, function as transcriptional co-activators and promote target gene expression mainly through interaction with TEAD family transcription factors. As oncoproteins, YAP and TAZ are frequently activated or highly expressed in various cancer specimens. Moreover, their activity has been linked to resistance to a few widely used anti-cancer drugs, and YAP activation contributes to cancer relapse. Thus, the Hippo pathway, especially YAP/TAZ-TEAD interaction, represents an attractive target for anti-cancer therapies. Here, we will discuss potential approaches to inhibit YAP/TAZ activity, and also review currently available small molecules targeting the Hippo pathway. PMID- 26429068 TI - Postprandial profiles of CCK after high fat and high carbohydrate meals and the relationship to satiety in humans. AB - CONTEXT: CCK is understood to play a major role in appetite regulation. Difficulties in measuring CCK have limited the potential to assess its profile in relation to food-induced satiety. Improvements in methodology and progress in theoretical understanding of satiety/satiation make it timely for this to be revisited. OBJECTIVE: First, examine how physiologically relevant postprandial CCK8/33(s) profiles are influenced by fat (HF) or carbohydrate (HCHO) meals. Second, to examine relationships between postprandial CCK and profiles of satiety (hunger/fullness) and satiation (meal size). PARTICIPANTS AND DESIGN: Sixteen overweight/obese adults (11 females/5 males) participated in a randomised crossover study (46 years, 29.8 kg/m(2)) in a university research centre. Plasma was collected preprandially and for 180 min postprandially. Simultaneously, ratings of hunger/fullness were tracked for 180 min before an ad libitum lunch was provided. RESULTS: CCK8/33(s) levels increased more rapidly and reached a higher peak following HF compared to HCHO breakfast (F(1,15)=14.737, p<0.01). Profiles of hunger/fullness did not differ between conditions (F(1,15)=0.505, p=0.488; F(1,15)=2.277, p=0.152). There was no difference in energy intake from the ad libitum meal (HF-3958 versus HCHO-3925 kJ; t(14)=0.201, p=0.844). CCK8/33(s) profiles were not associated with subjective appetite during early and late phases of satiety; nor was there an association between CCK8/33(s) and meal size. CONCLUSIONS: These results demonstrate CCK levels were higher after HF meal compared to HCHO isocaloric meal. There was no association between CCK levels and intensity of satiety, or with meal size. Under these circumstances, CCK does not appear to play a unique independent role in satiety/satiation. CCK probably acts in conjunction with other peptides and the action of the stomach. PMID- 26429070 TI - 5-Aminoisoquinolin-1-one (5-AIQ), a Water-Soluble Inhibitor of the Poly(ADP Ribose)Polymerases (PARPs). AB - 5-Aminoisoquinolin-1-one (5-AIQ) is a water-soluble inhibitor of the poly(ADPribose) polymerases (PARPs), lacking isoform-selectivity. Although of only moderate potency in vitro against PARP-1, it is highly active in many assays in cells and in models in vivo, indicating excellent uptake. Optimisation of the several synthetic sequences to 5-AIQ has led to development of a short and efficient route from 1-chloroisoquinoline. It has been used widely as a biochemical and pharmacological tool to study the effects of inhibition of the PARPs. It ameliorates the damage to cells and tissues following reperfusion of ischaemic tissue, showing significant protective activity in a rodent model of haemorrhagic shock at the remarkably low dose of 30 ug Kg(-1). Protection is also seen in models of myocardial infarction, ischaemic kidney and liver disorders, stroke and organ transplantation. Inhibition of PARP-1 by 5-AIQ causes down regulation of the activity of NF-kappaB, which then down-regulates the expression of several gene products. Thus 5-AIQ has anti-inflammatory activity in vivo, through modulating the expression of cytokines and adhesion molecules. This indirect inhibition of expression is relevant in the activity of 5-AIQ in models of arthritis, Parkinson's disease, multiple sclerosis, spinal cord injury, periodontitis and inflammatory conditions of the lung. Inhibition of expression of matrix metalloproteinases and other factors gives rise to anti-angiogenic activity and to remarkable anti-metastatic activity in a mouse model. Thus, although it has been overtaken by other PARP-inhibiting drugs in the oncological clinic, 5-AIQ remains a valuable tool to study the roles of PARPs in health and in diverse diseases. PMID- 26429071 TI - Trends of reported human cases of brucellosis, Kingdom of Saudi Arabia, 2004 2012. AB - Human brucellosis is an important zoonotic disease and is especially concerning in the Kingdom of Saudi Arabia (KSA), where livestock importation is significant. We analyzed reported human brucellosis disease trends in KSA over time to help policymakers understand the magnitude of the disease and guide the design of prevention and control measures. By using data from the national registry from 2004 to 2012, we calculated the cumulative numbers by age group and months. Trends of incidence rates (IRs) by gender, nationality, and region were also calculated. We found that there was a greater number of cases (19,130) in the 15 44 years age group than in any other age group. The IRs significantly decreased from 22.9 in 2004 [95% confidence interval (CI)=22.3, 23.5] to 12.5 in 2012 (95% CI=12.1, 13). Males had a significantly greater IR than females. Most cases were reported during spring and summer seasons. The IR of Saudi citizens was significantly greater than that of non-Saudis, but this difference reduced over time. The IRs of Al-Qassim, Aseer, and Hail were in the highest 25th percentile. Young, male Saudi citizens living in highly endemic areas were at greatest risk of acquiring brucellosis. We recommend vaccinating susceptible animals against brucellosis and increasing the public's awareness of preventive measures. PMID- 26429072 TI - Individual and contextual factors associated with community health workers' performance in Nyanza Province, Kenya: a multilevel analysis. AB - BACKGROUND: Several African and South Asian countries are currently investing in new cadres of community health workers (CHWs) as a major part of strategies aimed at reaching the Millennium Development Goals. However, one review concluded that community health workers did not consistently provide services likely to have substantial effects on health and that quality was usually poor. The objective of this research was to assess the CHWs' performance in Western Kenya and describe determinants of that performance using a multilevel analysis of the two levels, individual and supervisor/community. METHODS: This study conducted three surveys between August and September 2011 in Nyanza Province, Kenya. The participants of the three surveys were all 1,788 active CHWs, all their supervisors, and 2,560 randomly selected mothers who had children aged 12 to 23 months. CHW performance was generated by three indicators: reporting rate, health knowledge and household coverage. Multilevel analysis was performed to describe the determinants of that performance. RESULTS: The significant factors associated with the CHWs' performance were their marital status, educational level, the size of their household, their work experience, personal sanitation practice, number of supervisions received and the interaction between their supervisors' better health knowledge and the number of supervisions. CONCLUSION: A high quality of routine supervisions is one of the key interventions in sustaining a CHW's performance. In addition, decreasing the dropout rate of CHWs is important both for sustaining their performance and for avoiding the additional cost of replacing them. As for the selection criteria of new CHWs, good educational status, availability of supporters for household chores and good sanitation practices are all important in selecting CHWs who can maintain their high performance level. PMID- 26429074 TI - Simplified sleep restriction impacts objective but not subjective sleep for people with primary insomnia in primary care. PMID- 26429073 TI - Mechanisms underlying the antihypertensive effect of Alstonia scholaris. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Alstonia scholaris has a long history of use in the Ayurveda traditional treatment of various ailments including hypertension. We have reported the blood pressure lowering activity of the extract of A. scholaris. The following research aim to delineate the pharmacological mechanism involve in the antihypertensive action. MATERIALS AND METHOD: Vasorelaxant effect of the n-butanol fraction of A. scholaris (NBF-ASME) was evaluated on rat aorta pre-contracted with phenyelphrine (PE, 1 uM). Aortic rings preparation were pre incubated with various antagonists like 1H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1 one (ODQ 10 MUM), methylene blue (MB 10 MUM), Nomega-nitro-L-arginine methyl ester hydrochloride (l-NAME 10 MUM), atropine (10 MUM), indomethacin (1 MUM), ML 9 and various K(+) channel blockers such as glibenclamide (10 MUM) and tetraethyl ammonium (TEA 10 MUM) for mechanism study. RESULT: The results showed that pre incubation of aortic rings with the extract (0.5, 1 and 2mg/mL) significantly inhibit the contractile response of the rings to phenylephrine-induced contraction (p<0.05-0.001). Removal of endothelium, incubation with L-NAME, indomethacin, atropine and propranolol did not significantly affect the relaxation effect of NBF-ASME. Furthermore, the K(+) channel blockers, TEA and glibenclamide showed no inhibitory effect. However, aortic rings pretreated with ODQ and ML-9 showed a significant suppression of the relaxation curve of NBF-ASME (p<0.01-0.001). In Ca(2+)-free solution, NBF-ASME inhibits the release of intracellular Ca(2+) from the sarcoplasmic reticulum. NBF-ASME also inhibits calcium chloride (CaCl2)-induced contraction in endothelium-denuded aortic rings. CONCLUSION: The results from this study suggests that A. scholaris exerts vasodilation via calcium channels blockade, direct activation of soluble guanylate cyclase and possibly by also inhibiting the formation of inositol 1, 4, 5-triphosphate. PMID- 26429076 TI - Moving Toward Global Primordial Prevention in Cardiovascular Disease: The Heart of the Matter. PMID- 26429075 TI - The SI! Program for Cardiovascular Health Promotion in Early Childhood: A Cluster Randomized Trial. AB - BACKGROUND: The preschool years offer a unique window of opportunity to instill healthy life-style behaviors and promote cardiovascular health. OBJECTIVES: This study sought to evaluate the effect of a 3-year multidimensional school-based intervention to improve life-style-related behaviors. METHODS: We performed a cluster-randomized controlled intervention trial involving 24 public schools in Madrid, Spain, that were assigned to either the SI! Program intervention or the usual curriculum and followed for 3 years. The SI! Program aimed to instill and develop healthy behaviors in relation to diet, physical activity, and understanding how the human body and heart work. The primary outcome was change in the overall knowledge, attitudes, and habits (KAH) score (range 0 to 80). The intervention's effect on adiposity markers was also evaluated. RESULTS: A total of 2,062 children from 3 to 5 years of age were randomized. After 3 years of follow-up, the overall KAH score was 4.9% higher in children in the intervention group compared with the control group (21.7 vs. 16.4; p < 0.001). A peak effect was observed at the second year (improvement 7.1% higher than in the control group; p < 0.001). Physical activity was the main driver of the change in KAH at all evaluation times. Children in the intervention group for 2 years and 1 year showed greater improvement than control subjects (5.9%; p < 0.001 and 2.9%; p = 0.002, respectively). After 3 years, the intervention group showed a higher probability than the control group of reducing the triceps skinfold z-score by at least 0.1 (hazard ratio: 1.40, 95% confidence interval: 1.04 to 1.89; p = 0.027). CONCLUSIONS: The SI! Program is an effective strategy for instilling healthy habits among preschoolers, translating into a beneficial effect on adiposity, with maximal effect when started at the earliest age and maintained over 3 years. Wider adoption may have a meaningful effect on cardiovascular health promotion. (Evaluation of the Program SI! for Preschool Education: A School-Based Randomized Controlled Trial [Preschool_PSI!]; NCT01579708). PMID- 26429077 TI - Saturated Fats Compared With Unsaturated Fats and Sources of Carbohydrates in Relation to Risk of Coronary Heart Disease: A Prospective Cohort Study. AB - BACKGROUND: The associations between dietary saturated fats and the risk of coronary heart disease (CHD) remain controversial, but few studies have compared saturated with unsaturated fats and sources of carbohydrates in relation to CHD risk. OBJECTIVES: This study sought to investigate associations of saturated fats compared with unsaturated fats and different sources of carbohydrates in relation to CHD risk. METHODS: We followed 84,628 women (Nurses' Health Study, 1980 to 2010), and 42,908 men (Health Professionals Follow-up Study, 1986 to 2010) who were free of diabetes, cardiovascular disease, and cancer at baseline. Diet was assessed by a semiquantitative food frequency questionnaire every 4 years. RESULTS: During 24 to 30 years of follow-up, we documented 7,667 incident cases of CHD. Higher intakes of polyunsaturated fatty acids (PUFAs) and carbohydrates from whole grains were significantly associated with a lower risk of CHD comparing the highest with lowest quintile for PUFAs (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.73 to 0.88; p trend <0.0001) and for carbohydrates from whole grains (HR: 0.90, 95% CI: 0.83 to 0.98; p trend = 0.003). In contrast, carbohydrates from refined starches/added sugars were positively associated with a risk of CHD (HR: 1.10, 95% CI: 1.00 to 1.21; p trend = 0.04). Replacing 5% of energy intake from saturated fats with equivalent energy intake from PUFAs, monounsaturated fatty acids, or carbohydrates from whole grains was associated with a 25%, 15%, and 9% lower risk of CHD, respectively (PUFAs, HR: 0.75, 95% CI: 0.67 to 0.84; p < 0.0001; monounsaturated fatty acids, HR: 0.85, 95% CI: 0.74 to 0.97; p = 0.02; carbohydrates from whole grains, HR: 0.91, 95% CI: 0.85 to 0.98; p = 0.01). Replacing saturated fats with carbohydrates from refined starches/added sugars was not significantly associated with CHD risk (p > 0.10). CONCLUSIONS: Our findings indicate that unsaturated fats, especially PUFAs, and/or high-quality carbohydrates can be used to replace saturated fats to reduce CHD risk. PMID- 26429078 TI - Pharma Versus Farmer: Food as Heart Medicine. PMID- 26429080 TI - Analysis of Large Electronic Health Record Databases Supports Blood Pressure Incident Diabetes Association. PMID- 26429079 TI - Usual Blood Pressure and Risk of New-Onset Diabetes: Evidence From 4.1 Million Adults and a Meta-Analysis of Prospective Studies. AB - BACKGROUND: Reliable quantification of the association between blood pressure (BP) and risk of type 2 diabetes is lacking. OBJECTIVES: This study sought to determine the association between usual BP and risk of diabetes, overall and by participant characteristics. METHODS: A cohort of 4.1 million adults, free of diabetes and cardiovascular disease, was identified using validated linked electronic health records. Analyses were complemented by a meta-analysis of prospective studies that reported relative risks of new-onset diabetes per unit of systolic blood pressure (SBP). RESULTS: Among the overall cohort, 20 mm Hg higher SBP and 10 mm Hg higher diastolic BP were associated with a 58% and a 52% higher risk of new-onset diabetes (hazard ratio: 1.58; 95% confidence interval [CI]: 1.56 to 1.59; and hazard ratio: 1.52; 95% confidence interval: 1.51 to 1.54), respectively. There was no evidence of a nadir to a baseline BP of 110/70 mm Hg. The strength of the association per 20 mm Hg higher SBP declined with age and with increasing body mass index. Estimates were similar even after excluding individuals prescribed antihypertensive or lipid-lowering therapies. Systematic review identified 30 studies with 285,664 participants and 17,388 incident diabetes events. The pooled relative risk of diabetes for a 20 mm Hg higher usual SBP across these studies was 1.77 (1.53 to 2.05). CONCLUSIONS: People with elevated BP are at increased risk of diabetes. The strength of the association declined with increasing body mass index and age. Further research should determine if the observed risk is modifiable. PMID- 26429081 TI - The Contribution of Tobacco Use to High Health Care Utilization and Medical Costs in Peripheral Artery Disease: A State-Based Cohort Analysis. AB - BACKGROUND: Tobacco use is an important preventable cause of peripheral artery disease (PAD) and a major determinant of adverse clinical outcomes. OBJECTIVES: This study hypothesized that tobacco use by PAD patients would be associated with higher health care utilization and associated costs. METHODS: We conducted a retrospective, cross-sectional study using 2011 claims data from the largest Minnesota health plan. The total cohort included individuals with 12 months of continuous enrollment and >= 1 PAD-related claim. Tobacco cessation pharmacotherapy billing codes were queried in a subgroup with pharmacy benefits. Outcomes were total costs, annual proportion of members hospitalized, and primary discharge diagnoses. RESULTS: A PAD cohort of 22,203 was identified, comprising 1,995 (9.0%) tobacco users. A subgroup of 9,027 with pharmacy benefits included 1,158 (12.8%) tobacco users. The total cohort experienced 22,220 admissions. The pharmacy benefits subgroup experienced 8,152 admissions. Within 1 year, nearly one-half the PAD tobacco users were hospitalized, 35% higher than nonusers in the total cohort (p < 0.001) and 30% higher in the subgroup (p < 0.001). In both cohorts, users were more frequently admitted for peripheral or visceral atherosclerosis (p < 0.001), acute myocardial infarction (p < 0.001), and coronary heart disease (p < 0.05). Observed costs in the total cohort were $64,041 for tobacco users versus $45,918 for nonusers. Costs for tobacco users also were consistently higher for professional and facility-based care, persisting after adjustment for age, sex, comorbidities, and insurance type. CONCLUSIONS: Tobacco use in PAD is associated with substantial increases in PAD related hospitalizations, coronary heart disease and PAD procedures, and significantly greater costs. The results suggest that immediate provision of tobacco cessation programs may be especially cost effective. PMID- 26429082 TI - Tobacco Use in Peripheral Artery Disease: An Economic Drag. PMID- 26429083 TI - Psychological Distress Across the Life Course and Cardiometabolic Risk: Findings From the 1958 British Birth Cohort Study. AB - BACKGROUND: Research suggests cardiovascular and metabolic diseases are influenced by psychological distress in adulthood; however, this research is often limited to adult populations and/or a snapshot measure of distress. Given emerging recognition that cardiometabolic diseases have childhood origins, an important question is whether psychological distress earlier in life influences disease development. OBJECTIVES: This study sought to assess whether life course patterns of psychological distress assessed from childhood through adulthood predict biomarkers of cardiometabolic risk in adulthood and whether effects of sustained distress differ from more limited exposure. METHODS: The sample (n = 6,714) consists of members of the 1958 British Birth Cohort Study who completed repeated measures of psychological distress and a biomedical survey at age 45 years. Psychological distress profiles over the life course (no distress, childhood only, adulthood only, or persistent distress) were identified from 6 assessments between ages 7 and 42 years. Cardiometabolic risk was assessed by combining information on 9 biomarkers of immune, cardiovascular, and metabolic system function. Covariate adjusted linear regression models were used to assess associations between distress profiles and cardiometabolic risk. RESULTS: Compared with those with no distress, cardiometabolic risk was higher among people with psychological distress in childhood only (beta = 0.11, SE = 0.03, p = 0.0002), in adulthood only (beta = 0.09, SE = 0.03, p = 0.007), and persistent across the life course (beta = 0.26, SE = 0.04, p < 0.0001). CONCLUSIONS: Psychological distress at any point in the life course is associated with higher cardiometabolic risk. This is the first study to suggest that even if distress appears to remit by adulthood, heightened risk of cardiometabolic disease remains. Findings suggest early emotional development may be a target for primordial prevention and for promoting lifelong cardiovascular health. PMID- 26429084 TI - Psychological Distress and Susceptibility to Cardiovascular Disease Across the Lifespan: Implications for Future Research and Clinical Practice. PMID- 26429087 TI - New American College of Cardiology Population Health Agenda to Focus on Primary Prevention. PMID- 26429088 TI - Stratified Approach to Health: Integration of Science and Education at the Right Time for Each Individual. PMID- 26429086 TI - Fructose and Cardiometabolic Health: What the Evidence From Sugar-Sweetened Beverages Tells Us. AB - Recent attention has focused on fructose as having a unique role in the pathogenesis of cardiometabolic diseases. However, because we rarely consume fructose in isolation, the major source of fructose in the diet comes from fructose-containing sugars, sucrose and high fructose corn syrup, in sugar sweetened beverages and foods. Intake of sugar-sweetened beverages has been consistently linked to increased risk of obesity, type 2 diabetes, and cardiovascular disease in various populations. Putative underlying mechanisms include incomplete compensation for liquid calories, adverse glycemic effects, and increased hepatic metabolism of fructose leading to de novo lipogenesis, production of uric acid, and accumulation of visceral and ectopic fat. In this review we summarize the epidemiological and clinical trial evidence evaluating added sugars, especially sugar-sweetened beverages, and the risk of obesity, diabetes, and cardiovascular disease and address potential biological mechanisms with an emphasis on fructose physiology. We also discuss strategies to reduce intake of fructose-containing beverages. PMID- 26429089 TI - Personalized Lifestyle Counseling: An Opportunity for FITs and ECs. PMID- 26429090 TI - Prevalence of Ideal Cardiovascular Health Among Adults in the United States. PMID- 26429085 TI - Food Consumption and its Impact on Cardiovascular Disease: Importance of Solutions Focused on the Globalized Food System: A Report From the Workshop Convened by the World Heart Federation. AB - Major scholars in the field, on the basis of a 3-day consensus, created an in depth review of current knowledge on the role of diet in cardiovascular disease (CVD), the changing global food system and global dietary patterns, and potential policy solutions. Evidence from different countries and age/race/ethnicity/socioeconomic groups suggesting the health effects studies of foods, macronutrients, and dietary patterns on CVD appear to be far more consistent though regional knowledge gaps is highlighted. Large gaps in knowledge about the association of macronutrients to CVD in low- and middle-income countries particularly linked with dietary patterns are reviewed. Our understanding of foods and macronutrients in relationship to CVD is broadly clear; however, major gaps exist both in dietary pattern research and ways to change diets and food systems. On the basis of the current evidence, the traditional Mediterranean-type diet, including plant foods and emphasis on plant protein sources provides a well-tested healthy dietary pattern to reduce CVD. PMID- 26429091 TI - Adverse Lifestyle Trends Counter Improvements in Cardiovascular Risk Factor Management in Coronary Patients. PMID- 26429092 TI - The Unnatural History of Ventricular Septal Defect. PMID- 26429093 TI - Reply: The Unnatural History of Ventricular Septal Defect. PMID- 26429094 TI - Reply: Exploring the Role of Transcatheter Aortic Valve Replacement as the Preferred Treatment for Lower-Risk Patients. PMID- 26429095 TI - Exploring the Role of Transcatheter Aortic Valve Replacement as the Preferred Treatment for Lower-Risk Patients. PMID- 26429096 TI - Meta-Analyses of Dual Antiplatelet Therapy Following Drug-Eluting Stent Implantation: Do Bleeding and Stent Thrombosis Weigh Similar on Mortality? PMID- 26429097 TI - Complaint handling in healthcare: expectation gaps between physicians and the public; results of a survey study. AB - BACKGROUND: Patients who submit complaints about the healthcare they have received are often dissatisfied with the response to their complaints. This is usually attributed to the failure of physicians to respond adequately to what complainants want, e.g. an apology or an explanation. However, expectations of complaint handling among the public may colour how they evaluate the way their own complaint is handled. This descriptive study assesses expectations of complaint handling in healthcare among the public and physicians. Negative public expectations and the gap between these expectations and those of physicians may explain patients' dissatisfaction with complaints procedures. METHODS: We held two surveys; one among physicians, using a panel of 3366 physicians (response rate 57 %, containing all kinds of physicians like GP's, medical specialist and physicians working in a nursing home) and one among the public, using the Dutch Healthcare Consumer Panel (n = 1422, response rate 68 %). We asked both panels identical questions about their expectations of how complaints are handled in healthcare. Differences in expectation scores between the public and the physicians were tested using non-parametric tests. RESULTS: The public have negative expectations about how complaints are handled. Physician's expectations are far more positive, demonstrating large expectation gaps between physicians and the public. CONCLUSIONS: The large expectation gap between the public and physicians means that when they meet because of complaint, they are likely to start off with opposite expectations of the situation. This is no favourable condition for a positive outcome of a complaints procedure. The negative public preconceptions about the way their complaint will be handled will prove hard to change during the process of complaints handling. People tend to see what they thought would happen, almost inevitably leading to a negative judgement about how their complaint was handled. PMID- 26429098 TI - Sparing of the extraocular muscles in mdx mice with absent or reduced utrophin expression: A life span analysis. AB - Sparing of the extraocular muscles in muscular dystrophy is controversial. To address the potential role of utrophin in this sparing, mdx:utrophin(+/-) and mdx:utrophin(-/-) mice were examined for changes in myofiber size, central nucleation, and Pax7-positive and MyoD-positive cell density at intervals over their life span. Known to be spared in the mdx mouse, and contrary to previous reports, the extraocular muscles from both the mdx:utrophin(+/-) and mdx:utrophin(-/-) mice were also morphologically spared. In the mdx:utrophin(+/)( ) mice, which have a normal life span compared to the mdx:utrophin(-/-) mice, the myofibers were larger at 3 and 12 months than the wild type age-matched eye muscles. While there was a significant increase in central nucleation in the extraocular muscles from all mdx:utrophin(+/)(-) mice, the levels were still very low compared to age-matched limb skeletal muscles. Pax7- and MyoD-positive myogenic precursor cell populations were retained and were similar to age-matched wild type controls. These results support the hypothesis that utrophin is not involved in extraocular muscle sparing in these genotypes. In addition, it appears that these muscles retain the myogenic precursors that would allow them to maintain their regenerative capacity and normal morphology over a lifetime even in these more severe models of muscular dystrophy. PMID- 26429099 TI - A CHRNE frameshift mutation causes congenital myasthenic syndrome in young Jack Russell Terriers. AB - Congenital myasthenic syndromes (CMSs) are a group of rare genetic disorders of the neuromuscular junction resulting in structural or functional causes of fatigable weakness that usually begins early in life. Mutations in pre-synaptic, synaptic and post-synaptic proteins have been demonstrated in human cases, with more than half involving aberrations in nicotinic acetylcholine receptor (AChR) subunits. CMS was first recognized in dogs in 1974 as an autosomal recessive trait in Jack Russell Terriers (JRTs). A deficiency of junctional AChRs was demonstrated. Here we characterize a CMS in 2 contemporary cases of JRT littermates with classic clinical and electromyographic findings, and immunochemical confirmation of an approximately 90% reduction in AChR protein content. Loci encoding the 5 AChR subunits were evaluated using microsatellite markers, and CHRNB1 and CHRNE were identified as candidate genes. Sequences of the splice sites and exons of both genes revealed a single base insertion in exon 7 of CHRNE that predicts a frameshift mutation and a premature stop codon. We further demonstrated this pathogenic mutation in CHRNE in archival tissues from unrelated JRTs studied 34 years ago. PMID- 26429101 TI - Safety I and safety II: the past and future of safety management. PMID- 26429102 TI - Tips and tricks on Demodex density examination by standardized skin surface biopsy. PMID- 26429100 TI - Empowering smokers with a web-assisted tobacco intervention to use prescription smoking cessation medications: a feasibility trial. AB - BACKGROUND: Varenicline and bupropion, efficacious smoking cessation medications, have had suboptimal impact due to barriers at the patient, practitioner and system level. This study explored the feasibility of a web-assisted tobacco intervention offering free prescription smoking cessation medication by mail if the smoker visited a physician for authorization. METHODS: Adult Ontarians, smoking at least 10 cigarettes daily, intending to quit within 30 days, with no contraindications to bupropion or varenicline were eligible. After an online assessment, eligible participants received an electronic personalized printable prescription form for a 12-week course of varenicline or bupropion to bring to a physician within 3 weeks for authorization, if appropriate. The physician's office faxed prescriptions to an online pharmacy that couriered medication to the patient following medication counselling by telephone. Weekly motivational emails were sent during treatment. Participants were asked to complete follow-up questionnaires online at 7, 11, 15 and 41 weeks after enrollment. RESULTS: In total, 1214 individuals submitted an online assessment from April to September 2010 and 73.6 % (95 % confidence interval (CI) = 71.1-76.1 %; n = 893) were eligible. At least 65.8 % (95 % CI = 62.7-68.9 %; n = 588) of eligible participants subsequently visited a physician and 58.7 % (95 % CI = 55.5-61.9 %; n = 524) received medication (50.6 % varenicline [n = 265] and 49.4 % bupropion [n = 259]). Reasons for not filling a prescription were failure to visit a physician (80.1 %; 95 % CI = 73.8-86.5 %; n = 121), physician not prescribing the medication (15.9 %; 95 % CI = 10.1-21.7 %; n = 24) or other reasons (4.0 %; 95 % CI = 0.9-7.1 %; n = 6). Follow-up response rate was 66.7 % (95 % CI = 63.7-69.8 %; n = 596). Minimal issues were encountered with printing the prescription or medication delivery. CONCLUSIONS: This study establishes the feasibility of using the Internet and free medication to enable smokers to engage physicians to treat this addiction. Implementation of this intervention can be scaled up by leveraging existing healthcare systems to treat smokers on a population level. Further evaluation in a randomized controlled trial is necessary. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01023659. PMID- 26429103 TI - Repair and regeneration of lumbosacral nerve defects in rats with chitosan conduits containing bone marrow mesenchymal stem cells. AB - OBJECTIVES: Despite the great progress in surgical treatment of lumbosacral nerve injuries caused by high-energy trauma, functional recovery remains poor and insufficient. Bone marrow mesenchymal stem cells (BMSCs), which express neurotrophic factors and can also differentiate into nerve cells, have potential as an effective alternative therapy for lumbosacral nerve defects. The aim of the present study was to evaluate the functional recovery, nerve regeneration, motor neuron survival and apoptosis after lumbosacral nerve transection in rats receiving BMSC transplantation into the chitosan conduit. METHODS: The right L4 L6 nerve roots of rats were transected and bridged with three 1-cm-long chitosan conduits, which were further injected with the BMSCs (MSC-treated group) or culture medium (DMEM group). The nerve regeneration and motor function recovery were assessed by the sciatic functional index (SFI) and analysed electrophysiologically and morphologically. RESULTS: At 6 and 12 weeks after surgery, the SFI values in MSC-treated group were significantly higher than those in DMEM group (P<=0.05). The peak amplitude of CMAP (compound muscle action potential) and nerve conduction velocity in MSC-treated group were significantly higher than that in DMEM group (P<=0.01), while the latency of CMAP onset in MSC treated group was significantly shorter than that in DMEM group (P<=0.01). The diameter of the myelinated fibres and thickness of the myelin sheath in MSC treated group were significantly higher than those in DMEM group (P<=0.05). There was no difference in the number of motor neurons in the anterior horn of the spinal cord at 6 weeks post-operation (P>0.05), while the number of motor neurons was significantly greater in MSC-treated group than that in DMEM group at 12 weeks post-operation (P<=0.001). The number of apoptotic cells was also significantly lower (P<=0.01). CONCLUSIONS: The results of the present study showed that BMSCs treatment improved lumbosacral nerve regeneration and motor function. In addition, our data suggested that BMSCs inhibited motor neuron apoptosis, and improved motor neuron function and survival in the anterior horn of the spinal cord. PMID- 26429104 TI - Influence of obesity on surgical outcomes in type III paediatric supracondylar humeral fractures. AB - INTRODUCTION: Obesity was associated with poor treatment outcome in paediatric supracondylar humeral fractures. It is controversial about the association is related to more severe fractures in obese children or obesity directly affects treatment. The purpose of this study was to evaluate the influence of obesity on surgical outcomes after control of fracture severity. PATIENTS AND METHODS: This is a retrospective comparative study of 107 children treated for type III supracondylar humeral fractures between January 2009 and December 2013. Children were classified according to sex-specific body mass index (BMI)-for-age growth chart into 4 groups: underweight group (n=10); normal-weight group (n=71); overweight group (n=13); and obese group (n=13). Clinical outcomes were assessed using the Flynn criteria. Radiographic evaluation included the Baumann angle and the lateral humerocapitellar angle. Loss of reduction was defined by Skaggs' criteria. RESULTS: The mean age, sex, and Flynn criteria were comparable among the four BMI groups. Obese children were more likely to develop a varus change in the Baumann angle (p=0.017) and loss of reduction in varus (p=0.059) postoperatively. The risk for pin-related complications was significantly higher in overweight and obese children (p=0.013). CONCLUSIONS: Obesity was associated with more postoperative varus deformation and pin-related complications after surgical fixation for type III supracondylar fracture. These findings underline the importance of stable fixation and close post-operative monitoring in obese children. PMID- 26429106 TI - Remember Ebola? PMID- 26429105 TI - Predicting in-hospital mortality of traffic victims: A comparison between AIS-and ICD-9-CM-related injury severity scales when only ICD-9-CM is reported. AB - BACKGROUND AND AIM: Injury severity scores are important in the context of developing European and national goals on traffic safety, health-care benchmarking and improving patient communication. Various severity scores are available and are mostly based on Abbreviated Injury Scale (AIS) or International Classification of Diseases (ICD). The aim of this paper is to compare the predictive value for in-hospital mortality between the various severity scores if only International Classification of Diseases, 9th revision, Clinical Modification ICD-9-CM is reported. METHODOLOGY: To estimate severity scores based on the AIS lexicon, ICD-9-CM codes were converted with ICD Programmes for Injury Categorization (ICDPIC) and four AIS-based severity scores were derived: Maximum AIS (MaxAIS), Injury Severity Score (ISS), New Injury Severity Score (NISS) and Exponential Injury Severity Score (EISS). Based on ICD-9-CM, six severity scores were calculated. Determined by the number of injuries taken into account and the means by which survival risk ratios (SRRs) were calculated, four different approaches were used to calculate the ICD-9-based Injury Severity Scores (ICISS). The Trauma Mortality Prediction Model (TMPM) was calculated with the ICD-9-CM based model averaged regression coefficients (MARC) for both the single worst injury and multiple injuries. Severity scores were compared via model discrimination and calibration. Model comparisons were performed separately for the severity scores based on the single worst injury and multiple injuries. RESULTS: For ICD-9-based scales, estimation of area under the receiver operating characteristic curve (AUROC) ranges between 0.94 and 0.96, while AIS-based scales range between 0.72 and 0.76, respectively. The intercept in the calibration plots is not significantly different from 0 for MaxAIS, ICISS and TMPM. DISCUSSION: When only ICD-9-CM codes are reported, ICD-9-CM-based severity scores perform better than severity scores based on the conversion to AIS. PMID- 26429107 TI - PCMO L01-Setting Specifications for Biological Investigational Medicinal Products. AB - This paper provides overall guidance and best practices for the setting of specifications for clinical biological drug substances and drug products within the framework of ICH guidelines on pharmaceutical development [Q8(R2) and Q11], quality risk management (Q9), and quality systems (Q10). A review is provided of the current regulatory expectations for the specification setting process as part of a control strategy during product development, pointing to existing challenges for the investigational new drug/investigational medicinal product dossier (IND/IMPD) sponsor. A case study illustrates how the investigational medicinal product specification revision process can be managed within a flexible quality system, and how specifications can be set and justified for early and late development stages. LAY ABSTRACT: This paper provides an overview for the setting of product specifications for investigational medicinal products used in clinical trials. A case study illustrates how product specifications of investigational medicinal products can be justified and managed within a modern product quality system. PMID- 26429108 TI - Creating a Holistic Extractables and Leachables (E&L) Program for Biotechnology Products. AB - The risk mitigation of extractables and leachables presents significant challenges to regulators and drug manufacturers with respect to the development, as well as the lifecycle management, of drug products. A holistic program is proposed, using a science- and risk-based strategy for testing extractables and leachables from primary containers, drug delivery devices, and single-use systems for the manufacture of biotechnology products. The strategy adopts the principles and concepts from ICH Q9 and ICH Q8(R2). The strategy is phase-appropriate, progressing from extractables testing for material screening/selection/qualification through leachables testing of final products. The strategy is designed primarily to ensure patient safety and product quality of biotechnology products. The holistic program requires robust extraction studies using model solvents, with careful consideration of solvation effect, pH, ionic strength, temperature, and product-contact surface and duration. From a wide variety of process- and product-contact materials, such extraction studies have identified and quantified over 200 organic extractable compounds. The most commonly observed compounds were siloxanes, fatty acid amides, and methacrylates. Toxicology assessments were conducted on these compounds using risk-based decision analysis. Parenteral permitted daily exposure limits were derived, as appropriate, for the majority of these compounds. Analysis of the derived parenteral permitted daily exposure limits helped to establish action thresholds to target high-risk leachables in drug products on stability until expiry. Action thresholds serve to trigger quality investigations to determine potential product impact. The holistic program also evaluates the potential risk for immunogenicity. This approach for primary drug containers and delivery devices is also applicable to single-use systems when justified with a historical knowledge base and understanding of the manufacturing processes of biotechnology products. LAY ABSTRACT: In the development of a drug product, careful consideration is given to impurities that may originate from manufacturing equipment, process components, and packaging materials. The majority of such impurities are common chemical additives used to improve the physicochemical properties of a wide range of plastic materials. Suppliers and drug manufacturers conduct studies to extract chemical additives from the plastic materials in order to screen and predict those that may leach into a drug product. In this context, the term extractables refers to a profile of extracted compounds observed in studies under harsh conditions. In contrast, the term leachables refers to those impurities that leach from the materials under real-use conditions and may be present in final drug products. The purpose of this article is to present a holistic approach that effectively minimizes the risk of leachables to patient safety and product quality. PMID- 26429109 TI - Manufacturing of Plasma-Derived Medicinal Products: Qualification Process of Plasma Suppliers. AB - Manufacturers of human plasma-derived products ensure, through their qualification departments, the quality and safety of human plasma-the biological starting material of the industrial fractionation process. The qualification department has established written procedures to approve the plasma supplier (i.e., initial qualification) according to current regulations and to the manufacturer's plasma specifications. Once the plasma supplier is approved, a periodical assessment is necessary (i.e., continuous qualification) to guarantee the level of compliance. In addition, a signed quality agreement between the plasma supplier and the manufacturer defines the duties and the responsibilities of both parties. The qualification department implements the following requirements to ensure the quality of plasma from suppliers: (i) a regular audit program to confirm the satisfactory initiation of the quality arrangements and (ii) monitoring of the quality and safety of plasma including critical quality parameters. For several years, the Grifols Qualification Department has worked with several plasma suppliers of the European Union (EU) and has performed a detailed, continuous assessment of the audits, deviations, operational incidences, epidemiological data, and quality controls. In this article, we will report data from this Grifols assessment from 2010 through 2013 on plasma suppliers from four EU countries. In the future, additional data will be collected and studied to confirm and verify the conclusions and trends observed in this study. PMID- 26429111 TI - Introduction to BioPhorum Operations Group (BPOG) Special Section Editorials. PMID- 26429110 TI - Quality Culture Survey Report. AB - The Parenteral Drug Association conducted an anonymous global survey of quality culture in the pharmaceutical industry to determine whether there is a relationship between certain quality behaviors and certain quality attributes, and whether these quality attributes could be used as surrogates (or proxy variables) to assess quality culture. Other studies have shown that an unhealthy quality culture is a root cause of many quality or compliance issues seen by sites and organizations. Statistical analysis of survey data suggests that certain attributes are driving good behaviors, and the demographic data suggests that this relationship holds irrespective of the geographic location of the site. Executive survey respondents had a more optimistic view of the current state of quality culture than survey respondents at large, with cross-functional vision showing the biggest gap (P-value = 0.07, F-Test). The top five quality attributes that can serve as surrogates for quality culture were (1) Management communication that quality is everyone's responsibility, (2) Site has formal quality improvement objectives and targets, (3) Clear performance criteria for feedback and coaching, (4) Quality topics included in at least half of all-hands meetings, and (5) Collecting error prevention metrics. These identified mature quality attributes are related to management responsibility, and continual improvement of the pharmaceutical quality system sections of ICH Q10, and therefore may be amenable to be incorporated in audit programs or in regulatory inspections. Additional research and discussion is required to build a coherent approach, which the pharmaceutical industry and regulators can adopt. PMID- 26429112 TI - Overview of Best Practices for Biopharmaceutical Technology Transfers. AB - Technology transfer is a key foundational component in product commercialization. It is more than just the transfer of documents; it relates to all aspects of the transfer of knowledge and experience to the commercial manufacturing unit to ensure consistent, safe, and high-quality product. This is the first in a series of articles from the BioPhorum Operations Group (BPOG) member companies discussing best practices and benchmarking of biopharmaceutical technology transfer. In this article, we provide the common terminology developed by BPOG to accommodate both transferring and receiving organizations. We also review the key elements of a robust technology transfer business process, including critical milestones. Finally, we provide a brief overview of the articles in this series. PMID- 26429113 TI - Strategies for Maximizing Successful Drug Substance Technology Transfer Using Engineering, Shake-Down, and Wet Test Runs. AB - The technology transfer of biological products is a complex process requiring control of multiple unit operations and parameters to ensure product quality and process performance. To achieve product commercialization, the technology transfer sending unit must successfully transfer knowledge about both the product and the process to the receiving unit. A key strategy for maximizing successful scale-up and transfer efforts is the effective use of engineering and shake-down runs to confirm operational performance and product quality prior to embarking on good manufacturing practice runs such as process performance qualification runs. We consider key factors to consider in making the decision to perform shake-down or engineering runs. We also present industry benchmarking results of how engineering runs are used in drug substance technology transfers alongside the main themes and best practices that have emerged. Our goal is to provide companies with a framework for ensuring the "right first time" technology transfers with effective deployment of resources within increasingly aggressive timeline constraints. PMID- 26429114 TI - Changing the Performance Paradigm in Pharma/Biotech: Integrating Human Performance in Global Organizations. PMID- 26429115 TI - A Computerized Lifestyle Application to Promote Multiple Health Behaviors at the Workplace: Testing Its Behavioral and Psychological Effects. AB - BACKGROUND: Preventive health behaviors, such as regular physical activity and healthy nutrition, are recommended to maintain employability and to facilitate the health of employees. Theory-based workplace health promotion needs to include psychological constructs and consider the motivational readiness (so-called stages of change) of employees. According to the stages, people can be grouped as nonintenders (not motivated to change and not performing the goal behavior), intenders (decided to adopt the goal behavior but not started yet), or actors (performing the goal behavior already). The tailoring to these stages can be done computer based and should make workplace health promotion more effective. OBJECTIVE: It was tested whether a parsimonious computer-based health promotion program implemented at the workplace was effective in terms of lifestyle changes and psychological outcomes as well as body weight. We hypothesized that the stage matched intervention would outperform the one-size-fits-all active control condition (standard care intervention). METHODS: In a randomized controlled trial, a total of 1269 employees were recruited by a trained research assistant at their workplace during a routine medical examination. After excluding noneligible employees, 560 completed Time 1 (T1), and 384 also completed Time 2 (T2), achieving a retention rate of 68.6%. Two fully automated computer-based treatments were adopted: (1) an active control condition with information about benefits of exercise and healthy nutrition (n=52), or (2) a stage-matched multiple-behavior intervention that provided different psychological treatments to 9 subgroups, addressing stages of change (nonintenders, intenders, and actors per behavior; n=332). Baseline assessments (T1) on behavior, psychological constructs, and body weight were repeated after 4 weeks (T2). RESULTS: The stage matched intervention outperformed the active control condition for lifestyle changes containing physical activity and nutrition (chi(2) 1=3.5; P=.04, for N=384) as well as psychological variables (physical activity intention, P=.04; nutrition intention, P=.03; nutrition planning, P=.02; and general social support to live healthily, P=.01). When predicting a healthy lifestyle at follow-up, baseline lifestyle (odds ratio, OR, 2.25, 95% CI 1.73-2.92; P<.01) and the intervention (OR 1.96, 95% CI 1.00-3.82; P=.05) were found to be significant predictors. Physical activity planning mediated the effect of the intervention on the adoption of an overall healthy lifestyle (consisting of activity and nutrition, R(2) adj=.08; P<.01), indicating that if the stage-matched intervention increased planning, the adoption of a healthy lifestyle was more likely. CONCLUSIONS: Matching an intervention to the motivational readiness of employees can make a health promotion program effective. Employees' motivation, planning, social support, and lifestyle can be supported by a stage-matched intervention that focuses on both physical activity and healthy nutrition. Occupational settings provide a potential to implement parsimonious computer based health promotion programs and to facilitate multiple behavior change. PMID- 26429116 TI - Factors Affecting Attendance at an Adapted Cardiac Rehabilitation Exercise Program for Individuals with Mobility Deficits Poststroke. AB - OBJECTIVE: The aim of this study was to determine the factors affecting attendance at an adapted cardiac rehabilitation program for individuals poststroke. METHODS: A convenience sample of ambulatory patients with hemiparetic gait rated 20 potential barriers to attendance on a 5-point Likert scale upon completion of a 6-month program of 24 prescheduled weekly sessions. Sociodemographic characteristics, depressive symptoms, cardiovascular fitness, and comorbidities were collected by questionnaire or medical chart. RESULTS: Sixty-one patients attended 77.3 +/- 12% of the classes. The longer the elapsed time from stroke, the lower the attendance rate (r = -.34, P = .02). The 4 greatest barriers influencing attendance were severe weather, transportation problems, health problems, and traveling distance. Health problems included hospital readmissions (n = 6), influenza/colds (n = 6), diabetes and cardiac complications (n = 4), and musculoskeletal issues (n = 2). Of the top 4 barriers, people with lower compared to higher income had greater transportation issues (P = .004). Greater motor deficits of the stroke-affected leg were associated with greater barriers related to health issues (r = .7, P = .001). The only sociodemographic factor associated with a higher total mean barrier score was non English as the primary language spoken at home (P = .002); this factor was specifically related to the barriers of cost (P = .007), family responsibilities (P = .018), and lack of social support (P = .001). No other associations were observed. CONCLUSION: Barriers to attendance were predominantly related to logistic/transportation and health issues. People who were more disadvantaged socioeconomically (language, finances), and physically (stroke-related deficits) were more affected by these barriers. Strategies to reduce these barriers, including timely referral to exercise programs, need to be investigated. PMID- 26429117 TI - Role of sphingosine 1-phosphate receptors, sphingosine kinases and sphingosine in cancer and inflammation. AB - Sphingosine kinase (there are two isoforms, SK1 and SK2) catalyses the formation of sphingosine 1-phosphate (S1P), a bioactive lipid that can be released from cells to activate a family of G protein-coupled receptors, termed S1P1-5. In addition, S1P can bind to intracellular target proteins, such as HDAC1/2, to induce cell responses. There is increasing evidence of a role for S1P receptors (e.g. S1P4) and SK1 in cancer, where high expression of these proteins in ER negative breast cancer patient tumours is linked with poor prognosis. Indeed, evidence will be presented here to demonstrate that S1P4 is functionally linked with SK1 and the oncogene HER2 (ErbB2) to regulate mitogen-activated protein kinase pathways and growth of breast cancer cells. Although much emphasis is placed on SK1 in terms of involvement in oncogenesis, evidence will also be presented for a role of SK2 in both T-cell and B-cell acute lymphoblastic leukemia. In patient T-ALL lymphoblasts and T-ALL cell lines, we have demonstrated that SK2 inhibitors promote T-ALL cell death via autophagy and induce suppression of c-myc and PI3K/AKT pathways. We will also present evidence demonstrating that certain SK inhibitors promote oxidative stress and protein turnover via proteasomal degradative pathways linked with induction of p53-and p21-induced growth arrest. In addition, the SK1 inhibitor, PF-543 exacerbates disease progression in an experimental autoimmune encephalomyelitis mouse model indicating that SK1 functions in an anti-inflammatory manner. Indeed, sphingosine, which accumulates upon inhibition of SK1 activity, and sphingosine like compounds promote activation of the inflammasome, which is linked with multiple sclerosis, to stimulate formation of the pro-inflammatory mediator, IL 1beta. Such compounds could be exploited to produce antagonists that diminish exaggerated inflammation in disease. The therapeutic potential of modifying the SK-S1P receptor pathway in cancer and inflammation will therefore, be reviewed. PMID- 26429118 TI - Obstructive sleep apnea in Prader-Willi syndrome: risks and advantages of adenotonsillectomy. AB - Obstructive sleep apnea is a well-known clinical manifestation of Prader-Willi syndrome. The aim of our study is to evaluate the efficacy of adenotonsillectomy for the treatment of the disorder as well as the improvement of their post operative quality of life. Five patients with moderate to severe obstructive sleep apneas and adenotonsillar hypertrophy of grade III-IV underwent adenotonsillectomy. Pre- and postoperative apneas and Quality of Life were assessed respectively with a polysomnography with multi-sleep latency test and with the pediatric Quality of Life questionnaire, performed before and 6 months after surgery. A decrease of apnea/hypopnea index values has been detected between pre- and post-surgery (t=2.64, P=0.005), as well as oxygen desaturation index values (t=5.51, P=0.005), multi-sleep latency test (t=4.54, P=0.01), and of the values of pediatric Quality of Life questionnaire. No correlation has been detected between body mass index and apnea/hypopnea index, oxygen desaturation index and multi-sleep latency test values pre- and post-adenotonsillectomy. A correlation has been found between multi-sleep latency test and oxygen desaturation index values post-surgery (P=0.04). No post-operative complications were observed. Our data underline the efficacy of surgery in Prader-Willi patients with adenotonsillar hypertrophy in order to improve their quality of life. PMID- 26429119 TI - Laparoscopic herniorrhaphy in children. AB - The authors report their experience in laparoscopic repair of inguinal hernias in children. From May 2010 to November 2013, 122 patients with inguinal hernia underwent laparoscopic herniorrhaphy (92 males and 30 females). Telescope used was 5 mm, while trocars for the operative instruments were 3 or 2 mm. After introducing the camera at the umbilical level and trocars in triangulation, a 4-0 nonabsorbable monofilament suture was inserted directly through the abdominal wall. The internal inguinal ring was then closed by N or double N suture. All operations were performed in one-day surgery setting. In the case of association of inguinal and umbilical hernia an original technique was performed for positioning and fixing the umbilical trocar and for the primary closure of the abdominal wall defect. The postoperative follow-up consisted of outpatient visits at 1 week and 1, 3, and 6 months. The mean age of patients was 38.5 months. Of all patients, 26 were also suffering from umbilical hernia (19 males and 7 females). A total of 160 herniorrhaphies were performed; 84 were unilateral (66 inguinal hernia, 18 inguinal hernia associated with umbilical hernia), 38 bilateral (30 inguinal hernia, 8 inguinal hernia associated with umbilical hernia). Nine of 122 patients (6 males and 3 females) were operated in emergency for incarcerated hernia. A pre-operative diagnosis of unilateral inguinal hernia was performed in 106 cases. Of these patients, laparoscopy revealed a controlateral open internal inguinal ring in 22 cases (20.7%). The mean operative time was 29.9+/-15.9 min for the monolateral herniorrhaphies, while in case of bilateral repair the mean operative time was 41.5+/-10.4 min. The mean operative time for the repair of unilateral inguinal hernia associated with umbilical hernia was 30.1+/-7.4 while for the correction of bilateral inguinal hernia associated with umbilical hernia 39.5+/-10.6 min. There were 3 recurrences (1.8%): 2 cases in unilateral repair and 1 case a unilateral recurrence in a bilateral repair. No other complications were seen. Laparoscopic repair of inguinal hernia in children performed in this experience resulted a safe and effective procedure. PMID- 26429120 TI - Ureteral rupture after blunt abdominal trauma in a child with unknown horseshoe kidney. AB - More than 90% of renal injuries in children result from blunt abdominal trauma. A 10-year-old female had a blunt abdominal trauma with macro-hematuria. The computed tomography scan revealed the presence of a horseshoe kidney and a 3rd grade renal lesion and contrast leakage from the right ureter. The ureteral rupture was confirmed by cystoscopy and ascendant pyelography and than a double J stent was implanted. The stent was removed one month later. Non-surgical management has become the standard of care for both ureteral and renal lesions in children. Non-surgical treatment is a safe procedure for renal trauma with ureteral rupture in children. PMID- 26429121 TI - Mitotic crossover promotes leukemogenesis in children born with TEL-AML1 via the generation of loss of heterozygosity at 12p. AB - TEL-AML1 (ETV6-RUNX1) fusion gene which is formed prenatally in 1% of the newborns, is a common genetic abnormality in childhood Bcell precursor acute lymphoblastic leukemia. But only one child out of a hundred children born with this fusion gene develops leukemia (bottleneck phenomenon) later in its life, if contracts the second mutation. In other words, out of a hundred children born with TEL-AML1 only one child is at risk for leukemia development, which means that TEL-AML1 fusion gene is not sufficient for overt leukemia. There is a stringent requirement for a second genetic abnormality for leukemia development and this is the real or the ultimate cause of the leukemia bottleneck phenomenon. In most cases of TEL-AML1+ leukemia, the translocation t(12;21) is complemented with the loss of the normal TEL gene, not involved in the translocation, on the contralateral 12p. The loss of the normal TEL gene, i.e. loss of heterozygosity at 12p, occurs postnatally during the mitotic proliferation of TEL-AML1+ cell in the mitotic crossing over process. Mitotic crossing over is a very rare event with a frequency rate of 10-6 in a 10 kb region. The exploration and identification of the environmental exposure(s) that cause(s) proliferation of the TELAML1+ cell in which approximately 106 mitoses are generated to cause 12p loss of heterozygosity, i.e. TEL gene deletion, may contribute to the introduction of preventive measures for leukemia. PMID- 26429122 TI - Prevalence of child sexual abuse: a comparison among 4 Italian epidemiological studies. AB - Although many epidemiological studies defining child sexual abuse prevalence rates in many countries of the world are now available, Italy presents a lack of data regarding this specific issue. Only recently some attempts to define the epidemiology of this public health problem have been tried. Between 2003 and 2010, the Department of Public Health at University of Milan was in charge of one of the more important study of this kind in Italy, involving almost 3000 students aged 18 attending secondary schools in the City of Milan who filled out an anonymous questionnaire aiming at detecting their previous experiences of sexual victimization during childhood and adolescence. After this first edition, the study was replicated among students attending secondary schools in the city of Varese, in the area of Piedmont and in Basilicata (area of Lauria), using the same investigational model and questionnaire. This paper presents the main data collected through four different epidemiological studies using the same methodology and survey tool. Considering at least one of the five different forms of child sexual abuse surveyed (being exposed to pornography, being touched on private parts, being forced to masturbate an older person, being forced to perform oral sex, or being penetrated), the prevalence rate among our samples ranges between a minimum of 12.5% (Varese) and a maximum of 34.1% (Lauria). In Lauria the research reveals a higher prevalence rate of child sexual abuse, especially among the male population, for all typologies of abuse but being touched in their private parts. In all other geographical areas and for all typologies of abuse, there is always a higher prevalence among girls, with the only exception of abuse such as being exposed to pornographic materials. PMID- 26429123 TI - A rare case of discrete aortic coarctation in Williams-Beuren syndrome. Diagnostic and therapeutic considerations. AB - Williams-Beuren syndrome (WBS) is a genetic disorder caused by elastin gene deletions, and is characterized by cardiovascular malformations, primarily including supravalvular aortic stenosis and peripheral pulmonary stenosis. We report a case of a neonate who developed severe discrete aortic coarctation, underwent multiple surgical interventions, and was subsequently diagnosed with WBS. Severe discrete aortic coarctation is a rare event in WBS newborns. An abnormally thick aortic wall is present in these patients and is the basis of the failure of the classical approach towards coarctation repair, which consists of end-to-end anastomosis as first surgical choice. Our case, and a very few similar previously documented cases, have all demonstrated recoarctation, which only aortic patch implantation was able to successfully repair. In light of this, we would also like to underline the importance of early WBS diagnosis. Therefore, even in mild syndromic phenotype such as low birth weight or facial dysmorphism that raise the suspicion of a genetic syndrome, it is advisable to perform fluorescent in situ hybridization analysis rather than merely karyotypic one. PMID- 26429125 TI - SQUIRE 2.0 (Standards for QUality Improvement Reporting Excellence): Revised Publication Guidelines From a Detailed Consensus Process. PMID- 26429124 TI - Prevalence of overweight/obesity in relation to dietary habits and lifestyle among 7-17 years old children and adolescents in Lithuania. AB - BACKGROUND: Until recently increasing prevalence of overweight and obesity among pediatric population in Europe and worldwide contributes to major well-known risks for metabolic consequences in later life. The aim of this study was to determine the prevalence of overweight/obesity among children and adolescents in Lithuania and assess its association with energy balance related behaviors as well as familial demographic and socioeconomic factors. METHODS: Cross-sectional study included 3990 7-17 years old schoolchildren from 40 schools of Kaunas region, Lithuania. Study participants underwent anthropometric measurements. Body mass index (BMI) was evaluated according to International Obesity Task Force (IOTF) criteria for children and adolescents. Children and adolescents and their parents filled in the questionnaires on parental sociodemographic characteristics, dietary habits, TV watching time, and family socioeconomic status. RESULTS: The prevalence of underweight, overweight, and obesity among boys and girls was 6.9 and 11.7 % (P < 0.05), 12.6 and 12.6 % (P > 0.05), and 4.9 and 3.4 % (P < 0.05), respectively. Obesity was significantly more prevalent in the 7-9 years old group (6.7 and 4.8 % in boys and girls, respectively, P < 0.05). Lower meals frequency and breakfast skipping were directly associated with overweight/obesity (P < 0.05); however, physical inactivity was not associated with higher BMI. Children's overweight/obesity was directly associated with lower paternal education and unemployment (OR 1.30, P = 0.013 and OR 1.56, P = 0.003, respectively). CONCLUSIONS: The prevalence of overweight and obesity among 7-17 years old Lithuanian children and adolescents was more prevalent in younger age, still being one of the lowest across the European countries. Meals frequency, breakfast skipping, paternal education and unemployment as well as a family history of arterial hypertension were found to be associated with children's and adolescents' overweight/obesity. PMID- 26429126 TI - Factors associated with pain during vascular access intervention therapy. AB - OBJECTIVE: The objective of this study is to investigate and compare factors associated with pain during vascular access intervention therapy. SUBJECTS AND METHODS: Fifty patients provided informed consent to participate in a survey of pain by questionnaire after receiving dialysis treatment at our hospital. Balloons for use during the procedure were chosen at random in this prospective randomized control study. A numeric rating scale (NRS) was used for pain assessment. RESULTS: A semi-compliant balloon caused significantly worse pain as compared with the other types of balloons (NRS, 7.67 +/- 1.57 vs. 6.02 +/- 1.89; p<0.05). There was no correlation between maximum inflation pressure and pain, or between age and pain, and no difference between diabetic and non-diabetic patients. A comparison among vascular dilation locations, as well as a comparison of AVF with AVG also revealed no significant differences. CONCLUSIONS: The reason for severe pain with use of the semi-compliant balloon as compared with the other types might have been due to its characteristics during inflation, as increased diameter leads to an increase in pressure. Mismatching of balloon diameter to vascular diameter may also increase pain. PMID- 26429127 TI - An efficacy of intensive vitamin D delivery to neointimal hyperplasia in recurrent vascular access stenosis. AB - PURPOSE: Neointimal hyperplasia (NH) causes vascular access (VA) stenosis, which results in serious under-dialytic morbidity in hemodialysis patients. We sought to assess whether a vitamin D intervention to NH lesions leads to better VA patency and examined clinical and in vitro studies. METHODS: A pilot clinical study of six hemodialysis patients was conducted to elucidate whether 0.5 MUg calcitriol injection to stenotic lesion after balloon angioplasty (PTA) maintains better vessel patency until the next follow-up angiography. Localized vitamin D exposure was utilized by delivering and fixing calcitriol intensively at the stenotic lesion through a side-hole catheter with balloon clamping. We also performed vascular smooth muscle cell (VSMC) culture to detect both apoptosis (cell death detection assay) and cell viability (5-Bromo-2'-deoxy-uridine incorporation), and explored the efficacy of vitamin D to inhibit VSMC proliferation. Additionally, immunohistochemistry (IHC) was conducted to examine vitamin D receptor (VDR) expression at NH lesion, obtained from VA surgery. RESULTS: Percent patency, the proportion between stenotic and non-stenotic vessel diameters, increased significantly (p = 0.03) after directly catheter-delivered 0.5 MUg calcitriol administration. In vitro VSMC studies, 0.1 nM calcitriol significantly (p<0.05) enhanced apoptosis and cell-cycle inhibition for two different calcitriol exposure times (15 minutes and 24 hours). IHC staining revealed that VDR-positive hyperplastic cells were observed at NH lesion. CONCLUSIONS: Intensive vitamin D exposure at NH lesion has an ability to inhibit further VSMC proliferation, and presumably leads to greater patency rate for recurrent VA stenosis. Further studies are needed to clarify whether its unique property is exhibited through VDR-mediated mechanism. PMID- 26429128 TI - Vascular access for long-term hemodialysis/hemodiafiltration patients. AB - PURPOSE: We investigated the characteristics of patients who received long-term hemodialysis/hemodiafiltration (HD/HDF) treatment for over 30 years at our group of hospitals and type of vascular access (VA) used. SUBJECTS AND METHODS: As of August 2014, 950 patients were receiving HD/HDF treatment at one of our hospitals. Of those, we investigated 41 (4.3%) undergoing long-term treatment in regard to their characteristics and VA type. The items subjected to analysis were sex, primary illness, age at time of dialysis initiation, present age, duration (years) of HD/HDF, type of arteriovenous fistula (AVF) and arteriovenous graft (AVG), history of surgery and AVF persistence rate. RESULTS: The subjects consisted of 22 men and 19 women, and their mean HD/HDF duration was 33.4 +/- 2.8 years. For primary illness, the majority (n = 31) had chronic glomerulonephritis. The age at time of dialysis initiation was 31.7 +/- 7.76 years and present age was 64.5 +/- 7.65 years. They had received 3.8 VA surgeries. For present VA type, 23 patients (56.0%) had an AVF and 13 (31.7%) an AVG, while 4 AVF patients (9.7%) had a history of AVG use. One patient (2.4%) had a superficialized artery. The mean HD/HDF duration of the 13 AVG patients was 7 years and the longest was 18 years. AVF persistence rate estimated by the Kaplan-Meier method was 75% at 30 years after dialysis initiation. CONCLUSIONS: The present results suggest that the ratio of patients with AVG increased with prolonged HD/HDF treatment. AVG has a higher probability of complications and lower patency as compared to AVF, thus careful management is needed. On the other hand, AVG contributes more to a good long prognosis, as it offers efficient dialysis. In cases of vascular deterioration due to long-term hemodialysis, it is inevitable to change from AVF to AVG, thus the ratio of AVG patients is expected to increase in cases of long term HD/HDF. PMID- 26429129 TI - Clinical significance of perineural invasion in stages II and III colorectal cancer. AB - PURPOSE: This study aimed to determine the prognostic value of perineural invasion (PNI) in patients with colorectal cancer (CRC), particularly patients with TNM stage II and stage III. METHODS: A total of 159 CRC patients who had undergone radical resection were retrospectively analyzed. Histopathological evaluation of tissue samples was conducted on hematoxylin and eosin-stained sections. PNI was considered positive when cancer cells were observed inside the nerve sheath, or when at least 33% of the nerve periphery was surrounded by cancer cells. A 3-tier grading system (PNI0, PNI1, PNI2) based on the depth of PNI was used to assess the localization of PNI in the bowel. PNI and other prognostic factors were evaluated by survival analysis. RESULTS: PNI status in CRC significantly affected postoperative overall survival (P<0.001). The five year survival rates for PNI-negative and PNI-positive patients were 77% and 32%, respectively. PNI was closely correlated with tumor gross type, tumor grade, depth of invasion, lymph node metastasis, clinical stage, vessel invasion, tumor budding grade, and tumor growth pattern. Multivariate analysis revealed that PNI was an independent prognostic factor (HR=2.223, P=0.003). The survival of PNI positive patients was significantly poorer than that of PNI-negative patients in stages II and III (P=0.003 and P=0.008, respectively). The overall survival of colorectal patients was in the descending order of PNI-negative at stage II, PNI positive at stage II/PNI-negative at stage III, and PNI-positive at stage III (P<0.001). When the PNI status and T stage were considered together, overall survival curves of the PNI2 patients were significantly worse than those of PNI1 patients in pT4 stage (P=0.019). CONCLUSIONS: PNI is a poor independent prognostic factor for CRC. It could complement classic TNM staging classification in stratifying CRC patients in stages II and III. Assessment of the site-specific distribution of PNI may further enhance the impact of PNI contribution to the prognosis of CRC. PMID- 26429130 TI - Pharmacological and morphological characteristics of the muscular system of the giant liver fluke (Fascioloides magna - Bassi 1875). AB - Motility is required for feeding, reproduction and maintenance of the fluke in the host's liver. According to that, the neuromuscular system can be an attractive drugable target for chemotherapy. Musculature of the Fascioloides magna is organized into three layers, an outer circular layer, beneath this layer the longitudinal layer, and third, the oblique, or diagonal layer underlies the longitudinal layer. In our study, the administration of atropine or caffeine did not cause classic muscle contractions of F. magna muscle strips. However, the Electrical Field Stimulation (EFS) induced stable and repeatable contractions, which enabled us to examine their sensitivity to the various substances. Acetylcholine (ACh) (300 MUM and 1 mM), caused only a slight relaxation, without affecting the amplitude of spontaneous contractions or the amplitude of contractions induced by EFS. Contrary to that, atropine (100 MUM) caused a significant increase in the basal tone and an increase of EFS-induced contractions. If acetylcholine is an inhibitory neurotransmitter in trematodes, the described effects of atropine are achieved by the blockade of inhibitory neurotransmission. On the other hand, with respect to the process of excitation contraction coupling, the plant alkaloid ryanodine (30 MUM) significantly reduced the basal tone, as well as EFS-induced contractions of F. magna muscle strips. Ryanodine inhibited the potentiating effect of atropine on the basal tone and contractions caused by EFS, which indicates that the contractile effect of atropine is dependent on Ca(++) release from intracellular stores. Caffeine (500 MUM) caused relaxation of fluke muscle strips and at the same time significantly enhanced the EFS-induced contractions. Both effects of caffeine can be explained by entry of extracellular Ca(++) into muscle cells. The muscle contractility of F. magna depends both on the entry of extracellular calcium, and calcium release from intracellular stores, which are under the control of RyRs. Our results also suggest that antitrematodal drugs could potentially be developed from substances with selective anti-cholinergic activity. PMID- 26429131 TI - Allele repeat structure and designation update for the Y-STR loci DYF399S1, DYS526b and DYS626. PMID- 26429132 TI - Radical scavenging, prolyl endopeptidase inhibitory, and antimicrobial potential of a cultured Himalayan lichen Cetrelia olivetorum. AB - CONTEXT: Lichens are source of natural bioactive compounds which are traditionally used to cure a variety of ailments. OBJECTIVE: The objective of this study is to assess free radical scavenging, prolyl endopeptidase inhibitory (PEPI), and antimicrobial potential of a high altitude lichen species Cetrelia olivetorum (Nyl.) W. L. Culb. & C. F. Culb (Parmeliaceae). MATERIALS AND METHODS: Lichen C. olivetorum has been cultured in vitro, and optimized culture conditions were implemented in bioreactor to obtain high quantity of biomass for the study of radical scavenging, PEPI, and antimicrobial activities. Radical scavenging activity of methanol extract of Cetrelia olivetorum (MECO) was tested at 100 ug/mL, PEPI activity at 25 and 50 ug/mL, and antimicrobial activity at 5, 25, 50, and 100 ug/mL conc. All the biological activities of natural thallus extract and its derived culture extract were evaluated spectrophotometrically. RESULTS: Murashige and Skoog medium supplemented with 3% glucose and 100 ppb indole-3 butyric acid (IBA) supported biomass growth at flask level and yielded 5.095 g biomass in bioreactor. MECO of both the cultured and the natural lichen exhibited half inhibiting concentration (IC50) for radical scavenging activities in the range of 50-60 ug/mL, whereas the IC50 value of standard antioxidants was found to be in the range of 12-29 ug/mL. The IC50 value of lichen extract for PEPI activity was 144-288 ug/mL, whereas the IC50 value of standard prolyl endopeptidase inhibitor, Z-pro-prolinal, was 57.73 ug/mL. As far as the antimicrobial activity of MECO is concerned, minimum inhibitory concentration (MIC) value of lichen extracts against tested microorganisms was obtained in the range of 50-104 ug/mL and found to be more effective than commercially available standard erythromycin. DISCUSSION: Murashige and Skoog medium containing IBA was found to be suitable for maximum biomass production of C. olivetorum under bioreactor conditions. The cultured lichen biomass extract also showed antioxidant, PEPI, and antimicrobial potential. CONCLUSION: The present study indicates therapeutic potential of Himalayan lichen C. olivetorum against neurodegenerative diseases owing to its radical scavenging, PEPI, and antimicrobial activities. Further, the result encourages its commercial exploitation through mass culture for production of its bioactive components and their use in pharmaceutical and nutraceutical industries. PMID- 26429133 TI - Re: Trans-cranial motor evoked potential detection of femoral nerve injury in trans-psoas lateral lumbar interbody fusion by Justin W. Silverstein. PMID- 26429134 TI - Accuracy and precision of transcardiopulmonary thermodilution in patients with cardiogenic shock. AB - Hemodynamic monitoring plays a crucial role in the supportive treatment of critically ill patients. In this setting, the use of the pulmonary artery catheter (PAC) is a standard procedure. In this study we prospectively compare the accuracy and precision of pulmonary thermodilution (PTD) by PAC and transcardiopulmonary thermodilution (TC-PTD) in patients with cardiogenic shock following an acute cardiac event. In this prospective study 77 hemodynamic measurements were taken in 11 patients presenting cardiogenic shock (CS) treated at the medical intensive care unit of our university hospital. Hemodynamic parameters were measured simultaneously by PTD and by TC-PTD. Both techniques assessed showed a strong correlation in the obtained hemodynamic parameters. The mean bias of cardiac index between measured by PTD (CIpa) and by TC-PTD (CIpi) was 0.04 +/- 0.35 L/min/m2. During intra-aortic balloon pump (IABP) counterpulsation and therapeutic hypothermia (TH) in post-resuscitation care, mean bias between CIpa and CIpi was 0.04 +/- 0.36 and 0.04 +/- 0.34 L/min/m2, respectively. Similarly, patients presenting mitral or tricuspid regurgitation showed interchangeable parameters. Preload parameters obtained by TC-PTD showed significant differences in patients with left ventricular ejection fraction (LVEF) <35 %, compared to patients with LVEF >=35 %. In contrast, pulmonary arterial occlusion pressure showed no significant difference. Hemodynamic measurements by PTD and TC-PTD are interchangeable during therapy of CS, including patients IABP, TH, mitral or tricuspid regurgitation. Preload parameters measured by TC-PTD seem to be more accurate in these patients than pressure parameters of PTD to gather the acute hemodynamic situation. PMID- 26429135 TI - Comparison of cardiac output measures by transpulmonary thermodilution, pulse contour analysis, and pulmonary artery thermodilution during off-pump coronary artery bypass surgery: a subgroup analysis of the cardiovascular anaesthesia registry at a single tertiary centre. AB - Cardiac output measurement has a long history in haemodynamic management and many devices are now available with varying levels of accuracy. The purpose of the study was to compare the agreement and trending abilities of cardiac output, as measured by transpulmonary thermodilution and calibrated pulse contour analysis, using the VolumeViewTM system, continuous thermodilution via a pulmonary artery catheter, and uncalibrated pulse contour analysis, using FloTracTM with pulmonary artery bolus thermodilution. Twenty patients undergoing off-pump coronary artery bypass surgery using a pulmonary artery catheter and the VolumeViewTM and FloTracTM systems were included in this subgroup analysis of the cardiovascular anaesthesia registry at a single tertiary centre. During surgery, cardiac output was assessed after the induction of anaesthesia, after sternotomy, during the harvesting of grafts, during revascularization of the anterior and posterior/lateral wall, after protamine infusion, and after sternal fixation. In total, 145 sets of measurements were evaluated using Bland-Altman with % error calculation, correlation, concordance, and polar plot analyses. The percentage error (bias, limits of agreement) was 12.6 % (-0.12, -0.64 to 0.41 L/min), 26.7 % (-0.38, -1.50 to 0.74 L/min), 29.3 % (-0.08, -1.32 to 1.15 L/min), and 33.8 % ( 0.05, -1.47 to 1.37 L/min) for transpulmonary thermodilution, pulmonary artery continuous thermodilution, calibrated, and uncalibrated pulse contour analysis, respectively, compared with pulmonary artery bolus thermodilution. All pairs of measurements showed significant correlations (p < 0.001), whereas only transpulmonary thermodilution revealed trending ability (concordance rate of 95.1 %, angular bias of 1.33 degrees , and radial limits of agreement of 28.71 degrees ) compared with pulmonary artery bolus thermodilution. Transpulmonary thermodilution using the VolumeViewTM system provides reliable data on cardiac output measurement and tracking the changes thereof when compared with pulmonary artery bolus thermodilution in patients with preserved cardiac function during off-pump coronary artery bypass surgery. Trial registration NCT01713192 (ClinicalTrials.gov). PMID- 26429136 TI - The washout effect during laundry on benzothiazole, benzotriazole, quinoline, and their derivatives in clothing textiles. AB - In two previous papers, the authors have shown that benzothiazole, benzotriazole, quinoline, and several of their derivatives are widespread in clothing textile articles. A number of these compounds exhibit allergenic and irritating properties and, due to their octanol-water partition coefficient, are prone to be absorbed by the skin. Moreover, they are slightly soluble in water, which could make washing of clothes a route of emission into the environment. In the present study, the washout effect of benzothiazole, benzotriazole, quinoline, and some of their derivatives has been investigated. Twenty-seven textile samples were analyzed before, as well as after five and ten times of washing. The most abundant analyte was found to be benzothiazole, which was detected in 85 % of the samples with an average concentration of 0.53 MUg/g (median 0.44 MUg/g), followed by quinoline, detected in 81 % of the samples with an average concentration of 2.42 MUg/g (median 0.21 MUg/g). The average decrease in concentration for benzothiazoles was 50 % after ten times washing, while it was around 20 % for quinolines. The average emission to household wastewater of benzothiazoles and quinolines during one washing (5 kg of clothes made from polyester materials) was calculated to 0.5 and 0.24 g, respectively. These results strongly indicate that laundering of clothing textiles can be an important source of release of these compounds to household wastewater and in the end to aquatic environments. It also demonstrates a potential source of human exposure to these chemicals since considerable amounts of the compounds remain in the clothes even after ten times of washing. PMID- 26429137 TI - Identifying spatial and seasonal patterns of river water quality in a semiarid irrigated agricultural Mediterranean basin. AB - A detailed understanding of the study area is essential to achieve key information and optimize the monitoring, analysis, and evaluation of water quality of natural ecosystems that have been highly transformed into agricultural areas. Using classification techniques like the hierarchical cluster analysis (CA) and partial triadic analysis (PTA), we assessed the sources of water pollution and the seasonal influence of human activities in water composition in a river basin from northeastern Spain. The results suggested that a strong connection existed between water quality and the seasonality of the human activities. The CA showed the spatial relationship between water chemistry and the adjacent land uses. The PTA associated the analyzed variables to their pollutant source. Electrical conductivity (EC), Cl(-), SO4(2-)-S, Na(+), and Mg(2+) ions were related with agricultural sources, whereas NH4(+)-N, PT, and PO4(3-)-P were linked with urban polluted sites. Concentration of NO3(-)-N was associated with urban land use. Differences in water composition according to the irrigation intensity were also found during the irrigation season. The statistical tools used in this work, especially the PTA, allowed us to jointly analyze the spatial and seasonal components of water pollutant trends. We obtained a more comprehensive knowledge of water quality patterns in the study area, which will be essential when taking measures to minimize the effects of water pollution. PMID- 26429138 TI - Microbial community characteristics during simultaneous nitrification denitrification process: effect of COD/TP ratio. AB - To evaluate the impact of chemical oxygen demand (COD)/total phosphorus (TP) ratio on microbial community characteristics during low-oxygen simultaneous nitrification and denitrification process, three anaerobic-aeration (low-oxygen) sequencing batch reactors, namely R1, R2, and R3, were performed under three different COD/TP ratios of 91.6, 40.8, and 27.6. The community structures of each reactor were analyzed via molecular biological technique. The results showed that the composition of ammonia-oxidizing bacteria (AOB) was affected, indicated by Shannon indexes of the samples from R1, R2, and R3. Nitrosomonas was identified to be the dominant AOB in all SBRs. Moreover, the copy numbers of nitrifiers were more than those of denitrifiers, and the phosphorus-accumulating organisms to glycogen-accumulating organisms ratio increased with the decrease of COD/TP ratio. PMID- 26429139 TI - Proteomics analysis of liver tissues from C57BL/6J mice receiving low-dose 137Cs radiation. AB - Differentially expressed proteins in liver tissues of C57BL/6J mice receiving low dose (137)Cs radiation were examined by proteomics analysis. Compared with the control group, 80 proteins were differentially expressed in the irradiated group. Among the 40 randomly selected proteins used for peptide mass fingerprinting analysis and bioinformatics, 24 were meaningful. These proteins were related to antioxidant defense, amino acid metabolism, detoxification, anti-tumor development, amino acid transport, anti-peroxidation, and composition of respiratory chain. Western blot analysis showed that catalase (CAT), glycine N methyltransferase (GNMT), and glutathione S-transferase P1 (GSTP1) were up regulated in the irradiated group; these results were in agreement with qPCR results. These results show that CAT, GNMT, and GSTP1 may be related to stress response induced by low-dose irradiation in mice liver. The underlying mechanism however requires further investigation. PMID- 26429141 TI - Stormwater infiltration and surface runoff pollution reduction performance of permeable pavement layers. AB - In this paper, the laboratory-scale permeable pavement layers, including a surface permeable brick layer, coarse sand bedding layers (thicknesses = 2, 3.5, and 5 cm), and single-graded gravel sub-base layers (thicknesses = 15, 20, 25, and 30 cm), were built to evaluate stormwater infiltration and surface runoff pollution reduction performance. And, the infiltration rate (I) and concentrations of suspended solids (SS), total phosphorus (TP), chemical oxygen demand (COD), ammonia nitrogen, and total nitrogen (TN) were measured under the simulated rainfall intensity of 72.4 mm/h over duration of 60 min. The results indicate that the thickness factor primarily influences the infiltration rate and pollutant removal rate. The highest steady infiltration rate was for surface brick layer 51.0 mm/h, for 5-cm sand bedding layer 32.3 mm/h, and for 30-cm gravel sub-base layer 42.3 mm/h, respectively. The SS average removal rate was relative higher (79.8 ~ 98.6 %) for all layers due to the interception and filtration. The average removal rates of TP and COD were for surface layer 71.2 and 24.1 %, for 5-cm bedding layer 54.8 and 9.0 %, and for 20-cm sub-base layer 72.2 and 26.1 %. Ammonia nitrogen and TN cannot steadily be removed by layers according to the experiment results. The optimal thickness of bedding sands was 5 cm, and that of sub-base gravels was 20 ~ 30 cm. PMID- 26429140 TI - Contaminant transport in the sub-surface soil of an uncontrolled landfill site in China: site investigation and two-dimensional numerical analysis. AB - A field investigation of contaminant transport beneath and around an uncontrolled landfill site in Huainan in China is presented in this paper. The research aimed at studying the migration of some chemicals present in the landfill leachate into the surrounding clayey soils after 17 years of landfill operation. The concentrations of chloride and sodium ions in the pore water of soil samples collected at depths up to 15 m were obtained through an extensive site investigation. The contents of organic matter in the soil samples were also determined. A two-dimensional numerical study of the reactive transport of sodium and chloride ion in the soil strata beneath and outside the landfill is also presented. The numerical modelling approach adopted is based on finite element/finite difference techniques. The domain size of approximately 300 * 30 m has been analysed and major chemical transport parameters/mechanisms are established via a series of calibration exercises. Numerical simulations were then performed to predict the long-term behaviour of the landfill in relation to the chemicals studied. The lateral migration distance of the chloride ions was more than 40 m which indicates that the advection and mechanical dispersion are the dominant mechanism controlling the contaminant transport at this site. The results obtained from the analysis of chloride and sodium migration also indicated a non-uniform advective flow regime of ions with depth, which were localised in the first few metres of the soil beneath the disposal site. The results of long-term simulations of contaminant transport indicated that the concentrations of ions can be 10 to 30 times larger than that related to the allowable limit of concentration values. The results of this study may be of application and interest in the assessment of potential groundwater and soil contamination at this site with a late Pleistocene clayey soil. The obtained transport properties of the soils and the contaminant transport mechanisms can also be used for the design of engineered barriers for the control of the long term pollution of the site. PMID- 26429142 TI - Biomechanical Changes After Thoracic Endovascular Aortic Repair in Type B Dissection: A Systematic Review. AB - Thoracic endovascular aortic repair (TEVAR) has evolved into an established treatment option for type B aortic dissection (TBAD) since it was first introduced 2 decades ago. Morbidity and mortality have decreased due to the minimally invasive character of TEVAR, with adequate stabilization of the dissection, restoration of true lumen perfusion, and subsequent positive aortic remodeling. However, several studies have reported severe setbacks of this technique. Indeed, little is known about the biomechanical behavior of implanted thoracic stent-grafts and the impact on the vascular system. This study sought to systematically review the performance and behavior of implanted thoracic stent grafts and related biomechanical aortic changes in TBAD patients in order to update current knowledge and future perspectives. PMID- 26429144 TI - Isolation, Characterization, and Antiproliferative Activities of Eudesmanolide Derivatives from the Flowers of Inula japonica. AB - Inula japonica belongs to the family Asteraceae, and its flowers have been used as dietary supplements and health tea in China. The study aimed to identify the bioactive components with the antiproliferative property. Ten 1,10-seco eudesmanolide derivatives, including four new compounds (1-4), were isolated from the flowers of I. japonica. Their structures were established on the basis of the interpretation of spectroscopic data and electronic circular dichroism (ECD) calculations. All of these isolates were evaluated for their antiproliferative activities against MCF-7 and MDA-MB-231 human breast cancer cells. Compound 4 possessed the most potent effects, with the IC50 values of 0.20 +/- 0.04 and 6.22 +/- 1.30 MUM against MCF-7 and MDA-MB-231 cells, respectively. The present investigation indicated that eudesmanolide derivatives from the flowers of I. japonica, especially compound 4, might be used as potential antitumor chemotherapy agent candidates. PMID- 26429145 TI - Early changes in morphology, bone mineral density and matrix composition of vertebrae lead to disc degeneration in aged collagen IX -/- mice. AB - Collagen IX (Col IX) is an important component of the cartilage extracellularmatrix and has been associated with degenerative cartilage disorders and chondrodysplasias in humans. Further, polymorphisms in Col IX are known risk factors for the development of early intervertebral disc (IVD) degeneration. To understand the role of Col IX in the pathogenesis of IVD disorders, the spine of newborn and older Col IX deficient mice was systematically analyzed and compared to C57BL/6N controls. Morphology and bone parameters of the spine from newborn, 6 and 10 months old animals were investigated using MUCT measurements. Histological staining was used to evaluate tissue structure and degree of degeneration. Localization and expression of extracellularmatrix proteins was analyzed in depth by immunofluorescence staining, immunoblotting, RT-PCR and in situ hybridization. High resolution imaging and stiffness measurements were performed by atomic force microscopy (AFM). Vertebral bodies of newborn Col IX-deficient mice were smaller and showed an increased mineral density compared to wild type animals. At birth, lack of Col IX led to a disrupted cellular organization in the cartilaginous endplate and a smaller nucleus pulposus of the IVD.Expression levels and localization of other extracellularmatrix proteins were strongly altered accompanied by a softening of cartilaginous tissues. In older animals, absence of Col IX caused earlier and more pronounced disc degeneration with annular fissures. The absence of Col IX induces early developmental, structural and biomechanical alterations in both vertebral body and intervertebral disc which eventually cause severe degenerative changes in the aging spine. PMID- 26429146 TI - One-Step Protein Conjugation to Upconversion Nanoparticles. AB - The emerging upconversion nanoparticles offer a fascinating library of ultrasensitive luminescent probes for a range of biotechnology applications from biomarker discovery to single molecule tracking, early disease diagnosis, deep tissue imaging, and drug delivery and therapies. The effective bioconjugation of inorganic nanoparticles to the molecule-specific proteins, free of agglomeration, nonspecific binding, or biomolecule deactivation, is crucial for molecular recognition of target molecules or cells. The current available protocols require multiple steps which can lead to low probe stability, specificity, and reproducibility. Here we report a simple and rapid protein bioconjugation method based on a one-step ligand exchange using the DNAs as the linker. Our method benefits from the robust DNA-protein conjugates as well as from multiple ions binding capability. Protein can be preconjugated via an amino group at the 3' end of a synthetic DNA molecule, so that the 5' end phosphoric acid group and multiple phosphate oxygen atoms in the phosphodiester bonds are exposed to replace the oleic acid ligands on the surface of upconversion nanoparticles due to their stronger chelating capability to lanthanides. We demonstrated that our method can efficiently pull out the upconversion nanoparticles from organic solvent into an aqueous phase. The upconversion nanoparticles then become hydrophilic, stable, and specific biomolecules recognition. This allows us to successfully functionalize the upconversion nanoparticles with horseradish peroxidise (HRP) for catalytic colorimetric assay and for streptavidin (SA) biotin immunoassays. PMID- 26429147 TI - Effect of hopelessness on the links between psychiatric symptoms and suicidality in a vulnerable population at risk of suicide. AB - The aim of this study was to examine the impact of two risk factors working together on a measure of suicide probability in a highly vulnerable group who were male prisoners identified as being at risk of self harm. The first risk factor was psychiatric symptoms, including general psychiatric symptoms and symptoms of personality disorder. The second risk factor was psychological precursors of suicidal thoughts and behaviours which were defeat, entrapment, and hopelessness. Sixty-five male prisoners from a high secure prison in NW England, UK, were recruited, all of whom were considered at risk of suicide by prison staff. General psychiatric symptoms and symptoms of personality disorders predicted the probability of suicide. Hopelessness amplified the strength of the positive relationship between general psychiatric symptoms and suicide probability. These amplification effects acted most strongly on suicidal ideation as opposed to negative self evaluations or hostility. In contrast, defeat, entrapment and hopelessness did not affect the relationship between personality disorders and suicide probability. Clinical assessments of highly vulnerable individuals, as exemplified by prisoners, should include measures of a range of general psychiatric symptoms, together with measures of psychological components, in particular perceptions of hopelessness. PMID- 26429148 TI - Relationships between cyberchondria and obsessive-compulsive symptom dimensions. AB - Researchers have recently begun to investigate a vicious cycle of escalating physical health concerns and online medical information seeking coined "cyberchondria". Research has shown that cyberchondria is strongly associated with health anxiety (HA), but there is a dearth of work investigating the potential relationships between cyberchondria and other anxiety-related pathologies. One such condition is obsessive-compulsive disorder (OCD), which could theoretically be related to cyberchondria given the physical health relevant focus of certain types of OC symptoms. The current study sought to investigate the potential relationship between cyberchondria OCD across OC symptom dimensions. Community participants (N=468) were recruited via online crowdsourcing to complete a battery of self-report questionnaires including cyberchondria and OC measures. Structural equation modeling revealed significant unique associations between both contamination/washing and responsibility for harm/checking symptoms, and cyberchondria, such that greater cyberchondria was associated with greater OC symptoms after controlling for HA and trait negative affect. These results suggest that similar to proposed models of cyberchondria and HA, cyberchondria could potentially play a role in the development/maintenance of two dimensions of OC symptoms, or vice versa. Future work will need to determine the causal nature of these relationships or whether they are simply co-occurring phenomena. PMID- 26429150 TI - ESPRESSO: A novel device for laser-assisted surgery of the anterior eye segment. AB - INTRODUCTION: Merging robotics with laser eye surgery could enhance precision, repeatability and automation. During some eye laser procedures the patient is awake, thus eye stabilization is desired to avoid movements that could affect the treatment. MATERIAL AND METHODS: The ESPRESSO platform has a two-stage actuation system to position a stabilization tool on the eye, a proximity sensing unit to monitor the stabilization tool position, and a sensing unit to monitor the pressure exerted on the eye. The platform is tested in-vitro and ex-vivo with clinicians. A maximum pressure to be exerted on the eye is defined with expert ophthalmic surgeons to be 22 mmHg: physiological intraocular pressure (IOP) range is 10-21 mmHg. This pressure corresponds to a force of 0.3 N. RESULTS: The necessary contact force to have eye fixation (according to the clinicians' feedback) is evaluated: maximum values resulted always below 0.3 N. A maximum IOP increase of 4.67 mmHg is observed, that is a slight variation with respect to the performance of other platforms (IOP elevations up to 328 mmHg). CONCLUSION: Design and initial assessment of the platform is presented. Eye stabilization is performed without exceeding the critical contact force value and causing large/sudden IOP increases. PMID- 26429149 TI - Transoral ultrasonic total laryngectomy (TOUSS-TL): description of a new endoscopic approach and report of two cases. AB - The minimally invasive total laryngectomy avoids a wide surgical field and so it has the potential benefit of reducing the local morbidity, especially on radiated patients. This approach has been previously described on a robotic basis, the transoral robotic total laryngectomy (TORS-TL). We have designed a minimally invasive approach for total laryngectomy (TL) using the transoral ultrasonic surgery technique (TOUSS). TOUSS is a transoral, endoscopic, non-robotic approach for laryngeal and pharyngeal tumors, based on the ultrasonic scalpel as a resection tool. Two patients with a laryngeal squamous cell carcinoma with indication for total laryngectomy were surgically treated: one primary TL for a subglottic carcinoma and one salvage TL with partial pharyngectomy for a local relapse after chemoradiotherapy of a glottic carcinoma. The tumors were completely removed with free surgical margin in both patients. The functional recovery was satisfactory in terms of swallowing and speech (a tracheoesophageal puncture and voice prosthesis placement were done in the same procedure). No intraoperative complications were observed. The patient with previous chemoradiotherapy had a pharyngocutaneous fistula which closed spontaneously without additional surgery. We have demonstrated that transoral endoscopic approach to the larynx and pharynx is feasible without a robotic platform. TOUSS TL can easily spread the transoral endoscopic philosophy as well as the benefits of a minimally invasive way to remove the entire larynx. Further research will show the advantages in terms of complications and functional outcomes. PMID- 26429151 TI - Thromboelastographic Clot Characteristics of Autologous Equine Blood Products After Activation by Autologous Thrombin, Bovine Thrombin, or Calcium Chloride. AB - OBJECTIVE: To compare clotting efficiency of platelet-rich plasma (PRP) and concentrated platelet-poor plasma (cPPP) to citrated whole blood after activation by autologous thrombin, bovine thrombin, or calcium chloride (CaCl2 ). STUDY DESIGN: Experimental study. ANIMALS: Healthy adult horses (n = 6). METHODS: PRP and cPPP were prepared by commercial devices. Using thromboelastography, clotting variables were compared after activation of citrated autologous blood, PRP, and cPPP by autologous thrombin, bovine thrombin, or CaCl2 , respectively. RESULTS: PRP had the greatest clot strength and quickest clot rate, whereas cPPP had the weakest clot strength, slowest clot rate, and longest clot initiation time. Bovine thrombin resulted in the shortest clot initiation time, quickest clot rate, and was similar to CaCl2 for greatest clot strength. CaCl2 also resulted in the longest clot initiation time and time to reach maximum clot strength. Autologous thrombin resulted in the lowest clot strength. CONCLUSION: When combined with either bovine thrombin or CaCl2 , PRP provided the best combinations for clinical use. Autologous thrombin was suboptimal, but could be an autologous alternative for clinical application. As prepared here, cPPP had inefficient clotting, but may be sufficient for plasma spray indications. PMID- 26429152 TI - Twin pregnancy: is it a risk factor for long-term cardiovascular disease? AB - OBJECTIVE: To investigate whether twin pregnancy increases the risk for long-term maternal cardiovascular disease (CVD). STUDY DESIGN: A retrospective population based cohort study compared the incidence of long-term CVD in a cohort of women with and without a previous twin delivery. SETTING: Deliveries occurred between the years 1988 and 2012. PATIENTS: Patients who had a twin birth between years 1988 and 2012 were included in the study, patient that had a singleton delivery included in the control group. MAIN OUTCOME MEASURES: CVD was divided into four categories according to severity and type. Kaplan-Meier survival curve was used to estimate cumulative incidence of cardiovascular hospitalizations. Cox proportional hazards model was used to estimate the adjusted hazard ratios (HR) for CVD. RESULTS: During the study period, there were 100 387 women that met the inclusion criteria, 4.6% (n = 4647) delivered twins at least once during the period. The incidence of CVD was 1% in women who had a twin delivery and 1.12% in women who had a singleton delivery. There was no difference in the cumulative incidence of cardiovascular hospitalizations among women who had twin deliveries as compared with singletons. When performing a Cox proportional hazard model, a history of twin delivery did not increase the risk for long-term maternal cardiovascular hospitalizations (adjusted HR = 1.0, 95% CI = 0.8-1.1, p = 0.698). CONCLUSIONS: Twin pregnancy is not associated with an increased risk for long term maternal CVD. PMID- 26429153 TI - Identification of drug candidates and repurposing opportunities through compound target interaction networks. AB - INTRODUCTION: System-wide identification of both on- and off-targets of chemical probes provides improved understanding of their therapeutic potential and possible adverse effects, thereby accelerating and de-risking drug discovery process. Given the high costs of experimental profiling of the complete target space of drug-like compounds, computational models offer systematic means for guiding these mapping efforts. These models suggest the most potent interactions for further experimental or pre-clinical evaluation both in cell line models and in patient-derived material. AREAS COVERED: The authors focus here on network based machine learning models and their use in the prediction of novel compound target interactions both in target-based and phenotype-based drug discovery applications. While currently being used mainly in complementing the experimentally mapped compound-target networks for drug repurposing applications, such as extending the target space of already approved drugs, these network pharmacology approaches may also suggest completely unexpected and novel investigational probes for drug development. EXPERT OPINION: Although the studies reviewed here have already demonstrated that network-centric modeling approaches have the potential to identify candidate compounds and selective targets in disease networks, many challenges still remain. In particular, these challenges include how to incorporate the cellular context and genetic background into the disease networks to enable more stratified and selective target predictions, as well as how to make the prediction models more realistic for the practical drug discovery and therapeutic applications. PMID- 26429154 TI - Metal-based nanosystems for diagnosis. AB - The impressive diversity related to etiologic factors and the distinctive genetic and immunological behavior attained by various conditions represent the fundamental reasons for high-rated inefficient and eventual hazardous strategies entailed by conventional healthcare practice. Thanks to the tremendous progress reported in nanotechnology during the last decades, various unconventional and promising strategies have been successfully developed and examined with respect to potential genuine biomedical applications. Given the amazing possibility to manipulate matter at a molecular and atomic level and the incessant need to design and implement personalized therapies, various nanosized systems have thus been engineered. Among the newly developed nanomaterials, metallic nanoparticles have gain attention during the intense biomedical research activity, thanks to their peculiar size-conditioned properties. An efficient therapeutic strategy begins with an accurate diagnosis result, so the immediate requirement of such specific detection tools is conspicuous. The use of silver and gold in day-to-day activities is acknowledged since ancient times, but the novel technological opportunities extended their particular applications towards personalized medicine. It is worthy to mention that the unexpected nanodimension-related features of the aforementioned noble metals strongly recommend them for a large number of current applications in nanomedicine, including novel and specific metallic nanostructures used in diagnostics. PMID- 26429155 TI - Current understanding of the neurobiology of major depressive disorder. AB - Depression is highly prevalent worldwide and associated with significant morbidity and mortality. Approximately 340 million people worldwide suffer from depression at any given time. Based on estimates from the World Health Organization (WHO), depression is responsible for the greatest proportion of burden associated with non-fatal health outcomes and accounts for approximately 12% total years lived with disability. Probably no single risk factor can be completely isolated in major depressive disorder (MDD), as interactions between many sources of vulnerability are the most likely explanation. Buttressing the identification of grief, demoralization, hopelessness and styles of psychological coping of the depressed patient are vital, ongoing scientific developments that flow from an increased understanding of this interplay amongst the immune system, endocrine system and brain. The rapidly accumulating body of neurobiological knowledge has catalyzed fundamental changes in how we conceptualize depressive symptoms and has important implications regarding the treatment and even prevention of depressive symptoms in patients. PMID- 26429156 TI - Morphological features of melanocytic tumors with depigmented halo: review of the literature and personal results. AB - Halo (Sutton's) phenomenon has been described as a depigmented halo that is associated most commonly with acquired melanocytic nevi; but it may be associated with various types of melanocytic skin tumors, melanoma being the most concerning. Different authors have been preoccupied with elucidating morphological features of melanocytic tumors associated with a depigmented halo. We reviewed the literature and discussed the main features of melanocytic halo tumors regarding histopathological, immune microenvironment profile and dermatoscopic appearance. We highlighted similarities and differences between Sutton's nevus and halo melanoma, also presenting relevant aspects of our results. Depigmented halo must be regarded as a phenomenon that may be associated with different types of melanocytic tumors and with a broad spectrum of histopathological atypia degree. Certain correlations between the shape, diameter, symmetry observed in clinical examination, histopathological appearance, dermatoscopic aspect of peritumoral halo and central tumor type could not be established due to insufficient data and contrasting results. Further studies are expected to add valuable information regarding the depigmented halo tumors features. PMID- 26429157 TI - Correlation of angiogenesis with other immunohistochemical markers in cutaneous basal and squamous cell carcinomas. AB - The aim of this study was to establish an immunoprofile of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), and to explore as first time in literature the possible correlation between maspin, DOG-1, p16 protein and angiogenesis in these tumors. For SCCs, the histological grade of differentiation was also taken into account. The angiogenesis was quantified in 38 randomly selected cases of SCCs and 17 BCCc, respectively, using the antibodies vascular endothelial growth factor (VEGF-A) and COX-2, while the microvessel density (MVD) was evaluated with the CD31. RESULTS: In SCCs, maspin cytoplasm to nuclear shift was an indicator of a deeper tissue invasion and dedifferentiation in the invasion front. The poorly differentiated cases, compared to G1/G2-SCCs, expressed more frequent the markers p16 (30.77% vs. 8%) and VEGF-A (53.85% vs. 32%), regardless the MVD. However, the p16 positivity was more frequent in BCCs than SCCs (52.94% vs. 15.79%). All of the p16-positive carcinomas were located in the head and neck area. DOG-1 marked 21.05% of SCCs and 5.88% of BCCs, being directly correlated with COX-2 positivity. Eccrine glands and hair follicles also expressed DOG-1. CONCLUSIONS: In cutaneous SCCs located in the head and neck area, sun-dependent p16/VEGF interaction seems to be responsible by tumor dedifferentiation, whereas maspin cytoplasm to nuclear shift might indicate a high degree of invasiveness. This is the first report about DOG-1 positivity in BCCs and eccrine glands, the significance of this pattern being unknown. PMID- 26429158 TI - KRAS gene mutations - prognostic factor in colorectal cancer? AB - The colorectal cancer (CRC) modern therapy is using adjuvant and neoadjuvant companion therapeutic agents, part of them having an anti-angiogenic action. Their benefic effect can be annulated by some gene mutations, which are interfering in signal transduction pathways. One of the more frequent activating mutations is occurring in the KRAS gene. We assessed the KRAS mutations by two molecular methods, in a group of patients with a follow-up until 144 months, aiming to establish eventual correlations between the presence of mutations and the evolution of patients. We tried to appreciate the prognostic value of these mutations. A retrospective study was conducted on 74 patients treated by radical surgery; the surgical specimens were analyzed macroscopically and the histopathological type and degree were established. PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) and pyrosequencing were performed on paraffin-embedded tumor specimens. Statistical analysis showed significant differences in survival between patients with wild type gene and patients with mutation in codon 13; the same results were also obtained regarding TNM I, II stages or Dukes type A and B cases. However, for the patients in stage IV pTNM, the evolution was slightly better in association with a KRAS mutation than in wild type cases. PMID- 26429159 TI - Preliminary study of correlations between the intratumoral microvessel density and the morphological profile of colorectal carcinoma. AB - AIM: New blood vessel formation (angiogenesis) is a fundamental event in the process of tumor growth and metastatic dissemination. The aim was to evaluate intratumoral vascular density (ITMVD) and to analyze possible correlations between ITMVD and the morphological profile of colorectal carcinoma. MATERIALS AND METHODS: The studied group consisted of 50 patients that underwent surgery for colorectal tumors, 12 of them receiving preoperatory radiotherapy. The analyzed morphological parameters were tumor site, tumor gross aspect, tumor longitudinal and transverse diameter, tumor grading, local invasion (pT), regional invasion (pN), distant metastases (pM) and intratumoral microvessel density (ITMVD) expressed as number of capillaries/mm2. The malignant tissue samples were included in paraffin blocks and serial tissue sections were cut both for Hematoxylin-Eosin staining and CD34 immunomarking. For each case, five consecutive fields without necrosis were randomly selected with *10 objective. Quantitative measurements were performed using special software for image analysis. RESULTS: For non-irradiated colorectal tumors, ITMVD was the highest in rectal localization, in infiltrative tumors, in circumferential tumors, in tumors with low longitudinal extension, in moderately differentiated (G2) tumors and in pT4, pN0 and pM1 tumors. DISCUSSION: Correlations showed different trends of ITMVD depending on each parameter: ITMVD was higher when the tumor was closer to the rectum, when it was more infiltrative, more circumferential or with low longitudinal diameter. These trends might be exploited in defining future anti angiogenic therapeutic strategies. CONCLUSIONS: There were some interesting correlations between ITMVD and studied morphological parameters that have to be validated on larger series of cases. PMID- 26429160 TI - Toxicity of L-DOPA coated iron oxide nanoparticles in intraperitoneal delivery setting - preliminary preclinical study. AB - Iron oxide nanoparticles are promising candidates for theranostics in cancer, that aims to achieve in one-step precise tumor imaging by magnetic resonance, and targeted therapy through surface attached anti-cancer drugs. The aim of this study was to investigate in preclinical setting the biocompatibility of new iron oxide-based nanoparticles that were coated with L-DOPA for improved dispersion in biological media. These nanostructures (NPs) were designed for biomedical applications as contrast agents and/or drug carriers. We investigated the effect exerted in vitro by NPs and L-DOPA on the viability and proliferation of normal mouse L929 fibroblasts. NPs exhibited good biocompatibility against these cells. Moreover, L-DOPA contained in NPs sustained fibroblasts proliferation and/or limited anti-proliferative effects of naked nanoparticles. In the animal study, C57BL/6 mice were injected intraperitoneally with a single dose of NPs (approximately 125 mg/kg body weight). We followed up hematological and histological parameters for one, three and seven days after NPs administration. Results indicated that NPs possibly induced local inflammation and consequent recruitment of peripheral lymphocytes, whilst the decrease of platelet counts may reflect tissue lesions caused by NPs. The histopathological study showed mild to moderate alterations in the hepatocytes, splenic and renal cells, while the brain parenchyma only presented nonspecific congestive changes. Taken altogether, the preclinical study indicated that the new iron oxide nanoparticles coated with L DOPA were biocompatible against fibroblasts and had a convenient toxicological profile when administered intraperitoneally in a single dose to C57BL/6 mice. Accordingly, the proposed nanostructure is a promising candidate for imaging and treating dispersed peritoneal tumors. PMID- 26429161 TI - Expression pattern of beta-catenin during the development of human fetal spinal cord. AB - Development of the human fetal spinal cord is a very complicated process involving numerous signaling pathways including Wnt signaling pathways. These pathways are critical for the development and function of the mammalian nervous system. beta-Catenin is a key molecule in the canonical Wnt signaling pathway. However, the distributions of beta-catenin during development of the human fetal spinal cord have not been well characterized. Therefore, in this study, we performed immunohistochemical analysis of the beta-catenin distribution in the developing human spinal cord from 35 fetuses at three weeks to eight months of gestation. As early as E3W and E4W, beta-catenin was mainly expressed in the internal limiting membrane of the neural tube and neuroepithelium (E: Embryos; W: Weeks). During developmental stages, beta-catenin was widely expressed in various structures and cells including the neuroepithelium, internal limiting membrane, mantle layer, marginal layer, basal plate, alar plate, ependyma, gray matter, white matter, neurons with multiple processes, glial cells, and nerve fibers. This study clarifies the morphological developmental characteristics of the human fetal spinal cord as well as the distribution and expression pattern of beta catenin in chronological and spatial aspects. Our results suggest that the Wnt/beta-catenin signaling pathway might play a crucial role in various stages of the formation and differentiation of the human fetal spinal cord. PMID- 26429162 TI - Real-time quantitative PCR detection of WT1 and M-BCR-ABL expressions in chronic myeloid leukemia. AB - The Philadelphia chromosome and the resulting BCR-ABL fusion gene represent the hallmark event in chronic myeloid leukemia (CML) and their discoveries radically changed the management of these patients. Currently Wilms tumor 1 gene (WT1) is intensively investigated as high WT1 expression levels have been demonstrated in case of multiple solid tumors and malignant hematological syndromes (acute myeloid and lymphoid leukemia, myelodysplastic syndromes and chronic myeloid leukemia). The aim of our study was to investigate the WT1 expression in CML patients and its possible contribution to disease evolution. PATIENTS AND METHODS: In the Laboratory of Molecular Biology, University of Medicine and Pharmacy of Tirgu Mures, Romania, we regularly determined the M-BCR-ABL and WT1 expression levels by RQ-PCR (real-time quantitative polymerase chain reaction) testing in case of 19 CML patients: six patients monitorized from the diagnosis and 13 patients first tested during therapy. RESULTS: Eight CML (four advanced stage and four CP) patients showed high WT1 expression level, and in case of 11 patients the WT1 expression levels were undetectable or lower than 0.02%. The only significant difference between the high and low WT1 expression groups was represented by the clinical stage. In the majority of pretreated patients (10 out of 13 patients), the WT1 expression levels were low or undetectable. CONCLUSIONS: High WT1 expression in CML patients is detected especially in the advanced stages of the disease. Efficient Imatinib therapy may contribute to low WT1 levels in CP patients. PMID- 26429163 TI - Interplay between expression of leptin receptors and mucin histochemical aberrations in colorectal adenocarcinoma. AB - BACKGROUND: There is no information on the effects of leptin receptors expression on mucin-histochemical alterations in human colorectal adenocarcinoma. AIM: Testing the correlation of leptin receptors expression with histochemical dysregulation of mucins in colorectal adenocarcinoma. PATIENTS AND METHODS: The study included 75 patients with colorectal adenocarcinoma who underwent surgical resection. Following a routine histopathological tissue analysis, 3-4 MUm thick cuts were made onto resected tumors, which underwent a routine Hematoxylin-Eosin, histochemical Alcian Blue-Periodic Acid Schiff, pH 2.5, and High Iron Diamine Alcian Blue, pH 2.5, methods for mucin differentiation and immunohistochemical Avidin-Biotin peroxidase complex method with anti-Ki67 and anti-leptin receptor antibodies. Following the quantification of results for the statistical analysis, the statistical software package SPSS for Windows (13.0) was used, and the tests for analyzing the significance of differences and correlation analysis - Spearman's rank correlation coefficient, were conducted. RESULTS: Increased expression of leptin receptors is with highly significant correlation coefficient associated with hypersecretion of sialomucins. Significant positive correlation coefficient exists between the leptin receptors expression against neutral fucomucins secretion. With weak and negative, but a significant correlation coefficient, leptin receptors expression is associated to the sulfomucins generation. CONCLUSIONS: Increased expression of leptin receptors in colorectal adenocarcinoma is associated with mucin-histochemical abnormalities that are manifested by sialomucins hypersecretion and reduction, ultimately resulting in the absence of sulfomucins secretion. PMID- 26429164 TI - c-abl and YWHAZ gene expression in gastric cancer. AB - This study aims to determine the gene expression for c-abl and YWHAZ in gastric cancer and the differences between the c-abl and YWHAZ gene expression inside the tumor versus healthy tissue (at the resection edges). This prospective study included 34 patients with gastric neoplasia, 21 men and 13 women, aged between 49 and 79 years (65.5 years median). After the surgical procedure, in these cases, we collected two tissue samples: one sample was obtained from inside the tumoral tissue and another sample from the gastric tissue, which was identified as normal apparently, as far as possible from the tumor (resection edge). For determining the c-abl and YWHAZ gene expression, we used the quantitative real-time polymerase chain reaction. Regarding the c-abl gene expression in gastric cancer, c-abl expression was identified as lower inside tumor cells comparing to the normal gastric tissue (resection limit). This difference of gene expression emphasize the role of the c-abl gene in normal tissue growth and the involvement in apoptosis induction when alteration of DNA occurs, as a result to different agents actions as stress, ionizing radiations. The loss of expression or even the down-regulation of the c-abl is a fundamental event that leads to genesis and progression of tumors. No significant differences of the YWHAZ gene expression between the tumoral and normal gastric tissue probes were recorded in our study. PMID- 26429165 TI - Enhanced expression of vascular endothelial growth factor and increased microvascular density in women with endometrial hyperplasia: a possible relationship with uterine natural killer cells. AB - This case-control study aimed to investigate the expression of natural killer cells (NKCs) and the integrated optical density (IOD) of vascular endothelial growth factor (VEGF) and to quantify microvascular density (MVD) in endometrial biopsies from women with endometrial hyperplasia (EH) relative to normal subjects. Histological data from four groups were analyzed. The study population included 30 women with simple EH without atypia, 25 patients with complex EH without atypia, 25 with complex EH with atypia and 25 healthy women with non hyperplastic endometrium (control group). Paraffin sections were immunostained with antibodies against CD56, VEGF-A and CD34 using an Avidin-Biotin-Peroxidase technique. The evaluation of NKC density and IOD of VEGF expression and measurement of MVD were performed using light microscopy examination and image analysis techniques. Increased numbers of NKCs were documented in cases of complex EH with atypia compared with the other groups (p<0.001). The number of NKCs was lower in cases of hyperplasia without atypia compared with the controls, but the difference was not significant. The IOD of VEGF-A and MVD increased significantly with progression from the non-hyperplastic endometrium through the three groups of EH (p<0.001). We observed a significant correlation between the MVD and the IOD of VEGF-A in the studied groups (r=0.434; p<0.001). Additionally, NKCs density was correlated significantly with IOD of VEGF-A (r=0.661; p<0.001) and with the MVD (r=0.473; p<0.001). These results suggest that NKC-count, IOD of VEGF and endometrial MVD are all related to the histological changes of the endometrium and that endometrial hyperplasia exhibits distinct immunological backgrounds in the context of NKC infiltration and VEGF production. PMID- 26429166 TI - A hardware approach for histological and histopathological digital image stain normalization. AB - Advances in technology made the migration of pathological diagnosis to digital slides possible. As the need for objectivity and automation emerged, new computer software algorithms were proposed. Computer algorithms demand accurate color and intensity values in order to provide reliable results. The tissue samples undergo several processing steps from histological preparation to digitalization, which cannot be completely standardized. Thus, non-standardized input data generates unreliable output data. In this article, we discuss a new computational normalization algorithm for histopathological stained slides that uses a hardware color marker. The marker is added to the glass slide together with the tissue section, exposed to all the processing steps and altered in the same manner as the biological material of interest, thus becoming a solid color marker for image normalization. The results of the proposed method are numerically and perceptually tested in order to prove the advantages of the method. We conclude that our combined hardware-software technique for staining normalization of digital slides is superior to the existing methods based on only software normalization, and that its implementation will tackle not only the acquisition errors but also the technical errors that may occur during the staining process. PMID- 26429167 TI - Ovariectomized rats' femur treated with fibrates and statins. Assessment of pore size distribution by 1H-NMR relaxometry. AB - The effects of two wonder drugs, simvastatins and fenofibrates on the proximal part of the femoris of a series of ovariectomized and non-ovariectomized Wistar albino rats was estimated qualitatively and semi-quantitatively by the modern method of 1D 1H-NMR T2-distribution. The 72 rats subjected to this study were divided in six groups and were sacrificed at two, four, six and eight weeks after ovariectomy and the proximal part of femoris was harvested. The CPMG (Carr Purcell-Meiboom-Gill) echoes train curves were measured for the bones fully saturated with water during two months after two months of natural drying. These decays were analyzed by Laplace inversion and an average of normalized T2 distributions was considered for all rat's groups. The 1D averaged T2 distributions present four peaks, which were associated with protons in four major environments, from which the free water protons are used as spy molecules to explore the boundaries of cavities. In the approximation of spherical pores, the averaged T2-distributions were transformed in distributions of pores diameters. These were found in the range from 2 MUm up to 2 mm. The relative amplitudes, widths and position of deconvoluted distributions of small, medium and large cavities are used for a qualitatively analysis of the effect of our lipid-lowering drugs. For a semi-quantitatively analysis, we chose the diameter d of proximal part of femoris' trabecular cavities. We show that the positive or negative effects of treatments with simvastatins and fenofibrates are strongly dependent on the duration of treatment. Moreover, the treatment of healthy bone is generally counter-indicated. PMID- 26429168 TI - The assessment of lower face morphology changes in edentulous patients after prosthodontic rehabilitation, using two methods of measurement. AB - Using two measurement methods (a three-dimensional laser scanning system and a digital caliper), this study compares the lower face morphology of complete edentulous patients, before and after prosthodontic rehabilitation with bimaxillary complete dentures. Fourteen edentulous patients were randomly selected from the Department of Prosthodontics, at the Faculty of Dental Medicine, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania. The changes that occurred in the lower third of the face after prosthodontic treatment were assessed quantitatively by measuring the vertical projection of the distances between two sets of anthropometric landmarks: Subnasale - cutaneous Pogonion (D1) and Labiale superius - Labiale inferius (D2). A two-way repeated measures ANOVA model design was carried out to test for significant interactions, main effects and differences between the two types of measuring devices and between the initial and final rehabilitation time points. The main effect of the type of measuring device showed no statistically significant differences in the measured distances (p=0.24 for D1 and p=0.39 for D2), between the initial and the final rehabilitation time points. Regarding the main effect of time, there were statistically significant differences in both the measured distances D1 and D2 (p=0.001), between the initial and the final rehabilitation time points. The two methods of measurement were equally reliable in the assessment of lower face morphology changes in edentulous patients after prosthodontic rehabilitation with bimaxillary complete dentures. The differences between the measurements taken before and after prosthodontic rehabilitation proved to be statistically significant. PMID- 26429169 TI - The storage period of the formalin-fixed paraffin-embedded tumor blocks does not influence the concentration and purity of the isolated DNA in a series of 83 renal and thyroid carcinomas. AB - Optimal recovery of nucleic acids from formalin-fixed paraffin-embedded (FFPE) tissues is highly dependent on a series of pre-extraction steps, mainly related (but not limited) to fixation. The aim of our study was to investigate if the storage period of the FFPE blocks had a significant effect on the isolated DNA. We examined the quantity and purity of the isolated DNA from 83 FFPE blocks, corresponding to malignant thyroid (n=28) and renal (n=55) carcinomas that had been stored in our department for up to eight years. The DNA extraction protocol was based on a precipitation method (MasterPureTM DNA Purification Kit, Epicentre), in accordance to the manufacturer instructions, optimized in our laboratory. A spectrophotometer was used to determine the yield (A260) and purity (A260/A280 ratio) of the isolated DNA. We successfully isolated good DNA quantity and purity from all our study cases (mean concentration: 223.4 +/- 104.16 ng/MUL; mean A260/A280 ratio: 1.68 +/- 0.09). Moreover, no statistically significant differences were observed between tumor blocks stored for 2-3 years and 7-8 years, respectively, both in terms of DNA quantity (p=0.196) and purity (p=0.663). In conclusion, we successfully validated an efficient, reproducible DNA extraction technique that provided a good range of DNA concentrations and purity, regardless the type of tissue (thyroid or kidney). Moreover, we demonstrated that the storage period of the FFPE blocks does not have a significant influence on the DNA quantity and purity. PMID- 26429170 TI - Etiopathogenic, therapeutic and histopathological aspects upon the anterior vaginal wall prolapse. AB - The pelvine organ prolapse (POP) is a condition affecting million of women, with a major impact upon the social and professional life of the patients. According to various studies, it affects approximately 40% of the women aged over 50 years. About 10% of women with POP require a surgical procedure for POP or urinary incontinence. Our study comprised a number of 14 patients, aged between 55 and 70 years, hospitalized and treated in the Clinic of Urology within the Emergency County Hospital of Craiova, Romania, between 2011 and 2013, for second-degree cystocele. Of these, 11 (78.57%) patients had more than two natural deliveries, 10 suffered more than three abortions, and eight (57.14%) women suffered from obesity. The increase of abdominal pressure, induced by chronic coughing, constipation or hard physical work, was identified in more patients. Thus, six (42.8%) patients presented chronic bronchitis, four (28.57%) patients were smokers, eight (57.14%) patients presented chronic constipation, and 10 (71.42%) patients stated that they had performed hard physical work. The presence of effort urinary incontinence, associated to the cystocele, was found in eight (57.14%) cases. The surgical intervention consisted in the performance of a direct cystopexia with a synthetic tent, placed in a transobturatory way, in a "tension free" manner (Perigee System). The post-operatory evolution was a good one; the results after six months showed that 12 (85.71%) women were cured, two (14.29%) cases of cystocele relapsed, while in two patients there maintained the effort urinary incontinence. The histopathological examination of the anterior vaginal wall fragments, harvested during the surgical intervention, showed the presence of a chronic inflammatory infiltrate in the lamina propria of the uterine mucosa, which may cause the post-operatory relapses. We consider that the reduction of the inflammatory process through the administration of anti inflammatory drugs could reduce the POP onset and progress. PMID- 26429171 TI - Electron microscopic aspects of the effects of certain prostaglandin analogs on mouse testes. AB - Prostaglandins were highlighted in the seminal plasma and then in the rest of the male and female genital tract. Prostaglandin analogs, firstly used in obstetrics and gynecology, are now widespread in both sexes, especially in the treatment of gastric and duodenal ulcers, glaucoma, etc. Therefore, we tried to highlight the effects of repeated administration of Cloprostenol and CIPG isopropyl ester (both prostaglandin F2alpha analogs) for the male gonad. In our experiment, we used Cloprostenol and CIPG isopropyl ester. We used three groups of white, male mice, aged 50-80 days, kept in standard laboratory conditions, which received the same feed. Each group included 12 mice. The first batch was the control group and received no substance at all. The second batch received 25 MUg/kg of Cloprostenol dose per body per day, intraperitoneal administration (a single dose per day) on a daily basis for a four weeks period of time. The third batch received a 25 MUg/kg CIPG isopropyl ester dose per body/day intraperitoneal administration (a single dose per day) on a daily basis for a four weeks period of time. After 7, 14 and 28 days of treatment, we sacrificed four animals in each of the batches by cutting their carotid arteries. The prostanoid analogs we used, Cloprostenol and CIPG isopropyl ester, have similar actions on male gonad in mice. These analogs induced significant changes in the evolution of the spermatogenesis and spermiogenesis. In relation to the treatment duration there were cellular changes suggesting apoptosis in different stages. With regard to spermiogenesis, the ultrastructural aspects indicate a decrease of the sperm structuring processes, especially in the acrosomal apparatus and chromatin. PMID- 26429172 TI - Vascular calcification in continuous ambulatory peritoneal dialysis patients. AB - Vascular calcifications represent a severe complication of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) stage 5. The factors influencing the development of this complication are in close relation with the pathology of chronic dialysis premorbid condition, and with therapy as well. The present article highlights the association between several factors and the development or the aggravation of vascular calcifications in continuous ambulatory peritoneal dialysis (CAPD) patients. The results are not always in accordance with similar literature data, but there is a lack of researches regarding mineral metabolism in peritoneal dialysis patients versus those on chronic hemodialysis. PMID- 26429173 TI - Studies regarding the protective effects exhibited by antidepressants on cell models. AB - The study aimed to assess in vitro the short-term effects exerted by fluoxetine, sertraline and venlafaxine on certain physiological properties in two different study models: U937 monocytes and erythrocytes isolated from patients treated with the above-mentioned molecules. Results on U937 cell suspensions revealed the depolarization of the cell membrane induced by the three antidepressants. The maximal depolarization effect was registered after 15 minutes of cell exposure and was concentration-dependent, in a non-monotonic manner. The effect was also dependent on the tested compound, fluoxetine presenting the strongest depolarizing effect compared to sertraline and venlafaxine. The erythrocyte susceptibility to lipid peroxidation and glucose-6-phosphate dehydrogenase activity were assessed on red blood cells isolated from patients with depressive disorder. Our results revealed that antidepressant treatment induced the antioxidant defense, by decreasing erythrocyte susceptibility to lipid peroxidation and increasing glucose-6-phosphate dehydrogenase activity. The effect is more intense in the case of severe pathology and less evident in the case of moderate or minor disorder, as expressed by MADRS (Montgomery-Asberg Depression Rating Scale) score. Our results could indicate that selected antidepressants at therapeutic concentrations, besides their known pharmacological effects, exhibit a protective effect against oxidative stress and also influence cells with immune properties. PMID- 26429174 TI - Histological and immunohistochemical aspects of papillary thyroid cancer. AB - Papillary thyroid carcinoma is one of the most common malignancies of the endocrine system. In recent years, its incidence has increased worldwide, including children, which concerns the entire community. Although the histopathological diagnosis seems rather easy, the existence of particular forms of thyroid cancer and the inclusion of the follicular aspect as a variant of papillary carcinoma lead to diagnostic confusion. Therefore, in the last 20 years were reviewed several immunohistochemical markers, which are useful in the positive and differential diagnosis, and which offer better data on disease prognosis. Our study included a total of 27 cases of papillary carcinomas, which we evaluated the immunohistochemical expression of Ki-67, p53, p63, E-cadherin, CD56, calretinin, and bcl-2 markers. The most intense expression was found in p53, E-cadherin, and bcl-2. Ki-67 and p63 expression were moderate and inconsistent, and CD56 and calretinin had a negative expression in all cases. PMID- 26429175 TI - Histological differences between laser-assisted and suction-assisted lipoplasty aspirates - a comparative study. AB - INTRODUCTION: The authors aimed to assess the histological differences between the traditional suction-assisted lipoplasty (SAL) and the more recently developed laser-assisted lipoplasty (LAL) aspirates, in a 20-case comparative study. PATIENTS AND METHODS: Between March of 2011 and March of 2012, we operated on 20 healthy female patients seeking body contouring procedures of the abdomen, flanks and outer thighs, all having good to moderate skin tone and moderate to heavy adipose deposits and no previous treatment of the interested areas. After initial aspiration of a 100 mL sample of fat tissue through the SAL technique, we applied the LAL protocol, using a Lipolite device with a 1064 nm Nd:YAG laser, again sampling the aspirate for histological study. RESULTS: The analyzed samples revealed significant histological difference between the two aspirates: the adipose tissue architecture, after conducting the LAL procedure, appeared to be disrupted, consisting of deformed and ruptured fat cells surrounded by coagulation-modified collagen, small lymphocytic inflammatory infiltrate, coagulated small blood vessel and intact nerves. In contrast, the cytological patterns of the adipose tissue after using the SAL technique resembled normal fat tissue structure. CONCLUSIONS: Our study succeeded in demonstrating significant histological differences between SAL and LAL aspirates, many of which could explain certain disparities between the clinical outcomes of the two procedures. PMID- 26429176 TI - Histological and immunohistochemical study of the eyelid basal cell carcinomas. AB - The eyelids represent a frequent site for numerous malignant tumors, which generally present subtle symptoms or can imitate benignant tumors. Our study was carried on 80 patients, 48 males and 32 females aged between 48 and 92 years. The patients were hospitalized in the Ophthalmology Clinic of the Emergency County Hospital of Craiova, Romania. The study was conducted over five years, between 2010 and 2014. Our study included 80 basal cell carcinomas of the eyelids, of which 48 (60%) were nodular basal cell carcinomas, 15 (18.75%) were adenoid basal cell carcinomas, 10 (12.5%) were cystic and seven (8.75%) were morpheaform basal cell carcinoma. Our study showed a moderate expression of bcl-2 marker in the nodular type of basal cell carcinoma and a high expression in the other histopathological types, thus inducing an increased malignancy comparing to the nodular type. E-cadherin was absent in nodular, cystic and adenoid basal cell carcinomas and had a moderate expression in morpheaform basal cell carcinoma. Morpheaform and adenoid types presented 20% expression of Ki67 of the malignant cells nuclei, while the cystic type presented Ki67 expression in less than 10% of the malignant cells nuclei. Due to high morbidity and increasing incidence, basal cell carcinoma of the eyelid represents an important health issue nowadays. PMID- 26429177 TI - Chondrosarcoma of the hyoid bone: a case report. AB - Chondrosarcoma is a malignancy of the mesenchymal tissue derived from transformed cells that produce the cartilage matrix. In the neck area, it represents less than 0.5% of malignant tumor pathology. Chondrosarcoma of the hyoid bone is extremely rare, only 20 cases having been published so far (PubMed 2014). We present the case of a 30-year-old patient from the urban area, admitted in the ENT (Ear, Nose & Throat) Emergency Service with inspiratory dyspnea, dysphagia, stomatolalia, with evolutive and progressive clinical history of 2-3 months. Endoscopic examination revealed a pharyngolaryngeal tumor process located in the right vallecula, who by mass effect displaces the above-hyoid epiglottis. CT (computerized tomography) scan described a cervical polycystic tumor aspect, with multiple septae and inside calcifications with a diameter of 3-4 mm. Surgery consisted in removal of the tumor process together with the hyoid bone. Histopathological and especially immunohistochemical examination established the diagnosis of low-grade chondrosarcoma of the hyoid bone. For assessment of the phenotype of the tumor cells, the following immunohistochemical markers were used: p53, Ki67. The patient followed radiochemotherapic oncological treatment and returned for regular follow-ups. There was a positive development with no signs of regional or remote relapse or metastasis for 24 months after surgical treatment. Surgery is the treatment of choice, with complete removal of the tumor, with chemoradiation playing an adjuvant role. Regular tracking of the patient is mandatory. PMID- 26429178 TI - A challenging case of ocular melanoma. AB - Ocular melanoma is a rare malignancy found in clinical practice. In this paper, we present a case of highly aggressive ocular melanoma, which was surgically removed at the Department of Ophthalmology and diagnosed at the Department of Pathology, Emergency University Hospital, Bucharest, Romania, using conventional histopathological techniques. Uveal melanoma, a subset of ocular melanoma, has a distinct behavior in comparison to cutaneous melanoma and has a widely divergent prognosis. Approximately half of patients with ocular melanoma will develop metastatic disease, predominantly with hepatic, pulmonary or cerebral location, over a 10 to 15 years period. No systemic therapy was associated with an evident clinical outcome for patients with advanced disease and overall survival rate remains poor. PMID- 26429179 TI - Congenital solitary kidney with multiple renal arteries: case report using MDCT angiography. AB - A congenital solitary kidney with multiple renal arteries is a rare congenital abnormality that can occur in the presence of multiple other anomalies. We describe an atypical case of a right congenital solitary kidney with three renal arteries (RA) one main RA and two additional renal arteries in a 75-year-old woman with uterine didelphys. The main RA had an intraluminal diameter larger than the diameter of the additional renal arteries (AdRAs) at the origin (0.53 cm for the main RA; 0.49 cm and 0.32 cm for the two AdRAs). Both the AdRAs had a greater length than the main RA (3.51 cm for the main RA; 3.70 cm and 4.77 cm for the two AdRAs). The calculated volume of the kidney was 283 cm3, while the volume of the renal parenchyma was 258 cm3. Knowledge of this variant is extremely important in clinical practice as it has been found to be associated with proteinuria, hypertension and renal insufficiency. PMID- 26429180 TI - Solitary trichoepithelioma: clinical, dermatoscopic and histopathological findings. AB - Trichoepithelioma is part of the adnexal carcinomas. It is a benign, small tumor, usually under a centimeter in diameter, which develops in the basal cells of the hair follicle. CASE REPORT: We present the case of a 30-year-old female patient, from rural area, which was hospitalized in the Clinic of Dermatology, Emergency County Hospital, Craiova, Romania, in March 2015, for the presence of a skin tumor, with round-oval shape, 0.5 cm in diameter, brownish colored, located on the left cervical region. The patient had no past medical history. The skin tumor appeared two years ago, and it was slowly increasing in size. Physical examination was in normal ranges. The dermatoscopic examination reveal a pearly white background covered with tumor islands that were oval shaped, with hyperpigmentation, centered by keratin cysts and surrounded by collagen. During hospitalization, we performed tumor biopsy. The histopathological examination showed microscopic structure of trichoepithelioma. After history taking, physical examination, dermatoscopic examination and histopathological result, our diagnosis was left cervical trichoepithelioma. CONCLUSIONS: Trichoepithelioma is a rare trichogenic tumor, which appears at any age, including newborns, with potential for local recurrence. Our case report represents a classic dermatoscopic aspect of trichoepithelioma, that can have close resemblance to basal cell carcinoma and other skin adnexal tumors, clinically, dermatoscopic and histopathological. PMID- 26429181 TI - A rare case of concomitant tuberculosis of the nose, paranasal sinuses and larynx: clinical, histological and immunohistochemical aspects. A case report. AB - Extrapulmonary tuberculosis is a rare condition determined by Mycobacterium tuberculosis. It can affect any organ, and has a higher incidence with the increase of HIV infection, or in countries with high pulmonary tuberculosis. Diagnosis is difficult, mostly because of non-specific symptoms and a low rate of presentation for medical consult when symptoms do occur. Complete diagnosis is usually set by histological, immunohistochemical examinations, and also with Polymerase Chain Reaction (PCR) in selected cases. The authors present a case of concomitant tuberculosis of the nose, paranasal sinuses and subglottic larynx, without primary involvement of the lungs. The diagnosis was imposed by histological examination and immunostaining of probes obtained in surgery. The treatment was surgical debridement followed by specific antituberculosis medication. PMID- 26429182 TI - Low-grade appendiceal mucinous neoplasm mimicking an adnexal mass. AB - We present a rare case of malignant epithelial neoplasm of the appendix, an uncommon disorder encountered in clinical practice, which poses a variety of diagnostic and therapeutic challenges. We report a particular case in which the appendix was abnormally located in the pelvis, mimicking an adnexal mass. Therefore, it was difficult to make the preoperative diagnosis on clinical examination, imaging studies and laboratory tests and we discovered the lesion during the diagnostic laparoscopy. No lymphadenopathy or mucinous ascites were found. The case was completely handled via the laparoscopic approach keeping the appendix intact during the operation. The frozen section, the detailed histopathology overview as well as multiple immunostaining with a complex panel of markers report diagnosed a low-grade appendiceal mucinous neoplasm (LAMN) with no invasion of the wall. No adjuvant therapy was considered needed. At a one-year follow-up oncological assessment, the patient was free of disease. In women with cystic mass in the right iliac fossa an appendiceal mucocele should be considered in the differential diagnosis. Laparoscopic appendectomy can represent an adequate operation for the appendiceal mucinous neoplasm if the histological report is clear and surgical precautionary measures are taken. PMID- 26429183 TI - Inflamed molluscum contagiosum in a 6-year-old boy: a case report. AB - The precise prevalence of molluscum contagiosum (MC) is still unknown. The pediatric studies showed a cumulative incidence of 17% in children less than 15 years, but there are no studies available for Romania. The papular skin lesions are generally less than 5 mm, but the immunocompromised patients may develop large uncommon lesions. The pediatric cases are located mostly on the limbs, trunk or the face. The lab investigations are not usually required because the clinical features are typical. A biopsy followed by a light microscopy may help in some cases. We are presenting the case of a 6-year-old boy suffering from MC since almost a year. When examined in our clinic, the child developed 2 to 4 mm dome-shaped flesh-colored papules with central umbilication on his trunk diagnosed as MC. The microscopic examination revealed bud-like proliferation of the epidermis, molluscum bodies and moderate chronic inflammation of the dermis. In about one month of treatment, all the lesions disappeared without other local or general complications. PMID- 26429184 TI - Necrotizing fasciitis in oro-maxillo-facial area after radiotherapy for squamous cell carcinoma of the soft palate. AB - The fascia's and subcutaneous adipose tissue's impairment by mono or polymicrobial infection, which also can involve the skin and the muscles, is rarely seen in oro-maxillo-facial area. The present case report is presenting a case of necrotizing fasciitis in a patient who had a history of an invasive squamous cell carcinoma of the soft palate, with surgical treatment and with radiotherapy. He was admitted in our Clinic with malaise and subsequently developed a toxico-septic shock. Clinical symptoms, serological and bacteriological analysis and histopathological examination confirmed the diagnosis of necrotizing fasciitis (NF). The patient subsequently underwent a series of surgical reconstruction and aesthetic treatments because of the complications that had arised in the meantime. Postoperative evolution was favorable towards complete closure of the defect. The prognosis of this disease is generally reserved, the favorable evolution depending on the possibility of wound sterilization and the surgery is required despite its mutilating effect. PMID- 26429185 TI - Early intrauterine development of mixed giant intracranial teratoma in newborn: a case report. AB - Teratoma is one of the most frequent fetal intracranial tumors, but it usually grows very quickly and the fetus is generally a stillborn. Rare cases have slow development or are located in areas that afford immediate surgery after birth with variable chances of survival. Even more rare cases survive days or weeks, but with no chance of surgical treatment and with prolonged palliative care. We present a 34 weeks premature infant, born by C-section with a giant intracranial tumor, whose origin could not be ascertained, occupied almost all-intracranial space and survived 25 days with supportive care. The histological examination established a G3 mixed teratoma, predominantly with immature cells from all three embryonic layers. The cerebellum was normal and infra-mesencephalic structures were present. The infant presented with severe anemia and mild respiratory distress, and was out of neurosurgical therapeutic resources. Antenatal examination was normal until 30 weeks, when fetal ultrasound described a degree of hydrocephalus, but no tumor was individualized. CONCLUSIONS: G3 type complex teratoma, even rare, can be localized at cerebral level and get giant development and growth only in the third trimester of pregnancy, ending with a neonate that has no chance of survival. Such cases cannot benefit of therapeutic interruption of pregnancy and generate serious difficulties for parents and clinicians. PMID- 26429186 TI - Neuroendocrine tumor arising de novo in the left upper thigh: a case report. AB - Neuroendocrine tumors (NETs) originate in the neuroendocrine cells of the neural crest (Kulchitsky cells). If neuroendocrine tumors arising in the digestive tract or lung may occasionally result in skin metastases, primary soft tissue or skin NETs are infrequent. The current paper presents the case of an elderly woman patient with neuroendocrine tumors arising de novo in the left upper thigh, accompanied by lymph nodes metastases in the left groin and in the left pelvic sidewall, in close vicinity of the iliac vessels. The diagnosis of NET was performed based on immunohistochemical tests. Such tumors show a slow growth and, generally, have a good prognosis. It is emphasized that complete surgical excision, in some cases associated with adjuvant external radiotherapy is the optimal therapeutic modality in dealing with such lesions. PMID- 26429187 TI - Fenestration of the middle cerebral artery in a patient who presented with transient ischemic attack. AB - Cerebral artery fenestrations are usually detected incidentally during angiography, have a reported incidence ranging from of 0.03% to 1%, and rarely cause neurological symptoms. They can, however, be associated with aneurysmal dilatation at the proximal or distal end of the fenestration, cerebral arteriovenous malformations, or (rarely) ischemic symptoms. We present a case of a 54-year-old obese woman who presented with a large convex-lens-like fenestration of the right middle cerebral artery (MCA) at the M1 segment (distal to the origin of the temporopolar artery) associated with a transient ischemic attack. The MCA fenestration caused a local change in hemodynamic blood flow, which leads to cerebral ischemia. Magnetic resonance angiography (MRA) also revealed an associated small slit-like fenestration of the basilar artery (BA), hypoplasia of the A1 segment of the right anterior cerebral artery, bilateral fetal posterior cerebral arteries, and bilateral absence of the posterior communicating arteries. To our knowledge, this is the sixth reported case of MCA fenestration with an associated ischemic attack. In our case, fenestrations of the MCA, the BA, and hypoplasia of the A1 segment of ACA were not associated with any aneurysms. PMID- 26429188 TI - Prosthodontic management of an extreme atrophy of the mandible correlated with a prominent genial tubercle - a clinical report. AB - Extreme atrophy of the mandibular alveolar crest can pose a great prosthodontic challenge, especially when the genial tubercles remain as a bony projection in the floor of the mouth. This article is a clinical report on the prosthodontic management of a severe mandible atrophy correlated with a prominent genial tubercle. A complete denture was carefully designed and fabricated in order to restore both the function and esthetics of the patient. PMID- 26429189 TI - Choriocarcinoma developed in a tubal pregnancy - a case report. AB - Carcinoma of the Fallopian tube is the least frequent tumor of the female genital tract. The diagnosis is difficult but could be made more frequently if the causes of abnormal bleeding were thoroughly investigated by means of cytology and endometrial curettage. Treatment is by resection of the tumor, total hysterectomy, and bilateral salpingo-oophorectomy followed by chemotherapy. A 25 year-old patient, presented herself at the emergency room, accusing intense lower abdominal pains, accompanied by vaginal bleeding. The histological aspect corroborated with the Ki-67 index is strongly suggestive for a choriocarcinoma developed in a tubal ectopic pregnancy. PMID- 26429190 TI - An unusual duplication of the inferior vena cava in a patient with endovascular repair for abdominal aortic aneurysm. AB - A 66-year-old Caucasian male, with sensation of abdominal pulsation was admitted to our hospital. In multidetector 64-row computed tomography (CT) angiography, an abdominal aortic aneurysm was observed. Endovascular aortic repair was performed. Control CT confirmed prosperity with stent graft fixation and absence of any vascular complications. Investigation also showed asymmetrical duplication of the inferior vena cava (IVC). Right (RIVC) and left (LIVC) inferior vena cava arose from the confluence of the right and left iliac veins. The LIVC continued as left renal vein. PMID- 26429191 TI - Waardenburg syndrome type 2: an orthodontic perspective. AB - Waardenburg syndrome is a rare form of neurocristopathy. It is a disorder in the development of neural crest cells, caused by an altered cellular migration during the embryonic phase. That alteration causes an association of different abnormalities such as pigmentary disturbances of the hair, iris, skin, stria vascularis of the cochlea, dystopia canthorum and sensorineural hearing loss. We report a case of a 14-year-old Romanian male, with a family history of Waardenburg syndrome (mother) and Usher syndrome (father - congenitally sensorineural hearing loss and retinal degeneration). The case particularities are: the correlation between malocclusion and Waardenburg syndrome due to hypoplastic alae nasi and also factors that produced hearing loss, which could be Waardenburg syndrome, Usher syndrome or the presence of the connexin 26 (W24X) gene mutation. PMID- 26429192 TI - Ethical issues in therapeutic endoscopy - can communication between patient and physician make a difference? AB - Therapeutic endoscopy represents a major step in evidence-based medicine with great potential in the evolution of non-invasive surgery. The evolutionary status of endoscopy has reached a level where some of the surgical intervention can be performed in a minimal invasive way, with great benefits for the patient. However, this rises up some ethical issues regarding the patient's comfort zone, possible risks and complications and subjected the physician to possible litigation situations if not well trained. A rather good interaction and communication between patient and endoscopist is mandatory, as the health-care experience might be more satisfying. Unfortunate situations may also be avoided if intensive training and up to date knowledge and skills are acquired before jumping to therapeutic endoscopy. The continuous development and general focus on interventional endoscopy seems to have a key role on current medical standings. Therefore, in the following paper we have tried to underline the potential ethical problems that both the patient and the physician should take into consideration towards a better therapeutic endoscopic result. PMID- 26429193 TI - Protective Effects of UCF-101 on Cerebral Ischemia-Reperfusion (CIR) is Depended on the MAPK/p38/ERK Signaling Pathway. AB - This study was aimed to investigate the treatment mechanisms of 5-[5-(2 nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101) in cerebral ischemia-reperfusion (CIR) model rats. Total of 54 healthy male Wistar rats were randomly assigned into three groups, namely sham group, vehicle group, and UCF-101 group. The CIR-injured model was established by right middle cerebral artery occlusion and reperfusion. Neurological function was assessed by an investigator according to the Longa neurologic deficit scores. Meanwhile, the cerebral tissue morphology and apoptotic neurons were evaluated by H&E and TUNEL staining, respectively. Additionally, the expressions of caspase 3, p-p38, and p ERK were detected by immunohistochemistry or/and Western blotting assays. As results, neurologic deficit and pathological damage were obviously enhanced and TUNEL positive neurons were significantly increased in CIR-injured rats, as compared with those in sham group. Furthermore, the expressions of caspase 3, p p38, and p-ERK were also significantly increased in vehicle group than those in sham group (P < 0.05). However, UCF-101 treatment could markedly weaken the neurologic deficit with lower scores and improve pathological condition. After UCF-101 treatment, TUNEL positive neurons as well as the expression of caspase 3 were significantly decreased than those in vehicle group (P < 0.05). Besides, p p38 was decreased while p-ERK was increased in UCF-101 group than those in vehicle group (P < 0.05). Therefore, we concluded that the protective effects of UCF-101 might be associated with apoptosis process and MAPK signaling pathway in the CIR-injured model. PMID- 26429194 TI - Appropriate experimental approach is critical for identifying neurotransmitter substances: application to enteric purinergic neurotransmission. PMID- 26429195 TI - Response to Mutafova-Yambolieva and Sanders. PMID- 26429196 TI - ["I do the right thing only against payment": A critique of pay for performance in psychiatry]. AB - This paper takes a critical look at pay for performance (P4P) as a model for introducing new incentives in psychiatry. This model is to be seen as a tool of commercialism, and such a restructuring of psychiatry represents a wide-reaching political maneuver which actively introduces economical parameters into the field and will have a great impact on psychiatry. P4P starts with the false premise that medicine has to be structured like industry. This premise is false because psychiatry has to do with relationships to patients, and not with the production of a product. Therefore, it is essential to reflect critically upon the premises and consequences of P4P for psychiatry. Only this critical reflection can help psychiatry to keep its identity as a humane service for suffering people. PMID- 26429197 TI - Intra-prosthetic dislocation of dual-mobility cups after total hip arthroplasty: potential causes from a clinical and biomechanical perspective. AB - INTRODUCTION: Recurrent dislocation of total hip arthroplasty is a frequent indication for revision surgery. Hip joint stability depends on implant design, cup position and crucially on femoral head diameter. Due to an effective ultra large diameter femoral head, dual-mobility cups are considered an attractive solution to prevent dislocation in unstable conditions. Although patients obviously benefit for many years in terms of mobility and pain, an increase of intra-prosthetic dislocation reports using dual-mobility cups has been recently observed. However, the failure mechanism of this implant-specific complication, which is characterized by the loss of the positive-locking between the femoral head and the mobile liner, is not yet completely understood. METHODS: A comprehensive search was performed with the PubMed database and a search engine to overview this topic and to identify potential causes for this implant-specific failure from a clinical and biomechanical perspective. RESULTS: Peri-operative findings indicate extensive fibrosis at the large articulation as well as cup loosening as potential causes. In addition, current research has shown that the failure mechanism is affected by the surface topography of the femoral neck and in particular by the design of the mobile liner. DISCUSSION: In clinical practice it is necessary to differentiate a classic dislocation between the mobile liner and the metallic shell from an intra-prosthetic dislocation between the femoral head and the liner. CONCLUSION: Due to the increasing popularity of dual-mobility cups in total hip arthroplasty, the understanding of which implant-specific features or tissue response may increase the risk of intra-prosthetic dislocation is of major importance for reduced revision rates by using optimized surgical techniques and implant designs. PMID- 26429198 TI - Expression and Localization of Aquaporin 4 and Aquaporin 5 along the Large Intestine of Colostrum-Suckling Buffalo Calves. AB - Aquaporins (AQPs) are membrane channel proteins that play a role in regulating water permeability in many tissues. To date, seven isoforms of AQPs have been reported in the gastrointestinal tract in different mammalian species. In contrast, both tissue distribution and expression of AQPs are unknown in the buffalo. The purpose of this study was to investigate the expression of both AQP4 and AQP5 mRNAs and their relative proteins in the large intestinal tracts of buffalo calves after colostrum suckling using reverse transcriptase polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry. Our results revealed a diversified tissue AQP4 and AQP5 immunolocalization accompanied by their highest expression in the tissues of colostrum-suckling buffalo calves confirmed by Western blotting. In particular, AQP4 was distributed along the endothelium and enterocytes while AQP5 in the endocrine cells. These findings provide direct evidence for AQP4 and AQP5 expression in the large intestine, suggesting that different AQPs collaborate functionally and distinctively in water handling during intestinal development, especially during the first period after delivery. PMID- 26429199 TI - Recognizing drug targets using evolutionary information: implications for repurposing FDA-approved drugs against Mycobacterium tuberculosis H37Rv. AB - Drug repurposing to explore target space has been gaining pace over the past decade with the upsurge in the use of systematic approaches for computational drug discovery. Such a cost and time-saving approach gains immense importance for pathogens of special interest, such as Mycobacterium tuberculosis H37Rv. We report a comprehensive approach to repurpose drugs, based on the exploration of evolutionary relationships inferred from the comparative sequence and structural analyses between targets of FDA-approved drugs and the proteins of M. tuberculosis. This approach has facilitated the identification of several polypharmacological drugs that could potentially target unexploited M. tuberculosis proteins. A total of 130 FDA-approved drugs, originally intended against other diseases, could be repurposed against 78 potential targets in M. tuberculosis. Additionally, we have also made an attempt to augment the chemical space by recognizing compounds structurally similar to FDA-approved drugs. For three of the attractive cases we have investigated the probable binding modes of the drugs in their corresponding M. tuberculosis targets by means of structural modelling. Such prospective targets and small molecules could be prioritized for experimental endeavours, and could significantly influence drug-discovery and drug-development programmes for tuberculosis. PMID- 26429202 TI - Gout and Association with Erectile Dysfunction. PMID- 26429201 TI - Featured Article: Nuclear export of opioid growth factor receptor is CRM1 dependent. AB - Opioid growth factor receptor (OGFr) facilitates growth inhibition in the presence of its specific ligand opioid growth factor (OGF), chemically termed [Met(5)]-enkephalin. The function of the OGF-OGFr axis requires the receptor to translocate to the nucleus. However, the mechanism of nuclear export of OGFr is unknown. In this study, endogenous OGFr, as well as exogenously expressed OGFr EGFP, demonstrated significant nuclear accumulation in response to leptomycin B (LMB), an inhibitor of CRM1-dependent nuclear export, suggesting that OGFr is exported in a CRM1-dependent manner. One consensus sequence for a nuclear export signal (NES) was identified. Mutation of the associated leucines, L217 L220 L223 and L225, to alanine resulted in decreased nuclear accumulation. NES-EGFP responded to LMB, indicating that this sequence is capable of functioning as an export signal in isolation. To determine why the sequence functions differently in isolation than as a full length protein, the localization of subNES was evaluated in the presence and absence of MG132, a potent inhibitor of proteosomal degradation. MG132 had no effect of subNES localization. The role of tandem repeats located at the C-terminus of OGFr was examined for their role in nuclear trafficking. Six of seven tandem repeats were removed to form deltaTR. DeltaTR localized exclusively to the nucleus indicating that the tandem repeats may contribute to the localization of the receptor. Similar to the loss of cellular proliferation activity (i.e. inhibition) recorded with subNES, deltaTR also demonstrated a significant loss of inhibitory activity indicating that the repeats may be integral to receptor function. These experiments reveal that OGFr contains one functional NES, L217 L220 L223 and L225 and can be exported from the nucleus in a CRM1-dependent manner. PMID- 26429200 TI - MicroRNAs as biomarkers of hepatotoxicity in a randomized placebo-controlled study of simvastatin and ubiquinol supplementation. AB - Statins are potent cholesterol-lowering drugs and are generally well tolerated. Hepatotoxicity is a rare but serious adverse effect of statins; however, its mechanisms are not clear. Coenzyme Q10 deficiency has been suggested, and supplementation of reduced coenzyme Q10 (ubiquinol) has been shown to have hepatoprotective effects. MicroRNAs (miRNAs) are small nucleotides that have been shown to be up-regulated in drug-induced liver injury. We hypothesized that circulating miRNAs may be differentially regulated after simvastatin treatment and by comparing with that of simvastatin and ubiquinol supplementation could potentially uncover signatory miRNA profile for simvastatin-induced liver injury. In this double-blind, prospective, randomized-controlled trial, miRNA profiles and liver enzymes were compared between simvastatin-treated patients, with and without ubiquinol supplementation, over 12 weeks compared to baseline. miRNA expression was further validated in HepG2 liver cell lines by real-time PCR. Changes in miR-192, miR-146a, miR-148a, miR-15a, and miR-21 were positively correlated (p<0.05) with alanine aminotransferase in simvastatin-only treated patients. In ubiquinol supplementation group, alanine aminotransferase and alkaline phosphatase were significantly down-regulated after 12 weeks and changes in miR-15a, miR-21 and miR-33a were negatively correlated with alkaline phosphatase (p < 0.05). Bioinformatics analyses predicted that miRNA regulation in simvastatin group was related to reduce proliferation and adenosine triphosphate-binding cassette transporters. Ubiquinol supplementation additionally regulated miRNAs that inhibit apoptotic and inflammatory pathways, suggesting potential hepatoprotective effects. Our results suggest that 20 mg/day of simvastatin does not have significant risk of hepatotoxicity and ubiquinol supplementation may, at the miRNA level, provide potential beneficial changes to reduce the effects of coenzyme Q10 deficiency in the liver. PMID- 26429203 TI - The Renaissance of Antineutrophil Cytoplasmic Antibodies as a Predictor of Relapse: Ippon for Japan. PMID- 26429204 TI - Do "Evidence-Based Recommendations" Need to Reveal the Evidence? Minimal Criteria Supporting an "Evidence Claim". PMID- 26429205 TI - Dysphagia Related to Esophagus Compression by Anterior Cervical Ossification in a Patient with Ankylosing Spondylitis. PMID- 26429206 TI - Levamisole-induced Vasculitis in a Cocaine User. PMID- 26429207 TI - Switching from Intravenous to Subcutaneous Formulation of Abatacept: Different Results in a Series of 21 Patients. PMID- 26429208 TI - Dr. Genovese comments. PMID- 26429209 TI - Dr. Reggia, et al, reply. PMID- 26429210 TI - 14-3-3eta in "Seronegative" Rheumatoid Arthritis. PMID- 26429211 TI - Metallocorroles as Nonprecious-Metal Catalysts for Oxygen Reduction. AB - The future of affordable fuel cells strongly relies on the design of earth abundant (non-platinum) catalysts for the electrochemical oxygen reduction reaction (ORR). However, the bottleneck in the overall process occurs therein. We have examined herein trivalent Mn, Fe, Co, Ni, and Cu complexes of beta-pyrrole brominated corrole as ORR catalysts. The adsorption of these complexes on a high surface-area carbon powder (BP2000) created a unique composite material, used for electrochemical measurements in acidic aqueous solutions. These experiments disclosed a clear dependence of the catalytic activity on the metal center of the complexes, in the order of Co>Fe>Ni>Mn>Cu. The best catalytic performance was obtained for the Co(III) corrole, whose onset potential was as positive as 0.81 V versus the reversible hydrogen electrode (RHE). Insight into the properties of these systems was gained by spectroscopic and computational characterization of the reduced and oxidized forms of the metallocorroles. PMID- 26429212 TI - Regulation and innovation in healthcare. PMID- 26429214 TI - Restrictive regulation constrains delivery of an integrated, collaborative and responsive health sector. PMID- 26429215 TI - Restrictive regulatory practice. PMID- 26429216 TI - Motor neuron disease: current management and future prospects. AB - Motor neuron disease (MND) is characterised by progressive neurological deterioration and coexistence of upper and lower motor neuron signs. Over the past decade, evidence has emerged of unique pathophysiological processes, including glutamate-mediated excitotoxicity, which has resulted in the development of novel diagnostic investigations and uncovered potential therapeutic targets. Advances in genetics, including the recently discovered C9orf72 gene, have radically changed the pathological mindset, from MND being classified as a neuromuscular disease to one that MND forms a continuum with other primary neurodegenerative disorders, including frontotemporal dementia. The present review will highlight the improvements that have occurred in clinical care, in conjunction with recent scientific developments. PMID- 26429217 TI - Disseminated Mycobacterium haemophilum skeletal disease in a patient with interferon-gamma deficiency. AB - Disseminated non-tuberculous mycobacterial (NTM) infection is rare in immunocompetent adults. Anti-interferon-gamma (IFN-gamma) autoantibodies have recently been associated with NTM infections, particularly in patients of Asian ethnicity. We describe a case of disseminated Mycobacterium haemophilum skeletal infection due to anti IFN-gamma autoantibodies in a 71-year-old Cambodian man. He responded to a combination of anti-mycobacterial antibiotics without requirement for immunomodulator therapy. Testing for acquired IFN-gamma deficiency due to IFN gamma autoantibodies should be considered when standard tests for immunodeficiency are negative in patients with unusual or severe opportunistic infections, including NTM. PMID- 26429218 TI - Intravenous cyclophosphamide as a therapeutic option for severe refractory gastric antral vascular ectasia in systemic sclerosis. AB - Gastric antral vascular ectasia (GAVE) is a rare but important cause of upper gastrointestinal bleeding. It is commonly associated with autoimmune conditions such as systemic sclerosis, and standard treatment involves both supportive measures, as well as endoscopic interventional therapies. While the current therapies are effective for most patients, a few patients develop severe and refractory bleeding. Herein we report two cases of refractory GAVE in patients with diffuse scleroderma, which improved significantly after the administration of intravenous cyclophosphamide. One of these cases is, to our knowledge, the first reported case of cyclophosphamide being used specifically for the treatment of refractory GAVE. PMID- 26429219 TI - Compliance of males with stage 1 testicular germ cell tumours on an active surveillance protocol. AB - The aim of this retrospective study was to determine the rate of compliance among 57 males with stage 1 testicular germ cell tumours on an active surveillance protocol at a single Australian centre. At median follow up of 24 months, 81% had adequate compliance with the follow-up regimen, 12% were lost to follow up, and 16% relapsed; none between protocol visits. Active surveillance is an acceptable alternative to adjuvant therapy for stage 1 testicular germ cell tumours, with reduced toxicity for most and equivalent survival, but requires efforts to maintain adequate compliance with follow up to avoid late detection of recurrence. PMID- 26429220 TI - Dangerous liaisons: doctors-in-training and the pharmaceutical industry. AB - Interaction between doctors and the pharmaceutical industry is long-standing and ingrained in modern practice. Doctors-in-training are at a vulnerable stage of their careers, both in requiring knowledge and forming lasting relationships. There is evidence that limiting contact between industry and junior doctors has a positive effect on subsequent clinical behaviour. Currently in Australia, there is no limitation on pharmaceutical representatives approaching doctors-in training, and the majority of education sessions are sponsored by pharmaceutical companies. This purposefully creates a sense of reciprocity, which may have adverse long-term consequences on attitudes, behaviours and patient care. Several guidelines exist that may assist junior doctors in navigating these potential interactions, most notably the Royal Australasian College of Physicians' own Guidelines for Ethical Relationships between Physicians and Industry. Despite this, there is no reflection of its importance or necessity within subspecialty curricula. This should be rectified, to the benefit of both the profession and public. PMID- 26429221 TI - Hypertrophic osteoarthropathy with imatinib therapy. PMID- 26429222 TI - Two cases of spondylodiscitis caused by Parvimonas micra. PMID- 26429223 TI - Systemic Bacillus Calmette-Guerin sepsis manifesting as hypercalcaemia and thrombocytopenia as a complication of intravesical Bacillus Calmette-Guerin therapy. PMID- 26429224 TI - Angiotensin-converting enzyme inhibitor-induced angioedema and icatibant: a new hope. PMID- 26429225 TI - Generic substitution in contravention of doctor's prescriptions. PMID- 26429226 TI - Author reply. PMID- 26429227 TI - Conflict of interest statements: clarification. PMID- 26429229 TI - "I Was a Spectacle... A Freak Show at the Circus": A Transgender Person's ED Experience and Implications for Nursing Practice. PMID- 26429228 TI - Mechanisms Influencing Circadian Blood Pressure Patterns Among Individuals with HIV. AB - HIV+ individuals have an increased risk for cardiovascular disease (CVD), but the mechanisms behind this association are poorly understood. While hypertension is a well-established CVD risk factor, clinic-based blood pressure (BP) assessment by itself cannot identify several important BP patterns, including white coat hypertension, masked hypertension, nighttime hypertension, and nighttime BP dipping. These BP patterns can be identified over a 24-h period by ambulatory BP monitoring (ABPM). In this review, we provide an overview of the potential value of conducting ABPM in HIV+ individuals. ABPM phenotypes associated with increased CVD risk include masked hypertension (i.e., elevated out-of-clinic BP despite non elevated clinic BP), nighttime hypertension, and a non-dipping BP pattern (i.e., a drop in BP of <10 % from daytime to nighttime). These adverse ABPM phenotypes may be highly relevant in the setting of HIV infection, given that increased levels of inflammatory biomarkers, high psychosocial burden, high prevalence of sleep disturbance, and autonomic dysfunction have been commonly reported in HIV+ persons. Additionally, although antiretroviral therapy (ART) is associated with lower AIDS-related morbidity and CVD risk, the mitochondrial toxicity, oxidative stress, lipodystrophy, and insulin resistance associated with long-term ART use potentially lead to adverse ABPM phenotypes. Existing data on ABPM phenotypes in the setting of HIV are limited, but suggest an increased prevalence of a non dipping BP pattern. In conclusion, identifying ABPM phenotypes may provide crucial information regarding the mechanisms underlying the excess CVD risk in HIV+ individuals. PMID- 26429230 TI - Nanoparticle conversion to biofilms: in vitro demonstration using serum-derived mineralo-organic nanoparticles. AB - AIMS: Mineralo-organic nanoparticles (NPs) detected in biological fluids have been described as precursors of physiological and pathological calcifications in the body. Our main objective was to examine the early stages of mineral NP formation in body fluids. MATERIALS & METHODS: A nanomaterial approach based on atomic force microscopy, dynamic light scattering, electron microscopy and spectroscopy was used. RESULTS: The mineral particles, which contain the serum proteins albumin and fetuin-A, initially precipitate in the form of round amorphous NPs that gradually grow in size, aggregate and coalesce to form crystalline mineral films similar to the structures observed in calcified human arteries. CONCLUSION: Our study reveals the early stages of particle formation and provides a platform to analyze the role(s) of mineralo-organic NPs in human tissues. PMID- 26429231 TI - Is compliance with hospital accreditation associated with length of stay and acute readmission? A Danish nationwide population-based study. AB - OBJECTIVE: To examine the association between compliance with hospital accreditation and length of stay (LOS) and acute readmission (AR). DESIGN: A nationwide population-based follow-up study from November 2009 to December 2012. SETTING: Public, non-psychiatric Danish hospitals. PARTICIPANTS: In-patients admitted with one of 80 diagnoses. INTERVENTION: Accreditation by the first version of The Danish Healthcare Quality Programme. Using an on-site survey, surveyors assessed the level of compliance with the standards. The hospital was awarded either fully (n = 11) or partially accredited (n = 20). MAIN OUTCOME MEASURES: LOS including transfers between hospitals and all-cause AR within 30 days after discharge. The Cox Proportional Hazard regression was used to compute hazard ratios (HRs) adjusted for potential confounding factors and cluster effect at hospital level. RESULTS: For analyses of LOS, 275 589 in-patients were included of whom 266 532 were discharged alive and included in the AR analyses. The mean LOS was 4.51 days (95% confidence interval (CI): 4.46-4.57) at fully and 4.54 days (95% CI: 4.50-4.57) at partially accredited hospitals, respectively. After adjusting for confounding factors, the adjusted HR for time to discharge was 1.07 (95% CI: 1.01-1.14). AR within 30 days after discharge was 13.70% (95% CI: 13.45-13.95) at fully and 12.72% (95% CI: 12.57-12.86) at partially accredited hospitals, respectively, corresponding to an adjusted HR of 1.01 (95% CI: 0.92-1.10). CONCLUSION: Admissions at fully accredited hospitals were associated with a shorter LOS compared with admissions at partially accredited hospitals, although the difference was modest. No difference was observed in AR within 30 days after discharge. PMID- 26429232 TI - Point/Counterpoint. Only a therapist should operate an HDR unit for patient treatments. PMID- 26429233 TI - Daily QA of linear accelerators using only EPID and OBI. AB - PURPOSE: As treatment delivery becomes more complex, there is a pressing need for robust quality assurance (QA) tools to improve efficiency and comprehensiveness while simultaneously maintaining high accuracy and sensitivity. This work aims to present the hardware and software tools developed for comprehensive QA of linear accelerator (LINAC) using only electronic portal imaging devices (EPIDs) and kV flat panel detectors. METHODS: A daily QA phantom, which includes two orthogonally positioned phantoms for QA of MV-beams and kV onboard imaging (OBI) is suspended from the gantry accessory holder to test both geometric and dosimetric components of a LINAC and an OBI. The MV component consists of a 0.5 cm water-equivalent plastic sheet incorporating 11 circular steel plugs for transmission measurements through multiple thicknesses and one resolution plug for MV-image quality testing. The kV-phantom consists of a Leeds phantom (TOR-18 FG phantom supplied by Varian) for testing low and high contrast resolutions. In the developed process, the existing LINAC tools were used to automate daily acquisition of MV and kV images and software tools were developed for simultaneous analysis of these images. A method was developed to derive and evaluate traditional QA parameters from these images [output, flatness, symmetry, uniformity, TPR20/10, and positional accuracy of the jaws and multileaf collimators (MLCs)]. The EPID-based daily QA tools were validated by performing measurements on a detuned 6 MV beam to test its effectiveness in detecting errors in output, symmetry, energy, and MLC positions. The developed QA process was clinically commissioned, implemented, and evaluated on a Varian TrueBeam LINAC (Varian Medical System, Palo Alto, CA) over a period of three months. RESULTS: Machine output constancy measured with an EPID (as compared against a calibrated ion-chamber) is shown to be within +/-0.5%. Beam symmetry and flatness deviations measured using an EPID and a 2D ion-chamber array agree within +/-0.5% and +/ 1.2% for crossline and inline profiles, respectively. MLC position errors of 0.5 mm can be detected using a picket fence test. The field size and phantom positioning accuracy can be determined within 0.5 mm. The entire daily QA process takes ~15 min to perform tests for 5 photon beams, MLC tests, and imaging checks. CONCLUSIONS: The exclusive use of EPID-based QA tools, including a QA phantom and simultaneous analysis software tools, has been demonstrated as a viable, efficient, and comprehensive process for daily evaluation of LINAC performance. PMID- 26429234 TI - Technical Note: Synchrotron-based high-energy x-ray phase sensitive microtomography for biomedical research. AB - PURPOSE: Propagation-based phase-contrast CT (PPCT) utilizes highly sensitive phase-contrast technology applied to x-ray microtomography. Performing phase retrieval on the acquired angular projections can enhance image contrast and enable quantitative imaging. In this work, the authors demonstrate the validity and advantages of a novel technique for high-resolution PPCT by using the generalized phase-attenuation duality (PAD) method of phase retrieval. METHODS: A high-resolution angular projection data set of a fish head specimen was acquired with a monochromatic 60-keV x-ray beam. In one approach, the projection data were directly used for tomographic reconstruction. In two other approaches, the projection data were preprocessed by phase retrieval based on either the linearized PAD method or the generalized PAD method. The reconstructed images from all three approaches were then compared in terms of tissue contrast-to-noise ratio and spatial resolution. RESULTS: The authors' experimental results demonstrated the validity of the PPCT technique based on the generalized PAD based method. In addition, the results show that the authors' technique is superior to the direct PPCT technique as well as the linearized PAD-based PPCT technique in terms of their relative capabilities for tissue discrimination and characterization. CONCLUSIONS: This novel PPCT technique demonstrates great potential for biomedical imaging, especially for applications that require high spatial resolution and limited radiation exposure. PMID- 26429236 TI - Lung motion estimation using dynamic point shifting: An innovative model based on a robust point matching algorithm. AB - PURPOSE: Image-guided radiotherapy is an advanced 4D radiotherapy technique that has been developed in recent years. However, respiratory motion causes significant uncertainties in image-guided radiotherapy procedures. To address these issues, an innovative lung motion estimation model based on a robust point matching is proposed in this paper. METHODS: An innovative robust point matching algorithm using dynamic point shifting is proposed to estimate patient-specific lung motion during free breathing from 4D computed tomography data. The correspondence of the landmark points is determined from the Euclidean distance between the landmark points and the similarity between the local images that are centered at points at the same time. To ensure that the points in the source image correspond to the points in the target image during other phases, the virtual target points are first created and shifted based on the similarity between the local image centered at the source point and the local image centered at the virtual target point. Second, the target points are shifted by the constrained inverse function mapping the target points to the virtual target points. The source point set and shifted target point set are used to estimate the transformation function between the source image and target image. RESULTS: The performances of the authors' method are evaluated on two publicly available DIR-lab and POPI-model lung datasets. For computing target registration errors on 750 landmark points in six phases of the DIR-lab dataset and 37 landmark points in ten phases of the POPI-model dataset, the mean and standard deviation by the authors' method are 1.11 and 1.11 mm, but they are 2.33 and 2.32 mm without considering image intensity, and 1.17 and 1.19 mm with sliding conditions. For the two phases of maximum inhalation and maximum exhalation in the DIR-lab dataset with 300 landmark points of each case, the mean and standard deviation of target registration errors on the 3000 landmark points of ten cases by the authors' method are 1.21 and 1.04 mm. In the EMPIRE10 lung registration challenge, the authors' method ranks 24 of 39. According to the index of the maximum shear stretch, the authors' method is also efficient to describe the discontinuous motion at the lung boundaries. CONCLUSIONS: By establishing the correspondence of the landmark points in the source phase and the other target phases combining shape matching and image intensity matching together, the mismatching issue in the robust point matching algorithm is adequately addressed. The target registration errors are statistically reduced by shifting the virtual target points and target points. The authors' method with consideration of sliding conditions can effectively estimate the discontinuous motion, and the estimated motion is natural. The primary limitation of the proposed method is that the temporal constraints of the trajectories of voxels are not introduced into the motion model. However, the proposed method provides satisfactory motion information, which results in precise tumor coverage by the radiation dose during radiotherapy. PMID- 26429235 TI - Thermal safety of ultrasound-enhanced ocular drug delivery: A modeling study. AB - PURPOSE: Delivery of sufficient amounts of therapeutic drugs into the eye for treatment of various ocular diseases is often a challenging task. Ultrasound was shown to be effective in enhancing ocular drug delivery in the authors' previous in vitro and in vivo studies. METHODS: The study reported here was designed to investigate the safety of ultrasound application and its potential thermal effects in the eye using PZFlex modeling software. The safety limit in this study was set as a temperature increase of no more than 1.5 degrees C based on regulatory recommendations and previous experimental safety studies. Acoustic and thermal specifications of different human eye tissues were obtained from the published literature. The tissues of particular interest in this modeling safety study were cornea, lens, and the location of optic nerve in the posterior eye. Ultrasound application was modeled at frequencies of 400 kHz-1 MHz, intensities of 0.3-1 W/cm(2), and exposure duration of 5 min, which were the parameters used in the authors' previous drug delivery experiments. The baseline eye temperature was 37 degrees C. RESULTS: The authors' results showed that the maximal tissue temperatures after 5 min of ultrasound application were 38, 39, 39.5, and 40 degrees C in the cornea, 39.5, 40, 42, and 43 degrees C in the center of the lens, and 37.5, 38.5, and 39 degrees C in the back of the eye (at the optic nerve location) at frequencies of 400, 600, 800 kHz, and 1 MHz, respectively. CONCLUSIONS: The ocular temperatures reached at higher frequencies were considered unsafe based on current recommendations. At a frequency of 400 kHz and intensity of 0.8 W/cm(2) (parameters shown in the authors' previous in vivo studies to be optimal for ocular drug delivery), the temperature increase was small enough to be considered safe inside different ocular tissues. However, the impact of orbital bone and tissue perfusion should be included in future modeling efforts to determine the safety of this method in the whole orbit especially regarding potential adverse optic nerve heating at the location of the bone. PMID- 26429237 TI - Angular dependence of dose sensitivity of nanoDot optically stimulated luminescent dosimeters in different radiation geometries. AB - PURPOSE: A type of in vivo dosimeter, an optically stimulated luminescent dosimeter, OSLD, may have dose sensitivity that depends on the angle of incidence of radiation. This work measures how angular dependence of a nanoDot changes with the geometry of the phantom in which irradiation occurs and with the intrinsic structure of the nanoDot. METHODS: The OSLDs used in this work were nanoDot dosimeters (Landauer, Inc., Glenwood, IL), which were read with a MicroStar reader (Landauer, Inc., Glenwood, IL). Dose to the OSLDs was delivered by 6 MV x rays. NanoDots with various intrinsic sensitivities were irradiated in numerous phantoms that had geometric shapes of cylinders, rectangles, and a cube. RESULTS: No angular dependence was seen in cylindrical phantoms, cubic phantoms, or rectangular phantoms with a thickness to width ratio of 0.3 or 1.5. An angular dependence of 1% was observed in rectangular phantoms with a thickness to width of 0.433-0.633. A group of nanoDots had sensitive layers with mass density of 2.42-2.58 g/cm(3) and relative sensitivity of 0.92-1.09 and no difference in their angular dependence. Within experimental uncertainty, nanoDot measurements agree with a parallel-plate ion chamber at a depth of maximum dose. CONCLUSIONS: When irradiated in cylindrical, rectangular, and cubic phantoms, nanoDots show a maximum angular dependence of 1% or less at an incidence angle of 90 degrees . For a sample of 78 new nanoDots, the range of their relative intrinsic sensitivity is 0.92-1.09. For a sample of ten nanoDots, on average, the mass in the sensitive layer is 73.1% Al2O3:C and 26.9% polyester. The mass density of the sensitive layer of a nanoDot disc is between 2.42 and 2.58 g/cm(3). The angular dependence is not related to Al2O3:C loading of the nanoDot disc. The nanoDot at the depth of maximum dose has no more angular dependence than a parallel-plate ion chamber. PMID- 26429238 TI - Automatic detection of large pulmonary solid nodules in thoracic CT images. AB - PURPOSE: Current computer-aided detection (CAD) systems for pulmonary nodules in computed tomography (CT) scans have a good performance for relatively small nodules, but often fail to detect the much rarer larger nodules, which are more likely to be cancerous. We present a novel CAD system specifically designed to detect solid nodules larger than 10 mm. METHODS: The proposed detection pipeline is initiated by a three-dimensional lung segmentation algorithm optimized to include large nodules attached to the pleural wall via morphological processing. An additional preprocessing is used to mask out structures outside the pleural space to ensure that pleural and parenchymal nodules have a similar appearance. Next, nodule candidates are obtained via a multistage process of thresholding and morphological operations, to detect both larger and smaller candidates. After segmenting each candidate, a set of 24 features based on intensity, shape, blobness, and spatial context are computed. A radial basis support vector machine (SVM) classifier was used to classify nodule candidates, and performance was evaluated using ten-fold cross-validation on the full publicly available lung image database consortium database. RESULTS: The proposed CAD system reaches a sensitivity of 98.3% (234/238) and 94.1% (224/238) large nodules at an average of 4.0 and 1.0 false positives/scan, respectively. CONCLUSIONS: The authors conclude that the proposed dedicated CAD system for large pulmonary nodules can identify the vast majority of highly suspicious lesions in thoracic CT scans with a small number of false positives. PMID- 26429239 TI - Quantitative early decision making metric for identifying irregular breathing in 4DCT. AB - PURPOSE: To develop a quantitative early decision making metric for prediction of breathing pattern and irregular breathing and validate the metric in a large patient population receiving clinical phase-sorted four-dimensional computed tomography (4DCT). METHODS: This study employed three patient cohorts. The first cohort contained 47 patients, imaged with a nonclinical tidal volume metric. The second cohort contained a sample of 256 patients who received a clinical 4DCT. The third cohort contained 86 patients who received three 4DCT scans at 1-week increment during the course of radiotherapy. The second and third cohorts did not have tidal volume measurements, as per standard radiation oncology clinical practice. Based on a previously published technique that used a single abdominal surrogate, the ratio of extreme inhalation tidal volume to normal inhalation tidal volume (kappa) metric was calculated and the patient breathing pattern was characterized. The use of a single surrogate precluded the use of a kappa determined by tidal volume, so a kappa(rel) was defined based on the amplitude of the surrogate. Patients were classified as either Type 1 or Type 2, based on a previously published technique, where Type 1 patients were apneic at end of exhalation and Type 2 patients exhibited forced respiration. The Ansari-Bradley test was used to determine the statistical similarity between the Type 1 and Type 2 distributions. A Kruskal-Wallis one way analysis of variance was used to determine the statistical similarities among the classified breathing types, kappa(rel), and the qualified medical physicist denoted breathing classification (regular or irregular). Receiver operator characteristic curves were used to quantitatively determine optimal cutoff value j(kappa) and efficiency cutoff value (tau(kappa)) kappa(rel) to provide a quantitative early warning of irregular breathing during 4DCT procedures. RESULTS: The statistical tests show a significant consistency for the breathing pattern classifications between the physiologically measured cohort #1 and the remaining cohorts. The classification types were statistically different between Type 1 and Type 2 patients over all cohorts. Values of kappa(rel) in excess of 1.72 indicated a substantial presence of irregular breathing that could negatively affect the quality of a 4DCT image dataset. Values of kappa(rel) in lower than 1.45 indicated minimal presence of irregular breathing. For values of kappa(rel) such that j(kappa) <= kappa(rel) <= tau(kappa), the decision to reacquire the 4DCT would be at the discretion of the physician. This accounted for only 11.9% of the patients in this study. The magnitude of kappa(rel) held consistent over three weeks of treatment for 73% of the patients in cohort #3. CONCLUSIONS: The decision making metric based on kappa was shown to be an accurate classifier of regular and irregular breathing patterns in a large patient population. Breathing type, as defined in a previous published work, was accurately classified by kappa(rel) with the use of a single respiratory surrogate compared to the physiological use of multiple respiratory surrogates. This work provided a quantitative early decision making metric to quickly and accurately assess breathing patterns as well as the presence and magnitude of irregular breathing during 4DCT. PMID- 26429240 TI - Measurement with microscopic MRI and simulation of flow in different aneurysm models. AB - PURPOSE: The impact and the development of aneurysms depend to a significant degree on the exchange of liquid between the regular vessel and the pathological extension. A better understanding of this process will lead to improved prediction capabilities. The aim of the current study was to investigate fluid exchange in aneurysm models of different complexities by combining microscopic magnetic resonance measurements with numerical simulations. In order to evaluate the accuracy and applicability of these methods, the fluid-exchange process between the unaltered vessel lumen and the aneurysm phantoms was analyzed quantitatively using high spatial resolution. METHODS: Magnetic resonance flow imaging was used to visualize fluid-exchange in two different models produced with a 3D printer. One model of an aneurysm was based on histological findings. The flow distribution in the different models was measured on a microscopic scale using time of flight magnetic resonance imaging. The whole experiment was simulated using fast graphics processing unit-based numerical simulations. The obtained simulation results were compared qualitatively and quantitatively with the magnetic resonance imaging measurements, taking into account flow and spin lattice relaxation. RESULTS: The results of both presented methods compared well for the used aneurysm models and the chosen flow distributions. The results from the fluid-exchange analysis showed comparable characteristics concerning measurement and simulation. Similar symmetry behavior was observed. Based on these results, the amount of fluid-exchange was calculated. Depending on the geometry of the models, 7% to 45% of the liquid was exchanged per second. CONCLUSIONS: The result of the numerical simulations coincides well with the experimentally determined velocity field. The rate of fluid-exchange between vessel and aneurysm was well-predicted. Hence, the results obtained by simulation could be validated by the experiment. The observed deviations can be caused by the noise in the measurement and by the limited resolution of the simulation. The resulting differences are small enough to allow reliable predictions of the flow distribution in vessels with stents and for pulsed blood flow. PMID- 26429242 TI - Monte Carlo reference data sets for imaging research: Executive summary of the report of AAPM Research Committee Task Group 195. AB - The use of Monte Carlo simulations in diagnostic medical imaging research is widespread due to its flexibility and ability to estimate quantities that are challenging to measure empirically. However, any new Monte Carlo simulation code needs to be validated before it can be used reliably. The type and degree of validation required depends on the goals of the research project, but, typically, such validation involves either comparison of simulation results to physical measurements or to previously published results obtained with established Monte Carlo codes. The former is complicated due to nuances of experimental conditions and uncertainty, while the latter is challenging due to typical graphical presentation and lack of simulation details in previous publications. In addition, entering the field of Monte Carlo simulations in general involves a steep learning curve. It is not a simple task to learn how to program and interpret a Monte Carlo simulation, even when using one of the publicly available code packages. This Task Group report provides a common reference for benchmarking Monte Carlo simulations across a range of Monte Carlo codes and simulation scenarios. In the report, all simulation conditions are provided for six different Monte Carlo simulation cases that involve common x-ray based imaging research areas. The results obtained for the six cases using four publicly available Monte Carlo software packages are included in tabular form. In addition to a full description of all simulation conditions and results, a discussion and comparison of results among the Monte Carlo packages and the lessons learned during the compilation of these results are included. This abridged version of the report includes only an introductory description of the six cases and a brief example of the results of one of the cases. This work provides an investigator the necessary information to benchmark his/her Monte Carlo simulation software against the reference cases included here before performing his/her own novel research. In addition, an investigator entering the field of Monte Carlo simulations can use these descriptions and results as a self teaching tool to ensure that he/she is able to perform a specific simulation correctly. Finally, educators can assign these cases as learning projects as part of course objectives or training programs. PMID- 26429241 TI - Determinants of the reliability of ultrasound tomography sound speed estimates as a surrogate for volumetric breast density. AB - PURPOSE: High breast density, as measured by mammography, is associated with increased breast cancer risk, but standard methods of assessment have limitations including 2D representation of breast tissue, distortion due to breast compression, and use of ionizing radiation. Ultrasound tomography (UST) is a novel imaging method that averts these limitations and uses sound speed measures rather than x-ray imaging to estimate breast density. The authors evaluated the reproducibility of measures of speed of sound and changes in this parameter using UST. METHODS: One experienced and five newly trained raters measured sound speed in serial UST scans for 22 women (two scans per person) to assess inter-rater reliability. Intrarater reliability was assessed for four raters. A random effects model was used to calculate the percent variation in sound speed and change in sound speed attributable to subject, scan, rater, and repeat reads. The authors estimated the intraclass correlation coefficients (ICCs) for these measures based on data from the authors' experienced rater. RESULTS: Median (range) time between baseline and follow-up UST scans was five (1-13) months. Contributions of factors to sound speed variance were differences between subjects (86.0%), baseline versus follow-up scans (7.5%), inter-rater evaluations (1.1%), and intrarater reproducibility (~0%). When evaluating change in sound speed between scans, 2.7% and ~0% of variation were attributed to inter- and intrarater variation, respectively. For the experienced rater's repeat reads, agreement for sound speed was excellent (ICC = 93.4%) and for change in sound speed substantial (ICC = 70.4%), indicating very good reproducibility of these measures. CONCLUSIONS: UST provided highly reproducible sound speed measurements, which reflect breast density, suggesting that UST has utility in sensitively assessing change in density. PMID- 26429243 TI - Correcting scan-to-scan response variability for a radiochromic film-based reference dosimetry system. AB - PURPOSE: In radiochromic film dosimetry systems, measurements are usually obtained from film images acquired on a CCD-based flatbed scanner. The authors investigated factors affecting scan-to-scan response variability leading to increased dose measurement uncertainty. METHODS: The authors used flatbed document scanners to repetitively scan EBT3 radiochromic films exposed to doses 0 1000 cGy, together with three neutral density filters and three blue optical filters. Scanning was performed under two conditions: scanner lid closed and scanner lid opened/closed between scans. The authors also placed a scanner in a cold room at 9 degrees C and later in a room at 22 degrees C and scanned EBT3 films to explore temperature effects. Finally, the authors investigated the effect of altering the distance between the film and the scanner's light source. RESULTS: Using a measurement protocol to isolate the contribution of the CCD and electronic circuitry of the scanners, the authors found that the standard deviation of response measurements for the EBT3 film model was about 0.17% for one scanner and 0.09% for the second. When the lid of the first scanner was opened and closed between scans, the average scan-to-scan difference of responses increased from 0.12% to 0.27%. Increasing the sample temperature during scanning changed the RGB response values by about -0.17, -0.14, and -0.05%/ degrees C, respectively. Reducing the film-to-light source distance increased the RBG response values about 1.1, 1.3, and 1.4%/mm, respectively. The authors observed that films and film samples were often not flat with some areas up to 8 mm away from the scanner's glass window. CONCLUSIONS: In the absence of measures to deal with the response irregularities, each factor the authors investigated could lead to dose uncertainty >2%. Those factors related to the film-to-light source distance could be particularly impactful since the authors observed many instances where the curl of film samples had the potential to cause dose uncertainty in excess of 5%. Two expedients will eliminate the uncertainties: a transparent sheet (preferably glass) placed over the scanned film keeps the film to-light source distance constant, and an EBT3 reference film included in all scans provides correction factors for measured response values. PMID- 26429244 TI - Three-dimensional reconstruction of a vascular network by dynamic tracking of magnetite nanoparticles. AB - PURPOSE: Visualization of small blood vessels feeding tumor sites provides important information on the tumors and their microenvironment. This information plays an important role in targeted drug therapies using magnetic gradients. However, capabilities of current clinical imaging modalities may be insufficient to resolve complex microvascular networks. The purpose of this study is to map the vascular network, 3D, based on the magnetic susceptibility contrast. METHODS: Magnetic particles induce an inhomogeneity in the MRI's magnetic field in an order much larger than their real size. This is an approach to compensate the spatial resolution insufficiency of a clinical MR scanner. Micron-sized agglomerations of magnetite nanoparticles were injected in a 3D phantom vascular network, and a fast multislice, multiacquisition MR sequence was applied to track the agglomerations along their trajectories. The experiment was performed twice for two different imaging planes: coronal and transversal. The susceptibility artifact in the images indicated the presence and the position of the agglomerations. The calculated positions through multiple images were assembled to build up the 3D distribution of the vascular network. RESULTS: The calculated points were compared with the centerline of the channels, extracted from the 3D reference image, to determine the absolute measurement error. The mean error was measured to be approximately half of the pixel's size. It was found that the positioning error on the axis perpendicular to the imaging slice was nearly twice as high as on the imaging plane axes due to the slice thickness. In order to compensate for the lack of resolution on the perpendicular axis, the reconstruction was performed using a combination of coronal and transversal data. The combination of the coordinates led to a significant decrease in the mean measurement error at each segment in the vascular network (p < 0.001). CONCLUSIONS: A method for 3D reconstruction of a microvascular network based on the susceptibility contrast in MRI and using a clinical scanner and a commercial receiver coil was proposed. The method presents a novel approach for reconstruction of vascular networks using the susceptibility effect. The proposed method may be applied to resolve vascular networks at a micrometric scale. PMID- 26429245 TI - Monte Carlo simulations of the dose from imaging with GE eXplore 120 micro-CT using GATE. AB - PURPOSE: Small animals are increasingly used as translational models in preclinical imaging studies involving microCT, during which the subjects can be exposed to large amounts of radiation. While the radiation levels are generally sublethal, studies have shown that low-level radiation can change physiological parameters in mice. In order to rule out any influence of radiation on the outcome of such experiments, or resulting deterministic effects in the subjects, the levels of radiation involved need to be addressed. The aim of this study was to investigate the radiation dose delivered by the GE eXplore 120 microCT non invasively using Monte Carlo simulations in GATE and to compare results to previously obtained experimental values. METHODS: Tungsten X-ray spectra were simulated at 70, 80, and 97 kVp using an analytical tool and their half-value layers were simulated for spectra validation against experimentally measured values of the physical X-ray tube. A Monte Carlo model of the microCT system was set up and four protocols that are regularly applied to live animal scanning were implemented. The computed tomography dose index (CTDI) inside a PMMA phantom was derived and multiple field of view acquisitions were simulated using the PMMA phantom, a representative mouse and rat. RESULTS: Simulated half-value layers agreed with experimentally obtained results within a 7% error window. The CTDI ranged from 20 to 56 mGy and closely matched experimental values. Derived organ doses in mice reached 459 mGy in bones and up to 200 mGy in soft tissue organs using the highest energy protocol. Dose levels in rats were lower due to the increased mass of the animal compared to mice. The uncertainty of all dose simulations was below 14%. CONCLUSIONS: Monte Carlo simulations proved a valuable tool to investigate the 3D dose distribution in animals from microCT. Small animals, especially mice (due to their small volume), receive large amounts of radiation from the GE eXplore 120 microCT, which might alter physiological parameters in a longitudinal study setup. PMID- 26429246 TI - SPEQTACLE: An automated generalized fuzzy C-means algorithm for tumor delineation in PET. AB - PURPOSE: Accurate tumor delineation in positron emission tomography (PET) images is crucial in oncology. Although recent methods achieved good results, there is still room for improvement regarding tumors with complex shapes, low signal-to noise ratio, and high levels of uptake heterogeneity. METHODS: The authors developed and evaluated an original clustering-based method called spatial positron emission quantification of tumor-Automatic Lp-norm estimation (SPEQTACLE), based on the fuzzy C-means (FCM) algorithm with a generalization exploiting a Hilbertian norm to more accurately account for the fuzzy and non Gaussian distributions of PET images. An automatic and reproducible estimation scheme of the norm on an image-by-image basis was developed. Robustness was assessed by studying the consistency of results obtained on multiple acquisitions of the NEMA phantom on three different scanners with varying acquisition parameters. Accuracy was evaluated using classification errors (CEs) on simulated and clinical images. SPEQTACLE was compared to another FCM implementation, fuzzy local information C-means (FLICM) and fuzzy locally adaptive Bayesian (FLAB). RESULTS: SPEQTACLE demonstrated a level of robustness similar to FLAB (variability of 14% +/- 9% vs 14% +/- 7%, p = 0.15) and higher than FLICM (45% +/ 18%, p < 0.0001), and improved accuracy with lower CE (14% +/- 11%) over both FLICM (29% +/- 29%) and FLAB (22% +/- 20%) on simulated images. Improvement was significant for the more challenging cases with CE of 17% +/- 11% for SPEQTACLE vs 28% +/- 22% for FLAB (p = 0.009) and 40% +/- 35% for FLICM (p < 0.0001). For the clinical cases, SPEQTACLE outperformed FLAB and FLICM (15% +/- 6% vs 37% +/- 14% and 30% +/- 17%, p < 0.004). CONCLUSIONS: SPEQTACLE benefitted from the fully automatic estimation of the norm on a case-by-case basis. This promising approach will be extended to multimodal images and multiclass estimation in future developments. PMID- 26429247 TI - Theoretical detection threshold of the proton-acoustic range verification technique. AB - PURPOSE: Range verification in proton therapy using the proton-acoustic signal induced in the Bragg peak was investigated for typical clinical scenarios. The signal generation and detection processes were simulated in order to determine the signal-to-noise limits. METHODS: An analytical model was used to calculate the dose distribution and local pressure rise (per proton) for beams of different energy (100 and 160 MeV) and spot widths (1, 5, and 10 mm) in a water phantom. In this method, the acoustic waves propagating from the Bragg peak were generated by the general 3D pressure wave equation implemented using a finite element method. Various beam pulse widths (0.1-10 MUs) were simulated by convolving the acoustic waves with Gaussian kernels. A realistic PZT ultrasound transducer (5 cm diameter) was simulated with a Butterworth bandpass filter with consideration of random noise based on a model of thermal noise in the transducer. The signal-to noise ratio on a per-proton basis was calculated, determining the minimum number of protons required to generate a detectable pulse. The maximum spatial resolution of the proton-acoustic imaging modality was also estimated from the signal spectrum. RESULTS: The calculated noise in the transducer was 12-28 mPa, depending on the transducer central frequency (70-380 kHz). The minimum number of protons detectable by the technique was on the order of 3-30 * 10(6) per pulse, with 30-800 mGy dose per pulse at the Bragg peak. Wider pulses produced signal with lower acoustic frequencies, with 10 MUs pulses producing signals with frequency less than 100 kHz. CONCLUSIONS: The proton-acoustic process was simulated using a realistic model and the minimal detection limit was established for proton-acoustic range validation. These limits correspond to a best case scenario with a single large detector with no losses and detector thermal noise as the sensitivity limiting factor. Our study indicated practical proton-acoustic range verification may be feasible with approximately 5 * 10(6) protons/pulse and beam current. PMID- 26429248 TI - Monte Carlo modeling of ultrasound probes for image guided radiotherapy. AB - PURPOSE: To build Monte Carlo (MC) models of two ultrasound (US) probes and to quantify the effect of beam attenuation due to the US probes for radiation therapy delivered under real-time US image guidance. METHODS: MC models of two Philips US probes, an X6-1 matrix-array transducer and a C5-2 curved-array transducer, were built based on their megavoltage (MV) CT images acquired in a Tomotherapy machine with a 3.5 MV beam in the EGSnrc, BEAMnrc, and DOSXYZnrc codes. Mass densities in the probes were assigned based on an electron density calibration phantom consisting of cylinders with mass densities between 0.2 and 8.0 g/cm(3). Beam attenuation due to the US probes in horizontal (for both probes) and vertical (for the X6-1 probe) orientation was measured in a solid water phantom for 6 and 15 MV (15 * 15) cm(2) beams with a 2D ionization chamber array and radiographic films at 5 cm depth. The MC models of the US probes were validated by comparison of the measured dose distributions and dose distributions predicted by MC. Attenuation of depth dose in the (15 * 15) cm(2) beams and small circular beams due to the presence of the probes was assessed by means of MC simulations. RESULTS: The 3.5 MV CT number to mass density calibration curve was found to be linear with R(2) > 0.99. The maximum mass densities in the X6-1 and C5-2 probes were found to be 4.8 and 5.2 g/cm(3), respectively. Dose profile differences between MC simulations and measurements of less than 3% for US probes in horizontal orientation were found, with the exception of the penumbra region. The largest 6% dose difference was observed in dose profiles of the X6-1 probe placed in vertical orientation, which was attributed to inadequate modeling of the probe cable. Gamma analysis of the simulated and measured doses showed that over 96% of measurement points passed the 3%/3 mm criteria for both probes placed in horizontal orientation and for the X6-1 probe in vertical orientation. The X6 1 probe in vertical orientation caused the highest attenuation of the 6 and 15 MV beams, which at 10 cm depth accounted for 33% and 43% decrease compared to the respective (15 * 15) cm(2) open fields. The C5-2 probe in horizontal orientation, on the other hand, caused a dose increase of 10% and 53% for the 6 and 15 MV beams, respectively, in the buildup region at 0.5 cm depth. For the X6-1 probe in vertical orientation, the dose at 5 cm depth for the 3-cm diameter 6 MV and 5-cm diameter 15 MV beams was attenuated compared to the corresponding open fields to a greater degree by 65% and 43%, respectively. CONCLUSIONS: MC models of two US probes used for real-time image guidance during radiotherapy have been built. Due to the high beam attenuation of the US probes, the authors generally recommend avoiding delivery of treatment beams that intersect the probe. However, the presented MC models can be effectively integrated into US-guided radiotherapy treatment planning in cases for which beam avoidance is not practical due to anatomy geometry. PMID- 26429249 TI - An iterative reduced field-of-view reconstruction for periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) MRI. AB - PURPOSE: To propose a new reduced field-of-view (rFOV) strategy for iterative reconstructions in a clinical environment. Iterative reconstructions can incorporate regularization terms to improve the image quality of periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) MRI. However, the large amount of calculations required for full FOV iterative reconstructions has posed a huge computational challenge for clinical usage. By subdividing the entire problem into smaller rFOVs, the iterative reconstruction can be accelerated on a desktop with a single graphic processing unit (GPU). METHODS: This rFOV strategy divides the iterative reconstruction into blocks, based on the block-diagonal dominant structure. A near real-time reconstruction system was developed for the clinical MR unit, and parallel computing was implemented using the object-oriented model. In addition, the Toeplitz method was implemented on the GPU to reduce the time required for full interpolation. Using the data acquired from the PROPELLER MRI, the reconstructed images were then saved in the digital imaging and communications in medicine format. RESULTS: The proposed rFOV reconstruction reduced the gridding time by 97%, as the total iteration time was 3 s even with multiple processes running. A phantom study showed that the structure similarity index for rFOV reconstruction was statistically superior to conventional density compensation (p < 0.001). In vivo study validated the increased signal-to-noise ratio, which is over four times higher than with density compensation. Image sharpness index was improved using the regularized reconstruction implemented. CONCLUSIONS: The rFOV strategy permits near real-time iterative reconstruction to improve the image quality of PROPELLER images. Substantial improvements in image quality metrics were validated in the experiments. The concept of rFOV reconstruction may potentially be applied to other kinds of iterative reconstructions for shortened reconstruction duration. PMID- 26429250 TI - Technical Note: Influence of Compton currents on profile measurements in small volume ion chambers. AB - PURPOSE: This work is to evaluate the effects of Compton current generation in three small-volume ionization chambers on measured beam characteristics for electron fields. METHODS: Beam scans were performed using Exradin A16, A26, and PTW 31014 microchambers. Scans with varying chamber components shielded were performed. Static point measurements, output factors, and cable only irradiations were performed to determine the contribution of Compton currents to various components of the chamber. Monte Carlo simulations were performed to evaluate why one microchamber showed a significant reduction in Compton current generation. RESULTS: Beam profiles demonstrated significant distortion for two of the three chambers when scanned parallel to the chamber axis, produced by electron deposition within the wire. Measurements of ionization produced within the cable identified Compton current generation as the cause of these distortions. The size of the central collecting wire was found to have the greatest influence on the magnitude of Compton current generation. CONCLUSIONS: Microchambers can demonstrate significant (>5%) deviations from properties as measured with larger volume chambers (0.125 cm(3) and above). These deviations can be substantially reduced by averaging measurements conducted at opposite polarities. PMID- 26429251 TI - Evaluation of in vivo quantification accuracy of the Ingenuity-TF PET/MR. AB - PURPOSE: The quantitative accuracy of standardized uptake values (SUVs) and tracer kinetic uptake parameters in patient investigations strongly depends on accurate determination of regional activity concentrations in positron emission tomography (PET) data. This determination rests on the assumption that the given scanner calibration is valid in vivo. In a previous study, we introduced a method to test this assumption. This method allows to identify discrepancies in quantitative accuracy in vivo by comparison of activity concentrations of urine samples measured in a well-counter with activity concentrations extracted from PET images of the bladder. In the present study, we have applied this method to the Philips Ingenuity-TF PET/MR since at the present stage, absolute quantitative accuracy of combined PET/MR systems is still under investigation. METHODS: Twenty one clinical whole-body F18-FDG scans were included in this study. The bladder region was imaged as the last bed position and urine samples were collected afterward. PET images were reconstructed including MR-based attenuation correction with and without truncation compensation and 3D regions-of-interest (ROIs) of the bladder were delineated by three observers. To exclude partial volume effects, ROIs were concentrically shrunk by 8-10 mm. Then, activity concentrations were determined in the PET images for the bladder and for the urine by measuring the samples in a calibrated well-counter. In addition, linearity measurements of SUV vs singles rate and measurements of the stability of the coincidence rate of "true" events of the PET/MR system were performed over a period of 4 months. RESULTS: The measured in vivo activity concentrations were significantly lower in PET/MR than in the well-counter with a ratio of the former to the latter of 0.756 +/- 0.060 (mean +/- std. dev.), a range of 0.604-0.858, and a P value of 3.9 ? 10(-14). While the stability measurements of the coincidence rate of "true" events showed no relevant deviation over time, the linearity scans revealed a systematic error of 8%-11% (avg. 9%) for the range of singles rates present in the bladder scans. After correcting for this systematic bias caused by shortcomings of the manufacturers calibration procedure, the PET to well-counter ratio increased to 0.832 +/- 0.064 (0.668 -0.941), P = 1.1 ? 10( 10). After compensating for truncation of the upper extremities in the MR-based attenuation maps, the ratio further improved to 0.871 +/- 0.069 (0.693-0.992), P = 3.9 ? 10(-8). CONCLUSIONS: Our results show that the Philips PET/MR underestimates activity concentrations in the bladder by 17%, which is 7 percentage points (pp.) larger than in the previously investigated PET and PET/CT systems. We attribute this increased underestimation to remaining limitations of the MR-based attenuation correction. Our results suggest that only a 2 pp. larger underestimation of activity concentrations compared to PET/CT can be observed if compensation of attenuation truncation of the upper extremities is applied. Thus, quantification accuracy of the Philips Ingenuity-TF PET/MR can be considered acceptable for clinical purposes given the +/-10% error margin in the EANM guidelines. The comparison of PET images from the bladder region with urine samples has proven a useful method. It might be interesting for evaluation and comparison of the in vivo quantitative accuracy of PET, PET/CT, and especially PET/MR systems from different manufacturers or in multicenter trials. PMID- 26429252 TI - Technical Note: Initial characterization of the new EBT-XD Gafchromic film. AB - PURPOSE: To assess the dosimetric accuracy and energy dependence of the new EBT eXtended Dose (XD) Gafchromic film and to compare the lateral response artifact (LRA) between EBT-XD and EBT3 film. METHODS: EBT3 and EBT-XD calibration curves were created by exposing films to known doses from 0 to 3000 cGy using a 6 MV beam. To assess the accuracy and dynamic range of EBT-XD, a 60 degrees enhanced dynamic wedge (EDW) was used to deliver a dose range of approximately 200-2900 cGy. Comparison to treatment planning system (TPS) calculation was made using a gamma analysis with 2%/2 mm passing criteria. To assess and compare the LRA between EBT3 and EBT-XD, 21 * 21 cm(2) open fields delivered doses of 1000, 2000, and 3000 cGy to both types of film. Films were placed at the center of the scanner, and ratios of measured to TPS predicted doses were calculated at 50 and 80 mm lateral from the scanner center in order to quantitatively assess the LRA. To evaluate the energy dependence of EBT-XD film, seven known doses ranging from 400 to 3000 cGy were delivered using both 6 and 18 MV beams and the resulting optical densities (ODs) compared. RESULTS: The gamma passing rate was 99.1% for the 6 MV EDW delivery. EBT-XD film exhibited minimal LRA (<1%) up to 3000 cGy. In contrast, EBT3 demonstrated an under-response of 11.3% and 22.7% at lateral positions of 50 and 80 mm, respectively, for the 3000 cGy exposure. Differences between ODs of the EBT-XD films exposed to known doses from 6 to 18 MV beams were <0.8% suggesting minimal energy dependence throughout this energy range. CONCLUSIONS: The LRA of EBT-XD is greatly reduced when compared to EBT3. This in combination with its accuracy from 0 to 3000 cGy and minimal energy dependence from 6 to 18 MV makes EBT-XD film well suited for dosimetric measurements in high dose SRS/SBRT applications. PMID- 26429253 TI - Geometric validation of self-gating k-space-sorted 4D-MRI vs 4D-CT using a respiratory motion phantom. AB - PURPOSE: MRI is increasingly being used for radiotherapy planning, simulation, and in-treatment-room motion monitoring. To provide more detailed temporal and spatial MR data for these tasks, we have recently developed a novel self-gated (SG) MRI technique with advantage of k-space phase sorting, high isotropic spatial resolution, and high temporal resolution. The current work describes the validation of this 4D-MRI technique using a MRI- and CT-compatible respiratory motion phantom and comparison to 4D-CT. METHODS: The 4D-MRI sequence is based on a spoiled gradient echo-based 3D projection reconstruction sequence with self gating for 4D-MRI at 3 T. Respiratory phase is resolved by using SG k-space lines as the motion surrogate. 4D-MRI images are reconstructed into ten temporal bins with spatial resolution 1.56 * 1.56 * 1.56 mm(3). A MRI-CT compatible phantom was designed to validate the performance of the 4D-MRI sequence and 4D-CT imaging. A spherical target (diameter 23 mm, volume 6.37 ml) filled with high-concentration gadolinium (Gd) gel is embedded into a plastic box (35 * 40 * 63 mm(3)) and stabilized with low-concentration Gd gel. The phantom, driven by an air pump, is able to produce human-type breathing patterns between 4 and 30 respiratory cycles/min. 4D-CT of the phantom has been acquired in cine mode, and reconstructed into ten phases with slice thickness 1.25 mm. The 4D images sets were imported into a treatment planning software for target contouring. The geometrical accuracy of the 4D MRI and CT images has been quantified using target volume, flattening, and eccentricity. The target motion was measured by tracking the centroids of the spheres in each individual phase. Motion ground-truth was obtained from input signals and real-time video recordings. RESULTS: The dynamic phantom has been operated in four respiratory rate (RR) settings, 6, 10, 15, and 20/min, and was scanned with 4D-MRI and 4D-CT. 4D-CT images have target stretching, partial-missing, and other motion artifacts in various phases, whereas the 4D-MRI images are visually free of those artifacts. Volume percentage difference for the 6.37 ml target ranged from 5.3% +/- 4.3% to 10.3% +/- 5.9% for 4D-CT, and 1.47 +/- 0.52 to 2.12 +/- 1.60 for 4D-MRI. With an increase of respiratory rate, the target volumetric and geometric deviations increase for 4D CT images while remaining stable for the 4D-MRI images. Target motion amplitude errors at different RRs were measured with a range of 0.66-1.25 mm for 4D-CT and 0.2-0.42 mm for 4D-MRI. The results of Mann-Whitney tests indicated that 4D-MRI significantly outperforms 4D-CT in phase-based target volumetric (p = 0.027) and geometric (p < 0.001) measures. Both modalities achieve equivalent accuracy in measuring motion amplitude (p = 0.828). CONCLUSIONS: The k-space self-gated 4D MRI technique provides a robust method for accurately imaging phase-based target motion and geometry. Compared to 4D-CT, the current 4D-MRI technique demonstrates superior spatiotemporal resolution, and robust resistance to motion artifacts caused by fast target motion and irregular breathing patterns. The technique can be used extensively in abdominal targeting, motion gating, and toward implementing MRI-based adaptive radiotherapy. PMID- 26429254 TI - Multidimensional dosimetry of 106Ru eye plaques using EBT3 films and its impact on treatment planning. AB - PURPOSE: The purpose of this study was to establish a method to perform multidimensional radiochromic film measurements of (106)Ru plaques and to benchmark the resulting dose distributions against Monte Carlo simulations (MC), microdiamond, and diode measurements. METHODS: Absolute dose rates and relative dose distributions in multiple planes were determined for three different plaque models (CCB, CCA, and COB), and three different plaques per model, using EBT3 films in an in-house developed polystyrene phantom and the mcnp6 MC code. Dose difference maps were generated to analyze interplaque variations for a specific type, and for comparing measurements against MC simulations. Furthermore, dose distributions were validated against values specified by the manufacturer (BEBIG) and microdiamond and diode measurements in a water scanning phantom. Radial profiles were assessed and used to estimate dosimetric margins for a given combination of representative tumor geometry and plaque size. RESULTS: Absolute dose rates at a reference depth of 2 mm on the central axis of the plaque show an agreement better than 5% (10%) when comparing film measurements (mcnp6) to the manufacturer's data. The reproducibility of depth-dose profile measurements was <7% (2 SD) for all investigated detectors and plaque types. Dose difference maps revealed minor interplaque deviations for a specific plaque type due to inhomogeneities of the active layer. The evaluation of dosimetric margins showed that for a majority of the investigated cases, the tumor was not completely covered by the 100% isodose prescribed to the tumor apex if the difference between geometrical plaque size and tumor base <=4 mm. CONCLUSIONS: EBT3 film dosimetry in an in-house developed phantom was successfully used to characterize the dosimetric properties of different (106)Ru plaque models. The film measurements were validated against MC calculations and other experimental methods and showed a good agreement with data from BEBIG well within published tolerances. The dosimetric information as well as interplaque comparison can be used for comprehensive quality assurance and for considerations in the treatment planning of ophthalmic brachytherapy. PMID- 26429256 TI - Increasing efficiency of BEAMnrc-simulated Co-60 beams using directional source biasing. AB - PURPOSE: This study describes the implementation of a directional source biasing (DSB) scheme for efficiently simulating Cobalt-60 treatment heads using the BEAMnrc Monte Carlo code. Previous simulation of Co-60 beams with BEAMnrc was impractical because of the time required to track photons not directed into the treatment field and to simulate secondary charged particles. METHODS: In DSB, efficiency is increased by splitting each photon emitted by the Co-60 source a user-defined number of times. Only those split primary photons directed into a user-defined splitting field (encompassing the treatment field) are sampled, yielding many low-weight photons directed into the field. Efficiency can be further increased by taking advantage of radial symmetry at the top of the treatment head to reduce the number of split primary photons tracked in this portion. There is also an option to generate contaminant electrons in DSB. RESULTS: The DSB scheme in BEAMnrc increases the photon fluence calculation efficiency in a 10 * 10 cm(2) Co-60 beam by a factor of 1800 with a concurrent increase in contaminant electron fluence calculation efficiency by a factor of 1200. Implementation of DSB in beampp, a C++ code for accelerator simulations based on EGSnrc and the C++ class library, egspp, increases photon fluence efficiency by a factor of 2800 and contaminant electron fluence efficiency by a factor of 1600. Optimum splitting numbers are in the range of 20,000-40,000. For dose calculations in a water phantom (0.5 * 0.5 * 0.5 cm(3) voxels) this translates into a factor of ~400 increase in dose calculation efficiency (all doses > 0.5 * Dmax). An example calculation of the ratio of dose to water to dose to chamber (the basis of the beam quality correction factor) to within 0.2% in a realistic chamber using a full simulation of a Co-60 treatment head as a source indicates the practicality of Co-60 simulations with DSB. CONCLUSIONS: The efficiency improvement resulting from DSB makes Monte Carlo commissioning of Co 60 beams and calculation of beam quality correction factors feasible. PMID- 26429255 TI - Estimating patient-specific and anatomically correct reference model for craniomaxillofacial deformity via sparse representation. AB - PURPOSE: A significant number of patients suffer from craniomaxillofacial (CMF) deformity and require CMF surgery in the United States. The success of CMF surgery depends on not only the surgical techniques but also an accurate surgical planning. However, surgical planning for CMF surgery is challenging due to the absence of a patient-specific reference model. Currently, the outcome of the surgery is often subjective and highly dependent on surgeon's experience. In this paper, the authors present an automatic method to estimate an anatomically correct reference shape of jaws for orthognathic surgery, a common type of CMF surgery. METHODS: To estimate a patient-specific jaw reference model, the authors use a data-driven method based on sparse shape composition. Given a dictionary of normal subjects, the authors first use the sparse representation to represent the midface of a patient by the midfaces of the normal subjects in the dictionary. Then, the derived sparse coefficients are used to reconstruct a patient-specific reference jaw shape. RESULTS: The authors have validated the proposed method on both synthetic and real patient data. Experimental results show that the authors' method can effectively reconstruct the normal shape of jaw for patients. CONCLUSIONS: The authors have presented a novel method to automatically estimate a patient-specific reference model for the patient suffering from CMF deformity. PMID- 26429257 TI - Characterization of the onboard imaging unit for the first clinical magnetic resonance image guided radiation therapy system. AB - PURPOSE: To characterize the performance of the onboard imaging unit for the first clinical magnetic resonance image guided radiation therapy (MR-IGRT) system. METHODS: The imaging performance characterization included four components: ACR (the American College of Radiology) phantom test, spatial integrity, coil signal to noise ratio (SNR) and uniformity, and magnetic field homogeneity. The ACR phantom test was performed in accordance with the ACR phantom test guidance. The spatial integrity test was evaluated using a 40.8 * 40.8 * 40.8 cm(3) spatial integrity phantom. MR and computed tomography (CT) images of the phantom were acquired and coregistered. Objects were identified around the surfaces of 20 and 35 cm diameters of spherical volume (DSVs) on both the MR and CT images. Geometric distortion was quantified using deviation in object location between the MR and CT images. The coil SNR test was performed according to the national electrical manufacturers association (NEMA) standards MS-1 and MS-9. The magnetic field homogeneity test was measured using field camera and spectral peak methods. RESULTS: For the ACR tests, the slice position error was less than 0.10 cm, the slice thickness error was less than 0.05 cm, the resolved high-contrast spatial resolution was 0.09 cm, the resolved low-contrast spokes were more than 25, the image intensity uniformity was above 93%, and the percentage ghosting was less than 0.22%. All were within the ACR recommended specifications. The maximum geometric distortions within the 20 and 35 cm DSVs were 0.10 and 0.18 cm for high spatial resolution three-dimensional images and 0.08 and 0.20 cm for high temporal resolution two dimensional cine images based on the distance-to-phantom-center method. The average SNR was 12.0 for the body coil, 42.9 for the combined torso coil, and 44.0 for the combined head and neck coil. Magnetic field homogeneities at gantry angles of 0 degrees , 30 degrees , 60 degrees , 90 degrees , and 120 degrees were 23.55, 20.43, 18.76, 19.11, and 22.22 ppm, respectively, using the field camera method over the 45 cm DSV. CONCLUSIONS: The onboard imaging unit of the first commercial MR-IGRT system meets ACR, NEMA, and vendor specifications. PMID- 26429258 TI - Calibration of EBT2 film using a red-channel PDD method in combination with a modified three-channel technique. AB - PURPOSE: Ashland Inc. EBT2 and EBT3 films are widely used in quality assurance for radiation therapy; however, there remains a relatively high degree of uncertainty [B. Hartmann, M. Martisikova, and O. Jakel, "Homogeneity of Gafchromic EBT2 film," Med. Phys. 37, 1753-1756 (2010)]. Micke et al. (2011) recently improved the spatial homogeneity using all color channels of a flatbed scanner; however, van Hoof et al. (2012) pointed out that the corrected nonuniformity still requires further investigation for larger fields. To reduce the calibration errors and the uncertainty, the authors propose a new red-channel percentage-depth-dose method in combination with a modified three-channel technique. METHODS: For the ease of comparison, the EBT2 film image used in the authors' previous study (2012) was reanalyzed using different approaches. Photon beams of 6-MV were delivered to two different films at two different beam on times, resulting in the absorption doses of ranging from approximately 30 to 300 cGy at the vertical midline of the film, which was set to be coincident with the central axis of the beam. The film was tightly sandwiched in a 30(3)-cm(3) polystyrene phantom, and the pixel values for red, green, and blue channels were extracted from 234 points on the central axis of the beam and compared with the corresponding depth doses. The film was first calibrated using the multichannel method proposed by Micke et al. (2010), accounting for nonuniformities in the scanner. After eliminating the scanner and dose-independent nonuniformities, the film was recalibrated via the dose-dependent optical density of the red channel and fitted to a power function. This calibration was verified via comparisons of the dose profiles extracted from the films, where three were exposed to a 60 degrees physical wedge field and three were exposed to composite fields, and all of which were measured in a water phantom. A correction for optical attenuation was implemented, and treatment plans of intensity modulated radiation therapy and volumetric modulated arc therapy were evaluated. RESULTS: The method described here demonstrated improved accuracy with reduced uncertainty. The relative error compared with the measurements of a water phantom was less than 1%, and the overall calibration uncertainty was less than 2%. Verification tests revealed that the results were close to those of the authors' previous study, and all differences were within 3%, except those with a high-dose gradient. The gamma pass rates (2%/2 mm) of the treatment plan evaluated using the method described here were greater than 99%, and no obvious stripe patterns were observed in the dose-difference maps. CONCLUSIONS: Spatial homogeneity was significantly improved via the calibration method described here. This technique is both convenient and time-efficient because it does not require cutting the film, and only two exposures are necessary. PMID- 26429259 TI - A two-stage method for microcalcification cluster segmentation in mammography by deformable models. AB - PURPOSE: Segmentation of microcalcification (MC) clusters in x-ray mammography is a difficult task for radiologists. Accurate segmentation is prerequisite for quantitative image analysis of MC clusters and subsequent feature extraction and classification in computer-aided diagnosis schemes. METHODS: In this study, a two stage semiautomated segmentation method of MC clusters is investigated. The first stage is targeted to accurate and time efficient segmentation of the majority of the particles of a MC cluster, by means of a level set method. The second stage is targeted to shape refinement of selected individual MCs, by means of an active contour model. Both methods are applied in the framework of a rich scale-space representation, provided by the wavelet transform at integer scales. Segmentation reliability of the proposed method in terms of inter and intraobserver agreements was evaluated in a case sample of 80 MC clusters originating from the digital database for screening mammography, corresponding to 4 morphology types (punctate: 22, fine linear branching: 16, pleomorphic: 18, and amorphous: 24) of MC clusters, assessing radiologists' segmentations quantitatively by two distance metrics (Hausdorff distance-HDISTcluster, average of minimum distance AMINDISTcluster) and the area overlap measure (AOMcluster). The effect of the proposed segmentation method on MC cluster characterization accuracy was evaluated in a case sample of 162 pleomorphic MC clusters (72 malignant and 90 benign). Ten MC cluster features, targeted to capture morphologic properties of individual MCs in a cluster (area, major length, perimeter, compactness, and spread), were extracted and a correlation-based feature selection method yielded a feature subset to feed in a support vector machine classifier. Classification performance of the MC cluster features was estimated by means of the area under receiver operating characteristic curve (Az +/- Standard Error) utilizing tenfold cross-validation methodology. A previously developed B-spline active rays segmentation method was also considered for comparison purposes. RESULTS: Interobserver and intraobserver segmentation agreements (median and [25%, 75%] quartile range) were substantial with respect to the distance metrics HDISTcluster (2.3 [1.8, 2.9] and 2.5 [2.1, 3.2] pixels) and AMINDISTcluster (0.8 [0.6, 1.0] and 1.0 [0.8, 1.2] pixels), while moderate with respect to AOMcluster (0.64 [0.55, 0.71] and 0.59 [0.52, 0.66]). The proposed segmentation method outperformed (0.80 +/- 0.04) statistically significantly (Mann-Whitney U-test, p < 0.05) the B-spline active rays segmentation method (0.69 +/- 0.04), suggesting the significance of the proposed semiautomated method. CONCLUSIONS: Results indicate a reliable semiautomated segmentation method for MC clusters offered by deformable models, which could be utilized in MC cluster quantitative image analysis. PMID- 26429260 TI - Projections onto the Pareto surface in multicriteria radiation therapy optimization. AB - PURPOSE: To eliminate or reduce the error to Pareto optimality that arises in Pareto surface navigation when the Pareto surface is approximated by a small number of plans. METHODS: The authors propose to project the navigated plan onto the Pareto surface as a postprocessing step to the navigation. The projection attempts to find a Pareto optimal plan that is at least as good as or better than the initial navigated plan with respect to all objective functions. An augmented form of projection is also suggested where dose-volume histogram constraints are used to prevent that the projection causes a violation of some clinical goal. The projections were evaluated with respect to planning for intensity modulated radiation therapy delivered by step-and-shoot and sliding window and spot-scanned intensity modulated proton therapy. Retrospective plans were generated for a prostate and a head and neck case. RESULTS: The projections led to improved dose conformity and better sparing of organs at risk (OARs) for all three delivery techniques and both patient cases. The mean dose to OARs decreased by 3.1 Gy on average for the unconstrained form of the projection and by 2.0 Gy on average when dose-volume histogram constraints were used. No consistent improvements in target homogeneity were observed. CONCLUSIONS: There are situations when Pareto navigation leaves room for improvement in OAR sparing and dose conformity, for example, if the approximation of the Pareto surface is coarse or the problem formulation has too permissive constraints. A projection onto the Pareto surface can identify an inaccurate Pareto surface representation and, if necessary, improve the quality of the navigated plan. PMID- 26429261 TI - Induced magnetic moment in stainless steel components of orthodontic appliances in 1.5 T MRI scanners. AB - PURPOSE: Most orthodontic appliances are made of stainless steel materials and induce severe magnetic susceptibility artifacts in brain MRI. In an effort for correcting these artifacts, it is important to know the value of induced magnetic moments in all parts of orthodontic appliances. In this study, the induced magnetic moment of stainless steel orthodontic brackets, molar bands, and arch wires from several vendors is measured. METHODS: Individual stainless steel brackets, molar bands, and short segments of arch-wire were positioned in the center of spherical flask filled with water through a thin plastic rod. The induced magnetic moment at 1.5 T was determined by fitting the B0 map to the z component of the magnetic dipole field using a computer routine. RESULTS: The induced magnetic moment at 1.5 T was dominated by the longitudinal component mz, with a small contribution from the transverse components. The mz was insensitive to the orientation of the metal parts. The orthodontic brackets collectively dominated the magnetic dipole moment in orthodontic appliances. In brackets from six vendors, the total induced mz from 20 brackets for nonmolar teeth ranged from 0.108 to 0.158 (median 0.122) A ? m(2). The mz in eight molar bands with bracket attachment from two vendors ranged from 0.0004 to 0.0166 (median 0.0035) A ? m(2). Several full length arch wires had induced magnetic moment in the range of 0.006-0.025 (median 0.015) A ? m(2). CONCLUSIONS: Orthodontic brackets collectively contributed most to the total magnetic moment. Different types of brackets, molar bands, and arch wires all exhibit substantial variability in the induced magnetic moment. PMID- 26429262 TI - Vision 20/20: Simultaneous CT-MRI--Next chapter of multimodality imaging. AB - Multimodality imaging systems such as positron emission tomography-computed tomography (PET-CT) and MRI-PET are widely available, but a simultaneous CT-MRI instrument has not been developed. Synergies between independent modalities, e.g., CT, MRI, and PET/SPECT can be realized with image registration, but such postprocessing suffers from registration errors that can be avoided with synchronized data acquisition. The clinical potential of simultaneous CT-MRI is significant, especially in cardiovascular and oncologic applications where studies of the vulnerable plaque, response to cancer therapy, and kinetic and dynamic mechanisms of targeted agents are limited by current imaging technologies. The rationale, feasibility, and realization of simultaneous CT-MRI are described in this perspective paper. The enabling technologies include interior tomography, unique gantry designs, open magnet and RF sequences, and source and detector adaptation. Based on the experience with PET-CT, PET-MRI, and MRI-LINAC instrumentation where hardware innovation and performance optimization were instrumental to construct commercial systems, the authors provide top-level concepts for simultaneous CT-MRI to meet clinical requirements and new challenges. Simultaneous CT-MRI fills a major gap of modality coupling and represents a key step toward the so-called "omnitomography" defined as the integration of all relevant imaging modalities for systems biology and precision medicine. PMID- 26429264 TI - Local respiratory motion correction for PET/CT imaging: Application to lung cancer. AB - PURPOSE: Despite multiple methodologies already proposed to correct respiratory motion in the whole PET imaging field of view (FOV), such approaches have not found wide acceptance in clinical routine. An alternative can be the local respiratory motion correction (LRMC) of data corresponding to a given volume of interest (VOI: organ or tumor). Advantages of LRMC include the use of a simple motion model, faster execution times, and organ specific motion correction. The purpose of this study was to evaluate the performance of LMRC using various motion models for oncology (lung lesion) applications. METHODS: Both simulated (NURBS based 4D cardiac-torso phantom) and clinical studies (six patients) were used in the evaluation of the proposed LRMC approach. PET data were acquired in list-mode and synchronized with respiration. The implemented approach consists first in defining a VOI on the reconstructed motion average image. Gated PET images of the VOI are subsequently reconstructed using only lines of response passing through the selected VOI and are used in combination with a center of gravity or an affine/elastic registration algorithm to derive the transformation maps corresponding to the respiration effects. Those are finally integrated in the reconstruction process to produce a motion free image over the lesion regions. RESULTS: Although the center of gravity or affine algorithm achieved similar performance for individual lesion motion correction, the elastic model, applied either locally or to the whole FOV, led to an overall superior performance. The spatial tumor location was altered by 89% and 81% for the elastic model applied locally or to the whole FOV, respectively (compared to 44% and 39% for the center of gravity and affine models, respectively). This resulted in similar associated overall tumor volume changes of 84% and 80%, respectively (compared to 75% and 71% for the center of gravity and affine models, respectively). The application of the nonrigid deformation model in LRMC led to over an order of magnitude gain in computational efficiency of the correction relative to the application of the deformable model to the whole FOV. CONCLUSIONS: The results of this study support the use of LMRC as a flexible and efficient correction approach for respiratory motion effects for single lesions in the thoracic area. PMID- 26429263 TI - Gold nanoparticle induced vasculature damage in radiotherapy: Comparing protons, megavoltage photons, and kilovoltage photons. AB - PURPOSE: The purpose of this work is to investigate the radiosensitizing effect of gold nanoparticle (GNP) induced vasculature damage for proton, megavoltage (MV) photon, and kilovoltage (kV) photon irradiation. METHODS: Monte Carlo simulations were carried out using tool for particle simulation (TOPAS) to obtain the spatial dose distribution in close proximity up to 20 MUm from the GNPs. The spatial dose distribution from GNPs was used as an input to calculate the dose deposited to the blood vessels. GNP induced vasculature damage was evaluated for three particle sources (a clinical spread out Bragg peak proton beam, a 6 MV photon beam, and two kV photon beams). For each particle source, various depths in tissue, GNP sizes (2, 10, and 20 nm diameter), and vessel diameters (8, 14, and 20 MUm) were investigated. Two GNP distributions in lumen were considered, either homogeneously distributed in the vessel or attached to the inner wall of the vessel. Doses of 30 Gy and 2 Gy were considered, representing typical in vivo enhancement studies and conventional clinical fractionation, respectively. RESULTS: These simulations showed that for 20 Au-mg/g GNP blood concentration homogeneously distributed in the vessel, the additional dose at the inner vascular wall encircling the lumen was 43% of the prescribed dose at the depth of treatment for the 250 kVp photon source, 1% for the 6 MV photon source, and 0.1% for the proton beam. For kV photons, GNPs caused 15% more dose in the vascular wall for 150 kVp source than for 250 kVp. For 6 MV photons, GNPs caused 0.2% more dose in the vascular wall at 20 cm depth in water as compared to at depth of maximum dose (Dmax). For proton therapy, GNPs caused the same dose in the vascular wall for all depths across the spread out Bragg peak with 12.7 cm range and 7 cm modulation. For the same weight of GNPs in the vessel, 2 nm diameter GNPs caused three times more damage to the vessel than 20 nm diameter GNPs. When the GNPs were attached to the inner vascular wall, the damage to the inner vascular wall can be up to 207% of the prescribed dose for the 250 kVp photon source, 4% for the 6 MV photon source, and 2% for the proton beam. Even though the average dose increase from the proton beam and MV photon beam was not large, there were high dose spikes that elevate the local dose of the parts of the blood vessel to be higher than 15 Gy even for 2 Gy prescribed dose, especially when the GNPs can be actively targeted to the endothelial cells. CONCLUSIONS: GNPs can potentially be used to enhance radiation therapy by causing vasculature damage through high dose spikes caused by the addition of GNPs especially for hypofractionated treatment. If GNPs are designed to actively accumulate at the tumor vasculature walls, vasculature damage can be increased significantly. The largest enhancement is seen using kilovoltage photons due to the photoelectric effect. Although no significant average dose enhancement was observed for the whole vasculature structure for both MV photons and protons, they can cause high local dose escalation (>15 Gy) to areas of the blood vessel that can potentially contribute to the disruption of the functionality of the blood vessels in the tumor. PMID- 26429265 TI - Technical Note: Characterization of custom 3D printed multimodality imaging phantoms. AB - PURPOSE: Imaging phantoms are important tools for researchers and technicians, but they can be costly and difficult to customize. Three dimensional (3D) printing is a widely available rapid prototyping technique that enables the fabrication of objects with 3D computer generated geometries. It is ideal for quickly producing customized, low cost, multimodal, reusable imaging phantoms. This work validates the use of 3D printed phantoms by comparing CT and PET scans of a 3D printed phantom and a commercial "Micro Deluxe" phantom. This report also presents results from a customized 3D printed PET/MRI phantom, and a customized high resolution imaging phantom with sub-mm features. METHODS: CT and PET scans of a 3D printed phantom and a commercial Micro Deluxe (Data Spectrum Corporation, USA) phantom with 1.2, 1.6, 2.4, 3.2, 4.0, and 4.8 mm diameter hot rods were acquired. The measured PET and CT rod sizes, activities, and attenuation coefficients were compared. A PET/MRI scan of a custom 3D printed phantom with hot and cold rods was performed, with photon attenuation and normalization measurements performed with a separate 3D printed normalization phantom. X-ray transmission scans of a customized two level high resolution 3D printed phantom with sub-mm features were also performed. RESULTS: Results show very good agreement between commercial and 3D printed micro deluxe phantoms with less than 3% difference in CT measured rod diameter, less than 5% difference in PET measured rod diameter, and a maximum of 6.2% difference in average rod activity from a 10 min, 333 kBq/ml (9 MUCi/ml) Siemens Inveon (Siemens Healthcare, Germany) PET scan. In all cases, these differences were within the measurement uncertainties of our setups. PET/MRI scans successfully identified 3D printed hot and cold rods on PET and MRI modalities. X-ray projection images of a 3D printed high resolution phantom identified features as small as 350 MUm wide. CONCLUSIONS: This work shows that 3D printed phantoms can be functionally equivalent to commercially available phantoms. They are a viable option for quickly distributing and fabricating low cost, customized phantoms. PMID- 26429266 TI - Influence of radiation dose and reconstruction algorithm in MDCT assessment of airway wall thickness: A phantom study. AB - PURPOSE: Wall thickness (WT) is an airway feature of great interest for the assessment of morphological changes in the lung parenchyma. Multidetector computed tomography (MDCT) has recently been used to evaluate airway WT, but the potential risk of radiation-induced carcinogenesis-particularly in younger patients-might limit a wider use of this imaging method in clinical practice. The recent commercial implementation of the statistical model-based iterative reconstruction (MBIR) algorithm, instead of the conventional filtered back projection (FBP) algorithm, has enabled considerable radiation dose reduction in many other clinical applications of MDCT. The purpose of this work was to study the impact of radiation dose and MBIR in the MDCT assessment of airway WT. METHODS: An airway phantom was scanned using a clinical MDCT system (Discovery CT750 HD, GE Healthcare) at 4 kV levels and 5 mAs levels. Both FBP and a commercial implementation of MBIR (Veo(TM), GE Healthcare) were used to reconstruct CT images of the airways. For each kV-mAs combination and each reconstruction algorithm, the contrast-to-noise ratio (CNR) of the airways was measured, and the WT of each airway was measured and compared with the nominal value; the relative bias and the angular standard deviation in the measured WT were calculated. For each airway and reconstruction algorithm, the overall performance of WT quantification across all of the 20 kV-mAs combinations was quantified by the sum of squares (SSQs) of the difference between the measured and nominal WT values. Finally, the particular kV-mAs combination and reconstruction algorithm that minimized radiation dose while still achieving a reference WT quantification accuracy level was chosen as the optimal acquisition and reconstruction settings. RESULTS: The wall thicknesses of seven airways of different sizes were analyzed in the study. Compared with FBP, MBIR improved the CNR of the airways, particularly at low radiation dose levels. For FBP, the relative bias and the angular standard deviation of the measured WT increased steeply with decreasing radiation dose. Except for the smallest airway, MBIR enabled significant reduction in both the relative bias and angular standard deviation of the WT, particularly at low radiation dose levels; the SSQ was reduced by 50%-96% by using MBIR. The optimal reconstruction algorithm was found to be MBIR for the seven airways being assessed, and the combined use of MBIR and optimal kV-mAs selection resulted in a radiation dose reduction of 37%-83% compared with a reference scan protocol with a dose level of 1 mGy. CONCLUSIONS: The quantification accuracy of airway WT is strongly influenced by radiation dose and reconstruction algorithm. The MBIR algorithm potentially allows the desired WT quantification accuracy to be achieved with reduced radiation dose, which may enable a wider clinical use of MDCT for the assessment of airway WT, particularly for younger patients who may be more sensitive to exposures with ionizing radiation. PMID- 26429267 TI - Spatial fractionation of the dose using neon and heavier ions: A Monte Carlo study. AB - PURPOSE: This work explores a new radiation therapy approach which might trigger a renewed use of neon and heavier ions to treat cancers. These ions were shown to be extremely efficient in radioresistant tumor killing. Unfortunately, the efficient region also extends into the normal tissue in front of the tumor. The strategy the authors propose is to profit from the well-established sparing effect of thin spatially fractionated beams, so that the impact on normal tissues might be minimized while a high tumor control is achieved. The main goal of this work is to provide a proof of concept of this new approach. With that aim, a dosimetric study was carried out as a first step to evaluate the interest of further explorations of this avenue. METHODS: The gate/geant4 v.6.1 Monte Carlo simulation platform was employed to simulate arrays of rectangular minibeams (700 MUm * 2 cm) of four ions (Ne, Si, Ar, and Fe). The irradiations were performed with a 2 cm-long spread-out Bragg peak centered at 7 cm-depth. Dose distributions in a water phantom were scored considering two minibeams center-to-center distances: 1400 and 3500 MUm. Peak and valley doses, peak-to-valley dose ratios (PVDRs), beam penumbras, and relative contribution of nuclear fragments and electromagnetic processes were assessed as figures of merit. In addition, the type and proportion of the secondary nuclear fragments were evaluated in both peak and valley regions. RESULTS: Extremely high PVDR values (>100) and low valley doses were obtained. The higher the atomic number (Z) of the primary ion is, the lower the valleys and the narrower the penumbras. Although the yield of secondary nuclear products increases with Z, the actual dose being deposited by the secondary nuclear fragments in the valleys starts to be the dominant contribution at deeper points, helping in the sparing of proximal normal tissues. Additionally, a wider center-to-center distance leads to a minimized contribution of heavier secondary fragments in valleys. CONCLUSIONS: The computed dose distributions suggest that a spatial fractionation of the dose combined to the use of submillimetric field sizes might allow profiting from the high efficiency of neon and heavier ions for the treatment of radioresistant tumors, while preserving normal tissues. The authors' results support the further exploration of this avenue. Next steps include the realization of biological experiment to confirm the shifting of normal tissue complication probability curves. PMID- 26429268 TI - Measurement of gold nanofilm dose enhancement using unlaminated radiochromic film. AB - PURPOSE: Bombarding high-Z material with x-ray radiation releases Auger electrons and Coster-Kronig electrons, along with deeper penetrating fluorescent x-rays and photoelectrons. The Auger and Coster-Kronig electron penetration distance is on the order of nanometers to micrometers in water or tissue, creating a large dose enhancement accompanied by a RBE greater than 1 at the cellular level. The authors' aim is to measure the gold nanofilm dose enhancement factor (DEF) at the cellular level with unlaminated radiochromic film via primary 50 kVp tungsten x ray spectrum interaction, similar to an electronic brachytherapy spectrum. METHODS: Unlaminated Gafchromic((r)) EBT2 film and Monte Carlo modeling were combined to derive DEF models. Gold film of thickness 23.1 +/- 4.3 nm and surface roughness of 1.2 +/- 0.2 nm was placed in contact with unlaminated radiochromic film in a downstream orientation and exposed to a 50 kVp tungsten bremsstrahlung, mean energy 19.2 keV. Film response correction factors were derived by Monte Carlo modeling of electron energy deposition in the film's active layer, and by measuring film energy dependence from 4.5 keV to 50 kVp. RESULTS: The measured DEF within a 13.6 MUm thick water layer was 0.29 with a mean dose of 94 +/- 9.4 cGy from Au emissions and 324 +/- 32.4 cGy from the 50 kVp primary beam. Monte Carlo derived correction factors allowed determination of Au contributed dose in shallower depths at 0.25 MUm intervals. Maximum DEF of 18.31 was found in the first 0.25 MUm water depth. CONCLUSIONS: Dose enhancement from Au nanofilm can be measured at the cellular level using unlaminated radiochromic film. Complementing the measured dose value with Monte Carlo calculations allows estimation of dose enhancement at depth increments within the cellular range. PMID- 26429269 TI - DECT evaluation of noncalcified coronary artery plaque. AB - PURPOSE: Composition of the coronary artery plaque is known to have critical role in heart attack. While calcified plaque can easily be diagnosed by conventional CT, it fails to distinguish between fibrous and lipid rich plaques. In the present paper, the authors discuss the experimental techniques and obtain a numerical algorithm by which the electron density (rho(e)) and the effective atomic number (Z(eff)) can be obtained from the dual energy computed tomography (DECT) data. The idea is to use this inversion method to characterize and distinguish between the lipid and fibrous coronary artery plaques. METHODS: For the purpose of calibration of the CT machine, the authors prepare aqueous samples whose calculated values of (rho(e), Z(eff)) lie in the range of (2.65 * 10(23) <= rho(e) <= 3.64 * 10(23)/cm(3)) and (6.80 <= Z(eff) <= 8.90). The authors fill the phantom with these known samples and experimentally determine HU(V1) and HU(V2), with V1,V2 = 100 and 140 kVp, for the same pixels and thus determine the coefficients of inversion that allow us to determine (rho(e), Z(eff)) from the DECT data. The HU(100) and HU(140) for the coronary artery plaque are obtained by filling the channel of the coronary artery with a viscous solution of methyl cellulose in water, containing 2% contrast. These (rho(e), Z(eff)) values of the coronary artery plaque are used for their characterization on the basis of theoretical models of atomic compositions of the plaque materials. These results are compared with histopathological report. RESULTS: The authors find that the calibration gives rho(e) with an accuracy of +/-3.5% while Z(eff) is found within +/-1% of the actual value, the confidence being 95%. The HU(100) and HU(140) are found to be considerably different for the same plaque at the same position and there is a linear trend between these two HU values. It is noted that pure lipid type plaques are practically nonexistent, and microcalcification, as observed in histopathology, has to be taken into account to explain the nature of the observed (rho(e), Z(eff)) data. This also enables us to judge the composition of the plaque in terms of basic model which considers the plaque to be composed of fibres, lipids, and microcalcification. CONCLUSIONS: This simple and reliable method has the potential as an effective modality to investigate the composition of noncalcified coronary artery plaques and thus help in their characterization. In this inversion method, (rho(e), Z(eff)) of the scanned sample can be found by eliminating the effects of the CT machine and also by ensuring that the determination of the two unknowns (rho(e), Ze(ff)) does not interfere with each other and the nature of the plaque can be identified in terms of a three component model. PMID- 26429270 TI - Technical Note: Characterization and correction of gradient nonlinearity induced distortion on a 1.0 T open bore MR-SIM. AB - PURPOSE: Distortions in magnetic resonance imaging (MRI) compromise spatial fidelity, potentially impacting delineation and dose calculation. We characterized 2D and 3D large field of view (FOV), sequence-independent distortion at various positions in a 1.0 T high-field open MR simulator (MR-SIM) to implement correction maps for MRI treatment planning. METHODS: A 36 * 43 * 2 cm(3) phantom with 255 known landmarks (~1 mm(3)) was scanned using 1.0 T high field open MR-SIM at isocenter in the transverse, sagittal, and coronal axes, and a 465 * 350 * 168 mm(3) 3D phantom was scanned by stepping in the superior inferior direction in three overlapping positions to achieve a total 465 * 350 * 400 mm(3) sampled FOV yielding >13 800 landmarks (3D Gradient-Echo, TE/TR/alpha = 5.54 ms/30 ms/28 degrees , voxel size = 1 * 1 * 2 mm(3)). A binary template (reference) was generated from a phantom schematic. An automated program converted MR images to binary via masking, thresholding, and testing for connectivity to identify landmarks. Distortion maps were generated by centroid mapping. Images were corrected via warping with inverse distortion maps, and temporal stability was assessed. RESULTS: Over the sampled FOV, non-negligible residual gradient distortions existed as close as 9.5 cm from isocenter, with a maximum distortion of 7.4 mm as close as 23 cm from isocenter. Over six months, average gradient distortions were -0.07 +/- 1.10 mm and 0.10 +/- 1.10 mm in the x and y directions for the transverse plane, 0.03 +/- 0.64 and -0.09 +/- 0.70 mm in the sagittal plane, and 0.4 +/- 1.16 and 0.04 +/- 0.40 mm in the coronal plane. After implementing 3D correction maps, distortions were reduced to <1 pixel width (1 mm) for all voxels up to 25 cm from magnet isocenter. CONCLUSIONS: Inherent distortion due to gradient nonlinearity was found to be non-negligible even with vendor corrections applied, and further corrections are required to obtain 1 mm accuracy for large FOVs. Statistical analysis of temporal stability shows that sequence independent distortion maps are consistent within six months of characterization. PMID- 26429271 TI - Quality control for quantitative multicenter whole-body PET/MR studies: A NEMA image quality phantom study with three current PET/MR systems. AB - PURPOSE: Integrated positron emission tomography/magnetic resonance (PET/MR) systems derive the PET attenuation correction (AC) from dedicated MR sequences. While MR-AC performs reasonably well in clinical patient imaging, it may fail for phantom-based quality control (QC). The authors assess the applicability of different protocols for PET QC in multicenter PET/MR imaging. METHODS: The National Electrical Manufacturers Association NU 2 2007 image quality phantom was imaged on three combined PET/MR systems: a Philips Ingenuity TF PET/MR, a Siemens Biograph mMR, and a GE SIGNA PET/MR (prototype) system. The phantom was filled according to the EANM FDG-PET/CT guideline 1.0 and scanned for 5 min over 1 bed. Two MR-AC imaging protocols were tested: standard clinical procedures and a dedicated protocol for phantom tests. Depending on the system, the dedicated phantom protocol employs a two-class (water and air) segmentation of the MR data or a CT-based template. Differences in attenuation- and SUV recovery coefficients (RC) are reported. PET/CT-based simulations were performed to simulate the various artifacts seen in the AC maps (MU-map) and their impact on the accuracy of phantom-based QC. RESULTS: Clinical MR-AC protocols caused substantial errors and artifacts in the AC maps, resulting in underestimations of the reconstructed PET activity of up to 27%, depending on the PET/MR system. Using dedicated phantom MR-AC protocols, PET bias was reduced to -8%. Mean and max SUV RC met EARL multicenter PET performance specifications for most contrast objects, but only when using the dedicated phantom protocol. Simulations confirmed the bias in experimental data to be caused by incorrect AC maps resulting from the use of clinical MR-AC protocols. CONCLUSIONS: Phantom-based quality control of PET/MR systems in a multicenter, multivendor setting may be performed with sufficient accuracy, but only when dedicated phantom acquisition and processing protocols are used for attenuation correction. PMID- 26429272 TI - The SRT reconstruction algorithm for semiquantification in PET imaging. AB - PURPOSE: The spline reconstruction technique (SRT) is a new, fast algorithm based on a novel numerical implementation of an analytic representation of the inverse Radon transform. The mathematical details of this algorithm and comparisons with filtered backprojection were presented earlier in the literature. In this study, the authors present a comparison between SRT and the ordered-subsets expectation maximization (OSEM) algorithm for determining contrast and semiquantitative indices of (18)F-FDG uptake. METHODS: The authors implemented SRT in the software for tomographic image reconstruction (stir) open-source platform and evaluated this technique using simulated and real sinograms obtained from the GE Discovery ST positron emission tomography/computer tomography scanner. All simulations and reconstructions were performed in stir. For OSEM, the authors used the clinical protocol of their scanner, namely, 21 subsets and two iterations. The authors also examined images at one, four, six, and ten iterations. For the simulation studies, the authors analyzed an image-quality phantom with cold and hot lesions. Two different versions of the phantom were employed at two different hot-sphere lesion-to-background ratios (LBRs), namely, 2:1 and 4:1. For each noiseless sinogram, 20 Poisson realizations were created at five different noise levels. In addition to making visual comparisons of the reconstructed images, the authors determined contrast and bias as a function of the background image roughness (IR). For the real-data studies, sinograms of an image-quality phantom simulating the human torso were employed. The authors determined contrast and LBR as a function of the background IR. Finally, the authors present plots of contrast as a function of IR after smoothing each reconstructed image with Gaussian filters of six different sizes. Statistical significance was determined by employing the Wilcoxon rank-sum test. RESULTS: In both simulated and real studies, SRT exhibits higher contrast and lower bias than OSEM at the cold lesions. This improvement is achieved at the expense of increasing the noise in the reconstructed images. For the hot lesions, SRT exhibits a small improvement in contrast and LBR over OSEM with 21 subsets and two iterations; however, this improvement is not statistically significant. As the number of iterations increases, the performance of OSEM improves over SRT but again without statistical significance. The curves of contrast and LBR as a function of IR after Gaussian blurring indicate that the advantage of SRT in the cold regions is maintained even after decreasing the noise level by Gaussian blurring. CONCLUSIONS: SRT, at the expense of slightly increased noise in the reconstructed images, reconstructs images of higher contrast and lower bias than the clinical protocol of OSEM. This improvement is particularly evident for images involving cold regions. Thus, it appears that SRT should be particularly useful for the quantification of low-count and cold regions. PMID- 26429273 TI - In-plane ultrasonic needle tracking using a fiber-optic hydrophone. AB - PURPOSE: Accurate and efficient guidance of needles to procedural targets is critically important during percutaneous interventional procedures. Ultrasound imaging is widely used for real-time image guidance in a variety of clinical contexts, but with this modality, uncertainties about the location of the needle tip within the image plane lead to significant complications. Whilst several methods have been proposed to improve the visibility of the needle, achieving accuracy and compatibility with current clinical practice is an ongoing challenge. In this paper, the authors present a method for directly visualizing the needle tip using an integrated fiber-optic ultrasound receiver in conjunction with the imaging probe used to acquire B-mode ultrasound images. METHODS: Needle visualization and ultrasound imaging were performed with a clinical ultrasound imaging system. A miniature fiber-optic ultrasound hydrophone was integrated into a 20 gauge injection needle tip to receive transmissions from individual transducer elements of the ultrasound imaging probe. The received signals were reconstructed to create an image of the needle tip. Ultrasound B-mode imaging was interleaved with needle tip imaging. A first set of measurements was acquired in water and tissue ex vivo with a wide range of insertion angles (15 degrees -68 degrees ) to study the accuracy and sensitivity of the tracking method. A second set was acquired in an in vivo swine model, with needle insertions to the brachial plexus. A third set was acquired in an in vivo ovine model for fetal interventions, with insertions to different locations within the uterine cavity. Two linear ultrasound imaging probes were used: a 14-5 MHz probe for the first and second sets, and a 9-4 MHz probe for the third. RESULTS: During insertions in tissue ex vivo and in vivo, the imaged needle tip had submillimeter axial and lateral dimensions. The signal-to-noise (SNR) of the needle tip was found to depend on the insertion angle. With the needle tip in water, the SNR of the needle tip varied with insertion angle, attaining values of 284 at 27 degrees and 501 at 68 degrees . In swine tissue ex vivo, the SNR decreased from 80 at 15 degrees to 16 at 61 degrees . In swine tissue in vivo, the SNR varied with depth, from 200 at 17.5 mm to 48 at 26 mm, with a constant insertion angle of 40 degrees . In ovine tissue in vivo, within the uterine cavity, the SNR varied from 46.4 at 25 mm depth to 18.4 at 32 mm depth, with insertion angles in the range of 26 degrees -65 degrees . CONCLUSIONS: A fiber-optic ultrasound receiver integrated into the needle cannula in combination with single-element transmissions from the imaging probe allows for direct visualization of the needle tip within the ultrasound imaging plane. Visualization of the needle tip was achieved at depths and insertion angles that are encountered during nerve blocks and fetal interventions. The method presented in this paper has strong potential to improve the safety and efficiency of ultrasound-guided needle insertions. PMID- 26429274 TI - Paddle-based rotating-shield brachytherapy. AB - PURPOSE: The authors present a novel paddle-based rotating-shield brachytherapy (P-RSBT) method, whose radiation-attenuating shields are formed with a multileaf collimator (MLC), consisting of retractable paddles, to achieve intensity modulation in high-dose-rate brachytherapy. METHODS: Five cervical cancer patients using an intrauterine tandem applicator were considered to assess the potential benefit of the P-RSBT method. The P-RSBT source used was a 50 kV electronic brachytherapy source (Xoft AxxentTM). The paddles can be retracted independently to form multiple emission windows around the source for radiation delivery. The MLC was assumed to be rotatable. P-RSBT treatment plans were generated using the asymmetric dose-volume optimization with smoothness control method [Liu et al., Med. Phys. 41(11), 111709 (11pp.) (2014)] with a delivery time constraint, different paddle sizes, and different rotation strides. The number of treatment fractions (fx) was assumed to be five. As brachytherapy is delivered as a boost for cervical cancer, the dose distribution for each case includes the dose from external beam radiotherapy as well, which is 45 Gy in 25 fx. The high-risk clinical target volume (HR-CTV) doses were escalated until the minimum dose to the hottest 2 cm(3) (D(2cm(3)) of either the rectum, sigmoid colon, or bladder reached their tolerance doses of 75, 75, and 90 Gy3, respectively, expressed as equivalent doses in 2 Gy fractions (EQD2 with alpha/beta = 3 Gy). RESULTS: P-RSBT outperformed the two other RSBT delivery techniques, single-shield RSBT (S-RSBT) and dynamic-shield RSBT (D-RSBT), with a properly selected paddle size. If the paddle size was angled at 60 degrees , the average D90 increases for the delivery plans by P-RSBT on the five cases, compared to S-RSBT, were 2.2, 8.3, 12.6, 11.9, and 9.1 Gy10, respectively, with delivery times of 10, 15, 20, 25, and 30 min/fx. The increases in HR-CTV D90, compared to D-RSBT, were 16.6, 12.9, 7.2, 3.7, and 1.7 Gy10, respectively. P-RSBT HR-CTV D90-values were insensitive to the paddle size for paddles angled at less than 60 degrees . Increasing the paddle angle from 5 degrees to 60 degrees resulted in only a 0.6 Gy10 decrease in HR-CTV D90 on average for five cases when the delivery times were set to 15 min/fx. The HR-CTV D90 decreased to 2.5 and 11.9 Gy10 with paddle angles of 90 degrees and 120 degrees , respectively. CONCLUSIONS: P-RSBT produces treatment plans that are dosimetrically and temporally superior to those of S-RSBT and D-RSBT, although P-RSBT systems may be more mechanically challenging to develop than S-RSBT or D-RSBT. A P-RSBT implementation with 4-6 shield paddles would be sufficient to outperform S-RSBT and D-RSBT if delivery times are constrained to less than 15 min/fx. PMID- 26429275 TI - Factors that may determine the targeting accuracy of image-guided radiosurgery. AB - PURPOSE: The AAPM TG-135 report is a landmark recommendation for the quality assurance (QA) of image-guided robotic radiosurgery. The purpose of this paper is to present results pertaining to intentionally offsetting the phantom as recommended by TG-135 and to present data on targeting algorithm accuracy as a function of imager parameters in less than ideal circumstances, which had not been available at the time of publication of TG-135. METHODS: All tests in this study were performed at the Cooper University Hospital CyberKnife Center in Mt. Laurel, NJ. For intentional offsets, initial tests were performed on the Accuray supplied anthropomorphic head and neck phantom, whereas for subsequent tests, the Accuray-supplied alignment quality assurance (AQA) phantom was used. To simulate the effects of imager parameters for larger patients, slabs of Blue Water (Standard Imaging, Inc., Middleton, WI) were added to attenuate the x-ray images in some of the tests. In conjunction with attenuated x-ray tests, the number of fiducials was varied by systematically deselecting them one at a time at the CyberKnife console. RESULTS: Tests using the AQA phantom verified that submillimeter alignments were consistently achieved even with intentional shifts and rotations of up to 10.0 mm and 1.0 degrees , respectively. An analysis of 17 months of daily QA alignment tests showed that submillimeter alignments were achieved more than 99% of the time even with such intentional shifts and rotations of the phantom. When additional slabs of Blue Water were added to simulate patient attenuation of the x-ray images, targeting errors could be induced depending on imager parameters and the amount of Blue Water used. A series of consecutive tests showed that two helpful variables to ensure good accuracy of the system were (1) the fiducial extraction confidence level (FECL) system parameter and (2) the number of targeted fiducials. When fewer than four fiducials were used, the FECL reported by the CyberKnife was sometimes high even when a false lock occurred, so using multiple fiducials helped to ensure reliable targeting. CONCLUSIONS: Radiosurgery requires the highest degree of targeting accuracy, and in our experience, the CyberKnife has been able to maintain submillimeter accuracy consistently. It has been verified that our CyberKnife can correct for phantom shifts of up to 10.0 mm and rotations of up to 1.0 degrees . It has also been discovered that false locks are more likely to occur with a single fiducial than with multiple fiducials. Although targeting accuracy can only be measured on a phantom, the insight gained from analyzing the QA tests can help us in devising better strategies for achieving the best treatment for our patients. PMID- 26429276 TI - The influence of focal spot blooming on high-contrast spatial resolution in CT imaging. AB - PURPOSE: The objective of this work was to investigate focal spot blooming effects on the spatial resolution of CT images and to evaluate an x-ray tube that uses dynamic focal spot control for minimizing focal spot blooming. METHODS: The influence of increasing tube current at a fixed tube potential of 80 kV on high contrast spatial resolution of seven different CT scanner models (scanners A-G), including one scanner that uses dynamic focal spot control to reduce focal spot blooming (scanner A), was evaluated. Spatial resolution was assessed using a wire phantom for the modulation transfer function (MTF) calculation and a copper disc phantom for measuring the slice sensitivity profile (SSP). The impact of varying the tube potential was investigated on two scanner models (scanners A and B) by measuring the MTF and SSP and also by using the resolution bar pattern module of the ACR CT phantom. The phantoms were scanned at 70-150 kV on scanner A and 80 140 kV on scanner B, with tube currents from 100 mA up to the maximum tube current available on each scanner. The images were reconstructed using a slice thickness of 0.6 mm with both smooth and sharp kernels. Additionally, focal spot size at varying tube potentials and currents was directly measured using pinhole and slit camera techniques. RESULTS: Evaluation of the MTF and SSP data from the 7 CT scanner models evaluated demonstrated decreased focal spot blooming for newer scanners, as evidenced by decreasing deviations in MTF and SSP as tube current varied. For scanners A and B, where focal spot blooming effects as a function of tube potential were assessed, the spatial resolution variation in the axial plane was much smaller on scanner A compared to scanner B as tube potential and current changed. On scanner A, the 50% MTF never decreased by more than 2% from the 50% MTF measured at 100 mA. On scanner B, the 50% MTF decreased by as much as 19% from the 50% MTF measured at 100 mA. Assessments of the SSP, the bar patterns in the ACR phantom and the pinhole and slit camera measurements were consistent with the MTF calculations. CONCLUSIONS: Focal spot blooming has a noticeable effect on spatial resolution in CT imaging. The focal spot shaping technology of scanner A greatly reduced blooming effects. PMID- 26429277 TI - A virtual simulator designed for collision prevention in proton therapy. AB - PURPOSE: In proton therapy, collisions between the patient and nozzle potentially occur because of the large nozzle structure and efforts to minimize the air gap. Thus, software was developed to predict such collisions between the nozzle and patient using treatment virtual simulation. METHODS: Three-dimensional (3D) modeling of a gantry inner-floor, nozzle, and robotic-couch was performed using SolidWorks based on the manufacturer's machine data. To obtain patient body information, a 3D-scanner was utilized right before CT scanning. Using the acquired images, a 3D-image of the patient's body contour was reconstructed. The accuracy of the image was confirmed against the CT image of a humanoid phantom. The machine components and the virtual patient were combined on the treatment room coordinate system, resulting in a virtual simulator. The simulator simulated the motion of its components such as rotation and translation of the gantry, nozzle, and couch in real scale. A collision, if any, was examined both in static and dynamic modes. The static mode assessed collisions only at fixed positions of the machine's components, while the dynamic mode operated any time a component was in motion. A collision was identified if any voxels of two components, e.g., the nozzle and the patient or couch, overlapped when calculating volume locations. The event and collision point were visualized, and collision volumes were reported. RESULTS: All components were successfully assembled, and the motions were accurately controlled. The 3D-shape of the phantom agreed with CT images within a deviation of 2 mm. Collision situations were simulated within minutes, and the results were displayed and reported. CONCLUSIONS: The developed software will be useful in improving patient safety and clinical efficiency of proton therapy. PMID- 26429278 TI - Radiobiologically optimized couch shift: A new localization paradigm using cone beam CT for prostate radiotherapy. AB - PURPOSE: To present a novel positioning strategy which optimizes radiation delivery by utilizing radiobiological response knowledge and evaluate its use during prostate external beam radiotherapy. METHODS: Five patients with low or intermediate risk prostate cancer were evaluated retrospectively in this IRB approved study. For each patient, a VMAT plan with one 358 degrees arc was generated on the planning CT (PCT) to deliver 78 Gy in 39 fractions. Five representative pretreatment cone beam CTs (CBCT) were selected for each patient. The CBCT images were registered to PCT by a human observer, which consisted of an initial automated registration with three degrees-of-freedom, followed by manual adjustment for agreement at the prostate/rectal wall interface. To determine the optimal treatment position for each CBCT, a search was performed centering on the observer-matched position (OM-position) utilizing a score function based on radiobiological and dosimetric indices (EUDprostate, D99prostate, NTCPrectum, and NTCPbladder) for the prostate, rectum, and bladder. We termed the optimal treatment position the radiobiologically optimized couch shift position (ROCS position). RESULTS: The dosimetric indices, averaged over the five patients' treatment plans, were (mean +/- SD) 79.5 +/- 0.3 Gy (EUDprostate), 78.2 +/- 0.4 Gy (D99prostate), 11.1% +/- 2.7% (NTCPrectum), and 46.9% +/- 7.6% (NTCPbladder). The corresponding values from CBCT at the OM-positions were 79.5 +/- 0.6 Gy (EUDprostate), 77.8 +/- 0.7 Gy (D99prostate), 12.1% +/- 5.6% (NTCPrectum), and 51.6% +/- 15.2% (NTCPbladder), respectively. In comparison, from CBCT at the ROCS positions, the dosimetric indices were 79.5 +/- 0.6 Gy (EUDprostate), 77.3 +/- 0.6 Gy (D99prostate), 8.0% +/- 3.3% (NTCPrectum), and 46.9% +/- 15.7% (NTCPbladder). Excessive NTCPrectum was observed on Patient 5 (19.5% +/- 6.6%) corresponding to localization at OM-position, compared to the planned value of 11.7%. This was mitigated with radiobiologically optimized localization, resulting in a reduced NTCPrectum value of 11.3% +/- 3.5%. Overall, the treatment position optimization resulted in similar target dose coverage with reduced risk to rectum. CONCLUSIONS: These encouraging results illustrate the potential advantage of applying radiobiologically optimized correction for online image guided radiotherapy of prostate patients. PMID- 26429279 TI - Detector dose response in megavoltage small photon beams. I. Theoretical concepts. AB - PURPOSE: To explain the reasons for significant quality correction factors in megavoltage small photon fields and clarify the underlying concepts relevant to dosimetry under such conditions. METHODS: The validity of cavity theory and the requirement of charged particle equilibrium (CPE) are addressed from a theoretical point of view in the context of nonstandard beams. Perturbation effects are described into four main subeffects, explaining their nature and pointing out their relative importance in small photon fields. RESULTS: It is demonstrated that the failure to meet classical cavity theory requirements, such as CPE, is not the reason for significant quality correction factors. On the contrary, it is shown that the lack of CPE alone cannot explain these corrections and that what matters most, apart from volume averaging effects, is the relationship between the lack of CPE in the small field itself and the density of the detector cavity. The density perturbation effect is explained based on Fano's theorem, describing the compensating effect of two main contributions to cavity absorbed dose. Using the same approach, perturbation effects arising from the difference in atomic properties of the cavity medium and the presence of extracameral components are explained. Volume averaging effects are also discussed in detail. CONCLUSIONS: Quality correction factors of small megavoltage photon fields are mainly due to differences in electron density between water and the detector medium and to volume averaging over the detector cavity. Other effects, such as the presence of extracameral components and differences in atomic properties of the detection medium with respect to water, can also play an accentuated role in small photon fields compared to standard beams. PMID- 26429280 TI - Detector dose response in megavoltage small photon beams. II. Pencil beam perturbation effects. AB - PURPOSE: To quantify detector perturbation effects in megavoltage small photon fields and support the theoretical explanation on the nature of quality correction factors in these conditions. METHODS: In this second paper, a modern approach to radiation dosimetry is defined for any detector and applied to small photon fields. Fano's theorem is adapted in the form of a cavity theory and applied in the context of nonstandard beams to express four main effects in the form of perturbation factors. The pencil-beam decomposition method is detailed and adapted to the calculation of perturbation factors and quality correction factors. The approach defines a perturbation function which, for a given field size or beam modulation, entirely determines these dosimetric factors. Monte Carlo calculations are performed in different cavity sizes for different detection materials, electron densities, and extracameral components. RESULTS: Perturbation effects are detailed with calculated perturbation functions, showing the relative magnitude of the effects as well as the geometrical extent to which collimating or modulating the beam impacts the dosimetric factors. The existence of a perturbation zone around the detector cavity is demonstrated and the approach is discussed and linked to previous approaches in the literature to determine critical field sizes. CONCLUSIONS: Monte Carlo simulations are valuable to describe pencil beam perturbation effects and detail the nature of dosimetric factors in megavoltage small photon fields. In practice, it is shown that dosimetric factors could be avoided if the field size remains larger than the detector perturbation zone. However, given a detector and beam quality, a full account for the detector geometry is necessary to determine critical field sizes. PMID- 26429281 TI - Analytic reconstruction algorithms for triple-source CT with horizontal data truncation. AB - PURPOSE: This paper explores a triple-source imaging method with horizontal data truncation to enlarge the field of view (FOV) for big objects. METHODS: The study is conducted by using theoretical analysis, mathematical deduction, and numerical simulations. The proposed algorithms are implemented in c + + and matlab. While the basic platform is constructed in matlab, the computationally intensive segments are coded in c + +, which are linked via a mex interface. RESULTS: A triple-source circular scanning configuration with horizontal data truncation is developed, where three pairs of x-ray sources and detectors are unevenly distributed on the same circle to cover the whole imaging object. For this triple source configuration, a fan-beam filtered backprojection-type algorithm is derived for truncated full-scan projections without data rebinning. The algorithm is also extended for horizontally truncated half-scan projections and cone-beam projections in a Feldkamp-type framework. Using their method, the FOV is enlarged twofold to threefold to scan bigger objects with high speed and quality. The numerical simulation results confirm the correctness and effectiveness of the developed algorithms. CONCLUSIONS: The triple-source scanning configuration with horizontal data truncation cannot only keep most of the advantages of a traditional multisource system but also cover a larger FOV for big imaging objects. In addition, because the filtering is shift-invariant, the proposed algorithms are very fast and easily parallelized on graphic processing units. PMID- 26429282 TI - Automating linear accelerator quality assurance. AB - PURPOSE: The purpose of this study was 2-fold. One purpose was to develop an automated, streamlined quality assurance (QA) program for use by multiple centers. The second purpose was to evaluate machine performance over time for multiple centers using linear accelerator (Linac) log files and electronic portal images. The authors sought to evaluate variations in Linac performance to establish as a reference for other centers. METHODS: The authors developed analytical software tools for a QA program using both log files and electronic portal imaging device (EPID) measurements. The first tool is a general analysis tool which can read and visually represent data in the log file. This tool, which can be used to automatically analyze patient treatment or QA log files, examines the files for Linac deviations which exceed thresholds. The second set of tools consists of a test suite of QA fields, a standard phantom, and software to collect information from the log files on deviations from the expected values. The test suite was designed to focus on the mechanical tests of the Linac to include jaw, MLC, and collimator positions during static, IMRT, and volumetric modulated arc therapy delivery. A consortium of eight institutions delivered the test suite at monthly or weekly intervals on each Linac using a standard phantom. The behavior of various components was analyzed for eight TrueBeam Linacs. RESULTS: For the EPID and trajectory log file analysis, all observed deviations which exceeded established thresholds for Linac behavior resulted in a beam hold off. In the absence of an interlock-triggering event, the maximum observed log file deviations between the expected and actual component positions (such as MLC leaves) varied from less than 1% to 26% of published tolerance thresholds. The maximum and standard deviations of the variations due to gantry sag, collimator angle, jaw position, and MLC positions are presented. Gantry sag among Linacs was 0.336 +/- 0.072 mm. The standard deviation in MLC position, as determined by EPID measurements, across the consortium was 0.33 mm for IMRT fields. With respect to the log files, the deviations between expected and actual positions for parameters were small (<0.12 mm) for all Linacs. Considering both log files and EPID measurements, all parameters were well within published tolerance values. Variations in collimator angle, MLC position, and gantry sag were also evaluated for all Linacs. CONCLUSIONS: The performance of the TrueBeam Linac model was shown to be consistent based on automated analysis of trajectory log files and EPID images acquired during delivery of a standardized test suite. The results can be compared directly to tolerance thresholds. In addition, sharing of results from standard tests across institutions can facilitate the identification of QA process and Linac changes. These reference values are presented along with the standard deviation for common tests so that the test suite can be used by other centers to evaluate their Linac performance against those in this consortium. PMID- 26429283 TI - Technical Note: Simulation of 4DCT tumor motion measurement errors. AB - PURPOSE: To determine if and by how much the commercial 4DCT protocols under- and overestimate tumor breathing motion. METHODS: 1D simulations were conducted that modeled a 16-slice CT scanner and tumors moving proportionally to breathing amplitude. External breathing surrogate traces of at least 5-min duration for 50 patients were used. Breathing trace amplitudes were converted to motion by relating the nominal tumor motion to the 90th percentile breathing amplitude, reflecting motion defined by the more recent 5DCT approach. Based on clinical low pitch helical CT acquisition, the CT detector moved according to its velocity while the tumor moved according to the breathing trace. When the CT scanner overlapped the tumor, the overlapping slices were identified as having imaged the tumor. This process was repeated starting at successive 0.1 s time bin in the breathing trace until there was insufficient breathing trace to complete the simulation. The tumor size was subtracted from the distance between the most superior and inferior tumor positions to determine the measured tumor motion for that specific simulation. The effect of the scanning parameter variation was evaluated using two commercial 4DCT protocols with different pitch values. Because clinical 4DCT scan sessions would yield a single tumor motion displacement measurement for each patient, errors in the tumor motion measurement were considered systematic. The mean of largest 5% and smallest 5% of the measured motions was selected to identify over- and underdetermined motion amplitudes, respectively. The process was repeated for tumor motions of 1-4 cm in 1 cm increments and for tumor sizes of 1-4 cm in 1 cm increments. RESULTS: In the examined patient cohort, simulation using pitch of 0.06 showed that 30% of the patients exhibited a 5% chance of mean breathing amplitude overestimations of 47%, while 30% showed a 5% chance of mean breathing amplitude underestimations of 36%; with a separate simulation using pitch of 0.1 showing, respectively, 37% overestimation and 61% underestimation. CONCLUSIONS: The simulation indicates that commercial low-pitch helical 4DCT processes potentially yield large tumor motion measurement errors, both over- and underestimating the tumor motion. PMID- 26429284 TI - Technical Note: MRI only prostate radiotherapy planning using the statistical decomposition algorithm. AB - PURPOSE: In order to enable a magnetic resonance imaging (MRI) only workflow in radiotherapy treatment planning, methods are required for generating Hounsfield unit (HU) maps (i.e., synthetic computed tomography, sCT) for dose calculations, directly from MRI. The Statistical Decomposition Algorithm (SDA) is a method for automatically generating sCT images from a single MR image volume, based on automatic tissue classification in combination with a model trained using a multimodal template material. This study compares dose calculations between sCT generated by the SDA and conventional CT in the male pelvic region. METHODS: The study comprised ten prostate cancer patients, for whom a 3D T2 weighted MRI and a conventional planning CT were acquired. For each patient, sCT images were generated from the acquired MRI using the SDA. In order to decouple the effect of variations in patient geometry between imaging modalities from the effect of uncertainties in the SDA, the conventional CT was nonrigidly registered to the MRI to assure that their geometries were well aligned. For each patient, a volumetric modulated arc therapy plan was created for the registered CT (rCT) and recalculated for both the sCT and the conventional CT. The results were evaluated using several methods, including mean average error (MAE), a set of dose-volume histogram parameters, and a restrictive gamma criterion (2% local dose/1 mm). RESULTS: The MAE within the body contour was 36.5 +/- 4.1 (1 s.d.) HU between sCT and rCT. Average mean absorbed dose difference to target was 0.0% +/- 0.2% (1 s.d.) between sCT and rCT, whereas it was -0.3% +/- 0.3% (1 s.d.) between CT and rCT. The average gamma pass rate was 99.9% for sCT vs rCT, whereas it was 90.3% for CT vs rCT. CONCLUSIONS: The SDA enables a highly accurate MRI only workflow in prostate radiotherapy planning. The dosimetric uncertainties originating from the SDA appear negligible and are notably lower than the uncertainties introduced by variations in patient geometry between imaging sessions. PMID- 26429286 TI - 3D localization of electrophysiology catheters from a single x-ray cone-beam projection. AB - PURPOSE: X-ray images allow the visualization of percutaneous devices such as catheters in real time but inherently lack depth information. The provision of 3D localization of these devices from cone beam x-ray projections would be advantageous for interventions such as electrophysiology (EP), whereby the operator needs to return a device to the same anatomical locations during the procedure. A method to achieve real-time 3D single view localization (SVL) of an object of known geometry from a single x-ray image is presented. svl exploits the change in the magnification of an object as its distance from the x-ray source is varied. The x-ray projection of an object of interest is compared to a synthetic x-ray projection of a model of said object as its pose is varied. METHODS: svl was tested with a 3 mm spherical marker and an electrophysiology catheter. The effect of x-ray acquisition parameters on svl was investigated. An independent reference localization method was developed to compare results when imaging a catheter translated via a computer controlled three-axes stage. svl was also performed on clinical fluoroscopy image sequences. A commercial navigation system was used in some clinical image sequences for comparison. RESULTS: svl estimates exhibited little change as x-ray acquisition parameters were varied. The reproducibility of catheter position estimates in phantoms denoted by the standard deviations, (sigma(x), sigma(y), sigma(z)) = (0.099 mm, 0.093 mm, 2.2 mm), where x and y are parallel to the detector plane and z is the distance from the x-ray source. Position estimates (x, y, z) exhibited a 4% systematic error (underestimation) when compared to the reference method. The authors demonstrated that EP catheters can be tracked in clinical fluoroscopic images. CONCLUSIONS: It has been shown that EP catheters can be localized in real time in phantoms and clinical images at fluoroscopic exposure rates. Further work is required to characterize performance in clinical images as well as the sensitivity to clinical image quality. PMID- 26429285 TI - Computational and human observer image quality evaluation of low dose, knowledge based CT iterative reconstruction. AB - PURPOSE: Aims in this study are to (1) develop a computational model observer which reliably tracks the detectability of human observers in low dose computed tomography (CT) images reconstructed with knowledge-based iterative reconstruction (IMRTM, Philips Healthcare) and filtered back projection (FBP) across a range of independent variables, (2) use the model to evaluate detectability trends across reconstructions and make predictions of human observer detectability, and (3) perform human observer studies based on model predictions to demonstrate applications of the model in CT imaging. METHODS: Detectability (d') was evaluated in phantom studies across a range of conditions. Images were generated using a numerical CT simulator. Trained observers performed 4-alternative forced choice (4-AFC) experiments across dose (1.3, 2.7, 4.0 mGy), pin size (4, 6, 8 mm), contrast (0.3%, 0.5%, 1.0%), and reconstruction (FBP, IMR), at fixed display window. A five-channel Laguerre-Gauss channelized Hotelling observer (CHO) was developed with internal noise added to the decision variable and/or to channel outputs, creating six different internal noise models. Semianalytic internal noise computation was tested against Monte Carlo and used to accelerate internal noise parameter optimization. Model parameters were estimated from all experiments at once using maximum likelihood on the probability correct, PC. Akaike information criterion (AIC) was used to compare models of different orders. The best model was selected according to AIC and used to predict detectability in blended FBP-IMR images, analyze trends in IMR detectability improvements, and predict dose savings with IMR. Predicted dose savings were compared against 4-AFC study results using physical CT phantom images. RESULTS: Detection in IMR was greater than FBP in all tested conditions. The CHO with internal noise proportional to channel output standard deviations, Model-k4, showed the best trade-off between fit and model complexity according to AICc. With parameters fixed, the model reasonably predicted detectability of human observers in blended FBP-IMR images. Semianalytic internal noise computation gave results equivalent to Monte Carlo, greatly speeding parameter estimation. Using Model-k4, the authors found an average detectability improvement of 2.7 +/- 0.4 times that of FBP. IMR showed greater improvements in detectability with larger signals and relatively consistent improvements across signal contrast and x-ray dose. In the phantom tested, Model-k4 predicted an 82% dose reduction compared to FBP, verified with physical CT scans at 80% reduced dose. CONCLUSIONS: IMR improves detectability over FBP and may enable significant dose reductions. A channelized Hotelling observer with internal noise proportional to channel output standard deviation agreed well with human observers across a wide range of variables, even across reconstructions with drastically different image characteristics. Utility of the model observer was demonstrated by predicting the effect of image processing (blending), analyzing detectability improvements with IMR across dose, size, and contrast, and in guiding real CT scan dose reduction experiments. Such a model observer can be applied in optimizing parameters in advanced iterative reconstruction algorithms as well as guiding dose reduction protocols in physical CT experiments. PMID- 26429288 TI - Hormone Replacement Therapy and Risk of Breast Cancer in Korean Women: A Quantitative Systematic Review. AB - OBJECTIVES: The epidemiological characteristics of breast cancer incidence by age group in Korean women are unique. This systematic review aimed to investigate the association between hormone replacement therapy (HRT) and breast cancer risk in Korean women. METHODS: We searched electronic databases such as KoreaMed, KMbase, KISS, and RISS4U as well as PubMed for publications on Korean breast cancer patients. We also conducted manual searching based on references and citations in potential papers. All of the analytically epidemiologic studies that obtained individual data on HRT exposure and breast cancer occurrence in Korean women were selected. We restricted the inclusion of case-control studies to those that included age-matched controls. Estimates of summary odds ratio (SOR) with 95% confidence intervals (CIs) were calculated using random effect models. RESULTS: One cohort and five case-control studies were finally selected. Based on the heterogeneity that existed among the six studies (I-squared=70.2%), a random effect model was applied. The summary effect size of HRT history from the six articles indicated no statistical significance in breast cancer risk (SOR, 0.983; 95% CI, 0.620 to 1.556). CONCLUSIONS: These facts support no significant effect of HRT history in the risk of breast cancer in Korean women. It is necessary to conduct a pooled analysis. PMID- 26429289 TI - A Study of Predictive Factors Affecting Health: Promoting Behaviors of North Korean Adolescent Refugees. AB - OBJECTIVES: The present study aimed to analyze the factors that could affect the health-promoting behaviors of North Korean adolescent refugees residing in South Korea. METHODS: Questions about their sociodemographic variables, subjective health status, healthy living habits, and health-promoting behaviors were asked. RESULTS: Statistically significant differences were found in religion (t=2.30, p<0.05), having family members in South Korea (t=2.02, p<0.05), and subjective health status (t=4.96, p<0.01). Scores on health-responsible behaviors were higher with higher age (t=2.90, p<0.01) and for subjects without family or friends (t=2.43, p<0.05). Higher physical-activity behaviors were observed in males (t=3.32, p<0.01), in those with better subjective health status (t=3.46, p<0.05) and lower body mas index (t=3.48, p<0.05), and in smokers (t=3.17, p<0.01). Nutritional behaviors were higher in those who followed a religion (t=2.17, p<0.05). Spiritual growth behaviors were higher in those who followed a religion (t=4.21, p<0.001), had no family in South Korea (t=2.04, p<0.05), and had higher subjective health status (t=5.74, p<0.01). Scores on interpersonal relationships and stress-management behaviors were higher for those with higher subjective health status. A multiple regression analysis showed greater effects on health-promoting behaviors when subjective health status was better. Older people and non-smokers exhibited more health-responsible behaviors, while more physical-activity behaviors and spiritual growth activities were observed when subjective health status was better. Interpersonal relationship behaviors had positive effects on those with good subjective heath status and on non-smokers. CONCLUSIONS: Based on the results of the current study, an alternative was suggested for promoting health in North Korean adolescent refugees. PMID- 26429290 TI - Assessing Reliability of Medical Record Reviews for the Detection of Hospital Adverse Events. AB - OBJECTIVES: The purpose of this study was to assess the inter-rater reliability and intra-rater reliability of medical record review for the detection of hospital adverse events. METHODS: We conducted two stages retrospective medical records review of a random sample of 96 patients from one acute-care general hospital. The first stage was an explicit patient record review by two nurses to detect the presence of 41 screening criteria (SC). The second stage was an implicit structured review by two physicians to identify the occurrence of adverse events from the positive cases on the SC. The inter-rater reliability of two nurses and that of two physicians were assessed. The intra-rater reliability was also evaluated by using test-retest method at approximately two weeks later. RESULTS: In 84.2% of the patient medical records, the nurses agreed as to the necessity for the second stage review (kappa, 0.68; 95% confidence interval [CI], 0.54 to 0.83). In 93.0% of the patient medical records screened by nurses, the physicians agreed about the absence or presence of adverse events (kappa, 0.71; 95% CI, 0.44 to 0.97). When assessing intra-rater reliability, the kappa indices of two nurses were 0.54 (95% CI, 0.31 to 0.77) and 0.67 (95% CI, 0.47 to 0.87), whereas those of two physicians were 0.87 (95% CI, 0.62 to 1.00) and 0.37 (95% CI, -0.16 to 0.89). CONCLUSIONS: In this study, the medical record review for detecting adverse events showed intermediate to good level of inter-rater and intra-rater reliability. Well organized training program for reviewers and clearly defining SC are required to get more reliable results in the hospital adverse event study. PMID- 26429291 TI - Interaction of Vitamin D and Smoking on Inflammatory Markers in the Urban Elderly. AB - OBJECTIVES: Epidemiological studies have reported that vitamin D deficiency is associated with inflammatory disease. Smoking is a well-known risk factor for inflammation. However, few studies have investigated the interactive effect of vitamin D deficiency and smoking on inflammation. This study aims to investigate the interaction of vitamin D and smoking with inflammatory markers in the urban elderly. METHODS: We used data from the Korean Elderly Environmental Panel Study, which began in August 2008 and ended in August 2010, and included 560 Koreans >=60 years old living in Seoul. Data was collected via questionnaires that included items about smoking status at the first visit. Vitamin D levels, high sensitivity C-reactive protein (hs-CRP), and white blood cell (WBC) counts were repeatedly measured up to three times. RESULTS: The association of vitamin D and hs-CRP was significant after adjusting for known confounders (beta=-0.080, p=0.041). After separate analysis by smoking status, the association of vitamin D deficiency and hs-CRP in smokers was stronger than that in nonsmokers (smokers: beta=-0.375, p=0.013; non-smokers: beta=-0.060, p=0.150). Smoking status was an effect modifier that changed the association between vitamin D deficiency and hs CRP (interaction estimate: beta=-0.254, p=0.032). Vitamin D was not significantly associated with WBC count (beta=0.003, p=0.805). CONCLUSIONS: Vitamin D deficiency was associated with hs-CRP in the urban elderly. Smoking status was an effect modifier of this association. Vitamin D deficiency was not significantly associated with WBC count. PMID- 26429292 TI - Prevalence of Depressive Disorder of Outpatients Visiting Two Primary Care Settings. AB - OBJECTIVES: Although the prevalence of depressive disorders in South Korea's general population is known, no reports on the prevalence of depression among patients who visit primary care facilities have been published. This preliminary study was conducted to identify the prevalence of depressive disorder in patients that visit two primary care facilities. METHODS: Among 231 consecutive eligible patients who visited two primary care settings, 184 patients consented to a diagnostic interview for depression by psychiatrists following the Diagnostic and Statistical Manual of Mental Disorders-IV criteria. There were no significant differences in sociodemographic characteristics such as gender, age, or level of education between the groups that consented and declined the diagnostic examination. The prevalence of depressive disorder and the proportion of newly diagnosed patients among depressive disorder patients were calculated. RESULTS: The prevalence of depressive disorder of patients in the two primary care facilities was 14.1% (95% confidence interval [CI], 9.1 to 19.2), with major depressive disorder 5.4% (95% CI, 2.1 to 8.7), dysthymia 1.1% (95% CI, 0.0 to 2.6), and depressive disorder, not otherwise specified 7.6% (95% CI, 3.7 to 11.5). Among the 26 patients with depressive disorder, 19 patients were newly diagnosed. CONCLUSIONS: As compared to the general population, a higher prevalence of depressive disorders was observed among patients at two primary care facilities. Further study is needed with larger samples to inform the development of a primary care setting-based depression screening, management, and referral system to increase the efficiency of limited health care resources. PMID- 26429293 TI - Candida lusitaniae MICs to the echinocandins are elevated but FKS-mediated resistance is rare. AB - MIC values were generated for caspofungin, micafungin, and anidulafungin against 106 isolates of C. lusitaniae, and these values were compared to established epidemiologic cutoff values. The majority of isolates were wild type both by MIC value as well as by FKS1 hotspot sequencing. Although C. lusitaniae isolates have MIC values to the echinocandins that are elevated compared to other common species, with regard to known mechanisms of resistance to the echinocandins, isolates with MIC values at or below the epidemiological cutoff values of 0.5 and 1 MUg/mL for micafungin and anidulafungin, respectively, should be considered wild type. PMID- 26429294 TI - Correlation between genetic features of the mef(A)-msr(D) locus and erythromycin resistance in Streptococcus pyogenes. AB - We investigated the correlation between the genetic variation within mef(A) msr(D) determinants of efflux-mediated erythromycin resistance in Streptococcus pyogenes and the level of erythromycin resistance. Twenty-eight mef(A)-positive strains were selected according to erythromycin MIC (4-32 MUg/mL), and their mef(A)-msr(D) regions were sequenced. Strains were classified according to the bacteriophage carrying mef(A)-msr(D). A new Phim46.1 genetic variant was found in 8 strains out of 28 and named VP_00501.1. Degree of allelic variation was higher in mef(A) than in msr(D). Hotspots for recombination were mapped within the locus that could have shaped the apparent mosaic structure of the region. There was a general correlation between mef(A)-msr(D) sequence and erythromycin resistance level. However, lysogenic conversion of susceptible strains by mef(A)-msr(D) carrying Phim46.1 indicated that key determinants may not all reside within the mef(A)-msr(D) locus and that horizontal gene transfer could contribute to changes in the level of antibiotic resistance in S. pyogenes. PMID- 26429295 TI - Correlation of Organic Cation/Carnitine Transporter 1 and Multidrug Resistance Associated Protein 1 Transport Activities With Protein Expression Levels in Primary Cultured Human Tracheal, Bronchial, and Alveolar Epithelial Cells. AB - Understanding how transporters contribute to the distribution of inhaled drugs in the lung is important for the discovery and development of such drugs. Protein expression levels may be useful to predict and understand drug distribution. As previously reported, organic cation/carnitine transporter 1 (OCTN1) and multidrug resistance-associated protein 1 (MRP1) have higher levels of protein expression among transporters in primary cultured human lung cells. Nevertheless, it is unclear to what extent transport activity correlates with transporter protein expression. The purpose is to evaluate whether differences in OCTN1 and MRP1 protein expression govern the respective transport activity in primary cultured human lung cells. The model substrates of 4-[4-(dimethylamino) styryl]-N methylpyridinium iodide (ASP(+)) and carboxy-dichlorofluorescein (CDF) for OCTN1 and MRP1, respectively, were used in the lung cells from five donors. Significant correlation was found between the kinetic parameter Vmax for ASP(+) and OCTN1 protein expression in plasma membrane of tracheal, bronchial, and alveolar cells (r(2) = 0.965, 0.834, and 0.877, respectively), and between the efflux of CDF and MRP1 protein expression in plasma membrane of tracheal, bronchial, and alveolar cells (r(2) = 0.800, 0.904, and 0.790, respectively). These findings suggest that OCTN1 and MRP1 protein concentrations are determinants for drug distribution in the lung. PMID- 26429296 TI - The relationship between quantitative human epidermal growth factor receptor 2 gene expression by the 21-gene reverse transcriptase polymerase chain reaction assay and adjuvant trastuzumab benefit in Alliance N9831. AB - INTRODUCTION: The N9831 trial demonstrated the efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2 (HER2) locally positive tumors by protein or gene analysis. We used the 21-gene assay to examine the association of quantitative HER2 messenger RNA (mRNA) gene expression and benefit from trastuzumab. METHODS: N9831 tested the addition of trastuzumab to chemotherapy in stage I-III HER2-positive breast cancer. For two of the arms of the trial, doxorubicin and cyclophosphamide followed by paclitaxel (AC-T) and doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab concurrent chemotherapy-trastuzumab (AC-TH), recurrence score (RS) and HER2 mRNA expression were determined by the 21-gene assay (Oncotype DX(r)) (negative <10.7, equivocal 10.7 to <11.5, and positive >=11.5 log2 expression units). Cox regression was used to assess the association of HER2 expression with trastuzumab benefit in preventing distant recurrence. RESULTS: Median follow-up was 7.4 years. Of 1,940 total patients, 901 had consent and sufficient tissue. HER2 by reverse transcriptase polymerase chain reaction (RT-PCR) was negative in 130 (14 %), equivocal in 85 (9 %), and positive in 686 (76 %) patients. Concordance between HER2 assessments was 95 % for RT-PCR versus central immunohistochemistry (IHC) (>10 % positive cells = positive), 91 % for RT-PCR versus central fluorescence in situ hybridization (FISH) (>=2.0 = positive) and 94 % for central IHC versus central FISH. In the primary analysis, the association of HER2 expression by 21-gene assay with trastuzumab benefit was marginally nonsignificant (nonlinear p = 0.057). In hormone receptor-positive patients (local IHC) the association was significant (p = 0.002). The association was nonlinear with the greatest estimated benefit at lower and higher HER2 expression levels. CONCLUSIONS: Concordance among HER2 assessments by central IHC, FISH, and RT-PCR were similar and high. Association of HER2 mRNA expression with trastuzumab benefit as measured by time to distant recurrence was nonsignificant. A consistent benefit of trastuzumab irrespective of mHER2 levels was observed in patients with either IHC-positive or FISH-positive tumors. Trend for benefit was observed also for the small groups of patients with negative results by any or all of the central assays. TRIAL REGISTRATION: Clinicaltrials.gov NCT00005970 . Registered 5 July 2000. PMID- 26429298 TI - Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective. AB - High-throughput screening (HTS) represents a major cornerstone of drug discovery. The availability of an innovative, relevant and high-quality compound collection to be screened often dictates the final fate of a drug discovery campaign. Given that the chemical space to be sampled in research programs is practically infinite and sparsely populated, significant efforts and resources need to be invested in the generation and maintenance of a competitive compound collection. The European Lead Factory (ELF) project is addressing this challenge by leveraging the diverse experience and know-how of academic groups and small and medium enterprises (SMEs) engaged in synthetic and/or medicinal chemistry. Here, we describe the novelty, diversity, structural complexity, physicochemical characteristics and overall attractiveness of this first batch of ELF compounds for HTS purposes. PMID- 26429297 TI - Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. AB - BACKGROUND: The standard busulfan-cyclophosphamide myeloablative conditioning regimen is associated with substantial non-relapse mortality in patients older than 40 years with acute myeloid leukaemia who are undergoing allogeneic stem cell transplantation. Because the combination of busulfan plus fludarabine has been proposed to reduce non-relapse mortality, we aimed to compare this treatment with busulfan plus cyclophosphamide as a preparative regimen in these patients. METHODS: We did an open-label, multicentre, randomised, phase 3 trial for patients with acute myeloid leukaemia at 25 hospital transplant centres in Italy and one in Israel. Eligible patients were aged 40-65 years, had an Eastern Cooperative Oncology Group performance status less than 3, and were in complete remission. Patients were randomly assigned 1:1 to receive intravenous busulfan plus cyclophosphamide or busulfan plus fludarabine. Treatment allocations were not masked to investigators or patients. Randomisation was done centrally via a dedicated web-based system using remote data entry, with patients stratified by donor type and complete remission status. Patients allocated to busulfan plus cyclophosphamide received intravenous busulfan 0.8 mg/kg four times per day during 2 h infusions for four consecutive days (16 doses from days -9 through -6; total dose 12.8 mg/kg) and cyclophosphamide at 60 mg/kg per day for two consecutive days (on days -4 and -3; total dose 120 mg/kg). Patients allocated to busulfan plus fludarabine received the same dose of intravenous busulfan (from days -6 through -3) and fludarabine at 40 mg/m(2) per day for four consecutive days (from days -6 through -3; total dose 160 mg/m(2)). The primary endpoint was 1-year non-relapse mortality, which was assessed on an intention-to-treat basis; safety outcomes were assessed in the per-protocol population. This trial has been completed and is registered with ClinicalTrials.gov, number NCT01191957. FINDINGS: Between Jan 3, 2008, and Dec 20, 2012, we enrolled and randomly assigned 252 patients to receive busulfan plus cyclophosphamide (n=125) or busulfan plus fludarabine (n=127). Median follow-up was 27.5 months (IQR 9.8 44.3). 1-year non-relapse mortality was 17.2% (95% CI 11.6-25.4) in the busulfan plus cyclophosphamide group and 7.9% (4.3-14.3) in the busulfan plus fludarabine group (Gray's test p=0.026). The most frequently reported grade 3 or higher adverse events were gastrointestinal events (28 [23%] of 121 patients in the busulfan plus cyclophosphamide group and 26 [21%] of 124 patients in the busulfan plus fludarabine group) and infections (21 [17%] patients in the busulfan plus cyclophosphamide group and 13 [10%] patients in the busulfan plus fludarabine group had at least one such event). INTERPRETATION: In older patients with acute myeloid leukaemia, the myeloablative busulfan plus fludarabine conditioning regimen is associated with lower transplant-related mortality than busulfan plus cyclophosphamide, but retains potent antileukaemic activity. Accordingly, this regimen should be regarded as standard of care during the planning of allogeneic transplants for such patients. FUNDING: Agenzia Italiana del Farmaco. PMID- 26429299 TI - Expression levels of heat shock protein 60 and glucose-regulated protein 78 in response to trimethylamine-N-oxide treatment in murine macrophage J774A.1 cell line. AB - Trimethylamine N-oxide (TMAO), a common metabolite in animals and humans, can induce changes in the expression or conformation of heat shock proteins. It has also been introduced as a risk factor for atherosclerosis and a biomarker for kidney problems. On the other hand, increased levels of heat shock proteins 60 and 70 KDa are associated with increased atherosclerosis risk. This study was therefore designed to evaluate the possible effect(s) of TMAO on the expression of HSP60 and GRP78 at the mRNA and protein levels. Murine macrophage J774A.1 cells were treated with micromolar concentrations of TMAO and 4-phenylbutyric acid (4-PBA), a chemical chaperon, for different time intervals. Tunicamycin was also used as a control for induction of endoplasmic reticulum stress. Tunicamycin greatly increased both mRNA and protein levels of GRP78. Similarly but to a lesser extent compared to tunicamycin, TMAO also increased mRNA and protein levels of GRP78 in a dose and time-dependent manner. In contrast, 4-PBA failed to induce any changes. Similar to GRP78, HSP60 was also increased only at mRNA level in TMAO treated cells. 4-PBA also increased HSP60 mRNA levels, whereas, tunicamycin did not show any effect on either protein or mRNA levels of HSP60. Since both heat shock proteins are stress inducible and the elevation of GRP78 is a hallmark for endoplasmic reticulum stress induction, it can be concluded that TMAO may induce endoplasmic reticulum stress or may act through elevation of these heat shock proteins. PMID- 26429300 TI - Comparative phenotypic and genotypic discrimination of methicillin resistant and susceptible Staphylococcus aureus in Egypt. AB - The present study was designed to elucidate the phenotypic and genotypic characterization of S. aureus isolates in Egypt. The antibiotic susceptibility pattern of 133 identified S. aureus isolates revealed that over 70% of the isolates were multi-drug resistant (MDR). Fifty MDR isolates were characterized using antibiotyping and different molecular typing methods. Amplification of mecA gene confirmed 30 strains as methicillin-resistant S. aureus (MRSA) and 20 as methicillin-sensitive S. aureus (MSSA). Generally, 22 MRSA (73.33%) and ten MSSA (50%) harbored Panton-Valentine leukocidin (pvl) gene with no statistically significant difference (p=0.093). Staphylococcal cassette chromosome (SCC) mec typing revealed that 48% of the typeable MRSA isolates possessed SCCmec type IV. SCCmec and antimicrobial susceptibility typing signified the presence of community-acquired (CA)-MRSA in Egypt. Surprisingly, all isolates of SCCmec types I, II and III and 50% of both MRSA isolates of SCCmec types IV and V possessed pvl gene. It was clear that staphylococcal protein A (spa) and coagulase (coa) typing discriminated the isolates into eight different groups, whilst polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) of coagulase gene yielded ten distinct RFLP banding patterns. This study presented the first baseline information on the characterization of MRSA and MSSA in Egypt. PMID- 26429301 TI - Production and purification of novel thermostable alkaline protease from Anoxybacillus sp. KP1. AB - In this study, an extracellular novel alkaline protease (EC 3.4.21-24, 99) from a thermophilic and aerobic strain of Anoxybacillus sp. KP1 has been studied. Maximum protease activity was obtained at 50 degC at pH 9.0 after 24 hours of incubation. Among the carbon and nitrogen sources used; the optimum protease production was with soluble starch, maltose, urea and casamino acid. The enzyme was purified by ammonium sulphate precipitation and Sephadex G-75 gel chromatography. Molecular weight of purified enzyme was determined as 106 kDa by SDS-PAGE. Purified protease was stable at 50-60 degrees C and at pH 9.0 for 1 h. The enzyme activity was increased in the presence of Ca2+, Cu2+, Tween 80 and Triton X-100, however the enzyme activity was inhibited in the presence of Hg2+, ethylene diamine tetra acetic acid (EDTA) and H2O2. Proteolytic activity was completely inhibited by phenyl methyl sulfonyl fluoride (PMSF). The enzyme seems to be a serine alkaline protease. In the presence of detergents, the protease was clearly stable and residual activity was between 73-82%. PMID- 26429302 TI - Targeting microbiota-mitochondria inter-talk: Microbiota control mitochondria metabolism. AB - Our aim is to highlight the subtle relationship that exists between microbiota and mitochondria. Microbiota targets mitochondria by modulating the Reactive Oxygen Species (ROS) production and the mitochondrial activity through interactions with toxins, proteins or other metabolites released by gut microbiota. The intriguing relationship that exists between mitochondria and microbiota is strengthened by the probable prokaryotic origin of mitochondria. Emerging data implicates a role for ROS, nitric oxide, Short Chain Fatty Acids and hydrogen sulfide in the cross-talk between microbiota - mitochondria and REDOX signaling. Several studies have shown that microbiota act and modulate mitochondrial activity, and use it as a relay to strengthen host-microbiotal interaction. This modulation depends on the gut bacterial strain quality and diversity to increase its pathogenic versus beneficial effects. Furthermore, based on conclusions from new studies, it is possible that microbiota can directly interact with the host cell gene expression by favoring bacterial and mitochondrial DNA insertion in the nuclear genome. The emerging knowledge of mitochondria-microbiota interaction may be of great importance to better understand the mechanism of mitochondrial and metabolic diseases, and the syndromes associated with change in quality and quantity of microbiotal species. We suggest that microbiota via mitochondrial modulation influence cell homeostasis and metabolism. The challenge will be to find strategies to modulate the quality and diversity of microbiota rather than acting on microbiota metabolites and microbiota related factors. The medicine of tomorrow will be completely personalized. Firstly there will be a test to show the quality, quantity and diversity of microbiota, and secondly a preventive or therapeutic strategy will be administrated (probiotics, diet, prodrug or fecal transplantation). The era of digital medicine is here. PMID- 26429303 TI - Biomarkers predicting chemotherapy response in head and neck squamous cell carcinoma: a review. AB - BACKGROUND: Biomarkers are increasingly being used in many cancers to select patients for oncological treatment paradigms based on their inherent genetic properties. However, in head and neck cancers, there are no personalised therapies available outside the context of a clinical trial. A number of studies suggest there are intrinsic tumour properties of head and neck cancers that affect their response to chemotherapeutic agents. This paper aimed to review their evidence base. METHOD: A narrative review was conducted following a search of the PubMed database. RESULTS AND CONCLUSION: The review identified a number of biomarkers predicting response to chemotherapy in head and neck cancers. The paper discusses these in detail, and explores where future research could be directed in order to deliver personalised therapies for patients with head and neck cancers. PMID- 26429304 TI - Association of FCGR2A p.R131H and CCL2 c.-2518 A>G gene variants with thrombocytopenia in patients with dengue virus infection. AB - FCGR2A and CCL2 gene variants are important in dengue pathogenesis and were investigated in 122 dengue patients (DENs) [89 dengue fever (DF) and 33 dengue hemorrhagic fever (DHF)] and 107 healthy controls (HCs) to find out their association with severity of dengue. Genotype frequencies of FCGR2A p.R131H and CCL2 c.-2518 A > G polymorphisms were not different between DF, DHF and HC. Significantly higher frequency of R/R genotype of FCGR2A p.R131H was observed in DEN cases with thrombocytopenia (TP) while the G/G genotype of CCL2 c.-2518 A > G was observed only in DEN cases with TP (p < 0.005). These results suggest that FCGR2A and CCL2 gene variants were associated with the risk of TP in dengue infections. PMID- 26429307 TI - Improved flow cytometry based cytotoxicity and binding assay for clinical antibody HLA crossmatching. AB - The presence of preformed donor-specific HLA antibodies leads to early antibody mediated kidney allograft rejection. Therefore, detection and avoidance of donor reactive HLA antibodies prior to transplantation is of outmost importance in order to minimize the risk of rejection. Detection of pre-formed HLA antibodies is currently performed using complement-dependent cytotoxicity (CDC) assay alone or together with a flow cytometry based crossmatch (FCXM). This study was initiated to further evaluate our recently developed flow cytometry based procedure for determination of both cytotoxicity of and IgG binding to donor derived lymphocytes by HLA antibodies. Highly enriched immuno-magnetic bead purified T and B lymphocytes were used as target cells for patient sera using 96 well plates. Importantly, the assay shows high sensitivity and specificity as determined by HLA typed donor cells and serum with defined HLA antibody IgG and C1q. Based on this and additional data generated in this paper, such as evaluation of appropriate serum and complements incubation times and assay reproducibility and stability, will enable us to more rapidly implement this assay in our clinical laboratory routines. In addition, we demonstrate that FCtox crossmatching of deceased donor cells has superior specificity compared to conventional CDC assay especially regarding high frequencies of false-positive reactions. PMID- 26429308 TI - WITHDRAWN: Association between interleukin 8 -251 A/T and +781 C/T polymorphisms and coronary artery disease risk. PMID- 26429305 TI - Characterization of CD4/CD8+ alphabeta and Vgamma2Vdelta2+ T cells in HIV negative individuals with different Mycobacterium tuberculosis infection statuses. AB - BACKGROUND: The immune responses of T cell subsets among patients with different Mycobacterium tuberculosis (M.tb) infection statuses [i.e., active tuberculosis (ATB), latent tuberculosis infection (LTBI) and non-infection (healthy control, HC)] have not been fully elucidated in HIV-negative individuals. Specifically, data are limiting in high tuberculosis epidemic regions in China. To investigate the distributions and functions of T cell subsets (i.e., CD3+, CD4+, CD8+ alphabeta and Vgamma2Vdelta2+ T cells) in HIV-negative subjects with different M.tb infection statuses, we conducted a case-control study that enrolled 125 participants, including ATB patients (n = 46), LTBI subjects (n = 34), and HC (n = 45). RESULTS: An IFN-gamma release assay (IGRA) was employed to screen LTBI subjects. Whole blood cell surface staining and flow cytometry were used to detect phenotypic distributions of T cells in the peripheral blood mononuclear cells (PBMCs) and tuberculous pleural fluid mononuclear cells (PFMCs). PPD and the phosphorylated antigen HMBPP were employed as stimulators for the detection of M.tb antigen-specific T cell functions via intracellular cytokine staining (ICS). The absolute numbers of T cell subsets, including CD3+ CD4+, CD3+ CD8+ alphabeta and Vgamma2Vdelta2+ T cells, were significantly reduced in active tuberculosis compared with latent tuberculosis or the healthy controls. Importantly, PPD-specific CD3+ CD4+ and CD3+ CD8+ alphabeta T cells and HMBPP specific Vgamma2Vdelta2+ T cells in ATB patients were also significantly reduced compared to the LTBI/HC subjects (P<0.05). In contrast, the proportion of CD4+ T cells in PFMCs was higher compared to PBMCs, while CD8+ and Vgamma2Vdelta2+ T cells in PFMCs were lower compared to PBMCs (all P < 0.05). PPD-specific CD4+ T cells predominated among CD3+ T cells in PFMCs. CONCLUSIONS: Cellular immune responses are impaired in ATB patients. Antigen-specific CD4+ T cell may migrate from the periphery to the lesion site, where they exert anti-tuberculosis functions. PMID- 26429306 TI - Contribution of dendritic cell immunoreceptor (DCIR) polymorphisms in susceptibility of systemic lupus erythematosus and primary Sjogren's syndrome. AB - Dendritic cell immunoreceptor (DCIR) has previously shown an association with rheumatoid arthritis (RA) in Caucasians and Han Chinese. This study was aimed to further investigate whether DCIR polymorphisms are novel susceptibility factors for other autoimmune diseases, i.e. systemic lupus erythematosus (SLE) and primary Sjogren's syndrome (SS). A total of 1502 patients with SLE, 476 patients with primary SS, and 1278 non-related healthy controls were enrolled in the study. The single-nucleotide polymorphisms (SNPs) rs2377422 and rs10840759 were genotyped using TaqMan assay. The differences in allelic and genotypic distribution between two groups were assessed using Pearson chi-square test, and logistic regression adjusting for age and sex, respectively. P-value < 0.025 was considered statistically significant by Bonferroni correction. The SNP rs2377422 confers an increased susceptibility risk to both SLE (allele model: P = 7.65 * 10(-4), OR 1.20; genotype recessive model: P = 0.012, OR 1.29), and primary SS (allele model: P = 3.74 * 10(-4), OR 1.31; genotype dominant model: P = 1.62 * 10(-4), OR 2.02). There is no association between rs10840759 and SLE or primary SS. In conclusion, DCIR SNP rs2377422 is a novel genetic susceptibility factor for both SLE and primary SS. PMID- 26429309 TI - Genetic variation in Micro-RNA genes of host genome affects clinical manifestation of symptomatic Human Cytomegalovirus infection. AB - BACKGROUND: Micro-RNAs are implicated in various physiological and pathologic processes. In this study, we tested whether Micro-RNA gene variants of host genome affect clinical manifestation of symptomatic HCMV infection. METHODOLOGY: HCMV infection was detected by fluorescent PCR and immuno-histochemistry. The detection of genetic variants of four studied Micro-RNA tag-SNPs was done through PCR-RFLP assay and validated with DNA sequencing. RESULTS: We observed an increased risk ranged from 3-folds to 5-folds among symptomatic HCMV cases for mutant genotype of rs2910164 (crude OR=3.11, p=0.009 and adjusted OR=3.25, p=0.007), rs11614913 (crude OR=3.20, p=0.006 and adjusted OR=3.48, p=0.004) and rs3746444 (crude OR=4.91, p=0.002 and adjusted OR=5.28, p=0.002) tag-SNPs. Interestingly, all the tag-SNPs that were significant after multiple comparisons at a FDR of 5% in symptomatic HCMV cases remained significant even after bootstrap analysis, providing internal validation to these results. Multifactor Dimensionality Reduction (MDR) analysis revealed 5-folds increased risk for symptomatic HCMV cases under the four-factor model (rs2910164, rs2292832, rs11614913 and rs3746444). CONCLUSIONS: These results suggest that Micro-RNA gene variants of host-genome may affect clinical manifestation of symptomatic HCMV infection. PMID- 26429310 TI - Single nucleotide polymorphisms in immune system genes and their association with clinical symptoms persistence in dengue-infected persons. AB - This study was undertaken to determine the prevalence of dengue clinical symptom persistence during 60days of disease follow up, in patients of Espirito Santo state (ES)-Brazil and to evaluate the relation of single nucleotide polymorphisms (SNPs) in FcgammaRIIa, CD209, VDR, TNF-alpha, IL-4, IL-6 and IFN-gamma genes with symptom persistence. During 2012-2013, 96 blood samples from individuals diagnosed with symptomatic dengue were collected. Clinical symptom persistence in 60days of follow-up was assessed by a clinical and epidemiological questionnaire filled in 4 interviews. SNP genotyping was performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). In two months of monitoring the dengue infection, we observed that symptoms persisted in 38.5% (37/96) of dengue patients at the end of the first month (D30) and in 11.5% (11/96) of dengue patients at the end of the second month (D60). Our results show an association between FcgammaRIIa, TNF-alpha and IL-6 gene SNPs and symptom persistence and an association trend with CD209, IL-4 and IFN-gamma gene SNPs. Our findings may increase the knowledge on the pathophysiological mechanisms of persistent symptoms of infection with the dengue virus (DENV) and thus help the clinical management of patients. PMID- 26429311 TI - SOCS3 and its role in associated diseases. AB - Cell-cell communication depends on cytokine and growth factor network. Bound to their receptors on the surface of target cell, these glycoproteins initiate a range of intracellular events. Subsequent dissipation of receptor signaling is essential to ensure the response of the cell does not become pathogenic. The Suppressors of cytokine signaling (SOCS) proteins are a family of proteins induced to attenuate cytokine signal transduction in response to signals from a diverse range of cytokines and growth factors. Current evidence indicates that intracellular JAK-STAT (Janus kinase-signal transducer and activator of transcription) signaling not only governs cytokine-induced immunological responses but also rapidly initiates SOCS expression and its biological functions. This review focuses on current understanding of SOCS3, a member of SOCS family. SOCS3 binds to JAK, certain cytokine receptors in intracellular domain, and some signaling molecules, which results in suppressing further signaling events in the cell. Studies using conditional knockout mice have shown that SOCS3 protein is the key physiological regulator and plays an important pathological role in immune homeostasis. Dysregulation of SOCS3 functions can cause a variety of diseases, including allergy, autoimmune diseases, inflammation and cancer. PMID- 26429312 TI - Association of a coding polymorphism in Fc gamma receptor 2A and graft survival in re-transplant candidates. AB - The family of Fc gamma receptors (FcgammaRs) is involved in mediating immunological effector functions. FcgammaRs are differentially expressed on immune cells and can act either activating or inhibitory, with FcgammaR2A belonging to the first group. The polymorphism H131R (rs1801274) in FCGR2A has been associated with acute rejection and can shift the overall balance between activating and inhibitory FcgammaRs. Anti-HLA allo-antibodies in transplant recipients have been identified as risk factor for organ survival after transplantation. In this study we genotyped FCGR2A H131R in 200 patients who had undergone kidney transplantation and experienced loss of graft function. FCGR2A polymorphism was related to graft survival and anti-HLA antibodies. Graft survival was calculated as the time interval between transplantation and return to chronic dialysis after transplantation. The gene frequency of FCGR2A R/R131 was found significantly more often in patients with earlier (?60months) compared to patients with later (>60months) graft failure. Overall patients homozygous for R/R131 had a significantly shorter graft survival, compared to H/H131 or H/R131 which is even more pronounced, when anti-HLA antibodies were present. These data suggest, that FCGR2A polymorphisms constitute a risk factor for graft loss following kidney transplantation and that this effect is related to anti-HLA antibodies. PMID- 26429313 TI - Impact of population admixture on the distribution of immune response co stimulatory genes polymorphisms in a Brazilian population. AB - Co-stimulatory molecules are essential in the orchestration of immune response and polymorphisms in their genes are associated with various diseases. However, in the case of variable allele frequencies among continental populations, this variation can lead to biases in genetic studies conducted in admixed populations such as those from Brazil. The aim of this study was to evaluate the influence of genomic ancestry on distributions of co-stimulatory genes polymorphisms in an admixed Brazilian population. A total of 273 individuals from the north of Brazil participated in this study. Nine single nucleotide polymorphisms in 7 genes (CD28, CTLA4, ICOS, CD86, CD40, CD40L and BLYS) were determined by polymerase chain reaction-restriction fragment length polymorphism. We also investigated 48 insertion/deletion ancestry markers to characterize individual African, European and Amerindian ancestry proportions in the samples. The analysis showed that the main contribution was European (43.9%) but also a significant contribution of African (31.6%) and Amerindian (24.5%) ancestry. ICOS, CD40L and CD86 polymorphisms were associated with genomic ancestry. However there were no significant differences in the proportions of ancestry for the other SNPs and haplotypes studied. Our findings reinforce the need to apply AIMs in genetic association studies involving these polymorphisms in the Brazilian population. PMID- 26429314 TI - Repressing PU.1 by miR-29a* in NK cells of HCV patients, diminishes its cytolytic effect on HCV infected cell models. AB - OBJECTIVES: Natural killer cells are immune safeguards against HCV infection. PU.1 is a pivotal transcription factor in the development of NK cells. This study aimed at studying the regulatory effect of miRNAs on both development and function of NK cells isolated from HCV patients. METHODS: NK cells were isolated from 17 chronic HCV patients and 12 healthy controls; after which miRNA and mRNA were quantified using qRT-PCR. Manipulating miRNA expression using mimics and antagomirs, was performed followed by investigating downstream targets as well as viral abundance. RESULTS: PU.1 expression levels were upregulated in NK cells of HCV patients. In silico analysis revealed PU.1 to be a potential downstream target of miR-29a(*), where miR-29a(*) overexpression in NK cells caused a significant downregulation in PU.1 mRNA. Forcing miR-29a(*) caused a downregulation of the cytotoxicity determinant NK activating receptor (NKG2D) via upregulation of miR-155. Moreover, perforin-1 mRNA was found to be downregulated upon forcing the expression of miR-29a(*) in NK cells of HCV patients. This decrease in NK cytolytic function was accompanied by an 80% viral load increase in cocultured HCVcc cell models. CONCLUSIONS: This study showed that HCV infection might abrogate NK cytotoxic potential through altering PU.1, NKG2D receptor and perforin molecules. PMID- 26429315 TI - Association of PTPN22 gene polymorphisms with chronic hepatitis B virus infection in Chinese Han population. AB - Lymphoid protein tyrosine phosphatase encoded by protein tyrosine phosphatase non receptor 22 (PTPN22) gene plays an important regulatory role in T- and B-cell activation. This study investigated PTPN22 -1123G/C and intron 16 T/C polymorphisms in 372 patients with chronic hepatitis B virus (HBV) infection, 72 HBV infection resolvers and 273 healthy controls. Genotypic association tests between groups assuming codominant, dominant or log-additive genetic models were performed. In recessive model, PTPN22 -1123G/C genotype GG in healthy controls was more frequent than infection resolvers (P=0.037, OR=3.606, 95%CI=1.079 12.053) and this genotype in HBV patients was more frequent than resolvers although the difference was not significant (P=0.059). The PTPN22 intron 16 T/C genotype TC in cirrhosis patients was significantly higher than asymptomatic carriers (ASC) in codominant (P=0.028, OR=9.792, 95%CI=1.281-74.832) and overdominant (P=0.025, OR=10.142, 95%CI=1.332-77.214) models. This genotype in hepatocellular carcinoma (HCC) patients was significantly higher than ASC in codominant (P=0.034, OR=9.200, 95%CI=1.176-71.990) and overdominant (P=0.030, OR=9.677, 95%CI=1.241-75.442) models. These findings suggest that PTPN22 polymorphisms may predispose the chronicity or the development of cirrhosis and HCC in HBV infection. PMID- 26429316 TI - The prevalence of Selective Immunoglobulin M Deficiency (SIgMD) in Iranian volunteer blood donors. AB - BACKGROUND: Selective Immunoglobulin M Deficiency (SIgMD) is known as a rare primary immunodeficiency characterized by an isolated deficiency of serum IgM. Other immunoglobulin levels and T-cell immunity are usually normal; although IgE may be elevated. SIgMD can be asymptomatic or with various bacterial and viral infections. It can also be associated with autoimmune diseases or malignancies. In the present study, we report for the first time, the prevalence of SIgMD in Iranian healthy adult population. MATERIALS AND METHODS: A total of 3436 healthy donors were examined in the study; from August, 2006 to April, 2008. Serum IgM concentration was measured using the nephelometric method. We considered serum IgM less than 30 mg/dl as IgM deficiency. RESULTS: Among 3436 participants, 65% were male and 34% were female; aging from 17 to 72 years (38.18+/-10.78). Thirteen individuals were detected as IgM deficient subjects with the male to female ratio of 11/2, the prevalence of 0.37% and the frequency of 1/265. The mean serum IgM level was 24+/-4.56 (16-29 mg/dl) in these cases. Among 13 IgM deficient subjects, 7 cases were available for evaluating the clinical manifestations. In addition to atopic dermatitis which was the most common symptom in these patients, others were allergic rhinitis, food allergy, urinary tract infection and skin fungal infection. Two patients had no history of infectious disease or atopic conditions. CONCLUSION: In the present study we could determine the prevalence of SIgMD in our adult population (0.37%). The most common comorbid condition was atopy. Neither severe or life-threatening infections, nor autoimmune diseases (based on their history; the antibody screening was not performed as part of this study) or malignancies were found in these patients. Further evaluation is recommended to elucidate the prevalence of SIgMD among patients with recurrent infections. PMID- 26429317 TI - Functional relevance for type 1 diabetes mellitus-associated genetic variants by using integrative analyses. AB - AIM: Type 1 diabetes mellitus (type 1 DM) is an autoimmune disease. Although genome-wide association studies (GWAS) and meta-analyses have successfully identified numerous type 1 DM-associated susceptibility loci, the underlying mechanisms for these susceptibility loci are currently largely unclear. METHODS: Based on publicly available datasets, we performed integrative analyses (i.e., integrated gene relationships among implicated loci, differential gene expression analysis, functional prediction and functional annotation clustering analysis) and combined with expression quantitative trait loci (eQTL) results to further explore function mechanisms underlying the associations between genetic variants and type 1 DM. RESULTS: Among a total of 183 type 1 DM-associated SNPs, eQTL analysis showed that 17 SNPs with cis-regulated eQTL effects on 9 genes. All the 9 eQTL genes enrich in immune-related pathways or Gene Ontology (GO) terms. Functional prediction analysis identified 5 SNPs located in transcription factor (TF) binding sites. Of the 9 eQTL genes, 6 (TAP2, HLA-DOB, HLA-DQB1, HLA-DQA1, HLA-DRB5 and CTSH) were differentially expressed in type 1 DM-associated related cells. Especially, rs3825932 in CTSH has integrative functional evidence supporting the association with type 1 DM. CONCLUSIONS: These findings indicated that integrative analyses can yield important functional information to link genetic variants and type 1 DM. PMID- 26429318 TI - Frequent IgG subclass and mannose binding lectin deficiency in patients with chronic fatigue syndrome. AB - Chronic fatigue syndrome (CFS) is a severe disease characterized by various symptoms of immune dysfunction. CFS onset is typically with an infection and many patients suffer from frequently recurrent viral or bacterial infections. Immunoglobulin and mannose binding lectin (MBL) deficiency are frequent causes for increased susceptibility to infections. In this study we retrospectively analysed 300 patients with CFS for immunoglobulin and MBL levels, and B-cell subset frequencies. 25% of the CFS patients had decreased serum levels of at least one antibody class or subclass with IgG3 and IgG4 subclass deficiencies as most common phenotypes. However, we found elevated immunoglobulin levels with an excess of IgM and IgG2 in particular in another 25% of patients. No major alteration in numbers of B cells and B-cell subsets was seen. Deficiency of MBL was found in 15% of the CFS patients in contrast to 6% in a historical control group. In a 2nd cohort of 168 patients similar frequencies of IgG subclass and MBL deficiency were found. Thus, humoral immune defects are frequent in CFS patients and are associated with infections of the respiratory tract. PMID- 26429319 TI - Influence of dopamine receptor gene polymorphisms on circulating T lymphocytes: A pilot study in healthy subjects. AB - Dopamine is a key transmitter in the neuroimmune network, acting through five dopaminergic receptors (DR): the D1-like D1 and D5 and the D2-like D2, D3 and D4. Several DR gene variants exist and may affect DR expression and activity. We assessed total lymphocytes, CD3+, CD4+ and CD8+ T lymphocytes in peripheral blood of healthy subjects and their association with selected DR gene variants (DRD1 rs4532 and rs686, DRD5 rs6283, DRD2 rs1800497 and rs6277, DRD3 rs6280 and rs1800828, DRD4 rs747302 and 7 48-base pair VNTR). DRD1 rs4532 and rs686 and DRD5 rs6283 were associated with total lymphocytes, and with CD3+ and CD4+ (but not CD8+) T lymphocytes, while none of the D2-like DR gene variants showed any association with lymphocyte counts. An arbitrary score based on the activity of D1-like vs D2-like DR correlated with total lymphocytes, CD3+ and CD4+ T cells (but not with CD8+ T cells). The association between D1-like DR gene variants and lymphocyte count, and in particular with CD4+ (but not CD8+) T lymphocytes, may imply a functional prevalence of D1-like over D2-like DR in CD4+ T cells. This is the first study showing an influence of DR gene polymorphisms on lymphocyte count, and in particular on CD4+ T cells. Future studies should address the possible association between DR gene variants and the immune function in health and disease. The relevance of these findings for the immune effects of dopaminergic agents should be also carefully examined. PMID- 26429320 TI - Association analysis of class II cytokine and receptor genes in vitiligo patients. AB - The loss of melanocytes in vitiligo is mainly attributed to defective autoimmune mechanisms and lately autoinflammatory mediators have become more emphasized. Among these, a number of class II cytokines and their receptors have displayed altered expression patterns in vitiligo. Thus, we selected 30 SNPs from the regions of respective genes to be genotyped in Estonian case-control sample (109 and 328 individuals, respectively). For more precise analyses, patients were divided into subgroups based on vitiligo progression activity, age of onset, sex, occurrence of vitiligo among relatives, extent of depigmented areas, appearance of Kobner's phenomenon, existence of halo nevi, occurrence of spontaneous repigmentation, and amount of thyroid peroxidase antibodies. No associations appeared in whole vitiligo group. In subgroups, several allelic and haplotype associations were found. The strongest involved SNPs rs12301088 (near IL26 gene), that was associated with familial vitiligo and existence of halo nevi, and rs2257167 (IFNAR1 gene), that was associated with female vitiligo. Additionally, haplotypes consisting of rs12301088 and rs12321603 alleles (IL26-IL22 genes), that were associated with familial vitiligo and existence of halo nevi. In conclusion, several genetic associations with vitiligo subphenotypes were revealed and functional explanations to these remain to be determined in respective studies. PMID- 26429321 TI - Counteractive functions are encrypted in the residues of CD154. AB - CD40, as a single receptor that binds CD154 (CD40-ligand or CD40L), regulates counteractive effector functions such as production of pro- and anti-inflammatory cytokines. Therefore, we examined whether such dual messages are encrypted in CD40L. As such message encryption was never investigated, we hypothesized that mutation of certain amino acid residues should in principle enhance pro inflammatory cytokine production whereas mutation of some others would enhance anti-inflammatory cytokine secretion. We mutated six such residues, which were previously showed to participate in CD40L function. Here, we report that the mutant CD154 129E->V was superior to the wild-type CD154 in killing of Leishmania donovani, induction of inducible nitric oxide synthase (iNOS) and production of IL-12 and relative phosphorylation of p38MAPK and ERK-1/2 in PBMC-derived macrophages. By contrast, 128S->V promoted L. donovani survival, reducing iNOS, but increasing IL-10 expression and predominant ERK-1/2 phosphorylation. The mutant 144G->V did not have significant effects. Other mutants (142E->V, 143K->A, 145Y->F) mimicked the wild-type CD154. Molecular dynamics simulation suggested that these mutations induced differential conformational changes in the CD40 CD154 complex. Therefore, assortment of the contrasting messages encrypted in a given ligand performing counteractive functions presents a novel fundamental biological principle that can be used for devising various therapies. PMID- 26429322 TI - Study of genetic diversity of KIR and TLR in the Rabhas, an endogamous primitive tribe of India. AB - The Rabha tribe is a little known small endogamous population belonging to Indo mongoloid group of north-eastern India. We have analyzed 16 KIR and 5 TLR gene polymorphisms in the Rabha population of northern West Bengal, India for the first time. The observed frequencies of the KIR genes (except framework and pseudogene loci) ranged between 0.26 (KIR2DS3) and 0.96 (KIR2DL1). Comparisons based on KIR polymorphism have revealed that although the Rabhas are of Indian origin the presence of mongoloid component in their gene pool cannot be denied. The frequencies of the 5 TLR genes ranged between 0.90 (TLR4) and 0.46 (TLR5). TLR variations found in the Rabhas may play a synergistic role in fighting against the bacterial invasions. Our results may contribute to the understanding of (1) genetic background and extent of genetic admixture in the Rabhas, (2) population migration events and (3) KIR-disease-TLR interactions. PMID- 26429323 TI - Therapeutic potential of IL-15 in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic, destructive inflammatory autoimmune disease. Cytokine-mediated immunity has been found to play an important role in the pathogenesis of autoimmune diseases including RA. Recently, much attention has been paid on the role of IL-15, which is a member of the 4 alpha-helix bundle cytokine family. IL-15 was detected in serum and synovial fluid from RA patients and arthritis mice models. Moreover, administration of IL-15 leads to the development of severe inflammatory arthritis, suggesting that IL-15 may be therapeutically relevant in RA. Therefore, targeting IL-15 may be significantly important and valuable. In this article, we discuss the biological features and effects of IL-15 and summarize recent advances on the pathological roles of IL-15 in RA and treatment for RA. PMID- 26429324 TI - Receptor for advanced glycation end products (RAGE) gene polymorphism and cardiovascular disease in end-stage renal disease patients. AB - BACKGROUND/OBJECTIVES: Receptor for advanced glycation end products (RAGE) contributes to the pathogenesis of vascular and inflammatory diseases. We investigated whether the functional polymorphism in the promoter region of the RAGE gene (-374 T/A) influences development of cardiovascular disease in the end stage renal disease (ESRD) patients. METHODS: The cohorts of 1866 ESRD patients and 1143 healthy subjects were genotyped by polymerase chain reaction (PCR) for the RAGE variant rs1800624. RESULTS: The genotype and allele frequencies did not differ significantly between ESRD patients and controls. There was no significant difference in the genotype distribution when patients with CVD were compared to those without it (p for A allele = 0.62). After stratifying CVD patients according to CVD clinical phenotype, the ESRD patients with stroke had a lower frequency of A allele than patients without CVD (0.12 vs. 0.21, p = 0.027). To confirm this finding, we genotyped 163 patients with ischemic stroke but without renal disease. In this group, the AA/TA genotypes were also significantly associated with lower risk of stroke (OR 0.46, p = 0.0002). CONCLUSION: Our data suggest that the presence of the A allele of -374 T/A polymorphism in the RAGE gene has a protective effect against stroke. PMID- 26429325 TI - Poor functional immune recovery in aged HIV-1-infected patients following successfully treatment with antiretroviral therapy. AB - Aging is now a well-recognized characteristic of the HIV-infected population and both AIDS and aging are characterized by a deficiency of the T-cell compartment. The objective of the present study was to evaluate the impact of antiretroviral (ARV) therapy in recovering functional response of T cells to both HIV-1-specific ENV peptides (ENV) and tetanus toxoid (TT), in young and aged AIDS patients who responded to ARV therapy by controlling virus replication and elevating CD4(+) T cell counts. Here, we observed that proliferative response of T-cells to either HIV-1-specific Env peptides or tetanus toxoid (TT) was significantly lower in older antiretroviral (ARV)-treated patients. With regard to cytokine profile, lower levels of IFN-gamma, IL-17 and IL-21, associated with elevated IL-10 release, were produced by Env- or TT-stimulated T-cells from older patients. The IL-10 neutralization by anti-IL-10 mAb did not elevate IFN-gamma and IL-21 release in older patients. Finally, even after a booster dose of TT, reduced anti TT IgG titers were quantified in older AIDS patients and it was related to both lower IL-21 and IFN-gamma production and reduced frequency of central memory T cells. Our results reveal that ARV therapy, despite the adequate recovery of CD4(+) T cell counts and suppression of viremia, was less efficient in recovering adequate immune response in older AIDS patients. PMID- 26429326 TI - FAS -670 A/G polymorphism may be associated with the depletion of CD4(+) T lymphocytes in HIV-1 infection. AB - In this study, the polymorphisms in the FAS and FASL genes was investigated in a sample of 198 HIV-1-seropositive individuals and 191 seronegative controls to evaluate a possible association between polymorphisms and the infection. The identification of the A and G alleles of the FAS -670 polymorphism was accomplished through polymerase chain reaction assays followed by digestion with the restriction enzyme MvaI. The identification of the A and G alleles of the FAS -124 polymorphism and the T and delT alleles of the FAS -169 polymorphism were performed using the amplification-created restriction site method followed by restriction fragment length polymorphism reactions. The comparative analysis of allelic and genotypic frequencies between the groups did not reveal any significant differences. However, the quantitative analysis of CD4(+) T lymphocytes suggests that the G allele of the FAS -670 A/G polymorphism can be a protective factor against the depletion of these cells in the course of an HIV-1 infection. Polymorphisms in the FAS and FASL genes were not associated with the number of CD8(+) T lymphocytes or the plasma viral load. Our findings suggest that the FAS -670 polymorphism may be associated with apoptosis of CD4(+) T lymphocytes after infection by HIV-1. PMID- 26429327 TI - Role of stem cells in spondyloarthritis: Pathogenesis, treatment and complications. AB - Spondyloarthritis (SpA) is a family of interrelated inflammatory arthritis that includes ankylosing spondylitis (AS), psoriatic arthritis, reactive arthritis, arthritis related to inflammatory bowel disease and undifferentiated SpA. The classification, epidemiology, pathogenesis and treatment of SpA have been extensively reviewed in the published literature. Reviews on the use of stem cells in various autoimmune diseases in general are also common. However, a review on the role of stem cells in SpA is currently lacking. This review focuses on the involvement of stem cells in the pathogenesis of SpA and the application of different types of stem cells in the treatment of SpA. It also addresses some of the complications which may arise as a result of the use of stem cells in the treatment of SpA. PMID- 26429328 TI - Comparative analysis of how immune sensitization is defined prior to lung transplantation. AB - BACKGROUND: Immune sensitization prior to lung transplantation may be associated with worse survival. Using solid phase assays to define sensitization, we assessed the relationship between PRA status, donor specific anti-HLA antibodies (DSA) pre-transplant, cytotoxic cross match results and the clinical outcomes following lung transplantation. METHODS: Luminex assays determined the presence of antibodies to class I and class II MHC molecules prior to lung transplantation. At the time of transplant, the PRA status, the presence of DSA and prospective cytotoxic cross match result were analysed in 195 patients undergoing lung transplantation between June 2008 and June 2012. Clinical outcomes analysed included acute cellular and antibody-mediated rejection, chronic lung allograft dysfunction (CLAD) and mortality. RESULTS: At the time of transplant, 45% of patients had a positive PRA and 29% had DSA. On univariate analysis, the presence of pre-transplant class I or II anti-HLA donor-specific antibodies was not associated with the development of chronic lung allograft dysfunction (CLAD) despite significant associations with PRA status and B-cell crossmatch. CONCLUSION: Defining sensitization using solid phase assays provide additional details regarding donor-specific sensitization but did not provide additional prognostic information to that provided by historically available cell based cross-match assays. PMID- 26429329 TI - A review of 42 cases of intestinal pseudo-obstruction in patients with systemic lupus erythematosus based on case reports. AB - Intestinal pseudo-obstruction (IpsO) is considered a severe manifestation of systemic lupus erythematosus (SLE) characterized by clinical and radiological evidence of intestinal obstruction with no identifiable mechanical lesion. We performed a systematic review to document IpsO in SLE. Twenty-eight articles with 42 patients were included. The median age of onset of IpsO was 27.5 (10-57) years. The female to male ratio was 38:4. Twenty-two (52.4%) patients had IpsO as the initial presentation of their underlying lupus. Three (7.1%) patients manifested in inactive lupus. The duration of abdominal symptoms before admitted ranged from 3 days to 3 years, however most of the patients responded well to systemic corticosteroid or immunosuppressive treatment within 2 days to about 3 months. Concomitant ureterohydronephrosis was present in approximately three fourths of the cases. More interestingly, 4 patients presented hepatobiliary dilatation without mechanical obstruction together with IPO and ureterohydronephrosis. In conclusion, IpsO is an uncommon but important manifestation of SLE. The finding of coexisting ureterohydronephrosis and hepatobiliary dilatation suggests that there may be generalized visceral muscle dysmotility. Early recognition of IpsO is necessary to institute appropriate medical treatment and to avoid inappropriate surgical intervention. PMID- 26429330 TI - Role of galectin-3 in the pathogenesis of bladder transitional cell carcinoma. AB - Galectins constitute an evolutionary conserved family that binds to beta galactosides. There is growing evidence that galectins are implicated in essential biological processes such as cellular communication, inflammation, differentiation and apoptosis. Galectin-3 is one of the best-known galectins, which is found in vertebrates. Galectin-3 has been shown to be expressed in some cell lines and plays important roles in several physiological and pathological processes, including cell adhesion, cell activation and chemoattraction, cell cycle, apoptosis, cell growth, and differentiation. Moreover, this galectin is of interest due to its involvement in regulation of cancer. Changes in galectin-3 expression are commonly seen in cancerous and pre-cancerous conditions and galectin-3 may be involved in the regulation of cancer cell activities that contribute to tumourigenesis, cancer progression and metastasis. Finally, galectin-3 seems to be involved in cell events in tumor microenvironment, and therefore it could be considered as a target in transitional cell carcinoma therapies. This review aims to describe recent progress in understanding the role of galectin-3 in cancer biology, with emphasis on bladder tumor progression and metastasis. PMID- 26429331 TI - Association of monocyte chemoattractant protein 1 (MCP-1) gene polymorphism with lupus nephritis in Egyptian patients. AB - BACKGROUND AND STUDY AIM: Monocyte chemoattractant protein-1 (MCP-1) is a member of CC chemokine that plays an important role in the recruitment of monocytes/macrophages into renal tubulointerstitium. A biallelic A/G polymorphism at position ~2518 in the MCP-1 gene was found to regulate MCP-1 expression. MCP-1 and its A/G gene polymorphism have been implicated in the pathogenesis of some renal diseases. The aim of the study was to investigate the role of the MCP-1 gene polymorphism as early predictors of the development of glomerulonephropathy in SLE patients. We also aimed to measure the serum and urinary levels of MCP-1 in patients with SLE, to find out its relation to clinical disease activity. METHODS: 140 SLE patients (100 with nephritis and 40 without nephritis) and 80 controls were included in this study. MCP-1 gene polymorphism was analyzed by polymerase chain reaction. Serum and urine MCP-1 level were measured using high sensitivity enzyme-linked immunosorbent assay. RESULTS: The A/A genotype was more common in controls than in SLE patients, whereas both the A/G (P<0.000) and G/G (P<0.000) genotypes were more frequent in SLE patients. Carriers of G allele of the MCP-1 ~2518 polymorphism had more than 7 fold increased risk to develop glomerulo-nephropathy in patients with SLE. High MCP-1 circulating levels production from patients with A/G and G/G genotypes was significantly higher than in A/A genotype. In addition there were significant differences in the mean levels of serum MCP-1 (P<0.001) and urinary MCP-1 (P<0.001) between patients and controls. CONCLUSION: The present study provides a new evidence that the presence of MCP-1 A (-2518) G gene polymorphism and high circulating MCP-1 levels can play an important role in the development of SLE and nephropathy in Egyptians. PMID- 26429332 TI - ER stress-inducible protein MANF selectively expresses in human spleen. AB - Mesencephalic astrocyte-derived neurotrophic factor (MANF; also known as arginine rich, mutated in early tumors; ARMET), is an ER stress-inducible protein, and widely expressed in mammalian tissues. In this study, we are interested in the profile of MANF expression in human splenocytes. Three patients with spleen trauma were enrolled in this study. Immunohistochemistry and immunofluorescence were used to detect MANF expression in the four types of cells, including T cells, B cells, plasma cells, and macrophages in spleens by using the specific antibodies of anti-CD3, anti-CD20, anti-CD138, and anti-CD68, respectively. We found that MANF-positive cells extensively distributed in the red pulp and marginal-zone of spleen, and MANF was almost localized in the cytoplasm of splenocytes. Double immunofluorescent staining results showed that MANF localized mainly in the plasma cells and macrophages, but not in T and B cells. Meanwhile, we found that some MANF-positive cells expressed ER stress-related proteins, including ATF6, XBP1s, BiP, and CHOP. These results suggest that the selective expression of MANF in splenocytes may be involved in plasma cell differentiation and immune regulation. PMID- 26429333 TI - Psychosocial Aspects of Hearing Loss in Children. AB - Pediatric hearing loss changed more in the past two decades than it had in the prior 100 years with children now identified in the first weeks of life and fit early with amplification. Dramatic improvements in hearing technology allow children the opportunity to listen, speak and read on par with typically hearing peers. National laws mandate that public and private schools, workplaces, and anywhere people go must be accessible to individuals with disabilities. In 2015, most children with hearing loss attended mainstream schools with typically hearing peers. Psychosocial skills still present challenges for some children with hearing loss. PMID- 26429334 TI - Diagnostic Evaluation of Children with Sensorineural Hearing Loss. AB - The cause of pediatric sensorineural hearing loss is diverse, comprising genetic, acquired, and idiopathic conditions. Identifying the specific cause requires that children undergo thorough otolaryngologic and audiometric evaluations, which generally include laboratory tests and temporal bone imaging studies. Clinical genetics and ophthalmologic consultations are also frequently warranted. A sequential diagnostic approach has been shown to be both prudent and cost effective. Although a definitive cause is being established, amplification and a comprehensive treatment strategy should be initiated to ensure that developmental, auditory, and speech and language delays are minimized. PMID- 26429335 TI - Parasite clearance after malaria therapy: staying a step ahead of drug resistance. AB - The discovery and development of the artemisinin class of antimalarial drugs is one of the great recent success stories of global health. However, after at least two decades of successful use, resistance has finally emerged and appears to be spreading rapidly throughout South-East Asia in spite of our best efforts at containment. If this were also to occur in Africa, it would have disastrous implications for the continent subject to the world's greatest burden of Plasmodium falciparum. The earliest indications of incipient artemisinin resistance may be a slowing of the rate at which parasites are cleared from the blood following treatment. The Worldwide Antimalarial Resistance Network have analysed data from 29,493 patients from 84 clinical trials in order to define the nature and determinants of early parasite clearance following artemisinin-based treatment in African populations. In doing so, they lay the foundation for systems intended to enable the earliest possible detection of emerging artemisinin resistance in Africa. Please see related article: http://www.biomedcentral.com/1741-7015/13/212. PMID- 26429336 TI - Age- and gender-dependent myocardial transcription patterns of cytokines and extracellular matrix remodelling enzymes in cats with non-cardiac diseases. AB - BACKGROUND: Age, gender and systemic diseases all influence cardiac function and remodelling. In cats, age and gender associated myocardial remodelling and the effect of systemic diseases on the myocardium have so far not been studied. The aim of the study was therefore to investigate whether relevant cytokines and extracellular matrix (ECM) remodelling enzymes are expressed in the myocardium of cats with non-cardiac diseases and whether transcription levels are influenced by age and gender. METHODS: The study was performed on myocardial samples from 26 cats aged between 2 and 19 years that had died with non-cardiac diseases. Seventeen cats were female (2 entire) and nine were male (1 entire). Of these, nine cats were diagnosed with diseases unlikely to affect the myocardium (control cats). The remaining 17 cats suffered from diseases with likely systemic effects. All hearts were assessed for any pathological changes, and the myocardium was analysed for interleukin (IL)-1, -2, -4, -6, -18, tumour necrosis factor (TNF) alpha, interferon (IFN)-gamma, transforming growth factor (TGF)-beta, matrix metalloproteinase (MMP)-2, -3, -13, tissue inhibitor of MMP (TIMP)-1, -2 and -3 transcriptions using quantitative RT-PCR assays. RESULTS: Despite the absence of any histological evidence of myocardial damage, inflammation and fibrosis, the myocardium of all the cats was found to constitutively transcribe cytokines and ECM remodelling enzymes, with generally higher mRNA concentrations in the atria than in the ventricles. The young and male cats exhibited higher transcription levels throughout the myocardium in comparison to the older and female cats. Furthermore, age-associated transcription pattern differed between male and female cats. CONCLUSION: The constitutive transcription of ECM remodelling enzymes suggests continuous myocardial remodelling throughout the entire life of a cat. The myocardium of young and male cats appears to be in a pro-inflammatory state, whereas in older and female cats the myocardium exhibits a reduced inflammatory reaction to systemic disease. Age-associated cardiac remodelling seems to be influenced by non-hormonal factors in male and female cats. PMID- 26429338 TI - Telepsychiatry intervention is better for ADHD symptoms than usual treatment augmented by telemedicine consultation. PMID- 26429337 TI - Qualitative analysis of patient-centered decision attributes associated with initiating hepatitis C treatment. AB - BACKGROUND: In this era of a constantly changing landscape of antiviral treatment options for chronic viral hepatitis C (CHC), shared clinical decision-making addresses the need to engage patients in complex treatment decisions. However, little is known about the decision attributes that CHC patients consider when making treatment decisions. We identify key patient-centered decision attributes, and explore relationships among these attributes, to help inform the development of a future CHC shared decision-making aid. METHODS: Semi-structured qualitative interviews with CHC patients at four Veterans Health Administration (VHA) hospitals, in three comparison groups: contemplating CHC treatment at the time of data collection (Group 1), recently declined CHC treatment (Group 2), or recently started CHC treatment (Group 3). Participant descriptions of decision attributes were analyzed for the entire sample as well as by patient group and by gender. RESULTS: Twenty-nine Veteran patients participated (21 males, eight females): 12 were contemplating treatment, nine had recently declined treatment, and eight had recently started treatment. Patients on average described eight (range 5-13) decision attributes. The attributes most frequently reported overall were: physical side effects (83%); treatment efficacy (79%), new treatment drugs in development (55%); psychological side effects (55%); and condition of the liver (52%), with some variation based on group and gender. Personal life circumstance attributes (such as availability of family support and the burden of financial responsibilities) influencing treatment decisions were also noted by all participants. Multiple decision attributes were interrelated in highly complex ways. CONCLUSIONS: Participants considered numerous attributes in their CHC treatment decisions. A better understanding of these attributes that influence patient decision-making is crucial in order to inform patient-centered clinical approaches to care (such as shared decision-making augmented with relevant decision-making aids) that respond to patients' needs, preferences, and circumstances. PMID- 26429339 TI - Challenges in recruiting subjects to a pilot trial of patient-managed in-hospital insulin. AB - BACKGROUND: To examine the feasibility of implementing clinician-supported inpatient self-managed insulin to aid in the planning of a randomized clinical trial. RESULTS: We conducted a proof-of-concept interventional study of inpatients with diabetes mellitus who had hospital orders for basal-bolus or sliding scale insulin. Patients meeting inclusion criteria were offered the opportunity to manage their own basal-bolus insulin with support from a diabetes nurse practitioner. Over a three-month screening period, we conducted 361 screens in 336 patients, only eleven of whom met all inclusion criteria. None of these eleven eligible patients elected to enroll. The most common reason for refusal was lack of interest in self-managing insulin while acutely ill (36 %). DISCUSSION: Future studies of patient-managed in-hospital insulin should consider enrolling less acutely ill patients with longer anticipated lengths of stay. TRIALS REGISTRATION: NCT02144441. PMID- 26429340 TI - In Memoriam: Patricia (Dr Pat) Charache, MD. PMID- 26429341 TI - High Proportion of Asymptomatic Infections in an Outbreak of Hepatitis E Associated With a Spit-Roasted Piglet, France, 2013. AB - BACKGROUND: On 11 December 2013, 3 clustered cases of hepatitis E were reported on a French coastal island. Individuals had taken part in a wedding meal that included a spit-roasted piglet. The piglet had been stuffed with a raw stuffing partly made from the liver. Investigations were carried out to identify the vehicle of contamination and evaluate the dispersion of the hepatitis E virus (HEV) in the environment. METHODS: A questionnaire was administered to 98 wedding participants who were asked to give a blood sample. Cases were identified by reverse transcription-polymerase chain reaction and serological tests. A retrospective cohort study was conducted among 38 blood-sampled participants after the exclusion of 14 participants with evidence of past HEV infection. Relative risks (RR) and 95% confidence intervals were calculated based on food consumed at the wedding meal using univariate and multivariable Poisson regressions. Phylogenetic analyses were performed to compare the clinical HEV strains. Strains were detected in the liquid manure sampled at the farm where the piglet was born and in the untreated island wastewater. RESULTS: Seventeen cases were identified, 70.6% were asymptomatic. Acute HEV infection was independently associated with piglet stuffing consumption (RR = 1.69 [1.04-2.73], P = .03). Of clinical strains from the index cases, veterinary and environmental HEV strains were identical. CONCLUSIONS: Our investigation attributed this large HEV outbreak to the consumption of an undercooked pig liver-based stuffing. After infection, the cases became a temporary reservoir for HEV, which was detected in the island's untreated wastewater. PMID- 26429343 TI - Knee arthrodesis with modular nail after failed TKA due to infection. AB - INTRODUCTION: Knee arthrodesis is an established procedure for limb salvage after failed total knee arthroplasty (TKA) in cases of recurrent infection, soft tissue damage, reduced bone stock or with a deficient extensor mechanism. Walking with an arthrodesis is more efficient and less costly in terms of energy expenditure than above-knee amputation. Surgical options include an arthrodesis nail, external fixator or compression plate. We present our results of knee arthrodesis using the modular Wichita Fusion Nail((r)) in patients after infected TKA. METHODS: Fifteen patients with irretrievably failed TKA, due to infection, who underwent arthrodesis with the Wichita Fusion Nail((r)) from 2004 to 2012 were retrospectively reviewed to assess fusion rate, time to fusion, complication rate, including new infections, and ambulatory status. RESULTS: Three patients were lost to follow-up. Mean follow-up was 33 months (6-132 months). At their most recent follow-up, all patients were walking with full weight bearing on a fused arthrodesis. Mean time to union was 9 months (3-29 months). Three patients necessitated a revision arthrodesis to achieve union after a mean of 5 months after the last procedure. CONCLUSION: Arthrodesis with the Wichita Fusion Nail((r)) provides satisfactory results in patients with failure after infected TKA, with 75 % primary union rate and no new or persistent infection at last follow-up visit. Although burdened with a high complication rate, it represents an acceptable option for limb salvage in this particular pathology. PMID- 26429345 TI - An Analog Filter Approach to Frequency Domain Fluorescence Spectroscopy. AB - The rate equations found in frequency domain fluorescence spectroscopy are the same as those found in electronics under analog filter theory. Laplace transform methods are a natural way to solve the equations, and the methods can provide solutions for arbitrary excitation functions. The fluorescence terms can be modelled as circuit components and cascaded with drive and detection electronics to produce a global transfer function. Electronics design tools such as SPICE can be used to model fluorescence problems. In applications, such as remote sensing, where detection electronics are operated at high gain and limited bandwidth, a global modelling of the entire system is important, since the filter terms of the drive and detection electronics affect the measured response of the fluorescence signals. The techniques described here can be used to separate signals from fast and slow fluorophores emitting into the same spectral band, and data collection can be greatly accelerated by means of a frequency comb driver waveform and appropriate signal processing of the response. The simplification of the analysis mathematics, and the ability to model the entire detection chain, make it possible to develop more compact instruments for remote sensing applications. PMID- 26429342 TI - Antibacterial coating of implants in orthopaedics and trauma: a classification proposal in an evolving panorama. AB - Implanted biomaterials play a key role in current success of orthopedic and trauma surgery. However, implant-related infections remain among the leading reasons for failure with high economical and social associated costs. According to the current knowledge, probably the most critical pathogenic event in the development of implant-related infection is biofilm formation, which starts immediately after bacterial adhesion on an implant and effectively protects the microorganisms from the immune system and systemic antibiotics. A rationale, modern prevention of biomaterial-associated infections should then specifically focus on inhibition of both bacterial adhesion and biofilm formation. Nonetheless, currently available prophylactic measures, although partially effective in reducing surgical site infections, are not based on the pathogenesis of biofilm-related infections and unacceptable high rates of septic complications, especially in high-risk patients and procedures, are still reported.In the last decade, several studies have investigated the ability of implant surface modifications to minimize bacterial adhesion, inhibit biofilm formation, and provide effective bacterial killing to protect implanted biomaterials, even if there still is a great discrepancy between proposed and clinically implemented strategies and a lack of a common language to evaluate them.To move a step forward towards a more systematic approach in this promising but complicated field, here we provide a detailed overview and an original classification of the various technologies under study or already in the market. We may distinguish the following: 1. Passive surface finishing/modification (PSM): passive coatings that do not release bactericidal agents to the surrounding tissues, but are aimed at preventing or reducing bacterial adhesion through surface chemistry and/or structure modifications; 2. Active surface finishing/modification (ASM): active coatings that feature pharmacologically active pre-incorporated bactericidal agents; and 3. Local carriers or coatings (LCC): local antibacterial carriers or coatings, biodegradable or not, applied at the time of the surgical procedure, immediately prior or at the same time of the implant and around it. Classifying different technologies may be useful in order to better compare different solutions, to improve the design of validation tests and, hopefully, to improve and speed up the regulatory process in this rapidly evolving field. PMID- 26429344 TI - The service impact of failed locking plate fixation of distal tibial fractures: a service and financial evaluation at a major trauma centre. AB - INTRODUCTION: The surgical treatment of distal tibial fractures is challenging and controversial. Recently, locking plate fixation has become popular, but the outcomes of this treatment are mixed with complication rates as high as 50 % in the published literature. There are no reports specifically relating to the financial and resource costs of failed treatment in the literature. METHOD: Retrospective service analysis of patients who had undergone locking plate fixation of a distal third tibial fracture between 2008 and 2011 with at least 12 months follow-up. Rates of readmission, reoperation, bony union and infection were ascertained. The financial and resource (hospital stay and number of outpatient appointments) implications of failed treatment were calculated. RESULTS: Forty-two patients were identified. There were 31 type A fractures, one type B fracture and 10 type C fractures. Three injuries were open. Twenty patients were treated with minimally invasive percutaneous osteosynthesis (MIPO). The readmission and reoperation rates were 26 % (n = 11) and 19 % (n = 8), respectively. A total of 89 % of readmissions were due to infection. All patients had received appropriate antibiotic regimens. The average costs of successful and failed treatment were L 5538 and L 18,335, respectively. The average time to union was 24.5 weeks. The rate of non-union was 21 % (n = 9). The rate of infection was 28 % (n = 12), with all patients with open fracture incurring an infection. Tourniquet time had no effect on the incidence of complications. Smokers were more likely to incur a complication (p < 0.05), and non-union was lower in the MIPO group (p < 0.05). The length and total cost of inpatient care were significantly lower in the MIPO group (p < 0.05). MIPO patients were five times less likely to incur readmission or reoperation. Failed treatment was three times more expensive and four times longer than successful treatment. CONCLUSION: The study identified a large burden to the service following failure of locking plate treatment of these fractures, but the outcomes were similar to series published in the literature. Readmission rates were high following these injuries, and failed treatment was costly and had a significant impact on hospital resources. The implementation of major trauma networks and centralised subspecialised units should improve quality and value for money. PMID- 26429346 TI - Making the case for a fracture liaison service: a qualitative study of the experiences of clinicians and service managers. AB - BACKGROUND: To develop services, healthcare professionals must make business cases to managerial bodies within Hospital Trusts and if approved, to commissioning bodies. Patients with hip fracture are at high risk of subsequent fracture. To prevent this, guidance recommends structuring fracture prevention services around coordinator based models. These are known as Fracture Liaison Services (FLS). METHODS: 33 semi-structured qualitative interviews were conducted with healthcare professionals with experience of making business cases for FLS. Data was analysed thematically. RESULTS: Challenges in the development of business cases included collecting all the relevant data and negotiating compartmentalised budgets that impeded service development. Participants described communication and cooperation between providers and commissioners as variable. They felt financial considerations were the most important factor in funding decisions, while improved quality of care was less influential. Other factors included national guidelines and political priorities. The personalities of clinicians championing services, and the clinical interests of commissioners were seen to influence the decision-making process, suggesting that participants felt that decisions were not always made on the basis of evidence-based care. Effective strategies included ways of providing support, demonstrating potential cost effectiveness and improved quality of care. Using a range of sources including audit data collected on the successful Glasgow FLS, and improving cooperation between stakeholders was advocated. Participants felt that the work of commissioners and providers should be better integrated and suggested strategies for doing this. CONCLUSIONS: This study provides information to healthcare professionals about how best to develop business cases for FLS. We conclude with recommendations on how to develop effective cases. These include using guidance such as toolkits, aligning the aims of FLS with national priorities and benchmarking services against comparators. Introducing a 'Local Champion' to work alongside the service manager and establishing a multi disciplinary working team would facilitate communication between stakeholders. Involving commissioners in service design would help integrate the roles of purchasers and providers. PMID- 26429347 TI - Design of wireless multi-parameter monitoring system for oral feeding of premature infants. AB - Premature infants often cannot successfully and coordinately complete their oral feeding. Mature sucking, swallowing, and respiration activities are crucial indicators for the survival of newborn infants. Due to the vulnerability and unobvious muscle activities of premature infants, current clinical care givers mainly depend on the subjective behavioral observation of infants during oral feeding. There is still lack of an integrated oral feeding monitoring system to objectively and quantifiably monitor the related physiological parameters of premature infants. In this study, a wireless multi-parameter monitoring system for oral feeding of premature infants was proposed to monitor the sucking swallowing-respiratory activities and the heart rate variability to provide quantitative indices of oral feeding. Here, a novel sucking pressure sensing module was also developed to monitor the premature infant's sucking pressure under oral feeding to avoid the immersion influence of milk. The experimental results showed that the proposed system detected the related physiological parameters of premature infants during oral feeding effectively and may provide an objective clinical evaluation tool for oral feeding ability and safety of premature infants in the future. PMID- 26429348 TI - An adaptive integrated algorithm for noninvasive fetal ECG separation and noise reduction based on ICA-EEMD-WS. AB - High-resolution fetal electrocardiogram (FECG) plays an important role in assisting physicians to detect fetal changes in the womb and to make clinical decisions. However, in real situations, clear FECG is difficult to extract because it is usually overwhelmed by the dominant maternal ECG and other contaminated noise such as baseline wander, high-frequency noise. In this paper, we proposed a novel integrated adaptive algorithm based on independent component analysis (ICA), ensemble empirical mode decomposition (EEMD), and wavelet shrinkage (WS) denoising, denoted as ICA-EEMD-WS, for FECG separation and noise reduction. First, ICA algorithm was used to separate the mixed abdominal ECG signal and to obtain the noisy FECG. Second, the noise in FECG was reduced by a three-step integrated algorithm comprised of EEMD, useful subcomponents statistical inference and WS processing, and partial reconstruction for baseline wander reduction. Finally, we evaluate the proposed algorithm using simulated data sets. The results indicated that the proposed ICA-EEMD-WS outperformed the conventional algorithms in signal denoising. PMID- 26429349 TI - Detecting freezing of gait with a tri-axial accelerometer in Parkinson's disease patients. AB - Freezing of gait (FOG) is a common motor symptom of Parkinson's disease (PD), which presents itself as an inability to initiate or continue gait. This paper presents a method to monitor FOG episodes based only on acceleration measurements obtained from a waist-worn device. Three approximations of this method are tested. Initially, FOG is directly detected by a support vector machine (SVM). Then, classifier's outputs are aggregated over time to determine a confidence value, which is used for the final classification of freezing (i.e., second and third approach). All variations are trained with signals of 15 patients and evaluated with signals from another 5 patients. Using a linear SVM kernel, the third approach provides 98.7% accuracy and a geometric mean of 96.1%. Moreover, it is investigated whether frequency features are enough to reliably detect FOG. Results show that these features allow the method to detect FOG with accuracies above 90% and that frequency features enable a reliable monitoring of FOG by using simply a waist sensor. PMID- 26429350 TI - Combined treatment with parathyroid hormone (1-34) and beta-tricalcium phosphate had an additive effect on local bone formation in a rat defect model. AB - The objective of this study was to evaluate the effect of following combined treatment with parathyroid hormone (1-34) (PTH) and beta-tricalcium phosphate (beta-TCP) on local bone formation in a rat 3-mm critical-size defect at distal femur. Twelve weeks after bilateral ovariectomy (OVX) and sham operation (sham), all animals were randomly divided into four groups: group OVX, group OVX + beta TCP, group sham, and group sham + beta-TCP, then all rats underwent bone defect in the bilateral distal femurs, and beta-TCP were implanted into critical-sized defects for group OVX + beta-TCP and group sham + beta-TCP. After defect operation, all animals were received following subcutaneous injections with PTH (60 MUg/kg, three times a week) until death at 4 and 8 weeks. The defected area in distal femurs of rats was harvested for evaluation by histology, micro-CT, and biomechanics. The results of our study show that systemic usage of PTH or local usage of beta-TCP can increase the healing of defects in OVX or sham rats. Furthermore, treatments with PTH and beta-TCP showed a stronger effect on accelerating the local bone formation than used alone. Osteoporosis can limit the function of PTH and/or beta-TCP. The results from our study demonstrate that combination of PTH and beta-TCP had an additive effect on local bone formation in non-osteoporosis and/or osteoporosis rats. PMID- 26429351 TI - Numerical simulation of pharyngeal airflow applied to obstructive sleep apnea: effect of the nasal cavity in anatomically accurate airway models. AB - Repetitive brief episodes of soft-tissue collapse within the upper airway during sleep characterize obstructive sleep apnea (OSA), an extremely common and disabling disorder. Failure to maintain the patency of the upper airway is caused by the combination of sleep-related loss of compensatory dilator muscle activity and aerodynamic forces promoting closure. The prediction of soft-tissue movement in patient-specific airway 3D mechanical models is emerging as a useful contribution to clinical understanding and decision making. Such modeling requires reliable estimations of the pharyngeal wall pressure forces. While nasal obstruction has been recognized as a risk factor for OSA, the need to include the nasal cavity in upper-airway models for OSA studies requires consideration, as it is most often omitted because of its complex shape. A quantitative analysis of the flow conditions generated by the nasal cavity and the sinuses during inspiration upstream of the pharynx is presented. Results show that adequate velocity boundary conditions and simple artificial extensions of the flow domain can reproduce the essential effects of the nasal cavity on the pharyngeal flow field. Therefore, the overall complexity and computational cost of accurate flow predictions can be reduced. PMID- 26429353 TI - suPAR: A Cardiac Biomarker With a Future? PMID- 26429352 TI - The 2014 Atrial Fibrillation Guidelines Companion: A Practical Approach to the Use of the Canadian Cardiovascular Society Guidelines. AB - The Canadian Cardiovascular Society (CCS) Atrial Fibrillation Guidelines Program has generated a comprehensive series of documents regarding the management of atrial fibrillation (AF) between 2010 and 2014. The guidelines provide evidence based consensus management recommendations in a broad range of areas. These guidelines have proven useful in informing clinical practice, but often lack detail in specifications related to practical application, particularly for areas in which the evidence base is limited or conflicting. Based on feedback from the community, the CCS Atrial Fibrillation Guidelines Committee has identified a number of areas that require clarification to address commonly asked practical questions related to guidelines application. In the present article a number of such questions are presented and suggestions about how they can be answered are suggested. Among the issues considered are: (1) What duration of AF is clinically significant? (2) How are the risk factors in the CCS Algorithm for selecting anticoagulation therapy derived and defined? (3) How is valvular heart disease defined and how do different forms of valve disease affect the choice of anticoagulant therapy for AF patients? (4) How should we quantify renal dysfunction and how does it affect therapeutic choices? The response to these questions and the underlying logic are provided, along with an indication of future research needed where no specific approach can presently be recommended based on the literature. PMID- 26429354 TI - Reduction in incidence of invasive fungal infection in patients receiving allogeneic stem cell transplantation using combined diagnostic-driven approach and itraconazole oral solution. AB - Invasive fungal infections are an important cause of morbidity and mortality after allogeneic haematopoietic stem cell transplantation. We evaluated, in our allogeneic stem cell transplant patients, the effect on the incidence of invasive fungal infection during neutropenia of a strategy combining a diagnostic-driven approach with chemoprophylaxis during higher risk periods of graft vs. host disease and prolonged neutropenia, using itraconazole oral solution with parenteral voriconazole bridging. One hundred and thirty patients admitted for allogeneic stem cell transplantation within two predefined 20 month periods were included in the study. Data for all patients were collected prospectively. Implementation of the protocol resulted in the administration of more prophylactic antifungals to more patients. Following implementation, there was a non-significant decrease in the overall number of invasive fungal infections (IFI) [11 of 65 patients (17.2%) vs. 4 of 65 patients (6.2%, P = 0.051)], as well as in the occurrence of invasive mould infections [8 of 65 patients (12.5%) vs. 2 of 65 patients (3.1%, P = 0.054)]. Survival rates at three and 6 months were not significantly affected. A combined diagnostic-driven approach and antifungal prophylaxis with oral itraconazole and an intravenous voriconazole bridging protocol, was associated with a reduced, albeit non-statistically significant, number of IFI in our medical centre. PMID- 26429355 TI - Acute respiratory failure in patients with hematological malignancies: outcomes according to initial ventilation strategy. A groupe de recherche respiratoire en reanimation onco-hematologique (Grrr-OH) study. AB - BACKGROUND: In patients with hematological malignancies and acute respiratory failure (ARF), noninvasive ventilation was associated with a decreased mortality in older studies. However, mortality of intubated patients decreased in the last years. In this study, we assess outcomes in those patients according to the initial ventilation strategy. METHODS: We performed a post hoc analysis of a prospective multicentre study of critically ill hematology patients, in 17 intensive care units in France and Belgium. Patients with hematological malignancies admitted for ARF in 2010 and 2011 and who were not intubated at admission were included in the study. A propensity score-based approach was used to assess the impact of NIV compared to oxygen only on hospital mortality. RESULTS: Among 1011 patients admitted to ICU during the study period, 380 met inclusion criteria. Underlying diseases included lymphoid (n = 162, 42.6 %) or myeloid (n = 141, 37.1 %) diseases. ARF etiologies were pulmonary infections (n = 161, 43 %), malignant infiltration (n = 65, 17 %) or cardiac pulmonary edema (n = 40, 10 %). Mechanical ventilation was ultimately needed in 94 (24.7 %) patients, within 3 [2-5] days of ICU admission. Hospital mortality was 32 % (123 deaths). At ICU admission, 142 patients received first-line noninvasive ventilation (NIV), whereas 238 received oxygen only. Fifty-five patients in each group (NIV or oxygen only) were matched according the propensity score. NIV was not associated with decreased hospital mortality [OR 1.5 (0.62-3.65)]. CONCLUSIONS: In hematology patients with acute respiratory failure, initial treatment with NIV did not improve survival compared to oxygen only. CLINICAL TRIAL: gov number NCT 01172132. PMID- 26429356 TI - The effect of parenteral selenium on outcomes of mechanically ventilated patients following sepsis: a prospective randomized clinical trial. AB - BACKGROUND: Sepsis and septic shock is characterized by oxidative stress that mainly promotes systemic inflammation and organ failure due to excessive free radical production and depletion of antioxidant defenses. Therefore, we investigated the effect of selenium administration on antioxidant status, levels of cytokines and clinical outcomes. METHODOLOGY: This study was a prospective randomized control trial (RCT) whereby patients received selenium as sodium selenite (2 mg IV bolus followed by 1.5 mg continuous infusion for 14 days) plus standard therapy. The control group received standard therapy without selenium. The primary endpoint was 28-day mortality. The changes in the mean levels of glutathione peroxidase (GPX) activity, IL-6, IL-8 and IL-10, the incidence of ventilator-associated pneumonia (VAP) and other secondary endpoints were also recorded. VAP was broken down into early VAP and late VAP to see the clinical significance of each. We also recorded any adverse outcomes from selenium infusion. RESULTS: Over 24-month period, 54 patients were recruited and randomized and an intention to treat (ITT) principle was applied (selenium, n = 29; control, n = 25) in the final analysis. There was no statistically significant difference between the two groups in 28-day mortality although it was lower in the selenium group compared with the control group: 9 (31 %) in the selenium versus 10 (40 %) in the control groups (p = 0.49). At day 0, GPX activity was 0.185 +/- 0.3 versus 0.19 +/- 0.3 U/mL (p = 0.9), day 3, GPX activity was 0.52 +/- 0.5 versus 0.17 +/- 0.2 U/mL (p = 0.02), at day 7 it was 0.55 +/- 0.5 versus 0.24 +/- 0.3 U/mL (p = 0.032), at day 10 it was 0.62 +/- 0.7 versus 0.33 +/- 0.4 U/mL (p = 0.048) and at day 14 it was 1.1 +/- 1 versus 0.89 +/- 1 U/mL (p = 0.70) for the selenium versus control groups, respectively. However, there were no significant differences between the mean plasma levels of all the three inflammatory cytokines at any point in time between the two groups. There was a significant reduction in occurrence of VAP in the selenium group compared with the control group (55.2 versus 84 %, p = 0.023), respectively. CONCLUSION: High-dose selenium administration within the time frame of early goal directed therapy was not resulted in reduction of 28-day mortality, but increased the activity of glutathione peroxidase with no effect on the levels of inflammatory cytokines at any point in time in mechanically ventilated septic patients. However, selenium supplementation in mechanically ventilated patients following sepsis was associated with reduced occurrence of VAP. TRIAL REGISTRATION: IRCT201212082887N4 at WHO Clinical Trial Registry, August 29, 2014. PMID- 26429357 TI - Trends in use and impact on outcome of empiric antibiotic therapy and non invasive ventilation in COPD patients with acute exacerbation. AB - BACKGROUND: Empiric antibiotic therapy is routinely prescribed in patients with acute COPD exacerbations (AECOPD) requiring ventilatory support on the basis of studies including patients conventionally ventilated. Whether this practice remains valid to current management with first-line non-invasive ventilation (NIV) is unclear. METHODS: In a cohort of ICU patients admitted between 2000 and 2012 for AECOPD, we analyzed the trends in empiric antibiotic therapy and in primary ventilatory support strategy, and their respective impact on patients' outcome. RESULTS: 440 patients admitted for 552 episodes were included; primary NIV use increased from 29 to 96.7 % (p < 0.001), whereas NIV failure rate decreased significantly (p = 0.004). In parallel, ventilator-associated pneumonia (VAP) rate, VAP density and empiric antibiotic therapy use decreased (p = 0.037, p = 0.002, and p < 0.001, respectively). These figures were associated with a trend toward lower ICU mortality rate (p = 0.058). Logistic regression showed that primary NIV use per se was protective against fatal outcome [odds ratios (OR) = 0.08, 95 %CI 0.03-0.22; p < 0.001], whereas NIV failure, VAP occurrence, and cardiovascular comorbidities were associated with increased ICU mortality [OR = 17.6 (95 %CI 5.29-58.93), 11.5 (95 %CI 5.17-25.45), and 3 (95 %CI 1.37-6.63), respectively]. Empiric antibiotic therapy was associated with decreased VAP rate (log rank; p < 0.001), but had no effect on mortality (log rank; p = 0.793). CONCLUSIONS: The sustained increase in NIV use allowed a decrease in empiric antibiotic prescriptions in AECOPD requiring ventilatory support. Primary NIV use and its success, but not empiric antibiotic therapy, were associated with a favorable impact on patients' outcome. PMID- 26429358 TI - Oncology health workers' views and experiences on caring for ethnic minority patients: A mixed method systematic review. AB - OBJECTIVES: To investigate what published research reveals about the views and experiences of oncology health workers when caring for ethnic minority patients. DESIGN: Systematic review of qualitative and quantitative studies. DATA SOURCES: The following databases were systematically screened: PubMed, CINAHL, Web of Science, and AnthroSource. Reference lists were checked for additional articles. REVIEW METHODS: Empirical studies or systematic reviews (1/2000 to 12/2013) were included if they concerned the oncology setting and the views or experiences of healthcare workers and care users belonging to an ethnic or cultural minority group. The methodological quality of each individual study was assessed using the Critical Appraisal Skills Programme for Qualitative Studies and the Quality Assessment Tool for Quantitative Studies. RESULTS: Eighteen publications met the inclusion criteria. Thirteen articles had a qualitative, four a quantitative, and one a mixed methods design. The results in the individual studies were heterogeneous. Most studies reported challenges or barriers when caring for ethnic minority patients, whereas fewer than half of the articles discussed facilitating factors and opportunities. Oncology health workers participating in the included studies sought to provide professional standards of care and tried to adapt care to the needs of ethnic minority patients. However, they experienced formidable communication barriers and they feared doing things that might be considered culturally insensitive. The organizational aspects of care for the oncology patient appeared to have a significant influence on how healthcare providers view and experience oncology care for ethnic minority patients. CONCLUSIONS: Views and experiences of participating oncology health workers were characterized by a willingness to provide proper care for ethnic minority patients, but this was hampered by a tangle of interrelated issues such as linguistic barriers, fear and uncertainty, and assumptions about cultural matters. Organizational aspects were shown to be a strong influence on healthcare workers caring for ethnic minority patients. Due to methodological limitations of the included studies, conclusions should be viewed with caution. PMID- 26429359 TI - "Golden View" of the Porcine Wet Lab to Understand the Anatomy of the Mitral Valve by Transesophageal Echocardiography. PMID- 26429360 TI - Dexmedetomidine Attenuates Myocardial Injury in Off-Pump Coronary Artery Bypass Graft Surgery. AB - OBJECTIVE: To investigate the cardioprotective effect of the continuous administration of dexmedetomidine using serum cardiac troponin I (cTnI) and creatine kinase MB (CK-MB) concentrations as biomarkers during off-pump coronary artery bypass grafting (OPCAB) surgery. DESIGN: A prospective, randomized, parallel-group controlled study. SETTING: A university hospital. PARTICIPANTS: One hundred sixteen patients undergoing OPCAB surgery. INTERVENTIONS: Patients were divided randomly into 3 experimental groups that were separated by the dexmedetomidine administration protocol: a high-dose group (loading dose, 1 MUg/kg; maintenance dose, 0.6 MUg/kg/h); low-dose group (loading dose, 0.6 MUg/kg; maintenance dose, 0.3 MUg/kg/h); and control group (the same amount of 0.9% saline as placebo). Serum cTnI and CK-MB levels were measured before surgery and 24 hours and 48 hours after surgery. MEASUREMENTS AND MAIN RESULTS: Serum cTnI and CK-MB levels in patients of the high-dose group were less than those of the other 2 groups 48 hours after surgery. The administration of dexmedetomidine significantly decreased the heart rate. Compared with the control group, there was a significantly reduced requirement of sevoflurane in the other 2 groups (p<0.05). The intraoperative and postoperative cumulative volumes of urine output in the high-dose group were greater than those of the other 2 groups (p<0.05). The authors also found that the extubation time and length of stay in the intensive care unit were prolonged in the high-dose group. CONCLUSIONS: Myocardial damage was reduced by the administration of a 1 MUg/kg loading dose and a 0.6 MUg/kg/h infusion dose of dexmedetomidine. However, further studies are needed to understand the underlying mechanism and to confirm that high doses of dexmedetomidine could be administered safely in patients undergoing OPCAB surgery. PMID- 26429361 TI - Watermark Compression in Medical Image Watermarking Using Lempel-Ziv-Welch (LZW) Lossless Compression Technique. AB - In teleradiology, image contents may be altered due to noisy communication channels and hacker manipulation. Medical image data is very sensitive and can not tolerate any illegal change. Illegally changed image-based analysis could result in wrong medical decision. Digital watermarking technique can be used to authenticate images and detect as well as recover illegal changes made to teleradiology images. Watermarking of medical images with heavy payload watermarks causes image perceptual degradation. The image perceptual degradation directly affects medical diagnosis. To maintain the image perceptual and diagnostic qualities standard during watermarking, the watermark should be lossless compressed. This paper focuses on watermarking of ultrasound medical images with Lempel-Ziv-Welch (LZW) lossless-compressed watermarks. The watermark lossless compression reduces watermark payload without data loss. In this research work, watermark is the combination of defined region of interest (ROI) and image watermarking secret key. The performance of the LZW compression technique was compared with other conventional compression methods based on compression ratio. LZW was found better and used for watermark lossless compression in ultrasound medical images watermarking. Tabulated results show the watermark bits reduction, image watermarking with effective tamper detection and lossless recovery. PMID- 26429362 TI - Negotiation and Decision Making with Collaborative Software: How MarineMap 'Changed the Game' in California's Marine Life Protected Act Initiative. AB - Environmental managers and planners have become increasingly enthusiastic about the potential of decision support tools (DSTs) to improve environmental decision making processes as information technology transforms many aspects of daily life. Discussions about DSTs, however, rarely recognize the range of ways software can influence users' negotiation, problem-solving, or decision-making strategies and incentives, in part because there are few empirical studies of completed processes that used technology. This mixed-methods study-which draws on data from approximately 60 semi-structured interviews and an online survey--examines how one geospatial DST influenced participants' experiences during a multi-year marine planning process in California. Results suggest that DSTs can facilitate communication by creating a common language, help users understand the geography and scientific criteria in play during the process, aid stakeholders in identifying shared or diverging interests, and facilitate joint problem solving. The same design features that enabled the tool to aid in decision making, however, also presented surprising challenges in certain circumstances by, for example, making it difficult for participants to discuss information that was not spatially represented on the map-based interface. The study also highlights the importance of the social context in which software is developed and implemented, suggesting that the relationship between the software development team and other participants may be as important as technical software design in shaping how DSTs add value. The paper concludes with considerations to inform the future use of DSTs in environmental decision-making processes. PMID- 26429363 TI - Hydrological Responses to Land-Use Change Scenarios under Constant and Changed Climatic Conditions. AB - This study quantified the hydrological responses to land-use change scenarios in the upper and middle Heihe River basin (HRB), northwest China, under constant and changed climatic conditions by combining a land-use/cover change model (dynamic conversion of land use and its effects, Dyna-CLUE) and a hydrological model (soil and water assessment tool, SWAT). Five land-use change scenarios, i.e., historical trend (HT), ecological protection (EP), strict ecological protection (SEP), economic development (ED), and rapid economic development (RED) scenarios, were established. Under constant climatic condition, hydrological variations are only induced by land-use changes in different scenarios. The changes in mean streamflow at the outlets of the upper and the middle HRB are not pronounced, although the different scenarios produce different outcomes. However, more pronounced changes are observed on a subbasin level. The frequency of extreme flood is projected to decrease under the SEP scenario, while under the other scenarios, no changes can be found. Two emission scenarios (A1B and B1) of three general circulation models (HadCM3, CGCM3, and CCSM3) were employed to generate future possible climatic conditions. Under changed climatic condition, hydrological variations are induced by the combination of land-use and climatic changes. The results indicate that the impacts of land-use changes become secondary when the changed climatic conditions have been considered. The frequencies of extreme flood and drought are projected to decrease and increase, respectively, under all climate scenarios. Although some agreements can be reached, pronounced difference of hydrological responses can be observed for different climate scenarios of different GCMs. PMID- 26429364 TI - A Systematic Review of Acquired Left Ventricle to Right Atrium Shunts (Gerbode Defects). PMID- 26429365 TI - Applying Evidence-Based Medicine in Actual Clinical Practice: Can We Bridge the Gap? A Review of the Literature. PMID- 26429366 TI - Parenteral Anticoagulants in Acute Coronary Syndromes and Interventional Cardiology: A Consensus Document. PMID- 26429367 TI - Evaluation of Oxidative Stress Markers and Catecholamine Changes in Patients with Dilated Cardiomyopathy Before and After Cardiopulmonary Exercise Testing. AB - INTRODUCTION: The aim of this study was to evaluate oxidative stress markers (OSM) and catecholamine levels in patients with dilated cardiomyopathy (DCM) before and after cardiopulmonary exercise testing, and to investigate the association between changes in these markers and the New York Heart Association classification (NYHA) and left ventricular ejection fraction (LVEF) in these patients. METHODS: We evaluated 74 patients with DCM and 80 control subjects without DCM. Patients were grouped according to NYHA stages I/II or III/IV. Eligible participants were considered to be those with LVEF values <45%. The OSM analysed included superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPX). The catecholamines analysed included adrenaline, noradrenaline, and dopamine. Vitamin C was also evaluated. All values were obtained before and after cardiopulmonary exercise testing. RESULTS: There was a significant increase in GR, adrenaline, and noradrenaline after testing in the DCM patients. A significant difference between controls and patients in CAT and evaluated catecholamines was observed after testing. A significant increase in GR, GPX, adrenaline, and noradrenaline for patients in NYHA I/ II, and in CAT, GR, adrenaline, noradrenaline, and dopamine for patients in NYHA III/IV, was found between the different times of observation. LVEF before testing showed a significant positive correlation with GPX, and a negative correlation with noradrenaline and adrenaline. After testing a significant negative correlation was found with SOD and GR. CONCLUSIONS: The results of our study demonstrate the complexity of the neurohumoral mechanisms and physiological alterations in the failing heart in DCM patients. Further studies are needed, including other biomarkers and larger samples of patients, in order to improve our understanding of the aetiopathogenesis of DCM development and progression. PMID- 26429368 TI - Studying Systemic Oxidative Stress in Heart Failure: Does It Have Any Role in Clinical Practice? PMID- 26429370 TI - Rheumatoid Arthritis and Atherosclerosis: Could Common Pathogenesis Translate Into Common Therapies? PMID- 26429369 TI - Effect of Long-Term TNF-alpha Inhibition with Infliximab on Left Ventricular Torsion in Patients with Rheumatoid Arthritis. AB - INTRODUCTION: We evaluated the impact of tumor necrosis factor alpha (TNF-alpha) inhibition on left ventricular torsion (LVtor) in patients with rheumatoid arthritis (RA) using speckle-tracking echocardiography (STE). METHODS: Thirty eight RA patients without cardiovascular disease and 30 healthy subjects were enrolled in the study. Twenty patients received infliximab, a monoclonal antibody against TNF-alpha, and 18 patients received increasing doses of prednisolone for 180 days. Global systolic longitudinal strain (G-LS), global systolic radial strain (G-RS) and global systolic circumferential strain (G-CS) were determined by STE. LV basal and apical rotations from the base and apex were obtained and used for calculation of LVtor. Pre-treatment LVtor levels were compared with LVtor levels after therapy in both treatment groups. RESULTS: RA patients had lower G-LS (-16.5 +/- 2.9; p<0.01), G-RS (37.6 +/- 1.5; p<0.01) and higher GCS ( 23.6 +/- 3.5; p=0.04) compared with control subjects (-20.0 +/- 2.8, 40.7 +/- 4.8, -22.4 +/- 2.5, respectively; p<0.01). LVtor levels were significantly higher in RA patients compared to controls (16.4 +/- 2.7 vs. 15.1 +/- 2.5; p=0.04), which might be attributed to higher values of apical rotation (9.7 +/- 2.4 vs. 8.8 +/- 2.3; p=0.01). Patients treated with infliximab experienced a significant decrease in LVtor (p=0.04), and a significant increase in G-LS (p<0.01) and G-RS (p<0.01). No significant changes were observed among patients treated with prednisolone. Percentage changes in LVtor were correlated with percent changes in C-reactive protein CRP (r=0.58; p<0.01), disease activity score (r=0.78; p<0.01), and G-LS (r=-0.40; p=0.04) in patients treated with infliximab. CONCLUSIONS: RA is characterized by increased LVtor. Long term TNF-alpha inhibition improves LV longitudinal and radial systolic deformation and decreases LVtor. PMID- 26429371 TI - Aortic Flow Patterns After Simulated Implantation of Transcatheter Aortic Valves. AB - INTRODUCTION: The functional behavior and hemodynamic characteristics of percutaneously implanted bioprosthetic valves are not known. METHODS: We created aortic models after the simulated implantation of two of the most widely used bioprosthetic valves: the Edwards SAPIEN, and the Medtronic CoreValve. By using computational fluid dynamics analysis we sought to investigate variations in the aortic flow patterns induced by the two valve designs and their association with detrimental phenomena such as vascular remodeling, vascular wall damage and thrombosis. RESULTS: The simulated implantation of models that resemble the two valves resulted in different aortic flow conditions. Vortex formation in the upper ascending aorta was more persistent in the case of the simulated Medtronic valve. The ranges of average wall shear stress (WSS) values were 2.4-3.5 Pa for Edwards and 3.0-5.3 Pa for Medtronic; the calculated WSS values induced endothelial quiescence and an atheroprotective setting in both valves. The average shear stress on the simulated valve leaflets was low; however, hotspots were present in both valves (155.0 Pa for Edwards and 250.0 Pa for Medtronic) which would in theory be able to cause platelet activation and thus promote thrombosis. The pressure drops along the aorta were slightly lower for the Edwards compared to the Medtronic valve (198.0 Pa versus 218.0 Pa). CONCLUSIONS: The presented method allows the assessment of aortic flow conditions following the implantation of bioprosthetic valves. It may be useful in predicting detrimental flow phenomena, thus facilitating the selection of appropriate valve designs. PMID- 26429372 TI - Are All Valves for All Aortas? PMID- 26429373 TI - Fatty Myocardial Foci in Tuberous Sclerosis. PMID- 26429374 TI - Myocardial Ischemia as an Indication for Surgical Intervention in Sinus Valsalva Aneurysm. PMID- 26429375 TI - Percutaneous Transvenous Retrieval of Intracardiac Port-A Catheter Using a Snare. PMID- 26429376 TI - Giant Unruptured Left Sinus of Valsalva Aneurysm as an Unusual Cause of Ischemic Heart Failure. PMID- 26429377 TI - A Rare Case of Angiosarcoma of the Left Ventricle Detected by Cardiac Magnetic Resonance Imaging. PMID- 26429378 TI - Acute Coronary Syndromes and Anaemia. PMID- 26429379 TI - The Need for More Research in Europe. PMID- 26429380 TI - The state of critical care nursing education in Europe: an international survey. PMID- 26429381 TI - Effects of a rapid infusion of 20% human serum albumin solution on acid-base status and electrolytes in critically ill patients. PMID- 26429382 TI - A new definition of biological effective dose: The dose distribution effects. AB - A new biological effective dose (BED) is proposed in this note. This new BED definition takes into account the fact that dose distribution is non-uniform for tumors in patients' treatments. This new BED can be calculated from the dose distribution within a tumor, making it practical and useful for clinical applications. PMID- 26429383 TI - GafChromic((r)) EBT3 films for patient specific IMRT QA using a multichannel approach. AB - PURPOSE: To evaluate EBT3 for pre-treatment patient specific quality assurance (QA). The method we propose combines the experience gained in our center with the guidelines of the protocol proposed by Lewis et al. in 2012. To compare the multichannel approach with the single channel dosimetry. METHODS: Gafchromic(r) EBT3 films were irradiated both at linac and TomoTherapy and calibration curves were obtained. A series of irradiations with simple fields (uniform dose distributions on regular shaped targets) was performed. In a second stage, films were exposed to full clinical plans at linac (step and shoot IMRT and VMAT). At TomoTherapy dose maps were obtained for a clinical plan in three different coronal planes. Films were digitized using an Epson 10000XL scanner and FilmQATM Pro software was employed for the analysis. RESULTS: The measured calibration curves suggest that, at least for the two beams taken into account (6 MV linac and TomoTherapy), a single calibration can be successfully adopted for each film lot. The application of the multichannel optimization method strongly improves the results in terms of gamma passing rates of the comparison between measured and calculated maps. CONCLUSIONS: Up to now EBT films, although attractive, were not preferred for routine patient specific QA due to their complex and time consuming processing and to the challenging work of characterization. The application of the mentioned protocol, together with some additional precautions, and the adoption of the multichannel optimization dosimetry, make this detector a handy and reliable tool for patient specific QA. PMID- 26429384 TI - Sensitivity of a helical diode array dosimeter to Volumetric Modulated Arc Therapy delivery errors. AB - PURPOSE: To study the sensitivity of an ArcCHECK dosimeter in detecting delivery errors during the delivery of Volumetric Modulated Arc Therapy (VMAT). METHODS: Three types of errors in Multi Leaf Collimator (MLC) position and dose delivery were simulated separately in the delivery of five prostate and five head and neck (H&N) VMAT plans: (i) Gantry independent: a systematic shift in MLC position and variation in output to the whole arc; (ii) Gantry dependent: sag in MLC position and output variation as a function of gantry angle; (iii) Control point specific MLC and output errors introduced to only a specific number of Control Points (CP). The difference in local and global gamma (gamma) pass rate between the no error and error-simulated measurements with 2%/2 mm and 3%/3 mm tolerances was calculated to assess the sensitivity of ArcCHECK. The clinical impact of these errors was also calculated. RESULTS: ArcCHECK was able to detect a minimum 3 mm MLC error and 3% output error for Gantry independent errors using either local or global gamma with 2%/2 mm tolerance. For the Gantry dependent error scenario a minimum 3 mm MLC error and 3% dose error was identifiable by ArcCHECK using either global or local gamma with 2%/2 mm tolerance. In errors introduced to specific CPs a MLC error of 10 mm and dose error of 100% introduced to 4CPs were detected by ArcCHECK. CONCLUSION: ArcCHECK used with either local or global gamma analysis and 2%/2 mm criteria can be confidently used in the clinic to detect errors above the stated error values. PMID- 26429385 TI - Semi-automatic 3D segmentation of carotid lumen in contrast-enhanced computed tomography angiography images. AB - The atherosclerosis disease is one of the major causes of the death in the world. Atherosclerosis refers to the hardening and narrowing of the arteries by plaques. Carotid stenosis is a narrowing or constriction of carotid artery lumen usually caused by atherosclerosis. Carotid artery stenosis can increase risk of brain stroke. Contrast-enhanced Computed Tomography Angiography (CTA) is a minimally invasive method for imaging and quantification of the carotid plaques. Manual segmentation of carotid lumen in CTA images is a tedious and time consuming procedure which is subjected to observer variability. As a result, there is a strong and growing demand for developing computer-aided carotid segmentation procedures. In this study, a novel method is presented for carotid artery lumen segmentation in CTA data. First, the mean shift smoothing is used for uniformity enhancement of gray levels. Then with the help of three seed points, the centerlines of the arteries are extracted by a 3D Hessian based fast marching shortest path algorithm. Finally, a 3D Level set function is performed for segmentation. Results on 14 CTA volumes data show 85% of Dice similarity and 0.42 mm of mean absolute surface distance measures. Evaluation shows that the proposed method requires minimal user intervention, low dependence to gray levels changes in artery path, resistance to extreme changes in carotid diameter and carotid branch locations. The proposed method has high accuracy and can be used in qualitative and quantitative evaluation. PMID- 26429386 TI - A new method to evaluate the residual activity in patients undergoing (131)I thyroid therapy. AB - The radioiodine administration is a standard therapeutic approach to both benign thyroid diseases, such as hyperthyroidism, and carcinomas. The high administered (131)I activities are of radiation protection concern, due to relevant patient residual contamination. The aim of this work was to develop a new procedure based on external radiometric surveys and on a mathematical model in order to estimate the (131)I activity in patients undergoing hyperthyroidism radioiodine therapy. In the first stage of this study, a suitable detector was chosen and its response vs. activity was characterized. The experimental verification was performed measuring the ambient dose equivalent rate from patients receiving radioiodine administration. The results confirm the reliability of the proposed method, as shown by the slight differences between the administered activities and the ones calculated from external measurements. Furthermore, the same procedure was applied to detect the percentage residual activity in patients at two preset time intervals: 4 hours and 4 days after the radioiodine administration. The obtained results clearly highlight that the method can ensure a level of reliability compatible with the radiation protection purposes. PMID- 26429388 TI - [The added value of robotic surgery]. AB - Robotic surgery has recently emerged as a feasible alternative to open and laparoscopic procedures for the treatment of many urological diseases. The use of robotics allows the surgeon to overcome the limitations of standard laparoscopy while maintaining the advantages of a minimally invasive approach. Robotic assisted radical prostatectomy is the most frequent surgery performed robotically, resulting in better functional outcomes and comparable oncological results with respect to open surgery. Given its advantages, the indications for robotic surgery have progressively extended to different fields, and there is increasing evidence for its effectiveness in high-risk prostate cancer, bladder cancer, kidney cancer, and adrenal disease. Based on the available evidence in the literature, robotic surgery should be considered a viable option for the treatment of many urological conditions, with the final aim of optimizing patients' outcomes. PMID- 26429387 TI - Transposable elements and early evolution of sex chromosomes in fish. AB - In many organisms, the sex chromosome pair can be recognized due to heteromorphy; the Y and W chromosomes have often lost many genes due to the absence of recombination during meiosis and are frequently heterochromatic. Repetitive sequences are found at a high proportion on such heterochromatic sex chromosomes and the evolution and emergence of sex chromosomes has been connected to the dynamics of repeats and transposable elements. With an amazing plasticity of sex determination mechanisms and numerous instances of independent emergence of novel sex chromosomes, fish represent an excellent lineage to investigate the early stages of sex chromosome differentiation, where sex chromosomes often are homomorphic and not heterochromatic. We have analyzed the composition, distribution, and relative age of TEs from available sex chromosome sequences of seven teleost fish. We observed recent bursts of TEs and simple repeat accumulations around young sex determination loci. More strikingly, we detected transposable element (TE) amplifications not only on the sex determination regions of the Y and W sex chromosomes, but also on the corresponding regions of the X and Z chromosomes. In one species, we also clearly demonstrated that the observed TE-rich sex determination locus originated from a TE-poor genomic region, strengthening the link between TE accumulation and emergence of the sex determination locus. Altogether, our results highlight the role of TEs in the initial steps of differentiation and evolution of sex chromosomes. PMID- 26429389 TI - [Robotic surgery in urology: the Italian contribution]. AB - The introduction of robotic technology has given a major boost to the urologic surgery by expanding the indications of minimally-invasive surgery. The Italian urological community has played a major role in this revolution, by contributing to the development and dissemination of technological innovation in urology, with several key publications stemming from this research. The most important revolution has been observed in radical prostatectomy, with robotic technology allowing to achieve better functional results. Nephron-sparing surgery has also been expanded, and leading Italian centers are being involved in international research groups focused on these topics. Major impact has been observed for pyeloplasty, where Italy has been a leader in the field with the introduction of robot-assisted single-site technique. In summary, the advent of robotics has improved collaborations between Italy and other Countries, with increased scientific activity, continuous improvement of surgical techniques and effective training of young urologists. PMID- 26429390 TI - [Positive surgical margin status after minimally invasive radical prostatectomy: a multicenter study]. AB - UNLABELLED: The aim of our study is to evaluate the status of positive margins (PSMs) comparing their incidence between aparoscopic radical prostatectomy (LRP) and robot assisted radical prostatectomy (RARP) in centers with medium case-load (50-150 cases/year). We also analyzed the correlations between surgical technique, nerve-sparing approach (NS), and incidence of PSMs, stratifying our results by pathological stage. MATERIALS AND METHODS: We analyzed 1992 patients who underwent RP in various urologic centers. We evaluated the incidence of PSMs, and then we compared the stage-related incidence of PSMs, for both the techniques. RESULTS: We did not find a statistically significant difference between the two surgical modalities in the study regarding the overall incidence of PSMs. CONCLUSIONS: In our retrospective study, we did not find any difference in terms of PSMs in RARP versus LRP. Our PSMs were not negligible, particularly in pT3 stages, compared with high-volume centers; surgical experience and patients' selection can be a possible explanation. PMID- 26429391 TI - [Current status of robotic urologic surgery in Italy]. AB - The introduction of robot-assisted surgery represents a milestone in the history of surgery. Today, many surgical disciplines make use of the DaVinci robotic system in performing surgery, even complex ones. Italy stands as one of the countries with a greater diffusion of robotics in surgery, particularly in urological surgery. In Italy, every year, numerous urological surgeries are performed with the DaVinci robot; however, costs of this technology are high and, although likely to decrease, constitute a limit to the spread of the same and restricting its use to shared areas. PMID- 26429392 TI - [The robotic surgeon training]. AB - The widespread robotic surgery in the world highlighted the relevance of the training programs for young urologists and residents. In the last years, urologic societies and some independent robotic surgeons strongly worked to standardize some general and specific training modules. Theoretical and practical sections of robotic training programs have been recently specified. The role of simulators, dry and wet laboratories, bedside assistance, and modular (step-by-step) training at console represent the most relevant elements of robotic surgeon training. Ideally, these didactic tools should be available in modern training centers. The development of structured robotic training programs should be considered as one of the priorities that the urologic community must take into account in the near future. PMID- 26429393 TI - Survival in Patients with Advanced Non-cystic Fibrosis Bronchiectasis Versus Cystic Fibrosis on the Waitlist for Lung Transplantation. AB - BACKGROUND: Survival in non-cystic fibrosis (CF) bronchiectasis is not well studied. METHODS: The United Network for Organ Sharing database was queried from 1987 to 2013 to compare survival in adult patients with non-CF bronchiectasis to patients with CF listed for lung transplantation (LTx). Each subject was tracked from waitlist entry date until death or censoring to determine survival differences between the two groups. RESULTS: Of 2112 listed lung transplant candidates with bronchiectasis (180 non-CF, 1932 CF), 1617 were used for univariate Cox and Kaplan-Meier survival function analysis, 1173 for multivariate Cox models, and 182 for matched-pairs analysis based on propensity scores. Compared to CF, patients with non-CF bronchiectasis had a significantly lower mortality by univariate Cox analysis (HR 0.565; 95 % CI 0.424, 0.754; p < 0.001). Adjusting for potential confounders, multivariate Cox models identified a significant reduction in risk for death associated with non-CF bronchiectasis who were lung transplant candidates (HR 0.684; 95 % CI 0.475, 0.985; p = 0.041). Results were consistent in multivariate models adjusting for pulmonary hypertension and forced expiratory volume in one second. CONCLUSIONS: Non-CF bronchiectasis with advanced lung disease was associated with significantly lower mortality hazard compared to CF bronchiectasis on the waitlist for LTx. Separate referral and listing criteria for LTx in non-CF and CF populations should be considered. PMID- 26429394 TI - Knockdown of AKR1C3 exposes a potential epigenetic susceptibility in prostate cancer cells. AB - BACKGROUND: The aldo-keto reductase 1C3 (AKR1C3) has been heavily implicated in the propagation of prostate malignancy. AKR1C3 protein is elevated within prostate cancer tissue, it contributes to the formation of androgens and downstream stimulation of the androgen receptor (AR). Elevated expression of AKR1C3 is also reported in acute myeloid leukemia but the target nuclear receptors have been identified as members of the peroxisome-proliferator activated receptor (PPARs) subfamily. Thus, AKR1C3 cancer biology is likely to be tissue dependent and hormonally linked to the availability of ligands for both the steroidogenic and non-steroidogenic nuclear receptors. METHODS: In the current study we investigated the potential for AKR1C3 to regulate the availability of prostaglandin-derived ligands for PPARg mainly, prostaglandin J2 (PGJ2). Using prostate cancer cell lines with stably reduced AKR1C3 levels we examined the impact of AKR1C3 upon proliferation mediated by PPAR ligands. RESULTS: These studies revealed knockdown of AKR1C3 had no effect upon the sensitivity of androgen receptor independent prostate cancer cells towards PPAR ligands. However, the reduction of levels of AKR1C3 was accompanied by a significantly reduced mRNA expression of a range of HDACs, transcriptional co regulators, and increased sensitivity towards SAHA, a clinically approved histone deacetylase inhibitor. CONCLUSIONS: These results suggest a hitherto unidentified link between AKR1C3 levels and the epigenetic status in prostate cancer cells. This raises an interesting possibility of a novel rational to target AKR1C3, the utilization of AKRIC3 selective inhibitors in combination with HDAC inhibition as part of novel epigenetic therapies in androgen deprivation therapy recurrent prostate cancer. PMID- 26429395 TI - Adipose-specific Vdr deletion alters body fat and enhances mammary epithelial density. AB - Vitamin D status has been associated with obesity, metabolic syndrome and several cancers including colon and breast. Since adipocytes express VDR and obesity is a known risk factor for cancer, vitamin D actions in adipose tissue may contribute to its cancer protective effects. In the mammary gland, signaling from adipocytes to epithelial cells is necessary for breast cancer initiation, but the impact of vitamin D on this cross-talk is unclear. To examine the role of VDR in adipose tissue, particularly in the context of the mammary gland, we crossed Vdr-flox mice with Fabp4-cre mice to generate mice with adipose-specific Vdr deletion (termed CVF mice). CVF mice and Fabp4-cre control mice (termed CN1 mice) were reared on high calcium "rescue" diets (for comparison to global VDRKO mice) or on high fat diets (to stimulate adiposity). Vdr expression was significantly reduced in adipose tissue of CVF mice compared to CN1 mice. In contrast to global VDRKO mice (which exhibit adipose atrophy), female CVF mice exhibited higher growth rates and increased visceral fat pad weight compared to control mice. Expression of Ucp1 and Pparg were elevated in white adipose tissue of CVF mice supporting these genes as Vdr targets in mature adipocytes. Adipose-specific Vdr deletion did not impair glucose tolerance or alter the weight of brown adipose tissue, liver, pancreas or bone in response to high fat feeding. In contrast to the effect of adipose-specific Vdr deletion on visceral fat pads, the weight of the subcutaneous (mammary) fat pad was not increased in high fat fed CVF female mice compared to control mice. Quantitative analysis of mammary ductal development on whole mounts and H&E stained sections indicated that adipose-deletion of Vdr significantly enhanced mammary epithelial density and branching. Collectively, these data support the hypothesis that Vdr in mature adipocytes alters the metabolic response to high fat diets and exerts anti-proliferative effects on the mammary epithelium. PMID- 26429396 TI - Biological evaluation of new vitamin D2 analogues. AB - 1,25-dihydroxyvitamin D3 (1,25D), a steroid hormone which regulates calcium/phosphate homeostasis, has a broad spectrum of anti-cancer activities, including differentiation of acute myeloid leukemia (AML) cells. In order to avoid undesirable side effects such as hypercalcemia, low-calcemic analogues should be produced for therapeutic purposes. In this paper, we describe biological activities of double-point modified analogues of vitamin D2 and we compare them to 1,25D and to paricalcitol, the drug used to treat secondary hyperparathyroidism. In vivo, our new analogues have lower calcemic effects, and lower toxicity in comparison to 1,25D. They have enhanced pro-differentiating and transcription-inducing activities in AML cells. Interestingly, differentiation effects do not correlate with the affinities of the analogues to the vitamin D receptor (VDR). PMID- 26429397 TI - Amplification of lipotoxic cardiomyopathy in the VDR gene knockout mouse. AB - Previous studies demonstrated that the liganded vitamin D receptor (VDR) plays an important role in controlling cardiovascular homeostasis. Both the whole animal VDR gene knockout (VDR-/-) and the myocyte-specific VDR gene deletion result in changes in cardiac structure and function. Clinical states associated with cardiac steatosis (obesity and diabetes mellitus) are also associated with low circulating 25 OH vitamin D levels. We, therefore, examined the effects of VDR deficiency (VDR-/- mouse) in a murine model of cardiac steatosis that expresses the terminal enzyme involved in triglyceride synthesis, diacylglycerol acyltransferase 1 (DGAT1), selectively in the cardiac myocyte. These mice display early cardiac dysfunction and late cardiomyopathy and heart failure. In the present study, we demonstrate that mice harboring both genetic modifications (i.e., MHC-DGAT1 Tg and VDR-/-) exhibit an increase in myocyte size, heart weight/body weight ratio and natriuretic peptide gene expression, all markers of cardiac hypertrophy, that exceed that seen in either VDR-/- or the MHC-DGAT1 Tg mice alone. This was accompanied by a dramatic increase in interstitial fibrosis and increased expression of collagen 1a1 and collagen 3a1, as well as the osteopontin and matrix metalloproteinase 2, genes. At a functional level, this resulted in a 37% reduction in ejection fraction and 55% reduction in fractional shortening in the DGAT1; VDR-/- mice relative to the controls. Collectively, these data demonstrate that deficiency in the vitamin D signaling system enhances the pathological phenotype in this experimental cardiomyopathy and suggest an important role for vitamin D in modulating disease severity in common cardiovascular disorders. PMID- 26429398 TI - St. Gallen endocrine response classes predict recurrence rates over time. AB - BACKGROUND: In 2007 the St. Gallen consensus panel defined three endocrine response classes: highly endocrine responsive (ER-H), incomplete endocrine responsive (ER-I) and non-endocrine responsive tumours (ER-N). However, it is uncertain whether ER-I tumours are less responsive than ER-H tumours. We investigated whether recurrence rates vary over time between response classes. Additionally, we investigated the most predictive response class definition for tamoxifen benefit. PATIENTS AND METHODS: We recollected tumours from 646 patients who participated in a randomized trial of adjuvant tamoxifen vs. OBSERVATION: Estrogen receptor (ER), progesterone receptor (PgR), HER2 status and tumour grade were revised centrally. St. Gallen classes were evaluated for recurrence free interval (RFI). Change in hazards over time was assessed. Subsequently, 6 alternative response class definitions were compared to optimize the cut-off for PgR and ER. RESULTS: Schoenfeld residuals indicate a failure of proportional hazards between the endocrine response groups (p = 0.0001). The HR for recurrence risk shifted over time with the ER-H group initially being at lower risk (HR ER-H vs. ER-I 0.5), but after six years the recurrence risk increased (HR 1.9). The cut-off values for ER and PgR that statistically best discriminated RFI in the first 4 years for lymph node positive patients were ER >= 50% and PgR >= 75%. CONCLUSION: We demonstrated a marked variability in endocrine therapy benefit. Patients with ER-H tumours have a larger benefit during adjuvant tamoxifen and in the first years after accomplishing of the therapy, but suffer from late recurrences. This might have implications for optimal treatment duration. PMID- 26429399 TI - Technical innovation in adjuvant radiotherapy: Evolution and evaluation of new treatments for today and tomorrow. AB - Recent innovations in breast cancer radiotherapy include intensity modulated radiotherapy, brachytherapy and intraoperative radiotherapy and current trials are seeking to evaluate their value in optimizing local control while maintaining cosmetic effects. Future clinical dividends in local control and survival may come from the identification of molecular signatures of breast cancer radiosensitivity, the development of predictive signatures and identification of immunohistochemical markers of risk of local recurrence. The importance of tumour heterogeneity is being increasingly recognized as an important factor in determining radiotherapy response and an improved understanding of the biology of the tumour microenvironment may identify targets that allow enhanced radiosensitisation or reversal of radioresistance when inhibited. This review describes recent developments in these areas. PMID- 26429400 TI - Should we offer prenatal testing for 17q12 microdeletion syndrome to all cases with prenatally diagnosed echogenic kidneys? Prenatal findings in two families with 17q12 microdeletion syndrome and review of the literature. AB - OBJECTIVE: The objective of this study is to report the prenatal ultrasound scan findings in four fetuses from two families postnatally diagnosed with 17q12 microdeletion syndrome on microarray CGH and review the literature. METHODS: We report two families presenting with prenatally detected hyperechogenic kidneys. In family 1, the mother had three pregnancies complicated by anhydramnios with bilateral hyperechogenic kidneys, hyperechogenic enlarged cystic kidneys, and bilateral hyperechogenic kidneys with polyhydramnios respectively. In family 2, prenatal ultrasound scans detected hyperechogenic kidneys. A pubmed search for all reported cases of 17q12 deletion between 2005 and 2015 was performed. All publications were reviewed, and findings summarised. RESULTS: Fourteen publications were deemed suitable for literature review; there was a diagnosis of 17q12 deletion with documented prenatal findings in 25 cases. Prenatal renal anomalies were reported in 88% of these cases. Anomalies were documented from 15 weeks, and most common presentation was hyperechogenic, muticystic, or enlarged kidneys. Both oligohydramnios and polyhydramnios were seen. Postnatal renal ultrasound scan findings were of muticystic or multicystic dysplastic kidney. There did not appear to be correlation of prenatal presentation and severity of renal disease. CONCLUSION: Prenatal testing should be offered to all cases of hyperechogenic kidneys, with unknown cause. PMID- 26429401 TI - Cardiovascular disease and mortality in patients with type 2 diabetes after bariatric surgery in Sweden: a nationwide, matched, observational cohort study. AB - BACKGROUND: In patients with diabetes and obesity specifically, no studies have examined mortality after bariatric surgery. We did a nationwide study in Sweden to examine risks of cardiovascular disease and mortality in patients with obesity and diabetes who had undergone bariatric surgery (Roux-en-Y gastric bypass [RYGB]). METHODS: In this nationwide, matched, observational cohort study, we merged data for patients who had undergone RYGB registered in the Scandinavian Obesity Surgery Registry with other national databases, and identified matched controls (on the basis of sex, age, BMI, and calendar time [year]) who had not undergone bariatric surgery from the National Diabetes Registry. We assessed risks of cardiovascular disease and death using a Cox proportional-hazards regression model and other methods to examine the treatment effect while accounting for residual confounding. Primary outcomes were total mortality, cardiovascular death, and fatal or non-fatal myocardial infarction. FINDINGS: Between Jan 1, 2007, and Dec 31, 2014, we obtained data for 6132 patients who had undergone RYGB and 6132 control patients who had not. Median follow-up was 3.5 years (IQR 2.1-4.7). We noted a 58% relative risk reduction (hazard ratio [HR] 0.42, 95% CI 0.30-0.57; p<0.0001) in overall mortality in the RYGB group compared with the controls. The risk of fatal or non-fatal myocardial infarction was 49% lower (HR 0.51, 0.29-0.91; p=0.021) and that of cardiovascular death was 59% lower (0.41, 0.19-0.90; p=0.026) in the RYGB group than in the control group. 5 year absolute risks of death were 1.8% (95% CI 1.5-2.2) in the RYGB group and 5.8% (5.0-6.8) in the control group. INTERPRETATION: Our findings provide support for the benefits of RYGB surgery for patients with obesity and type 2 diabetes. The causes of these beneficial effects may be the weight reduction per se, changes in physiology and metabolism, improved care and treatment, improvements in lifestyle and risk factors, or combinations of these factors. FUNDING: Swedish Association of Local Authorities and Regions and Region Vastra Gotaland. PMID- 26429403 TI - Weight loss surgery and cardiovascular risk and mortality in patients with type 2 diabetes. PMID- 26429402 TI - Reduction of cardiovascular risk in chronic kidney disease by mineralocorticoid receptor antagonism. AB - Cardiovascular disease is the leading cause of death and morbidity in people with chronic kidney disease, but there are few evidence-based treatments for reducing cardiovascular events in these patients. The failure of novel drug candidates to delay progression to end-stage renal disease and limit or abrogate cardiovascular morbidity and mortality has led to increased interest in a mineralocorticoid receptor (MR) antagonist-based treatment model to reduce cardiovascular risk in patients with chronic kidney disease and end-stage renal disease. Aldosterone concentrations and MR signalling are associated with an enhanced risk of cardiovascular injury and the incidence of sudden death, and MR blockade decreases the risk of cardiovascular events and sudden death in patients with reduced glomerular filtration rate. Since evidence from clinical trials shows that treatment with MR antagonists confers a morbidity and mortality advantage for patients with cardiovascular disorders, similar benefits might also accrue in patients with chronic kidney disease. Large prospective trials are urgently needed to answer this question. In this Review, I argue that despite differences in the pathophysiology and clinical features of cardiovascular disease in patients with and without chronic kidney disease, MR antagonists could provide cardiovascular benefit in patients with chronic kidney disease. PMID- 26429404 TI - Dead Space Management After Orthopaedic Trauma: Tips, Tricks, and Pitfalls. AB - Dead space is defined as the residual tissue void after tissue loss. This may occur due to tissue necrosis after high-energy trauma, infection, or surgical debridement of nonviable tissue. This review provides an update on the state of the art and recent advances in the management of osseous and soft tissue defects. Specifically, our focus will be on the initial dead space assessment, provisional management of osseous and soft tissue defects, techniques for definitive reconstruction, and dead space management in the setting of infection. LEVEL OF EVIDENCE: Therapeutic Level V. See Instructions for Authors for a complete description of levels of evidence. PMID- 26429405 TI - Significant differences between local reporting and central assessment of radiological complications in a prospective, multicenter study about locking plate fixation of proximal humerus fractures. AB - OBJECTIVES: To compare radiological complication reporting outcomes undertaken by an independent review board and the responsible on-site study personnel in a multicenter study about locking plate fixation of proximal humeral fractures. DESIGN: prospective, multicenter study SETTING:: Level I trauma centers PATIENTS:: One-hundred and fifty patients with a radiological confirmed, closed, displaced proximal humeral fracture fixed with a locking plate and aged between fifty and ninety years. INTERVENTION: Re-evaluation of all radiological data according to pre-defined criteria after finished collection of all study radiographs by an independent review board. MAIN OUTCOME MEASUREMENTS: Differences in outcomes between the review board and the sites assessment were tested with a paired t-test. Inter-rater agreements between the central review board and sites assessments were estimated by means of kappa statistics. RESULTS: The review board revealed significant more radiological complications than the sites assessment (p = 0.006), except for the complication 'head necrosis'. The inter-rater agreement was slight to moderate in all calculated categories. CONCLUSIONS: To prevent underreporting of radiological complications by on-site assessment, the implementation of a complication review board, using pre-defined criteria, is recommended for clinical studies that focus on radiological complications. PMID- 26429406 TI - What Is the Role of Vitamin D Supplementation in Acute Fracture Patients? A Systematic Review and Meta-Analysis of the Prevalence of Hypovitaminosis D and Supplementation Efficacy. AB - OBJECTIVES: The objectives of this systematic review and meta-analyses are (1) to estimate the prevalence of hypovitaminosis D in fracture patients and (2) to summarize the available evidence on the efficacy of vitamin D supplementation in fracture patients. DATA SOURCES: A comprehensive search of the MEDLINE, Embase, PubMed, and Cochrane Central Register of Controlled Trials databases was conducted. Conference abstracts from relevant meetings were also searched. STUDY SELECTION: We included studies that investigate vitamin D insufficiency or examine the effect of vitamin D supplementation on 25-hydroxy-vitamin D (25(OH)D) serum levels in fracture patients. DATA EXTRACTION: Two authors independently extracted data using a predesigned form. DATA SYNTHESIS: We performed a pooled analysis to determine the prevalence of postfracture hypovitaminosis D and mean postfracture 25(OH)D levels. We present detailed summaries of each of the studies evaluating the impact of vitamin D supplementation. RESULTS: The weighted pooled prevalence of hypovitaminosis D was 70.0% (95% confidence interval: 63.7%-76.0%, I = 97.7). The mean postfracture serum 25(OH)D was 19.5 ng/mL. The studies that evaluated the efficacy of vitamin D supplementation suggest that vitamin D supplementation safely increases serum 25(OH)D levels. Only 1 meeting abstract showed a trend toward reduced risk of nonunion after a single large loading dose of vitamin D. CONCLUSIONS: This review found a high prevalence of hypovitaminosis D in fracture patients and that vitamin D supplementation at a range of doses safely increases 25(OH)D serum levels. To date, only 1 pilot study published as a meeting abstract has demonstrated a trend toward improved fracture healing with vitamin D supplementation. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 26429407 TI - Surgical Treatment of Femoral Neck Fractures After 24 Hours in Patients Between the Ages of 18 and 49 Is Associated With Poor Inpatient Outcomes: An Analysis of 1361 Patients in the National Trauma Data Bank. AB - OBJECTIVE: To determine (1) the incidence of delayed surgical treatment, (2) risk factors associated with delayed surgical intervention, (3) inpatient adverse events and discharge disposition, and (4) the association of delayed surgery with inpatient adverse events. DESIGN: Retrospective cohort study. SETTING: 2011 and 2012 National Trauma Data Bank. PATIENTS/PARTICIPANTS: All adult patients younger than 50 years of age with femoral neck fractures. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: (1) Time to surgical intervention after inpatient admission, (2) odds ratio (OR) for delayed surgery (later than 24 hours after admission), (3) incidence of inpatient adverse events and discharge disposition, (3) rates of inpatient adverse events and discharge disposition, and (4) OR for occurrence of serious adverse events, minor adverse events, and any adverse events. RESULTS: Of a total of 1361 patients, 67.8% of patients underwent surgery within 24 hours of presentation. In multivariate analysis (controlling for patient and injury characteristics), Charlson comorbidity index of 3+ compared with Charlson comorbidity index of 0 (OR: 3.62), pelvic fracture (OR: 2.01), and treatment at an American College of Surgeons level I trauma center (compared with levels II-IV; OR: 1.56) were associated with delayed surgery. The overall rate of mortality and inpatient adverse events was 0.2% and 12.1%, respectively. Delayed surgery was independently associated with increased occurrence of serious adverse events, minor adverse events, and any adverse events. CONCLUSIONS: Although a majority of nonelderly patients with femoral neck fractures underwent surgery within the first 24 hours of admission and had good outcomes in the short-term, certain subpopulations have a higher risk of delayed surgery. As delayed surgery is associated with worse outcomes, and short-term and long-term outcomes, efforts should focus on expediting care of these patients. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 26429408 TI - Are Locking Constructs in Distal Femoral Fractures Always Best? A Prospective Multicenter Randomized Controlled Trial Comparing the Less Invasive Stabilization System With the Minimally Invasive Dynamic Condylar Screw System. AB - OBJECTIVES: The purpose of this clinical study is to determine whether the rate of fracture healing and fracture union, repaired with a locked device, will be as good as or better than standard nonlocking bicortical fixation in distal femoral fractures. DESIGN: Institutional review board-approved, multicenter prospective randomized controlled trial. SETTING: Seven level 1 trauma centers across Canada. PATIENTS: Fifty-two patients with distal femoral fractures (AO/OTA 33A1 to 33C2) were enrolled in the randomized trial. Twelve AO/OTA 33C3 fractures were excluded from the randomized trial but followed up as a nonrandomized cohort. INTERVENTION: Patients were treated through a standardized minimally invasive approach. Fractures were randomized 1:1 to treatment with the locked Less Invasive Stabilization System (LISS; Synthes, Paoli, PA) or the dynamic condylar screw (DCS). The nonrandomized cohort was treated at the surgeon's discretion. MAIN OUTCOME MEASUREMENTS: Primary outcomes were time to radiological union and number of delayed/nonunions at 12 months. Secondary outcomes were postoperative function and complications. RESULTS: Fifty-two patients were randomized including 34 women and 18 men. The mean age was 59 years. Twenty-eight patients were treated with the LISS and 24 with the DCS. There was no statistically significant difference between the LISS and the DCS in terms of the number of fractures healed, time to union, or functional scores. Complications and revisions were more common in the LISS group. There were 7 reoperations in the LISS group and one in the DCS group. Only 52% of the LISS group healed without intervention by 12 months compared with 91% in the DCS group. CONCLUSIONS: There was no advantage to the locking plate design in the management of distal femoral fractures in this study. The higher cost of the locking plates, challenges in technique, and lack of superiority have led the authors to discontinue the use of this lateral unicortical locking device in favor of other devices that allow locked or nonlocked bicortical fixation, articular compression, and bridging of the comminuted fracture segments. The cost-effective treatment for a subgroup or periarticular fractures may be a fixed-angle nonlocked device in patients with reasonable bone quality. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 26429409 TI - Metabolism of kurarinone by human liver microsomes and its effect on cytotoxicity. AB - CONTEXT: Kurarinone, the most abundant prenylated flavonoid in Sophora flavescens Aiton (Leguminosae), is a promising antitumor therapeutic. However, it shows significant hepatotoxicity. Furthermore, how kurarinone is metabolized in humans remains unclear. OBJECTIVE: The objective of this study is to investigate kurarinone metabolism in human liver microsomes (HLMs) and the role of metabolism in kurarinone-induced cytotoxicity. MATERIALS AND METHODS: The UDP glucuronosyltransferase isoforms (UGTs) involved in kurarinone glucuronidation were identified using chemical inhibitors (100-1000 uM phenylbutazone; 10-100 uM beta-estradiol; 10-100 uM 1-naphthol; 10-500 uM propofol; and 100-1000 uM fluconazole) and recombinant human UGTs. Kurarinone (2-500 uM) was incubated with HLMs and UGTs (0.5 mg/mL) for 15 min to determine enzyme kinetic parameters. The IC50 value of kurarinone (10-200 uM) was evaluated in a HLMs/3T3 cell co-culture system. RESULTS: Kurarinone is extensively converted to two glucuronides (M3 and M4) in HLMs. M3 formation was catalyzed by multiple UGT1As, with UGT1A3 showing the highest intrinsic clearance (120.60 mL/min/mg). M4 formation was catalyzed by UGT1A1, UGT2B4, and UGT2B7. UGT1A1 showed the highest intrinsic clearance (60.61 mL/min/mg). The kinetic profiles of the five main UGTs and HLMs fit substrate inhibition kinetics, with Km values ranging from 5.20 to 46.52 uM, Vmax values ranging from 0.20 to 3.06 umol/min/mg, and Ksi values ranging from 25.58 to 230.30 uM. The kurarinone IC50 value was 93 MUM in the control group, 102 MUM in HLMs with NADPH, and 160 MUM in HLMs with UDPGA. DISCUSSION AND CONCLUSION: Kurarinone glucuronidation is a detoxification pathway. This information may help to elucidate the risk factors regulating kurarinone toxicity. PMID- 26429410 TI - Molecular and functional identification of three interleukin-17A/F (IL-17A/F) homologues in large yellow croaker (Larimichthys crocea). AB - The interleukin-17 (IL-17) cytokine family plays a central role in the coordination of inflammatory responses. In fish species, three genes that have a similar homology to both IL-17A and IL-17F were designated IL-17A/F1, 2, and 3. In this study, we identified three IL-17A/F homologues (LycIL-17A/F1, 2, and 3) from large yellow croaker (Larimichthys crocea). The deduced LycIL-17A/F1 and 3 had four cysteine residues conserved in teleost IL-17A/F1 and 3 homologues and shared a domain similar to the B chain of human IL-17F. The deduced LycIL-17A/F2 possessed the unique arrangement of six cysteine residues as teleost IL-17A/F2 (except Fugu IL-17A/F2) and higher vertebrate IL-17A and F, and shared a domain similar to the D/E chain of human IL-17A. Phylogenetic analysis showed that teleost IL-17A/F1 and 3 fall into a major clade, whereas IL-17A/F2 forms a separated clade and is clustered with IL-17N. Based on structural and phylogenetic analyses, we suggest that teleost IL-17A/Fs may be classified into two subgroups: one consisting of IL-17A/F1 and 3, and the other composed of IL 17A/F2. The three LycIL-17A/Fs were constitutively expressed in all tissues examined although at a different level. Following challenge with Aeromonas hydrophila, expression of these three LycIL-17A/Fs was rapidly increased in head kidney and gills. The in vivo assays showed that recombinant LycIL-17A/F1, 2, and 3 all were able to enhance the expression of pro-inflammatory cytokines (IL 1beta, IL-6, and TNF-alpha2), chemokines (CXCL8 and CXCL13), and antimicrobial peptide hepcidin in head kidney. Furthermore, LycIL-17A/Fs appeared to mediate pro-inflammatory responses via NF-kappaB signalling. These results therefore reveal similar functions between the two subgroup members,LycIL-17A/F1 and 3 and LycIL-17A/F2, in promoting inflammation and host defences. PMID- 26429412 TI - Identification of a CD4 variant in Microminipigs not detectable with available anti-CD4 monoclonal antibodies. AB - The Microminipig is an extra-small sized novel miniature pig developed in Japan. In the process of peripheral blood mononuclear cells analysis by flow cytometry, CD4+ cells could not be detected in some pigs with an anti-pig CD4 antibody (clone 74-12-4), or in some pigs with two other antibodies from different clones (MIL17 and PT90A). In a herd of 178 Microminipigs, 87 pigs (48.9%) were reactive with the anti-CD4 antibody (designated as CD4.A), and 91 pigs (51.1%) were non reactive (designated as CD4.B). The CD4 types of piglets delivered from parents with CD4.A were CD4.A or CD4.B, and piglets delivered from parents with CD4.B were only CD4.B. This implies that the CD4.A pigs were homozygous for CD4.A or heterozygous for CD4.A and CD4.B, and the CD4.B pigs were homozygous for CD4.B. The CD4.B trait might be recessive. Significant differences could not be found in the percentage of CD3+ and CD8+ cells in whole lymphocytes between CD4.A and CD4.B animals. In the profile of CD4.B pigs, CD4+CD8+ T cells appeared to be detected in the CD4-CD8+ T cell region because the CD8 dull T cell population was observed. Thus, we considered that the CD4 molecules may be expressed on helper T cells, but the CD4 expressing cells could not be detected with the three anti-pig CD4 antibodies. Clinical abnormalities have not been observed in CD4.B pigs. Significant differences were not observed in immunoglobulin concentrations between CD4.A and CD4.B, though lower tendency was observed in plasma IgM concentrations from CD4.B pigs >36-months-old. These results imply that the CD4.B does not affect basic humoral immunity in vivo. PMID- 26429413 TI - Local and systemic inflammatory and immunologic reactions to cyathostomin larvicidal therapy in horses. AB - Encysted cyathostomin larvae are ubiquitous in grazing horses. Arrested development occurs in this population and can lead to an accumulation of encysted larvae. Large numbers of tissue larvae place the horse at risk for developing larval cyathostominosis. This disease complex is caused by mass emergence of these larvae and is characterized by a generalized acute typhlocolitis and manifests itself as a profuse protein-losing watery diarrhea with a reported case fatality rate of about 50%. Two anthelmintic formulations have a label claim for larvicidal therapy of these encysted stages; moxidectin and a five-day regimen of fenbendazole. There is limited knowledge about inflammatory and immunologic reactions to larvicidal therapy. This study was designed to evaluate blood acute phase reactants as well as gene expression of pro-inflammatory cytokines, both locally in the large intestinal walls and systemically. Further, mucosal tissue samples were evaluated histopathologically as well as analyzed for gene expression of pro- and anti-inflammatory cytokines, cluster of differentiation (CD) cell surface proteins, and select transcription factors. Eighteen juvenile horses with naturally acquired cyathostomin infections were randomly assigned to three treatment groups; one group served as untreated controls (Group 1), one received a five-day regimen of fenbendazole (10mg/kg) (Group 2), and one group received moxidectin (0.4mg/kg) (Group 3). Horses were treated on day 0 and euthanatized on days 18-20. Serum and whole blood samples were collected on days 0, 5, and 18. All horses underwent necropsy with collection of tissue samples from the ventral colon and cecum. Acute phase reactants measured included serum amyloid A, iron and fibrinogen, and the cytokines evaluated included interferon gamma, tumor necrosis factor alpha, transforming growth factor (TGF)-beta, and interleukins 1beta, 4, 5, 6, and 10. Transcription factors evaluated were FoxP3, GATA3 and tBet, and CD markers included CD163, CD3z, CD4, CD40, and CD8b. Histopathology revealed an inflammatory reaction with higher levels of lymphocytes, T cells, B cells, eosinophils and fibrous tissue in the moxidectin treated group compared to controls or horses treated with fenbendazole. No apparent systemic reactions were observed. Expression of IL-5 and TGF-beta in intestinal tissues was significantly lower in Group 3 compared to Group 1. This study revealed a subtle inflammatory reaction to moxidectin, which is unlikely to cause clinical issues. PMID- 26429411 TI - The zebrafish galectins Drgal1-L2 and Drgal3-L1 bind in vitro to the infectious hematopoietic necrosis virus (IHNV) glycoprotein and reduce viral adhesion to fish epithelial cells. AB - The infectious hematopoietic necrosis virus (IHNV; Rhabdoviridae, Novirhabdovirus) infects teleost fish, such as salmon and trout, and is responsible for significant losses in the aquaculture industry and in wild fish populations. Although IHNV enters the host through the skin at the base of the fins, the viral adhesion and entry mechanisms are not fully understood. In recent years, evidence has accumulated in support of the key roles played by protein carbohydrate interactions between host lectins secreted to the extracellular space and virion envelope glycoproteins in modulating viral adhesion and infectivity. In this study, we assessed in vitro the potential role(s) of zebrafish (Danio rerio) proto type galectin-1 (Drgal1-L2) and a chimera galectin 3 (Drgal3-L1) in IHNV adhesion to epithelial cells. Our results suggest that the extracellular Drgal1-L2 and Drgal3-L1 interact directly and in a carbohydrate dependent manner with the IHNV glycosylated envelope and glycans on the epithelial cell surface, significantly reducing viral adhesion. PMID- 26429414 TI - The predictors of endoleaks after endovascular repair of experimentally produced fusiform carotid aneurysm in canine. AB - OBJECTIVE: Endoleaks constitute the main concern regarding the use of covered stents in the treatment of intracranial aneurysms. We investigated immediate/late endoleaks after stent-graft placement for the treatment of experimentally created carotid fusiform aneurysm (FA) in a canine model. MATERIAL AND METHODS: Eighteen carotid FAs in nine dogs receiving covered stents were followed. Their procedural and angiographic data were collected immediately and six months after stenting. Univariate analysis and multivariate logistic regression analysis were performed to determine the factors predictive of immediate/late endoleaks. Receiver operating characteristic curve analysis was performed to determine the best cutoff values of the independent factors. RESULTS: All carotid FAs were successfully treated with Willis covered stents and received a six-month follow up. The rate of immediate and late endoleaks after stenting was 38.89% and 16.67%, respectively. Anchoring length was identified as independent predictor of immediate endoleaks (P =0.037) and its best cutoff value was 3.06 mm (95% confidence interval: 2.39-3.72). No parameters were identified to be independent predictors of late endoleaks. CONCLUSIONS: Treating carotid FAs with Willis covered stents is technically feasible. Most endoleaks heal spontaneously and significantly correlate with anchoring length. PMID- 26429415 TI - Feasibility of Using the Omaha System for Community-level Observations. AB - OBJECTIVES: The purpose of this study was to determine the feasibility of using a standardized language, the Omaha System, to capture community-level observations to facilitate population assessment and electronic information exchange. The objectives were: (1) to evaluate the feasibility of using the Omaha System at the community level to reflect community observations and (2) to describe preliminary results of community observations across international settings. DESIGN AND SAMPLE: Descriptive. A dataset of 284 windshield surveys (community observations) completed by nursing students in five countries: Mexico, New Zealand, Norway, Turkey, and the United States. MEASURES: The Omaha System Problem Classification Scheme provided standardized terms for assessment of communities in an online checklist of 11 problems and their respective signs/symptoms. RESULTS: Feasibility was demonstrated: students were able to describe community observations using standardized terminology from the Omaha System. Preliminary results describe variations in community signs and symptoms by location. CONCLUSIONS: The Omaha System appears to be a useful tool for community-level observations and a promising strategy for electronic exchange of population health assessments. PMID- 26429416 TI - Were Plasma Trace Element Levels Changed in the Children with ADHD? PMID- 26429417 TI - Serum Zinc Concentration and C-Reactive Protein in Individuals with Human Immunodeficiency Virus Infection: the Positive Living with HIV (POLH) Study. AB - Low zinc levels and chronic inflammation are common in individuals infected with human immunodeficiency virus (HIV). Zinc deficiency may promote systemic inflammation, but research on the role of zinc in inflammation among HIV-positive individuals taking account of anti-retroviral therapy is lacking. We assessed the association between serum zinc and C-reactive protein (CRP) concentration in a cohort of HIV-positive individuals. A cross-sectional survey was conducted among 311 HIV-positive individuals (177 men and 134 women) aged 18-60 years residing in Kathmandu, Nepal. High-sensitive or regular serum CRP concentrations were measured by the latex agglutination nephelometry or turbidimetric method, and zinc concentrations were measured by the atomic absorption method. Relationships were assessed using multiple linear regression analysis. The geometric means of zinc in men and women were 73.83 and 71.93 ug/dL, respectively, and of CRP were 1.64 and 0.96 mg/L, respectively. Mean serum CRP concentration was significantly decreased with increasing serum zinc concentration across zinc tertiles (P for trend = 0.010), with mean serum CRP concentration in the highest tertile of serum zinc concentration was 44.2 % lower than that in the lowest tertile. The mean serum CRP concentrations in men and women in the highest tertile of serum zinc concentrations were 30 and 35.9 % lower, respectively, than that in the lowest tertile (P for trend = 0.263 and 0.162, respectively). We found a significant inverse relation between log zinc and log CRP concentrations (beta for 1 unit change in log zinc; beta = -1.79, p = 0.0003). Serum zinc concentration may be inversely associated with serum CRP concentration in HIV-positive individuals. PMID- 26429418 TI - Acute Kidney Injury in Children with Plasmodium falciparum Malaria: Determinants for Mortality. AB - ? BACKGROUND: Acute kidney injury (AKI) in P. falciparum malaria infection is an important morbidity in children. The purpose of the present study was done to observe the renal involvement, associated morbidities and outcome. ? METHODS: Out of 156 patients with severe P. falciparum malaria, diagnosed on the basis of compatible clinical presentations and positive malarial parasites in the peripheral blood smear and/or histidine rich protein 2 antigen, 31 had AKI at presentation and were analyzed. ? RESULTS: Of 31 (19.9%) patients with AKI, 4 were classified at risk, 11 injury, and 16 failure stage, as per pRIFLE criteria (pediatric version of RIFLE [R = risk, I = injury, F = failure, L = loss E = end stage kidney disease]). Mean age of children with AKI was 7.7 +/- 3.2 years. A significantly higher proportion of patients with AKI had hypoglycemia (41.9%), pulmonary edema (32.2%), and disseminated intravascular coagulation (DIC) (29.0%) compared to those without AKI (18.4%, 4.8%, and 3.2%, respectively). Twelve patients (38.7%) required peritoneal dialysis (PD), 8 (25.8%) died, and all were in failure stage. The non-survivors had significantly higher blood urea (p = 0.005) and serum creatinine levels (p = 0.042), lower glomerular filtration rate (p < 0.001), longer duration of illness (p = 0.003), and oliguria/anuria (p = 0.001) than survivors at admission. On logistic regression analysis, the disseminated intravascular coagulation (DIC), jaundice and parasite density (>= 3+) were found to be significant factors contributing to mortality in children with AKI. ? CONCLUSIONS: Acute kidney injury in falciparum malaria is one of the severe systemic complications. Duration of illness and presence of comorbidities adversely affected the outcome. PMID- 26429419 TI - Patient Acceptability of the Yorkshire Dialysis Decision Aid (YoDDA) Booklet: A Prospective Non-Randomized Comparison Study Across 6 Predialysis Services. AB - ? BACKGROUND: Patients are satisfied with their kidney care but want more support in making dialysis choices. Predialysis leaflets vary across services, with few being sufficient to enable patients' informed decision making. We describe the acceptability of a patient decision aid and feasibility of evaluating its effectiveness within usual predialysis practice. ? METHODS: Prospective non randomized comparison design, Usual Care or Usual Care Plus Yorkshire Dialysis Decision Aid Booklet (+YoDDA), in 6 referral centers (Yorkshire-Humber, UK) for patients with sustained deterioration of kidney function. Consenting (C) patients completed questionnaires after predialysis consultation (T1), and 6 weeks later (T2). Measures assessed YoDDA's utility to support patients' decisions and integration within usual care. ? RESULTS: Usual Care (n = 105) and +YoDDA (n = 84) participant characteristics were similar: male (62%), white (94%), age (mean = 62.6; standard deviation [SD] 14.4), kidney disease severity (glomerular filtration rate [eGFR] mean = 14.7; SD 3.7); decisional conflict was < 25; choice preference for home versus hospital dialysis approximately 50:50. Patients valued receiving YoDDA, reading it on their own (96%), and sharing it with family (72%). The +YoDDA participants had higher scores for understanding kidney disease, reasoning about options, feeling in control, sharing their decision with family. Study engagement varied by center (estimated range 14 - 49%; mean 45%); participants varied in completion of decision quality measures. ? CONCLUSIONS: Receiving YoDDA as part of predialysis education was valued and useful to patients with worsening kidney disease. Integrating YoDDA actively within predialysis programs will meet clinical guidelines and patient need to support dialysis decision making in the context of patients' lifestyle. PMID- 26429420 TI - Simultaneous Catheter Replacement for Infectious and Mechanical Complications Without Interruption of Peritoneal Dialysis. AB - ? BACKGROUND: Conventional management for peritoneal dialysis (PD)-related infectious and mechanical complications that fails treatment includes catheter removal and hemodialysis (HD) via a central venous catheter with the end result that the majority of patients will not return to PD. Simultaneous catheter replacement (SCR) can retain patients on PD by avoiding the scenario of staged removal and reinsertion of catheters. The aim of this study was to evaluate a protocol for SCR without interruption of PD. ? METHODS: Clinical outcomes were analyzed for 55 consecutive SCRs performed from 2002 through 2012 and followed through 2013. ? RESULTS: Simultaneous catheter replacements were performed for 28 cases of relapsing peritonitis, 12 cases of tunnel infection, and 15 cases of mechanical catheter complications. All cases for peritonitis and tunnel infection and 80% for mechanical complications continued PD on the day of surgery using a low-volume, intermittent automated PD protocol. Systemic antibiotics were continued for 2 weeks postoperatively (up to 4 weeks for Pseudomonas). Simultaneous catheter replacement was performed as an outpatient procedure in 89.1% of cases. Only 1 of 55 procedures was complicated by peritonitis within 8 weeks. No catheter losses occurred during this postoperative timeframe. Long term, SCR enabled a median technique survival of 5.1 years. ? CONCLUSIONS: In most instances, SCR can be safely performed without interruption of PD for selected cases of peritonitis and tunnel infection and for mechanical catheter complications. The procedure spares the patient from a central venous catheter, a shift to HD, the psychological ordeal of a change in dialysis modality, and a second surgery to insert a new catheter. PMID- 26429422 TI - Invited Article: A novel calibration method for the JET real-time far infrared polarimeter and integration of polarimetry-based line-integrated density measurements for machine protection of a fusion plant. AB - In this paper, we present the work in the implementation of a new calibration for the JET real-time polarimeter based on the complex amplitude ratio technique and a new self-validation mechanism of data. This allowed easy integration of the polarimetry measurements into the JET plasma density control (gas feedback control) and as well as machine protection systems (neutral beam injection heating safety interlocks). The new addition was used successfully during 2014 JET Campaign and is envisaged that will operate routinely from 2015 campaign onwards in any plasma condition (including ITER relevant scenarios). This mode of operation elevated the importance of the polarimetry as a diagnostic tool in the view of future fusion experiments. PMID- 26429423 TI - The spectral imaging facility: Setup characterization. AB - The SPectral IMager (SPIM) facility is a laboratory visible infrared spectrometer developed to support space borne observations of rocky bodies of the solar system. Currently, this laboratory setup is used to support the DAWN mission, which is in its journey towards the asteroid 1-Ceres, and to support the 2018 Exo Mars mission in the spectral investigation of the Martian subsurface. The main part of this setup is an imaging spectrometer that is a spare of the DAWN visible infrared spectrometer. The spectrometer has been assembled and calibrated at Selex ES and then installed in the facility developed at the INAF-IAPS laboratory in Rome. The goal of SPIM is to collect data to build spectral libraries for the interpretation of the space borne and in situ hyperspectral measurements of planetary materials. Given its very high spatial resolution combined with the imaging capability, this instrument can also help in the detailed study of minerals and rocks. In this paper, the instrument setup is first described, and then a series of test measurements, aimed to the characterization of the main subsystems, are reported. In particular, laboratory tests have been performed concerning (i) the radiation sources, (ii) the reference targets, and (iii) linearity of detector response; the instrumental imaging artifacts have also been investigated. PMID- 26429421 TI - Longitudinal Trend in Lipid Profile of Incident Peritoneal Dialysis Patients is Not Influenced by the Use of Biocompatible Solutions. AB - ? BACKGROUND: The longitudinal trends of lipid parameters and the impact of biocompatible peritoneal dialysis (PD) solutions on these levels remain to be fully defined. The present study aimed to a) evaluate the influence of neutral pH, low glucose degradation product (GDP) PD solutions on serum lipid parameters, and b) explore the capacity of lipid parameters (total cholesterol [TC], triglyceride [TG], high density lipoprotein [HDL], TC/HDL, low density lipoprotein [LDL], very low density lipoprotein [VLDL]) to predict cardiovascular events (CVE) and mortality in PD patients. ? METHODS: The study included 175 incident participants from the balANZ trial with at least 1 stored serum sample. A composite CVE score was used as a primary clinical outcome measure. Multilevel linear regression and Poisson regression models were fitted to describe the trend of lipid parameters over time and its ability to predict composite CVE, respectively. ? RESULTS: Small but statistically significant increases in serum TG (coefficient 0.006, p < 0.001), TC/HDL (coefficient 0.004, p = 0.001), and VLDL cholesterol (coefficient 0.005, p = 0.001) levels and a decrease in the serum HDL cholesterol levels (coefficient -0.004, p = 0.009) were observed with longer time on PD, whilst the type of PD solution (biocompatible vs standard) received had no significant effect on these levels. Peritoneal dialysis glucose exposure was significantly associated with trends in TG, TC/HDL, HDL and VLDL levels. Baseline lipid parameter levels were not predictive of composite CVEs or all-cause mortality. ? CONCLUSION: Serum TG, TC/HDL, and VLDL levels increased and the serum HDL levels decreased with increasing PD duration. None of the lipid parameters were significantly modified by biocompatible PD solution use over the time period studied or predictive of composite CVE or mortality. PMID- 26429424 TI - A polarized digital shearing speckle pattern interferometry system based on temporal wavelet transformation. AB - Digital shearing speckle pattern interferometry (DSSPI) has been recognized as a practical tool in testing strain. The DSSPI system which is based on temporal analysis is attractive because of its ability to measure strain dynamically. In this paper, such a DSSPI system with Wollaston prism has been built. The principles and system arrangement are described and the preliminary experimental result of the displacement-derivative test of an aluminum plate is shown with the wavelet transformation method and the Fourier transformation method. The simulations have been conducted with the finite element method. The comparison of the results shows that quantitative measurement of displacement-derivative has been realized. PMID- 26429425 TI - Development of ion beam figuring system with electrostatic deflection for ultraprecise X-ray reflective optics. AB - We developed an ion beam figuring system that utilizes electrostatic deflection. The system can produce an arbitrary shape by deterministically scanning the ion beam. The scan of the ion beam, which can be precisely controlled using only an electrical signal, enables us to avoid degradation of the mirror shape caused by imperfect acceleration or deceleration of a mechanically scanning stage. Additionally, this surface figuring method can easily be combined with X-ray metrology because the workpiece remains fixed during the figuring. We evaluated the figuring accuracy of the system by fabricating a plano-elliptical mirror for X-ray focusing. A mirror with a shape error of 1.4 nm root mean square (RMS) with a maximum removal depth of 992 nm, which corresponds to figuring accuracy of 0.14% RMS, was achieved. After the second shape corrections, an elliptical shape with a shape error of approximately 1 nm peak-to-valley, 0.48 nm RMS could be fabricated. Then, the mirror surface was smoothed by a low-energy ion beam. Consequently, a micro-roughness of 0.117 nm RMS, measured by atomic force microscopy, was achieved over an area of 1 * 1 MUm(2). PMID- 26429426 TI - Room-temperature calorimeter for x-ray free-electron lasers. AB - We have developed a room-temperature calorimeter for absolute radiant power measurements of x-ray free-electron lasers. This room-temperature calorimeter is an electrical substitution device based on the equivalence of electrical and radiant heating. Consequently, the measured radiant powers are traceable to electrical standards, i.e., the International System Units (SI). We demonstrated the performance of the room-temperature calorimeter by electrical power measurements (offline tests). In the offline tests, the room-temperature calorimeter was proven to be able to measure external powers up to at least 6.9 mW, which exceeds the upper limit (~4 mW) of a cryogenic radiometer (the primary standard detector in Japan). In addition, measurement uncertainties of the room temperature calorimeter were evaluated to be less than 1.0%, which is adequate for the radiant power measurements of x-ray free-electron lasers. An indirect comparison with the cryogenic radiometer was performed using a synchrotron radiation source to confirm the validity of the absolute radiant powers measured with the room-temperature calorimeter. The absolute radiant powers measured by the calorimeter agreed with those measured by the cryogenic radiometer within 0.6%, which is less than the relative standard uncertainty of the comparison (1.0%). PMID- 26429427 TI - A closed-loop pump-driven wire-guided flow jet for ultrafast spectroscopy of liquid samples. AB - We describe the design and provide the results of the full characterization of a closed-loop pump-driven wire-guided flow jet system. The jet has excellent optical quality with a wide range of liquids spanning from alcohol to water based solutions, including phosphate buffers used for biological samples. The thickness of the jet film varies depending on the flow rate between 90 MUm and 370 MUm. The liquid film is very stable, and its thickness varies only by 0.76% under optimal conditions. Measured transmitted signal reveals a long term optical stability (hours) with a RMS of 0.8%, less than the overall noise of the spectroscopy setup used in our experiments. The closed loop nature of the overall jet design has been optimized for the study of precious biological samples, in limited volumes, to remove window contributions from spectroscopic observables. This feature is particularly important for femtosecond studies in the UV range. PMID- 26429428 TI - Demonstration of the high collection efficiency of a broadband Mo/Si multilayer mirror with a graded multilayer coating on an ellipsoidal substrate. AB - A graded and broadband Mo/Si multilayer mirror for EUV spectroscopy is demonstrated. This mirror has an average reflectivity profile of 16% in the wavelength region from 15 nm to 17 nm and an effective area of 1100-1500 mm(2). This reflectivity is about 4 times larger than that of a standard Mo/Si multilayer mirror on a 1 in. diameter substrate, showing that the mirror can be used for measuring EUV fluorescence at wavelengths in the region around 15 nm to 17 nm. PMID- 26429429 TI - Vapor phase tri-methyl-indium seeding system suitable for high temperature spectroscopy and thermometry. AB - Tri-methyl-indium (TMI) is used as an indium transport molecule to introduce indium atoms to reactive hot gas flows/combustion environments for spectroscopic diagnostics. A seeding system was constructed to allow the addition of an inert TMI laden carrier gas into an air/fuel mixture burning consequently on a burner. The amount of the seeded TMI in the carrier gas can be readily varied by controlling the vapor pressure through the temperature of the container. The seeding process was calibrated using the fluorescent emission intensity from the indium 6(2)S1/2 -> 5(2)P1/2 and 6(2)S1/2 -> 5(2)P3/2 transitions as a function of the calculated TMI seeding concentration over a range of 2-45 ppm. The response was found to be linear over the range 3-22.5 ppm; at concentrations above 25 ppm there is a loss of linearity attributable to self-absorption or loss of saturation of TMI vapor pressure in the carrier gas flow. When TMI was introduced into a post-combustion environment via an inert carrier gas, molecular transition from InH and InOH radicals were observed in the flame emission spectrum. Combined laser-induced fluorescence and absorption spectroscopy were applied to detect indium atoms in the TMI seeded flame and the measured atomic indium concentration was found to be at the ppm level. This method of seeding organometallic vapor like TMI to a reactive gas flow demonstrates the feasibility for quantitative spectroscopic investigations that may be applicable in various fields, e.g., chemical vapor deposition applications or temperature measurement in flames with two-line atomic fluorescence. PMID- 26429430 TI - Measurement of vacuum pressure with a magneto-optical trap: A pressure-rise method. AB - The lifetime of an atom trap is often limited by the presence of residual background gases in the vacuum chamber. This leads to the lifetime being inversely proportional to the pressure. Here, we use this dependence to estimate the pressure and to obtain pressure rate-of-rise curves, which are commonly used in vacuum science to evaluate the performance of a system. We observe different rates of pressure increase in response to different levels of outgassing in our system. Therefore, we suggest that this is a sensitive method which will find useful applications in cold atom systems, in particular, where the inclusion of a standard vacuum gauge is impractical. PMID- 26429431 TI - A new compact soft x-ray spectrometer for resonant inelastic x-ray scattering studies at PETRA III. AB - We present a newly designed compact grating spectrometer for the energy range from 210 eV to 1250 eV, which would include the Kalpha(1,2) emission lines of vital elements like C, N, and O. The spectrometer is based on a grazing incidence spherical varied line spacing grating with 2400 l/mm at its center and a radius of curvature of 58 542 mm. First, results show a resolving power of around 1000 at an energy of 550 eV and a working spectrometer for high vacuum (10(-4) mbar) environment without losing photon intensity. PMID- 26429432 TI - Compton polarimeter for 10-30 keV x rays. AB - We present a simple and versatile polarimeter for x rays in the energy range of 10-30 keV. It uses Compton scattering in low-Z materials such as beryllium or boron carbide. The azimuthal distribution of the scattered x rays is sampled by an array of 12 silicon PIN diodes operated at room temperature. We evaluated the polarimetry performance using Monte-Carlo simulations and show experimental results. PMID- 26429433 TI - Dissemination stability and phase noise characteristics in a cascaded, fiber based long-haul radio frequency dissemination network. AB - To study the dissemination stability and phase noise characteristics of the cascaded fiber-based RF dissemination, we perform an experiment using three sets of RF modulated frequency dissemination systems. The experimental results show that the total transfer stability of the cascaded system can be given by sigma(T)(2)=?(i=1)(N)sigma(i)(2) (sigma(i) is the frequency dissemination stability of the ith segment and N is the quantity of segments). Furthermore, for each segment, the phase noise of recovered frequency signal is also measured. The results show that for an N-segment, cascaded dissemination system, its stability degrades only by a factor of N. This sub-linear relation makes the cascaded, RF dissemination method a very attractive one for long-haul, time and frequency dissemination network. PMID- 26429434 TI - A hybrid electron cyclotron resonance metal ion source with integrated sputter magnetron for the production of an intense Al+ ion beam. AB - A metal ion source prototype has been developed: a combination of magnetron sputter technology with 2.45 GHz electron cyclotron resonance (ECR) ion source technology-a so called magnetron ECR ion source (MECRIS). An integrated ring shaped sputter magnetron with an Al target is acting as a powerful metal atom supply in order to produce an intense current of singly charged metal ions. Preliminary experiments show that an Al(+) ion current with a density of 167 MUA/cm(2) is extracted from the source at an acceleration voltage of 27 kV. Spatially resolved double Langmuir probe measurements and optical emission spectroscopy were used to study the plasma states of the ion source: sputter magnetron, ECR, and MECRIS plasma. Electron density and temperature as well as Al atom density were determined as a function of microwave and sputter magnetron power. The effect of ECR heating is strongly pronounced in the center of the source. There the electron density is increased by one order of magnitude from 6 * 10(9) cm(-3) to 6 * 10(10) cm(-3) and the electron temperature is enhanced from about 5 eV to 12 eV, when the ECR plasma is ignited to the magnetron plasma. Operating the magnetron at constant power, it was observed that its discharge current is raised from 1.8 A to 4.8 A, when the ECR discharge was superimposed with a microwave power of 2 kW. At the same time, the discharge voltage decreased from about 560 V to 210 V, clearly indicating a higher plasma density of the MECRIS mode. The optical emission spectrum of the MECRIS plasma is dominated by lines of excited Al atoms and shows a significant contribution of lines arising from singly ionized Al. Plasma emission photography with a CCD camera was used to prove probe measurements and to identify separated plasma emission zones originating from the ECR and magnetron discharge. PMID- 26429435 TI - Screens versus microarrays for ruggedized retarding potential analyzers. AB - An array of highly miniaturized electrostatic lenses is shown to be a viable replacement for meshes or screens in a retarding potential analyzer (RPA) where mechanical ruggedness or the ability to intercept large currents of energetic particles is desirable. Data from a prototype device are presented cross calibrated with a traditional planar RPA indicating how the so-called microarray configuration avoids energy-dependent transparency (either reduced or enhanced) associated with meshes or screens while providing accurate energy analysis with reasonable energy resolution. In contrast, another ruggedized configuration employing a screen is presented, showing the severity of energy-dependent enhanced transparency, verified by numerical simulation. PMID- 26429436 TI - Beam based alignment and its relevance in Indus-2. AB - Initially in the Indus-2 storage ring, the closed orbit distortion (COD) could be best corrected to 1.3 mm rms in the horizontal and 0.43 mm rms in the vertical plane. The strength of the corrector magnets required high values for COD correction. This revealed that offsets in COD readout by the beam position monitors (BPMs) played a role in not achieving a rms COD lower than the above value. Thus, the offset between the electrical center of BPMs and the magnetic center of the nearest quadrupole magnet could be estimated using the beam based alignment (BBA) method. It prefers that the quadrupole magnet is able to be controlled individually and active shunt power supply (ASPS) system was designed for this purpose that works efficiently. This paper describes the methodology of BBA, topology of ASPS and its performance, and COD minimization using the measured BPM offsets. After BBA, the COD could be reduced to 0.45 mm rms and 0.2 mm rms in horizontal and vertical planes, respectively. PMID- 26429437 TI - Commissioning of a frequency-resolved optical gating system at the OMEGA EP laser facility: SpecFROG. AB - We present the design and commissioning of a new single-shot, frequency-resolved optical gating system on the OMEGA EP laser facility - dubbed "SpecFROG" - for characterizing the instantaneous intensity and phase of ~10 ps pulses used to study ultra-intense laser-plasma interactions. A polarization-gating geometry is employed to ensure tha the diagnostic is broadband and has unambiguous time directionality. SpecFROG is capable of characterizing ~10 s of mJ pulses with durations between 0.5-25 ps with ?285 fs geometrical temporal blurring and ~0.1% spectral shift resolutions over an adjustable total spectral shifting window of ~15% of the carrier wavelength lambdao; configurations currently exist for both the fundamental (1omega, lambdao = 1.054 MUm) and second harmonic (2omega, lambdao = 0.527 MUm) of the EP pulse. Initial specular reflectivity measurements of the ~1 kJ, ~10 ps OMEGA EP laser off solid density aluminum targets suggest drastically different scalings for specular pulse properties compared to picosecond-scale pulses of comparable intensities. PMID- 26429438 TI - Development of a stereo-symmetrical nanosecond pulsed power generator composed of modularized avalanche transistor Marx circuits. AB - Avalanche transistors have been widely studied and used in nanosecond high voltage pulse generations. However, output power improvement is always limited by the low thermal capacities of avalanche transistors, especially under high repetitive working frequency. Parallel stacked transistors can effectively improve the output current but the controlling of trigger and output synchronism has always been a hard and complex work. In this paper, a novel stereo symmetrical nanosecond pulsed power generator with high reliability was developed. By analyzing and testing the special performances of the combined Marx circuits, numbers of meaningful conclusions on the pulse amplitude, pulse back edge, and output impedance were drawn. The combining synchronism of the generator was confirmed excellent and lower conducting current through the transistors was realized. Experimental results showed that, on a 50 Omega resistive load, pulses with 1.5-5.2 kV amplitude and 5.3-14.0 ns width could be flexibly generated by adjusting the number of combined modules, the supply voltage, and the module type. PMID- 26429439 TI - Two-dimensional wave-number spectral analysis techniques for phase contrast imaging turbulence imaging data on large helical device. AB - An analysis method for unfolding the spatially resolved wave-number spectrum and phase velocity from the 2D CO2 laser phase contrast imaging system on the large helical device is described. This is based on the magnetic shear technique which identifies propagation direction from 2D spatial Fourier analysis of images detected by a 6 * 8 detector array. Because the strongest modes have wave-number at the lower end of the instrumental k range, high resolution spectral techniques are necessary to clearly resolve the propagation direction and hence the spatial distribution of fluctuations along the probing laser beam. Multiple-spatial point cross-correlation averaging is applied before calculating the spatial power spectrum. Different methods are compared, and it is found that the maximum entropy method (MEM) gives best results. The possible generation of artifacts from the over-narrowing of spectra are investigated and found not to be a significant problem. The spatial resolution Deltarho (normalized radius) around the peak wave-number, for conventional Fourier analysis, is ~0.5, making physical interpretation difficult, while for MEM, Deltarho ~ 0.1. PMID- 26429440 TI - The prototype imaging motional Stark effect diagnostic for ASDEX upgrade. AB - This paper presents the development and testing of the prototype Imaging Motional Stark-Effect (IMSE) diagnostic, designed for ASDEX upgrade. A detailed description of the core hardware, theory of operation, and application to complex MSE spectra are presented and analytical evaluation methods suitable for the required accuracy are developed. The diagnostic is tested with a MSE-like polarised spectrum to assess the accuracy of different modulation modes suggested in previous works. Each is found to have small systematic errors due to non-ideal effects of the components, which must be carefully examined. In particular, the effect of intrinsic contrast that results from imperfect parallelism of the birefringent plates is found to have a strong effect. Methods to mitigate and correct for this are discussed. With the necessary corrections and calibrations, the accuracy of polarisation orientation is shown to be within +/-0.2 degrees . The effect of finite ellipticity is examined and the possibility to measure this to an accuracy of +/-2.0 degrees is demonstrated. The system is shown to be insensitive to broadband polarised background light, temperature variations, and critically to variations in the details of the MSE spectrum. PMID- 26429441 TI - Phillips-Tikhonov regularization with a priori information for neutron emission tomographic reconstruction on Joint European Torus. AB - A method of tomographic reconstruction of the neutron emissivity in the poloidal cross section of the Joint European Torus (JET, Culham, UK) tokamak was developed. Due to very limited data set (two projection angles, 19 lines of sight only) provided by the neutron emission profile monitor (KN3 neutron camera), the reconstruction is an ill-posed inverse problem. The aim of this work consists in making a contribution to the development of reliable plasma tomography reconstruction methods that could be routinely used at JET tokamak. The proposed method is based on Phillips-Tikhonov regularization and incorporates a priori knowledge of the shape of normalized neutron emissivity profile. For the purpose of the optimal selection of the regularization parameters, the shape of normalized neutron emissivity profile is approximated by the shape of normalized electron density profile measured by LIDAR or high resolution Thomson scattering JET diagnostics. In contrast with some previously developed methods of ill-posed plasma tomography reconstruction problem, the developed algorithms do not include any post-processing of the obtained solution and the physical constrains on the solution are imposed during the regularization process. The accuracy of the method is at first evaluated by several tests with synthetic data based on various plasma neutron emissivity models (phantoms). Then, the method is applied to the neutron emissivity reconstruction for JET D plasma discharge #85100. It is demonstrated that this method shows good performance and reliability and it can be routinely used for plasma neutron emissivity reconstruction on JET. PMID- 26429442 TI - Blind source separation based x-ray image denoising from an image sequence. AB - Blind source separation (BSS) based x-ray image denoising from an image sequence is proposed. Without priori knowledge, the useful image signal can be separated from an x-ray image sequence, for original images are supposed as different combinations of stable image signal and random image noise. The BSS algorithms such as fixed-point independent component analysis and second-order statistics singular value decomposition are used and compared with multi-frame averaging which is a common algorithm for improving image's signal-to-noise ratio (SNR). Denoising performance is evaluated in SNR, standard deviation, entropy, and runtime. Analysis indicates that BSS is applicable to image denoising; the denoised image's quality will get better when more frames are included in an x ray image sequence, but it will cost more time; there should be trade-off between denoising performance and runtime, which means that the number of frames included in an image sequence is enough. PMID- 26429443 TI - A simple and non-contact optical imaging probe for evaluation of corneal diseases. AB - Non-contact imaging techniques are preferred in ophthalmology. Corneal disease is one of the leading causes of blindness worldwide, and a possible way of detection is by analyzing the shape and optical quality of the cornea. Here, a simple and cost-effective, non-contact optical probe system is proposed and illustrated. The probe possesses high spatial resolutions and is non-dependent on coupling medium, which are significant for a clinician and patient friendly investigation. These parameters are crucial, when considering an imaging system for the objective diagnosis and management of corneal diseases. The imaging of the cornea is performed on ex vivo porcine samples and subsequently on small laboratory animals, in vivo. The clinical significance of the proposed study is validated by performing imaging of the New Zealand white rabbit's cornea infected with Pseudomonas. PMID- 26429444 TI - Microwave soft x-ray microscopy for nanoscale magnetization dynamics in the 5-10 GHz frequency range. AB - We present a scanning transmission x-ray microscopy setup combined with a novel microwave synchronization scheme for studying high frequency magnetization dynamics at synchrotron light sources. The sensitivity necessary to detect small changes in the magnetization on short time scales and nanometer spatial dimensions is achieved by combining the excitation mechanism with single photon counting electronics that is locked to the synchrotron operation frequency. Our instrument is capable of creating direct images of dynamical phenomena in the 5 10 GHz range, with high spatial resolution. When used together with circularly polarized x-rays, the above capabilities can be combined to study magnetic phenomena at microwave frequencies, such as ferromagnetic resonance (FMR) and spin waves. We demonstrate the capabilities of our technique by presenting phase resolved images of a ~6 GHz nanoscale spin wave generated by a spin torque oscillator, as well as the uniform ferromagnetic precession with ~0.1 degrees amplitude at ~9 GHz in a micrometer-sized cobalt strip. PMID- 26429445 TI - Scanning nonlinear dielectric potentiometry. AB - Measuring spontaneous polarization and permanent dipoles on surfaces and interfaces on the nanoscale is difficult because the induced electrostatic fields and potentials are often influenced by other phenomena such as the existence of monopole fixed charges, screening charges, and contact potential differences. A method based on tip-sample capacitance detection and bias feedback is proposed which is only sensitive to polarization- or dipole-induced potentials, unlike Kelvin probe force microscopy. The feasibility of this method was demonstrated by simultaneously measuring topography and polarization-induced potentials on a reconstructed Si(111)-(7 * 7) surface with atomic resolution. PMID- 26429446 TI - Simultaneous differential spinning disk fluorescence optical sectioning microscopy and nanomechanical mapping atomic force microscopy. AB - Combined microscopy techniques offer the life science research community a powerful tool to investigate complex biological systems and their interactions. Here, we present a new combined microscopy platform based on fluorescence optical sectioning microscopy through aperture correlation microscopy with a Differential Spinning Disk (DSD) and nanomechanical mapping with an Atomic Force Microscope (AFM). The illumination scheme of the DSD microscope unit, contrary to standard single or multi-point confocal microscopes, provides a time-independent illumination of the AFM cantilever. This enables a distortion-free simultaneous operation of fluorescence optical sectioning microscopy and atomic force microscopy with standard probes. In this context, we discuss sample heating due to AFM cantilever illumination with fluorescence excitation light. Integration of a DSD fluorescence optical sectioning unit with an AFM platform requires mitigation of mechanical noise transfer of the spinning disk. We identify and present two solutions to almost annul this noise in the AFM measurement process. The new combined microscopy platform is applied to the characterization of a DOPC/DOPS (4:1) lipid structures labelled with a lipophilic cationic indocarbocyanine dye deposited on a mica substrate. PMID- 26429447 TI - Neutron, fluorescence, and optical imaging: An in situ combination of complementary techniques. AB - An apparatus which enables the simultaneous combination of three complementary imaging techniques, optical imaging, fluorescence imaging, and neutron radiography, is presented. While each individual technique can provide information on certain aspects of the sample and their time evolution, a combination of the three techniques in one setup provides a more complete and consistent data set. The setup can be used in transmission and reflection modes and thus with optically transparent as well as opaque samples. Its capabilities are illustrated with two examples. A polymer hydrogel represents a transparent sample and the diffusion of fluorescent particles into and through this polymer matrix is followed. In reflection mode, the absorption of solvent by a nile red functionalized mesoporous silica powder and the corresponding change in fluorescent signal are studied. PMID- 26429448 TI - Compact low temperature scanning tunneling microscope with in-situ sample preparation capability. AB - We report on the design of a compact low temperature scanning tunneling microscope (STM) having in-situ sample preparation capability. The in-situ sample preparation chamber was designed to be compact allowing quick transfer of samples to the STM stage, which is ideal for preparing temperature sensitive samples such as ultra-thin metal films on semiconductor substrates. Conventional spring suspensions on the STM head often cause mechanical issues. To address this problem, we developed a simple vibration damper consisting of welded metal bellows and rubber pads. In addition, we developed a novel technique to ensure an ultra-high-vacuum (UHV) seal between the copper and stainless steel, which provides excellent reliability for cryostats operating in UHV. The performance of the STM was tested from 2 K to 77 K by using epitaxial thin Pb films on Si. Very high mechanical stability was achieved with clear atomic resolution even when using cryostats operating at 77 K. At 2 K, a clean superconducting gap was observed, and the spectrum was easily fit using the BCS density of states with negligible broadening. PMID- 26429449 TI - Dynamic tunneling force microscopy for characterizing electronic trap states in non-conductive surfaces. AB - Dynamic tunneling force microscopy (DTFM) is a scanning probe technique for real space mapping and characterization of individual electronic trap states in non conductive films with atomic scale spatial resolution. The method is based upon the quantum mechanical tunneling of a single electron back and forth between a metallic atomic force microscopy tip and individual trap states in completely non conducting surface. This single electron shuttling is measured by detecting the electrostatic force induced on the probe tip at the shuttling frequency. In this paper, the physical basis for the DTFM method is unfolded through a physical model and a derivation of the dynamic tunneling signal as a function of several experimental parameters is shown. Experimental data are compared with the theoretical simulations, showing quantitative consistency and verifying the physical model used. The experimental system is described and representative imaging results are shown. PMID- 26429450 TI - A widefield fluorescence microscope with a linear image sensor for image cytometry of biospecimens: Considerations for image quality optimization. AB - Linear image sensors have been widely used in numerous research and industry applications to provide continuous imaging of moving objects. Here, we present a widefield fluorescence microscope with a linear image sensor used to image translating objects for image cytometry. First, a calibration curve was characterized for a custom microfluidic chamber over a span of volumetric pump rates. Image data were also acquired using 15 MUm fluorescent polystyrene spheres on a slide with a motorized translation stage in order to match linear translation speed with line exposure periods to preserve the image aspect ratio. Aspect ratios were then calculated after imaging to ensure quality control of image data. Fluorescent beads were imaged in suspension flowing through the microfluidics chamber being pumped by a mechanical syringe pump at 16 MUl min(-1) with a line exposure period of 150 MUs. The line period was selected to acquire images of fluorescent beads with a 40 dB signal-to-background ratio. A motorized translation stage was then used to transport conventional glass slides of stained cellular biospecimens. Whole blood collected from healthy volunteers was stained with 0.02% (w/v) proflavine hemisulfate was imaged to highlight leukocyte morphology with a 1.56 mm * 1.28 mm field of view (1540 ms total acquisition time). Oral squamous cells were also collected from healthy volunteers and stained with 0.01% (w/v) proflavine hemisulfate to demonstrate quantifiable subcellular features and an average nuclear to cytoplasmic ratio of 0.03 (n = 75), with a resolution of 0.31 MUm pixels(-1). PMID- 26429451 TI - Sub-Kelvin magnetic and electrical measurements in a diamond anvil cell with in situ tunability. AB - We discuss techniques for performing continuous measurements across a wide range of pressure-field-temperature phase space, combining the milli-Kelvin temperatures of a helium dilution refrigerator with the giga-Pascal pressures of a diamond anvil cell and the Tesla magnetic fields of a superconducting magnet. With a view towards minimizing remnant magnetic fields and background magnetic susceptibility, we characterize high-strength superalloy materials for the pressure cell assembly, which allows high fidelity measurements of low-field phenomena such as superconductivity below 100 mK at pressures above 10 GPa. In situ tunability and measurement of the pressure permit experiments over a wide range of pressure, while at the same time making possible precise steps across abrupt phase transitions such as those from insulator to metal. PMID- 26429452 TI - A rotational and axial motion system load frame insert for in situ high energy x ray studies. AB - High energy x-ray characterization methods hold great potential for gaining insight into the behavior of materials and providing comparison datasets for the validation and development of mesoscale modeling tools. A suite of techniques have been developed by the x-ray community for characterizing the 3D structure and micromechanical state of polycrystalline materials; however, combining these techniques with in situ mechanical testing under well characterized and controlled boundary conditions has been challenging due to experimental design requirements, which demand new high-precision hardware as well as access to high energy x-ray beamlines. We describe the design and performance of a load frame insert with a rotational and axial motion system that has been developed to meet these requirements. An example dataset from a deforming titanium alloy demonstrates the new capability. PMID- 26429453 TI - Compact AC susceptometer for fast sample characterization down to 0.1 K. AB - We report a new design of an AC magnetic susceptometer compatible with the Physical Properties Measurement System (PPMS) by Quantum Design, as well as with its adiabatic demagnetization refrigerator option. With the elaborate compact design, the susceptometer allows simple and quick sample mounting process. The high performance of the susceptometer down to 0.1 K is demonstrated using several superconducting and magnetic materials. This susceptometer provides a method to quickly investigate qualities of a large number of samples in the wide temperature range between 0.1 and 300 K. PMID- 26429454 TI - Producing and imaging a thin line of He*2 molecular tracers in helium-4. AB - Cryogenic helium-4 has long been recognized as a useful material in fluids research. The unique properties of helium-4 in the gaseous phase and the normal liquid phase allow for the generation of turbulent flows with exceptionally high Reynolds and Rayleigh numbers. In the superfluid phase, helium-4 exhibits two fluid hydrodynamics and possesses fascinating properties due to its quantum nature. However, studying the flows in helium-4 has been very challenging largely due to the lack of effective visualization and velocimetry techniques. In this article, we discuss the development of novel instrumentation for flow visualization in helium based on the generation and imaging of thin lines of metastable He*2 tracer molecules. These molecular tracers are created via femtosecond-laser field-ionization of helium atoms and can be imaged using a laser-induced fluorescence technique. By observing the displacement and distortion of the tracer lines in helium, quantitative information about the flow field can be extracted. We present experimental results in the study of thermal counterflow in superfluid helium that validate the concept of this technique. We also discuss anticipated future developments of this powerful visualization technique. PMID- 26429455 TI - Quick scanning monochromator for millisecond in situ and in operando X-ray absorption spectroscopy. AB - The design and capabilities of a novel Quick scanning Extended X-ray Absorption Fine Structure (QEXAFS) monochromator are presented. The oscillatory movement of the crystal stage is realized by means of a unique open-loop driving scheme operating a direct drive torque motor. The entire drive mechanics are installed inside of a goniometer located on the atmospheric side of the vacuum chamber. This design allows remote adjustment of the oscillation frequency and spectral range, giving complete control of QEXAFS measurements. It also features a real step-scanning mode, which operates without a control loop to prevent induced vibrations. Equipped with Si(111) and Si(311) crystals on a single stage, it facilitates an energy range from 4.0 keV to 43 keV. Extended X-ray absorption fine structure spectra up to k = 14.4 A(-1) have been acquired within 17 ms and X ray absorption near edge structure spectra covering more than 200 eV within 10 ms. The achieved data quality is excellent as shown by the presented measurements. PMID- 26429456 TI - Aerodynamic levitator for large-sized glassy material production. AB - Containerless aerodynamic levitation processing is a unique technology for the fabrication of bulk non-crystalline materials. Using conventional aerodynamic levitation, a high reflective index (RI) material (BaTi2O5 and LaO3/2-TiO2-ZrO2 system) was developed with a RI greater than approximately 2.2, which is similar to that of diamond. However, the glass size was small, approximately 3 mm in diameter. Therefore, it is essential to produce large sized materials for future optical materials applications, such as camera lenses. In this study, a new aerodynamic levitator was designed to produce non-crystalline materials with diameters larger than 6 mm. The concept of this new levitator was to set up a reduced pressure at the top of the molten samples without generating turbulent flow. A numerical simulation was also performed to verify the concept. PMID- 26429457 TI - Image analysis of speckle patterns as a probe of melting transitions in laser heated diamond anvil cell experiments. AB - The precision of melting curve measurements using laser-heated diamond anvil cell (LHDAC) is largely limited by the correct and reliable determination of the onset of melting. We present a novel image analysis of speckle interference patterns in the LHDAC as a way to define quantitative measures which enable an objective determination of the melting transition. Combined with our low-temperature customized IR pyrometer, designed for measurements down to 500 K, our setup allows studying the melting curve of materials with low melting temperatures, with relatively high precision. As an application, the melting curve of Te was measured up to 35 GPa. The results are found to be in good agreement with previous data obtained at pressures up to 10 GPa. PMID- 26429458 TI - Tandem ion mobility spectrometry coupled to laser excitation. AB - This manuscript describes a new experimental setup that allows to perform tandem ion mobility spectrometry (IMS) measurements and which is coupled to a high resolution time-of-flight mass spectrometer. It consists of two 79 cm long drift tubes connected by a dual ion funnel assembly. The setup was built to permit laser irradiation of the ions in the transfer region between the two drift tubes. This geometry allows selecting ions according to their ion mobility in the first drift tube, to irradiate selected ions, and examine the ion mobility of the product ions in the second drift tube. Activation by collision is possible in the same region (between the two tubes) and between the second tube and the time-of flight. IMS-IMS experiments on Ubiquitin are reported. We selected a given isomer of charge state +7 and explored its structural rearrangement following collisional activation between the two drift tubes. An example of IMS-laser-IMS experiment is reported on eosin Y, where laser irradiation was used to produce radical ions by electron photodetachment starting from doubly deprotonated species. This allowed measuring the collision cross section of the radical photo product, which cannot be directly produced with an electrospray source. PMID- 26429459 TI - An adaptable multiple power source for mass spectrometry and other scientific instruments. AB - An Adaptable Multiple Power Source (AMPS) system has been designed and constructed. The AMPS system can provide up to 16 direct current (DC) (+/-400 V; 5 mA), 4 radio frequency (RF) (two 500 VPP sinusoidal signals each, 0.5-5 MHz) channels, 2 high voltage sources (+/-6 kV), and one ~40 W, 250 degrees C temperature-regulated heater. The system is controlled by a microcontroller, capable of communicating with its front panel or a computer. It can assign not only pre-saved fixed DC and RF signals but also profiled DC voltages. The AMPS system is capable of driving many mass spectrometry components and ancillary devices and can be adapted to other instrumentation/engineering projects. PMID- 26429460 TI - Influence of temperature on period of torsion pendulum with a high-Q fused silica fiber. AB - Due to the high-Q fused silica fiber's extreme sensitivity to temperature change, the period estimation of torsion pendulum with high precision depends on the effective correction of the thermoelastic effect. In the measurement of G with the time-of-swing method, we analyze the complex relation between temperature and the pendulum's period and propose a developed method to find the shear thermoelasticity coefficient as well as isolate the influence of temperature on period alone. The result shows that the shear thermoelasticity coefficient is 101(2) * 10(-6)/ degrees C, the resultant correction to Delta(omega(2)) is 9.16(0.18) ppm, and the relative uncertainty to G is less than 1 ppm. PMID- 26429461 TI - Conducted noise analysis and protection of 45 kJ/s, +/-50 kV capacitor charging power supply when interfaced with repetitive Marx based pulse power system. AB - Pulse power systems with highly dynamic loads like klystron, backward wave oscillator (BWO), and magnetron generate highly dynamic noise. This noise leads to frequent failure of controlled switches in the inverter stage of charging power supply. Designing a reliable and compatible power supply for pulse power applications is always a tricky job when charging rate is in multiples of 10 kJ/s. A +/-50 kV and 45 kJ/s capacitor charging power supply based on 4th order LCLC resonant topology has been developed for a 10 Hz repetitive Marx based system. Conditions for load independent constant current and zero current switching (ZCS) are derived mathematically. Noise generated at load end due to dynamic load is tackled effectively and reduction in magnitude noise voltage is achieved by providing shielding between primary and secondary of high voltage high frequency transformer and with LCLC low pass filter. Shielding scales down the ratio between coupling capacitance (Cc) and the collector-emitter capacitance of insulated gate bi-polar transistor switch, which in turn reduces the common mode noise voltage magnitude. The proposed 4th order LCLC resonant network acts as a low pass filter for differential mode noise in the reverse direction (from load to source). Power supply has been tested repeatedly with 5 Hz repetition rate with repetitive Marx based system connected with BWO load working fine without failure of single switch in the inverter stage. PMID- 26429462 TI - A time domain based method for the accurate measurement of Q-factor and resonance frequency of microwave resonators. AB - We present a novel method to determine the resonant frequency and quality factor of microwave resonators which is faster, more stable, and conceptually simpler than the yet existing techniques. The microwave resonator is pumped with the microwave radiation at a frequency away from its resonance. It then emits an exponentially decaying radiation at its eigen-frequency when the excitation is rapidly switched off. The emitted microwave signal is down-converted with a microwave mixer, digitized, and its Fourier transformation (FT) directly yields the resonance curve in a single shot. Being a FT based method, this technique possesses the Fellgett (multiplex) and Connes (accuracy) advantages and it conceptually mimics that of pulsed nuclear magnetic resonance. We also establish a novel benchmark to compare accuracy of the different approaches of microwave resonator measurements. This shows that the present method has similar accuracy to the existing ones, which are based on sweeping or modulating the frequency of the microwave radiation. PMID- 26429463 TI - Impact of laser phase and amplitude noises on streak camera temporal resolution. AB - Streak cameras are now reaching sub-picosecond temporal resolution. In cumulative acquisition mode, this resolution does not entirely rely on the electronic or the vacuum tube performances but also on the light source characteristics. The light source, usually an actively mode-locked laser, is affected by phase and amplitude noises. In this paper, the theoretical effects of such noises on the synchronization of the streak system are studied in synchroscan and triggered modes. More precisely, the contribution of band-pass filters, delays, and time walk is ascertained. Methods to compute the resulting synchronization jitter are depicted. The results are verified by measurement with a streak camera combined with a Ti:Al2O3 solid state laser oscillator and also a fiber oscillator. PMID- 26429464 TI - A magneto-optical microscope for quantitative measurement of magnetic microstructures. AB - An optical system is presented to quantitatively map the stray magnetic fields of microscale magnetic structures, with field resolution down to 50 MUT and spatial resolution down to 4 MUm. The system uses a magneto-optical indicator film (MOIF) in conjunction with an upright reflective polarizing light microscope to generate optical images of the magnetic field perpendicular to the image plane. A novel single light path construction and discrete multi-image polarimetry processing method are used to extract quantitative areal field measurements from the optical images. The integrated system including the equipment, image analysis software, and experimental methods are described. MOIFs with three different magnetic field ranges are calibrated, and the entire system is validated by measurement of the field patterns from two calibration samples. PMID- 26429465 TI - Low-noise and high-speed photodetection system using optical feedback with a current amplification function. AB - A photodetection system with an optical-feedback circuit accompanied by current amplification was fabricated to minimize the drawbacks associated with a transimpedance amplifier (TIA) with a very high resistance feedback resistor. Current amplification was implemented by extracting an output light from the same light source that emitted the feedback light. The current gain corresponds to the ratio of the photocurrent created by the output light to that created by the feedback light because the feedback current value is identical to the input photocurrent value generated by an input light to be measured. The current gain has no theoretical limit. The output light was detected by a photodiode with a TIA having a small feedback resistance. The expression for the input-referred noise current of the optical-feedback photodetection system was derived, and the trade-off between sensitivity and response, which is a characteristic of TIA, was found to considerably improve. An optical-feedback photodetection system with an InGaAs pin photodiode was fabricated. The measured noise equivalent power of the system was 1.7 fW/Hz(1/2) at 10 Hz and 1.3 MUm, which is consistent with the derived expression. The time response of the system was found to deteriorate with decreasing photocurrent. The 50% rise time for a light pulse input increased from 3.1 MUs at a photocurrent of 10 nA to 15 MUs at photocurrents below 10 pA. The bandwidth of the input-referred noise current was 7 kHz, which is consistent with rise times below 10 pA. PMID- 26429466 TI - A compact, high-voltage pulsed charging system based on an air-core pulse transformer. AB - Charging systems of pulsed power generators on mobile platforms are expected to be compact and provide high pulsed power, high voltage output, and high repetition rate. In this paper, a high-voltage pulsed charging system with the aforementioned characteristics is introduced, which can be applied to charge a high-voltage load capacitor. The operating principle of the system and the technical details of the components in the system are described in this paper. The experimental results show that a 600 nF load capacitor can be charged to 60 kV at 10 Hz by the high-voltage pulsed charging system for a burst of 0.5 s. The weight and volume of the system are 60 kg and 600 * 500 * 380 mm(3), respectively. PMID- 26429467 TI - Simple-design ultra-low phase noise microwave frequency synthesizers for high performing Cs and Rb vapor-cell atomic clocks. AB - We report on the development and characterization of novel 4.596 GHz and 6.834 GHz microwave frequency synthesizers devoted to be used as local oscillators in high-performance Cs and Rb vapor-cell atomic clocks. The key element of the synthesizers is a custom module that integrates a high spectral purity 100 MHz oven controlled quartz crystal oscillator frequency-multiplied to 1.6 GHz with minor excess noise. Frequency multiplication, division, and mixing stages are then implemented to generate the exact output atomic resonance frequencies. Absolute phase noise performances of the output 4.596 GHz signal are measured to be -109 and -141 dB rad(2)/Hz at 100 Hz and 10 kHz Fourier frequencies, respectively. The phase noise of the 6.834 GHz signal is -105 and -138 dB rad(2)/Hz at 100 Hz and 10 kHz offset frequencies, respectively. The performances of the synthesis chains contribute to the atomic clock short term fractional frequency stability at a level of 3.1 * 10(-14) for the Cs cell clock and 2 * 10( 14) for the Rb clock at 1 s averaging time. This value is comparable with the clock shot noise limit. We describe the residual phase noise measurements of key components and stages to identify the main limitations of the synthesis chains. The residual frequency stability of synthesis chains is measured to be at the 10( 15) level for 1 s integration time. Relevant advantages of the synthesis design, using only commercially available components, are to combine excellent phase noise performances, simple-architecture, low-cost, and to be easily customized for signal output generation at 4.596 GHz or 6.834 GHz for applications to Cs or Rb vapor-cell frequency standards. PMID- 26429468 TI - New methodology for the thermal characterization of thermoelectric liquids. AB - A new and accurate method for the thermal characterization of thermoelectric liquids is proposed. The experiment is based on a self-generated voltage due to the Seebeck effect. This voltage is provided by the sample when one of its two faces is thermally excited using a modulated laser. The sample used is tetradodecylammonium nitrate salt/1-octanol mixture, with high Seebeck coefficient. The thermal properties of the used sample (thermal diffusivity, effusivity, and conductivity) are found and compared to those obtained by other photothermal techniques. In addition to this, a study of the electrolyte thermal parameters with the variation of tetradodecylammonium nitrate concentration was also carried out. This new method is promising due to its accuracy and its simplicity. PMID- 26429469 TI - A novel voice coil motor-driven compliant micropositioning stage based on flexure mechanism. AB - This paper presents a 2-degrees of freedom flexure-based micropositioning stage with a flexible decoupling mechanism. The stage is composed of an upper planar stage and four vertical support links to improve the out-of-plane stiffness. The moving platform is driven by two voice coil motors, and thus it has the capability of large working stroke. The upper stage is connected with the base through six double parallel four-bar linkages mechanisms, which are orthogonally arranged to implement the motion decoupling in the x and y directions. The vertical support links with serially connected hook joints are utilized to guarantee good planar motion with heavy-loads. The static stiffness and the dynamic resonant frequencies are obtained based on the theoretical analyses. Finite element analysis is used to investigate the characteristics of the developed stage. Experiments are carried out to validate the established models and the performance of the developed stage. It is noted that the developed stage has the capability of translational motion stroke of 1.8 mm and 1.78 mm in working axes. The maximum coupling errors in the x and y directions are 0.65% and 0.82%, respectively, and the motion resolution is less than 200 nm. The experimental results show that the developed stage has good capability for trajectory tracking. PMID- 26429470 TI - Influence of cavity loss on an extrinsic Fabry-Perot cavity intensity-based pressure sensor. AB - We present an extrinsic Fabry-Perot cavity intensity-based pressure sensor that mainly comprises a single-mode fiber end and an elastic monocrystalline silicon layer bonded to a silicon diaphragm. We investigated the influence of cavity loss on the performance indexes (PIS) of the intensity-based extrinsic Fabry-Perot cavity optical fiber pressure sensor. A buffer unit made of three incompressible oil cavities attenuated outside pressure and transformed pressure information into cavity length microchange information. Experimental results indicated that, under center quadrature-points within the linear regions of adjacent fringes, for an applied 40 kPa external pressure, cavity length was modulated by pressures of 69.9 kPa-109.9 kPa, 150.1 kPa-190 kPa, 220.1 kPa-259.9 kPa, and 279.9 kPa-319.9 kPa, output intensity ranges increased as 1 MUW, 1.02 MUW, 1.03 MUW, and 1.05 MUW, sensitivity increased as 0.01909 MUW/kPa, 0.01986 MUW/kPa, 0.02127 MUW/kPa, and 0.02387 MUW/kPa, but linearity degraded, as indicated by the standard deviation of linear fits of 0.02607, 0.02664, 0.02935, and 0.04879 due to cavity loss. Furthermore, the pressure ranges within the same quarter period decreased as 40 kPa, 37.45 kPa, 32.4 kPa, and 30.15 kPa. Consequently, the same lengths of linear regions within adjacent fringes of an approximately sinusoidal curve corresponded to different measurement ranges, linearities, and sensitivities. Initial cavity length must be chosen to optimize both signal strength and the PIS studied here in manufacturing this type sensor. PMID- 26429472 TI - A novel full-angle scanning light scattering profiler to quantitatively evaluate forward and backward light scattering from intraocular lenses. AB - Glare, glistenings, optical defects, dysphotopsia, and poor image quality are a few of the known deficiencies of intraocular lenses (IOLs). All of these optical phenomena are related to light scatter. However, the specific direction that light scatters makes a critical difference between debilitating glare and a slightly noticeable decrease in image quality. Consequently, quantifying the magnitude and direction of scattered light is essential to appropriately evaluate the safety and efficacy of IOLs. In this study, we introduce a full-angle scanning light scattering profiler (SLSP) as a novel approach capable of quantitatively evaluating the light scattering from IOLs with a nearly 360 degrees view. The SLSP method can simulate in situ conditions by controlling the parameters of the light source including angle of incidence. This testing strategy will provide a more effective nonclinical approach for the evaluation of IOL light scatter. PMID- 26429471 TI - A fully integrated standalone portable cavity ringdown breath acetone analyzer. AB - Breath analysis is a promising new technique for nonintrusive disease diagnosis and metabolic status monitoring. One challenging issue in using a breath biomarker for potential particular disease screening is to find a quantitative relationship between the concentration of the breath biomarker and clinical diagnostic parameters of the specific disease. In order to address this issue, we need a new instrument that is capable of conducting real-time, online breath analysis with high data throughput, so that a large scale of clinical test (more subjects) can be achieved in a short period of time. In this work, we report a fully integrated, standalone, portable analyzer based on the cavity ringdown spectroscopy technique for near-real time, online breath acetone measurements. The performance of the portable analyzer in measurements of breath acetone was interrogated and validated by using the certificated gas chromatography-mass spectrometry. The results show that this new analyzer is useful for reliable online (online introduction of a breath sample without pre-treatment) breath acetone analysis with high sensitivity (57 ppb) and high data throughput (one data per second). Subsequently, the validated breath analyzer was employed for acetone measurements in 119 human subjects under various situations. The instrument design, packaging, specifications, and future improvements were also described. From an optical ringdown cavity operated by the lab-set electronics reported previously to this fully integrated standalone new instrument, we have enabled a new scientific tool suited for large scales of breath acetone analysis and created an instrument platform that can even be adopted for study of other breath biomarkers by using different lasers and ringdown mirrors covering corresponding spectral fingerprints. PMID- 26429473 TI - Broadband high-sensitivity current-sensing device utilizing nonlinear magnetoelectric medium and nanocrystalline flux concentrator. AB - A broadband current-sensing device with frequency-conversion mechanism consisting of Terfenol-D/Pb(Zr.Ti)O3 (PZT)/Terfenol-D magnetoelectric laminate and Fe73.5Cu1Nb3Si13.5B9 nanocrystalline flux concentrator is fabricated and characterized. For the purpose of acquiring resonance-enhanced sensitivity within broad bandwidth, a frequency-modulation mechanism is introduced into the presented device through the nonlinearity of field-dependence giant magnetostrictive materials. The presented configuration provides a solution to monitor the weak currents and achieves resonance-enhanced sensitivity of 178.4 mV/A at power-line frequency, which exhibits ~3.86 times higher than that of direct output at power-line frequency of 50 Hz. Experimental results demonstrate that a weak step-change input current of 1 mA can be clearly distinguished by the output amplitude or phase. This miniature current-sensing device provides a promising application in power-line weak current measurement. PMID- 26429474 TI - A dynamic pressure view cell for acoustic stimulation of fluids--Micro-bubble generation and fluid movement in porous media. AB - The development and baseline operation of an acoustic view cell for observing fluids, and fluid-fluid and fluid-solid interfaces in porous media over the frequency range of 10-5000 Hz is described. This range includes the industrially relevant frequency range 500-5000 Hz that is not covered by existing devices. Pressure waveforms of arbitrary shape are generated in a 17.46 mm ID by 200 mm and 690.5 mm long glass tubes at flow rates up to 200 ml/min using a syringe pump. Peak-to-peak amplitudes exceeding 80 kPa are readily realized at frequencies from 10 to 5000 Hz in bubble free fluids when actuated with 20 Vpp as exemplified using castor oil. At resonant frequencies, peak-to-peak pressure amplitudes exceeding 500 kPa were obtained (castor oil at 2100 Hz when actuated with 20 Vpp). Impacts of vibration on macroscopic liquid-liquid and liquid-vapour interfaces and interface movement are illustrated. Pressure wave transmission and attenuation in a fluid saturated porous medium, randomly packed 250-330 MUm spherical silica beads, is also demonstrated. Attenuation differences and frequency shifts in resonant peaks are used to detect the presence and generation of dispersed micro-bubbles (<180 MUm diameter), and bubbles within porous media that are not readily visualized. Envisioned applications include assessment of the impacts of vibration on reaction, mass transfer, and flow/flow pattern outcomes. This knowledge will inform laboratory and pilot scale process studies, where nuisance vibrations may affect the interpretation of process outcomes, and large scale or in situ processes in aquifers or hydrocarbon reservoirs where imposed vibration may be deployed to improve aspects of process performance. Future work will include miscible interface observation and quantitative measurements in the bulk and in porous media where the roles of micro-bubbles comprise subjects of special interest. PMID- 26429475 TI - A new apparatus design for high temperature (up to 950 degrees C) quasi-elastic neutron scattering in a controlled gaseous environment. AB - A design for a sample cell system suitable for high temperature Quasi-Elastic Neutron Scattering (QENS) experiments is presented. The apparatus was developed at the Spallation Neutron Source in Oak Ridge National Lab where it is currently in use. The design provides a special sample cell environment under controlled humid or dry gas flow over a wide range of temperature up to 950 degrees C. Using such a cell, chemical, dynamical, and physical changes can be studied in situ under various operating conditions. While the cell combined with portable automated gas environment system is especially useful for in situ studies of microscopic dynamics under operational conditions that are similar to those of solid oxide fuel cells, it can additionally be used to study a wide variety of materials, such as high temperature proton conductors. The cell can also be used in many different neutron experiments when a suitable sample holder material is selected. The sample cell system has recently been used to reveal fast dynamic processes in quasi-elastic neutron scattering experiments, which standard probes (such as electrochemical impedance spectroscopy) could not detect. In this work, we outline the design of the sample cell system and present results demonstrating its abilities in high temperature QENS experiments. PMID- 26429476 TI - Using stepped anvils to make even insulation layers in laser-heated diamond-anvil cell samples. AB - We describe a method to make even insulation layers for high-pressure laser heated diamond-anvil cell samples using stepped anvils. The method works for both single-sided and double-sided laser heating using solid or fluid insulation. The stepped anvils are used as matched pairs or paired with a flat culet anvil to make gasket insulation layers and not actually used at high pressures; thus, their longevity is ensured. We compare the radial temperature gradients and Soret diffusion of iron between self-insulating samples and samples produced with stepped anvils and find that less pronounced Soret diffusion occurs in samples with even insulation layers produced by stepped anvils. PMID- 26429477 TI - New sample carrier systems for thermogravimetric analysis under forced flow conditions and their influence on microkinetic results. AB - For thermogravimetric analysis, it has been shown that, depending on the type of sample container, different kinetic results could be obtained despite regarding the same reaction under constant conditions. This is due to limiting macrokinetic effects which are strongly dependant on the type of sample carrying system. This prompted the need for sample containers which deliver results minimally limited by diffusive mass transport. In this way, two container systems were developed, both characterized by a forced flow stream through a solid, porous bed: one from bottom to top (counter-current flow) and one from top to bottom (co-current flow). Optical test measurements were performed, the results indicating that reaction proceedings are almost fully independent of the geometrical shape of the sample containers. The Boudouard reaction was investigated with a standard crucible and the new developed systems; the reaction rates determined differed significantly, up to a factor of 6.2 at 1373 K. PMID- 26429478 TI - Development of a high magnetic field assisted pulsed laser deposition system. AB - A high magnetic field assisted pulsed laser deposition (HMF-PLD) system has been developed to in situ grow thin films in a high magnetic field up to 10 T. In this system, a specially designed PLD cylindrical vacuum chamber is horizontally located in the bore configuration of a superconducting magnet with a bore diameter of 200 mm. To adjust the focused pulsed laser into the target in such a narrow PLD vacuum chamber, an ingeniously built-in laser leading-in chamber is employed, including a laser mirror with a reflection angle of 65 degrees and a damage threshold up to 3.4 J/cm(2). A laser alignment system consisting of a built-in video-unit leading-in chamber and a low-energy alignment laser is applied to monitor and align the pulsed laser propagation in the PLD vacuum chamber. We have grown La0.7Sr0.3MnO3 (LSMO) thin films on (LaAlO3)0.3(Sr2AlTaO6)0.7 (001) [LSAT (001)] substrates by HMF-PLD. The results show that the nanostructures of the LSMO films can be tuned from an epitaxially continuous film structure without field to a vertically aligned nanorod structure with an applied high magnetic field above 5 T, and the dimension size of the nanorods can be tuned by the strength of the magnetic field. The associated magnetic anisotropy is found to be highly dependent on the nanorod structures. We show how the HMF-PLD provides an effective route toward tuning the nanostructures and the physical properties of functional thin films, giving it an important role in development of nanodevices and their application. PMID- 26429479 TI - Microscopic observation of magnetic bacteria in the magnetic field of a rotating permanent magnet. AB - Magnetotactic bacteria are ubiquitous and can be found in both freshwater and marine environments. Due to intracellular chains of magnetic single domain particles, they behave like swimming compass needles. In external magnetic fields like the Earth's magnetic field, a torque is acting on the chain. This will cause the bacterium to be rotated and aligned with the external field. The swimming direction of magnetotactic bacteria can be controlled with external magnetic fields, which makes it convenient to study them under a light microscope. Usually, a special set of coils arranged around a light microscope is used to control the swimming magnetotactic bacteria. Here, we present a simple mechanical system with a permanent magnet, which produces a rotating magnetic field of nearly constant amplitude in the focal plane of a light microscope. The device is placed beside the light microscope and easily adaptable to almost any microscope and thus convenient for field experiments. To describe the trajectories qualitatively, a theoretical model of the trajectories is presented. This device can be used to control the swimming direction of magnetotactic bacteria and also for studying their magnetic and hydrodynamic properties. PMID- 26429480 TI - Design of a simple, lightweight, passive-elastic ankle exoskeleton supporting ankle joint stiffness. AB - In this study, a passive-elastic ankle exoskeleton (PEAX) with a one-way clutch mechanism was developed and then pilot-tested with vertical jumping to determine whether the PEAX is sufficiently lightweight and comfortable to be used in further biomechanical studies. The PEAX was designed to supplement the function of the Achilles tendon and ligaments as they passively support the ankle torque with their inherent stiffness. The main frame of the PEAX consists of upper and lower parts connected to each other by tension springs (N = 3) and lubricated hinge joints. The upper part has an offset angle of 5 degrees with respect to the vertical line when the springs are in their resting state. Each spring has a slack length of 8 cm and connects the upper part to the tailrod of the lower part in the neutral position. The tailrod freely rotates with low friction but has a limited range of motion due to the stop pin working as a one-way clutch. Because of the one-way clutch system, the tension springs store the elastic energy only due to an ankle dorsiflexion when triggered by the stop pin. This clutch mechanism also has the advantage of preventing any inconvenience during ankle plantarflexion because it does not limit the ankle joint motion during the plantarflexion phase. In pilot jumping tests, all of the subjects reported that the PEAX was comfortable for jumping due to its lightweight (approximately 1 kg) and compact (firmly integrated with shoes) design, and subjects were able to nearly reach their maximum vertical jump heights while wearing the PEAX. During the countermovement jump, elastic energy was stored during dorsiflexion by spring extension and released during plantarflexion by spring restoration, indicating that the passive spring torque (i.e., supportive torque) generated by the ankle exoskeleton partially supported the ankle joint torque throughout the process. PMID- 26429481 TI - Enhanced analogue front-end for the measurement of the high state of wide-band voltage pulses with 87 dB common-mode rejection ratio and +/-0.65 ppm 1-day offset stability. AB - An improved analogue front-end for measuring the high state of trapezoidal voltage pulses with transition duration of 3 MUs is presented. A new measurement system, composed by a front-end and the state-of-the-art acquisition board NI PXI 5922, has been realized with improved Common Mode Rejection Ratio (CMRR) of more than 87 dB at DC and 3-sigma stability of +/-0.65 ppm over 1 day. After highlighting the main design enhancements with respect to state-of-the-art solutions, the CMRR measurement is reported. The output drift due to temperature and humidity is assessed to be negligible. Finally, the worst-case repeatability is measured both with shorted-to-ground inputs and with an applied common-mode voltage of 10 V, which represents the nominal working condition. PMID- 26429482 TI - Stiffness modeling of compliant parallel mechanisms and applications in the performance analysis of a decoupled parallel compliant stage. AB - This paper investigates the stiffness modeling of compliant parallel mechanism (CPM) based on the matrix method. First, the general compliance matrix of a serial flexure chain is derived. The stiffness modeling of CPMs is next discussed in detail, considering the relative positions of the applied load and the selected displacement output point. The derived stiffness models have simple and explicit forms, and the input, output, and coupling stiffness matrices of the CPM can easily be obtained. The proposed analytical model is applied to the stiffness modeling and performance analysis of an XY parallel compliant stage with input and output decoupling characteristics. Then, the key geometrical parameters of the stage are optimized to obtain the minimum input decoupling degree. Finally, a prototype of the compliant stage is developed and its input axial stiffness, coupling characteristics, positioning resolution, and circular contouring performance are tested. The results demonstrate the excellent performance of the compliant stage and verify the effectiveness of the proposed theoretical model. The general stiffness models provided in this paper will be helpful for performance analysis, especially in determining coupling characteristics, and the structure optimization of the CPM. PMID- 26429483 TI - An ultra-high vacuum chamber for scattering experiments featuring in-vacuum continuous in-plane variation of the angle between entrance and exit vacuum ports. AB - A concept that enables in-vacuum continuous variation of the angle between two ports in one plane has been developed and implemented. The vacuum chamber allows for measuring scattering cross sections as a function of scattering angle and is intended for resonant inelastic X-ray scattering experiments. The angle between the ports can be varied in the range of 30 degrees -150 degrees , while the pressure change is less than 2 * 10(-10) mbars. PMID- 26429484 TI - Point contact tunneling spectroscopy apparatus for large scale mapping of surface superconducting properties. AB - We describe the design and testing of a point contact tunneling spectroscopy device that can measure material surface superconducting properties (i.e., the superconducting gap Delta and the critical temperature T(C)) and density of states over large surface areas with size up to mm(2). The tip lateral (X,Y) motion, mounted on a (X,Y,Z) piezo-stage, was calibrated on a patterned substrate consisting of Nb lines sputtered on a gold film using both normal (Al) and superconducting (PbSn) tips at 1.5 K. The tip vertical (Z) motion control enables some adjustment of the tip-sample junction resistance that can be measured over 7 orders of magnitudes from a quasi-ohmic regime (few hundred Omega) to the tunnel regime (from tens of kOmega up to few GOmega). The low noise electronic and LabVIEW program interface are also presented. The point contact regime and the large-scale motion capabilities are of particular interest for mapping and testing the superconducting properties of macroscopic scale superconductor-based devices. PMID- 26429485 TI - Deformation behavior of micro-indentation defects under uniaxial and biaxial loads. AB - The microdefects of structure frequently act as the source to generate initial cracks and lead to the fracture failure. Study on the deformation behaviors of embedded defects would be conducive to better understand the failure mechanisms of structural materials. Micro-indentation technique was applied to prepare the initial indentations as embedded surface defects at the gauge length section and central section of a cross-shaped AZ31B magnesium alloy specimen. A novel in situ biaxial tensile device was developed to apply the synchronous biaxial loads. Via the observation by an optical microscope with three-dimensional imaging and measurement functions, the changing laws of the indentation topographies under uniaxial and biaxial tensile loads were discussed. Compared with the gauge length section, the increasing trend of the indentation length of the central section was relatively flat, and the decreasing trend of the indentation depth was more significant. The changes of indentation topographies were explained by the Poisson effect, and the significant plastic tensile stress has led to the releasing of the residual stress around the indentation location and also promoted the planarization of the pileup. PMID- 26429486 TI - Industry-relevant magnetron sputtering and cathodic arc ultra-high vacuum deposition system for in situ x-ray diffraction studies of thin film growth using high energy synchrotron radiation. AB - We present an industry-relevant, large-scale, ultra-high vacuum (UHV) magnetron sputtering and cathodic arc deposition system purposefully designed for time resolved in situ thin film deposition/annealing studies using high-energy (>50 keV), high photon flux (>10(12) ph/s) synchrotron radiation. The high photon flux, combined with a fast-acquisition-time (<1 s) two-dimensional (2D) detector, permits time-resolved in situ structural analysis of thin film formation processes. The high-energy synchrotron-radiation based x-rays result in small scattering angles (<11 degrees ), allowing large areas of reciprocal space to be imaged with a 2D detector. The system has been designed for use on the 1-tonne, ultra-high load, high-resolution hexapod at the P07 High Energy Materials Science beamline at PETRA III at the Deutsches Elektronen-Synchrotron in Hamburg, Germany. The deposition system includes standard features of a typical UHV deposition system plus a range of special features suited for synchrotron radiation studies and industry-relevant processes. We openly encourage the materials research community to contact us for collaborative opportunities using this unique and versatile scientific instrument. PMID- 26429487 TI - A novel compact three-dimensional laser-sintered collimator for neutron scattering. AB - Improvements in the available flux at neutron sources are making it increasingly feasible to obtain refineable neutron diffraction data from samples smaller than 1 mm(3). The signal is typically too weak to introduce any further sample environment in the 30-50 mm diameter surrounding the sample (such as the walls of a pressure cell) due to the high ratio of background to sample signal, such that even longer count times fail to reveal reflections from the sample. Many neutron instruments incorporate collimators to reduce parasitic scattering from the instrument and from any surrounding material and larger pieces of sample environment, such as cryostats. However, conventional collimation is limited in the volume it can focus on due to difficulties in producing tightly spaced neutron-absorbing foils close to the sample and in integrating this into neutron instruments. Here we present the design of a novel compact 3D rapid-prototyped (or "printed") collimator which reduces these limitations and is shown to improve the ratio of signal to background, opening up the feasibility of using additional sample environment for neutron diffraction from small sample volumes. The compactness and ease of customisation of the design allows this concept to be integrated with existing sample environment and with designs that can be tailored to individual detector geometries without the need to alter the setup of the instrument. Results from online testing of a prototype collimator are presented. The proof of concept shows that there are many additional collimator designs which may be manufactured relatively inexpensively, with a broad range of customisation, and geometries otherwise impossible to manufacture by conventional techniques. PMID- 26429488 TI - Note: Design and fabrication of a simple versatile microelectrochemical cell and its accessories. AB - A microelectrochemical cell housed in an optical microscope and custom-made accessories have been designed and fabricated, which allows performing spatially resolved corrosion measurements. The cell assembly was designed to directly integrate the reference electrode close to the capillary tip to avoid air bubbles. A hard disk along with an old optical microscope was re-engineered into a microgrinder, which made the vertical grinding of glass capillary tips very easy. A stepper motor was customized into a microsyringe pump to dispense a controlled volume of electrolyte through the capillary. A force sensitive resistor was used to achieve constant wetting area. The functionality of the developed instrument is demonstrated by studying MU-electrochemical behavior of worn surface on AA2014-T6 alloy. PMID- 26429489 TI - Note: Design and realization of a portable edge illumination X-ray phase contrast imaging system. AB - We discuss a portable edge illumination x-ray phase contrast imaging system based on compact piezoelectric motors, which enables its transportation to different environments, e.g., hosting different x-ray source technologies. The analysis of images of standard samples reveals an angular sensitivity of 270 +/- 6 nrad, which compares well with the 260 +/- 10 nrad reported for previous systems based on stepper motors, demonstrating that system portability can be achieved without affecting phase sensitivity. The results can also be considered a test of the performance of the piezoelectric motors, and as such could be of interest to researchers planning their use in other imaging systems. PMID- 26429490 TI - Note: Utilization of polymer gel as a bolus compensator and a dosimeter in the near-surface buildup region for breast-conserving therapy. AB - Tangential beam radiotherapy is routinely used for radiation therapy after breast conserving surgery. A tissue-equivalent bolus placed on the irradiated area shifts the depth of the dose distribution; this bolus provides uniform dose distribution to the breast. The gel bolus made by the BANG-Pro((r)) polymer gel and in an oxygen non-transmission pack was applicable as a dosimeter to measure dose distribution in near-surface buildup region. We validated the use of the gel bolus to improve in the whole-breast/chest wall, including the near-surface buildup region. PMID- 26429491 TI - Note: A small roll angle measurement method with enhanced resolution based on a heterodyne interferometer. AB - Small roll angle is hard to be measured directly by commercial interferometer instruments due to their low sensitivities in axial direction. A method for its measurement based on a heterodyne interferometer is presented, which adopts accessories including a half wave plate, a multiple-reflector, and a phase meter to achieve test by detecting phase differences between the measurement and reference arms. Mathematical model reveals the resolution will be improved by increasing pass times through the half wave plate. The theoretical resolution is up to 0.19 in. when the pass times increase to three and the phase meter resolution is 0.01 degrees . The proposed method is proved by the experiment. PMID- 26429492 TI - Note: Detector collimators for the nanoscale ordered materials diffractometer instrument at the Spallation Neutron Source. AB - Five neutron collimator designs were constructed and tested at the nanoscale ordered materials diffractometer (NOMAD) instrument. Collimators were made from High Density PolyEthylene (HDPE) or 5% borated HDPE. In all cases, collimators improved the signal to background ratio and reduced detection of secondary scattering. In the Q-range 10-20 A(-1), signal to background ratio improved by factors of approximately 1.6 and 2.0 for 50 and 100 mm deep collimators, respectively. In the Q-range 40-50 A(-1), the improvement factors were 1.8 and 2.7. Secondary scattering as measured at Q ~ 9.5 A(-1) was significantly decreased when the collimators were installed. PMID- 26429493 TI - Note: A resonating reflector-based optical system for motion measurement in micro cantilever arrays. AB - A robust, compact optical measurement unit for motion measurement in micro cantilever arrays enables development of portable micro-cantilever sensors. This paper reports on an optical beam deflection-based system to measure the deflection of micro-cantilevers in an array that employs a single laser source, a single detector, and a resonating reflector to scan the measurement laser across the array. A strategy is also proposed to extract the deflection of individual cantilevers from the acquired data. The proposed system and measurement strategy are experimentally evaluated and demonstrated to measure motion of multiple cantilevers in an array. PMID- 26429494 TI - Note: Model-based identification method of a cable-driven wearable device for arm rehabilitation. AB - Cable-driven exoskeletons have used active cables to actuate the system and are worn on subjects to provide motion assistance. However, this kind of wearable devices usually contains uncertain kinematic parameters. In this paper, a model based identification method has been proposed for a cable-driven arm exoskeleton to estimate its uncertainties. The identification method is based on the linearized error model derived from the kinematics of the exoskeleton. Experiment has been conducted to demonstrate the feasibility of the proposed model-based method in practical application. PMID- 26429495 TI - Note: Directly measuring the direct digital synthesizer frequency chirp-rate for an atom interferometer. AB - During gravity measurements with Raman type atom interferometry, the frequency of the laser used to drive Raman transition is scanned by chirping the frequency of a direct digital synthesizer (DDS), and the local gravity is determined by precisely measuring the chip rate alpha of DDS. We present an effective method that can directly evaluate the frequency chirp rate stability of our DDS. By mixing a pair of synchronous linear sweeping signals, the chirp rate fluctuation is precisely measured with a frequency counter. The measurement result shows that the relative alpha instability can reach 5.7 * 10(-11) in 1 s, which is neglectable in a 10(-9) g level atom interferometry gravimeter. PMID- 26429496 TI - Note: Resonance magnetoelectric interactions in laminate of FeCuNbSiB and multilayer piezoelectric stack for magnetic sensor. AB - This paper develops a simple miniature magnetoelectric (ME) laminate FeCuNbSiB/PZT-stack made up of magnetostrictive Fe73.5Cu1Nb3Si13.5B9 (FeCuNbSiB) foils and piezoelectric Pb(Zr, Ti)O3 (PZT) multilayer stack vibrator. Resonant ME interactions of FeCuNbSiB/PZT-stack with different layers of FeCuNbSiB foil (L) are investigated in detail. The experimental results show that the ME voltage coefficient reaches maximum value of 141.5 (V/cm Oe) for FeCuNbSiB/PZT-stack with L = 6. The AC-magnetic sensitivities can reach 524.29 mV/Oe and 1.8 mV/Oe under resonance 91.6 kHz and off-resonance 1 kHz, respectively. The FeCuNbSiB/PZT-stack can distinguish small dc-magnetic field of ~9 nT. The results indicate that the proposed ME composites are very promising for the cheap room-temperature magnetic field sensing technology. PMID- 26429497 TI - Note: An improved 3D imaging system for electron-electron coincidence measurements. AB - We demonstrate an improved imaging system that can achieve highly efficient 3D detection of two electrons in coincidence. The imaging system is based on a fast frame complementary metal-oxide semiconductor camera and a high-speed waveform digitizer. We have shown previously that this detection system is capable of 3D detection of ions and electrons with good temporal and spatial resolution. Here, we show that with a new timing analysis algorithm, this system can achieve an unprecedented dead-time (<0.7 ns) and dead-space (<1 mm) when detecting two electrons. A true zero dead-time detection is also demonstrated. PMID- 26429498 TI - Note: Design of a laser feedback interferometer with double diffraction system. AB - A novel laser feedback interferometer with double diffraction system is proposed in this paper. A beam emitted from the laser is incident onto a transmission grating. The mth order beam is vertically reflected by a mirror and diffracted again by the grating. The double-diffracted beam returns into the laser cavity and mixes with the light inside the active cavity, thus generating a modulation of both the amplitude and the frequency of the lasing field. Theoretical analysis and experimental observations show that the output signal of the proposed system depends on the grating pitch and the direction of the phase movement can be obtained from inclination of the interference signal. It provides a potential displacement sensor with high stability and quite a compact configuration. PMID- 26429500 TI - Adaptive Designs with Discrete Test Statistics and Consideration of Overrunning. AB - BACKGROUND: Interim analyses are used in clinical trials in order to enable early decisions for medical, ethical, and economic reasons. However, it appears unfeasible to stop a trial during such an interim analysis. New patients will thus enter the trial while the interim analysis is ongoing. Moreover, depending on the event kinetics of the specific disease, the trial design, and the corresponding endpoints, some patients might still be unevaluable at the interim analysis due to not yet completed follow-up. Occurrence of these types of patients is characteristic for sequentially analyzed trials. Such patients are referred to as interim patients. In trials with multiple primary endpoints, another type of interim patients occurs. If some but not all null hypotheses can be rejected at the interim analysis, the trial might be continued to a second stage in order to answer the remaining questions. These second stage patients, however, provide new data to all trial questions including the already rejected ones and thus formally act as interim patients regarding the already rejected null hypotheses. Although all kinds of interim patients are not part of the interim analysis, the data collected on those patients have to be sent to the office of regulatory affairs and will be analyzed. If a smaller or contrasting treatment effect is observed in interim patients, this might lead to a withdrawal of an earlier superiority proof. OBJECTIVES: Presently, interim patients and their data are usually not considered in the confirmatory test. We offer a strategy to deal with interim patients in sequentially analyzed trials with discrete test statistics. The method covers sequentially analyzed single- and multi-arm trials with one or multiple primary endpoints. METHODS: When planning adaptive designs, it is common practice to assume that the stage-wise p-values are independent and standard uniformly distributed under the null hypothesis. In the context of discrete test statistics, this implies conservative tests. We provide an algorithm which iteratively optimizes an initially given design while adjusting for both discreteness of test statistics and interim patients. The algorithm is described verbally, graphically and formally to facilitate immediate implementation in computer software. RESULTS: The optimized design exploits the aspired significance level better and is more powerful than the initial one. The algorithm applies to fixed sample and planned flexible adaptive designs for single- and multi-arm trials with one or multiple primary endpoints. The benefit increases with the number of interim patients. CONCLUSIONS: When planning a trial with interim analyses, the rules for decisions must be adjusted to interim patients. Otherwise, the test procedure is conservative resulting in loss of power. This is essential in situations where the number of interim patients is important compared to the first stage, particularly in trials with multiple primary endpoints. PMID- 26429501 TI - 3D Light-Sheet Fluorescence Microscopy of Cranial Neurons and Vasculature during Zebrafish Embryogenesis. AB - Precise 3D spatial mapping of cells and their connections within living tissues is required to fully understand developmental processes and neural activities. Zebrafish embryos are relatively small and optically transparent, making them the vertebrate model of choice for live in vivo imaging. However, embryonic brains cannot be imaged in their entirety by confocal or two-photon microscopy due to limitations in optical range and scanning speed. Here, we use light-sheet fluorescence microscopy to overcome these limitations and image the entire head of live transgenic zebrafish embryos. We simultaneously imaged cranial neurons and blood vessels during embryogenesis, generating comprehensive 3D maps that provide insight into the coordinated morphogenesis of the nervous system and vasculature during early development. In addition, blood cells circulating through the entire head, vagal and cardiac vasculature were also visualized at high resolution in a 3D movie. These data provide the foundation for the construction of a complete 4D atlas of zebrafish embryogenesis and neural activity. PMID- 26429503 TI - Reinforcing cerclage for a short cervix at follow-up after the primary cerclage procedure. AB - OBJECTIVE: To determine whether a reinforcing cerclage (RC) for a short cervix measured after the primary cerclage procedure prolonged pregnancy. METHODS: We conducted a retrospective cohort study of 157 women with singleton gestations who underwent cerclage for standard indications. Women were grouped according to cervical length (CL) at the time of follow-up 1-2 weeks after the initial cerclage placement: >=25 mm (106 women) and <25 mm with (20 women) or without RC (31 women). Gestational age (GA) at delivery was compared by ANOVA. Survival risk analysis was applied to model GA at delivery adjusted for indication and CL before and after the first cerclage. RESULTS: Women with CL >=25mm delivered later than women with CL < 25mm after the first cerclage (p < 0.01). RC did not delay delivery for women with CL < 25 mm (p = 0.17) after the primary procedure. Indication for the primary cerclage (p < 0.01) and CL (p < 0.01) after the primary cerclage were the best predictors for GA at delivery. CONCLUSION: Placement of RC for short cervix did not prolong duration of pregnancy, GA at delivery or modify the probability of preterm birth. PMID- 26429502 TI - NMAAP1 Expressed in BCG-Activated Macrophage Promotes M1 Macrophage Polarization. AB - Macrophages are divided into two subpopulations: classically activated macrophages (M1) and alternatively activated macrophages (M2). BCG (Bacilli Calmette-GuC)rin) activates disabled naC/ve macrophages to M1 macrophages, which act as inflammatory, microbicidal and tumoricidal cells through cell-cell contact and/or the release of soluble factors. Various transcription factors and signaling pathways are involved in the regulation of macrophage activation and polarization. We discovered that BCG-activated macrophages (BAM) expressed a new molecule, and we named it Novel Macrophage Activated Associated Protein 1 (NMAAP1). The current study found that the overexpression of NMAAP1 in macrophages results in M1 polarization with increased expression levels of M1 genes, such as inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-N1), Interleukin 6 (IL-6), Interleukin 12 (IL-12), Monocyte chemoattractant protein-1 (MCP-1) and Interleukin-1 beta (IL-1N2), and decreased expression of some M2 genes, such as Kruppel-like factor 4 (KLF4) and suppressor of cytokine signaling 1 (SOCS1), but not other M2 genes, including arginase-1 (Arg-1), Interleukin (IL-10), transforming growth factor beta (TGF-N2) and found in inflammatory zone 1 (Fizz1). Moreover, NMAAP1 overexpression in the RAW264.7 cell line increased cytotoxicity against MCA207 tumor cells, which depends on increased inflammatory cytokines rather than cell-cell contact. NMAAP1 also substantially enhanced the phagocytic ability of macrophages, which implies that NMAAP1 promoted macrophage adhesive and clearance activities. Our results indicate that NMAAP1 is an essential molecule that modulates macrophages phenotype and plays an important role in macrophage tumoricidal functions. PMID- 26429504 TI - A structural model for multimodular NRPS assembly lines. AB - This viewpoint article focuses on the structures of the dissected catalytic domains of non-ribosomal peptide synthetases (NRPSs) associated with substrate selection and activation (A domain), substrate shuttling among the active sites (PCP domain), peptide bond formation (C domain) and product release (TE domain). Structural details of these essential components of the NRPS machinery, integrated in a didomain (PCP-C) and an elongation module (C-A-PCP), were used to generate a model for a multimodular NRPS assembly line. PMID- 26429506 TI - The safety of treatments for angioedema with hereditary C1 inhibitor deficiency. AB - INTRODUCTION: Angioedema is a localized and self-limiting edema of the subcutaneous and submucosal tissue. Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is the best characterized form of hereditary angioedema. In C1-INH-HAE, the reduced plasma levels of C1-INH cause instability of the contact system with release of bradykinin, the key mediator of angioedema. C1-INH HAE is characterized by recurrent skin swelling, abdominal pain, and potentially life-threatening upper airways obstruction. Knowledge of the molecular mechanisms leading from C1-INH deficiency to angioedema allowed the development of several therapies. AREAS COVERED: The aim of this review article is to discuss the safety of currently available treatments of C1-INH-HAE. The authors give an insight on the mechanism of action and safety profile of drugs for treatment of acute attacks and for short- and long-term prophylaxis. Evidence from systematic reviews, clinical trials, retrospective studies, and case reports is summarized in this review. EXPERT OPINION: C1-INH-HAE is a disabling, life-threatening condition that lasts life-long. Different therapeutic approaches with different drugs provide significant benefit to patients. Safety profiles of these therapies are critical for optimal therapeutic decision and need to be known by C1-INH-HAE treating physicians for appropriate risk/benefit evaluation. PMID- 26429505 TI - Fatigue induced changes in conical implant-abutment connections. AB - OBJECTIVES: Based on the current lack of data and understanding of the wear behavior of dental two-piece implants, this study aims for evaluating the microgap formation and wear pattern of different implants in the course of cyclic loading. METHODS: Several implant systems with different conical implant-abutment interfaces were purchased. The implants were first evaluated using synchrotron X ray high-resolution radiography (SRX) and scanning electron microscopy (SEM). The implant-abutment assemblies were then subjected to cyclic loading at 98N and their microgap was evaluated after 100,000, 200,000 and 1 million cycles using SRX, synchrotron micro-tomography (MUCT). Wear mechanisms of the implant-abutment connection (IAC) after 200,000 cycles and 1 million cycles were further characterized using SEM. RESULTS: All implants exhibit a microgap between the implant and abutment prior to loading. The gap size increased with cyclic loading with its changes being significantly higher within the first 200,000 cycles. Wear was seen in all implants regardless of their interface design. The wear pattern comprised adhesive wear and fretting. Wear behavior changed when a different mounting medium was used (brass vs. polymer). SIGNIFICANCE: A micromotion of the abutment during cyclic loading can induce wear and wear particles in conical dental implant systems. This feature accompanied with the formation of a microgap at the IAC is highly relevant for the longevity of the implants. PMID- 26429507 TI - Management of complex anal fistulae. PMID- 26429508 TI - Acute diverticulitis: a complex management challenge. PMID- 26429509 TI - Challenges in the management of invasive pulmonary zygomycosis: the Alfred experience. PMID- 26429510 TI - Novel method of surgical mask tying to prevent spectacle slippage. PMID- 26429511 TI - Response to Re: Role of inflammatory markers as predictors of laparotomy in patients presenting with acute abdomen. PMID- 26429512 TI - Re: Role of inflammatory markers as predictors of laparotomy in patients presenting with acute abdomen. PMID- 26429513 TI - Incidence of gallbladder torsion in acute cholecystectomy patients. PMID- 26429514 TI - Report card from the 'ragged' school of anatomy. PMID- 26429515 TI - Ultra-Tuning of the Rare-Earth fcu-MOF Aperture Size for Selective Molecular Exclusion of Branched Paraffins. AB - Using isoreticular chemistry allows the design and construction of a new rare earth metal (RE) fcu-MOF with a suitable aperture size for practical steric adsorptive separations. The judicious choice of a relatively short organic building block, namely fumarate, to bridge the 12-connected RE hexanuclear clusters has afforded the contraction of the well-defined RE-fcu-MOF triangular window aperture, the sole access to the two interconnected octahedral and tetrahedral cages. The newly constructed RE (Y(3+) and Tb(3+)) fcu-MOF analogues display unprecedented total exclusion of branched paraffins from normal paraffins. The resultant window aperture size of about 4.7 A, regarded as a sorbate-size cut-off, enabled a complete sieving of branched paraffins from normal paraffins. The results are supported by collective single gas and mixed gas/vapor adsorption and calorimetric studies. PMID- 26429518 TI - Editorial overview: New technologies. PMID- 26429519 TI - Occurrence of otitis media in children and assessment of treatment options. PMID- 26429521 TI - The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies. AB - BACKGROUND: Antiphospholipid syndrome is defined by the combination of thrombotic events and/or obstetric morbidity in patients who have tested positive persistently for antiphospholipid antibodies. With good treatment, approximately 70% of pregnant women with antiphospholipid syndrome will deliver a viable live infant. However, current management does not prevent all maternal, fetal, and neonatal complications of antiphospholipid syndrome. OBJECTIVES: This observational, retrospective, single-center cohort study aimed to assess pregnancy outcome in women with antiphospholipid antibodies who were treated with hydroxychloroquine in addition to conventional treatment during pregnancy. STUDY DESIGN: One-hundred seventy pregnancies in 96 women with persistent antiphospholipid antibodies were analyzed: (1) 51 pregnancies that occurred in 31 women were treated with hydroxychloroquine for at least 6 months before pregnancy, and the therapy continued throughout gestation (group A); (2) 119 pregnancies that occurred in 65 women with antiphospholipid antibodies that were not treated with hydroxychloroquine were included as controls (group B). RESULTS: Hydroxychloroquine-treatment was associated with a higher rate of live births (67% group A vs 57% group B; P = .05) and a lower prevalence of antiphospholipid antibodies-related pregnancy morbidity (47% group A vs 63% B; P = .004). The association of hydroxychloroquine with a lower rate of any complication in pregnancy was confirmed after multivariate analysis (odds ratio, 2.2; 95% confidence interval, 1.2-136; P = .04). Fetal losses at >10 weeks of gestation (2% vs 11%; P = .05) and placenta-mediated complications (2% vs 11%; P = .05) were less frequent in group A than group B. Pregnancy duration was longer in group A than group B (27.6 [6-40] vs 21.5 [6-40] weeks; P = .03). There was a higher rate of spontaneous vaginal labor in hydroxychloroquine-treated women compared with group B (37.3% vs 14.3%; P = .01). CONCLUSIONS: Despite the heterogeneity in the 2 groups in terms of systemic lupus erythematosus prevalence and previous pregnancy history, our results support the concept that women with antiphospholipid antibodies may benefit from treatment with hydroxychloroquine during pregnancy to improve pregnancy outcome. The addition of hydroxychloroquine to conventional treatment is worthy of further assessment in a proper designed randomized controlled trial. PMID- 26429520 TI - Bronchopulmonary infection-colonization patterns in Spanish cystic fibrosis patients: Results from a national multicenter study. AB - BACKGROUND: Clinical and demographical knowledge on Spanish cystic fibrosis (CF) patients is incomplete as no national registry exists. CF-microbiology has not been studied at national level. The results of the first Spanish multicenter study on CF microbiology are presented. METHODS: 24 CF-Units for adult (n=12) and pediatric (n=12) patients from 17 hospitals provided sputa and clinical data from 15 consecutive patients. Cultures and susceptibility testing were performed. Colonization impact on pulmonary function was assessed. RESULTS: 341 patients [mean (SD) age 21 (11) years, 180>=18years, mean (SD) FEV1=68 (25)%] were included. Pseudomonas aeruginosa was reported as chronic, intermittent or absent in 46%, 22% and 32% of patients, respectively. The annual prevalence was 62%. Positive P. aeruginosa and methicillin-resistant Staphylococcus aureus cultures were significantly associated with lower FEV1 (p<0.001 and p=0.003, respectively). CONCLUSIONS: The representative subset of the Spanish CF population which has been clinically, demographically and microbiologically characterized will serve as a reference for future CF studies in Spain. PMID- 26429522 TI - Tamsulosin does not increase 1-week passage rate of ureteral stones in ED patients. AB - OBJECTIVE: The objective of the study is to determine if tamsulosin initiated in the emergency department (ED) decreases the time to ureteral stone passage at 1 week or time to pain resolution, compared to placebo. METHODS: We performed a prospective, randomized, double-blinded, placebo-controlled trial of tamsulosin vs placebo in ED patients with ureterolithiasis on computed tomography. Patients were identified and enrolled between April 2007 and February 2009 and were randomized to either 0.4 mg of tamsulosin or placebo for 1 week. We contacted participants using a telephone survey on post-ED visit days 1, 2, 3, and 7. The primary outcome was time to stone passage, with secondary outcomes being maximum pain score and amount of pain medication required. RESULTS: Of the 127 patients enrolled during this study, 15 were lost to follow-up, and 12 required surgical interventions before the 7-day mark, leaving 100 patients for analysis. Of the 100 patients, 53 received tamsulosin and 47 received placebo. There was no difference between groups in percentage of male, mean age, initial serum creatinine, average stone size, stone location, and history of prior stone. The probability that the patient did not pass a stone at 7 days was not different between tamsulosin and placebo, 62.1% (95% confidence interval, 49.1%-75.1%) vs 54.4% (95% confidence interval, 40.3%-68.6%; P = .58). There was no significant difference in the high pain score (P = .12) or hydrocodone/acetaminophen intake (P = .76) between treatment groups at any of the time points. CONCLUSION: This study reveals no difference in the proportion of stone passage or high pain score and pain medication utilization at 7 days between tamsulosin and placebo. PMID- 26429523 TI - Chloroquine and Hydroxychloroquine Are Novel Inhibitors of Human Organic Anion Transporting Polypeptide 1A2. AB - Chloroquine (CQ) and hydroxychloroquine (HCQ) are widely used to treat malaria and inflammatory diseases, long-term usage of which often causes severe side effects, especially retinopathy. Solute carrier transporters (SLCs) are important proteins responsible for the cellular uptake of endogenous and exogenous substances. Inhibitors competing with transporter substrates for SLCs often results in unfavorable toxicities and unsatisfactory therapeutic outcomes. We investigated the inhibitory effect of CQ and HCQ on substrate uptake mediated through a range of important SLC transporters in overexpressing human embryonic kidney (HEK293) cells. Our data revealed that both CQ and HCQ potently inhibit the uptake activity of organic anion transporting polypeptide 1A2 (OATP1A2). We recently reported OATP1A2 to be expressed in human retinal pigment epithelium (RPE), where it mediates cellular uptake of all-trans-retinol (atROL), a key step in the classical visual cycle. In this study, we demonstrate that CQ and HCQ could markedly impair atROL uptake in OATP1A2-expressing HEK293 cells and more importantly, in primary human RPE cells. Our study shows that CQ and HCQ are novel inhibitors of OATP1A2 and significantly impair OATP1A2-mediated substrate uptake, particularly transport of atROL into the RPE. This effect may compromise the function of the classic visual cycle leading to vision impairment and contribute to the retinopathy observed clinically in patients using CQ or HCQ. PMID- 26429524 TI - Ultrasound and physical models shed light on the respiratory system of embryonic dogfishes. AB - Embryos of live-bearing elasmobranchs (sharks, skates, and rays) must acquire oxygen in the uterus for several months to more than a year, but the mechanisms of delivery and uptake are still largely unknown. Diagnostic sonography performed on a captive Japanese dogfish (Squalus japonicus) showed that a late-stage embryo used buccal movement to pump uterine fluid, suggesting that the embryo acquires oxygen from uterine fluid via gill ventilation. It has been assumed that embryonic respiration in aplacental sharks depends on oxygen supplied by the uterine wall. To test this hypothesis, the rate of oxygen diffusion was estimated by applying a physical model to the uterine wall of two dogfish species (Squalus cf. mitsukurii and Squalus cubensis). The model calculations indicate that the supply of oxygen via diffusion through the uterine villi contributes less than 15 30% of the total oxygen demand of late-stage embryos. Some previous authors have suggested that pregnant dogfish intermittently exchange uterine fluid with external seawater during late gestation. Thus, late-stage embryos may acquire oxygen primarily from uterine seawater introduced from the external environment. PMID- 26429525 TI - The seminal receptacle and implications for reproductive processes in the invasive gastropod Crepidula fornicata. AB - The calyptraeid gastropod Crepidula fornicata is the object of considerable research attention, due to its invasive status in the North-Eastern Atlantic, its introduction to habitats throughout the Northern hemisphere, and its scientific interest as a model organism for the study of developmental and reproductive processes in the Metazoa. Since the knowledge concerning the structural foundations for its reproductive processes is surprisingly weak, we investigated the seminal receptacle, a key structure in the reproductive biology of other metazoans, using histology, scanning electron and transmission electron microscopy. The seminal receptacle consists of 9-11 lobes, each subdivided into small, narrow lobules. The inner epithelium of the lobules appears to be highly dynamic, characterised by the perforation and attachment of received spermatozoa, the progressive degeneration of this epithelium, and the concomitant detachment of the spermatozoa. The allocation of spermatozoa to many different lobules, in different phases, may explain the extended reproductive season of C. fornicata, and thereby contribute to its colonizing and invasive success. The same compartmentalisation, as well as the complete covering of the inner epithelium of the lobules by spermatozoa and the large amount of spermatozoan debris in the lumina, suggest that the C. fornicata seminal receptacle may be a site of sperm competition in this polyandrous species. PMID- 26429526 TI - [Effects of simulated weightlessness on biological activity of human NK cells induced by IL-2]. AB - OBJECTIVE: To investigate the effects of simulated weightlessness on the activity of human natural killer (NK) cells induced by interleukin 2 (IL-2). METHODS: Primary human NK cells were cultured under simulated weightlessness condition. The viability of NK cells was determined by CCK-8 assay; cell apoptosis was analyzed by flow cytometry combined with annexin V-FITC/PI staining; the level of interferon gamma (IFN-gamma) was examined by ELISA; the mRNA levels of IL-12 receptor genes were detected by reverse transcription PCR. RESULTS: Compared with control cells cultured in normal gravity, IL-2-induced cell proliferation rate of NK cells cultured in simulated weightlessness decreased by 13.6% and 31% at 24 and 48 hours, respectively; the cell apoptotic rate increased by 8% and 19%; IL-2 induced IFN-gamma production was inhibited by 25.2% and 47.8%; the cytotoxicity of NK cells induced by IL-2 was reduced by 7% and 18%; IL-12-induced IFN-gamma production was suppressed by 21.8% and 58.8% in IL-2 pretreated cells at 24 and 48 hours, respectively. In addition, the mRNA levels of IL-12 beta1 and beta2 receptor genes were significantly down-regulated in the cells cultured in simulated weightlessness. CONCLUSION: Simulated weightlessness can inhibit the proliferation of NK cells induced by IL-2, promote NK cell apoptosis, impair IL-2 induced IFN-gamma production and cytotoxicity in NK cells, and inhibit IL-12 induced IFN-gamma production through down-regulating IL-12 receptor gene expression in NK cells. PMID- 26429527 TI - [IL-37 inhibits the proliferation, invasion and migration of SMMC-7721 cells in vitro]. AB - OBJECTIVE: To analyze the impact of interleukin-37 (IL-37) on proliferation, migration and invasion of SMMC-7721 hepatocellular carcinoma cells and the related molecular mechanism. METHODS: SMMC-7721 cells cultured in vitro were divided into the (50, 100, 200, 500) ng/mL recombinant human IL-37 (rhIL-37) treated groups and control group. Cell proliferation ability was detected by CCK 8 assay. Wound healing assay was used to observe cell migration ability. Transwell(TM) assay was performed to test the cell invasion ability. The levels of signal transducers and activators of transcription 3 (STAT3), phospho-STAT3 (p STAT3) and matrix metalloproteinase-2 (MMP-2) were determined using Western blotting. RESULTS: CCK-8 assay showed that rhIL-37 inhibited the proliferation of SMMC-7721 cells. Wound healing assay revealed that rhIL-37 inhibited the migration of SMMC-7721 cells. Transwell(TM) indicated that rhIL-37 inhibited the invasion of SMMC-7721 cells. Western blotting demonstrated that rhIL-37 down regulated the expressions of p-STAT3 and MMP-2. CONCLUSION: IL-37 can inhibit the proliferation, migration and invasion of SMMC-7721 cells. It may be related with the down-regulation of p-STAT3 and MMP-2. PMID- 26429528 TI - [Over-expression of human S-phase kinase-associated protein 2 (Skp2) promotes proliferation of MCF-7 breast cancer cells and increases the number of S phase cells]. AB - OBJECTIVE: To construct a eukaryotic expression vector for the human gene S-phase kinase-associated protein 2 (Skp2) with a FLAG tag (pcDNA3-FLAG-Skp2) and detect the effect of Skp2 over-expression on the cell growth and cell cycle in MCF-7 breast cancer cells. METHODS: Skp2 was amplified from MDA-MB-231 breast cancer cells by reverse-transcription polymerase chain reaction (RT-PCR) and then used to construct the eukaryotic expression vector pcDNA3-FLAG-Skp2. Integration of Skp2 into the vector was confirmed via restriction digest and sequencing; The pcDNA3-FLAG-Skp2 was then transfected into MCF-7 breast cancer cells. Expression of Skp2 protein was verified by Western blotting. Cell growth was assessed by Alamar blue proliferation assay, cell cycle analysis was carried out by flow cytometry. RESULTS: The PCR amplified fragment was matched up with the anticipated result and its sequence was the same as the data published on GenBank, indicating that the recombinant plasmid pcDNA3-FLAG-Skp2 was constructed successfully. Western blotting revealed that the expression of Skp2 protein was markedly up-regulated in the pcDNA3-FLAG-Skp2 transfected MCF-7 cells at 48 hours. Furthermore, cell growth was significantly promoted in Skp2 over-expressed MCF-7 cells, and the cell count in S phase were also raised. CONCLUSION: The recombinant eukaryotic expression vector pcDNA3-FLAG-Skp2 has been constructed and expressed in MCF-7 breast cancer cells successfully. Over-expression of Skp2 resulted in the increased cell growth and number of S phase cells in Skp2 transfected MCF-7 cells. PMID- 26429529 TI - [Culture supernatants of lymphocytes from different lymphoid tissues induce transdifferentiation of Caco2 cells into M-like cells]. AB - OBJECTIVE: To establish the microfold (M)-like cell model in vitro and identify M like cells through detecting the capacity of transporting fluorescent beads and the levels of the associated genes, and to observe the effects of lymphocyte culture supernatants stimulated by concanavalin A (Con A) from different lymphoid tissues on the differentiation of Caco2 cells into M-like cells. METHODS: The isolated lymphocytes of Peyer's patch (PP), mesenteric lymph node (MLN) and spleen (Sp) were incubated with 3 MUg/mL Con A for 3 days. The culture supernatants were collected and co-cultured with Caco2 cells. The fluorescent bead suspension was added into the upper compartment of the TranswellTM inserts, and then basolateral solutions were then sampled and analyzed. The number of transported fluorescent beads was measured by flow cytometry. The expressions of M-like cells-associated genes, such as chemokine (C-C motif) ligand 20 (CCL20), claudin4 (CLDN4), tumor necrosis factor receptor superfamily member 9 (TNFRSF9), and Spi-B were detected by reverse transcription PCR. RESULTS: Compared with blank control group, the number of fluorescent beads transported by induced Caco2 cells and the levels of CCL20, CLDN4, TNFRSF9 and Spi-B mRNAs significantly increased in induced Caco2 cells treated with the culture supernatants of lymphocytes from PP, MLN and Sp. After Con A stimulation, the number of fluorescent beads transported by induced Caco2 cells and the levels of CCL20, CLDN4, TNFRSF9 and Spi-B mRNAs were higher than those in the unstimulated group. CONCLUSION: The lymphocyte culture supernatants stimulated or unstimulated by Con A can induce the transdifferentiation of Caco2 cells into M-like cells. PMID- 26429530 TI - [miR-135b promotes the invasion and metastasis of hepatocellular carcinoma cells]. AB - OBJECTIVE: To explore the effect of miR-135b on the invasion and metastasis of hepatocellular carcinoma cells and the underlying molecular mechanism. METHODS: The invasive and metastasis abilities were detected by Transwell(TM) assay in hepatocellular carcinoma cells with over-expressed or down-regulated miR135b. The hepatocellular carcinoma cell growth and tumor formation abilities in vivo were examined by xenograft model. Downstream genes targeted by miR-135b were detected by Western blotting and dual-luciferase report assay. RESULTS: Up-regulated miR 135b was observed in highly invasive MHCC97 hepatocellular carcinoma cell lines. Over-expression of miR-135b enhanced the invasive and migratory abilities in vitro and in vivo of HepG2 and Bel-7402 cells. The invasive and migratory abilities in vitro and in vivo were significantly suppressed in miR-135b down regulated MHCC97 hepatocellular carcinoma cells silenced by the pcDNA-miR-135b Sponge plasmid. Western blotting and dual-luciferase report system analysis showed that multiple key components in the Hippo pathway, including large tumor suppressor homolog 2 (LATS2), beta-transducin repeats-containing proteins (beta TrCP), N-myc downstream-regulated gene 2 (NDR2) as well as leucine zipper tumor suppressor gene 1 (LZTS1) were targeted by miR-135b. CONCLUSION: miR-135b promotes the invasion and metastasis possibly by targeting the Hippo pathway genes. PMID- 26429531 TI - [Inhibition of HBV replication by constructing an artificial transcription factor]. AB - OBJECTIVE: To construct a zinc finger protein-artificial transcription factor (ZFP-ATF) specifically bound to hepatitis B virus (HBV) enhancer 1 (Enh1), then detect its expression in HepG2.2.15 cells, observe its effect on cell growth and its role in inhibiting the replication and expression of HBV DNA. METHODS: The zinc finger protein (ZFP) specifically bound to HBV Enh1 was fused with a Krvppel associated box (KRAB) transcriptional repression domain to produce an artificial transcription factor (ATF). After relative modification and optimization, the synthetic ATF nucleic acid sequence was inserted into the eukaryotic expression plasmid vector pcDNA3.1+ and its sequence was identified. Then pcDNA3.1-ATF was transfected into HepG2.2.15 cells through X-tremeGENE HP. The expression of ATF was detected by confocal microscope. The impact of ATF on cell growth was measured by CCK-8 assay. The inhibitory effect on HBV DNA by ATF was assured by real-time quantitative PCR (qRT-PCR), ELISA and Western blotting at 24, 48 and 72 hours after transfection. RESULTS: The pcDNA3.1-ATF (nls-ZFP-KRAB-FLAG) eukaryotic expression plasmid vector was successfully constructed. ATF was expressed in HepG2.2.15 cells as expected without obvious influence on cell growth. ATF repressed the replication and expression of HBV DNA, especially at 72 hours post-transfection when the inhibition rate was 68%. CONCLUSION: The synthetic ATF can be expressed in HepG2.2.15 cells normally without toxic effect on the cells and exert an inhibitory effect on the replication and expression of HBV DNA by specifically bound to HBV Enh1. PMID- 26429532 TI - [Protective effect of salidroside against high altitude hypoxia-induced brain injury in rats]. AB - OBJECTIVE: To observe the protective effect of salidroside against brain injury in rats exposed to hypobaric hypoxia, and investigate the molecular mechanism of salidroside in the prevention of hypobaric hypoxia-induced brain injury. METHODS: Rats were placed in experiment module simulating 6000 m altitude to establish acute hypobaric hypoxia-induced brain injury models. Their respiratory frequency was observed and recorded. Cell apoptosis in the hippocampal dentate gyrus (DG) was detected by TUNEL assay; the expressions of Ras homolog family member A (RhoA), phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated c-Jun N-terminal kinase (p-JNK) were detected by Western blotting. RESULTS: After acute exposure to 6000 m altitude, the respiratory frequency of the rats increased remarkably. The simulation of hypobaric hypoxia induced cell apoptosis in hippocampal DG region, and salidroside intervention inhibited the process of cell apoptosis. The expressions of RhoA, p-ERK, p-JNK decreased after hypobaric hypoxia exposure. Salidroside intervention reversed RhoA expression and raised the levels of p-ERK and p-JNK. CONCLUSION: Acute exposure to hypobaric hypoxia can induce cell apoptosis in rat hippocampal DG, and salidroside can protect the cells from the exposure-induced apoptosis. PMID- 26429533 TI - [The changes of Wnt7b/beta-catenin signaling pathway molecules in the differentiation of fetal alveolar epithelial type II cells]. AB - OBJECTIVE: To investigate the changes of Wnt7b/beta-catenin signaling pathway molecules in the differentiation of fetal rat alveolar epithelial type II cells (fAEC2). METHODS: Fetal rat lung tissues were extracted from pregnant SD rats (19 days), and then fAEC2 were isolated and purified. After fAEC2 were cultured for 48, 72, 96 hours, the morphological changes of fAEC2 and the expression of beta catenin were respectively observed by inverted microscope and immunofluorescence. The mRNA expressions of Wnt7b, cyclin D1, pulmonary surfactant C (SP-C) and aquaporin 5 (AQP5) were detected by real-time quantitative PCR. The protein expressions of cyclin D1, nucleus beta-catenin, SP-C and AQP5 were measured by Western blotting. RESULTS: beta-catenin was expressed in cell membrane when fAEC2 were cultured for 48 hours; the expression of beta-catenin decreased in cell membrane while enhanced in cytoplasm and nucleus at 72 hours; whole-cell beta catenin expression was lowered at 96 hours. The expressions of Wnt7b and cyclin D1 mRNAs were significantly raised at 72 hours and reduced obviously at 96 hours compared with 48 hours. SP-C mRNA expression level went down gradually with the extended culture time, and AQP5 mRNA level went up gradually. The protein expressions of cyclin D1 and nucleus beta-catenin were significantly enhanced at 72 hours and weakened at 96 hours compared with 48 hours. SP-C protein expression was down-regulated with the prolonged culture time, and AQP5 protein expression was up-regulated. CONCLUSION: Wnt7b/beta-catenin signaling pathway may play an important role in fAEC2 transdifferentiation. PMID- 26429534 TI - [Roles of Toll-like receptor 2 (TLR2) and TLR4 in immune responses to Chlamydia trachomatis genital tract infection in mice]. AB - OBJECTIVE: To evaluate the roles of Toll-like receptor 2 (TLR2) and TLR4 in immune responses to Chlamydia trachomatis (Ct) genital tract infection in mice. METHODS: The wild type (WT, n=11), TLR2(-/-) (n=14) and TLR4(-/-) (n=11) mice were inoculated intravaginally with 1*10(4) inclusion forming units (IFUs) of live C.muridarum (strain MoPn/Nigg) to establish the models of Ct genital tract infection. The vaginal swabs were taken at the 3rd, 7th, 10th, 17th, 24th, 31st, 38th, 45th day after the infection. Immunofluorescence assay was used to quantify live organisms from each swab. The inflammatory cytokines interleukin-1alpha (IL 1alpha), IL-6 and macrophage inflammatory protein 2 (MIP-2) were measured using ELISA. The 70th day post infection, the titers of mouse serum Ct-specific antibody isotypes were determined using an immunofluorescence technique; after the macrophages harvested from peritoneal cavity were infected with MoPn strain for 24 hours, the culture supernatants were examined for the contents of cytokines IL-1alpha, IL-6 and MIP-2 using ELISA. The harvested splenocytes were stimulated with UV-inactivated chlamydial antigens for 72 hours, and the culture supernatants were measured for the levels of cytokines interferon gamma (IFN gamma), IL-17, IL-4 and IL-5 using ELISA. RESULTS: No significant difference was observed in the number of IFUs from the vaginal swabs at any time points post infection among WT, TLR2(-/-) and TLR4(-/-) mice. All mice displayed similar time course of live organism shedding. Until the 38th day, all mice cleared live organism. Macrophages lacking TLR2 produced significantly decreased amounts of IL 1alpha, IL-6 and MIP-2 compared with those in WT mice; however, there was no significant difference between WT and TLR4(-/-) mice. The vaginal swab samples from TLR2(-/-) mice also had lower levels of inflammatory cytokines. Splenocytes from the three groups of mice all produced high levels of both IFN-gamma and IL 17, and low levels of both IL-4 and IL-5, and no significant difference was found among the three groups. The ratio of serum IgG2a/IgG1 in the three groups of mice was greater than 1, and no significant difference was found among the three groups. CONCLUSION: TLR2, rather than TLR4 mediates early immune response following Ct genital tract infection in mice. However, neither TLR4 nor TLR2 is required for adaptive immune responses induced by Ct genital tract infection. PMID- 26429535 TI - [Effects of subunit influenza vaccines in a mouse model of asthma]. AB - OBJECTIVE: To explore the effects of subunit influenza vaccines on mouse model of asthma. METHODS: Six-week-old female BALB/c mice were randomly divided into PBS control group, asthma control group and subunit influenza vaccine group. Mice in the asthma control group and the subunit influenza vaccine group were sensitized on the 0, 7th, 14th day by intraperitoneal injection of 50 MUg ovalbumin (OVA) emulsified in 2 mg aluminum hydroxide. The PBS control animals were given an equal volume of PBS. The mice in the subunit influenza vaccine group were immunized intramuscularly with 0.1 mL subunit influenza vaccines on the 21st day, and were boosted intranasally with 40 MUL vaccines on the 28th day. Subsequently, the mice in the asthma control group and the subunit influenza vaccine group were exposed to OVA aerosol challenge for 3 consecutive days (the 42nd, 43rd, 44th day). Within 48 hours after the last challenge, all mice were sacrificed after the blood was obtained, and the bronchoalveolar lavage fluid (BALF) samples were collected for cell counting and classification. Lung tissues were prepared and HE staining and PAS staining were used to evaluate pulmonary inflammation and mucus production. IgE levels in sera and interleukine 4 (IL-4), IL-5, IL-13, interferon gamma (IFN-gamma) levels in BALF were measured by ELISA. RESULTS: Compared with the PBS control group, the pulmonary inflammation and mucus production significantly increased in the asthma control group and the subunit influenza vaccine group, and the levels of IL-4, IL-5, IL-13, IFN-gamma in BALF and serum IgE were also significantly elevated. However, no significant difference was found between the subunit influenza vaccine group and the asthma control group. CONCLUSION: In mouse model of asthma, the use of subunit influenza vaccine does not exacerbate asthma symptoms, and is relatively safe. PMID- 26429536 TI - [Rich selenium-Banqiao-Codonopsis Pilosula mixture enhances immune function of aging mice]. AB - OBJECTIVE: To investigate the effect of rich selenium-Banqiao-Codonopsis Pilosula (RSBCP) mixture on the immune functions of the aging mice. METHODS: Sixty Kunming mice (half male and half female) were randomly divided into high-, middle- and low-dose RSBCP mixture groups, model group and control group, with twelve mice in each group. The control group was injected intraperitoneally with 500 mg/(kg.d) normal saline and the other groups were injected with the same amount of D galactose. The RSBCP mixture high-, middle- and low-dose groups were respectively gavaged with 100, 50, 25 g/(kg.d) RSBCP mixture at the moment when D-galactose was injected. The model group and control group were given the same amount of distilled water instead. The mice were killed at the 30th days and the indexes of thymus and spleen were measured. The serum levels of IgG, IgM, C3, C4, interleukine 2 (IL-2), IL-6 and tumor necrosis factor alpha (TNF-alpha) were detected by ELISA and the major T-cell subsets of splenocytes were analyzed by flow cytometry. RESULTS: Compared with the control group, the indexes of thymus and spleen in the model group decreased obviously; the serum levels of IgG, IgM, C3, C4, IL-2 and IL-6 were reduced significantly and the level of TNF-alpha increased significantly. Compared with the model group, the indexes of thymus and spleen in the RSBCP mixture groups increased obviously; the levels of IgG, IgM, C3, C4, IL-2 and IL-6 were raised significantly and the level of TNF-alpha decreased significantly. Compared with the control group, the indexes of thymus and spleen in the RSBCP mixture high-dose group increased obviously; the levels of IgG, IgM, C3, C4, IL-2 and IL-6 were lifted significantly and the level of TNF alpha decreased significantly. The indexes of thymus and spleen and the levels of IgG, IgM, C3, C4, IL-2 and IL-6 in the RSBCP mixture middle- and low-dose groups had no obvious differences from those of the control group. Compared with the control group, the model group showed significantly decreased numbers of CD3+ T, CD4+ T, CD44+ T cells and significantly increased number of CD8+ T cells. Compared with the model group, the RSBCP mixture groups showed significantly increased numbers of CD3+ T, CD4+ T, both the high- and middle-dose groups showed significantly increased numbers of CD44+ T cells and significantly decreased number of CD8+ T cells. CONCLUSION: RSBCP mixture could delay the atrophy of thymus and spleen in the aging mice, dramatically elevate serum levels of IgG, IgM, C3, C4, IL-2, IL-6, lower the level of TNF-alpha, and influence the proportions of T cell subsets. The mixture plays a role in enhancing the immune function of aging mice. PMID- 26429537 TI - [Total saponins of Chaenomeles speciosa inhibit the degranulation of primary mouse bone marrow-derived mast cells in vitro]. AB - OBJECTIVE: To study the effects of total saponins of Chaenomeles speciosa on the degranulation of mouse bone marrow-derived mast cells (BMMCs). METHODS: Bone marrow cells were isolated from C57BL/6 mice and were cultured in RPMI1640 medium containing 100 mL/L fetal bovine serum, 20 ng/mL IL-3 and 40 ng/mL stem cell factor (SCF). After four-week culture, flow cytometry was used to identify the purity of double-positive (CD117(+)FcEpsilonRIalpha(+)) mast cells; toluidine blue was used to detect the maturity of mast cells. After total saponins of Chaenomeles speciosa was added into the medium of BMMCs, CCK-8 assay was performed to assess the toxic effects of total saponins of Chaenomeles speciosa on BMMCs; the amount of beta-hexosaminidase release was detected by fluorescence spectrophotometry; the content of tryptase in cell supernatants was detected by ELISA. RESULTS: After cultured for four weeks, the purity of double-positive cells was more than 95%, and the cells presented the features of mature mast cells, with blue nuclear and purple cytoplasm by toluidine blue staining. After BMMCs were cultured in the presence of total saponins of Chaenomeles speciosa (0.01, 0.03, 0.10 mg/mL) for 12 hours, CCK-8 assay indicated that the total saponins did not exert the toxic effects on the BMMCs. Fluorescence spectrophotometry revealed that the release amount and release rate of beta hexosaminidase decreased in the cells treated with the total saponins of Chaenomeles speciosa, DNP-BSA and A23187 compared with the controls, and ELISA assay showed that the amount of tryptase release in the supernatants was reduced as well. CONCLUSION: Total saponins of Chaenomeles speciosa can inhibit the degranulation of primary mouse BMMCs stimulated by different antigens with a clear dose-effect relationship. PMID- 26429538 TI - [Effects of different processing methods and durations of blood specimens on the level of soluble CD100 in peripheral blood]. AB - OBJECTIVE: To investigate the effects of different processing methods and durations of blood specimens on the level of soluble CD100 (sCD100) in peripheral blood. METHODS: We included a total of 15 healthy individuals without any significant signs or symptoms of microbial infection. Blood samples were collected in tubes with and without additives, as well as tubes containing citrate, EDTA and heparin, respectively, and processed for different durations of time. The serum samples were allowed to clot for 1 hour, 4, 8 hours after venipuncture before centrifugation. Then the sCD100 levels were measured with ELISA. RESULTS: Serum sCD100 levels were higher than those in plasma, and no significant differences were observed among the citrate, EDTA or heparin treated plasma groups. The sera in the tubes without additives showed lower levels of sCD100 than those in the tubes with additives. The concentrations of sCD100 in sera increased with the prolonged processing time in room temperature. CONCLUSION: The measurement of sCD100 in blood samples may be interfered by the in vitro release from platelets. Thus, pre-treating methods for the collection of serum or plasma samples are critical in the assessment of sCD100 concentrations and should be carefully considered for the measurement of this important biomarker in both basic and clinical studies. PMID- 26429539 TI - [Up-regulation of serum- and glucocorticoid-inducible kinase 1 (SGK1) of CD4+ T cells is positively related to RORC and IL-17A in patients with Kawasaki disease]. AB - OBJECTIVE: To investigate the expression of serum- and glucocorticoid-inducible kinase 1 (SGK1) in Kawasaki disease (KD) and explore the correlations between SGK1 and Th17 cell-related cytokines [retinoic-acid-related orphan nuclear receptor C (RORC), interleukin 17A (IL-17A), IL-6] in KD. METHODS: Thirty patients with KD [(2.8 +/- 1.4) years old], 30 healthy volunteers [(2.6 +/- 1.6) years old] and 25 patients with infectious disease (ID) [(2.2 +/- 1.5) years old] were recruited. The percentage of Th17 cells in CD4+ T cells was analyzed using flow cytometry. The mRNA levels of RORC and SGK1 in CD4+ T cells were detected using real-time quantitative PCR. The serum levels of IL-17A and IL-6 were analyzed by ELISA. RESULTS: Compared with healthy volunteers and patients with ID, the percentage of Th17 cells in CD4+ T cells significantly increased in KD [(3.57 +/- 0.62)% vs (0.51 +/- 0.07)% or (1.72 +/- 0.36)%]. The serum levels of IL-17A and IL-6 in KD were much higher than those in healthy volunteers and patients with ID. The mRNA levels of RORC and SGK1 in KD were remarkably elevated compared with healthy volunteers and patients with ID. The level of SGK1 in coronary artery lesion (CAL) group of KD was significantly higher than that in KD patients with normal coronary artery (CAN). SGK1 was reduced in KD after intravenous immunoglobulin (IVIG) treatment. What's more, the decrease of SGK1 was more obviously in the CAL group than in the CAN group. In addition, SGK1 expression in KD was positively correlated with RORC and IL-17A, but not with IL 6. CONCLUSION: SGK1 was up-regulated in CD4+ T cells and was positively correlated with RORC and IL-17A in the patients with KD. PMID- 26429540 TI - [The differentiation and clinical significance of follicular helper T cells during acute exacerbation in asthma patients]. AB - OBJECTIVE: To observe the differentiation of follicular helper T (Tfh) cells in asthma patients during acute exacerbation and post-treatment periods, and explore the clinical significance of Tfh cells in asthma. METHODS: We detected the percentages of CD4+CXCR5+, CD4+ICOS+, CD4+CXCR5+ICOS+ T cells in peripheral blood mononuclear cells (PBMCs) by flow cytometry, the level of Bcl-6 mRNA in CD4+ T cells by reverse transcription PCR, and the level of interleukin 21 (IL-21) in plasma by ELISA in healthy controls and asthma patients during acute exacerbation and post-treatment release periods. The linear regression analysis was used to analyze the correlations of the level of IL-21 in plasma with forced expiratory volume in one second/forced vital capacity (FEV1/FVC) and forced expiratory volume in one second/prediction (FEV1/Pre) in acute exacerbation period of asthma patients. RESULTS: The percentages of CD4+CXCR5+, CD4+CXCR5+ICOS+ T cells in PBMCs, the level of Bcl-6 mRNA in CD4+T cells, and the level of IL-21 in plasma increased in acute exacerbation of the asthma patients compared to the healthy controls. After treatment, the percentages of CD4+CXCR5+, CD4+ICOS+, CD4+CXCR5+ICOS+ T cells in PBMCs, the level of Bcl-6 mRNA in CD4+T cells, and the level of IL-21 in plasma in asthma patients were all reduced as compared with the acute exacerbation period. There were negative correlations between IL-21 and lung function parameters such as FEV1/FVC and FEV1/Pre. CONCLUSION: The differentiation of Tfh cells was enhanced in acute exacerbation of asthma patients, and ameliorated after treatment. Tfh cells may participate in the inflammatory reaction of asthma, and the differentiation degree of Tfh cells may reflect the extent of airway limitation in asthma patients. PMID- 26429541 TI - [The frequency of peripheral blood CD14(+)HLA-DR(-/low) MDSCs is negatively correlated with the inflammation in patients with chronic hepatitis B]. AB - OBJECTIVE: To study the frequency of CD14+HLA-DR(-/low) myeloid-derived suppressor cells (MDSCs) in the peripheral blood of chronic hepatitis B (CHB) patients and the relationship with biochemical characteristics, viral load and liver pathology. METHODS: The frequency of CD14+HLA-DR(-/low) MDSCs in the peripheral blood of 96 patients with CHB and 20 healthy control cases were detected by flow cytometry. Ultrasound-guided liver biopsies as well as HBV related serological tests were performed in HBV-infected individuals to analyze the biochemical characteristics, viral load and pathology. The data were assessed using Spearman correlation analysis. RESULTS: The frequency of the peripheral blood CD14+HLA-DR(-/low) MDSCs in the 96 CHB cases was (6.03 +/- 0.09)%, which was significantly higher than that of the 20 healthy control cases (1.87 +/- 0.05)%. The group of HBeAg positive cases had a significantly higher frequency of the peripheral blood CD14+HLA-DR(-/low) MDSCs compared with the group of HBeAg negative cases and the healthy control group. The frequency of CD14+HLA-DR(-/low) MDSCs in the peripheral blood was negatively correlated with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. There was no correlation between the frequency of peripheral blood CD14+HLA-DR(-/low) MDSCs and HBV load. The frequency of CD14+HLA-DR(-/low) MDSCs in the peripheral blood was negatively correlated with the liver inflammation grade, but not related with the fibrosis stage in patients with CHB. CONCLUSION: The frequency of CD14+HLA DR(-/low) MDSCs is negatively correlated with the inflammation of CHB. PMID- 26429543 TI - [Development and characterization of polyclonal antibody against regeneration (rgn) of Drosophila]. AB - OBJECTIVE: To prepare and characterize rat polyclonal antibodies highly specific for Drosophila regeneration (rgn). METHODS: Gene fragments rgn were cloned from Drosophila W(1118) cDNAs by PCR and then subcloned into vector pRSETA. Its expression was induced in E.coli JM109(DE3). Then the fusion protein was purified by Ni-NTA superflow chromatography. After the products was identified by Western blotting, SD male rats were immunized with the rgn fusion protein. The polyclonal antibodies were obtained from the rat serum. The specificity and titer of the polyclonal antibodies were detected by Western blotting and immunohistochemistry. RESULTS: Through the recombinant plasmid pRSETA-rgn, 6*His-rgn fusion protein was expressed abundantly in E.coli JM109(DE3). After purification, it was used to immunize SD rats as antigen to generate the polyclonal antibodies against rgn. Immunohistochemistry showed that rgn is located in the cytoplasm of hemocytes of the third instar larvae of Drosophila. CONCLUSION: The experiment has prepared high-specificity rat polyclonal antibodies against rgn. PMID- 26429542 TI - [Cytomegalovirus infection down-regulates the expressions of CD226 and CD16 in blood NK cells of the renal transplant recipient]. AB - OBJECTIVE: To investigate the effect of cytomegalovirus (CMV) infection after renal transplantation on the expressions of the activation receptors CD226 and sCD16 in natural killer (NK) cells. METHODS: Peripheral blood samples were obtained from these kidney transplant recipients with CMV infection, stable recipients, and normal healthy controls, and the expressions of CD3, CD56, CD16 and CD226 of all the samples were analyzed by flow cytometry. RESULTS: Compared with patients recovered from CMV infection, normal healthy controls and the stable recipients, the percentage of NK population in lymphocytes did not vary among these groups (P=0.18). However, the percentage of peripheral blood CD226+NK cells in NK population of the CMV infection group [(75.06 +/- 13.65)%] was significantly lower than that of the healthy controls [(88.28 +/- 11.98)%] and stable recipients [(87.53+/-6.43)%]. While the percentage was recovered during CMV infection recovery stage [(88.37+/-8.91)%], which was not different from that of normal healthy controls and the stable recipients. The mean fluorescence intensity (MFI) of CD226 was not significantly different among the health controls, stable recipients and CMV infection patients, while it was significantly higher in the patients recovered from CMV infection than in the above three groups. A decrease in the percentage of CD16(+)NK cells in NK population was observed in the group of CMV infection [(75.06 +/- 13.65)%], which was significantly lower than that of the stable recipients [(88.28 +/- 11.98)%] and health controls [(90.35 +/- 10.07)%]. The CD16 expression on NK cells was elevated to (86.30 +/- 14.01)% when the infection was controlled, which was not different from the stable recipients and healthy controls. The MFI of CD16MFI in NK cells was similar in all groups. CONCLUSION: CMV infection down-regulates the expressions of CD226 and CD16 in NK cells of patients after kidney transplantation. When the infection was controlled, the expressions of CD226 and CD16 on NK cells were recovered. These results indicated that the membrane CD226 and CD16 molecules were involved in NK cell-mediated anti-CMV infection. PMID- 26429544 TI - [Single chain antibody against beta-site of amyloid precursor protein inhibits the generation of beta-amyloid peptide]. AB - OBJECTIVE: To construct and express a single chain fragment of variety region (scFv) against beta-site of amyloid precursor protein (APP), and evaluate the effect of scFv on alpha- and beta-processing of APP. METHODS: The beta-site specific scFv 2H10 was amplified and fused with signal sequence Igkappa and myc tag by PCR to create the expression cassette, which was then subcloned into expression vector pcDNA3.1hyg+. The plasmid was transferred into CHO cells over expressing Swedish mutation type human APP695 (APP695sw/CHO). The positive clones were identified by hygromycin B. The concentrations of Abeta40 and soluble APPalpha (sAPPalpha) in the conditioned media supernatant were measured by sandwich ELISA. RESULTS: The recombinant eukaryotic expression plasmids were identified by PCR, restriction endonuclease digestion and DNA sequencing. The expression of scFv was confirmed by Western blotting. When scFv 2H10 was stably expressed in APP695sw/CHO, the extracellular level of Abeta40 decreased by 30.4%, while sAPPalpha increased by 23.1%. CONCLUSION: The APP beta-site scFv 2H10 could inhibit the secretion of Abeta. Meanwhile, it might be favorable for the alpha processing of APP. Hence it can be explored as an inhibitor of beta-site APP cleaving enzyme (BACE). PMID- 26429545 TI - Does the EU migration level of chromium VI in toys need to be lowered? PMID- 26429546 TI - Connectivity, contest and the ties of self-management support for type 2 diabetes: a meta-synthesis of qualitative literature. AB - This paper presents a meta-synthesis of the literature on community-based self management to support experiences of people diagnosed with type 2 diabetes. The aim was to synthesise findings on both formal and informal self-management support with particular reference to the relevance and influence of the social context operating at different levels. The review forms part of EU-WISE, a project financed through EU's 7th Framework Programme. The review was performed by systematically searching MEDLINE, PubMed, EMBASE, CINAHL, PsycINFO and Web of Science for English language publications between 2005 and 2014 presenting research conducted in Europe on the experiences and perspectives of self management concerns of patients diagnosed with type 2 diabetes. The search yielded 587 abstracts, which were reduced through search strategy refinement and eligibility and quality criteria to 29 papers that were included in the review. This review highlights the relevance of contextual factors operating at micro- and macro-levels. The synthesis yielded six second-order thematic constructs relating to self-management: sense of agency and identity, the significance and meaning of social networks, minimal disruption of everyday life, economic hardship, the problem of assigning patients' responsibility and structural influences of primary care. Using a line of argument synthesis, these themes were revisited, and a third-order construct, connectivity emerged which refers to how links in daily life are interwoven with peoples' social networks, local communities, economic and ideological conditions in society in a way which support self-management activities. This meta-synthesis indicates a need to heed the notion of connectivity as a means of mobilising and supporting the self management strategies of people with type 2 diabetes in everyday life. PMID- 26429548 TI - Outcomes of Bone Grafting of Bone Cysts After Total Ankle Arthroplasty. AB - BACKGROUND: The operative treatment of bone cysts after total ankle replacements (TAR) is not well described. Bone cysts may cause component migration, implant failure, and pain. Surgery is performed on cysts with the goals of reducing pain and preventing component failure. METHODS: We retrospectively evaluated a consecutive series of 726 primary TARs performed between January 1998 and May 2013 and identified those who had a subsequent bone cyst grafting procedure. We identified cyst location and method of treatment. Clinical outcomes including secondary procedures, infection rate, complications, and failure rate were recorded. Thirty-one patients were treated with a total of 33 operative procedures for bone cysts after TAR. Of these patients, 22 (71.0%) were males with an average age of 62.2 and median follow-up 65.9 months. RESULTS: Intraoperatively, 22 tibial cysts (71.0%), 20 talar cysts (64.5%), 5 fibular cysts (16.1%), and 13 multiple cysts (41.9%) were treated. Allograft was used in 25 procedures (75.8%), calcium phosphate in 4 (12.1%), cement in 3 (9.1%), and autograft in 1 (3.0%). These procedures were supplemented by calcaneus autograft, allograft mixed with mesenchymal stem cells, platelet-rich plasma, recombinant human bone morphogenic protein-2, and demineralized bone matrix. There were no infections or wound complications. Of the 27 subjects with a successful second surgery, the success rate for bone grafting of cysts was 90.9% (95% CI: 50.8, 98.7%) at 24 months and 60.6% (95% CI: 25.1%, 83.4%) at 48 months. One patient needed a repeat bone grafting. The 4 failures observed postprocedure resulted in 3 tibial and talar component revisions, and 1 tibiotalocalcaneal (TTC) fusion. CONCLUSIONS: Grafting bone cysts without revision of TAR was in general an effective and safe means for treating patients with peri-prosthetic bone cysts. Treatment with grafting and supplemental materials may improve implant survivorship and might improve the structural support surrounding the implant. Further exploration of the etiology of bone cysts may aid in the prevention and treatment of cystic formation in the TAR. LEVEL OF EVIDENCE: Level IV, case series. PMID- 26429547 TI - Impact of flanking chromosomal sequences on localization and silencing by the human non-coding RNA XIST. AB - BACKGROUND: X-chromosome inactivation is a striking example of epigenetic silencing in which expression of the long non-coding RNA XIST initiates the heterochromatinization and silencing of one of the pair of X chromosomes in mammalian females. To understand how the RNA can establish silencing across millions of basepairs of DNA we have modelled the process by inducing expression of XIST from nine different locations in human HT1080 cells. RESULTS: Localization of XIST, depletion of Cot-1 RNA, perinuclear localization, and ubiquitination of H2A occurs at all sites examined, while recruitment of H3K9me3 was not observed. Recruitment of the heterochromatic features SMCHD1, macroH2A, H3K27me3, and H4K20me1 occurs independently of each other in an integration site dependent manner. Silencing of flanking reporter genes occurs at all sites, but the spread of silencing to flanking endogenous human genes is variable in extent of silencing as well as extent of spread, with silencing able to skip regions. The spread of H3K27me3 and loss of H3K27ac correlates with the pre-existing levels of the modifications, and overall the extent of silencing correlates with the ability to recruit additional heterochromatic features. CONCLUSIONS: The non coding RNA XIST functions as a cis-acting silencer when expressed from nine different locations throughout the genome. A hierarchy among the features of heterochromatin reveals the importance of interaction with the local chromatin neighborhood for optimal spread of silencing, as well as the independent yet cooperative nature of the establishment of heterochromatin by the non-coding XIST RNA. PMID- 26429549 TI - Vitamin D Status in an Elective Orthopedic Surgical Population. AB - BACKGROUND: Adequate vitamin D availability is required for normal bone metabolism. Hypovitaminosis D is highly prevalent in latitudes above 30 degrees. The goal of this prospective study was to determine the prevalence of hypovitaminosis D in an unselected population of patients undergoing major ankle or hindfoot arthrodesis in Burlington, Vermont (latitude 44.5 degrees N). METHODS: One hundred eighteen patients undergoing a major ankle, hindfoot, or midfoot arthrodesis between May 2012 and February 2014 were eligible for the study, of which 81 participated. All clinical data, including comorbidities, demographics, and lab values, were obtained from the comprehensive electronic medical record system that encompassed all inpatient and outpatient care. Based on the recommendations published by the Vitamin D Task Force Committee of the Endocrine Society, vitamin D levels above 30 ng/mL were considered normal. Statistical analyses were performed using a significance level of P <.05. RESULTS: Of 81 patients tested, 54 (67%) had low serum vitamin D. Older patients had lower risk for hypovitaminosis D (RR = 0.953, CI = 0.908, 0.999, P = .046), whereas a Charlson Index >=3 had increased risk (RR = 16.8, CI = 1.5, 192.3, P = .023). Of the 16 patients retested after vitamin supplementation, only 9 (56%) corrected to normal. CONCLUSIONS: In an unselected population in Vermont undergoing hindfoot and ankle arthrodesis, there was a high prevalence of hypovitaminosis D, even in patients without predisposing risk factors. Consequently, routine testing or presumptive high-dose vitamin D replenishment therapy should be considered for all patients scheduled for such surgery, primarily to promote adequate skeletal calcium metabolism. LEVEL OF EVIDENCE: Level II, prospective study. PMID- 26429550 TI - Culture and molecular identification of fungal contaminants in edible bird nests. AB - Widespread food poisoning due to microbial contamination has been a major concern for the food industry, consumers and governing authorities. This study is designed to determine the levels of fungal contamination in edible bird nests (EBNs) using culture and molecular techniques. Raw EBNs were collected from five house farms, and commercial EBNs were purchased from five Chinese traditional medicine shops (companies A-E) in Peninsular Malaysia. The fungal contents in the raw and commercial EBNs, and boiled and unboiled EBNs were determined. Culturable fungi were isolated and identified. In this study, the use of these methods revealed that all EBNs had fungal colony-forming units (CFUs) that exceeded the limit set by Standards and Industrial Research Institute of Malaysia (SIRIM) for yeast and moulds in EBNs. There was a significant difference (p < 0.05) in the number of types of fungi isolated from raw and commercial EBNs, but no significant difference in the reduction of the number of types of fungi after boiling the EBNs (p > 0.05). The types of fungi isolated from the unboiled raw EBNs were mainly soil, plant and environmental fungi, while the types of fungi isolated from the boiled raw EBNs, unboiled and boiled commercial EBNs were mainly environmental fungi. Aspergillus sp., Candida sp., Cladosporium sp., Neurospora sp. and Penicillum sp. were the most common fungi isolated from the unboiled and boiled raw and commercial EBNs. Some of these fungi are mycotoxin producers and cause opportunistic infections in humans. Further studies to determine the mycotoxin levels and methods to prevent or remove these contaminations from EBNs for safe consumption are necessary. The establishment and implementation of stringent regulations for the standards of EBNs should be regularly updated and monitored to improve the quality of the EBNs and consumer safety. PMID- 26429551 TI - Astaxanthin Protecting Membrane Integrity against Photosensitized Oxidation through Synergism with Other Carotenoids. AB - Incorporation of astaxanthin or zeaxanthin in giant unilamellar vesicles (GUVs) of phosphatidylcholine resulted in a longer lag phase than incorporation of beta carotene or lycopene for the onset of budding induced by chlorophyll a photosensitization and quantified by a dimensionless entropy parameter using optical microscopy and digital image heterogeneity analysis. The lowest initial rate of GUV budding after the lag phase was seen for GUVs with astaxanthin as the least reducing carotenoid, while the lowest final level of entropy appeared for those with lycopene or beta-carotene as a more reducing carotenoid. The combination of astaxanthin and lycopene gave optimal protection against budding with respect to both a longer lag phase and lower final level of entropy by combining good electron acceptance and good electron donation. Quenching of singlet oxygen by carotenoids close to chlorophyll a in the membrane interior in parallel with scavenging of superoxide radicals by astaxanthin anchored in the surface may explain the synergism between carotenoids involving both type I and type II photosensitization by chlorophyll a. PMID- 26429552 TI - Temperatures of storage areas in large animal veterinary practice vehicles in the summer and comparison with drug manufacturers' storage recommendations. AB - BACKGROUND: Large animal veterinarians carry drugs in their practice vehicles in storage areas that are not typically refrigerated. The most common upper limits of manufacturers' storage temperatures for United States (U.S.)-approved non refrigerated drugs are 25 or 30 degrees C. Because ambient temperatures in many locations in the U.S. exceed these temperatures during the summer, we measured storage area temperatures over 4 months in the summer of 2013 to evaluate the extent to which labeled storage temperatures are exceeded. METHODS: A convenience sample of 12 vehicles from 5 central Texas practices and 12 vehicles from 4 south central Nebraska practices was used. Temperatures were recorded in one drug storage compartment in each vehicle from May 15 - September 16, 2013, at 15 minute intervals using a self-contained, battery operated temperature recording device. RESULTS: The highest temperatures recorded in a storage unit were 54.4 and 47.7 degrees C in Texas and Nebraska, respectively. The mean temperature recorded across all 24 storage units was 29.1 degrees C, with a mean of 26.9 degrees C in Nebraska and 31.4 degrees C in Texas. In Nebraska, at least one temperature over 25 degrees C was recorded on a mean of 111/124 days and a mean of 63 % of total logger readings. In Texas, temperatures over 25 degrees C were recorded on a mean of 123/124 days and a mean of 95 % of total logger readings. CONCLUSIONS: Temperatures in storage units in participating veterinary practice vehicles exceeded labeled drug storage temperatures a significant portion of the summer of 2013. More research is needed to determine whether these excursions above the manufacturers' recommended storage temperatures alter efficacy of stored drugs. PMID- 26429553 TI - Multiple fractures in a 22-year-old man after a simple fall. AB - We present the case of a 22-year-old male with longstanding progressive fatigue, weakness and pain around his hips due to an undiagnosed parathyroid adenoma. The resultant primary hyperparathyroidism ultimately caused pathologic fractures. He was admitted to the hospital for further assessment and excision of the parathyroid adenoma. A few days after admission, he fell down while walking and was referred to our team. X-rays showed a displaced left femoral neck fracture (FNF) and right humeral shaft fracture with poor bone quality. His humeral fracture was treated conservatively, and the FNF was treated with total hip replacement. Three days later, he underwent parathyroidectomy. This case demonstrates the importance of a thorough investigation of progressive weakness even in a young individual and illustrates the importance of early diagnosis of parathyroid adenoma to avoid the devastating end results of this condition. PMID- 26429554 TI - Postcoital hemoperitoneum caused by ruptured corpus luteal cyst: a hidden etiology. AB - Corpus luteal rupture is a common gynecologic cause for hemoperitoneum. Recent sexual intercourse is usually a preceding factor. However, postcoital hemoperitoneum without evident vaginal injury or trauma is rarely reported. We present a 34-year-old female who presented to the emergency department with severe bilateral lower quadrant abdominal pain after sexual intercourse. CT of the abdomen and pelvis revealed an intra-abdominal hematoma with extravasation of contrast questionable to be from one of the branches of the left internal iliac artery, and no adnexal abnormalities. Left internal iliac artery angiogram was performed and revealed no active extravasation. Exploratory laparotomy was performed and revealed an actively bleeding left ovarian ruptured area that was repaired and biopsied. No evidence of cysts was observed. Histopathological examination revealed a hemorrhagic corpus luteal cyst. Suspicion for corpus luteal rupture as a cause of postcoital hemoperitoneum should be maintained despite nonevidence of cysts on CT or intraoperatively. PMID- 26429555 TI - Heterotopic ossification in chronic fibrosing otitis externa. AB - Acquired external auditory canal atresia is a rare complication of chronic inflammatory otitis, and is generally fibrous or soft tissue in nature. Here, we present the first reported case of heterotopic ossification within chronic fibrosing otitis externa in a 25-year-old male patient with a childhood history of granular myringitis and failed tympanoplasty. A calcified mass was demonstrated adjacent to the tympanic membrane on CT imaging, and surgical exploration revealed a cohesive bar of bone traversing the medial external auditory canal. Drill canaloplasty and split-thickness skin graft coverage of the lateral tympanic membrane resulted in an improvement in the pure tone average from 79 to 55 dB. As the treatment for chronic fibrosing otitis externa involves the surgical widening of the external auditory canal, we alert surgeons to the possibility of cohesive bone formation as a potential cause of navigational confusion and inadvertent over- or under-drilling of the canal stenosis. PMID- 26429556 TI - Monoamine Oxidase Inhibitory Action of Chalcones: A Mini Review. AB - INTRODUCTION: Chalcones are one of the major classes of naturally occurring compounds and have a vast significance in medicinal chemistry, presenting with a wide scope of pharmacological actions. DISCUSSION: The present review focused our attention onto the monoamine oxidase inhibitory activity of natural and synthetic chalcones. The review also emphasises the structure-activity relationship studies and molecular recognition of chalcones towards MAO-A and B inhibition. CONCLUSION: Many of the studies clearly revealed that most of the chalcones showed selective, reversible and potent MAO-B inhibition compared to MAO-A. Recent studies also showed that heteroaryl-based chalcones are potent MAO-A inhibitors. PMID- 26429557 TI - Fully Automated Sample Preparation for Ultrafast N-Glycosylation Analysis of Antibody Therapeutics. AB - There is a growing demand in the biopharmaceutical industry for high-throughput, large-scale N-glycosylation profiling of therapeutic antibodies in all phases of product development, but especially during clone selection when hundreds of samples should be analyzed in a short period of time to assure their glycosylation-based biological activity. Our group has recently developed a magnetic bead-based protocol for N-glycosylation analysis of glycoproteins to alleviate the hard-to-automate centrifugation and vacuum-centrifugation steps of the currently used protocols. Glycan release, fluorophore labeling, and cleanup were all optimized, resulting in a <4 h magnetic bead-based process with excellent yield and good repeatability. This article demonstrates the next level of this work by automating all steps of the optimized magnetic bead-based protocol from endoglycosidase digestion, through fluorophore labeling and cleanup with high-throughput sample processing in 96-well plate format, using an automated laboratory workstation. Capillary electrophoresis analysis of the fluorophore-labeled glycans was also optimized for rapid (<3 min) separation to accommodate the high-throughput processing of the automated sample preparation workflow. Ultrafast N-glycosylation analyses of several commercially relevant antibody therapeutics are also shown and compared to their biosimilar counterparts, addressing the biological significance of the differences. PMID- 26429558 TI - An Empirical Comparison of Competing Factor Structures for the Repeatable Battery for the Assessment of Neuropsychological Status: A Project FRONTIER Study. AB - The original factor structure of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has received little empirical support, but at least eight alternative factor structures have been identified in the literature. The current study used confirmatory factor analysis to compare the original RBANS model with eight alternatives, which were adjusted to include a general factor. Participant data were obtained from Project FRONTIER, an epidemiological study of rural health, and comprised 341 adults (229 women, 112 men) with mean age of 61.2 years (SD = 12.1) and mean education of 12.4 years (SD = 3.3). A bifactor version of the model proposed by Duff and colleagues provided the best fit to the data (CFI = 0.98; root-mean-squared error of approximation = 0.07), but required further modification to produce appropriate factor loadings. The results support the inclusion of a general factor and provide partial replication of the Duff and colleagues RBANS model. PMID- 26429559 TI - Efficacy of memory training in healthy community-dwelling older people: study protocol for a randomized controlled trial. AB - BACKGROUND: There is limited evidence on the efficacy and social utility of cognitive training. To address this, we have designed a randomized controlled trial to assess the effectiveness of memory training workshops for healthy older people in terms of their short- and long-term impact on cognitive function, health-related quality of life, and functionality. METHODS/DESIGN: A randomized controlled trial will be performed in health care centers in Barcelona (Spain) through comparison of a group of individuals participating in memory training workshops (experimental group) with another group with similar characteristics not participating in the workshops (control group). The intervention will consist of twelve 90-minute group sessions imparted once a week by a psychologist specialized in memory training. The groups will each comprise approximately 15 people, for a total number of 230 patients involved in the study. Each session has its own objectives, materials and activities. The content of the intervention is based on memory training from different perspectives, including cognitive and emotional aspects and social and individual skills. Data will be collected at baseline, at 3-4 months and at 6 months. To assess the efficacy of the intervention on cognitive function, health-related quality of life and functionality, a statistical analysis will be performed by fitting a repeated measures mixed effects model for each main outcome: Self-perceived memory, measured by a Subjective Self-reported Memory Score (from 0 to 10) and by the Memory Failures in Everyday life questionnaire (MFE); Everyday memory, measured using the Rivermead Behavioural Memory Test-3 (RBMT-3) and Executive control abilities, measured in terms of visual-perceptual ability, working memory and task-switching ability with the Trail Making Test (TMT) and with the digit span scale of the Wechsler Adult Intelligence Scale III (WAIS III). DISCUSSION: The results of this study will be highly useful for social and public health policies related to older people. Given the continuous increase in the prevalence of older people, a large number of interventions targeting memory loss are funded by public resources. To ensure transparency and effective prioritization, research such as the present study is needed to provide evidence of the effectiveness and usefulness of these interventions. TRIAL REGISTRATION: Number: NCT02431182 . PMID- 26429560 TI - Survey on the use of insulin pumps in Italy: comparison between pediatric and adult age groups (IMITA study). AB - AIMS: The aim of the study was to evaluate and compare continuous subcutaneous insulin infusion (CSII) use in pediatric and adult age groups. METHODS: Data were collected with a questionnaire sent by e-mail to CSII-experienced Diabetes Centers. The questionnaire assessed: (1) number of CSII-treated patients; (2) patient demographic data and characteristics; (3) structure and organization of Diabetes Centers providing CSII therapy; (4) pump characteristics (conventional pump, sensor-augmented pump); and (5) CSII dropouts. RESULTS: A total of 217 out of 1093 Italian centers participated: 51 pediatric (23.5 %) and 166 (76.5 %) adult centers (AP). Compared to a survey performed in 2005, there was a significant increase in the number of pediatric units when compared to adult units (112 vs 37 %, respectively, p < 0.05). Pediatric age is characterized by a greater concern for quality of life and injections, and a higher dropout rate (10.6 vs 8.9 %) mainly related to pump wearability and site reactions. A complete diabetes-care team is associated with a superior use of technology (fewer dropouts, increased CGM and advanced bolus use) which is, however, still used in a small percentage of patients. CONCLUSIONS: In Italy, the number of CSII-treated pediatric patients (PP) is growing more significantly when compared to adults. Only 60 % of all patients are using advanced functions and 20 % are using CGMs continuously. This confirms the great interest in diabetes technology that is growing in pediatric diabetologists. However, much improvement is warranted in the organization and specialized training of pediatric, adult and transitional facilities. PMID- 26429561 TI - Prognostic Role of PD-L1 Expression in Renal Cell Carcinoma. A Systematic Review and Meta-Analysis. AB - BACKGROUND: Several clinical trials have reported that therapies targeting programmed death-1 (PD1) and its ligand (PD-L1) improve patient outcomes, while tumor response has been related to PD-L1 expression. OBJECTIVE: To investigate the prognostic role of PD-L1 expression in patients affected by renal cell carcinoma (RCC). METHODS: MEDLINE/PubMed, the Cochrane Library, and ASCO University were searched for studies investigating the prognostic role of PD-L1 expression in RCC. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: Six studies and 1323 cases were included in the final analysis. PD-L1 was expressed in 24.2 % of clear cell tumors compared to 10.9 % of non-clear cell tumors (p = 0.002). In the overall population, a higher level of PD-L1 expression increased the risk of death by 81 % (HR; 1.81, 95 % CI 1.31-2.49; p < 0.001). When the analysis was restricted to cases evaluated by immunohistochemistry alone, the higher expression of PD-L1 more than doubled the risk of death (HR; 2.05, 95 % CI 1.38-3.05; p < 0.001). In clear cell histology, higher PD-L1 expression increased the risk of death by 53 % (HR; 1.53, 95 % CI 1.27-1.84; p < 0.001), while in metastatic patients, the evaluation of PD-L1 expression on primary tumors revealed that it retains its prognostic role (HR; 1.45, 95 % CI 1.08-1.93; p = 0.01). LIMITATIONS: Significant heterogeneity has been identified among the included studies. As a consequence, cautious interpretation of the results is recommended. CONCLUSION: This meta-analysis indicates that a higher level of PD-L1 expression is a negative prognostic factor in RCC. Its validation as an independent prognostic factor compared to other traditionally used clinical parameters in localized or advanced disease is recommended. PMID- 26429562 TI - PyMine: a PyMOL plugin to integrate and visualize data for drug discovery. AB - BACKGROUND: Tremendous amount of chemical and biological data are being generated by various high-throughput biotechnologies that could facilitate modern drug discovery. However, lack of integration makes it very challenging for individual scientists to access and understand all the data related to a specific protein of interest. FINDINGS: To overcome this challenge, we developed PyMine, a PyMOL plugin that retrieves chemical, structural, pathway and other related biological data of a receptor and small molecules from a variety of high-quality databases and presents them in a graphic and uniformed way. CONCLUSIONS: Developed as an interactive and user-friendly tool, PyMine can be used as a central data-hub for users to access and visualize multiple types of data and to generate new ideas intuitively for structure-based molecule design. PMID- 26429563 TI - Dyscholesterolemia Protects Against Ischemia-Induced Ventricular Arrhythmias. AB - BACKGROUND: Hypercholesterolemia protects against ventricular fibrillation in patients with myocardial infarction. We hypothesize that hypercholesterolemia protects against ischemia-induced reentrant arrhythmias because of altered ion channel function. METHODS AND RESULTS: ECGs were measured in low-density lipoprotein receptor knockout (LDLr(-/-)), apolipoprotein A1 knockout (ApoA1(-/ )), and wild-type (WT) mice. Action potentials, calcium handling, and ion currents were recorded in ventricular myocytes. Gene expression was determined by quantitative polymerase chain reaction and Western blot. In isolated perfused hearts, regional ischemia was induced and arrhythmia inducibility was tested. Serum low-density lipoprotein (LDL) cholesterol was higher in LDLr(-/-) mice than in WT mice (2.6 versus 0.4 mmol/L), and high-density lipoprotein cholesterol was significantly lower in ApoA1(-/-) mice than in WT mice (0.3 versus 1.8 mmol/L). LDLr(-/-) and ApoA1(-/-) myocytes contained more cholesterol than WT (34.4+/-2.8 and 36.5+/-2.4 versus 25.5+/-0.4 MUmol/g protein). The major potassium currents were not different in LDLr(-/-) and ApoA1(-/-) compared with WT mice. The L-type calcium current (I(Ca)), however, was larger in LDLr(-/-) and ApoA1(-/-) than in WT (12.1+/-0.7 and 12.8+/-0.8 versus 9.4+/-1.1 pA/pF). Calcium transient amplitude and fractional sarcoplasmic reticulum calcium release were larger and action potential and QTc duration longer in LDLr(-/-) and ApoA1(-/-) than in WT mice (action potential duration at 90% of repolarization: 102+/-4 and 106+/-3 versus 84+/-3.1 ms; QTc: 50.9+/-1.3 and 52.8+/-0.8 versus 43.5+/-1.2 ms). During ischemia, ventricular tachycardia/ventricular fibrillation inducibility was larger in WT than in LDLr(-/-) and ApoA1(-/-) hearts. Expression of sodium channel and Ca-handling genes were not significantly different between groups. CONCLUSIONS: Dyscholesterolemia is associated with action potential prolongation because of increased I(Ca) and reduces occurrence of reentrant arrhythmias during ischemia. PMID- 26429564 TI - Impact of 30 mg/kg amikacin and 8 mg/kg gentamicin on serum concentrations in critically ill patients with severe sepsis. AB - OBJECTIVES: Low first-dose peak serum concentrations of amikacin and gentamicin are commonly reported in ICU patients. The present study aimed to assess whether 30 mg/kg amikacin or 8 mg/kg gentamicin achieved target concentrations in ICU patients with severe sepsis. PATIENTS AND METHODS: Sixty-three ICU patients (Simplified Acute Physiology Score II = 43 +/- 16) with severe sepsis and an indication for intravenous amikacin (n = 47) or gentamicin (n = 16) were included. The first (30 mg/kg amikacin; 8 mg/kg gentamicin) and subsequent doses and corresponding peak concentrations (30 min after the completion of an infusion) were recorded. French guideline target concentrations were >=60 and >=30 mg/L for amikacin and gentamicin, respectively. A target pharmacokinetic/pharmacodynamic ratio of 10 * MIC was also measured. RESULTS: Pulmonary, abdominal and urinary tract infections were diagnosed in 56 patients. Infection was confirmed in 37 patients (59%). The targeted first-dose peak concentration was achieved in 37/63 patients (59%) [amikacin 36/47 (77%) and gentamicin 1/16 (6%)], and 59/63 patients (94%) achieved the pharmacokinetic/pharmacodynamic ratio using the MIC data that were available from 21 patients. However, the second dose of aminoglycoside was withheld because of high trough concentrations in nearly half of patients who did not have renal dysfunction. CONCLUSIONS: In this study, 30 mg/kg amikacin and 8 mg/kg gentamicin led to target peak serum concentrations in 59% of patients. PMID- 26429565 TI - Amiodarone increases positive-strand RNA virus replication in vitro: implications for its use in patients with viral infections. PMID- 26429566 TI - Educating healthcare professionals in antimicrobial stewardship: can online learning solutions help? AB - Education is widely recognized as one of the cornerstones of successful antimicrobial stewardship programmes. There is evidence of important knowledge flaws around antimicrobial prescribing among both medical students and clinicians. Educational interventions improve antimicrobial prescribing, but traditional tools may be insufficient to deliver training to meet the complex demands of global healthcare professionals working across a diverse range of healthcare and resource settings. The educational solutions increasingly need to be timely, efficient, pragmatic, high quality, aligned to the needs of the professional in a specific context, sustainable and cost-effective. Online learning has been playing a growing role in education about antimicrobial stewardship and the recent phenomenon of massive open online courses (MOOCs) offers novel and additional opportunities to deliver relevant information to a wide range of people. Additional research on MOOCs as an educational approach is needed in order to define their effectiveness, sustainability and the best ways to achieve the intended results. Although the precise value of new online strategies such as MOOCs is ill defined, they certainly will have an important place in increasing awareness and improving antimicrobial prescribing. PMID- 26429567 TI - Mechanical debridement versus radiofrequency in knee chondroplasty with concomitant medial meniscectomy: 10-year results from a randomized controlled study. AB - PURPOSE: We compared the effectiveness of mechanical debridement (MD) and bipolar radiofrequency chondroplasty (RF) with regard to clinical outcome, rate of revision, and progression of knee osteoarthritis. METHODS: Sixty patients with MRI-detected grade III cartilage lesions on the medial femoral condyle were considered for the study. For MD (group 1; n = 30), each lesion was debrided using a mechanical shaver. For RF (group 2; n = 30), each lesion was smoothed using a temperature-controlled RF probe set at 50 degrees C. RESULTS: The 10 year follow-up was available for 47 patients (78.3 %). Sixty per cent of group 1 (n = 18) underwent revision during the follow-up period. In contrast, the revision rate in group 2 was 23.3 % (n = 7; p = 0.061). The mean survival was 94.1 months (95 % CI 77.1-111.3) and 62.5 months (95 % CI 45.9-79.2) for group 2 and group 1, respectively. Patients who did not require revision (group 1, n = 9; group 2, n = 13) were assessed before surgery and 1, 4, and 10 years after surgery using the knee injury and osteoarthritis outcome score (KOOS). At follow up, the KOOS was higher for group 2 than group 1. At the time of surgery, no patient showed any radiological signs of osteoarthritis. The width of the medial joint was 5.4 mm (95 % CI 4.3-6.5) and 5.6 mm (95 % CI 4.9-6.3) in the MD and RF groups, respectively (n.s.). During the follow-up period, the joint space width narrowed continuously in both groups (p < 0.001), but more rapidly in the group 1 (n.s). CONCLUSION: Compared to conventional MD, 50 degrees RF treatment appears to be a superior method based on short- and medium-term clinical outcomes and the progression of knee osteoarthritis. Clear predictors for the indications of different cartilage treatments and more randomized clinical trials are needed. LEVEL OF EVIDENCE: I. PMID- 26429568 TI - Ischiofemoral impingement and hamstring dysfunction as a potential pain generator after ischial tuberosity apophyseal fracture non-union/malunion. AB - PURPOSE: The purpose of this study was to describe the occurrence of ischiofemoral impingement (IFI) and hamstring dysfunction following malunion or non-union of ischial tuberosity apophyseal avulsion fractures and report the short-term outcomes of surgical treatment with regard to alleviating symptomatic extra-articular impingement. METHODS: All patients who underwent surgery for recalcitrant hip and buttock pain in the setting of prior ischial tuberosity avulsion fracture at three tertiary-level hip preservation centres were included for this review. A total of ten patients met our inclusion criteria and underwent sciatic neurolysis, resection of the ischial tuberosity fragment and hamstring reattachment. Clinical outcomes scores were collected post-operatively including the Modified Harris Hip Score (mHHS) and the Hip Outcomes Score (HOS). RESULTS: Ten patients with a mean age of 18 years (range 14-28) underwent surgery for symptomatic ischiofemoral impingement after ischial tuberosity avulsion fracture. At a mean of 2.2-year follow-up (range 1.7-3.5), the median post-operative mHHS was 89.7 (65.7-96.8) and HOS ADL and Sport subscales were 90 % or greater in all cases. Five patients (50 %) rated their hip as normal, and five patients (50 %) rated their hip as near normal. CONCLUSION: Malunion or non-union following ischial tuberosity apophyseal fracture can lead to IFI and hamstring dysfunction. Clinically, the resultant pain and dysfunction is often chronic, and can be debilitating. In select cases, a reliable surgical technique is presented to improve hamstring function and correct ischiofemoral impingement in this setting with good-to-excellent outcomes in the majority of cases at short-term follow-up. LEVEL OF EVIDENCE: IV. PMID- 26429569 TI - Thought Disorder in Preschool Children with Attention Deficit/Hyperactivity Disorder (ADHD). AB - Preschool identification of and intervention for psychiatric symptoms has the potential for lifelong benefits. However, preschool identification of thought disorder, a symptom associated with long term risk for social and cognitive dysfunction, has received little attention with previous work limited to examining preschoolers with severe emotional and behavioral dysregulation. Using story-stem methodology, 12 children with ADHD and 12 children without ADHD, ages 4.0-6.0 years were evaluated for thought disorder. Thought disorder was reliably assessed (Cronbach's alpha = .958). Children with ADHD were significantly more likely than children without ADHD to exhibit thought disorder (75 vs 25 %; Fischer's Exact Test = .0391). Thought disorder can be reliably assessed in preschool children and is present in preschool children with psychiatric illness including preschool children with ADHD. Thought disorder may be identifiable in preschool years across a broad range of psychiatric illnesses and thus may be an appropriate target of intervention. PMID- 26429570 TI - Moderating Effects of Gender on Outcomes Associated with Stressful Life Events Among Elementary School-Age Youth. AB - Stressful life events have been associated with child and adolescent maladjustment, including elevated levels of aggression and anxiety (Attar et al. in J Clin Child Psychol 23:391-400, 1994; Fox et al. in J Adolesc 33:43-54, 2010). However, gender specific outcomes associated with stressful life events among elementary school-age youth are less known. Accordingly, the current study examined the role of gender in the associations between stressful life events and anxiety and proactive and reactive aggression. Participants included 294 elementary school-age children (M = 8.71, SD = 1.17, 50.7 % male). Regression analyses indicated that stressful life events were positively associated with anxiety and reactive, but not proactive, aggression. There were no gender differences with regard to the associations with anxiety symptoms or proactive aggression. However, gender moderated the association between stressful life events and reactive aggression, such that stressful life events were only positively associated with reactive aggression for boys. Future directions and implications of this research are presented. PMID- 26429571 TI - Vitamin D supplementation and systemic inflammation in relapsing-remitting multiple sclerosis. AB - Observational studies have suggested that vitamin D may reduce inflammation in relapsing-remitting multiple sclerosis (RRMS), but this has not been clearly confirmed in randomized controlled trials. To further explore the possible anti inflammatory effects of vitamin D in RRMS, we examined the effect of high-dose oral vitamin D3 on eleven markers of systemic inflammation in 68 RRMS patients enrolled in a double-blinded randomized placebo-controlled trial of vitamin D3 supplementation (20,000 IU/week) (NCT00785473). Serum inflammation markers and 25 hydroxyvitamin D (25(OH)D) were measured at baseline and week 96, and no restrictions were set on additional standard immunomodulatory treatment for RRMS. The mean 25(OH)D level rose from 56 +/- 29 to 123 +/- 34 nmol/L among patients receiving vitamin D3 supplementation, whereas only a minor increase from 57 +/- 22 to 63 +/- 24 nmol/L was seen in the placebo group. However, no significant differences appeared between the vitamin D group and the placebo group for any of the inflammation markers. Patients on immunomodulatory therapy had significantly higher levels of interleukin-1 receptor antagonist and chemokine (C-X-C motif) ligand 16 than patients without immunomodulatory treatment, but there were no clear synergistic effects between immunomodulatory therapy and vitamin D3 supplementation on any of the inflammation markers. The rise in 25(OH)D levels after vitamin D3 supplementation was unaffected by immunomodulatory treatment. We conclude that in this study of RRMS patients, high-dose oral vitamin D3 supplementation prominently increased serum 25(OH)D levels without affecting markers of systemic inflammation, while a more anti-inflammatory phenotype was found among patients on immunomodulatory treatment. PMID- 26429572 TI - Complications are reduced with a protocol to standardize timing of fixation based on response to resuscitation. AB - BACKGROUND: Our group developed a protocol, entitled Early Appropriate Care (EAC), to determine timing of definitive fracture fixation based on presence and severity of metabolic acidosis. We hypothesized that utilization of EAC would result in fewer complications than a historical cohort and that EAC patients with definitive fixation within 36 h would have fewer complications than those treated at a later time. METHODS: Three hundred thirty-five patients with mean age 39.2 years and mean Injury Severity Score (ISS) 26.9 and 380 fractures of the femur (n = 173), pelvic ring (n = 71), acetabulum (n = 57), and/or spine (n = 79) were prospectively evaluated. The EAC protocol recommended definitive fixation within 36 h if lactate <4.0 mmol/L, pH >=7.25, or base excess (BE) >=-5.5 mmol/L. Complications including infections, sepsis, DVT, organ failure, pneumonia, acute respiratory distress syndrome (ARDS), and pulmonary embolism (PE) were identified and compared for early and delayed patients and with a historical cohort. RESULTS: All 335 patients achieved the desired level of resuscitation within 36 h of injury. Two hundred sixty-nine (80%) were treated within 36 h, and 66 had protocol violations, treated on a delayed basis, due to surgeon choice in 71%. Complications occurred in 16.3% of patients fixed within 36 h and in 33.3% of delayed patients (p = 0.0009). Hospital and ICU stays were shorter in the early group: 9.5 versus 17.3 days and 4.4 versus 11.6 days, respectively, both p < 0.0001. This group of patients when compared with a historical cohort of 1443 similar patients with 1745 fractures had fewer complications (16.3 versus 22.1%, p = 0.017) and shorter length of stay (LOS) (p = 0.018). CONCLUSIONS: Our EAC protocol recommends definitive fixation within 36 h in resuscitated patients. Early fixation was associated with fewer complications and shorter LOS. The EAC recommendations are safe and effective for the majority of severely injured patients with mechanically unstable femur, pelvis, acetabular, or spine fractures requiring fixation. PMID- 26429573 TI - The Afro-Cardiac Study: Cardiovascular Disease Risk and Acculturation in West African Immigrants in the United States: Rationale and Study Design. AB - Cardiovascular disease (CVD) remains the leading cause of death in the United States (US). African-descent populations bear a disproportionate burden of CVD risk factors. With the increase in the number of West African immigrants (WAIs) to the US over the past decades, it is imperative to specifically study this new and substantial subset of the African-descent population and how acculturation impacts their CVD risk. The Afro-Cardiac study, a community-based cross-sectional study of adult WAIs in the Baltimore-Washington metropolis. Guided by the PRECEDE PROCEED model, we used a modification of the World Health Organization Steps survey to collect data on demographics, socioeconomic status, migration-related factors and behaviors. We obtained physical, biochemical, acculturation measurements as well as a socio-demographic and health history. Our study provides critical data on the CVD risk of WAIs. The framework used is valuable for future epidemiological studies addressing CVD risk and acculturation among immigrants. PMID- 26429574 TI - Patient Activation is Inconsistently Associated with Positive Health Behaviors Among Obese Safety Net Patients. AB - We examine the association of patient activation and physical activity and fruit and vegetable consumption among obese safety net patients. Adult obese patients (n = 198) of three safety net clinics completed a survey assessing patient activation, physical activity, fruit and vegetable consumption, care experiences, and health status. Multivariate logistic regression models incrementally assessed the adjusted relation of patient activation and physical activity and fruit and vegetable consumption. In adjusted analyses, higher activated patients had higher odds [Odds ratio (OR) 1.58, p < 0.01] of consuming fruits and vegetables daily than less activated patients. There was no significant association between patient activation and regular physical activity. Engaging in regular physical activity appears to be difficult, even for highly activated patients. In contrast, additional fruit and vegetable consumption is a relatively easier change. Patient activation was inconsistently associated with two positive health behaviors among obese safety net patients. PMID- 26429578 TI - Colored Sticky Traps to Selectively Survey Thrips in Cowpea Ecosystem. AB - The bean flower thrips, Megalurothrips usitatus (Bagrall) (Thysanoptera: Thripidae), is an important pest of legume crops in South China. Yellow, blue, or white sticky traps are currently recommended for monitoring and controlling thrips, but it is not known whether one is more efficient than the other or if selectivity could be optimized by trap color. We investigated the response of thrips and beneficial insects to different-colored sticky traps on cowpea, Vigna unguiculata. More thrips were caught on blue, light blue, white, and purple traps than on yellow, green, pink, gray, red, or black traps. There was a weak correlation on the number of thrips caught on yellow traps and survey from flowers (r = 0.139), whereas a strong correlation was found for blue traps and thrips' survey on flowers (r = 0.929). On commercially available sticky traps (Jiaduo(r)), two and five times more thrips were caught on blue traps than on white and yellow traps, respectively. Otherwise, capture of beneficial insects was 1.7 times higher on yellow than on blue traps. The major natural enemies were the predatory ladybird beetles (63%) and pirate bugs Orius spp. (29%), followed by a number of less representative predators and parasitoids (8%). We conclude the blue sticky trap was the best to monitor thrips on cowpea in South China. PMID- 26429577 TI - Are there differences between stemless and conventional stemmed shoulder prostheses in the treatment of glenohumeral osteoarthritis? AB - BACKGROUND: Conventional stemmed anatomical shoulder prostheses are widely used in the treatment of glenohumeral osteoarthritis. The stemless shoulder prosthesis, in contrast, is a new concept, and fewer outcome studies are available. Therefore, the purpose of the study was to investigate the early functional outcome and postoperative proprioception of a stemless prosthesis in comparison with a standard stemmed anatomic shoulder prosthesis. METHODS: Twelve patients (mean age 68.3 years [SD +/- 5.4]; 5 female, 7 male) with primary glenohumeral osteoarthritis of the shoulder were enrolled, who underwent total shoulder arthroplasty (TSA) with a stemless total shoulder prosthesis, Total Evolution Shoulder System (TESS; Biomed, France). The control group consisted of twelve (age and gender matched) patients (mean age 67.8 years; [SD +/- 7.1]; 9 female, 3 male), getting a TSA with a standard anatomic stemmed prosthesis, Aequalis Shoulder (Tournier, Lyon, France). Patients were examined the day before and six months after surgery. The pre- and postoperative Constant Score (CS) was evaluated and proprioception was measured in a 3D video motion analysis study using an active angle-reproduction (AAR) test. RESULTS: Comparing the postoperative CS, there was no significant difference between the groups treated with the TESS prosthesis (48.0 +/- 13.8 points) and the Aequalis prosthesis (49.3 +/- 8.6 points; p = 0.792). There was no significant difference in postoperative proprioception between the TESS group (7.2 degrees [SD +/- 2.8]) and the Aequalis group(8.7 degrees [SD +/- 2.7]; p = 0.196), either. Comparison of in the results of CS and AAR test pre- and postoperatively showed no significant differences between the groups. DISCUSSION: In patients with glenohumeral osteoarthritis, treated with TSA, the functional and the proprioceptive outcome is comparable between a stemless and a standard stemmed anatomic shoulder prosthesis at early followup. CONCLUSION: Further follow-up is necessary regarding the long-term performance of this prosthesis. TRIAL REGISTRATION: Current Controlled Trials DRKS 00007528 . Registered 17 November 2014. PMID- 26429579 TI - Neotropical Polistinae (Vespidae) and the Progression Rule Principle: the Round Trip Hypothesis. AB - The progression rule principle is based on the relation between centers of origin and basal forms, and the prediction that recently colonized areas are where novelties commonly occur. Using this concept as the null hypothesis, the aim of the present study was to test whether intuitive predictions of this model are confirmed in the Neotropical paper wasps, a group fairly studied through phylogenetic frameworks. The analyses consisted of a careful review of the distribution of different wasps of the subfamily Polistinae with available phylogenies and the association of this information with colonization routes. This procedure allowed the determination of a two-step colonization process in the Neotropical region based on the progression rule principle, for which the round-trip hypothesis is proposed. The first route (east to west) is seen in a small group of Polistes. This route is rare but strengthens the arising of paper wasps in the Americas in a Gondwanan scenario. The second route (west to east) is remarkably repeated in several other lineages. Thus, the northwestern Neotropics, mainly Amazon Forest, is proposed as the major center of origins for living Neotropical Polistinae and the round-trip hypothesis may explain both earlier and later colonization routes of the paper wasps analyzed. PMID- 26429580 TI - Immature Development of Spodoptera dolichos (Fabricius) (Lepidoptera: Noctuidae). AB - We provide detailed temporal and morphological parameters of the immature stages of Spodoptera dolichos (Fabricius) larvae fed on artificial diet under controlled conditions (25 +/- 1 degrees C, 70 +/- 10% RH, and 14 h photophase). The viability of the egg, larval, pupal, and prepupal stages was 97.5%, 97.0%, 93.1%, and 98.9%, respectively. The average duration of the egg, larval, prepupal, and pupal stages was 5.0, 23.4, 3.2, and 21.5 days, respectively. Females took longer at the larval stage than males, with 10.5% of them having seven instars. The growth rate of female larvae that developed through six and seven instars was 1.72 and 1.54, respectively. Female pupae were significantly larger, exhibiting slower development than males. PMID- 26429581 TI - Did Adult Diurnal Activity Influence the Evolution of Wing Morphology in Opoptera Butterflies? AB - The butterfly genus Opoptera includes eight species, three of which have diurnal habits while the others are crepuscular (the usual activity period for members of the tribe Brassolini). Although never measured in the field, it is presumed that diurnal Opoptera species potentially spend more time flying than their crepuscular relatives. If a shift to diurnal habits potentially leads to a higher level of activity and energy expenditure during flight, then selection should operate on increased aerodynamic and energetic efficiency, leading to changes in wing shape. Accordingly, we ask whether diurnal habits have influenced the evolution of wing morphology in Opoptera. Using phylogenetically independent contrasts and Wilcoxon rank sum tests, we confirmed our expectation that the wings of diurnal species have higher aspect ratios (ARs) and lower wing centroids (WCs) than crepuscular congeners. These wing shape characteristics are known to promote energy efficiency during flight. Three Opoptera wing morphotypes established a priori significantly differed in AR and WC values. The crepuscular, cloud forest dweller Opoptera staudingeri (Godman & Salvin) was exceptional in having an extended forewing tip and the highest AR and lowest WC within Opoptera, possibly to facilitate flight in a cooler environment. Our study is the first to investigate how butterfly wing morphology might evolve as a response to a behavioral shift in adult time of activity. PMID- 26429582 TI - Hemocytes of the Rose Sawfly Arge ochropus (Gmelin) (Hymenoptera: Argidae). AB - We characterized individual morphological types of the rose sawfly, Arge ochropus (Gmelin) (Hymenoptera: Argidae), hemocytes for the first time by means of light and differential interference contrast microscopy and scanning and transmission electron microscopy. Four types of hemocytes were identified in the hemolymph of larvae and pupae of A. ochropus: prohemocytes, plasmatocytes, granulocytes, and oenocytoids. Prohemocytes are the smallest type of hemocytes, rounded to ovoid cells with large nuclei. Plasmatocytes are polymorphic and variable in size. Granulocytes are oval and spherical cells variable in size, with variable number of rough endoplasmic reticulum, mitochondria, and microtubules in the cytoplasm. Oenocytoids contain eccentric nucleus and cytoplasm with small mitochondria and few rough endoplasmic reticula. Differential hemocyte counts indicated that plasmatocytes are the most abundant hemocyte type during early instars while granulocytes are the most abundant hemocyte type in the last instar. The pattern of total hemocyte count changed during rose sawfly development and reached its peak in prepupae and then declined slowly in the pupal stage. PMID- 26429583 TI - Long-Term Outcomes of Iris-sutured Posterior Chamber Intraocular Lenses in Children. AB - PURPOSE: To report the long-term outcomes and complications of iris-sutured posterior chamber intraocular lenses (PCIOLs) in the pediatric population. DESIGN: Retrospective interventional case study. METHODS: This study involved 12 consecutive pediatric patients (17 eyes) who underwent placement of foldable iris sutured PCIOLs between September 2004 and September 2007. Outcome measures included change in visual acuity and complications. RESULTS: Of the 17 eyes were reviewed, 6 (35%) had hereditary or idiopathic ectopia lentis, 5 (29%) had Marfan syndrome, 2 (12%) were aphakic after pars plana vitrectomy and 4 (24%) were aphakic after surgical intervention for trauma. Average follow-up was 4.69 +/- 3.21 years and mean age of surgery was 7.21 +/- 3.78 years. Seven eyes suffered dislocation of the PCIOL an average of 12.11 +/- 11.97 months after surgery, with 2 patients undergoing dislocation a second time. There was a higher rate of dislocation in patients with a history of ectopia lentis due to Marfan syndrome, idiopathic causes, or hereditary causes than in patients being treated for aphakia resulting from other causes (71% vs 29%). Mean visual acuity improved in 12 of 17 patients (71%), from 0.80 +/- 0.6 logMAR preoperatively to 0.35 +/- 0.5 logMAR at most recent visit, P = .009. One eye of a Marfan patient sustained a retinal detachment 8 months after dislocation of the PCIOL, and 1 patient experienced iris capture of the PCIOL after surgery. CONCLUSIONS: Iris-sutured intraocular lenses have been used as an alternative to transsclerally sutured intraocular lenses to correct aphakia in pediatric patients. Dislocation of the intraocular lenses can occur frequently, however. The procedure should be considered with caution in pediatric patients. PMID- 26429584 TI - Outcomes of 27 Gauge Microincision Vitrectomy Surgery for Posterior Segment Disease. AB - PURPOSE: To report the initial experience, clinical outcomes, and safety profile of 27 gauge pars plana vitrectomy (PPV) in eyes with posterior segment disease. DESIGN: Multicenter, retrospective, interventional case series. METHODS: setting: Private practice and tertiary care settings. STUDY POPULATION: Eyes undergoing 27 gauge PPV for a vitreoretinal surgery indication. INTERVENTION: Three-port, transconjunctival 27 gauge PPV. MAIN OUTCOME MEASURES: Change in visual acuity and occurrence of intraoperative and postoperative complications with minimum follow-up of 90 days. RESULTS: Ninety-five eyes met the inclusion criteria. Surgical indications included epiretinal membrane (n = 26), diabetic tractional retinal detachment (n = 14), full-thickness macular hole (n = 11), rhegmatogenous retinal detachment with (n = 7) or without (n = 9) proliferative vitreoretinopathy (PVR), vitreous hemorrhage (n = 10), vitreous opacities (n = 8), endophthalmitis (n = 4), sub-silicone oil retinal detachment (n = 3), retained lens material (n = 1), submacular hemorrhage (n = 1), and aqueous misdirection (n = 1). Mean logMAR visual acuity improved from 1.08 +/- 0.71 (20/240 Snellen equivalent) preoperatively to 0.53 +/- 0.65 (20/67 Snellen equivalent) postoperatively (P < .001). Mean follow-up was 144 days (median 127 days, range 90-254 days). There were no intraoperative complications and no case required conversion to 20, 23, or 25 gauge instrumentation. A total of 3 sclerotomy sites (1.1%) were sutured at the conclusion of surgery. Postoperative complications included transient ocular hypertension in 8 eyes (8.4%), transient hypotony in 5 eyes (5.3%), and vitreous hemorrhage in 5 eyes (5.3%). No cases of postoperative endophthalmitis, sclerotomy-related retinal tears, or choroidal detachments were encountered in the follow-up period. CONCLUSION: The 27 gauge PPV was well tolerated with low rates of intraoperative and postoperative complications across varied surgical indications. PMID- 26429585 TI - Regenerated Cellulose Capsules for Controlled Drug Delivery, Part 2: Modulating Membrane Permeability by Incorporation of Depolymerized Cellulose and Altering Membrane Thickness. AB - For application of regenerated cellulose (RC) membranes in capsule dosage forms, the methods to modify drug release from these membranes are described. Membranes were fabricated by blending native and depolymerized celluloses dissolved in dimethyl sulfoxide and paraformaldehyde solvent system, prior to casting on molds, precipitation in water, and thermal annealing. The effect of laminating layers of RC to fabricate membranes with increasing thickness was also investigated. Solute diffusion studies using ionic and hydrophobic solutes, as well as large protein molecules, were conducted in side-by-side diffusion cells. Microscopic as well as physiological evaluation of these membranes indicated that pore size, porosity, and water uptake decreased as the fraction of depolymerized cellulose increased in the membranes. Permeability analysis of small ionic and hydrophobic solutes indicated that the solute transport across the hydrated membrane occurs through diffusion in the water-filled pores that are formed in situ. The apparent path for solute diffusion increases as the fraction of depolymerized cellulose increases. Permeability analysis of large protein molecules indicated that the pore sizes and distribution in these membranes is heterogeneous. Increasing the membrane thickness by lamination of RC does not influence porosity but causes formation of dead-end pores because of blocking by subsequent laminate layers. PMID- 26429586 TI - Quantitative Assessment of Scalene Muscle Block for the Diagnosis of Suspected Thoracic Outlet Syndrome. AB - PURPOSE: To measure changes in upper limb work and power capacity before and after anterior scalene muscle block (ASMB) to suggest thoracic outlet syndrome caused by costoclavicular space compression. METHODS: We evaluated 34 patients disabled by symptoms suggesting thoracic outlet syndrome. An ASMB was performed via a supraclavicular injection. The sternocleidomastoid muscle was injected as a control. We captured data obtained from work simulator measurements before and after ASMB. Each patient performed a push-pull test with the forearm at waist level (test 1), an overhead bar push-pull test with the arm elevated (test 2), and the extremity abduction stress test with repetitive hand gripping during static arm elevation (test 3). We measured the work product, time to fatigue, and power generation. Sensory testing was performed after ASMB to rule out improved performance associated with possible sensory nerve block. RESULTS: In contrast to sternocleidomastoid injection controls, symptomatic and functional improvement was noted in all patients (n = 34) after ASMB. Work product measurement improved 93%, 108%, and 104% for tests 1, 2, and 3, respectively. Time to fatigue and power output also increased after the block. CONCLUSIONS: Temporary symptomatic improvement after ASMB may be anticipated in patients with TOS. This study documents a significant concurrent increase in upper limb motor function after the block. Increased work and power measurements after ASMB may draw diagnostic inference regarding a dynamic change in the scalene muscle and the costoclavicular space associated with symptomatic thoracic outlet syndrome. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III. PMID- 26429587 TI - A new method for segmentation of FDG PET metabolic tumour volume using the peritumoural halo layer and a 10-step colour scale. A study in patients with papillary thyroid carcinoma. AB - AIM: We observed a layer between tumour activity and background on FDG PET/CT with the 10-step colour scale and the window level set properly. We named the layer peritumoral halo layer (PHL). We performed this study to establish the reliability of metabolic tumor volume (MTV) segmentation using PHL (MTV(PHL)) in patients with papillary thyroid carcinoma. PATIENTS, METHODS: Of a total of 140 papillary thyroid carcinoma (PTC) patients, 70 (50.0%) had FDG-avid PTC. In these patients, MTV(PHL), MTV segmented according to fixed 50% SUVmax (MTV(50%)), and fixed SUV with 2.5 to 4.0 (MTV(2.5) to MTV(4.0)) were compared with pathologic tumour volume (PTV). The absolute percentage difference between MTV(PHL) and PTV was compared in micropapillary carcinoma (MPTC) and non-micropapillary carcinoma (non-MPTC) subgroups. The % SUVmax and SUV thresholds of MTV(PHL) were compared with tumour SUVmax. RESULTS: Among the MTVs, MTV(50%) was not correlated with PTV (r = -0.16, p = 0.182) and was not reliable according to the Bland-Altman plot. Although MTV(2.5), MTV(3.0), MTV(3.5), and MTV(4.0) correlated with PTV (r = 0.85, 0.86, 0.87, and 0.87, respectively; p < 0.001), these MTVs were not reliable on Bland-Altman analyses. MTV(PHL) was significantly correlated with PTV (r = 0.80, p < 0.001), and the Bland-Altman plot did not show systemic error. The MTV(PHL) was more accurate in non-MPTC than in MPTC (p < 0.001), and the absolute % difference was smaller as PTV became larger (sigma = -0.65, p < 0.001). The MTV(PHL) thresholds had correlations with SUVmax (% SUVmax threshold: sigma = 0.87, p < 0.001; SUV threshold: r = 0.88, p < 0.001). CONCLUSIONS: MTV(PHL) was more reliable than MTV(%SUVmax) or MTV(SUV). The reliability of MTV(PHL) improved with larger PTVs. The threshold of the MTV(PHL) was naturally altered by PHL according to SUVmax. PMID- 26429589 TI - Current Concepts on Diagnosis and Prognosis of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia. AB - Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an uncommon cardiac disease characterized by progressive right ventricular dysfunction due to fibrofatty replacement of myocytes and risk of sudden cardiac death from malignant arrhythmias. ARVC/D is a disease of the cardiac desmosome, with genetic mutations in genes encoding proteins critical to this structure found in the majority of patients. The diagnosis of ARVC/D is based on fulfilling a combination of clinical, imaging, pathologic, and/or genetic criteria set forth by the 2010 modified Task Force Criteria. Cardiac magnetic resonance (CMR) is included in these criteria and plays an important role in the management of ARVC/D, demonstrating pathologic structural changes in the right and left ventricles that provide both diagnostic and prognostic information. The purpose of this article is to provide a background on the pathophysiology and genetics of ARVC/D and focus on the role of CMR in management of ARVC/D including diagnosis, prognosis, and treatment decisions. Common CMR pitfalls that can lead to misdiagnosis will also be reviewed. PMID- 26429588 TI - Current Smoking Status Is Associated With Lower Quantitative CT Measures of Emphysema and Gas Trapping. AB - PURPOSE: The purposes of this study were to evaluate the effect of smoking status on quantitative computed tomography CT measures of low-attenuation areas (LAAs) on inspiratory and expiratory CT and to provide a method of adjusting for this effect. MATERIALS AND METHODS: A total of 6762 current and former smokers underwent spirometry and volumetric inspiratory and expiratory CT. Quantitative CT analysis was completed using open-source 3D Slicer software. LAAs were defined as lung voxels with attenuation values <=-950 Hounsfield units (HU) on inspiratory CT and <=-856 HU on expiratory CT and were expressed as percentage of CT lung volume (%LAAI-950 and %LAAE-856). Multiple linear regression was used to determine the effect of smoking status on %LAAI-950 and %LAAE-856 while controlling for demographic variables, spirometric lung function, and smoking history, as well as total lung capacity (%LAAI-950) or functional residual capacity (%LAAE-856). Quantile normalization was used to align the %LAAI-950 distributions for current and former smokers. RESULTS: Mean %LAAI-950 was 4.2+/ 7.1 in current smokers and 7.7+/-9.7 in former smokers (P<0.001). After adjusting for confounders, %LAAI-950 was 3.5 percentage points lower and %LAAE-856 was 6.0 percentage points lower in current smokers than in former smokers (P<0.001). After quantile normalization, smoking status was an insignificant variable in the inspiratory regression model, with %LAAI-950 being 0.27 percentage points higher in current smokers (P=0.13). CONCLUSIONS: After adjusting for patient demographics and lung function, current smokers display significantly lower %LAAI 950 and %LAAE-856 than do former smokers. Potential methods for adjusting for this effect would include adding a fixed value (eg, 3.5%) to the calculated percentage of emphysema in current smokers, or quantile normalization. PMID- 26429590 TI - Molluscicidal activity of Solanum elaeagnifolium seeds against Galba truncatula intermediate host of Fasciola hepatica: Identification of beta-solamarine. AB - CONTEXT: The persistence of fascioliasis in many developing countries urges the search for simple, cheap, and effective substances. In this view, plants provide interesting molluscicidal activities thanks to the secondary metabolites they produce. The genus Solanum is known for its potent effect on vector snails. OBJECTIVE: The molluscicidal activity of Solanum elaeagnifolium Cav. (Solanaceae) seeds against Galba truncatula Mull. (Lymnaeidae), intermediate host of Fasciola hepatica L. (Fasciolidae), was evaluated. MATERIALS AND METHODS: Solanum elaeagnifolium seeds were powdered and successively extracted using n-hexane, methylene chloride, acetone, and methanol, for 20 h each. After filtration, solvents were evaporated. An acid-base treatment was conducted on seed methanolic extract to isolate total alkaloids and beta-solamarine. Total saponins fraction was obtained after successive macerations and evaporations. The molluscicidal activity was evaluated by subjecting snails, in groups of 10, for 48 h to 500 mL of extracts, fractions, and pure product aqueous solutions, each containing amounts, ranging from 1 to 50 mg of plant material in 5 mg increments. RESULTS: The methanolic extract of seeds, beta-solamarine isolated for the first time from this plant and total saponins fraction showed very potent activities on snails, giving respective median lethal concentrations (LC50) of 1.18, 0.49, and 0.94 mg/L. Total alkaloids fraction obtained from the methanolic extract was less active giving an LC50 value of 14.67 mg/L. DISCUSSION AND CONCLUSION: This study emphasizes that glycoalkaloids and saponins of Solanum elaeagnifolium are potent molluscicidal agents. Seed methanolic extract, beta-solamarine, and total saponins fraction may be used as molluscicides. PMID- 26429591 TI - Innovative use of the integrative review to evaluate evidence of technology transformation in healthcare. AB - Healthcare is in a period significant transformational activity through the accelerated adoption of healthcare technologies, new reimbursement systems that emphasize shared savings and care coordination, and the common place use of mobile technologies by patients, providers, and others. The complexity of healthcare creates barriers to transformational activity and has the potential to inhibit the desired paths toward change envisioned by policymakers. Methods for understanding how change is occurring within this complex environment are important to the evaluation of delivery system reform and the role of technology in healthcare transformation. This study examines the use on an integrative review methodology to evaluate the healthcare literature for evidence of technology transformation in healthcare. The methodology integrates the evaluation of a broad set of literature with an established evaluative framework to develop a more complete understanding of a particular topic. We applied this methodology and the framework of punctuated equilibrium (PEq) to the analysis of the healthcare literature from 2004 to 2012 for evidence of technology transformation, a time during which technology was at the forefront of healthcare policy. The analysis demonstrated that the established PEq framework applied to the literature showed considerable potential for evaluating the progress of policies that encourage healthcare transformation. Significant inhibitors to change were identified through the integrative review and categorized into ten themes that describe the resistant structure of healthcare delivery: variations in the environment; market complexity; regulations; flawed risks and rewards; change theories; barriers; ethical considerations; competition and sustainability; environmental elements, and internal elements. We hypothesize that the resistant nature of the healthcare system described by this study creates barriers to the direct consumer involvement and engagement necessary for transformational change. Future policies should be directed at removing these barriers by demanding and emphasizing open technologies and unrestricted access to data versus as currently prescribed by technology vendors, practitioners, and policies that perpetuate market equilibrium. PMID- 26429592 TI - Cluster-based query expansion using external collections in medical information retrieval. AB - Utilizing external collections to improve retrieval performance is challenging research because various test collections are created for different purposes. Improving medical information retrieval has also gained much attention as various types of medical documents have become available to researchers ever since they started storing them in machine processable formats. In this paper, we propose an effective method of utilizing external collections based on the pseudo relevance feedback approach. Our method incorporates the structure of external collections in estimating individual components in the final feedback model. Extensive experiments on three medical collections (TREC CDS, CLEF eHealth, and OHSUMED) were performed, and the results were compared with a representative expansion approach utilizing the external collections to show the superiority of our method. PMID- 26429593 TI - The transsexual brain--A review of findings on the neural basis of transsexualism. AB - Transsexualism describes the condition when a person's psychological gender differs from his or her biological sex and is commonly thought to arise from a discrepant cerebral and genital sexual differentiation. This review intends to give an extensive overview of structural and functional neurobiological correlates of transsexualism and their course under cross-sex hormonal treatment. Research in this field enables insight into the stability or variability of gender differences and their relation to hormonal status. For a number of sexually dimorphic brain structures or processes, signs of feminisation or masculinisation are observable in transsexual individuals, which, during hormonal treatment, partly seem to further adjust to characteristics of the desired sex. Still, it appears the data are quite inhomogeneous, mostly not replicated and in many cases available for male-to-female transsexuals only. As the prevalence of homosexuality is markedly higher among transsexuals than among the general population, disentangling correlates of sexual orientation and gender identity is a major problem. To resolve such deficiencies, the implementation of specific research standards is proposed. PMID- 26429594 TI - New WHO guidance on prevention and treatment of maternal peripartum infections. PMID- 26429595 TI - The effect of lactic acid bacterial starter culture and chemical additives on wilted rice straw silage. AB - Lactic acid bacteria (LAB) are suitable for rice straw silage fermentation, but have been studied rarely, and rice straw as raw material for ensiling is difficult because of its disadvantages, such as low nutrition for microbial activities and low abundances of natural populations of LAB. So we investigated the effect of application of LAB and chemical additives on the fermentation quality and microbial community of wilted rice straw silage. Treatment with chemical additives increased the concentrations of crude protein (CP), water soluble carbohydrate (WSC), acetic acid and lactic acid, reduced the concentrations of acid detergent fiber (ADF) and neutral detergent fiber (NDF), but did not effectively inhibit the growth of spoilage organisms. Inoculation with LABs did not improve the nutritional value of the silage because of poor growth of LABs in wilted rice straw. Inoculation with LAB and addition of chemical materials improved the quality of silage similar to the effects of addition of chemical materials alone. Growth of aerobic and facultatively anaerobic bacteria was inhibited by this mixed treatment and the LAB gradually dominated the microbial community. In summary, the fermentation quality of wilted rice straw silage had improved by addition of LAB and chemical materials. PMID- 26429596 TI - TiO2 Microboxes with Controlled Internal Porosity for High-Performance Lithium Storage. AB - Titanium dioxide (TiO2) is considered a promising anode material for high-power lithium ion batteries (LIBs) because of its low cost, high thermal/chemical stability, and good safety performance without solid electrolyte interface formation. However, the poor electronic conductivity and low lithium ion diffusivity of TiO2 result in poor cyclability and lithium ion depletion at high current rates, which hinder them from practical applications. Herein we demonstrate that hierarchically structured TiO2 microboxes with controlled internal porosity can address the aforementioned problems for high-power, long life LIB anodes. A self-templating method for the synthesis of mesoporous microboxes was developed through Na2 EDTA-assisted ion exchange of CaTiO3 microcubes. The resulting TiO2 nanorods were organized into microboxes that resemble the microcube precursors. This nanostructured TiO2 material has superior lithium storage properties with a capacity of 187 mAh g(-1) after 300 cycles at 1 C and good rate capabilities up to 20 C. PMID- 26429597 TI - A novel cause for primordial dwarfism revealed: defective tRNA modification. AB - A mutation in the WDR4 gene, coding for a tRNA-modifying enzyme, leads to reduced levels of guanosine methylation in tRNA in patients with primordial dwarfism. PMID- 26429598 TI - Clinical indications for augmentation in children with neurogenic urinary incontinence following bladder outlet procedures: Results of a 14-year observational study. AB - PURPOSE: We report continence, upper tract changes, and augmentation indications and rates in consecutive patients undergoing bladder outlet surgery without augmentation for neurogenic urinary incontinence. METHODS: From 2000 to 2007, 37 patients underwent bladder neck sling (BNS), and from 2007 to 2013, 45 patients had Leadbetter/Mitchell bladder neck revision plus sling (LMS), all without augmentation. Mitrofanoff channels were created in all cases. Twenty children with persistent outlet insufficiency underwent bladder neck closure (BNC). All patients had pre- and postoperative urodynamic testing (UD). RESULTS: Mean follow up was 60 months after BNS, 38 months after LMS, and 29 months after BNC. Continence (dry, no pads) was achieved significantly more often with LMS versus BNS (66% vs. 37%). There were no significant differences between these patients in preoperative UD % capacity, end filling pressure (EFP), or compliance. Those that became dry had a greater % capacity on postoperative UD, but postoperative EFP was similar between dry and wet LMS and BNS patients. BNC resulted in dryness in 65% of patients, with most incontinence occurring from the Mitrofanoff stoma associated with filling pressures > 40 cm. A total of 10 (12%) children had augmentation, seven after BNC. Clinical indications were end filling pressures > 40 cm plus hydronephrosis >= grade 3, and/or persistent incontinence. Need for augmentation was not predicted by preoperative urodynamic parameters. Postoperative UD in those who were augmented showed significantly less % capacity and compliance, and significantly greater EFP, than those not augmented. CONCLUSIONS: Dryness was achieved in only 33% of BNS versus 66% of LMS and BNC patients. Twelve percent of consecutive children undergoing bladder outlet surgery for neurogenic incontinence developed clinical parameters leading to augmentation. These occurred most often after BNC. PMID- 26429599 TI - Statistical interpretation, Re: "Further analysis of the Glans-Urethral Meatus Shaft (GMS) hypospadias score: Correlation with postoperative complications". PMID- 26429600 TI - Characteristics of sleep apnea in infants with Pierre-Robin sequence: Is there improvement with advancing age? AB - OBJECTIVES: To investigate changes in obstructive sleep apnea (OSA) and central sleep apnea (CSA) in infants with Pierre-Robin sequence (PRS) with advancing age and after mandibular distraction osteogenesis (MDO). METHODS: Charts from 141 infants with PRS that presented to our tertiary-care children's hospital between 2005 and 2015 were retrospectively reviewed. Forty-five patients received a polysomnogram (PSG) prior to surgical intervention. Linear regression was utilized to compare age at pre-operative PSG with apnea-hypopnea index (AHI), obstructive apnea-hypopnea index (OAHI), and central apnea index (CAI). We then analyzed a subset of 9 patients who underwent MDO with pre- and post-operative PSGs. Wilcoxon signed-rank test was utilized to examine differences in pre- and post-operative OSA and CSA scores. RESULTS: Forty-five patients received pre operative PSGs. Of these, 80.0% demonstrated severe sleep apnea (AHI>=10), 68.9% demonstrated severe obstructive sleep apnea (OAHI>=10), and 55.6% demonstrated central sleep apnea (CAI>=1). There was no significant pattern of decrease in AHI, OAHI, and CAI with increased age up to 1 year. Among the 9 patients who underwent MDO with pre- and post-operative PSGs, significant reductions in AHI, OAHI, CAI, and percentage of total sleep time with arterial oxygen saturation (SaO2) <90% and significant increases in SaO2 nadir were identified after MDO. CONCLUSIONS: Contrary to previously examined literature in non-PRS patients, we did not find a decreased severity of central or obstructive sleep apnea with advancing age. Infants with PRS who underwent MDO demonstrated significant decreases in both obstructive and central apnea indices. PMID- 26429601 TI - Follow-up audiometry after bilateral myringotomy and tympanostomy tube insertion. AB - OBJECTIVE: There are no evidence-based guidelines regarding timing of postoperative audiometric follow-up for children undergoing tympanostomy tube insertion. Given the variability of follow-up among physicians, we attempt to guide the timing of postoperative audiograms using objective data. STUDY DESIGN: Retrospective chart review. METHODS: All pediatric patients undergoing primary bilateral myringotomy and tympanostomy tube insertion for otitis media with effusion who had audiometric data available at two follow-up times were identified from 2014. Patients were classified according to the type of audiometry performed and were further categorized into those who had tympanostomy tube insertion only and those who had concurrent adenotonsillectomies. RESULTS: 34 patients were included in the study. Among patients assessed by sound field audiometry, the mean sound field threshold value was 29.2dB preoperatively and improved to 21dB 2 weeks postoperatively and 17.9dB 6 to 10 weeks postoperatively. The difference between the two postoperative means was significant (p<0.0001). For patients evaluated by pure-tone audiometry, the mean preoperative air-bone gap was 20.1dB; this improved to 10dB at the first postoperative visit and 7.3dB at the second visit. The difference between the two means was significant (p<0.0001). For the subgroups in which adjunct adenotonsillectomy was performed, the greater improvement at the later follow-up was still statistically significant. CONCLUSIONS: Progressive hearing improvement was demonstrated from 2 weeks to 6 to 10 weeks postoperatively. We recommend testing no fewer than 6 weeks after tympanostomy tube insertion. Earlier audiometry underestimates the degree of hearing improvement. PMID- 26429602 TI - Management of the critical airway when an EXIT procedure is not an option: A case report. AB - Perinatal imaging facilitates detection of congenital head and neck masses to plan fetal procedures which secure the airway. Ex utero intrapartum therapy (EXIT) procedures are preferred to protect the neonatal airway. Herein we present a case in which a neonate with a large oropharyngeal lymphovascular malformation was delivered and the airway successfully managed without an EXIT procedure using a multidisciplinary approach. Preparations for the non-EXIT delivery and critical airway management are described. PMID- 26429603 TI - Epigenetic markers for newborn congenital heart defect (CHD). AB - OBJECTIVE: Our objective was to determine whether there were significant differences in genome-wide DNA methylation in newborns with major congenital heart defect (CHD) compared to controls. We also evaluated methylation of cytosines in CpG motifs for the detection of these CHDs. METHODS: Genome-wide DNA methylation analysis was performed on DNA from 60 newborns with various CHDs, including hypoplastic left heart syndrome, ventricular septal deficit, atrial septal defect, pulmonary stenosis, coarctation of the aorta and Tetralogy of Fallot, and 32 controls. RESULTS: Highly significant differences in cytosine methylation were seen in a large number of genes throughout the genome for all CHD categories. Gene ontology analysis of CHD overall indicated over-represented biological processes involving cell development and differentiation, and anatomical structure morphogenesis. Methylation of individual cytosines in CpG motifs had high diagnostic accuracy for the detection of CHD. For example, for coarctation one predictive model based on levels of particular cytosine nucleotides achieved a sensitivity of 100% and specificity of 93.8% (AUC = 0.974, p < 0.00001). CONCLUSION: Profound differences in cytosine methylation were observed in hundreds of genes in newborns with different types of CHD. There appears to be the potential for development of accurate genetic biomarkers for CHD detection in newborns. PMID- 26429604 TI - Conjugated Polyelectrolyte-Induced Self-Assembly of Alkynylplatinum(II) 2,6 Bis(benzimidazol-2'-yl)pyridine Complexes. AB - Water-soluble cationic alkynylplatinum(II) 2,6-bis(benzimidazol-2'-yl)pyridine (bzimpy) complexes have been demonstrated to undergo supramolecular assembly with anionic polyelectrolytes in aqueous buffer solution. Metal-metal-to-ligand charge transfer (MMLCT) absorptions and triplet MMLCT ((3) MMLCT) emissions have been found in UV/Vis absorption and emission spectra of the electrostatic assembly of the complexes with non-conjugated polyelectrolytes, driven by Pt???Pt and pi-pi interactions among the complex molecules. Interestingly, the two-component ensemble formed by [Pt(bzimpy-Et){C?CC6 H4 (CH2 NMe3 -4)}]Cl2 (1) with para linked conjugated polyelectrolyte (CPE), PPE-SO3 (-) , shows significantly different photophysical properties from that of the ensemble formed by 1 with meta-linked CPE, mPPE-Ala. The helical conformation of mPPE-Ala allows the formation of strong mPPE-Ala-1 aggregates with Pt???Pt, electrostatic, and pi-pi interactions, as revealed by the large Stern-Volmer constant at low concentrations of 1. Together with the reasonably large Forster radius, large HOMO-LUMO gap and high triplet state energy of mPPE-Ala to minimize both photo induced charge transfer (PCT) and Dexter triplet energy back-transfer (TEBT) quenching of the emission of 1, efficient Forster resonance energy transfer (FRET) from mPPE-Ala to aggregated 1 molecules and strong (3) MMLCT emission have been found, while the less strong PPE-SO3 (-) -1 aggregates and probably more efficient PCT and Dexter TEBT quenching would account for the lack of (3) MMLCT emission in the PPE-SO3 (-) -1 ensemble. PMID- 26429605 TI - Vancomycin Tissue Pharmacokinetics in Patients with Lower-Limb Infections via In Vivo Microdialysis. AB - BACKGROUND: Vancomycin is a common treatment option for skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Given the increasing prevalence of MRSA, vancomycin is widely used as empirical therapy. In patients with lower-limb infections, antimicrobial penetration is often reduced because of decreased vascular perfusion. In this study, we evaluated the tissue concentrations of vancomycin in hospitalized patients with lower-limb infections. METHODS: An in vivo microdialysis catheter was inserted near the margin of the wound and was perfused with lactated Ringer's solution. Tissue and serum samples were obtained after steady state for one dosing interval. Tissue concentrations were corrected for percentage of in vivo recovery using the retrodialysis technique. RESULTS: Nine patients were enrolled (mean +/- SD: age, 54 +/- 19 years; weight, 105.6 +/- 31.5 kg). Patients received a mean of 12.8 mg/kg of vancomycin every 12 hours (n = 7), every 8 hours (n = 1), or every 24 hours (n = 1). Mean +/- SD steady-state trough vancomycin concentrations in serum and tissue were 11.1 +/- 3.3 and 6.0 +/- 2.6 MUg/mL. The mean +/- SD 24 hour free drug areas under the curve for serum and wound were 283.7 +/- 89.4 and 232.8 +/- 75.7 MUg*h/mL, respectively. The mean +/- SD tissue penetration ratio was 0.8 +/- 0.2. CONCLUSIONS: These data suggest that against MRSA with minimum inhibitory concentrations of 1 MUg/mL or less, vancomycin achieved blood pharmacodynamic targets required for the likelihood of success. Reduced concentrations may contribute to poor outcomes and the development of resistance. As other literature suggests, alternative agents may be needed when the pathogen of interest has a minimum inhibitory concentration greater than 1 MUg/mL. PMID- 26429606 TI - Plate Fixation of Proximal Fifth Metatarsal Fracture. AB - BACKGROUND: Intramedullary screw fixation of fractures of the proximal fifth metatarsal bone may not be satisfactory in comminuted fractures or when the lateral metatarsal bowing has to be restored. We report our experience with plate fixation in these circumstances. METHODS: Between June 1, 2009, and January 31, 2013, 13 patients who had comminuted fracture or nonunion of fracture of the proximal fifth metatarsal bone underwent plate fixation. Study patients were followed up for a mean of 500 days (range, 51-1238 days). Their medical records and radiographs were retrospectively reviewed for demographic and operative data and radiologic evidence of fracture healing. At their most recent follow-up, patients were evaluated for pain levels with a visual analog scale, for foot function with the Foot and Ankle Disability Index, and for quality of life with the 12-Item Short-Form Health Survey. RESULTS: Fracture union was evident in 12 patients after a mean of 56.8 days (range, 30-92 days). There was only one major complication of sural nerve neuroma and reflex sympathetic dystrophy. Four patients required reoperation for plate removal. Plate fixation of proximal fifth metatarsal comminuted fractures is associated with high union rates, relief of pain, and patient satisfaction. However, plate removal for various reasons was required in approximately one-third of the study patients. This high revision rate might be avoided by better selection of patients and meticulous intraoperative identification and preservation of the sural nerve. CONCLUSIONS: We recommend reserving plate fixation for proximal fifth metatarsal fractures for cases of laterally bowed fifth metatarsal or comminuted fractures. PMID- 26429607 TI - Candida albicans Immunotherapy for Verrucae Plantaris. AB - BACKGROUND: Verrucae plantaris is a viral disease caused by human papilloma virus that is commonly seen in the office setting and is often challenging to treat owing to its high recurrence rate and recalcitrant profile. Candida albicans intralesional injections have been hypothesized to incite an immunogenic response toward the virus. METHODS: We report on the immunotherapeutic effect of intralesional injection of C albicans into plantar verrucae with a retrospective medical record analysis of 80 patients. Using a luer-lock syringe, 0.1 to 0.3 mL of C albicans antigen was injected into either the first known lesion or the largest lesion. RESULTS: The success rate of intralesional C albicans, defined as total clearance of the lesion, was 65%, which may be underestimated because patients lost to follow-up were included in the 35% failure rate. It was also found that female patients with a previous tissue-destructive treatment process were more than four times more likely to respond to C albicans therapy, whereas this effect was less pronounced in the male patient population. CONCLUSIONS: These results indicate that a series of intralesional injections of C albicans is an effective and efficient method of treatment for verrucae plantaris. PMID- 26429608 TI - Reduction in Size and Number of Plantar Verrucae in Human Immunodeficiency Virus Infected Individuals After the Implementation of Highly Active Antiretroviral Therapy. AB - BACKGROUND: Implementation of highly active antiretroviral therapy (HAART) significantly increased the life expectancy of those living with human immunodeficiency virus (HIV). Except for prevalence, scientific reports regarding clinical manifestations of plantar verrucae in the post-HAART era are lacking. The objective of this study was to compare clinical manifestations of plantar verrucae between HIV-infected and noninfected individuals and then to compare these findings with those observed before the implementation of HAART. METHODS: Nineteen patients with plantar verrucae (ten with HIV and nine without HIV) were examined to determine the size, number, and clinical type of verrucae present. The two groups were first compared with each other and then with previously collected data from a similar analysis conducted in 1995, before the implementation of HAART. Statistical significance was determined using the Fisher exact test or the Wilcoxon rank sum test. RESULTS: No significant differences were observed in the size, number, or clinical type of verrucae between HIV negative and HIV-positive patients. Compared with the 1995 data, there was a significant decrease in the number of verrucae lesions per individual and a nonsignificant decrease in the average size of verrucae in HIV-positive patients. CONCLUSIONS: Study results indicate that the implementation of HAART has impacted the clinical manifestations of plantar verrucae in HIV-positive individuals. Further analyses with a larger number of patients are required to confirm and substantiate these findings. PMID- 26429609 TI - Efinaconazole Topical Solution, 10% Efficacy in Patients with Onychomycosis and Coexisting Tinea Pedis. AB - BACKGROUND: We sought to evaluate the efficacy of efinaconazole topical solution, 10%, in patients with onychomycosis and coexisting tinea pedis. METHODS: We analyzed 1,655 patients, aged 18 to 70 years, randomized (3:1) to receive efinaconazole topical solution, 10%, or vehicle from two identical multicenter, double-blind, vehicle-controlled 48-week studies evaluating safety and efficacy. The primary end point was complete cure rate (0% clinical involvement of the target toenail and negative potassium hydroxide examination and fungal culture findings) at week 52. Three groups were compared: patients with onychomycosis and coexisting interdigital tinea pedis on-study (treated or left untreated) and those with no coexisting tinea pedis. RESULTS: Treatment with efinaconazole topical solution, 10%, was significantly more effective than vehicle use irrespective of the coexistence of tinea pedis or its treatment. Overall, 352 patients with onychomycosis (21.3%) had coexisting interdigital tinea pedis, with 215 of these patients (61.1%) receiving investigator-approved topical antifungal agents for their tinea pedis in addition to their randomized onychomycosis treatment. At week 52, efinaconazole complete cure rates of 29.4% were reported in patients with onychomycosis when coexisting tinea pedis was treated compared with 16.1% when coexisting tinea pedis was not treated. Both cure rates were significant compared with vehicle (P = .003 and .045, respectively), and in the latter subgroup, no patients treated with vehicle achieved a complete cure. CONCLUSIONS: Treatment of coexisting tinea pedis in patients with onychomycosis enhances the efficacy of once-daily topical treatment with efinaconazole topical solution, 10%. PMID- 26429610 TI - Static Foot Posture and Mobility Associated With Postural Sway in Elderly Women Using a Three-dimensional Foot Scanner. AB - BACKGROUND: Maintaining balance is a complex phenomenon that is influenced by a range of sensorimotor factors. Foot posture and mobility may also influence balance and postural sway. Recently, three-dimensional foot scanners have been used to assess foot posture. This tool allows many individuals to be scanned quickly and easily and helps eliminate patients' radiation exposure. The objective of this study was to determine whether static foot posture and mobility are independently associated with postural sway in a large community sample of older women using objective measures of balance status and the recently launched technology of three-dimensional foot scanning. METHODS: This cross-sectional study included 140 community-dwelling elderly women (mean +/- SD age, 73.9 +/- 5.1 years) recruited in Kasama City, Japan. The postural sway variables were total path length and area and were measured by force plate. We measured static foot posture, sitting and standing navicular height, and mobility using a three dimensional foot scanner. Foot mobility was determined as the amount of vertical navicular excursion between the positions of the subtalar joint, from neutral in sitting position to relaxed bilateral standing. RESULTS: After adjusting for potential cofounders, analysis of covariance revealed that sitting navicular height was associated with total path length (P = .038) and area (P = .031). Foot mobility was associated with total path length (P = .018). CONCLUSIONS: These findings suggest that sitting navicular height and foot mobility are associated with postural sway in elderly women and might be an important factor in defining balance control in older adults. PMID- 26429611 TI - Medical and Economic Impact of a Free Student-Run Podiatric Medical Clinic A Preliminary Analysis. AB - BACKGROUND: Data from the free student-run podiatric medical clinic at Clinica Tepati at the University of California, Davis, were used to analyze medical and economic impacts on health-care delivery and to extrapolate the economic impact to the national level. Clinica Tepati also provides an excellent teaching environment and services to the uninsured Hispanic population in the Greater Sacramento area. METHODS: In this analysis, we retrospectively reviewed patient medical records for podiatric medical encounters during 15 clinic days between November 2010 and February 2012. The economic impact was evaluated by matching diagnoses and treatments with Medicare reimbursement rates using International Classification of Diseases codes, Current Procedural Terminology codes, and the prevailing Medicare reimbursement rates. RESULTS: Sixty-three podiatric medical patients made 101 visits during this period. Twenty patients returned to the clinic for at least one follow-up visit or for a new medical concern. Thirty-nine different diagnoses were identified, and treatments were provided for all 101 patient encounters/visits. Treatments were limited to those within the clinic's resources. This analysis estimates that $17,332.13 worth of services were rendered during this period. CONCLUSIONS: These results suggest that the free student-run podiatric medical clinic at Clinica Tepati had a significant medical and economic impact on the delivery of health care at the regional level, and when extrapolated, nationally as well. These student-run clinics also play an important role in medical education settings. PMID- 26429612 TI - A Mobile Health Service to Manage Diabetic Foot in Homeless Patients. AB - BACKGROUND: Homeless people live in poverty, with limited access to public health services. They are likely to experience chronic medical conditions, such as diabetes mellitus; however, they do not always receive the necessary services to prevent complications. This study was designed to determine the effectiveness of a volunteer health service outreach to reduce disparity in diabetic foot care for homeless people. METHODS: The research was conducted on 21 patients with diabetic ulcers of 930 homeless people visited between 2008 and 2013. Each ulcer was treated with regular medication every week for a mean +/- SD of 17.6 +/- 12 months. The inclusion criteria were 1) homeless with a previous diagnosis of diabetes or a blood glucose level greater than 126 mg/dL at first check and 2) foot ulcer caused by diabetic vasculopathy or neuropathy. The efficacy of the interventions was assessed against the number of successfully cured diabetic feet based on a reduced initial Wagner classification score for each ulcer. RESULTS: Clinical improvement was observed in 18 patients (86%), whose pathologic condition was completely resolved after 3 years and, therefore, no longer needed medication. One patient died of septic shock and kidney failure, and two patients needed amputation owing to clinical worsening of ulcers (Wagner class 4 at the last visit). CONCLUSIONS: Most homeless people who have diabetes and diabetic foot encounter many difficulties managing their disease, and a volunteer health care unit could be a suitable option to bridge these gaps. PMID- 26429613 TI - Perceived Stress and Coffee and Energy Drink Consumption Predict Poor Sleep Quality in Podiatric Medical Students A Cross-sectional Study. AB - BACKGROUND: A cross-sectional survey administered to first- and second-year podiatric medical students aimed to investigate the effect of coffee intake, energy drink consumption, and perceived stress on sleep quality in medical students during their preclinical studies. METHODS: Ninety-eight of 183 students contacted (53.6%) completed a questionnaire comprising standard instruments measuring sleep quality (Pittsburgh Sleep Quality Index), daytime sleepiness (Epworth Sleepiness scale), and perceived stress (ten-item Perceived Stress Scale). Furthermore, we investigated coffee and energy drink consumption. Logistic regression was conducted to identify factors associated with poor sleep quality and the relation between sleep quality and academic performance (grade point average). RESULTS: High prevalences of poor sleep quality, excessive daytime sleepiness, and perceived stress were reported. In addition, higher odds of developing poor sleep quality were associated with coffee and energy drink intake, perceived stress, and excessive daytime sleepiness. The total Pittsburgh Sleep Quality Index score was inversely correlated with grade point average. CONCLUSIONS: First- and second-year podiatric medical students have poor sleep quality. Further research is needed to identify effective strategies to reduce stress and decrease coffee and energy drink intake to minimize their negative effect on sleep quality and academic performance in podiatric medical students. PMID- 26429614 TI - Pediatric Subtalar Joint Synovial Chondromatosis Report of a Case and an Up-to date Review. AB - Synovial chondromatosis is a rare, usually benign disorder affecting the population predominantly in the third and fourth decades of life and mainly involving the large weightbearing joints of the lower limb-the knees and the hip. In this report, we highlight an unusual pediatric clinical presentation of synovial osteochondromatosis involving the subtalar joint and discuss its surgical management; we also provide a comprehensive up-to-date literature review of the disorder. This patient was successfully treated with en masse surgical excision. He has been doing well, with complete pain relief and improved range of motion at 1-year follow-up. An exceptional involvement of the subtalar joint and an unusual presentation in the pediatric age group makes this case unique. PMID- 26429615 TI - A Novel Case of an Acrochordon Occurring on the Plantar Foot. AB - We report on a 63-year-old male who was found to have an acrochordon on his plantar foot. Although acrochordons constitute a common benign clinical finding, this observation represents, to our knowledge, only the second case reported on the foot and the first occuring on the plantar surface. PMID- 26429616 TI - True Pathologic Abnormality versus Artifact Foot Position and Magic Angle Artifact in the Peroneal Tendons with 3T Imaging. AB - Magnetic resonance imaging is a commonly ordered examination by many foot and ankle surgeons for ankle pain and suspected peroneal tendon pathologic abnormalities. Magic angle artifact is one of the complexities associated with this imaging modality. Magic angle refers to the increased signal on magnetic resonance images associated with the highly organized collagen fibers in tendons and ligaments when they are orientated at a 55 degrees angle to the main magnetic field. We present several examples from a clinical practice setting using 3T imaging illustrating a substantial reduction in magic angle artifact of the peroneal tendon in the prone plantarflexed position compared with the standard neutral (right angle) position. PMID- 26429618 TI - Evidence-Based Approach to Advanced Wound Care Products. AB - There is increasing pressure from industry to use advanced wound care products and technologies. Many are very expensive but promise to reduce overall costs associated with wound care. Compelling anecdotal evidence is provided that inevitably shows wounds that failed all other treatments but responded positively to the subject product. Evidence-based medicine is the standard by which physician-scientists must make their clinical care decisions. In an attempt to provide policy makers with the most current evidence on advanced wound care products, the Department of Veteran Affairs conducted an Evidence-based Synthesis Program review of advanced wound care products. This paper suggests how to take this information and apply it to policy to drive evidence-based care to improve outcomes and fiduciary responsibility. PMID- 26429617 TI - Kyrle Disease A Rare Dermatologic Condition Associated with the Diabetic Foot. AB - We report two cases of biopsy-confirmed Kyrle disease. Kyrle disease is one of the perforating dermatoses associated with diabetic patients undergoing renal dialysis. In this report, we describe the clinical and histopathologic features, the differential diagnoses, and successful treatment of this unusual disorder. PMID- 26429619 TI - Our APMA. PMID- 26429625 TI - Effect of concurrent walking and interlocutor distance on conversational speech intensity and rate in Parkinson's disease. AB - Previous studies have demonstrated a negative effect of concurrent walking and talking on gait in Parkinson's disease (PD) but there is limited information about the effect of concurrent walking on speech production. The present study examined the effect of sitting, standing, and three concurrent walking tasks (slow, normal, fast) on conversational speech intensity and speech rate in fifteen individuals with hypophonia related to idiopathic Parkinson's disease (PD) and fourteen age-equivalent controls. Interlocuter (talker-to-talker) distance effects and walking speed were also examined. Concurrent walking was found to produce a significant increase in speech intensity, relative to standing and sitting, in both the control and PD groups. Faster walking produced significantly greater speech intensity than slower walking. Concurrent walking had no effect on speech rate. Concurrent walking and talking produced significant reductions in walking speed in both the control and PD groups. In general, the results of the present study indicate that concurrent walking tasks and the speed of concurrent walking can have a significant positive effect on conversational speech intensity. These positive, "energizing" effects need to be given consideration in future attempts to develop a comprehensive model of speech intensity regulation and they may have important implications for the development of new evaluation and treatment procedures for individuals with hypophonia related to PD. PMID- 26429626 TI - Characteristics of innate lymphoid cells (ILCs) and their role in immunological disorders (an update). AB - Innate lymphoid cells (ILCs) are a novel family of hematopoietic effectors and regulators of innate immunity. Although these cells are morphologically similar to B cells and T cells, however they do not express antigen receptors. ILCs seems to have emerging roles in innate immune responses against infectious or non infectious microorganisms, protection of the epithelial barrier, lymphoid organogenesis and inflammation, tissue remodeling and regulating homeostasis of tissue stromal cells. In addition, it has recently been reported that ILCs have a crucial role in several disorders such as allergy and autoimmunity. Based on their phenotype and functions, ILCs are classified into three major groups called ILCs1, ILCs2, and ILCs3. Here we reviewed the most recent data concerning diverse ILC phenotypes, subclasses, functions in immune responses as well as in immune mediated disorders. PMID- 26429627 TI - Rationalizing thymic selection for functional T-cells: A commentary. AB - What are the minimum specificity requirements of a thymic selective process that establishes (1) restrictive recognition of peptide, (2) the Self (S)-Nonself (NS) discrimination, and (3) the categories of effector function? Given an answer to that question, how well does it fit with the observed selective processes in thymus where T-cells are generated? Any discrepancies between the two must be rationalized. The goal of this essay is to attempt just that. PMID- 26429628 TI - Carcinogenicity of glycidamide in B6C3F1 mice and F344/N rats from a two-year drinking water exposure. AB - Acrylamide is a contaminant in baked and fried starchy foods, roasted coffee, and cigarette smoke. Previously we reported that acrylamide is a multi-organ carcinogen in B6C3F1 mice and F344/N rats, and hypothesized that acrylamide is activated to an ultimate carcinogen through metabolism to the epoxide glycidamide. We have now examined the carcinogenic effects of glycidamide administered at 0, 0.0875, 0.175, 0.35 and 0.70 mM in drinking water to the same strains of rodents for two years. In male and female mice, there were significant increases in tumors of the Harderian gland, lung, forestomach, and skin. Female mice also had an increased incidence of tumors of the mammary gland and ovary. In male and female rats, there were significant increases in thyroid gland and oral cavity neoplasms and mononuclear cell leukemia. Male rats also had increases in tumors of the epididymis/testes and heart, while female rats demonstrated increases in tumors of the mammary gland, clitoral gland, and forestomach. A similar spectrum of tumors was obtained in mice and rats administered acrylamide. These data indicate that, under the conditions of these bioassays, acrylamide is efficiently metabolized to glycidamide and that the carcinogenic activity of acrylamide is due to its conversion into glycidamide. PMID- 26429629 TI - The absorption and metabolism of a single L-menthol oral versus skin administration: Effects on thermogenesis and metabolic rate. AB - We investigated the absorption and metabolism pharmacokinetics of a single L menthol oral versus skin administration and the effects on human thermogenesis and metabolic rate. Twenty healthy adults were randomly distributed into oral (capsule) and skin (gel) groups and treated with 10 mg kg(-1) L-menthol (ORALMENT; SKINMENT) or control (lactose capsule: ORALCON; water application: SKINCON) in a random order on two different days. Levels of serum L-menthol increased similarly in ORALMENT and SKINMENT (p > 0.05). L-menthol glucuronidation was greater in ORALMENT than SKINMENT (p < 0.05). Cutaneous vasoconstriction, rectal temperature and body heat storage showed greater increase following SKINMENT compared to ORALMENT and control conditions (p < 0.05). Metabolic rate increased from baseline by 18% in SKINMENT and 10% in ORALMENT and respiratory exchange ratio decreased more in ORALMENT (5.4%) than SKINMENT (4.8%) compared to control conditions (p < 0.05). Levels of plasma adiponectin and leptin as well as heart rate variability were similar to control following either treatment (p > 0.05). Participants reported no cold, shivering, discomfort, stress or skin irritation. We conclude that a single L-menthol skin administration increased thermogenesis and metabolic rate in humans. These effects are minor following L-menthol oral administration probably due to faster glucuronidation and greater blood menthol glucuronide levels. PMID- 26429630 TI - Foundational perspectives on causality in large-scale brain networks. AB - A profusion of recent work in cognitive neuroscience has been concerned with the endeavor to uncover causal influences in large-scale brain networks. However, despite the fact that many papers give a nod to the important theoretical challenges posed by the concept of causality, this explosion of research has generally not been accompanied by a rigorous conceptual analysis of the nature of causality in the brain. This review provides both a descriptive and prescriptive account of the nature of causality as found within and between large-scale brain networks. In short, it seeks to clarify the concept of causality in large-scale brain networks both philosophically and scientifically. This is accomplished by briefly reviewing the rich philosophical history of work on causality, especially focusing on contributions by David Hume, Immanuel Kant, Bertrand Russell, and Christopher Hitchcock. We go on to discuss the impact that various interpretations of modern physics have had on our understanding of causality. Throughout all this, a central focus is the distinction between theories of deterministic causality (DC), whereby causes uniquely determine their effects, and probabilistic causality (PC), whereby causes change the probability of occurrence of their effects. We argue that, given the topological complexity of its large-scale connectivity, the brain should be considered as a complex system and its causal influences treated as probabilistic in nature. We conclude that PC is well suited for explaining causality in the brain for three reasons: (1) brain causality is often mutual; (2) connectional convergence dictates that only rarely is the activity of one neuronal population uniquely determined by another one; and (3) the causal influences exerted between neuronal populations may not have observable effects. A number of different techniques are currently available to characterize causal influence in the brain. Typically, these techniques quantify the statistical likelihood that a change in the activity of one neuronal population affects the activity in another. We argue that these measures access the inherently probabilistic nature of causal influences in the brain, and are thus better suited for large-scale brain network analysis than are DC-based measures. Our work is consistent with recent advances in the philosophical study of probabilistic causality, which originated from inherent conceptual problems with deterministic regularity theories. It also resonates with concepts of stochasticity that were involved in establishing modern physics. In summary, we argue that probabilistic causality is a conceptually appropriate foundation for describing neural causality in the brain. PMID- 26429631 TI - A TMS study on the contribution of visual area V5 to the perception of implied motion in art and its appreciation. AB - Over the last decade, researchers have sought to understand the brain mechanisms involved in the appreciation of art. Previous studies reported an increased activity in sensory processing regions for artworks that participants find more appealing. Here we investigated the intriguing possibility that activity in cortical area V5-a region in the occipital cortex mediating physical and implied motion detection-is related not only to the generation of a sense of motion from visual cues used in artworks, but also to the appreciation of those artworks. Art naive participants viewed a series of paintings and quickly judged whether or not the paintings conveyed a sense of motion, and whether or not they liked them. Triple-pulse TMS applied over V5 while viewing the paintings significantly decreased the perceived sense of motion, and also significantly reduced liking of abstract (but not representational) paintings. Our data demonstrate that V5 is involved in extracting motion information even when the objects whose motion is implied are pictorial representations (as opposed to photographs or film frames), and even in the absence of any figurative content. Moreover, our study suggests that, in the case of untrained people, V5 activity plays a causal role in the appreciation of abstract but not of representational art. PMID- 26429632 TI - Quality assessment and antiplasmodial activity of West African Cochlospermum species. AB - The present study focuses on development of phytochemical methods for quality assessment of two West-African Cochlospermum species (Cochlospermum planchonii and Cochlospermum tinctorium) traditionally used for malaria treatment in Burkina Faso. Antimalarial activity of preparations from dried rhizomes (decoction) was tested against the chloroquine-sensitive Plasmodium strain 3D7 using the histidine-rich protein II (HRP2) drug susceptibility assay and compared with extract preparations using organic solvents of different polarity. Two main apocarotenoids were isolated from rhizomes of C. planchonii and unambiguously identified as dihydrocochloxanthine and cochloxanthine by spectroscopic methods. Comparative HPLC analyses of thirty-nine (39) samples from markets and from collections in natural habitats of both species showed a high variability in the accumulation of cochloxanthines and related carotenoids which were proven to be characteristic for rhizomes of both species and generally absent in leaves. Furthermore, content of total phenolics and antioxidant activities (DPPH and FRAP) as well as haemolytic activity of various extracts was tested. The HPLC method presented here was validated and provides a good separation of both compounds including 10 minor carotenoids. Extracts from both species and pure cochloxanthine offered pronounced antioxidant activities and weak haemolytic activity while, in contrast, dihydrocochloxanthine had a strong haemolytic effect at the highest concentration analysed. However, cochloxanthine as well as dihydrocochloxanthine showed erythroprotective effects against the haemolytic activity of the reference saponin. Moderate antiplasmodial activity between 16 and 63 MUg/ml were observed with all tested extracts, and lower IC50 values were obtained with pure dihydrocochloxanthine (IC50=6.9 MUg/ml), cochloxanthine (IC50=6.8 MUg/ml), the DCM fraction (IC50=2.4 MUg/ml) and the ethyl acetate fraction (IC50=11.5MUg/ml) derived from a methanolic extract of C. planchonii. This study shows a major variability of carotenoid content and antiplasmodial activity of both C. planchonii and C. tinctorium. The high haemolytic activity of dihydrocochloxanthine (at 100 MUg/ml) should be considered as a selection criterion for choosing species phenotypes for treatment. PMID- 26429633 TI - Mortality From Malignant Melanoma in an Era of Nationwide Skin Cancer Screening. PMID- 26429634 TI - Skin Cancer Screening in Germany. Documenting Melanoma Incidence and Mortality From 2008 to 2013. AB - BACKGROUND: Nationwide skin cancer screening was introduced in Germany in 2008. The positive results of a pilot project carried out in 2003-4 in the federal state of Schleswig-Holstein had implied that screening would lower the mortality from melanoma. METHODS: Data on the incidence of invasive malignant melanoma of the skin (MM; ICD-10: C43) were extracted from the databases of the Association of Population-based Cancer Registries in Germany (GEKID) and from the Schleswig Holstein cancer registry. Mortality rates were extracted from the official cause of-death statistics. RESULTS: With the beginning of nationwide screening in 2008, the age-standardized incidence rate in Germany increased by approximately 28% to 18.2 cases per 100 000 persons in 2010. In Schleswig-Holstein, the incidence fell after the pilot project ended and has been comparable to the nationwide incidence since 2008. For Germany overall, there has been no downward trend in MM mortality since the introduction of nationwide screening; in 2013, the mortality rate was 2.3 deaths per 100 000 persons per year. In the area of the pilot study, mortality declined to a level of 1.0/100 000/year until 2008 and then began to rise again. At present, the mortality due to MM in Schleswig- Holstein is once again the same as that in Germany overall (2.4/100 000/year). CONCLUSION: The introduction of nationwide skin cancer screening in 2008 has not yet led to any measurable decline in mortality due to melanoma. The current method of screening seems to be less thorough than that used in the pilot project; this may explain the absence of a decline in MM-related mortality in Germany overall up to the year 2013, as well as the rising mortality in Schleswig-Holstein since the end of the pilot program. The generation of a robust set of data on how skin cancer screening can be optimized now seems urgently necessary. PMID- 26429635 TI - Screening for Lung Cancer: Balancing Hope With Doubt About Applicability. PMID- 26429637 TI - Genotyping of Toxic Pufferfish Based on Specific PCR-RFLP Products As Determined by Liquid Chromatography/Quadrupole-Orbitrap Hybrid Mass Spectrometry. AB - A method based on liquid chromatography-electrospray mass spectrometric analysis of the enzymatically digested amplicons derived from the mitochondrial 16S rRNA gene was established for the discrimination of toxic pufferfish. A MonoBis C18 narrow-bore silica monolith column (Kyoto Monotech) and a Q Exactive mass spectrometer (Thermo Fisher) were employed for separation and detection, respectively. Monoisotopic masses of the oligonucleotides were calculated using Protein Deconvolution 3.0 software (Thermo Fisher). Although a lock mass standard was not used, excellent accuracy (mass error, 0.83 ppm on average) and precision (relative standard deviation, 0.49 ppm on average) were achieved, and a mass accuracy of <2.8 ppm was maintained for at least 180 h without additional calibration. The present method was applied to 29 pufferfish samples, and results were consistent with Sanger sequencing. PMID- 26429636 TI - Lung Cancer Screening Using Low Dose CT Scanning in Germany. Extrapolation of results from the National Lung Screening Trial. AB - BACKGROUND: It is now debated whether the screening of heavy smokers for lung cancer with low dose computed tomography (low dose CT) might lower their mortality due to lung cancer. We use data from the National Lung Screening Trial (NLST) in the USA to predict the likely effects of such screening in Germany. METHODS: The number of heavy smokers aged 55-74 in Germany was extrapolated from survey data obtained by the Robert Koch Institute. Published data from the NLST were then used to estimate the likely effects of low dose CT screening of heavy smokers in Germany. RESULTS: If low dose CT screening were performed on 50% of the heavy smokers in Germany aged 55-74, an estimated 1 329 506 persons would undergo such screening. If the screening were repeated annually, then, over three years, 916 918 screening CTs would reveal suspect lesions, and the diagnosis of lung cancer would be confirmed thereafter in 32 826 persons. At least one positive test result in three years would be obtained in 39.1% of the participants (519 837 persons). 4155 deaths from lung cancer would be prevented over 6.5 years, and the number of persons aged 55-74 who die of lung cancer in Germany would fall by 2.6%. 12 449 persons would have at least one complication, and 1074 persons would die in the 60 days following screening. CONCLUSION: The screening of heavy smokers for lung cancer can lower their risk of dying of lung cancer by 20% in relative terms, corresponding to an absolute risk reduction of 0.3 percentage points. These figures can provide the background for a critical discussion of the putative utility of this type of screening in Germany. PMID- 26429638 TI - Correlates of Healthy Lifestyle Beliefs and Behaviors in Parents of Overweight or Obese Preschool Children Before and After a Cognitive Behavioral Therapy Intervention With Text Messaging. AB - INTRODUCTION: Significant gaps exist in the published literature regarding the treatment of overweight/obesity in preschool-aged children, especially in primary care settings. Parental influence plays an important factor in the development of healthy behaviors in children, yet there is no consensus about why some behavior change intervention strategies for parents of young children are more influential and effective than others. OBJECTIVE: The purpose of this secondary data analysis was to assess correlations among the study variables (healthy lifestyle beliefs, perceived difficulty, and healthy lifestyle behaviors) in parents of overweight/obese preschool children. A second aim explored if the parent's level of cognitive beliefs and perceived difficulty of engaging in healthy lifestyle behaviors correlated with text messaging cognitive behavioral support. METHODS: Fifteen preschool-parent dyads from primary care clinics completed a 7-week cognitive behavioral skills building intervention. Beck's Cognitive Theory guided the intervention content, and Fogg's Behavior Model guided the implementation. The intervention was delivered using a combination of face-to-face clinic visits and ecological momentary interventions using text messaging. RESULTS: Supported are the interconnected relationships among the study variables, that is, parental healthy lifestyle beliefs, thoughts, and behaviors. At baseline, parental healthy lifestyle belief scores significantly correlated with perceived difficulty (rs = 0.598, p < .05) and healthy lifestyle behaviors (rs = 0.545, p < .05). These associations strengthened after the intervention. Furthermore, as parental healthy lifestyle beliefs increased and perceived difficulty lessened, their response rate and subsequent feedback lessened to the static text messaging support. DISCUSSION: Findings from this study support the interconnections between parents' thoughts, feelings, and actions toward healthy lifestyles. As parental beliefs became stronger through cognitive behavioral skills building and tailored text messaging, the need for general support via text messaging lessened, warranting additional research. PMID- 26429639 TI - Synergistic cytotoxicity against human tumor cell lines by oncolytic adenovirus dl1520 (ONYX-015) and melphalan. AB - AIMS AND BACKGROUND: In light of the need for more selective anticancer therapy, much work has been directed at developing compounds or biological agents that target functions specific to cancer cells. To this end, numerous viruses have been engineered to exploit the dependence of cancer cells on particular anomalies that contribute to their rogue proliferative activity, such as dysfunctional p53, overactive mitogenic signaling, or a defective interferon response. The oncolytic human adenovirus dl1520 (ONYX-015) was engineered to propagate specifically in p53-deficient tumors, which comprise over half of all tumors. Based on successes in clinical trials, the full potential of dl1520 and other oncolytic viruses may be even better realized by using them in combination with conventional chemotherapy drugs. METHODS: As a model system in which to test this potential, representative cell lines from 2 common cancer types, oral squamous cell carcinoma (HN-5a) and colon adenocarcinoma (HT-29), were chosen, as well as platinum-drug-resistant variants of each. RESULTS: Following preliminary screening of virus and drug combinations, dl1520 and melphalan were found to synergistically inhibit proliferation of all the cancer cell lines. Melphalan pretreatment or cotreatment with dl1520 enhanced inhibition of proliferation by dl1520 by up to 60% and increased apoptosis by up to 25%. The tight-junction protein CAR (coxsackie and adenovirus receptor), via which adenovirus enters cells, was not upregulated by treatment with melphalan, suggesting that other mechanisms contribute to synergy. CONCLUSIONS: The synergy between melphalan and dl1520 suggests that tumor-selective cell killing by oncolytic viruses may be augmented by combining with cytotoxic drugs. PMID- 26429640 TI - Internal mammary node drainage in patients with early breast cancer. PMID- 26429641 TI - Lactate dehydrogenase and body mass index are prognostic factors in patients with recurrent small cell lung cancer receiving amrubicin. AB - AIMS AND BACKGROUND: Amrubicin monotherapy can be an effective treatment option for patients with recurrent small cell lung cancer (SCLC). We conducted this retrospective study to investigate the prognostic factors in patients with recurrent SCLC receiving amrubicin monotherapy. METHODS: The associations between survival and clinical data, including the performance status, body mass index (BMI), plasma lactate dehydrogenase (LDH) level, and plasma neuron-specific enolase level, were evaluated in patients with recurrent SCLC, and a subset analysis of patients with platinum-resistant disease was conducted. RESULTS: In all, 37 patients were evaluated. The median survival from the date of initiation of amrubicin monotherapy was 9.1 months (95% confidence interval 4.7-12.0 months). Multivariate analysis using a Cox proportional hazard model identified the plasma LDH level (p = 0.049), BMI (p = 0.031), and platinum resistance (p = 0.032) as independent factors associated with survival. The same associations were also observed in the subset of patients with platinum-resistant disease. CONCLUSIONS: Our findings suggest that the plasma LDH level and BMI may be useful prognostic factors in patients with SCLC receiving amrubicin monotherapy, including patients with platinum-resistant disease. PMID- 26429642 TI - Impact of aspirin on clinical outcomes for African American men with prostate cancer undergoing radiation. AB - AIMS AND BACKGROUND: Preclinical and clinical studies have suggested that aspirin (ASA) may exhibit antineoplastic activity. Particularly in prostate cancer, several reports have suggested that ASA plays a role in improved outcomes. Therefore, we studied the role of ASA in a uniquely African American population, which is known to harbor more aggressive and biologically different disease compared to the general population. METHODS: We identified 289 African American men with prostate cancer who were treated with definitive radiation therapy to a dose of >=7560 cGy. The median follow-up was 76 months. Kaplan-Meier analysis was used to analyze biochemical failure-free survival (bFFS), distant progression free survival (DMPFS), and prostate cancer-specific survival (PCSS). Multivariate Cox regression was used to analyze the impact of covariates on all endpoints. RESULTS: There were 147 men who were ASA+ and 142 who were ASA-. The 7-year bFFS was 80.9% for ASA+ men and 70.3% for ASA- men (p = 0.03). On multivariate analysis, ASA use was associated with a significant reduction in biochemical recurrences (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.34-0.93, p = 0.03). The 7-year DMPFS was 98.4% for ASA+ and 91.8% for ASA- men (p = 0.04). On multivariate analysis, ASA use was associated with a decreased risk of distant metastases (HR 0.23, 95% CI 0.06-0.91, p = 0.04). The 7-year PCSS was 99.3% for ASA+ and 96.9% for ASA- men (p = 0.07). CONCLUSIONS: In this study, ASA use was associated with improved biochemical outcomes and reduced distant metastases. This indicates that ASA appears to play an important antineoplastic role in African American men. PMID- 26429643 TI - VATS lobectomy combined with limited Shaw-Paulson thoracotomy for posterolateral Pancoast tumor. AB - PURPOSE: Several techniques have been proposed for the challenging surgical resection of Pancoast tumors. We describe a hybrid approach that combines video assisted thoracic surgery (VATS) lobectomy and limited Shaw-Paulson thoracotomy. METHODS: We report a case of Pancoast tumor in a 57-year-old man, staged as cT3N0M0, that was treated with induction chemoradiotherapy prior to the hybrid surgical approach. After thoracoscopic pleural cavity inspection, an upper right VATS lobectomy by a 3-port standard approach was performed. The chest wall was resected through a limited paravertebral incision, allowing the extraction of the lobe together with the rib segments. The posterior chest wall defect was repaired with a synthetic patch. RESULTS: The postoperative period was uneventful and the pain never exceed a score of 3 on a visual analogue scale. Pathological examination revealed nonvital tumor cells in the specimen (ypT0N0M0). The patient is disease free at 6 months' follow-up. CONCLUSIONS: With this approach we experienced excellent access to both the apical and hilar structures. Further experiences are needed to validate the role of VATS lobectomy in the multidisciplinary management of posterior Pancoast tumor. PMID- 26429644 TI - Management of advanced pancreatic cancer in daily clinical practice. AB - PURPOSE: The aim of this outcome study was to evaluate the management of advanced pancreatic cancer in a real-world clinical practice; few such experiences have been reported in the literature. METHODS: A retrospective analysis was performed of all consecutive patients with advanced pancreatic ductal adenocarcinoma followed at our medical oncology unit between January 2003 and December 2013. RESULTS: We evaluated 78 patients, mostly with metastatic disease (64.1%). Median follow-up was 10.77 months, by which time 74 patients (94.9%) had died. Median overall survival was 8.29 months. Median age was 67 years. In univariate analysis, pain at onset (p = 0.020), ECOG performance status (p<0.001), stage (p = 0.047), first-line chemotherapy (p<0.001), second-line chemotherapy (p<0.001) and weight loss at diagnosis (p = 0.029) were factors that had an impact on overall survival. In multivariate analysis, the presence of pain at onset (p = 0.043), stage (p = 0.003) and second-line chemotherapy (p = 0.004) were confirmed as independent prognostic factors. CONCLUSIONS: Our data, derived from daily clinical practice, confirmed advanced pancreatic cancer as an aggressive malignant disease with a very short expected survival. Second-line treatment seems to provide an advantage in terms of overall survival in patients who showed a partial response as their best response to first-line treatment. PMID- 26429645 TI - The key role of 18F-FDG PET/CT for correct diagnosis, staging, and treatment in a patient with simultaneous NPC and TB lymphadenitis: case report. AB - AIMS AND BACKGROUND: The coexistence of tuberculous lymphadenitis of the neck region and head and neck cancer is extremely rare. In this clinical situation, the use of positron emission and computed tomography using fluorine-18 fluorodeoxyglucose (18F-FDG PET/CT) may facilitate the differentiation between malignancy and tuberculosis. CASE REPORT: We present a case of an Eastern European man with nasopharyngeal cancer and concurrent tuberculous lymphadenitis. RESULTS AND CONCLUSION: The adequate and critical interpretation of pretreatment 18F-FDG PET/CT scan addressed the multidisciplinary team to the proper staging of disease and to the correct therapeutic approach. PMID- 26429646 TI - Management of internal mammary nodes in early-stage breast cancer: response to comments by De Cicco et al. PMID- 26429647 TI - Mass-forming extramedullary hematopoiesis in multiple myeloma: 18F-FDG PET/CT is useful in excluding extramedullary myeloma involvement. AB - AIMS AND BACKGROUND: Extramedullary hematopoiesis (EMH), a benign condition, is usually observed in patients with hematologic disorders. We report the first case of mass-forming EMH detected on a 18F-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) scan in a patient with multiple myeloma (MM). METHODS: A 58-year-old woman underwent workup for bicytopenia, and was diagnosed with MM based on the results of bone marrow aspiration and serum protein electrophoresis. An 18F-FDG PET/CT scan revealed a paravertebral mass with mild FDG avidity, suggesting a tumorous condition. RESULTS: Biopsy was performed to exclude malignancy and the mass was eventually confirmed as EMH. CONCLUSIONS: Differential diagnosis of a mildly FDG-avid paravertebral mass in MM should include EMH. PMID- 26429648 TI - Misregulation of the dependence receptor DCC and its upstream lincRNA, LOC100287225, in colorectal cancer. AB - BACKGROUND: Long non-coding RNAs (lncRNAs), a class of regulatory RNAs, play a major role in various cellular processes. Long intergenic non-coding RNAs (lincRNAs), a subclass of lncRNAs, are involved in the trans- and cis-regulation of gene expression. In the case of cis-regulation, by recruiting chromatin modifying complexes, lincRNAs influence adjacent gene expression. METHODS: We used quantitative real-time reverse-transcription polymerase chain reaction (qRT PCR) to evaluate the coexpression of LOC100287225, a lincRNA, and DCC, one of its adjacent genes that is often decreased in colorectal cancer, in pairs of tumor and adjacent tumor-free tissues of 30 colorectal cancer patients. RESULTS: The qRT-PCR results revealed the misregulation of these genes during tumorigenesis. Their relative expression levels were significantly lower in tumor tissues than adjacent tumor-free tissues. However, the analysis found no significant correlation between reduced expression of these genes. CONCLUSIONS: Our study demonstrated the concurrent misregulation of DCC and LOC100287225 in colorectal cancer. PMID- 26429649 TI - Radiotherapy for early-stage prostate cancer in men under 70 years of age. AB - AIMS: To demonstrate that radiotherapy (RT) is a valid alternative to surgery in men <=70 years old with localized prostate cancer. METHODS: From 1988 to 2009, 214 patients with T1-2 N0 M0 prostate cancer were treated with RT. The effects of patient- and treatment-related risk factors on toxicity were investigated. RESULTS: Median follow-up was 105 months (range 14.2-180). The 5-, 10-, and 15 year biochemical relapse-free survival for all 214 patients was 80%, 61.9%, and 57.5%, respectively. In bivariate analysis, age (<=65 vs 65-70 years) was not a significant factor for biochemical relapse, while radiation dose was (p = 0.05) in multivariate analysis. Cancer-specific survival rates at 5, 10, and 15 years were 98.4%, 93.2%, and 69.7%, respectively. Median overall survival (OS) was 167 months (95% confidence interval 147.3-186.7). The OS rates at 5, 10, and 15 years were 91.8%, 75.8%, and 42.5%, respectively. Acute genitourinary (GU) and gastrointestinal (GI) toxicities occurred in 105 (49%) and 98 patients (45.8%), respectively, with only 2 cases of grade III GI toxicity. Late GU and GI toxicities occurred in 17 (7.9%) and 20 (9.3%) patients, respectively, with 1 grade III GI toxicity and 2 grade III GU toxicities. Risk factors for late toxicity were age and RT dose and technique, which were unrelated to acute toxicity. CONCLUSIONS: Age <=70 years does not consistently confer a negative prognosis for localized prostate cancer. Radiotherapy appears to be a viable alternative to surgery, offering excellent long-term cancer control. PMID- 26429650 TI - Outcome of definitive and postoperative radiotherapy in patients with sinonasal squamous cell carcinomas. AB - AIMS: To evaluate outcomes in patients with sinonasal squamous cell carcinoma (SCC) treated with definitive radiotherapy (DRT) and postoperative radiotherapy (PORT). METHODS: Between 1990 and 2013, 73 patients with sinonasal SCC were treated with radiotherapy. Fifty-two patients (71.2%) were treated with DRT and 21 (28.8%) were treated with PORT. The primary tumor sites were the maxillary sinus in 47 patients (64.4%), the nasal cavity in 18 (24.7%), the ethmoid sinus in 7 (9.6%), and the frontal sinus in 1 (1.4%). Four (5.4%), 11 (15.1%), 24 (32.9%), 17 (23.3%), and 17 (23.3%) patients had T1, T2, T3, T4a, and T4b tumors, respectively. N stage was N0, N1, N2a, N2b, N2c, and N3 in 60 (82.2%), 6 (8.2%), 2 (2.7%), 2 (2.7%), and 3 (4.1%) patients, respectively. The median follow-up period was 23 months (range 3-196). RESULTS: The 5-year local progression-free survival (LPFS), regional progression-free survival (RPFS), distant metastasis free survival (DMFS), and overall survival (OS) in the DRT and PORT groups were 50.6%, 82.1%, 91.1%, and 84.4% and 85.7%, 72.1%, 76.1%, and 83.5%, respectively, without any statistically significant differences. CONCLUSIONS: The LPFS, RPFS, DMFS, and OS were not significantly different between the DRT and PORT groups. Given the possibility of functional disability and cosmetic disfigurement with facial surgery, DRT might be considered as a surrogate to surgery followed by PORT for patients with locally advanced sinonasal SCC. PMID- 26429651 TI - Hypercholesterolemia-induced ocular disorder: Ameliorating role of phytotherapy. AB - The ocular region is a complex structure that allows conscious light perception and vision. It is of ecto-mesodermal origin. Cholesterol and polyunsaturated fatty acids are involved in retinal cell function; however, hypercholesterolemia and diabetes impair its function. Retinal damage, neovascularization, and cataracts are the main complications of cholesterol overload. Dietary supplementation of selected plant products can lead to the scavenging of free reactive oxygen species, thereby protecting the ocular regions from the damage of hypercholesterolemia. This review illustrates the dramatic effects of increased cholesterol levels on the ocular regions. The effect of phytotherapy is discussed in relation to the different regions of the eye, including the retina, cornea, and lens. PMID- 26429652 TI - Selenium status in preschool children receiving a Brazil nut-enriched diet. AB - OBJECTIVE: The Brazilian Amazon region has selenium (Se)-rich soil, which is associated with higher Se levels in populations fed locally grown produce. Brazil nuts are a major source of dietary Se and are included with meals offered to children enrolled in public preschool in Macapa. The aim of this study was to examine Se intake and status of these children. METHODS: The Macapa group consisted of 41 children from a public preschool who received 15 to 30 g of Brazil nuts 3 d/wk. The control group included 88 children from the nearby city of Belem who did not receive Brazil nut-enriched meals. In both groups, school meals comprised >=90% of the children's total food consumption. Selenium was assessed using hydride generation quartz tube atomic absorption spectroscopy in plasma, erythrocytes, nails, hair and urine. Dietary intakes (macronutrients and Se) were evaluated using the duplicate-portion method. RESULTS: Both groups received inadequate intakes of energy and macronutrients. Selenium intake was excessive in both groups (155.30 and 44.40 MUg/d, in Macapa and Belem, respectively). Intake was potentially toxic in Macapa on days when Brazil nuts were added to meals. Although biomarkers of Se exposure exceeded reference levels in the Macapa group, no clinical symptoms of Se overload (selenosis) were observed. CONCLUSIONS: The inclusion of Brazil nuts in school meals provided to children with already high dietary Se intakes increased Se levels and may result in an increased risk for toxicity. As selenosis is associated with some chronic diseases, we recommend continued monitoring of Se intake and status in this population. PMID- 26429653 TI - A single FTO gene variant rs9939609 is associated with body weight evolution in a multiethnic extremely obese population that underwent bariatric surgery. AB - OBJECTIVES: The rs9939609 single nucleotide polymorphism (SNP) in the fat mass and obesity-associated (FTO) gene is involved in obesity. Few studies have been conducted on patients who underwent bariatric surgery. The aim of this study was to evaluate the influence of FTO SNPs on body weight, body composition, and weight regain during a 60-mo follow-up period after bariatric surgery. METHODS: The rs9939609 was genotyped in 146 individuals using a real-time polymerase chain reaction TaqMan assay. Data for lifestyle, comorbidities, body weight, body mass index (BMI), excess weight loss (EWL), and body composition were obtained before and 6, 12, 18, 24, 36, 48, and 60 mo after surgery. Data were analyzed by comparing two groups of patients according to rs9939609 FTO gene polymorphism. Mixed-regression models were constructed to evaluate the dynamics of body weight, BMI, and EWL over time in female patients. RESULTS: No differences were observed between the groups during the first 24 mo after surgery. After 36, 48, and 60 mo, body weight, fat mass, and BMI were higher, whereas fat-free mass and EWL were lower in the FTO-SNP patient group. Weight regain was more frequent and occurred sooner in the FTO-SNP group. CONCLUSIONS: There is a different evolution of weight loss in obese carriers of the FTO gene variant rs9939609 after bariatric surgery. However, this pattern was evident at only 2 y postbariatric surgery, inducing a lower proportion of surgery success and a greater and earlier weight regain. PMID- 26429654 TI - Obstructive sleep apnea is independently associated with inflammation and insulin resistance, but not with blood pressure, plasma catecholamines, and endothelial function in obese subjects. AB - OBJECTIVES: Obstructive sleep apnea (OSA) is associated with an increased risk of cardiovascular disease (CVD). Several of the proposed mechanisms for the development of CVD in OSA are similar to those proposed for the increased risk of CVD in obesity, so that it is difficult to determine the influence of OSA on these pathogenic mechanisms in obese individuals. The aim of this study was to evaluate the relationship of OSA with endothelial function, oxidative stress, inflammatory biomarkers, metabolic profile, sympathetic nervous system activity, and blood pressure (BP) in obese individuals. METHODS: This cross-sectional study included 53 obese adults (28 women). Sleep study was performed with WatchPAT 200 (Itamar Medical, Caesarea, Israel) and the diagnosis of OSA was made when apnea hypopnea index (AHI) >=5 events/h (n = 33). All participants underwent evaluation of: body adiposity, BP, plasma catecholamines, high sensitivity C-reactive protein (hs-CRP), adiponectin, malondialdehyde, glucose, insulin, lipid profile, and endothelial function (EndoPAT 2000). RESULTS: In univariate analysis, participants with OSA compared with those without OSA exhibited higher values of neck circumference, glucose, noradrenaline, and systolic BP. After adjustment for confounders, including adiposity, only glucose and hs-CRP were significantly higher in OSA patients. In correlation analysis, after controlling for confounders, AHI was positively and significantly associated with neck circumference and hs-CRP, while minimum O2 saturation was associated negatively and significantly with neck circumference, insulin and homeostatic model assessment-insulin resistance (HOMA-IR). CONCLUSIONS: The present study suggests that in obese individuals OSA is independently associated with inflammation and insulin resistance, but not with BP, plasma catecholamines and endothelial function. PMID- 26429655 TI - Efficacy of zinc sulfate supplement on febrile seizure recurrence prevention in children with normal serum zinc level: A randomised clinical trial. AB - OBJECTIVE: Serum zinc level might be related to pathogenesis of febrile seizure (FS). The purpose of this study was to evaluate efficacy and safety of oral zinc supplementation on FS recurrence prevention in non-zinc-deficient children. MATERIALS AND METHODS: In a randomized clinical study, one hundred 18 to 60 mo old children with normal zinc level with first simple FS were referred to Shahid Sadoughi Hospital, Yazd, Iran from May 2012 to June 2013, were randomly assigned to two groups to receive 2 mg/kg/d zinc sulfate for six consecutive months or placebo as control group and were followed up for 1 y for FS recurrence. RESULTS: 41 girls and 59 boys with mean age of 2.47 +/- 1.01 y were evaluated. Race, mean weight, height and body fat were similar in both groups. FS recurrence occurred in 19 children (38%) in the control group [95% confidence interval (CI): 19.45% 53.95%] and in 11 children (22%) in the zinc sulfate (95% CI: 57.47%-89.13%) groups, respectively; and the zinc group had lower FS recurrence (P = 0.03). The mean serum zinc level before intervention was lower in children with FS recurrence (72.43 +/- 14.58 MUg/dL versus 96.33 +/- 12.69 MUg/dL, P = 0.04). Gastrointestinal side effects (vomiting in five children, heartburn in two children and abdominal pain in one child) were seen in 16% of the zinc group and vomiting occurred in two children (4%) in control group and frequency of adverse events was similar in the two groups (P = 0.1). CONCLUSION: Zinc supplementation should be considered as effective and safe in prevention of FS recurrence. PMID- 26429656 TI - Association between nutritional status and disease severity using the amyotrophic lateral sclerosis (ALS) functional rating scale in ALS patients. AB - OBJECTIVE: The nutritional status of patients with amyotrophic lateral sclerosis (ALS) has been shown to be associated with mortality. However, there have not been, to our knowledge, any studies on the association between nutritional status and disease severity. The present study investigated the hypothesis that nutritional status was negatively associated with disease severity using the ALS functional rating scale (ALSFRS-R). METHODS: One hundred ninety-three Korean ALS patients were divided into tertiles based on their ALSFRS-R score. Dietary intake was measured using 24 h recall and nutritional status was determined by body mass index (BMI) and geriatric nutritional risk index (GNRI). RESULTS: BMI and GNRI were significantly lower in patients in the lowest tertile of ALSFRS-R. BMI and GNRI also correlated with ALSFRS-R score, bulbar score, albumin levels, total lymphocyte count, and total daily energy expenditure. Intakes of energy and most nutrients were significantly lower in patients in the lowest tertiles of ALSFRS R, but significances disappeared after adjusting for energy intake. Intakes of vegetables, grains, seasonings, and oils were also significantly lower in patients in the lowest tertile of ALSFRS-R. In addition, patients in the lowest tertile of ALSFRS-R were significantly younger at disease onset, had a longer duration of ALS, less regular exercise, and less sun exposure. CONCLUSION: Nutritional status, as assessed by BMI and GNRI, was negatively associated with disease severity using ALSFRS-R. The present study suggested that intake of nutrients decreases with disease progression in ALS patients. PMID- 26429657 TI - Should patients with ALS gain weight during their follow-up? AB - It was recently postulated that a nutritional intervention aiming at achieving weight gain might increase survival in ALS patients. This article discusses the effect of nutritional status and weight gain on survival, respiratory status and physical function. Based on the available literature, it remains unknown whether weight gain during the progression of the disease improves survival whatever the baseline body weight is. A high body mass index may impair respiratory muscle function and passive mobilization of paretic patients. Future research should evaluate the effect of changes in weight and body composition on clinical outcome while taking into account respiratory muscle strength and physical function. PMID- 26429658 TI - Patient Generated Subjective Global Assessment as a prognosis tool in women with gynecologic cancer. AB - OBJECTIVES: The aim of this study was to assess the nutritional status (NS) of women hospitalized for gynecologic tumors and relate it to such outcomes as hospital length of stay and 1-y mortality. METHODS: We assessed 146 women diagnosed with gynecologic tumors who were admitted to a referral oncologic hospital in November 2012. Data collected included medical history, duration and reason for admission, and cases of death within 1 y. RESULTS: NS was assessed using Patient-Generated Subjective Global Assessment (PG-SGA). The receiver operating characteristic curve was used to define the best cutoff point for discriminating individuals who did or did not die. We used proportional hazards regression to assess associations between malnutrition and 1-y mortality. According to the PG-SGA, 62.4% of the women were classified as being at nutritional risk or having moderate or severe malnutrition. Sorting patients by stage of cancer, there was no statistical difference in NS classification according to the different cancer sites. The median hospital stay, in days, was statistically lower in patients classified as well nourished. Individuals with a score above the cutoff point of 10 were 30.7 times more likely (95% confidence interval, 11.8-79.4) to die. There was a 52.1% rate of mortality within 1 y. Patients classed as having some degree of malnutrition had a significantly lower median survival rate. A diagnosis of cervical cancer and severe malnourishment increases the likelihood of death. CONCLUSIONS: Our findings suggest that the PG SGA can be considered not just as an indicator of nutritional risk, but also as a major predictor of prognosis and mortality in this population. PMID- 26429659 TI - Association between oral feeding intolerance and quality of life in acute pancreatitis: A prospective cohort study. AB - OBJECTIVE: Oral feeding intolerance (OFI) is a common complication of nutritional management in acute pancreatitis (AP) and is associated with significantly worse clinical outcomes and increased cost of treatment. However, changes in patient reported outcomes associated with OFI during AP and effect of OFI on quality of life (QoL) have, to our knowledge, never been studied. The aim of this study was to investigate the relationship between OFI and QoL in patients with AP. METHODS: We conducted a prospective cohort study of patients with AP. Patients were grouped according to whether they developed OFI during hospitalization. QoL was recorded daily during hospitalization and at 1 and 4 wk after discharge. One-way analysis of covariance and repeated measures analysis were conducted. P < 0.05 was accepted as statistically significant. RESULTS: The study included 131 patients with AP. Fifty-two (40%) developed OFI during hospitalization. Overall QoL was significantly impaired in the OFI group (mean difference = -16.1; 95% confidence interval, -24.4 to -7.8; P <= 0.001). Five individual domains-physical limitations, psychological function, sleep, pain, and visceral function-were significantly impaired in the OFI group during hospitalization. Overall QoL improved significantly within each group from hospitalization to follow-up (P < 0.001) with no significant difference between the two groups at follow-up (mean difference = -2; 95% confidence interval, -7.1 to 3.2; P = 0.449). CONCLUSIONS: QoL is significantly impaired in patients with AP who develop OFI. Nutritional management of acute pancreatitis needs to be optimized to prevent the occurrence of OFI. PMID- 26429660 TI - Association of nutritional risk and adverse medical outcomes across different medical inpatient populations. AB - OBJECTIVE: The aim of this study was to examine the prevalence of nutritional risk and its association with multiple adverse clinical outcomes in a large cohort of acutely ill medical inpatients from a Swiss tertiary care hospital. METHODS: We prospectively followed consecutive adult medical inpatients for 30 d. Multivariate regression models were used to investigate the association of the initial Nutritional Risk Score (NRS 2002) with mortality, impairment in activities of daily living (Barthel Index <95 points), hospital length of stay, hospital readmission rates, and quality of life (QoL; adapted from EQ5 D); all parameters were measured at 30 d. RESULTS: Of 3186 patients (mean age 71 y, 44.7% women), 887 (27.8%) were at risk for malnutrition with an NRS >=3 points. We found strong associations (odds ratio/hazard ratio [OR/HR], 95% confidence interval [CI]) between nutritional risk and mortality (OR/HR, 7.82; 95% CI, 6.04 10.12), impaired Barthel Index (OR/HR, 2.56; 95% CI, 2.12-3.09), time to hospital discharge (OR/HR, 0.48; 95% CI, 0.43-0.52), hospital readmission (OR/HR, 1.46; 95% CI, 1.08-1.97), and all five dimensions of QoL measures. Associations remained significant after adjustment for sociodemographic characteristics, comorbidities, and medical diagnoses. Results were robust in subgroup analysis with evidence of effect modification (P for interaction < 0.05) based on age and main diagnosis groups. CONCLUSION: Nutritional risk is significant in acutely ill medical inpatients and is associated with increased medical resource use, adverse clinical outcomes, and impairments in functional ability and QoL. Randomized trials are needed to evaluate evidence-based preventive and treatment strategies focusing on nutritional factors to improve outcomes in these high-risk patients. PMID- 26429661 TI - Association between basal metabolic function and bone metabolism in postmenopausal women with type 2 diabetes. AB - OBJECTIVE: Diabetes is a risk factor for osteoporosis, and glycemic control is critical during osteoporosis treatment in patients with type 2 diabetes (T2D). However, diabetic therapies have potentially adverse effects on bone metabolism. Additionally, biomarkers for bone metabolism are directly affected by drug therapies for osteoporosis. This study examined resting energy expenditure (REE) and respiratory quotient (RQ) as indices of bone metabolism in postmenopausal Japanese women with T2D. METHODS: Forty-six postmenopausal Japanese women with T2D were examined. Procollagen type 1 N-terminal propeptide (P1NP, a fasting serum bone formation marker) and carboxy-terminal collagen cross-links-1 (CTX-1, a resorption marker) were evaluated, along with intact parathyroid hormone, 25 hydroxyvitamin D (25[OH]D), urine microalbumin, motor nerve conduction velocity, sensory nerve conduction velocity, R-R interval, body composition, REE, RQ, and bone mineral density at the nondominant distal radius. RESULTS: The mean T-score was low with high variance (-1.7 +/- 1.6), and 18 patients (39%) met the criteria for osteoporosis. REE was positively correlated with body mass index (beta = 0.517; r(2) = 0.250), serum calcium (beta = 0.624; r(2) = 0.200), glycated hemoglobin A1C for the previous 6 mo (beta = 0.395; r(2) = 0.137), and the serum P1NP/CTX-1 ratio (beta = 0.380; r(2) = 0.144). RQ was positively correlated with serum 25(OH)D (beta = 0.387; r(2) = 0.131). CONCLUSION: The basal metabolic rate and diabetic pathophysiology are interrelated with bone turnover. PMID- 26429662 TI - Vitamin A exerts its antiinflammatory activities in colitis through preservation of mitochondrial activity. AB - OBJECTIVES: The aim of this study was to assess the protective effects of vitamin A in a rat model of colitis to elucidate a possible mechanism of action. METHODS: Male rats were fed for 21 d with either a normal diet or high vitamin A diet (5000 IU/d). On day 22, colitis was induced with 2,4,6-trinitrobenzenesulfonic acid (TNBS). Rats were sacrificed after 24 h and colonic tissue was removed for evaluation. RESULTS: Morphologically, in the supplemented group preservation of tissue architecture, no vasculitis or necroses were detected. Biochemically, decreased myeloperoxidase activity and protection of the mitochondria as evaluated by preserving tissue oxygen consumption, mitochondrial DNA, and expression of cytochrome c, was observed. Vitamin A supplementation also increased the levels of nuclear respiratory factor (NFR)-1 and mitochondrial transcription factor-A (TFAM) in normal colon tissue and in colon tissue under inflammatory conditions. CONCLUSION: The results indicate that tissue damage in colitis is accompanied by the arrest of mitochondrial respiration, loss of mitochondrial DNA, and the expression of mitochondrial proteins. Vitamin A effectively protects colon mitochondria by upregulation of mitochondrial transcription factors, NFR-1 and TFAM, and prevents inflammatory and necrotic changes in colitis. Vitamin A is therefore a potential therapeutic agent in inflammatory bowel disease. PMID- 26429663 TI - Oxidative damage and antioxidant defense in thymus of malnourished lactating rats. AB - OBJECTIVE: Malnutrition has been associated with oxidative damage by altered antioxidant protection mechanisms. Specifically, the aim of this study was to evaluate oxidative damage (DNA and lipid) and antioxidant status (superoxide dismutase [SOD], glutathione peroxidase [GPx], and catalase [CAT] mRNA, and protein expression) in thymus from malnourished rat pups. METHODS: Malnutrition was induced during the lactation period by the food competition method. Oxidative DNA damage was determined quantifying 8-oxo-7, 8-dihydro-2'-deoxyguanosine adduct by high-performance liquid chromatography. Lipid peroxidation was assessed by the formation of thiobarbituric acid-reactive substances. Levels of gene and protein expression of SOD, GPx, and CAT were evaluated by real-time polymerase chain reaction and Western blot, respectively. Antioxidant enzyme activities were measured spectrophotometrically. RESULTS: Oxidative DNA damage and lipid peroxidation significantly increased in second-degree (MN-2) and third-degree malnourished (MN-3) rats compared with well-nourished rats. Higher amounts of oxidative damage, lower mRNA expression, and lower relative concentrations of protein, as well as decreased antioxidant activity of SOD, GPx, and CAT were associated with the MN-2 and MN-3 groups. CONCLUSIONS: The results of this study demonstrated that higher body-weight deficits were related to alterations in antioxidant protection, which contribute to increased levels of damage in the thymus. To our knowledge, this study demonstrated for the first time that early in life, malnutrition leads to increased DNA and lipid oxidative damage, attributable to damaged antioxidant mechanisms including transcriptional and enzymatic activity alterations. These findings may contribute to the elucidation of the causes of previously reported thymus dysfunction, and might explain partially why children and adults who have overcome child undernourishment experience immunologic deficiencies. PMID- 26429664 TI - Effects and mechanisms of auricular vagus nerve stimulation on high-fat-diet- induced obese rats. AB - OBJECTIVE: Obesity is a major public health problem. Regulating food intake and promoting metabolism of fat are two important options for treating obesity. Auricular vagus nerve stimulation (AVNS) is considered as an alternative approach to vagal nerve stimulation. The aim of this study was to investigate the effects of AVNS and its mechanisms on obesity in obese rats. METHODS: Male Sprague-Dawley rats were fed either a high-fat diet (HFD) or a normal diet for 8 wk. Qualified HFD rats were randomly divided into three groups: the HFD group, the AVNS group, and the sham group for 6 wk treatment. Body weight and daily energy intake were recorded weekly. The rats were sacrificed for measurement of weight of bilateral perirenal, epididymal white adipose tissue (WAT), dorsal brown adipose tissue (BAT), and gastric emptying. Serum cholecystokinin (CCK), peptide YY3 to 36 (PYY3 36) and norepinephrine (NE) were assayed by enzyme-linked immunosorbent assay. Real-time quantitative polymerase chain reaction was used to assess the mRNA expressions of CCK subtype receptor a (CCKa) in the antrum, PYY3-36 receptor in the distal ileum, beta3-adrenoceptor, and uncoupling protein gene 1 (UCP1) in the BAT. RESULTS: Compared with HFD group, AVNS significantly reduced body weight and epididymal WAT and increased BAT weight, serum NE, mRNA expressions of beta3 adrenoceptors, and UCP1 of the BAT, but had no effect on daily energy intake, perirenal WAT weight, gastric emptying, serum levels of CCK and PYY, or mRNA expressions of CCKa receptor and PYY3-36 receptor in the relevant tissues. The sham group, as a comparison group for AVNS, saw less effect in any of the indexes compared with the HFD group. AVNS had more effect on weight loss, reduction of perirenal WAT, and increase of NE, beta3-adrenoceptor, and UCP1 than sham. CONCLUSIONS: AVNS was more effective in reducing body weight and causing visceral fat loss. Biochemical tests found more NE released in the serum and more beta3 adrenoceptor and UCP1 expression in the BAT. All of these features suggested that energy expenditure might play an important role in obesity management by AVNS. PMID- 26429665 TI - omega-3 Fatty acids reverse lipotoxity through induction of autophagy in nonalcoholic fatty liver disease. AB - OBJECTIVE: The aim of this study was to evaluate the effect of omega-3 fatty acids on nonalcoholic fatty liver disease concerning hepatocyte lipid accumulation as well as apoptosis induced by free fatty acids (FFAs) and to explore the underlying mechanism involving autophagy. METHODS: Hepatocytes were incubated with a mixture of free fatty acids (FFAs) to mimic in vitro lipotoxicity in the pathogenesis of nonalcoholic fatty liver disease, presented by lipid accumulation and cellular apoptosis. Chemical inhibitor or inducer of autophagy and genetic deficit cells, as well as omega-3 fatty acids were used as intervention. The autophagic role of omega-3 fatty acids was investigated using Western blot and immunofluorescence. The underlying mechanism of omega-3 fatty acids involving autophagy was preliminarily explored by quantitative real-time polymerase chain reaction and Western blot. RESULTS: FFAs induce lipid accumulation and apoptosis in hepatocytes. Inhibition or genetic defect of autophagy increases lipid accumulation induced by FFA, whereas induction acts inversely. omega-3 Fatty acids reduced lipid accumulation and inhibited apoptosis induced by FFA. omega-3 Fatty acids induced autophagy by downregulating stearoyl CoA desaturase 1 expression in hepatocytes. CONCLUSION: omega-3 Fatty acids exert protective effects on hepatocytes against lipotoxicity through induction of autophagy, as demonstrated by inhibition of lipid accumulation and apoptosis. PMID- 26429667 TI - Addition of lipids to parenteral nutrition does not cause fungal infections. AB - Parenteral nutrition (PN) that includes lipid emulsion is considered to increase both bacterial and fungal central venous catheter-related bloodstream infections. This concept is based on several erroneous metrics: Reports in age-old literature at a time when preparing PN admixtures lacked stringent quality control, when its infusion, the techniques of insertion, maintenance of vascular access devices, and delivery systems were not well identified or enforced. Additionally, concepts of glucohomeostasis were different and higher glucose levels were accepted. We provide updated information with supporting literature to show that associating PN with lipids with an increase in bloodstream infections is not justified. PMID- 26429666 TI - Dietary fats significantly influence the survival of penumbral neurons in a rat model of chronic ischemic by modifying lipid mediators, inflammatory biomarkers, NOS production, and redox-dependent apoptotic signals. AB - OBJECTIVE: Brain stroke is the third most important cause of death in developed countries. We studied the effect of different dietary lipids on the outcome of a permanent ischemic stroke rat model. METHODS: Wistar rats were fed diets containing 7% commercial oils (S, soybean; O, olive; C, coconut; G, grape seed) for 35 d. Stroke was induced by permanent middle cerebral artery occlusion. Coronal slices from ischemic brains and sham-operated animals were supravitally stained. Penumbra and core volumes were calculated by image digitalization after 24, 48, and 72 h poststroke. Homogenates and mitochondrial fractions were prepared from different zones and analyzed by redox status, inflammatory markers, ceramide, and arachidonate content, phospholipase A2, NOS, and proteases. RESULTS: Soybean (S) and G diets were mainly prooxidative and proinflammatory by increasing the liberation of arachidonate and its transformation into prostaglandins. O was protective in terms of redox homeostatic balance, minor increases in lipid and protein damage, conservation of reduced glutathione, protective activation of NOS in penumbra, and net ratio of anti-to proinflammatory cytokines. Apoptosis (caspase-3, milli- and microcalpains) was less activated by O than by any other diet. CONCLUSION: Dietary lipids modulate NOS and PLA2 activities, ceramide production, and glutathione import into the mitochondrial matrix, finally determining the activation of the two main protease systems involved in programmed cell death. Olive oil appears to be a biological source for the isolation of protective agents that block the expansion of brain core at the expense of penumbral neurons. PMID- 26429668 TI - A glance at ... telomeres, oxidative stress, antioxidants, and biological aging. PMID- 26429669 TI - Institutional logic in self-management support: coexistence and diversity. AB - The prevalence of chronic conditions in Europe has been the subject of health political reforms that have increasingly targeted collaboration between public, private and voluntary organisations for the purpose of supporting self-management of long-term diseases. The international literature describes collaboration across sectors as challenging, which implies that their respective logics are conflicting or incompatible. In line with the European context, recent Norwegian health policy advocates inter-sectorial partnerships. The aim of this policy is to create networks supporting better self-management for people with chronic conditions. The purpose of our qualitative study was to map different understandings of self-management support in private for-profit, volunteer and public organisations. These organisations are seen as potential self-management support networks for individuals with chronic conditions in Norway. From December 2012 to April 2013, we conducted 50 semi-structured interviews with representatives from relevant health and well-being organisations in different parts of Norway. According to the theoretical framework of institutional logic, representatives' statements are embedded with organisational understandings. In the analysis, we systematically assessed the representatives' different understandings of self-management support. The institutional logic we identified revealed traits of organisational historical backgrounds, and transitions in understanding. We found that the merging of individualism and fellowship in contemporary health policy generates different types of logic in different organisational contexts. The private for-profit organisations were concerned with the logic of a healthy appearance and mindset, whereas the private non-profit organisations emphasised fellowship and moral responsibility. Finally, the public, illness-oriented organisations tended to highlight individual conditions for illness management. Different types of logic may attract different users, and simultaneously, a diversity of logic types may challenge collaboration at the user's expense. Moral implications embed institutional logic implying a change towards individual responsibility for disease. Policy makers ought to consider complexities of logic in order to tailor the different needs of users. PMID- 26429670 TI - Retinal detachment postphacoemulsification in Bichon Frises: a retrospective study of 54 dogs. AB - OBJECTIVE: To compare rates of retinal detachment (RD) postphacoemulsification in American Bichon Frises with and without prophylactic retinopexy. PROCEDURES: Medical records of 54 Bichon Frises undergoing phacoemulsification with or without prophylactic retinopexy between 2003 and 2013 in one or both eyes were reviewed from five Midwestern university veterinary teaching hospitals. Inclusion criteria were preoperative ERG, at least 6 months of follow-up postphacoemulsification, and the absence of preexisting RD as determined by ophthalmic examination and/or ultrasound. Statistical analyses were performed using chi-squared test, and Wilcoxon rank-sum tests and Wilson confidence intervals with the P-value <0.05 were considered significant. RESULTS: Phacoemulsification was performed without retinopexy in 79 eyes (42 dogs, non-PR group) and with prophylactic retinopexy in 23 eyes (12 dogs, PR group). Incidence of diabetes mellitus was 10/42 and 3/12 in the non-PR and the PR groups, respectively (P = 0.93). Intraocular lens implantation was performed in 40/42 non PR dogs and 11/12 PR dogs (P = 0.63, 73/79 vs. 21/23 eyes). At final re examination, RD occurred in 4/79 eyes without retinopexy, compared to 0/23 RD in the retinopexy group. There was no statistically significant difference in RD rates between the two groups (P = 0.27). CONCLUSIONS: These data provide no statistical evidence to support prophylactic retinopexy in Bichon Frises. Due to the low rate of retinal detachment following phacoemulsification without prophylactic retinopexy, the procedure appears to offer limited benefit to offset cost, procedural risk, and risk of extended or repeated anesthesia in Bichon Frises. PMID- 26429671 TI - Exploring views about mindfulness groups for voice-hearing from the perspective of service users and staff: A Q-methodology study. AB - OBJECTIVES: Despite prevailing beliefs about the potential benefits and harmfulness of mindfulness for people who hear voices, there is a paucity of research into staff and service user views. Q-methodology was used to explore views about mindfulness groups for voice-hearers. METHOD: Opportunistic sampling of mental healthcare staff (N = 14) and service users with psychosis (N = 17). Both samples were analysed using principle components factor analysis to identify the range of attitudes held by staff and service users. RESULTS: Staff participants were particularly knowledgeable and interested in mindfulness. A single staff consensus factor was found suggesting mindfulness is helpful, and not harmful for mental health, but uncertainty surrounded its usefulness for voice-hearers. Service users held four distinct attitudes: (i) mindfulness helps to calm a racing mind; (ii) mindfulness helps to manage stress; (iii) mindfulness improves well-being, and does not alter the brain, reality beliefs, or cause madness; and (iv) mindfulness helps with managing thoughts, fostering acceptance, and is acceptable when delivered in a group format. CONCLUSIONS: Staff viewed mindfulness groups for psychosis as helpful, not harmful, but were uncertain about their utility. Consistent with previous research, service users viewed mindfulness groups as useful to promote well-being and reduce distress for individuals experiencing psychosis. PMID- 26429672 TI - A novel calcium-independent cellular PLA2 acts in insect immunity and larval growth. AB - Phospholipase A2 (PLA2) catalyzes the position-specific hydrolysis of fatty acids linked to the sn-2 position of phospholipids (PLs). PLA2s make up a very large superfamily, with more than known 15 groups, classified into secretory PLA2 (sPLA2), Ca(2+)-dependent cellular PLA2 (sPLA2) and Ca(2+)-independent cellular PLA2 (iPLA2). Only a few insect sPLA2s, expressed in venom glands and immune tissues, have been characterized at the molecular level. This study aimed to test our hypothesis that insects express iPLA2, using the beet armyworm, Spodoptera exigua, our model insect. Substantial PLA2 activities under calcium-free condition were recorded in several larval tissue preparations. The PLA2 activity was significantly reduced in reactions conducted in the presence of a specific iPLA2 inhibitor, bromoenol lactone (BEL). Analysis of a S. exigua hemocyte transcriptome identified a candidate iPLA2 gene (SeiPLA2-A). The open reading frame encoded 816 amino acid residues with a predicted molecular weight of 90.5 kDa and 6.15 pI value. Our phylogenetic analysis clustered SeiPLA2-A with the other vertebrate iPLA2s. SeiPLA2-A was expressed in all tissues we examined, including hemocytes, fat body, midgut, salivary glands, Malpighian tubules and epidermis. Heterologous expression in Sf9 cells indicated that SeiPLA2-A was localized in cytoplasm and exhibited significant PLA2 activity, which was independent of Ca(2+) and inhibited by BEL. RNA interference (RNAi) of SeiPLA2-A using its specific dsRNA in the fifth instar larvae significantly suppressed iPLA2 expression and enzyme activity. dsSeiPLA2-A-treated larvae exhibited significant loss of cellular immune response, measured as nodule formation in response to bacterial challenge, and extended larval-to-pupal developmental time. These results support our hypothesis, showing that SeiPLA2-A predicted from the transcriptome analysis catalyzes hydrolysis of fatty acids from cellular PLs and plays crucial physiological roles in insect immunity and larval growth. PMID- 26429673 TI - Investigational drugs for the treatment of osteoarthritis. AB - INTRODUCTION: Osteoarthritis (OA) is a common joint disease with multiple pathophysiological processes, affecting the whole joint. Current therapeutic options such as NSAIDs can provide a palliative effect on symptoms but have limited effect on disease progression. New drugs targeting OA structures may retard disease progression at an earlier stage and delay the need for joint replacement. AREAS COVERED: Some drugs have entered into clinical trials and a few, such as strontium ranelate, do have improvements in both pain and structure changes. However, most of them have failed in clinical trials largely due to increased side effects or the failure to identify the right OA phenotype for the right drug in clinical design. This review describes various investigational drugs developed for the treatment of OA covering those at stages from preclinical experiments to early phase clinical trials. They include drugs for slowing cartilage degradation, regulating cartilage metabolism, targeting subchondral bone, controlling inflammation and relieving pain. EXPERT OPINION: Treatment options for OA remain limited. However, with the emergence of sensitive tools to detect early disease progression and identification of different OA phenotypes, disease-modifying anti-OA drugs with increased benefit and reduced risks will become available for OA treatment in the near future. PMID- 26429674 TI - Association of antibodies to the NR1 subunit of N-methyl-D-aspartate receptors with neuropsychiatric systemic lupus erythematosus. AB - OBJECTIVE: To determine epitope reactivity of autoantibodies to N-methyl-D aspartate (NMDA) receptor NR1 subunit and their association with neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Paired serum and CSF specimens were obtained from 41 patients with NPSLE (22 with diffuse psychiatric/neuropsychological syndromes [diffuse NPSLE] and 19 with neurologic syndromes or polyneuropathy [focal NPSLE]), 21 patients with various rheumatic diseases other than SLE (non-SLERD). Sera were also obtained from 27 SLE patients without neuropsychiatric manifestations (non-CNS SLE). Antibodies to murine NR1 (mNR1) or to 4 different preparations of synthetic 25-amino-acid (AA) peptides of human NR1 were measured by enzyme-linked immune sorbent assay (ELISA). RESULTS: Serum anti-mNR1 levels were significantly higher in NPSLE than in non-SLERD. Sera from NPSLE patients bound efficiently to the AA residues 19-44 from the N terminus of NR1 (NR1-A) or 56-81 (NR1-C). Accordingly, serum anti-NR1-A and anti NR1-C were also elevated in NPSLE compared with non-SLERD. Of note, anti-NR1-A as well as anti-NR1-C levels in CSF, but not in sera, were significantly elevated in diffuse NPSLE compared with focal NPSLE or with non-SLERD. CONCLUSION: These results suggest that autoantibodies to NMDA receptor NR1, especially to the AA residues 19-44 and 56-81 from the N-terminus play a pivotal role in the pathogenesis of diffuse NPSLE. PMID- 26429676 TI - Prophylactic HPV vaccination: past, present, and future. AB - Human papillomavirus (HPV) is the necessary cause of cervical cancer, the fourth most common cancer and cause of cancer-related death in females worldwide. HPV also causes anal, vaginal, vulvar, penile, and oropharyngeal cancer. Prophylactic HPV vaccines based on recombinantly expressed virus-like particles have been developed. Two first-generation, U.S. Food and Drug Administration (FDA)-approved vaccines prevent infections and disease caused by HPV16 and HPV18, the two HPV genotypes that cause approximately 70% of cervical cancer, and one of these vaccines also prevents HPV6 and HPV11, the two HPV genotypes that cause 90% of genital warts. A next-generation vaccine, recently approved by the U.S. FDA, targets HPV16, HPV18, and five additional HPV genotypes that together causes approximately 90% of cervical cancer as well as HPV6 and HPV11. In clinical trials, these vaccines have shown high levels of efficacy against disease and infections caused by the targeted HPV genotypes in adolescent females and males and older females. Data indicate population effectiveness, and therefore cost effectiveness, is highest in HPV-naive young females prior to becoming sexually active. Countries that implemented HPV vaccination before 2010 have already experienced decreases in population prevalence of targeted HPV genotypes and related anogenital diseases in women and via herd protection in heterosexual men. Importantly, after more than 100 million doses given worldwide, HPV vaccination has demonstrated an excellent safety profile. With demonstrated efficacy, cost effectiveness, and safety, universal HPV vaccination of all young, adolescent women, and with available resources at least high-risk groups of men, should be a global health priority. Failure to do so will result in millions of women dying from avertable cervical cancers, especially in low- and middle-income countries, and many thousands of women and men dying from other HPV-related cancers. PMID- 26429675 TI - [Antidepressants in the elderly]. AB - Depression in the elderly is a changing, difficult and common disorder. At this age, there are more relapses and more long-life treatment is required. The pharmacology approach is a challenge because of concurrent factors that make their treatment more difficult. It is very important to have a basic antidepressant scheme, in order to help treat this disorder with efficiency and success from Primary Care. There are no drugs without side effects, and their characteristics have to be known in order to make the right selection depending on effectiveness, safety and tolerance. PMID- 26429677 TI - Assessment of Pain Intensity in Patients with Dentin Hypersensitivity After Application of Prophylaxis Paste Based on Calcium Sodium Phosphosilicate Formula. AB - BACKGROUND: One of many functions of the pulp-dentin complex is sensory function. Acute, situated, receding pain after the cessation of the stimulus action is called dentin pain. Dentin hypersensitivity has been described as one of the most painful and least successfully treated chronic ailments of teeth. The aim of this research was the clinical evaluation of the effectiveness of professional polishing paste containing calcium sodium phosphosilicate formula (NovaMin) in eliminating dentin hypersensitivity after a single application. MATERIAL AND METHODS: The study comprised 92 teeth with dentin hypersensitivity diagnosed on the basis of history and clinical examination. The pain reaction of exposed dentine was induced by tactile and dehydrating stimuli, asking patients to assess the severity of pain on the VAS scale. Clinical trial and survey were carried out twice: before and 1 week after the application of the polishing paste. RESULTS: After the application of the examined paste, the percentage of teeth reacting with a severe pain to the touch of the probe decreased from 16.3% to 4.3%, and with a moderate pain from 42.4% to 12%. Examination after applying dehydrating stimulus a week after carrying out the application showed a decrease in the proportion of teeth with strong pain from 28.3% to 0% and moderate pain from 38% to 15.2%. The lack of pain increased from 12% to about 50%. CONCLUSIONS: The use of prophylactic professional paste with NovaMin formula in in-office procedure provides the reduction of dentin hypersensitivity noticeable by 1 week after application. PMID- 26429678 TI - Psychiatric classification - a developmental perspective. AB - Current classification systems treat developmental and adult psychopathologies as separate. However, as risk factors for psychiatric disorders are identified it is increasingly clear that these can lead to multiple outcomes across different developmental stages. Research and classification schemes will therefore in the future need to adopt a lifespan approach to risk. PMID- 26429679 TI - Mood instability: significance, definition and measurement. AB - Mood instability is common, and an important feature of several psychiatric disorders. We discuss the definition and measurement of mood instability, and review its prevalence, characteristics, neurobiological correlates and clinical implications. We suggest that mood instability has underappreciated transdiagnostic potential as an investigational and therapeutic target. PMID- 26429680 TI - The famous case of Alice Cooper - psychiatry in pictures. PMID- 26429681 TI - Psychological treatment for depression and anxiety associated with dementia and mild cognitive impairment. AB - Depression and anxiety are commonly associated with cognitive impairment. A systematic review of psychological treatments that appears in this issue of the Journal highlights the current paucity of good-quality data, but suggests these interventions hold promise. Given the increasing burden of dementia in our community, novel adequately powered randomised controlled trials in this area are urgently needed. PMID- 26429682 TI - Early intervention in psychosis: still the 'best buy'? AB - High-quality services for people with psychosis are essential. However, in this debate David Castle questions whether separate early intervention services are the best option and argues instead for an integrated approach. Swaran Singh responds, robustly defending the value of early intervention services. PMID- 26429686 TI - Association between poor oral health and eating disorders: systematic review and meta-analysis. AB - BACKGROUND: There is a well-established link between oral pathology and eating disorders in the presence of self-induced vomiting. There is less information concerning this relationship in the absence of self-induced vomiting, in spite of risk factors such as psychotropic-induced dry mouth, nutritional deficiency or acidic diet. AIMS: To determine the association between eating disorder and poor oral health, including any difference between patients with and without self induced vomiting. METHOD: A systematic search was made of Medline, PsycINFO, EMBASE and article bibliographies. Outcomes were dental erosion, salivary gland function and the mean number of decayed, missing and filled teeth or surfaces (DMFT/S). RESULTS: Ten studies had sufficient data for a random effects meta analysis (psychiatric patients n = 556, controls n = 556). Patients with an eating disorder had five times the odds of dental erosion compared with controls (95% CI 3.31-7.58); odds were highest in those with self-induced vomiting (odds ratio (OR) = 7.32). Patients also had significantly higher DMFS scores (mean difference 3.07, 95% CI 0.66-5.48) and reduced salivary flow (OR = 2.24, 95% CI 1.44-3.51). CONCLUSIONS: These findings highlight the importance of collaboration between dental and medical practitioners. Dentists may be the first clinicians to suspect an eating disorder given patients' reluctance to present for psychiatric treatment, whereas mental health clinicians should be aware of the oral consequences of inappropriate diet, psychotropic medication and self-induced vomiting. PMID- 26429684 TI - Psychological treatments for depression and anxiety in dementia and mild cognitive impairment: systematic review and meta-analysis. AB - BACKGROUND: Anxiety and depression are common in people with dementia and mild cognitive impairment (MCI), but there is uncertainty about the effectiveness of both pharmacological and psychological therapies. AIMS: To evaluate the evidence of effectiveness of psychological treatments in treating depression and anxiety in people with dementia and MCI. METHOD: We carried out a systematic review and meta-analysis of randomised controlled trials (RCTs) of psychological treatment versus usual care in people with dementia and MCI. Primary outcomes were symptoms of anxiety and depression. Secondary outcomes were quality of life, ability to perform daily activities, neuropsychiatric symptoms, cognition and caregivers' self-rated depressive symptoms. RESULTS: We included six RCTs, involving 439 participants with dementia, which used cognitive-behavioural therapy, interpersonal therapy, counselling or multimodal interventions including a specific psychological therapy. We found beneficial effects for both depression and anxiety. Overall, the quality of the evidence was moderate for depression and low for anxiety, due to the methodological limitations of the studies we identified and the limited number of trials. CONCLUSIONS: The evidence from six RCTs suggests that psychological treatments are effective in reducing symptoms of depression and anxiety for people with dementia. There is a need for high quality, multicentre trials including standardised, well-defined interventions. PMID- 26429687 TI - Could Marcus Aurelius be the missing link in the insanity defence? - psychiatry in history. PMID- 26429688 TI - Ethnic differences in BDNF Val66Met polymorphism. PMID- 26429689 TI - Authors' reply. PMID- 26429690 TI - Relevance of 123I-FP-CIT SPECT brain scans in routine clinical settings. PMID- 26429692 TI - Correction. PMID- 26429691 TI - Authors' reply. PMID- 26429693 TI - Kaleidoscope. PMID- 26429696 TI - [The femoral vein alternate path as for cardiac pacing final: Experience center]. PMID- 26429697 TI - The role of high flow oxygen therapy in acute respiratory failure. AB - Acute respiratory failure represents one of the most common causes of intensive care unit admission and oxygen therapy remains the first-line therapy in the management of these patients. In recent years, high-flow oxygen via nasal cannula has been described as a useful alternative to conventional oxygen therapy in patients with acute respiratory failure. High-flow oxygen via nasal cannula rapidly alleviates symptoms of acute respiratory failure and improves oxygenation by several mechanisms, including dead space washout, reduction in oxygen dilution and inspiratory nasopharyngeal resistance, a moderate positive airway pressure effect that may generate alveolar recruitment and an overall greater tolerance and comfort with the interface and the heated and humidified inspired gases. However, the experience in adults is still limited and there are no clinical guidelines to establish recommendations for their use. This article aims to review the existing evidence on the use of high-flow oxygen via nasal cannula in adults with acute respiratory failure and its possible applications, advantages and limitations. PMID- 26429698 TI - Fc Receptor-mediated Effector Function Contributes to the Therapeutic Response of Anti-TNF Monoclonal Antibodies in a Mouse Model of Inflammatory Bowel Disease. AB - BACKGROUND AND AIMS: Anti-tumour necrosis factor [TNF] monoclonal antibodies [infliximab, adalimumab] induce complete mucosal healing in a proportion of patients with Crohn's disease whereas a TNF receptor fusion protein [etanercept] is not effective and the anti-TNF F[ab']2 fragment [certolizumab] shows a very low rate of complete mucosal healing. In contrast, all four TNF-neutralising drugs have demonstrated efficacy in the treatment of rheumatoid arthritis. These observations suggest that factors other than neutralisation of TNF may contribute to clinical outcomes in Crohn's disease. Here we tested the hypothesis that Fc receptor [FcR]-mediated effects may contribute to the therapeutic response of anti-TNF antibodies in inflammatory bowel disease. METHODS: We modified an IgG2c mouse anti-TNF antibody that binds the high-affinity FcRs to generate an IgG1 isotype with strongly diminished binding. We examined the therapeutic effects of both antibodies in the T cell transfer model of inflammatory bowel disease and the collagen-induced arthritis model. RESULTS: The IgG2c anti-TNF antibody prevented colonic inflammation in the T cell transfer model of colitis, whereas the IgG1 anti-TNF did not. Conversely, both the IgG2c and IgG1 anti-TNFs were similarly effective in reducing the severity of articular inflammation in mouse collagen-induced arthritis. CONCLUSION: These data support the concept that the mechanism of action for TNF-neutralising drugs may differ across immune-mediated diseases and, potentially, between therapeutics within a particular disease. Our data suggest a specific role of Fc-mediated immune regulation in the resolution of intestinal inflammation by anti-TNF monoclonal antibodies. PMID- 26429699 TI - Shotgun assembly of the mitochondrial genome from Fenneropenaeus penicillatus with phylogenetic consideration. AB - The complete mitochondrial genome is of great importance for better understanding of the genome-level characteristics and phylogenetic relationships among related species. In this study, Fenneropenaeus penicillatus mitochondrial genome sequence was determined by next-generation sequencing. The complete genome DNA was 16,040 bp in length and consisted of a typical set of 13 protein-coding genes, 22 transfer RNA (tRNA) genes, two ribosomal RNA (rRNA) genes and a putative control region (CR). The gene arrangement is identical to the pancrustacean pattern. The overall base composition of its mitochondrial genome is estimated to be 34.1% for A, 34.1% for T, 12.5% for G and 19.3% for C with a high A+T content (68.2%). The analysis of the average Ka/Ks in the 13 mitochondrial protein-coding genes of penaeid shrimps indicated a strong purifying selection within this group. The phylogenetic analysis based on mitochondrial sequences and 13 concatenated protein-coding genes showed strong statistic support for the following relationship among the five genera ((Penaeus s.s+Fenneropenaeus)+(Litopenaeus+Farfantepenaeus))+Marsupenaeus. The sequence data of F. penicillatus can provide useful information for the studies on molecular systematics, population structure, stock evaluation and conservation genetics. PMID- 26429701 TI - Prevention of malaria in pregnancy: a fork in the road? PMID- 26429700 TI - Intermittent screening and treatment or intermittent preventive treatment with dihydroartemisinin-piperaquine versus intermittent preventive treatment with sulfadoxine-pyrimethamine for the control of malaria during pregnancy in western Kenya: an open-label, three-group, randomised controlled superiority trial. AB - BACKGROUND: Every year, more than 32 million pregnancies in sub-Saharan Africa are at risk of malaria infection and its adverse consequences. The effectiveness of the intermittent preventive treatment with sulfadoxine-pyrimethamine strategy recommended by WHO is threatened by high levels of parasite resistance. We aimed to assess the efficacy and safety of two alternative strategies: intermittent screening with malaria rapid diagnostic tests and treatment of women who test positive with dihydroartemisinin-piperaquine, and intermittent preventive treatment with dihydroartemisinin-piperaquine. METHODS: We did this open-label, three-group, randomised controlled superiority trial at four sites in western Kenya with high malaria transmission and sulfadoxine-pyrimethamine resistance. HIV-negative pregnant women between 16 and 32 weeks' gestation were randomly assigned (1:1:1), via computer-generated permuted-block randomisation (block sizes of three, six, and nine), to receive intermittent screening and treatment with dihydroartemisinin-piperaquine, intermittent preventive treatment with dihydroartemisinin-piperaquine, or intermittent preventive treatment with sulfadoxine-pyrimethamine. Study participants, study clinic nurses, and the study coordinator were aware of treatment allocation, but allocation was concealed from study investigators, delivery unit nurses, and laboratory staff. The primary outcome was malaria infection at delivery, defined as a composite of peripheral or placental parasitaemia detected by placental histology, microscopy, or rapid diagnostic test. The primary analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01669941. FINDINGS: Between Aug 21, 2012, and June 19, 2014, we randomly assigned 1546 women to receive intermittent screening and treatment with dihydroartemisinin-piperaquine (n=515), intermittent preventive treatment with dihydroartemisinin-piperaquine (n=516), or intermittent preventive treatment with sulfadoxine-pyrimethamine (n=515); 1368 (88%) women comprised the intention-to-treat population for the primary endpoint. Prevalence of malaria infection at delivery was lower in the intermittent preventive treatment with dihydroartemisinin-piperaquine group than in the intermittent preventive treatment with sulfadoxine-pyrimethamine group (15 [3%] of 457 women vs 47 [10%] of 459 women; relative risk 0.32, 95% CI 0.18-0.56; p<0.0001), but not in the intermittent screening and treatment with dihydroartemisinin-piperaquine group (57 [13%] of 452 women; 1.23, 0.86-1.77; p=0.26). Compared with intermittent preventive treatment with sulfadoxine pyrimethamine, intermittent preventive treatment with dihydroartemisinin piperaquine was associated with a lower incidence of malaria infection during pregnancy (192.0 vs 54.4 events per 100 person-years; incidence rate ratio [IRR] 0.28, 95% CI 0.22-0.36; p<0.0001) and clinical malaria during pregnancy (37.9 vs 6.1 events; 0.16, 0.08-0.33; p<0.0001), whereas intermittent screening and treatment with dihydroartemisinin-piperaquine was associated with a higher incidence of malaria infection (232.0 events; 1.21, 1.03-1.41; p=0.0177) and clinical malaria (53.4 events; 1.41, 1.00-1.98; p=0.0475). We recorded 303 maternal and infant serious adverse events, which were least frequent in the intermittent preventive treatment with dihydroartemisinin-piperaquine group. INTERPRETATION: At current levels of rapid diagnostic test sensitivity, intermittent screening and treatment is not a suitable alternative to intermittent preventive treatment with sulfadoxine-pyrimethamine in the context of high sulfadoxine-pyrimethamine resistance and malaria transmission. However, dihydroartemisinin-piperaquine is a promising alternative drug to replace sulfadoxine-pyrimethamine for intermittent preventive treatment. Future studies should investigate the efficacy, safety, operational feasibility, and cost effectiveness of intermittent preventive treatment with dihydroartemisinin piperaquine. FUNDING: The Malaria in Pregnancy Consortium, which is funded through a grant from the Bill & Melinda Gates Foundation to the Liverpool School of Tropical Medicine. PMID- 26429702 TI - Rescue microsurgery with bypass and stent removal following Pipeline treatment of a giant internal carotid artery terminus aneurysm. AB - We report the microsurgical rescue and removal of a Pipeline stent embolization of a giant internal carotid artery terminus aneurysm. After the initial placement of a Pipeline Embolization Device (PED), it migrated proximally to the cavernous carotid with the distal end free in the middle of the aneurysm, resulting in only partial aneurysm neck coverage. The patient underwent microsurgical rescue with trapping, bypass, and opening of the aneurysm with PED removal. The vessel remained patent in the proximal segment previously covered by the Pipeline stent. Microsurgical rescue for definitive aneurysm treatment with PED removal can be safe and effective for aneurysms unsuccessfully treated with PED. PMID- 26429703 TI - Reply letter to the editor: the continuing story of George Gershwin and his brain tumor--would the outcome have been different today? PMID- 26429704 TI - Economic burden and catastrophic cost among people living with type2 diabetes mellitus attending a tertiary health institution in south-east zone, Nigeria. AB - BACKGROUND: Diabetes mellitus (DM) is a life-long illness that affects the quality of life, requiring close monitoring and control. Type 2 DM is preventable and controllable but increasing cost of care could hinder access to quality care because of inability to pay leading to high morbidity, mortality and productivity losses. The people living with diabetes mellitus (PLWD) in Nigeria have high risk for high economic burden and catastrophic expenditure not only because they make frequent visits to the health facilities, report late with complications but also pay out of pocket at the point of accessing care. The aim of this study was to assess the magnitude of economic burden borne and catastrophic costs incurred by PLWD in Nigeria. METHODS: Cross-sectional descriptive survey design was used to study a sample of 308 type2 PLWD managed at a tertiary health institution, South east Nigeria using semi-structured, prevalidated questionnaire. Data collection period was 2 months. RESULTS: The major findings were economic burden of type 2 DM of N56,245 ($356). Catastrophic direct cost was 45 % at 30 % threshold (the determinant level for catastrophic spending set). All socio-economic status (SES) groups suffered catastrophic expenditure but the poorest quartile had the highest incidence. CONCLUSIONS: Economic burden of DM was high for PLWD who also suffered high catastrophic costs due to the impact of out of pocket payment. PLWD need financial protection especially for the poorest since they buy from the same market and incur same costs. Policy decision making to assist the PLWD cope with cost of care is needful in Nigeria and nations with related problems. PMID- 26429705 TI - Social determinants of duration of last nursing home stay at the end of life in Switzerland: a retrospective cohort study. AB - BACKGROUND: Due to demographic ageing and increasing life expectancy, a growing demand for long-term nursing home care can be expected. Stays in nursing homes appear to be more socially determined than hospital stays. We therefore looked at the impact of socio-demographic and health care variables on the length of the last nursing home stay. METHODS: Nationwide individual data from nursing homes and hospitals in Switzerland were linked with census and mortality records. Gender-specific negative binomial regression models were used to analyze N = 35,739 individuals with an admission age of at least 65 years and deceased in 2007 or 2008 in a nursing home. RESULTS: Preceding death, men spent on average 790 days and women 1250 days in the respective nursing home. Adjusted for preceding hospitalizations, care level, cause of death and multimorbidity, a low educational level, living alone or being tenant as well as a low care level at the admission time increased the risk for longer terminal stays. Conversely, a high educational level, being homeowner, being married as well as a high care level at the admission time decreased the risk for longer stays. DISCUSSION: The length of the last nursing home stay before death was not only dependent on health-related factors alone, but also substantially depended on socio demographic determinants such as educational level, homeownership or marital status. The support of elderly people at the admission time of a presumably following nursing home stay should be improved and better evaluated in order to reduce unnecessary and undesired long terminal nursing home stays. CONCLUSIONS: Health policy should aim at diminishing the role of situational, non-health related factors in order to empower people to spend the last years before death according to individual needs and preferences. PMID- 26429706 TI - Idiopathic Inflammatory Myopathies and Malignancy: a Comprehensive Review. AB - The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of autoimmune diseases (collectively known as myositis) affecting the skeletal muscles as well as other organ systems such as skin, lungs, and joints. The primary forms of myositis include polymyositis (PM), dermatomyositis (PM), and immune-mediated necrotizing myopathy (IMNM). Patients with these diseases experience progressive proximal muscle weakness, have characteristic muscle biopsy findings, and produce autoantibodies that are associated with unique clinical features. One distinguishing feature of these patients is that they are also known to have an increased risk of cancer. Since the first description of the association in 1916, it has been extensively reported in the medical literature. However, there have been significant variations between the different studies with regard to the degree of cancer risk in patients with IIM. These discrepancies can, in part, be attributed to differences in the definition of malignancy-associated myositis used in different studies. In recent years, significant advances have been made in defining specific features of IIM that are associated with the development of malignancy. One of these has been myositis specific antibodies (MSAs), which are linked to distinct clinical phenotypes and categorize patients into groups with more homogeneous features. Indeed, patients with certain MSAs seem to be at particularly increased risk of malignancy. This review attempts a systematic evaluation of research regarding the association between malignancy and myositis. PMID- 26429707 TI - Idiopathic Inflammatory Myopathies: an Update on Classification and Treatment with Special Focus on Juvenile Forms. AB - Juvenile inflammatory myopathies represent a heterogeneous group of rare and potentially fatal disorders of unknown aetiology, characterised by inflammation and proximal and symmetric muscle weakness. Beyond many similarities, specific clinical, laboratoristic and histopathologic features underlie different subsets with distinguishing demographic, prognostic and therapeutic peculiarities. Over time, several forms of inflammatory idiopathic myopathies have been described, including macrophagic myofascitis, immune-mediated necrozing myopathy and the spectrum of amyopathic dermatomyositis that include hypomyopathic dermatomyositis, inclusion body myositis and cancer-associated myositis occurring almost exclusively in adults. However, juvenile dermatomyositis is the most frequent in childhood, whereas polymyositis is relatively more frequent in adults. The aetiology is nowadays widely unclear; however, current theories contemplate a combination of environmental triggers, immune dysfunction and specific tissue responses involving muscle, skin and small vessels endothelium in genetically susceptible individuals. Myositis-specific autoantibodies, found almost exclusively in patients with myositis and myositis-associated autoantibodies, detectable both among patients with myositis and in subjects suffering from other autoimmune diseases, have an important clinical role because of their relation to specific clinical features, response to therapy and prognosis. The gold standard treatment for juvenile dermatomyositis is represented by corticosteroids, along with adjunctive steroid-sparing immunosuppressive therapies, which are used to counteract disease activity, prevent mortality, and reduce long-term disability. Further treatment approach such as biologic agents and autologous stem cell transplantation are emerging during the last years, in particular in patients difficult to treat and with poor prognosis. Therefore, a highly medical specialised approach is required for diagnosis and management of these conditions. This review comprehensively examines juvenile inflammatory myopathies focusing on clinical and laboratory classifications as well as on the current treatment approaches, referring in particular on biologic agents and latest therapeutic opportunities. PMID- 26429708 TI - TumorTracer: a method to identify the tissue of origin from the somatic mutations of a tumor specimen. AB - BACKGROUND: A substantial proportion of cancer cases present with a metastatic tumor and require further testing to determine the primary site; many of these are never fully diagnosed and remain cancer of unknown primary origin (CUP). It has been previously demonstrated that the somatic point mutations detected in a tumor can be used to identify its site of origin with limited accuracy. We hypothesized that higher accuracy could be achieved by a classification algorithm based on the following feature sets: 1) the number of nonsynonymous point mutations in a set of 232 specific cancer-associated genes, 2) frequencies of the 96 classes of single-nucleotide substitution determined by the flanking bases, and 3) copy number profiles, if available. METHODS: We used publicly available somatic mutation data from the COSMIC database to train random forest classifiers to distinguish among those tissues of origin for which sufficient data was available. We selected feature sets using cross-validation and then derived two final classifiers (with or without copy number profiles) using 80 % of the available tumors. We evaluated the accuracy using the remaining 20 %. For further validation, we assessed accuracy of the without-copy-number classifier on three independent data sets: 1669 newly available public tumors of various types, a cohort of 91 breast metastases, and a set of 24 specimens from 9 lung cancer patients subjected to multiregion sequencing. RESULTS: The cross-validation accuracy was highest when all three types of information were used. On the left out COSMIC data not used for training, we achieved a classification accuracy of 85 % across 6 primary sites (with copy numbers), and 69 % across 10 primary sites (without copy numbers). Importantly, a derived confidence score could distinguish tumors that could be identified with 95 % accuracy (32 %/75 % of tumors with/without copy numbers) from those that were less certain. Accuracy in the independent data sets was 46 %, 53 % and 89 % respectively, similar to the accuracy expected from the training data. CONCLUSIONS: Identification of primary site from point mutation and/or copy number data may be accurate enough to aid clinical diagnosis of cancers of unknown primary origin. PMID- 26429710 TI - From 2D to 3D--a New Dimension for Modelling the Effect of Natural Products on Human Tissue. AB - Natural products, or their synthetic derivatives are a treasure trove to find potential candidates for novel drugs for human treatment. The selection of diamonds from the huge pile of worthless stone is a critical--and difficult- stage in the discovery pipeline. Of all the factors to be considered, perhaps the most important, is that the compound should have the desired effect on the tissue in vivo. Since it is not possible (or ethical) to test all compounds in vivo one must preselect using a surrogate assay system. While animal models have the advantage of being holistic and current 3D culture systems are reductionistic, they at least can be constructed from human cell types. In this review we will consider some of the evidence demonstrating that cells grown in 3D cultures have physiological performances that mimic functions seen in human tissues significantly better than cells grown using classical 2D culture systems. We will discuss advantages and disadvantages of these new culture technologies and highlight theoretical reasons for the differences. 3D cell culture technologies are more labour intensive than 2D culture systems and therefore their introduction is a trade-off between the value of obtaining data that is more relevant to the human condition against their through-put. It is already clear that future in vitro 3D systems will become more complex, using multiple cell types to more faithfully represent a particular tissue or even organ system. And one thing is sure - the diamonds are not easy to find! PMID- 26429709 TI - Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with irinotecan: results of an open-label, phase 1 study. AB - PURPOSE: The oral Bcl-2 inhibitor navitoclax demonstrated activity in solid and hematologic malignancies as monotherapy and in combination with other cytotoxic agents in preclinical and early clinical studies. We evaluated the safety, pharmacokinetics (PK), and antitumor activity of navitoclax plus irinotecan. METHODS: In this multicenter, open-label, phase 1 dose escalation study, adults with advanced solid tumors received navitoclax (starting dose 150 mg/day) in combination with 1 of 2 irinotecan schedules during a 21-day cycle: a once-every 3-week regimen (Q3W 180, 250, or 350 mg/m(2)) or a once-weekly regimen (QW 75 or 100 mg/m(2)). Enrollment occurred until a maximum tolerated dose (MTD) and/or recommended phase 2 dose (RPTD) was reached. RESULTS: All patients (Q3W, n = 14; QW, n = 17) were evaluable for safety, PK, and efficacy. The most common adverse event in both groups was diarrhea (Q3W 92.9 %; QW 76.5 %), which was the most frequent grade 3/grade 4 adverse event (Q3W 42.9 %; QW 29.4 %). The study was amended to exclude 4 UGT1A1*28 7/7 homozygous patients due to frequent irinotecan related grade 3/grade 4 diarrhea and/or febrile neutropenia. No apparent PK interactions between navitoclax and irinotecan were observed. The MTD of the combination was exceeded in the Q3W group at the lowest dose administered. In the QW group, the MTD and RPTD for navitoclax were 150 mg when combined with irinotecan 75 mg/m(2). One patient in each group achieved a partial response. CONCLUSION: The RPTD of navitoclax in combination with irinotecan 75 mg/m(2) QW during a 21-day cycle was 150 mg in these heavily pretreated patients. PMID- 26429711 TI - New Approaches With Natural Product Drugs for Overcoming Multidrug Resistance in Cancer. AB - Resistance to chemotherapeutic drugs is one of the main obstacles to effective cancer treatment. Multidrug resistance (MDR) is defined as resistance to structurally and/or functionally unrelated drugs, and has been extensively investigated for the last three decades. There are two types of MDR: intrinsic and acquired. Tumor microenvironment selection pressure leads to the development of intrinsic MDR, while acquired resistance is a consequence of the administered chemotherapy. A central issue in chemotherapy failure is the existence of heterogeneous populations of cancer cells within one patient and patient-to patient variability within each type of cancer. Numerous genes and pathways contribute to the development of MDR in cancer. Point mutations, gene amplification or other genetic or epigenetic changes all affect biological functions and may lead to the occurrence of MDR phenotype. Similar to the characteristics of cancerogenesis, the main features of MDR include abnormal tumor vasculature, regions of hypoxia, aerobic glycolysis, and a lower susceptibility to apoptosis. In order to achieve a lethal effect on cancer cells, drugs need to reach their intracellular target molecules. The overexpression of the efflux transporter P-glycoprotein (P-gp) in MDR cancer cells leads to decreased uptake of the drug and intracellular drug accumulation, minimising drug target interactions. New agents being or inspired by natural products that successfully target these mechanisms are the main subject of this review. Two key approaches in combating MDR in cancer are discussed (i) finding agents that preserve cytotoxicity toward MDR cancer cells; (ii) developing compounds that restore the cytotoxic activity of classic anticancer drugs. PMID- 26429713 TI - Natural Products and Cancer Stem Cells. AB - The development of modern technologies casts a new light on the natural products as an invaluable source of lead compounds that could guide drug discovery. Cancer stem cells are a subpopulation of cancer cells with a high clonogenic capacity and the ability to reform the parental tumours upon transplantation. They have been proposed to drive tumorigenesis and metastases. In this review, we present the ability of forty-nine different natural products to influence the biology of cancer stem cells. PMID- 26429712 TI - Natural Products as Promising Therapeutics for Treatment of Influenza Disease. AB - The influenza virus represents a permanent global health threat because it circulates not only within but also between numerous host populations, thereby frequently causing unexpected outbreaks in animals and humans with a generally unpredictable course of disease and epidemiology. Conventional influenza therapy is directed against the viral neuraminidase protein, which promotes virus release from infected cells, and the viral ion channel M2, which facilitates viral uncoating. However, these drugs, albeit effective, have a major drawback: their targets are of a highly variable sequence. As a consequence, the virus can readily acquire resistance by mutating the drug targets. Indeed, most seasonal A/H1N1 viruses and the 2009 H1N1 virus are resistant to M2 inhibitors, and a significant proportion of the seasonal A/H1N1 viruses are resistant to the neuraminidase inhibitor oseltamivir. Development of new effective drugs for treatment of disease during the regular influenza seasons and the possible influenza pandemic represents an important goal. The results presented here point out natural products as a promising source of low toxic and widely accessible drug candidates for treatment of the influenza disease. Natural products combined with new therapeutic targets and drug repurposing techniques, which accelerate development of new drugs, serve as an important platform for development of new influenza therapeutics. PMID- 26429714 TI - Indolo[2,3-a]quinolizidines and Derivatives: Bioactivity and Asymmetric Synthesis. AB - Corynantheine alkaloids with a tetracyclic indole[2,3-a]-quinolizidine motif are an important issue in academia and in the life science industries due to their broad bioactivity profile. In particular, the main biological effects described for indoloquinolizidines include analgesic, anti-inflammatory, antihypertensive, and antiarrhythmic activities, as well as inhibition of multiple ion channels, affinity for opioid receptors, and activity against Leishmania. For that reason, in the last decades, numerous efforts have been invested in the development of novel synthetic strategies to obtain the indole[2,3-a]-quinolizidine system. This review focuses on the synthetic methodologies developed to target the most important alkaloids of this family, and highlights the potential use of these alkaloids or analogs to treat several diseases, ranging from cancer to neurodegenerative disorders. PMID- 26429715 TI - Thapsigargin, Origin, Chemistry, Structure-Activity Relationships and Prodrug Development. AB - Thapsigargin was originally isolated from the roots of the Mediterranean umbelliferous plant Thapsia garganica in order to characterize the skin irritant principle. Characteristic chemical properties and semi-syntheses are reviewed. The biological activity was related to the subnanomolar affinity for the sarco/endoplasmic reticulum calcium ATPase. Prolonged inhibition of the pump afforded collapse of the calcium homeostasis and eventually apoptosis. Structure activity relationships enabled design of an equipotent analogue containing a linker. Conjugation of the analogue containing the linker with peptides, which only are substrates for either prostate specific antigen (PSA) or prostate specific membrane antigen (PSMA) enabled design of prodrugs targeting a number of cancer diseases including prostate cancer (G115) and hepatocellular carcinoma (G202). Prodrug G202 has under the name of mipsagargin in phase II clinical trials shown promising properties against hepatocellular carcinoma. PMID- 26429716 TI - "Non-Taxifolin" Derived Flavonolignans: Phytochemistry and Biology. AB - Flavonolignans are plant natural products, composed of a flavonoid moiety and a lignan (phenylpropanoid) part. Current literature focuses on flavonolignans formed from taxifolin and coniferyl alcohol as e.g. silybin and its congeners from fruit extract from the purple variety of the milk thistle (Silybum marianum) denoted as "silymarin". This review describes chemistry and biological activity of so far neglected "non-taxifolin" based flavonolignans, derived from apigenin, luteolin, tricin, chrysoeriol, naringenin and eriodictyol, as the flavonoid part. Up-to-date knowledge on hydnocarpin, hydnocarpin-D, pseudotsuganol, hydnowightin, neohydnocarpin, palstatin, salcolins A and B, anastatins A and B, sinaiticin, silyamandin and silandrin is summarized in the present paper. Most of non taxifolin derived flavonolignans have been shown to exhibit in vitro and/or in vivo anti-hepatotoxic, anti-oxidant, free radical scavenging, anti-inflammatory, anti-proliferative, anti-cancer, chemotherapy potentiating, anti-melanogenic, anti-bacterial, vasorelaxing, anti-platelet aggregation and/or hypotriglyceridemic activity, often stronger than silybin. Many of these compounds inhibited Staphylococcus aureus multidrug resistance pump NorA and sensitized multidrug resistant cancer cell lines showing a potential as adjuvants. Non-taxifolin derived flavonolignans are a relatively unexplored group of compounds with interesting biological activity and great application potential. Their detailed study could provide a new insight into the biomimetic synthesis in order to obtain new compounds with greater activity and identify new lead structures for the biomedicinal research. PMID- 26429717 TI - Xenicane Natural Products: Biological Activity and Total Synthesis. AB - The xenicanes are a large class of mostly bicyclic marine diterpenoids featuring a cyclononane ring as a common structural denominator. After a brief introduction into the characteristic structural features of xenicanes and some biogenetic considerations, the major focus of this review will be on the various biological activities that have been reported for xenicanes and on efforts towards the total synthesis of these structures. Several xenicanes have been shown to be potent antiproliferative agents in vitro, but activities have also been reported in relation to inflammatory processes. However, so far, data on the possible in vivo activity of xenicanes are lacking. The major challenge in the total synthesis of xenicanes is the construction of the nine-membered ring. Different strategies have been pursued to establish this crucial substructure, including Grob fragmentation, ring-closing olefin metathesis, or Suzuki cross coupling as the enabling transformations. PMID- 26429718 TI - Synthesis and Pharmacological Effects of the Anti-Cancer Agent 2 Methoxyestradiol. AB - The endogenous steroid 2-methoxyestradiol (2-ME) is a metabolite of 17beta estradiol and its biosynthesis is well established. Moreover, 2-ME is also biosynthesized from estrone. For several years, 2-ME was perceived as an inactive metabolite devoid of any interesting biological activities. Since the late 1980s, a number of biological and pharmacological studies have revealed that 2-ME possesses interesting anti-cancer effects without any undesirable estrogen activity. In particular, the anti-vascular effects and anti-angiogenic activities that 2-ME exhibit, are of great interest and importance, in view of the development of new anti-cancer drugs based on 2-ME. Several clinical trial development programs have been initiated using the steroid 2-ME. In addition, based on the many pharmacological activities reported for 2-ME, but also due to the general interest in total and semi-synthesis of endogenous steroids, several research groups working with organic synthesis have prepared this steroid. Herein, the anti-cancer effects, the results from the clinical trial development programs and the synthetic studies towards 2-ME, are reviewed. PMID- 26429719 TI - Pentoxifylline-Induced Thrombocytopenia: A Case Report. AB - Pentoxifylline-induced thrombocytopenia is rare, and information is lacking about its presentation. We describe a 72-year-old Chinese male who developed thrombocytopenia after initiation of pentoxifylline for the treatment of chronic lower limb ischemia due to peripheral artery disease. Venous thromboembolism had been ruled out with an ultrasound. Vascular surgeons had also determined there was no indication for surgical intervention. Four days after initiation of pentoxifylline, he developed thrombocytopenia, and his platelets were 68 * 10(3)/MUL. He was not in overt disseminated intravascular coagulation (DIC), based on his International Society for Thrombosis and Hemostasis (ISTH) DIC score of 4. Dengue fever, which is endemic in Singapore, was ruled out. Pseudothrombocytopenia was also excluded with a peripheral blood film. When his platelets continued to fall, pentoxifylline was discontinued on the fifth day of treatment, and platelets normalized 48 hours after discontinuation. Pentoxifylline was a probable cause of thrombocytopenia using the Naranjo Adverse Drug Reaction Probability Scale (score = 7). The patient did not receive further doses of pentoxifylline. Prescribers should be aware of the risk of thrombocytopenia with pentoxifylline therapy and discontinue its use promptly if it is suspected. PMID- 26429720 TI - Outcomes of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion in Patients with High-Grade, High-Volume Disseminated Mucinous Appendiceal Neoplasms. AB - BACKGROUND: High-grade (HG) mucinous appendiceal neoplasms (MAN) have a worse prognosis than low-grade histology. Our objective was to assess the safety and efficacy of cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS/HIPEC) in patients with high-grade, high-volume (HG-HV) peritoneal metastases in whom the utility of this aggressive approach is controversial. METHODS: Prospectively collected perioperative data were compared between patients with peritoneal metastases from HG-HV MAN, defined as simplified peritoneal cancer index (SPCI) >=12, and those with high-grade, low-volume (HG LV; SPCI <12) disease. Kaplan-Meier curves and multivariate Cox regression models identified prognostic factors affecting oncologic outcomes. RESULTS: Overall, 54 patients with HG-HV and 43 with HG-LV peritoneal metastases underwent CRS/HIPEC. The HG-HV group had longer operative time, increased blood loss/transfusion, and increased intensive care unit length of stay (p < 0.05). Incomplete macroscopic cytoreduction (CC-1/2/3) was higher in the HG-HV group compared with the HG-LV group (68.5 vs. 32.6 %; p = 0.005). Patients with HG-HV disease demonstrated worse survival than those with HG-LV disease (overall survival [OS] 17 vs. 42 m, p = 0.009; time to progression (TTP) 10 vs. 14 m, p = 0.024). However, when complete macroscopic resection (CC-0) was achieved, the OS and progression-free survival of patients with HG-HV disease were comparable with HG-LV disease (OS 56 vs. 52 m, p = 0.728; TTP 20 vs. 19 m, p = 0.393). In a multivariate Cox proportional hazard regression model, CC-0 resection was the only significant predictor of improved survival for patients with HG-HV disease. CONCLUSIONS: Although patients with HG-HV peritoneal metastases from MAN have worse prognosis compared with patients with HG-LV disease, their survival is comparable when complete macroscopic cytoreduction is achieved. PMID- 26429721 TI - Brevibacterium metallicus sp. nov., an endophytic bacterium isolated from roots of Prosopis laegivata grown at the edge of a mine tailing in Mexico. AB - A Gram-positive, aerobic, nonmotile strain, NM2E3(T) was identified as Brevibacterium based on the 16S rRNA gene sequence analysis and had the highest similarities to Brevibacterium jeotgali SJ5-8(T) (97.3 %). This novel bacterium was isolated from root tissue of Prosopis laegivata grown at the edge of a mine tailing in San Luis Potosi, Mexico. Its cells were non-spore-forming rods, showing catalase and oxidase activities and were able to grow in LB medium added with 40 mM Cu(2+), 72 mM As(5+) and various other toxic elements. Anteiso-C15:0 (41.6 %), anteiso-C17:0 (30 %) and iso-C15:0 (9.5 %) were the major fatty acids. MK-8(H2) (88.4 %) and MK-7(H2) (11.6 %) were the major menaquinones. The DNA G + C content of the strain NM2E3(T) was 70.8 mol % (Tm). DNA-DNA hybridization showed that the strain NM2E3(T) had 39.8, 21.7 and 20.3 % relatedness with B. yomogidense JCM 17779(T), B. jeotgali JCM 18571(T) and B. salitolerans TRM 45(T), respectively. Based on the phenotypic and genotypic analyses, the strain NM2E3(T) (=CCBAU 101093(T) = HAMBI 3627(T) = LMG 8673(T)) is reported as a novel species of the genus Brevibacterium, for which the name Brevibacterium metallicus sp. nov., is proposed. PMID- 26429722 TI - Metaboreflex activity in multiple sclerosis patients. AB - PURPOSE: The muscle metaboreflex activation has been shown essential to reach normal hemodynamic response during exercise. It has been demonstrated that patients with multiple sclerosis (MS) have impaired autonomic functions and cardiovascular regulation during exercise. However, to the best of our knowledge, no previous research to date has studied the metaboreflex in MS patients. The purpose of this study was to investigate the hemodynamic response to metaboreflex activation in patients with MS (n = 43) compared to an age-matched, control group (CTL, n = 21). METHODS: Cardiovascular response during the metaboreflex was evaluated using the post-exercise muscle ischemia (PEMI) method and during a control exercise recovery (CER) test. The difference in hemodynamics between the PEMI and the CER test was calculated and this procedure allowed for the assessment of the metaboreflex response. Hemodynamics was estimated by impedance cardiography. RESULTS: The MS group showed a normal mean blood pressure (MBP) response as compared to the CTL group (+6.5 +/- 6.9 vs. +8 +/- 6.8 mmHg, respectively), but this response was achieved with an increase in systemic vascular resistance, that was higher in the MS with respect to the CTL group (+137.6 +/- 300.5 vs. -14.3 +/- 240 dyne . s(-1) cm(-5), respectively). This was the main consequence of the MS group's incapacity to raise the stroke volume ( 0.65 +/- 10.6 vs. +6.2 +/- 12.8 ml, respectively). CONCLUSION: It was concluded that MS patients have an impaired capacity to increase stroke volume (SV) in response to low level metaboreflex, even if they could sustain the MBP response by vasoconstriction. This was probably a consequence of their chronic physical de conditioning. PMID- 26429723 TI - A slouched body posture decreases arm mobility and changes muscle recruitment in the neck and shoulder region. AB - PURPOSE: Long-term use of unfavorable postures, congenital deformations and degenerative processes associated with aging or disease may generate an increased thoracic curvature resulting in pain and disability. We wanted to examine whether a slouched postural alignment with increased thoracic kyphosis changes the shoulder kinematics and muscle activity in upper trapezius (UT), lower trapezius (LT) and serratus anterior (SA) during arm elevation. The aim was to determine if a slouched posture influences range of motion, muscle activation patterns, maximal muscle activity and the total muscle work required when performing arm elevations. METHOD: Twelve male subjects (23.3 +/- 1.5 years) performed maximum arm elevations in upright and slouched postures. A combined 3D movement and EMG system recorded arm movements and spine curvature simultaneously with EMG activity in the UT, LT and SA. RESULTS: Slouched posture affected the biomechanical conditions by significantly decreasing maximum arm elevation by ~15 degrees (p < 0.001) and decreasing arm movement velocity by ~8 % during movements upwards (p < 0.001) and downwards (p = 0.034). The peak muscle activity increased in all muscles: UT (p = 0.034, +32.3 %), LT (p = 0.001, +48.6 %) and SA (p = 0.007, +20.9 %). The total muscle work increased significantly in the slouched posture during movements upwards: UT (p = 0.003, +36.6 %), LT (p < 0.001, +89.0 %), SA (p = 0.002, +19.4 %) and downwards: UT (p = 0.012, +29.8 %) and LT (p < 0.001, +122.5 %). CONCLUSION: An increased thoracic kyphosis was found associated with marked increased physical costs when performing arm movements. Hence, patients suffering from neck-shoulder pain and disability should be investigated and treated for defective thoracic curvature issues. PMID- 26429724 TI - GNL3 and SKA3 are novel prostate cancer metastasis susceptibility genes. AB - Prostate cancer (PC) is very common in developed countries. However, the molecular determinants of PC metastasis are unclear. Previously, we reported that germline variation influences metastasis in the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of PC. These mice develop prostate tumors similar to a subset of poor outcome, treatment-associated human PC tumors. Here, we used TRAMP mice to nominate candidate genes and validate their role in aggressive human PC in PC datasets and cell lines. Candidate metastasis susceptibility genes were identified through quantitative trait locus (QTL) mapping in 201 (TRAMP * PWK/PhJ) F2 males. Two metastasis-associated QTLs were identified; one on chromosome 12 (LOD = 5.86), and one on chromosome 14 (LOD = 4.41). Correlation analysis using microarray data from (TRAMP * PWK/PhJ) F2 prostate tumors identified 35 metastasis-associated transcripts within the two loci. The role of these genes in susceptibility to aggressive human PC was determined through in silico analysis using multiple datasets. First, analysis of candidate gene expression in two human PC datasets demonstrated that five candidate genes were associated with an increased risk of aggressive disease and lower disease-free survival. Second, four of these genes (GNL3, MAT1A, SKA3, and ZMYM5) harbored SNPs associated with aggressive tumorigenesis in the PLCO/CGEMS GWAS of 1172 PC patients. Finally, over-expression of GNL3 and SKA3 in the PC-3 human PC cell line decreased in vitro cell migration and invasion. This novel approach demonstrates how mouse models can be used to identify metastasis susceptibility genes, and gives new insight into the molecular mechanisms of fatal PC. PMID- 26429725 TI - Risk factors for renal dysfunction after total hip joint replacement; a retrospective cohort study. AB - BACKGROUND AND PURPOSE OF THE STUDY: Renal injury and dysfunction are serious complications after major surgery, which may lead to increased morbidity and mortality. The objective of our study was to identify the possible risk factors for renal dysfunction after total hip joint replacement surgery. METHODS: A retrospective study was conducted among 599 consecutive primary hip joint replacements performed between January 2011 and December 2013. According to the RIFLE criteria, increased postoperative serum creatinine was considered indicative of postoperative renal injury. The Welch two-sample test, chi-square test, and Fisher exact test were used for statistical analysis. RESULTS: Eighty one patients (13.8%) had significant moderate or severe postoperative renal dysfunction in which 10 patients (1.7%) acquired severe and permanent renal impairment. CONCLUSION: We identified advanced age, hypertension, general anesthesia, high ASA scores, low intra-operative systolic BP, and prophylactic dicloxacillin as significant risk factors. Low baseline systolic BP, low baseline diastolic blood pressure, and hip fracture diagnosis were independent risk factors for postoperative increase in serum creatinine. Smoking, diabetes mellitus, high BMI, gender, and duration of surgery were not identified as significant risk factors. PMID- 26429726 TI - Treatment outcomes for veterans with PTSD and substance use: Impact of specific substances and achievement of abstinence. AB - BACKGROUND: Scant longitudinal data exists about the interplay between specific substances of abuse, the achievement of abstinence, and clinical outcomes in the treatment of dually diagnosed Veterans with post-traumatic stress disorder (PTSD). METHODS: As part of a national program evaluation, Veterans admitted from the community to specialized intensive PTSD programs were assessed at intake and 4 months after discharge. Seven mutually exclusive groups were identified from admission self-report data (N=22,948): no substance use, exclusive use of alcohol, opiates, sedatives, cocaine, marijuana, and use of three or more substances. Analysis of covariance, adjusting for potentially confounding baseline variables was used to compare change among these seven groups in non substance use outcomes (PTSD symptoms, violent behavior, suicidality, medical problems, and employment). The effect of abstinence on specific groups was evaluated as the interaction of group membership by abstinence. RESULTS: All outcome measures except for employment showed significant improvement, with few differences between the groups. Although rate of abstinence differed markedly between the groups, abstinence achievement was associated with greater improvement on all the outcomes except employment in every group. No significant differences in the effect of abstinence across the substance abuse groups were observed. CONCLUSION: The specific type of substance used prior to entry into treatment among dually diagnosed PTSD patients seems to have limited effect on treatment outcomes. However, attainment of abstinence at 4 months after treatment, irrespective of the substances abused, was strongly associated with improvement in PTSD symptoms, violence, suicidality and medical problems. PMID- 26429727 TI - Maternal age and trajectories of cannabis use. AB - BACKGROUND: Becoming a mother is a developmental transition that has been linked to desistance from substance use. However, timing of motherhood may be a key determinant of cannabis use in women, based on preliminary evidence from teenage mothers. The goal of this study was to identify trajectories of maternal cannabis use, and to determine if maternal age was associated with different trajectories of use. METHODS: This prospective study examined 456 pregnant women recruited at a prenatal clinic, ranging in age from 13 to 42 years. The women were interviewed about their cannabis use 1 year prior to pregnancy and during each trimester of pregnancy, and at 6, 10, 14, and 16 years post-partum. RESULTS: A growth mixture model of cannabis use reported at each time point clearly delineated four groups: non/unlikely to use, decreasing likelihood of use, late desistance, and increasing likelihood/chronic use (Lo-Mendell-Rubin adjusted LRT test statistic=35.7, p<.001). The youngest mothers were least likely to be in the "non/unlikely to use" group. Younger maternal age also differentiated between late desistance and increasing likelihood/chronic use, versus decreasing likelihood of use post-partum. CONCLUSIONS: This is the first study to demonstrate that younger mothers are more likely to use cannabis across 17 years, including later desistance post-partum and increasing/chronic use. Other substance use and chronic depressive symptoms were also associated with more frequent use. These findings have implications for both prevention and treatment of cannabis use in mothers. PMID- 26429729 TI - Spirituality Moderates Hopelessness, Depression, and Suicidal Behavior among Malaysian Adolescents. AB - Suicide is an important public health problem for adolescents, and it is essential to increase our knowledge concerning the etiology of suicide among adolescent students. Therefore, this study was designed to examine the associations between hopelessness, depression, spirituality, and suicidal behavior, and to examine spirituality as a moderator between hopelessness, depression, and suicidal behavior among 1376 Malaysian adolescent students. The participants completed measures of depression, hopelessness, daily spiritual experience, and suicidal behavior. Structural equation modeling indicated that adolescent students high in hopelessness and depression, but also high in spirituality, had less suicidal behavior than others. These findings reinforce the importance of spirituality as a protective factor against hopelessness, depression, and suicidal behavior among Malaysian adolescent students. PMID- 26429728 TI - The selective dopamine D3 receptor antagonist, SR 21502, reduces cue-induced reinstatement of heroin seeking and heroin conditioned place preference in rats. AB - BACKGROUND: Because the role of dopamine (DA) D3 receptors has been investigated primarily in relation to cocaine-related behaviors little is known of the role of these receptors in heroin seeking. PURPOSES: To investigate the effect of the selective DA D3 receptor antagonist, SR 21502, on cue-induced reinstatement of heroin seeking and heroin conditioned place preference (CPP). METHODS: In experiment 1, rats were trained to self-administer intravenous heroin for 15 days followed by extinction. Following extinction animals were treated with one of several SR 21502 doses (0, 7.5, 10 or 15mg/kg) and a cue-induced reinstatement test was conducted. In experiment 2, animals were conditioned to experience heroin in one compartment of a CPP apparatus and saline in the other. On the test day animals were treated with 0, 3.75, 7.5, 10 or 15mg/kg of SR 21502 and tested for their CPP. RESULTS: The results from experiment 1 showed a significant dose related reduction in cue-induced reinstatement of active lever pressing in the 7.5 and 10mg groups and an absence of the reinstatement effect in the 15mg group. In experiment 2, animals treated with vehicle or 3.75mg of SR 21502 showed significant heroin place preferences but those treated with the higher doses showed no CPP. CONCLUSIONS: Our findings suggest that DA D3 receptors play a significant role in heroin approach behaviors driven by conditioned stimuli. As such, we propose that SR 21502 holds potential as an effective pharmacotherapeutic agent for relapse prevention and should be studied further. PMID- 26429730 TI - Effect of Religious Beliefs on the Smoking Behaviour of University Students: Quantitative Findings From Malaysia. AB - The Malaysian official Islamic authorities have issued a "fatwa" (Islamic ruling) regarding smoking practice which prohibits Muslims from smoking because of its potential harm to health. Since the prevalence of smoking among Malaysian students is high, this study was designed to explore the perceptions and opinions of Malaysian Muslim students towards smoking in International Islamic University of Malaysia. A prospective, cross-sectional study was conducted among School of Science students in International Islamic University Malaysia. Convenience sampling approach was used to recruit 323 students based on sample size calculation. A content- and face-validated questionnaire was used to collect the data from the participants. Non-smokers highly supported the fatwa on smoking forbiddance than smokers (94 vs 64.3 %, p = 0.001). A significant proportion of non-smokers believed that Islam prohibits smoking because of its potential harm (94.9 vs 71.4 %, p = 0.001). Majority of smokers agreed that addiction is the main barrier towards smoking cessation (78.6 vs 61.5 %, p = 0.019). The results showed positive influences of Islamic beliefs on the non-smokers. Further studies are required to validate these findings by surveying other universities of Malaysia. PMID- 26429732 TI - Biceps Femoris Architecture and Strength in Athletes with a Previous Anterior Cruciate Ligament Reconstruction. AB - PURPOSE: This study aimed to determine whether limbs with a history of anterior cruciate ligament (ACL) injury reconstructed from the semitendinosus display different biceps femoris long head (BFlh) architecture and eccentric strength, assessed during the Nordic hamstring exercise, compared with the contralateral uninjured limb. METHODS: The architectural characteristics of the BFlh were assessed at rest and at 25% of a maximal voluntary isometric contraction (MVIC) in the control group (n = 52) and in the group who had previous ACL injury (n = 15) using two-dimensional ultrasonography. Eccentric knee flexor strength was assessed during the Nordic hamstring exercise. RESULTS: Fascicle length was shorter (P = 0.001; d range, 0.90-1.31) and pennation angle (P range, 0.001 0.006; d range, 0.87-0.93) was greater in the BFlh of the ACL-injured limb compared with those in the contralateral uninjured limb at rest and during a 25% MVIC. Eccentric strength was lower in the ACL-injured limb when compared with the contralateral uninjured limb. Fascicle length, MVIC, and eccentric strength were not different between the left and right limb in the control group. CONCLUSIONS: Limbs with a history of ACL injury reconstructed from the semitendinosus have shorter fascicles and greater pennation angles in the BFlh compared with those of the contralateral uninjured side. Eccentric strength during the Nordic hamstring exercise of the ACL-injured limb is significantly lower than that of the contralateral side. These findings have implications for ACL rehabilitation and hamstring injury prevention practices, which should consider altered architectural characteristics. PMID- 26429731 TI - Double-Edged Roles of Nitric Oxide Signaling on APP Processing and Amyloid-beta Production In Vitro: Preliminary Evidence from Sodium Nitroprusside. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is thought to be caused in part by the age-related accumulation of amyloid-beta (Abeta) in the brain. Recent findings have revealed that nitric oxide (NO) modulates the processing of amyloid-beta precursor protein (APP) and alters Abeta production; however, the previously presented data are contradictory and the underlying molecular mechanisms are still incomplete. Here, using human SH-SY5Y neuroblastoma cells stably transfected with wild-type APPwt695, we found that NO, derived from NO donor sodium nitroprusside (SNP), bi-directionally modulates APP processing in vitro. The data from ELISA and Western blot (WB) tests indicated that SNP at lower concentrations (0.01 and 0.1 MUM) inhibits BACE1 expression, thus consequently suppresses APP beta-cleavage and decreases Abeta production. In contrast, SNP at higher concentrations (10 and 20 MUM) biases the APP processing toward the amyloidogenic pathway as evidenced by an increased BACE1 but a decreased ADAM10 expression, together with an elevated Abeta secretion. This bi directional modulating activity of SNP on APP processing was completely blocked by specific NO scavenger c-PTIO, indicating NO-dependent mechanisms. Moreover, the anti-amyloidogenic activity of SNP is sGC/cGMP/PKG-dependent as evidenced by its reversal by sGC/PKG inhibitions, whereas the amyloidogenic activity of SNP is peroxynitrite-related and can be reversed by peroxynitrite scavenger uric acid. In summary, these present findings predict a double-edged role of NO in APP processing in vitro. Low (physiological) levels of NO inhibit the amyloidogenic processing of APP, whereas extra-high (pathological) concentrations of NO favor the amyloidogenic pathway of APP processing. This preliminary study may provide further evidence to clarify the molecular roles of NO and NO-related signaling in AD and supply potential molecular targets for AD treatment. PMID- 26429733 TI - Seasonal Variation in Children's Physical Activity and Sedentary Time. AB - PURPOSE: Understanding seasonal variation in physical activity is important for informing public health surveillance and intervention design. The aim of the current study was to describe seasonal variation in children's objectively measured physical activity and sedentary time. METHODS: Data are from the UK Millennium Cohort Study. Participants were invited to wear an accelerometer for 7 d on five occasions between November 2008 and January 2010. Outcome variables were sedentary time (<100 counts per minute, min.d(-1)) and moderate to vigorous physical activity (MVPA) (>2241 counts per minute, min.d(-1)). The season was characterized using a categorical variable (spring, summer, autumn, or winter) and a continuous function of day of the year. Cross-classified linear regression models were used to estimate the association of each of these constructs with the outcome variables. Modification of the seasonal variation by sex, weight status, urban/rural location, parental income, and day of the week (weekday/weekend) was examined using interaction terms in regression models. RESULTS: At least one wave of valid accelerometer data was obtained from 704 participants (47% male; baseline age, 7.6 (0.3) yr). MVPA was lower in autumn and winter relative to spring, with the magnitude of this difference varying by weekday/weekend, sex, weight status, urban/rural location, and family income (P for interaction <0.05 in all cases). Total sedentary time was greater in autumn and winter compared with spring; the seasonal effect was stronger during the weekend than during the weekday (P for interaction <0.01). CONCLUSIONS: Lower levels of MVPA and elevated sedentary time support the implementation of intervention programs during autumn and winter. Evidence of greater seasonal variation in weekend behavior and among certain sociodemographic subgroups highlights targets for tailored intervention programs. PMID- 26429734 TI - The Effect of Heterozygosity for the ACTN3 Null Allele on Human Muscle Performance. AB - alpha-Actinin-3 is primarily expressed in fast (Type II) fibers in the human skeletal muscle. Over 70% of the global population has at least one copy of a loss of function allele because of a premature stop codon in the ACTN3 gene (R577X). Homozygosity for this variant (577XX) occurs in approximately 16% of humans worldwide and results in complete alpha-actinin-3 deficiency, which is detrimental to sprint/power performance and alters adaptation to changing physical demands. The functional implications of alpha-actinin-3 deficiency have been the subject of over 90 studies; however, the effect of heterozygosity for the ACTN3 null allele is not well documented or understood. PURPOSE: We reviewed the literature to focus on the most common ACTN3 genotype (577RX) and its effect on human muscle performance. Specifically, we aimed to determine whether the ACTN3 X allele exerts its effect on human performance only when two copies are present (i.e., in an autosomal recessive fashion). RESULTS: Across a spectrum of conditions, three genotype models (additive, dominant, and recessive) were reported. Most studies assessing healthy adults demonstrated that 577RX heterozygotes performed intermediately (additive model) and/or similarly to the RR genotypes (recessive model). Other studies, (aging, disease/injury, elite sprint performance) showed no definitive genetic model. CONCLUSIONS: Assessment of the biological link between dosage, regulation, and function for each ACTN3 genotype is required to improve our understanding of its functional effect and biological penetrance in healthy, aging, and disease populations. PMID- 26429735 TI - A case control study of sarcosine as an early prostate cancer detection biomarker. AB - BACKGROUND: Sarcosine has been investigated as a prostate cancer biomarker with mixed results concerning its predictive power. We performed a case-control evaluation of the predictive value of serum sarcosine for early detection in a population-based cohort of men undergoing prostate-specific antigen (PSA) screening. METHODS: For analysis we used 251 cancer cases and 246 age-matched non cancer cases from the San Antonio Biomarkers Of Risk (SABOR) screening study. For cancer cases, pre-diagnostic serum was utilized for sarcosine measurement. Controls were defined as men who had been followed at least for 5 years on study with no prostate cancer diagnosis; sarcosine was measured on the initial baseline serum. HPLC-electrospray ionization mass spectrometry was used for serum sarcosine quantification. The association of sarcosine with prostate cancer was assessed using area underneath the receiver-operating characteristic curve (AUC), and logistic regression adjusting for PSA, digital rectal exam, family history, age, race, and history of a prior negative biopsy. Among cancer cases, nominal logistic regression was used for the association of sarcosine with Gleason grade. RESULTS: Sarcosine levels were overlapping between the prostate cancer cases (median 15.8 uM, range 6.2 to 42.5 uM) and controls (median 16.2 uM, range 6.4 to 53.6 uM). The AUC of sarcosine was not statistically different from random chance either for participants with any PSA value (52.2 %) or those with PSA values in the range of 2 to 10 ng/mL (54.3 %). Sarcosine was not predictive of Gleason score and added no independent predictive power to standard prostate cancer risk factors for detection of prostate cancer (all p-values > 0.05). CONCLUSIONS: Serum sarcosine should not be pursued further as a marker for the early detection of prostate cancer. PMID- 26429736 TI - Utility of immune response-derived biomarkers in the differential diagnosis of inflammatory disorders. AB - Differentiating between inflammatory disorders is difficult, but important for a rational use of antimicrobial agents. Biomarkers reflecting the host immune response may offer an attractive strategy to predict the etiology of an inflammatory process and can thus be of help in decision making. We performed a review of the literature to evaluate the diagnostic value of inflammatory biomarkers in adult patients admitted to the hospital with suspected systemic acute infections. Elevated procalcitonin (PCT) concentrations indicate a bacterial infection in febrile patients with an auto-immune disease, rather than a disease flare. CD64 expression on neutrophils can discriminate between non infectious systemic inflammation and sepsis, and limited evidence suggests the same for decoy receptor 3. PCT is useful for both diagnosing bacterial infection complicating influenza and guiding antibiotic treatment in lower respiratory tract infections in general. In undifferentiated illnesses, increased CD35 expression on neutrophils distinguishes bacterial from viral infections. Compared to bacterial infections, invasive fungal infections are characterized by low concentrations of PCT. No biomarker predicting a specific infecting agent could be identified. PMID- 26429737 TI - A multidisciplinary management of a type III dens invaginatus in a maxillary permanent canine. AB - BACKGROUND: Dens invaginatus affects 0.3-10% of the population; however, few reports document its occurrence in maxillary canines. Management of associated periradicular infections is often challenging. The benefits of computed tomography are well documented in these situations, providing greater clinical information for diagnosis, prognosis and practical management. Many previous reports in the literature utilise this technology but often focus on an endodontic management approach. CASE REPORT: Details of the treatment of a complex type III invagination affecting a maxillary canine, combined with hypodontia and malocclusion is described. Endodontic treatment was deemed inappropriate resulting in extraction of the invaginated canine. The multidisciplinary planning and approach, highlighted the need for close teamwork, shared care and a patient-centred approach. FOLLOW-UP: A 5-year follow-up and review recorded a successful outcome. CONCLUSIONS: This case reinforces the importance of careful investigation and planning in ensuring an optimal outcome when addressing multiple dental anomalies. Extensive consideration of the initial treatment strategy is required, coupled with evaluation of the outcome and longevity of any potential treatment modality to be employed. The consideration of inevitable future restorative treatment is fundamental, highlighting the importance of multidisciplinary planning at diagnosis. Moreover, orthodontic, aesthetic, behavioural and/or social factors may further complicate management in adolescents. PMID- 26429738 TI - Infrared and Fluorescence Spectroscopic Investigations of the Acyl Surface Modification of Hydrogel Beads for the Deposition of a Phospholipid Coating. AB - The scaffolded vesicle has been employed as an alternative means of developing natural model membranes and envisioned as a potential nutraceutical transporter. Furthering the research of the scaffolded vesicle system, a nucleophilic substitution reaction was implemented to form an ester linkage between palmitate and terminal hydroxyl groups of dextran in order to hydrophobically modify the hydrogel scaffold. An average tilt angle of 38 degrees of the hydrophobic palmitate modifying layer on the surface of the hydrogel was determined from dichroic ratios obtained from infrared spectra collected in the attenuated total reflection (ATR) configuration. ATR-IR studies of the DMPC-coated acylated hydrogel demonstrated that the hydrocarbon chains of the DMPC coating was similar to those of the DMPC bilayers and that the underlying palmitate layer had a negligible effect on the average tilt angle (26 degrees ) of the DMPC coating. The permeability of this acylated hydrogel was investigated with fluorescence spectroscopy and the terbium/dipicolinic acid assay. The hydrophobic modification on the surface of the hydrogel bead allowed for an efficient deposition of a DMPC layer that served as an impermeable barrier to terbium efflux. About 72% of DMPC coated acylated hydrogel beads showed ideal barrier properties. The remaining 28% were leaking, but the half-life of terbium efflux of the DMPC-coated acylated hydrogel was increasing, and the total amount of leaked terbium was decreasing with the incubation time. The half-life time and the retention were considered a marked improvement relative to past scaffolded vesicle preparations. The process of acylating hydrogel beads for efficient DMPC deposition has been identified as another viable method for controlling the permeability of the scaffolded vesicle. PMID- 26429740 TI - Virus-Specific Cellular Response in Hepatitis C Virus Infection. AB - Studies performed on chimpanzees and humans have revealed that strong, multispecific and sustained CD4(+) and CD8(+) T cell immune responses is a major determinant of hepatitis C virus (HCV) clearance. However, spontaneous elimination of the virus occurs in minority of infected individuals and cellular response directed against HCV antigens is not persistent in individuals with chronic infection. This review presents characteristics of the HCV-specific T cell response in patients with different clinical course of infection, including acute and chronic infection, persons who spontaneously eliminated HCV and non infected subjects exposed to HCV. Detection of HCV-specific response, especially in non-infected subjects exposed to HCV, may be indicative of HCV prevalence in population and rate of spontaneous viral clearance. Understanding the mechanisms and role of HCV-specific cellular immune response would contribute to better understanding of HCV epidemiology, immunopathogenesis and may help to design an effective vaccine. PMID- 26429739 TI - Cripto-1 ablation disrupts alveolar development in the mouse mammary gland through a progesterone receptor-mediated pathway. AB - Cripto-1, a member of the epidermal growth factor-Cripto-1/FRL-1/Cryptic family, is critical for early embryonic development. Together with its ligand Nodal, Cripto-1 has been found to be associated with the undifferentiated status of mouse and human embryonic stem cells. Several studies have clearly shown that Cripto-1 is involved in regulating branching morphogenesis and epithelial mesenchymal transition of the mammary gland both in vitro and in vivo and together with the cofactor GRP78 is critical for the maintenance of mammary stem cells ex vivo. Our previous studies showed that mammary-specific overexpression of human Cripto-1 exhibited dramatic morphological alterations in nulliparous mice mammary glands. The present study shows a novel mechanism for Cripto-1 regulation of mammary gland development through direct effects on progesterone receptor expression and pathways regulated by progesterone in the mammary gland. We demonstrate a strict temporal regulation of mouse Cripto-1 (mCripto-1) expression that occurs during mammary gland development and a stage-specific function of mCripto-1 signaling during mammary gland development. Our data suggest that Cripto-1, like the progesterone receptor, is not required for the initial ductal growth but is essential for subsequent side branching and alveologenesis during the initial stages of pregnancy. Dissection of the mechanism by which this occurs indicates that mCripto-1 activates receptor activator NF-kappaB/receptor activator NF-kappaB ligand, and NF-kappaB signaling pathways. PMID- 26429741 TI - Value of a Joint Cardiac Surgery-Cardiac Electrophysiology Approach to Lead Extraction. AB - We report three cases of vascular injury during laser lead extractions, requiring urgent surgical correction. Immediate sternotomy and cardiopulmonary bypass were possible because of an institutional collaboration where cardiac surgeon and cardiac electrophysiologist jointly perform these cases, and all patients survived. We propose this joint approach is ultimately the best option for patients undergoing lead extraction. PMID- 26429742 TI - Outcome of adenotonsillectomy for children with sleep apnea. AB - BACKGROUND AND OBJECTIVES: The prevalence of obstructive sleep apnea syndrome is about 1%-4.9% in children aged 2-18 years. This is a prospective study carried out to evaluate the role of adenotonsillectomy (AT) in pediatric sleep apnea. METHODS: Fifty children aged less than 15 years presenting with the chief complaints of snoring, mouth breathing, recurrent upper respiratory infections, and adenotonsillar hypertrophy were included in the study. Physical examination included body mass index (BMI) z-score, orodental and nasal examination, modified Mallampati scoring; whole-night level I polysomnography was conducted and repeated after three to six months of AT. RESULTS: The mean preoperative BMI z score was -0.76, which improved significantly to -0.15 (p < 0.001) after AT. A negative correlation was seen between respiratory distress index (RDI) and pre surgery BMI z-score. As per pre-operative RDI, OSA was classified mild in 6.7% children (31.1% as per apnea-hypopnea index [AHI]), moderate in 35.6% (31.1% as per AHI), and severe in 57.8% (37.8% as per AHI). The average RDI value reduced significantly from 16.2 +/- 10.7 to 6.46 +/- 4.8 (p < 0.001) and AHI from 8.5 (SD +/- 5.7) to 1.3 (SD +/- 1) post-operatively. Only 6.7% children could be cured with surgery, of whom none belonged to moderate or severe category. Multivariate analysis shows that initial severity of disease, modified Mallampati scores III and IV, high-arched palate, and age above eight years were associated with significant residual disease after AT. CONCLUSION: AT was associated with a statistically significant change in RDI and AHI. However, complete resolution of OSA could be seen in a small percentage of patients with a mild degree of disease. PMID- 26429743 TI - Pupillometric findings in children with obstructive sleep apnea. AB - BACKGROUND: Obstructive sleep apnea (OSA) leads to intermittent hypoxia, activation of the sympathetic nervous system, and eventually cardiovascular morbidity. Alterations in autonomic nervous system (ANS) tone and reflexes are likely to play major roles in OSA-associated morbidities, and have been identified in a subset of children with OSA. OBJECTIVES: To evaluate whether pupillometry, a noninvasive and rapid bedside test for the assessment of autonomic nervous system dysfunction (ANS), would detect abnormal ANS function in children with OSA. METHODS: Children ages 2-12 years underwent polysomnography (PSG), and were divided based on PSG findings into two groups; Habitual Snorers (HS; AHI < 1 h/TST, n = 17) and OSA (AHI > 1 h/TST, n = 49), the latter then sub divided into AHI severity categories (>1 but <5, >5 but <10, and >10 h/TST). Pupillometric measurements were performed during the clinic visit in a dark room using an automated pupillometer device. RESULTS: A total of 66 subjects with a mean age of 7.3 +/- 2.6 years were recruited. There were no statistically significant differences between any of the groups, even when comparing severe OSA (n = 15) and HS in any of the measures related to pupillary reflexes. However, mild, yet significant increases in systolic blood pressure and morning plasma norepinephrine levels were detected in the severe OSA group. CONCLUSION: Although ANS perturbations are clearly present in a proportion of children with OSA, particularly those with severe disease, pupillary responses do not appear to provide a sensitive method for the detection of ANS dysfunction in OSA children. PMID- 26429744 TI - Association between sleep and working memory in children with ADHD: a cross sectional study. AB - OBJECTIVE/BACKGROUND: This study aimed to examine the relationship between sleep problems and working memory in children aged 5-13 years with attention deficit/hyperactivity disorder (ADHD). PATIENTS/METHODS: Children with ADHD were recruited into a randomized controlled trial from 21 paediatric practices in VIC, Australia. Cross-sectional data for intervention and control children were pooled at 6 months post randomization for the current analyses (n = 189). Children who met the Diagnostic Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for ADHD and had a parent-reported moderate/severe sleep problem that fulfilled diagnostic criteria for a behavioural sleep disorder were recruited into the study. Sleep was assessed by detailed parent (Children's Sleep Habits Questionnaire) and self-reports (Self-Sleep Report). Working memory was measured using the Working Memory Test Battery for Children (low and very low working memory defined as <25th and <10th percentiles, respectively). Analyses were adjusted for child age and gender, internalizing and externalizing comorbidities, and socio-economic status. RESULTS: Self-reported sleep problem severity was associated with poorer working memory; for each standard deviation increase in self-reported sleep problems, working memory scores decreased by -3.8 points (95% confidence interval (CI): -6.7, -0.8; p = 0.01). There was some evidence that self-reported sleep problems were associated with low (p = 0.06) and very low working memory (p = 0.01). There was minimal evidence that parent-reported sleep problems were associated with poorer working memory with the exception of bedtime resistance problems. CONCLUSIONS: Behavioural sleep problems and working memory are associated in children with ADHD, particularly when sleep is assessed by self report. PMID- 26429746 TI - Empirical validation of a short version of the Adolescent Sleep-Wake Scale using a sample of ethnically diverse adolescents from an economically disadvantage community. AB - OBJECTIVE: There is a need for brief, psychometrically sound instruments to assess adolescent sleep, particularly for ethnic minority and economically disadvantaged adolescents. A 10-item short version of the Adolescent Sleep-Wake Scale was recently proposed based upon exploratory factor analysis with primarily Caucasian healthy adolescents from middle- to high-income families. The aim of this study was to expand the utility of the short version of the Adolescent Sleep Wake Scale by investigating the empirical and construct validity of the measure on an ethnically diverse sample of adolescents from an economically disadvantaged community. MATERIALS AND METHODS: Participants included 467 adolescents (40% African American, 35.5% Caucasian, 16.5% Latino, and 7.9% multiethnic), aged 12 18 years (mean = 15.27 years, SD = 1.96 years), who completed the Adolescent Sleep-Wake Scale. A confirmatory factor analysis (CFA) was conducted with Mplus 7 based on the three-factor solution proposed by Essner et al. (2014). RESULTS: CFA indicated that the three-factor structure was a good fit for the data (chi(2) (29) = 52.053, p = 0.005, root mean square error of approximation (RMSEA) = 0.04, CFI = 0.98, TLI = 0.96, standardized root mean residuals (SRMR) = 0.03), and factor loadings for each item were >0.40. Cronbach's alphas by ethnicity indicated that the scale has acceptable reliability (0.70 <= alpha <= 0.90) for African American, Caucasian, and multiethnic adolescents, but not for Latino adolescents. CONCLUSION: Our results support the use of the Adolescent Sleep-Wake Scale short form for the majority of ethnic minority and economically disadvantaged adolescents. PMID- 26429747 TI - Poor sleep and neurocognitive function in early adolescence. AB - BACKGROUND: Evidence regarding the associations between sleep duration and quality, and neurocognitive function in adolescents remains scanty. This study examined the associations in early adolescence between: sleep duration; efficiency; fragmentation; wake-after-sleep-onset (WASO); catch-up sleep; intelligence; memory; and executive function, including attention. METHODS: This study included 354 girls and boys with a mean age 12.3 years (SD = 0.5) from a birth cohort born in 1998. Sleep was measured with accelerometers for an average of eight nights. Cognitive function was evaluated with subtests from the Wechsler Intelligence Scale for Children-III (WISC-III), the Developmental Neuropsychological Assessment 2 (NEPSY-2), the Wisconsin Card Sorting Task (WCST), Conners' Continuous Performance Task (CPT), and the Trail Making Test (TMT). RESULTS: In girls, a higher WASO and fragmentation index were associated with poorer executive functioning (higher number of perseverative errors in the WCST), and longer catch-up sleep was associated with longer reaction times and better performance in one verbal intelligence test (Similarities subtest of the WISC-III). In boys, shorter sleep duration, lower efficiency, higher WASO, higher sleep fragmentation and shorter catch-up sleep were associated with lower executive functioning (more commission errors, shorter reaction times, and had lower D Prime scores in CPT). CONCLUSIONS: In adolescent girls, poorer sleep quality was only weakly associated with poorer executive functioning, while in boys, poorer sleep quantity and quality were associated with an inattentive pattern of executive functioning. The amount of catch-up sleep during weekends showed mixed patterns in relation to neurocognitive function. PMID- 26429748 TI - The interactive effects of nocturnal sleep and daytime naps in relation to serum C-reactive protein. AB - BACKGROUND AND AIM: C-reactive protein (CRP) is a general marker of inflammation that has been differentially linked with sleep. Elevated CRP (ie, high inflammation) has been associated with either short/insufficient sleep duration or long sleep duration, both, or neither. Daytime napping has also been tied to increased and decreased inflammation. We attempted to unify these findings by examining the relationship between CRP and sleep duration in conjunction with napping in a healthy young adult cohort. PARTICIPANTS: Participants were young adults (mean age = 29.05 years, n = 2147) from the National Longitudinal Study of Adolescent Health (Add Health) cohort, a nationally representative longitudinal sample. METHODS/RESULTS: Analysis of covariance (ANCOVA) tests examined whether self-reported sleep duration (short, medium, or long) and nap frequency (none-few days/week; most days/week; every day) interacted in relation to CRP. Standard covariates (ie, age, gender, race/ethnicity, body mass index, physical activity, depression, snoring, systolic blood pressure, clinical symptoms, and household income) were used. There was a linear increase in CRP with increased napping [contrast estimate = 0.265, 95% confidence interval (CI) (0.045-0.485), P = 0.018]. There was also an interaction between sleep duration and napping frequency in relation to CRP (F4,2128 = 2.90, P = 0.021). Inflammation differed between nap groups within the long and short sleep groups. CONCLUSIONS: Our results suggest that increased napping is an independent predictor of inflammation in young adults. These results also provide evidence for interactive effects of inflammation, nocturnal sleep, and daytime naps. Our findings confirm that excess sleep, insufficient sleep, frequent napping, and infrequent napping can all be linked with elevated CRP, but these relationships depend on both nocturnal and daytime sleep patterns. These analyses will guide future work to more specifically examine sleep-inflammation processes and directionality. PMID- 26429745 TI - Infarct location and sleep apnea: evaluating the potential association in acute ischemic stroke. AB - BACKGROUND: The literature about the relationship between obstructive sleep apnea (OSA) and stroke location is conflicting with some studies finding an association and others demonstrating no relationship. Among acute ischemic stroke patients, we sought to examine the relationship between stroke location and the prevalence of OSA; OSA severity based on apnea-hypopnea index (AHI), arousal frequency, and measure of hypoxia; and number of central and obstructive respiratory events. METHODS: Data were obtained from patients who participated in a randomized controlled trial (NCT01446913) that evaluated the effectiveness of a strategy of diagnosing and treating OSA among patients with acute ischemic stroke and transient ischemic attack. Stroke location was classified by brain imaging reports into subdivisions of lobes, subcortical areas, brainstem, cerebellum, and vascular territory. The association between acute stroke location and polysomnographic findings was evaluated using logistic regression for OSA presence and negative binomial regression for AHI. RESULTS: Among 73 patients with complete polysomnography and stroke location data, 58 (79%) had OSA. In unadjusted models, no stroke location variable was associated with the prevalence or severity of OSA. Similarly, in multivariable modeling, groupings of stroke location were also not associated with OSA presence. CONCLUSIONS: These results indicate that OSA is present in the majority of stroke patients and imply that stroke location cannot be used to identify a group with higher risk of OSA. The results also suggest that OSA likely predated the stroke. Given this high overall prevalence, strong consideration should be given to obtaining polysomnography for all ischemic stroke patients. PMID- 26429749 TI - Actigraphic and self-reported sleep quality in women: associations with ovarian hormones and mood. AB - BACKGROUND: Sleep and mood disturbances in women have often been linked to the menstrual cycle, implying an ovarian hormonal causation. However, most studies in this area have used self-reported menstrual cycle phase rather than direct measurement of ovarian hormone concentrations. Further, many studies have focused primarily on peri- and postmenopausal populations reporting clinical sleep difficulty. In this study, we examined the associations among sleep quality, mood, and ovarian hormone concentration in a random sample of community-dwelling, nonclinical women of reproductive age. METHODS: Our sample consisted of 19 non help-seeking women aged 18-43 years, each contributing an average of 39.5 nights of data. Over the 42 days of the study, we collected self-reported and actigraphic sleep-quality data, concentrations of urinary estrogen and progesterone metabolites (estrone-3-glucuronide (E1G) and pregnanediol-3 glucuronide [PdG], respectively), and daily mood ratings. Linear-mixed models were used to estimate associations, clustering longitudinal observations by the participant. RESULTS: We found a significant positive association between Sleep Efficiency and E1G, and a significant negative association between Sleep Efficiency and PdG. Otherwise, the self-reported and actigraphic sleep measures were not associated with ovarian hormone concentrations. Self-reported sleep was strongly associated with mood, whereas actigraphic sleep was associated with only two of the 11 individual mood items, "Feeling on Top of Things" and "Difficulty Coping." CONCLUSIONS: In this community sample of women of reproductive age, ovarian hormones play little, if any, role in day-to-day sleep quality. Our findings additionally highlight the different associations that self-reported and actigraphic sleep show with hormones and mood. PMID- 26429750 TI - Associations between poor sleep quality and different measures of obesity. AB - OBJECTIVE: Poor sleep may be a risk factor for obesity. Previous studies have mainly investigated the effects of sleep duration on body mass index, but research considering overall sleep quality and other anthropometric measures is scarce. The aim of this study was to examine the association between sleep quality and different measures of obesity (general obesity, abdominal obesity, body composition) in a population-based sample of adults. METHODS: The study included 753 participants aged 35-65 years from the BiDirect Study, conducted in Munster, Germany. Participants completed the Pittsburgh Sleep Quality Index (PSQI) on sleep characteristics. Weight, height, and waist circumference were measured by trained study nurses. Body composition (fat mass and fat-free mass) was assessed using bioelectrical impedance analysis. The cross-sectional relationship between sleep quality and measures of obesity was investigated using logistic regression analysis. RESULTS: Among the participants, 65.3% reported good (PSQI <= 5) and 34.7% poor (PSQI > 5) sleep quality. We observed a significant association of poorer sleep quality assessed by the continuous PSQI score with general obesity and high body fat (for both, odds ratio = 1.07, 95% confidence interval = 1.01-1.13), adjusted for socio-demographic and lifestyle factors. Further adjustment for depressive symptoms and somatic comorbidities attenuated the relationship. The observed association was mainly driven by the PSQI components sleep latency, sleep disturbances, and daytime dysfunction. CONCLUSIONS: The present study suggests that poor sleep quality may predict obesity and high body fat mass among adults. However, a causal relationship still has to be confirmed by prospective studies with objective measurements of sleep and obesity. PMID- 26429751 TI - Putting the periodicity back into the periodic leg movement index: an alternative data-driven algorithm for the computation of this index during sleep and wakefulness. AB - OBJECTIVE: To evaluate an alternative index for periodic leg movements during sleep (PLMS) and wakefulness (PLMW) expected to be similar to the standard index when leg movement activity is genuinely periodic, but significantly lower when periodicity is low. SUBJECTS AND METHODS: One-hundred-and-seven subjects with restless legs syndrome (RLS) were retrospectively identified and included (47 males, 60 females, mean age 56.9 years), along with 63 controls (33 males, 30 females, 42.2 years). Night-to-night variability was analysed in a subgroup of 17 subjects with RLS. PLMW were evaluated in a subgroup of 66 RLS subjects. Two 'alternative' PLMS/PLMW indices were calculated: one increased the lower limit of the inter-movement intervals from 5 to 10 s ('Alt1') and another additionally considered only series not interrupted by LMs with a short inter-movement interval ('Alt2'). RESULTS: Despite a high correlation between methods, only the Alt2 algorithm provided significantly different results, with PLMS/PLMW indices being consistently lower than those provided by the other two methods. The difference was more evident in the controls and during wakefulness, when periodicity was lower. The difference between the Alt2 and the standard PLMS index showed a significantly negative correlation with the Periodicity Index. Night-to-night variability was similar for all PLMS indices and significantly higher than the variability seen in the Periodicity Index. CONCLUSION: This methodological study introduces an alternative to the standard PLMS/PLMW indices, initiating the validation process for a new way of computing the PLMS/PLMW index, more adherent to the parameters that allows a reliable evaluation of their periodicity. PMID- 26429753 TI - Effect of melatonin on sleep disorders in a monkey model of Parkinson's disease. AB - OBJECTIVES: To evaluate and compare the effects of melatonin and levodopa (L dopa) on sleep disorders in a monkey model of Parkinson's disease. MATERIALS AND METHODS: The daytime and nighttime sleep patterns of four macaques that were rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) were recorded using polysomnography in four conditions: at baseline, during the parkinsonian condition; after administration of L-dopa, and after administration of a combination of melatonin with L-dopa. RESULTS: It was confirmed that MPTP intoxication induces sleep disorders, with sleep episodes during daytime and sleep fragmentation at nighttime. L-dopa treatment significantly reduced the awake time during the night and tended to improve all other sleep parameters, albeit not significantly. In comparison to the parkinsonian condition, combined treatment with melatonin and L-dopa significantly increased total sleep time and sleep efficiency, and reduced the time spent awake during the night in all animals. A significant decrease in sleep latencies was also observed in three out of four animals. Compared with L-dopa alone, combined treatment with melatonin and L-dopa significantly improved all these sleep parameters in two animals. On the other hand, combined treatment had no effect on sleep architecture and daytime sleep. CONCLUSION: These data demonstrated, for the first time, objective improvement on sleep parameters of melatonin treatment in MPTP-intoxicated monkeys, showing that melatonin treatment has a real therapeutic potential to treat sleep disturbances in people with Parkinson's disease. PMID- 26429752 TI - Prevalence and associations of respiratory-related leg movements: the MrOS sleep study. AB - OBJECTIVES: Obstructive respiratory events often terminate with an associated respiratory-related leg movement (RRLM). Such leg movements are not scored as periodic leg movements (periodic limb movements during sleep, PLMS), although the criteria for distinguishing RRLM from PLMS differ between the American Academy of Sleep Medicine (AASM) and the World Association of Sleep Medicine (WASM)/ International Restless Legs Syndrome Study Group (IRLSSG) scoring manuals. Such LMs may be clinically significant in patients with obstructive sleep apnea (OSA). The prevalence and correlation of RRLM in men with OSA were examined. METHODS: A case-control sample of 575 men was selected from all men with an apnea-hypopnea index (AHI, >=3% desaturation criteria) >= 10 and good data from piezoelectric leg movement sensors at the first in-home sleep study in the MrOS cohort (mean age = 76.8 years). Sleep studies were rescored for RRLMs using five different RRLM definitions varying in both latency of leg movement onset from respiratory event termination and duration of the leg movement. The quartile of RRLM% (the number of RRLM/the number of hypopneas + apneas) was derived. RESULTS: The nonparametric densities of RRLM% were most influenced by alterations in the latency rather than the duration of the LM. The most liberal RRLM definition (latency 0-5 s, duration 0.5-10 s) led to a median RRLM% of 23.4 (interquartile range 12.41, 37.12) in this sample. The average AHI and arousal index increased as the quartile of RRLM% increased, as well as the prevalence of chronic obstructive pulmonary disease (COPD). The prevalence of those with a history of hypertension decreased as RRLM% increased. The non-Caucasian race was associated with lower RRLM%. CONCLUSION: Within an elderly sample with moderate to severe OSA, piezoelectric-defined RRLM% is associated with a number of sleep-related and demographic factors. Further study of the optimal definition, predictors, and consequences of RRLM is warranted. PMID- 26429754 TI - Natural course of restless legs syndrome/Willis-Ekbom disease: long-term observation of a large clinical cohort. AB - OBJECTIVE: Although restless legs syndrome (RLS)/Willis-Ekbom disease (WED) is a common neurological disorder, data on the long-term course and management of the disease are scarce. The aim of the current study was to extend the knowledge on the long-term clinical course and treatment outcome of RLS/WED. METHODS: In this retrospective analysis, we performed a chart review of consecutive visits of 160 patients with definite RLS/WED from the RLS/WED database of the Innsbruck Medical University. RESULTS: A total of 160 patients (58.8% female, aged 58.9 years, range 21.5-86.8 years) met inclusion criteria of two or more visits during a follow-up of at least five years. The duration of the observational period was 8.1 +/- 2.9 years. During the observational period, the percentage of treated patients increased (first vs last visit: 67.5% vs 77.5%). Of the patients, 59.4% had one or more switches of medication. Overall the RLS/WED severity, evaluated using a combined severity score (CSS) ranging from 1 to 5, decreased between the first and last visits (median [range], first visit: 3 [1-5] vs last visit 2.5 [1 5]; p <0.001). Symptoms improved in 55.0% of patients, worsened in 10.6%, and remained unchanged in 34.4% during the observational period. Augmentation of RLS/WED occurred in 42 patients (13/42 as the presenting cause; 29/42 occurring during treatment after 4.1 years). The annual rate of augmentation for subjects on dopaminergic medication was 8.1%. CONCLUSIONS: Our data suggest that, with the possibility of regular treatment adjustments, RLS/WED remains treatable in the majority of patients over years. Nevertheless, in this study, despite the overall decreased severity, RLS symptoms remained unchanged or worsened in 45% of the patients during the observational period. PMID- 26429755 TI - Sleep-wake habits and circadian preference in Mexican secondary school. AB - OBJECTIVE: The current study aimed to determine the differences between sleep wake habits and circadian preference in Mexican adolescents attending classes at a morning shift or an afternoon shift. METHODS: The sample consisted of 568 students of a secondary school in Reynosa, northeastern Mexico, of whom 280 were boys and 288 were girls (mean age 14.08 +/- 0.72 years, age range 13-16 years). In the morning shift, 287 students attend classes on a schedule from 7:30 to 13:00 and the afternoon shift, 281 students, on a schedule from 13:20 to 19:00. Students completed a general information questionnaire, the Sleep Timing Questionnaire and the Spanish version of the Morningness-Eveningness Questionnaire. RESULTS: The adolescents who attended the morning shift had earlier bedtime and waking time, but shorter sleep duration than those who attended the afternoon shift. Those oriented to eveningness had later bedtime, waking time, and a shorter sleep duration than those oriented to morningness. Two interactions were found between school shift and chronotype. First, with regard to waking time during weekdays, students who attended the afternoon shift and were oriented to eveningness woke up later than those who attended the morning shift and were oriented to eveningness; during weekdays, there were no differences between the waking time of morning-type and evening-type students who attended the morning shift. Second, with regard to sleep duration on weekdays, students who attended the morning shift and were oriented to eveningness had the shortest sleep duration. Furthermore, there were no differences between sleep duration on weekdays in evening-type and morning-type students of the afternoon shift. CONCLUSION: Adolescents who attend classes in the morning shift and are oriented to eveningness are the most sleep deprived. Those who attend the afternoon shift will have optimal sleep duration, regardless of their circadian preference. PMID- 26429756 TI - Transcranial magnetic stimulation for evaluation of motor cortical excitability in restless legs syndrome/Willis-Ekbom disease. AB - There is no consensus about mechanisms underlying restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED). Cortical excitability may be abnormal in RLS. Transcranial magnetic stimulation (TMS) can provide insight about cortical excitability. We reviewed studies about measures of excitability to TMS in RLS. Original studies published between January 1999 and January 2015 were searched in PubMed, Scopus, and Web of Science databases. Inclusion criteria were as follows: original studies involving primary RLS in patients from both sexes and ages between 18 and 85 years; TMS protocols clearly described; and they were written in English, in peer-reviewed journals. Fifteen manuscripts were identified. TMS protocols were heterogeneous across studies. Resting motor threshold, active motor threshold, and amplitudes of motor-evoked potentials were typically reported to be normal in RLS. A reduction in short-interval intracortical inhibition (SICI) was the most consistent finding, whereas conflicting results were described in regard to short-interval intracortical facilitation and the contralateral silent period. Decreased SICI can be reversed by treatment with dopaminergic agonists. Plasticity in the motor cortex and sensorimotor integration may be disrupted. TMS may become a useful biomarker of responsiveness to drug treatment in RLS. The field can benefit from increases in homogeneity and sizes of samples, as well as from decrease in methodological variability across studies. PMID- 26429757 TI - Childhood abuse is associated with stress-related sleep disturbance and poor sleep quality in pregnancy. AB - OBJECTIVES: Childhood abuse is associated with increased risks of adult psychiatric disorders and physical health conditions. Mounting evidence documents associations of childhood abuse with sleep disturbances in adulthood. However, to date, no study has evaluated associations of childhood abuse and sleep disturbances among pregnant women. METHODS: This cross-sectional study included 634 pregnant Peruvian women. To collect information regarding socio-demographic characteristics, history of childhood abuse, and complaints of sleep disturbances, face-to-face interviews were conducted with women in early pregnancy. Ford Insomnia Response to Stress Test (FIRST-S) and the Pittsburgh Sleep Quality Index (PSQI-S), translated from English to Spanish, were used to assess stress-related sleep disturbance and sleep quality, respectively. Logistic regression was used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (95% CIs). RESULTS: Women who experienced any childhood abuse had a 1.65-fold increased odds of stress-related sleep disturbance (aOR = 1.65; 95% CI: 1.15-2.38) and 2.11-fold increased odds of poor sleep quality during early pregnancy (aOR = 2.11; 95% CI: 1.35-3.30) as compared with women who reported no abuse. Women who reported both physical and sexual abuse during childhood were more than twice as likely to suffer from stress-related sleep disturbance (aOR = 2.26; 95% CI: 1.44-3.53) and poor sleep quality (aOR = 2.43; 95% CI: 1.45-4.09) in comparison to women who reported no childhood abuse. CONCLUSIONS: A history of childhood abuse is associated with increased odds of stress-related sleep disturbance and poor sleep quality during pregnancy. These findings, if replicated, should be used to inform the development of trauma-informed care for such sleep disturbances induced by childhood trauma. PMID- 26429758 TI - Sleep duration and growth outcomes across the first two years of life in the GUSTO study. AB - BACKGROUND AND AIM: Short sleep duration is thought to be a factor contributing to increased body mass index (BMI) in both school-age children and adults. Our aim was to determine whether sleep duration associates with growth outcomes during the first two years of life. STUDY DESIGN: Participants included 899 children enrolled in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort study. Anthropometric data (weight and body length) and parental reports of sleep duration were collected at 3, 6, 9, 12, 18, and 24 months of age. A mixed-model analysis was used to evaluate the longitudinal association of BMI and body length with sleep duration. In subgroup analyses, effects of ethnicity (Chinese, Indian, and Malay) and short sleep at three months of age (<=12 h per day) were examined on subsequent growth measures. RESULTS: In the overall cohort, sleep duration was significantly associated with body length (beta = 0.028, 95% confidence interval [CI] 0.002-0.053, p = 0.033), but not BMI, after adjustment for potential confounding factors. Only in Malay children, shorter sleep was associated with a higher BMI (beta = -0.042, 95% CI -0.071 to 0.012, p = 0.005) and shorter body length (beta = 0.079, 95% CI 0.030-0.128, p = 0.002). In addition, shorter sleep was associated with a higher BMI and shorter body length in children who slept <=12 h per day at three months of age. CONCLUSION: The association between sleep duration and growth outcomes begins in infancy. The small but significant relationship between sleep and growth anthropometric measures in early life might be amplified in later childhood. PMID- 26429759 TI - Correlated response of peripheral blood cytokines with selection for reduced mycoplasma pneumonia of swine lesions in Landrace pigs. AB - Mycoplasma pneumonia of swine (MPS) is responsible for significant economic losses in the swine industry. We selected Landrace pigs for reduced MPS pulmonary lesions over five generations, and measured concentrations of the following cytokines: interleukin (IL)-10, IL-13, IL-17, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma to estimate their correlation with MPS lesions. Sheep red blood cells (SRBC) were injected twice intramuscularly at 70 and 95 kg body weight. Blood serum samples were collected after 1 week of secondary SRBC inoculation and cytokine concentrations were analyzed by ELISA. Genetic parameters and breeding values were estimated. The heritability estimates of IL 10, IL-13, IL-17, TNF-alpha and IFN-gamma were 0.20 +/- 0.06, 0.12 +/- 0.06, 0.27 +/- 0.07, 0.20 +/- 0.10 and 0.05 +/- 0.03, respectively. Genetic correlations of IL-17 and TNF-alpha with pulmonary MPS lesions were high (-0.86 +/- 0.13 and 0.69 +/- 0.29, respectively) and those of IFN-gamma and IL-13 with MPS lesions were moderately negative (-0.45). Through selection, the breeding values of IL-17 and IFN-gamma increased substantially and those of TNF-alpha decreased. These results suggest that innate and cellular immunity are more important for the suppression of pulmonary lesions in MPS than humoral-mediated immunity, such as antibody response. PMID- 26429761 TI - Optical Coherence Tomography and Virtual-Histology Intravascular Ultrasound: Strange Bedfellows? ... or Not? PMID- 26429760 TI - Direct Comparison of Virtual-Histology Intravascular Ultrasound and Optical Coherence Tomography Imaging for Identification of Thin-Cap Fibroatheroma. AB - BACKGROUND: Although rupture of thin-cap fibroatheroma (TCFA) underlies most myocardial infarctions, reliable TCFA identification remains challenging. Virtual histology intravascular ultrasound (VH-IVUS) and optical coherence tomography (OCT) can assess tissue composition and classify plaques. However, direct comparisons between VH-IVUS and OCT are lacking and it remains unknown whether combining these modalities improves TCFA identification. METHODS AND RESULTS: Two hundred fifty-eight regions-of-interest were obtained from autopsied human hearts, with plaque composition and classification assessed by histology and compared with coregistered ex vivo VH-IVUS and OCT. Sixty-seven regions-of interest were classified as fibroatheroma on histology, with 22 meeting criteria for TCFA. On VH-IVUS, plaque (10.91+/-4.82 versus 8.42+/-4.57 mm(2); P=0.01) and necrotic core areas (1.59+/-0.99 versus 1.03+/-0.85 mm(2); P=0.02) were increased in TCFA versus other fibroatheroma. On OCT, although minimal fibrous cap thickness was similar (71.8+/-44.1 MUm versus 72.6+/-32.4; P=0.30), the number of continuous frames with fibrous cap thickness <=85 MUm was higher in TCFA (6.5 [1.75-11.0] versus 2.0 [0.0-7.0]; P=0.03). Maximum lipid arc on OCT was an excellent discriminator of fibroatheroma (area under the curve, 0.92; 95% confidence interval, 0.87-0.97) and TCFA (area under the curve, 0.86; 95% confidence interval, 0.81-0.92), with lipid arc >=80 degrees the optimal cut-off value. Using existing criteria, the sensitivity, specificity, and diagnostic accuracy for TCFA identification was 63.6%, 78.1%, and 76.5% for VH-IVUS and 72.7%, 79.8%, and 79.0% for OCT. Combining VH-defined fibroatheroma and fibrous cap thickness <=85 MUm over 3 continuous frames improved TCFA identification, with diagnostic accuracy of 89.0%. CONCLUSIONS: Both VH-IVUS and OCT can reliably identify TCFA, although OCT accuracy may be improved using lipid arc >=80 degrees and fibrous cap thickness <=85 MUm over 3 continuous frames. Combined VH IVUS/OCT imaging markedly improved TCFA identification. PMID- 26429762 TI - Perovskites with the Framework-Forming Xenon. AB - The Group 18 elements (noble gases) were the last ones in the periodic system to have not been encountered in perovskite structures. We herein report the synthesis of a new group of double perovskites KM(XeNaO6) (M = Ca, Sr, Ba) containing framework-forming xenon. The structures of the new compounds, like other double perovskites, are built up of the alternating sequence of corner sharing (XeO6) and (NaO6) octahedra arranged in a three-dimensional rocksalt order. The fact that xenon can be incorporated into the perovskite structure provides new insights into the problem of Xe depletion in the atmosphere. Since octahedrally coordinated Xe(VIII) and Si(IV) exhibit close values of ionic radii (0.48 and 0.40 A, respectively), one could assume that Xe(VIII) can be incorporated into hyperbaric frameworks such as MgSiO3 perovskite. The ability of Xe to form stable inorganic frameworks can further extend the rich and still enigmatic chemistry of this noble gas. PMID- 26429763 TI - Alkenyl sex pheromone analogs in the hemolymph of an arctiid Eilema japonica and several non-arctiid moths. AB - The majority of moth species utilize compounds derived from de novo synthesized fatty acids as their sex pheromones (type I). In contrast, species belonging to two recently diverged moth families, Arctiidae and Geometridae, utilize alkenes and their epoxides, which are derived from dietary essential fatty acids (EFAs), as their sex pheromones (type II). In the latter species, EFAs are considered to be converted into alkenes, often after chain elongation, in specialized cells called oenocytes. These alkenes are transported through the hemolymph to the pheromone gland, from which they are secreted with or without further modifications. We confirmed that the appearance of EFA-derived alkenes in the hemolymph was closely associated with the completion of pheromone gland formation in an arctiid moth Eilema japonica. Analyses of the hemolymph of several moth species utilizing type-I sex pheromones demonstrated the occurrence of (Z,Z,Z) 3,6,9-tricosatriene (T23), a typical type-II component, in the hemolymph of a noctuid Mamestra brassicae and two crambids Ostrinia furnacalis and Ostrinia scapulalis. Our results demonstrated that moths utilizing type-I pheromones have the ability to synthesize type-II sex pheromones, and suggested that recently diverged groups of moths may have secondarily exploited EFA-derived alkenes as sex pheromones. PMID- 26429764 TI - Myoepithelial carcinoma in the mediastinum involving the left atrium. AB - We report a case of a 56-year-old male who presented with typical atrial flutter and was diagnosed with a large mediastinal mass, posterior to the ascending aorta, noted within the left atrium, compressing the superior vena cava and right superior pulmonary vein, and measuring >9.0 cm at its greatest diameter. Histopathological studies showed a myoepithelial carcinoma. The patient underwent tumor debulking and radiation therapy. This is the first report of a mediastinal myoepithelial carcinoma involving cardiac chambers. PMID- 26429765 TI - Harvesting rice's dispensable genome. AB - A rapid and cost-effective approach has been developed to harvest and map the dispensable genome, that is, population-level natural sequence variation within a species that is not present in static genome assemblies. PMID- 26429766 TI - Diversity-Oriented Synthesis of Substituted Benzo[b]thiophenes and Their Hetero Fused Analogues through Palladium-Catalyzed Oxidative C-H Functionalization/Intramolecular Arylthiolation. AB - An efficient, high yielding route to multisubstituted benzo[b]thiophenes has been developed through palladium-catalyzed intramolecular oxidative C-H functionalization-arylthiolation of enethiolate salts of alpha-aryl-beta (het)aryl/alkyl-beta-mercaptoacrylonitriles/acrylates or acrylophenones. The overall strategy involves a one-pot, two-step process in which enethiolate salts [generated in situ through base-mediated condensation of substituted arylacetonitriles, deoxybenzoins, or arylacetates with (het)aryl (or alkyl) dithioates] are subjected to intramolecular C-H functionalization-arylthiolation under the influence of a palladium acetate (or palladium chloride)/cupric acetate catalytic system and tetrabutylammonium bromide as additive in N,N dimethylformamide (DMF) as solvent. In a few cases, the yields of benzo[b]thiophenes were better in a two-step process by employing the corresponding enethiols as substrates. In a few examples, Pd(OAc)2 (or PdCl2) catalyst in the presence of oxygen was found to be more efficient than cupric acetate as reoxidant, furnishing benzothiophenes in improved yields by avoiding formation of side products. The method is compatible with a diverse range of substituents on the aryl ring as well as on the 2- and 3-positions of the benzothiophene scaffold. The protocol could also be extended to the synthesis of a raloxifene precursor and a tubulin polymerization inhibitor in good yields. The versatility of this newly developed method was further demonstrated by elaborating it for the synthesis of substituted thieno-fused heterocycles such as thieno[2,3-b]thiophenes, thieno[2,3-b]indoles, thieno[3,2-c]pyrazole, and thieno[2,3-b]pyridines in high yields. A probable mechanism involving intramolecular electrophilic arylthiolation via either a Pd-S adduct or palladacycle intermediate has been proposed on the basis of experimental studies. PMID- 26429767 TI - (R)-[11C]Emopamil as a novel tracer for imaging enhanced P-glycoprotein function. AB - INTRODUCTION: 2-Isopropyl-5-[methyl-(2-phenylethyl)amino]-2-phenylpentanenitrile (emopamil; EMP) is a calcium channel blocker of the phenylalkylamine class, with weak substrate properties for P-glycoprotein (P-gp). A weak substrate for P-gp would be suitable for measuring enhanced P-gp function. This study was performed to synthesise (R)- and (S)-[(11)C]EMP and characterise their properties as P-gp tracers. METHODS: We synthesised (R)- and (S)-[(11)C]EMP and compared their biodistribution, peripheral metabolism, and effects of the P-gp inhibitor cyclosporine A (CsA, 50 mg/kg). We compared the brain pharmacokinetics of (R) [(11)C]EMP and (R)-[(11)C]verapamil [(R)-[(11)C]VER] at baseline and CsA pretreatment with small animal positron emission tomography (PET). RESULTS: (R)- and (S)-[(11)C]EMP were synthesised from (R)- and (S)-noremopamil, respectively, by methylation with [(11)C]methyl triflate in the presence of NaOH at room temperature. (R)- and (S)-[(11)C]EMP yields were ~30%, with specific activity>74 GBq/MUmol and radiochemical purity>99%. (R)-[(11)C]EMP showed significantly greater uptake in the mouse brain than (S)-[(11)C]EMP. Both showed homogeneous non-stereoselective regional brain distributions. (R)- and (S)-[(11)C]EMP were rapidly metabolised to hydrophilic metabolites. Unchanged plasma (S)-[(11)C]EMP level was significantly lower than that of (R)-[(11)C]EMP 15 minutes post injection, whilst>88% of radioactivity in the brain was intact at 15 minutes post injection and was non-stereoselective. CsA pretreatment increased brain activity ~3-fold in mice, but was non-stereoselective. The baseline area-under-the-curve (AUC) of brain radioactivity (0-60 minutes) of (R)-[(11)C]EMP was 2-fold higher than that of (R)-[(11)C]VER, but their AUCs after CsA pretreatment were comparable. CONCLUSIONS: (R)-[(11)C]EMP is a novel tracer for imaging P-gp function with higher baseline uptake than (R)-[(11)C]VER. PMID- 26429768 TI - Impact attenuation properties of new and used lacrosse helmets. AB - The National Operating Committee on Standards for Athletic Equipment (NOCSAE) has developed impact attenuation thresholds that protective helmets worn in sport must meet to be commercially available in an attempt to prevent injury. It remains unknown how normal helmet use in athletic activity alters the force attenuation ability of lacrosse helmets. We tested 3 new and 3 randomly selected used helmets from 2 popular lacrosse models (Cascade Pro7, Cascade CPXR). All used helmets had been worn for 3 collegiate seasons prior to testing and had never been refurbished. Helmets were drop-tested using 3 prescribed impact velocities at 6 locations according to the NOCSAE lacrosse helmet standard, and we compared the Gadd Severity Index (GSI) scores between new and used helmets using a repeated measure ANOVA with location as the repeated variable and data separated by impact velocity. All 12 helmets passed the NOCSAE GSI threshold for all testing conditions; however 1 used helmet shell cracked resulting in a failed test. We found a significant main effect for helmet age at the low (F5,50=2.98, P=.02), medium (F5,50=3.71, P=.006), and high (F5,50=2.70, P=.03) velocities. We suspect that helmet use can degrade materials under some conditions, but improve performance in others due to changes in helmet composition from use. The clinical implications of the differences in GSI scores noted remain unclear. Because one helmet shell cracked resulting in a failed test, used helmets should be regularly inspected for cracks or other signs of mechanical fatigue that may weaken helmet integrity. PMID- 26429769 TI - The envelope of passive motion allowed by the capsular ligaments of the hip. AB - Laboratory data indicate the hip capsular ligaments prevent excessive range of motion, may protect the joint against adverse edge loading and contribute to synovial fluid replenishment at the cartilage surfaces of the joint. However, their repair after joint preserving or arthroplasty surgery is not routine. In order to restore their biomechanical function after hip surgery, the positions of the hip at which the ligaments engage together with their tensions when they engage is required. Nine cadaveric left hips without pathology were skeletonised except for the hip joint capsule and mounted in a six-degrees-of-freedom testing rig. A 5 N m torque was applied to all rotational degrees-of-freedom separately to quantify the passive restraint envelope throughout the available range of motion with the hip functionally loaded. The capsular ligaments allowed the hip to internally/externally rotate with a large range of un-resisted rotation (up to 50+/-10 degrees ) in mid-flexion and mid-ab/adduction but this was reduced towards the limits of flexion/extension and ab/adduction such that there was a near-zero slack region in some positions (p<0.014). The slack region was not symmetrical; the mid-slack point was found with internal rotation in extension and external rotation in flexion (p<0.001). The torsional stiffness of the capsular ligamentous restraint averaged 0.8+/-0.3 N m/ degrees and was greater in positions where there were large slack regions. These data provide a target for restoration of normal capsular ligament tensions after joint preserving hip surgery. Ligament repair is technically demanding, particularly for arthroscopic procedures, but failing to restore their function may increase the risk of osteoarthritic degeneration. PMID- 26429770 TI - Effect of propolis as a root canal irrigant on bond strength to dentin. AB - PURPOSE: The purpose of this in vitro study was to evaluate the effect of propolis on bond strength to dentin of a self-etch adhesive when used as a final irrigant. METHODS: 126 human third molars were sectioned 3 mm below the occlusal level and then randomly divided into 7 groups (n = 18). The exposed dentin surfaces were treated with irrigation solutions as follows: Group 1: 5.25% NaOCl; Group 2: 5.25% NaOCl followed by 17% EDTA; Group 3: 5.25% NaOCl followed by Tubulicid Plus (Temrex, Freeport, NY, USA); Group 4: 5.25% NaOCl followed by MTAD; Group 5: 5.25% NaOCl followed by 20% propolis; Group 6: 5.25% NaOCl followed by 2% CHX; Group 7: distilled water (control). Irrigated specimens were bonded using Clearfil SE Bond (Kuraray, Osaka, Japan) with Tygon (Saint-Gobain, Saint-Gobain Performance Plastics, France), tubes for microshear bond strength testing. Data was analyzed using a one-way ANOVA and Tukey test. RESULTS: Among the tested groups, although the lowest bond strength values were detected in Group 1 (11.25 +/- 1.97), a significant statistical difference was detected only between this group and Group 4 (18.70 +/- 1.82) and Group 5 (16.75 +/- 3.70) (p = 0.0012). CONCLUSIONS: 20% propolis solution as a final irrigant was found to have a favorable effect on the dentin bond strength of the tested self-etch adhesive to coronal dentin when compared with other irrigation solutions. PMID- 26429771 TI - Qualitative interviews with non-national tuberculosis patients in Cairo, Egypt: understanding the financial and social cost of treatment adherence. AB - Limited data are available about the challenges of non-national TB patients undergoing long-term treatment courses in an urban setting. This study aimed to understand the financial and social cost of adherence of non-national TB patients in Cairo, Egypt as a means to inform the development of context-specific interventions to support treatment adherence. In 2011, 22 in-depth interviews were conducted with TB patients from Sudan, Ethiopia, Eritrea, Somalia and Djibouti to obtain qualitative data. Analysis was based on thematic analysis that aimed to identify recurrent themes and codes from the narratives. The study identified a number of factors that influence TB treatment adherence. Uncertain financial status due to limited or no employment was frequently discussed in interviews, which resulted in fear of not being able to support family, loss of pride, dependence on family and friends, fear of losing housing, food insecurity and limited food options. Respondents also feared infecting other household members and longed for opportunities to discuss their illness and treatment experiences with other individuals but their social networks were often limited. TB-related stigma was driven by shame and blame of infection. Respondents also believed stigma was based on their foreign origin. Stigma manifested in distancing and exclusion in various ways, resulting in isolation, psychological distress and reluctance to disclose TB status to others. Poverty-related factors and social context with a special focus on stigma should be considered when developing strategies for supporting long-term treatment courses for non-national patients in Cairo and other similar urban settings. PMID- 26429772 TI - Youth motivation as a predictor of treatment outcomes in a community mental health system. AB - OBJECTIVE: The purpose of this study was to examine the relationship between youth motivation and psychotherapy outcomes in routine community mental health settings. METHOD: One hundred fifty youth, ages 12-17, from three community mental health clinics completed the Youth Outcome Questionnaire and Treatment Support Measure at frequent intervals over the course of treatment. RESULTS: Increases in motivation followed a curvilinear trajectory. On average, youth motivation significantly increased over the course of therapy according to both self- and parent reports (p < .001). The slope for youth motivation over the course of therapy was negatively associated with the slope for mental health symptoms (p < .001). Initial youth motivation did not predict overall change or the rate of change in symptoms. However, there was significant individual variability in patterns of youth motivation. CONCLUSIONS: Our findings demonstrate that youth show increases in motivation over the course of therapy with most gains occurring in the first few sessions. Because increases in motivation over the course of therapy were related to decreases in mental health symptoms, further research is needed to examine how treatment interventions or other factors such as parent motivation may moderate this relationship. Additional research examining the likely complex relationship between initial youth motivation and treatment outcomes in community mental health settings is needed. PMID- 26429773 TI - Drug-induced secretory diarrhea: A role for CFTR. AB - Many medications induce diarrhea as a side effect, which can be a major obstacle to therapeutic efficacy and also a life-threatening condition. Secretory diarrhea can be caused by excessive fluid secretion in the intestine under pathological conditions. The cAMP/cGMP-regulated cystic fibrosis transmembrane conductance regulator (CFTR) is the primary chloride channel at the apical membrane of intestinal epithelial cells and plays a major role in intestinal fluid secretion and homeostasis. CFTR forms macromolecular complexes at discreet microdomains at the plasma membrane, and its chloride channel function is regulated spatiotemporally through protein-protein interactions and cAMP/cGMP-mediated signaling. Drugs that perturb CFTR-containing macromolecular complexes in the intestinal epithelium and upregulate intracellular cAMP and/or cGMP levels can hyperactivate the CFTR channel, causing excessive fluid secretion and secretory diarrhea. Inhibition of CFTR chloride-channel activity may represent a novel approach to the management of drug-induced secretory diarrhea. PMID- 26429774 TI - A characteristic of polymorphic membrane protein F of Chlamydia trachomatis isolated from male urogenital tracts in Japan. AB - Although sexually transmitted disease due to Chlamydia trachomatis occurs similarly in both men and women, the female urogenital tract differs from that of males anatomically and physiologically, possibly leading to specific polymorphisms of the bacterial surface molecules. In the present study, we therefore characterized polymorphic features in a high-definition phylogenetic marker, polymorphic outer membrane protein (Pmp) F of C. trachomatis strains isolated from male urogenital tracts in Japan (Category: Japan-males, n = 12), when compared with those isolated from female cervical ducts in Japan (Category: Japan-females, n = 11), female cervical ducts in the other country (Category: Ref females, n = 12) or homosexual male rectums in the other country (Category: Ref males, n = 7), by general bioinformatics analysis tool with MAFFT software. As a result, phylogenetic reconstruction of the PmpF amino acid sequences showing three distinct clusters revealed that the Japan-males were limited into cluster 1 and 2, although there were only four clusters even though including an outgroup. Meanwhile, the phylogenetic distance values of PmpF passenger domain without hinge region, but not its full-length sequence, showed that the Japan-males were more stable and displayed less diversity when compared with the other categories, supported by the sequence conservation features. Thus, PmpF passenger domain is a useful phylogenetic maker, and the phylogenic features indicate that C. trachomatis strains isolated from male urogenital tracts in Japan may be unique, suggesting an adaptation depending on selective pressure, such as the presence or absence of microbial flora, furthermore possibly connecting to sexual differentiation. PMID- 26429775 TI - Stenting in paediatric and adult congenital heart diseases: A French multicentre study in the current era. AB - BACKGROUND: Many stents are used "off-label" during the management of congenital heart diseases (CHD). AIMS: To describe indications for, results of, and adverse events associated with stenting in CHD in current practice. METHODS: Participation in this study was proposed to all catheterization laboratories that specialize in CHD in France (M3C network). All paediatric and adult CHD cases with stent implantation in 2013 were included retrospectively. RESULTS: Overall, 207 stents were implanted in 151 patients across 11 centres. Median age was 13.7 years (range, 5 days to 70.1 years). Main procedure indications were branch pulmonary artery angioplasty (n=46, 29.1%), aortic (re)coarctation stenting (n=43, 27.2%), percutaneous pulmonary valve implantation (n=32, 20.2%) and ductus arteriosus stenting (n=14, 8.9%). The main stents implanted were the CP StentTM (n=61, 29.5%), the MaxTM LD stent (n=43, 20.8%), the Valeo((r)) stent (n=28, 13.5%) and valved stents (n=30, 14.5%). Procedures were considered successful in 96.8% of cases (95% confidence interval [CI] 92.8-99.0%). Adverse events were observed in 23 procedures (14.7%, 95% CI 9.5-21.0%). Ductus arteriosus stenting (odds ratio 12.4, 95% CI 2.0-77.5; P<0.01) and pulmonary revalvulation (odds ratio 5.9, 95% CI 1.1-32.3; P=0.04) were risk markers for stent-related adverse events. CONCLUSIONS: Stents are used in various CHD catheterization procedures, from infancy to adult age. The adverse events rate is significant and is related to the type of procedure. PMID- 26429776 TI - Editorial: Identification of in vivo markers for human polarized macrophages: a need that's finally met. PMID- 26429777 TI - Editorial: "Crowning" eosinophils in adipose tissue: does location matter? PMID- 26429779 TI - Standardization of FT4 and harmonization of TSH measurements: a request for input from endocrinologists and other physicians. PMID- 26429778 TI - Adenovirus infection in children with acute lower respiratory tract infections in Beijing, China, 2007 to 2012. AB - BACKGROUND: Human adenoviruses (HAdV) play a significant role in pediatric respiratory tract infections. To date, over 60 types of HAdV have been identified. Here, HAdV types are characterized in children in the Beijing area with acute lower respiratory tract infections (ALRTIs) and the clinical features and laboratory findings of hospitalized HAdV-infected cases are described. METHODS: Respiratory specimens were collected from pediatric patients with ALRTIs in the emergency department or from those admitted to Beijing Children's Hospital between March 2007 and December 2012. Infections with common respiratory viruses were determined by PCR or RT-PCR. HAdV positive samples were further typed by PCR and sequencing. RESULTS: Among 3356 patients with ALRTIs, 194 (5.8 %) were found to have HAdV infection. HAdV infection was primarily confined to children (88.35 %) less than 5 years of age. A total of 11 different types of HAdV were detected throughout the study period, with HAdV-B7 (49.0 %) and HAdV-B3 (26.3 %) as the most prevalent types, followed by HAdV-C2 (7.7 %) and HAdVC1 (4.6 %). Newly emerging and re-emergent types or variants, HAdV-B55 (n = 5), HAdV-C57 (n = 3), and HAdV-B14p1 (n = 1), were identified. Results also included the reported first case of co-infection with HAdV-C2 and HAdV-C57. Clinical entities of patients with single HAdV infection (n = 49) were similar to those with mixed HAdV/respiratory syncytial virus (RSV) infections (n = 41). Patients with HAdV-B7 infection had longer duration of fever and higher serum levels of muscle enzymes than HAdV-B3-infected patients. CONCLUSIONS: During the study period, HAdV-B7 and HAdV-B3 were the predominant types identified in pediatric ALRTIs. HAdV-B7 infection tends to have more severe clinical consequences. The presence of newly emerging types or variants and co-infection with different types of HAdV highlights the need for constant and close surveillance of HAdV infection. PMID- 26429782 TI - Primary iliopsoas abscess in a patient with diabetic foot. PMID- 26429780 TI - The association of obesity with hearing thresholds in women aged 18-40 years. AB - An elevation in hearing thresholds and decrease in hearing sensitivity in adults, particularly due to aging, are quite common. Recent studies have shown that, apart from aging, various other factors also play a role in auditory changes. Studies on the association of hearing loss (HL) with obesity are limited in advanced age cases and present contradictions. In this study, the association between obesity and hearing thresholds in women aged 18-40 years has been assessed. Forty women diagnosed with obesity (mean age, 31.8 years) and 40 healthy non-obese female controls (mean age, 30.5 years) were included in this prospective study. Each subject was tested with low (250, 500, 1000 and 2000 Hz) and high (4000, 6000 and 8000 Hz) frequency audiometry. In the case and control groups, the average hearing thresholds at low frequencies were 16.03 +/- 4.72 and 16.15 +/- 2.72 (p = 0.885) for the right ear, respectively, and 16.15 +/- 5.92 and 14.71 +/- 3.18 (p = 0.180) for the left ear, respectively. The average hearing threshold levels at high frequencies were 20.70 +/- 10.23 and 15.33 +/- 3.87 (p = 0.003), respectively, for the right ear, and 22.91 +/- 15.54 and 15.87 +/- 4.35 (p = 0.007), respectively, for the left ear with statistical significance. This is the first report on the association of obesity with hearing threshold in women aged 18-40 years. We have demonstrated that obesity may affect hearing function, particularly that related to high frequencies. Hearing loss can be prevented by avoidance or control of obesity and its risk factors. Moreover, an auditory screening of obese cases at an early stage may provide early diagnosis of HL and may also contribute to their awareness in the fight against obesity. PMID- 26429781 TI - Increased osteoporosis risk in dermatomyositis or polymyositis independent of the treatments: a population-based cohort study with propensity score. AB - We investigated the relationship between dermatomyositis/polymyositis (DM/PM) and the risk of subsequent osteoporosis development. A population-based retrospective cohort analysis was conducted using the National Health Insurance Research Database and the Catastrophic Illness Patients Database of Taiwan. We included 1179 patients and 4716 patients from 1999 to 2008 as the DM/PM cohort and the comparison cohort, respectively, and calculated the incidence rates of newly diagnosed osteoporosis. We used Cox proportional hazards models stratified on matched pair to assess the effect of DM/PM. The Kaplan-Meier method was applied to estimate the cumulative osteoporosis incidence curves. Patients with DM/PM were 2.99 times more likely to experience osteoporosis than those without DM/PM. The risk for osteoporosis in DM/PM patients was higher than comparisons in different propensity score quartiles. DM/PM cohort, no matter treated with or without corticosteroids and immunosuppressant, had a higher risk than the comparison cohort. The incidence of osteoporosis in Taiwan is associated with a priori DM/PM history. This risk was independent of the corticosteroids and immunosuppressant treatment. PMID- 26429783 TI - Diabetes as a model for the disparate public response to acute versus chronic diseases. AB - The public health outcry toward infectious entities appears to dwarf chronic diseases such as diabetes. This disparity is particularly astonishing given the considerable prevalence of diabetes and prediabetes. Diseases associated with short-term morbidity and mortality therefore seem to garner attention and demand an immediate public health response, whereas chronic illnesses, which can be considerably more devastating in the longer term, receive relatively less notoriety. It should not, however, be misconstrued that one disease entity is more important than the other--it is critical that both acute and chronic entities are given balanced attention in the public health, governmental, and scientific realms. The current perspective reflects on the disparate public health purviews toward acute and chronic illnesses, describes why prevention is so difficult and challenging, and addresses what can be done to reverse this trend. If there is any hope of conquering the spiraling prediabetes and diabetes epidemics, the medical community must grapple with the complex issues herein raised. PMID- 26429784 TI - Common Non-classically Secreted Bacterial Proteins with Experimental Evidence. AB - The non-classically secreted proteins are the proteins that are located in the extracellular milieu despite the absence of known signal peptides or other targeting peptides. Numerous experimental studies have discovered many non classically secreted proteins, but there are many inconsistencies in these reports even on a specific organism. In order to reduce the impact of artefactual contamination of protein samples and cell lysis, this review listed 45 common non classically secreted proteins. The list of non-classically secreted proteins was complied from studies carried out by different groups in various bacterial species. The complied list can provide a reliable experimental material for further research on non-classical protein secretion. It is noticeable that some of these proteins are hyper-secreted when expressed in specific species or under some induction conditions. So we also discussed the possibilities of using the non-classical secretion pathway for the production of recombinant proteins in the review. PMID- 26429785 TI - Clinical application of a surgical navigation system based on virtual laparoscopy in laparoscopic gastrectomy for gastric cancer. AB - PURPOSE: Knowledge of the specific anatomical information of a patient is important when planning and undertaking laparoscopic surgery due to the restricted field of view and lack of tactile feedback compared to open surgery. To assist this type of surgery, we have developed a surgical navigation system that presents the patient's anatomical information synchronized with the laparoscope position. This paper presents the surgical navigation system and its clinical application to laparoscopic gastrectomy for gastric cancer. METHODS: The proposed surgical navigation system generates virtual laparoscopic views corresponding to the laparoscope position recorded with a three-dimensional (3D) positional tracker. The virtual laparoscopic views are generated from preoperative CT images. A point-based registration aligns coordinate systems between the patient's anatomy and image coordinates. The proposed navigation system is able to display the virtual laparoscopic views using the registration result during surgery. RESULTS: We performed surgical navigation during laparoscopic gastrectomy in 23 cases. The navigation system was able to present the virtual laparoscopic views in synchronization with the laparoscopic position. The fiducial registration error was calculated in all 23 cases, and the average was 14.0 mm (range 6.1-29.8). CONCLUSION: The proposed surgical navigation system can provide CT-derived patient anatomy aligned to the laparoscopic view in real time during surgery. This system enables accurate identification of vascular anatomy as a guide to vessel clamping prior to total or partial gastrectomy. PMID- 26429786 TI - Automatic 3D modelling of human diaphragm from lung MDCT images. AB - PURPOSE: The thoracic diaphragm separates the thorax and abdomen cavity and also performs an important function in respiration. An automatic algorithm to model the human full diaphragm from multi-detector computed tomography (MDCT) images has been developed and tested. METHOD: The modelling algorithm comprises these steps: (i) diaphragm top boundary estimation (ii) diaphragm side boundary estimation and (iii) full diaphragm modelling in 3D. Diaphragm top boundary is estimated based on lungs' diaphragmatic surfaces with three different methods including: linear interpolation and fitting fourth and fifth degree polynomial surfaces. Diaphragm side boundary is assumed as the inner surfaces of the lower ribs, spinal column and costal cartilages, estimated via interpolation. As the last step, the full diaphragm is modelled by employing 3D active contours that are initiated from a predefined mesh and expand towards the estimated boundaries of the diaphragm. The proposed algorithm was tested on MDCT datasets from 15 patients, and the result were compared to reference masks provided by an experienced radiologist. RESULTS: Based on quantitative evaluations, the accuracy of the algorithm highly depends on the diaphragm top surface estimation, e.g., the proposed algorithm failed on two datasets, both with enlarged pericardial fat pad that cuts off the left lung from the diaphragm. The proposed algorithm was tested on the remaining 13 datasets in which lungs' lower surfaces have normal contact with the diaphragm. To perform quantitative evaluations, four slices per dataset including an axial, mid-coronal and one-fourth of the sagittal planes from left and right, were compared to the ground truth. Hausdorff distance and mean distance to the closest point were measured to be 11.61 and 3.46 mm respectively, when the diaphragm top surface is modelled by a fourth degree polynomial surface. CONCLUSION: Human full diaphragm can be automatically modelled with 3D active contours bounded by the lower surfaces of the lungs and inner surfaces of the lower ribs, spinal column and costal cartilages. PMID- 26429787 TI - Vision-based real-time position control of a semi-automated system for robot assisted joint fracture surgery. AB - PURPOSE: Joint fracture surgery quality can be improved by robotic system with high-accuracy and high-repeatability fracture fragment manipulation. A new real time vision-based system for fragment manipulation during robot-assisted fracture surgery was developed and tested. METHODS: The control strategy was accomplished by merging fast open-loop control with vision-based control. This two-phase process is designed to eliminate the open-loop positioning errors by closing the control loop using visual feedback provided by an optical tracking system. Evaluation of the control system accuracy was performed using robot positioning trials, and fracture reduction accuracy was tested in trials on ex vivo porcine model. RESULTS: The system resulted in high fracture reduction reliability with a reduction accuracy of 0.09 mm (translations) and of [Formula: see text] (rotations), maximum observed errors in the order of 0.12 mm (translations) and of [Formula: see text] (rotations), and a reduction repeatability of 0.02 mm and [Formula: see text]. CONCLUSIONS: The proposed vision-based system was shown to be effective and suitable for real joint fracture surgical procedures, contributing a potential improvement of their quality. PMID- 26429788 TI - Association of Intraluminal Thrombus, Hemodynamic Forces, and Abdominal Aortic Aneurysm Expansion Using Longitudinal CT Images. AB - While hemodynamic forces and intraluminal thrombus (ILT) are believed to play important roles on abdominal aortic aneurysm (AAA), it has been suggested that hemodynamic forces and ILT also interact with each other, making it a complex problem. There is, however, a pressing need to understand relationships among three factors: hemodynamics, ILT accumulation, and AAA expansion for AAA prognosis. Hence this study used longitudinal computer tomography scans from 14 patients and analyzed the relationship between them. Hemodynamic forces, represented by wall shear stress (WSS), were obtained from computational fluid dynamics; ILT accumulation was described by ILT thickness distribution changes between consecutives scans, and ILT accumulation and AAA expansion rates were estimated from changes in ILT and AAA volume. Results showed that, while low WSS was observed at regions where ILT accumulated, the rate at which ILT accumulated occurred at the same rate as the aneurysm expansion. Comparison between AAAs with and without thrombus showed that aneurysm with ILT recorded lower values of WSS and higher values of AAA expansion than those without thrombus. Findings suggest that low WSS may promote ILT accumulation and submit the idea that by increasing WSS levels ILT accumulation may be prevented. PMID- 26429789 TI - Physical and Biological Modification of Polycaprolactone Electrospun Nanofiber by Panax Ginseng Extract for Bone Tissue Engineering Application. AB - Medicinal plants as a therapeutic agent with osteogenic properties can enhance fracture-healing process. In this study, the osteo-inductive potential of Asian Panax Ginseng root extract within electrospun polycaprolactone (PCL) based nanofibers has been investigated. Scanning electron microscopy images revealed that all nanofibers were highly porous and beadles with average diameter ranging from 250 to 650 nm. The incorporation of ginseng extract improved the physical characteristics (i.e., hydrophilicity) of PCL nanofibers, as well as the mechanical properties. Although ginseng extract increased the degradation rate of pure PCL nanofibers, the porous structure and morphology of fibers did not change significantly after 42 days. It was found that nanofibrous scaffolds containing ginseng extract had higher proliferation (up to ~1.5 fold) compared to the pristine PCL. The qRT-PCR analysis demonstrated the addition of ginseng extract into PCL nanofibers induced significant expression of osteogenic genes (Osteocalcin, Runx-2 and Col-1) in MSCs in a concentration dependent manner. Moreover, higher calcium content, alkaline phosphatase activity and higher mineralization of MSCs were observed compared to the pristine PCL fibers. Our results indicated the promising potential of ginseng extract as an additive to enhance osteo-inductivity, mechanical and physical properties of PCL nanofibers for bone tissue engineering application. PMID- 26429790 TI - Surgical management of secondary hyperparathyroidism in chronic kidney disease--a consensus report of the European Society of Endocrine Surgeons. AB - BACKGROUND: Despite advances in the medical management of secondary hyperparathyroidism due to chronic renal failure and dialysis (renal hyperparathyroidism), parathyroid surgery remains an important treatment option in the spectrum of the disease. Patients with severe and complicated renal hyperparathyroidism (HPT), refractory or intolerant to medical therapy and patients with specific requirements in prospect of or excluded from renal transplantation may require parathyroidectomy for renal hyperparathyroidism. METHODS: Present standard and actual controversial issues regarding surgical treatment of patients with hyperparathyroidism due to chronic renal failure were identified, and pertinent literature was searched and reviewed. Whenever applicable, evaluation of the level of evidence concerning diagnosis and management of renal hyperparathyroidism according to standard criteria and recommendation grading were employed. Results were discussed at the 6th Workshop of the European Society of Endocrine Surgeons entitled Hyperparathyroidism due to multiple gland disease: An evidence-based perspective. RESULTS: Presently, literature reveals scant data, especially, no prospective randomized studies to provide sufficient levels of evidence to substantiate recommendations for surgery in renal hyperparathyroidism. Appropriate surgical management of renal hyperparathyroidism involves standard bilateral exploration with bilateral cervical thymectomy and a spectrum of four standardized types of parathyroid resection that reveal comparable outcome results with regard to levels of evidence and recommendation. Specific patient requirements may favour one over the other procedure according to individualized demands. CONCLUSIONS: Surgery for patients with renal hyperparathyroidism in the era of calcimimetics continues to play an important role in selected patients and achieves efficient control of hyperparathyroidism. The overall success rate and long-term control of renal hyperparathyroidism and optimal handling of postoperative metabolic effects also depend on the timely indication, individually suitable type of parathyroid resection and specialized endocrine surgery. PMID- 26429791 TI - Emotional traits predict individual differences in amphetamine-induced positive mood in healthy volunteers. AB - BACKGROUND: Previous research on emotional correlates of individual differences in subjective responses to D-amphetamine has focused on relatively broad personality traits. Yet, emotional functioning is best characterized by several narrow subcomponents, each of which may contribute uniquely to amphetamine response. Here, we examine several specific subdomains of emotional functioning in relation to acute amphetamine response. METHOD: At a baseline session, healthy stimulant-naive volunteers (N = 97) completed measures of several subdomains of baseline trait emotional functioning and then completed two counterbalanced experimental sessions during which they received a single oral dose of 20 mg D amphetamine or placebo. Acute subjective drug response measures were completed at repeated intervals before and after drug administration. Data from subjective measures that were significantly modulated by amphetamine were reduced using principal component analysis (amphetamine or placebo) into three higher-order factors of "positive mood," "arousal," and "drug high." Amphetamine did not significantly alter any "negative" subjective states. Separate multiple regression analyses were conducted regressing these three drug factors on baseline trait emotional functioning scales. RESULTS: The combined set of trait emotional functioning indicators accounted for approximately 22 % of the variance in acute amphetamine-induced positive mood changes. Greater anticipatory pleasure and greater anxious distress each uniquely predicted greater amphetamine-induced positive mood. Trait emotional functioning did not significantly predict amphetamine-induced changes in arousal or drug high. DISCUSSION: Emotional traits appear to moderate drug-induced positive mood but not other dimensions of amphetamine effects. Different facets of emotional functioning may differentially modulate amphetamine's subjective effect profile. PMID- 26429792 TI - Contact in the Classroom: Developing a Program Model for Youth Mental Health Contact-Based Anti-stigma Education. AB - This study evaluated eighteen Canadian anti-stigma programs targeting high-school students. The purpose was to identify critical domains and develop a program model of contact-based interventions. Three steps were implemented. The first step involved collecting program information through twenty in-depth interviews with stakeholders and field observations of seven programs. The second step involved constructing critical ingredients into domains for conceptual clarity and component modeling. The third step involved validating the program model by stakeholders review and initial fidelity testing with program outcomes. A program model with an overarching theme "engaging contact reduces stigma" and three underlying constructs (speakers, message, and interaction) were developed. Within each construct three specific domains were identified to explain the concepts. Connection, engagement, and empowerment are critical domains of anti-stigma programs for the youth population. Findings from this study have built on the scientific knowledge about the change theory underpinning youth contact-based intervention. PMID- 26429793 TI - Cyclic mechanical strain of myocytes modifies CapZbeta1 post translationally via PKCepsilon. AB - The heart is exquisitely sensitive to mechanical stimuli and adapts to increased demands for work by enlarging the cardiomyocytes. In order to determine links between mechano-transduction mechanisms and hypertrophy, neonatal rat ventricular myocytes (NRVM) were subjected to physiologic strain for analysis of the dynamics of the actin capping protein, CapZ, and its post-translational modifications (PTM). CapZ binding rates were assessed after strain by fluorescence recovery after photobleaching (FRAP) of green fluorescent protein (GFP) expressed by a GFP CapZbeta1 adenovirus. To assess the role of the protein kinase C epsilon isoform (PKCepsilon), rest or cyclic strain were combined with specific PKCepsilon activation by constitutively active PKCepsilon, or by inhibition with dominant negative PKCepsilon (dnPKCepsilon) expression. Significant increases of CapZ FRAP kinetics with strain were blunted by dnPKCepsilon, suggesting that PKCepsilon is involved in mechano-transduction signaling. Similar combinations of strain and PKC regulation in NRVMs were studied by PTM profiles of CapZbeta1 using quantitative two-dimensional gel electrophoresis. The significantly increased charge on CapZ seen with mechanical strain was reversed by the addition of dnPKCepsilon. Potential clinical relevance was confirmed in vivo by PTMs of CapZ in the failing heart of one-year old transgenic mice over-expressing PKCepsilon. Furthermore, with strain there was significant PKCepsilon translocation to the Z disc and co-localization with CapZbeta1 or alpha-actinin, which was quantified on confocal images. A hypothetical model is presented proposing that one destination of the mechanotransduction signaling pathways might be for PTMs of CapZ thereby regulating actin capping and filament assembly. PMID- 26429795 TI - Cost-analysis of teledentistry in residential aged care facilities. AB - INTRODUCTION: The purpose of this research was to conduct a cost-analysis, from a public healthcare perspective, comparing the cost and benefits of face-to-face patient examination assessments conducted by a dentist at a residential aged care facility (RACF) situated in rural areas of the Australian state of Victoria, with two teledentistry approaches utilizing virtual oral examination. METHODS: The costs associated with implementing and operating the teledentistry approach were identified and measured using 2014 prices in Australian dollars. Costs were measured as direct intervention costs and programme costs. A population of 100 RACF residents was used as a basis to estimate the cost of oral examination and treatment plan development for the traditional face-to-face model vs. two teledentistry models: an asynchronous review and treatment plan preparation; and real-time communication with a remotely located oral health professional. RESULTS: It was estimated that if 100 residents received an asynchronous oral health assessment and treatment plan, the net cost from a healthcare perspective would be AU$32.35 (AU$27.19-AU$38.49) per resident. The total cost of the conventional face-to-face examinations by a dentist would be AU$36.59 ($30.67 AU$42.98) per resident using realistic assumptions. Meanwhile, the total cost of real-time remote oral examination would be AU$41.28 (AU$34.30-AU$48.87) per resident. DISCUSSION: Teledental asynchronous patient assessments were the lowest cost service model. Access to oral health professionals is generally low in RACFs; however, the real-time consultation could potentially achieve better outcomes due to two-way communication between the nurse and a remote oral health professional via health promotion/disease prevention delivered in conjunction with the oral examination. PMID- 26429794 TI - Assessing quality of life in severe obesity: development and psychometric properties of the ORWELL-R. AB - PURPOSE: Several health-related quality-of-life (HRQoL) dimensions are affected by obesity. Our goal was to characterize the psychometric properties of the ORWELL-R, a new obesity-related quality-of-life instrument for assessing the "individual experience of overweightness". METHODS: This psychometric assessment included two different samples: one multicenter clinical sample, used for assessing internal consistency, construct validity and temporal reliability; and a community sample (collected through a cross-sectional mailing survey design), used for additional construct validity assessment and model fit confirmation. RESULTS: Overall, 946 persons participated (188 from the clinical sample; 758 from community sample). An alpha coefficient of 0.925 (clinical sample) and 0.934 (community sample) was found. Three subscales were identified (53.2 % of variance): Body environment experience (alpha = 0.875), Illness perception and distress (alpha = 0.864), Physical symptoms (alpha = 0.674). Adequate test-retest reliability has been confirmed (ICC: 0.78 for the overall score). ORWELL-R scores were worse in the clinical sample. Worst HRQoL, as measured by higher ORWELL-R scores, was associated with BMI increases. ORWELL-R scores were associated with IWQOL-Lite and lower scores in happiness. CONCLUSIONS: ORWELL-R shows good internal consistency and adequate test-retest reliability. Good construct validity was also observed (for convergent and discriminant validity) and confirmed through confirmatory factor analysis (in both clinical and community samples). Presented data sustain ORWELL-R as a reliable and useful instrument to assess obesity-related QoL, in both research and clinical contexts. PMID- 26429796 TI - Reality versus regulation. PMID- 26429797 TI - Commentary on the OPTIDUAL trial results: how to optimise prolonged dual antiplatelet treatment and independent randomised clinical trials. PMID- 26429798 TI - Nox4 NADPH oxidase: emerging from the veil of darkness. PMID- 26429800 TI - Co(2+)@Mesoporous Silica Monoliths: Tailor-Made Nanoreactors for Confined Soft Chemistry. AB - Mesoporous silica monoliths with various ordered nanostructures containing transition metal M(2+) cations in variable amounts were elaborated and studied. A phase diagram depicting the different phases as a function of the M(2+) salt/tetramethyl orthosilicate (TMOS) and surfactant P123/TMOS ratios was established. Thermal treatment resulted in mesoporous monoliths containing isolated, accessible M(2+) species or condensed metal oxides, hydroxides, and salts, depending on the strength of the interactions between the metal species and the ethylene oxide units of P123. The ordered mesoporosity of the monoliths containing accessible M(2+) ions was used as a nanoreactor for the elaboration of various transition metal compounds (Prussian blue analogues, Hofmann compounds, metal-organic frameworks), and this opens the way to the elaboration of a large range of nanoparticles of multifunctional materials. PMID- 26429799 TI - Catheter-based interventions for acute ischaemic stroke. AB - Catheter-based interventions for acute ischaemic stroke currently include clot removal (usually from the medial cerebral artery) with modern stent-retrievers and in one of five patients (who have simultaneous or stand-alone internal carotid occlusion) also extracranial carotid intervention. Several recently published randomized trials clearly demonstrated superiority of catheter-based interventions (with or without bridging thrombolysis) over best medical therapy alone. The healthcare systems should adopt the new strategies for acute stroke treatment (including fast track to interventional lab) to offer the benefits to all suitable acute stroke patients. PMID- 26429801 TI - Fatty acid hydration activity of a recombinant Escherichia coli-based biocatalyst is improved through targeting the oleate hydratase into the periplasm. AB - Whole-cell biotransformation of fatty acids can be influenced by the activities of catalytic enzymes and by the efficiency of substrate transport into host cells. Here, we improved fatty acid hydration activity of the recombinant Escherichia coli expressing an oleate hydratase of Stenotrophomonas maltophilia by targeting the catalytic enzyme into the periplasm instead of the cytoplasm. Recombinant E. coli producing OhyA in the periplasm under guidance of the PelB signal sequence (E. coli OhyA_PP) exhibited significantly greater hydration activity with oleic acid and linoleic acid compared to a recombinant E. coli producing OhyA in the cytoplasm (E. coli OhyA_CS). For example, the oleate double bond hydration rate of E. coli OhyA_PP was >400 MUmol/g dry cells/min (400 U/g dry cells), which is >10-fold higher than that of E. coli OhyA_CS. As the specific activities of the enzymes targeted into the cytoplasm and periplasm were comparable, we assumed that targeting OhyA into the periplasm could accelerate fatty acid transport to the catalytic enzymes by skipping the major mass transport barrier of the cytoplasmic membrane. Our results will contribute to the development of whole-cell biocatalysts for fatty acid biotransformation. PMID- 26429803 TI - Identification of a new HLA-A*24 allele, A*24:313. AB - The new allele, A*24:313, showed one nucleotide difference with A*24:02:01 (595G>A). PMID- 26429804 TI - The role of inflammatory cells in tendinopathy: is the picture getting any clearer? PMID- 26429802 TI - Matrigel Mattress: A Method for the Generation of Single Contracting Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. AB - RATIONALE: The lack of measurable single-cell contractility of human-induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs) currently limits the utility of hiPSC-CMs for evaluating contractile performance for both basic research and drug discovery. OBJECTIVE: To develop a culture method that rapidly generates contracting single hiPSC-CMs and allows quantification of cell shortening with standard equipment used for studying adult CMs. METHODS AND RESULTS: Single hiPSC-CMs were cultured for 5 to 7 days on a 0.4- to 0.8-mm thick mattress of undiluted Matrigel (mattress hiPSC-CMs) and compared with hiPSC-CMs maintained on a control substrate (<0.1-mm thick 1:60 diluted Matrigel, control hiPSC-CMs). Compared with control hiPSC-CMs, mattress hiPSC-CMs had more rod shape morphology and significantly increased sarcomere length. Contractile parameters of mattress hiPSC-CMs measured with video-based edge detection were comparable with those of freshly isolated adult rabbit ventricular CMs. Morphological and contractile properties of mattress hiPSC-CMs were consistent across cryopreserved hiPSC-CMs generated independently at another institution. Unlike control hiPSC-CMs, mattress hiPSC-CMs display robust contractile responses to positive inotropic agents, such as myofilament calcium sensitizers. Mattress hiPSC-CMs exhibit molecular changes that include increased expression of the maturation marker cardiac troponin I and significantly increased action potential upstroke velocity because of a 2-fold increase in sodium current (INa). CONCLUSIONS: The Matrigel mattress method enables the rapid generation of robustly contracting hiPSC-CMs and enhances maturation. This new method allows quantification of contractile performance at the single-cell level, which should be valuable to disease modeling, drug discovery, and preclinical cardiotoxicity testing. PMID- 26429805 TI - Looking back over 20 years of sports medicine prevention and treatment: progress, but still a lot to achieve. PMID- 26429806 TI - Response to: 'The search for size: a doping risk factor in adolescent rugby'. PMID- 26429807 TI - Exercise genomics--a paradigm shift is needed: a commentary. AB - The overarching goal of exercise genomics is to illuminate exercise biology and behaviour in order to better understand the preventive and therapeutic values of exercise. An ancillary aim is to understand the role of genomic variation in human physical attributes and sports performance. The aim of this report is to briefly comment on the current status of exercise genetics and genomics and to suggest potential improvements to the research agenda and translational activities. First, the genomic features of interest to the biology of exercise are defined. Then, the limit of the current focus on common variants and their implications for exercise genomics is highlighted. The need for a major paradigm shift in exercise genomics research is discussed with an emphasis on study designs and appropriately powered studies as well as on more mechanistic and functional research. Finally, a summary of current practices in translational activities compared with what best practice demands is introduced. One suggestion is that the research portfolio of exercise genomics be composed of a larger fraction of experimental and mechanistic investigations and a smaller fraction of observational studies. It is also recommended that research should shift to unbiased exploration of the genome using all the power of genomics, epigenomics and transcriptomics in combination with large observational but preferably experimental study designs, including Mendelian randomisation. In all cases, emphasis on replications is of paramount importance. This represents an extraordinary challenge that can only be met with large-scale collaborative and multicentre research programmes. PMID- 26429808 TI - Cognitive and physical symptoms of concussive injury in children: a detailed longitudinal recovery study. AB - BACKGROUND: Recovery from concussion sustained in childhood and adolescence is poorly understood. We explored patterns of recovery for neurocognition and postconcussive symptoms following concussion in children and adolescents. METHODS: Using a prospective, longitudinal design, we collected baseline data on 728 children and adolescents aged 10-17 years. 10 participants sustained a concussive injury (n=10) in the 12 months following baseline testing and they were reviewed at day 5, 10 and 30 postconcussion. Assessments included the CogSport for Kids computerised test battery to evaluate neurocognitive function and self-report, and parent measures of postconcussive symptoms. At day 30, parents also completed measures rating their child's quality of life and executive functions. RESULTS: Children and adolescents displayed a gradual reduction in postconcussive symptoms over the 30 days following injury. At day 5, 87% of participants were reporting physical and cognitive symptoms, with a generalised reduction in all symptoms by day 10 (40% of participants). On the computerised measure, reaction time was slower after concussion, but returned to baseline levels by day 30. At day 30, 10% of participants demonstrated ongoing postconcussive symptoms. Number of previous concussions was related to speed of symptom resolution. CONCLUSIONS: At 5 days postconcussion, the majority of children and adolescents experienced debilitating postconcussive symptoms. However, by 30 days postinjury, 90% demonstrated recovery to normal for both neurocognition and postconcussive symptoms. PMID- 26429809 TI - Is cardiovascular screening in athletes justified? Inconsistent messages from the American Heart Association. PMID- 26429810 TI - Genetic defects in a His-Purkinje system transcription factor, IRX3, cause lethal cardiac arrhythmias. AB - AIM: Ventricular fibrillation (VF), the main cause of sudden cardiac death (SCD), occurs most frequently in the acute phase of myocardial infarction: a certain fraction of VF, however, develops in an apparently healthy heart, referred as idiopathic VF. The contribution of perturbation in the fast conduction system in the ventricle, the His-Purkinje system, for idiopathic VF has been implicated, but the underlying mechanism remains unknown. Irx3/IRX3 encodes a transcription factor specifically expressed in the His-Purkinje system in the heart. Genetic deletion of Irx3 provides a mouse model of ventricular fast conduction disturbance without anatomical or contraction abnormalities. The aim of this study was to examine the link between perturbed His-Purkinje system and idiopathic VF in Irx3-null mice, and to search for IRX3 genetic defects in idiopathic VF patients in human. METHODS AND RESULTS: Telemetry electrocardiogram recording showed that Irx3-deleted mice developed frequent ventricular tachyarrhythmias mostly at night. Ventricular tachyarrhythmias were enhanced by exercise and sympathetic nerve activation. In human, the sequence analysis of IRX3 exons in 130 probands of idiopathic VF without SCN5A mutations revealed two novel IRX3 mutations, 1262G>C (R421P) and 1453C>A (P485T). Ventricular fibrillation associated with physical activities in both probands with IRX3 mutations. In HL-1 cells and neonatal mouse ventricular myocytes, IRX3 transfection up-regulated SCN5A and connexin-40 mRNA, which was attenuated by IRX3 mutations. CONCLUSION: IRX3 genetic defects and resultant functional perturbation in the His-Purkinje system are novel genetic risk factors of idiopathic VF, and would improve risk stratification and preventive therapy for SCD in otherwise healthy hearts. PMID- 26429812 TI - SPVS calls for vets to be returned to the occupational shortage list. PMID- 26429811 TI - A GWAS SNP for Schizophrenia Is Linked to the Internal MIR137 Promoter and Supports Differential Allele-Specific Expression. AB - Single nucleotide polymorphisms (SNPs) within the MIR137 gene locus have been shown to confer risk for schizophrenia through genome-wide association studies (GWAS). The expression levels of microRNA-137 (miR-137) and its validated gene targets have also been shown to be disrupted in several neuropsychiatric conditions, including schizophrenia. Regulation of miR-137 expression is thus imperative for normal neuronal functioning. We previously characterized an internal promoter domain within the MIR137 gene that contained a variable number tandem repeat (VNTR) polymorphism and could alter the in vitro levels of miR-137 in a stimulus-induced and allele-specific manner. We now demonstrate that haplotype tagging-SNP analysis linked the rs1625579 GWAS SNP for schizophrenia to this internal MIR137 promoter through a proxy SNP rs2660304 located at this domain. We postulated that the rs2660304 promoter SNP may act as predisposing factor for schizophrenia through altering the levels of miR-137 expression in a genotype-dependent manner. Reporter gene analysis of the internal MIR137 promoter containing the common VNTR variant demonstrated genotype-dependent differences in promoter activity with respect to rs2660304. In line with previous reports, the major allele of the rs2660304 proxy SNP, which has previously been linked with schizophrenia risk through genetic association, resulted in downregulation of reporter gene expression in a tissue culture model. The genetic influence of the rs2660304 proxy SNP on the transcriptional activity of the internal MIR137 promoter, and thus the levels of miR-137 expression, therefore offers a distinct regulatory mechanism to explain the functional significance of the rs1625579 GWAS SNP for schizophrenia risk. PMID- 26429813 TI - Veterinary contributions to the elimination of rabies. PMID- 26429814 TI - Change and challenges during a presidential year. PMID- 26429816 TI - Vets suspended from the RCVS Register for lying about a fatal operation. PMID- 26429817 TI - RCVS begins audit of vets' CPD compliance. PMID- 26429818 TI - Pet identification: call for harmonised rules across the EU. PMID- 26429819 TI - Charting progress to a TB-free Wales. PMID- 26429820 TI - Veterinary medicines update. AB - The following information has been produced for Veterinary Record by the Veterinary Medicines Directorate (VMD) to provide an update for veterinary surgeons on recent changes to marketing authorisations for veterinary medicines in the UK and on other relevant issues. PMID- 26429821 TI - Coccidiosis in suckled calves at grass. AB - Prepatent burden in calves with low coccidial oocyst counts, Lead poisoning in cattle, Suspect Ureaplasma species infection in a day-old calf, Lamb dysentery in a five-week-old lamb, Oedema disease in pigs. These are among matters discussed in the disease surveillance report for June from SAC Consulting: Veterinary Services (SAC C VS). PMID- 26429822 TI - Building capacity to reduce biological threats in the Middle East. PMID- 26429823 TI - Veterinary nurses and interprofessional working. PMID- 26429824 TI - Use of stored samples and images in research. PMID- 26429825 TI - Drenching gun injuries in cattle. PMID- 26429833 TI - Giving something back. AB - Gabriel Varga leads the team that developed AFSCAN--the African Small Companion Animal Network, which aims to 'transform the veterinary landscape across Africa'. Dr Varga's veterinary journey began in Kosice, which at the time was part of Czechoslovakia; he is now director of business operations for Zoetis north Europe. PMID- 26429834 TI - A Systematic Review of the Literature on the Sustainability of Community Health Collaboratives. AB - Recent interest in community health collaboratives has been driven by the potential of these types of organizations to solve complex health problems at the local level by bringing together stakeholders that have traditionally operated independently, and often at cross-purposes. Much of the work that is central to the mission of collaboratives can take years to reach fruition, however, and there are a number of challenges to sustaining their activities. In this article, we systematically reviewed the theoretical and empirical literature on health care collaborative sustainability, focusing on definitions and antecedents of sustainability. Given the diversity and fragmentation of this literature, we used this review as a foundation to develop a synthesized definition, conceptual groups of antecedents, and potential research propositions to help guide future research, planning, and practice of sustainable community health collaboratives. PMID- 26429835 TI - Deliberation Makes a Difference: Preparation Strategies for TeamSTEPPS Implementation in Small and Rural Hospitals. AB - Small and rural hospitals face special challenges to implement and sustain organization-wide quality improvement (QI) initiatives due to limited resources and infrastructures. We studied the implementation of TeamSTEPPS, a national QI initiative, in 14 critical access hospitals. Drawing on QI and organization development theories, we propose five strategic preparation steps for TeamSTEPPS: assess needs, reflect on the context, set goals, develop a shared understanding, and select change agents. We explore how hospitals' practices correspond to suggested best practices by analyzing qualitative data collected through quarterly interviews with key informants. We find that the level of deliberation was a key factor that differentiated hospitals' practices. Hospitals that were more deliberate in preparing for the five strategic steps were more likely to experience engagement, perceive efficacy, foresee and manage barriers, and achieve progress during implementation. We discuss potential steps that hospitals may take to better prepare for TeamSTEPPS implementation. PMID- 26429837 TI - Classic Tower of Hanoi, Planning Skills, and the Indian Elderly. AB - OBJECTIVE: Elderly populations are vulnerable to age-related cognitive decline. Planning, a frontal lobe function, is reported to be affected in the elderly population. There is a paucity of studies which assessed planning skills in the elderly Indian population. The present study aimed to examine the utility of the classic Tower of Hanoi in the assessment of planning skills of elderly Indian subjects. METHODS: A total of 215 (60 of whom were females, all aged 55-80 years) cognitively normal elders and 24 patients with mild Alzheimer's disease were recruited. All subjects provided informed consent and their planning skills were assessed using the classic Tower of Hanoi. Performance at each level was measured by the total time taken to solve, number of moves to solve, and the number of rule violations. Receiver operating characteristic curve analysis was exploratively performed to test the utility of the Tower of Hanoi in differentiating patients with mild Alzheimer's disease from those who were cognitively normal. RESULTS: Performance measures of cognitively normal group steeply worsened with increasing complexity. With receiver operating characteristic curve analysis, patients with mild Alzheimer's disease were poorly differentiated from cognitively normal group according to their Tower of Hanoi performance. CONCLUSION: The Tower of Hanoi test is of limited value for the assessment of planning skills in the Indian elderly population. There is a need to modify and develop a suitable neuropsychology tool to assess the planning skills of elderly Indian subjects and further validate it. PMID- 26429836 TI - Antidepressant Prescription Pattern in the Presence of Medical Co-morbidity: REAP AD 2013 Study. AB - OBJECTIVE: To evaluate the prescription pattern of antidepressants in patients with medical co-morbidity from major psychiatric centres in Asia. METHODS: The Research on Asian Psychotropic Prescription Pattern for Antidepressants (REAP-AD 2013) collected data from 42 psychiatric centres in 10 Asian countries and regions. Antidepressant prescriptions of 2320 patients with various psychiatric disorders were evaluated. Of these, 370 patients who had specified medical co morbidities formed the study cohort. RESULTS: Escitalopram (20%) and mirtazapine (20%) were the most commonly prescribed antidepressants in patients with medical co-morbidity followed by sertraline (16%), trazodone (15%), and paroxetine (12%). Overall, more than half (52%; 247/476) of prescriptions comprised selective serotonin reuptake inhibitors. Slightly less than two-thirds (63%; n = 233) of patients received at least 1 selective serotonin reuptake inhibitor. In addition, 79% of patients were prescribed only 1 antidepressant. The mean number of antidepressants used per patient was 1.25 (standard deviation, 0.56). There were subtle differences in the most preferred antidepressant across medical illnesses such as diabetes mellitus, liver dysfunction, acid peptic disease, and cerebrovascular disease. Differences were also seen in prescription patterns across different countries. CONCLUSION: Although selective serotonin reuptake inhibitors formed the bulk of antidepressant prescriptions in the presence of medical co-morbidity, mirtazapine was also commonly used in the presence of medical co-morbidities. Specified medical morbidities do influence the selection of antidepressants. PMID- 26429838 TI - Frequency and Correlates of Distant Visual Impairment in Patients with Schizophrenia, Bipolar Disorder, and Major Depressive Disorder. AB - OBJECTIVE: Distant visual impairment in the severely mentally ill is under researched. This study aimed to assess the frequency and correlates of distant visual impairment in a cohort of Chinese psychiatric patients, including its effect on their quality of life. METHODS: Adult psychiatric inpatients with schizophrenia, bipolar disorder, and major depressive disorder consecutively admitted to a psychiatric hospital in Beijing, China underwent assessments of psychopathology (Brief Psychiatric Rating Scale, 16-item Quick Inventory of Depressive Symptomatology [Self-Report]), quality of life (12-item Short-Form Medical Outcomes Study [SF-12], 25-item National Eye Institute Visual Function Questionnaire [NEI-VFQ25]), adverse effects (Udvalg for Kliniske Undersogelser Side Effect Rating Scale), and presenting (as opposed to uncorrected) distant visual acuity (Logarithm of the Minimum Angle of Resolution [LogMAR] chart with patients wearing spectacles, if they owned them). Distant visual impairment was defined as binocular distant visual acuity of a LogMAR score of >= 0.5 (< 6/18 Snellen acuity). RESULTS: Among 356 patients who met the study criteria, the frequency of distant visual impairment was 12.6% (15.2% with schizophrenia, 11.9% with bipolar disorder, 8.8% with major depressive disorder). In multiple logistic regression analysis, distant visual impairment was significantly associated with ocular disease only (p = 0.002, odds ratio = 3.2, 95% confidence interval = 1.5 6.7). Controlling for the confounding effect of ocular disease, patients with distant visual impairment had a lower quality of life in the general vision domain of the NEI-VFQ25 (F[2, 353] = 9.5, p = 0.002) compared with those without. No differences in the physical and mental domains of the SF-12 and in other domains of the NEI-VFQ25 were noted in these 2 groups. CONCLUSION: One-eighth of middle-aged severely mentally ill patients had distant visual impairment. Considering the impact of distant visual impairment on daily functioning, severely mentally ill patients need to be screened for impaired eyesight as part of their comprehensive health assessment. PMID- 26429839 TI - Homelessness and Cognitive Impairment: An Exploratory Study in Tokyo, Japan. AB - OBJECTIVE: Homelessness has frequently been associated with neuropsychological impairment. This has been observed using general screening tests for dementia as well as tests of more focal abilities, particularly executive function. Most studies have been of homeless individuals from North America with none reported from Japan. METHODS: In this exploratory study we interviewed a sample of 16 homeless adults from Tokyo, Japan, and performed tests of cognitive function, assessed head injury, addictive behaviours (drug use, gambling, alcohol abuse), and recorded details of homelessness history. The cognitive examination involved the Japanese Adult Reading Test to estimate premorbid intelligence quotient, the Wisconsin Card Sorting Test to measure frontal lobe-related cognitive function, and the Mini-Mental State Examination to measure global cognitive impairment associated with dementia. RESULTS: Among the 16 homeless individuals, 7 (44%) displayed global cognitive impairment. In addition, executive function tended to be poor. In contrast, estimated premorbid intelligence quotient was within the normal range. Substance abuse in general was not at a level to cause clinical concern, although a high level of pathological gambling was observed. There were no associations between cognitive function and clinical and addictive behaviour variables, although associations were noted between cognitive scores and time spent homeless. CONCLUSION: The results suggest high levels of neuropsychological impairment in this sample of homeless adults in Japan. Furthermore, cognitive impairment is acquired rather than developmental in origin, and is proportional to the length of time spent homeless. PMID- 26429840 TI - Psychiatric Morbidity in Chinese Adults with Type 1 Diabetes in Hong Kong. AB - OBJECTIVES: To determine the prevalence of psychiatric morbidity and identify the correlates, as well as to evaluate the effectiveness of the Hospital Anxiety and Depression Scale and the 12-item General Health Questionnaire to screen for psychiatric morbidity in Chinese adults with type 1 diabetes. METHODS: Subjects were recruited from a local public diabetes specialist outpatient clinic from August 2013 to January 2014. Demographic and clinical factors were recorded. Psychiatric diagnosis was established using the Chinese-bilingual version of the Structured Clinical Interview for the DSM-IV Axis I disorders. Scores for the Hospital Anxiety and Depression Scale and the 12-item General Health Questionnaire were compared with the psychiatric diagnosis. RESULTS: Of the 136 patients, the point prevalence of overall psychiatric, depressive, and anxiety disorders was 39.7%, 23.5%, and 25.7%, respectively. Family history of mental illness, smoking status, history of mental illness, presence of social problems, perceived absence of confidant, presence of neuropathy and hyperlipidaemia, as well as higher level of glycosylated haemoglobin were found to be the associated factors. CONCLUSION: Psychiatric disorders were common in Chinese adults with type 1 diabetes. Finding out associated factors and using the Hospital Anxiety and Depression Scale and the 12-item General Health Questionnaire as a screening tool helped to identify patients in a diabetes clinic with psychiatric disorders. PMID- 26429841 TI - Is Add-on Psycho-education Effective in the Treatment of Depression? PMID- 26429842 TI - Authors' reply. PMID- 26429843 TI - The Best and the Brightest: 40 under 40. PMID- 26429844 TI - Highlights from the Current Issue: October 2015. PMID- 26429845 TI - Interpretation of Coronary Angiograms Recorded Using Google Glass: A Comparative Analysis. AB - INTRODUCTION: Google Glass (Google, Inc) is a voice-activated, hands-free, optical head-mounted display device capable of taking pictures, recording videos, and transmitting data via wi-fi. In the present study, we examined the accuracy of coronary angiogram interpretation, recorded using Google Glass. METHODS: Google Glass was used to record 15 angiograms with 17 major findings and the participants were asked to interpret those recordings on: (1) an iPad (Apple, Inc); or (2) a desktop computer. Interpretation was compared with the original angiograms viewed on a desktop. Ten physicians (2 interventional cardiologists and 8 cardiology fellows) participated. One point was assigned for each correct finding, for a maximum of 17 points. RESULTS: The mean angiogram interpretation score for Google Glass angiogram recordings viewed on an iPad or a desktop vs the original angiograms viewed on a desktop was 14.9 +/- 1.1, 15.2 +/- 1.8, and 15.9 +/- 1.1, respectively (P=.06 between the iPad and the original angiograms, P=.51 between the iPad and recordings viewed on a desktop, and P=.43 between the recordings viewed on a desktop and the original angiograms). In a post-study survey, one of the 10 physicians (10%) was "neutral" with the quality of the recordings using Google Glass, 6 physicians (60%) were "somewhat satisfied," and 3 physicians (30%) were "very satisfied." CONCLUSION: This small pilot study suggests that the quality of coronary angiogram video recordings obtained using Google Glass may be adequate for recognition of major findings, supporting its expanding use in telemedicine. PMID- 26429846 TI - Heads Up! Introducing Wearable Health Technologies in Cardiology. PMID- 26429847 TI - ECMO and the Intraaortic Balloon Pump: In Search of the Ideal Mechanical Circulatory Support Device. PMID- 26429848 TI - Evaluation of the Safety of Everolimus-Eluting Bioresorbable Vascular Scaffold (BVS) Implantation in Patients With Chronic Total Coronary Occlusions: Acute Procedural and Short-Term Clinical Results. AB - AIMS: The bioresorbable vascular scaffold (BVS) (Abbott Vascular) provides temporary scaffolding while eluting everolimus. There are limited data on its use in daily practice, especially in patients with stable angina pectoris referred for elective percutaneous coronary intervention (PCI) of chronic total occlusions (CTOs). The current study aims to investigate the safety and efficacy of BVS implantation in a selected patient cohort with CTO. METHODS: A total of 70 consecutive patients, who underwent successful recanalization of CTO with BVS between September 13, 2012 and September 20, 2014 in three cardiac centers (Department of Cardiology, Bezmialem Vakif University, Istanbul, Turkey; Department of Interventional Cardiology, San Raffaele Hospital, Milan, Italy; and EMO-GVM Centro Cuore Columbus, Milan, Italy) were included in this CTO registry. Endpoints analyzed included: (1) the composite of all-cause death and non-fatal myocardial infarction (MI); and (2) the composite safety endpoint of major adverse cardiovascular events (MACEs), including death, MI and symptom-driven target lesion revascularization (TLR). RESULTS: Clinical data were obtained for 70 patients (mean age, 56.9 +/- 9.4 years; 90.0% male) with a total number of 76 CTOs. At a median follow-up of 11.0 months (interquartile range, 7-18 months), both MACE and TLR rates were 4.3%. Two patients suffered from ischemia-driven TLR (1 patient at 6 months and 1 patient at 9 months after implantation). No death, MI, or stent thrombosis was observed during the follow-up period. CONCLUSION: Treatment of CTOs with BVS seems to be safe and effective, with a high technical success rate and acceptable MACE at short-term follow-up. PMID- 26429849 TI - Transcatheter Aortic Valve Implantation in Patients of Extreme Age: Age is Just a Number. PMID- 26429850 TI - Physiologic Guidance of Infrainguinal Vascular Interventions Using the Pressure Wire. AB - OBJECTIVES: To assess the relationship between the resting (RG) and hyperemic (HG) translesional peripheral gradients, with the functional and anatomic parameters before and after an infrainguinal endovascular procedure. BACKGROUND: RGs and HGs are objective tools in defining the hemodynamic significance of an arterial stenosis. METHODS: In 25 subjects with infrainguinal arterial stenosis, RG and HG were measured via a pressure wire before and after angioplasty. Before and after the procedure, all subjects had an ankle-brachial index (ABI) and Duplex ultrasound evaluation, recording prelesion and in-lesion peak systolic velocity (PSV-L), and calculating a peak systolic velocity ratio (PSV-R). A Pearson R correlation coefficient was calculated. RESULTS: The mean age was 73 +/ 12 years, 70% were men, median Rutherford class 3. At baseline and after angioplasty, mean ABI was 0.78 +/- 0.2 and 0.99 +/- 0.1, mean PSV-L was 459 +/- 110 cm/s and 126 +/- 35 cm/s, and mean PSV-R was 6.7 +/- 4 and 1.2 +/- 0.5, respectively. RG and HG significantly improved (P<.001) from baseline to after angioplasty (28.7 +/- 20.5 mm Hg to 5 +/- 13 mm Hg and 40.2 +/- 21.4 mm Hg to 10 +/- 13 mm Hg, respectively). RG before and after the procedure correlated well with ABI (r = -0.58; r = -0.41), PSV-L (r = 0.40; r = 0.52), and PSV-R (r = 0.46; r = 0.42). An improvement of 9 mm Hg in RG predicted a change of 0.1 in ABI. CONCLUSIONS: Improvement in RG during endovascular intervention in superficial femoral artery correlates well with the improvement in ABI, PSV-L, and PSV-R. A postprocedural decrease in RG of 9 mm HG predicts an improvement in ABI of 0.1. PMID- 26429851 TI - Effect of Extended-Release Niacin on Saphenous Vein Graft Atherosclerosis: Insights from the Atherosclerosis Lesion Progression Intervention Using Niacin Extended Release in Saphenous Vein Grafts (ALPINE-SVG) Pilot Trial. AB - BACKGROUND: Intermediate saphenous vein graft (SVG) lesions have high rates of progression. The purpose of this study was to examine the impact of extended release niacin (ER-niacin) vs placebo on intermediate SVG lesions. METHODS: Patients with intermediate (30%-60% diameter stenosis) SVG lesions were randomized to ER-niacin vs placebo for 12 months. Quantitative coronary angiography (QCA), intravascular ultrasonography (IVUS), and optical coherence tomography (OCT) were performed at baseline and at 12 months. The primary endpoint was change in percent atheroma volume (DeltaPAV). Enrollment was planned for 138 patients for 90% power to detect >=2.5% difference in the primary endpoint of DeltaPAV, but stopped early after publication of two negative outcome trials of ER-niacin, with enrolled patients completing the 12-month trial protocol. RESULTS: Thirty-eight patients were randomized to niacin (n = 19) or placebo (n = 19), yielding power of 47% to detect the primary planned treatment effect of 2.5 +/- 4.0% difference in DeltaPAV. Between baseline and 12-month follow-up, no significant difference was found between study groups in DeltaPAV ( 1.31 +/- 6.05% vs 1.05 +/- 17.8%; P=.60). By OCT, the ER-niacin vs placebo group had less plaque rupture within the intermediate SVG lesion (0.0% vs 36.0%; P=.01). CONCLUSION: Administration of ER-niacin did not significantly impact intermediate SVG disease, with the notable limitation of compromised statistical power due to early termination of enrollment. PMID- 26429852 TI - Frequency, Indications, and Outcomes of Guide Catheter Extension Use in Percutaneous Coronary Intervention. AB - BACKGROUND: The frequency and outcomes of guide catheter extension use during percutaneous coronary intervention (PCI) have received limited study. METHODS: We retrospectively examined 1539 consecutive PCIs performed between May 2010 and November 2013 to determine the frequency and outcomes of guide catheter extension utilization. RESULTS: During the study period, a guide catheter extension was used in 83 cases (5.4%; 95% confidence interval, 4.3%-6.6%) in 86 vessels. The PCI target vessel was the left anterior descending artery (11%), circumflex (23%), right coronary artery (50%), left main (1%), or a saphenous vein bypass graft (15%). The indications for use (non-mutually exclusive) were to facilitate equipment delivery or provide vessel support/ engagement (84.7%), thrombus aspiration (10.5%), retrieval of lost devices (2.3%), facilitation of reverse controlled antegrade and retrograde tracking and dissection (1%), and selective vessel visualization with contrast (1%). Guide catheter extension success rate was 73.3% and technical and procedural success rates were 91.6% and 90.4%, respectively. Four patients (4.8%) experienced a guide catheter extension-related complication: vessel dissection/injury in 2 cases (1 case required emergency coronary artery bypass graft surgery and 1 case required stenting) and equipment loss in 2 cases (1 detachment of the distal guide-extension marker and 1 shearing of a guidewire tip that embolized to the renal artery). CONCLUSIONS: In a contemporary patient population undergoing PCI, a guide catheter extension was used in approximately 1 of 20 PCIs. Guide catheter extensions can facilitate procedural success, but also carry low risk for device-related complications. PMID- 26429853 TI - TAVR Through Heavily Calcified Aorta Following Atheroma Retrieval With the "Elevator" Technique. AB - An 86-year-old Caucasian female with severe symptomatic, inoperable aortic stenosis was accepted for high-risk transfemoral transcatheter aortic valve replacement (TAVR) approach due to severe calcification of the aorta. During initial passage of a 22 Fr sheath, there was dislodgment with proximal migration of a circumferential tunnel of calcium from the infrarenal aorta. A novel "elevator" technique was used to secure and retrieve the dislodged aorta en bloc back to its original infrarenal aortic position and allow in situ fixation with stenting. A new TAVR system was then successfully placed through the stent and a 23 mm Edwards Sapien valve (Edwards Lifesciences) was implanted as planned. In case of calcification protruding into the lumen of the aorta and limiting the passage of the large valve delivery system sheath, the obstruction can be managed by stenting the calcification against the luminal wall under fluoroscopic and intravascular-ultrasound guidance, allowing successful passage of the valve delivery system. The elevator technique allows axial transportation of any calcified vascular fragments, should they become dislodged. PMID- 26429854 TI - First Reported Successful Femoral Valve-in-Valve Transcatheter Aortic Valve Replacement Using the Edwards Sapien 3 Valve. AB - OBJECTIVES: Management of degenerated aortic valve bioprosthesis classically requires redo surgery, but transcatheter aortic valve-in-valve implantation is becoming a valid alternative in selected cases. In the case of a degenerated Mitroflow bioprosthesis, TAVR is associated with an additional challenge due to a specific risk of coronary occlusion. We aimed to assess the safety and feasibility of transfemoral valve-in-valve implantation of the new Edwards Sapien 3 (Edwards Lifesciences) in a degenerated Mitroflow bioprosthesis (Sorin Group, Inc). METHODS: We report here the safety and feasibility of transfemoral valve-in valve implantation of a 23 mm Edwards Sapien 3 in a degenerated 25 mm Mitroflow valve and describe the specific assessment of the risk of coronary obstruction using a multi-imaging modality. RESULTS: The final result showed an absence of aortic regurgitation and a mean transvalvular gradient of 14 mm Hg. The patient had no major adverse cardiovascular events at 30-day follow-up. CONCLUSION: Transcatheter valve-in-valve implantation of an Edwards Sapien 3 in a degenerated Mitroflow is feasible and safe, considering a careful assessment of the risk of coronary obstruction with Mitroflow bioprosthesis due to leaflets mounted externally to the stent. PMID- 26429855 TI - Chordal Rupture Following MitraClip Implantation Resulting in Massive Mitral Regurgitation. AB - MitraClip (Abbott Vascular) therapy has been reported to be a safe and effective treatment for mitral regurgitation, even when the commissures are targeted. However, complications during the procedure may occur. We present a 44-year-old patient who underwent MitraClip implantation complicated by chordal rupture, resulting in emergent mitral valve replacement. PMID- 26429856 TI - Paravalvular Regurgitation After TAVR: Time Heals, or Not? PMID- 26429857 TI - The New Occlutech Duct Occluder. PMID- 26429858 TI - Palpation Versus Ultrasound in Femoral Artery Catheterization: Figure Error Notification. PMID- 26429860 TI - Focused ultrasound enhanced molecular imaging and gene therapy for multifusion reporter gene in glioma-bearing rat model. AB - The ability to monitor the responses of and inhibit the growth of brain tumors during gene therapy has been severely limited due to the blood-brain barrier (BBB). A previous study has demonstrated the feasibility of noninvasive in vivo imaging with 123I-2'-fluoro-2'-deoxy-5-iodo-1-beta-D-arabinofuranosyluracil (123I FIAU) for monitoring herpes simplex virus type 1 thymidine kinase (HSV1-tk) cancer gene expression in an experimental animal model. Here, we tested the enhancement of SPECT with 123I-FIAU and ganciclovir (GCV) treatment in brain tumors after BBB disruption induced by focused ultrasound (FUS) in the presence of microbubbles. We established an orthotopic F98 glioma-bearing rat model with trifusion reporter genes. The results of this study showed that the rat model of HSV1-tk-expressing glioma cells could be successfully detected by SPECT imaging after FUS-induced BBB disruption on day 10 after implantation. Compared to the control group, animals receiving the GCV with or without sonication exhibited a significant antitumor activity (P < 0.05) of glioma cells on day 16 after implantation. Moreover, combining sonication with GCV significantly inhibited tumor growth compared with GCV alone. This study demonstrated that FUS may be used to deliver a wide variety of theranostic agents to the brain for molecular imaging and gene therapy in brain diseases. PMID- 26429859 TI - HDAC inhibitor AR-42 decreases CD44 expression and sensitizes myeloma cells to lenalidomide. AB - Multiple myeloma (MM) is a hematological malignancy of plasma cells in the bone marrow. Despite multiple treatment options, MM is inevitably associated with drug resistance and poor outcomes. Histone deacetylase inhibitors (HDACi's) are promising novel chemotherapeutics undergoing evaluation in clinical trials for the potential treatment of patients with MM. Although in preclinical studies HDACi's have proven anti-myeloma activity, but in the clinic single-agent HDACi treatments have been limited due to low tolerability. Improved clinical outcomes were reported only when HDACi's were combined with other drugs. Here, we show that a novel pan-HDACi AR-42 downregulates CD44, a glycoprotein that has been associated with lenalidomide and dexamethasone resistance in myeloma both in vitro and in vivo. We also show that this CD44 downregulation is in part mediated by miR-9-5p, targeting insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), which directly binds to CD44 mRNA and increases its stability. Importantly, we also demonstrate that AR-42 enhances anti-myeloma activity of lenalidomide in primary MM cells isolated from lenalidomide resistant patients and in in vivo MM mouse model. Thus, our findings shed light on potential novel combinatorial therapeutic approaches modulating CD44 expression, which may help overcome lenalidomide resistance in myeloma patients. PMID- 26429862 TI - Autophagy manages disease-associated stress granules. PMID- 26429863 TI - Physical, Cognitive, Social, and Emotional Mediators of Activity Involvement and Health in Later Life. AB - The current study tests the indirect effect of activity-related physical activity, cognitive activity, social interaction, and emotional exchange on the relationship between activity involvement and health (physical and emotional) in later life. Longitudinal data from the Health and Retirement Study (N = 5,442) were used to estimate a series of linear regression models. We found significant indirect effects for social interaction and benefit to others (emotional exchange) on emotional health (depressive symptoms) and indirect effects for use of body and benefit to others (physical) on physical health (frailty). The most potent indirect effect associated with emotional and physical health was experienced by those engaged in all four domains (use of body, use of mind, social interaction, and benefit to others). While effect sizes are small and results should be interpreted with caution, findings shed light on ways in which public health interventions aimed toward increasing role engagement in later life could be improved. PMID- 26429864 TI - Decoding poxvirus genome. PMID- 26429861 TI - IL-17 producing mast cells promote the expansion of myeloid-derived suppressor cells in a mouse allergy model of colorectal cancer. AB - Food allergy can influence the development of colorectal cancer, although the underlying mechanisms are unclear. While mast cells (MC) store and secrete histamine, immature myeloid cells (IMC) are the major site of histidine decarboxylase (HDC) expression, the enzyme responsible for histamine production. From our earlier work, we hypothesized that histamine is central to the association between allergy and colorectal carcinogenesis through its influence on the MC-MDSC axis. Here, we show that in wild type (WT) mice, ovalbumin (OVA) immunization elicits a typical TH2 response. In contrast, in HDC-/- mice, the response to OVA allergy is skewed towards infiltration by IL-17 expressing MCs. This response is inhibited by histamine treatment. The HDC-/- allergic IL-17 expressing MCs promote MDSC proliferation and upregulation of Cox-2 and Arg-1. OVA allergy in HDC-/- mice increases the growth of colon tumor cells in both the MC38 tumor cell implantation model and the AOM/DSS carcinogenesis model. Taken together, our results show that histamine represses IL-17-expressing MCs and their subsequent activation of MDSCs, attenuating the risk of colorectal cancer in the setting of food allergy. Targeting the MC-MDSC axis may be useful for cancer prevention and treatment in patients, particularly in those with food allergy. PMID- 26429865 TI - Passive virus movements with organelle dynamics. PMID- 26429866 TI - Architecture of viral replication factories. PMID- 26429867 TI - High-intensity interval training-induced metabolic adaptation coupled with an increase in Hif-1alpha and glycolytic protein expression. AB - It is known that repeated bouts of high-intensity interval training (HIIT) lead to enhanced levels of glycolysis, glycogenesis, and lactate transport proteins in skeletal muscle; however, little is known about the molecular mechanisms underlying these adaptations. To decipher the mechanism leading to improvement of skeletal muscle glycolytic capacity associated with HIIT, we examined the role of hypoxia-inducible factor-1alpha (Hif-1alpha), the major transcription factor regulating the expression of genes related to anaerobic metabolism, in the adaptation to HIIT. First, we induced Hif-1alpha accumulation using ethyl 3,4 dihydroxybenzoate (EDHB) to assess the potential role of Hif-1alpha in skeletal muscle. Treatment with EDHB significantly increased the protein levels of Hif 1alpha in gastrocnemius muscles, accompanied by elevated expression of genes related to glycolysis, glycogenesis, and lactate transport. Daily administration of EDHB for 1 wk resulted in elevated glycolytic enzyme activity in gastrocnemius muscles. Second, we examined whether a single bout of HIIT could induce Hif 1alpha protein accumulation and subsequent increase in the expression of genes related to anaerobic metabolism in skeletal muscle. We observed that the protein levels of Hif-1alpha and expression of the target genes were elevated 3 h after an acute bout of HIIT in gastrocnemius muscles. Last, we examined the effects of long-term HIIT. We found that long-term HIIT increased the basal levels of Hif 1alpha as well as the glycolytic capacity in gastrocnemius muscles. Our results suggest that Hif-1alpha is a key regulator in the metabolic adaptation to high intensity training. PMID- 26429868 TI - In vivo maximal fascicle-shortening velocity during plantar flexion in humans. AB - Interindividual variability in performance of fast movements is commonly explained by a difference in maximal muscle-shortening velocity due to differences in the proportion of fast-twitch fibers. To provide a better understanding of the capacity to generate fast motion, this study aimed to 1) measure for the first time in vivo the maximal fascicle-shortening velocity of human muscle; 2) evaluate the relationship between angular velocity and fascicle shortening velocity from low to maximal angular velocities; and 3) investigate the influence of musculo-articular features (moment arm, tendinous tissues stiffness, and muscle architecture) on maximal angular velocity. Ultrafast ultrasound images of the gastrocnemius medialis were obtained from 31 participants during maximal isokinetic and light-loaded plantar flexions. A strong linear relationship between fascicle-shortening velocity and angular velocity was reported for all subjects (mean R(2) = 0.97). The maximal shortening velocity (V(Fmax)) obtained during the no-load condition (NLc) ranged between 18.8 and 43.3 cm/s. V(Fmax) values were very close to those of the maximal shortening velocity (V(max)), which was extrapolated from the F-V curve (the Hill model). Angular velocity reached during the NLc was significantly correlated with this V(Fmax) (r = 0.57; P < 0.001). This finding was in agreement with assumptions about the role of muscle fiber type, whereas interindividual comparisons clearly support the fact that other parameters may also contribute to performance during fast movements. Nevertheless, none of the biomechanical features considered in the present study were found to be directly related to the highest angular velocity, highlighting the complexity of the upstream mechanics that lead to maximal-velocity muscle contraction. PMID- 26429869 TI - Eccentric exercise slows in vivo microvascular reactivity during brief contractions in human skeletal muscle. AB - Unaccustomed exercise involving eccentric contractions results in muscle soreness and an overall decline in muscle function, however, little is known about the effects of eccentric exercise on microvascular reactivity in human skeletal muscle. Fourteen healthy men and women performed eccentric contractions of the dorsiflexor muscles in one leg, while the contralateral leg served as a control. At baseline, and 24 and 48 h after eccentric exercise, the following were acquired bilaterally in the tibialis anterior muscle: 1) transverse relaxation time (T2)-weighted magnetic resonance images to determine muscle cross-sectional area (mCSA) and T2; 2) blood oxygen level-dependent (BOLD) images during and following brief, maximal voluntary contractions (MVC) to monitor the hyperemic responses with participants positioned supine in a 3T magnet; 3) muscle strength; and 4) pain pressure threshold. Compared with the control leg, eccentric exercise resulted in soreness, decline in strength (~20%), increased mCSA (~7%), and prolonged T2 (~7%) at 24 and 48 h (P < 0.05). The BOLD response to a brief MVC was altered 24 and 48 h after eccentric exercise, such that time-to-peak (~35%, P < 0.05) and time-to-half-recovery (~23%, P < 0.05) were prolonged. The altered contraction-induced hyperemic response suggests slowed microvascular reactivity and altered matching of O2 delivery to O2 utilization within muscle tissue showing signs of muscle damage. These changes in microvascular regulation after eccentric exercise may impede rapid adjustments in muscle blood flow at exercise onset and during activities involving brief bursts of muscle activation, which may impair O2 delivery and contribute to reduced muscle function after eccentric exercise. PMID- 26429870 TI - Cardiorespiratory and sensory responses to exercise in adults with mild cystic fibrosis. AB - The purpose of this study was to evaluate cardiorespiratory fitness and reasons for exercise curtailment in a contemporary adult cystic fibrosis (CF) cohort with mild lung disease. Adults with mild CF (n = 19, forced expiratory volume in 1 s = 95 +/- 17% predicted) were age-, sex-, ethnicity-, and body mass index-matched to healthy controls (n = 19) and underwent a detailed cardiopulmonary cycle exercise test. While CF subjects had a reduced peak oxygen uptake compared with controls, the values were normal when expressed as %predicted in 14/19 (74%) of subjects. Both groups demonstrated a normal cardiovascular limitation to exercise and stopped exercise primarily because of leg fatigue. Despite not being exercise limited by respiratory factors, there was some evidence of ventilatory abnormalities as patients with mild CF had increased end-inspiratory lung volumes and reached an inflection/plateau in tidal volume relative to minute ventilation at lower exercise intensities compared with controls. Subjects with CF were not more likely to demonstrate expiratory flow limitation compared with controls and did not have evidence of dynamic hyperinflation during exercise. Despite increased end-inspiratory lung volumes and an earlier tidal volume inflection/plateau, CF subjects did not experience higher levels of dyspnea. In an exploratory analysis, a significant inverse correlation was observed between sweat chloride and peak work rate. Adult CF subjects with relatively well preserved spirometry have normal exercise performance relative to reference values and are primarily limited by nonrespiratory factors. However, ventilatory abnormalities were detected even in this mild CF cohort and should be evaluated in future therapeutic trials focused on disease-modifying therapies in mild CF. PMID- 26429871 TI - Good syndrome presenting with CD8+ T-Cell large granular lymphocyte leukemia. AB - Good Syndrome is an adult-onset combined immunodeficiency defined by hypogammaglobulinemia, low or absent number of B cells, T cell deficiency and thymic tumor. We have characterized CD8+ T cells from a patient with Good syndrome that presented with CD8+T-cell large granular lymphocytic leukemia (LGL). Characterization of peripheral blood CD8+ T cells revealed that majority of CD8+ T cells were terminally differentiated effector memory phenotype (TEMRA; CD8+CCR7-CD45RA+), and were PD-1high (CD279), ICOSlow (CD278), and granzymehigh. Almost all CD8+ T cells were IFN-gamma+. CD8 Treg (CD8+CD183+CCR7+CD45RA-) were decreased. TEMRA phenotype along with CD279high, demonstrates that these are exhausted CD8+ T cells. This phenotype along with CD278low may also explain severe T cell functional deficiency in our patient. In the present patient, T-LGL appears to be a clonal expansion of CD279+granzyme+IFN-gamma+CD8+TEMRA cells. To best of our knowledge this is the first case of CD8+T-cell LGL leukemia associated with Good syndrome. PMID- 26429872 TI - Application of functional vincristine plus dasatinib liposomes to deletion of vasculogenic mimicry channels in triple-negative breast cancer. AB - Standard chemotherapy cannot eradicate triple-negative breast cancer (TNBC) while the residual cancer cells readily form the vasculogenic mimicry (VM) channels, which lead to the relapse of cancer after treatment. In this study, the functional vincristine plus dasatinib liposomes, modified by a targeting molecule DSPE-PEG2000-c(RGDyK), were fabricated to address this issue. The investigations were performed on TNBC MDA-MB-231 cells and MDA-MB-231 xenografts in nude mice. The liposomes exhibited the superior performances in the following aspects: the enhancement of cellular uptake via targeted action; the induction of apoptosis via activation of caspase 8, 9, and 3, increased expression of Bax, decreased expression of Mcl-1, and generation of reactive oxygen species (ROS); and the deletion of VM channels via inhibitions on the VM channel indicators, which consisted of vascular endothelial-cadherin (VE-Cad), focal adhesion kinase (FAK), phosphatidylinositide 3-kinase (PI3K), and matrix metallopeptidases (MMP-2, and MMP-9). Furthermore, the liposomes displayed the prolonged circulation time in the blood, the increased accumulation in tumor tissue, and the improved therapeutic efficacy along with deletion of VM channels in the TNBC-bearing mice. In conclusion, the nanostructured functional drug-loaded liposomes may provide a promising strategy for the treatment of invasive TNBC along with deletion of VM channels. PMID- 26429873 TI - Genomic landscape of endometrial stromal sarcoma of uterus. AB - Although recurrent gene fusions such as JAZF1-JJAZ1 are considered driver events for endometrial stromal sarcoma (ESS) development, other genomic alterations remain largely unknown. In this study, we performed whole-exome sequencing, transcriptome sequencing and copy number profiling for five ESSs (three low-grade ESS (LG-ESS) and two undifferentiated uterine sarcomas (UUSs)). All three LG-ESSs exhibited either one of JAZF1-SUZ12, JAZF1-PHF1 and MEAF6-PHF1 fusions, whereas the two UUSs did not. All ESSs except one LG-ESS exhibited copy number alterations (CNAs), many of which encompassed cancer-related genes. In UUSs, five CNAs encompassing cancer-related genes (EZR, CDH1, RB1, TP53 and PRKAR1A) accompanied their expressional changes, suggesting that they might stimulate UUS development. We found 81 non-silent mutations (35 from LG-ESSs and 46 from UUSs) that included 15 putative cancer genes catalogued in cancer-related databases, including PPARG and IRF4 mutations. However, they were non-recurrent and did not include any well-known mutations, indicating that point mutations may not be a major driver for ESS development. Our data show that gene fusions and CNAs are the principal drivers for LG-ESS and USS, respectively, but both may require additional genomic alterations including point mutations. These differences may explain the different biologic behaviors between LG-ESS and UUS. Our findings suggest that ESS development requires point mutations and CNAs as well as the gene fusions. PMID- 26429874 TI - URGCP/URG4 promotes apoptotic resistance in bladder cancer cells by activating NF kappaB signaling. AB - Cisplatin is a well-known chemotherapeutic agent, it could cause DNA damage and induce apoptotic cell death, but the cisplatin resistance also appears, it's important to reveal the mechanisms of cisplatin resistance [1]. URGCP/URG4 is overexpressed in various tumors and plays critical role during tumor development. We found URGCP/URG4 was upregulated in bladder cancer cells and tissues, URGCP/URG4 overexpression increased the resistance to cisplatin-induced apoptosis in bladder cancer, and promoted anti-apoptotic genes expression, such as Bcl-2, Survivin, MCL-1, FLIP, and downregulated Caspase-3 expression, Knockdown of URGCP/URG4 decreased the resistance to cisplatin-induced apoptosis, and inhibited anti-apoptotic genes expression, such as Bcl-2, Survivin, MCL-1, FLIP, and upregulated Caspase-3 expression. Mechanism analysis found URGCP/URG4 activated NF-kappaB pathway which is a well-known anti-apoptotic pathway and promoted the expression of NF-kappaB targeted genes. So we speculated URGCP/URG4 regulates cisplatin-induced apoptosis by activating NF-kappaB pathway. We also analyzed the correlation between URGCP/URG4 expression and clinical clinicopathologic, and found its expression was positively correlated with bladder cancer progression, it can serve as a valuable prognostic factor. In summary, URGCP/URG4 promotes the resistance to cisplatin-induced apoptosis by activating NF-kappaB pathway, and is an unfavorable prognostic factor for bladder cancer. PMID- 26429875 TI - URGCP promotes non-small cell lung cancer invasiveness by activating the NF kappaB-MMP-9 pathway. AB - Invasion and metastasis are main traits of tumor progression and responsible for the poor prognosis of advanced non-small cell lung cancer (NSCLC). The molecular mechanisms underlying the malignant behaviors of NSCLC remain incompletely understood. The present study demonstrate that up-regulator of cell proliferation (URGCP), a recently identified tumor-promoting gene found in several tumor types, is markedly overexpressed in human NSCLC cell lines and clinical NSCLC samples. URGCP upregulation correlates significantly with the progression and poor prognosis of this disease. In vitro and in vivo studies demonstrate that increasing URGCP expression accelerates invasion, migration, and distant metastasis of NSCLC cells whereas downregulating URGCP suppresses these malignant traits. Notably, silencing URGCP expression almost completely abrogates the metastatic ability of NSCLC cells. At the molecular level, URGCP markedly promotes MMP-9 expression by activating NF-kappaB signaling. Additionally, URGCP and MMP-9 expression are positively correlated in various cohorts of human NSCLC specimens, and NF-kappaB-activated MMP-9 expression contributes to URGCP-induced invasiveness of NSCLC cell lines. Collectively, these findings indicate that URGCP plays an important role in promoting NSCLC cell invasion and metastasis by enhancing NF-kappaB-activated MMP-9 expression and may serve as a potential therapeutic target and prognostic marker. PMID- 26429876 TI - IGK with conserved IGKappaV/IGKappaJ repertoire is expressed in acute myeloid leukemia and promotes leukemic cell migration. AB - We have previously reported that immunoglobulin heavy chain genes were expressed in myeloblasts and mature myeloid cells. In this study, we further demonstrated that rearranged Ig kappa light chain was also frequently expressed in acute myeloid leukemia cell lines (6/6), primary myeloblasts from patients with acute myeloid leukemia (17/18), and mature monocytes (11/12) and neutrophils (3/12) from patients with non-hematopoietic neoplasms, but not or only rarely expressed in mature neutrophils (0/8) or monocytes (1/8) from healthy individuals. Interestingly, myeloblasts and mature monocytes/neutrophils shared several restricted IGKV and IGKJ gene usages but with different expression frequency. Surprisingly, almost all of the acute myeloid leukemia-derived IGKV showed somatic hypermutation; in contrast, mature myeloid cells-derived IGKV rarely had somatic hypermutation. More importantly, although IGK expression appeared not to affect cell proliferation, reduced IGK expression led to a decrease in cell migration in acute myeloid leukemia cell lines HL-60 and NB4, whereas increased IGK expression promoted their motility. In summary, IGK is expressed in myeloblasts and mature myeloid cells from patients with non-hematopoietic neoplasms, and is involved in cell migration. These results suggest that myeloid cells-derived IgK may have a role in leukemogenesis and may serve as a novel tumor marker for monitoring minimal residual disease and developing target therapy. PMID- 26429878 TI - Parsimonious covariate selection for a multicategory ordered response. AB - We propose a flexible continuation ratio (CR) model for an ordinal categorical response with potentially ultrahigh dimensional data that characterizes the unique covariate effects at each response level. The CR model is the logit of the conditional discrete hazard function for each response level given covariates. We propose two modeling strategies, one that keeps the same covariate set for each hazard function but allows regression coefficients to arbitrarily change with response level, and one that allows both the set of covariates and their regression coefficients to arbitrarily change with response. Evaluating a covariate set is accomplished by using the nonparametric bootstrap to estimate prediction error and their robust standard errors that do not rely on proper model specification. To help with interpretation of the selected covariate set, we flexibly estimate the conditional cumulative distribution function given the covariates using the separate hazard function models. The goodness-of-fit of our flexible CR model is assessed with graphical and numerical methods based on the cumulative sum of residuals. Simulation results indicate the methods perform well in finite samples. An application to B-cell acute lymphocytic leukemia data is provided. PMID- 26429877 TI - Simultaneous targeting of 5-LOX-COX and EGFR blocks progression of pancreatic ductal adenocarcinoma. AB - Cyclooxygenase-2 (COX-2), 5-Lipoxygenase (5-LOX), and epidermal growth factor receptor (EGRF) are over-expressed in human pancreatic ductal adenocarcinoma (PDAC). Using next-generation sequencing (NGS) analysis, we show significant increase in COX-2, 5-LOX, and EGFR expression during PDAC progression. Targeting complementary pathways will achieve better treatment efficacy than a single agent high-dose strategy that could increase risk of side effects and tumor resistance. To target COX-2, 5-LOX, and EGFR simultaneously, we tested effects of licofelone (dual 5-LOX-COX inhibitor), and gefitinib (EGFR inhibitor), individually and in combination, on pancreatic intraepithelial neoplasms (PanINs) and their progression to PDAC using genetically engineered mice. Individually, licofelone (L) and gefitinib (G) significantly inhibited incidence of PDAC in male (72% L, 90% G, p < 0.0001) and female (90% L, 85% G, p < 0.0001) mice. The combination drug treatment produced complete inhibition of PDAC in both genders. Pancreata of mice receiving combination treatment showed significantly fewer Dclk1-positive cancer stem-like cells, inhibition of COX-2, 5-LOX, PCNA, EGFR and beta-catenin expression (p < 0.05-0.0002), increased p21 expression. Significant changes in tumor immune responses and desmoplastic reaction was observed by NGS analysis in combination treatment (p < 0.05). In summary, early simultaneous targeting of 5 LOX-COX- and EGFR pathways may provide additive inhibitory effects leading to complete suppression of PDAC. PMID- 26429880 TI - Role of eukaryotic-like serine/threonine kinases in bacterial cell division and morphogenesis. AB - Bacteria possess a repertoire of versatile protein kinases modulating diverse aspects of their physiology by phosphorylating proteins on various amino acids including histidine, cysteine, aspartic acid, arginine, serine, threonine and tyrosine. One class of membrane serine/threonine protein kinases possesses a catalytic domain sharing a common fold with eukaryotic protein kinases and an extracellular mosaic domain found in bacteria only, named PASTA for 'Penicillin binding proteins And Serine/Threonine kinase Associated'. Over the last decade, evidence has been accumulating that these protein kinases are involved in cell division, morphogenesis and developmental processes in Firmicutes and Actinobacteria. However, observations differ from one species to another suggesting that a general mechanism of activation of their kinase activity is unlikely and that species-specific regulation of cell division is at play. In this review, we survey the latest research on the structural aspects and the cellular functions of bacterial serine/threonine kinases with PASTA motifs to illustrate the diversity of the regulatory mechanisms controlling bacterial cell division and morphogenesis. PMID- 26429879 TI - Extracellular vesicle-mediated transfer of CLIC1 protein is a novel mechanism for the regulation of glioblastoma growth. AB - Little progresses have been made in the treatment of glioblastoma (GBM), the most aggressive and lethal among brain tumors. Recently we have demonstrated that Chloride Intracellular Channel-1 (CLIC1) is overexpressed in GBM compared to normal tissues, with highest expression in patients with poor prognosis. Moreover, CLIC1-silencing in cancer stem cells (CSCs) isolated from human GBM patients negatively influences proliferative capacity and self-renewal properties in vitro and impairs the in vivo tumorigenic potential. Here we show that CLIC1 exists also as a circulating protein, secreted via extracellular vesicles (EVs) released by either cell lines or GBM-derived CSCs. Extracellular vesicles (EVs), comprising exosomes and microvesicles based on their composition and biophysical properties, have been shown to sustain tumor growth in a variety of model systems, including GBM. Interestingly, treatment of GBM cells with CLIC1 containing EVs stimulates cell growth both in vitro and in vivo in a CLIC1-dose dependent manner. EVs derived from CLIC1-overexpressing GBM cells are strong inducers of proliferation in vitro and tumor engraftment in vivo. These stimulations are significantly attenuated by treatment of GBM cells with EVs derived from CLIC1-silenced cells. However, CLIC1 modulation appears to have no direct role in EV structure, biogenesis and secretion. These findings reveal that, apart from the function of CLIC1 cellular reservoir, CLIC1 contained in EVs is a novel regulator of GBM growth. PMID- 26429881 TI - Metallic ground state in an ion-gated two-dimensional superconductor. AB - Recently emerging two-dimensional (2D) superconductors in atomically thin layers and at heterogeneous interfaces are attracting growing interest in condensed matter physics. Here, we report that an ion-gated zirconium nitride chloride surface, exhibiting a dome-shaped phase diagram with a maximum critical temperature of 14.8 kelvin, behaves as a superconductor persisting to the 2D limit. The superconducting thickness estimated from the upper critical fields is ? 1.8 nanometers, which is thinner than one unit-cell. The majority of the vortex phase diagram down to 2 kelvin is occupied by a metallic state with a finite resistance, owing to the quantum creep of vortices caused by extremely weak pinning and disorder. Our findings highlight the potential of electric-field induced superconductivity, establishing a new platform for accessing quantum phases in clean 2D superconductors. PMID- 26429882 TI - Direct sampling of electric-field vacuum fluctuations. AB - The ground state of quantum systems is characterized by zero-point motion. This motion, in the form of vacuum fluctuations, is generally considered to be an elusive phenomenon that manifests itself only indirectly. Here, we report direct detection of the vacuum fluctuations of electromagnetic radiation in free space. The ground-state electric-field variance is inversely proportional to the four dimensional space-time volume, which we sampled electro-optically with tightly focused laser pulses lasting a few femtoseconds. Subcycle temporal readout and nonlinear coupling far from resonance provide signals from purely virtual photons without amplification. Our findings enable an extreme time-domain approach to quantum physics, with nondestructive access to the quantum state of light. Operating at multiterahertz frequencies, such techniques might also allow time resolved studies of intrinsic fluctuations of elementary excitations in condensed matter. PMID- 26429883 TI - FOOD SCIENCE. Designing a sustainable diet. PMID- 26429884 TI - A GABAergic projection from the zona incerta to cortex promotes cortical neuron development. AB - gamma-Aminobutyric acid (GABA) is the major inhibitory transmitter in the mature brain but is excitatory in the developing cortex. We found that mouse zona incerta (ZI) projection neurons form a GABAergic axon plexus in neonatal cortical layer 1, making synapses with neurons in both deep and superficial layers. A similar depolarizing GABAergic plexus exists in the developing human cortex. Selectively silencing mouse ZI GABAergic neurons at birth decreased synaptic activity and apical dendritic complexity of cortical neurons. The ZI GABAergic projection becomes inhibitory with maturation and can block epileptiform activity in the adult brain. These data reveal an early-developing GABAergic projection from the ZI to cortical layer 1 that is essential for proper development of cortical neurons and balances excitation with inhibition in the adult cortex. PMID- 26429885 TI - A brain circuit that synchronizes growth and maturation revealed through Dilp8 binding to Lgr3. AB - Body-size constancy and symmetry are signs of developmental stability. Yet, it is unclear exactly how developing animals buffer size variation. Drosophila insulin like peptide Dilp8 is responsive to growth perturbations and controls homeostatic mechanisms that coordinately adjust growth and maturation to maintain size within the normal range. Here we show that Lgr3 is a Dilp8 receptor. Through the use of functional and adenosine 3',5'-monophosphate assays, we defined a pair of Lgr3 neurons that mediate homeostatic regulation. These neurons have extensive axonal arborizations, and genetic and green fluorescent protein reconstitution across synaptic partners show that these neurons connect with the insulin-producing cells and prothoracicotropic hormone-producing neurons to attenuate growth and maturation. This previously unrecognized circuit suggests how growth and maturation rate are matched and co-regulated according to Dilp8 signals to stabilize organismal size. PMID- 26429887 TI - Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive. AB - Calcineurin inhibitors, such as cyclosporine A and FK506, are used as immunosuppressant drugs, but their adverse effects on male reproductive function remain unclear. The testis expresses somatic calcineurin and a sperm-specific isoform that contains a catalytic subunit (PPP3CC) and a regulatory subunit (PPP3R2). We demonstrate herein that male mice lacking Ppp3cc or Ppp3r2 genes (knockout mice) are infertile, with reduced sperm motility owing to an inflexible midpiece. Treatment of mice with cyclosporine A or FK506 creates phenocopies of the sperm motility and morphological defects. These defects appear within 4 to 5 days of treatment, which indicates that sperm-specific calcineurin confers midpiece flexibility during epididymal transit. Male mouse fertility recovered a week after we discontinued treatment. Because human spermatozoa contain PPP3CC and PPP3R2 as a form of calcineurin, inhibition of this sperm-specific calcineurin may lead to the development of a reversible male contraceptive that would target spermatozoa in the epididymis. PMID- 26429888 TI - New clues to the understanding of animal development. PMID- 26429886 TI - Retroviruses use CD169-mediated trans-infection of permissive lymphocytes to establish infection. AB - Dendritic cells can capture and transfer retroviruses in vitro across synaptic cell-cell contacts to uninfected cells, a process called trans-infection. Whether trans-infection contributes to retroviral spread in vivo remains unknown. Here, we visualize how retroviruses disseminate in secondary lymphoid tissues of living mice. We demonstrate that murine leukemia virus (MLV) and human immunodeficiency virus (HIV) are first captured by sinus-lining macrophages. CD169/Siglec-1, an I type lectin that recognizes gangliosides, captures the virus. MLV-laden macrophages then form long-lived synaptic contacts to trans-infect B-1 cells. Infected B-1 cells subsequently migrate into the lymph node to spread the infection through virological synapses. Robust infection in lymph nodes and spleen requires CD169, suggesting that a combination of fluid-based movement followed by CD169-dependent trans-infection can contribute to viral spread. PMID- 26429890 TI - Efficacy of raltegravir-containing regimens in antiretroviral-naive and experienced individuals in routine clinical practice. AB - Raltegravir is one of the standard antiretroviral therapy (ART) options in treatment-experienced and -naive patients. However, efficacy data from clinical practice are scarce. Therefore, the efficacy of raltegravir-containing ART in clinical practice was investigated retrospectively. In all, 295 treatment-naive and -experienced patients were analysed using two different cut-offs for virological failure (200 or 50 copies/ml). The response at week 24 and onwards was evaluated as a 'time to loss of virological response' analysis and estimated as a survival function. Additionally, dual therapy regimens (raltegravir plus boosted protease inhibitor) were compared to standard combinations in experienced patients performing a snapshot analysis at weeks 24 and 48, as well as a time to loss of virological response analysis. A total of 86.2% of the 64 treatment-naive patients maintained virological suppression using a cut-off of 200 copies/ml (c/ml), while 67.7% maintained virological suppression with a 50 copies/ml cut off from week 24 until the end of observation. Among the 231 treatment experienced patients, 84.8% maintained virological suppression from week 24 onwards using a cut-off of 200 copies/ml; and 71.0% using 50 copies/ml, respectively. In the subgroup snapshot analysis at week 24, 98.3% (86.7% using a cut-off of 50 copies/ml) and at week 48, 93.3% (80.0%) of patients responded to dual therapy. Patients who were receiving a standard background therapy responded in 88.3% (81.3%) at week 24 and in 86.0% (80.7%) at week 48. Differences were not significant. This study shows again the overall long-term efficacy of raltegravir based ART and furthermore gives reference for a comparable efficacy of dual and standard nucleos(t)ide reverse transcriptase inhibitor-backbone regimens in experienced patients on raltegravir over a period of 48 weeks in a real-life cohort where patients with severe comorbidities were included. PMID- 26429889 TI - A human laterality disorder caused by a homozygous deleterious mutation in MMP21. AB - BACKGROUND: Laterality in the vertebrate embryo is determined by left-right asymmetric gene expression driven by the flow of extraembryonic fluid across the embryonic node. Defects in these processes cause heterotaxy, the abnormal formation and arrangement of visceral organs that can range from complete inversion of symmetry to the selective misarrangement of organs. However, our understanding of the genetic causality for laterality defects in human beings remains relatively limited. METHODS: We performed whole exome sequencing in a consanguineous family with heterotaxia. To interrogate the pathogenic potential of the discovered variant, we used an in vivo system in which the potential of the candidate gene to induce L-R asymmetry was tested by transient suppression and CRISPR/Cas9-induced deletions. We also used in vitro assays to test a possible link between our exome-derived candidate and Notch signaling. RESULTS: We identified a homozygous 2 bp deletion in MMP21, encoding matrix metalloproteinase-21, as the sole coding mutation that segregated with the phenotype. Transient suppression or CRISPR/Cas9-mediated deletion of mmp21 in zebrafish embryos induced cardiac looping defects, with concomitant disruption of laterality markers in the lateral plate mesoderm and disrupted notch signalling in vitro and in vivo. CONCLUSIONS: Our data implicate loss of MMP21 as a cause of heterotaxy in humans with concomitant defects in Notch signaling. In support of this finding, a homozygous missense mutation in MMP21 was identified previously in mice with N-Ethyl-N-Nitrosourea (ENU)-induced heterotaxy. Taken together, these observations suggest a role of matrix metalloproteinases in the establishment of asymmetric organ development, likely through the regulation of morphogenetic signals. PMID- 26429891 TI - Invasive shigellosis in MSM. AB - Shigella flexneri is an emerging pathogen in men who have sex with men (MSM); recent outbreaks related to sexual practices have been noted in this population in the UK and other developed countries. While the majority of cases of shigellosis present with gastroenteritis, some vulnerable patients with underlying immunosuppression can develop complications like bacteraemia and may present atypically as an acute surgical emergency. This case report highlights such a case of S. flexneri bacteraemia in a man who had sex with men. PMID- 26429892 TI - A national survey of nurse-led and delivered services within sexual health across the United Kingdom. AB - This was a cross-sectional study using an online survey to evaluate the provision of nurse-led and delivered services within genitourinary medicine in the UK. Results showed that such services are being widely utilised and are generally well supported by medical staff. The delivery of nurse-led and delivered services appears to be quite variable. Clinical guidelines and standards may help to ensure a more uniform approach to these services and help to maintain high standards of care. PMID- 26429893 TI - A cross sectional survey of the barriers for implementing rapid HIV testing among French general practitioners. AB - In France, almost 30,000 people are unaware of their HIV-positive status. Innovative screening strategies are essential to reach this population. The aim of this study was to describe the acceptability of rapid HIV testing (RHT) among French general practitioners (GPs) working in the south of France and barriers for implementing this strategy. We analysed an anonymous questionnaire sent by mail to GPs about demographic data, routine practice, knowledge of RHT and barriers to its use. Between 1 April and 30 September 2013, out of the 165 GPs contacted, 78 returned the questionnaires. The GPs' mean age was 52 years; 49 were men. Fifty-one GPs reported that their registered patients included at least one HIV-infected person and 70 GPs reported taking care of high-risk patients. Sixty-three percent of GPs reported being interested in using RHT in their daily practice. The main reasons reported by uninterested GPs were: greater confidence in standard HIV testing, difficulties including RHT during the routine consultation, difficulties to screen for other sexually transmitted infections simultaneously, and difficulties to deliver a positive result. French National Authorities for Health propose to screen the population at least once in their lifetime and high-risk people at least once a year. In order to achieve this aim, RHT should be included in the GPs' arsenal for HIV testing. We showed a high acceptability of RHT by GPs. If specific and adapted training is developed, and if solutions to barriers reported by GPs are found, RHT could be implemented in to their routine activity. PMID- 26429894 TI - Adverse pregnancy outcomes following syphilis treatment in pregnancy in the UK. AB - Syphilis infection in pregnancy is known to cause a number of severe adverse pregnancy outcomes, including second-trimester miscarriage, stillbirth, very pre term delivery and neonatal death, in addition to congenital syphilis. A retrospective review of women with positive syphilis serology and a pregnancy outcome between 2005 and 2012 in Leeds, UK, was performed. In all, 57 cases of positive syphilis serology in pregnancy were identified: 24 with untreated syphilis treated in the current pregnancy (Group 1); seven with reported but unconfirmed prior treatment who were retreated (Group 2); and 26 adequately treated prior to pregnancy (Group 3). The rate of severe adverse pregnancy outcomes in Group 1 at 21% was significantly higher than the 0% outcome of Group 3 (p = 0.02). The severe adverse pregnancy outcomes were two second-trimester miscarriages, two pre-term births at 25 and 28 weeks and one stillbirth at 32 weeks. There were no cases of term congenital syphilis or term neonatal death, but we observed high rates of other adverse pregnancy outcomes despite treatment during pregnancy. Rapid referral for treatment is needed before 18 weeks in order to minimise adverse pregnancy outcomes. PMID- 26429895 TI - A Scottish multi-centre service evaluation examining the prevalence and diagnosis of Trichomonas vaginalis in symptomatic women attending sexual health clinics. AB - Trichomoniasis caused by the protozoan parasite Trichomonas vaginalis (TV) is one of the most commonly occurring sexually transmitted infections of non-viral origin. This study examines the prevalence of TV infection amongst consenting symptomatic women attending three of the largest sexual health clinics in Scotland, United Kingdom. In addition, an evaluation of three testing methods to identify TV from vaginal fluid was performed involving the commercial Hologic APTIMA TV transcription-mediated amplification assay, a real-time PCR assay and microscopy. A total of 398 patients consented to participation and all were tested by the three methods. The prevalence of TV was 2.8% (n = 11), with both molecular assays correctly detecting an additional two cases of TV compared to microscopy. The prevalence of three other sexually transmitted pathogens, namely Chlamydia trachomatis, Neisseria gonorrhoeae and herpes simplex virus were 7.3% (n = 31), 0.3% (n = 1) and 1.5% (n = 6), respectively. The majority of TV cases (78%; n = 8) occurred in women greater than 29 years of age compared to most Chlamydia trachomatis cases, who were aged 30 or less (97%; n = 30). PMID- 26429896 TI - Letter Regarding: Survival Analysis of the Single- and Double-Coated STAR Ankle up to 20 Years: Long-term Follow-up of 324 Cases From the Swedish Ankle Registry. PMID- 26429897 TI - Response to "Letter Regarding: Survival Analysis of the Single- and Double-Coated STAR Ankle up to 20 Years: Long-term Follow-up of 324 Cases From the Swedish Ankle Registry". PMID- 26429898 TI - Letter Regarding: Single-Photon-Emission Computed Tomography in Painful Total Ankle Replacements. PMID- 26429899 TI - Response to "Letter Regarding: Single-Photon-Emission Computed Tomography in Painful Total Ankle Replacements". PMID- 26429900 TI - Letter Regarding: Comparison of Cannulated Screws Versus Compression Staples for Subtalar Arthrodesis Fixation. PMID- 26429901 TI - Response to "Letter Regarding: Comparison of Cannulated Screws Versus Compression Staples for Subtalar Arthrodesis Fixation". PMID- 26429903 TI - Ccn1, a molecular switch that imposes a self-limiting control on inflammation and wound healing in a multitude of organs? PMID- 26429904 TI - Reply to Dr. Weiskirchen. PMID- 26429905 TI - Retraction. AB - Foster WM, Adler KB, Crews AL, Potts EN, Fischer BM, Voynow JA. MARCKS-related peptide modulates in vivo the secretion of airway Muc5ac. Am J Physiol Lung Cell Mol Physiol 299: L345-L352; doi: 10.1152/ajplung.00067.2010. The authors have discovered that Figs. 1, 2, and 6 are not reliable. We offer our sincere apologies for the errors and for any inconvenience associated with the publication of the article. The paper is therefore being retracted by the American Physiological Society at the request of Dr. Voynow, and with the approval of the coauthors. PMID- 26429906 TI - Device therapy in cardiac disease: a success story. PMID- 26429907 TI - Keith Fox: Caledonian collaborations and translational triumphs. PMID- 26429908 TI - The effect of fall prevention exercise programmes on fall induced injuries in community dwelling older adults. AB - STUDY QUESTION: Are fall prevention exercise interventions for older people living in the community effective in preventing different types of fall related injuries? SUMMARY ANSWER: Exercise programmes designed to prevent falls in older adults seem also to prevent injuries caused by falls, including the most severe injuries. Such programmes also reduce the rate of falls leading to medical care. PMID- 26429909 TI - Molecular Mechanisms and Kinetic Effects of FXYD1 and Phosphomimetic Mutants on Purified Human Na,K-ATPase. AB - Phospholemman (FXYD1) is a single-transmembrane protein regulator of Na,K-ATPase, expressed strongly in heart, skeletal muscle, and brain and phosphorylated by protein kinases A and C at Ser-68 and Ser-63, respectively. Binding of FXYD1 reduces Na,K-ATPase activity, and phosphorylation at Ser-68 or Ser-63 relieves the inhibition. Despite the accumulated information on physiological effects, whole cell studies provide only limited information on molecular mechanisms. As a complementary approach, we utilized purified human Na,K-ATPase (alpha1beta1 and alpha2beta1) reconstituted with FXYD1 or mutants S63E, S68E, and S63E,S68E that mimic phosphorylation at Ser-63 and Ser-68. Compared with control alpha1beta1, FXYD1 reduces Vmax and turnover rate and raises K0.5Na. The phosphomimetic mutants reverse these effects and reduce K0.5Na below control K0.5Na. Effects on alpha2beta1 are similar but smaller. Experiments in proteoliposomes reconstituted with alpha1beta1 show analogous effects of FXYD1 on K0.5Na, which are abolished by phosphomimetic mutants and also by increasing mole fractions of DOPS in the proteoliposomes. Stopped-flow experiments using the dye RH421 show that FXYD1 slows the conformational transition E2(2K)ATP -> E1(3Na)ATP but does not affect 3NaE1P -> E2P3Na. This regulatory effect is explained simply by molecular modeling, which indicates that a cytoplasmic helix (residues 60-70) docks between the alphaN and alphaP domains in the E2 conformation, but docking is weaker in E1 (also for phosphomimetic mutants). Taken together with previous work showing that FXYD1 also raises binding affinity for the Na(+)-selective site III, these results provide a rather comprehensive picture of the regulatory mechanism of FXYD1 that complements the physiological studies. PMID- 26429910 TI - Concentration-dependent Effects of Nuclear Lamins on Nuclear Size in Xenopus and Mammalian Cells. AB - A fundamental question in cell biology concerns the regulation of organelle size. While nuclear size is exquisitely controlled in different cell types, inappropriate nuclear enlargement is used to diagnose and stage cancer. Clarifying the functional significance of nuclear size necessitates an understanding of the mechanisms and proteins that control nuclear size. One structural component implicated in the regulation of nuclear morphology is the nuclear lamina, a meshwork of intermediate lamin filaments that lines the inner nuclear membrane. However, there has not been a systematic investigation of how the level and type of lamin expression influences nuclear size, in part due to difficulties in precisely controlling lamin expression levels in vivo. In this study, we circumvent this limitation by studying nuclei in Xenopus laevis egg and embryo extracts, open biochemical systems that allow for precise manipulation of lamin levels by the addition of recombinant proteins. We find that nuclear growth and size are sensitive to the levels of nuclear lamins, with low and high concentrations increasing and decreasing nuclear size, respectively. Interestingly, each type of lamin that we tested (lamins B1, B2, B3, and A) similarly affected nuclear size whether added alone or in combination, suggesting that total lamin concentration, and not lamin type, is more critical to determining nuclear size. Furthermore, we show that altering lamin levels in vivo, both in Xenopus embryos and mammalian tissue culture cells, also impacts nuclear size. These results have implications for normal development and carcinogenesis where both nuclear size and lamin expression levels change. PMID- 26429911 TI - Poly(ADP-ribosyl)ation of FOXP3 Protein Mediated by PARP-1 Protein Regulates the Function of Regulatory T Cells. AB - Poly(ADP-ribose) polymerase 1 (PARP-1) is an ADP-ribosylating enzyme participating in diverse cellular functions. The roles of PARP-1 in the immune system, however, have not been well understood. Here we find that PARP-1 interacts with FOXP3 and induces its poly(ADP-ribosyl)ation. By using PARP-1 inhibitors, we show that reduced poly(ADP-ribosyl)ation of FOXP3 results in not only FOXP3 stabilization and increased FOXP3 downstream genes but also enhanced suppressive function of regulatory T cells. Our results suggest that PARP-1 negatively regulates the suppressive function of Treg cells at the posttranslational level via FOXP3 poly(ADP-ribosyl)ation. This finding has implications for developing PARP-1 inhibitors as potential agents for the prevention and treatment of autoimmune diseases. PMID- 26429912 TI - Structural Basis for Clonal Diversity of the Public T Cell Response to a Dominant Human Cytomegalovirus Epitope. AB - Cytomegalovirus (CMV) is a ubiquitous and persistent human pathogen that is kept in check by CD8(+) cytotoxic T lymphocytes. Individuals expressing the major histocompatibility complex (MHC) class I molecule HLA-A2 produce cytotoxic T lymphocytes bearing T cell receptors (TCRs) that recognize the immunodominant CMV epitope NLVPMVATV (NLV). The NLV-specific T cell repertoire is characterized by a high prevalence of TCRs that are frequently observed in multiple unrelated individuals. These public TCRs feature identical, or nearly identical, complementarity-determining region 3alpha (CDR3alpha) and/or CDR3beta sequences. The TCRs may express public CDR3alpha motifs alone, public CDR3beta motifs alone, or dual public CDR3alphabeta motifs. In addition, the same public CDR3alpha motif may pair with different CDR3beta motifs (and the reverse), giving rise to highly diverse NLV-specific TCR repertoires. To investigate the structural underpinnings of this clonal diversity, we determined crystal structures of two public TCRs (C7 and C25) in complex with NLV.HLA-A2. These TCRs utilize completely different CDR3alpha and CDR3beta motifs that, in addition, can associate with multiple variable alpha and variable beta regions in NLV-specific T cell repertoires. The C7.NLV.HLA-A2 and C25.NLV.HLA-A2 complexes exhibit divergent TCR footprints on peptide-MHC such that C25 is more focused on the central portion of the NLV peptide than is C7. These structures combined with molecular modeling show how the public CDR3alpha motif of C25 may associate with different variable alpha regions and how the public CDR3alpha motif of C7 may pair with different CDR3beta motifs. This interchangeability of TCR V regions and CDR3 motifs permits multiple structural solutions to binding an identical peptide-MHC ligand and thereby the generation of a clonally diverse public T cell response to CMV. PMID- 26429913 TI - Essential Role of the EF-hand Domain in Targeting Sperm Phospholipase Czeta to Membrane Phosphatidylinositol 4,5-Bisphosphate (PIP2). AB - Sperm-specific phospholipase C-zeta (PLCzeta) is widely considered to be the physiological stimulus that triggers intracellular Ca(2+) oscillations and egg activation during mammalian fertilization. Although PLCzeta is structurally similar to PLCdelta1, it lacks a pleckstrin homology domain, and it remains unclear how PLCzeta targets its phosphatidylinositol 4,5-bisphosphate (PIP2) membrane substrate. Recently, the PLCdelta1 EF-hand domain was shown to bind to anionic phospholipids through a number of cationic residues, suggesting a potential mechanism for how PLCs might interact with their target membranes. Those critical cationic EF-hand residues in PLCdelta1 are notably conserved in PLCzeta. We investigated the potential role of these conserved cationic residues in PLCzeta by generating a series of mutants that sequentially neutralized three positively charged residues (Lys-49, Lys-53, and Arg-57) within the mouse PLCzeta EF-hand domain. Microinjection of the PLCzeta EF-hand mutants into mouse eggs enabled their Ca(2+) oscillation inducing activities to be compared with wild type PLCzeta. Furthermore, the mutant proteins were purified, and the in vitro PIP2 hydrolysis and binding properties were monitored. Our analysis suggests that PLCzeta binds significantly to PIP2, but not to phosphatidic acid or phosphatidylserine, and that sequential reduction of the net positive charge within the first EF-hand domain of PLCzeta significantly alters in vivo Ca(2+) oscillation inducing activity and in vitro interaction with PIP2 without affecting its Ca(2+) sensitivity. Our findings are consistent with theoretical predictions provided by a mathematical model that links oocyte Ca(2+) frequency and the binding ability of different PLCzeta mutants to PIP2. Moreover, a PLCzeta mutant with mutations in the cationic residues within the first EF-hand domain and the XY linker region dramatically reduces the binding of PLCzeta to PIP2, leading to complete abolishment of its Ca(2+) oscillation inducing activity. PMID- 26429914 TI - Phosphorylation of Glutathione S-Transferase P1 (GSTP1) by Epidermal Growth Factor Receptor (EGFR) Promotes Formation of the GSTP1-c-Jun N-terminal kinase (JNK) Complex and Suppresses JNK Downstream Signaling and Apoptosis in Brain Tumor Cells. AB - Under normal physiologic conditions, the glutathione S-transferase P1 (GSTP1) protein exists intracellularly as a dimer in reversible equilibrium with its monomeric subunits. In the latter form, GSTP1 binds to the mitogen-activated protein kinase, JNK, and inhibits JNK downstream signaling. In tumor cells, which frequently are characterized by constitutively high GSTP1 expression, GSTP1 undergoes phosphorylation by epidermal growth factor receptor (EGFR) at tyrosine residues 3, 7, and 198. Here we report on the effect of this EGFR-dependent GSTP1 tyrosine phosphorylation on the interaction of GSTP1 with JNK, on the regulation of JNK downstream signaling by GSTP1, and on tumor cell survival. Using in vitro and in vivo growing human brain tumors, we show that tyrosine phosphorylation shifts the GSTP1 dimer-monomer equilibrium to the monomeric state and facilitates the formation of the GSTP1-JNK complex, in which JNK is functionally inhibited. Targeted mutagenesis and functional analysis demonstrated that the increased GSTP1 binding to JNK results from phosphorylation of the GSTP1 C-terminal Tyr-198 by EGFR and is associated with a >2.5-fold decrease in JNK downstream signaling and a significant suppression of both spontaneous and drug-induced apoptosis in the tumor cells. The findings define a novel mechanism of regulatory control of JNK signaling that is mediated by the EGFR/GSTP1 cross-talk and provides a survival advantage for tumors with activated EGFR and high GSTP1 expression. The results lay the foundation for a novel strategy of dual EGFR/GSTP1 for treating EGFR+ve, GSTP1 expressing GBMs. PMID- 26429915 TI - Alteration/Deficiency in Activation 3 (ADA3) Protein, a Cell Cycle Regulator, Associates with the Centromere through CENP-B and Regulates Chromosome Segregation. AB - ADA3 (alteration/deficiency in activation 3) is a conserved component of several transcriptional co-activator and histone acetyltransferase (HAT) complexes. Recently, we generated Ada3 knock-out mice and demonstrated that deletion of Ada3 leads to early embryonic lethality. The use of Ada3(FL/FL) mouse embryonic fibroblasts with deletion of Ada3 using adenovirus Cre showed a critical role of ADA3 in cell cycle progression through mitosis. Here, we demonstrate an association of ADA3 with the higher order repeat region of the alpha-satellite region on human X chromosome centromeres that is consistent with its role in mitosis. Given the role of centromere proteins (CENPs) in mitosis, we next analyzed whether ADA3 associates with the centromere through CENPs. Both an in vivo proximity ligation assay and immunofluorescence studies confirmed the association of ADA3 with CENP-B protein, a highly conserved centromeric protein that binds to the 17-bp DNA sequences on alpha-satellite DNA. Deletional analysis showed that ADA3 directly associates with CENP-B through its N terminus, and a CENP-B binding-deficient mutant of ADA3 was incompetent in cell proliferation rescue. Notably, knockdown of ADA3 decreased binding of CENP-B onto the centromeres, suggesting that ADA3 is required for the loading of CENP-B onto the centromeres. Finally, we show that deletion of Ada3 from Ada3(FL/FL) mouse embryonic fibroblasts exhibited various chromosome segregation defects. Taken together, we demonstrate a novel ADA3 interaction with CENP-B-centromere that may account for its previously known function in mitosis. This study, together with its known function in maintaining genomic stability and its mislocalization in cancers, suggests an important role of ADA3 in mitosis. PMID- 26429916 TI - Interaction of Heat Shock Protein Cpn10 with the Cyclin E/Cdk2 Substrate Nuclear Protein Ataxia-Telangiectasia (NPAT) Is Involved in Regulating Histone Transcription. AB - Precise modulation of histone gene transcription is critical for cell cycle progression. As a direct substrate of Cyclin E/CDK2, nuclear protein ataxia telangiectasia (NPAT) is a crucial factor in regulating histone transcription and cell cycle progression. Here we identified that Cpn10/HSPE, a 10-kDa heat shock protein, is a novel interacting partner of NPAT. A pool of Cpn10 is colocalized with NPAT foci during G1 and S phases in nuclei. Gain- and loss-of-function experiments unraveled an essential role of Cpn10 in histone transcription. A conserved DLFD motif within Cpn10 was critical for targeting NPAT and modulating histone transcription. More importantly, knockdown of Cpn10 disrupted the focus formation of both NPAT and FADD-like interleukin-1beta-converting enzyme associated huge protein without affecting Coilin-positive Cajal bodies. Finally, Cpn10 is important for S phase progression and cell proliferation. Taken together, our finding revealed a novel role of Cpn10 in the spatial regulation of NPAT signaling and disclosed a previously unappreciated link between the heat shock protein and histone transcription regulation. PMID- 26429917 TI - Syk Is Recruited to Stress Granules and Promotes Their Clearance through Autophagy. AB - Syk is a cytoplasmic kinase that serves multiple functions within the immune system to couple receptors for antigens and antigen-antibody complexes to adaptive and innate immune responses. Recent studies have identified additional roles for the kinase in cancer cells, where its expression can either promote or suppress tumor cell growth, depending on the context. Proteomic analyses of Syk binding proteins identified several interacting partners also found to be recruited to stress granules. We show here that the treatment of cells with inducers of stress granule formation leads to the recruitment of Syk to these protein-RNA complexes. This recruitment requires the phosphorylation of Syk on tyrosine and results in the phosphorylation of proteins at or near the stress granule. Grb7 is identified as a Syk-binding protein involved in the recruitment of Syk to the stress granule. This recruitment promotes the formation of autophagosomes and the clearance of stress granules from the cell once the stress is relieved, enhancing the ability of cells to survive the stress stimulus. PMID- 26429919 TI - You're Not Big--You're Just Tall, That's All! PMID- 26429918 TI - Long-term effects of pegvisomant on comorbidities in patients with acromegaly: a retrospective single-center study. AB - CONTEXT: The effect of pegvisomant on IGF1 levels in patients with acromegaly is well documented, but little is known of its long-term impact on comorbidity. AIM: The aim of this retrospective study was to evaluate the effects of long-term pegvisomant therapy on cardiorespiratory and metabolic comorbidity in patients with acromegaly. PATIENTS AND METHODS: We analyzed the long-term (up to 10 years) effect of pegvisomant therapy given alone (n=19, 45%) or in addition to somatostatin analogues and/or cabergoline (n=23, 55%) on echocardiographic, polysomnographic and metabolic parameters in respectively 42, 12 and 26 patients with acromegaly followed in Bicetre hospital. RESULTS: At the first cardiac evaluation, 20+/-16 months after pegvisomant introduction, IGF1 levels normalized in 29 (69%) of the 42 patients. The left ventricular ejection fraction (LVEF) improved significantly in patients whose basal LVEF was <=60% and decreased in those whose LVEF was >70%. The left ventricular mass index (LVMi) decreased from 123+/-25 to 101+/-21 g/m(2) (P<0.05) in the 17 patients with a basal LVMi higher than the median (91 g/m(2)), while it remained stable in the other patients. Pegvisomant reduced the apnoea-hypopnea index and cured obstructive sleep apnea (OSA) in four of the eight patients concerned. Long-term follow-up of 22 patients showed continuing improvements in cardiac parameters. The BMI and LDL cholesterol level increased minimally during pegvisomant therapy, and other lipid parameters were not modified. CONCLUSIONS: Long-term pegvisomant therapy not only normalizes IGF1 in a large proportion of patients but also improves cardiac and respiratory comorbidity. PMID- 26429920 TI - Association of Height with Elevated Mortality Risk in ESRD: Variation by Race and Gender. AB - The association of adult height with mortality has been extensively investigated in the general population, but little is known about this relationship among dialysis patients. We explored the relationship between height and mortality in a retrospective cohort study of 1,171,842 adults who began dialysis in the United States from 1995 to 2008 and were followed until December 31, 2010. We evaluated height-mortality associations in sex-specific quintiles of increasing height (Q1 Q5) using multivariable Cox regression models adjusted for demographics, comorbid conditions, lifestyle and disability indicators, socioeconomic status, and body weight. For men, compared with the referent quintile (Q1 <167 cm), successive height quintiles had significantly increased hazard ratios (HRs [95% confidence interval]) for mortality: 1.04 (1.02-1.06), 1.08 (1.06-1.10), 1.12 (1.11-1.14), and 1.18 (1.16-1.20) for Q2-Q5, respectively. For women (referent Q1 <155 cm), HRs for mortality were 1.00 (0.99-1.02), 1.05 (1.03-1.06), 1.05 (1.03-1.07), and 1.08 (1.06-1.10) for Q2-Q5, respectively. However, stratification by race showed the pattern of association differed significantly by race (P<0.001 for interaction). For black men, unlike other race groups, height only associated with mortality in Q5, with an HR of 1.06 (1.02-1.09). For black women, HRs for mortality were 0.94 (0.91-0.97), 0.98 (0.95-1.02), 0.96 (0.93-0.99), and 0.99 (0.96-1.02) for Q2-Q5, respectively. These results indicate tallness is associated with higher mortality risks for adults starting dialysis, but this association did not extend to black patients. PMID- 26429921 TI - Three-dimensional echocardiography vs. computed tomography for transcatheter aortic valve replacement sizing. AB - AIMS: The accuracy of transcatheter aortic valve replacement (TAVR) sizing using three-dimensional transoesophageal echocardiography (3D-TEE) compared with the gold-standard multi-slice computed tomography (MSCT) remains unclear. We compare aortic annulus measurements assessed using these two imaging modalities. METHODS AND RESULTS: We performed a single-centre prospective cohort study, including 53 consecutive patients undergoing TAVR, who had both MSCT and 3D-TEE for aortic annulus sizing. Aortic annular dimensions, expected transcatheter heart valve (THV) oversizing, and hypothetical valve size selection based on CT and TEE were compared. 3D-TEE and CT cross-sectional mean diameter (r = 0.69), perimeter (r = 0.70), and area (r = 0.67) were moderately to highly correlated (all P-values <0.0001). 3D-TEE-derived measurements were significantly smaller compared with MSCT: perimeter (68.6 +/- 5.9 vs. 75.1 +/- 5.7 mm, respectively; P < 0.0001); area (345.6 +/- 64.5 vs. 426.9 +/- 68.9 mm(2), respectively; P < 0.0001). The percentage difference between 3D-TEE and MSCT measurements was around 9%. Agreement between MSCT- and 3D-TEE-based THV sizing (perimeter) occurred in 44% of patients. Using the 3D-TEE perimeter annular measurements, up to 50% of patients would have received an inappropriate valve size according to manufacturer-recommended, area-derived sizing algorithms. CONCLUSION: Aortic annulus measurements for pre-procedural TAVR assessment by 3D-TEE are significantly smaller than MSCT. In this study, such discrepancy would have resulted in up to 50% of all patients receiving the wrong THV size. 3D-TEE should be used for TAVR sizing, only when MSCT is not available or contraindicated. The clinical impact of this information requires further study. PMID- 26429923 TI - Sexual Selection of Protamine 1 in Mammals. AB - Protamines have a crucial role in male fertility. They are involved in sperm chromatin packaging and influence the shape of the sperm head and, hence, are important for sperm performance. Protamine structure is basic with numerous arginine-rich DNA-binding domains. Postcopulatory sexual selection is thought to play an important role in protamine sequence evolution and expression. Here, we analyze patterns of evolution and sexual selection (in the form of sperm competition) acting on protamine 1 gene sequence in 237 mammalian species. We assessed common patterns as well as differences between the major mammalian subclasses (Eutheria, Metatheria) and clades. We found that a high arginine content in protamine 1 associates with a lower sperm head width, which may have an impact on sperm swimming velocity. Increase in arginine content in protamine 1 across mammals appears to take place in a way consistent with sexual selection. In metatherians, increase in sequence length correlates with sexual selection. Differences in selective pressures on sequences and codon sites were observed between mammalian clades. Our study revealed a complex evolutionary pattern of protamine 1, with different selective constraints, and effects of sexual selection, between mammalian groups. In contrast, the effect of arginine content on head shape, and the possible involvement of sperm competition, was identified across all mammals. PMID- 26429922 TI - Evolution of DNA-Binding Sites of a Floral Master Regulatory Transcription Factor. AB - Flower development is controlled by the action of key regulatory transcription factors of the MADS-domain family. The function of these factors appears to be highly conserved among species based on mutant phenotypes. However, the conservation of their downstream processes is much less well understood, mostly because the evolutionary turnover and variation of their DNA-binding sites (BSs) among plant species have not yet been experimentally determined. Here, we performed comparative ChIP (chromatin immunoprecipitation)-seq experiments of the MADS-domain transcription factor SEPALLATA3 (SEP3) in two closely related Arabidopsis species: Arabidopsis thaliana and A. lyrata which have very similar floral organ morphology. We found that BS conservation is associated with DNA sequence conservation, the presence of the CArG-box BS motif and on the relative position of the BS to its potential target gene. Differences in genome size and structure can explain that SEP3 BSs in A. lyrata can be located more distantly to their potential target genes than their counterparts in A. thaliana. In A. lyrata, we identified transposition as a mechanism to generate novel SEP3 binding locations in the genome. Comparative gene expression analysis shows that the loss/gain of BSs is associated with a change in gene expression. In summary, this study investigates the evolutionary dynamics of DNA BSs of a floral key regulatory transcription factor and explores factors affecting this phenomenon. PMID- 26429924 TI - Evidence for neurotoxicity associated with amoxicillin in juvenile rats. AB - Amoxicillin (AMX) is one of the most commonly prescribed antibiotics for children, and childhood is the period to have the highest risk for toxicity cases including drug-induced adverse reactions. Some neurological adverse effects (anxiety, hyperactivity, confusion, convulsions, and behavioral changes) have been reported related to AMX treatment. In the present study, we aimed to determine the neurotoxic effects of AMX administration at clinically relevant doses in female juvenile rats. AMX was administered in single oral daily doses of 25 and 50 mg/kg for 14 days. According to our results, while AMX administration caused a significant increase in the immobility time of animals, swimming time of these animals significantly decreased. AMX administration significantly reduced the onset of pentylenetetrazole-induced convulsions. The serotonin levels of brain tissues in the AMX-administered groups were decreased significantly, which is thought to be related to depression. The glutamate levels in brain tissues increased significantly in AMX-administered groups, which is thought to be related to convulsion. Otherwise, superoxide dismutase and catalase activities were significantly decreased in brain tissues of AMX-administered groups. In conclusion, AMX administration triggered depression and shortened the time of the appearance of first seizure in juvenile rats. Also, altered brain neurotransmitter levels and increased oxidative stress observed in our study were thought to be the possible underlying mechanisms of AMX-induced neurotoxicity. PMID- 26429925 TI - Does rosmarinic acid treatment have protective role against sepsis-induced oxidative damage in Wistar Albino rats? AB - Reactive oxygen species are believed to be involved in the development of sepsis. Plant-derived phenolic compounds are thought to be possible therapeutic agents against sepsis because of their antioxidant properties. Rosmarinic acid (RA) is a phenolic compound commonly found in various plants, which has many biological activities including antioxidant activity. The aim of this study was to investigate the effects of RA on sepsis-induced DNA damage in the lymphocytes and liver and kidney cells of Wistar albino rats by alkaline comet assay with and without formamidopyrimidine DNA glycosylase protein. The oxidative stress parameters such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and total glutathione (GSH) and malondialdehyde (MDA) levels in the liver and kidney tissues and an inflammatory cytokine, tumor necrosis factor alpha (TNF-alpha) level in plasma were also evaluated. It is found that DNA damage in the lymphocytes, livers, and kidneys of the RA-treated rats was significantly lower than that in the sepsis-induced rats. RA treatment also decreased the MDA levels and increased the GSH levels and SOD and GSH-Px activities in the livers and kidneys of the sepsis-induced rats. Plasma TNF-alpha level was found to be decreased in the RA-treated rats. It seems that RA might have a role in the attenuation of sepsis-induced oxidative damage not only by decreasing the DNA damage but also by increasing the antioxidant status and DNA repair capacity of the animals. PMID- 26429926 TI - Bcl-2 and Fas expression in peripheral blood leukocytes of patients with alcoholic and autoimmune liver disorders. AB - BACKGROUND: This article is devoted to the inquiry of three diseases of the liver: alcoholic liver disease (ALD), primary biliary cirrhosis (PBC), and autoimmune hepatitis (AIH). The aim of the study was to assess the changes in populations of circulating lymphocytes expressing antiapoptotic bcl-2 molecule and proapoptotic Fas (cluster of differentiation 95(CD95)) receptor in patients with ALD, AIH, and PBC. MATERIALS AND METHODS: The study population consisted of 110 patients with ALD (n = 50), PBC (n = 30), and AIH (n = 30) and age-matched healthy volunteers (n = 25). Peripheral blood lymphocytes were isolated, stained with monoclonal antibodies against CD4, CD8, and CD19 antigen; intracellular bcl 2; and surface Fas receptor (CD95) antigens, and estimated using the flow cytometric method. RESULTS: Bcl-2 expression was the highest in CD4+ and CD19+ T lymphocytes in ALD; however, only the differences in median/mean fluorescence intensity values of CD4+bcl-2+ lymphocytes between ALD and PBC group and CD19+bcl 2+ between ALD and PBC groups were statistically significant, indicating the different role of B cells in pathology of ALD and PBC. In contrast to that, statistically significant higher percentage of CD4+, CD8+, and CD19+ bearing Fas receptor in all groups of patients with liver diseases in comparison with the control subjects were estimated. The highest expression of Fas in CD4+ lymphocytes in ALD and in CD8+ cells of PBC and AIH groups were detected. CONCLUSION: Low expression of bcl-2 molecule and high expression of Fas in peripheral blood lymphocytes indicate significant dysregulation of apoptotic mechanisms not only in the liver but also in peripheral blood lymphocytes in all examined groups, especially in ALD group. PMID- 26429927 TI - Evaluation of matrix metalloproteinase, myeloperoxidase, and oxidative damage in mesenteric ischemia-reperfusion injury. AB - BACKGROUND: In this study, we investigated the alterations of matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinases (TIMPs), acute inflammation, and oxidative damage in the circulatory system and the intestine in response to mesenteric ischemia/reperfusion (I/R). METHODS: Twenty one rats were divided randomly into the following three groups (n = 7 in each group): a sham group (CG), an ischemic group (IG), and an I/R group (I/RG). MMP 9, TIMP-1, and myeloperoxidase (MPO) were measured using the enzyme-linked immunosorbent assay method, and lipid peroxidation (quantified as thiobarbituric acid reactive substances (TBARS) content), ischemia-modified albumin, the prooxidant-antioxidant balance (PAB), and ferric-reducing antioxidant power (FRAP) were measured spectrophotometrically. The degree of intestinal injury was evaluated according to the Chiu scoring system. RESULTS: A significant difference between the mean serum TIMP-1 and MMP-9 levels and the alanine transaminase activity was found among the groups. Compared with the I/RG group a significant difference in the mean tissue MMP-9, MPO, and TBARS levels in addition to the PAB and FRAP was found between the CG and IG groups. The level of MMP-9 also demonstrated a strong, positive, and valid correlation with the TBA-RS levels. A significant morphological change was observed in both the IG and the I/RG groups. The degree of intestinal injury was more severe in the I/R group and was characterized by either villous denudation or villous loss. CONCLUSIONS: These results suggest that MMP-9, TIMP-1, MPO, and oxidative stress may be important in the intestinal injury development that is induced by acute mesenteric I/R in a rat model. MMP-9 overexpression may increase the extent of intestinal villous loss, particularly when MMP-9 is upregulated by the TBARS present in the intestinal injury. PMID- 26429928 TI - Coadministration of alloxan and nicotinamide in rats produces biochemical changes in blood and pathological alterations comparable to the changes in type II diabetes mellitus. AB - BACKGROUND: In the present study, thirty six male Sprague Dawley rats were randomly divided into six groups and were injected with varying doses of alloxan (Ax) and nicotinamide (NA). The serum levels of glucose, insulin, and adiponectin were measured weekly up to 4 weeks. RESULTS: Elevated levels of glucose were observed in all groups on days 7, 14, 21, and 28, except in groups a and f (control). The serum insulin levels were significantly elevated in groups b and c on day 7, when compared with that in group f, whereas a decrease in the serum insulin levels was observed in groups d and e on days 21 and 28. The adiponectin levels showed inconsistencies on days 7 and 14. However, significant decrease in the adiponectin levels was observed on days 21 and 28. Histological section of the pancreas showed mild (group a), moderate (group b) to severe (groups c, d, and e) degenerative changes. Concomitant fatty changes in the liver and inflammatory infiltration of the kidney were markedly observed in all the treated groups, when compared to control. CONCLUSION: These results suggested that the use of selective combination of Ax120 + NA50 injection demonstrated type II diabetes mellitus in rats. PMID- 26429929 TI - Combination of paracetamol or ketamine with meperidine enhances antinociception. AB - OBJECTIVES: Dealing with pain is one of the most important issues of medicine. All of the studies aim to find a drug or combination of drugs in order to have more effective analgesia and less side effects. In this study, we aimed to investigate the antinociceptive effects of combination of paracetamol or ketamine with meperidine. METHODS: In this study, we evaluated the systemic antinociceptive effects of meperidine, paracetamol, and ketamine one by one with their combinations. We used 50 mice (weighing 25-30 g), which were divided into 5 groups with each group consisting of 10 mice. Meperidine was applied to animals with increasing doses and their tail flick latencies (TFL) were noted at 20, 40, 60, 90, 120, 180, and 240 min. The same protocol was repeated after the combination of meperidine with paracetamol or ketamine. RESULTS: There was no analgesic effect on low doses of ketamine and paracetamol at TFL measurements. But the combination of low doses of these drugs with meperidine significantly increased TFL (p < 0.05). CONCLUSION: It was observed that meperidine + ketamine and meperidine + paracetamol combinations have potent analgesic effect. PMID- 26429930 TI - The compromise of dynamic disulfide/thiol homeostasis as a biomarker of oxidative stress in trichloroethylene exposure. AB - In this study, we aimed to investigate disulfide/thiol homeostasis in trichloroethylene (TCE) exposure. The study was carried out in 30 nonsmoker TCE exposed workers with a variety of occupations. Additionally, 30 healthy nonsmoker volunteers were recruited as the control group. TCE exposure was determined by measuring urinary trichloroacetic acid (TCA) concentration. Median urinary TCA levels of exposed workers (20.5 mg/L) were significantly higher than control subjects (5 mg/L). Thiol and disulfide concentrations were determined using a novel automated method. Disulfide/thiol ratio was significantly higher in the exposed group (p < 0.001). Thiol/disulfide homeostasis was found to be disturbed in TCE-exposed workers. We predict that in TCE-exposed workers this disturbance can be a therapeutic target, and the efficiency of the treatment can easily be monitored by the novel method we used. PMID- 26429931 TI - Biocompatibility evaluation of orthodontic composite by real-time cell analysis. AB - INTRODUCTION: The aim of this study was to evaluate the cytotoxic effects of three different light-cured orthodontic composites. MATERIAL AND METHODS: Light Bond (Reliance orthodontic products), Grengloo (Ormco corporation), and Kurasper F (Kuraray Europe GmbH) were selected for the experiment. Specimens were prepared according to the manufacturers' instructions, measuring 5 mm in diameter and 2 mm in thickness. Fibroblast cells were obtained from healthy gingival connective tissues. The composite cylinders were incubated in Dulbecco's modified Eagle's culture medium for 72 h according to ISO 10993-5 standards. The xCELLigence method was used to evaluate fibroblast cell vitality. After seeding 200 mL of the cell suspensions into the wells (20,000 cells/well) of the E-plate 96, gingival fibroblasts were treated with bioactive components released by the orthodontic composite materials and monitored every 15 min for 121 h. RESULTS: There were no significant differences between the human gingival fibroblast (HGF) cell indexes of the control and all testing groups (p > 0.05) at 24 and 48 h. Light Bond demonstrated statistically significant decrease in HGF index (p < 0.05) at 72 h, but there was no significant difference among the Kurasper F, Grengloo, and untreated control groups (p > 0.05). Light Bond (p < 0.001) and Grengloo (p < 0.05) groups had lower HGF cell index values when compared to untreated control group, but Kurasper F demonstrated no significant differences between the control groups at 96 h (p > 0.05). CONCLUSION: Orthodontic composite materials include biologically active components and may change oral tissue. So, biocompatible orthodontic bonding composites should be used. PMID- 26429932 TI - Differential effects of grape juice on gastric emptying and renal function from cisplatin-induced acute adverse toxicity. AB - Grape skin and seeds contain large amounts of phytochemicals such as polyphenols, resveratrol, and proanthocyanidins, which possess antioxidant activities. Cisplatin is widely used in the treatment of cancer. High doses of cisplatin have also been known to produce acute adverse effects. The aim of this study was to investigate the protective effects of antioxidant properties of whole grape juice (with skin and seeds) on cisplatin-induced acute gastrointestinal tract disorders and nephrotoxicity in Wistar rats. Gastric emptying is significantly increased in whole grape juice-pretreated rats when compared to cisplatin treatment alone. The expression of ghrelin mRNA of stomach is increased in rats with whole grape juice. However, pretreatment with whole grape juice did not reduce renal function markers in acute renal toxicity. No significant changes were recorded in the oxidative stress/antioxidant status parameters of any study group. In contrast, pretreatment with whole grape juice slightly improved tubular cell vacuolization, tubular dilatation, and cast formation in renal tubules. These results show that consumption of whole grape juice induces somewhat beneficial effects in preventing cisplatin-mediated dyspepsia but does not offer protection against cisplatin-induced acute renal toxicity. PMID- 26429935 TI - "PEAR-ing" Genomic and Epigenomic Analyses for Cancer Gene Discovery. AB - Somatic structural variants in tumor genomes can deregulate transcription through repositioning of enhancer elements. A new method, PEAR-ChIP, leverages paired-end H3K27ac chromatin immunoprecipitation combined with high-throughput sequencing and current computational methods to identify such events. PMID- 26429936 TI - T Regulatory Cells Gone Bad: An Oncogenic Immune Response against Enterotoxigenic B. fragilis Infection Leads to Colon Cancer. AB - T regulatory cells trigger an oncogenic immune response against enterotoxigenic B. fragilis infection. The implications of an overall shift in the colonic homeostasis are discussed. PMID- 26429937 TI - Rational Engineering Defines a Molecular Switch That Is Essential for Activity of Spider-Venom Peptides against the Analgesics Target NaV1.7. AB - Many spider-venom peptides are known to modulate the activity of the voltage gated sodium (NaV) subtype 1.7 (NaV1.7) channel, which has emerged as a promising analgesic target. In particular, a class of spider-venom peptides (NaSpTx1) has been found to potently inhibit NaV1.7 (nanomolar IC50), and has been shown to produce analgesic effects in animals. However, one member of this family [u-TRTX Hhn2b (Hhn2b)] does not inhibit mammalian NaV channels expressed in dorsal root ganglia at concentrations up to 100 uM. This peptide is classified as a NaSpTx1 member by virtue of its cysteine spacing and sequence conservation over functionally important residues. Here, we have performed detailed structural and functional analyses of Hhn2b, leading us to identify two nonpharmacophore residues that contribute to human NaV1.7 (hNaV1.7) inhibition by nonoverlapping mechanisms. These findings allowed us to produce a double mutant of Hhn2b that shows nanomolar inhibition of hNaV1.7. Traditional structure/function analysis did not provide sufficient resolution to identify the mechanism underlying the observed gain of function. However, by solving the high-resolution structure of both the wild-type and mutant peptides using advanced multidimensional NMR experiments, we were able to uncover a previously unknown network of interactions that stabilize the pharmacophore region of this class of venom peptides. We further monitored the lipid binding properties of the peptides and identified that one of the key amino acid substitutions also selectively modulates the binding of the peptide to anionic lipids. These results will further aid the development of peptide-based analgesics for the treatment of chronic pain. PMID- 26429938 TI - An Essential Role of cAMP Response Element Binding Protein in Ginsenoside Rg1 Mediated Inhibition of Na+/Glucose Cotransporter 1 Gene Expression. AB - The Na(+)/glucose cotransporter 1 (SGLT1) is responsible for glucose uptake in intestinal epithelial cells. It has been shown that the intestinal SGLT1 level is significantly increased in diabetic individuals and positively correlated with the pathogenesis of diabetes. The development of targeted therapeutics that can reduce the intestinal SGLT1 expression level is, therefore, important. In this study, we showed that ginsenoside Rg1 effectively decreased intestinal glucose uptake through inhibition of SGLT1 gene expression in vivo and in vitro. Transient transfection analysis of the SGLT1 promoter revealed an essential cAMP response element (CRE) that confers the Rg1-mediated inhibition of SGLT1 gene expression. Chromatin immunoprecipitation assay and targeted CRE-binding protein (CREB) silencing demonstrated that Rg1 reduced the promoter binding of CREB and CREB binding protein associated with an inactivated chromatin status. In addition, further studies showed that the epidermal growth factor receptor (EGFR) signaling pathway also plays an essential role in the inhibitory effect of Rg1; taken together, our study demonstrates the involvement of the EGFR-CREB signaling pathway in the Rg1-mediated downregulation of SGLT1 expression, which offers a potential strategy in the development of antihyperglycemic and antidiabetic treatments. PMID- 26429939 TI - Nicotine Dependence Reveals Distinct Responses from Neurons and Their Resident Nicotinic Receptors in Medial Habenula. AB - Nicotinic acetylcholine receptors (nAChRs) are the molecular target of nicotine. nAChRs in the medial habenula (MHb) have recently been shown to play a role in nicotine dependence, but it is not clear which nAChR subtypes or MHb neuron types are most important. To identify MHb nAChRs and/or cell types that play a role in nicotine dependence, we studied these receptors and cells with brain slice electrophysiology using both acute and chronic nicotine application. Cells in the ventroinferior (MHbVI) and ventrolateral MHb (MHbVL) subregions expressed functional nAChRs with different pharmacology. Further, application of nicotine to cells in these subregions led to different action potential firing patterns. The latter result was correlated with a differing ability of nicotine to induce nAChR desensitization. Chronic nicotine caused functional upregulation of nAChRs selectively in MHbVI cells, but did not change nAChR function in MHbVL. Importantly, firing responses were also differentially altered in these subregions following chronic nicotine. MHbVI neurons treated chronically with nicotine exhibited enhanced basal pacemaker firing but a blunted nicotine-induced firing response. MHbVL neurons did not change their firing properties in response to chronic nicotine. Together, these results suggest that acute and chronic nicotine differentially affect nAChR function and output of cells in MHb subregions. Because the MHb extensively innervates the interpeduncular nucleus, an area critical for both affective and somatic signs of withdrawal, these results could reflect some of the neurophysiological changes thought to occur in the MHb to the interpeduncular nucleus circuit in human smokers. PMID- 26429940 TI - The influence of blood storage time and general anaesthesia on chromosomal radiosensitivity assessment. AB - The micronucleus assay (MN assay) is a well-established assay in genetic toxicology, biomonitoring of mutagen-exposed populations and chromosomal radiosensitivity testing. To evaluate the effect of storage time on the chromosomal radiosensitivity assessment in lymphocytes, micronuclei (MN) yields in blood samples received and processed on the same day were compared with MN yields obtained when blood cultures were set up 24 and 48h after blood sampling. Furthermore, the influence of general anaesthesia on MN and binucleated cells (BN) yields in the MN assay was considered. Blood samples of 10 healthy donors were irradiated and blood cultures were set up during the same day of blood sampling or with a delay of 24 or 48h. The MN assay was also performed on two blood samples from 60 women undergoing breast surgery. The first blood sample was taken before general anaesthesia and the second sample, 2h after anaesthesia induction. Fifty percent of the blood samples were transported to the cytogenetics lab within 2h while the other 50% reached the lab after 24h. The results of this study show a decrease in BN and an increase in MN yields with increasing storage time before irradiation and setting up of the MN assay for both healthy controls and patients. The administration of general anaesthesia in patients resulted in lower BN yields, higher spontaneous MN yields but no differences in radiation-induced MN yields. In conclusion, this study indicates that the time between blood sampling and the in vitro irradiation of the samples for the MN assay influences the MN yields. Delays of more than 24h should be avoided. To assess chromosomal radiosensitivity in patients, blood samples should be taken before induction of general anaesthesia as anaesthesia can have an impact on the reliability of the MN results. PMID- 26429941 TI - Egg consumption and incident type 2 diabetes: are there any advantages to excessive consumption of eggs? PMID- 26429942 TI - Reply to T Kawada. PMID- 26429943 TI - Is this the end of (-)-epicatechin, or not? New study highlights the complex challenges associated with research into the cardiovascular health benefits of bioactive food constituents. PMID- 26429944 TI - Reply to H Schroeter et al. PMID- 26429945 TI - Sales response to price promotions in Great Britain: effect size 1/100 of that claimed. PMID- 26429947 TI - Erratum for Nakamura et al. Price promotions on healthier compared with less healthy foods: a hierarchical regression analysis of the impact on sales and social patterning of responses to promotions in Great Britain. Am J Clin Nutr 2015;101:808-16. PMID- 26429946 TI - Reply to MD Chatfield. PMID- 26429948 TI - Erratum for Kim et al. Effects of egg consumption on carotenoid absorption from co-consumed, raw vegetables. Am J Clin Nutr 2015;102:75-83. PMID- 26429949 TI - Erratum for Adebamowo et al. Association between intakes of magnesium, potassium, and calcium and risk of stroke: 2 cohorts of US women and updated meta-analyses. Am J Clin Nutr 2015;101:1269-77. PMID- 26429951 TI - Global research productivity of N-acetylcysteine use in paracetamol overdose: A bibliometric analysis (1976-2012). AB - PURPOSE: The main objective of this study was to examine the publication pattern of N-acetylcysteine (NAC) research output for paracetamol overdose at the global level. METHODS: Data were searched for documents that contained specific words regarding NAC and paracetamol as keywords in the title and/or abstract and/or keywords. Scientific output was evaluated based on a methodology developed and used in other bibliometric studies. Research productivity was adjusted to the national population and nominal gross domestic product per capita. RESULTS: The criteria were met by 367 publications from 33 countries. The highest number of articles associated with the use of NAC in paracetamol overdose was from the United States of America (USA; 39.78%), followed by the United Kingdom (UK; 11.99%). After adjusting for economy and population power, USA (2.822), Iran (1.784) and UK (1.125) had the highest research productivity. The total number of citations at the time of data analysis (14 March 2014) was 8785 with an average of 23.9 citations per document and a median (interquartile range) of 6 (1-22). The h-index of the retrieved documents was 48. The highest h-index was 32 for USA, followed by 20 for UK. Furthermore, the highest number of collaborations with international authors for each country was held by USA with 11 countries, followed by Canada with 7 countries. CONCLUSION: The amount of NAC-based research activity was low in some countries, and more effort is needed to bridge this gap and to promote better evaluation of NAC use worldwide. Our findings demonstrate that NAC use for paracetamol overdose remains a hot issue in scientific research and may have a larger audience compared with other toxicological aspects. Editors and authors in the field of toxicology might usefully promote the submission of work on NAC in future to improve their journal's impact. PMID- 26429952 TI - Roundtable on the Future of Nuclear Medicine Training. PMID- 26429953 TI - uPAR as a Glioma Imaging Target. PMID- 26429954 TI - Reply: Roundtable on the Future of Nuclear Medicine Training. PMID- 26429955 TI - Urokinase-Type Plasminogen Activator Receptor as a Potential PET Biomarker in Glioblastoma. AB - Glioblastoma is one of the most malignant types of human cancer, and the prognosis is poor. The development and validation of novel molecular imaging biomarkers has the potential to improve tumor detection, grading, risk stratification, and treatment monitoring of gliomas. The aim of this study was to explore the potential of PET imaging of the urokinase-type plasminogen activator receptor (uPAR) in glioblastoma. METHODS: The uPAR messenger RNA expression of tumors from 19 glioblastoma patients was analyzed, and a cell culture derived from one of these patients was used to establish an orthotopic xenograft model of glioblastoma. Tumor growth was monitored using bioluminescence imaging. Five to six weeks after inoculation, all mice were scanned with small-animal PET/CT using two new uPAR PET ligands ((64)Cu-NOTA-AE105 and (68)Ga-NOTA-AE105) and, for comparison, O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET). One MRI scan was obtained for each mouse to confirm tumor location. The uPAR specificity of (64)Cu NOTA-AE105 was confirmed by alignment of hematoxylin- and eosin-stained and uPAR immunohistochemistry-stained slides of the brain with the activity distribution as determined using autoradiography. RESULTS: uPAR expression was found in all 19 glioblastoma patient tumors, and high expression of uPAR correlated with decreased overall survival (P = 0.04). Radiolabeling of NOTA-AE105 with (64)Cu and (68)Ga was straightforward, resulting in a specific activity of approximately 20 GBq/MUmol and a radiochemical purity of more than 98% for (64)Cu-NOTA-AE105 and more than 97% for (68)Ga-NOTA-AE105. High image contrast resulting in clear tumor delineation was found for both (68)Ga-NOTA-AE105 and (64)Cu-NOTA-AE105. Absolute uptake in tumor was higher for (18)F-FET (3.5 +/- 0.8 percentage injected dose [%ID]/g) than for (64)Cu-NOTA-AE105 (1.2 +/- 0.4 %ID/g) or (68)Ga NOTA-AE105 (0.4 +/- 0.1 %ID/g). A similar pattern was observed in background brain tissue, where uptake was 1.9 +/- 0.1 %ID/g for (18)F-fluorothymidine, compared with 0.05 +/- 0.01 %ID/g for (68)Ga-NOTA-AE105 and 0.11 +/- 0.02 %ID/g for (64)Cu-NOTA-AE105. The result was a significantly higher tumor-to-background ratio for both (68)Ga-NOTA-AE105 (7.6 +/- 2.1, P < 0.05) and (64)Cu-NOTA-AE105 (10.6 +/- 2.3, P < 0.01) than for (18)F-FET PET (1.8 +/- 0.3). Autoradiography of brain slides confirmed that the accumulation of (64)Cu-NOTA-AE105 corresponded well with uPAR-positive cancer cells. CONCLUSION: On the basis of our translational study, uPAR PET may be a highly promising imaging biomarker for glioblastoma. Further clinical exploration of uPAR PET in glioblastoma is therefore justified. PMID- 26429956 TI - Dose-Finding Quantitative 18F-FDG PET Imaging Study with the Oral Pan-AKT Inhibitor GSK2141795 in Patients with Gynecologic Malignancies. AB - AKT (a serine/threonine-specific protein kinase) regulates many cellular processes contributing to cytotoxic drug resistance. This study's primary objective examined the relationship between GSK2141795, an oral, pan-AKT inhibitor, and (18)F-FDG PET markers of glucose metabolism in tumor tissue to determine whether (18)F-FDG PET could be used to guide personalized dosing of GSK2141795. Biomarker analysis of biopsies was also undertaken. METHODS: Twelve patients were enrolled in 3 cohorts; all underwent dynamic (18)F-FDG PET scans and serial pharmacokinetic sampling at baseline, week 2, and week 4 with tumor biopsies before treatment and at week 4. Response was evaluated by RECIST v1.1 and Gynecologic Cancer Intergroup criteria. Biopsy samples were analyzed for mutations and protein expression. RESULTS: GSK2141795 did not significantly influence blood glucose levels. No dose-response relationship was observed between GSK2141795 pharmacokinetics and (18)F-FDG PET pharmacodynamic measures; however, an exposure-response relationship was seen between maximum drug concentrations and maximal decrease in (18)F-FDG uptake in the best-responding tumor. This relationship also held for pharmacokinetic parameters of exposure and 1,5-anhydroglucitol (a systemic measure of glucose metabolism). Phospho-AKT upregulation at week 4 in biopsies confirmed AKT inhibition by GSK2141795. Single agent activity was observed with a clinical benefit rate of 27% (3/11) and 30% (3/10) CA125 response in the study's platinum-resistant ovarian patients. AKT pathway activation by PIK3CA/PIK3R1 mutation did not correlate with clinical activity, whereas RAS/RAF pathway mutations did segregate with resistance to AKT inhibition. CONCLUSION: GSK2141795 demonstrated an exposure-response relationship with decreased (18)F-FDG uptake and is active and tolerable. This study's design integrating (18)F-FDG PET, pharmacokinetics, and biomarker analyses demonstrates the potential for clinical development for personalized treatment. PMID- 26429959 TI - Imaging-Based Treatment Adaptation in Radiation Oncology. AB - In many tumor types, significant effort is being put into patient-tailored adaptation of treatment to improve outcome and preferably reduce toxicity. These opportunities first arose with the introduction of modern irradiation techniques (e.g., intensity-modulated radiotherapy) combined with functional imaging for more precise delineation of target volume. On the basis of functional CT, MRI, and PET results, radiation target volumes are altered during the course of treatment, or subvolumes inside the primary tumor are defined to enhance the dosing strategy. Moreover, the probability of complications to normal tissues is predicted using anatomic or functional imaging, such as in the use of CT or PET to predict radiation pneumonitis. Besides focusing, monitoring, and adapting photon therapy for solid tumors, PET also has a role in verifying proton-beam therapy. This article discusses the current state and remaining challenges of imaging-based treatment adaptation in radiation oncology. PMID- 26429958 TI - 68Ga-NOTA-PRGD2 PET/CT for Integrin Imaging in Patients with Lung Cancer. AB - This study was designed to assess the diagnostic value of (68)Ga-NOTA-PRGD2 (NOTA PRGD2 is NOTA-PEG4-E[c(RGDfK)]2) PET/CT in lung cancer. METHODS: Ninety-one patients (48 men and 43 women; age, 22-82 y) with suspected lung lesions on CT were enrolled with informed consent. Immediately after intravenous injection of 117.7 +/- 37.7 MBq of (68)Ga-NOTA-PRGD2, 15 patients underwent dynamic whole-body PET/CT scans for 1-2 h, and the remaining 76 patients underwent whole-body PET/CT scans at 30 +/- 10 min after bolus injection. Each patient also underwent standard (18)F-FDG PET/CT for comparison. RESULTS: No side effect was found after (68)Ga-NOTA-PRGD2 injection. (68)Ga-NOTA-PRGD2 was rapidly cleared from the blood pool and primarily excreted through the urinary system. The standardized uptake values of proven malignancies were significantly higher than those of the benign ones. With an average standardized uptake value of greater than 1.3 being considered malignant, the sensitivity, specificity, and accuracy of (68)Ga-NOTA PRGD2 PET/CT in diagnosing lung cancer were 83.8% (57/68), 91.3% (21/23), and 85.7% (78/91), respectively. The diagnostic value of (68)Ga-NOTA-PRGD2 for lung cancer is comparable to that of (18)F-FDG PET/CT. However, (68)Ga-NOTA-PRGD2 PET/CT is more specific than (18)F-FDG PET/CT in assessing lymph node metastasis, with positive and negative predictive values of 90.0% (27/30) and 93.8% (121/129), respectively, whereas those of (18)F-FDG PET/CT were 30.2% (29/96) and 90.5% (57/63), respectively. CONCLUSION: This study indicates the efficacy of (68)Ga-NOTA-PRGD2 PET/CT in lung cancer diagnosis. (68)Ga-NOTA-PRGD2 PET/CT shows significant advantage over (18)F-FDG PET/CT in judging metastatic lymph nodes with higher specificity. PMID- 26429960 TI - Reply: Simplified Methods for Quantification of 18F-Fluoromethylcholine Uptake: Is SUVAUC,PP Actually an SUV? PMID- 26429961 TI - 64Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with 68Ga-DOTATOC in 60 Patients. AB - The somatostatin receptor subtype 2 is expressed on macrophages, an abundant cell type in the atherosclerotic plaque. Visualization of somatostatin receptor subtype 2, for oncologic purposes, is frequently made using the DOTA-derived somatostatin analogs DOTATOC or DOTATATE for PET. We aimed to compare the uptake of the PET tracers (68)Ga-DOTATOC and (64)Cu-DOTATATE in large arteries, in the assessment of atherosclerosis by noninvasive imaging technique, combining PET and CT. Further, the correlation of uptake and cardiovascular risk factors was investigated. METHODS: Sixty consecutive patients with neuroendocrine tumors underwent both (68)Ga-DOTATOC and (64)Cu-DOTATATE PET/CT scans, in random order. For each scan, the maximum and mean standardized uptake values (SUVs) were calculated in 5 arterial segments. In addition, the blood-pool-corrected target to-background ratio was calculated. Uptake of the tracers was correlated with cardiovascular risk factors collected from medical records. RESULTS: We found detectable uptake of both tracers in all arterial segments studied. Uptake of (64)Cu-DOTATATE was significantly higher than (68)Ga-DOTATOC in the vascular regions both when calculated as maximum and mean uptake. There was a significant association between Framingham risk score and the overall maximum uptake of (64)Cu-DOTATATE using SUV (r = 0.4; P = 0.004) as well as target-to-background ratio (r = 0.3; P = 0.04), whereas no association was found with (68)Ga-DOTATOC. The association of risk factors and maximum SUV of (64)Cu-DOTATATE was found driven by body mass index, smoking, diabetes, and coronary calcium score (P < 0.001, P = 0.01, P = 0.005, and P = 0.03, respectively). CONCLUSION: In a series of oncologic patients, vascular uptake of (68)Ga-DOTATOC and (64)Cu-DOTATATE was found, with highest uptake of the latter. Uptake of (64)Cu-DOTATATE, but not of (68)Ga-DOTATOC, was correlated with cardiovascular risk factors, suggesting a potential role for (64)Cu-DOTATATE in the assessment of atherosclerosis. PMID- 26429962 TI - Dual-Receptor-Targeted Radioimmunotherapy of Human Breast Cancer Xenografts in Athymic Mice Coexpressing HER2 and EGFR Using 177Lu- or 111In-Labeled Bispecific Radioimmunoconjugates. AB - One mechanism of resistance to trastuzumab in human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) is increased epidermal growth factor receptor (EGFR) expression. We have developed (111)In-labeled bispecific radioimmunoconjugates (bsRICs) that bind HER2 and EGFR on BC cells by linking trastuzumab Fab fragments through a polyethylene glycol (PEG24) spacer to epidermal growth factor (EGF). We hypothesized that tumors coexpressing HER2 and EGFR could be treated by dual-receptor-targeted radioimmunotherapy with these bsRICs labeled with the beta-particle emitter (177)Lu or the Auger electron emitter (111)In. METHODS: The binding of (177)Lu-DOTA-Fab-PEG24-EGF to tumor cells (MDA-MB-231, SK-OV-3, MDA-MB-231/H2N, or TrR1) coexpressing HER2 and EGFR was assessed in competition assays. The clonogenic survival of these cells was measured after exposure to (177)Lu-DOTA-Fab-PEG24-EGF or (111)In-DTPA-Fab-PEG24 EGF or to monospecific (177)Lu- or (111)In-labeled trastuzumab Fab or EGF. The tumor and normal tissue biodistribution of (177)Lu-DOTA-Fab-PEG24-EGF was studied at 48 h after injection in athymic mice bearing subcutaneous MDA-MB-231/H2N tumors. Radiation-absorbed doses to tumors and normal tissues were estimated and compared for (111)In- and (177)Lu-labeled bsRICs. The maximum injected amount of (177)Lu-DOTA-Fab-PEG24-EGF that caused no observable adverse effects (NOAEL) was identified in BALB/c mice. Athymic CD1 nu/nu mice bearing subcutaneous trastuzumab-sensitive MDA-MB-231/H2N or trastuzumab-resistant TrR1 tumors were treated with (177)Lu-DOTA-Fab-PEG24-EGF or (111)In-DTPA-Fab-PEG24-EGF at the NOAEL, or with unlabeled immunoconjugates or normal saline. Tumor growth was evaluated over a period of 49 d. RESULTS: (177)Lu-DOTA-Fab-PEG24-EGF bound specifically to HER2 and EGFR on tumor cells. Monospecific (177)Lu- and (111)In labeled trastuzumab Fab or EGF killed tumor cells that predominantly expressed HER2 or EGFR, respectively, whereas bsRICs were cytotoxic to cells that displayed either HER2 or EGFR or both receptors. bsRICs were more effective than monospecific agents. (177)Lu-DOTA-Fab-PEG24-EGF was more cytotoxic than (111)In DTPA-Fab-PEG24-EGF. The tumor uptake of (177)Lu-DOTA-Fab-PEG24-EGF was 2-fold greater than (177)Lu-DOTA-trastuzumab Fab or (177)Lu-DOTA-EGF. The NOAEL for (177)Lu-DOTA-Fab-PEG24-EGF was 11.1 MBq (10 MUg). Trastuzumab-sensitive MDA-MB 231/H2N and trastuzumab-resistant TrR1 tumors were growth-inhibited by (177)Lu DOTA-Fab-PEG24-EGF or (111)In-DTPA-Fab-PEG24-EGF. Unlabeled immunoconjugates had no effect on tumor growth. (177)Lu-DOTA-Fab-PEG24-EGF inhibited tumor growth more effectively than (111)In-DTPA-Fab-PEG24-EGF because of a 9.3-fold-higher radiation-absorbed dose (55.0 vs. 5.9 Gy, respectively). CONCLUSION: These results are encouraging for further development of these bsRICs for dual-receptor targeted radioimmunotherapy of BC coexpressing HER2 and EGFR, including trastuzumab-resistant tumors. PMID- 26429963 TI - MAGiC: VOC remains but kids with SCA appear. AB - In this issue of Blood, Brousseau et al report results from the Magnesium for Children in Crisis (MAGiC; #NCT01197417) trial. This multicenter, double-blind, placebo-controlled trial compared the effects of intravenous magnesium to saline in children with sickle cell anemia (SCA) admitted to the hospital for acute vaso occlusive pain (VOC). Although magnesium was found to be ineffective, MAGiC illustrates an effective strategy for rapid and efficient patient accrual in pediatric SCA studies. PMID- 26429964 TI - Is the open mouth mightier than the needle? AB - In this issue of Blood, Bernard et al provide evidence that ibrutinib, the orally administered inhibitor of Bruton tyrosine kinase (BTK), crosses the blood-brain barrier and has activity against mantle cell lymphoma (MCL) in the central nervous system (CNS). PMID- 26429965 TI - Platelet-derived VWF in the stroke spotlight. AB - In this issue of Blood, Verhenne et al present data showing the role of platelet derived von Willebrand factor (VWF) in mediating ischemic stroke injury using a murine model. They created mice with either endothelial VWF or platelet-derived VWF and examined each phenotype for bleeding and thrombosis. Their intriguing findings were that mice lacking platelet-derived VWF, but with adequate endothelial VWF stores, demonstrated normal hemostasis in a tail bleeding model and normal carotid artery thrombosis. Mice with only platelet-derived VWF had defective hemostasis and defective carotid artery thrombosis, but experienced significant cerebral infarction using a stroke model with middle cerebral artery occlusion (see figure). In contrast, minimal infarcts were seen for VWF-deficient mice. These data suggest that platelet-derived VWF plays a specific role in stroke pathology. PMID- 26429966 TI - How's your microbiota? Let's check your urine. AB - In this issue of Blood, Weber and colleagues demonstrate that in the first 10 days following allogeneic hematopoietic transplantation, urinary 3-indoxyl sulfate is a biomarker of intestinal microbiota health and predicts reduced intestinal graft-versus-host disease (GVHD) and treatment-related mortality, as well as improved overall survival. PMID- 26429967 TI - NOTCH2 missplicing can occur in relation to apoptosis. PMID- 26429968 TI - An extended dsRBD is required for post-transcriptional modification in human tRNAs. AB - In tRNA, dihydrouridine is a conserved modified base generated by the post transcriptional reduction of uridine. Formation of dihydrouridine 20, located in the D-loop, is catalyzed by dihydrouridine synthase 2 (Dus2). Human Dus2 (HsDus2) expression is upregulated in lung cancers, offering a growth advantage throughout its ability to interact with components of the translation apparatus and inhibit apoptosis. Here, we report the crystal structure of the individual domains of HsDus2 and their functional characterization. HsDus2 is organized into three major modules. The N-terminal catalytic domain contains the flavin cofactor involved in the reduction of uridine. The second module is the conserved alpha helical domain known as the tRNA binding domain in HsDus2 homologues. It is connected via a flexible linker to an unusual extended version of a dsRNA binding domain (dsRBD). Enzymatic assays and yeast complementation showed that the catalytic domain binds selectively NADPH but cannot reduce uridine in the absence of the dsRBD. While in Dus enzymes from bacteria, plants and fungi, tRNA binding is essentially achieved by the alpha-helical domain, we showed that in HsDus2 this function is carried out by the dsRBD. This is the first reported case of a tRNA-modifying enzyme carrying a dsRBD used to bind tRNAs. PMID- 26429969 TI - Genome-wide profiling of nucleosome sensitivity and chromatin accessibility in Drosophila melanogaster. AB - Nucleosomal DNA is thought to be generally inaccessible to DNA-binding factors, such as micrococcal nuclease (MNase). Here, we digest Drosophila chromatin with high and low concentrations of MNase to reveal two distinct nucleosome types: MNase-sensitive and MNase-resistant. MNase-resistant nucleosomes assemble on sequences depleted of A/T and enriched in G/C-containing dinucleotides, whereas MNase-sensitive nucleosomes form on A/T-rich sequences found at transcription start and termination sites, enhancers and DNase I hypersensitive sites. Estimates of nucleosome formation energies indicate that MNase-sensitive nucleosomes tend to be less stable than MNase-resistant ones. Strikingly, a decrease in cell growth temperature of about 10 degrees C makes MNase-sensitive nucleosomes less accessible, suggesting that observed variations in MNase sensitivity are related to either thermal fluctuations of chromatin fibers or the activity of enzymatic machinery. In the vicinity of active genes and DNase I hypersensitive sites nucleosomes are organized into periodic arrays, likely due to 'phasing' off potential barriers formed by DNA-bound factors or by nucleosomes anchored to their positions through external interactions. The latter idea is substantiated by our biophysical model of nucleosome positioning and energetics, which predicts that nucleosomes immediately downstream of transcription start sites are anchored and recapitulates nucleosome phasing at active genes significantly better than sequence-dependent models. PMID- 26429970 TI - Detection of uracil within DNA using a sensitive labeling method for in vitro and cellular applications. AB - The role of uracil in genomic DNA has been recently re-evaluated. It is now widely accepted to be a physiologically important DNA element in diverse systems from specific phages to antibody maturation and Drosophila development. Further relevant investigations would largely benefit from a novel reliable and fast method to gain quantitative and qualitative information on uracil levels in DNA both in vitro and in situ, especially since current techniques does not allow in situ cellular detection. Here, starting from a catalytically inactive uracil-DNA glycosylase protein, we have designed several uracil sensor fusion proteins. The designed constructs can be applied as molecular recognition tools that can be detected with conventional antibodies in dot-blot applications and may also serve as in situ uracil-DNA sensors in cellular techniques. Our method is verified on numerous prokaryotic and eukaryotic cellular systems. The method is easy to use and can be applied in a high-throughput manner. It does not require expensive equipment or complex know-how, facilitating its easy implementation in any basic molecular biology laboratory. Elevated genomic uracil levels from cells of diverse genetic backgrounds and/or treated with different drugs can be demonstrated also in situ, within the cell. PMID- 26429972 TI - Nuclear domain 'knock-in' screen for the evaluation and identification of small molecule enhancers of CRISPR-based genome editing. AB - CRISPR is a genome-editing platform that makes use of the bacterially-derived endonuclease Cas9 to introduce DNA double-strand breaks at precise locations in the genome using complementary guide RNAs. We developed a nuclear domain knock-in screen, whereby the insertion of a gene encoding the green fluorescent protein variant Clover is inserted by Cas9-mediated homology directed repair (HDR) within the first exon of genes that are required for the structural integrity of subnuclear domains such as the nuclear lamina and promyelocytic leukemia nuclear bodies (PML NBs). Using this approach, we compared strategies for enhancing CRISPR-mediated HDR, focusing on known genes and small molecules that impact non homologous end joining (NHEJ) and homologous recombination (HR). Ultimately, we identified the small molecule RS-1 as a potent enhancer of CRISPR-based genome editing, enhancing HDR 3- to 6-fold depending on the locus and transfection method. We also characterized U2OS human osteosarcoma cells expressing Clover tagged PML and demonstrate that this strategy generates cell lines with PML NBs that are structurally and functionally similar to bodies in the parental cell line. Thus, the nuclear domain knock-in screen that we describe provides a simple means of rapidly evaluating methods and small molecules that have the potential to enhance Cas9-mediated HDR. PMID- 26429971 TI - Molecular basis for the substrate specificity and catalytic mechanism of thymine 7-hydroxylase in fungi. AB - TET proteins play a vital role in active DNA demethylation in mammals and thus have important functions in many essential cellular processes. The chemistry for the conversion of 5mC to 5hmC, 5fC and 5caC catalysed by TET proteins is similar to that of T to 5hmU, 5fU and 5caU catalysed by thymine-7-hydroxylase (T7H) in the nucleotide anabolism in fungi. Here, we report the crystal structures and biochemical properties of Neurospora crassa T7H. T7H can bind the substrates only in the presence of cosubstrate, and binding of different substrates does not induce notable conformational changes. T7H exhibits comparable binding affinity for T and 5hmU, but 3-fold lower affinity for 5fU. Residues Phe292, Tyr217 and Arg190 play critical roles in substrate binding and catalysis, and the interactions of the C5 modification group of substrates with the cosubstrate and enzyme contribute to the slightly varied binding affinity and activity towards different substrates. After the catalysis, the products are released and new cosubstrate and substrate are reloaded to conduct the next oxidation reaction. Our data reveal the molecular basis for substrate specificity and catalytic mechanism of T7H and provide new insights into the molecular mechanism of substrate recognition and catalysis of TET proteins. PMID- 26429973 TI - Risk Factors for Puncture Site Complications After Endovascular Procedures in Patients With Peripheral Arterial Disease. AB - OBJECTIVE: To compare femoral access site closure techniques and to highlight risk factors for puncture site complications after lower extremity endovascular procedures. METHODS: This retrospective study included 787 patients. Procedures were performed according to a standardized protocol. Puncture site complications within 24 hours were regarded as study end points. RESULTS: Ninety (11.5%) puncture site complications were registered. Conventional manual compression (n = 87, 11.1%) was significantly associated with puncture site complications (odds ratio [OR] 2.08, P = .03). Body mass index > 25 kg/m(2) (OR 0.54, P = .01) and prothrombin time > 70% (OR 0.38, P = .04) were protective. All bleeding occurred in procedures >45 minutes. Blood pressure >200 mm Hg and below the knee (BTK) procedures were strong predictors for access site complications (OR 4.21, P = .01 and OR 3.33, P = .02). CONCLUSIONS: We observed an inferiority of conventional manual compression. Age, procedure duration > 45 minutes, BTK procedures, uncontrolled hypertension, and impaired coagulation were risk factors. PMID- 26429974 TI - Multicentre randomized controlled trial of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker withdrawal in advanced renal disease: the STOP-ACEi trial. AB - BACKGROUND: Blood pressure (BP) control and reduction of urinary protein excretion using agents that block the renin-angiotensin aldosterone system are the mainstay of therapy for chronic kidney disease (CKD). Research has confirmed the benefits in mild CKD, but data on angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) use in advanced CKD are lacking. In the STOP-ACEi trial, we aim to confirm preliminary findings which suggest that withdrawal of ACEi/ARB treatment can stabilize or even improve renal function in patients with advanced progressive CKD. METHODS: The STOP-ACEi trial (trial registration: current controlled trials, ISRCTN62869767) is an investigator-led multicentre open-label, randomized controlled clinical trial of 410 participants with advanced (Stage 4 or 5) progressive CKD receiving ACEi, ARBs or both. Patients will be randomized in a 1:1 ratio to either discontinue ACEi, ARB or combination of both (experimental arm) or continue ACEi, ARB or combination of both (control arm). Patients will be followed up at 3 monthly intervals for 3 years. The primary outcome measure is eGFR at 3 years. Secondary outcome measures include the number of renal events, participant quality of life and physical functioning, hospitalization rates, BP and laboratory measures, including serum cystatin-C. Safety will be assessed to ensure that withdrawal of these treatments does not cause excess harm or increase mortality or cardiovascular events such as heart failure, myocardial infarction or stroke. RESULTS: The rationale and trial design are presented here. The results of this trial will show whether discontinuation of ACEi/ARBs can improve or stabilize renal function in patients with advanced progressive CKD. It will show whether this simple intervention can improve laboratory and clinical outcomes, including progression to end-stage renal disease, without causing an increase in cardiovascular events. PMID- 26429975 TI - MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance. AB - Establishing a diagnosis in patients suspected of having a myelodysplastic syndrome (MDS) can be challenging and could be informed by the identification of somatic mutations. We performed a prospective study to examine the frequency and types of mutations encountered in 144 patients with unexplained cytopenias. Based on bone marrow findings, 17% were diagnosed with MDS, 15% with idiopathic cytopenias of undetermined significance (ICUS) and some evidence of dysplasia, and 69% with ICUS and no dysplasia. Bone marrow DNA was sequenced for mutations in 22 frequently mutated myeloid malignancy genes. Somatic mutations were identified in 71% of MDS patients, 62% of patients with ICUS and some dysplasia, and 20% of ICUS patients and no dysplasia. In total, 35% of ICUS patients carried a somatic mutation or chromosomal abnormality indicative of clonal hematopoiesis. We validated these results in a cohort of 91 lower-risk MDS and 249 ICUS cases identified over a 6-month interval. Mutations were found in 79% of those with MDS, in 45% of those with ICUS with dysplasia, and in 17% of those with ICUS without dysplasia. The spectrum of mutated genes was similar with the exception of SF3B1 which was rarely mutated in patients without dysplasia. Variant allele fractions were comparable between clonal ICUS (CCUS) and MDS as were mean age and blood counts. We demonstrate that CCUS is a more frequent diagnosis than MDS in cytopenic patients. Clinical and mutational features are similar in these groups and may have diagnostic utility once outcomes in CCUS patients are better understood. PMID- 26429978 TI - AACR Cancer Progress Report 2015: Transforming Lives Through Precision Medicine. PMID- 26429979 TI - CCR 20th Anniversary Commentary: Bevacizumab in the Treatment of Glioblastoma- The Progress and the Limitations. AB - Vredenburgh and colleagues conducted the first phase II study of bevacizumab plus irinotecan in recurrent malignant glioma, confirming the safety and efficacy of bevacizumab. This study, which was published in the February 15, 2007, issue of Clinical Cancer Research, was a stepping stone for subsequent research, leading to regulatory approval of bevacizumab for recurrent glioblastoma. PMID- 26429976 TI - High DeltaNp73/TAp73 ratio is associated with poor prognosis in acute promyelocytic leukemia. AB - The TP73 gene transcript is alternatively spliced and translated into the transcriptionally active (TAp73) or inactive (DeltaNp73) isoforms, with opposite effects on the expression of p53 target genes and on apoptosis induction. The imbalance between DeltaNp73 and TAp73 may contribute to tumorigenesis and resistance to chemotherapy in human cancers, including hematologic malignancies. In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance in determining response to therapy and contribution to leukemogenesis remains unknown. Here, we provide the first evidence that a higher DeltaNp73/TAp73 RNA expression ratio is associated with lower survival, lower disease-free survival, and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid and anthracycline-based chemotherapy, according to the International Consortium on Acute Promyelocytic Leukemia (IC-APL) study. Cox proportional hazards modeling showed that a high DeltaNp73/TAp73 ratio was independently associated with shorter overall survival (hazard ratio, 4.47; 95% confidence interval, 1.64-12.2; P = .0035). Our data support the hypothesis that the DeltaNp73/TAp73 ratio is an important determinant of clinical response in APL and may offer a therapeutic target for enhancing chemosensitivity in blast cells. PMID- 26429980 TI - Molecular Pathways: Clinical Applications and Future Direction of Insulin-like Growth Factor-1 Receptor Pathway Blockade. AB - The IGF1R signaling pathway is a complex and tightly regulated network that is critical for cell proliferation, growth, and survival. IGF1R is a potential therapeutic target for patients with many different malignancies. This brief review summarizes the results of clinical trials targeting the IGF1R pathway in patients with breast cancer, sarcoma, and non-small cell lung cancer (NSCLC). Therapeutic agents discussed include both monoclonal antibodies to IGF1R (dalotuzumab, figitumumab, cixutumumab, ganitumab, R1507, AVE1642) and newer IGF1R pathway targeting strategies, including monoclonal antibodies to IGF1 and IGF2 (MEDI-573 and BI 836845) and a small-molecule tyrosine kinase inhibitor of IGF1R (linsitinib). The pullback of trials in patients with breast cancer and NSCLC based on several large negative trials is noted and contrasted with the sustained success of IGF1R inhibitor monotherapy in a subset of patients with sarcoma. Several different biomarkers have been examined in these trials with varying levels of success, including tumor expression of IGF1R and its pathway components, serum IGF ligand levels, alternate pathway activation, and specific molecular signatures of IGF1R pathway dependence. However, there remains a critical need to define predictive biomarkers in order to identify patients who may benefit from IGF1R-directed therapies. Ongoing research focuses on uncovering such biomarkers and elucidating mechanisms of resistance, as this therapeutic target is currently being analyzed from the bedside to bench. PMID- 26429981 TI - Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients. AB - PURPOSE: FoxP3(+) Tregs inhibit immune responses against tumors. KW-0761 is a humanized anti-human CCR4 monoclonal antibody (mAb) that has antibody-dependent cellular cytotoxicity activity. Depletion of CCR4-expressing FoxP3(+) CD4 Tregs by KW-0761 infusion was investigated in solid cancer patients. EXPERIMENTAL DESIGN: We conducted a phase Ia clinical trial of KW-0761 infusion in 7 lung and 3 esophageal cancer patients. Toxicity, clinical efficacy, changes in lymphocyte subpopulations, including Tregs, and induction of immune responses were analyzed. RESULTS: The results showed that KW-0761 infusion in a dose range between 0.1 mg/kg and 1.0 mg/kg was safe and well tolerated. No dose-limiting toxicity was observed. Four of 10 patients showed stable disease during treatment and were long survivors. The monitoring of FoxP3(+) Tregs in the peripheral blood mononuclear cells during treatment indicated efficient depletion of those cells, even at the lowest dose of 0.1 mg/kg used. The reduction in Th 1 CD4 T cells and CD8 T cells was limited, whereas a significant reduction was observed with Th 2 and Th 17 CD4 T cells. Immune responses to cancer/testis (CT) antigens and an autoantibody response to thyroid peroxidase were observed in some patients. CONCLUSIONS: The findings showed Tregs depletion and the possible occurrence of an immune response following KW-0761 infusion. Combined use of KW-0761 to deplete FoxP3(+) Tregs with other immunotherapies, such as cancer vaccines or checkpoint inhibitors, is a promising approach to augment immune responses. PMID- 26429983 TI - Ancient Retrovirus Targeted by Engineered T Cells in Melanoma--Letter. PMID- 26429982 TI - Targeting of HPV-16+ Epithelial Cancer Cells by TCR Gene Engineered T Cells Directed against E6. AB - PURPOSE: The E6 and E7 oncoproteins of HPV-associated epithelial cancers are in principle ideal immunotherapeutic targets, but evidence that T cells specific for these antigens can recognize and kill HPV(+) tumor cells is limited. We sought to determine whether TCR gene engineered T cells directed against an HPV oncoprotein can successfully target HPV(+) tumor cells. EXPERIMENTAL DESIGN: T-cell responses against the HPV-16 oncoproteins were investigated in a patient with an ongoing 22 month disease-free interval after her second resection of distant metastatic anal cancer. T cells genetically engineered to express an oncoprotein-specific TCR from this patient's tumor-infiltrating T cells were tested for specific reactivity against HPV(+) epithelial tumor cells. RESULTS: We identified, from an excised metastatic anal cancer tumor, T cells that recognized an HLA-A*02:01 restricted epitope of HPV-16 E6. The frequency of the dominant T-cell clonotype from these cells was approximately 400-fold greater in the patient's tumor than in her peripheral blood. T cells genetically engineered to express the TCR from this clonotype displayed high avidity for an HLA-A*02:01-restricted epitope of HPV-16, and they showed specific recognition and killing of HPV-16(+) cervical, and head and neck cancer cell lines. CONCLUSIONS: These findings demonstrate that HPV-16(+) tumors can be targeted by E6-specific TCR gene engineered T cells, and they provide the foundation for a novel cellular therapy directed against HPV 16(+) malignancies, including cervical, oropharyngeal, anal, vulvar, vaginal, and penile cancers. PMID- 26429984 TI - Correction: Pancreatic Cancer-Derived Exosomes Causes Paraneoplastic beta-cell Dysfunction. PMID- 26429985 TI - Correction: The Prostate Cancer Susceptibility Variant rs2735839 Near KLK3 Gene Is Associated with Aggressive Prostate Cancer and Can Stratify Gleason Score 7 Patients. PMID- 26429986 TI - Will LHINs ever become the "eyes and ears" of the Health Minister for local community wisdom? AB - This commentary reflects on the intent of the legislation establishing the Local Health Integration Networks (LHINs) and comments on the performance gap between the vision for what could have been and the actual performance. A nine-point action plan to restore the LHINs' potential role as a positive force for health system integration and transformation at the local level is provided. PMID- 26429987 TI - Are LHINs influencing the patient experience in Ontario? AB - Patient engagement and patient experience have become an important focal point for health policy development in Ontario. Many healthcare delivery and planning organizations are exploring how to use patient experience information and data to improve the quality of their services and processes. Local Health Integration Networks (LHINs) are also beginning to include patient experience as a measure of local health system improvement. This article reviews the role of LHINs in developing patient experience information over their 10 year history and highlights current initiatives. PMID- 26429988 TI - The LHIN adventure: The journey continues. AB - The Local Health Integration Network (LHIN) adventure began 10 years ago with the intent of transforming the Ontario health system by providing system-based leadership and building collaborative capacity among health service providers. The LHIN construct has continued its evolution during this time and is still in the midst of testing and reshaping the boundaries of its mandate and authority. Working closely and in tandem with the Ministry of Health and Long-Term Care, LHINs have grappled with governance, funding, integration, and engagement, changing the nature of relationships and the dynamics inherent across the health system. The next decade holds considerable promise for LHINs and the health system in Ontario as a whole. PMID- 26429989 TI - [Les inegalites dans l'acces aux soins du cancer au Canada: un point de vue ethique]. AB - La capacite d'offrir des soins du cancer de qualite depend en grande partie de l'accessibilite des services a ceux qui en ont besoin. Dans l'etat actuel des choses, on constate des disparites en matiere d'acces aux services de cancerologie au Canada, ce qui constitue un probleme sur le plan de l'ethique. Le present article fait ressortir les points de vue ethiques et strategiques lies a l'equite dans l'acces aux soins du cancer au Canada. S'inspirant des principes de la bioethique, soit la beneficience, la non-maleficience et la justice, plusieurs strategies sont recommandees pour ameliorer l'acces aux soins du cancer au pays. PMID- 26429990 TI - By 2025 a million more UK people will be living with life threatening conditions, warns royal college. PMID- 26429992 TI - GPs are inadequately equipped to manage growing demand for cancer care, study warns. PMID- 26429991 TI - AACR Cancer Progress Report 2015. PMID- 26429994 TI - Response to Letter Regarding Article, "Hypotension During Endovascular Treatment of Ischemic Stroke Is a Risk Factor for Poor Neurological Outcome". PMID- 26429993 TI - Honoring Roots in Multiple Worlds: Professionals' Perspectives on Healthy Development of Latino Youth. AB - PURPOSE: To obtain contextualized insights from professionals regarding factors that contribute to or inhibit the healthy development of Latino youth. METHOD: A community-engaged study in which semistructured in-depth interviews were conducted with 30 professionals who work extensively with Latino youth in urban clinics, schools, and other community-based settings. RESULTS: Every key informant expressed opinions regarding factors that contribute to healthy development of Latino youth, ranging from cultural identity and a sense of belonging to family connectedness and adult role models. Contributing and inhibiting factors were characterized by being either intrinsic to the individual (e.g., sense of belonging, hope) or extrinsic (e.g., family support and love, community support). CONCLUSION: Recognition of and appreciation for the importance of cultural influences in the lives of Latino youth is a critical starting point on which professionals must build to respectfully and successfully encourage healthy youth development. Factors that contribute to the healthy development of Latino youth range from cultural identity and cultural pride to family connectedness, adult role models, and a sense of belonging. In working with Latino young people, professionals must recognize and appreciate cultural influences as foundational to this population's health and well-being. PMID- 26429995 TI - Brief History of Endovascular Acute Ischemic Stroke Treatment. PMID- 26429996 TI - Letter by Zhang et al Regarding Article, "Hypotension During Endovascular Treatment of Ischemic Stroke Is a Risk Factor for Poor Neurological Outcome". PMID- 26429997 TI - Re: "analyzing seasonal variations in suicide with Fourier Poisson time-series regression: a registry-based study From Norway, 1969-2007". PMID- 26429998 TI - Asymptotically Unbiased Estimation of Exposure Odds Ratios in Complete Records Logistic Regression. AB - Missing data are a commonly occurring threat to the validity and efficiency of epidemiologic studies. Perhaps the most common approach to handling missing data is to simply drop those records with 1 or more missing values, in so-called "complete records" or "complete case" analysis. In this paper, we bring together earlier-derived yet perhaps now somewhat neglected results which show that a logistic regression complete records analysis can provide asymptotically unbiased estimates of the association of an exposure of interest with an outcome, adjusted for a number of confounders, under a surprisingly wide range of missing-data assumptions. We give detailed guidance describing how the observed data can be used to judge the plausibility of these assumptions. The results mean that in large epidemiologic studies which are affected by missing data and analyzed by logistic regression, exposure associations may be estimated without bias in a number of settings where researchers might otherwise assume that bias would occur. PMID- 26429999 TI - The authors reply. PMID- 26430000 TI - Former US army physician sentenced to prison for medical device kickback scheme. PMID- 26430001 TI - Training and education: new ways and new challenges. PMID- 26430002 TI - The treatment of arthritis of the wrist. AB - Arthritis of the wrist is a painful disabling condition that has various causes and presentations. The traditional treatment has been a total wrist fusion at a price of the elimination of movement. However, forms of treatment which allow the preservation of movement are now preferred. Modern arthroplasties of the wrist are still not sufficiently robust to meet the demands of many patients, nor do they restore normal kinematics of the wrist. A preferable compromise may be selective excision and partial fusion of the wrist using knowledge of the aetiology and pattern of degenerative change to identify which joints can be sacrificed and which can be preserved. This article provides an overview of the treatment options available for patients with arthritis of the wrist and an algorithm for selecting an appropriate surgical strategy. PMID- 26430003 TI - Evidence-based surgical training in orthopaedics: how many arthroscopies of the knee are needed to achieve consultant level performance? AB - Despite being one of the most common orthopaedic operations, it is still not known how many arthroscopies of the knee must be performed during training in order to develop the skills required to become a Consultant. A total of 54 subjects were divided into five groups according to clinical experience: Novices (n = 10), Junior trainees (n = 10), Registrars (n = 18), Fellows (n = 10) and Consultants (n = 6). After viewing an instructional presentation, each subject performed a simple diagnostic arthroscopy of the knee on a simulator with visualisation and probing of ten anatomical landmarks. Performance was assessed using a validated global rating scale (GRS). Comparisons were made against clinical experience measured by the number of arthroscopies which had been undertaken, and ROC curve analysis was used to determine the number of procedures needed to perform at the level of the Consultants. There were marked differences between the groups. There was significant improvement in performance with increasing experience (p < 0.05). ROC curve analysis identified that approximately 170 procedures were required to achieve the level of skills of a Consultant. We suggest that this approach to identify what represents the level of surgical skills of a Consultant should be used more widely so that standards of training are maintained through the development of an evidenced-based curriculum. PMID- 26430004 TI - Arthroscopy of the hip for patients with mild to moderate developmental dysplasia of the hip and femoroacetabular impingement: Outcomes following hip arthroscopy for treatment of chondrolabral damage. AB - The purpose of this study was to determine patient-reported outcomes of patients with mild to moderate developmental dysplasia of the hip (DDH) and femoroacetabular impingement (FAI) undergoing arthroscopy of the hip in the treatment of chondrolabral pathology. A total of 28 patients with a centre-edge angle between 15 degrees and 19 degrees were identified from an institutional database. Their mean age was 34 years (18 to 53), with 12 female and 16 male patients. All underwent labral treatment and concomitant correction of FAI. There were nine reoperations, with two patients requiring revision arthroscopy, two requiring periacetabular osteotomy and five needing total hip arthroplasty. Patients who required further major surgery were more likely to be older, male, and to have more severe DDH with a larger alpha angle and decreased joint space. At a mean follow-up of 42 months (24 to 89), the mean modified Harris hip score improved from 59 (20 to 98) to 82 (45 to 100; p < 0.001). The mean Western Ontario and McMaster Universities Osteoarthritis Index score improved from 30 (1 to 61) to 16 (0 to 43; p < 0.001). Median patient satisfaction was 9.0/10 (1 to 10). Patients reported excellent improvement in function following arthroscopy of the hip. This study shows that with proper patient selection, arthroscopy of the hip can be successful in the young patient with mild to moderate DDH and FAI. PMID- 26430005 TI - Comparison of contemporary periacetabular osteotomy for hip dysplasia with total hip arthroplasty for hip osteoarthritis. AB - We report patient-reported outcomes and complications associated with contemporary periacetabular osteotomy (PAO) surgery in treating symptomatic acetabular dysplasia and compare these outcomes with total hip arthroplasty (THA) in patients with similar demographic details. Two consecutive cohorts included patients between aged 18 to 40 years who had undergone either PAO (100 hips; 24 male, 76 female) or THA (55 hips; 18 male, 37 female). At a mean follow-up of 5.9 years (2 to 13), there was significant improvement in the modified Harris hip pain (p < 0.001, PAO and p < 0.001, THA), function (p < 0.001, PAO and p = 0.001, THA), and total scores (p < 0.001, PAO and p < 0.001, THA) within each cohort. There were no significant differences in the clinical outcome scores between the groups. Complication rates were low and similar in each cohort (p = 0.68). Similar to THA, contemporary PAO surgery is a clinically effective procedure that improves function and activity levels, provides pain relief and is associated with an acceptable complication rate. PMID- 26430006 TI - A longitudinal study of MARS MRI scanning of soft-tissue lesions around metal-on metal total hip arthroplasties and disease progression. AB - We investigated the changes seen on serial metal artefact reduction magnetic resonance imaging scans (MARS-MRI) of metal-on-metal total hip arthroplasties (MoM THAs). In total 155 THAs, in 35 male and 100 female patients (mean age 70.4 years, 42 to 91), underwent at least two MRI scans at a mean interval of 14.6 months (2.6 to 57.1), at a mean of 48.2 months (3.5 to 93.3) after primary hip surgery. Scans were graded using a modification of the Oxford classification. Progression of disease was defined as an increase in grade or a minimum 10% increase in fluid lesion volume at second scan. A total of 16 hips (30%) initially classified as 'normal' developed an abnormality on the second scan. Of those with 'isolated trochanteric fluid' 9 (47%) underwent disease progression, as did 7 (58%) of 'effusions'. A total of 54 (77%) of hips initially classified as showing adverse reactions to metal debris (ARMD) progressed, with higher rates of progression in higher grades. Disease progression was associated with high blood cobalt levels or an irregular pseudocapsule lining at the initial scan. There was no association with changes in functional scores. Adverse reactions to metal debris in MoM THAs may not be as benign as previous reports have suggested. Close radiological follow-up is recommended, particularly in high-risk groups. PMID- 26430007 TI - Acetabular revision with impaction bone grafting and a cemented polyethylene acetabular component: comparison of the Kaplan-Meier analysis to the competing risk analysis in 62 revisions with 25 to 30 years follow-up. AB - We present the results of 62 consecutive acetabular revisions using impaction bone grafting and a cemented polyethylene acetabular component in 58 patients (13 men and 45 women) after a mean follow-up of 27 years (25 to 30). All patients were prospectively followed. The mean age at revision was 59.2 years (23 to 82). We performed Kaplan-Meier (KM) analysis and also a Competing Risk (CR) analysis because with long-term follow-up, the presence of a competing event (i.e. death) prevents the occurrence of the endpoint of re-revision. A total of 48 patients (52 hips) had died or had been re-revised at final review in March 2011. None of the deaths were related to the surgery. The mean Harris hip score of the ten surviving hips in ten patients was 76 points (45 to 99). The KM survivorship at 25 years for the endpoint 're-revision for any reason' was 58.0% (95% confidence interval (CI) 38 to 73) and for 're-revision for aseptic loosening' 72.1% (95% CI 51 to 85). With the CR analysis we calculated the KM analysis overestimates the failure rate with respectively 74% and 93% for these endpoints. The current study shows that acetabular impaction bone grafting revisions provide good clinical results at over 25 years. PMID- 26430008 TI - Neurolysis for the treatment of sciatic nerve palsy associated with total hip arthroplasty. AB - Sciatic nerve palsy following total hip arthroplasty (THA) is a relatively rare yet potentially devastating complication. The purpose of this case series was to report the results of patients with a sciatic nerve palsy who presented between 2000 and 2010, following primary and revision THA and were treated with neurolysis. A retrospective review was made of 12 patients (eight women and four men), with sciatic nerve palsy following THA. The mean age of the patients was 62.7 years (50 to 72; standard deviation 6.9). They underwent interfascicular neurolysis for sciatic nerve palsy, after failing a trial of non-operative treatment for a minimum of six months. Following surgery, a statistically and clinically significant improvement in motor function was seen in all patients. The mean peroneal nerve score function improved from 0.42 (0 to 3) to 3 (1 to 5) (p < 0.001). The mean tibial nerve motor function score improved from 1.75 (1 to 4) to 3.92 (3 to 5) (p = 0.02).The mean improvement in sensory function was a clinically negligible 1 out of 5 in all patients. In total, 11 patients reported improvement in their pain following surgery. We conclude that neurolysis of the sciatic nerve has a favourable prognosis in patients with a sciatic nerve palsy following THA. Our findings suggest that surgery should not be delayed for > 12 months following injury. PMID- 26430009 TI - Quantification of material loss from the neck piece taper junctions of a bimodular primary hip prosthesis. A retrieval study from 27 failed Rejuvenate bimodular hip arthroplasties. AB - The early failure and revision of bimodular primary total hip arthroplasty prostheses requires the identification of the risk factors for material loss and wear at the taper junctions through taper wear analysis. Deviations in taper geometries between revised and pristine modular neck tapers were determined using high resolution tactile measurements. A new algorithm was developed and validated to allow the quantitative analysis of material loss, complementing the standard visual inspection currently used. The algorithm was applied to a sample of 27 retrievals (in situ from 2.9 to 38.1 months) of the withdrawn Rejuvenate modular prosthesis. The mean wear volumes on the flat distal neck piece taper was 3.35 mm(3) (0.55 to 7.57), mainly occurring in a characteristic pattern in areas with high mechanical loading. Wear volume tended to increase with time to revision (r2 = 0.423, p = 0.001). Implant and patient specific data (offset, stem size, patient's mass, age and body mass index) did not correlate with the amount of material loss observed (p > 0.078). Bilaterally revised implants showed higher amounts of combined total material loss and similar wear patterns on both sides. The consistent wear pattern found in this study has not been reported previously, suggesting that the device design and materials are associated with the failure of this prosthesis. PMID- 26430010 TI - The five-year radiological results of the uncemented Oxford medial compartment knee arthroplasty. AB - This study reports on the first 150 consecutive Oxford cementless unicompartmental knee arthroplasties (UKA) performed in an independent centre (126 patients). All eligible patients had functional scores (Oxford knee score and high activity arthroplasty score) recorded pre-operatively and at two- and five-years of follow-up. Fluoroscopically aligned radiographs were taken at five years and analysed for any evidence of radiolucent lines (RLLs), subsidence or loosening. The mean age of the cohort was 63.6 years (39 to 86) with 81 (53.1%) males. Excellent functional scores were maintained at five years and there were no progressive RLLs demonstrated on radiographs. Two patients underwent revision to a total knee arthroplasty giving a revision rate of 0.23/100 (95% confidence interval 0.03 to 0.84) component years with overall component survivorship of 98.7% at five years. There were a further four patients who underwent further surgery on the same knee, two underwent bearing exchanges for dislocation and two underwent lateral UKAs for disease progression. This was a marked improvement from other UKAs reported in New Zealand Joint Registry data and supports the designing centre's early results. PMID- 26430011 TI - Ray amputation for the treatment of foot macrodactyly in children. AB - Macrodactyly of the foot is a rare but disabling condition. We present the results of surgery on 18 feet of 16 patients, who underwent ray amputation and were followed-up for more than two years at a mean of 80 months (25 to 198). We radiologically measured the intermetatarsal width and forefoot area pre operatively and at six weeks and two years after surgery. We also evaluated the clinical results using the Oxford Ankle Foot Questionnaire for children (OxAFQ-C) and the Questionnaire for Foot Macrodactyly. The intermetatarsal width and forefoot area ratios were significantly decreased after surgery. The mean OxAFQ-C score was 42 (16 to 57) pre-operatively, improving to 47 (5 to 60) at two years post-operatively (p = 0.021). The mean questionnaire for Foot Macrodactyly score two years after surgery was 8 (6 to 10). Ray amputation gave a measurable reduction in foot size with excellent functional results. For patients with metatarsal involvement, a motionless toe, or involvement of multiple digits, ray amputation is a clinically effective option which is acceptable to patients. PMID- 26430012 TI - Defining the role of intramedullary nailing for fractures of the distal radius: a systematic review. AB - This article is a systematic review of the published literature about the biomechanics, functional outcome and complications of intramedullary nailing of fractures of the distal radius. We searched the Medline and EMBASE databases and included all studies which reported the outcome of intramedullary (IM) nailing of fractures of the distal radius. Data about functional outcome, range of movement (ROM), strength and complications, were extracted. The studies included were appraised independently by both authors using a validated quality assessment scale for non-controlled studies and the CONSORT statement for randomised controlled trials (RCTs). The search strategy revealed 785 studies, of which 16 were included for full paper review. These included three biomechanical studies, eight case series and five randomised controlled trials (RCTs). The biomechanical studies concluded that IM nails were at least as strong as locking plates. The clinical studies reported that IM nailing gave a comparable ROM, functional outcome and grip strength to other fixation techniques. However, the mean complication rate of intramedullary nailing was 17.6% (0% to 50%). This is higher than the rates reported in contemporary studies for volar plating. It raises concerns about the role of intramedullary nailing, particularly when comparative studies have failed to show that it has any major advantage over other techniques. Further adequately powered RCTs comparing the technique to both volar plating and percutaneous wire fixation are needed. PMID- 26430013 TI - Hemiarthroplasty for irreparable distal humeral fractures: medium-term follow-up of 42 patients. AB - We report our experience of performing an elbow hemiarthroplasty in the treatment of comminuted distal humeral fractures in the elderly patients. A cohort of 42 patients (three men and 39 women, mean age 72; 56 to 84) were reviewed at a mean of 34.3 months (24 to 61) after surgery. Functional outcome was measured with the Mayo Elbow Performance Score (MEPS) and range of movement. The disabilities of the arm, shoulder and hand questionnaire (DASH) was used as a patient rated evaluation. Complications and ulnar nerve function were recorded. Plain radiographs were obtained to assess prosthetic loosening, olecranon wear and heterotopic bone formation. The mean extension deficit was 23.5 degrees (0 degrees to 60 degrees ) and mean flexion was 126.8 degrees (90 degrees to 145 degrees ) giving a mean arc of 105.5 degrees (60 degrees to 145 degrees ). The mean MEPS was 90 (50 to 100) and a mean DASH score of 20 (0 to 63). Four patients had additional surgery for limited range of movement and one for partial instability. One elbow was revised due to loosening, two patients had sensory ulnar nerve symptoms, and radiographic signs of mild olecranon wear was noted in five patients. Elbow hemiarthroplasty for comminuted intra-articular distal humeral fractures produces reliable medium-term results with functional outcome and complication rates, comparable with open reduction and internal fixation and total elbow arthroplasty. PMID- 26430014 TI - Age-related differences in the use of total shoulder arthroplasty over time: use and outcomes. AB - We assessed the age-related differences in the use of total shoulder arthroplasty (TSA) and outcomes, and associated time-trends using the United States Nationwide Inpatient Sample (NIS) between 1998 and 2010. Age was categorised as < 50, 50 to 64, 65 to 79 and >= 80 years. Time-trends in the use of TSA were compared using logistic regression or the Cochran Armitage test. The overall use of TSA increased from 2.96/100 000 in 1998 to 12.68/100,000 in 2010. Significantly lower rates were noted between 2009 and 2010, compared with between 1998 and 2000, for: mortality, 0.1% versus 0.2% (p = 0.004); discharge to an inpatient facility, 13.3% versus 14.5% (p = 0.039), and hospital stay > median, 29.4% versus 51.2% (p < 0.001). The rates of use of TSA/100,000 by age groups, < 50, 50 to 64, 65 to 79 and >= 80 years were: 0.32, 4.62, 17.82 and 12.56, respectively in 1998 (p < 0.001); and 0.65, 17.49, 75.27 and 49.05, respectively in 2010 (p < 0.001) with an increasing age-related difference over time (p < 0.001). Across the age categories, there were significant differences in the proportion: discharged to an inpatient facility, 3.2% versus 4.2% versus 14.7% versus 36.5%, respectively in 1998 (p < 0.001) and 1.8% versus 4.3% versus 12.5% versus 35.5%, respectively in 2010 (p < 0.001) and the proportion with hospital stay > median, 39.7% versus 40.2% versus 53% versus 69%, respectively in 1998 (p < 0.001) and 17.2% versus 20.6% versus 28.7% versus 50.7%, respectively in 2010 (p < 0.001). In a nationally representative sample, we noted a time-related increase in the use of TSA and increasing age-related differences in outcomes indicating a changing epidemiology of the use of TSA. Age-related differences in outcomes suggest that attention should focus on groups with the worst outcomes. PMID- 26430015 TI - Cauda equina syndrome: is the current management of patients presenting to district general hospitals fit for purpose? A personal view based on a review of the literature and a medicolegal experience. AB - There is no universally agreed definition of cauda equina syndrome (CES). Clinical signs of CES including direct rectal examination (DRE) do not reliably correlate with cauda equina (CE) compression on MRI. Clinical assessment only becomes reliable if there are symptoms/signs of late, often irreversible, CES. The only reliable way of including or excluding CES is to perform MRI on all patients with suspected CES. If the diagnosis is being considered, MRI should ideally be performed locally in the District General Hospitals within one hour of the question being raised irrespective of the hour or the day. Patients with symptoms and signs of CES and MRI confirmed CE compression should be referred to the local spinal service for emergency surgery. CES can be subdivided by the degree of neurological deficit (bilateral radiculopathy, incomplete CES or CES with retention of urine) and also by time to surgical treatment (12, 24, 48 or 72 hour). There is increasing understanding that damage to the cauda equina nerve roots occurs in a continuous and progressive fashion which implies that there are no safe time or deficit thresholds. Neurological deterioration can occur rapidly and is often associated with longterm poor outcomes. It is not possible to predict which patients with a large central disc prolapse compressing the CE nerve roots are going to deteriorate neurologically nor how rapidly. Consensus guidelines from the Society of British Neurological Surgeons and British Association of Spinal Surgeons recommend decompressive surgery as soon as practically possible which for many patients will be urgent/emergency surgery at any hour of the day or night. PMID- 26430016 TI - Outcome of lumbar spinal fusion surgery in obese patients: a systematic review and meta-analysis. AB - The aim of this study was to determine whether obesity affects pain, surgical and functional outcomes following lumbar spinal fusion for low back pain (LBP). A systematic literature review and meta-analysis was made of those studies that compared the outcome of lumbar spinal fusion for LBP in obese and non-obese patients. A total of 17 studies were included in the meta-analysis. There was no difference in the pain and functional outcomes. Lumbar spinal fusion in the obese patient resulted in a statistically significantly greater intra-operative blood loss (weighted mean difference: 54.04 ml; 95% confidence interval (CI) 15.08 to 93.00; n = 112; p = 0.007) more complications (odds ratio: 1.91; 95% CI 1.68 to 2.18; n = 43858; p < 0.001) and longer duration of surgery (25.75 mins; 95% CI 15.61 to 35.90; n = 258; p < 0.001). Obese patients have greater intra-operative blood loss, more complications and longer duration of surgery but pain and functional outcome are similar to non-obese patients. Based on these results, obesity is not a contraindication to lumbar spinal fusion. PMID- 26430017 TI - Changes in cardiac function after pedicle subtraction osteotomy in patients with a kyphosis due to ankylosing spondylitis. AB - Cardiac disease in patients with ankylosing spondylitis (AS) has previously been studied but not in patients with a kyphosis or in those who have undergone an operation to correct it. The aim of this study was to measure the post-operative changes in cardiac function of patients with an AS kyphosis after pedicle subtraction osteotomy (PSO). The original cohort consisted of 39 patients (33 men, six women). Of these, four patients (two men, two women) were lost to follow up leaving 35 patients (31 men, four women) to study. The mean age of the remaining patients was 37.4 years (22.3 to 47.8) and their mean duration of AS was 17.0 years (4.6 to 26.4). Echocardiographic measurements, resting heart rate (RHR), physical function score (PFS), and full-length standing spinal radiographs were obtained before surgery and at the two-year follow-up. The mean pre operative RHR was 80.2 bpm (60.6 to 112.3) which dropped to a mean of 73.7 bpm (60.7 to 90.6) at the two-year follow-up (p = 0.0000). Of 15 patients with normal ventricular function pre-operatively, two developed mild left ventricular diastolic dysfunction (LVDD) at the two-year follow-up. Of 20 patients with mild LVDD pre-operatively only five had this post-operatively. Overall, 15 patients had normal LV diastolic function before their operation and 28 patients had normal LV function at the two-year follow-up. The clinical improvement was 15 out of 20 (75.0%): cardiac function in patients with AS whose kyphosis was treated by PSO was significantly improved. PMID- 26430018 TI - Impact of lumbar instrumented circumferential fusion on the development of adjacent vertebral compression fracture. AB - We evaluated the impact of lumbar instrumented circumferential fusion on the development of adjacent level vertebral compression fractures (VCFs). Instrumented posterior lumbar interbody fusion (PLIF) has become a popular procedure for degenerative lumbar spine disease. The immediate rigidity produced by PLIF may cause more stress and lead to greater risk of adjacent VCFs. However, few studies have investigated the relationship between PLIF and the development of subsequent adjacent level VCFs. Between January 2005 and December 2009, a total of 1936 patients were enrolled. Of these 224 patients had a new VCF and the incidence was statistically analysed with other covariants. In total 150 (11.1%) of 1348 patients developed new VCFs with PLIF, with 108 (72%) cases at adjacent segment. Of 588 patients, 74 (12.5%) developed new subsequent VCFs with conventional posterolateral fusion (PLF), with 37 (50%) patients at an adjacent level. Short-segment fusion, female and age older than 65 years also increased the development of new adjacent VCFs in patients undergoing PLIF. In the osteoporotic patient, more rigid fusion and a higher stress gradient after PLIF will cause a higher adjacent VCF rate. PMID- 26430019 TI - Hexapod external fixator closed distraction in the management of stiff hypertrophic tibial nonunions. AB - Tibial nonunion represents a spectrum of conditions which are challenging to treat, and optimal management remains unclear despite its high rate of incidence. We present 44 consecutive patients with 46 stiff tibial nonunions, treated with hexapod external fixators and distraction to achieve union and gradual deformity correction. There were 31 men and 13 women with a mean age of 35 years (18 to 68) and a mean follow-up of 12 months (6 to 40). No tibial osteotomies or bone graft procedures were performed. Bony union was achieved after the initial surgery in 41 (89.1%) tibias. Four persistent nonunions united after repeat treatment with closed hexapod distraction, resulting in bony union in 45 (97.8%) patients. The mean time to union was 23 weeks (11 to 49). Leg-length was restored to within 1 cm of the contralateral side in all tibias. Mechanical alignment was restored to within 5 degrees of normal in 42 (91.3%) tibias. Closed distraction of stiff tibial nonunions can predictably lead to union without further surgery or bone graft. In addition to generating the required distraction to achieve union, hexapod circular external fixators can accurately correct concurrent deformities and limb-length discrepancies. PMID- 26430020 TI - Combined local and systemic antibiotic delivery improves eradication of wound contamination: An animal experimental model of contaminated fracture. AB - Systemic antibiotics reduce infection in open fractures. Local delivery of antibiotics can provide higher doses to wounds without toxic systemic effects. This study investigated the effect on infection of combining systemic with local antibiotics via polymethylmethacrylate (PMMA) beads or gel delivery. An established Staphylococcus aureus contaminated fracture model in rats was used. Wounds were debrided and irrigated six hours after contamination and animals assigned to one of three groups, all of which received systemic antibiotics. One group had local delivery via antibiotic gel, another PMMA beads and the control group received no local antibiotics. After two weeks, bacterial levels were quantified. Combined local and systemic antibiotics were superior to systemic antibiotics alone at reducing the quantity of bacteria recoverable from each group (p = 0.002 for gel; p = 0.032 for beads). There was no difference in the bacterial counts between bead and gel delivery (p = 0.62). These results suggest that local antibiotics augment the antimicrobial effect of systemic antibiotics. Although no significant difference was found between vehicles, gel delivery offers technical advantages with its biodegradable nature, ability to conform to wound shape and to deliver increased doses. Further study is required to see if the gel delivery system has a clinical role. PMID- 26430021 TI - Slipped capital femoral epiphysis: is it worth the risk and cost not to offer prophylactic fixation of the contralateral hip? AB - Controversy remains whether the contralateral hip should be fixed in patients presenting with unilateral slipped capital femoral epiphysis (SCFE). This retrospective study compares the outcomes and cost of those patients who had prophylactic fixation with those who did not. Between January 2000 and December 2010 a total of 50 patients underwent unilateral fixation and 36 had prophylactic fixation of the contralateral hip. There were 54 males and 32 females with a mean age of 12.3 years (9 to 16). The rate of a subsequent slip without prophylactic fixation was 46%. The risk of complications was greater, the generic health measures (Short Form-12 physical (p < 0.001) and mental (p = 0.004) summary scores) were worse. Radiographic cam lesions in patients presenting with unilateral SCFE were only seen in patients who did not have prophylactic fixation. Furthermore, prophylactic fixation of the contralateral hip was found to be a cost-effective procedure, with a cost per quality adjusted life year gained of L1431 at the time of last follow-up. Prophylactic fixation of the contralateral hip is a cost-effective operation that limits the morbidity from the complications of a further slip, and the diminished functional outcome associated with unilateral fixation. PMID- 26430022 TI - The radiological assessment of pelvic obliquity in cerebral palsy and the impact on hip development. AB - Pelvic obliquity is a common finding in adolescents with cerebral palsy, however, there is little agreement on its measurement or relationship with hip development at different gross motor function classification system (GMFCS) levels. The purpose of this investigation was to study these issues in a large, population based cohort of adolescents with cerebral palsy at transition into adult services. The cohort were a subset of a three year birth cohort (n = 98, 65M: 33F, with a mean age of 18.8 years (14.8 to 23.63) at their last radiological review) with the common features of a migration percentage greater than 30% and a history of adductor release surgery. Different radiological methods of measuring pelvic obliquity were investigated in 40 patients and the angle between the acetabular tear drops (ITDL) and the horizontal reference frame of the radiograph was found to be reliable, with good face validity. This was selected for further study in all 98 patients. The median pelvic obliquity was 4 degrees (interquartile range 2 degrees to 8 degrees ). There was a strong correlation between hip morphology and the presence of pelvic obliquity (effect of ITDL on Sharpe's angle in the higher hip; rho 7.20 (5% confidence interval 5.59 to 8.81, p < 0.001). This was particularly true in non-ambulant adolescents (GMFCS IV and V) with severe pelvic obliquity, but was also easily detectable and clinically relevant in ambulant adolescents with mild pelvic obliquity. The identification of pelvic obliquity and its management deserves closer scrutiny in children and adolescents with cerebral palsy. PMID- 26430023 TI - Prediction of hip displacement in children with cerebral palsy: development of the CPUP hip score. AB - Hip displacement, defined in this study as a migration percentage (MP) of more than 40%, is a common, debilitating complication of cerebral palsy (CP). In this prospective study we analysed the risk of developing hip displacement within five years of the first pelvic radiograph. All children with CP in southern and western Sweden are invited to register in the hip surveillance programme CPUP. Inclusion criteria for the two groups in this study were children from the CPUP database born between 1994 and 2009 with Gross Motor Function Classification System (GMFCS) III to V. Group 1 included children who developed hip displacement, group 2 included children who did not develop hip displacement over a minimum follow-up of five years. A total of 145 children were included with a mean age at their initial pelvic radiograph of 3.5 years (0.6 to 9.7). The odds ratio for hip displacement was calculated for GMFCS-level, age and initial MP and head-shaft angle. A risk score was constructed with these variables using multiple logistic regression analysis. The predictive ability of the risk score was evaluated using the area under the receiver operating characteristics curve (AUC). All variables had a significant effect on the risk of a MP > 40%. The discriminatory accuracy of the CPUP hip score is high (AUC = 0.87), indicating a high ability to differentiate between high- and low-risk individuals for hip displacement. The CPUP hip score may be useful in deciding on further follow-up and treatment in children with CP. PMID- 26430024 TI - Draft Genome Sequence of Bacillus licheniformis S127, Isolated from a Sheep Udder Clinical Infection. AB - Bacillus licheniformis is a Gram-positive biofilm- and endospore-forming bacterium, which contaminates dairy products and can be pathogenic to humans. The draft genome sequencing for B. licheniformis strain S127 is reported here, providing genetic data relevant to the ability of this strain to sustain its survival in the dairy industry. PMID- 26430025 TI - Genome Sequence of a Distinct Infectious Bursal Disease Virus. AB - Infectious bursal disease virus is a relevant avian pathogen that affects poultry production. Here, we report the full-length coding sequence of the Uruguayan strain dIBDV/UY/2014/2202, isolated from a commercial broiler flock. The strain belongs to the distinct IBDV lineage that is widely distributed in South America. PMID- 26430026 TI - Genome Sequences of 64 Non-O157:H7 Shiga Toxin-Producing Escherichia coli Strains. AB - Shiga toxin-producing Escherichia coli (STEC) strains are human pathogens. Although >400 non-O157 serotypes have been involved in human disease, whole genome sequencing information is missing for many serotypes. We sequenced 64 STEC strains comprising 38 serotypes, isolated from clinical sources, animals, and environmental samples, to improve the phylogenetic understanding of these important foodborne pathogens. PMID- 26430027 TI - Draft Genome Sequences of Burkholderia pseudomallei and Staphylococcus aureus, Isolated from a Patient with Chronic Rhinosinusitis. AB - Here, we report the draft genome sequences of Burkholderia pseudomallei and Staphylococcus aureus causing chronic rhinosinusitis. Whole-genome sequencing determined the B. pseudomallei as sequence type (ST) 1381 and the S. aureus as ST8. B. pseudomallei possessed the blaOXA-59 gene. This study illustrates the potential emergence of B. pseudomallei in cases of chronic rhinosinusitis. PMID- 26430028 TI - Complete Genome Sequences of Six South African Rabies Viruses. AB - South African rabies viruses (RABVs) from dogs and jackals (canid viruses) are highly related and most likely originated from a single progenitor. RABV is the cause of most global human rabies cases. The complete genome sequences of 3 RABVs from South Africa and Zimbabwe are reported here. PMID- 26430029 TI - Draft Genome Sequences of 17 French Clostridium botulinum Group III Strains. AB - Animal botulism is mainly associated with Clostridium botulinum group III strains producing neurotoxin types C, C/D, D, and D/C. In this report, we present the draft genome sequences of fourteen strains of Clostridium botulinum producing type C/D and two strains producing type D/C isolated in France, and one strain producing type D/C that originated from New Caledonia. PMID- 26430030 TI - Mining Genomes of Three Marine Sponge-Associated Actinobacterial Isolates for Secondary Metabolism. AB - Here, we report the draft genome sequences of three actinobacterial isolates, Micromonospora sp. RV43, Rubrobacter sp. RV113, and Nocardiopsis sp. RV163 that had previously been isolated from Mediterranean sponges. The draft genomes were analyzed for the presence of gene clusters indicative of secondary metabolism using antiSMASH 3.0 and NapDos pipelines. Our findings demonstrated the chemical richness of sponge-associated actinomycetes and the efficacy of genome mining in exploring the genomic potential of sponge-derived actinomycetes. PMID- 26430031 TI - Genome Sequence of Streptococcus agalactiae Strain H002, Serotype III, Isolated in China from a Pregnant Woman. AB - Here, we report the first whole-genome sequence of Streptococcus agalactiae strain H002, serotype III, isolated in China from a woman 32 weeks pregnant. This sequence represents an important addition to the published genomes and will promote comparative genomic studies of S. agalactiae spp. isolated from diverse regions, particularly when compared with Chinese strains. PMID- 26430032 TI - Genome Sequencing of Ralstonia solanacearum Race 4, Biovar 4, and Phylotype I, Strain YC45, Isolated from Rhizoma kaempferiae in Southern China. AB - Ralstonia solanacearum is an important phytopathogen that attacks over 400 plant species, including Zingiberaceae plants. Here, we report the complete genome sequence of strain YC45, which was isolated from Rhizoma kaempferiae in southern China. PMID- 26430033 TI - Complete Genome Sequence of a Cyanotroph, Pseudomonas fluorescens NCIMB 11764, Employing Single-Molecule Real-Time Technology. AB - We report here the application of single-molecule real-time sequencing for determining the entire genome structure of the cyanotroph Pseudomonas fluorescens NCIMB 11764. PMID- 26430034 TI - Draft Genome Sequence of the Strict Anaerobe Clostridium homopropionicum LuHBu1 (DSM 5847). AB - Here, we report the draft genome sequence of Clostridium homopropionicum LuHBu1 (DSM 5847(T)), a strictly anaerobic bacterium, which performs propionate fermentation and is capable of growing with 2-, 3-, or 4-hydroxybutyrate as its sole substrate. The genome consists of a single chromosome of 3.65 Mb. PMID- 26430035 TI - Correction for Sheflo et al., Complete Genome Sequences of Five Brevibacillus laterosporus Bacteriophages. PMID- 26430036 TI - Genome Sequence of Stachybotrys chartarum Strain 51-11. AB - The Stachybotrys chartarum strain 51-11 genome was sequenced by shotgun sequencing utilizing Illumina HiSeq 2000 and PacBio technologies. Since S. chartarum has been implicated as having health impacts within water-damaged buildings, any information extracted from the genomic sequence data relating to toxins or the metabolism of the fungus might be useful. PMID- 26430037 TI - Complete Genome Sequence of Noncytopathic Bovine Viral Diarrhea Virus 1 Contaminating a High-Passage RK-13 Cell Line. AB - A high-passage rabbit kidney RK-13 cell line (HP-RK-13[KY], originally derived from the ATCC CCL-37 cell line) used in certain laboratories worldwide is contaminated with noncytopathic bovine viral diarrhea virus (ncpBVDV). On complete genome sequence analysis, the virus strain was found to belong to BVDV group 1b. PMID- 26430038 TI - Complete Genome Sequence of Spiroplasma litorale TN-1T (DSM 21781), a Bacterium Isolated from a Green-Eyed Horsefly (Tabanus nigrovittatus). AB - Spiroplasma litorale TN-1(T) (DSM 21781) was isolated from the gut of a green eyed horsefly (Tabanus nigrovittatus), collected at Ocracoke Island in North Carolina in 1983. Here, we report the complete genome sequence of this bacterium to facilitate the investigation of its biology. PMID- 26430039 TI - Draft Genome Sequence of Erwinia billingiae OSU19-1, Isolated from a Pear Tree Canker. AB - Plant-associated Erwinia include pathogenic and nonpathogenic species. We report the 5.6-Mb genome sequence of Erwinia billingiae OSU19-1, isolated from a canker on a pear tree inoculated with Erwinia amylovora. OSU19-1 and a closely related European isolate, E. billingiae Eb661(T), share many similarities including 40 kb of plasmid sequence. PMID- 26430040 TI - Genome Sequence of Antibiotic-Producing Bacillus amyloliquefaciens Strain KCTC 13012. AB - We report the 4.0-Mb draft genome sequence of Bacillus amyloliquefaciens (syn. Bacillus velezensis) KCTC 13012, which exhibits a broad spectrum of antagonistic activity against bacteria and fungi and promotes plant growth as well. The genome contains an array of biosynthetic gene clusters for secondary metabolites that are comparable to those in Bacillus amyloliquefaciens subsp. plantarum FZB42(T). PMID- 26430041 TI - Complete Genome Sequence of Rothia mucilaginosa Strain NUM-Rm6536, Isolated from a Human Oral Cavity. AB - Here, we present the complete genome sequence of Rothia mucilaginosa NUM-Rm6536, a strain isolated from the tongue plaque of a healthy human adult. This strain is amenable to genetic manipulation by transformation and so provides a useful foundation for more detailed investigation of this species. PMID- 26430042 TI - Complete Genome Sequence of Mycobacterium bovis Clinical Strain 1595, Isolated from the Laryngopharyngeal Lymph Node of South Korean Cattle. AB - Mycobacterium bovis strain 1595 was isolated from the lymph node of South Korean native cattle. The complete genome sequence of strain 1595 was determined in 2 contigs and was found to be 4,351,712 bp in size, with a 65.64% G+C content and 4,358 predicted protein-coding genes. PMID- 26430043 TI - Complete Genome Sequence of Xanthomonas arboricola pv. juglandis 417, a Copper Resistant Strain Isolated from Juglans regia L. AB - Here, we report the complete genome sequence of Xanthomonas arboricola pv. juglandis 417, a copper-resistant strain isolated from a blighted walnut fruit (Juglans regia L. cv. Chandler). The genome consists of a single chromosome (5,218 kb). PMID- 26430044 TI - Genome Comparison of an Ancestral Isolate and a Modern Isolate of Mycobacterium tuberculosis of the Beijing Lineage from Sao Paulo, Brazil. AB - Mycobacterium tuberculosis of the Bejing subtype (MtbB) is transmitted efficiently in high burden countries for this genotype. A higher virulence was associated with isolates of the "modern" Beijing genotype sub-lineages when compared to "ancient" ones. Here, we report the full genomes of the strain representing these two genotypes from Brazil, a country with a low incidence of MtbB. PMID- 26430045 TI - Complete Genome Sequence of Caulobacter crescentus Siphophage Seuss. AB - Caulobacter crescentus is a water-dwelling bacterium known to have a dimorphic life cycle. Here, we announce the complete genome of Seuss, a C. crescentus icosahedral siphophage, and describe key features. Seuss is unique among phages deposited in GenBank, with genes encoding novel hypothetical proteins composing 45% of its genome. PMID- 26430046 TI - Complete Genome Sequence of Citrobacter freundii Myophage Merlin. AB - Bacteriophage Merlin is a T4-like myophage which infects Citrobacter freundii, a member of the Enterobacteriaceae family. C. freundii is an opportunistic pathogen that is a common cause of nosocomial infections. This report announces the complete genome of myophage Merlin and describes its features. PMID- 26430047 TI - Complete Genome Sequence of Citrobacter freundii Myophage Michonne. AB - Citrobacter freundii is a Gram-negative opportunistic pathogen that causes dangerous infections such as neonatal meningitis. C. freundii also harbors antibiotic resistance, making phages infecting this host valuable tools. Here, we announce the complete genome of the C. freundii FelixO1-like myophage Michonne and describe its notable features. PMID- 26430048 TI - Complete Genome Sequence of Enterotoxigenic Escherichia coli Myophage Murica. AB - Murica is an rv5-like myophage that infects enterotoxigenic Escherichia coli. Pathogenic E. coli strains are responsible for many intestinal diseases, and phages that infect these bacteria may prove useful in preventing severe health issues. The following is a report of the complete genome sequence of Murica and its important features. PMID- 26430049 TI - Complete Genome Sequence of Carbapenemase-Producing Klebsiella pneumoniae Myophage Matisse. AB - Klebsiella pneumoniae is a leading cause of nosocomial infections in the United States. Due to the emergence of multidrug-resistant strains, phages targeting K. pneumoniae may be a useful alternative against this pathogen. Here, we announce the complete genome of K. pneumoniae pseudo-T-even myophage Matisse and describe its features. PMID- 26430050 TI - Complete Genome Sequence of Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae Myophage Miro. AB - Klebsiella pneumoniae is a Gram-negative pathogen frequently associated with antibiotic-resistant nosocomial infections. Bacteriophage therapy against K. pneumoniae may be possible to combat these infections. The following describes the complete genome sequence and key features of the pseudo-T-even K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae myophage Miro. PMID- 26430051 TI - Draft Genome Sequences of Four Genetically Distinct Human Isolates of Streptococcus dysgalactiae subsp. equisimilis. AB - beta-Hemolytic group C and group G streptococci (GCS-GGS; Streptococcus dysgalactiae subsp. equisimilis) emerged as human pathogens in the late 1970s. We report here the draft genome sequences of four genetically distinct human strains of GCS-GGS isolated between the 1960s and 1980s. Comparative analysis of these genomes may provide a deeper understanding of GCS-GGS genome and virulence evolution. PMID- 26430052 TI - Complete Genome Sequences of Evolved Arsenate-Resistant Metallosphaera sedula Strains. AB - Metallosphaera sedula is a thermoacidophilic crenarchaeote with a 2.19-Mb genome. Here, we report the genome sequences of several evolved derivatives of M. sedula generated through adaptive laboratory evolution for enhanced arsenate resistance. PMID- 26430053 TI - Draft Genome Sequence of a Heterotrophic Facultative Anaerobic Thermophilic Bacterium, Ardenticatena maritima Strain 110ST. AB - Ardenticatena maritima strain 110S(T) is a filamentous bacterium isolated from an iron-rich coastal hydrothermal field, and it is a unique isolate capable of dissimilatory iron or nitrate reduction among the members of the bacterial phylum Chloroflexi. Here, we report the draft genome sequence comprising 3,569,367 bp, containing 3,355 predicted coding sequences (CDSs). PMID- 26430054 TI - Draft Genome Sequence of a Necrotoxigenic Escherichia coli Isolate. AB - Here, we present the draft genome sequence of a necrotoxigenic Escherichia coli strain isolated from a patient following a very rapidly evolving, lethal necrotizing fasciitis. PMID- 26430055 TI - Scotland is to scrap QOF, health minister announces. PMID- 26430056 TI - The Degeneration of Meniscus Roots Is Accompanied by Fibrocartilage Formation, Which May Precede Meniscus Root Tears in Osteoarthritic Knees. AB - BACKGROUND: Fibrocartilage metaplasia in tendons and ligaments is an adaptation to compression as well as a pathological feature during degeneration. Medial meniscus posterior roots are unique ligaments that resist multidirectional forces, including compression. PURPOSE: To characterize the degeneration of medial meniscus posterior root tears in osteoarthritic knees, with an emphasis on fibrocartilage and calcification. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Samples of medial meniscus posterior roots were harvested from cadaveric specimens and patients during knee replacement surgery and grouped as follows: normal reference, no tear, partial tear, and complete tear. Degeneration was analyzed with histology, immunohistochemistry, and real-time polymerase chain reaction. Uniaxial tensile tests were performed on specimens with and without fibrocartilage. Quantifiable data were statistically analyzed by the Kruskal-Wallis test with the Dunn comparison test. RESULTS: Thirty, 28, and 42 samples harvested from 99 patients were allocated into the no tear, partial tear, and complete tear groups, respectively. Mean modified Bonar tendinopathy scores for each group were 3.97, 9.31, and 14.15, respectively, showing a higher degree of degeneration associated with the extent of the tear (P < .05 for all groups). The characterization of root matrices revealed an increase in fibrocartilage according to the extent of the tear. Tear margins revealed fibrocartilage in 59.3% of partial tear samples and 76.2% of complete tear samples, with a distinctive cleavage-like shape. Root tears with a similar shape were induced within fibrocartilaginous areas during uniaxial tensile testing. Even in the no tear group, 56.7% of samples showed fibrocartilage in the anterior margin of the root, adjacent to the meniscus. An increased stained area of calcification and expression of the ectonucleotide pyrophosphatase/phosphodiesterase 1 gene were observed in the complete tear group compared with the no tear group (P < .0001 and P = .24, respectively). CONCLUSION: Fibrocartilage and calcification increased in medial meniscus posterior roots, associated with the degree of the tear. Both findings, which impair the ligament's resistance to tension, may play a pivotal role during the pathogenesis of degenerative meniscus root tears in osteoarthritic knees. Fibrocartilage and calcification may be useful as diagnostic markers as well as markers of degeneration, which may aid in determining the treatment modality in meniscus root tears. The presence of fibrocartilage in intact roots may suggest an impending tear in osteoarthritic knees. PMID- 26430057 TI - Clinical and Radiographic Predictors for Worsened Clinical Outcomes After Hip Arthroscopic Labral Preservation and Capsular Closure in Developmental Dysplasia of the Hip. AB - BACKGROUND: Patients with developmental dysplasia of the hip (DDH) have a greater risk of acetabular labral tearing and joint instability, which predispose them to developing osteoarthritis. The arthroscopic management of DDH, however, remains controversial. HYPOTHESIS: Specific clinical characteristics and radiographic parameters correlate with and predict a worsened clinical outcome after hip arthroscopic surgery for DDH. STUDY DESIGN: Case control study; Level of evidence, 3. METHODS: Of patients with DDH who underwent an arthroscopic procedure between March 2009 and June 2011, there were 28 hips in 28 patients (6 male and 22 female) that met the inclusion criteria. The mean patient age was 28.4 years. Clinical and radiographic follow-up evaluations up to a minimum of 2 years after surgery were performed for all patients. Failure of the procedure was defined as conversion to subsequent surgery or having a Tonnis osteoarthritis grade of 2 and modified Harris Hip Score (mHHS) that remained <85, and success was defined as patients who did not need subsequent surgery and had an mHHS >85. Univariate analysis and Cox hazard proportional analysis were performed on the 2 subpopulations. RESULTS: There were 9 patients in the failure group (including 3 hips with T nnis grade 2) and 19 patients in the success group. In 22 of 28 patients, the mean mHHS significantly improved from 61.6 +/- 18.8 (range, 12.0 85.0) preoperatively to 94.3 +/- 7.0 (range, 73.7-100.0) at final follow-up, and the mean Non-Arthritic Hip Score (NAHS) improved from 56.2 +/- 13.9 (range, 35.0 81.3) preoperatively to 92.7 +/- 9.5 (range, 65.0-100.0) at final follow-up (P < .001, Wilcoxon signed-rank test). Univariate analysis showed that a broken Shenton line was significantly more prevalent in the failure group compared with the success group (8/9 [89%] vs 3/19 [16%] patients, respectively; P < .001). High-grade cartilage delamination (Multicenter Arthroscopy of the Hip Outcomes Research Network [MAHORN] grades 3-5) was significantly higher in the failure group than in the success group (8/9 [89%] vs 3/19 [16%] patients, respectively; P < .001). The median femoral neck-shaft (FNS) angle in the failure group was significantly higher than that in the success group (139 degrees vs 134 degrees , respectively; P = .01). Further, Cox hazard proportional analysis of the failure group showed that the predictors for a poor clinical outcome were the presence of a broken Shenton line, FNS angle >140 degrees , center-edge (CE) angle <19 degrees , body mass index (BMI) >23 kg/m(2), acetabular cartilage damage (MAHORN grades 3-5), and cartilage damage of the femoral head (International Cartilage Repair Society grades 2-4). The most important predictors for a poor clinical outcome at the time of surgery were a broken Shenton line and an FNS angle >140 degrees . CONCLUSION: Patients with a broken Shenton line, FNS angle >140 degrees , CE angle <19 degrees , or BMI >23 kg/m(2) at the time of surgery are not good candidates for the arthroscopic management of DDH. PMID- 26430058 TI - The Fate of Meniscus Tears Left In Situ at the Time of Anterior Cruciate Ligament Reconstruction: A 6-Year Follow-up Study From the MOON Cohort. AB - BACKGROUND: The management of meniscus tears identified at the time of primary anterior cruciate ligament (ACL) reconstruction is highly variable and includes repair, meniscectomy, and nontreatment. HYPOTHESIS/PURPOSE: The purpose of this study was to determine the reoperation rate for meniscus tears left untreated at the time of ACL reconstruction with a minimum follow-up of 6 years. The hypothesis was that small peripheral tears identified at the time of ACL reconstruction managed with "no treatment" would have successful clinical outcomes. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Patients with meniscus tears left untreated at the time of primary ACL reconstruction were identified from a multicenter study group with a minimum 6-year follow-up. Patient, tear, and reoperation data were obtained for analysis. The need for reoperation was used as the primary endpoint, with analysis performed to determine patient and tear characteristics associated with reoperation. RESULTS: There were 194 patients with 208 meniscus tears (71 medial, 137 lateral) left in situ without treatment with a complete follow-up for analysis. Of these, 97.8% of lateral and 94.4% of medial untreated tears required no reoperation. Sixteen tears (7.7%) left in situ without treatment underwent subsequent reoperation: 9 tears (4.3%) underwent reoperation in the setting of revision ACL reconstruction, and 7 tears (3.4%) underwent reoperation for an isolated meniscus injury. The patient age was significantly lower in patients requiring reoperation, while tears measuring >=10 mm more frequently required reoperation. CONCLUSION: Lateral and medial meniscus tears left in situ at the time of ACL reconstruction did not require reoperation at a minimum 6-year follow-up for 97.8% and 94.4% of tears, respectively. These findings re-emphasize the low reoperation rate after the nontreatment of small, peripheral lateral meniscus tears while noting less predictable results for medial meniscus tears left without treatment. PMID- 26430059 TI - Processes Driving the Adaptive Radiation of a Tropical Tree (Diospyros, Ebenaceae) in New Caledonia, a Biodiversity Hotspot. AB - Due to its special geological history, the New Caledonian Archipelago is a mosaic of soil types, and in combination with climatic conditions this results in a heterogeneous environment across relatively small distances. A group of over 20 endemic species of Diospyros (Ebenaceae) has rapidly and recently radiated on the archipelago after a single long-distance dispersal event. Most of the Diospyros species in the radiating group are morphologically and ecologically well differentiated, but they exhibit low levels of DNA variability. To investigate the processes that shaped the diversification of this group we employed restriction site associated DNA sequencing (RADseq). Over 8400 filtered SNPs generally confirm species delimitations and produce a well-supported phylogenetic tree. Our analyses document local introgression, but only a limited potential for gene flow over longer distances. The phylogenetic relationships point to an early regional clustering among populations and species, indicating that allopatric speciation with respect to macrohabitat (i.e., climatic conditions) may have had a role in the initial differentiation within the group. A later, more rapid radiation involved divergence with respect to microhabitat (i.e., soil preference). Several sister species in the group show a parallel divergence in edaphic preference. Searches for genomic regions that are systematically differentiated in this replicated phenotypic divergence pointed to loci potentially involved in ion binding and cellular transport. These loci appear meaningful in the context of adaptations to soil types that differ in heavy-metal and mineral content. Identical nucleotide changes affected only two of these loci, indicating that introgression may have played a limited role in their evolution. Our results suggest that both allopatric diversification and (parapatric) ecological divergence shaped successive rounds of speciation in the Diospyros radiation on New Caledonia. PMID- 26430060 TI - Rumbling Orchids: How To Assess Divergent Evolution Between Chloroplast Endosymbionts and the Nuclear Host. AB - Phylogenetic relationships inferred from multilocus organellar and nuclear DNA data are often difficult to resolve because of evolutionary conflicts among gene trees. However, conflicting or "outlier" associations (i.e., linked pairs of "operational terminal units" in two phylogenies) among these data sets often provide valuable information on evolutionary processes such as chloroplast capture following hybridization, incomplete lineage sorting, and horizontal gene transfer. Statistical tools that to date have been used in cophylogenetic studies only also have the potential to test for the degree of topological congruence between organellar and nuclear data sets and reliably detect outlier associations. Two distance-based methods, namely ParaFit and Procrustean Approach to Cophylogeny (PACo), were used in conjunction to detect those outliers contributing to conflicting phylogenies independently derived from chloroplast and nuclear sequence data. We explored their efficiency of retrieving outlier associations, and the impact of input data (unit branch length and additive trees) between data sets, by using several simulation approaches. To test their performance using real data sets, we additionally inferred the phylogenetic relationships within Neotropical Catasetinae (Epidendroideae, Orchidaceae), which is a suitable group to investigate phylogenetic incongruence because of hybridization processes between some of its constituent species. A comparison between trees derived from chloroplast and nuclear sequence data reflected strong, well-supported incongruence within Catasetum, Cycnoches, and Mormodes. As a result, outliers among chloroplast and nuclear data sets, and in experimental simulations, were successfully detected by PACo when using patristic distance matrices obtained from phylograms, but not from unit branch length trees. The performance of ParaFit was overall inferior compared to PACo, using either phylograms or unit branch lengths as input data. Because workflows for applying cophylogenetic analyses are not standardized yet, we provide a pipeline for executing PACo and ParaFit as well as displaying outlier associations in plots and trees by using the software R. The pipeline renders a method to identify outliers with high reliability and to assess the combinability of the independently derived data sets by means of statistical analyses. PMID- 26430061 TI - Expression Divergence of Chemosensory Genes between Drosophila sechellia and Its Sibling Species and Its Implications for Host Shift. AB - Drosophila sechellia relies exclusively on the fruits of Morinda citrifolia, which are toxic to most insects, including its sibling species Drosophila melanogaster and Drosophila simulans. Although several odorant binding protein (Obp) genes and olfactory receptor (Or) genes have been suggested to be associated with the D. sechellia host shift, a broad view of how chemosensory genes have contributed to this shift is still lacking. We therefore studied the transcriptomes of antennae, the main organ responsible for detecting food resource and oviposition, of D. sechellia and its two sibling species. We wanted to know whether gene expression, particularly chemosensory genes, has diverged between D. sechellia and its two sibling species. Using a very stringent definition of differential gene expression, we found a higher percentage of chemosensory genes differentially expressed in the D. sechellia lineage (7.8%) than in the D. simulans lineage (5.4%); for upregulated chemosensory genes, the percentages were 8.8% in D. sechellia and 5.2% in D. simulans. Interestingly, Obp50a exhibited the highest upregulation, an approximately 100-fold increase, and Or85c--previously reported to be a larva-specific gene--showed approximately 20-fold upregulation in D. sechellia. Furthermore, Ir84a (ionotropic receptor 84a), which has been proposed to be associated with male courtship behavior, was significantly upregulated in D. sechellia. We also found expression divergence in most of the chemosensory gene families between D. sechellia and the two sibling species. Our observations suggest that the host shift of D. sechellia was associated with the enrichment of differentially expressed, particularly upregulated, chemosensory genes. PMID- 26430064 TI - Physical activity across the life-span: Does feeling physically younger help you to plan physical activities? AB - We tested whether the relationship between subjective physical age and physical activity is mediated by planning. Participants came from a broad age range (25-78 years, M = 39.57, standard deviation = 10.75) and reported relatively good health ( M = 3.36, standard deviation = 0.90). The model supported the suggested mediation ( beta = -.01, standard error = .01, p = .042). Feeling physically younger is associated with higher planning to adopt higher levels of physical activity and more planning is associated with more subsequent physical activity. Results open avenues for interventions that help people to become more active by focusing on subjective age. One way to do so might be tailoring approaches for interventions. PMID- 26430062 TI - Recombining without Hotspots: A Comprehensive Evolutionary Portrait of Recombination in Two Closely Related Species of Drosophila. AB - Meiotic recombination rate varies across the genome within and between individuals, populations, and species in virtually all taxa studied. In almost every species, this variation takes the form of discrete recombination hotspots, determined in some mammals by a protein called PRDM9. Hotspots and their determinants have a profound effect on the genomic landscape, and share certain features that extend across the tree of life. Drosophila, in contrast, are anomalous in their absence of hotspots, PRDM9, and other species-specific differences in the determination of recombination. To better understand the evolution of meiosis and general patterns of recombination across diverse taxa, we present a truly comprehensive portrait of recombination across time, combining recently published cross-based contemporary recombination estimates from each of two sister species with newly obtained linkage-disequilibrium-based historic estimates of recombination from both of these species. Using Drosophila pseudoobscura and Drosophila miranda as a model system, we compare recombination rate between species at multiple scales, and we suggest that Drosophila replicate the pattern seen in human-chimpanzee in which recombination rate is conserved at broad scales. We also find evidence of a species-wide recombination modifier(s), resulting in both a present and historic genome-wide elevation of recombination rates in D. miranda, and identify broad scale effects on recombination from the presence of an inversion. Finally, we reveal an unprecedented view of the distribution of recombination in D. pseudoobscura, illustrating patterns of linked selection and where recombination is taking place. Overall, by combining these estimation approaches, we highlight key similarities and differences in recombination between Drosophila and other organisms. PMID- 26430063 TI - Single-cell RNA-seq reveals changes in cell cycle and differentiation programs upon aging of hematopoietic stem cells. AB - Both intrinsic cell state changes and variations in the composition of stem cell populations have been implicated as contributors to aging. We used single-cell RNA-seq to dissect variability in hematopoietic stem cell (HSC) and hematopoietic progenitor cell populations from young and old mice from two strains. We found that cell cycle dominates the variability within each population and that there is a lower frequency of cells in the G1 phase among old compared with young long term HSCs, suggesting that they traverse through G1 faster. Moreover, transcriptional changes in HSCs during aging are inversely related to those upon HSC differentiation, such that old short-term (ST) HSCs resemble young long-term (LT-HSCs), suggesting that they exist in a less differentiated state. Our results indicate both compositional changes and intrinsic, population-wide changes with age and are consistent with a model where a relationship between cell cycle progression and self-renewal versus differentiation of HSCs is affected by aging and may contribute to the functional decline of old HSCs. PMID- 26430065 TI - How Multidimensional Health Locus of Control predicts utilization of emergency and inpatient hospital services. AB - Health locus of control may be an important predictor of health care utilization. We analyzed associations between health locus of control and frequency of emergency department visits and hospital admissions, and investigated self-rated health as a potential mediator. Overall, 863 patients in an urban emergency department completed the Multidimensional Health Locus of Control instrument, and self-reported emergency department use and hospital admissions in the last year. We found small but significant associations between Multidimensional Health Locus of Control and utilization, all of which were mediated by self-rated health. We conclude that interventions to shift health locus of control may change patients' perceptions of their own health, thereby impacting utilization. PMID- 26430066 TI - Discerning the impact of personal and situational variables in risk perception of coronary heart disease. AB - Research into how people perceive risk has highlighted the interaction between the available information and personal variables and their impact on judgement. This study sought to identify demographic and health variables that influenced risk and the influence of individual risk assessment, dispositional optimism and negative affect on judgement. A total of 476 participants were asked to make risks judgements of 24 vignettes depicting hypothetical risk scenarios. The findings showed that while people are able to correctly recognise, in others, relevant risk factors for coronary heart disease, risk perception is likely to imply a personal consideration of the same risk factors in themselves. PMID- 26430067 TI - Low sense of coherence during postoperative recovery is associated with a poorer lumbar spinal stenosis - surgical outcome: A 5-year follow-up study. AB - This study investigated the association between the 3-month postoperative sense of coherence and the 5-year postoperative outcome of decompressive surgery for lumbar spinal stenosis. The participants with a lower sense of coherence at the 3 month follow-up had a poorer functional ability and lower satisfaction with surgery, higher pain ratings, lower life satisfaction and more depressive symptoms 5 years postoperatively. A low 3-month sense of coherence associated with greater pain and a poorer functional ability 5 years postoperatively. Evaluating sense of coherence and depressive symptoms in patients who have had lumbar spinal stenosis surgery may help in identifying those in need of enhanced support for postoperative recovery. PMID- 26430068 TI - Emotional management and quality of life in mother living versus multi-organ donor renal transplant recipients. AB - The aim of this study was to evaluate psychological differences and quality of life between kidney recipients from living (mother) and multi-organ donor. Overall, 40 patients who had undergone both living (mother) and multi-organ kidney transplantation 3-6 months before were asked to complete four self-report instruments: Toronto Alexithymia Scale, Short Form Health Survey, Regulatory Emotional Self-efficacy, and Attachment Style Questionnaire. A greater difficulty in emotional, social, and mental health functioning was found in recipients receiving kidney from mother living donor. Moreover, in these patients, higher levels of avoidant attachment dimensions were associated with a worse quality of life. PMID- 26430069 TI - Prevalence of burnout in Polish anesthesiologists and anesthetist nursing professionals: A comparative non-randomized cross-sectional study. AB - The purpose of the study was to assess the burnout levels in nurses ( N = 161) versus physicians ( N = 373). The levels of burnout were evaluated by the Polish adaptation of the Spanish Burnout Inventory (Cronbach's alpha > .70). High burnout level was found in 18.63 percent nurses and 12.06 percent anesthesiologists, and critical level in 3.74 percent nurses and 5.90 percent anesthetists. There were statistically significant differences in Burnout global score, Enthusiasm toward the job, Psychological exhaustion, and Indolence subscales between nurses and physicians. No significant differences were found between sexes in any variable. PMID- 26430070 TI - Mass Spectrometry Selectivity, Specifically. PMID- 26430071 TI - The Rise of Mass Spectrometry and the Fall of Edman Degradation. PMID- 26430072 TI - Rapid Measurement of Cyclosporine and Sirolimus in Whole Blood by Paper Spray Tandem Mass Spectrometry. PMID- 26430073 TI - Clonotypic Light Chain Peptides Identified for Monitoring Minimal Residual Disease in Multiple Myeloma without Bone Marrow Aspiration. AB - BACKGROUND: Analytically sensitive techniques for measuring minimal residual disease (MRD) in multiple myeloma (MM) currently require invasive and costly bone marrow aspiration. These methods include immunohistochemistry (IHC), flow cytometry, quantitative PCR, and next-generation sequencing. An ideal MM MRD test would be a serum-based test sensitive enough to detect low concentrations of Ig secreted from multifocal lesions. METHODS: Patient serum with abundant M-protein before treatment was separated on a 1-dimensional SDS-PAGE gel, and the Ig light chain (LC) band was excised, trypsin digested, and analyzed on a Q Exactive mass spectrometer by LC-MS/MS. We used the peptide's abundance and sequence to identify tryptic peptides that mapped to complementary determining regions of Ig LCs. The clonotypic target tryptic peptides were used to monitor MRD in subsequent serum samples with prior affinity enrichment. RESULTS: Sixty-two patients were tested, 20 with no detectable disease by IHC and 42 with no detectable disease by 6-color flow cytometry. A target peptide that could be monitored was identified in 57 patients (91%). Of these 57, detectable disease by LC-MS/MS was found in 52 (91%). CONCLUSIONS: The ability to use LC-MS/MS to measure disease in patients who are negative by bone marrow-based methodologies indicates that a serum-based approach has more analytical sensitivity and may be useful for measuring deeper responses to MM treatment. The method requires no bone marrow aspiration. PMID- 26430074 TI - High-Resolution Mass Spectrometry for Characterizing the Metabolism of Synthetic Cannabinoid THJ-018 and Its 5-Fluoro Analog THJ-2201 after Incubation in Human Hepatocytes. AB - BACKGROUND: Despite increasing prevalence of novel psychoactive substances, no human metabolism data are currently available, complicating laboratory documentation of intake in urine samples and assessment of the drugs' pharmacodynamic, pharmacokinetic, and toxicological properties. In 2014, THJ-018 and THJ-2201, synthetic cannabinoid indazole analogs of JWH-018 and AM-2201, were identified, with the National Forensic Laboratory Information System containing 220 THJ-2201 reports. Because of numerous adverse events, the Drug Enforcement Administration listed THJ-2201 as Schedule I in January 2015. METHODS: We used high-resolution mass spectrometry (HR-MS) (TripleTOF 5600(+)) to identify optimal metabolite markers after incubating 10 MUmol/L THJ-018 and THJ-2201 in human hepatocytes for 3 h. Data were acquired via full scan and information-dependent acquisition triggered product ion scans with mass defect filter. In silico metabolite predictions were performed with MetaSite and compared with metabolites identified in human hepatocytes. RESULTS: Thirteen THJ-018 metabolites were detected, with the major metabolic pathways being hydroxylation on the N-pentyl chain and further oxidation or glucuronidation. For THJ-2201, 27 metabolites were observed, predominantly oxidative defluorination plus subsequent carboxylation or glucuronidation, and glucuronidation of hydroxylated metabolites. Dihydrodiol formation on the naphthalene moiety was observed for both compounds. MetaSite prediction matched well with THJ-018 hepatocyte metabolites but underestimated THJ-2201 oxidative defluorination. CONCLUSIONS: With HR-MS for data acquisition and processing, we characterized THJ-018 and THJ-2201 metabolism in human hepatocytes and suggest appropriate markers for laboratories to identify THJ-018 and THJ-2201 intake and link observed adverse events to these new synthetic cannabinoids. PMID- 26430075 TI - CLSI C62-A: A New Standard for Clinical Mass Spectrometry. PMID- 26430076 TI - First Steps toward Harmonization of LC-MS/MS Thyroglobulin Assays. PMID- 26430077 TI - Multiplexed Quantification of Proglucagon-Derived Peptides by Immunoaffinity Enrichment and Tandem Mass Spectrometry after a Meal Tolerance Test. AB - BACKGROUND: Proglucagon-derived peptides (PGDPs), which include glucagon-like peptide (GLP)-1, glucagon, and oxyntomodulin, are key regulators of glucose homeostasis and satiety. These peptide hormones are typically measured with immuno-based assays (e.g., ELISA, RIA), which often suffer from issues of selectivity. METHODS: We developed a multiplexed assay for measuring PGDPs including GLP-1 (7-36) amide, GLP-1 (9-36) amide, glucagon, and oxyntomodulin by mass spectrometry and used this assay to examine the effect of a meal tolerance test on circulating concentrations of these hormones. Participants fasted overnight and were either given a meal (n = 8) or continued to fast (n = 4), with multiple blood collections over the course of 3 h. Plasma samples were analyzed by microflow immunoaffinity (IA)-LC-MS/MS with an isotope dilution strategy. RESULTS: Assay performance characteristics were examined and established during analytical validation for all peptides. Intra- and interassay imprecision were found to be 2.2%-10.7% and 6.8%-22.5%, respectively. Spike recovery was >76%, and dilution linearity was established up to a 16-fold dilution. Immediately after the meal tolerance test, GLP-1 and oxyntomodulin concentrations increased and had an almost identical temporal relationship, and glucagon concentrations increased with a slight delay. CONCLUSIONS: IA-LC-MS/MS was used for the simultaneous and selective measurement of PGDPs. This work includes the first indication of the physiological concentrations and modulation of oxyntomodulin after a meal. PMID- 26430079 TI - The Earth is no longer a square, the knee was never a hinge. PMID- 26430078 TI - A Novel N-Tetrasaccharide in Patients with Congenital Disorders of Glycosylation, Including Asparagine-Linked Glycosylation Protein 1, Phosphomannomutase 2, and Mannose Phosphate Isomerase Deficiencies. AB - BACKGROUND: Primary deficiencies in mannosylation of N-glycans are seen in a majority of patients with congenital disorders of glycosylation (CDG). We report the discovery of a series of novel N-glycans in sera, plasma, and cultured skin fibroblasts from patients with CDG having deficient mannosylation. METHOD: We used LC-MS/MS and MALDI-TOF-MS analysis to identify and quantify a novel N-linked tetrasaccharide linked to the protein core, an N-tetrasaccharide (Neu5Acalpha2,6Galbeta1,4-GlcNAcbeta1,4GlcNAc) in plasma, serum glycoproteins, and a fibroblast lysate from patients with CDG caused by ALG1 [ALG1 (asparagine linked glycosylation protein 1), chitobiosyldiphosphodolichol beta mannosyltransferase], PMM2 (phosphomannomutase 2), and MPI (mannose phosphate isomerase). RESULTS: Glycoproteins in sera, plasma, or cell lysate from ALG1-CDG, PMM2-CDG, and MPI-CDG patients had substantially more N-tetrasaccharide than unaffected controls. We observed a >80% decline in relative concentrations of the N-tetrasaccharide in MPI-CDG plasma after mannose therapy in 1 patient and in ALG1-CDG fibroblasts in vitro supplemented with mannose. CONCLUSIONS: This novel N-tetrasaccharide could serve as a diagnostic marker of ALG1-, PMM2-, or MPI-CDG for screening of these 3 common CDG subtypes that comprise >70% of CDG type I patients. Its quantification by LC-MS/MS may be useful for monitoring therapeutic efficacy of mannose. The discovery of these small N-glycans also indicates the presence of an alternative pathway in N-glycosylation not recognized previously, but its biological significance remains to be studied. PMID- 26430080 TI - Unicompartmental knee arthroplasty: is the glass half full or half empty? AB - There is a large amount of evidence available about the relative merits of unicompartmental and total knee arthroplasty (UKA and TKA). Based on the same evidence, different people draw different conclusions and as a result, there is great variability in the usage of UKA. The revision rate of UKA is much higher than TKA and so some surgeons conclude that UKA should not be performed. Other surgeons believe that the main reason for the high revision rate is that UKA is easy to revise and, therefore, the threshold for revision is low. They also believe that UKA has many advantages over TKA such as a faster recovery, lower morbidity and mortality and better function. They therefore conclude that UKA should be undertaken whenever appropriate. The solution to this argument is to minimise the revision rate of UKA, thereby addressing the main disadvantage of UKA. The evidence suggests that this will be achieved if surgeons use UKA for at least 20% of their knee arthroplasties and use implants that are appropriate for these broad indications. PMID- 26430081 TI - Long-term results of compartmental arthroplasties of the knee: Long term results of partial knee arthroplasty. AB - Partial knee arthroplasty (PKA), either medial or lateral unicompartmental knee artroplasty (UKA) or patellofemoral arthroplasty (PFA) are a good option in suitable patients and have the advantages of reduced operative trauma, preservation of both cruciate ligaments and bone stock, and restoration of normal kinematics within the knee joint. However, questions remain concerning long-term survival. The goal of this review article was to present the long-term results of medial and lateral UKA, PFA and combined compartmental arthroplasty for multicompartmental disease. Medium- and long-term studies suggest reasonable outcomes at ten years with survival greater than 95% in UKA performed for medial osteoarthritis or osteonecrosis, and similarly for lateral UKA, particularly when fixed-bearing implants are used. Disappointing long-term outcomes have been observed with the first generation of patellofemoral implants, as well as early Bi-Uni (i.e., combined medial and lateral UKA) or Bicompartmental (combined UKA and PFA) implants due to design and fixation issues. Promising short- and med term results with the newer generations of PFAs and bicompartmental arthroplasties will require long-term confirmation. PMID- 26430082 TI - Alignment and fixation in total knee arthroplasty: changing paradigms. AB - Many aspects of total knee arthroplasty have changed since its inception. Modern prosthetic design, better fixation techniques, improved polyethylene wear characteristics and rehabilitation, have all contributed to a large change in revision rates. Arthroplasty patients now expect longevity of their prostheses and demand functional improvement to match. This has led to a re-examination of the long-held belief that mechanical alignment is instrumental to a successful outcome and a focus on restoring healthy joint kinematics. A combination of kinematic restoration and uncemented, adaptable fixation may hold the key to future advances. PMID- 26430083 TI - The management of an infected total knee arthroplasty. AB - Periprosthetic joint infection (PJI) is one of the most feared and challenging complications following total knee arthroplasty. We provide a detailed description of our current understanding regarding the management of PJI of the knee, including diagnostic aids, pre-operative planning, surgical treatment, and outcome. PMID- 26430084 TI - The difficult primary total knee arthroplasty: a review. AB - Primary total knee arthroplasty (TKA) is a reliable procedure with reproducible long-term results. Nevertheless, there are conditions related to the type of patient or local conditions of the knee that can make it a difficult procedure. The most common scenarios that make it difficult are discussed in this review. These include patients with many previous operations and incisions, and those with severe coronal deformities, genu recurvatum, a stiff knee, extra-articular deformities and those who have previously undergone osteotomy around the knee and those with chronic dislocation of the patella. Each condition is analysed according to the characteristics of the patient, the pre-operative planning and the reported outcomes. When approaching the difficult primary TKA surgeons should use a systematic approach, which begins with the review of the existing literature for each specific clinical situation. PMID- 26430085 TI - The constraints on day-case total knee arthroplasty: the fastest fast track. AB - Total knee arthroplasty (TKA) is a major orthopaedic intervention. The length of a patient's stay has been progressively reduced with the introduction of enhanced recovery protocols: day-case surgery has become the ultimate challenge. This narrative review shows the potential limitations of day-case TKA. These constraints may be social, linked to patient's comorbidities, or due to surgery related adverse events (e.g. pain, post-operative nausea and vomiting, etc.). Using patient stratification, tailored surgical techniques and multimodal opioid sparing analgesia, day-case TKA might be achievable in a limited group of patients. The younger, male patient without comorbidities and with an excellent social network around him might be a candidate. Demographic changes, effective recovery programmes and less invasive surgical techniques such as unicondylar knee arthroplasty, may increase the size of the group of potential day-case patients. The cost reduction achieved by day-case TKA needs to be balanced against any increase in morbidity and mortality and the cost of advanced follow up at a distance with new technology. These factors need to be evaluated before adopting this ultimate 'fast-track' approach. PMID- 26430086 TI - Pain after total knee arthroplasty: a narrative review focusing on the stratification of patients at risk for persistent pain. AB - The patient with a painful arthritic knee awaiting total knee arthroplasty (TKA) requires a multidisciplinary approach. Optimal control of acute post-operative pain and the prevention of chronic persistent pain remains a challenge. The aim of this paper is to evaluate whether stratification of patients can help identify those who are at particular risk for severe acute or chronic pain. Intense acute post-operative pain, which is itself a risk factor for chronic pain, is more common in younger, obese female patients and those suffering from central pain sensitisation. Pre-operative pain, in the knee or elsewhere in the body, predisposes to central sensitisation. Pain due to osteoarthritis of the knee may also trigger neuropathic pain and may be associated with chronic medication like opioids, leading to a state of nociceptive sensitisation called 'opioid-induced hyperalgesia'. Finally, genetic and personality related risk factors may also put patients at a higher risk for the development of chronic pain. Those identified as at risk for chronic pain would benefit from specific peri-operative management including reduction in opioid intake pre-operatively, the peri-operative use of antihyperalgesic drugs such as ketamine and gabapentinoids, and a close post operative follow-up in a dedicated chronic pain clinic. PMID- 26430087 TI - Examination of Potential Modifiers of the Association of APOL1 Alleles with CKD Progression. AB - BACKGROUND AND OBJECTIVES: Common apolipoprotein L1 (APOL1) variants are associated with increased risk of progressive CKD; however, not all individuals with high-risk APOL1 variants experience CKD progression. Identification of factors contributing to heterogeneity has important scientific and clinical implications. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using multivariable Cox models, we analyzed data from 693 participants in the African American Study of Kidney Disease and Hypertension to identify factors that modify the association between APOL1 genotypes and CKD progression (doubling of serum creatinine or incident ESRD). RESULTS: Participant mean age was 54 years old, median GFR was 49 ml/min per 1.73 m(2), and 23% had the APOL1 high-risk genotype (two copies of the high-risk allele). Over a mean follow-up of 7.8 years, 288 (42%) participants experienced CKD progression. As previously reported, the high risk genotype was associated with higher risk of CKD progression compared with the low-risk genotype (hazard ratio [HR], 1.88; 95% confidence interval [95% CI], 1.46 to 2.41). Although we found some suggestion that obesity (HR, 1.48; 95% CI, 1.05 to 2.08 and HR, 2.44; 95% CI, 1.66 to 3.57 for body mass index >= 30 versus <30 kg/m(2); P interaction =0.04) and increased urinary excretion of urea nitrogen (HR, 1.43; 95% CI, 0.98 to 2.09 versus HR, 2.33; 95% CI, 1.65 to 3.30 for urine urea nitrogen >= 8 versus <8 g/d; P interaction =0.04) were associated with lower APOL1-associated risk for CKD progression, these findings were not robust in sensitivity analyses with alternative cut points. No other sociodemographic (e.g., education and income), clinical (e.g., systolic BP and smoking), or laboratory (e.g., net endogenous acid production, urinary sodium and potassium excretions, 25-hydroxy vitamin D, intact parathyroid hormone, or fibroblast growth factor 23) variables modified the association between APOL1 and CKD progression (P interaction >0.05 for each). CONCLUSIONS: Sociodemographic factors and common risk factors for CKD progression do not seem to alter APOL1 related CKD progression. Additional investigation is needed to identify nontraditional factors that may affect the association between APOL1 and progressive CKD. PMID- 26430089 TI - Long-Term Risk of Cancer in Survivors of Pediatric ESRD. AB - BACKGROUND AND OBJECTIVES: ESRD is associated with an increased risk of malignancies. We analyzed the incidence of cancer in patients with pediatric ESRD after long-term follow-up. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All Dutch patients born before 1979 who were transplanted at age <15 years old in 1972-1992 were followed until 2010. We explored type and incidence of malignancies in patients compared with the general population using the National Cancer Registry. RESULTS: After a median of 25.3 years (1.3-37.8) of transplantation and at a median age of 33.5 years old (11.0-49.0), 105 primary malignancies had occurred in 54 of 249 patients. Among them, cutaneous squamous cell carcinoma was most frequent. Patients ages 25-30 years old had developed 16.5 times (95% confidence interval, 7.9 to 34.6) as many de novo tumors and 991 times (95% confidence interval, 313 to 3137) as many de novo cutaneous squamous cell carcinomas as their general population counterparts; in survivors ages 45-50 years old, these numbers were 81.5 (95% confidence interval, 50.7 to 131.1) and 2610 (95% confidence interval, 1596 to 4267), respectively. Cumulative incidence competing risk analysis showed that, after 30 years of transplantation, 41% of the survivors had developed cancer; 31% had developed a second de novo cancer <1 year after initial cancer diagnosis. CONCLUSIONS: Cancer is highly prevalent among patients with pediatric ESRD after 25.3 years of transplantation, with a high rate of recurrence. PMID- 26430090 TI - The promise of neurotechnology. PMID- 26430088 TI - Risk Stratification for Rejection and Infection after Kidney Transplantation. AB - BACKGROUND AND OBJECTIVES: Definition of individual risk profile is the first step to implement strategies to keep the delicate balance between under- and overimmunosuppression after kidney transplantation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used data from the Efficacy Limiting Toxicity Elimination Symphony Study (1190 patients between 2002 and 2004) to model risk of rejection and infection in the first year after kidney transplantation. External validation was performed in a study population from the Fixed-Dose Concentration Controlled Trial (630 patients between 2003 and 2006). RESULTS: Despite different temporal dynamics, rejections and severe infections had similar overall incidences in the first year after transplantation (23.4% and 25.5%, respectively), and infections were the principal cause of death (43.2% of all deaths). Recipient older age, deceased donor, higher number of HLA mismatches, and high risk for cytomegalovirus disease were associated with infection; deceased donor, higher number of HLA mismatches, and immunosuppressive therapy including cyclosporin A (compared with tacrolimus), with rejection. These factors were integrated into a two-dimensional risk stratification model, which defined four risk groups: low risk for infection and rejection (30.8%), isolated risk for rejection (36.1%), isolated risk for infection (7.0%), and high risk for infection and rejection (26.1%). In internal validation, this model significantly discriminated the subgroups in terms of composite end point (low risk for infection/rejection, 24.4%; isolated risk for rejection and isolated risk for infection, 31.3%; high risk for infection/rejection, 54.4%; P<0.001), rejection episodes (isolated risk for infection and low risk for infection/rejection, 13.0%; isolated risk for rejection and high risk for infection/rejection, 24.2%; P=0.001), and infection episodes (low risk for infection/rejection and isolated risk for rejection, 12.0%; isolated risk for infection and high risk for infection/rejection, 37.6%; P<0.001). External validation confirmed the applicability of the model to an independent cohort. CONCLUSIONS: We propose a two-dimensional risk stratification model able to disentangle the individual risk for rejection and infection in the first year after kidney transplantation. This concept can be applied to implement a personalized immunosuppressive and antimicrobial treatment approach. PMID- 26430093 TI - Q&A. Talking science and God with the pope's new astronomer. PMID- 26430092 TI - BIOLOGY. New proteins may expand, improve genome editing. PMID- 26430095 TI - PARTICLE PHYSICS. Have physicists seen the dying flash of dark matter? PMID- 26430094 TI - BIOTECHNOLOGY. Europe's rifts over transgenic crops deepen at key deadline. PMID- 26430096 TI - HYDRAULIC ENGINEERING. Holland's giant wavemaker has splashy debut. PMID- 26430097 TI - The storm king. PMID- 26430098 TI - How two pioneers took the tropics' pulse. PMID- 26430099 TI - Pooling resources. PMID- 26430102 TI - POLYMER CHEMISTRY. Safer fuels by integrating polymer theory into design. PMID- 26430103 TI - STRUCTURAL BIOLOGY. Locking down the core of the pore. PMID- 26430104 TI - CLIMATE CHANGE. The IPCC at a crossroads: Opportunities for reform. PMID- 26430105 TI - CLIMATE CHANGE. Added value from IPCC approval sessions. PMID- 26430106 TI - NEUROSCIENCE. A tree of the human brain. PMID- 26430107 TI - ECOLOGY/PALEONTOLOGY. How stable are food webs during a mass extinction? PMID- 26430108 TI - PLANETARY SCIENCE. Eyeing up a Jupiter-like exoplanet. PMID- 26430109 TI - ATMOSPHERIC SCIENCE. Clouds resolved. PMID- 26430110 TI - NEUROSCIENCE. It takes the world to understand the brain. PMID- 26430111 TI - Slow or fast? A tale of synaptic vesicle recycling. PMID- 26430112 TI - Brain crystals. PMID- 26430113 TI - Dopamine and serotonin signals for reward across time scales. PMID- 26430114 TI - End-bonded contacts for carbon nanotube transistors with low, size-independent resistance. AB - Moving beyond the limits of silicon transistors requires both a high-performance channel and high-quality electrical contacts. Carbon nanotubes provide high performance channels below 10 nanometers, but as with silicon, the increase in contact resistance with decreasing size becomes a major performance roadblock. We report a single-walled carbon nanotube (SWNT) transistor technology with an end bonded contact scheme that leads to size-independent contact resistance to overcome the scaling limits of conventional side-bonded or planar contact schemes. A high-performance SWNT transistor was fabricated with a sub-10 nanometer contact length, showing a device resistance below 36 kilohms and on current above 15 microampere per tube. The p-type end-bonded contact, formed through the reaction of molybdenum with the SWNT to form carbide, also exhibited no Schottky barrier. This strategy promises high-performance SWNT transistors, enabling future ultimately scaled device technologies. PMID- 26430115 TI - Megasupramolecules for safer, cleaner fuel by end association of long telechelic polymers. AB - We used statistical mechanics to design polymers that defy conventional wisdom by self-assembling into "megasupramolecules" (>=5000 kg/mol) at low concentration (<=0.3 weight percent). Theoretical treatment of the distribution of individual subunits-end-functional polymers-among cyclic and linear supramolecules (ring chain equilibrium) predicts that megasupramolecules can form at low total polymer concentration if, and only if, the backbones are long (>400 kg/mol) and end association strength is optimal. Viscometry and scattering measurements of long telechelic polymers having polycyclooctadiene backbones and acid or amine end groups verify the formation of megasupramolecules. They control misting and reduce drag in the same manner as ultralong covalent polymers. With individual building blocks short enough to avoid hydrodynamic chain scission (weight-average molecular weights of 400 to 1000 kg/mol) and reversible linkages that protect covalent bonds, these megasupramolecules overcome the obstacles of shear degradation and engine incompatibility. PMID- 26430116 TI - State shift in Deccan volcanism at the Cretaceous-Paleogene boundary, possibly induced by impact. AB - Bolide impact and flood volcanism compete as leading candidates for the cause of terminal-Cretaceous mass extinctions. High-precision (40)Ar/(39)Ar data indicate that these two mechanisms may be genetically related, and neither can be considered in isolation. The existing Deccan Traps magmatic system underwent a state shift approximately coincident with the Chicxulub impact and the terminal Cretaceous mass extinctions, after which ~70% of the Traps' total volume was extruded in more massive and more episodic eruptions. Initiation of this new regime occurred within ~50,000 years of the impact, which is consistent with transient effects of impact-induced seismic energy. Postextinction recovery of marine ecosystems was probably suppressed until after the accelerated volcanism waned. PMID- 26430117 TI - Ultrafast 2D IR spectroscopy of the excess proton in liquid water. AB - Despite decades of study, the structures adopted to accommodate an excess proton in water and the mechanism by which they interconvert remain elusive. We used ultrafast two-dimensional infrared (2D IR) spectroscopy to investigate protons in aqueous hydrochloric acid solutions. By exciting O-H stretching vibrations and detecting the spectral response throughout the mid-IR region, we observed the interaction between the stretching and bending vibrations characteristic of the flanking waters of the Zundel complex, [H(H2O)2](+), at 3200 and 1760 cm(-1), respectively. From time-dependent shifts of the stretch-bend cross peak, we determined a lower limit on the lifetime of this complex of 480 femtoseconds. These results suggest a key role for the Zundel complex in aqueous proton transfer. PMID- 26430118 TI - Multiple repressive mechanisms in the hippocampus during memory formation. AB - Memory stabilization after learning requires translational and transcriptional regulations in the brain, yet the temporal molecular changes that occur after learning have not been explored at the genomic scale. We used ribosome profiling and RNA sequencing to quantify the translational status and transcript levels in the mouse hippocampus after contextual fear conditioning. We revealed three types of repressive regulations: translational suppression of ribosomal protein-coding genes in the hippocampus, learning-induced early translational repression of specific genes, and late persistent suppression of a subset of genes via inhibition of estrogen receptor 1 (ESR1/ERalpha) signaling. In behavioral analyses, overexpressing Nrsn1, one of the newly identified genes undergoing rapid translational repression, or activating ESR1 in the hippocampus impaired memory formation. Collectively, this study unveils the yet-unappreciated importance of gene repression mechanisms for memory formation. PMID- 26430119 TI - Holographic measurements of inhomogeneous cloud mixing at the centimeter scale. AB - Optical properties and precipitation efficiency of atmospheric clouds are largely determined by turbulent mixing with their environment. When cloud liquid water is reduced upon mixing, droplets may evaporate uniformly across the population or, in the other extreme, a subset of droplets may evaporate completely, leaving the remaining drops unaffected. Here, we use airborne holographic imaging to visualize the spatial structure and droplet size distribution at the smallest turbulent scales, thereby observing their response to entrainment and mixing with clear air. The measurements reveal that turbulent clouds are inhomogeneous, with sharp transitions between cloud and clear air properties persisting to dissipative scales (<1 centimeter). The local droplet size distribution fluctuates strongly in number density but with a nearly unchanging mean droplet diameter. PMID- 26430120 TI - Community stability and selective extinction during the Permian-Triassic mass extinction. AB - The fossil record contains exemplars of extreme biodiversity crises. Here, we examined the stability of terrestrial paleocommunities from South Africa during Earth's most severe mass extinction, the Permian-Triassic. We show that stability depended critically on functional diversity and patterns of guild interaction, regardless of species richness. Paleocommunities exhibited less transient instability-relative to model communities with alternative community organization and significantly greater probabilities of being locally stable during the mass extinction. Functional patterns that have evolved during an ecosystem's history support significantly more stable communities than hypothetical alternatives. PMID- 26430122 TI - Function of the nucleus accumbens in motor control during recovery after spinal cord injury. AB - Motivation facilitates recovery after neuronal damage, but its mechanism is elusive. It is generally thought that the nucleus accumbens (NAc) regulates motivation-driven effort but is not involved in the direct control of movement. Using causality analysis, we identified the flow of activity from the NAc to the sensorimotor cortex (SMC) during the recovery of dexterous finger movements after spinal cord injury at the cervical level in macaque monkeys. Furthermore, reversible pharmacological inactivation of the NAc during the early recovery period diminished high-frequency oscillatory activity in the SMC, which was accompanied by a transient deficit of amelioration in finger dexterity obtained by rehabilitation. These results demonstrate that during recovery after spinal damage, the NAc up-regulates the high-frequency activity of the SMC and is directly involved in the control of finger movements. PMID- 26430121 TI - Somatic mutation in single human neurons tracks developmental and transcriptional history. AB - Neurons live for decades in a postmitotic state, their genomes susceptible to DNA damage. Here we survey the landscape of somatic single-nucleotide variants (SNVs) in the human brain. We identified thousands of somatic SNVs by single-cell sequencing of 36 neurons from the cerebral cortex of three normal individuals. Unlike germline and cancer SNVs, which are often caused by errors in DNA replication, neuronal mutations appear to reflect damage during active transcription. Somatic mutations create nested lineage trees, allowing them to be dated relative to developmental landmarks and revealing a polyclonal architecture of the human cerebral cortex. Thus, somatic mutations in the brain represent a durable and ongoing record of neuronal life history, from development through postmitotic function. PMID- 26430123 TI - Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons. AB - Midbrain dopamine neurons are an essential component of the basal ganglia circuitry, playing key roles in the control of fine movement and reward. Recently, it has been demonstrated that gamma-aminobutyric acid (GABA), the chief inhibitory neurotransmitter, is co-released by dopamine neurons. Here, we show that GABA co-release in dopamine neurons does not use the conventional GABA synthesizing enzymes, glutamate decarboxylases GAD65 and GAD67. Our experiments reveal an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1). Moreover, GABA co-release is modulated by ethanol (EtOH) at concentrations seen in blood alcohol after binge drinking, and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. These findings provide insights into the functional role of GABA co-release in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction. PMID- 26430124 TI - After the bombs. PMID- 26430125 TI - Erratum for the Report "A neoplastic gene fusion mimics trans-splicing of RNAs in normal human cells" by H. Li, J. Wang, G. Mor, J. Sklar. PMID- 26430126 TI - Erratum for the Report "Spreading depression triggers headache by activating neuronal Panx1 channels" by H. Karatas, S. E. Erdener, Y. Gursoy-Ozdemir, S. Lule, E. Eren-Kocak, Z. D. Sen, T. Dalkara. PMID- 26430127 TI - Genetic determinants of in vivo fitness and diet responsiveness in multiple human gut Bacteroides. AB - Libraries of tens of thousands of transposon mutants generated from each of four human gut Bacteroides strains, two representing the same species, were introduced simultaneously into gnotobiotic mice together with 11 other wild-type strains to generate a 15-member artificial human gut microbiota. Mice received one of two distinct diets monotonously, or both in different ordered sequences. Quantifying the abundance of mutants in different diet contexts allowed gene-level characterization of fitness determinants, niche, stability, and resilience and yielded a prebiotic (arabinoxylan) that allowed targeted manipulation of the community. The approach described is generalizable and should be useful for defining mechanisms critical for sustaining and/or approaches for deliberately reconfiguring the highly adaptive and durable relationship between the human gut microbiota and host in ways that promote wellness. PMID- 26430130 TI - Surgical removal of failed ruptured Sinus of Valsalva Aneurysm device. AB - A Sinus of Valsalva Aneurysm can cause aortic insufficiency, coronary artery flow compromise, cardiac arrhythmia, or aneurysm rupture. There are different management plans available, ranging from open surgery to percutaneous device closure, but sometimes, device closure may be life-threatening. We report a case of ruptured Sinus of Valsalva Aneurysm in a 42-year-old woman, which was managed by percutaneous device closure that failed and required surgical removal of the device. PMID- 26430131 TI - Internal mammary artery with side-branch. AB - We present the case of a 72-year-old man who underwent off-pump coronary artery bypass grafting of 4 coronary arteries with exclusive use of the left internal mammary artery with a side-branch (mediastinal artery). Before discharge from the hospital, contrast computed tomography angiography confirmed the patency of all 4 coronary grafts. Use of the mediastinal artery side-branch of the internal mammary artery allowed grafting of 4 coronary arteries using only one internal thoracic artery. PMID- 26430128 TI - Three methods of delivering clinic-based training on syndromic management of sexually transmitted diseases in South Africa: a pilot study. AB - INTRODUCTION: The South African National Department of Health sought to improve syndromic management of sexually transmitted infections (STIs). Continuing medical education on STIs was delivered at primary healthcare (PHC) clinics using one of three training methods: (1) lecture, (2) computer and (3) paper-based. Clinics with training were compared with control clinics. METHODS: Ten PHC clinics were randomly assigned to control and 10 to each training method arm. Clinicians participated in on-site training on six modules; two per week for three weeks. Each clinic was visited by three or four unannounced standardised patient (SP) actors pre-training and post-training. Male SPs reported symptoms of male urethritis syndrome and female SPs reported symptoms of vaginal discharge syndrome. Quality of healthcare was measured by whether or not clinicians completed five tasks: HIV test, genital exam, correct medications, condoms and partner notification. RESULTS: An average of 31% of clinicians from each PHC attended each module. Quality of STI care was low. Pre-training (n=128) clinicians completed an average of 1.63 tasks. Post-training (n=114) they completed 1.73. There was no change in the number of STI tasks completed in the control arm and an 11% increase overall in the training arms relative to the control (ratio of relative risk (RRR)=1.11, 95% CI 0.67 to 1.84). Across training arms, there was a 26% increase (RRR=1.26, 95% CI 0.77 to 2.06) associated with lecture, 17% increase (RRR=1.17, 95% CI 0.59 to 2.28) with paper-based and 13% decrease (RRR=0.87, 95% CI 0.40 to 1.90) with computer arm relative to the control. CONCLUSIONS: Future interventions should address increasing training attendance and computer-based training effectiveness. TRIAL REGISTRATION NUMBER: AEARCTR-0000668. PMID- 26430132 TI - Video-assisted thoracic surgery for cancer after thoracic aortic aneurysm repair. AB - Video-assisted thoracoscopic surgery is increasingly accepted as an alternative to open thoracotomy and has established efficacy in the management of non-small cell lung cancer, but the presence of extensive intrapleural adhesions has been considered a deterrent to a minimally invasive approach. We report the successful use of video-assisted thoracoscopic surgery in 3 patients with history of open thoracic aortic aneurysm repair who presented with left lower lobe stage I non small-cell lung cancer. While this approach is feasible, it is technically demanding and thus, at the present time, we recommend that its use be limited to high-volume video-assisted thoracoscopic surgery centers. PMID- 26430134 TI - The Shared Experience Help the Bereavement to Flow: A Family Support Group Evaluation. AB - When a family member dies, a bereavement period is taking place for all family members. The death of a parent during childhood is a highly stressful event. This study evaluates families' experiences of family support groups when a parent has died. Families were participate in groups for children, teenagers, young adults, and parents in seven sessions. The same topic which was discussed in all groups. The support groups were evaluated qualitatively and quantitatively. The participants were satisfied with the groups and experienced that the shared experience facilitated bereavement to proceed. The results indicate that families' experiences is being more open about feelings in their own family. A support group can be one possibility to help the whole family in the bereavement. PMID- 26430133 TI - Pediatric Primary Care Involvement in End-of-Life Care for Children. AB - OBJECTIVES: To examine the relationship between pediatric primary care involvement and hospice and home health care use at end of life. METHODS: California Medicaid data were used to estimate the relationship between pediatric primary care involvement and use of hospice and home health care using generalized estimating equations. RESULTS: Of the 2037 children who died between 2007 and 2010, 11% used hospice and 23% used home health. Among all children, primary care was not related to hospice use and was associated with home health use, usual source of care (OR = 1.83, P < .05), comprehensive care (OR = 1.60, P < .05), and continuous care (low: OR = 1.49, P < .05; moderate: OR = 2.57, P < .05; high: OR = 2.12, P < .05). Primary care for children aged 15 to 20 years was related to hospice use, usual source of care (OR = 4.06, P < .05) and continuous care (low: OR = 4.92, P < .05; moderate OR = 4.09, P < .05; high OR = 3.92, P < .05). Primary care for children under 5 years was associated with home health use, usual source of care (OR = 2.59, P < .05), comprehensive care (OR = 2.49, P < .05), and continuous care (low: OR = 2.22, P < .05; moderate: OR = 3.64, P < .05; high: OR = 3.62, P < .05). For children aged 6 to 14 years, this association was seen with continuous care (moderate: OR = 2.38, P < .05; high: OR = 2.13, P < .05). Home health for children aged 15 to 20 years was related to continuous care (moderate: OR = 2.32, P < .05). CONCLUSION: Primary care involvement affected hospice use among older age-groups and home health use among younger age-groups. These findings underscore the need for clinical knowledge about end-of-life care for children of all ages among primary care providers. PMID- 26430135 TI - Medical Students' Professionalism Narratives Reveal That Experiences With Death, Dying, or Palliative Care Are More Positive Than Other Experiences During Their Internal Medicine Clerkship. AB - PURPOSE: More physicians need to acquire the skills of primary palliative care. Medical students' clerkship experiences with death, dying, and palliative care (DDPC), however, may create barriers to learning such skills during residency. Whether professional development is differentially affected by DDPC is unknown. This knowledge gap potentially hinders the development of educational strategies to optimize students' preparedness for primary palliative care. METHOD: Third year students submitted professionalism narratives (N = 4062) during their internal medicine clerkship between 2004 and 2011. We identified DDPC-related narratives and then randomly selected control narratives. Narratives were compared by valence (positive or negative) and professionalism-related themes. RESULTS AND CONCLUSION: Less than 10% of the narratives were related to DDPC, but the majority was positive. There was a significant overlap in professionalism themes between DDPC and control narratives. The results suggest student preparedness for primary palliative care may be improved by addressing the common professionalism challenges of clinical clerkships. PMID- 26430137 TI - Mellon et al. Should All Deaf Children Learn Sign Language? Pediatrics. 2015;136(1):170-176. PMID- 26430138 TI - Devore CD, Schutze GE; AAP, Council on School Health, Committee on Infectious Dises. Head Lice. Pediatrics. 2015;135(5):e1355-1365. PMID- 26430136 TI - Long-Term Outcomes and Causes of Death in Patients With Renovascular Disease Undergoing Renal Artery Stenting. AB - Renovascular disease (RVD) can lead to hypertension and chronic kidney disease (CKD). Patients with advanced peripheral arterial disease (PAD) have a 5-year mortality of ~30%. Rate and causes of death in patients with significant RVD, who share similar risk factors with patients having PAD, are not well defined. We assessed consecutive patients with RVD who underwent renal artery stenting at our institution over 6 years. Specific causes of death were ascertained, and the probability of survival was estimated. Cox models were fit to identify predictors of outcomes. We identified 281 patients with RVD who underwent renal stenting. Follow-up was available for all patients (median 5.1 years). All-cause mortality was 24.2% at 5 years and 33.7% at 7 years (compounded annualized death rate: 5.5%). Of the 68 deaths, 36 (52.9%) were cardiovascular (13.2% acute myocardial infarction, 13.2% stroke, 11.8% sudden death, and 10.3% congestive heart failure) and 32 (47.1%) deaths had noncardiovascular causes. In patients with RVD undergoing stenting, cardiovascular events are the most common causes of death. Compared to patients with advanced PAD, RVD may have a lower 5-year mortality. PMID- 26430139 TI - Campbell et al. Critical Elements in the Medical Evaluation of Suspected Child Physical Abuse. Pediatrics. 2015;136(1):35-43. PMID- 26430140 TI - Ralston SL, Lieberthal AS, Meissner HC, et al. Clinical Practice Guideline: The Diagnosis, Management, and Prevention of Bronchiolitis. Pediatrics. 2014;134(5):e1474-e1502. PMID- 26430141 TI - Kurowski et al. Online Problem-Solving Therapy for Executive Dysfuntion After Child Traumatic Brain Injury. Pediatrics. 2013;132(1):e158-e166. PMID- 26430143 TI - Risk of Misinterpretation and Limitation of the Diagnostic Accuracy. PMID- 26430144 TI - Authors' Response. PMID- 26430145 TI - 2015 SNMMI Highlights Lecture: Neurosciences. PMID- 26430149 TI - A vision for ubiquitous sequencing. AB - Genomics has recently celebrated reaching the $1000 genome milestone, making affordable DNA sequencing a reality. With this goal successfully completed, the next goal of the sequencing revolution can be sequencing sensors--miniaturized sequencing devices that are manufactured for real-time applications and deployed in large quantities at low costs. The first part of this manuscript envisions applications that will benefit from moving the sequencers to the samples in a range of domains. In the second part, the manuscript outlines the critical barriers that need to be addressed in order to reach the goal of ubiquitous sequencing sensors. PMID- 26430150 TI - Biological data sciences in genome research. AB - The last 20 years have been a remarkable era for biology and medicine. One of the most significant achievements has been the sequencing of the first human genomes, which has laid the foundation for profound insights into human genetics, the intricacies of regulation and development, and the forces of evolution. Incredibly, as we look into the future over the next 20 years, we see the very real potential for sequencing more than 1 billion genomes, bringing even deeper insight into human genetics as well as the genetics of millions of other species on the planet. Realizing this great potential for medicine and biology, though, will only be achieved through the integration and development of highly scalable computational and quantitative approaches that can keep pace with the rapid improvements to biotechnology. In this perspective, I aim to chart out these future technologies, anticipate the major themes of research, and call out the challenges ahead. One of the largest shifts will be in the training used to prepare the class of 2035 for their highly interdisciplinary world. PMID- 26430151 TI - Parlez-vous VUS? AB - Human genome sequencing is routine and will soon be a staple in research and clinical genetics. However, the promise of sequencing is often just that, with genome data routinely failing to reveal useful insights about disease in general or a person's health in particular. Nowhere is this chasm between promise and progress more evident than in the designation, "variant of uncertain significance" (VUS). Although it serves an important role, careful consideration of VUS reveals it to be a nebulous description of genomic information and its relationship to disease, symptomatic of our inability to make even crude quantitative assertions about the disease risks conferred by many genetic variants. In this perspective, I discuss the challenge of "variant interpretation" and the value of comparative and functional genomic information in meeting that challenge. Although already essential, genomic annotations will become even more important as our analytical focus widens beyond coding exons. Combined with more genotype and phenotype data, they will help facilitate more quantitative and insightful assessments of the contributions of genetic variants to disease. PMID- 26430152 TI - Functional genomics bridges the gap between quantitative genetics and molecular biology. AB - Deep characterization of molecular function of genetic variants in the human genome is becoming increasingly important for understanding genetic associations to disease and for learning to read the regulatory code of the genome. In this paper, I discuss how recent advances in both quantitative genetics and molecular biology have contributed to understanding functional effects of genetic variants, lessons learned from eQTL studies, and future challenges in this field. PMID- 26430153 TI - Genomic approaches for understanding the genetics of complex disease. AB - There are thousands of known associations between genetic variants and complex human phenotypes, and the rate of novel discoveries is rapidly increasing. Translating those associations into knowledge of disease mechanisms remains a fundamental challenge because the associated variants are overwhelmingly in noncoding regions of the genome where we have few guiding principles to predict their function. Intersecting the compendium of identified genetic associations with maps of regulatory activity across the human genome has revealed that phenotype-associated variants are highly enriched in candidate regulatory elements. Allele-specific analyses of gene regulation can further prioritize variants that likely have a functional effect on disease mechanisms; and emerging high-throughput assays to quantify the activity of candidate regulatory elements are a promising next step in that direction. Together, these technologies have created the ability to systematically and empirically test hypotheses about the function of noncoding variants and haplotypes at the scale needed for comprehensive and systematic follow-up of genetic association studies. Major coordinated efforts to quantify regulatory mechanisms across genetically diverse populations in increasingly realistic cell models would be highly beneficial to realize that potential. PMID- 26430155 TI - Linking RNA biology to lncRNAs. AB - The regulatory potential of RNA has never ceased to amaze: from RNA catalysis, to RNA-mediated splicing, to RNA-based silencing of an entire chromosome during dosage compensation. More recently, thousands of long noncoding RNA (lncRNA) transcripts have been identified, the majority with unknown function. Thus, it is tempting to think that these lncRNAs represent a cadre of new factors that function through ribonucleic mechanisms. Some evidence points to several lncRNAs with tantalizing physiological contributions and thought-provoking molecular modalities. However, dissecting the RNA biology of lncRNAs has been difficult, and distinguishing the independent contributions of functional RNAs from underlying DNA elements, or the local act of transcription, is challenging. Here, we aim to survey the existing literature and highlight future approaches that will be needed to link the RNA-based biology and mechanisms of lncRNAs in vitro and in vivo. PMID- 26430156 TI - Half dozen of one, six billion of the other: What can small- and large-scale molecular systems biology learn from one another? AB - Small-scale molecular systems biology, by which we mean the understanding of a how a few parts work together to control a particular biological process, is predicated on the assumption that cellular regulation is arranged in a circuit like structure. Results from the omics revolution have upset this vision to varying degrees by revealing a high degree of interconnectivity, making it difficult to develop a simple, circuit-like understanding of regulatory processes. We here outline the limitations of the small-scale systems biology approach with examples from research into genetic algorithms, genetics, transcriptional network analysis, and genomics. We also discuss the difficulties associated with deriving true understanding from the analysis of large data sets and propose that the development of new, intelligent, computational tools may point to a way forward. Throughout, we intentionally oversimplify and talk about things in which we have little expertise, and it is likely that many of our arguments are wrong on one level or another. We do believe, however, that developing a true understanding via molecular systems biology will require a fundamental rethinking of our approach, and our goal is to provoke thought along these lines. PMID- 26430157 TI - The Mendelian disorders of the epigenetic machinery. AB - The Mendelian disorders of the epigenetic machinery are genetic disorders that involve disruption of the various components of the epigenetic machinery (writers, erasers, readers, and remodelers) and are thus expected to have widespread downstream epigenetic consequences. Studying this group may offer a unique opportunity to learn about the role of epigenetics in health and disease. Among these patients, neurological dysfunction and, in particular, intellectual disability appears to be a common phenotype; however, this is often seen in association with other more specific features in respective disorders. The specificity of some of the clinical features raises the question whether specific cell types are particularly sensitive to the loss of these factors. Most of these disorders demonstrate dosage sensitivity as loss of a single allele appears to be sufficient to cause the observed phenotypes. Although the pathogenic sequence is unknown for most of these disorders, there are several examples where disrupted expression of downstream target genes accounts for a substantial portion of the phenotype; hence, it may be useful to systematically map such disease-relevant target genes. Finally, two of these disorders (Rubinstein-Taybi and Kabuki syndromes) have shown post-natal rescue of markers of the neurological dysfunction with drugs that lead to histone deacetylase inhibition, indicating that some of these disorders may be treatable causes of intellectual disability. PMID- 26430154 TI - Enabling functional genomics with genome engineering. AB - Advances in genome engineering technologies have made the precise control over genome sequence and regulation possible across a variety of disciplines. These tools can expand our understanding of fundamental biological processes and create new opportunities for therapeutic designs. The rapid evolution of these methods has also catalyzed a new era of genomics that includes multiple approaches to functionally characterize and manipulate the regulation of genomic information. Here, we review the recent advances of the most widely adopted genome engineering platforms and their application to functional genomics. This includes engineered zinc finger proteins, TALEs/TALENs, and the CRISPR/Cas9 system as nucleases for genome editing, transcription factors for epigenome editing, and other emerging applications. We also present current and potential future applications of these tools, as well as their current limitations and areas for future advances. PMID- 26430158 TI - Epigenomics and the structure of the living genome. AB - Eukaryotic genomes are packaged into an extensively folded state known as chromatin. Analysis of the structure of eukaryotic chromosomes has been revolutionized by development of a suite of genome-wide measurement technologies, collectively termed "epigenomics." We review major advances in epigenomic analysis of eukaryotic genomes, covering aspects of genome folding at scales ranging from whole chromosome folding down to nucleotide-resolution assays that provide structural insights into protein-DNA interactions. We then briefly outline several challenges remaining and highlight new developments such as single-cell epigenomic assays that will help provide us with a high-resolution structural understanding of eukaryotic genomes. PMID- 26430159 TI - Defining cell types and states with single-cell genomics. AB - A revolution in cellular measurement technology is under way: For the first time, we have the ability to monitor global gene regulation in thousands of individual cells in a single experiment. Such experiments will allow us to discover new cell types and states and trace their developmental origins. They overcome fundamental limitations inherent in measurements of bulk cell population that have frustrated efforts to resolve cellular states. Single-cell genomics and proteomics enable not only precise characterization of cell state, but also provide a stunningly high-resolution view of transitions between states. These measurements may finally make explicit the metaphor that C.H. Waddington posed nearly 60 years ago to explain cellular plasticity: Cells are residents of a vast "landscape" of possible states, over which they travel during development and in disease. Single cell technology helps not only locate cells on this landscape, but illuminates the molecular mechanisms that shape the landscape itself. However, single-cell genomics is a field in its infancy, with many experimental and computational advances needed to fully realize its full potential. PMID- 26430160 TI - The first five years of single-cell cancer genomics and beyond. AB - Single-cell sequencing (SCS) is a powerful new tool for investigating evolution and diversity in cancer and understanding the role of rare cells in tumor progression. These methods have begun to unravel key questions in cancer biology that have been difficult to address with bulk tumor measurements. Over the past five years, there has been extraordinary progress in technological developments and research applications, but these efforts represent only the tip of the iceberg. In the coming years, SCS will greatly improve our understanding of invasion, metastasis, and therapy resistance during cancer progression. These tools will also have direct translational applications in the clinic, in areas such as early detection, noninvasive monitoring, and guiding targeted therapy. In this perspective, I discuss the progress that has been made and the myriad of unexplored applications that still lie ahead in cancer research and medicine. PMID- 26430164 TI - 20 Years of Genome Research. Preface. PMID- 26430161 TI - The path to routine use of genomic biomarkers in the cancer clinic. AB - It has been almost 15 years since the first microarray-based studies creating multigene biomarkers to subtype and predict survival of cancer patients. This Perspective looks at why only a handful of genomic biomarkers have reached clinical application and what advances are needed over the next 15 years to grow this number. I discuss challenges in creating biomarkers and reproducing them at the genomic and computational levels, including the problem of spatio-genomic heterogeneity in an individual cancer. I then outline the challenges in translating newly discovered genome-wide or regional events, like trinucleotide mutation signatures, kataegis, and chromothripsis, into biomarkers, as well as the importance of incorporating prior biological knowledge. Lastly, I outline the practical problems of pharmaco-economics and adoption: Are new biomarkers viewed as economically rational by potential funders? And if they are, how can their results be communicated effectively to patients and their clinicians? Genomic based diagnostics have immense potential for transforming the management of cancer. The next 15 years will see a surge of research into the topics here that, when combined with a stream of new targeted therapies being developed, will personalize the cancer clinic. PMID- 26430162 TI - The intersection of microbiome and host at the skin interface: genomic- and metagenomic-based insights. AB - The past two decades have been marked by a surge in research to understand the microbial communities that live in association with the human body, in part stimulated by affordable, high-throughput DNA sequencing technology. In the context of the skin, this Perspective focuses on the current state of genomic- and metagenomic-based host-microbe research and future challenges and opportunities to move the field forward. These include elucidating nonbacterial components of the skin microbiome (i.e., viruses); systematic studies to address common perturbations to the skin microbiome (e.g., antimicrobial drugs, topical cosmetic/hygienic products); improved approaches for identifying potential microbial triggers for skin diseases, including species- and strain-level resolution; and improved, clinically relevant models for studying the functional and mechanistic roles of the skin microbiome. In the next 20 years, we can realistically expect that our knowledge of the skin microbiome will inform the clinical management and treatment of skin disorders through diagnostic tests to stratify patient subsets and predict best treatment modality and outcomes and through treatment strategies such as targeted manipulation or reconstitution of microbial communities. PMID- 26430163 TI - Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer. AB - Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1-14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer. PMID- 26430165 TI - Examination of Associations Among Three Distinct Subjective Aging Constructs and Their Relevance for Predicting Developmental Correlates. AB - Objectives: This study examined (a) the empirical associations among three subjective aging (SA) constructs: felt age, attitudes toward own aging (ATOA), and awareness of age-related change (AARC); (b) the moderating role of chronological age in these associations; and (c) the predictive relevance of the SA constructs with regard to two developmental correlates: functional health and satisfaction with life. Method: Participants were 819 adults aged 40-98 years from the United States and Germany. Parallel multiple mediation, moderated mediation, and hierarchical regression analyses were used. Results: As hypothesized, AARC mediated the association between the global measures of SA (felt age and ATOA) and the developmental correlates. Specifically, more negative global subjective aging predicted more AARC losses, which predicted poorer health and well-being. Furthermore, this mediation pathway was moderated by chronological age, such that, with increasing age, greater AARC was more strongly related to poorer functional health (but not well-being). The multidimensional measure, AARC, accounted for a significant amount of the variance in the developmental correlates over and above the unidimensional SA constructs. A consistent pattern emerged supporting the role of domain specificity and valence. Discussion: These findings support the need for conceptualizing SA across different behavioral domains and for distinguishing between positive and negative SA. PMID- 26430167 TI - Early Identification and Interventions for Autism Spectrum Disorder: Executive Summary. PMID- 26430168 TI - Early Identification of Autism Spectrum Disorder: Recommendations for Practice and Research. AB - Early identification of autism spectrum disorder (ASD) is essential to ensure that children can access specialized evidence-based interventions that can help to optimize long-term outcomes. Early identification also helps shorten the stressful "diagnostic odyssey" that many families experience before diagnosis. There have been important advances in research into the early development of ASDs, incorporating prospective designs and new technologies aimed at more precisely delineating the early emergence of ASD. Thus, an updated review of the state of the science of early identification of ASD was needed to inform best practice. These issues were the focus of a multidisciplinary panel of clinical practitioners and researchers who completed a literature review and reached consensus on current evidence addressing the question "What are the earliest signs and symptoms of ASD in children aged <=24 months that can be used for early identification?" Summary statements address current knowledge on early signs of ASD, potential contributions and limitations of prospective research with high risk infants, and priorities for promoting the incorporation of this knowledge into clinical practice and future research. PMID- 26430169 TI - Early Screening of Autism Spectrum Disorder: Recommendations for Practice and Research. AB - This article reviews current evidence for autism spectrum disorder (ASD) screening based on peer-reviewed articles published to December 2013. Screening provides a standardized process to ensure that children are systematically monitored for early signs of ASD to promote earlier diagnosis. The current review indicates that screening in children aged 18 to 24 months can assist in early detection, consistent with current American Academy of Pediatrics' recommendations. We identify ASD-specific and broadband screening tools that have been evaluated in large community samples which show particular promise in terms of accurate classification and clinical utility. We also suggest strategies to help overcome challenges to implementing ASD screening in community practice, as well as priorities for future research. PMID- 26430170 TI - Early Intervention for Children With Autism Spectrum Disorder Under 3 Years of Age: Recommendations for Practice and Research. AB - This article reviews current evidence for autism spectrum disorder (ASD) interventions for children aged <3 years, based on peer-reviewed articles published up to December 2013. Several groups have adapted treatments initially designed for older, preschool-aged children with ASD, integrating best practice in behavioral teaching methods into a developmental framework based on current scientific understanding of how infants and toddlers learn. The central role of parents has been emphasized, and interventions are designed to incorporate learning opportunities into everyday activities, capitalize on "teachable moments," and facilitate the generalization of skills beyond the familiar home setting. Our review identified several comprehensive and targeted treatment models with evidence of clear benefits. Although some trials were limited to 8- to 12-week outcome data, enhanced outcomes associated with some interventions were evaluated over periods as long as 2 years. Based on this review, recommendations are proposed for clinical practice and future research. PMID- 26430171 TI - Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib. AB - Ibrutinib is associated with bleeding-related adverse events of grade <= 2 in severity, and infrequently with grade >= 3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated trial of single agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade <= 2 bleeding-related adverse events in 55% of 85 patients. No grade >= 3 events occurred. Median time to event was 49 days. The cumulative incidence of an event plateaued by 6 months, suggesting that the risk of bleeding decreases with continued therapy. At baseline, von Willebrand factor and factor VIII levels were often high and normalized on treatment. Platelet function measured via the platelet function analyzer (PFA-100TM) was impaired in 22 patients at baseline and in an additional 19 patients on ibrutinib (often transiently). Collagen and adenosine diphosphate induced platelet aggregation was tested using whole blood aggregometry. Compared to normal controls, response to both agonists was decreased in all patients with chronic lymphocytic leukemia, whether on ibrutinib or not. Compared to untreated chronic lymphocytic leukemia patients, response to collagen showed a mild further decrement on ibrutinib, while response to adenosine diphosphate improved. All parameters associated with a significantly increased risk of bleeding-related events were present at baseline, including prolonged epinephrine closure time (HR 2.74, P=0.012), lower levels of von Willebrand factor activity (HR 2.73, P=0.009) and factor VIII (HR 3.73, P=0.0004). In conclusion, both disease and treatment-related factors influence the risk of bleeding. Patients at greater risk for bleeding of grade <= 2 can be identified by clinical laboratory tests and counseled to avoid aspirin, non-steroidal anti-inflammatory drugs and fish oils. ClinicalTrials.gov identifier NCT01500733. PMID- 26430172 TI - Nodular lymphocyte predominant Hodgkin lymphoma: a Lymphoma Study Association retrospective study. AB - Nodular lymphocyte predominant Hodgkin lymphoma represents a distinct entity from classical Hodgkin lymphoma. We conducted a retrospective study to investigate the management of patients with nodular lymphocyte predominant Hodgkin lymphoma. Clinical characteristics, treatment and outcome of adult patients with nodular lymphocyte predominant Hodgkin lymphoma were collected in Lymphoma Study Association centers. Progression-free survival (PFS) and overall survival (OS) were analyzed, and the competing risks formulation of a Cox regression model was used to control the effect of risk factors on relapse or death as competing events. Among 314 evaluable patients, 82.5% had early stage nodular lymphocyte predominant Hodgkin lymphoma. Initial management consisted in watchful waiting (36.3%), radiotherapy (20.1%), rituximab (8.9%), chemotherapy or immuno chemotherapy (21.7%), combined modality treatment (12.7%), or radiotherapy plus rituximab (0.3%). With a median follow-up of 55.8 months, the 10-year PFS and OS estimates were 44.2% and 94.9%, respectively. The 4-year PFS estimates were 79.6% after radiotherapy, 77.0% after rituximab alone, 78.8% after chemotherapy or immuno-chemotherapy, and 93.9% after combined modality treatment. For the whole population, early treatment with chemotherapy or radiotherapy, but not rituximab alone (Hazard ratio 0.695 [0.320-1.512], P=0.3593) significantly reduced the risk of progression compared to watchful waiting (HR 0.388 [0.234-0.643], P=0.0002). Early treatment appears more beneficial compared to watchful waiting in terms of progression-free survival, but has no impact on overall survival. Radiotherapy in selected early stage nodular lymphocyte predominant Hodgkin lymphoma, and combined modality treatment, chemotherapy or immuno-chemotherapy for other patients, are the main options to treat adult patients with a curative intent. PMID- 26430174 TI - A 'Healthy Islands' framework for climate change in the Pacific. AB - Small Pacific Island countries (PICs) are among the most vulnerable countries in the world to the anticipated detrimental health effects of climate change. The assessment of health vulnerabilities and planning adaptation strategies to minimize the impacts of climate change on health tests traditional health governance structures and depends on strong linkages and partnerships between actors involved in these vital processes. This article reviews the actors, processes and contexts of the climate change and health vulnerability assessment and adaptation planning project carried out by the World Health Organization and health sector partners in three island countries in the Micronesian region of the Pacific throughout 2010 and 2011: Federated States of Micronesia, Marshall Islands and Palau. Despite their shared history and cultural characteristics, the findings and implications of this article are considered to have substantial relevance and potential application to other PICs. The modified 'Healthy Islands' framework for climate change and health adaptation presented in this article draws upon real-world experience and governance theory from both the health and climate change literature and, for the first time, places health systems adaptation within the vision for 'Healthy Islands' in the Pacific region. PMID- 26430175 TI - Retail therapy. PMID- 26430173 TI - Red blood cell alloimmunization is influenced by the delay between Toll-like receptor agonist injection and transfusion. AB - Murine models of red blood cell transfusion show that inflammation associated with viruses or methylated DNA promotes red blood cell alloimmunization. In vaccination studies, the intensity of antigen-specific responses depends on the delay between antigen and adjuvant administration, with a short delay limiting immune responses. In mouse models of alloimmunization, the delay between the injection of Toll-like receptor agonists and transfusion is usually short. In this study, we hypothesized that the timing of Toll-like receptor 3 agonist administration affects red blood cell alloimmunization. Poly(I:C), a Toll-like receptor 3 agonist, was administered to B10BR mice at various time points before the transfusion of HEL-expressing red blood cells. For each time point, we measured the activation of splenic HEL-presenting dendritic cells, HEL-specific CD4(+) T cells and anti-HEL antibodies in serum. The phenotype of activated immune cells depended on the delay between transfusion and Toll-like receptor dependent inflammation. The production of anti-HEL antibodies was highest when transfusion occurred 7 days after agonist injection. The proportion of HEL presenting CD8alpha(+) dendritic cells producing interleukin-12 was highest in mice injected with poly(I:C) 3 days before transfusion. Although the number of early-induced HEL-specific CD4(+) T cells was similar between groups, a high proportion of these cells expressed CD134, CD40 and CD44 in mice injected with poly(I:C) 7 days before transfusion. This study clearly shows that the delay between transfusion and Toll-like receptor-induced inflammation influences the immune response to transfused red blood cells. PMID- 26430176 TI - 'Part of the problem, part of the solution' - adult physicians' role in adolescent and young adult health. PMID- 26430177 TI - Establishing an infrastructure to support the development and delivery of clinical research in patients with kidney disease. AB - The UK Kidney Research Consortium (UKKRC) was established in 2007 to promote clinical research in adults and children affected by kidney disease. Clinical study groups (CSGs) are the core subgroups of UKKRC. The aim of the CSGs is to generate a portfolio of clinical studies that can and should be undertaken in the UK. Since 2007 the CSGs have helped develop and secure funding for 13 studies to a total value of L13443648. Funders include Kidney Research UK, Medical Research Council, British Heart Foundation and National Institute of Health Research (NIHR). The studies address the full translational pathway. UKKRC is thus a unique structure that dovetails with the NIHR Renal Disorders Specialty Group to generate and deliver a portfolio of high-quality renal studies. PMID- 26430178 TI - Transcatheter aortic valve implantation - what the general physician needs to know. AB - With an increasingly elderly population, the incidence of aortic stenosis (AS) is rising. While surgical aortic valve replacement remains the gold standard treatment for patients with severe symptomatic AS, transcatheter aortic valve implantation (TAVI) has emerged as the treatment of choice for patients who are inoperable or high surgical risk. TAVI has been shown to be associated with a clear mortality benefit when compared with medical therapy and to be at least as good as surgical aortic valve replacement in this patient group. The last few years have seen rapid development in this revolutionary technology in conjunction with increasing centre and operator experience, and indications for the procedure are swiftly expanding. In this review, we summarise the current evidence base and discuss factors that need to be considered by the general physician when contemplating TAVI as a treatment option, including practical aspects, emerging indications and future directions. PMID- 26430179 TI - Improving the management of spontaneous bacterial peritonitis in cirrhotic patients: assessment of an intervention in trainee doctors. AB - Spontaneous bacterial peritonitis (SBP) in cirrhotic patients is a serious complication associated with a high mortality rate. A baseline audit of the acute medical take (AMT) at Northwick Park suggested a lack of awareness regarding management. A questionnaire based on contemporary SBP guidelines was circulated to all trainee doctors (FY1 to SpR). Ascitic fluid testing requests were analysed over a six-month period. The electronic requesting system was updated to include prompts and direct links to Trust SBP guidelines, and a one-hour lecture to all members of the AMT, supported by an educational booklet on SBP, was performed. Re audit was carried out six months post-intervention, the AMT completed a second questionnaire and ascitic fluid testing requests were re-audited. In comparable pre- and post-intervention AMT cohorts, a clinical and educational intervention led to a significant improvement in understanding of when to investigate (p<=0.001), samples (p = 0.002) and containers (p<=0.001) required, urgency of obtaining results (p<=0.001), and initiation of treatment for suspected SBP (p = 0.007). Significantly more ascitic samples were sent, with specific suspicion of SBP more readily documented, crucial to expediting laboratory processing. Targeted education and production of a clinical algorithm has significantly improved the management of patients with SBP. PMID- 26430180 TI - Recognition and management of acute kidney injury in hospitalised patients can be partially improved with the use of a care bundle. AB - Acute kidney injury (AKI) is common in hospitalised patients but is known be suboptimally managed; the National Confidential Enquiry into Patient Outcomes and Death (NCEPOD) report in 2009 identified significant failings in AKI care. An audit, using standards suggested by the NCEPOD report, of all adult inpatients with AKI in a large central-London NHS hospital in a 7-day period in 2011 showed poor recognition and management of AKI. In response, an AKI 'care bundle' was developed and deployed throughout the hospital along with a programme of enhanced education. Re-audit in 2013 showed that AKI was significantly more likely to have been recognised by the clinical team than in 2011, and patients with AKI were significantly more likely to have had fluid status clinically assessed and nephrotoxic medication stopped in 2013 than in 2011. There was no significant improvement in fluid administration if assessed as hypovolaemic and compliance with the guideline for prevention of contrast nephropathy. In 2011, all audit measures were met in 3.7% of patient-days versus 8.4% in 2013. More in-depth work is necessary to better understand the factors which limit optimal care. PMID- 26430181 TI - Experience from two decades of the Cambridge Rapid Access Neurology Clinic. AB - We report on the evolution of the rapid access neurology clinic (established in 1995) at Addenbrooke's Hospital, Cambridge. Annualised attendance data demonstrate an ever increasing demand, with primary headache disorders now accounting for more than 40% of referrals. Secondary causes of headache (including intracranial tumours, idiopathic intracranial hypertension, carotid or vertebral artery dissection and subdural haematomas) remain infrequent. In all such cases, there were additional diagnostic clues. The number of patients referred with problems related to chronic neurological diseases has fallen considerably, reflecting the roles of specialist nurses and clinics. Imaging investigation of choice shifted from computerised tomography scan (45 to 16%) towards magnetic resonance imaging (17 to 47%). Management is increasingly on an outpatient basis, often without the need for a follow-up appointment. The experience presented here should inform further development of rapid access neurology clinics across the UK and suggests the need for acute headache services, in line with those for transient ischaemic attack and first seizure. PMID- 26430182 TI - Management of cardiovascular conditions in a cohort of patients with HIV: experience from a joint HIV/cardiology clinic. AB - The aim of this study was to assess cardiovascular diagnoses and management in a cohort of patients diagnosed with HIV, and the performance of a joint HIV/Cardiology Clinic in a tertiary hospital setting. A retrospective analysis was performed on all patients referred to a joint HIV/Cardiology Clinic at our hospital. Data on 120 patients were collected. In this predominantly male population (male 101 and female 19) coronary artery disease (CAD) was the most common diagnosis (34%, n = 41). Other diseases included hypertension (12.5%, n = 15), cardiomyopathy (12.5%, n = 15) and arrhythmia (6%, n = 8). The majority of remaining cases included non-cardiac chest pain and palpitations. In addition to usual primary and secondary preventive measures for CAD, complex procedures, such as percutaneous coronary intervention, cardiac resynchronisation therapy for left ventricular systolic dysfunction and radiofrequency ablation for arrhythmias, were carried out. Overall cardiovascular mortality among the group was 2.5% (n = 3) over 4 years. The results indicate the efficacy of a specialist joint HIV/Cardiology Clinic in diagnosing and managing various cardiac conditions in a complex cohort of patients with HIV. PMID- 26430183 TI - Sexual health issues in adolescents and young adults. AB - Adolescence is a time of sexual risk-taking and experimentation but also vulnerability. Young people may present to general physicians with systemic symptoms of sexually transmitted infections (STIs), such as arthritis, hepatitis or rash, but may not necessarily volunteer information about sexual activity. It is important for physicians to ask directly about sexual risks and if appropriate test for STIs and pregnancy. Knowing how to take a sexual history and consent a patient for an HIV test are core medical skills that all physicians should be trained to competently perform. Safeguarding young people is the responsibility of all healthcare professionals who come into contact with them, and young victims of abuse may present with physical symptoms such as abdominal pain or deliberate self-harm. We must all be aware of indicators of both child sexual exploitation and HIV infection and not be afraid to ask potentially awkward questions. If we don't we may miss vital opportunities to prevent or minimise harm to young people. PMID- 26430184 TI - Drug therapies in severe asthma - the era of stratified medicine. AB - Difficult-to-treat asthma affects up to 20% of patients with asthma and is associated with significant healthcare cost. It is an umbrella term that defines a heterogeneous clinical problem including incorrect diagnosis, comorbid conditions and treatment non-adherence; when these are effectively addressed, good symptom control is frequently achieved. However, in 3-5% of adults with difficult-to-treat asthma, the problem is severe disease that is unresponsive to currently available treatments. Current treatment guidelines advise the 'stepwise' increase of corticosteroids, but it is now recognised that many aspects of asthma are not corticosteroid responsive, and that this 'one size fits all' approach does not deliver clinical benefit in many patients and can also lead to side effects. The future of management of severe asthma will involve optimisation with currently available treatments, particularly corticosteroids, including addressing non-adherence and defining an 'optimised' corticosteroid dose, allied with the use of 'add-on' target-specific novel treatments. This review examines the current status of novel treatments and research efforts to identify novel targets in the era of stratified medicines in severe asthma. PMID- 26430185 TI - Tackling emerging infections: clinical and public health lessons from the West African Ebola virus disease outbreak, 2014-2015. AB - The magnitude of the 2014-2015 West African Ebola virus disease outbreak was unforeseen at its onset and the initial international response was slow. The high mortality and the panic that this outbreak induced had a major effect on health systems. In this article we discuss some of the key public health and clinical lessons from this Ebola outbreak, including combining epidemiology, modelling and anthropology, and the initial evidence for the importance of fluid and antibiotic management. PMID- 26430186 TI - Stroke rehabilitation: long-term rehabilitation after stroke. AB - Many stroke survivors, despite improvements in mortality and morbidity, remain dependent on others for everyday activities. People with stroke need access to effective specialist multidisciplinary rehabilitation services that are organised and integrated within the whole system of health and social care. They also commonly come under the care of generalists in various clinical contexts, including intercurrent illness. This Clinical Medicine Concise Guideline abstracts key recommendations from the National Institute for Health and Care Excellence Clinical Guideline 162 on stroke rehabilitation of particular relevance to clinicians in general medicine, to inform their front-line practice and promote liaison and collaboration with the specialist service. PMID- 26430187 TI - Diabetes in older people. AB - The management of diabetes in older people is often challenging and poorly researched. The prevalence of cognitive impairment, chronic kidney disease and other co-existing comorbidities increase with age and have a significant impact on glycaemic control targets and treatment options. This conference examined current clinical practice, highlighted differences in the management of diabetes in the older person and suggested potential areas of future research. PMID- 26430188 TI - Acute liver failure. AB - Acute liver failure (ALF) is a rare critical illness with high mortality whose successful management requires early recognition and effective initial management. Though it may result from a wide variety of causes, in the UK and much of the developed world most cases result from paracetamol-induced hepatotoxicity, and administration of antidotal N-acetyl cysteine at first recognition is key. Involvement of local critical care services should occur at an early stage for stabilisation, monitoring and supportive care with parallel discussion with specialist liver centres to identify those patients who may benefit from transfer. Prognostic criteria are applied to identify patients for emergency liver transplantation, and candidates for surgery are prioritised on waitlisting schemes. Outcomes now approach that of elective surgery. However, the majority of cases, and particularly those with paracetamol-induced disease, recover with supportive medical care alone. Overall outcomes for patients with ALF have improved dramatically over the last three decades, but mortality remains unacceptable and further advances in care are required. PMID- 26430189 TI - Management of acute severe ulcerative colitis (NICE CG 166). AB - Ulcerative colitis (UC) presents as an acute severe flare in 10-15% of new cases and it occurs in 15% of patients with established disease. Acute severe UC can lead to significant morbidity and mortality in predominantly younger patients without other comorbidities. Inpatient hospital admission and a multidisciplinary approach are vital in appropriate and timely management. Important but simple aspects in the initial work-up and treatment of such patients are frequently overlooked during the acute medical take. An overview of the general and more specialist management of this important presentation are discussed herein. PMID- 26430190 TI - Acute oesophageal symptoms. AB - Acute oesophageal symptoms include acute dysphagia or food bolus impaction (most commonly due to strictures, Schatzki ring and eosinophilic oesophagitis), acute chest pain with odynophagia due to oesophageal infections, motility disorders and acute oesophageal rupture (of which oesophageal intramural haematoma is a subtype). Acute full thickness oesophageal rupture carries a high mortality if not recognised early; the clinical features and conditions with which this may be confused are presented and discussed. PMID- 26430191 TI - Acute upper gastrointestinal bleeding. AB - Acute upper gastrointestinal bleeding (AUGIB) is a frequently encountered medical emergency with an incidence of 84-160/100000 and associated with mortality of approximately 10%. Guidelines from the National Institute for Care and Care Excellence outline key features in the management of AUGIB. Patients require prompt resuscitation and risk assessment using validated tools. Upper gastrointestinal endoscopy provides accurate diagnosis, aids in estimating prognosis and allows therapeutic intervention. Endoscopy should be undertaken immediately after resuscitation in unstable patients and within 24 hours in all other patients. Interventional radiology may be required for bleeding unresponsive to endoscopic intervention. Drug therapy depends on the cause of bleeding. Intravenous proton pump inhibitors should be used in patients with high risk ulcers. Terlipressin and broad-spectrum antibiotics should be used following variceal haemorrhage. Hospitals admitting patients with AUGIB need to provide well organised services and ensure access to relevant services for all patients, and particularly to out of hours endoscopy. PMID- 26430192 TI - Acute alcohol toxicity and withdrawal in the emergency room and medical admissions unit. AB - Alcohol-related hospital attendances and admissions continue to escalate despite a fall in alcohol consumption levels in the UK population overall. People with alcohol-related problems pose a significant and often disproportionate burden on acute medical services as their management is often complex and challenging. This article focuses on the management of alcohol intoxication, with particular emphasis on aggressive and possibly violent behaviour; alcohol withdrawal; fitting; and the prevention and treatment of Wernicke's encephalopathy. PMID- 26430194 TI - Lesson of the month 1: A cough that doesn't fit the mould. AB - Aspergillus disease has a wide spectrum of manifestations within the lungs; however invasive Aspergillus is most commonly associated with immunocompromise or pre-existing respiratory disease. Here we present a case of Aspergillus tracheobronchitis causing right middle lobe collapse, masquerading as late-onset asthma in a patient with no pre-existing risk factors following massive inhalation of Aspergillus spores from working with compost. This case highlights the importance of having a high index of suspicion for Aspergillus-related disease even in those with no traditional risk factors. PMID- 26430195 TI - Lesson of the month 2: An unusual presentation of hyperinsulinaemic hypoglycaemia with possible underlying diagnosis of glucose-sensitive insulinoma or islet cell hyperplasia. AB - Postprandial hypoglycaemia can occur in islet cell hyperplasia and in reactive hypoglycaemia. Less commonly, it can occur with insulinoma. A case is described where the differential diagnosis was glucose-sensitive insulinoma or islet cell hyperplasia. Typical provocation was prolonged exertion or fasting followed by ingestion of sugary snacks resulting in hypoglycaemic seizures and collapse. Biochemistry and computerised tomography imaging were consistent with an insulinoma in the pancreatic tail, but this was not confirmed on endoscopic ultrasound. Selective intra-arterial calcium stimulation with hepatic venous sampling results suggested a diagnosis of islet cell hyperplasia. Ten years later, repeat imaging was consistent with a neuroendocrine tumour. Surgical resection has resulted in remission of symptoms. The patient will be monitored long term to ensure no recurrence. PMID- 26430196 TI - Image of the month: Chest pain after cocaine use. PMID- 26430197 TI - Letters to the editor. PMID- 26430198 TI - Letters to the editor. PMID- 26430199 TI - Impact of stroke services on geriatric medicine in Wales. PMID- 26430200 TI - On-going lessons in fluid prescription: assessment of adherence to weight-based intravenous fluid prescribing in medical inpatients. PMID- 26430202 TI - Meeting report--9th IRIC International Symposium on Molecular Targets in Cancer Genomics. AB - Graduate students and postdoctoral fellows at the Institute for Research in Immunology and Cancer (IRIC) organized the 9th IRIC International Symposium on 14 15 May, 2015. The symposium was held at the IRIC, an ultra-modern research hub and training center located on the hilltop of the Universite de Montreal campus in Montreal, Canada. This year's title was 'Molecular Targets in Cancer Genomics', reflecting the common interest of the IRIC student community. Through four broadly themed sessions, organizers sought to highlight the new generation of anti-cancer strategies including targeted therapies directed against actionable cancer-specific mutations, and immunotherapies, which enhance immune responses against cancer. Both targeted and immunotherapies are tailored to cancer-specific features, and require precise knowledge of cancer cells, from their genome to their proteome. The focus of this symposium was on translating the molecular basis of cancer into a functional understanding of aberrant pathways, and to uncover novel targets to be exploited for cancer therapeutic strategies. PMID- 26430203 TI - Ingested and Aspirated Foreign Bodies. AB - Esophageal and aspirated foreign bodies have important clinical significance, and both should be considered carefully when the history or physical examination findings raise sufficient suspicion. The published evidence regarding the diagnosis and management of foreign body ingestion or aspiration is weighted disproportionately with observational studies, case controls, expert opinion, and systematic reviews. Most of the publications would receive a categorization of C (observational studies including case-control and cohort design) and D (expert opinion, case reports, and clinical reasoning). One of the few prospective studies examining the diagnostic evaluation of foreign body aspiration in children could be considered level B evidence (randomized clinical trials, systematic reviews, or diagnostic studies with minor limitations). This study found that the medical history is the most important predictive part of the evaluation. There is evidence for considering bronchoscopy if there is significant history suggestive of foreign body aspiration, even in the setting of normal physical examination findings. (28). Most ingested foreign bodies spontaneously pass without incident. However, special attention should be paid to objects in the esophagus as well as to batteries and magnets. Based on a systematic review of the literature (level B evidence) and the potential for rapid and life-threatening damage, batteries in the esophagus should be removed immediately. (10) Other objects, such as coins, may be observed for passage in an asymptomatic patient. In addition, given the high risk of significant complications, ingestion of high-powered magnets should be quickly and carefully evaluated. Although single magnets are likely to pass without complication, multiple magnets or magnets ingested with other metal objects can cause significant damage and should be removed if there is any concern for mural entrapment, bowel perforation, or failure to progress. (10)(16)(17)(18)(19). Lastly, another systematic review of the literature (level B evidence) about the aspiration of food objects in children suggests that this is a significant public health concern with potentially devastating consequences. Despite clear legislation and regulation by the Consumer Product Safety Commission regarding toys, there is no similar regulation of high-risk foods. The data suggest that there is opportunity for improvement in legislation about the production and packaging of high-risk items as well as in the education of caregivers. (22) PMID- 26430204 TI - Return to Play. AB - Based primarily on consensus and some research evidence, young athletes with musculoskeletal and cervical spine injuries should not return to play until they have full range of motion, resolution of pain, normal strength, psychological readiness, and the ability to demonstrate adequate sport-specific skills. Based primarily on consensus, young athletes with suspected concussion should not return to sport until they have returned to their baseline physical and cognitive activities and successfully completed a return-to-play protocol. Based on consensus and some research evidence, any young athlete with a significant eye injury, visual changes, or abnormal findings on ophthalmologic examination results should not return to play until evaluated by an ophthalmologist. A significant number of eye injuries can be prevented by the use of approved protective eyewear. PMID- 26430205 TI - Patient Safety and Quality Improvement: Reducing Risk of Harm. AB - Most medical errors and preventable adverse events represent failures of complex systems. Pediatric clinicians must ensure a safe environment for health-care delivery to children. To do so, they must recognize risk factors for errors and adverse events; ensure effective communication with patients, parents, and colleagues; heighten situation awareness; develop high-functioning, high reliability teams; implement and employ technology carefully; and provide integrated, ongoing education to trainees. PMID- 26430206 TI - Case 1: Hepatomegaly and Growth Failure in an 11-year-old Girl With Type 1 Diabetes. PMID- 26430207 TI - Case 2: Ankle Pain, Swelling, and Fever after Trauma in a 15-year-old Boy. PMID- 26430208 TI - Case 3: Acute Onset of Headache, Fever, and Right Arm Weakness in 12-year-old Boy. PMID- 26430209 TI - Corrections. PMID- 26430210 TI - Complementary, Holistic, and Integrative Medicine: Yoga. PMID- 26430211 TI - Visual Diagnosis: A 7-Month-Old Girl With Cyanotic Spells. AB - Infants can develop acquired methemoglobinemia due to intake of well water high in nitrate concentrations. Although methemoglobinemia usually presents with more severe symptoms, this diagnosis should be considered in an infant with intermittent cyanosis in the absence of underlying heart or lung disease. Well water should be avoided in infancy unless properly tested. PMID- 26430212 TI - Rabaptin5 is recruited to endosomes by Rab4 and Rabex5 to regulate endosome maturation. AB - Rab GTPases control membrane identity, fusion and transport by interaction with effector proteins. Effectors that influence the activation-inactivation cycle of their own or other Rab proteins contribute to the timely conversion of Rab membrane identities. Rab5 and its effector rabaptin5 (Rbpt5, also known as RABEP1) are generally considered the prime example for a positive-feedback loop in which Rab5-GTP recruits Rbpt5 in complex with Rabex5 (also known as RABGEF1), the GDP/GTP exchange factor of Rab5, to early endosomes, thus maintaining the Rab5 membrane identity. By deletion analysis, we found that the membrane recruitment of Rabaptin5 required binding to Rab4 and Rabex5, but not Rab5. Deletion of either one of the two Rab5-binding domains or silencing of Rab5 expression did not affect Rabaptin5 recruitment, but produced giant endosomes with early and late endosomal characteristics. The results contradict the model of feedback activation of Rab5 and instead indicate that Rbpt5 is recruited by both Rabex5 recognizing ubiquitylated cargo and by Rab4 to activate Rab5 in a feed-forward manner. PMID- 26430213 TI - Regulation of polycystin-1 ciliary trafficking by motifs at its C-terminus and polycystin-2 but not by cleavage at the GPS site. AB - Failure to localize membrane proteins to the primary cilium causes a group of diseases collectively named ciliopathies. Polycystin-1 (PC1, also known as PKD1) is a large ciliary membrane protein defective in autosomal dominant polycystic kidney disease (ADPKD). Here, we developed a large set of PC1 expression constructs and identified multiple sequences, including a coiled-coil motif in the C-terminal tail of PC1, regulating full-length PC1 trafficking to the primary cilium. Ciliary trafficking of wild-type and mutant PC1 depends on the dose of polycystin-2 (PC2, also known as PKD2), and the formation of a PC1-PC2 complex. Modulation of the ciliary trafficking module mediated by the VxP ciliary targeting sequence and Arf4 and Asap1 does not affect the ciliary localization of full-length PC1. PC1 also promotes PC2 ciliary trafficking. PC2 mutations truncating its C-terminal tail but not those changing the VxP sequence to AxA or impairing the pore of the channel, leading to a dead channel, affect PC1 ciliary trafficking. Cleavage at the GPCR proteolytic site (GPS) of PC1 is not required for PC1 trafficking to cilia. We propose a mutually dependent model for the ciliary trafficking of PC1 and PC2, and that PC1 ciliary trafficking is regulated by multiple cis-acting elements. As all pathogenic PC1 mutations tested here are defective in ciliary trafficking, ciliary trafficking might serve as a functional read-out for ADPKD. PMID- 26430214 TI - NRIP is newly identified as a Z-disc protein, activating calmodulin signaling for skeletal muscle contraction and regeneration. AB - Nuclear receptor interaction protein (NRIP, also known as DCAF6 and IQWD1) is a Ca(2+)-dependent calmodulin-binding protein. In this study, we newly identify NRIP as a Z-disc protein in skeletal muscle. NRIP-knockout mice were generated and found to have reduced muscle strength, susceptibility to fatigue and impaired adaptive exercise performance. The mechanisms of NRIP-regulated muscle contraction depend on NRIP being downstream of Ca(2+) signaling, where it stimulates activation of both 'calcineurin-nuclear factor of activated T-cells, cytoplasmic 1' (CaN-NFATc1; also known as NFATC1) and calmodulin-dependent protein kinase II (CaMKII) through interaction with calmodulin (CaM), resulting in the induction of mitochondrial activity and the expression of genes encoding the slow class of myosin, and in the regulation of Ca(2+) homeostasis through the internal Ca(2+) stores of the sarcoplasmic reticulum. Moreover, NRIP-knockout mice have a delayed regenerative capacity. The amount of NRIP can be enhanced after muscle injury and is responsible for muscle regeneration, which is associated with the increased expression of myogenin, desmin and embryonic myosin heavy chain during myogenesis, as well as for myotube formation. In conclusion, NRIP is a novel Z-disc protein that is important for skeletal muscle strength and regenerative capacity. PMID- 26430215 TI - Vertebrate Reproduction. AB - Vertebrate reproduction requires a myriad of precisely orchestrated events-in particular, the maternal production of oocytes, the paternal production of sperm, successful fertilization, and initiation of early embryonic cell divisions. These processes are governed by a host of signaling pathways. Protein kinase and phosphatase signaling pathways involving Mos, CDK1, RSK, and PP2A regulate meiosis during maturation of the oocyte. Steroid signals-specifically testosterone-regulate spermatogenesis, as does signaling by G-protein-coupled hormone receptors. Finally, calcium signaling is essential for both sperm motility and fertilization. Altogether, this signaling symphony ensures the production of viable offspring, offering a chance of genetic immortality. PMID- 26430216 TI - Transcription-Factor-Dependent Control of Adult Hippocampal Neurogenesis. AB - Adult-generated dentate granule neurons have emerged as major contributors to hippocampal plasticity. New neurons are generated from neural stem cells through a complex sequence of proliferation, differentiation, and maturation steps. Development of the new neuron is dependent on the precise temporal activity of transcription factors, which coordinate the expression of stage-specific genetic programs. Here, we review current knowledge in transcription factor-mediated regulation of mammalian neural stem cells and neurogenesis and will discuss potential mechanisms of how transcription factor networks, on one hand, allow for precise execution of the developmental sequence and, on the other hand, allow for adaptation of the rate and timing of adult neurogenesis in response to complex stimuli. Understanding transcription factor-mediated control of neuronal development will provide new insights into the mechanisms underlying neurogenesis dependent plasticity in health and disease. PMID- 26430217 TI - Long-Range Chromatin Interactions. AB - To accommodate genomes in the limited space of the cell nucleus and ensure the correct execution of gene expression programs, genomes are packaged in complex fashion in the three-dimensional cell nucleus. As a consequence of the extensive higher-order organization of chromosomes, distantly located genomic regions on the same or distinct chromosomes undergo long-range interactions. This article discusses the nature of long interactions, mechanisms of their formation, and their emerging functional roles in gene regulation and genome maintenance. PMID- 26430226 TI - Isolated aortitis: a rare cause of febrile illness. AB - Febrile illness often presents a challenge for the clinician. The main causes of febrile illness are infections, solid or haematological malignancies and connective tissue disorders, including vasculitis. A 49-year-old woman sought medical attention because of intermittent fever that lasted 2 weeks. She presented no further symptoms or physical signs to suggest the aetiology. The epidemiological context was irrelevant. Analyses revealed anaemia of chronic disease and significant elevations of inflammatory parameters. A comprehensive study was performed, which revealed presence of an aortitis. Investigation of infectious and immunological causes was negative. We arrived at the definitive diagnosis of isolated aortitis. She was treated with corticosteroid and methotrexate, with resolution of symptoms and clinical abnormalities. PMID- 26430225 TI - A Physiological and Behavioral Mechanism for Leaf Herbivore-Induced Systemic Root Resistance. AB - Indirect plant-mediated interactions between herbivores are important drivers of community composition in terrestrial ecosystems. Among the most striking examples are the strong indirect interactions between spatially separated leaf- and root feeding insects sharing a host plant. Although leaf feeders generally reduce the performance of root herbivores, little is known about the underlying systemic changes in root physiology and the associated behavioral responses of the root feeders. We investigated the consequences of maize (Zea mays) leaf infestation by Spodoptera littoralis caterpillars for the root-feeding larvae of the beetle Diabrotica virgifera virgifera, a major pest of maize. D. virgifera strongly avoided leaf-infested plants by recognizing systemic changes in soluble root components. The avoidance response occurred within 12 h and was induced by real and mimicked herbivory, but not wounding alone. Roots of leaf-infested plants showed altered patterns in soluble free and soluble conjugated phenolic acids. Biochemical inhibition and genetic manipulation of phenolic acid biosynthesis led to a complete disappearance of the avoidance response of D. virgifera. Furthermore, bioactivity-guided fractionation revealed a direct link between the avoidance response of D. virgifera and changes in soluble conjugated phenolic acids in the roots of leaf-attacked plants. Our study provides a physiological mechanism for a behavioral pattern that explains the negative effect of leaf attack on a root-feeding insect. Furthermore, it opens up the possibility to control D. virgifera in the field by genetically mimicking leaf herbivore-induced changes in root phenylpropanoid patterns. PMID- 26430218 TI - Perisynaptic Schwann Cells at the Neuromuscular Synapse: Adaptable, Multitasking Glial Cells. AB - The neuromuscular junction (NMJ) is engineered to be a highly reliable synapse to carry the control of the motor commands of the nervous system over the muscles. Its development, organization, and synaptic properties are highly structured and regulated to support such reliability and efficacy. Yet, the NMJ is also highly plastic, able to react to injury and adapt to changes. This balance between structural stability and synaptic efficacy on one hand and structural plasticity and repair on another hand is made possible by the intricate regulation of perisynaptic Schwann cells, glial cells at this synapse. They regulate both the efficacy and structural plasticity of the NMJ in a dynamic, bidirectional manner owing to their ability to decode synaptic transmission and by their interactions via trophic-related factors. PMID- 26430227 TI - Ruptured intercostal artery pseudoaneurysm: a rare cause of acute back pain. AB - A 63-year-old man with no relevant medical history presented with acute non traumatic back pain and was found to have a T8 intercostal artery pseudoaneurysm associated with haemomediastinum on CT of the chest. He was taken to angiography with interventional radiology and the aneurysm was coiled without complication. PMID- 26430228 TI - Amitraz: a mimicker of organophosphate poisoning. AB - Amitraz is used as an ectoparasiticide for dogs and cattle. Human poisoning due to amitraz may be misdiagnosed as organophosphate/carbamate (OPC) toxicity, since amitraz poisoning shares several clinical features (miosis, bradycardia and hypotension) encountered with OPC poisoning. A 19-year-old man with an alleged history of suicidal ingestion of a pesticide presented with drowsiness and was found to have constricted pupils, hypotension and bradycardia. He was diagnosed as a case of OPC poisoning and was treated with atropine and pralidoxime prior to presentation to our centre. Absence of a hypersecretory state, and the presence of hyperglycaemia and hypothermia along with a normal serum cholinesterase level suggested an alternate possibility. Retrieval of the poison container confirmed the diagnosis of amitraz poisoning. The patient made a rapid recovery with supportive management. Clinician awareness is key to successful management of this poisoning, which carries a good prognosis. PMID- 26430229 TI - Laparoscopic treatment of a large uterine cystic adenomyosis in a young patient. AB - We describe a rare case of a young woman with a large cystic adenomyotic lesion that was treated laparoscopically. The patient presented with severe dysmenorrhoea refractory to common analgaesics. She was initially diagnosed with right-sided ovarian endometrioma. MRI revealed a cystic lesion of 4 cm attached to the right uterine wall. Under laparoscopic vision, the uterine lesion was identified on the right portion of the uterine fundus close to the round ligament. Monopolar diathermy was used to dissect the lesion. When the incision reached the cystic cavity, dark-brown content flowed from the cyst. After resection was complete, the surgical wound was closed with two-layer interrupted sutures. The patient made a good recovery and was discharged the following day. Since patients with cystic adenomyosis are young, a minimally invasive procedure such as laparoscopic excision is considered optimal. The exact topography of the lesion is crucial in determining the site of the incision. PMID- 26430230 TI - Imaging of leiomyomas arising from Mullerian remnants in a case of Mayer Rokitansky-Kuster-Hauser syndrome. AB - Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a rare congenital abnormality characterised by varying degrees of aplasia or hypoplasia of the uterus and vagina. Very rarely, leiomyomas or adenomyosis can develop in the Mullerian remnant tissue or rudimentary uterus. We present a case of a 43-year-old woman with MRKH syndrome, who presented with primary amenorrhoea and lower abdominal pain. On examination, a large pelvic mass was palpated and a provisional diagnosis of ovarian tumour was made. MRI showed multiple large leiomyomas arising from the Mullerian remnant tissue, and chronic torsion of the right ovary. PMID- 26430231 TI - Peutz-Jeghers syndrome: early clinical expression of a new STK11 gene variant. AB - Genetic heterogeneity has been recognised in Peutz-Jeghers syndrome (PJS) (over 230 STK11 gene mutations reported). We report a rare PJS phenotype with early extensive gastrointestinal (GI) presentation and a new genetic variant. The case presented as haematochezia and mucocutaneous pigmentation (the patient was 3 years of age). Endoscopy showed several polyps throughout the stomach/colon (PJ type hamartomas); the larger polyps were resected. Small bowel imaging detected multiple jejunum/ileum small polyps. During 8 years of follow-up of this asymptomatic patient, an increasing number of diffusely distributed polyps was observed and polypectomies were performed. Subsequently, the patient failed consultations; when the patient was 13 years of age, emergency surgery was required due to small bowel intussusception (ileal polyp). A STK11 gene study identified two missense variants in heterozygous (yet unknown significance but probably pathogenic): c.854T>A (exon 6) and c.446C>T* (exon 2) (*not previously reported). We report two STK11 gene variants (one not previously described) of yet undetermined causality in a paediatric patient presenting with extensive GI involvement at a very early age, with no family medical history. Structural and functional repercussion of the newly described variants should be further investigated. PMID- 26430232 TI - Hyperreactio luteinalis encountered during caesarean delivery of an uncomplicated spontaneous singleton pregnancy. AB - We report a rare case of hyperreactio luteinalis presenting as an incidental finding during caesarean section in an uncomplicated spontaneous singleton pregnancy. Caesarean section was performed due to failure to progress in labour, and delivered a healthy male neonate. The mother's analytical tests revealed a hyperandrogenic state without any other relevant alterations. Ovarian volume and testosterone serum concentration normalised in 2 months. The expectant management of this case permitted conservation of both ovaries in a young woman without adding morbidity. PMID- 26430233 TI - Juvenile fibromyalgia in an adolescent patient with sickle cell disease presenting with chronic pain. AB - Juvenile fibromyalgia in children with sickle cell disease has not been reported in the literature. We report an adolescent patient with sickle cell whose pain symptoms progressed from having recurrent acute sickle cell pain crisis episodes to a chronic pain syndrome over several years. He was eventually diagnosed with juvenile fibromyalgia based on the clinical history and myofascial tender points and his pain symptoms responded better to multidisciplinary strategies for chronic fibromyalgia pain. Chronic pain in sickle cell disease is an area of poor research, and in addition there is inconsistency in the definition of chronic pain in sickle cell disease. Central sensitisation to pain is shown to occur after recurrent painful stimuli in a genetically vulnerable individual. In a chronic pain condition such as fibromyalgia central sensitisation is thought to play a key role. Fibromyalgia should be considered as one of the main differential diagnosis in any sickle cell patient with chronic pain. PMID- 26430234 TI - Rock climbing-related subclavian vein thrombosis. AB - Paget-Schroetter syndrome, also known as upper extremity deep venous thrombosis (UEDVT), is a rare condition, characterised by a (sub-) total occlusion of the axillary-subclavian venous system due to thrombosis. UEDVT is the most common vascular condition among athletes so far; although the general incidence is low, this problem will become more frequent as a result of increased participation in climbing sports. The purpose of this report is to illustrate two cases in rock climbers where UEDVT developed during rock climbing or bouldering. Fortunately, both patients were diagnosed relatively early after the symptoms began, despite the ambiguity of UEDVT symptoms. This relatively unfamiliar condition may become more highly recognised as a potentially serious differential diagnosis of unspecific pain of the shoulder. Rock climbers are disposed to develop UEDVT due to frequent stress on the upper extremities during training or competition. PMID- 26430235 TI - Budesonide-related adrenal insufficiency. AB - Iatrogenic adrenal insufficiency is a potential harmful side effect of treatment with corticosteroids. It manifests itself when an insufficient cortisol response to biological stress leads to an Addisonian crisis: a life-threatening situation. We describe a case of a patient who developed an Addisonian crisis after inappropriate discontinuation of budesonide (a topical steroid used in Crohn's disease) treatment. Iatrogenic adrenal insufficiency due to budesonide use has been rarely reported. Prescribers should be aware of the resulting risk for an Addisonian crisis. PMID- 26430236 TI - Coevolution of parasite virulence and host mating strategies. AB - Parasites are thought to play an important role in sexual selection and the evolution of mating strategies, which in turn are likely to be critical to the transmission and therefore the evolution of parasites. Despite this clear interdependence we have little understanding of parasite-mediated sexual selection in the context of reciprocal parasite evolution. Here we develop a general coevolutionary model between host mate preference and the virulence of a sexually transmitted parasite. We show when the characteristics of both the host and parasite lead to coevolutionarily stable strategies or runaway selection, and when coevolutionary cycling between high and low levels of host mate choosiness and virulence is possible. A prominent argument against parasites being involved in sexual selection is that they should evolve to become less virulent when transmission depends on host mating success. The present study, however, demonstrates that coevolution can maintain stable host mate choosiness and parasite virulence or indeed coevolutionary cycling of both traits. We predict that choosiness should vary inversely with parasite virulence and that both relatively long and short life spans select against choosy behavior in the host. The model also reveals that hosts can evolve different behavioral responses from the same initial conditions, which highlights difficulties in using comparative analysis to detect parasite-mediated sexual selection. Taken as a whole, our results emphasize the importance of viewing parasite-mediated sexual selection in the context of coevolution. PMID- 26430237 TI - E1 of alpha-ketoglutarate dehydrogenase defends Mycobacterium tuberculosis against glutamate anaplerosis and nitroxidative stress. AB - Enzymes of central carbon metabolism (CCM) in Mycobacterium tuberculosis (Mtb) make an important contribution to the pathogen's virulence. Evidence is emerging that some of these enzymes are not simply playing the metabolic roles for which they are annotated, but can protect the pathogen via additional functions. Here, we found that deficiency of 2-hydroxy-3-oxoadipate synthase (HOAS), the E1 component of the alpha-ketoglutarate (alpha-KG) dehydrogenase complex (KDHC), did not lead to general metabolic perturbation or growth impairment of Mtb, but only to the specific inability to cope with glutamate anaplerosis and nitroxidative stress. In the former role, HOAS acts to prevent accumulation of aldehydes, including growth-inhibitory succinate semialdehyde (SSA). In the latter role, HOAS can participate in an alternative four-component peroxidase system, HOAS/dihydrolipoyl acetyl transferase (DlaT)/alkylhydroperoxide reductase colorless subunit gene (ahpC)-neighboring subunit (AhpD)/AhpC, using alpha-KG as a previously undescribed source of electrons for reductase action. Thus, instead of a canonical role in CCM, the E1 component of Mtb's KDHC serves key roles in situational defense that contribute to its requirement for virulence in the host. We also show that pyruvate decarboxylase (AceE), the E1 component of pyruvate dehydrogenase (PDHC), can participate in AceE/DlaT/AhpD/AhpC, using pyruvate as a source of electrons for reductase action. Identification of these systems leads us to suggest that Mtb can recruit components of its CCM for reactive nitrogen defense using central carbon metabolites. PMID- 26430239 TI - Correction for Jimenez-Diaz et al., (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium. PMID- 26430238 TI - Evolutionary paths of least resistance. PMID- 26430241 TI - Correction for Colaianni et al., The myokine irisin increases cortical bone mass. PMID- 26430240 TI - Regulation of outer kinetochore Ndc80 complex-based microtubule attachments by the central kinetochore Mis12/MIND complex. AB - Multiple protein subcomplexes of the kinetochore cooperate as a cohesive molecular unit that forms load-bearing microtubule attachments that drive mitotic chromosome movements. There is intriguing evidence suggesting that central kinetochore components influence kinetochore-microtubule attachment, but the mechanism remains unclear. Here, we find that the conserved Mis12/MIND (Mtw1, Nsl1, Nnf1, Dsn1) and Ndc80 (Ndc80, Nuf2, Spc24, Spc25) complexes are connected by an extensive network of contacts, each essential for viability in cells, and collectively able to withstand substantial tensile load. Using a single-molecule approach, we demonstrate that an individual MIND complex enhances the microtubule binding affinity of a single Ndc80 complex by fourfold. MIND itself does not bind microtubules. Instead, MIND binds Ndc80 complex far from the microtubule-binding domain and confers increased microtubule interaction of the complex. In addition, MIND activation is redundant with the effects of a mutation in Ndc80 that might alter its ability to adopt a folded conformation. Together, our results suggest a previously unidentified mechanism for regulating microtubule binding of an outer kinetochore component by a central kinetochore complex. PMID- 26430243 TI - Illuminating the dark matter in metabolomics. PMID- 26430242 TI - Endothelial Bmx tyrosine kinase activity is essential for myocardial hypertrophy and remodeling. AB - Cardiac hypertrophy accompanies many forms of heart disease, including ischemic disease, hypertension, heart failure, and valvular disease, and it is a strong predictor of increased cardiovascular morbidity and mortality. Deletion of bone marrow kinase in chromosome X (Bmx), an arterial nonreceptor tyrosine kinase, has been shown to inhibit cardiac hypertrophy in mice. This finding raised the possibility of therapeutic use of Bmx tyrosine kinase inhibitors, which we have addressed here by analyzing cardiac hypertrophy in gene-targeted mice deficient in Bmx tyrosine kinase activity. We found that angiotensin II (Ang II)-induced cardiac hypertrophy is significantly reduced in mice deficient in Bmx and in mice with inactivated Bmx tyrosine kinase compared with WT mice. Genome-wide transcriptomic profiling showed that Bmx inactivation suppresses myocardial expression of genes related to Ang II-induced inflammatory and extracellular matrix responses whereas expression of RNAs encoding mitochondrial proteins after Ang II administration was maintained in Bmx-inactivated hearts. Very little or no Bmx mRNA was expressed in human cardiomyocytes whereas human cardiac endothelial cells expressed abundant amounts. Ang II stimulation of endothelial cells increased Bmx phosphorylation, and Bmx gene silencing inhibited downstream STAT3 signaling, which has been implicated in cardiac hypertrophy. Furthermore, activation of the mechanistic target of rapamycin complex 1 pathway by Ang II treatment was decreased in the Bmx-deficient hearts. Our results demonstrate that inhibition of the cross-talk between endothelial cells and cardiomyocytes by Bmx inactivation suppresses Ang II-induced signals for cardiac hypertrophy. These results suggest that the endothelial Bmx tyrosine kinase could provide a target to attenuate the development of cardiac hypertrophy. PMID- 26430244 TI - Reply to Sun et al.: Confirming the evidence for Late Oligocene-Early Miocene birth of the Taklimakan Desert. PMID- 26430245 TI - Refuting the evidence for an earlier birth of the Taklimakan Desert. PMID- 26430247 TI - The UK Risk-Sharing Scheme for interferon-beta and glatiramer acetate in multiple sclerosis. Outcome of the year-6 analysis. PMID- 26430246 TI - FOXL2 down-regulates vitellogenin expression at mature stage in Eriocheir sinensis. AB - Ovarian development in crustaceans is characterized by rapid production of egg yolk protein in a process called vitellogenesis. In the present study, we investigated the involvement of a DEAD (Asp-Glu-Ala-Asp) box RNA helicase 20 (DDX20), forkhead transcription factor (FOXL)2 and fushi tarazu factor (FTZ-F)1 in the regulation of vitellogenesis. Based on ESTs from the testis and accessory gland of Eriocheir sinensis, we cloned the full-length cDNAs of foxl2 and fushitarazu factor 1 (ftz-f1), which include the conserved structural features of the forkhead family and nuclear receptor 5A (NR5A) family respectively. The expression of foxl2 mRNA surged at the mature stage of the ovary, when vtg mRNA swooped, suggesting that foxl2 negatively affects the vitellogenin (VTG) synthesis at this developmental stage. Etoposide (inducing germ cell apoptosis) treatment up-regulated FOXL2 and DDX20 at both the mRNA and the protein levels, primarily in the follicular cells as shown by immunofluorescence analysis. Furthermore, foxl2, ddx20 and ftz-f1 mRNA levels increased significantly with right-eyestalk ablation. Interactions between FOXL2 and DDX20 or FTZ-F1 were confirmed by co-immunoprecipitation and the forkhead domain of FOXL2 was identified as the specific structure interacting with FTZ-F1. In conclusion, FOXL2 down-regulates VTG expression by binding with DDX20 in regulation of follicular cell apoptosis and with FTZ-F1 to repress the synthesis of VTG at the mature stage. This report is the first to describe the molecular mechanism of VTG synthesis in E. sinensis and may shed new light on the regulation of cytochrome P450 enzyme by FOXL2 and FTZ-F1 in vitellogenesis. PMID- 26430248 TI - A wolf in sheep's clothing. PMID- 26430249 TI - Isolation of Chloroplasts from Plant Protoplasts. AB - Chloroplasts can be isolated from higher plants directly following homogenization; however, the resulting yield, purity, and intactness are often low, necessitating a large amount of starting material. This protocol is optimized to produce a high yield of pure chloroplasts from isolated Arabidopsis protoplasts. The two-part method is a simple, scaled-down, and low-cost procedure that readily provides healthy mesophyll protoplasts, which are then ruptured to release intact chloroplasts. Chloroplasts isolated using this method are competent for use in biochemical, cellular, and molecular analyses. PMID- 26430250 TI - Induction of Liver Tumors in Mice with N-Ethyl-N-Nitrosourea or N Nitrosodiethylamine. AB - Since the groundbreaking studies in the middle part of the last century showing liver cancer in rodents exposed to aromatic amines, the liver has been widely used as a model target organ of chemical carcinogenesis. This protocol describes a method for inducing liver tumors by injecting mice with the widely used alkylating agents N-ethyl-N-nitrosourea (ENU) and N-nitrosodiethylamine (DEN). ENU does not require metabolic activation and readily induces tumors in a number of tissues, including the lungs, stomach, and ovaries, as well as inducing lymphomas. Mice injected with DEN can also develop other tumors, including those of the gastrointestinal tract, skin, lungs, and lymphocytes, but because DEN is metabolized in the liver, it is most effective at inducing liver tumors. PMID- 26430251 TI - Induction and Analysis of Synchronous Meiotic Yeast Cultures. AB - Meiosis in Saccharomyces cerevisiae can be induced by deprivation of nutrients. Here, we present a protocol for inducing synchronous meiosis in SK1, the most efficient and synchronous yeast strain for meiosis, by exposing SK1 cells to liquid medium that contains potassium acetate as a nonfermentable carbon source and lacks nitrogen. These synchronous meiotic yeast cultures can be subjected to a range of molecular and cytological analyses, making them useful for investigating the genetic and molecular determinants of meiosis. PMID- 26430252 TI - Analysis of Meiotic Recombination and Homolog Interaction during Yeast Meiosis. AB - During meiosis, one round of genome duplication is followed by two rounds of chromosome segregation, resulting in the halving of the genetic complement and the formation of haploid reproductive cells. In most organisms, intimate juxtaposition of homologous chromosomes and homologous recombination during meiotic prophase are required for meiotic success. Here we present a general protocol for visualizing chromosomal proteins and homolog interaction on surface spread nuclei and a widely used protocol for analyzing meiotic recombination based on an engineered hotspot referred to as HIS4::LEU2. PMID- 26430253 TI - Visualizing Lysosomal Membrane Permeabilization by Fluorescent Dextran Release. AB - Lysosomal membrane permeabilization (LMP) is an effective programmed cell death pathway triggered in response to a variety of cytotoxic stimuli and cellular conditions. In the method presented here, LMP is monitored by first taking advantage of the steady endocytic capacity of cells to load fluorescent dextran into lysosomes, and then simply observing the translocation of lysosomally localized dextran into the cytosol after an LMP-inducing insult. Fluorescent dextran in healthy cells appears in punctate structures representing intact lysosomes, whereas after LMP, a diffuse staining pattern throughout the cytoplasm is observed. Using this method, LMP can be followed in real time using time-lapse imaging. The size of pores formed in the membrane during LMP by size exclusion can also be determined using dextrans of different sizes and colors. PMID- 26430254 TI - A Method to Monitor Lysosomal Membrane Permeabilization by Immunocytochemistry. AB - Programmed cell death involving lysosomal membrane permeabilization (LMP) is a common phenomenon--more the rule than the exception under various cytotoxic stimuli and stressful cellular conditions. The protocol presented here is based on immunocytochemical staining of cathepsin B or L to visualize translocation from the lysosomal lumen to the cytosol. In healthy cells, cathepsins appear in localized punctate structures representing intact lysosomes, whereas LMP results in a diffuse staining pattern throughout the cytoplasm. LMP can be triggered upstream, downstream, or independently of the classical apoptotic death pathway involving mitochondrial outer membrane permeabilization (MOMP). Co-staining with antibodies recognizing the active form of Bax allows investigation of the order of events between LMP and MOMP in death signaling. PMID- 26430255 TI - Purification and Injection of Retroviral Vectors. AB - Retroviral vectors are powerful tools for genetic manipulation. This protocol discusses the production, purification, and use of replication-deficient retroviral vectors based on Moloney murine leukemia virus and lentivirus. It also describes the injection of a retroviral vector into the dentate gyrus of young adult mice to fluorescently label live murine brain tissue. PMID- 26430256 TI - Imaging Newborn Granule Cells in Fixed Sections. AB - This protocol describes the harvesting of brain tissue from mice that have had the retroviral vector CAG-GFP injected into the dentate gyrus. Brain tissue from these mice is dissected, the tissue is fixed, and the sections are prepared. The fixed sections are imaged using fluorescent confocal microscopy, and newborn granule cells containing GFP are visualized and are characterized. PMID- 26430257 TI - Analysis of Spine Motility of Newborn Granule Cells in Acute Brain Slices. AB - In this protocol, acute brain slices are prepared from mice in which newborn granule cells have been labeled using retroviral vector technology. Using a live cell imaging stage and confocal microscopy coupled to imaging software, dendritic spines are analyzed. PMID- 26430258 TI - Generation of Thy1 Constructs for Pronuclear Injection. AB - With easy access to core facilities or commercial providers of pronuclear injections, generating simple Thy1-XFP transgenic mice (where XFP stands for any fluorescent protein) is now a possibility even for small laboratories. The generation of new Thy1 transgenic lines generally consists of five steps: (1) engineering and characterization of the desired fluorescent reporter protein, (2) cloning of the reporter protein into the Thy1 vector, (3) linearization and purification of the new Thy1 construct, (4) pronuclear injection to generate founders, and (5) screening of founder progeny to establish transgenic lines. Here, we provide a protocol for Steps 2 and 3. The sequence for a desired fluorescent reporter protein is cloned into the XhoI restriction site of the Thy1 vector. This usually involves blunt-end cloning because the traditional Thy1 vector does not carry an intact multiple cloning site. Following successful cloning, the DNA is prepared for pronuclear injection by linearizing it using EcoRI and PvuI restriction enzymes. The purified linearized DNA must then be sent to a facility specializing in pronuclear injection to generate transgenic founder mice. PMID- 26430260 TI - Preparation and Use of Retroviral Vectors for Labeling, Imaging, and Genetically Manipulating Cells. AB - Retroviral vectors are a powerful technology for achieving long-term genetic manipulation. This introduction provides some background on replication-deficient retroviral vectors based on Moloney murine leukemia virus and lentivirus. Details, examples, and associated protocols are provided for using these vectors to fluorescently label, genetically alter, and image both live and fixed murine brain tissue. PMID- 26430261 TI - Generation and Screening of Transgenic Mice with Neuronal Labeling Controlled by Thy1 Regulatory Elements. AB - Major progress has been made using in vivo imaging in mice to study mammalian nervous system development, plasticity, and disease. This progress has depended in part on the wide availability of two-photon microscopy, which is capable of penetrating deep into scattering tissue. Equally important, however, is the generation of suitable transgenic mouse models, which provide a "Golgi staining" like labeling of neurons that is sparse and bright enough for in vivo imaging. Particularly prominent among such transgenic mice are the so-called Thy1-XFP mice (in which XFP stands for any fluorescent protein) that are used in numerous studies, especially to visualize spine plasticity in the cortex and remodeling in peripheral synapses. New generations of Thy1-XFP mice are now being generated at a high rate, and these have allowed previously difficult experiments to become feasible. Moreover, with easy access to core facilities or commercial providers of pronuclear injections, generating simple Thy1 transgenic mice is now a possibility even for small laboratories. In this introduction, we discuss the Thy1 regulatory elements used to generate transgenic lines with neuronal labeling. We provide a brief overview of currently available Thy1 transgenic mice, including lines labeling neuronal organelles or reporting neuronal function. PMID- 26430259 TI - Animal Models of Chemical Carcinogenesis: Driving Breakthroughs in Cancer Research for 100 Years. AB - The identification of carcinogens in the workplace, diet, and environment through chemical carcinogenesis studies in animals has directly contributed to a reduction of cancer burden in the human population. Reduced exposure to these carcinogens through lifestyle changes, government regulation, or change in industry practices has reduced cancer incidence in exposed populations. In addition to providing the first experimental evidence for cancer's relationship to chemical and radiation exposure, animal models of environmentally induced cancer have and will continue to provide important insight into the causes, mechanisms, and conceptual frameworks of cancer. More recently, combining chemical carcinogens with genetically engineered mouse models has emerged as an invaluable approach to study the complex interaction between genotype and environment that contributes to cancer development. In the future, animal models of environmentally induced cancer are likely to provide insight into areas such as the epigenetic basis of cancer, genetic modifiers of cancer susceptibility, the systems biology of cancer, inflammation and cancer, and cancer prevention. PMID- 26430262 TI - MEET THE PRESIDENT. PMID- 26430263 TI - A Year in Third Person. PMID- 26430264 TI - AJPE Welcomes Fjortoft and Schlesselman as Associate Editors. PMID- 26430265 TI - An Interprofessional Education Panel on Development, Implementation, and Assessment Strategies. AB - This report provides a primer for implementing interprofessional education (IPE) within pharmacy and health sciences curricula. In 2013, a panel of administrators and faculty members, whose institutions offered IPE, funded by the Josiah Macy Jr. Foundation, shared best collaborative practice models at the American Association of Colleges of Pharmacy (AACP) Annual Meeting. These presenters subsequently collaborated to write a primer as guidance for other institutions interested in successfully implementing and continuously enhancing the quality of IPE programs. In this article, these IPE faculty members provide a rationale for creating IPE reforms, discuss successful strategies for innovative IPE programs, and share lessons learned for implementing effective assessment tools. A structure and process for determining outcomes of IPE models are presented and strategies for exploring shared education opportunities across health professions and for integrating top-down and bottom-up methods for IPE programs are given. PMID- 26430266 TI - Personal Digital Branding as a Professional Asset in the Digital Age. AB - In recent years, society's rapid adoption of social media has made the boundary between professional and private life nearly indistinguishable. The literature provides guidance on how to demonstrate professionalism via social media platforms. Social media policies within health professions education tend to be legalistic in nature, serving primarily to highlight behaviors students should avoid. One missing element in social media literature is the concept of online invisibility. In this paper, we define personal digital branding, discuss the professional implications of choosing to abstain from social media use, and urge educators to recognize that the personal digital branding may be an emerging asset for young professionals in the twenty-first century. PMID- 26430267 TI - Outcomes of a Multi-faceted Educational Intervention to Increase Student Scholarship. AB - Objective. To increase the percentage of state, national, or international student presentations and publications. Design. A multi-faceted intervention to increase student scholarly output was developed that included: (1) a 120-minute lecture on publication of quality improvement or independent study research findings; (2) abstract workshops; (3) poster workshops; and (4) a reminder at an advanced pharmacy practice experience (APPE) meeting encouraging students to publish or present posters. The intervention effect was measured as the percent of students who presented at meetings and the number of student projects published. Assessment. A significant increase occurred in the percent of students who presented posters or published manuscripts after the intervention (64% vs 81%). Total student productivity increased from 84 to 147 posters, publications, and presentations. The number of projects presented or published increased from 50 to 77 in one year. Conclusion. This high-impact, low-cost intervention increased scholarly output and may help students stand out in a competitive job market. PMID- 26430268 TI - A Learner-led, Discussion-based Elective on Emerging Infectious Disease. AB - Objective. To implement a learner-led, discussion-based course aimed at exposing second-year pharmacy learners to the study of emerging infectious diseases from a global health perspective and to assess the role and importance of pharmacists in the management of disease outbreaks. Design. Learners examined literature pertinent to an emerging infectious disease in a 3-credit, discussion-based course and participated in peer discussion led by a designated learner. Instructional materials included journal articles, audio-visual presentations, documentaries, book chapters, movies, newspaper/magazine articles, and other materials. Learning outcomes were measured based on the ability of learners to perform critical thinking and analysis, communicate with their peers, and participate in class discussions. Assessment. The course was offered to 2 consecutive cohorts consisting of 14 and 16 learners, respectively. Overall, every learner in the first cohort achieved a final grade of A for the course. In the second cohort, the overall grade distribution consisted of grades of A, B, and C for the course. Learner evaluations indicated that the active-learning, discussion-based environment significantly enhanced interest in the topic and overall performance in the course. Conclusion. The elective course on emerging infectious diseases provided in-depth exposure to disease topics normally not encountered in the pharmacy curriculum. Learners found the material and format valuable, and the course enhanced their appreciation of infectious diseases, research methodology, critical thinking and analysis, and their roles as pharmacists. PMID- 26430269 TI - Evolution of a Natural Products and Nutraceuticals Course in the Pharmacy Curriculum. AB - Objective. To develop, implement, and modify a required, second-year pharmacy course that provides an understanding of the scientific, therapeutic, and clinical principles, as well as the evidence-based medicine underlying the use of natural products. Design. A 28-hour, multi-faculty course was developed and offered in 2008. The course was modified over the years to enhance students' practice skills in the use of natural products. A course evaluation and survey were administered to assess the students' opinions. Assessment. Students performed well in the course and provided favorable evaluations, especially for the latest offering. Students reported significantly improved skills in providing advice to patients regarding the use of natural products. Conclusion. The course increased the students' knowledge and application of information and counseling skills regarding natural products. PMID- 26430271 TI - Limited Predictive Utility of Admissions Scores and Objective Structured Clinical Examinations for APPE Performance. AB - OBJECTIVE: To examine the relationship between admissions, objective structured clinical examination (OSCE), and advanced pharmacy practice experience (APPE) scores. METHODS: Admissions, OSCE, and APPE scores were collected for students who graduated from the doctor of pharmacy (PharmD) program in spring of 2012 and spring of 2013 (n=289). Pearson correlation was used to examine relationships between variables, and independent t test was used to compare mean scores between groups. RESULTS: All relationships among admissions data (undergraduate grade point average, composite PCAT scores, and interview scores) and OSCE and APPE scores were weak, with the strongest association found between the final OSCE and ambulatory care APPEs. Students with low scores on the final OSCE performed lower than others on the acute care, ambulatory care, and community APPEs. CONCLUSION: This study highlights the complexities of assessing student development of noncognitive professional skills over the course of a curriculum. PMID- 26430270 TI - Fostering Interdisciplinary Communication between Pharmacy and Nursing Students. AB - Objective. To evaluate pharmacy and nursing student self-perceptions of interdisciplinary communication skills, faculty member perceptions of interdisciplinary communication skills, and changes in those skills after increasing the interdisciplinary education content. Design. Two cohorts of pharmacy and nursing (bachelors of science in nursing, BSN) students in respective, semester-long research courses engaged in active learning on interdisciplinary communication, with the second cohort receiving additional content on the topic. At semester completion, students presented a research project at an interdisciplinary poster session. Assessment. Self-, peer-, and faculty evaluations (4 items; 5-point Likert-type) assessing self-confidence and actual interdisciplinary communication skills were completed during the poster session. Overall, students responded they were "very confident" or "extremely confident" regarding the skills, with greater confidence reported by the second cohort. Faculty members agreed that students exhibited effective interdisciplinary communication skills, with stronger agreement for the second cohort. Conclusion. Including interdisciplinary education and experiences in a curriculum increases students' interdisciplinary communication skills. Using multiple interdisciplinary experiences may result in greater increases in these skills. PMID- 26430272 TI - Pharmacy Students' Knowledge and Attitudes Regarding Medical Marijuana. AB - OBJECTIVE: To determine pharmacy students' knowledge of and attitudes toward medical marijuana and to determine if pharmacy students need additional education on the topic. METHODS: Pharmacy students were asked to complete a survey on medical marijuana that assessed their knowledge of, medical uses of, adverse effects with, and attitudes toward medical marijuana through 23 Likert-scale questions. RESULTS: Three hundred eleven students completed the survey. Fifty eight percent of the students felt that medical marijuana should be legalized in all states. However, the majority of students did not feel comfortable answering consumers' questions regarding efficacy, safety, or drug interactions related to the substance. Accurate responses for diseases or conditions for permitted medical marijuana use was low, with only cancer (91%) and glaucoma (57%) identified by more than half the students. CONCLUSION: With an increasing number of states adopting medical marijuana use, pharmacy schools need to evaluate the adequacy of medical marijuana education in their curriculum. PMID- 26430273 TI - Assessment of Communications-related Admissions Criteria in a Three-year Pharmacy Program. AB - OBJECTIVE: To determine if there is a correlation between TOEFL and other admissions criteria that assess communications skills (ie, PCAT variables: verbal, reading, essay, and composite), interview, and observational scores and to evaluate TOEFL and these admissions criteria as predictors of academic performance. METHODS: Statistical analyses included two sample t tests, multiple regression and Pearson's correlations for parametric variables, and Mann-Whitney U for nonparametric variables, which were conducted on the retrospective data of 162 students, 57 of whom were foreign-born. RESULTS: The multiple regression model of the other admissions criteria on TOEFL was significant. There was no significant correlation between TOEFL scores and academic performance. However, significant correlations were found between the other admissions criteria and academic performance. CONCLUSION: Since TOEFL is not a significant predictor of either communication skills or academic success of foreign-born PharmD students in the program, it may be eliminated as an admissions criterion. PMID- 26430274 TI - Collaborative Examination Item Review Process in a Team-Taught, Self-Care Sequence. AB - OBJECTIVE: To improve examination item quality by educating and involving course instructors in evidence-based item review and encouraging use of this process in future courses. METHODS: A peer-review process was implemented in a 2-course sequence (intervention) that involved training and review sessions before each examination and was compared to the previous year's courses (control). Instructors completed a presurvey and postsurvey on training, experience, self confidence, and self-rated success in multiple-choice item writing. Statistics were calculated for all items in the control and intervention sequences and compared using independent t tests. Items also were classified into levels based on difficulty and discrimination, and distribution into these levels was compared between sequences with independent t tests. RESULTS: No significant difference was found between control and intervention sequence items with regard to mean difficulty (86.3% and 84.4%) or discrimination (0.23- and 0.25), respectively, although item classification distribution did appear to change between the control and intervention sequences' subjective feelings of confidence, and success in item writing increased between presurvey and postsurvey. Confidence in ability to peer-review test items and to implement a formal item evaluation process also increased. CONCLUSION: Item statistics did not change significantly, but reviewed and edited items distributed more favorably into item statistic based categories. This method of review positively affected instructors' perceptions of their item-writing confidence and success and improved self-rated opinions of their ability to edit items and train others to do so. PMID- 26430275 TI - Career Placement of Doctor of Pharmacy Graduates at Eight U.S. Midwestern Schools. AB - OBJECTIVE: To characterize postgraduation placement plans of 2013 doctor of pharmacy (PharmD) graduates. METHODS: A cross-sectional survey of PharmD graduates from 8 midwestern colleges of pharmacy was designed to capture a comprehensive picture of graduating students' experiences and outcomes of their job search. RESULTS: At graduation, 81% of 2013 respondents had postgraduate plans, with approximately 40% accepting jobs and 40% accepting residencies or fellowships. Eighty-four percent of graduates reported being pleased with offers received, and 86% received placement in their preferred practice setting. Students perceived that securing residencies was more difficult than securing jobs. Students who participated in key activities had a nearly sevenfold increase in successful residency placement. CONCLUSION: While the demand for pharmacists decreased in recent years, responses indicated successful placement by the majority of 2013 graduates at the time of graduation. PMID- 26430276 TI - Development and Assessment of a Horizontally Integrated Biological Sciences Course Sequence for Pharmacy Education. AB - OBJECTIVE: To design and assess a horizontally integrated biological sciences course sequence and to determine its effectiveness in imparting the foundational science knowledge necessary to successfully progress through the pharmacy school curriculum and produce competent pharmacy school graduates. DESIGN: A 2-semester course sequence integrated principles from several basic science disciplines: biochemistry, molecular biology, cellular biology, anatomy, physiology, and pathophysiology. Each is a 5-credit course taught 5 days per week, with 50-minute class periods. ASSESSMENT: Achievement of outcomes was determined with course examinations, student lecture, and an annual skills mastery assessment. The North American Pharmacist Licensure Examination (NAPLEX) results were used as an indicator of competency to practice pharmacy. CONCLUSION: Students achieved course objectives and program level outcomes. The biological sciences integrated course sequence was successful in providing students with foundational basic science knowledge required to progress through the pharmacy program and to pass the NAPLEX. The percentage of the school's students who passed the NAPLEX was not statistically different from the national percentage. PMID- 26430277 TI - Using the Jigsaw Technique to Teach Clinical Controversy in a Clinical Skills Course. AB - OBJECTIVE: To evaluate the effectiveness and student perception of the jigsaw technique to engage students in a clinical controversy exercise and to assess student engagement level during each step of the process. DESIGN: Students were assigned individual readings pertaining to the controversy surrounding the drug oxybutynin switching from prescription to nonprescription. They met with an expert group and teaching groups during mandatory laboratory time and worked together to formulate a recommendation on the appropriateness of nonprescription conversion for a drug. ASSESSMENT: A quiz taken individually was used to measure effectiveness. Student perception and level of engagement was assessed using surveys. CONCLUSION: The jigsaw technique was successful in teaching the concepts involved in the clinical controversy. Group members rated themselves and fellow participants' level of engagement as high during both the expert group and teaching group sessions. Most students reported they learned about the same or more with the jigsaw technique compared to another cooperative learning technique used in the curriculum. PMID- 26430279 TI - What Can We Learn from TED Talks? PMID- 26430278 TI - Evaluating the Effects of Flexible Learning about Aseptic Compounding on First year Students in a Pharmacy Skills Laboratory. AB - OBJECTIVE: To evaluate how flexible learning via online video review affects the ability and confidence of first-year (P1) pharmacy students to accurately compound aseptic preparations. DESIGN: Customary instructions and assignments for aseptic compounding were provided to students, who were given unlimited access to 5 short review videos in addition to customary instruction. Student self confidence was assessed online, and faculty members evaluated students' aseptic technique at the conclusion of the semester. ASSESSMENT: No significant difference on final assessment scores was observed between those who viewed videos and those who did not. Student self-confidence scores increased significantly from baseline, but were not significantly higher for those who viewed videos than for those who did not. CONCLUSION: First-year students performed well on final aseptic compounding assessments, and those who viewed videos had a slight advantage. Student self-confidence improved over the semester regardless of whether or not students accessed review videos. PMID- 26430280 TI - Response to Letter Regarding TED Talks. PMID- 26430281 TI - Capitalizing on Foundations in Citizenship Address of the 2014-2015 President elect to the 2015 AACP House of Delegates. PMID- 26430282 TI - The Production of Inequality: The Gender Division of Labor Across the Transition to Parenthood. AB - Using longitudinal time diary and survey data from a community sample of dual earner couples across the transition to parenthood, the authors examined change in divisions of paid and unpaid work and assessed the accuracy of survey data for time use measurement. Mothers, according to the time diaries, shouldered the majority of child care and did not decrease their paid work hours. Furthermore, the gender gap was not present prebirth but emerged postbirth with women doing more than 2 hours of additional work per day compared to an additional 40 minutes for men. Moreover, the birth of a child magnified parents' overestimations of work in the survey data, and had the authors relied only on survey data, gender work inequalities would not have been apparent. The findings have important implications for (a) the state of the gender revolution among couples well positioned to obtained balanced workloads and (b) the utility of survey data to measure parents' division of labor. PMID- 26430283 TI - Phosphate Tether-Mediated Ring-Closing Metathesis for the Generation of Medium to Large, P-Stereogenic Bicyclo[n.3.1]phosphates. AB - A phosphate tether-mediated ring-closing metathesis study towards the synthesis of P-stereogenic bicyclo[6.3.1]-, bicyclo[7.3.1]-, and bicyclo[8.3.1]phosphates is reported. This study demonstrates expanded utility of phosphate tether mediated desymmetrization of C2-symmetric, 1,3-anti-diol dienes in generating complex medium to large, P-stereogenic bicyclo[n.3.1]phosphates.. PMID- 26430284 TI - Filipino-American Nurses' Knowledge, Perceptions, Beliefs and Practice of Genetics and Genomics. AB - INTRODUCTION: There is limited information on the knowledge, perceptions, beliefs, and practice, about genetics and genomics among Filipino-American nurses. The National Coalition of Ethnic Minority Organizations (NCEMNA), in which the Philippine Nurses Association of America (PNAA) is a member organization, conducted an online survey to describe the genomic knowledge, perceptions, beliefs, and practice of minority nurses. This study reports on responses from Filipino-American survey participants, which is a subset analysis of the larger NCEMNA survey. OBJECTIVE: The purpose of this study was to explore the knowledge, perceptions, beliefs, practice and genomic education of Filipino American nurses. METHOD: An online survey of 112 Filipino-American nurses was conducted to describe the knowledge, perceptions, beliefs, and practice of genetics/genomics. Survey responses were analyzed using descriptive statistics. RESULTS: Most (94%) Filipino-American nurses wanted to learn more about genetics. Although 41% of the respondents indicated good understanding of genetics of common diseases, 60% had not attended any related continuing education courses since RN licensure, and 73% reported unavailability of genetic courses to take. The majority (83%) of PNAA respondents indicated that they would attend genetics/genomics awareness training if it was offered by their national organization during their annual conference, and 86% reported that the national organization should have a visible role in genetics/genomics initiatives in their community. CONCLUSION: Filipino-American nurses wanted to learn more about genetics and were willing to attend genetics/genomics trainings if offered by PNAA. The study findings can assist PNAA in planning future educational programs that incorporates genetics and genomics information. PMID- 26430285 TI - A review of radio channel models for body centric communications. AB - The human body is an extremely challenging environment for the operation of wireless communications systems, not least because of the complex antenna-body electromagnetic interaction effects which can occur. This is further compounded by the impact of movement and the propagation characteristics of the local environment which all have an effect upon body centric communications channels. As the successful design of body area networks (BANs) and other types of body centric system is inextricably linked to a thorough understanding of these factors, the aim of this paper is to conduct a survey of the current state of the art in relation to propagation and channel models primarily for BANs but also considering other types of body centric communications. We initially discuss some of the standardization efforts performed by the Institute of Electrical and Electronics Engineers 802.15.6 task group before focusing on the two most popular types of technologies currently being considered for BANs, namely narrowband and Ultrawideband (UWB) communications. For narrowband communications the applicability of a generic path loss model is contended, before presenting some of the scenario specific models which have proven successful. The impacts of human body shadowing and small-scale fading are also presented alongside some of the most recent research into the Doppler and time dependencies of BANs. For UWB BAN communications, we again consider the path loss as well as empirical tap delay line models developed from a number of extensive channel measurement campaigns conducted by research institutions around the world. Ongoing efforts within collaborative projects such as Committee on Science and Technology Action IC1004 are also described. Finally, recent years have also seen significant developments in other areas of body centric communications such as off-body and body-to-body communications. We highlight some of the newest relevant research in these areas as well as discussing some of the advanced topics which are currently being addressed in the field of body centric communications. PMID- 26430286 TI - Comparison of two confocal micro-XRF spectrometers with different design aspects. AB - Two different confocal micro X-ray fluorescence spectrometers have been developed and installed at Osaka City University and the Vienna University of Technology Atominstitut. The Osaka City University system is a high resolution spectrometer operating in air. The Vienna University of Technology Atominstitut spectrometer has a lower spatial resolution but is optimized for light element detection and operates under vacuum condition. The performance of both spectrometers was compared. In order to characterize the spatial resolution, a set of nine specially prepared single element thin film reference samples (500 nm in thickness, Al, Ti, Cr, Fe Ni, Cu, Zr, Mo, and Au) was used. Lower limits of detection were determined using the National Institute of Standards and Technology standard reference material glass standard 1412. A paint layer sample (cultural heritage application) and paint on automotive steel samples were analyzed with both instruments. The depth profile information was acquired by scanning the sample perpendicular to the surface. (c) 2013 The Authors. X-Ray Spectrometry published by John Wiley & Sons, Ltd. PMID- 26430287 TI - Perpetrators of Alcohol-Involved Sexual Assaults: How Do They Differ From Other Sexual Assault Perpetrators and Nonperpetrators? AB - Approximately 50% of sexual assaults involve alcohol. Researchers have documented situational characteristics that distinguish between sexual assaults that do and do not involve alcohol, but little attention has been paid to differences between the perpetrators of these two types of assault. In this study, discriminant function analysis was used to distinguish between college men (N = 356) who reported perpetrating sexual assault that involved alcohol, sexual assault that did not involve alcohol, or no sexual assault. Predictors of sexual assault perpetration that have been documented in past research differentiated nonperpetrators from both types of perpetrators. Perpetrators of sexual assaults that involved alcohol were in most ways similar to perpetrators of sexual assaults that did not, although they did differ on impulsivity, alcohol consumption in sexual situations, and beliefs about alcohol. These findings suggest mechanisms through which alcohol is involved in sexual assault that are relevant to theory and prevention. PMID- 26430288 TI - Reciprocity as a Foundation of Financial Economics. AB - This paper argues that the subsistence of the fundamental theorem of contemporary financial mathematics is the ethical concept 'reciprocity'. The argument is based on identifying an equivalence between the contemporary, and ostensibly 'value neutral', Fundamental Theory of Asset Pricing with theories of mathematical probability that emerged in the seventeenth century in the context of the ethical assessment of commercial contracts in a framework of Aristotelian ethics. This observation, the main claim of the paper, is justified on the basis of results from the Ultimatum Game and is analysed within a framework of Pragmatic philosophy. The analysis leads to the explanatory hypothesis that markets are centres of communicative action with reciprocity as a rule of discourse. The purpose of the paper is to reorientate financial economics to emphasise the objectives of cooperation and social cohesion and to this end, we offer specific policy advice. PMID- 26430289 TI - Early Language and Reading Development of Bilingual Preschoolers From Low-Income Families. AB - Learning to read is a complex process and a number of factors affect a child's success in beginning reading. This complexity increases when a child's home language differs from that of the school and when the child comes from a home with limited economic resources. This article discusses factors that have been shown to contribute to children's success in early reading, namely-phonological awareness, letter-word identification, oral language, and the home literacy environment. Preliminary evidence suggests that bilingual children from low income backgrounds initially perform poorly on phonological awareness and letter identification tasks, but appear to acquire these abilities quickly in kindergarten once these abilities are emphasized in early reading instruction. In addition, the findings show that bilingual preschoolers' receptive language abilities in English and Spanish positively impact their early letter-word identification abilities at the end of kindergarten. A positive relationship between bilingual preschoolers' home literacy environment and early reading outcomes has not been found to date. Educational implications for serving young, bilingual children from programs such as Head Start are discussed. PMID- 26430290 TI - A Real-Time Skin Dose Tracking System for Biplane Neuro-Interventional Procedures. AB - A biplane dose-tracking system (Biplane-DTS) that provides a real-time display of the skin-dose distribution on a 3D-patient graphic during neuro-interventional fluoroscopic procedures was developed. Biplane-DTS calculates patient skin dose using geometry and exposure information for the two gantries of the imaging system acquired from the digital system bus. The dose is calculated for individual points on the patient graphic surface for each exposure pulse and cumulative dose for both x-ray tubes is displayed as color maps on a split screen showing frontal and lateral projections of a 3D-humanoid graphic. Overall peak skin dose (PSD), FOV-PSD and current dose rates for the two gantries are also displayed. Biplane-DTS uses calibration files of mR/mAs for the frontal and lateral tubes measured with and without the table in the beam at the entrance surface of a 20 cm thick PMMA phantom placed 15 cm tube-side of the isocenter. For neuro-imaging, conversion factors are applied as a function of entrance field area to scale the calculated dose to that measured with a Phantom Laboratory head phantom which contains a human skull to account for differences in backscatter between PMMA and the human head. The software incorporates inverse-square correction to each point on the skin and corrects for angulation of the beam through the table. Dose calculated by Biplane DTS and values measured by a 6-cc ionization chamber placed on the head phantom at multiple points agree within a range of -3% to +7% with a standard deviation for all points of less than 3%. PMID- 26430291 TI - Estimating ROI activity concentration with photon-processing and photon-counting SPECT imaging systems. AB - Recently a new class of imaging systems, referred to as photon-processing (PP) systems, are being developed that uses real-time maximum-likelihood (ML) methods to estimate multiple attributes per detected photon and store these attributes in a list format. PP systems could have a number of potential advantages compared to systems that bin photons based on attributes such as energy, projection angle, and position, referred to as photon-counting (PC) systems. For example, PP systems do not suffer from binning-related information loss and provide the potential to extract information from attributes such as energy deposited by the detected photon. To quantify the effects of this advantage on task performance, objective evaluation studies are required. We performed this study in the context of quantitative 2-dimensional single-photon emission computed tomography (SPECT) imaging with the end task of estimating the mean activity concentration within a region of interest (ROI). We first theoretically outline the effect of null space on estimating the mean activity concentration, and argue that due to this effect, PP systems could have better estimation performance compared to PC systems with noise-free data. To evaluate the performance of PP and PC systems with noisy data, we developed a singular value decomposition (SVD)-based analytic method to estimate the activity concentration from PP systems. Using simulations, we studied the accuracy and precision of this technique in estimating the activity concentration. We used this framework to objectively compare PP and PC systems on the activity concentration estimation task. We investigated the effects of varying the size of the ROI and varying the number of bins for the attribute corresponding to the angular orientation of the detector in a continuously rotating SPECT system. The results indicate that in several cases, PP systems offer improved estimation performance compared to PC systems. PMID- 26430292 TI - Objective evaluation of reconstruction methods for quantitative SPECT imaging in the absence of ground truth. AB - Quantitative single-photon emission computed tomography (SPECT) imaging is emerging as an important tool in clinical studies and biomedical research. There is thus a need for optimization and evaluation of systems and algorithms that are being developed for quantitative SPECT imaging. An appropriate objective method to evaluate these systems is by comparing their performance in the end task that is required in quantitative SPECT imaging, such as estimating the mean activity concentration in a volume of interest (VOI) in a patient image. This objective evaluation can be performed if the true value of the estimated parameter is known, i.e. we have a gold standard. However, very rarely is this gold standard known in human studies. Thus, no-gold-standard techniques to optimize and evaluate systems and algorithms in the absence of gold standard are required. In this work, we developed a no-gold-standard technique to objectively evaluate reconstruction methods used in quantitative SPECT when the parameter to be estimated is the mean activity concentration in a VOI. We studied the performance of the technique with realistic simulated image data generated from an object database consisting of five phantom anatomies with all possible combinations of five sets of organ uptakes, where each anatomy consisted of eight different organ VOIs. Results indicate that the method provided accurate ranking of the reconstruction methods. We also demonstrated the application of consistency checks to test the no-gold-standard output. PMID- 26430293 TI - Application of Regulatory Focus Theory to Search Advertising. AB - PURPOSE: The purpose of this paper is to test the utility of regulatory focus theory principles in a real-world setting; specifically, Internet hosted text advertisements. Effect of compatibility of the ad text with the regulatory focus of the consumer was examined. DESIGN/METHODOLOGY/APPROACH: Advertisements were created using Google AdWords. Data were collected for the number of views and clicks each ad received. Effect of regulatory fit was measured using logistic regression. FINDINGS: Logistic regression analyses demonstrated that there was a strong main effect for keyword, such that users were almost six times as likely to click on a promotion advertisement as a prevention advertisement, as well as a main effect for compatibility, such that users were twice as likely to click on an advertisement with content that was consistent with their keyword. Finally, there was a strong interaction of these two variables, such that the effect of consistent advertisements was stronger for promotion searches than for prevention searches. RESEARCH LIMITATIONS/IMPLICATIONS: The effect of ad compatibility had medium to large effect sizes, suggesting that individuals' state may have more influence on advertising response than do individuals' traits (e.g. personality traits). Measurement of regulatory fit was limited by the constraints of Google AdWords. PRACTICAL IMPLICATIONS: The results of this study provide a possible framework for ad creation for Internet advertisers. ORIGINALITY/VALUE: This paper is the first study to demonstrate the utility of regulatory focus theory in online advertising. PMID- 26430294 TI - Uncertain future, non-numeric preferences, and the fertility transition: A case study of rural Mozambique. AB - In many high-fertility countries, and especially in sub-Saharan Africa, substantial proportions of women give non-numeric responses when asked about desired family size. Demographic transition theory has interpreted responses of "don't know" or "up to God" as evidence of fatalistic attitudes toward childbearing. Alternatively, these responses can be understood as meaningful reactions to uncertainty about the future. Following this latter approach, we use data from rural Mozambique to test the hypothesis that non-numeric responses are more common when uncertainty about the future is greater. We expand on previous research linking child mortality and non-numeric fertility preferences by testing the predictive power of economic conditions, marital instability, and adult mortality. Results show that uncertainty related to adult and child mortality and to economic conditions predicts non-numeric responses, while marital stability is less strongly related. PMID- 26430295 TI - Challenges of a healthy lifestyle for socially disadvantaged people of Dutch, Moroccan and Turkish origin in the Netherlands: a focus group study. AB - Lifestyle interventions often fail to successfully reach individuals with lower socio-economic status (SES), possibly because of the individual behavioural orientation to health behaviour and because limited research has included the target groups' perspectives in the development of interventions. Certainly, in order to make lifestyle interventions more applicable, target groups' viewpoints should to be taken into account. In order to tailor an effective lifestyle intervention to groups with lower SES of different ethnic origins, 14 focus group interviews were conducted with Turkish, Moroccan and Dutch male and female groups. The target groups' responses highlight their viewpoint and their dilemmas with regard to physical activity behaviour and healthy eating. Exploration of the target groups' behaviour in terms of their own logic revealed three prominent themes. Firstly, some individuals find it difficult to maintain healthy eating habits and regular physical activities, as their concept of a healthy life comprises competing values and activities. Secondly, social norms and social practices of others influence health behaviour. Thirdly, respondents' answers reflect how they deal with the dilemma of competing values and norms. They use different ways of reasoning to make sense of their own (health) behaviour. Taken together, the results of this study suggest that considering physical activity and eating as collective social practices rather than as determinants of health will provide new opportunities to initiate healthy lifestyles and to make lifestyle interventions more applicable to target groups' realities. PMID- 26430296 TI - Shear bond strength of computer-aided design and computer-aided manufacturing feldspathic and nano resin ceramics blocks cemented with three different generations of resin cement. AB - AIM: To evaluate the shear bond strength between the dentin substrate and computer-aided design and computer-aided manufacturing feldspathic ceramic and nano resin ceramics blocks cemented with resin cement. MATERIALS AND METHODS: Sixty cuboidal blocks (5 mm * 5 mm * 5 mm) were fabricated in equal numbers from feldspathic ceramic CEREC((r)) Blocs PC and nano resin ceramic LavaTM Ultimate, and randomly divided into six groups (n = 10). Each block was cemented to the dentin of 60 extracted human premolar using Variolink((r)) II/Syntac Classic (multi-steps etch-and-rinse adhesive bonding), NX3 Nexus((r)) (two-steps etch-and rinse adhesive bonding) and RelyXTM U200 self-adhesive cement. All specimens were thermocycled, and shear bond strength testing was done using the universal testing machine at a crosshead speed of 1.0 mm/min. Data were analyzed using one way ANOVA. RESULTS: Combination of CEREC((r)) Blocs PC and Variolink((r)) II showed the highest mean shear bond strength (8.71 Mpa), while the lowest of 2.06 Mpa were observed in LavaTM Ultimate and RelyXTM U200. There was no significant difference in the mean shear bond strength between different blocks. CONCLUSION: Variolink((r)) II cement using multi-steps etch-and-rinse adhesive bonding provided a higher shear bond strength than the self-adhesive cement RelyX U200. The shear bond strength was not affected by the type of blocks used. PMID- 26430297 TI - Effect of bromelain enzyme for dentin deproteinization on bond strength of adhesive system. AB - AIMS: To assess the deproteinizing effect of bromelain enzyme and compare it with 5% sodium hypochlorite (NaOCl) on shear bond strength before application of the adhesive system. MATERIALS AND METHODS: A total of 30 extracted human premolars were divided into three groups, each one consisted of 10 teeth. The occlusal surface was wet ground to expose superficial dentin. In Group 1, teeth were etched; in Group 2, teeth were etched and deproteinized with bromelain enzyme; in Group 3, teeth were etched and deproteinized with 5% NaOCl. Upon completion of the adhesive procedures, resin composite was inserted into the plastic tube and light-polymerized. All specimens were stored at 37 degrees C in water for 24 h, and the specimens were transferred to the universal testing machine, and then subjected to shear bond strength analysis at a crosshead speed of 1.0 mm/min. STATISTICAL ANALYSIS USED: Data were statistically analyzed using one-way analysis of variance and unpaired t-test at a significance level of 0.05. The statistical analysis was performed using SPSS version 12.0.1 for Windows (SPSS Inc., Chicago, IL, USA). RESULTS: The bond strength results were significantly influenced by the application of bromelain enzyme. Statistically significant differences were not demonstrated in control group and NaOCl-treated group. The highest bond strength was seen in bromelain enzyme-treated group. CONCLUSIONS: Within the limitations of the present study, it was concluded that removal of unsupported collagen fiber with bromelain enzyme after acid etching results in improved bond strength. PMID- 26430298 TI - Comparative clinical evaluation of the efficacy of a new method for caries diagnosis and excavation. AB - AIM: The purpose of this study is to compare the efficiency of fluorescence-aided caries excavation (FACE) to remove carious dentin primary teeth with that of conventional methods. METHODS AND MATERIALS: After caries excavation was carried out, dentin surfaces were conventionally inspected using visual tactile criteria and 415 cavities which were classified as caries-free, re-inspected with Face Light and caries detector dye (CDD) methods. Orange-red fluorescing areas classified as carious dentin, as well as stained carious dentin. All the data were recorded according to localization of the caries and determination efficiency of the methods. X(2) test was used to compare the mean values of both Face-Light and dye applications, while Wilcoxon test performed to evaluate the effectiveness for each diagnostic method. RESULTS: A total of 273 patients with 415 Class II (OM/OD) cavities (1.65 +/- 0.52 teeth per patient) with carious lesions in molar and premolar teeth, were examined. Out of 415 teeth, in 149 teeth (35.9%) no caries findings had been illustrated. While FACE detected remaining carious or partially removed areas in 237 teeth (57.2%), CDD stained only 29 teeth by itself (P < 0.05). CONCLUSION: In conclusion, FACE has a higher detectability compared to visual inspection and caries detector dye in diagnosis and removal of carious dentin. PMID- 26430299 TI - Comparative evaluation of microshear bond strength of the caries-affected dentinal surface treated with conventional method and chemomechanical method (papain). AB - BACKGROUND: There is a growing interest in chemomechanical excavation (papain) in permanent molar teeth. There are several studies dealing with primary molar teeth. AIM: The aim of this study was to evaluate the influence of conventional method and Carie-care (chemomechanical method) on the microshear bond strength (MUSBS) and the type of failure of an adhesive system to caries-affected dentin of permanent molar teeth. MATERIALS AND METHODS: Twenty permanent molar teeth with carious lesions extending into the dentin were selected. Through the center of the carious lesion, teeth were sectioned mesiodistally and divided into two groups based on the method of caries excavation (conventional and chemomechanical method). The time required for the completion of excavation procedure was noted. Samples were again divided into two subgroups in each according to the method of restoration (Ketac N100 and Filtek Z350 composite). The bonded interface was subjected to MUSBS testing in a universal testing machine. Fractured surfaces were examined under a stereomicroscope, and representative specimens were examined under scanning electron microscope for the type of failure. STATISTICAL ANALYSIS: It was achieved with unpaired t-test and Kruskal-Wallis H-test at 5% level of significance. RESULTS: The MUSBS values of Carie-care groups were similar to that of the conventional method. The MUSBSs of resin composite were significantly (P < 0.001) more than that of resin glass ionomer bonded irrespective of the method of caries excavation. CONCLUSION: A papain-based chemomechanical agent can be used safely as a method for caries removal when employing conventional adhesive systems. PMID- 26430300 TI - Smear layer removal efficacy of combination of herbal extracts in two different ratios either alone or supplemented with sonic agitation: An in vitro scanning electron microscope study. AB - OBJECTIVES: The study aimed to evaluate the effectiveness of the combination of two natural extracts in varying ratios for removal of smear layer either alone or supplemented with sonic agitation. MATERIALS AND METHODS: Fifty extracted single rooted teeth were collected, disinfected and decoronated below the cementoenamel junction to obtain standardized root length of 10 mm. Root canals were instrumented using rotary files at working length 1 mm short of the apex. Specimens were divided into six groups according to the irrigation protocol as follows: Group A - Distilled water, Group B - 17% ethylenediaminetetraacetic acid, Group C - Herbal extracts in 1:1 ratio, Group D - Herbal extracts in 1:1 ratio supplemented with sonic agitation, Group E - Herbal extracts in 2:1 ratio, Group F - Herbal extracts in 2:1 ratio supplemented with sonic agitation. Specimens were longitudinally sectioned and evaluated under scanning electron microscope for smear layer removal efficacy. Obtained scores were statistically analyzed using one-way analysis of variance and post-hoc test. RESULTS: Among all, Group B showed the best results followed by Group F. Remaining other groups showed inferior outcome (P < 0.05). CONCLUSION: The combination of two extracts in 2:1 ratio was slightly better than 1:1 ratio and the smear layer removal efficacy was further improved when accompanied with sonic agitation. PMID- 26430301 TI - Micro-tensile bond strength of different adhesive systems on sound dentin and resin-based composite: An in-vitro study. AB - AIM: To analyze the difference in the micro-tensile bond strength of specimens made with two different adhesive systems and compare them with two homogenous substrates. MATERIALS AND METHODS: Sixty permanent mandibular molars were mounted in acrylic blocks and sectioned with exposed dentin surfaces. Samples were then divided into four groups. To Group-I Adper Single Bond 2 and to Group-II Adper Self-Etch plus bonding agents were applied. For Group-I and Group-II beams consisted of resin composite in the upper half and dentin in the lower half. In Group-III beams were made of only dentin. In Group-IV beams were made of only composite. Fifteen specimens of each group were taken for the micro-tensile bond strength test. STATISTICAL ANALYSIS: The results are analyzed using one-way analysis of variance and Critical Difference test. RESULTS: The interface bonded with the two adhesive systems had lower micro-tensile bond strength than those of dentin and resin composite and the self-etching adhesive Adper Self-Etch plus had comparable bond strength with total-etch adhesive Adper Single Bond 2. CONCLUSION: The bond strength values for current adhesive systems cannot be compared to the micro-tensile bond strength of dentin and resin composite, and self-etching adhesives have comparable bond strength with total-etch adhesives. PMID- 26430302 TI - Shrinkage, stress, and modulus of dimethacrylate, ormocer, and silorane composites. AB - PURPOSE: to evaluate the shrinkage, polymerization stress, elastic and bulk modulus resulting from composites formulated by siloranes, 2(nd) generation ormocers, and dimethacrylates. MATERIALS AND METHODS: The bonded disc method was used to evaluate volumetric shrinkage. The polymerization stress was evaluated by mean of the Bioman. Cylindrical specimens (5 mm thickness and 6 mm diameter) were submitted to gradual loading. Young's and bulk modulus were obtained from the slope of the stress/strain curve. Data were analyzed using one-way analysis of variance and Tukey's test (5%). RESULTS: Grandio and ormocer showed significant higher elastic and bulk modulus. Silorane presented significant lowest bulk modulus and maximum shrinkage. Ormocer and silorane presented lower values for the maximum rate of shrinkage. Extra-low shrinkage (ELS) composite presented the greatest maximum shrinkage. The higher maximum rate of shrinkage was attained by Grandio and ELS, statistically similar from each other. The silorane showed lower values of maximum stress and maximum rate of stress. The higher values of maximum stress were presented by ELS and Grandio, statistical similar between them. Grandio showed the significantly greatest maximum rate of stress. CONCLUSION: Silorane showed to promote lower shrinkage/stress among the composites, with the lowest elastic modulus. Ormocer showed lower shrinkage/stress than methacrylates despite of its high modulus. PMID- 26430303 TI - Comparison of efficacy of three different desensitizing agents for in-office relief of dentin hypersensitivity: A 4 weeks clinical study. AB - AIM: To evaluate the effectiveness of three different pastes containing 5% NovaMin, 8% arginine, and 15% hydroxyapatite nanoparticles (n-HA) respectively in the treatment of dentin hypersensitivity (DH). MATERIALS AND METHODS: A 4 weeks study was conducted on 45 adult patients with cervical abrasions leading to hypersensitivity of two or more teeth anterior to molars. Patients were divided into three toothpaste groups. Group I: 5% NovaMin, Group II: 8% arginine, Group III: 15% n-HA. Sensitivity was assessed at baseline, immediately after application and after 1-week and 4 weeks. Tactile stimuli response using a visual analog scale and standard cold air blast using Schiff cold air sensitivity scale were used to compare the efficacies of toothpastes after a single application. STATISTICAL ANALYSIS: Two-way analysis of variance and post-hoc Tukey test were used and P <= 0.05 was considered statistically significant. RESULTS: Visual analog scale analysis: Group III and Group II showed statistically significant reduction in DH at all-time intervals when compared with Group I. In SCA analysis there is no statistically significant difference between Group II and Group III immediately after application. CONCLUSION: Toothpaste containing 15% n-HA was found to be most effective in reduction of DH after a single application up to a period of 4 weeks followed by 8% arginine and 5% NovaMin toothpastes. PMID- 26430304 TI - Influence of translucence/opacity and shade in the flexural strength of lithium disilicate ceramics. AB - BACKGROUND: Lithium disilicate ceramic system consists of glass ceramic ingots with different grades of translucence which may influence its flexural strength. AIMS: To assess the three-point flexural strength of the different lithium disilicate-based ceramic ingots (IPS e.max Press/Ivoclar Vivadent) with different levels of translucence and shade. MATERIALS AND METHODS: Six groups of ceramic ingots were selected to represent different levels of translucence and shade (HTA1, HTBL2, LTA2, LTB2, MO2, and HO). They measured 25 mm * 5 mm * 2 mm (n = 10), according to ISO 6872 specifications, and tested on a universal test machine (EMIC). STATISTICAL ANALYSIS USED: A one-way analysis of variance (ANOVA) was used (alpha = 0.05). RESULTS: The results (in MPa) were: HTA1 = 392.98; HTBL2 = 390.74; LTA2 = 390.46; LTB2 = 389.92; MO2 = 390.43; HO = 391.96. ANOVA showed no significant difference among groups (P = 0.1528). CONCLUSIONS: Different levels of translucence, opacity and shade of ingots did not affect their mechanical strength, and the use of these ceramics should be guided by the esthetic demands of each clinical situation. PMID- 26430305 TI - An ex-vivo comparative study of root-end marginal adaptation using grey mineral trioxide aggregate, white mineral trioxide aggregate, and Portland cement under scanning electron microscopy. AB - CONTEXT: Where nonsurgical endodontic intervention is not possible, or it will not solve the problem, surgical endodontic treatment must be considered. A major cause of surgical endodontic failures is an inadequate apical seal, so the use of the suitable substance as root-end filling material that prevents egress of potential contaminants into periapical tissue is very critical. AIMS: The aim of the present ex-vivo study was to compare and evaluate the three root-end filling materials of mineral trioxide aggregate (MTA) family (white MTA [WMTA], grey MTA [GMTA] and Portland cement [PC]) for their marginal adaptation at the root-end dentinal wall using scanning electron microscopy (SEM). MATERIALS AND METHODS: Sixty human single-rooted teeth were decoronated, instrumented, and obturated with Gutta-percha. After the root-end resection and apical cavity preparation, the teeth were randomly divided into three-experimental groups (each containing 20 teeth) and each group was filled with their respective experimental materials. After longitudinal sectioning of root, SEM examination was done to determine the overall gap between retrograde materials and cavity walls in terms of length and width of the gap (maximum) at the interface. Descriptive statistical analysis was performed to calculate the means with corresponding standard errors, median and ranges along with an analysis of variance and Tukey's test. RESULTS: The least overall gap was observed in GMTA followed by PC and WMTA. While after statistically analyzing the various data obtained from different groups, there was no significant difference among these three groups in terms of marginal adaptation. CONCLUSION: GMTA showed the best overall adaptation to root dentinal wall compared to PC and WMTA. Being biocompatible and cheaper, the PC may be an alternative but not a substitute for MTA. PMID- 26430306 TI - Apical extrusion of debris and irrigants using ProTaper hand, M-two rotary and WaveOne single file reciprocating system: An ex vivo study. AB - AIMS: The purpose of this ex vivo study was to evaluate and compare the weight of debris and volume of irrigant extruded apically from teeth using different preparation techniques. SUBJECTS AND METHODS: Thirty extracted human mandibular premolars with single canals and similar lengths were instrumented using hand ProTaper F2 (25, 0.08; Dentsply Maillefer, Ballaigues, Switzerland), M-two (25, 0.06; VDW, Munich, Germany) and WaveOne Primary (25, 0.08; Dentsply Maillefer, Ballaigues, Switzerland). Debris and irrigant extruded during instrumentation were collected into preweighed Eppendorf tubes. The volume of the irrigant was measured, and then the tubes were stored in an incubator at 70 degrees C for 2 days. The Eppendorf tubes were weighed to obtain the final weight when the extruded debris was included. Three consecutive weights were obtained for each tube. STATISTICAL ANALYSIS USED: Data were statistically analyzed by one-way analysis of variance and Student's t-test. RESULTS: There were no statistically significant differences among the groups. The WaveOne reciprocating system showed the maximum amount of apical extrusion of debris and irrigant among all the groups. The least amount of debris and irrigant was observed in ProTaper hand instrument (P > 0.05). CONCLUSION: All instrumentation techniques were associated with debris and irrigant extrusion. PMID- 26430307 TI - Comparing marginal microleakage of three Bulk Fill composites in Class II cavities using confocal microscope: An in vitro study. AB - AIM: This study aims to evaluate and compare microleakage at the occlusal wall and cervical wall in Class II cavities restored with one SonicFill Bulk Fill composite and two conventional Bulk Fill composites. MATERIALS AND METHODS: Thirty freshly extracted teeth were divided into three groups of 10 teeth each. Standardized Class II cavities were made on the mesial and distal surfaces of each tooth and restored using SonicFill Bulk Fill composite and two conventional Bulk Fill composites, Tetric Evo Ceram, and X-tra fil. After storage, thermocycling and immersion in 0.6% rhodamine dye solution specimens were sectioned and evaluated for microleakage at the occlusal and cervical walls using confocal microscope. STATISTICAL ANALYSIS USED: Kruskal-Wallis test, Wilcoxon Signed-Rank test and Mann-Whitney U-test. RESULTS: The results demonstrated that in the occlusal wall and cervical wall, SonicFill Bulk Fill composite, showed significantly less marginal microleakage than the other groups. CONCLUSION: Based on the results of this study, SonicFill Bulk Fill composite showed less microleakage than the other conventional Bulk Fill composites. PMID- 26430308 TI - Effect of intracanal medicaments on push-out bond strength of Smart-Seal system. AB - AIM: To evaluate the effects of calcium hydroxide (CH), triple and double antibiotic pastes (DAPs) on the bond strength of Smart-Seal obturation, C-points with Endosequence Bio-ceramic (BC) sealer to the root canal dentin. MATERIALS AND METHODS: Sixty-four freshly extracted single-rooted human mandibular premolars were de-coronated and prepared using rotary Pro-taper system with full sequence till F3. The specimens were randomly divided into a control group (without intracanal dressing) and 3 experimental groups that received an intracanal dressing with either CH, DAP, or triple antibiotic paste (TAP) (n = 16). The intracanal dressing was removed after 3 weeks by rinsing with 10 mL 17% ethylenediaminetetraacetic acid, followed by 10 mL 3% sodium hypochlorite. The root canals were then obturated with C-points and Endosequence BC sealer. A push out test was used to measure the bond strength between the root canal dentin and the obturating system. The data were analyzed using two-way analysis of variance and Tukey post-hoc test. RESULTS: The push-out bond strength values were significantly affected by the intracanal medicaments (P < 0.001), but not by the root canal thirds (P > 0.05). In the middle and apical third, the bond strength of the TAP group was higher than those of the CH and DAP groups (P < 0.05). CONCLUSIONS: The DAP and CH did not affect the bond strength of the novel hydrophilic obutrating system. TAP improved the bond strength of Smart-Seal system in the middle and apical thirds. PMID- 26430309 TI - Endodontic management of a mandibular first molar with six root canal systems. AB - Internal anatomy of pulp is complex. The first mandibular molars typically have two roots, one mesial with two root canals and another distal root, which contains one or two canals. A 20-year-old female patient reported with intermittent pain and incomplete root canal treatment in left lower back region since 1-week. Refined access cavity revealed initially two canals in mesial and two canals in the distal root. With operating microscope and cone beam computerized tomography, two additional canals (L-mesio-buccal and B-mesio lingual) were identified in mesial root. One-year follow-up showed patient was asymptomatic and complete healing of periapical radiolucency. PMID- 26430310 TI - Resurrecting an unsalvageable lower incisor with a mono-block approach. AB - Contemporary techniques, as well as the availability of bioactive and adhesive materials in endodontics, have helped revivifying teeth that were deemed hopeless. These newer materials and techniques would enable the clinician: (a) to predictably stop microbial activity (b) to achieve a total corono-apical fluid tight seal and (c) to strengthen mutilated teeth by obtaining intra-radicular reinforcement through mono-block effect. This case report demonstrates the successful treatment of a mutilated anterior tooth with the use of bioactive and adhesive materials to obtain a total seal and mono-block effect. This article also shows the use of a simple method in the placement of root filling cement into the root canal. PMID- 26430312 TI - Standardization of "In-House fatty meal" methodology for cholescintigraphy. AB - AIM: This study was aimed at standardizing the "In-House fatty meal" methodology in cholescintigraphy and to determine gall bladder ejection fraction (GBEF) with this standardized meal. MATERIALS AND METHODS: This is a prospective case-control study where 61 patients having right upper quadrant pain and postprandial bloating and 59 healthy volunteers were included. They underwent (99m)Tc mebrofenin fatty meal cholescintigraphy following a standard protocol. Dynamic acquisitions over 120 min were done, with a fatty meal being given between 45- and 60-min. Gallbladder emptying kinetics was studied by assessing the time activity curves and calculation of GBEFs were made at 30-min, 45-min, and at 60 min and assessed. RESULTS: The GBEF at 30-min was 74.42% +/- 8.26% (mean +/- standard deviation), at 45-min was 82.61% +/- 6.5%, and at 60-min was 89.37% +/- 4.48% in the volunteer group. The lower limit of GBEF in volunteers at 30-min was 58%, 45-min was 69%, and at 60-min was 81%. Receiver operating characteristic (ROC) analysis showed that 30-min GBEF provided the best separation between healthy and diseased subjects with an area under curve of 0.952 (95% confidence interval = 0.914-0.989). The lower limit of GBEF at 30-min was 58%. CONCLUSIONS: An in-House standard fatty meal could be a reproducible alternative to cholecystokinin as it is well-tolerated. Based on ROC curve analysis, we propose that 30-min GBEF provides good separation between healthy and diseased people with this in-House fatty meal. Hence, dynamic acquisitions beyond 30-min postingestion of the fatty meal may not be warranted. PMID- 26430311 TI - Dimercaptosuccinic acid: A multifunctional cost effective agent for imaging and therapy. AB - Dimercaptosuccinic acid (DMSA) is an analog of dimercaprol used as metal chelating moiety in variety of conditions. In nuclear medicine itself two types of Tc-99m DMSA complexes are used, trivalent and pentavalent forms. In this review, we have discussed the mechanism of uptake of both complexes as well as diagnostic and therapeutic application in a clinical scenario. PMID- 26430313 TI - Predictive value of pyramidal lobe, percentage thyroid uptake and age for ablation outcome after 15 mCi fixed dose of radioiodine-131 in Graves' disease. AB - PURPOSE: The purpose was to find out the efficacy of fixed 15 mCi radioactive iodine-131 (RAI) dose and predictive values of various factors for inducing hypothyroidism in Graves' disease (GD). MATERIALS AND METHODS: Retrospective study conducted from January 2012 till August 2014. Patients with GD who had a technetium-99m thyroid scan, thyroid antibodies, received fixed 15 mCi RAI and did follow endocrine clinics for at least 6 months were selected. RAI was considered successful if within 6 months of RAI therapy patients developed hypothyroidism. RESULTS: Of the 370 patients with GD who had RAI during study period, 210 (57%) qualified study criteria. Mean age of patients was 48 +/- 15 years with female: male ratio of 69:31, positive thyroid antibodies in 61%, means thyroid uptake of 15.09 +/- 11.23%, and presence of pyramidal lobe in 40% of total population. Hypothyroidism was achieved in 161 (77%) patients while 49 (23%) patients failed to achieve it (remained either hyperthyroid or euthyroid on antithyroid medication). Patients who became hypothyroid were significantly younger with higher proportion of presence of thyroid antibodies and pyramidal lobe and lower percentage thyroid uptake than those who failed. Multiple logistic regression analysis revealed that age (odds ratio; OR = 2.074), pyramidal lobe (OR = 3.317), thyroid antibodies (OR = 8.198), and percentage thyroid uptake (OR = 3.043) were found to be significant prognostic risk factors for post-RAI hypothyroidism. Gender was found to have nonsignificant association with the development of hypothyroidism. Receiver operating characteristic analysis revealed age <42 years and thyroid uptake <15% as threshold values for the development of post-RAI hypothyroidism. CONCLUSION: We conclude that fixed (15 mCi) RAI dose is highly effective in rendering hypothyroidism in patients with GD. Age (<=42 years), thyroid uptake (<=15%) and presence of pyramidal lobe are strong predictors of hypothyroidism and must be considered for selecting optimal RAI dose. PMID- 26430314 TI - Dual time point fluorodeoxyglucose positron emission tomography/computed tomography in differentiation between malignant and benign lesions in cancer patients. Does it always work? AB - OBJECTIVES: Assess the added value of dual time point F-18-fluorodeoxyglucose positron emission tomography/computed tomography (DTP F-18-FDG-PET/CT) in the differentiation of malignant from a benign lesion in cancer patients. MATERIALS AND METHODS: Totally, 140 F-18-FDG PET/CT scans of 60 cancer patients who underwent DTP protocol (early whole body PET/CT [E] at 60 min [range, 45-76 min] and delayed limited PET/CT [D] on areas of interest at 120 min [range, 108-153 min] after the tracer injection) were retrospectively reviewed. Visual and semi quantitative analysis was performed on both early and delayed images. All findings were confirmed by histopathology and/or at least 3 months follow-up (F 18-FDG PET/CT, CT, or magnetic resonance imaging). The result was considered true positive (TP) if delayed standardized uptake value (SUV) of suspicious lesions increased and confirmed to be malignant, false positive (FP) if delayed SUV increased and confirmed to be benign, true negative (TN) if delayed SUV unchanged or decreased and confirmed to be benign, and false negative (FN) if delayed SUV unchanged or decreased and confirmed to be malignant. RESULTS: A total of 164 suspicious lesions were detected (20 presacral lesions, 18 lung nodules, 18 Hodgkin's disease (HD) lesions, 16 rectal lesions, 16 head and neck (H and N) lesions, 14 hepatic lesions, 14 non-Hodgkin's lymphoma (NHL) lesions, 12 mediastinal lymph nodes (LNs), 10 focal gastric uptake, 10 soft tissue lesions, 8 breast lesions, 4 peritoneal nodule, and 4 others). Sixty-four lesions were pathologically confirmed, and 100 lesions were confirmed based on 3-6 months follow-up. There were 62 TP lesions, 44 FP, 58 TN and no FN results. The overall sensitivity was 100% of DTP F-18-FDG PET/CT in detecting suspicious lesions. The specificity was 57% in differentiating malignant from benign lesions, and the accuracy was 73%. Positive predictive value was 59%, negative predictive value (NPV) 100%. All hepatic lesions were TP. Accuracy in metastatic hepatic lesions HD, presacral soft tissue, lung nodules, H, and N cancer, breast cancer, NHL and mediastinal LN was100%, 88.8%, 80%, 78%, 75%, 75%, 71%, and 33.3%, respectively. CONCLUSIONS: DTP F-18-FDG-PET/CT protocol does not always work in differentiation between benign and malignant lesions. However; it has high NPV, and promising results was noted in hepatic lesions, lymphoma, and recurrent rectal cancer. PMID- 26430315 TI - Patterns of brown fat uptake of 18F-fluorodeoxyglucose in positron emission tomography/computed tomography scan. AB - Fluorodeoxyglucose (FDG) positron emission tomography (PET) has become the common imaging modality in oncological practice. FDG uptake is seen in brown adipose tissue in a significant number of patients. Recognizing the uptake patterns is important for optimal FDG PET interpretation. The introduction of PET/computed tomography (PET/CT) revolutionized PET imaging, bringing much-needed anatomical information. Careful review and correlation of FDG PET images with anatomical imaging should be performed to characterize accurately any lesion having high FDG uptake. PMID- 26430316 TI - Pictorial essay of developmental thyroid anomalies identified by Technetium thyroid scintigraphy. AB - Developmental anomalies and anatomic variations of the thyroid gland in the general population with no known thyroid dysfunction usually goes unnoticed. Only those patients with neck swellings, incidentally detected hypo or hyperthyroidism, and those with a maternal history of hypothyroidism undergo screening for the thyroid gland. Neck ultrasound and scintigraphic techniques are the imaging tools routinely used to identify these anomalies. We present interesting technetium (Pertechnetate and sestaMIBI) scintigraphic images of adults and children who presented to our department with thyroid dysfunction showing developmental anomalies of the thyroid. PMID- 26430317 TI - 18F-fluorodeoxyglucose positron emission tomography/computed tomography for primary thyroid langerhans histiocytosis: A case report and literature review. AB - Langerhans cell histiocytosis (LCH) is a rare clonal proliferative disease, with an incidence rate of 4.0-5.4/1 million individuals. LCH encompasses a spectrum of disorders with diverse clinical presentations ranging from a single organ to multiple organ involvement. LCH rarely involves the thyroid gland. We presented a case with LCH of thyroid gland. The patient had painless progressive neck enlargement and then diabetes insipidus. Ultrasonic scan and magnetic resonance imaging scan revealed nodular goiter and pituitary stalk enlargement, respectively. Histopathological analysis revealed features of histiocytoid cells. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) was performed in order to rule out the presence of whole body infiltration. 18F-FDG PET/CT also demonstrated increased uptake in the thickening pituitary stalk and maxillofacial skin lesion, in addition to the bilateral thyroid nodules, CT showed the left lung nodule and the skull destruction without 18F-FDG uptake. This report emphasizes the role of 18F-FDG PET/CT in multiple organs involvement of patients with LCH. PMID- 26430319 TI - Malignant chondroid syringoma of the pinna. AB - Chondroid syringoma (CS) represents the cutaneous counterpart of mixed tumor (pleomorphic adenoma) of salivary glands. The malignant counterpart of CS, termed as "malignant CS" is a malignant eccrine neoplasm which lacks distinctive clinical features, often delaying initial diagnosis. Unlike its benign counterpart which often localizes in the head and neck region, malignant CS most often encountered in the trunk and the extremities. We report a rare case of an aggressive malignant CS of the left pinna with cervical lymph node metastasis. Our patient, to the best of our knowledge, possibly is the first case of malignant CS of the pinna and the fourth to arise in the head and neck region. The diagnostic challenges with an added emphasis on the role of positron emission tomography-computed tomography in aiding the management of this rare tumor are discussed. PMID- 26430318 TI - A rare tumor with unusual clinical presentation detected by positron emission tomography-computed tomography. AB - Primary hepatic lymphoma represents <1% of extranodal lymphoma and predominantly seen in men older than 50 years of age. Exact etiology for these tumors is not certain yet, but presumed to be caused by certain viruses like Epstein-Barr virus and hepatitis C virus due to the frequent association of these viruses with disease. Most of these tumors are diffuse large B cell non-Hodgkin lymphoma. Direct tissue histopathology with immunochemistry may give clues about diagnosis and prognosis up to certain extent. The rituximab-based chemotherapy is the mainstay of therapy for these tumors; the role of radiotherapy is still not clear but used for management for bulky tumors. PMID- 26430320 TI - Dual thyroid ectopia-role of thyroid scintigraphy and neck ultrasonography. AB - Ectopic thyroid tissue (ETT) is a rare developmental anomaly of the thyroid tissue where the thyroid gland is not located in its usual position. Dual thyroid ectopia is far rarer. This case of a 5-year-old euthyroid girl with thyroglossal cyst was planned for surgery. Presurgical ultrasonography (USG) of the neck followed by thyroid scintigraphy was performed. There was absent normal thyroid gland with single ETT in neck swelling on USG. However, thyroid scintigraphy revealed two ectopic foci of thyroid tissue; one was corresponding to neck swelling, and other was superior to it at the base of the tongue along with absent eutopic thyroid gland. The repeat neck USG could demonstrate the same. The present case emphasizes that, if the thyroid gland is not visible by USG; ETT should be evaluated with thyroid scintigraphy in case of thyroid dysgenesis. PMID- 26430321 TI - Nodular Graves' disease with medullary thyroid cancer. AB - Co-existence of thyroid nodules with Graves' disease has been reported in various studies. 10-15% of such nodules harbor thyroid cancer with papillary thyroid cancer being the commonest. Medullary thyroid cancer (MTC) in nodules associated with Graves' disease is rare. On literature survey, we came across 11 such cases reported so far. We report a 62-year-old female with Graves' disease who also had a thyroid nodule that on fine-needle aspiration cytology and the subsequent postthyroidectomy histopathological examination was reported to be MTC. PMID- 26430322 TI - Bilateral breast uptake of radioiodine in a male patient with gynecomastia: A case report. AB - A 56-year-old male patient with papillary thyroid carcinoma was given radioiodine for the treatment of persistent disease. Post radioiodine whole body scan revealed uptake at the thyroidal region and bilateral uptake at the upper thoracic region. Single photon emission computed tomography/computed tomography (SPECT/CT) confirmed uptake at the left thyroid lobe, and additional symmetrical mammary gland uptake was observed at both breasts. The patient had obesity related gynecomastia, but he did not have any history of breast cancer, mastitis, hyperprolactinemia, or galactorrhea. Although breast uptake of radioiodine is a common finding in postpartum or lactating women, it is uncommon in male patients. To our knowledge, this is the first case of a male patient with breast uptake of radioiodine documented with SPECT/CT. SPECT/CT is useful in male patients in the differentiation of benign breast uptake with lung metastases or axillary metastases of thyroid cancer. PMID- 26430323 TI - Hiatal hernia uptake of iodine-131 mimicking mediastinal metastasis of papillary thyroid carcinoma. AB - There are a few case reports of hiatal hernia demonstrating thoracic uptake on I 131 scintigraphy. In this case, high thyroglobulin levels in combination with misinterpretation of I-131 uptake in the mediastinum, leaded to mismanagement of the patient. Here we present a case of focal I-131 uptake within a hiatal hernia initially mimicking an isolated mediastinal metastasis. There are many potential causes of false-positive I-131 scan result. In this case, adjunctive chest computed tomography and gastroesophageal barium study helped to elucidate the true nature of this I-131 uptake. False-positive findings may be caused by a wide variety of nonthyroidal carcinomas, which can concentrate radioiodine or from skin contamination. Several organs, such as the gastric, salivary glands, renal cyst, pericardial effusion, and ovarian can accumulate I-131. It should be borne in mind as a potential source of false-positive whole-body I-131 imaging. PMID- 26430324 TI - Flip-flop phenomenon in systemic sclerosis on fluorodeoxyglucose positron emission tomography/computed tomography. AB - Systemic sclerosis (SSc) is a rare autoimmune disease, which may affect multiple organ systems. Fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) can demonstrate the degree and anatomical extent of involvement in the entire body and coexisting malignancies in connective tissue diseases. We present a case of SSc with an increased 18F-FDG uptake in the cutaneous and subcutaneous tissues even higher than the neighboring skeletal muscles ("flip-flop phenomenon," that is, an increased 18F-FDG uptake in the skin but a decreased 18F-FDG uptake in the skeletal muscles). PMID- 26430325 TI - Venous thrombosis of sarcoidosis as an unusual incidental finding on 18F fluorodeoxyglucose positron emission tomography/computed tomography. AB - Sarcoidosis is defined as a multisystem granulomatous disorder of unknown cause. Venous thrombosis (VT) in the sarcoidosis is rare. The routine use of 18F fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has resulted in clinicians detecting many incidental findings, which have proven to be clinically significant such as thrombosis. Here, we present a case with VT of sarcoidosis in the inferior vena cava and portal vein as an unusual incidental finding on 18F-FDG PET/CT. PMID- 26430326 TI - Role of fluorine-18 fluorodeoxyglucose positron emission tomography in a case of renal cell carcinoma to differentiate tumor thrombus from bland thrombus. AB - Tumor thrombus is a rare complication of many solid tumors. We present a case of renal cell carcinoma whose baseline contrast-enhanced computerized tomography (CT) revealed an heterogeneously enhancing mass in the upper half of right kidney with tumor thrombus in the right renal vein extending to suprarenal inferior vena cava (IVC), crossing the cavoatrial junction and reaching up to the right atrium (Grade IV). Fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT imaging revealed large irregular right renal mass, hypermetabolic tumor thrombus extending from the right renal vein to suprarenal IVC reaching up to the right atrium. There was no FDG uptake noted in the infrarenal IVC and bilateral iliofemoral venous thrombi. Thus, 18F-FDG PET/CT was not only helpful in the staging, but was also helpful in differentiating tumor thrombus from bland thrombus in our patient. PMID- 26430327 TI - Unusual case of hepatic metastasis in follicular thyroid carcinoma detected using I-131 whole body scintigraphy and single-photon emission computerized tomography/computerized tomography. AB - Papillary and follicular thyroid carcinomas, together known as differentiated thyroid carcinomas (DTC), are among the most curable of cancers. Distant metastases are rare events at the onset of DTC. Among these presentations, metastasis to the liver is even more unusual. Only 11 cases of DTC with liver metastasis were previously reported in the literature. We present a 55-year-old male on Iodine-131 whole body scintigraphy showed intense uptake in thyroid bed, metastasis in both lungs and right lobe of the liver. Radioiodine concentration in liver metastases made him amenable to high-dose radioiodine therapy patient. PMID- 26430329 TI - Lung or liver: An imaging dilemma on Tc-99m macroaggregated albumin lung perfusion scintigraphy. AB - We present a 10-year-old boy having the bronchiectasis who was subjected to lung perfusion scintigraphy before lung resection surgery to assess the lung parenchymal function. It revealed unusual tracer distribution in right upper body that was mimicking to be liver. It was unusual unless there were some shunts bypassing the lung uptake or faulty radiopharmaceutical preparation. However by bringing down the image window, it became clear that radiopharmaceutical distribution was in thorax only correlating with lung uptake, and not in the liver. Corresponding X-ray chest and computed tomography thorax demonstrated multiple cystic lesions in left lung parenchyma. PMID- 26430328 TI - Dystrophic calcification in muscles of legs in calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia syndrome: Accurate evaluation of the extent with (99m)Tc-methylene diphosphonate single photon emission computed tomography/computed tomography. AB - We present the case of a 35-year-old man with calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia variant scleroderma who presented with dysphagia, Raynaud's phenomenon and calf pain. (99m)Tc-methylene diphosphonate bone scintigraphy was performed to identify the extent of the calcification. It revealed extensive dystrophic calcification in the left thigh and bilateral legs which was involving the muscles and was well-delineated on single photon emission computed tomography/computed tomography. Calcinosis in scleroderma usually involves the skin but can be found in deeper periarticular tissues. Myopathy is associated with a poor prognosis. PMID- 26430330 TI - Accurately localizing the thyroid tissue in mature cystic teratoma of ovary by single-photon emission computerized tomography/computerized tomography. AB - A 30-year-old woman with hyperthyroidism was admitted to hospital. Although increased thyroid function was found, the gland was normal in ultrasonography (USG). Additionally, thyroid iodine uptake and Tc-99m pertechnetate scintigraphy was normal. Abdomen USG detected a cystic pelvic mass in left ovary. A whole-body scan was performed 48 hours after oral ingestion of 29.6 MBq (0.8 mCi) I-131 (iodine-131) revealed a round structure located to the left lower abdomen. Iodine uptake was detected in this cyst which was compatible with functional thyroid tissue demonstrated by SPECT/CT. The patient was underwent surgical operation and histopathology confirmed mature cystic teratoma. Accurate localization and depiction of thyroid tissue in ovary mass was provided with SPECT/CT. PMID- 26430331 TI - A rare case mimicking positron emission tomography/computed tomography mismatch: Hepatic subcapsular hematoma. AB - Subcapsular collections of bile, air or blood in the liver have been described following transhepatic procedures due to the leakage of bile and blood from the percutaneous puncture at the surface of the liver. Herein we presented the subcapsular collection led to a mismatch between functional and anatomical boundaries of the liver. PMID- 26430332 TI - Seminal vesicle metastasis from carcinoma lung: A very unusual metastatic site detected with (18)F-Fluorodeoxyglucose positron emission tomography/computed tomography. PMID- 26430333 TI - Splenic metastasis of breast cancer: A rare metastatic site depicted on fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography. PMID- 26430334 TI - Measuring family satisfaction in an Indian Intensive Care Unit. PMID- 26430335 TI - Critical care: Are we customer friendly? AB - OBJECTIVE: Assessing and enhancing family satisfaction are imperative for the provision of comprehensive intensive care. There is a paucity of Indian data exploring family's perception of Intensive Care Unit (ICU) patients. We wanted to explore family satisfaction and whether it differed in families of patients admitted under intensivists and nonintensivists in our semi-open ICU. METHODOLOGY: We surveyed family members of 200 consecutive patients, between March and September 2009 who were in ICU for >3 days. An internationally validated family satisfaction survey was adapted and was administered to a family member, on day 4 of the patient's stay. The survey consisted of 15 questions in five categories - patient care, medical counseling, staff interaction, visiting hours, and facilities and was set to a Likert scale of 1-4. Mean, median, and proportions were computed to describe answers for each question and category. RESULTS: A total of 515 patients were admitted during the study period, of which 200 patients stayed in the ICU >3 days. One family member each of the 200 patients completed the survey with 100% response rate. Families reported the greatest satisfaction with patient care (94.5%) and least satisfaction with visiting hours (60.5%). Chi-square tests performed for each of the five categories revealed no significant difference between satisfaction scores of intensivists and nonintensivists' patients. CONCLUSION: Family members of ICU patients were satisfied with current care and communication, irrespective of whether they were admitted under intensivists or nonintensivists. Family members preferred open visiting hours policy than a time limited one. PMID- 26430336 TI - Calcium homeostasis disorder during and after neonatal extracorporeal membrane oxygenation. AB - BACKGROUND AND AIMS: Extracorporeal membrane oxygenation (ECMO) is used during pediatric resuscitation in case of refractory hypoxemia or septic shock under maximum therapy. Previous studies describe calcium homeostasis dysregulation. The aim of this study was to confirmed of calcium homeostasis dysregulation in neonates under ECMO and supposed news explanation. SUBJECTS AND METHODS: From November 2012 to July 2013, we performed a prospective single center observational study. Eleven neonatal patients were included. Blood was obtained before and during ECMO (day 7, 14 and 21) for parathyroid hormone (PTH), protein adjusted serum calcium, ionized calcium, magnesium, and calcitriol levels. All surviving patients underwent a consultation up to 6 months after ECMO weaning. RESULTS: During ECMO PTH was inadequately high with normal serum calcium on day 7 (PTH: 73.54 +/- 40 ng/l; calcemia: 2.33 +/- 0.21 mmol/l), day 14 (PTH: 57.63 +/- 29.57 ng/l; calcemia: 2.44 +/- 0.43 mmol/l) and day 21 (PTH: 54.93 +/- 8.43 ng/l; calcemia: 2.13 +/- 0.09 mmol/l). The absence of correlation between serum calcium and PTH levels seem to confirm the dysregulation of PTH - serum calcium metabolism during ECMO. Six months after ECMO weaning, we noticed hypercalcemia with normal PTH. CONCLUSIONS: We confirmed the existence of severe disturbances of calcium homeostasis in neonates on ECMO and supposed the possible damage of calcium regulation. We did not succeed in finding clear explanations of these disturbances. PMID- 26430337 TI - Assessing nutrition in the critically ill elderly patient: A comparison of two screening tools. AB - CONTEXT: Few malnutrition screening tests are validated in the elderly Intensive Care Unit (ICU) patient. AIM: Having previously established malnutrition as a cause of higher mortality in this population, we compared two screening tools in elderly patients. SUBJECTS AND METHODS: For this prospective study, 111 consecutive patients admitted to the ICU and > 65 years underwent the Malnutrition Universal Screening Tool (MUST), and the Geriatric Nutrition Risk Index (GNRI) screening tests. STATISTICAL ANALYSIS: Standard definition of malnutrition risk was taken as the gold standard to evaluate the sensitivity, specificity and predictive values of the tools. The k statistic was calculated to measure the agreement between the tools. The Shrout classification was used to interpret its values. RESULTS: The mean age of the patients screened was 74.7 +/- 8.4 (65-97 years). The standard definition, MUST and GNRI identified 52.2%, 65.4%, and 64.9% to be malnourished, respectively. The sensitivity and specificity of the tests were 96.5% computed tomography (CI) (87.9-99.5%) and 72.3% CI (57.5-84.5%) for MUST and 89.5% CI (75.2-96.7%) and 55.0% CI (75.2 96.9%) for GNRI, respectively. Screening was not possible by GNRI and MUST tool in 31% versus 4% of patients, respectively. The agreement between the tools was moderate for Standard-MUST k = 0.65 and MUST-GNRI k = 0.60 and fair for Standard GNRI k = 0.43. CONCLUSIONS: The risk of malnutrition is high among our patients as identified by all the tools. Both GNRI and MUST showed a high sensitivity with MUST showing a higher specificity and greater applicability. PMID- 26430338 TI - Neonatal mechanical ventilation: Indications and outcome. AB - BACKGROUND AND AIMS: Decreasing mortality in sick and ventilated neonates is an endeavor of all neonatologists. To reduce the high mortality in this group of neonates, identification of risk factors is important. This study was undertaken to find out the indications of ventilation and complications in ventilated neonates and also study possible predictors of outcome. SUBJECTS: Age <1-month; mechanically ventilated; not having suspected metabolic disorders or congenital anomalies; excluding postoperative patients. METHODS: Neonates consecutively put on mechanical ventilation during the study period (October 2011 to November 2013) enrolled. Primary disease of the neonates along with complications present listed. Clinical and laboratory parameters analyzed to find the predictors of mortality. RESULTS: Total 300 neonates were ventilated. 52% were male. Mean age, weight, and gestational age were 21 +/- 62 h, 2320 +/- 846.2 g, and 35.2 +/- 4.9 weeks, respectively. 130 (43%) neonates died. Respiratory distress syndrome (RDS) (31.1%), sepsis (22.7%), and birth asphyxia (18%) were the most common indications for ventilation. Mortality in ventilated patients with sepsis, pneumonia, RDS or birth asphyxia was 64.7%, 60%, 44.6%, and 33.3%, respectively. Weight <2500 g, gestation <34 weeks, initial pH <7.1, presence of sepsis, apnea, shock, pulmonary hemorrhage, hypoglycemia, neutropenia, and thrombocytopenia were significantly associated with mortality (P < 0.05). Resuscitation at birth, seizures, intra ventricular hemorrhage, pneumothorax, ventilator-associated pneumonia, PO2, or PCO2 did not have a significant association with mortality. On logistic regression, gestation <34 weeks, initial pH <7.1, pulmonary hemorrhage, or shock were independently significant predictors of mortality. CONCLUSIONS: Weight <2500 g, gestation <34 weeks, initial arterial pH <7.1, shock, pulmonary hemorrhage, apnea, hypoglycemia, neutropenia, and thrombocytopenia were significant predictors of mortality in ventilated neonates. PMID- 26430339 TI - Critical care medicine for emerging Middle East respiratory syndrome: Which point to be considered? AB - The Middle East respiratory syndrome (MERS) is a new emerging respiratory tract infection. This coronavirus infection is firstly reported from the Middle East, and it becomes threat for the global public health at present due to its existence in a remote area such as USA and Korea. The concern on the management of the patients is very important. Since most of the patients can develop severe respiratory illness and critical care management is needed, the issue on critical care for MERS is the topic to be discussed in critical medicine. PMID- 26430340 TI - Use of metabolic monitors in a multidisciplinary Intensive Care Unit: A prospective pilot study of 20 patients. AB - INTRODUCTION: Caloric intake of critically ill patients are usually calculated using predictive equations. Recent advances in gas exchange measurements have the potential to estimate energy expenditure at the bedside and at different time periods. MATERIALS AND METHODS: Energy needs of critically ill patients were estimated over a period of 3 months using simplistic formula of 25 kcal/kg/day estimated energy expenditure (EEE), Harris-Benedict equation (HBE) (Basal energy expenditure [BEE]) and M-COVXTM metabolic monitor resting energy expenditure (REE) on day 4 of Intensive Care Unit (ICU) admission. Calculations based on HBE were taken as standard, and percentage errors (PE) were calculated for each patient for values derived from simplistic formula and metabolic monitor. Adequacy of nutritional intake in ICU was also assessed. RESULTS: Metabolic monitor could be used in only 20/70 patients. The mean age of patients was 40 years, 65% were males, and average body mass index was 23.69 kg/m(2). Intermittent intolerance to feeds was reported in 50%. Values of REE and EEE were greater than BEE in 70% of patients. A significant difference was reported in values of PE of <=20% and >=30%; P = 0.0003 and 0.0001, respectively estimated using REE and EEE. CONCLUSIONS: It is not feasible to use metabolic monitors in all patients. Variability in readings is large and further studies are needed to establish the validity of its measurements. Calculations using simplistic formulas are much closer to values obtained using HBE. PMID- 26430341 TI - Targeted temperature management: Current evidence and practices in critical care. AB - Targeted temperature management (TTM) in today's modern era, especially in intensive care units represents a promising multifaceted therapy for a variety of conditions. Though hypothermia is being used since Hippocratic era, the renewed interest of late has been since early 21(st) century. There have been multiple advancements in this field and varieties of cooling devices are available at present. TTM requires careful titration of its depth, duration and rewarming as it is associated with side-effects. The purpose of this review is to find out the best evidence-based clinical practice criteria of therapeutic hypothermia in critical care settings. TTM is an unique therapeutic modality for salvaging neurological tissue viability in critically ill patients viz. Post-cardiac arrest, traumatic brain injury (TBI), meningitis, acute liver failure and stroke. TTM is standard of care in post-cardiac arrest situations; there has been a lot of controversy of late regarding temperature ranges to be used for the same. In patients with TBI, it reduces intracranial pressure, but has not shown any favorable neurologic outcome. Hypothermia is generally accepted treatment for hypoxic ischemic encephalopathy in newborns. The current available technology to induce and maintain hypothermia allows for precise temperature control. Future studies should focus on optimizing hypothermic treatment to full benefit of our patients and its application in other clinical scenarios. PMID- 26430342 TI - Anaphylaxis to scorpion antivenin and its management following envenomation by Indian red scorpion, Mesobuthus tamulus. AB - Mesobuthus tamulus is an Indian red scorpion that is responsible for numerous cases of scorpion stings in the Indian subcontinent. Antivenin, vasodilators, and benzodiazepines are medications of choice in the treatment of scorpion bites. Adverse reactions such as anaphylaxis to antivenin have been infrequently described in the literature. We, herein, present a case of a 42-year-old man stung by Indian red scorpion while gardening at home in India, who presented with extreme pain at the sting site and signs of cardio-toxicity. He was treated with scorpion antivenin and vasodilators but developed anaphylaxis to antivenin. We discuss management strategies. Anaphylaxis to antivenin should be on the differential during management of scorpion bites because classical signs of anaphylaxis may be absent. PMID- 26430343 TI - An unusually dry story. AB - We present a middle-aged woman with a prior history of central nervous system (CNS) demyelinating disorder who presented with an acute onset quadriparesis and respiratory failure. The evaluation revealed distal renal tubular acidosis with hypokalemia and medullary nephrocalcinosis. Weakness persisted despite potassium correction, and ongoing evaluation confirmed recurrent CNS and long-segment spinal cord demyelination with anti-aquaporin-4 antibodies. There was no history of dry eyes or dry mouth. Anti-Sjogren's syndrome A antigen antibodies were elevated, and there was reduced salivary flow on scintigraphy. Coexistent antiphospholipid antibody syndrome with inferior vena cava thrombosis was also found on evaluation. The index patient highlights several rare manifestations of primary Sjogren's syndrome (pSS) as the presenting features and highlights the differential diagnosis of the clinical syndromes in which pSS should be considered in the Intensive Care Unit. PMID- 26430344 TI - Crimean-Congo hemorrhagic fever: An emerging threat for the intensivist. AB - We present the case of a 55-year-old female, who presented with 15 days of fever with rash, pancytopenia, and altered behavior. She was investigated for routine causes of fever with rash and multi organ dysfunction and treated for the same. As she tested negative for all routine causes of such an illness and did not show improvement to therapy, she was investigated for Crimean-Congo hemorrhagic fever and tested positive for the same. She was started on ribavirin, but eventually succumbed to her illness. This disease has rarely been reported from the Northern India and we need to have high clinical suspicion for this deadly disease so that appropriate therapy can be started in time for the patient and prophylaxis given to all inadvertently exposed. PMID- 26430345 TI - Difficult airway management from Emergency Department till Intensive Care Unit. AB - We report a case of "can ventilate but can't intubate" situation which was successfully managed in the Emergency Department and Intensive Care Unit by the use of ProSeal laryngeal mask airway and Frova Intubating Introducer as bridging rescue devices. Use of appropriate technique while strictly following the difficult airway algorithm is the mainstay of airway management in unanticipated difficult airway situations. Although the multiple airway devices were used but each step took not more than 2 min and "don't struggle, skip to the next step principle" was followed. With the availability of many advanced airway management tools, the intensivists should have a training and experience along with preparedness in order to perform such lifesaving airway managements. PMID- 26430346 TI - Should intensivist do routine abdominal ultrasound? AB - Roundworm infestation is common in tropical climate population with a low socioeconomic status. We describe a case of a young male with polytrauma accident who presented with small bowel dysfunction with a high gastric residual volume during enteral feeding. While searching the etiology, the intensivist performed bedside abdominal ultrasound (USG) as a part of whole body USG screening along with clinical examination using different frequency probes to examine bowel movement and ultimately found ascariasis to be the cause. This case report will boost up the wide use of bedside USG by critical care physicians in their patient workup. PMID- 26430347 TI - Severe masseter spasms in a Rett syndrome during rapid sequence intubation: A succinylcholine severe side effect. PMID- 26430348 TI - System of adverse drug reactions reporting: What, where, how, and whom to report? PMID- 26430349 TI - Factors for early death in rabies- the bitter truth. PMID- 26430350 TI - Novel Use of Proteomic Profiles in a Convex-Hull Ensemble Classifier to Predict Gynecological Cancer Patients' Susceptibility to Gastrointestinal Mucositis as Side Effect of Radiation Therapy. AB - BACKGROUND: Whole-pelvis radiation therapy is common practice in the post surgical treatment of cervical and endometrial cancer. Gastrointestinal mucositis is an adverse side effect of radiation therapy, and is a primary concern in patient management. We investigate whether proteomic information obtained from blood samples drawn from patients scheduled to receive radiation therapy for gynecological cancers could be used to predict which patients are most susceptible to radiation-induced gastrointestinal mucositis, in order to improve the individualization of radiation therapy. METHODS: We use 132 proteins measured on 17 gynecological cancer patients in a convex-hull-based, selective-voting ensemble classifier to classify each patient into one of two classes: patients who would not (class 1) or would (class 2) develop gastrointestinal mucositis. We employ 20 repetitions of 10-fold cross-validation to measure classification accuracy. RESULTS: We achieved a 95% confidence interval on average prediction accuracy of (0.711, 0.771) using pre-radiation proteomic profiles to predict which patients would experience gastrointestinal mucositis. Pathway analysis of the 12 most prominent proteins indicated that they could be assembled into a single interaction network with direct associations. The function associated with the highest number of these 12 proteins was cell-to-cell signaling and interaction. CONCLUSIONS: Pre-radiation proteomic profiles have the potential to classify cervical/endometrial cancer patients with high accuracy as to their susceptibility to gastrointestinal mucositis following radiation therapy. Further study of the network of 12 identified proteins is warranted with a larger patient sample to confirm that these proteins are predictive of gastrointestinal mucositis in this patient population. PMID- 26430351 TI - Cultural Difference in Conflict Management Strategies of Children and Its Development: Comparing 3- and 5-Year-Olds Across China, Japan, and Korea. AB - Research Findings: The purpose of this study was to examine differences in the development of conflict management strategies, focusing on 3- and 5-year-olds, through a comparison of 3 neighboring Asian cultures, those of China (n = 114), Japan (n = 98), and Korea (n = 90). The dual concern model of conflict management was adopted to probe which strategy children would prefer to use in 2 hypothetical conflict situations. Results indicated that, first, for disagreement, 3-year-olds in the 3 countries equally preferred the dominating strategy. For competition for resources, 3-year-olds differed in their strategy preference across all cultures. Second, the observed strategy preference of 3- to 5-year-old children in this study was more or less different from that of older schoolchildren, regardless of culture. Practice or Policy: These findings suggest the significance of the context, the complexity of the phenomenon of the development of cultural differences, and the significance of cohort sampling. PMID- 26430352 TI - Spatial Moran Models I. Stochastic Tunneling in the Neutral Case. AB - We consider a multistage cancer model in which cells are arranged in a d dimensional integer lattice. Starting with all wild-type cells, we prove results about the distribution of the first time when two neutral mutations have accumulated in some cell in dimensions d >= 2, extending work done by Komarova [12] for d = 1. PMID- 26430353 TI - Fingering in Stochastic Growth Models. AB - Motivated by the widespread use of hybrid-discrete cellular automata in modeling cancer, two simple growth models are studied on the two dimensional lattice that incorporate a nutrient, assumed to be oxygen. In the first model the oxygen concentration u(x, t) is computed based on the geometry of the growing blob, while in the second one u(x, t) satisfies a reaction-diffusion equation. A threshold theta value exists such that cells give birth at rate beta(u(x, t) - theta)+ and die at rate delta(theta - u(x, t)+. In the first model, a phase transition was found between growth as a solid blob and "fingering" at a threshold thetac = 0.5, while in the second case fingering always occurs, i.e., thetac = 0. PMID- 26430354 TI - Risk Assessment's New Era, Part 3: Vision of the AIHA(r) Risk Assessment Committee. PMID- 26430355 TI - Relationship between School Administrators' Reports of Parental Involvement in School and Students' Substance Use: A National Study. AB - This study examines the relationship between student substance use and school level parental involvement as reported by administrators. Questionnaires were administered to school administrators and 111,652 students in 1,011 U.S. schools. Hierarchical logistic regression analyses conducted on 1998-2003 data from students and administrators indicate significantly lower prevalence of alcohol use among 8th graders in schools where administrators reported high parental involvement. Overall, administrators' reports of high parental involvement were unrelated to prevalence of substance use among 10th graders, and were associated with higher prevalence of alcohol use among 12th-graders. Implications and limitations are discussed, along with suggestions for future research. PMID- 26430356 TI - The effect of implant angulation and splinting on stress distribution in implant body and supporting bone: A finite element analysis. AB - OBJECTIVE: The aim of this study was to investigate the influence of implant crown splinting and the use of angulated abutment on stress distribution in implant body and surrounding bone by three-dimensional finite element analysis. MATERIALS AND METHODS: For this study, three models with two implants at the site of mandibular right second premolar and first molar were designed (1): Both implants, parallel to adjacent teeth, with straight abutments (2): Anterior implant with 15 mesial angulations and posterior implant were placed parallel to adjacent tooth, (3): Both implants with 15 mesial angulations and parallel to each other with 15 degrees angulated abutments. Restorations were modeled in two shapes (splinted and nonsplinted). Loading in tripod manner as each point 50 N and totally 300 N was applied. Stress distribution in relation to splinting or nonsplinting restorations and angulations was done with ABAQUS6.13. RESULTS: Splinting the restorations in all situations, led to lower stresses in all implant bodies, cortical bone and spongy bone except for the spongy bone around angulated first molar. Angulated implant in nonsplinted restoration cause lower stresses in implant body and bone but in splinted models more stresses were seen in implant body in comparison with straight abutment (model 2). Stresses in nonsplinted and splinted restorations in cortical bone of angulated molar region were more than what was observed in straight molar implant (model 3). CONCLUSION: Implant restorations splinting lead to a better distribution of stresses in implant bodies and bone in comparison with nonsplinted restorations, especially when the load is applied off center to implant body. Angulations of implant can reduce stresses when the application of the load is in the same direction as the implant angulation. PMID- 26430357 TI - The influence of type 2 diabetes mellitus on salivary matrix metalloproteinase-8 levels and periodontal parameters: A study in an Indian population. AB - OBJECTIVE: Although many studies reported more severe periodontal disease and the existing proinflammatory conditions in patients with diabetes but only few have examined the effect of type 2 diabetes mellitus (DM) on salivary matrix metalloproteinase-8 (MMP-8) level and other periodontal parameters. This study aims to evaluate the effect of type 2 DM on salivary MMP-8 levels and periodontal parameters, which might be useful in monitoring periodontal disease in diabetes. MATERIALS AND METHODS: A total of 90 subjects were selected for the study and were divided into three groups: Group I included 30 healthy subjects; Group II included 30 subjects without type 2 DM but with chronic periodontitis, and Group III included 30 subjects with type 2 DM and chronic periodontitis. Periodontal parameters such as plaque index (PI), gingival index (GI), pocket probing depth (PPD), and clinical attachment level (CAL) were taken. The salivary MMP-8 level was estimated by Quantikine Human total MMP-8 immunoassay kit using ELISA method. RESULTS: The mean value of the salivary MMP-8 of Group III was highest followed by Group II and Group I, the least. The other periodontal parameters PI, GI, PPD, CAL, was comparatively highest for Group III. CONCLUSION: This study suggests that diabetes is associated with an increased prevalence, extent, and severity of periodontitis. Furthermore, the increased levels of MMP-8 indicate the influence of diabetes on their salivary concentration. PMID- 26430358 TI - Relationship between periodontal status and degree of visual impairment in institutionalized individuals. AB - OBJECTIVE: Periodontal disease is a set of inflammatory infections that affect the supporting structures of the dentition. Patients with visual impairment (VI) may have more difficulty in cleaning and maintaining oral health. The purpose of this study was to investigate the possible relationship between periodontal status and degree of VI in institutionalized individuals. MATERIALS AND METHODS: Fifty-two visually impaired individuals were included in this cross-sectional study. The periodontal parameters assessed were clinical attachment level (CAL), probing depth (PD), and visible plaque index. The degree of VI was established as: Group 1 (mild or moderate VI), Group 2 (severe or profound VI), and Group 3 (completely blind); and the types of VI were considered as congenital and acquired. Fisher's exact, Kruskal-Wallis, Mann-Whitney, and Spearman correlation coefficient test were used. The level of significance was set at 5%. RESULT: Only plaque index was higher on proximal surfaces of subjects with mild/moderate VI when compared to the other degrees of VI (P = 0.01). Furthermore, we observed higher values for interproximal CAL (P = 0.01), total PD (P = 0.04), and interproximal PD in subjects with acquired VI when compared to subjects with congenital VI (P = 0.01). CONCLUSIONS: These findings suggest that periodontal status may be more related to the type of disability than with the degree of VI. Acquired VI people presented a worse periodontal health than the group with congenital VI. PMID- 26430359 TI - Evaluation of stress distributions in peri-implant and periodontal bone tissues in 3- and 5-unit tooth and implant-supported fixed zirconia restorations by finite elements analysis. AB - OBJECTIVE: In this study, it is aimed to compare the distribution of stress on periodontal and peri-implant bone tissues in 3- and 5-unit-dental and implant supported zirconia restorations using finite element analysis. MATERIALS AND METHODS: Stress distribution formed in periodontal and peri-implant bone tissues as a result of chewing forces was analyzed in dental and implant-supported three dimensional (3D) finite element models of zirconia restoration with 5-unit placed on the numbers of 43, 44, 45, 46, and 47 and with 3-unit placed on the number of 45, 46, and 47. Four different loading conditions were used. 200 N force was applied in 30 degrees from the buccal inclination of number 43, 45, and 47 restorations separately and totally 850 N force was applied in 30 degrees from the buccal inclination of whole restoration. The study was performed through static nonlinear analysis with the 3D finite element analysis method. RESULTS: Stress accumulation in bone tissues in the tooth-supported model was found less than in implant-supported models. Stress accumulation was observed in the cervical portion of the implant in implant-supported models, and stress accumulation was observed surrounding bone of roots in tooth-supported models. The highest stress values were occurred in 5 unit implant-supported model in all loadings. CONCLUSION: In posterior restorations increased in the number of supported teeth and implant can reduce the destructive forces on periodontal and peri-implant bone tissues and may allow longer period retention of the restorations in the mouth. PMID- 26430360 TI - Effect of dietary combinations on plaque pH recovery after the intake of pediatric liquid analgesics. AB - OBJECTIVES: To study the effect of water, halloumi cheese and sugar-free (SF) chewing gum on plaque pH recovery after the intake of sweetened PLAs. SETTINGS AND DESIGN: A randomized clinical trial was conducted on 17 children (10 females, 7 males) aged 11-12 years with DFT/dft of more than 3. MATERIALS AND METHODS: Each volunteer tested paracetamol and ibuprofen suspension alone or followed with water, halloumi cheese or SF gum, as well as 10% sucrose and 10% sorbitol as controls. Plaque pH was measured using the sampling method before and after 5, 10, 15, 20, 30 min of ingestion. STATISTICAL ANALYSIS: Statistical analysis was performed using analysis of variance followed by least significant difference test to assess minimum pH (min pH), maximum pH drop (DeltapH), and the area under baseline pH, and P value was set as 0.05. RESULTS: Both ibuprofen and paracetamol were not significantly different from 10% sucrose in terms of min pH, DeltapH, and area under baseline pH except for min pH of ibuprofen (P = 0.034). Water and halloumi cheese did not have a significant effect on plaque pH recovery after the intake of both analgesics as min pH, DeltapH, and area under baseline pH were similar to 10% sucrose except for min pH of ibuprofen + water (P = 0.048). However, plaque pH variables after chewing SF gum for 20 min were similar to 10% sorbitol. CONCLUSION: Chewing SF gum immediately after the intake of sweetened PLAs for 20 min restores plaque pH and could be recommended as a complementary aid in caries prevention. PMID- 26430361 TI - Shaping ability of reciprocating single-file and full-sequence rotary instrumentation systems in simulated curved canals. AB - OBJECTIVE: The purpose of this study was to evaluate the shaping ability of three nickel-titanium systems in simulated curved canals. MATERIALS AND METHODS: Sixty simulated canals were prepared to apical size 25 with Reciproc, S5, and twisted file (TF) instruments. Standardized pre and postoperative images were taken using a digital camera, were superimposed and aberrations were recorded. Material removal was measured at five points: The canal orifice, halfway to the orifice, beginning of the curve, the apex of the curve, and end-point. The data were analyzed using Kolmogorov-Smirnov, analysis of variance, and Tukey tests. RESULTS: The mean total width of the prepared canals in the Reciproc group was greater than the TF and S5 groups at halfway to the orifice, the beginning of the curve, the apex of the curve, and the end-point (P < 0.05). Mean absolute transportation was always <0.16 mm; however, significant differences occurred between the three systems at the orifice, halfway to the orifice, and the beginning of the curve (P < 0.05). TF created minimal absolute transportation at halfway to the orifice and the beginning of the curve, and greater absolute transportation at the orifice compared with the Reciproc and S5 instruments. However, the difference between the S5 and TF groups was not statistically significant at halfway to the orifice (P > 0.05). CONCLUSIONS: Under the conditions of the study, Reciproc produced widest canal shapes. TF provided more centered apical preparation and maintained the original canal shape well. PMID- 26430362 TI - Pleasantness of facial profile and its correlation with soft tissue cephalometric parameters: Perception of orthodontists and lay people. AB - OBJECTIVE: This study was aimed to evaluate the perception of orthodontists and of lay people about the facial profile and its possible correlation with cephalometrics parameters. MATERIALS AND METHODS: A total of 20 evaluators were divided into two groups (10 orthodontists and 10 people with no relation to such area - lay people). They were asked to evaluate the photographs of 25 young males and of 25 young females, aged 17-24-year-old (mean age of 22.3 years, standard deviation 2.41 years). Photographs were randomly arranged in a photo album. The evaluators rated each photograph by means of a scale ranging from "good" to "deficient" based on the pleasantness of their facial profile. Nasolabial angle, Holdaway's H-line and the distance from H-line to nose tip were measured, in order to verify a possible relation between these soft tissue profile cephalometric measurements and the subjective ratings. RESULTS: The kappa statistics test showed a concordance of 0.23 among orthodontists and 0.24 among lay people. Regarding the perception of orthodontists and lay people on facial profile, no significant divergence could be detected. For the correlation between cephalometric parameters and subjective ratings, there was a statistically significant correlation between the measures H and H-nose and the rating ascribed to the profile. CONCLUSIONS: It was concluded that smaller the difference from the normal cephalometric pattern, the higher was the rating given to the profile, demonstrating an important relation between subjective and objective criteria. PMID- 26430363 TI - The prevalence and consequences of burnout on a group of preclinical dental students. AB - OBJECTIVE: The aim of this study is to investigate the prevalence of burnout among a group of Turkish preclinical dental students, to compare the level of burnout and to determine the consequences in structural equation model. MATERIALS AND METHODS: Preclinical dental students (n = 329, 50.5% of females and 49.5% of males) aged between 18 and 24 took part in the study. Maslach burnout inventory student version, academic satisfaction scale, and personal information sheet were used to gather data. Pearson correlation analyses, t-test, and one-way ANOVA were used for statistical analysis. The proposed theoretical model was tested via observed variable path analysis using maximum likelihood parameter estimation with AMOS 7.0. RESULTS: About 22.3% of students had high level of emotional exhaustion, 16.7% of students had high level of cynicism, and 17.9% of students suffered from high level of reduced academic efficacy. While the students attending the first grade reported higher level of reduced academic efficacy, the students in the third grade reported higher level of emotional exhaustion. Academic workload played an important role in the development of burnout. As consequences of burnout, students with high levels of burnout intended to change their current major and did not to plan to continue to postgraduate education. Students with high level of burnout reported less level of academic satisfaction and academic achievement. CONCLUSIONS: Creating awareness on the burnout of dental students from the preclinical period may be useful for prevention and more compatible dental education environment. PMID- 26430364 TI - Expression of E-cadherin in normal oral mucosa, in oral precancerous lesions and in oral carcinomas. AB - OBJECTIVE: The aim of the present study was to assess the expression of E-cad in oral precancerous lesions and conditions and oral carcinomas in comparison with normal mucosa. MATERIALS AND METHODS: Total of 50 samples were selected for the study and were categorized into five groups and 10 samples in each group as Group I-oral leukoplakia (OL), Group II-oral lichen planus (OLP), Group III-oral submucous fibrosis (OSMF), Group IV-oral squamous cell carcinoma (OSCC) and Group V-normal oral mucosa (NOM) as control group. All the samples were assessed for the expression of E-cad by immunohistochemical study. RESULTS: Upon assessing the expression of E-cad in OL, OSMF, OLP and OSCC, as majority of the samples with OSCC (90%), OL (80%), OLP (70%) and OSMF (60%) showed mild to moderate expression of E-cad staining, which was suggestive of reduction in dysplastic cells on comparison to NOM cells. This difference in expression and variation of E-cad upon comparison with normal mucosa was statistically significant (P < 0.001). CONCLUSION: There is significant (P < 0.001) variation of expression of E-cad with the histopathological dysplasia of the oral precancerous lesions and conditions, and the tumor differentiation of the oral cancers. However, there was no correlation of the degree of loss of expression of E-cad with the degree of dysplasia or the tumor differentiation of oral cancers. We conclude with our study that, there is a variation in the expression of E-cad but its value as a prognostic marker is questionable. PMID- 26430365 TI - Impact of different malocclusion types on the vertical mandibular asymmetry in young adult sample. AB - OBJECTIVE: The aim of this study was to investigate the vertical mandibular asymmetry in a group of adult patients with different types of malocclusions, based on Angle's dental classification. MATERIALS AND METHODS: A sample of 102 patients (age range 19-28) who went for routine orthodontic treatment in the institution were divided into four groups: Class I, 26 patients; Class II/1, 30 patients; Class III, 23 patients; and control group (CG) with normal occlusion, 23 patients. Condylar asymmetry index (CAI), ramal asymmetry index (RAI), condylar-plus-ramal asymmetry index values were measured for all patients on panoramic radiographs. Data were analyzed using Kruskal-Wallis and Mann-Whitney U test at the 95% confidence level (P < 0.05). RESULTS: The results of the analysis showed that different occlusal types significantly affected the vertical symmetry of the mandible at the condylar level. Class I and Class II/1 malocclusion groups showed a significant difference in CAI values relative to the CG (P < 0.05, P < 0.001). No statistically significant difference was found between the CG and Class III malocclusion group (P > 0.05). Comparisons between Class II/1 and Class I malocclusions revealed a significant difference in CAI values (P < 0.01). CONCLUSIONS: Both Class II/1 and Class I malocclusions patients had significantly higher CAI values compared to CG and Class III group. CAI value was significantly higher in Class II/1 malocclusion compared to Class I malocclusion. Both these malocclusions could act as a predisposing factor for having asymmetric condyles if left untreated. PMID- 26430366 TI - Effect of spreader size on microleakage of roots filled with cold lateral compaction technique. AB - OBJECTIVES: To evaluate the effect of spreader size on apical leakage of maxillary incisor teeth. MATERIALS AND METHODS: A total of 75 permanent human teeth with no carious and no fracture or crack were used for this study. After removing the crown from the cementoenamel junction and the standardization of the root lengths, the specimens were randomly divided into five groups: Group 1 - Roots were not instrumented. Group 2 - Root canals were enlarged using the step back technique to a #40 file and filled using cold lateral compaction (CLC) of gutta-percha (GP). Group 3 - During the filling procedure, the first spreader used was size 40. Group 4 - The first spreader used was size 35. Group 5 - The initial spreader used was size 25. The amount of leakage through the filled root canals was evaluated by computerized fluid filtration model. Statistical analyzes were done using Kruskal-Wallis test and Mann-Whitney test (P < 0.05). RESULTS: There were statistically significant differences among the groups (P < 0.05). While the uninstrumented group (Group 1) had no leakage, instrumented but not filled roots (Group 2) demonstrated the highest leakage values. There were no differences between Group 3 and 4. Group 5 showed significantly less leakage than Group 3 and 4. CONCLUSION: Spreader size used during CLC of GP appeared to be a significant factor on apical leakage of roots. Using smaller size spreader during CLC may provide relatively less leakage. PMID- 26430367 TI - The influence of removable partial dentures on the periodontal health of abutment and non-abutment teeth. AB - OBJECTIVE: The aim of this study was to evaluate the influence of removable partial dentures (RPD) on the periodontal health of abutment and non-abutment teeth. MATERIALS AND METHODS: A total 107 patients with RPD participated in this study. It was examined 138 RPD, they were 87 with clasp-retained and 51 were RPD with attachments. The following periodontal parameters were evaluated for abutment and non-abutment teeth, plaque index (PLI), calculus index (CI), bleeding on probing (BOP), probing depth (PD) (mm) and tooth mobility (TM) index. These clinical measurements were taken immediately before insertion the RPD, then one and 3 months after insertion. The level of significance was set at (P < 0.05). RESULTS: The mean scores for PLI, CI, BOP, PD, and TM index, of the abutment teeth and non-abutment teeth were no statistically significant at the time of insertion of RPD. After 1-month, PLI was statistically significant (0.57 +/- 0.55 for abutment and 0.30 +/- 0.46 for non-abutment teeth). After 3 months, there were significant differences between abutment and non-abutment teeth with regard to the BOP (1.53 +/- 0.50 and 1.76 +/- 0.43 respectively), PD (0.28 +/- 0.45 and 0.12 +/- 0.33 respectively) and PLI (1.20 +/- 0.46 and 0.75 +/- 0.64 respectively). No significant mean difference in TM and CI was found between the abutment and non-abutment teeth (P > 0.05). CONCLUSIONS: With carefully planned prosthetic treatment and adequate maintenance of the oral and denture hygiene, we can prevent the periodontal diseases. PMID- 26430368 TI - Single nucleotide polymorphism at -1087 locus of interleukin-10 gene promoter is associated with severe chronic periodontitis in nonsmoking patients. AB - OBJECTIVE: Single nucleotide polymorphisms (SNPs) in the promoter region of interleukin (IL)-10 gene, which codes for the anti-inflammatory cytokine IL-10, have been associated with its level of production in chronic periodontitis. The prevalence of promoter SNP genotypes is known in other populations with chronic periodontitis, while its association in the Indian population is not known. Hence, the present study was designed to investigate the prevalence of IL-10 promoter polymorphism in a racially defined group of Indians with severe chronic periodontitis as the Indian population is known to be genetically diverse. MATERIALS AND METHODS: Genomic deoxyribonucleic acid was extracted from 46 nonsmoking patients with severe chronic periodontitis and 45 subjects with healthy periodontium. A SNP locus at -1087 of IL-10 was chosen, as this locus has been frequently associated with chronic periodontitis in other population. Genotyping was carried out using allele-specific polymerase chain reaction (AS PCR), and the frequencies of genotype were analyzed between the groups. RESULTS: The distribution of genotype and allele frequencies showed significant differences between the study groups. The prevalence of genotype AA alleles at 1087 locus of IL-10 was significantly higher in severe chronic periodontitis patients compared to the healthy controls (P = 0.05). CONCLUSION: The study has identified a positive association between the occurrence of AA allele at -1087 locus of IL-10 gene and severe chronic periodontitis in nonsmoking patients. PMID- 26430369 TI - Establishment of a new relationship between posed smile width and lower facial height: A cross-sectional study. AB - OBJECTIVE: The present study is intended to add a new parameter that would be useful in orthodontic clinical evaluation, treatment planning, and determination of vertical dimension (at occlusion). MATERIALS AND METHODS: Standardized videographic recording of 79 subjects during posed smile was captured. Each video was then cut into 30 photos using the free studio software. The widest commissure to-commissure posed smile frame (posed smile width [SW]) was selected as one of 10 or more frames showing an identical smile. Lower third of the face is measured from subnasale to soft tissue menton using a digital vernier caliper. Two values were then compared. Ratio between lower facial height and posed SW was calculated. RESULTS: The co-relation between smiling width and lower facial height was found to be statistically significant (P < 0.01). The ratio of lower facial height and smiling width was calculated as 1.0016 with a standard deviation (SD) = 0.04 in males and 1.0301 with an SD = 0.07 in females. The difference between the mean lower facial height in males and females was statistically significant with a t = 10.231 and P = 0.000. The difference between the mean smiling width in males and females was also statistically significant with a t = 5.653 and P = 0.000. CONCLUSION: In class I subjects with pleasing appearance, normal facial proportions, normal overjet and overbite, and average Frankfort mandibular angle, the lower facial height (subnasale to soft tissue menton) is equal to posed SW. PMID- 26430370 TI - The relationship between occlusal support and maxillary development: An animal study. AB - OBJECTIVE: To test the hypothesis that maxillary development may be affected by occlusal support. MATERIALS AND METHODS: The sample was composed by Wistar rats (5 weeks old) divided into three groups: Control (n = 10), extraction of mandibular molar teeth - left side (n = 10), extraction mandibular molar teeth - left and right sides (n = 10). The rats were sacrificed 8 weeks postextraction. Cone beam computed tomography scan images were taken for posterior measurement of maxillary length and width. Data were analyzed by one-way analysis of variance (Tukey test as post-hoc test). RESULTS: Maxillary length was significantly shorter (P < 0.005) in both groups after tooth extraction. No difference was observed regarding maxillary width and body weight. CONCLUSION: Reduced occlusal support may impair the development of the maxilla in rats. PMID- 26430371 TI - Periodontal health status in patients treated with the Invisalign((r)) system and fixed orthodontic appliances: A 3 months clinical and microbiological evaluation. AB - OBJECTIVE: The aim of this prospective study was to compare the periodontal health and the microbiological changes via real-time polymerase chain reaction (PCR) in patients treated with fixed orthodontic appliances and Invisalign((r)) system (Align Technology, Santa Clara, California). MATERIALS AND METHODS: Seventy-seven patients were enrolled in this study and divided into three groups (Invisalign((r)) group, fixed orthodontic appliances group and control group). Plaque index, probing depth, bleeding on probing were assessed. Total biofilm mass and periodontal pathogens were analyzed and detected via real-time PCR. All these data were analyzed at the T0 (beginning of the treatment) T1 (1-month) and T2 (3 months); and statistically compared using the Mann-Whitney test for independent groups. RESULTS: After 1-month and after 3 months of treatment there was only one sample with periodontopathic anaerobes found in patient treated using fixed orthodontic appliances. The Invisalign((r)) group showed better results in terms of periodontal health and total biofilm mass compared to the fixed orthodontic appliance group. A statistical significant difference (P < 0.05) at the T2 in the total biofilm mass was found between the two groups. CONCLUSION: Patients undergoing orthodontic treatment with the Invisalign((r)) System show a superior periodontal health in the short-term when compared to patients in treatment with fixed orthodontic appliances. Invisalign((r)) should be considered as a first treatment option in patients with risk of developing periodontal disease. PMID- 26430372 TI - Antimicrobial activity of a temporary sealant used in endodontic treatment: An in vitro study. AB - OBJECTIVE: The present study is aimed to evaluate the antimicrobial action of Coltosol((r)) in direct contact with human saliva. MATERIALS AND METHODS: Twelve different individuals were selected. Saliva samples were evaluated at four different time periods: Baseline 1 (T1-initial control), T2 (2 h), T4 (24 h after contact with a standardized sample of a coronary sealer) and baseline 2 (T3-final control). Seeded plates were incubated at 37 degrees C in a bacterial incubator for a period of 48-72 h. After the incubation period, the colony forming units were counted, and the results compared. RESULTS: Differences were statistically significant. There was an inhibition of bacterial growth after the first 2 h of contact and an increase in the number of bacteria after 24 h of direct contact between the material and the saliva. Coltosol((r)) presented bacterial growth inhibition in direct contact with saliva. This inhibitory effect tended to decrease over time, as shown by the two periods when the material was in contact with different samples of saliva. CONCLUSIONS: The antimicrobial activity of the material is an important feature; however, other physical and chemical properties of the coronary temporary sealer should be considered. PMID- 26430373 TI - Evaluation of non-surgical therapy on glutathione levels in chronic periodontitis. AB - OBJECTIVE: To compare the levels of glutathione (GSH), both oxidized and reduced forms in patients with and without chronic periodontitis in gingival crevicular fluid (GCF). MATERIALS AND METHODS: Twenty GCF samples from maxillary quadrants were collected using capillary micropipettes from the chronic periodontitis patients (test group) at baseline before treatment, at 1-month, 3 months, and 6 months after scaling and root planing and samples from 20 patients without chronic periodontitis (control group) from maxillary quadrants were also collected. GSH, oxidized glutathione (GSSG) levels and GSH: GSSG ratios were determined using the spectrophotometric method. STATISTICAL ANALYSIS: Results were concluded for the test over control groups using paired Student's t-test. RESULTS: Lower concentrations of GSH (P < 0.001) and GSSG (P < 0.001) were detected in GCF in patients with chronic periodontitis (test group) than patients without chronic periodontitis (control group) at baseline. Treatment had a significant effect in improving the GSH and reducing GSSG levels postscaling and root planing at 1-month and 3 months but not significant effect at 6 months. Scaling and root planing increased the GSH: GSSG ratio (P < 0.001) in the test group as compared to the control group (P < 0.001). CONCLUSIONS: The concentrations of GSH within GCF are reduced in chronic periodontitis patients. Scaling and root planing (nonsurgical therapy) restores GSH concentration in GCF post 1-month and 3 months along with redox balance (GSH: GSSG ratio), but at 6 months the balance is not maintained. Adjunctive use of micronutritional supplements to boost antioxidant concentration in tissues by preserving GSH or by elevating its level at the inflamed sites is recommended, as nonsurgical periodontal therapy alone is not able to maintain redox balance for longer duration. PMID- 26430374 TI - Pulp tissue dissolution capacity of QMix 2in1 irrigation solution. AB - OBJECTIVE: The aim of this study was to evaluate the tissue dissolution efficacy of four root canal irrigation solutions (sodium hypochlorite [NaOCl], chlorhexidine gluconate [CHX], Octenidine [OCT], and QMix 2in1) on bovine pulp tissue. MATERIALS AND METHODS: Fifty bovine pulp tissue samples, each weighing 6.55 mg, were prepared and randomly divided into four experimental groups and one control group (n = 10) according to the dissolution irrigants used: (1) 5.25% NaOCl group; (2) 2% CHX group; (3) OCT group; (4) QMix 2in1 group; and (5) control group (saline solution). These samples were then placed into special bovine dentin reservoir models and immersed for 1 h with each test solution (0.1 mL of each) at room temperature. The pulp samples were then blotted dry and weighed again. The percentage of weight loss was calculated. Statistically analyzed with one-way analysis of variance and post-hoc Tukey tests (P = 0.05). RESULTS: Saline solution did not dissolve the bovine pulp tissue. All groups, except OCT, dissolved pulp samples more effectively than the control group (P < 0.05). The highest tissue dissolution was observed in 5.25% NaOCl group (P < 0.05). No statistically significant difference was found between the tissue dissolving effect between QMix 2in1 and those of 2% CHX. CONCLUSIONS: Within the limitations of this in vitro study, NaOCl exhibited the best tissue-dissolving effect out of all solutions tested. CHX and QMix 2in1 were able to dissolve pulp tissue but less than NaOCl. OCT and saline solutions could not exhibit significantly tissue-dissolving effectiveness. This study shown that QMix 2in1 has little capacity to dissolve pulp tissue therefore used alone is not sufficient for this purpose. PMID- 26430375 TI - Stress distribution of endodontically treated teeth with titanium alloy post and carbon fiber post with different alveolar bone height: A three-dimensional finite element analysis. AB - OBJECTIVE: A three-dimensional (3D) finite element analysis (FEA) on the stress distribution of endodontically treated teeth with titanium alloy post and carbon fiber post with different alveolar bone height. MATERIALS AND METHODS: The 3D model was fabricated using software to represent an endodontically treated mandibular second premolar with post and restored with a full ceramic crown restoration, which was then analyzed using FEA using FEA ANSYS Workbench V13.0 (ANSYS Inc., Canonsburg, Pennsylvania, U.S.A) software. RESULTS: The FEA showed the maximum stresses of 137.43 Mpa in dentin with alveolar bone height of 4 mm when the titanium post was used, 138.48 Mpa when carbon fiber post was used as compared to 105.91 Mpa in the model with alveolar bone height of 2 mm from the cement enamel junction (CEJ) when the titanium post was used and 107.37 Mpa when the carbon fiber post was used. CONCLUSIONS: Stress was observed more in alveolar bone height level of 4 mm from CEJ than 2 mm from CEJ. Stresses in the dentin were almost similar when the carbon fiber post was compared to titanium post. However, stresses in the post and the cement were much higher when titanium post was used as compared to carbon fiber post. PMID- 26430376 TI - A different wax sculpture technique for implant-retained auricular prosthesis. AB - Replacement of missing ears is a challenging task in which extensive array of materials and techniques have been employed. This article describes a different and simplified procedure for fabricating auricular prostheses very similar to the intact left ear of the patient. A 65-year-old male patient was referred to the Department of Prosthodontics with the loss of the right ear. In this case, the impression was made using hydrocolloid material (alginate) from the both defected and the opposite side. After hardening of the stone casts, a custom-made transparent splint plate was designed for the left auricular side. The splint was reversed and a cast model of the right auricular side was obtained as pouring the dental stone into transparent orthodontic splint. After getting the impression from cast model, conventional wax pattern and try on process was done. Finally, silicone elastomer was polymerized and the retention of the prosthesis acquired with the magnetic attachments. The technique described is economical, conventional, and time-saving. Furthermore, the prosthesis imitates the patient's intact auricular tissue. PMID- 26430377 TI - Unusual intraosseous capillary hemangioma of the mandible. AB - Intraosseous hemangioma is a benign vascular neoplasm, which is mostly seen in vertebrae, maxillofacial bones, and long bones. Intraosseous hemangioma is rarely seen on jaw bones compared to other skeletal bones and usually occurs in the cavernous form. Capillary intraosseous hemangioma of jaws is an uncommon form of intraosseous hemangioma and has not been thoroughly described so far. In this study, a case of capillary intraosseous hemangioma of the mandible was presented with relevant literature review. PMID- 26430378 TI - Implant-supported hybrid prosthesis: Conventional treatment method for borderline cases. AB - An implant-supported hybrid prosthesis is an acrylic resin complete fixed dental prosthesis and supported by implants might be a solution in extreme cases that the need of the restoration for esthetics, function, lip support, and speech. This clinical report aims to present the esthetic and functional prosthetic rehabilitation of three borderline cases with implant-supported hybrid prostheses. Patient 1 (62-year-old man) and Patient 2 (61-year-old man) presented a chief complaint of a compromised esthetic. After clinical evaluations, in Patient 1, 8 implants in the maxilla and 7 implants in mandibula were observed. Patient 2 had 7 implants in the maxilla and 7 implants in mandibula, which were previously placed. The intra-arch dimension of both patients was excessive and an insufficient peri-oral soft tissue support was observed. Patient 3 was a 61-year old man had 2 implants with a history of previously implanted graft infection and implant loss on his maxillary posterior jaw. An excessive intra-arch dimension was observed in clinical examination. In addition, massive bone defect and insufficient soft tissue support were examined. In all patients, implant supported hybrid prostheses were successfully performed. The clinical and radiologic findings were satisfactory. After 3 years of follow-up, no functional, phonetic, or esthetic problems with the restorations were noted. These case reports suggest that implant-supported hybrid prostheses can be a reliable alternative treatment procedure when a porcelain-fused metal fixed restoration does not satisfy a patient's requirements for esthetics, phonetics, oral hygiene, and oral comfort. PMID- 26430379 TI - Erythematous candidiasis leading to systemic manifestations of human immunodeficiency virus co-infection with secondary syphilis: A diagnostic and therapeutic dilemma. AB - The intensification of human immunodeficiency virus (HIV) and rising frequency of immunocompromised individuals have resulted in a resurgence of opportunistic infections. The most common opportunistic oral fungal infection in HIV-positive individuals is oral candidiasis. The classical presentation is as white scrapable form called as thrush, which is easily diagnosed and treated. The clinician is presented with a diagnostic and management dilemma when these lesions appear in new facades such as erythematous candidiasis, the latter's prevalence with HIV and AIDS being well established. In this case report, we present a case of Erythematous Candidiasis, which was associated with type 1 HIV co-infected with syphilis. We highlight the diagnostic importance of a naive looking manifestation of the tongue which was followed by a series of challenging presentations of secondary syphilis. Since the patient had a negative Veneral Disease Research Laboratory and left us with a management dilemma, the article also features the importance of prozone phenomenon (seen in 2% cases of secondary syphilis), and it's higher association with HIV co-infected individuals. With confusing clinical oral manifestations associated with these diseases, the dentist might be the first person to encounter such lesions, who should be able to recognize erythematous candidiasis and correlate them with the underlying pathology. PMID- 26430380 TI - Verrucous carcinoma and squamous cell papilloma of the oral cavity: Report of two cases and review of literature. AB - Verrucous carcinoma (VC) of oral cavity is a rare variant of well-differentiated squamous cell carcinoma and squamous papilloma is a benign proliferation of the stratified squamous epithelium, which results in a papillary or verrucous exophytic mass. There is a certain clinical similarity between squamous cell papilloma and VC. We presented a report of two cases which are VC and squamous cell papilloma that are showed the same clinical appearance but different pathological appearance, with a review of the literature. PMID- 26430381 TI - Conservation planning in agricultural landscapes: hotspots of conflict between agriculture and nature. AB - AIM: Conservation conflict takes place where food production imposes a cost on wildlife conservation and vice versa. Where does conservation impose the maximum cost on production, by opposing the intensification and expansion of farmland? Where does conservation confer the maximum benefit on wildlife, by buffering and connecting protected areas with a habitable and permeable matrix of crop and non crop habitat? Our aim was to map the costs and benefits of conservation versus production and thus to propose a conceptual framework for systematic conservation planning in agricultural landscapes. LOCATION: World-wide. METHODS: To quantify these costs and benefits, we used a geographic information system to sample the cropland of the world and map the proportion of non-crop habitat surrounding the cropland, the number of threatened vertebrates with potential to live in or move through the matrix and the yield gap of the cropland. We defined the potential for different types of conservation conflict in terms of interactions between habitat and yield (potential for expansion, intensification, both or neither). We used spatial scan statistics to find 'hotspots' of conservation conflict. RESULTS: All of the 'hottest' hotspots of conservation conflict were in sub Saharan Africa, which could have impacts on sustainable intensification in this region. MAIN CONCLUSIONS: Systematic conservation planning could and should be used to identify hotspots of conservation conflict in agricultural landscapes, at multiple scales. The debate between 'land sharing' (extensive agriculture that is wildlife friendly) and 'land sparing' (intensive agriculture that is less wildlife friendly but also less extensive) could be resolved if sharing and sparing were used as different types of tool for resolving different types of conservation conflict (buffering and connecting protected areas by maintaining matrix quality, in different types of matrix). Therefore, both sharing and sparing should be prioritized in hotspots of conflict, in the context of countryside biogeography. PMID- 26430382 TI - Exposure to English Before and After Entry into Head Start: Bilingual Children's Receptive Language Growth in Spanish and English. AB - This investigation examined the Spanish and English receptive vocabulary and language comprehension abilities of bilingual preschoolers who attended Head Start over a two-year period. It was hypothesised that bilingual children's development would follow linear trajectories and that the development of children who were only exposed to Spanish in the home prior to school entry would differ from children with exposure to Spanish and English from birth. Results revealed that the two groups' language abilities in Spanish and English differed at the beginning of the study as measured by raw and standard scores and that these differences were maintained over the two years. The exceptions to this were found in the children's vocabulary abilities, with the difference between the two groups' English standard scores narrowing over time and the difference between their Spanish standard scores increasing during the two-year period. Similar to research on monolingual and bilingual children with low socioeconomic status (SES), children's development in both languages essentially followed linear trajectories. Children's raw scores on the English receptive vocabulary test accelerated, similar to research findings on monolingual children of middle SES. Also, children's standard scores on the Spanish language comprehension measure decelerated after an initial period of linear growth. Future directions for research are discussed. PMID- 26430383 TI - Extinction of an introduced warm-climate alien species, Xenopus laevis, by extreme weather events. AB - Invasive, non-native species represent a major threat to biodiversity worldwide. The African amphibian Xenopus laevis is widely regarded as an invasive species and a threat to local faunas. Populations originating at the Western Cape, South Africa, have been introduced on four continents, mostly in areas with a similar Mediterranean climate. Some introduced populations are also established in cooler environments where persistence for many decades suggests a capacity for long-term adaptation. In these cases, recent climate warming might enhance invasion ability, favouring range expansion, population growth and negative effects on native faunas. In the cool temperate UK, populations have been established for about 50 years in Wales and for an unknown period, probably >20 years, in England (Lincolnshire). Our field studies over 30 and 10 years, respectively, show that in favourable conditions there may be good recruitment, fast individual growth rates and large body size; maximum longevity exceeds 23 years. Nevertheless, areas of distribution remained limited, with numbers <500 in each population. In 2010, only a single individual was captured at each locality and further searching failed to record any others in repeated sampling up to 2014. We conclude that both populations are now extinct. The winters of 2009-2010 and 2010 2011 experienced extreme cold and drought (December 2010 was the coldest in 120 years and the third driest in 100 years). The extinction of X. laevis in these areas indicates that even relatively long-established alien species remain vulnerable to rare extreme weather conditions. PMID- 26430384 TI - Dark-matter production through loop-induced processes at the LHC: the s-channel mediator case. AB - We show how studies relevant for mono-X searches at the LHC in simplified models featuring a dark-matter candidate and an s-channel mediator can be performed within the MadGraph5_aMC@NLO framework. We focus on gluon-initiated loop-induced processes, mostly relevant to the case where the mediator couples preferentially to third generation quarks and in particular to the top quark. Our implementation allows us to study signatures at hadron colliders involving missing transverse energy plus jets or plus neutral bosons ([Formula: see text]), possibly including the effects of extra radiation by multi-parton merging and matching to the parton shower. PMID- 26430385 TI - Global patterns of freshwater species diversity, threat and endemism. AB - AIM: Global-scale studies are required to identify broad-scale patterns in the distributions of species, to evaluate the processes that determine diversity and to determine how similar or different these patterns and processes are among different groups of freshwater species. Broad-scale patterns of spatial variation in species distribution are central to many fundamental questions in macroecology and conservation biology. We aimed to evaluate how congruent three commonly used metrics of diversity were among taxa for six groups of freshwater species. LOCATION: Global. METHODS: We compiled geographical range data on 7083 freshwater species of mammals, amphibians, reptiles, fishes, crabs and crayfish to evaluate how species richness, richness of threatened species and endemism are distributed across freshwater ecosystems. We evaluated how congruent these measures of diversity were among taxa at a global level for a grid cell size of just under 1 degrees . RESULTS: We showed that although the risk of extinction faced by freshwater decapods is quite similar to that of freshwater vertebrates, there is a distinct lack of spatial congruence in geographical range between different taxonomic groups at this spatial scale, and a lack of congruence among three commonly used metrics of biodiversity. The risk of extinction for freshwater species was consistently higher than for their terrestrial counterparts. MAIN CONCLUSIONS: We demonstrate that broad-scale patterns of species richness, threatened-species richness and endemism lack congruence among the six freshwater taxonomic groups examined. Invertebrate species are seldom taken into account in conservation planning. Our study suggests that both the metric of biodiversity and the identity of the taxa on which conservation decisions are based require careful consideration. As geographical range information becomes available for further sets of species, further testing will be warranted into the extent to which geographical variation in the richness of these six freshwater groups reflects broader patterns of biodiversity in fresh water. PMID- 26430386 TI - Analysis of stable states in global savannas: is the CART pulling the horse? AB - Multiple stable states, bifurcations and thresholds are fashionable concepts in the ecological literature, a recognition that complex ecosystems may at times exhibit the interesting dynamic behaviours predicted by relatively simple biomathematical models. Recently, several papers in Global Ecology and Biogeography, Proceedings of the National Academy of Sciences USA, Science and elsewhere have attempted to quantify the prevalence of alternate stable states in the savannas of Africa, Australia and South America, and the tundra-taiga grassland transitions of the circum-boreal region using satellite-derived woody canopy cover. While we agree with the logic that basins of attraction can be inferred from the relative frequencies of ecosystem states observed in space and time, we caution that the statistical methodologies underlying the satellite product used in these studies may confound our ability to infer the presence of multiple stable states. We demonstrate this point using a uniformly distributed 'pseudo-tree cover' database for Africa that we use to retrace the steps involved in creation of the satellite tree-cover product and subsequent analysis. We show how classification and regression tree (CART)-based products may impose discontinuities in satellite tree-cover estimates even when such discontinuities are not present in reality. As regional and global remote sensing and geospatial data become more easily accessible for ecological studies, we recommend careful consideration of how error distributions in remote sensing products may interact with the data needs and theoretical expectations of the ecological process under study. PMID- 26430387 TI - Markedly divergent estimates of Amazon forest carbon density from ground plots and satellites. AB - AIM: The accurate mapping of forest carbon stocks is essential for understanding the global carbon cycle, for assessing emissions from deforestation, and for rational land-use planning. Remote sensing (RS) is currently the key tool for this purpose, but RS does not estimate vegetation biomass directly, and thus may miss significant spatial variations in forest structure. We test the stated accuracy of pantropical carbon maps using a large independent field dataset. LOCATION: Tropical forests of the Amazon basin. The permanent archive of the field plot data can be accessed at: http://dx.doi.org/10.5521/FORESTPLOTS.NET/2014_1. METHODS: Two recent pantropical RS maps of vegetation carbon are compared to a unique ground-plot dataset, involving tree measurements in 413 large inventory plots located in nine countries. The RS maps were compared directly to field plots, and kriging of the field data was used to allow area-based comparisons. RESULTS: The two RS carbon maps fail to capture the main gradient in Amazon forest carbon detected using 413 ground plots, from the densely wooded tall forests of the north-east, to the light-wooded, shorter forests of the south-west. The differences between plots and RS maps far exceed the uncertainties given in these studies, with whole regions over- or under-estimated by > 25%, whereas regional uncertainties for the maps were reported to be < 5%. MAIN CONCLUSIONS: Pantropical biomass maps are widely used by governments and by projects aiming to reduce deforestation using carbon offsets, but may have significant regional biases. Carbon-mapping techniques must be revised to account for the known ecological variation in tree wood density and allometry to create maps suitable for carbon accounting. The use of single relationships between tree canopy height and above-ground biomass inevitably yields large, spatially correlated errors. This presents a significant challenge to both the forest conservation and remote sensing communities, because neither wood density nor species assemblages can be reliably mapped from space. PMID- 26430388 TI - Evolutionary impact assessment: accounting for evolutionary consequences of fishing in an ecosystem approach to fisheries management. AB - Managing fisheries resources to maintain healthy ecosystems is one of the main goals of the ecosystem approach to fisheries (EAF). While a number of international treaties call for the implementation of EAF, there are still gaps in the underlying methodology. One aspect that has received substantial scientific attention recently is fisheries-induced evolution (FIE). Increasing evidence indicates that intensive fishing has the potential to exert strong directional selection on life-history traits, behaviour, physiology, and morphology of exploited fish. Of particular concern is that reversing evolutionary responses to fishing can be much more difficult than reversing demographic or phenotypically plastic responses. Furthermore, like climate change, multiple agents cause FIE, with effects accumulating over time. Consequently, FIE may alter the utility derived from fish stocks, which in turn can modify the monetary value living aquatic resources provide to society. Quantifying and predicting the evolutionary effects of fishing is therefore important for both ecological and economic reasons. An important reason this is not happening is the lack of an appropriate assessment framework. We therefore describe the evolutionary impact assessment (EvoIA) as a structured approach for assessing the evolutionary consequences of fishing and evaluating the predicted evolutionary outcomes of alternative management options. EvoIA can contribute to EAF by clarifying how evolution may alter stock properties and ecological relations, support the precautionary approach to fisheries management by addressing a previously overlooked source of uncertainty and risk, and thus contribute to sustainable fisheries. PMID- 26430390 TI - The Interdependence of Adult Relationship Quality and Parenting Behaviours among African American and European Couples in Rural, Low-Income Communities. AB - The present study extends the spillover and crossover hypotheses to more carefully model the potential interdependence between parent-parent interaction quality and parent-child interaction quality in family systems. Using propensity score matching, the present study attempted to isolate family processes that are unique across African American and European American couples that are independent of other socio-demographic factors to further clarify how interparental relationships may be related to parenting in a rural, low-income sample. The Actor-Partner Interdependence Model (APIM), a statistical analysis technique that accounts for the interdependence of relationship data, was used with a sample of married and non-married cohabiting African American and European American couples (n = 82 dyads) to evaluate whether mothers' and fathers' observed parenting behaviours are related to their behaviours and their partner's behaviours observed in a couple problem-solving interaction. Findings revealed that interparental withdrawal behaviour, but not conflict behaviour, was associated with less optimal parenting for fathers but not mothers, and specifically so for African American fathers. Our findings support the notion of interdependence across subsystems within the family and suggest that African American fathers may be specifically responsive to variations in interparental relationship quality. PMID- 26430391 TI - Maternal Behavior Modifications during Pretense and Their Long-Term Effects on Toddlers' Understanding of Pretense. AB - Recent studies indicate the need to investigate the sources of toddlers' understanding of another person's pretense. The present study is a cultural and longitudinal extension of the work of Lillard and Witherington (2004), who claimed that mothers modify their behaviors during pretense and that the some of these behavior modifications help their toddlers understand maternal pretense. Experiment 1 investigated whether mothers would change their behaviors during pretense with a sample of 31 Japanese mother-infant pairs. Experiment 2, with a subsample of 20 mother-child pairs who had participated in Experiment 1, examined whether the maternal behavior modifications at 18 months predicted their toddlers' understanding of pretense at 24 months. The results of Experiment 1 indicated that Japanese mothers smiled more frequently, gazed at their toddlers longer, used sound effects more frequently, and engaged in more frequent snack related actions in a "pretense condition" than in a "real condition." In addition, some of these behaviors were significantly related to their toddlers' apparent understanding of pretense. Experiment 2 showed that both the frequency of maternal smiles and the number of sound effects in the pretense condition at 18 months predicted toddlers' understanding of the pretense enacted by a strange adult at 24 months. This research indicates the impact of maternal behavior modifications during pretense on the development of symbolic thought in the 2nd year of life. PMID- 26430389 TI - Biomarkers and severe asthma: a critical appraisal. AB - Severe asthma (SA) is a clinically and etiologically heterogeneous respiratory disease which affects among 5-10 % of asthmatic patients. Despite high-dose therapy, a large patients percentage is not fully controlled and has a poor quality of life. In this review, we describe the biomarkers actually known in scientific literature and used in clinical practice for SA assessment and management: neutrophils, eosinophils, periostin, fractional exhaled nitric oxide, exhaled breath condensate and galectins. Moreover, we give an overview on clinical and biological features characterizing severe asthma, paying special attention to the potential use of these ones as reliable markers. We finally underline the need to define different biomarkers panels to select patients affected by severe asthma for specific and personalized therapeutic approach. PMID- 26430392 TI - Update in Urothelial Carcinoma: Novel Agents and Targeted Therapy. AB - Urothelial carcinoma (UC) is a chemosensitive disease with high response rates to platinum-based combination chemotherapy in locally advanced or advanced disease. However, de novo or emergence of cisplatin-resistance limits the duration of response, patients are frequently ineligible for cisplatin, and therapies tested thus far have minimal activity as second-line therapy. The first wave of clinical trials of novel agents and targeted therapy have modestly advanced the field and laid the foundations for future studies. These trials include the deployment of monoclonal antibodies and tyrosine kinase inhibitors that target mediators of angiogenesis and growth receptors. Novel cytotoxic agents have also been tested as single-agents in the second-line setting and together with the first-line combination of gemcitabine with cisplatin. To date, these novel agents have yet to demonstrate the ability to substantially improve the overall survival of patients with bladder cancer. Comparative trials of chemotherapy with or without a novel agent are ongoing and have the potential to improve upon current standard therapy. Moreover, state-of-the-art technologies have been developed that will likely identify the molecular alterations which drive both UC and platinum resistance and in turn provide opportunities for drug development. The latter includes an interrogation of microRNAs and the integrated study of genetic mutations in extreme phenotypes of the disease. In essence, this ongoing work paired with physician and patient commitments to clinical trial participation will ultimately lead to advances in the care of patients with urothelial cancer. PMID- 26430393 TI - Transmembrane helices in "classical" nuclear reproductive steroid receptors: a perspective. AB - Steroid receptors of the nuclear receptor superfamily are proposed to be either: 1) located in the cytosol and moved to the cell nucleus upon activation, 2) tethered to the inside of the plasma membrane, or 3) retained in the nucleus until free steroid hormone enters and activates specific receptors. Using computational methods to analyze peptide receptor topology, we find that the "classical" nuclear receptors for progesterone (PRB/PGR), androgen (ARB/AR) and estrogen (ER1/ESR1) contain two transmembrane helices (TMH) within their ligand binding domains (LBD).The MEMSAT-SVM algorithm indicates that ARB and ER2 (but not PRB or ER1) contain a pore-lining (channel-forming) region which may merge with other pore-lining regions to form a membrane channel. ER2 lacks a TMH, but contains a single pore-lining region. The MemBrain algorithm predicts that PRB, ARB and ER1 each contain one TMH plus a half TMH separated by 51 amino acids.ER2 contains two half helices. The TM-2 helices of ARB, ER1 and ER2 each contain 9-13 amino acid motifs reported to translocate the receptor to the plasma membrane, as well as cysteine palmitoylation sites. PoreWalker analysis of X-ray crystallographic data identifies a pore or channel within the LBDs of ARB and ER1 and predicts that 70 and 72 residues are pore-lining residues, respectively. The data suggest that (except for ER2), cytosolic receptors become anchored to the plasma membrane following synthesis. Half-helices and pore-lining regions in turn form functional ion channels and/or facilitate passive steroid uptake into the cell. In perspective, steroid-dependent insertion of "classical" receptors containing pore-lining regions into the plasma membrane may regulate permeability to ions such as Ca(2+), Na(+) or K(+), as well as facilitate steroid translocation into the nucleus. PMID- 26430394 TI - Continuous-flow Ferrohydrodynamic Sorting of Particles and Cells in Microfluidic Devices. AB - A new sorting scheme based on ferrofluid hydrodynamics (ferrohydrodynamics) was used to separate mixtures of particles and live cells simultaneously. Two species of cells, including Escherichia coli and Saccharomyces cerevisiae, as well as fluorescent polystyrene microparticles were studied for their sorting throughput and efficiency. Ferrofluids are stable magnetic nanoparticles suspensions. Under external magnetic fields, magnetic buoyancy forces exerted on particles and cells lead to size-dependent deflections from their laminar flow paths and result in spatial separation. We report the design, modeling, fabrication and characterization of the sorting device. This scheme is simple, low-cost and label free compared to other existing techniques. PMID- 26430396 TI - What ails the Pakistani medical institutions? PMID- 26430395 TI - Exposure to 50 Hz electromagnetic field changes the efficiency of the scorpion alpha toxin. AB - BACKGROUND: Extremely low-frequency (50 Hz) electromagnetic field (ELF-EMF) is produced by electric power transmission lines and electronic devices of everyday use. Some phenomena are proposed as "first effects" of ELF-EMF: the discrete changes in the membrane potential and the increase of the calcium channel activity as well as the intracellular concentration of Ca(2+). Interaction of the scorpion alpha toxin with the sodium channel depends on the orientation of the charges and may be perturbed by changes in the membrane polarization. The toxin induces overexcitability in the nervous system and an increase in the neurotransmitters released with different consequences, mainly the paralysis of muscles. We assumed that the exposure to ELF-EMF 0.7 mT will change the effects of the insect selective scorpion alpha toxin (recombinant LqhalphaIT from Leiurus quinquestriatus hebraeus) at the level of the cercal nerve function, the synaptic transmission and on the level of entire insect organism. Taking into account the compensatory mechanisms in organisms, we tested in addition ten times higher ELF EMF on whole insects. METHODS: Experiments were performed in vivo on cockroaches (Periplaneta americana) and in vitro - on isolated cockroach abdominal nerve cord with cerci. In biotests, the effects of LqhalphaIT (10(-8) M) were estimated on the basis of the insect ability to turn back from dorsal to ventral side. Three groups were compared: the control one and the two exposed to ELF-EMF - 0.7 and 7 mT. Bioelectrical activity of the cercal nerve and of the connective nerve that leaves the terminal abdominal ganglion was recorded using extracellular electrodes. LqhalphaIT (5 * 10(-8) M) induced modifications of neuronal activity that were observed in the control cockroach preparations and in the ones exposed to ELF-EMF (0.7 mT). The exposure to ELF-EMF was carried out using coils with a size appropriate to the examined objects. RESULTS: The exposure to ELF-EMF (0.7 mT) modified the effects of LqhalphaIT (5 * 10(-8) M) on activity of the cercal nerve and of the connective nerve. We observed a decrease of the toxin effect on the cercal nerve activity, but the toxic effect of LqhalphaIT on the connective nerve was increased. Biotests showed that toxicity of LqhalphaIT (10(-8) M) on cockroaches was reduced by the exposure to ELF-EMF (0.7 and 7 mT). CONCLUSIONS: The exposure to 50 Hz ELF-EMF modified the mode of action of the anti-insect scorpion alpha toxin LqhalphaIT at cellular level of the cockroach nervous system and in biotests. Toxin appeared as a usefull tool in distinguishing between the primary and the secondary effects of ELF-EMF. PMID- 26430397 TI - Comparison of microcoils and polyvinyl alcohol particles in selective microcatheter angioembolization of non variceal acute gastrointestinal hemorrhage. AB - OBJECTIVES: To compare the efficacy of polyvinyl alcohol (PVA) particles with microcoils in angiembolisation of non variceal acute gastrointestinal haemorrhage. METHODS: This is a retrospective cross-sectional study of patients who underwent transcatheter angioembolization from January, 1995 to December, 2013 at Aga Khan University Hospital, Karachi. Patients were divided into two groups on basis of use of either microcoils or PVA particles and compared in terms of technical success, clinical success, re-bleeding and ischemic complication rates. Chi (chi(2)) square and Fisher's exact tests were applied and a P-value of less than 0.05 was considered statistically significant. RESULTS: Fifty seven patients underwent angioembolization. Microcoil and PVA particles embolization was performed in 63% (36/57) and 35% (20/57) cases respectively. Technical success was achieved in all cases (100%). Clinical success rate was higher in microcoils group (92%) than PVA particles group (75%) with statistically significant P value (p=0.048). Ischemic complication was seen in one case (3%) in the microcoil group, while no such complications were seen in the PVA particles group. CONCLUSION: In angioembolization of non variceal acute gastrointestinal haemorrhage microcoils are better than Polyvinyl alcohol particles with higher clinical success and lower re-bleed rates. PMID- 26430398 TI - Perceptions of clinical years' medical students and interns towards assessment methods used in King Abdulaziz University, Jeddah. AB - OBJECTIVES: The study was done to determine the perception of clinical years' medical students and interns about assessment methods used in Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. METHODS: A cross sectional study was conducted during the educational year 2012/2013. A multistage stratified random sample method was used to select 600 senior medical students (4(th)-6(th)) and interns. Perception of medical students and interns about different assessment formats was inquired using 3 points Likert scale. RESULTS: About two-fifths of participants agreed that assessment methods are comprehensive, reflecting what they taught, and challenging them. MCQs were the commonest (56.8%) preferred written assessment format. OSCE (74.1%) and OSPE (70.6%) were seen as good tools for assessing clinical competencies. Students had good perceptions towards peer assessment, log-book and open book exams. Males preferred peer assessment method more than females, with a statistical significant difference (chi(2) = 6.43, p< 0.05). CONCLUSION: Assessment plan needs further improvements and should be designed prospectively along with learning outcomes, as only about 40 % of participants agreed with assessment items. The current development of the faculty Assessment Unit will provide much help. This will lead to better preparation of medical students for their future responsibility as tomorrow's doctors. PMID- 26430399 TI - Can living donor liver transplantation offer similar outcomes to deceased donor liver transplantation using expanded selection criteria for hepatocellular carcinoma? AB - OBJECTIVE: To compare the outcomes of living donor liver transplantation (LDLT) versus deceased donor liver transplantation (DDLT) for patients with hepatocellular carcinoma (HCC) in different selection criteria. METHODS: Data of patients with HCC who underwent liver transplantation between 2005 and 2013 at our center were reviewed. Clinical data of LDLT recipients and DDLT recipients were compared. The postoperative recurrence-free survival (RFS) rate and overall survival (OS) rate after LDLT versus DDLT were compared in the Milan recipients, the University of California, San Francisco (UCSF) recipients, the up-to-seven recipients, the Hangzhou recipients and the Chengdu recipients. RESULTS: Data of 255 patients were retrospectively reviewed in this study. Seventeen DDLT recipient and 9 LDLT recipients died during the perioperative period. Among the remaining 229 recipients (NLDLT=66, NDDLT=163), 96 patients met the Milan criteria, 123 recipients met the UCSF criteria, 135 patients met the up-to-seven criteria, 216 patients met the Hangzhou criteria, and 229 recipients met the Chengdu criteria. The overall RFS and OS rates of the Milan recipients, the UCSF recipients, the up-to-seven recipients, the Hangzhou recipients and the Chengdu recipients after LDLT and DDLT were all similar. CONCLUSION: Using well-studied selection criteria, LDLT offers similar outcomes to DDLT for patient with HCC, even using expanded selection criteria. PMID- 26430400 TI - The effectiveness of trendelenburg positioning on the cross-sectional area of the right internal jugular vein in obese patients. AB - OBJECTIVE: Trendelenburg positioning is a common approach used during internal jugular vein (IJV) cannulation. No evidence indicates that Trendelenburg positioning significantly increases the cross-sectional area (CSA) of the IJV in obese patients. The primary aim of this study was to determine the effectiveness of Trendelenburg positioning on the CSA of the right internal jugular vein assessed with ultrasound measurement in obese patients. METHODS: Forty American Society of Anesthesiologists II patients with body mass index >=30 kg/m(2) undergoing various elective surgeries under general endotracheal anesthesia were enrolled. Ultrasound images of the right IJV were obtained in a transverse orientation at the cricoid level. We measured the CSA of the right IJV two different conditions in a sealed envelope were applied in random order: State 0, table flat (no tilt), with the patients in the supine position, and State T, in which the operating table was tilted 20 degrees to the Trendelenburg position. RESULTS: The change in the CSA of the IJV from the supine to the Trendelenburg position (1.80 cm(2) vs 2.08cm(2)) was not significantly different. The CSA was paradoxically decreased in 10 of 36 patients when the position changed from State 0 to State T. CONCLUSIONS: Trendelenburg positioning does not significantly increase the mean CSA of the right IJV in obese patients. In fact, in some patients, this position decreases the CSA. The use of the Trendelenburg position for IJV cannulation in obese patients can no longer be supported. PMID- 26430401 TI - Occupational lead toxicity in battery workers. AB - OBJECTIVE: To estimate blood lead level (BLL) and to assess the features of lead toxicity among lead acid battery (LAB) industrial workers. METHODS: This prospective study was carried out in the medical centre of PCSIR Laboratories, Karachi from March 2012 - March 2013. Fifty LAB industry workers, males and females between 17-65 years were included in the study. They were divided into group 1 with 40 workers- directly related and group 2 with 10 workers -indirectly related, (administration staff members) to LAB manufacture. Detailed history, complete physical examination and BLL estimation by flameless atomic absorption spectrophotometer was done. RESULTS: Total 34 patients in group 1 and 3 patients in group 2 had elevated BLL. Comparison of group 1 and 2 revealed anemia (40v/s4), bone pain (38v/s7), abdominal pain (38 v/s 2), nausea (32v/s6), head ache & irritability (24v/s6), weakness & lethargy (21v/s6), tremors (13v/s0) insomnia (5v/s4), lead line (4v/s 0) and blood pressure above 140/90 mm of Hg (12v/s0) respectively. CONCLUSION: High blood lead level and features attributable to lead toxicity were prevalent among LAB industry workers of Karachi. PMID- 26430402 TI - Is Gemcitabine and Cisplatin Induction Chemotherapy Superior in Locoregionally Advanced Nasopharyngeal Carcinoma? AB - OBJECTIVE: To investigate the outcome of locoregionally advanced nasopharyngeal carcinoma (NPC) treated with induction chemotherapy followed by chemoradiotherapy. METHODS: Between June 2005 and October 2007, 604 patients with locoregionally advanced NPC were analyzed, of whom 399 and 205 were treated with conventional radiotherapy and intensity-modulated radiotherapy (IMRT) respectively. Meanwhile, 153 patients received concurrent chemotherapy, and 520 were given induction chemotherapy. RESULTS: With a median follow-up time of 65 months, the 3-, and 5-year overall survival (OS), locoregional free survival (LRFS), and distant-metastasis free survival (DMFS) rates were 82.5% vs. 72.6%, 90.6% vs. 87.1%, and 82.5% vs. 81.2%, respectively. Induction chemotherapy was not an independent prognostic factor for OS (P=0.193) or LRFS, but there was a positive tendency for DMFS (P=0.088). GP regimen (gemcitabine + cisplatin) was an independent prognostic factor for OS (P = 0.038) and it had a trend toward improved DMFS (P = 0.109). TP regimen (taxol + cisplatin) was only a significant prognostic factor for DMFS (P =0.038). CONCLUSIONS: Adding induction chemotherapy had no survival benefit, but GP regimen benefited overall survival and had a trend toward improved DMFS. GP regimen may be superior to TP/FP regimen (fluorouracil + cisplatin) in treating locoregionally advanced NPC. PMID- 26430403 TI - The effects of blood transfusion on renal functions in orthopaedic surgery. AB - OBJECTIVE: The effects of perioperative blood transfusion on renal functions have been studied in various studies. In this study, we investigated the effects of blood transfusion on postoperative kidney functions in patients who underwent orthopaedic surgeries. METHOD: Total 136 patients who were operated for several orthopedic pathologies between June 2013 and December 2014 were evaluated. The patients were divided into two groups according to the amounts of blood transfusion. Ninety five patients (69.8%) who were transfused less than 3 units were included in Group 1 and 41 patients (30.2%) who received 3 and more units of blood were included in Group 2. RESULTS: There were no statistical difference between the two groups in terms of preoperative gender, hypertension, diabetes mellitus, chronical renal failure and smoking habbits (P > 0.05). No statistical differences between the groups were seen in terms of postoperative hospital stay, pulmonary and other complications as well as mortality (P > 0.05). When the two groups were compared for blood parameters showing postoperative renal and other system functions, no statistical differences were detected (P > 0.05). CONCLUSION: Blood transfusion does not have negative effects on postoperative BUN and creatinine levels in patients operated for orthopaedic pathologies. PMID- 26430404 TI - Influenza and respiratory syncytial viruses: Efficacy of different diagnostic assays. AB - OBJECTIVE: To determine the efficacy of cell culture, immunoflourescence Assay (IFA) and real time polymerase chain reaction (rRT-PCR) in relation to diagnosis of influenza and Respiratory Syncytial Virus (RSV). METHODS: Total 2781 specimens of throat swabs and nasopharyngeal aspirates were obtained from patients suspected of respiratory viruses' infections from January 2009 to December 2011 at Universiti Kebangsaan Malaysia Medical Centre(UKMMC). The specimens were processed by cell culture and immunoflurescence assay (IFA) and (rRT-PCR). RESULTS: Thirty three (1.19%) specimens were positive for influenza virus A and 42 (1.51%) were positive for RSV by cell culture and IFA. On the other hand, rRT PCR was able to identify 189 of 505 (37.43%) specimens in which 65 were influenza A virus and 124 were RSV. Sensitivity of rRT-PCR was 100% for both influenza A virus and RSV and specificity was 88% and 77% for influenza A virus and RSV, respectively. CONCLUSION: rRT-PCR diagnosed respiratory viruses in shorter time with a high level of sensitivity in comparison to conventional assays - cell culture and IFA. These advantages help in managing patients by saving cost and hospitalization stay. PMID- 26430405 TI - Practices and challenges of infectious waste management: A qualitative descriptive study from tertiary care hospitals in Pakistan. AB - BACKGROUND AND OBJECTIVE: Infectious waste management practices among health care workers in the tertiary care hospitals have been questionable. The study intended to identify issues that impede a proper infectious waste management. METHODS: Besides direct observation, in-depths interviews were conducted with the hospital administrators and senior management involved in healthcare waste management during March 2014. We looked at the processes related to segregation, collection, storage and disposal of hospital waste, and identified variety of issues in all the steps. RESULTS: Serious gaps and deficiencies were observed related to segregation, collection, storage and disposal of the hospital wastes, hence proving to be hazardous to the patients as well as the visitors. Poor safety, insufficient budget, lack of trainings, weak monitoring and supervision, and poor coordination has eventually resulted in improper waste management in the tertiary hospitals of Rawalpindi. CONCLUSION: Study has concluded that the poor resources and lack of healthcare worker's training in infectious waste results in poor waste management at hospitals. PMID- 26430406 TI - Readiness for Self-Directed learning among first year Saudi Medical students: A descriptive study. AB - OBJECTIVES: The objectives of the present study was to explore the readiness for Self Directed Learning (SDL) among first year Saudi Medical students enrolled at King Saud University (KSU) and Princess NourahBintAbdulrahman University (PNU) in Saudi Arabia. METHODS: First year medical students were invited to participate in a descriptive cross sectional study design. Data were collected using a Self Directed Learner Readiness Scale (SDLRS) which is a self- assessment tool aimed to assess three main components: self-management, desire for learning and self control. The students responded to each item of the SDLRS on a 5-point Likert scale. Data were analyzed using SPSS, mean, median and total scores were calculated and were compared among student's groups. RESULTS: The mean score for the desire of learning was the highest (4.08+/- 0.5) of all the three components of the SDLRS followed by self-control (3.9+/- 0.9), while the least mean score was for self-management (3.7+/-0.5). Overall, differences between student's groups were not statistically significant. CONCLUSION: The present study revealed that the overall SDL readiness of participants was good, students were highly motivated for self-learning and had the ability for self-control. However, they need assistance to improve their self-management skills. PMID- 26430407 TI - Serum Levels of MDC and MMP-9 and the Relationship Between Serum Levels and Disease Activity in the Patients with Systemic Lupus Erythematosus. AB - BACKGROUND AND OBJECTIVE: Systemic lupus erythematosus (SLE) is a complicated autoimmune disease. Although its pathogenesis is not clear, cytokine may be involved in it. So we investigated serum levels of macrophage-derived chemokine (MDC), and matrix metalloproteinase-9 (MMP-9), and to determine the relationship between serum levels and the disease activity of SLE. METHODS: Serum levels of MDC and MMP-9 were measured by enzyme-linked immuno sorbent assay (ELISA). RESULTS: Significantly decreased serum levels of MDC and MMP-9 were found in SLE as compared to those in controls (P<0.001 P<0.001), but serum levels of MDC and MMP-9 increased after treatment (P<0.001 P<0.05). Serum levels of MDC and MMP-9 were lower in patients with active disease than those with inactive disease (P<0.001 P<0.05). Significantly decreased serum levels of MDC and MMP-9 were found in patients with renal damage than those without the damage (P<0.001 P<0.05). Serum level of MDC was lower in patients with arthritis than those without the damage (P<0.001), but serum level of MMP-9 has no significant difference in two groups (P>0.05). CONCLUSION: The present data suggest that MDC and MMP-9 may be involved in the pathogenesis of SLE, and serum levels of MDC and MMP-9 could be markers of monitoring disease activity, renal damage, disease progression and improvement in SLE. PMID- 26430408 TI - Prognostic factors for stereopsis in refractive accommodative esotropia. AB - OBJECTIVE: To determine the prognostic factors affecting stereoacuity in patients with refractive accommodative esotropia (RAE) according to the results of long follow- up period. METHODS: We reviewed the charts of 70 patients with RAE between the years 1985-2014. Patients were classified into three groups. G-1: Stereoacuity score 40 second/arc. G-2: Stereoacuity score >40 second/arc (50 3000). G-3: No binocular vision. Initiation age of RAE, duration of deviation, refractive error, amblyopia, amblyopia treatment, anisometropia, visual acuity, family history, angle of deviation for distance and near at each group and the prognostic factors affecting stereoacuity were analyzed. RESULTS: The mean initiation age of RAE was 2.7+/-1.5 years, the mean age at first visit was 6.4+/ 4.2 years. The mean follow up time was 7.3+/-4.4 years. Seven patients had 40 second/arc, 48 patients had 50 to 3000 second/arc stereoacuity, 15 patients had no binocular vision. Mean deviation for near was statistically higher in group 2 and 3. Visual acuity levels were higher in group 1 and 2 and was statistically significant. Low visual acuity (p=0.001, 0.008), higher angle of deviation at near (p=0.01), increased duration of deviation (p=0.01), presence of amblyopia (p=0.001) and irregularity of amblyopia treatment (p=0.01) were significantly related with poor stereoacuity. CONCLUSION: According to the prognostic factors low stereoacuity was mostly related with amblyopia as a result the late presentation of the patients in seeking care. Appropriate treatment as full refractive correction and amblyopia treatment during the RAE is important for development of good stereopsis. Also angle of deviation at near and duration of deviation can be a useful predictor for poor stereoacuity levels. PMID- 26430409 TI - Comparison of higher order aberrations in patients with various refractive errors. AB - OBJECTIVE: To compare the mean root mean square (RMS) of total higher order aberrations (HOAs), coma and spherical aberrations in individuals with myopia, hypermetropia and myopic astigmatism. METHODS: This prospective analytical study was conducted at Armed Forces Institute of Ophthalmology, Rawalpindi, Pakistan from Jan 2014 to Dec 2014. Two hundred eyes of 121 patients with age ranging from 18-40 years were included in the study. Patients were divided into 4 group namely Low myopia, High myopia, Astigmatism and Hypermetropia on the basis of refractive error. Included were the patients who had refractive error more than +/- 0.5D and best corrected visual acuity (BCVA) of 0.00 or better. Patients who had history of surgery and / or eye disease were excluded from the study. Visual acuity (VA), Spherical equivalent (SE) of refractive error, RMS value of total HOAs, coma and spherical aberrations were evaluated. HOAs were measured with aberrometer (Wavelight analyzer version 1073) at 6 mm pupil size. RESULTS: Age of the patients ranged from 18 years to 40 years with mean age of 29.10+/-10.6 years. Seventy one (35.5%) were males and 129 (64.5%) were female. Mean RMS value of HOAs, coma and spherical aberrations was calculated in all four groups. RMS of total HOAs and spherical aberrations in hypermetropia was 0.96+/-0.96 and 0.30+/ 0.42 respectively and it was higher than other three groups. CONCLUSIONS: In overall comparison the mean RMS of total HOAs and spherical aberrations was significantly increased in hypermetropia group and there was a statistically significant negative correlation of SE of hypermetropia with RMS of total HOAs and spherical aberration. PMID- 26430410 TI - Prevalence of obesity and hypertension among University students' and their knowledge and attitude towards risk factors of Cardiovascular Disease (CVD) in Jeddah, Saudi Arabia. AB - OBJECTIVES: To investigate the prevalence of obesity and hypertension among University students' and their knowledge and attitude towards risk factors of cardiovascular disease (CVD) in Jeddah,: Saudi Arabia. METHODS: A total of 610 male students were selected for present cross sectional study and their blood pressure (BP) and body mass index (BMI) was determined, other data was gathered through a questionnaire, and SPSS-16 was used for analyzing data. RESULTS: Out of 610 students, 7.5% were hypertensive (systolic 2.6% and diastolic 6.3%) while the BMI of 51.6% was in the normal range, 29.8% were overweight and 10.7% were moderately obese and 7.9% were severely obese. Majority of the participants considered that smoking, increased fatty food intake, obesity, high BP, and increased LDL-cholesterol level, are the main causes of the CVD. Most of the participants agreed that one should know his BP, blood sugar, serum cholesterol and one should maintain normal body weight and should do regular exercise. They were also aware that healthy lifestyle could prevent CVD. However, majority of the participants were not practicing healthy lifestyle. CONCLUSION: A huge gap exists in the knowledge, attitude and practice regarding risk factors of CVD among the university students. PMID- 26430411 TI - Psychosocial risk factors of myocardial infarction and adverse effects of streptokinase in public sector hospitals. AB - OBJECTIVES: This study investigated the psychosocial risk factors of myocardial infarction and time related adverse effects of administration of streptokinase on short-term morbidity and mortality in patients with ST-segment-elevation myocardial infarction (STEMI). METHODS: One hundred patients with STEMI treated with streptokinase in the hospital setting were prospectively enrolled in the study. The primary outcome parameter was the incidence of major adverse cardiac events. During hospital stay the psychosocial and demographic risk factors were also investigated. RESULTS: The overall mortality rate was similar in both groups and it was not significant. (5.7% vs 14.5%; P = 0.18). The number of recurrent chest pain was significantly higher in the group 2 compared to the group 1 (25% vs 62.5%; P = .01). The number of hypotesion was significantly higher in the group 1 as compared to the group 2 (30.7% vs 6.2%; P = .009). The demographic and psychosocial risk factors were recorded. CONCLUSIONS: The early intravenous administration of streptokinase in the hospital setting leads to a reduced rate of major cardiovascular events compared to delayed administration beyond 2 hours. However, mortality rates were not significantly affected. Secondary prevention should be targeted on modifiable demographic, dietary, and psychosocial risk factors of STEMI. PMID- 26430412 TI - Child sexual abuse among adolescents in southeast Nigeria: A concealed public health behavioral issue. AB - BACKGROUND AND OBJECTIVE: Child sexual abuse among adolescents is an often overlooked issue in pediatrics, yet it is a major cause of low self esteem and stigmatization in adolescents. The objective of this study was to determine the socioeconomic determinant and pattern of child sexual abuse among adolescent attending secondary schools in South East Nigeria. METHODS: This was a cross sectional study that was carried out among children in three secondary schools in Enugu and Ebonyi states of Nigeria. Five hundred and six adolescents who met inclusion criteria were consecutively recruited into our prospective study between June and October, 2014. RESULTS: One hundred and ninety nine (40 %) of the respondents had been abused and the commonest form of abuse was to look at pornographic pictures, drawings, films, videotapes or magazine 93(18.4%). Fifty eight (11.5%) adolescents stated that they were abused once with age at first exposure being 7-12 years 57 (11.4%). When grouped together, family members and relatives are perpetrators of child sexual abuse. There was significant difference in sex abuse between males and females (p=0.014) while there were no significant difference for age (p=0.157) and social class (p=0.233). CONCLUSION: Overall prevalence and one time prevalence rates of sexual abuse among adolescents in south east Nigeria was 40% and 11.5% respectively with male perpetrators. There is no link between socioeconomic class, age and child sexual abuse among adolescents. PMID- 26430413 TI - Acute Post Surgical Pain may result in chronic post surgical pain: A Systemic Review and Meta Analysis. AB - OBJECTIVE: Chronic post surgical pain (CPSP) occurres frequently (from 10% to 50%) and has serious effects on the mood and activities of patients. This study was designed to evaluate the relationship between acute post surgical pain and chronic post surgical pain. METHODS: Electronic search databases included PubMed, EMBASE, Cochrane database and web of science. 9-stars Newcastle-Ottawa Scale was used to evaluate the quality of included studies. The odds ratio was used as a summary statistic index. Heterogeneity was assessed with I (2). RESULTS: We collected data from 4 case-control studies with or without chronic post surgical pain and compared those with patients who had acute post surgical pain or not. The age, sex was controlled as confounding factors. We collected 765 patients with chronic post surgical pain, of which 38.82% used to have acute post surgical pain. The risk ratio of patients with acute post surgical pain, as compared with no acute post surgical pain, was 3.10 for chronic post surgical pain (95% CI: 2.44, 3.96). CONCLUSION: Acute post surgical pain is a rick factor for chronic post surgical pain. We need to pay much attention to this phenomenon. However, more studies with high quality were still needed to confirm these findings. PMID- 26430414 TI - The prevalence and causes of visual impairment in young Turkish men. AB - OBJECTIVE: To explore the causes and prevalence of visual impairment in young Turkish men. METHODS: The health examination data of the candidates that are saved in National Defense Ministry of Turkey was used. The data of the candidates examined between 1 January 2009 and 31 December 2011 were evaluated. The total number of the candidates was 1777500. The candidates requiring advanced examination are referred to secondary and tertiary examination hospitals. RESULTS: Fourteen thousand eight hundred sixty two(14862) out of 1777500 candidates were declared unfit for compulsory military service because of ophthalmic causes. The prevalence of ophthalmologic diseases causing unfitness for military service was found 0.746% for 2009, 0.871% for 2010 and 0.889% for 2011. These included high refractive errors which was the most frequent pathology causing unfitness (40.1%). Nonsurgical retina, vitreous and optic nerve diseases were the most frequent cause of visual impairment (0.212%). Corneal and lens pathologies were the second most frequent cause of blindness (0.101%). CONCLUSIONS: The data bank in National Defense Ministry analyzed in this study is not directly intended to explore the causes and prevalence of visual impairment in Turkey. However this study gives considerable knowledge about the causes and prevalence of visual impairment in Turkey. PMID- 26430415 TI - Response Guided Interferon Therapy for Genotype 3 of Chronic Hepatitis C: Compliance and Outcome. AB - OBJECTIVE: To determine compliance and improvement in sustained viral response (SVR) by following response guided therapy (RGT) plan of interferon and ribavirin, for genotype 3 in chronic hepatitis C. METHODS: Patients with chronic hepatitis C genotype 3, who were eligible for interferon-ribavirin therapy and consented for RGT, were included. Those with no rapid viral response (RVR), having coarse echotexture of liver or undergoing re-treatment, were advised 48 week treatment whereas, rest had 24 week standard therapy. PCR for HCV RNA checked 6 months after discontinuing treatment, was the primary end point of study. RESULTS: Of 154 patients, included in the study with mean age of 39.9 (+/ 10.84) and male to female ratio 1.4/1 (94/60), majority of patients, 136 (88.4%) were treatment naive whereas, 18 (11.6%) were being retreated. On ultrasound, 63 (40.9%) patients had coarse liver and 33 (21.4%) had splenomegaly. RVR was achieved in 99 (64.3%) patients. Overall 66(42.8%) patients merited extended duration of therapy as per RGT plan but only 22 (33%) were compliant. Treatment related side effects were the dominant reason for declining RGT in 33 (75%) patients. SVR was noted in 111 (72.1%) patients. Those patients with extended therapy (RGT), had SVR 90.9% (20/22), although, better but statistically not significant than those who stopped therapy at 6 months 77.2% (34/44) (p value 0.11). CONCLUSION: Response guided therapy plan did not improve SVR to pegylatedinterferon and ribavirin therapy in patients with genotype 3 and it has low patient compliance due to treatment related side effects. PMID- 26430416 TI - Knowledge and practice of implant-retained restorations among dental students in Saudi Arabia. AB - OBJECTIVES: The aim of the study was to assess the knowledge and practice of implant retained restorations (IRR) among senior dental students in Saudi Arabia. METHODS: Four hundred questionnaires were distributed among senior dental students of five dental schools in Saudi Arabia. Student's knowledge was assessed regarding which implant restoration [cement retained restoration (CRR) or screw retained restoration (SRR)] better provides the desired clinical properties. Students' practice of IRR, perception of their knowledge and need for further education related to IRR were also assessed. Descriptive statistics and chi square test were employed to assess collected data. RESULTS: Three hundred and fifty four senior dental students responded at a response rate of 88.5%. Thirty three percent respondents did not have any practical experience of IRR. Students showed a clear preference for CRR with regards to aesthetics (71.4%), passive fit (55.3%), fabrication ease (57.3%) and fracture resistance (40%). SRR were considered to provide better retention (59.6%), soft tissue health (51.1%) and ease of retrievability (72%). Nearly 40% of students agreed that they did not get sufficient information related to IRR in undergraduate courses. CONCLUSIONS: Clinical training of IRR is compromised in the undergraduate curriculum in dental schools of Saudi Arabia. The knowledge of dental students regarding IRR was broadly in line with current evidence. PMID- 26430417 TI - Effect of different pH solvents on micro-hardness and surface topography of dental nano-composite: An in vitro analysis. AB - OBJECTIVE: Erosion of tooth surface is attributed to recent shift in diet pattern and frequent use of beverages. The aim of this research was to evaluate the effects of different beverages on surface topography and hardness of nano-filled composite material. METHODS: Sixty flat disc shaped resin composite samples were fabricated and placed in distilled water for 24 hours. After 24 hours test samples were dried and divided into 4 groups. Group A (n=15) specimens were placed in tight amber bottle comprising 25 ml of artificial saliva. Similarly Group B, C and D were stored in equal amounts of orange juice, milk and coca cola drink respectively. Samples were checked for hardness and surface changes were evaluated with scanning electron microscopy. RESULTS: There were strong significant difference observed in samples immersed in orange juice and artificial saliva. A strong significant difference was seen between Group D and Group A. Group A and Group C showed no significant difference. The micro-hardness test showed reduced values among all samples. CONCLUSION: Beverages consumed daily have a negative influence on hardness and surface degradation of nano filled dental composite. Comparatively, nano-filled composites possess higher surface area to volume ratio of their fillers particle size may lead to higher surface roughness than other resin based dental biomaterials. PMID- 26430418 TI - Dietary Practices in Saudi Cerebral Palsy Children. AB - OBJECTIVES: To determine the dietary practices of Saudi cerebral palsy (CP) children. METHODS: A self-administered questionnaire was used to collect the following information from parents of CP children: demographics, main source of dietary information, frequency of main meals, foods/drinks used for main meals and in-between-meals. RESULTS: Parents of 157 CP children participated. Parents were divided into three, while children were divided into two age groups. The main sources of dietary information included popular media (46.5%) and dentist (36.3%). Most of the children had three meals (71.3%) or two meals (24.8%) daily. Choices for main meals included meats (68.8%), vegetables (65.6%), fruits (28.4%) and puddings (38.9%). The main three drinks choices with main meals included packed juices (59.9%), bottled water (58.8%) and fresh fruit juices (33.1%). The choices for in-between meals snacks included biscuits (61.1%), potato chips (51.6%), fruits (43.9%) and chocolates (41.4%). The choice of drinks with snacks was similar to that used with main meals. In cross-tabulation, older parents used meat (p=.03) and soft drinks (p=.04) more often for their children's main meals. Older children were given meat (p=.004) and soft drinks (p=.04) more often with main meals. Older children were given potato chips as snacks more often than younger children (p=.02), and there was a trend towards use of chocolates as snacks in older children (p=.08). CONCLUSION: Parents of CP children need to be educated about dietary practices of their children especially in areas such as the use of packed juices, dairy products, soft drinks and chocolates. PMID- 26430419 TI - Prevalence of celiac disease in adult type 1 patients with diabetes. AB - OBJECTIVES: Celiac disease, an autoimmune disease, is related to immune mediated intolerance to gluten. Some studies suggest that Celiac Disease was 20 times more frequent in type 1 patients with diabetes. The objective of our study was to evaluate the prevalence of celiac disease in hospital based type 1 diabetic adults. METHODS: Our study was carried out retrospectively in Medeniyet University Goztepe Training and Educational Hospital in Istanbul between 2012 2013. The cohort comprised 482 type 1 patients with diabetes attending the diabetes outpatient clinic. The data were analyzed by SPSS 10.5 package program. Student's t tests is used for comparative analyses. A p-value less than 0.05 was considered statistically significant. RESULTS: The cohort included 482 type 1 patients with diabetes. Fifty seven of them were not evaluated for Endomysium antibody positivity. Fifteen of the remaining 425 patients were positive for anti endomysial antibody (3.5%). The prevalence of biopsy proven celiac disease was 2.3% (10/425). There was no significant difference between Endomysial antibody positive and negative groups in regard of age, sex, or duration of the disease. CONCLUSION: This study confirms that the celiac disease is common in type 1 diabetic patients. Since a small proportion of celiac patients are symptomatic this disorder should be screened in all adult type 1 patients with diabetes by antiendomysium antibody. PMID- 26430420 TI - Correlation between uterine fibroids with various magnetic resonance imaging features and therapeutic effects of high-intensity focused ultrasound ablation. AB - OBJECTIVE: To explore the correlation between magnetic resonance imaging (MRI) features of uterine fibroids (UFs) and therapeutic effects of high-intensity focused ultrasound ablation (HIFUA), and to provide evidence for UFs diagnosis with MRI in clinical practice. METHODS: Forty-three UFs patients who were treated in our hospital from April 2012 to June 2014 were selected, including 72 UFs (48 multiple and 24 single UFs). Transverse, sagittal and coronal MRI scanning was performed one week before and after HIFUA to record UF number, location, type (intramural fibroid, submucosal fibroid and subserosal fibroid), mean diameter, hemoperfusion state, volume and ablation rate. The patients were followed up in the postoperative 1st, 2nd and 3rd months. RESULTS: HIFUA exerted the best ablative effect on fibroids on the anterior uterine wall (F=26.763, P=0.036). Various types of fibroids were ablated significantly differently (F=3.406, P<0.05) by HIFUA that was most effective for ablating the subserosal ones. Having significantly different ablative effects on UFs with different radial line lengths (F=29.94, P<0.05), HIFUA ablated those with radial line lengths of 3-5 cm most effectively. For UFs with different T2WI signal intensities, HIFUA also functioned significantly differently (F=3.179, P=0. 03). CONCLUSION: HIFUA exerted significantly different ablative effects on UFs with various MRI features. Therefore, these features were well correlated with the therapeutic effects of HIFUA, allowing MRI as a promising diagnostic protocol. PMID- 26430421 TI - Brief culturally adapted cognitive behaviour therapy for obsessive compulsive disorder: A pilot study. AB - OBJECTIVE: To demonstrate the effectiveness of Brief Culturally adapted Cognitive Behavior Therapy (CaCBT) in the treatment of Obsessive Compulsive Disorder (OCD). METHODS: This pre and post design study was conducted on out-patients with OCD at Centre for Cognitive Behaviour Therapy, Fountain House, Lahore, from April 2011 to April 2012. A semi structured questionnaire was developed to document demographic details of all the patients. All the participants were assessed at baseline (Pre Therapy session) with Yale Brown Obsessive Compulsive Disorder Scale (Y-BOCS), Hospital Anxiety & Depression Scale (Depression Subscale & Anxiety Subscale) and Brief Disability Questionnaire (BDQ). They were re-assessed on the same scales at the end of therapy in a follow up assessment session. Feedback from patients and their family member, who were trained as co-therapist, was obtained at the end of the therapy for assessing the satisfaction with the therapy. All the patients received six sessions of brief culturally adapted cognitive behavior therapy (CaCBT). Statistical analyses were carried out using SPSS v.22. RESULTS: The mean age of the sample (n=21) was 31.14+/-11.9 years. There were significant differences post CBT between the scores of Y-BOCS (p=0.000), HADS - Depression subscale (p=0.001), HADS - Anxiety subscale (p=0.000) and BDQ (p=0.000). CONCLUSION: This study provides preliminary evidence for effectiveness of culturally adapted CBT for OCD. PMID- 26430422 TI - Estrogen Receptor Alpha (ESR1) Gene Polymorphisms in Pre-eclamptic Saudi Patients. AB - OBJECTIVES: Pre-eclampsia causes maternal mortality worldwide. Estrogen receptor alpha (ESR1) gene polymorphisms were responsible for cardiovascular diseases. This case control study was conducted to investigate whether 2 polymorphic genes of ESR1 are associated with pre-eclampsia among Saudi women in Madina city, Saudi Arabia. METHODS: Blood samples from 97 pre-eclamptic and 94 healthy pregnant women were analyzed using restriction fragment length polymorphism-polymerase chain reaction method. All the subjects were recruited randomly from outpatient clinics of Madina Maternity Children Hospital (MMCH), Madina, Saudi Arabia, between Dec. 2012 and Jan. 2014. RESULTS: There was no association between pre eclampsia and PvuII and XbaI ESR1 gene polymorphisms individually. TT/AA and TT/AG genotype combination existed significantly in pre-eclamptic patients compared to control. The frequency of PvuII and XbaI combined TT/AA genotypes between pre-eclamptic women was 36.1% vs 9.6%, however, frequency of PvuII and XbaI combined TT/AG genotypes between pre-eclamptic women was 3.1% vs 17%, compared to control. The homozygous T-A haplotype carriers showed high pre eclampsia risk, independent of pregnancy, BMI and smoking status (adjusted odds ratio (OR): 3.26, 95% confidence interval (CI):1.71-9.21). The heterozygous T-A haplotype carriers did not differ from that of non-carriers (adjusted OR: 1.12, 95% CI: 0.47-2.75). No association was observed between pre-eclampsia and T-G, C G and C-A haplotype of PvuII and XbaIESR1 gene polymorphisms. CONCLUSIONS: T-A haplotype of homozygous associated with pre eclampsia not heterozygous carriers of ESR 1 PvuII and XbaI gene polymorphisms elicited high risk of pre-eclampsia. GG genotype of XbaI polymorphism decreased pre-eclampsia risk. Further studies using larger sample size are recommended to investigate the ESR 1 gene polymorphisms associated with pre-eclampsia. PMID- 26430423 TI - Gender difference in components of metabolic syndrome among patients of type 2 diabetes. AB - BACKGROUND AND OBJECTIVES: Diabetes mellitus, hypertension, obesity and dyslipidemia are the integral components that constitute metabolic syndrome. It has emerged as cause of substantial mortality with gender difference. To compare the gender characteristics of metabolic syndrome in subjects of type 2 diabetes mellitus. METHODS: This observational comparative prospective study was conducted in medical ward of BVH Bahawalpur over period of 6 month from January 2014 to June 2014. Sample size of 100 diagnosed cases of type 2 diabetics (comprising equal number of males and females) were collected. As defined by WHO and IDF, variables of metabolic syndrome studied were BMI, hypertension, hyperglycemia and hyperlipidemia. The lipid values were interpreted in normal or high risk category by applying NCEP ATPIII criterion. Fasting sample were collected for sugar and lipid profile. Anthropometric, demographic and biochemical data was tabulated. Continuous and categorical variables were displayed as mean +/- standard deviation and percentage respectively. Student 't' test was use to assess the difference for the lipid profile at 5% significance level. RESULTS: Female patients were found to be overweight, hypertensive and had uncontrolled hyperglycemia as compared to male subjects. Their systolic blood pressure was 150+/-25.75 and diastolic was 90+/-17mm/hg. The mean blood glucose concentration was 246.64+/-105mg/dl. In age group 35-44 years, the mean triglycerides and cholesterol levels in females were 184.54+/-42.05 and 192.5+/-34mg/dl respectively. HDL-C was 33.2+/-5.19mg/dl. In females with age group of 45-54 years, the mean concentration of triglycerides, total cholesterol and HDL-C were 217.75+/-77.6mg/dl, 190.95+/-14.4mg/dl and 31.75+/-3.8mg/dl respectively, and all were in high risk category when compared to cut off values determined by NCEP/ADA. While in females of age group 55-64 years, the values of TGs, total cholesterol and HDL-C were 204+/-154.11mg/dl, 200.09+/- 47.8 mg/dl and 33.4+/ 4.6mg/dl respectively and again all these values were significantly raised. CONCLUSION: Female genders were affected in all respects. They had higher BMI, hypertension, hyperglycemia and hyperlipidemia as compared to male counterparts. PMID- 26430424 TI - Histopathological examination of appendicectomy specimens at a district hospital of Saudi Arabia. AB - BACKGROUND AND OBJECTIVE: Appendicectomy for acute appendicitis is one of the most commonly performed surgical procedures. Acute appendicitis has remained a clinical entity and an ongoing diagnostic challenge. A retrospective study was performed to determine histological diagnosis, demographic data, the rate of perforated appendicitis and negative appendicectomies. METHODS: Histopathological records of 480 resected appendices submitted to histopathology department at Arar Central Hospital in the Northern Border Province of Saudi Arabia over the period of 3 years from July 2011 to June 2014 were reviewed retrospectively, to determine acute appendicitis, complication (gangrene, perforation) rate, negative appendicectomy rate, histopathological diagnosis and unusual finding on histology. RESULTS: Out of 480 specimens of appendix, appendicitis accounted for 466 (97.0%) with peak occurrence in the age group of 11 to 50 years in male and 11 to 40 years in female. Histopathological diagnosis include acute appendicitis 250 (52.0%), suppurative appendicitis 135 (28.0%) acute gangrenous appendicitis 60 (12.5%), perforated appendicitis 9 (2.0%), chronic appendicitis 12 (2.5%). Negative appendicectomy rate was 14 (3%) and two time more common in female with peak occurrence in the age group of 20-30 yrs. There was no unusual histological finding like carcinoid tumour of appendix. CONCLUSION: The present study showed a high number of appendicitis in adolescents and young adults. Negative appendectomy was more common in females. The study support routine histological examination of all the appendicectomy specimens to avoid missing of any clinically important and treatable condition. PMID- 26430425 TI - Frequency of Hepatitis-B and C in patients undergoing cataract surgery in a tertiary care Centre. AB - OBJECTIVE: To analyze the frequency of hepatitis B and C in patients undergoing cataract surgery. METHODS: This descriptive study was conducted at department of Ophthalmology Jinnah Post Graduate Medical Centre. The duration of study was seven months from May 2013 to November 2013. After taking informed consent from the patient and hospital ethical committee all patients presenting with cataract and undergoing cataract surgery were evaluated for the existence of hepatitis C and B. Diagnosis of hepatitis C or B was made on the criteria that a patient must be positive for either Anti-HCV or HBsAg or both. Proformas were filled and data was collected and analysis was done. Pearson's correlation coefficients were calculated to calculate the occurrence of hepatitis C and B in general population undergoing cataract surgery. RESULTS: Six hundred and forty-eight patients were operated on for cataract surgery at Jinnah Post Graduate Medical Centre during the study period. Mean age of patients was 63 years, 300 (46.29%) were male and 348 (53.70%) female. Out of them 57 (8.79%) patients were carriers of either Hepatitis C or B. Hepatitis B accounted for 17 cases (2.62%) however Hepatitis C positive were 40 cases (6.17%). Nobody was simultaneously affected by both hepatitis C and B. CONCLUSION: Significant number of asymptomatic carriers of hepatitis C and B were found in preoperative cataract patients. It is recommended that preoperative screening of all cataract patients should be done so that asymptomatic carriers might not become a threat for spread of disease. PMID- 26430426 TI - Diagnostic value of urinary protein and creatinine in combination with renal ultrasound examination in early renal damage of patients with hypertension. AB - OBJECTIVE: To evaluate the diagnostic value of urinary protein and creatinine in combination with renal Doppler ultrasound examination in early renal damage of patients with hypertension. METHODS: One hundred twenty two hypertensive patients who were treated in our hospital from December 2013 to June 2014 were selected for this study, including 33, 41 and 48 cases of Stage I, Stage II and Stage III hypertension respectively. Meanwhile, 30 healthy subjects were selected as the control group. They received urinary protein, creatinine and renal Doppler ultrasound examination. RESULTS: The urinary protein levels of Stage I, II and Stage III hypertensive patients were significantly different from that of the control group (p<0.05). Urinary creatinine levels were similar (p>0.05) in stage I and II but different from control (p<0.05) in stage III. Doppler ultrasound examination showed that Stage I hypertensive patients had similar renal longest diameter (RLD), renal parenchymal thickness (RPT) and ratio of RPT/renal sinus thickness to those of the control group (p>0.05), and RLDs of Stage II hypertensive patients and the control group were not significantly different (p>0.05). CONCLUSION: Urinary protein and creatinine levels in combination with renal Doppler ultrasound examination could diagnose early renal damage in patients with hypertension. PMID- 26430427 TI - Caudal ropivacaine and bupivacaine for postoperative analgesia in infants undergoing lower abdominal surgery. AB - OBJECTIVE: To compare the postoperative analgesic efficacy of ropivacaine 0.175% and bupivacaine 0.175% injected caudally into infants for lower abdominal surgery. METHODS: Eighty infants, aged 3-12 months, ASA I-II scheduled to undergo lower abdominal surgery were randomly allocated to one of the two groups: Group R received 1ml.kg(-1) 0.175% ropivacaine and Group B received 1ml.kg(-1) 0.175% bupivacaine via caudal route. Postoperative analgesia, sedation and motor block were evaluated with modified objective pain scale, three-point scale and modified Bromage scale respectively. Postoperative measurements including mean arterial pressure (MAP), heart rate (HR), pain (OPS), sedation and motor block score were recorded for four hours in the postoperative recovery room. Parents were contacted by telephone after 24 hours to question duration of analgesia and side effects. RESULTS: No significant differences were found among the groups in demographic data, MAP, HR, OPS and sedation scores during four hours postoperatively. The duration of analgesia was 527.5+/-150.62 minutes in Group R, 692.77+/-139.01 minutes in Group B (p=0.004). Twelve (30%) patients in Group R, 16 (40%) patients in groupB needed rescue analgesics (p=0.348). Rescue analgesics were administered (1 time/2 times) (9/3) (22.5/7.5%) in Group R and 16/0 (40/0%) in Group B, where no statistically significant difference was determined between the groups (p=0.071). Motor blockade was observed in 7 (17.5%) patients in Group R, and 8 (20%) patients in Group B (p=0.774). CONCLUSION: This study indicated, that a concentration of 0.175% ropivacaine and 0.175% bupivacaine administered to the infants via caudal route both provided effective and similar postoperative pain relief in infants, who underwent lower abdominal surgery. PMID- 26430428 TI - Early outcome of Coronary Artery Bypass Graft Surgery in patients with significant Left Main Stem stenosis at a tertiary cardiac care center. AB - OBJECTIVE: Primary objective of this study was to evaluate the impact of significant left main stem (LMS) stenosis on the early outcome of coronary artery bypass graft (CABG) surgery. METHODS: A Retrospective non-randomized analytical study was conducted in Cardiac surgery department, Chaudhary Pervaiz Elahi Institute of Cardiology (CPEIC) Multan, Pakistan. The data of patients who underwent isolated CABG at our institution from February 2008 to March 2014 were analyzed. Two thousand six hundred two (2602) patients of isolated CABG were divided into 2 groups according to the LMS disease. Group I (n=2088): without significant LMS disease and Group II (n=514): with LMS disease. Data was analyzed using SPSS V16. The groups were compared using Student's t-test for numeric variables. Chi-square test and Fishers Exact test were used for categorical variables. P-value <= 0.05 was considered as significant difference. RESULTS: Out of two thousand six hundred two, 2088 patients were in Non.LMS group (Control Group) and five hundred fourteen were in LMS Group (Study Group). Patients with LMS disease were older. In both groups there was no statistically significant difference regarding gender distribution, risk factors of IHD, pre-operative renal function and preoperative CKMB levels. Significant number 50 (9.7%) of patients were unstable in LMS group and they needed urgent surgery (p-value <0.0001). Need and duration for inotropic support and intra-aortic balloon counter-pulsation support were significantly high in LMS group (p-value <0.0001, 0.002, 0.003 respectively). Similarly Mechanical ventilation time and hospital stay were higher in LMS group. Incidence of pulmonary complications and operative mortality were significantly higher in LMS group (p-value 0.005 and 0.001 respectively). Mortality of CABG patients with significant left main coronary stenosis was 13 out of five hundred fourteen (2.5%) as compared to just 17 out of two thousand eighty eight (0.8%) in control group. CONCLUSION: This study showed that significant LMS disease is an independent risk factor for early cardiopulmonary morbidity and mortality after CABG surgery. PMID- 26430429 TI - Thyroid function status and its impact on clinical outcome in patients admitted to critical care. AB - OBJECTIVE: To analyze alterations in thyroid function and the correlation between results of thyroid function test and mortality in medical and surgical intensive care unit (ICU) patients. It also aimed to evaluate the effect of thyroid dysfunction in ICU patients and their need for mechanical ventilation (MV). METHODS: A single-center, prospective, observational study was conducted on patients admitted to medical and surgical ICU between 2013-2014.. Clinical and paraclinical findings (free triiodothyronine, free thyroxine and thyroid stimulating hormone) were documented for all patients. Regression analysis and chi-square were used for death and MV outcome variables. RESULTS: We included 502 patients. Of these, 340 (67.7%) were admitted to the medical ICU. Results of thyroid function tests were normal in 320 (64%) and 162 (32.3%) medical and surgical ICU patients, respectively. Euthyroid sick syndrome (ESS) was documented in 86 patients (17%). Mortality was twice higher among surgical ICU patients with ESS compared to those with normal thyroid function (p=0.085), which is not statistically significant. Based on thyroid function status, no differences in the risk to be mechanically ventilated was found between medical or surgical ICU patients. CONCLUSION: There is a significant association between ESS and mortality in ICU patients. Future studies should determine whether abnormal thyroid function increases the risk for MV in ICU patients. PMID- 26430430 TI - Analysis of uterine rupture at university teaching hospital Pakistan. AB - OBJECTIVE: To determine the risk factors, management modalities, fetomaternal outcome of uterine rupture cases at University teaching hospital in Pakistan. METHODS: This retrospective descriptive study was conducted at the Department of Gynaecology and Obstetrics Liaquat University of Medical and Health Sciences (LUMHS) for a period of one year from January 1st to December 31st 2012. Main outcome measures were frequency, age, parity, booking status, risk factors, management modalities, fetal and maternal mortality associated with uterine rupture. The data was collected on pre-designed proforma analysed using SPSS Version 16 statistical package. RESULTS: The frequency of ruptured uteri was calculated to be 0.67%, giving a ratio of 1:148 deliveries. Highest incidence was found in age group 25-30 (44.26%) with mean age of 30.36 years. and parity group 2-3 (57.37%) with mean parity 4.08. The risk factors for ruptured uterus include Caesarean section 43(70.49%), injudicious use of oxytocin 33(54.09%), obstructed labour 15 (24.59%) and multiparty 18 (29.50%). Repair of uterus was performed in 47(77.04%) cases. Maternal case fatality was 5(8.19%), while foetal wastage was 51 (83.60%). CONCLUSION: This study confirms the existence of a serious preventable obstetric problem, with significant maternal mortality and foetal wastage. Integrated efforts include Health education, focused antenatal care, skilled attendance, avoidance of injudicious use of oxytocin, and need of hospital based deliveries in patients with caesarean section which should be intensified to reduce this drastic obstetrical complication. PMID- 26430431 TI - Diagnosis and treatment of acute urogenital and genitalia tract traumas: 10-year clinical experience. AB - OBJECTIVE: To report our 10-year diagnosis and treatment experience of acute urogenital and genitalia tract traumas and outline the management of the traumatic injury. METHODS: We reviewed the diagnoses and treatments of 208 cases of acute kidney, ureter, bladder, urethra, or male genitalia injuries in our department between March 2002 and March 2012. The patient data including general information, injury position and mechanism, diagnosis and treatment, the follow up information was analyzed and summarized. RESULTS: Of 62 patients with renal injury examined by ultrasound and computed tomography (CT) examination, 45 were treated conservatively, 9 with superselective arterial embolization, and 8 with nephrectomy. Intravenous pyelogram (IVP) was conducted in two patients with ureteral injury, one was treated with cystoscopic ureteral catheterization and the other with ureteric reimplantation. Bladder injury (6 patients) confirmed with a waterflood susceptibility test combined with CT scans underwent laparotomy and the bladder suturing was done. Of 92 patients with urethral injury, 6 were treated with a nonoperative approach (indwelling catheter), 18 with urethral realignment, 35 with cystoscopic urethral realignment, 29 with end-to-end anastomotic urethroplasty, and 4 with urethral repairmen. Of the 24 cases with penile injuries, 1 underwent conservative treatment, 8 were treated with debridement and suture ligation, and 15 were managed with suture repair of the penis white membrane. Of the 24 cases with penile injuries, 1 underwent conservative treatment, 8 were treated with debridement and suture ligation, and 15 were managed with suture repair of the penis white membrane. During the follow up period, 62 patients with renal injury had normal renal function. Neither of the two patients with ureteral injury developed hydronephrosis. Twenty-nine patients with urethral injury suffered from urethral structure. All patients with vesical or genital injury recovered. CONCLUSIONS: Urethra and kidney injuries are the most common acute urogenital system traumas. Superselective arterial embolization can effectively cease bleeding and maximally protect renal function and ureterorenoscopic realignment is an easily operative and minimally invasive technique in the treatment of urethral injuries. As diagnosis and treatment techniques continue to evolve, minimally invasive procedures should be widely used in acute urogenital trauma. PMID- 26430432 TI - Treatment of displaced supracondylar fracture of the humerus in children by open pining from lateral approach: an investigation of clinical and radiographical results. AB - BACKGROUND AND OBJECTIVE: Supracondylar fracture of the humerus is the most common elbow fracture in children. This fracture needs immediate diagnosis and treatment, otherwise, it may lead to significant neurovascular and functional problems. The aim of this study was to assess the short term outcome of displaced supracondylar fracture of the humerus in children by open reduction and pining from lateral approach. METHODS: During a period of 15 months from June 2012 to September 2013, 48 patients (25 boys and 23 girls) less than 10 years old were enrolled in the study. Inclusion criteria were extension type supracondylar fractures of humerus, Gaartland type III that closed reduction was unsuccessful and failed as the initial treatment. The clinical and radiographic results of the treatment using open reduction and internal fixation by lateral pinning were evaluated. Outcomes were assessed according to the Flynn's criteria. RESULTS: The average age of the patients was 6.3 years. The most prevalent range of age was found about 6-9 years old. All patients had extension type fracture (Gartland type III). Overall, 47 (98%) patients had closed fracture and only one (2%) had open fracture. Eighteen patients (37.5%) and 30 patients (62.5%) had involvement of the dominant and non-dominant extremity respectively. No vascular injury and infection was seen in patients. One patient (2%) was identified with the radial nerve injury which, recovered after three months. In the three and six month follow-up, one patient (2%) was found with the median nerve injury. Since 15 patients were lost to follow-up, the analysis of the clinical and radiographical results at the end of the 6(th) month were done for 33 patients. According to the Flynn's criteria, the cosmetic results in 30 out of 33 patients that completed their follow-up (90.09%) were excellent, in 2 patients (6.1%) were good and one case (3%) was fair (P=0.051). Also, the functional results in 31 patients (93.9%) were excellent and in 2 patients (6.1%) were good. Overall, all cases were graded satisfactory (P=0.047). CONCLUSIONS: Treatment of the supracondylar humeral fracture in children by open reduction and internal fixation through lateral pinning is a safe approach with predictable good clinical and radiographical results. PMID- 26430433 TI - Cytogenetic and Molecular Analyses of Philadelphia Chromosome Variants in CML (chronic myeloid leukemia) Patients from Sindh using Karyotyping and RT-PCR. AB - OBJECTIVE: To determine the frequency of Philadelphia chromosome (Ph) and its variants in chronic myeloid leukemia (CML) cases at a tertiary care hospital of Sindh. METHODS: The study was conducted at the Department of Pathology, Liaquat University of Medical and Health Sciences, Jamshoro and Isra University Hospital, Hyderabad during May-to-September 2014. Bone marrow and peripheral blood samples from a total of 145 diagnosed cases of CML were collected. Cytogenetic analyses were performed using karyotyping as per the International System for Human Cytogenetic Nomenclature guidelines. All karyotypic images were analyzed using the Cytovision software. In order to identify BCR-ABL transcripts, RT-PCR was performed. Statistical analysis of the data was done using SPSS-version-21.0. RESULTS: Of the 145 samples, a total of 133 (91.7%) were positive for the Ph (Ph+) while 12 (8.3%) were negative for the Ph (Ph-). Of the 133 Ph+ samples, standard karyotypes were noted in 121 (91%), simple variants in 9 (6.7%) and complex variants in 3 (2.3%) of the samples. All the Ph+ samples (n=133) showed BCR-ABL positivity. Of the 12 Ph- samples, a total of 7 (58.3%) were BCR-ABL positive and 5 (41.6%) were BCR-ABL-negative. CONCLUSION: Frequency of the Ph was found to be of 90.9% in CML patients using a highly sensitive technique, the RT PCR. Cytogenetic abnormalities were at a lower frequency. Cytogenetic and molecular studies must be conducted for better management of CML cases. These findings could be very useful in guiding the appropriate therapeutic options for CML patients. PMID- 26430434 TI - Is handgrip strength and key pinch measurement related with biochemical parameters of nutrition in peritoneal dialysis patients? AB - BACKGROUNDS & OBJECTIVE: End-stage renal disease (ESRD) frequently causes Protein Energy Wasting (PEW), which is an important morbidity and mortality factor. Although it is difficult to assess PEW with a reliable method, there are various methods such as Handgrip strength test (HST), serum albumin, cholesterol, etc. HST is a simple and reliable antropometric method which is used for nutritional status and body muscle strength. This study aims to assess the relationship between HST and biochemical markers in evolution of nutritional status of ESRD patients. METHODS: This cross-sectional study included 36 consecutive patients, who are on peritoneal dialysis and 36 healthy -control subjects. Jamar-hand dynamometer was used for handgrip strength test; a pinch gauge was used for key pinch. Other antropometric tests included skin fold thicknesses at biceps, triceps, umbilical, suprailiac and subscapular regions; circumferences at waist hip, neck and midarm. Biochemical tests were performed only in Peritoneal Dialysis (PD) group. SPSS for Windows ver. 15.0 was used for statistics. RESULTS: The mean age of patients was 49.3+/-14.4, and mean age of control group was 43.8+/-10.6 (p=0.075). In PD group dominant hand dynamometer test 1,2 and 3 results were 19.3+/-9.3 kg, 25.3+/-10.8 kg, 25.5+/- 10.6 kg and; 34.2+/-10.3 kg, 34.4+/-9.8 kg, 34.6+/-10.0 kg for control group (p< 0,001). Right key pinch results were 6.7+/-1.9 kg for patients; 13.5+/-4.5 kg for control group (p<0.001). Left key pinch results were 6.8+/-1.9 kg for patients; 13.2+/-4.4 kg for control group (p<0.001). There was not any significant relationship concerning handgrip or key pinch tests with biochemical parameters. CONCLUSION: Handgrip Strength Test and key pinch may be reliable, cheap and easily performed tests for the diagnosis of Protein Energy Wasting in patients on Peritoneal Dialysis. PMID- 26430435 TI - Comparing the effectiveness of airway management devices in pre-hospital emergency care: A randomized clinical trial. AB - OBJECTIVE: To assess the effectiveness of laryngeal mask airway, endotracheal tube and oropharyngeal airway for airway management in prehospital emergency care. METHODS: The study sample of this randomized clinical trial was 54 patients needing pre-hospital airway management. All cases of intubation (ETI); after two failed attempts (37 patients), were randomly assigned to the oropharyngeal airway (OPA), and the laryngeal mask airway (LMA) groups. Patients' hemodynamic, SaO2 and airway management parameters, were compared in three groups. The study data were analyzed by the Chi-square and one-way ANOVA, Bonferroni post-hoc, using SPSS, v. 18.0. RESULTS: The results demonstrated that before and after the study, there was no significant difference among the study groups in terms of hemodynamic variables (P > 0.05) expect SaO2 (P < 0.001). The results also revealed that in the ETI group (n=17), the number of attempts and the time spent on inserting the airway device was significantly more than other two groups (P < 0.05). CONCLUSION: Laryngeal mask airway is as effective as oropharyngial airway for pre-hospital airway management by paramedics. PMID- 26430436 TI - Selective lymphadenectomy in endometrial cancer: Retrospective analysis of morbidity and survival data at a tertiary care centre. AB - OBJECTIVE: To compare perioperative morbidity and survival data between patients with early-stage endometrial cancer who did or did not undergo selective lymphadenectomy. METHODS: Retrospective analysis of 180 patients with early-stage endometrial carcinoma treated between 1999 and 2008 was performed in Aga Khan University Hospital, Karachi, Pakistan. RESULTS: Data from 180 patients were analysed. The selective lymphadenectomy group contained 108 women (60%) and the no lymphadenectomy group contained 72 women (40%). The median number of lymph nodes removed was 9. The mean age and extent of disease, as assessed by staging, tumour size, myometrial invasion, and lymphovascular invasion were comparable between groups. Upstaging of the disease to stage 3 and 4 occurred in 11% of patients in the lymphadenectomy group. There were no significant differences in the medical or surgical complications between groups. At a median follow-up of 26 months, both groups had comparable survival (lymphadenectomy versus no lymphadenectomy: 34 versus 32 months). Similar survival was noted for patients who underwent the removal of more or less than 5 pelvic lymph nodes. CONCLUSION: Selective lymphadenectomy offers the advantage of improved surgical staging but no therapeutic benefit in terms of overall survival. PMID- 26430437 TI - Arthroscopic Synovectomy and Postoperative Assisted Radiotherapy for Treating Diffuse Pigmented Villonodular Synovitis of the Knee: An observational retrospective study. AB - OBJECTIVE: This retrospective observational study aims to explore the treatment procedure and outcomes of arthroscopically assisted radiotherapy for diffuse pigmented villonodular synovitis (PVNS) of the knee joint. METHODS: From September 2006 to August 2011, 28 diffuse PVNS patients were diagnosed and treated under arthroscopy. Twenty six underwent post-operative radiotherapy. All patients were followed up, and the average follow-up period was 54 months (range: 24 to 72 months). RESULTS: All 26 patients who received external radiotherapy showed no recurrence at post-operative follow-up; The Lysholm knee joint function score increased from 54.3+/-9.0 at pre-operation to 71.2+/-6.7 at post-operation (paired t-test, t = -13.35, P< 0.01). CONCLUSIONS: Arthroscopic synovectomy is an ideal treatment for PVNS of the knee. Adjuvant post-operative external radiotherapy prevents the recurrence of diffuse PVNS. PMID- 26430438 TI - Control of bleeding by silk ligation and diathermy coagulation during tonsillectomy: A comparison of efficacy of the two techniques in the first 24 hours after surgery. AB - OBJECTIVE: To assess and compare the relative efficacy of silk ligation and diathermy coagulation techniques in controlling bleeding during tonsillectomy in the first 24 hours. METHODS: This prospective study was conducted at the Department of ENT, Khalifa Gul Nawaz Teaching Hospital, Bannu and this department related consultants' private clinics from January 1, 2012 to December 31, 2014. The study included 180 cases. All patients included were having history of recurrent, acute tonsillitis, with more than 6-7 episodes in one year, five episodes per year for two years, or three episodes per year for three years. All the surgeries were performed by dissection method. Haemostasis during the procedure was secured by either ligation with silk 1 or using diathermy. The results were analyzed using SPSS 16.0 for windows. RESULTS: A total of180 cases were included in the study. The ages of the patients ranged from 5 to 40 years with the mean age of 15.56 years and a std.deviation of +/- 8.24. The male to female ratio was 1.25:1. The number of hemorrhages occurring was greater in the 'diathermy coagulation' group as compared to the 'silk ligation' group. However, the observed difference was statistically insignificant (p >.05). CONCLUSION: Primary haemorrhage occurring during tonsillectomy is a serious threat and control of bleeding during the procedure should therefore be meticulous. Both suture ligation and coagulation diathermy for control of bleeders during the procedure by dissection method are equally effective. PMID- 26430439 TI - Differences in various biochemical and clinical parameters with respect to family history of Non Communicable Diseases in fourth year MBBS students of Karachi, Pakistan. AB - OBJECTIVE: To observe the differences of various biochemical and clinical parameters with respect to Family History (FH) of Non-communicable Diseases (NCDs) in fourth year Bachelor of Medicine, Bachelor of Surgery (MBBS) students. METHODS: This observational study was conducted at Baqai Institute of Diabetology & Endocrinology from December 2013 to January 2014. Total 50 medical students from Dow University of Health Sciences (DUHS) participated in the study. Statistical Package for Social Sciences (SPSS) version 13 was used to analyze the data. For cross tabulation and mean comparison z-test and t test were applied. RESULTS: Out of 50 subjects, there were 26 (52%) females. Mean age of the study population was 21.56 +/- 0.90 years. Mean serum cholesterol levels with positive FH of NCDs was significantly higher than negative FH of NCDs (p=0.005). Mean value of low density lipoprotein (LDL) of positive family history of NCDs was found higher than those with negative FH (p=0.006) being statistically significant. The insulin levels in subjects with positive FH of NCDs were higher than subjects with negative FH of NCDs (p=0.685). However, serum leptin and plasma renin showed no significant difference with the negative FH of NCDs being higher compared to positive FH of NCDs (p=0.068) and (p=0.884) respectively. However, Waist circumference, Body mass index and central obesity in subjects with positive FH of NCDs shows increasing trend but no statistically significant difference (p > 0.05) was observed. CONCLUSION: In our study of various biochemical and clinical parameters with respect to FH of NCDs, Serum Cholesterol and LDL levels were observed higher and statistically significant. PMID- 26430440 TI - Bone mineral density and diet of teachers of College of Home Economics at Lahore. AB - OBJECTIVE: To evaluate the Bone Mineral Density (BMD) and diet of teachers of a Govt. College of Home Economics in Lahore. METHODS: It was survey research. Purposive sampling technique was adopted for the selection of 50 teachers from Govt. College of Home Economics of age group 30 - 60 years. RESULTS: About 46% of the subjects had BMD ratio in between -2.58 to -4.0 (Osteoporotic category). The root cause of low BMD ratio was not really age related but in majority of the sample it was due to sedentary life style and lack of awareness about the importance of exercise in relation to bone health. CONCLUSION: The total mineral and vitamin intake required for bone health (calcium, magnesium, phosphorus & vitamin D) was below the recommended, among majority of the sample. PMID- 26430441 TI - It is not "Just Circumcision". AB - OBJECTIVE: Circumcision is one of the most commonly performed operations during childhood. The procedure is often underestimated in areas where it is frequently executed due to social and religion-based indications. In fact it might be an opportunity to detect and to correct any existing penile anomaly. The aim of the study was to retrospectively evaluate the boys who were admitted to a hospital for circumcision and the outcome of the procedure. METHODS: The boys who were brought to outpatient clinics for circumcision between 2009-2015, were retrospectively evaluated. The indications for hospital admission and the presence of associated penile anomalies were searched. All the boys were examined and operated by a single surgeon of the institution. RESULTS: Nine hundred forty four boys were brought to pediatric surgery outpatient clinics in order to be circumcised. The operation was performed in 318 of them. The physical examination revealed penile anomalies in 29 of the 318 cases. The detected anomalies were webbed penis, penile torsion, hypospadias, chordee without hypospadias and meatal stenosis. CONCLUSIONS: The proper examination of the boys by a physician prior to circumcision provides the detection of penile anomalies which can be corrected at the same session. The arrangements for performing circumcision in hospitals by the medical staff should be favored. The misleading perception of underestimation of the procedure where it is ritually performed, should be corrected. PMID- 26430442 TI - Diagnostic accuracy of ultrasonography in detection of blunt abdominal trauma and comparison of early and late ultrasonography 24 hours after trauma. AB - OBJECTIVE: Despite the advantages of ultrasound scan, its use as a screening tool in blunt abdominal trauma is controversial. The aim of this study was to evaluate the diagnostic value of early and late ultrasound in patients with blunt abdominal trauma (BAT). METHODS: In this study which was performed in a level I trauma center, firstly, 2418 patients with BAT had ultrasound (US) examination by two trauma expert radiologists. Results were compared with the best available gold standards such as laparotomy, CT, repeated ultrasound or clinical course follow-up. Then, 400 patients with BAT were examined by a trained residency student. RESULTS: In the first phase, sensitivity, specificity, negative predictive value, positive predictive value and accuracy of ultrasound were 97%, 98.1%, 99.7%, 83% and 98% respectively. In the second phase, they were 97.3%, 97.2%, 97.7%, 96.8% and 97.3% for the early and 98.5%, 97.6%, 98.5%, 97.5% and 98% for the late ultrasound respectively. CONCLUSION: Results obtained from this study indicate that negative ultrasound findings associated with negative clinical observation virtually exclude abdominal injury, and confirmation by performing other tests is unnecessary. High sensitivity and negative predictive value is achieved if ultrasound is performed by expert trauma radiologist. PMID- 26430443 TI - Frequency of ABO blood groups and RhD factor in the female population of District Peshawar. AB - OBJECTIVE: To determine the frequency of ABO blood group and Rhesus (Rh) D antigen in the females of "District" Peshawar, Khyber Pakhtunkhwa Province, Pakistan. METHODS: This cross-sectional study was conducted on 429 women having pregnancy induced hypertension, admitted in the three teaching hospitals of Peshawar, over a period of one year. Blood sample was collected from each subject after taking informed consent. The antigen antibody agglutination slide test for "blood grouping (ABO)" and RhD factors was done by using IgM and IgG monoclonal reagents. The antisera used were from Biolaboratory, USA. Data was analyzed for percentage calculation. RESULTS: The blood group distribution was 134 (31.2%), 43 (10.1%), 116 (27%), 136 (31.7%) for blood groups A, AB, O and B, respectively. Subjects having blood group B was slightly more dominant, followed by A and O, while blood group AB was rare in these females. Blood group A Rh negative is more in female 12 (37.5%) followed by group O 10 (31.3%), group B 09 (28.1%) and group AB 01 (3.1%). CONCLUSION: Frequency of "Rh-positive blood group" is B, A, O and AB, whereas the frequency of the most common Rh-negative blood group are A, O, B and AB respectively. The determination of the frequency of blood groups in the region would not only help in blood transfusion services, but also reduce the risk of erythroblastosis foetalis in the neonates. PMID- 26430445 TI - Significant association of serum creatinine with HbA1C in impaired glucose tolerant Pakistani subjects. AB - OBJECTIVE: The present study was conducted to assess the serum concentration of creatinine and determine its relationship with potential risk factors of diabetes in Impaired Glucose tolerance subjects. METHODS: This cross sectional study was conducted on 100 IGT patients who attended Amin Hayat diabetic center in Lahore from January 2011- June 2011. Patients with age group 34-67 years, (both sexes) were included in the study. Different demographic parameters as age, BMI, WHR, B.P, personal history and socioeconomic status were recorded. Oral Glucose Tolerance Test was performed. The biochemical parameters including HbA1c, lipid profile, urea, uric acid, creatinine and bilirubin level were measured by chemistry analyzer. RESULTS: A strong correlation between creatinine and HbA1c was observed. The level of creatinine was also significantly associated with age in IGT subjects. Creatinine is non-significantly correlated with Cholesterol, LDL Chol and TG while negatively significantly associated with BMI, fasting blood glucose and HDL-Chol. CONCLUSION: The present study concluded significant association of serum creatinine with HbA1c, BMI and HDL cholesterol. PMID- 26430444 TI - Outcome of four years experience in laparoscopic ventral hernia repair. AB - OBJECTIVE: To find out the short term outcomes of laparoscopic ventral hernia repair (LVHR) during the last four years. METHODS: It was a descriptive and prospective case series of 53 consecutive patients out of 107 at Department of General Surgery, Jinnah Post Graduate Medical Center, Unit II, Karachi, from January 2009 to December 2012. These patients were admitted through out patient department with complain of lump, pain and discomfort. Most of the patients were obese. All patients were clinically examined and baseline investigations done. Fifty three (49.5%) patients underwent laparoscopic repair with mesh placement and remaining 54 by open surgical repair. RESULTS: Among 53 patients, mean age was 46 years range (30 - 55). While females were 33(62.2%) and males 20(37.7%). We observed variety of hernias, in which midline and epigastric hernia were predominant. The commonest symptom was lump and dragging sensation. The duration of symptoms ranged between 6 months to one year. About 53 patients (49.5%) had laparoscopic repair with mesh placement. Average hospital stay was two days. Out of 53 patients, 4 (7.5%) had cellulitis at trocar site, seroma in 2(3.7%), 2(3.7%) patient complained of persistent pain postoperatively, port site minor infection was in 2(3.7%) patients, while conversion to open approach was done in 2 (3.7%), postoperative ileus was observed in one (1.8%) patients. CONCLUSIONS: This study provides the evidence that, laparoscopic repair with mesh placement in ventral hernia is safe and effective approach compared to open surgical procedure. It has a low complication rate, less hospital stay and low recurrence. PMID- 26430446 TI - Success of hydrocone (TORIS-K) soft contact lens for keratoconus and traumatic keratopathy. AB - OBJECTIVE: To present success of Toris-K contact lenses in keratoconus and traumatic keratopathy with irregular corneal surface. METHODS: Toris-K contact lenses were used to treat 7 eyes of 4 patients with traumatic keratopathy (Case 1) or keratoconus (Case 2, Case 3, and Case 4). All cases had a complete eye examination before the contact lens application. The case with traumatic keratopathy was a 32-year-old male who had corneal penetrating injury due to hobnail strike 23 months ago. The other 3 keratoconus cases were females at the age of 14, 16 and 22 years old. They had high myopia and irregular astigmatism due to keratoconus. All patients refused using rigid gas permeable contact lens because of intolerance. Toris-K contact lenses were fitted on all eyes. All patients were followed-up for 28 months with a complete ophthalmic examination and corneal topography every two months. RESULTS: Improvement of BCVA of the cases was remarkable. All cases were comfortable with their Toris-K contact lenses for 28 months. There was no significant distortion on the lenses during follow-up period. CONCLUSION: Toris-K lenses may be an effective alternative treatment option for the patients with keratoconus and traumatic keratopathy, especially who cannot tolerate rigid gas permeable contact lenses. PMID- 26430447 TI - The panacea statistical toolbox of a biomedical peer reviewer. AB - The main role of a peer reviewer is to make judgments on the research articles by asking a number of questions to evaluate the quality of the research article. Statistics is a major part of any biomedical research article, and most reviewers gain their experiences in manuscript reviewing by undertaking it but not through an educational process. Therefore, reviewers of the biomedical journals normally do not have enough knowledge and skills to evaluate the validity of statistical methods used in biomedical research articles submitted for consideration. Hence, inappropriate statistical analysis in medical journals can lead to misleading conclusions and incorrect results. In this paper, the most common basic statistical guidelines are described that might be a road map to the biomedical reviewers. It is not meant for statisticians or medical editors who have special interest and expertise in statistical analysis. PMID- 26430448 TI - Association of smoking with restenosis and major adverse cardiac events after coronary stenting: A meta-analysis. AB - BACKGROUND AND OBJECTIVE: The association between smoking and clinical outcomes after coronary stenting is controversial. The aim of this meta-analysis was to assess the association between smoking and in stent restenosis (ISR), major adverse cardiac events (MACE), or major adverse cardiac and cerebrovascular events (MACCE) after coronary stenting. METHODS: A search for studies published before December 2014 was conducted in PubMed, Embase, and Cochrane library. An inverse random weighted meta-analysis was conducted using logarithm of the odds ratio (OR) and its standard error for each study. RESULTS: Ten studies investigated the association between smoking and ISR. Overall, smoking was not associated with ISR (OR: 1.05, 95% CI: 0.79-1.41; I(2) = 47.8%). Subgroup analysis also failed to show a significant association between smoking and ISR risk regardless of bare metal stent (BMS) and drug-eluting stent (DES) implantation. Eight studies explored the association between smoking and MACE, but no association was found (OR: 0.92, 95% CI: 0.77-1.10; I(2) = 25.5%), and subgroup analysis revealed that no distinct difference was found between BMS and DES implantation. Three studies investigated the association between smoking and MACCE and significant association was found (OR: 2.09, 95% CI: 1.43-3.06; I(2) = 21.6%). CONCLUSIONS: Our results suggest that in patients undergoing percutaneous coronary intervention with stent implantation, smoking is not associated with ISR and MACE; however, smoking is an independent risk factor for MACCE. PMID- 26430449 TI - Fulminant hepatic failure (FHF) due to acute hepatitis C. AB - Acute hepatitis C (HCV) infection has been identified as an important cause of fulminant hepatic failure (FHF), characterized by rapid deterioration of liver function from massive hepatic necrosis leading to encephalopathy and multi-organ failure. We admitted a female patient at Shalamar Hospital with jaundice, fever, encephalopathy and coagulopathy of short duration with no history of any comorbidity. Her hepatitis viral screen revealed positive anti HCV. Her viral loads were also high. A diagnosis of FHF due to acute HCV infection was made. Patient was treated conservatively and improved gradually. In summary, acute HCV can cause FHF and should be ruled out in patients with FHF of unknown cause in an endemic country for HCV like Pakistan. PMID- 26430450 TI - Rare cause of bilateral groin swelling: Round ligament varicosities. AB - Round ligament varicosity (RLV) is rare and almost all cases are pregnant women. RLV appears as a unilateral or bilateral groin swelling. Pain and tenderness may present. Clinical evaluation is inadequate for exact diagnosis because inguinal hernia has similar findings. Ultrasonography (US) is essential when a groin swelling is detected in a pregnant woman. We present gray scale US and colour Doppler US findings of a 32-week pregnant woman with bilateral RLVs at the inguinal canal, parauterine area and in the myometrium. PMID- 26430451 TI - Hepatic metastasis complicated by abscess formation. AB - Hepatic abscesses and hepatic metastasis are common diseases. However, hepatic abscesses seldom occur in patients with hepatic metastases. We describe a case of a 67-year-old female patient with abdominal pain in the right upper quadrant. Magnetic resonance imaging revealed several lesions, with the largest lesion displaying features of both hepatic pyogenic abscess and liver metastasis. These features included iso- or hypointense signaling on T1WI and T2WI, hyperintense signaling on diffusion weighted imaging of the thick wall, and mixed hyperintense signal in the center on DWI, as well as dramatic and irregular peripheral enhancement was detected on LAVA dynamic contrast scanning. Aspiration and culture of the largest lesions revealed Klebsiella pneumoniae and a pathologic diagnosis of adenocarcinoma. At this point, the patient admitted a history of colon adenocarcinoma 9 years ago treated with hemicolectomy. Therefore, this patient was considered to have a hepatic pyogenic abscesses complicated by hepatic metastasis. The patient began treatment for the responsible pathogens and underwent chemoembolization of the liver lesions. In special cases, we could attempt to pursue a more detailed search for coexistence of microorganism infection and tumor. PMID- 26430452 TI - Neglected Bilateral Posterior Shoulder Fracture Dislocation in an Uncontrolled Seizure patient. AB - Posterior dislocation of the shoulder is a rare injury that occurs secondary to trauma and seizures. Diagnosis is often missed and treatment is challenging. Neglected posterior dislocation is associated with Hill-Sachs lesion which leads to locking of dislocation. Correct diagnosis is achieved by history taking, a physical examination and appropriate imaging. In neglected shoulder dislocation with uncontrolled seizure and humeral head defects of up to 45% the McLaughlin procedure shows excellent results at follow-up. PMID- 26430453 TI - Chitosan based hydrogels: characteristics and pharmaceutical applications. AB - Hydrogel scaffolds serve as semi synthetic or synthetic extra cellular matrix to provide an amenable environment for cellular adherence and cellular remodeling in three dimensional structures mimicking that of natural cellular environment. Additionally, hydrogels have the capacity to carry small molecule drugs and/or proteins, growth factors and other necessary components for cell growth and differentiation. In the context of drug delivery, hydrogels can be utilized to localize drugs, increase drugs concentration at the site of action and consequently reduce off-targeted side effects. The current review aims to describe and classify hydrogels and their methods of production. The main highlight is chitosan-based hydrogels as biocompatible and medically relevant hydrogels for drug delivery. PMID- 26430455 TI - Minocycline potentiates the anti-hyperalgesic effect of ceftriaxone in CCI induced neuropathic pain in rats. AB - Glutamate neurotoxicity and pro-inflammatory cytokines have an important role in the central sensitization of neuropathic pain. The purpose of the present study was to evaluate anti-hyperalgesic effect of repeated administration of ceftriaxone, which selectively activates and increases the expression of glutamate transporter, as well as minocycline, a selective inhibitor of microglia activation, either alone or together in Wistar rats subjected to the chronic constriction injury (CCI) of sciatic nerve. Ceftriaxone (100, 150 and 200 mg/kg) and minocycline (25, 50 and 100 mg/kg) were administered intraperitoneally from the day of surgery for seven consecutive days. Thermal hyperalgesia was assessed by focal radiant heat source on the hind paw of animals one day before surgery and on 3, 5, 7, 10 and 14 days following that. Ceftriaxone dose dependently, attenuated thermal hyperalgesia in animals. None of the administered doses of minocycline affected the CCI induced-thermal hyperalgesia in neuropathic animals. A fixed dose of minocycline (50 mg/kg) combined with three different doses of ceftriaxone administered for 7 consecutive days yielded a potentiating effect in the enhancing latency time to noxious thermal stimulus remaining until the 14th day post-surgery. The results suggest that modulation of microglia activity could have a supportive role in the improvement of CCI-induced thermal hyperalgesia and combination of such classes of drugs which have no antibiotic effects could be a new and promising therapeutic strategy for treatment. PMID- 26430454 TI - Formulation and optimization of solid lipid nanoparticle formulation for pulmonary delivery of budesonide using Taguchi and Box-Behnken design. AB - Budesonide is a potent non-halogenated corticosteroid with high anti-inflammatory effects. The lungs are an attractive route for non-invasive drug delivery with advantages for both systemic and local applications. The aim of the present study was to develop, characterize and optimize a solid lipid nanoparticle system to deliver budesonide to the lungs. Budesonide-loaded solid lipid nanoparticles were prepared by the emulsification-solvent diffusion method. The impact of various processing variables including surfactant type and concentration, lipid content organic and aqueous volume, and sonication time were assessed on the particle size, zeta potential, entrapment efficiency, loading percent and mean dissolution time. Taguchi design with 12 formulations along with Box-Behnken design with 17 formulations was developed. The impact of each factor upon the eventual responses was evaluated, and the optimized formulation was finally selected. The size and morphology of the prepared nanoparticles were studied using scanning electron microscope. Based on the optimization made by Design Expert 7((r)) software, a formulation made of glycerol monostearate, 1.2 % polyvinyl alcohol (PVA), weight ratio of lipid/drug of 10 and sonication time of 90 s was selected. Particle size, zeta potential, entrapment efficiency, loading percent, and mean dissolution time of adopted formulation were predicted and confirmed to be 218.2 +/- 6.6 nm, -26.7 +/- 1.9 mV, 92.5 +/- 0.52 %, 5.8 +/- 0.3 %, and 10.4 +/- 0.29 h, respectively. Since the preparation and evaluation of the selected formulation within the laboratory yielded acceptable results with low error percent, the modeling and optimization was justified. The optimized formulation co-spray dried with lactose (hybrid microparticles) displayed desirable fine particle fraction, mass median aerodynamic diameter (MMAD), and geometric standard deviation of 49.5%, 2.06 MUm, and 2.98 MUm; respectively. Our results provide fundamental data for the application of SLNs in pulmonary delivery system of budesonide. PMID- 26430456 TI - Molecular expression of adenosine receptors in OVCAR-3, Caov-4 and SKOV-3 human ovarian cancer cell lines. AB - Adenosine receptors (A1, A2a, A2b and A3) have several physiological and pathological roles in cancer cell lines. The present study was carried out to evaluate the mRNA and protein expression profile and functional role of adenosine receptors in OVCAR-3, Caov-4 and SKOV-3 ovarian cancer cell lines. The levels of mRNA and protein expression of A1, A2a, A2b and A3 adenosine receptors in the ovarian cancer cell lines were measured by Real-time PCR and western blotting. The functional roles of adenosine receptors were investigated through measurement of cAMP levels after agonist treatment. The mRNA and protein of all adenosine receptors subtypes were expressed in the ovarian cancer cell lines. Our findings demonstrated that A2b and A3 had the most mRNA and protein expression. Moreover, cAMP assay confirmed the functional role of A2b and A3 adenosine receptors. This findings demonstrated that A2b and A3 subtypes are most important adenosine receptors in humn ovarian cancer cell lines. This information provide a strong possibility into the relationship of A2b and A3 adenosine receptor and ovarian cancer. PMID- 26430457 TI - 3,7,10,14,15-pentaacetyl-5-butanoyl-13,17-epoxy-8-myrsinene a novel compound isolated from Pycnocycla spinosa extract with potent anti-spasmodic and antidiarrheal properties. AB - Bioassay monitoring of hydroalcoholic extract from the aerial part of Pyconcycla spinosa revealed that it contains components with spasmolytic activity in vitro. In addition, P. spinosa extract at oral dose of 1-5 mg/kg inhibits diarrhoea in animal models. Pharmacological screening of pure compounds isolated from P. spinosa hydroalcoholic extract led to the identification of 3,7,10,14,15 pentaacetyl-5-butanoyl-13,17-epoxy-8-myrsinene (PABEM) which is a new diterpene. In this research, we have investigated antispasmodic and antidiarrheal effects of PABEM for comparison with P. spinosa extract. Aerial parts of P. spinosa were extracted with ethanol. For antispasmodic studies, rat isolated ileum was suspended in Tyrode's solution in an organ bath. The ileum was contracted by acetylcholine (ACh, 0.5 MUM), serotonin (5-HT, 5 MUM) or electrical field stimulation (EFS). P. spinosa extract in a concentration dependent manner (10-640 MUg/ml) inhibited ileum contractions induced by ACh, 5-HT or EFS. The new compound isolated form P. spinosa extract "PABEM" in a similar manner inhibited the contractile response to ACh, 5-HT and EFS. However, the inhibitory effects of PABEM were observed at much lower bath concentrations. The relaxation effect of PABEM was started at 40 ng/ml bath concentration and with 2.5 MUg/ml PABEM in the bath, the contractile responses of ileum were completely abolished. Both hydroalcoholic extract of P. spinosa and PABEM reduced intestinal meal transit and castor oil and MgSO4 induced diarrhoea in mice. However, PABEM was about 10 times more potent than its parent extract. This research shows that PABEM is probably the main component responsible for antispasmodic and antidiarrheal actions of P. spinosa extract. PMID- 26430458 TI - A structural model of the anaphase promoting complex co-activator (Cdh1) and in silico design of inhibitory compounds. AB - Anaphase promoting complex (APC) controls cell cycle and chromosome segregation. The APC activation occurs after binding of co-activators, cdh1 and cdc20. Cdh1 plays a role in cancer pathogenesis and is known as a potential drug target. The main aim of this study was prediction of 3D structure of cdh1 and designing the inhibitory compounds based on the structural model. First, 3D structure of cdh1 was predicted by means of homology modelling and molecular dynamics tools, MODELLER and Gromacs package, respectively. Then, inhibitory compounds were designed using virtual screening and molecular docking by means AutoDock package. The overall structure of cdh1 is propeller like and each DW40 repeat contains four anti-parallel beta-sheets. Moreover, binding pocket of the inhibitory compounds was determined. The results might be helpful in finding a suitable cdh1 inhibitor for the treatment of cancer. PMID- 26430459 TI - Evaluation of protective effect of amifostine on dacarbazine induced genotoxicity. AB - Anticancer therapy with alkylating agents has been used for many years. Dacarbazine (DTIC) as an alkylating agent is used alone or in combination with other chemotherapy drugs. In order to inhibit the formation of secondary cancers resulting from chemotherapy with DTIC, preventional strategies is necessary. The present study was undertaken to evaluate the genoprotective effect of amifostine on the genotoxic effects of DTIC in cell culture condition. To determine the optimum genotoxic concentration of DTIC, HepG2 cells were incubated with various DTIC concentrations including 5, 10 and 20 MUg/ml for 2 h and the genotoxic effects were evaluated by the comet assay. The result of this part of the study showed that incubation of HepG2 cells with DTIC at 5 MUg/ml was sufficient to produce genotoxic effect. In order to determine the protective effects of amifostine on genotoxicity induced by DTIC, HepG2 cells were incubated with different concentrations of amifostine (2, 3 and 5 mg/ml) for 1 h which was followed by incubation with DTIC at 5 MUg/ml for 2 h. One hour incubation of cells with different concentrations of amifostine before incubation with DITC indicated that at least 5 mg/ml concentration of amifostine can prevent genotoxic effects induced by DTIC on HepG2 cells under described condition. In conclusion amifostine could prevent DNA damage induced by DTIC on HepG2 cells. PMID- 26430460 TI - Optimization of a single-chain antibody fragment overexpression in Escherichia coli using response surface methodology. AB - Human epidermal growth factor receptor (HER) family plays an important role in various types of cancers. As a result, antibodies against HER and the mechanism of antigen-antibody binding action are under active investigation. We previously constructed a single-chain variable fragment (ScFv) against HER2, i.e. anti-Her2 ScFv, for expressing in the Escherichia coli. In the present study, we report the optimization of anti-Her2 ScFv expression in an E. coli host of BL21 (DE3) pLysS using response surface methodology based on tuning of three cultivation variables, including isopropyl-beta-D-thiogalactopyranoside (IPTG) concentration, temperature and post-induction time. A model for protein expression according to the Box-Behnken design predicted a maximal anti-Her2 ScFv expression at 37 degrees C, a post-induction time of 10.45 h and 0.75 mM IPTG. In addition, strategies based on inclusion body isolation and affinity chromatography were applied to purify anti-Her2 ScFv. The purity of the final product for inclusion bodies isolation and purification by Ni-NTA resin were 70 % and 95 %, respectively. The solubilization of the inclusion bodies was carried out using two denaturant agents, guanidine hydrochloride and urea. The present study showed that guanidine hydrochloride was more effective than urea in solubilizing the inclusion bodies. PMID- 26430461 TI - Molecualr Cloning of the capsular antigen F1 of Yersinia pestis in pBAD/gIII plasmid. AB - Yersinia pestis which is the causative agent of pneumonic plague and distributed in all continents has led to many deaths during the history. Because of its high mortality rate, it must be diagnosed and treated at the earliest time post infection and therefore, rapid diagnostic tests are required. In the present study, we cloned the coding sequence of F1 capsular antigen of the bacteria in the pBAD/gIII plasmid for later expression and purification of the protein to produce poly and monoclonal antibodies against this antigen, and subsequently to develop rapid and efficient diagnostics tools for Y. pestis infections. PMID- 26430462 TI - Essential oil composition of Hypericum triquetrifolium Turra growing wild in Iran. AB - The chemical composition of the volatile oil from aerial parts of Hypericum triquetrifolium Turra was studied by GC-MS. Fifty components (97.1% of the total composition) were detected in the volatile oil. Germacrene-D (21.7%), beta caryophyllene (18.3%), delta-cadinene (6.4%), trans-beta-farnesene (4.3%), alpha humulene (3.8%), beta-selinene (3.7%), gamma-cadinene (3.3%) and trans-phytol (3.2%) were found to be the major constituents of the oil. The oil of H. triquetrifolium consisted of five monoterpene hydrocarbons (3.4%), two oxygenated monoterpenes (0.4%), twenty-two sesquiterpene hydrocarbons (77.1%), eight oxygenated sesquiterpenes (7.9%) and one oxygenated diterpene (3.2%). Twelve nonterpenic compounds were also consisted 5.1% of the oil. In conclusion, the oil of H. triquetrifolium was characterized by a high content of sesquiterpenes (85.0%), whereas monoterpenes contained only 3.8% of the essential oil. PMID- 26430463 TI - Vulnerability of Brazilian municipalities to hantavirus infections based on multi criteria decision analysis. AB - BACKGROUND: Hantavirus infection is an emerging zoonosis transmitted by wild rodents. In Brazil, high case-fatality rates among humans infected with hantavirus are of serious concern to public health authorities. Appropriate preventive measures partly depend on reliable knowledge about the geographical distribution of this disease. METHODS: Incidence of hantavirus infections in Brazil (1993-2013) was analyzed. Epidemiological, socioeconomic, and demographic indicators were also used to classify cities' vulnerability to disease by means of multi-criteria decision analysis (MCDA). RESULTS: From 1993 to 2013, 1752 cases of hantavirus were registered in 16 Brazilian states. The highest incidence of hantavirus was observed in the states of Mato Grosso (0.57/100,000) and Santa Catarina (0.13/100,000). Based on MCDA analysis, municipalities in the southern, southeastern, and midwestern regions of Brazil can be classified as highly vulnerable. Most municipalities in northern and northeastern Brazil were classified as having low vulnerability to hantavirus cardiopulmonary syndrome. CONCLUSIONS: Although most human infections by hantavirus registered in Brazil occurred in the southern region of the country, a greater vulnerability to hantavirus was found in the Brazilian Midwest. This result reflects the need to strengthen surveillance where the disease has thus far gone unreported. PMID- 26430464 TI - iDNA from terrestrial haematophagous leeches as a wildlife surveying and monitoring tool - prospects, pitfalls and avenues to be developed. AB - Invertebrate-derived DNA (iDNA) from terrestrial haematophagous leeches has recently been proposed as a powerful non-invasive tool with which to detect vertebrate species and thus to survey their populations. However, to date little attention has been given to whether and how this, or indeed any other iDNA derived data, can be combined with state-of-the-art analytical tools to estimate wildlife abundances, population dynamics and distributions. In this review, we discuss the challenges that face the application of existing analytical methods such as site-occupancy and spatial capture-recapture (SCR) models to terrestrial leech iDNA, in particular, possible violations of key assumptions arising from factors intrinsic to invertebrate parasite biology. Specifically, we review the advantages and disadvantages of terrestrial leeches as a source of iDNA and summarize the utility of leeches for presence, occupancy, and spatial capture recapture models. The main source of uncertainty that attends species detections derived from leech gut contents is attributable to uncertainty about the spatio temporal sampling frame, since leeches retain host-blood for months and can move after feeding. Subsequently, we briefly address how the analytical challenges associated with leeches may apply to other sources of iDNA. Our review highlights that despite the considerable potential of leech (and indeed any) iDNA as a new survey tool, further pilot studies are needed to assess how analytical methods can overcome or not the potential biases and assumption violations of the new field of iDNA. Specifically we argue that studies to compare iDNA sampling with standard survey methods such as camera trapping, and those to improve our knowledge on leech (and other invertebrate parasite) physiology, taxonomy, and ecology will be of immense future value. PMID- 26430466 TI - Training and capacity development: the foundation of interventions to support young children affected by HIV and AIDS in sub-Saharan Africa. AB - Many programs to support young children and families affected by HIV and AIDS depend substantially on a model of cascaded training from international nongovernmental organizations, through in-country groups and organizations to services on the ground. In this paper, we describe the training and capacity building - as described in proposals, progress reports, and individualized questionnaires - offered by 10 international organizations funded by the Conrad N. Hilton Foundation to provide supportive services for young children and their families in five southern and eastern African countries. We related the findings to effective features of training described in the literature. Training and capacity development were found to be the most substantial activities in rendering services to children and families, both in terms of effort and human and financial resources. A total of 67 trainings were conducted over a period of 18 months. Almost all trainings combine lecture-based instruction, group work/discussions, and role play, but only half of the trainings report some form of mentoring, supervision or coaching following the training. Drawing on the literature, it is likely that more purposeful planning is required in terms of the selection of trainees, local adaptation and development of materials, participatory training approaches, and techniques to develop and sustain skills as well as knowledge. Demonstration and mentorship in the field together with quality assurance procedures, pre-and post-assessment to evaluate training, processes to transfer learning into subsequent practice, as well as certification, are all fundamental steps to ensure that training plays a supportive role in the behavior changes necessary to support young children affected by HIV and AIDS and their families. PMID- 26430467 TI - Does science need bioethicists? Ethics and science collaboration in biomedical research. AB - Biomedical research is an increasingly multidisciplinary activity bringing together a range of different academic fields and forms of expertise to investigate diseases that are increasingly understood to be complex and multifactorial. Recently the discipline of ethics has been starting to find a place in large-scale biomedical collaborations. In this article we draw from our experience of working with the Malaria Genomic Epidemiology Network (MalariaGEN) and other research projects to reflect upon the integration of ethics into biomedical research. We examine the way in which ethics input may be valuable to research, the forms it tends to take, and also the problems and limitations of such collaborations. PMID- 26430465 TI - Does vitamin-D intake during resistance training improve the skeletal muscle hypertrophic and strength response in young and elderly men? - a randomized controlled trial. AB - INTRODUCTION: Recent studies have shown that vitamin-D intake can improve skeletal muscle function and strength in frail vitamin-D insufficient individuals. We investigated whether vitamin-D intake can improve the muscular response to resistance training in healthy young and elderly individuals, respectively. METHODS: Healthy untrained young (n = 20, age 20-30) and elderly (n = 20, age 60-75) men were randomized to 16 weeks of daily supplementary intake of either 48 MUg of vitamin-D + 800 mg calcium (Vitamin-D-group) or 800 mg calcium (Placebo-group) during a period and at a latitude of low sunlight (December April, 56 degrees N). During the last 12 weeks of the supplementation the subjects underwent progressive resistance training of the quadriceps muscle. Muscle hypertrophy, measured as changes in cross sectional area (CSA), and isometric strength of the quadriceps were determined. Muscle biopsies were analyzed for fiber type morphology changes and mRNA expression of vitamin-D receptor (VDR), cytochrome p450 27B1 (CYP27B1) and Myostatin. RESULTS: In the vitamin-D groups, serum 25(OH)D concentration increased significantly and at week 12 was significantly different from placebo in both young men (71.6 vs. 50.4 nmol/L, respectively) and elderly men (111.2 vs. 66.7 nmol/L, respectively). After 12 weeks of resistance training, quadriceps CSA and isometric strength increased compared to baseline in young (CSA p < 0.0001, strength p = 0.005) and elderly (CSA p = 0.001, strength p < 0.0001) with no difference between vitamin-D and placebo groups. Vitamin-D intake and resistance training increased strength/CSA in elderly compared to young (p = 0.008). In the young vitamin-D group, the change in fiber type IIa percentage was greater after 12 weeks training (p = 0.030) and Myostatin mRNA expression lower compared to the placebo group (p = 0.006). Neither resistance training nor vitamin-D intake changed VDR mRNA expression. CONCLUSION: No additive effect of vitamin-D intake during 12 weeks of resistance training could be detected on either whole muscle hypertrophy or muscle strength, but improved muscle quality in elderly and fiber type morphology in young were observed, indicating an effect of vitamin-D on skeletal muscle remodeling. TRIAL REGISTRATION: ClinicalTrials with nr. NCT01252381. PMID- 26430468 TI - Internal displacement and the Syrian crisis: an analysis of trends from 2011 2014. AB - BACKGROUND: Since the start of the Syrian crisis in 2011, civil unrest and armed conflict in the country have resulted in a rapidly increasing number of people displaced both within and outside of Syria. Those displaced face immense challenges in meeting their basic needs. This study sought to characterize internal displacement in Syria, including trends in both time and place, and to provide insights on the association between displacement and selected measures of household well-being and humanitarian needs. METHODS: This study presents findings from two complementary methods: a desk review of displaced population estimates and movements and a needs assessment of 3930 Syrian households affected by the crisis. The first method, a desk review of displaced population estimates and movements, provides a retrospective analysis of national trends in displacement from March 2011 through June 2014. The second method, analysis of findings from a 2014 needs assessment by displacement status, provides insight into the displaced population and the association between displacement and humanitarian needs. RESULTS: Findings indicate that while displacement often corresponds to conflict levels, such trends were not uniformly observed in governorate-level analysis. Governorate level IDP estimates do not provide information on a scale detailed enough to adequately plan humanitarian assistance. Furthermore, such estimates are often influenced by obstructed access to certain areas, unsubstantiated reports, and substantial discrepancies in reporting. Secondary displacement is not consistently reported across sources nor are additional details about displacement, including whether displaced individuals originated within the current governorate or outside of the governorate. More than half (56.4 %) of households reported being displaced more than once, with a majority displaced for more than one year (73.3 %). Some differences between displaced and non-displaced population were observed in residence crowding, food consumption, health access, and education. CONCLUSIONS: Differences in reported living conditions and key health, nutrition, and education indicators between displaced and non-displaced populations indicate a need to better understand migration trends in order to inform planning and provision of live saving humanitarian assistance. PMID- 26430469 TI - Erratum to: An interstitial deletion at 8q23.1-q24.12 associated with Langer Giedion syndrome/ Trichorhinophalangeal syndrome (TRPS) type II and Cornelia de Lange syndrome 4. AB - [This corrects the article DOI: 10.1186/s13039-015-0169-9.]. PMID- 26430470 TI - New statistical learning theory paradigms adapted to breast cancer diagnosis/classification using image and non-image clinical data. AB - The automated decision paradigms presented in this work address the false positive (FP) biopsy occurrence in diagnostic mammography. An EP/ES stochastic hybrid and two kernelized Partial Least Squares (K-PLS) paradigms were investigated with following studies: methodology performance comparisonsautomated diagnostic accuracy assessments with two data sets. The findings showed: the new hybrid produced comparable results more rapidlythe new K-PLS paradigms train and operate Essentially in real time for the data sets studied. Both advancements are essential components for eventually achieving the FP reduction goal, while maintaining acceptable diagnostic sensitivities. PMID- 26430471 TI - A systematic review and meta-analysis of Harmonic Focus in thyroidectomy compared to conventional techniques. AB - INTRODUCTION: Several meta-analyses have been performed comparing the use of a variety of ultrasonic devices in thyroidectomy to conventional procedures. These studies have shown the superiority of ultrasonic devices for most outcomes studied including faster operative time and less blood loss, and equivalent or better safety for recurrent laryngeal nerve paresis and hypocalcemia. The current work is the first to examine a single ultrasonic device specifically designed for thyroid surgery, the Harmonic Focus, in order to confirm its efficacy and safety in thyroidectomy. METHODS: A comprehensive literature search without language restrictions was performed for randomized clinical trials comparing Harmonic Focus and conventional clamp, cut and tie in thyroidectomy. Outcome measures included operating time, blood loss, post-operative pain, length of hospital stay, hypocalcemia and recurrent laryngeal nerve paresis. Risk of bias was analyzed for all studies. Meta-analysis was performed using random effects models with the inverse-variance method for mean differences of continuous variables and the Mantel-Haenszel method for risk ratios of dichotomous variables. RESULTS: A total of 14 studies met the inclusion criteria. Harmonic Focus reduced operative time by 29 min, a 31 % decrease (p < 0.001), intra-operative blood loss by 45 ml (p < 0.001), post-operative pain (p < 0.001), length of hospital stay by 0.68 days (p = 0.005), drainage volume by 29 ml (p = 0.01), and occurrence of transient hypocalcemia by 40 % (p = 0.001). There were no significant differences between Harmonic Focus and conventional procedures in rate of persistent hypocalcemia, or rates of transient and persistent recurrent laryngeal nerve paresis. CONCLUSION: This is the first meta-analysis of Harmonic Focus in thyroid surgery. In agreement with meta-analyses previously performed on ultrasonic devices, use of the Harmonic Focus has been shown to be a more effective surgical procedure compared to conventional methods in thyroidectomy. The low occurrence of hypocalcemia and recurrent laryngeal nerve paresis confirms that Harmonic Focus can improve thyroidectomy efficiency without increasing the risk of complications. PMID- 26430473 TI - Quality of preventive care before and after prostate cancer diagnosis. AB - OBJECTIVE: To examine if the use of general preventive services were diminished in a cohort of men following their diagnosis of prostate cancer. PATIENTS AND METHODS: 16,604 men enrolled in Kaiser Permanente Southern California who were newly diagnosed with prostate cancer from January 1, 2002 through December 31, 2009 were passively followed through electronic medical records to determine the use of preventive services, including screening for colorectal cancer (colonoscopy and/or fecal occult blood tests (FOBT)), tests for diabetes (glucose and hemoglobin A1c) and heart disease (serum cholesterol, high density lipoprotein (HDL) and triglycerides) and vaccinations (influenza and pneumococcal). Preventive service use was compared in the two years prior to and following prostate cancer diagnosis using matched odds ratios (MOR) and 95% confidence intervals (CI) in 2013. RESULTS: Men were more likely to receive a flu vaccine (MOR: 2.70, 95% CI: 2.52-2.90), lipid tests (MOR: 1.51, 95% CI: 1.42 1.61), diabetes tests (MOR: 2.13, 95% CI: 2.00-2.26) and screening for colorectal cancer (MOR: 1.80, 95% CI: 1.71-1.89) in the two years after prostate cancer diagnosis compared to before. Men with advanced disease at diagnosis were more likely to receive all types of preventive services after diagnosis when compared to men with localized disease. CONCLUSIONS: Once diagnosed with prostate cancer in this setting, no less attention was paid to general preventive care, although there remains room for improvement in pneumococcal vaccination and colon cancer screening rates. The delivery of high-quality continuing care after diagnosis is critical for aging cancer patients. PMID- 26430472 TI - Histone modifications rather than the novel regional centromeres of Zymoseptoria tritici distinguish core and accessory chromosomes. AB - BACKGROUND: Supernumerary chromosomes have been found in many organisms. In fungi, these "accessory" or "dispensable" chromosomes are present at different frequencies in populations and are usually characterized by higher repetitive DNA content and lower gene density when compared to the core chromosomes. In the reference strain of the wheat pathogen, Zymoseptoria tritici, eight discrete accessory chromosomes have been found. So far, no functional role has been assigned to these chromosomes; however, they have existed as separate entities in the karyotypes of Zymoseptoria species over evolutionary time. In this study, we addressed what-if anything-distinguishes the chromatin of accessory chromosomes from core chromosomes. We used chromatin immunoprecipitation combined with high throughput sequencing ("ChIP-seq") of DNA associated with the centromere-specific histone H3, CENP-A (CenH3), to identify centromeric DNA, and ChIP-seq with antibodies against dimethylated H3K4, trimethylated H3K9 and trimethylated H3K27 to determine the relative distribution and proportion of euchromatin, obligate and facultative heterochromatin, respectively. RESULTS: Centromeres of the eight accessory chromosomes have the same sequence composition and structure as centromeres of the 13 core chromosomes and they are of similar length. Unlike those of most other fungi, Z. tritici centromeres are not composed entirely of repetitive DNA; some centromeres contain only unique DNA sequences, and bona fide expressed genes are located in regions enriched with CenH3. By fluorescence microscopy, we showed that centromeres of Z. tritici do not cluster into a single chromocenter during interphase. We found dramatically higher enrichment of H3K9me3 and H3K27me3 on the accessory chromosomes, consistent with the twofold higher proportion of repetitive DNA and poorly transcribed genes. In contrast, no single histone modification tested here correlated with the distribution of centromeric nucleosomes. CONCLUSIONS: All centromeres are similar in length and composed of a mixture of unique and repeat DNA, and most contain actively transcribed genes. Centromeres, subtelomeric regions or telomere repeat length cannot account for the differences in transfer fidelity between core and accessory chromosomes, but accessory chromosomes are greatly enriched in nucleosomes with H3K27 trimethylation. Genes on accessory chromosomes appear to be silenced by trimethylation of H3K9 and H3K27. PMID- 26430474 TI - Transactional Sex: Supply and Demand Among European Men Who have Sex with Men (MSM) in the Context of Local Laws. AB - Objectives: Transactional sex (TS) is generally defined as the trading of sex for material goods. Cast within the broader context of prostitution laws, we examined variations in the sociodemographic profile of men who have sex with men engaging in TS by payment direction (buying/selling). Methods: The data were collected as part of the 38-country European Men who have sex with men Internet Survey project, conducted in 2010. Results: About 12% of respondents reported engaging in TS in the past year. TS was associated with laws, age, education, employment, and residence. Conclusions: The striking sociodemographic differences in TS by payment direction suggest a power differential and a leading role of socioeconomic factors in TS. PMID- 26430475 TI - Epidemiology of Helicobacter pylori infection in dyspeptic Ghanaian patients. AB - INTRODUCTION: Helicobacter pylori is a gram-negative urease-producing bacterium causally linked with gastritis, peptic ulcer disease and gastric adenocarcinoma. Infection is more frequent and acquired at an earlier age in developing countries compared to European populations. The incidence of Helicobacter pylori infection in dyspeptic Ghanaian patients was 75.4%. However, epidemiological factors associated with infection vary across populations. METHODS: This study used a cross-sectional design to consecutively sample dyspeptic patients at the Endoscopy Unit of the Korle-Bu Teaching Hospital, Accra between 2010 and 2012. The study questionnaire elicited their epidemiological clinical characteristics. Helicobacter pylori infection was confirmed by rapid-urease examination of antral biopsies at upper Gastro-intestinal endoscopy. RESULTS: The sample population of dyspeptic patients attending the Endoscopy Unit for upper GI endoscopy yielded 242 patients of which 47.5% were females. The age distribution of H. pylori infection was even across most age - groups, ranging from 69.2% (61 - 70) years to 80% (21 - 30) years. Helicobacter pylori prevalence decreased across areas mapping to the three residential classes in accordance with increasing affluence with rural areas having the highest prevalence. The unemployed and patients in farming had relatively high Helicobacter pylori infection rates of 92.3% and 91.7% respectively. CONCLUSION: Helicobacter pylori is endemic in Ghana but the persistently high prevalence across age groups despite significant community anti microbial use suggests likely recrudescence or re-infection from multiple sources in a developing country. Socio-cultural factors such as residential class and farming may be facilitating factors for its continued prevalence. PMID- 26430476 TI - [Auricular zona complicated by an invalidating vestibular syndrome]. PMID- 26430478 TI - [Systemic lupus erythematosus induced by isoniazid: a rare complication to fear]. PMID- 26430477 TI - [Oncoplastie with breast conservation in breast cancer treatment: about 16 cases]. PMID- 26430479 TI - Age and sex prevalence of infectious dermatoses among primary school children in a rural South-Eastern Nigerian community. AB - INTRODUCTION: Various dermatoses, due to their morbidity characteristics, have been shown to negatively impact on learning. The most epidemiologically important seem to be the infectious types because of their transmissibility and amenability to simple school-health measures. The aim of this study was to assess the prevalence and sex/age correlates of infectious dermatoses in a rural South eastern Nigerian community. METHODS: The pupils were proportionately recruited from the three primary schools based on school population. Stratified simple random sampling method was adopted and a table of random numbers was used to select required pupils from each arm. Clinical and laboratory examination was done to establish diagnoses of infectious skin disease. Data collected were analyzed using SPSS version 16. RESULTS: The 400 pupils consisted of 153 males and 247 females. Age range was between 6 and 12 years. The prevalence of infectious dermatoses was 72.3%. The five most prevalent clinical forms of infectious dermatoses, in order of decreasing prevalence, were tinea capitis (35.2%), scabies (10.5%), tinea corporis (5.8%), tinea pedis (5.5%), and impetigo (5.0%). More cases, generally, occurred among males than females (80.4% vs 67.2%)); while some specific clinical types, pediculosis and seborrheic dermatitis, exhibited predilection for females. Pyodermas and scabies were significantly more prevalent in the 7-9 age-group; while tinea capitis, tinea corporis, seborrheic dermatitis and pediculosis were more associated with >=10 age-group. CONCLUSION: Infectious dermatoses were highly prevalent in the surveyed population. Many of the clinical types exhibited sex- and age specificity. PMID- 26430480 TI - [Skin and nasal involvement: do not ignore sarcoidosis]. PMID- 26430481 TI - [Neglected capitellum fracture in an adult: report of a case and review of literature]. PMID- 26430482 TI - [Gravido-puerperal pancreatitis: report of 6 cases]. PMID- 26430483 TI - Aural foreign body extraction in children: a double-edged sword. AB - INTRODUCTION: Foreign body insertion into the ear in children is common world wide. The goal of this work is to describe the procedural complications of aural foreign body extraction in children. METHODS: A retrospective analysis of records of children with aural foreign bodies was conducted. Patients' bio data, type of foreign bodies, referrals, techniques of removal and complications were extracted from the case files. The foreign bodies were categorized into graspable and non graspable objects. Patients with complications caused directly by the foreign body were excluded. RESULTS: There were 136 cases. Eighty-seven (64.0%) were males while forty-nine (36.0%) were females. Their age range from 5 days to 16 years with 109 (80.2%) aged below 8 years. Eighty-nine (65.4%) and 47 (34.6%) cases were treated by otolaryngologists and non-otolaryngologists with a complication rate of 15.7% and 68.1% respectively. One case suffered severe hearing loss following complicated attempt at removing foreign body in the only hearing ear. Overall, the complication rate was higher (44.4%) with removal of non-graspable than (28.6%) with graspable objects. CONCLUSION: Procedural complication is an ever-present hazard of aural foreign body extraction in children. Its occurrence can be prevented or largely reduced if health care givers know their limitation based on their clinical skills and acquaint themselves with established criteria for referral. As a rule, we suggest that, foreign body in the only hearing ear and failed attempted first removal should be considered criteria for otolaryngologic referral. PMID- 26430484 TI - Hoffa's fat pad tumours like: results of the arthroscopic resection. AB - We performed a retrospective cohort study to increase awareness in orthopaedic community of this rare but interesting disease which is often misdiagnosed as meniscal pathology and to analyze present results of arthroscopic resection in seven patients. we retrospectively reviewed records from 2008-2012 and identified 7 patients with symptomatic Hoffa's fat pad impingement. The diagnosis was made by clinical exam, MRI imaging and verified arthroscopically. Of the 7 patients 2 were excluded due to receiving open resection. The remaining five underwent arthroscopic resection. Lysholm and American knee society scores were obtained pre and post operative and at final follow up. There was a significant improvement in their symptoms and function after the surgery at an average follow up of 14 months. The one poor result was because of paresthesia over the distribution of the infrapatellar branch of the saphenous nerve after open resection. tumours like of the fat pad should be treated by arthroscopic resection because of less residual pain and less complication was found using arthroscopy. In case of high volume of tumours only open excision can provide complete excision. PMID- 26430485 TI - Contribution and performance of female Community-Directed Distributors in the treatment of onchocerciasis with Ivermectin in Sub-Saharan Africa: a systematic review. AB - The African Program for Onchocerciasis Control (APOC) was launched in 1995 with the main goal being to boost the fight against onchocerciasis in Africa. In 2011, over 80 million people benefited from this intervention thanks to the contribution of 268.718 Community-Directed Distributors (CDD). These significant results obscure the role of women CDD in this fight. Indeed, the insufficient involvement of female CDD has been identified as a concern by the APOC partners early in the program. The present study aims to assess the contribution and performance of women involved in a strategy to control onchocerciasis by community-directed treatment with ivermectin in sub Saharan Africa. We searched the following electronic databases from January 1995 to July 2013: Medline, Embase (Excerpta Medica Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), LILAS (Latin American and Caribbean Literature on Health Sciences), International Bibliography of Social Sciences, Social Services Abstracts, and Sociological Abstracts. Two research team members independently conducted data extraction from the final sample of articles by using a pre established data extraction sheet. The primary outcome was the contribution of female CDD in the control of onchocerciasis by community-directed treatment with Ivermectin. Of 25 hits, 7 papers met the inclusion criteria. For the management of onchocerciasis, female CDDs are elected by the health committee from the communities they will serve. The significant proportion of those treated (about 61%) were women, although only 24% of CDDs were women. Many community members reported that women were more committed, persuasive and more patient than men in the distribution of ivermectin. Some studies have identified underutilization of female CDD as one reason for the limited effectiveness or, in some cases, pure failure related to the distribution of Ivermectin interventions in the fight against onchocerciasis in sub-Saharan Africa. Evidence from this review suggests that female CDD contribute to the treatment of onchocerciasis with Ivermectin in sub-Saharan Africa. Large-scale rigorous studies including Randomized controlled trials (RCTs) are needed to compare Community-Directed intervention involving men and women CDDs. PMID- 26430486 TI - Treatment Outcomes of Long-Pulsed Nd: YAG Laser for Two Different Subtypes of Rosacea. AB - BACKGROUND: A variety of lasers have been used for the treatment of rosacea. However, treatment of this condition with long-pulsed neodymium-doped yttrium aluminium garnet laser has not been reported yet. OBJECTIVE: To assess the efficacy and safety of long-pulsed neodymium-doped yttrium aluminium garnet laser in two different subtypes (erythematotelangiectatic and papulopustular) of rosacea. METHODS: A total of 66 patients were enrolled in the study. All of the patients were treated with long-pulsed neodymium-doped yttrium aluminium garnet laser with 3- to 4-week intervals. Rosacea severity score was assessed by using photographs. Improvement in severity was defined as the percentage reduction in severity scores from baseline to the end of treatment. Patients were also asked about their own opinions of improvement at the end of the treatment. Side effects were also documented. RESULTS: Good to excellent improvement was achieved in up to 50 percent of the patients in the erythematotelangiectatic and papulopustular groups. Percent improvement of global severity was significantly greater in the erythematotelangiectatic patients than in the papulopustular patients. The majority of patients from both groups noted a significant improvement of the lesions. Hypopigmented atrophic scars were seen in two patients. CONCLUSION: The long-pulsed neodymium-doped yttrium aluminium garnet laser is a safe and effective treatment for vascular and inflammatory lesions of rosacea. PMID- 26430487 TI - Impact of Guidance Provided by a Multispectral Digital Skin Lesion Analysis Device Following Dermoscopy on Decisions to Biopsy Atypical Melanocytic Lesions. AB - OBJECTIVE: To determine how a multispectral digital skin lesion analysis (MSDSLA) device data affects the biopsy performance of dermatologists and non dermatologist practitioners following clinical and dermoscopic pigmented lesion evaluation. DESIGN: MSDSLA employs near infrared light to image and analyze pigmented skin lesions. MSDSLA generates a "classifier score" based on morphological disorganization. Using a logistical regression model, 1) a probability of being melanoma and, 2) a probability of being melanoma, atypical melanocytic hyperplasia, or a high grade dysplastic nevus is computed. PARTICIPANTS were shown clinical images of 12 lesions (2 melanomas in situ, 3 invasive melanomas, and 7 low grade DNs). They were asked first if they would biopsy the lesion based on clinical images, again after observing dermoscopy images, and once more when presented with MSDSLA probability information. SETTING: National dermoscopy conference. PARTICIPANTS: Sixty-four healthcare providers; 30 dermatologists and 34 non-dermatologist practitioners. MEASUREMENTS: Sensitivity, specificity, diagnostic accuracy, biopsy rates Results: For the 30 dermatologists, sensitivity was 65 percent after clinical evaluation (C) and 65% post-dermoscopy (D) but improved to 91% after MSDSLA. For the 34 non-dermatologist practitioners, sensitivity improved from 66 percent (C) to 70 percent (D) to 95 percent after MSDSLA. With MSDSLA information, dermatologist specificity increased from 40 percent (D) to 58 percent while non dermatologist practitioners specificity increased from 34 percent (D) to 55 percent. Diagnostic accuracy of malignant and benign lesions decreased for both groups 55 percent (C) to 51 percent (D) for dermatologists and 54 percent (C) to 49 percent (D) for non-dermatologist practitioners. However, diagnostic accuracy increased to 72 percent for dermatologists and 72 percent for non-dermatologist practitioners with MSDSLA data. Non-melanoma biopsy percentages by dermatologists increased from 53 percent (C) to 60 percent (D), but decreased to 42 percent when provided with MSDSLA data. Similarly, non-dermatologist practitioners' biopsy percentages of nonmelanomas increased from 55 percent (C) to 66 percent (D) and decreased to 45 percent with MSDSLA. CONCLUSION: Decisions to biopsy atypical melanocytic lesions were more sensitive and specific when MSDSLA information was provided for both dermatologists and nondermatologist practitioners. Both groups were also less likely to biopsy nonmelanomas after MSDSLA evaluation. The authors' results suggest providing practitioners with MSDSLA data leads to improved biopsy accuracy decreasing the number of nonessential biopsies for nonmelanocytic lesions even after dermoscopic evaluation. PMID- 26430488 TI - Randomized, Observer-blind, Split-face Compatibility Study with Clindamycin Phosphate 1.2%/Benzoyl Peroxide 3.75% gel and Facial Foundation Makeup. AB - BACKGROUND: Cosmetic compatibility in the treatment of acne is an important issue significantly impacting quality of life, but often overlooked, as dermatologists commonly recommended avoidance of cosmetic foundations when treating adult female patients. Fixed combinations of clindamycin/benzoyl peroxide are widely used in the treatment of acne, but little is known about the impact of their concomitant use with facial foundation. OBJECTIVE: To assess the compatibility of clindamycin phosphate 1. 2%/benzoyl peroxide 3. 75% gel with foundation makeup for up to six hours after application. METHODS: Twenty-nine female subjects applied makeup to their face after randomly applying clindamycin phosphate 1. 2%/benzoyl peroxide 3. 75% gel to one side of the face. Investigator and subject self- assessment included facial skin attributes, facial tolerability, and cosmetic compatibility post-application and at Hour 6; as well as cutaneous tolerability. RESULTS: No statistical difference was noted between the treated and untreated side of the face in terms of coverage, blotchiness, appearance, skin tone, or visual smoothness. Tolerability was excellent, with no erythema, edema, dryness, and peeling post-makeup application. For both the treated and untreated side, there was a slight lack of improvement in cosmetic appearance six hours post-makeup application. CONCLUSION: Clindamycin/benzoyl peroxide 3. 75% gel was shown to have excellent cosmetic compatibility with facial foundation. PMID- 26430489 TI - Evaluation of a Topical Anti-inflammatory/Antifungal Combination Cream in Mild-to moderate Facial Seborrheic Dermatitis: An Intra-subject Controlled Trial Examining Treated vs. Untreated Skin Utilizing Clinical Features and Erythema directed Digital Photography. AB - OBJECTIVE: To evaluate if nonprescription topical agents may provide positive outcomes in the management of mild-to-moderate facial seborrheic dermatitis by reducing inflammation and scale production through clinical evaluation and erythema-directed digital photography. SETTING: Open-label, prospective, not blinded, intra-patient, controlled, clinical trial (target area). PARTICIPANTS: Twenty adult subjects affected by mild-to-moderate facial seborrheic dermatitis were enrolled and instructed to apply the study cream two times daily, initially on a selected target area only for seven days. If the subject developed visible improvement, it was advised to extend the application to all facial affected area for 21 additional days. MEASUREMENT: Efficacy was evaluated by measuring the grade of erythema (by clinical examination and by erythema-directed digital photography), desquamation (by clinical examination), and pruritus (by subject completed visual analog scale). Additionally, at the end of the protocol, a Physician Global Assessment was carried out. RESULTS: Eighteen subjects completed the study, whereas two subjects were lost to follow-up for nonadherence and personal reasons, respectively. Day 7 data from target areas showed a significant reduction in erythema. At the end of study, a significant improvement was recorded for erythema, desquamation, and pruritus compared to baseline. Physician Global Assessment showed improvement in 89 percent of patients, with a complete response in 56 percent of cases. CONCLUSION: These preliminary results indicate that the study cream may be a viable nonprescription therapeutic option for patients affected by facial seborrheic dermatitis able to determine early and significant improvement. This study also emphasizes the advantages of using an erythema-directed digital photography system for assisting in a simple, more accurate erythema severity grading and therapeutic monitoring in patients affected by seborrheic dermatitis. PMID- 26430491 TI - Q-Switched Alexandrite Laser-induced Chrysiasis. AB - BACKGROUND: Chyriasis is an uncommon side effect that occurs in patients who are receiving prolonged treatment with either intravenous or intramuscular gold as a distinctive blue-gray pigmentation of light-exposed skin. Laser-induced chrysiasis is a rarely described phenomenon in individuals who have received systemic gold and are subsequently treated with a Q-switched laser. PURPOSE: To describe the characteristics of patients with laser-induced chrysiasis. METHODS: The authors describe a 60-year-old woman who developed chrysiasis at Q-switched alexandrite laser treatment sites. They also reviewed the medical literature using PubMed, searching the terms chrysiasis, gold, and laser-induced. Patient reports and previous reviews of these subjects were critically assessed and the salient features are presented. RESULTS: Including the authors' patient, laser induced chrysiasis has been described in five Caucasian arthritis patients (4 women and 1 man); most of the patients had received more than 8g of systemic gold therapy during a period of 3 to 13 years. Gold therapy was still occurring or had been discontinued as long as 26 years prior to laser treatment. All of the patients immediately developed blue macules at the Q-switched laser treatment site. Resolution of the dyschromia occurred in a 70-year-old woman after two treatment sessions with a long-pulsed ruby laser and the authors' patient after a sequential series of laser sessions using a long-pulsed alexandrite laser, followed by a nonablative fractional laser and an ablative carbon dioxide laser. CONCLUSION: Laser-induced chrysiasis has been observed following treatment with Q switched lasers in patients who are receiving or have previously been treated with systemic gold. It can occur decades after treatment with gold has been discontinued. Therefore, inquiry regarding a prior history of treatment with gold particularly in older patients with arthritis-should be considered prior to treatment with a Q-switched laser. Also, treatment with a long-pulsed laser should be entertained in patients with either idiopathic or laser-induced chrysiasis. (JClinAesthetDermatol. 2015;8(9):48-53.) Chrysiasis is a distinctive blue-gray pigmentation of light exposed skin occurring in individuals who are receiving parenteral gold therapy.1 The 755nm Q-switched alexandrite laser is effective for the treatment of facial lentigines since the melanin granules absorb a high proportion of the laser energy and other chromophores offer little competitive absorption.2 The authors describe a woman who developed chrysiasis at Q-switched alexandrite laser treatment sites and whose dyschromia was successfully treated with a sequential series of laser sessions using a long pulsed alexandrite laser, followed by a nonablative fractional laser and an ablative carbon dioxide laser. PMID- 26430490 TI - The Tricky Tear Trough: A Review of Topical Cosmeceuticals for Periorbital Skin Rejuvenation. AB - There is a growing demand for noninvasive anti-aging products for which the periorbital region serves as a critical aspect of facial rejuvenation. This article reviews a multitude of cosmeceutical ingredients that have good scientific data, specifically for the periorbital region. Topical treatment options have exponentially grown from extensively studied retinoids, to recently developed technology, such as growth factors and peptides. With a focus on the periorbital anatomy, the authors review the mechanisms of action of topical cosmeceutical ingredients, effectiveness of ingredient penetration through the stratum corneum, and validity of clinical trials. PMID- 26430492 TI - Erratum to: 'Draft genome sequence of Bacillus azotoformans MEV2011, a (Co-) denitrifying strain unable to grow with oxygen'. AB - [This corrects the article DOI: 10.1186/1944-3277-10-4.]. PMID- 26430494 TI - The Effect of Lipopolysaccharide on Ischemic-Reperfusion Injury of Heart: A Double Hit Model of Myocardial Ischemia and Endotoxemia. AB - INTRODUCTION: Myocardial ischemia may coincide and interact with sepsis and inflammation. Our objective was to examine the effects of bacterial endotoxin on myocardial functions and cell injury during acute ischemia. METHODS: Rabbits were pretreated with incremental doses of E. Coli lipopolysaccharide (LPS) or normal saline. Myocardial ischemia was induced by 50-minute occlusion of left anterior descending artery. S-TNFaR was additionally used to block the effects LPS. RESULTS: Ventricular contractility as it was measured by dp/dt during systole decreased from 2445+/- 1298 to 1422 +/- 944 mm Hg/s, P = .019. Isovolumetric relaxation time as an index of diastolic function was prolonged from 50+/-18 ms to 102+/- 64 ms following ischemia. Pretreatment with low concentrations of LPS (<1 MUg) had no effect on dp/dt, while at higher concentrations it suppressed both contractility and prolonged IVRT. Cell injury as measured by cardiac troponin I level increased to 15.1+/- 3.2 ng/dL following ischemia and continued to rise with higher doses of LPS. While blocking TNFa did not improve the myocardial contractility after ischemia, it eliminated additional deleterious effects of LPS. CONCLUSION: Lower doses of LPS had no deleterious effect on myocardial function, whereas higher doses of this endotoxin cause cardiac dysfunction and increased extent of injury. PMID- 26430495 TI - Real Time 3D Echocardiographic Evaluation of Iatrogenic Atrial Septal Defects After Percutaneous Transvenous Mitral Commissurotomy. AB - INTRODUCTION: Percutaneous transvenous mitral commissurotomy (PTMC) is a safe and effective procedure for relief of severe mitral stenosis. PTMC is being done widely and many transseptal procedures requiring large diameter catheters, sheaths are becoming popular. The knowledge of iatrogenic atrial septal defect (iASD) is vital. This study assessed the use of real-time 3D echocardiography (RT3DE) and incidence of iASD in a cohort of patients undergoing transseptal catheterization during PTMC. METHODS: One hundred ten patients underwent PTMC. The reliability and accuracy of RT3DE for iASD detection was determined, RT3DE was compared with 2D echocardiography (2DE) for iASD occurrence, influencing variables analyzed and followed up for 1 year. RESULTS: RT3DE is more reliable and accurate for the study of iASD than 2DE. Color RT3DE detected iASD in 94 (85.5%), with 2DE iASD was detected in 74 (67.3%) (P < .0001).On follow up 85% had iASD post procedure, 56% at 6 months, 19% at 1 year follow up. The mean iASD diameter was 5.41 +/- 3.12 mm and area 6.57 +/- 3.81 mm(2). iASD correlated with patient height, Wilkins score, pre-PTMC LA 'v', and post-PTMC LVEDP. CONCLUSION: RT3DE imaging is superior in accuracy to traditional 2DE techniques. All the modes of RT3DE are useful in the assessment of iASD. iASD measured by RT3DE correlates with several patient, procedural and echocardiographic variables. PMID- 26430496 TI - Cardiac Rehabilitation Improves the QRS Fragmentation in Patients With ST Elevation Myocardial Infarction. AB - INTRODUCTION: We aimed to evaluate the effect of exercise-based cardiac rehabilitation (CR) on the fragmented QRS (fQRS) in patients with ST elevation myocardial infarction (STEMI). METHODS: Ninety-seven patients with STEMI participated CR and 81 patients as a control group were included to the study. The trained patients were grouped according to the presence and persistence of QRS fragmentation on the electrocardiogram (ECG) before and after CR. If the fragmentation was present on the ECG at the beginning of the CR but not on the ECG at the end of CR; the transient group, if the fQRS persists after CR; the persistent fQRS group. ECGs obtained from the control group were grouped according to the presence of a fQRS on ECG. RESULTS: Among the trained patients, 45 (46%) did not have a fQRS before CR, whereas 52 (54%) presented a fQRS before CR, which was persistent in 35 patients (the persistent fQRS group) and transient in 17 patients (the transient fQRS group). Among 81 patients included in the control group, fQRS was persistent in 41 patients. Presence of fQRS on the ECG was significantly decreased with CR and it is better in trained group than the control group (P = .034). There were not significant correlations with other characteristics, except hypertension. CONCLUSION: The existence of the fQRS decreases after CR in patients with STEMI especially in hypertensive individuals, which may be related to improved electrical stability in the myocardium as a predictor of increase in survival and decrease in major cardiac events. PMID- 26430493 TI - Dynamics in Transcriptomics: Advancements in RNA-seq Time Course and Downstream Analysis. AB - Analysis of gene expression has contributed to a plethora of biological and medical research studies. Microarrays have been intensively used for the profiling of gene expression during diverse developmental processes, treatments and diseases. New massively parallel sequencing methods, often named as RNA sequencing (RNA-seq) are extensively improving our understanding of gene regulation and signaling networks. Computational methods developed originally for microarrays analysis can now be optimized and applied to genome-wide studies in order to have access to a better comprehension of the whole transcriptome. This review addresses current challenges on RNA-seq analysis and specifically focuses on new bioinformatics tools developed for time series experiments. Furthermore, possible improvements in analysis, data integration as well as future applications of differential expression analysis are discussed. PMID- 26430497 TI - Biosynthetic Versus Polytetrafluoroethylene Graft in Extra-anatomical Bypass Surgery of Takayasu Arteritis Patients With Supra-aortic Disease. AB - INTRODUCTION: To evaluate treatment outcomes of patients diagnosed with Takayasu arteritis (TA), who underwent extra-anatomical bypass surgery using biosynthetic grafts. METHODS: This retrospective study included 12 TA patients considered eligible for surgical revascularization between January 2005 and May 2011 from two vascular surgical units in Turkey. Control group consisted of 12 peripheral arterial disease patients who underwent supra-aortic extra-anatomical bypass surgery using polytetrafluoroethylene (PTFE) graft. Preoperatively, all patients underwent Doppler ultrasound and arteriography. Patients were examined every 3 months for clinical findings after monthly follow-up during the first 6 months, first, second and third year controls. Graft patencies were evaluated by Doppler ultrasound at each visit. RESULTS: The mean age was 38.6 +/- 4.2 years and the mean follow-up time was 37.9 +/- 6.9 months for the study group. In Biosynthetic Group, subclavian-subclavian (n = 2), axillo-axillary (n =9) and carotico subclavian (n = 1) bypass operations were performed. In PTFE group, subclavian subclavian (n = 3), axillo-axillary (n = 7), subclavian-left ulnar (n = 1), subclavian-distal brachial (n = 1) bypass operations were performed. Graft occlusion occurred in four patients in PTFE Group during follow-up period. These occlusive lesions were treated successfully according to the routine of each vascular unit. CONCLUSION: We concluded that in inflammatory diseases like TA, biosynthetic grafts have promising patency, postoperative clinical findings and lower rates of complications requiring reintervention in mid-term. PMID- 26430498 TI - Effects of Selenium in the MAPK Signaling Cascade. AB - INTRODUCTION: This study aimed to discover by which mechanism selenium (Se) suppresses stimulated platelets stimulation in oxidative stress underlying diseases. METHODS: Human platelets pretreated with Se and stimulated by Cu(2+) oxidized low density of lipoprotein (OxLDL) or thrombin before assessment of P selectin and phosphorylated p38 mitogen-activated protein kinase (p-p38MAPK), phosphorylated Jun N-terminal kinase (p- JNK), and phosphorylated extracellular signal-regulated kinases (p-ERK1/2). All variables were measured by solid phase sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: Se significantly decreased Cu(2+)-OxLDL induced P-selectin expression, as well as p38 and JNK phosphorylation in platelets, but could not significantly reduce ERK1/2 phosphorylation. CONCLUSION: Se suppresses inflamed platelets. This effect maybe partly mediated by the p38 or c-JNK signaling pathways. These results create possibility of new co-anti-inflammatory insight for Se in atherosclerosis. PMID- 26430500 TI - Investigation of the Association Between 584C/T Polymorphism of EL Gene and Risk of Premature Coronary Artery Disease in Fars Province. AB - INTRODUCTION: Endothelial lipase (EL) is a protein from the triglyceride lipase family which plays an important role in high-density lipoprotein (HDL) metabolism. One of the most frequently studied variants is 584C/T which causes the amino acid threonine at codon 111 to convert to isoleucine. Many studies have shown the association of this variant with HDL-C level and CAD disease. METHODS: The population of this study consists of 140 patients (all males) with angiographically confirmed coronary artery disease (CAD) and 80 controls. Polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) was carried out for genotyping of LIPG 584C/T. Data were analyzed using SPSS. RESULTS: The results of the study indicated that the frequency of T allele was significantly lower among CAD patients than among controls (0.27 vs 0.36, P = .004). However, no significant correlation was found between the 584C/T variant and serum HDL-C level. Multivariate regression analysis confirmed that the T allele is significantly associated with CAD disregarding the age, hypertension, hypercholesterolemia, diabetes and HDL-C (OR = 0.494, 95% CI = 0.253- 0.968, P =.040). CONCLUSION: It was concluded that the T allele was associated with protection from CAD in Fars province independent of HDL-C level. PMID- 26430501 TI - The Effect of Pulmonary Valve Replacement (PVR) Surgery on Hemodynamics of Patients Who Underwent Repair of Tetralogy of Fallot (TOF). AB - INTRODUCTION: Pulmonary insufficiency (PI) frequently develops in patients who underwent repair of tetralogy of fallot (TOF). The aim of present study was to assess the effect of pulmonary valve replacement (PVR) on hemodynamics of patients who underwent repair of TOF. METHODS: This retrospective cohort carried out between July 2010 and October 2012 among consecutive PVRs of 19 patients who underwent TOF surgery. The PVRs was performed using bioprosthetic (n=17) and mechanical (n=2) valves. Our data was collected during follow up visits within 6 to 12 month after PVR. RESULTS: Our results show that PVR significantly decreased right ventricular end-diastolic volume (180.89+/-13.78 vs. 107.21+/-12.02 ml/m(2), P < .01), right ventricular end-systolic volume (105.42+/-15.98 vs. 58.15+/-11.67 ml/m(2), P < .01), RV mass (47.78+/-6.20 vs. 30.68+/-8.95 g/m(2), P < .01), and PI (48.21+/-1.43% vs. 12.68+/-5.60%, P < .01). Moreover, left ventricular end-diastolic volume significantly increased (78.05+/-17.21 vs. 90.78+/-14.82 ml/m(2), P < .01) after PVR. The other hemodynamics indexes did not change, significantly. CONCLUSION: Despite the controversies about efficacy of PVR after repair of TOF, the remarkable improvement of hemodynamic is a supportive rationale for performing PVR surgery in TOF patients. PMID- 26430499 TI - Correlation of Serum Levels of Vitronectin, Malondialdehyde and Hs- CRP With Disease Severity in Coronary Artery Disease. AB - INTRODUCTION: Vitronectin (VN), malondialdehyde (MDA) and high-sensitivity C reactive rotein (hs-CRP) are cooperative agents involved in the atherosclerosis process. The study was conducted to assess the correlation of VN, MDA and hs-CRP with the severity of coronary artery disease (CAD). METHODS: Parameters such as serum VN, MDA and hs-CRP were measured in 250 subjects including 200 patients with angiographically diagnosed CAD (50 subjects with non-significant CAD, 50 with single vessel disease, 50 with double vessel disease, and 50 with triple vessel disease) and 50 CAD-free subjects as a control group. Serum VN was measured with ELISA; MDA was measured based on reaction with thiobarbituric acid (TBA); and hs-CRP level was measured by a Commercial Kit by Immunoturbidimetry. RESULTS: Serum VN, MDA and hs-CRP were significantly higher in patient groups compared to control group (P < .05). The mean value of MDA between 1 vessel and 3 vessel groups had significant difference (P = .01), also mean value of MDA between 2 vessel and control group and normal group showed significant difference (P < .001). The difference of MDA between 3 vessel and normal and 1 vessel and control group was significant (P < .001). CONCLUSION: The association and correlation between VN, MDA and hs-CRP indicate their involvement in the atherosclerosis process that may lead to progression of CAD. Also, these findings suggested that serum levels of VN, MDA and hs-CRP can help as diagnostic and monitoring markers in CAD patients and as markers of disease severity. PMID- 26430502 TI - Right Valsalva Sinus Aneurysm Protruding Into the Right Ventricle: A Case Report. AB - A separation between the aortic media and annulus fibrosus causes a rare cardiac abnormality called sinus of Valsalva aneurysm (SVA) that may be congenital or acquired. It is more prevalent in the right coronary sinus (65%-85%) but it has been seen rarely in non-coronary (10%-30%) or Left coronary sinus (<5%). The most common complication is rupture of the Aneurysm. We present an 80-year-old male with expanding right Valsalva sinus aneurysm and protruding into right ventricle. The conventional treatment is surgical repair under cardio-pulmonary bypass or percutaneous catheter closure. The aneurysm was successfully excised surgically under direct guidance of trans-esophageal echocardiography (TEE). PMID- 26430503 TI - Silent Fistula of the Ascending Aorta to Pericardium by Brucella Endocarditis. AB - We report the case of a 26-year-old male patient with 2-week history of Brucella aortic valve endocarditis that was referred from general hospital to our hospital emergency room with pallor of the skin and mucous membranes accompanied by systemic hypotension and chest pain. Trans esophageal echocardiography (TEE) revealed a 30-mm ascending aorta at the pulmonary trunk with no evidence of the false lumen or intimal flap. TEE also showed a large vegetation of the aortic valve that limited to noncoronary sinus with moderate pericardial effusion. TEE did not showed fistula tract of nonaortic coronary sinus ring to intra mural of aorta and to pericardial cavity. The patient underwent open heart surgery with resection of destructed aortic valve and vegetation and replacement of aortic valve with prosthetic valve (Carbomedics, Sorin group. 23 mm sizes) with separated pledged suture. Debridement of aortic intra mural fistula tract and its replacement with fresh pericardial patch than performed. The pericardial cavity had moderate bloody effusion. The patient recovered uneventfully and was discharged in the 15th postoperative day. In this case, we report a rare silent clinical presentation of aortic wall fistula by vegetation and aortic ring abscess and periaortic wall hematoma, and reviewed its medical and surgical treatment. PMID- 26430504 TI - Post Cardiopulmonary Bypass Changes in Liver Function: Comment on "J Cardiovasc Thorac Res 2015;7:49-54". PMID- 26430505 TI - Cobalt-Catalysed Asymmetric Hydrovinylation of 1,3-Dienes. AB - In the presence of bidentate 1,n-bis-diphenylphosphinoalkane-CoCl2 complexes {Cl2Co[P~P]} and Me3Al or methylaluminoxane, acyclic (E)-1,3-dienes react with ethylene (1 atmosphere) to give excellent yields of hydrovinylation products. The regioselectivity (1,4- or 1,2-addition) and the alkene configuration (E- or Z-) of the resulting product depend on the nature of the ligand and temperature at which the reaction is carried out. Cobalt(II)-complexes of 1,1 diphenylphosphinomethane and similar ligands with narrow bite angles give mostly 1,2-addition, retaining the E-geometry of the original diene. Complexes of most other ligands at low temperature (-40 degrees C) give almost exclusively a single branched product, (Z)-3-alkylhexa-1,4-diene, which arises from a 1,4 hydrovinylation reaction. A minor product is the linear adduct, a 5-alkyl-hexa 1,4-diene, also arising from a 1,4-addition of ethylene. As the temperature is increased, a higher proportion of the major 1,4-adduct appears as the (E)-isomer. The unexpectedly high selectivity seen in the Co-catalysed reaction as compared to the corresponding Ni-catalysed reaction can be rationalized by invoking the intermediacy of an eta4-[(diene)[P~P]CoH]+-complex and its subsequent reactions. The enhanced reactivity of terminal E-1,3-dienes over the corresponding Z-dienes can also be explained on the basis of the ease of formation of this eta4-complex in the former case. The lack of reactivity of the X2Co(dppb) (X = Cl, Br) complexes in the presence of Zn/ZnI2 makes the Me3Al-mediated reaction different from the previously reported hydroalkenylation of dienes. Electron-rich phospholanes, bis-oxazolines and N-heterocyclic carbenes appear to be poor ligands for the Co(II)-catalysed hydrovinylation of 1,3-dienes. An extensive survey of chiral ligands reveals that complexes of DIOP, BDDP and Josiphos ligands are quite effective for these reactions even at -45 degrees C and enantioselectivities in the range of 90-99 % ee can be realized for a variety of 1,3-dienes. Cobalt(II)-complex of an electron-deficient Josiphos ligand is especially active, requiring only <1 mol% catalyst to effect the reactions. PMID- 26430506 TI - High Israeli mortality rates from diabetes and renal failure - Can international comparison of multiple causes of death reflect differences in choice of underlying cause? AB - BACKGROUND: The age-adjusted mortality rate in Israel is low compared to most Western countries although mortality rates from diabetes and renal failure in Israel are amongst the highest, while those from cardiovascular diseases (CVD) are amongst the lowest. This study aims to assess validity of choice of underlying causes (UC) in Israel by analyzing Israeli and international data on the prevalence of these diseases as multiple causes of death (MCOD) compared to UC, and data on comorbidity (MCOD based). METHODS: Age-adjusted death rates were calculated for UC and MCOD and the corresponding ratio of multiple to underlying cause of death (SRMU) for available years between 1999 and 2012. Comorbidity was explored by calculating cause of death association indicators (CDAI) and frequency of comorbid disease. These results were compared to data from USA, France, Italy, Australia and the Czech Republic for 2009 or other available year. RESULTS: Mortality rates for all these diseases except renal failure have decreased in Israel between 1999 and 2012 as UC and MCOD. In 2009, the SRMU for diabetes was 2.7, slightly lower than other Western countries (3.0-3.5) showing more frequent choice as UC. Similar results were found for renal failure. In contrast, the SRMU for ischemic heart disease (IHD) and cerebrovascular disease were 2.0 and 2.6, respectively, higher than other countries (1.4-1.6 and 1.7-1.9, respectively), showing less frequent choice as UC. CDAI data showed a strong association between heart and cerebrovascular disease, and diabetes in all countries. In Israel, 40 % of deaths with UC diabetes had IHD and 24 % had cerebrovascular disease. Renal disease was less strongly associated with IHD. CONCLUSION: This international comparison suggests that diabetes and renal failure may be coded more frequently in Israel as UC, sometimes instead of heart and cerebrovascular disease. Even with some changes in coding, mortality rates would be high compared to other countries, similar to the comparatively high diabetes prevalence in Israel at older ages and high rate of end-stage renal failure. This study highlights the importance of physician training on death certification practice and need for further progress towards automation in recording and coding death causes. PMID- 26430507 TI - Perception of the threat of War in Israel- implications for future preparedness planning. AB - BACKGROUND: It has been recently reported that the preparedness of the Israeli public to a war scenario is mediocre. These findings suggest a need to study the psychosocial mechanisms behind individual motivation to engage in preparedness behavior. One component of these mechanisms is the perception of threat. The purpose of this study is to portray the perception of the threat of war by the Israeli public and to deduce possible implications for resilience-promoting policies. METHODS: Portions of the data accumulated in a telephone-based random sampling of 503 households (representing the Israeli population) performed in October 2013 were utilized to examine the perception of the threat of war by Israelis. The questionnaire was used to examine the level of household preparedness, as well as attitudes toward perception of threat, preparedness responsibility, willingness to search for information, and sense of preparedness. Statistical analysis was performed to determine the correlations between different components of threat perception, and to evaluate the preparedness promoting features of specific perception factors. RESULTS: The data suggest that the perception of threat is influenced by different socio-demographic factors. In particular, age, religion and education seem to play an important role in the perception of threat. Compared to data collected almost a decade ago, the likelihood perception and threat intrusiveness rates were significantly reduced. The regression analysis suggests that perception of the severity of the impact on a family's routine and willingness to search for information, two known preparedness promoting factors, can be predicted by various socio-demographic and threat perception components. CONCLUSION: The data suggest that the Israeli public, post the Second Lebanon War (2006) and the Gaza conflicts of 2009 and 2012, perceives the probabilities of war and being affected by it as diminished. The Israeli public demonstrates what can be considered as the unique characteristics of a war-victimized population. Implications for a future resilience-promoting policy were discussed. PMID- 26430508 TI - Policy issues related to educating the future Israeli medical workforce: an international perspective. AB - A 2014 external review of medical schools in Israel identified several issues of importance to the nation's health. This paper focuses on three inter-related policy-relevant topics: planning the physician and healthcare workforce to meet the needs of Israel's population in the 21(st) century; enhancing the coordination and efficiency of medical education across the continuum of education and training; and the financing of medical education. All three involve both education and health care delivery. The physician workforce is aging and will need to be replenished. Several physician specialties have been in short supply, and some are being addressed through incentive programs. Israel's needs for primary care clinicians are increasing due to growth and aging of the population and to the increasing prevalence of chronic conditions at all ages. Attention to the structure and content of both undergraduate and graduate medical education and to aligning incentives will be required to address current and projected workforce shortage areas. Effective workforce planning depends upon data that can inform the development of appropriate policies and on recognition of the time lag between developing such policies and seeing the results of their implementation. The preclinical and clinical phases of Israeli undergraduate medical education (medical school), the mandatory rotating internship (stage), and graduate medical education (residency) are conducted as separate "silos" and not well coordinated. The content of basic science education should be relevant to clinical medicine and research. It should stimulate inquiry, scholarship, and lifelong learning. Clinical exposures should begin early and be as hands-on as possible. Medical students and residents should acquire specific competencies. With an increasing shift of medical care from hospitals to ambulatory settings, development of ambulatory teachers and learning environments is increasingly important. Objectives such as these will require development of new policies. Undergraduate medical education (UME) in Israel is financed primarily through universities, and they receive funds through VATAT, an education-related entity. The integration of basic science and clinical education, development of earlier, more hands-on clinical experiences, and increased ambulatory and community-based medical education will demand new funding and operating partnerships between the universities and the health care delivery system. Additional financing policies will be needed to ensure the appropriate infrastructure and support for both educators and learners. If Israel develops collaborations between various government agencies such as the Ministries of Education, Health, and Finance, the universities, hospitals, and the sick funds (HMOs), it should be able to address successfully the challenges of the 21st century for the health professions and meet its population's needs. PMID- 26430509 TI - Attainment rate as a surrogate indicator of the intervertebral neutral zone length in lateral bending: an in vitro proof of concept study. AB - BACKGROUND: Lumbar segmental instability is often considered to be a cause of chronic low back pain. However, defining its measurement has been largely limited to laboratory studies. These have characterised segmental stability as the intrinsic resistance of spine specimens to initial bending moments by quantifying the dynamic neutral zone. However these measurements have been impossible to obtain in vivo without invasive procedures, preventing the assessment of intervertebral stability in patients. Quantitative fluoroscopy (QF), measures the initial velocity of the attainment of intervertebral rotational motion in patients, which may to some extent be representative of the dynamic neutral zone. This study sought to explore the possible relationship between the dynamic neutral zone and intervertebral rotational attainment rate as measured with (QF) in an in vitro preparation. The purpose was to find out if further work into this concept is worth pursuing. METHOD: This study used passive recumbent QF in a multi-segmental porcine model. This assessed the intrinsic intervertebral responses to a minimal coronal plane bending moment as measured with a digital force guage. Bending moments about each intervertebral joint were calculated and correlated with the rate at which global motion was attained at each intervertebral segment in the first 10 degrees of global motion where the intervertebral joint was rotating. RESULTS: Unlike previous studies of single segment specimens, a neutral zone was found to exist during lateral bending. The initial attainment rates for left and right lateral flexion were comparable to previously published in vivo values for healthy controls. Substantial and highly significant levels of correlation between initial attainment rate and neutral zone were found for left (Rho = 0.75, P = 0.0002) and combined left-right bending (Rho = 0.72, P = 0.0001) and moderate ones for right alone (Rho = 0.55, P = 0.0012). CONCLUSIONS: This study found good correlation between the initial intervertebral attainment rate and the dynamic neutral zone, thereby opening the possibility to detect segmental instability from clinical studies. However the results must be treated with caution. Further studies with multiple specimens and adding sagittal plane motion are warranted. PMID- 26430510 TI - Culture and detection of primary cilia in endothelial cell models. AB - BACKGROUND: The primary cilium is a sensor of blood-induced forces in endothelial cells (ECs). Studies that have examined EC primary cilia have reported a wide range of cilia incidence (percentage of ciliated cells). We hypothesise that this variation is due to the diversity in culture conditions in which the cells are grown. We studied two EC types: human umbilical vein endothelial cells (HUVECs) and human microvascular endothelial cells (HMEC-1s). Both cell types were grown in media containing foetal bovine serum (FBS) at high (20 % FBS and 10 % FBS for HUVECs and HMEC-1s, respectively) or low (2 % FBS) concentrations. Cells were then either fixed at confluence, serum-starved or grown post-confluence for 5 days in corresponding expansion media (cobblestone treatment). For each culture condition, we quantified cilia incidence and length. RESULTS: HUVEC ciliogenesis is dependent on serum concentration during the growth phase; low serum (2 % FBS) HUVECs were not ciliated, whereas high serum (20 % FBS) confluent HUVECs have a cilia incidence of 2.1 +/- 2.2 % (median +/- interquartile range). We report, for the first time, the presence of cilia in the HMEC-1 cell type. HMEC-1s have between 2.2 and 3.5 times greater cilia incidence than HUVECs (p < 0.001). HMEC 1s also have shorter cilia compared to HUVECs (3.0 +/- 1.0 MUm versus 5.1 +/- 2.4 MUm, at confluence, p = 0.003). CONCLUSIONS: We demonstrate that FBS plays a role in determining the prevalence of cilia in HUVECs. In doing so, we highlight the importance of considering a commonly varied parameter (% FBS), in the experimental design. We recommend that future studies examining large blood vessel EC primary cilia use confluent HUVECs grown in high serum medium, as we found these cells to have a higher cilia incidence than low serum media HUVECs. For studies interested in microvasculature EC primary cilia, we recommend using cobblestone HMEC-1s grown in high serum medium, as these cells have a 19.5 +/- 6.2 % cilia incidence. PMID- 26430512 TI - Mesenchymal stromal cells support endothelial cell interactions in an intramuscular islet transplantation model. AB - BACKGROUND: Mesenchymal stromal cells (MSC) have been under investigation for a number of therapies and have lately been in focus as immunosuppressive actors in the field of transplantation. Herein we have extended our previously published in vitro model of MSC-islets in an experimental setting of islet transplantation to the abdominal muscle. Human islets coated with luciferase-GFP transduced human MSC were transplanted to the abdomen muscle tissue of NOD-scid ILR2gamma(null) mice and cellular interactions were investigated by confocal microscopy. RESULTS: The MSC reduced fibrotic encapsulation and facilitated endothelial cell interactions. In particular, we show a decreased fraction of alphaSMA expressing fibrotic tissue surrounding the graft in presence of MSC-islets compared to islets solely distributed into the muscle tissue. Also, in the presence of MSC, human islet endothelial cells migrated from the center of the graft out into the surrounding tissue forming chimeric blood vessels with recipient endothelial cells. Further, in the graft periphery, MSC were seen interacting with infiltrating macrophages. CONCLUSIONS: Here, in our experimental in vivo model of composite human islets and luciferase-GFP-transduced human MSC, we enable the visualization of close interactions between the MSC and the surrounding tissue. In this model of transplantation the MSC contribute to reduced fibrosis and increased islet endothelial cell migration. Furthermore, the MSC interact with the recipient vasculature and infiltrating macrophages. PMID- 26430511 TI - Review of the nutritional benefits and risks related to intense sweeteners. AB - BACKGROUND: The intense sweeteners currently authorised in Europe comprise ten compounds of various chemical natures. Their overall use has sharply risen in the last 20 years. These compounds are mainly used to formulate reduced-calorie products while maintaining sweetness. METHODS: This extensive analysis of the literature reviews the data currently available on the potential nutritional benefits and risks related to the consumption of products containing intense sweeteners. RESULTS AND CONCLUSIONS: Regarding nutritional benefits, the available studies, while numerous, do not provide proof that the consumption of artificial sweeteners as sugar substitutes is beneficial in terms of weight management, blood glucose regulation in diabetic subjects or the incidence of type 2 diabetes. Regarding nutritional risks (incidence of type 2 diabetes, habituation to sweetness in adults, cancers, etc.), it is not possible based on the available data to establish a link between the occurrence of these risks and the consumption of artificial sweeteners. However, some studies underline the need to improve knowledge of the links between intense sweeteners consumption and certain risks. PMID- 26430513 TI - Foraging behavior links climate variability and reproduction in North Pacific albatrosses. AB - BACKGROUND: Climate-driven environmental change in the North Pacific has been well documented, with marked effects on the habitat and foraging behavior of marine predators. However, the mechanistic linkages connecting climate-driven changes in behavior to predator populations are not well understood. We evaluated the effects of climate-driven environmental variability on the reproductive success and foraging behavior of Laysan and Black-footed albatrosses breeding in the Northwest Hawaiian Islands during both brooding and incubating periods. We assessed foraging trip metrics and reproductive success using data collected from 2002-2012 and 1981-2012, respectively, relative to variability in the location of the Transition Zone Chlorophyll Front (TZCF, an important foraging region for albatrosses), sea surface temperature (SST), Multivariate ENSO Index (MEI), and the North Pacific Gyre Oscillation index (NPGO). RESULTS: Foraging behavior for both species was influenced by climatic and oceanographic factors. While brooding chicks, both species traveled farther during La Nina conditions, when NPGO was high and when the TZCF was farther north (farther from the breeding site). Models showed that reproductive success for both species showed similar trends, correlating negatively with conditions observed during La Nina events (low MEI, high SST, high NPGO, increased distance to TZCF), but models for Laysan albatrosses explained a higher proportion of the variation. Spatial correlations of Laysan albatross reproductive success and SST anomalies highlighted strong negative correlations (>95 %) between habitat use and SST. Higher trip distance and/or duration during brooding were associated with decreased reproductive success. CONCLUSIONS: Our findings suggest that during adverse conditions (La Nina conditions, high NPGO, northward displacement of the TZCF), both Laysan and Black-footed albatrosses took longer foraging trips and/or traveled farther during brooding, likely resulting in a lower reproductive success due to increased energetic costs. Our results link climate variability with both albatross behavior and reproductive success, information that is critical for predicting how albatross populations will respond to future climate change. PMID- 26430514 TI - Systemic lupus erythematosus complicated by diffuse alveolar haemorrhage: risk factors, therapy and survival. AB - OBJECTIVES: While diffuse alveolar haemorrhage (DAH) is recognised as a life threatening complication of systemic lupus erythematosus (SLE), little is known about its risk factors and response to treatment. We describe 22 cases of DAH in a US lupus cohort of approximately 1000 patients, and compare them to 66 controls from the same outpatient cohort. METHODS: We captured variables pertaining to diagnoses of SLE and secondary antiphospholipid syndrome (APS), and analysed them by univariate testing. Those variables with p values <0.05 were then further considered in a multivariate model. Kaplan-Meier curves were constructed for each group, and survival was analysed by Log-rank test. RESULTS: Of the 22 patients with DAH, 59% were diagnosed with DAH within 5 years of lupus diagnosis. By univariate testing, several manifestations of SLE and APS were more common in patients with DAH, including history of thrombocytopenia, cardiac valve disease, low C3, leucopenia, neuropsychiatric features, haemolysis, arterial thrombosis, lupus anticoagulant, secondary APS and low C4. On multivariate analysis, history of thrombocytopenia and low C3 were maintained as independent risk factors. Importantly, only two patients had platelet counts <50 000/uL at the time of the DAH episode, arguing that DAH was not simply a haemorrhagic complication of thrombocytopenia. All patients were treated with increased immunosuppression, including various combinations of corticosteroids, plasmapheresis, cyclophosphamide, rituximab and mycophenolate mofetil. Notably, all patients in the cohort survived their initial episode of DAH. While the patients with DAH did well in the short-term, their long-term survival was significantly worse than controls. Several of the deaths were attributable to thrombotic complications after recovering from DAH. CONCLUSIONS: To the best of our knowledge, this is the largest case-control study of lupus DAH to date. History of thrombocytopenia was strongly predictive of DAH (OR ~40). A number of APS manifestations correlated with DAH by univariate analysis, and deserve further consideration in larger studies. PMID- 26430515 TI - Assessing the extent to which current clinical research is consistent with patient priorities: a scoping review using a case study in patients on or nearing dialysis. AB - PURPOSE OF REVIEW: There is growing acknowledgement that engaging patients to identify their research priorities is important. Using a case study of patients on or nearing dialysis, we sought to assess the extent to which recently completed and ongoing clinical research was consistent with priorities identified by patients, caregivers, and clinicians. SOURCES OF INFORMATION: Over a 4-year sampling frame (January 2010 to December 2013), we systematically searched the medical literature (top 5 nephrology and top 10 general medicine journals accessed through MEDLINE via Ovid), international randomized controlled trial (RCT) registries, and national government and kidney research funding organizations (Canada, U.S., Australia, and U.K.) for published clinical studies, registered RCTs, and funded clinical studies, respectively. Published clinical studies, registered RCTs, and funded clinical studies were categorized as to whether or not they were consistent with the top 10 research priorities identified by patients, their caregivers, and clinicians in a recent comprehensive research priority setting exercise. FINDINGS: The search yielded 4293 published articles, 688 RCTs, and 70 funded studies, of which 1116 articles, 315 RCTs, and 70 funded studies were eligible for inclusion. Overall 194 published studies (17.4 %), 71 RCTs (22.5 %), and 15 funded studies (21.4 %) included topics consistent with the top 10 research priorities identified by patients. Four of the top 10 research priorities, including strategies to improve the management of itching, increase access to kidney transplantation, assess the psychosocial impact of kidney failure, and determine the effects of dietary restriction received virtually no attention. LIMITATIONS: The top 10 priorities we used to categorize included studies were identified by Canadian patients, caregivers, and clinicians. The top research priorities may vary across different countries. The proportion of published studies that are consistent with the top 10 priorities could be different in nephrology journals with lower impact factors. Studies related to kidney transplantation and the psychosocial impact of kidney failure may have been published in journals not included in our search strategy. IMPLICATIONS: The majority of recently completed or ongoing clinical studies in patients on or nearing dialysis do not address the top research priorities of patients, raising concerns that current clinical research may not be meeting the needs of the ultimate consumer, in this case, patients on or nearing dialysis. Greater involvement of patients in research is required to bridge the gap between research and patients' needs. PMID- 26430516 TI - Thymic Hassall's corpuscles in Nandanam chicken - light and electronmicroscopic perspective (Gallus domesticus). AB - The present study was aimed to study the light and electron microscopic studies of thymic Hassall's corpuscles was done in various age groups of Nandanam Chicken ranging from day-old to forty weeks. Hassall's corpuscles are special, unique structures present in thymic medulla and also in the cortex of all the age groups of Nandanam chicken (from hatch to forty weeks) in the present study. Size of the Hassall's corpuscles in the medulla is larger than the ones present in the cortical region of thymus. The Hassall's corpuscles are made up of structureless eosinophilic mass surrounded by concentrically arranged reticuloepithelial cells. Under electron microscope, the Hassall's corpuscles were composed of reticuloepithelial cells interconnected by many desmosomes. The epithelial cells had abundance of cytoplasmic fibrils and desmosomes with few mitochondria and ribosomes. The nucleus was oval or round which was slightly indented. The centre of the Hassall's corpuscles was appeared either solid or cystic. The cystic corpuscles had cell debris within the cyst lumen. PMID- 26430517 TI - Project Management of Randomized Clinical Trials: A Narrative Review. AB - CONTEXT: A well-structured protocol for a clinical trial may be able to answer clinical questions, but it cannot be deemed enough to ensure success in the face of incompetent management of time as well as human and economic resources. To address this problem, in this article, we present our literature review on evidence as to how a good knowledge of proper management among researchers can enhance the likelihood of the success of clinical trial projects. EVIDENCE ACQUISITION: Using multiple search strategies, we conducted a literature review on published studies in the English language from 2002 to 2012 by searching the Cochrane Database of Systematic Reviews, MEDLINE, Google Scholar, and EMBASE. RESULTS: Our review suggests that a successful trial requires a work plan or work scope as well as a timeline. The trial manager should subsequently manage the study in accordance with the plan and the timeline. Many research units have called for a clinical project manager with scientific background and regulatory skills to effect coordination among various aspects of a clinical trial. CONCLUSIONS: Project management may benefit both the managerial and scientific aspects of medical projects and reduce fund waste. However, little has been written to date on project management in the context of clinical research. The suggestions represent the views of the individual authors. To provide a high level of evidence in this regard, we recommend that a randomized controlled trial be performed to compare trial projects progressed with and without the use of project management. PMID- 26430518 TI - Determining Functional Vitamin B12 Deficiency in the Elderly. AB - BACKGROUND: Elevated concentration of serum total homocysteine usually occurs in vitamin B-12 deficiency. This metabolite can be measured and used for screening functional vitamin B-12 deficiency. OBJECTIVES: We assessed functional vitamin B12 deficiency in Tehranian elderly admitted to elderly research center, University of Social Welfare and Rehabilitation Sciences. PATIENTS AND MATERIALS: A cross-sectional study was performed on 232 elderly admitted to elderly research center in Tehran, Iran in 2012. According to other studies, individuals were classified into two groups: high risk of vitamin B-12 deficiency (< 220 pmol/L) and borderline vitamin B-12 (220-258 pmol/L) accompanied by elevated homocysteine (> 15 micmol/L). RESULTS: Cut-off of 15.0 pmol/L for homocysteine was identified for persons with normal or elevated concentrations. Among persons aged 65-74 and >= 75 years, respectively, 56% and 93% were at high risk of vitamin B-12 deficiency. CONCLUSIONS: The prevalence of B12 deficiency was higher in this study compared to other studies, so more attention and massive efficacious policy should be designed to reduce the deficiency of this vitamin. PMID- 26430520 TI - Gastrointestinal Complications of Ferrous Sulfate in Pregnant Women: A Randomized Double-Blind Placebo-Controlled Trial. AB - BACKGROUND: Some pregnant women discontinue iron supplements consumption due to Gastrointestinal (GI) complications, whereas pregnancy induces the same complications physiologically. OBJECTIVES: The aim of the present study was to assess GI complications of ferrous sulfate in pregnant women. PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled clinical trial was performed on 176 pregnant women referred to prenatal care clinic of Maryam Hospital from April 2011 to February 2012. Pregnant women with Hb >= 13.2 gr/dL at 13(th) - 18(th) weeks of gestation were selected based on the inclusion criteria and were randomly assigned to the ferrous sulfate and placebo groups. The ferrous sulfate group (n = 90) received a 50-mg ferrous sulfate tablet daily from the 20(th) week to the end of pregnancy and the placebo group (n = 89) received one placebo tablet in the same way. All participants were visited twice at 24(th) - 28(th) and 32(nd) - 36(th) weeks to assess the GI complications as well as Hb level to determine the Hb changes in two groups. Chi-square test, t test and Kolmogorov-Smirnov test were used to analyze the data. P value of < 0.05 and confidence level of 95% were considered as statistically significant. RESULTS: None of the GI complications were significantly different between the ferrous sulfate and placebo groups at 24(th) - 28(th) and 32(nd) - 36(th) weeks. Hemoglobin drop lower than 10.5 gr/dL at 24(th) - 28(th) weeks or lower than 11 g/dL at 32(nd) - 36(th) weeks was not observed in any cases. CONCLUSIONS: It can be concluded that GI complications in pregnant women using ferrous sulfate are mostly caused by physiologic changes of pregnancy rather than ferrous sulfate; therefore, it is not reasonable to stop using ferrous sulfate due to GI complications. PMID- 26430519 TI - A Safe Method of Tracheal Polyflex Stent Placement: A Review of 20 Patients. AB - BACKGROUND: Surgery is an appropriate therapeutic approach for tracheal stenosis due to various benign and malignant conditions. When surgery is postponed for certain reasons, other options are chosen for airway patency. One alternative is using airway stents. OBJECTIVES: We aimed to introduce a safe method of tracheal polyflex stent placement in patients with tracheal stenoses. PATIENTS AND METHODS: During a 7-year period (2002 - 2008), polyflex stents were used 29 times among 20 patients for various indications. After encountering many difficulties in earlier cases, we gradually developed our new method and used it in most of our patients. In this method, without using large rigid bronchoscopes, the introducer tube could be used as a bronchoscope with the aid of a zero-degree lens and ventilating apparatus. In this method, the rate of possible trauma to the airway can be minimized by avoiding the use of thick rigid bronchoscopies and the stent can be placed faster and more accurately. RESULTS: Polyflex stents were used in 11 men (55%) and 9 women with a mean age of 38.5 years. Stents were removed and changed in 12 cases and replaced with another type of stent in 3 patients. Indications were recurrence of tracheal stenosis (7), multisegmental tracheal stenosis (3), anesthesia limitations (3), tracheal tumors (2), dehiscence of tracheal anastomosis (1), severe inflammation of the tracheal mucosa (1), esophagobronchial fistula (1), and external pressure on the left main bronchus (1). In one patient, a stent was used to open a kinked Dumon stent as a temporary life-saving procedure. We found 6 cases of stent migration, 3 cases of granulation tissue formation, 1 case of infection, and 1 case of surgical site dehiscence. CONCLUSIONS: Stents would be regarded as a temporary means of reaching the ideal condition for resection and reconstruction in most patients with tracheal stenoses. Although an optimal stent has not been introduced yet, we used polyflex stents in most of our patients with tracheal stenosis due to its availability and ease of use. We suggest that this method is safe and less time consuming than its traditional method of placement. PMID- 26430521 TI - The DSM-5 Levels of Personality Functioning and Severity of Iranian Patients With Antisocial and Borderline Personality Disorders. AB - BACKGROUND: Fundamental problems with Personality Disorders (PD) diagnostic system in the previous version of DSM, led to the revision of DSM. Therefore, a multidimensional system has been proposed for diagnosis of personality disorder features in DSM-5. In the dimensional approach of DSM-5, personality disorders diagnosis is based on levels of personality functioning (Criteria A) and personality trait domains (Criteria B). OBJECTIVES: The purpose of this study was firstly, to examine the DSM-5 levels of personality functioning in antisocial and borderline personality disorders, and second, to explore which levels of personality functioning in patients with antisocial and borderline personality disorders can better predicted severity than others. PATIENTS AND METHODS: This study had a cross sectional design. The participants consisted of 252 individuals with antisocial (n = 122) and borderline personality disorders (n = 130). They were recruited from Tehran prisoners, and clinical psychology and psychiatry centers of Razi and Taleghani Hospitals, Tehran, Iran. The sample was selected based on judgmental sampling. The SCID-II-PQ, SCID-II and DSM-5 levels of personality functioning were used to diagnose and assess personality disorders. The data were analyzed by correlation and multiple regression analysis. All statistical analyses were performed using the SPSS 16 software. RESULTS: Firstly, it was found that DSM-5 levels of personality functioning have a strong correlation with antisocial and borderline personality symptoms, specially intimacy and self-directedness (P < 0.001). Secondly, the findings showed that identity, intimacy and self-directedness significantly predicted antisocial personality disorder severity (P < 0.0001). The results showed that intimacy and empathy were good predictors of borderline personality disorder severity, as well (P < 0.0001). CONCLUSIONS: Overall, our findings showed that levels of personality functioning are a significant predictor of personality disorders severity. The results partially confirm existing studies. PMID- 26430522 TI - The Effect of Herbal Tea Containing Fenugreek Seed on the Signs of Breast Milk Sufficiency in Iranian Girl Infants. AB - BACKGROUND: One of the important reasons behind termination of breast-feeding in the first six months after childbirth is insufficient production of breast milk. OBJECTIVES: The aim of this study was to determine the effect of herbal tea containing fenugreek seed on the signs of breast milk sufficiency in Iranian girl infants aged 0 - 4 months, at the medical health centers of Tehran university of medical sciences. PATIENTS AND METHODS: This study was a clinical trial with a control group. Seventy-eight girl infants, 0 - 4 months old that were exclusively breastfed by their mothers, were randomly assigned to the intervention group (received herbal tea containing 7.5 g fenugreek seed powder in addition to 3 g of black tea, three times a day) and the control group (received herbal tea containing 3 g of black tea powder, three times a day). Before and during the four weeks of study, the signs of breast milk sufficiency were evaluated through measurement of growth parameters and use of follow-up forms for measuring the number of wet diapers in one day, frequency of defecation and infant breast feeding times in a day. RESULTS: Before the intervention there was no significant difference between weight, height, head circumference, the number of wet diapers and frequency of defecation between the two groups (P > 0.05), yet the number of breast feeding times of the control group was more than the Fenugreek group. At the end of the fourth week in proportion to the pre-intervention conditions, the weight of the infants in the fenugreek group increased significantly from 5282.0513 +/- 1021.51121 to 6383.0769 +/- 952.06190, while head circumference increased from 38.3103 +/- 1.62736 to 39.9256 +/- 1.50660, number of wet diapers from 5.2821 +/- 0.93044 to 8.1648 +/- 1.20620, frequency of defecation from 1.8846 +/- 1.08495 to 2.7326 +/- 0.94771 and the number of breast feeding times from 9.1795 +/- 1.39778 to 15.9597 +/- 1.45056 (P < 0.001). However, there was no significant effect on height variation (P = 0.078). While in the control group there was no significant difference between the mentioned variables (P > 0.05). CONCLUSIONS: Herbal tea of fenugreek seed in comparison to the control group improves the signs of breast milk sufficiency. PMID- 26430523 TI - Child Abuse Reporting Barriers: Iranian Nurses' Experiences. AB - BACKGROUND: Although in many countries child abuse reporting is mandated, Iranian nurses report abused cases voluntary. Some of the cases are reported to the police and others are referred to welfare organizations or other non-governmental organizations. Absence of a uniform reporting system along with a lack of legal support in the specific cultural context of Iran has resulted challenges for the reporters of child abuse. OBJECTIVES: The aim of this study was to explore the Iranian nurses' experiences of reporting child abuse as well as to explore the existing barriers. PATIENTS AND METHODS: A qualitative study with conventional content analysis was conducted to explore the barriers of reporting child abuse. Individual interviews between 30 and 45 minutes in duration were conducted with a purposive sample of 16 nurses with direct experience of dealing with children who had been abused. Graneheim and Lundman's method was used for data analysis. RESULTS: The data were classified to five themes including "knowledge deficit", "previous unpleasant experiences about child abuse reporting", "ethical challenges"," legal challenges" and "cultural beliefs". CONCLUSIONS: According to the findings, enhancement of nurses and public knowledge about child abuse, legal issues and jurisprudence along with legislation of clear and simple laws, are mandatory to protect abused children in Iran. PMID- 26430524 TI - Heart Surgery Waiting Time: Assessing the Effectiveness of an Action. AB - BACKGROUND: Waiting time is an index assessing patient satisfaction, managerial effectiveness and horizontal equity in providing health care. Although heart surgery centers establishment is attractive for politicians. They are always faced with the question of to what extent they solve patient's problems. OBJECTIVES: The objective of this study was to evaluate factors influencing waiting time in patients of heart surgery centers, and to make recommendations for health-care policy-makers for reducing waiting time and increasing the quality of services from this perspective. PATIENTS AND METHODS: This cross sectional study was performed in 2013. After searching articles on PubMed, Elsevier, Google Scholar, Ovid, Magiran, IranMedex, and SID, a list of several criteria, which relate to waiting time, was provided. Afterwards, the data on waiting time were collected by a researcher-structured checklist from 156 hospitalized patients. The data were analyzed by SPSS 16. The Kolmogorov Smirnov and Shapiro tests were used for determination of normality. Due to the non-normal distribution, non-parametric tests, such as Kruskal-Wallis and Mann-Whitney were chosen for reporting significance. Parametric tests also used reporting medians. RESULTS: Among the studied variables, just economic status had a significant relation with waiting time (P = 0.37). Fifty percent of participants had diabetes, whereas this estimate was 43.58% for high blood pressure. As the cause of delay, 28.2% of patients reported financial problems, 18.6% personal problem and 13.5% a delay in providing equipment by the hospital. CONCLUSIONS: It seems the studied hospital should review its waiting time arrangements and detach them, as far as possible, from subjective and personal (specialists) decisions. On the other hand, ministries of health and insurance companies should consider more financial support. It is also recommend that hospitals should arrange preoperational psychiatric consultation for increasing patients' emotionally readiness. PMID- 26430525 TI - Study of Serum Levels of Leptin, C-Reactive Protein and Nutritional Status in Hemodialysis Patients. AB - BACKGROUND: Leptin is secreted by adipose tissue and decreases appetite. However, the role of leptin in the pathogenesis of hemodialysis (HD)-related malnutrition has not been fully evaluated. OBJECTIVES: The aim of study was to investigate the association between the serum leptin levels, serum C-reactive protein (CRP) levels, and nutritional status in hemodialysis patients. PATIENTS AND METHODS: This analytical descriptive study included 45 hemodialysis patients and 40 healthy subjects. Biochemical parameters and serum leptin levels were measured. The nutritional status was evaluated using a food frequency questionnaire (FFQ) and the calculation of the body mass index (BMI). RESULTS: Serum leptin (P < 0.05) and albumin (P < 0.0001) levels and BMI (P < 0.001) of HD patients were significantly lower, while CRP levels were significantly higher than those of controls (P < 0.0001). HD patients consumed the lower daily servings of the food groups compared to the control subjects (P < 0.0001). A significant positive correlation between serum levels of leptin and albumin and BMI was demonstrated. No significant correlations were identified between leptin level, CRP level, and other variables. CONCLUSIONS: The findings suggest that low levels of leptin may be a contributory factor for malnutrition in HD patients. Further studies are required to ascertain the significance of leptin levels in relation to nutritional factors in hemodialysis patients. PMID- 26430526 TI - Prevalence of Urinary Tract Infection Among Pregnant Women and its Complications in Their Newborns During the Birth in the Hospitals of Dezful City, Iran, 2012 - 2013. AB - BACKGROUND: Urinary tract infection (UTI) is the most common disorder caused by bacterial agents in pregnancy, which can lead to important complications in newborn of such mothers in case of inappropriate diagnosis and treatment. OBJECTIVES: The purpose of this study was to study the prevalence of UTI among pregnant women and its complications in their newborns during the birth in the hospitals of Dezful City, Iran, during 2012 - 2013. PATIENTS AND METHODS: In this cross-sectional retrospective study, 1132 women admitted to Dr. Ganjavian and Ayatollah Nabavi Hospitals in Dezful City, Iran, during 2012 - 2013 were randomly allocated into the case and control groups and were matched based on their age, numbers of pregnancy, sex and diseases of their children. UTI was the only difference between the two groups. RESULTS: Twenty-two thousand six hundred deliveries occurred within the course of this study. Due to UTI, 5% of deliveries led to hospitalization of mothers (1132 patients).Weight and height of newborn infants of mothers afflicted with UTI (P < 0.001) were significantly lower compared to newborns of healthy women (P < 0.001). There was a significant association between the two groups of pregnant women with UTI in terms of type of delivery (normal and caesarean section) (P < 0.008). CONCLUSIONS: The lower incidence of UTI in pregnant women compared to other areas of Iran represents the role of climate and weather in the prevalence of UTI. In addition, the increased number of low-birth-weight infants had a remarkable correlation with UTI, which can influence the health of the next generation. PMID- 26430527 TI - Alpha-Amanitin Poisoning, Nephrotoxicity and Oxidative Stress: An Experimental Mouse Model. AB - BACKGROUND: Alpha-amanitin (alpha-AMA) plays a major role in Amanita phalloides poisoning, showing toxic effects on multi-organs, particularly on the liver and kidneys. Studies have shown a relationship between alpha-AMA-related injuries and reactive oxygen species. OBJECTIVES: We aimed to investigate whether there is renal injury and its relationship with oxidative stress after intraperitoneal injection of alpha-AMA in mice experimental poisoning models. MATERIALS AND METHODS: There were 37 male BALB/c laboratory mice treated with alpha-AMA, according to the study groups: control group (n = 7); low dose (0.2 mg/kg) (n = 10); moderate dose (0.6 mg/kg) (n = 10), and high dose (1 mg/kg) (n = 10). The sample size was detected according to the ethical committee's decision as well as similar studies in the literature. After a 48-hour follow-up period, all the subjects were sacrificed for pathological and biochemical assays. The study was held in Turkey. RESULTS: alpha-AMA poisoning in mice results in inflammatory changes and necrosis in renal structures. There were statistically significant differences between the study groups regarding measured levels of catalase, superoxide dismutase, glutathione peroxidase, total antioxidant status (TAS), total oxidant status (TOS) and malonyl dialdehyde in renal homogenates of mice (P < 0.001, P < 0.001, P < 0.001, P < 0.001, P < 0.001, and P = 0.001, respectively). The TOS and TAS measurements helped to eliminate cumbersome analysis of diverse oxidant and antioxidant molecules. The TOS levels in renal homogenate of mice were significantly higher in all the intoxication groups compared to the control group (5.73, 7.02, 7.77, and 9.65 mmol trolox eq/g protein and P = 0.002, P = 0.001, and P = 0.001, respectively). The TAS levels in moderate and high-dose groups were significantly lower than all the other groups treated with alpha-AMA (0.130, 0.152, 0.065, and 0.087 mmol trolox eq/g protein and P = 0.031, P = 0.001, and P = 0.001, respectively). CONCLUSIONS: Our results indicated that alpha-AMA poisoning in mice led to inflammatory changes and necrosis in renal structures. Biochemical analysis showed a shift in the oxidative/anti-oxidative balance towards the oxidative status. PMID- 26430528 TI - Sex Differences in Neuroanatomy of the Human Mirror Neuron System: Impact on Functional Recovery of Ischemic Hemiparetic Patients. AB - BACKGROUND: Considering the higher activity of mirror neuron system in females, they frequently have better performance in empathy, interpersonal sensitivity, and emotional recognition compared to males. OBJECTIVES: The purpose of this study was to assess whether gender difference in neuroanatomy of the human mirror neuron system has any impact on functional recovery of ischemic hemiparetic patients. PATIENTS AND METHODS: This single-blind clinical trial was conducted on 24 patients with cerebrovascular accident (CVA) in the age range of 45 - 60 years, referring at a rehabilitation center in Tehran, Iran, during 2013 - 2014. Sampling method was stratified random sampling. The subjects were assigned to 2 groups of 12 males and 12 females. Then, each group was randomly divided into 2 groups (totally 4 groups, n = 6 for each group): women watching functional movies, control women, men watching functional movies, and control men. Movies were shown to patients and then, they were evaluated by Timed Up and Go (TUG), Six-minute walk test (SMW), Barthel index (BI), and Berg balance scale (BBS). RESULTS: Comparison of all variables related to functional activities of all groups before and after watching movies revealed significant differences. The highest percentage of change and improvement was observed in groups 1 and 3 watching the functional movies (P = 0.0001). Percentage of improvement in women of groups 1 and 2 was higher than men in groups 3 and 4 (P = 0.0003). The changes in group of females watching the functional movies (group 1) were significantly greater than in other groups (P < 0.0001). CONCLUSIONS: The Sex differences in the neuroanatomy of the human mirror neuron system affect functional recovery of patients with hemiparesis. The improvement in studied women was found to be significantly greater than studied men. The results indicate a higher chance of recovery among hemiparetic women, especially those watching functional movies. PMID- 26430529 TI - Better Hemodynamic Profile of Laryngeal Mask Airway Insertion Compared to Laryngoscopy and Tracheal Intubation. AB - BACKGROUND: Laryngoscopy and tracheal intubation can cause serious cardiovascular responses in patients such as hypertension, tachycardia, and arrhythmias. Alternative airway maintenance techniques may attenuate these hemodynamic stress responses. OBJECTIVES: This study aimed to compare the immediate hemodynamic effects of the insertion of laryngeal mask airway supreme (LMA-S) and classic (LMA-C) with laryngoscopy and Endotracheal Intubation (ETT). PATIENTS AND METHODS: This study was a prospective, double-blind, and randomized clinical trial conducted on 150 patients aged 18 to 50 years with ASA I (American Society of Anesthesiologists), in the general operating room of Shahid Mohammadi hospital, Hormozgan university of medical sciences, Bandar Abbas, Iran. In the ETT group, endotracheal intubation was performed using the Macintosh laryngoscope; while for the LMA-C and LMA-S groups, LMA Classic and LMA Supreme were inserted, respectively. The induction and maintenance of anesthesia were similar in all patients. The hemodynamic parameters such as heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were measured before (baseline) and after induction of anesthesia at 4 different time points. The statistical analysis was done and P value less than 0.05 was considered significant. RESULTS: Participants in all groups were similar in terms of gender, age, weight, height, and Mallampati class. The mean +/- SD of SBPs (105.62 +/- 12.12, 112.90 +/- 12.2, and 112.48 +/- 15.14 mm Hg, respectively for ETT, LMA-C, and LMA-S) and DBPs (64.64 +/- 10.23, 73.78 +/- 9.70, and 71.20 +/- 12.27 mm Hg, respectively for ETT, LMA-C, and LMA-S) were significantly lower in the ETT group compared to LMA groups 5 minutes after device insertion (P < 0.01 for SBPs and P < 0.001 for DBPs); however these values were lower than the baseline values in all groups. There were no differences in the mean SBP and DBPs between the three groups at the other time points. The mean +/- SD heart rates in the ETT group, compared to the LMA-C and LMA-S groups, were considerably higher in the first minute (100.06 +/- 18.27, 82.50 +/- 10.52, and 82.00 +/- 13.60 bpm, respectively for ETT, LMA-C, and LMA-S), third minute (91.04 +/- 17.12, 78.84 +/- 11.23, and 78.90 +/- 13.41 bpm, respectively for ETT, LMA-C, and LMA-S) and fifth minute (85.82 +/- 16.01, 75.78 +/- 11.73, and 75.04 +/- 13.90 bpm, respectively for ETT, LMA-C, and LMA-S) after intubation (P < 0.001). There were no significant differences between the LMA-C and LMA-S groups in terms of hemodynamic parameters. CONCLUSIONS: Maintaining the airway using laryngeal mask airway is associated with less cardiovascular responses compared to direct laryngoscopy and tracheal intubation. PMID- 26430530 TI - Effect of Acupressure on Cervical Ripening. AB - BACKGROUND: Cervical ripening is one of the main stages of initiation labor. Acupressure in Chinese medicine is considered as an invasive technique, which through reliving oxytocin ripens the cervix. Acupoint Sanyinjiao (SP6) was selected in this study because it is the acupoint selected in gynecology and it is easy for women to locate and apply pressure without medical assistance. OBJECTIVES: The aim of this study was to determine the effect of acupressure on cervical ripening. PATIENTS AND METHODS: In this randomized clinical trial, 150 primigravida with term pregnancy who had referred to Deziani hospital in Gorgan were chosen and divided to three groups: in the first group acupressure was done by the researcher while in the second groups this was performed by the mother her self, and the third group served as a control and only received routine care. For both intervention groups the pressure was applied on Sp6 for about 20 minutes during one to five days. Elements were checked from cervical ripening at 48 and 96 hours after intervention and at the time of hospitalization. The tools for gathering information included demographic characteristics and midwifery history questionnaire, daily records and follow up forms. Content validity was used for validity of tools. Reliability of the observation check-list and physical examination was confirmed by inter-rater scores (inter observer), and daily records by test-re-test. Data was analyzed by analysis of variance (ANOVA), Kruskal-Wallis and Chi-squared tests (P <= 0.05). RESULTS: There was a significant difference between mothers' educations in the three groups. Most of the mothers (59.5%) in the researcher-performed acupressure group had secondary education. Cervical ripening was significantly different between the three groups after 48 hours (P <= 0.05), yet there was no significant difference after 96 hours and at the time of admission. Mean Bishop score was enhanced after 48 hours in the researcher-performed acupressure group (P <= 0.021) and the self-performed acupressure group (P <= 0.007) in comparison to the control group. CONCLUSIONS: The results showed that acupressure is a safe technique and leads to cervical ripening. Thus, regarding the desired results that were achieved when mothers applied acupressure themselves, it could be suggested that it is beneficial for mothers to be trained to apply this method at home. PMID- 26430531 TI - Embryonal Rhabdomyosarcoma of the Adult's Vocal Cord: A Case Report. AB - INTRODUCTION: Although embryonal rhabdomyosarcomas (ERMS) represent the most common (50% - 60%) clinical form of rhabdomyosarcoma, these are extremely rare in adult's vocal cords. To date, only five cases of laryngeal ERMS have been reported in adults and only one of them involved the vocal cords. CASE PRESENTATION: Herein, we reported a case of a 22-year-old woman diagnosed with ERMS, T1N0M0 stage, localized at the right vocal cord. Tumor was successfully treated with a radical excision and selective neck dissection and followed-up for 5 years with no evidence of local recurrence. CONCLUSIONS: Immunohistochemistry combined with computerized tomography (CT) and color Doppler solography of the neck and thorax should be performed. This study suggested that surgical resection was suitable for the treatment of this disease and reported the evaluations of an extremely rare case for five years. PMID- 26430532 TI - Examination of the Factorial Structure of Adverse Childhood Experiences and Recommendations for Three Subscale Scores. AB - OBJECTIVE: The purpose of the current investigation is to assess and validate the factor structure of the Behavioral Risk Factor Surveillance System's (BRFSS) Adverse Childhood Experience (ACE) module. METHOD: ACE data available from the 2009 BRFSS survey were fit using exploratory factor analysis (EFA) to estimate an initial factorial structure. The exploratory solution was then validated using confirmatory factor analysis (CFA) with data from the 2010 BRFSS survey. Lastly, ACE factors were tested for measurement invariance using multiple group factor analysis. RESULTS: EFA results suggested that a 3-factor solution adequately fit the data. Examination of factor loadings and item content suggested the factors represented the following construct areas: Household Dysfunction, Emotional/Physical Abuse, and Sexual Abuse. Subsequent CFA results confirmed the 3-factor solution and provided preliminary support for estimation of an overall latent ACE score summarizing the responses to all available items. Measurement invariance was supported across both gender and age. CONCLUSIONS: Results of this study provides support for the use of the current ACE module scoring algorithm, which uses the sum of the number of items endorsed to estimate exposure. However, the results also suggest potential benefits to estimating 3 separate composite scores to estimate the specific effects of exposure to Household Dysfunction, Emotional/Physical Abuse, and Sexual Abuse. PMID- 26430533 TI - Serum procalcitonin is a marker for prediction of readmission from an intermediate care to an acute care hospital in neurosurgical patients. AB - BACKGROUND: Readmission of patients to acute hospitals contributes significantly toward inefficient utilization of healthcare resources, with studies quoting up to 90% being preventable. We aim to report and analyze the factors involved in the readmission of neurosurgical patients who had been previously transferred to an intermediate step-down care facility, and explore possible predictive markers for such readmissions. METHODS: We conducted a retrospective analysis of all 129 neurosurgical patients who were transferred from out acute tertiary hospital to an intermediate care facility. The cases were segregated into those who were readmitted and those who were not readmitted back to our acute center. The demographic data, clinical features, diagnoses, treatment modalities, pretransfer laboratory findings, and inpatient complications were compared with readmission rate. RESULTS: There were 23 patients (17.8%) who were readmitted to our acute hospital. The most common causes of readmission was infection (n = 12, 52.2%). We found a statistically significant correlation between the higher pretransfer procalcitonin levels with the readmission of our patients (P = 0.037). There was also a significant difference noted between ethnic groups (P = 0.026) and having no complications of disease or treatment (P = 0.008), with readmission. CONCLUSION: Procalcitonin is a pro-hormone known to correlate with infection and poor neurological status. We have found that its serum values correlate significantly with the readmission rates of neurosurgical patients in our study. We postulate that by ensuring normality in procalcitonin levels prior to transfer to an intermediate care facility, potentially half of neurosurgical readmissions can be prevented. PMID- 26430534 TI - A conceptual model for translating omic data into clinical action. AB - Genomic, proteomic, epigenomic, and other "omic" data have the potential to enable precision medicine, also commonly referred to as personalized medicine. The volume and complexity of omic data are rapidly overwhelming human cognitive capacity, requiring innovative approaches to translate such data into patient care. Here, we outline a conceptual model for the application of omic data in the clinical context, called "the omic funnel." This model parallels the classic "Data, Information, Knowledge, Wisdom pyramid" and adds context for how to move between each successive layer. Its goal is to allow informaticians, researchers, and clinicians to approach the problem of translating omic data from bench to bedside, by using discrete steps with clearly defined needs. Such an approach can facilitate the development of modular and interoperable software that can bring precision medicine into widespread practice. PMID- 26430535 TI - Whole slide image with image analysis of atypical bile duct brushing: Quantitative features predictive of malignancy. AB - BACKGROUND: Whole slide images (WSIs) involve digitally capturing glass slides for microscopic computer-based viewing and these are amenable to quantitative image analysis. Bile duct (BD) brushing can show morphologic features that are categorized as indeterminate for malignancy. The study aims to evaluate quantitative morphologic features of atypical categories of BD brushing by WSI analysis for the identification of criteria predictive of malignancy. MATERIALS AND METHODS: Over a 3-year period, BD brush specimens with indeterminate diagnostic categorization (atypical to suspicious) were subjected to WSI analysis. Ten well-visualized groups with morphologic atypical features were selected per case and had the quantitative analysis performed for group area, individual nuclear area, the number of nuclei per group, N: C ratio and nuclear size differential. RESULTS: There were 28 cases identified with 17 atypical and 11 suspicious. The average nuclear area was 63.7 um(2) for atypical and 80.1 um(2) for suspicious (+difference 16.4 um(2); P = 0.002). The nuclear size differential was 69.7 um(2) for atypical and 88.4 um(2) for suspicious (+difference 18.8 um(2); P = 0.009). An average nuclear area >70 um(2) had a 3.2 risk ratio for suspicious categorization. CONCLUSION: The quantitative criteria findings as measured by image analysis on WSI showed that cases categorized as suspicious had more nuclear size pleomorphism (+18.8 um(2)) and larger nuclei (+16.4 um(2)) than those categorized as atypical. WSI with morphologic image analysis can demonstrate quantitative statistically significant differences between atypical and suspicious BD brushings and provide objective criteria that support the diagnosis of carcinoma. PMID- 26430537 TI - Validation of whole slide imaging for frozen section diagnosis in surgical pathology. AB - BACKGROUND: Whole slide imaging (WSI) using high-resolution scanners is gaining acceptance as a platform for consultation as well as for frozen section (FS) evaluation in surgical pathology. We report results of an intra-observer concordance study comparing evaluation of WSI of scanned FS microscope slides with the original interpretation of the same microscope slides after an average lag time of approximately 1-year. METHODS: A total of 70 FS cases (148 microscope slides) originally interpreted by 2 pathologists were scanned at *20 using Aperio CS2 scanner (Leica Biosystems, San Diego, CA, USA). Reports were redacted such that the study pathologists reviewed images using eSlide Manager Healthcare Network application (Leica Biosystems) accompanied by the same clinical information available at the time of original FS evaluation. Discrepancies between the original FS diagnosis and WSI diagnosis were categorized as major (impacted patient care) or minor (no impact on patient care). RESULTS: Lymph nodes, margins for head and neck cancer resections, and arthroplasty specimens to exclude infection, were the most common FS specimens. The average wash-out interval was 380 days (range: 303-466 days). There was one major discrepancy (1.4% of 70 cases) where the original FS was interpreted as severe squamous dysplasia, and the WSI FS diagnosis was mild dysplasia. There were two minor discrepancies; one where the original FS was called focal moderate squamous dysplasia and WSI FS diagnosis was negative for dysplasia. The second case was an endometrial adenocarcinoma that was originally interpreted as Federation of Gynecology and Obstetrics (FIGO) Grade I, while the WSI FS diagnosis was FIGO Grade II. CONCLUSIONS: These findings validate and support the use of WSI to provide interpretation of FS in our network of affiliated hospitals and ambulatory surgery centers. PMID- 26430536 TI - TissueCypher(TM): A systems biology approach to anatomic pathology. AB - BACKGROUND: Current histologic methods for diagnosis are limited by intra- and inter-observer variability. Immunohistochemistry (IHC) methods are frequently used to assess biomarkers to aid diagnoses, however, IHC staining is variable and nonlinear and the manual interpretation is subjective. Furthermore, the biomarkers assessed clinically are typically biomarkers of epithelial cell processes. Tumors and premalignant tissues are not composed only of epithelial cells but are interacting systems of multiple cell types, including various stromal cell types that are involved in cancer development. The complex network of the tissue system highlights the need for a systems biology approach to anatomic pathology, in which quantification of system processes is combined with informatics tools to produce actionable scores to aid clinical decision-making. AIMS: Here, we describe a quantitative, multiplexed biomarker imaging approach termed TissueCypherTM that applies systems biology to anatomic pathology. Applications of TissueCypherTM in understanding the tissue system of Barrett's esophagus (BE) and the potential use as an adjunctive tool in the diagnosis of BE are described. PATIENTS AND METHODS: The TissueCypherTM Image Analysis Platform was used to assess 14 epithelial and stromal biomarkers with known diagnostic significance in BE in a set of BE biopsies with nondysplastic BE with reactive atypia (RA, n = 22) and Barrett's with high-grade dysplasia (HGD, n = 17). Biomarker and morphology features were extracted and evaluated in the confirmed BE HGD cases versus the nondysplastic BE cases with RA. RESULTS: Multiple image analysis features derived from epithelial and stromal biomarkers, including immune biomarkers and morphology, showed significant differences between HGD and RA. CONCLUSIONS: The assessment of epithelial cell abnormalities combined with an assessment of cellular changes in the lamina propria may serve as an adjunct to conventional pathology in the assessment of BE. PMID- 26430538 TI - A Case of Secondary Angiosarcoma of the Breast after Breast-conserving Surgery and Radiation: Review of Radiologic and Pathologic Findings. AB - Angiosarcoma of the breast is a rare and potentially life-threatening disease. It can present as a palpable mass or subtle erythematous lesion, depending on the predisposing clinical factors. Erythematous skin lesions may be confused for a benign process, which may lead to a delay in diagnosis. We present a case of an 80-year-old woman who developed secondary angiosarcoma after undergoing breast conserving therapy for Stage IA breast cancer. In this article, we review our experience with a case of secondary angiosarcoma of the breast and discuss the presentation, evaluation, and treatment of this disease. This case demonstrates the importance of vigilance regarding erythematous or papular breast lesions in the setting of prior local radiation. PMID- 26430539 TI - Intrapetrous Anastomosis between the Internal Jugular Vein and the Superior Petrosal Sinus: Cone Beam Computed Tomography Incidental Finding. AB - This is a case report of a 62-year-old male who presented to the Ear, Nose, and Throat clinic for a follow-up exam for hearing loss stemming from a fall from a horse in his infancy. A Cone Beam Computed Tomography (CBCT) examination revealed an intrapetrous communication between the internal jugular vein bulb and the superior petrosal sinus. Three-dimensional bone and soft tissues volume renderings were generated to demonstrate this incidental anatomical variant. PMID- 26430540 TI - Malignant Transformation of Hepatic Adenoma in Glycogen Storage Disease Type-1a: Report of an Exceptional Case Diagnosed on Surveillance Imaging. AB - Hepatocellular adenoma is a heterogeneous group of benign neoplasms arising from hepatocellular cells and can be subclassified into four major groups based on genotypic and phenotypic characteristics. These four subtypes are hepatocyte nuclear factor (HNF) 1alpha-inactivated, beta-catenin-activated, inflammatory, and unclassified adenomas. Immunohistochemistry studies have demonstrated that since beta-catenin-activated adenomas have a higher risk of malignant transformation, the identification of the subtype of adenoma remains crucial in patient management. However, malignant transformation of hepatic adenoma without beta-catenin overexpression can be seen in 30-65% cases. We report a case of malignant transformation of hepatic adenoma without overexpression of beta catenin in a 31-year-old man with a known glycogen storage disease (GSD) Type-1a, which was diagnosed on surveillance magnetic resonance imaging (MRI). The MRI showed a mild interval increase in one lesion with relative stability of the other adenomas. The lesion was presumed to be suspicious for a hepatocellular carcinoma (HCC) and was confirmed on pathology. PMID- 26430541 TI - Identification of Cardiac and Aortic Injuries in Trauma with Multi-detector Computed Tomography. AB - Blunt and penetrating cardiovascular (CV) injuries are associated with a high morbidity and mortality. Rapid detection of these injuries in trauma is critical for patient survival. The advent of multi-detector computed tomography (MDCT) has led to increased detection of CV injuries during rapid comprehensive scanning of stabilized major trauma patients. MDCT has the ability to acquire images with a higher temporal and spatial resolution, as well as the capability to create multiplanar reformats. This pictorial review illustrates several common and life threatening traumatic CV injuries from a regional trauma center. PMID- 26430542 TI - Multiple Mycotic Aneurysms of the Abdominal Aorta Illustrated on MDCT Scanner. AB - Infective mycotic aneurysm of the aorta is a rare and life-threatening disease. A patient presenting with constitutional symptoms and pulsatile abdominal mass should raise a suspicion of mycotic aneurysm. Early detection of aortic mycotic lesions in such patients should play a key role in the treatment of aortic aneurysms. Multiple mycotic aneurysms of abdominal aorta in a young male are a rare manifestation of the disease. Multidetector computerized tomography (CT) is an essential tool in identifying the etiology, pathogenesis, protean manifestations of systemic tuberculosis, and ultimately deciding the course of treatment. PMID- 26430543 TI - Radiologic-Pathologic Correlation: Metastatic Pulmonary Epithelioid Hemangioendothelioma of Bone Primary. AB - Epithelioid hemangioendothelioma is a rare vascular malignancy often characterized by a clinically indolent course and delayed diagnosis. The authors present the radiologic and pathologic features of a case of pulmonary epithelioid hemangioendothelioma which was initially thought to be calcified granulomas. PMID- 26430544 TI - Searching for the elusive mitochondrial longevity signal in C. elegans. AB - There is a growing list of examples where perturbed mitochondrial function is associated with increased longevity, yet the exact mechanisms have remained elusive. This phenomenon was first documented, and has been studied most extensively, in C. elegans. One prominent model proposed that lifespan extension resulting from electron transport chain inhibition is due to induction of the mitochondrial unfolded protein response. This model requires revision in light of recent data showing that the mitochondrial unfolded protein response, as defined by the field, is neither necessary nor sufficient for lifespan extension in C. elegans. Several additional factors have been proposed to underlie this lifespan extension, which is likely to be multifactorial and complex. PMID- 26430545 TI - Acquired resistance to monepantel in C. elegans: What about parasitic nematodes? AB - In 2008, Novartis Animal Health developed a new class of anthelmintics, the amino acetonitrile derivatives (AAD) of which monepantel is the most prominent compound. Monepantel was designed for the treatment of sheep against the parasitic nematode Haemonchus contortus. Because monepantel acts through a different mechanism, it is effective against nematodes that have acquired resistance to long-standing anthelmintics. In order to benefit from a maximum lifespan and efficacy of this new compound, the mode of action of monepantel needs to be understood. Studies on the model nematode Caenorhabditis elegans led to the identification of at least one target of monepantel: the monovalent cation channel ACR-23. Here we comment on the effects of monepantel on C. elegans and on the development of resistant parasitic nematode strains. PMID- 26430546 TI - ICeE an interface for C. elegans experiments. AB - An increasing number of laboratories are using the COPAS BiosortTM to implement high-throughput approaches to tackle diverse biological problems. While providing a powerful tool for generating quantitative data, the utility of the Biosort is currently limited by the absence of resources for data management. We describe a simple electronic database designed to allow easy storage and retrieval of Biosort data for C. elegans, but that has a wide potential application for organizing electronic files and data sets. ICeE is an Open Source application. The code and accompanying documentation are freely available via the web at http://www.ciml.univ-mrs.fr/EWBANK_jonathan/software.html. PMID- 26430547 TI - From head to tail it's a 2 way street for neuro-immune communication. AB - Animals need to be able to rapidly and effectively respond to changes in their external and internal environment. To achieve this the nervous and immune systems need to coordinate their responses, integrating multiple cues including presence of potential pathogens, and availability of food. In our recent study (1) we demonstrate that signaling by sensory neurons in the head using the classical neurotransmitter serotonin can negatively regulate the rectal epithelial immune response upon infection of C. elegans with the naturally occurring bacterial pathogen Microbacterium nematophilum (M. nematophilum). The complicated nature of the mammalian brain and immune system has made it difficult to identify the molecular mechanisms mediating these interactions. With its simple, well described, nervous system and a rapidly growing understanding of its immune system, C. elegans has emerged as an excellent model to study the mechanisms by which animals recognize pathogens and coordinate behavioral and cellular immune responses to infection. PMID- 26430548 TI - Membrane lipids and the endoplasmic reticulum unfolded protein response: An interesting relationship. AB - The unfolded protein response of the endoplasmic reticulum (UPR(ER)) is a conserved signaling circuit that ensures ER protein homeostasis (proteostasis). In the UPR(ER) of higher eukaryotes, multiple sensors cooperatively perceive proteostatic disturbances in the ER lumen and induce downstream adaptive changes. Besides direct proteotoxic insults, altered lipid profiles can also lead to UPR(ER) activation, evidently because abnormal lipid composition impairs protein folding. However, 2 recent studies propose an alternative mechanism of UPR(ER) sensor activation. In one report, UPR(ER) activation occurred in cells expressing UPR(ER) sensors lacking the very domains that sense unfolded proteins; the other study found that Caenorhabditis elegans worms displayed UPR(ER) activation without apparent proteostatic imbalance in the ER lumen. Collectively, these studies suggest that lipid disequilibrium-activated UPR(ER) is not strictly accompanied by compromised ER proteostasis and hint at a lipid membrane monitoring role of the UPR(ER). These discoveries raise several important questions: does the UPR(ER) monitor and maintain homeostasis of the ER membrane and/or its lipids? In turn, does the UPR(ER) initiate downstream regulatory events that specifically alleviate lipid or proteostatic imbalance? And what is the physiological significance of proteostasis-independent UPR(ER) activation? In this commentary, we will discuss these issues and highlight the utility of C. elegans as an in vivo model to study lipid disequilibrium-induced UPR(ER) and related pathways. PMID- 26430549 TI - Investigating heart-specific toxicity of amyloidogenic immunoglobulin light chains: A lesson from C. elegans. AB - Abnormalities in protein folding are involved in many localized and systemic diseases, all of which are characterized by insoluble amyloid formation and deposition. In immunoglobulin light chain (LC) amyloidosis, the most frequent systemic form of amyloidosis, the amyloid involvement of the heart dictates the prognosis and the elucidation of the mechanism of heart targeting and toxicity is essential for designing and testing new effective treatments. To this end, the availability of an appropriate animal model is crucial. We recently described the use of C. elegans as an innovative experimental system to investigate in vivo the pathogenic effects of monoclonal LC. This idea stems from the knowledge that the worm's pharynx is an "ancestral heart" with the additional ability to recognize stressor compounds. The feeding of worms with LC purified from patients suffering from cardiomyopathy, selectively and permanently impaired the pharyngeal function. This irreversible damage resulted in time, in a significant reduction in the lifespan of worms. We also reported that the ability of LC to generate reactive oxygen species was associated with their toxic effects and was counteracted by anti-oxidant compounds. This new nematode-based assay represents a promising model for elucidating the heart-specific toxicity of LC and for a rapid screening of new therapeutic strategies. PMID- 26430550 TI - An intimate look at LET-23 EGFR trafficking in the vulval cells of live C. elegans larvae. AB - Precise cell fate specification is essential for organ formation. A simple view is that one or several signal sending cells emit a ligand to a group of signal receiving cells that express the corresponding receptor, which transduces the signal through intracellular enzyme pathways. All these events must be spatio temporally regulated to achieve the proper strength, duration and output of the signaling pathways. In particular, the production and secretion of the ligand has to be coordinated with the expression and accessibility of the receptor in the signal receiving cells. Furthermore, removal of the ligand or receptor is key to achieve proper signal termination and prevent excess cell differentiation and proliferation. Improper regulation of any of these events may cause developmental defects and human disease. C. elegans is an excellent model to systematically identify genes that control the localization and activity of the Epidermal Growth Factor Receptor (EGFR) homolog LET-23. To identify regulators of LET-23 trafficking, Haag et al. observed LET-23 localization in the vulva precursor cells (VPCs) of RNAi treated larvae by live fluorescent microscopy. In this comment, we provide an overview of the newly identified regulators of LET-23 trafficking and discuss the role of the Ezrin/Radixin/Moesin homolog ERM-1 as a temporal regulator of EGFR signaling. PMID- 26430551 TI - Microtubule dynamics followed through cell differentiation and tissue biogenesis in C. elegans. AB - Microtubules (MTs) are cytoskeletal filaments essential for many processes in eukaryotic cells. Assembled of tubulin subunits, MTs are dynamic structures that undergo successive and stochastic phases of polymerization and depolymerization, a behavior called dynamic instability. Dynamic instability has been extensively studied in cultured cells and in vitro using cytoplasmic extracts or reconstituted MTs. However, how MTs behave in intact tissues and how their dynamics are affected by or affect tissue function are poorly understood. Recent advances in high-resolution live imaging have helped overcome technical limitation in order to visualize MTs in intact living organisms including Drosophila or Caenorhabditis elegans. We recently took advantage of the well characterized development, small size and transparency of C. elegans to monitor MT dynamics throughout tissue biogenesis with high spatial and temporal resolution. Using the sex myoblast lineage that generates the egg-laying muscles from 2 mitotic precursors, we identified selective dynamics in precursor versus differentiated cells, and molecular regulation of MT dynamics changes that occur during cell differentiation. We discuss here how this approach led to novel insights into the regulation of MTs dynamics and organization in vivo. PMID- 26430552 TI - Should I stay or should I go? Identification of novel nutritionally regulated developmental checkpoints in C. elegans. AB - After embryogenesis, developing organisms typically secure their own nutrients to enable further growth. The fitness of an organism depends on developing when food is abundant and slowing or stopping development during periods of scarcity. Although several key pathways that link nutrition with development have been identified, a mechanistic understanding of how these pathways coordinate growth with nutritional conditions is lacking. We took advantage of the stereotyped development and experimental accessibility of C. elegans to study nutritional control of late larval development. We discovered that C. elegans larval development is punctuated by precisely time checkpoints that globally arrest growth when nutritional conditions are unfavorable. Arrest at the checkpoints is regulated by insulin- and insulin-like signaling and steroid hormone signaling. These pathways are conserved in mammals, suggesting that similar mechanisms could regulate growth and development in humans. We highlight several implications of our research, including quiescence of diverse cellular behaviors as an adaptive response to unfavorable growth conditions, the existence of oscillatory checkpoints that coordinate development across tissues, and the connections between systemic and cell-autonomous regulators of nutritional response. Together, our findings describe a fascinating developmental strategy in C. elegans that we expect will not only provide insight into nutritional regulation of development, but also into poorly understood cellular processes such as quiescence and aging. PMID- 26430553 TI - Evidence of a MOF histone acetyltransferase-containing NSL complex in C. elegans. AB - Regulation of chromatin is a key process in the developmental control of gene expression. Many multi-subunit protein complexes have been found to regulate chromatin through the modification of histone residues. One such complex is the MOF histone acetyltransferase-containing NSL complex. While the composition of the human and Drosophila NSL complexes has been determined and the functions of these complexes investigated, the existence of an equivalent complex in nematodes such as Caenorhabditis elegans has not yet been explored. Here we summarise evidence, from our own work and that of others, that homologues of NSL complex components are found in C. elegans. We review data suggesting that nematode proteins SUMV-1 and SUMV-2 are homologous to NSL2 and NSL3, respectively, and that SUMV-1 and SUMV-2 may form a complex with MYS-2, the worm homolog of MOF. We propose that these interactions suggest the existence of a nematode NSL-like complex and discuss the roles of this putative NSL complex in worms as well as exploring the possibility of crosstalk between NSL and COMPASS complexes via components that are common to both. We present the groundwork from which a full characterization of a nematode NSL complex may begin. PMID- 26430554 TI - The soft genome. AB - Caenorhabditis elegans (C. elegans) nematodes transmit small RNAs across generations, a process that enables transgenerational regulation of genes. In contrast to changes to the DNA sequence, transgenerational transmission of small RNA-mediated responses is reversible, and thus enables "soft" or "flexible" inheritance of acquired characteristics. Until very recently only introduction of foreign genetic material (viruses, transposons, transgenes) was shown to directly lead to inheritance of small RNAs. New discoveries however, demonstrate that starvation also triggers inheritance of endogenous small RNAs in C.elegans. Multiple generations of worms inherit starvation-responsive endogenous small RNAs, and starvation also results in heritable extension of the progeny's lifespan. In this Commentary paper we explore the intriguing possibility that large parts of the genome and many additional traits are similarly subjected to heritable small RNA-mediated regulation, and focus on the potential influence of transgenerational RNAi on the worm's physiology. While the universal relevance of this mechanism remains to be discovered, we will examine how the discoveries made in worms already challenge long held dogmas in genetics and evolution. PMID- 26430555 TI - Splicing factor SUP-12 and the molecular complexity of apparent cooperativity. AB - The splicing factor SUP-12 from C. elegans, in combination with either ASD-1 or FOX-1 from the Fox-1 (RBFOX) family, is required for generating a muscle-specific isoform of the fibroblast growth factor receptor EGL-15. Biophysical techniques have revealed the sequence preference for the RNA Recognition Motif (RRM) domain from SUP-12 as well as the structural details of the RNA-bound complex. Detailed genetics have identified a requisite need for the presence of both SUP-12 and ASD 1/FOX-1 to regulate the alternative splicing event, prompting speculation of a cooperative mechanism between these proteins on binding RNA. In contrast, the interplay between SUP-12 and ASD-1 suggests that although the RRM domains from each protein are in direct contact on the egl-15 pre-mRNA, there is no simple contribution of binding cooperativity. Evidence for an independent binding mechanism by SUP-12 and ASD-1 will be discussed, including a model in which both positive and negative contributions are balanced during complex assembly. The ability to monitor tissue-specific alternative splicing in live nematodes will continue to provide a powerful method to test in vivo mechanistic models derived from atomic-level investigation. PMID- 26430556 TI - SNF-10 connects male-derived signals to the onset of sperm motility in C. elegans. AB - Sperm from the nematode C. elegans gain motility during a process termed activation, which they initiate in response to specific environmental signals. During this process, a number of subcellular rearrangements occur, culminating in an altered morphology that allows the cell to crawl toward and fertilize oocytes. Both hermaphrodites and males produce sperm, and redundant, sex-biased pathways regulate the sperm's activation. The male-derived signal for sperm activation involves TRY-5, a trypsin-like serine protease in seminal fluid, but until recently it was unknown what factors were active downstream of TRY-5. In our recent paper, we reported the discovery of SNF-10, a solute carrier 6 (SLC6) family protein that is expressed by sperm and connects the activation signal to changes in sperm morphology and, ultimately, the onset of motility. Here, we review our recent results, focusing on potential models for SNF-10's function in C. elegans, and additionally discuss the role SLC6 transporters may play in male reproductive biology from invertebrates to mammals. PMID- 26430557 TI - Pharyngeal pumping inhibition and avoidance by acute exposure to high CO2 levels are both regulated by the BAG neurons via different molecular pathways. AB - Carbon dioxide (CO2) is a key molecule in many biological processes. Studies in humans, mice, D. melanogaster, C. elegans, unicellular organisms and plants have shed light on the molecular pathways activated by elevated levels of CO2. However, the mechanisms that organisms use to sense and respond to high CO2 levels remain largely unknown. Previous work has shown that C. elegans quickly avoid elevated CO2 levels using mechanisms that involve the BAG, ASE and AFD neurons via cGMP- and calcium- signaling pathways. Here, we discuss our recent finding that exposure of C. elegans to high CO2 levels leads to a very rapid cessation in the contraction of the pharynx muscles. Surprisingly, none of the tested CO2 avoidance mutants affected the rapid pumping inhibition response to elevated CO2 levels. A forward genetic screen identified that the hid-1-mediated pathway of dense core vesicle maturation regulates the pumping inhibition, probably through affecting neuropeptide secretion. Genetic studies and laser ablation experiments showed that the CO2 response of the pharyngeal muscle pumping is regulated by the BAG neurons, the same neurons that mediate CO2 avoidance. PMID- 26430558 TI - The two faces of TOE-2. AB - The C. elegans Q lineage provides a unique context for studying how cells divide asymmetrically to generate cells fated to die. The Q cell divides to form the Q.a and Q.p neuroblasts, each of which divides to produce neurons and a cell that dies by apoptosis; however, these neuroblasts employ different mechanisms to divide asymmetrically.(1) We discovered 2 distinct roles for TOE-2, a protein previously shown to be a target of the C. elegans ERK ortholog MPK-1, in promoting apoptosis in each of these neuroblast divisions. In this commentary, we discuss possible molecular mechanisms by which TOE-2 promotes apoptosis. Specifically, we will discuss potential roles for TOE-2 interacting proteins, a possible nuclear function for TOE-2, and a potential link to the Wnt pathway. PMID- 26430559 TI - Syncytium biogenesis: It's all about maintaining good connections. AB - At the end of mitosis, cells typically complete their division with cytokinesis. In certain tissues however, incomplete cytokinesis can give rise to cells that remain connected by intercellular bridges, thus forming a syncytium. Examples include the germline of many species, from fruitfly to humans, yet the mechanisms regulating syncytial formation and maintenance is unclear, and the biological relevance of syncytial organization remains largely speculative. To better understand these processes, we recently used the germline of Caenorhabditis elegans as a model for syncytium development. Analysis of the germline syncytial architecture throughout development revealed that it arises progressively during larval growth and that it relies on the activity of 2 actomyosin scaffold proteins of the Anillin family. Our work also showed that the gonad can sustain elastic deformation when under mechanical stress and that this property may be conferred by the malleability of syncytial openings. We suggest that elasticity and resistance to mechanical stress constitutes a general property of syncytial tissues. PMID- 26430560 TI - The C. elegans embryonic fate specification factor EGL-18 (GATA) is reutilized downstream of Wnt signaling to maintain a population of larval progenitor cells. AB - In metazoans, stem cells in developing and adult tissues can divide asymmetrically to give rise to a daughter that differentiates and a daughter that retains the progenitor fate. Although the short-lived nematode C. elegans does not possess adult somatic stem cells, the lateral hypodermal seam cells behave in a similar manner: they divide once per larval stage to generate an anterior daughter that adopts a non-dividing differentiated fate and a posterior daughter that retains the seam fate and the ability to divide further. Wnt signaling pathway is known to regulate the asymmetry of these divisions and maintain the progenitor cell fate in one daughter, but how activation of the Wnt pathway accomplished this was unknown. We describe here our recent work that identified the GATA transcription factor EGL-18 as a downstream target of Wnt signaling necessary for maintenance of a progenitor population of larval seam cells. EGL-18 was previously shown to act in the initial specification of the seam cells in the embryo. Thus the acquisition of a Wnt-responsive cis-regulatory module allows an embryonic fate specification factor to be reutilized later in life downstream of a different regulator (Wnt signaling) to maintain a progenitor cell population. These results support the use of seam cell development in C. elegans as a simple model system for studying stem and progenitor cell biology. PMID- 26430561 TI - The mysterious relationship between reproduction and longevity. AB - A negative correlation between fertility and longevity has been documented in many species under a variety of conditions, but the association is not always observed,(1) leading to heated discussion about the nature of the reproduction longevity relationship.(2) This debate is further fueled by the fact that no genes or molecules have been clearly shown to link the 2 traits. A recent study by Thondamal et al., in the nematode C. elegans has identified one potential link. The authors showed that the steroid signaling pathway, which regulates reproduction, is activated in response to dietary restriction (DR) and is in fact required for DR-induced lifespan extension.(3) Steroid signaling mutants subjected to DR not only failed to undergo lifespan extension but also exhibited altered germline plasticity. Interestingly, the requirement for steroid signaling was bypassed when germline plasticity was restored, suggesting that the DR response is mediated, at least in part, by signals from the germline. In this commentary, I discuss the implications of these findings. Several theories of aging have proposed the existence of an energetic trade-off between reproduction and lifespan,(4,5) but mechanistic details are lacking. I propose that revisiting and dissecting at the molecular level the link between reproduction, nutrition, and lifespan, will lead to a better understanding of the aging process and its connection to reproduction. PMID- 26430562 TI - Workshop report: Caenorhabditis nematodes as model organisms to study trait variation and its evolution. AB - A fundamental problem in biology is to understand how genome expression translates into variation in molecular, cellular, developmental, physiological, behavioral, or life-history traits. During the summer of 2014, worm biologists with a keen interest in evolutionary biology and natural ecology met in Les Treilles (France) to define the problems of trait variation better and to discuss empirical approaches using Caenorhabditis species to address these problems. Compared with other model organisms, Caenorhabditis has several advantages, such as well-defined traits that can be subjected to highly controlled environmental and genetic manipulation and the possibility for long-term experimental evolution that can be coupled with genome-wide mapping of trait variation. The Les Treilles workshop brought together researchers studying the evolution of phenotypic plasticity, gene-networks, genome structure and population genetics, sex determination and development in the laboratory, behavior and the life-history of natural Caenorhabditis populations. Here, we outline the key aims of this workshop and summarize the contributions of each participant. PMID- 26430563 TI - Plasticity of chemoreceptor gene expression: Sensory and circuit inputs modulate state-dependent chemoreceptors. AB - Animals dramatically modify their chemosensory behaviors when starved, which could allow them to alter and optimize their food-search strategies. Dynamic changes in the gene expression of chemoreceptors may be a general mechanism underlying food and state-dependent changes in chemosensory behaviors. In our recent study,(1) we identified chemoreceptors in the ADL sensory neuron type of C. elegans that are modulated by feeding state and food availability. Here, we highllight our recent findings by which sensory inputs into ADL, neuronal outputs from ADL, and circuit inputs from the RMG interneuron, which is electrically connected to ADL, are required to regulate an ADL-expressed chemoreceptor. This sensory and circuit-mediated regulation of chemoreceptor gene expression is dependent on cell-autonomous pathways acting in ADL, e.g. KIN-29, DAF-2, OCR-2 and calcium signaling, and circuit inputs from RMG mediated by NPR-1. Based on these findings, we propose an intriguing but speculative feedback modulatory circuit mechanism by which sensory perception of food and internal state signals may be coupled to regulate ADL-expressed chemoreceptors, which may allow animals to precisely regulate and fine-tune their chemosensory neuron responses as a function of feeding state. PMID- 26430564 TI - Engineering new synaptic connections in the C. elegans connectome. AB - Most of what we currently know about how neural circuits work we owe to methods based on the electrical or optical recording of neural activity. This is changing dramatically. First, the advent of optogenetic techinques has enabled precise manipulation of the activity of specific neurons. Second, the development of super-resolution methods for obtaining detailed maps of synaptic connectivity has paved the way for uncovering the connectomes of entire brains or brain regions. We describe a third and complementary new strategy for investigating and manipulating neural circuits: the artificial insertion of new synapses into existing neural circuits using genetic engineering tools. We have successfully accomplished this in C. elegans. Thus, In addition to being the first animal with an entirely mapped connectome, C. elegans is now also the first animal to have an editable connectome. Variations on this approach may be applicable in more complex nervous systems. PMID- 26430565 TI - Translational activation maintains germline tissue homeostasis during adulthood. AB - Adult tissue maintenance is achieved through a tightly controlled equilibrium of 2 opposing cell fates: stem cell proliferation and differentiation. In recent years, the germ line emerged as a powerful in vivo model tissue to investigate the underlying gene expression mechanisms regulating this balance. Studies in numerous organisms highlighted the prevalence of post-transcriptional mRNA regulation, which relies on RNA-targeting factors that influence mRNA fates (e.g. decay or translational efficiency). Conserved translational repressors were identified that build negative feedback loops to ensure one or the other cell fate. However, to facilitate a fast and efficient transition between 2 opposing cell fates, translational repression per se appears not to be sufficient, suggesting the involvement of additional modes of gene expression regulation. Cytoplasmic poly(A) polymerases (cytoPAPs) represent a unique class of post transcriptional mRNA regulators that modify mRNA 3' ends and positively influence cytoplasmic mRNA fates. We recently discovered that the 2 main cytoPAPs, GLD-2 and GLD-4, use distinct mechanisms to promote gene expression and that cytoPAP mediated mRNA activation is important for regulating the size of the proliferative germ cell pool in the adult Caenorhabditis elegans gonad. Here, we comment on the different mechanisms of the 2 cytoPAPs as translational activators in germ cell development and focus on their biological roles in maintaining the balance between germline stem cell proliferation and differentiation in the Caenorhabditis elegans gonad. PMID- 26430566 TI - SLC30A10: A novel manganese transporter. AB - Homozygous mutations in SLC30A10 cause familial parkinsonism associated with manganese (Mn) retention. We recently identified SLC30A10 to be a cell surface localized Mn efflux transporter and demonstrated that parkinsonism-causing mutations block its intracellular trafficking and efflux function. In C. elegans, SLC30A10 over-expression protected against Mn-induced lethality and dopaminergic neurotoxicity, consistent with results in mammalian systems. Here, we present new data about SLC30A10 function in C. elegans. SLC30A10 expression did not protect worms against ZnSO4toxicity, suggesting that SLC30A10 does not mediate Zn export in C. elegans. Furthermore, while a blast search identified 5 potential SLC30A10 homologs in worms (cdf-1, cdf-2, ttm-1 and toc-1; sequence identity <35%), knock down of these genes showed a tendency of increased survival after Mn exposure (although only ttm-1 was statistically significant), suggesting that the worm homologs may function differently. PMID- 26430567 TI - Trans-splicing in metazoans: A link to translational control? AB - The trans-splicing of a spliced-leader RNA to a subset of mRNAs is a phenomenon that occurs in many species, including Caenorhabditis elegans, and yet the driving force for its evolution in disparate groups of animals remains unclear. Polycistronic mRNA resulting from the transcription of operons is resolved via trans-splicing, but operons comprise only a sub-set of trans-spliced genes. Using the marine chordate, Oikopleura dioica, we recently tested the hypothesis that metazoan operons accelerate recovery from growth arrest. We found no supporting evidence for this in O. dioica. Instead we found a striking relationship between trans-splicing and maternal mRNA in O. dioica, C. elegans and the ascidian, Ciona intestinalis. Furthermore, in O. dioica and C. elegans, we found evidence to suggest a role for mTOR signaling in the translational control of growth-related, trans-spliced maternal mRNAs. We propose that this may be a mechanism for adjusting egg number in response to nutrient levels in these species. PMID- 26430568 TI - 20 Years of unc-119 as a transgene marker. AB - This fall marks 20 years since the cloning of unc-119 was reported. Despite having a strong phenotype that makes animals somewhat difficult to grow and handle, unc-119 mutant rescue has become one of the most frequently-used markers for C. elegans transformation. In this Commentary, I describe the history of how unc-119 rescue traveled through the worm community, contributing to the development of transgene methods in C. elegans. PMID- 26430569 TI - In the proper context: Neuropeptide regulation of behavioral transitions during food searching. AB - Neuromodulation enables transient restructuring of anatomically fixed neural circuits, generating alternate outputs and distinct states that allow for flexible organismal responses to changing conditions. We recently identified a requirement for the neuropeptide-like protein NLP-12, a Caenorhabditis elegans homolog of mammalian Cholecystokinin (CCK), in the control of behavioral responses to altered food availability. We showed that deletion of nlp-12 impairs turning during local food searching while nlp-12 overexpression is sufficient to induce deep body bends and enhance turning. nlp-12 is solely expressed in the DVA interneuron that is located postsynaptic to the dopaminergic PDE neurons and presynaptic to premotor and motor neurons, well-positioned for modulating sensorimotor tasks. Interestingly, DVA was previously implicated in a NLP-12 mediated proprioceptive feedback loop during C. elegans locomotion. Here, we discuss the modulatory effects of NLP-12 with an emphasis on the potential for circuit level integration with olfactory information about food availability. In addition, we propose potential mechanisms by which DVA may integrate distinct forms of sensory information to regulate NLP-12 signaling and mediate context dependent modulation of the motor circuit. PMID- 26430570 TI - Interfacing mitochondrial biogenesis and elimination to enhance host pathogen defense and longevity. AB - Mitochondria are highly dynamic and semi-autonomous organelles, essential for many fundamental cellular processes, including energy production, metabolite synthesis and calcium homeostasis, among others. Alterations in mitochondrial activity not only influence individual cell function but also, through non-cell autonomous mechanisms, whole body metabolism, healthspan and lifespan. Energy homeostasis is orchestrated by the complex interplay between mitochondrial biogenesis and mitochondria-selective autophagy (mitophagy). However, the cellular and molecular pathways that coordinate these 2 opposing processes remained obscure. In our recent study, we demonstrate that DCT-1, the Caenorhabditis elegans homolog of the mammalian BNIP3 and BNIP3L/NIX, is a key mediator of mitophagy, and functions in the same genetic pathway with PINK-1 and PDR-1 (the nematode homologs of PINK1 and Parkin respectively) to promote longevity and prevent cell damage under stress conditions. Interestingly, accumulation of damaged mitochondria activates SKN-1 (SKiNhead-1), the nematode homolog of NRF2, which in turn initiates a compensatory retrograde signaling response that impinges on both mitochondrial biogenesis and removal. In this commentary, we discuss the implications of these new findings in the context of innate immunity and aging. Unraveling the regulatory network that governs the crosstalk between mitochondrial biogenesis and mitophagy will enhance our understanding of the molecular mechanisms that link aberrant energy metabolism to aging and disease. PMID- 26430572 TI - 18F-FDG PET/CT Imaging of Gallbladder Adenocarcinoma - A Pictorial Review. AB - Gallbladder adenocarcinoma is an uncommon and serious disease. The primary disease grows rapidly with local invasion into the liver and with distant spread to lymph nodes. It is often detected late, due to which management can be challenging. Despite routine use of computed tomography (CT) and ultrasonography (US) for detection, magnetic resonance imaging (MRI) is often considered for a detailed assessment of the anatomic behavior of these tumors. We share three cases where 18-FDG PET/CT played a role in management thereof. PMID- 26430571 TI - The SKN-1 hunger games: May the odds be ever in your favor. AB - Animals must continually assess nutrient availability to develop appropriate strategies for survival and reproductive success. It is no secret that nutritional state plays a large role in both aging and health.(1-7) Appropriate cellular energy usage is not only crucial for animal starvation survival, but is also important for diseases such as obesity and cancer, which characteristically have metabolic dysfunction.(8-10) C. elegans are exceptionally well poised to handle bouts of starvation as resource availability in the wild varies greatly.(11,12) We recently discovered an evolutionarily conserved pathway, regulated by the cytoprotective transcription factor SKN-1/Nrf2, which integrates diet composition and availability with utilization for survival.(13,14) These responses have potent impact on organismal physiology and remarkably are influenced by current and parental life history events, including choice of diet. In this commentary we will focus on recent insights concerning dietary intake and the impact that this can have throughout the life history of the nematode, Caenorhabditis elegans. In light of the strong impact that diet plays throughout life we urge caution when interpreting previous studies that make use of only one diet and suggest a reinvestigation utilizing a different diet is warranted. PMID- 26430573 TI - Therapeutic Potential of Adjuvant Stereotactic Body Radiotherapy for Gallbladder Cancer. AB - Surgical treatment remains the only curative treatment for gallbladder cancer. However, even after liver resection, locoregional failure seems to be a significant problem. While there is no Level I evidence, multiple studies have shown benefit for adjuvant radiation in high-risk patients. After extensive liver resection, tolerance to conventional chemoradiation may be limited by potential liver toxicity. Stereotactic body radiotherapy has been used safely and effectively in hepatobiliary malignancies. We present a case report, highlighting the potential therapeutic role of adjuvant stereotactic body radiotherapy (SBRT) for gallbladder cancer. PMID- 26430574 TI - An Unusual MRI Appearance of Osseous Metastases. AB - Bone metastases can present in a wide variety of appearances across all imaging modalities. We present a unique appearance of a distal femoral metastasis in a patient who initially complained of knee pain. The radiographic and CT findings were initially suspicious for calcium pyrophosphate deposition (CPPD) arthropathy; however, an MRI demonstrated multiple lesions with a lamellated appearance confirmed on biopsy to be metastatic disease. This unusual lamellated appearance has not been previously described. We present this case to help distinguish this entity radiographically and better classify this finding as a manifestation of metastatic disease. PMID- 26430575 TI - Surgical Management of Sacral Chordomas: Illustrative Cases and Current Management Paradigms. AB - Sacral chordomas represent more than 50% of all sacral tumors. These slow growing, malignant lesions present insidiously and are often large and intimately involved with sacral neurovascular and pelvic structures. En bloc resection is the only well-established predictor of progression-free survival. Optimal surgical management requires a complex multi-disciplinary approach. Here, we describe two cases of sacral chordoma and review current management paradigms. PMID- 26430576 TI - Association of Diabetic Neuropathy with Duration of Type 2 Diabetes and Glycemic Control. AB - INTRODUCTION: Diabetes mellitus is associated with severe microvascular and macrovascular complications with major implications for public health. Diabetic neuropathy is a very problematic complication of diabetes mellitus. It is associated with severe morbidity, mortality, and a huge economic burden. The present study was designed with two aims: 1) to analyze the association of diabetic neuropathy with the glycemic index (levels of fasting blood glucose, random blood glucose, and Hb1Ac) in patients with Type 2 diabetes, and 2) to analyze the association of diabetic neuropathy with time passed since the diagnosis of diabetes. METHODS: This case-control study was undertaken between June 2013 and February 2015 in the Armed Forces Institute of Rehabilitation Medicine (AFIRM), Rawalpindi, Pakistan. Type 2 diabetics with an age range of 30 60 years were recruited from outpatient departments of AFIRM, Rawalpindi. Data were collected and recorded on a form with four sections recording the following: 1) demographics of patients and number of years passed since diagnosis of diabetes; 2) clinical examination for touch, pressure, power, pain, vibration, and ankle reflex; 3) nerve conduction studies for motor components of the common peroneal nerve and tibial nerve and the sensory component of median nerve and sural nerve; 4) glycemic index, including fasting blood glucose levels (BSF), random blood glucose (BSR) levels, and HbA1c levels. Data were analyzed in SPSS v. 20. Chi-square and phi statistics and logistic regression analysis were run to analyze associations between diabetic neuropathy and time passed since diagnosis of diabetes and glycemic index. RESULTS: In total, 152 patients were recruited. One-half of those patients had neuropathy (76 patients) and the other half (76 patients) had normal nerve function. The mean (standard deviation [SD]) duration of diabetes was nine years (6.76), BSF levels 7.98 mmol/l (2.18), BSR 9.5 mmol/l (3.19), and HbA1c 6.5% (2.18). Logistic regression analysis predicted 87.5% of the model correctly. Duration since the diagnosis of diabetes and HbA1c levels were significantly associated with the diagnosis of neuropathy in diabetics. CONCLUSION: The presence of diabetic neuropathy was significantly associated with HbA1c levels and the duration of diabetes. PMID- 26430577 TI - A Report on the Clinical Outcome after High-Dose Rate (HDR) Brachytherapy as Monotherapy in Early Prostate Cancer. AB - BACKGROUND: To report the clinical outcome after a single implant, high dose rate (HDR) brachytherapy in early prostate cancer. MATERIALS AND METHODS: All clinically localized prostate cancer patients who underwent high-dose rate (HDR) brachytherapy as monotherapy (no external beam radiotherapy) from February 2006 to September 2011 were analyzed prospectively. Acute and chronic toxicity were assessed as per Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. Biochemical recurrence was analyzed using the Kaplan Meir method. A log rank analysis was done to compare the factors affecting the outcome. RESULTS: Forty-four patients with organ-confined prostate cancer opted for HDR brachytherapy between February 2006 to September 2011 with a median follow-up of 68 months The five-year biochemical recurrence-free survival (bRFS) rate was 91%. Late Grade 2 genitourinary (GU) toxicity was observed in 9% of patients. The predictors of late Grade 2 GU toxicity were urethra V125 >= 0.2 cc (urethral volume receiving >= 125% of the prescribed dose) and PTV 150 >= 35% ( planning target volume receiving >= 150% of the prescribed dose) with p-value = 0.001 and 0.002, respectively. Erectile function was preserved in 72% of the patients who had Grade 0-1 erectile dysfunction before brachytherapy. CONCLUSION: HDR brachytherapy in early prostate cancer results in high local control rates with minimal side-effects. PMID- 26430578 TI - Human Nocardia Infections: A Review of Pulmonary Nocardiosis. AB - Human nocardiosis may present as an acute or a chronic infection. Although a saprophyte Nocardia spp are responsible for superficial skin infections, pulmonary infections, and disseminated nocardiosis usually involving patients who are immunosuppressed and debilitated. Infections in immunocompetent individuals are usually chronic and present non-specific symptoms. Invasive and disseminated nocardiosis is common among patients with weakened cellular immune systems. Clinical diagnosis of pulmonary nocardiosis is difficult owing to the similarity of its presentation with other respiratory pathogens that include Actinomycetes members and Mycobacterium tuberculosis. Laboratory diagnosis of human nocardiosis is plagued by the fact that a culture of Nocardia spp requires prolonged incubation periods for isolation which most laboratories fail to follow. The lack of clinical, laboratory, and epidemiological data on the incidence of nocardiosis in humans undermines its significance as a potential pathogen. This review attempts to reexamine the pathogenic potential of Nocardia in human infections. PMID- 26430579 TI - Preservation of Pituitary Function after Endonasal Craniopharyngioma Surgery: Case Report and Review of the Literature. AB - Craniopharyngiomas comprise approximately 3% of all intracranial tumors. Preservation of pituitary function after resection represents a significant challenge due to their location in the anterior skull base and aggressive local behavior. We report a case of a 79-year-old woman with a large suprasellar craniopharyngioma who presented with visual loss. MRI revealed a suprasellar cystic mass with mass effect on the optic chiasm and pituitary gland. Following endoscopic endonasal gross total resection of the tumor, the patient's pituitary function returned to normal. PMID- 26430580 TI - Surgical Management of Musculoskeletal Injuries after 2015 Nepal Earthquake: Our Experience. AB - We report our experience of handling 80 major musculoskeletal injuries in a brief span of three days immediately after the major earthquake of Nepal in April 2015. Planning, proper utilization of resources, and prioritizing the patients for surgical intervention is highlighted. The value of damage control by orthopaedics in these disasters is discussed. Timely and appropriate surgical treatment by a skilled orthopaedic team not only can save these injured limbs but also the lives of the victims of a major disaster. PMID- 26430581 TI - Cervical Epidural Hematoma after Chiropractic Spinal Manipulation Therapy in a Patient with an Undiagnosed Cervical Spinal Arteriovenous Malformation. AB - Spinal epidural hematoma (SEH) occurring after chiropractic spinal manipulation therapy (CSMT) is a rare clinical phenomenon. Our case is unique because the patient had an undiagnosed cervical spinal arteriovenous malformation (AVM) discovered on pathological analysis of the evacuated hematoma. Although the spinal manipulation likely contributed to the rupture of the AVM, there was no radiographic evidence of the use of excessive force, which was seen in another reported case. As such, patients with a known AVM who have not undergone surgical intervention should be cautioned against symptomatic treatment with CSMT, even if performed properly. Regardless of etiology, SEH is a surgical emergency and its favorable neurological recovery correlates inversely with time to surgical evacuation. PMID- 26430582 TI - Vertebral Artery Dissection and Cord Infarction - an Uncommon Cause of Brown Sequard and Horner Syndromes. AB - This case report illustrates the neuroanatomy and neurovascular anatomy of the cervical spinal cord by exploring the pathophysiology of cervical cord infarction secondary to vertebral artery injury. The spinal cord is made up of several important tracts, including the dorsal column medial lemniscus system, corticospinal tracts, and the anterolateral system. Injury to one or more of these pathways can result in localizing neurological symptoms. Also contributing to the complexity of spinal vascular pathophysiology is the considerable variation to the cervical cord vascular anatomy. Understanding spinal cord function and neuroanatomy can aid in prompt diagnosis and management of ischemic cord lesions. In combination with a thorough clinical exam, advanced imaging techniques, such as diffusion tensor imaging, can not only localize the injury but also potentially help predict functional outcome. PMID- 26430583 TI - Effect of DNA Methylation in Various Diseases and the Probable Protective Role of Nutrition: A Mini-Review. AB - DNA methylation, a process of adding a methyl group to DNA done by a DNA methyltransferase is a heritable (epigenetic) alteration leading to cancer, atherosclerosis, nervous disorders (Imprinting disorders), and cardiovascular diseases. The role of nutrition in DNA methylation is revealed by identification of methyl variable positions (MVP) on DNA. These regions are more susceptible to DNA methylations. Nutritional supplementation of folic acid and methionine in utero and in adults decreased epigenetic modifications due to its role in DNA metabolism (one carbon metabolism). Thus, in utero and adult supplementation of folic acid and methionine may reduce DNA methylation. This review attempts to highlight the process of DNA methylation, its effect on various diseases, and the probable protective role of nutrition. PMID- 26430585 TI - Endonasal Endoscopic Transsphenoidal Resection of Tuberculum Sella Meningioma with Anterior Cerebral Artery Encasement. AB - Anterior cerebral artery (ACA) encasement is often considered a contraindication for an endonasal endoscopic transsphenoidal approach. We report a patient with a tuberculum sella meningioma with ACA encasement, in whom a gross total excision was achieved through an endonasal endoscopic transsphenoidal transtuberculum, transplanum approach. The tumor was sharply dissected along the left ACA using meticulous bimanual sharp dissection after internal decompression. Moreover, the medial optic canals were opened and the optic nerves decompressed. A gasket seal closure with a nasoseptal flap was performed, and the patient was discharged on postoperative day four with improved vision. This case highlights the ability to remove planum and tuberculum meningiomas with vascular encasement through an endonasal endoscopic approach with the potential for safe vascular dissection. The absence of luminal narrowing can be used to assure the likelihood of a safe arachnoid plane. PMID- 26430584 TI - Hand Hygiene: Knowledge and Attitudes of Fourth-Year Clerkship Medical Students at Alfaisal University, College of Medicine, Riyadh, Saudi Arabia. AB - INTRODUCTION: Little is known about the clerkship (clinical) medical students' knowledge of hand hygiene as the single most important precautionary measure to reduce nosocomial healthcare-associated infections. The aim of this study is to explore the knowledge of, and attitudes towards, hand hygiene practices among fourth-year clerkship medical students at Alfaisal University, College of Medicine, Riyadh, Saudi Arabia. MATERIALS AND METHODS: A cross-sectional, paper based, Yes/No formatted questionnaire was administered to explore the students' knowledge of, and attitudes towards, hand hygiene practices. Data were decoded in Microsoft Excel sheet and presented as numbers and percentages. RESULTS: One hundred and eleven students (n=111/147) participated in the questionnaire (response rate: 76%). Although the majority of students had a fair knowledge of hand hygiene practices, a number of them had some misconceptions. Only 14% of students correctly agreed to the statement: "Traditional hand washing (water, plus regular soap) decreases the number of germs." Furthermore, only 32% of students correctly answered that "hand washing with a regular soap, instead of an antiseptic soap, is better in limiting the transmission of clostridium difficile infections". Almost all students (93%) agreed to the importance of hand hygiene education in medical curricula and its awareness in healthcare centers. Despite the importance of hand hygiene, only 13% of students reviewed the respective WHO and CDC guidelines before starting their clinical training in the teaching hospital. DISCUSSION: The students' inadequate knowledge about hand hygiene needs to be enriched by well-structured curricular and extra-curricular programs as well as more positive attitudes by healthcare workers. PMID- 26430586 TI - Prospective Evaluation of Ventriculostomy Infections. AB - INTRODUCTION: Hospital-acquired infections associated with external drainage of ventricular cerebrospinal fluid (CSF) are a significant source of concern for the patients and the provider team alike. Traditional rates of ventriculostomy infection range from 10-17% in a time-dependent fashion. Changing physician and nursing practices fueled this concern over infections. OBJECTIVE: We sought to prospectively identify the risk factors associated with ventriculostomy infections as part of a quality assurance project. METHODS: One hundred consecutive patients were evaluated and data were collected on 91. The primary indications for ventriculostomy were subarachnoid hemorrhage (46%), intracerebral hemorrhage (24%), and trauma (22%). Variables prospectively evaluated included pre-incision antibiotics, sterile technique bundling, setting of placement (operating room versus intensive care unit), experience of operator (attending, resident, or physician assistant), catheter type (antibiotic impregnated or not), use of a post-insertion dressing, and in-dwell time of the catheter. RESULTS: There was only one infection in 91 patients (1.1%). This infection occurred in a patient without an antibiotic-impregnated catheter that was inserted by a resident physician. Compliance with pre-insertion antibiotics was very high, but most other variables had modest deviations in compliance. CONCLUSION: Infection rate related to external ventricular drainage is very low. Our data suggest that non-antibiotic impregnated catheters may be associated with infection, but that other variables thought to be critical may be of less value. PMID- 26430587 TI - Social Media and the Online World: The New Frontier. PMID- 26430588 TI - Annulus Fibrosus Can Strip Hyaline Cartilage End Plate from Subchondral Bone: A Study of the Intervertebral Disk in Tension. AB - Study Design Biomechanical study on cadaveric spines. Objective Spinal bending causes the annulus to pull vertically (axially) on the end plate, but failure mechanisms in response to this type of loading are poorly understood. Therefore, the objective of this study was to identify the weak point of the intervertebral disk in tension. Methods Cadaveric motion segments (aged 79 to 88 years) were dissected to create midsagittal blocks of tissue, with ~10 mm of bone superior and inferior to the disk. From these blocks, 14 bone-disk-bone slices (average 4.8 mm thick) were cut in the frontal plane. Each slice was gripped by its bony ends and stretched to failure at 1 mm/s. Mode of failure was recorded using a digital camera. Results Of the 14 slices, 10 failed by the hyaline cartilage being peeled off the subchondral bone, with the failure starting opposite the lateral annulus and proceeding medially. Two slices failed by rupturing of the trabecular bone, and a further two failed in the annulus. Conclusions The hyaline cartilage-bone junction is the disk's weak link in tension. These findings provide a plausible mechanism for the appearance of bone and cartilage fragments in herniated material. Stripping cartilage from the bony end plate would result in the herniated mass containing relatively stiff cartilage that does not easily resorb. PMID- 26430589 TI - Asymptomatic Stenosis in the Cervical and Thoracic Spines of Patients with Symptomatic Lumbar Stenosis. AB - Study Design Retrospective study. Objective Studies on age-related degenerative changes causing concurrent stenoses in the cervical, thoracic, and lumbar spines (triple stenosis) are rare in the literature. Our objectives were to determine: (1) the incidence of asymptomatic radiologic cervical and thoracic stenosis in elderly patients with symptomatic lumbar stenosis, (2) the incidence of concurrent radiologic spinal stenosis in the cervical and thoracic spines, and (3) the radiologic features of cervical stenosis that might predict concurrent thoracic stenosis. Methods Whole-spine T2 sagittal magnetic resonance images of patients older than 80 and diagnosed with lumbar spinal stenosis between January 2003 and January 2012 were evaluated retrospectively. We included patients with asymptomatic spondylotic cervical and thoracic stenosis. We measured the anteroposterior diameters of the vertebral body, bony spinal canal, and spinal cord, along with the Pavlov ratio and anterior or posterior epidural stenosis at the level of the disk for each cervical and thoracic level. We compared the radiologic parameters between the subgroups of cervical stenosis with and without thoracic stenosis. Results Among the 460 patients with lumbar stenosis, 110 (23.9%) had concurrent radiologic cervical stenosis and 112 (24.3%) had concurrent radiologic thoracic stenosis. Fifty-six patients (12.1%) had combined radiologic cervical and thoracic stenosis in addition to their symptomatic lumbar stenosis (triple stenosis). Anterior epidural stenosis at C7-T1 was associated with a high prevalence of thoracic stenosis. Conclusions It appears that asymptomatic radiologic cervical and thoracic stenosis is common in elderly patients with symptomatic lumbar stenosis. PMID- 26430590 TI - Distal Junctional Disease after Occipitothoracic Fusion for Rheumatoid Cervical Disorders: Correlation with Cervical Spine Sagittal Alignment. AB - Study Design Retrospective radiographic study. Objective We have performed occipitothoracic (OT) fusion for severe rheumatoid cervical disorders since 1991. In our previous study, we reported that the distal junctional disease occurred in patients with fusion of O-T4 or longer due to increased mechanical stress. The present study further evaluated the association between the distal junctional disease and the cervical spine sagittal alignment. Methods Among 60 consecutive OT fusion cases between 1991 and 2010, 24 patients who underwent O-T5 fusion were enrolled in this study. The patients were grouped based on whether they developed postoperative distal junctional disease (group F) or not (group N). We measured pre- and postoperative O-C2, C2-C7, and O-C7 angles and evaluated the association between these values and the occurrence of distal junctional disease. Results Seven (29%) of 24 patients developed adjacent-level vertebral fractures as distal junctional disease. In group F, the mean pre- and postoperative O-C2, C2-C7, and O-C7 angles were 12.1 and 16.8, 7.2 and 11.2, and 19.4 and 27.9 degrees, respectively. In group N, the mean pre- and postoperative O-C2, C2-C7, and O-C7 angles were 15.9 and 15.0, 4.9 and 5.8, and 21.0 and 20.9 degrees, respectively. There were no significant differences between the two groups. The difference in the O-C7 angle (postoperative angle - preoperative angle) in group F was significantly larger than that in group N (p = 0.04). Conclusion Excessive correction of the O-C7 angle (hyperlordotic alignment) is likely to cause postoperative distal junctional disease following the OT fusion. PMID- 26430591 TI - A Worldwide Analysis of the Reliability and Perceived Importance of an Injury to the Posterior Ligamentous Complex in AO Type A Fractures. AB - Study Design Survey of spine surgeons. Objective To determine the reliability with which international spine surgeons identify a posterior ligamentous complex (PLC) injury in a patient with a compression-type vertebral body fracture (type A). Methods A survey was sent to all AOSpine members from the six AO regions of the world. The survey consisted of 10 cases of type A fractures (2 subtype A1, 2 subtype A2, 3 subtype A3, and 3 subtype A4 fractures) with appropriate imaging (plain radiographs, computed tomography, and/or magnetic resonance imaging), and the respondent was asked to identify fractures with a PLC disruption, as well as to indicate if the integrity of the PLC would affect their treatment recommendation. Results Five hundred twenty-nine spine surgeons from all six AO regions of the world completed the survey. The overall interobserver reliability in determining the integrity of the PLC was slight (kappa = 0.11). No substantial regional or experiential difference was identified in determining PLC integrity or its absence; however, a regional difference was identified (p < 0.001) in how PLC integrity influenced the treatment of type A fractures. Conclusion The results of this survey indicate that there is only slight international reliability in determining the integrity of the PLC in type A fractures. Although the biomechanical importance of the PLC is not in doubt, the inability to reliably determine the integrity of the PLC may limit the utility of the M1 modifier in the AOSpine Thoracolumbar Spine Injury Classification System. PMID- 26430592 TI - Surgical Anatomy of the Uncinate Process and Transverse Foramen Determined by Computed Tomography. AB - Study Design Computed tomography-based cohort study. Objective Although there are publications concerning the relationship between the vertebral artery and uncinate process, there is no practical guide detailing the dimensions of this region to use during decompression of the intervertebral foramen. The purpose of this study is to determine the anatomic parameters that can be used as a guide for thorough decompression of the intervertebral foramen. Methods Fifty-one patients with three-dimensional computed tomography scans of the cervical spine from 2003 to 2012 were included. On axial views, we measured the distance from the midline to the medial and lateral cortices of the pedicle bilaterally from C3 to C7. On coronal reconstructed views, we measured the minimum height of the uncinate process from the cranial cortex of the pedicle adjacent to the posterior cortex of vertebral body and the maximal height of the uncinate process from the cranial cortex of the pedicle at the midportion of the vertebral body bilaterally from C3 to C7. Results The mean distances from midline to the medial and lateral cortices of the pedicle were 10.1 +/- 1.3 mm and 13.9 +/- 1.5 mm, respectively. The mean minimum height of the uncinate process from the cranial cortex of the pedicle was 4.6 +/- 1.6 mm and the mean maximal height was 6.1 +/- 1.7 mm. Conclusions Our results suggest that in most cases, one can thoroughly decompress the intervertebral foramen by removing the uncinate out to 13 mm laterally from the midline and 4 mm above the pedicle without violating the transverse foramen. PMID- 26430593 TI - Impact of Preoperative Hematocrit Level on Length of Stay after Surgery on the Lumbar Spine. AB - Study Design Retrospective case series. Objective Recent studies suggest that baseline hematocrit (Hct) levels may affect the surgical outcomes after orthopedic procedures. The authors examined whether preoperative Hct values had a significant effect on the hospital length of stay (LoS) after lumbar spinal procedures. Methods We retrospectively reviewed patients who underwent routine lumbar spine procedures from November 2012 through September 2013. Patients were included if they had both a baseline Hct and hospital LoS recorded. Patients were divided into two groups: those with an Hct >= 40% (nonanemic) and those with an Hct < 40% (anemic). LoS after surgery was evaluated for each group. Results One hundred seventeen patients underwent lumbar spine procedures for lumbar stenosis (n = 34), symptomatic lumbar disk herniation (n = 39), lumbar spondylolisthesis (n = 26), lumbar adjacent segment disease (n = 8), or symptomatic recurrent lumbar disk herniation (n = 10). Mean LoS was 3.3 and 2.4 days in anemic (27 patients) and nonanemic groups (90 patients), respectively (p = 0.02). The linear regression analysis demonstrated that a decrease in Hct was associated with a longer stay. A decrease from preoperative to postoperative day 1 Hct of 3.5 points resulted in an increased LoS of 1 day (R (2) = 0.145; p = 0.002). The correlation of Hct decrease with longer LoS remained (beta = 0.167, p = 0.006) after adjusting for other variables with multivariate regression analysis. Conclusions Lower preoperative Hct or a substantial decrease in Hct may contribute to longer hospitalization after lumbar spine surgery. These findings should prompt an investigation into the strategies for optimizing Hct levels in patients with preoperative anemia prior to lumbar spine procedures. PMID- 26430594 TI - The Occupancy of the Components in the Cervical Spine and Their Changes with Extension and Flexion. AB - Study Design Retrospective case series. Objectives The kinematics of the cervical spine has been investigated by many researchers. However, the occupancy of the disk bulges, spinal cord, ligamentum flavum, and the rest of the canal as well as the changes of these structures with motion have not yet been investigated. The goal of this study is to investigate these dynamic changes. Methods The kinetic magnetic resonance images of 248 patients (124 men and 124 women) were evaluated, and the occupancy of each structure for each cervical level at neutral, flexion, and extension were calculated. Results Whole canal anteroposterior (AP) diameters showed significant differences between neutral-extension and flexion-extension at the C4-C5 and C5-C6 levels (p < 0.05). The mean disk bulges showed significant differences between neutral-flexion and flexion-extension at the C4-C5, C5-C6, C6 C7, and C7-T1 levels (p < 0.01). The mean spinal canal AP diameter showed significant differences between flexion-extension and neutral-extension at the C3 C4, C4-C5, C5-C6, and C6-C7 levels (p < 0.05). There were significant differences between neutral-flexion at the C4-C5, C5-C6, and C6-C7 levels (p < 0.05). The mean thickness of the ligamentum flavum showed significant differences between flexion-extension at the C3-C4, C4-C5, C5-C6, and C6-C7 levels (p < 0.001). There were significant differences between neutral-extension at the C3-C4 and C5-C6 levels (p < 0.05). There were significant differences between neutral-flexion at the C5-C6 and C6-C7 levels (p < 0.05). The mean thickness of the spinal cord showed significant differences between neutral-flexion at the C2-C3 and C3-C4 levels (p < 0.05). There were significant differences between flexion-extension at the C3-C4 and C4-C5 levels (p < 0.01). The rest of the canal showed significant differences between neutral-extension and flexion-extension at the C3 C4, C4-C5, C5-C6, and C6-C7 levels (p < 0.005). There were significant differences between neutral-flexion at the C5-C6 and C6-C7 levels (p < 0.01). Conclusions The occupancy of each structure in the cervical spine for each level was revealed by this study. In addition, the dynamic changes in the cervical spine with flexion and extension were seen to have different characteristics for each level. PMID- 26430595 TI - Inter- and Intraobserver Agreement of Morphological Grading for Central Lumbar Spinal Stenosis on Magnetic Resonance Imaging. AB - Study Design Validation study of a morphological grading system for central lumbar spinal stenosis. Objective To evaluate and validate the inter- and intraobserver agreement of a morphological grading system for central lumbar spinal stenosis on magnetic resonance imaging between neurosurgeons and radiologists. Methods Two neurosurgeons and two radiologists independently assessed the morphological grading of lumbar spinal stenosis on pretreatment magnetic resonance imaging of 84 patients. Inter- and intrarater agreements were calculated by comparing the observers' evaluations level to level on the grading method. The results of both clinicians were compared with the assessment of both radiologists. Results On axial magnetic resonance images, 189 lumbar disk levels were evaluated for the grade of stenosis. The interobserver agreement between the clinicians was substantial. The interobserver agreement between clinician 1 and both radiologists was substantial, and it was moderate between clinician 2 and both radiologists. The clinicians' intraobserver agreement was almost perfect, and the radiologists' intraobserver agreement was substantial. Conclusions The interobserver agreement of this morphological grading for lumbar spinal stenosis was high between both the clinicians and radiologists, whereas the intraobserver agreement was almost perfect. Experienced clinicians may safely evaluate lumbar magnetic resonance images using this morphological grading for central lumbar spinal stenosis. PMID- 26430596 TI - Utility of Computed Tomography following Anterior Cervical Diskectomy and Fusion. AB - Study Design Retrospective case series. Objective To assess the utility of postoperative computed tomography (CT) following anterior cervical diskectomy and fusion (ACDF) and to determine the clinical circumstances most likely to lead to an abnormal CT scan. Methods Patients who underwent ACDF at a tertiary center over a span of 5 years were investigated. Only patients who had a minimum of 6 months' postoperative follow-up and a CT within 2 years after the surgery were included in the study group. All the postoperative notes were reviewed to determine indications for the CT, abnormalities identified, and whether the scan led to an alteration in the treatment course. Results The charts of 690 patients who underwent ACDF were reviewed. Of the 690 patients, 45 (7%) had postoperative CTs. These patients accounted for 53 postoperative CT scans, 45 (85%) of which were taken for patients who expressed persistent postoperative symptoms and/or had abnormal imaging. There were no indications for 8 (15%) of the CTs. Patients who had a CT for persistent symptoms and/or abnormal preliminary imaging were significantly more likely to have an abnormal CT (p = 0.03) and/or an alteration in treatment course (p = 0.04) compared with those with no symptomatic or radiologic indication for CT. Conclusions CT is associated with minimal utility regarding the alteration of treatment course when employed in asymptomatic patients. Postoperative CT should be ordered solely for symptomatic patients or those with other abnormal preliminary imaging. Judicious use of postoperative CT will limit the radiation exposure and cost. PMID- 26430597 TI - Factors Associated with Life Expectancy in Patients with Metastatic Spine Disease from Adenocarcinoma of the Lung. AB - Study Design Retrospective study. Objective Our objective was to identify preoperative prognostic factors associated with survival in patients with spinal metastasis from lung carcinoma. Methods A retrospective analysis of 26 patients diagnosed with lung carcinoma metastatic to the spinal column was performed to determine factors associated with survival. We used 3 months survival as the clinical cutoff for whether surgical intervention should be performed. We analyzed patients who survived less than 3 months compared with those who survived more than 3 months. Demographic, preoperative, operative, and postoperative factors including functional scores were collected for analysis. Results The median survival for all patients in our study was 3.5 months. We found a statistically significant difference between the group that survived less than 3 months and the group that survived greater than 3 months in terms of extrathoracic metastasis, visceral metastasis, and average postoperative modified Rankin score. Conclusion Determining which patients with lung cancer spinal metastases will benefit from surgical intervention is often dictated by the patient's predicted life expectancy. Factors associated with poorer prognosis include age, functional status, visceral metastases, and extrathoracic metastases. Although the prognosis for patients with lung cancer spinal metastases is poor, some patients may experience long-term benefit from surgical intervention. PMID- 26430599 TI - The Relationship between Preoperative Expectations and the Short-Term Postoperative Satisfaction and Functional Outcome in Lumbar Spine Surgery: A Systematic Review. AB - Study Design Systematic review. Objective To examine the relationship between the patient's preoperative expectations and short-term postoperative satisfaction and functional outcome in lumbar spine surgery. Methods The Medline, Embase, and Cochrane databases were queried using a predefined search algorithm to identify all lumbar spine studies analyzing the influence of preoperative expectations on postoperative satisfaction and functional outcome. Two independent reviewers and a third independent mediator reviewed the literature and performed study screening, selection, methodological assessment, and data extraction using an objective protocol. Results Of 444 studies identified, 13 met the inclusion criteria. Methodological quality scores ranged from 59 to 100% with the greatest variability in defining patient characteristics and the methods of assessing patient expectations. Patient expectations were assessed in 22 areas, most frequently back and leg pain expectations and general expectations. Functional outcome was assessed by 13 tools; the most common were the visual analog scale, Oswestry Disability Index (ODI), and Short Form Health Survey (SF-36). Positive expectations for symptomatology, activity, general health, and recovery correlated with satisfaction. General expectations correlated with higher SF-36 Physical Subcomponent scores, better global function, and lower ODI outcome. Conclusions on the influence of the expectations for pain were limited due to the study heterogeneity, but the evidence suggests a positive correlation between the expectation and outcome for back and leg pain. Conclusions Positive expectations correlated significantly with short-term postoperative satisfaction and functional outcome, including higher SF-36 scores, earlier return to work, and decreased ODI scores. Future expectation-based investigations will benefit from implementation of the standardized methods of expectation, satisfaction, and outcome analysis discussed herein. PMID- 26430598 TI - Intramedullary Spinal Cord Tumors: Part I-Epidemiology, Pathophysiology, and Diagnosis. AB - Study Design Broad narrative review. Objectives Intramedullary spinal cord tumors (IMSCT) are rare neoplasms that can potentially lead to severe neurologic deterioration, decreased function, poor quality of life, or death. As such, a better understanding of these lesions is needed. The following article, part one of a two-part series, addresses IMSCT with regards to their epidemiology, histology, pathophysiology, imaging characteristics, and clinical manifestations. Methods The authors performed an extensive review of the peer-reviewed literature addressing the aforementioned objectives. Results Numerous IMSCT exist with varying epidemiology. Each IMSCT has its own hallmark characteristics and may vary with regards to how aggressively they invade the spinal cord. These lesions are often difficult to detect and are often misdiagnosed. Furthermore, radiographically and clinically, these lesions may be difficult to distinguish from one another. Conclusions Awareness and understanding of IMSCT is imperative to facilitate an early diagnosis and plan management. PMID- 26430600 TI - Spontaneously Resolved Recurrent Cervical Epidural Hematoma in a 37-Week Primigravida. AB - Study Design Case report. Objective To describe a patient with a recurrent spontaneous spinal epidural hematoma (SSEH) during pregnancy that had spontaneous remission. Methods A 27-year-old primigravida at 37 weeks' gestation suddenly felt a strong left shoulder pain without any trauma. She had a history of fenestration for a spontaneous cervical hematoma when she was 18 years old. An emergency magnetic resonance imaging revealed a recurrence of the cervical epidural hematoma at the C4-T1 level, but she had no paralysis. Results The patient subsequently underwent a cesarean section and delivered a healthy male infant. Her spinal epidural hematoma disappeared. Multislice computed tomography showed no evidence for a vascular malformation or tumor. Three years after the initial cesarean section, she underwent a second one and delivered another male infant. Conclusions We report on a rare case of recurrent SSEH during pregnancy with no neurologic deficits that was treated nonoperatively with close observation and resulted in spontaneous resolution. In such patients with no neurologic deficits, nonoperative management with close observation may be a reasonable alternative. PMID- 26430601 TI - Sacroiliac Coalition: First Description and Report of a Successful Resection. AB - Study Design Case report. Objective This report describes the first case of a sacroiliac coalition, its clinical features, the diagnostic difficulties, and the surgical treatment chosen in this case. Methods A 33-year-old man presented to our outpatient clinics complaining of severe left-sided low back pain with an intermitted nondermatomal radiation into the left thigh. The only abnormality on a pelvic radiograph was a coin-size, faint hyperdensity, which was almost overlooked. Subsequent computed tomography (CT) and magnetic resonance imaging (MRI) confirmed two bridging bone spurs on the anterior surface of the left joint with a fibrous interruption at the apex. After the conservative treatment failed, a surgical treatment was offered to the patient. The coalition was resected via an anterior retroperitoneal approach and through the tissue plane between the psoas and the iliacus muscles. A histopathologic examination was performed and confirmed the diagnosis of a coalition. Results The patient's pain resolved immediately after surgery. After 8 months, a follow-up CT scan showed complete removal of the coalition without any signs of recurrence, and at 12 months' follow-up, the patient remained pain-free. Conclusions This is the first published case of a sacroiliac coalition. The only sign of this rare condition on the plain radiographs was very easy to miss. As has been discussed in the literature, CT and MRI are important in the differential diagnostics of such lesions. The histopathologic findings included that of a fibrous bar, confirming the diagnosis, which is further corroborated by the complete resolution of the symptoms. PMID- 26430602 TI - Acute Spinal Subdural Hematoma after Vertebroplasty: A Case Report Emphasizing the Possible Etiologic Role of Venous Congestion. AB - Study Design Case report and literature review. Objective Spinal subdural hematomas are rare events that often progress with severe neurologic deficits. Although there have been several case reports in the literature of spontaneous spinal subdural hematomas in the setting of anticoagulation, antiplatelet therapy, or coagulation disorders, the exact pathophysiology of such phenomena remains obscure. Methods We present the first report of a subdural hematoma after a percutaneous vertebroplasty and provide a comprehensive review on the anatomy of venous drainage of the vertebral bodies with emphasis on the possible effects of venous congestion caused by cement obstruction. Results Because the subdural hematoma occurred in the absence of major cement extravasation to the spinal canal and two levels above the site of the vertebroplasty, we discuss the possible role of venous congestion as the main etiologic factor leading to rupture of the fragile, valveless radiculomedullary veins into the subdural space. Conclusions The reported case supports a possible new pathophysiological scheme for the development of spinal subdural hematoma in which venous congestion plays a pivotal etiologic role. The reported findings suggests that future anatomical and histologic studies investigating the response of the radiculomedullary veins to congestive venous hypertension may shed new light into the pathophysiology of spinal subdural hematomas. PMID- 26430603 TI - Idiopathic Spinal Subarachnoid Hemorrhage: A Case Report and Review of the Literature. AB - Study Design Case report. Objective Spinal subarachnoid hemorrhage (SSAH) makes up less than 1.5% of all the cases of subarachnoid hemorrhage. Most cases of spontaneous SSAH occur in association with coagulopathy, lumbar punctures, or minor trauma. Idiopathic SSAH is extremely rare with only 17 cases published. Idiopathic SSAH presents a diagnostic dilemma, and the appropriate investigations and treatment remain a matter of controversy. We report a case of idiopathic SSAH and a review of the literature regarding its clinical presentation, diagnosis, and treatment. Methods A 73-year-old woman presented to the emergency department after spontaneously developing severe right leg and lower back pain while bending over to vomit. After a review of the patient's history and examination, the magnetic resonance imaging (MRI) of the thoracolumbar spine revealed T1 hyperintensity and T2 hypointensity, a diffusion-restricted collection at the T11 T12 level, and a posterior collection from L3 to S1 producing a mild displacement of the thecal sac. Results The patient was taken for an L5 laminectomy. Intraoperatively, rust-colored, xanthochromic fluid was drained from the subarachnoid space, confirming SSAH. The thecal sac was decompressed. The cultures and Gram stains were negative. Computer tomography (CT) and CT angiography of the brain were normal. She recovered postoperatively with resolution of the pain and no further episodes of hemorrhage after 2 years of follow-up. Repeat thoracolumbar MRI, selective spinal angiogram, and six-vessel cerebral angiogram did not reveal pathology. Conclusion We suggest a clinical algorithm to aid in the diagnosis and management of such patients. PMID- 26430604 TI - Spinal Metastases from a Primary Fallopian Tube Serous Adenocarcinoma: A Case Report. AB - Study Design Case report. Objective This case exemplifies the importance of a high index of suspicion when dealing with intractable pain and neurologic symptoms in patients with a history of cancer. Fallopian tube cancer is relatively uncommon, accounting for less than 0.2% of all female malignancies. Because of a low index of suspicion, it is often detected at an advanced stage. From an orthopedic perspective, osseous metastasis from primary fallopian tube malignancies is rare with only a few documented cases in the medical literature. Methods This case report documents a 68-year-old woman who developed back pain and leg weakness after undergoing surgical resection with adjuvant therapy of a primary fallopian tube adenocarcinoma. Her hospital course and follow-up are documented. Results Imaging revealed a compression fracture in the L1 vertebral body that when a biopsy confirmed a soft tissue diagnosis of a high-grade serous papillary adenocarcinoma of fallopian tube origin. The patient underwent a surgical decompression, posterior stabilization, and tumor debulking with postoperative resolution of her symptoms. Conclusions This is the first reported case of a spine metastasis from a fallopian tube serous carcinoma in a living patient. This case documents the diagnosis of a pathologic vertebral fracture due to metastasis of an atypical cancer. PMID- 26430605 TI - Sacral Stress Fracture Mimicking Lumbar Radiculopathy in a Mounted Police Officer: Case Report and Literature Review. AB - Study Design Case report and review of the literature. Objective To present a unique case of L5 radiculopathy caused by a sacral stress fracture without neurologic compression. Methods We present our case and its clinical evolution and review the available literature on similar pathologies. Results Relief of the unusual mechanical loading causing sacral stress fracture led to rapid resolution of radiculopathy. Conclusion L5 radiculopathy can be caused by a sacral stress fracture and can be relieved by simple mechanical treatment of the fracture. PMID- 26430606 TI - Radiation-Induced Intraspinal Chondrosarcoma: A Case Report. AB - Study Design Case report and review of the literature. Objective To report a unique case of an intraspinal chondrosarcoma that was diagnosed 18 years after radiotherapy for a cervical carcinoma and its remarkably unusual clinical presentation. Methods A retrospective case description of an intraspinal mass lesion that occurred 6 weeks after previous spinal surgery. Results Within ~9 weeks, the tumor had infiltrated the peritoneal cavity and reached the lumbar subcutaneous tissue. Conclusion Radiation-induced sarcomas are rare, are highly aggressive, and may be difficult to diagnose. Furthermore, the only means of achieving long-term survival is through early and extensive surgery. PMID- 26430607 TI - Dysphagia Secondary to Anterior Osteophytes of the Cervical Spine. AB - Study Design Retrospective case series. Objective Diffuse idiopathic skeletal hyperostosis (DISH) or Forestier disease involves hyperostosis of the spinal column. Hyperostosis involving the anterior margin of the cervical vertebrae can cause dysphonia, dyspnea, and/or dysphagia. However, the natural history pertaining to the risk factors remain unknown. We present the surgical management of two cases of dysphagia secondary to cervical hyperostosis and discuss the etiology and management of DISH based on the literature review. Methods This is a retrospective review of two patients with DISH and anterior cervical osteophytes. We reviewed the preoperative and postoperative images and clinical history. Results Two patients underwent anterior cervical osteophytectomies due to severe dysphagia. At more than a year follow-up, both patients noted improvement in swallowing as well as their associated pain. Conclusion The surgical removal of cervical osteophytes can be highly successful in treating dysphagia if refractory to prolonged conservative therapy. PMID- 26430608 TI - Against the Odds: Massive Lumbar Intradural Disk Herniation in the Elderly. AB - Study Design Case report. Objective Presentation of an unusual case of an elderly patient with massive intradural disk herniation at the L2-L3 level. Methods Clinical and imaging data are presented after obtaining informed consent from the patient. Results A 90-year-old man suffering from sudden-onset neurogenic bladder dysfunction and lower back pain but no further neurologic deficits initially presented with magnetic resonance imaging and laboratory values suggestive of an intraspinal infection. However, intraoperative inspection proved the unexpected finding of a large intradural lumbar disk herniation at the L2-L3 level. Conclusions Lumbar soft disk herniation to the intradural space is a rare event and has never been described in a patient over the age of 75. This case of a 90 year-old man with acute-onset bladder dysfunction underlines the necessity to consider this as a differential diagnosis in the case of a newly diagnosed intradural mass. PMID- 26430609 TI - Treatment of Hepatic Adenomatosis. AB - Hepatic adenomatosis and hepatocellular adenomas share risk factors and the same pathophysiologic spectrum. The presence in the liver of 10 hepatocellular adenomas defines hepatic adenomatosis. The diagnosis may be established incidentally during a liver radiologic examination in the asymptomatic patient, or after associated right upper quadrant pain, hepatomegaly or liver test abnormalities. Upon the diagnosis of hepatic adenomatosis or either of its life threatening complications - hemorrhage and progression to hepatocellular carcinoma - consideration should be given to potential medical, radiologic and surgical interventions including: observation (estrogens and androgens withdrawal), resection, transarterial embolization, radiofrequency ablation and liver transplantation. The management of patients with hepatic adenomatosis can be challenging. These patients should be ideally referred to centers with expertise in the management of liver diseases. PMID- 26430611 TI - Discrimination and Stigma. PMID- 26430610 TI - Sleep in patients with schizophrenia. AB - Numerous electrophysiological and neuroimaging studies have reported neurophysiological and cognitive deficits in schizophrenia patients during wakefulness. However, these findings have been inconsistently replicated across different groups of patients, thus complicating the identification of underlying neuronal defects. Sleep minimizes possible waking-related confounds, including decreased motivation and presence of active symptoms. Additionally, the two main sleep rhythms, slow waves and spindles, reflect the intrinsic activity of corticothalamic circuits and are associated with cognitive activities, including learning and memory, occurring during wakefulness. In this review I will present the most relevant sleep findings in schizophrenia, with particular emphasis on several recent studies that have consistently reported sleep spindle deficits in patients with schizophrenia. I will then elaborate on how these findings may contribute to a better understanding of the neurobiology of schizophrenia as well as to the development of novel pharmacological and non-pharmacological interventions to ameliorate the symptoms and cognitive impairments of schizophrenia patients. PMID- 26430612 TI - Experience of Late-Middle-Aged Women who Reside in Small and Medium-Sized Cities in Becoming Psychologically Mature Women. AB - OBJECTIVES: The purpose of this study is to search the inner world of postmenopausal women in late-middle age who are facing senescence and live in small and medium-sized cities. METHODS: The methods of the study were the investigation and classification of answers to questions according to a declarative ethnography analysis. The questions asked to late-middle-aged women living in small and medium-sized cities were "How do you interpret and recognize the changes in the body after menopause?" and "Which methods do you choose and practice to maintain your health in relation to aging during middle age?". RESULTS: Four positive topics and two negative topics were drawn from the study. The four positive themes were: ambition; completion of a great mission; life with a sense of affection; and gratitude for maintaining health. The negative themes were: undulating emotion; and filling the emptiness. CONCLUSION: The recognition of changes in the body after menopause in late-middle-aged women in small and medium-sized cities can affect their preparation processes towards senescence. It is critical to find the means to manage emergency health cases from early adulthood to middle age, based on the outcomes of the study. The study also emphasizes the importance of the woman's family's alternative strategies and supportive systems, which can fit into the cultural context of the community. PMID- 26430613 TI - The Use of Task-based Cognitive Tests for Defining Vocational Aptness of Individuals with Disabilities. AB - OBJECTIVES: The purpose of this study was to demonstrate the use of task-based cognitive tests to detect potential problems in the assessment of work training for vocational rehabilitation. METHODS: Eleven participants with a normal range of cognitive functioning scores were recruited for this study. Participants were all trainees who participated in a vocational training program. The Rey Complex Figure Test and the Allen Cognitive Level Screen were randomly administered to all participants. Responses to the tests were qualitatively analyzed with matrix and scatter charts. RESULTS: Observational outcomes derived from the tests indicated that response errors, distortions, and behavioral problems occurred in most participants. These factors may impede occupational performance despite normal cognitive function. These findings suggest that the use of task-based tests may be beneficial for detecting potential problems associated with the work performance of people with disabilities. CONCLUSION: Specific analysis using the task-based tests may be necessary to complete the decision-making process for vocational aptness. Furthermore, testing should be led by professionals with a higher specialization in this field. PMID- 26430614 TI - A Study on the Characteristics of Infrequent and Frequent Outpatients Visiting Korean Traditional Medical Facilities. AB - OBJECTIVES: This study was intended to analyze the characteristics of infrequent and frequent outpatients visiting Korean medical facilities, and find the related variables of frequent users. METHODS: The data source was the Report on the Usage and Consumption of Korean Medicine (2011) published by the Ministry of Health and Welfare and Korea Institute for Health and Social Affairs. We analyzed outpatient data using SAS 9.2. RESULTS: As much as 46.6% of the patients used Korean medical services over 11 times in 3 months. The proportion of frequent users increased depending on age, and their proportion was high in the low-income and low education group. People with musculoskeletal disease, stroke, hypertension, and obesity were more likely to use Korean medical services. In general, patients were satisfied with their treatment, with frequent outpatients being more satisfied than infrequent outpatients. In logistic regression analysis, age and musculoskeletal disease were significant determinants of frequency of use of Korean medical services. CONCLUSION: Age, musculoskeletal disease, and specific diseases were highly associated with frequent Korean medical utilization. PMID- 26430615 TI - Modification of AxSYM Human Immunodeficiency Virus Assay to Identify Recent Human Immunodeficiency Virus Infections in Korean Human Immunodeficiency Virus-Positive Individuals. AB - OBJECTIVES: To estimate human immunodeficiency virus (HIV) incidence using HIV avidity assays in Korea, we established a serological testing method to differentiate recent HIV infections from long-standing ones. METHODS: We adopted two incidence assays, the BED HIV-1 incidence test (Calypte Biomedical) and an HIV avidity assay (using Abbott AxSYM HIV Antigen/Antibody Combo), and performed them on Korean HIV samples obtained from 81 HIV seroconverters (n = 193), 135 HIV positive samples, and three HIV commercial incidence panels (PRB965, PRB933, and PRB601 from SeaCare). To determine the most optimal concentration of the chaotropic agent (Guanidine) and the cutoff value for the avidity assay, we evaluated the sensitivity and specificity of the assay at different concentration levels. RESULTS: We determined that the concentration of Guanidine to be used in the avidity assay was 1.5M. The cutoff value of the avidity index (AI) was 0.8, and the sensitivity and specificity were 90.2% and 83.8%, respectively, under this condition. The gray zone for the avidity assay was 0.75-0.85 AI. The mean of coefficient of variation was low, at 5.43%. CONCLUSION: An optimized avidity assay for the diagnosis of recent HIV infections using Korean samples was established. This assay will be applied to investigate the level of recent infection and will provide basic data to the HIV prevention policy in Korea. PMID- 26430616 TI - Identifying Barriers to Human Immunodeficiency Virus Testing for Men Who Have Sex with Men in South Korea. AB - OBJECTIVES: The principal objective of this study was to identify the barriers to testing for men who have sex with men (MSM) in Korea, something that might prove useful in future studies of this nature. METHODS: This study was conducted at gay bars nationwide in Korea. After considering several offline locations (gay bars) where MSM candidates are commonly located, random recruitment was performed using time-location sampling. A total of 944 individuals participated in this survey. A total sample of 921 cases (23 cases were excluded) was used for analysis. A self administered questionnaire measuring the individuals' demographics, human immunodeficiency virus (HIV)/AIDS knowledge, stigma, phobia, optimism bias, self efficacy for condom use, and sexual practices was used. RESULTS: About 61.8% (N = 569) of respondents reported having been tested at least once in their lifetime, and 38.9% (N = 358) acknowledged being tested within the past 12 months. After adjusting for age, education, and number of partners in a logistic regression analysis, awareness of testing place [odds ratio (OR) = 4.04], exposure to HIV prevention campaign (1.54), fear (OR = 1.13), and discrimination toward people with HIV/AIDS (OR = 0.94) were the main factors associated with HIV testing. CONCLUSION: To accomplish widespread HIV testing for Korean MSM, the accessibility of testing centers and advertisement of voluntary counseling and testing to MSM are needed. PMID- 26430618 TI - Joint Disease Mapping of Two Digestive Cancers in Golestan Province, Iran Using a Shared Component Model. AB - OBJECTIVES: Recent studies have suggested the occurrence patterns and related diet factor of esophagus cancer (EC) and gastric cancer (GC). Incidence of these cancers was mapped either in general and stratified by sex. The aim of this study was to model the geographical variation in incidence of these two related cancers jointly to explore the relative importance of an intended risk factor, diet low in fruit and vegetable intake, in Golestan, Iran. METHODS: Data on the incidence of EC and GC between 2004 and 2008 were extracted from Golestan Research Center of Gastroenterology and Hepatology, Hamadan, Iran. These data were registered as new observations in 11 counties of the province yearly. The Bayesian shared component model was used to analyze the spatial variation of incidence rates jointly and in this study we analyzed the data using this model. Joint modeling improved the precision of estimations of underlying diseases pattern, and thus strengthened the relevant results. RESULTS: From 2004 to 2008, the joint incidence rates of the two cancers studied were relatively high (0.8-1.2) in the Golestan area. The general map showed that the northern part of the province was at higher risk than the other parts. Thus the component representing diet low in fruit and vegetable intake had larger effect of EC and GC incidence rates in this part. This incidence risk pattern was retained for female but for male was a little different. CONCLUSION: Using a shared component model for joint modeling of incidence rates leads to more precise estimates, so the common risk factor, a diet low in fruit and vegetables, is important in this area and needs more attention in the allocation and delivery of public health policies. PMID- 26430617 TI - High Prevalence of AmpC beta-Lactamases in Clinical Isolates of Escherichia coli in Ilam, Iran. AB - OBJECTIVES: Widespread use of beta-lactam antibiotics could cause resistance to this group of antibiotics in pathogenic bacteria through the production of the enzyme beta-lactamases. The aim of this study is to determine the molecular detection of AmpC beta-lactamases among clinical Escherichia coli isolated from Ilam hospitals in Ilam, Iran. METHODS: One hundred and twelve clinical isolates of E. coli were collected from hospitalized patients and were identified by biochemical tests. They were evaluated for extended spectrum beta-lactamases (ESBLs) production, and the positive strains were subjected to AmpC enzymes; for detection of AmpC cluster genes, multiplex polymerase chain reaction was applied. RESULTS: The analysis showed 62.5% of isolates were ESBLs positive and that five strains revealed the AmpC cluster genes. This is the first report of FOXM cluster genes in E. coli in Iran. CONCLUSION: Based on our results, the prevalence of AmpC beta-lactamases is increasing in Iran, which caused failure in antibiotic therapy. So, the current study recommended the revision of antibiotic policy in Iranian hospitals. PMID- 26430619 TI - Korea Community Health Survey Data Profiles. AB - In 2008, Korea Centers for Disease Control and Prevention initiated the first nationwide survey, Korea Community Health Survey (KCHS), to provide data that could be used to plan, implement, monitor, and evaluate community health promotion and disease prevention programs. This community-based cross-sectional survey has been conducted by 253 community health centers, 35 community universities, and 1500 interviewers. The KCHS standardized questionnaire was developed jointly by the Korea Centers for Disease Control and Prevention staff, a working group of health indicators standardization subcommittee, and 16 metropolitan cities and provinces with 253 regional sites. The questionnaire covers a variety of topics related to health behaviors and prevention, which is used to assess the prevalence of personal health practices and behaviors related to the leading causes of disease, including smoking, alcohol use, drinking and driving, high blood pressure control, physical activity, weight control, quality of life (European Quality of Life-5 Dimensions, European Quality of Life-Visual Analogue Scale, Korean Instrumental Activities of Daily Living ), medical service, accident, injury, etc. The KCHS was administered by trained interviewers, and the quality control of the KCHS was improved by the introduction of a computer-assisted personal interview in 2010. The KCHS data allow a direct comparison of the differences of health issues among provinces. Furthermore, the provinces can use these data for their own cost-effective health interventions to improve health promotion and disease prevention. For users and researchers throughout the world, microdata (in the form of SAS files) and analytic guidelines can be downloaded from the KCHS website (http://KCHS.cdc.go.kr/) in Korean. PMID- 26430620 TI - The History and Future of Plastic and Reconstructive Surgery. PMID- 26430621 TI - How You Become Who You Are: A New Concept of Beauty for Plastic Surgery. PMID- 26430622 TI - Development of Facial Rejuvenation Procedures: Thirty Years of Clinical Experience with Face Lifts. AB - Facial rejuvenation procedures can be roughly divided into face lift surgery and nonoperative, less invasive procedures, such as fat grafts, fillers, botulinum toxin injections, thread lifts, or laserbrasion. Face lift surgery or rhytidectomy is the procedure most directly associated with rejuvenation, due to its fundamental ability to restore the anatomical changes caused by aging. Various methods of face lift surgery have been developed over the last hundred years, thanks to advances in the understanding of facial anatomy and the mechanisms of aging, as well as the dedication of innovative surgeons. However, no generally applicable standard method exists, because the condition of each patient is different, and each operative method has advantages and disadvantages. Specific characteristics of the skin of Asians and their skeletal anatomy should be considered when determining the operative method to be used on Asian patients. Plastic surgeons should improve their ability to analyze the original aesthetic properties and problem areas of each patient, drawing on scientific knowledge about the aging process, and they should develop the skills necessary to perform various rejuvenative techniques. In the present article, we reviewed various face lift procedures and the current methods of modified double plane face lift, based on our clinical experience of over 30 years. PMID- 26430624 TI - Comparative Analysis of the Extracellular Matrix Composition in Proliferating and Involuted Infantile Hemangiomas. AB - BACKGROUND: Changes in the composition of the extracellular matrix (ECM) occur between the proliferating and involuted phases of infantile hemangiomas (IH), and are associated with angiogenic growth. We examined the composition of the ECM in proliferating and involuted IHs and assessed correlations between the composition of the ECM and whether the IH was in the proliferating or the involuted phase. METHODS: We evaluated IH samples from a cohort of patients who had five proliferating IHs and five involuted IHs. The following ECM molecules were analyzed using enzyme-linked immunosorbent assays and immunohistochemistry: laminin, fibronectin, collagen type I, collagen type II, and collagen type III. RESULTS: The involuted IHs had higher levels of deposition of collagen type III than the proliferating IHs. The median values (interquartile ranges) were 1.135 (0.946-1.486) and 1.008 (0.780-1.166) (P=0.019), respectively. The level of laminin was higher in involuted IHs than in proliferating IHs, with median values (interquartile ranges) of 3.191 (2.945-3.191) and 2.479 (1.699-3.284) (P=0.047), respectively. Abundant collagen type III staining was found in involuted IHs. Laminin alpha4 chain staining was clearly present within the basement membrane adjacent to the blood vessels, and was significantly more intense in involuted IHs than in proliferative IHs. CONCLUSIONS: Involuted hemangiomas showed extensive deposition of collagen III and laminin, suggesting that differences in the composition of the ECM reflect stages of the development of IHs. This pattern may be due to the rapid senescence of IHs. PMID- 26430623 TI - Capsular Contracture after Breast Augmentation: An Update for Clinical Practice. AB - Capsular contracture is the most common complication following implant based breast surgery and is one of the most common reasons for reoperation. Therefore, it is important to try and understand why this happens, and what can be done to reduce its incidence. A literature search using the MEDLINE database was conducted including search terms 'capsular contracture breast augmentation', 'capsular contracture pathogenesis', 'capsular contracture incidence', and 'capsular contracture management', which yielded 82 results which met inclusion criteria. Capsular contracture is caused by an excessive fibrotic reaction to a foreign body (the implant) and has an overall incidence of 10.6%. Risk factors that were identified included the use of smooth (vs. textured) implants, a subglandular (vs. submuscular) placement, use of a silicone (vs. saline) filled implant and previous radiotherapy to the breast. The standard management of capsular contracture is surgical via a capsulectomy or capsulotomy. Medical treatment using the off-label leukotriene receptor antagonist Zafirlukast has been reported to reduce severity and help prevent capsular contracture from forming, as has the use of acellular dermal matrices, botox and neopocket formation. However, nearly all therapeutic approaches are associated with a significant rate of recurrence. Capsular contracture is a multifactorial fibrotic process the precise cause of which is still unknown. The incidence of contracture developing is lower with the use of textured implants, submuscular placement and the use of polyurethane coated implants. Symptomatic capsular contracture is usually managed surgically, however recent research has focussed on preventing capsular contracture from occurring, or treating it with autologous fat transfer. PMID- 26430625 TI - Clinical Experience of the Klippel-Trenaunay Syndrome. AB - BACKGROUND: The Klippel-Trenaunay syndrome (KTS) is characterized by three clinical features, namely cutaneous capillary malformations, venous malformations, and soft tissue and/or bony hypertrophy of the extremities. The varied manifestations are attributed to the unpredictable clinical nature and prognosis of the syndrome. To elucidate the clinical characteristics of this disease, we reviewed a relatively large number of KTS patients who presented to our vascular anomalies center. METHODS: We conducted a retrospective study with 19 patients who were diagnosed with KTS and treated in our vascular anomalies clinic between 2003 and 2014, and examined their demographic characteristics, their clinical features, and the treatments administered. RESULTS: The sex distribution was balanced, with 9 (47%) males and 10 (53%) females. The mean follow-up period was 4.1 years (range, 7 months-9 years). Most of the patients received conservative treatments such as medication or physiotherapy. Compression therapies such as wearing of elastic garments/bandages were also administered, and surgical interventions were considered only when the patients became excessively symptomatic. Other treatments included laser therapy and sclerotherapy, and all the treatments were adjusted according to each case, tailored to the conditions of the individual patients. CONCLUSIONS: KTS is an extremely rare, multifactorial disorder that induces widely varied symptoms. Because of this unique feature, plastic surgeons, when not careful, tend to attach a one-sided importance to typical symptoms such as limb hypertrophy or capillary malformation and thus overlook other symptoms and clinical features. KTS can be suspected in all infants who show capillary malformations or limb hypertrophy and require a multi-disciplinary approach for comprehensive management. PMID- 26430626 TI - The 50 Most Cited Papers in Craniofacial Anomalies and Craniofacial Surgery. AB - BACKGROUND: Citation analysis is a recognized scientometric method of classifying cited articles according to the frequency of which they have been referenced. The total number of citations an article receives is considered to reflect it's significance among it's peers. METHODS: Until now, a bibliometric analysis has never been performed in the specialty of craniofacial anomalies and craniofacial surgery. This citation analysis generates an extensive list of the 50 most influential papers in this developing field. Journals specializing in craniofacial surgery, maxillofacial surgery, plastic surgery, neurosurgery, genetics and pediatrics were searched to demonstrate which articles have cultivated the specialty within the past 55 years. RESULTS: The results show an intriguing compilation of papers which outline the fundamental knowledge of craniofacial anomalies and the developments of surgical techniques to manage these patients. CONCLUSIONS: This citation analysis provides a summation of the current most popular trends in craniofacial literature. These esteemed papers aid to direct our decision making today within this specialty. PMID- 26430627 TI - Effects of Bariatric Surgery on Facial Features. AB - BACKGROUND: Bariatric surgeries performed in the USA has increased twelve-fold in the past two decades. The effects of rapid weight loss on facial features has not been previously studied. We hypothesized that bariatric surgery will mimic the effects of aging thus giving the patient an older and less attractive appearance. METHODS: Consecutive patients were enrolled from the bariatric surgical clinic at our institution. Pre and post weight loss photographs were taken and used to generate two surveys. The surveys were distributed through social media to assess the difference between the preoperative and postoperative facial photos, in terms of patients' perceived age and overall attractiveness. 102 respondents completed the first survey and 95 respondents completed the second survey. RESULTS: Of the 14 patients, five showed statistically significant change in perceived age (three more likely to be perceived older and two less likely to be perceived older). The patients were assessed to be more attractive postoperatively, which showed statistical significance. CONCLUSIONS: Weight loss does affect facial aesthetics. Mild weight loss is perceived by survey respondents to give the appearance of a younger but less attractive patient, while substantial weight loss is perceived to give the appearance of an older but more attractive patient. PMID- 26430628 TI - A Multicenter Noncomparative Clinical Study on Midface Rejuvenation Using a Nonabsorbable Polypropylene Mesh: Evaluation of Efficacy and Safety. AB - BACKGROUND: Facial rejuvenation can be achieved using a variety of techniques. Since minimally invasive procedures for face lifting have become popular because of their convenience and short operating time, numerous minimally invasive surgical procedures have been developed. In this study, a nonabsorbable polypropylene mesh is introduced as a new face lifting instrument, with the nasolabial fold as the main target area. In this paper, we report the efficacy and safety of a polypropylene mesh in midface rejuvenation. METHODS: Thirty-three subjects with moderate-to-severe nasolabial folds were enrolled from two medical institutions for a noncomparative single-sample study. A mesh was inserted above the superficial muscular aponeurotic system layer, reaching the nasolabial folds through a temporal scalp incision. After 3 weeks, the temporal end of the mesh was pulled to provide a lifting effect. Then, the mesh was fixed to the deep temporal fascia using nonabsorbable sutures. To evaluate efficacy, we compared the scores on the Wrinkle Severity Rating Scale and a visual analog scale for patient satisfaction between the baseline and 7 weeks postoperatively. In addition, we evaluated safety based on the incidence of adverse events. RESULTS: The treatment was deemed effective at improving wrinkles in 23 of 28 cases, and patient satisfaction improved significantly during the study period. There were seven cases of skin or subcutaneous tissue complications, including edema and erythema, but there were no suspected serious adverse events. CONCLUSIONS: Face lifting using a nonabsorbable mesh can improve nasolabial folds without serious adverse effects. Thus, this technique is safe and effective for midface rejuvenation. PMID- 26430630 TI - Radiation Therapy Following Total Keloidectomy: A Retrospective Study over 11 Years. AB - BACKGROUND: Radiotherapy treatment after keloidectomy is known to be an effective method for reducing the rate of recurrence. However, to date, the appropriate total radiation dose and fractionation have not yet been confirmed. The authors performed a retrospective analysis to identify the appropriate radiation dose and fractionation in post-keloidectomy radiotherapy. METHODS: From May 2000 to February 2011, postoperative radiotherapy was performed on 39 lesions in 28 patients after total keloidectomy. The keloid lesions were confined to the ear lobes. Between May 2000 and May 2004, 14 keloids were treated with surgical excision, followed by a total radiation dose of 1,200 cGy in three fractions over four to five days (group 1). Between June 2004 to February 2011, 25 keloids were treated with surgical excision, followed by a total radiation dose of 1,500 cGy in three fractions over four to five days (group 2). Patients were given a survey asking them to report their experiences regarding reoperation, recurrence of symptoms, recurrence of the lesion, and satisfaction with the operation. RESULTS: Of the 28 patients who were treated, 20 underwent follow-up. Group 2 had more cases showing elevation with erythematous changes, whereas group 1 had more cases showing progressive stages of elevation than group 2. These differences were statistically significant. Moreover, a correlation was observed between the level of keloid elevation and the extent of symptoms. CONCLUSIONS: We suggest 1,500 cGy of radiation in three fractions following keloidectomy for ear lobe keloids. A further randomized study is needed to assess the recurrence of keloids after radiotherapy. PMID- 26430629 TI - Lateral Brow Lift: A Multi-Point Suture Fixation Technique. AB - BACKGROUND: Descent of the lateral aspect of the brow is one of the earliest signs of aging. The purpose of this study was to describe an open surgical technique for lateral brow lifts, with the goal of achieving reliable, predictable, and long-lasting results. METHODS: An incision was made behind and parallel to the temporal hairline, and then extended deeper through the temporoparietal fascia to the level of the deep temporal fascia. Dissection was continued anteriorly on the surface of the deep temporal fascia and subperiosteally beyond the temporal crest, to the level of the superolateral orbital rim. Fixation of the lateral brow and tightening of the orbicularis oculi muscle was achieved with the placement of sutures that secured the tissue directly to the galea aponeurotica on the lateral aspect of the incision. An additional fixation was made between the temporoparietal fascia and the deep temporal fascia, as well as between the temporoparietal fascia and the galea aponeurotica. The excess skin in the temporal area was excised and the incision was closed. RESULTS: A total of 519 patients were included in the study. Satisfactory lateral brow elevation was obtained in most of the patients (94.41%). The following complications were observed: total relapse (n=8), partial relapse (n=21), neurapraxia of the frontal branch of the facial nerve (n=5), and limited alopecia in the temporal incision (n=9). CONCLUSIONS: We consider this approach to be a safe and effective procedure, with long-lasting results. PMID- 26430631 TI - Scar Wars: Preferences in Breast Surgery. AB - BACKGROUND: The uptake of breast reconstruction is ever increasing with procedures ranging from implant-based reconstructions to complex free tissue transfer. Little emphasis is placed on scarring when counseling patients yet they remain a significant source of morbidity and litigation. The aim of this study was to examine the scarring preferences of men and women in breast oncoplastic and reconstructive surgery. METHODS: Five hundred men and women were asked to fill out a four-page questionnaire in two large Irish centres. They were asked about their opinions on scarring post breast surgery and were also asked to rank the common scarring patterns in wide local excisions, oncoplastic procedures, breast reconstructions as well as donor sites. RESULTS: Fifty-eight percent of those surveyed did not feel scars were important post breast cancer surgery. 61% said that their partners' opinion of scars were important. The most preferred wide local excision scar was the lower lateral quadrant scar whilst the scars from the deep inferior epigastric artery perforator (DIEP) flap were most favoured. The superior gluteal artery perforator flap had the most preferred donor site while surprisingly, the DIEP had the least favourite donor site. CONCLUSIONS: Scars are often overlooked when planning breast surgery yet the extent and position of the scar needs to be outlined to patients and it should play an important role in selecting a breast reconstruction option. This study highlights the need for further evaluation of patients' opinions regarding scar patterns. PMID- 26430632 TI - Nipple-Areola Complex Necrosis after Nipple-Sparing Mastectomy with Immediate Autologous Breast Reconstruction. AB - BACKGROUND: Autologous or implant-based breast reconstruction after nipple sparing mastectomy is increasingly preferred worldwide as a breast cancer treatment option. However, postoperative nipple-areola complex (NAC) necrosis is the most significant complication of nipple-sparing mastectomy. The purpose of our study was to identify the risk factors for NAC necrosis, and to describe the use of our skin-banking technique as a solution. METHODS: We reviewed cases of immediate autologous breast reconstruction after nipple-sparing mastectomy at our institution between June 2005 and January 2014. The patients' data were reviewed and the risk of NAC necrosis was analyzed based on correlations between patient variables and NAC necrosis. Moreover, data pertaining to five high-risk patients who underwent the donor skin-banking procedure were included in the analysis. RESULTS: Eighty-five patients underwent immediate autologous breast reconstruction after nipple-sparing mastectomy during the study period. Partial or total NAC necrosis occurred in 36 patients (43.4%). Univariate analysis and binary regression modeling found that body mass index, smoking history, radiation therapy, and mastectomy volume were significantly associated with NAC necrosis. Of the 36 cases of NAC necrosis, 31 were resolved with dressing changes, debridement, or skin grafting. The other five high-risk patients underwent our prophylactic skin-banking technique during breast reconstruction surgery. CONCLUSIONS: NAC necrosis is common in patients with multiple risk factors. The use of the skin-banking technique in immediate autologous breast reconstruction is an attractive option for high-risk patients. Banked skin can be used in such cases without requiring additional donor tissue, with good results in terms of aesthetic and reconstructive outcomes. PMID- 26430633 TI - Comparison of Clinical and Functional Outcomes Using Pectoralis Major and Cutaneous Free Flaps for Hypopharyngeal Squamous Cell Carcinoma. AB - BACKGROUND: The purpose of this study was to compare postoperative morbidities and functional outcomes of pectoralis major myocutaneous (PMMC) flap and cutaneous free flap reconstruction approaches in hypopharyngeal squamous cell carcinoma patients. METHODS: We retrospectively reviewed records from 99 patients who underwent hypopharyngeal reconstruction with a cutaneous free flap (n=85) or PMMC flap (n=14) between 1995 and 2013. Morbidity was classified into hospitalization, medical, or flap-related complications. Functional outcomes were classified into oral re-alimentation and decannulation time. RESULTS: The overall flap-related complication rate was higher in the PMMC flap group (n=8, 57.1%; P=0.019), but the medical morbidity rate was higher in the cutaneous free flap group (n=68, 80%; P=0.006). The rate of pneumonia was higher in the cutaneous free flap group (n=48, 56.5%; P=0.020). Pulmonary premorbidity was the variable most significantly associated with pneumonia (odds ratio=3.012, P=0.012). There was no statistically significant difference in oral re-alimentation and decannulation time between the two groups. CONCLUSIONS: Although the functional superiority of free flaps has been reported in many studies, our results do not support this hypothesis. One limitation of our study is the relatively smaller flap size and fewer PMMC flap cases compared with the cutaneous free flap group. The low postoperative medical morbidity incidence rate in the PMMC flap group was clinically significant; however, the free flap group had more flap-related complications. Thus, PMMC flaps should be considered a viable option, especially for patients with pulmonary premorbidities. PMID- 26430634 TI - Short-Term Strength Deficit Following Zone 1 Replantations. AB - BACKGROUND: Hand strength deficit following digital replantation is usually attributed to the mechanical deficiency of the replanted digit. Zone 1 replantation, however, should not be associated with any mechanical deficit, as the joint and tendon are intact. We evaluate short-term motor functions in patients who have undergone single-digit zone 1 replantation. METHODS: A single institution retrospective review was performed for all patients who underwent zone 1 replantation. Hand and pinch strengths were evaluated using standard dynamometers. Each set of measurements was pooled according to follow-up periods (within 1 month, 1 to 2 months, 2 to 3 months, and after 3 months). The uninjured hand was used as reference for measurements. RESULTS: The review identified 53 patients who had undergone zone 1 replantation and presented for follow-up visits. Compared to the uninjured hand, dynamometer measurements revealed significantly less strength for the hand with replanted digit at one month. The relative mean grip, pulp, and key pinch strength were 31%, 46%, and 48% of the uninjured hand. These three strength measurements gradually increased, with relative strength measurements of 59%, 70%, and 78% for 4-month follow up. CONCLUSIONS: Despite the lack of joint or tendon injury, strength of the injured hand was significantly lower than that of the uninjured hand during the 4 months following replantation. Improved rehabilitation strategies are needed to diminish the short-term negative impact that an isolated zone 1 replantation has on the overall hand strength. PMID- 26430635 TI - Reconstruction of Ankle and Heel Defects with Peroneal Artery Perforator-Based Pedicled Flaps. AB - BACKGROUND: The reconstruction of ankle and heel defects remains a significant problem for plastic surgeons. The following options exist for reconstructing such defects: local random flaps, reverse flow island flaps, and free flaps. However, each of these methods has certain drawbacks. Peroneal artery perforators have many advantages; in particular, they are predictable and reliable for ankle and heel reconstructions. In this study, we report our clinical experience with peroneal artery perforator-based pedicled flaps in ankle and heel reconstructions. METHODS: From July 2005 to October 2012, 12 patients underwent the reconstruction of soft tissue defects in the ankle and heel using a peroneal artery perforator-based pedicled flap. These 12 cases were classified according to the anatomical area involved. The cause of the wound, comorbidities, flap size, operative results, and complications were analyzed through retrospective chart review. RESULTS: The mean age of the patients was 52.4 years. The size of the flaps ranged from 5*4 to 20*8 cm(2). The defects were classified into two groups based on whether they occurred in the Achilles tendon (n=9) or heel pad (n=3). In all 12 patients, complete flap survival was achieved without significant complications; however, two patients experienced minor wound dehiscence. Nevertheless, these wounds healed in response to subsequent debridement and conservative management. No patient had any functional deficits of the lower extremities. CONCLUSIONS: Peroneal artery perforator-based pedicled flaps were found to be a useful option for the reconstruction of soft tissue defects of the ankle and heel. PMID- 26430636 TI - Optical Biopsy of Peripheral Nerve Using Confocal Laser Endomicroscopy: A New Tool for Nerve Surgeons? AB - Peripheral nerve injuries remain a challenge for reconstructive surgeons with many patients obtaining suboptimal results. Understanding the level of injury is imperative for successful repair. Current methods for distinguishing healthy from damaged nerve are time consuming and possess limited efficacy. Confocal laser endomicroscopy (CLE) is an emerging optical biopsy technology that enables dynamic, high resolution, sub-surface imaging of live tissue. Porcine sciatic nerve was either left undamaged or briefly clamped to simulate injury. Diluted fluorescein was applied topically to the nerve. CLE imaging was performed by direct contact of the probe with nerve tissue. Images representative of both damaged and undamaged nerve fibers were collected and compared to routine H&E histology. Optical biopsy of undamaged nerve revealed bands of longitudinal nerve fibers, distinct from surrounding adipose and connective tissue. When damaged, these bands appear truncated and terminate in blebs of opacity. H&E staining revealed similar features in damaged nerve fibers. These results prompt development of a protocol for imaging peripheral nerves intraoperatively. To this end, improving surgeons' ability to understand the level of injury through real time imaging will allow for faster and more informed operative decisions than the current standard permits. PMID- 26430637 TI - Treatment of Pseudoangiomatous Stromal Hyperplasia of the Breast: Implant-Based Reconstruction with a Vascularized Dermal Sling. AB - Pseudoangiomatous stromal hyperplasia (PASH) of the breast is a benign mesenchymal lesion with incidental histologic findings. Surgical excision is recommended as the treatment of choice for PASH, although the recurrence rates after excision range from 15% to 22%. A 46-year-old-female presented with a six month history of bilateral breast enlargement and painful sensation mimicking inflammatory carcinoma. Imaging studies demonstrated innumerable enhancing nodules in both breasts. Due to the growth of the lesions and progressive clinical symptoms, bilateral subcutaneous mastectomy was performed. Grossly, the specimens were round and well-circumscribed, and the histologic examination revealed PASH. After mastectomy, we created a pocket with the pectoralis major muscle and a lower skin flap, which was deepithelized. Anatomical mammary implants were inserted, and the nipple areolar complex was transferred to a new position as a free graft. The aesthetic result was satisfactory after twelve months of follow-up. PMID- 26430638 TI - Letter: A Consideration of Breast Imagery in Art as Depicted through Western Painting. PMID- 26430639 TI - Response to Letter: A Consideration of Breast Imagery in Art as Depicted through Western Painting. PMID- 26430641 TI - Isolated Congenital Nasal Bifid Septum Separated by a Wide Layer of Soft Tissue. PMID- 26430640 TI - Nasal Reconstruction of a Frontonasal Dysplasia Deformity Using Aesthetic Rhinoplasty Techniques. PMID- 26430642 TI - Capsular Contracture after Calf Augmentation with Silicone Implant Insertion. PMID- 26430643 TI - The Modified Trap Door Flap for Reconstruction of Posterior Pinna and Concha Defects. PMID- 26430644 TI - The Oblique Rectus Abdominis Musculocutaneous Flap for Reconstruction after Resection of a Spermatic Cord Liposarcoma. PMID- 26430645 TI - Technical Considerations to Avoid Microvascular Complications during Groin Lymph Node Free Flap Transfer. PMID- 26430646 TI - Breakthrough Technique for Free Tissue Transfer of Poorly Vascularized Lower Extremity: Arteriovenous Loop Revisited. PMID- 26430647 TI - Segmental Hemihyperplasia-Related Macrodactyly with Congenital Renal Agenesis: A Hand Surgeon's Point of View. PMID- 26430649 TI - Solitary Gluteus Maximus Muscle Metastasis in a Breast Cancer Patient. PMID- 26430648 TI - Median Nerve Compression by the Feeding Vessels of a Large Arteriovenous Malformation in the Axilla. PMID- 26430650 TI - Endoscopic Excision of Osteochondroma of the Mandibular Angle. PMID- 26430651 TI - Langerhans Cell Histiocytosis with Frontal Bone Indentation by an Adjoining Primary Soft Tissue Lesion in a 17-Month-Old Asian Male Child. PMID- 26430652 TI - Lymphoepithelioma-like Carcinoma of the Skin in the Cheek with a Malignant Metastatic Cervical Lymph Node. PMID- 26430653 TI - Cosmetic Surgery: Is It Science or Art? PMID- 26430654 TI - The early outcome of single-incision versus multi-port laparoscopic cholecystectomy. AB - BACKGROUND: Single-incision laparoscopic cholecystectomy (SILC) is a newly developed method of performing cholecystectomy and has been increasingly used. The aim of this study is to see if SILC has any advantages over conventional (three-port) laparoscopic cholecystectomy (CLC). MATERIALS AND METHODS: In this cross-sectional study, 52 patients who underwent SILC (group A) during the period from May 2011 to March 2013 were compared with 62 patients who underwent CLC (group B) at two centers affiliated to Shiraz University of Medical Sciences in Shiraz, Iran. Data were gathered on operation time, pre- and postoperative complications, patients' postoperative pain, pain reliever use, duration of hospital stay, and return to work, and these data were compared using SPSS software version 16. RESULTS: The mean age of patients was 38.01 +/- 13.24 in group A and 44.82 +/- 15.11 in group B. Mean body mass index (BMI) was 23.97 +/- 4.78 and 26.22 +/- 4.67 in groups A and B, respectively. The mean operation time was 76.4 +/- 29.0 min in group A and 72.9 +/- 24.1 min in group B (P = 0.496). Preoperative complications were 3.8% in group A and 0 in group B (P = 0.206). Postoperative complications were 17.3% in group A and 11.3% in group B (P = 0.423). The mean for early postoperative pain revealed no significant difference (P = 0.814), but the mean pain on discharge was significantly higher in group A patients (P = 0.034). Regarding the mean admission time and return to normal activity, we found no significant differences. CONCLUSION: SILC does not have any special advantages over CLC with regard to surgical outcomes, but it can be a safe alternative to CLC, especially in patients concerned about cosmoses. PMID- 26430655 TI - Pure gonadal dysgenesis (46 XX type) with a familial pattern. AB - 46, XX gonadal dysgenesis without the phenotype of Turner's syndrome is described as "pure". Although, previous investigations obtained that commonly gonadal dysgenesis did not cause breast development as a result of low levels of circulating estradiol. However, in this study, we aimed to report a familial pure gonadal dysgenesis with and without normal secondary sexual characteristics. In this study, we reported three siblings with pure gonadal dysgenesis with and without normal secondary sexual characteristics. The elder two sisters had a normal female phenotype and the youngest had amenorrhea with no breast development (B1) and pubic hair. In addition, it seems that the absence of pubic hair occurred due to delayed constitutional puberty. According to results, it seems that clinicians should consider different presentations for pure gonadal dysgenesis with familial pattern. PMID- 26430656 TI - Placental expression of D6 decoy receptor in preeclampsia. AB - OBJECTIVE: The purpose of this study was to investigate the expression of the D6 decoy receptor that can bind chemokines and target them for degradation, resulting in inhibition of inflammation in placentas from preeclamptic and normal pregnancies. METHODS: The current study was carried out in 35 pregnant women (23 patients with preeclampsia and 12 healthy, normotensive pregnant women) during the third trimester of pregnancy. The expressions of D6 decoy receptor in the placenta were determined with real time reverse transcriptase polymerase chain reaction and western blotting. RESULTS: The mRNA and protein of D6 decoy receptor were detected in all of placentas from preeclamptic and normal pregnancies. Placental D6 decoy receptor mRNA expression was significantly lower in patients with preeclampsia than in patients with normal pregnancies. Western blot analyses revealed decreased protein expression in cases of preeclampsia. CONCLUSION: The expression of the D6 decoy receptor in preeclamptic placentas was significantly lower than in normal placentas. Further studies are needed to clarify the underlying mechanisms that link decreased expression of placental D6 decoy receptor and preeclampsia. PMID- 26430657 TI - Performance of Momguard, a new non-invasive prenatal testing protocol developed in Korea. AB - OBJECTIVE: To evaluate the performance of Momguard, non-invasive prenatal test (NIPT) for detecting trisomy (T) 21, T18, T13, and sex-chromosome abnormalities recently developed in Korea. METHODS: This preliminary study formed part of a large prospective cohort study conducted at Asan Medical Center, Seoul, Korea. Only pregnant women who underwent both NIPT and confirmatory karyotyping were included in this study. NIPT results were compared with those of karyotype analyses. RESULTS: Among 93 eligible cases, NIPT results could not be obtained in one case due to a low fetal cell-free DNA fraction. Based on NIPT, eight cases of fetal aneuploidies, including T21 (n=5), T18 (n=2), and T13 (n=1), were identified. For T21 and T18, the sensitivity and specificity of NIPT were both 100%, with a false-positive and false-negative rate of 0% and a positive predictive value of 100%. One patient classified as having intermediate risk for T13 by NIPT was confirmed to have T13 by karyotyping, and there were no false negative cases. No cases of sex-chromosome anomalies were detected by NIPT or karyotyping during the study period. CONCLUSION: Momguard is a reliable screening tool for detecting T21 and T18. For T13 and sex-chromosome anomalies, further prospective studies are necessary to confirm its utility. PMID- 26430658 TI - Risk of cesarean section after induced versus spontaneous labor at term gestation. AB - OBJECTIVE: To investigate whether the cesarean section (CS) rate is increased in women whose labor was induced compared to those who had spontaneous labor at term pregnancy. METHODS: A retrospective study was performed in women whose labor was either induced (induction group, n=497) or spontaneous (spontaneous group, n=878) at 37+0 to 41+6 weeks of gestation from January 2008 to June 2009. Maternal age, parity, body mass index (BMI), Bishop scores, gestational age, hypertension, diabetes, delivery mode, indications for CS, neonatal outcome were compared between the two groups. Multiple logistic regression analysis was used to examine the association between the CS rate and labor induction after adjusting for potential confounding variables. RESULTS: CS (17.3% vs. 5.3%, P<0.001) and vacuum assisted delivery (10.7% vs. 6.4%, P<0.001) rates were significantly higher in the induction group compared to the spontaneous group. The CS rate in the induction group was higher than the spontaneous group not only in nulliparous women (25.3% vs. 8.6%, P<0.001), but also in multiparous women (3.8% vs. 0.3%, P=0.002). However, after adjusting confounding factors, the higher CS rate was significantly associated with advanced maternal age, higher BMI, lower Bishop scores and nulliparity, with no demonstrable tie to labor induction. Neonatal outcome in the two groups were comparable. CONCLUSION: Although CS rate was higher in women whose labor was induced than those who had spontaneous labor, this higher rate was associated with maternal age, BMI, Bishop scores and parity, but was not impacted by labor induction per se. PMID- 26430659 TI - Correlation between postpartum depression and premenstrual dysphoric disorder: Single center study. AB - OBJECTIVE: To describe the prevalence and correlates of the postpartum depression and premenstrual dysphoric disorder. METHODS: One hundred sixty six women were assessed around 10th to 14th days after delivery in Gangneung Asan Hospital, Korea, from September 2011 to March 2012. We checked their risk factors for postpartum depressive disorders using the Beck Depression Inventory and the Edinburgh Postnatal Depression Scale. Premenstrual dysphoric disorder was evaluated retrospectively and was defined as having more than 5 of the following 10 symptoms: breast tenderness, bloating, headache, peripheral edema (hand and foot), depressive symptoms, anger, irritability, anxiety, oversensitivity, and exaggerated mood swings. RESULTS: The prevalence rate of postpartum depression using the Edinburgh Postnatal Depression Scale >=10 and Beck Depression Inventory >=10 was 13.9% (23/166). We found statistical differences (P<0.01) between the postpartum depression group and the postpartum non-depression group in smoking history, past history of psychiatric problems, and level of marital satisfaction. The prevalence rate of premenstrual syndrome (PMS) was 9% (15/166) and among 23 women in the postpartum depression group, eight were determined to have premenstrual dysphoric disorder, yielding a prevalence rate of 34.8% (8/23). Among 143 women in the postpartum non-depression group, seven were determined to have PMS, yielding a prevalence rate of 4.9% (7/143). A correlation between postpartum depression and PMS was thus found (P<0.01). CONCLUSION: PMS appears to be associated with postpartum depression. This means that a hormone-related etiology appears to be one risk factor for postpartum depression. PMID- 26430660 TI - Preoperative hypoalbuminemia is a risk factor for 30-day morbidity after gynecological malignancy surgery. AB - OBJECTIVE: To determine the relationship between preoperative hypoalbuminemia and the development of complications after gynecological cancer surgery, as well as postoperative bowel function and hospital stay. METHODS: The medical records of 533 patients with gynecological cancer surgery at Konkuk University Hospital between 2005 and 2013 were reviewed. Serum albumin level <3.5 g/dL was defined as hypoalbuminemia. All perioperative complications within 30-days after surgery, time to resumption of normal diet and length of postoperative hospital stay, were analyzed. Regression models were used to assess predictors of postoperative morbidity. RESULTS: The median age was 49 years (range, 13 to 85 years). Eighty patients (15%) had hypoalbuminemia. Hypoalbuminemic patients had significantly higher consumption of alcohol >2 standard drinks per day, lower American Society of Anesthesiologist score, higher frequency of ascites, and more advanced stage compared with non-hypoalbuminemic patients. Overall complication rate within 30 days after surgery was 20.3% (108 out of 533). Hypoalbuminemic patients were more likely to develop postoperative complications compared to non-hypoalbuminemic patients (34.3% vs. 17.8%, P=0.022), and had significantly longer median time to resumption of normal diet (3.3 [1-6] vs. 2.8 [0-15] days, P=0.005) and length of postoperative hospital stay (0 [7-50] vs. 9 [1-97] days, P=0.014). In multivariate analysis, age >50 (odds ratio [OR], 2.478; 95% confidence interval [CI], 1.310 to 4.686; P=0.005), operation time (OR, 1.006; 95% CI, 1.002 to 1.009; P=0.006), and hypoalbuminemia (OR, 2.367; 95% CI, 1.021 to 5.487; P=0.044) were the significant risk factor for postoperative complications. CONCLUSION: Preoperative hypoalbuminemia in patients with elective surgery for gynecologic malignancy is an independent predictor of 30-days postoperative complications. Identification of this subset and preoperative optimization of nutritional status may improve surgical outcomes. PMID- 26430661 TI - The prognostic value of squamous cell carcinoma antigen for predicting tumor recurrence in cervical squamous cell carcinoma patients. AB - OBJECTIVE: The aim of this study was to evaluate the prognostic value of squamous cell carcinoma antigen (SCC-Ag) and the optimal cut-off value for predicting recurrence in cervical squamous cell carcinoma patients with complete remission after primary treatment. METHODS: We reviewed the records of 783 cervical squamous cell cancer patients who underwent primary therapy and showed complete remission at our institution between January 2000 and April 2014. A receiver operating characteristic curve was used to determine the optimal SCC-Ag threshold to predict recurrence. Cox regression model for disease free survival was used to assess differences in outcome. RESULTS: The median follow-up period was 41.2 months, and 154 patients (19.7%) had recurrent disease. The median pretreatment and posttreatment SCC-Ag level was 2.6 ng/mL (range, 0.1 to 532.0 ng/mL) and 0.7 ng/mL (range, 0.0 to 46.8 ng/mL), respectively. Both pretreatment and posttreatment SCC-Ag levels were higher in the recurrence group (P=0.017 and P=0.039). Optimal cut-off value of pretreatment and posttreatment SCC-Ag for predicting recurrence was 1.86 ng/mL (area under the curve, 0.663; P=0.000), and 0.9 ng/mL (area under the curve, 0.581; P=0.002), respectively. In the multivariate Cox regression model, pretreatment SCC-Ag >1.86 ng/mL (odds ratio, 2.11; 95% confidence interval, 1.38 to 3.22; P=0.001) and posttreatment SCC-Ag >0.9 ng/mL (odds ratio, 1.64; 95% confidence interval, 1.18 to 2.28; P=0.003) were significantly associated with poor disease free survival. CONCLUSION: Patients with pretreatment SCC-Ag >1.86 ng/mL or posttreatment SCC-Ag >0.9 ng/mL should be considered at high risk for cancer recurrence after complete remission, and therefore, closer surveillance is needed. PMID- 26430663 TI - Prediction of lymph node metastasis in patients with apparent early endometrial cancer. AB - OBJECTIVE: The purpose of this study is to investigate the incidence of lymph node metastasis in early endometrial cancer patients and to evaluate preoperative clinicopathological factors predicting lymph node metastasis. METHODS: We identified 142 patients with endometrial cancer between January 2000 and February 2013. All patients demonstrated endometrioid adenocarcinoma with grade 1 or 2 on preoperative endometrial biopsy. Preoperative magnetic resonance imaging showed that tumors were confined to the uterine corpus with superficial myometrial invasion (less than 50%), and there were no lymph nodes enlargements. All patients had complete staging procedures and were surgically staged according to the 2009 FIGO (International Federation of Gynecology and Obstetrics) staging system. Clinical and pathological data were obtained from medical records and statistically analyzed. RESULTS: Of the 142 patients, 127 patients (89.4%) presented with stage 1A, 8 (5.6%) with stage IB, 3 (2.1%) with stage II, and 4 (2.8%) with stage III disease. Three patients (2.1%) had lymph node metastasis-2 IIIC1 and 1 IIIC2 disease. Age, preoperative tumor grade, and myometrial invasion less than 50% on preoperative MRI were not associated with lymph node metastasis. A high preoperative serum CA-125 level (>35 IU/mL) was a statistically significant factor for predicting lymph node metastasis on univariate and multivariate analyses. Lymph node metastasis was only found in patients with preoperative grade 2 tumors or a high serum CA-125 level. CONCLUSION: Preoperative tumor grade and serum CA-125 level can predict lymph node metastasis in apparent early endometrial cancer patients. PMID- 26430662 TI - Learning curve analysis of laparoscopic radical hysterectomy for gynecologic oncologists without open counterpart experience. AB - OBJECTIVE: To evaluate the learning curve of laparoscopic radical hysterectomy (LRH) for gynecologic oncologists who underwent residency- and fellowship training on laparoscopic surgery without previous experience in performing abdominal radical hysterectomy (ARH). METHODS: We retrospectively reviewed 84 patients with FIGO (International Federation of Gynecology and Obstetrics) stage IB cervical cancer who underwent LRH (Piver type III) between April 2006 and March 2014. The patients were divided into two groups (surgeon A group, 42 patients; surgeon B group, 42 patients) according to the surgeon with or without ARH experience. Clinico-pathologic data were analyzed between the 2 groups. Operating times were analyzed using the cumulative sum technique. RESULTS: The operating time in surgeon A started at 5 to 10 standard deviations of mean operating time and afterward steeply decreased with operative experience (Pearson correlation coefficient=-0.508, P=0.001). Surgeon B, however, showed a gentle slope of learning curve within 2 standard deviations of mean operating time (Pearson correlation coefficient=-0.225, P=0.152). Approximately 18 cases for both surgeons were required to achieve surgical proficiency for LRH. Multivariate analysis showed that tumor size (>4 cm) was significantly associated with increased operating time (P=0.027; odds ratio, 4.667; 95% confidence interval, 1.187 to 18.352). CONCLUSION: After completing the residency- and fellowship training course on gynecologic laparoscopy, gynecologic oncologists, even without ARH experience, might reach an acceptable level of surgical proficiency in LRH after approximately 20 cases and showed a gentle slope of learning curve, taking less effort to initially perform LRH. PMID- 26430665 TI - Efficacy and safety of a 24-day regimen of drospirenone-containing combined oral contraceptive in Korean women. AB - This study assesses the efficacy and safety of a 24-day regimen of drospirenone containing combined oral contraceptive, and demonstrates that it is an effective and safe option for contraception, releasing symptom of premenstrual dysphoric disorder and acne in Korean women. PMID- 26430664 TI - Expression of angiogenic factors in cryopreserved mouse ovaries after heterotopic autotransplantation. AB - OBJECTIVE: Revascularization is critical for successful ovarian tissue transplantation. Vascular endothelial growth factor (VEGF) and angiopoietin-2 (angpt-2) are the principal mediators of neovascularization. This study was designed to assess VEGF and angpt-2 levels in cryopreserved ovarian tissue after heterotopic autotransplantation. METHODS: Ovarian tissues harvested from ICR mice at 5 to 6 weeks of age were stratified as follows: no cryopreservation (controls, group I); vitrification in VFS-40 (vitrification, group II); and gradual freezing in dimethyl sulfoxide (slow-freezing, group III). Frozen specimens were thawed at room temperature, assaying VEGF and angpt-2 levels 1 week after cryopreservation and 2 weeks after autotransplantation. RESULTS: VEGF and angpt-2 protein levels were significantly lower in cryopreserved ovaries of groups II and III than in controls (group I, P<0.05), whereas groups II and III did not differ significantly in this regard. After autotransplantation of cryopreserved ovarian tissue, VEGF and angpt-2 protein levels did not differ significantly by technique but tended to be lower than corresponding levels in controls. CONCLUSION: Expression of angiogenic factors in ovarian tissue is thought to vary by method of cryopreservation. Our findings indicate that levels of angiogenic factors expressed in cryopreserved ovarian tissue after autotransplantation do not differ appreciably from control levels, regardless of cryopreservation technique. PMID- 26430666 TI - Hybrid laparoscopic myomectomy: A novel technique. AB - The objective of this study was to report on a new surgical technique, hybrid laparoscopic myomectomy that integrates the advantages of transumbilical laparoendoscopic single-site surgery and those of isobaric laparoscopy, and the initial experience with 14 cases. All of the procedures were performed by a single surgeon who has over 18 years of experience in laparoscopic surgery and 4 years of experience in laparoendoscopic single-site surgery. All cases of hybrid laparoscopic myomectomy were completed safely and effectively without conversion to conventional laparoscopic procedure. The median operative time was 75 minutes (range, 30 to 100 minutes). No postoperative complication was observed. The findings show that hybrid laparoscopic myomectomy is a safe and feasible surgical technique, and therefore can be a feasible, minimally invasive alternative to either abdominal or laparoendoscopic single-site surgery myomectomy. PMID- 26430667 TI - Prenatal diagnosis of congenital mesoblastic nephroma. AB - Congenital mesoblastic nephroma is a rare renal tumor that is diagnosed during pregnancy and is associated with polyhydramnios, prematurity, and neonatal hypertension. Differential diagnoses include Wilms tumor, adrenal neuroblastoma, and other abdominal tumors. We report a case of congenital mesoblastic nephroma detected by prenatal ultrasonography as a large fetal renal mass with polyhydramnios at 32 weeks of gestation. Ultrasonography showed a 6*6-cm complex, solid, hyperechoic, round mass in the right kidney. At 35 weeks of gestation, the patient was admitted with preterm premature rupture of membranes and the baby was delivered vaginally. Postnatal ultrasonography and computed tomography showed a heterogeneous solid mass on the right kidney. At the end of the first week of life, a right nephrectomy was performed and subsequent pathological examination confirmed a cellular variant of congenital mesoblastic nephroma with a high mitotic count. Postoperative adjuvant chemotherapy was administered. The newborn was discharged in good condition. PMID- 26430668 TI - Successful pregnancy outcome in a Korean patient with symptomatic Wilson's disease. AB - Wilson's disease is an inherited disease of copper metabolism leading to the toxic accumulation of copper, primarily in the liver and brain. Although the literature shows successful outcomes after proper treatment, pregnant patients with Wilson's disease still need close monitoring and management. Here, we report the case of a successful pregnancy in a Korean woman with Wilson's disease. A 33 year-old primigravid patient with Wilson's disease visited our antenatal clinic. Of her own volition, she had stopped her medication 2 years earlier. Oral zinc oxide therapy was started, and she was closely monitored throughout her pregnancy. She delivered a healthy female infant weighing 3.13 kg through a cesarean section. After delivery, the clinical course of both the mother and the baby were uneventful. We review crucial points in the treatment and the management dilemmas raised by the patient. PMID- 26430669 TI - Intrapelvic dissemination of early low-grade endometrioid stromal sarcoma due to electronic morcellation. AB - Endometrioid stromal sarcoma is a rare malignancy that originates from mesenchymal cells. It is classified into low-grade endometrioid stromal sarcoma (LGESS) and high-grade endometrioid stromal sarcoma. Ultrasonographic findings of LGESS resemble those of submucosal myomas, leading to the possible preoperative misdiagnosis of LGESS as uterine leiomyoma. Electronic morcellation during laparoscopic surgery in women with LGESS can result in iatrogenic intraabdominal dissemination and a poorer prognosis. Here, we report a patient with LGESS who underwent a supracervical hysterectomy and electronic morcellation for a presumed myoma in another hospital. Disseminated metastatic lesions of LGESS in the posterior cul-de-sac and rectal serosal surface were absent on primary surgery, but found during reexploration. In conclusion, when LGESS is found incidentally following previous morcellation during laparoscopic surgery for presumed benign uterine disease, we highly recommend surgical reexploration, even when there is no evidence of a metastatic lesion in imaging studies. PMID- 26430670 TI - Successful delivery after conservative resectoscopic surgery in a patient with a uterine tumor resembling ovarian sex cord tumor with myometrial invasion. AB - Uterine tumor resembling ovarian sex cord tumors (UTROSCT) is an extremely rare type of uterine stromal neoplasm that exhibits prominent sex cord-like differentiation. The clinical characteristics of a UTROSCT are not fully understood. Most reported cases of UTROSCT were treated by hysterectomy with or without bilateral salpingo-oophorectomy; however, a few cases have been treated by only tumor resection in patients who had a strong desire to preserve their fertility. We present a case of UTROSCT with myometrial invasion, which resulted in a successful delivery after the patient was treated by resectoscopic surgery and conservation of the uterus, and a brief review of the literature. PMID- 26430671 TI - Adult granulosa cell tumor presenting with massive ascites, elevated CA-125 level, and low (18)F-fluorodeoxyglucose uptake on positron emission tomography/computed tomography. AB - Adult granulosa cell tumors (AGCTs) presenting with massive ascites and elevated serum CA-125 levels have rarely been described in the literature. An ovarian mass, massive ascites, and elevated serum CA-125 levels in postmenopausal women generally suggest a malignant ovarian tumor, particularly advanced epithelial ovarian cancer. AGCT has low (18)F-fluorodeoxyglucose uptake on positron emission tomography/computed tomography due to its low metabolic activity. In the present report, we describe a case of an AGCT with massive ascites, elevated serum CA-125 level, and low (18)F-fluorodeoxyglucose uptake on positron emission tomography/computed tomography. PMID- 26430672 TI - Massive hemoperitoneum due to a ruptured corpus luteum cyst in a patient with congenital hypofibrinogenemia. AB - Congenital afibrinogenemia/hypofibrinogenemia is a rare inherited hematologic disorder in which a patient lacks or has insufficient level of fibrinogen, the blood coagulation factor I. The incidence of this uncommon disease is 1 to 2 per 1 million individuals. Hence, massive hemoperitoneum caused by ovulation in a woman with congenital afibrogenemia is also a very rare clinical condition. Massive hemoperitoneum usually presents as acute abdominal pain with potential findings of peritonitis including abdominal distention, hypotension and tachycardia with critical consequences. We performed emergent endoscopic surgery for hemoperitoneum caused by a ruptured corpus luteum cyst in a patient with congenital hypofibrinogenemia. To the best of our knowledge, this was the first case report of such treatment in Korea. PMID- 26430673 TI - Laparoscopic uterine artery occlusion before cervical curettage in cervical ectopic pregnancy: Safe and effective for preventing massive bleeding. AB - Cervical ectopic pregnancy is associated with high risk for massive bleeding conditions. Cervical ectopic pregnancy can usually be treated by methotrexate injection or surgery. We present 4 cases of cervical ectopic pregnancy that were treated successfully with different uterine-conserving methods. By comparing our experience of 4 cases managed in different ways, we found that laparoscopic uterine artery occlusion before cervical curettage is more effective method for preventing massive bleeding. PMID- 26430674 TI - Current status of infrastructures of obstetrics and gynecology in South Korea. PMID- 26430676 TI - Determining the level of awareness of the physicians in using the variety of electronic information resources and the effecting factors. AB - BACKGROUND: Understanding of the medical society's from the types of information resources for quick and easy access to information is an imperative task in medical researches and management of the treatment. The present study was aimed to determine the level of awareness of the physicians in using various electronic information resources and the factors affecting it. MATERIALS AND METHODS: This study was a descriptive survey. The data collection tool was a researcher-made questionnaire. The study population included all the physicians and specialty physicians of the teaching hospitals affiliated to Isfahan University of Medical Sciences and numbered 350. The sample size based on Morgan's formula was set at 180. The content validity of the tool was confirmed by the library and information professionals and the reliability was 95%. Descriptive statistics were used including the SPSS software version 19. RESULTS: On reviewing the need of the physicians to obtain the information on several occasions, the need for information in conducting the researches was reported by the maximum number of physicians (91.9%) and the usage of information resources, especially the electronic resources, formed 65.4% as the highest rate with regard to meeting the information needs of the physicians. Among the electronic information databases, the maximum awareness was related to Medline with 86.5%. Among the various electronic information resources, the highest awareness (43.3%) was related to the E-journals. The highest usage (36%) was also from the same source. The studied physicians considered the most effective deterrent in the use of electronic information resources as being too busy and lack of time. CONCLUSION: Despite the importance of electronic information resources for the physician's community, there was no comprehensive knowledge of these resources. This can lead to less usage of these resources. Therefore, careful planning is necessary in the hospital libraries in order to introduce the facilities and full capabilities of the mentioned resources and methods of information retrieval. PMID- 26430677 TI - Applying and comparing empirical and full Bayesian models in study of evaluating relative risk of suicide among counties of Ilam province. AB - INTRODUCTION: Disease mapping includes a set of statistical techniques that provides maps based on estimates of diseases rates. Bayesian ones are the most important models in this field. They consider prior information on changes in the disease rates in overall map and spatial pattern of the disease. These include a broad range of models with their own formulation, characteristics, strengths, and weaknesses. In the present study, we explain and compare three important and widely-used Bayesian models in the study of evaluating relative risk of suicide in Ilam province. MATERIALS AND METHODS: In this applied-ecological research, suicide incidence in Ilam province in 2008 and 2009 was analyzed by use of Gamma Poisson, Log-normal, and BYM Bayesian models. Models were fitted to data using WinBUGS software. RESULTS: Fitting the three models showed that Darehshahr and Shirvan-Chrdavol had the highest and the lowest relative risk of suicide, respectively (relative risks based on Gamma-Poisson, Log-normal, and BYM models were 2.243, 2.275, and 2.279 for Dareshahr and 0.321, 0.321, and 0.319 for Shirvan-Chrdavol, respectively). CONCLUSION: Despite some differences in estimates, the ranks of relative risks in counties in all three models are the same. The counties based on the relative risks of suicide from the most to the least are: Darehshahr, Ilam, Dehloran, Eyvan, Abdanan, Mehran, Malekshahi, and Shirvan-Chrdavol. PMID- 26430678 TI - The effect of educational intervention on health promoting lifestyle: Focusing on middle-aged women. AB - BACKGROUND: Lifestyle affects people's health and life length, however, no sufficient studies have been done on the effect of lifestyle on middle-ageing, as the transitional period from adulthood to old-ageing, this study has been conducted to study the effect of educational intervention on health promoting lifestyle of middle-aged women in Lenjan city of Isfahan Province, Iran. METHODS: This quasi-experimental study was conducted on 88 middle-aged women were selected through randomized sampling from two health centers in Lenjan, and then were categorized into experimental and control groups. To collect data, a researcher made demographic and life style questionnaire was used. The educational intervention was performed in five sessions. Data were collected from both groups in two stages: Before the intervention and 3 months after the education. Data were analyzed with using SPSS-20 and P < 0.05 were considered statistically significant. RESULTS: The results showed that educational program had a positive significant effect on increasing the mean scores in the intervention group, considering the physical activity, mental health, and interpersonal relationship, P < 0.001. However, regarding the nutrition, the mean increase was not significant (P = 0.113). CONCLUSION: According to the findings, it is evident that educational intervention is beneficial for various aspects of middle-aged women's lifestyle. Therefore, applying a healthy lifestyle seems essential for having a healthy aging period, and educational intervention can be effective. PMID- 26430675 TI - Experimental Models of Microvascular Immunopathology: The Example of Cerebral Malaria. AB - Human cerebral malaria is a severe and often lethal complication of Plasmodium falciparum infection. Complex host and parasite interactions should the precise mechanisms involved in the onset of this neuropathology. Adhesion of parasitised red blood cells and host cells to endothelial cells lead to profound endothelial alterations that trigger immunopathological changes, varying degrees of brain oedema and can compromise cerebral blood flow, cause cranial nerve dysfunction and hypoxia. Study of the cerebral pathology in human patients is limited to clinical and genetic field studies in endemic areas, thus cerebral malaria (CM) research relies heavily on experimental models. The availability of malaria models allows study from the inoculation of Plasmodium to the onset of disease and permit invasive experiments. Here, we discuss some aspects of our current understanding of CM, the experimental models available and some important recent findings extrapolated from these models. PMID- 26430679 TI - Learning challenges of nursing students in clinical environments: A qualitative study in Iran. AB - BACKGROUND: Clinical learning environment is a complex social entity. This environment is effective on the learning process of nursing students in the clinical area. However, learning in clinical environment has several benefits, but it can be challenging, unpredictable, stressful, and constantly changing. In attention to clinical experiences and factors contributing to the learning of these experiences can waste a great deal of time and energy, impose heavy financial burden on educational systems, cause mental, familial and educational problems for students, and compromise the quality of patient care. Therefore, this study was carried out with the goal of determining the learning challenges of nursing students in clinical environments in Iran. MATERIALS AND METHODS: In this qualitative study carried out in 2012-2013, 18 undergraduate nursing students were selected by using purposive sampling method from the Faculty of Nursing and Midwifery of Tehran and Shahid Beheshti Universities. Semi-structured interviews were used to collect data. The content analysis method was used to determine relevant themes. RESULTS: Two themes were derived from the data analysis, which represented the students' clinical learning challenges. These two themes included insufficient qualification of nursing instructors and unsupportive learning environment. CONCLUSIONS: Identification of the students' clinical learning challenges and actions to remove or modify them will create more learning opportunities for the students, improve the achievement of educational goals, provide training to nursing students with the needed competencies to meet the complex demands of caring and for application of theories in practice, and improve the quality of healthcare services. PMID- 26430680 TI - The Effect of nutrition education on knowledge, attitude, and performance about junk food consumption among students of female primary schools. AB - BACKGROUND: Undoubtedly, proper nutrition has important role in safeguarding the individual from many diseases, especially chronic ones, and increasing ones physical and intellectual efficiency. Considering the importance of nutrition education to school-age kids, this research was done with the purpose of determining the effect of nutrition education on the knowledge, attitude, and performance of female students at primary school about junk food consumption. MATERIALS AND METHODS: This is an experimental intervention study in Shahr-e-kord city about the reduction of junk foods consumption in 2011. Seventy-two primary girl students were randomly divided into 2 groups, experimental (36) and controls (36). Before of the educational program, self-administrative questionnaire and FFQ (Food Frequency Questionnaire) questionnaire were filled out for both the groups. The self-administrative questionnaire was completed 3 times (before, immediately, and 2 months after education), and FFQ questionnaire was completed 2 times (before and 2 months after education) by students. After pre-test, 4 educational session classes in experimental group were performed. Finally, data were collected and analyzed by SPSS 16 computer software. RESULTS: Demographic variables of the studied population in 2 groups were similar. Before intervention, there were no significant differences regarding the knowledge, attitude, and performance in 2 groups (P > 0/05). After intervention, there were significant differences in the levels of knowledge, attitude, and performance between experimental and control groups (P < 0.001). CONCLUSION: According to the results, intervention has positive impact on pattern of nutrition, and it can be concluded that intervention is effective on increasing or improving the knowledge, attitude, and performance of the students. PMID- 26430681 TI - Investigating selected patient safety indicators using medical records data. AB - INTRODUCTION: Medical errors in hospitals kill more people every year than AIDS, breast cancer and auto accidents combined. Widespread consensus exists that health care organizations can reduce patient injuries by improving the environment for safety from implementing different alternatives from technical and managerial improvements to considering medical record data. Considering the preventability of medical errors, the Agency for Healthcare Quality and Research (AHRQ) developed patient safety indicators (PSIs). This study analyzes the PSIs calculated in Alzahra Hospital of Isfahan. MATERIALS AND METHODS: This study was conducted retrospectively using the inpatient medical record data of hospitalized patients in a six month period, from October 2010 to March 2011. An experienced team in the fields of medical record, health management and health information technology was involved in data reviewing. Based on a prior consultation and reviewing, some PSIs were selected. Indicators were calculated considering AHRQ guidelines. Excel software and hospital information system software were used. RESULTS: Across all studied medical records of patients, out of 25,164 discharges, below measures were calculated. -8 Foreign Body cases (PSI 5) (0.31 per 1000). -30 Postoperative Hemorrhage or Hematoma cases (PS I9) (2.2 per 1000). -5 Accidental Puncture or Laceration cases (PSI 15) (0.3 per1000). -8 Complications of Anesthesia cases (PSI 1) (2.2 per 1000). -96 Selected Infections Due to Medical Care cases (PSI 7) (3.8 per1000). -17 cases of Postoperative Wound Dehiscence (PSI 14) (3.7per1000). -1 Birth Trauma - Injury to Neonate case, and (PSI 17) (1.7 per 1000). - 18 Obstetric Trauma - Cesarean Delivery cases (PSI 20) (40 per 1000) were flagged by studied PSIs developed by AHRQ. CONCLUSION: Comparing with the reported rates by other studies and AHRQ study in 2006, all of calculated indicators have inadequate condition; i.e. these are far from empirical estimated rates. The hospital administrators should be more sensitive to this issue and perform some improvement programs. PMID- 26430683 TI - Mustard gas exposure in Iran-Iraq war - A scientometric study. AB - BACKGROUND: The Iranian victims of sulfur mustard attack are now more than 20 years post-exposure and form a valuable cohort for studying the chronic effects of an exposure to sulfur mustard. Articles on sulfur mustard exposure in Iran Iraq war were reviewed using three known international databases such as Scopus, Medline, and ISI. The objectives of the study were measurement of the author-wise distribution, year-wise distribution, subject area wise, and assessment of highly cited articles. MATERIALS AND METHODS: We searched three known international databases, Scopus, Medline, and the international statistical institute (ISI), for articles related to mustard gas exposure in Iran-Iraq war, published between 1988 and 2012. The results were analyzed using scientometric methods. RESULTS: During the 24 years under examination, about 90 papers were published in the field of mustard gas in Iran-Iraq war. Original article was the most used document type forming 51.4% of all the publications. The number of articles devoted to mustard gas and Iran-Iraq war research increased more than 10-fold, from 1 in 1988 to 11 in 2011. Most of the published articles (45.7%) included clinical and paraclinical investigations of sulfur mustard in Iranian victims. The most highly productive author was Ghanei who occupied the first rank in the number of publications with 20 papers. The affiliation of most of the researchers was Baqiyatallah Medical Sciences University (research center of chemical injuries and dermatology department) in Iran. CONCLUSION: This article has highlighted the quantitative share of Iran in articles on sulfur mustard and lays the groundwork for further research on various aspects of related problems. PMID- 26430682 TI - Positive changes after breast cancer: A qualitative study. AB - INTRODUCTION: Traumatic events such as breast cancer along with negative effects on patients also have positive effects. These cases have been studied less in Iran. Therefore, this study was conducted with the aim of explanation of positive changes after breast cancer by using a qualitative approach. MATERIALS AND METHODS: This qualitative study was conducted in 2012 in one of the specialized centers for cancer affiliated to Isfahan University of Medical Sciences. In this study, it was interviewed with 19 women with breast cancer about positive changes after cancer by using individual, open and deep methods. The interviews were analyzed with conventional content analysis method. RESULTS: The titles of the three major categories were included as behavioral changes to maintain and promote health (acquisition of health information and adopting promoting health behaviors), spiritual development (attention to the God and sense of meaning in life, revising the values and priorities, strengthening moral and behavioral traits) and personal growth and flourish (feeling empowerment, confidence and efforts to achieve the goals and desires). These three categories have led to emerge themes in this study as the "Awakening after cancer." CONCLUSIONS: The results of this study indicated positive changes after breast cancer. Considering such changes while providing care and consulting to patients with breast cancer in addition to facilitate and accelerate positive changes will be prompted to provide care and proper and influential consulting to promote patient health. PMID- 26430684 TI - Resources of learning through hidden curriculum: Iranian nursing students' perspective. AB - BACKGROUND: Students tend to internalize and perpetuate the patterns of behavior and the values surrounding them. Review of literature showed that there are several student learning sources through the hidden curriculum, but they have not been identified in nursing yet. Hence, the purpose of this study is explanation of learning resources in the hidden curriculum in the view of baccalaureate nursing students. MATERIALS AND METHODS: This qualitative study was carried out in 2012 with the participation of 32 baccalaureate nursing students in Nursing and Midwifery College of Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran by purposeful sampling strategies. Data were collected by semi-structured interviews and continued to the level of data saturation and themes' emergence. Data analysis was performed through inductive content analysis method. RESULT: "Instructor as the unique learning element," "various learning resources in the clinical setting," and "instructive nature of the education environment" were extracted as the main themes, each of which incorporated some categories. CONCLUSION: Baccalaureate undergraduate nursing students learnt the hidden curriculum by the resources such as instructors, resources existing in the clinical setting, and the university campus. Therefore, more research is recommended for the identification of other resources. In order to promote positive messages and reduce the negative messages of the hidden curricula running at academic and clinical settings, nursing educators and nurses need to learn more about this issue in the nursing profession. PMID- 26430685 TI - Meta-analysis of the efficacy of psychological and educational interventions to improve academic performance of students with learning disabilities in Iran. AB - INTRODUCTION: with due attention to the importance of learning disabilities and necessity of presenting interventions for improvement of these disorders in order to prevent future problems, this study used meta-analysis of the research model on the impact of psychological and educational interventions to improve academic performance of students with learning disabilities. METHODS: with the use of meta analysis method by integrating the results of various researches, this study specifies the effect of psychological and educational interventions. In this order, 57 studies, which their methodology was accepted, were selected and meta analysis was performed on them. The research instrument was a meta-analysis checklist. RESULTS: The effect size for the effectiveness of psychological educational interventions on improving the academic performance of students with mathematics disorder (0.57), impaired writing (0.50) and dyslexia (0.55) were reported. CONCLUSIONS: The result of meta-analysis showed that according to Cohen's table, the effect size is above average, and it can be said that educational and psychological interventions improve the academic performance of students with learning disabilities. PMID- 26430686 TI - Investigating the mental health and coping strategies of parents with major thalassemic children in Bandar Abbas. AB - INTRODUCTION: Major thalassemia is a hereditary, chronic blood disease caused by the synthesis deficiency of one or more polypeptide chains of globin during childhood. This leads to the rise of blood pressure and family tensions. Therefore, the coping strategies of the family could seriously affect and facilitate the thalassemic child's healthy growth. The present research sought to investigate the mental health and coping strategies of families with major thalassemic children in Bandar Abbas in 2013. MATERIALS AND METHODS: This study is of a descriptive-analytical and cross-sectional type. Research population consisted of 140 parents of major thalassemic children who visited Shahid Mohammadi Hospital of Bandar Abbas. The instruments used were the 12-item General Health Questionnaire of Goldberg and Williams along with the coping strategies questionnaire. Nonprobabilistic, convenient sampling method was used. To analyze the data, Spearman's correlation coefficient, Chi-square and descriptive statistical tests were used. The significance level was set at P < 0.05. RESULTS: Data analysis showed that parents' mental health (32 +/- 4.25) along with their coping strategy scores (45 +/- 7.50) was about the average. The most prevalent coping strategies among the parents were represented as: "I trust in God in order to get my problems solved" (87%), "to get mentally and spiritually relieved, I would visit mosques and holy shrines" (53%), and "to overcome problems, I make harder attempts" (50.7%). A significant correlation was found between the parents' coping strategies and general health (P < 0.001). A significant correlation was also observed between mother's educational level (P = 0.044), age (P = 0.022) and general health. DISCUSSION AND CONCLUSION: According to the results of this research, it is categorical for the ministry of health and medical education and those in charge to pay special and adequate attention to the social, spiritual, and mental health of these children and their families. PMID- 26430687 TI - Nejat Briefcase: A tool for drug education. AB - BACKGROUND: On account of the prevalence of psychoactive substances and drug abuse and its diversity of forms and methods of use, along with the reduction in the age of drug abuse, a continuing medical educationof physicians with these issues is necessary. Although it is legally forbidden, most physicians have no close contact to these drugs, and this is not effective for training, prevention and treatment of drug addiction. In this regard, offering an educational tool is needed, if in close contact to these drugs. The 'Nejat Briefcase' is a tool designed for the purpose of training and familiarization of psychoactive substances and drugs. The aim of this study is to investigate the points of view of the participants in the continuing medical education program, 'Introduction to types of psychoactive substances and drugs' and about the Nejat Briefcase, in the Isfahan University of Medical Sciences (IUMS). MATERIALS AND METHODS: In this descriptive, cross-sectional study, all the general physicians (108 people) who participated in the continuing medical education program, 'Introducing types of psychoactive substances and drugs,' in the Isfahan University of Medical Sciences (IUMS), in 2012 - 2013, were considered. In this program, in order to introduce various types of psychoactive substances and drugs to the physicians, as well as acquaint them with their forms, methods of use, and prices, the new educational tool (Nejat Briefcase), containing various types of psychoactive substances and drugs and the related educational packages, such as, booklets and brochures, was used. A researcher-made, valid and reliable questionnaire was distributed at the end of program to gather the participants' points of view about the educational program. Data was analyzed by the SPSS and t-test and descriptive statistical tests. RESULTS AND DISCUSSION: The response rate to the questionnaire was 83%. Forty-four people (41%) were women and 64 (59%) were men. The mean total score of the participants' points of view was 4/58 +/- 0/45 (out of 5), which indicated the positive points of view of the participants. Ninety-seven people (90%) were satisfied with the program. CONCLUSIONS: On account of the participants' positive points of view on the Nejat Briefcase and their consent to it, using varied and attractive educational tools for psychoactive substances and drug training and producing tools similar to the Nejat Briefcase are proposed. PMID- 26430688 TI - An investigation of the effects of therapeutic touch plan on acute chemotherapy induced nausea in women with breast cancer in Isfahan, Iran, 2012-2013. AB - INTRODUCTION: Nausea is the worst and most prevalent chemotherapy-induced complication experienced by 70-80% of patients despite mediation therapy. Reduction of nausea is one of the most important roles of oncologist nurses. Today, complementary therapies in addition to classic medicine, because of their lower costs, receive much attention. Nonetheless, their safety and effectiveness are not yet proven. The purpose of this research was to investigate the effect of therapeutic touch plan as a complementary therapy on acute nausea in women with breast cancer in 2012-2013 in Isfahan, Iran. MATERIALS AND METHODS: A quasi experimental, single-blind, randomized control trial with three groups (control, placebo and intervention) was performed at the Isfahan Seyedolshohada (AS) Teaching Hospital, Isfahan, in 2012-2013. The intervention was therapeutic touch plan on women with breast cancer, with the three groups receiving the same medicine regimen. Information was recorded by a checklist after infusion of chemotherapy drugs. Data analysis was performed by SPSS, ANOVA and Kruskal-Wallis tests. RESULTS: The ANOVA test showed that the therapeutic touch plan was significantly effective in reducing the duration of nausea compared with the control and placebo groups (P < 0.001). The Kruskal-Wallis test showed that the frequency of occurrence of nausea was also reduced in the intervention and placebo groups compared with the control group (P < 0.001). The therapeutic touch plan was significantly effective in delaying the onset of nausea compared with the control and placebo groups (P < 0.001). CONCLUSION: This research showed that the therapeutic touch plan is effective in reducing acute chemotherapy-induced nausea; thus, education and implementation of the therapeutic touch plan is proposed for clinical nurses. PMID- 26430689 TI - One of early maladaptive schemas' causal relationship through metacognitive beliefs with borderline and antisocial personality patterns. AB - INTRODUCTION: This study aimed at determining the causal relationship of metacognitive beliefs as a mediator between one of early maladaptive schemas including (emotional deprivation, abandonment, mistrust/abuse, social isolation/alienation and defectiveness/shame) and borderline and antisocial personality patterns. MATERIALS AND METHODS: The study type has been relational and seeking causal modeling of path analysis has been used. The population used in this study included outpatients in counseling, psychological and psychiatric centers in 2012-2013. We randomly distributed 350 questionnaires in five centers out of three parts in Isfahan, and finally 230 valid questionnaires were evaluated and analyzed. Data collection tool has been Millon Clinical Multiaxial Inventory-III's (MCMI-III's) personality questionnaire, Yang's schema questionnaire (75 items), Metacognition Questionnaire-30 (30 items). Reliability of the Yang's Schema Questionnaire in this study was calculated by Cronbach's alpha (alpha =96%), and that of metacognition was calculated the same way (alpha =87%). Data analysis has been done using MCMI-III's software for Millon's personality questionnaire, and SPSS-16 and AMOS-18 software. We used path analysis method for testing each model in statistical data analysis. RESULT: The results of this study suggest a possible causal relationship between the number of one of the early maladaptive schemas and the patterns of anti-social and borderline personalities through some metacognitive beliefs. CONCLUSION: This study showed that cognitive beliefs can be activators of the early schema and continuation's coping behaviors in personality patterns. PMID- 26430690 TI - The impact of emotional intelligence on managers' performance: Evidence from hospitals located in Tehran. AB - CONTEXT: Most of the studies show that emotional intelligence (EI) is an important factor for effective leadership and team performance in organizations. AIMS: This research paper aims to provide an exploratory analysis of EI in the hospitals managers located in Tehran, and examine its relation to their performance. SETTINGS AND DESIGN: The present research was an analytical and cross-sectional study. Setting of the study was hospitals located in Tehran, Iran. SUBJECTS AND METHODS: We conducted a cross-sectional study from a matched sample of 120 managers and 360 subordinates in hospitals located in Tehran. Cyberia shrink EI measure was used for assessing the EI of the participants. Moreover, a management performance Questionnaire is specifically developed for the present study. The total of 480 questionnaires analyzed throughout Kolmogorov Smirnov, Mann-Whitney, and Kruskal-Wallis tests in SPSS. RESULTS: The findings suggested a poor EI among hospital managers. As for EI subscales, social skills and self-motivation were in the highest and lowest levels respectively. Moreover, the results indicated that EI increases with experience. The results also showed there is no significant relationship between the components of EI and the performance of hospital managers. CONCLUSIONS: Present research indicated that higher levels of EI did not necessarily lead to better performance in hospital managers. PMID- 26430691 TI - The effect of intervention based on Health Action Model to promote workers' safe behavior in Isfahan Steel Company. AB - BACKGROUND: The worldwide concern for safety has created the need for new and effective methods to improve safety in the workplace. This study was designed to determine the effect of educational intervention based on Health Action Model on the safe behavior among workers in Isfahan Steel Company. MATERIALS AND METHODS: This study was designed as a quasi-experimental research with experimental and control groups with pre- and post- intervention measurements. The experimental group received intervention based on the Health Action Model. The control group did not receive any intervention except that they participated in the current safety courses of the company. The sample size was 270 workers who were randomly selected and divided into two groups: Experimental (n = 135) and control (n = 135). Data were collected using a questionnaire and a checklist after and before the intervention and were analyzed. Based on the distribution of variables, parametric (t-test, paired t-test) or nonparametric (Chi-square, Wilcoxon) tests were utilized to analyze data. P value less than 0.05 was considered significant. RESULTS: The results indicated that before intervention, the experimental and control groups were similar in model structures. After intervention, the mean scores of knowledge, attitude, and behaviors in relation to safety in the experimental group increased statistically significantly and the observed difference in the control group was not significant. The results also indicated that unsafe behaviors in the experimental group decreased following the educational intervention. This difference also was not statistically significant in the control group. CONCLUSION: The results showed that application of Health Action Model has an acceptable and positive influence on promoting safe behaviors, knowledge, normative system, and facilitating factors among workers in Isfahan Steel Company. It is, therefore, recommended that Health Action Model based intervention be used for other and similar industries. PMID- 26430692 TI - The effect of three ergonomics interventions on body posture and musculoskeletal disorders among stuff of Isfahan Province Gas Company. AB - BACKGROUND: Prevalence of work-related musculoskeletal disorders (WMSDs) is high among computer users. The study investigates the effect of three ergonomic interventions on the incidence of musculoskeletal disorders among the staff of Isfahan Province Gas Company, including training, sport, and installation of software. MATERIALS AND METHODS: The study was performed in the summer of 2013 on 75 (52 men, 23 women) Isfahan Province Gas Company employees in three phases (phase 1: Evaluation of present situation, phase 2: Performing interventions, and phase 3: Re-evaluation). Participants were divided into three groups (training, exercise, and software). The Nordic Musculoskeletal Questionnaire (NMQ) and rapid upper limb assessment (RULA) were used. Data collected were analyzed using SPSS software and McNemar test, t-test, and Chi-square test. RESULTS: Based on the evaluations, there was a decrease in musculoskeletal symptoms among the trained group participants after they received the training. McNemar test showed that the lower rate of pain in low back, neck, knee, and wrist was significant (P < 0.05). The results obtained from the RULA method for evaluation of posture showed an average 25 points decrease in the right side of the body and 20 points decrease in the left side of the body in the group subjected to training. Based on t-test, the decrease was significant. CONCLUSION: The study demonstrated that majority of the participants accepted interventions, which indicates that most of the people were unsatisfied with the work settings and seeking improvement at the workplace. Overall, the findings show that training, chair adjustment, and arrangement in workplace could decrease musculoskeletal disorders. PMID- 26430693 TI - A study of the academic performance of medical students in the comprehensive examination of the basic sciences according to the indices of emotional intelligence and educational status. AB - BACKGROUND: Considering the increasing importance of emotional intelligence (EI) in different aspects of life, such as academic achievement, the present survey is aimed to predict academic performance of medical students in the comprehensive examination of the basic sciences, according to the indices of emotional intelligence and educational status. MATERIALS AND METHODS: The present survey is a descriptive, analytical, and cross-sectional study performed on the medical students of Isfahan, Tehran, and Mashhad Universities of Medical Sciences. Sampling the universities was performed randomly after which selecting the students was done, taking into consideration the limitation in their numbers. Based on the inclusion criteria, all the medical students, entrance of 2005, who had attended the comprehensive basic sciences examination in 2008, entered the study. The data collection tools included an Emotional Intelligence Questionnaire (standardized in Isfahan), the average score of the first to fifth semesters, total average of each of the five semesters, and the grade of the comprehensive basic sciences examination. The data were analyzed through stepwise regression coefficient by SPSS software version 15. RESULTS: The results indicated that the indicators of independence from an emotional intelligence test and average scores of the first and third academic semesters were significant in predicting the students' academic performance in the comprehensive basic sciences examination. CONCLUSION: According to the obtained results, the average scores of students, especially in the earlier semesters, as well as the indicators of independence and the self-esteem rate of students can influence their success in the comprehensive basic sciences examination. PMID- 26430694 TI - The effect of supplementary calcium on blood pressure in healthy adult women aged 18-30 years in Tehran, Iran. AB - INTRODUCTION: Cardiovascular disease is the major cause of mortality in developed countries and has an increasing trend in developing countries. There are some evidences that calcium supplementation may decrease blood pressure and consequently cardiovascular disease, but they are not conclusive and there is no agreement in this respect. The aim of the present study was to assess the effect of supplementary calcium on systolic and diastolic blood pressure in healthy adult women aged 18-30 years. MATERIALS AND METHODS: Seventy-five normotensive volunteers were randomly divided into two groups, the treatment group received 1000 mg/day calcium (four doses of 625 mg calcium carbonate) for 1 month and the control group received placebo (dextrose). Systolic and diastolic blood pressure was determined before and after intervention in supine position after 10 min of rest. RESULTS: The mean daily calcium intake from food was 773.9 mg in treatment and 721 mg in control group (no significant difference) but in both the groups dietary calcium intake was less than the recommended dietary allowance: After calcium supplementation, the mean change of systolic blood pressure was not significant in the two groups, but diastolic blood pressure reduced in treatment group and increased in control group (-4.9 vs 2.6 mmHg) (P < 0.05). CONCLUSIONS: These results suggest that, calcium supplementation does not have any effect on systolic blood pressure of our volunteers but can decrease diastolic blood pressure significantly and therefore it seems that calcium supplementation may be useful for people with increased diastolic blood pressure, especially for those who receive less calcium than recommended dietary allowance. PMID- 26430696 TI - Anatomical sketching and education: The next steps. PMID- 26430695 TI - Prevalence of high normal FBS and prediabetes among adolescents in Birjand, East of Iran, 2012. AB - BACKGROUND AND OBJECTIVES: To determine the prevalence of impaired fasting glucose in adolescents in Birjand city in eastern Iran. MATERIALS AND METHODS: This cross-sectional study was done on 2653 students aged 11-18 years selected through multi-stage stratified and random sampling. Fasting blood glucose (FBS) of these students was measured applying the enzymatic process. The obtained data were analyzed by means of SPSS software (V: 15) and statistical tests T and X2. RESULTS: The mean age of individual was 14.5 +/- 2 years. Mean FBS of the whole population was 89.8 +/- 9.8 mg/dl, but it was significantly higher among boys than girls (P < 0.001). Out of the whole subjects (92.4%), 1,328 (95.1%) of the girls and 1,122 (89.3%) of the boys, FBS was less than 100 mg/dl among whom 64.4% had FBS above 86 mg/dl. In 200 subjects (7.5%) of whole population, FBS was 100 125 mg/dl; with that of the boys was 2.3 times than the girls revealing a prediabetes condition: OR = 2.3(CI: 1.7-3.2). Among the students, 3 (0.1%) had an FBS > 126 mg/dl. Mean blood glucose was significant regarding age and sex. CONCLUSIONS: High prevalence of high FBS (within normal range) among adolescents is warning and requires special attention of health officials. Screening of children and adolescents in order to identify those at risk and plan for intervening is urgent to prevent type-2 diabetes epidemic and following cardiovascular complications in the Society. PMID- 26430697 TI - Improving Influenza and Pneumococcal Vaccination Rates in Ambulatory Specialty Practices. AB - Background. Influenza and pneumococcal vaccinations are recommended for elderly and high-risk patients; however, rates of adherence are low. We sought to implement influenza and pneumococcal vaccine initiatives in 4 different ambulatory specialty practices, using 3 unique approaches. Methods. Four specialties with high-risk patient populations were selected for intervention: allergy (asthma), infectious disease (ID) (human immunodeficiency virus), pulmonary (chronic lung disease), and rheumatology (immunocompromised). Allergy and ID focused on influenza vaccination, and pulmonary and rheumatology focused on pneumococcal vaccination. We used 3 strategies for quality improvement: physician reminders, patient letters, and a nurse-driven model. Physicians were provided their performance data on a monthly basis and presented trended data on a quarterly basis at staff meetings. Results. All 4 specialties developed processes for improving vaccination rates with all showing some increase. Higher rates were achieved with pneumococcal vaccine than influenza. Pneumococcal vaccine rates showed steady improvement from year to year while influenza vaccine rates remained relatively constant. Allergy's influenza rate was 59% in 2011 and 64% in the 2014 flu season. Infectious disease influenza rates moved from 74% in the 2011 flu season to 86% for the 2014 season. Pneumococcal vaccine in pulmonary patients' rate was 52% at the start of intervention in February 2009 and 79% as of January 2015. Rheumatology rates rose from 50% in February 2009 to 87% in January 2015. Conclusions. Integrated routine workflow and performance data sharing can effectively engage specialists and staff in vaccine adherence improvement. Influenza vaccination may require other approaches to achieve the rates seen with pneumococcal vaccine. PMID- 26430698 TI - A Prospective Controlled Trial of an Electronic Hand Hygiene Reminder System. AB - Background. The use of electronic hand hygiene reminder systems has been proposed as an approach to improve hand hygiene compliance among healthcare workers, although information on efficacy is limited. We prospectively assessed whether hand hygiene activities among healthcare workers could be increased using an electronic hand hygiene monitoring and reminder system. Methods. A prospective controlled clinical trial was conducted in 2 medical intensive care units (ICUs) at an academic medical center with comparable patient populations, healthcare staff, and physical layout. Hand hygiene activity was monitored concurrently in both ICUs, and the reminder system was installed in the test ICU. The reminder system was tested during 3 administered phases including: room entry/exit chimes, display of real-time hand hygiene activity, and a combination of the 2. Results. In the test ICU, the mean number of hand hygiene events increased from 1538 per day at baseline to 1911 per day (24% increase) with the use of a combination of room entry/exit chimes, real-time displays of hand hygiene activity, and manager reports (P < .001); in addition, the ratio of hand hygiene to room entry/exit events also increased from 26.1% to 36.6% (40% increase, P < .001). The performance returned to baseline (1473 hand hygiene events per day) during the follow-up phase. There was no significant change in hand hygiene activity in the control ICU during the course of the trial. Conclusions. In an ICU setting, an electronic hand hygiene reminder system that provided real-time feedback on overall unit-wide hand hygiene performance significantly increased hand hygiene activity. PMID- 26430699 TI - Coxiella burnetii Infection With Severe Hyperferritinemia in an Asplenic Patient. AB - Q fever is an uncommon but likely underreported zoonotic infection. Severe hyperferritinemia has been associated with hemophagocytic lymphohistiocytosis and other infectious diseases. In this study, we report a case of Coxiella burnetii infection in an asplenic patient complicated by severe hyperferritinemia and bone marrow infiltration. In this case, the marked ferritin elevation may have been an indicator of profound systemic macrophage activation due to preferential intracellular infection of this cell type by C burnetii, perhaps exacerbated by altered mononuclear phagocyte system function in the setting of asplenia. PMID- 26430700 TI - Multiple Pathways Control the Reactivation of Telomerase in HTLV-I-Associated Leukemia. AB - While telomerase (hTERT) activity is absent from normal somatic cells, reactivation of hTERT expression is a hallmark of cancer cells. Telomerase activity is required for avoiding replicative senescence and supports immortalization of cellular proliferation. Only a minority of cancer cells rely on a telomerase-independent process known as alternative lengthening of telomeres, ALT, to sustain cancer cell proliferation. Multiple genetic, epigenetic, and viral mechanisms have been found to de-regulate telomerase gene expression, thereby increasing the risk of cellular transformation. Here, we review the different strategies used by the Human T-cell leukemia virus type 1, HTLV-I, to activate hTERT expression and stimulate its enzymatic activity in virally infected CD4 T cells. The implications of hTERT reactivation in HTLV-I pathogenesis and disease treatment are discussed. PMID- 26430701 TI - Titanates and Titanate-Metal Compounds in Biological Contexts. AB - Metal ions are notorious environmental contaminants, some causing toxicity at exquisitely low (ppm-level) concentrations. Yet, the redox properties of metal ions make them attractive candidates for bio-therapeutics. Titanates are insoluble particulate compounds of titanium and oxygen with crystalline surfaces that bind metal ions; these compounds offer a means to scavenge metal ions in environmental contexts or deliver them in therapeutic contexts while limiting systemic exposure and toxicity. In either application, the toxicological properties of titanates are crucial. To date, the accurate measurement of the in vitro toxicity of titanates has been complicated by their particulate nature, which interferes with many assays that are optical density (OD)-dependent, and at present, little to no in vivo titanate toxicity data exist. Compatibility data garnered thus far for native titanates in vitro are inconsistent and lacking in mechanistic understanding. These data suggest that native titanates have little toxicity toward several oral and skin bacteria species, but do suppress mammalian cell metabolism in a cells-pecific manner. Titanate compounds bind several types of metal ions, including some common environmental toxins, and enhance delivery to bacteria or cells. Substantial work remains to address the practical applicability of titanates. Nevertheless, titanates have promise to serve as novel vehicles for metal-based therapeutics or as a new class of metal scavengers for environmental applications. PMID- 26430702 TI - Transcription Factor Activity Mapping of a Tissue-Specific in vivo Gene Regulatory Network. AB - A wealth of physical interaction data between transcription factors (TFs) and DNA has been generated, but these interactions often do not have apparent regulatory consequences. Thus, equating physical interaction data with gene regulatory networks (GRNs) is problematic. Here, we comprehensively assay TF activity, rather than binding, to construct a network of gene regulatory interactions in the C. elegans intestine. By manually observing the in vivo tissue-specific knockdown of 921 TFs on a panel of 19 fluorescent transcriptional reporters, we identified a GRN of 411 interactions between 19 promoters and 177 TFs. This GRN shows only modest overlap with physical interactions, indicating that many regulatory interactions are indirect. We applied nested effects modeling to uncover information flow between TFs in the intestine that converges on a small set of physical TF-promoter interactions. We found numerous cell nonautonomous regulatory interactions, illustrating tissue-to-tissue communication. Altogether, our study illuminates the complexity of gene regulation in the context of a living animal. PMID- 26430703 TI - CNS reservoirs for HIV: implications for eradication. AB - Controversy exists as to whether the central nervous system (CNS) serves as a reservoir site for HIV, in part reflecting the varying perspectives on what constitutes a 'reservoir' versus a mere site of latent viral integration. However, if the CNS proves to be a site of HIV persistence capable of replicating and reseeding the periphery, leading to failure of virological control, this privileged anatomical site would need dedicated consideration during the development of HIV cure strategies. In this review we discuss the current literature focused on the question of the CNS as a reservoir for HIV, covering the clinical evidence for continued CNS involvement despite suppressive therapy, the theorised dynamics of HIV integration into the CNS, as well as studies indicating that HIV can replicate independently and compartmentalise in the CNS. The unique cellular and anatomical sites of HIV integration in the CNS are also reviewed, as are the potential implications for HIV cure strategies. PMID- 26430704 TI - Elaine R. Monsen, PhD, RD--A Remembrance. PMID- 26430705 TI - Retraction. Position of the Academy of Nutrition and Dietetics: Vegetarian Diets. PMID- 26430706 TI - Robert Spiro Obituary. PMID- 26430707 TI - ClinGen and Genetic Testing. PMID- 26430708 TI - Nurses' voices in the forefront. PMID- 26430709 TI - Awakening the 'sleeping giant'. PMID- 26430710 TI - How Places Shape Identity: The Origins of Distinctive LBQ Identities in Four Small U.S. Cities. AB - Tools from the study of neighborhood effects, place distinction, and regional identity are employed in an ethnography of four small cities with growing populations of lesbian, bisexual, and queer-identified (LBQ) women to explain why orientations to sexual identity are relatively constant within each site, despite informants' within-city demographic heterogeneity, but vary substantially across the sites, despite common place-based attributes. The author introduces the concept of "sexual identity cultures"--and reveals the defining role of cities in shaping their contours. She finds that LBQ numbers and acceptance, place narratives, and newcomers' encounters with local social attributes serve as touchstones. The article looks beyond major categorical differences (e.g., urban/rural) to understand how and why identities evolve and vary and to reveal the fundamental interplay of demographic, cultural, and other city features previously thought isolatable. The findings challenge notions of identity as fixed and emphasize the degree to which self-understanding and group understanding remain collective accomplishments. PMID- 26430711 TI - The Sound of Stigmatization: Sonic Habitus, Sonic Styles, and Boundary Work in an Urban Slum. AB - Based on focus groups and interviews with student renters in an Israeli slum, the article explores the contributions of differences in sonic styles and sensibilities to boundary work, social categorization, and evaluation. Alongside visual cues such as broken windows, bad neighborhoods are characterized by sonic cues, such as shouts from windows. Students understand "being ghetto" as being loud in a particular way and use loudness as a central resource in their boundary work. Loudness is read as a performative index of class and ethnicity, and the performance of middle-class studentship entails being appalled by stigmatized sonic practices and participating in their exoticization. However, the sonic is not merely yet another resource of boundary work. Paying sociological attention to senses other than vision reveals complex interactions between structures anchored in the body, structures anchored in language, and actors' identification strategies, which may refine theorizations of the body and the senses in social theory. PMID- 26430712 TI - Caste and Choice: The Influence of Developmental Idealism on Marriage Behavior. AB - Is the marriage behavior of young people determined by their socioeconomic characteristics or their endorsement of developmental idealism? This article addresses this question using a unique longitudinal data set from Nepal and provides the first individual-level test of developmental idealism theory. The authors find that unmarried individuals with greater endorsement of developmental idealism in 2008 were more likely by 2012 to choose their own spouse, including a spouse of a different caste, rather than have an arranged marriage. Those with salaried work experience were also less likely to have arranged marriages, but urban proximity and education were not significant. The authors conclude that both developmental idealism and socioeconomic characteristics influence marriage and that their influences are largely independent. PMID- 26430714 TI - Human induced pluripotent stem cell-derived beating cardiac tissues on paper. AB - There is a growing interest in using paper as a biomaterial scaffold for cell based applications. In this study, we made the first attempt to fabricate a paper based array for the culture, proliferation, and direct differentiation of human induced pluripotent stem cells (hiPSCs) into functional beating cardiac tissues and create "a beating heart on paper." This array was simply constructed by binding a cured multi-well polydimethylsiloxane (PDMS) mold with common, commercially available paper substrates. Three types of paper material (print paper, chromatography paper and nitrocellulose membrane) were tested for adhesion, proliferation and differentiation of human-derived iPSCs. We found that hiPSCs grew well on these paper substrates, presenting a three-dimensional (3D) like morphology with a pluripotent property. The direct differentiation of human iPSCs into functional cardiac tissues on paper was also achieved using our modified differentiation approach. The cardiac tissue retained its functional activities on the coated print paper and chromatography paper with a beating frequency of 40-70 beats per min for up to three months. Interestingly, human iPSCs could be differentiated into retinal pigment epithelium on nitrocellulose membrane under the conditions of cardiac-specific induction, indicating the potential roles of material properties and mechanical cues that are involved in regulating stem cell differentiation. Taken together, these results suggest that different grades of paper could offer great opportunities as bioactive, low-cost, and 3D in vitro platforms for stem cell-based high-throughput drug testing at the tissue/organ level and for tissue engineering applications. PMID- 26430713 TI - Competition and collaboration between different actin assembly pathways allows for homeostatic control of the actin cytoskeleton. AB - Tremendous insight into actin-associated proteins has come from careful biochemical and cell biological characterization of their activities and regulation. However, many studies of their cellular behavior have only considered each in isolation. Recent efforts reveal that assembly factors compete for polymerization-competent actin monomers, suggesting that actin is homeostatically regulated. It seems that a major regulatory component is competition between Arp2/3-activating nucleation promoting factors and profilin for actin monomers. The result is differential delivery of actin to different pathways, allowing for simultaneous assembly of competing F-actin structures and collaborative building of higher order cellular structures. Although there are likely to be additional factors that regulate actin homeostasis, especially in a cell type-dependent fashion, we advance the notion that competition between actin assembly factors results in a tunable system that can be adjusted according to extracellular and intracellular cues. PMID- 26430715 TI - Increased insulin-like growth factor 1 receptor (IGF1R) expression in small cell lung cancer and the effect of inhibition of IGF1R expression by RNAi on growth of human small cell lung cancer NCI-H446 cell. AB - Insulin-like growth factor 1 receptor (IGF1R) is a tyrosine kinase receptor implicated in tumourigenesis that may be an attractive target for anti-cancer treatment. In this study, the expression and clinical significance of IGF1R were investigated in serum and lung cancer tissues from small cell lung cancinoma (SCLC). We also compared the effect of IGF1R up-regulation and IGF1R inhibition on viability and apoptosis of NCI-H446 cells. We found the concentration of IGF1R in blood serum was significantly increased and positive IGF1R protein in cancer tissue was more prevalent in SCLC. A statistically significant correlation among IGF1R-positve tumors, lymph node metastasis and local invasion was discussed. Furthermore, IGF1R overexpression lead to an increase of cell survival and suppressed cell apoptosis, IGF1R silencing mediated by RNAi abrogate this response of NCI-H446 cells. Our results further demonstrated that the effects of these treatments may be assigned to the effective inhibition of lung cancer cells from Akt/P27(Kip1) pathway in IGF-1R signaling. These features may have important implications for future anti-IGF1R therapeutic approaches. PMID- 26430716 TI - Cross-border outbreak of Salmonella enterica ssp. enterica serovar Bovismorbificans: multiple approaches for an outbreak investigation in Germany and Switzerland. AB - QUESTION UNDER STUDY: In July 2014, an outbreak of Salmonella enterica ssp. enterica serovar Bovismorbificans was detected in Switzerland. The goal of the outbreak investigation was to rapidly identify and eliminate the contamination source in order to prevent new cases. METHODS: A case-case study design was applied comprising reported cases of S. Bovismorbificans and cases of other serovars. A trawling questionnaire was administered by telephone interview. Data were collected for 34 cases (20 S. Bovismorbificans and 14 Salmonella spp.) pertaining to food consumption during the 72 hours prior to symptom onset. RESULTS: A statistically significant association between an S. Bovismorbificans infection and the consumption of 'salads' (odds ratio [OR] 14.3, 95% confidence interval [CI] 1.47-138.27) as well as the consumption of 'sprouts' (OR 10.6, 95% CI 1.16-97.59) was found. Principal places of consumption of 'salads' and 'sprouts' in outbreak cases were restaurants in southern Germany (80.0%, 95% CI 56.3%-94.3%). Microbiological analysis in Germany identified S. Bovismorbificans on sprouts, and genotype analysis confirmed that Swiss and German cases shared the same outbreak strain. The contaminated products were removed from the market in Germany, preventing an on-going outbreak. CONCLUSION: The combination of the applied methods and the collaboration between the two countries proved to be crucial elements of this investigation. A series of sprouts-associated salmonellosis outbreaks underpin the importance of this vegetable as a potential food-borne pathogen carrier. PMID- 26430717 TI - One-Pot Synthesis of Pyrrolo[3,2,1-kl]phenothiazines through Copper-Catalyzed Tandem Coupling/Double Cyclization Reaction. AB - A novel and efficient synthesis of pyrrolo[3,2,1-kl]phenothiazines has been developed through a Cu(I)-catalyzed tandem C-S coupling/double cyclization process. Using 2-alkynyl-6-iodoanilines and o-bromobenzenethiols as the starting materials, a wide range of pyrrolo[3,2,1-kl]phenothiazine derivatives were facilely and efficiently generated in one pot under Cu(I) catalysis. PMID- 26430718 TI - Iron Catalyzed Dual-Oxidative Dehydrogenative (DOD) Tandem Annulation of Glycine Derivatives with Tetrahydrofurans. AB - A novel iron-catalyzed dual-oxidative dehydrogenative (DOD) tandem annulation of glycine derivatives with tetrahydrofurans (THFs) for the synthesis of high value quinoline fused lactones has been developed. The reactions were performed under mild reaction conditions. And the use of cheap substrates (glycine derivatives and THF) and an even cheaper simple inorganic iron salt as the catalyst makes this protocol very attractive for potential synthetic applications. PMID- 26430719 TI - Cervical spinal cord compression from delayed epidural scar tissue formation around plate lead for SCS. Case report and literature review. AB - : Cervical spinal compression is a serious and rare complication of spinal cord stimulation (SCS) that can occur using leads placed via open surgical approach. The present report describe a case of cervical plate lead implant that developed spinal and radicular compression symptoms after seven years due to the growth of fibrotic epidural mass at the level of lead. A review of literature is provided. CASE PRESENTATION: A 59-year-old woman with 3-year history of left arm post traumatic complex regional pain syndrome (CRPS) was treated with SCS performed with the implant of paddle lead in the epidural space from C3-C5. Seven years later she reported progressive paresthesia along the spine and the limbs, gait ataxia with sensation of weakness in the legs, increased muscle tone and tendon reflexes in the lower extremities and decrease in effectiveness of stimulation. Cervical CT showed a tissue mass into the cervical canal posteriorly to the lead. This finding was confirmed by MR performed after lead removal that also allowed to document the amount of spinal cord compression. The patient underwent C4-C5-C6 laminectomy and a thick scar was removed from the dura. After surgery there was progressive and incomplete improvement of neurological signs but symptoms related to algodystrophy recurred partly. CONCLUSION: The formation of hypertrophic epidural scar tissue at the level of lead implant must be taken into consideration in presence of the onset of progressive cervical myelopathy in patient treated with SCS using laminectomy lead. PMID- 26430720 TI - Long-Term Follow-Up of HIV-Infected Women with Cervical Dysplasia. PMID- 26430721 TI - Depression and HIV Serostatus Disclosure to Sexual Partners Among Newly HIV Diagnosed Men Who Have Sex with Men. AB - HIV disclosure to sexual partners facilitates joint decision-making and risk reduction strategies for safer sex behaviors, but disclosure may be impacted by depression symptoms. Disclosure is also associated with disclosure self-efficacy, which in turn may also be influenced by depressive symptoms. This study examined the relationship between depression and HIV disclosure to partners following diagnosis among men who have sex with men (MSM), mediated by disclosure self efficacy. Newly HIV-diagnosed MSM (n=92) who reported sexual activity after diagnosis completed an assessment soon after diagnosis which measured depressive symptoms, and another assessment within 3 months of diagnosis that measured disclosure self-efficacy and disclosure. Over one-third of the sample reported elevated depressive symptoms soon after diagnosis and equal proportions (one third each) disclosed to none, some, or all partners in the 3 months after diagnosis. Depressive symptoms were negatively associated with disclosure self efficacy and disclosure to partners, while disclosure self-efficacy was positively associated with disclosure. Disclosure self-efficacy partially mediated the relationship between depression and disclosure, accounting for 33% of the total effect. These findings highlight the importance of addressing depression that follows diagnosis to enhance subsequent disclosure to sexual partners. PMID- 26430722 TI - Concomitant JAK2 V617F-positive polycythemia vera and BCR-ABL-positive chronic myelogenous leukemia treated with ruxolitinib and dasatinib. PMID- 26430723 TI - The expression level of BAALC-associated microRNA miR-3151 is an independent prognostic factor in younger patients with cytogenetic intermediate-risk acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a heterogeneous disease whose prognosis is mainly related to the biological risk conferred by cytogenetics and molecular profiling. In elderly patients (?60 years) with normal karyotype AML miR-3151 have been identified as a prognostic factor. However, miR-3151 prognostic value has not been examined in younger AML patients. In the present work, we have studied miR 3151 alone and in combination with BAALC, its host gene, in a cohort of 181 younger intermediate-risk AML (IR-AML) patients. Patients with higher expression of miR-3151 had shorter overall survival (P=0.0025), shorter leukemia-free survival (P=0.026) and higher cumulative incidence of relapse (P=0.082). Moreover, in the multivariate analysis miR-3151 emerged as independent prognostic marker in both the overall series and within the unfavorable molecular prognostic category. Interestingly, the combined determination of both miR-3151 and BAALC improved this prognostic stratification, with patients with low levels of both parameters showing a better outcome compared with those patients harboring increased levels of one or both markers (P=0.003). In addition, we studied the microRNA expression profile associated with miR-3151 identifying a six-microRNA signature. In conclusion, the analysis of miR-3151 and BAALC expression may well contribute to an improved prognostic stratification of younger patients with IR AML. PMID- 26430724 TI - Gene expression of INPP5F as an independent prognostic marker in fludarabine based therapy of chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is a heterogeneous disease. Various disease related and patient-related factors have been shown to influence the course of the disease. The aim of this study was to identify novel biomarkers of significant clinical relevance. Pretreatment CD19-separated lymphocytes (n=237; discovery set) and peripheral blood mononuclear cells (n=92; validation set) from the REACH trial, a randomized phase III trial in relapsed CLL comparing rituximab plus fludarabine plus cyclophosphamide with fludarabine plus cyclophosphamide alone, underwent gene expression profiling. By using Cox regression survival analysis on the discovery set, we identified inositol polyphosphate-5-phosphatase F (INPP5F) as a prognostic factor for progression-free survival (P<0.001; hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.35-1.98) and overall survival (P<0.001; HR, 1.47; 95% CI, 1.18-1.84), regardless of adjusting for known prognostic factors. These findings were confirmed on the validation set, suggesting that INPP5F may serve as a novel, easy-to-assess future prognostic biomarker for fludarabine-based therapy in CLL. PMID- 26430725 TI - Rate of CRL4(CRBN) substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells by regulation of c-Myc and IRF4. AB - Recent discoveries suggest that the critical events leading to the anti proliferative activity of the IMiD immunomodulatory agents lenalidomide and pomalidomide in multiple myeloma (MM) cells are initiated by Cereblon-dependent ubiquitination and proteasomal degradation of substrate proteins Ikaros (IKZF1) and Aiolos (IKZF3). By performing kinetic analyses, we found that the downregulation or proteasomal degradation of Ikaros and Aiolos led to specific and sequential downregulation of c-Myc followed by IRF4 and subsequent growth inhibition and apoptosis. Notably, to ensure growth inhibition and cell death, sustained downregulation of Ikaros and Aiolos, c-Myc or IRF4 expression was required. In addition, we found that the half-maximal rate, rather than the final extent of Ikaros and Aiolos degradation, correlated to the relative efficacy of growth inhibition by lenalidomide or pomalidomide. Finally, we observed that all four transcription factors were elevated in primary MM samples compared with normal plasma cells. Taken together, our results suggest a functional link between Ikaros and Aiolos, and the pathological dysregulation of c-Myc and IRF4, and provide a new mechanistic understanding of the relative efficacy of lenalidomide and pomalidomide based on the kinetics of substrate degradation and downregulation of their downstream targets. PMID- 26430726 TI - Nurse-like cells mediate ibrutinib resistance in chronic lymphocytic leukemia patients. PMID- 26430727 TI - Patients with relapsed/refractory chronic lymphocytic leukaemia may benefit from inclusion in clinical trials irrespective of the therapy received: a case-control retrospective analsysis. PMID- 26430728 TI - A case of pre-eclampsia and foetal growth restriction after embolisation for a postmolar uterine arteriovenous malformation. PMID- 26430729 TI - Tdap vaccine attitudes and utilization among pregnant women from a high-risk population. AB - Infants infected with Bordatella pertussis experience high morbidity and significant mortality. Vaccinating pregnant mothers with the tetanus-diphtheria acellular pertussis (Tdap) vaccine is a recommended strategy for preventing infant pertussis. This is especially important for mothers living in poverty and from racial and ethnic minority populations as these groups are at increased risk of having a pertussis-affected infant. Using the Health Belief Model as a framework, we surveyed a convenience sample of pregnant mothers representing these high-risk populations to understand factors associated with Tdap vaccine uptake during their pregnancy. Among the 316 mothers surveyed, 82% had gotten or planned to get Tdap that same day even though 63% of the sample had concerns about the safety of the vaccine during pregnancy. Perceived benefits and norms were the Health Belief Model constructs most consistently associated with Tdap vaccination. Although 32% of women reported prior Tdap vaccine receipt, this factor was not associated with Tdap vaccination during the current pregnancy, contrasting studies of vaccination done in non-pregnant populations. Important variations in attitudes were apparent, with Spanish-speaking women significantly more likely to have concerns about the vaccine's safety and efficacy than English speaking women. This study indicates that among this high-risk population acceptance of Tdap vaccine during pregnancy is high. However, our results suggest that it may be important to modify information conveyed about the safety and importance of Tdap during pregnancy based on individual level factors such as language or acculturation. PMID- 26430730 TI - Tobacco outlet density, retailer cigarette sales without ID checks and enforcement of underage tobacco laws: associations with youths' cigarette smoking and beliefs. AB - AIMS: To estimate the relationships of tobacco outlet density, cigarette sales without ID checks and local enforcement of underage tobacco laws with youth's life-time cigarette smoking, perceived availability of tobacco and perceived enforcement of underage tobacco laws and changes over time. DESIGN: The study involved: (a) three annual telephone surveys, (b) two annual purchase surveys in 2000 tobacco outlets and (c) interviews with key informants from local law enforcement agencies. Analyses were multi-level models (city, individual, time). SETTING: A sample of 50 mid-sized non-contiguous cities in California, USA. PARTICIPANTS: A total of 1478 youths (aged 13-16 at wave 1, 52.2% male); 1061 participated in all waves. MEASUREMENTS: Measures at the individual level included life-time cigarette smoking, perceived availability and perceived enforcement. City-level measures included tobacco outlet density, cigarette sales without ID checks and compliance checks. FINDINGS: Outlet density was associated positively with life-time smoking [OR = 1.12, P < 0.01]. An interaction between outlet density and wave (OR = 0.96, P < 0.05) suggested that higher density was associated more closely with life-time smoking at the earlier waves when respondents were younger. Greater density was associated positively with perceived availability (beta = 0.02, P < 0.05) and negatively with perceived enforcement (beta = -0.02, P < 0.01). Sales rate without checking IDs was related to greater perceived availability (beta = 0.01, P < 0.01) and less perceived enforcement (beta = -0.01, P < 0.01). Enforcement of underage tobacco laws was related positively to perceived enforcement (beta = 0.06, P < 0.05). CONCLUSIONS: Higher tobacco outlet density may contribute to life-time smoking among youths. Density, sales without ID checks and enforcement levels may influence beliefs about access to cigarettes and enforcement of underage tobacco sales laws. PMID- 26430731 TI - Compromised Prefrontal Cognitive Control Over Emotional Interference in Adolescents with Internet Gaming Disorder. AB - Increased reports of impulsivity and aggression in male adolescents with Internet gaming might reflect their dysfunction in emotion regulation, particularly in suppression of negative emotions, which should affect the various stages of Internet gaming disorder. This study tested the hypothesis that adolescents with Internet gaming disorder would be more disturbed by the emotional interference and demonstrate compromised dorsal anterior cingulate cortex (dACC) activation during a Stroop Match-to-Sample task. In addition, functional connectivity analysis was conducted to examine the interplays between neural correlates involved in emotional processing and how they were altered in adolescents with Internet gaming disorder. The Internet gaming disorder group demonstrated weaker dACC activation and stronger insular activations to interfering angry facial stimuli compared with the healthy control group. Negative functional connectivity between stronger insular activation and weaker dorsolateral prefrontal activation correlated with higher cognitive impulsivity in adolescents with Internet gaming disorder. These findings provide evidence of the compromised prefrontal cognitive control over emotional interference in adolescents with Internet gaming disorder. PMID- 26430732 TI - t-Darpp overexpression in HER2-positive breast cancer confers a survival advantage in lapatinib. AB - Drug resistance is a major barrier to successful cancer treatment. For patients with HER2-positive breast cancer who initially respond to therapy, the majority develop resistance within one year of treatment. Patient outcomes could improve significantly if we can find and exploit common mechanisms of acquired resistance to different targeted therapies. Overexpression of t-Darpp, a truncated form of the dual kinase/phosphatase inhibitor Darpp-32, has been linked to acquired resistance to trastuzumab, a front-line therapy for HER2-positive breast cancer. Darpp-32 reverses t-Darpp's effect on trastuzumab resistance. In this study, we examined whether t-Darpp could be involved in resistance to lapatinib, another HER2-targeted therapeutic. Lapatinib-resistant SKBR3 cells (SK/LapR) showed a marked change in the Darpp-32:t-Darpp ratio toward a predominance of t-Darpp. Overexpression of t-Darpp alone was not sufficient to confer lapatinib resistance, but cells that overexpress t-Darpp partially mimicked the molecular resistance phenotype observed in SK/LapR cells exposed to lapatinib. SK/LapR cells failed to down-regulate Survivin and failed to induce BIM accumulation in response to lapatinib; cells overexpressing t-Darpp exhibited only the failed BIM accumulation. t-Darpp knock-down reversed this phenotype. Using a fluorescence based co-culture system, we found that cells overexpressing t-Darpp formed colonies in lapatinib within 3-4 weeks, whereas parental cells in the same co culture did not. Overall, t-Darpp appears to mediate a survival advantage in lapatinib, possibly linked to failed lapatinib-induced BIM accumulation. t-Darpp might also be relevant to acquired resistance to other cancer drugs that rely on BIM accumulation to induce apoptosis. PMID- 26430733 TI - Rapid Removal of Tetrabromobisphenol A by Ozonation in Water: Oxidation Products, Reaction Pathways and Toxicity Assessment. AB - Tetrabromobisphenol A (TBBPA) is one of the most widely used brominated flame retardants and has attracted more and more attention. In this work, the parent TBBPA with an initial concentration of 100 mg/L was completely removed after 6 min of ozonation at pH 8.0, and alkaline conditions favored a more rapid removal than acidic and neutral conditions. The presence of typical anions and humic acid did not significantly affect the degradation of TBBPA. The quenching test using isopropanol indicated that direct ozone oxidation played a dominant role during this process. Seventeen reaction intermediates and products were identified using an electrospray time-of-flight mass spectrometer. Notably, the generation of 2,4,6-tribromophenol was first observed in the degradation process of TBBPA. The evolution of reaction products showed that ozonation is an efficient treatment for removal of both TBBPA and intermediates. Sequential transformation of organic bromine to bromide and bromate was confirmed by ion chromatography analysis. Two primary reaction pathways that involve cleavage of central carbon atom and benzene ring cleavage concomitant with debromination were thus proposed and further justified by calculations of frontier electron densities. Furthermore, the total organic carbon data suggested a low mineralization rate, even after the complete removal of TBBPA. Meanwhile, the acute aqueous toxicity of reaction solutions to Photobacterium Phosphoreum and Daphnia magna was rapidly decreased during ozonation. In addition, no obvious difference in the attenuation of TBBPA was found by ozone oxidation using different water matrices, and the effectiveness in natural waters further demonstrates that ozonation can be adopted as a promising technique to treat TBBPA-contaminated waters. PMID- 26430735 TI - Cultural influences on HIV testing among Latino youth. AB - Young Latinos aged 13-24 years in the USA are disproportionately impacted upon by HIV. Despite the elevated risk, lower rates of HIV testing have been documented among Latino youth relative to other racial/ethnic groups. The objective of the current study was to examine the influence of acculturation and cultural values on HIV testing among Latino youth. The study consisted of 51 sexually experienced young Latinos aged 13-16 years from a major city in the Southeastern USA. Participants completed a survey on HIV testing history, cultural orientation and Latino cultural values. Results indicate that 21.6% of the young people had been tested for HIV. The number of times tested ranged from one to four (M = 1.9 +/- 1.0). HIV testing was associated with US American cultural orientation and familism (and emphasis on strong family commitment, family support and emotional closeness). Participants with greater orientation to US American culture were more likely, whereas those who endorsed higher familism value were less likely, to have had an HIV test. For participants scoring high on familism, the desire to maintain family honour may serve as a deterrent to testing. Incorporating culturally relevant strategies, such as promoting sexual communication and conversations on HIV prevention within the family, may enhance testing and narrow the gap in HIV infection between Latino youth and other ethnic groups. PMID- 26430734 TI - No Observed Effect of Landscape Fragmentation on Pathogen Infection Prevalence in Blacklegged Ticks (Ixodes scapularis) in the Northeastern United States. AB - Pathogen prevalence within blacklegged ticks (Ixodes scapularis Say, 1821) tends to vary across sites and geographic regions, but the underlying causes of this variation are not well understood. Efforts to understand the ecology of Lyme disease have led to the proposition that sites with higher host diversity will result in lower disease risk due to an increase in the abundance of inefficient reservoir species relative to the abundance of species that are highly competent reservoirs. Although the Lyme disease transmission cycle is often cited as a model for this "dilution effect hypothesis", little empirical evidence exists to support that claim. Here we tested the dilution effect hypothesis for two pathogens transmitted by the blacklegged tick along an urban-to-rural gradient in the northeastern United States using landscape fragmentation as a proxy for host biodiversity. Percent impervious surface and habitat fragment size around each site were determined to assess the effect of landscape fragmentation on nymphal blacklegged tick infection with Borrelia burgdorferi and Anaplasma phagocytophilum. Our results do not support the dilution effect hypothesis for either pathogen and are in agreement with the few studies to date that have tested this idea using either a landscape proxy or direct measures of host biodiversity. PMID- 26430736 TI - Multi-Parametric Evaluation of Chronic Kidney Disease by MRI: A Preliminary Cross Sectional Study. AB - BACKGROUND: The current clinical classification of chronic kidney disease (CKD) is not perfect and may be overestimating both the prevalence and the risk for progressive disease. Novel markers are being sought to identify those at risk of progression. This preliminary study evaluates the feasibility of magnetic resonance imaging based markers to identify early changes in CKD. METHODS: Fifty nine subjects (22 healthy, 7 anemics with no renal disease, 30 subjects with CKD) participated. Data using 3D volume imaging, blood oxygenation level dependent (BOLD) and Diffusion MRI was acquired. BOLD MRI acquisition was repeated after 20 mg of iv furosemide. RESULTS: Compared to healthy subjects, those with CKD have lower renal parenchymal volumes (329.6+/-66.4 vs. 257.1+/-87.0 ml, p<0.005), higher cortical R2* values (19.7+/-3.2 vs. 23.2+/-6.3 s(-1), p = 0.013) (suggesting higher levels of hypoxia) and lower response to furosemide on medullary R2* (6.9+/-3.3 vs. 3.1+/-7.5 s(-1), p = 0.02). All three parameters showed significant correlation with estimated glomerular filtration rate (eGFR). When the groups were matched for age and sex, cortical R2* and kidney volume still showed significant differences between CKD and healthy controls. The most interesting observation is that a small number of subjects (8 of 29) contributed to the increase in mean value observed in CKD. The difference in cortical R2* between these subjects compared to the rest were highly significant and had a large effect size (Cohen's d = 3.5). While highly suggestive, future studies may be necessary to verify if such higher levels of hypoxia are indicative of progressive disease. Diffusion MRI showed no differences between CKD and healthy controls. CONCLUSIONS: These data demonstrate that BOLD MRI can be used to identify enhanced hypoxia associated with CKD and the preliminary observations are consistent with the chronic hypoxia model for disease progression in CKD. Longitudinal studies are warranted to further verify these findings and assess their predictive value. PMID- 26430737 TI - TLR1, 2, 4, 6 and 9 Variants Associated with Tuberculosis Susceptibility: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Studies investigating the influence of toll-like receptor (TLR) polymorphisms and tuberculosis susceptibility have yielded varying and often contradictory results in different ethnic groups. A meta-analysis was conducted to investigate the relationship between TLR variants and susceptibility to tuberculosis, both across and within specific ethnic groups. METHODS: An extensive database search was performed for studies investigating the relationship between TLR and tuberculosis (TB) susceptibility. Data was subsequently extracted from included studies and statistically analysed. RESULTS: 32 articles involving 18907 individuals were included in this meta-analysis, and data was extracted for 14 TLR polymorphisms. Various genetic models were employed. An increased risk of TB was found for individuals with the TLR2 rs3804100 CC and the TLR9 rs352139 GA and GG genotypes, while decreased risk was identified for those with the AG genotype of TLR1 rs4833095. The T allele of TLR6 rs5743810 conferred protection across all ethnic groups. TLR2 rs5743708 subgroup analysis identified the A allele to increase susceptibility to TB in the Asian ethnic group, while conferring protection in the Hispanic group. The T allele of TLR4 rs4986791 was also found to increase the risk of TB in the Asian subgroup. All other TLR gene variants investigated were not found to be associated with TB in this meta-analysis. DISCUSSION: Although general associations were identified, most TLR variants showed no significant association with TB, indicating that additional studies investigating a wider range of pattern recognition receptors is required to gain a better understanding of this complex disease. PMID- 26430738 TI - Antibiotic Resistance of Pseudomonas aeruginosa in Pneumonia at a Single University Hospital Center in Germany over a 10-Year Period. AB - BACKGROUND: Pseudomonas aeruginosa is a common cause of community-acquired and nosocomial-acquired pneumonia. The development of resistance of P. aeruginosa to antibiotics is increasing globally due to the overuse of antibiotics. This article examines, retrospectively, the antibiotic resistance in patients with community-acquired versus nosocomial-acquired pneumonia caused by P. aeruginosa or multidrug-resistant (MDR) P. aeruginosa. METHODS: Data from patients with community-acquired and nosocomial-acquired pneumonia caused by P. aeruginosa and MDR P. aeruginosa were collected from the hospital charts at the HELIOS Clinic, Witten/Herdecke University, Wuppertal, Germany, between January 2004 and August 2014. An antibiogram was created from all study patients with community-acquired and nosocomial-acquired pneumonia caused by P. aeruginosa or MDR P. aeruginosa. RESULTS: A total of 168 patients with mean age 68.1 +/- 12.8 (113 [67.3% males and 55 [32.7%] females) were identified; 91 (54.2%) had community-acquired and 77 (45.8%) had nosocomial-acquired pneumonia caused by P. aeruginosa. Patients with community-acquired versus nosocomial-acquired pneumonia had a mean age of 66.4 +/ 13.8 vs. 70.1 +/- 11.4 years [59 vs. 54 (64.8% vs. 70.1%) males and 32 vs. 23 (35.2% vs. 29.9%) females]. They included 41 (24.4%) patients with pneumonia due to MDR P. aeruginosa: 27 (65.9%) community-acquired and 14 (34.1%) nosocomial acquired cases. P. aeruginosa and MDR P. aeruginosa showed a very high resistance to fosfomycin (community-acquired vs. nosocomial-acquired) (81.0% vs. 84.2%; 0 vs. 85.7%). A similar resistance pattern was seen with ciprofloxacin (35.2% vs. 24.0%; 70.4% vs. 61.5%), levofloxacin (34.6% vs. 24.5%; 66.7% vs. 64.3%), ceftazidime (15.9% vs. 30.9; 33.3% vs. 61.5%), piperacillin (24.2% vs. 29.9%; 44.4% vs. 57.1%), imipenem (28.6% vs. 27.3%; 55.6% vs. 50.0%), piperacillin and tazobactam (23.1% vs. 28.6%; 44.4% vs. 50.0%), tobramycin (28.0% vs. 17.2%; 52.0% vs. 27.3%), gentamicin (26.4% vs. 18.2%; 44.4% vs. 21.4%), and meropenem (20.2% vs. 20.3%; 42.3% vs. 50.0%). An elevated resistance of P. aeruginosa and MDR P. aeruginosa was found for cefepime (11.1% vs. 23.3%; 25.9% vs. 50.0%), and amikacin (10.2% vs. 9.1%; 27.3% vs. 9.1%). Neither pathogen was resistant to colistin (P = 0.574). CONCLUSION: While P. aeruginosa and MDR P. aeruginosa were resistant to a variety of commonly used antibiotics, they were not resistant to colistin in the few isolates recovered from patients with pneumonia. PMID- 26430739 TI - MicroRNA Expression in Myocardial Tissue and Plasma of Patients with End-Stage Heart Failure during LVAD Support: Comparison of Continuous and Pulsatile Devices. AB - AIM: Pulsatile flow left ventricular assist devices (pf-LVADs) are being replaced by continuous flow LVADs (cf-LVADs) in patients with end-stage heart failure (HF). MicroRNAs (miRs) play an important role in the onset and progression of HF. Our aim was to analyze cardiac miR expression patterns associated with each type of device, to analyze differences in the regulation of the induced cardiac changes. METHODS AND RESULTS: Twenty-six miRs were selected (based on micro-array data and literature studies) and validated in myocardial tissue before and after pf- (n = 17) and cf-LVAD (n = 17) support. Of these, 5 miRs displayed a similar expression pattern among the devices (miR-129*, miR-146a, miR-155, miR-221, miR 222), whereas others only changed significantly during pf-LVAD (miR-let-7i, miR 21, miR-378, miR-378*) or cf-LVAD support (miR-137). In addition, 4 miRs were investigated in plasma of cf-LVAD supported patients (n = 18) and healthy controls (n = 10). Circulating miR-21 decreased at 1, 3, and 6 months after LVAD implantation. MiR-146a, miR-221 and miR-222 showed a fluctuating time pattern post-LVAD. CONCLUSION: Our data show a different miR expression pattern after LVAD support, suggesting that differentially expressed miRs are partially responsible for the cardiac morphological and functional changes observed after support. However, the miR expression patterns do not seem to significantly differ between pf- and cf-LVAD implying that most cardiac changes or clinical outcomes specific to each device do not relate to differences in miR expression levels. PMID- 26430740 TI - Beyond Testis Size: Links between Spermatogenesis and Sperm Traits in a Seasonal Breeding Mammal. AB - Spermatogenesis is a costly process that is expected to be under selection to maximise sperm quantity and quality. Testis size is often regarded as a proxy measure of sperm investment, implicitly overlooking the quantitative assessment of spermatogenesis. An enhanced understanding of testicular function, beyond testis size, may reveal further sexual traits involved in sperm quantity and quality. Here, we first estimated the inter-male variation in testicular function and sperm traits in red deer across the breeding and non-breeding seasons. Then, we analysed the relationships between the testis mass, eight parameters of spermatogenic function, and seven parameters of sperm quality. Our findings revealed that the Sertoli cell number and function parameters vary greatly between red deer males, and that spermatogenic activity co-varies with testis mass and sperm quality across the breeding and non-breeding seasons. For the first time in a seasonal breeder, we found that not only is the Sertoli cell number important in determining testis mass (r = 0.619, p = 0.007 and r = 0.248, p = 0.047 for the Sertoli cell number assessed by histology and cytology, respectively), but also sperm function (r = 0.703, p = 0.002 and r = 0.328, p = 0.012 for the Sertoli cell number assessed by histology and cytology, respectively). Testicular histology also revealed that a high Sertoli cell number per tubular cross-section is associated with high sperm production (r = 0.600, p = 0.009). Sperm production and function were also positively correlated (r = 0.384, p = 0.004), suggesting that these traits co-vary to maximise sperm fertilisation ability in red deer. In conclusion, our findings contribute to the understanding of the dynamics of spermatogenesis, and reveal new insights into the role of testicular function and the Sertoli cell number on testis size and sperm quality in red deer. PMID- 26430741 TI - MicroRNA-199a-5p Regulates the Proliferation of Pulmonary Microvascular Endothelial Cells in Hepatopulmonary Syndrome. AB - BACKGROUND/AIMS: Pulmonary microvascular endothelial cell (PMVEC) proliferation and angiogenesis contribute to the development of hepatopulmonary syndrome (HPS). MicroRNA-199a-5p (miR-199a-5p) has emerged as a potent regulator of angiogenesis, and its expression levels significantly decrease in the serum of patients with hepatopathy. However, it has not been reported about whether miR-199a-5p might control PMVEC proliferation. Here, we described the miR-199a-5p governing PMVEC proliferation in HPS. METHODS: PMVECs were treated with rat serum from common bile duct ligation (CBDL) or sham. MiR-199a-5p mimic or inhibitor was used to change the miR-199a-5p expression. Knockdown of caveolin-1 (Cav-1) was performed using siRNA. NSC-23766 was used to inhibit Rac1 activity. Gene and protein expressions were quantified by qRT-PCR and western blot. Cell proliferation was analyzed by 3H-TdR incorporation and CCK-8 assays. Stress fibers were detected by immunofluorescence. RESULTS: CBDL rat serum induced the down-regulation of miR 199a-5p. Delivery of miR-199a-5p suppressed the CBDL rat serum-induced PMVEC proliferation whereas knockdown of miR-199a-5p promoted PMVEC proliferation. This was accompanied by a decrease and an increase in Cav-1 expression, respectively. Cav-1 siRNA abolished the enhancement of PMVEC proliferation induced by the miR 199a-5p inhibition. Although stress fibers were disrupted in Cav-1 deficient cells, NSC-23766 increased stress fibers and contributed to cell proliferation. CONCLUSIONS: CBDL rat serum induced down-regulation of miR-199a-5p in PMVECs, which led to an increase of Cav-1 gene expression. Increased Cav-1 expression, by inhibiting Rac1 activity, led to the formation of stress fibers, which contribute to PMVEC proliferation and thus the pathogenesis of HPS. PMID- 26430746 TI - Angiotensin II Type 1 Receptor-Mediated Electrical Remodeling in Mouse Cardiac Myocytes. AB - We recently characterized an autocrine renin angiotensin system (RAS) in canine heart. Activation of Angiotensin II Type 1 Receptors (AT1Rs) induced electrical remodeling, including inhibition of the transient outward potassium current Ito, prolongation of the action potential (AP), increased calcium entry and increased contractility. Electrical properties of the mouse heart are very different from those of dog heart, but if a similar system existed in mouse, it could be uniquely studied through genetic manipulations. To investigate the presence of a RAS in mouse, we measured APs and Ito in isolated myocytes. Application of angiotensin II (A2) for 2 or more hours reduced Ito magnitude, without affecting voltage dependence, and prolonged APs in a dose-dependent manner. Based on dose inhibition curves, the fast and slow components of Ito (Ito,fast and IK,slow) appeared to be coherently regulated by [A2], with 50% inhibition at an A2 concentration of about 400 nM. This very high K0.5 is inconsistent with systemic A2 effects, but is consistent with an autocrine RAS in mouse heart. Pre application of the microtubule destabilizing agent colchicine eliminated A2 effects on Ito and AP duration, suggesting these effects depend on intracellular trafficking. Application of the biased agonist SII ([Sar1-Ile4-Ile8]A2), which stimulates receptor internalization without G protein activation, caused Ito reduction and AP prolongation similar to A2-induced changes. These data demonstrate AT1R mediated regulation of Ito in mouse heart. Moreover, all measured properties parallel those measured in dog heart, suggesting an autocrine RAS may be a fundamental feedback system that is present across species. PMID- 26430747 TI - Determinants of Bed Net Use in Southeast Nigeria following Mass Distribution of LLINs: Implications for Social Behavior Change Interventions. AB - Millions of long-lasting insecticide treated nets (LLINs) have been distributed as part of the global malaria control strategy. LLIN ownership, however, does not necessarily guarantee use. Thus, even in the ideal setting in which universal coverage with LLINs has been achieved, maximal malaria protection will only be achieved if LLINs are used both correctly and consistently. This study investigated the factors associated with net use, independent of net ownership. Data were collected during a household survey conducted in Ebonyi State in southeastern Nigeria in November 2011 following a statewide mass LLIN distribution campaign and, in select locations, a community-based social behavior change (SBC) intervention. Logistic regression analyses, controlling for household bed net ownership, were conducted to examine the association between individual net use and various demographic, environmental, behavioral and social factors. The odds of net use increased among individuals who were exposed to tailored SBC in the context of a home visit (OR = 17.11; 95% CI 4.45-65.79) or who received greater degrees of social support from friends and family (ptrend < 0.001). Factors associated with decreased odds of net use included: increasing education level (ptrend = 0.020), increasing malaria knowledge level (ptrend = 0.022), and reporting any disadvantage of bed nets (OR = 0.39; 95% CI 0.23-0.78). The findings suggest that LLIN use is significantly influenced by social support and exposure to a malaria-related SBC home visit. The malaria community should thus further consider the importance of community outreach, interpersonal communication and social support on adoption of net use behaviors when designing future research and interventions. PMID- 26430748 TI - Variations in the Quality of Care at Large Public Hospitals in Beijing, China: A Condition-Based Outcome Approach. AB - BACKGROUND: Public hospitals deliver over ninety percent of all outpatient and inpatient services in China. Their quality is graded into three levels (A, B, and C) largely based on structural resources, but empirical evidence on the quality of process and outcome of care is extremely scarce. As expectations for quality care rise with higher living standards and cost of care, such evidence is urgently needed and vital to improve care and to inform future health reforms. METHODS: We compiled and analyzed a multicenter database of over 4 million inpatient discharge summary records to provide a comprehensive assessment of the level and variations in clinical outcomes of hospitalization at 39 tertiary hospitals in Beijing. We assessed six outcome measures of clinical quality: in hospital mortality rates (RSMR) for AMI, stroke, pneumonia and CABG, post procedural complication rate (RS-CR), and failure-to-rescue rate (RS-FTR). The measures were adjusted for pre-admission patient case-mix using indirect standardization method with hierarchical linear mixed models. RESULTS: We found good overall quality with large variations by hospital and condition (mean/range, in %): RSMR-AMI: 6.23 (2.37-14.48), RSMR-stroke: 4.18 (3.58-4.44), RSMR pneumonia: 7.78 (7.20-8.59), RSMR-CABG: 1.93 (1.55-2.23), RS-CR: 11.38 (9.9 12.88), and RS-FTR: 6.41 (5.17-7.58). Hospital grade was not significantly associated with any risk-adjusted outcome measures. CONCLUSIONS: Going to a higher grade public hospital does not always lead to better patient outcome because hospital grade only contains information about hospital structural resources. A hospital report card with some outcome measures of quality would provide valuable information to patients in choosing providers, and for regulators to identify gaps in health care quality. Reducing the variations in clinical practice and patient outcome should be a focus for policy makers in the next round of health sector reforms in China. PMID- 26430749 TI - A Pilot Study of EEG Source Analysis Based Repetitive Transcranial Magnetic Stimulation for the Treatment of Tinnitus. AB - OBJECTIVE: Repetitive Transcranial Magnetic Stimulation (rTMS) is a novel therapeutic tool to induce a suppression of tinnitus. However, the optimal target sites are unknown. We aimed to determine whether low-frequency rTMS induced lasting suppression of tinnitus by decreasing neural activity in the cortex, navigated by high-density electroencephalogram (EEG) source analysis, and the utility of EEG for targeting treatment. METHODS: In this controlled three-armed trial, seven normal hearing patients with tonal tinnitus received a 10-day course of 1-Hz rTMS to the cortex, navigated by high-density EEG source analysis, to the left temporoparietal cortex region, and to the left temporoparietal with sham stimulation. The Tinnitus handicap inventory (THI) and a visual analog scale (VAS) were used to assess tinnitus severity and loudness. Measurements were taken before, and immediately, 2 weeks, and 4 weeks after the end of the interventions. RESULTS: Low-frequency rTMS decreased tinnitus significantly after active, but not sham, treatment. Responders in the EEG source analysis-based rTMS group, 71.4% (5/7) patients, experienced a significant reduction in tinnitus loudness, as evidenced by VAS scores. The target site of neuronal generators most consistently associated with a positive response was the frontal lobe in the right hemisphere, sourced using high-density EEG equipment, in the tinnitus patients. After left temporoparietal rTMS stimulation, 42.8% (3/7) patients experienced a decrease in tinnitus loudness. CONCLUSIONS: Active EEG source analysis based rTMS resulted in significant suppression in tinnitus loudness, showing the superiority of neuronavigation-guided coil positioning in dealing with tinnitus. Non-auditory areas should be considered in the pathophysiology of tinnitus. This knowledge in turn can contribute to investigate the pathophysiology of tinnitus. PMID- 26430754 TI - Integration of photoperiod and cold temperature signals into flowering genetic pathways in Arabidopsis. AB - Appropriate timing of flowering is critical for propagation and reproductive success in plants. Therefore, flowering time is coordinately regulated by endogenous developmental programs and external signals, such as changes in photoperiod and temperature. Flowering is delayed by a transient shift to cold temperatures that frequently occurs during early spring in the temperate zones. It is known that the delayed flowering by short-term cold stress is mediated primarily by the floral repressor FLOWERING LOCUS C (FLC). However, how the FLC mediated cold signals are integrated into flowering genetic pathways is not fully understood. We have recently reported that the INDUCER OF CBF EXPRESSION 1 (ICE1), which is a master regulator of cold responses, FLC, and the floral integrator SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1) constitute an elaborated feedforward-feedback loop that integrates photoperiod and cold temperature signals to regulate seasonal flowering in Arabidopsis. Cold temperatures promote the binding of ICE1 to FLC promoter to induce its expression, resulting in delayed flowering. However, under floral inductive conditions, SOC1 induces flowering by blocking the ICE1 activity. We propose that the ICE1-FLC-SOC1 signaling network fine-tunes the timing of photoperiodic flowering during changing seasons. PMID- 26430755 TI - Correction: Alcohol Advertising in Sport and Non-Sport TV in Australia, during Children's Viewing Times. PMID- 26430750 TI - Role of Opioid Receptors Signaling in Remote Electrostimulation--Induced Protection against Ischemia/Reperfusion Injury in Rat Hearts. AB - AIMS: Our previous studies demonstrated that remote electro-stimulation (RES) increased myocardial GSK3 phosphorylation and attenuated ischemia/ reperfusion (I/R) injury in rat hearts. However, the role of various opioid receptors (OR) subtypes in preconditioned RES-induced myocardial protection remains unknown. We investigated the role of OR subtype signaling in RES-induced cardioprotection against I/R injury of the rat heart. METHODS & RESULTS: Male Spraque-Dawley rats were used. RES was performed on median nerves area with/without pretreatment with various receptors antagonists such as opioid receptor (OR) subtype receptors (KOR, DOR, and MOR). The expressions of Akt, GSK3, and PKCepsilon expression were analyzed by Western blotting. When RES was preconditioned before the I/R model, the rat's hemodynamic index, infarction size, mortality and serum CK-MB were evaluated. Our results showed that Akt, GSK3 and PKCepsilon expression levels were significantly increased in the RES group compared to the sham group, which were blocked by pretreatment with specific antagonists targeting KOR and DOR, but not MOR subtype. Using the I/R model, the duration of arrhythmia and infarct size were both significantly attenuated in RES group. The mortality rates of the sham RES group, the RES group, RES group + KOR antagonist, RES group + DOR/MOR antagonists (KOR left), RES group + DOR antagonist, and RES group + KOR/MOR antagonists (DOR left) were 50%, 20%, 67%, 13%, 50% and 55%, respectively. CONCLUSION: The mechanism of RES-induced myocardial protection against I/R injury seems to involve multiple target pathways such as Akt, KOR and/or DOR signaling. PMID- 26430760 TI - Correction: Pelvic Belt Effects on Health Outcomes and Functional Parameters of Patients with Sacroiliac Joint Pain. PMID- 26430761 TI - Preterm birth and/or low birth weight are associated with periodontal disease and the increased placental immunohistochemical expression of inflammatory markers. AB - The objective of this study was to determine whether gynecological and periodontal clinical parameters and the immunohistochemical expression in placental chorionic villi of the markers cyclooxygenase-2 (COX-2), interleukin (IL)-1beta, vascular endothelial growth factor receptor 1 (VEGFR1), podoplanin, and Heat Shock Protein 70 (HSP70) are associated with preterm birth (PB) and/or low birth weight (LBW) neonates. MATERIAL AND METHODS: An observational case control study was performed in 130 puerperal women: mothers of PB/LBW neonates (cases, n=65) and mothers of full-term normal-weight neonates (controls, n=65). Data were gathered from all participants on socio-demographic, gynecological, and periodontal variables and on placental immunohistochemical COX-2, IL-1beta, VEGFR1, podoplanin, and HSP70 expression. RESULTS: Among the 42 women with mild/moderate periodontitis or gingivitis, the studied periodontal variables were significantly worse and the placental COX-2 (p=0.043), HSP70 (p=0.001), IL-1beta (p=0.001), VEGFR1 (p=0.032), and podoplanin (p=0.058) expressions were significantly higher in the cases than in the controls. In comparison to the mothers without periodontitis, only COX-2 (p=0.026) and VEGFR1 (p=0.005) expressions were significantly increased in those with the disease. Increased COX 2 values were detected in the women with a history of genitourinary infection (p=0.036), premature rupture of membrane (p=0.012), or drug treatment (p=0.050). CONCLUSIONS: The etiology of preterm birth and/or low birth weight is multifactorial and involves consumption habits, social-health factors, and infectious episodes. These adverse pregnancy outcomes were associated with periodontitis and the increased placental expression of IL-1beta, COX-2, VEGFR1, and HSP70. PMID- 26430763 TI - Oscillatory Positive Expiratory Pressure in Chronic Obstructive Pulmonary Disease. AB - Evidence-based guidance for the use of airway clearance techniques (ACT) in chronic obstructive pulmonary disease (COPD) is lacking in-part because well established measurements of pulmonary function such as the forced expiratory volume in 1s (FEV1) are relatively insensitive to ACT. The objective of this crossover study was to evaluate daily use of an oscillatory positive expiratory pressure (oPEP) device for 21-28 days in COPD patients who were self-identified as sputum-producers or non-sputum-producers. COPD volunteers provided written informed consent to daily oPEP use in a randomized crossover fashion. Participants completed baseline, crossover and study-end pulmonary function tests, St. George's Respiratory Questionnaire (SGRQ), Patient Evaluation Questionnaire (PEQ), Six-Minute Walk Test and (3)He magnetic resonance imaging (MRI) for the measurement of ventilation abnormalities using the ventilation defect percent (VDP). Fourteen COPD patients, self-identified as sputum-producers and 13 COPD-non-sputum-producers completed the study. Post-oPEP, the PEQ-ease bringing-up-sputum was improved for sputum-producers (p = 0.005) and non-sputum producers (p = 0.04), the magnitude of which was greater for sputum-producers (p = 0.03). There were significant post-oPEP improvements for sputum-producers only for FVC (p = 0.01), 6MWD (p = 0.04), SGRQ total score (p = 0.01) as well as PEQ patient-global-assessment (p = 0.02). Clinically relevant post-oPEP improvements for PEQ-ease-bringing-up-sputum/PEQ-patient-global-assessment/SGRQ/VDP were observed in 8/7/9/6 of 14 sputum-producers and 2/0/3/3 of 13 non-sputum producers. The post-oPEP change in (3)He MRI VDP was related to the change in PEQ ease-bringing-up-sputum (r = 0.65, p = 0.0004) and FEV1 (r = -0.50, p = 0.009). In COPD patients with chronic sputum production, PEQ and SGRQ scores, FVC and 6MWD improved post-oPEP. FEV1 and PEQ-ease-bringing-up-sputum improvements were related to improved ventilation providing mechanistic evidence to support oPEP use in COPD. Clinical Trials # NCT02282189 and NCT02282202. PMID- 26430762 TI - Identification of Target Genes Involved in Wound Healing Angiogenesis of Endothelial Cells with the Treatment of a Chinese 2-Herb Formula. AB - Angiogenesis is vitally important in diabetic wound healing. We had previously demonstrated that a Chinese 2-herb formula (NF3) significantly stimulated angiogenesis of HUVEC in wound healing. However, the molecular mechanism has not yet been elucidated. In line with this, global expression profiling of NF3 treated HUVEC was performed so as to assess the regulatory role of NF3 involved in the underlying signaling pathways in wound healing angiogenesis. The microarray results illustrated that different panels of differentially expressed genes were strictly governed in NF3-treated HUVEC in a time-regulated manner. The microarray analysis followed by qRT-PCR and western blotting verification of NF3 treated HUVEC at 6 h revealed the involvement of various genes in diverse biological process, e.g., MAP3K14 in anti-inflammation; SLC5A8 in anti tumorogenesis; DNAJB7 in protein translation; BIRC5, EPCAM, INSL4, MMP8 and NPR3 in cell proliferation; CXCR7, EPCAM, HAND1 and MMP8 in migration; CXCR7, EPCAM and MMP8 in tubular formation; and BIRC5, CXCR7, EPCAM, HAND1, MMP8 and UBD in angiogenesis. After 16 h incubation of NF3, other sets of genes were shown with differential expression in HUVEC, e.g., IL1RAPL2 and NR1H4 in anti-inflammation; miR28 in anti-tumorogenesis; GRIN1 and LCN1 in anti-oxidation; EPB41 in intracellular signal transduction; PRL and TFAP2A in cell proliferation; miR28, PRL and SCG2 in cell migration; PRL in tubular formation; and miR28, NR1H4 and PRL in angiogenesis. This study provided concrete scientific evidence in support of the regulatory role of NF3 on endothelial cells involved in wound healing angiogenesis. PMID- 26430764 TI - Mitochondrial Profile and Responses to TGF-beta Ligands in Keratoconus. AB - PURPOSE: Keratoconus (KC) is a complex corneal dystrophy with multifactorial etiology. Previous studies have shown evidence of mitochondrial abnormalities in KC; however, the exact cause of these abnormalities remains unknown. The aim of this study was to identify if transforming growth factor-beta (TGF-beta) isoforms play a role in the regulation of mitochondrial proteins in human KC cells (HKC). MATERIALS AND METHODS: Human corneal fibroblasts (HCF) and HKC were isolated and cultured for 4 weeks in three different conditions: (a) CONTROL: MEM + 10%FBS, (b) MEM + 10%FBS + TGF-beta1 and (c) MEM + 10%FBS + TGF-beta3. All samples were processed for mitochondrial damage analysis using real-time PCR. RESULTS: We quantified and analyzed 84 mitochondrial and five housekeeping genes in HCFs and HKCs. Our data showed that when TGF-beta1 and/or TGF-beta3 were compared with control in HCFs, nine genes were significantly different; however, no genes were significantly regulated by the TGF-beta isoforms in HKCs. Significant differences were also seen in seven genes when HFCs were compared with HKCs, in all three conditions. CONCLUSIONS: Overall, our data support the growing consensus that mitochondrial dysfunction is a key player in KC disease. These in vitro data show clear links between mitochondrial function and TGF-beta isoforms, with TGF-beta1 severely disrupting KC-mitochondrial function, while TGF-beta3 maintained it, thus suggesting that TGF-beta may play a role in KC-disease treatment. PMID- 26430765 TI - Identification of Pol IV and RDR2-dependent precursors of 24 nt siRNAs guiding de novo DNA methylation in Arabidopsis. AB - In Arabidopsis thaliana, abundant 24 nucleotide small interfering RNAs (24 nt siRNA) guide the cytosine methylation and silencing of transposons and a subset of genes. 24 nt siRNA biogenesis requires nuclear RNA polymerase IV (Pol IV), RNA dependent RNA polymerase 2 (RDR2) and DICER-like 3 (DCL3). However, siRNA precursors are mostly undefined. We identified Pol IV and RDR2-dependent RNAs (P4R2 RNAs) that accumulate in dcl3 mutants and are diced into 24 nt RNAs by DCL3 in vitro. P4R2 RNAs are mostly 26-45 nt and initiate with a purine adjacent to a pyrimidine, characteristics shared by Pol IV transcripts generated in vitro. RDR2 terminal transferase activity, also demonstrated in vitro, may account for occasional non-templated nucleotides at P4R2 RNA 3' termini. The 24 nt siRNAs primarily correspond to the 5' or 3' ends of P4R2 RNAs, suggesting a model whereby siRNAs are generated from either end of P4R2 duplexes by single dicing events. PMID- 26430766 TI - Rapid cell-free forward engineering of novel genetic ring oscillators. AB - While complex dynamic biological networks control gene expression in all living organisms, the forward engineering of comparable synthetic networks remains challenging. The current paradigm of characterizing synthetic networks in cells results in lengthy design-build-test cycles, minimal data collection, and poor quantitative characterization. Cell-free systems are appealing alternative environments, but it remains questionable whether biological networks behave similarly in cell-free systems and in cells. We characterized in a cell-free system the 'repressilator', a three-node synthetic oscillator. We then engineered novel three, four, and five-gene ring architectures, from characterization of circuit components to rapid analysis of complete networks. When implemented in cells, our novel 3-node networks produced population-wide oscillations and 95% of 5-node oscillator cells oscillated for up to 72 hr. Oscillation periods in cells matched the cell-free system results for all networks tested. An alternate forward engineering paradigm using cell-free systems can thus accurately capture cellular behavior. PMID- 26430767 TI - Endoscopic ultrasound-guided FNA and ProCore biopsy in sampling pancreatic and intra-abdominal masses. AB - BACKGROUND: ProCore fine-needle biopsy (FNB) was introduced to improve the diagnostic yield of endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) sampling. The aim of this study was to evaluate EUS-guided sampling of intra-abdominal masses and compare the diagnostic utility of conventional EUS-FNA and ProCore FNB. METHODS: EUS-guided biopsy samples (FNA and/or EchoTip ProCore FNB) were retrospectively retrieved over the course of 23 months. Clinical findings, pathology reports, and available histological materials were reviewed. All cell blocks were reviewed, and their cellularity was scored (range, 0-3). RESULTS: Fifty-six masses from 58 cases were acquired, and they included 40 pancreatic sites and 16 other intra-abdominal sites. Among the 31 FNB-only cases, 71% were satisfactory, 65% were positive for malignancy at the time of final diagnosis, and their cell blocks were moderately cellular. For the cases with both FNB and FNA performed, more FNB samples than FNA samples were satisfactory (83% vs 76%) and were positive for malignancy (65% vs 48%) at final diagnosis, and the former had more cellular cell blocks (mean score, 1.58 vs 1.29); however, the differences were not statistically significant. Significantly more FNB samples were used for immunostains (48% vs 10%; P = .005). CONCLUSIONS: These data show that a wide variety of intra-abdominal masses were amenable to sampling by ProCore FNB. In this subset of cases with prior/concurrent indeterminate FNAs, FNB showed slightly better diagnostic yield, and had more cellular tissue samples and more material for ancillary studies than matched FNAs. PMID- 26430768 TI - Efficacy and safety of biapenem against lower respiratory tract infections in elderly Chinese patients and optimal dosing regimen based on pharmacokinetic/pharmacodynamic analysis. AB - The present study evaluated the efficacy and safety of biapenem in elderly Chinese patients with lower respiratory tract infections (LRTIs) and proposed optimal dosage regimen on the basis of pharmacokinetic/pharmacodynamic (PK/PD) analysis. The clinical efficacy, bacterial eradication and comprehensive therapeutic effect rates of biapenem were 70.3 (78/111), 68.5 (37/54) and 61.1% (33/54), respectively. Drug-related adverse reactions were seen in 12.6% of patients (14/111). The total protein level, Acute Physiology and Chronic Health Evaluation (APACHE) II score, %fT>MIC, fAUC24/MIC and fCmax/MIC values of patients had significant impacts (P < 0.05) on clinical and bacteriological efficacy. However, logistic regression analysis showed that only %fT>MIC independently influenced comprehensive therapeutic effect (P < 0.01, odds ratio = 1.064). The cut-off value for predicting comprehensive therapeutic effect using %fT>MIC was 75.0%; the sensitivity and specificity were 87.9 and 85.7%, respectively. Monte Carlo simulations revealed that the usual dosage regimen (300 mg every 12 hours, 0.5 hour infusion) was considered to be insufficient to obtain satisfactory therapeutic outcomes against low susceptible pathogens for elderly Chinese patients with LRTIs (CLcr = 70 ml/min). PMID- 26430769 TI - Cationic Peptides Facilitate Iron-induced Mutagenesis in Bacteria. AB - Pseudomonas aeruginosa is the causative agent of chronic respiratory infections and is an important pathogen of cystic fibrosis patients. Adaptive mutations play an essential role for antimicrobial resistance and persistence. The factors that contribute to bacterial mutagenesis in this environment are not clear. Recently it has been proposed that cationic antimicrobial peptides such as LL-37 could act as mutagens in P. aeruginosa. Here we provide experimental evidence that mutagenesis is the product of a joint action of LL-37 and free iron. By estimating mutation rate, mutant frequencies and assessing mutational spectra in P. aeruginosa treated either with LL-37, iron or a combination of both we demonstrate that mutation rate and mutant frequency were increased only when free iron and LL-37 were present simultaneously. Colistin had the same effect. The addition of an iron chelator completely abolished this mutagenic effect, suggesting that LL-37 enables iron to enter the cells resulting in DNA damage by Fenton reactions. This was also supported by the observation that the mutational spectrum of the bacteria under LL-37-iron regime showed one of the characteristic Fenton reaction fingerprints: C to T transitions. Free iron concentration in nature and within hosts is kept at a very low level, but the situation in infected lungs of cystic fibrosis patients is different. Intermittent bleeding and damage to the epithelial cells in lungs may contribute to the release of free iron that in turn leads to generation of reactive oxygen species and deterioration of the respiratory tract, making it more susceptible to the infection. PMID- 26430770 TI - Characterization of a Novel Dengue Serotype 4 Virus-Specific Neutralizing Epitope on the Envelope Protein Domain III. AB - The dengue virus (DENV) envelope protein domain III (ED3) has been suggested to contain receptor recognition sites and the critical neutralizing epitopes. Up to date, relatively little work has been done on fine mapping of neutralizing epitopes on ED3 for DENV4. In this study, a novel mouse type-specific neutralizing antibody 1G6 against DENV4 was obtained with both prophylactic and therapeutic effects. The epitope was mapped to residues 387-390 of DENV4 envelope protein. Furthermore, site-directed mutagenesis assay identified two critical residues (T388 and H390). The epitope is variable among different DENV serotypes but is highly conserved among four DENV4 genotypes. Affinity measurement showed that naturally occurring variations in ED3 outside the epitope region did not alter the binding of mAb 1G6. These findings expand our understanding of the interactions between neutralizing antibodies and the DENV4 and may be valuable for rational design of DENV vaccines and antiviral drugs. PMID- 26430772 TI - Violence Against Older Women: Activism, Social Justice, and Social Change. AB - The Older Women's Network (OWN) of New South Wales (NSW) is an activist organization dedicated to promoting the rights of older women, preventing gender- and aged-based violence, and working toward social justice and social change. In 2007, the OWN NSW Inc. initiated the Prevention of Violence Against Older Women Working Party to research and document current knowledge and understanding of violence against older women; focus public attention on this issue; and bring about changes in public perceptions, policy, and practice. Presented here is an overview of the major achievements of the OWN Working Party, including a meta analysis of three research projects, with their findings, recommendations, and outcomes. In conclusion, research conducted by activist organizations such as OWN can make a significant contribution to furthering our understanding of violence against older women and to policy and practice. PMID- 26430771 TI - Frequency and Distribution of Refractive Error in Adult Life: Methodology and Findings of the UK Biobank Study. AB - PURPOSE: To report the methodology and findings of a large scale investigation of burden and distribution of refractive error, from a contemporary and ethnically diverse study of health and disease in adults, in the UK. METHODS: U K Biobank, a unique contemporary resource for the study of health and disease, recruited more than half a million people aged 40-69 years. A subsample of 107,452 subjects undertook an enhanced ophthalmic examination which provided autorefraction data (a measure of refractive error). Refractive error status was categorised using the mean spherical equivalent refraction measure. Information on socio demographic factors (age, gender, ethnicity, educational qualifications and accommodation tenure) was reported at the time of recruitment by questionnaire and face-to-face interview. RESULTS: Fifty four percent of participants aged 40 69 years had refractive error. Specifically 27% had myopia (4% high myopia), which was more common amongst younger people, those of higher socio-economic status, higher educational attainment, or of White or Chinese ethnicity. The frequency of hypermetropia increased with age (7% at 40-44 years increasing to 46% at 65-69 years), was higher in women and its severity was associated with ethnicity (moderate or high hypermetropia at least 30% less likely in non-White ethnic groups compared to White). CONCLUSIONS: Refractive error is a significant public health issue for the UK and this study provides contemporary data on adults for planning services, health economic modelling and monitoring of secular trends. Further investigation of risk factors is necessary to inform strategies for prevention. There is scope to do this through the planned longitudinal extension of the UK Biobank study. PMID- 26430773 TI - Corneal Confocal Microscopy Detects Small Fibre Neuropathy in Patients with Upper Gastrointestinal Cancer and Nerve Regeneration in Chemotherapy Induced Peripheral Neuropathy. AB - There are multiple neurological complications of cancer and its treatment. This study assessed the utility of the novel non-invasive ophthalmic technique of corneal confocal microscopy in identifying neuropathy in patients with upper gastrointestinal cancer before and after platinum based chemotherapy. In this study, 21 subjects with upper gastrointestinal (oesophageal or gastric) cancer and 21 healthy control subjects underwent assessment of neuropathy using the neuropathy disability score, quantitative sensory testing for vibration perception threshold, warm and cold sensation thresholds, cold and heat induced pain thresholds, nerve conduction studies and corneal confocal microscopy. Patients with gastro-oesophageal cancer had higher heat induced pain (P = 0.04) and warm sensation (P = 0.03) thresholds with a significantly reduced sural sensory (P<0.01) and peroneal motor (P<0.01) nerve conduction velocity, corneal nerve fibre density (CNFD), nerve branch density (CNBD) and nerve fibre length (CNFL) (P<0.0001). Furthermore, CNFD correlated significantly with the time from presentation with symptoms to commencing chemotherapy (r = -0.54, P = 0.02), and CNFL (r = -0.8, P<0.0001) and CNBD (r = 0.63, P = 0.003) were related to the severity of lymph node involvement. After the 3rd cycle of chemotherapy, there was no change in any measure of neuropathy, except for a significant increase in CNFL (P = 0.003). Corneal confocal microscopy detects a small fibre neuropathy in this cohort of patients with upper gastrointestinal cancer, which was related to disease severity. Furthermore, the increase in CNFL after the chemotherapy may indicate nerve regeneration. PMID- 26430775 TI - Thermal Analysis by Structural Characterization as a Method for Assessing Heterogeneity in Complex Solid Pharmaceutical Dosage Forms. AB - Characterizing inter- and intrasample heterogeneity of solid and semisolid pharmaceutical products is important both for rational design of dosage forms and subsequent quality control during manufacture; however, most pharmaceutical products are multicomponent formulations that are challenging in this regard. Thermal analysis, in particular differential scanning calorimetry, is commonly used to obtain structural information, such as degree of crystallinity, or identify the presence of a particular polymorph, but the results are an average over the whole sample; it cannot directly provide information about the spatial distribution of phases. This study demonstrates the use of a new thermo-optical technique, thermal analysis by structural characterization (TASC), that can provide spatially resolved information on thermal transitions by applying a novel algorithm to images acquired by hot stage microscopy. We determined that TASC can be a low cost, relatively rapid method of characterizing heterogeneity and other aspects of structure. In the examples studied, it was found that high heating rates enabled screening times of 3-5 min per sample. In addition, this study demonstrated the higher sensitivity of TASC for detecting the metastable form of polyethylene glycol (PEG) compared to conventional differential scanning calorimetry (DSC). This preliminary work suggests that TASC will be a worthwhile additional tool for characterizing a broad range of materials. PMID- 26430774 TI - Transient Elastography in End-Stage Renal Disease Patients on Hemodialysis: The Effect of Net Fluid Withdrawal. AB - BACKGROUND/AIMS: The impact of volume status on liver stiffness measurement (LSM) as measured by transient elastography (TE) as in end-stage renal disease (ESRD) was unclear. We evaluated LSM before and after hemodialysis (HD) and identified the associated factors if the difference of LSM existed. METHODS: A cross sectional study was conducted in ESRD patients on regular HD. Subjects underwent TE and bioelectrical impedance before and after HD. RESULTS: Thirty-six patients were enrolled. Mean (SD) net fluid withdrawal volume (NFWV) per session was 2.55 (0.9) l. Median (range) pre- and post-HD LSMs were 5.38 (2.8-25.7) and 5.4 (2.8 26) kPa, respectively (p = 0.712). Mean differences of pre- and post-HD LSMs correlated with NFWV (r = 0.49, 95% CI 0.19-0.71, p = 0.002). CONCLUSION: In ESRD on regular HD, LSM is not affected by HD. TE can be done before or after HD with similar results. However, fluid excess at pre-HD can cause inaccurately high LSM. PMID- 26430776 TI - Vitamin D Deficiency Increases the Risk for Moderate to Severe Disease Activity in Crohn's Disease Patients in South Africa, Measured by the Harvey Bradshaw Index. AB - OBJECTIVE: Vitamin D has immunoregulatory properties and appears to influence disease outcomes in patients with Crohn's disease (CD). The primary aim of this study was to evaluate the association between vitamin D status and CD activity in South Africa. METHODS: In a cross-sectional study performed between September 2011 and January 2013, serum 25-hydroxyvitamin D (25(OH)D) was measured in 186 consecutive patients with CD seen at 2 inflammatory bowel disease (IBD) centers and 199 healthy controls in the Western Cape, South Africa. Lifestyle and clinical variables were identified using an investigator-administered questionnaire, as well as clinical examination and patient case notes. Vitamin D status was evaluated in 2 ways: <= 20 ng/mL vs >= 21 ng/mL and <= 29 ng/mL vs >= 30 ng/mL. Disease activity was measured by the Harvey Bradshaw Index (HBI). Various 25(OH)D threshold concentrations for predicting a higher HBI score were also investigated. RESULTS: On multiple log-binomial regression analysis, higher HBI scores and not having taken vitamin D supplementation in the 6 months prior to enrollment were identified as risk factors for vitamin D deficiency in patients with CD, defined either as <= 20 ng/mL or as <= 29 ng/mL (p < 0.03). Compared to patients with HBI < 5, those with HBI >= 8 were 2.5 times more likely to have 25(OH)D concentrations <= 21 ng/mL (prevalence risk [PR] = 2.5; 95% confidence interval [CI], 1.21-6.30). The risk was similar, though not as high, when defined as <= 29 ng/mL (PR = 2.0; 95% CI, 1.13-3.51). When vitamin D deficiency was defined as <20, <30, <40, and <50 ng/mL, the sensitivity and specificity obtained were 44.9% and 78.8%; 75.5% and 62.4%; 86.7% and 44.7%; and 92.9% and 23.5%, respectively (area under the curve = 0.71; p < 0.0001). CONCLUSION: Low serum 25(OH)D was associated with increased CD activity in a South African cohort. PMID- 26430777 TI - Stanhope Speer, Physician and Alpinist: In 1853, First to Describe Mountain Sickness? AB - In 1853, Stanhope Templeman Speer published a two-part paper in The Association Medical Journal on Mountain Sickness. Speer was a physician who had worked at the Brompton Hospital for Chest Diseases in London and had been Professor of Medicine in Dublin. He was also an Alpine climber and had made the first ascent of one of the Wetterhorn peaks. His article ran to ten and a half pages in the Journal and to 50 pages in a reprint. It consists of anecdotal accounts of symptoms suffered at altitude from the literature and from his own experiences in the European Alps. He asks three pertinent questions. Is there a condition of mountain sickness? Are these symptoms felt by all persons alike and at the same height? What are the causes, and whence the explanation of such phenomena? In the course of the article, he answers the first two questions but, like us, 162 years later, is unable to answer the third. This article seeks to present Speer's original work and such facts about his life as I have been able to discover. PMID- 26430778 TI - Challenge of mimicking the influences of the cellular environment on RNA structure by PEG-induced macromolecular crowding. AB - There are large differences between the cellular environment and the conditions widely used to study RNA in vitro. SHAPE RNA structure probing in Escherichia coli cells has shown that the cellular environment stabilizes both long-range and local tertiary interactions in the adenine riboswitch aptamer domain. Synthetic crowding agents are widely used to understand the forces that stabilize RNA structure and in efforts to recapitulate the cellular environment under simplified experimental conditions. Here, we studied the structure and ligand binding ability of the adenine riboswitch in the presence of the macromolecular crowding agent, polyethylene glycol (PEG). Ethylene glycol and low-molecular mass PEGs destabilized RNA structure and caused the riboswitch to sample secondary structures different from those observed in simple buffered solutions or in cells. In the presence of larger PEGs, longer-range loop-loop interactions were more similar to those in cells than in buffer alone, consistent with prior work showing that larger PEGs stabilize compact RNA states. Ligand affinity was weakened by low-molecular mass PEGs but increased with high-molecular mass PEGs, indicating that PEG cosolvents exert complex chemical and steric effects on RNA structure. Regardless of polymer size, however, nucleotide-resolution structural characteristics observed in cells were not recapitulated in PEG solutions. Our results reveal that the cellular environment is difficult to recapitulate in vitro; mimicking the cellular state will likely require a combination of crowding agents and other chemical species. PMID- 26430779 TI - The Introduction of Human Heme Oxygenase-1 and Soluble Tumor Necrosis Factor alpha Receptor Type I With Human IgG1 Fc in Porcine Islets Prolongs Islet Xenograft Survival in Humanized Mice. AB - Apoptosis during engraftment and inflammation induce poor islet xenograft survival. We aimed to determine whether overexpression of human heme oxygenase-1 (HO-1) or soluble tumor necrosis factor-alpha receptor type I with human IgG1 Fc (sTNF-alphaR-Fc) in porcine islets could improve islet xenograft survival. Adult porcine islets were transduced with adenovirus containing human HO-1, sTNF-alphaR Fc, sTNF-alphaR-Fc/HO-1 or green fluorescent protein (control). Humanized mice were generated by injecting human cord blood-derived CD34(+) stem cells into NOD scid-IL-2Rgamma(null) mice. Both HO-1 and sTNF-alphaR-Fc reduced islet apoptosis under in vitro hypoxia or cytokine stimuli and suppressed RANTES induction without compromising insulin secretion. Introduction of either gene into islets prolonged islet xenograft survival in pig-to-humanized mice transplantation. The sTNF-alphaR-Fc/HO-1 group showed the best glucose tolerance. Target genes were successfully expressed in islet xenografts. Perigraft infiltration of macrophages and T cells was suppressed with decreased expression of RANTES, tumor necrosis factor-alpha and IL-6 in treatment groups; however, frequency of pig-specific interferon-gamma-producing T cells was not decreased, and humoral response was not significant in any group. Early apoptosis of islet cells was suppressed in the treatment groups. In conclusion, overexpression of HO-1 or sTNF-alphaR-Fc in porcine islets improved islet xenograft survival by suppressing both apoptosis and inflammation. HO-1 or sTNF-alphaR-Fc transgenic pigs have potential for islet xenotransplantation. PMID- 26430780 TI - Oxygenation of Organoboronic Acids by a Nonheme Iron(II) Complex: Mimicking Boronic Acid Monooxygenase Activity. AB - Phenolic compounds are important intermediates in the bacterial biodegradation of aromatic compounds in the soil. An Arthrobacter sp. strain has been shown to exhibit boronic acid monooxygenase activity through the conversion of different substituted phenylboronic acids to the corresponding phenols using dioxygen. While a number of methods have been reported to cleave the C-B bonds of organoboronic acids, there is no report on biomimetic iron complex exhibiting this activity using dioxygen as the oxidant. In that direction, we have investigated the reactivity of a nucleophilic iron-oxygen oxidant, generated upon oxidative decarboxylation of an iron(II)-benzilate complex [(Tp(Ph2))Fe(II)(benzilate)] (Tp(Ph2) = hydrotris(3,5-diphenyl-pyrazol-1 yl)borate), toward organoboronic acids. The oxidant converts different aryl/alkylboronic acids to the corresponding oxygenated products with the incorporation of one oxygen atom from dioxygen. This method represents an efficient protocol for the oxygenation of boronic acids with dioxygen as the terminal oxidant. PMID- 26430781 TI - Interleukin-12 Immunomodulation Delays the Onset of Lethal Peritoneal Disease of Ovarian Cancer. AB - The omental fat band (OFB) is the predominant site for metastatic seeding of ovarian cancer. Previously, we highlighted the influx and accumulation of neutrophils and macrophages in the OFB following syngeneic ovarian cancer cell seeding as an important factor in the development of a protumorigenic cascade. Here we investigated localized immunomodulation as a means of promoting a successful protective response. As an important TH1-type immunomodulator, interleukin (IL)-12 has previously been investigated clinically as an anticancer therapeutic. However, systemic IL-12 administration was associated with serious side effects, galvanizing the development of immune or accessory cells engineered to express secreted or membrane-bound IL-12 (mbIL-12). Using an mbIL-12 expressing cell variant, we demonstrate that localized IL-12 in the tumor microenvironment significantly delays disease development. The mbIL-12-mediated decrease in tumor burden was associated with a significant reduction in neutrophil and macrophage infiltration in the OFB, and correlated with a reduced expression of neutrophil and macrophage chemoattractants (CXCL1, -2, -3 and CCL2, -7). Vaccination with mitotically impaired tumor cells did not confer protection against subsequent tumor challenge, indicating that IL-12 did not impact the immunogenicity of the cancer cells. Our findings are in agreement with previous reports suggesting that IL-12 may hold promise when delivered in a targeted and sustained manner to the omental microenvironment. Furthermore, resident cells within the omental microenvironment may provide a reservoir that can be activated and mobilized to prevent metastatic seeding within the peritoneum and, therefore, may be targets for chemotherapeutics. PMID- 26430782 TI - Proposal of a new staging system for intrahepatic cholangiocarcinoma: Analysis of surgical patients from a nationwide survey of the Liver Cancer Study Group of Japan. AB - BACKGROUND: In the current American Joint Committee on Cancer/International Union Against Cancer staging system (seventh edition) for intrahepatic cholangiocarcinoma (ICC), tumor size was excluded, and periductal invasion was added as a new tumor classification-defining factor. The objective of the current report was to propose a new staging system for ICC that would be better for stratifying the survival of patients based on data from the nationwide Liver Cancer Study Group of Japan database. METHODS: Of 756 patients who underwent surgical resection for ICC between 2000 and 2005, multivariate analyses of the clinicopathologic factors of 419 patients who had complete data sets were performed to elucidate relevant factors for inclusion in a new tumor classification and staging system. RESULTS: Overall survival data were best stratified using a cutoff value of 2 cm using a minimal P value approach to discriminate patient survival. The 5-year survival rate of 15 patients who had ICC measuring <= 2 cm in greatest dimension without lymph node metastasis or vascular invasion was 100%, and this cohort was defined as T1. Multivariate analysis of prognostic factors for 267 patients with lymph node-negative and metastasis-negative (N0M0) disease indicated that the number of tumors, the presence arterial invasion, and the presence major biliary invasion were independent and significant prognostic factors. The proposed new system, which included tumor number, tumor size, arterial invasion, and major biliary invasion for tumor classification, provided good stratification of overall patient survival according to disease stage. Macroscopic periductal invasion was associated with major biliary invasion and an inferior prognosis. CONCLUSIONS: The proposed new staging system, which includes a tumor cutoff size of 2 cm and major biliary invasion, may be useful for assigning patients to surgery. PMID- 26430783 TI - Patterns of Emphysema Heterogeneity. AB - BACKGROUND: Although lobar patterns of emphysema heterogeneity are indicative of optimal target sites for lung volume reduction (LVR) strategies, the presence of segmental, or sublobar, heterogeneity is often underappreciated. OBJECTIVE: The aim of this study was to understand lobar and segmental patterns of emphysema heterogeneity, which may more precisely indicate optimal target sites for LVR procedures. METHODS: Patterns of emphysema heterogeneity were evaluated in a representative cohort of 150 severe (GOLD stage III/IV) chronic obstructive pulmonary disease (COPD) patients from the COPDGene study. High-resolution computerized tomography analysis software was used to measure tissue destruction throughout the lungs to compute heterogeneity (>=15% difference in tissue destruction) between (inter-) and within (intra-) lobes for each patient. Emphysema tissue destruction was characterized segmentally to define patterns of heterogeneity. RESULTS: Segmental tissue destruction revealed interlobar heterogeneity in the left lung (57%) and right lung (52%). Intralobar heterogeneity was observed in at least one lobe of all patients. No patient presented true homogeneity at a segmental level. There was true homogeneity across both lungs in 3% of the cohort when defining heterogeneity as >=30% difference in tissue destruction. CONCLUSION: Many LVR technologies for treatment of emphysema have focused on interlobar heterogeneity and target an entire lobe per procedure. Our observations suggest that a high proportion of patients with emphysema are affected by interlobar as well as intralobar heterogeneity. These findings prompt the need for a segmental approach to LVR in the majority of patients to treat only the most diseased segments and preserve healthier ones. PMID- 26430785 TI - Knowledge and Perceptions of Highly Pathogenic Avian Influenza (HPAI) among Poultry Traders in Live Bird Markets in Bali and Lombok, Indonesia. AB - Highly Pathogenic Avian Influenza (HPAI) has been prevalent in Indonesia since 2003 causing major losses to poultry production and human deaths. Live bird markets are considered high risk areas due to the density of large numbers of mixed poultry species of unknown disease status. Understanding trader knowledge and perceptions of HPAI and biosecurity is critical to reducing transmission risk and controlling the disease. An interview-administered survey was conducted at 17 live bird markets on the islands of Bali and Lombok in 2008 and 2009. A total of 413 live poultry traders were interviewed. Respondents were mostly male (89%) with a mean age of 45 years (range: 19-81). The main source of AI information was TV (78%), although personal communication was also identified to be an important source, particularly among female traders (60%) and respondents from Bali (43%). More than half (58%) of live poultry traders interviewed knew that infected birds can transmit HPAI viruses but were generally unaware that viruses can be introduced to markets by fomites. Cleaning cages and disposing of sick and dead birds were recognized as the most important steps to prevent the spread of disease by respondents. Two thirds (n = 277) of respondents were unwilling to report sudden or suspicious bird deaths to authorities. Bali vendors perceive biosecurity to be of higher importance than Lombok vendors and are more willing to improve biosecurity within markets than traders in Lombok. Collectors and traders selling large numbers (>214) of poultry, or selling both chickens and ducks, have better knowledge of HPAI transmission and prevention than vendors or traders selling smaller quantities or only one species of poultry. Education was strongly associated with better knowledge but did not influence positive reporting behavior. Our study reveals that most live poultry traders have limited knowledge of HPAI transmission and prevention and are generally reluctant to report bird deaths. Greater efforts are needed to engage local government, market managers and traders in education and awareness programs, regulatory measures and incentive mechanisms. Understanding and evaluating the social responses to such an integrated approach could lead to more effective HPAI prevention and control. PMID- 26430786 TI - Trans-generational Immune Priming Protects the Eggs Only against Gram-Positive Bacteria in the Mealworm Beetle. AB - In many vertebrates and invertebrates, offspring whose mothers have been exposed to pathogens can exhibit increased levels of immune activity and/or increased survival to infection. Such phenomena, called "Trans-generational immune priming" (TGIP) are expected to provide immune protection to the offspring. As the offspring and their mother may share the same environment, and consequently similar microbial threats, we expect the immune molecules present in the progeny to be specific to the microbes that immune challenged the mother. We provide evidence in the mealworm beetle Tenebrio molitor that the antimicrobial activity found in the eggs is only active against Gram-positive bacteria, even when females were exposed to Gram-negative bacteria or fungi. Fungi were weak inducers of TGIP while we obtained similar levels of anti-Gram-positive activity using different bacteria for the maternal challenge. Furthermore, we have identified an antibacterial peptide from the defensin family, the tenecin 1, which spectrum of activity is exclusively directed toward Gram-positive bacteria as potential contributor to this antimicrobial activity. We conclude that maternal transfer of antimicrobial activity in the eggs of T. molitor might have evolved from persistent Gram-positive bacterial pathogens between insect generations. PMID- 26430787 TI - Metformin: A Novel but Controversial Drug in Cancer Prevention and Treatment. AB - Metformin, a biguanide derivative that is widely used for treating type 2 diabetes mellitus, has recently been shown to exert potential anticancer effects. Many retrospective data and laboratory studies suggest the idea that metformin has antineoplastic activity, but some other studies reach conflicting conclusions. Although the precise molecular mechanisms by which metformin affects various cancers have not been fully elucidated, activation of AMPK-dependent and AMPK-independent pathways along with energy metabolism aberration, cell cycle arrest and apoptosis or autophagy induction have emerged as crucial regulators in this process. In this Review, we describe the role of metformin in the prevention and treatment of a variety of cancers and summarize the molecular mechanisms that are currently well documented in the ability of metformin as an anticancer agent. In addition, the scientific and clinical hurdles regarding the potential role of metformin in cancer will be discussed. PMID- 26430784 TI - Amyloid-Related Memory Decline in Preclinical Alzheimer's Disease Is Dependent on APOE epsilon4 and Is Detectable over 18-Months. AB - High levels of beta-amyloid (Abeta) in the brain and carriage of the APOE epsilon4 allele have each been linked to cognitive impairment in cognitively normal (CN) older adults. However, the relationship between these two biomarkers and cognitive decline is unclear. The aim of this study was to investigate the relationship between cerebral Abeta level, APOE epsilon4 carrier status, and cognitive decline over 18 months, in 317 cognitively healthy (CN) older adults (47.6% males, 52.4% females) aged between 60 and 89 years (Mean = 69.9, SD = 6.8). Cognition was assessed using the Cogstate Brief Battery (CBB) and the California Verbal Learning Test, Second Edition (CVLT-II). Planned comparisons indicated that CN older adults with high Abeta who were also APOE epsilon4 carriers demonstrated the most pronounced decline in learning and working memory. In CN older adults who were APOE epsilon4 non-carriers, high Abeta was unrelated to cognitive decline in learning and working memory. Carriage of APOE epsilon4 in CN older adults with low Abeta was associated with a significantly increased rate of decline in learning and unexpectedly, improved cognitive performance on measures of verbal episodic memory over 18 months. These results suggest that Abeta and APOE epsilon4 interact to increase the rate of cognitive decline in CN older adults and provide further support for the use of Abeta and APOE epsilon4 as biomarkers of early Alzheimer's disease. PMID- 26430788 TI - Cohort Profile: Growing Up in Wales: The Environments for Healthy Living study. PMID- 26430789 TI - Cohort Profile: The UK Women's Cohort Study (UKWCS). PMID- 26430790 TI - Time trends in avoidable cancer mortality in Switzerland and neighbouring European countries 1996-2010. AB - QUESTION UNDER STUDY: What are the trends in avoidable cancer mortality in Switzerland and neighbouring countries? METHODS: Mortality data and population estimates 1996-2010 were obtained from the Swiss Federal Statistical Office for Switzerland and the World Health Organization Mortality Database (http://www.who.int/healthinfo/mortality_data/en/) for Austria, Germany, France and Italy. Age standardised mortality rates (ASMRs, European standard) per 100 000 person-years were calculated for the population <75 years old by sex for the following groups of cancer deaths: (1) avoidable through primary prevention; (2) avoidable through early detection and treatment; (3) avoidable through improved treatment and medical care; and (4) remaining cancer deaths. To assess time trends in ASMRs, estimated annual percentage changes (EAPCs) with 95% confidence intervals (95% CIs) were calculated. RESULTS: In Switzerland and neighbouring countries cancer mortality in persons <75 years old continuously decreased 1996 2010. Avoidable cancer mortality decreased in all groups of avoidable cancer deaths in both sexes, with one exception. ASMRs for causes avoidable through primary prevention increased in females in all countries (in Switzerland from 16.2 to 20.3 per 100 000 person years, EAPC 2.0 [95% CI 1.4 to 2.6]). Compared with its neighbouring countries, Switzerland showed the lowest rates for all groups of avoidable cancer mortality in males 2008-2010. CONCLUSION: Overall avoidable cancer mortality decreased, indicating achievements in cancer care and related health policies. However, increasing trends in avoidable cancer mortality through primary prevention for females suggest there is a need in Switzerland and its European neighbouring countries to improve primary prevention. PMID- 26430791 TI - Managing Risk in Hodgkin Lymphoma. AB - Approximately 90% of patients with limited-stage Hodgkin lymphoma are cured. The cure rate in advanced-stage Hodgkin lymphoma is dramatically better than it once was, but it is still lower than the rate in patients with limited disease. The choice of treatment is based on several factors, including symptoms, disease stage, extent of tumor burden, and prognosis. Positron emission tomography scanning can be used to assess the patient's stage of disease, which can allow further individualization of therapy. Traditional frontline treatment options include doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and, for high risk patients, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP). Autologous stem cell transplantation cures approximately 50% of patients. The antibody-drug conjugate brentuximab vedotin is very active in relapsed/refractory Hodgkin lymphoma. Data presented at the 2014 meeting of the American Society of Hematology (ASH) showed that brentuximab vedotin was beneficial in several settings, including as consolidation therapy posttransplant in patients at high risk for relapse, as first-line salvage therapy in relapsed/refractory Hodgkin lymphoma prior to autologous hematopoietic cell transplantation, and in combination with bendamustine in relapsed/refractory disease. The ASH meeting also offered promising data on novel agents, such as the programmed cell death 1 (PD-1) inhibitors. In this monograph, 4 experts in the management of Hodgkin lymphoma discuss various aspects of the disease and provide their perspectives on the new data presented at the ASH meeting. PMID- 26430796 TI - Stable Tricyclic Antitubercular Ozonides Derived from Artemisinin. AB - New, highly stable tricyclic antitubercular ozonides 9 and 10 derived from artemisinin are reported in 39 and 9% yields, respectively. The ozonide groups of 9 and 10 were found to be stable under strong basic and acidic conditions. The absolute configuration of ozonides 9 was confirmed by X-ray crystallography. Ozonide 10 shows promising antitubercular activity against M. tuberculosis H37Ra and M. tuberculosis H37Rv with MIC values of 0.39 and 3.12 MUg/mL, respectively. PMID- 26430797 TI - Catalyst-Free Regioselective C-3 Thiocyanation of Imidazopyridines. AB - A direct and straightforward approach for highly regioselective thiocyanation of imidazoheterocycles through sp(2) C-H functionalization has been realized at room temperature. Various C-3 thiocyanated imidazopyridines are formed in moderate to good yield. The present method exhibits a mild and selective access to a variety of imidazopyridine derivatives of pharmacological interest. PMID- 26430798 TI - A vesicular stomatitis virus glycoprotein epitope-incorporated oncolytic adenovirus overcomes CAR-dependency and shows markedly enhanced cancer cell killing and suppression of tumor growth. AB - Utility of traditional oncolytic adenovirus (Ad) has been limited due to low expression of coxsackie and adenovirus receptor (CAR) in cancer cells which results in poor infectivity of Ads. Here with an aim of improving the efficiency of Ad's entry to the cell, we generated a novel tropism-expanded oncolytic Ad which contains the epitope of vesicular stomatitis virus glycoprotein (VSVG) at the HI-loop of Ad fiber. We generated 9 variants of oncolytic Ads with varying linkers and partial deletion to the fiber. Only one VSVG epitope-incorporated variant, RdB-1L-VSVG, which contains 1 linker and no deletion to fiber, was produced efficiently. Production of 3-dimensionaly stable fiber in RdB-1L-VSVG was confirmed by immunoblot analysis. RdB-1L-VSVG shows a remarkable improvement in cytotoxicity and total viral yield in cancer cells. RdB-1L-VSVG demonstrates enhanced cytotoxicity in cancer cells with subdued CAR-expression as it can be internalized by an alternate pathway. Competition assays with a CAR-specific antibody (Ab) or VSVG receptor, phosphatidyl serine (PS), reveals that cell internalization of RdB-1L-VSVG is mediated by both CAR and PS. Furthermore, treatment with RdB-1L-VSVG significantly enhanced anti-tumor effect in vivo. These studies demonstrate that the strategy to expand oncolytic Ad tropism may significantly improve therapeutic profile for cancer treatment. PMID- 26430799 TI - Polystyrene Nanofiber Materials for Visible-Light-Driven Dual Antibacterial Action via Simultaneous Photogeneration of NO and O2((1)Deltag). AB - This contribution reports on the preparation, characterization, and biological evaluation of electrospun polystyrene nanofiber materials engineered with a covalently grafted NO photodonor and ionically entangled tetracationic porphyrin and phthalocyanine photosensitizers. These photofunctional materials exhibit an effective and simultaneous photogeneration of two antibacterial species such as nitric oxide (NO) and singlet oxygen, O2((1)Deltag) under illumination with visible light, as demonstrated by their direct detection using amperometric and time-resolved spectroscopic techniques. Dual-mode photoantibacterial action is demonstrated by antibacterial tests carried out on Escherichia coli. PMID- 26430800 TI - Academic Research Partnerships for Long-Term Care: The Time Has Come. PMID- 26430801 TI - Dynamic orientation transition of the lyotropic lamellar phase at high shear rates. AB - The dynamic orientation behavior of the lamellar phase of a triblock copolymer is studied in a wide range of shear rates as a function of solvent composition. We find that various phases can be induced by increasing the shear rate. At low shear rates, the onion phase forms from planar lamellae with many defects. A further increase of the shear rate caused the onion structure to break down, and the lamellar phase recovers with fewer defects. Finally, the transition of the orientation from parallel to perpendicular is observed at high shear rates. In the orientation transition at high shear rates, a stable intermediate structure, to our knowledge, is found for the first time. We also find that the critical shear stress of the rupture of the onion phase coincides with the orientation transition. The consistency of the critical shear stress suggests that all orientation transitions at a high shear rate are dominated by a mechanical balance between the applied viscous stress and the internal relaxation mode of the lamellae. PMID- 26430802 TI - Alternative Splicing QTLs in European and African Populations. AB - With the advent of RNA-sequencing technology, we can detect different types of alternative splicing and determine how DNA variation regulates splicing. However, given the short read lengths used in most population-based RNA-sequencing experiments, quantifying transcripts accurately remains a challenge. Here we present a method, Altrans, for discovery of alternative splicing quantitative trait loci (asQTLs). To assess the performance of Altrans, we compared it to Cufflinks and MISO in simulations and Cufflinks for asQTL discovery. Simulations show that in the presence of unannotated transcripts, Altrans performs better in quantifications than Cufflinks and MISO. We have applied Altrans and Cufflinks to the Geuvadis dataset, which comprises samples from European and African populations, and discovered (FDR = 1%) 1,427 and 166 asQTLs with Altrans and 1,737 and 304 asQTLs with Cufflinks for Europeans and Africans, respectively. We show that, by discovering a set of asQTLs in a smaller subset of European samples and replicating these in the remaining larger subset of Europeans, both methods achieve similar replication levels (95% for both methods). We find many Altrans specific asQTLs, which replicate to a high degree (93%). This is mainly due to junctions absent from the annotations and hence not tested with Cufflinks. The asQTLs are significantly enriched for biochemically active regions of the genome, functional marks, and variants in splicing regions, highlighting their biological relevance. We present an approach for discovering asQTLs that is a more direct assessment of splicing compared to other methods and is complementary to other transcript quantification methods. PMID- 26430804 TI - Imputation of KIR Types from SNP Variation Data. AB - Large population studies of immune system genes are essential for characterizing their role in diseases, including autoimmune conditions. Of key interest are a group of genes encoding the killer cell immunoglobulin-like receptors (KIRs), which have known and hypothesized roles in autoimmune diseases, resistance to viruses, reproductive conditions, and cancer. These genes are highly polymorphic, which makes typing expensive and time consuming. Consequently, despite their importance, KIRs have been little studied in large cohorts. Statistical imputation methods developed for other complex loci (e.g., human leukocyte antigen [HLA]) on the basis of SNP data provide an inexpensive high-throughput alternative to direct laboratory typing of these loci and have enabled important findings and insights for many diseases. We present KIR*IMP, a method for imputation of KIR copy number. We show that KIR*IMP is highly accurate and thus allows the study of KIRs in large cohorts and enables detailed investigation of the role of KIRs in human disease. PMID- 26430806 TI - Live-birth rate in euthyroid women with recurrent miscarriage and thyroid peroxidase antibodies. AB - Thyroid autoimmunity with normal thyroid function is associated with recurrent miscarriage (RM), but the association with live birth is less clear. Therefore, we determined the association between thyroid peroxidase antibodies (TPO-Ab) and live-birth rate (LBR) in a retrospective cohort of euthyroid women with unexplained RM. We included 202 women of which 28 were TPO-Ab positive (13.9%) and 174 were TPO-Ab negative. TPO-Ab positive women (n = 10) without levothyroxine treatment had a lower LBR (29%) compared to TPO-Ab negative women (51%) (HR 0.23, 0.07-0.72, p = 0.012). The LBR in women with TPO-Ab receiving levothyroxine was not different compared women without TPO-Ab (60% versus 51%, p = 0.50). In conclusion, TPO-Ab are associated with a lower LBR in euthyroid women with unexplained RM and these women may benefit from treatment with levothyroxine. PMID- 26430807 TI - Gut-derived lymphocyte recruitment to liver and induce liver injury in non alcoholic fatty liver disease mouse model. AB - BACKGROUND AND AIM: Most studies focus on gut-derived factors like microbiota and its products and how they contribute to non-alcoholic fatty liver disease (NAFLD) progression. This study investigated whether the gut-derived lymphocytes could migrate to the liver and induce liver injury in NAFLD. METHODS: A high-fat diet induced an NAFLD mouse model, and lymphocytes were labeled with 1,1-dioctadecyl 3,3,3,3 tetramethylindotricarbocyanine iodide and carboxy-fluorescein succinimidyl ester, respectively, and intravenously injected to mice to monitor lymphocyte migration. RESULTS: Adoptive transfer model results indicated that compared with lymphocytes from the spleen, bone marrow and thymus of NAFLD donor mice, mesenteric lymph nodes (MLN) cells from NAFLD donor mice predominately accumulated in the livers of NAFLD recipient mice. The frequencies of central memory CD4(+) T and CD8(+) T cells in livers of NAFLD mice were significantly increased; however, the activated T cells were not significantly altered. After adoptively transferred MLN cells, the frequencies of the activated CD4(+) T and CD8(+) T cells increased in livers of NAFLD recipient mice. By contrast, the frequencies of central memory and naive CD4(+) T and CD8(+) T cells decreased. MLN cells also induced liver injury in NAFLD recipient mice, as reflected by elevated serum alanine aminotransferase and glutamic oxaloacetic transaminase serums. Moreover, the chemotaxis assay showed that CCL5 mediated the MLN cell migration to the liver. Also, blocking the CCL5 inhibited MLN cell migration to the liver in vitro. CONCLUSIONS: Gut-derived lymphocytes from NAFLD mice could migrate to the liver and induce liver injury and hepatic CD4(+) T and CD8(+) T cells activation. The migration was associated with the upregulation of CCL5 in the liver. PMID- 26430808 TI - Next-Generation Sequencing of a Cohort of Pulmonary Large Cell Carcinomas Reclassified by World Health Organization 2015 Criteria. AB - CONTEXT: The classification of pulmonary large cell carcinoma has undergone a major revision with the recent World Health Organization (WHO) 2015 Classification. Many large cell carcinomas are now reassigned to either adenocarcinoma with solid pattern or nonkeratinizing squamous cell carcinoma based on immunopositivity for adenocarcinoma markers or squamous cell carcinoma markers, respectively. Large cell carcinomas that are negative for adenocarcinoma and squamous cell carcinoma immunomarkers are now classified as large cell carcinoma with null immunohistochemical features (LCC-N). Although a few studies investigated the mutation profile of large cell carcinomas grouped by immunostain profile before the publication of the new WHO classification, investigation of tumors previously diagnosed as large cell carcinoma and reclassified according to the 2015 WHO classification has not, to our knowledge, been reported. OBJECTIVE: To determine the mutation profiles of pulmonary large cell carcinomas reclassified by WHO 2015 criteria. DESIGN: Archival cases of non-small cell lung carcinoma with large cell carcinoma morphology (n = 17) were reclassified according to 2015 WHO criteria. To determine mutation profile, we employed Ion Torrent (Life Technologies, Carlsbad, California)-based next-generation sequencing (50 genes; more than 2800 mutations) in addition to real-time quantitative reverse transcription polymerase chain reaction for ALK translocation detection. RESULTS: Two of 17 cases (12%) were reclassified as LCC N, and both had mutations-BRAF D594N in one case and KRAS G12C in the other case. Seven of 17 cases (41%) were reclassified in the adenocarcinoma with solid pattern group, which showed one KRAS G12C and one EGFR E709K + G719C double mutation in addition to mutations in TP53. Eight of 17 cases (47%) were reclassified in the nonkeratinizing squamous cell carcinoma group, which showed mutations in PIK3CA, CDKN2A, and TP53. No ALK translocations or amplifications were detected. CONCLUSIONS: The adenocarcinoma with solid pattern group showed mutations typical of adenocarcinoma, whereas the nonkeratinizing squamous cell carcinoma group showed mutations typical of squamous cell carcinoma. Both LCC-N cases had mutations associated with adenocarcinoma, supporting the hypothesis that LCC-N is related to adenocarcinoma. PMID- 26430805 TI - How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling. AB - Mitosis entails the bona fide segregation of duplicated chromosomes. This process is accomplished by the attachment of kinetochores on chromosomes to microtubules (MTs) of the mitotic spindle. Once the appropriate attachment is achieved, the spindle assembly checkpoint (SAC) that delays the premature onset of anaphase needs to be silenced for the cell to proceed to anaphase and cytokinesis. Therefore, while it is imperative to preserve the SAC when kinetochores are unattached, it is of paramount importance that SAC components are removed post kinetochore microtubule (kMT) attachment. Precise knowledge of how kMT attachments trigger the removal of SAC components from kinetochores or how the checkpoint proteins feedback in to the attachment machinery remains elusive. This review aims to describe the recent advances that provide an insight into the interplay of molecular events that coordinate and regulate the SAC activity in response to kMT attachment during cell division. PMID- 26430809 TI - Validation of the Lung Subtyping Panel in Multiple Fresh-Frozen and Formalin Fixed, Paraffin-Embedded Lung Tumor Gene Expression Data Sets. AB - Context .- A histologic classification of lung cancer subtypes is essential in guiding therapeutic management. Objective .- To complement morphology-based classification of lung tumors, a previously developed lung subtyping panel (LSP) of 57 genes was tested using multiple public fresh-frozen gene-expression data sets and a prospectively collected set of formalin-fixed, paraffin-embedded lung tumor samples. Design .- The LSP gene-expression signature was evaluated in multiple lung cancer gene-expression data sets totaling 2177 patients collected from 4 platforms: Illumina RNAseq (San Diego, California), Agilent (Santa Clara, California) and Affymetrix (Santa Clara) microarrays, and quantitative reverse transcription-polymerase chain reaction. Gene centroids were calculated for each of 3 genomic-defined subtypes: adenocarcinoma, squamous cell carcinoma, and neuroendocrine, the latter of which encompassed both small cell carcinoma and carcinoid. Classification by LSP into 3 subtypes was evaluated in both fresh frozen and formalin-fixed, paraffin-embedded tumor samples, and agreement with the original morphology-based diagnosis was determined. Results .- The LSP-based classifications demonstrated overall agreement with the original clinical diagnosis ranging from 78% (251 of 322) to 91% (492 of 538 and 869 of 951) in the fresh-frozen public data sets and 84% (65 of 77) in the formalin-fixed, paraffin embedded data set. The LSP performance was independent of tissue-preservation method and gene-expression platform. Secondary, blinded pathology review of formalin-fixed, paraffin-embedded samples demonstrated concordance of 82% (63 of 77) with the original morphology diagnosis. Conclusions .- The LSP gene expression signature is a reproducible and objective method for classifying lung tumors and demonstrates good concordance with morphology-based classification across multiple data sets. The LSP panel can supplement morphologic assessment of lung cancers, particularly when classification by standard methods is challenging. PMID- 26430810 TI - Employer Expectations for Newly Trained Pathologists: Report of a Survey From the Graduate Medical Education Committee of the College of American Pathologists. AB - CONTEXT: -Multiple sources have identified challenges that training programs face in preparing graduates for the "real world" practice of pathology, and many training programs have sought to decrease the gap between skills acquired during training and those required in practice. However, there exists the possibility that some of the difficulty experienced by newly trained pathologists and employers might arise from differences between employer expectations of new hires and what applicants expect from their first job. OBJECTIVE: -To define the constellation of skills and attributes employers prioritize when hiring newly trained pathologists. DESIGN: -A survey of fellows of the College of American Pathologists in practice for 5 or more years in the United States was administered and the results were analyzed. RESULTS: -A total of 630 pathologists who were responsible for hiring a new-in-practice pathologist completed the survey. Regardless of practice setting, certain skills and attributes were rated critically important in new hires, including ethics/integrity, work ethic, and professionalism. Seventy-one percent reported having some difficulty hiring entry level pathologists and cited inadequate training/experience during residency, and applicants having unrealistic expectations regarding work load/hours as the most common reasons. CONCLUSIONS: -Prospective employers not only expect well developed diagnostic skills in their job applicants, but also require evidence of a strong work ethic and outstanding professionalism. Successful applicants must display willingness to assume responsibilities and flexibility regarding existing and new responsibilities. A secondary but important finding of this survey was that most jobs are garnered through word-of-mouth recommendations; therefore, it is crucial for pathologists-in-training to hone their networking skills. PMID- 26430811 TI - RAS mutations - for better or for worse in multiple myeloma? PMID- 26430812 TI - Two-tiered subdivision of atypia on urine cytology can improve patient follow-up and optimize the utility of UroVysion. AB - BACKGROUND: The annual incidence of urothelial carcinoma continues to increase, and it is projected that greater than 70,000 new cases will occur in the year 2015. However, as much as 23% of cytologic specimens will demonstrate some degree of atypia without meeting the criteria for urothelial carcinoma and thus will be reported as atypical. METHODS: The authors conducted 2 laboratory information searches and 1 survey. In total, 311 patients who had atypical cytology-biopsy pairs available were identified from the initial data search. The second data search identified 942 patients who had fluorescence in situ hybridization (FISH) results available. RESULTS: There was fair agreement between FISH results and cytology results (kappa = 0.34; 95% confidence interval, 0.27-0.41). The analysis did not reveal any benefits of using additional atypical subcategories beyond the 2 suggested in the literature. It was determined that 2 strategies would provide an optimal balance: standardizing patient management and facilitating the adoption of universally recognized templates. CONCLUSIONS: When combining cytology and the 2-tiered atypical classification system with FISH testing, a marked increase in sensitivity and an accompanying decrease in specificity were observed compared with either test individually. Thus, highly sensitive FISH testing may help to identify high-risk patients among those in the group with uncertain atypical findings. PMID- 26430813 TI - Nicotine delivery, retention and pharmacokinetics from various electronic cigarettes. AB - AIMS: To measure the systemic retention of nicotine, propylene glycol (PG) and vegetable glycerin (VG) in electronic cigarette (e-cigarette) users, and assess the abuse liability of e-cigarettes by characterizing nicotine pharmacokinetics. DESIGN: E-cigarette users recruited over the internet participated in a 1-day research ward study. Subjects took 15 puffs from their usual brand of e cigarette. Exhaled breath was trapped in gas-washing bottles and blood was sampled before and several times after use. SETTING: San Francisco, California, USA. PARTICIPANTS: Thirteen healthy, experienced adult e-cigarette users (six females and seven males). MEASUREMENTS: Plasma nicotine was analyzed by gas chromatography-mass spectrometry (GC-MS/MS) and nicotine, VG and PG in e-liquids and gas traps were analyzed by LC-MS/MS. Heart rate changes and subjective effects were assessed. FINDINGS: E-cigarettes delivered an average of 1.33 (0.87 1.79) mg [mean and 95% confidence interval (CI)] of nicotine, and 93.8% of the inhaled dose, 1.22 (0.80-1.66) was systemically retained. Average maximum plasma nicotine concentration (Cmax ) was 8.4 (5.4-11.5) ng/ml and time of maximal concentration (Tmax ) was 2-5 minutes. One participant had Tmax of 30 minutes. 84.4% and 91.7% of VG and PG, respectively, was systemically retained. Heart rate increased by an average of 8.0 beats per minute after 5 minutes. Withdrawal and urge to smoke decreased and the e-cigarettes were described as satisfying. CONCLUSIONS: E-cigarettes can deliver levels of nicotine that are comparable to or higher than typical tobacco cigarettes, with similar systemic retention. Although the average maximum plasma nicotine concentration in experienced e cigarette users appears to be generally lower than what has been reported from tobacco cigarette use, the shape of the pharmacokinetic curve is similar, suggesting addictive potential. PMID- 26430803 TI - Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores. AB - Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase. PMID- 26430820 TI - Poster Awards Finalist Abstracts. PMID- 26430814 TI - Recombinant and epitope-based vaccines on the road to the market and implications for vaccine design and production. AB - Novel vaccination approaches based on rational design of B- and T-cell epitopes - epitope-based vaccines - are making progress in the clinical trial pipeline. The epitope-focused recombinant protein-based malaria vaccine (termed RTS,S) is a next-generation approach that successfully reached phase-III trials, and will potentially become the first commercial vaccine against a human parasitic disease. Progress made on methods such as recombinant DNA technology, advanced cell-culture techniques, immunoinformatics and rational design of immunogens are driving the development of these novel concepts. Synthetic recombinant proteins comprising both B- and T-cell epitopes can be efficiently produced through modern biotechnology and bioprocessing methods, and can enable the induction of large repertoires of immune specificities. In particular, the inclusion of appropriate CD4+ T-cell epitopes is increasingly considered a key vaccine component to elicit robust immune responses, as suggested by results coming from HIV-1 clinical trials. In silico strategies for vaccine design are under active development to address genetic variation in pathogens and several broadly protective "universal" influenza and HIV-1 vaccines are currently at different stages of clinical trials. Other methods focus on improving population coverage in target populations by rationally considering specificity and prevalence of the HLA proteins, though a proof-of-concept in humans has not been demonstrated yet. Overall, we expect immunoinformatics and bioprocessing methods to become a central part of the next-generation epitope-based vaccine development and production process. PMID- 26430819 TI - Virtual Reality-Enhanced Cognitive-Behavioral Therapy for Morbid Obesity: A Randomized Controlled Study with 1 Year Follow-Up. AB - It is well known that obesity has a multifactorial etiology, including biological, environmental, and psychological causes. For this reason, obesity treatment requires a more integrated approach than the standard behavioral treatment based on dietary and physical activity only. To test the long-term efficacy of an enhanced cognitive-behavioral therapy (CBT) of obesity, including a virtual reality (VR) module aimed at both unlocking the negative memory of the body and to modify its behavioral and emotional correlates, 163 female morbidly obese inpatients (body mass index >40) were randomly assigned to three conditions: a standard behavioral inpatient program (SBP), SBP plus standard CBT, and SBP plus VR-enhanced CBT. Patients' weight, eating behavior, and body dissatisfaction were measured at the start and upon completion of the inpatient program. Weight was assessed also at 1 year follow-up. All measures improved significantly at discharge from the inpatient program, and no significant difference was found among the conditions. However, odds ratios showed that patients in the VR condition had a greater probability of maintaining or improving weight loss at 1 year follow-up than SBP patients had (48% vs. 11%, p = 0.004) and, to a lesser extent, than CBT patients had (48% vs. 29%, p = 0.08). Indeed, only the VR-enhanced CBT was effective in further improving weight loss at 1 year follow-up. On the contrary, participants who received only the inpatient program regained back, on average, most of the weight they had lost. Findings support the hypothesis that a VR module addressing the locked negative memory of the body may enhance the long-term efficacy of standard CBT. PMID- 26430822 TI - Distinct DNA Damage Spectra Induced by Ionizing Radiation in Normoxic and Hypoxic Cells. AB - Ionizing radiation induces more cell death under normoxic conditions than under hypoxic conditions. This phenomenon, which is known as the oxygen enhancement effect, occurs primarily because ionizing radiation causes more DNA lesions in the presence of oxygen than in its absence. However, the roles these lesions play in terms of cell survival and chromosome damage have not been fully characterized. We exposed a panel of chicken DT40 mutant cells to ionizing radiation to categorize the type of lesion induced and the DNA-repair pathway involved under both normoxic and hypoxic conditions. Among the mutant panel, RAD54(-/-)/KU70(-/-) cells exhibited the greatest radiosensitivity, which was found to be significantly higher under normoxic conditions. This indicates that double-strand breaks (DSBs) were the major cause of cell death and that ionizing radiation induces more DSBs under normoxic condition. Interestingly, the sensitivity of the REV3(-/-) cells increased under hypoxic conditions. Indeed, the REV3(-/-) mutant exhibited a greater number of chromosomal aberrations under hypoxic conditions than under normoxic conditions. These results suggest that the Rev3-mediated translesion-synthesis pathway is more critical for cellular tolerance to ionizing radiation in hypoxic cells than in normoxic cells, and that more chemically modified DNA might be induced under hypoxic conditions. In this study, we identify a previously unappreciated radiation-induced pattern of DNA damage under hypoxic conditions. PMID- 26430821 TI - A Diet Containing Beta-Hydroxy-Beta-Methylbutyrate, L-Glutamine and L-Arginine Ameliorates Chemoradiation-Induced Gastrointestinal Injury in Rats. AB - The aim of this study was to investigate the effects of a specific diet, containing beta-hydroxy-beta-methylbutyrate, L-glutamine and L-arginine (HMB/Glu/Arg), on chemoradiation-induced injuries of the rat gastrointestinal mucosa. Wistar albino rats were divided into 4 groups: control (n = 5); radiation (n = 14); 5-fluorouracil treatment (5-FU; n = 14); and radiation and 5-FU treatment (n = 14). Rats were fed either a standard diet or a specific diet (SpD) containing HMB/Glu/Arg supplementation for 7 days prior to radiation exposure and/or 5-FU treatment. The irradiated groups were exposed to an 1 Gy dose of 6 MV x rays delivered to the who-abdominal. The animals receiving 5-FU treatment were given a 100 mg/kg dose of the drug. In the radiation and 5-FU treatment group, the 5-FU was administered 30 min prior to irradiation. After irradiation and/or 5 FU treatment, feeding with either the standard rat diet or specific diet continued as before. All animals were sacrificed on day 4 after irradiation and 5 FU treatment. Data collected included microbiological, histological and immunohistochemical end points. We found that bacterial colony counts in the ceca and mesenteric lymph nodes of irradiated rats treated with 5-FU were significantly lower in the specific diet (SpD) group than in the standard diet group (P = 0.002-0.05). Morphometrically, gastric, duodenal and colonic mucosal injuries were less severe in the irradiated animals fed the specific diet, as well as the 5-FU-treated animals fed the specific diet, compared to the similarly treated standard diet groups. Apoptosis, measured by TUNEL, revealed significantly lower numbers of TUNEL positive cells in irradiated animals fed the specific diet, and irradiated animals treated with 5-FU and fed the specific diet compared to irradiated animals fed the standard diet, and irradiated animals treated with 5-FU and fed the standard diet. In the 5-Fu-treated and SpD group, the extent of apoptosis was significantly lower than that of the 5-Fu-treated and standard diet group in both the stomach and duodenum (P = 0.0001), but not in the colon. Apoptosis, measured by caspase 3 staining, was significantly less in all three organs of the SpD groups. In conclusion, these findings suggest that a diet supplemented with HMB/Glu/Arg may ameliorate the effect of radiation-induced gastrointestinal injury, coinciding with reduced bacterial growth. PMID- 26430823 TI - Charge control of the inverse trans-influence. AB - The synthesis and characterization of uranium(VI) mono(imido) complexes, by the oxidation of corresponding uranium(V) species, are presented. These experimental results, paired with DFT analyses, allow for the comparison of the electronic structure of uranium(VI) mono(oxo) and mono(imido) ligands within a conserved ligand framework and demonstrate that the magnitude of the ground state stabilization derived from the inverse trans-influence (ITI) is governed by the relative charge localization on the multiply bonded atom or group. PMID- 26430824 TI - Cytoprotective Effects of a Novel Nrf2 Activator, RS9, in Rhodopsin Pro347Leu Rabbits. AB - PURPOSE: Rhodopsin Pro347Leu transgenic rabbits were previously generated as models of retinitis pigmentosa (RP). While the mechanism underlying the retinal deterioration in these rabbits remains unresolved, it is likely that oxidative stress is one of the factors triggering cellular loss. We have recently succeeded in obtaining a novel activator (RS9) of nuclear factor erythroid 2-related factor (Nrf2, also known as NFE2L2), which regulates antioxidant transcriptional factors. The purpose of this study was to investigate whether RS9 delays progressive retinal degeneration in the transgenic rabbits. METHODS: RS9 microspheres (3 mM, 50 uL) were injected into the vitreous of rhodopsin Pro347Leu transgenic rabbits at 6 weeks, after which outer nuclear layer (ONL) thickness was measured by optical coherence tomography. Rabbits were sacrificed at 15 weeks. RESULTS: After intravitreal injection of RS9 microspheres, the concentration of RS9 in the vitreous was maintained at 1 nM for 2 weeks. At a concentration of 0.3 mM and 50 uL, RS9 significantly inhibited thinning of the ONL in transgenic rabbits compared to vehicle-injected transgenic rabbits. In RS9 injected transgenic rabbits, Nrf2-targeted genes had increased significantly, and levels of interleukin-6 mRNA decreased. CONCLUSIONS: Activation of Nrf2 signaling has potential as a novel approach for the prevention and treatment of RP, not only by driving intrinsic antioxidant enzymes, but also by inhibiting inflammatory responses. Although microspheres were employed in this study, small implants that release more compounds might be a realistic method for clinical trials. PMID- 26430825 TI - Pharmacokinetics of once and twice daily dosing of intravenous tobramycin in paediatric patients with cystic fibrosis. AB - The optimal dosing of intravenous tobramycin for treatment of pulmonary exacerbations in paediatric cystic fibrosis (CF) patients has not been completely delineated. We performed a retrospective study evaluating the pharmacokinetics and pharmacodynamics of once daily dosing (ODD) of IV tobramycin compared to twice daily dosing (TDD). Fifty-nine and 44 patients were included in the ODD and TDD groups, respectively. Once daily dosing achieved higher Cmax as compared to TDD (29.5 +/- 11.0 vs 19.0 +/- 4.9, P < 0.001), lower 24 hour AUC (92.8 +/- 28.7 vs 128.5 +/- 34.6, P < 0.001), and greater time that drug concentration was below the minimum inhibitory concentration (MIC) (13.4 +/- 1.7 vs 3.9 +/- 3.1 hour, P < 0.001). Twice daily dosing failed to achieve goal Cmax:MIC for MICs >1.0 mg/l. Twice daily dosing may be a viable alternative to ODD in treating organisms with MICs <= 1.0 mg/l; however, with MICs >1.0 mg/l, ODD is likely necessary to achieve goal Cmax:MIC ratios. PMID- 26430826 TI - Effects of Multistrain Probiotic Supplementation on Glycemic and Inflammatory Indices in Patients with Nonalcoholic Fatty Liver Disease: A Double-Blind Randomized Clinical Trial. AB - OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is a condition defined by exceeding triglycerides accumulation in the liver. The condition can develop into fibrosis, cirrhosis, and hepatocellular carcinoma. Considering the ever increasing prevalence of NAFLD, the aim of the present study was to investigate the effects of probiotic supplementation on glycemic and inflammatory indices in patients with NAFLD. METHODS: This randomized clinical trial was conducted on 42 patients with NAFLD who had been referred to a gastroenterology clinic. Subjects in the intervention and control groups consumed 2 capsules/day probiotic or placebo, respectively, for 8 weeks. Fasting blood sugar (FBS), insulin, insulin resistance, tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) were measured at baseline and at the end of the study. RESULTS: Means of FBS, insulin, insulin resistance, and IL-6 were significantly different between groups after intervention (p < 0.05), whereas TNF-alpha was not significantly modified (p > 0.05). In the probiotic group, insulin, insulin resistance, TNF-alpha, and IL-6 decreased significantly at the end of the study compared to the beginning of study. CONCLUSION: Considering the effects of probiotic supplementation on the reduction of glycemic and inflammatory indices in patients with NAFLD, consumption of probiotics is recommended as a complementary therapy in these patients. PMID- 26430832 TI - Hypoalbuminemia and hypergammaglobulinemia are associated with an increased infection risk in patients with myeloid malignancies treated with azacitidine. A 3-year monocentric retrospective study. PMID- 26430833 TI - Did Buddha turn the other cheek too? A comparison of posing biases between Jesus and Buddha. AB - People tend to exhibit a leftward bias in posing. Various studies suggest that posing to the left portrays a stronger emotion, whereas posing to the right portrays a more neutral emotion. Religions such as Christianity emphasize the role of strong emotions in religious experience, whereas religions such as Buddhism emphasize the calming of emotions as being important. In the present study, we investigated if the emphasis on emotionality of a religion influences the depiction of their religious figures. Specifically, we coded 484 paintings of Jesus and Buddha from online art databases for whether the deity exhibited a left bias, right bias, or central face presentation. The posing biases were analysed to discover whether paintings of Jesus would more frequently depict a leftward bias than paintings of Buddha. Jesus is more commonly depicted with a leftward bias than Buddha, and Buddha is more commonly depicted with a central face presentation than Jesus. These findings support the idea that the amount of emotionality that is to be conveyed in artwork influences the whether the subject is posed with a leftward bias. PMID- 26430834 TI - Synthesis and Substrate Evaluation of (E)-5-[(3-Selenophene-2-Carboxamido)Prop-1 en-1-yl]-Uridine-5'-O-Triphosphate for RNA Polymerase. AB - Design, synthesis and T7 RNA polymerase substrate evaluation of (E)-5-[(3 selenophene-2-carboxamido)prop-1-en-1-yl]-uridine-5'-O-triphosphate is reported. The title compound is shown to be a good substrate for RNA polymerase by RNA labeling through in vitro transcription. pTRI-plasmid DNA with beta-actin gene sequence (~300 base pairs) with T7 promoter was used as a template for the in vitro transcription. Transcribed product is characterized for incorporation by gel assay and for integrity, full length and size by bioanalyzer. The title compound will be very useful in biophysical techniques to obtain information on dynamics and recognition properties in real time as well as 3D structure of nucleic acids. PMID- 26430836 TI - Expression of Concern: Dual regeneration of muscle and nerve by intravenous administration of human amniotic fluid-derived mesenchymal stem cells regulated by stromal cell-derived factor-1alpha in a sciatic nerve injury model. PMID- 26430837 TI - Neurosurgical patients' perceptions of the "surgeon+": a qualitative study. AB - OBJECTIVE: Neurosurgical patients bear a varying degree of anxiety when confronted with having to undergo surgery or even visit with a neurosurgeon in consultation. Previous studies have suggested that patient perceptions can heavily influence the patient-physician encounter. Accordingly, a better understanding of these perceptions can marshal our knowledge regarding strategies for improving patient-physician interactions during such an apprehensive time. The aim of the present study was to qualitatively examine patient values and preferences for a neurosurgeon who participates in extraclinical activities (i.e., a "neurosurgeon+") and understand the factors that influence these perceptions. METHODS: Semistructured face-to-face interviews with 47 neurosurgical patients were conducted. Patients were recruited from the Toronto Western Hospital neurosurgery clinics for cranial and spinal conditions. Descriptive summary statistics were used to characterize the study participants. Family members were encouraged to contribute to the interviews. Interviews were audio-recorded, transcribed, and subjected to thematic analysis by using open and axial coding. RESULTS: Patients generally indicated that they want to feel confident in their neurosurgeon. A number of factors contribute to this confidence, including a strong positive referral from another physician. Patients are inclined to search for information pertaining to the qualifications of neurosurgeons online, and a perception of the neurosurgeon's adeptness given his or her qualifications is important for patients. Although there were some differences in patient values between those in the cranial and spinal groups, overall, neurosurgical patients tend to positively view their neurosurgeon's involvement in extraclinical duties. CONCLUSIONS: This study details the first comprehensive clinical qualitative study of patient perceptions of neurosurgeons and provides a descriptive framework for understanding patient values in this clinical domain. PMID- 26430838 TI - Utility of tubular retractors to minimize surgical brain injury in the removal of deep intraparenchymal lesions: a quantitative analysis of FLAIR hyperintensity and apparent diffusion coefficient maps. AB - OBJECTIVE: Brain retraction systems are frequently required to achieve surgical exposure of deep-seated brain lesions. Spatula-based systems can be associated with injury to the cortex and deep white matter, particularly adjacent to the sharp edges, which can result in uneven pressure on the parenchyma over the course of a long operation. The use of tubular retractor systems has been proposed as a method to overcome these limitations. There have been no studies assessing the degree of brain injury associated with the use of tubular retractors. METHODS :Twenty patients were retrospectively identified at Weill Cornell Medical College who underwent resection of deep-seated brain lesions between 2005 and 2014 with the aid of a METRx tubular retractor system. Using the Brainlab software, pre- and postoperative images were analyzed to assess volume, depth, extent of resection, and change in postoperative MR FLAIR hyperintensity and restricted diffusion on diffusion-weighted imaging (DWI). RESULTS: The mean preoperative tumor volume was 16.25 +/- 17.6 cm(3). Gross-total resection was achieved in 75%, near-total resection in 10%, and subtotal resection in 15% of patients. There was a small but not statistically significant increase in average FLAIR hyperintensity volume by 3.25 +/- 10.51 cm(3) (p = 0.16). The average postoperative volume of DWI high signal area with restricted diffusion on apparent diffusion coefficient maps was 8.35 +/- 3.05 cm(3). Assuming that the volume of restricted diffusion on DWI around tumor was 0 preoperatively, this represented a statistically significant increase on DWI (p < 0.001). CONCLUSIONS: Although tubular retractors do not appear to significantly increase FLAIR signal in the brain, DWI intensity around the retractors can be identified. These data indicate that although tubular retractors may minimize damage to surrounding tissues, they still cause cytotoxic edema and cellular damage. Objective comparison against other retraction methods, as compared by 3D volumetric analysis or similar methods, will be important in determining the true advantage of tubular retractor systems. PMID- 26430839 TI - Retraction: Enhancement of regeneration with glia cell line-derived neurotrophic factor-transduced human amniotic fluid mesenchymal stem cells after sciatic nerve crush injury. PMID- 26430840 TI - Retraction: The effect of exercise on mobilization of hematopoietic progenitor cells involved in the repair of sciatic nerve crush injury. PMID- 26430841 TI - Results of wrist extension reconstruction in C5-8 brachial plexus palsy by transferring the pronator quadratus motor branch to the extensor carpi radialis brevis muscle. AB - OBJECT The objective of this study was to report the results of pronator quadratus (PQ) motor branch transfers to the extensor carpi radialis brevis (ECRB) motor branch to reconstruct wrist extension in C5-8 root lesions of the brachial plexus. METHODS Twenty-eight patients, averaging 24 years of age, with C5-8 root injuries underwent operations an average of 7 months after their accident. In 19 patients, wrist extension was impossible at baseline, whereas in 9 patients wrist extension was managed by activating thumb and wrist extensors. When these 9 patients grasped an object, their wrist dropped and grasp strength was lost. Wrist extension was reconstructed by transferring the PQ motor to the ECRB motor branch. After surgery, patients were followed for at least 12 months, with final follow-up an average of 22 months after surgery. RESULTS Successful reinnervation of the ECRB was demonstrated in 27 of the 28 patients. In 25 of the patients, wrist extension scored M4, and in 2 it scored M3. CONCLUSIONS In C5-8 root injuries, wrist extension can be predictably reconstructed by transferring the PQ motor branch to reinnervate the ECRB. PMID- 26430842 TI - Letter to the Editor: Surgical treatment of VA stenosis in the endovascular era. PMID- 26430843 TI - Distinct displacements of the optic radiation based on tumor location revealed using preoperative diffusion tensor imaging. AB - OBJECT Visual field defects (VFDs) due to optic radiation (OR) injury are a common complication of temporal lobe surgery. The authors analyzed whether preoperative visualization of the optic tract would reduce this complication by influencing the surgeon's decisions about surgical approaches. The authors also determined whether white matter shifts caused by temporal lobe tumors would follow predetermined patterns based on the tumor's topography. METHODS One hundred thirteen patients with intraaxial tumors of the temporal lobe underwent preoperative diffusion tensor imaging (DTI) fiber tracking. In 54 of those patients, both pre- and postoperative VFDs were documented using computerized perimetry. Brainlab's iPlan 2.5 navigation software was used for tumor reconstruction and fiber visualization after the fusion of DTI studies with their respective magnetization-prepared rapid gradient-echo (MP-RAGE) images. The tracking algorithm was as follows: minimum fiber length 100 mm, fractional anisotropy threshold 0.1. The lateral geniculate body and the calcarine cortex were employed as tract seeding points. Shifts of the OR caused by tumor were visualized in comparison with the fiber tracking of the patient's healthy hemisphere. RESULTS Temporal tumors produced a dislocation of the OR but no apparent fiber destruction. The shift of white matter tracts followed fixed patterns dependent on tumor location: Temporolateral tumors resulted in a medial fiber shift, and thus a lateral transcortical approach is recommended. Temporopolar tumors led to a posterior shift, always including Meyer's loop; therefore, a pterional transcortical approach is recommended. Temporomesial tumors produced a lateral and superior shift; thus, a transsylvian-transcisternal approach will result in maximum sparing of the fibers. Temporocentric tumors also induced a lateral fiber shift. For those tumors, a transsylvian-transopercular approach is recommended. Tumors of the fusiform gyrus generated a superior (and lateral) shift; consequently, a subtemporal approach is recommended to avoid white matter injury. In applying the approaches recommended above, new or worsened VFDs occurred in 4% of the patient cohort. Total neurological and surgical morbidity were less than 10%. In 90% of patients, gross-total resection was accomplished. CONCLUSIONS Preoperative visualization of the OR may help in avoiding postoperative VFDs. PMID- 26430844 TI - Endoscopic fenestration of intraventricular cerebrospinal fluid cysts: the contralateral approach. AB - OBJECTIVE: The endoscopic fenestration of intraventricular CSF cysts has evolved into a well-accepted treatment modality. However, definition of the optimal trajectory for endoscopic fenestration may be difficult. Distorted ventricular anatomy and poor visibility within the cyst due to its contents can make endoscopic fenestration challenging if approached from the ipsilateral side. In addition, transcortical approaches can theoretically cause injury to eloquent cortex, particularly in patients with dominant-sided lesions. The aim of this study was to examine the value of the contralateral transcortical transventricular approach in patients with dominant-sided ventricular cysts. METHODS: During a 5-year period between 2007 and 2011, 31 patients with intraventricular CSF cysts underwent surgery by the senior author (R.R.). Fourteen of these patients had cysts located on the dominant side. An image guided endoscopic cyst fenestration via the contralateral transcortical transventricular approach was performed in 11 patients. A retrospective chart review was performed in all these patients to extract data on clinical presentation, operative technique, and surgical outcome. RESULTS: The most common presenting symptom was headache, followed by memory deficits and cognitive deterioration. In all cases CSF cysts were space occupying, with associated obstructive hydrocephalus in 8 patients. Image-guided endoscopic fenestration was successfully performed in all cases, with septum pellucidotomy necessary in 6 cases, and endoscopic third ventriculostomy in 1 case for additional aqueductal occlusion. Postoperative clinical outcome was excellent, with no associated permanent neurological or neuropsychological morbidity. No recurrent cysts were observed over a mean follow-up period of 2 years and 3 months. CONCLUSIONS: The contralateral approach to ventricular cysts can achieve excellent surgical outcomes while minimizing approach-related trauma to the dominant hemisphere. Careful case selection is essential to ensure that the contralateral endoscopic trajectory is the best possible exposure for sufficient cyst fenestration and restoration of CSF circulation. PMID- 26430845 TI - Reversal of intraoperative arterial thrombosis with a fibrinolytic agent when treating large and giant partially thrombosed aneurysms of the middle cerebral artery. AB - OBJECTIVE: Thrombosis of the cerebral arteries is one of the complications of microsurgical operations for partially thrombosed intracranial aneurysms. The object of this study was to assess the frequency of intraoperative arterial thrombosis (IAT) during microsurgical treatment of large and giant partially thrombosed aneurysms of the middle cerebral artery (MCA) and also to assess the efficacy of the treatment of this complication. MATERIALS: The authors analyzed a consecutive series of 53 patients who underwent surgery for partially thrombosed aneurysms of the MCA at the Burdenko Neurosurgical Institute between January 2005 and September 2014. Thirty-two patients had large aneurysms (15-25 mm) and 21 had giant aneurysms (> 25 mm). Clipping of aneurysms was performed in 47 patients, trapping was performed in 3, and wrapping was performed in 3. RESULTS: IAT was diagnosed in 10 patients (18.9%). The authors describe a technique for IAT reversal involving the injection of modified human recombinant prourokinase (mr proUK). Of the 7 patients who underwent injection of mr-proUK in the thrombosed artery, 5 (71.4%) were discharged without any change in neurological status, 1 (14.3%) experienced moderate deterioration (modified Rankin Scale [mRS] score of 2), and 1 (14.3%) experienced severe deterioration (mRS score of 4). Among the 3 patients who had complications and did not receive an injection of mr-proUK, 2 experienced severe deterioration (mRS score of 3 and 4) and 1 had moderate deterioration (mRS score of 2). CONCLUSIONS: The primary risk factor of thrombectomy with temporary trapping is thrombosis in the MCA branches. The injection of a fibrinolytic agent into thrombosed MCA branches is an effective method for the treatment of IAT. PMID- 26430846 TI - Live-cell imaging to detect phosphatidylserine externalization in brain endothelial cells exposed to ionizing radiation: implications for the treatment of brain arteriovenous malformations. AB - OBJECT Stereotactic radiosurgery (SRS) is an established intervention for brain arteriovenous malformations (AVMs). The processes of AVM vessel occlusion after SRS are poorly understood. To improve SRS efficacy, it is important to understand the cellular response of blood vessels to radiation. The molecular changes on the surface of AVM endothelial cells after irradiation may also be used for vascular targeting. This study investigates radiation-induced externalization of phosphatidylserine (PS) on endothelial cells using live-cell imaging. METHODS An immortalized cell line generated from mouse brain endothelium, bEnd.3 cells, was cultured and irradiated at different radiation doses using a linear accelerator. PS externalization in the cells was subsequently visualized using polarity sensitive indicator of viability and apoptosis (pSIVA)-IANBD, a polarity sensitive probe. Live-cell imaging was used to monitor PS externalization in real time. The effects of radiation on the cell cycle of bEnd.3 cells were also examined by flow cytometry. RESULTS Ionizing radiation effects are dose dependent. Reduction in the cell proliferation rate was observed after exposure to 5 Gy radiation, whereas higher radiation doses (15 Gy and 25 Gy) totally inhibited proliferation. In comparison with cells treated with sham radiation, the irradiated cells showed distinct pseudopodial elongation with little or no spreading of the cell body. The percentages of pSIVA-positive cells were significantly higher (p = 0.04) 24 hours after treatment in the cultures that received 25- and 15-Gy doses of radiation. This effect was sustained until the end of the experiment (3 days). Radiation at 5 Gy did not induce significant PS externalization compared with the sham-radiation controls at any time points (p > 0.15). Flow cytometric analysis data indicate that irradiation induced growth arrest of bEnd.3 cells, with cells accumulating in the G2 phase of the cell cycle. CONCLUSIONS Ionizing radiation causes remarkable cellular changes in endothelial cells. Significant PS externalization is induced by radiation at doses of 15 Gy or higher, concomitant with a block in the cell cycle. Radiation induced markers/targets may have high discriminating power to be harnessed in vascular targeting for AVM treatment. PMID- 26430847 TI - Importance of RNF213 polymorphism on clinical features and long-term outcome in moyamoya disease. AB - OBJECT Moyamoya disease (MMD) is an idiopathic cerebrovascular occlusive disorder prevalent in East Asia. In the pathogenesis of MMD, the important role of genetic factors is being elucidated, and RNF213 has recently been identified as a susceptibility gene for MMD. The aim of this retrospective study was to investigate the RNF213 genotype in patients with MMD and to determine their genotype-phenotype associations. METHODS The study involved 165 Korean MMD patients from 155 unrelated families who were diagnosed with MMD at a single center from 1995 to 2013. Their demographic, radiological, and clinical findings were evaluated. Direct sequencing of the major RNF213 single nucleotide polymorphisms was performed. The association of the common RNF213 variant with MMD risk was evaluated using historical controls for comparison. Correlations between RNF213 genotype and phenotype were statistically analyzed. RESULTS The c.14429G>A (p.R4810K) variant was identified in 125 (75.8%) of 165 MMD patients. Most patients (112) were heterozygous, and 13 patients had 2 copies of the c.14429G>A variant. A novel heterozygous variant, c.12086A>G (p.Q4029R), was found in 1 additional patient. The minor allele frequency of the c.14429G>A variant was significantly higher in the MMD group (138 [41.8%] of 330 patients) than in the control group (8 [1.36%] of 588 subjects; p < 0.001). The c.14429G>A (p.R4810K) variant significantly increased the risk of MMD in Korean patients, with an OR of 52.11 (p < 0.001) compared with controls. Moreover, c.14429G>A (p.R4810K) genotypes occurred more frequently in patients with a family history of MMD. The homozygous variant was highly associated with early-onset MMD (age at onset < 5 years), cerebral infarction at diagnosis, and cognitive impairment in long-term outcome. CONCLUSIONS The findings indicate that the c.14429G>A (p.R4810K) allele of RNF213 is strongly associated with Korean patients with MMD. The homozygous c.14429G>A (p.R4810K) variant is particularly related to early onset MMD, severe symptomatic manifestations at diagnosis, and poor prognosis. This genotypic variant may be a useful biomarker for early-onset MMD or unstable MMD with cerebral infarction, which requires early diagnosis and revascularization treatment. PMID- 26430848 TI - Gamma Knife radiosurgery for vestibular schwannomas: evaluation of tumor control and its predictors in a large patient cohort in The Netherlands. AB - OBJECT The authors of this study sought to assess tumor control and complication rates in a large cohort of patients who underwent Gamma Knife radiosurgery (GKRS) for vestibular schwannoma (VS) and to identify predictors of tumor control. METHODS The records of 420 patients treated with GKRS for VS with a median marginal dose of 11 Gy were retrospectively analyzed. Patients with neurofibromatosis Type 2 or who had undergone treatment for VS previously were excluded. The authors assessed tumor control and complication rates with chart review and used the Cox proportional hazards model to identify predictors of tumor control. Preservation of serviceable hearing, defined as Gardner-Robertson Class I-II, was evaluated in a subgroup of 71 patients with serviceable hearing at baseline and with available follow-up audiograms. RESULTS The median VS tumor volume was 1.4 cm(3), and the median length of follow-up was 5.1 years. Actuarial 5-and 10-year tumor control rates were 91.3% and 84.8%, respectively. Only tumor volume was a statistically significant predictor of tumor control rate. The tumor control rate decreased from 94.1% for tumors smaller than 0.5 cm(3) to 80.7% for tumors larger than 6 cm(3). Thirteen patients (3.1%) had new or increased permanent trigeminal nerve neuropathy, 4 (1.0%) had new or increased permanent facial weakness, and 5 (1.2%) exhibited new or increased hydrocephalus requiring a shunting procedure. Actuarial 3-year and 5-year hearing preservation rates were 65% and 42%, respectively. CONCLUSIONS The 5-year actuarial tumor control rate of 91.3% in this cohort of patients with VS compared slightly unfavorably with the rates reported in other large studies, but the complication and hearing preservation rates in this study were similar to those reported previously. Various factors may contribute to the observed differences in reported outcomes. These factors include variations in treatment indication and in the definition of treatment failure, as well as a lack of standardization of terminology and of evaluation of complications. Last, differences in dosimetric variables may also be an explanatory factor. PMID- 26430850 TI - Endoscope-assisted retrosigmoid infralabyrinthine approach to jugular foramen tumors. AB - OBJECTIVE: Removal of jugular foramen (JF) tumors usually requires extensive skull base approaches and is frequently associated with postoperative morbidities such as lower cranial nerve injury. The endoscope-assisted retrosigmoid infralabyrinthine approach is a relatively new approach to tumors extending into the bony canal of the JF. The authors present their experience with this approach. METHODS: The endoscope-assisted retrosigmoid infralabyrinthine approach was used in 7 patients, including 5 with schwannomas and 2 with paragangliomas. The access to the tumor, extent of its removal, postoperative neurological outcome, and approach-related morbidities were evaluated. RESULTS: Two patients had a history of previous partial tumor removal, and 1 was treated by embolization followed by two courses of Gamma Knife radiosurgery. In this latter patient near-total resection was achieved. Gross-total resection was possible in the remaining 6 patients. Five patients benefited from endoscopic assistance: in 2 patients it showed a tumor remnant after microscopic tumor removal, while in 3 patients it allowed safe removal of the intraforaminal tumor by visualizing the surrounding structures. No permanent neurological deficit was observed after the operation. Two patients presenting with swallowing disturbance had temporary postoperative worsening that improved later. One patient developed CSF leakage that was managed with a lumbar drain. CONCLUSIONS: This study shows that the judicious application of the endoscope-assisted retrosigmoid infralabyrinthine approach is safe and effective for removal of the schwannomas extending into the JF and selected paragangliomas without significant luminal invasion of the sigmoid-jugular system. PMID- 26430849 TI - Quality of survival the 1st year with glioblastoma: a longitudinal study of patient-reported quality of life. AB - OBJECTIVE: By exploring longitudinal patient-reported health-related quality of life (HRQoL), the authors sought to assess the quality of survival for patients in the 1st year after diagnosis of glioblastoma. METHODS: Thirty unselected patients >= 18 years who underwent primary surgery for glioblastoma in the period 2011-2013 were included. Using the generic HRQoL questionnaire EQ-5D 3L, baseline HRQoL was assessed before surgery and at postoperative follow-up after 1, 2, 4, 6, 8, 10, and 12 months. RESULTS: There was an apparent correlation between deterioration in HRQoL scores and tumor progression. Patients with permanent deterioration in HRQoL early after surgery represented a subgroup with rapid progression and short survival. Both positive and negative changes in HRQoL were more often seen after surgery than after radio- or chemotherapy. Patients with gross-total resection (GTR) reported better and more stable HRQoL. In a multivariable analysis preoperative cognitive symptoms (p = 0.02), preoperative functional status (p = 0.03), and GTR (p = 0.01) were independent predictors of quality of survival (area under the curve for EQ-5D 3L index values). CONCLUSIONS: The results indicate that progression-free survival is not only a surrogate marker for survival, but also for quality of survival. Quality of survival seems to be associated with GTR, which adds further support for opting for extensive resections in glioblastoma patients with good preoperative functional levels. PMID- 26430852 TI - Structural, Optical, and Electrical Characterization of Yttrium-Substituted BiFeO3 Ceramics Prepared by Mechanical Activation. AB - Ceramics of Bi(1-x)Y(x)FeO3 solid solutions (x = 0.02, 0.07, and 0.10) have been prepared by mechanical activation followed by sintering. The effect of yttrium content on the structural, electrical, and optical properties of the materials has been studied. Thus, single-phase solid solutions with rhombohedral R3c structure have been achieved for x = 0.02 and 0.07, while for x = 0.10 the main R3c phase has been detected together with a small amount of the orthorhombic Pbnm phase. Multiferroic properties of the samples, studied by differential scanning calorimetry (DSC), showed that both T(N) and T(C) (temperatures of the antiferromagnetic-paramagnetic and ferroelectric-paraelectric transitions, respectively) decrease with increasing yttrium content. The nature of the ferroelectric-paraelectric transition has been studied by temperature-dependent X ray diffraction (XRD), which revealed rhombohedral R3c to orthorhombic Pbnm phase transitions for x = 0.07 and 0.10. On the other hand, for x = 0.02 the high temperature phase was indexed as Pnma. Optical properties of the samples, as studied by diffuse reflectance spectroscopy, showed low optical band gap that decreases with increasing yttrium content. Prepared ceramics were highly insulating at room temperature and electrically homogeneous, as assayed by impedance spectroscopy, and the conductivity increased with x. PMID- 26430851 TI - Blood is thicker than booze: Examining the role of familism and gender in alcohol use and related consequences among Hispanic college students. AB - The present study evaluated cultural, ethnic, and gender differences in drinking and alcohol-related problems among Hispanic students. Familism protects against negative outcomes in Hispanic populations, thus we expected familism to buffer against alcohol problems. Participants (N = 623; 53% female) completed a battery of measures. Results suggested that familism was protective against drinking. Furthermore, alcohol use mediated the association between familism and alcohol related problems. In sum, understanding that culture plays an important role in people's behaviors and identifying protective factors is critical to inform culturally sensitive prevention and intervention efforts. PMID- 26430853 TI - Radiation-associated sarcoma after recurrent colorectal primary tumor: A complex surgical case. AB - Radiation associated sarcoma is a significant consequence of cancer therapy. Incidence of radiation associated sarcoma correlates with overall radiotherapy exposure. Prognosis is generally poor with 5 year survival rates lower than that for spontaneously occurring sarcomas. Surgical management presents many challenges including having to work in irradiated tissue planes while trying to achieve negative margins. We present a patient with a rare radiation associated pelvic sarcoma whose course illustrates the complexity of this problem. PMID- 26430854 TI - Nature plus nurture: the triggering of multiple sclerosis. AB - Recent clinical and experimental studies indicate that multiple sclerosis develops as consequence of a failed interplay between genetic ("nature") and environmental ("nurture") factors. A large number of risk genes favour an autoimmune response against the body's own brain matter. New experimental data indicate that the actual trigger of this attack is however provided by an interaction of brain-specific immune cells with components of the regular commensal gut flora, the intestinal microbiota. This concept opens the way for new therapeutic approaches involving modulation of the microbiota by dietary or antibiotic regimens. PMID- 26430855 TI - Bacterial diversity and community composition from seasurface to subseafloor. AB - We investigated compositional relationships between bacterial communities in the water column and those in deep-sea sediment at three environmentally distinct Pacific sites (two in the Equatorial Pacific and one in the North Pacific Gyre). Through pyrosequencing of the v4-v6 hypervariable regions of the 16S ribosomal RNA gene, we characterized 450,104 pyrotags representing 29,814 operational taxonomic units (OTUs, 97% similarity). Hierarchical clustering and non-metric multidimensional scaling partition the samples into four broad groups, regardless of geographic location: a photic-zone community, a subphotic community, a shallow sedimentary community and a subseafloor sedimentary community (?1.5 meters below seafloor). Abundance-weighted community compositions of water-column samples exhibit a similar trend with depth at all sites, with successive epipelagic, mesopelagic, bathypelagic and abyssopelagic communities. Taxonomic richness is generally highest in the water-column O2 minimum zone and lowest in the subseafloor sediment. OTUs represented by abundant tags in the subseafloor sediment are often present but represented by few tags in the water column, and represented by moderately abundant tags in the shallow sediment. In contrast, OTUs represented by abundant tags in the water are generally absent from the subseafloor sediment. These results are consistent with (i) dispersal of marine sedimentary bacteria via the ocean, and (ii) selection of the subseafloor sedimentary community from within the community present in shallow sediment. PMID- 26430857 TI - A Tribute to Dr. Diane Billings. PMID- 26430856 TI - Discordant temporal development of bacterial phyla and the emergence of core in the fecal microbiota of young children. AB - The colonization pattern of intestinal microbiota during childhood may impact health later in life, but children older than 1 year are poorly studied. We followed healthy children aged 1-4 years (n=28) for up to 12 months, during which a synbiotic intervention and occasional antibiotics intake occurred, and compared them with adults from the same region. Microbiota was quantified with the HITChip phylogenetic microarray and analyzed with linear mixed effects model and other statistical approaches. Synbiotic administration increased the stability of Actinobacteria and antibiotics decreased Clostridium cluster XIVa abundance. Bacterial diversity did not increase in 1- to 5-year-old children and remained significantly lower than in adults. Actinobacteria, Bacilli and Clostridium cluster IV retained child-like abundances, whereas some other groups were converting to adult-like profiles. Microbiota stability increased, with Bacteroidetes being the main contributor. The common core of microbiota in children increased with age from 18 to 25 highly abundant genus-level taxa, including several butyrate-producing organisms, and developed toward an adult like composition. In conclusion, intestinal microbiota is not established before 5 years of age and diversity, core microbiota and different taxa are still developing toward adult-type configuration. Discordant development patterns of bacterial phyla may reflect physiological development steps in children. PMID- 26430858 TI - Providing Continuing Education for International Nurses. AB - In an increasingly globalized world, providing continuing education (CE) for nurses is becoming a more common opportunity for U.S. educators. It is important for educators to provide CE programs in a culturally competent and sensitive environment. The challenges involved include effective communication, appropriate teaching methodologies, contextually appropriate content, and awareness of cultural-specific needs and customs. PMID- 26430859 TI - Pupillometry: Cutting Edge Biometrics for Early Intervention in Increased Intracranial Pressure. AB - The pupillometer, a cutting-edge biometric device, is a valuable assessment tool that can aid in the early detection and prompt treatment of neurological abnormalities. Pupil assessment is a critical component of the neurological examination, and manual pupil assessment leaves much room for error. Automated pupillometry improves the quality and reliability of pupillary and neurological assessments, ultimately improving patient outcomes. PMID- 26430860 TI - The Professional Development Educator as a FITness Trainer. AB - Professional development educators play an important role in advancing leadership development by ensuring a FIT (Fun and Forgiveness, Intelligence and Integrity, Teamwork and Transparency) workforce. This article addresses the complementarity of FIT as an organizing model for leadership development. PMID- 26430861 TI - The Language of Scholarship: How to Rapidly Locate and Avoid Common APA Errors. AB - This article is relevant for nurses and nursing students who are writing scholarly documents for work, school, or publication and who have a basic understanding of American Psychological Association (APA) style. Common APA errors on the reference list and in citations within the text are reviewed. Methods to quickly find and reduce those errors are shared. PMID- 26430862 TI - Continuing Education in Patient Safety: Massive Open Online Courses as a New Training Tool. AB - OBJECTIVES: Describe the use of two massive open online courses designed to provide education on patient safety. Review follow-up evaluation data from the courses. DISCLOSURE STATEMENT: Neither the planners nor the authors have any conflicts of interest to disclose. BACKGROUND: The Nursing School of the University of Cantabria conducted a training session on patient safety through two massive open online courses (MOOCs) aimed at the general population and especially Spanish-speaking health professionals. This study aimed to analyze the profile of health professionals who have completed the courses, their degree of satisfaction, and the percentage of completion. METHOD: In this retrospective and observational study, two MOOCs on clinical safety were created through an online platform (MiriadaX). Quantitative analysis of the profile of health professionals, their degree of satisfaction, and the percentage of completion was performed. RESULTS: A total of 12,400 students were enrolled, and the average completion rate was 32%. The profile of the average student was female, 37 years old, college educated, a nurse in a hospital, and interested in the course because it may be useful for performing her work. Fifty-five percent of students were very satisfied with the course. CONCLUSION: MOOCs are considered to be effective and easily accessible, with quality content for professional continuing education that encourages interdisciplinary work and meeting professionals from around the world. PMID- 26430864 TI - From Transition Shock to Competent Practice: Developing Preceptors to Support New Nurse Transition. AB - BACKGROUND: It is well known that new graduate nurses (NGRNs) are likely to have a difficult transition from nursing school into professional practice and often experience a phenomenon known as transition shock. Evidence suggests using preceptors as an effective method supporting the NGRNs through this difficult transition. METHOD: This project evaluated the effectiveness of a structured preceptor development program by measuring perceptions of transition to practice and first-year retention of two groups of former graduate nurses-the first comprising preceptors trained through a preceptor development program, and the second comprising preceptors who did not participate in structured training. RESULTS: Graduate nurses who had well-trained preceptors had higher, more positive perceptions about their ability to render safe and optimal care, as well as higher first-year retention. CONCLUSION: A structured preceptor-training program may contribute to an improved transition to practice and improved first year retention rates of NGRNs. PMID- 26430865 TI - Baseline Indicators and Implementation Strategies in a Statewide Correctional Nurse Competencies Program: Mid-Year Report. AB - BACKGROUND: This 3-year, public-academic workforce development project aimed to establish indicators for quality correctional nursing care to empirically test the translation of correctional nursing standards into practical and applied competencies. METHOD: Approaches to document indicators and achieve implementation of a correctional nurse competency system include (a) knowledge transfer and exchange, (b) system mapping, (c) adherence to implementation plan and strategy, and (d) practice-based action research. RESULTS: Indicators were established. Twenty-five percent (n = 111) of nurses maintained clinical credentials beyond the basic requirements; 86% (n = 381) of nurses received continuing nursing education certificates, 98% (n = 434) of nurses were satisfied with the program, and 43% (n = 9,052) of inmate/patients were satisfied with clinical care. Quality ratings of program educators averaged 4.79 on a 5-point scale. CONCLUSION: Innovation is supported by adding continuous improvement components to the implementation of a correctional nurse competency system effort. Team members' consensus decision making enabled them to apply their domain-specific knowledge to assess the success of the implementation strategy. PMID- 26430866 TI - Implementation of a Preceptor Training Program. AB - A residency program in hospitals that use preceptorships is an important strategy for the retention of new graduate RNs. Preceptors need training to be effective in their role, and this education involves knowing how to implement the roles of the preceptor, such as role model, socializer, educator, and evaluator. A large regional medical center identified the need for a preceptor education program to improve the preceptor program experience for the preceptor and increase the retention of newly hired RNs. A preceptor training program was developed, using a blended approach. The approach included use of online modules of key concepts related to the roles of the preceptor, followed by a face-to-face class that reinforced the concepts. Increased knowledge of the preceptor's roles can help the preceptor work with the preceptee in his or her individual unit and promote retention of the new graduate RNs as they transition to practice in their first year of employment. PMID- 26430867 TI - Engaging Clinical Nurses in Quality Improvement Projects. AB - Clinical nurses have the knowledge and expertise required to provide efficient and proficient patient care. Time and knowledge deficits can prevent nurses from developing and implementing quality improvement or evidence-based practice projects. This article reviews a process for professional development of clinical nurses that helped them to define, implement, and analyze quality improvement or evidence-based practice projects. The purpose of this project was to educate advanced clinical nurses to manage a change project from inception to completion, using the Six Sigma DMAIC (Define, Measure, Analyze, Improve, Control) Change Acceleration Process as a framework. One-to-one mentoring and didactic in services advanced the knowledge, appreciation, and practice of advanced practice clinicians who completed multiple change projects. The projects facilitated clinical practice changes, with improved patient outcomes; a unit cultural shift, with appreciation of quality improvement and evidence-based projects; and engagement with colleagues. Project outcomes were displayed in poster presentations at a hospital exposition for knowledge dissemination. PMID- 26430868 TI - Thyroid carcinoma: epidemiology, histology, and diagnosis. PMID- 26430869 TI - Local treatment of differentiated thyroid carcinoma. PMID- 26430870 TI - Targeted therapy for advanced or metastatic differentiated thyroid carcinoma. PMID- 26430871 TI - New and emerging therapeutic options for thyroid carcinoma: A&A discussion. PMID- 26430872 TI - Reaction Intermediates Kinetics in Solution Investigated by Electrospray Ionization Mass Spectrometry: Diaurated Complexes. AB - A new method to investigate the reaction kinetics of intermediates in solution by electrospray ionization mass spectrometry is presented. The method, referred to as delayed reactant labeling, allows investigation of a reaction mixture containing isotopically labeled and unlabeled reactants with different reaction times. It is shown that we can extract rate constants for the degradation of reaction intermediates and investigate the effects of various reaction conditions on their half-life. This method directly addresses the problem of the relevance of detected gaseous ions toward the investigated reaction solution. It is demonstrated for geminally diaurated intermediates formed in the gold mediated addition of methanol to alkynes. Delayed reactant labeling allows us to directly link the kinetics of the diaurated intermediates with the overall reaction kinetics determined by NMR spectroscopy. It is shown that the kinetics of protodeauration of these intermediates mirrors the kinetics of the addition of methanol demonstrating they are directly involved in the catalytic cycle. Formation as well as decomposition of diaurated intermediates can be drastically slowed down by employing bulky ancillary ligands at the gold catalyst; the catalytic cycle then proceeds via monoaurated intermediates. The reaction is investigated for 1-phenylpropyne (Ph-CC-CH3) using [AuCl(PPh3)]/AgSbF6 and [AuCl(IPr)]/AgSbF6 as model catalysts. Delayed reactant labeling is achieved by using a combination of CH3OH and CD3OH or Ph-CC-CH3 and Ph-CC-CD3. PMID- 26430874 TI - NMR Spectra of Glycine Isotopomers in Anisotropic Media: Subtle Chiral Interactions. AB - NMR spectra of deuterated glycine-2-(13)C revealed interactions between chiral anisotropic gelatin and kappa-carrageenan gels and the prochiral and chiral isotopomers. The (1)H, (2)H and (13)C NMR spectra of mixtures of racemic mono- and prochiral bis-deuterated glycine-2-(13)C were resolved and well simulated using distinct dipolar coupling constants DCalphaH and DCalphaD for the enantiomers and also for the -(13)CalphaD2- group (DC,DA, and DC,DB). The orientation of the proton or deuteron on the (13)Calpha-atom of glycine was assigned by analogy with alanine and lactate assuming that the molecular orientation of glycine isotopomers is the same. The assignment of the prochiral sites was derived from chiral analogues. PMID- 26430875 TI - Development of (Trifluoromethyl)zinc Reagent as Trifluoromethyl Anion and Difluorocarbene Sources. AB - The trifluoromethylation of carbonyl compounds is accomplished by the stable (trifluoromethyl)zinc reagent generated and then isolated from CF3I and ZnEt2, which can be utilized as a trifluoromethyl anion source (CF3(-)). The reaction proceeds smoothly with diamine as a ligand and ammonium salt as an initiator, providing the corresponding trifluoromethylated alcohol products. Moreover, the (trifluoromethyl)zinc reagent can also be employed as a difluorocarbene source (:CF2) not only for gem-difluoroolefination of carbonyl compounds with phosphine but also for gem-difluorocyclization of alkenes or alkynes via the thermal decomposition, respectively. PMID- 26430873 TI - Targeting MCM2 function as a novel strategy for the treatment of highly malignant breast tumors. AB - Highly malignant tumors express high levels of the minichromosome maintenance 2 (MCM2) protein, which is associated with advanced tumor grade, advanced stage, and poor prognosis. In a previous study, we showed that Friend leukemia virus (FLV) envelope protein gp70 bound MCM2, impaired its nuclear translocation, and enhanced DNA-damage-induced apoptosis in FLV-infected hematopoietic cells when the cells expressed high levels of MCM2. Here, we show that MCM2 is highly expressed in clinical samples of invasive carcinoma of the breast, especially triple-negative breast cancer (TNBC), and in cancer stem cell (CSC) marker positive breast cancer cells. To generate a cancer therapy model using gp70, we introduced the gp70 protein into the cytoplasm of murine breast cancer cells that express high levels of MCM2 by conjugating the protein transduction domain (PTD) of Hph-1 to gp70 (Hph-1-gp70). Hph-1-gp70 was successfully transduced into the cytoplasm of breast cancer cells. The transduced protein enhanced the DNA damage induced apoptosis of cancer cells in vitro and in vivo. Therefore, an MCM2 targeted strategy using Hph-1-gp70 treatment to induce DNA damage might be a successful therapy for highly malignant breast cancers such as TNBC and for the eradication of CSC-like cells from breast cancer tissue. PMID- 26430876 TI - Noncovalent Ruthenium(II) Complexes-Single-Walled Carbon Nanotube Composites for Bimodal Photothermal and Photodynamic Therapy with Near-Infrared Irradiation. AB - To enhance the efficacy and optimize the treatment of cancers, the integration of multimodal treatment strategies leading to synergistic effects is a promising approach. The coassembly of multifunctional agents for systematic therapies has received considerable interest in cancer treatment. Herein, Ru(II) complex functionalized single-walled carbon nanotubes (Ru@SWCNTs) are developed as nanotemplates for bimodal photothermal and two-photon photodynamic therapy (PTT TPPDT). SWCNTs have the ability to load a great amount of Ru(II) complexes (Ru1 or Ru2) via noncovalent pi-pi interactions. The loaded Ru(II) complexes are efficiently released by the photothermal effect of irradiation from an 808 nm diode laser (0.25 W/cm(2)). The released Ru(II) complexes produce singlet oxygen species ((1)O2) upon two-photon laser irradiation (808 nm, 0.25 W/cm(2)) and can be used as a two-photon photodynamic therapy (TPPDT) agent. Based on the combination of photothermal therapy and two-photon photodynamic therapy, Ru@SWCNTs have greater anticancer efficacies than either PDT using Ru(II) complexes or PTT using SWCNTs in two-dimensional (2D) cancer cell and three dimensional (3D) multicellular tumor spheroid (MCTS) models. Furthermore, in vivo tumor ablation is achieved with excellent treatment efficacy under a diode laser (808 nm) irradiation at the power density of 0.25 W/cm(2) for 5 min. This study examines an efficacious bimodal PTT and TPPDT nanoplat form for the development of cancer therapeutics. PMID- 26430877 TI - Enzyme-Free Amplification by Nano Sticky Balls for Visual Detection of ssDNA/RNA Oligonucleotides. AB - Visual detection of nucleic acids provides simple and rapid screening for infectious diseases or environmental pathogens. However, sensitivity is the current bottleneck, which may require enzymatic amplification for targets in low abundance and make them incompatible with detection at resource-limited sites. Here we report an enzyme-free amplification that provides a sensitive visual detection of ssDNA/RNA oligonucleotides on the basis of nano "sticky balls". When target oligonucleotides are present, magnetic microparticles (MMPs) and gold nanoparticles (AuNPs) were linked together, allowing the collection of AuNPs after magnetic attraction. Subsequently, the collected AuNPs, which carry many oligonucleotides, were used as the sticky balls to link a second pair of MMPs and polymer microparticles (PMPs). Thus, because the magnetic field can attract the MMPs as well as the linked PMPs to the sidewall, the reduction of suspended PMPs yields a change of light transmission visible by the naked eye. Our results demonstrate that the limit of detection is 10 amol for ssDNAs (228 fM in 45 MUL) and 75 amol for ssRNAs (1.67 pM in 45 MUL). This method is also compatible with the serum environment and detection of a microRNA, miR-155, derived from human breast cancer cells. With significantly improved sensitivity for visual detection, it provides great potential for point-of-care applications at resource limited sites. PMID- 26430878 TI - Synthesis of Fluorine-Containing Phosphodiesterase 10A (PDE10A) Inhibitors and the In Vivo Evaluation of F-18 Labeled PDE10A PET Tracers in Rodent and Nonhuman Primate. AB - A series of fluorine-containing PDE10A inhibitors were designed and synthesized to improve the metabolic stability of [(11)C]MP-10. Twenty of the 22 new analogues had high potency and selectivity for PDE10A: 18a-j, 19d-j, 20a-b, and 21b had IC50 values <5 nM for PDE10A. Seven F-18 labeled compounds [(18)F]18a-e, [(18)F]18g, and [(18)F]20a were radiosynthesized by (18)F-introduction onto the quinoline rather than the pyrazole moiety of the MP-10 pharmacophore and performed in vivo evaluation. Biodistribution studies in rats showed ~2-fold higher activity in the PDE10A-enriched striatum than nontarget brain regions; this ratio increased from 5 to 30 min postinjection, particularly for [(18)F]18a d and [(18)F]20a. MicroPET studies of [(18)F]18d and [(18)F]20a in nonhuman primates provided clear visualization of striatum with suitable equilibrium kinetics and favorable metabolic stability. These results suggest this strategy may identify a (18)F-labeled PET tracer for quantifying the levels of PDE10A in patients with CNS disorders including Huntington's disease and schizophrenia. PMID- 26430879 TI - Lipopolysaccharide-Induced Differential Expression of miRNAs in Male and Female Rhipicephalus haemaphysaloides Ticks. AB - Lipopolysaccharide (LPS) stimulates the innate immune response in arthropods. In tick vectors, LPS activates expression of immune genes, including those for antibacterial peptides. miRNAs are 21-24 nt non-coding small RNAs that regulate target mRNAs at the post-transcriptional level. However, our understanding of tick innate immunity is limited to a few cellular immune reactions and some characterized immune molecules. Moreover, there is little information on the regulation of the immune system in ticks by miRNA. Therefore, this study aimed to analyze the differential expression of miRNAs in male and female ticks after LPS injection. LPS was injected into male and female Rhipicephalus haemaphysaloides ticks to stimulate immune response, with phosphate buffered saline (PBS)-injected ticks as negative controls. miRNAs from each group were sequenced and analyzed. In the PBS- and LPS-injected female ticks, 11.46 and 12.82 million reads of 18-30 nt were obtained respectively. There were 13.92 and 15.29 million reads of 18-30 nt obtained in the PBS- and LPS-injected male ticks, respectively. Expression of miRNAs in male ticks was greater than that in female ticks. There were 955 and 984 conserved miRNA families in the PBS- and LPS-injected female ticks, respectively, and correspondingly 1684 and 1552 conserved miRNA families in male ticks. Nine novel miRNAs were detected as common miRNAs in two or more tested samples. There were 37 known miRNAs up-regulated >10-fold and 33 down-regulated >10-fold in LPS-injected female ticks; and correspondingly 52 and 59 miRNAs in male ticks. Differential expression of miRNAs in PBS- and LPS-injected samples supports their involvement in the regulation of innate immunity. These data provide an important resource for more detailed functional analysis of miRNAs in this species. PMID- 26430880 TI - Characterization of Biofilm Formation in [Pasteurella] pneumotropica and [Actinobacillus] muris Isolates of Mouse Origin. AB - [Pasteurella] pneumotropica biotypes Jawetz and Heyl and [Actinobacillus] muris are the most prevalent Pasteurellaceae species isolated from laboratory mouse. However, mechanisms contributing to their high prevalence such as the ability to form biofilms have not been studied yet. In the present investigation we analyze if these bacterial species can produce biofilms in vitro and investigate whether proteins, extracellular DNA and polysaccharides are involved in the biofilm formation and structure by inhibition and dispersal assays using proteinase K, DNase I and sodium periodate. Finally, the capacity of the biofilms to confer resistance to antibiotics is examined. We demonstrate that both [P.] pneumotropica biotypes but not [A.] muris are able to form robust biofilms in vitro, a phenotype which is widely spread among the field isolates. The biofilm inhibition and dispersal assays by proteinase and DNase lead to a strong inhibition in biofilm formation when added at the initiation of the biofilm formation and dispersed pre-formed [P.] pneumotropica biofilms, revealing thus that proteins and extracellular DNA are essential in biofilm formation and structure. Sodium periodate inhibited the bacterial growth when added at the beginning of the biofilm formation assay, making difficult the assessment of the role of beta-1,6-linked polysaccharides in the biofilm formation, and had a biofilm stimulating effect when added on pre-established mature biofilms of [P.] pneumotropica biotype Heyl and a majority of [P.] pneumotropica biotype Jawetz strains, suggesting that the presence of beta-1,6-linked polysaccharides on the bacterial surface might attenuate the biofilm production. Conversely, no effect or a decrease in the biofilm quantity was observed by biofilm dispersal using sodium periodate on further biotype Jawetz isolates, suggesting that polysaccharides might be incorporated in the biofilm structure. We additionally show that [P.] pneumotropica cells enclosed in biofilms were less sensitive to treatment with amoxicillin and enrofloxacin than planktonic bacteria. Taken together, these findings provide a first step in understanding of the biofilm mechanisms in [P.] pneumotropica, which might contribute to elucidation of colonization and pathogenesis mechanisms for these obligate inhabitants of the mouse mucosa. PMID- 26430881 TI - A Unique Expression of Keratin 14 in a Subset of Trophoblast Cells. AB - The placenta, a transient organ in human, is essential for pregnancy maintenance and for fetal growth and development. Trophoblast and stromal cells are the main cell types present in human placenta. Trophoblast cells are present in different subtypes depending on their differentiation state and their temporal and spatial location during pregnancy. The stromal cells are of extraembryonic mesenchymal origin and are important for villous formation and maintenance. Interestingly, many pregnancy-related diseases are associated with defect in trophoblast differentiation and villous integrity. Therefore, it's crucial to specifically identify each type of placental cells using specific markers. Keratins (CK) are widely used as marker of epithelial cells, cancer origin identification and in some cases as marker of stem/progenitor cells. Vimentin is widely used as marker of mesenchymal cells. The aim of this study is to characterize the presence of different keratins in human trophoblast cells and vimentin in stromal cells. Using immunohistochemistry on term placental sections, our results show that vimentin is solely expressed in stromal-mesenchymal cells while keratins 5, 7, 8, 14 and 19 are expressed in trophoblast cells. Interestingly, all keratins tested, except for keratin 14, were evenly expressed in all trophoblast cells. Keratin 14 was expressed in a subset of CK7 positive cells. Moreover, the same results were obtained when using freshly isolated cytotrophoblast cells or BeWo cells. In conclusion, this study is a crucial step in the advancement of our knowledge in placental cell type identification and characterization. PMID- 26430882 TI - Altered Monocyte Phenotype in HIV-1 Infection Tends to Normalize with Integrase Inhibitor-Based Antiretroviral Therapy. AB - BACKGROUND: Monocytes are increasingly implicated in the inflammatory consequences of HIV-1 disease, yet their phenotype following antiretroviral therapy (ART) initiation is incompletely defined. Here, we define more completely monocyte phenotype both prior to ART initiation and during 48 weeks of ART. METHODS: Cryopreserved peripheral blood mononuclear cells (PBMCs) were obtained at baseline (prior to ART initiation) and at weeks 12, 24, and 48 of treatment from 29 patients participating in ACTG clinical trial A5248, an open label study of raltegravir/emtricitibine/tenofovir administration. For comparison, cryopreserved PBMCs were obtained from 15 HIV-1 uninfected donors, each of whom had at least two cardiovascular risk factors. Thawed samples were stained for monocyte subset markers (CD14 and CD16), HLA-DR, CCR2, CX3CR1, CD86, CD83, CD40, CD38, CD36, CD13, and CD163 and examined using flow cytometry. RESULTS: In untreated HIV-1 infection there were perturbations in monocyte subset phenotypes, chiefly a higher frequency and density (mean fluorescence intensity-MFI) of HLA DR (%-p = 0.004, MFI-p = .0005) and CD86 (%-p = 0.012, MFI-p = 0.005) expression and lower frequency of CCR2 (p = 0.0002) expression on all monocytes, lower CCR2 density on inflammatory monocytes (p = 0.045) when compared to the expression and density of these markers in controls' monocytes. We also report lower expression of CX3CR1 (p = 0.014) on patrolling monocytes at baseline, compared to levels seen in controls. After ART, these perturbations tended to improve, with decreasing expression and density of HLA-DR and CD86, increasing CCR2 density on inflammatory monocytes, and increasing expression and density of CX3CR1 on patrolling monocytes. CONCLUSIONS: In HIV-1 infected patients, ART appears to attenuate the high levels of activation (HLA-DR, CD86) and to increase expression of the chemokine receptors CCR2 and CX3CR1 on monocyte populations. Circulating monocyte phenotypes are altered in untreated infection and tend to normalize with ART; the role of these cells in the inflammatory environment of HIV-1 infection warrants further study. PMID- 26430884 TI - A Fab-Selective Immunoglobulin-Binding Domain from Streptococcal Protein G with Improved Half-Life Extension Properties. AB - BACKGROUND: Half-life extension strategies have gained increasing interest to improve the pharmacokinetic and pharmacodynamic properties of protein therapeutics. Recently, we established an immunoglobulin-binding domain (IgBD) from streptococcal protein G (SpGC3) as module for half-life extension. SpGC3 is capable of binding to the Fc region as well as the CH1 domain of Fab arms under neutral and acidic conditions. METHODOLOGY/PRINCIPAL FINDINGS: Using site directed mutagenesis, we generated a Fab-selective mutant (SpGC3Fab) to avoid possible interference with the FcRn-mediated recycling process and improved its affinity for mouse and human IgG by site-directed mutagenesis and phage display selections. In mice, this affinity-improved mutant (SpGC3FabRR) conferred prolonged plasma half-lives compared with SpGC3Fab when fused to small recombinant antibody fragments, such as single-chain Fv (scFv) and bispecific single-chain diabody (scDb). Hence, the SpGC3FabRR domain seems to be a suitable fusion partner for the half-life extension of small recombinant therapeutics. CONCLUSIONS/SIGNIFICANCE: The half-life extension properties of SpGC3 can be retained by restricting binding to the Fab fragment of serum immunoglobulins and can be improved by increasing binding activity. The modified SpGC3 module should be suitable to extend the half-life of therapeutic proteins and, thus to improve therapeutic activity. PMID- 26430883 TI - Design of a New Type of Compact Chemical Heater for Isothermal Nucleic Acid Amplification. AB - Previous chemical heater designs for isothermal nucleic acid amplification have been based on solid-liquid phase transition, but using this approach, developers have identified design challenges en route to developing a low-cost, disposable device. Here, we demonstrate the feasibility of a new heater configuration suitable for isothermal amplification in which one reactant of an exothermic reaction is a liquid-gas phase-change material, thereby eliminating the need for a separate phase-change compartment. This design offers potentially enhanced performance and energy density compared to other chemical and electric heaters. PMID- 26430885 TI - Reversing Stimulus Timing in Visual Conditioning Leads to Memories with Opposite Valence in Drosophila. AB - Animals need to associate different environmental stimuli with each other regardless of whether they temporally overlap or not. Drosophila melanogaster displays olfactory trace conditioning, where an odor is followed by electric shock reinforcement after a temporal gap, leading to conditioned odor avoidance. Reversing the stimulus timing in olfactory conditioning results in the reversal of memory valence such that an odor that follows shock is later on approached (i.e. relief conditioning). Here, we explored the effects of stimulus timing on memory in another sensory modality, using a visual conditioning paradigm. We found that flies form visual memories of opposite valence depending on stimulus timing and can associate a visual stimulus with reinforcement despite being presented with a temporal gap. These results suggest that associative memories with non-overlapping stimuli and the effect of stimulus timing on memory valence are shared across sensory modalities. PMID- 26430886 TI - Genotyping by Sequencing for SNP-Based Linkage Map Construction and QTL Analysis of Chilling Requirement and Bloom Date in Peach [Prunus persica (L.) Batsch]. AB - Low-cost, high throughput genotyping methods are crucial to marker discovery and marker-assisted breeding efforts, but have not been available for many 'specialty crops' such as fruit and nut trees. Here we apply the Genotyping-By-Sequencing (GBS) method developed for cereals to the discovery of single nucleotide polymorphisms (SNPs) in a peach F2 mapping population. Peach is a genetic and genomic model within the Rosaceae and will provide a template for the use of this method with other members of this family. Our F2 mapping population of 57 genotypes segregates for bloom time (BD) and chilling requirement (CR) and we have extensively phenotyped this population. The population derives from a selfed F1 progeny of a cross between 'Hakuho' (high CR) and 'UFGold' (low CR). We were able to successfully employ GBS and the TASSEL GBS pipeline without modification of the original methodology using the ApeKI restriction enzyme and multiplexing at an equivalent of 96 samples per Illumina HiSeq 2000 lane. We obtained hundreds of SNP markers which were then used to construct a genetic linkage map and identify quantitative trait loci (QTL) for BD and CR. PMID- 26430889 TI - Correction: A Differential Effect of E. coli Toxin-Antitoxin Systems on Cell Death in Liquid Media and Biofilm Formation. PMID- 26430887 TI - Risk Knowledge in Relapsing Multiple Sclerosis (RIKNO 1.0)--Development of an Outcome Instrument for Educational Interventions. AB - BACKGROUND: Adequate risk knowledge of patients is a prerequisite for shared decision making but few attempts have been made to develop assessment tools. Multiple Sclerosis (MS) is a chronic inflammatory disease of young adults with an increasing number of partially effective immunotherapies and therefore a paradigmatic disease to study patient involvement. OBJECTIVE/METHODS: Based on an item bank of MS risk knowledge items and patient feedback including perceived relevance we developed a risk knowledge questionnaire for relapsing remitting (RR) MS (RIKNO 1.0) which was a primary outcome measure in a patient education trial (192 early RRMS patients). RESULTS: Fourteen of the RIKNO 1.0 multiple choice items were selected based on patient perceived relevance and item difficulty indices, and five on expert opinion. Mean item difficulty was 0.58, ranging from 0.14 to 0.79. Mean RIKNO 1.0 score increased after the educational intervention from 10.6 to 12.4 (p = 0.0003). Selected items were particularly difficult (e.g. those on absolute risk reductions of having a second relapse) and were answered correctly in only 30% of the patients, even after the intervention. CONCLUSION: Despite its high difficulty, RIKNO 1.0 is a responsive instrument to assess risk knowledge in RRMS patients participating in educational interventions. PMID- 26430888 TI - The Suramin Derivative NF449 Interacts with the 5-fold Vertex of the Enterovirus A71 Capsid to Prevent Virus Attachment to PSGL-1 and Heparan Sulfate. AB - NF449, a sulfated compound derived from the antiparasitic drug suramin, was previously reported to inhibit infection by enterovirus A71 (EV-A71). In the current work, we found that NF449 inhibits virus attachment to target cells, and specifically blocks virus interaction with two identified receptors--the P selectin ligand, PSGL-1, and heparan sulfate glycosaminoglycan--with no effect on virus binding to a third receptor, the scavenger receptor SCARB2. We also examined a number of commercially available suramin analogues, and newly synthesized derivatives of NF449; among these, NF110 and NM16, like NF449, inhibited virus attachment at submicromolar concentrations. PSGL-1 and heparan sulfate, but not SCARB2, are both sulfated molecules, and their interaction with EV-A71 is thought to involve positively charged capsid residues, including a conserved lysine at VP1-244, near the icosahedral 5-fold vertex. We found that mutation of VP1-244 resulted in resistance to NF449, suggesting that this residue is involved in NF449 interaction with the virus capsid. Consistent with this idea, NF449 and NF110 prevented virus interaction with monoclonal antibody MA28 7, which specifically recognizes an epitope overlapping VP1-244 at the 5-fold vertex. Based on these observations we propose that NF449 and related compounds compete with sulfated receptor molecules for a binding site at the 5-fold vertex of the EV-A71 capsid. PMID- 26430890 TI - Quantification of Pathologic Air Trapping in Lung Transplant Patients Using CT Density Mapping: Comparison with Other CT Air Trapping Measures. AB - To determine whether density mapping (DM) is more accurate for detection and quantification of pathologic air trapping (pAT) in patients after lung transplantation compared to other CT air trapping measures. One-hundred forty seven lung and heart-lung transplant recipients underwent CT-examinations at functional residual capacity (FRC) and total lung capacity (TLC) and PFT six months after lung transplantation. Quantification of air trapping was performed with the threshold-based method in expiration (EXP), density mapping (DM) and the expiratory to inspiratory ratio of the mean lung density (E/I-ratio MLD). A non rigid registration of inspiration-expiration CT-data with a following voxel-to voxel mapping was carried out for DM. Systematic variation of attenuation ranges was performed for EXP and DM and correlated with the ratio of residual volume to total lung capacity (RV/TLC) by Spearman rank correlation test. AT was considered pathologic if RV/TLC was above the 95th percentile of the predicted upper limit of normal values. Receiver operating characteristic (ROC) analysis was performed. The optimal attenuation range for the EXP method was from -790 HU to -950 HU (EXP(-790 to -950HU)) (r = 0.524, p<0.001) to detect air trapping. Within the segmented lung parenchyma, AT was best defined as voxel difference less than 80 HU between expiration and registered inspiration using the DM method. DM correlated best with RV/TLC (r = 0.663, p<0.001). DM and E/I-ratio MLD showed a larger AUC (0.78; 95% CI 0.69-0.86; 0.76, 95% CI 0.67-0.85) than EXP(-790 HU to 950 HU) (0.71, 95% CI 0.63-0.78). DM and E/I-ratio MLD showed better correlation with RV/TLC and are more suited quantitative CT-methods to detect pAT in lung transplant patients than the EXP(-790HU to -950HU). PMID- 26430891 TI - Porcine SOX9 Gene Expression Is Influenced by an 18 bp Indel in the 5' Untranslated Region. AB - Sex determining region Y-box 9 (SOX9) is an important regulator of sex and skeletal development and is expressed in a variety of embryonal and adult tissues. Loss or gain of function resulting from mutations within the coding region or chromosomal aberrations of the SOX9 locus lead to a plethora of detrimental phenotypes in humans and animals. One of these phenotypes is the so called male-to-female or female-to-male sex-reversal which has been observed in several mammals including pig, dog, cat, goat, horse, and deer. In 38,XX sex reversal French Large White pigs, a genome-wide association study suggested SOX9 as the causal gene, although no functional mutations were identified in affected animals. However, besides others an 18 bp indel had been detected in the 5' untranslated region of the SOX9 gene by comparing affected animals and controls. We have identified the same indel (Delta18) between position +247 bp and +266 bp downstream the transcription start site of the porcine SOX9 gene in four other pig breeds; i.e., German Large White, Laiwu Black, Bamei, and Erhualian. These animals have been genotyped in an attempt to identify candidate genes for porcine inguinal and/or scrotal hernia. Because the 18 bp segment in the wild type 5'-UTR harbours a highly conserved cAMP-response element (CRE) half-site, we analysed its role in SOX9 expression in vitro. Competition and immunodepletion electromobility shift assays demonstrate that the CRE half-site is specifically recognized by CREB. Both binding of CREB to the wild type as well as the absence of the CRE half-site in Delta18 reduced expression efficiency in HEK293T, PK-15, and ATDC5 cells significantly. Transfection experiments of wild type and Delta18 SOX9 promoter luciferase constructs show a significant reduction of RNA and protein levels depending on the presence or absence of the 18 bp segment. Hence, the data presented here demonstrate that the 18 bp indel in the porcine SOX9 5' UTR is of functional importance and may therefore indeed be a causative variation in SOX9 associated traits. PMID- 26430892 TI - Albuminuria as a Risk Factor for Anemia in Chronic Kidney Disease: Result from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD). AB - BACKGROUND: Anemia is a common complication among patients with chronic kidney disease (CKD), and it is associated with unfavorable clinical outcomes in patients with CKD independent of the estimated glomerular filtration rate (eGFR). We assessed the association of the urinary albumin-to-creatinine ratio (ACR) and eGFR with anemia in CKD patients. METHODS: We conducted a cross-sectional study using baseline data from the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD). Multiple regression analysis was performed to identify the independent association of albuminuria with anemia. Furthermore, odds ratios for anemia were calculated by cross-categorization of ACR and eGFR. RESULTS: Among 1,456 patients, the mean age was 53.5 +/- 12.4 years, and the mean eGFR and ACR were 51.9 +/- 30.5 mL/min per 1.73 m2 and 853.2 +/- 1,330.3 mg/g, respectively. Anemia was present in 644 patients (40.5%). Multivariate analysis showed that the odds ratio of anemia increased according to ACR levels, after adjusting for age, sex, eGFR, body mass index, pulse pressure, cause of CKD, use of erythropoiesis stimulating agents, serum calcium and ferritin (ACR < 30 mg/g as a reference group; 30-299 mg/g, adjusted odds ratio (OR) = 1.43, 95% confidence interval (CI) = 0.88-2.33; >=300 mg/g, adjusted OR = 1.86, 95% CI = 1.12-3.10). In addition, graded associations were observed in cross-categorized groups of a higher ACR and eGFR compared to the reference group with an ACR <30 mg/g and eGFR >=60 mL/min per 1.73 m2. CONCLUSION: The present study demonstrated that albuminuria was a significant risk factor for anemia in CKD patients independent of the eGFR. PMID- 26430893 TI - The Role of Self-Compassion in Buffering Symptoms of Depression in the General Population. AB - Self-compassion, typically operationalized as the total score of the Self Compassion Scale (SCS; Neff, 2003b), has been shown to be related to increased psychological well-being and lower depression in students of the social sciences, users of psychology websites and psychotherapy patients. The current study builds on the existing literature by examining the link between self-compassion and depressive symptomatology in a sample representative of the German general population (n = 2,404). The SCS subscales of self-judgment, isolation, and over identification, and the "self-coldness", composite score, which encompass these three negative subscales, consistently differed between subsamples of individuals without any depressive symptoms, with any depressive syndromes, and with major depressive disorder. The contribution of the positive SCS subscales of self kindness, common humanity, and mindfulness to the variance in depressive symptomatology was almost negligible. However, when combined to a "self compassion composite", the positive SCS subscales significantly moderated the relationship between "self-coldness" and depressive symptoms in the general population. This speaks for self-compassion having the potential to buffer self coldness related to depression--providing an argument for interventions that foster self-caring, kind, and forgiving attitudes towards oneself. PMID- 26430894 TI - Enhanced Immune Response to DNA Vaccine Encoding Bacillus anthracis PA-D4 Protects Mice against Anthrax Spore Challenge. AB - Anthrax has long been considered the most probable bioweapon-induced disease. The protective antigen (PA) of Bacillus anthracis plays a crucial role in the pathogenesis of anthrax. In the current study, we evaluated the efficiency of a genetic vaccination with the fourth domain (D4) of PA, which is responsible for initial binding of the anthrax toxin to the cellular receptor. The eukaryotic expression vector was designed with the immunoglobulin M (IgM) signal sequence encoding for PA-D4, which contains codon-optimized genes. The expression and secretion of recombinant protein was confirmed in vitro in 293T cells transfected with plasmid and detected by western blotting, confocal microscopy, and enzyme linked immunosorbent assay (ELISA). The results revealed that PA-D4 protein can be efficiently expressed and secreted at high levels into the culture medium. When plasmid DNA was given intramuscularly to mice, a significant PA-D4-specific antibody response was induced. Importantly, high titers of antibodies were maintained for nearly 1 year. Furthermore, incorporation of the SV40 enhancer in the plasmid DNA resulted in approximately a 15-fold increase in serum antibody levels in comparison with the plasmid without enhancer. The antibodies produced were predominantly the immunoglobulin G2 (IgG2) type, indicating the predominance of the Th1 response. In addition, splenocytes collected from immunized mice produced PA-D4-specific interferon gamma (IFN-gamma). The biodistribution study showed that plasmid DNA was detected in most organs and it rapidly cleared from the injection site. Finally, DNA vaccination with electroporation induced a significant increase in immunogenicity and successfully protected the mice against anthrax spore challenge. Our approach to enhancing the immune response contributes to the development of DNA vaccines against anthrax and other biothreats. PMID- 26430895 TI - Analysis of Food Pairing in Regional Cuisines of India. AB - Any national cuisine is a sum total of its variety of regional cuisines, which are the cultural and historical identifiers of their respective regions. India is home to a number of regional cuisines that showcase its culinary diversity. Here, we study recipes from eight different regional cuisines of India spanning various geographies and climates. We investigate the phenomenon of food pairing which examines compatibility of two ingredients in a recipe in terms of their shared flavor compounds. Food pairing was enumerated at the level of cuisine, recipes as well as ingredient pairs by quantifying flavor sharing between pairs of ingredients. Our results indicate that each regional cuisine follows negative food pairing pattern; more the extent of flavor sharing between two ingredients, lesser their co-occurrence in that cuisine. We find that frequency of ingredient usage is central in rendering the characteristic food pairing in each of these cuisines. Spice and dairy emerged as the most significant ingredient classes responsible for the biased pattern of food pairing. Interestingly while individual spices contribute to negative food pairing, dairy products on the other hand tend to deviate food pairing towards positive side. Our data analytical study highlighting statistical properties of the regional cuisines, brings out their culinary fingerprints that could be used to design algorithms for generating novel recipes and recipe recommender systems. It forms a basis for exploring possible causal connection between diet and health as well as prospection of therapeutic molecules from food ingredients. Our study also provides insights as to how big data can change the way we look at food. PMID- 26430896 TI - Role and Variation of the Amount and Composition of Glomalin in Soil Properties in Farmland and Adjacent Plantations with Reference to a Primary Forest in North Eastern China. AB - The glycoprotein known as glomalin-related soil protein (GRSP) is abundantly produced on the hyphae and spores of arbuscular mycorrhizal fungi (AMF) in soil and roots. Few studies have focused on its amount, composition and associations with soil properties and possible land-use influences, although the data hints at soil rehabilitation. By choosing a primary forest soil as a non-degraded reference, it is possible to explore whether afforestation can improve degraded farmland soil by altering GRSP. In this paper, close correlations were found between various soil properties (soil organic carbon, nitrogen, pH, electrical conductivity (EC), and bulk density) and the GRSP amount, between various soil properties and GRSP composition (main functional groups, fluorescent substances, and elements). Afforestation on farmland decreased the EC and bulk density (p < 0.05). The primary forest had a 2.35-2.56-fold higher GRSP amount than those in the plantation forest and farmland, and GRSP composition (tryptophan-like and fulvic acid-like fluorescence; functional groups of C-H, C-O, and O-H; elements of Al, O, Si, C, Ca, and N) in primary forest differed from those in plantation forest and farmland (p < 0.05). However, no evident differences in GRSP amount and composition were observed between the farmland and the plantation forest. Our finding highlights that 30 years poplar afforestation on degraded farmland is not enough to change GRSP-related properties. A longer period of afforestation with close-to-nature managements may favor the AMF-related underground recovery processes. PMID- 26430898 TI - XXV Annual Meeting of the Latin American Pediatric Endocrinology Society (SLEP), Puerto Varas, Chile, November 3-6, 2015: Abstract. PMID- 26430897 TI - Family-Based Association Study of Pulmonary Function in a Population in Northeast Asia. AB - The spirometric measurement of pulmonary function by measuring the forced expiratory volume in one second (FEV1) is a heritable trait that reflects the physiological condition of the lung and airways. Genome-wide linkage and association studies have identified a number of genes and genetic loci associated with pulmonary function. However, limited numbers of studies have been reported for Asian populations. In this study, we aimed to investigate genetic evidence of pulmonary function in a population in northeast Asia. We conducted a family-based association test with 706 GENDISCAN study participants from 72 Mongolian families to determine candidate genetic determinants of pulmonary function. For the replication, we chose seven candidate single nucleotide polymorphisms (SNPs) from the 5 loci, and tested 1062 SNPs for association with FEV1 from 2,729 subjects of the Korea Healthy Twin study. We identified TMEM132C as a potential candidate gene at 12q24.3, which is a previously reported locus of asthma and spirometric indices. We also found two adjacent candidate genes (UNC93A and TTLL2) in the 6q27 region, which has been previously identified as a pulmonary function locus in the Framingham cohort study. Our findings suggest that novel candidate genes (TMEM132C, UNC93A and TTLL2) in two different regions are associated with pulmonary function in a population in northeast Asia. PMID- 26430900 TI - 47,XY,+der(X)t(X;18)(p11.4;p11.22): A Unique Aneuploidy Associated with Klinefelter Syndrome due to an Extra Derivative X Chromosome Inherited Maternally. AB - A derivative X chromosome formed by translocation involving an X chromosome and a chromosome 18 in a Klinefelter syndrome (KS) patient with a 47,XXY karyotype has not been reported before. In this study, we present the clinical and molecular cytogenetic characteristics. The patient presented with small testes and azoospermia. G-banding analysis identified the karyotype as 47,XY,del(X)(p?11.4). Array CGH detected a 10.36-Mb duplication of chromosome region 18p11.22p11.32 (14,316-10,377,516) and a 111.18-Mb duplication of chromosome region Xp11.4q28 (61,931, 689-155,111,583), in addition to the normal chromosome 18 and an X chromosome. FISH results further revealed the extra 18p located at the end of the short arm of a deleted X chromosome, forming a derivative X chromosome. Finally, we identified the karyotype of the patient as 47,XY,+der(X)t(X;18)(p11.4;p11.22). The derivative X chromosome was maternally inherited. To our knowledge, this rare karyotype has not yet been reported in the literature. The present study may suggest a novel karyotype associated with KS. PMID- 26430899 TI - Precursor-Directed Combinatorial Biosynthesis of Cinnamoyl, Dihydrocinnamoyl, and Benzoyl Anthranilates in Saccharomyces cerevisiae. AB - Biological synthesis of pharmaceuticals and biochemicals offers an environmentally friendly alternative to conventional chemical synthesis. These alternative methods require the design of metabolic pathways and the identification of enzymes exhibiting adequate activities. Cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates are natural metabolites which possess beneficial activities for human health, and the search is expanding for novel derivatives that might have enhanced biological activity. For example, biosynthesis in Dianthus caryophyllus is catalyzed by hydroxycinnamoyl/benzoyl CoA:anthranilate N-hydroxycinnamoyl/ benzoyltransferase (HCBT), which couples hydroxycinnamoyl-CoAs and benzoyl-CoAs to anthranilate. We recently demonstrated the potential of using yeast (Saccharomyces cerevisiae) for the biological production of a few cinnamoyl anthranilates by heterologous co-expression of 4 coumaroyl:CoA ligase from Arabidopsis thaliana (4CL5) and HCBT. Here we report that, by exploiting the substrate flexibility of both 4CL5 and HCBT, we achieved rapid biosynthesis of more than 160 cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates in yeast upon feeding with both natural and non-natural cinnamates, dihydrocinnamates, benzoates, and anthranilates. Our results demonstrate the use of enzyme promiscuity in biological synthesis to achieve high chemical diversity within a defined class of molecules. This work also points to the potential for the combinatorial biosynthesis of diverse and valuable cinnamoylated, dihydrocinnamoylated, and benzoylated products by using the versatile biological enzyme 4CL5 along with characterized cinnamoyl-CoA- and benzoyl-CoA-utilizing transferases. PMID- 26430901 TI - Calcitonin Gene-Related Peptide Improves Hypoxia-Induced Inflammation and Apoptosis via Nitric Oxide in H9c2 Cardiomyoblast Cells. AB - OBJECTIVES: The aim of this work was to investigate whether calcitonin gene related peptide (CGRP) plays a protective role in cardiomyocytes against hypoxia induced inflammation and apoptosis via an NO-mediated pathway. METHODS: H9c2 cardiac cells were exposed to hypoxia for 2 h to establish a model of myocardial hypoxic-ischemic injury. The cells were pretreated with either CGRP or nitric oxide synthase (NOS) inhibitor (L-NAME) before being exposed to hypoxia for 30 min. Cell viability was analyzed using a cell counter kit 8 (CCK-8). The levels of IL-6 and TNF-alpha were determined by the corresponding enzyme-linked immunosorbent assay. The expression levels of several apoptosis proteins (p53, caspase-3, cytochrome C) and NOS were detected by Western blot assays. An NO kit was used to evaluate the production of NO. RESULTS: Pretreatment of H9c2 cardiac cells with CGRP for 30 min prior to exposure to hypoxia markedly improved cell viability (83.57 +/- 3.21 vs. 62.83 +/- 8.30%, p < 0.001); the same effect was observed following pretreatment with the NOS inhibitor L-NAME (89.34 +/- 5.95 vs. 75.01 +/- 5.61%, p < 0.01). Pretreatment with CGRP also significantly attenuated the inflammatory responses induced by hypoxia, as evidenced by decreases of the levels of both IL-6 (193.21 +/- 13.54 vs. 293.38 +/- 56.49%, p < 0.001) and TNF alpha (207.71 +/- 44.27 vs. 281.46 +/- 64.88%, p < 0.001). Additionally, CGRP significantly decreased the hypoxia-induced overexpression of the apoptotic proteins (p53: 0.27 +/- 0.10 vs. 0.87 +/- 0.30, p < 0.001; caspase-3: 0.65 +/- 0.15 vs. 0.98 +/- 0.26, p < 0.001; cytochrome C: 1.51 +/- 0.39 vs. 2.80 +/- 0.69, p < 0.001) and enhanced the expression of both endothelial NOS (eNOS; 0.59 +/- 0.24 vs. 0.37 +/- 0.14, p < 0.05) and phosphorylated eNOS (0.60 +/- 0.13 vs. 0.40 +/- 0.07, p < 0.05). Furthermore, the application of both L-NAME and CGRP attenuated the hypoxia-induced expression of inducible NOS (iNOS; p < 0.05) and enhanced a hypoxia-mediated decrease in NO (p < 0.01). Interestingly, the expression levels of cell apoptosis (p < 0.05), iNOS and eNOS (p < 0.05) were decreased with L-NAME and CGRP cotreatment following 2 h of acute hypoxia, but the apoptotic factors (p < 0.05) were increased compared with only CGRP pretreatment. CONCLUSION: CGRP protects cardiomyocytes from hypoxia-induced inflammation and apoptosis by modulating NO production. PMID- 26430902 TI - Coupled Human-Environment Dynamics of Forest Pest Spread and Control in a Multi Patch, Stochastic Setting. AB - BACKGROUND: The transportation of camp firewood infested by non-native forest pests such as Asian long-horned beetle (ALB) and emerald ash borer (EAB) has severe impacts on North American forests. Once invasive forest pests are established, it can be difficult to eradicate them. Hence, preventing the long distance transport of firewood by individuals is crucial. METHODS: Here we develop a stochastic simulation model that captures the interaction between forest pest infestations and human decisions regarding firewood transportation. The population of trees is distributed across 10 patches (parks) comprising a "low volume" partition of 5 patches that experience a low volume of park visitors, and a "high volume" partition of 5 patches experiencing a high visitor volume. The infestation spreads within a patch--and also between patches- according to the probability of between-patch firewood transportation. Individuals decide to transport firewood or buy it locally based on the costs of locally purchased versus transported firewood, social norms, social learning, and level of concern for observed infestations. RESULTS: We find that the average time until a patch becomes infested depends nonlinearly on many model parameters. In particular, modest increases in the tree removal rate, modest increases in public concern for infestation, and modest decreases in the cost of locally purchased firewood, relative to baseline (current) values, cause very large increases in the average time until a patch becomes infested due to firewood transport from other patches, thereby better preventing long-distance spread. Patches that experience lower visitor volumes benefit more from firewood movement restrictions than patches that experience higher visitor volumes. Also, cross patch infestations not only seed new infestations, they can also worsen existing infestations to a surprising extent: long-term infestations are more intense in the high volume patches than the low volume patches, even when infestation is already endemic everywhere. CONCLUSIONS: The success of efforts to prevent long distance spread of forest pests may depend sensitively on the interaction between outbreak dynamics and human social processes, with similar levels of effort producing very different outcomes depending on where the coupled human and natural system exists in parameter space. Further development of such modeling approaches through better empirical validation should yield more precise recommendations for ways to optimally prevent the long-distance spread of invasive forest pests. PMID- 26430903 TI - Structure of Bolaamphiphile Sophorolipid Micelles Characterized with SAXS, SANS, and MD Simulations. AB - The micellar structure of sophorolipids, a glycolipid bolaamphiphile, is analyzed using a combination of small-angle X-ray scattering (SAXS), small-angle neutron scattering (SANS), and molecular dynamics (MD) simulations. Numerical modeling of SAXS curves shows that micellar morphology in the noncharged system (pH< 5) is made of prolate ellipsoids of revolution with core-shell morphology. Opposed to most surfactant systems, the hydrophilic shell has a nonhomogeneous distribution of matter: the shell thickness in the axial direction of the ellipsoid is found to be practically zero, while it measures about 12 A at its cross-section, thus forming a "coffee bean"-like shape. The use of a contrast-matching SANS experiment shows that the hydrophobic component of sophorolipids is actually distributed in a narrow spheroidal region in the micellar core. These data seem to indicate a complex distribution of sophorolipids within the micelle, divided into at least three domains: a pure hydrophobic core, a hydrophilic shell, and a region of less defined composition in the axial direction of the ellipsoid. To account for these results, we make the hypothesis that sophorolipid molecules acquire various configurations within the micelle including bent and linear, crossing the micellar core. These results are confirmed by MD simulations which do show the presence of multiple sophorolipid configurations when passing from spherical to ellipsoidal aggregates. Finally, we also used Rb(+) and Sr(2+) counterions in combination with anomalous SAXS experiments to probe the distribution of the COO(-) group of sophorolipids upon small pH increase (5 < pH < 7), where repulsive intermicellar interactions become important. The poor ASAXS signal shows that the COO(-) groups are rather diffused in the broad hydrophilic shell rather than at the outer micellar/water interface. PMID- 26430904 TI - Review of Bioptic Gleason Scores by Central Pathologist Modifies the Risk Classification in Prostate Cancer. AB - OBJECTIVES: The Gleason score (GS) is the primary classification of clinical risk in prostate cancer (PCa). Here, we estimated the factors predictive of accordance of local and central pathologist-dependent GS and clinical risk classification in an increased number of cases. METHODS: Between January 2009 and December 2013, 388 patients were diagnosed with PCa by 80 independent pathologists from local communities and were referred to our hospital. Validation of the GS with needle core biopsy specimens was carried out by a single central pathologist, and clinical risk, according to the D'Amico risk classification, was determined. Discrepancies between the GS and risk classification, based on the GS estimated by the local or central pathologist, were reviewed, and predictive factors for accordance of clinical risk classification were estimated. RESULTS: When pathological results were compared, 59.5% of cases were given concordant GSs by local and central pathologists. A significant discrepancy existed in the classification of intermediate risk (p < 0.0001). Multivariate analysis indicated that local pathologist-dependent GS7, lower prostate-specific antigen (<= 10 ng/ml), and lower T stage (T1 or T2a) were significant predictive factors for discordance with the central pathologist-dependent risk classification. CONCLUSION: Review of bioptic GSs by central pathologists affected discrepancies in risk classification in patients with PCa. PMID- 26430906 TI - The spontaneous formation and plasmonic properties of ultrathin gold-silver nanorods and nanowires stabilized in oleic acid. AB - Ultrathin Au-Ag alloy nanorods and nanowires of different lengths and ca. 1.9 nm diameter are prepared through a low-temperature decomposition of the precursor [Au2Ag2(C6F5)4(OEt2)2]n in oleic acid. This nanostructure formation has been studied through TEM, HRTEM, EDS, HS-SPME-GC-MS and (19)F NMR spectroscopy. The UNRs and UNWs display a length-dependent broad band in the mid-IR region that is related to the longitudinal mode of the surface plasmon resonance of the ultrathin nanostructures. PMID- 26430905 TI - Pain in older adults: development of a tool for measuring knowledge of residential aged care staff. AB - OBJECTIVE: To develop a psychometrically sound tool for measuring the knowledge of nursing and care staff about the experience, assessment and management of pain in older people (including people with dementia) for use in the residential aged care setting. METHODS: The Pain in Older Adults Knowledge Survey (POAKS) was developed and tested in two phases. Phase 1 involved developing an initial item pool with good content validity based on a review of the research literature and a modified Delphi technique involving national and international experts. A pool of 24 items was developed for testing. Initial testing of the psychometric properties of the POAKS with 30 university employees led to refinement and final wording of items. Phase 2 involved testing of the psychometric properties of the POAKS with 279 respondents, including first year (n = 176) and third year (n = 70) nursing students and staff in a residential aged care service (n = 33). RESULTS: Results established the content validity and internal consistency of the POAKS and supported its use as an instrument to measure nursing staff knowledge about the experience, assessment and management of pain in older people. CONCLUSIONS: The POAKS will enable residential aged care facilities to measure the level of knowledge among nursing and care staff about pain in older people (including people with dementia). The measure provides a basis for the development and implementation of educational interventions to address knowledge gaps that may impact on the quality of care provided. PMID- 26430907 TI - Comparison of conventional versus three-dimensional ultrasound in fetal renal pelvis measurement and their potential prediction of neonatal uropathies. AB - OBJECTIVE: To establish a threshold value for fetal renal pelvis dilatation measured by automatic volume calculation (SonoAVC) in the third trimester of pregnancy to predict neonatal uropathies, and to compare these results with conventional antero-posterior (AP) measurement, fetal kidney 3D volume and renal parenchymal thickness. METHODS: In a prospective cohort study, 125 fetuses with renal pelvis AP diameter of >=5 mm both at 20 weeks of gestation and in the third trimester, underwent an additional 3D volume measurement of the fetal kidney in the third trimester. Receiver operating characteristic (ROC) curves for establishing threshold values for fetal renal pelvis volume, AP measurement, fetal kidney volume and renal parenchymal thickness to predict neonatal uropathies were analyzed. Also, sensitivity, specificity, area under the curve (AUC) and likelihood ratios were calculated. RESULTS: A cut-off point of 1.58 cm3 was identified in the third trimester of pregnancy (AUC 0.865 (95% CI 0.789 0.940), sensitivity 76.3%, specificity 87.4%, LR+ 6.06, LR- 0.27) for measurements with SonoAVC. A cut-off value of 11.5 mm was established in the third trimester of pregnancy (AUC 0.828 (95% CI 0.737-0.918), sensitivity 71.1%, specificity 85.1%, LR+ 4.77, LR- 0.34) for the conventional AP measurement. A cut off point for fetal kidney volume was calculated at 13.29 cm3 (AUC 0.769 (95% CI 0.657-0.881), sensitivity 71%, specificity 66%, LR+ 2.09, LR- 0.44). For renal parenchymal thickness, a cut-off point of 8.4 mm was established (AUC 0.216 (95% CI 0.117-0.315), sensitivity 31.6%, specificity 32.6%, LR+ 0.47, LR- 2.10). CONCLUSION: This study demonstrates that 3D fetal renal pelvis volume measurements and AP measurements both have a good and comparable diagnostic performance, fetal renal volume a fair accuracy and renal parenchymal thickness a poor accuracy in predicting postnatal renal outcome. PMID- 26430908 TI - Charge screening in RNA: an integral route for dynamical enhancements. AB - Electrostatic interactions of RNA are at the center of determining the dynamical flexibility and structural stability. By analysing neutron scattering spectroscopy, we show that fast dynamics of hydrated tRNA on ps to ns timescales increases with stronger charge screening, while its structural stability either increases or remains largely unchanged. An unprecedented electrostatic threshold for the onset of additional flexibility is induced from the correlation between the charge-screening density of counterions and the promoted dynamical properties. The results demonstrate that the enhanced dynamical flexibility of tRNA originates from local conformational relaxation coupled with stabilized charge screening rather than governed by fluctuation of hydrated counterions. The present study casts light on the specificity of electrostatic interactions in the thermodynamic balance between the dynamical flexibility and structural stability of RNA. PMID- 26430910 TI - Imatinib discontinuation for hypereosinophilic syndrome harboring the FIP1L1 PDGFRA transcript. PMID- 26430909 TI - FANCI Regulates Recruitment of the FA Core Complex at Sites of DNA Damage Independently of FANCD2. AB - The Fanconi anemia (FA)-BRCA pathway mediates repair of DNA interstrand crosslinks. The FA core complex, a multi-subunit ubiquitin ligase, participates in the detection of DNA lesions and monoubiquitinates two downstream FA proteins, FANCD2 and FANCI (or the ID complex). However, the regulation of the FA core complex itself is poorly understood. Here we show that the FA core complex proteins are recruited to sites of DNA damage and form nuclear foci in S and G2 phases of the cell cycle. ATR kinase activity, an intact FA core complex and FANCM-FAAP24 were crucial for this recruitment. Surprisingly, FANCI, but not its partner FANCD2, was needed for efficient FA core complex foci formation. Monoubiquitination or ATR-dependent phosphorylation of FANCI were not required for the FA core complex recruitment, but FANCI deubiquitination by USP1 was. Additionally, BRCA1 was required for efficient FA core complex foci formation. These findings indicate that FANCI functions upstream of FA core complex recruitment independently of FANCD2, and alter the current view of the FA-BRCA pathway. PMID- 26430911 TI - Microbes, Mineral Evolution, and the Rise of Microcontinents-Origin and Coevolution of Life with Early Earth. AB - Earth is the most mineralogically diverse planet in our solar system, the direct consequence of a coevolving geosphere and biosphere. We consider the possibility that a microbial biosphere originated and thrived in the early Hadean-Archean Earth subseafloor environment, with fundamental consequences for the complex evolution and habitability of our planet. In this hypothesis paper, we explore possible venues for the origin of life and the direct consequences of microbially mediated, low-temperature hydrothermal alteration of the early oceanic lithosphere. We hypothesize that subsurface fluid-rock-microbe interactions resulted in more efficient hydration of the early oceanic crust, which in turn promoted bulk melting to produce the first evolved fragments of felsic crust. These evolved magmas most likely included sialic or tonalitic sheets, felsic volcaniclastics, and minor rhyolitic intrusions emplaced in an Iceland-type extensional setting as the earliest microcontinents. With the further development of proto-tectonic processes, these buoyant felsic crustal fragments formed the nucleus of intra-oceanic tonalite-trondhjemite-granitoid (TTG) island arcs. Thus microbes, by facilitating extensive hydrothermal alteration of the earliest oceanic crust through bioalteration, promoted mineral diversification and may have been early architects of surface environments and microcontinents on young Earth. We explore how the possible onset of subseafloor fluid-rock-microbe interactions on early Earth accelerated metavolcanic clay mineral formation, crustal melting, and subsequent metamorphic mineral evolution. We also consider environmental factors supporting this earliest step in geosphere-biosphere coevolution and the implications for habitability and mineral evolution on other rocky planets, such as Mars. PMID- 26430913 TI - Lipid-based nanocarriers for breast cancer treatment - comprehensive review. AB - Breast cancer is the second leading cancer-related disease as the most common non cutaneous malignancy among women. Curative options for breast cancer are limited, therapeutically substantial and associated with toxicities. Emerging nanotechnologies exhibited the possibility to treat or target breast cancer. Among the nanoparticles, various lipid nanoparticles namely, liposomes, solid lipid nanoparticles, nanostructured lipid carriers and lipid polymer hybrid nanoparticles have been developed over the years for the breast cancer therapy and evidences are documented. Concepts are confined in lab scale, which needs to be transferred to large scale to develop active targeting nanomedicine for the clinical utility. So, the present review highlights the recently published studies in the development of lipid-based nanocarriers for breast cancer treatment. PMID- 26430912 TI - The Role of the Y Box Binding Protein 1 C-Terminal Domain in Vascular Endothelial Cell Proliferation, Apoptosis, and Angiogenesis. AB - Different domains of the multifunctional transcription factor Y-box binding protein 1 (YB1) regulate proliferation, differentiation, and apoptosis by transactivating or repressing the promoters of various genes. Here we report that the C-terminal domain of YB1 (YB1 CTD) is involved in endothelial cell proliferation, apoptosis, and tube formation. The oligo pull-down assays demonstrated that YB1 directly binds double-stranded GC box sequences in endothelial cells through the 125-220 amino acids. Adenovirus expression vectors harboring green fluorescent protein (GFP) or GFP-tagged YB1 CTD were constructed and used to infect EA.hy926 endothelial cells. Overexpression of the YB1 CTD significantly increased p21 expression, decreased cyclin B1 expression, and inhibited the proliferation of EA.hy926 cells. YB1 CTD overexpression also increased Bax and active caspase 3 expression, decreased Bcl-2 expression, and induced apoptosis in EA.hy926 cells. Furthermore, overexpression of the YB1 CTD significantly suppressed migration and tube formation in EA.hy926 cells. Finally, YB1 CTD decreased ERK1/2 phosphorylation in EA.hy926 cells. These findings demonstrated vital roles for YB1 in endothelial cell proliferation, apoptosis, and tube formation through transcriptional regulation of GC box-related genes. PMID- 26430919 TI - Constructing a three-dimensional electrical model of a living cochlear implant user's cochlea. AB - BACKGROUND: Hearing performance varies greatly among users of cochlear implants. Current three-dimensional cochlear models that predict the electrical fields inside a stimulated cochlea and their effect on neural excitation are generally based on a generic human or guinea pig cochlear shape that does not take inter user morphological variations into account. This precludes prediction of user specific performance. AIMS: The aim of this study is to develop a model of the implanted cochlea of a specific living human individual and to assess if the inclusion of morphological variations in cochlear models affects predicted outcomes significantly. METHODS: Five three-dimensional electric volume conduction models of the implanted cochleae of individual living users were constructed from standard CT scan data. These models were embedded in head models that include monopolar return electrodes in accurate anatomic positions. Potential distributions and neural excitation patterns were predicted for each of the models. RESULTS: Modeled potential distributions and neural excitation profiles (threshold amplitudes, center frequencies, and bandwidths) are affected by user-specific cochlear morphology and electrode placement within the cochlea. CONCLUSIONS: This work suggests that the use of user-specific models is indicated when more detailed analysis is required than what is available from generic models. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26430918 TI - Generation of a MDCK cell line with constitutive expression of the Enteropathogenic E. coli effector protein Map as an in vitro model of pathogenesis. AB - Enteropathogenic E. coli (EPEC) cause diarrhea and are the major cause of mortality in developing countries. EPEC use a type III secretion system to deliver effector proteins into the host epithelial cells. To understand the functions of these effectors, majority of studies on EPEC pathogenesis have relied on infections of animals or cell lines with wild type strains of EPEC or mutant strains deficient in one or more effectors. While these studies have provided valuable data, it can be difficult to assess functions of an individual effector in the presence of other EPEC effectors. Recent studies have reported the use of transient transfections with plasmids encoding various EPEC effectors into different cell lines. However, variable transfection efficiencies and expression levels of the effector proteins coupled with their expression for relatively short periods of time pose a problem if the long term effects of these effectors need to be examined. We have generated a MDCK cell line with constitutive expression of the EPEC effector Map (Mitochondrial associated protein) for efficient stable expression of EGFP-tagged Map. We observed that the constitutive expression of Map increased the permeability of charged and non charged molecules. We also generated polyclonal antibodies against Map and checked for their specificity in MDCK-Map expressing cells. Map has been reported to contribute to the onset of diarrhea but the underlying mechanism is yet to be identified. The MDCK-Map cell line and the anti-Map antibodies generated by us can be used for in vitro studies to examine the role of Map in EPEC pathogenesis. PMID- 26430920 TI - Derivation of a Cross-Domain Embedded Performance Validity Measure in Traumatic Brain Injury. AB - OBJECTIVE: Performance validity assessment is increasingly considered standard practice in neuropsychological evaluations. The current study extended research on logistically derived performance validity tests (PVTs) by utilizing neuropsychological measures from multiple cognitive domains instead of from a single measure or a single cognitive domain. METHOD: A logistic-derived PVT was calculated using several measures from multiple cognitive domains, including verbal memory (California Verbal Learning Test-II Trial 5, Total Hits, and False Positives), attention (Brief Test of Attention Total score), and language (Boston Naming Test T-score, and Animal Fluency T-score). Due to its cross-domain nature, the cross-domain logistic-derived embedded PVT was hypothesized to have excellent classification accuracy for non-credible performance. Participants included 224 patients who completed all measures and were moderate to severe traumatic brain injury (STBI) patients (N = 66), possible mild TBI (MTBI-FAIL) patients who failed at least 2 independent PVTs (N = 67), and possible mild TBI patients who passed all PVTs (MTBI-PASS; N = 91). Logistic regression and ROC analyses were conducted on the MTBI-FAIL group and the STBI group. RESULTS: Multivariate analysis of variance indicated that the MTBI-FAIL group was significantly lower on all measures than the MTBI-PASS and the STBI groups. Using logistic regression, CVLT Total Hits, BTA, and the CVLT False Positives best differentiated between the MTBI-FAIL and STBI groups. The logistically derived PVT had excellent classification accuracy (area under the curve [AUC] = .84), with sensitivity at .54 when specificity was set at .90, higher than any individual variable. CONCLUSIONS: Findings support the use of this logistical derived variable as an embedded PVT and support further research with this type of methodology. PMID- 26430922 TI - Validity of self-reported sedentary time differs between Australian rural men engaged in office and farming occupations. AB - Rural Australians have a higher likelihood of chronic disease than urban Australians, particularly male farmers. Chronic disease has been associated with occupational sedentary time. The aim was to validate the self-report of sedentary time in men in contrasting rural occupations. Farmers (n = 29) and office workers (n = 28), age 30-65 years, were recruited from the Riverland region of South Australia. Daily sedentary time and number of breaks in sedentary time were self reported and measured objectively using body-worn inclinometers. Correlational analyses were conducted between self-reported and objectively measured variables, separately by occupation. There was a significant correlation between self reported and objectively measured sedentary time in the whole sample (r = 0.44, P = 0.001). The correlation among office workers was significant (r = 0.57, P = 0.003) but not among farmers (r = 0.08, P = 0.68). There were no significant correlations between self-reported and measured number of breaks in sedentary time, for the whole sample (rho = -0.03, P = 0.83), office workers (rho = 0.17, P = 0.39) and farmers (rho = -0.22, P = 0.25). In conclusion, the validity of self report of sedentary behaviours by farmers was poor. Further research is needed to develop better performing self-report instruments or more accessible objective measures of sedentary behaviour in this population. PMID- 26430923 TI - The Effect of Systemic Tamsulosin Hydrochloride on Choroidal Thickness Measured by Enhanced Depth Imaging Spectral Domain Optical Coherence Tomography. PMID- 26430921 TI - Pneumococcal nasopharyngeal carriage in children <5 years of age visiting the pediatric emergency room in relation to PCV7 and PCV13 introduction in southern Israel. AB - The 7-valent and the 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13, respectively) were introduced to the Israeli National Immunization plan in July 2009 and November 2010, respectively. Our aim was to assess pneumococcal conjugate vaccines (PCVs) uptake and dynamics in serotype-specific pneumococcal nasopharyngeal (NP) carriage in children <5 years old in southern Israel, during the immediate 5 y following PCV introduction. This was an ongoing, prospective, population-based, active surveillance, from July 2009 through December 2014. PCVs uptake and NP cultures were obtained daily from children seen at the Pediatric Emergency Room for any reason. Overall, 10,702 vaccine status and 7,610 NP swabs were obtained. Both PCV7 and PCV13 uptake were high, reaching ~90% by July 2012 and December 2013, respectively. All-pneumococcal carriage rates significantly declined by 10%, from 54.3% in the early-PCV7 period, to 49.1% in the PCV13 impact period. The respective declines for PCV7, 6A and additional PCV13 serotypes carriage rates were 76%, 90% and 66%. In contrast, non-PCV13 serotypes carriage rates increased significantly throughout the study by 71%. All pneumococcal carriage rates in children <12 months old decreased significantly by 15%, with similar trends observed in other age groups. Initially, all pneumococcal carriage rates were 45.7%, and 61.9% in Jewish and Bedouin children, respectively (P < 0.001), with a significant 17% reduction throughout the study observed only in Bedouins. While early carriage rates were higher in unvaccinated children compared to vaccinated children, PCV impact on carriage were similar in both groups. In conclusion, a relatively moderate decline in pneumococcal carriage rates, facilitated by a substantial decrease of vaccine-serotypes and increase of non-vaccine serotypes was observed in the immediate period following PCVs introduction in southern Israel. PMID- 26430924 TI - Downregulation of Proteinase-Activated Receptor-2, Interleukin-17, and Other Proinflammatory Genes by Subantimicrobial Doxycycline Dose in a Rat Periodontitis Model. AB - BACKGROUND: Subantimicrobial dose doxycycline (SDD) has been used as an adjunct in periodontal treatment because of its matrix metalloproteinase inhibition properties. Although the benefits of SDD therapy, such as improvement in the parameters of periodontal probing depth and clinical attachment level, have been proven in multiple clinical studies, the comprehension of other biologic mechanisms of action on periodontitis remains poorly investigated. Therefore, this animal-model study evaluated the effects of SDD monotherapy on the expressions of the following key proinflammatory genes: proteinase-activated receptor-2 (PAR2), tumor necrosis factor (TNF)-alpha, interleukin (IL)-17, and IL 1beta. METHODS: Male Wistar rats were assigned randomly to the following: 1) control group: no ligature-induced periodontitis and no treatment; 2) ligature group: ligature-induced periodontitis and placebo treatment; and 3) ligature + doxycycline group: ligature-induced periodontitis and SDD treatment. After the experimental time, animals were sacrificed, and reverse transcription-polymerase chain reaction was performed to analyze the mRNA expression of IL-1beta, IL-17, TNF-alpha, and PAR2 in gingival tissue samples. Histologic analyses were performed on the furcation region and mesial gingiva of mandibular first molars to measure periodontal bone loss and collagen content. RESULTS: SDD administration significantly downregulated PAR2, IL-17, TNF-alpha, and IL-1beta mRNA expressions (P <0.05). In addition, SDD treatment was accompanied by lower rates of alveolar bone loss (P <0.05) and maintenance of the amount of gingival collagen fibers. CONCLUSION: These findings reveal new perspectives regarding SDD efficacy because it can be partially related to proinflammatory gene expression modulation, even considering PAR2 and IL-17, which has not been investigated thus far. PMID- 26430925 TI - Analyses of Gingival Adhesion Molecules in Periodontitis: Theoretical In Silico, Comparative In Vivo, and Explanatory In Vitro Models. AB - BACKGROUND: A deeper understanding of periodontitis pathophysiology is central to future development of novel biomarkers and therapeutics. The following is reported here: 1) an in silico network model of interactions among cell adhesion molecules and a network-focused microarray analysis of the corresponding genes in periodontitis; 2) analysis of secretions of adhesion molecules in gingival tissue samples from patients with periodontitis and healthy controls; and 3) effect of the human neutrophilic peptide-1 (HNP-1) on epithelial adhesion molecules. METHODS: The network model identified 85 nodes in relation to the interactions of adhesion molecules. Subsequently, the relative gene expression was overlaid on the network model. Differential gene expression was analyzed, and false discovery rate control was performed for statistical assessment of the microarray data. Both tissue and cell culture samples were immunostained for desmocollin (DSC)2, occludin (OCLN), desmoglein (DSG)1, tight junction protein 2, and gap junction protein alpha. RESULTS: The differential gene expression analysis revealed that the epithelial adhesion molecules were significantly lower in abundance in individuals with periodontitis than controls. In contrast, the genes for leukocyte adhesion molecules showed a significant upregulation. Immunostainings revealed elevated secretions of both DSG1 and OCLN in periodontitis. An in vitro model suggested reduced DSC2 and OCLN secretions in the presence of HNP-1. CONCLUSIONS: Gene expression of gingival adhesion molecules in periodontitis is regulated by leukocyte transmigration, whereas the neutrophilic antimicrobial peptide HNP-1 is noted as a putative regulator of epithelial adhesion molecules. These observations contribute to the key mechanisms by which future biomarkers might be developed for periodontitis. PMID- 26430926 TI - Pilot Study on Oral Health Status as Assessed by an Active Matrix Metalloproteinase-8 Chairside Mouthrinse Test in Adolescents. AB - BACKGROUND: Matrix metalloproteinase (MMP)-8 is a major destructive collagenase involved in periodontitis and can be regarded as a periodontitis biomarker. A neutrophil collagenase 2 (active MMP-8 [aMMP-8]) oral fluid immunoassay has recently been demonstrated to be a periodontitis risk indicator among adults. The aim of this study is to investigate whether a point-of-care mouthrinse test based on an aMMP-8 immunoassay could identify patients with oral inflammatory burden (periodontitis and caries) among adolescents with early pathologic findings. METHODS: This cross-sectional study was carried out at the Kotka Health Center, Finland. First, the aMMP-8 chairside mouthrinse test was performed on enrolled individuals (adolescents aged 15 to 17 years, n = 47), and the results were read based on a color change within 5 minutes. Then, full-mouth clinical parameters of oral health were assessed, including periodontal, oral mucosal, and caries status. RESULTS: The sensitivity and specificity of the test for bleeding on probing were 71.8% and 77.5%, respectively (P = 0.05); for >=1 site with probing depth (PD) >=4 mm, 48.3% and 100% (P <0.001); for >=2 sites with PD >=4 mm, 63.6% and 100% (P <0.001); and for >2 sites with PD >=4 mm, 76.5% and 96.7% (P <0.01). Regarding periodontitis (>=1 site with PD >=4 mm), hardly any false-positive results were identified. The sensitivity of the immunoassay for >=1 caries lesions was 76.5%, and the specificity was 96.7% (P <0.01). CONCLUSIONS: In 5 minutes, the aMMP-8 chairside test showed promising results, recognizing oral inflammatory burden in adolescents with early initial signs of periodontitis. Caries lesions could also be detected, but less efficiently. PMID- 26430927 TI - Microbial Profiling in Experimentally Induced Biofilm Overgrowth Among Patients With Various Periodontal States. AB - BACKGROUND: This study measures microbial composition changes during biofilm overgrowth and subsequent removal among patients with various states of periodontal disease. METHODS: In this prospective cohort study, 175 participants with various periodontal states (five biofilm-gingival interface [BGI] groups) abstained from oral hygiene while using an acrylic stent. At day 21, participants reinstituted oral hygiene and were followed for 4 weeks. Clinical parameters were recorded, and subgingival plaque samples were analyzed at baseline, peak of induction (day 21), and resolution using 16S rRNA probes (human oral microbe identification microarray [HOMIM]). Using the change score (peak at induction minus baseline) for bleeding on probing and probing depth (PD), the patients were separated into high and low clinical responders. RESULTS: At baseline, synergistetes were more abundant in moderate and severe periodontitis (BGI-P2 and -P3) compared to mild periodontitis (BGI-P1), health (BGI-H), and gingivitis (BGI G) (P = 0.005). Overall, at day 21 there was an increase in HOMIM scores of firmicutes (P <=0.001), fusobacteria (P = 0.003), proteobacteria (P <=0.001), synergistetes (P = 0.04), and bacteroidetes (P <=0.001). At resolution, these phyla returned to baseline, except for synergistetes. Levels of synergistetes were significantly higher at day 21 (P <=0.0001) and resolution (P = 0.0002) for high clinical responders compared to low responders. CONCLUSION: The association of synergistetes as a baseline predictor of incident PD increase, as well as the higher levels at day 21, indicates a pathogenic role for these organisms in disease progression in addition to the previously characterized fusobacteria, proteobacteria, firmicutes, and bacteroidetes. PMID- 26430928 TI - Comparison of Clinical and Radiographic Periodontal Status Between Habitual Water Pipe Smokers and Cigarette Smokers. AB - BACKGROUND: There is a dearth of studies that have compared clinical and radiologic markers of periodontal inflammation between water-pipe smokers (WPs) and cigarette smokers (CSs). The aim of the present study is to compare the clinical and radiographic periodontal status between habitual WPs and CSs. METHODS: In total, 200 males (50 WPs, 50 CSs, and 100 controls) with comparable mean age and education were included. Demographic information was recorded using a questionnaire. Periodontal parameters (plaque index [PI], bleeding on probing [BOP], probing depth [PD], clinical attachment loss [AL], and marginal bone loss [MBL]) and numbers of missing teeth (MT) were recorded. RESULTS: The duration of each smoking session for WPs and CSs was 50.2 +/- 6.7 and 15.3 +/- 0.4 minutes, respectively. Number of MT [P <0.0001], PI [P <0.0001], AL [P <0.0001], PD >=4 mm [P <0.0001], and MBL [P <0.0001]) was significantly higher among WPs and CSs than controls. BOP was significantly higher among controls than WPs (P <0.0001) and CSs (P <0.0001). There was no statistically significant difference in the aforementioned parameters between WPs and CSs. CONCLUSIONS: Males in a Saudi Arabian community who were CSs or WPs had more MT and poorer periodontal condition than never smokers. The periodontal condition of WPs was equally as poor as CSs. Additional clinical observational studies with emphasis on sex and sociodemographic characteristics are needed. PMID- 26430929 TI - The Consumption of Synbiotic Bread Containing Lactobacillus sporogenes and Inulin Affects Nitric Oxide and Malondialdehyde in Patients with Type 2 Diabetes Mellitus: Randomized, Double-Blind, Placebo-Controlled Trial. AB - OBJECTIVES: To our knowledge, no reports are available indicating the effects of synbiotic bread consumption on nitric oxide (NO), biomarkers of oxidative stress, and liver enzymes among patients with type 2 diabetes mellitus (T2DM). This study was performed to determine the effects of the daily consumption of synbiotic bread on NO, biomarkers of oxidative stress, and liver enzymes in patients with T2DM. METHODS: This randomized, double-blind, placebo-controlled trial was performed among 81 patients with diabetes, aged 35-70 years old. After a 2-week run-in period, patients were randomly divided into 3 groups: group A (n = 27) received synbiotic bread containing viable and the heat-resistant probiotic Lactobacillus sporogenes (1 * 108 CFU) and 0.07 g inulin per 1 g, group B (n = 27) received probiotic bread containing Lactobacillus sporogenes (1 * 108 CFU), and group C (n = 27) received control bread for 8 weeks. Patients were asked to consume the synbiotic, probiotic, or control breads 3 times a day in 40 g packages for a total of 120 g/day. Fasting blood samples were taken at baseline and after an 8-week intervention for quantificationof related markers. RESULTS: After 8 weeks, the consumption of synbiotic bread compared to the probiotic and control breads resulted in a significant rise in plasma NO (40.6 +/- 34.4 vs 18.5 +/- 36.2 and -0.8 +/- 24.5 umol/L, respectively, p < 0.001) and a significant reduction in malondialdehyde (MDA) levels (-0.7 +/- 0.7 vs 0.6 +/- 1.7 and 0.5 +/ 1.5 umol/L, respectively, p = 0.001). We did not find any significant effect of the synbiotic bread consumption on plasma total antioxidant capacity (TAC), plasma glutathione (GSH), catalase, serum liver enzymes, calcium, iron, magnesium levels, and blood pressure compared to the probiotic and control breads. CONCLUSION: In conclusion, consumption of the synbiotic bread for 8 weeks among patients with T2DM had beneficial effects on plasma NO and MDA levels; however, it did not affect plasma TAC, GSH, catalase levels, serum liver enzymes, calcium, iron, magnesium levels, and blood pressure. PMID- 26430938 TI - Inconsistent handers show higher psychopathy than consistent handers. AB - Three hundred and forty-two university students completed the Short Dark Triad (SD3) and the Edinburgh Handedness Inventory (EHI). Inconsistent handers showed higher psychopathy scores than consistent handers, and no handedness differences were observed for narcissism or Machiavellianism. Participants were further subdivided by quartile into low, moderately low, moderately high, and high psychopathy groups (non-clinical). Absolute EHI scores were equally distributed among low and moderate groups, but were significantly lower for the high psychopathy group. These findings suggest that inconsistent handedness is only associated with the upper quartile of psychopathy scores. Also, males showed significantly higher psychopathy scores than females, and the ratio of male to female inconsistent handers decreased as psychopathy score increased. No gender * handedness interaction indicated that both female and male inconsistent handers have higher psychopathy scores than consistent handers. Although significant, the effects were small and 99.6% of participants were not in the range of a potential clinical diagnosis. The reader, therefore, is strongly cautioned against equating inconsistent handedness with psychopathy. PMID- 26430939 TI - Low Prevalence of Carbapenem-Resistant Bacteria in River Water: Resistance Is Mostly Related to Intrinsic Mechanisms. AB - Carbapenems are last-resort antibiotics to handle serious infections caused by multiresistant bacteria. The incidence of resistance to these antibiotics has been increasing and new resistance mechanisms have emerged. The dissemination of carbapenem resistance in the environment has been overlooked. The main goal of this research was to assess the prevalence and diversity of carbapenem-resistant bacteria in riverine ecosystems. The presence of frequently reported carbapenemase-encoding genes was inspected. The proportion of imipenem-resistant bacteria was on average 2.24 CFU/ml. Imipenem-resistant strains (n=110) were identified as Pseudomonas spp., Stenotrophomonas maltophilia, Aeromonas spp., Chromobacterium haemolyticum, Shewanella xiamenensis, and members of Enterobacteriaceae. Carbapenem-resistant bacteria were highly resistant to other beta-lactams such as quinolones, aminoglycosides, chloramphenicol, tetracyclines, and sulfamethoxazole/trimethoprim. Carbapenem resistance was mostly associated with intrinsically resistant bacteria. As intrinsic resistance mechanisms, we have identified the blaCphA gene in 77.3% of Aeromonas spp., blaL1 in all S. maltophilia, and blaOXA-48-like in all S. xiamenensis. As acquired resistance mechanisms, we have detected the blaVIM-2 gene in six Pseudomonas spp. (5.45%). Integrons with gene cassettes encoding resistance to aminoglycosides (aacA and aacC genes), trimethoprim (dfrB1b), and carbapenems (blaVIM-2) were found in Pseudomonas spp. Results suggest that carbapenem resistance dissemination in riverine ecosystems is still at an early stage. Nevertheless, monitoring these aquatic compartments for the presence of resistance genes and its host organisms is essential to outline strategies to minimize resistance dissemination. PMID- 26430940 TI - Antibiotic Resistance, Virulence, and Genetic Background of Community-Acquired Uropathogenic Escherichia coli from Algeria. AB - The aim of the study was to investigate antibiotic resistance mechanisms, virulence traits, and genetic background of 150 nonrepetitive community-acquired uropathogenic Escherichia coli (CA-UPEC) from Algeria. A rate of 46.7% of isolates was multidrug resistant. bla genes detected were blaTEM (96.8% of amoxicillin-resistant isolates), blaCTX-M-15 (4%), overexpressed blaAmpC (4%), blaSHV-2a, blaTEM-4, blaTEM-31, and blaTEM-35 (0.7%). All tetracycline-resistant isolates (51.3%) had tetA and/or tetB genes. Sulfonamides and trimethoprim resistance genes were sul2 (60.8%), sul1 (45.9%), sul3 (6.7%), dfrA14 (25.4%), dfrA1 (18.2%), dfrA12 (16.3%), and dfrA25 (5.4%). High-level fluoroquinolone resistance (22.7%) was mediated by mutations in gyrA (S83L-D87N) and parC (S80I E84G/V or S80I) genes. qnrB5, qnrS1, and aac(6')-Ib-cr were rare (5.3%). Class 1 and/or class 2 integrons were detected (40.7%). Isolates belonged to phylogroups B2+D (50%), A+B1 (36%), and F+C+Clade I (13%). Most of D (72.2%) and 38.6% of B2 isolates were multidrug resistant; they belong to 14 different sequence types, including international successful ST131, ST73, and ST69, reported for the first time in the community in Algeria and new ST4494 and ST4529 described in this study. Besides multidrug resistance, B2 and D isolates possessed virulence factors of colonization, invasion, and long-term persistence. The study highlighted multidrug-resistant CA-UPEC with high virulence traits and an epidemic genetic background. PMID- 26430941 TI - Biocide Susceptibility of Staphylococcus aureus CC398 and CC30 Isolates from Pigs and Identification of the Biocide Resistance Genes, qacG and qacC. AB - OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA), in particular clonal complex (CC) 398, is increasingly found in livestock. Recently, MRSA CC30 was identified in Danish pigs. We determined the susceptibility of porcine S. aureus isolates of CC398 and CC30 to disinfectants used in pig farming (benzalkonium chloride, hydrogen peroxide, formaldehyde, sodium hypochlorite, and caustic soda). Furthermore, efflux pump activity, antimicrobial resistance profiles, hemolysis properties, and the presence of toxic shock syndrome toxin-1 (TSST-1) and Panton-Valentine Leukocidin (PVL)-encoding virulence factors were investigated. METHODS: Susceptibilities to biocides and antimicrobial agents of 79 porcine S. aureus isolates were determined by the microdilution method. Isolates comprised 21 methicillin-sensitive S. aureus (MSSA) and 40 MRSA isolates belonging to CC398 and 13 MSSA and 5 MRSA isolates belonging to CC30. The presence of quaternary ammonium compound (QAC) resistance efflux pumps was analyzed using an ethidium bromide accumulation assay. The presence of qac resistance genes in active efflux pump positive isolates was determined by whole genome sequencing data. All isolates were screened for lukPV and tst genes with PCR, and hemolytic activities were determined using an agar plate assay. RESULTS: S. aureus isolates did not show reduced susceptibility to the biocides tested. However, the QAC resistance gene, qacG, was detected in three MRSA CC30 isolates and the qacC in one MRSA CC30 isolate. CC30 isolates were generally more susceptible to non-beta-lactam antibiotics than CC398. Isolates generally had low hemolytic activity and none encoded PVL or TSST-1. CONCLUSION: The presence of qac genes in European porcine S. aureus isolates and in livestock-associated MRSA CC30 is for the first time described in this study. This finding is concerning as it ultimately may compromise disinfection with QACs and thereby contribute to the selection and spread of MRSA CC30. PMID- 26430942 TI - Increasing Trend of Heterogeneous Vancomycin Intermediate Staphylococcus aureus in a Tertiary Care Center of Northern India. AB - Heterogeneous vancomycin intermediate Staphylococcus aureus (hVISA) strains are increasingly reported, and their association with vancomycin treatment failure is a well-known problem worldwide. A total of 500 clinical isolates of methicillin resistant S. aureus were screened for hVISA by four different methods from May 2011 to May 2014. The number of strains screened for hVISA from May to April in 2011-2012, 2012-2013, and 2013-2014 were 198, 123, and 179, respectively. hVISA strains were studied by transmission electron microscopy (TEM) for cell wall thickness and also for their ability to form biofilm on a polystyrene microtiter plate. hVISA strains detected by four different methods-brain heart infusion agar with vancomycin with 4 mg/L/gradient plate/macro E-test/and glycopeptide resistance detection (GRD) E test-were as follows: 11.6%/10%/9%, and 9.5% in 2011 2012, 12.1%/9.7%/8.9%, and 10.5% in 2012-2013, and 13.9%/11.7%/11.1%, and 12.8% in 2013-2014, respectively. Population analysis profile-area under curve analysis confirmed hVISA in 4.5% (9/198), 6.5% (8/123), and 6.7% (12/179) in respective years; 24% (7/29) of hVISA isolates were nonsusceptible to daptomycin. TEM showed a significant increase in cell wall thickness of hVISA isolates (p<0.001) with a distinct reduction in their biofilm formation ability. PMID- 26430943 TI - Susceptibility of Group A Streptococcus to Antimicrobial Agents in Northern Israel: A Surveillance Study. AB - BACKGROUND: Resistant pathogens are an increasing threat affecting millions of people globally. More complicated patients are presented with pathogens harboring new resistance mechanisms, while the pipeline of new antimicrobials hardly proposes solutions. In such a scenario, more severely ill patients remain with no adequate treatment to offer. In addition, massive misuse of antimicrobials, including excessive length of treatment or wrong dosage, also contributes to increasing the rate of pathogens resistance to antimicrobials. Isolation of Streptococcus pyogenes (Group A Streptococcus-GAS) is the main indication for antibiotic treatment to patients diagnosed with acute tonsillitis. Hence, GAS resistance to antibiotics requires periodic monitoring. OBJECTIVES: To assess susceptibility rates of GAS to penicillin, macrolides, clindamycin, and tetracycline in northern Israel and to compare the findings to the high antimicrobial susceptibility of GAS isolates reported in the same region in 2004 and to other geographical areas. METHODS: Throat samples from 300 outpatients were collected and cultured at the regional laboratory of Emek Medical Center during September to October 2011. RESULTS: In 300 samples, the susceptibility rates of GAS to penicillin, erythromycin, azithromycin, clindamycin, and tetracycline in northern Israel still remain very high. CONCLUSIONS: Continuous control of antimicrobials usage and periodic surveillance of susceptibility rates, together with educational programs and appropriate and targeted treatment protocols, are essential and highly recommended to keep these high susceptibility rates for as long as possible. PMID- 26430945 TI - Design of Pore Size and Functionality in Pillar-Layered Zn-Triazolate Dicarboxylate Frameworks and Their High CO2/CH4 and C2 Hydrocarbons/CH4 Selectivity. AB - In the design of new materials, those with rare and exceptional compositional and structural features are often highly valued and sought after. On the other hand, materials with common and more accessible modes can often provide richer and unsurpassed compositional and structural variety that makes them a more suitable platform for systematically probing the composition-structure-property correlation. We focus here on one such class of materials, pillar-layered metal organic frameworks (MOFs), because different pore size and shape as well as functionality can be controlled and adjusted by using pillars with different geometrical and chemical features. Our approach takes advantage of the readily accessible layered Zn-1,2,4-triazolate motif and diverse dicarboxylate ligands with variable length and functional groups, to prepare seven Zn-triazolate dicarboxylate pillar-layered MOFs. Six different gases (N2, H2, CO2, C2H2, C2H4, and CH4) were used to systematically examine the dependency of gas sorption properties on chemical and geometrical properties of those MOFs as well as their potential applications in gas storage and separation. All of these pillar-layered MOFs show not only remarkable CO2 uptake capacity, but also high CO2 over CH4 and C2 hydrocarbons over CH4 selectivity. An interesting observation is that the BDC ligand (BDC = benzenedicarboxylate) led to a material with the CO2 uptake outperforming all other metal-triazolate-dicarboxylate MOFs, even though most of them are decorated with amino groups, generally believed to be a key factor for high CO2 uptake. Overall, the data show that the exploration of the synergistic effect resulting from combined tuning of functional groups and pore size may be a promising strategy to develop materials with the optimum integration of geometrical and chemical factors for the highest possible gas adsorption capacity and separation performance. PMID- 26430944 TI - Characteristics and Outcomes of Acinetobacter baumannii Infections in Critically Ill Patients with Cancer: A Matched Case-Control Study. AB - AIM: To describe the characteristics and outcomes of Acinetobacter baumannii (AB) infections in critically ill cancer patients and to evaluate the impact of AB on mortality and length of stay (LOS). RESULTS: In a 4-year case-control study of critically ill cancer patients, we identified 161 patients with AB infections and 232 matched patients who were treated in the intensive care unit (ICU) during the same time period, but had no AB cultures. The case and control groups were matched for APACHE II, age, gender, type of malignancy, and mechanical ventilation. Most AB isolates were carbapenem-resistant (n=142, 88.2%). The majority of positive cultures were collected from the respiratory tract (58%) and blood (21.8%). The median ICU LOS and mortality rate for patients with AB infections were higher than those for the control group (12 days [IQR 6-23] vs. 3 days [IQR 1-7], p<0.0001 and 73.3% vs. 61.5%, p=0.015, respectively). AB infection was independently associated with ICU LOS and mortality: OR 1.108 (95% CI, 1.077-1.139), OR 1.658 (95% CI, 1.017-2.703), respectively. CONCLUSION: AB infections in critically ill cancer patients were independently associated with increased mortality and increased ICU LOS. Measures to improve the outcomes of critically ill cancer patients infected with AB are necessary. PMID- 26430946 TI - Corrigendum: Simple Copy Number Determination with Reference Query Pyrosequencing (RQPS). PMID- 26430947 TI - Evidence Base Update for Autism Spectrum Disorder. AB - This evidence base update examines the level of empirical support for interventions for children with autism spectrum disorder (ASD) younger than 5 years old. It focuses on research published since a previous review in this journal (Rogers & Vismara, 2008 ). We identified psychological or behavioral interventions that had been manualized and evaluated in either (a) experimental or quasi-experimental group studies or (b) systematic reviews of single-subject studies. We extracted data from all studies that met these criteria and were published after the previous review. Interventions were categorized across two dimensions. First, primary theoretical principles included applied behavior analysis (ABA), developmental social-pragmatic (DSP), or both. Second, practice elements included scope (comprehensive or focused), modality (individual intervention with the child, parent training, or classrooms), and intervention targets (e.g., spoken language or alternative and augmentative communication). We classified two interventions as well-established (individual, comprehensive ABA and teacher-implemented, focused ABA + DSP), 3 as probably efficacious (individual, focused ABA for augmentative and alternative communication; individual, focused ABA + DSP; and focused DSP parent training), and 5 as possibly efficacious (individual, comprehensive ABA + DSP; comprehensive ABA classrooms; focused ABA for spoken communication; focused ABA parent training; and teacher-implemented, focused DSP). The evidence base for ASD interventions has grown substantially since 2008. An increasing number of interventions have some empirical support; others are emerging as potentially efficacious. Priorities for future research include improving outcome measures, developing interventions for understudied ASD symptoms (e.g., repetitive behaviors), pinpointing mechanisms of action in interventions, and adapting interventions for implementation with fidelity by community providers. PMID- 26430948 TI - Psychological Science and Innovative Strategies for Informing Health Care Redesign: A Policy Brief. AB - Recent health care legislation and shifting health care financing strategies are transforming health and behavioral health (a broad term referring to mental health, substance use, and health behavior) care in the United States. Advances in knowledge regarding effective treatment and services coupled with incentives for innovation in health and behavioral health care delivery systems make this a unique time for mobilizing our science to enhance the success of health and behavioral health care redesign. To optimize the potential of our current health care environment, a team was formed composed of leaders from the Societies of Clinical Child & Adolescent Psychology, Pediatric Psychology, and Child and Family Policy and Practice (Divisions 53, 54, and 37 of the American Psychological Association). This team was charged with reviewing the scientific and policy literature with a focus on five major issues: (a) improving access to care and reducing health disparities, (b) integrating behavioral health care within primary care, (c) preventive services, (d) enhancing quality and outcomes of care, and (e) training and workforce development. The products of that work are summarized here, including recommendations for future research, clinical, training, and policy directions. We conclude that the current emphasis on accountable care and evaluation of the outcomes of care offer numerous opportunities for psychologists to integrate science and practice for the benefit of our children, families, and nation. The dramatic changes that are occurring in psychological and behavioral health care services and payment systems also require evolution in our practice and training models. PMID- 26430951 TI - Factor structure and invariance test of the alcohol use disorder identification test (AUDIT): Comparison and further validation in a U.S. and Philippines college student sample. AB - The Alcohol Use Disorder Identification Test's factor structure varies depending on population and culture. Because of this inconsistency, this article examined the factor structure of the test and conducted a factorial invariance test between a U.S. and a Philippines college sample. Confirmatory factor analyses indicated that a three-factor solution outperforms the one- and two-factor solution in both samples. Factorial invariance analyses further supports the confirmatory findings by showing that factor loadings were generally invariant across groups; however, item intercepts show non-invariance. Country differences between factors show that Filipino consumption factor mean scores were significantly lower than their U.S. counterparts. PMID- 26430952 TI - Association of treatment factors with surgical outcomes in tri-modality therapy for esophageal cancer. AB - BACKGROUND AND OBJECTIVES: To identify the impact of the interval between chemoradiation to surgery on morbidity and mortality in patients undergoing tri modality therapy for esophageal cancer. METHODS: Eighty-five patients completed chemoradiation followed by esophagectomy between 2006 and 2011. The interval between completion of chemoradiation and surgery was calculated for each patient. We evaluated the association of quartiles and 3-week groups with morbidity and mortality using logistic regression. Other treatment and clinical factors were also assessed. RESULTS: A total of 59 patients(69%) experienced at least one complication. When examining specific complications, patients with pulmonary complications had a longer mean time interval from chemoradiation to surgery (P = 0.02). Linear regression showed an association between longer interval between chemoradiation to surgery and hospital length of stay (LOS) >14 days when analyzing by both interval quartile (P = 0.04) and 3-week intervals (P = 0.04). On multivariable analysis, increased time interval predicted for pulmonary complications (P < 0.01) and LOS >14 days (P = 0.03). When examining other treatment factors, squamous cell histology (P = 0.02) also predicted for a hospital length of stay >14 days. CONCLUSIONS: Factors such as interval between completion of chemoradiation and surgery and squamous cell histology may be associated with surgical morbidity. Further data is warranted to confirm these findings. PMID- 26430953 TI - Leptospirosis: a report on a series of five autochthonous cases in a Greek region. AB - Leptospirosis is a worldwide zoonotic disease difficult to diagnose both to the clinic and the laboratory. Many risk factors have been involved, such as planting, hunting, harvesting and butchering or sports, such as rafting. We reported our experience through a period of 20 months and we tried to investigate prognostic factors predicting clinical outcomes. Five male patients were admitted to our Department with a median age of 40 years. Overall, three out of five patients presented to other hospital and were transferred to ours with a wrong or delayed diagnosis. In terms of clinical signs and symptoms, all presented with fever, myalgia, headache and jaundice, whereas conjunctival suffusion was present in 80% of them. Acute renal injury and liver deficiency were diagnosed in all subjects. Acute renal failure management required dialysis in 3/5 patients, whereas renal recovery was achieved soon after clinical improvement. However, clinical awareness and serology are the most important tools for accurate and quick diagnosis in order to administer the appropriate therapy. PMID- 26430954 TI - Valence Virtual Orbitals: An Unambiguous ab Initio Quantification of the LUMO Concept. AB - Many chemical concepts hinge on the notion of an orbital called the lowest unoccupied molecular orbital, or LUMO. This hypothetical orbital and the much more concrete highest occupied molecular orbital (HOMO) constitute the two "frontier orbitals", which rationalize a great deal of chemistry. A viable LUMO candidate should have a sensible energy value, a realistic shape with amplitude on those atoms where electron attachment or reduction or excitation processes occur, and often an antibonding correspondence to one of the highest occupied MOs. Unfortunately, today's quantum chemistry calculations do not yield useful empty orbitals. Instead, the empty canonical orbitals form a large sea of orbitals, where the interesting valence antibonds are scrambled with the basis set's polarization and diffuse augmentations. The LUMO is thus lost within a continuum associated with a detached electron, as well as many Rydberg excited states. A suitable alternative to the canonical orbitals is proposed, namely, the valence virtual orbitals. VVOs are found by a simple algorithm based on singular value decomposition, which allows for the extraction of all valence-like orbitals from the large empty canonical orbital space. VVOs are found to be nearly independent of the working basis set. The utility of VVOs is demonstrated for construction of qualitative MO diagrams, for prediction of valence excited states, and as starting orbitals for more sophisticated calculations. This suggests that VVOs are a suitable realization of the LUMO, LUMO + 1, ... CONCEPT: VVO generation requires no expert knowledge, as the number of VVOs sought is found by counting s-block atoms as having only a valence s orbital, transition metals as having valence s and d, and main group atoms as being valence s and p elements. Closed shell, open shell, or multireference wave functions and elements up to xenon may be used in the present program. PMID- 26430956 TI - New and Emerging Treatment Options for Gastroenteropancreatic Neuroendocrine Tumors. AB - Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare, generally indolent neoplasms that can arise throughout the gastrointestinal system. Some GEP-NETs, known as functional, secrete hormones that can lead to a complex of symptoms. Classical carcinoid syndrome is associated with flushing, diarrhea, bronchospasm, and symptoms of valvular heart disease. GEP-NETs are classified according to the primary tumor site, functionality of the disease, and histology. Treatment is guided by the resectability of the tumor, the location and extent of metastases, and the presence of clinical symptoms. Typically, first-line treatment of patients with unresectable disease includes the use of somatostatin analogs, such as octreotide LAR depot or lanreotide depot/autogel, which was recently approved by the US Food and Drug Administration for treatment of GEP NETs. Somatostatin analogs can improve the severe diarrhea/flushing episodes that may be associated with metastatic carcinoid tumors. For patients with pancreatic NETs, additional approved treatment options include the targeted agents everolimus and sunitinib, which have demonstrated antitumor activity. Chemotherapy may also have a selective role, particularly in pancreatic NETs. Localized approaches, including cytoreductive surgery, hepatic arterial embolization, and ablative therapies, may be used for palliative treatment in patients with liver metastases. PMID- 26430960 TI - Solvent Structure around Lanthanoid(III) Ions in Liquid DMSO As Revealed by Polarizable Molecular Dynamics Simulations. AB - We present a study of the solvation of lanthanoid(III) ions in liquid dimethyl sulfoxide (DMSO) using molecular dynamics simulations employing a newly developed polarizable force field. The van der Waals (vdW) parameters were obtained for La(3+) and Lu(3+) (the first and the last in the lanthanoid(III) series) using ab initio data. The parameters of the other ions can be extrapolated based on physical considerations without additional (and costly) quantum chemistry calculations. This extrapolation procedure has been successfully applied to Gd(3+). The outcomes of our simulations turn out to be in agreement with both the experimental data available in the literature and the ab initio results. A small adjustment of the vdW parameters further increases the agreement with experiments and has allowed us to provide structures, geometrical parameters, and coordination numbers. For heavy lanthanoids (Gd and Lu) we obtain clearly an 8 fold coordination, with a distorted square antiprism (SAP) geometry in agreement with EXAFS and XANES experiments; for the La(3+) ion, our force field predicts a mixed situation with both the 8-fold SAP and 9-fold geometry where the SAP structure is capped by a ninth molecule added over one face. PMID- 26430955 TI - Silica-Supported Oligomeric Benzyl Phosphate (Si-OBP) and Triazole Phosphate (Si OTP) Alkylating Reagents. AB - The syntheses of silica-supported oligomeric benzyl phosphates (Si-OBP(n)) and triazole phosphates (Si-OTP(n)) using ring-opening metathesis polymerization (ROMP) for use as efficient alkylating reagents is reported. Ease of synthesis and grafting onto the surface of norbornenyl-tagged (Nb-tagged) silica particles has been demonstrated for benzyl phosphate and triazole phosphate monomers. It is shown that these silica polymer hybrid reagents, Si-OBP(n) and Si-OTP(n), can be used to carry out alkylation reactions with an array of different nucleophiles to afford the corresponding benzylated and (triazolyl)methylated products in good yield and high purity. PMID- 26430961 TI - Overexpression of caldesmon is associated with tumor progression in patients with primary non-muscle-invasive bladder cancer. AB - The expression and function of caldesmon (CAD) in urothelial bladder carcinoma (BC) have not been reported. Here, we investigated the expression, prognostic value, and potential functional mechanism of CAD in primary non-muscle-invasive bladder cancer (NMIBC). Protein profiling of tissue samples using antibody microarrays showed significantly higher CAD expression in muscle-invasive BC tissues compared with NMIBC tissues. We then validated the CAD expression in BC cells by immunohistochemistry analysis using paraffin-embedded tissue blocks and western blots using BC cell lines. In addition, we examined the expression of CAD variants by reverse transcription-polymerase chain reaction, and confirmed the expression of low-molecular-weight isoforms (L-CAD), specifically encoded by WI 38 L-CAD II (transcript variant 2), in BC cells. Survival analysis in an independent primary NMIBC cohort comprising 132 patients showed that positive CAD expression was significantly associated with poorer prognosis than no CAD expression with regard to recurrence- and progression-free survival (p = 0.001 and 0.014, respectively). Multivariate analyses further indicated that positive CAD expression was an independent predictor of progression-free survival (p = 0.032; HR = 5.983). Data obtained from in vitro silencing and overexpression studies indicated that L-CAD promotes migration and invasiveness of BC cells. Immunofluorescence assays showed dramatic structural changes in the actin cytoskeleton of BC cells after L-CAD overexpression. Our findings collectively suggest that L-CAD overexpression in primary NMIBC is significantly associated with tumor progression and that a possible mechanism for L-CAD's activity is implicated in increased cell motility and invasive characteristics through morphological changes in BC cells. PMID- 26430962 TI - Protein kinase CK2alpha catalytic subunit is overexpressed and serves as an unfavorable prognostic marker in primary hepatocellular carcinoma. AB - Protein kinase CK2 alpha (CK2alpha), one isoform of the catalytic subunit of serine/threonine kinase CK2, has been indicated to participate in tumorigenesis of various malignancies. We conducted this study to investigate the biological significances of CK2alpha expression in hepatocellular carcinoma (HCC) development. Real-time quantitative polymerase and western blotting analyses revealed that CK2alpha expression was significantly increased at mRNA and protein levels in HCC tissues. Immunohistochemical analyses indicated that amplified expression of CK2alpha was highly correlated with poor prognosis. And functional analyses (cell proliferation and colony formation assays, cell migration and invasion assays, cell cycle and apoptosis assays) found that CK2alpha promoted cell proliferation, colony formation, migration and invasion, as well as inhibited apoptosis in hepatoma cell lines in vitro. CK2alpha-silenced resulted in significant apoptosis in cells that was demonstrated been associated with downregulation of expression of Bcl-2, p-AKT (ser473) and upregulation of expression of total P53, p-P53, Bax, caspase3 and cleaved-caspase3 in HCC cells. In addition, experiments with a mouse model revealed that the stimulative effect of CK2alpha on tumorigenesis in nude mice. Our results suggest that CK2alpha might play an oncogenic role in HCC, and therefore it could serve as a biomarker for prognostic and therapeutic applications in HCC. PMID- 26430963 TI - The transcription factor c-Fos coordinates with histone lysine-specific demethylase 2A to activate the expression of cyclooxygenase-2. AB - Cyclooxygenase-2 (COX-2) is overexpressed in a variety of human epithelial cancers, including lung cancer, and is highly associated with a poor prognosis and a low survival rate. Understanding how COX-2 is regulated in response to carcinogens will offer insight into designing anti-cancer strategies and preventing cancer development. Here, we analyzed COX-2 expression in several human lung cancer cell lines and found that COX-2 expression was absent in the H719 and H460 cell lines by a DNA methylation-independent mechanism. The re expression of COX-2 was observed after 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment in both cell lines. Further investigation found that H3K36 dimethylation was significantly reduced near the COX-2 promoter because histone demethylase 2A (KDM2A) was recruited to the COX-2 promoter after TPA treatment. In addition, the transcription factor c-Fos was found to be required to recruit KDM2A to the COX-2 promoter for reactivation of COX-2 in response to TPA treatment in both the H719 and H460 cell lines. Together, our data reveal a novel mechanism by which the carcinogen TPA activates COX-2 expression by regulating H3K36 dimethylation near the COX-2 promoter. PMID- 26430964 TI - Overexpression of Bcl-2 induces STAT-3 activation via an increase in mitochondrial superoxide. AB - We recently reported a novel interaction between Bcl-2 and Rac1 and linked that to the ability of Bcl-2 to induce a pro-oxidant state in cancer cells. To gain further insight into the functional relevance of this interaction, we utilized computer simulation based on the protein pathway dynamic network created by Cellworks Group Inc. STAT3 was identified among targets that positively correlated with Rac1 and/or Bcl-2 expression levels. Validating this, the activation level of STAT3, as marked by p-Tyr705, particularly in the mitochondria, was significantly higher in Bcl-2-overexpressing cancer cells. Bcl 2-induced STAT3 activation was a function of GTP-loaded Rac1 and NADPH oxidase (Nox)-dependent increase in intracellular superoxide (O2*-). Furthermore, ABT199, a BH-3 specific inhibitor of Bcl-2, as well as silencing of Bcl-2 blocked STAT3 phosphorylation. Interestingly, while inhibiting intracellular O2*- blocked STAT3 phosphorylation, transient overexpression of wild type STAT3 resulted in a significant increase in mitochondrial O2*- production, which was rescued by the functional mutants of STAT3 (Y705F). Notably, a strong correlation between the expression and/or phosphorylation of STAT3 and Bcl-2 was observed in primary tissues derived from patients with different sub-sets of B cell lymphoma. These data demonstrate the presence of a functional crosstalk between Bcl-2, Rac1 and activated STAT3 in promoting a permissive redox milieu for cell survival. Results also highlight the potential utility of a signature involving Bcl-2 overexpression, Rac1 activation and STAT3 phosphorylation for stratifying clinical lymphomas based on disease severity and chemoresistance. PMID- 26430965 TI - A functional variant in HOXA11-AS, a novel long non-coding RNA, inhibits the oncogenic phenotype of epithelial ovarian cancer. AB - The homeobox A (HOXA) region of protein-coding genes impacts female reproductive system embryogenesis and ovarian carcinogenesis. The 5-prime end of HOXA includes three long non-coding RNAs (lncRNAs) (HOXA10-AS, HOXA11-AS, and HOTTIP) that are underexplored in epithelial ovarian cancer (EOC). We evaluated whether common genetic variants in these lncRNAs are associated with EOC risk and/or have functional roles in EOC development. Using genome-wide association study data from 1,201 serous EOC cases and 2,009 controls, an exonic variant within HOXA11 AS, rs17427875 (A>T), was marginally associated with reduced serous EOC risk (OR = 0.88 (95% CI: 0.78-1.01, p = 0.06). Functional studies of ectopic expression of HOXA11-AS minor allele T in EOC cells showed decreased survival, proliferation, migration, and invasion compared to common allele A expression. Additionally, stable expression of HOXA11-AS minor allele T reduced primary tumor growth in mouse xenograft models to a greater extent than common allele A. Furthermore, HOXA11-AS expression levels were significantly lower in human EOC tumors than normal ovarian tissues (p < 0.05), suggesting that HOXA11-AS has a tumor suppressor function in EOC which may be enhanced by the T allele. These findings demonstrate for the first time a role for HOXA11-AS in EOC with effects that could be modified by germline variants. PMID- 26430966 TI - Systemic delivery of HER2-retargeted oncolytic-HSV by mesenchymal stromal cells protects from lung and brain metastases. AB - Fully retargeted oncolytic herpes simplex viruses (o-HSVs) gain cancer specificity from redirection of tropism to cancer-specific receptors, and are non attenuated. To overcome the hurdles of systemic delivery, and enable oncolytic viruses (o-viruses) to reach metastatic sites, carrier cells are being exploited. Mesenchymal stromal cells (MSCs) were never tested as carriers of retargeted o viruses, given their scarse-null expression of the cancer-specific receptors. We report that MSCs from different sources can be forcedly infected with a HER2 retargeted oncolytic HSV. Progeny virus spread from MSCs to cancer cells in vitro and in vivo. We evaluated the organ distribution and therapeutic efficacy in two murine models of metastatic cancers, following a single i.v. injection of infected MSCs. As expected, the highest concentration of carrier-cells and of viral genomes was in the lungs. Viral genomes persisted throughout the body for at least two days. The growth of ovarian cancer lung metastases in nude mice was strongly inhibited, and the majority of treated mice appeared metastasis-free. The treatment significantly inhibited also breast cancer metastases to the brain in NSG mice, and reduced by more than one-half the metastatic burden in the brain. PMID- 26430968 TI - Can Computerized Neuropsychological Testing in the Emergency Department Predict Recovery for Young Athletes With Concussions? AB - OBJECTIVE: The objective of this study was to determine if computerized neurocognitive testing (Immediate Post-Concussion Assessment and Cognitive Testing [ImPACT]) in the emergency department (ED) can be used as a prognostic tool to detect young athletes at risk of having protracted concussive symptoms. METHODS: This was a prospective cohort study of athletes aged 11 to 18 years who presented to an ED less than 24 hours after sustaining a sports-related concussion. ImPACT was administered in the ED, and performance was categorized as "poor" if the athlete had 3 (of 4) or greater low domain scores. Participants completed the Post-Concussion Symptom Scale (PCSS) in the ED and by phone at 1 and 2 weeks after injury. Athletes were symptomatic if their PCSS score was more than 6 in males and more than 8 in females. RESULTS: One hundred nine patients were enrolled; 60% and 36% remained symptomatic at 1 and 2 weeks after injury, respectively. "Poor" ImPACT performance was not particularly useful in predicting athletes with protracted symptoms (at 1 week: positive predictive value, 70.8%; negative predictive value, 43.5%; at 2 weeks: positive predictive value, 47.8%; negative predictive value, 68.9%). In bivariate analysis, a higher ED PCSS score was associated with protracted symptoms (at 1 week: odds ratio, 1.1 [confidence interval, 1.0-1.1]; at 2 weeks: odds ratio, 1.0 [confidence interval, 1.0-1.1]). CONCLUSIONS: Computerized neurocognitive testing in the ED has limited usefulness in predicting protracted symptoms. Total acute symptom burden may be a useful prognostic tool in the ED evaluation of concussed young athletes, yet further research is necessary. PMID- 26430967 TI - Novel Potent N-Methyl-d-aspartate (NMDA) Receptor Antagonists or sigma1 Receptor Ligands Based on Properly Substituted 1,4-Dioxane Ring. AB - Two series of 1,4-dioxanes (4-11 and 12-19) were rationally designed and prepared to interact either with the phencyclidine (PCP) binding site of the N-methyl-d aspartate (NMDA) receptor or with sigma1 receptors, respectively. The biological profiles of the novel compounds were assessed using radioligand binding assays, and the compounds with the highest affinities were investigated for their functional activity. The results were in line with the available pharmacophore models and highlighted that the 1,4-dioxane scaffold is compatible with potent antagonist activity at NMDA receptor or high affinity for sigma1 receptors. The primary amines 6b and 7 bearing a cyclohexyl and a phenyl ring or two phenyl rings in position 6, respectively, were the most potent noncompetitive antagonists at the NMDA receptor with IC50 values similar to those of the dissociative anesthetic (S)-(+)-ketamine. The 5,5-diphenyl substitution associated with a benzylaminomethyl moiety in position 2, as in 18, favored the interaction with sigma1 receptors. PMID- 26430969 TI - Localized Ion-Beam Irradiation-Induced Wrinkle Patterns. AB - We observe a localized irradiation-induced wrinkle pattern on poly(dimethylsiloxane) (PDMS) via a long pattern mask. Localized ion-beam irradiation induces an inhomogeneous wrinkle pattern on the treated region. To confirm the inhomogeneity of the entire wrinkle pattern, its morphology was investigated using optical microscopy, which revealed separated regions in the wrinkle pattern. We used atomic force microscopy for quantitative analysis of the wrinkle pattern morphology and analyzed the angular distribution and the direction of compressive stress of the irradiated area. We confirmed the direction of stress release along the distance from the edges, and we achieved control of the orientation of the wrinkle pattern by altering the width of the irradiated area. Investigation of the inhomogeneities in a localized wrinkle formation provides an understanding of the formation mechanism to enhance its performance and application in various fields. PMID- 26430970 TI - Characterization of the Leukocyte Response in Acute Vocal Fold Injury. AB - Macrophages location in the superficial layer of the vocal fold (VF) is not only at the first line of defense, but in a place of physiologic importance to voice quality. This study characterizes and compares macrophage function in two models of acute injury. Porcine VF injuries were created bilaterally by either surgical biopsy or lipopolysaccharide (LPS) (1.5 MUg/kg) injection. Animals were sacrificed at 1- or 5-day post LPS or 3-, 7-, or 23-days post-surgical injury (n = 3/time/injury). Flow cytometry characterized immunophenotypes and RT-PCR quantified cytokine gene expression. Uninjured VF were used as controls. Post surgical and LPS injury, SWC9+/SWC3- cells identified as hi SLA-DR+ (p<0.05) compared to controls along with hi CD16+ expression at 1-day and 3-days respectively compared to all other time points (p<0.05). Surgical injuries, SWC9+/SWC3- cells exhibited hi CD163+ (p<0.05) at 3-days along with upregulation in TNFalpha and TGFbeta1 mRNA compared to 23-days (p<0.05). No measurable changes to IL-12, IFNgamma, IL-10, IL-4 mRNA post-surgery. LPS injuries induced upregulation of TNFalpha, IL-12, IFNgamma, IL-10, and IL-4 mRNA at 1- and 5-days compared to controls (p<0.05). Higher levels of IL-10 mRNA were found 1-day post LPS compared to 5-days (p<0.05). No changes to CD163 or CD80/86 post-LPS were measured. Acute VF injuries revealed a paradigm of markers that appear to associate with each injury. LPS induced a regulatory phenotype indicated by prominent IL-10 mRNA expression. Surgical injury elicited a complex phenotype with early TNFalpha mRNA and CD163+ and persistent TGFbeta1 transcript expression. PMID- 26430971 TI - Effects of Oil-Contaminated Sediments on Submerged Vegetation: An Experimental Assessment of Ruppia maritima. AB - Oil spills threaten the productivity of ecosystems through the degradation of coastal flora and the ecosystem services these plants provide. While lab and field investigations have quantified the response of numerous species of emergent vegetation to oil, the effects on submerged vegetation remain uncertain. Here, we discuss the implications of oil exposure for Ruppia maritima, one of the most common species of submerged vegetation found in the region affected by the recent Deepwater Horizon oil spill. We grew R. maritima in a range of manipulated sediment oil concentrations: 0, 0.26, 0.53, and 1.05 mL oil /L tank volume, and tracked changes in growth (wet weight and shoot density/length), reproductive activity (inflorescence and seed production), root characteristics (mass, length, diameter, and area), and uprooting force of plants. While no statistical differences were detected in growth, plants exhibited significant changes to reproductive output, root morphology, and uprooting force. We found significant reductions in inflorescences and fruiting bodies at higher oil concentrations. In addition, the roots growing in the high oil were shorter and wider. Plants in medium and high oil required less force to uproot. A second experiment was performed to separate the effects of root morphology and oiled sediment properties and indicated that there were also changes to sediment cohesion that contributed to a reduction in uprooting forces in medium and high oil. Given the importance of sexual reproduction for these plants, oil contamination may have substantial population-level effects. Moreover, areas containing buried oil may be more susceptible to high energy storm events due to the reduction in uprooting force of foundation species such as R. maritima. PMID- 26430972 TI - Improving the Precision of Weak Measurements by Postselection Measurement. AB - Postselected weak measurement is a useful protocol for amplifying weak physical effects. However, there has recently been controversy over whether it gives any advantage in precision. While it is now clear that retaining failed postselections can yield more Fisher information than discarding them, the advantage of postselection measurement itself still remains to be clarified. In this Letter, we address this problem by studying two widely used estimation strategies: averaging measurement results, and maximum likelihood estimation, respectively. For the first strategy, we find a surprising result that squeezed coherent states of the pointer can give postselected weak measurements a higher signal-to-noise ratio than standard ones while all standard coherent states cannot, which suggests that raising the precision of weak measurements by postselection calls for the presence of "nonclassicality" in the pointer states. For the second strategy, we show that the quantum Fisher information of postselected weak measurements is generally larger than that of standard weak measurements, even without using the failed postselection events, but the gap can be closed with a proper choice of system state. PMID- 26430973 TI - Majorana Braiding with Thermal Noise. AB - We investigate the self-correcting properties of a network of Majorana wires, in the form of a trijunction, in contact with a parity-preserving thermal environment. As opposed to the case where Majorana bound states are immobile, braiding Majorana bound states within a trijunction introduces dangerous error processes that we identify. Such errors prevent the lifetime of the memory from increasing with the size of the system. We confirm our predictions with Monte Carlo simulations. Our findings put a restriction on the degree of self correction of this specific quantum computing architecture. PMID- 26430974 TI - Landauer's Principle in Multipartite Open Quantum System Dynamics. AB - We investigate the link between information and thermodynamics embodied by Landauer's principle in the open dynamics of a multipartite quantum system. Such irreversible dynamics is described in terms of a collisional model with a finite temperature reservoir. We demonstrate that Landauer's principle holds, for such a configuration, in a form that involves the flow of heat dissipated into the environment and the rate of change of the entropy of the system. Quite remarkably, such a principle for heat and entropy power can be explicitly linked to the rate of creation of correlations among the elements of the multipartite system and, in turn, the non-Markovian nature of their reduced evolution. Such features are illustrated in two exemplary cases. PMID- 26430975 TI - Nonclassicality of Temporal Correlations. AB - The results of spacelike separated measurements are independent of distant measurement settings, a property one might call two-way no-signaling. In contrast, timelike separated measurements are only one-way no-signaling since the past is independent of the future but not vice versa. For this reason some temporal correlations that are formally identical to nonclassical spatial correlations can still be modeled classically. We propose a new formulation of Bell's theorem for temporal correlations; namely, we define nonclassical temporal correlations as the ones which cannot be simulated by propagating in time the classical information content of a quantum system given by the Holevo bound. We first show that temporal correlations between results of any projective quantum measurements on a qubit can be simulated classically. Then we present a sequence of general measurements on a single m-level quantum system that cannot be explained by propagating in time an m-level classical system and using classical computers with unlimited memory. PMID- 26430976 TI - Quasilocal Conserved Operators in the Isotropic Heisenberg Spin-1/2 Chain. AB - Composing higher auxiliary-spin transfer matrices and their derivatives, we construct a family of quasilocal conserved operators of isotropic Heisenberg spin 1/2 chain and rigorously establish their linear independence from the well-known set of local conserved charges. PMID- 26430977 TI - Universality at Breakdown of Quantum Transport on Complex Networks. AB - We consider single-particle quantum transport on parametrized complex networks. Based on general arguments regarding the spectrum of the corresponding Hamiltonian, we derive bounds for a measure of the global transport efficiency defined by the time-averaged return probability. For treelike networks, we show analytically that a transition from efficient to inefficient transport occurs depending on the (average) functionality of the nodes of the network. In the infinite system size limit, this transition can be characterized by an exponent which is universal for all treelike networks. Our findings are corroborated by analytic results for specific deterministic networks, dendrimers and Vicsek fractals, and by Monte Carlo simulations of iteratively built scale-free trees. PMID- 26430978 TI - High-Energy Cosmic Ray Self-Confinement Close to Extra-Galactic Sources. AB - The ultrahigh-energy cosmic rays observed on the Earth are most likely accelerated in extra-Galactic sources. For the typical luminosities invoked for such sources, the electric current associated to the flux of cosmic rays that leave them is large. The associated plasma instabilities create magnetic fluctuations that can efficiently scatter particles. We argue that this phenomenon forces cosmic rays to be self-confined in the source proximity for energies Enu_{tau} oscillations in appearance mode, i.e., by detecting the tau leptons produced in charged current nu_{tau} interactions. The experiment took data from 2008 to 2012 in the CERN Neutrinos to Gran Sasso beam. The observation of the nu_{MU}->nu_{tau} appearance, achieved with four candidate events in a subsample of the data, was previously reported. In this Letter, a fifth nu_{tau} candidate event, found in an enlarged data sample, is described. Together with a further reduction of the expected background, the candidate events detected so far allow us to assess the discovery of nu_{MU}->nu_{tau} oscillations in appearance mode with a significance larger than 5sigma. PMID- 26430992 TI - Joint Measurements of Terahertz Wave Generation and High-Harmonic Generation from Aligned Nitrogen Molecules Reveal Angle-Resolved Molecular Structures. AB - We report the synchronized measurements of terahertz wave generation and high harmonic generation from aligned nitrogen molecules in dual-color laser fields. Both yields are found to be alignment dependent, showing the importance of molecular structures in the generation processes. By calibrating the angular ionization rates with the terahertz yields, we present a new way of retrieving the angular differential photoionization cross section (PICS) from the harmonic signals which avoids specific model calculations or separate measurements of the alignment-dependent ionization rates. The measured PICS is found to be consistent with theoretical predications, although some discrepancies exist. This all optical method provides a new alternative for investigating molecular structures. PMID- 26430987 TI - Search for Nucleon and Dinucleon Decays with an Invisible Particle and a Charged Lepton in the Final State at the Super-Kamiokande Experiment. AB - Search results for nucleon decays p->e^{+}X, p->MU^{+}X, n->nugamma (where X is an invisible, massless particle) as well as dinucleon decays np->e^{+}nu, np >MU^{+}nu, and np->tau^{+}nu in the Super-Kamiokande experiment are presented. Using single-ring data from an exposure of 273.4 kton.yr, a search for these decays yields a result consistent with no signal. Accordingly, lower limits on the partial lifetimes of tau_{p->e^{+}X}>7.9*10^{32} yr, tau_{p >MU^{+}X}>4.1*10^{32} yr, tau_{n->nugamma}>5.5*10^{32} yr, tau_{np >e^{+}nu}>2.6*10^{32} yr, tau_{np->MU^{+}nu}>2.2*10^{32} yr, and tau_{np >tau^{+}nu}>2.9*10^{31} yr at a 90% confidence level are obtained. Some of these searches are novel. PMID- 26430994 TI - Coulomb Bound States of Strongly Interacting Photons. AB - We show that two photons coupled to Rydberg states via electromagnetically induced transparency can interact via an effective Coulomb potential. This interaction gives rise to a continuum of two-body bound states. Within the continuum, metastable bound states are distinguished in analogy with quasibound states tunneling through a potential barrier. We find multiple branches of metastable bound states whose energy spectrum is governed by the Coulomb potential, thus obtaining a photonic analogue of the hydrogen atom. Under certain conditions, the wave function resembles that of a diatomic molecule in which the two polaritons are separated by a finite "bond length." These states propagate with a negative group velocity in the medium, allowing for a simple preparation and detection scheme, before they slowly decay to pairs of bound Rydberg atoms. PMID- 26430993 TI - Light-Dressing Effect in Laser-Assisted Elastic Electron Scattering by Xe. AB - The light-dressing effect in Xe atoms was identified in laser-assisted elastic electron scattering (LAES) signals. In the angular distribution of LAES signals with energy shifts of +/-homega recorded by the scattering of 1 keV electrons by Xe in an intense nonresonant laser field, a peak profile appeared at small scattering angles (<0.5 degrees ). This peak was interpreted as evidence of the light dressing of Xe atoms induced by an intense laser field on the basis of a numerical simulation in which the light-dressing effect is included. PMID- 26430995 TI - Wake-Driven Dynamics of Finite-Sized Buoyant Spheres in Turbulence. AB - Particles suspended in turbulent flows are affected by the turbulence and at the same time act back on the flow. The resulting coupling can give rise to rich variability in their dynamics. Here we report experimental results from an investigation of finite-sized buoyant spheres in turbulence. We find that even a marginal reduction in the particle's density from that of the fluid can result in strong modification of its dynamics. In contrast to classical spatial filtering arguments and predictions of particle models, we find that the particle acceleration variance increases with size. We trace this reversed trend back to the growing contribution from wake-induced forces, unaccounted for in current particle models in turbulence. Our findings highlight the need for improved multiphysics based models that account for particle wake effects for a faithful representation of buoyant-sphere dynamics in turbulence. PMID- 26430996 TI - Absolute Instability near the Band Edge of Traveling-Wave Amplifiers. AB - Applying the Briggs-Bers "pole-pinch" criterion to the exact transcendental dispersion relation of a dielectric traveling wave tube (TWT), we find that there is no absolute instability regardless of the beam current. We extend this analysis to the circuit band edges of a linear beam TWT by approximating the circuit mode as a hyperbola in the frequency-wave-number (omega-k) plane and consider the weak coupling limit. For an operating mode whose group velocity is in the same direction as the beam mode, we find that the lower band edge is not subjected to absolute instability. At the upper band edge, we find a threshold beam current beyond which absolute instability is excited. The nonexistence of absolute instability in a linear beam TWT and the existence in a gyrotron TWT, both at the lower band edge, is contrasted. The general study given here is applicable to some contemporary TWTs such as metamaterial-based and advanced Smith-Purcell TWTs. PMID- 26430997 TI - Quasiperpendicular High Mach Number Shocks. AB - Shock waves exist throughout the Universe and are fundamental to understanding the nature of collisionless plasmas. Reformation is a process, driven by microphysics, which typically occurs at high Mach number supercritical shocks. While ongoing studies have investigated this process extensively both theoretically and via simulations, their observations remain few and far between. In this Letter we present a study of very high Mach number shocks in a parameter space that has been poorly explored and we identify reformation using in situ magnetic field observations from the Cassini spacecraft at 10 AU. This has given us an insight into quasiperpendicular shocks across 2 orders of magnitude in Alfven Mach number (M_{A}) which could potentially bridge the gap between modest terrestrial shocks and more exotic astrophysical shocks. For the first time, we show evidence for cyclic reformation controlled by specular ion reflection occurring at the predicted time scale of ~0.3tau_{c}, where tau_{c} is the ion gyroperiod. In addition, we experimentally reveal the relationship between reformation and M_{A} and focus on the magnetic structure of such shocks to further show that for the same M_{A}, a reforming shock exhibits stronger magnetic field amplification than a shock that is not reforming. PMID- 26430998 TI - Spatial Patterns in Rydberg Excitations from Logarithmic Pair Interactions. AB - The collective excitations in ensembles of dissipative, laser driven ultracold atoms exhibit crystal-like patterns, a many-body effect of the Rydberg blockade mechanism. These crystalline structures are revealed in an experiment from a postselection of configurations with fixed numbers of excitations. Here, we show that these subensembles can be well represented by ensembles of effective particles that interact via logarithmic pair potentials. This allows one to study the emergent patterns with a small number of effective particles to determine the phases of Rydberg crystals and to systematically study contributions from N-body terms. PMID- 26430999 TI - Impurity in a Bose-Einstein Condensate and the Efimov Effect. AB - We investigate the zero-temperature properties of an impurity particle interacting with a Bose-Einstein condensate (BEC), using a variational wave function that includes up to two Bogoliubov excitations of the BEC. This allows one to capture three-body Efimov physics, as well as to recover the first nontrivial terms in the weak-coupling expansion. We show that the energy and quasiparticle residue of the dressed impurity (polaron) are significantly lowered by three-body correlations, even for weak interactions where there is no Efimov trimer state in a vacuum. For increasing attraction between the impurity and the BEC, we observe a smooth crossover from atom to Efimov trimer, with a superposition of states near the Efimov resonance. We furthermore demonstrate that three-body loss does not prohibit the experimental observation of these effects. Our results thus suggest a route to realizing Efimov physics in a stable quantum many-body system for the first time. PMID- 26431000 TI - Electromagnetic Saturation of Angstrom-Sized Quantum Barriers at Terahertz Frequencies. AB - Metal-graphene-metal hybrid structures allow angstrom-scale van der Waals gaps, across which electron tunneling occurs. We squeeze terahertz electromagnetic waves through these lambda/10 000 000 gaps, accompanied by giant field enhancements. Unprecedented transmission reduction of 97% is achieved with the transient voltage across the gap saturating at 5 V. Electron tunneling facilitated by the transient electric field strongly modifies the gap index, starting a self-limiting process related to the barrier height. Our work enables greater interplay between classical optics and quantum tunneling, and provides optical indices to the van der Waals gaps. PMID- 26431001 TI - Fractional Chern Insulators in Harper-Hofstadter Bands with Higher Chern Number. AB - The Harper-Hofstadter model provides a fractal spectrum containing topological bands of any integer Chern number C. We study the many-body physics that is realized by interacting particles occupying Harper-Hofstadter bands with |C|>1. We formulate the predictions of Chern-Simons or composite fermion theory in terms of the filling factor nu, defined as the ratio of particle density to the number of single-particle states per unit area. We show that this theory predicts a series of fractional quantum Hall states with filling factors nu=r/(r|C|+1) for bosons, or nu=r/(2r|C|+1) for fermions. This series includes a bosonic integer quantum Hall state in |C|=2 bands. We construct specific cases where a single band of the Harper-Hofstadter model is occupied. For these cases, we provide numerical evidence that several states in this series are realized as incompressible quantum liquids for bosons with contact interactions. PMID- 26431002 TI - Observation of the Zero Hall Plateau in a Quantum Anomalous Hall Insulator. AB - We report experimental investigations on the quantum phase transition between the two opposite Hall plateaus of a quantum anomalous Hall insulator. We observe a well-defined plateau with zero Hall conductivity over a range of magnetic field around coercivity when the magnetization reverses. The features of the zero Hall plateau are shown to be closely related to that of the quantum anomalous Hall effect, but its temperature evolution exhibits a significant difference from the network model for a conventional quantum Hall plateau transition. We propose that the chiral edge states residing at the magnetic domain boundaries, which are unique to a quantum anomalous Hall insulator, are responsible for the novel features of the zero Hall plateau. PMID- 26431003 TI - Electrical Tuning of Exciton Binding Energies in Monolayer WS_{2}. AB - We demonstrate continuous tuning of the exciton binding energy in monolayer WS_{2} by means of an externally applied voltage in a field-effect transistor device. Using optical spectroscopy, we monitor the ground and excited excitonic states as a function of gate voltage and track the evolution of the quasiparticle band gap. The observed decrease of the exciton binding energy over the range of about 100 meV, accompanied by the renormalization of the quasiparticle band gap, is associated with screening of the Coulomb interaction by the electrically injected free charge carriers at densities up to 8*10^{12} cm^{-2}. Complete ionization of the excitons due to the electrical doping is estimated to occur at a carrier density of several 10^{13} cm^{-2}. PMID- 26431004 TI - Dirac Semimetals in Two Dimensions. AB - Graphene is famous for being a host of 2D Dirac fermions. However, spin-orbit coupling introduces a small gap, so that graphene is formally a quantum spin Hall insulator. Here we present symmetry-protected 2D Dirac semimetals, which feature Dirac cones at high-symmetry points that are not gapped by spin-orbit interactions and exhibit behavior distinct from both graphene and 3D Dirac semimetals. Using a two-site tight-binding model, we construct representatives of three possible distinct Dirac semimetal phases and show that single symmetry protected Dirac points are impossible in two dimensions. An essential role is played by the presence of nonsymmorphic space group symmetries. We argue that these symmetries tune the system to the boundary between a 2D topological and trivial insulator. By breaking the symmetries we are able to access trivial and topological insulators as well as Weyl semimetal phases. PMID- 26431005 TI - Charge Number Dependence of the Dephasing Rates of a Graphene Double Quantum Dot in a Circuit QED Architecture. AB - We use an on-chip superconducting resonator as a sensitive meter to probe the properties of graphene double quantum dots at microwave frequencies. Specifically, we investigate the charge dephasing rates in a circuit quantum electrodynamics architecture. The dephasing rates strongly depend on the number of charges in the dots, and the variation has a period of four charges, over an extended range of charge numbers. Although the exact mechanism of this fourfold periodicity in dephasing rates is an open problem, our observations hint at the fourfold degeneracy expected in graphene from its spin and valley degrees of freedom. PMID- 26431006 TI - Fractional Quantum Hall States at nu=13/5 and 12/5 and Their Non-Abelian Nature. AB - Topological quantum states with non-Abelian Fibonacci anyonic excitations are widely sought after for the exotic fundamental physics they would exhibit, and for universal quantum computing applications. The fractional quantum Hall (FQH) state at a filling factor of nu=12/5 is a promising candidate; however, its precise nature is still under debate and no consensus has been achieved so far. Here, we investigate the nature of the FQH nu=13/5 state and its particle-hole conjugate state at 12/5 with the Coulomb interaction, and we address the issue of possible competing states. Based on a large-scale density-matrix renormalization group calculation in spherical geometry, we present evidence that the essential physics of the Coulomb ground state (GS) at nu=13/5 and 12/5 is captured by the k=3 parafermion Read-Rezayi state (RR_{3}), including a robust excitation gap and the topological fingerprint from the entanglement spectrum and topological entanglement entropy. Furthermore, by considering the infinite-cylinder geometry (topologically equivalent to torus geometry), we expose the non-Abelian GS sector corresponding to a Fibonacci anyonic quasiparticle, which serves as a signature of the RR_{3} state at 13/5 and 12/5 filling numbers. PMID- 26431007 TI - Alloy Engineering of Defect Properties in Semiconductors: Suppression of Deep Levels in Transition-Metal Dichalcogenides. AB - Developing practical approaches to effectively reduce the amount of deep defect levels in semiconductors is critical for their use in electronic and optoelectronic devices, but this still remains a very challenging task. In this Letter, we propose that specific alloying can provide an effective means to suppress the deep defect levels in semiconductors while maintaining their basic electronic properties. Specifically, we demonstrate that for transition-metal dichalcogenides, such as MoSe_{2} and WSe_{2}, where anion vacancies are the most abundant defects that can induce deep levels, the deep levels can be effectively suppressed in Mo_{1-x}W_{x}Se_{2} alloys at low W concentrations. This surprising phenomenon is associated with the fact that the band edge energies can be substantially tuned by the global alloy concentration, whereas the defect level is controlled locally by the preferred locations of Se vacancies around W atoms. Our findings illustrate a concept of alloy engineering and provide a promising approach to control the defect properties of semiconductors. PMID- 26431008 TI - Enhanced Bulk-Edge Coulomb Coupling in Fractional Fabry-Perot Interferometers. AB - Recent experiments use Fabry-Perot (FP) interferometry to claim that the nu=5/2 quantum Hall state exhibits non-Abelian topological order. We note that the experiments appear inconsistent with a model neglecting bulk-edge Coulomb coupling and Majorana tunneling, so we reexamine the theory of FP devices. Even a moderate Coulomb coupling may strongly affect some fractional plateaus, but very weakly affect others, allowing us to model the data over a wide range of plateaus. While experiments are consistent with the nu=5/2 state harboring Moore Read topological order, they may have measured Coulomb effects rather than an "even-odd effect" due to non-Abelian braiding. PMID- 26430984 TI - First Observation of CP Violation in B[over -]^{0}->D_{CP}^{(*)}h^{0} Decays by a Combined Time-Dependent Analysis of BABAR and Belle Data. AB - We report a measurement of the time-dependent CP asymmetry of B[over -]^{0} >D_{CP}^{(*)}h^{0} decays, where the light neutral hadron h^{0} is a pi^{0}, eta, or omega meson, and the neutral D meson is reconstructed in the CP eigenstates K^{+}K^{-}, K_{S}^{0}pi^{0}, or K_{S}^{0}omega. The measurement is performed combining the final data samples collected at the Upsilon(4S) resonance by the BABAR and Belle experiments at the asymmetric-energy B factories PEP-II at SLAC and KEKB at KEK, respectively. The data samples contain (471+/-3)*10^{6} BB[over ] pairs recorded by the BABAR detector and (772+/-11)*10^{6} BB[over -] pairs recorded by the Belle detector. We measure the CP asymmetry parameters eta_{f}S=+0.66+/-0.10(stat)+/-0.06(syst) and C=-0.02+/-0.07(stat)+/-0.03(syst). These results correspond to the first observation of CP violation in B[over ]^{0}->D_{CP}^{(*)}h^{0} decays. The hypothesis of no mixing-induced CP violation is excluded in these decays at the level of 5.4 standard deviations. PMID- 26431009 TI - Semiconductor-Nanowire-Based Superconducting Qubit. AB - We introduce a hybrid qubit based on a semiconductor nanowire with an epitaxially grown superconductor layer. Josephson energy of the transmonlike device ("gatemon") is controlled by an electrostatic gate that depletes carriers in a semiconducting weak link region. Strong coupling to an on-chip microwave cavity and coherent qubit control via gate voltage pulses is demonstrated, yielding reasonably long relaxation times (~0.8 MUs) and dephasing times (~1 MUs), exceeding gate operation times by 2 orders of magnitude, in these first generation devices. Because qubit control relies on voltages rather than fluxes, dissipation in resistive control lines is reduced, screening reduces cross talk, and the absence of flux control allows operation in a magnetic field, relevant for topological quantum information. PMID- 26431010 TI - Realization of Microwave Quantum Circuits Using Hybrid Superconducting Semiconducting Nanowire Josephson Elements. AB - We report the realization of quantum microwave circuits using hybrid superconductor-semiconductor Josephson elements comprised of InAs nanowires contacted by NbTiN. Capacitively shunted single elements behave as transmon circuits with electrically tunable transition frequencies. Two-element circuits also exhibit transmonlike behavior near zero applied flux but behave as flux qubits at half the flux quantum, where nonsinusoidal current-phase relations in the elements produce a double-well Josephson potential. These hybrid Josephson elements are promising for applications requiring microwave superconducting circuits operating in a magnetic field. PMID- 26431011 TI - Bound States of a Ferromagnetic Wire in a Superconductor. AB - We consider the problem of bound states in strongly anisotropic ferromagnetic impurities in a superconductor, motivated by recent experiments that claim to observe Majorana modes at the ends of ferromagnetic wires on a superconducting substrate [S. Nadj-Perge et al., Science 346, 602 (2014)]. Generalizing the successful theory of bound states of spherically symmetric impurities, we consider a wirelike potential using both analytical and numerical approaches. We find that away from the ends of the wire the bound states form bands with pronounced van Hove singularities, giving rise to subgap peaks in the local density of states. For sufficiently strong magnetization of the wire, we show that this process generically produces a sharp peak at zero energy in the local density of states near the ends of the wire. This zero-energy peak has qualitative similarities to the claimed signature of a Majorana mode observed in the aforementioned experiment. PMID- 26431012 TI - Charge-Induced Spin Torque in Anomalous Hall Ferromagnets. AB - We demonstrate that spin-orbit coupled electrons in a magnetically doped system exert a spin torque on the local magnetization, without a flowing current, when the chemical potential is modulated in a magnetic field. The spin torque is proportional to the anomalous Hall conductivity, and its effective field strength may overcome the Zeeman field. Using this effect, the direction of the local magnetization is switched by gate control in a thin film. This charge-induced spin torque is essentially an equilibrium effect, in contrast to the conventional current-induced spin-orbit torque, and, thus, devices using this operating principle possibly have higher efficiency than the conventional ones. In addition to a comprehensive phenomenological derivation, we present a physical understanding based on a model of a Dirac-Weyl semimetal, possibly realized in a magnetically doped topological insulator. The effect might be realized also in nanoscale transition materials, complex oxide ferromagnets, and dilute magnetic semiconductors. PMID- 26431013 TI - Spin Fluctuations from Hertz to Terahertz on a Triangular Lattice. AB - The temporal magnetic correlations of the triangular-lattice antiferromagnet NiGa_{2}S_{4} are examined through 13 decades (10^{-13}-1 sec) using ultrahigh resolution inelastic neutron scattering, muon spin relaxation, and ac and nonlinear susceptibility measurements. Unlike the short-ranged spatial correlations, the temperature dependence of the temporal correlations show distinct anomalies. The spin fluctuation rate decreases precipitously upon cooling towards T^{*}=8.5 K, but fluctuations on the microsecond time scale then persist in an anomalous dynamical regime for 4 K24 h with 50% of drug release. The in vivo results indicated that transferrin-targeted TPGS micelles could be a promising carrier for brain targeting due to nano-sized drug delivery, solubility enhancement and permeability which provided an improved and prolonged brain targeting of DTX in comparison to the non-targeted micelles and marketed formulation. PMID- 26431066 TI - The relationship between autoimmunity and specific immunotherapy for allergic diseases. AB - The aim of this study was to perform a 20-year post-specific immunotherapy (SIT) observational evaluation for an assessment of any manifestations of autoimmune disease or the appearance of autoantibodies in serum. In total, 1,888 patients (902 women and 986 men) were observed. The mean age of the patients was 34.1 +/- 12.4 y at the start of the prospective observation after finishing SIT. New incidences of autoimmune disease and/or the presence of autoantibodies in serum were monitored. The SIT group was compared with control groups consisting of allergic patients who had very received SIT and with non-allergic subjects. There were no significant differences in the autoimmune disease prevalence between the allergic patients with or without SIT. However, significantly higher prevalence of 4 different autoimmune diseases (AID) were observed in the non-allergic patients during the same period. Additionally, the incidence of 8 different autoantibodies was significantly higher in non-allergic patients than in control subjects. Hashimoto disease was the most common autoimmune disease observed. The results of this long-term observational study indicated a lack of a significant prevalence of new instances of autoimmune disease during 20 y of observation post SIT and at a rate lower than that of non-allergic control subjects, suggesting that SIT is safe in this regard in the long term. PMID- 26431065 TI - Lactoferrin Expression in Human and Murine Ocular Tissue. AB - PURPOSE: Lactoferrin (LF) is a multifunctional protein known to provide innate defense due to its antimicrobial and anti-inflammatory properties. In the eye, LF has been identified in the tears and vitreous humor. Its presence in other ocular tissues has not been determined. Our aim is to assess the presence of LF in the cornea, iris, retina and retinal pigment epithelium (RPE) of humans and mice. METHODS: To test for the endogenous production of LF, reverse transcription polymerase chain reaction was performed in cultured human cells from the cornea and RPE and in murine tissues. To confirm LF localization in specific ocular tissue, immunohistochemistry was performed on flat mounts of cornea, retina and RPE in human donor eyes. The presence of LF was assessed by western blotting in human and mouse ocular tissue and human culture cells (cornea and RPE). To verify antibody specificity, purified human LF and transferrin (TF) were used on 1D and 2D western blots. RESULTS: LF gene expression was confirmed in the cornea and RPE cell cultures from humans, suggesting that LF is an endogenously produced protein. PCR results from mouse ocular tissue showed LF expression in cornea, iris, RPE, but not in retina. These results were also consistent with immunohistochemical localization of LF in human donor tissue. Antibody reaction for human LF was specific and western blotting showed its presence in the cornea, iris and RPE tissues. A faint reaction for the retina was observed but was likely due to contamination from other ocular tissues. Multiple commercially available antibodies for murine LF cross-reacted with TF, so no reliable results were obtained for murine western blot. CONCLUSION: LF is expressed in multiple eye tissues of humans and mice. This widespread expression and multifunctional activity of LF suggests that it may play an important role in protecting eye tissues from inflammation-associated diseases. PMID- 26431067 TI - Ochratoxin A in artisan salami produced in Veneto (Italy). AB - Fifty samples of artisan salami purchased in Veneto (Italy) were analysed for the determination of ochratoxin A (OTA). The analytical method, based on a sample preparation procedure with immunoaffinity columns (IACs), together with analysis by high-performance liquid chromatography with fluorescence detection (HPLC-FD), has guaranteed a high rate of recovery (about 97%), limit of detection (LOD) and limit of quantification (LOQ), respectively, of 0.06 ug kg(-1) and 0.20 ug kg( 1). OTA was detected in five samples, but only one exceeded the guideline value (1 ug kg(-1)) established by the Italian Ministry of Health for pork meat and derived products. The results would seem to suggest that salami made with the traditional, non-industrial production method can be considered safe as regards contamination by OTA. However, the very high concentration observed in one sample proves that a high OTA contamination is also possible in this type of product. Thus, the controls of mycotoxin contamination must consider also salami. PMID- 26431068 TI - An unusual case of schwannomatosis with bilateral maxillary sinus schwannomas and a novel SMARCB1 gene mutation. AB - Schwannomas are benign tumors that arise from Schwann cells in the peripheral nervous system. Patients with multiple schwannomas without signs and symptoms of neurofibromatosis Type 1 or 2 have the rare disease schwannomatosis. Tumors in these patients occur along peripheral nerves throughout the body. Mutations of the SMARCB1 gene have been described as one of the predisposing genetic factors in the development of this disease. This report describes a patient who was observed for 6 years after having undergone removal of 7 schwannomas, including bilateral maxillary sinus schwannomas, a tumor that has not been previously reported. Genetic analysis revealed a novel mutation of c.93G>A in exon 1 of the SMARCB1 gene. PMID- 26431069 TI - Induction of proinflammatory cytokine production in intervertebral disc cells by macrophage-like THP-1 cells requires mitogen-activated protein kinase activity. AB - OBJECTIVE: To determine the role played by mitogen-activated protein kinase (MAPK) signaling in the interactions between macrophages and intervertebral disc (IVD) cells, it was hypothesized that MAPK inhibition would modulate the production of the proinflammatory cytokines associated with inflammatory reaction in IVD cells. METHODS: Human annulus fibrosus (AF) and nucleus pulposus (NP) cells were cocultured with phorbol myristate acetate-stimulated macrophage-like THP-1 cells, with and without SB202190 (a p38-alpha and -beta inhibitor), SP600125 (a c-Jun N-terminal kinase [JNK] inhibitor), and PD98059 (an extracellular signal-regulated kinase [ERK] 1/2 inhibitor). The cytokines in conditioned media from cocultured and macrophage-exposed (nemotic) cells were assayed using enzyme-linked immunosorbent assays (ELISAs). RESULTS: Interleukin (IL)-6 and IL-8 were secreted in greater quantities by the cocultured cells compared with naive IVD cells and macrophages (MPhi) cultured alone. The tumor necrosis factor (TNF)- alpha and IL-6 levels produced by the NP cells cocultured with MPhis (NP-MPhi) were significantly lower than those produced by AF cells cocultured with MPhis (AF-MPhi). SB202190 dose-dependently suppressed IL-6 secretion by AF-MPhi and NP-MPhi cocultures, and 10 MUM SB202190 significantly decreased IL-6 and IL-8 production in nemotic AF and NP pellets. SP600125 at 10 MUM significantly suppressed the production of TNF alpha IL-6. and IL-8 in AF MPhi and NP-MPhi cocultures and significantly suppressed IL-1beta production in the NP-MPhi coculture. Administration of 10 MUM PD98059 significantly decreased IL-6 levels in the AF-MPhi coculture, and decreased the levels of TNF alpha and IL-8 in both the AF-MPhi and NP-MPhi cocultures. CONCLUSIONS: The present study shows that inhibitors of p38 MAPK effectively controlled IL-6 production during inflammatory reactions and that JNK and ERK1/2 inhibitors successfully suppressed the production of major proinflammatory cytokines during interactions between macrophages and IVD cells. Therefore, selective blockade of these signals may serve as a therapeutic approach to symptomatic IVD degeneration. PMID- 26431070 TI - Correlation between cervical spine sagittal alignment and clinical outcome after cervical laminoplasty for ossification of the posterior longitudinal ligament. AB - OBJECTIVE: The goal of this study was to determine the relationship between cervical spine sagittal alignment and clinical outcomes after cervical laminoplasty in patients with ossification of the posterior longitudinal ligament (OPLL). METHODS: Fifty consecutive patients who underwent a cervical laminoplasty for OPLL between January 2012 and January 2013 and who were followed up for at least 1 year were analyzed in this study. Standing plain radiographs of the cervical spine, CT (midsagittal view), and MRI (T2-weighted sagittal view) were obtained (anteroposterior, lateral, flexion, and extension) pre- and postoperatively. Cervical spine alignment was assessed with the following 3 parameters: the C2-7 Cobb angle, C2-7 sagittal vertical axis (SVA), and T-1 slope minus C2-7 Cobb angle. The change in cervical sagittal alignment was defined as the difference between the post- and preoperative C2-7 Cobb angles, C2-7 SVAs, and T-1 slope minus C2-7 Cobb angles. Outcome assessments (visual analog scale [VAS], Oswestry Neck Disability Index [NDI], 36-Item Short-Form Health Survey [SF 36], and Japanese Orthopaedic Association [JOA] scores) were obtained in all patients pre- and postoperatively. RESULTS: The average patient age was 56.3 years (range 38-72 years). There were 34 male patients and 16 female patients. Cervical laminoplasty for OPLL helped alleviate radiculomyelopathy. Compared with the preoperative scores, improvement was seen in postoperative VAS and JOA scores. After laminoplasty, 35 patients had kyphotic changes, and 15 had lordotic changes. However, cervical sagittal alignment after laminoplasty was not significantly associated with clinical outcomes in terms of postoperative improvement of the JOA score (C2-7 Cobb angle: p = 0.633; C2-7 SVA: p = 0.817; T 1 slope minus C2-7 lordosis: p = 0.554), the SF-36 score (C2-7 Cobb angle: p = 0.554; C2-7 SVA: p = 0.793; T-1 slope minus C2-7 lordosis: p = 0.829), the VAS neck score (C2-7 Cobb angle: p = 0.263; C2-7 SVA: p = 0.716; T-1 slope minus C2-7 lordosis: p = 0.497), or the NDI score (C2-7 Cobb angle: p = 0.568; C2-7 SVA: p = 0.279; T-1 slope minus C2-7 lordosis: p = 0.966). Similarly, the change in cervical sagittal alignment was not related to the JOA (p = 0.604), SF-36 (p = 0.308), VAS neck (p = 0.832), or NDI (p = 0.608) scores. CONCLUSIONS: Cervical laminoplasty for OPLL improved radiculomyelopathy. Cervical laminoplasty increased the probability of cervical kyphotic alignment. However, cervical sagittal alignment and clinical outcomes were not clearly related. PMID- 26431071 TI - How do spinal schwannomas progress? The natural progression of spinal schwannomas on MRI. AB - OBJECTIVE: Little is known about the progression of spinal schwannomas. The aim of this study was to determine the natural progression of spinal schwannomas and establish the risk of tumor growth. METHODS: This study retrospectively analyzed data from 23 patients (12 men and 11 women, 40-89 years old) with schwannomas detected by MRI. The mean follow-up period was 5 years (range 2-10 years). The absolute and relative growth rates of the tumors were calculated. RESULTS: The average tumor size was 1495 mm(3) at the initial visit and 2224 mm(3) at the final follow-up. The average absolute growth rate was 139 mm(3) per year, and the average relative growth rate was 5.3% per year. Tumors were classified into 3 groups based on enhancement patterns: isointense/hyperintense (iso/high; 11 cases), rim enhancement when enhancement was peripheral (high/rim; 5 cases), and heterogeneous/heterogeneous (hetero/hetero; 7 cases) based on Gd-enhanced T2 weighted MRI. The average absolute growth rates of the 3 lesion groups were 588 mm(3), 957 mm(3), and 3379 mm(3), respectively (p < 0.01). CONCLUSIONS: Although the tumors classified as iso/high and high/rim on T2-weighted Gd-enhanced MR images were small and grew very little, most tumors with hetero/hetero classification increased in size. Hetero/hetero-type tumors should be followed closely and may require surgery. PMID- 26431072 TI - Anterior corpectomy via the mini-open, extreme lateral, transpsoas approach combined with short-segment posterior fixation for single-level traumatic lumbar burst fractures: analysis of health-related quality of life outcomes and patient satisfaction. AB - OBJECTIVE: The authors present clinical outcome data and satisfaction of patients who underwent minimally invasive vertebral body corpectomy and cage placement via a mini-open, extreme lateral, transpsoas approach and posterior short-segment instrumentation for lumbar burst fractures. METHODS: Patients with unstable lumbar burst fractures who underwent corpectomy and anterior column reconstruction via a mini-open, extreme lateral, transpsoas approach with short segment posterior fixation were reviewed retrospectively. Demographic information, operative parameters, perioperative radiographic measurements, and complications were analyzed. Patient-reported outcome instruments (Oswestry Disability Index [ODI], 12-Item Short Form Health Survey [SF-12]) and an anterior scar-specific patient satisfaction questionnaire were recorded at the latest follow-up. RESULTS: Twelve patients (7 men, 5 women, average age 42 years, range 22-68 years) met the inclusion criteria. Lumbar corpectomies with anterior column support were performed (L-1, n = 8; L-2, n = 2; L-3, n = 2) and supplemented with short-segment posterior instrumentation (4 open, 8 percutaneous). Four patients had preoperative neurological deficits, all of which improved after surgery. No new neurological complications were noted. The anterior incision on average was 6.4 cm (range 5-8 cm) in length, caused mild pain and disability, and was aesthetically acceptable to the large majority of patients. Three patients required chest tube placement for pleural violation, and 1 patient required reoperation for cage subsidence/hardware failure. Average clinical follow-up was 38 months (range 16-68 months), and average radiographic follow-up was 37 months (range 6-68 months). Preoperative lumbar lordosis and focal lordosis were significantly improved/maintained after surgery. Patients were satisfied with their outcomes, had minimal/moderate disability (average ODI score 20, range 0 52), and had good physical (SF-12 physical component score 41.7% +/- 10.4%) and mental health outcomes (SF-12 mental component score 50.2% +/- 11.6%) after surgery. CONCLUSIONS: Anterior corpectomy and cage placement via a mini-open, extreme lateral, transpsoas approach supplemented by short-segment posterior instrumentation is a safe, effective alternative to conventional approaches in the treatment of single-level unstable burst fractures and is associated with excellent functional outcomes and patient satisfaction. PMID- 26431073 TI - Building an electronic health record integrated quality of life outcomes registry for spine surgery. AB - OBJECTIVE: Demonstrating the value of spine care requires adequate outcomes assessment. Long-term outcomes are best measured as overall improvement in quality of life (QOL) after surgical intervention. Present registries often require parallel data entry, introducing inefficiencies and limiting compliance. The authors detail the methodology of constructing an integrated electronic health record (EHR) system to collect QOL metrics and demonstrate the effect of data collection on routine clinical workflow. A streamlined approach to collecting QOL data can capture patient data without requiring dual data entry and without increasing clinic visit times. METHODS: Through extensive literature review, a combination of QOL assessments was selected, consisting of the Patient Health Questionnaire-2 and -9, Oswestry Disability Index, Neck Disability Index, and visual analog scale for pain. These metrics were used to provide assessment of QOL following spine surgery and were incorporated into standard clinic workflow by a multidisciplinary team of surgeons, advanced practice providers, and health care information technology specialists. A clinical dashboard tracking more than 25 patient variables was developed. Clinic flow was assessed and opportunities for improvement reviewed. Duration of clinic visits before and after initiation of QOL measure capture was recorded, with assessment of mean clinic visit times for the 12 months before and the 12 months after implementation. RESULTS: The integrated QOL capture was instituted for 3 spine surgeons in a tertiary care academic center. In the 12-month period prior to initiating collection of QOL data, 806 new patient visits were completed with an average visit time of 127.9 +/- 51.5 minutes. In the 12 months after implementation, 1013 new patient visits were recorded, with 791 providing QOL measures with an average visit time of 117.0 +/- 45.7 minutes. Initially the primary means of collecting patient outcome data was via paper form, with gradual transition to collection via entry into the electronic medical records system. To improve electronic data capture, paper forms were eliminated and an online portal used as part of the patient rooming process. This improved electronic capture to nearly 98% without decreasing the number of patients enrolled in the process. CONCLUSIONS: A systematic approach to collecting spine-related QOL data within an EHR system is feasible and offers distinct advantages over registries that require dual data entry. The process of data collection does not impact patients' clinical visit or providers' clinical workflow. This approach is scalable, and may form the foundation for a decentralized outcomes registry network. PMID- 26431074 TI - Are we ready to assess the value of treatment options in oncology? PMID- 26431075 TI - Misfit stabilized embedded nanoparticles in metallic alloys. AB - Nanoscale inhomogeneities are typical for numerous metallic alloys and crucially important for their practical applications. At the same time, stabilization mechanisms of such a state are poorly understood. We present a general overview of the problem, together with a more detailed discussion of the prototype example, namely, Guinier-Preston zones in Al-based alloys. It is shown that coherent strain due to a misfit between inclusion and host crystal lattices plays a decisive role in the emergence of the inhomogeneous state. We suggest a model explaining the formation of ultrathin plates (with the thickness of a few lattice constants) typical for Al-Cu alloys. Discreteness of the array of misfit dislocations and long-ranged elastic interactions between them are the key ingredients of the model. This opens a way for a general understanding of the nature of (meta)stable embedded nanoparticles in practically important systems. PMID- 26431076 TI - A Systematic Review of Financial Incentives for Physical Activity: The Effects on Physical Activity and Related Outcomes. AB - The aim of this review is to give an overview of the available evidence on the effects of financial incentives to stimulate physical activity. Therefore, a systematic literature search was performed for randomized trials that investigate the effects of physical-activity-related financial incentives for individuals. Twelve studies with unconditional incentives (eg, free membership sport facility) and conditional incentives (ie, rewards for reaching physical-activity goals) related to physical activity were selected. Selected outcomes were physical activity, sedentary behavior, fitness, and weight. Results show that unconditional incentives do not affect physical activity or the other selected outcomes. For rewards, some positive effects were found and especially for rewards provided for physical-activity behavior instead of attendance. In conclusion, rewards seem to have positive effects on physical activity, while unconditional incentives seem to have no effect. However, it should be kept in mind that the long-term effects of financial incentives are still unclear. PMID- 26431077 TI - Negotiating the equivocality of palliative care: a grounded theory of team communicative processes in inpatient medicine. AB - In the majority of U.S. hospitals, inpatient medicine teams make palliative care decisions in the absence of a formalized palliative system. Using a grounded theory approach, interviews with inpatient team members were systematically analyzed to uncover how participants conceptualize palliative care and how they regard the communicative structures that underlie its delivery. During analysis, Weick's model of organizing emerged as a framework that fit the data. The 39 participant inpatient team members discussed palliative care as primarily a communicative process. Themes describing the meaning of palliative care emerged around the concepts of receiver of care, timeline of care, and location of care. The emerging model included four stages in the communicative processes of inpatient palliative care: (a) interpret the need, (b) initiate the conversation, (c) integrate the processes, and (d) identify what works. In contrast to stable, focused palliative care teams or hospice care teams, which have prescribed patient populations and processes, the inpatient medicine team faces the equivocality of providing palliative care within a broader practice. This research offers a four-phase model to show how these inpatient teams communicate within this context. Implications for the provision of palliative care are discussed. PMID- 26431078 TI - Determination of synergy between sulbactam, meropenem and colistin in carbapenem resistant Klebsiella pneumoniae and Acinetobacter baumannii isolates and correlation with the molecular mechanism of resistance. AB - Treatment of infections with carbapenem-resistant Gram negative organism is a major challenge especially among intensive care patients. Combinations of sulbactam, meropenem and colistin was studied for its synergistic activity against 100 invasive isolates of carbapenem-resistant Klebsiella pneumoniae and Acinetobacter baumannii-calcoaceticus complex by checkerboard assay and time kill assay (TKA). In addition, presence of carbapenemase production was determined by multiplex PCR. Time kill assay detected more synergy than checkerboard assay. Good bactericidal activity of 70-100% was noted with the combinations tested. Among K. pneumoniae, isolates producing NDM carbapenemase alone showed significantly more synergy than isolates producing OXA-48-like carbapenemases. In treatment of infection with carbapenem-resistant organisms, the site of infection and the carbapenemase produced may help determine the combination most likely to clear the infection. PMID- 26431079 TI - A Single-Component Conductor Based on a Radical Gold Dithiolene Complex with Alkyl-Substituted Thiophene-2,3-dithiolate Ligand. AB - Alkyl-substituted thiophene-2,3-dithiolate ligands are prepared through a Thio Claisen rearrangement of 4,5-bis(propargylthio)-1,3-dithiole-2-thione derivatives. The two novel dithiolate ligands, namely, 4,5-dimethyl-thiophene-2,3 dithiolate (alpha-Me2tpdt) and 4-ethyl-5-methyl-thiophene-2,3-dithiolate (alpha EtMetpdt), are engaged in anionic Au(III) square planar complexes formulated as [Au(alpha-Me2tpdt)2](-) and [Au(alpha-EtMetpdt)2](-), isolated as Ph4P(+) salts. Monoelectronic oxidation gives the neutral radical complexes [Au(alpha Me2tpdt)2](*) and [Au(alpha-EtMetpdt)2](*). The latter crystallizes into uniform stacks with limited interstack interactions, giving rise to a calculated half filled band structure. It exhibits a semiconducting behavior with room temperature conductivity of 3 * 10(-3) S cm(-1), indicating that this single component conductor can be described as a Mott insulator. The different structures observed in [Au(alpha-EtMetpdt)2](*) and the known [Au(Et thiazdt)2](*) complex (Et-thiazdt: N-ethyl-thiazoline-2-thione-4,5-dithiolate), despite their very similar shapes, are tentatively attributed to differences in the electronic structures of the ligand skeleton. PMID- 26431089 TI - Role Of Vitamin D And Adipose Tissue Hormones In Women With Reproductive Disorders. AB - The role of vitamin D beyond that it plays in bone metabolism and calcium homeostasis has been lately quite emphasized. In this respect, vitamin D deficiency has been associated with higher risk of cardiovascular disease, metabolic syndrome, and reproductive disorders. Growing evidence has suggested that vitamin D deficiency is implicated in the pathogenesis of insulin resistance and the development of metabolic disorders in the polycystic ovary syndrome. The goal of the review is to present contemporary concepts of the relationship between hormones affecting the metabolic body status, serum vitamin D levels and the reproductive function. PMID- 26431088 TI - Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling. AB - Suppression of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to occur during cholestatic liver injury. Furthermore, we have demonstrated that in a model of cholestasis, serum bile acids gain entry into the brain via a leaky blood brain barrier and that hypothalamic bile acid content is increased. Therefore, the aim of the current study was to determine the effects of bile acid signaling on the HPA axis. The data presented show that HPA axis suppression during cholestatic liver injury, specifically circulating corticosterone levels and hypothalamic corticotropin releasing hormone (CRH) expression, can be attenuated by administration of the bile acid sequestrant cholestyramine. Secondly, treatment of hypothalamic neurons with various bile acids suppressed CRH expression and secretion in vitro. However, in vivo HPA axis suppression was only evident after the central injection of the bile acids taurocholic acid or glycochenodeoxycholic acid but not the other bile acids studied. Furthermore, we demonstrate that taurocholic acid and glycochenodeoxycholic acid are exerting their effects on hypothalamic CRH expression after their uptake through the apical sodium-dependent bile acid transporter and subsequent activation of the glucocorticoid receptor. Taken together with previous studies, our data support the hypothesis that during cholestatic liver injury, bile acids gain entry into the brain, are transported into neurons through the apical sodium-dependent bile acid transporter and can activate the glucocorticoid receptor to suppress the HPA axis. These data also lend themselves to the broader hypothesis that bile acids may act as central modulators of hypothalamic peptides that may be altered during liver disease. PMID- 26431090 TI - Strategies For Immobilization Of Bioactive Organic Molecules On Titanium Implant Surfaces - A Review. AB - Numerous approaches have been used to improve the tissue-implant interface of titanium (Ti) and titanium alloy (Ti6Al4V). They all aim at increasing cell migration and attachment to the metal, preventing unspecific protein adsorption and improving post-implantation healing process. Promising methods for titanium and titanium alloy surface modification are based on the immobilization of biologically active organic molecules. New and interesting biochemical approaches to such surface modification include layer-by-layer deposition of polyelectrolyte films, phage display-selected surface binding peptides and self-assembled DNA monolayer systems. The present review summarizes the scientific information about these methods, which are at in vitro or in vivo development stages, and hopes to promote their future application in dental implantology and in oral and maxillofacial surgery. PMID- 26431091 TI - Autism Spectrum Disorder - A Complex Genetic Disorder. AB - Autism spectrum disorder is an entity that reflects a scientific consensus that several previously separated disorders are actually a single spectrum disorder with different levels of symptom severity in two core domains - deficits in social communication and interaction, and restricted repetitive behaviors. Autism spectrum disorder is diagnosed in all racial, ethnic and socioeconomic groups and because of its increased prevalence, reported worldwide through the last years, made it one of the most discussed child psychiatric disorders. In term of aetiology as several other complex diseases, Autism spectrum disorder is considered to have a strong genetic component. PMID- 26431092 TI - Selection Of The Optimal Level Of Distal Fixation For Correction Of Scheuermann's Hyperkyphosis. AB - OBJECTIVE: To analyze the efficacy of the method for selecting the distal level of fusion in treatment of thoracic hyperkyphosis in patients with Scheuermann's disease. BACKGROUND: The fusion area needs to include all the kyphotic deformity in Scheuermann patients; however, precise levels of the distal fixation have not been determined yet. STUDY DESIGN: Retrospective cohort review. MATERIALS AND METHODS: Thirty-six patients were operated in the Department of Children and Adolescent Spine Pathology between 2007 and 2010. These patients were divided into two groups: in group I (n = 29) a lower instrumented vertebra corresponded to the sagittal stable one and in group II (n = 7) - this vertebra located proximally. RESULTS: The mean preoperative kyphosis was 79.3 degrees +/- 11.6 degrees , the postoperative - 40.6 degrees +/- 11.9 degrees (correction of 49.9%), loss of correction was 4.9 degrees +/- 7.0 degrees . Sagittal balance changed from -0.3 +/- 3.2 cm before surgery to -1.7 +/- 2.1 cm after surgery. Distal junctional kyphosis developed in 1 case (4%) in Group I, and in 5 cases (71%) in Group II. CONCLUSION: A distal level of instrumentation ending at the first lordotic vertebra is not justified and causes violation of sagittal balance and development of distal junctional kyphosis. The inclusion of a sagittal stable vertebra in fusion prevents the development of this undesirable situation. PMID- 26431093 TI - Reconstruction Of Glenoid Bone Deficiency With Porous Titanium Nickelide In Recurrent Anterior Shoulder Instability. AB - INTRODUCTION: One of the main causes of recurrent shoulder instability is a bone defect of the front edge of the glenoid. The available techniques for reconstruction of this bone defect, however, have some disadvantages. OBJECTIVE: The aim of this study was to develop a new method that can reduce the number of postoperative complications and improve the efficiency of surgical treatment of recurrent anterior shoulder instability with glenoid bone defect. MATERIALS AND METHODS: We present here a new method for surgical treatment of post-traumatic recurrent anterior shoulder instability with bony defects using porous NiTi. We operated 5 patients using this method. Computed tomography was used in the preoperative preparation of the NiTi graft. The graft was sawed from a cylindrical billet about 1 cm in thickness. Two screw holes were then made with a drill. The prepared graft was subsequently installed in the area of the glenoid bone defect. RESULTS: There were no recurrences of the dislocation after the surgical treatment. All patients returned to their previous levels of physical activity. CONCLUSIONS: The proposed method is an alternative to Latarjet procedure and iliac crest bone grafting. The advantages of this method are accurate reconstruction of the bone defect, minimal risk of recurrences, no resorption, and reduction of procedure time. PMID- 26431094 TI - NLRs Challenge Impacts Tight Junction Claudins In Sertoli Cells. AB - AIM: The present study aims to investigate the NALP3 system and its effect on claudins in Sertoli cells using a mouse adult Sertoli cell line as a model. We focus on the Sertoli cell biology looking for the possible implications for male reproductive functions. MATERIALS AND METHODS: Adult Sertoli cells were transfected with NAPL3 siRNA and treated with NOD1 (ie-DAP) and NOD2 (MDP) receptor ligands. Two dimensional gel electrophoresis was performed on lysates of non-challenged and MDP-treated Sertoli cells. RESULTS: There were positive claudin-5 and claudin-11 expression levels on transcript (RT-qPCR) levels. Specific protein spots in 2D gels were detected after bioinformatics analysis. This study demonstrates direct induction of tight-junction proteins probably favouring junction stability. CONCLUSIONS: The innate immunity and tight-junction pathway integration probably have a protective role for both blood-testis immune barrier and spermatogenesis compartmentalisation maintained by the very same barrier. This integration also points the way for mechanistic research of the disturbances inflicted during an inflammatory response in the testis niche. PMID- 26431095 TI - Morphological Study Of Border Area Of Pulp-Capping Materials And Er:YAG Laser Prepared Hard Dental Surface. AB - INTRODUCTION: Vital pulp therapy involves biologically based therapeutic activities aimed at restoring health and preserving the vitality of cariously or traumatically damaged pulp. Adaptation of pulp-capping materials to the prepared tooth surface may be the key to the success of biological tooth treatment. AIM: To investigate the area of adaptation of synthetic tricalcium silicate cement, calcium hydroxide cement and mineral trioxide-aggregate to the dentin surface, prepared with the help of Er:YAG dental laser. MATERIAL AND METHODS: Four extracted human tooth cavities were prepared with the help of Er:YAG dental laser (LiteTouch, Syneron, Israel), establishing microcommunication with the pulp chamber less than 1 mm in diameter. As pulp-capping materials in the cavities we used tricalcium silicate cement (Biodentine, Septodont, France), calcium hydroxide cement (Dycal) and mineral-trioxide aggregate (ProRoot MTA), stirred and administered according to manufacturers' instructions. The first material fills the whole cavity and the other two are spread in a thin layer and sealed with glass ionomer cement. Thus prepared, the samples were left for three days at 37 degrees C in humidified environment. The samples were prepared for scanning electron microscopy (SEM) by standard methodology. The border area surfaces of the materials and the dentin were scanned using electron microscopy. RESULTS: The morphological changes occurring to the Er:YAG laser prepared dentin and the structural characteristics of the studied pulp-capping materials are demonstrated using scanograms. The border areas where good contact of materials and dentinal tubules is established are thoroughly studied. Good adaptation is seen in three calcium silicate cement, followed by mineral trioxide aggregate and calcium hydroxide cement. CONCLUSION: The dentin surface, prepared with Er:YAG laser demonstrates a very good adaptation of the three tested pulp-capping materials. PMID- 26431097 TI - Cutaneous Leishmaniasis - Dermoscopic Findings And Cryotherapy. AB - We present a 60-year-old male patient who, three months after a holiday in Southern Greece, found a small 'pimple' on his back, which gradually got as big as a small walnut, the central part becoming ulcerated and scabby. Dermatological examination found an erythematous-to-livid nodular lesion on the right shoulder; it was 16 mm in diameter with central ulceration, covered with brownish crust which discharged pus-like secretion upon pressure. Microscope examination of Romanowsky-Giemsa stained lesion material detected amastigote forms of Leishmania tropica. The culture investigation and serological tests for leishmaniasis were negative. Dermoscopy of the lesion found the following features: erythema, hyperkeratosis, central ulceration covered with brownish crust, "yellow tears like" structures and "white starburst-like" patterns, and various vascular structures (including dotted vessels, comma-shaped vessels, hairpin- and glomerular-like vessels). The patient was diagnosed with cutaneous leishmaniasis and underwent four cryotherapy sessions every other week with excellent therapeutic results - complete resolution of infiltrate with subsequent gentle hypopigmented scarring. In conclusion, dermoscopy is an easily accessible non invasive method which can be useful for the diagnosis of cutaneous leishmaniasis. Cryotherapy is the treatment of choice for single skin lesions. PMID- 26431096 TI - Economic Burden And Health-Related Quality Of Life Of Patients With Cystic Fibrosis In Bulgaria. AB - OBJECTIVE: The aim of this study was to determine the economic burden from a societal perspective and health-related quality of life (HRQOL) of patients with cystic fibrosis (CF) in Bulgaria. MATERIALS AND METHODS: We conducted a cross sectional study of 33 patients with CF and 17 caregivers from Bulgaria. Data on socio-demographic characteristics, health resource utilisation, informal care, labor productivity losses and HRQOL were collected from questionnaires completed by patients or their caregivers. HRQOL was evaluated with the EuroQol 5-domain (EQ-5D-3L) questionnaire. RESULTS: Median annual costs of CF in Bulgaria were ? 24 152 per patient in 2012 as a reference year. Median annual costs for children were found to be significantly higher than those for adults - ? 31 945 vs. ? 15 714 (p = 0.012). This outcome came from statistically significant differences in costs for main informal carer (p < 0.001) and costs for other informal carers (p = 0.022). As a single cost item, drugs had the biggest monetary impact. Median annual drug costs were ? 13 059. Bulgarian CF patients showed low HRQOL results - 50 median VAS score and 0.592 median health utilities. A quarter of patients even rated their health state as worse than death. CONCLUSION: CF patients from Eastern Europe remain a vulnerable population with risk factors for worse health outcomes. Our study provided a state-of-the art analysis that facilitates the elaboration, adoption and application of targeted public health policies to tackle CF-related problems at national and European level. PMID- 26431098 TI - Thoracic Meningioma In Combination With Severe Lumbar Spinal Stenosis Presenting With Atypical Neurological Deficit. AB - We report on a case of a 47-year-old female patient with a long history of low back pain irradiating bilaterally to the legs. Twenty days before admission to our clinic, she had developed progressive weakness in the legs, more pronounced on the left side. The initial neurological examination revealed signs of damage to both the cauda equina and the spinal cord. The neuroimaging studies (computed tomography, myelography and magnetic-resonance tomography) found spinal stenosis most severe at L4-L5 level, and right lateral thoracic intradural-extramedullary tumor at T9-T10 level. The patient underwent two neurosurgical procedures. The first stage included microsurgical resection of the thoracic lesion and the second stage aimed at decompressing the lumbar spinal stenosis. To avoid missing a diagnosis of thoracic lesions, it is necessary to perform a thorough neurological examination of the spinal cord motor and sensory functions. In addition, further MRI examination of upper spinal segment is needed if the neuroimaging studies of the lumbar spine fail to provide reasonable explanation for the existing neurological symptoms. PMID- 26431099 TI - Ulcerated Hemangioma - Surveillance Only. AB - Infantile hemangiomas are reported in 10-12% of children less than 1 year of age, with ulceration in about 5-13% of cases. Little is known about the mechanism of this disease and explanations are still being looked for. We present a 4-month old female infant with haemangioma on the left buttock; the hemangioma was noticed at 2 weeks of age, progressively enlarging and ulcerated. PMID- 26431100 TI - Urothelial Carcinoma Concomitant With Malakoplakia In Non-Functioning Nephrolithic Kidneys. AB - Nephrolithic non-functioning kidney and malakoplakia are major health problems. Kidney function cannot be fulfilled and also this leads to a high risk of development of urothelial neoplasm. We report herein a case of urothelial carcinoma concomitant with malakoplakia in non-functioning nephrolithic kidneys. PMID- 26431101 TI - Suberoylanilide hydroxamic acid (SAHA) promotes the epithelial mesenchymal transition of triple negative breast cancer cells via HDAC8/FOXA1 signals. AB - Inhibitor of histone deacetylases (HDACIs) have great therapeutic value for triple negative breast cancer (TNBC) patients. Interestingly, our present study reveals that suberoyl anilide hydroxamic acid (SAHA), one of the most advanced pan-HDAC inhibitor, can obviously promote in vitro motility of MDA-MB-231 and BT 549 cells via induction of epithelial-mesenchymal transition (EMT). SAHA treatment significantly down-regulates the expression of epithelial markers E cadherin (E-Cad) while up-regulates the mesenchymal markers N-cadherin (N-Cad), vimentin (Vim) and fibronectin (FN). However, SAHA has no effect on the expression and nuclear translocation of EMT related transcription factors including Snail, Slug, Twist and ZEB. While SAHA treatment down-regulates the protein and mRNA expression of FOXA1 and then decreases its nuclear translocation. Over-expression of FOXA1 markedly attenuates SAHA induced EMT of TNBC cells. Further, silence of HDAC8, while not HDAC6, alleviates the down regulation of FOXA1 and up-regulation of N-Cad and Vim in MDA-MB-231 cells treated with SAHA. Collectively, our present study reveals that SAHA can promote EMT of TNBC cells via HDAC8/FOXA1 signals, which suggests that more attention should be paid when SAHA is used as anti-cancer agent for cancer treatment. PMID- 26431102 TI - Synthesis of pyranopyrazolo N-glycoside and pyrazolopyranopyrimidine C-glycoside derivatives as promising antitumor and antimicrobial agents. AB - As a part of systematic investigation of the synthesis and biological activities of pyrazole analogues linked to various heterocyclic systems, a new series of pyrazolo-N-glycoside derivatives, pyrazolopyranopyrimidine and C-glycoside of pyrazolopyranotriazolo-pyrimidine derivatives was synthesized through the reaction of the key intermediate 6-amino-3-methyl-4-(substituted-phenyl)-1,4 dihydropyrano[2,3-c]pyrazole-5-carbonitrile (3a,b) with different reagents. Structures of the newly synthesized compounds were elucidated by elemental microanalysis and spectroscopic methods. The compounds were subjected to in vitro antitumor evaluation using the MTT assay. N-(beta-D-ribofuranosyl)- and N-(beta-D xylofuranosyl)-6{[(1E)-4-chlorophenyl)-methylene] amino}4-(4-florophenyl)-3 methyl-1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitrile (6a,b) were the most active compounds against three human cancer cell lines. Also, most of the newly synthesized compounds exhibited high activity towards Gram-negative and Gram positive bacteria. Compound 6a exhibited excellent activity towards bacteria compared to ofloxacine as the reference drug. PMID- 26431103 TI - Dissolution profiles of perindopril and indapamide in their fixed-dose formulations by a new HPLC method and different mathematical approaches. AB - A new HPLC method was introduced and validated for simultaneous determination of perindopril and indapamide. Validation procedure included specificity, sensitivity, robustness, stability, linearity, precision and accuracy. The method was used for the dissolution test of perindopril and indapamide in three fixed dose formulations. The dissolution procedure was optimized using different media, different pH of the buffer, surfactants, paddle speed and temperature. Similarity of dissolution profiles was estimated using different model-independent and model dependent methods and, additionally, by principal component analysis (PCA). Also, some kinetic models were checked for dissolved amounts of drugs as a function of time. PMID- 26431104 TI - Conventional versus ultrasound and microwave assisted synthesis: Some new environmentally friendly functionalized picolinium-based ionic liquids with potential antibacterial activity. AB - A green chemistry approach has been adopted for the synthesis of thirty-four new picolinium-based ionic liquids using microwave (MW) and ultrasound (US) irradiation as well as conventional thermal heating. Their structures were confirmed by FT-IR, 1H NMR, 13C NMR, 11B NMR, 19F NMR, 31P NMR, mass spectra and elemental analyses. The antimicrobial profile of the novel ionic liquids was evaluated and the minimum inhibitory concentration (MIC) showed their moderate to low antimicrobial activity against eight types of human pathogens. PMID- 26431105 TI - Anti-breast cancer activity of some novel quinoline derivatives. AB - To discover new bioactive lead compounds for medicinal purposes, 2-cyano-3-(4 substituted)-N-(quinolin-3-yl) acrylamide derivatives 2-24, chromenes 25, 26 and benzochromenes 27, 28 were synthesized. The structures of the newly synthesized compounds were confirmed by elemental analyses, IR, 1H NMR and 13C NMR spectroscopies. In addition, the structure of compound 1 was confirmed through X ray crystallography. All the newly synthesized compounds were evaluated for their cytotoxic activity against the breast cancer cell line MCF7. The corresponding 2 cyano-3-(4-hydroxy-3-methoxyphenyl)-N-(quinolin-3-yl) acrylamide (15), 3-oxo-N (quinolin-3-yl)-3H-benzol[f] chromene-2-carboxamide (27), 2-cyano-3-(4 fluorophenyl-N-(quinolin-3-yl) acrylamide (7), 2-cyano-5-(4-(dimethyl-amino) phenyl)-N-(quinolin-3-yl) penta-2,4-dienamide (19) exhibited higher activity compared to doxorubicin (with IC50 value of 47.9 MUmol L-1) as a reference drug, with IC50 values of 29.8, 39.0, 40.0, 40.4 MUmol L-1, resp. Also, quinoline acrylamides containing 2,3,4-trimethoxyphenyl 17, 2-chlorophenyl 10, benzo[d][1,3]dioxol 12, 2-methoxynaphthalen 22, 2,4-dichlorophenyl 18 and quinoline carrying a chromene-3-carboxamide moiety 25 were nearly as active as doxorubicin, while quinoline acrylamides incorporating unsubstituted phenyl 2, p tolyl 3, 2,4-dienamide 8, 3-nitrophenyl 13, 4-nitrophenyl 14, 3,4-dimethoxyphenyl 16 and chromene 26 exhibited a moderate activity. In addition, quinoline with acetamide 1, 4-hydroxyphenyl 4, 4-dimethylaminophenyl 9, 4-chlorophenyl 11, 3 bromophenyl 20, 4-bromophenyl 21 and 3-thienyl moiety 24 showed less activity than doxorubicin. On the other hand, quinoline having 2-methoxyphenyl 5, 4 methoxyphenyl 6, 4-metho xynaphthalene 23 and chromene-2-carboxamide 28 showed no activity. PMID- 26431106 TI - Curcumin phytosomal softgel formulation: Development, optimization and physicochemical characterization. AB - Curcumin, a naturally occurring lipophilic molecule can exert multiple and diverse bioactivities. However, its limited aqueous solubility and extensive presystemic metabolism restrict its bioavailability. Curcumin phytosomes were prepared by a simple solvent evaporation method where free flowing powder was obtained in addition to a newly developed semisolid formulation to increase curcumin content in softgels. Phytosomal powder was characterized in terms of drug content and zeta potential. Thirteen different softgel formulations were developed using oils such as Miglyol 812, castor oil and oleic acid, a hydrophilic vehicle such as PEG 400 and bioactive surfactants such as Cremophor EL and KLS P 124. Selected formulations were characterized in terms of curcumin in vitro dissolution. TEM analysis revealed good stability and a spherical, self closed structure of curcumin phytosomes in complex formulations. Stability studies of chosen formulations prepared using the hydrophilic vehicle revealed a stable curcumin dissolution pattern. In contrast, a dramatic decrease in curcumin dissolution was observed in case of phytosomes formulated in oily vehicles. PMID- 26431107 TI - Novel 4-aminoquinazoline derivatives as new leads for anticancer drug discovery. AB - A novel series of quinazoline derivatives 2-8, 10-12 were designed and synthesized. Structures of the newly synthesized compounds were confirmed by elemental analyses, IR, 1H and 13C NMR spectral data. All the newly synthesized compounds were evaluated for in vitro cytotoxic activity against the breast cancer cell line MCF-7. Seven of the novel compounds exhibited higher activity than the reference drug doxorubicin. The corresponding compounds 3, 4, 5, 8, 10, 11 and 12 exhibited higher activity with IC50 values from 22.75 to 43.44 MUmol L 1, compared to the reference drug doxorubicin with IC50 value of 47.90 MUmol L-1. Also, compounds 1, 6, and 9 are nearly as active as doxorubicin with IC50 values of 48.31, 48.90, and 48.91 MUmol L-1, respectively, while compounds 2 and 7 exhibited a moderate activity with IC50 values of 50.44 and 52.37 MUmol L-1. In addition, compound 13 showed no activity. Cytotoxic screening of the tested compounds offered an encouraging framework that may lead to the discovery of potent anti-breast cancer activity. PMID- 26431108 TI - Contribution to diagnostics/prognostics of tuberculosis in children. I. New methods of assaying zinc and simultaneously copper and zinc in diluted sera by flame atomic-absorption spectrometry. AB - In an attempt to provide a reliable status of metal ions in children, new methods of analysis of children's sera are proposed. New flame atomic-absorption spectrometric (FAAS) methods are simple, cost- and time-effective and, above all, labor-, reagent- and sample-saving. Two methods were suggested: method A for simultaneous determination of Cu and Zn from 5-fold diluted sera, and method B, for assaying zinc alone in 10-fold diluted samples. Both methods are based on a single-step sample pretreatment (deproteinization with 3 mol dm-3 HCl). Method A uses a single-step calibration with a mixed standard. The main advantage of method B is an additional reduction in sample consumption. Both methods were fully validated against reference methods. Accuracy, sensitivity and precision have proven them to be comparable to the reference methods in terms of analytical performance, and applicable to analyses of children's sera. PMID- 26431109 TI - Contribution to diagnostics/prognostics of tuberculosis in children. II. Indicative value of metal ions and biochemical parameters in serum. AB - Newly introduced methods of assaying simultaneously copper and zinc and zinc alone in serum by flame atomic-absorption spectrometry are simple and economical, especially in saving the consumption of serum material. Along with biochemical parameters, they have been successfully applied to diagnostics/prognostics of tuberculosis in children, through analyses of sera from pediatric patients with lung tuberculosis or suspected tuberculosis, enabling the follow-up of therapeutic efficiency. The prognostic strength of Cu and Cu/Zn ratio together with C-reactive protein, complement components C3 and C4, and erythrocyte sedimentation rate have been documented. PMID- 26431110 TI - Development of a high-throughput screening system for identification of novel reagents regulating DNA damage in human dermal fibroblasts. AB - Ultraviolet (UV) radiation is a major inducer of skin aging and accumulated exposure to UV radiation increases DNA damage in skin cells, including dermal fibroblasts. In the present study, we developed a novel DNA repair regulating material discovery (DREAM) system for the high-throughput screening and identification of putative materials regulating DNA repair in skin cells. First, we established a modified lentivirus expressing the luciferase and hypoxanthine phosphoribosyl transferase (HPRT) genes. Then, human dermal fibroblast WS-1 cells were infected with the modified lentivirus and selected with puromycin to establish cells that stably expressed luciferase and HPRT (DREAM-F cells). The first step in the DREAM protocol was a 96-well-based screening procedure, involving the analysis of cell viability and luciferase activity after pretreatment of DREAM-F cells with reagents of interest and post-treatment with UVB radiation, and vice versa. In the second step, we validated certain effective reagents identified in the first step by analyzing the cell cycle, evaluating cell death, and performing HPRT-DNA sequencing in DREAM-F cells treated with these reagents and UVB. This DREAM system is scalable and forms a time-saving high-throughput screening system for identifying novel anti-photoaging reagents regulating DNA damage in dermal fibroblasts. PMID- 26431111 TI - Investigation of the effects of vitamin D and calcium on intestinal motility: In vitro tests and implications for clinical treatment. AB - The presence of vitamin D receptors in small intestine muscle cells may lead one to think that vitamin D may act locally, influencing intracellular calcium concentration and contributing to the contraction-relaxation regulation of the intestinal smooth muscle cells. This study investigates the potential effects of vitamin D and calcium on intestinal motility using an in vitro test. Different calcium concentrations added to the tissue not pre-treated with 1,25 dihydroxycholecalciferol [1alpha,25(OH)2D3] produced no response at low doses (1.25 * 10-3 and 2.0 * 10-3 mol L-1) and only a very weak response at higher concentration (3.0 * 10-3 mol L-1). The addition of 1alpha,25(OH)2D3 (1.44 * 10 10 mol L-1) had no effect on isolated ileum motility. When calcium (3.0 * 10-3 mol L-1) was added after at least 3 hours, it evoked evident and persistent contractions for 60-90 minutes. The contractions were at about 40 % of the peak produced by acetylcholine. Thus, simultaneous intake of vitamin D and calcium might be a useful co-adjuvant in intestinal atony therapy aimed to stimulate normal gut motility in humans. These findings imply that supplemental vitamin D may be important in all cases where calcium has to be prescribed. PMID- 26431117 TI - Validation of the Amsterdam Beverage Picture Set: A Controlled Picture Set for Cognitive Bias Measurement and Modification Paradigms. AB - BACKGROUND: Alcohol research may benefit from controlled and validated picture sets. We have constructed the Amsterdam Beverage Picture Set (ABPS), which was designed for alcohol research in general and cognitive bias measurement and modification in particular. Here, we first formulate a position on alcohol stimulus validity that prescribes that alcohol-containing pictures, compared to nonalcohol-containing pictures, should induce a stronger urge to drink in heavy drinkers than in light drinkers. Because a perceptually simple picture might induce stronger cognitive biases but the presence of a drinking context might induce a stronger urge to drink, the ABPS contains pictures with and without drinking context. By limiting drinking contexts to simple consumption scenes instead of real-life scenes, complexity was minimized. A validation study was conducted to establish validity, to examine ABPS drinking contexts, and to explore the role of familiarity, valence, arousal, and control. METHODS: Two hundred ninety-one psychology students completed the Alcohol Use Disorders Identification Test, as well as rating and recognition tasks for a subset of the ABPS pictures. RESULTS: The ABPS was well-recognized, familiar, and heavy drinkers reported a greater urge to drink in response to the alcohol-containing pictures only. Alcohol presented in drinking context did not elicit a stronger urge to drink but was recognized more slowly than alcohol presented without context. CONCLUSIONS: The ABPS was found to be valid, although pictures without context might be preferable for measuring cognitive biases than pictures with context. We discuss how an explicit approach to picture construction may aid in creating variations of the ABPS. Finally, we describe how ABPS adoption across studies may allow more reproducible and comparable results across paradigms, while allowing researchers to apply picture selection criteria that correspond to a wide range of theoretical positions. The latter is exemplified by ABPS derivatives and adoptions that are currently under way. PMID- 26431118 TI - Cap-aspiration lumpectomy for small submucosal tumors originating from the muscularis propria of the gastric fundus: a preliminary study (with videos). AB - OBJECTIVE: Small fundal submucosal tumors (SMTs) originated from the muscularis propria pose great difficulties to conventional therapies. We aimed to evaluate the feasibility and safety of endoscopic cap-aspiration lumpectomy (CASL) as a new and simple full-thickness resection for the treatment of small fundal SMTs. METHODS: From July 2013 to February 2014, patients with small fundal SMTs of <=10 mm in diameter that were originated from muscularis propria were included in the study. CASL was performed by suctioning SMTs into a transparent cap, ligating with a metal snare and resecting the tumors. The wall deficit was closed by using endoclips. RESULTS: Altogether 28 patients were included in the study. CASL achieved an en bloc resection rate of 100%, with a mean total procedure time of 23.9 min. Active perforation was found in 20 (71.4%) patients, and endoclips closed the wall defect in all 20 cases. One patient developed pneumoperitoneum and self-limited peritonitis was found in two patients, all of whom were managed successfully. Pathological examination showed that 71.4% (20/28) of the tumors were gastrointestinal stromal tumors. No tumor recurrence was observed during the follow-up. CONCLUSIONS: CASL may be a feasible and safe full-thickness resection modality for the treatment of small fundal SMTs arising from the muscularis propria. Further randomized studies are needed to confirm the results. PMID- 26431119 TI - Palladium(II)-Catalyzed Formal [3 + 2] Cycloaddition of Aziridines with 3 Substituted Indoles: Synthesis of Enantioenriched Pyrroloindolines. AB - A Pd-catalyzed enantiospecific formal [3 + 2] cycloaddition between chiral aziridines and indoles has been developed. With this method, chiral pyrroloindolines in enantiomerically pure forms were constructed in high yields and diastereoselectivities under mild conditions. PMID- 26431116 TI - Commonalities and Distinctions Among Mechanisms of Addiction to Alcohol and Other Drugs. AB - BACKGROUND: Alcohol abuse is comorbid with abuse of many other drugs, some with similar pharmacology and others quite different. This leads to the hypothesis of an underlying, unitary dysfunctional neurobiological basis for substance abuse risk and consequences. METHODS: In this review, we discuss commonalities and distinctions of addiction to alcohol and other drugs. We focus on recent advances in preclinical studies using rodent models of drug self-administration. RESULTS: While there are specific behavioral and molecular manifestations common to alcohol, psychostimulant, opioid, and nicotine dependence, attempts to propose a unifying theory of the addictions inevitably face details where distinctions are found among classes of drugs. CONCLUSIONS: For alcohol, versus other drugs of abuse, we discuss and compare advances in: (i) neurocircuitry important for the different stages of drug dependence; (ii) transcriptomics and genetical genomics; and (iii) enduring effects, noting in particular the contributions of behavioral genetics and animal models. PMID- 26431120 TI - Effects of Systemic Magnesium on Post-operative Analgesia: Is the Current Evidence Strong Enough? AB - BACKGROUND: Clinical studies have been previously carried out on the efficacy of systemic magnesium to minimize postoperative pain, however, with controversial results. A quantitative meta-analysis was performed to evaluate the analgesic efficacy and safety of systemic magnesium on post-operative pain. STUDY DESIGN: Comprehensive systematic review of all relevant, publsished randomized controlled trials. METHODS: A search was conducted of published literature in MEDLINE, PsycINFO, Scopus, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to Sep-Oct 2014. Randomized controlled trials (RCTs) that compared magnesium with placebo were identified. Effects were summarized using standardized mean differences (SMDs), weighed mean differences (WMD), or odds ratio (OR) with suitable effect model. RESULTS: Twenty-seven RCTs involving 1,504 patients were included. In total, peri-operative magnesium significantly reduced the pain score at rest (SMD, -1.43, 95% CI, -2.74 to -0.12, < 0.01). Magnesium significantly reduced analgesic consumption (SMD, -1.72, 95% CI, -3.21 to -0.23) in patients undergoing urogenital, orthopaedic, and cardiovascular surgeries, but was inconclusive for patients receiving gastrointestinal surgeries. The obvious analgesia of systemic magnesium was observed on reducing the pain score during movement at 24 hours after operation (SMD, -0.05, 95% CI, -0.43 to 0.32). Moreover, magnesium administration showed a beneficial effect with regard to intra-operative hemodynamics and reduced extubation time in the cardiovascular surgery patients (WMD, -29.34 min, 95% CI, 35.74 to -22.94, P < 0.01). LIMITATIONS: Focused only on the quality of analgesia on postoperative pain with regards to surgery type. CONCLUSIONS: Our study suggests that systemic magnesium during general anesthesia significantly decreases post-operative pain scores without increasing adverse events. It should be noted that since there are 18 ongoing RCTs without published data, it is still premature to draw conclusions on the long-term analgesic effects of magnesium as well as potential gender or age difference. PMID- 26431121 TI - The Association of rs4753426 Polymorphism in the Melatonin Receptor 1B (MTNR1B) Gene and Susceptibility to Adolescent Idiopathic Scoliosis: A Systematic Review and Meta-analysis. AB - BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a tridimensional structural deformity of the spine that may deteriorate progressively, leading to significant functional limitations and pain problems. Several previous studies have implicated the rs4753426 single nucleotide polymorphism in the melatonin receptor 1B (MTNR1B) gene in the etiology of AIS. However the sample sizes were limited and the findings of those studies were inconsistent. An overall assessment of the evidence supporting this association has not been previously conducted. OBJECTIVES: To provide a comprehensive assessment and synthesis of the currently available evidence on the association between rs4753426 and AIS. STUDY DESIGN: A systematic review and meta-analysis. SETTING: University hospital, China. METHODS: This review followed the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. PubMed (MEDLINE), EMBASE, Scopus databases, and WANFANG databases were systematically searched through December 2014 to identify relevant studies following a sensitive strategy. Statistical analysis was performed using the Review Manager 5.2 software. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using the fixed effect inverse variance model for allelic (C vs. T) and genotypic comparisons. RESULTS: Four papers including 5 studies which involved 2,552 AIS cases and 2,738 controls were identified for this meta-analysis. The results showed that C allele of the rs4753426 was significantly associated with AIS (OR = 1.12, 95% CI: 1.03 1.21, P = 0.01). CT and CC genotypes were 26% (OR = 1.26, 95% CI: 1.04-1.53, P = 0.01) and 28% (OR = 1.28, 95% CI: 1.05-1.56, P = 0.01), respectively, more likely to have AIS compared with CC genotype. As for the dominant model (CC+TT vs. TT), summary ORs showed statistically significant association with AIS (OR = 1.28, 95% CI: 1.06-1.53, P = 0.009). Compared with the CT+TT genotype, the summary ORs of the CC genotype showed marginally statistically significant association with AIS (OR = 1.11, 95 % CI: 0.99-1.24, P = 0.07). The subgroup meta-analysis results showed the C allele and each genotype were significantly associated with AIS in the Asian group but not in the Caucasian group. LIMITATIONS: Paucity of available literature. CONCLUSIONS: To our knowledge, there has been no meta-analysis to analyze the association between rs4753426 polymorphism in the MTNR1B gene and AIS. This systematic review was a comprehensive analysis of the currently available evidence, and found an overall significant association of rs4753426 polymorphism with the risk of AIS, especially in the Asian population. Further investigation of this association is necessary in other populations. PMID- 26431122 TI - Predictors of Persistent Neuropathic Pain--A Systematic Review. AB - BACKGROUND: Characterization of the prognostic variables for persistent neuropathic pain (PNP) remains incomplete despite multiple articles addressing this topic. To provide more insight into the recovery and prognosis of neuropathic pain, high-quality data are required that provide information about the predictors that contribute to the development of PNP. OBJECTIVE: To determine the methodological quality of studies about predictors for PNP and to summarize findings of predictors found in high-quality studies. STUDY DESIGN: A systematic review. SETTING: VU University Medical Center, Amsterdam, The Netherlands. METHODS: Studies were identified by searching the electronic databases PubMed, Embase, and Cochrane Library. Methodological quality of each article was independently assessed by 2 reviewers. RESULTS: Forty-six relevant studies were identified, classified into 4 different neuropathic pain (NP)-syndromes: postherpetic neuralgia (n = 35), radicular pain and sciatica (n = 3), postsurgical pain (n = 6), and other types of NP (n = 2). Seven studies were of high quality. The 3 high-quality studies found for PHN reported male gender, older age, smoking, trauma at the site of lesion, missed antiviral prescriptions, higher acute pain severity, higher rash severity, more neuropathic characteristics, shorter rash duration, and a lower health status as predictors for PNP. For persistence of radicular pain one high-quality study reported negative outcome expectancies, pain-related fear of movement, and passive pain coping as predictors for PNP. Psychological distress, acute pain, breast cancer surgery, higher body mass index, area of secondary hyperalgesia, neuropathic characteristics, hypoesthesia, and hyperesthesia were found to be predictive for postsurgical pain in 3 high-quality studies. LIMITATIONS: Some publications may have been missed during literature search. The low-quality of the studies could be the result of an incomplete description of their methods. CONCLUSIONS: High quality studies mainly assessed factors related to disease functions and structures. Due to shortcomings in methodological quality and limited areas of predictor selection, there is a need for high-quality studies focusing on predictor measurement, statistical analysis and the use of a standardized set of predictors. PMID- 26431123 TI - Effect of Individually Tailored Biopsychosocial Workplace Interventions on Chronic Musculoskeletal Pain and Stress Among Laboratory Technicians: Randomized Controlled Trial. AB - BACKGROUND: Chronic musculoskeletal pain is prevalent among laboratory technicians and work-related stress may aggravate the problem. OBJECTIVES: This study investigated the effect of a multifaceted worksite intervention on pain and stress among laboratory technicians with chronic musculoskeletal pain using individually tailored physical and cognitive elements. STUDY DESIGN: This trial uses a single-blind randomized controlled design with allocation concealment in a 2-armed parallel group format among laboratory technicians. The trial "Implementation of physical exercise at the Workplace (IRMA09)--Laboratory technicians" was registered at ClinicalTrials.gov prior to participant enrolment. SETTING: The study was conducted at the head division of a large private pharmaceutical company's research and development department in Denmark. The study duration was March 2014 (baseline) to July 2014 (follow-up). METHODS: Participants (n = 112) were allocated to receive either physical, cognitive, and mindfulness group-based training (PCMT group) or a reference group (REF) for 10 weeks at the worksite. PCMT consisted of 4 major elements: 1) resistance training individually tailored to the pain affected area, 2) motor control training, 3) mindfulness, and 4) cognitive and behavioral therapy/education. Participants of the REF group were encouraged to follow ongoing company health initiatives. The predefined primary outcome measure was pain intensity (VAS scale 0-10) in average of the regions: neck, shoulder, lower and upper back, elbow, and hand at 10 week follow-up. The secondary outcome measure was stress assessed by Cohen's perceived stress questionnaire. In addition, an explorative dose-response analysis was performed on the adherence to PCMT with pain and stress, respectively, as outcome measures. RESULTS: A significant (P < 0.0001) treatment by time interaction in pain intensity was observed with a between-group difference at follow-up of -1.0 (95%CI: -1.4 to -0.6). No significant effect on stress was observed (treatment by time P = 0.16). Exploratory analyses for each body region separately showed significant pain reductions of the neck, shoulders, upper back and lower back, as well as a tendency for hand pain. Within the PCMT group, general linear models adjusted for age, baseline pain, and stress levels showed significant associations for the change in pain with the number of physical-cognitive training sessions per week (-0.60 [95%CI -0.95 to -0.25]) and the number of mindfulness sessions (0.15 [95%CI 0.02 to 0.18]). No such associations were found with the change in stress as outcome. LIMITATIONS: Limitations of behavioral interventions include the inability to blind participants to which intervention they receive. Self-reported outcomes are a limitation as they may be influenced by placebo effects and outcome expectations. CONCLUSIONS: We observed significant reductions in chronic musculoskeletal pain following a 10-week individually adjusted multifaceted intervention with physical training emphasizing dynamic joint mobility and mindfulness coupled with fear-avoidance and de-catastrophizing behavioral therapy compared to a reference group encouraged to follow on-going company health initiatives. A higher dose of physical-cognitive training appears to facilitate pain reduction, whereas a higher dose of mindfulness appears to increase pain. Hence, combining physical training with mindfulness may not be an optimal strategy for pain reduction. TRIAL REGISTRATION: NCT02047669. PMID- 26431124 TI - Intraarticular Facet Injections for Low Back Pain: Design Considerations, Consensus Methodology to Develop the Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Since the publication of guidelines by the UK National Institute for Health and Care Excellence (NICE) and the American Pain Society guidelines for low back pain in 2009 there have been deep divisions in the pain treatment community about the use of therapeutic intraarticular facet joint injections. While evidence for the effectiveness or not of intraarticular facet joint injections remains sparse, uncertainty will remain. The Warwick feasibility study, along with a concurrent study with a different design led by another group, aims to provide a stable platform from which the effectiveness and cost effectiveness of intraarticular facet joint injections added to normal care could be evaluated in randomized controlled trials (RCTs). OBJECTIVES: To reach consensus on key design considerations for the Warwick facet feasibility study from which the study protocol and working manuals will be developed. STUDY DESIGN: A consensus conference involving expert professionals and lay members. METHODS: Preliminary work identified 5 key design considerations for deliberation at our consensus conference. Three concerned patient assessment and treatment: diagnosis of possible facet joint pain, interaarticular facet joint injection technique, and best usual care. Two concerned trial analysis: a priori sub-groups and minimally important difference and are reported elsewhere. We did systematic evidence reviews of the design considerations and summarized the evidence. Our design questions and evidence summaries were distributed to all delegates. This formed the basis for discussions on the day. Clinical experts in all aspects of facet joint injection from across the UK along with lay people were invited via relevant organizations. Nominal group technique was used in 15 facilitated initial small group discussions. Further discussion and ranking was undertaken in plenary. All small group and plenary results were recorded and checked and verified post conference. Where necessary participants were contacted via email to resolve outstanding issues. RESULTS: Fifty-two delegates attended the conference with lay people and all relevant professions represented. Consensus was reached on the details of how to assess patients for facet joint pain, undertake the injections, and deliver usual care. Where post conference checking of results revealed errors in calculating ranking results on the day, consensus was reached by email consultation. All but 3 delegates agreed to be associated with the outcome. LIMITATIONS: Allocating one day for discussing a wide range of topics imposed time pressure on discussion and calculation of the numerous rankings. CONCLUSIONS: Through the use of an evidence-based, systematic, inclusive, and transparent process we have established consensus from expert health professionals in the UK, with lay input, on the clinical assessment of suspected facet joint pain, interaarticular injection for facet joint pain, and best usual care for use in a feasibility study for a proposed pragmatic clinical trial of interaarticular facet joint injections. This provides a strong basis for a clinical trial that will be acceptable to the pain treatment community. PMID- 26431125 TI - Radiologic Analysis and Clinical Study of the Upper One-third Joint Technique for Fluoroscopically Guided Sacroiliac Joint Injection. AB - BACKGROUND: Sacroiliac intraarticular injection by the traditional technique can be challenging to perform when the joint is covered with osteophytes or is extremely narrow. OBJECTIVE: To examine whether there is enough space for the needle to be advanced from the L5-S1 interspinous space to the upper one-third sacroiliac joint (SIJ) by magnetic resonance image (MRI) analysis as an alternative to fluoroscopically guided SIJ injection with the lower one-third joint technique, and to determine the feasibility of this novel technique in clinical practice. STUDY DESIGN: MRI analysis and observational study. SETTING: An interventional pain management practice at a university hospital. METHODS: We analyzed 200 axial T2-weighted MRIs between the L5 and S1 vertebrae of 100 consecutive patients. The following measurements were obtained on both sides: 1) the thickness of fat in the midline; 2) the distance between the midline (Point C) and the junction (Point A) of the skin and the imaginary line that connects the SIJ and the most medial cortex of the ilium; 3) the distance between the midline (Point C) and the junction (Point B) of the skin and the imaginary line that connects the SIJ and the L5 spinous process; 4) the distance between the SIJ and midline (Point C) on the skin, or between the SIJ and the midpoint (Point C') of the line from Point A to Point B; and 5) the angle between the sagittal line and the imaginary line that connects the SIJ and the midline on the skin. The upper one-third joint technique was performed to establish the feasibility of the alternative technique in 20 patients who had unsuccessful sacroiliac intraarticular injections using the lower one-third joint technique. RESULTS: The mean distances from the midline to Point A and to Point B were 21.9 +/- 13.7 mm and 27.8 +/- 13.6 mm, respectively. The mean distance between the SIJ and Point C (or Point C') was 81.0 +/- 13.3 mm. The angle between the sagittal line and the imaginary line that connects the SIJ and the midline on the skin was 42.8 +/- 5.1 degrees . The success rate of sacroiliac intraarticular injections with the upper one-third joint technique was 90% (18/20). LIMITATIONS: This was an observational study and lacked a control group. CONCLUSIONS: Sacroiliac intraarticular injections with the upper one-third joint technique are advisable when it is hard to perform them with the lower one-third joint technique. PMID- 26431127 TI - In errata. PMID- 26431126 TI - Peripheral Nerve Stimulation for the Treatment of Chronic Intractable Headaches: Long-term Efficacy and Safety Study. AB - BACKGROUND: Despite the various modalities available for treating headaches, typical therapy does not provide adequate pain relief for some patients. OBJECTIVES: This study explored the efficacy and safety of long-term peripheral nerve stimulation (PNS) for intractable chronic headaches. STUDY DESIGN: Retrospective study of refractory headache patients at academic pain center. METHODS: The medical records of all patients (N = 46) permanently implanted with PNS between January 2005 and January 2012 were reviewed retrospectively. Patient records and phone interviews were used to quantify the levels of pain intensity, headache days per month, and overall patient satisfaction with treatment. The correlation between headache duration and effectiveness of PNS was also assessed. RESULTS: Pain intensity on the 11-point Numeric Rating Scale decreased from 7.60 +/- 1.73 before implantation to 3.78 +/- 2.41, 3.32 +/- 2.67, 3.42 +/- 2.74, and 2.04 +/- 2.27 at one, 6, 12, and > 12 (19-98) months after implantation, respectively (P < .001). The mean number of headache days per month decreased by about 14 days from the base line. No correlation (r = -.33) was found between the number of years the patients had suffered from headaches and the efficacy of treatment. LIMITATIONS: Due to the limitation of a retrospective study, the data collected via chart reviews and phone interviews are susceptible to selection and information biases. CONCLUSIONS: PNS is an effective modality in the long-term management of intractable chronic headaches. Despite long histories of chronic headaches, the majority of patients had significant reductions in pain scores and the number of headache days per month. The outcomes were not dependent on the number of years the patients had suffered from headaches before PNS treatment. PMID- 26431128 TI - Survival Strategies for Tsunami of ICD-10-CM for Interventionalists: Pursue or Perish! AB - The unfunded mandate for the implementation of International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) is scheduled October 1, 2015. The development of ICD-10-CM has been a complicated process. We have endeavored to keep Interventional Pain Management doctors apprised via a variety of related topical manuscripts. The major issues relate to the lack of formal physician participation in its preparation. While the American Health Information Management Association (AHIMA) and American Hospital Association (AHA) as active partners in its preparation. Centers for Medicare and Medicaid Services (CMS) and Centers for Disease Control and Prevention (CDC) are major players; 3M and Blue Cross Blue Shield Association are also involved. The cost of ICD-10-CM implementation is high, similar to the implementation of electronic health records (EHRs), likely consuming substantial resources. While ICD-10, utilized worldwide, includes 14,400 different codes, ICD-10-CM, specific for the United States, has expanded to 144,000 codes, which also includes procedural coding system. It is imperative for physicians to prepare for the mandatory implementation. Conversion from ICD-9-CM to ICD-10-CM coding in interventional pain management is not a conversion of one to one that can be easily obtained from software packages. It is a both a difficult and time-consuming task with each physician, early on, expected to spend on estimation at least 10 minutes per visit on extra coding for established and new patients. For interventional pain physicians, there have been a multitude of changes, including creation of new codes and confusing conversion of existing codes. This manuscript describes a variety of codes that are relevant to interventional pain physicians and often utilized in daily practices. It is our objective that this manuscript will provide coding assistance to interventional pain physicians. PMID- 26431129 TI - Systematic Review of the Diagnostic Accuracy and Therapeutic Effectiveness of Sacroiliac Joint Interventions. AB - BACKGROUND: The sacroiliac joint is well known as a cause of low back and lower extremity pain. Prevalence estimates are 10% to 25% in patients with persistent axial low back pain without disc herniation, discogenic pain, or radiculitis based on multiple diagnostic studies and systematic reviews. However, at present there are no definitive management options for treating sacroiliac joint pain. OBJECTIVE: To evaluate the diagnostic accuracy and therapeutic effectiveness of sacroiliac joint interventions. STUDY DESIGN: A systematic review of the diagnostic accuracy and therapeutic effectiveness of sacroiliac joint interventions. METHODS: The available literature on diagnostic and therapeutic sacroiliac joint interventions was reviewed. The quality assessment criteria utilized were the Quality Appraisal of Reliability Studies (QAREL) checklist for diagnostic accuracy studies, Cochrane review criteria to assess sources of risk of bias, and Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment (IPM-QRB) criteria for randomized therapeutic trials and Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment for Nonrandomized Studies (IPM-QRBNR) for observational therapeutic assessments. The level of evidence was based on a best evidence synthesis with modified grading of qualitative evidence from Level I to Level V. Data sources included relevant literature published from 1966 through March 2015 that were identified through searches of PubMed and EMBASE, manual searches of the bibliographies of known primary and review articles, and all other sources. OUTCOME MEASURES: For the diagnostic accuracy assessment, and for the therapeutic modalities, the primary outcome measure of pain relief and improvement in functional status were utilized. RESULTS: A total of 11 diagnostic accuracy studies and 14 therapeutic studies were included. The evidence for diagnostic accuracy is Level II for dual diagnostic blocks with at least 70% pain relief as the criterion standard and Level III evidence for single diagnostic blocks with at least 75% pain relief as the criterion standard. The evidence for cooled radiofrequency neurotomy in managing sacroiliac joint pain is Level II to III. The evidence for conventional radiofrequency neurotomy, intraarticular steroid injections, and periarticular injections with steroids or botulinum toxin is limited: Level III or IV. LIMITATIONS: The limitations of this systematic review include inconsistencies in diagnostic accuracy studies with a paucity of high quality, replicative, and consistent literature. The limitations for therapeutic interventions include variations in technique, variable diagnostic standards for inclusion criteria, and variable results. CONCLUSION: The evidence for the accuracy of diagnostic and therapeutic effectiveness of sacroiliac joint interventions varied from Level II to Level IV. PMID- 26431130 TI - Improving Analgesic Efficacy and Safety of Thoracic Paravertebral Block for Breast Surgery: A Mixed-Effects Meta-Analysis. AB - BACKGROUND: While most trials of thoracic paravertebral nerve blocks (TPVB) for breast surgery show benefit, their effect on postoperative pain intensity, opioid consumption, and prevention of chronic postsurgical pain varies substantially across studies. Variability may result from use of different drugs and techniques. OBJECTIVES: To examine the use of TPVB in breast surgery, and to determine which method(s) provide optimal efficacy and safety. STUDY DESIGN: Mixed-Effects Meta-Analysis. METHODS: We conducted a systematic review of randomized trials comparing TPVB to no intervention using random-effects models. To evaluate the contributions of various techniques, clinical approaches were included as moderators in mixed-effects models. RESULTS: A total of 24 randomized controlled trials (RCTs) with 1,822 patients were included. Use of TPVB decreased postoperative pain scores at rest and movement at the first 2, 24, 48, and 72 hours. TPVB modestly decreased intraoperative and postoperative opioid consumption, reduced nausea and vomiting, and shortened hospitalization, but to a probably clinically irrelevant degree. Blocks also appeared to reduce the incidence of chronic postsurgical pain at 6 months. Adding fentanyl to the TPVB improved pain at rest (at 24, 48, and 72 hours) and movement (at 24 and 72 hours). Multilevel blocks provided better postoperative pain control, but only during movement (at 2, 48, and 72 hours). Fewer procedural complications (especially hypotension, epidural spread, and Horner's syndrome) occurred when anatomical landmarks were supplemented with ultrasound guidance. LIMITATIONS: The number of studies available was limited in the meta-analytic model of incidence of chronic post-surgical pain. CONCLUSION: TPVB reduces postoperative pain and opioid consumption, and has a limited beneficial effect on the quality of recovery. From all the techniques that were evaluated, only the addition of fentanyl, and performing multilevel blocks were associated with improved acute analgesia. TPVB may reduce chronic postsurgical pain at 6 months. PMID- 26431131 TI - Value of Examination Under Fluoroscopy for the Assessment of Sacroiliac Joint Dysfunction. AB - BACKGROUND: Pain emanating from the sacroiliac (SI) joint can have variable radiation patterns. Single physical examination tests for SI joint pain are inconsistent with multiple tests increasing both sensitivity and specificity. OBJECTIVE: To evaluate the use of fluoroscopy in the diagnosis of SI joint pain. STUDY DESIGN: Prospective double blind comparison study. SETTING: Pain clinic and radiology setting in urban Veterans Administration (VA) in New Orleans, Louisiana. METHODS: Twenty-two adult men, patients at a southeastern United States VA interventional pain clinic, presented with unilateral low back pain of more than 2 months' duration. Patients with previous back surgery were excluded from the study. Each patient was given a Gapping test, Patrick (FABERE) test, and Gaenslen test. A second blinded physician placed each patient prone under fluoroscopic guidance, asking each patient to point to the most painful area. Pain was provoked by applying pressure with the heel of the palm in that area to determine the point of maximum tenderness. The area was marked with a radio opaque object and was placed on the mark with a fluoroscopic imgage. A site within 1 cm of the SI joint was considered as a positive test. This was followed by a diagnostic injection under fluoroscopy with 1 mL 2% lidocaine. A positive result was considered as more than 2 hours of greater than 75% reduction in pain. Then, in 2-3 days this was followed by a therapeutic injection under fluoroscopy with 1 mL 0.5% bupivacaine and 40 mg methylprednisolone. RESULTS: Each patient was reassessed after 6 weeks. The sensitivity and specificity in addition to the positive and negative predictive values were determined for both the conventional examinations, as well as the examination under fluoroscopy. Finally, a receiver operating characteristic (ROC) curve was constructed to evaluate test performance. The sensitivity and specificity of the fluoroscopic examination were 0.82 and 0.80 respectively; Positive predictive value and negative predictive value were 0.93 and 0.57 respectively. The area under ROC curve was 0.812 which is considered a "good" test; however the area under ROC for the conventional examination were between 0.52-0.58 which is considered "poor to fail". LIMITATIONS: Variation in anatomy of the SI joint, small sample size. CONCLUSIONS: Multiple structures of the SI joint complex can result in clinical symptoms of pain. These include intra-articular structures (degenerative arthritis, and inflammatory conditions) as well as extra-articular structures (ligaments, muscles, etc.). PMID- 26431132 TI - Contrast Dispersion Pattern and Efficacy of Corticosteroid at the Glenohumeral Joint in Adhesive Capsulitis. AB - BACKGROUND: Corticosteroid injection has a wide range of success in adhesive capsulitis but the reason for this has not yet been explained. We hypothesized that this difference might be due to the distribution of the corticosteroids injected into the joint cavity because particulate steroid deposits in the capsule and will not be moved over time by shoulder motion. OBJECTIVES: The purpose of this study is to determine whether the therapeutic efficacy of particulate corticosteroid injection into the glenohumeral joint differs according to the dispersion pattern. STUDY DESIGN: Prospective evaluation. SETTING: Outpatient clinics at a tertiary university hospital. METHODS: Seventy two patients diagnosed as having adhesive capsulitis received a corticosteroid injection at the glenohumeral joint. The posterior capsule and the subscapular bursa were selected as dispersion sites and the dispersion of contrast dye was expressed as a ratio (%). Two weeks and 3 months after the injection clinical improvement ("not improved," "slightly improved," "much improved"), numeric rating scale (NRS), and passive range of motions (PROM) were evaluated. The dispersion of the contrast dye was compared according to the clinical improvements by an analysis of variance test. Pearson correlation test was done to find the relationship between PROM and the dispersion and between change of NRS and the dispersion. RESULTS: The distribution in the subscapular area was 30.0% in the "much improved" group, 22.0% in the "slightly improved" group, and 37.1% in the "no improvement" group which was not significantly different (P = 0.179). Correlations between changes of NRS and the dye distribution were not statistically significant (P = 0.429 at 2 weeks and P = 0.629 at 3 months). The change of passive external rotation 3 months after the injection was significantly correlated with the dye distribution (P = 0.035). LIMITATIONS: Because of diverse pathologic findings in adhesive capsulitis, further studies will be needed to address the effect of the dye distribution on the pain improvement according to pathologic findings revealed by magnetic resonance imaging (MRI). CONCLUSION: External rotation of the shoulder in adhesive capsulitis has greater improvement as the corticosteroid solutions injected into the glenohumeral joint are increasingly dispersed to the subscapularis area. However, this does not affect the pain improvement after the injection. PMID- 26431133 TI - Effectiveness and Safety of Pulsed Radiofrequency Treatment Guided by Computed Tomography for Refractory Neuralgia of Infraorbital Nerve: A Pilot Study. AB - BACKGROUND: There is no truly optimal treatment to cure refractory neuralgia of the infraorbital nerve. Recently, nondestructive pulsed radiofrequency (PRF) has become one of the most attractive interventional techniques for painful disorders. However, use of the technique for infraorbital neuralgia has been seldom reported. OBJECTIVE: The purpose of this prospective study is to observe the effectiveness and safety of PRF treatment for neuralgia of the infraorbital nerve. STUDY DESIGN: Prospective case series clinical outcome study. SETTING: University Medical Center, Beijing, China. METHODS: From January 2011 to November 2012, 36 consecutive patients, following ineffective conservative therapy, underwent PRF treatment and completed 2-year follow-up. Numeric rating scales (NRS), effective rate, additional carbamazepine dosage, and side effects were recorded at postoperative day one, week one, week 2, month one, month 3, month 6, year one, and year 2. Patients were divided into effective group and ineffective group based on postoperative one -month total pain relief or more than 50% reduction in NRS and patients were satisfied with the effect, and possible factors affecting efficacy were compared between the 2 groups. RESULTS: Effective rates were 69%, 69%, 64%, 50%, and 50% at postoperative month one, month 3, month 6, year one, and year 2, respectively. No serious side effects were observed, except that 9 patients felt short-term (one -month duration) mild numbness. Output voltage and tissue resistance in the effective group were significantly higher than the ineffective group (P < 0.01). Intraoperative output voltage was negatively correlated with postoperative one -month NRS (r = -0.332, P < 0.05). LIMITATIONS: The non-controlled and single-centered design of the study. CONCLUSIONS: Results demonstrated PRF treatment under computed tomography (CT) guidance for infraorbital neuralgia is safe, effective, and is expected to become an alternative for patients experiencing ineffective conservative therapy. Increasing the output voltage of PRF could be the chosen method to improve the efficacy. PMID- 26431134 TI - Effect of the Location of Endplate Cement Extravasation on Adjacent Level Fracture in Osteoporotic Patients Undergoing Vertebroplasty and Kyphoplasty. AB - BACKGROUND: The most widely researched risk/complication following vertebroplasty (VP) or kyphoplasty (KP) is that of adjacent level fracture (ALF). Current literature results regarding the effect of intradiscal extravasation of cement on the risk of ALF is conflicting with about half of the studies concluding there is no added risk with endplate extravasation and half of the studies reporting opposite conclusions. OBJECTIVE: The purpose of the study is to further stratify the data to determine whether specifically the location and extent of endplate cement extravasation more strongly affect ALF risk in osteoporotic patients following either VP or balloon KP. STUDY DESIGN: Retrospective cohort study. SETTING: University teaching hospital. METHODS: One hundred and fifty-six cemented levels in 80 patients, treated at a single center between 2008 and 2012 were reviewed. Age, gender, T-score, body mass index, and osteoporosis type (primary or secondary) were recorded. An ALF was defined as a fracture: 1) in a non-cemented vertebra; 2) adjacent to a cemented level; and 3) not due to trauma or malignancy. Location of the cement extravasation (anterior, middle, or posterior third of the vertebral body) and extravasation extent (percentage of the intervertebral disc height occupied by the bolus) were measured. A logistic modeling strategy permitted examining the association between the location and extent of extravasation and the odds of ALF. RESULTS: ALF occurred in 14 of the 52 patients (27%) and 20 of the 98 levels (20.4%) remaining after exclusions. Odds of ALF were 5.9 times higher (95% CI: 1.6 to 21.2, P = 0.008) with extravasation when compared to no leakage. Odds of ALF in a given patient were 22.6 times higher (95% CI: 3.0 to 170.9, P = 0.003) with anterior extravasation when compared to no leakage. Leakage in the middle or posterior thirds and extent of extravasation were not associated with ALF. LIMITATIONS: Limitations of the study include the retrospective study design and small sample size as well as the retrospective implementation of follow-up criteria posing risk of selection bias. CONCLUSIONS: Cement endplate extravasation isolated to the anterior third of the vertebral body is associated with is significantly higher odds of ALF after VP or KP in patients with osteoporosis. PMID- 26431135 TI - Lidocaine Injection in the Intramuscular Innervation Zone Can Effectively Treat Chronic Neck Pain Caused by MTrPs in the Trapezius Muscle. AB - BACKGROUND: An increasing number of people suffer from neck pain due to life style and prolonged use of computers. Research has revealed that myofascial trigger points (MTrPs) and the intramuscular innervation zone (IZ) are involved in neck pain. MTrPs are induced mainly by IZ dysfunction of the affected skeletal muscle and the 2 do not overlap in location. The question is whether injection treatment in MTrPs or in the IZ is more effective to relieve MTrPs-associated pains. The precise location and body-surface map of the intramuscular IZ in the trapezius muscle and a clinical injection study in the IZ may provide a useful answer to the question. OBJECTIVES: This study aimed to investigate the efficacy of lidocaine injection in the intramuscular IZ for the treatment of chronic neck pain caused by MTrPs in the trapezius muscle. STUDY DESIGN: Prospective observational study, approved by the local research ethics. SETTING: University hospital, departments of Anesthesiology and Anatomy. METHODS: First, for the determination of IZ distribution and body-surface mapping, a modified intramuscular Sihler's neural staining technique was applied to elucidate nerve distribution patterns of the trapezius muscle. Then, 120 patients with myofascial pain syndrome (MPS) of the trapezius muscle were randomly divided into 5 groups for analysis. Group 1 (n = 24) received injections of saline (0.9% NaCl) at the MTrPs. Group 2 (n = 24) received injections of 0.5% lidocaine at the MTrPs. Group 3 (n = 24) received injections of saline (0.9% NaCl) at the mid-upper trapezius (Point E). Group 4 (n = 24) received injections of 0.5% lidocaine at Point E. Group 5 (n = 24) received a combined injection of 0.5% lidocaine treatment at both Point E and the lower trapezius (Point F). The injection dose was 4 mL at each injection site. All patients received injections once a week for 4 weeks. The visual analogue scale (VAS) and the frequency of painful days per month (FPD) were obtained before treatment and at 2, 4, and 6 months after treatment. RESULTS: The intramuscular terminal nerve branches presented a "dendritic" distribution in the trapezius muscle and were connected with each other to form an S-shaped IZ belt in the middle of the muscle belly. Compared with the MTrP injection group, lidocaine-injection therapy in the IZ significantly reduced the degree and frequency of neck pain in patients at 6 months after treatment, especially the combined lidocaine-injection therapy in the IZ of both the mid upper trapezius and the lower trapezius are more effective (all P < 0.05). CONCLUSIONS: This study confirms that lidocaine-injection therapy in the IZ significantly reduces the degree and frequency of neck pain in patients at 6 months after treatment. The combined lidocaine-injection therapy in the IZ of both the mid-upper trapezius and the lower trapezius is more effective. In addition, this study establishes a clear distribution map of intramuscular nerves that will be conducive to the future use of chemical blockers and electrical stimulation in the nervous system in treating MPS of the trapezius muscle. LIMITATIONS: The small number of patients and the short duration of follow-up. PMID- 26431136 TI - Incidence and Demographics of Post-Operative Naloxone Administration: A 13-Year Experience at a Major Tertiary Teaching Institution. AB - BACKGROUND: Perioperative use of opioids is associated with the risk of opioid induced respiratory depression. Naloxone is a competitive opioid antagonist typically administered to reverse opioid-induced respiratory depression. Postoperative administration of naloxone may be considered a proxy for significant postoperative opioid-induced respiratory depression and data regarding its use may be utilized as a quality measure. Few large studies have been done to characterize the population and define an incidence of naloxone recipients in the postoperative inpatient setting. OBJECTIVES: We aimed to characterize the demographics of patients receiving postoperative naloxone, as well as the incidence of administration in the first 72 post-operative hours at a large urban academic medical center in the United States. STUDY DESIGN: This is a retrospective cohort study. SETTING: Major urban tertiary teaching institution. METHODS: The robust electronic record database of The Department of Anesthesiology at The Icahn School of Medicine at Mount Sinai, as well as the institution's data warehouse were instrumental in allowing almost 450,000 surgical cases performed between 2001 and 2014 to be screened for naloxone administration within the first 72 postoperative hours. Organ harvests, outside of OR intubations, cancelled cases, and patients age less than or equal to 18 were excluded from the total case count. RESULTS: Naloxone was administered 433 times in a total of 442,699 postoperative cases. This yielded an incidence of 0.1%. Additionally, the demographics of the group receiving naloxone were described. The mean age was 60, mean body mass index (BMI) was 27, 60% were women, and the mean American Society of Anesthesiologists (ASA) status was 3. Average time to naloxone administration was 21 hours (standard deviation 7) after surgery. Thirteen percent of the cases were emergent. Breakdown of anesthetic technique revealed that 81% of the cases were performed under general anesthesia, 7% with monitored anesthesia care (MAC), and 12% under neuraxial anesthesia. This study lays the groundwork for further elucidating risk factors for postoperative administration of naloxone. LIMITATIONS: This is a retrospective study. CONCLUSION: The overall incidence of postoperative naloxone administration over a 13 year period in approximately 450,000 patients was 0.1%. Demographics of this group were older, ASA 3 women, qualifying as overweight, but not obese, undergoing elective surgery with a general anesthetic technique. Average time to administration was 21 hours postoperatively. PMID- 26431137 TI - Catheter-tip Granulomas Associated with Intrathecal Drug Delivery--A Two-Center Experience Identifying 13 Cases. AB - BACKGROUND: Intrathecal (IT) drug therapy with implanted pumps is an effective treatment modality for chronic pain and/or spasticity, especially after non invasive treatment has failed. Long-term use of intrathecal opioids may cause formation of inflammatory masses at the tip of intrathecal catheters, possibly leading to neurological deficits and/or catheter revision. OBJECTIVE: We aimed to identify risk factors for catheter-tip granuloma (CG) formation. STUDY DESIGN: Retrospective study. SETTING: Tertiary Spine Centers in Germany and Switzerland. METHODS: We retrospectively reviewed data at 2 Swiss centers (Kantonsspital St. Gallen, Swiss Paraplegic Centre Nottwil) between 01/1994 and 10/2013. Collected data were age at operation, gender, smoking status, previous spinal operations, spinal level of catheter-tip, clinical symptoms, catheter testing with contrast agent, applied drugs, drug concentration, as well as cumulative daily drug dosages. RESULTS: Thirteen patients with a mean age of 52.6 years and CG formation after a mean of 6.9 years of follow-up were identified and compared to 54 patients of similar age and length of follow-up (48.6 years, P = 0.535; follow up 5.3 years, P = 0.236) without CG. In the analysis of risk factors, catheter ending in the middle thoracic spine (Th4-8; 38.5 vs. 6.5%; P = 0.010), previous spinal surgery (75 vs. 41%; P = 0.051), and chronic pain as an underlying primary symptom for IT drug therapy (100 vs. 56%, P = 0.003) were associated with CG formation. IT drug therapy for spasticity appeared to be much less associated with CG formation (0 vs. 44%, P = .0003). As the symptomatology is closely related to the medical treatment applied, patients with CG were more likely to be treated with IT morphine (77 vs. 20%; P < 0.001), and as tendency with IT clonidine (54 vs. 26%; P = 0.092) and IT bupivacaine (46 vs. 20%; P = 0.077). Average in-pump morphine concentration (30.3 vs. 19.5 mg/mL; P = 0.05) as well as average daily dose of morphine (12.5 vs. 6.2 mg/d; P = 0.037) were significantly higher in the CG group. Smoking could not be identified as risk factor for CG formation. LIMITATIONS: Limitations include the retrospective approach, the limited group size of granuloma patients, as well as missing data in the investigated patient groups. CONCLUSION: Our patient cohort with CG differed in some features, of which some like catheter localization, choice, dosage, and the concentration of drugs are potentially modifiable. These results could contribute to the prevention of CG in the future. PMID- 26431138 TI - Associations Between Cognitive Performance and Pain in Chronic Fatigue Syndrome: Comorbidity with Fibromyalgia Does Matter. AB - BACKGROUND: In addition to the frequently reported pain complaints, performance based cognitive capabilities in patients with chronic fatigue syndrome (CFS) with and without comorbid fibromyalgia (FM) are significantly worse than those of healthy controls. In various chronic pain populations, cognitive impairments are known to be related to pain severity. However, to the best of our knowledge, the association between cognitive performance and experimental pain measurements has never been examined in CFS patients. OBJECTIVES: This study aimed to examine the association between cognitive performance and self-reported as well as experimental pain measurements in CFS patients with and without FM. STUDY DESIGN: Observational study. SETTING: The present study took place at the Vrije Universiteit Brussel and the University of Antwerp. METHODS: Forty-eight (18 CFS only and 30 CFS+FM) patients and 30 healthy controls were studied. Participants first completed 3 performance-based cognitive tests designed to assess selective and sustained attention, cognitive inhibition, and working memory capacity. Seven days later, experimental pain measurements (pressure pain thresholds [PPT], temporal summation [TS], and conditioned pain modulation [CPM]) took place and participants were asked to fill out 3 questionnaires to assess self-reported pain, fatigue, and depressive symptoms. RESULTS: In the CFS+FM group, the capacity of pain inhibition was significantly associated with cognitive inhibition. Self-reported pain was significantly associated with simple reaction time in CFS-only patients. The CFS+FM but not the CFS-only group showed a significantly lower PPT and enhanced TS compared with controls. LIMITATIONS: The cross-sectional nature of this study does not allow for inferences of causation. CONCLUSIONS: The results underline disease heterogeneity in CFS by indicating that a measure of endogenous pain inhibition might be a significant predictor of cognitive functioning in CFS patients with FM, while self-reported pain appears more appropriate to predict cognitive functioning in CFS patients without FM. PMID- 26431139 TI - High Prevalence of Hypovitaminosis D in Indian Chronic Low Back Patients. AB - BACKGROUND: Vitamin D has a significant role to play in bone metabolism and neuromuscular function. Several researchers have indicated that Vitamin D deficiency may be possibly related to chronic musculoskeletal pain including chronic low back pain (CLBP). OBJECTIVES: The present study was conducted to determine the prevalence of hypovitaminosis D and its contribution to chronic lower back pain. STUDY DESIGN: Controlled study. SETTING: Outpatient pain clinic of tertiary care hospital. METHODS: Data presented in this manuscript are from patients who were screened for inclusion in an open label, single arm clinical trial aimed to assess the effectiveness of vitamin D supplementation in patients with CLBP. Consecutive patients visiting the outpatient pain clinic of a tertiary care hospital with a diagnosis of CLBP with or without leg pain were recruited. A visual analogue scale (VAS) was used to measure low back pain intensity, and the Modified Oswestry disability questionnaire (MODQ) was used to measure functional ability. Plasma 25-OHD levels of all patients were measured and the prevalence of hypovitaminosis D was calculated. The multivariate logistic regression model was used to investigate the association between vitamin D deficiency and patient characteristics. RESULTS: A total of 328 patients were included in the study. Mean age of the study population was 43.8 years. Two hundred eighty-two (86%) (men 153/172 [89%], women 129/156 [83%]) of patients had below normal plasma vitamin D levels. Among these, 217 (66%) (men 126 [73%], women 91 [58%]) were found to be deficient and 65 (20%) (men 27 [16%], women 38 [24%]) were had insufficient levels. Multivariate regression analysis found that men were significantly more prone to have deficiency as compared to women (OR = 1.78 (1.10 2.88), P = 0.02). We also found a significantly positive relationship between vitamin D deficiency and increased functional disability (OR = 1.53 (1.24-1.87), P = 0.01). However, we did not find any relationship with pain severity, presence of other co-morbidities and educational level. LIMITATIONS: Not possible to access a good quality data on sun exposure and vitamin D dietary inake dieat in study population. No bone scans were performed. CONCLUSION: The result of this study provides a message about the high prevalence of hypovitaminosis D in the Indian CLBP population. Clinical guidelines for managing CLBP should include assessment of vitamin D status, together with advice on appropriate vitamin D supplementation in those found to be deficient. CLINICAL TRIAL REGISTRATION: CTRI/2014/03/004459. PMID- 26431140 TI - Chronic Pain in the Elderly: The Case for New Therapeutic Strategies. AB - BACKGROUND: Elderly patients in general exhibit a higher incidence of chronic and neuropathic pain conditions. This group poses a particular clinical challenge due to age-related pharmacokinetic and pharmacodynamic issues, comorbid conditions, and polypharmacy, as well as frailty and cognitive decline. Poor control of pain has consistently been identified as an issue for older people. The identification of safe and efficacious treatments for chronic pain remains a critical public health concern, especially considering the progressive increase of the world's elderly population. OBJECTIVES: This narrative review deals with the principal alterations of the somatosensory system together with changes in non-neuronal cells in the course of aging. The possibility to control chronic pain based on an innovative strategy which addresses non-neuronal cell dysregulation control will also be discussed. STUDY DESIGN: Narrative review. RESULTS: Peripheral nerves display functional, structural, and biochemical changes with aging that mainly involve Adelta fibers. Alteration in the responses to heat pain in the middle insular cortex and primary somatosensory cortex are also observed in the elderly. In general, pain threshold increases with age while the threshold of pain tolerance remains unchanged or decreases. Additionally, other important modifications of the pain perception system in this age group consist in a clear reduction in the descending inhibitory capacity with an associated increase in central sensitization. Furthermore, different changes concern immune system cells, such as mast cells and microglia, that with age show an increase in their sensitivity to noxious stimuli and a decreased capability to be regulated by homeostatic endogenous systems. Since these cells are the primary interlocutors for pain neurons, their alterations lead to changes that promote persistent neuroinflammation, thereby impacting pain neuronal cell functionality. LIMITATION: This review is not an exhaustive review for the current evidence supporting the role of immune cells in influencing pain somatosensory neuron functions. It is also important to stress the small number of studies designed to determine the efficacy and safety of anti-pain therapies in elderly patients. CONCLUSION: Non-neuronal cells of immune system origin such as microglia and mast cells, along with astrocytes, are capable of influencing pain somatosensory neuron functions. These nervous system non-neuronal cells may thus be viewed as innovative targets for persistent pain control. Among therapies aiming at preserving the functionality of non-neuronal cells, palmitoylethanolamide, with its high efficacy/risk ratio, may be an excellent co-treatment for the ever growing elderly population with chronic pain. PMID- 26431141 TI - Is Serum Hypovitaminosis D Associated with Chronic Widespread Pain Including Fibromyalgia? A Meta-analysis of Observational Studies. AB - BACKGROUND: Chronic widespread pain (CWP) is a global musculoskeletal disorder leading to disability and a reduced quality of life. Low levels of serum vitamin D has long been proposed to be associated with CWP, but previous research remains inconclusive. OBJECTIVES: To determine whether hypovitaminosis D was independently associated with CWP. STUDY DESIGN: Meta-analysis of observational study. METHODS: Electronic databases were searched for studies published up to November 2014 comparing the prevalence of hypovitaminosis D and serum vitamin D levels between participants with and without CWP. The crude and adjusted odds ratios (ORs) of hypovitaminosis D with CWP were calculated. Subgroup analysis according to gender, threshold of hypovitaminosis, and definition of patients was performed, as well as meta-regression to test the linear relationship between crude ORs and the latitude of study locations. RESULTS: Twelve studies were included, comprising 1,854 patients with CWP. The patient group showed a significantly higher risk of hypovitaminosis D than the control group (crude OR, 1.63; 95% CI, 1.20-2.23). The association was slightly attenuated after adjusting confounders, with a pooled adjusted OR of 1.41 (95% CI, 1.00-2.00). There was an increase in ORs of hypovitaminosis D using a lower diagnostic value of serum vitamin D (8 and 10 ng/mL). The subgroup analysis according to gender and definition of CWP did not reveal significant between-group differences. The meta regression showed no linear relationship between latitude and the crude ORs. CONCLUSIONS: There was a positive crude association between hypovitaminosis D and CWP, and the association was likely to remain after adjusting confounding factors. Use of a cut-off value of hypovitaminosis D (8-10 ng/mL) could better define the population with and without CWP. Further prospective follow-up studies are warranted to clarify the causal relationship between hypovitaminosis D and CWP. PMID- 26431142 TI - Prevalence of Neuropathic Pain in Patients Scheduled for Lumbar Spine Surgery: Nationwide, Multicenter, Prospective Study. AB - BACKGROUND: There is limited evidence about surgical outcomes after lumbar spinal surgery in patients with neuropathic pain (NP) or the prevalence of NP proportions among patients with degenerative lumbar diseases who are candidates for a surgical interventions. OBJECTIVE: The objectives of this study were to investigate the prevalence of NP among patients scheduled for lumbar spinal surgery and the relationship between health-related quality of life (HRQoL) and NP. This study also aimed to identify the risk factors related to NP and compare the clinical outcomes after surgical treatment between patients with and without NP. STUDY DESIGN: This study was a nationwide, multicenter, prospective, and observational study. It was conducted from Sep-Oct 2011 to May 2013, and included a total of 1,109 patients who were scheduled for lumbar spinal surgery from 44 spinal centers (both orthopedics and neurosurgeons). SETTING: Multicenter study. METHODS: Patients were diagnosed of having NP if the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale was = 12 points. The patients were investigated to assess the differences in their clinical outcomes one week and 3 months after surgery and were followed-up with regards to pain and HRQoL to explore the risk factors affecting NP. RESULTS: Of 1,109 recruited patients, 404 (36.4%) suffered from NP (mean age 62.06 years; 37.9% men) with mean LANSS score of 17.44 +/- 4.06, while 705 (63.6%) had nociceptive pain with mean LANSS score of 6.03 +/- 3.52. At baseline, patients with NP showed lower HRQoL and more severe pain compared to nociceptive pain patients. However, 3 months after surgical treatment, the NP group showed greater improvement in pain NRS (P = 0.087) and EQ-5D (P = 0.029) as compared to nociceptive pain group. Longer symptom duration was identified as a risk factor for NP (OR 1.003, respectively, P = 0.020). CONCLUSION: There was a high prevalence of NP in Korean patients scheduled for lumbar spine surgery, and these patients suffered greater pain and lower HRQoL than nociceptive pain patients. The more remarkable improvement NP patients showed after treatment highlights the importance of appropriate diagnosis and treatment of NP. PMID- 26431143 TI - Accuracy of Ultrasound-Guided Genicular Nerve Block: A Cadaveric Study. AB - BACKGROUND: Genicular nerve block has recently emerged as a novel alternative treatment in chronic knee pain. The needle placement for genicular nerve injection is made under fluoroscopic guidance with reference to bony landmarks. OBJECTIVE: To investigate the anatomic landmarks for medial genicular nerve branches and to determine the accuracy of ultrasound-guided genicular nerve block in a cadaveric model. STUDY DESIGN: Cadaveric accuracy study. SETTING: University hospital anatomy laboratory. METHODS: Ten cadaveric knee specimens without surgery or major procedures were used in the study. The anatomic location of the superior medial genicular nerve (SMGN) and the inferior medial genicular nerve (IMGN) was examined using 4 knee dissections. The determined anatomical sites of the genicular nerves in the remaining 6 knee specimens were injected with 0.5 mL red ink under ultrasound guidance. The knee specimens were subsequently dissected to assess for accuracy. If the nerve was dyed with red ink, it was considered accurate placement. All other locations were considered inaccurate. RESULTS: The course of the SMGN is that it curves around the femur shaft and passes between the adductor magnus tendon and the femoral medial epicondyle, then descends approximately one cm anterior to the adductor tubercle. The IMGN is situated horizontally around the tibial medial epicondyle and passes beneath the medial collateral ligament at the midpoint between the tibial medial epicondyle and the tibial insertion of the medial collateral ligament. The adductor tubercle for the SMGN and the medial collateral ligament for the IMGN were determined as anatomic landmarks for ultrasound. The bony cortex one cm anterior to the peak of the adductor tubercle and the bony cortex at the midpoint between the peak of the tibial medial epicondyle and the initial fibers inserting on the tibia of the medial collateral ligament were the target points for the injections of SMGN and IMGN, respectively. In the cadaver dissections both genicular nerves were seen to be dyed with red ink in all the injections of the 6 knees. LIMITATIONS: The small number of cadavers might have led to some anatomic variations of genicular nerves being overlooked. CONCLUSIONS: The result of this cadaveric study suggests that ultrasound-guided medial genicular nerve branch block can be performed accurately using the above-stated anatomic landmarks. PMID- 26431144 TI - Successful Spinal Cord Stimulator Trial and Permanent Implant in Patient with Diabetic Peripheral Neuropathy on Chronic Dual Antiplatelet Therapy. AB - The safety of neuraxial anesthetic techniques in the setting of oral and parenteral anticoagulation is an area of growing interest and clinical inquiry as the multitude of anticoagulant medications rapidly increases. Additionally, the indications for spinal cord stimulation therapy are evolving as both technique and technology in the field continue to advance. The estimated incidence of spinal hematoma following epidural injection has been estimated to be 1 in 150,000-200,000. However, there is very little data on the risk of indwelling spinal cord simulation leads and chronic use of anticoagulant medications. We would like to report a recent case for consideration in which a spinal cord stimulator trial was successful and led to permanent spinal cord stimulator implantation in a patient with diabetic peripheral neuropathy taking life-long aspirin and clopidogrel therapy secondary to extensive coronary and carotid atherosclerosis. The report serves as a novel case to encourage exploration into the topic of anticoagulation therapy with indwelling spinal cord stimulator leads. The case brings up a number of critical questions that cannot clearly be answered with the current literature and some interesting topics for discussion including the need for acute systemic anticoagulation in the future for vascular interventions and risk stratification for those patients selected for spinal cord stimulation. PMID- 26431145 TI - Lumbar Sympathetic Block with Botulinum Toxin Type B for Complex Regional Pain Syndrome: A Case Study. AB - Lumbar sympathetic block (LSB) is an effective method for relief of sympathetically mediated pain in the lower extremities. To prolong the sympathetic blockade, sympathetic destruction with alcohol or radiofrequency has been used. The pre-ganglionic sympathetic nerves are cholinergic, and botulinum toxin (BTX) has been found to inhibit the release of acetylcholine at the cholinergic nerve terminals. Moreover, BTX type B (BTX-B) is more convenient to use than BTX type A. Based on these findings, we performed LSB on the 2 patients with complex regional pain syndrome (CRPS) in the lower extremity. Levobupivacaine 0.25% 5 mL mixed with BTX-B 5,000 IU was given under fluoroscopic guidance. Two months after LSB with BTX-B, pain intensity and the Leeds assessment of neuropathic symptoms and signs (LANSS) score were significantly reduced. Allodynia and coldness disappeared and skin color came back to normal. In conclusion, BTX-B can produce an efficacious and durable sympathetic blocking effect on patients with CRPS. PMID- 26431146 TI - Brachial Plexus Block for Cancer-Related Pain: A Case Series. AB - Neoplastic brachial plexopathy (NBP) is caused by a cancerous infiltration into the brachial plexus, presenting often as severe pain in the affected upper extremity. Such pain can be resistant to medical treatment. Invasive interventions such as brachial plexus neurolysis with phenol or cordotomy may result in severe complications including permanent neurological damage and death. Continuous brachial plexus and paravertebral block with local anesthetic have been reported to successfully control pain from NBP, but these techniques are logistically challenging and frequently have catheter-related complications. We report a series of patients who received single-shot brachial plexus blocks with a mixture of local anesthetic and corticosteroid (bupivacaine 0.25% with methyl prednisolone 20-120 mg) for the treatment of refractory cancer-related pain in the brachial plexus territory, mostly from NBP. Theoretically, such blocks could provide immediate analgesia from the local anesthetic and a longer-lasting analgesia from the slow-release steroids. Responders reported a sustained decrease in their pain (lasting from 2 weeks to 10 months), a significant decrease in their opioid and non-opioid (ketamine, gabapentin) consumption, overall satisfaction with the block, and unchanged or improved function of their limb. The ideal candidate for this procedure is a patient who has pain that is predominantly neuropathic from a lesion within the brachial plexus and with anatomy amenable to ultrasound-guided nerve block. Our case series suggests that, in the appropriately selected patient, this technique can safely and effectively alleviate pain from NBP. The procedure is simple, spares limb function, and can be diagnostic, predicting response to more complex procedures. To the best of our knowledge, this is the first report using this technique for NBP. PMID- 26431147 TI - Sacral Insufficiency Fracture: An Insidious Cause for Low Back Pain. PMID- 26431148 TI - Treatment of Abdominal Segmental Hernia, Constipation, and Pain Following Herpes Zoster with Paravertebral Block. AB - Herpes zoster (HZ) most commonly occurs in elderly patients and involves sensory neurons resulting in pain and sensory changes. Clinically significant motor deficits and visceral neuropathies are thought to be relatively rare. A 72-year old man presented with abdominal segmental hernia, constipation, and pain following HZ in the left T9-10 dermatome. Sixteen days before presentation, he had developed a painful herpetic rash in the left upper abdominal quadrant. Approximately 10 days after the onset of the rash, constipation occurred and was managed with daily oral medication with bisacodyl 5 mg. In addition, 14 days after the onset of HZ, the patient noticed a protrusion of the left upper abdominal wall. Abdominal x-ray, ultrasound of the abdomen, and electrolyte analysis showed no abnormalities. General physical examination revealed a reducible bulge in his left upper quadrant and superficial abdominal reflexes were diminished in the affected region. Electromyographic testing revealed denervational changes limited to the left thoracic paraspinal muscles and supraumbilical muscles, corresponding to the affected dermatomes. He was prescribed with 500 mg of famciclovir 3 times a day for 7 days, and pregabalin 75 mg twice a day and acetaminophen 650 mg 3 times a day for 14 days. However, his pain was rated at an intensity of 5 on the numerical analogue scale from 0 (no pain) to 10 (worst pain imaginable). A paravertebral block was performed at T9-10 with a mixture of 0.5% lidocaine 3 mL and triamcinolone 40 mg. One day after the procedure, the abdominal pain disappeared. In addition, 5 days after the intervention, the abdominal protrusion and constipation were resolved. He currently remains symptom free at a 6 month follow-up. PMID- 26431149 TI - "Bursitis De Novo": A Clinical Case of Ischiofemoral Impingement. PMID- 26431150 TI - Landmark of Ultrasound-Guided Trigeminal Block: Lateral Pterygoid Muscle. PMID- 26431151 TI - Response. PMID- 26431152 TI - Pain Relief Following Shoulder Arthroscopy In Patients Receiving Preoperative Stellate Ganglion Block--Some More Facts! PMID- 26431153 TI - Description of Optimal Angle of Needle Insertion For L5 Transforaminal Epidural Injection Leads to Complications. PMID- 26431154 TI - Development of a Phase-Transfer-Catalyzed, [2,3]-Wittig Rearrangement. AB - An investigation into the use of phase-transfer catalysis for the [2,3] sigmatropic rearrangement of allyloxy carbonyl compounds is described. Initial studies focused on identifying viable substrate classes that would undergo selective [2,3]-rearrangement under phase-transfer catalysis. Under certain conditions, the [2,3]-sigmatropic rearrangement of allyloxy carbonyl compounds takes place in the presence of a phase-transfer agent, providing a rare example of a phase-transfer-catalyzed unimolecular reaction. In the course of this investigation, it was found that catalysis is dependent on several variables including base concentration, catalyst structure, and substrate lipophilicity. Preliminary testing of chiral, nonracemic phase-transfer catalysts has shown promising levels of enantioselectivity for future development. PMID- 26431155 TI - MicroRNAs in Serum and Bile of Patients with Primary Sclerosing Cholangitis and/or Cholangiocarcinoma. AB - BACKGROUND AND AIM: Patients with primary sclerosing cholangitis (PSC) are at high risk for the development of cholangiocarcinoma (CC). Analysis of micro ribonucleic acid (MiRNA) patterns is an evolving research field in biliary pathophysiology with potential value in diagnosis and therapy. Our aim was to evaluate miRNA patterns in serum and bile of patients with PSC and/or CC. METHODS: Serum and bile from consecutive patients with PSC (n = 40 (serum), n = 52 (bile)), CC (n = 31 (serum), n = 19 (bile)) and patients with CC complicating PSC (PSC/CC) (n = 12 (bile)) were analyzed in a cross-sectional study between 2009 and 2012. As additional control serum samples from healthy individuals were analyzed (n = 12). The miRNA levels in serum and bile were determined with global miRNA profiling and subsequent miRNA-specific polymerase chain reaction-mediated validation. RESULTS: Serum analysis revealed significant differences for miR-1281 (p = 0.001), miR-126 (p = 0.001), miR-26a (p = 0.001), miR-30b (p = 0.001) and miR-122 (p = 0.034) between patients with PSC and patients with CC. All validated miRNAs were significantly lower in healthy individuals. MiR-412 (p = 0.001), miR 640 (p = 0.001), miR-1537 (p = 0.003) and miR-3189 (p = 0.001) were significantly different between patients with PSC and PSC/CC in bile. CONCLUSIONS: Patients with PSC and/or CC have distinct miRNA profiles in serum and bile. Furthermore, miRNA concentrations are different in bile of patients with CC on top of PSC indicating the potential diagnostic value of these miRNAs. PMID- 26431157 TI - Insights into Structure-Activity Relationships of Bacterial RNA Polymerase Inhibiting Corallopyronin Derivatives. AB - The new compound precorallopyronin A is a stable precursor in the biosynthesis of the antibiotic corallopyronin A. This natural product was isolated from the producer strain Corallococcus coralloides B035. Together with various semisynthetically obtained corallopyronin A derivatives its antibacterial effects were evaluated. In combination with an X-ray crystallization model limitations of derivatization possibilities were revealed. The antibiotic potential of the novel precorallopyronin A is comparable to that of the structurally more complex corallopyronin A, which highlights that the additional chiral center is not essential for activity. PMID- 26431158 TI - Reduction in Renal Ischemia-Reperfusion Injury in Mice by a Phosphoinositide 3 Kinase p110gamma-Specific Inhibitor. AB - BACKGROUND: Although renal ischemia-reperfusion injury (IRI) can cause delayed graft function, a targeted therapy is not yet available. Because phosphoinositide 3-kinases (PI3K) p110gamma and p110delta play important roles in immune cell migration and function, we investigated the effects of PI3K p110gamma- and p110delta-specific inhibitors in a murine renal IRI model. METHODS: Renal function was assessed by serum creatine and hematoxylin-eosin staining. Immune cell migration was assessed by flow cytometry and an in vitro cell migration assay using Transwell plates. Gene expression analysis and a multiplex cytokine/chemokine assay were performed to find cytokines/chemokines whose expression was upregulated in renal IRI and affected by p110gamma-specific inhibitor. RESULTS: The PI3K p110gamma-specific inhibitor, but not p110delta specific inhibitor, significantly reduced serum creatine levels and acute tubular necrosis. These were accompanied by reduced infiltration of B cells and reduced expression of CXCL9, a CXCR3 ligand, suggesting that p110gamma plays an important role in B-cell migration toward injured kidneys. An in vitro cell migration assay revealed for the first time that B-cell migration to injured kidney cells and to CXCL9 requires p110gamma. CONCLUSIONS: p110gamma-specific inhibitor ameliorates renal IRI by reducing necrosis and immune cell migration. This inhibitor may have the potential to reduce renal graft failure caused by renal IRI. PMID- 26431156 TI - Interferon Lambda 4 Genotype Is Not Associated with Recurrence of Oral or Genital Herpes. AB - IFNL4-DeltaG/TT (rs368234815) genotype is associated with hepatitis C virus clearance and may play a role in other infections. IFN-lambda4 protein is generated only in individuals who carry the IFNL4-DeltaG allele. The IFNL4 rs12979860-T allele, which is in strong linkage disequilibrium with IFNL4-DeltaG, was recently reported to be associated with more frequent and severe oral herpes episodes. We investigated the association of IFNL4-DeltaG/TT with herpes simplex virus (HSV)-related outcomes among 2,192 African American and European American participants in the Women's Interagency HIV Study (WIHS). WIHS is a prospective cohort study of human immunodeficiency virus (HIV)-infected and at-risk women that began in 1994. This report includes follow-up through 2013. Available data included: HSV-1 and HSV-2 antibodies at study entry; bi-annually ascertained episodes of (self-reported) oral herpes, (self-reported) genital sores and (clinician-observed) genital ulcers; HSV-2 DNA in cervicovaginal lavage (CVL) specimens. IFNL4-DeltaG/TT genotyping was determined by TaqMan. We compared women with IFNL4-DeltaG/DeltaG or IFNL4-TT/DeltaG genotypes (i.e., IFNL4-DeltaG carriers) to those with the IFNL4-TT/TT genotype, adjusting for age, race and HIV status. For outcomes with repeated measurements, the adjusted odds ratio (aOR), 95% confidence interval [CI] and p-value were determined using a generalized estimating equations approach. Median participant age at enrollment was 36 years; 81% were African American, 74% were HIV-infected. Among 1,431 participants tested for antibodies, 72.8% were positive for HSV-1 and 79.0% were positive for HSV-2. We observed no association between IFNL4-DeltaG/TT genotype and any outcome: HSV 1 or HSV-2 antibody prevalence (p>0.1, all comparisons); oral herpes (aOR, 1.2; p = 0.35); genital sores (aOR, 1.0; p = 0.71); genital ulcers (aOR, 1.1; p = 0.53); detectable HSV-2 DNA in CVL (N = 322; aOR, 0.71; p = 0.49); HSV-2 DNA level (p = 0.68). In this large prospective study, IFNL4-DeltaG/TT genotype was not associated with HSV-related outcomes, including episodes of oral or genital herpes. PMID- 26431159 TI - Osteogenesis Imperfecta Associated with Dendriform Pulmonary Ossification. PMID- 26431160 TI - NTHL1 defines novel cancer syndrome. PMID- 26431161 TI - HSP60: a double edge sword in autoimmunity. PMID- 26431162 TI - Synergistic effects of p53 activation via MDM2 inhibition in combination with inhibition of Bcl-2 or Bcr-Abl in CD34+ proliferating and quiescent chronic myeloid leukemia blast crisis cells. AB - The Bcr-Abl tyrosine kinase regulates several Bcl-2 family proteins that confer resistance to apoptosis in chronic myeloid leukemia (CML) cells. Given p53's ability to modulate the expression and activity of Bcl-2 family members, we hypothesized that targeting Bcr-Abl, Bcl-2, and p53 concomitantly could have therapeutic benefits in blast crisis (BC) CML and in quiescent CML CD34+ cells that are insensitive to tyrosine kinase inhibitors (TKI). We examined the effects of the MDM2 inhibitor nutlin3a and its combination with the dual Bcl-2 and Bcl-xL inhibitor ABT-737, and the Bcr-Abl inhibitor nilotinib on BC CML patient samples. We found that in quiescent CD34+ progenitors, p53 expression is significantly lower, and MDM2 is higher, compared to their proliferating counterparts. Treatment with nutlin3a induced apoptosis in bulk and CD34+CD38- cells, and in both proliferating and quiescent CD34+ progenitor CML cells. Nutlin3a synergized with ABT-737 and nilotinib, in part by inducing pro-apoptotic, and suppressing anti-apoptotic, Bcl-2 proteins. Nilotinib inhibited the expression of Bcl-xL and Mcl-1 in BC CML cells. These results demonstrate that p53 activation by MDM2 blockade can sensitize BC CML cells, including quiescent CD34+ cells, to Bcl-2 inhibitor- and TKI-induced apoptosis. This novel strategy could be useful in the therapy of BC CML. PMID- 26431163 TI - Mdm2 inhibition confers protection of p53-proficient cells from the cytotoxic effects of Wee1 inhibitors. AB - Pharmacological inhibition of the cell cycle regulatory kinase Wee1 represents a promising strategy to eliminate cancer cells. Wee1 inhibitors cooperate with chemotherapeutics, e. g. nucleoside analogues, pushing malignant cells from S phase towards premature mitosis and death. However, considerable toxicities are observed in preclinical and clinical trials. A high proportion of tumor cells can be distinguished from all other cells of a patient's body by inactivating mutations in the tumor suppressor p53. Here we set out to develop an approach for the selective protection of p53-proficient cells against the cytotoxic effects of Wee1 inhibitors. We pretreated such cells with Nutlin-3a, a prototype inhibitor of the p53-antagonist Mdm2. The resulting transient cell cycle arrest effectively increased the survival of cells that were subsequently treated with combinations of the Wee1 inhibitor MK-1775 and/or the nucleoside analogue gemcitabine. In this constellation, Nutlin-3a reduced caspase activation and diminished the phosphorylation of Histone 2AX, an indicator of the DNA damage response. Both effects were strictly dependent on the presence of p53. Moreover, Nutlin pre treatment reduced the fraction of cells that were undergoing premature mitosis in response to Wee1 inhibition. We conclude that the pre-activation of p53 through Mdm2 antagonists serves as a viable option to selectively protect p53-proficient cells against the cytotoxic effects of Wee1 inhibitors, especially when combined with a nucleoside analogue. Thus, Mdm2 antagonists might prove useful to avoid unwanted side effects of Wee1 inhibitors. On the other hand, when a tumor contains wild type p53, care should be taken not to induce its activity before applying Wee1 inhibitors. PMID- 26431166 TI - Nanoscale Electrostructural Characterization of Compositionally Graded Al(x)Ga(1 x)N Heterostructures on GaN/Sapphire (0001) Substrate. AB - We report on AlxGa1-xN heterostructures resulting from the coherent growth of a positive then a negative gradient of the Al concentration on a [0001]-oriented GaN substrate. These polarization-doped p-n junction structures were characterized at the nanoscale by a combination of averaging as well as depth resolved experimental techniques including: cross-sectional transmission electron microscopy, high-resolution X-ray diffraction, Rutherford backscattering spectrometry, and scanning probe microscopy. We observed that a small miscut in the substrate orientation along with the accumulated strain during growth led to a change in the mosaic structure of the AlxGa1-xN film, resulting in the formation of macrosteps on the surface. Moreover, we found a lateral modulation of charge carriers on the surface which were directly correlated with these steps. Finally, using nanoscale probes of the charge density in cross sections of the samples, we have directly measured, semiquantitatively, both n- and p-type polarization doping resulting from the gradient concentration of the AlxGa1-xN layers. PMID- 26431165 TI - RAGE mediated intracellular Abeta uptake contributes to the breakdown of tight junction in retinal pigment epithelium. AB - Intracellular amyloid beta (Abeta) has been implicated in neuronal cell death in Alzheimer's disease (AD). Intracellular Abeta also contributes to tight junction breakdown of retinal pigment epithelium (RPE) in age-related macular degeneration (AMD). Although Abeta is predominantly secreted from neuronal cells, the mechanism of Abeta transport into RPE remains to be fully elucidated. In this study, we demonstrated that intracellular Abeta was found concomitantly with the breakdown of tight junction in RPE after subretinal injection of Abeta into the mouse eye. We also presented evidence that receptor for advanced glycation end products (RAGE) contributed to endocytosis of Abeta in RPE. siRNA-mediated knockdown of RAGE prevented intracellular Abeta accumulation as well as subsequent tight junction breakdown in RPE. In addition, we found that RAGE mediated p38 MAPK signaling contributed to endocytosis of Abeta. Blockade of RAGE/p38 MAPK signaling inhibited Abeta endocytosis, thereby preventing tight junction breakdown in RPE. These results implicate that intracellular Abeta contributes to the breakdown of tight junction in RPE via the RAGE/p38 MAPK mediated endocytosis. Thus, we suggest that RAGE could be a potential therapeutic target for intracellular Abeta induced outer BRB breakdown in AMD. PMID- 26431164 TI - The dark side of ZNF217, a key regulator of tumorigenesis with powerful biomarker value. AB - The recently described oncogene ZNF217 belongs to a chromosomal region that is frequently amplified in human cancers. Recent findings have revealed that alternative mechanisms such as epigenetic regulation also govern the expression of the encoded ZNF217 protein. Newly discovered molecular functions of ZNF217 indicate that it orchestrates complex intracellular circuits as a new key regulator of tumorigenesis. In this review, we focus on recent research on ZNF217 driven molecular functions in human cancers, revisiting major hallmarks of cancer and highlighting the downstream molecular targets and signaling pathways of ZNF217. We also discuss the exciting translational medicine investigating ZNF217 expression levels as a new powerful biomarker, and ZNF217 as a candidate target for future anti-cancer therapies. PMID- 26431172 TI - Correction: Advantages of Task-Specific Multi-Objective Optimisation in Evolutionary Robotics. PMID- 26431171 TI - Genetics, Synergists, and Age Affect Insecticide Sensitivity of the Honey Bee, Apis mellifera. AB - The number of honey bee colonies in the United States has declined to half of its peak level in the 1940s, and colonies lost over the winter have reached levels that are becoming economically unstable. While the causes of these losses are numerous and the interaction between them is very complex, the role of insecticides has garnered much attention. As a result, there is a need to better understand the risk of insecticides to bees, leading to more studies on both toxicity and exposure. While much research has been conducted on insecticides and bees, there have been very limited studies to elucidate the role that bee genotype and age has on the toxicity of these insecticides. The goal of this study was to determine if there are differences in insecticide sensitivity between honey bees of different genetic backgrounds (Carniolan, Italian, and Russian stocks) and assess if insecticide sensitivity varies with age. We found that Italian bees were the most sensitive of these stocks to insecticides, but variation was largely dependent on the class of insecticide tested. There were almost no differences in organophosphate bioassays between honey bee stocks (<1 fold), moderate differences in pyrethroid bioassays (1.5 to 3-fold), and dramatic differences in neonicotinoid bioassays (3.4 to 33.3-fold). Synergism bioassays with piperonyl butoxide, amitraz, and coumaphos showed increased phenothrin sensitivity in all stocks and also demonstrated further physiological differences between stocks. In addition, as bees aged, the sensitivity to phenothrin significantly decreased, but the sensitivity to naled significantly increased. These results demonstrate the variation arising from the genetic background and physiological transitions in honey bees as they age. This information can be used to determine risk assessment, as well as establishing baseline data for future comparisons to explain the variation in toxicity differences for honey bees reported in the literature. PMID- 26431173 TI - Anthropogenically-Mediated Density Dependence in a Declining Farmland Bird. AB - Land management intrinsically influences the distribution of animals and can consequently alter the potential for density-dependent processes to act within populations. For declining species, high densities of breeding territories are typically considered to represent productive populations. However, as density dependent effects of food limitation or predator pressure may occur (especially when species are dependent upon separate nesting and foraging habitats), high territory density may limit per-capita productivity. Here, we use a declining but widespread European farmland bird, the yellowhammer Emberiza citrinella L., as a model system to test whether higher territory densities result in lower fledging success, parental provisioning rates or nestling growth rates compared to lower densities. Organic landscapes held higher territory densities, but nests on organic farms fledged fewer nestlings, translating to a 5 times higher rate of population shrinkage on organic farms compared to conventional. In addition, when parental provisioning behaviour was not restricted by predation risk (i.e., at times of low corvid activity), nestling provisioning rates were higher at lower territory densities, resulting in a much greater increase in nestling mass in low density areas, suggesting that food limitation occurred at high densities. These findings in turn suggest an ecological trap, whereby preferred nesting habitat does not provide sufficient food for rearing nestlings at high population density, creating a population sink. Habitat management for farmland birds should focus not simply on creating a high nesting density, but also on ensuring heterogeneous habitats to provide food resources in close proximity to nesting birds, even if this occurs through potentially restricting overall nest density but increasing population-level breeding success. PMID- 26431174 TI - Prediction of Neurological Impairment in Cervical Spondylotic Myelopathy using a Combination of Diffusion MRI and Proton MR Spectroscopy. AB - PURPOSE: In the present study we investigated a combination of diffusion tensor imaging (DTI) and magnetic resonance spectroscopic (MRS) biomarkers in order to predict neurological impairment in patients with cervical spondylosis. METHODS: Twenty-seven patients with cervical spondylosis were evaluated. DTI and single voxel MRS were performed in the cervical cord. N-acetylaspartate (NAA) and choline (Cho) metabolite concentration ratios with respect to creatine were quantified, as well as the ratio of choline to NAA. The modified mJOA scale was used as a measure of neurologic deficit. Linear regression was performed between DTI and MRS parameters and mJOA scores. Significant predictors from linear regression were used in a multiple linear regression model in order to improve prediction of mJOA. Parameters that did not add value to model performance were removed, then an optimized multiparametric model was established to predict mJOA. RESULTS: Significant correlations were observed between the Torg-Pavlov ratio and FA (R2 = 0.2021, P = 0.019); DTI fiber tract density and FA, MD, Cho/NAA (R2 = 0.3412, P = 0.0014; R2 = 0.2112, P = 0.016; and R2 = 0.2352, P = 0.010 respectively); along with FA and Cho/NAA (R2 = 0.1695, P = 0.033). DTI fiber tract density, MD and FA at the site of compression, along with Cho/NAA at C2, were significantly correlated with mJOA score (R2 = 0.05939, P < 0.0001; R2 = 0.4739, P < 0.0001; R2 = 0.7034, P < 0.0001; R2 = 0.4649, P < 0.0001). A combination biomarker consisting of DTI fiber tract density, MD, and Cho/NAA showed the best prediction of mJOA (R2 = 0.8274, P<0.0001), with post-hoc tests suggesting fiber tract density, MD, and Cho/NAA were all significant contributors to predicting mJOA (P = 0.00053, P = 0.00085, and P = 0.0019, respectively). CONCLUSION: A linear combination of DTI and MRS measurements within the cervical spinal cord may be useful for accurately predicting neurological deficits in patients with cervical spondylosis. Additional studies may be necessary to validate these observations. PMID- 26431175 TI - Host-Associated Metagenomics: A Guide to Generating Infectious RNA Viromes. AB - BACKGROUND: Metagenomic analyses have been widely used in the last decade to describe viral communities in various environments or to identify the etiology of human, animal, and plant pathologies. Here, we present a simple and standardized protocol that allows for the purification and sequencing of RNA viromes from complex biological samples with an important reduction of host DNA and RNA contaminants, while preserving the infectivity of viral particles. PRINCIPAL FINDINGS: We evaluated different viral purification steps, random reverse transcriptions and sequence-independent amplifications of a pool of representative RNA viruses. Viruses remained infectious after the purification process. We then validated the protocol by sequencing the RNA virome of human body lice engorged in vitro with artificially contaminated human blood. The full genomes of the most abundant viruses absorbed by the lice during the blood meal were successfully sequenced. Interestingly, random amplifications differed in the genome coverage of segmented RNA viruses. Moreover, the majority of reads were taxonomically identified, and only 7-15% of all reads were classified as "unknown", depending on the random amplification method. CONCLUSION: The protocol reported here could easily be applied to generate RNA viral metagenomes from complex biological samples of different origins. Our protocol allows further virological characterizations of the described viral communities because it preserves the infectivity of viral particles and allows for the isolation of viruses. PMID- 26431177 TI - Fat Chance for Neural Stem Cells in Alzheimer's Disease. AB - Identifying factors driving neural stem cell dysfunction in age-related neurodegenerative diseases remains critical for the development of potential regenerative therapies. Now in Cell Stem Cell,Hamilton et al. (2015) find that lipid accumulation observed during early stages of Alzheimer's disease impairs neural stem cell activity in the adult brain. PMID- 26431176 TI - Cellular Expression of Cyclooxygenase, Aromatase, Adipokines, Inflammation and Cell Proliferation Markers in Breast Cancer Specimen. AB - Current evidences suggest that expression of Ki67, cyclooxygenase (COX), aromatase, adipokines, prostaglandins, free radicals, beta-catenin and alpha-SMA might be involved in breast cancer pathogenesis. The main objective of this study was to compare expression/localization of these potential compounds in breast cancer tissues with tissues collected adjacent to the tumor using immunohistochemistry and correlated with clinical pathology. The breast cancer specimens were collected from 30 women aged between 49 and 89 years who underwent breast surgery following cancer diagnosis. Expression levels of molecules by different stainings were graded as a score on a scale based upon staining intensity and proportion of positive cells/area or individually. AdipoR1, adiponectin, Ob-R, leptin, COX-1, COX-2, aromatase, PGF2alpha, F2-isoprostanes and alpha-SMA were localised on higher levels in the breast tissues adjacent to the tumor compared to tumor specimens when considering either score or staining area whereas COX-2 and AdipoR2 were found to be higher considering staining intensity and Ki67 on score level in the tumor tissue. There was no significant difference observed on beta-catenin either on score nor on staining area and intensity between tissues adjacent to the tumor and tumor tissues. A positive correlation was found between COX-1 and COX-2 in the tumor tissues. In conclusion, these suggest that Ki67, COXs, aromatase, prostaglandin, free radicals, adipokines, beta-catenin and alpha-SMA are involved in breast cancer. These further focus the need of examination of tissues adjacent to tumor, tumor itself and compare them with normal or benign breast tissues for a better understanding of breast cancer pathology and future evaluation of therapeutic benefit. PMID- 26431178 TI - Moving Toward the Ground State. AB - Transferring mouse ESCs to a media supplemented with Mek and Gsk3beta inhibitors (2i) provokes marked transcriptional and epigenetic changes, embodying a shift toward ground-state pluripotency. In this issue of Cell Stem Cell, Kolodziejczyk et al. (2015) examine population structures of ESCs while Galonska et al. (2015) unravel the mechanisms underlying regulatory network rewiring during 2i-mediated reprogramming. PMID- 26431179 TI - Two Fresh Streams to Fill the Liver's Hepatocyte Pool. AB - Differentiated hepatocytes are known for their capacity to regenerate the adult liver. Two papers discussed here show that distinct subpopulations of adult hepatocytes may be the crucial populations underpinning such regeneration. PMID- 26431180 TI - IGFBP3 and T1D: Systemic Factors in Colonic Stem Cell Function and Diabetic Enteropathy. AB - Patients with type 1 diabetes (T1D) often experience gastrointestinal enteropathy (DE) of unclear etiology. Now in Cell Stem Cell, D'Addio et al. (2015) utilize organoid culture models to study the roles of stem cells in DE and show that circulating IGF/IGFBP3 controls colonic stem cell function during homeostasis and in T1D patients. PMID- 26431181 TI - Adult Mammalian Neural Stem Cells and Neurogenesis: Five Decades Later. AB - Adult somatic stem cells in various organs maintain homeostatic tissue regeneration and enhance plasticity. Since its initial discovery five decades ago, investigations of adult neurogenesis and neural stem cells have led to an established and expanding field that has significantly influenced many facets of neuroscience, developmental biology, and regenerative medicine. Here we review recent progress and focus on questions related to adult mammalian neural stem cells that also apply to other somatic stem cells. We further discuss emerging topics that are guiding the field toward better understanding adult neural stem cells and ultimately applying these principles to improve human health. PMID- 26431184 TI - Hypertension-related mortality and morbidity. PMID- 26431182 TI - Single Cell RNA-Sequencing of Pluripotent States Unlocks Modular Transcriptional Variation. AB - Embryonic stem cell (ESC) culture conditions are important for maintaining long term self-renewal, and they influence cellular pluripotency state. Here, we report single cell RNA-sequencing of mESCs cultured in three different conditions: serum, 2i, and the alternative ground state a2i. We find that the cellular transcriptomes of cells grown in these conditions are distinct, with 2i being the most similar to blastocyst cells and including a subpopulation resembling the two-cell embryo state. Overall levels of intercellular gene expression heterogeneity are comparable across the three conditions. However, this masks variable expression of pluripotency genes in serum cells and homogeneous expression in 2i and a2i cells. Additionally, genes related to the cell cycle are more variably expressed in the 2i and a2i conditions. Mining of our dataset for correlations in gene expression allowed us to identify additional components of the pluripotency network, including Ptma and Zfp640, illustrating its value as a resource for future discovery. PMID- 26431185 TI - Reference values for local arterial stiffness. Part A: carotid artery. AB - OBJECTIVE: Non-invasive measures of common carotid artery properties, such as diameter and distension, and pulse pressure, have been widely used to determine carotid artery distensibility coefficient - a measure of carotid stiffness (stiffness ~1/distensibility coefficient). Carotid stiffness has been associated with incident cardiovascular disease (CVD) and may therefore be a useful intermediate marker for CVD. We aimed to establish age and sex-specific reference intervals of carotid stiffness. METHODS: We combined data on 22 708 individuals (age range 15-99 years, 54% men) from 24 research centres worldwide. Individuals without CVD and established cardiovascular risk factors constituted a healthy sub population (n = 3601, 48% men) and were used to establish sex-specific equations for percentiles of carotid distensibility coefficient across age. RESULTS: In the sub-population without CVD and treatment (n = 12 906, 52% men), carotid distensibility coefficient Z-scores based on these percentile equations were independently and negatively associated, in men and women, respectively, with diabetes {-0.28 [95% confidence interval (CI) -0.41; -0.15] and -0.27 (-0.43; 0.12)}, mean arterial pressure [-0.26 (-0.29; -0.24) and -0.32 (-0.35; -0.29)], total-to-high-density lipoprotein cholesterol ratio [-0.05 (-0.09; -0.02) and 0.05 (-0.11; 0.01)] and BMI [-0.06 (-0.09; -0.04) and -0.05 (-0.08; -0.02)], whereas these were positively associated with smoking [0.30 (0.24; 0.36) and 0.24 (0.18; 0.31)]. CONCLUSIONS: We estimated age and sex-specific percentiles of carotid stiffness in a healthy population and assessed the association between cardiovascular risk factors and carotid distensibility coefficient Z-scores, which enables comparison of carotid stiffness values between (patient) groups with different cardiovascular risk profiles, helping interpretation of such measures. PMID- 26431183 TI - Circulating IGF-I and IGFBP3 Levels Control Human Colonic Stem Cell Function and Are Disrupted in Diabetic Enteropathy. AB - The role of circulating factors in regulating colonic stem cells (CoSCs) and colonic epithelial homeostasis is unclear. Individuals with long-standing type 1 diabetes (T1D) frequently have intestinal symptoms, termed diabetic enteropathy (DE), though its etiology is unknown. Here, we report that T1D patients with DE exhibit abnormalities in their intestinal mucosa and CoSCs, which fail to generate in vitro mini-guts. Proteomic profiling of T1D+DE patient serum revealed altered levels of insulin-like growth factor 1 (IGF-I) and its binding protein 3 (IGFBP3). IGFBP3 prevented in vitro growth of patient-derived organoids via binding its receptor TMEM219, in an IGF-I-independent manner, and disrupted in vivo CoSC function in a preclinical DE model. Restoration of normoglycemia in patients with long-standing T1D via kidney-pancreas transplantation or in diabetic mice by treatment with an ecto-TMEM219 recombinant protein normalized circulating IGF-I/IGFBP3 levels and reestablished CoSC homeostasis. These findings demonstrate that peripheral IGF-I/IGFBP3 controls CoSCs and their dysfunction in DE. PMID- 26431186 TI - Reference values for local arterial stiffness. Part B: femoral artery. AB - OBJECTIVE: Carotid-femoral pulse wave velocity (PWV) is considered the gold standard measure of arterial stiffness, representing mainly aortic stiffness. As compared with the elastic carotid and aorta, the more muscular femoral artery may be differently associated with cardiovascular risk factors (CV-RFs), or, as shown in a recent study, provide additional predictive information beyond carotid femoral PWV. Still, clinical application is hampered by the absence of reference values. Therefore, our aim was to establish age and sex-specific reference values for femoral stiffness in healthy individuals and to investigate the associations with CV-RFs. METHODS: Femoral artery distensibility coefficient, the inverse of stiffness, was calculated as the ratio of relative diastolic-systolic distension (obtained from ultrasound echo-tracking) and pulse pressure among 5069 individuals (49.5% men, age range: 15-87 years). Individuals without cardiovascular disease (CVD), CV-RFs and medication use (n = 1489; 43% men) constituted a healthy subpopulation used to establish sex-specific equations for percentiles of femoral artery distensibility coefficient across age. RESULTS: In the total population, femoral artery distensibility coefficient Z-scores were independently associated with BMI, mean arterial pressure (MAP) and total to high density lipoprotein (HDL) cholesterol ratio. Standardized betas, in men and women, respectively, were -0.18 [95% confidence interval (95% CI) -0.23 to -0.13] and -0.19 (-0.23 to -0.14) for BMI; -0.13 (-0.18 to -0.08) and -0.05 (-0.10 to 0.01) for MAP; and -0.07 (-0.11 to -0.02) and -0.16 (-0.20 to -0.11) for total-to HDL cholesterol ratio. CONCLUSION: In young and middle-aged men and women, normal femoral artery stiffness does not change substantially with age up to the sixth decade. CV-RFs related to metabolic disease are associated with femoral artery stiffness. PMID- 26431187 TI - Carotid structure and flow relationship: a potential but unproven prognostic index. PMID- 26431188 TI - Blood pressure control in type 2 diabetes over time - what can we learn from different trajectories? PMID- 26431189 TI - Blood pressure and early neurological deterioration in acute ischemic stroke. PMID- 26431190 TI - Blood pressure control after a stroke: a continuing challenge! PMID- 26431191 TI - Cerebral small vessel disease: role of aortic stiffness and pulsatile hemodynamics. PMID- 26431193 TI - Association between serum phosphate and calcium, long-term blood pressure, and mortality in treated hypertensive adults. AB - OBJECTIVES: Abnormalities of bone mineral parameters are associated with cardiovascular morbidity and mortality in patients with chronic kidney disease and the general population. METHODS: We assessed the impact of baseline serum phosphate and calcium on longitudinal blood pressure (BP) control and survival in hypertensive adults. We studied 9260 hypertensive adults followed for 40 years (151 789 person-years). Changes in BP over initial 5-year follow-up were analysed using generalized estimating equations. Survival analyses were performed using Cox proportional hazards model. RESULTS: Serum phosphate levels were higher in hypertensive women (1.10 mmol/l +/- 0.20) than compared to men (1.02 mmol/l +/- 0.21). In treated hypertensive patients, higher baseline serum phosphate was significantly associated with poor longitudinal SBP reduction (one standard deviation increase in phosphate was associated with 0.22 and 0.59 mmHg higher SBP at 5 years in men and women, respectively). Higher serum phosphate was significantly associated with all-cause and cardiovascular mortality in men, whereas in men and women, serum calcium significantly predicted all-cause and noncardiovascular mortality. In hypertensive patients with chronic kidney disease, higher phosphate was significantly associated with poorer survival. CONCLUSION: In hypertensive patients, serum phosphate and calcium are significantly associated with reduced all-cause and cardiovascular survival and this appears not to be related to BP control. PMID- 26431192 TI - Incidence and predictors of hypertension in adults with HIV-initiating antiretroviral therapy in south-western Uganda. AB - OBJECTIVE: The successful scale-up of antiretroviral therapy (ART) in sub-Saharan Africa has led to increasing life expectancy, and thus increased risk of hypertension. We aimed to describe the incidence and predictors of hypertension in HIV patients receiving ART at a publicly funded clinic in rural Uganda. METHODS: We abstracted data from medical records of adult patients who initiated ART at an HIV clinic in south-western Uganda during 2010-2012. We defined hypertension as at least two consecutive clinical visits, with a SBP at least 140 mmHg and/or SBP of at least 90 mmHg, or prescription for an antihypertensive medication. We calculated the incidence of hypertension and fit multivariable Cox proportional-hazards models to identify predictors of hypertension. RESULTS: A total of 3389 patients initiated ART without a prior diagnosis of hypertension during the observation period. Over 3990 person-years of follow-up, 445 patients developed hypertension, for a crude incidence of 111.5/1000 (95% confidence interval 101.9-121.7) person-years. Rates were highest among men aged at least 40 years (158.8 per/1000 person-years) and lowest in women aged 30-39 years (80/1000 person-years). Lower CD4 cell count at ART initiation, as well as traditional risk factors including male sex, increasing age, and obesity, were independently associated with hypertension. CONCLUSION: We observed a high incidence of hypertension in HIV-infected persons on ART in rural Uganda, and increased risk with lower nadir CD4 cell counts. Our findings call for increased attention to screening of and treatment for hypertension, along with continued prioritization of early ART initiation. PMID- 26431194 TI - Increased arterial stiffness is an independent predictor of atrial fibrillation in hypertensive patients. AB - OBJECTIVE: Atrial fibrillation is the most common arrhythmia, and confers a high risk of stroke and heart failure. Hypertension and ageing are two important risk factors of incident atrial fibrillation and are both associated with increased arterial stiffness. The possible relationship between arterial stiffness and atrial fibrillation is insufficiently documented and is probably complex. We tested these relations in a cohort of hypertensive patients. METHODS: The population belongs to a registry which includes patients referred before administration of antihypertensive treatment and fulfilling the following criteria: office blood pressure (BP) above 140/90 mmHg, essential hypertension, no history of cardiovascular events, type 1 diabetes or atrial fibrillation, 24-h ambulatory measurement of BP coupled with the measurement of timing of Korotkoff sounds to assess arterial stiffness [indexed theoretical value of QKD interval for a SBP of 100 mmHg, at heart rate (HR) of 60 b.p.m., indexed for height and QRS duration (QKDh)]. An echocardiographic examination was carried out at baseline in the majority of patients. Atrial fibrillation-free survival was analysed with a Cox model including sex, diabetes, smoking, hypercholesterolaemia, QKDh, average 24-h pulse pressure and mean BP, mean 24-h HR, BMI and left atrial diameter (LAD), when available. RESULTS: We included 853 patients and recorded 67 new onsets of atrial fibrillation (mean follow-up = 102 +/- 62 months). Analysis found three variables significantly and independently linked to the occurrence of atrial fibrillation: age, QKDh and 24-h average HR. When LAD was introduced (n = 480, 35 incident atrial fibrillation), three variables were linked to incident atrial fibrillation: age, QKDh and LAD. CONCLUSION: Arterial stiffness is a strong predictor of future atrial fibrillation in hypertensive patients, independently of age, 24-h pulse pressure and LAD. PMID- 26431195 TI - Hypertension screening in children: is it necessary? PMID- 26431196 TI - Ligand-Based Virtual Screening in a Search for Novel Anti-HIV-1 Chemotypes. AB - In a search for new anti-HIV-1 chemotypes, we developed a multistep ligand-based virtual screening (VS) protocol combining machine learning (ML) methods with the privileged structures (PS) concept. In its learning step, the VS protocol was based on HIV integrase (IN) inhibitors fetched from the ChEMBL database. The performances of various ML methods and PS weighting scheme were evaluated and applied as VS filtering criteria. Finally, a database of 1.5 million commercially available compounds was virtually screened using a multistep ligand-based cascade, and 13 selected unique structures were tested by measuring the inhibition of HIV replication in infected cells. This approach resulted in the discovery of two novel chemotypes with moderate antiretroviral activity, that, together with their topological diversity, make them good candidates as lead structures for future optimization. PMID- 26431197 TI - Correction: Functional Role of the Disulfide Isomerase ERp57 in Axonal Regeneration. PMID- 26431198 TI - Bayesian Population Physiologically-Based Pharmacokinetic (PBPK) Approach for a Physiologically Realistic Characterization of Interindividual Variability in Clinically Relevant Populations. AB - Interindividual variability in anatomical and physiological properties results in significant differences in drug pharmacokinetics. The consideration of such pharmacokinetic variability supports optimal drug efficacy and safety for each single individual, e.g. by identification of individual-specific dosings. One clear objective in clinical drug development is therefore a thorough characterization of the physiological sources of interindividual variability. In this work, we present a Bayesian population physiologically-based pharmacokinetic (PBPK) approach for the mechanistically and physiologically realistic identification of interindividual variability. The consideration of a generic and highly detailed mechanistic PBPK model structure enables the integration of large amounts of prior physiological knowledge, which is then updated with new experimental data in a Bayesian framework. A covariate model integrates known relationships of physiological parameters to age, gender and body height. We further provide a framework for estimation of the a posteriori parameter dependency structure at the population level. The approach is demonstrated considering a cohort of healthy individuals and theophylline as an application example. The variability and co-variability of physiological parameters are specified within the population; respectively. Significant correlations are identified between population parameters and are applied for individual- and population-specific visual predictive checks of the pharmacokinetic behavior, which leads to improved results compared to present population approaches. In the future, the integration of a generic PBPK model into an hierarchical approach allows for extrapolations to other populations or drugs, while the Bayesian paradigm allows for an iterative application of the approach and thereby a continuous updating of physiological knowledge with new data. This will facilitate decision making e.g. from preclinical to clinical development or extrapolation of PK behavior from healthy to clinically significant populations. PMID- 26431199 TI - Understanding Host-Switching by Ecological Fitting. AB - Despite the fact that parasites are highly specialized with respect to their hosts, empirical evidence demonstrates that host switching rather than co speciation is the dominant factor influencing the diversification of host parasite associations. Ecological fitting in sloppy fitness space has been proposed as a mechanism allowing ecological specialists to host-switch readily. That proposal is tested herein using an individual-based model of host switching. The model considers a parasite species exposed to multiple host resources. Through time host range expansion can occur readily without the prior evolution of novel genetic capacities. It also produces non-linear variation in the size of the fitness space. The capacity for host colonization is strongly influenced by propagule pressure early in the process and by the size of the fitness space later. The simulations suggest that co-adaptation may be initiated by the temporary loss of less fit phenotypes. Further, parasites can persist for extended periods in sub-optimal hosts, and thus may colonize distantly related hosts by a "stepping-stone" process. PMID- 26431200 TI - Phospho-dependent Regulation of SAMHD1 Oligomerisation Couples Catalysis and Restriction. AB - SAMHD1 restricts HIV-1 infection of myeloid-lineage and resting CD4+ T-cells. Most likely this occurs through deoxynucleoside triphosphate triphosphohydrolase activity that reduces cellular dNTP to a level where reverse transcriptase cannot function, although alternative mechanisms have been proposed recently. Here, we present combined structural and virological data demonstrating that in addition to allosteric activation and triphosphohydrolase activity, restriction correlates with the capacity of SAMHD1 to form "long-lived" enzymatically competent tetramers. Tetramer disruption invariably abolishes restriction but has varied effects on in vitro triphosphohydrolase activity. SAMHD1 phosphorylation also ablates restriction and tetramer formation but without affecting triphosphohydrolase steady-state kinetics. However phospho-SAMHD1 is unable to catalyse dNTP turnover under conditions of nucleotide depletion. Based on our findings we propose a model for phosphorylation-dependent regulation of SAMHD1 activity where dephosphorylation switches housekeeping SAMHD1 found in cycling cells to a high-activity stable tetrameric form that depletes and maintains low levels of dNTPs in differentiated cells. PMID- 26431202 TI - Non-Steroid Anti-Inflammatory Drugs Are Better than Acetaminophen on Fever Control at Acute Stage of Fracture. AB - In addition to adequate surgical fixation and an aggressive rehabilitation program, pain relief is one of the most critical factors in the acute stage of fracture treatment. The most common analgesics are nonsteroid anti-inflammatory drugs and Acetaminophen, both of which relieve pain and reduce body temperature. In clinical experiences, they exhibit effective pain control; however, their influence on body temperature remains controversial. This study is aimed at determining the effects of analgesics at the acute stage of traumatic fracture by performing a clinical retrospective study of patients with fractures and a fracture animal model. The retrospective study revealed that, in the acetaminophen group, the mean value of postmedication body temperature (BT) was significantly higher than that of the premedication BT. The change in BT was highly related with the medication rather than other risk factors. Forty eight 12 week-old male Wistar rats were divided into 6 groups: a control group, fracture group, fracture-Acetaminophen group, Acetaminophen group, fracture-Arcoxia group, and Arcoxia group. Fracture rats were prepared by breaking their unilateral tibia and fibula. Their inflammation conditions were evaluated by measuring their serum cytokine level and their physiological status was evaluated by estimating their central temperature, heart rate, and mean blood pressure. The hepatic adverse effects were assessed by measuring the serum levels of aspartate aminotransferase (sGOT) and alanine aminotransferase (sGPT). The central temperature in the fracture-Acetaminophen group exceeded that in the groups fed normal saline water or Arcoxia. Accumulated hepatic injury was presented as steadily ascending curves of sGOT and sGPT. Inflammation-related cytokine levels were not higher in the Acetaminophen fracture group and were significantly lower in the fracture-Arcoxia group. Fever appeared to be aggravated by acetaminophen and more related to the elevation of hepatic enzymes than to the change in the inflammation-related cytokines. We suggest that acetaminophen may aggravate fever at the acute stage of fracture. This response is highly related to the accumulated and exacerbated side effects of hepatitis that are caused by the medication and trauma. PMID- 26431203 TI - Re-Classification of Drosophila melanogaster Trichoid and Intermediate Sensilla Using Fluorescence-Guided Single Sensillum Recording. AB - Drosophila olfactory receptor neurons are found within specialized sensory hairs on antenna and maxillary palps. The linking of odorant-induced responses to olfactory neuron activities is often accomplished via Single Sensillum Recordings (SSR), in which an electrode inserted into a single sensory hair records the neuronal activities of all the neurons housed in that sensillum. The identification of the recorded sensillum requires matching the neuronal responses with known odor-response profiles. To record from specific sensilla, or to systematically screen all sensillar types, requires repetitive and semi-random SSR experiments. Here, we validate an approach in which the GAL4/UAS binary expression system is used for targeting specific sensilla for recordings. We take advantage of available OrX-Gal4 lines, in combination with recently generated strong membrane targeted GFP reporters, to guide electrophysiological recordings to GFP-labeled sensilla. We validate a full set of reagents that can be used to rapidly screen the odor-response profiles of all basiconic, intermediate, and trichoid sensilla. Fluorescence-guided SSR further revealed that two antennal trichoid sensilla types should be re-classified as intermediate sensilla. This approach provides a simple and practical addition to a proven method for investigating olfactory neurons, and can be extended by the addition of UAS-geneX effectors for gain-of-function or loss-of-function studies. PMID- 26431201 TI - Exploration of Novel Inhibitors for Class I Histone Deacetylase Isoforms by QSAR Modeling and Molecular Dynamics Simulation Assays. AB - Histone deacetylases (HDAC) are metal-dependent enzymes and considered as important targets for cell functioning. Particularly, higher expression of class I HDACs is common in the onset of multiple malignancies which results in deregulation of many target genes involved in cell growth, differentiation and survival. Although substantial attempts have been made to control the irregular functioning of HDACs by employing various inhibitors with high sensitivity towards transformed cells, limited success has been achieved in epigenetic cancer therapy. Here in this study, we used ligand-based pharmacophore and 2-dimensional quantitative structure activity relationship (QSAR) modeling approaches for targeting class I HDAC isoforms. Pharmacophore models were generated by taking into account the known IC50 values and experimental energy scores with extensive validations. The QSAR model having an external R2 value of 0.93 was employed for virtual screening of compound libraries. 10 potential lead compounds (C1-C10) were short-listed having strong binding affinities for HDACs, out of which 2 compounds (C8 and C9) were able to interact with all members of class I HDACs. The potential binding modes of HDAC2 and HDAC8 to C8 were explored through molecular dynamics simulations. Overall, bioactivity and ligand efficiency (binding energy/non-hydrogen atoms) profiles suggested that proposed hits may be more effective inhibitors for cancer therapy. PMID- 26431204 TI - Increased Duration of Heating Boosts Local Drug Deposition during Radiofrequency Ablation in Combination with Thermally Sensitive Liposomes (ThermoDox) in a Porcine Model. AB - INTRODUCTION: Radiofrequency ablation (RFA) is used for the local treatment of liver cancer. RFA is effective for small (<3 cm) tumors, but for tumors > 3 cm, there is a tendency to leave viable tumor cells in the margins or clefts of overlapping ablation zones. This increases the possibility of incomplete ablation or local recurrence. Lyso-Thermosensitive Liposomal Doxorubicin (LTLD), is a thermally sensitive liposomal doxorubicin formulation for intravenous administration, that rapidly releases its drug content when exposed to temperatures >40 degrees C. When used with RFA, LTLD releases its doxorubicin in the vasculature around the zone of ablation-induced tumor cell necrosis, killing micrometastases in the ablation margin. This may reduce recurrence and be more effective than thermal ablation alone. PURPOSE: The purpose of this study was to optimize the RFA procedure used in combination with LTLD to maximize the local deposition of doxorubicin in a swine liver model. Pigs were anaesthetized and the liver was surgically exposed. Each pig received a single, 50 mg/m2 dose of the clinical LTLD formulation (ThermoDox(r)). Subsequently, ablations were performed with either 1, 3 or 6 sequential, overlapping needle insertions in the left medial lobe with total ablation time of 15, 45 or 90 minutes respectively. Two different RFA generators and probes were evaluated. After the final ablation, the ablation zone (plus 3 cm margin) was dissected out and examined for doxorubicin concentration by LC/MS and fluorescence. CONCLUSION: The mean Cmax of plasma total doxorubicin was 26.5 MUg/ml at the end of the infusion. Overall, increased heat time from 15 to 45 to 90 minutes shows an increase in both the amount of doxorubicin deposited (up to ~100 MUg/g) and the width of the ablation target margin to which doxorubicin is delivered as determined by tissue homogenization and LC/MS detection of doxorubicin and by fluorescent imaging of tissues. PMID- 26431205 TI - Global Metabolomic Profiling of Mice Brains following Experimental Infection with the Cyst-Forming Toxoplasma gondii. AB - The interplay between the Apicomplexan parasite Toxoplasma gondii and its host has been largely studied. However, molecular changes at the metabolic level in the host central nervous system and pathogenesis-associated metabolites during brain infection are largely unexplored. We used a global metabolomics strategy to identify differentially regulated metabolites and affected metabolic pathways in BALB/c mice during infection with T. gondii Pru strain at 7, 14 and 21 days post infection (DPI). The non-targeted Liquid Chromatography-Mass Spectrometry (LC-MS) metabolomics analysis detected approximately 2,755 retention time-exact mass pairs, of which more than 60 had significantly differential profiles at different stages of infection. These include amino acids, organic acids, carbohydrates, fatty acids, and vitamins. The biological significance of these metabolites is discussed. Principal Component Analysis and Orthogonal Partial Least Square Discriminant Analysis showed the metabolites' profile to change over time with the most significant changes occurring at 14 DPI. Correlated metabolic pathway imbalances were observed in carbohydrate metabolism, lipid metabolism, energetic metabolism and fatty acid oxidation. Eight metabolites correlated with the physical recovery from infection-caused illness were identified. These findings indicate that global metabolomics adopted in this study is a sensitive approach for detecting metabolic alterations in T. gondii-infected mice and generated a comparative metabolic profile of brain tissue distinguishing infected from non infected host. PMID- 26431206 TI - Assessment of Alveolar Bone Status in Middle Aged Chinese (40-59 Years) with Chronic Periodontitis--Using CBCT. AB - OBJECTIVE: This study used con-beam computed tomography (CBCT) to investigate the prevalence and severity of alveolar bone loss in middle-aged (40-59 years) Chinese with chronic periodontitis. MATERIALS AND METHODS: The study group comprised 145 dentate individuals aged 40 to 59 years residing in China who suffered from chronic periodontitis. CBCT and the application of NNT software were used to examine the level and location of alveolar bone loss. RESULTS: The study revealed that 40-59 year old patients with chronic periodontitis had severe bone loss. At 5,286 sites (34.7%), alveolar bone loss was mild; severe alveolar bone loss was found at 5,978 sites (39.2%). A comparison of bone loss in different jaws revealed that the area with the highest degree of bone loss was on the lingual side of the maxillary molar (56.3 +/- 7.2%), and that the area with the lowest degree was primarily on the lingual side of the mandibular canine (27.5 +/- 6.3%). There was a lower degree of alveolar bone loss in males than females. Differences were observed when comparing the incidence of bone loss between males and females (P < 0.05). Menopause in females and smoking in both genders may affect the level of bone loss. Male smokers experienced a greater degree of bone loss (41.67 +/- 5.76%) than male non-smokers (32.95 +/- 4.31%). A 42.23 +/- 6.34% bone loss was found in menopausal females versus 31.35 +/- 3.62% in non-menopausal females. CONCLUSIONS: The study revealed that different sites and teeth exhibited a diverse degree of bone loss. In middle-aged patients with chronic periodontitis, the highest degrees of bone loss in the incisors, premolars, and molars were on the lingual side, mesial side and lingual side, respectively. Menopause in females and smoking may affect the level of bone loss. PMID- 26431208 TI - Retinal Detachment Due to Retinal Dialysis: Surgical Outcome After Scleral Buckling. AB - PURPOSE: The aim of this study was to determine the efficacy and safety of scleral buckling surgery in retinal detachment due to retinal dialysis. DESIGN: This study was a prospective, interventional case series. METHODS: A total of 48 eyes of 48 consecutive patients were included after obtaining informed written consent. Besides taking a thorough history, all eyes were examined by a retinal surgeon. The macula status, site, and extent of retinal dialysis and rhegmatogenous retinal detachment (RRD) were particularly noted. Proliferative vitreoretinopathy grading was done. Buckling was performed by a single surgeon. At every follow-up, visual acuity, intraocular pressure, retina status, and buckle position were noted. Any complication found was recorded. Follow-up was done for at least 6 months. SPSS version 16 was used for data analysis. RESULTS: We included 48 cases of RRD due to retinal dialysis. The mean +/- SD age of the patients was 26.85 +/- 15.1 years. The macula was detached in 85.4% of the cases, and proliferative vitreoretinopathy grade C was found in 25% of the cases. A surgical reattachment rate of 95.8% was attained after a single primary buckling procedure. Final Snellen best-corrected visual acuity of 6/18 or better was attained in 12.5% of the cases. However, 62.5% of the cases had best-corrected visual acuity in the range of 6/24 to 6/60. Subretinal hemorrhage occurred in 8.3% of cases intraoperatively after subretinal fluid drainage. CONCLUSIONS: We conclude that scleral buckling has a definite role in the management of RRD due to retinal dialysis. PMID- 26431207 TI - CUL4-DDB1-CDT2 E3 Ligase Regulates the Molecular Clock Activity by Promoting Ubiquitination-Dependent Degradation of the Mammalian CRY1. AB - The CUL4-DDB1 E3 ligase complex serves as a critical regulator in various cellular processes, including cell proliferation, DNA damage repair, and cell cycle progression. However, whether this E3 ligase complex regulates clock protein turnover and the molecular clock activity in mammalian cells is unknown. Here we show that CUL4-DDB1-CDT2 E3 ligase ubiquitinates CRY1 and promotes its degradation both in vitro and in vivo. Depletion of the major components of this E3 ligase complex, including Ddb1, Cdt2, and Cdt2-cofactor Pcna, leads to CRY1 stabilization in cultured cells or in the mouse liver. CUL4A-DDB1-CDT2 E3 ligase targets lysine 585 within the C-terminal region of CRY1 protein, shown by the CRY1 585KA mutant's resistance to ubiquitination and degradation mediated by the CUL4A-DDB1 complex. Surprisingly, both depletion of Ddb1 and over-expression of Cry1-585KA mutant enhance the oscillatory amplitude of the Bmal1 promoter activity without altering its period length, suggesting that CUL4A-DDB1-CDT2 E3 targets CRY1 for degradation and reduces the circadian amplitude. All together, we uncovered a novel biological role for CUL4A-DDB1-CDT2 E3 ligase that regulates molecular circadian behaviors via promoting ubiquitination-dependent degradation of CRY1. PMID- 26431209 TI - Visual Outcomes of Congenital Cataract Surgery in a Tertiary Public Hospital in Bangladesh. AB - PURPOSE: The purpose of this study was to look at the visual outcomes of bilateral congenital cataract surgery. DESIGN: A prospective study was conducted. METHODS: A total of 102 eyes of 51 children aged between 2 and 12 months undergoing bilateral congenital cataract surgery from January 2008 to December 2008 with a 3-year follow-up were included in this study. The study was performed at a tertiary public hospital. Data were analyzed using SPSS version 17. Chi square (chi2) tests were performed to identify the association between visual outcome and age at surgery. P values less than 0.05 were considered statistically significant. RESULTS: Among the 102 eyes, 32 (31.4%) eyes were operated on when the subjects were aged between 2 and 3 months, and 70 (68.6%) eyes were operated on at the age of 3 to 12 months. The subjects were followed up for 3 years after surgery. Postoperative best-corrected visual acuity was measured. Visual outcomes were significantly poor in children aged 3 months or older (P < 0.001) as compared with children aged between 2 and 3 months. CONCLUSIONS: Early detection and treatment with long-term postoperative rehabilitation is vital to improve visual outcomes of children with congenital cataract. PMID- 26431210 TI - Investigation on Abnormal Iron Metabolism and Related Inflammation in Parkinson Disease Patients with Probable RBD. AB - OBJECTIVE: To investigate potential mechanisms involving abnormal iron metabolism and related inflammation in Parkinson disease (PD) patients with probable rapid eye movement sleep behavior disorder (PRBD). METHODS: Total 210 PD patients and 31 controls were consecutively recruited. PD patients were evaluated by RBD Screening Questionnaire (RBDSQ) and classified into PRBD and probable no RBD (NPRBD) groups. Demographics information were recorded and clinical symptoms were evaluated by series of rating scales. Levels of iron and related proteins and inflammatory factors in cerebrospinal fluid (CSF) and serum were detected. Comparisons among control, NPRBD and PRBD groups and correlation analyses between RBDSQ score and levels of above factors were performed. RESULTS: (1) The frequency of PRBD in PD patients is 31.90%. (2) PRBD group has longer disease duration, more advanced disease stage, severer motor symptoms and more non-motor symptoms than NPRBD group. (3) In CSF, levels of iron, transferrin, NO and IL 1beta in PRBD group are prominently increased. RBDSQ score is positively correlated with the levels of iron, transferrin, NO and IL-1beta in PD group. Iron level is positively correlated with the levels of NO and IL-1beta in PD group. (4) In serum, transferrin level is prominently decreased in PRBD group. PGE2 level in PRBD group is drastically enhanced. RBDSQ score exhibits a positive correlation with PGE2 level in PD group. CONCLUSIONS: PRBD is common in PD patients. PRBD group has severer motor symptoms and more non-motor symptoms. Excessive iron in brain resulted from abnormal iron metabolism in central and peripheral systems is correlated with PRBD through neuroinflammation. PMID- 26431211 TI - P53 Contributes to Cisplatin Induced Renal Oxidative Damage via Regulating P66shc and MnSOD. AB - BACKGROUND/AIMS: Cisplatin is widely used to treat malignancies. However, its major limitation is the development of dose-dependent nephrotoxicity. The precise mechanisms of cisplatin-induced kidney damage remain unclear. Previous study demonstrated the central role of mitochondrial ROS (mtROS) in the pathogenesis of cisplatin nephrotoxicity. The purpose of this study was to explore the mechanism of mtROS regulation in cisplatin nephrotoxicity. METHODS: p53, MnSOD and p66shc were detected at mRNA and protein levels by qPCR and western blot in HK2 cells. mtROS levels were determined by DCFDA and MitoSOX staining. Cell viability and cell apoptosis were accessed by CCK-8 assay, TUNEL assay and flow cytometry, respectivesly. siRNAs were used to knock down p53 and p66shc expression and subsequent changes were observed. In vivo assays using a mouse model of cisplatin induced acute kidney injury were used to validate the in vitro results. RESULTS: In HK2 cells, cisplatin exposure decreased the MnSOD and increased the expression of p53 and p66shc. MnTBAP, a MnSOD mimic, blocked cisplatin-induced the generation of mtROS and cell injury. P66shc and p53 siRNAs rendered renal cells resistant to cisplatin-induced mtROS production and cell death. Furthermore, knockdown of p53 restored MnSOD and inhibiting p66shc. Consistent with these results, we revealed that p53 inhibitor reduced cisplatin-induced oxidative stress and apoptosis by regulating MnSOD and p66shc in the kidney of cisplatin treated mice. CONCLUSION: Our study identifies activation of p53 signalling as a potential strategy for reducing the nephrotoxicity associated with cisplatin treatments and, as a result, broadens the therapeutic window of this chemotherapeutic agent. PMID- 26431213 TI - Enhancing Asthma Self-Management in Rural School-Aged Children: A Randomized Controlled Trial. AB - PURPOSE: To test the effects of 2 modes of delivering an asthma educational intervention on health outcomes and asthma self-management in school-aged children who live in rural areas. METHODS: Longitudinal design with data collected 4 times over 12 months. The target sample was composed of children in grades 2-5 who had a provider diagnosis of asthma. Elementary schools were stratified into high or low socioeconomic status based on student enrollment in the free or reduced-cost lunch program. Schools were then randomly assigned to 1 of 3 treatment arms: in-school asthma class, asthma day camp, or the attention control group. FINDINGS: Sample retention was good (87.7%) and equally distributed by study arm. Improvements in emergency department visits and office visits were related to attending either the asthma class or asthma day camp. Asthma severity significantly decreased in both asthma treatment groups. Other factors such as hospitalizations, parent asthma management, and child asthma management improved for all groups. CONCLUSIONS: Both asthma class and asthma day camp yielded significant reductions in asthma severity. There were reductions in the emergency department and office visits for the 2 asthma arms, and hospitalizations declined significantly for all groups. Asthma self-management also improved in all groups, while it was somewhat higher in the asthma arms. This may be due to the attention being drawn to asthma management by study participation and the action of completing questionnaires about asthma management, asthma symptoms, and health outcomes. PMID- 26431212 TI - Molecular switches under TGFbeta signalling during progression from cardiac hypertrophy to heart failure. AB - Cardiac hypertrophy is a mechanism to compensate for increased cardiac work load, that is, after myocardial infarction or upon pressure overload. However, in the long run cardiac hypertrophy is a prevailing risk factor for the development of heart failure. During pathological remodelling processes leading to heart failure, decompensated hypertrophy, death of cardiomyocytes by apoptosis or necroptosis and fibrosis as well as a progressive dysfunction of cardiomyocytes are apparent. Interestingly, the induction of hypertrophy, cell death or fibrosis is mediated by similar signalling pathways. Therefore, tiny changes in the signalling cascade are able to switch physiological cardiac remodelling to the development of heart failure. In the present review, we will describe examples of these molecular switches that change compensated hypertrophy to the development of heart failure and will focus on the importance of the signalling cascades of the TGFbeta superfamily in this process. In this context, potential therapeutic targets for pharmacological interventions that could attenuate the progression of heart failure will be discussed. PMID- 26431214 TI - Prophylactic corticosteroids in pulmonary oil embolism after hysterosalpingography. PMID- 26431215 TI - Bioimaging of microRNA34c in a single sperm using a molecular beacon. AB - The VisuFect-conjugated molecular beacon was developed for non-invasive visualization of microRNA34c in a living single mouse sperm. PMID- 26431216 TI - The Gateway Hypothesis, Common Liability to Addictions or the Route of Administration Model A Modelling Process Linking the Three Theories. AB - BACKGROUND: The aim of this study was to describe the transitions between tobacco (T), cannabis (C) and other illicit drugs (OIDs) initiations, to simultaneously explore several substance use theories: gateway theory (GT), common liability model (CLM) and route of administration model (RAM). METHODS: Data from 2 French nationwide surveys conducted in 2005 and 2010 were used (16,421 subjects aged 18 34). Using reported ages at initiations, we reconstituted a retrospective cohort describing all initiation sequences between T, C and OID. Transition probabilities between the substances were computed using a Markov multi-state model that also tested the effect of 2 latent variables (item response theory scores reflecting propensity for early onset and further substance use) on all transitions. RESULTS: T initiation was associated with increased likelihood of subsequent C initiation, but the reverse relationship was also observed. While the most likely initiation sequence among subjects who initiated the 3 groups of substances was the 'gateway' sequence T x2192; C x2192; OID, this pattern was not associated with substance use propensity more than alternative sequences. Early use propensity was associated with the 'gateway' sequence but also with some alternative ones beginning with T, C or OID. CONCLUSION: If the gateway sequence appears as the most likely pattern, in line with GT, the effects of early onset and substance use propensities were also observed for some alternative sequences, which is more in line with CLM. RAM could explain reciprocal interactions observed between T and C. This suggests shared influences of individual (personality traits) and environmental (substance availability, peer influence) characteristics. PMID- 26431217 TI - Responses to Intensity-Shifted Auditory Feedback During Running Speech. AB - PURPOSE: Responses to intensity perturbation during running speech were measured to understand whether prosodic features are controlled in an independent or integrated manner. METHOD: Nineteen English-speaking healthy adults (age range = 21-41 years) produced 480 sentences in which emphatic stress was placed on either the 1st or 2nd word. One participant group received an upward intensity perturbation during stressed word production, and the other group received a downward intensity perturbation. Compensations for perturbation were evaluated by comparing differences in participants' stressed and unstressed peak fundamental frequency (F0), peak intensity, and word duration during perturbed versus baseline trials. RESULTS: Significant increases in stressed-unstressed peak intensities were observed during the ramp and perturbation phases of the experiment in the downward group only. Compensations for F0 and duration did not reach significance for either group. CONCLUSIONS: Consistent with previous work, speakers appear sensitive to auditory perturbations that affect a desired linguistic goal. In contrast to previous work on F0 perturbation that supported an integrated-channel model of prosodic control, the current work only found evidence for intensity-specific compensation. This discrepancy may suggest different F0 and intensity control mechanisms, threshold-dependent prosodic modulation, or a combined control scheme. PMID- 26431219 TI - Progress and Challenges from the Seventh Summit on Breastfeeding. PMID- 26431218 TI - Chronic Kidney Disease in Non-Diabetic Older Adults: Associated Roles of the Metabolic Syndrome, Inflammation, and Insulin Resistance. AB - BACKGROUND: The aims of the study were to examine the association between CKD and the metabolic syndrome (MetS) and its components in older adults. We also explored two possible pathways linking the metabolic syndrome with CKD: inflammation as measured by high sensitivity C-Reactive Protein (hsCRP) and insulin resistance as measured by HOMA-IR. METHODS: Community-dwelling non diabetic 70+ adults from the Einstein Aging Study participated in the study. We defined CKD as eGFR below 60mL/min/1.73m2. MetS was defined according to recent guidelines from the National Cholesterol Education Program. Binary logistic regressions were used to assess the association between the metabolic syndrome, its components and CKD with adjustments for demographics, HOMA-IR and hsCRP. RESULTS: Of 616 participants (mean age = 79.3 years, 65.5% female), 25% had MetS and 26.5% had CKD. Participants with CKD had a significantly higher prevalence of the MetS than individuals without CKD (34.4% vs. 24.3%). Binary logistic regression models showed that CKD was associated with MetS (OR = 1.72, 95%CI = 1.13-2.61). The association was unaltered by adjustment for hsCRP but altered by adjustment for HOMA-IR. As the number of MetS components increased the relative odds of CKD also increased. None of the individual components was independently associated with CKD. CONCLUSION: MetS is associated with CKD in non-diabetic older adults. Results showed that as the number of MetS components increased so did the odds for CKD. HOMA-IR seems to be in the casual pathway linking MetS to CKD. PMID- 26431220 TI - The Power of Nutrition and the Power of Breastfeeding. PMID- 26431221 TI - Breastfeeding Research Supported by the NICHD. PMID- 26431222 TI - Making the Healthy Choice the Easy Choice. PMID- 26431231 TI - More Gun Control Ideas. PMID- 26431225 TI - Endocannabinoid Signaling in the Stress Response of Male and Female Songbirds. AB - Endocannabinoid (eCB) signaling plays an important role in the stress response pathways of the mammalian brain, yet its role in the avian stress response has not been described. Understanding eCB signaling in avian species (such as the European starling, Sturnus vulgaris) allows a model system that exhibits natural attenuation of hypothalamic-pituitary-adrenal (HPA) responsiveness to stressors. Specifically, seasonally breeding birds exhibit the highest HPA activity during the breeding season and subsequently exhibit a robust HPA down-regulation during molt. Because eCB signaling in mammals has an overall inhibitory effect on HPA activity, we expected shifts in eCB signaling to regulate the seasonal HPA down regulation during molt. However, our data did not support a role for eCB signaling in the molt-related suppression of HPA activity. For example, injection of the cannabinoid receptor (CB1) antagonist, AM251, did not potentiate molt suppressed HPA activity. Instead, our data suggest eCB regulation of HPA plasticity as birds transition from breeding to molt. In support of this hypothesis, birds in the late breeding season demonstrated a more dynamic response at the level of avian amygdala eCB content in response to acute stress. The response and directionality of this effect match that seen in mammals. Overall, our data suggest that eCB signaling may allow for a dynamic range in HPA responsiveness (eg, breeding), but the signaling pathway's role may be limited when the HPA response is restrained (eg, molt). This first characterization of eCB signaling in the avian stress response also emphasizes that although the system functions similarly to other species, its exact role may be species specific. PMID- 26431226 TI - Development of an Enhanced Sensitivity Bead-Based Immunoassay for Real-Time In Vivo Detection of Pancreatic beta-Cell Death. AB - There is a clinical need for plasma tests to detect and quantify the in vivo destruction of pancreatic beta-cells in type 1 diabetes. We previously developed a time-resolved fluorescence immunoassay (TRFIA) to glutamate decarboxylase 65 kDa (GAD65) (GAD65-TRFIA) that was able to detect the synchronous necrotic destruction of transplanted beta-cells in the hours after their infusion in the liver. This GAD65-TRFIA, however, lacked sensitivity to detect continued beta cell rejection beyond this acute phase. The aim of present study was to gain at least an order of magnitude in analytical sensitivity by switching to Becton Dickinson cytometric bead array (CBA) (GAD65-CBA) enhanced sensitivity format, using the same couple of monoclonal antibodies. We compared the performances of GAD65-CBA and GAD65-TRFIA using Clinical and Laboratory Standards Institute protocols for linearity, imprecision, specificity, limit of detection, and functional sensitivity. We conducted a method comparison and assessed the biologic potential on samples from human recipients of islet grafts. The GAD65 CBA showed acceptable linearity and imprecision. Switching from TRFIA to CBA lowered functional sensitivity by a factor 35 and lowered limit of detection by a factor 11 with minimal need for method optimization. The enhanced sensitivity greatly expands the application domain of our biomarker and allowed for the first time to detect ongoing beta-cell destruction up to at least 1 day after islet transplantation. We conclude that the GAD65-CBA is suitable for biological and clinical assessment of the real-time destruction of beta-cells in intraportal transplantation. PMID- 26431232 TI - Postpartum Depression Screening. PMID- 26431233 TI - A 13-Year-Old Boy with Pancytopenia and a Sacrococcygeal Abscess. PMID- 26431234 TI - How Much is Too Much? Getting Children Involved, but Not Too Involved. AB - In the pediatric office, the summer months are filled with well-child visits and sports physicals. It is during these visits that it is important to evaluate our patients as a whole, remembering to discuss both physical and emotional concerns. It is also important to discuss the upcoming school year so concerns by both parents and children can be addressed. Extracurricular activities play a vital role in developing social skills, building a sense of community, and allowing children to discover life-long activities they truly enjoy. However, it is important to remind parents that as a family they must find a balance between a busy extracurricular activity schedule and time for rest, relaxation, and family. PMID- 26431235 TI - Chest Pain in a 17-Year-Old Girl with Chickenpox. PMID- 26431236 TI - Two Young Children with Rashes on Their Trunk and Extremities. PMID- 26431238 TI - Adolescent Girls and Abortion. AB - Abortion is an extremely common procedure in the United States, with approximately 2% of women having an abortion before age 19 years. Although most pediatricians do not provide abortions, many will care for a young woman who is either considering an abortion or has already had one; therefore, the pediatrician should be able to provide accurate and appropriate counseling about this option. To provide the best care for adolescent patients considering abortion, pediatricians must be knowledgeable of aspects of abortion that are universal to all women and have an understanding of considerations specific to the adolescent patient. The purpose of this article is to (1) review recent statistics about teenagers and abortion, (2) explain the different types of abortion available to teenagers who desire to terminate an unwanted pregnancy, (3) discuss aspects of abortion unique to the adolescent population, such as insurance coverage and parental involvement laws, and (4) address common misconceptions about abortion. [Pediatr Ann. 2015;44(9):384-385,388,390,392.]. PMID- 26431239 TI - What's Normal? Accurately and Efficiently Assessing Menstrual Function. AB - Many young women are unsure of what constitutes normal menses. By asking focused questions, pediatric providers can quickly and accurately assess menstrual function and dispel anxiety and myths. In this article, we review signs and symptoms of normal versus pathologic menstrual functioning and provide suggestions to improve menstrual history taking. PMID- 26431240 TI - Evaluation and Management of Adolescents with Abnormal Uterine Bleeding. AB - The International Federation of Gynecology and Obstetrics and the American Congress of Obstetricians and Gynecologists support the use of new terminology for abnormal uterine bleeding (AUB) to consistently categorize AUB by etiology. The term AUB can be further classified as AUB/heavy menstrual bleeding (HMB) (replacing the term "menorrhagia") or AUB/intermenstrual bleeding (replacing the term "metrorrhagia"). Although many cases of AUB in adolescent women are attributable to immaturity of the hypothalamic-pituitary-ovarian axis, underlying bleeding disorders should be considered in women with AUB/HMB. This article reviews the new terminology for AUB, discusses important relevant features of history and examination, presents the laboratory evaluation of HMB, and describes hormonal (oral contraceptive pills, progestin-only methods, long-acting reversible contraceptives including intrauterine systems), hematologic (tranexamic acid and desmopressin), and surgical management options for AUB/HMB. PMID- 26431241 TI - Diagnosis and Management of Polycystic Ovary Syndrome in Adolescent Girls. AB - Polycystic ovary syndrome (PCOS) is a common endocrine disorder in adolescent girls that has both reproductive and metabolic implications. Patients with PCOS typically present to their pediatrician for evaluation of menstrual irregularity and/or signs of hyperandrogenism, such as hirsutism and acne. The diagnosis of PCOS is made by clinical symptoms and laboratory evaluation. Because of the long term health consequences that can accompany the disorder, pediatricians should consider PCOS in their initial evaluation of menstrual irregularity. Lifestyle modification is the cornerstone of treatment for girls with PCOS; however, hormonal medication such as oral contraceptive pills and insulin-sensitizing agents are useful and effective adjuncts to therapy. The goals of treatment for girls with PCOS are to improve clinical manifestations of the disorder, health related quality of life, and long-term health outcomes. PMID- 26431242 TI - Monthly Periods--Are They Necessary? AB - Menstrual suppression--the use of hormones to delay or eliminate menses--is often used in adolescents to manage conditions associated with the menstrual cycle and to accommodate lifestyle preferences. Reducing the frequency of menstrual bleeding does not cause any known physiologic harm and has potential short-term and long-term advantages. Different methods used for menstrual suppression, however, have associated risks and side effects that need to be weighed against the benefits of controlling menses. This article reviews the advantages and disadvantages of menstrual suppression and the different methods available for adolescents. PMID- 26431243 TI - Letter to the Editor: Congenital spinal dermal sinus. PMID- 26431244 TI - Rapid-onset paraparesis and quadriparesis in patients with intramedullary spinal dermoid cysts: report of 10 cases. AB - OBJECT Intramedullary dermoid cysts are rare tumors of the spinal cord. Presentation with rapid onset of paraparesis or quadriparesis (onset within 2 weeks) is rarer still. The authors present their experience in the management and outcome of patients with such a presentation. METHODS Patient records between 2000 and 2014 were retrospectively reviewed to identify those with intraspinal dermoid cysts who presented with rapid-onset paraparesis or quadriparesis. Their clinical, radiological, operative, and follow-up data were analyzed. RESULTS Of a total of 50 patients with intraspinal dermoid cysts managed during the study period, 10 (20%) presented with rapid-onset paraparesis or quadriparesis; 9 patients ranged in age from 8 months to 2 years, and 1 patient was 25 years old. A dermal sinus was seen in the lumbar region of 4 patients, the sacral region of 3, and the thoracic region of 1, and in 1 patient no sinus was found. All except 1 patient presented with rapid-onset paraparesis secondary to infection of the intramedullary dermoid cyst. One patient presented with rupture of a dermoid cyst with extension into the central canal up to the medulla. Early surgery was done soon after presentation in all except 2 patients. Among the 9 patients who underwent surgery (1 patient did not undergo surgery), total excision of the intramedullary dermoid cyst was done in 3 patients, near-total excision in 4 patients, and partial excision in 2 patients. Of the 9 patients who underwent surgery, 8 showed significant improvement in their neurological status, and 1 patient remained stable. The 1 patient who did not undergo surgery died as a result of an uncontrolled infection after being discharged to a local facility for management of wound infection. CONCLUSIONS Early recognition of a dermal sinus and the associated intraspinal dermoid cyst and timely surgical intervention can eliminate the chances of acute deterioration of neurological function. Even after an acute onset of paraparesis or quadriparesis, appropriate antibiotic therapy and prompt surgery can provide reasonably good outcomes in these patients. PMID- 26431245 TI - Health-related quality of life in pediatric Chiari Type I malformation: the Chiari Health Index for Pediatrics. AB - OBJECT The purpose of this study was to design and validate a patient-reported health-related quality of life (HRQOL) instrument for pediatric Chiari Type I malformation (CM-I), the Chiari Health Index for Pediatrics (CHIP). METHODS The CHIP has 45 items with 4 components making up 2 domain scores, physical (pain frequency, pain severity, nonpain symptoms) and psychosocial; physical and psychosocial scores are combined to create an overall HRQOL score. Increasing scores (0 to 1) represent increasing HRQOL. Fifty-five patients with CM-I (mean age 12 +/- 4 years, 53% male) were enrolled and completed the CHIP and Health Utilities Index Mark 3 (HUI3). Twenty-five healthy controls (mean age 11.9 +/- 4 years, 40% male) also completed the CHIP. CHIP scores were compared between these groups via the Mann-Whitney U-test. For CHIP discriminative function, subscore versus presence of CM-I was compared via receiver operating characteristic curve analysis. CHIP scores in the CM-I group were stratified by symptomatology (asymptomatic, headaches, and paresthesias) and compared via Kruskal-Wallis test with Mann-Whitney U-test with Bonferroni correction (p < 0.0167). CHIP was compared with HUI3 (Health Utilities Index Mark 3) via univariate and multivariate linear regression. RESULTS CHIP physical and psychosocial subscores were, respectively, 24% and 18% lower in CM-I patients than in controls (p < 0.001); the overall HRQOL score was 23% lower as well (p < 0.001). The area under the curve (AUC) for CHIP physical subscore versus presence of CM-I was 0.809. CHIP physical subscore varied significantly with symptomatology (p = 0.001) and HUI3 pain-related quality of life (R(2) = 0.311, p < 0.001). The AUC for CHIP psychosocial subscore versus presence of CM-I was 0.754. CHIP psychosocial subscore varied significantly with HUI3 cognitive- (R(2) = 0.324, p < 0.001) and emotion-related (R(2) = 0.155, p = 0.003) quality of life. The AUC for CHIP HRQOL versus presence of CM-I was 0.820. Overall CHIP HRQOL score varied significantly with symptomatology (p = 0.001) and HUI3 multiattribute composite HRQOL score (R(2) = 0.440, p < 0.001). CONCLUSIONS The CHIP is a patient-reported, CM-I specific HRQOL instrument, with construct validity in assessing pain-, cognitive , and emotion-related quality of life, as well as symptomatic features unique to CM-I. It holds promise as a discriminative HRQOL index in CM-I outcomes assessment. PMID- 26431246 TI - Repair of a traumatic subarachnoid-pleural fistula with the percutaneous injection of fibrin glue in a 2-year-old. AB - Subarachnoid-pleural fistulas (SPFs) are rare clinical entities that occur after severe thoracic trauma or iatrogenic injury during anterolateral approaches to the spine. Treatment of these fistulas often entails open repair of the dural defect. The authors present the case of an SPF in a 2-year-old female after a penetrating injury to the chest. The diagnosis of an SPF was suspected given the high chest tube output and was confirmed with a positive beta2-transferrin test of the chest tube fluid, as well as visualization of dural defects on MRI. The dural defects were successfully repaired with CT-guided percutaneous epidural injection of fibrin glue alone. This case represents the youngest pediatric patient with a traumatic SPF to be treated percutaneously. This technique can be safely used in pediatric patients, offers several advantages over open surgical repair, and could be considered as an alternative first-line therapy for the obliteration of SPFs. PMID- 26431247 TI - Association of postoperative furosemide use with a reduced blood transfusion rate in sagittal craniosynostosis surgery. AB - OBJECT A major challenge in sagittal craniosynostosis surgery is the high transfusion rate (50%-100%) related to blood loss in small pediatric patients. Several approaches have been proposed to prevent packed red blood cell (PRBC) transfusion, including endoscopic surgery, erythropoietin ortranexamic acid administration, and preoperative hemodilution. The authors hypothesized that a significant proportion of postoperative anemia observed in pediatric patients is actually dilutional. Consequently, since 2005, at CHU Sainte-Justine, furosemide has been administered to correct the volemic status and prevent PRBC transfusion. The purpose of this study was to evaluate the impact of postoperative furosemide administration on PRBC transfusion rates. METHODS This was a retrospective study of 96 consecutive patients with sagittal synostosis who underwent surgery at CHU Sainte-Justine between January 2000 and May 2012. The mean age at surgery was 4.9 +/- 1.5 months (range 2.8-8.7 months). Patients who had surgery before 2005 constituted the control group. Those who had surgery in 2005 or 2006 were considered part of an implementation phase because furosemide administration was not routine. Patients who had surgery after 2006 were part of the experimental (or furosemide) group. Transfusion rates among the 3 groups were compared. The impact of furosemide administration on transfusion requirement was also measured while accounting for other variables of interest in a multiple logistic regression model. RESULTS The total transfusion rate was significantly reduced in the furosemide group compared with the control group (31.3% vs 62.5%, respectively; p = 0.009), mirroring the decrease in the postoperative transfusion rate between the groups (18.3% vs 50.0%, respectively; p = 0.003). The postoperative transfusion threshold remained similar throughout the study (mean hemoglobin 56.0 g/dl vs 60.9 g/dl for control and furosemide groups, respectively; p = 0.085). The proportion of nontransfused patients with recorded hemoglobin below 70 g/dl did not differ between the control and furosemide groups (41.7% vs 28.6%, respectively; p = 0.489). Surgical procedure, preoperative hemoglobin level, estimated blood loss, and furosemide administration significantly affected the risk of receiving a postoperative PRBC transfusion. When these variables were analyzed in a multiple logistic regression model, furosemide administration remained strongly associated with a reduced risk of being exposed to a blood transfusion (OR 0.196, p = 0.005). There were no complications related to furosemide administration. CONCLUSIONS A significant part of the postoperative anemia observed in patients who underwent sagittal craniosynostosis surgery was due to hypervolemic hemodilution. Correction of the volemic status with furosemide administration significantly reduces postoperative PRBC transfusion requirements in these patients. PMID- 26431248 TI - Atypical pediatric ganglioglioma is common and associated with a less favorable clinical course. AB - OBJECT Ganglioglioma (GG) is commonly recognized as a low-grade tumor located in the temporal lobe, often presenting with seizures. Most are amenable to complete resection and are associated with excellent oncological outcome. The authors encountered several GGs in various locations, which seem to have a less favorable clinical course than GGs in the temporal lobe. METHODS The authors performed a single-center retrospective review of all children with a histological diagnosis of GG who were treated at Children's Hospital Colorado between 1997 and 2013. Each tumor was categorized by 2 pediatric neuroradiologists as typical or atypical based on preoperative MRI appearance. Typical lesions were cortically based, within a single cerebral lobe, well-circumscribed, and solid or mixed solid/cystic. The treatment and clinical course of each patient was analyzed. RESULTS Thirty-seven children were identified, with a median age at presentation of 8.2 years and median follow-up of 38.0 months. Eighteen tumors (48.6%) were typical and 19 (51.4%) were atypical. All typical lesions presented with seizures, whereas no atypical lesions did so. Sixteen (88.9%) typical lesions were located in the temporal lobe. In the atypical group, tumor location was variable, including 11 (57.9%) in the brainstem. Death during follow-up was statistically more common in the atypical group (31.6% vs 0%, p = 0.02). Gross total resection (GTR) was achieved for 15 of 16 typical tumors (93.8%), compared with 3 atypical tumors (15.8%, p < 0.0001). Presentation with seizure or non brainstem location were each associated with survival (p = 0.02 and 0.004, respectively). The presence of mutation in BRAF exon 15 did not differ between the 2 groups. CONCLUSIONS Pediatric GG with typical imaging features is associated with excellent rates of GTR and overall survival. Atypical GG is commonly encountered, less amenable to GTR, and associated with a worse outcome. This may relate to anatomical or biological characteristics and merits further investigation. PMID- 26431249 TI - Insulin analogues in pregnancy and specific congenital anomalies: a literature review. AB - Insulin analogues are commonly used in pregnant women with diabetes. It is not known if the use of insulin analogues in pregnancy is associated with any higher risk of congenital anomalies in the offspring compared with use of human insulin. We performed a literature search for studies of pregnant women with pregestational diabetes using insulin analogues in the first trimester and information on congenital anomalies. The studies were analysed to compare the congenital anomaly rate among foetuses of mothers using insulin analogues with foetuses of mothers using human insulin. Of 29 studies, we included 1286 foetuses of mothers using short-acting insulin analogues with 1089 references of mothers using human insulin and 768 foetuses of mothers using long-acting insulin analogues with 685 references of mothers using long-acting human insulin (Neutral Protamine Hagedorn). The congenital anomaly rate was 4.84% and 4.29% among the foetuses of mothers using lispro and aspart. For glargine and detemir, the congenital anomaly rate was 2.86% and 3.47%, respectively. No studies on the use of insulin glulisine and degludec in pregnancy were found. There was no statistically significant difference in the congenital anomaly rate among foetuses exposed to insulin analogues (lispro, aspart, glargine or detemir) compared with those exposed to human insulin or Neutral Protamine Hagedorn insulin. The total prevalence of congenital anomalies was not increased for foetuses exposed to insulin analogues. The small samples in the included studies provided insufficient statistical power to identify a moderate increased risk of specific congenital anomalies. PMID- 26431250 TI - Drugs with susceptible sites for free radical induced oxidative transformations: the case of a penicillin. AB - Penicillins, as bactericidal antibiotics, have been widely used to treat infections for several decades. Their structure contains both aromatic and thioether moieties susceptible to free radical oxidation. The (*)OH induced oxidation mechanism of amoxicillin was investigated by pulse radiolysis techniques and by final product analysis performed after steady-state gamma irradiation. The predominant sites of the (*)OH attack are suggested to be the thioether group, initially yielding an (*)OH adduct to the sulfur, and the aromatic ring. This adduct to the sulfur converts to sulfur radical cation, which has three competitive reaction paths: (1) by deprotonation at the adjacent carbon alpha-(alkylthio)alkyl radicals form, which undergo disproportionation leading presumably to sulfoxide as main product; (2) via the pseudo-Kolbe mechanism it may transform to alpha-aminoalkyl radicals; (3) the radical cation can be stabilized through intramolecular S..O bond formation. The reaction mechanism suggests the presence of a short-living and a stabilized (via hydrogen bonding) long-living (*)OH adduct to the sulfur. The three-electron bonded dimers of amoxicillin were not formed owing to steric hindrance. Thiyl radicals were also present in equilibrium with alpha-aminoalkyl radicals. In the presence of dissolved oxygen, aromatic ring hydroxylation occurred along with complex reactions resulting in e.g. oxidation of the methyl groups. The formation of the sulfoxide is especially effective in the presence of dissolved oxygen, under anaerobic condition, however, it is also generated owing to H2O2 and alpha (alkylthio)alkyl radicals. The thioether moiety appears to be more sensitive to oxidation compared to the aromatic ring in case of amoxicillin. PMID- 26431251 TI - Frequency, Type and Cause of Artifacts in Swept-Source and Cirrus HD Optical Coherence Tomography in Cases of Glaucoma and Suspected Glaucoma. AB - PURPOSE: To evaluate and compare the frequency, type and cause of imaging artifacts incurred when using swept-source optical coherence tomography (SS OCT) and Cirrus HD OCT in the same patients on the same day. MATERIALS AND METHODS: From left eye OCT results of 72 patients, disc area and macular area data could be compared between the two types of OCT. For each scan, the final printout report and source data were examined. For comparison between the two types of OCT, only source image data were used because of differences in the final printout report format. RESULTS: There were no significant differences in the artifact frequencies between the two groups in either area (disc area: 35.9% of SS OCT, 42.2% of Cirrus OCT, p = 0.523; Macular area: 24.2% of SS OCT, 22.7% of Cirrus OCT, p = 1.00). The overall results of artifact comparison between the two types of OCTs also showed no significant differences. Boundary misidentification was the most common type of artifact observed, and ocular pathology was the most common cause of artifact in both types of OCTs. Among ocular pathologies, the epiretinal membrane (ERM) was the most common cause of OCT artifact production in both types of OCTs. CONCLUSIONS: There was no significant difference in the frequency, type and cause of artifacts between SS OCT and Cirrus HD OCT. Artifacts in OCT can influence the interpretation of OCT results. In particular, ERM around the optic disc could contribute to OCT artifacts and should be considered in glaucoma diagnosis or during patient follow-up using OCT. PMID- 26431252 TI - Immunogenicity and safety of early vs delayed BCG vaccination in moderately preterm (31-33 weeks) infants. AB - Minimum gestation at which infant can be given BCG (Bacillus Calmette-Guerin) vaccine safely at birth is not clearly defined. Our objectives were the following: to compare Mantoux test after 6 months of BCG immunization in moderately preterm babies (31-33 weeks) vaccinated at birth and 34 weeks post conception age and to compare in above groups:(a) Interferon - gamma (IFN-gamma) levels in BCG vaccinated infants who did not react to Mantoux test (b) Local BCG reaction at 6, 10, 14 weeks and 6 months (c) Complications of BCG vaccination. Interventional, randomized comparative trial. Moderately preterm infants (31-33 weeks), 90 in each group. At birth, 180 moderately preterm infants were recruited and randomly allocated into 2 groups. Two ml venous blood was drawn for estimation of IFN-gamma levels. Infants were given BCG vaccine within 72 hours of birth and followed up after 2, 4, 6, 10, 14 weeks and 6 months (group 1). Infants were recruited at birth and held up till 34 weeks post conception age (group 2) and then given BCG vaccine and followed up similarly as group 1. At each visit, local BCG reaction, any local or unusual complication and anthropometric measurements were noted. At six months, Mantoux test was done and 2 ml venous blood sample was collected for IFN-gamma levels post vaccination. Presence or absence of BCG local reaction, PPD conversion rates and complications were analyzed using Chi square or Fisher's exact test. IFN-gamma levels were analyzed by ANOVA. In all 117 infants could be followed till 6 months after BCG immunization in 2 groups, and Mantoux test was positive in 38.4% of them. The rate of Mantoux test positivity was similar irrespective of the age of giving BCG immunization (group 1- 39.1% vs group 2- 37.5%; p > 0.05). IFN-gamma levels were significantly raised at 6 months in 60% (n = 21/41) and 65% (n = 15/27) Mantoux negative infants in group 1 and group 2 respectively. The sequence and order of local BCG reaction at 2, 4, 6, 10, 14 weeks and 6 months was in the form of papule, pustule, ulcer, scab and scar. Scar was formed in 94.2% and 89.5% infants in group 1 and group 2 respectively. One infant in group 1 showed abortive reaction (0.85%). Only 3.4% of infants developed lymphadenopathy and was similar in both the groups. Moderately preterm infants (31-33 weeks) exhibited 98.3% immunogenicity after BCG immunization at birth and can be safely vaccinated without any risk of severe complications. PMID- 26431253 TI - Use of Pentamidine As Secondary Prophylaxis to Prevent Visceral Leishmaniasis Relapse in HIV Infected Patients, the First Twelve Months of a Prospective Cohort Study. AB - BACKGROUND: Visceral leishmaniasis (VL) has become an important opportunistic infection in persons with HIV-infection in VL-endemic areas. The co-infection leads to profound immunosuppression and high rate of annual VL recurrence. This study assessed the effectiveness, safety and feasibility of monthly pentamidine infusions to prevent recurrence of VL in HIV co-infected patients. METHODS: A single-arm, open-label trial was conducted at two leishmaniasis treatment centers in northwest Ethiopia. HIV-infected patients with a VL episode were included after parasitological cure. Monthly infusions of 4 mg/kg pentamidine-isethionate diluted in normal-saline were started for 12 months. All received antiretroviral therapy (ART). Time-to-relapse or death was the primary end point. RESULTS: Seventy-four patients were included. The probability of relapse-free survival at 6 months and at 12 months was 79% and 71% respectively. Renal failure, a possible drug-related serious adverse event, occurred in two patients with severe pneumonia. Forty-one patients completed the regimen taking at least 11 of the 12 doses. Main reasons to discontinue were: 15 relapsed, five died and seven became lost to follow-up. More patients failed among those with a CD4+cell count <= 50 cells/MUl, 5/7 (71.4%) than those with counts above 200 cells/MUl, 2/12 (16.7%), (p = 0.005). CONCLUSION: Pentamidine secondary prophylaxis led to a 29% failure rate within one year, much lower than reported in historical controls (50%-100%). Patients with low CD4+cell counts are at increased risk of relapse despite effective initial VL treatment, ART and secondary prophylaxis. VL should be detected and treated early enough in patients with HIV infection before profound immune deficiency installs. PMID- 26431255 TI - Incremental Benefit of a Home Visit Following Discharge for Patients with Multiple Chronic Conditions Receiving Transitional Care. AB - Transitional care management is effective at reducing hospital readmissions among patients with multiple chronic conditions, but evidence is lacking on the relative benefit of the home visit as a component of transitional care. The sample included non-dual Medicaid recipients with multiple chronic conditions enrolled in Community Care of North Carolina (CCNC), with a hospital discharge between July 2010 and December 2012. Using claims data and care management records, this study retrospectively examined whether home visits reduced the odds of 30-day readmission compared to less intensive transitional care support, using multivariate logistic regression to control for demographic and clinical characteristics. Additionally, the researchers examined group differences within clinical risk strata on inpatient admissions and total cost of care in the 6 months following hospital discharge. Of 35,174 discharges receiving transitional care from a CCNC care manager, 21% (N = 7468) included a home visit. In multivariate analysis, home visits significantly reduced the odds of readmission within 30 days (odds ratio = 0.52, 95% confidence interval 0.48-0.57). At the 6 month follow-up, home visits were associated with fewer inpatient admissions within 4 of 6 clinical risk strata, and lower total costs of care for highest risk patients (average per member per month cost difference $970; P < 0.01). For complex chronic patients, home visits reduced the likelihood of a 30-day readmission by almost half compared to less intensive forms of nurse-led transitional care support. Higher risk patients experienced the greatest benefit in terms of number of inpatient admissions and total cost of care in the 6 months following discharge. (Population Health Management 2016;19:163-170). PMID- 26431254 TI - Metabolic control of the cell cycle. AB - Cell division is a metabolically demanding process, requiring the production of large amounts of energy and biomass. Not surprisingly therefore, a cell's decision to initiate division is co-determined by its metabolic status and the availability of nutrients. Emerging evidence reveals that metabolism is not only undergoing substantial changes during the cell cycle, but it is becoming equally clear that metabolism regulates cell cycle progression. Here, we overview the emerging role of those metabolic pathways that have been best characterized to change during or influence cell cycle progression. We then studied how Notch signaling, a key angiogenic pathway that inhibits endothelial cell (EC) proliferation, controls EC metabolism (glycolysis) during the cell cycle. PMID- 26431256 TI - Geriatric Telemedicine. PMID- 26431258 TI - Using Telehealth to Train Providers of a Cancer Support Intervention. AB - BACKGROUND: Group interventions are effective for addressing the transition from cancer treatment to survivorship but are not widely available outside of urban areas. In addition, minimal training is available for group facilitators outside of the mental healthcare discipline. Telehealth as a medium can facilitate conversation and interactive learning and make learning accessible to individuals in areas that lack resources for traditional classroom teaching. Little is known, however, regarding the feasibility and acceptability of a telehealth training program for group leaders. This project aimed to investigate the utility of a telehealth training program for the delivery of a copyrighted, manualized psychosocial group intervention, Cancer Transitions: Moving Beyond Treatment. MATERIALS AND METHODS: Nine group leaders attended one in-person orientation, four telehealth training classes, and four telehealth supervision sessions, completing self-report measures of content knowledge, quality satisfaction, and self-confidence. Following the completion of their last Cancer Transitions facilitation, group leaders participated in a focus group to provide qualitative feedback regarding their experiences in training for and leading the respective groups in eight urban and rural North Carolina communities. RESULTS: Group leaders rated the training program highly across the domains of content knowledge, quality satisfaction, and self-confidence. Satisfaction with the technology itself was equivocal. CONCLUSIONS: Telehealth represents a feasible avenue for training and supporting leaders of psychosocial interventions. In addition, telehealth is particularly well suited to the need for training group leaders in areas outside urban centers or academic communities. PMID- 26431257 TI - Wearable Sensor/Device (Fitbit One) and SMS Text-Messaging Prompts to Increase Physical Activity in Overweight and Obese Adults: A Randomized Controlled Trial. AB - BACKGROUND: Studies have shown self-monitoring can modify health behaviors, including physical activity (PA). This study tested the utility of a wearable sensor/device (Fitbit((r)) OneTM; Fitbit Inc., San Francisco, CA) and short message service (SMS) text-messaging prompts to increase PA in overweight and obese adults. MATERIALS AND METHODS: Sixty-seven adults wore a Fitbit One tracker for 6 weeks; half were randomized to also receive three daily SMS-based PA prompts. The Fitbit One consisted of a wearable tracker for instant feedback on performance and a Web site/mobile application (app) for detailed summaries. Outcome measures were objectively measured steps and minutes of PA by intensity using two accelerometers: ActigraphTM (Pensacola, FL) GT3X+ (primary measure) at baseline and Week 6 and Fitbit One (secondary measure) at baseline and Weeks 1, 2, 3, 4, 5, and 6. RESULTS: Mixed-model repeated-measures analysis of primary measures indicated a significant within-group increase of +4.3 (standard error [SE]=2.0) min/week of moderate- to vigorous-intensity PA (MVPA) at 6-week follow up (p=0.04) in the comparison group (Fitbit only), but no study group differences across PA levels. Secondary measures indicated the SMS text-messaging effect lasted for only 1 week: the intervention group increased by +1,266 steps (SE=491; p=0.01), +17.8 min/week MVPA (SE=8.5; p=0.04), and +38.3 min/week total PA (SE=15.9; p=0.02) compared with no changes in the comparison group, and these between-group differences were significant for steps (p=0.01), fairly/very active minutes (p<0.01), and total active minutes (p=0.02). CONCLUSIONS: These data suggest that the Fitbit One achieved a small increase in MVPA at follow-up and that the SMS-based PA prompts were insufficient in increasing PA beyond 1 week. Future studies can test this intervention in those requiring less help and/or test strategies to increase participants' engagement levels. PMID- 26431259 TI - Expediting Time from Symptoms to Medical Contact Utilizing a Telemedicine Call Center. AB - BACKGROUND: No definitive solution has been forthcoming for the often dangerously long interval between symptom onset and seeking medical care in the prehospital setting. We examined the implementation of telemedicine technology and characterization of its utilizers for its efficacy in reducing this possibly life threatening time lag. MATERIALS AND METHODS: A retrospective observational study was performed on the working database of an operational telemedicine facility that included all subscribers. Time-to-contact measurements throughout 2012 were retrieved from its medical files, and data on age, gender, medical history, and main complaint were analyzed. RESULTS: Throughout 2012, 22,274 of a total of 46,556 calls (47.8%) were made <=60 min from symptom onset. It is important that 26.9% of all calls (12,522/46,556) were made in <15 min. Significantly more males (10,794/22,229 [49%]) contacted in <=60 min compared with females (11,480/24,327 [47%], p<0.03). Subjects <60 years of age (2,889/5,717 [51%]) called earlier than those >60 years (19,386/40,839 [47%], p<0.001). Patients with prior resuscitation and/or myocardial infarction contacted significantly more rapidly than those with other cardiac diseases. Over one-half of patients with cardiac complaints contacted the call center <=60 min from symptom onset, as did those who suffered physical trauma, but not patients with gastrointestinal symptoms or pain elsewhere. CONCLUSIONS: A telemedicine system with rapid accessibility to a professional call center and prompt triage thereafter could be an additional promising strategy for shortening the interval between symptom onset and call for medical assistance. Implementation of a widespread telemedicine infrastructure may bridge the unmet gap between occurrence of symptoms to initiation of medical treatment. PMID- 26431260 TI - A Telemedicine Service as Partial Replacement of Face-to-Face Physical Rehabilitation: The Relevance of Use. AB - BACKGROUND: Different kinds of telemedicine services have made their entry into healthcare. In this article we focus on a telerehabilitation service for physical exercise, designed and implemented as partial replacement of a 3-day outpatient rehabilitation program for chronic disease patients. The aim of this article is to examine the use pattern of this telerehabilitation service by chronic disease patients and to examine the association between actual use and clinical benefit experienced by these patients. MATERIALS AND METHODS: Chronic lower back pain (CLBP) patients and pulmonary disease (PD) patients referred to the physical outpatient rehabilitation programs were asked to participate in and to use the telerehabilitation service. The actual use was expressed as frequency and duration of use, and the measurement of clinical benefit focused on complaints and physical functioning. RESULTS: Sixty-two patients finished the outpatient rehabilitation using the telerehabilitation service. During the weeks of home rehabilitation the majority of the patients used the service. On average the service was used one or two times a week for a total of 35-38 min for both pathologies, with this value being lower than the time that was replaced. Frequency of use was significantly associated with the change in physical functioning outcome for both pathologies (CLBP, r=0.41, p=0.02; PD, r=0.55, p=0.003). CONCLUSIONS: Chronic disease patients used a telerehabilitation service as partial replacement of their face-to-face rehabilitation program, and more frequent use was positively related to higher clinical benefit. PMID- 26431261 TI - Development and Evaluation of an Evaluation Tool for Healthcare Smartphone Applications. AB - INTRODUCTION: Various types of healthcare smartphone applications (apps) have been released in recent years, making it possible for people to manage their health anytime and anywhere. As a healthcare provider, who has the responsibility to provide guidance as to which apps can be used? The purpose of this study was to develop and evaluate an evaluation tool for the various aspects of healthcare smartphone apps. MATERIALS AND METHODS: In the first phase, a provisional version of an evaluation tool for healthcare smartphone apps was developed from a review of previous studies. In the second phase, the provisional tool was modified and edited after verification by five experts with regard to its content validity. In the third phase, from September 25 to October 4, 2013, 200 responses were collected to verify the construct validity and reliability of the tool. RESULTS: The edited tool had 23 evaluating items with three evaluating factors along with seven subevaluating factors as a result of confirmatory factor analysis. The reliability was found to be high (0.905). CONCLUSIONS: This study is meaningful because it demonstrates a healthcare smartphone app evaluation tool that is proven in terms of its validity and reliability. The evaluation tool developed and tested in this study is an appropriate and widely applicable tool with which to evaluate healthcare smartphone apps to determine if they are reliable and useful. However, this evaluation tool represents the beginning of the research in this area. PMID- 26431262 TI - Attitudes Toward and Predictors of Videoconferencing Use Among Frequent Family Visitors to Nursing Home Residents in Taiwan. AB - BACKGROUND: Videoconferencing with family members benefits nursing home residents by decreasing their depression and loneliness. Nevertheless, the rate of participation in videoconferencing by family members is low. The purpose of this study was to explore attitudes toward and factors related to videoconferencing by family visitors to nursing home residents in Taiwan. MATERIALS AND METHODS: For this cross-sectional study, data were collected from 231 family members of residents at 16 medium to large (>70 beds) nursing homes in Taiwan. Data were collected on participants' and residents' demographic and clinical characteristics, acceptance of and attitudes toward using videoconferencing as a form of nursing home visit, and reasons for/roles during visits to nursing home residents. Factors related to the use of videoconferencing were analyzed by logistic regression. RESULTS: Family members' acceptance rate of videoconferencing use was low (7.8%). The findings also showed that videoconference use was predicted by hiring a private caregiver (odds ratio=6.90), the role during/reason for family visits being to maintain residents' emotional status (odds ratio=5.46), and the frequency of in-person visits to the nursing home. CONCLUSIONS: We recommend encouraging family use of videoconferencing by available equipment such as smartphones or tablet programs that can address residents' emotional issues in a timely fashion. We also suggest developing more interactive content for videoconferencing, such as a family oriented picture program to help broaden topics of conversation. PMID- 26431263 TI - Origin of photogenerated carrier recombination at the metal-active layer interface in polymer solar cells. AB - The role of the metal-active layer interface in photogenerated recombination has been investigated using nanoscale current sensing atomic force microscopy (CS AFM) and intensity modulated photocurrent spectroscopy (IMPS) in as-deposited, pre-annealed and post-annealed bulk heterojunction (BHJ) solar cells. Aluminum (Al) confined post-annealed BHJ solar cells exhibited a significantly improved device efficiency compared to pre-annealed BHJ solar cells having similar photocarrier harvesting ability in the active layer. The nanoscale topography and CS-AFM results indicate a uniform PCBM rich phase at the metal-active layer interface in the post-annealed cells, but PCBM segregation in the pre-annealed cells. These two different annealing processes showed different carrier dynamics revealed using IMPS under various light intensities. The IMPS results suggest reduced photo generated carrier recombination in uniform PCBM rich post-annealed BHJ solar cells. This study reveals the importance of the metal-bend interface in BHJ solar cells in order to obtain efficient charge carrier extraction for high efficiency. PMID- 26431264 TI - Cochrane Reviews: Four Proposals for Improvement. PMID- 26431265 TI - Bioorthogonal Chemoenzymatic Functionalization of Calmodulin for Bioconjugation Applications. AB - Calmodulin (CaM) is a widely studied Ca(2+)-binding protein that is highly conserved across species and involved in many biological processes, including vesicle release, cell proliferation, and apoptosis. To facilitate biophysical studies of CaM, researchers have tagged and mutated CaM at various sites, enabling its conjugation to fluorophores, microarrays, and other reactive partners. However, previous attempts to add a reactive label to CaM for downstream studies have generally employed nonselective labeling methods or resulted in diminished CaM function. Here we report the first engineered CaM protein that undergoes site-specific and bioorthogonal labeling while retaining wild-type activity levels. By employing a chemoenzymatic labeling approach, we achieved selective and quantitative labeling of the engineered CaM protein with an N-terminal 12-azidododecanoic acid tag; notably, addition of the tag did not interfere with the ability of CaM to bind Ca(2+) or a partner protein. The specificity of our chemoenzymatic labeling approach also allowed for selective conjugation of CaM to reactive partners in bacterial cell lysates, without intermediate purification of the engineered protein. Additionally, we prepared CaM-affinity resins that were highly effective in purifying a representative CaM binding protein, demonstrating that the engineered CaM remains active even after surface capture. Beyond studies of CaM and CaM-binding proteins, the protein engineering and surface capture methods described here should be translatable to other proteins and other bioconjugation applications. PMID- 26431266 TI - Pre-Operative Antisepsis Protocol Compliance and the Effect on Bacterial Load Reduction. AB - BACKGROUND: Adequate skin preparation is essential to preventing surgical site infection. Many products are available, each with specific manufacturers' directions. This lack of standardization may lead to incorrect use of the agents and affect the bacterial load reduction. We hypothesize that a lack of adherence to utilization protocols for surgical skin antiseptics affects bacterial load reduction. METHODS: Thirty subjects who routinely perform surgical skin preparation were recruited from four hospitals. Participants completed a questionnaire of both demographics and familiarity with two of the most common skin prep formulas: Chlorhexidine gluconate-isopropyl alcohol (CHG-IPA) and povidone-iodine (PVI) scrub and paint. Randomly selecting one formula, subjects performed skin preparation for ankle surgery on a healthy standardized patient. This was repeated using the second formula on the opposite ankle. Performance was recorded and reviewed by two independent evaluators using standardized dichotomous checklists created against the manufacturer's recommended application. Swabs of the patients' first interweb space and medial malleolus were obtained before, 1 min after, and 30 min after prep, and plated on Luria Bertani agar. Bacterial loads were measured in colony forming units (CFUs) for each anatomical site. Data was analyzed using a univariate linear regression. RESULTS: Subjects had an average of 12.7 +/- 2.2 y operating room experience and 8.8 +/- 1.5 y of skin prep experience. Despite this, no participant performed 100% of the manufacturers' steps correctly. All essential formula-specific steps were performed 90% of the time for CHG-IPA and 33.3% for PVI (p = 0.0001). No correlation was found between experience or familiarity and number of correct steps for either formula. Average reduction in CFUs was not different between CHG IPA and PVI at 30 min for all anatomical sites (75.2 +/- 5.4% vs. 73.7 +/- 4.5%, p = 0.7662). Bacterial reductions at 30 min following skin prep were not substantially correlated with operator experience, protocol compliance, or total prep time for either formula. CONCLUSION: This study demonstrates existing problems with infection prevention as those tasked with pre-operative skin preparation do so with tremendous incongruence according to manufacturer guidelines. No effect on bacterial load was identified, however with a larger sample size this may be noted. Standardization of the prep solutions as well as simplification and education of the correct techniques may enhance protocol compliance. PMID- 26431267 TI - Pressure-Induced Structures and Properties in Indium Hydrides. AB - The structures, electron properties, and potential superconductivity of indium hydrides are systematically studied under high pressure by first-principles density functional calculations. Upon compression, two stable stoichiometries (InH3 and InH5) are predicted to be thermodynamically stable. Particularly, in the two compounds, all hydrogen atoms exist in the form of H2 or H3 units. The stable phases present metallic features with the overlap between the conduction and the valence bands. The Bader analysis indicates that charges transfer from In atoms to H atoms. Electron-phonon calculations show that the estimated transition temperatures (Tc) of InH3 and InH5 are 34.1-40.5 and 22.4-27.1 K at 200 and 150 GPa, respectively. PMID- 26431268 TI - Role of linezolid therapeutic drug monitoring in the treatment of MRSA tracheo pulmonary infection in a 10-month-old infant. AB - The paper reports on the use of therapeutic drug monitoring for linezolid in the decision-making process to continue or not its administration in an infant. Linezolid is effective against methicillin-resistant Staphylococcus aureus but is off-label in pediatrics. The use of therapeutic drug monitoring, as in our case, allows an informed decision on administration of the drug (in this case on withdrawal) increasing patients safety. PMID- 26431269 TI - Diminished Interoceptive Awareness in Fibromyalgia Syndrome. AB - Sensitivity to signals arising within the body (interoceptive awareness) has been implicated in emotion processing; interindividual differences in interoceptive awareness modulate both subjective and physiological indicators of emotional experience and the regulation of emotion-related behaviors. This study investigated interoceptive awareness in patients with fibromyalgia syndrome (FMS), a chronic pain condition accompanied by various affective symptoms. Interoceptive awareness was assessed in 45 FMS patients and 31 healthy individuals using a heartbeat perception task. Cognitive performance, comorbid psychiatric disorders and medication use were assessed as possible confounding variables. Concerning the primary outcome, patients exhibited markedly reduced heartbeat perception compared to healthy individuals. Moreover, there was an inverse relationship between interoceptive awareness and FMS symptom severity. Reduced interoceptive awareness may be involved in the affective aspects of FMS pathology. Poor access to bodily signals may restrict patients' ability to integrate these signals during emotional processing, which, by extension, may preclude optimal emotional self-regulation. PMID- 26431270 TI - A response for a cross-sectional case-control study on Parkinson's disease. PMID- 26431271 TI - A Larger Body Mass Index is Associated with Increased Atherogenic Dyslipidemia, Insulin Resistance, and Low-Grade Inflammation in Individuals with Metabolic Syndrome. AB - BACKGROUND: The consequences of increased body mass index (BMI) on the metabolic disorders associated with metabolic syndrome (MetS) have not been thoroughly examined. METHODS: We analyzed data from 262 individuals, 97 men and 165 women (aged 18-70 years), classified with MetS to investigate whether variations in BMI could be associated with parameters of dyslipidemia, insulin resistance, or low grade inflammation. We hypothesized that increases in BMI would positively correlate with the major dysregulations in metabolism that define MetS. For this purpose, individuals were separated into four subgroups based on their BMI: normal weight (<25 kg/m(2)), overweight (>=25 to <30 kg/m(2)), obese (>=30 to <40 kg/m(2)), and morbidly obese (>=40 kg/m(2)). RESULTS: As expected, body weight and waist circumference increased significantly as BMI increased (P < 0.0001). Both systolic and diastolic blood pressure were lower in the normal BMI group compared with the other three BMI groups (P = 0.001). Markers of HDL metabolism were adversely impacted in elevated BMI groups, as both high-density lipoprotein cholesterol (HDL-C) and large HDL decreased as BMI increased (P = 0.01). BMI was negatively correlated with HDL-C (r = -0.193, P = 0.002), HDL size (r = (-)0.227, P = 0.002), and large HDL (r = -0.147, P = 0.037). In addition, plasma insulin was highest in subjects classified as morbidly obese (P < 0.0001). There was also a strong positive correlation between BMI and plasma insulin (r = 0.413, P < 0.0001), whereas adiponectin, a marker of insulin sensitivity, was negatively correlated with BMI (r = -0.288, P = 0.001). Finally, BMI was positively correlated with proinflammatory C-reactive protein (r = 0.312, P = 0.0001) and interleukin-6 (r = 0.238, P = 0.001). CONCLUSIONS: The data from this study suggest that the physiological factors associated with increased BMI exacerbate the metabolic abnormalities characteristic of MetS. PMID- 26431272 TI - Validation of the Greek Cypriot Translation of the Triarchic Psychopathy Measure. AB - Psychopathy is conceived of as a pathological constellation of personality traits, manifested in aberrant behavioral, interpersonal, and emotional tendencies. This study examined within a Greek-speaking nonclinical sample (N = 419) associations between differing phenotypic dimensions of psychopathy (boldness, meanness, disinhibition) assessed via the Triarchic Psychopathy Measure (TriPM) and self-report criterion measures of psychopathology, personality, and history of abuse and neglect. Consistent with predictions of the triarchic model of psychopathy, evidence was found for distinct correlates of the 3 phenotypic dimensions. Boldness was associated with both adaptive (immunity to anxiety/distress, fearlessness, low hostility) and maladaptive tendencies (grandiose manipulative traits, Machiavellian features including desire for control/status, and verbal aggression). Meanness was related to callous and unemotional traits, features of Machiavellianism (e.g., amoral manipulation and distrust of others), physical aggression, and absence of positive parenting. Disinhibition, by contrast, was characterized by anxiety and distress, exposure to violence, and retrospective accounts of abuse history, along with impulsive, irresponsible, and hostile tendencies. These findings indicate that the Greek Cypriot translation of the TriPM effectively assesses the constructs of the triarchic model and extend what we know about their empirical correlates. PMID- 26431274 TI - Endothelial tyrosine kinase receptor B prevents VE-cadherin cleavage and protects against atherosclerotic lesion development in ApoE-/- mice. AB - Tyrosine kinase receptor B (TrkB) is a high-affinity receptor for brain-derived neurotrophic factor (BDNF). In addition to its nervous system functions, TrkB is also expressed in the aortic endothelium. However, the effects of endothelial TrkB signaling on atherosclerosis remained unknown. Immunofluorescence analysis revealed that TrkB expression is downregulated in the endothelium of atherosclerotic lesions from ApoE-/- mice compared with the atheroma-free aorta of WT mice. Endothelial TrkB knockdown led to increased lesion size, lipid deposition and inflammatory responses in the atherosclerotic lesions of the ApoE /- mice compared with the control mice. Mechanistic studies showed that TrkB activation prevented VE-cadherin shedding by enhancing the interaction between vascular endothelial protein tyrosine phosphatase and VE-cadherin, maintaining VE cadherin in a dephosphorylated state. Our data demonstrate that TrkB is an endothelial injury-response molecule in atherogenesis. Endothelial BDNF/TrkB signaling reduces VE-cadherin shedding and protects against atherosclerotic lesion development in ApoE-/- mice. PMID- 26431273 TI - Caveolin-1, a stress-related oncotarget, in drug resistance. AB - Caveolin-1 (Cav-1) is both a tumor suppressor and an oncoprotein. Cav-1 overexpression was frequently confirmed in advanced cancer stages and positively associated with ABC transporters, cancer stem cell populations, aerobic glycolysis activity and autophagy. Cav-1 was tied to various stresses including radiotherapy, fluid shear and oxidative stresses and ultraviolet exposure, and interacted with stress signals such as AMP-activated protein kinase. Finally, a Cav-1 fluctuation model during cancer development is provided and Cav-1 is suggested to be a stress signal and cytoprotective. Loss of Cav-1 may increase susceptibility to oncogenic events. However, research to explore the underlying molecular network between Cav-1 and stress signals is warranted. PMID- 26431275 TI - Antigen spreading-induced CD8+T cells confer protection against the lethal challenge of wild-type malignant mesothelioma by eliminating myeloid-derived suppressor cells. AB - A key focus in cancer immunotherapy is to investigate the mechanism of efficacious vaccine responses. Using HIV-1 GAG-p24 in a model PD1-based DNA vaccine, we recently reported that vaccine-elicited CD8+ T cells conferred complete prevention and therapeutic cure of AB1-GAG malignant mesothelioma in immunocompetent BALB/c mice. Here, we further investigated the efficacy and correlation of protection on the model vaccine-mediated antigen spreading against wild-type AB1 (WT-AB1) mesothelioma. We found that this vaccine was able to protect mice completely from three consecutive lethal challenges of AB1-GAG mesothelioma. Through antigen spreading these animals also developed tumor specific cytotoxic CD8+ T cells, but neither CD4+ T cells nor antibodies, rejecting WT-AB1 mesothelioma. A majority of these protected mice (90%) were also completely protected against the lethal WT-AB1 challenge. Adoptive cell transfer experiments further demonstrated that antigen spreading-induced CD8+ T cells conferred efficacious therapeutic effects against established WT-AB1 mesothelioma and prevented the increase of exhausted PD-1+ and Tim-3+ CD8+ T cells. A significant inverse correlation was found between the frequency of functional PD1 Tim3- CD8+ T cells and that of MDSCs or tumor mass in vivo. Mechanistically, we found that WT-AB1 mesothelioma induced predominantly polymorphonuclear (PMN) MDSCs in vivo. In co-cultures with efficacious CD8+ T cells, a significant number of PMN-MDSCs underwent apoptosis in a dose-dependent way. Our findings indicate that efficacious CD8+ T cells capable of eliminating both tumor cells and MDSCs are likely necessary for fighting wild-type malignant mesothelioma. PMID- 26431278 TI - Dendritic cell metabolism: immunity and tolerance. PMID- 26431277 TI - PAR1 participates in the ability of multidrug resistance and tumorigenesis by controlling Hippo-YAP pathway. AB - The Hippo pathway significantly correlates with organ size control and tumorigenesis. The activity of YAP/TAZ, a transducer of the Hippo pathway, is required to sustain self-renewal and tumor-initiation capacities in cancer stem cells (CSCs). But, upstream signals that control the mammalian Hippo pathway have not been well understood. Here, we reveal a connection between the Protease activated receptor 1 (PAR1) signaling pathway and the Hippo-YAP pathway in gastric cancer stem-like cells. The selective PAR1 agonist TFLLR-NH2 induces an increase in the fraction of side population cells which is enriched in CSCs, and promotes tumorigenesis, multi cancer drug resistance, cell morphological change, and cell invasion which are characteristics of CSCs. In addition, PAR1 activation inhibits the Hippo-YAP pathway kinase Lats via Rho GTPase. Lats kinase inhibition in turn results in increased nuclear localization of dephosphorylated YAP. Furthermore, PAR1 activation confers CSCs related traits via the Hippo-YAP pathway, and the Hippo-YAP pathway correlates with epithelial mesenchymal transition which is induced by PAR1 activation. Our research suggests that the PAR1 signaling deeply participates in the ability of multi drug resistance and tumorigenesis through interactions with the Hippo-YAP pathway signaling in gastric cancer stem-like cells. We presume that inhibited YAP is a new therapeutic target in the treatment human gastric cancer invasion and metastasis by dysregulated PAR1 or its agonists. PMID- 26431276 TI - Bortezomib enhances expression of effector molecules in anti-tumor CD8+ T lymphocytes by promoting Notch-nuclear factor-kappaB crosstalk. AB - The immunosuppressive tumor microenvironment usurps host antitumor immunity by multiple mechanisms including interference with the Notch system, which is important for various metazoan cell fate decisions and hematopoietic cell differentiation and function. We observed that treatment with the proteasome inhibitor bortezomib in mice bearing various solid tumors resulted in an upregulated expression of various Notch signaling components in lymphoid tissues, thereby increasing CD8+T-lymphocyte IFNgamma secretion and expression of effector molecules, perforin and granzyme B, as well as the T-box transcription factor eomesodermin. Bortezomib also neutralized TGFbeta-mediated suppression of IFNgamma and granzyme B expression in activated CD8+T-cells. Of note, bortezomib reversed tumor-induced downregulation of Notch receptors, Notch1 and Notch2, as well as increased the levels of cleaved Notch intracellular domain (NICD) and downstream targets Hes1 and Hey1 in tumor-draining CD8+T-cells. Moreover, bortezomib promoted CD8+T-cell nuclear factor-kappaB (NFkappaB) activity by increasing the total and phosphorylated levels of the IkappaB kinase and IkappaBalpha as well as the cytoplasmic and nuclear levels of phosphorylated p65. Even when we blocked NFkappaB activity by Bay-11-7082, or NICD cleavage by gamma secretase inhibitor, bortezomib significantly increased expression of Notch Hes1 and Hey1 genes as well as perforin, granzyme B and eomesodermin in activated CD8+T-cells. Data suggest that bortezomib can rescue tumor-induced dysfunction of CD8+T-cells by its intrinsic stimulatory effects promoting NICD-NFkappaB crosstalk. These findings provide novel insights on using bortezomib not only as an agent to sensitize tumors to cell death but also to provide lymphocyte stimulatory effects, thereby overcoming immunosuppressive actions of tumor on anti-tumor T-cell functions. PMID- 26431279 TI - Naa10 in development and disease. PMID- 26431280 TI - Vinculin-cell membrane interactions. PMID- 26431291 TI - Approaches to treatment 2: Comparison of American Association of Clinical Endocrinologists (AACE) and American Diabetes Association (ADA) type 2 diabetes treatment guidelines. PMID- 26431292 TI - Letter to the Editor: Screening for Retinopathy of Prematurity in a Tertiary Ophthalmology Department in Turkey: Incidence, Outcomes, and Risk Factors. PMID- 26431293 TI - Current Management of Polypoidal Choroidal Vasculopathy. PMID- 26431294 TI - Optical Coherence Tomography Angiography of Diabetic Retinopathy in Human Subjects. AB - BACKGROUND AND OBJECTIVE: Optical coherence tomography angiography (OCTA) is a novel, non-invasive OCT technique capable of imaging the retinal vasculature. This study aims to evaluate the retinal microvasculature in diabetic human subjects with OCTA and assess potential clinical applications. PATIENTS AND METHODS: Cross-sectional study of 33 subjects with diabetic retinopathy. OCTA was performed on 3 mm * 3 mm sections using a swept-source OCTA prototype and a phase and intensity-based contrasting algorithm. OCT angiograms were studied with corresponding clinical examination and fluorescein angiograms, when available, to assess accuracy and clinical utility. RESULTS: OCTA was able to demonstrate most clinically relevant vascular changes in subjects with diabetic retinopathy, including microaneurysms, impaired vascular perfusion, some forms of intraretinal fluid, vascular loops, intraretinal microvascular abnormalities, neovascularization, and cotton-wool spots that were largely consistent with fluorescein angiography. CONCLUSION: OCTA generates high-resolution angiograms that illustrate many of the clinically relevant findings in diabetic retinopathy and offers a novel complement or alternative to fluorescein angiography. Although currently an investigational technique, OCTA in combination with standard OCT imaging is at least as good as fluorescein angiography in the evaluation of the macular complications of diabetic retinopathy. PMID- 26431295 TI - The Characteristics and Short-term Refractive Error Outcomes of Cystoid Macular Edema in Premature Neonates as Detected by Spectral-Domain Optical Coherence Tomography. AB - BACKGROUND AND OBJECTIVE: To explore characteristics associated with cystoid macular edema (CME) in neonates screened for retinopathy of prematurity (ROP). PATIENTS AND METHODS: In this institutional review board-approved, prospective, observational study, premature neonates underwent imaging with handheld spectral domain optical coherence tomography. RESULTS: Of 73 included infants (median gestational age [GA]: 28 weeks, range 23-33 weeks; birth weight: 966 g, range 506 g-1695 g), 28 (38%) had CME and 17/28 (61%) had ROP. CME was associated with ROP (P=.03) and younger GA (P=.04), but not associated with sex, race, birth weight, postmenstrual age at imaging, ROP severity, or myopia at median 6 months corrected age. CME resolved in three cases after bevacizumab treatment for type 1 ROP and in five cases without treatment. CME appeared in two cases several weeks following injections. CONCLUSION: CME was associated with ROP and younger GA, but not with myopia. Intravitreal bevacizumab for type 1 ROP has inconclusive effects on CME. PMID- 26431296 TI - Choroidal Thickness in Eyes With Central Geographic Atrophy Secondary to Stargardt Disease and Age-Related Macular Degeneration. AB - BACKGROUND AND OBJECTIVE: Choroidal thickness (CT) measurements from eyes with similar areas of macular geographic atrophy (GA) secondary to age-related macular degeneration (AMD) and Stargardt disease (STGD) were compared to determine whether GA from different diseases had a similar or different effect on the underlying subfoveal choroid. PATIENTS AND METHODS: Eyes with the diagnosis of central GA secondary to STGD and AMD were matched, with subfoveal CT measurements obtained from the central B-scan using an enhanced depth imaging protocol. The area of GA was measured using fundus autofluorescence (FAF) imaging. AMD eyes were divided into those with and without reticular pseudodrusen. RESULTS: A total of 22 eyes of 22 patients were included in the STGD and AMD groups and were matched with respect to the area of GA. The mean age of the STGD patients was 48.9 years (standard deviation [SD]=17.1), and the mean age was 81.8 years (SD=6.2) for the AMD patients. Mean area measurements of GA for the STGD and AMD groups were 5.4 mm2 (SD=4.1) and 5.1 mm2 (SD=4.0), respectively (P=.83). After adjusting for age and axial length, eyes with STGD had a mean CT measurement greater than the AMD eyes (336.1 um vs. 198.1 um, respectively; P=.039). However, this difference was driven by AMD eyes with reticular pseudodrusen (RPD) and by a single Stargardt case with a very thick choroid. Eyes with RPD had statistically thinner subfoveal CT measurements when compared with all other groups. CONCLUSION: A small but statistically significant increase in the CT of STGD eyes was observed when compared with normal controls and AMD eyes without RPD. However, this small increase in CT was driven by a single case with a markedly thicker choroid within the STGD group, so it is unlikely that a clinically significant difference exists. However, AMD eyes with GA and RPD had significantly thinner subfoveal CT measurements. PMID- 26431297 TI - SLO-Microperimetry in Wet Age-Related Macular Degeneration During Anti-VEGF Therapy. AB - BACKGROUND AND OBJECTIVE: To evaluate the morphological and functional outcome of wet age-related macular degeneration (AMD) during antivascular endothelial growth factor therapy with bevacizumab using SLO microperimetry (SLO-MP) with eye tracking. PATIENTS AND METHODS: First, reproducibility was tested over the choroidal neovascularization (CNV) in 21 eyes of 19 patients with wet AMD. Second, 21 eyes of 19 patients with active CNV were studied longitudinally during bevacizumab therapy. Best-corrected visual acuity, SLO-MP, spectral-domain optical coherence tomography and fluorescein angiography were performed. RESULTS: There was good reproducibility with a concordance correlation coefficient of 0.85. In the longitudinal study, eyes with anatomical response demonstrated a significant increase of retinal sensitivity. Non-responders showed no change in SLO-MP. Retinal sensitivity at baseline had a significant predictive value for the change in retinal sensitivity during therapy with bevacizumab (P=.032). CONCLUSION: SLO-MP is able to analyze retinal function overlying lesions in wet AMD and can be a useful tool to monitor therapy in patients with macular diseases. PMID- 26431298 TI - A Central Hyporeflective Subretinal Lucency Correlates With a Region of Focal Leakage on Fluorescein Angiography in Eyes With Central Serous Chorioretinopathy. AB - BACKGROUND AND OBJECTIVE: To correlate the appearance of a hyporeflective lucency on spectral-domain optical coherence tomography (SD-OCT) with a focal leak on fluorescein angiography (FA) in eyes with central serous chorioretinopathy (CSC). PATIENTS AND METHODS: Multimodal imaging of 18 patients with CSC who had hyperreflective fibrin surrounding a hyporeflective lucency on SD-OCT was analyzed to investigate any potential correlation with an active leak on FA. The lucent area was evaluated using en face imaging and followed for resolution of the active leak. RESULTS: High-resolution SD-OCT images of the lucency were found to correlate with the active leak. In certain cases, the lucent area could be visualized as communicating with a defect in a pigment epithelial detachment. En face imaging of the lucency revealed a smoke-stack appearance, and resolution of the leak correlated with the disappearance of the lucency on SD-OCT. CONCLUSION: Visualization of a lucency within surrounding fibrin may suggest an active leak. En face imaging of the lucency may provide insight into the pathophysiology of the smoke-stack leak on FA. PMID- 26431299 TI - Randomized Clinical Trial to Compare Micropulse Photocoagulation Versus Half-dose Verteporfin Photodynamic Therapy in the Treatment of Central Serous Chorioretinopathy. AB - BACKGROUND AND OBJECTIVE: To evaluate subthreshold diode-laser micropulse (SDM) versus half-dose verteporfin photodynamic therapy (hd-PDT) in central serous chorioretinopathy (CSC). PATIENTS AND METHODS: 62 eyes of 62 patients were prospectively followed for changes in fluorescein angiography (FA), fundus autofluorescence (FAF), central macular thickness (CMT), best-corrected visual acuity (BCVA), and contrast visual acuity (CVA) after SDM (n=20) or hdPDT (n=24). CSC observation served as control group (n=18). RESULTS: Both treatment groups (60% SDM vs. 66.7% hdPDT) showed significant improvement in reduction of leakage activity compared to the control group (37.5%) at 16 weeks. CMT decreased by 69.7 um (SDM), 109.8 um (hdPDT), and 89 um (control). BCVA improved by +6.7 (SDM group), +8.5 (hdPDT), and +1.5 ETDRS letters (control). CVA was best improved in the hdPDT group. No secondary RPE alterations could be detected by FAF after any intervention. CONCLUSION: In comparison to the control group, hdPDT and SDM resulted in reduced leakage activity in FA and enhanced photopic and scotopic visual acuity in patients with CSC. PMID- 26431300 TI - Bevacizumab Versus Ranibizumab in the Treatment of Macular Edema Due to Retinal Vein Occlusion: 6-Month Results of the CRAVE Study. AB - BACKGROUND AND OBJECTIVE: To compare efficacy of monthly treatment with bevacizumab or ranibizumab for macular edema due to retinal vein occlusion. PATIENTS AND METHODS: Randomized, multicenter, comparative trial (ClinicalTrials.gov identifier: NCT01428388). Participants were randomized 1:1 to receive monthly treatment with bevacizumab or ranibizumab. The primary outcome was change in central foveal thickness at 6 months compared to baseline. RESULTS: The trial randomized 98 patients to treatment with bevacizumab or ranibizumab. At 6 months, there were no differences in change in central foveal thickness between groups (bevacizumab: mean reduction of 212.6 um, 95% confidence interval [CI], 288.3 to -137.0; ranibizumab: mean reduction of 243.8 um, 95% CI, -309.6 to 178.0; P=.72, analysis of variance [ANOVA]). Both groups showed similar functional outcomes (bevacizumab: 0.33 logMAR gain, 95% CI, -0.47 to -0.18; ranibizumab: 0.34 logMAR gain, 95% CI, -0.45 to -0.23; P=.38, ANOVA). CONCLUSION: In the treatment of retinal vein occlusion, bevacizumab and ranibizumab have similar effects on reducing macular thickness and improving visual acuity. PMID- 26431301 TI - Central Microscotoma: A Rare Presentation of Epiretinal Membranes. AB - BACKGROUND AND OBJECTIVE: Patients with a symptomatic epiretinal membrane (ERM) typically complain of metamorphopsia and decreased visual acuity. We describe three patients who presented with the single complaint of a central microscotoma due to ERM, an infrequent initial symptom of this entity. PATIENTS AND METHODS: This is a retrospective, interventional, non-comparative case series. Three patients with the chief complaint of a central microscotoma related to ERMs who underwent pars plana vitrectomy by a single surgeon experienced full resolution of the preoperative microscotoma. Best-corrected visual acuity, fundus photography, and optical coherence tomography were obtained at each examination. A comprehensive neuro-ophthalmologic evaluation was performed in all cases, including magnetic resonance imaging of the orbits and brain, automated visual fields, multifocal electroretinography, multifocal visually evoked potentials, and blood tests. RESULTS: Three eyes of three patients who presented with the initial sole complaint of a central microscotoma due to ERM are included in this series. A comprehensive neuro-ophthalmologic evaluation ruled out non-retinal etiologies. After months of observation, a pars plana vitrectomy with ERM and internal limiting membrane peeling was performed in all patients. Postoperatively, the patients experienced a complete resolution of their initial, isolated complaint of a central microscotoma. CONCLUSION: Central microscotoma, as a rare stand-alone presentation of ERM, is described. This symptom resolved after a successful removal of the ERM. A greater awareness among clinicians that ERMs may present in this manner may help avoid excessive and costly medical evaluations. PMID- 26431302 TI - Management of Symptomatic Floaters: Current Attitudes, Beliefs, and Practices Among Vitreoretinal Surgeons. AB - BACKGROUND AND OBJECTIVE: To assess the current attitudes, beliefs, and practice patterns among vitreoretinal surgeons when dealing with symptomatic floaters in patients with otherwise healthy eyes. PATIENTS AND METHODS: A cross-sectional, Internet-based anonymous survey of 10 questions was distributed via email to vitreoretinal specialists practicing in the United States. RESULTS: The survey response rate was 6.1% (159 of 2,600). Forty of 159 respondents (25%) reported they would perform pars plana vitrectomy (PPV) to reduce symptomatic floaters, and 110 of 159 (69%) had previously performed PPV for this indication. When compared to those unlikely to intervene for symptomatic floaters, 33 of 40 (83%) of those likely to intervene performed more than 100 vitrectomy surgical cases annually (P<.05). Between those that had and had not performed PPV for symptomatic floaters in the past, statistically significant differences were observed regarding the likelihood to perform PPV for symptomatic floaters in the future (35% vs. 4%; P<.0001) and tendency to elect a procedure if the surgeon's own vision were impacted by symptomatic floaters (55% vs. 8%; P<.001). When compared to those likely to perform surgery for symptomatic floaters, those unlikely to intervene identified three statistically significant barriers: the surgical risks involved with PPV (28% vs. 86%; P<.001), unrealistic patient expectations (25% vs 58%; P<.001), and the possibility of ridicule from the local retina community (10% vs. 32%; P<.01). CONCLUSION: Vitreoretinal specialists are more likely to intervene for symptomatic floaters if they have previously done so and if they perform more than 100 surgical cases per year. The major barriers preventing physicians from performing an intervention for floaters are standard risks associated with PPV, the fear of unreasonable patient expectations, and the possibility of ridicule within the local retina community. PMID- 26431303 TI - Use of the Toric Surgical Marker to Aid in Intraoperative Plaque Placement for the USC Eye Physics Plaques to Treat Uveal Melanoma: A New Surgical Technique. AB - BACKGROUND AND OBJECTIVE: To describe a new surgical technique for intraoperative placement of Eye Physics (EP) plaques for uveal melanoma using a toric marker. PATIENTS AND METHODS: A toric marker is designed for cataract surgery to align the axis of astigmatism; its use was modified in this protocol to mark the axis of suture coordinates as calculated by Plaque Simulator (PS) software. RESULTS: The toric marker can be used to localize suture coordinates, in degrees, during intraoperative plaque placement. Linear marking using the toric marker decreases potential inaccuracies associated with the surgeon estimating 'clock-hours' by dot placement. CONCLUSION: Use of the toric marker aided surgical placement of EP plaques. The EP planning protocol is now designed to display the suture coordinates either by clock-hours or degrees, per surgeon preference. Future research is necessary to determine whether routine use of the toric marker improves operative efficiency. [Ophthalmic Surg Lasers Imaging Retina. 2015;46:866-870.]. PMID- 26431304 TI - Image Scaling Difference Between a Confocal Scanning Laser Ophthalmoscope and a Flash Fundus Camera. AB - BACKGROUND AND OBJECTIVE: To evaluate scaling and measurement differences between flash and scanning laser fundus images. PATIENTS AND METHODS: The authors analyzed fundus autofluorescence images of patients with geographic atrophy secondary to age-related macular degeneration imaged with both 30o confocal scanning laser ophthalmoscope (cSLO) and 50o flash fundus camera (FFC). Multiple vessel-crossing points served as landmarks. RESULTS: The mean (+/-SD; range) scaling factor between cSLO and FFC images (by GRADOR) for the horizontal dimension was 1.217 (+/-0.0487; 1.0474-1.272) versus 1.138 (+/-0.0311; 1.0841 1.193) for the vertical dimension. The mean percentage difference between horizontal and vertical scaling factors was 7.48 (+/-2.29; 2.30-10.70). Refractive error (focus) and aperture size (or field of view of the image) were positively correlated and aspect ratio was negatively correlated with landmark pair measurements. CONCLUSION: Inherent image-scaling differences between fundus autofluorescence imaging systems are not restricted to simple pixel-to-millimeter calibration variances, but appear to vary depending on measurement orientation. Differences should be considered when comparing measurements obtained using different imaging systems, particularly for clinical trials. PMID- 26431305 TI - Outer Retinal Changes Preceding Secondary Macular Hole Formation Years After Vitreomacular Traction Release Demonstrated on Spectral-Domain OCT. AB - This report describes changes documented on spectral-domain optical coherence tomography (SD-OCT) in the right eye of a 58-year-old woman who eventually developed a secondary full-thickness macular hole (FTMH). She had a history of vitreomacular traction (VMT) that had resolved spontaneously with a complete posterior vitreous detachment. Despite VMT resolution, a hyperreflective band from the internal to the external limiting membrane and evidence of photoreceptor disruption persisted on SD-OCT for 2 years, at which point an FTMH developed. Despite VMT release, the unexpected FTMH coupled with the preceding outer retinal changes suggest persistent secondary damage to Muller cells as a potential factor. PMID- 26431306 TI - Documentation of Spontaneous Macular Hole Closure in Macular Telangiectasia Type 2 Using Multimodal Imaging. AB - Macular holes in the setting of macular telangiectasia type 2 can be difficult to manage. The rates of anatomical closure after macular hole surgery are less favorable in patients with macular telangiectasia than in those with idiopathic macular holes. These differences may be due to the influence of unique pathogenic mechanisms that modulate macular hole dynamics in patients with macular telangiectasia. In this report, the authors document the multimodal imaging findings of a patient with macular telangiectasia demonstrating spontaneous macular hole closure. These findings may improve the understanding of the natural course of this entity and may have relevance for clinical management. PMID- 26431307 TI - Flat Electroretinography and Acute Visual Loss After Ocriplasmin Injection for Vitreomacular Adhesion Complicating Macular Schisis. AB - A 53-year-old woman with macular and diffuse retinoschisis complicated by presumed vitreomacular traction underwent unilateral intravitreal ocriplasmin injection. Within hours after injection, she noted a loss of vision and the perception of "negative" images in the treated eye. Electrophysiologic testing revealed flat waveforms, and optical coherence tomography (OCT) showed initial decreased central macular thickness at day 1, followed by massive increased macular thickness with subfoveal neurosensory retinal detachment at 1 week. Her central macular thickness on OCT slowly returned to baseline during a period of 1 month until development of a macula-off rhegmatogenous retinal detachment at 6 months after injection. The authors believe this unique case of vitreomacular adhesion and macular schisis complicated by post-injection visual loss and electroretinography changes may offer further insight into this unusual complication. PMID- 26431308 TI - Aggressive Surgical Therapy With Early Vitrectomy, Panretinal Photocoagulation, and Silicone Oil Tamponade for Streptococcus mitis Endophthalmitis. AB - An 87-year-old woman presented with acute, painful vision loss in her right eye after intravitreal injection. Examination disclosed hypopyon and vitritis, as well as discrete inflammatory collections in the vitreous and widespread retinal hemorrhages. The patient underwent vitrectomy with injection of intravitreal antibiotics. Vitreous cultures were positive for Streptococcus mitis, a pathogen associated with severe tissue damage and poor clinical outcomes. Clinical deterioration prompted repeat vitrectomy with silicone oil tamponade and panretinal photocoagulation two weeks later, resulting in more favorable anatomic and visual outcomes. Endophthalmitis caused by exotoxin-producing bacterial species such as S. mitis is often associated with severe vision loss or loss of the eye. Aggressive surgical intervention--prompted by concerning clinical findings and vitreous cultures--may play a role in improving outcomes in these patients. PMID- 26431310 TI - High-Strength Single-Walled Carbon Nanotube/Permalloy Nanoparticle/Poly(vinyl alcohol) Multifunctional Nanocomposite Fiber. AB - Magnetic nanocomposite fibers are a topic of intense research due to their potential breakthrough applications such as smart magnetic-field-response devices and electromagnetic interference (EMI) shielding. However, clustering of nanoparticles in a polymer matrix is a recognized challenge for obtaining a property-controllable nanocomposite fiber. Another challenge is that the strength and ductility of the nanocomposite fiber decrease significantly with increased weight loading of magnetic nanoparticles in the fiber. Here, we report high strength single-walled carbon nanotube (SWNT)/permalloy nanoparticle (PNP)/poly(vinyl alcohol) multifunctional nanocomposite fibers fabricated by wet spinning. The weight loadings of SWNTs and PNPs in the fiber were as high as 12.0 and 38.0%, respectively. The tensile strength of the fiber was as high as 700 MPa, and electrical conductivity reached 96.7 S m(-1). The saturation magnetization (Ms) was as high as 24.8 emu g(-1). The EMI attenuation of a fabric woven from the prepared fiber approached 100% when tested with electromagnetic waves with a frequency higher than 6 GHz. The present study demonstrates that a magnetic-field-response device can be designed using the fabricated multifunctional nanocomposite fiber. PMID- 26431309 TI - Reconstituting Intracellular Vesicle Fusion Reactions: The Essential Role of Macromolecular Crowding. AB - Intracellular vesicle fusion is mediated by SNAREs and Sec1/Munc18 (SM) proteins. Despite intensive efforts, the SNARE-SM mediated vesicle fusion reaction has not been faithfully reconstituted in biochemical assays. Here, we present an unexpected discovery that macromolecular crowding is required for reconstituting the vesicle fusion reaction in vitro. Macromolecular crowding is known to profoundly influence the kinetic and thermodynamic behaviors of macromolecules, but its role in membrane transport processes such as vesicle fusion remains unexplored. We introduced macromolecular crowding agents into reconstituted fusion reactions to mimic the crowded cellular environment. In this crowded assay, SNAREs and SM proteins acted in concert to drive efficient membrane fusion. In uncrowded assays, by contrast, SM proteins failed to associate with the SNAREs and the fusion rate decreased more than 30-fold, close to undetectable levels. The activities of SM proteins were strictly specific to their cognate SNARE isoforms and sensitive to biologically relevant mutations, further supporting that the crowded fusion assay accurately recapitulates the vesicle fusion reaction. Using this crowded fusion assay, we also showed that the SNARE SM mediated fusion reaction can be modulated by two additional factors: NSF and alpha-SNAP. These findings suggest that the vesicle fusion machinery likely has been evolutionarily selected to function optimally in the crowded milieu of the cell. Accordingly, macromolecular crowding should constitute an integral element of any reconstituted fusion assay. PMID- 26431311 TI - Sexual Violence against Men Who Have Sex with Men and Transgender Women in Mongolia: A Mixed-Methods Study of Scope and Consequences. AB - The role of sexual violence in health and human rights-related outcomes, including HIV, is receiving increasing attention globally, yet the prevalence, patterns, and correlates of sexual violence have been little-studied among men who have sex with men (MSM) and transgender women in low and middle income countries. A mixed-methods study with quantitative and qualitative phases was conducted among MSM and transgender women in Ulaanbaatar, Mongolia. Methods included respondent-driven sampling (RDS) with structured socio-behavioral surveys (N = 313) as well as qualitative methods including 30 in-depth interviews and 2 focus group discussions. Forced sex in the last three years was reported by 14.7% of respondents (RDS-weighted estimate, 95%CI: 9.4-20.1; crude estimate 16.1%, 49/307) in the quantitative phase. A descriptive typology of common scenarios was constructed based on the specific incidents of sexual violence shared by respondents in the qualitative phase (37 incidents across 28 interviews and 2 focus groups). Eight major types of sexual violence were identified, most frequent of which were bias-motivated street violence and alcohol-involved party related violence. Many vulnerabilities to and consequences of sexual violence described during the qualitative phase were also independently associated with forced sex, including alcohol use at least once per week (AOR = 3.39, 95% CI:1.69 6.81), and having received payment for sex (AOR = 2.77, 95% CI:1.14-6.75). Building on the promising strategies used in other settings to prevent and respond to sexual violence, similar strengthening of legal and social sector responses may provide much needed support to survivors and prevent future sexual violence. PMID- 26431312 TI - Advanced Structural Determination of Diterpene Esters Using Molecular Modeling and NMR Spectroscopy. AB - Three new jatrophane esters (1-3) were isolated from Euphorbia amygdaloides ssp. semiperfoliata, including an unprecedented macrocyclic jatrophane ester bearing a hemiketal substructure, named jatrohemiketal (3). The chemical structures of compounds 1-3 and their relative configurations were determined by spectroscopic analysis. The absolute configuration of compound 3 was determined unambiguously through an original strategy combining NMR spectroscopy and molecular modeling. Conformational search calculations were performed for the four possible diastereomers 3a-3d differing in their C-6 and C-9 stereocenters, and the lowest energy conformer was used as input structure for geometry optimization. The prediction of NMR parameters ((1)H and (13)C chemical shifts and (1)H-(1)H coupling constants) by density functional theory (DFT) calculations allowed identifying the most plausible diastereomer. Finally, the stereostructure of 3 was solved by comparison of the structural features obtained by molecular modeling for 3a-3d with NMR-derived data (the values of dihedral angles deduced from the vicinal proton-proton coupling constants ((3)JHH) and interproton distances determined by ROESY). The methodology described herein provides an efficient way to solve or confirm structural elucidation of new macrocyclic diterpene esters, in particular when no crystal structure is available. PMID- 26431313 TI - Meta-research: Evaluation and Improvement of Research Methods and Practices. AB - As the scientific enterprise has grown in size and diversity, we need empirical evidence on the research process to test and apply interventions that make it more efficient and its results more reliable. Meta-research is an evolving scientific discipline that aims to evaluate and improve research practices. It includes thematic areas of methods, reporting, reproducibility, evaluation, and incentives (how to do, report, verify, correct, and reward science). Much work is already done in this growing field, but efforts to-date are fragmented. We provide a map of ongoing efforts and discuss plans for connecting the multiple meta-research efforts across science worldwide. PMID- 26431316 TI - Correction: Cysteine String Protein Limits Expression of the Large Conductance, Calcium-Activated K+ (BK) Channel. PMID- 26431314 TI - A 24-Hour Study of the Hypothalamo-Pituitary Axes in Huntington's Disease. AB - BACKGROUND: Huntington's disease is an inherited neurodegenerative disorder characterised by motor, cognitive and psychiatric disturbances. Patients exhibit other symptoms including sleep and mood disturbances, muscle atrophy and weight loss which may be linked to hypothalamic pathology and dysfunction of hypothalamo pituitary axes. METHODS: We studied neuroendocrine profiles of corticotropic, somatotropic and gonadotropic hypothalamo-pituitary axes hormones over a 24-hour period in controlled environment in 15 healthy controls, 14 premanifest and 13 stage II/III Huntington's disease subjects. We also quantified fasting levels of vasopressin, oestradiol, testosterone, dehydroepiandrosterone sulphate, thyroid stimulating hormone, free triiodothyronine, free total thyroxine, prolactin, adrenaline and noradrenaline. Somatotropic axis hormones, growth hormone releasing hormone, insulin-like growth factor-1 and insulin-like factor binding protein-3 were quantified at 06:00 (fasting), 15:00 and 23:00. A battery of clinical tests, including neurological rating and function scales were performed. RESULTS: 24-hour concentrations of adrenocorticotropic hormone, cortisol, luteinizing hormone and follicle-stimulating hormone did not differ significantly between the Huntington's disease group and controls. Daytime growth hormone secretion was similar in control and Huntington's disease subjects. Stage II/III Huntington's disease subjects had lower concentration of post-sleep growth hormone pulse and higher insulin-like growth factor-1:growth hormone ratio which did not reach significance. In Huntington's disease subjects, baseline levels of hypothalamo-pituitary axis hormones measured did not significantly differ from those of healthy controls. CONCLUSIONS: The relatively small subject group means that the study may not detect subtle perturbations in hormone concentrations. A targeted study of the somatotropic axis in larger cohorts may be warranted. However, the lack of significant results despite many variables being tested does imply that the majority of them do not differ substantially between HD and controls. PMID- 26431315 TI - Comparative Analysis of Cell-Associated HIV DNA Levels in Cerebrospinal Fluid and Peripheral Blood by Droplet Digital PCR. AB - BACKGROUND: Measurement of HIV DNA-bearing cells in cerebrospinal fluid (CSF) is challenging because few cells are present. We present a novel application of the sensitive droplet digital (dd)PCR in this context. METHODS: We analyzed CSF cell pellets and paired peripheral blood mononuclear cells (PBMC) from 28 subjects, 19 of whom had undetectable HIV RNA (<48 copies/mL) in both compartments. We extracted DNA from PBMC using silica-based columns and used direct lysis on CSF cells. HIV DNA and the host housekeeping gene (RPP30) were measured in CSF and PBMC by (dd)PCR. We compared HIV DNA levels in virally-suppressed and unsuppressed subgroups and calculated correlations between HIV DNA and RNA levels in both compartments using non-parametric tests. RESULTS: HIV DNA was detected in 18/28 (64%) CSF cell pellets, including 10/19 (53%) samples with undetectable HIV RNA. HIV DNA levels in CSF cell pellets were not correlated with RPP30 (p = 0.3), but correlated positively with HIV RNA in CSF (p = 0.04) and HIV DNA in PBMC (p = 0.03). Cellular HIV DNA in CSF was detected in comparable levels in HIV RNA suppressed and unsuppressed subjects (p = 0.14). In contrast, HIV DNA levels in PBMC were significantly lower in HIV RNA-suppressed than in unsuppressed subjects (p = 0.014). Among subjects with detectable HIV DNA in both compartments, HIV DNA levels in CSF were significantly higher than in PBMC (p<0.001). CONCLUSIONS: Despite low mononuclear cell numbers in CSF, HIV DNA was detected in most virally suppressed individuals. In contrast to PBMC, suppressive ART was not associated with lower HIV DNA levels in CSF cells, compared to no ART, perhaps due to poorer ART penetration, slower decay of HIV DNA, or enrichment of HIV DNA-bearing mononuclear cells into the CSF, compared to blood. Future studies should determine what fraction of HIV DNA is replication-competent in CSF leukocytes, compared to PBMC. PMID- 26431317 TI - Synergistic Gene Expression Signature Observed in TK6 Cells upon Co-Exposure to UVC-Irradiation and Protein Kinase C-Activating Tumor Promoters. AB - Activation of stress response pathways in the tumor microenvironment can promote the development of cancer. However, little is known about the synergistic tumor promoting effects of stress response pathways simultaneously induced in the tumor microenvironment. Therefore, the purpose of this study was to establish gene expression signatures representing the interaction of pathways deregulated by tumor promoting agents and pathways induced by DNA damage. Human lymphoblastoid TK6 cells were pretreated with the protein kinase C activating tumor promoter 12 O-tetradecanoylphorbol-13-acetate (TPA) and exposed to UVC-irradiation. The time and dose-responsive effects of the co-treatment were captured with RNA-sequencing (RNA-seq) in two separate experiments. TK6 cells exposed to both TPA and UVC had significantly more genes differentially regulated than the theoretical sum of genes induced by either stress alone, thus indicating a synergistic effect on global gene expression patterns. Further analysis revealed that TPA+UVC co exposure caused synergistic perturbation of specific genes associated with p53, AP-1 and inflammatory pathways important in carcinogenesis. The 17 gene signature derived from this model was confirmed with other PKC-activating tumor promoters including phorbol-12,13-dibutyrate, sapintoxin D, mezerein, (-)-Indolactam V and resiniferonol 9,13,14-ortho-phenylacetate (ROPA) with quantitative real-time PCR (QPCR). Here we show a novel gene signature that may represent a synergistic interaction in the tumor microenvironment that is relevant to the mechanisms of chemical induced tumor promotion. PMID- 26431318 TI - Effectiveness of probiotics in type 2 diabetes: a meta-analysis. AB - INTRODUCTION: An increasing number of studies suggest that the use of probiotics may have a beneficial effect in patients with type 2 diabetes. OBJECTIVES: The aim of the study was to assess the ability of probiotics to modify selected cardiometabolic risk factors in subjects with type 2 diabetes. METHODS: PubMed, Embase, Cochrane Library, and Scopus databases were thoroughly reviewed up to January 2015 to search for randomized controlled trials (RCTs) that examined the effect of probiotics on selected modifiable cardiometabolic parameters in patients with type 2 diabetes. The following endpoints were considered: fasting plasma glucose (FPG), insulin concentration, insulin resistance, hemoglobin A1c (HbA1c), as well as the levels of total cholesterol, triglycerides, low-density and high-density lipoprotein cholesterols, and C-reactive protein (CRP). A total of 571 RCTs were initially identified, of which 8 trials with 438 individuals were selected for meta-analysis. The effects of probiotics were calculated for each parameter. RESULTS: The meta-analysis showed a significant effect of probiotics on reducing HbA1c levels (standardized mean difference [SMD], -0.81; confidence interval [CI], -1.33 to -0.29, P = 0.0023; I2 = 68.44%; P = 0.0421 for heterogeneity) and HOMA-IR (SMD, -2.10; CI -3.00 to -1.20, P <0.001; I2 = 82.91%; P = 0.0029 for heterogeneity). Supplementation with probiotics did not have a significant effect on FPG, insulin, and CRP levels as well as the lipid profile. CONCLUSIONS: Our meta-analysis suggests that probiotic supplementation might improve, at least to some extent, metabolic control in subjects with type 2 diabetes. However, larger well-designed, longterm RCTs are needed to confirm any potentially beneficial relationship between the use of probiotics and modifiable cardiometabolic risk factors in patients with type 2 diabetes. PMID- 26431319 TI - In Vitro Coinfection and Replication of Classical Swine Fever Virus and Porcine Circovirus Type 2 in PK15 Cells. AB - Increasing clinical lines of evidence have shown the coinfection/superinfection of porcine circovirus type 2 (PCV2) and classical swine fever virus (CSFV). Here, we investigated whether PCV2 and CSFV could infect the same cell productively by constructing an in vitro coinfection model. Our results indicated that PCV2-free PK15 cells but not ST cells were more sensitive to PCV2, and the PK15 cell line could stably harbor replicating CSFV (PK15-CSFV cells) with a high infection rate. Confocal and super-resolution microscopic analysis showed that PCV2 and CSFV colocalized in the same PK15-CSFV cell, and the CSFV E2 protein translocated from the cytoplasm to the nucleus in PK15-CSFV cells infected with PCV2. Moreover, PCV2-CSFV dual-positive cells increased gradually in PK15-CSFV cells in a PCV2 dose-dependent manner. In PK15-CSFV cells, PCV2 replicated well, and the production of PCV2 progeny was not influenced by CSFV infection. However, CSFV reproduction decreased in a PCV2 dose-dependent manner. In addition, cellular apoptosis was not strengthened in PK15-CSFV cells infected with PCV2 in comparison with PCV2-infected PK15 cells. Moreover, using this coinfection model we further demonstrated PCV2-induced apoptosis might contribute to the impairment of CSFV HCLV strain replication in coinfected cells. Taken together, our results demonstrate for the first time the coinfection/superinfection of PCV2 and CSFV within the same cell, providing an in vitro model to facilitate further investigation of the underlying mechanism of CSFV and PCV2 coinfection. PMID- 26431320 TI - Intraovarian Transplantation of Female Germline Stem Cells Rescue Ovarian Function in Chemotherapy-Injured Ovaries. AB - Early menopause and infertility often occur in female cancer patients after chemotherapy (CTx). For these patients, oocyte/embryo cryopreservation or ovarian tissue cryopreservation is the current modality for fertility preservation. However, the above methods are limited in the long-term protection of ovarian function, especially for fertility preservation (very few females with cancer have achieved pregnancy with cryopreserved ovarian tissue or eggs until now). In addition, the above methods are subject to their scope (females with no husband or prepubertal females with no mature oocytes). Thus, many females who suffer from cancers would not adopt the above methods pre- and post-CTx due to their uncertainty, safety and cost-effectiveness. Therefore, millions of women have achieved long-term survival after thorough CTx treatment and have desired to rescue their ovarian function and fertility with economic, durable and reliable methods. Recently, some studies showed that mice with infertility caused by CTx can produce normal offspring through intraovarian injection of exogenous female germline stem cells (FGSCs). Though exogenous FGSC can be derived from mice without immune rejection in the same strain, it is difficult to obtain human female germline stem cells (hFGSCs), and immune rejection could occur between different individuals. In this study, infertility in mice was caused by CTx, and the ability of FGSCs to restore ovarian function or even produce offspring was assessed. We had successfully isolated and purified the FGSCs from adult female mice two weeks after CTx. After infection with GFP-carrying virus, the FGSCs were transplanted into ovaries of mice with infertility caused by CTx. Finally, ovarian function was restored and the recipients produced offspring long-term. These findings showed that mice with CTx possessed FGSCs, restoring ovarian function and avoiding immune rejection from exogenous germline stem cells. PMID- 26431322 TI - Novel Management Options for Adult Patients With Progressive Acute Lymphoblastic Leukemia: A Case-Study Compendium. AB - Acute lymphoblastic leukemia (ALL) is a heterogeneous hematologic malignancy characterized by highly proliferative immature lymphoid cells in the bone marrow and peripheral blood. In adults, ALL accounts for approximately 20% of all adult leukemias. ALL carries a poor prognosis in adults. The 5-year overall survival is 24% in patients ages 40 to 59 years and 18% in patients ages 60 to 69 years. ALL can be grouped into different categories according to its cell lineage (B cell or T cell), the presence or absence of the Philadelphia chromosome, and various cytogenetic and molecular classifications. A main goal of treatment is to allow the patient to achieve a complete remission and to consolidate this remission with either a maintenance regimen or an allogeneic stem cell transplant. Although the overall rate of complete remission following frontline therapy for newly diagnosed ALL is high, the majority of patients experience a disease relapse. In general, the duration of initial complete remission impacts the patient's prognosis and response to further therapies. Subsequent treatments must balance the goal of achieving a remission with the need for the patient to maintain or improve quality of life. Recently approved agents, such as blinatumomab and vincristine sulfate liposome injection, offer the promise of a second remission that can serve as a bridge to allogeneic stem cell transplant while still maintaining quality of life. A novel approach using adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cells is associated with extremely robust responses. PMID- 26431321 TI - Genetically and Phenotypically Distinct Pseudomonas aeruginosa Cystic Fibrosis Isolates Share a Core Proteomic Signature. AB - The opportunistic pathogen Pseudomonas aeruginosa is among the main colonizers of the lungs of cystic fibrosis (CF) patients. We have isolated and sequenced several P. aeruginosa isolates from the sputum of CF patients and compared them with each other and with the model strain PAO1. Phenotypic analysis of CF isolates showed significant variability in colonization and virulence-related traits suggesting different strategies for adaptation to the CF lung. Genomic analysis indicated these strains shared a large set of core genes with the standard laboratory strain PAO1, and identified the genetic basis for some of the observed phenotypic differences. Proteomics revealed that in a conventional laboratory medium PAO1 expressed 827 proteins that were absent in the CF isolates while the CF isolates shared a distinctive signature set of 703 proteins not detected in PAO1. PAO1 expressed many transporters for the uptake of organic nutrients and relatively few biosynthetic pathways. Conversely, the CF isolates expressed a narrower range of transporters and a broader set of metabolic pathways for the biosynthesis of amino acids, carbohydrates, nucleotides and polyamines. The proteomic data suggests that in a common laboratory medium PAO1 may transport a diverse set of "ready-made" nutrients from the rich medium, whereas the CF isolates may only utilize a limited number of nutrients from the medium relying mainly on their own metabolism for synthesis of essential nutrients. These variations indicate significant differences between the metabolism and physiology of P. aeruginosa CF isolates and PAO1 that cannot be detected at the genome level alone. The widening gap between the increasing genomic data and the lack of phenotypic data means that researchers are increasingly reliant on extrapolating from genomic comparisons using experimentally characterized model organisms such as PAO1. While comparative genomics can provide valuable information, our data suggests that such extrapolations may be fraught with peril. PMID- 26431326 TI - Rapamycin preserves gut homeostasis during Drosophila aging. AB - Gut homeostasis plays an important role in maintaining the overall body health during aging. Rapamycin, a specific inhibitor of mTOR, exerts prolongevity effects in evolutionarily diverse species. However, its impact on the intestinal homeostasis remains poorly understood. Here, we demonstrate that rapamycin can slow down the proliferation rate of intestinal stem cells (ISCs) in the aging guts and induce autophagy in the intestinal epithelium in Drosophila. Rapamycin can also significantly affect the FOXO associated genes in intestine and up regulate the negative regulators of IMD/Rel pathway, consequently delaying the microbial expansion in the aging guts. Collectively, these findings reveal that rapamycin can delay the intestinal aging by inhibiting mTOR and thus keeping stem cell proliferation in check. These results will further explain the mechanism of healthspan and lifespan extension by rapamycin in Drosophila. PMID- 26431327 TI - Identification of ageing-associated naturally occurring peptides in human urine. AB - To assess normal and pathological peptidomic changes that may lead to an improved understanding of molecular mechanisms underlying ageing, urinarypeptidomes of 1227 healthy and 10333 diseased individuals between 20 and 86 years of age were investigated. The diseases thereby comprised diabetes mellitus, renal and cardiovascular diseases. Using age as a continuous variable, 116 peptides were identified that significantly (p < 0.05; |rho|>=0.2) correlated with age in the healthy cohort. The same approach was applied to the diseased cohort. Upon comparison of the peptide patterns of the two cohorts 112 common age-correlated peptides were identified. These 112 peptides predominantly originated from collagen, uromodulin and fibrinogen. While most fibrillar and basement membrane collagen fragments showed a decreased age-related excretion, uromodulin, beta-2 microglobulin and fibrinogen fragments showed an increase. Peptide-based in silico protease analysis was performed and 32 proteases, including matrix metalloproteinases and cathepsins, were predicted to be involved in ageing. Identified peptides, predicted proteases and patient information were combined in a systems biology pathway analysis to identify molecular pathways associated with normal and/or pathological ageing. While perturbations in collagen homeostasis, trafficking of toll-like receptors and endosomal pathways were commonly identified, degradation of insulin-like growth factor-binding proteins was uniquely identified in pathological ageing. PMID- 26431328 TI - Caspase 3 in dying tumor cells mediates post-irradiation angiogenesis. AB - Cytotoxic radiotherapy unfavorably induces tumor cells to generate various proangiogenic substances, promoting post-irradiation angiogenesis (PIA), which is one of major causes of radiotherapy failure. Though several studies have reported some mechanisms behind PIA, they have not yet described the beginning proangiogenic motivator buried in the irradiated microenvironment. In this work, we revealed that dying tumor cells induced by irradiation prompted PIA via a caspase 3 dependent mechanism. Proteolytic inactivation of caspase 3 in dying tumor cells by transducing a dominant-negative version weakened proangiogenic effects in vitro and in vivo. In addition, inhibition of caspase 3 activity suppressed tumor angiogenesis and tumorigenesis in xenograft mouse model. Importantly, we identified vascular endothelial growth factor (VEGF)-A as a downstream proangiogenic factor regulated by caspase 3 possibly through Akt signaling. Collectively, these findings indicated that besides acting as a key executioner in apoptosis, caspase 3 in dying tumor cells may play a central role in driving proangiogenic response after irradiation. Thus, radiotherapy in combination with caspase 3 inhibitors may be a novel promising therapeutic strategy to reduce tumor recurrence due to restrained PIA. PMID- 26431330 TI - Subcellular localization of PUMA regulates its pro-apoptotic activity in Burkitt's lymphoma B cells. AB - The BH3-only protein PUMA (p53-upregulated modulator of apoptosis) is a major regulator of apoptosis. It belongs to the Bcl-2 family of proteins responsible for maintaining mitochondrial outer membrane integrity by controlling the intrinsic (mitochondrial) apoptotic pathway. We describe here a new pathway regulating PUMA activation through the control of its subcellular distribution. Surprisingly, neither PUMA upregulation in normal activated human B lymphocytes nor high levels of PUMA in Burkitt's lymphoma (BL) were associated with cell death. We show that PUMA is localized to the cytosol in these cells. By contrast, various apoptosis-triggering signals were found to promote the translocation of PUMA to the mitochondria in these cells, leading to their death by apoptosis. This apoptosis was associated with the binding of mitochondrial PUMA to anti apoptotic members of the Bcl-2 family, such as Bcl-2 and Mcl-1. This translocation was caspase-independent but was prevented by inhibiting or knocking down the expression of the MAPK kinase p38. Our data suggest that the accumulation of PUMA in the cytosol may be important for the participation of this protein in apoptosis without the need for prior transcription. This regulatory pathway may be an important feature of differentiation and tumorigenic processes. PMID- 26431329 TI - DNA damage response (DDR) and senescence: shuttled inflamma-miRNAs on the stage of inflamm-aging. AB - A major issue in aging research is how cellular phenomena affect aging at the systemic level. Emerging evidence suggests that DNA damage response (DDR) signaling is a key mechanism linking DNA damage accumulation, cell senescence, and organism aging. DDR activation in senescent cells promotes acquisition of a proinflammatory secretory phenotype (SASP), which in turn elicits DDR and SASP activation in neighboring cells, thereby creating a proinflammatory environment extending at the local and eventually the systemic level. DDR activation is triggered by genomic lesions as well as emerging bacterial and viral metagenomes. Therefore, the buildup of cells with an activated DDR probably fuels inflamm aging and predisposes to the development of the major age-related diseases (ARDs). Micro (mi)-RNAs - non-coding RNAs involved in gene expression modulation are released locally and systemically by a variety of shuttles (exosomes, lipoproteins, proteins) that likely affect the efficiency of their biological effects. Here we suggest that some miRNAs, previously found to be associated with inflammation and senescence - miR-146, miR-155, and miR-21 - play a central role in the interplay among DDR, cell senescence and inflamm-aging. The identification of the functions of shuttled senescence-associated miRNAs is expected to shed light on the aging process and on how to delay ARD development. PMID- 26431331 TI - 18F-EF5 PET Is Predictive of Response to Fractionated Radiotherapy in Preclinical Tumor Models. AB - We evaluated the relationship between pre-treatment positron emission tomography (PET) using the hypoxic tracer 18F-[2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3- pentafluoropropyl) acetamide] (18F-EF5) and the response of preclinical tumor models to a range of fractionated radiotherapies. Subcutaneous HT29, A549 and RKO tumors grown in nude mice were imaged using 18F-EF5 positron emission tomography (PET) in order to characterize the extent and heterogeneity of hypoxia in these systems. Based on these results, 80 A549 tumors were subsequently grown and imaged using 18F-EF5 PET, and then treated with one, two, or four fraction radiation treatments to a total dose of 10-40 Gy. Response was monitored by serial caliper measurements of tumor volume. Longitudinal post-treatment 18F-EF5 PET imaging was performed on a subset of tumors. Terminal histologic analysis was performed to validate 18F-EF5 PET measures of hypoxia. EF5-positive tumors responded more poorly to low dose single fraction irradiation relative to EF5 negative tumors, however both groups responded similarly to larger single fraction doses. Irradiated tumors exhibited reduced 18F-EF5 uptake one month after treatment compared to control tumors. These findings indicate that pre- treatment 18F-EF5 PET can predict the response of tumors to single fraction radiation treatment. However, increasing the number of fractions delivered abrogates the difference in response between tumors with high and low EF5 uptake pre-treatment, in agreement with traditional radiobiology. PMID- 26431334 TI - Correction: Engraftment of Human Glioblastoma Cells in Immunocompetent Rats through Acquired Immunosuppression. PMID- 26431332 TI - Differentiation-Dependent KLF4 Expression Promotes Lytic Epstein-Barr Virus Infection in Epithelial Cells. AB - Epstein-Barr virus (EBV) is a human herpesvirus associated with B-cell and epithelial cell malignancies. EBV lytically infects normal differentiated oral epithelial cells, where it causes a tongue lesion known as oral hairy leukoplakia (OHL) in immunosuppressed patients. However, the cellular mechanism(s) that enable EBV to establish exclusively lytic infection in normal differentiated oral epithelial cells are not currently understood. Here we show that a cellular transcription factor known to promote epithelial cell differentiation, KLF4, induces differentiation-dependent lytic EBV infection by binding to and activating the two EBV immediate-early gene (BZLF1 and BRLF1) promoters. We demonstrate that latently EBV-infected, telomerase-immortalized normal oral keratinocyte (NOKs) cells undergo lytic viral reactivation confined to the more differentiated cell layers in organotypic raft culture. Furthermore, we show that endogenous KLF4 expression is required for efficient lytic viral reactivation in response to phorbol ester and sodium butyrate treatment in several different EBV infected epithelial cell lines, and that the combination of KLF4 and another differentiation-dependent cellular transcription factor, BLIMP1, is highly synergistic for inducing lytic EBV infection. We confirm that both KLF4 and BLIMP1 are expressed in differentiated, but not undifferentiated, epithelial cells in normal tongue tissue, and show that KLF4 and BLIMP1 are both expressed in a patient-derived OHL lesion. In contrast, KLF4 protein is not detectably expressed in B cells, where EBV normally enters latent infection, although KLF4 over-expression is sufficient to induce lytic EBV reactivation in Burkitt lymphoma cells. Thus, KLF4, together with BLIMP1, plays a critical role in mediating lytic EBV reactivation in epithelial cells. PMID- 26431333 TI - Functional Brain Dysfunction in Patients with Benign Childhood Epilepsy as Revealed by Graph Theory. AB - There is growing evidence that brain networks are altered in epileptic subjects. In this study, we investigated the functional connectivity and brain network properties of benign childhood epilepsy with centrotemporal spikes using graph theory. Benign childhood epilepsy with centrotemporal spikes is the most common form of idiopathic epilepsy in young children under the age of 16 years. High density EEG data were recorded from patients and controls in resting state with eyes closed. Data were preprocessed and spike and spike-free segments were selected for analysis. Phase locking value was calculated for all paired combinations of channels and for five frequency bands (delta, theta, alpha, beta1 and beta2). We computed the degree and small-world parameters--clustering coefficient (C) and path length (L)--and compared the two patient conditions to controls. A higher degree at epileptic zones during interictal epileptic spikes (IES) was observed in all frequency bands. Both patient conditions reduced connection at the occipital and right frontal regions close to the epileptic zone in the alpha band. The "small-world" features (high C and short L) were deviated in patients compared to controls. A changed from an ordered network in the delta band to a more randomly organized network in the alpha band was observed in patients compared to healthy controls. These findings show that the benign epileptic brain network is disrupted not only at the epileptic zone, but also in other brain regions especially frontal regions. PMID- 26431335 TI - Hyperglycemic Stress Impairs the Stemness Capacity of Kidney Stem Cells in Rats. AB - The incidence of acute kidney injury in patients with diabetes is significantly higher than that of patients without diabetes, and may be associated with the poor stemness capacity of kidney stem cells (KSCs) and limited recovery of injured renal tubules. To investigate the effects of hyperglycemic stress on KSC stemness, KSCs were isolated from the rat renal papilla and analyzed for their self-renewal and differentiation abilities. Our results showed that isolated KSCs expressed the mesenchymal stem cell markers N-cadherin, Nestin, CD133, CD29, CD90, and CD73. Moreover, KSCs co-cultured with hypoxia-injured renal tubular epithelial cell (RTECs) induced the expression of the mature epithelial cell marker CK18, suggesting that the KSCs could differentiate into RTECs in vitro. However, KSC proliferation, differentiation ability and tolerance to hypoxia were decreased in high-glucose cultures. Taken together, these results suggest the high-glucose microenvironment can damage the reparative ability of KSCs. It may result in a decreased of recovery capability of renal tubules from injury. PMID- 26431336 TI - Effects of Prenatal Multiple Micronutrient Supplementation on Fetal Growth Factors: A Cluster-Randomized, Controlled Trial in Rural Bangladesh. AB - Prenatal multiple micronutrient (MM) supplementation improves birth weight through increased fetal growth and gestational age, but whether maternal or fetal growth factors are involved is unclear. Our objective was to examine the effect of prenatal MM supplementation on intrauterine growth factors and the associations between growth factors and birth outcomes in a rural setting in Bangladesh. In a double-blind, cluster-randomized, controlled trial of MM vs. iron and folic acid (IFA) supplementation, we measured placental growth hormone (PGH) at 10 weeks and PGH and human placental lactogen (hPL) at 32 weeks gestation in maternal plasma (n = 396) and insulin, insulin-like growth factor-1 (IGF-1), and IGF binding protein-1 (IGFBP-1) in cord plasma (n = 325). Birth size and gestational age were also assessed. Early pregnancy mean (SD) BMI was 19.5 (2.4) kg/m2 and birth weight was 2.68 (0.41) kg. There was no effect of MM on concentrations of maternal hPL or PGH, or cord insulin, IGF-1, or IGFBP-1. However, among pregnancies of female offspring, hPL concentration was higher by 1.1 mg/L in the third trimester (95% CI: 0.2, 2.0 mg/L; p = 0.09 for interaction); and among women with height <145 cm, insulin was higher by 59% (95% CI: 3, 115%; p = 0.05 for interaction) in the MM vs. IFA group. Maternal hPL and cord blood insulin and IGF-1 were positively, and IGFBP-1 was negatively, associated with birth weight z score and other measures of birth size (all p<0.05). IGF-1 was inversely associated with gestational age (p<0.05), but other growth factors were not associated with gestational age or preterm birth. Prenatal MM supplementation had no overall impact on intrauterine growth factors. MM supplementation altered some growth factors differentially by maternal early pregnancy nutritional status and sex of the offspring, but this should be examined in other studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00860470. PMID- 26431337 TI - A Curated Database of Rodent Uterotrophic Bioactivity. AB - BACKGROUND: Novel in vitro methods are being developed to identify chemicals that may interfere with estrogen receptor (ER) signaling, but the results are difficult to put into biological context because of reliance on reference chemicals established using results from other in vitro assays and because of the lack of high-quality in vivo reference data. The Organisation for Economic Co operation and Development (OECD)-validated rodent uterotrophic bioassay is considered the "gold standard" for identifying potential ER agonists. OBJECTIVES: We performed a comprehensive literature review to identify and evaluate data from uterotrophic studies and to analyze study variability. METHODS: We reviewed 670 articles with results from 2,615 uterotrophic bioassays using 235 unique chemicals. Study descriptors, such as species/strain, route of administration, dosing regimen, lowest effect level, and test outcome, were captured in a database of uterotrophic results. Studies were assessed for adherence to six criteria that were based on uterotrophic regulatory test guidelines. Studies meeting all six criteria (458 bioassays on 118 unique chemicals) were considered guideline-like (GL) and were subsequently analyzed. RESULTS: The immature rat model was used for 76% of the GL studies. Active outcomes were more prevalent across rat models (74% active) than across mouse models (36% active). Of the 70 chemicals with at least two GL studies, 18 (26%) had discordant outcomes and were classified as both active and inactive. Many discordant results were attributable to differences in study design (e.g., injection vs. oral dosing). CONCLUSIONS: This uterotrophic database provides a valuable resource for understanding in vivo outcome variability and for evaluating the performance of in vitro assays that measure estrogenic activity. CITATION: Kleinstreuer NC, Ceger PC, Allen DG, Strickland J, Chang X, Hamm JT, Casey WM. 2016. A curated database of rodent uterotrophic bioactivity. Environ Health Perspect 124:556-562; http://dx.doi.org/10.1289/ehp.1510183. PMID- 26431338 TI - Whole Blood Transcriptome Analysis of Mycoplasma mycoides Subsp. mycoides Infected Cattle Confirms Immunosuppression but Does Not Reflect Local Inflammation. AB - Contagious bovine pleuropneumonia (CBPP), caused by Mycoplasma mycoides subsp. mycoides (Mmm), is a severe respiratory disease of cattle responsible for major economic losses in sub-Saharan Africa. Disease control relies mainly on the use of empirically attenuated vaccines that provide limited protection. Thus, understanding the virulence mechanisms used by Mmm as well as the role of the host immune system in disease development, persistence, and control is a prerequisite for the development of new, rationally designed control strategies. The aim of this study was to assess the use of whole blood transcriptome analysis to study cattle-Mmm interactions, starting by the characterization of the bovine response to Mmm infection during the acute form of the disease. For that purpose, we compared the transcriptome profile of whole blood from six cattle, before challenge by contact with Mmm-infected animals and at the appearance of first clinical signs, using a bovine microarray. Functional analysis revealed that 680 annotated genes were differentially expressed, with an overwhelming majority of down-regulated genes characterizing an immunosuppression. The main bio-functions affected were "organismal survival", "cellular development, morphology and functions" and "cell-to cell signaling and interactions". These affected functions were consistent with the results of previous in vitro immunological studies. However, microarray and qPCR validation results did not highlight pro inflammatory molecules (such as TNFalpha, TLR2, IL-12B and IL-6), whereas inflammation is one of the most characteristic traits of acute CBPP. This global gene expression pattern may be considered as the result, in blood, of the local pulmonary response and the systemic events occurring during acute CBPP. Nevertheless, to understand the immune events occurring during disease, detailed analyses on the different immune cell subpopulations, either in vivo, at the local site, or in vitro, will be required. Whole blood transcriptome analysis remains an interesting approach for the identification of bio-signatures correlating to recovery and protection, which should facilitate the evaluation and validation of novel vaccine formulations. PMID- 26431339 TI - Development of Physiologically Based Pharmacokinetic/Pharmacodynamic Model for Indomethacin Disposition in Pregnancy. AB - Findings of a recent clinical study showed indomethacin has lower plasma levels and higher steady-state apparent clearance in pregnant subjects when compared to those in non-pregnant subjects reported in separate studies. Thus, in the current work we developed a pregnancy physiological based pharmacokinetic/pharmacodynamic (PBPK/PD) model for indomethacin to explain the differences in indomethacin pharmacokinetics between pregnancy and non-pregnancy. A whole-body PBPK model with key pregnancy-related physiological changes was developed to characterize indomethacin PK in pregnant women and compare these parameters to those in non pregnant subjects. Data related to maternal physiological and biological changes were obtained from literature and incorporated into the structural PBPK model that describes non-pregnant PK data. Changes in indomethacin area under the curve (AUC), maximum concentration (Cmax) and average steady-state concentration (Cave) in pregnant women were predicted. Model-simulated PK profiles were in agreement with observed data. The predicted mean ratio (non-pregnant:second trimester (T2)) of indomethacin Cave was 1.6 compared to the observed value of 1.59. In addition, the predicted steady-state apparent clearance (CL/Fss) ratio was almost similar to the observed value (0.46 vs. 0.42). Sensitivity analysis suggested changes in CYP2C9 activity, and to a lesser extent UGT2B7, as the primary factor contributing to differences in indomethacin disposition between pregnancy and non pregnancy. The developed PBPK model which integrates prior physiological knowledge, in vitro and in vivo data, allowed the successful prediction of indomethacin disposition during T2. Our PBPK/PD model suggested a higher indomethacin dosing requirement during pregnancy. PMID- 26431340 TI - Modeling and Implementation of Cattle/Beef Supply Chain Traceability Using a Distributed RFID-Based Framework in China. AB - In recent years, traceability systems have been developed as effective tools for improving the transparency of supply chains, thereby guaranteeing the quality and safety of food products. In this study, we proposed a cattle/beef supply chain traceability model and a traceability system based on radio frequency identification (RFID) technology and the EPCglobal network. First of all, the transformations of traceability units were defined and analyzed throughout the cattle/beef chain. Secondly, we described the internal and external traceability information acquisition, transformation, and transmission processes throughout the beef supply chain in detail, and explained a methodology for modeling traceability information using the electronic product code information service (EPCIS) framework. Then, the traceability system was implemented based on Fosstrak and FreePastry software packages, and animal ear tag code and electronic product code (EPC) were employed to identify traceability units. Finally, a cattle/beef supply chain included breeding business, slaughter and processing business, distribution business and sales outlet was used as a case study to evaluate the beef supply chain traceability system. The results demonstrated that the major advantages of the traceability system are the effective sharing of information among business and the gapless traceability of the cattle/beef supply chain. PMID- 26431341 TI - Risk Factors for Sporadic Domestically Acquired Campylobacter Infections in Norway 2010-2011: A National Prospective Case-Control Study. AB - BACKGROUND: Campylobacteriosis is the most frequently reported food- and waterborne infection in Norway. We investigated the risk factors for sporadic Campylobacter infections in Norway in order to identify areas where control and prevention measures could be improved. METHODS: A national prospective case control study of factors associated with Campylobacter infection was conducted from July 2010 to September 2011. Cases were recruited from the Norwegian Surveillance System of Communicable Diseases (MSIS). Controls were randomly selected from the Norwegian Population Registry. Cases and controls were mailed a paper questionnaire with a prepaid return envelope. Univariable analyses using logistic regression were conducted for all exposures. A final parsimonious multivariable model was developed using regularized/penalized logistic regression, and adjusted odds ratios were calculated. RESULTS: A total of 995 cases and 1501 controls were included in the study (response proportion 55% and 30%, respectively). Exposures that had significant increases in odds of Campylobacter infection in multivariable analysis were drinking water directly from river, stream, or lake (OR: 2.96), drinking purchased bottled water (OR: 1.78), eating chicken (1.69), eating meat that was undercooked (OR: 1.77), eating food made on a barbecue (OR: 1.55), living on a farm with livestock (OR: 1.74), having a dog in the household (OR: 1.39), and having household water supply serving fewer than 20 houses (OR: 1.92). CONCLUSIONS: Consumption of poultry and untreated water remain important sources of Campylobacter infection in Norway, despite ongoing control efforts. The results justify the need for strengthening education for consumers and food handlers about the risks of cross-contamination when preparing poultry and with consuming raw or undercooked chicken. The public should also be reminded to take precautions when drinking untreated water in nature and ensure continued vigilance in order to protect and maintain the quality of water from small-scale water supply systems. PMID- 26431343 TI - The Effect of Preserved Residual Renal Function on Left Ventricular Structure in Non-Anuric Peritoneal Dialysis Patients. AB - BACKGROUND/AIMS: Residual renal function (RRF) has been shown to influence survival of peritoneal dialysis (PD) patients. This study examined the relations between RRF and left ventricular hypertrophy (LVH) before switching on dialysis treatment and observed during 18 months on PD treatment. METHODS: A prospective longitudinal study was performed in 50 non-anuric (defined as >200 mL urine output in a 24-hour period) PD patients. Echocardiography, RRF and other known risk factors for the increase of LV mass index (LVMi) were determined at study baseline and the end of follow-up. RESULTS: There was 78% patients with LVH in end-stage renal disease (ESRD) baseline and 60% at the end of follow-up. RRF at the start of the study showed no significant difference between patients with normal and increased LVMi, as well as in daily collection of urine. After 18 months, patients with decreased LVMi had better RRF, lower CRP and better Kt/V compared to patients with increased LVMi (p < 0.001). Patients with better preserved RRF not only had significantly higher total Kt/V, but were less anemic and hypoproteinemic and lesser presence of LVH. CONCLUSIONS: PD in non-anuric ESRD patients the first 18 months has a positive effect on the preservation of RRF and partial regression of left ventricular remodeling. PMID- 26431342 TI - Cancer statistics: Breast cancer in situ. AB - An estimated 60,290 new cases of breast carcinoma in situ are expected to be diagnosed in 2015, and approximately 1 in 33 women is likely to receive an in situ breast cancer diagnosis in her lifetime. Although in situ breast cancers are relatively common, their clinical significance and optimal treatment are topics of uncertainty and concern for both patients and clinicians. In this article, the American Cancer Society provides information about occurrence and treatment patterns for the 2 major subtypes of in situ breast cancer in the United States ductal carcinoma in situ and lobular carcinoma in situ-using data from the North American Association of Central Cancer Registries and the 13 oldest Surveillance, Epidemiology, and End Results registries. The authors also present an overview of in situ breast cancer detection, treatment, risk factors, and prevention and discuss research needs and initiatives. PMID- 26431344 TI - Sympathetic Neurotransmitters Modulate Osteoclastogenesis and Osteoclast Activity in the Context of Collagen-Induced Arthritis. AB - Excessive synovial osteoclastogenesis is a hallmark of rheumatoid arthritis (RA). Concomitantly, local synovial changes comprise neuronal components of the peripheral sympathetic nervous system. Here, we wanted to analyze if collagen induced arthritis (CIA) alters bone marrow-derived macrophage (BMM) osteoclastogenesis and osteoclast activity, and how sympathetic neurotransmitters participate in this process. Therefore, BMMs from Dark Agouti rats at different CIA stages were differentiated into osteoclasts in vitro and osteoclast number, cathepsin K activity, matrix resorption and apoptosis were analyzed in the presence of acetylcholine (ACh), noradrenaline (NA) vasoactive intestinal peptide (VIP) and assay-dependent, adenylyl cyclase activator NKH477. We observed modulation of neurotransmitter receptor mRNA expression in CIA osteoclasts without affecting protein level. CIA stage-dependently altered marker gene expression associated with osteoclast differentiation and activity without affecting osteoclast number or activity. Neurotransmitter stimulation modulated osteoclast differentiation, apoptosis and activity. VIP, NA and adenylyl cyclase activator NKH477 inhibited cathepsin K activity and osteoclastogenesis (NKH477, 10(-6) M NA) whereas ACh mostly acted pro-osteoclastogenic. We conclude that CIA alone does not affect metabolism of in vitro generated osteoclasts whereas stimulation with NA, VIP plus specific activation of adenylyl cyclase induced anti-resorptive effects probably mediated via cAMP signaling. Contrary, we suggest pro-osteoclastogenic and pro-resorptive properties of ACh mediated via muscarinic receptors. PMID- 26431345 TI - Ovarian granulosa cell tumour and letrozole: A case report. PMID- 26431347 TI - A Simple Chiral Cu(II) Complex as an Effective Phase-Transfer Catalyst for the Enantioselective Alkylation of Dissymmetric Glycinate Ketimines. AB - Catalytic asymmetric benzylation of a dissymmetric tert-butylglycinate ketimine, incorporating 1-naphthyl and phenyl groups as the Schiff base substituents, under phase-transfer conditions was investigated. It was interesting to note that the sense of asymmetric induction of the alkylation of Z-imine stereoisomer is opposite to that of the corresponding E stereoisomer with a similar degree of enantioselectivity. More interestingly, the chiral Cu(II) complex of the Schiff base derived from (R)-2-phenylglycinol and 2-hydroxy-1-naphthaldehyde was found to catalyze the same reaction under solid-liquid conditions with comparable enantioselectivity (up to 60% ee) with respect to known cinchona alkaloid catalysts. The solvent/base-system parameter was shown to control the optimal catalytic activity. PMID- 26431346 TI - Risk Factors for Central Lymph Node Metastasis in CN0 Papillary Thyroid Carcinoma: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Central lymph node metastasis (CLNM) is common in papillary thyroid carcinoma (PTC). Prophylactic central lymph node dissection (PCLND) for patients with clinically negative central compartment lymph nodes (CN0) remains controversial. The phrase "clinically negative" is used to indicate that patients exhibited no clinical evidence of CLNM by ultrasonography (US) or computerized tomography (CT) preoperatively. In this study, we analyze the risk factors for CLNM in CN0 patients. METHODS: The PUBMED and SCIE databases were systematically searched for works published through January 31, 2015. All of the patients included in this study underwent thyroidectomy+PCLND. Revman 5.3 software was used to analyze the data. RESULTS: Twenty studies and 9084 patients were included in this meta-analysis. The following variables were associated with an increased risk of CLNM in CN0 patients: age < 45 years (OR = 1.59, 95% CI = 1.42-1.78, p<0.00001), male sex (OR = 1.95, 95% CI = 1.63-2.32, p<0.00001), multifocality (OR = 1.43, 95% CI = 1.22-1.67, p<0.00001), tumor size > 2 cm for PTC patients (OR = 2.98, 95% CI 2.08-4.28, p<0.00001) or tumor size > 0.5 cm for papillary thyroid microcarcinoma (PTMC) patients (OR = 2.30, 95% CI = 1.71-3.09, p<0.00001), location of the primary tumor in the central area and low pole (OR = 1.86, 95% CI = 1.48-2.33, p<0.00001), lymphovascular invasion (OR = 4.35, 95% CI = 2.24-8.46, p<0.0001), extrathyroidal extension (OR = 2.27, 95% CI = 1.76-2.94, p<0.00001), and capsular invasion (OR = 1.72, 95% CI = 1.39-2.41, p<0.00001). PTC (tumor size > 1 cm) exhibited a higher risk factor associated with CLNM than PTMC (tumor size < 1 cm) (OR = 2.83, 95% CI = 2.15-3.72, p<0.00001). Bilateral tumors (OR = 1.21, 95% CI = 0.92-1.58, p = 0.17) and lymphocytic thyroiditis (OR = 0.88, 95% CI = 0.71-1.09, p = 0.25) had no association with CLNM in CN0 patients. CONCLUSIONS: Our systematic review identified several clinical features associated with CLNM in CN0 patients, including age, sex, multifocality, size, location, lymphovascular invasion, capsular invasion, and extrathyroidal extension. These factors should guide the application of PCLND in CN0 patients. PMID- 26431348 TI - Anti-Inflamm-Aging Effects of Long-Term Caloric Restriction via Overexpression of SIGIRR to Inhibit NF-kappaB Signaling Pathway. AB - BACKGROUND: Chronic inflammation is thought to be a determinant of the aging rate and longevity. Caloric restriction (CR) attenuates age-related increases in the systemic levels of several pro-inflammatory mediators, but the anti-inflammatory mechanisms of CR in the aging process remain unclear. METHODS: Fisher 344 rats in a CR group were fed an amount of food corresponding to 60% of that fed to an ad libitum-fed (AL) group for 8 months. Biochemical analyses and renal pathological grading were used to analyze physiological status. Important signaling molecules in the Toll-like receptor/nuclear factor kappa-light-chain-enhancer of activated B cells (TLR/NF-kappaB) pathway were also analyzed by western blotting, immunofluorescence and immunohistochemistry. RESULTS: 1) Compared with AL feeding, CR decreased aging-mediated increases in both biochemical marker levels and renal pathological grading. 2) Single immunoglobulin IL-1 (IL-1)-related receptor (SIGIRR) expression decreased with increasing age, but CR led to overexpression. 3) The expression of TLR4 was significantly higher in the CR group than in the AL group. 4) SIGIRR overexpression decreased the expression of the adaptor molecules myeloid differentiation factor 88 (MyD88), IL-1 receptor associated kinase 4 (IRAK4) and tumor necrosis factor receptor-associated factor 6 (TRAF6). 5) The levels of the inflammatory markers phospho-IkappaBalpha and phospho-NF-kappaB p65 decreased in the CR group. CONCLUSIONS: The inflammatory response might be alleviated by SIGIRR via blockade of the TLR4/NF-kappaB signaling pathway. Therefore, CR can decrease inflammation via SIGIRR overexpression, and SIGIRR might be a new target to delay aging. PMID- 26431349 TI - An amorphous CoSe film behaves as an active and stable full water-splitting electrocatalyst under strongly alkaline conditions. AB - It is attractive but still remains a big challenge to develop non-noble metal bifunctional electrocatalysts efficient for both oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) under alkaline conditions. Herein, an amorphous CoSe film electrodeposited on a Ti mesh (a-CoSe/Ti) is demonstrated to exhibit high electrocatalytic activity and stability for both reactions in 1.0 M KOH. It needs overpotentials of 292 and 121 mV to drive 10 mA cm(-2) for OER and HER, respectively. The two-electrode alkaline water electrolyzer affords a water splitting current of 10 mA cm(-2) at a cell voltage of 1.65 V. This work offers an attractive cost-effective catalytic material toward full water splitting applications. PMID- 26431350 TI - 'What do you think?' the collaborative practices of choice and care in a Danish obstetric ultrasound unit. AB - This paper is based on ethnographic fieldwork at an obstetric ultrasound unit in Denmark and explores the few, intense minutes of clinical interaction following a high-risk screening result for Down's syndrome. The category of high-risk transforms the routine ultrasound into a situation of inescapable choice, where the health of the foetus is questioned and decisions must be made. The clinical interactions following a high-risk result are investigated as processes of production, and the concepts of logic of choice and the logic of care are employed as analytical tools for identifying different rationales at play in the situation. The analysis shows that sonographers and women/couples collaboratively engage in logics of choice and care. Their mutual aim is to make the high-risk results meaningful and manageable so that a decision can be made. In this process initiative is shifted back and forth. Through a logic of care, complexity is reduced and statistics transformed by emphasising certain interpretations and leaving others unspoken. However, the logic of choice is also collectively maintained by positioning the women/couples as decision-makers. It is argued that in the obstetric ultrasound unit, the logic of choice provides a powerful frame, with the logic of care filling in the gaps and discontinuities to facilitate decisions. In this context, the logics are complementary rather than competing, and thus the analysis add new perspectives to the original concepts. In sum, the logics of choice and care provide a valuable analytical tool for interpreting and understanding the complex and collaborative practices of clinical interaction. PMID- 26431351 TI - Differences in Outcomes in Prenatally Diagnosed Congenital Diaphragmatic Hernia Compared to Postnatal Detection: A Single-Center Experience. AB - OBJECTIVES: To compare outcomes in pregnancies with a prenatal detection of congenital diaphragmatic hernia (CDH) with children diagnosed after birth, treated at the same institution, and to determine the ability to predict prognosis through measurements of the observed to expected lung-to-head ratio (O/E LHR). METHODS: This is a retrospective review of all children with CDH treated at our institution during 2006-2014. We compared outcomes of infants referred for surgery after postnatal diagnosis with outcomes of infants with prenatally diagnosed CDH. RESULTS: In the prenatal group, O/E LHR was significantly different between survivors and deceased patients, with a cutoff at 35% O/E LHR. Survival to discharge and 1-year survival were significantly higher in the postnatal group that required intubation within 24 h; i.e., 92 and 89% versus 85 and 73% in the prenatal group (p < 0.05). There was less need for extracorporeal membrane oxygenation (ECMO), 41 versus 60%, and patch, 41 versus 75% (p < 0.001), in the postnatal group with early diagnosis compared with the prenatal group, respectively. CONCLUSION: Children with prenatally diagnosed CDH represent a population with a more severe condition compared to infants diagnosed after birth. They have poorer outcomes with higher needs for ECMO or use of patch, and lower survival rates were observed at an O/E LHR below 35%. PMID- 26431352 TI - Performance of Four Transport and Storage Systems for Molecular Detection of Multidrug-Resistant Tuberculosis. AB - BACKGROUND: Detection of drug-resistant tuberculosis is essential for the control of the disease but it is often hampered by the limitation of transport and storage of samples from remote locations to the reference laboratory. We performed a retrospective field study to evaluate the performance of four supports enabling the transport and storage of samples to be used for molecular detection of drug resistance using the GenoType MTBDRplus. METHODS: Two hundred Mycobacterium tuberculosis strains were selected and spotted on slides, FTA cards, GenoCards, and in ethanol. GenoType MTBDRplus was subsequently performed with the DNA extracted from these supports. Sensitivity and specificity were calculated and compared to the results obtained by drug susceptibility testing. RESULTS: For all supports, the overall sensitivity and specificity for detection of resistance to RIF was between 95% and 100%, and for INH between 95% and 98%. CONCLUSION: The four transport and storage supports showed a good sensitivity and specificity for the detection of resistance to RIF and INH in M. tuberculosis strains using the GenoType MTBDRplus. These supports can be maintained at room temperature and could represent an important alternative cost-effective method useful for rapid molecular detection of drug-resistant TB in low-resource settings. PMID- 26431353 TI - Effects of Maternal Exposure to Piperonyl Butoxide (PBO) on Behavioral Development in F1-Generation Mice. AB - Female mice were exposed maternally to piperonyl butoxide (PBO) through diet to provide dietary levels of 0% (control), 0.01%, 0.03%, and 0.09% during gestation and lactation periods, and selected reproductive and neurobehavioral parameters were measured in the F1 generation. There was no adverse effect of PBO on litter size, litter weight, or sex ratio at birth. The average body weights of male offspring decreased significantly in dose-related manners on postnatal days (PNDs) 0, 4, 7, and 14 (p = 0.0019, 0.0096, 0.033, and 0.038, respectively) during the lactation period. In female offspring, the average body weights decreased in dose-related manners on PNDs 0, 4, 7, and 14 (p = 0.0027, 0.0104, 0.0193, and 0.0062, respectively). The survival of dams slightly decreased (p = 0.0209) in the high-dose group during the lactation period. With respect to behavioral developmental parameters, surface righting on PND 7 of male and female offspring was delayed significantly in a dose-related manner (p < 0.001 in each). Swimming direction on PND 7 of male offspring was delayed significantly in a dose related manner (p < 0.01), and for female offspring it was delayed significantly in the high-dose group (p < 0.05). Swimming head angle on PND 7 of male offspring was delayed significantly in a dose-related manner (p < 0.05). Spontaneous behavior examination in males indicated that rearing increased in the high-dose group in the F1 generation. The dose levels of PBO in the present study produced some adverse effects in neurobehavioral parameters in mice. PMID- 26431358 TI - Generation and preclinical characterization of an antibody specific for SEMA4D. AB - Semaphorin 4D (SEMA4D or CD100) is a member of the semaphorin family of proteins and an important mediator of the movement and differentiation of multiple cell types, including those of the immune, vascular, and nervous systems. Blocking the binding of SEMA4D to its receptors can result in physiologic changes that may have implications in cancer, autoimmune, and neurological disease. To study the effects of blocking SEMA4D, we generated, in SEMA4D-deficient mice, a panel of SEMA4D-specific hybridomas that react with murine, primate, and human SEMA4D. Utilizing the complementarity-determining regions from one of these hybridomas (mAb 67-2), we generated VX15/2503, a humanized IgG4 monoclonal antibody that is currently in clinical development for the potential treatment of various malignancies and neurodegenerative disorders, including multiple sclerosis and Huntington's disease. This work describes the generation and characterization of VX15/2503, including in vitro functional testing, epitope mapping, and an in vivo demonstration of efficacy in an animal model of rheumatoid arthritis. PMID- 26431359 TI - TGF-beta3 and IGF-1 synergy ameliorates nucleus pulposus mesenchymal stem cell differentiation towards the nucleus pulposus cell type through MAPK/ERK signaling. AB - This study aimed to investigate the synergy between transforming growth factor beta 3 (TGF-beta3) and insulin-like growth factor 1 (IGF-1) on nucleus pulposus derived mesenchymal stem cells (NP-MSCs) and the underlying mechanism using a serum-free culture system. NP-MSC proliferation and viability were measured using a CCK-8 assay and annexin V-FITC/propidium iodide, respectively. NP-MSCs in micromasses were investigated for differentiation towards nucleus pulposus cells (NPCs). SOX-9, collagen-I, collagen-II, aggrecan and decorin expressions were detected by RT-PCR and immunoblotting. Matrix deposition was assessed by sulfated glycosaminoglycan (sGAG) analysis. Novel chondrogenic and nucleus pulposus (NP) genes were detected to distinguish differentiated cell types. MAPK/ERK and TGF/Smad signaling pathways were also examined. As a result, the synergy between TGF-beta3 and IGF-1 enhanced NP-MSC viability, extracellular matrix (ECM) biosynthesis and differentiation towards NPCs, partly through the activation of the MAPK/ERK signaling pathway. Therefore, the synergy between TGF-beta3 and IGF 1 ameliorates NP-MSC viability, differentiation and promotes intervertebral disc regeneration. PMID- 26431365 TI - Adding transcutaneous electrical nerve stimulation to visual scanning training does not enhance treatment effect on hemispatial neglect: a randomized, controlled, double-blind study. AB - BACKGROUND: Left-sided transcutaneous electrical nerve stimulation (TENS) increases right hemispheric activity, which may improve the rehabilitative outcome of hemispatial neglect. OBJECTIVE: To examine the behavioral effect of electrical stimulation of the nerve afferents of the left hand during early neuropsychological rehabilitation of post-stroke patients with hemispatial neglect. METHODS: This randomized, controlled, double-blind study included 29 patients (enrolled in the experimental or control group) with left hemispatial neglect after right hemispheric stroke. For 3 weeks, patients received 15 therapeutic sessions involving TENS (active or sham) with a mesh glove applied on the entire left hand during the first 30 minutes of a 45-minute conventional visual scanning training (VST). Signs of hemispatial neglect were assessed using a psychometric test before and after treatment. RESULTS: Univariate analysis of covariance revealed that differences between the control and experimental groups were not significant after treatment (F(1, 22) = 0.294, P = 0.593) when adjusted for pre-treatment scores and time since stroke onset. This suggested that electrical stimulation failed to mitigate the severity of hemispatial neglect symptoms. CONCLUSION: Our study did not provide evidence of the effectiveness of TENS when added to VST during early rehabilitation for patients with post-stroke hemispatial neglect. Other techniques (applied alone or together) should be sought to improve recovery in this population. PMID- 26431367 TI - Attenuating microwave radiation by absorption through controlled nanoparticle localization in PC/PVDF blends. AB - Nanoscale ordering in a polymer blend structure is indispensable to obtain materials with tailored properties. It was established here that controlling the arrangement of nanoparticles, with different characteristics, in co-continuous PC/PVDF (polycarbonate/poly(vinylidene fluoride)) blends can result in outstanding microwave absorption (ca. 90%). An excellent reflection loss (RL) of ca. -71 dB was obtained for a model blend structure wherein the conducting (multiwall carbon nanotubes, MWNTs) and the magnetic inclusions (Fe3O4) are localized in PVDF and the dielectric inclusion (barium titanate, BT) is in PC. The MWNTs were modified using polyaniline, which facilitates better charge transport in the blends. Furthermore, by introducing surface active groups on BT nanoparticles and changing the macroscopic processing conditions, the localization of BT nanoparticles can be tailored, otherwise BT nanoparticles would localize in the preferred phase (PVDF). In this study, we have shown that by ordered arrangement of nanoparticles, the incoming EM radiation can be attenuated. For instance, when PANI-MWNTs were localized in PVDF, the shielding was mainly through reflection. Now by localizing the conducting inclusion and the magnetic lossy materials in PVDF and the dielectric materials in PC, an outstanding shielding effectiveness of ca. -37 dB was achieved where shielding was mainly through absorption (ca. 90%). Thus, this study clearly demonstrates that lightweight microwave absorbers can be designed using polymer blends as a tool. PMID- 26431366 TI - Global Burden of Leptospirosis: Estimated in Terms of Disability Adjusted Life Years. AB - BACKGROUND: Leptospirosis, a spirochaetal zoonosis, occurs in diverse epidemiological settings and affects vulnerable populations, such as rural subsistence farmers and urban slum dwellers. Although leptospirosis can cause life-threatening disease, there is no global burden of disease estimate in terms of Disability Adjusted Life Years (DALYs) available. METHODOLOGY/PRINCIPAL FINDINGS: We utilised the results of a parallel publication that reported global estimates of morbidity and mortality due to leptospirosis. We estimated Years of Life Lost (YLLs) from age and gender stratified mortality rates. Years of Life with Disability (YLDs) were developed from a simple disease model indicating likely sequelae. DALYs were estimated from the sum of YLLs and YLDs. The study suggested that globally approximately 2.90 million DALYs are lost per annum (UIs 1.25-4.54 million) from the approximately annual 1.03 million cases reported previously. Males are predominantly affected with an estimated 2.33 million DALYs (UIs 0.98-3.69) or approximately 80% of the total burden. For comparison, this is over 70% of the global burden of cholera estimated by GBD 2010. Tropical regions of South and South-east Asia, Western Pacific, Central and South America, and Africa had the highest estimated leptospirosis disease burden. CONCLUSIONS/SIGNIFICANCE: Leptospirosis imparts a significant health burden worldwide, which approach or exceed those encountered for a number of other zoonotic and neglected tropical diseases. The study findings indicate that highest burden estimates occur in resource-poor tropical countries, which include regions of Africa where the burden of leptospirosis has been under-appreciated and possibly misallocated to other febrile illnesses such as malaria. PMID- 26431368 TI - SLC38A9: A lysosomal amino acid transporter at the core of the amino acid-sensing machinery that controls MTORC1. AB - The mechanistic target of rapamycin (serine/threonine kinase) complex 1 (MTORC1) acts as a crucial regulator of cellular metabolism by integrating growth factor presence, energy and nutrient availability to coordinate anabolic and catabolic processes, and controls cell growth and proliferation. Amino acids are critical for MTORC1 activation, but the molecular mechanisms involved in sensing their presence are just beginning to be understood. We recently reported that the previously uncharacterized amino acid transporter SLC38A9 is a member of the lysosomal sensing machinery that signals amino acid availability to MTORC1. SLC38A9 is the first component of this complex shown to physically engage amino acids, suggesting a role at the core of the amino acid-sensing mechanism. PMID- 26431369 TI - Virulence of Bacteria Colonizing Vascular Bundles in Ischemic Lower Limbs. AB - BACKGROUND: We documented previously the presence of bacterial flora in vascular bundles, lymphatics, and lymph nodes of ischemic lower limbs amputated because of multifocal atheromatic changes that made them unsuitable for reconstructive surgery and discussed their potential role in tissue destruction. The question arose why bacterial strains inhabiting lower limb skin and considered to be saprophytes become pathogenic once they colonize deep tissues. Bacterial pathogenicity is evoked by activation of multiple virulence factors encoded by groups of genes. METHODS: We identified virulence genes in bacteria cultured from deep tissue of ischemic legs of 50 patients using a polymerase chain reaction technique. RESULTS: The staphylococcal virulence genes fnbA (fibronectin-binding protein A), cna (collagen adhesin precursor), and ica (intercellular adhesion) were present in bacteria isolated from both arteries and, to a lesser extent, skin. The IS256 gene, whose product is responsible for biofilm formation, was more frequent in bacteria retrieved from the arteries than skin bacteria. Among the virulence genes of Staphylococcus epidermidis encoding autolysin atlE, icaAB (intercellular adhesion), and biofilm insert IS256, only the latter was detected in arterial specimens. Bacteria cultured from the lymphatics did not reveal expression of eta and IS256 in arteries. The Enterococcus faecalis asa 373 (aggregation substance) and cylA (cytolysin activator) frequency was greater in arteries than in skin bacteria, as were the E. faecium cyl A genes. All Pseudomonas aeruginosa virulence genes were present in bacteria cultured from both the skin and arteries. Staphylococci colonizing arterial bundles and transported to tissues via ischemic limb lymphatics expressed virulence genes at greater frequency than did those dwelling on the skin surface. Moreover, enterococci and Pseudomonas isolated from arterial bundles expressed many virulence genes. CONCLUSIONS: These findings may add to the understanding of the mechanism of development of destructive changes in lower limb ischemic tissues by the patient's, but not hospital-acquired, bacteria, as well as the generally unsatisfactory results of antibiotic administration in these cases. More aggressive antibiotic therapy targeted at the virulent species should be applied. PMID- 26431370 TI - Tailoring the Pore Size and Functionality of UiO-Type Metal-Organic Frameworks for Optimal Nerve Agent Destruction. AB - Evaluation of UiO-66 and UiO-67 metal-organic framework derivatives as catalysts for the degradation of soman, a chemical warfare agent, showed the importance of both the linker size and functionality. The best catalysts yielded half-lives of less than 1 min. Further testing with a nerve agent simulant established that different rate-assessment techniques yield similar values for degradation half lives. PMID- 26431371 TI - Risk factors for mortality in patients with Staphylococcus aureus bloodstream infection. AB - In this two year retrospective analysis, we evaluated the epidemiology and risk factors for mortality of Staphylococcus aureus bloodstream infection (SaBSI). Methicillin-susceptible S. aureus (MSSA) was isolated in 84 (44.2%) and methicillin-resistant S. aureus (MRSA) in 106 episodes (55.8%). The mortality rate after 21 days was 16.4%. At univariate analysis older age, no removal of central venous catheter (CVC), prosthetic heart valves, severe sepsis, septic shock and high APACHE II score were significantly associated with mortality, whereas treatment duration > 48 hours, appropriate targeted therapy and prolonged treatment duration were significantly associated with survival. At multivariate analysis, prosthetic valves, septic shock and fever 48 hours after the diagnosis were significantly related to mortality. In this study, the mortality was associated with clinical rather than microbiological factors. PMID- 26431372 TI - Comorbidity in Migraine with Functional Somatic Syndromes, Psychiatric Disorders and Inflammatory Diseases: A Matter of Central Sensitization? AB - To approach the questions as to why migraine appears to be associated with functional somatic syndromes (FSSs) and whether central sensitization may be an underlying mechanism, the present study investigated (a) comorbidity with diagnoses of three FSSs, three psychiatric disorders, and three inflammatory diseases, (b) degree of mental health problems (stress, burnout, anxiety, depression and somatization), and (c) prevalence of ten cognitive/affective and nine airway symptoms in persons with migraine in the general population. From a randomized and stratified Swedish adult sample, questionnaire data were analyzed from 151 individuals with a diagnosis of migraine and 3,255 without migraine. The results showed (a) significant comorbidity in migraine with all FSSs, psychiatric disorders and inflammatory diseases, (b) significantly elevated scores on stress, burnout, anxiety, depression, and somatization, and (c) relatively high prevalence rates on almost all symptoms. Taken together, the results motivate future study of central sensitization as a mechanism underlying migraine. PMID- 26431373 TI - Effect of antiretroviral therapy on hemoglobin A2 values can have implications in antenatal beta-thalassemia screening programs. AB - BACKGROUND: Raised hemoglobin-A2 (HbA2) is the diagnostic hallmark of beta thalassemia trait (betaTT). Diagnostic difficulties may arise in HIV-positive patients on antiretroviral therapy (ART). We compared the effect of various antiretroviral drugs on HbA2 levels. We attempted to determine which drugs elevate HbA2 levels causing a false-positive diagnosis of betaTT and correlate the findings with red cell indices. METHODS: A retrospective analysis of the records of an antenatal thalassemia screening program was carried out for 78 HIV positive adults (70 antenatal women and 8 husbands) to study the effect of antiretroviral drugs on HbA2 levels. Three had betaTT; 20 treatment-naive subjects constituted controls. The effects of zidovudine (36 cases), stavudine (7 cases), and tenofovir (12 cases) were evaluated. High-performance liquid chromatography was done for HbA2 levels. Values of 3.5-3.9% were borderline and >= 4% with hypochromic microcytosis was considered to be betaTT. RESULTS: Twenty individuals not on ART had normal HbA2%. Three patients had betaTT and showed hypochromic microcytosis despite being on zidovudine. Fourteen of 55 patients on treatment (25.5%) had borderline HbA2 values (mean 3.7%): 11 were on a zidovudine based regimen and 3 on a stavudine-based regimen. One patient on zidovudine had 4.1% HbA2 with normal Hb and severe macrocytosis (MCV 128.5 fl), leading to a false suspicion of betaTT. All patients on tenofovir had normal HbA2. Hematological parameters, including mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), and HbA2 levels were increased due to antiretroviral drugs zidovudine and stavudine. CONCLUSION: Treatment-naive subjects and those on tenofovir showed no effect on HbA2 levels compared with zidovudine and stavudine. A proportion of patients on zidovudine or stavudine had borderline elevated HbA2 levels, which could lead to a false impression of betaTT. PMID- 26431375 TI - Flirting with Danger: Power and Choice in Heterosexual Relationships, Produced, directed, and edited by Sut Jhally and Andrew Killoy. PMID- 26431374 TI - Endogenous Sex Steroid Hormones, Lipid Subfractions, and Ectopic Adiposity in Asian Indians. AB - BACKGROUND: Estradiol, testosterone (T), and sex hormone binding globulin (SHBG) levels are associated with lipid subfractions in men and women. Our objective was to determine if associations are independent from adipose tissue area among Asian Indians. METHODS: We used data from 42 women and 57 Asian Indian men who did not use exogenous steroids or lipid-lowering medications. Lipoprotein subfractions including low-density lipoprotein cholesterol (LDL), very low-density lipoprotein cholesterol (VLDL), and intermediate density lipoprotein (IDL) were assessed by ion mobility spectrometry. Intra-abdominal adiposity was assessed by computed tomography. Multivariable regression models estimated the association between sex hormones with lipoprotein subfractions before and after adjustment for adiposity. RESULTS: Among women, lower logSHBG levels were associated with smaller logLDL particle size and higher logtriglycerides, logVLDL, and logIDL, although these associations were attenuated with adjustment for visceral adiposity in particular. Among women, lower logSHBG levels was significantly associated with lower logmedium LDL and logsmall LDL concentrations even after consideration of visceral and hepatic adiposity and insulin resistance as represented by the homeostasis model assessment of insulin resistance (HOMA-IR). Among men, lower logSHBG was also associated with smaller logLDL peak diameter size and higher logtriglycerides and logVLDL, even after adjustment for HOMA-IR and adiposity. Relationships between sex steroids and lipid subfractions were not significant among women. Among men, higher total testosterone was associated with higher logHDL and logLDL particle size, and lower logtriglycerides and logVLDL, but these associations were partially attenuated with adjustment for adiposity and HOMA-IR. CONCLUSIONS: Among Asian Indians, SHBG is associated with more favorable lipid subfraction concentrations, independent of hepatic and visceral fat. PMID- 26431376 TI - Vesicular stomatitis virus expressing interferon-beta is oncolytic and promotes antitumor immune responses in a syngeneic murine model of non-small cell lung cancer. AB - Vesicular stomatitis virus (VSV) is a potent oncolytic virus for many tumors. VSV that produces interferon-beta (VSV-IFNbeta) is now in early clinical testing for solid tumors. Here, the preclinical activity of VSV and VSV-IFNbeta against non small cell lung cancer (NSCLC) is reported. NSCLC cell lines were treated in vitro with VSV expressing green fluorescence protein (VSV-GFP) and VSV-IFNbeta. VSV-GFP and VSV-IFNbeta were active against NSCLC cells. JAK/STAT inhibition with ruxolitinib re-sensitized resistant H838 cells to VSV-IFNbeta mediated oncolysis. Intratumoral injections of VSV-GFP and VSV-IFNbeta reduced tumor growth and weight in H2009 nude mouse xenografts (p < 0.01). A similar trend was observed in A549 xenografts. Syngeneic LM2 lung tumors grown in flanks of A/J mice were injected with VSV-IFNbeta intratumorally. Treatment of LM2 tumors with VSV IFNbeta resulted in tumor regression, prolonged survival (p < 0.0001), and cure of 30% of mice. Intratumoral injection of VSV-IFNbeta resulted in decreased tumor infiltrating regulatory T cells (Treg) and increased CD8+ T cells. Tumor cell expression of PDL-1 was increased after VSV-IFNbeta treatment. VSV-IFNbeta has potent antitumor effects and promotes systemic antitumor immunity. These data support further clinical investigation of VSV-IFNbeta for NSCLC. PMID- 26431377 TI - Pharmacologic regulation of AMPK in breast cancer affects cytoskeletal properties involved with microtentacle formation and re-attachment. AB - The presence of tumor cells in the circulation is associated with a higher risk of metastasis in patients with breast cancer. Circulating breast tumor cells use tubulin-based structures known as microtentacles (McTNs) to re-attach to endothelial cells and arrest in distant organs. McTN formation is dependent on the opposing cytoskeletal forces of stable microtubules and the actin network. AMP-activated protein kinase (AMPK) is a cellular metabolic regulator that can alter actin and microtubule organization in epithelial cells. We report that AMPK can regulate the cytoskeleton of breast cancer cells in both attached and suspended conditions. We tested the effects of AMPK on microtubule stability and the actin-severing protein, cofilin. AMPK inhibition with compound c increased both microtubule stability and cofilin activation, which also resulted in higher McTN formation and re-attachment. Conversely, AMPK activation with A-769662 decreased microtubule stability and cofilin activation with concurrent decreases in McTN formation and cell re-attachment. This data shows for the first time that AMPK shifts the balance of cytoskeletal forces in suspended breast cancer cells, which affect their ability to form McTNs and re-attach. These results support a model where AMPK activators may be used therapeutically to reduce the metastatic efficiency of breast tumor cells. PMID- 26431378 TI - Auranofin induces apoptosis by ROS-mediated ER stress and mitochondrial dysfunction and displayed synergistic lethality with piperlongumine in gastric cancer. AB - Gastric cancer (GC) is one of the leading causes of cancer mortality in the world. In addressing the need of treatments for relapsed disease, we report the identification of an existing U.S. Food and Drug Administration-approved small molecule drug to repurpose for GC treatment. Auranofin (AF), clinically used to treat rheumatic arthritis, but it exhibited preclinical efficacy in GC cells. By increasing intracellular reactive oxygen species (ROS) levels, AF induces a lethal endoplasmic reticulum stress response and mitochondrial dysfunction in cultured GC cells. Blockage of ROS production reversed AF-induced ER stress and mitochondrial pathways activation as well as apoptosis. In addition, AF displays synergistic lethality with an ROS-generating agent piperlongumine, which is a natural product isolated from the long pepper Piper longum L. Taken together, this work provides a novel anticancer candidate for the treatment of gastric cancer. More importantly, it reveals that increased ROS generation might be an effective strategy in treating human gastric cancer. PMID- 26431379 TI - Metformin and temozolomide act synergistically to inhibit growth of glioma cells and glioma stem cells in vitro and in vivo. AB - Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. In spite of advances in diagnosis and therapy, the prognosis of patients with GBM has remained dismal. The fast recurrence and multi-drug resistance are some of the key challenges in combating brain tumors. Glioma stem cells (GSCs) which are considered the source of relapse and chemoresistance, the need for more effective therapeutic options is overwhelming. In our present work, we found that combined treatment with temozolomide (TMZ) and metformin (MET) synergistically inhibited proliferation and induced apoptosis in both glioma cells and GSCs. Combination of TMZ and MET significantly reduced the secondary gliosphere formation and expansion of GSCs. We first demonstrated that MET effectively inhibited the AKT activation induced by TMZ, and a combination of both drugs led to enhanced reduction of mTOR, 4EBP1 and S6K phosphorylation. In addition, the combination of the two drugs was accompanied with a powerful AMP-activated protein kinase (AMPK) activation, while this pathway is not determinant. Xenografts performed in nude mice demonstrate in vivo demonstrated that combined treatment significantly reduced tumor growth rates and prolonged median survival of tumor-bearing mice. In conclusion, TMZ in combination with MET synergistically inhibits the GSCs proliferation through downregulation of AKT-mTOR signaling pathway. The combined treatment of two drugs inhibits GSCs self-renewal capability and partly eliminates GSCs in vitro and in vivo. This combined treatment could be a promising option for patients with advanced GBM. PMID- 26431380 TI - Usp22 deficiency impairs intestinal epithelial lineage specification in vivo. AB - Epigenetic regulatory mechanisms play a central role in controlling gene expression during development, cell differentiation and tumorigenesis. Monoubiquitination of histone H2B is one epigenetic modification which is dynamically regulated by the opposing activities of specific ubiquitin ligases and deubiquitinating enzymes (DUBs). The Ubiquitin-specific Protease 22 (USP22) is the ubiquitin hydrolase component of the human SAGA complex which deubiquitinates histone H2B during transcription. Recently, many studies have investigated an oncogenic potential of USP22 overexpression. However, its physiological function in organ maintenance, development and its cellular function remain largely unknown. A previous study reported embryonic lethality in Usp22 knockout mice. Here we describe a mouse model with a global reduction of USP22 levels which expresses the LacZ gene under the control of the endogenous Usp22 promoter. Using this reporter we found Usp22 to be ubiquitously expressed in murine embryos. Notably, adult Usp2(2lacZ/lacZ) displayed low residual Usp22 expression levels coupled with a reduced body size and weight. Interestingly, the reduction of Usp22 significantly influenced the frequency of differentiated cells in the small intestine and the brain while H2B and H2Bub1 levels remained constant. Taken together, we provide evidence for a physiological role for USP22 in controlling cell differentiation and lineage specification. PMID- 26431381 TI - Inhibition of testicular embryonal carcinoma cell tumorigenicity by peroxisome proliferator-activated receptor-beta/delta- and retinoic acid receptor-dependent mechanisms. AB - Peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) has important physiological functions in control of cell growth, lipid and glucose homeostasis, differentiation and inflammation. To investigate the role of PPARbeta/delta in cancer, stable human testicular embryonal carcinoma cell lines were developed that constitutively express PPARbeta/delta. Expression of PPARbeta/delta caused enhanced activation of the receptor, and this significantly decreased proliferation, migration, invasion, anchorage-independent growth, and also reduced tumor mass and volume of ectopic xenografts derived from NT2/D1 cells compared to controls. The changes observed in xenografts were associated with decreased PPARbeta/delta-dependent expression of proliferating cell nuclear antigen and octamer-binding transcription factor-3/4, suggesting suppressed tumor proliferation and induction of differentiation. Inhibition of migration and invasion was mediated by PPARbeta/delta competing with formation of the retinoic acid receptor (RAR)/retinoid X receptor (RXR) complex, resulting in attenuation of RARalpha-dependent matrix metalloproteinase-2 expression and activity. These results demonstrate that PPARbeta/delta mediates attenuation of human testicular embryonal carcinoma cell progression through a novel RAR-dependent mechanism and suggest that activation of PPARbeta/delta inhibits RAR/RXR dimerization and represents a new therapeutic strategy. PMID- 26431383 TI - Predicted vitamin D status during pregnancy in relation to offspring forearm fractures in childhood: a study from the Danish National Birth Cohort. AB - In a prospective cohort study, the association between maternal vitamin D status during pregnancy and offspring forearm fractures during childhood and adolescence was analysed in 30 132 mother and child pairs recruited to the Danish National Birth Cohort between 1996 and 2002. Data on characteristics, dietary factors and lifestyle factors were collected on several occasions during pregnancy. We analysed the association between predicted vitamin D status, based on a subsample with 25-hydroxyvitamin D (25(OH)D) biomarker measurements (n 1497) from gestation week 25, and first-time forearm fractures among offspring between birth and end of follow-up. Diagnoses were extracted from the Danish National Patient Register. Multivariable Cox regression models using age as the underlying time scale indicated no overall association between predicted vitamin D status (based on smoking, season, dietary and supplementary vitamin D intake, tanning bed use and outdoor physical activity) in pregnancy and offspring forearm fractures. Likewise, measured 25(OH)D, tanning bed use and dietary vitamin D intake were not associated with offspring forearm fractures. In mid-pregnancy, 91 % of the women reported intake of vitamin D from dietary supplements. Offspring of women who took >10 ug/d in mid-pregnancy had a significantly increased risk for fractures compared with the reference level of zero intake (hazard ratios (HR) 1.31; 95% CI 1.06, 1.62), but this was solely among girls (HR 1.48; 95% CI 1.10, 2.00). Supplement use in the peri-conceptional period exhibited similar pattern, although not statistically significant. In conclusion, our data indicated no protective effect of maternal vitamin D status with respect to offspring forearm fractures. PMID- 26431382 TI - Cigarette side-stream smoke lung and bladder carcinogenesis: inducing mutagenic acrolein-DNA adducts, inhibiting DNA repair and enhancing anchorage-independent growth cell transformation. AB - Second-hand smoke (SHS) is associated with 20-30% of cigarette-smoke related diseases, including cancer. Majority of SHS (>80%) originates from side-stream smoke (SSS). Compared to mainstream smoke, SSS contains more tumorigenic polycyclic aromatic hydrocarbons and acrolein (Acr). We assessed SSS-induced benzo(a)pyrene diol epoxide (BPDE)- and cyclic propano-deoxyguanosine (PdG) adducts in bronchoalveolar lavage (BAL), lung, heart, liver, and bladder-mucosa from mice exposed to SSS for 16 weeks. In SSS exposed mice, Acr-dG adducts were the major type of PdG adducts formed in BAL (p < 0.001), lung (p < 0.05), and bladder mucosa (p < 0.001), with no significant accumulation of Acr-dG adducts in heart or liver. SSS exposure did not enhance BPDE-DNA adduct formation in any of these tissues. SSS exposure reduced nucleotide excision repair (p < 0.01) and base excision repair (p < 0.001) in lung tissue. The levels of DNA repair proteins, XPC and hOGG1, in lung tissues of exposed mice were significantly (p < 0.001 and p < 0.05) lower than the levels in lung tissues of control mice. We found that Acr can transform human bronchial epithelial and urothelial cells in vitro. We propose that induction of mutagenic Acr-DNA adducts, inhibition of DNA repair, and induction of cell transformation are three mechanisms by which SHS induces lung and bladder cancers. PMID- 26431390 TI - Using Virtual Technology to Promote Functional Communication in Aphasia: Preliminary Evidence From Interactive Dialogues With Human and Virtual Clinicians. AB - PURPOSE: We investigated the feasibility of using a virtual clinician (VC) to promote functional communication abilities of persons with aphasia (PWAs). We aimed to determine whether the quantity and quality of verbal output in dialogues with a VC would be the same or greater than those with a human clinician (HC). METHOD: Four PWAs practiced dialogues for 2 sessions each with a HC and VC. Dialogues from before and after practice were transcribed and analyzed for content. We compared measures taken before and after practice in the VC and HC conditions. RESULTS: Results were mixed. Participants either produced more verbal output with the VC or showed no difference on this measure between the VC and HC conditions. Participants also showed some improvement in postpractice narratives. CONCLUSION: Results provide support for the feasibility and applicability of virtual technology to real-life communication contexts to improve functional communication in PWAs. PMID- 26431391 TI - Problems and Pitfalls in the Analysis of Amygdalin and Its Epimer. AB - alpha-[(6-O-beta-d-Glucopyranosyl-beta-d-glucopyranosyl)oxy]-(alphaR) benzeneacetonitrile, or R-amygdalin, is the most common cyanogenic glycoside found in seeds and kernels of the Rosaceae family and other plant genera such as Passiflora. Many commercially important seeds are analyzed for amygdalin content. In "alternative medicine", amygdalin has been sold as a treatment for cancer for several decades without any rigorous scientific support for its efficacy. We have found that there are some inconsistencies and possible problems in the published analytical chemistry of amygdalin. It is shown that some analytical approaches do not account for the presence of the S-isomer; therefore, a fast reliable method was developed using a chiral stationary phase and HPLC. This approach allows "real-time" monitoring and complete and highly efficient separations. It is found that the S-amygdalin continuously forms in aqueous solutions. A striking result is that the conversion of amygdalin is glassware dependent. "Clean" vials from various vendors can show drastically different reaction rates of the conversion to the isomer (S-amygdalin, also called neo-amygdalin). The epimerization kinetics are dependent on the solvent, temperature, pH, and the nature of the container. For example, epimerization in water was complete in <15 min in a new glass vial taken from the box, whereas it can take >1 h in specially cleaned glassware. Conversely, epimerization can be significantly delayed at high temperature if high-density polyethylene is used as the container. Hence, inert plastic containers are recommended for storage of aqueous amygdalin solutions. Commercial preparations of R-amygdalin actually contain greater quantities of S amygdalin and ~ 5% of other degradation products. PMID- 26431392 TI - Highly Efficient Copper-Indium-Selenide Quantum Dot Solar Cells: Suppression of Carrier Recombination by Controlled ZnS Overlayers. AB - Copper-indium-selenide (CISe) quantum dots (QDs) are a promising alternative to the toxic cadmium- and lead-chalcogenide QDs generally used in photovoltaics due to their low toxicity, narrow band gap, and high absorption coefficient. Here, we demonstrate that the photovoltaic performance of CISe QD-sensitized solar cells (QDSCs) can be greatly enhanced simply by optimizing the thickness of ZnS overlayers on the QD-sensitized TiO2 electrodes. By roughly doubling the thickness of the overlayers compared to the conventional one, conversion efficiency is enhanced by about 40%. Impedance studies reveal that the thick ZnS overlayers do not affect the energetic characteristics of the photoanode, yet enhance the kinetic characteristics, leading to more efficient photovoltaic performance. In particular, both interfacial electron recombination with the electrolyte and nonradiative recombination associated with QDs are significantly reduced. As a result, our best cell yields a conversion efficiency of 8.10% under standard solar illumination, a record high for heavy metal-free QD solar cells to date. PMID- 26431393 TI - Synthesis and Properties of the 5-Methyluridine Derivative of 3,4-Dihydro-2H pyran-Bridged Nucleic Acid (DpNA). AB - A novel 2'-O,4'-C-bridged nucleic acid, 3,4-dihydro-2H-pyran bridge moiety (DpNA), with a dioxabicyclo[3.2.1]oct-3-ene ring was designed. Construction of the dihydropyran bridge was achieved by dehydration of a six-membered hemiacetal ring, and the DpNA monomer was synthesized in 10 steps from 5-methyluridine (total yield 9%). The synthesized DpNA monomer was incorporated into oligonucleotides to examine the properties of the modified oligonucleotides. The DpNA-modified oligonucleotides possessed high affinity toward ssRNA and were more resistant to nucleases compared to the corresponding natural oligonucleotide. PMID- 26431394 TI - Chalcones from Angelica keiskei: Evaluation of Their Heat Shock Protein Inducing Activities. AB - Five new chalcones, 4,2',4'-trihydroxy-3'-[(2E,5E)-7-methoxy-3,7-dimethyl-2,5 octadienyl]chalcone (1), (+/-)-4,2',4'-trihydroxy-3'-[(2E)-6-hydroxy-7-methoxy 3,7-dimethyl-2-octenyl]chalcone (2), 4,2',4'-trihydroxy-3'-[(2E)-3-methyl-5-(1,3 dioxolan-2-yl)-2-pentenyl]chalcone (3), 2',3'-furano-4-hydroxy-4'-methoxychalcone (4), and (+/-)-4-hydroxy-2',3'-(2,3-dihydro-2-methoxyfurano)-4'-methoxychalcone (5), were isolated from the aerial parts of Angelica keiskei Koidzumi together with eight known chalcones, 6-13, which were identified as (+/-)-4,2',4' trihydroxy-3'-[(6E)-2-hydroxy-7-methyl-3-methylene-6-octenyl]chalcone (6), xanthoangelol (7), xanthoangelol F (8), xanthoangelol G (9), 4-hydroxyderricin (10), xanthoangelol D (11), xanthoangelol E (12), and xanthoangelol H (13), respectively. Chalcones 1-13 were evaluated for their promoter activity on heat shock protein 25 (hsp25, murine form of human hsp27). Compounds 1 and 6 activated the hsp25 promoter by 21.9- and 29.2-fold of untreated control at 10 MUM, respectively. Further protein expression patterns of heat shock factor 1 (HSF1), HSP70, and HSP27 by 1 and 6 were examined. Compound 6 increased the expression of HSF1, HSP70, and HSP27 by 4.3-, 1.5-, and 4.6-fold of untreated control, respectively, without any significant cellular cytotoxicities, whereas 1 did not induce any expression of these proteins. As a result, 6 seems to be a prospective HSP inducer. PMID- 26431395 TI - Exome Capture with Heterologous Enrichment in Pig (Sus scrofa). AB - The discovery of new protein-coding DNA variants related to carcass traits is very important for the Italian pig industry, which requires heavy pigs with higher thickness of subcutaneous fat for Protected Designation of Origin (PDO) productions. Exome capture techniques offer the opportunity to focus on the regions of DNA potentially related to the gene and protein expression. In this research a human commercial target enrichment kit was used to evaluate its performances for pig exome capture and for the identification of DNA variants suitable for comparative analysis. Two pools of 30 pigs each, crosses of Italian Duroc X Large White (DU) and Commercial hybrid X Large White (HY), were used and NGS libraries were prepared with the SureSelectXT Target Enrichment System for Illumina Paired-End Sequencing Library (Agilent). A total of 140.2 M and 162.5 M of raw reads were generated for DU and HY, respectively. Average coverage of all the exonic regions for Sus scrofa (ENSEMBL Sus_scrofa.Sscrofa10.2.73.gtf) was 89.33X for DU and 97.56X for HY; and 35% of aligned bases uniquely mapped to off target regions. Comparison of sequencing data with the Sscrofa10.2 reference genome, after applying hard filtering criteria, revealed a total of 232,530 single nucleotide variants (SNVs) of which 20.6% mapped in exonic regions and 49.5% within intronic regions. The comparison of allele frequencies of 213 randomly selected SNVs from exome sequencing and the same SNVs analyzed with a Sequenom MassARRAY(r) system confirms that this "human-on-pig" approach offers new potentiality for the identification of DNA variants in protein-coding genes. PMID- 26431396 TI - Bilateral Pneumothoraces Following BiV ICD Placement: A Case of Buffalo Chest Syndrome. AB - BACKGROUND: Contralateral pneumothorax following device implantation on the left side has been reported in a few cases. The majority of contralateral pneumothoraces showed evidence of atrial perforation on computed tomography (CT), echocardiography, or chest x-rays and required lead revision. To the best of our knowledge there is only 1 other reported case of contralateral pneumothorax without evidence of macro-displacement of the atrial lead. In that case the patient experienced a right-sided pneumothorax on day 1 after undergoing repositioning of the atrial lead. CASE REPORT: The current case is unique on several accounts, including timing of the contralateral pneumothorax and no evidence of associated atrial lead perforation on device interrogation or CT imaging. Furthermore, the appearance of contralateral pneumothorax within 8 hours of clamping of the ipsilateral chest tube argues in favor of a pleuro-pleural fistula. CONCLUSIONS: The term 'buffalo chest' refers to a single pleural space, with no anatomical separation of the 2 hemithoraces, as seen in an American buffalo or bison. We believe this to be a case of buffalo chest syndrome. PMID- 26431397 TI - Etiology of Non-Cystic Fibrosis Bronchiectasis in Adults and Its Correlation to Disease Severity. AB - RATIONALE: Testing for underlying etiology is a key part of bronchiectasis management, but it is unclear whether the same extent of testing is required across the spectrum of disease severity. OBJECTIVES: The aim of the present study was to identify the etiology of bronchiectasis across European cohorts and according to different levels of disease severity. METHODS: We conducted an analysis of seven databases of adult outpatients with bronchiectasis prospectively enrolled at the bronchiectasis clinics of university teaching hospitals in Monza, Italy; Dundee and Newcastle, United Kingdom; Leuven, Belgium; Barcelona, Spain; Athens, Greece; and Galway, Ireland. All the patients at every site underwent the same comprehensive diagnostic workup as suggested by the British Thoracic Society. MEASUREMENTS AND MAIN RESULTS: Among the 1,258 patients enrolled, an etiology of bronchiectasis was determined in 60%, including postinfective (20%), chronic obstructive pulmonary disease related (15%), connective tissue disease related (10%), immunodeficiency related (5.8%), and asthma related (3.3%). An etiology leading to a change in patient's management was identified in 13% of the cases. No significant differences in the etiology of bronchiectasis were present across different levels of disease severity, with the exception of a higher prevalence of chronic obstructive pulmonary disease-related bronchiectasis (P < 0.001) and a lower prevalence of idiopathic bronchiectasis (P = 0.029) in patients with severe disease. CONCLUSIONS: Physicians should not be guided by disease severity in suspecting specific etiologies in patients with bronchiectasis, although idiopathic bronchiectasis appears to be less common in patients with the most severe disease. PMID- 26431398 TI - Biofilm Formation Mechanisms of Pseudomonas aeruginosa Predicted via Genome-Scale Kinetic Models of Bacterial Metabolism. AB - A hallmark of Pseudomonas aeruginosa is its ability to establish biofilm-based infections that are difficult to eradicate. Biofilms are less susceptible to host inflammatory and immune responses and have higher antibiotic tolerance than free living planktonic cells. Developing treatments against biofilms requires an understanding of bacterial biofilm-specific physiological traits. Research efforts have started to elucidate the intricate mechanisms underlying biofilm development. However, many aspects of these mechanisms are still poorly understood. Here, we addressed questions regarding biofilm metabolism using a genome-scale kinetic model of the P. aeruginosa metabolic network and gene expression profiles. Specifically, we computed metabolite concentration differences between known mutants with altered biofilm formation and the wild type strain to predict drug targets against P. aeruginosa biofilms. We also simulated the altered metabolism driven by gene expression changes between biofilm and stationary growth-phase planktonic cultures. Our analysis suggests that the synthesis of important biofilm-related molecules, such as the quorum sensing molecule Pseudomonas quinolone signal and the exopolysaccharide Psl, is regulated not only through the expression of genes in their own synthesis pathway, but also through the biofilm-specific expression of genes in pathways competing for precursors to these molecules. Finally, we investigated why mutants defective in anthranilate degradation have an impaired ability to form biofilms. Alternative to a previous hypothesis that this biofilm reduction is caused by a decrease in energy production, we proposed that the dysregulation of the synthesis of secondary metabolites derived from anthranilate and chorismate is what impaired the biofilms of these mutants. Notably, these insights generated through our kinetic model-based approach are not accessible from previous constraint-based model analyses of P. aeruginosa biofilm metabolism. Our simulation results showed that plausible, non-intuitive explanations of difficult to-interpret experimental observations could be generated by integrating genome scale kinetic models with gene expression profiles. PMID- 26431399 TI - Ovarian Transcriptome Analysis of Portunus trituberculatus Provides Insights into Genes Expressed during Phase III and IV Development. AB - Enhancing the production of aquatic animals is crucial for fishery management and aquaculture applications. Ovaries are specialized tissues that play critical roles in producing oocytes and hormones. Significant biochemical changes take place during the sexual maturation of Portunus trituberculatus, but the genetics of this process has not been extensively studied. Transcriptome sequencing can be used to determine gene expression changes within specific periods. In the current study, we used transcriptome sequencing to produce a comprehensive transcript dataset for the ovarian development of P. trituberculatus. Approximately 100 million sequencing reads were generated, and 126,075 transcripts were assembled. Functional annotation of the obtained transcripts revealed important pathways in ovarian development, such as those involving the vitellogenin gene. Also, we performed deep sequencing of ovaries in phases III and IV of sexual maturation in P. trituberculatus. Differential analysis of gene expression identified 506 significantly differentially expressed genes, which belong to 20 pathway, transporters, development, transcription factors, metabolism of other amino acids, carbohydrate and lipid, solute carrier family members, and enzymes. Taken together, our study provides the first comprehensive transcriptomic resource for P. trituberculatus ovaries, which will strengthen understanding of the molecular mechanisms underlying the sexual maturation process and advance molecular nutritional studies of P. trituberculatus. PMID- 26431401 TI - Correction: Phosphatidylcholine Supply to Peroxisomes of the Yeast Saccharomyces cerevisiae. PMID- 26431400 TI - 'Only Fathers Smoking' Contributes the Most to Socioeconomic Inequalities: Changes in Socioeconomic Inequalities in Infants' Exposure to Second Hand Smoke over Time in Japan. AB - BACKGROUND: Exposure to second hand smoke (SHS) is one of the major causes of premature death and disease among children. While socioeconomic inequalities exist for adult smoking, such evidence is limited for SHS exposure in children. Thus, this study examined changes over time in socioeconomic inequalities in infants' SHS exposure in Japan. METHODS: This is a repeated cross-sectional study of 41,833 infants born in 2001 and 32,120 infants born in 2010 in Japan from nationally representative surveys using questionnaires. The prevalence of infants' SHS exposure was determined and related to household income and parental education level. The magnitudes of income and educational inequalities in infants' SHS exposure were estimated in 2001 and 2010 using both absolute and relative inequality indices. RESULTS: The prevalence of SHS exposure in infants declined from 2001 to 2010. The relative index of inequality increased from 0.85 (95% confidence interval [CI], 0.80 to 0.89) to 1.47 (95% CI, 1.37 to 1.56) based on income and from 1.22 (95% CI, 1.17 to 1.26) to 2.09 (95% CI, 2.00 to 2.17) based on education. In contrast, the slope index of inequality decreased from 30.9 (95% CI, 29.3 to 32.6) to 20.1 (95% CI, 18.7 to 21.5) based on income and from 44.6 (95% CI, 43.1 to 46.2) to 28.7 (95% CI, 27.3 to 30.0) based on education. Having only a father who smoked indoors was a major contributor to absolute income inequality in infants' SHS exposure in 2010, which increased in importance from 45.1% in 2001 to 67.0% in 2010. CONCLUSIONS: The socioeconomic inequalities in infants' second hand smoke exposure increased in relative terms but decreased in absolute terms from 2001 to 2010. Further efforts are needed to encourage parents to quit smoking and protect infants from second hand smoke exposure, especially in low socioeconomic households that include non-smoking mothers. PMID- 26431403 TI - Highlights in GEP-NETs From the 2015 American Society of Clinical Oncology Annual Meeting. PMID- 26431402 TI - Factors Associated to Prevalence and Incidence of Carbapenem-Resistant Enterobacteriaceae Fecal Carriage: A Cohort Study in a Mexican Tertiary Care Hospital. AB - BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) infections have emerged as a serious threat to health worldwide. They are associated with increased morbidity and mortality and are capable of silently colonizing the gastrointestinal tract. Because of this, there is great interest to characterize the epidemiology of CRE carriage and acquisition in healthcare facilities. The aim of this study was to determine the prevalence and factors associated with CRE fecal carriage (CRE-fc), and risk factors for incident cases. METHODS/RESULTS: A cohort study was conducted at a tertiary care hospital from January 1st to April 30th, 2014 during a CRE outbreak. Weekly rectal swabs were performed in patients considered at risk until discharge. CRE-fc prevalence was 10.9% (CI 95% 7.7-14.7) among 330 patients. Treatment with carbapenems (OR 2.54, CI 95% 1.15-5.62); transfer from an institution (OR 2.16, CI 95% 1.02-4.59); multi-drug resistant infection within the previous six months (OR 2.81, CI 95% 1.47-5.36); intensive care unit admission (OR 0.42, CI 95% 0.20-0.88); hematologic malignancy (OR 4.02, CI 95% 1.88-8.06); invasive procedures (OR 2.18, CI 95% 1.10-4.32); and sharing a room with a known CRE carrier (OR 3.0, CI 95% 1.43-6.31) were independently associated factors for CRE-fc. Risk factors associated with CRE-fc incidence were determined for 87 patients initially negative and with subsequent screening; the incidence rate was 2.5 cases, per 1000 person-years (CI 95% 1.5-3.9). Independently associated risk factors were carbapenem treatment (HR 2.68, CI 95% 1.03-6.98), hematologic malignancy (HR 5.74, 95% CI 2.46-13.4) and a mean daily colonization pressure >=10% (HR 5.03, IC 95% 1.77-14.28). OXA-48-like (OXA-232) and CTX-M-15 were the predominantly identified mechanisms of resistance. CONCLUSIONS: We found an elevated incidence and prevalence of CRE-fc in our hospital. Hematologic patients need to be considered a population at risk, and antibiotic stewardship along with infection control programs need to be improved to avoid nosocomial spread. PMID- 26431410 TI - Academic-Industry Partnerships in Alcohol and Gambling: a Continuum of Benefits and Harms. AB - There are many reasons why collaboration between academic institutions and private industry should be encouraged. At the same time, such collaborations raise the potential for profound conflicts of interest. Furthermore, there may be different kinds of issues in different kinds of industry, as is reflected in the metaphors we employ to think about them. The pharmaceutical industry is at times viewed as a "good" industry that can go wrong, while the tobacco industry is analogously viewed as a "bad" industry that can do little right. The alcohol and gambling industries may be particularly useful to think through insofar as they arguably require a continuum of benefits and harms to be acknowledged. I consider a number of initiatives by the alcohol and gambling industry in South Africa, and argue that there are real opportunities for delineating and developing more robust models of academic-industry collaboration, which ensure that public health is maximized in that country and elsewhere. PMID- 26431409 TI - Overcoming Stagnation in the Levels and Distribution of Child Mortality: The Case of the Philippines. AB - BACKGROUND: Health-related within-country inequalities continue to be a matter of great interest and concern to both policy makers and researchers. This study aims to assess the level and the distribution of child mortality outcomes in the Philippines across geographical and socioeconomic indicators. METHODOLOGY: Data on 159,130 children ever borne were analysed from five waves of the Philippine Demographic and Health Survey. Direct estimation was used to construct under-five and neonatal mortality rates for the period 1980-2013. Rate differences and ratios, and where possible, slope and relative indices of inequality were calculated to measure disparities on absolute and relative scales. Stratification was undertaken by levels of rural/urban location, island groups and household wealth. FINDINGS: National under-five and neonatal mortality rates have shown considerable albeit differential reductions since 1980. Recently released data suggests that neonatal mortality has declined following a period of stagnation. Declines in under-five mortality have been accompanied by decreases in wealth and geography-related absolute inequalities. However, relative inequalities for the same markers have remained stable over time. For neonates, mixed evidence suggests that absolute and relative inequalities have remained stable or may have risen. CONCLUSION: In addition to continued reductions in under-five mortality, new data suggests that the Philippines have achieved success in addressing the commonly observed stagnated trend in neonatal mortality. This success has been driven by economic improvement since 2006 as well as efforts to implement a nationwide universal health care campaign. Yet, such patterns, nonetheless, accorded with persistent inequalities, particularly on a relative scale. A continued focus on addressing universal coverage, the influence of decentralisation and armed conflict, and issues along the continuum of care is advocated. PMID- 26431411 TI - Differential Associations Between Depression, Risk Factors for Insulin Resistance and Diabetes Incidence in a Large U.S. Sample. AB - BACKGROUND: Depression frequently co-occurs with diabetes. The associations between risk factors for insulin resistance and depression and diabetes can help determine the relative importance of factors that contribute toward the comorbidity. METHOD: Analyses of the NHANES I (n = 10,025) to examine the cross sectional relationships between depression and risk factors for insulin resistance at baseline using logistic regression and to explore the longitudinal relationships between risk factors for insulin resistance and diabetes incidence using Cox proportional hazards modeling. RESULTS: Many risk factors for insulin resistance were associated with depression and diabetes incidence. Depression was cross-sectionally associated with diabetes, but did not increase the risk for diabetes incidence.These counterintuitive results can be explained primarily by the differing relationships between risk factors for insulin resistance, depression, and diabetes. LIMITATIONS: Lack of repeated measures of depression. CONCLUSIONS: Lack of physical activity, hypertension, and inadequate sleep were the risk factors for insulin resistance with the highest associations with both depression and diabetes incidence. PMID- 26431412 TI - Psychopathology and its Early Impact on Parenting Behaviors in Mothers: The Interface between Adult and Infant Psychiatry. AB - Parenting is, in its essence, the domain where adult mental health and infant's mental and physical health meet in a complex and dynamic interplay. Becoming a parent is a developmental challenge in itself, and often exacerbates an existing mental illness, and in turn, maladaptive parenting impinges on the early parent infant relationship, and on the infant's socio-emotional development and later functioning. The capacity for mentalization is brought as a bridging concept between adult and infant psychiatry. A few clinical vignettes illustrate the dynamic interplay between very young children's vulnerabilities and needs and their parents' strengths and weaknesses, leading to a complex interaction and often to symptoms in both child and parent. In the light of the compelling data about the impact of parental psychopathology on parenting behaviors and children outcomes, there is an imperative need for a working alliance and on-going communication between child and adult psychiatrists. PMID- 26431413 TI - The Outcome of Severe Internalizing and Disruptive Disorders from Preschool into Adolescence:A Follow-up Study. AB - PURPOSE: In this study we aimed to examine the outcome of children's severe psychiatric disorders from preschool into later childhood and adolescence. METHOD: Forty preschool children (28 boys and 12 girls) treated in a tertiary referral mental health center, evaluated at admission and 5.5 +/- 1.2 years thereafter. RESULTS: Seven (58.3%) children diagnosed with internalizing disorders at baseline were free of any psychiatric diagnosis at follow-up (p=0.02). Conversely, only one child (8.3%) diagnosed with comorbid disruptive internalizing disorders at baseline was free of any psychiatric disorder at follow-up (p=1.0). Seven (43.7%) children diagnosed with disruptive disorders at baseline were free of psychiatric diagnoses at follow-up (p=0.02). LIMITATIONS: The small sample size and naturalistic nature of the study. CONCLUSION: The trajectories of severe psychiatric disorders at preschool years are similar to those reported in community samples and differ according to the baseline diagnosis. Children with internalizing disorders show a much better recovery rate than those with comorbid disruptive and internalizing disorders. PMID- 26431414 TI - Feasibility of a Dual Evaluation/Intervention Program for Morbidly Obese Adolescents. AB - BACKGROUND: In the absence of evidence-based guidelines for screening adolescent candidates for bariatric surgery, or improving their adherence to preoperative recommendations, we designed a dual-phase multidisciplinary program aiming for observation-based preoperative assessment/ intervention, as well as for post operative/ conservative follow up. METHODS: This study focused on the preoperative 3-month phase. Fifteen morbidly obese adolescents attending the eating disorders unit of a pediatric hospital underwent the program protocol consisting of medical examinations/ tests, psychological measures, self monitoring, tailored diet, physical activity schedule, individual and group cognitive behavior-oriented therapy, and psycho educational parent training. RESULTS: All patients completed the preoperative phase. Most of them (70%) followed the structured diet with a significant reduction in BMI. The patients complied with self-monitoring, and body dissatisfaction score improved. Parental participation in therapy was poor. Four patients with low adherence were found ineligible for surgery. CONCLUSIONS: The findings support the feasibility of our dual screening/intervention protocol. Measures to improve parental participation are warranted. PMID- 26431415 TI - Dental Health and the Type of Antipsychotic Treatment in Inpatients with Schizophrenia. AB - AIM: This study examined the association between dental conditions in hospitalized patients with ICD-10 schizophrenia and type of antipsychotic treatment. Based on the literature suggesting that atypical antipsychotics are thought to be more tolerable than typical antipsychotics, we hypothesized that hospitalized patients with schizophrenia treated with atypicals would have better dental health than those treated with typicals alone or with a combination of both (combined group). METHODS: A representative sample of 348 patients (69% males), aged 51.4 (SD=14.5, range 31-58) years, was assessed on the standardized criteria of the Decayed, Missing and Filled Teeth (DMFT) index and component scores. Data on medication were extracted from patients' electronic medical records. RESULTS: Patients treated with typicals had significantly higher DMFT index scores than those who received atypicals (23.5+/-9.9 vs. 19.0+/-10.5; p < 0.05), and higher Missing (20.2+/-11.6 vs. 13.5+/-11.2; p < 0.01) and lower Filled (1.0+/-2.4 vs. 2.1+/-3.9; p < 0.05) teeth component scores. No between group differences in Decayed component scores were found (2.3+/-3.4 and 3.4+/ 5.0, respectively; p > 0.05). The combined treatment group was situated in between the typicals and atypicals groups on all measures. CONCLUSIONS: The results suggest that patients with schizophrenia maintained on atypicals have better dental health than patients treated with typicals or with a combination of both. From an oral health perspective, monotherapy with atypicals is superior to both typical and atypical/typical treatments. Although the choice between typical and atypical antipsychotic agents is based mainly on clinical psychiatric efficacy, the benefit of atypicals with regard to dental health should be taken into consideration in clinician's decision making. PMID- 26431416 TI - Severity of Psychiatric Disorders and Dental Health Among Psychiatric Outpatients in Jerusalem, Israel. AB - The association between severity of psychiatric disorder and dental disease has not been adequately studied. The aim of the present study was to examine the level of dental caries morbidity and the association with Severe Mental Illness (SMI) and mild/moderate psychiatric disorders. The population sample included patients aged 30 to 50, treated at the Hadassah psychiatric outpatient clinic, after giving written informed consent. Exclusion criteria included eating disorders which are recognized as being associated with several dental pathologies. The term SMI, frequently used in the literature (1), refers to psychiatric patients suffering from a significant mental disorder and implies a greater burden of illness and dysfunction. The SMI group in this study included patients suffering from schizophrenia, bipolar disorder, resistant depression and chronic post-traumatic stress disorder (PTSD). The mild/ moderate illness group consisted of all other psychiatric disorders on Axis I or II according to DSM IV TR (2). PMID- 26431417 TI - Validation of the HCR-20 Scale for Assessing Risk of Violent Behavior in Israeli Psychiatric Inpatients. AB - BACKGROUND: Assessment of risk of violent behavior in forensic psychiatric practice is a complex and responsible clinical task and the use of a valid instrument can make the expert's work more effective. The Historical Clinical and Risk Management scale 20 (HCR-20) is a widely accepted measure of the risk of violence, sexual and criminal behavior. The aim of this study was to validate the HCR-20 in Israeli psychiatric inpatient settings. METHOD: In a prospective design, data were collected on 150 male patients aged 15-65, diagnosed with ICD 10 schizophrenia, who were hospitalized in three wards: an acute psychiatric ward (n=50), a high security ward (n=50), and an open ward (n=50). The HCR-20, as the predictor measure, and the Positive and Negative Syndrome Scale, as a concurrent measure, werecompleted at baseline, and the Violence Assessment Scale, as the outcome measure, was completed at 6-, 12- and 18-month follow-up points. RESULTS: Internal consistency reliability was good for the total HCR-20 scale, satisfactory for the H-subscale, but low for the C- and R-subscales. Concurrent validity was good for the C-subscale, and discriminative validity was reasonable for the C- and H-subscales. The total scale as well as the Historical and Clinical subscales predicted the risk of physical as well as physical/sexual violent behavior at both 6- and 18-month follow-up points. CONCLUSIONS: Appropriate psychometric properties of the HCR-20 suggest that it can serve as a useful measure of the risk of violent behavior in psychiatric settings in Israel. Further research is necessary to confirm norms and cut-off scores, using a larger representative sample. PMID- 26431418 TI - Negative and Positive Automatic thoughts in Social Anxiety Disorder. AB - BACKGROUND: Social Anxiety Disorder (SAD) is characterized by fear and avoidance in social situations where one is exposed to scrutiny by others. It is possible that automatic thoughts either cause the disorder or maintain it, and thus their examination is warranted. METHOD: 30 SAD subjects diagnosed with the MiniInternational Neuropsychiatric Interview (MINI) and 30 healthy controls were administered the Liebowitz Social Anxiety Scale (LSAS), the Automatic Thoughts Questionnaires (ATQ-Negative and ATQ-Positive), the Sheehan Disability Scale (SDS) and the Beck Depression Inventory (BDI). It was hypothesized that the SAD subjects would display more depression and disability, more negative automatic thoughts and fewer positive automatic thoughts than the healthy controls, and that the automatic thoughts will predict the severity of SAD. RESULTS: SAD patients had higher scores of depression and disability, higher scores on the ATQ Negative questionnaire and lower scores on the ATQ-Positive questionnaire. The scores of the LSAS subscales were predicted by the scores of the ATQ-Positive and the BDI questionnaires. LIMITATIONS: Moderate sample size and limits of the questionnaires used in the study. CONCLUSIONS: Automatic thoughts may be an important area of research with larger samples. Further studies should be carried out in order to examine if strengthening positive thinking and ablation of negative thinking can reduce SAD symptoms during cognitive behavioral treatment. PMID- 26431419 TI - Voluntary Departure of Family Physicians from their Workplace: A Reflective Outlook. AB - OBJECTIVES: The objective of this study was to highlight and assess the important topic of the voluntary departure of the physician from his/her clinic. We used the topic of the voluntary departure of a family physician from the clinic as an example. The physician's leaving challenges the personal credo regarding the continuity of care, which is a basic concept in Family Medicine, and other professions, too: Psychiatrists are also devoted to long-term doctor-patient care. Leaving a place of work is a significant life event that can be accompanied by stress and even a crisis for the doctor, patients, and staff. METHODS: In this article, we will present four stories, of four family physicians who voluntarily left their practices, written from a reflective point of view, either before or after the actual departure. The stories will be analyzed in a qualitative way, and the central themes and narratives will be defined. RESULTS: The personal departure stories revealed important personal and systemic themes that emerge from and influence the departure process. Among the themes were: practical and emotional work circumstances; leaving as a grief process; and reactions of patients, staff, and management. CONCLUSION: Qualitative analysis revealed that the voluntary departure of the family physician has complex personal and systemic implications. PRACTICAL IMPLICATIONS: The combination of Balint group discussions and written reflections can help the physician better cope with the departure and also help patients and staff deal with the separation process. PMID- 26431420 TI - Evaluating the Quality of Cardiopulmonary Resuscitation in the Emergency Department by Real-Time Video Recording System. AB - OBJECTIVES: To compare cardiopulmonary resuscitation (CPR) quality between manual CPR and miniaturized chest compressor (MCC) CPR. To improve CPR quality through evaluating the quality of our clinical work of resuscitation by real-time video recording system. METHODS: The study was a retrospective observational study of adult patients who experienced CPR at the emergency department of Shanghai Tenth People's Hospital from March 2013 to August 2014. All the performance of CPR were checked back by the record of "digital real-time video recording system". Average chest compression rate, actual chest compression rate, the percentage of hands off period, time lag from patient arrival to chest compression, time lag from patient arrival to manual ventilation, time lag from patient arrival to first IV establish were compared. Causes of chest compression hands-off time were also studied. RESULTS: 112 cases of resuscitation attempts were obtained. Average chest compression rate was over 100 compression per minute (cpm) in the majority of cases. However, indicators such as percentage of hands-off periods, time lag from patient arrival to the first manual ventilation and time lag from patient arrival to the first IV establish seemed to be worse in the manual CPR group compared to MCC CPR group. The saving of operators change time seemed to counteract the time spent on MCC equipment. Indicators such as percentage of hands-off periods, time lag between patient arrival to the first chest compression, time lag between patient arrival to the first manual ventilation and time lag from patient arrival to the first IV establish may influence the survival. CONCLUSION: Our CPR quality remained to be improved. MCC may have a potentially positive role in CPR. PMID- 26431421 TI - MAP-Kinase Activated Protein Kinase 2 Links Endothelial Activation and Monocyte/macrophage Recruitment in Arteriogenesis. AB - Arteriogenesis, the growth of natural bypass arteries, is triggered by hemodynamic forces within vessels and requires a balanced inflammatory response, involving induction of the chemokine MCP-1 and recruitment of leukocytes. However, little is known how these processes are coordinated. The MAP-kinase activated-proteinkinase-2 (MK2) is a critical regulator of inflammatory processes and might represent an important link between cytokine production and cell recruitment during postnatal arteriogenesis. Therefore, the present study investigated the functional role of MK2 during postnatal arteriogenesis. In a mouse model of hindlimb ischemia (HLI) MK2-deficiency (MK2KO) significantly impaired ischemic blood flow recovery and growth of collateral arteries as well as perivascular recruitment of mononuclear cells and macrophages. This was accompanied by induction of endothelial MCP-1 expression in wildtype (WT) but not in MK2KO collateral arteries. Following HLI, MK2 activation rapidly occured in the endothelium of growing WT arteries in vivo. In vitro, inflammatory cytokines and cyclic stretch activated MK2 in endothelial cells, which was required for stretch- and cytokine-induced release of MCP-1. In addition, a monocyte cell autonomous function of MK2 was uncovered potentially regulating MCP-1-dependent monocyte recruitment to vessels: MCP-1 stimulation of WT monocytes induced MK2 activation and monocyte migration in vitro. The latter was reduced in MK2KO monocytes, while in vivo MK2 was activated in monocytes recruited to collateral arteries. In conclusion, MK2 regulates postnatal arteriogenesis by controlling vascular recruitment of monocytes/macrophages in a dual manner: regulation of endothelial MCP-1 expression in response to hemodynamic and inflammatory forces as well as MCP-1 dependent monocyte migration. PMID- 26431422 TI - The role of pain acceptance on function in individuals with disabilities: a longitudinal study. AB - Having higher levels of pain acceptance has been shown to be associated positively with quality of life in patients with chronic pain, but its role in adjustment to chronic pain among individuals with physical disabilities living in the community is not known. Moreover, issues related to item overlap between measures of pain acceptance and measures of patient function have limited the conclusions that can be drawn from previous research in this area. To better understand the role that pain acceptance plays in patient function, we administered measures of pain acceptance, pain intensity, depressive symptoms, and function to 392 individuals with physical disabilities, and the pain, symptom, and function measures were readministered 3.5 years later. Analyses evaluated the main and interaction effects of initial pain acceptance on subsequent changes in pain and function. Having higher levels of pain acceptance in particular as reflected by a willingness to engage in activities despite pain resulted in less increase in pain intensity and more improvements in pain interference, physical function, depressive symptoms, and sleep quality. The findings indicate that previous research supporting the importance of pain acceptance to function in patients from health care settings extends to individuals with chronic pain living in the community. Moreover, they indicate that pain acceptance may have long-lasting (up to 3.5 years) beneficial effects on subsequent pain and function and on the association between change in pain and depression. Research to examine the potential benefits of community-based treatments that increase pain acceptance is warranted. PMID- 26431423 TI - Meta-analytic evidence for decreased heart rate variability in chronic pain implicating parasympathetic nervous system dysregulation. AB - Both sympathetic and parasympathetic nervous systems are involved in regulating pain states. The activity of these systems seems to become disturbed in states of chronic pain. This disruption in autonomic balance can be measured through the assessment of heart rate variability (HRV), that is, the variability of the interval between consecutive heart beats. However, there is yet to be a systematic evaluation of the body of literature concerning HRV across several chronic pain conditions. Moreover, modern meta-analytical techniques have never been used to validate and consolidate the extent to which HRV may be decreased in chronic pain. Following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement guidelines, this study systematically evaluated and critically appraised the literature concerning HRV in people living with chronic pain. After screening 17,350 sources, 51 studies evaluating HRV in a chronic pain group met the inclusion criteria. Twenty-six moderate-high quality studies were included in quantitative meta-analyses. On average, the quality of studies was moderate. There were 6 frequency-domain and time-domain measures of HRV across a broad range of chronic pain conditions. High heterogeneity aside, pooled results from the meta-analyses reflected a consistent, moderate-to-large effect of decreased high-frequency HRV in chronic pain, implicating a decrease in parasympathetic activation. These effects were heavily influenced by fibromyalgia studies. Future research would benefit from wider use of standardised definitions of measurement, and also investigating the synergistic changes in pain state and HRV throughout the development and implementation of mechanism-based treatments for chronic pain. PMID- 26431425 TI - Geminivirus Activates ASYMMETRIC LEAVES 2 to Accelerate Cytoplasmic DCP2-Mediated mRNA Turnover and Weakens RNA Silencing in Arabidopsis. AB - Aberrant viral RNAs produced in infected plant cells serve as templates for the synthesis of dsRNAs. The derived virus-related small interfering RNAs (siRNA) mediate cleavage of viral RNAs by post-transcriptional gene silencing (PTGS), thus blocking virus multiplication. Here, we identified ASYMMETRIC LEAVES2 (AS2) as a new component of plant P body complex which mediates mRNA decapping and degradation. We found that AS2 promotes DCP2 decapping activity, accelerates mRNA turnover rate, inhibits siRNA accumulation and functions as an endogenous suppressor of PTGS. Consistent with these findings, as2 mutant plants are resistant to virus infection whereas AS2 over-expression plants are hypersensitive. The geminivirus nuclear shuttle protein BV1 protein, which shuttles between nuclei and cytoplasm, induces AS2 expression, causes nuclear exit of AS2 to activate DCP2 decapping activity and renders infected plants more sensitive to viruses. These principles of gene induction and shuttling of induced proteins to promote mRNA decapping in the cytosol may be used by viral pathogens to weaken antiviral defenses in host plants. PMID- 26431424 TI - Subcellular Partitioning of Protein Tyrosine Phosphatase 1B to the Endoplasmic Reticulum and Mitochondria Depends Sensitively on the Composition of Its Tail Anchor. AB - The canonical protein tyrosine phosphatase PTP1B is an important regulator of diverse cellular signaling networks. PTP1B has long been thought to exert its influence solely from its perch on the endoplasmic reticulum (ER); however, an additional subpopulation of PTP1B has recently been detected in mitochondria extracted from rat brain tissue. Here, we show that PTP1B's mitochondrial localization is general (observed across diverse mammalian cell lines) and sensitively dependent on the transmembrane domain length, C-terminal charge and hydropathy of its short (<=35 amino acid) tail anchor. Our electron microscopy of specific DAB precipitation revealed that PTP1B localizes via its tail anchor to the outer mitochondrial membrane (OMM), with fluorescence lifetime imaging microscopy establishing that this OMM pool contributes to the previously reported cytoplasmic interaction of PTP1B with endocytosed epidermal growth factor receptor. We additionally examined the mechanism of PTP1B's insertion into the ER membrane through heterologous expression of PTP1B's tail anchor in wild-type yeast and yeast mutants of major conserved ER insertion pathways: In none of these yeast strains was ER targeting significantly impeded, providing in vivo support for the hypothesis of spontaneous membrane insertion (as previously demonstrated in vitro). Further functional elucidation of the newly recognized mitochondrial pool of PTP1B will likely be important for understanding its complex roles in cellular responses to external stimuli, cell proliferation and diseased states. PMID- 26431426 TI - Proteomic Characterization of Annexin l (ANX1) and Heat Shock Protein 27 (HSP27) as Biomarkers for Invasive Hepatocellular Carcinoma Cells. AB - To search for reliable biomarkers and drug targets for management of hepatocellular carcinoma (HCC), we performed a global proteomic analysis of a pair of HCC cell lines with distinct differentiation statuses using 2-DE coupled with MALDI-TOF MS. In total, 106 and 55 proteins were successfully identified from the total cell lysate and the cytosolic, nuclear and membrane fractions in well-differentiated (HepG2) and poorly differentiated (SK-Hep-1) HCC clonal variants, respectively. Among these proteins, nine spots corresponding to proteins differentially expressed between HCC cell types were selected and confirmed by immunofluorescence staining and western blotting. Notably, Annexin 1 (ANX1), ANX-2, vimentin and stress-associated proteins, such as GRP78, HSP75, HSC 70, protein disulfide isomerase (PDI), and heat shock protein-27 (HSP27), were exclusively up-regulated in SK-Hep-1 cells. Elevated levels of ANX-4 and antioxidant/metabolic enzymes, such as MnSOD, peroxiredoxin, NADP-dependent isocitrate dehydrogenase, alpha-enolase and UDP-glucose dehydrogenase, were observed in HepG2 cells. We functionally demonstrated that ANX1 and HSP27 were abundantly overexpressed only in highly invasive types of HCC cells, such as Mahlavu and SK-Hep-1. Knockdown of ANX1 or HSP27 in HCC cells resulted in a severe reduction in cell migration. The in-vitro observations of ANX1 and HSP27 expressions in HCC sample was demonstrated by immunohistochemical stains performed on HCC tissue microarrays. Poorly differentiated HCC tended to have stronger ANX1 and HSP27 expressions than well-differentiated or moderately differentiated HCC. Collectively, our findings suggest that ANX1 and HSP27 are two novel biomarkers for predicting invasive HCC phenotypes and could serve as potential treatment targets. PMID- 26431427 TI - Improving the Health Forecasting Alert System for Cold Weather and Heat-Waves In England: A Proof-of-Concept Using Temperature-Mortality Relationships. AB - OBJECTIVES: In this study a prototype of a new health forecasting alert system is developed, which is aligned to the approach used in the Met Office's (MO) National Severe Weather Warning Service (NSWWS). This is in order to improve information available to responders in the health and social care system by linking temperatures more directly to risks of mortality, and developing a system more coherent with other weather alerts. The prototype is compared to the current system in the Cold Weather and Heatwave plans via a case-study approach to verify its potential advantages and shortcomings. METHOD: The prototype health forecasting alert system introduces an "impact vs likelihood matrix" for the health impacts of hot and cold temperatures which is similar to those used operationally for other weather hazards as part of the NSWWS. The impact axis of this matrix is based on existing epidemiological evidence, which shows an increasing relative risk of death at extremes of outdoor temperature beyond a threshold which can be identified epidemiologically. The likelihood axis is based on a probability measure associated with the temperature forecast. The new method is tested for two case studies (one during summer 2013, one during winter 2013), and compared to the performance of the current alert system. CONCLUSIONS: The prototype shows some clear improvements over the current alert system. It allows for a much greater degree of flexibility, provides more detailed regional information about the health risks associated with periods of extreme temperatures, and is more coherent with other weather alerts which may make it easier for front line responders to use. It will require validation and engagement with stakeholders before it can be considered for use. PMID- 26431428 TI - Scaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant N-(1H-Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12). AB - Recent data suggest that inhibition of dual leucine zipper kinase (DLK, MAP3K12) has therapeutic potential for treatment of a number of indications ranging from acute neuronal injury to chronic neurodegenerative disease. Thus, high demand exists for selective small molecule DLK inhibitors with favorable drug-like properties and good CNS penetration. Herein we describe a shape-based scaffold hopping approach to convert pyrimidine 1 to a pyrazole core with improved physicochemical properties. We also present the first crystal structures of DLK. By utilizing a combination of property and structure-based design, we identified inhibitor 11, a potent, selective, and brain-penetrant inhibitor of DLK with activity in an in vivo nerve injury model. PMID- 26431429 TI - Bioinformatics Analysis of Proteome Changes in Calu-3 Cell Infected by Influenza A Virus (H5N1). AB - AIM: This paper aimed to identify the differentially expressed proteins (DEPs) in Calu-3 cells infected by influenza A virus (IAV) subtype H5N1. METHODS: We downloaded proteome data (BTO: 0000762) from the Proteomics Identifications database and identified the DEPs in the IAV-infected Calu-3 cells. Then we constructed a protein-protein interaction network and a transcriptional regulatory network of the proteins. Finally, we performed gene ontology (GO) analysis to study the IAV infection at a functional level. RESULTS: A total of 4 protein groups between the normal cells and the Calu-3 cells infected by IAV, severe acute respiratory syndrome or swine influenza were identified. In the networks, we found 5 significant proteins including FAN, CPSF2, AGO1, AGO2 and PAX5. In addition, we demonstrated those proteins were associated with GO terms such as phosphate metabolic process, calcium ion transport, cell division and regulation of cell motion. STAT1, NS2, CD5, NCKX6 and PDGFB were significant DEPs in these GO terms. CONCLUSIONS: By referring to the previous studies, we suggest that proteins including FAN, CPSF2, AGO1, AGO2, PAX5, STAT1 and PDGFB can be used as therapeutic targets of IAV infection. PMID- 26431430 TI - The Global Cognition, Frontal Lobe Dysfunction and Behavior Changes in Chinese Patients with Multiple System Atrophy. AB - BACKGROUND: Studies on cognition in multiple system atrophy (MSA) patients are limited. METHODS: A total of 110 MSA patients were evaluated using Addenbrooke's Cognitive Examination-Revised (ACE-R), Frontal Assessment Battery (FAB), Frontal Behavioral Inventory (FBI), and Unified MSA Rating Scale (UMSARS) tests. Fifty five age-, sex-, education- and domicile-matched healthy controls were recruited to perform the FAB and ACE-R scales. RESULTS: Approximately 32.7% of the patients had global cognitive deficits with the most impaired domain being verbal fluency and visuospatial ability (26.4%), followed by memory (24.5%), language (20%) and orientation/attention (20%) based on a cut-off score of ACE-R <= 70. A total of 41.6% of the patients had frontal lobe dysfunction, with inhibitory control (60.9%) as the most impaired domain based on a cut-off score of FAB <=14. Most patients (57.2%) showed moderate frontal behavior changes (FBI score 4-15), with incontinence (64.5%) as the most impaired domain. The binary logistic regression model revealed that an education level < 9 years (OR:13.312, 95% CI:2.931-60.469, P = 0.001) and UMSARS >= 40 (OR: 2.444, 95%CI: 1.002-5.962, P< 0.049) were potential determinants of abnormal ACE-R, while MSA-C (OR: 4.326, 95%CI: 1.631 11.477, P = 0.003), an education level < 9 years (OR:2.809 95% CI:1.060-7.444, P = 0.038) and UMSARS >= 40 (OR:5.396, 95%CI: 2.103-13.846, P < 0.0001) were potential determinants of abnormal FAB. CONCLUSIONS: Cognitive impairment is common in Chinese MSA patients. MSA-C patients with low education levels and severe motor symptoms are likely to experience frontal lobe dysfunction, while MSA patients with low education levels and severe motor symptoms are likely to experience global cognitive deficits. These findings strongly suggest that cognitive impairment should not be an exclusion criterion for the diagnosis of MSA. PMID- 26431431 TI - Effects of Omega-3 Fatty Acid Supplementation on Glucose Control and Lipid Levels in Type 2 Diabetes: A Meta-Analysis. AB - BACKGROUND: Many studies assessed the impact of marine omega-3 fatty acids on glycemic homeostasis and lipid profiles in patients with type 2 diabetes (T2DM), but reported controversial results. Our goal was to systematically evaluate the effects of omega-3 on glucose control and lipid levels. METHODS: Medline, Pubmed, Cochrane Library, Embase, the National Research Register, and SIGLE were searched to identify eligible randomized clinical trials (RCTs). Extracted data from RCTs were analyzed using STATA 11.0 statistical software with fixed or random effects model. Effect sizes were presented as weighted mean differences (WMD) with 95% confidence intervals (95% CI). Heterogeneity was assessed using the Chi-square test with significance level set at p < 0.1. RESULTS: 20 RCT trials were included into this meta-analysis. Among patients with omega-3 supplementation, triglyceride (TG) levels were significantly decreased by 0.24 mmol/L. No marked change in total cholesterol (TC), HbA1c, fasting plasma glucose, postprandial plasma glucose, BMI or body weight was observed. High ratio of EPA/DHA contributed to a greater decreasing tendency in plasma insulin, HbAc1, TC, TG, and BMI measures, although no statistical significance was identified (except TG). FPG levels were increased by 0.42 mmol/L in Asians. No evidence of publication bias was observed in this meta-analysis. CONCLUSIONS: The ratio of EPA/DHA and early intervention with omega 3 fatty acids may affect their effects on glucose control and lipid levels, which may serve as a dietary reference for clinicians or nutritionists who manage diabetic patients. PMID- 26431432 TI - Persons with Haemophilia in Sweden- Experiences and Strategies in Everyday Life. A Single Centre Study. AB - INTRODUCTION/AIM: Haemophilia is caused by deficiency in coagulation factor VIII or IX. Treatment with the missing coagulation factors has been available in most developed countries for several decades. The aim was to explore the experiences of adults living with severe or moderate haemophilia and their coping strategies at a single centre in Sweden. METHOD: The interview study had a qualitative empirical approach and was analyzed on the basis of the method empirical phenomenological psychology. The sample included 14 participants, mean age 42 (19 80 y), who met the inclusion criteria and to saturation of information. RESULTS: General characteristics were; All were satisfied with and grateful for access to medication. An acceptance of the disorder and willingness to live a normal life was identified among all participants. They were all content with the care provided by Haemophilia Treatment Centre (HTC) and felt supported by its multidisciplinary team. Four typologies were identified; Protective adults and assertive children during up-bringing, finding a role in social context, symptoms and treatments, fear of limited resources in the future. Task-, emotional- and avoidance coping strategies were seen in the interviews. The most prominent coping strategy was task oriented. CONCLUSION: This interview study with Swedish PWH shows that they strive for normality and adaptation in social activities throughout life finding their own niche. The PWH expressed the importance of knowledge and support from the comprehensive medical team at HTC and therefore it seems important to continue comprehensive medical care at HTC in order to follow up the haemophilia persons regularly. PMID- 26431434 TI - Performance Evaluation of the Verigene Gram-Positive and Gram-Negative Blood Culture Test for Direct Identification of Bacteria and Their Resistance Determinants from Positive Blood Cultures in Hong Kong. AB - BACKGROUND: A multicenter study was conducted to evaluate the diagnostic performance and the time to identifcation of the Verigene Blood Culture Test, the BC-GP and BC-GN assays, to identify both Gram-positive and Gram-negative bacteria and their drug resistance determinants directly from positive blood cultures collected in Hong Kong. METHODS AND RESULTS: A total of 364 blood cultures were prospectively collected from four public hospitals, in which 114 and 250 cultures yielded Gram-positive and Gram-negative bacteria, and were tested with the BC-GP and BC-GN assay respectively. The overall identification agreement for Gram positive and Gram-negative bacteria were 89.6% and 90.5% in monomicrobial cultures and 62.5% and 53.6% in polymicrobial cultures, respectively. The sensitivities for most genus/species achieved at least 80% except Enterococcus spp. (60%), K.oxytoca (0%), K.pneumoniae (69.2%), whereas the specificities for all targets ranged from 98.9% to 100%. Of note, 50% (7/14) cultures containing K.pneumoniae that were missed by the BC-GN assay were subsequently identified as K.variicola. Approximately 5.5% (20/364) cultures contained non-target organisms, of which Aeromonas spp. accounted for 25% and are of particular concern. For drug resistance determination, the Verigene test showed 100% sensitivity for identification of MRSA, VRE and carbapenem resistant Acinetobacter, and 84.4% for ESBL-producing Enterobacteriaceae based on the positive detection of mecA, vanA, blaOXA and blaCTXM respectively. CONCLUSION: Overall, the Verigene test provided acceptable accuracy for identification of bacteria and resistance markers with a range of turnaround time 40.5 to 99.2 h faster than conventional methods in our region. PMID- 26431436 TI - Bone Morphogenetic Protein-7 Inhibits EMT-Associated Genes in Breast Cancer. AB - BACKGROUND/AIMS: Bone morphogenetic protein-7 (BMP7) has been shown to reduce the severity of injury-induced fibrosis through counteracting the fibrotic effects of transforming growth factor beta 1 (TGFbeta1). However, this model in the carcinogenesis of breast cancer is unknown. METHODS: We analyzed the effects of BMP7 and TGFbeta1 on gene transcripts and protein levels of EMT-related factors in breast cancer cells by RT-qPCR and Western blot, respectively. The effects of BMP7 and TGFbeta1 on cell invasiveness and migration were evaluated by scratch wound healing assay and transwell cell migration assay. The cell growth was measured by MTT assay. RESULTS: BMP7 did not alter the TGFbeta1-stimulated phosphorylation of TGFbeta receptor, but significantly inhibited the TGFbeta1 activated epithelial-mesenchymal transition (EMT)-related genes in breast cancer cells, resulting in a significant reduction in TGFbeta1-triggered cell growth and cell metastasis. CONCLUSION: Our data suggest that besides being a well-known antagonist for TGFbeta1 in fibrosis, BMP7 may also antagonize TGFbeta1 in tumorigenesis-associated EMT in breast cancer. Thus, BMP7 may be a promising therapeutic target for treating breast cancer. PMID- 26431433 TI - The Dual Role of an ESCRT-0 Component HGS in HBV Transcription and Naked Capsid Secretion. AB - The Endosomal Sorting Complex Required for Transport (ESCRT) is an important cellular machinery for the sorting and trafficking of ubiquitinated cargos. It is also known that ESCRT is required for the egress of a number of viruses. To investigate the relationship between ESCRT and hepatitis B virus (HBV), we conducted an siRNA screening of ESCRT components for their potential effect on HBV replication and virion release. We identified a number of ESCRT factors required for HBV replication, and focused our study here on HGS (HRS, hepatocyte growth factor-regulated tyrosine kinase substrate) in the ESCRT-0 complex. Aberrant levels of HGS suppressed HBV transcription, replication and virion secretion. Hydrodynamic delivery of HGS in a mouse model significantly suppressed viral replication in the liver and virion secretion in the serum. Surprisingly, overexpression of HGS stimulated the release of HBV naked capsids, irrespective of their viral RNA, DNA, or empty contents. Mutant core protein (HBc 1-147) containing no arginine-rich domain (ARD) failed to secrete empty virions with or without HGS. In contrast, empty naked capsids of HBc 1-147 could still be promoted for secretion by HGS. HGS exerted a strong positive effect on the secretion of naked capsids, at the expense of a reduced level of virions. The association between HGS and HBc appears to be ubiquitin-independent. Furthermore, HBc is preferentially co-localized with HGS near the cell periphery, instead of near the punctate endosomes in the cytoplasm. In summary, our work demonstrated the importance of an optimum level of HGS in HBV propagation. In addition to an effect on HBV transcription, HGS can diminish the pool size of intracellular nucleocapsids with ongoing genome maturation, probably in part by promoting the secretion of naked capsids. The secretion routes of HBV virions and naked capsids can be clearly distinguished based on the pleiotropic effect of HGS involved in the ESCRT-0 complex. PMID- 26431435 TI - On the Computing Potential of Intracellular Vesicles. AB - Collision-based computing (CBC) is a form of unconventional computing in which travelling localisations represent data and conditional routing of signals determines the output state; collisions between localisations represent logical operations. We investigated patterns of Ca2+-containing vesicle distribution within a live organism, slime mould Physarum polycephalum, with confocal microscopy and observed them colliding regularly. Vesicles travel down cytoskeletal 'circuitry' and their collisions may result in reflection, fusion or annihilation. We demonstrate through experimental observations that naturally occurring vesicle dynamics may be characterised as a computationally-universal set of Boolean logical operations and present a 'vesicle modification' of the archetypal CBC 'billiard ball model' of computation. We proceed to discuss the viability of intracellular vesicles as an unconventional computing substrate in which we delineate practical considerations for reliable vesicle 'programming' in both in vivo and in vitro vesicle computing architectures and present optimised designs for both single logical gates and combinatorial logic circuits based on cytoskeletal network conformations. The results presented here demonstrate the first characterisation of intracelluar phenomena as collision-based computing and hence the viability of biological substrates for computing. PMID- 26431437 TI - Villitis of unknown aetiology: Clinical implications in preterm population. AB - Villitis of unknown aetiology (VUE) is a chronic inflammatory process of chorionic villi which is reported to occur in up to 15% of term placentas. The present study aimed to investigate the association between VUE and perinatal complications in a population who delivered before term. Patients with VUE had a significantly higher rate of intrauterine growth restriction than the control group (47.1% vs. 20.6%, p < 0.01). In addition patients with VUE had a higher rate of deliveries due to absent diastolic flow on umbilical artery doppler than the control group (17.6% vs. 4.4%, p: 0.03). The rate of spontaneous preterm birth or pre-eclampsia was similar in patients with VUE and control groups. The present study provides some evidence that VUE is associated with abnormal perinatal outcomes in pregnant women who give birth before term. PMID- 26431438 TI - Cancer survivors face steep economic burdens: Excessive medical expenses and loss of productivity at work plague some, even years after initial diagnosis. PMID- 26431439 TI - Immunotherapy drug improves survival of patients with squamous non-small cell lung cancer. PMID- 26431440 TI - Diastolic dysfunction common among breast cancer patients receiving anthracycline. PMID- 26431444 TI - Synthesis, Photophysics, and Self-Assembly of Furan-Embedded Heteroarenes. AB - A series of pyrene/phenanthrene-fused furan derivatives (1-8) were synthesized by a simple condensation reaction between pyrene-4,5-diketone/phenanthrenequinone and substituted phenol/naphthol in the presence of trifluoromethanesulfonic acid in 1,2-dichlorobenzene heated at reflux. The formed compounds can emit strong blue light in organic solvents. Additionally, the self-assembly behaviors of two of the compounds (3 and 5) were studied through re-precipitation method and the resulting nanostructures were characterized by UV/Vis, fluorescence spectra, and field-emission scanning electron microscopy (FESEM). The findings showed that the shape and size of compounds 3 and 5 could be tuned by the ratio of THF and hexadecyl trimethyl ammonium bromide (CTAB) solution in water. PMID- 26431447 TI - Folivory as a Constraint on Social Behaviour of Langurs in South India. AB - Folivory, being a dietary constraint, can affect the social time of colobines. In the present study, we compared food items and activity budgets of two closely related species of colobines inhabiting South India, i.e. the Hanuman langur (Semnopithecus hypoleucos) and Nilgiri langur (Semnopithecus johnii), to determine whether folivory had an impact on social time in these species. Our study established that Nilgiri langurs were more folivorous than Hanuman langurs. Nilgiri langurs spent much less time on social activities, but more time on resting, although the social organization of S. hypoleucos was similar to that of the Nilgiri langur. The enforced resting time for fermentation of leafy food items may have reduced the time available for social interactions, which in turn affected the social time in Nilgiri langurs. By comparing the data from previous studies on other Hanuman langur species, we found that S. hypoleucos spent a similar amount of time on social activities as Semnopithecus entellus. Hence, the social behaviour of S. entellus and S. hypoleucos is phylogenetically highly conservative. PMID- 26431448 TI - Management of oromandibular dystonia on a chorea acanthocytosis: a brief review of the literature and a clinical case. AB - BACKGROUND: Chorea acanthocytosis is an extremely rare neurodegenerative condition characterized by neuropsychiatric disturbances, movement disorders, neuropathy, seizures, and acanthocytosis. In this case report, the authors will present the management of the oromandibular movement disorders associated with this disease. CASE DESCRIPTION: This case report describes the focal management of the severe orofacial manifestations associated with this condition. The therapeutic approach adopted to reduce the severe oromandibular movements, dysphagia, and the numerous oral ulcers was selective electromyography (EMG) guided botulinum toxin application to the inferior head of the lateral pterygoid muscles and masseters. This would be applied to control severe and sudden oromandibular dystonia. RESULTS: Through this procedure, the authors were able to reduce these severe oral manifestations, which had a major impact on the patient's quality of life, and temporarily improve vital functions, such as mastication, deglutition, and speech articulation. CONCLUSIONS: Electromyography guided botulinum toxin application may be a useful tool in the multimodal management of this condition. PMID- 26431449 TI - Benzylic C-H trifluoromethylation of phenol derivatives. AB - Phenol derivatives were trifluoromethylated using copper/Togni reagent. In dimethylformamide, the benzylic C-H bond at the para position of the hydroxyl group was selectively substituted with a CF3 group. In contrast, aromatic C-H trifluoromethylation occurred in alcoholic solvents. Practical utility of the reactions was demonstrated by application to the synthesis of a potent enoyl-acyl carrier protein reductase (FabI) inhibitor. PMID- 26431450 TI - Equisetin, reutericyclin and streptolodygin as natural product lead structures for novel antibiotic libraries. AB - The emergence of antimicrobial resistance has created a need for the development of novel antibacterial therapies to treat infection. Natural products that exhibit antibacterial activity offer validated starting points for library generation, and the authors report here that small molecule mimics of tetramate containing natural products may show antibacterial activity and offer the potential for further optimization. PMID- 26431451 TI - Demodicosis in Renal Transplant Recipients. AB - Solid organ transplant recipients have an increased incidence of skin infections resulting from immunosuppression. Common pathogens include herpes simplex virus, varicella zoster virus, Gram-positive bacteria and dermatophytes; however, the contribution of multicellular parasitic organisms to dermatologic disease in this population remains less studied. Demodex folliculorum and brevis are commensal mites that reside on human skin. Proliferation of Demodex mites, or demodicosis, is associated with rosacea and rosacea-like disorders, particularly in immunocompromised populations, although their ability to cause disease is still the subject of debate. We present a case series of four renal transplant recipients with the singular chief complaint of acne rosacea who we diagnosed with demodicosis. Although one of the four patients showed complete resolution following initial antiparasitic therapy, the other three required subsequent antibacterial treatment to fully resolve their lesions. We suggest that demodicosis may be more prevalent than once thought in solid organ transplant recipients and showed that Demodex-associated acne rosacea can be effectively treated in this population. PMID- 26431456 TI - Fixed-dose combination products and unintended drug interactions: urgent need for pharmacogenetic evaluation. PMID- 26431457 TI - The effect of NaCl on stomatal opening in Arabidopsis wild type and agb1 heterotrimeric G-protein mutant plants. AB - Salinity is a major agricultural problem that affects crop yield. Na(+) is transported to the shoot through the transpiration stream. The mutant of the sole Arabidopsis heterotrimeric G protein beta subunit, agb1, is hypersensitive to salinity in part due to a higher transpiration rate. Here, we investigated the direct effect of Na(+) on stomatal opening using detached epidermal peels of wild type and agb1 plants. In both genotypes, NaCl is equally as effective as KCl in mediating stomatal opening at the concentrations tested. In both genotypes, ABA is less effective in inhibiting Na(+) mediated stomatal opening than K(+) mediated stomatal opening. The agb1 mutant is hyposensitive to ABA inhibition of K(+)-mediated but not Na(+)-mediated stomatal opening. These results suggest that the greater transpiration observed in agb1 plants grown in saline conditions is likely not mediated by differential genotypic direct effects of Na(+) on stomatal apertures. PMID- 26431458 TI - Change in Quality of Life for Patients with Irritable Bowel Syndrome following Referral to a Gastroenterologist: A Cohort Study. AB - BACKGROUND: Irritable bowel syndrome (IBS), a chronic functional condition, considerably reduces quality of life (QoL) and referral to gastroenterology is common. Until now, however, the impact of seeing a gastroenterologist for IBS on patients' QoL and utility has not been assessed. METHODS: Patients referred with "probable IBS" to the Nottingham Treatment Centre between October 2012 and March 2014 were invited to complete a QoL questionnaire (EuroQol-5 Dimension) before their first appointment. Patients with confirmed IBS who completed this baseline assessment were sent follow-up questionnaires three and twelve months later. Global QoL and utility were measured at each time point and change from baseline calculated. Paired t-tests analysed the significance of any change. RESULTS: Of 205 invited patients, 69 were eligible and recruited. Response at three and twelve months was 45% and 17% respectively. Median global QoL at baseline was 67.5 (Interquartile range [IQR] 50.0 to 80.0), with a mean increase of 3.25 (95% confidence interval [CI] -5.38 to 11.88) three months later and a mean decrease of -1.82 (95% CI -16.01 to 12.38) after one year. The median utility at baseline was 0.76 (IQR 0.69 to 0.80), with a mean increase of 0.06 (95%CI -0.01 to 0.14) at three months and no change, 0.00 (-0.16 to 0.16), after one year. CONCLUSION: Patients experienced a small but not statistically significant increase in QoL and utility three months after seeing a gastroenterologist for IBS, which was not maintained. Gastroenterology referral does not appear to appreciably improve Qol for most people with IBS. PMID- 26431462 TI - Kinetics of hematopoietic stem cells and supportive activities of stromal cells in a three-dimensional bone marrow culture system. AB - In the bone marrow, hematopoietic cells proliferate and differentiate in close association with a three-dimensional (3D) hematopoietic microenvironment. Previously, we established a 3D bone marrow culture system. In this study, we analyzed the kinetics of hematopoietic cells, and more than 50% of hematopoietic progenitor cells, including CFU-Mix, CFU-GM and BFU-E in 3D culture were in a resting (non-S) phase. Furthermore, we examined the hematopoietic supportive ability of stromal cells by measuring the expression of various mRNAs relevant to hematopoietic regulation. Over the 4 weeks of culture, the stromal cells in the 3D culture are not needlessly activated and "quietly" regulate hematopoietic cell proliferation and differentiation during the culture, resulting in the presence of resting hematopoietic stem cells in the 3D culture for a long time. Thus, the 3D culture system may be a new tool for investigating hematopoietic stem cell stromal cell interactions in vitro. PMID- 26431463 TI - ncRDeathDB: A comprehensive bioinformatics resource for deciphering network organization of the ncRNA-mediated cell death system. AB - Programmed cell death (PCD) is a critical biological process involved in many important processes, and defects in PCD have been linked with numerous human diseases. In recent years, the protein architecture in different PCD subroutines has been explored, but our understanding of the global network organization of the noncoding RNA (ncRNA)-mediated cell death system is limited and ambiguous. Hence, we developed the comprehensive bioinformatics resource (ncRDeathDB, www.rna-society.org/ncrdeathdb ) to archive ncRNA-associated cell death interactions. The current version of ncRDeathDB documents a total of more than 4600 ncRNA-mediated PCD entries in 12 species. ncRDeathDB provides a user friendly interface to query, browse and manipulate these ncRNA-associated cell death interactions. Furthermore, this resource will help to visualize and navigate current knowledge of the noncoding RNA component of cell death and autophagy, to uncover the generic organizing principles of ncRNA-associated cell death systems, and to generate valuable biological hypotheses. PMID- 26431464 TI - Declining trend of Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) mutant alleles after the withdrawal of Sulfadoxine-Pyrimethamine in North Western Ethiopia. AB - Antimalarial drug resistance is one of the major challenges in global efforts of malaria control and elimination. In 1998, chloroquine was abandoned and replaced with sulfadoxine/pyrimethamine, which in turn was replaced with artemether/lumefantrine for the treatment of uncomplicated falciparum malaria in 2004. Sulfadoxine/pyrimethamine resistance is associated with mutations in dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes. The prevalence of mutation in Pfdhfr and Pfdhps genes were evaluated and compared for a total of 159 isolates collected in two different time points, 2005 and 2007/08, from Pawe hospital, in North Western Ethiopia. The frequency of triple Pfdhfr mutation decreased significantly from 50.8% (32/63) to 15.9% (10/63) (P<0.001), while Pfdhps double mutation remained high and changed only marginally from 69.2% (45/65) to 55.4% (40/65) (P = 0.08). The combined Pfdhfr/Pfdhps quintuple mutation, which is strongly associated with sulfadoxine/pyrimethamine resistance, was significantly decreased from 40.7% (24/59) to 13.6% (8/59) (P<0.0001). On the whole, significant decline in mutant alleles and re-emergence of wild type alleles were observed. The change in the frequency is explained by the reduction of residual drug-resistant parasites caused by the strong drug pressure imposed when sulfadoxine/pyrimethamine was the first-line drug, followed by lower fitness of these resistant parasites in the absence of drug pressure. Despite the decrease in the frequency of mutant alleles, higher percentages of mutation remain prevalent in the study area in 2007/08 in both Pfdhfr and Pfdhps genes. Therefore, further multi-centered studies in different parts of the country will be required to assess the re-emergence of sulfadoxine/pyrimethamine sensitive parasites and to monitor and prevent the establishment of multi drug resistant parasites in this region. PMID- 26431465 TI - A Dye-Decolorizing Peroxidase from Vibrio cholerae. AB - The dye-decolorizing peroxidase (DyP) protein from Vibrio cholerae (VcDyP) was expressed in Escherichia coli, and its DyP activity was assayed by monitoring degradation of a typical anthraquinone dye, reactive blue 19 (RB19). Its kinetic activity was obtained by fitting the data to the Michaelis-Menten equation, giving kcat and Km values of 1.3 +/- 0.3 s(-1) and 50 +/- 20 MUM, respectively, which are comparable to those of other DyP enzymes. The enzymatic activity of VcDyP was highest at pH 4. A mutational study showed that two distal residues, Asp144 and Arg230, which are conserved in a DyP family, are essential for the DyP reaction. The crystal structure and resonance Raman spectra of VcDyP indicate the transfer of a radical from heme to the protein surface, which was supported by the formation of the intermolecular covalent bond in the reaction with H2O2. To identify the radical site, each of nine tyrosine or two tryptophan residues was substituted. It was clarified that Tyr129 and Tyr235 are in the active site of the dye degradation reaction at lower pH, while Tyr109 and Tyr133 are the sites of an intermolecular covalent bond at higher pH. VcDyP degrades RB19 at lower pH, while it loses activity under neutral or alkaline conditions because of a change in the radical transfer pathway. This finding suggests the presence of a pH dependent switch of the radical transfer pathway, probably including His178. Although the physiological function of the DyP reaction is unclear, our findings suggest that VcDyP enhances the DyP activity to survive only when it is placed under a severe condition such as being in gastric acid. PMID- 26431466 TI - Safety and immunogenicity of influenza vaccine among HIV-infected adults: Conventional vaccine vs. intradermal vaccine. AB - Several studies have reported poor immune responses to conventional influenza vaccines in HIV-infected individuals. This study sought to elicit more potent immunogenicity in HIV-infected adults using an intradermal vaccine compared with a conventional intramuscular vaccine. This multicenter, randomized, controlled, open-label study was conducted at 3 university hospitals during the 2011/2012 pre influenza season. Three vaccines were used in HIV-infected adults aged 18 - 60 years: an inactivated intramuscular vaccine (Agrippal), a reduced-content intradermal vaccine (IDflu9MUg) and a standard-content intradermal vaccine (IDflu15MUg). Serum hemagglutination-inhibiting (HI) antibodies and INF-gamma ELISpot assay were measured at the time of vaccination and 1 month after vaccination. Adverse events were recorded for 7 d. A total of 28 Agrippal, 30 IDflu9MUg, and 28 IDflu15MUg volunteers were included in this analysis. One month after vaccination, the GMTs and differences in INF-gamma ELISpot assay results were similar among the 3 groups. Seroprotection rates, seroconversion rates and mean fold increases (MFI) among the 3 groups were also similar, at approximately 80%, 50-60% and 2.5 - 10.0, respectively. All three vaccines satisfied the CHMP criteria for the A/H1N1 and A/H3N2 strains, but not those for the B strain. In univariate analysis, no demographic or clinical factors, including age, CD4+ T cell counts, HIV viral load, ART status and vaccine type, were related to failure to achieve seroprotection. The three vaccines were all well-tolerated and all reported reactions were mild to moderate. However, there was a tendency toward a higher incidence of local and systemic reactions in the intradermal vaccine groups. The intradermal vaccine did not result in higher immunogenicity compared to the conventional intramuscular vaccine, even with increased antigen dose. PMID- 26431467 TI - Resonance Raman and vibrational mode analysis used to predict ligand geometry for docking simulations of a water soluble porphyrin and tubulin. AB - The ability to modify the conformation of a protein by controlled partial unfolding may have practical applications such as inhibiting its function or providing non-native photosensitive properties. A water-soluble porphyrin, meso tetrakis (p-sulfonatophenyl) porphyrin (TSPP), non-covalently bound to tubulin can be used as a photosensitizer, which upon irradiation can lead to conformational changes of the protein. To fully understand the mechanism responsible for this partial unfolding and determine the amino acid residues and atoms involved, it is essential to find the most likely binding location and the configuration of the ligand and protein. Techniques typically used to analyze atomic position details, such as nuclear magnetic resonance and X-ray crystallography, require large concentrations, which are incompatible with the dilute conditions required in experiments for photoinduced mechanisms. Instead, we develop an atomistic description of the TSPP-tubulin complex using vibrational mode analysis from density functional theory calculations correlated to resonance Raman spectra of the porphyrin paired with docking simulations. Changes in the Raman peaks of the porphyrin molecule correlate with changes in its structural vibrational modes when bound to tubulin. The data allow us to construct the relative geometry of the porphyrin when bound to protein, which are then used with docking simulations to find the most likely configuration of the TSPP tubulin complex. PMID- 26431468 TI - The State of Health in Older Adults in Japan: Trends in Disability, Chronic Medical Conditions and Mortality. AB - Both life expectancy and healthy life expectancy in Japan have been increasing and are among the highest in the world, but the gap between them has also been widening. To examine the recent trends in old age disability, chronic medical conditions and mortality in Japan, we retrospectively analyzed three nationally representative datasets: Comprehensive Survey of Living Conditions (2001-2013), Patient Survey (1996-2011) and Vital Statistics (1995-2010). We obtained the sex- and age-stratified trends in disability rate, treatment rates of nine selected chronic medical conditions (cerebrovascular diseases, joint disorders, fractures, osteoporosis, ischemic heart disease, diabetes mellitus, hypertension, pneumonia and malignant neoplasms), total mortality rate and mortality rates from specific causes (cerebrovascular diseases, heart diseases, pneumonia and malignant neoplasms) in both sexes in four age strata (65-69, 70-74, 75-79, 80-84 years). Disability rates declined significantly in both sexes. Treatment rates of all selected medical conditions also decreased significantly, except for fractures in women and pneumonia. Both total mortality rate and cause-specific mortality rates decreased in both sexes. We concluded that the recent decline in disability rates, treatment rates of chronic medical conditions and mortality rates points toward overall improvement in health conditions in adults over the age of 65 years in Japan. Nonetheless, considering the increase in the number of older adults, the absolute number of older adults with disability or chronic medical conditions will continue to increase and challenge medical and long-term care systems. PMID- 26431470 TI - Safety, tolerability and pharmacokinetics of multiple oral doses of AFN-1252 administered as immediate release (IR) tablets in healthy subjects. AB - BACKGROUND: AFN-1252 is a novel inhibitor of FabI, which is essential in Staphylococcus spp. This study evaluated the safety, tolerability and pharmacokinetics of multiple oral doses of AFN-1252 immediate-release tablets. METHODS: Part I evaluated AFN-1252 as a single 200 mg dose in fed versus fasted subjects. Part II evaluated 200, 300 and 400 mg doses of AFN-1252 administered once-daily for 10 days. RESULTS: Pharmacokinetics indicated good absorption with a median Tmax of 2-3 hours, and a mean t1/2 of 7-10 hours, for all doses. Cmax and AUC responses were non-linear. A high-fat meal reduced AUC0-t and Cmax values by 62% and 48%, respectively, and delayed Tmax by 2.5 hours. All adverse events, including possibly drug-related headache and nausea, were mild or moderate. CONCLUSIONS: Multiple ascending doses of AFN-1252 were safe and well tolerated. AFN-1252 has potential for once- or twice-daily dosing in the treatment of staphylococcal infections. PMID- 26431469 TI - A Western dietary pattern is associated with overweight and obesity in a national sample of Lebanese adolescents (13-19 years): a cross-sectional study. AB - Adolescent obesity is associated with both immediate and longer-term health implications. This study aims to identify dietary patterns among a nationally representative sample of Lebanese adolescents aged between 13 and 19 years (n 446) and to assess the association of these patterns with overweight and obesity. Through face-to-face interviews, socio-demographic, lifestyle and anthropometric variables were collected. Dietary intake was assessed using a sixty-one-item FFQ. Dietary patterns were derived by factor analysis. The following two dietary patterns were identified: Western and traditional Lebanese. The Western pattern was characterised by high consumption of red meat, eggs and fast-food sandwiches. The traditional Lebanese pattern reflected high intakes of fruits and vegetables, legumes and fish. Female sex and a higher maternal education level were associated with a greater adherence to the traditional Lebanese pattern. As for the Western pattern, the scores were negatively associated with crowding index, physical activity and frequency of breakfast consumption. After adjustment, subjects belonging to the 3rd tertile of the Western pattern scores had significantly higher odds of overweight compared with those belonging to the 1st tertile (OR 2.3; 95% CI 1.12, 4.73). In conclusion, two distinct dietary patterns were identified among adolescents in Lebanon: the traditional Lebanese and the Western, with the latter pattern being associated with an increased risk of overweight. The findings of this study may be used to guide the development of evidence-based preventive nutrition interventions to curb the obesity epidemic in this age group. PMID- 26431471 TI - Indices of central and general obesity and cardiometabolic risk among adolescents in three ethnic groups in north-west China. AB - BACKGROUND: 'A Body Shape Index-Adolescents' (ABSI-Adolescents) and waist-to height ratio are recently proposed indices that quantify central obesity in adolescents. AIMS: To investigate the scaling exponents to standardise waist circumference (WC) for body mass index (BMI) and height and to investigate the association between BMI, WC-based indices and cardiometabolic outcomes in adolescents of three ethnic groups. SUBJECTS AND METHODS: A cross-sectional study of 1755 adolescents (516 Hans, 565 Uygurs, 674 Kazakhs) was conducted in north west China. Correlation between indices of obesity and blood pressure (BP) and fasting blood glucose (FBG) were estimated and compared. RESULTS: Two ethnic groups (Han and Kazakh) had WC-BMI-height profiles different from the previously proposed ABSI-Adolescents and, therefore, required different scaling exponents for WC standardization. After adjustment for age and gender, WC and BMI have similar associations with BP and FBG. After further adjustment for BMI, WC remained significantly associated with FBG in all three ethnic groups (each p < 0.01) and with BP in Han and Kazakh adolescents (each p < 0.05). CONCLUSION: Body proportionality varied between the ethnic groups. WC and WC-based indices were associated with blood pressure and fasting blood glucose in adolescents of three ethnicities. The WC-based indices did not out-perform WC per se. PMID- 26431472 TI - Route to the Smallest Doped Semiconductor: Mn(2+)-Doped (CdSe)13 Clusters. AB - Doping semiconductor nanocrystals with magnetic transition-metal ions has attracted fundamental interest to obtain a nanoscale dilute magnetic semiconductor, which has unique spin exchange interaction between magnetic spin and exciton. So far, the study on the doped semiconductor NCs has usually been conducted with NCs with larger than 2 nm because of synthetic challenges. Herein, we report the synthesis and characterization of Mn(2+)-doped (CdSe)13 clusters, the smallest doped semiconductors. In this study, single-sized doped clusters are produced in large scale. Despite their small size, these clusters have semiconductor band structure instead of that of molecules. Surprisingly, the clusters show multiple excitonic transitions with different magneto-optical activities, which can be attributed to the fine structure splitting. Magneto optically active states exhibit giant Zeeman splittings up to elevated temperatures (128 K) with large g-factors of 81(+/-8) at 4 K. Our results present a new synthetic method for doped clusters and facilitate the understanding of doped semiconductor at the boundary of molecules and quantum nanostructure. PMID- 26431473 TI - Integrated photoacoustic and diffuse optical tomography system for imaging of human finger joints in vivo. AB - In this study, we developed a dual-modality tomographic system that integrated photoacoustic imaging (PAI) and diffuse optical tomography (DOT) into a single platform for imaging human finger joints with fine structures and associated optical properties. In PAI, spherical focused transducers were utilized to collect acoustic signals, and the concept of virtual detector was applied in a conventional back-projection algorithm to improve the image quality. A finite element based reconstruction algorithm was employed to quantitatively recover optical property distribution in the objects for DOT. The phantom results indicate that PAI has a maximum lateral resolution of 70 um in resolving structures of targets. DOT was able to recover both optical absorption and reduced scattering coefficients of targets accurately. To validate the potential of this system in clinical diagnosis of joint diseases, the distal interphalangeal (DIP) joints of 4 healthy female volunteers were imaged. We successfully obtained high-resolution images of the phalanx and the surrounding soft tissue via PAI, and recovered both optical absorption and reduced scattering coefficients of phalanx using DOT. The in vivo results suggest that this dual modality system has the potential for the early diagnosis of joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA). Integrated PAI/DOT imaging interface (top) and typical reconstruction of structures and associated optical properties of a female finger joint via PAI and DOT (bottom). PMID- 26431475 TI - Functional Impact of Collagens on the Activity Directed by the Promoter of the alpha5 Integrin Subunit Gene in Corneal Epithelial Cells. AB - PURPOSE: The early step of corneal wound healing is characterized by the massive production of fibronectin (FN), whose secretion is progressively replaced by collagens from the basal membrane as wound healing proceeds. Here, we examined whether expression of the gene encoding the alpha5 subunit from the FN-binding integrin alpha5beta1 changes as corneal epithelial cells (CECs) are cultured in the presence of collagen type I (CI) or type IV (CIV). METHODS: Responsiveness of the alpha5 gene toward collagen was determined by transfection of alpha5 promoter/chloramphenicol acetyltransferase (CAT) plasmids into rabbit and human CECs cultured on BSA or collagens. Electrophoretic mobility shift assays and Western blots were used to monitor the transcription factors required for basal alpha5 gene transcription in the presence of collagens. Gene profiling on microarrays was used to determine the impact of collagens on the patterns of genes expressed by CECs. RESULTS: All collagen types repressed the full-length alpha5/CAT promoter activity in confluent CECs. A moderate increase was observed in subconfluent rabbit CECs grown on CIV but not on CI. These collagen-dependent regulatory influences also correlated with alterations in the transcription factors Sp1/Sp3, NFI, and AP-1 that ensure alpha5 gene basal transcription. Microarray analyses revealed that CI more profoundly altered the pattern of genes expressed by human CECs than CIV. CONCLUSIONS: Collagens considerably suppressed alpha5 gene expression in CECs, suggesting that during wound healing, they may interfere with the influence FN exerts on CECs by altering their adhesive and migratory properties through a mechanism involving a reduction in alpha5 gene expression. PMID- 26431474 TI - Erp29 Attenuates Cigarette Smoke Extract-Induced Endoplasmic Reticulum Stress and Mitigates Tight Junction Damage in Retinal Pigment Epithelial Cells. AB - PURPOSE: Endoplasmic reticulum protein 29 (ERp29) is a novel chaperone that was recently found decreased in human retinas with AMD. Herein, we examined the effect of ERp29 on cigarette smoke-induced RPE apoptosis and tight junction disruption. METHODS: Cultured human RPE (HRPE) cells (ARPE-19) or mouse RPE eyecup explants were exposed to cigarette smoke extract (CSE) for short (up to 24 hours) or long (up to 3 weeks) periods. Expression of ERp29 was up- and downregulated by adenovirus and siRNA, respectively. Endoplasmic reticulum stress markers, apoptosis, and cell death, the expression and distribution of tight junction protein ZO-1, transepithelial electrical resistance (TEER), and F-actin expression were examined. RESULTS: Endoplasmic reticulum protein 29 was significantly increased by short-term exposure to CSE in ARPE-19 cells or eyecup explants but was reduced after 3-week exposure. Overexpression of ERp29 increased the levels of GRP78, p58(IPK), and Nrf-2, while reducing p-eIF2alpha and C/EBP homologous protein (CHOP), and protected RPE cells from CSE-induced apoptosis. In contrast, knockdown of ERp29 decreased the levels of p58(IPK) and Nrf2, but increased p-eIF2alpha and CHOP and exacerbated CSE-triggered cell death. In addition, overexpression of ERp29 attenuated CSE-induced reduction in ZO-1 and enhanced the RPE barrier function, as measured by TEER. Knockdown of ERp29 decreased the level of ZO-1 protein. These effects were associated with changes in the expression of cytoskeleton F-actin. CONCLUSIONS: Endoplasmic reticulum protein 29 attenuates CSE-induced ER stress and enhances cell viability and barrier integrity of RPE cells, and therefore may act as a protective mechanism for RPE survival and activity. PMID- 26431477 TI - Erratum. PMID- 26431476 TI - The Usefulness of Gaze Tracking as an Index of Visual Field Reliability in Glaucoma Patients. AB - PURPOSE: We evaluated the usefulness of gaze tracking (GT) results as an index of visual field reliability in glaucoma. METHODS: The study population consisted of 631 eyes of 400 patients with open angle glaucoma in an institutional practice, with 10 visual fields (VFs). For the observational procedure, visual fixation was assessed using the gaze fixation chart at the bottom of the VF (Humphrey Field Analyzer, 30-2 SITA standard) printout. Average frequency of eye movement between 1 degrees and 2 degrees (move(1-2)), 3 degrees and 5 degrees (move(3-5)), and greater than or equal to 6 degrees (move(>=6)) were calculated. In addition, average tracking failure frequency (TFF) and average blinking frequency (BF) were calculated. The relationship between mean deviation (MD), fixation losses (FLs), false-positives (FPs), false-negatives (FNs), move(1-2), move(3-5), move(>=6), TFF, BF, and pattern standard deviation (PSD) were evaluated using linear modeling. Main outcome measures included parameters related to over- or underestimation of MD values. RESULTS: Patients' mean MD progression rate was 0.23 dB/y. The best model to predict MD values included FL rate, FP rate, move(3 5), move(>=6), TFF, BF, and PSD as dependent variables with coefficients of 0.90, 9.2, -0.57, -0.52, -2.2, -1.1, and -0.56, respectively (P < 0.001). CONCLUSIONS: High FL and FP rates tend to raise MD values. By contrast, high values of move(3 5), move(>=6), TFF, BF, and PSD tend to lower MD values. Thus, GT parameters can be used as new indices of VF reliability through the prediction of over- or underestimation of VF results. PMID- 26431478 TI - Evaluation of the Association Between Common Genetic Variants Near the ABCA1 Gene and Primary Angle Closure Glaucoma in a Han Chinese Population. AB - PURPOSE: Recently, three large genome-wide association studies have identified multiple variants associated with primary open angle glaucoma (POAG) near the ABCA1 gene. Considering that POAG and primary angle closure glaucoma (PACG) share many similar clinical manifestations, the present study was conducted to investigate whether these genetic variants were also associated with PACG in a Han Chinese population. METHODS: A case-control association study of 1122 cases (PACG/PAC) and 1311 normal, matched controls was undertaken. Seven single nucleotide polymorphisms (SNPs) near the ABCA1 gene, including rs2422493, rs2487042, rs2472496, rs2472493, rs2487032, rs2472459, and rs2472519, were genotyped. Genotype and allele frequencies were assessed using chi2 tests. Linkage disequilibrium (LD) structure was analyzed by computer software. RESULTS: Among the SNPs genotyped, no association was observed between these SNPs and PACG. However, we discovered that two haplotypes, CATTTAC (corrected P = 0.048) and CGCCCGC (corrected P = 0.048), remained significantly associated with PACG/PAC after Bonferroni correction. Subjects with the CATTTAC haplotype have a 1.71-fold increased possibility of having PACG/PAC, whereas subjects with the CGCCCGC haplotype have 0.47-fold decreased possibility of developing PACG. CONCLUSIONS: Our findings suggest that the genetic backgrounds of PACG and POAG might be different. However, whether or not ABCA1 plays a role in the development of PACG is still not made certain by this study. Thus, further research is needed to find the role of ABCA1 in the progress of PACG. PMID- 26431481 TI - Assessment of Visual and Chromatic Functions in a Rodent Model of Retinal Degeneration. AB - PURPOSE: We evaluated the photoreceptor response of pigmented P23H and normal pigmented Long Evans (LE) rats over time using functional tests in variable lighting conditions. METHODS: Pigmented P23H rats were studied by optomotor testing and electroretinogram (ERG) recordings at P30, P150, and P240. Pigmented LE rats were used as a normal wild-type control. Stimuli were modified with colored filters. Neutral density filters were used to reduce luminance. RESULTS: Age-related decreases in visual acuity (VA) and contrast sensitivity (CS) were observed in P23H rats. Good correlations in measurements without filter and with green filter were observed between LE and P23H P30 rat values. Differences between groups were smaller with red and purple filters. A strong relationship with luminance was observed in LE rats (VA and CS) and with P23H P30 rats (CS). A decline in the ERG responses of P23H rats was consistent with the gradual loss of photoreceptors. Differences in a- and b-wave amplitudes with different colored filters were negligible with the exception of the red filter, which resulted in smaller responses. CONCLUSIONS: Visual function parameters decreased with age in pigmented P23H rats. Irrespective of luminance, color filter, and retinal degeneration, minimum thresholds of VA and CS were found. Smaller differences than expected were found using color filters. Responses to functional tests at long wavelengths were observed, where there is very low photoreceptor spectral sensitivity. The use of filters with functional testing could minimize light induced retinal damage in rats. PMID- 26431479 TI - Evolutionary Characterization of the Retinitis Pigmentosa GTPase Regulator Gene. AB - PURPOSE: The evolutionary conservation of the retinitis pigmentosa GTPase regulator (RPGR) gene was examined across vertebrate and invertebrate lineages to elucidate its function. METHODS: Orthologous RPGR sequences from vertebrates and invertebrates were selected. Multiple sequence alignments, phylogenetic analyses, synteny, and gene structure comparisons were carried out. Expression of the alternatively spliced constitutive (RPGR(const) or RPGR(ex1-19)) and RPGR(ORF15) isoforms was examined in developing and adult zebrafish. RESULTS: Phylogenetic analyses and syntenic relationships were consistent with the selected sequences being true orthologues, although whole genome duplications in teleost fish resulted in a more complex picture. The splice form RPGR(const) was present in all vertebrate and invertebrate species but the defining carboxyl (C)-terminal exon of RPGR(ORF15) was absent from all invertebrates. The regulator of chromosome condensation (RCC1)-like domain adopts a seven-bladed beta-propeller structure, which was present in both major splice forms and strongly conserved across evolution. The repetitive acidic region of RPGR(ORF15) showed a high rate of in-frame deletions/insertions across nine primate species, compared with flanking sequences, consistent with an unstable and rapidly evolving region. In zebrafish, RPGR(const) transcripts were most strongly expressed in early development, while the RPGR(ORF15) isoform showed highest expression in adult eye. CONCLUSIONS: The regulator of chromosome condensation 1-like domain of RPGR was conserved in vertebrates and invertebrates, but RPGR(ORF15) was unique to vertebrates, consistent with a proposed role in the ciliary-based transport of cargoes such as rhodopsin, which is ~10 times more abundant in vertebrate than invertebrate photoreceptors. The repetitive acidic region of RPGR(ORF15) shows a rapid rate of evolution, consistent with a mutation "hot spot." PMID- 26431480 TI - Effects of Cytokine Activation and Oxidative Stress on the Function of the Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells. AB - PURPOSE: In several retinal complications, such as age-dependent macular degeneration (AMD), oxidative stress is increased and cytokine level is elevated. These are shown to alter the activation and expression of matrix metalloproteinase (MMP) both in human primary and immortalized retinal pigment epithelial (RPE) cells. However, the effects on human embryonic stem cell (hESC) derived RPE cells remain to be elucidated. METHODS: The mature hESC-RPE cells were exposed to inflammatory cytokines (IFN-gamma or TNF-alpha) for 24 hours or oxidative stress (H2O2) for 1 hour. Effects on barrier properties were analyzed with transepithelial electrical resistance (TEER), the expression of MMP-1, MMP 2, MMP-3, MMP-9, collagen I, and collagen IV genes with quantitative RT-PCR, and the expression of MMP-1 and MMP-3 proteins with Western blot or ELISA, respectively. Also, activation and secretion of MMP-2 and -9 proteins were analyzed with zymography. RESULTS: In normal state, mature hESC-RPE cells expressed MMP-1, -2, -3, and -9 genes in low levels, respectively. Tumor necrosis factor-alpha increased MMP-1 and -2 gene expression, and H2O2 increased MMP-3 and -9 gene expression. Zymography revealed IFN-gamma- and TNF-alpha-induced secretion of MMP-2 and high-molecular-weight species of MMP (HMW MMP), but H2O2 decreased their secretion. Furthermore, TNF-alpha and H2O2 significantly decreased barrier properties. CONCLUSIONS: Here, cytokines induced the MMP-1 and 2 gene and protein expression. Also, H2O2 induced MMP-3 and -9 gene expression, but not their protein secretion. These data propose that under oxidative stress and cytokine stimuli, mature hESC-RPE cells resemble their native counterpart in the human eye in regard to MMP secretion and expression and could be used to model retinal disorders involving alterations in MMP activity such as AMD, diabetic retinopathy, or proliferative vitreoretinopathy in vitro. PMID- 26431482 TI - Combined 60 degrees Wide-Field Choroidal Thickness Maps and High-Definition En Face Vasculature Visualization Using Swept-Source Megahertz OCT at 1050 nm. AB - PURPOSE: To demonstrate ultrahigh-speed swept-source optical coherence tomography (SS-OCT) at 1.68 million A-scans/s for choroidal imaging in normal and diseased eyes over a ~60 degrees field of view. To investigate and correlate wide-field three-dimensional (3D) choroidal thickness (ChT) and vascular patterns using ChT maps and coregistered high-definition en face images extracted from a single densely sampled Megahertz-OCT (MHz-OCT) dataset. METHODS: High-definition, ~60 degrees wide-field 3D datasets consisting of 2088 * 1024 A-scans were acquired using a 1.68 MHz prototype SS-OCT system at 1050 nm based on a Fourier-domain mode-locked laser. Nine subjects (nine eyes) with various chorioretinal diseases or without ocular pathology are presented. Coregistered ChT maps, choroidal summation maps, and depth-resolved en face images referenced to either the retinal pigment epithelium or the choroidal-scleral interface were generated using manual segmentation. RESULTS: Wide-field ChT maps showed a large inter- and intraindividual variance in peripheral and central ChT. In only four of the nine eyes, the location with the largest ChT was coincident with the fovea. The anatomy of the large lumen vessels of the outer choroid seems to play a major role in determining the global ChT pattern. Focal ChT changes with large thickness gradients were observed in some eyes. CONCLUSIONS: Different ChT and vascular patterns could be visualized over ~60 degrees in patients for the first time using OCT. Due to focal ChT changes, a high density of thickness measurements may be favorable. High-definition depth-resolved en face images are complementary to cross sections and thickness maps and enhance the interpretation of different ChT patterns. PMID- 26431484 TI - Increasing Attentional Load Boosts Saccadic Adaptation. AB - PURPOSE: Visual exploration relies on saccadic eye movements and attention processes. Saccadic adaptation mechanisms, which calibrate the oculomotor commands to continuously maintain the accuracy of saccades, have been suggested to act at downstream (motor) and upstream (visuoattentional) levels of visuomotor transformation. Conversely, whether attention can directly affect saccadic adaptation remains unknown. To answer this question, we manipulated the level of attention engaged in a visual discrimination task performed during saccadic adaptation. METHODS: Participants performed low or high attention demanding orientation discrimination tasks on largely or faintly oriented Gabor patches, respectively, which served as targets for reactive saccades. Gabor patches systematically jumped backward during eye motion to elicit an adaptive shortening of saccades, and replaced 50 msec later (100 msec in two subjects) by a mask. Subjects judged whether Gabors' orientation was "nearly horizontal" versus "nearly vertical" (low attention demanding) or "slightly left" versus "slightly right" (high attention demanding), or made no discrimination (control task). RESULTS: We found that the build-up and the retention of adaptation of reactive saccades were larger in the "high attention demanding" condition than in the "low attention demanding" and the no-discrimination control conditions. CONCLUSIONS: These results indicate that increasing the level of attention to the perceptual processing of otherwise identical targets boosts saccadic adaptation, and suggest that saccadic adaptation mechanisms and attentional load effects may functionally share common neural substrates. PMID- 26431483 TI - Systemic Retinaldehyde Treatment Corrects Retinal Oxidative Stress, Rod Dysfunction, and Impaired Visual Performance in Diabetic Mice. AB - PURPOSE: Diabetes appears to induce a visual cycle defect because rod dysfunction is correctable with systemic treatment of the visual cycle chromophore 11-cis retinaldehyde. However, later studies have found no evidence for visual cycle impairment. Here, we further examined whether photoreceptor dysfunction is corrected with 11-cis-retinaldehyde. Because antioxidants correct photoreceptor dysfunction in diabetes, the hypothesis that exogenous visual chromophores have antioxidant activity in the retina of diabetic mice in vivo was tested. METHODS: Rod function in 2-month-old diabetic mice was evaluated using transretinal electrophysiology in excised retinas and apparent diffusion coefficient (ADC) MRI to measure light-evoked expansion of subretinal space (SRS) in vivo. Optokinetic tracking was used to evaluate cone-based visual performance. Retinal production of superoxide free radicals, generated mostly in rod cells, was biochemically measured with lucigenin. Diabetic mice were systemically treated with a single injection of either 11-cis-retinaldehyde, 9-cis-retinaldehyde (a chromophore surrogate), or all-trans-retinaldehyde (the photoisomerization product of 11-cis retinaldehyde). RESULTS: Consistent with previous reports, diabetes significantly reduced (1) dark-adapted rod photo responses (transretinal recording) by ~18%, (2) rod-dominated light-stimulated SRS expansion (ADC MRI) by ~21%, and (3) cone dominated contrast sensitivity (using optokinetic tracking [OKT]) by ~30%. Both 11-cis-retinaldehyde and 9-cis-retinaldehyde largely corrected these metrics of photoreceptor dysfunction. Higher-than-normal retinal superoxide production in diabetes by ~55% was also significantly corrected following treatment with 11-cis retinaldehyde, 9-cis-retinaldehyde, or all-trans-retinaldehyde. CONCLUSIONS: Collectively, data suggest that retinaldehydes improve photoreceptor dysfunction in diabetic mice, independent of the visual cycle, via an antioxidant mechanism. PMID- 26431486 TI - From WCl6 to WCl2: Properties of Intermediate Fe-W-Cl Phases. AB - Phenomenological studies of WCl6 reduction with transition metal powders M = Mn, Fe, and Co have been recently reported. These reactions involve a series of reductive intercalation steps of M atoms into layered tungsten chloride arrangements, followed by exsolution of MCl2. In the series M = Fe, the presence of divalent iron is evidenced for Fe(x)WCl6, FeW2Cl10, Fe2W2Cl10, and (Fe,W)Cl2 by Mossbauer spectroscopy. Magnetic properties are reported. Bonding characteristics between tungsten atoms in edge-sharing [W2Cl10](n-) bioctahedra reveal that a double bond can be addressed to FeW2Cl10. A similar situation appears for Fe2W2Cl10, due to the localized and thus nonbonding character of the two electrons in the delta orbitals of this compound. PMID- 26431485 TI - Integrin Alpha-9 Mediates Lymphatic Valve Formation in Corneal Lymphangiogenesis. AB - PURPOSE: We recently reported that corneal lymphatic vessels develop integrin alpha-9 (Itga-9)-positive valves during inflammatory lymphangiogenesis. The purpose of this study was to further investigate the role of Itga-9 in corneal lymphatic valve formation in vivo and lymphatic endothelial cell (LEC) functions in vitro. METHODS: Standard murine suture placement model was used to study the effect of Itga-9 blockade on lymphatic valve formation in vivo using Itga-9 neutralizing antibody. Whole-mount corneas were harvested for immunofluorescent microscopic analysis. Additionally, human LEC culture system was used to examine the effect of Itga-9 gene knockdown on cell functions using small interfering RNAs (siRNAs). RESULTS: Itga-9 blockade in vivo significantly reduced the number of lymphatic valves formed in the inflamed cornea. Moreover, Itga-9 gene knockdown in human LECs suppresses cell functions of proliferation, adhesion, migration, and tube formation. CONCLUSIONS: Itga-9 is critically involved in corneal lymphatic valve formation. Further investigation of the Itga-9 pathway may provide novel strategies to treat lymphatic-related diseases occurring both inside and outside the eye. PMID- 26431487 TI - Creative Self-Efficacy: An Exploration of Its Antecedents, Consequences, and Applied Implications. AB - Creativity and innovation are at the core of important outcomes such as economic and sales growth, production of articles and students' learning. Thus, it is not surprising to find research articles on creativity and innovation across different disciplines such as business, psychology, and education. Given the importance of understanding creativity and innovation, we reviewed the empirical literature examining the antecedents and consequences of creative self-efficacy in the work domain. Our review used the theory of individual creative action and social cognitive theory as guiding frameworks to place creative self-efficacy in the creativity and innovation process, define creativity and innovation, explore how creative self-efficacy has been measured, examine the antecedents and consequences of creative self-efficacy, point out gaps in knowledge and offer suggestions for future research and provide some applied implications. One important finding was that creative self-efficacy has made a significant contribution as a process variable explaining how several organizational and personal factors influence creative outcomes via their influence on creative self efficacy. PMID- 26431488 TI - Metagenomic Human Repiratory Air in a Hospital Environment. AB - Hospital-acquired infection (HAI) or nosocomial infection is an issue that frequent hospital environment. We believe conventional regulated Petri dish method is insufficient to evaluate HAI. To address this problem, metagenomic sequencing was applied to screen airborne microbes in four rooms of Beijing Hospital. With air-in amount of sampler being setup to one person's respiration quantity, metagenomic sequencing identified huge numbers of species in the rooms which had already qualified widely accepted petridish exposing standard, imposing urgency for new technology. Meanwhile,the comparative culture only got small portion of recovered species and remain blind for even cultivable pathogens reminded us the limitations of old technologies. To the best of our knowledge, the method demonstrated in this study could be broadly applied in hospital indoor environment for various monitoring activities as well as HAI study. It is also potential as a transmissible pathogen real-time modelling system worldwide. PMID- 26431489 TI - Identification of thyroid tumor cell vulnerabilities through a siRNA-based functional screening. AB - The incidence of thyroid carcinoma is rapidly increasing. Although generally associated with good prognosis, a fraction of thyroid tumors are not cured by standard therapy and progress to aggressive forms for which no effective treatments are currently available. In order to identify novel therapeutic targets for thyroid carcinoma, we focused on the discovery of genes essential for sustaining the oncogenic phenotype of thyroid tumor cells, but not required to the same degree for the viability of normal cells (non-oncogene addiction paradigm). We screened a siRNA oligonucleotide library targeting the human druggable genome in thyroid cancer BCPAP cell line in comparison with immortalized normal human thyrocytes (Nthy-ori 3-1). We identified a panel of hit genes whose silencing interferes with the growth of tumor cells, while sparing that of normal ones. Further analysis of three selected hit genes, namely Cyclin D1, MASTL and COPZ1, showed that they represent common vulnerabilities for thyroid tumor cells, as their inhibition reduced the viability of several thyroid tumor cell lines, regardless the histotype or oncogenic lesion. This work identified non-oncogenes essential for sustaining the phenotype of thyroid tumor cells, but not of normal cells, thus suggesting that they might represent promising targets for new therapeutic strategies. PMID- 26431491 TI - Long non-coding RNA profiling links subgroup classification of endometrioid endometrial carcinomas with trithorax and polycomb complex aberrations. AB - BACKGROUND: Integrative analysis of endometrioid endometrial carcinoma (EEC) using multiple platforms has distinguished four molecular subgroups. However, the landscape of expressed long non-coding RNAs (lncRNA) and their role in charting EEC subgroups and determining clinical aggressiveness remain largely unknown. RESULTS: Using stringent criteria, we identified 1,931 expressed lncRNAs and predicted potential drivers through integrative analysis. Unsupervised clustering of lncRNA expression revealed three robust categories: basal-like, luminal-like and CTNNB1-enriched subgroups. Basal-like subgroup was enriched for aggressive tumors with higher pathological grade (p < 0.0001), TNM stage (p = 0.01), and somatic mutations in trithorax-group genes (MLL, MLL2 and MLL3); and it overexpressed polycomb genes EZH2 and CBX2. In contrast to the luminal-like subgroup, progesterone (PGR) and estrogen receptor (ESR1) genes were highly down regulated in the EEC basal-like subgroup. Consistent with its enrichment for CTNNB1 mutations (69%), lncRNA profile of the CTNNB1-enriched EEC subgroup was highly similar to that of the CTNNB1-enriched liver cancer subgroup. MATERIALS AND METHODS: We performed integrative analysis of lncRNAs in EEC using The Cancer Genome Atlas (TCGA) molecular RNAseq profiles of 191 primary tumors for which genomic data were also available. We established lncRNA subgroup classification, correlated it with chromatin modifying gene expression, and described correlations between our lncRNA classification and clinico-genomic tumor features. CONCLUSIONS: Our results reveal the utility of systematic characterization of clinically annotated EEC in three clinically relevant subgroups. They also highlight the convergence of aberrations in polycomb- and trithorax-group genes in aggressive basal EEC subtypes, providing a rationale for further investigation of epigenetic therapy in this setting. PMID- 26431490 TI - Nodal metastasis in cervical cancer occurs in clearly delineated fields of immune suppression in the pelvic lymph catchment area. AB - In cervical cancer, high frequencies of regulatory T cells (Tregs) and immunosuppressive PD-L1+CD14+ antigen-presenting cells dominate the microenvironment of tumor-positive lymph nodes (LN+). It is unknown whether this is restricted to LN+ or precedes metastasis, emanating from the primary tumor and spreading through tumor-draining lymph nodes (TDLNs). To investigate immunosuppression in the lymphatic basin of cervical tumors, all dissected TDLNs of five cervical cancer patients (in total 9 LN+ and 74 tumor-negative lymph nodes (LN-)) were analyzed for FoxP3+ Tregs, CD8+ T cells, HLA-DR+- and PD-L1+ myeloid cells by immunohistochemistry.Tregs and PD-L1+ cells were found to form an immunosuppressive cordon around metastatic tumor cells. Importantly, whereas high HLA-DR+- and PD-L1+ cell rates were strongly associated with LN+, elevated Treg levels and decreased CD8+ T cell/Treg ratios were found similar in LN+ and adjacent LN-, as compared to LN- at more distant anatomical localizations. These data suggest that delineated fields of Treg-associated immune suppression in anatomically co-localized TDLNs enable metastasis by creating metastatic niches. This may be of importance for decision-making regarding (surgical) intervention in cervical cancer. Future efforts should include the implementation of immunotherapeutic regimens to overcome this immune suppression, establish loco regional control and halt systemic tumor spread. PMID- 26431492 TI - Chitinase 3-like 1 induces survival and proliferation of intestinal epithelial cells during chronic inflammation and colitis-associated cancer by regulating S100A9. AB - Many host-factors are inducibly expressed during the development of inflammatory bowel disease (IBD), each having their unique properties, such as immune activation, bacterial clearance, and tissue repair/remodeling. Dysregulation/imbalance of these factors may have pathogenic effects that can contribute to colitis-associated cancer (CAC). Previous reports showed that IBD patients inducibly express colonic chitinase 3-like 1 (CHI3L1) that is further upregulated during CAC development. However, little is known about the direct pathogenic involvement of CHI3L1 in vivo. Here we demonstrate that CHI3L1 (aka Brp39) knockout (KO) mice treated with azoxymethane (AOM)/dextran sulphate sodium (DSS) developed severe colitis but lesser incidence of CAC as compared to that in wild-type (WT) mice. Highest CHI3L1 expression was found during the chronic phase of colitis, rather than the acute phase, and is essential to promote intestinal epithelial cell (IEC) proliferation in vivo. This CHI3L1-mediated cell proliferation/survival involves partial downregulation of the pro-apoptotic S100A9 protein that is highly expressed during the acute phase of colitis, by binding to the S100A9 receptor, RAGE (Receptor for Advanced Glycation End products). This interaction disrupts the S100A9-associated expression positive feedback loop during early immune activation, creating a CHI3L1hi S100A9low colonic environment, especially in the later phase of colitis, which promotes cell proliferation/survival of both normal IECs and tumor cells. PMID- 26431494 TI - Association of FGFR3 and FGFR4 gene polymorphisms with breast cancer in Chinese women of Heilongjiang province. AB - BACKGROUND: The fibroblast growth factor (FGF) receptor pathway is activated in many tumors. FGFR2 has been identified as a breast cancer susceptibility gene. Common variation in other FGF receptors might also affect breast cancer risk. We carried out a case-control study to investigate associations of variants in FGFR3 and FGFR4 with breast cancer in women from Heilongjiang Province. METHODS: SNP rs2234909 and rs3135848 in FGFR3 and rs1966265 and rs351855 in FGFR4 were successfully genotyped in 747 breast cancer patients and 716 healthy controls using the SNaPshot method. The associations between SNPs and breast cancer were examined by logistic regression. The associations between SNPs and disease characteristics were examined by chi-square tests or one-way ANOVA as needed. RESULTS: The minor alleles of rs1966265 and rs351855 in FGFR4 were strongly associated with breast cancer in the population, with odds ratios of 1.335 (95%CI = 1.154-1.545) and 1.364 (95%CI = 1.177-1.580), respectively. However, no significant associations were detected between other SNPs and breast cancer. Analyses of the disease characteristics showed that SNP rs351855 was associated with lymph-node-positive breast cancer with a dose-dependent effect of the minor allele (P = 0.008). CONCLUSIONS: SNPs rs1966265 and rs351855 in FGFR4 were associated with breast cancer in a northern Chinese population. PMID- 26431496 TI - ENT1 and treatment of viral diseases. PMID- 26431497 TI - Undoing SUMO aids polyQ AR. PMID- 26431493 TI - The molecular effect of metastasis suppressors on Src signaling and tumorigenesis: new therapeutic targets. AB - A major problem for cancer patients is the metastasis of cancer cells from the primary tumor. This involves: (1) migration through the basement membrane; (2) dissemination via the circulatory system; and (3) invasion into a secondary site. Metastasis suppressors, by definition, inhibit metastasis at any step of the metastatic cascade. Notably, Src is a non-receptor, cytoplasmic, tyrosine kinase, which becomes aberrantly activated in many cancer-types following stimulation of plasma membrane receptors (e.g., receptor tyrosine kinases and integrins). There is evidence of a prominent role of Src in tumor progression-related events such as the epithelial-mesenchymal transition (EMT) and the development of metastasis. However, the precise molecular interactions of Src with metastasis suppressors remain unclear. Herein, we review known metastasis suppressors and summarize recent advances in understanding the mechanisms of how these proteins inhibit metastasis through modulation of Src. Particular emphasis is bestowed on the potent metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1) and its interactions with the Src signaling cascade. Recent studies demonstrated a novel mechanism through which NDRG1 plays a significant role in regulating cancer cell migration by inhibiting Src activity. Moreover, we discuss the rationale for targeting metastasis suppressor genes as a sound therapeutic modality, and we review several examples from the literature where such strategies show promise. Collectively, this review summarizes the essential interactions of metastasis suppressors with Src and their effects on progression of cancer metastasis. Moreover, interesting unresolved issues regarding these proteins as well as their potential as therapeutic targets are also discussed. PMID- 26431495 TI - What links BRAF to the heart function? New insights from the cardiotoxicity of BRAF inhibitors in cancer treatment. AB - The RAS-related signalling cascade has a fundamental role in cell. It activates differentiation and survival. It is particularly important one of its molecules, B-RAF. B-RAF has been a central point for research, especially in melanoma. Indeed, it lacked effective therapeutic weapons since the early years of its study. Molecules targeting B-RAF have been developed. Nowadays, two classes of molecules are approved by FDA. Multi-target molecules, such as Sorafenib and Regorafenib, and selective molecules, such as Vemurafenib and Dabrafenib. Many other molecules are still under investigation. Most of them are studied in phase 1 trials. Clinical studies correlate B-RAF inhibitors and QT prolongation. Though this cardiovascular side effect is not common using these drugs, it must be noticed early and recognize its signals. Indeed, Oncologists and Cardiologists should work in cooperation to prevent lethal events, such as fatal arrhythmias or sudden cardiac death. These events could originate from an uncontrolled QT prolongation. PMID- 26431499 TI - Self-Assembly of Ferritin Nanoparticles into an Enzyme Nanocomposite with Tunable Size for Ultrasensitive Immunoassay. AB - The self-assembly of nanoparticles into larger superstructures is a powerful strategy to develop novel functional nanomaterials, as these superstructures display collective properties that are different to those displayed by individual nanoparticles or bulk samples. However, there are increasing bottlenecks in terms of size control and multifunctionalization of nanoparticle assemblies. In this study, we developed a self-assembly strategy for construction of multifunctional nanoparticle assemblies of tunable size, through rational regulation of the number of self-assembling interaction sites on each nanoparticle. As proof-of principle, a size-controlled enzyme nanocomposite (ENC) was constructed by self assembly of streptavidin-labeled horseradish peroxidase (SA-HRP) and autobiotinylated ferritin nanoparticles (bFNP). Our ENC integrates a large number of enzyme molecules, together with a streptavidin-coated surface, allowing for a drastic increase in enzymatic signal when the SA is bound to a biotinylated target molecule. As result, a 10 000-fold increase in sensitivity over conventional enzyme-linked immunosorbent assays (ELISA) methods was achieved in a cardiac troponin immunoassay. Our method presented here should provide a feasible approach for constructing elaborate multifunctional superstructures of tunable size useful for a broad range of biomedical applications. PMID- 26431498 TI - Tumor-targeting Salmonella typhimurium A1-R inhibits human prostate cancer experimental bone metastasis in mouse models. AB - Bone metastasis is a frequent occurrence in prostate cancer patients and often is lethal. Zoledronic acid (ZOL) is often used for bone metastasis with limited efficacy. More effective models and treatment methods are required to improve the outcome of prostate cancer patients. In the present study, the effects of tumor targeting Salmonella typhimurium A1-R were analyzed in vitro and in vivo on prostate cancer cells and experimental bone metastasis. Both ZOL and S. typhimurium A1-R inhibited the growth of PC-3 cells expressing red fluorescent protien in vitro. To investigate the efficacy of S. typhimurium A1-R on prostate cancer experimental bone metastasis, we established models of both early and advanced stage bone metastasis. The mice were treated with ZOL, S. typhimurium A1 R, and combination therapy of both ZOL and S. typhimurium A1-R. ZOL and S. typhimurium A1-R inhibited the growth of solitary bone metastases. S. typhimurium A1-R treatment significantly decreased bone metastasis and delayed the appearance of PC-3 bone metastases of multiple mouse models. Additionally, S. typhimurium A1 R treatment significantly improved the overall survival of the mice with multiple bone metastases. The results of the present study indicate that S. typhimurium A1 R is useful to prevent and inhibit prostate cancer bone metastasis and has potential for future clinical use in the adjuvant setting. PMID- 26431506 TI - Cognitive Performance at Late Adolescence and the Risk for Impaired Fasting Glucose Among Young Adults. AB - CONTEXT: Although dysglycemia is a risk factor for cognitive decline, it is unknown whether cognitive performance among young and apparently healthy adults affect the risk for impaired fasting glucose (IFG). OBJECTIVE: This study aimed to characterize the relationship between cognitive function and the risk for IFG among young adults. DESIGN AND SETTING: This was a retrospective cohort study utilizing data collected at pre-military recruitment assessments with information collected at the screening center of Israeli Army Medical Corps. PARTICIPANTS: Normoglycemic adults (n = 17 348) (free of IFG and diabetes; mean age 31.0 +/- 5.6 y; 87% men) of the Metabolic Lifestyle and Nutrition Assessment in Young Adults (MELANY) cohort with data regarding their General Intelligence Score (GIS), a comprehensive measure of cognitive function, at age 17 y. INTERVENTIONS: Fasting plasma glucose was assessed every 3-5 y at scheduled visits. Cox proportional hazards models were applied. MAIN OUTCOMES MEASURES: The main outcome of the study was incident IFG (>= 100 mg/dL and <126 mg/dL) at scheduled visits. RESULTS: During a median followup of 6.6 y, 1478 cases of IFG were recorded (1402 men). After adjustment for age and sex, participants in the lowest GIS category had a 1.9-fold greater risk for incident IFG compared with those in the highest GIS category. In multivariable analysis adjusted for age, sex, body mass index, fasting plasma glucose, family history of diabetes, country of origin, socioeconomic status, education, physical activity, smoking status, alcohol consumption, breakfast consumption, triglyceride level, white blood cell count, the risk for IFG was nearly doubled in the lowest GIS category compared with the highest GIS category (hazard ratio, 1.8; 95% confidence interval, 1.4 2.3; P < .001). These results persisted when GIS was treated as a continuous variable and when the model was adjusted also for body mass index at the end of followup. CONCLUSIONS: This study demonstrates that lower cognitive function at late adolescence is independently associated with an elevated risk IFG in both men and women. PMID- 26431507 TI - Genetic Predisposition to Polycystic Ovary Syndrome, Postpartum Weight Reduction, and Glycemic Changes: A Longitudinal Study in Women With Prior Gestational Diabetes. AB - CONTEXT: Polycystic ovary syndrome (PCOS) is a common condition in reproductive aged women and a major female-specific risk factor of obesity, impaired glucose tolerance, and diabetes. OBJECTIVE: We examined whether the genetic variation predisposing to PCOS affected glycemic changes in women with prior gestational diabetes mellitus (GDM) and whether such an effect was modified by changes in body adiposity, especially during and after pregnancy. DESIGN, SETTING, AND PARTICIPANTS: This is a longitudinal study in Tianjin, China. We genotyped 7 genome-wide association study-identified PCOS single nucleotide polymorphisms and assessed gestational weight gain and changes in glycemic traits and weight at 1 to 5 years postpartum in 1133 women with prior GDM. MAIN OUTCOME MEASURES: The main outcome measure was postpartum glycemic changes. RESULTS: The PCOS genetic risk score significantly interacted with postpartum weight reduction on changes in fasting glucose and 2-h glucose (P for interaction = .032 and .007; respectively) after multivariable adjustment. In women with postpartum weight reduction of >= 5 kg/y, the genetic risk score was associated with decreased fasting and 2-h glucose, whereas an opposite genetic effect was found in women who lost less weight. The association between postpartum weight reduction and glycemic improvement was more significant among women with a higher genetic risk score. CONCLUSIONS: In a large cohort of Chinese women with a history of GDM, our data for the first time indicate that the genetic predisposition to PCOS may interact with postpartum weight reduction on long-term glycemic changes, emphasizing the importance of postpartum weight management in prevention of diabetes in this subgroup of women. PMID- 26431508 TI - Low Frequency of Cardiomyopathy Using Cardiac Magnetic Resonance Imaging in an Acromegaly Contemporary Cohort. AB - CONTEXT: Left ventricular hypertrophy (LVH) and myocardial fibrosis are considered common findings of the acromegaly cardiomyopathy in echocardiography studies. OBJECTIVE: To evaluate the frequency of LVH, systolic dysfunction and myocardial fibrosis was undertaken in patients with acromegaly using cardiac magnetic resonance imaging (CMRi) before and after 12 months of octreotide long acting repeatable treatment. PATIENTS AND METHODS: Consecutive patients with active acromegaly submitted to biochemical analysis and CMRi before and after 12 months of treatment. Additionally, echocardiography was performed before treatment. RESULTS: Forty consecutive patients were evaluated using CMRi at baseline and 30 patients were reevaluated after 12 months of treatment. Additionally, 29 of these patients were submitted to echocardiography. Using CMRi, the frequency of LVH was 5%. The mean left ventricular mass index (LVMi) was 61.73 +/- 18.8 g/m(2). The mean left ventricular ejection fraction (LVEF) was 61.85 +/- 9.2%, and all patients had normal systolic function. Late gadolinium enhancement was present in five patients (13.5%), and one patient (3.5%) had an increased extracellular volume. After treatment, 12 patients (40%) had criteria for disease control. No clinically relevant differences in cardiac variables before and after treatment were observed. Additionally, there was no difference in LVMi and LVEF among patients with and without disease control. Using echocardiography, 31% of the patients had LVH, mean LVMi was 117.8 +/- 46.3 g/m(2) and mean LVEF was 67.3 +/- 4.4%. All patients had normal systolic function. CONCLUSIONS: We demonstrated by CMRi, the gold-standard method, that patients with active acromegaly might have a lower prevalence of cardiac abnormalities than previously reported. PMID- 26431509 TI - High Incidence of Heterozygous ABCC8 and HNF1A Mutations in Czech Patients With Congenital Hyperinsulinism. AB - CONTEXT: Congenital hyperinsulinism of infancy (CHI) represents a group of heterogeneous disorders characterized by oversecretion of insulin from pancreatic beta-cells causing severe hypoglycemia. OBJECTIVE: We studied the distribution of genetic causes of CHI in a Czech population. METHODS: Countrywide collection of patients with CHI included 40 subjects (12 females, median age of diagnosis, 1 wk [interquartile range, 1-612 wk]). We sequenced the ABCC8, KCNJ11, GLUD1, GCK, HADH, UCP2, SLC16A1, HNF4A, and HNF1A genes and investigated structural changes in the ABCC8 gene. We functionally tested novel variants in the ABCC8 gene by Rb(86+) efflux assay and novel variants in the HNF1A gene by transcriptional activation and DNA-binding tests. RESULTS: We found causal mutations in 20 subjects (50%): 19 carried a heterozygous mutation while one patient was homozygous for mutation in the ABCC8 gene. Specifically, we detected 11 mutations (seven novel) in ABCC8, one novel mutation in KCNJ11, five mutations (two novel) in HNF1A, two novel mutations in HNF4A, and one in GCK. We showed a decrease of activation by diazoxide in mutant KATP channels with novel ABCC8 variants by 41 91% (median, 82%) compared with wild-type (WT) channels and reduced transcriptional activity of mutant HNF1A proteins (2.9% for p.Asn62Lysfs93* and 22% for p.Leu254Gln) accompanied by no DNA-binding ability compared with WT HNF1A. CONCLUSION: We detected a higher proportion of heterozygous mutations causing CHI compared with other cohorts probably due to lack of consanguinity and inclusion of milder CHI forms. Interestingly, HNF1A gene mutations represented the second most frequent genetic cause of CHI in the Czech Republic. Based on our results we present a genetic testing strategy specific for similar populations. PMID- 26431510 TI - Malnutrition in Hospitals: It Was, Is Now, and Must Not Remain a Problem! AB - BACKGROUND: Malnutrition is an under-recognized problem in hospitalized patients. Despite systematic screening, the prevalence of malnutrition in the hospital did not decrease in the last few decades. The aim of our study was to evaluate the prevalence of malnutrition and to determine the explicit daily calorie intake of hospitalized patients, to identify the risk factors of developing malnutrition during hospitalization and the effect on the financial reimbursement according to the German DRG-system. MATERIAL AND METHODS: 815 hospitalized patients were included in this study. The detection of malnutrition was based on the nutritional-risk-screening (NRS) and subjective-global-assessment (SGA) scores. A trained investigator recorded the daily calorie and fluid intake of each patient. Furthermore, clinical parameters, and the financial reimbursement were evaluated. RESULTS: The prevalence of malnutrition was 53.6% according to the SGA and 44.6% according the NRS. During hospitalization, patients received on average 759.9+/ 546.8 kcal/day. The prevalence of malnutrition was increased in patients with hepatic and gastrointestinal disease and with depression or dementia. The most important risk factors for malnutrition were bed rest and immobility (OR=5.88, 95% CI 2.25-15.4). In 84.5% of patient records, malnutrition was not correctly coded, leading to increased financial losses according to the DRG-system (94.908 Euros). CONCLUSIONS: Hospitalized patients suffer from inadequate nutritional therapy and the risk for developing malnutrition rises during the hospital stay. The early screening of patients for malnutrition would not only improve management of nutritional therapy but also, with adequate coding, improve financial reimbursement according to the DRG-system. PMID- 26431512 TI - Improving Rural Health Through Support for Academic Progression. PMID- 26431511 TI - Validation of a Malay Version of the Smartphone Addiction Scale among Medical Students in Malaysia. AB - INTRODUCTION: This study was initiated to determine the psychometric properties of the Smart Phone Addiction Scale (SAS) by translating and validating this scale into the Malay language (SAS-M), which is the main language spoken in Malaysia. This study can distinguish smart phone and internet addiction among multi-ethnic Malaysian medical students. In addition, the reliability and validity of the SAS was also demonstrated. MATERIALS AND METHODS: A total of 228 participants were selected between August 2014 and September 2014 to complete a set of questionnaires, including the SAS and the modified Kimberly Young Internet addiction test (IAT) in the Malay language. RESULTS: There were 99 males and 129 females with ages ranging from 19 to 22 years old (21.7+/-1.1) included in this study. Descriptive and factor analyses, intra-class coefficients, t-tests and correlation analyses were conducted to verify the reliability and validity of the SAS. Bartlett's test of sphericity was significant (p <0.01), and the Kaiser Mayer-Olkin measure of sampling adequacy for the SAS-M was 0.92, indicating meritoriously that the factor analysis was appropriate. The internal consistency and concurrent validity of the SAS-M were verified (Cronbach's alpha = 0.94). All of the subscales of the SAS-M, except for positive anticipation, were significantly related to the Malay version of the IAT. CONCLUSIONS: This study developed the first smart phone addiction scale among medical students. This scale was shown to be reliable and valid in the Malay language. PMID- 26431513 TI - Qualitative Analysis of Student Perceptions of Bachelor of Science-to-Doctor of Philosophy in Nursing Programs. AB - BACKGROUND: To address the shortage of Doctor of Philosophy (PhD)-prepared nursing faculty, universities in the United States offer direct-entry Bachelor of Science in Nursing (BSN)-to-PhD nursing programs. Little research has been conducted to explore students' perceptions of these programs and to formally evaluate the successes and opportunities for growth of this academic track. METHOD: Focusing on the perceptions and experiential reflection of BSN-to-PhD education, a survey with open-ended questions was distributed among voluntary participants who are current BSN-to-PhD students or recent graduates (within 5 years) from various universities in the United States. Textual data were analyzed using a qualitative descriptive approach with thematic analysis. RESULTS: This article elaborates on opportunities, challenges, and suggestions related to this educational route, as recognized by 21 participants from seven universities. CONCLUSION: The study findings may facilitate discussion among nurse educators to revise programs to be congruent with the needs of current students while paving the way for future scholars. PMID- 26431514 TI - Development and Psychometric Assessment of the Nursing Competence Self-Efficacy Scale. AB - BACKGROUND: The study aim was to develop and psychometrically assess an instrument to measure baccalaureate nursing students' self-efficacy for practice competence. Social cognitive theory includes the construct of self-efficacy and supports this study. METHOD: Before the Nursing Competence Self-Efficacy Scale (NCSES) was administered to senior nursing students (N = 252), nursing experts in research, practice, instrument development, and psychometrics participated in a two-step validation process consisting of two reviews. Construct validity assessments included content, face, contrasting groups, criterion, and exploratory factor analysis (EFA). The chosen EFA solution consisted of 22 items, each moderately or highly loaded by one of four factors deemed to be interpretable and parsimonious. RESULTS: The initial psychometric assessment of the NCSES supported construct validity, internal consistency reliability (.919), and test-retest stability reliability (r = .831). CONCLUSION: With further psychometric assessment, the NCSES can be useful to evaluate new curriculum interventions aimed at increasing students' self-efficacy for comprehensive practice competence. PMID- 26431515 TI - Role of Self-Directed Learning in Communication Competence and Self-Efficacy. AB - BACKGROUND: Although effective self-directed learning (SDL) has been shown to improve clinical performance, little is known about its role between communication competence and communication self-efficacy in nursing students. This study aimed to identify whether SDL mediates the relationship between communication competence and communication self-efficacy. METHOD: A cross sectional survey was conducted with a sample of 213 nursing students taking a basic fundamentals of nursing course. A path diagram, using structural equation modeling, was used to estimate the direct and indirect effects of communication competence on communication self-efficacy, controlling for SDL as a mediator. RESULTS: A structural equation model confirmed direct and indirect effects of communication competence on communication self-efficacy when SDL was controlled as a mediator. An appropriate fit to the data was identified in this mediation model of SDL. CONCLUSIONS: For enhancing self-efficacy regarding communication skill, the specified SDL program based on the level of communication competence will yield more effective results. PMID- 26431516 TI - Bibliometric Patterns of Research Literature Production on Nursing Informatics Competence. AB - BACKGROUND: Nursing informatics competence is a prerequisite for successful information management, evidence-based practices optimizing patient care health promotion, and communication with information communication technology-literate patients. METHOD: The aim of this study was to assess the trends in the production of nursing informatics competence research literature and to identify the most productive bibliometric entities. In addition to the correspondence analysis, bibliometric analysis and mapping were used to achieve the aim. RESULTS: A total of 366 information sources were extracted, 14.5% of which were sponsored studies. The production of research literature on nursing informatics competence is growing, but this research is only occasionally published in the most recognized nursing journals. CONCLUSION: Identifying where the intensive research on nursing informatics competence is beneficial to care for the patient of the future and building user-friendly online lifelong learning platforms, where a required level of nursing informatics competence could be acquired, are two gaps in the current research that should be covered in future. PMID- 26431517 TI - A Systematic Review of the Experience of Using Second Life in the Education of Undergraduate Nurses. AB - BACKGROUND: The virtual world of Second Life((r)) is an emerging technology that is being considered as a simulation methodology for the education of professionals. Particularly for nursing, the adoption of simulation, although a response to technological advancement, is occurring during changes in population health care needs, the resultant impact on the workforce, and also the changing profile of students. METHOD: This systematic review aimed to establish the current applications of Second Life in the education of undergraduate nursing students. Databases searched were CINAHL((r)), Medline((r)), Education Research Complete(TM), ERIC(TM), Computers and Applied Sciences Complete(TM), and Library, Information Sciences and Technology(TM). RESULTS: Fourteen studies met the inclusion and exclusion criteria. Evidence identified included the themes of transferability from theory to practice, focus on learner centeredness, and evaluative processes. CONCLUSION: This review demonstrates that positive learning outcomes are achievable in Second Life. Evaluative research is in an early stage, and further investigation is warranted. PMID- 26431518 TI - Using Debates to Teach Evidence-Based Practice in Large Online Courses. AB - BACKGROUND: To engage in evidence-based practice (EBP), baccalaureate nursing graduates' competencies must include locating, interpreting, appraising, and applying research findings. Faculty are challenged to find effective ways to incorporate this content in large online courses. METHOD: Faculty in a thriving college of nursing used interactive debates to teach EBP skills in a large (200+ students) online undergraduate course. RESULTS: Students remain highly engaged while practicing critical thinking, team-work, leadership, delegation, communication skills, and peer evaluation through participation in a series of faculty-facilitated online debates. CONCLUSION: Meticulous course organization and use of structured debates allows one instructor to teach skills for EBP, while keeping students engaged with each other, the instructor, and the material. Use of debates and the amount of engagement among students and faculty achieved could not be accomplished in a large face-to-face course. PMID- 26431519 TI - Can Learning the ISBARR Framework Help to Address Nursing Students' Perceived Anxiety and Confidence Levels Associated With Handover Reports? AB - BACKGROUND: Standardized communication frameworks are believed to help students feel more confident and less anxious about handover reports. One of the handover communication frameworks being used in nursing programs was the ISBARR framework (Identify, Situation, Background, Assessment, Recommendation, and Repeat). The aim was to explore whether learning the ISBARR framework affected nursing students' perceived anxiety and confidence levels associated with handover reports. METHOD: The study tested null hypotheses by analyzing pre- and posttest data collected with the Competitive State Anxiety Inventory-2 (CSAI-2) survey. Three qualitative questions were included in the posttest to compare with the quantitative data. Statistical significance was set at p = .02. RESULTS: The results revealed that learning the framework had a strong effect in reducing the perceived somatic anxiety levels, a medium effect on increasing perceived confidence levels, and a medium effect in reducing the perceived cognitive anxiety levels. CONCLUSION: Findings suggested that learning the standardized framework may help to address students' perceived anxiety and confidence levels associated with handover reports and generate a mental picture of handover reports. PMID- 26431520 TI - Using Simulation Pedagogy in the Formation of Family-Focused Generalist Nurses. AB - BACKGROUND: Nursing practice with families is essential because a family member's illness affects the family and, reciprocally, the family influences health outcomes. Yet, nurses often report a lack of confidence in their ability to meet the needs of families, whereas family members often describe troubling experiences with nurses. These challenges may have beginning roots in nursing education. This article explores the use of simulation in the formation of family focused generalist nurses. METHOD: Simulation pedagogy was used to guide students in developing an understanding of the importance of family nursing care, gaining confidence in family practices, and developing family competencies. RESULTS: Innovative simulation learning experiences in an undergraduate nursing curriculum helped students to learn how to develop nurse-family relationships and gain humanistic skills of family nursing practices. Students and faculty reported that simulation guides students to achieve meaningful outcomes. CONCLUSION: In this curriculum, faculty consistently directs attention to the family in simulation learning experiences, and students value this pedagogy. PMID- 26431522 TI - Adapting a Social Media Strategy in the Classroom: PEET. PMID- 26431521 TI - Evolving the PICOT Method for the Digital Age: The PICOT-D. AB - BACKGROUND: Many articles written about the PICOT (Population, Intervention, Comparison, Outcome, Time) method for developing research questions focus on searching the existing evidence base to review the impact of interventions. The PICOT method evolved to craft questions that yield operative search terms. Currently, the PICOT method falls short in its utility for health care and doctoral education. For example, the Doctor of Nursing Practice scholarly practice projects evaluate the existing evidence base and compare the current real-world state with the evidence base, for which the current conceptualization of the PICOT method has limited applicability. METHOD: The PICOT-D adds digital data (D) components to the traditional PICOT, allowing for the explicit identification of data measures that form the basis of the evaluation of an intervention. RESULTS: the PICOT-D has the potential to improve student efficiency, efficacy, and confidence in the development of truly answerable questions that fully support improved patient care and systems-level change. CONCLUSION: This article demonstrates the need for the evolution of the PICOT format to the PICOT-D format. PMID- 26431524 TI - Correction: Evaluation of Commercial Diagnostic Assays for the Specific Detection of Avian Influenza A (H7N9) Virus RNA Using a Quality-Control Panel and Clinical Specimens in China. PMID- 26431523 TI - A New Method for Detecting Associations with Rare Copy-Number Variants. AB - Copy number variants (CNVs) play an important role in the etiology of many diseases such as cancers and psychiatric disorders. Due to a modest marginal effect size or the rarity of the CNVs, collapsing rare CNVs together and collectively evaluating their effect serves as a key approach to evaluating the collective effect of rare CNVs on disease risk. While a plethora of powerful collapsing methods are available for sequence variants (e.g., SNPs) in association analysis, these methods cannot be directly applied to rare CNVs due to the CNV-specific challenges, i.e., the multi-faceted nature of CNV polymorphisms (e.g., CNVs vary in size, type, dosage, and details of gene disruption), and etiological heterogeneity (e.g., heterogeneous effects of duplications and deletions that occur within a locus or in different loci). Existing CNV collapsing analysis methods (a.k.a. the burden test) tend to have suboptimal performance due to the fact that these methods often ignore heterogeneity and evaluate only the marginal effects of a CNV feature. We introduce CCRET, a random effects test for collapsing rare CNVs when searching for disease associations. CCRET is applicable to variants measured on a multi categorical scale, collectively modeling the effects of multiple CNV features, and is robust to etiological heterogeneity. Multiple confounders can be simultaneously corrected. To evaluate the performance of CCRET, we conducted extensive simulations and analyzed large-scale schizophrenia datasets. We show that CCRET has powerful and robust performance under multiple types of etiological heterogeneity, and has performance comparable to or better than existing methods when there is no heterogeneity. PMID- 26431525 TI - Effects of Prism Eyeglasses on Objective and Subjective Fixation Disparity. AB - In optometry of binocular vision, the question may arise whether prisms should be included in eyeglasses to compensate an oculomotor and/or sensory imbalance between the two eyes. The corresponding measures of objective and subjective fixation disparity may be reduced by the prisms, or the adaptability of the binocular vergence system may diminish effects of the prisms over time. This study investigates effects of wearing prisms constantly for about 5 weeks in daily life. Two groups of 12 participants received eyeglasses with prisms having either a base-in direction or a base-out direction with an amount up to 8 prism diopters. Prisms were prescribed based on clinical fixation disparity test plates at 6 m. Two dependent variables were used: (1) subjective fixation disparity was indicated by a perceived offset of dichoptic nonius lines that were superimposed on the fusion stimuli and (2) objective fixation disparity was measured with a video based eye tracker relative to monocular calibration. Stimuli were presented at 6 m and included either central or more peripheral fusion stimuli. Repeated measurements were made without the prisms and with the prisms after about 5 weeks of wearing these prisms. Objective and subjective fixation disparity were correlated, but the type of fusion stimulus and the direction of the required prism may play a role. The prisms did not reduce the fixation disparity to zero, but induced significant changes in fixation disparity with large effect sizes. Participants receiving base-out prisms showed hypothesized effects, which were concurrent in both types of fixation disparity. In participants receiving base-in prisms, the individual effects of subjective and objective effects were negatively correlated: the larger the subjective (sensory) effect, the smaller the objective (motor) effect. This response pattern was related to the vergence adaptability, i.e. the individual fusional vergence reserves. PMID- 26431526 TI - Phylogenesis and Biological Characterization of a New Glucose Transporter in the Chicken (Gallus gallus), GLUT12. AB - In mammals, insulin-sensitive GLUTs, including GLUT4, are recruited to the plasma membrane of adipose and muscle tissues in response to insulin. The GLUT4 gene is absent from the chicken genome, and no functional insulin-sensitive GLUTs have been characterized in chicken tissues to date. A nucleotide sequence is predicted to encode a chicken GLUT12 ortholog and, interestingly, GLUT12 has been described to act as an insulin-sensitive GLUT in mammals. It encodes a 596 amino acid protein exhibiting 71% identity with human GLUT12. First, we present the results of a phylogenetic study showing the stability of this gene during evolution of vertebrates. Second, tissue distribution of chicken SLC2A12 mRNA was characterized by RT-PCR. It was predominantly expressed in skeletal muscle and heart. Protein distribution was analysed by Western blotting using an anti-human GLUT12 antibody directed against a highly conserved region (87% of identity). An immuno-reactive band of the expected size (75kDa) was detected in the same tissues. Third a physiological characterization was performed: SLC2A12 mRNA levels were significantly lowered in fed chickens subjected to insulin immuno neutralization. Finally, recruitment of immuno-reactive GLUT12 to the muscle plasma membrane was increased following 1h of intraperitoneal insulin administration (compared to a control fasted state). Thus insulin administration elicited membrane GLUT12 recruitment. In conclusion, these results suggest that the facilitative glucose transporter protein GLUT12 could act in chicken muscle as an insulin-sensitive transporter that is qualitatively similar to GLUT4 in mammals. PMID- 26431527 TI - Using Mathematical Modelling to Explore Hypotheses about the Role of Bovine Epithelium Structure in Foot-And-Mouth Disease Virus-Induced Cell Lysis. AB - Foot-and-mouth disease (FMD) is a highly contagious disease of cloven-hoofed animals. FMD virus (FMDV) shows a strong tropism for epithelial cells, and FMD is characterised by cell lysis and the development of vesicular lesions in certain epithelial tissues (for example, the tongue). By contrast, other epithelial tissues do not develop lesions, despite being sites of viral replication (for example, the dorsal soft palate). The reasons for this difference are poorly understood, but hypotheses are difficult to test experimentally. In order to identify the factors which drive cell lysis, and consequently determine the development of lesions, we developed a partial differential equation model of FMDV infection in bovine epithelial tissues and used it to explore a range of hypotheses about epithelium structure which could be driving differences in lytic behaviour observed in different tissues. Our results demonstrate that, based on current parameter estimates, epithelial tissue thickness and cell layer structure are unlikely to be determinants of FMDV-induced cell lysis. However, differences in receptor distribution or viral replication amongst cell layers could influence the development of lesions, but only if viral replication rates are much lower than current estimates. PMID- 26431528 TI - Influence of Factors of Cryopreservation and Hypothermic Storage on Survival and Functional Parameters of Multipotent Stromal Cells of Placental Origin. AB - Human placenta is a highly perspective source of multipotent stromal cells (MSCs) both for the purposes of patient specific auto-banking and allogeneic application in regenerative medicine. Implementation of new GMP standards into clinical practice enforces the search for relevant methods of cryopreservation and short term hypothermic storage of placental MSCs. In this paper we analyze the effect of different temperature regimes and individual components of cryoprotective media on viability, metabolic and culture properties of placental MSCs. We demonstrate (I) the possibility of short-term hypothermic storage of these cells; (II) determine DMSO and propanediol as the most appropriate cryoprotective agents; (III) show the possibility of application of volume expanders (plasma substituting solutions based on dextran or polyvinylpyrrolidone); (IV) reveal the priority of ionic composition over the serum content in cryopreservation media; (V) determine a cooling rate of 1 degrees C/min down to -40 degrees C followed by immersion into liquid nitrogen as the optimal cryopreservation regime for this type of cells. This study demonstrates perspectives for creation of new defined cryopreservation methods towards GMP standards. PMID- 26431530 TI - A Putative PP2C-Encoding Gene Negatively Regulates ABA Signaling in Populus euphratica. AB - A PP2C homolog gene was cloned from the drought-treated cDNA library of Populus euphratica. Multiple sequence alignment analysis suggested that the gene is a potential ortholog of HAB1. The expression of this HAB1 ortholog (PeHAB1) was markedly induced by drought and moderately induced by ABA. To characterize its function in ABA signaling, we generated transgenic Arabidopsis thaliana plants overexpressing this gene. Transgenic lines exhibited reduced responses to exogenous ABA and reduced tolerance to drought compared to wide-type lines. Yeast two-hybrid analyses indicated that PeHAB1 could interact with the ABA receptor PYL4 in an ABA-independent manner. Taken together; these results indicated that PeHAB1 is a new negative regulator of ABA responses in poplar. PMID- 26431529 TI - The Effects of Different Repetitive Transcranial Magnetic Stimulation (rTMS) Protocols on Cortical Gene Expression in a Rat Model of Cerebral Ischemic Reperfusion Injury. AB - Although repetitive Transcranial Magnetic Stimulation (rTMS) in treatment of stroke in humans has been explored over the past decade the data remain controversial in terms of optimal stimulation parameters and the mechanisms of rTMS long-term effects. This study aimed to explore the potential of different rTMS protocols to induce changes in gene expression in rat cortices after acute ischemic-reperfusion brain injury. The stroke was induced by middle cerebral artery occlusion (MCAO) with subsequent reperfusion. Changes in the expression of 96 genes were examined using low-density expression arrays after MCAO alone and after MCAO combined with 1Hz, 5Hz, continuous (cTBS) and intermittent (iTBS) theta-burst rTMS. rTMS over the lesioned hemisphere was given for two weeks (with a 2-day pause) in a single daily session and a total of 2400 pulses. MCAO alone induced significant upregulation in the expression of 44 genes and downregulation in 10. Two weeks of iTBS induced significant increase in the expression of 52 genes. There were no downregulated genes. 1Hz and 5Hz had no significant effects on gene expression, while cTBS effects were negligible. Upregulated genes included those involved in angiogenesis, inflammation, injury response and cellular repair, structural remodeling, neuroprotection, neurotransmission and neuronal plasticity. The results show that long-term rTMS in acute ischemic reperfusion brain injury induces complex changes in gene expression that span multiple pathways, which generally promote the recovery. They also demonstrate that induced changes primarily depend on the rTMS frequency (1Hz and 5Hz vs. iTBS) and pattern (cTBS vs. iTBS). The results further underlines the premise that one of the benefits of rTMS application in stroke may be to prime the brain, enhancing its potential to cope with the injury and to rewire. This could further augment its potential to favorably respond to rehabilitation, and to restore some of the loss functions. PMID- 26431531 TI - The Overexpression of FEN1 and RAD54B May Act as Independent Prognostic Factors of Lung Adenocarcinoma. AB - Synthetic lethality arises when a combination of mutations in two or more genes leads to cell death. However, the prognostic role of concordant overexpression of synthetic lethality genes in protein level rather than a combination of mutations is not clear. In this study, we explore the prognostic role of combined overexpression of paired genes in lung adenocarcinoma. We used immunohistochemical staining to investigate 24 paired genes in 93 lung adenocarcinoma patients and Kaplan-Meier analysis and Cox proportional hazards models to evaluate their prognostic roles. Among 24 paired genes, only FEN1 (Flap endonuclease 1) and RAD54B (RAD54 homolog B) were overexpressed in lung adenocarcinoma patients with poor prognosis. Patients with expression of both FEN1 and RAD54B were prone to have advanced nodal involvement and significantly poor prognosis (HR = 2.35, P = 0.0230). These results suggest that intensive follow up and targeted therapy might improve clinical outcome for patients who show expression of both FEN1 and RAD54B. PMID- 26431532 TI - The Small Molecule DAM Inhibitor, Pyrimidinedione, Disrupts Streptococcus pneumoniae Biofilm Growth In Vitro. AB - Streptococcus pneumoniae persist in the human nasopharynx within organized biofilms. However, expansion to other tissues may cause severe infections such as pneumonia, otitis media, bacteremia, and meningitis, especially in children and the elderly. Bacteria within biofilms possess increased tolerance to antibiotics and are able to resist host defense systems. Bacteria within biofilms exhibit different physiology, metabolism, and gene expression profiles than planktonic cells. These differences underscore the need to identify alternative therapeutic targets and novel antimicrobial compounds that are effective against pneumococcal biofilms. In bacteria, DNA adenine methyltransferase (Dam) alters pathogenic gene expression and catalyzes the methylation of adenine in the DNA duplex and of macromolecules during the activated methyl cycle (AMC). In pneumococci, AMC is involved in the biosynthesis of quorum sensing molecules that regulate competence and biofilm formation. In this study, we examine the effect of a small molecule Dam inhibitor, pyrimidinedione, on Streptococcus pneumoniae biofilm formation and evaluate the changes in global gene expression within biofilms via microarray analysis. The effects of pyrimidinedione on in vitro biofilms were studied using a static microtiter plate assay, and the architecture of the biofilms was viewed using confocal and scanning electron microscopy. The cytotoxicity of pyrimidinedione was tested on a human middle ear epithelium cell line by CCK-8. In situ oligonucleotide microarray was used to compare the global gene expression of Streptococcus pneumoniae D39 within biofilms grown in the presence and absence of pyrimidinedione. Real-time RT-PCR was used to study gene expression. Pyrimidinedione inhibits pneumococcal biofilm growth in vitro in a concentration dependent manner, but it does not inhibit planktonic cell growth. Confocal microscopy analysis revealed the absence of organized biofilms, where cell-clumps were scattered and attached to the bottom of the plate when cells were grown in the presence of pyrimidinedione. Scanning electron microscopy analysis demonstrated the absence of an extracellular polysaccharide matrix in pyrimidinedione-grown biofilms compared to control-biofilms. Pyrimidinedione also significantly inhibited MRSA, MSSA, and Staphylococcus epidermidis biofilm growth in vitro. Furthermore, pyrimidinedione does not exhibit eukaryotic cell toxicity. In a microarray analysis, 56 genes were significantly up-regulated and 204 genes were significantly down-regulated. Genes involved in galactose metabolism were exclusively up-regulated in pyrimidinedione-grown biofilms. Genes related to DNA replication, cell division and the cell cycle, pathogenesis, phosphate-specific transport, signal transduction, fatty acid biosynthesis, protein folding, homeostasis, competence, and biofilm formation were down regulated in pyrimidinedione-grown biofilms. This study demonstrated that the small molecule Dam inhibitor, pyrimidinedione, inhibits pneumococcal biofilm growth in vitro at concentrations that do not inhibit planktonic cell growth and down regulates important metabolic-, virulence-, competence-, and biofilm-related genes. The identification of a small molecule (pyrimidinedione) with S. pneumoniae biofilm inhibiting capabilities has potential for the development of new compounds that prevent biofilm formation. PMID- 26431533 TI - The Timing of Stimulation and IL-2 Signaling Regulate Secondary CD8 T Cell Responses. AB - Memory CD8 T cells provide protection to immune hosts by eliminating pathogen infected cells during re-infection. While parameters influencing the generation of primary (1 degrees ) CD8 T cells are well established, the factors controlling the development of secondary (2 degrees ) CD8 T cell responses remain largely unknown. Here, we address the mechanisms involved in the generation and development of 2 degrees memory (M) CD8 T cells. We observed that the time at which 1 degrees M CD8 T cells enter into immune response impacts their fate and differentiation into 2 degrees M CD8 T cells. Late-entry of 1 degrees M CD8 T cells into an immune response (relative to the onset of infection) not only facilitated the expression of transcription factors associated with memory formation in 2 degrees effector CD8 T cells, but also influenced the ability of 2 degrees M CD8 T cells to localize within the lymph nodes, produce IL-2, and undergo Ag-driven proliferation. The timing of stimulation of 1 degrees M CD8 T cells also impacted the duration of expression of the high-affinity IL-2 receptor (CD25) on 2 degrees effector CD8 T cells and their sensitivity to IL-2 signaling. Importantly, by blocking or enhancing IL-2 signaling in developing 2 degrees CD8 T cells, we provide direct evidence for the role of IL-2 in controlling the differentiation of Ag-driven 2 degrees CD8 T cell responses. Thus, our data suggest that the process of 1 degrees M to 2 degrees M CD8 T cell differentiation is not fixed and can be manipulated, a notion with relevance for the design of future prime-boost vaccination approaches. PMID- 26431534 TI - Enhanced Activation of Canonical Wnt Signaling Confers Mesoderm-Derived Parietal Bone with Similar Osteogenic and Skeletal Healing Capacity to Neural Crest Derived Frontal Bone. AB - Bone formation and skeletal repair are dynamic processes involving a fine-tuned balance between osteoblast proliferation and differentiation orchestrated by multiple signaling pathways. Canonical Wnt (cWnt) signaling is known to playing a key role in these processes. In the current study, using a transgenic mouse model with targeted disruption of axin2, a negative regulator of cWnt signaling, we investigated the impact of enhanced activation of cWnt signaling on the osteogenic capacity and skeletal repair. Specifically, we looked at two calvarial bones of different embryonic tissue origin: the neural crest-derived frontal bone and the mesoderm-derived parietal bone, and we investigated the proliferation and apoptotic activity of frontal and parietal bones and derived osteoblasts. We found dramatic differences in cell proliferation and apoptotic activity between Axin2-/- and wild type calvarial bones, with Axin2-/- showing increased proliferative activity and reduced levels of apoptosis. Furthermore, we compared osteoblast differentiation and bone regeneration in Axin2-/- and wild type neural crest-derived frontal and mesoderm-derived parietal bones, respectively. Our results demonstrate a significant increase either in osteoblast differentiation or bone regeneration in Axin2-/- mice as compared to wild type, with Axin2-/- parietal bone and derived osteoblasts displaying a "neural crest-derived frontal bone-like" profile, which is typically characterized by higher osteogenic capacity and skeletal repair than parietal bone. Taken together, our results strongly suggest that enhanced activation of cWnt signaling increases the skeletal potential of a calvarial bone of mesoderm origin, such as the parietial bone to a degree similar to that of a neural crest origin bone, like the frontal bone. Thus, providing further evidence for the central role played by the cWnt signaling in osteogenesis and skeletal-bone regeneration. PMID- 26431535 TI - Newly Isolated Penicillium ramulosum N1 Is Excellent for Producing Protease Resistant Acidophilic Xylanase. AB - Penicillium ramulosum N1 was isolated from decaying wood. This strain produces extracellular xylanases and cellulases. The highest activities of xylanases (250 U/ml) and carboxymethyl cellulose (CMCase; 6.5 U/ml) were produced when 1% barley straw was added as a carbon source. The optimum temperature and pH for xylanase activity was 55 and 3.0 degrees C, respectively. The xylanases exhibited strong protease resistance. CMCase revealed maximum activities at pH 3.0 and in the range of 60-70 degrees C. Filter paper activity was optimally active at pH 5.0 and 55 degrees C. The zymograms produced by the SDS-PAGE resolution of the crude enzymes indicated that there are four bands of protein with xylanase activity and three bands of proteins with endoglucanase. The results revealed that P. ramulosum N1 is a promising acidophilic and protease-resistant xylanase-producing microorganism that has great potential to be used in animal feed and food industry applications. PMID- 26431536 TI - How Possibly Do Leisure and Social Activities Impact Mental Health of Middle-Aged Adults in Japan?: An Evidence from a National Longitudinal Survey. AB - OBJECTIVES: This study aimed to investigate longitudinal relations between leisure and social activities and mental health status, considering the presence or absence of other persons in the activity as an additional variable, among middle-aged adults in Japan. This study used nationally representative data in Japan with a five-year follow-up period. METHODS: This study focused on 16,642 middle-aged adults, age 50-59 at baseline, from a population-based, six-year panel survey conducted by the Japanese Ministry of Health, Labour and Welfare. To investigate the relations between two leisure activities ('hobbies or cultural activities' and 'exercise or sports') and four social activities ('community events', 'support for children', 'support for elderly individuals' and 'other social activities') at baseline and mental health status at follow-up, multiple logistic regression analysis was used. We also used multiple logistic regression analysis to investigate the association between ways of participating in these activities ('by oneself', 'with others', or 'both' (both 'by oneself' and 'with others')) at baseline and mental health status at follow-up. RESULTS: Involvement in both leisure activity categories, but not in social activities, was significantly and positively related to mental health status in both men and women. Furthermore, in men, both 'hobbies or cultural activities' and 'exercise or sports' were significantly related to mental health status only when conducted 'with others'. In women, the effects of 'hobbies or cultural activities' on mental health status were no differences regardless of the ways of participating, while the result of 'exercise or sports' was same as that in men. CONCLUSIONS: Leisure activities appear to benefit mental health status among this age group, whereas specific social activities do not. Moreover, participation in leisure activities would be effective especially if others are present. These findings should be useful for preventing the deterioration of mental health status in middle-aged adults in Japan. PMID- 26431537 TI - Trypanosoma cruzi and Its Soluble Antigens Induce NET Release by Stimulating Toll Like Receptors. AB - Neutrophils release fibrous traps of DNA, histones, and granule proteins known as neutrophil extracellular traps (NETs), which contribute to microbicidal killing and have been implicated in autoimmunity. The role of NET formation in the host response to nonbacterial pathogens is not well-understood. In this study, we investigated the release of NETs by human neutrophils upon their interaction with Trypanosoma cruzi (Y strain) parasites. Our results showed that human neutrophils stimulated by T. cruzi generate NETs composed of DNA, histones, and elastase. The release occurred in a dose-, time-, and reactive oxygen species-dependent manner to decrease trypomastigote and increase amastigote numbers of the parasites without affecting their viability. NET release was decreased upon blocking with antibodies against Toll-like receptors 2 and 4. In addition, living parasites were not mandatory in the release of NETs induced by T. cruzi, as the same results were obtained when molecules from its soluble extract were tested. Our results increase the understanding of the stimulation of NETs by parasites, particularly T. cruzi. We suggest that contact of T. cruzi with NETs during Chagas's disease can limit infection by affecting the infectivity/pathogenicity of the parasite. PMID- 26431538 TI - Antigen-Specific Th17 Cells Are Primed by Distinct and Complementary Dendritic Cell Subsets in Oropharyngeal Candidiasis. AB - Candida spp. can cause severe and chronic mucocutaneous and systemic infections in immunocompromised individuals. Protection from mucocutaneous candidiasis depends on T helper cells, in particular those secreting IL-17. The events regulating T cell activation and differentiation toward effector fates in response to fungal invasion in different tissues are poorly understood. Here we generated a Candida-specific TCR transgenic mouse reactive to a novel endogenous antigen that is conserved in multiple distant species of Candida, including the clinically highly relevant C. albicans and C. glabrata. Using TCR transgenic T cells in combination with an experimental model of oropharyngeal candidiasis (OPC) we investigated antigen presentation and Th17 priming by different subsets of dendritic cells (DCs) present in the infected oral mucosa. Candida-derived endogenous antigen accesses the draining lymph nodes and is directly presented by migratory DCs. Tissue-resident Flt3L-dependent DCs and CCR2-dependent monocyte derived DCs collaborate in antigen presentation and T cell priming during OPC. In contrast, Langerhans cells, which are also present in the oral mucosa and have been shown to prime Th17 cells in the skin, are not required for induction of the Candida-specific T cell response upon oral challenge. This highlights the functional compartmentalization of specific DC subsets in different tissues. These data provide important new insights to our understanding of tissue-specific antifungal immunity. PMID- 26431539 TI - Endocytosis-Mediated Invasion and Pathogenicity of Streptococcus agalactiae in Rat Cardiomyocyte (H9C2). AB - Streptococcus agalactiae infection causes high mortality in cardiovascular disease (CVD) patients, especially in case of setting prosthetic valve during cardiac surgery. However, the pathogenesis mechanism of S. agalactiae associate with CVD has not been well studied. Here, we have demonstrated the pathogenicity of S. agalactiae in rat cardiomyocytes (H9C2). Interestingly, both live and dead cells of S. agalactiae were uptaken by H9C2 cells. To further dissect the process of S. agalactiae internalization, we chemically inhibited discrete parts of cellular uptake system in H9C2 cells using genistein, chlorpromazine, nocodazole and cytochalasin B. Chemical inhibition of microtubule and actin formation by nocodazole and cytochalasin B impaired S. agalactiae internalization into H9C2 cells. Consistently, reverse- transcription PCR (RT-PCR) and quantitative real time-PCR (RT-qPCR) analyses also detected higher levels of transcripts for cytoskeleton forming genes, Acta1 and Tubb5 in S. agalactiae-infected H9C2 cells, suggesting the requirement of functional cytoskeleton in pathogenesis. Host survival assay demonstrated that S. agalactiae internalization induced cytotoxicity in H9C2 cells. S. agalactiae cells grown with benzyl penicillin reduced its ability to internalize and induce cytotoxicity in H9C2 cells, which could be attributed with the removal of surface lipoteichoic acid (LTA) from S. agalactiae. Further, the LTA extracted from S. agalactiae also exhibited dose dependent cytotoxicity in H9C2 cells. Taken together, our data suggest that S. agalactiae cells internalized H9C2 cells through energy-dependent endocytic processes and the LTA of S. agalactiae play major role in host cell internalization and cytotoxicity induction. PMID- 26431540 TI - Clinical Significance of Mycobacterium kansasii Isolates from Respiratory Specimens. AB - The clinical significance of Mycobacterium kansasii respiratory isolates is uncertain. The aims of this study were to determine the clinical relevance of M. kansasii isolates and to identify the clinical features and outcomes of M. kansasii lung disease. We reviewed the medical records of 104 patients from whom at least one respiratory M. kansasii isolate was obtained from January 2003 to July 2014 at Samsung Medical Center, South Korea. Of these 104 patients, 54 (52%) met the diagnostic criteria for nontuberculous mycobacterial lung disease; among them, 41 (76%) patients received antibiotic treatment for a median time of 15.0 months (interquartile range [IQR], 7.0-18.0 months). The remaining 13 (24%) without overt disease progression were observed for a median period of 24.0 months (IQR, 5.0-34.5 months). Patients with M. kansasii lung disease exhibited various radiographic findings of lung disease, including the fibrocavitary form (n = 24, 44%), the nodular bronchiectatic form (n = 17, 32%), and an unclassifiable form (n = 13, 24%). The fibrocavitary form was more common in patients who received treatment (n = 23, 56%), while the nodular bronchiectatic form was more common in patients with M. kansasii lung disease who did not receive treatment (n = 9, 70%). None of the patients with a single sputum isolate (n = 18) developed M. kansasii disease over a median follow-up period of 12.0 months (IQR, 4.0-26.5 months). In total, 52% of all patients with M. kansasii respiratory isolates exhibited clinically significant disease. Moreover, patients with M. kansasii lung disease displayed diverse radiographic findings in addition to the fibrocavitary form. The nodular bronchiectatic form was more common in patients with M. kansasii lung disease with an indolent clinical course. Thus, since the clinical significance of a single M. kansasii respiratory isolate is not definite, strict adherence to recommended diagnostic criteria is advised. PMID- 26431544 TI - Macrophage Polarization Modulates Development of Systemic Lupus Erythematosus. AB - BACKGROUND/AIMS: Macrophages have recently been shown to play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). However, the underlying mechanisms remain unclear. METHODS: Here, we used an activated lymphocyte-derived DNA (ALD-DNA) method to induce SLE in mice. We used a macrophage-specific eliminator clodronate to selectively deplete macrophages in mice. We isolated macrophages from bone marrow of the mice and used cytokines to differentiate M1 and M2 macrophages, respectively. Adoptive transplantation of M1 or M2 macrophages was performed in clodronate-treated mice. The effects on SLE were evaluated by serum anti-dsDNA autoantibody, by renal pathological changes, and by urine protein levels. RESULTS: ALD-DNA induced SLE-like features in mice, manifested by induction of serum anti-dsDNA autoantibody, by renal pathological changes, and by increases in urine protein levels. Clodronate significantly decreased macrophages in mice, which significantly increased SLE severity. Adoptive transplantation of M2, but not M1 macrophages significantly reduced SLE severity in clodronate- and ALD-DNA-treated mice. CONCLUSION: M1 and M2 macrophages play different roles in development of SLE. M1 macrophages increase the severity of SLE, while M2 macrophages reduce it. Modulation of macrophage polarity may be an attractive therapy for SLE. PMID- 26431545 TI - The Experience of Chinese Couples Undergoing In Vitro Fertilization Treatment: Perception of the Treatment Process and Partner Support. AB - BACKGROUND: Couples undergoing In Vitro Fertilization (IVF) Treatment suffer as dyads from the stressful experience of the painful treatment and the fear that the IVF cycle will fail. They are likely to report that their marital relationship has become unstable due to the prolonged period of treatment. METHODS: This is a qualitative study that was conducted to explore the experiences that Chinese couples have had with IVF treatment, especially their perceptions of the process and the support between couples. RESULTS: The interviews revealed that couples suffered from the process, experiencing physical and emotional pain, struggling with the urgency and inflexibility of bearing a child, and experiencing disturbances in their daily routines and work. The participants described how they endured the hardships as a couple and how it affected their relationship. The couples felt that sharing feelings and supporting each other contribute to psychological well-being and improves the marital relationship. They also identified some unfavorable aspects in their partner relationship. They were ambivalent about receiving social support from friends and family members. CONCLUSIONS: With the couples indicating that the support that they received from each other affected their experience during the treatment process, it is suggested that a supportive intervention that focuses on enhancing the partnership of the couples and dealing with their inflexibility on the issue of bearing a child might result in improvements in the psychological status and marital relationship of infertile couples undergoing IVF treatment. PMID- 26431546 TI - Spatial Distribution of Sand Fly Vectors and Eco-Epidemiology of Cutaneous Leishmaniasis Transmission in Colombia. AB - BACKGROUND: Leishmania is transmitted by Phlebotominae insects that maintain the enzootic cycle by circulating between sylvatic and domestic mammals; humans enter the cycles as accidental hosts due to the vector's search for blood source. In Colombia, leishmaniasis is an endemic disease and 95% of all cases are cutaneous (CL), these cases have been reported in several regions of the country where the intervention of sylvatic areas by the introduction of agriculture seem to have an impact on the rearrangement of new transmission cycles. Our study aimed to update vector species distribution in the country and to analyze the relationship between vectors' distribution, climate, land use and CL prevalence. METHODS: A database with geographic information was assembled, and ecological niche modeling was performed to explore the potential distribution of each of the 21 species of medical importance in Colombia, using thirteen bioclimatic variables, three topographic and three principal components derived from NDVI. Binary models for each species were obtained and related to both land use coverage, and a CL prevalence map with available epidemiological data. Finally, maps of species potential distribution were summed to define potential species richness in the country. RESULTS: In total, 673 single records were obtained with Lutzomyia gomezi, Lutzomyia longipalpis, Psychodopygus panamensis, Psathyromyia shannoni and Pintomyia evansi the species with the highest number of records. Eighteen species had significant models, considering the area under the curve and the jackknife results: L. gomezi and P. panamensis had the widest potential distribution. All sand fly species except for Nyssomyia antunesi are mainly distributed in regions with rates of prevalence between 0.33 to 101.35 cases per 100,000 inhabitants and 76% of collection data points fall into transformed ecosystems. DISCUSSION: Distribution ranges of sand flies with medical importance in Colombia correspond predominantly to disturbed areas, where the original land coverage is missing therefore increasing the domiciliation potential. We highlight the importance of the use of distribution maps as a tool for the development of strategies for prevention and control of diseases. PMID- 26431547 TI - De Novo Transcriptome Assembly and Comparative Analysis Elucidate Complicated Mechanism Regulating Astragalus chrysochlorus Response to Selenium Stimuli. AB - Astragalus species are medicinal plants that are used in the world for years. Some Astragalus species are known for selenium accumulation and tolerance and one of them is Astragalus chrysochlorus, a secondary selenium accumulator. In this study, we employed Illumina deep sequencing technology for the first time to de novo assemble A. chrysochlorus transcriptome and identify the differentially expressed genes after selenate treatment. Totally, 59,656 unigenes were annotated with different databases and 53,960 unigenes were detected in NR database. Transcriptome in A. chrysochlorus is closer to Glycine max than other plant species with 43,1 percentage of similarity. Annotated unigenes were also used for gene ontology enrichment and pathway enrichment analysis. The most significant genes and pathways were ABC transporters, plant pathogen interaction, biosynthesis of secondary metabolites and carbohydrate metabolism. Our results will help to enlighten the selenium accumulation and tolerance mechanisms, respectively in plants. PMID- 26431549 TI - Isolation and characterization of novel RECK tumor suppressor gene splice variants. AB - Glioblastoma multiforme is the most common and lethal of the central nervous system glial-derived tumors. RECK suppresses tumor invasion by negatively regulating at least three members of the matrix metalloproteinase family: MMP-9, MMP-2, and MT1-MMP. A positive correlation has been observed between the abundance of RECK expression in tumor samples and a more favorable prognosis for patients with several types of tumors. In the present study, novel alternatively spliced variants of the RECK gene: RECK-B and RECK-I were isolated by RT-PCR and sequenced. The expression levels and profiles of these alternative RECK transcripts, as well as canonical RECK were determined in tissue samples of malignant astrocytomas of different grades and in a normal tissue RNA panel by qRT-PCR. Our results show that higher canonical RECK expression, accompanied by a higher canonical to alternative transcript expression ratio, positively correlates with higher overall survival rate after chemotherapeutic treatment of GBM patients. U87MG and T98G cells over-expressing the RECK-B alternative variant display higher anchorage-independent clonal growth and do not display modulation of, respectively, MMP-2 and MMP-9 expression. Our findings suggest that RECK transcript variants might have opposite roles in GBM biology and the ratio of their expression levels may be informative for the prognostic outcome of GBM patients. PMID- 26431550 TI - mTOR Activation by PI3K/Akt and ERK Signaling in Short ELF-EMF Exposed Human Keratinocytes. AB - Several reports suggest that ELF-EMF exposures interact with biological processes including promotion of cell proliferation. However, the molecular mechanisms by which ELF-EMF controls cell growth are not completely understood. The present study aimed to investigate the effect of ELF-EMF on keratinocytes proliferation and molecular mechanisms involved. Effect of ELF-EMF (50 Hz, 1 mT) on HaCaT cell cycle and cells growth and viability was monitored by FACS analysis and BrdU assay. Gene expression profile by microarray and qRT-PCR validation was performed in HaCaT cells exposed or not to ELF-EMF. mTOR, Akt and MAPKs expressions were evaluated by Western blot analysis. In HaCaT cells, short ELF-EMF exposure modulates distinct patterns of gene expression involved in cell proliferation and in the cell cycle. mTOR activation resulted the main molecular target of ELF-EMF on HaCaT cells. Our data showed the increase of the canonical pathway of mTOR regulation (PI3K/Akt) and activation of ERK signaling pathways. Our results indicate that ELF-EMF selectively modulated the expression of multiple genes related to pivotal biological processes and functions that play a key role in physio-pathological mechanisms such as wound healing. PMID- 26431552 TI - ENDOCRINOLOGY OF PREGNANCY: Gestational diabetes mellitus: definition, aetiological and clinical aspects. AB - Gestational diabetes (GDM) is defined as a glucose intolerance resulting in hyperglycaemia of variable severity with onset during pregnancy. This review aims to revisit the pathogenesis and aetiology of GDM in order to better understand its clinical presentation and outcomes. During normal pregnancy, insulin sensitivity declines with advancing gestation. These modifications are due to placental factors, progesterone and estrogen. In a physiological situation, a compensatory increase in insulin secretion maintains a normal glucose homeostasis. GDM occurs if pancreatic beta-cells are unable to face the increased insulin demand during pregnancy. GDM is most commonly a forerunner of type 2 diabetes (T2D) - the most prevalent form of diabetes. These women share similar characteristics with predisposed subjects to T2D: insulin resistance before and after pregnancy, and carry more T2D risk alleles. Auto-immune and monogenic diabetes are more rare aetiologies of GDM. Adverse pregnancy outcomes of GDM are mainly related to macrosomia caused by fetal hyperinsulinism in response to high glucose levels coming from maternal hyperglycaemia. Screening recommendations and diagnosis criteria of GDM have been recently updated. High risk patients should be screened as early as possible using fasting plasma glucose, and if normal, at 24-28 weeks of gestation using 75 g oral glucose tolerance test. The treatment of GDM is based on education with trained nurses and dieticians, and if necessary insulin therapy. PMID- 26431551 TI - Definitive Characterization of CA 19-9 in Resectable Pancreatic Cancer Using a Reference Set of Serum and Plasma Specimens. AB - The validation of candidate biomarkers often is hampered by the lack of a reliable means of assessing and comparing performance. We present here a reference set of serum and plasma samples to facilitate the validation of biomarkers for resectable pancreatic cancer. The reference set includes a large cohort of stage I-II pancreatic cancer patients, recruited from 5 different institutions, and relevant control groups. We characterized the performance of the current best serological biomarker for pancreatic cancer, CA 19-9, using plasma samples from the reference set to provide a benchmark for future biomarker studies and to further our knowledge of CA 19-9 in early-stage pancreatic cancer and the control groups. CA 19-9 distinguished pancreatic cancers from the healthy and chronic pancreatitis groups with an average sensitivity and specificity of 70 74%, similar to previous studies using all stages of pancreatic cancer. Chronic pancreatitis patients did not show CA 19-9 elevations, but patients with benign biliary obstruction had elevations nearly as high as the cancer patients. We gained additional information about the biomarker by comparing two distinct assays. The two CA 9-9 assays agreed well in overall performance but diverged in measurements of individual samples, potentially due to subtle differences in antibody specificity as revealed by glycan array analysis. Thus, the reference set promises be a valuable resource for biomarker validation and comparison, and the CA 19-9 data presented here will be useful for benchmarking and for exploring relationships to CA 19-9. PMID- 26431553 TI - Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty. AB - CONTEXT AND OBJECTIVE: Idiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamic-pituitary-gonadal axis in the absence of identifiable central lesions. Mutations of the makorin RING finger 3 (MKRN3) gene are associated with iCPP. We aimed to assess the frequency of MKRN3 mutations in iCPP and to compare the phenotypes of patients with and without MKRN3 mutations. DESIGN: An observational study was carried out on patients recruited at pediatric hospitals in France and Italy. Forty-six index CPP cases were screened for mutations in the MKRN3 coding sequence: 28 index cases of familial cases and 18 cases did not report any familial history of CPP. The endocrine phenotype was compared between MKRN3 mutated and non-mutated patients. RESULTS: MKRN3 mutations were identified in one sporadic and 13 familial cases. We identified five new heterozygous missense mutations predicted to be deleterious for protein function and two frameshift mutations, one new and the other recurrent, predicted to result in truncated proteins. Age at puberty onset varied very little among patients with MKRN3 mutations and puberty occurred earlier in these patients than in those without MKRN3 mutations (6.0 years (5.4-6.0) vs 7.0 years (6.0-7.0), P=0.01). CONCLUSIONS: MKRN3 mutations are common in familial iCPP. MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis. PMID- 26431554 TI - Options in the Management of Reduced Vision in a Case of Ectopia Lentis. PMID- 26431555 TI - Black Dots and the Evil Eye! Bitot's spots. PMID- 26431556 TI - Liquid Crystals--Transformer That Meets the Eye. PMID- 26431557 TI - Macular Thickness in Highly Myopic Children. PMID- 26431558 TI - Familial Exudative Vitreoretinopathy: Presentation in the First Week of Life. PMID- 26431559 TI - Mizuo Nakamura Phenomenon. PMID- 26431560 TI - Bilateral Congenital Posterior Capsular Defects and Ectopic Cataracts. AB - Preexisting posterior capsular defects are rare and can be associated with infantile cataracts. The authors review possible etiologies of this condition and emphasize the importance of cautious preoperative planning and surgery. PMID- 26431561 TI - Debris ingestion by the Antillean Manatee (Trichechus manatus manatus). AB - The Antillean manatee inhabits coastal regions of North and Northeastern Brazil and currently is considered an endangered species in the country. Aiming to gather information for the development of public policies focusing on the conservation of manatees, the National Center for Research and Conservation of Aquatic Mammals of the Chico Mendes Institute for Biodiversity has been rescuing, rehabilitating and releasing these mammals since the 1980s. Over the last 36 years, 40 manatees were released by the CMA/ICMBio and four of them were rescued again due to debris ingestion. Two of these manatees died and the other two were taken back into captivity for a new rehabilitation process. The four mammals had confirmed diagnosis of plastic debris ingestion. These findings demonstrate that the environment where the manatees live after being released had a significant amount of garbage which may hinder the success of the species conservation in Brazil. PMID- 26431563 TI - Mitochondrial Cell Death Pathways in Caenorhabiditis elegans. AB - Programmed cell death is an evolutionarily conserved process essential for animal development and tissue homeostasis. Mitochondria have been demonstrated to play a central role in regulating both the activation and the execution of apoptosis. In particular, mitochondria release multiple proapoptotic factors from its intermembrane space, leading to both caspase-dependent and -independent cell death. Despite the pivotal roles of invertebrate animal models, Caenorhabiditis elegans and Drosophila melanogaster, in deciphering conserved pathways and mechanisms of programmed cell death, the importance of mitochondria to apoptosis of invertebrates remains elusive and largely unexplored. Recent studies have corroborated significant association between mitochondria and apoptosis in C. elegans, making it a thrust area of investigations. In this review, we detail the roles of mitochondrial proteins in mediating execution of cell death in C. elegans, including chromosome fragmentation, phosphatidylserine externalization, and elimination of mitochondria, and discuss the potential roles of mitochondria in the activation of C. elegans cell death. The combination of traditional powerful genetic tools and the emergence of the multiple new reverse genetic techniques, including the highly efficient CRISPR/Cas9 gene-editing method, should make C. elegans an ideal animal model for analyzing mitochondrial cell death pathways and associated regulatory mechanisms. PMID- 26431564 TI - Autophagy in Cell Life and Cell Death. AB - Macroautophagy (hereafter referred to as autophagy) is a process used by the cell to deliver cytoplasmic components to the lysosome for degradation. Autophagy is most often associated with cell survival, as it provides cells with molecular building blocks during periods of nutrient deprivation and also aids in the elimination of damaged organelles and protein aggregates. However, autophagy has also been implicated in cell death. Here, we review what is known about autophagy, its regulation, its role both in cell life and cell death, and what is known about autophagic cell death in vivo. PMID- 26431565 TI - The End of the Beginning: Cell Death in the Germline. AB - Programmed cell death occurs in the germline of many organisms, both as an essential part of development and throughout adult life. Germline cell death can be apoptotic or nonapoptotic, depending on the stimulus or stage of development. Here, we focus on the Drosophila ovary, which is a powerful model for studying diverse types of cell death. In Drosophila, the death of primordial germ cells occurs normally during embryonic development, and germline nurse cells are programmed to die during oocyte development in adult flies. Cell death of previtellogenic egg chambers in adults can also be induced by starvation or other environmental cues. Mid-oogenesis seems to be particularly sensitive to such cues and has been proposed to serve as a checkpoint to avoid the energetically expensive cost of egg production. After the germline dies in mid-oogenesis, the remnants are engulfed by an epithelial layer of follicle cells; thus, the fly ovary also serves as a highly tractable model for engulfment by epithelial cells. These examples of cell death in the fly ovary share many similarities to the types of cell death seen in the mammalian germline. Recent progress in elucidating the molecular mechanisms of cell death in the germline is discussed. PMID- 26431562 TI - Cell Death in C. elegans Development. AB - Cell death is a common and important feature of animal development, and cell death defects underlie many human disease states. The nematode Caenorhabditis elegans has proven fertile ground for uncovering molecular and cellular processes controlling programmed cell death. A core pathway consisting of the conserved proteins EGL-1/BH3-only, CED-9/BCL2, CED-4/APAF1, and CED-3/caspase promotes most cell death in the nematode, and a conserved set of proteins ensures the engulfment and degradation of dying cells. Multiple regulatory pathways control cell death onset in C. elegans, and many reveal similarities with tumor formation pathways in mammals, supporting the idea that cell death plays key roles in malignant progression. Nonetheless, a number of observations suggest that our understanding of developmental cell death in C. elegans is incomplete. The interaction between dying and engulfing cells seems to be more complex than originally appreciated, and it appears that key aspects of cell death initiation are not fully understood. It has also become apparent that the conserved apoptotic pathway is dispensable for the demise of the C. elegans linker cell, leading to the discovery of a previously unexplored gene program promoting cell death. Here, we review studies that formed the foundation of cell death research in C. elegans and describe new observations that expand, and in some cases remodel, this edifice. We raise the possibility that, in some cells, more than one death program may be needed to ensure cell death fidelity. PMID- 26431566 TI - The HOX-Apoptosis Regulatory Interplay in Development and Disease. AB - Apoptosis is a cellular suicide program, which is on the one hand used to remove superfluous cells thereby promoting tissue or organ morphogenesis. On the other hand, the programmed killing of cells is also critical when potentially harmful cells emerge in a developing or adult organism thereby endangering survival. Due to its critical role apoptosis is tightly controlled, however so far, its regulation on the transcriptional level is less studied and understood. Hox genes, a highly conserved gene family encoding homeodomain transcription factors, have crucial roles in development. One of their prominent functions is to shape animal body plans by eliciting different developmental programs along the anterior-posterior axis. To this end, Hox proteins transcriptionally regulate numerous processes in a coordinated manner, including cell-type specification, differentiation, motility, proliferation as well as apoptosis. In this review, we will focus on how Hox proteins control organismal morphology and function by regulating the apoptotic machinery. We will first focus on well-established paradigms of Hox-apoptosis interactions and summarize how Hox transcription factors control morphological outputs and differentially shape tissues along the anterior-posterior axis by fine-tuning apoptosis in a healthy organism. We will then discuss the consequences when this interaction is disturbed and will conclude with some ideas and concepts emerging from these studies. PMID- 26431567 TI - Programmed Cell Death and Caspase Functions During Neural Development. AB - Programmed cell death (PCD) is a fundamental component of nervous system development. PCD serves as the mechanism for quantitative matching of the number of projecting neurons and their target cells through direct competition for neurotrophic factors in the vertebrate peripheral nervous system. In addition, PCD plays roles in regulating neural cell numbers, canceling developmental errors or noise, and tissue remodeling processes. These findings are mainly derived from genetic studies that prevent cells from dying by apoptosis, which is a major form of PCD and is executed by activation of evolutionarily conserved cysteine protease caspases. Recent studies suggest that caspase activation can be coordinated in time and space at multiple levels, which might underlie nonapoptotic roles of caspases in neural development in addition to apoptotic roles. PMID- 26431568 TI - Regulation of Cell Death by IAPs and Their Antagonists. AB - Inhibitors of apoptosis (IAPs) family of genes encode baculovirus IAP-repeat domain-containing proteins with antiapoptotic function. These proteins also contain RING or UBC domains and act by binding to major proapoptotic factors and ubiquitylating them. High levels of IAPs inhibit caspase-mediated apoptosis. For these cells to undergo apoptosis, IAP function must be neutralized by IAP antagonists. Mammalian IAP knockouts do not exhibit obvious developmental phenotypes, but the cells are more sensitized to apoptosis in response to injury. Loss of the mammalian IAP-antagonist ARTS results in reduced stem cell apoptosis. In addition to the antiapoptotic properties, IAPs regulate the innate immune response, and the loss of IAP function in humans is associated with immunodeficiency. The roles of IAPs in Drosophila apoptosis regulation are more apparent, where the loss of IAP1, or the expression of IAP-antagonists in Drosophila cells, is sufficient to trigger apoptosis. In this organism, apoptosis as a fate is conferred by the transcriptional induction of the IAP-antagonists. Many signaling pathways often converge on shared enhancer regions of IAP antagonists. Cell death sensitivity is further regulated by posttranscriptional mechanisms, including those regulated by kinases, miRs, and ubiquitin ligases. These mechanisms are employed to eliminate damaged or virus-infected cells, limit neuroblast (neural stem cell) numbers, generate neuronal diversity, and sculpt tissue morphogenesis. PMID- 26431569 TI - Ubiquitin-Mediated Regulation of Cell Death, Inflammation, and Defense of Homeostasis. AB - Cell death and inflammation are ancient processes of fundamental biological importance in both normal physiology and human disease pathologies. The recent observation that apoptosis regulatory components have dual roles in cell death and inflammation suggests that these proteins function, not primarily to kill, but to coordinate tissue repair and remodeling. This perspective unifies cell death components as positive regulators of tissue repair that replaces malfunctioning or damaged tissues and enhances the resilience of epithelia to insult. It is now recognized that cells that die by apoptosis do not do so silently, but release a variety of paracrine signals to communicate with their cellular environment to ensure tissue regeneration, and wound healing. Moreover, inflammatory signaling pathways, such as those emanating from the TNF receptor or Toll-related receptors, take part in cell competition to eliminate developmentally aberrant clones. Ubiquitylation has emerged as crucial mediator of signal transduction in cell death and inflammation. Here, we focus on recent advances on ubiquitin-mediated regulation of cell death and inflammation, and how this is used to regulate the defense of homeostasis. PMID- 26431572 TI - Apoptotic Cell Clearance in Development. AB - Programmed cell death and its specific form apoptosis play an important role during development of multicellular organisms. They are crucial for morphogenesis and organ sculpting as well as for adjusting cell number in different systems. Removal of apoptotic cells is the last critical step of apoptosis. Apoptotic cells are properly and efficiently recognized and eliminated through phagocytosis, which is performed by professional and nonprofessional phagocytes. Phagocytosis of apoptotic cells or apoptotic cell clearance is a dynamic multistep process, involving interactions between phagocytic receptors and ligands on apoptotic cells, which are highly conserved in evolution. However, this process is extremely redundant in mammals, containing multiple factors playing similar roles in the process. Using model organisms such as Caenorhabditis elegans, Drosophila melanogaster, zebrafish, and mouse permits addressing fundamental questions in developmental cell clearance by a comprehensive approach including powerful genetics and cell biological tools enriched by live imaging. Recent studies in model organisms have enhanced significantly our understanding of the molecular and cellular basis of apoptotic cell clearance during development. Here, we review the current knowledge and illuminate the great potential of the research performed in genetic models, which opens new directions in developmental biology. PMID- 26431571 TI - Clearance of Apoptotic Cells and Pyrenocytes. AB - Apoptotic cells are engulfed and digested by macrophages to maintain homeostasis in animals. If dead cells are not engulfed swiftly, they undergo secondary necrosis and release intracellular components that activate the immune system. Apoptotic cells are efficiently cleared due to phosphatidylserine (PtdSer) exposed on the cell surface that acts as an "eat me" signal. PtdSer is exposed through the activation of phospholipid scramblase and the inactivation of phospholipid flippase, which are both caspase-mediated events. Macrophages express a variety of molecules to recognize PtdSer, and use a sophisticated mechanism to engulf apoptotic cells. In red blood cells, the nucleus is lost when it is extruded as a pyrenocyte during definitive erythropoiesis. These pyrenocytes (nuclei surrounded by plasma membrane) also expose PtdSer on their surface and are efficiently engulfed by macrophages in a PtdSer-dependent manner. Macrophages transfer the engulfed apoptotic cell or pyrenocyte into lysosomes, where the components of the dead cell or pyrenocyte are degraded. If lysosomes cannot digest the DNA from apoptotic cells or pyrenocytes, the undigested DNA accumulates in the lysosome and activates macrophages to produce type I interferon (IFN) via a STING-dependent pathway; in embryos, this causes severe anemia. Here, we discuss how macrophages clear apoptotic cells and pyrenocytes. PMID- 26431570 TI - The Sound of Silence: Signaling by Apoptotic Cells. AB - Apoptosis is a carefully choreographed process of cellular self-destruction in the absence of inflammation. During the death process, apoptotic cells actively communicate with their environment, signaling to both their immediate neighbors as well as distant sentinels. Some of these signals direct the anti-inflammatory immune response, instructing specific subsets of phagocytes to participate in the limited and careful clearance of dying cellular debris. These immunomodulatory signals can also regulate the activation state of the engulfing phagocytes. Other signals derived from apoptotic cells contribute to tissue growth control with the common goal of maintaining tissue integrity. Derangements in these growth control signals during prolonged apoptosis can lead to excessive cell loss or proliferation. Here, we highlight some of the most intriguing signals produced by apoptotic cells during the course of normal development as well as during physiological disturbances such as atherosclerosis and cancer. PMID- 26431573 TI - The Morphogenetic Role of Apoptosis. AB - Beyond safeguarding the organism from cell misbehavior and controlling cell number, apoptosis (or programmed cell death) plays key roles during animal development. In particular, it has long been acknowledged that apoptosis participates in tissue remodeling. Yet, until recently, this contribution to morphogenesis was considered as "passive," consisting simply in the local removal of unnecessary cells leading to a new shape. In recent years, applying live imaging methods to study the dynamics of apoptosis in various contexts has considerably modified our vision, revealing that in fact, dying cells remodel their neighborhood actively. Here, we first focus on the intrinsic cellular properties of apoptotic cells during their dismantling, in particular the role of the cytoskeleton during their characteristic morphological changes. Second, we review the various roles of apoptosis during developmental morphogenetic processes and pinpoint the crucial role of live imaging in revealing new concepts, in particular apoptosis as a generator of mechanical forces to control tissue dynamics. PMID- 26431574 TI - Preface. PMID- 26431575 TI - Refined 9-lead total QRS voltage criteria may offer a better diagnostic accuracy for left ventricular hypertrophy. PMID- 26431576 TI - No benefit to die from cancer with healthy coronary arteries, except in France. PMID- 26431577 TI - Predictors of short- and long-term outcomes of Takotsubo cardiomyopathy. AB - Takotsubo cardiomyopathy (TC) is a reversible cardiomyopathy with a benign short term prognosis but is associated with recurrence rate of 10%. Clinical variables that predict long-term mortality and recurrence are unknown; 56 consecutive patients presenting to a single urban medical center who fulfilled the Mayo Clinic criteria for the diagnosis of TC were included. Patients were followed with 100% completeness; >60 clinical factors were analyzed, including presentation, treatment, electrocardiogram, and echocardiographic, angiographic, and demographic variables. Survival analysis was performed using the Kaplan-Meier function and Cox proportional hazards regression models. There were 15 deaths during follow-up: 5 in-hospital, 4 before 90 days, and 6 after 90 days. Mean survival was 4.47 years (95% confidence interval 3.81 to 5.13). All short-term survivors had repeat ejection fraction evaluation demonstrating improvement; 45 of 56 patients were women and 96% were postmenopausal. The nonfatal recurrence rate was 1.8%. QTc interval at presentation was the factor most strongly predictive of overall outcome, after intubation. All patients with mortality had QTc intervals between 400 and 550 ms. In conclusion, this study demonstrates the prognostic significance of QTc prolongation at presentation in TC. Because the cause of TC involves intense catecholamine release and hyperadrenergic tone, the QTc may reflect the individual impact on myocardial repolarization and the balance between sympathetic innervation and parasympathetic compensation. In conclusion, in this series, TC was associated with an 8.9% in-hospital mortality, an additional 17.9% mortality after discharge, and a nonfatal recurrence rate of 1.8%. Moreover, the QTc on presentation with TC was predictive of outcome. PMID- 26431578 TI - Assessment of dose error due to nylon mesh of treatment couch. AB - PURPOSE: This study aims at the assessment of dose error in patients undergoing radiotherapy due to treatment couch of Co-60 teletherapy unit. MATERIALS AND METHODS: In this study beam attenuation due to treatment couch of Co-60 unit was measured in air for different gantry angles and field sizes. Polymethylmethacrylate (PMMA) phantom was used to estimate the effect of depth on attenuation. Impact of couch on surface dose was also evaluated. RESULTS: Beam attenuation due to couch was in the range of 0.5-28% for different gantry angles with standard field size of 10 * 10 cm(2) with optimum position of metallic cranks. Maximum attenuation (29%) was observed with smallest field size i.e. 5 * 5 cm(2). Beam attenuation has been found higher in phantom as compared to that in air However, no particular trend of attenuation has been noted with varying depth of phantom. A 6% increase in surface dose has also been observed due to couch insertion for normal beam incidence. Maximum error of 80% is also note-worthy for most unfavorable situation of irradiation at 180 degree through the metallic cranks. CONCLUSION: It has been determined that ignoring the treatment couch and its accessories can result in dose error of 0.5-80%, depending on gantry angle, field size and position of couch accessories. Therefore, consideration of dose error due to couch during treatment planning is recommended. PMID- 26431579 TI - Quantization accuracy of short-duration respiratory-gated PET/CT acquisitions. AB - PURPOSE: PET/CT acquisitions are affected by physiological motion, which lowers the quantization accuracy. Respiratory-gated PET/CT methods require a long acquisition time, which may not be compatible with the clinical schedule. The objective of the present study was to assess the quantization accuracy of short duration, respiratory-gated PET acquisitions and processing with the "CT-based" methodology developed in our laboratory. METHODS: Quantization accuracy was first assessed in a phantom study. A standard ("Ungated") PET/CT acquisition was followed by a 10-minute list-mode acquisition with simultaneous respiratory signal recording and a short breath-hold CT scan (BH-CT). These acquisitions were repeated 10 times. For the CT-based images, we reconstructed (i) 10 full-duration (FD-CT-based) volumes that took account of all events recorded in the position defined by BH-CT and (ii) 10 short-duration (SD-CT-based) volumes based on only 30 seconds of selected events. Using these volumes, we performed a bias-variance analysis to assess the effects of respiration-motion reduction and the counting statistics on the quantization accuracy. We also applied Ungated, FD- and SD-CT based methods to 16 patients (21 pulmonary lesions) and measured the maximum standardized uptake (SUVmax) values. RESULTS: The bias values were 71%, 40% and 44% for Ungated, FD- and SD-CT-based images, respectively. In the clinical study, there was a statistically significant difference in SUVmax between Ungated images and both the CT-Based images (p < 0.02) but not between the FD-CT-Based and SD-CT Based images (p = 0.42). CONCLUSION: Our findings demonstrated that the additional acquisition time required by the CT-based method can be reduced without altering quantitative accuracy. PMID- 26431580 TI - Hematopoietic prostaglandin D synthase defines a proeosinophilic pathogenic effector human T(H)2 cell subpopulation with enhanced function. AB - BACKGROUND: IL-5(+) pathogenic effector T(H)2 (peT(H)2) cells are a T(H)2 cell subpopulation with enhanced proinflammatory function that has largely been characterized in murine models of allergic inflammation. OBJECTIVE: We sought to identify phenotype markers for human peT(H)2 cells and characterize their function in patients with allergic eosinophilic inflammatory diseases. METHODS: Patients with eosinophilic gastrointestinal disease (EGID), patients with atopic dermatitis (AD), and nonatopic healthy control (NA) subjects were enrolled. peT(H)2 and conventional T(H)2 (cT(H)2) cell phenotype, function, and cytokine production were analyzed by using flow cytometry. Confirmatory gene expression was measured by using quantitative RT-PCR. Prostaglandin D2 levels were measured with ELISA. Gut T(H)2 cells were obtained by means of esophagogastroduodenoscopy. RESULTS: peT(H)2 cells were identified as chemoattractant receptor-homologous molecule expressed on T(H)2 cells-positive (CRTH2(+)), hematopoietic prostaglandin D synthase-positive CD161(hi) CD4 T cells. peT(H)2 cells expressed significantly greater IL-5 and IL-13 than did hematopoietic prostaglandin D synthase-negative and CD161(-) cT(H)2 cells. peT(H)2 cells were highly correlated with blood eosinophilia (r = 0.78-0.98) and were present in 30- to 40-fold greater numbers in subjects with EGID and those with AD versus NA subjects. Relative to cT(H)2 cells, peT(H)2 cells preferentially expressed receptors for thymic stromal lymphopoietin, IL-25, and IL-33 and demonstrated greater responsiveness to these innate pro-TH2 cytokines. peT(H)2 but not cT(H)2 cells produced prostaglandin D2. In patients with EGID and those with AD, peT(H)2 cells expressed gut- and skin-homing receptors, respectively. There were significantly greater numbers of peT(H)2 cells in gut tissue from patients with EGID versus NA subjects. CONCLUSION: peT(H)2 cells are the primary functional proinflammatory human T(H)2 cell subpopulation underlying allergic eosinophilic inflammation. The unambiguous phenotypic identification of human peT(H)2 cells provides a powerful tool to track these cells in future pathogenesis studies and clinical trials. PMID- 26431581 TI - Critical link between glycogen synthase kinase 3beta and forkhead box P3 in patients with chronic rhinosinusitis with nasal polyps. PMID- 26431582 TI - Petrolatum: Barrier repair and antimicrobial responses underlying this "inert" moisturizer. AB - BACKGROUND: Petrolatum is a common moisturizer often used in the prevention of skin infections after ambulatory surgeries and as a maintenance therapy of atopic dermatitis (AD). However, the molecular responses induced by petrolatum in the skin have never been assessed. OBJECTIVE: We sought to define the cutaneous molecular and structural effects induced by petrolatum. METHODS: Thirty-six healthy subjects and 13 patients with moderate AD (mean SCORAD score, 39) were studied by using RT-PCR, gene arrays, immunohistochemistry, and immunofluorescence performed on control skin, petrolatum-occluded skin, and skin occluded with a Finn chamber only. RESULTS: Significant upregulations of antimicrobial peptides (S100A8/fold change [FCH], 13.04; S100A9/FCH, 11.28; CCL20/FCH, 8.36; PI3 [elafin]/FCH, 15.40; lipocalin 2/FCH, 6.94, human beta defensin 2 [DEFB4A]/FCH, 4.96; P < .001 for all) and innate immune genes (IL6, IL8, and IL1B; P < .01) were observed in petrolatum-occluded skin compared with expression in both control and occluded-only skin. Application of petrolatum also induced expression of key barrier differentiation markers (filaggrin and loricrin), increased stratum corneum thickness, and significantly reduced T-cell infiltrates in the setting of "normal-appearing" or nonlesional AD skin, which is known to harbor barrier and immune defects. CONCLUSIONS: Petrolatum robustly modulates antimicrobials and epidermal differentiation barrier measures. These data shed light on the beneficial molecular responses of petrolatum in barrier defective states, such as AD and postoperative wound care. PMID- 26431583 TI - Faecalibacterium prausnitzii subspecies-level dysbiosis in the human gut microbiome underlying atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is a serious global epidemic associated with a modern lifestyle. OBJECTIVE: Although aberrant interactions between gut microbes and the intestinal immune system have been implicated in this skin disease, the nature of the microbiome dysfunction underlying the disease remains unclear. METHODS: The gut microbiome from 132 subjects, including 90 patients with AD, was analyzed by using 16S rRNA gene and metagenome sequence analyses. Reference genomes from the Human Microbiome Project and the KEGG Orthology database were used for metagenome analyses. Short-chain fatty acids in fecal samples were compared by using gas chromatographic-mass spectrometric analyses. RESULTS: We show that enrichment of a subspecies of the major gut species Faecalibacterium prausnitzii is strongly associated with AD. In addition, the AD microbiome was enriched in genes encoding the use of various nutrients that could be released from damaged gut epithelium, reflecting a bloom of auxotrophic bacteria. Fecal samples from patients with AD showed decreased levels of butyrate and propionate, which have anti-inflammatory effects. This is likely a consequence of an intraspecies compositional change in F prausnitzii that reduces the number of high butyrate and propionate producers, including those related to the strain A2 165, a lack of which has been implicated in patients with Crohn disease. CONCLUSIONS: The data suggest that feedback interactions between dysbiosis in F prausnitzii and dysregulation of gut epithelial inflammation might underlie the chronic progression of AD by resulting in impairment of the gut epithelial barrier, which ultimately leads to aberrant TH2-type immune responses to allergens in the skin. PMID- 26431584 TI - Characteristics and functions of lipid droplets and associated proteins in enterocytes. AB - Cytosolic lipid droplets (LDs) are observed in enterocytes of jejunum during lipid absorption. One important function of the intestine is to secrete chylomicrons, which provide dietary lipids throughout the body, from digested lipids in meals. The current hypothesis is that cytosolic LDs in enterocytes constitute a transient pool of stored lipids that provides lipids during interprandial period while lowering chylomicron production during the post prandial phase. This smoothens the magnitude of peaks of hypertriglyceridemia. Here, we review the composition and functions of lipids and associated proteins of enterocyte LDs, the known physiological functions of LDs as well as the role of LDs in pathological processes in the context of the intestine. PMID- 26431585 TI - Kinase active Misshapen regulates Notch signaling in Drosophila melanogaster. AB - Notch signaling pathway represents a principal cellular communication system that plays a pivotal role during development of metazoans. Drosophila misshapen (msn) encodes a protein kinase, which is related to the budding yeast Ste20p (sterile 20 protein) kinase. In a genetic screen, using candidate gene approach to identify novel kinases involved in Notch signaling, we identified msn as a novel regulator of Notch signaling. Data presented here suggest that overexpression of kinase active form of Msn exhibits phenotypes similar to Notch loss-of-function condition and msn genetically interacts with components of Notch signaling pathway. Kinase active form of Msn associates with Notch receptor and regulate its signaling activity. We further show that kinase active Misshapen leads to accumulation of membrane-tethered form of Notch. Moreover, activated Msn also depletes Armadillo and DE-Cadherin from adherens junctions. Thus, this study provides a yet unknown mode of regulation of Notch signaling by Misshapen. PMID- 26431587 TI - Fluctuating diplopia as an initial manifestation of polycythemia vera. PMID- 26431586 TI - PKCepsilon as a novel promoter of skeletal muscle differentiation and regeneration. AB - INTRODUCTION: Satellite cells are muscle resident stem cells and are responsible for muscle regeneration. In this study we investigate the involvement of PKCepsilon during muscle stem cell differentiation in vitro and in vivo. Here, we describe the identification of a previously unrecognized role for the PKCepsilon HMGA1 signaling axis in myoblast differentiation and regeneration processes. METHODS: PKCepsilon expression was modulated in the C2C12 cell line and primary murine satellite cells in vitro, as well as in an in vivo model of muscle regeneration. Immunohistochemistry and immunofluorescence, RT-PCR and shRNA silencing techniques were used to determine the role of PKCepsilon and HMGA1 in myogenic differentiation. RESULTS: PKCepsilon expression increases and subsequently re-localizes to the nucleus during skeletal muscle cell differentiation. In the nucleus, PKCepsilon blocks Hmga1 expression to promote Myogenin and Mrf4 accumulation and myoblast formation. Following in vivo muscle injury, PKCepsilon accumulates in regenerating, centrally-nucleated myofibers. Pharmacological inhibition of PKCepsilon impairs the expression of two crucial markers of muscle differentiation, namely MyoD and Myogenin, during injury induced muscle regeneration. CONCLUSION: This work identifies the PKCepsilon HMGA1 signaling axis as a positive regulator of skeletal muscle differentiation. PMID- 26431588 TI - Moderate consumption of white and fortified wine is associated with reduced odds of diabetic retinopathy. AB - AIM: To explore the association between alcohol consumption and the severity of diabetic retinopathy (DR). METHODS: In this cross-sectional study, patients with type 2 diabetes answered questions on consumption of low and full-strength beer, white wine/champagne, red wine, fortified wines, and spirits. Never, moderate and high consumption of each alcoholic beverage, and overall alcoholic beverage consumption, were defined as <1, 1-14 and >14 standard drinks/week, respectively. DR was categorized into none; non vision-threatening DR (VTDR) and VTDR. Multivariable logistic regression determined the associations between alcohol consumption and DR. RESULTS: Of the 395 participants (mean age+/-SD [standard deviation] 65.9+/-10.4years; males=253), 188 (47.6%) consumed alcohol and 235 (59.5%) had any DR. Compared to no alcohol consumption, moderate alcohol consumption (overall) was significantly associated with reduced odds of any DR (OR=0.47, 95% CI [confidence interval] 0.26-0.85). Moderate consumption of white wine/champagne or fortified wine was also associated with reduced odds of any DR (OR=0.48, 95% CI 0.25-0.91, and OR=0.15, 95% CI 0.04-0.62, respectively). Similar results were observed for non-VTDR and VTDR. CONCLUSIONS: The amount and type of alcohol are associated with risk of DR in patients with type 2 diabetes. A longitudinal study is needed to assess the protective effect of alcohol consumption and DR. PMID- 26431589 TI - Imaging Reporters for Proteasome Activity Identify Tumor- and Metastasis Initiating Cells. AB - Tumor-initiating cells, also designated as cancer stem cells, are proposed to constitute a subpopulation of malignant cells central to tumorigenesis, metastasis, and treatment resistance. We analyzed the activity of the proteasome, the primary organelle for targeted protein degradation, as a marker of tumor- and metastasis-initiating cells. Using human and mouse breast cancer cells expressing a validated fluorescent reporter, we found a small subpopulation of cells with low proteasome activity that divided asymmetrically to produce daughter cells with low or high proteasome activity. Breast cancer cells with low proteasome activity had greater local tumor formation and metastasis in immunocompromised and immunocompetent mice. To allow flexible labeling of cells, we also developed a new proteasome substrate based on HaloTag technology. Patient-derived glioblastoma cells with low proteasome activity measured by the HaloTag reporter show key phenotypes associated with tumor-initiating cells, including expression of a stem cell transcription factor, reconstitution of the original starting population, and enhanced neurosphere formation. We also show that patient-derived glioblastoma cells with low proteasome activity have higher frequency of tumor formation in mouse xenografts. These studies support proteasome function as a tool to investigate tumor- and metastasis-initiating cancer cells and a potential biomarker for outcomes in patients with several different cancers. PMID- 26431590 TI - Comparative study of the clinical features of patients with a tubo-ovarian abscess and patients with severe pelvic inflammatory disease. AB - OBJECTIVE: To determine the clinical characteristics that indicate the presence of tubo-ovarian abscess (TOA) among patients with severe pelvic inflammatory disease (PID). METHODS: An observational cohort study was performed from October 2011 to March 2013. The study included all patients with a diagnosis of TOA and PID admitted to a university hospital in Mexico. A complete medical history and physical examination were performed, and laboratory studies were reviewed. A logistic regression analysis was performed on variables with statistical significance. RESULTS: Overall, 26 patients with PID and TOA (TOA group) and 26 with PID without TOA (PID group) were included in the study. Significant differences between patients with TOA and PID were found with regard to the patients' age (39.3years vs 33.1years; P=0.04), educational level (only elementary, 13 [50%] vs 5 [19%]; P=0.14), presentation with fever (23 [88%] vs 16 [62%]; P=0.025), white blood cell count (21.8*10(9)/L vs 14.9*10(9)/L; P<0.001), number of deliveries (2.2 vs 1.1; P=0.01), and presence of diarrhea (16 [62%] vs 5 [19%]; P<0.001). The triad of fever, leukocytosis, and diarrhea was positively related to the presence of TOA. CONCLUSION: The triad of fever, leukocytosis, and diarrhea should alert clinicians to the possibility of TOA formation in patients with PID. PMID- 26431591 TI - Role of oxidative stress and serum lipid levels in stable chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) has been associated with increased oxidative stress or reduced antioxidant resources. The main goal of this study was to evaluate the levels of serum ischemia-modified albumin (IMA), oxidized low-density lipoprotein (ox-LDL), total oxidant status (TOS), and total antioxidant status in patients with stable COPD, compared with a control group. METHODS: This study was performed on 51 patients with stable COPD (42 men and 9 women; mean age 56.92 +/- 3.0 years) and 45 healthy control participants (32 men and 13 women; 54.8 +/- 3.8 years). The levels of serum lipids, IMA, total antioxidant status, TOS, and ox-LDL were measured in all participants. RESULTS: The levels of serum IMA, ox-LDL, and TOS were significantly higher in patients with COPD than those in control individuals. There was no difference between the levels of serum total antioxidant status, triglycerides, total cholesterol, and low-density lipoprotein cholesterol (LDL-C) of patients with COPD and those of control individuals. Serum high-density lipoprotein cholesterol levels were significantly lower in patients with COPD than in control individuals. CONCLUSION: Our study indicated that serum IMA, ox-LDL, and TOS may be increased as a result of chronic hypoxia, inflammation, and oxidative stress in patients with severe and very severe stable COPD. Our findings also revealed that IMA is higher in patients with Global Initiative for Chronic Obstructive Lung Disease Stages II, III, and IV, while TOS and ox-LDL are higher in patients with Global Initiative for Chronic Obstructive Lung Disease Stage IV. Measurements of serum IMA, TOS, and ox-LDL levels may be useful markers in the evaluation of stable COPD. PMID- 26431592 TI - Changes in platelet function independent of pharmacotherapy following coronary intervention in non-ST-elevation myocardial infarction patients. AB - BACKGROUND: High on treatment platelet reactivity (HTPR) is common in patients receiving clopidogrel following an acute coronary syndrome (ACS); it's also associated with increased morbidity and mortality. More potent and predictable antiplatelet drugs have addressed this issue at the expense of increased bleeding. Identification of HTPR and the targeted use of more potent antiplatelet drugs has, so far, broadly failed. We investigate this approach in terms of the timing of platelet function testing and how this can impact on the ability of these bedside tests to predict HTPR around the time of coronary intervention. METHODS: High risk ACS patients treated with 5 days of clopidogrel had platelet function assessed using the multiple electrode aggregometry system (MEA) pre, post and 24 h following percutaneous coronary intervention (PCI). Simultaneous detailed analysis of platelet status was undertaken with quantification of platelet bound and soluble p-selectin and mass spectrometry quantification of the eicosanoid 12-HETE. RESULTS: As assessed by MEA 40.5% of patients had HTPR pre PCI; mean aggregation units (AU) in response to ADP were 499.1 +/- 46.3 pre-PCI, 407.6 +/- 37.7 post-PCI and 269.1 +/- 24.6 AU 24 h post-PCI (pre to post PCI p > 0.05, pre to 24 h post-PCI p = 0.0002). This highly significant drop in platelet reactivity was contrasted with on-going expression of platelet bound p-selectin, increased soluble p-selectin and rising 12-HETE concentrations. CONCLUSIONS: This study outlines significant changes in ex-vivo platelet aggregation that occur within 24 h of PCI in high risk NSTEMI patients using bedside PFT. Whilst there were no changes in antiplatelet therapy during the study period its clear that timing is crucial when assessing high on treatment residual platelet activity. PMID- 26431594 TI - Difficult Biliary Access: Advanced Cannulation and Sphincterotomy Technique. AB - Many devices and techniques have been developed to assist in cases of difficult biliary cannulation. Guidewire-assisted cannulation has become the first-line technique for biliary cannulation. Precut sphincterotomy can be safe and effective if used soon after encountering difficulty. Pancreatic duct stents are an important adjunct to reduce the risk of post-endoscopic retrograde cholangiopancreatography pancreatitis in difficult access. Ultimately, cannulation success of greater than 95% and complication rates of less than 5% is the standard that endoscopists doing ERCP should achieve. PMID- 26431593 TI - Age matters: Developmental stage of Danio rerio larvae influences photomotor response thresholds to diazinion or diphenhydramine. AB - Because basic toxicological data is unavailable for the majority of industrial compounds, High Throughput Screening (HTS) assays using the embryonic and larval zebrafish provide promising approaches to define bioactivity profiles and identify potential adverse outcome pathways for previously understudied chemicals. Unfortunately, standardized approaches, including HTS experimental designs, for examining fish behavioral responses to contaminants are rarely available. In the present study, we examined movement behavior of larval zebrafish over 7 days (4-10 days post fertilization or dpf) during typical daylight workday hours to determine whether intrinsic activity differed with age and time of day. We then employed an early life stage approach using the Fish Embryo Test (FET) at multiple developmental ages to evaluate whether photomotor response (PMR) behavior differed with zebrafish age following exposure to diazinon (DZN), a well-studied orthophosphate insecticide, and diphenhydramine (DPH), an antihistamine that also targets serotonin reuptake transporters and the acetylcholine receptor. 72h studies were conducted at 1-4, 4-7 and 7-10dpf, followed by behavioral observations using a ViewPoint system at 4, 7 and 10dpf. Distance traveled and swimming speeds were quantified; nominal treatment levels were analytically verified by isotope-dilution LC-MSMS. Larval zebrafish locomotion displayed significantly different (p<0.05) activity profiles over the course of typical daylight and workday hours, and these time of day PMR activity profiles were similar across ages examined (4-10dpf). 10dpf zebrafish larvae were consistently more sensitive to DPH than either the 4 or 7dpf larvae with an environmentally realistic lowest observed effect concentration of 200ng/L. Though ELS and FET studies with zebrafish typically focus on mortality or teratogenicity in 0-4dpf organisms, behavioral responses of slightly older fish were several orders of magnitude more sensitive to DPH. Our observations highlight the importance of understanding the influence of time of day on intrinsic locomotor activity, and the age-specific hazards of aquatic contaminants to fish behavior. PMID- 26431595 TI - Endoscopic Retrograde Cholangiopancreatography in Surgically Altered Anatomy. AB - ERCP in surgically altered anatomy requires the endoscopist to fully understand the procedural goals and the reconstructed anatomy before proceeding. Altered anatomy presents a variety of challenges unique to enteroscopy, and others related to accessing the biliary or pancreatic duct from unusual orientations. Both side-viewing and forward-viewing endoscopes, as well as single and double balloon techniques, are available for ERCP in these settings. Endoscope selection largely depends on the anatomy and length of reconstructed intestinal limbs. Endoscopist experience with performing ERCP in surgically altered anatomy is the most important factor for determining outcomes and success rates. PMID- 26431596 TI - Endoscopic Retrograde Cholangiopancreatography for the Management of Common Bile Duct Stones and Gallstone Pancreatitis. AB - Biliary disease is a common cause of acute pancreatitis. Risk stratification for persistent pancreatobiliary obstruction is important for selecting a treatment approach. Most common bile duct stones are extracted with standard endoscopic techniques. However, prior foregut surgery, stones with extreme morphologic attributes, and at difficult positions within the biliary system are technically challenging and predict a need for advanced biliary endoscopic techniques. Surgical common bile duct exploration at the time of cholecystectomy is appropriate in centers with experience. We outline the options and approach for the clinician to successfully identify and manage patients with symptomatic choledocholithiasis with or without biliary pancreatitis. PMID- 26431597 TI - Diagnosing Biliary Malignancy. AB - The most common malignant causes of biliary strictures are pancreatic cancer and cholangiocarcinoma. Differentiating between malignant and benign causes of biliary strictures has remained a clinical challenge. Endoscopic retrograde cholangiopancreatography (ERCP) remains the mainstay and first-line method of tissue diagnosis but has a poor diagnostic yield. This article reviews the causes of biliary strictures, the initial clinical evaluation of biliary obstruction, the diagnostic yield of ERCP-based sampling methods, the role of newer tools in the armamentarium for evaluating strictures, and ways to address the ongoing challenge of stricture evaluation in patients with primary sclerosing cholangitis. PMID- 26431598 TI - Stenting in Malignant Biliary Obstruction. AB - Decompression of the biliary system in patients with malignant biliary obstruction has been widely accepted and implemented as part of the care. Despite a wealth of literature, there remains a significant amount of uncertainty as to which approach would be most appropriate in different clinical settings. This review covers stenting of the biliary system in cases of resectable or palliative malignant biliary obstruction, potential candidates for biliary drainage, technical aspects of the procedure, as well as management of biliary stent dysfunction. Furthermore, periprocedural considerations including proper mapping of the location of obstruction and the use of antibiotics are addressed. PMID- 26431599 TI - Benign Biliary Strictures and Leaks. AB - The major causes of benign biliary strictures include surgery, chronic pancreatitis, primary sclerosing cholangitis, and autoimmune cholangitis. Biliary leaks mainly occur after surgery and, rarely, abdominal trauma. These conditions may benefit from a nonsurgical approach in which endoscopic retrograde cholangiopancreatography (ERCP) plays a pivotal role in association with other minimally invasive approaches. This approach should be evaluated for any injury before deciding about the method for repair. ERCP, associated with peroral cholangioscopy, plays a growing role in characterizing undeterminate strictures, avoiding both unuseful major surgeries and palliative options that might compromise any further management. PMID- 26431600 TI - Preventing Postendoscopic Retrograde Cholangiopancreatography Pancreatitis. AB - Postendoscopic retrograde cholangiopancreatography pancreatitis is a common and potentially devastating complication of endoscopic retrograde cholangiopancreatography. Advances in risk-stratification, patient selection, procedure technique, and prophylactic interventions have substantially improved the ability to prevent this complication. This article presents the evidence based approaches to preventing postendoscopic retrograde cholangiopancreatography pancreatitis and discusses timely research questions in this important area. PMID- 26431601 TI - Endoscopic Treatment of Recurrent Acute Pancreatitis and Smoldering Acute Pancreatitis. AB - Recurrent acute pancreatitis (RAP) is a challenging condition that can lead to chronic pancreatitis and long-term morbidity. Etiology-based treatment can potentially have an impact on the natural history of RAP and its progression to chronic pancreatitis. In cases of divisum-associated RAP and idiopathic RAP, several studies have been performed to evaluate the efficacy of endoscopic therapy in alleviation of symptoms and frequency of AP events. This review discusses the literature available on these topic as well as touching on the role of endoscopic therapy in smoldering acute pancreatitis. PMID- 26431602 TI - Sphincter of Oddi Dysfunction. AB - This article reviews the diagnosis and management of sphincter of Oddi dysfunction (SOD), including the various factors to consider before embarking on endoscopic therapy for SOD. Selection starts with patient education to include possible patient misconceptions related to symptoms caused by the pancreaticobiliary sphincter as well as reinforcing the risks associated with the diagnosis and therapy. The likelihood of relief of recurrent abdominal pain attributed to SOD is related to the classification of SOD type and a crucial consideration before considering endoscopic therapy in light of recent evidence. PMID- 26431603 TI - Pancreatic Endotherapy for Chronic Pancreatitis. AB - Extracorporeal shock wave lithotripsy is recommended as the first-line therapy for large (>5-mm) obstructive pancreatic ductal stones. Dominant pancreatic duct strictures should be initially managed with a wide-bore single plastic stent with 3 monthly exchanges for a year, even in asymptomatic patients. Recent studies have evaluated multiple plastic and self-expanding covered metal stents for refractory pancreatic ductal stricture. Pancreatic pseudocysts should be treated endoscopically with or without endoscopic ultrasound guidance. PMID- 26431604 TI - Innovations in Intraductal Endoscopy: Cholangioscopy and Pancreatoscopy. AB - Cholangioscopy was first performed in the 1970s. We now use the term cholangiopancreatoscopy (CP) to reflect the wider application of these miniature reusable dual-operator "mother-daughter" endoscope systems and now fully disposable and digital single-operator optical catheters for evaluating the biliary or pancreatic duct. Cholangioscopy is an established modality for the management of large biliary stones and for the diagnosis and exclusion of biliary tumors. Pancreatoscopy is increasingly being performed to treat difficult pancreatic duct stones and may be used to distinguish malignant from benign ductal pathology. This review covers available CP technologies, indications, technique, efficacy, and complications. PMID- 26431605 TI - Biliary Tumor Ablation with Photodynamic Therapy and Radiofrequency Ablation. AB - Within the past two decades, major progress has been made in biliary endoscopy both with stenting and with ablative therapy. A primary goal in patients with malignant biliary lesions who are not candidates for surgery is to provide localized and efficient necrosis of the lesions. This article summarizes the current literature on biliary tumor ablation with photodynamic therapy and radiofrequency ablation. Prognosis, treatment technique, potential complications, treatment efficacy, and controversies are discussed. PMID- 26431606 TI - Endoscopic Ultrasound-Assisted Pancreaticobiliary Access. AB - Endoscopic retrograde cholangiopancreatography (ERCP) is the primary approach to drain an obstructed pancreatic or biliary duct. Failed biliary drainage is traditionally referred for percutaneous transhepatic biliary drainage or surgical bypass, which carry significantly higher morbidity and mortality rates compared with ERCP and transpapillary drainage. Endoscopic ultrasound provides a real-time imaging platform to access and deliver therapy to organs and tissues outside of the bowel lumen. The bile and pancreatic ducts can be directly accessed from the stomach and duodenum, offering an alternative to ERCP when this fails or is not feasible. PMID- 26431607 TI - Advances in Therapeutic Endoscopic Retrograde Cholangiopancreatography: Benefits Far Outweigh the Small Risks. PMID- 26431608 TI - Advances in Endoscopic Retrograde Cholangiopancreatography. PMID- 26431609 TI - Kaposi Sarcoma-associated Herpesvirus: mechanisms of oncogenesis. AB - Kaposi Sarcoma-associated Herpesvirus (KSHV, HHV8) causes three human malignancies, Kaposi Sarcoma (KS), an endothelial tumor, as well as Primary Effusion Lymphoma (PEL) and the plasma cell variant of Multicentric Castleman's Disease (MCD), two B-cell lymphoproliferative diseases. All three cancers occur primarily in the context of immune deficiency and/or HIV infection, but their pathogenesis differs. KS most likely results from the combined effects of an endotheliotropic virus with angiogenic properties and inflammatory stimuli and thus represents an interesting example of a cancer that arises in an inflammatory context. Viral and cellular angiogenic and inflammatory factors also play an important role in the pathogenesis of MCD. In contrast, PEL represents an autonomously growing malignancy that is, however, still dependent on the continuous presence of KSHV and the action of several KSHV proteins. PMID- 26431610 TI - The amount of mandibular setback influence on occlusal force following sagittal split ramus osteotomy. AB - PURPOSE: The purpose of this study was to examine the influence between the magnitude of setback in sagittal split ramus osteotomy (SSRO) and occlusal contact area and bite force without relapse after surgery. PATIENTS AND METHODS: Sixty female patients with a diagnosis of mandibular prognathism were divided into 3 groups according to the magnitude of setback: group 1 (<=5 mm), group 2 (>5 mm but <10 mm), and group 3 (>=10 mm). All patients underwent skeletal analysis by lateral and frontal cephalogrammetry and measured the occlusal contact area and bite force by the pressure-sensitive system (Dental Prescale, Dental Occlusion Pressuregraph FDP-705; Fuji Photo Film Co., Tokyo, Japan) preoperatively and postoperatively at 1 month, 3 months, 6 months, and 1 year. RESULTS: There were no significant differences in occlusal contact area and bite force between the 3 groups. Only group 3 showed a significant difference in occlusal contact area and bite force between the preoperative and 1-year measurements. CONCLUSION: The results indicate that the magnitude of setback did not influence the bite force or occlusal contact area in SSRO. PMID- 26431611 TI - Transgenerational effects of 17alpha-ethinyl estradiol on anxiety behavior in the guppy, Poecilia reticulata. AB - Environmental contaminants can cause alterations that can be transgenerationally transmitted to subsequent generations. Estrogens are among those contaminants shown to induce heritable changes that persist over generations in mammals. Results in other vertebrates are few. We have analyzed the effects on anxiety of 17alpha-ethinyl estradiol (EE2) in the F1 and F2 generations in guppies, Poecilia reticulata, obtained from F0 fish maternally exposed to 0 or 20ng/L EE2 until birth. F0 males and females were bred with fish of the same treatment but different families producing F1 offspring. Behavior in the novel tank test at 6months revealed that males with EE2-exposed parents had significantly longer latency to the upper half of the tank than control males, while no EE2 effects were observed in females. Also in F2, obtained from F1 as above, males in the EE2 group had longer latency time compared to control males, with no differences due to EE2-exposure of F0 observed in females. In the scototaxis (light/dark preference) test, latency to first transition to black compartment and total transitions to black were significantly altered in females due to EE2 exposure of F0 while the total time in black was higher in males with EE2-exposed F0 compared with controls. The increased anxiety in the F2 generation demonstrates a transgenerational anxiety phenotype and shows that non-reproductive behavior can be transgenerationally modified by estrogens in fish. PMID- 26431612 TI - Implications of monotreme and marsupial chromosome evolution on sex determination and differentiation. AB - Studies of chromosomes from monotremes and marsupials endemic to Australasia have provided important insight into the evolution of their genomes as well as uncovering fundamental differences in their sex determination/differentiation pathways. Great advances have been made this century into solving the mystery of the complicated sex chromosome system in monotremes. Monotremes possess multiple different X and Y chromosomes and a candidate sex determining gene has been identified. Even greater advancements have been made for marsupials, with reconstruction of the ancestral karyotype enabling the evolutionary history of marsupial chromosomes to be determined. Furthermore, the study of sex chromosomes in intersex marsupials has afforded insight into differences in the sexual differentiation pathway between marsupials and eutherians, together with experiments showing the insensitivity of the mammary glands, pouch and scrotum to exogenous hormones, led to the hypothesis that there is a gene (or genes) on the X chromosome responsible for the development of either pouch or scrotum. This review highlights the major advancements made towards understanding chromosome evolution and how this has impacted on our understanding of sex determination and differentiation in these interesting mammals. PMID- 26431613 TI - Endogenous control of sexual size dimorphism: Gonadal androgens have neither direct nor indirect effect on male growth in a Madagascar ground gecko (Paroedura picta). AB - Changes in the effect of gonadal androgens on male growth are considered as a possible mechanism allowing shifts in magnitude and even direction of sexual size dimorphism in vertebrates, particularly squamate reptiles. Positive effects of gonadal androgens on male growth were found in several male-larger species of lizards. Contrastingly, we document that in the male-larger Madagascar ground gecko (Paroedura picta) gonadal androgens do not affect male growth under constant thermal conditions. However, the absence of a thermal gradient might prevent the potential indirect effect of gonadal androgens on growth via the influence of circulating hormones on an individual's thermoregulation and hence metabolic rate. In order to study this, we monitored the growth and body temperature of socially isolated sham-operated and castrated males of the same species in a thermal gradient. We also compared the oxygen consumption and activity between the treatment groups in the open field to test the effect of gonadal hormones on these traits potentially affecting growth. Even under a thermal gradient we found no effect of gonadal androgens on growth rate or final body dimensions. Castration also did not significantly affect oxygen consumption or activity in the open field test. Together with our previous findings, we can exclude both the direct effect of male gonadal androgens on the ontogeny of sexual size dimorphism via the influence on the growth axis, and the indirect influence of gonadal androgens acting on the ontogeny of SSD through the effect on thermoregulation, metabolic rate and activity. PMID- 26431614 TI - Non-hazardous pesticide concentrations in surface waters: An integrated approach simulating application thresholds and resulting farm income effects. AB - Pesticide application rates are high and increasing in upland agricultural systems in Thailand producing vegetables, fruits and ornamental crops, leading to the pollution of stream water with pesticide residues. The objective of this study was to determine the maximum per hectare application rates of two widely used pesticides that would achieve non-hazardous pesticide concentrations in the stream water and to evaluate how farm household incomes would be affected if farmers complied with these restricted application rates. For this purpose we perform an integrated modeling approach of a hydrological solute transport model (the Soil and Water Assessment Tool, SWAT) and an agent-based farm decision model (Mathematical Programming-based Multi-Agent Systems, MPMAS). SWAT was used to simulate the pesticide fate and behavior. The model was calibrated to a 77 km(2) watershed in northern Thailand. The results show that to stay under a pre-defined eco-toxicological threshold, the current average application of chlorothalonil (0.80 kg/ha) and cypermethrin (0.53 kg/ha) would have to be reduced by 80% and 99%, respectively. The income effect of such reductions was simulated using MPMAS. The results suggest that if farm households complied with the application thresholds then their income would reduce by 17.3% in the case of chlorothalonil and by 38.3% in the case of cypermethrin. Less drastic income effects can be expected if methods of integrated pest management were more widely available. The novelty of this study is to combine two models from distinctive disciplines to evaluate pesticide reduction scenarios based on real-world data from a single study site. PMID- 26431615 TI - Patient assessment in polytrauma: current trends rely on multiple parameters to improve the prediction of complications and mortality. PMID- 26431616 TI - Spoilt for choice: A critical review on the chemical and biological assessment of current wastewater treatment technologies. AB - The knowledge we have gained in recent years on the presence and effects of compounds discharged by wastewater treatment plants (WWTPs) brings us to a point where we must question the appropriateness of current water quality evaluation methodologies. An increasing number of anthropogenic chemicals is detected in treated wastewater and there is increasing evidence of adverse environmental effects related to WWTP discharges. It has thus become clear that new strategies are needed to assess overall quality of conventional and advanced treated wastewaters. There is an urgent need for multidisciplinary approaches combining expertise from engineering, analytical and environmental chemistry, (eco)toxicology, and microbiology. This review summarizes the current approaches used to assess treated wastewater quality from the chemical and ecotoxicological perspective. Discussed chemical approaches include target, non-target and suspect analysis, sum parameters, identification and monitoring of transformation products, computational modeling as well as effect directed analysis and toxicity identification evaluation. The discussed ecotoxicological methodologies encompass in vitro testing (cytotoxicity, genotoxicity, mutagenicity, endocrine disruption, adaptive stress response activation, toxicogenomics) and in vivo tests (single and multi species, biomonitoring). We critically discuss the benefits and limitations of the different methodologies reviewed. Additionally, we provide an overview of the current state of research regarding the chemical and ecotoxicological evaluation of conventional as well as the most widely used advanced wastewater treatment technologies, i.e., ozonation, advanced oxidation processes, chlorination, activated carbon, and membrane filtration. In particular, possible directions for future research activities in this area are provided. PMID- 26431617 TI - Open your eyes and you will see. Changes in "eyes-open" versus "eyes-closed" small-world properties of EEG functional connectivity in amnesic mild cognitive impairment. PMID- 26431618 TI - Somatosensory-evoked potential modulation by quadripulse transcranial magnetic stimulation in patients with benign myoclonus epilepsy. AB - OBJECTIVE: In patients with benign myoclonus epilepsy (ME), giant sensory-evoked potential (SEP) reflects the hyperexcitability of the sensory cortex. The aim of this study was to compare the effect of quadripulse transcranial magnetic stimulation (QPS) on the median nerve SEP between ME patients and healthy subjects. METHODS: Ten healthy volunteers and six ME patients with giant SEP participated in this study. QPSs at interpulse intervals (IPIs) of 5, 30, 50, 100, 500 and 1250 ms were applied over the left primary motor cortex (M1) for 30 min. The peak-to-peak amplitudes of N20 to P25 (N20-P25) and P25 to N33 (P25-N33) components were measured at the left somatosensory cortex. RESULTS: In healthy participants, the P25-N33 was bidirectionally modulated by QPS over M1, following the Bienenstock-Cooper-Munro (BCM) theory. The N20-P25 was not affected by any QPSs. In ME patients, the giant P25-N33 was potentiated after any QPSs. Furthermore, the N20-P25 was also potentiated after QPS at IPIs of 5, 30, 50 100 or 500 ms. CONCLUSIONS: In ME patients, the cascade for long-term depression-like effects may be impaired. SIGNIFICANCE: The giant SEP was furthermore enhanced by QPS. PMID- 26431619 TI - [Antenatal palliative plan following diagnosis of fetal lethal condition: Rennes Teaching Hospital experience]. AB - OBJECTIVES: To study the pregnancies followed at Rennes University Hospital from 2006 to 2012, after prenatal diagnosis of lethal fetal condition and prenatal project of palliative care at birth consisting of comfort care emphasizing parent child encounters and bonding. MATERIAL AND METHODS: Retrospective study of 20 pregnancies with diagnosis of lethal fetal condition where parents accepted antenatally the proposal or sought for palliative care at birth. RESULTS: Diagnosis was made at a median age of 20 weeks gestation (12-33). Birth occurred at 37.4 WG, 6 caesarean sections were performed for maternal conditions. Six cases of hypoplastic left heart syndrome (HLHS) share common characteristics: good Apgar score, prolonged survival (26hours to 159days) transfer to neonatology ward (6) or later at home (4). In four multiple pregnancies, the choice of SP mainly contributed to protect healthy twins during pregnancy. In birth room, there was no need for invasive procedure or drugs. Death: one occurred during labor, 8 in birth room before H2, others in neonatal ward before d4 (excluding HLHS). CONCLUSION: These data will enable better antenatal preparation of both teams and parents. Lifetime, however short, allowed parents to meet with their child alive this permitting collection of memory traces and bonding. PMID- 26431620 TI - [Customized and non-customized French intrauterine growth curves. II - Comparison with existing curves and benefits of customization]. AB - OBJECTIVES: Our aim is to compare the new French EPOPe intrauterine growth curves, developed to address the guidelines 2013 of the French College of Obstetricians and Gynecologists, with reference curves currently used in France, and to evaluate the consequences of their adjustment for fetal sex and maternal characteristics. POPULATION AND METHODS: Eight intrauterine and birthweight curves, used in France were compared to the EPOPe curves using data from the French Perinatal Survey 2010. The influence of adjustment on the rate of SGA births and the characteristics of these births was analysed. RESULTS: Due to their birthweight values and distribution, the selected intrauterine curves are less suitable for births in France than the new curves. Birthweight curves led to low rates of SGA births from 4.3 to 8.5% compared to 10.0% with the EPOPe curves. The adjustment for maternal and fetal characteristics avoids the over representation of girls among SGA births, and reclassifies 4% of births. Among births reclassified as SGA, the frequency of medical and obstetrical risk factors for growth restriction, smoking (>=10 cigarettes/day), and neonatal transfer is higher than among non-SGA births (P<0.01). CONCLUSION: The EPOPe curves are more suitable for French births than currently used curves, and their adjustment improves the identification of mothers and babies at risk of growth restriction and poor perinatal outcomes. PMID- 26431621 TI - Effects of angiotensin II on leptin and downstream leptin signaling in the carotid body during acute intermittent hypoxia. AB - Angiotensin II (ANG II) is known to promote leptin production and secretion. Although ANG II type 1 receptors (AT1Rs) and leptin are expressed within the carotid body, it is not known whether AT1R and leptin are co-expressed in the same glomus cells nor if these peptides are affected within the carotid body by intermittent hypoxia (IH). This study was done to investigate whether ANG II modulated leptin signaling in the carotid body during IH. Rats were treated with captopril (Capt) or the AT1R blocker losartan (Los) in the drinking water for 3days prior to being exposed to IH (8h) or normoxia (8h). IH induced increases in plasma ANG II and leptin compared to normoxic controls. Capt treatment abolished the plasma leptin changes to IH, whereas Los treatment had no effect on the IH induced increase in plasma leptin. Additionally, carotid body glomus cells containing both leptin and the long form of the leptin receptor (OB-Rb) were found to co-express AT1R protein, and IH increased the expression of only AT1R protein within the carotid body in both Capt- and non-Capt-treated animals. On the other hand, Los treatment did not modify AT1R protein expression to IH. Additionally, Capt and Los treatment eliminated the elevated carotid body leptin protein expression, and the changes in phosphorylated signal transducer and activator of transcription three protein, the short form of the leptin receptor (OB-R100), suppressor of cytokine signaling 3, and phosphorylated extracellular signal-regulated kinase 1/2 protein expression induced by IH. However, Capt elevated the expression of OB-Rb protein, whereas Los abolished the changes in OB Rb protein to IH. These findings, taken together with the previous observation that ANG II modifies carotid body chemosensitivity, suggest that the increased circulating levels of ANG II and leptin induced by IH act at the carotid body to alter leptin signaling within the carotid body which in turn may influence chemoreceptor function. PMID- 26431622 TI - The effect of WIN 55,212-2 suggests a cannabinoid-sensitive component in the early toxicity induced by organic acids accumulating in glutaric acidemia type I and in related disorders of propionate metabolism in rat brain synaptosomes. AB - Several physiological processes in the CNS are regulated by the endocannabinoid system (ECS). Cannabinoid receptors (CBr) and CBr agonists have been involved in the modulation of the N-methyl-D-aspartate receptor (NMDAr) activation. Glutaric (GA), 3-hydroxyglutaric (3-OHGA), methylmalonic (MMA) and propionic (PA) acids are endogenous metabolites produced and accumulated in the brain of children affected by severe organic acidemias (OAs) with neurodegeneration. Oxidative stress and excitotoxicity have been involved in the toxic pattern exerted by these organic acids. Studying the early pattern of toxicity exerted by these metabolites is crucial to explain the extent of damage that they can produce in the brain. Herein, we investigated the effects of the synthetic CBr agonist WIN 55,212-2 (WIN) on early markers of GA-, 3-OHGA-, MMA- and PA-induced toxicity in brain synaptosomes from adult (90-day-old) and adolescent (30-day-old) rats. As pre-treatment, WIN exerted protective effects on the GA- and MMA-induced mitochondrial dysfunction, and prevented the reactive oxygen species (ROS) formation and lipid peroxidation induced by all metabolites. Our findings support a protective and modulatory role of cannabinoids in the early toxic events elicited by toxic metabolites involved in OAs. PMID- 26431623 TI - Reduced connectivity and inter-hemispheric symmetry of the sensory system in a rat model of vulnerability to developing depression. AB - Defining the markers corresponding to a high risk of developing depression in humans would have major clinical significance; however, few studies have been conducted since they are not only complex but also require homogeneous groups. This study compared congenital learned helpless (cLH) rats, selectively bred for high stress sensitivity and learned helplessness (LH) behavior, to congenital non learned helpless (cNLH) rats that were bred for resistance to uncontrollable stress. Naive cLH rats show some depression-like behavior but full LH behavior need additional stress, making this model ideal for studying vulnerability to depression. Resting-state functional connectivity obtained from seed correlation analysis was calculated for multiple regions that were selected by anatomy AND by a data-driven approach, independently. Significance was determined by t-statistic AND by permutation analysis, independently. A significant reduction in functional connectivity was observed by both analyses in the cLH rats in the sensory, motor, cingulate, infralimbic, accumbens and the raphe nucleus. These reductions corresponded primarily to reduced inter-hemispheric connectivity. The main reduction however was in the sensory system. It is argued that reduced connectivity and inter-hemispheric connectivity of the sensory system reflects an internal convergence state which may precede other depressive symptomatology and therefore could be used as markers for vulnerability to the development of depression. PMID- 26431625 TI - Adherence to Guidelines in Adult Patients with Traumatic Brain Injury: A Living Systematic Review. AB - Guidelines aim to improve the quality of medical care and reduce treatment variation. The extent to which guidelines are adhered to in the field of traumatic brain injury (TBI) is unknown. The objectives of this systematic review were to (1) quantify adherence to guidelines in adult patients with TBI, (2) examine factors influencing adherence, and (3) study associations of adherence to clinical guidelines and outcome. We searched EMBASE, MEDLINE, Cochrane Central, PubMed, Web of Science, PsycINFO, SCOPUS, CINAHL, and grey literature in October 2014. We included studies of evidence-based (inter)national guidelines that examined the acute treatment of adult patients with TBI. Methodological quality was assessed using the Research Triangle Institute item bank and Quality in Prognostic Studies Risk of Bias Assessment Instrument. Twenty-two retrospective and prospective observational cohort studies, reported in 25 publications, were included, describing adherence to 13 guideline recommendations. Guideline adherence varied considerably between studies (range 18-100%) and was higher in guideline recommendations based on strong evidence compared with those based on lower evidence, and lower in recommendations of relatively more invasive procedures such as craniotomy. A number of patient-related factors, including age, Glasgow Coma Scale, and intracranial pathology, were associated with greater guideline adherence. Guideline adherence to Brain Trauma Foundation guidelines seemed to be associated with lower mortality. Guideline adherence in TBI is suboptimal, and wide variation exists between studies. Guideline adherence may be improved through the development of strong evidence for guidelines. Further research specifying hospital and management characteristics that explain variation in guideline adherence is warranted. PMID- 26431624 TI - Progression and recovery of Parkinsonism in a chronic progressive MPTP-induction model in the marmoset without persistent molecular and cellular damage. AB - Chronic exposure to low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in marmoset monkeys was used to model the prodromal stage of Parkinson's disease (PD), and to investigate mechanisms underlying disease progression and recovery. Marmosets were subcutaneously injected with MPTP for a period of 12weeks, 0.5mg/kg once per week, and clinical signs of Parkinsonism, motor- and non-motor behaviors were recorded before, during and after exposure. In addition, postmortem immunohistochemistry and proteomics analysis were performed. MPTP induced parkinsonian clinical symptoms increased in severity during exposure, and recovered after MPTP administration was ended. Postmortem analyses, after the recovery period, revealed no alteration of the number and sizes of tyrosine hydroxylase (TH)-positive dopamine (DA) neurons in the substantia nigra. Also levels of TH in putamen and caudate nucleus were unaltered, no differences were observed in DA, serotonin or nor-adrenalin levels in the caudate nucleus, and proteomics analysis revealed no global changes in protein expression in these brain areas between treatment groups. Our findings indicate that parkinsonian symptoms can occur without detectable damage at the cellular or molecular level. Moreover, we show that parkinsonian symptoms may be reversible when diagnosed and treated early. PMID- 26431626 TI - Hepatic Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation: Risk Factors and Stratification, Prophylaxis, and Treatment. AB - Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), can develop in a subset of patients, primarily after myeloablative hematopoietic stem cell transplantation, but it also may occur after reduced-intensity conditioning. Severe VOD/SOS, typically characterized by multiorgan failure, has been associated with a mortality rate greater than 80%. Therefore, an accurate and prompt diagnosis of VOD/SOS is essential for early initiation of appropriate therapy to improve clinical outcomes. Moreover, some studies have support the use of prophylaxis for patients who are at high risk of developing VOD/SOS. This review summarizes risk factors associated with development of VOD/SOS, including pretransplantation patient characteristics and factors related to stem cell transplantation, that can facilitate patient stratification according to risk. The incidence of VOD/SOS, clinical features, and diagnostic criteria are reviewed. Data on emerging treatment strategies for patients with VOD/SOS are discussed in the context of recent treatment guidelines. Additionally, options for prophylaxis in individuals who are at increased risk are presented. Although historically only those patients with moderate to severe VOD/SOS have been treated, early therapy and prophylaxis may be appropriate for many patients and may have the potential to improve patients' outcomes and survival, including for those with nonsevere disease. PMID- 26431627 TI - Reply to "Pharmacokinetic and Analytical Issues in Busulfan Area Under the Curve Estimation and Simulation". PMID- 26431628 TI - Graft-versus-Host Disease-Associated Vulvovaginal Symptoms after Bone Marrow Transplantation. AB - We conducted a retrospective review to assess the prevalence of graft-versus-host disease (GVHD)-associated gynecologic conditions among bone marrow transplantation (BMT) patients at City of Hope Medical Center. We calculated the associations among the estimated risks of various gynecologic complications, including vaginal stenosis, by performing chi-square tests and t-test statistics. Between 2010 and 2014, 180 patients were referred to the gynecologic clinic after their BMT. One hundred twenty-four patients (69%) had GVHD; among these patients, 51 (41%) experienced dyspareunia and 43 (35%) had vaginal stenosis. GVHD patients were significantly more likely to have vaginal stenosis (P < .0001), more likely to have used a vaginal dilator (P = .0008), and less likely to have urinary incontinence (UI) than those without GVHD (P < .001). There was no difference in developing pelvic organ prolapse (POP) in patients with or without GVHD (P = .4373). GVHD was a common complication after allogenic BMT. Patients with BMT were more likely to have vulvovaginal symptoms, such as dyspareunia and pelvic pain. Patients with GVHD are at high risk for vaginal stenosis requiring the use of a vaginal dilator. However, they are at low risk for developing UI and POP. PMID- 26431629 TI - Pharmacokinetic and Analytical Issues in Busulfan Area Under the Curve Estimation and Simulation. PMID- 26431630 TI - Impact of Allele-Level HLA Mismatch on Outcomes in Recipients of Double Umbilical Cord Blood Transplantation. AB - The impact of allele-level HLA mismatch is uncertain in recipients of double umbilical cord blood (UCB) transplantation. We report a single-center retrospective study of the clinical effect of using allele-level HLA mismatch HLA A, -B, -C, -DRB1, and -DQB1 of the 2 UCB units. We studied 342 patients with hematologic malignancy. Donor-recipient pairs were grouped according to the number of matched HLA alleles, with 32 matched at 9-10/10, 202 at 6-8/10, and 108 at 2-5/10 alleles. The incidence of hematopoietic recovery, acute and chronic graft-versus-host disease, and nonrelapse mortality and treatment failure was similar between groups. In an exploratory analysis of 174 patients with acute leukemia, after adjusting for length of first remission and cytogenetic risk group, a 2-5/10 HLA match was associated with lower risk of relapse and treatment failure. These data indicate that a high degree of allele-level HLA mismatch does not adversely affect transplant outcomes and may be associated with reduced relapse risk in patients with acute leukemia. PMID- 26431631 TI - The Japanese diet from 1975 delays senescence and prolongs life span in SAMP8 mice. AB - OBJECTIVE: Life expectancy in Japan is high, suggesting that the Japanese diet, Nihon shoku (Japanese food), has significant health benefits. However, these benefits have been called into question over the past 50 y, during which time the Japanese diet has become increasingly Westernized. The aim of the present study was to focus on senescence delay and to examine the effects of Japanese diets from different years to identify which Japanese diet is most effective in enhancing life expectancy and delaying senescence. METHODS: Weekly menus from the years 1960, 1975, 1990, and 2005 were reproduced based on the National Health and Nutrition Survey in Japan and prepared as powdered foods. The senescence accelerated mouse prone 8 (SAMP8) mice were fed standard laboratory chow supplemented with a 30% mix of Japanese meals from various years ad libitum throughout their lifetime. Additionally, the control group was given standard laboratory chow only, to examine the development of mice reared under standard conditions. RESULTS: In the group that ingested the traditional 1975 Japanese diet, life span was prolonged, senescence was delayed, and learning and memory capacities were maintained compared with the group fed the 2005 Japanese diet. The life span of the group that ingested the 1990 Japanese diet showed a tendency to be longer than SAMP8 mice fed the 2005 diet. CONCLUSION: The results of the present study suggested that the traditional Japanese diet is more effective in enhancing life expectancy and delaying senescence than the current Japanese diet. PMID- 26431632 TI - Harnessing the microRNA pathway for cardiac regeneration. AB - Mounting evidence over the last few years has indicated that the rate of cardiomyocyte proliferation, and thus the extent of cardiac renewal, is under the control of the microRNA network. Several microRNAs (e.g. miR-1) regulate expansion of the cardiomyocyte pool and its terminal differentiation during the embryonic life; some not only promote cardiomyocyte proliferation but also their de-differentiation towards an embryonic cell phenotype (e.g. the miR-302/367 cluster); a few others are involved in the repression of cardiomyocyte proliferation occurring suddenly after birth (e.g. the miR-15 family); others again are not physiologically involved in the regulation of cardiomyocyte turnover, but nevertheless are able to promote cardiomyocyte proliferation and cardiac regeneration when delivered exogenously (e.g. miR-199a-3p). With a few exceptions, the molecular mechanisms underlying the pro-proliferative effect of these microRNAs, most of which appear to act at the level of already differentiated cardiomyocytes, remain to be thoroughly elucidated. The possibility of harnessing the miRNA network to achieve cardiac regeneration paves the way to exciting therapeutic applications. This could be achieved by either administering miRNA mimics or inhibitors, or transducing the heart with viral vectors expressing miRNA-encoding genes. PMID- 26431633 TI - Laparoscopic sleeve gastrectomy in children and adolescents with Prader-Willi syndrome: a matched-control study. AB - BACKGROUND: Obesity is a leading cause of mortality and morbidity in Prader-Willi syndrome (PWS). OBJECTIVES: To study weight loss and growth after laparoscopic sleeve gastrectomy (LSG) in pediatric patients with PWS compared with those without the syndrome. SETTING: Academic center with a standardized care pathway for pediatric bariatric surgery as a part of a prospective clinical outcome study on children and adolescents undergoing weight loss surgery. METHODS: Clinical data of all PWS patients who underwent LSG were abstracted from our prospective database, which included all pediatric patients who underwent bariatric surgery. These data were then compared with a 1:3 non-PWS group matched for age, gender, and body mass index (BMI). Data for up to 5 years follow-up were analyzed. RESULTS: The 24 PWS patients (mean age 10.7; 6<8 yr old, range 4.9-18) had a preoperative BMI of 46.2 +/- 12.2 kg/m(2). All PWS patients had obstructive sleep apnea (OSA), 62% had dyslipidemia, 43% had hypertension, and 29% had diabetes mellitus. BMI change at the first, second, third, fourth, and fifth annual visits was -14.7 (n = 22 patients), -15.0 (n = 18), 12.2 (n = 13), -12.7 (n = 11), and 10.7 (n = 7), respectively, in the PWS group, whereas the non-PWS group had a BMI change of -15.9 (n = 67), -18.0 (n = 50), -18.4 (n = 47), -18.9 (n = 26), and 19.0 (n = 20), respectively. No significant difference was observed in postoperative BMI change (P = .2-.7) or growth (postoperative height z-score P value at each annual visit = .2-.8); 95% of co-morbidities in both groups were in remission or improved, with no significant difference in the rate of co-morbidity resolution after surgery (P = .73). One PWS patient was readmitted 5 years after surgery with recurrence of OSA and heart failure. No other readmissions occurred, and there were no reoperations, postoperative leaks, or other complications. No mortality or major morbidity was observed during the 5 years of follow-up. Among the PWS patients who reached their follow-up visit time points the total follow up rate was 94.1%, whereas in the non-PWS group it was 97%. All patients who missed a follow-up visit were subsequently seen in future follow-ups, and no patient was lost to follow-up in either group. CONCLUSIONS: PWS children and adolescents underwent effective weight loss and resolution of co-morbidities after LSG, without mortality, significant morbidity, or slowing of growth. LSG should be offered to obese PWS patients with heightened mortality particularly because no other effective alternative therapy is available. PMID- 26431634 TI - The fossil record of ecdysis, and trends in the moulting behaviour of trilobites. AB - Ecdysis, the process of moulting an exoskeleton, is one of the key characters uniting arthropods, nematodes and a number of smaller phyla into Ecdysozoa. The arthropod fossil record, particularly trilobites, eurypterids and decapod crustaceans, yields information on moulting, although the current focus is predominantly descriptive and lacks a broader evolutionary perspective. We here review literature on the fossil record of ecdysis, synthesising research on the behaviour, evolutionary trends, and phylogenetic significance of moulting throughout the Phanerozoic. Approaches vary widely between taxonomic groups, but an overall theme uniting these works suggests that identifying moults in the palaeontological record must take into account the morphology, taphonomy and depositional environment of fossils. We also quantitatively analyse trends in trilobite ecdysis based on a newly generated database of published incidences of moulting behaviour. This preliminary work reveals significant taxonomic and temporal signal in the trilobite moulting fossil record, with free cheek moulting being prevalent across all Orders and throughout the Phanerozoic, and peaks of cephalic moulting in Phacopida during the Ordovician and rostral plate moulting in Redlichiida during the Cambrian. This study and a review of the literature suggest that it is feasible to extract large-scale evolutionary information from the fossil record of moulting. PMID- 26431635 TI - The branchiostegal lung of Uca vocans (Decapoda: Ocypodidae): Unreported complexity revealed by corrosion casting and MicroCT techniques. AB - The study of adaptation to terrestrial life in crabs poses several physiological questions. One of the major challenges the crabs have to face is respiration of air: most of the time, gills are unsuitable to perform oxygen exchange out of the water. Fiddler crabs, like other representatives of the Ocypodidae, have developed an additional mechanism of respiration by improving the circulation that lines the branchiostegal chamber, thus developing a branchiostegal lung. In the present study we describe the hitherto unreported complex morphology of the branchiostegal lung of the fiddler crab Uca vocans by means of corrosion casting techniques and 3D reconstruction. This complexity leads us to reconsider the degree of terrestriality of U. vocans and its evolutionary pathway towards land. PMID- 26431636 TI - The morphology of the eggs of three species of Zoraptera (Insecta). AB - The egg structure of Zorotypus magnicaudelli, Zorotypus hubbardi and Zorotypus impolitus was examined and described in detail. Major characteristics of zorapteran eggs previously reported were confirmed in these species, with the partial exception of Z. impolitus: 1) a pair of micropyles at the equator of the egg's ventral side, 2) a honeycomb pattern on the egg surface, 3) a two-layered chorion, 4) micropylar canals running laterally, 5) a flap covering the inner opening of the micropylar canal and 6) no region specialized for hatching. These features are probably part of the groundplan of the order. Three groups (A-C) and two subgroups (A1 and A2) of Zoraptera can be distinguished based on characters of the reproductive apparatus including eggs. However, information for more species is needed for a reliable interpretation of the complex and apparently fast evolving character system. The egg of Z. impolitus presumably shows apomorphic characteristics not occurring in other species, a chorion without layered construction and polygonal surface compartments with different sculptures on the dorsal and ventral sides of the egg. Another feature found in this species, distinct enlargement of the micropyles, is also found in Z. hubbardi. The increased micropylar size is likely correlated with the giant spermatozoa produced by males of these two species. These two features combined with the large size of the spermatheca are arguably a complex synapomorphy of Z. hubbardi and Z. impolitus. The phylogenetic placement of Zoraptera is discussed based on the egg structure. A clade of Zoraptera + Eukinolabia appears most plausible, but the issue remains an open question. PMID- 26431637 TI - The sperm pump of the hangingfly Bittacus planus Cheng (Mecoptera: Bittacidae). AB - The males of antliophoran insects usually use a sperm pump to transfer liquid sperm into the reproductive tract of the female. However, the fine structure of the sperm pump and its ejaculatory mechanism has not been thoroughly clarified in many groups of Mecoptera. In this paper, the structure of the sperm pump was investigated in the hangingfly Bittacus planus Cheng, 1949 using light and scanning electron microscopy. The sperm pump mainly consists of a piston fused with a piston-carrying sclerite, a pumping chamber enclosed by the genital folds, which comprises the posterior region of the ejaculatory sac, an ostial sclerite, a phallobase, and other associated structures and muscles. The piston crown plays a major role in the piston movement. The ostial sclerite serves as a discharge valve and is controlled by two antagonistic muscles. No depressor muscles were found attached to the piston. The sperm pumping activity is mainly controlled by the combination of the levator of the piston and the retractor and protractor of the ostial sclerite. The ejaculatory mechanism and phylogenetic significance are briefly discussed based on the structure of the sperm pump. PMID- 26431638 TI - Determination of death after circulatory arrest by intensive care physicians: A survey of current practice in the Netherlands. AB - PURPOSE: Determination of death is an essential part of donation after circulatory death (DCD). We studied the current practices of determination of death after circulatory arrest by intensive care physicians in the Netherlands, the availability of guidelines, and the occurrence of the phenomenon of autoresuscitation. METHODS: The Determination of Cardiac Death Practices in Intensive Care Survey was sent to all intensive care physicians. RESULTS: Fifty five percent of 568 Dutch intensive care physicians responded. Most respondents learned death determination from clinical practice. The most commonly used tests for death determination were flat arterial line tracing, flat electrocardiogram (standard 3-lead electrocardiogram), and fixed and dilated pupils. Rarely used tests were absence pulse by echo Doppler, absent blood pressure by noninvasive monitoring, and unresponsiveness to painful stimulus. No diagnostic test or procedure was uniformly performed, but 80% of respondents perceived a need for standardization of death determination. Autoresuscitation was witnessed by 37%, after withdrawal of treatment or after unsuccessful resuscitation. CONCLUSIONS: Extensive variability in the practice of determining death after circulatory arrest exists, and a need for guidelines and standardization, especially if organ donation follows death, is reported. Autoresuscitation is reported; this observation requires attention in further prospective observational studies. PMID- 26431639 TI - Reactive transport of uranium in fractured crystalline rock: Upscaling in time and distance. AB - Batch adsorption and breakthrough column experiments were conducted to evaluate uranium transport through altered material that fills fractures in a granite rock system at the Grimsel Test Site in Switzerland at pH 6.9 and 7.9. The role of adsorption and desorption kinetics was evaluated with reactive transport modeling by comparing one-, two-, and three-site models. Emphasis was placed on describing long desorption tails that are important for upscaling in time and distance. The effect of increasing pH in injection solutions was also evaluated. For pH 6.9, a three-site model with forward rate constants between 0.07 and 0.8 ml g(-1) h(-1), reverse rate constants between 0.001 and 0.06 h(-1), and site densities of 1.3, 0.104, and 0.026 MUmol g(-1) for 'weak/fast', 'strong/slow', and 'very strong/very slow' sites provided the best fits. For pH 7.9, a three-site model with forward rate constants between 0.05 and 0.8 mL g(-1) h(-1), reverse rate constants between 0.001 and 0.6 h(-1), and site densities of 1.3, 0.039, and 0.013 MUmol g(-1) for a 'weak/fast', 'strong/slow', and 'very strong/very slow' sites provided the best fits. Column retardation coefficients (Rd) were 80 for pH 6.9 and 10.3 for pH 7.9. Model parameters determined from the batch and column experiments were used in 50 year large-scale simulations for continuous and pulse injections and indicated that a three-site model is necessary at pH 6.9, although a Kd-type equilibrium partition model with one-site was adequate for large scale predictions at pH 7.9. Batch experiments were useful for predicting early breakthrough times in the columns while column experiments helped differentiate the relative importance of sorption sites and desorption rate constants on transport. PMID- 26431640 TI - Carbon storage potential by four macrophytes as affected by planting diversity in a created wetland. AB - Wetland creation has become a commonplace method for mitigating the loss of natural wetlands. Often mitigation projects fail to restore ecosystem services of the impacted natural wetlands. One of the key ecosystem services of newly created wetlands is carbon accumulation/sequestration, but little is known about how planting diversity (PD) affects the ability of herbaceous wetland plants to store carbon in newly created wetlands. Most mitigation projects involve a planting regime, but PD, which may be critical in establishing biologically diverse and ecologically functioning wetlands, is seldom required. Using a set of 34 mesocosms (~1 m(2) each), we investigated the effects of planting diversity on carbon storage potential of four native wetland plant species that are commonly planted in created mitigation wetlands in Virginia - Carex vulpinoidea, Eleocharis obtusa, Juncus effusus, and Mimulus ringens. The plants were grown under the four distinctive PD treatments [i.e., monoculture (PD 1) through four different species mixture (PD 4)]. Plant biomass was harvested after two growing seasons and analyzed for tissue carbon content. Competition values (CV) were calculated to understand how the PD treatment affected the competitive ability of plants relative to their biomass production and thus carbon storage potentials. Aboveground biomass ranged from 988 g/m(2) - 1515 g/m(2), being greatest in monocultures, but only when compared to the most diverse mixture (p = 0.021). However, carbon storage potential estimates per mesocosm ranged between 344 g C/m(2) in the most diverse mesocosms (PD 4) to 610 g C/m(2) in monoculture ones with no significant difference (p = 0.089). CV of E. obtusa and C. vulpinoidea showed a declining trend when grown in the most diverse mixtures but J. effusus and M. ringens displayed no difference across the PD gradient (p = 0.910). In monocultures, both M. ringens, and J. effusus appeared to store carbon as biomass more effectively than the other species, suggesting that the choice of plant species may play an important role in facilitating the development of carbon accumulation/storage in created wetlands. Plant community diversity provides many ecosystem services (e.g., habitat and floristic quality) other than carbon storage function. Thus, a further study is needed that will focus on investigating how other design elements such as microtopography and hydrologic connectivity may interact with PD in terms of enhancing the carbon storage potential of newly created wetlands. PMID- 26431641 TI - Stakeholder demands and corporate environmental coping strategies in China. AB - This paper examines how stakeholder demand and compliance capacity jointly shape corporate environmental coping strategies and subsequently environmental protection practices. A four-dimensional classification of coping strategies formalism, accommodation, referencing, and self-determination-is conceptualized. Drawing on survey and interview data collected from manufacturing enterprises in China between 2010 and 2012, the paper shows that compared with formalism and accommodation, coping strategies of referencing and self-determination are associated with stronger environmental protection practices. Enterprises adjust their coping strategies by taking into account the constraints defined by both their internal and external environments. The results also demonstrate the potential synergetic effects of state and non-state stakeholders working together in promoting better corporate environmental coping strategies and environmental practices in China. PMID- 26431642 TI - Evaluation of the stability of a nanoremediation strategy using barley plants. AB - This study evaluated the effectiveness of nZVI in reducing the availability of Cd, Cr or Zn in polluted soils. The influence of this nanoremediation process on the development of barley plants as well as its impact on soil properties and the stability of the metal immobilization afterwards were also evaluated in a greenhouse experiment. The application of nZVI reduced the availability of these metals in the soil, but the effectiveness of the immobilization and its stability depended on the metal chemical characteristics. Cadmium distribution in soil fractions showed an important change after the barley crop, favoring the immobilization of Cd in RS fraction for both nZVI-treated and untreated soils. The Cr immobilization was stable over the time studied and the doses of Cr were lethal for the barley plants. In contrast, the decrease of Cr availability reached after the nZVI treatment induced a reduction of soil phytotoxicity and an improvement in the development of the plants, which were able to complete their growing period. The Zn immobilization with nZVI was stable over time, but its effectiveness was moderate, and the growth of barley plants was poorer than that observed in the cases of Cd and Cr. Thus the best results of metal immobilization with nZVI were obtained for Cr-polluted soils. There was no overall increase of Fe in barley plants from nZVI-treated soils. In relation to the soil, no negative effects on its physico-chemical properties were observed after the time exposure with nZVI. Taking into account these results we can conclude that the use of nZVI is a promising remediation strategy, and its effectiveness would be conditioned to the soil properties and the bioavailable metal concentration. PMID- 26431643 TI - Evolutionary genetic consequences of facultative sex and outcrossing. AB - Explaining the selective forces that underlie different reproductive modes forms a major part of evolution research. Many organisms are facultative sexuals, with the ability to reproduce both sexually and asexually. Reduced sequencing costs means it is now possible to start investigating genome sequences of a wider number of these organisms in depth, but teasing apart the genetic forces underlying the maintenance of facultative sexual reproduction remains a challenge. An analogous problem exists when determining the genetic consequences of a degree of outcrossing (and recombination) in otherwise self-fertilizing organisms. Here, I provide an overview of existing research on the evolutionary basis behind different reproductive modes, with a focus on explaining the population genetic effects favouring low outcrossing rates in either partially selfing or asexual species. I review the outcomes that both self-fertilization and asexuality have on either purging deleterious mutations or fixing beneficial alleles, and what empirical data exist to support these theories. In particular, a greater application of mathematical models to genomic data has provided insight into the numerous effects that transitions to self-fertilization from outcrossing have on genetic architecture. Similar modelling approaches could be used to determine the forces shaping genetic diversity of facultative sexual species. Hence, a further unification of mathematical models with next-generation sequence data will prove important in exploring the genetic influences on reproductive system evolution. PMID- 26431644 TI - Relationship inference from the genetic data on parents or offspring: A comparative study. AB - Relationship inference in a population is of interest for many areas of research from anthropology to genetics. It is possible to directly infer the relationship between the two individuals in a couple from their genetic data or to indirectly infer it from the genetic data of one of their offspring. For this reason, one can wonder if it is more advantageous to sample couples or single individuals to study relationships of couples in a population. Indeed, sampling two individuals is more informative than sampling one as we are looking at four haplotypes instead of two, but it also doubles the cost of the study and is a more complex sampling scheme. To answer this question, we performed simulations of 1000 trios from 10 different relationships using real human haplotypes to have realistic genome-wide genetic data. Then, we compared the genome sharing coefficients and the relationship inference obtained from either a pair of individuals or one of their offspring using both single-point and multi-point approaches. We observed that for relationships closer than 1st cousin, pairs of individuals were more informative than one of their offspring for relationship inference, and kinship coefficients obtained from single-point methods gave more accurate or equivalent genome sharing estimations. For more remote relationships, offspring were more informative for relationship inference, and inbreeding coefficients obtained from multi-point methods gave more accurate genome sharing estimations. In conclusion, relationship inference on a parental pair or on one of their offspring provides complementary information. When possible, sampling trios should be encouraged as it could allow spanning a wider range of potential relationships. PMID- 26431646 TI - Research on curative effect of traditional Chinese medicine treating low-grade fever of children caused by respiratory system infection. AB - This study aims to explore the curative effect of traditional Chinese medicine treating low-grade fever of children caused by respiratory system infection. Sixty children who suffered low-grade fever caused by respiratory system infection were selected and divided into treatment group and control group randomly, each with 30 cases. Control group was treated with conventional methods including oxygen uptake, nebulization and anti-infection, etc, while treatment group was given boil-free granules of traditional Chinese medicine besides the treatment which control group received. Then clinical curative effect of two groups was compared. Results showed that 28 cases (93.3%) were cured in treatment group; while 21 cases (70.0%) were cured in control group. Compared with control group, the treatment group showed up better treatment efficiency and the difference between groups was of statistical significance (P<0.05). Comparison of results of two groups suggested that, traditional Chinese medicine granules has satisfactory curative effect in the treatment of low-grade fever of children caused by respiratory system infection; characterized by short treatment cycle and effective treatment effect, Chinese medicine granules in the combination with oxygen atomization inhalation is proved to be able to efficiently remit symptoms such as coughing, gasp and labored breathing, with outstanding curative effect in the treatment of low-grade fever of children caused by respiratory system infection, thus it is worthy of popularization and application clinically. PMID- 26431645 TI - Activity-triggered tetrapartite neuron-glial interactions following peripheral injury. AB - Recent studies continue to support the proposition that non-neuronal components of the nervous system, mainly glial cells and associated chemical mediators, contribute to the development of neuronal hyperexcitability that underlies persistent pain conditions. In the event of peripheral injury, enhanced or abnormal nerve input is likely the most efficient way to activate simultaneously central neurons and glia. Injury induces phenotypic changes in glia and triggers signaling cascades that engage reciprocal interactions between presynaptic terminals, postsynaptic neurons, microglia and astrocytes. While some responses to peripheral injury may help the nervous system to adapt positively to counter the disastrous effect of injury, the net effect often leads to long-lasting sensitization of pain transmission pathways and chronic pain. PMID- 26431647 TI - Effect of estrogen on recovering the injured nervous system. AB - Estrogen plays an important role in the recovery of injured nervous system. This study aims to discuss the effect of estrogen on glial cells in spinal cord and apoptosis of neuron at different time points with a hope to lay theoretical basis on treating acute spinal cord injury (SCI) in clinic. Totally 72 adult rats were divided into a simple injury group and an estrogen group. Then several animal models with SCI were prepared. The estrogen group was treated with intramuscular injection of 100 ug/kg estrogen every day till the death of animal models, while the simple injury group was treated with intramuscular injection of 0.5 mL saline every day. Then these animals were put to death in the 1st d, 3rd d, 5th d, 8th d, 14th d and 21st d after SCI respectively and tissue sections were prepared, followed by B-cell lymphoma-2 (Bcl-2) detection, Terminal Deoxynucleotidyl Transferase-mediated dUTP nick-end labeling (TUNEL) and detection of the cell apoptosis in animal models after SCI. In the 14th d after the injury of spinal cord nervous system, Gale grading and inclined plate maintenance tests were carried out. In the 1st d after SCI, there was a higher expression of Bcl-2 protein in the SCI tissues. Bcl-2 protein reached the peak in the 3rd d after SCI in the simple injured group, while the estrogen group reached the peak in the 8th d. At that time, Bcl-2 protein was both expressed in nerve cells, and in glial cells in a higher level. The expression began to decline in the 14th d after SCI, and with only a little expression in the 21st d after SCI (p<0.05). TUNEL detection results showed that, positive cells dominated by glial cells emerged in simple injured group only 24th h later; they reached the peak after 3~8 days, and then began to reduce. In the 21st d, positive cells still existed, and there was less cell apoptosis after treated with estrogen (p<0.05). Two weeks after SCI, Gale score and inclined plate maintenance rate were higher in the estrogen group than in the simple injured group (p<0.01). Adverse effects that occurred in injury group included blood dryness, necrosis, cyst cavity and cavity, while in estrogen group, adverse effects included focal bleeding, hydropic degeneration of neuron, disappearance of partial nissl bodies and neuraxial edema. All these findings suggest that, estrogen used for treating SCI can effectively inhibit the apoptosis of early nerve cells and glial cells in injured spinal cord nervous system by improving the micro-circulation, enhancing the expression of Bcl-2 protein, removing the free radicals and inhibiting the antioxidation. Thus, it can reduce the secondary SCI and promote the recovery of injured spinal cord nervous functions. PMID- 26431648 TI - Oxygen-driving and atomized mucosolvan inhalation combined with holistic nursing in the treatment of children severe bronchial pneumonia. AB - This paper aimed to discuss the method, effect and safety of oxygen-driving and atomized Mucosolvan inhalation combined with holistic nursing in the treatment of children severe bronchial pneumonia. Totally 90 children with severe bronchial pneumonia who were treated in our hospital from March 2013 to November 2013 were selected as the research objects. Based on randomized controlled principle, those children were divided into control group, test group I and test group II according to the time to enter the hospital, 30 in each group. Patients in control group was given conventional therapy; test group I was given holistic nursing combined with conventional therapy; test group II was given oxygen driving and atomized Mucosolvan inhalation combined with holistic nursing on the basis of conventional therapy. After test, the difference of main symptoms in control group, test group I and II was of no statistical significance (P>0.05). Test group II was found with the best curative effect, secondary was test group I and control group was the last. It can be concluded that, oxygen-driving and atomized Mucosolvan inhalation combined with holistic nursing has certain effect in the treatment of children severe bronchial pneumonia and is better than holistic nursing only. PMID- 26431649 TI - Drug-induced skin toxicity and clinical nursing of VitK cream on colorectal cancer patients. AB - To discuss the impact of 0.1% vitamin K1 (VitK1) cream on cetuximab-induced skin toxicity for colorectal cancer patients. 60 colorectal cancer patients with cetuximab therapy after hospitalization, were divided into experimental group (Ward A) and control group (Ward B) according to personnel sequential number, with 30 cases in each group. Routine nursing was implemented on control group. For experimental group, on the routine nursing basis, 0.1% VitK1 cream was smeared on face, neck, chest, back and nail (toenail) edge with three times one day at the application of cetuximab day. After cetuximab applied in 8 weeks, both skin itch and dry skin for patients in experimental group were significantly improved compared those in control group, showing statistically significant difference (W=708.000, P=0.001: W=662. 500, P=0.000). 0.1% VitK1 cream was conducive to improve both skin itch and dry skin symptoms in the cetuximab induced skin toxicity for colorectal cancer patients. PMID- 26431650 TI - Study on the clinical efficacy of Human Urinary Kalllikrein in the treatment of acute cerebral infarction according to TOAST classification. AB - To observe and evaluate the clinical efficacy of Human Urinary Kallikrein in the treatment of acute cerebral infarction (ACT) according to TOAST (The Trial of Org 10172 in Acute Stroke Treatment) classification. In accordance with randomized controlled trial, 110 patients with acute cerebral infarction were randomly assigned to kallikrein treatment group (55 cases) and control group (55 cases). TOAST classification and basic treatment were administrated on patients between two groups respectively. 0.15 PNA unit of Human Urinary Kallikrein injection plus 100 mL saline in intravenous infusion was performed in the kallikrein group, with once a day for 14 consecutive days. The National Institutes of Health Stroke Scale (NIHSS) scores in two groups were analyzed before and after the treatment. No difference was shown in the NIHSS scores before treatment among patients between two groups (P>0.05). While after the treatment, the NIHSS scores in both groups were reduced (P<0.05) and the NIHSS scores in the kallikrein treatment group were less than those in control group (P<0.05). Moreover, after the treatment, the NIHSS scores for large-artery atherosclerosis subtype (L) and small-artery occlusion lacunar subtype (S) as two subtypes of TOAST classification in the two groups were both reduced (P<0.05). After the treatment, NIHSS scores for L subtype in the kallikrein treatment were less than those in the control group (P<0.05). After the treatment, NIHSS scores for S subtype in the kallikrein treatment were less than those in the control group, without statistically significant difference. Comparisons on clinical efficacy indicated differences on the S subtype between two groups (P<0.05). The standardization effective rate was calculated, indicating 81.82% in the kallikrein treatment group and 54.55% in the control group, respectively. In TOAST classification, Human Urinary Kallikrein is able to remarkably improve the NIHSS scores for L subtype and S subtype patients with acute cerebral infarction and help to enhance the clinical efficacy. PMID- 26431651 TI - Comparative studies on antioxidant activity and polyphenolic content of Lycium barbarum L. and Lycium chinense Mill. leaves. AB - The purpose of this research was to bring new data regarding the phenolic composition and the antioxidant activity of L. barbarum L. and L. chinense Mill. leaves. The determination of the main polyphenolic compounds was performed using a HPLC-UV-MS method. The dominant compound found for both species was rutin, with its highest amount registered in L. chinense (24141.90+/-21.3 MU/g plant material) leaves. Among the flavonoidic aglycones, quercetin was found in both samples, being quantified in a higher amount in L. chinense. In the antioxidant assays, both extracts exhibited important antioxidant activities, as witnessed by the three methods, both correlated with their total polyphenolic content. PMID- 26431652 TI - Phytochemical and biological evaluation of Buddleja polystachya growing in Saudi Arabia. AB - Several Buddleja species were the target of phytochemical and biological studies; however, nothing was reported concerning the chemistry of Buddleja polystachya Fresen. growing in Saudi Arabia. Sixteen constituents were isolated from the aerial parts of B. polystachya using various chromatographic techniques and were identified by the help of different spectral techniques including 1D, 2D NMR and mass spectrometry. Moreover, the different fractions were evaluated for their anti-inflammatory and hypoglycemic activities. The isobenzofuranone derivative (4 hydroxy-7-methylisobenzofuranone) (4), has been isolated for the first time from this natural source, B. polystachya, along with fifteen known compounds namely; phenolic fatty acid ester, 1'(4-hydroxyphenyl) ethanol ester of docosanoic (1), uvaol (2), sakuranetin (3), kumatakenin (5), cirsimaritin (6), 5-hydroxy-3,7,4' trimethoxyflavone (7), oleanolic acid (8), herbacetin 3,7,8-trimethyl ether (9), ursolic acid (10), verbascoside (11), linarin (12), luteolin 7-O-beta-D-glucoside (13), luteolin 7-(6"-caffeoyl)-O-beta-D-glucopyranoside (14), luteolin (15), and 6-O-alpha-L-(4''-O-trans-cinnamoyl) rhamnopyranosylcatalpol (16). Regarding the biological activities investigated, the ethyl acetate fraction showed the most significant anti-inflammatory activity, followed by the n-butanol and the aqueous fractions. As for the petroleum ether and dichloromethane fractions, their anti inflammatory effects were moderate. The highest hypoglycemic activity was possessed by the ethyl acetate fraction, followed by the dichloromethane fraction and the n-butanol fraction showed the weakest activity. PMID- 26431653 TI - Clinical curative effect observation of therapy of Chinese drug iontophoresis in treatment of degenerative osteoarthropathy. AB - Degenerative osteoarthropathy is a kind of arthrosis induced by various factors, with main pathological feature of articular cartilage and syndesmophyte formation. In recent years, its morbidity increases year by year and tend to appear more among young people. Its curative effect has yet to be improved. This paper mainly discussed the clinical curative effect of therapy of Chinese drug iontophoresis in degenerative osteoarthropathy. A total of 296 cases of degenerative osteoarthropathy was randomly divided into two groups (with no consideration on gender): Chinese drug iontophoresis group: joint was treated by therapy of Chinese drug iontophoresis and MTZ-F experiment; frequency electrotherapy group: joint was only treated by medium frequency electrotherapy. Two groups were both treated for 30 min for one time, 1 time for a day, total for 4 weeks. Result of the study found that, total effective rate of medium frequency electrotherapy group was 74.3%, Chinese medicine iontophoresis group was 93.2%; curative effect of Chinese medicine iontophoresis group was superior to electrotherapy group. It indicates that, Chinese medicine iontophoresis has good clinical effect in the treatment of osteoarthropathy and deserves to be popularized and applied. PMID- 26431654 TI - Effectiveness evaluation of cardiovascular drugs based on CYP2C9 target protein. AB - This study is to discuss the effectiveness evaluation of cardiovascular drugs based on CYP2C9 target protein. Multilevel fuzzy comprehensive evaluation method was taken to evaluate the individualized medication effectiveness for cardiovascular drug under the function of CYP2P9 target protein. Then, it was established for the index system to affect drug efficacy and index weight was settled. This index system was applied on the study of valsartan drugs to evaluate the drug efficacy rate of sample. Results corresponded with the actual drug treatment, and received better verification. The beneficial exploration was performed for the effectiveness evaluation of individualized administration. PMID- 26431655 TI - Report: Clinical characteristics and treatment experience report of severe pulmonary infection after renal transplantation. AB - This study was to discuss the clinical diagnosis and treatment features of severe pulmonary infections after renal transplantation, in order to improve the cure rate. Retrospective research was applied to analyze the 52 cases of patients with serve pulmonary infection after renal transplantation in the department of organ transplantation in People's Hospital of Zhengzhou from July, 2008 to December, 2013. The pathogens which caused the pulmonary infection after renal transplantation were bacteria, virus, fungi, mycobacterium tuberculosis, combined infection and unknown pathogens, and the rate were respectively 28.85%, 15.38%, 7.69%, 3.85%, 21.15% and 23.08%. In the 52 cases, there were 41 cases of patients successfully survived, which was 78.85% and 11 cases died, which was 21.15%. The mortality rate of combined infection and unknown pathogens infection was significantly higher than that of single pathogen infection. Pulmonary infection after renal transplantation was of rapid deteriorated progress and high mortality rate. It was significant for patients to receive the comprehensive and integrated treatment. PMID- 26431656 TI - Study on antibacterial molecular drugs in Eucalyptus granlla wood extractives by GC-MS. AB - Eucalyptus granlla, which was one of dominant plantations in south China, was deemed as the important wood bio resources. However, the small molecules of Eucalyptus granlla wood weren't effectively reused. Thus the molecules of wood extractives in Eucalyptus granlla were extracted and studied so as to further utilize the resources. The result suggested that the optimal extraction time of ethanol/methanol extraction, petroleum ether/acetic ether extraction, and benzene/alcohol extraction were 5h, 7h and 4h, respectively. The wood extractives included hexanedioic acid, bis (2-ethylhexyl) ester, 3,3,7,11 tetramethyltricyclo[5.4.0.0(4,11)] undecan-1-ol, squalene, etc. and wood extractives of Eucalyptus granlla was suitable for extraction of 1,5-hexadien-3 yne and squalene. PMID- 26431657 TI - Proteomic analysis of Corylus heterophylla fisch in Changbai Mountain by shotgun approach. AB - Total proteins of Changbai Mountain hazelnut were extracted and then enzymolysed in solution. The mixture of peptides was separated on chromatograph and identified by shotgun proteomics approach. The identified proteins were analyzed by bioinformatics, 303 proteins were identified, of which 237 proteins (78.2%) were mainly distributing in a range of 10-70 kDa and 85 proteins (28.1%) were around pI 5-6. Based on the biological process cellular component and molecular function, these proteins were classified by Gene Ontology, the results showed that 183 proteins (73.8%) had catalytic activity (e.g. oxidoreductase, kinase, peptidase, etc.), and 170 proteins (68.5%) had binding activity. The protein profile provided a valuable basis for further research of hazelnut proteins and opened up new research avenues related to the function of these proteins. PMID- 26431658 TI - Comparison of clinical effect of dopamine and norepinephrine in the treatment of septic shock. AB - This study aims to compare the clinical effect of dopamine and nor epinephrine in the treatment of septic shock. Fifty cases with septic shock were randomly divided into two groups. Patients in both two groups revived after taking effective liquid. Then dopamine was pumped into central veins of patients in the research group (group DA) in 2 MU/(kg*min) upon the conventional treatment, while nor epinephrine was pumped into patients in the control group (group NE) in 0.1 MU/(kg*min), besides conventional treatment. The improvement of haemodynamics and microcirculation perfusion indexes were compared between two groups before and after treatment, as well as the improvement of tissue oxygen metabolism. The results demonstrated that, central venous pressure (CVP), mean arterial pressure (MAP), urine volume and central venous oxygen saturation (Scv O2) in both groups before treatment was not statistically significant (P>0.05); 6 h after treatment, CVP, MAP, urine volume and Scv O2 of group NE were higher than group DA; 12h and 24h after treatment, blood lactic acid clearance of group NE was superior than group DA (P<0.05). All the above findings suggested that, both dopamine and nor epinephrine are beneficial to improve microcirculation and tissue oxygen metabolism in the treatment of septic shock, and the clinical effect of nor epinephrine was distinctly better than dopamine. PMID- 26431659 TI - Hemorheological study and treatment with enema retention of Li Chong Tang combined with moxibustion in women suffering from chronic pelvic inflammatory diseases. AB - The study was undertaken to investigate the blood stasis of chronic pelvic inflammatory disease (PID) with scientific method, hemorheology. The whole blood viscosities of chronic PID increased significantly compared with normal level, which was consistent with the blood stasis of Traditional Chinese Medicine (TCM) theory. Moreover, sixty women suffering from chronic PID were treated with Enema Retention of Li Chong Tang Combined with Moxibustion (ERM) for 6 weeks. The chronic PID score and the whole blood viscosity were evaluated before and after the ERM. The parameters of whole blood viscosities at low, median and high shear rate of chronic PID group decreased from 12.32+/-0.31, 6.66+/-0.13 and 5.15+/ 0.52, to the normal levels, 9.19+/-0.13, 5.42+/-0.56 and 4.34+/-0.43 (p<0.05) after therapy of ERM and the symptoms score decreased from 13.73+/-3.7 to 3.8+/ 1.4 (p<0.05), which shows that the ERM is an effective therapy method to treat chronic PID. PMID- 26431660 TI - Clinical research on intravitreal injection of bevacizumab in the treatment of macula lutea and retinal edema of ocular fundus disease. AB - This paper aimed to explore clinically curative effect of intravitreal injection of bevacizumab in the treatment of macula lutea and retinal edema of ocular fundus disease. The number of 300 patients (390 eyes) with ocular fundus diseases including retinal vein occlusion (RVO), diabetic retinopathy (DR), age-related macular degeneration (ARMD), central serous chorioretinopathy (CSC), choridal new vessel (CNV) received and cured in the hospital from February 2010 to February 2014 were given intravitreal injection of bevacizumab (1.5mg) with once per month and a total of 2-3 times. Results of patients' vision and fluorescence fundus angiography (FFA), optical coherence tomography (OCT) before and after treatment were compared and curative effects were evaluated. Vision of 349 eyes (89.49%) improved obviously with the average of more than 2 lines, patient's intraocular pressure (IOP) was normal and all indexes were clearly better; vision of 26 eyes (6.67%) was stable before the treatment and without any changes after the treatment, the situation of fundus got better without increased IOP; vision of 15 eyes (3.85%) decreased to some extent, and the symptoms eased slightly after symptomatic treatment. In the 1st day after intravitreal injection, best corrected visual acuity increased to 0.239+/-0.175, best-corrected visual acuity in 1 m was 0.315+/-0.182, in 3m continuously climbed to 0.350+/-0.270, and in 6 m was 0.362+/-0.282. Compared with vision before injection, t value was t=3.184, t=7.213, t=9.274 and t=9.970 (P=0.002, P=0.000, P=0.000 and P=0.000) respectively, and all P were less than 0.01. Furthermore, the difference was significant if a=0.01, which could confirm that 1m best corrected visual acuity of patients after intravitreal injection improved clearly in combination with before injection and 3m and 6 m visions enhanced constantly after injection. To sum up, intravitreal injection of bevacizumab in treating ocular fundus disease improves patient's vision effectively, also relieves macula lutea, retinal edema and other symptoms obviously, and promotes the hemorrhage absorption of vitreous body and retina. PMID- 26431661 TI - Densitometric validation and analysis of biomarker beta-amyrin in different Acacia species (leaves) grown in Kingdom of Saudi Arabia by high performance thin layer chromatography. AB - Biomarker beta-amyrin was analyzed in the leaves of four different Acacia species (A. salicina, A. loreta, A. hamulosa and A. tortilis) grown in Kingdom of Saudi Arabia by a validated HPTLC method. The chromatography was performed on glass backed silica gel 60 F254 HPTLC plates using solvents toluene: methanol (9:1, v/v) as mobile phase. The developed TLC plate was derivatized with anisaldehyde and scanned at 520 nm. A sharp peak of beta-amyrin was found at Rf=0.58+/-0.01. The r2 and the linear regression equation for beta-amyrin was found to be 0.991 and 19.913X+107.803, respectively in the concentration range of 100-800 ng. The percentage of beta-amyrin was found to be maximum 2.70% w/w in A. tortilis, 1.85% w/w in A. loreta and 1.80% w/w in A. hamulosa while it was totally absent in A. salicina. This study conceives maiden reporting of quantification of beta-amyrin in four different species of Acacia by validated HPTLC method. The developed method for the analysis of beta-amyrin was proved to be reproducible by statistical analysis hence it can be employed for further analysis of beta-amyrin in plasma, other biological fluids and in finished products available in the market. PMID- 26431662 TI - The curative effect of adefovir dipivoxil treating HBeAg negative chronic hepatitis B and treating HBeAg positive chronic hepatitis B combining interferon alpha-2b. AB - This study aimed to research the efficiency of adefovir dipivoxil in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B treatment and in combination with alpha-2b interferon in the treatment of HBeAg-positive chronic hepatitis B. A total of 102 cases of adult patients with HBeAg chronic hepatitis B were selected for testing. HBeAg negative chronic hepatitis B patients took 10mg adefovir dipivoxil capsules once daily, while positive chronic hepatitis B patients were randomly divided into either a treatment group or a control group. The treatment group was administrated with 10mg adefovir dipivoxil capsules, 1 time daily, and injected with 5 million U Recombinant Human Interferon alpha-2b through muscle every other day. The control group was treated with 10mg adefovir dipivoxil capsules, 1 time per day. We examined alanine aminotransferase (ALT) normalization and the Hepatitis B Virus (HBV)-DNA negative rate (undetectable rate), as well as, HBeAg / hepatitis B e antibody (HBeAb) sero-conversion rate to detect treatment effects. The results proved that after 6 months of medication therapy, the ALT normalization rate was 49.9% and the HBV-DNA negative conversion rate was 54.3%. 18 months into the treatment, showed an ALT normalization rate of 73.2%, while the HBV-DNA negative conversion rate grew to 76.8%. The use of adefovir dipivoxil treatment of the negative chronic HBV has a certain extent combined with alpha-2b Interferon therapy in treatment of HbeAg positive chronic hepatitis B. After a 48-week observation period, ALT normalization and HBV-DNA rate could not be measured, HBeAg/HBeAb sero-conversion rose higher, indicating that the treatment of the combined drugs is more efficient than taking adefovir dipivoxil by itself, and the data were comparable with the control group (P<0.05). Thus adefovir dipivoxil can greatly improve the restrain function to HBV-DNA and improve the immunity and control ability of the body, with obvious short-term effects, in combination with Interferon. PMID- 26431663 TI - In vivo anti-inflammatory, analgesic and antipyretic activities of a medicinal plant, Caesalpinia bonducella F. AB - This research examined antipyretic, anti-inflammatory, and analgesic activities of ethanolic extract of C. bonducella whole seeds in experimental albino rats. Three doses, 100, 200 and 400 mg/kg of the whole seed ethanolic extract prepared as a suspension in 2 ml of 2% gum acacia were used. Acute inflammatory and antipyretic activities were evaluated in experimental animals by carrageenan induced paw edema and brewer's yeast-induced pyrexia models, respectively. A significant (p<0.05) reduction in paw volumes, and pyrexia was noted in experimental animals when compared with control animals. The ethanol see extract (400 mg/kg) displayed in vivo anti-inflammatory, antipyretic and analgesic in terms of reduction in paw edema, % writhes inhibition and rectal temperature by (0.24+/-0.03), (31.38%) and (36.2+/-0.1), respectively. Overall the whole ethanolic seed extract at all tested concentrations produced significant (p<0.05) anti-inflammatory, antipyretic and analgesic activities. The results obtained in this study clearly indicated the ethno-medicinal potential of C. bonducella in curing pain and inflammation related disorders, supporting its efficacy as a natural analgesic, antipyretic and anti-inflammatory agent. PMID- 26431664 TI - Identification of essential regulatory elements responsible for the explicit expression of IL-28Ralpha and their effect on critical SNPs using in-Silico methods. AB - IL-28Ralpha and IL10Rbeta collectively construct a fully functional hetero dimeric receptor for type III interferons (IFNs). IL-28Ralpha is the private chain for type III IFNs since their involvement in any other pathway has not been reported yet and they are highly expressed in response to certain viral attack or cancers. IL-28Ralpha is specific in their expression pattern and it expresses within few cell types only. The regulatory mechanisms governing the expression of IL-28Ralpha at the molecular level are not completely known yet and need to be scrutinized at primary levels. In the present study, various in-silico techniques were applied and it was observed that AP1-2, STAT 1-6, P-53, LyF-1 (lymphoid transcription factor), c-Jun, PU.1, CREB (cAMP response element-binding), PLAG (pleotropic adenoma gene), MYOD (myoblast determination protein 1), NOFL and KLFS as transcription factors that are selected with preference. Interestingly AP-2, c Jun, LyF-1, STAT, NF-Y and P53 have also been reported in literature recently as some of the key regulatory elements as well. Based on the fact that interlinking between different interferon stimulation genes (ISGs) is also not very clear and induction of one type of interferon can affect the efficacy of the other, we found that IFN-lambda4 induction can increase the expression of IL-28Ralpha, similar to IFN-lambda3 but contrary to type I IFNs, which has either no effect on the expression of IL-28Ralpha or can down regulate its expression at higher concentrations (data not published). PMID- 26431665 TI - The expression and significance of XIAP and C-jun on Condyloma acuminatum. AB - Objective of the study was to investigate the expression and significance of XIAP and c-jun in Condyloma acuminatum. The immunohistochemistry SABC method was adopted to detect the expression of XIAP and c-jun in Condyloma acuminatum. The positive expression rate of XIAP and c-jun in Condyloma acuminatum was 80% (32/40) and 90% (36/40) separately and the intensity of expression was usually ++ ~ +++. While in control group, the positive expression rate of XIAP and c-jun was 27.8% (5/18) and 16.7 % (3/18) separately, and the intensity of expression was - ~ ++. There was statistical significance of the positive expression rate and the expression intensity of XIAP and c-jun between the two groups (P<0.05). Besides, the positive correlation existed between expression of XIAP and c-jun (r=0.306 P<0.01). The over-expression of XIAP and c-jun in Condyloma acuminatum may be associated with the growth of Condyloma acuminatum. PMID- 26431666 TI - Report: Clinical curative effect of traditional Chinese medicine combined with doxycycline in the treatment of genital Chlamydia trachomatis and Urea plasma urealyticum infections. AB - This paper aims to study clinical curative effect of traditional Chinese medicine combined with doxycycline in treating genital Chlamydia trachomatis (Ct) and Urea plasma urealyticum (Uu) infections. The observed subjects in this paper were 60 patients who had been randomly divided into two groups, among which the control group was treated with doxycycline and the treatment group with Chinese medicine combined with doxycycline. Results showed that the curative effect of the treatment group was much better than that of the control. So it is proved that Chinese medicine combined with doxycycline is worth promoting because it is a convenient and safe way, which does not easily produce drug-resistant strain. PMID- 26431667 TI - Review: Effect study of sex hormone in the multiple sclerosis of common neurological disorders. AB - Multiple sclerosis (MS) is one of most common neurological disorders, mainly affecting women. The central nervous system (CNS) of this autoimmune disease is characterized by intermittent or chronic damage to the myelin sheaths (demyelination), local inflammation and axonal degeneration. During the early relapsing/remitting stages of MS, myelin can regenerate. However, as the disease progresses, both amount and activity of regenerated axons becomes insufficient, leading to impaired axon conduction, neurodegeneration and the worsening symptoms. Epidemiological study found that distinct symptom alleviation of diseases at a certain periods would be shown in women during pregnancy. The following basic researches indicated that sex hormones especially progesterone can significantly reduce the disease severity, moreover, the protective effect of sex hormone on the nervous system has become the research focus. PMID- 26431668 TI - Treatment as usual and routine care in research and clinical practice. AB - Treatment as usual (TAU) or routine care in the context of psychotherapy has been used both as a control condition in clinical trials of evidence-based psychotherapy (EBP) and as a primary therapeutic intervention. This article considers TAU from both perspectives in which it is used and evaluated. First, the strengths, limitations, and sources of ambiguity of using TAUs as control conditions are discussed. Second, the evidence in behalf of TAUs is evaluated. Reviews of the effectiveness of TAUs when contrasted with EBPs and when evaluated in clinical applications and benchmarked against EBPs from clinical trials suggest that both broad classes of treatments are effective and often equally effective. The effectiveness of TAUs and the often similar outcomes evident in comparison to EBPs raise research as well as clinical issues. The article discusses research priorities for the evaluation of TAUs and clinical practices that can improve both EBPs and TAUs in patient care. PMID- 26431670 TI - The synthesis of recombinant membrane proteins in yeast for structural studies. AB - Historically, recombinant membrane protein production has been a major challenge meaning that many fewer membrane protein structures have been published than those of soluble proteins. However, there has been a recent, almost exponential increase in the number of membrane protein structures being deposited in the Protein Data Bank. This suggests that empirical methods are now available that can ensure the required protein supply for these difficult targets. This review focuses on methods that are available for protein production in yeast, which is an important source of recombinant eukaryotic membrane proteins. We provide an overview of approaches to optimize the expression plasmid, host cell and culture conditions, as well as the extraction and purification of functional protein for crystallization trials in preparation for structural studies. PMID- 26431669 TI - Live imaging of muscles in Drosophila metamorphosis: Towards high-throughput gene identification and function analysis. AB - Time-lapse microscopy in developmental biology is an emerging tool for functional genomics. Phenotypic effects of gene perturbations can be studied non-invasively at multiple time points in chronological order. During metamorphosis of Drosophila melanogaster, time-lapse microscopy using fluorescent reporters allows visualization of alternative fates of larval muscles, which are a model for the study of genes related to muscle wasting. While doomed muscles enter hormone induced programmed cell death, a smaller population of persistent muscles survives to adulthood and undergoes morphological remodeling that involves atrophy in early, and hypertrophy in late pupation. We developed a method that combines in vivo imaging, targeted gene perturbation and image analysis to identify and characterize genes involved in muscle development. Macrozoom microscopy helps to screen for interesting muscle phenotypes, while confocal microscopy in multiple locations over 4-5 days produces time-lapse images that are used to quantify changes in cell morphology. Performing a similar investigation using fixed pupal tissues would be too time-consuming and therefore impractical. We describe three applications of our pipeline. First, we show how quantitative microscopy can track and measure morphological changes of muscle throughout metamorphosis and analyze genes involved in atrophy. Second, our assay can help to identify genes that either promote or prevent histolysis of abdominal muscles. Third, we apply our approach to test new fluorescent proteins as live markers for muscle development. We describe mKO2 tagged Cysteine proteinase 1 (Cp1) and Troponin-I (TnI) as examples of proteins showing developmental changes in subcellular localization. Finally, we discuss strategies to improve throughput of our pipeline to permit genome-wide screens in the future. PMID- 26431671 TI - Characterizing Energy Expenditure During Sedentary Behavior After Stroke. AB - OBJECTIVES: To measure and calculate the energy expended by people with stroke during near sedentary behaviors (lying, supported and unsupported sitting, standing, wheelchair propulsion, walking), under controlled laboratory conditions, and to compare these values with the energy expenditure of 1.5 metabolic equivalent task (MET) within the definition of sedentary behavior. DESIGN: Cross-sectional cohort study. SETTING: Rehabilitation institutions. PARTICIPANTS: People with stroke (N=27; mean age, 61.0+/-11.7y), categorized at Functional Ambulation Categories (FAC) 0 to 5. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Energy expenditure (measured using indirect calorimetry) expressed in METs. The recorded values were calculated for every participant and averaged for each activity: lying, supported and unsupported sitting, standing, wheelchair propulsion, and walking. Calculations were done for the total group and categorized by the FAC. RESULTS: For the total group the mean METs +/- SDs were 1.04+/-.11 for sitting supported, 1.09+/-.15 for sitting unsupported, 1.31+/ .25 for standing, 1.91+/-.42 for wheelchair propulsion, and 2.52+/-.55 for walking. People with stroke in all FAC had METs values >1.5 when propelling a wheelchair or walking. CONCLUSIONS: Energy expenditure during typical sedentary behaviors (ie, sitting) is narrowly bounded at approximately 1.0 MET. Energy expenditure during sitting and standing was <=1.5 MET for all FAC, with the exception of FAC 0 (1.6 MET during standing). Independent wheelchair propulsion and walking can be categorized as light activities (>=1.5 MET). PMID- 26431672 TI - Bone metabolism induced by denture insertion in positron emission tomography. AB - 18F-fluoride positron emission tomography (PET) can identify subtle functional variation prior to the major structural change detectable by X-ray. This study aims to investigate the mechanobiological bone reaction around the abutment tooth and in the residual ridge, induced by insertion of removable partial denture (RPD) within two different groups of patients: patients without denture experience (Group 1) and patients with denture experience before (Group 2), using 18F-fluoride PET imaging technique. 18F-fluoride PET/computerised tomography (CT) scan was performed to examine the bone metabolic change in mandible before and after the RPD treatment. Region of interests (ROIs) were placed in alveolar bone around abutment tooth and in residual bone beneath the RPD. Standardised uptake value (SUV), reflecting the accumulation of 18F-fluoride, was measured for each ROI. In all subjects of Group 1, SUVs after insertion were higher than before in both alveolar bone and residual bone, while there was less significant change in SUV in subjects of Group 2. This study demonstrated using longitudinal 18F fluoride PET scans to effectively examine the bone metabolic change in mandible induced by occlusal loading after RPD insertion. Using this technique, within the six subjects in this study, it was shown that bone metabolism around abutment tooth and residual ridge increased after RPD insertion in case of first-time denture user, while there was no big change in the patient with experience of denture before. This study revealed the effectiveness of applying PET to evaluate bone metabolic activity as mechanobiological reaction. PMID- 26431673 TI - Chemically induced dimerization: reversible and spatiotemporal control of protein function in cells. AB - Small-molecule perturbation of biological systems is able to tackle biological problems that are not accessible by classical genetic interference methods. Chemically induced dimerization (CID) has been used as a valuable tool to study various biological processes. Recent years have seen tremendous progress in the development of orthogonal and reversible CID systems. These new systems allow control over protein function with unprecedented precision and spatiotemporal resolution. While the primary application of CID has been on dissecting signal transductions, new emerging approaches have extended the scope of this technique to elucidating membrane and protein trafficking. PMID- 26431674 TI - Bioinformatics Prediction and In Vitro Analysis Revealed That miR-17 Targets Cyclin D1 mRNA in Triple Negative Breast Cancer Cells. AB - Breast cancer is one of the most prevalent malignancies among women worldwide. Triple negative breast cancer (TNBC) is a type of breast cancer in which estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER-2) are not expressed. There is no targeted therapy for this type of cancer, and available therapies have poor therapeutic effects. Performing a preliminary research, we selected cyclin D1 (CCND1) gene of Wnt signaling pathway which is a target of miRNAs, a promising set of biomolecules in diagnosis and treatment of breast cancer. In this study using bioinformatic analyses, miR-17 was selected as it targets the 3'UTR of CCND1 gene with the highest score. Luciferase assay results also confirmed the bioinformatic prediction. Decreased expression of miR 17 in MDA-MB-231 cell line was observed using qRT-PCR method. After lentiviral transduction of miR-17 to the target cells, gene expression analysis showed decreased expression of CCND1 gene. We found miR-17 as an attractive molecule that after intensive research can probably be used as a biomarker in TNBC. PMID- 26431676 TI - Switching between Epigenetic States at Pericentromeric Heterochromatin. AB - Pericentromeric DNA represents a large fraction of the mammalian genome that is usually assembled into heterochromatin. Recent advances have revealed that the composition of pericentromeric heterochromatin is surprisingly dynamic. Indeed, high levels of histone H3 trimethylation on lysine 9 (H3K9me3) and DNA methylation normally characterize the repressive environment of this region. However, in specific tissues and in cancer cells, Polycomb proteins can occupy pericentromeric heterochromatin and act as a molecular sink for transcriptional regulators. Restoring heterochromatin methylation marks could, thus, be an important way to bring back normal gene expression programs in disease. Here, I discuss the potential mechanisms by which Polycomb complexes are recruited to pericentromeric DNA. PMID- 26431677 TI - Forecasting waste compositions: A case study on plastic waste of electronic display housings. AB - Because of the rapid succession of technological developments, the architecture and material composition of many products used in daily life have drastically changed over the last decades. As a result, well-adjusted recycling technologies need to be developed and installed to cope with these evolutions. This is essential to guarantee continued access to materials and to reduce the ecological impact of our material consumption. However, limited information is currently available on the material composition of arising waste streams and even less on how these waste streams will evolve. Therefore, this paper presents a methodology to forecast trends in the material composition of waste streams. To demonstrate the applicability and value of the proposed methodology, it is applied to forecast the evolution of plastic housing waste from flat panel display (FPD) TVs, FPD monitors, cathode ray tube (CRT) TVs and CRT monitors. The results of the presented forecasts indicate that a wide variety of plastic types and additives, such as flame retardants, are found in housings of similar products. The presented case study demonstrates that the proposed methodology allows the identification of trends in the evolution of the material composition of waste streams. In addition, it is demonstrated that the recycling sector will need to adapt its processes to deal with the increasing complexity of plastics of end-of life electronic displays while respecting relevant directives. PMID- 26431675 TI - Buried Treasure: Evolutionary Perspectives on Microbial Iron Piracy. AB - Host-pathogen interactions provide valuable systems for the study of evolutionary genetics and natural selection. The sequestration of essential iron has emerged as a crucial innate defense system termed nutritional immunity, leading pathogens to evolve mechanisms of 'iron piracy' to scavenge this metal from host proteins. This battle for iron carries numerous consequences not only for host-pathogen evolution but also microbial community interactions. Here we highlight recent and potential future areas of investigation on the evolutionary implications of microbial iron piracy in relation to molecular arms races, host range, competition, and virulence. Applying evolutionary genetic approaches to the study of microbial iron acquisition could also provide new inroads for understanding and combating infectious disease. PMID- 26431678 TI - The use of organic wastes at different degrees of maturity as carbon sources for denitrification of landfill leachate. AB - In this study different garden refuses were investigated to ascertain their efficiency to act as carbon sources in a denitrification system. Six different garden refuse materials were studied: commercial and domestic garden refuse raw (CGR RAW, DGR RAW), immaturely composted domestic and commercial garden refuse (DGR 10 and CGR 10 respectively), commercial garden refuse composted by Dome Aeration Technology and by "turned windrow" technology (DAT and TW). Different concentrations of synthetic nitrate solution were used to assess the efficiency of each substrate. The results demonstrate that all substrates were able to sustain the denitrification process. However, due to its higher C/N ratio the CGR RAW was the better performing of the materials, reaching 100% removal after 8 and 12h for the 100 and 500 mg L(-1) respectively and after 11 days for 2000 mg L( 1). Kinetic studies revealed that the zero-order reaction better describes the process indicating a denitrification rate independent from the nitrate concentrations investigated when 100 and 500 mg L(-1) of nitrate were used. The study demonstrated the suitability of organic municipal solid wastes to sustain denitrification, opening a new scenario towards a low cost and in situ solution for treatment of landfill leachate by using wastes, otherwise disposed of in landfill. PMID- 26431679 TI - Cooking and disgust sensitivity influence preference for attending insect-based food events. AB - Insects are energy-efficient and sustainable sources of animal protein in a world with insufficient food resources to feed an ever-increasing population. However, much of the western world refuses to eat insects because they perceive them as disgusting. This research finds that both animal reminder disgust and core disgust reduced people's willingness to attend a program called "Bug Appetit" in which insects were served as food. Additionally, people who were low in sensitivity to animal reminder disgust were more willing to attend this program after having been primed to think about cooking. Cooking is a process by which raw ingredients are transformed into finished products, reducing the "animalness" of meat products that renders them disgusting. Sensitivity to core disgust did not interact with cooking to influence willingness to attend the program. While prior research has emphasized that direct education campaigns about the benefits of entomophagy (the consumption of insects) can increase willingness to attend events at which insect-based food is served, this is the first demonstration that indirect priming can have a similar effect among a subset of the population. PMID- 26431680 TI - Relationships between nutrition-related knowledge, self-efficacy, and behavior for fifth grade students attending Title I and non-Title I schools. AB - The Social Cognitive Theory (SCT) is a widely used theory for nutrition education programming. Better understanding the relationships between knowledge, self efficacy, and behavior among children of various income levels can help to form and improve nutrition programs, particularly for socioeconomically disadvantaged youth. The purpose of this study was to determine the relationships between knowledge, self-efficacy, and behavior among fifth grade students attending Title I (>=40% of students receiving free or reduced school meals) and non-Title I schools (<40% of students receiving free or reduced school meals). A validated survey was completed by 55 fifth grade students from Title I and 122 from non Title I schools. Differences in knowledge, self-efficacy, and behavior scores between groups were assessed using t test and adjusted for variations between participating schools. Regression analysis was used to determine the relationships between knowledge, self-efficacy, and behavior. In adjusted models, the Title I group had significantly lower scores on several knowledge items and summary knowledge (P = 0.04). The Title I group had significantly lower scores on several behavior variables including intakes of fruits (P = 0.02), vegetables (P = 0.0005), whole grains (P = 0.0003), and lean protein (P = 0.047), physical activity (P = 0.002) and summary behavior (P = 0.001). However the Title I group scored higher on self-efficacy for meal planning (P = 0.04) and choosing healthy snacks (P = 0.036). Both self-efficacy (beta = 0.70, P < 0.0001) and knowledge (beta = 0.35, P = 0.002) strongly predicted behavior; however, only self-efficacy remained significant in the Title I group (self-efficacy, beta = 0.82, P = 0.0003; knowledge, beta = 0.11, P = 0.59). Results demonstrate disparities in nutrition knowledge and behavior outcomes between students surveyed from Title I and non-Title I schools, suggesting more resources may be necessary for lower income populations. Findings suggest that future nutrition interventions should focus on facilitating the improvement of children's self-efficacy. PMID- 26431683 TI - Individual differences in bitter taste preferences are associated with antisocial personality traits. AB - In two studies, we investigated how bitter taste preferences might be associated with antisocial personality traits. Two US American community samples (total N = 953; mean age = 35.65 years; 48% females) self-reported their taste preferences using two complementary preference measures and answered a number of personality questionnaires assessing Machiavellianism, psychopathy, narcissism, everyday sadism, trait aggression, and the Big Five factors of personality. The results of both studies confirmed the hypothesis that bitter taste preferences are positively associated with malevolent personality traits, with the most robust relation to everyday sadism and psychopathy. Regression analyses confirmed that this association holds when controlling for sweet, sour, and salty taste preferences and that bitter taste preferences are the overall strongest predictor compared to the other taste preferences. The data thereby provide novel insights into the relationship between personality and the ubiquitous behaviors of eating and drinking by consistently demonstrating a robust relation between increased enjoyment of bitter foods and heightened sadistic proclivities. PMID- 26431682 TI - Exogenous glucagon-like peptide-1 acts in sites supplied by the cranial mesenteric artery to reduce meal size and prolong the intermeal interval in rats. AB - Three experiments were done to better assess the gastrointestinal (GI) site(s) of action of GLP-1 on food intake in rats. First, near-spontaneous nocturnal chow meal size (MS), intermeal intervals (IMI) length and satiety ratios (SR = MS/IMI) were measured after infusion of saline, 0.025 or 0.5 nmol/kg GLP-1 into the celiac artery (CA, supplying the stomach and upper duodenum), cranial mesenteric artery (CMA, supplying small and all of the large intestine except the rectum), femoral artery (FA, control) or portal vein (PV, control). Second, infusion of 0.5 nmol/kg GLP-1 was tested after pretreatment with the GLP-1 receptor (GLP-1R) antagonist exendin-4(3-39) via the same routes. Third, the regional distribution of GLP-1R in the rat GI tract was determined using rtPCR. CA, CMA and FA GLP-1 reduced first MS relative to saline, with the CMA route more effective than the others. Only CMA GLP-1 prolonged the IMI. None of the infusions affected second MS or later eating. CA and CMA GLP-1 increased the SR, with the CMA route more effective than the CA route. CMA exendin-4 (3-39) infusion reduced the effect of CMA GLP-1. Finally GLP-1R expression was found throughout the GI tract. The results suggest that exogenous GLP-1 acts in multiple GI sites to reduce feeding under our conditions and that GLP-1R in the area supplied by the CMA, i.e., the small and part of the large intestine, plays the leading role. PMID- 26431684 TI - Focus on the future: Episodic future thinking reduces discount rate and snacking. AB - Obesity seems related to a preference for immediate gratification. By changing this focus on short term benefits to a more future-oriented outlook, delay discounting (impulsive decision making) can be changed by a manipulation of episodic future thinking (EFT). EFT comprises a vivid mental simulation of general future experiences. EFT may also affect consumption of unhealthy foods, which can be seen as a choice for immediate gratification. Recent research shows that future orientation should be tailored to the behavior at outcome. We therefore hypothesize that the effectiveness of EFT on food intake could be enhanced by making the content food-related. We conducted a 2 (future vs past thinking) by 2 (food vs non-food related thoughts) between-subject design experiment in female undergraduates (N = 94), to compare the efficacy of EFT versus the recalling of episodic past events in reducing discount rate and caloric intake. Content of imagery was either unrestricted or food-related. Participants engaged in EFT or control episodic imagery while snacks were offered to freely consume, and next the Monetary Choice Questionnaire was completed as a measure of delay discounting, while again being engaged in EFT or control imagery. Both types of EFT reduced delay discounting, however, only food-related EFT lead to more restricted caloric consumption. Thus, we found evidence that EFT reduced discount rate during decision making. However, in order to restrict caloric intake, EFT should entail food-related imagery. As discount rate and caloric intake were not related in the current sample, the underlying mechanism remains to be discovered. Results however suggest that EFT is a promising technique to resist immediate gratification. PMID- 26431685 TI - An (un)healthy poster: When environmental cues affect consumers' food choices at vending machines. AB - Environmental cues can affect food decisions. There is growing evidence that environmental cues influence how much one consumes. This article demonstrates that environmental cues can similarly impact the healthiness of consumers' food choices. Two field studies examined this effect with consumers of vending machine foods who were exposed to different posters. In field study 1, consumers with a health-evoking nature poster compared to a pleasure-evoking fun fair poster or no poster in their visual sight were more likely to opt for healthy snacks. Consumers were also more likely to buy healthy snacks when primed by an activity poster than when exposed to the fun fair poster. In field study 2, this consumer pattern recurred with a poster of skinny Giacometti sculptures. Overall, the results extend the mainly laboratory-based evidence by demonstrating the health relevant impact of environmental cues on food decisions in the field. Results are discussed in light of priming literature emphasizing the relevance of preexisting associations, mental concepts and goals. PMID- 26431686 TI - Meeting report: 28th International Conference on Antiviral Research in Rome, Italy. AB - The 28th International Conference on Antiviral Research (ICAR) was held in Rome, Italy from May 11 to 15, 2015. This article summarizes the principal invited lectures. Phillip Furman, the Elion award recipient, described the research leading to sofosbuvir. Dennis Liotta, who received the Holy award, described how an investigation into HIV entry inhibitors led to a new therapy for cancer patients. Erica Ollmann Saphire, winner of the Prusoff Young Investigator award, explored the world of viral proteins and how they remodel to perform different essential roles in viral replication. The keynote addresses, by Raffaele De Francesco and Michael Manns, reported on the remarkable progress made in the therapy of chronic HCV infections. A third keynote address, by Armand Sprecher, related the difficulties and successes of Medicins Sans Frontieres in West Africa ravaged by the Ebola outbreak. There were three mini-symposia on RNA Viruses, Antiviral Chemistry and Emerging Viruses. There was a good collection of talks on RNA viruses (norovirus, rabies, dengue, HEV, HCV, and RSV). A highlight of the chemistry was the preparation of prodrugs for nucleotide triphosphates as this opens a door to new options. The third mini-symposium emphasized how research work in the antiviral area is continuing to expand and needs to do so with a sense of urgency. Although this meeting report covers only a few of the presentations, it aims to illustrate the great diversity of topics discussed at ICAR, bringing together knowledge and expertise from the whole spectrum of antiviral research. PMID- 26431681 TI - Managing temptation in obesity treatment: A neurobehavioral model of intervention strategies. AB - Weight loss outcomes in lifestyle interventions for obesity are primarily a function of sustained adherence to a reduced-energy diet, and most lapses in diet adherence are precipitated by temptation from palatable food. The high nonresponse and relapse rates of lifestyle interventions suggest that current temptation management approaches may be insufficient for most participants. In this conceptual review, we discuss three neurobehavioral processes (attentional bias, temporal discounting, and the cold-hot empathy gap) that emerge during temptation and contribute to lapses in diet adherence. Characterizing the neurobehavioral profile of temptation highlights an important distinction between temptation resistance strategies aimed at overcoming temptation while it is experienced, and temptation prevention strategies that seek to avoid or minimize exposure to tempting stimuli. Many temptation resistance and temptation prevention strategies heavily rely on executive functions mediated by prefrontal systems that are prone to disruption by common occurrences such as stress, insufficient sleep, and even exposure to tempting stimuli. In contrast, commitment strategies are a set of devices that enable individuals to manage temptation by constraining their future choices, without placing heavy demands on executive functions. These concepts are synthesized in a conceptual model that categorizes temptation management approaches based on their intended effects on reward processing and degree of reliance on executive functions. We conclude by discussing the implications of our model for strengthening temptation management approaches in future lifestyle interventions, tailoring these approaches based on key individual difference variables, and suggesting high-priority topics for future research. PMID- 26431687 TI - Immediate loading of two freestanding implants placed by computer-guided flapless surgery supporting a mandibular overdenture with magnetic attachments. AB - PURPOSE: The present article describes a novel clinical procedure for mandibular overdentures supported by two freestanding implants loaded immediately after placement via computer-guided flapless surgery. METHODS: A conventional acrylic complete denture was fabricated, and CT scans obtained using the denture as a radiographic guide. Preoperative computer-assisted planning was performed using commercially available software, permitting simulation of implant placement at optimal positions. Using simulation data, a surgical guide was manufactured and used during surgery. The surgical guide was placed and local anesthesia injected for drilling of anchor pins to stabilize the surgical guide. The drilling protocol for each osteotomy site achieved an insertion torque greater than 35 Ncm. Immediately after implant placement, a keeper of the magnetic attachment was connected to each implant, and the magnetic assembly incorporated into the denture. The mucosal surface of the denture around the magnet was relieved to avoid excessive tissue pressure. The patients were instructed to wear the denture in place continually for the following 7 days. After six months of healing and follow-up, a final denture with a metal framework may be fabricated if necessary. CONCLUSION: A novel treatment protocol for immediately loaded implant-supported mandibular overdentures is described in detail. The protocol ensures secure precise and safe implant placement, successful osseointegration, and immediate improvement of oral health-related quality of life for patients with unstable complete dentures. PMID- 26431688 TI - Molecular characterization and specific detection of Anaplasma species (AP-sd) in sika deer and its first detection in wild brown bears and rodents in Hokkaido, Japan. AB - A previously undescribed Anaplasma species (herein referred to as AP-sd) has been detected in sika deer, cattle and ticks in Japan. Despite being highly similar to some strains of A. phagocytophilum, AP-sd has never been detected in humans. Its ambiguous epidemiology and the lack of tools for its specific detection make it difficult to understand and interpret the prevalence of this Anaplasma species. We developed a method for specific detection, and examined AP-sd prevalence in Hokkaido wildlife. Our study included 250 sika deer (Cervus nippon yesoensis), 13 brown bears (Ursus arctos yesoensis) and 252 rodents including 138 (Apodemus speciosus), 45 (Apodemus argenteus), 42 (Myodes rufocanus) and 27 (Myodes rutilus) were collected from Hokkaido island, northern Japan, collected during 2010 to 2015. A 770 bp and 382 bp segment of the 16S rRNA and gltA genes, respectively, were amplified by nested PCR. Results were confirmed by cloning and sequencing of the positive PCR products. A reverse line blot hybridization (RLB) based on the 16S rRNA gene was then developed for the specific detection of AP sd. The prevalence of AP-sd by nested PCR in sika deer was 51% (128/250). We detected this Anaplasma sp. for the first time in wild brown bears and rodents with a prevalence of 15% (2/13) and 2.4% (6/252), respectively. The sequencing results of the 16S rRNA and gltA gene amplicons were divergent from the selected A. phagocytophilum sequences in GenBank. Using a newly designed AP-sd specific probe for RLB has enabled us to specifically detect this Anaplasma species. Besides sika deer and cattle, wild brown bears and rodents were identified as potential reservoir hosts for AP-sd. This study provided a high throughput molecular method that specifically detects AP-sd, and which can be used to investigate its ecology and its potential as a threat to humans in Japan. PMID- 26431689 TI - Diversity of VP7 genes of G1 rotaviruses isolated in Iran, 2009-2013. AB - Genotype G1 of rotaviruses (RVs) is the most prevalent strain in human RV infections around the world. The present study evaluated genetic variations in the VP7 gene of RV G1 genotype isolates from Iran. Genetic and phylogenetic analyses indicated that RV strains from Iran clustered with G1 lineages IA, IC, and IIC, showing highest average of similarity versus reference sequences of the G1 lineages I and II. This study highlights the genetic pattern of G1 RV on the basis of distinct lineages and sublineages and indicates the importance of continuous monitoring on genetic variation and evolution pattern of G1 RV strains across the Iranian population for the final aim of RV vaccine introduction. PMID- 26431690 TI - A deep phylogeny of viral and cellular right-hand polymerases. AB - Right-hand polymerases are important players in genome replication and repair in cellular organisms as well as in viruses. All right-hand polymerases are grouped into seven related protein families: viral RNA-dependent RNA polymerases, reverse transcriptases, single-subunit RNA polymerases, and DNA polymerase families A, B, D, and Y. Although the evolutionary relationships of right-hand polymerases within each family have been proposed, evolutionary relationships between families remain elusive because their sequence similarity is too low to allow classical phylogenetic analyses. The structure of viral RNA-dependent RNA polymerases recently was shown to be useful in inferring their evolution. Here, we address evolutionary relationships between right-hand polymerase families by combining sequence and structure information. We used a set of 22 viral and cellular polymerases representing all right-hand polymerase families with known protein structure. In contrast to previous studies, which focused only on the evolution of particular families, the current approach allowed us to present the first robust phylogenetic analysis unifying evolution of all right-hand polymerase families. All polymerase families branched into discrete lineages, following a fairly robust adjacency pattern. Only single-subunit RNA polymerases formed an inner group within DNA polymerase family A. RNA-dependent RNA polymerases of RNA viruses and reverse transcriptases of retroviruses formed two sister groups and were distinguishable from all other polymerases. DNA polymerases of DNA bacteriophages did not form a monophyletic group and are phylogenetically mixed with cellular DNA polymerase families A and B. Based on the highest genetic variability and structural simplicity, we assume that RNA dependent RNA polymerases are the most ancient group of right-hand polymerases, in agreement with the RNA World hypothesis, because RNA-dependent RNA polymerases are enzymes that could serve in replication of RNA genomes. Moreover, our results show that protein structure can be used in phylogenetic analyses of distantly related proteins that share only limited sequence similarity. PMID- 26431691 TI - Demographic and developmental differences in the content and sequence of adolescents' ideal romantic relationship behaviors. AB - This study utilizes data from 18,392 respondents (aged 12-19) in Wave 1 of the National Longitudinal Study of Adolescent to Adult Health (Add Health) to provide a detailed descriptive analysis of U.S. adolescents' desired behaviors in their ideal romantic relationships. Age, gender, and ethnic group differences in the desire for--and preferred sequence of--a set of activities that could occur in a hypothetical romantic relationship were explored within subsets of heterosexual (n = 17,274) and sexual minority adolescents (n = 1118). Non-sexual behaviors were more commonly desired compared to sexual behaviors. The typical desired behavioral sequence was: holding hands, going out alone, telling others they were a couple, kissing, saying "I love you," sexual touching, and finally having sex. Overall, more similarities than differences emerged across groups, with some notable differences in the percentages who desired sexual behaviors. Results provide a nuanced picture of adolescent relationship scripts, with implications for education and prevention. PMID- 26431692 TI - Maternal separation activates microglial cells and induces an inflammatory response in the hippocampus of male rat pups, independently of hypothalamic and peripheral cytokine levels. AB - Adult animals subjected to chronic stress show an inflammatory response in the hippocampus which has been related to cognitive dysfunction and psychopathology. However the immediate consequences of early life stress on hippocampal glial cells have not been studied. Here we analyzed the effects of maternal separation (MS) on astrocyte and microglial cell morphology in the hippocampal hilus, compared the expression of cytokines in the hippocampus and hypothalamus, and the peripheral response of cytokines, on postnatal day (PD) 15. Male rat pups of MS (3h/day, PD1-PD14) and Control (CONT) pups showed similar microglial cell densities in the hilus, but MS pups presented more activated microglia. MS decreased astrocyte density and the number of processes in the hilus. Cytokine mRNA expression (qPCR) was analyzed in MS and CONT groups, sacrificed (i) under basal (B) conditions or (ii) after a single stress event (SS) at PN15. In hippocampal extracts, MS increased IL-1beta mRNA, under B and SS conditions while IL-6 and TNF-alpha did not change. In hypothalamic tissue, MS increased TNF-alpha and IL-6 mRNA, but not IL-1b, after SS. Peripheral concentrations of IL-1beta were decreased under B and SS conditions in MS; IL-6 concentration increased after SS in MS pups, and TNF-alpha concentration was unchanged. In conclusion, MS activates microglial cells and decreases astrocyte density in the hippocampus. A differential cytokine expression is observed in the hippocampus and the hypothalamus after MS, and after SS. Also, MS triggers an independent response of peripheral cytokines. These specific responses together could contribute to decrease hippocampal neurogenesis and alter the neuroendocrine axis. PMID- 26431693 TI - It takes two to tango: Phagocyte and lymphocyte numbers in a small mammalian hibernator. AB - Immunity is energetically costly and competes for resources with other physiological body functions, which may result in trade-offs that impair fitness during demanding situations. Endocrine mediators, particularly stress hormones, play a central role in these relationships and directly impact leukocyte differentials. To determine the effects of external stressors, energetic restraints and competing physiological functions on immune parameters and their relevance for fitness, we investigated leukocyte profiles during the active season of a small obligate hibernator, the edible dormouse (Glis glis), in five different study sites in south-western Germany. The highly synchronized yearly cycle of this species and the close adaptation of its life history to the irregular abundance of food resources provide a natural experiment to elucidate mechanisms underlying variations in fitness parameters. In contrast to previous studies on hibernators, that showed an immediate recovery of all leukocyte subtypes upon emergence, our study revealed that hibernation results in depleted phagocyte (neutrophils and monocytes) stores that recovered only slowly. As the phenomenon of low phagocyte counts was even more pronounced at the beginning of a low food year and primarily immature neutrophils were present in the blood upon emergence, preparatory mechanisms seem to determine the regeneration of phagocytes before hibernation is terminated. Surprisingly, the recovery of phagocytes thereafter took several weeks, presumably due to energetic restrictions. This impaired first line of defense coincides with lowest survival probabilities during the annual cycle of our study species. Reduced survival could furthermore be linked to drastic increases in the P/L ratio (phagocytes/lymphocytes), an indicator of physiological stress, during reproduction. On the other hand, moderate augmentations in the P/L ratio occurred during periods of low food availability and were associated with increased survival, but reproductive failure. In this case, the stress response probably represents an adaptive reaction that contributes to survival by activating energy resources. In contrast to our expectation, we could not detect an amplification of stress through high population densities. Summarized, results of our study clearly reveal that the leukocyte picture of active edible dormice responds sensitively to physiological conditions associated with hibernation, reproductive activity and food availability and can be linked to fitness parameters such as survival. Thus edible dormice represent an excellent model organism to investigate regulatory mechanisms of the immune system under natural conditions. PMID- 26431694 TI - Urological complications, vesicoureteral reflux, and long-term graft survival rate after pediatric kidney transplantation. AB - To describe a single-center experience with kidney transplantation and then study some donor and recipient features that may impact on graft survival and urological complication rates. We reviewed our database searching for pediatric patients who underwent kidney transplantation from August 1985 through November 2012. Preoperative data and postoperative complications were recorded. Graft survival rates were analyzed and compared based on the type of donor, donor's age from deceased donors, and recipients' ESRD cause. Kaplan-Meier curves with log rank and Wilcoxon tests were used to perform the comparisons. There were 305 pediatric kidney transplants. The mean recipient's age was 11.7 yr. The mean follow-up was 11.0 yr. Arterial and venous thrombosis rates were 1.6% and 2.3%, respectively, while urinary fistula and symptomatic vesicoureteral reflux were diagnosed in 2.9% and 3.6% of cases, respectively. Deceased kidney transplantation had a lower graft survival rate than living kidney transplantation (log rank, p = 0.005). Donor's age (p = 0.420) and ESRD cause (p = 0.679) were not significantly related to graft survival rate. In long-term follow-up, type of donor, but not donor's age, impacts on graft survival rate. ESRD cause has no impact on graft survival rate, showing that well-evaluated recipients may have good outcomes. PMID- 26431695 TI - Validation of the howRu and howRwe questionnaires at the individual patient level. AB - BACKGROUND: The howRu and howRwe are new short questionnaires which are meant to measure health-related quality of life and patient experience. However, validation at the individual patient level has not yet taken place. We aimed to investigate the validity of both questionnaires at the individual patient level. METHODS: In this prospective validation study, patients were asked to complete both questionnaires and comment on their answers in a semi-structured in-depth interview. Based on the transcribed interviews, a panel of 45 general practitioners and 45 patients filled out the questionnaires as they thought the patients had completed them. The questionnaires were considered valid instruments when a reliable and acceptable level of agreement was reached between the patient's score and the score of a review panel, defined as a concordance correlation coefficient (CCC) of >=0.70. Bland-Altman plots were also made. RESULTS: Ninety patients were included. The CCC of the howRu total score of the review panel and patients was 0.80 (95 % CI 0.73 to 0.86). Bland-Altman plots showed a mean difference of -0.96 and the limits of agreement ranged from -2.87 to 0.95. The CCC of the howRwe total score was 0.57 (95 % CI 0.42 to 0.69). The mean difference on the Bland-Altman plots was -0.54 and the limits of agreement ranged from -3.59 to 2.52. CONCLUSIONS: The howRu seems to be a valid questionnaire for measuring health-related quality of life at the individual patient level. We do not advice to use the tested version of the howRwe questionnaire for assessing patient experience at the individual patient level. TRIAL REGISTRATION: The study was registered at clinicaltrials.gov NCT01830803 . Registration date: 5 April 2013. PMID- 26431696 TI - Prevalence and characteristics of coronary artery anomalies in an adult population undergoing multidetector-row computed tomography for the evaluation of coronary artery disease. AB - BACKGROUND: Congenital coronary anomalies are uncommon with an incidence ranging from 0.17 % in autopsy cases to 1.2 % in angiographically evaluated cases. The recent development of ECG-gated multi-detector row computed tomography (MDCT) coronary angiography allows accurate and noninvasive depiction of coronary artery anomalies. METHODS: This retrospective study included 2572 patients who underwent coronary 64-slice MDCT coronary angiography from January 2008 to March 2012. Coronary angiographic scans were obtained with injection of 80 ml nonionic contrast medium. Retrospective gating technique was used to synchronize data reconstruction with the ECG signal. Maximum intensity projection, multi-planar reformatted, and volume rendering images were derived from axial scans. RESULTS: Of the 2572 patients, sixty (2.33 %) were diagnosed with coronary artery anomalies (CAAs), with a mean age of 53.6 +/- 11.8 years (range 29-80 years). High take-off of the RCA was seen in 16 patients (0.62 %), of the left main coronary artery (LMCA) in 2 patients (0.08 %) and both of them in 2 patients (0.08 %). Separate origin of the left anterior descending artery (LAD) and left circumflex artery (LCx) from left sinus of Valsalva (LSV) was found in 15 patients (an incidence of 0.58 %). In 9 patients (0.35 %) the right coronary artery (RCA) arose from the opposite sinus of Valsalva with a separate ostium. In 6 patients (0.23 %) an abnormal origin of LCX from the right sinus of Valsalva (RSV) was found with a further posterior course within the atrioventricular groove. A single coronary artery was seen in 3 patients (0.12 %). It originated from the right sinus of Valsalva in one patient and from LSV in two patients. In two other patients (0.08 %) the left coronary trunk originated from the RSV with separate ostium from the RCA. LCA originating from the pulmonary artery was found in one patient (0.04 %). A coronary artery fistula, which is a termination anomaly, was detected in 4 patients (0.15 %). DISCUSSION: Although these anomalies, which are remarkably different from the normal structure, exist as early as birth, they are incidentally encountered during selective angiography or at autopsy. The incidence in reported angiographic series ranges from 0.6 % to 1.3 %. Variations in the frequency of primary congenital coronary anomalies may possibly have a genetic background. The largest angiographic series of 126595 patients, by Yamanaka and Hobbs, reported a 1.3 % incidence of anomalous coronary artery. CONCLUSION: The results of this study support the use MDCT coronary angiography as a safe and effective noninvasive imaging modality for defining CAAs in an appropriate clinical setting, providing detailed three-dimensional anatomic information that may be difficult to obtain with invasive angiography. PMID- 26431697 TI - Parental views of children's physical activity: a qualitative study with parents from multi-ethnic backgrounds living in England. AB - BACKGROUND: Guidelines recommend children and young people participate in at least 60 min of physical activity (PA) every day, however, findings from UK studies show PA levels of children vary across ethnic groups. Since parents play an instrumental role in determining children's PA levels, this article aims to explore parental views of children's PA in a multi-ethnic sample living in a large city in the North-West of England. METHODS: Six single-ethnic focus groups were conducted with 36 parents of school-aged children (4 to 16 years) with a predominantly low socio-economic status (SES). Parents self-identified their ethnic background as Asian Bangladeshi (n = 5), Black African (n = 4), Black Somali (n = 7), Chinese (n = 6), White British (n = 8) and Yemeni (n = 6). Focus group topics included understanding of PA, awareness of PA guidelines, knowledge of benefits associated with PA and perceived influences on PA in childhood. Data were analysed thematically using QSR NVivo 9.0. RESULTS: Parents from all ethnic groups valued PA and were aware of its benefits, however they lacked awareness of PA recommendations, perceived school to be the main provider for children's PA, and reported challenges in motivating children to be active. At the environmental level, barriers to PA included safety concerns, adverse weather, lack of resources and lack of access. Additional barriers were noted for ethnic groups from cultures that prioritised educational attainment over PA (Asian Bangladeshi, Chinese, Yemeni) and with a Muslim faith (Asian Bangladeshi, Black Somali, Yemeni), who reported a lack of culturally appropriate PA opportunities for girls. CONCLUSION: Parents from multi-ethnic groups lacked awareness of children's PA recommendations and faced barriers to promoting children's PA out of school, with certain ethnic groups facing additional barriers due to cultural and religious factors. It is recommended children's PA interventions address influences at all socio-ecological levels, and account for differences between ethnic groups. PMID- 26431699 TI - The North Atlantic Oscillation system and plant phenology. AB - The onset of flowering in 78 wild and domesticated terrestrial plant species recorded in South Moravia (Czech Republic) from 1965 to 2014 was correlated with the North Atlantic Oscillation (NAO) index of the preceding winter. Flowering occurred significantly earlier following positive winter NAO phases (causing spring to be warmer than normal in Central Europe) in nearly all early-flowering (March, April) species; high Pearson correlation values were recorded in, e.g., goat willow, spring snowflake, golden bell, cornelian cherry, sweet violet, cherry plum, grape hyacinth, apricot, blackthorn, common dandelion, cherry, southern magnolia, common apple, cuckoo flower, European bird cherry, and cherry laurel. In contrast, the timing of later-flowering plant species (May to July) did not correlate significantly with the winter NAO index. It was found that local temperature is obviously a proximate factor of plant phenology, while the winter NAO is the ultimate factor, affecting temperature and other meteorological phenomena in Central Europe during spring season. PMID- 26431698 TI - The Impact of Bariatric Surgery on Polycystic Ovary Syndrome: a Systematic Review and Meta-analysis. AB - Bariatric surgery has been proven to be a successful management strategy for morbid obesity, but limited studies exist on its effect on polycystic ovary syndrome (PCOS). A comprehensive search of electronic databases was completed. Meta-analysis was performed on PCOS, hirsutism, and menstrual irregularity outcomes following bariatric surgery. Thirteen primary studies involving a total of 2130 female patients were identified. The incidence of PCOS preoperatively was 45.6 %, which significantly decreased to 6.8 % (P < 0.001) and 7.1 % (P < 0.0002) at 12-month follow-up and study endpoint, respectively. The incidences of preoperative menstrual irregularity and hirsutism both significantly decreased at 12-month and at study end follow-up. Bariatric surgery effectively attenuates PCOS and its clinical symptomatology including hirsutism and menstrual irregularity in severely obese women. PMID- 26431700 TI - Diurnal variations of airborne pollen concentration and the effect of ambient temperature in three sites of Mexico City. AB - Pollen is an important cause of allergic respiratory ailments in the Mexico City Metropolitan Area (MCMA). However, very little is known if ambient air temperature correlates with the early blooming of plants observed in other urban areas around the world. A research study was conducted during the dry season of 2012-2013 at three representative sites of the MCMA with different urban characteristics with the aim to understand the relationships between the profusion and diversity of pollen against temperature and other meteorological variables and degree of urbanization. Pollen samples were collected using a Hirst type trap sampler in the sites: Merced (highly urbanized), Iztapalapa (medium high urbanized) and Coyoacan (moderately urbanized). Urbanization levels were determined using a composite index based on population density, proportion of surface covered by construction and asphalt, and urban heat island intensity. A set of representative pollen sampling tapes were assayed under a light microscope at magnification of *1,000 and converted to grains per cubic meter. The most representative pollen types found in the three sites were, regardless of urbanization levels were: Fraxinus, Cupressaceae/Taxodiaceae, Casuarina, Alnus, Myrtaceae, and Pinus. Total pollen concentration was greatest in the moderately urbanized area, although earlier blooming took place at the highly urbanized zone. Total pollen concentration in the medium-high urbanized site has the lowest because the green areas in this zone of MCMA are few. In a diurnal basis, the most abundant pollen types peaked near midday or in the afternoon evening at the three sites. A Spearman test showed a positive correlation among bihourly pollen concentrations, temperature and relative humidity in all sites, but wind speed just correlated in Iztapalapa and Coyoacan. The results obtained suggest that Urban Heat Island Intensity can disturb flowering periods and pollen concentrations, largely in the highly urbanized areas. A principal components analysis established that the concentrations of each pollen type differed across the urbanization gradients. Additionally, it was found that a large number of allergenic pollens are produced by ornamental trees, some only recently introduced by urban planners. PMID- 26431701 TI - The effects of different levels of Chlorella microalgae on blood biochemical parameters and trace mineral concentrations of laying hens reared under heat stress condition. AB - This study was conducted to investigate the effect of different supplementation levels of Chlorella microalgae on serum metabolites and the plasma content of minerals in laying hens reared under heat stress condition (27.5-36.7 degrees C, variable). A total number of 378 (40 weeks of age, with mean body weight of 1390 +/- 120 g) were randomly allocated to six treatments with seven replicates. The birds were randomly assigned to 6 treatments (C, T1, T2, T3, T4, and T5) with 7 replicate cages of 9 birds. C. microalgae at the rates of 100, 200, 300, 400, and 500 ppm with water were offered to groups T1, T2, T3, T4, and T5, respectively, while group C served as a control. At 71 days of trial, blood samples (14 samples per treatment) were taken for measuring serum metabolites and at 72 days for plasma mineral analysis. The results of this experiment showed that the supplementation of 200-500 ppm C. microalgae decreased the serum content of cholesterol, triglycerides, and LDL (P < 0.05) whereas HDL content increased (P < 0.05) in the hens supplemented with C. microalgae (300 or 400 and 500 ppm). C. microalgae at rates of 300-500 ppm caused a marked (P < 0.05) increase in the plasma content of manganese or iodine and selenium but other minerals were not statistically different among treatments. Overall, from the results of the present experiment, it can be concluded that supplementation of C. microalgae at high rates was beneficial on blood parameters of laying hens reared under heat stress. PMID- 26431702 TI - Meniscus transplantation. AB - Understanding the structure and function of the meniscus is critical to understanding its role in overall knee joint function. Injury to, or removal of, meniscal tissue may be associated with articular cartilage wear, knee instability, and, ultimately, the progression of osteoarthritis. While every effort is made for preserving and/or repairing damaged meniscal tissue, in some cases, the meniscus is not amenable to repair after injury. For appropriately indicated patients with symptomatic meniscal deficiency, meniscus allograft transplantation is an excellent surgical solution aimed at reducing pain and improving function. Indications for meniscus allograft transplantation are limited, and concomitant procedures such as osteotomy for malalignment, ligamentous, and/or articular cartilage restoration may be necessary in order to ensure an optimal result following meniscus allograft transplantation. Surgical techniques for meniscus allograft transplantation are variable and include soft tissue fixation versus bone plug fixation versus bone bridge fixation. Outcomes following meniscus allograft transplantation are generally good to excellent, though reoperation rates are relatively high. The purpose of this article is to provide a concise review of recently published data on meniscus allograft transplantation, with a focus on recent outcomes studies. PMID- 26431703 TI - Transgenic Cotton-Fed Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) Affects the Parasitoid Encarsia desantisi Viggiani (Hymenoptera: Aphelinidae) Development. AB - Cotton cultivars expressing Cry proteins are widely used to control lepidopteran pests. The effects of transgenic plants containing insecticidal Cry proteins on non-target species must be comprehended for a better and rational use of this technology for pest management. We investigated the influence of the Bt cotton cultivars NuOPAL and FM 975 on biological parameters of Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae), a non-target pest of Bt cotton cultivars and on its parasitoid Encarsia desantisi Viggiani (Hymenoptera: Aphelinidae). The experiments were conducted in a climatized room, and the non-transgenic near isolines were used for rearing whiteflies as control hosts. The effects of the Bt cotton cultivars on the period of embryonic and larval development and the percentage of adult emergence of B. tabaci were assessed. The period required for embryonic, larval, and pupal development and the percentage of emergence and longevity of E. desantisi females were determined using Bt cotton-fed and non-Bt cotton-fed B. tabaci as hosts. Both Bt cotton cultivars resulted in a decrease of approximately 20% of adult emergence of B. tabaci. Differently, an increase of approximately 10% of adult emergence of E. desantisi was observed for parasitoids that used hosts fed with both Bt cotton cultivars. However, female parasitoid longevity decreased when their hosts were fed on Bt cotton cultivars. Our data suggest that the use of Bt cotton cultivars in association with the biological control agent E. desantisi could be functional for the management of B. tabaci in Bt cotton crops. PMID- 26431704 TI - Heavy metal concentrations and enzymatic activities in the functional zone sediments of Haizhou Bay, Lianyungang, Jiangsu, China. AB - Surface sediments were collected at 31 sites covering five functional zones of Haizhou Bay, Lianyungang, Jiangsu, China. Heavy metal concentrations and enzymatic activity of phosphatase and urease were determined on a dry-weight basis of sediments. Metal concentrations in sediments were comparable to the Chinese National Standard of Marine Sediment Quality and were as follows: Cu, 8.60-55.8 mg kg(-1); Zn, 107-384 mg kg(-1); Pb, 33.6-200 mg kg(-1); Cd, 0.24-2.57 mg kg(-1); Cr, 30.3-92.1 mg kg(-1); As, 12.9-110 mg kg(-1); Ni, 15.8-49.6 mg kg( 1); Mn, 379-1272 mg kg(-1); and Fe, 13,790-38,240 mg kg(-1). A geoaccumulation index (I geo) was calculated to help researchers understand the status of pollutants in the sediments. I geo showed that Cd and As contamination existed in the study area. The mobility of the metals and the relationship between heavy metal concentrations of chemical fractions and enzymatic activities were also investigated. Results showed that Cd and Mn had higher mobility than other metals, and enzymatic activities may play an important role in controlling the bioavailability and transformation trend of heavy metals from one fraction to another in sediments. PMID- 26431705 TI - Arsenic levels in immigrant children from countries at risk of consuming arsenic polluted water compared to children from Barcelona. AB - Arsenic is a highly toxic element that pollutes groundwater, being a major environmental problem worldwide, especially in the Bengal Basin. About 40% of patients in our outpatient clinics come from those countries, and there is no published data about their arsenic exposure. This study compares arsenic exposure between immigrant and native children. A total of 114 children (57 natives, 57 immigrants), aged 2 months to 16 years, were recruited and sociodemographic and environmental exposure data were recorded. Total arsenic in urine, hair, and nails and arsenic-speciated compounds in urine were determined. We did not find significant differences in total and inorganic arsenic levels in urine and hair, but in organic arsenic monomethylarsenic acid (MMA) and dimethylarsinous acid (DMA) in urine and in total arsenic in nails. However, these values were not in the toxic range. There were significant differences between longer than 5 years exposure and less than 5 years exposure (consumption of water from tube wells), with respect to inorganic and organic MMA arsenic in urine and total arsenic in nails. There was partial correlation between the duration of exposure and inorganic arsenic levels in urine. Immigrant children have higher arsenic levels than native children, but they are not toxic. At present, there is no need for specific arsenic screening or follow-up in immigrant children recently arrived in Spain from exposure high-risk countries. PMID- 26431706 TI - Seasonal and spatial evolution of trihalomethanes in a drinking water distribution system according to the treatment process. AB - This paper comparatively shows the influence of four water treatment processes on the formation of trihalomethanes (THMs) in a water distribution system. The study was performed from February 2005 to January 2012 with analytical data of 600 samples taken in Aljaraque water treatment plant (WTP) and 16 locations along the water distribution system (WDS) in the region of Andevalo and the coast of Huelva (southwest Spain), a region with significant seasonal and population changes. The comparison of results in the four different processes studied indicated a clear link of the treatment process with the formation of THM along the WDS. The most effective treatment process is preozonation and activated carbon filtration (P3), which is also the most stable under summer temperatures. Experiments also show low levels of THMs with the conventional process of preoxidation with potassium permanganate (P4), delaying the chlorination to the end of the WTP; however, this simple and economical treatment process is less effective and less stable than P3. In this study, strong seasonal variations were obtained (increase of THM from winter to summer of 1.17 to 1.85 times) and a strong spatial variation (1.1 to 1.7 times from WTP to end points of WDS) which largely depends on the treatment process applied. There was also a strong correlation between THM levels and water temperature, contact time and pH. On the other hand, it was found that THM formation is not proportional to the applied chlorine dose in the treatment process, but there is a direct relationship with the accumulated dose of chlorine. Finally, predictive models based on multiple linear regressions are proposed for each treatment process. PMID- 26431707 TI - Endovascular treatment of complex aortic aneurysms: prevalence of acute kidney injury and effect on long-term renal function. AB - OBJECTIVES: To analyse predictors for short- and long-term renal function changes after fenestrated and branched endovascular aortic repair (EVAR). METHODS: A total of 157 patients underwent fenestrated and branched EVAR. Procedural intra arterial iodinated contrast volume was documented. Serum creatinine and estimated glomerular filtration rate (eGFR) at baseline, during 48 h following EVAR, at discharge and latest moment of follow-up were recorded. Development of post-EVAR acute kidney injury (AKI; according to AKIN criteria), and potential risk factors for renal failure were recorded. Multivariate regression analyses were used to identify independent risk factors for AKI and eGFR decrease during follow-up. RESULTS: Forty-three patients (28 %) developed post-EVAR AKI. Long procedure time and occlusion of accessory renal arteries were independent risk factors for development of AKI. (odds ratio (OR) 1.005 per minute, 95 % CI 1.001-1.01; p = 0.025 and OR 3.02, 95 % CI 1.19-8.16; p = 0.029). Post-EVAR AKI was associated with a significantly increased risk for eGFR decrease at discharge and latest follow-up (hazard ratio (HR) 3.47, 95 % CI 1.63-7.36, p = 0.001 and HR 3.01, 95 % CI 1.56-5.80; p = 0.001). Iodinated contrast volume was not an independent risk factor for AKI or eGFR decrease during follow-up. CONCLUSION: Development of post EVAR AKI is an independent risk factor for long-term renal function decrease. KEY POINTS: * Longer procedure time is associated with an increased risk for AKI. * Renal perfusion defects on angiography are associated with increased risk for AKI. * Post-EVAR AKI is associated with higher probability for long-term eGFR decrease. * Iodinated contrast volume is not an independent risk factor for AKI. * Iodinated contrast volume is not an independent risk factor for long-term eGFR decrease. PMID- 26431708 TI - Safety and efficiency of femoral artery access closure with a novel biodegradable closure device: a prospective single-centre pilot study. AB - OBJECTIVES: Vascular closure devices can accelerate haemostasis after arteriotomy, but induce scarring. The aim of the study was to prospectively analyse the feasibility of a novel biodegradable arterial closure device (CD). METHODS: Two hundred fifty-five patients (183 male; age 36-98 years) with an access vessel diameter >3 mm received the biodegradable CD after endovascular therapy. Technical success rate, time-to-haemostasis (TTH) and time-to-ambulation (TTA) were measured. Puncture site complications were categorized as minor (local hematoma, minor bleeding) or major (pseudoaneurysm, embolization, dissection, thrombotic occlusion, hematoma/major bleeding requiring surgery, access site infection). RESULTS: Technical success was achieved in 98.8 % (252 cases); device failure occurred in three cases (1.2 %). The average TTH and TTA were 11.3 +/- 26.9 s and 73.0 +/- 126.3 min. The major complication rate was 1.6 %, with three pseudoaneurysms and one retroperitoneal bleeding. The minor complication rate was 2.0 %, with five small hematomas. Neither cardiovascular risk factors nor access vessel characteristics had statistically significant influence on adverse events. Re-puncture was uncomplicated in 32 cases after 155.0 +/- 128.8 days. CONCLUSIONS: Handling of the new biodegradable CD is safe. The complication rates are tolerably low and comparable to other CDs. Post-procedural sonography showed no significant palpable subcutaneous changes in the access site. KEY POINTS: * VCDs can increase time efficiency and patient comfort after intervention. * In this prospective single-centre-study, biodegradable CD was safe and easily applicable. * Its major and minor complication rates are comparable to other CDs. * Its mean time-to-haemostasis and time-to-ambulation were 11.3 +/- 26.9 s and 73.0 +/- 126.3 min. * Post-procedural sonography showed no significant palpable subcutaneous changes at the access site. PMID- 26431709 TI - Energy and protein requirements of non-descript breed hair lambs of different sex classes in the semiarid region of Brazil. AB - The aim of this study was to determine the energy and protein requirements of non descript breed hair lambs (NDB) reared under Brazilian semiarid conditions. Sixty animals from three sex classes (20 intact males, 20 castrated males, and 20 females) with an average initial body weight of 18.1 +/- 0.4 kg and an average age of 5 months were used. The nutritional requirements were estimated using the comparative slaughter. The animals in the final slaughter group were distributed in a completely randomized design with a 3 * 3 factorial scheme (three sex classes and three feeding levels: ad libitum feeding (positive energy balance), 70% feed restriction (maintenance level), and 80% feed restriction (negative energy balance)). The net energy requirement for maintenance (NEm) did not differ between sex classes (P > 0.05) and it was 68 kcal/kg of metabolic empty body weight (EBW(0.75))/day (P < 0.05). The coefficients for the nonlinear regression of retained energy (RE) on the empty body weight gain (EBWG) were not different among the different sex classes (P > 0.05). The net energy requirement for weight gain (NEg) was estimated by NEg (Mcal/day) = 0.29 * EBW(0.75) * EBWG(0.86) for all sex classes (P < 0.05). The net protein requirement for weight gain (NPg) was estimated by NPg (g/day) = 224.45 * EBWG - 0.025 * RE for all sex classes (P < 0.05). The NEg increased and the NPg decreased with the increase in body weight of NDB lambs. PMID- 26431710 TI - Weight gain potential affects pregnancy rates in bovine embryo recipients raised under pasture conditions. AB - The aim of the present study was to evaluate the effect of differences in body weight gain after embryo transfer on the pregnancy rates of crossbred heifers used as recipients and raised under a grazing system. The study was performed during the dry (April to September) and the rainy (October to March) seasons. The embryos transferred were produced by in vitro fertilization. The body weight of each recipient was measured immediately before the embryo transfer and 23 to 25 days later, when the diagnosis of pregnancy was performed by ultrasonography. The associations among initial body weight (IBW), daily body weight gain (DWG), season, and pregnancy rate were evaluated using a logistic procedure that included the effect of the IBW, season, and linear and quadratic effects of the DWG. Altogether, there was no effect of season and pregnancy rates did not change between the dry and rainy seasons (42.3 vs. 45.8%, respectively; P > 0.05). However, the pregnancy rate was greater in the recipients with daily body weight gains over 250 g/day, regardless of the season. In addition, the pregnancy rate of the recipients was better (P < 0.04) explained by a logistic regression model that included the linear and quadratic effects of the DWG. The probability of each heifer to become pregnant according to DWG is explained by the follow equation: P(y = 1) = (Exp((-1.06703 + 0.0108 * DWG - 0.00002 * DWG ^ 2)))/(1 + Exp((-1.6703 + 0.0108 * DWG - 0.00002 * DWG ^ 2))). In conclusion, body weight gain potential is a critical factor for the pregnancy rates of in vitro embryo recipients managed under grazing systems. PMID- 26431713 TI - Mentally ill man should not be forced to have foot amputation, judge rules. PMID- 26431711 TI - Effects of live weight at slaughter on fatty acid composition of Longissimus dorsi and Biceps femoris muscles of indigenous Lori goat. AB - This study aimed to determine fatty acid (FA) composition of Longissimus dorsi (LD) and Biceps femoris (BF) muscles of an Iranian indigenous goat (Lori goat) at two live weights at slaughter (LWS). Twenty male Lori goats (5 to 8 months) raised in nomadic system were slaughtered either at LWS less than 20 kg (light) or LWS more than 30 kg (heavy). Carcass dressing and FA composition of intramuscular fat of LD and BF muscles as well as cholesterol content of LD muscle were determined. Heavy goats had higher dressing percentage than light ones (42.7vs.39.3%, P < 0.01). The predominant n-6 FA were C18:2, and C20:4 while C22:5, C20:5, C18:3, C20:3, and C22:6 were the n-3 FA detected. Polyunsaturated and saturated FA contributed 22% and 36% of the total FA in both muscles, respectively. Palmitic acid (C16:0) of LD was higher in heavy compared to the light goats (P < 0.05). BF muscle had higher alpha-linolenic acid (18:3 n-3) as percentage than LD muscle (P < 0.05). The ratio of n-6/n-3 FA and polyunsaturated/saturated FA were 3.8 and 0.6, respectively. Cholesterol content of LD muscle of light and heavy goats were 71.2 +/- 16 and 59.5 +/- 14 mg per 100 g fresh meat respectively. In conclusion, desirable PUFA/SFA (0.6) and n-3/n-6 ratio (3.8) found in indigenous Lori goat propose healthy source of lean meat for the consumers. PMID- 26431712 TI - Ingestive behavior and physiological parameters of goats fed diets containing peanut cake from biodiesel. AB - The experiment was conducted to evaluate the ingestive behavior and physiological parameters of confined goats fed peanut cake instead of soybean meal in their feed. We used 40 goats that were 3/4 Boer, uncastrated, and 5 months of age on average, with an average initial weight of 15.6 +/- 2.7 kg. The treatments consisted of diets with different levels of peanut cake replacing soybean meal in the concentrate (0.0, 33.33, 66.67, and 100%). The experimental design was completely randomized, with four treatments and ten repetitions. For the evaluation of feeding behavior, single animals were observed every 5 min for 24 h on 3 days. The physiological responses (respiratory rate; heart rate; rectal temperature, obtained with a rectal thermometer; and surface temperature) of the animals were evaluated at 09:00 and 15:00 h. The replacement of soybean meal with peanut cake did not change (P > 0.05) feeding behavior. The physiological parameters of the animals (P < 0.05) were altered; however, the changes appeared to be unrelated to the diet and to be due to the weather conditions. Peanut cake can replace soybean meal at 100% without causing negative effects on the feeding behavior or physiological parameters of confined 3/4 Boer goats. PMID- 26431714 TI - Functional Characterization of Carrier-Mediated Transport of Pravastatin across the Blood-Retinal Barrier in Rats. AB - Systemically administered pravastatin effectively treats diabetic retinopathy without central nervous system side effects. The efflux transport mechanism of pravastatin from the brain has already been clarified. In this study, the influx of pravastatin across the blood-retinal and blood-brain barriers (BRB and BBB) and the efflux of pravastatin from the retina were investigated using rats. Pravastatin influx (blood-to-tissues) was assessed using the retinal and brain uptake index (RUI and BUI) methods, and microdialysis was performed to investigate the efflux (retina-to-blood) transport of pravastatin. The RUI and BUI values for [(3)H]pravastatin were lower than those expected based on its lipophilicity, suggesting that the influx transport across the BRB and BBB was less than the reverse-direction transport. The RUI and BUI values for [(3)H]pravastatin were significantly decreased by pravastatin, digoxin, and probenecid, indicating that pravastatin undergoes carrier-mediated influx transport in the blood-to-tissues direction across the BRB and BBB. After intravitreal injection, [(3)H]pravastatin and the bulk flow marker [(14)C]d mannitol were found to be eliminated biexponentially from the vitreous humor. The elimination rate constant of [(3)H]pravastatin during the terminal phase was 1.66 fold greater than that of [(14)C]d-mannitol. Efflux transport was reduced in the retinal presence of pravastatin, digoxin, and benzylpenicillin, suggesting that pravastatin is transported via efflux transporters. In conclusion, pravastatin is transported across the BRB via uptake and efflux transporters in both the blood to-retina and retina-to-blood directions, and the retina-to-blood transporters are dominant, based on the lower values of the RUI compared with the values expected from the lipophilicity. PMID- 26431715 TI - To feed or not to feed? PMID- 26431716 TI - Prebiotics: why definitions matter. AB - The prebiotic concept was introduced twenty years ago, and despite several revisions to the original definition, the scientific community has continued to debate what it means to be a prebiotic. How prebiotics are defined is important not only for the scientific community, but also for regulatory agencies, the food industry, consumers and healthcare professionals. Recent developments in community-wide sequencing and glycomics have revealed that more complex interactions occur between putative prebiotic substrates and the gut microbiota than previously considered. A consensus among scientists on the most appropriate definition of a prebiotic is necessary to enable continued use of the term. PMID- 26431717 TI - Microbial oils as food additives: recent approaches for improving microbial oil production and its polyunsaturated fatty acid content. AB - In this short review, we summarize the latest research in the production of polyunsaturated microbial oils that are of interest in food technology. The current research targets the productivity of oleaginous microorganisms, as well as the biosynthesis of particular polyunsaturated fatty acids (PUFAs). The most important efforts target the efficiency of the oleaginous machinery, via overexpression of key-enzymes involved in lipid biosynthesis, as well as the minimization of lipid degradation, by repressing genes involved in the beta oxidation pathway. The production of specific PUFAs is approached by homologous or heterologous expression of specific desaturases and elongases involved in PUFA biosynthesis in oleaginous microorganisms. New perspectives, such as the production of triacylglycerols of specific structure and the employment of adaptive experimental evolution for creating robust oleaginous strains able to produce PUFAs are also discussed. PMID- 26431719 TI - Adjunctive therapy with inhaled nitric oxide for severe acute chest syndrome in patients with sickle cell disease. PMID- 26431718 TI - Inhaled nitric oxide for acute chest syndrome in adult sickle cell patients: a randomized controlled study. AB - PURPOSE: Previous clinical trials suggested that inhaled nitric oxide (iNO) could have beneficial effects in sickle cell disease (SCD) patients with acute chest syndrome (ACS). METHODS: To determine whether iNO reduces treatment failure rate in adult patients with ACS, we conducted a prospective, double-blind, randomized, placebo-controlled clinical trial. iNO (80 ppm, N = 50) gas or inhaled nitrogen placebo (N = 50) was delivered for 3 days. The primary end point was the number of patients with treatment failure at day 3, defined as any one of the following: (1) death from any cause, (2) need for endotracheal intubation, (3) decrease of PaO2/FiO2 >= 15 mmHg between days 1 and 3, (4) augmented therapy defined as new transfusion or phlebotomy. RESULTS: The two groups did not differ in age, gender, genotype, or baseline characteristics and biological parameters. iNO was well tolerated, although a transient decrease in nitric oxide concentration was mandated in one patient. There was no significant difference in the primary end point between the iNO and placebo groups [23 (46 %) and 29 (58 %); odds ratio (OR), 0.8; 95 % CI, 0.54-1.16; p = 0.23]. A post hoc analysis of the 45 patients with hypoxemia showed that those in the iNO group were less likely to experience treatment failure at day 3 [7 (33.3 %) vs 18 (72 %); OR = 0.19; 95 % CI, 0.06 0.68; p = 0.009]. CONCLUSIONS: iNO did not reduce the rate of treatment failure in adult SCD patients with mild to moderate ACS. Future trials should target more severely ill ACS patients with hypoxemia. CLINICAL TRIAL REGISTRATION: NCT00748423. PMID- 26431722 TI - [Strategic considerations on the design and choice of animal models for non clinical investigations of cell-based medicinal products]. AB - For the development of medicinal products animal models are still indispensable to demonstrate efficacy and safety prior to first use in humans. Advanced therapy medicinal products (ATMP), which include cell-based medicinal products (CBMP), differ in their pharmacology and toxicology compared to conventional pharmaceuticals, and thus, require an adapted regime for non-clinical development. Developers are, therefore, challenged to develop particular individual concepts and to reconcile these with regulatory agencies. Guidelines issued by the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA) and other sources can provide direction.The published approaches for non-clinical testing of efficacy document that homologous animal models where the therapeutic effect is investigated in a disease-relevant animal model utilizing cells derived from the same species are commonly used. The challenge is that the selected model should reflect the human disease in all critical features and that the cells should be comparable to the investigated human medicinal product in terms of quality and biological activity. This is not achievable in all cases. In these cases, alternative methods may provide supplemental information. To demonstrate the scientific proof-of-concept (PoC), small animal models such as mice or rats are preferred. During the subsequent product development phase, large animal models (i.e. sheep, minipigs, dogs) must be considered, as they may better reflect the anatomical or physiological situation in humans. In addition to efficacy, those models may also be suitable to prove some safety aspects of ATMP (e.g. regarding dose finding, local tolerance, or undesired interactions and effects of the administered cells in the target tissue). In contrast, for evaluation of the two prominent endpoints for characterizing the safety of ATMP (i.e. biodistribution, tumorigenicity) heterologous small animal models, especially immunodeficient mouse strains, are favourable due to their tolerance to the human cell therapy product. The execution of non-clinical studies under the principles of good laboratory practice (GLP) increases the acceptance of the results by authorities and the scientific community. PMID- 26431720 TI - Very high volume hemofiltration with the Cascade system in septic shock patients. AB - PURPOSE: We compared hemodynamic and biological effects of the Cascade system, which uses very high volume hemofiltration (HVHF) (120 mL kg(-1) h(-1)), with those of usual care in patients with septic shock. METHODS: Multicenter, prospective, randomized, open-label trial in three intensive care units (ICU). Adults with septic shock with administration of epinephrine/norepinephrine were eligible. Patients were randomized to usual care plus HVHF (Cascade group), or usual care alone (control group). Primary end point was the number of catecholamine-free days up to 28 days after randomization. Secondary end points were number of days free of mechanical ventilation, renal replacement therapy (RRT) or ICU up to 90 days, and 7-, 28-, and 90-day mortality. RESULTS: We included 60 patients (29 Cascade, 31 usual care). Baseline characteristics were comparable. Median number of catecholamine-free days was 22 [IQR 11-23] vs 20 [0 25] for Cascade vs control; there was no significant difference even after adjustment. There was no significant difference in number of mechanical ventilation-free days or ICU requirement. Median number of RRT-free days was 85 [46-90] vs 74 [0-90] for Cascade vs control groups, p = 0.42. By multivariate analysis, the number of RRT-free days was significantly higher in the Cascade group (up to 25 days higher after adjustment). There was no difference in mortality at 7, 28, or 90 days. CONCLUSION: Very HVHF using the Cascade system can safely be used in patients presenting with septic shock, but it was not associated with a reduction in the need for catecholamines during the first 28 days. PMID- 26431723 TI - [Effect of autologous platelet concentrates on the anatomical and functional outcome of late stage macular hole surgery: A retrospective analysis]. AB - BACKGROUND: The macular hole (MH) is a disorder of the visual center of the retina in humans. An untreated MH leads to loss of central visual acuity and reading ability. Surgery for early-stage macular holes has been very successful for many years and leads to very good anatomical and functional results. Despite continuous improvement of surgical procedures, the outcome for the later stages of MH is still unsatisfactory. METHOD: In a retrospective analysis, we investigated the effect of autologous platelet concentrates in patients presenting later stages of MHs (stage III-IV) with respect to anatomic success (hole closure) and recovery of vision. The application of platelets was performed during retinal surgery (pars plana vitrectomy, ppV). In addition, selected platelet concentrates were qualitatively analysed for growth factors and platelet adhesion. RESULTS: In the first group, 74% of the patients showed a good anatomical macular hole closure. The analyses of the platelet concentrates indicated a possible wound-healing effect due to growth factors (e.g. the platelet-derived growth factor, PDGF) and lesser to the ability of the platelets to adhere after ristocetin administration. Further optimization of the production process of platelet concentrates and of the surgical procedure in the second group of patients showed an increase of the anatomical success (92%) and a very rapid increase of visual acuity within six weeks. DISCUSSION: In the past, the primary goal of MH surgery was to optimize the surgical procedures. Only few concepts focused on wound healing. Based on our data, we postulate the use of autologous platelet concentrates in MH surgery as a healing concept, which helps to increase the functional success of late-stage macular hole surgery. PMID- 26431724 TI - Gender aspects of recreational sun-protective behavior: results of a representative, population-based survey among Austrian residents. AB - PURPOSE: Lifetime risk for melanoma skin cancer is enlarged by sunlight exposure and reduced by sun protection. Austrian melanoma incidence and mortality rates are constantly rising with higher rates in males. Thus, we aimed at investigating gender-specific recreational sun exposure habits among the Austrian population. METHODS: We conducted a telephone survey among 1500 adults (50.5% females) representing sociodemographic characteristics of the Austrian population. Using a structured questionnaire, we studied gender-specific sun exposure-related knowledge, motives to tan, and behavior. RESULTS: Overall, using sunscreen, wearing sunglasses, and seeking shade were among the three most frequent sun safe measures. Basic skin health knowledge and tanning motives were similar among genders, although females protected themselves more. In general, sunburn occurrence (odds ratio [OR] = 1.4, 95% confidence interval [CI] = 1.0-1.8), skin type IV (OR = 2.4, 95% CI = 1.3-4.5), ex-/non-smoking (OR = 1.4-1.6, 95% CI = 1.0 2.1), low motives to tan (both OR = 1.3, 95% CI = 1.0-1.7), no outdoor sport (OR = 1.3, 95% CI = 1.0-1.7), all P < 0.05, as well as the use of sunscreen with lower SPF values (OR = 1.0-3.0, 95% CI = 1.4-4.3) and male gender (OR = 1.6, 95% CI = 1.2-2.0), both P < 0.001, increased the odds of practicing low sun protection. CONCLUSION: The results of this investigation suggest considering gender specificity when planning Public (Skin) Health-related educative campaigns and programs, for example, by highlighting the appearance-related benefits of sun light avoidance. PMID- 26431725 TI - Halomonas salicampi sp. nov., a halotolerant and alkalitolerant bacterium isolated from a saltern soil. AB - A Gram-stain-negative, halotolerant and alkalitolerant bacterium, designated strain BH103T, was isolated from saltern soil in Gomso, Korea. Cells of strain BH103T were strictly aerobic, motile, straight rods and grew at pH 7.0-10.8 (optimum, pH 8.5), at 10-55 degrees C (optimum, 28 degrees C) and at salinities of 0-23 % (w/v) NaCl (optimum, 14 % NaCl). Phylogenetic analyses based on 16S rRNA gene sequences indicated that strain BH103T belongs to the genus Halomonas, showing highest sequence similarity to Halomonas boliviensis LC1T (97.7 %), Halomonas neptunia Eplume1T (97.7 %), Halomonas variabilis IIIT (97.7 %), Halomonas alkaliantarctica CRSST (97.7 %), Halomonas olivaria TYRC17T (97.5 %), Halomonas titanicae BH1T (97.2 %) and Halomonas sulfidaeris Esulfide1T (96.2 %). The predominant ubiquinone was Q-9. The major fatty acids were C18 : 1omega7c, C16 : 1omega7c and/or iso-C15 : 0 2-OH, C16 : 0 and C12 : 0 3-OH. The major polar lipids were phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, aminophospholipid and an unknown phospholipid. The DNA G+C content of this novel isolate was 54.7 mol%. DNA-DNA relatedness between strain BH103T and H. boliviensis KACC 16615T, H. neptunia KCTC 2888T, H. variabilis KCTC 2889T, H. alkaliantarctica KCTC 22844T, H. olivaria DSM 19074T, H. titanicae JCM 16411T and H. sulfidaeris DSM 15722T was 45, 41, 39, 32, 38, 45 and 35 %, respectively. On the basis of polyphasic analysis from this study, strain BH103T represents a novel species of the genus Halomonas, for which the name Halomonas salicampi sp. nov. is proposed. The type strain is BH103T ( = KACC 17609T = NBRC 109914T = NCAIM B 02528T). PMID- 26431726 TI - Perspective: Medical Malpractice Roller Coaster. PMID- 26431727 TI - In Reply to the Letter to the Editor, "3-Dimensional Printing Rapid Prototyping for Intracranial Aneurysm Coiling: A Good Example of Precise Medicine". PMID- 26431728 TI - Postoperative Visual Loss After Spine Surgery and the Role of the Neurosurgeon. PMID- 26431729 TI - Medical Malpractice and Hollywood: Liability Magnified by the Lens of Celebrity. PMID- 26431730 TI - PIPA, RISA, ATPA & Co.: The Efforts We Spent on Convincing Others to Do the Best for our Patients with Petroclival Meningiomas. PMID- 26431731 TI - Technical Description of the Medial and Lateral Anterior Temporal Approach for the Treatment of Complex Proximal Posterior Cerebral Artery Aneurysms. AB - BACKGROUND: Posterior cerebral artery (PCA) aneurysms are often fusiform and associated with multiple intracranial aneurysms. A bypass procedure in combination with proximal occlusion or aneurysm trapping is considered to be effective for the treatment of patients with complex PCA aneurysms. Because of the deep, narrowed surgical corridor and the surrounding sensitive neuroanatomic structures, microsurgical procedures applied to the PCA are technically demanding. The authors present a technical report of a complex aneurysm formation located at the postcommunicating segment of the PCA (PCA-P2) treated via an anterior temporal approach. METHODS: A 68-year-old woman had an unruptured PCA-P2 aneurysm formation, which was discovered incidentally. The fusiform aneurysm shape of the distal aneurysm aggravated direct microsurgical and endovascular treatment. After an individual case discussion, the patient underwent a microsurgical clipping of the proximal P2 segment aneurysm and the distal PCA-P2 segment aneurysm was treated by trapping after the application of a superficial temporal artery (STA) to PCA-P2 bypass using an anterior temporal approach. RESULTS: Postoperative computed tomography angiography showed the exclusion of the proximal PCA-P2 aneurysm and an adequate flow from the STA to PCA-P2 bypass to the distal PCA segments. The patient showed a modified Rankin scale of 0 after follow-up at 1 and 3 months. CONCLUSIONS: The anterior temporal approach is feasible for the microsurgical management of complex postcommunicating PCA aneurysms and the application of bypass procedures. PMID- 26431732 TI - In Reply to the Letter to the Editor, "Trigeminal Lymphoma and Its Many Faces". PMID- 26431733 TI - Petrosectomy and Topographical Anatomy in Traditional Kawase and Posterior Intradural Petrous Apicectomy (PIPA) Approach: An Anatomical Study. AB - OBJECTIVE: To compare the anatomical exposure and petrosectomy extent in the Kawase and posterior intradural petrous apicectomy (PIPA) approaches. METHODS: Kawase and PIPA approaches were performed on 4 fixed cadaveric heads (3 alcohol fixed, 1 formaldehyde-fixed silicone-injected; 4 Kawase and 4 PIPA approaches). The microsurgical anatomy was examined by means of Zeiss Opmi CS/NC-4 microscopes. HD Karl Storz Endoscopes (AIDA system) were used to display intradural exposure. Petrosectomy volumes was assessed by comparing pre- and postoperative thin-slice computed tomography scans (Analyze 12.0; AnalyzeDirect Mayo Clinic). RESULTS: The Kawase approach exposed the rhomboid fossa with Meckel's cave extradurally, the upper half of the clivus, superior cerebellopontine angle, ventrolateral brainstem, the intrameatal region, basilar apex, and the preganglionic root of cranial nerve (CN) V, CN III-IV-VI intradurally. The PIPA approach exposed the cerebello-pontine angle with CN VI XII, Meckel's cave, CN III-V, and the middle and lower clivus intradurally from a posterior view. The area of surgical exposure is wide in both approaches; however, the volume of petrosectomy, the working angle, and surgical corridor differ significantly. CONCLUSIONS: The Kawase approach allows wide exposure of the middle cranial fossa (MCF) and posterior cranial fossa, requiring extradural temporal lobe retraction and an extradural petrosectomy with preservation of the internal acoustic meatus and cochlea. No temporal lobe retraction and direct control of neurovascular structures make the PIPA approach a valid alternative for lesions extending mostly in the Posterior cranial fossa with minor extension in the MCF. The longer surgical corridor, cerebellar retraction, and limited exposure of the anterior brainstem make this approach less indicated for lesions with major extension in the MCF and the anterior cavernous sinus. PMID- 26431734 TI - Elevated Hemoglobin Concentration Affects Acute Severe Head Trauma After Recovery from Surgery of Neurologic Function in the Tibetan Plateau. AB - BACKGROUND: Long-lived inhabitants of the plateau region have a higher hemoglobin concentration, which is the leading cause of damage in various organs, especially the nervous system. The aim of this study was to investigate the effect of hemoglobin concentration on mortality and neural functions after decompressive craniectomy in patients with hypoxia. METHODS: Patients with acute severe head trauma were classified into an elevated hemoglobin concentration group (EHb) and a moderate hemoglobin concentration group (MHb). The survival rate was evaluated by comparing the Glasgow Coma Score on days 1, 3, 7, and 15 after surgery (Kaplan Meier survival curve). The Glasgow Outcome Scale classification method was used to evaluate recovery of neural function. RESULTS: The Glasgow Coma Score scores on days 3, 7, and 15 were lower in the EHb group compared with the MHb group (P < 0.05). Mortality was significantly higher in the EHb group compared with the MHb group (P < 0.05). After 6 months, the Glasgow Outcome Scale of the MHb group was significantly higher than that of the EHb group (P < 0.05). CONCLUSIONS: Elevated hemoglobin concentration has a serious impact on neurologic recovery and mortality, as seen in patients with acute severe head trauma after decompressive craniectomy. PMID- 26431735 TI - Combination Therapy of Salvianolic Acid and Fluoxetine Improves the Cognitive Function of Rats with Chronic Stress-induced Depression. AB - OBJECTIVE: To establish the beneficial effects of salvianolic acid and fluoxetine on the improvement of cognitive function and amelioration of depression-like symptoms of rats with chronic stress-induced depression. METHODS: Ninety-nine male Sprague-Dawley rats were randomly divided into 5 groups--a control group with no stress challenge and 4 chronic stress groups. Rats assigned to chronic stress groups were exposed to stress for 3 weeks, and then were given placebo, fluoxetine (20 mg/kg), salvianolic acid (40 mg/kg), or combined fluoxetine and salvianolic acid. Body weight of each rat was recorded throughout the study. Sucrose preference test and water maze experiment were performed after chronic stress challenge and after drug treatment to assess the effect of drug treatments on depressive-like symptoms and cognitive function. The sucrose preference test was also performed before chronic stress exposure for baseline measurement. RESULTS: Exposure of rats to chronic stress for 3 weeks significantly reduced body weight and sucrose preference values compared with the no stress control. The water maze experiment showed that chronic stress impaired the spatial learning of rats as well. Treatment of stress-challenged rats with fluoxetine and fluoxetine combined with salvianolic acid resulted in shorter training latency and longer time spent in the target quadrant during the exploration stage of the water maze experiment compared with placebo treatment. Effect of the combined regimen was found more obvious. CONCLUSIONS: Combination therapy of salvianolic acid and fluoxetine could alleviate depression-like symptoms and cognitive deficit induced by chronic stress. PMID- 26431736 TI - Can a Minimal Clinically Important Difference Be Achieved in Elderly Patients with Adult Spinal Deformity Who Undergo Minimally Invasive Spinal Surgery? AB - BACKGROUND: Older age has been considered a relative contraindication to complex spinal procedures. Minimally invasive surgery (MIS) techniques to treat patients with adult spinal deformity (ASD) have emerged with the potential benefit of decreased approach-related morbidity. OBJECTIVE: To determine whether a minimal clinically important difference (MCID) could be achieved in patients ages >= 65 years with ASD who underwent MIS. METHODS: Multicenter database of patients who underwent MIS for ASD was queried. Outcome metrics assessed were Oswestry Disability Index (ODI) and visual analog scale (VAS) scores for back and leg pain. On the basis of published reports, MCID was defined as a positive change of 12.8 ODI, 1.2 VAS back pain, and 1.6 VAS leg pain. RESULTS: Forty-two patients were identified. Mean age was 70.3 years; 31 (73.8%) were women. Preoperatively, mean coronal curve, pelvic tilt, pelvic incidence to lumbar lordosis mismatch, and sagittal vertical axis were 35 degrees , 24.6 degrees , 14.2 degrees , and 4.7 cm, respectively. Postoperatively, mean coronal curve, pelvic tilt, pelvic incidence to lumbar lordosis, and sagittal vertical axis were 18 degrees , 25.4 degrees , 11.9 degrees , and 4.9 cm, respectively. A mean of 5.0 levels was treated posteriorly, and a mean of 4.0 interbody fusions was performed. Mean ODI improved from 47.1 to 25.1. Mean VAS back and leg pain scores improved from 6.8 and 5.9 to 2.7 and 2.7, respectively. Mean follow-up was 32.1 months. For ODI, 64.3% of patients achieved MCID. For VAS back and leg pain, 82.9% and 72.2%, respectively, reached MCID. CONCLUSIONS: MCID represents the threshold at which patients feel a meaningful clinical improvement has occurred. Our study results suggest that the majority of elderly patients with modest ASD can achieve MCID with MIS. PMID- 26431737 TI - Theory-of-Mind Training Causes Honest Young Children to Lie. AB - Theory of mind (ToM) has long been recognized to play a major role in children's social functioning. However, no direct evidence confirms the causal linkage between the two. In the current study, we addressed this significant gap by examining whether ToM causes the emergence of lying, an important social skill. We showed that after participating in ToM training to learn about mental-state concepts, 3-year-olds who originally had been unable to lie began to deceive consistently. This training effect lasted for more than a month. In contrast, 3 year-olds who participated in control training to learn about physical concepts were significantly less inclined to lie than the ToM-trained children. These findings provide the first experimental evidence supporting the causal role of ToM in the development of social competence in early childhood. PMID- 26431738 TI - Detection of Apoptotic Cells in a Rabbit Model with Atherosclerosis-Like Lesions Using the Positron Emission Tomography Radiotracer [18F]ML-10. AB - [18F]ML-10 (2-(5-fluoro-pentyl)-2-methylmalonic acid) is a positron emission tomography (PET) radiotracer that accumulates in cells presenting apoptosis specific membrane alterations. The aim of this study was to test whether [18F]ML 10 allows for the detection of apoptotic cells located in atherosclerotic plaques in rabbits. Atherosclerotic plaques were induced in the aortas of five rabbits, and five additional rabbits were used as controls. Activity in the aortas was quantified in vivo and ex vivo. The localization of [18F]ML-10 to the aortic wall was identified by autoradiography. Average target to background ratios measured in vivo by PET were higher in the aortas of atherosclerotic rabbits compared with those of control rabbits (2.00 +/- 0.52 vs 1.22 +/- 0.30; p < .05). Differences in [18F]ML-10 uptake between atherosclerotic and control aortas were confirmed ex vivo by PET and gamma counting (23.9 +/- 11.2 vs 1.1 +/- 2.4 counts/pixel; p <.05; 3.6 +/- 2.0 vs 0.05 +/- 0.05 % of injected activity/g; p < .05, respectively). Strong correlation was observed between the accumulation of [18F]ML-10 in aortic segments as detected by autoradiography and the number of apoptotic cells on corresponding histologic sections (r2 = .75; p < .05). In this study, we found that atherosclerotic plaques rich in apoptotic cells can be detected with [18F]ML-10 and PET. PMID- 26431739 TI - Stage-Specific miRs in Chondrocyte Maturation: Differentiation-Dependent and Hypertrophy-Related miR Clusters and the miR-181 Family. AB - Human mesenchymal stromal cells (hMSC) differentiating toward the chondrogenic lineage recapitulate successive phases of embryonic chondrocyte maturation developing from progenitor cells to hypertrophic chondrocytes. Osteoarthritic cartilage is characterized by an alteration in chondrocyte metabolism and upregulation of hypertrophic differentiation markers. A number of studies point toward a functional role for microRNAs (miRs) in controlling chondrocyte differentiation and development of osteoarthritis (OA). However, information on miRs that may regulate a specific phase of chondrocyte maturation, especially hypertrophy, is lacking. We here aimed to unravel miR profiles modulated during chondrogenesis of hMSC to obtain new differentiation markers and potential new targets relevant for differentiation outcome and OA development. hMSC were subjected to transforming growth factor-beta (TGF-beta)-driven chondrogenesis and miR profiles were determined by microarray analysis at distinct developmental time points. Expression of selected miRs was compared to cultures lacking chondrogenesis and to redifferentiated nonhypertrophic articular chondrocytes. Among 1349 probed miRs, 553 were expressed and 169 (31%) were significantly regulated during chondrogenesis. Hierarchical clustering identified specific miR expression patterns representative for MSC, prechondrocytes, chondroblasts, chondrocytes, and hypertrophic chondrocytes, respectively. Regulation of miR-181 family members allowed discrimination of successive differentiation stages. Levels of several miRs, including miR-23b, miR-140, miR-181, and miR-210 positively correlated with successful chondrocyte formation. Hypertrophic MSC derived chondrocytes and nonhypertrophic articular chondrocytes showed differential expression of miR-181a, miR-210, and miR-31, but not miR-148a implicated in COL10A1-regulation. We conclude that the here identified stage dependent miR clusters may have imperative functions during chondrocyte differentiation providing novel diagnostic tools and targets of potential relevance for OA development. PMID- 26431740 TI - Impact of perinatal mental health education on student midwives' knowledge, skills and attitudes: A pre/post evaluation of a module of study. AB - BACKGROUND: Whilst midwives are well-placed to identify and address the mental health need of women in their care, many report lacking the ability to do so. Therefore, they ignore or brush aside women's mental health needs. To improve midwives' competency in this area, the first authors developed and delivered a module on perinatal mental health issues within their university. The module aimed to improve knowledge, skills, and attitudes in relation to working with women about mental health issues. In 2012, a post-survey evaluation of the module demonstrated positive findings; following a number of revisions to the module, this more robust pre/post evaluation was conducted. OBJECTIVES: The objective of this study was to examine the impact of the perinatal mental health module on student midwives' knowledge, skills, and attitudes in addressing mental health issues with women. Design Pre-module and Post-module Surveys were Used. PARTICIPANTS: Participants were students undertaking a 4-year undergraduate direct entry midwifery degree programme in Ireland. The pre-survey had 28 participants, the post-survey had 26 participants, and there were 25 matched pairs. METHODS: The data were analysed using SPSS Version 21.0. Descriptive, frequencies and paired sample t-tests were calculated. Qualitative data were analysed thematically. RESULTS: Comparison of the pre and post measures, based on paired samples t-tests, showed that the programme statistically increased participants' knowledge and skills. Whilst students' self-reported attitudes towards women and mental health issues were already quite positive, they reported even more positive attitudes following the course. Written feedback provided by students also supported these positive findings. CONCLUSION: This evaluation provides evidence that a module on perinatal mental health is effective at improving the self-reported knowledge, skills, and attitudes of student midwives towards women with mental health issues. It is recommended that educators consider the opportunity of including a similar module in their curriculum. PMID- 26431742 TI - "It's a Burden You Carry": Describing Moral Distress in Emergency Nursing. AB - INTRODUCTION: Moral distress in nursing has been studied in many settings, but there is a paucity of research on moral distress as it manifests in the emergency department. One study suggests a correlation between moral distress and aspects of burnout, and other researchers report that nurses have considered leaving their position or even their profession because of moral distress. Further exploration of these issues may provide insight into their effects on ED patient care and the emergency nursing profession. The purpose of this study was to explore the nature of moral distress as it is experienced and described by emergency nurses. METHODS: A qualitative, exploratory design was employed using semi-structured focus groups for data collection. Using an iterative process, transcripts were analyzed for emerging themes by the research team. Six researchers analyzed the transcripts using a thematic analysis approach. RESULTS: Themes from the data included dysfunctional practice arena, being overwhelmed, and adaptive/maladaptive coping. Participants described, overall, a profound feeling of not being able to provide patient care as they wanted to. DISCUSSION: Causes of moral distress in emergency nurses are environment driven, not incident driven, as is described in other settings, and include a high-acuity, high demand, technical environment with insufficient resources. Interventions should be targeted to improve environmental factors that contribute to the moral distress of emergency nurses. Future research should focus on the development and validation of an instrument to measure moral distress in this setting. PMID- 26431743 TI - Spectral entropy in monitoring anesthetic depth. AB - Monitoring the brain response to hypnotics in general anesthesia, with the nociceptive and hemodynamic stimulus interaction, has been a subject of intense investigation for many years. Nowadays, monitors of depth of anesthesia are based in processed electroencephalogram by different algorithms, some of them unknown, to obtain a simplified numeric parameter approximate to brain activity state in each moment. In this review we evaluate if spectral entropy suitably reflects the brain electric behavior in response to hypnotics and the different intensity nociceptive stimulus effect during a surgical procedure. PMID- 26431741 TI - Overexpression of the monocyte chemokine CCL2 in dorsal root ganglion neurons causes a conditioning-like increase in neurite outgrowth and does so via a STAT3 dependent mechanism. AB - Neuroinflammation plays a critical role in the regeneration of peripheral nerves following axotomy. An injury to the sciatic nerve leads to significant macrophage accumulation in the L5 DRG, an effect not seen when the dorsal root is injured. We recently demonstrated that this accumulation around axotomized cell bodies is necessary for a peripheral conditioning lesion response to occur. Here we asked whether overexpression of the monocyte chemokine CCL2 specifically in DRG neurons of uninjured mice is sufficient to cause macrophage accumulation and to enhance regeneration or whether other injury-derived signals are required. AAV5-EF1alpha CCL2 was injected intrathecally, and this injection led to a time-dependent increase in CCL2 mRNA expression and macrophage accumulation in L5 DRG, with a maximal response at 3 weeks post-injection. These changes led to a conditioning like increase in neurite outgrowth in DRG explant and dissociated cell cultures. This increase in regeneration was dependent upon CCL2 acting through its primary receptor CCR2. When CCL2 was overexpressed in CCR2-/- mice, macrophage accumulation and enhanced regeneration were not observed. To address the mechanism by which CCL2 overexpression enhances regeneration, we tested for elevated expression of regeneration-associated genes in these animals. Surprisingly, we found that CCL2 overexpression led to a selective increase in LIF mRNA and neuronal phosphorylated STAT3 (pSTAT3) in L5 DRGs, with no change in expression seen in other RAGs such as GAP-43. Blockade of STAT3 phosphorylation by each of two different inhibitors prevented the increase in neurite outgrowth. Thus, CCL2 overexpression is sufficient to induce macrophage accumulation in uninjured L5 DRGs and increase the regenerative capacity of DRG neurons via a STAT3-dependent mechanism. PMID- 26431744 TI - The use of pupillometry as monitoring of intraoperative analgesia in the consumption of analgesics during the first 12 hours after surgery. AB - INTRODUCTION: Intraoperative evaluation of analgesia remains today often based on heart rate and arterial pressure fluctuations. None of these parameters is specific. Incorrect handling during this process may increase surgical morbi mortality of the patients and their acute postoperative pain. The aim of this study was to evaluate the impact of intraoperative analgesia controlled by pupillometry on postoperative analgesic consumption and the pain intensity in the first 12h in the hospital room, after major gynecological surgery. PATIENTS AND METHODS: A prospective, cohort study with allocation of groups of sequentially according to programming of operating room was designed. ASA I-III patients scheduled for elective surgery of abdominal hysterectomy by laparotomy or laparoscopy through intravenous general anesthesia were included. Patients were divided into 2 groups: pupillometry group (P-1), in which intraoperative analgesia was guided by pupillometry, and hemodynamic group (H-2) according to values of blood pressure and heart rate. In the hospitalization room the values of visual analogue scale (VAS) were routinely registered with 3 courts for the study: 3, 8 and 12h of the postoperative period. Postoperative analgesia was standardized as follows: NSAIDs was administered if VAS was >= 3 or if the patient expressly requested an analgesic. After this, the efficacy of treatment was assessed. If the patient had pain, the next scheduled drug was given up to an VAS<3. Data for total analgesic consumption administered in the hospital room, VAS and adverse effects were collected within 12h postoperatively. RESULTS: A total of 59 patients, 30 group P-1 and 29 group H-2, were included. Group P-1 experienced less pain than group H-2, with statistical significance in each phase (VAS 3h, VAS 8h and VAS 12h). These data are consistent with the consumption of analgesics for patients. There was a statistically significant reduction (p<0.001) in the group P-1 (1.80 [DE 0.99]; medium 2, 95% confidence interval 1.43-2.17) compared with group H-2 (5.66 [1.58]; medium 6, 95% confidence interval 5.05-6.26). CONCLUSIONS: Monitoring of the intraoperative analgesia by pupillometry was able to reduce the intensity of the acute postoperative pain and analgesic consumption in the first 12h in the hospital room after major gynecological surgery. PMID- 26431745 TI - [Use of MRI before biopsy in diagnosis of prostate cancer: Single-operator study]. AB - The diagnostic for prostate cancer is changing. To improve the detection of this cancer, urologists expect a lot from the contribution of magnetic resonance imaging (MRI). What is the role of this imaging in prostate cancer detection? This is a retrospective study, from 2011 to 2013, mono-centric and single operator. Of the 464 needle biopsy of the prostate (BP), we excluded those with PSA>20 ng/mL or digital rectal examination (DRE)>T3. The remaining 430 BP were submitted or not to a 1.5 tesla MRI with pelvic antenna. The primary aim is the overall detection of prostate cancer. Secondary aim was the detection rate during the first series of BP and repeat BP, between the two groups in the MRI group. MRI and MRI without populations are comparable for age (63.3 vs 64.6), PSA (6.10 vs 6.13), DRE>T1c, prostate volume (55.4 cm(3) vs 51.7 cm(3)). There is no significant difference in overall detection between the two groups (P=0.12). There is no significant difference in cancer detection between the first BP (P=0.13) and the repeat BP (P=0.07). There is a significant difference in the early detection of BP MRI group (P=0.03) but not for the BP repeat MRI group (P=0.07). For 108 BP iterative MRI group, there were 67 BP targeted "mentally" with MRI: 18 cancers were detected, making a 25% detection rate. This study helps to highlight the value of MRI in the early rounds of BP but we can ask the value of this imaging during repeat biopsies. Targeted biopsies "mentally" do not have the expected detection sensitivity and seems to require a three-dimensional reconstruction to be more effective. LEVEL OF EVIDENCE: 5. PMID- 26431746 TI - What risk of prostate cancer led urologist to recommend prostate biopsies? AB - OBJECTIVE: The aim of this study was to estimate the risk of prostate cancer that led urologists to perform prostate biopsies. PATIENTS AND METHODS: Eight hundred and eight patients had prostate biopsies in 5 tertiary centres in 2010. Following data were collected: age, PSA, DRE, prostate volume, negative prior prostate biopsy and estimated life expectancy (> or <10 years). The risk of prostate cancer was calculated by validated nomogram of PCPT-CRC and SWOP-PRI and correlated with pathological biopsy results. RESULTS: In final analysis, 625 patients were included, 568 (90.9%) had a life expectancy greater than 10 years. Prostate cancer was found in 291 (46.6%) cases. These patients were older (66.7 +/- 6.8 vs 64.3 +/- 5.6 years, P < 0.001), had higher PSA values (10 +/- 7.9 vs 7.7 +/- 4.3 ng/mL, P < 0.0001) and the prostate volume decreased (43.8 +/- 19.8 vs 51.3 +/- 20.7 mL, P < 0.0001) compared with healthy subjects. Digital Rectal Examination was more frequently suspicious in the group of patients with prostate cancer (43.6% vs 18.9%, P < 0.0001). Risk of prostate cancer estimated was 50.6 +/- 14% for PCPT-CRC without ATCD, 56.2 +/- 12.8% with PCPT-CRC ATCD and 31.2 +/- 17.3% for SWOP-PRI. The likelihood of high-risk prostate cancer was 22.4 +/- 16.9% with the PCPT-CRC, and 14.8 +/- 18.2% with SWOP-PRI. CONCLUSION: This study showed that urologists performed prostate biopsies when the risk of cancer was high. PMID- 26431747 TI - Where do we stand? Functional imaging in acute and chronic pulmonary embolism with state-of-the-art CT. AB - Nowadays, CT pulmonary angiography (CTPA) is the diagnostic imaging modality of choice for acute and chronic pulmonary embolism (PE) in order to assess vascular anatomy and parenchymal morphology. Over the past decade, several prognostic CTPA markers associated with an increased risk of adverse clinical events and in hospital mortality have been evaluated, namely cardiac chamber dimensions, obstruction scores, and visualization of iodinated contrast material in the lung parenchyma by dual-energy (DE) CTPA. This article reviews the current status and potential prognostic advantages of CTPA or DE CTPA with its recent developments for accessing right ventricular dysfunction and the assessment of first pass lung perfusion with DE CTPA in the diagnosis of acute and chronic PE. PMID- 26431748 TI - The radiological assessment of colonic replacement of the esophagus in children: A review of 43 cases. AB - PURPOSE: To define the characteristic radiological features following colonic replacement of the esophagus in children. MATERIALS AND METHODS: The upper gastro intestinal contrast studies of 43 patients who underwent colonic replacement of the esophagus at our pediatric surgery unit were available for analysis. UGI contrast studies were performed routinely in the post-surgical period in 17 cases (first asymptomatic group), while the rest of contrast studies (26) belonged to a second group of out-patients complaining of dysphagia (18) or dyspepsia (8) following colonic replacement of the esophagus. Based on our observations, we proposed a grading system to describe the degree of colonic redundancy in the thorax. RESULTS: Redundancy of the colonic conduit in the thoracic cavity was a common radiological finding (62.8%). The redundancy was mild (grade 1) in 18 patients, moderate (grade 2) in eight, and severe (grade 3) in only one patient. In 88.9%, the redundancy was in the right hemi-thorax. Patients presenting with postoperative dysphagia had a stricture at the site of the esophago-colic anastomosis in the neck, which should be differentiated from other sites of anatomical narrowing at the inlet and outlet of the thoracic cavity. Gastro-colic reflux was common among patients who underwent colonic replacement of the esophagus without an anti-reflux procedure. CONCLUSION: Colonic replacement of the esophagus in children results in considerable anatomical alterations. Knowledge about the normal post-surgical changes and imaging features of the commonly encountered complications can increase the diagnostic confidence among radiologists and clinicians when dealing with these cases. PMID- 26431749 TI - Pseudoaneurysm of the Perforating Peroneal Artery After Ankle Fracture Fixation: Case Report and Review of the Literature. AB - Pseudoaneurysm formation around the ankle area is a very rare complication of an anatomic region that is highly exposed to trauma. A review of the published medical data revealed the rarity of the condition. Pseudoaneurysms of the perforating branch of the peroneal artery account for only 8 in the published data, with 6 (75%) cases related to sprain injury and only 2 (25%) to fracture fixation. We present a pseudoaneurysm of the perforating peroneal artery after a bimalleolar ankle fracture in a patient taking warfarin and a review of the published data. Our patient was treated successfully with thrombin embolization, and at 6 weeks after embolization, she remained completely free of symptoms. PMID- 26431750 TI - Guided Growth With Temporary Hemiepiphysiodesis to Treat Ankle Valgus in a Skeletally Immature Individual: A Case Report. AB - Guided growth is useful in correcting pediatric angular deformities. Ankle valgus is a coronal plane deformity and is often seen in skeletally immature patients with congenital or acquired lower extremity pathologic features. Temporary hemiepiphysiodesis with a percutaneous transphyseal medial malleolar screw is a surgical treatment capable of correcting the angular deformity and can offer effective correction. In the present case study, a 12-year-old male with dorsal lateral peritalar subluxation and ankle valgus underwent a reconstructive procedure and temporary hemiepiphysiodesis with a percutaneous medial malleolar screw. After removal of the screw, reduction of his peritalar subluxation was achieved, improving his lateral-distal tibial angle from 81 degrees preoperatively to 89 degrees at the final follow-up examination. The patient returned to his preoperative sporting activities and ambulated comfortably and pain free in sneakers with orthotics. In conclusion, temporary hemiepiphysiodesis with a transphyseal medial malleolar screw is an effective treatment option for ankle valgus in a skeletally immature individual. PMID- 26431751 TI - Integration of moral values during L2 sentence processing. AB - This study reports an event-related potential (ERP) experiment examining whether valuation (i.e., one's own values) is integrated incrementally and whether it affects L2 speakers' online interpretation of the sentence. We presented Spanish native speakers and French-Spanish mid-proficiency late L2 speakers with visual sentences containing value-consistent and value-inconsistent statements (e.g., 'Nowadays, paedophilia should be prohibited/tolerated across the world.'). Participants' brain activity was recorded as they were reading the sentences and indicating whether they agreed with the statements or not. Behaviourally, the two groups revealed identical valuation. The ERP analyses showed both a semantic (N400) and an affect-related response (LPP) to value-inconsistent statements in the native group, but only an LPP in the non-native group. These results suggest that valuation is integrated online (presence of LPP) during L2 sentence comprehension but that it does not interfere with semantic processing (absence of N400). PMID- 26431752 TI - Biomechanical response to ladder slipping events: Effects of hand placement. AB - Ladder falling accidents are a significant, growing and severe occupational hazard. The factors that contribute to falls from ladders and specifically those that influence the motor response from ladder falls are not well understood. The aims of this research were to determine the effects of hand placement (rung versus rail) on muscle activation onset and peak activity timing in response to slipping on a ladder and to sequence the timing of events following slip initiation. Fifteen unexpected slips from 11 experienced ladder climbers were induced with a freely spinning rung under the foot, while subjects were randomly assigned to a rung versus rail hand grasping strategy. EMG onset time and peak activity time from five bilateral muscles (semitendinosis, vastus lateralis, triceps, biceps and anterior deltoid) were analyzed. Results indicated that significantly slower muscle activation onset and peak response times occurred during rail hand placement, suggesting that grasping ladder rungs may be preferable for improving the speed of the motor response. The triceps muscle activated and reached peak activity earlier in the slip indicating that subjects may initially extend their arms prior to generating hand forces. The study also revealed that slips tended to occur around the time that a foot and hand were in motion and there were just two points of contact (one hand and the slipping foot). PMID- 26431753 TI - Compensatory mechanisms of balance to the scaling of arm-swing frequency. AB - The present study investigated the contribution of the Hof (2007) mechanism 1 (M1 moving the center of pressure (COP) with respect to the vertical projection of the center of mass (COMTotal)); and mechanism 2 (M2-rotating the trunk and upper limbs around the COMTotal) to postural control and the stability of COP-COMTotal cophase as a function of lateral arm-swing frequency. Young adults were instructed to stand still on a force platform while alternating their arm swinging from above the head to the side of their thigh to create perturbations to postural control. Scaling the frequency of arm-swing (random step changes of 0.2 Hz within a bandwidth of 0.2 to 1.6 Hz) increased the SD of COP but decreased the SD of COMTotal. Increments in arm-swing frequency induced a progressive increase in M1 and decrease in M2 in terms of their relative contribution to postural stability. The cophase between COP and COMTotal became more tightly in phase over increments of arm-swing frequency. These findings show an adaptive compensatory role of M1 and M2 within the stability of COP-COMTotal coupling in the regulation of human balance control. PMID- 26431754 TI - Wear simulation of total knee prostheses using load and kinematics waveforms from stair climbing. AB - Knee wear simulators are meant to perform load cycles on knee implants under physiological conditions, matching exactly, if possible, those experienced at the replaced joint during daily living activities. Unfortunately, only conditions of low demanding level walking, specified in ISO-14243, are used conventionally during such tests. A recent study has provided a consistent knee kinematic and load data-set measured during stair climbing in patients implanted with a specific modern total knee prosthesis design. In the present study, wear simulation tests were performed for the first time using this data-set on the same prosthesis design. It was hypothesised that more demanding tasks would result in wear rates that differ from those observed in retrievals. Four prostheses for total knee arthroplasty were tested using a displacement controlled knee wear simulator for two million cycles at 1.1 Hz, under kinematics and load conditions typical of stair climbing. After simulation, the corresponding damage scars on the bearings were qualified and compared with equivalent explanted prostheses. An average mass loss of 20.2+/-1.5 mg was found. Scanning digital microscopy revealed similar features, though the explant had a greater variety of damage modes, including a high prevalence of adhesive wear damage and burnishing in the overall articulating surface. This study confirmed that the results from wear simulation machines are strongly affected by kinematics and loads applied during simulations. Based on the present results for the full understanding of the current clinical failure of knee implants, a more comprehensive series of conditions are necessary for equivalent simulations in vitro. PMID- 26431756 TI - Reducing health disparities: the role of sleep deficiency and sleep disorders. AB - Decrements in sleep health, including insufficient sleep duration, irregular timing of sleep, poor sleep quality, and sleep/circadian disorders, are widespread in modern society and are associated with an array of disease risks and outcomes, including those contributing to health disparities (eg, cardiovascular disease, obesity and diabetes, psychiatric illness, and cancer). Recent findings have uncovered racial/ethnic and socioeconomic position differences in sleep health; however, the contribution of sleep deficiency to health disparities remains largely unexplored, and understanding the underlying causes of disparities in sleep health is only beginning to emerge. In 2011, the National Heart, Lung, and Blood Institute (NHLBI) convened a workshop, bringing together sleep and health disparities investigators, to identify research gaps and opportunities to advance sleep and health disparities science. This article provides a brief background and rationale for the workshop, and it disseminates the research recommendations and priorities resulting from the working group discussions. PMID- 26431757 TI - Cross-sectional sleep thresholds for optimal health and well-being in Australian 4-9-year-olds. AB - AIM: Using national Australian time-diary data, we aimed to empirically determine sleep duration thresholds beyond which children have poorer health, learning, quality of life, and weight status and parents have poorer mental health. METHODS: DESIGN/SETTING: Cross-sectional data from the first three waves of the Longitudinal Study of Australian Children. PARTICIPANTS: A nationally representative sample of 4983 4-5-year-olds, recruited in 2004 from the Australian Medicare database and followed biennially; 3631 had analyzable sleep information and a concurrent measure of health and well-being for at least one wave. MAIN MEASURES: EXPOSURE: At each wave, a parent completed 24-h time-use diaries for one randomly selected weekday and one weekend day, including a "sleeping/napping" category. OUTCOMES: Parent-reported child mental health, health-related quality of life, and maternal/paternal mental health; teacher reported child language, literacy, mathematical thinking, and approach to learning; and assessed child body mass index and girth. RESULTS: Linear regression analyses revealed weak, inconsistent relationships between sleep duration and outcomes at every wave. For example, children with versus without psychosocial health-related quality of life problems slept slightly less at 6-7 years (adjusted mean difference 0.12 h; 95% confidence interval 0.01-0.22, p = 0.03), but not at 4-5 (0.00; -0.10 to 0.11, p = 1.0) or 8-9 years (0.09; -0.02 to 0.22, p = 0.1). Empirical exploration using fractional polynomials demonstrated no clear thresholds for sleep duration and any adverse outcome at any wave. CONCLUSIONS: Present guidelines in terms of children's short sleep duration appear misguided. Other parameters such as sleep timing may be more meaningful for understanding optimal child sleep. PMID- 26431755 TI - Sleep disparity, race/ethnicity, and socioeconomic position. AB - Sleep represents a set of biological functions necessary for the maintenance of life. Performing these functions, though, requires that an individual engage in behaviors, which are affected by social and environmental factors. Race/ethnicity and socioeconomic position represent categories of factors that likely play a role in the experience of sleep in the community. Previous studies have suggested that racial/ethnic minorities and the socioeconomically disadvantaged may be more likely to experience sleep patterns that are associated with adverse health outcomes. It is possible that disparities in sleep represent a pathway by which larger disparities in health emerge. This review (1) contextualizes the concept of race/ethnicity in biomedical research, (2) summarizes previous studies that describe patterns of sleep attainment across race/ethnicity groups, (3) discusses several pathways by which race/ethnicity may be associated with sleep, (4) introduces the potential role of socioeconomic position in the patterning of sleep, and (5) proposes future research directions to address this issue. PMID- 26431759 TI - Medical Expulsive Therapy for Ureteric Colic: New Hard Evidence: Commentary on: Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. PMID- 26431760 TI - Editorial Comment. PMID- 26431761 TI - Reply: To PMID 26276574. PMID- 26431762 TI - Current State of Urologic Malpractice in Spain. PMID- 26431758 TI - Association between sleep deficiency and cardiometabolic disease: implications for health disparities. AB - BACKGROUND: Cardiometabolic diseases, which include obesity, diabetes, hypertension, and cardiovascular disease, are associated with reduced quality of life and reduced life expectancy. Unfortunately, there are racial/ethnic and socioeconomic disparities associated with these diseases such that minority populations, such as African Americans and Hispanics, and those of lower socioeconomic status, experience a greater burden. Several reports have indicated that there are differences in sleep duration and quality that mirror the disparities in cardiometabolic disease. The goal of this paper is to review the association between sleep and cardiometabolic disease risk because of the possibility that suboptimal sleep may partially mediate the cardiometabolic disease disparities. METHODS: We review both experimental studies that have restricted sleep duration or impaired sleep quality and examined biomarkers of cardiometabolic disease risk, including glucose metabolism and insulin sensitivity, appetite regulation and food intake, and immune function. We also review observational studies that have examined the association between habitual sleep duration and quality, and the prevalence or risk of obesity, diabetes, hypertension, and cardiovascular disease. CONCLUSION: Many experimental and observational studies do support an association between suboptimal sleep and increased cardiometabolic disease risk. PMID- 26431763 TI - Behavior and the cholinergic parameters in olfactory bulbectomized female rodents: Difference between rats and mice. AB - Olfactory bulbectomy (OBX) in rodents induces a wide spectrum of functional disturbances, including behavioral, neurochemical, and neuromorphological alterations. We have examined the effects of OBX on behavior and the parameters of the cholinergic system in female rats and mice. In rats, OBX resulted in the appearance of some depressive-like behavioral marks, such as the decreased sucrose consumption, hyperactivity, impaired short-term memory and anxiety-like behavioral features, such as shortened presence in the center of the open field arena or open arms of the elevated plus-maze and an enhancement of avoidance behavior. These behavioral abnormalities could be associated with disturbances in hippocampal function, this suggestion being supported by the presence of cellular changes in this brain structure. No effect of OBX on the number of cholinergic neurons in the medial septum-diagonal band as well as on the acetylcholine content and acetylcholinesterase activity in the septum, hippocampus, and neocortex could be detected. In contrast, in mice, OBX impaired spontaneous alternation behavior and decreased the number of cholinergic neurons in the medial septum-diagonal band. These data demonstrate that rats and mice differently respond to OBX, in particular, OBX does not significantly affect the cholinergic system in rats. PMID- 26431764 TI - A prolonged motor imagery session alter imagined and actual movement durations: Potential implications for neurorehabilitation. AB - Mental practice with motor imagery improves motor performance, for example reducing the duration of goal-directed movements. However, it is not known whether an experimental session involving prolonged sequences of motor imagery induces mental fatigue and alters motor and mental performances. In this study, participants imagined 100 point-to-point arm movements combined with actual pointing movements every 10 or 50 imagined movements. Participants reported a subjective feeling of mental fatigue after imagining 100 pointing movements. When participants performed actual movements every 50 imagined movements, the duration of both actual and imagined movements increased at the end of the protocol. On the contrary, no change in actual and imagined movement duration was observed when participants performed actual movements every 10 imagined movements. These results suggested that the repetition of many imagined movements induced mental fatigue and altered the mental simulation and the actual execution processes of the movement. However, the regular execution of actual movements seemed to counteract the negative effect of mental fatigue as both actual and imagined movement duration remained constant with actual trials inserted between mental rehearsals. We suggest that during training or rehabilitation programs, actual movements should be executed and/or imagined movement duration should be controlled to avoid the negative effects of mental fatigue on motor performance. PMID- 26431765 TI - Modulation of prism adaptation by a shift of background in the monkey. AB - Recent human behavioral studies have shown that the position of a visual target is instantly represented relative to the background (e.g., a large square) and used for evaluating the error in reaching the target. In the present study, we examined whether the same allocentric mechanism is shared by the monkey. We trained two monkeys to perform a fast and accurate reaching movement toward a visual target with a square in the background. Then, a visual shift (20mm or 4.1 degrees ) was introduced by wedge prisms to examine the process of decreasing the error during an exposure period (30 trials) and the size of the error upon removal of the prisms (aftereffect). The square was shifted during each movement, either in the direction of the visual displacement or in the opposite direction, by an amount equal to the size of the visual shift. The ipsilateral shift of the background increased the asymptote during the exposure period and decreased the aftereffect, i.e., prism adaptation was attenuated by the ipsilateral shift. By contrast, a contralateral shift enhanced adaptation. We further tested whether the shift of the square alone could cause an increase in the motor error. Although the target did not move, the shift of the square increased the motor error in the direction of the shift. These results were generally consistent with the results reported in human subjects, suggesting that the monkey and the human share the same neural mechanisms for representing a target relative to the background. PMID- 26431766 TI - Olfactory bulbectomy increases reinstatement of methamphetamine seeking after a forced abstinence in rats. AB - Drug addiction is commonly associated with depression and comorbid patients also suffer from higher cravings and increased relapse rate. To address this issue preclinically we combined the olfactory bulbectomy (OBX) model of depression and intravenous methamphetamine self-administration procedure in rats to assess differences in relapse-like behavior. Male Sprague-Dawley rats were divided randomly into two groups; in one group the bilateral olfactory bulbectomy (OBX) was performed while the other group was sham operated. After recovery, intracardiac catheter was implanted. Intravenous self-administration procedure was conducted in operant boxes using nose-poke operandi (Coulbourn Instruments, Inc., USA) under fixed ratio 1 schedule of reinforcement. Methamphetamine was available at dose 0.08 mg/kg/infusion. After stable methamphetamine intake was maintained, a period of forced abstinence was initiated and rats were kept in their home-cages for 14 days. Finally, one reinstatement session was conducted in operant boxes with no drug delivery. In the reinstatement session the mean of 138.4 active nose-pokes was performed by the OBX group, while the sham group displayed 41 responses, i.e. 140 % and 48 % of basal nose-poking during maintenance phase in OBX and sham operated group respectively. OBX group also showed significantly more passive nose-pokes indicating hyperactive behavioral traits in bulbectomized rats. However, the % of active operandum preference was equal in both groups. Olfactory bulbectomy model significantly increased reinstatement of methamphetamine seeking behavior. This paradigm can be used to evaluate potential drugs that are able to suppress the drug-seeking behavior. PMID- 26431767 TI - Evaluation of the short- and long-term safety and therapy outcomes of the everolimus-eluting bioresorbable vascular scaffold system in patients with coronary artery stenosis: Rationale and design of the German-Austrian ABSORB RegIstRy (GABI-R). AB - BACKGROUND: Third-generation drug-eluting metal stents are the gold standard for treatment of coronary artery disease. The permanent metallic caging of the vessel, however, can result in limited vasomotion, chronic inflammation, and late expansive remodeling, conditions that can lead to late and very late stent thrombosis. The development of bioresorbable scaffolds (BRSs) promises advantages over metal stents due to complete biodegradation within 2-4years. Theoretically, since vessel scaffolding is temporary and no permanent implant remains in the vessel, BRSs, as opposed to metal stents, once degraded would no longer be potential triggers for stent-related adverse events or side effects. METHODS/DESIGN: The short- and long-term outcome after implantation of an everolimus-eluting, poly-L-lactic acid-based bioresorbable scaffold system (ABSORB, Abbott Vascular, Santa Clara, CA, USA) in the world-wide greatest all comers cohort will be evaluated in the prospective, non-interventional, multicenter German-Austrian ABSORB RegIstRy (GABI-R). GABI-R will include over 5000 patients from about 100 study sites in Austria and Germany. Safety endpoints such as cardiac death, myocardial infarction, and clinically driven percutaneous or surgical target lesion and vessel revascularization will be evaluated during hospitalization and in the follow-up period (minimum of 5years). CONCLUSION: Although two randomized controlled trials and several registries have documented safety and efficacy as well as non-inferiority of this everolimus-eluting ABSORB device compared with drug-eluting metal stents, the current knowledge regarding clinical application, treatment success, and long-term safety of using this BRS in daily routine is limited. Thus, the goal of GABI-R is to address this lack of information. PMID- 26431768 TI - Reliability of measures of transient evoked otoacoustic emissions with contralateral suppression. AB - The reliability of measures of transient evoked otoacoustic emissions (TEOAEs) with contralateral suppression was examined. The effect of test session (i.e., initial test; retest without probe removal; retest with probe removal; and retest 1-2 days post initial test), gender, and ear was examined in 14 young adult females and 14 young adult males. TEOAEs were obtained bilaterally with 60 dB peSPL linear click stimuli with and without a contralateral 65 dB SPL broadband noise suppressor. Absolute TEOAE suppression and a normalized index of TEOAE suppression (i.e., percentage of suppression) were examined. Reliability of these measures was assessed with repeated measures linear mixed model analysis of variance, a coefficient of reliability, and Bland-Altman analyses. There were no statistically significant (p>0.05) main effects of test, gender, and ear or interactions for both absolute dB and % TEOAE suppression values. Cronbach's alpha were greater than 0.90 across the four tests for both TEOAE measures. Mean test differences or bias (i.e., between the initial and subsequent tests) for absolute and % TEOAE suppression ranged from -0.05 to 0.11 dB and -1.5% to 1.1%, respectively. There was no proportional/systematic bias with the mean differences of the first and subsequent measurements. Data herein were consistent with the view that bilateral TEOAE suppression measures are reliable across test sessions of 1-2 days among females and males and may provide a method to monitor medial olivocochlear efferent reflex status over time. PMID- 26431769 TI - Sit-and-wait versus active-search hunting: A behavioral ecological model of optimal search mode. AB - Drawing on Skellam's (1958) work on sampling animal populations using transects, we derive a behavioral ecological model of the choice between sit-and-wait and active-search hunting. Using simple, biologically based assumptions about the characteristics of predator and prey, we show how an empirically definable parameter space favoring active-search hunting expands as: (1) the average rate of movement of prey decreases, or (2) the energetic costs of hunter locomotion decline. The same parameter space narrows as: (3) prey skittishness increases as a function of a hunter's velocity, or (4) prey become less detectable as a function of a hunter's velocity. Under either search tactic, encounter rate increases as a function of increasing prey velocity and increasing detection zone radius. Additionally, we investigate the roles of habitat heterogeneity and spatial auto-correlation or grouping of prey on the optimal search mode of a hunter, finding that habitat heterogeneity has the potential to complicate application of the model to some empirical examples, while the effects of prey grouping lead to relatively similar model outcomes. As predicted by the model, the introduction of the horse to the Great Plains and the introduction of the snowmobile to Arctic foraging communities decreased the metabolic costs of active search and led to a change in normative hunting strategies that favored active search in place of sit-and-wait hunting. PMID- 26431770 TI - Additive genetic variation and evolvability of a multivariate trait can be increased by epistatic gene action. AB - Epistatic gene action occurs when mutations or alleles interact to produce a phenotype. Theoretically and empirically it is of interest to know whether gene interactions can facilitate the evolution of diversity. In this paper, we explore how epistatic gene action affects the additive genetic component or heritable component of multivariate trait variation, as well as how epistatic gene action affects the evolvability of multivariate traits. The analysis involves a sexually reproducing and recombining population. Our results indicate that under stabilizing selection conditions a population with a mixed additive and epistatic genetic architecture can have greater multivariate additive genetic variation and evolvability than a population with a purely additive genetic architecture. That greater multivariate additive genetic variation can occur with epistasis is in contrast to previous theory that indicated univariate additive genetic variation is decreased with epistasis under stabilizing selection conditions. In a multivariate setting, epistasis leads to less relative covariance among individuals in their genotypic, as well as their breeding values, which facilitates the maintenance of additive genetic variation and increases a population's evolvability. Our analysis involves linking the combinatorial nature of epistatic genetic effects to the ancestral graph structure of a population to provide insight into the consequences of epistasis on multivariate trait variation and evolution. PMID- 26431771 TI - Noise-plasticity correlations of gene expression in the multicellular organism Arabidopsis thaliana. AB - Gene expression levels exhibit stochastic variations among genetically identical organisms under the same environmental conditions (called gene expression "noise" or phenotype "fluctuation"). In yeast and Escherichia coli, positive correlations have been found between such gene expression noise and "plasticity" with environmental variations. To determine the universality of such correlations in both unicellular and multicellular organisms, we focused on the relationships between gene expression "noise" and "plasticity" in Arabidopsis thaliana, a multicellular model organism. In recent studies on yeast and E. coli, only some gene groups with specific properties of promoter architecture, average expression levels, and functions exhibited strong noise-plasticity correlations. However, we found strong noise-plasticity correlations for most gene groups in Arabidopsis; additionally, promoter architecture, functional essentiality of genes, and circadian rhythm appeared to have only a weak influence on the correlation strength. The differences in the characteristics of noise-plasticity correlations may result from three-dimensional chromosomal structures and/or circadian rhythm. PMID- 26431772 TI - Bifurcations analysis of oscillating hypercycles. AB - We investigate the dynamics and transitions to extinction of hypercycles governed by periodic orbits. For a large enough number of hypercycle species (n>4) the existence of a stable periodic orbit has been previously described, showing an apparent coincidence of the vanishing of the periodic orbit with the value of the replication quality factor Q where two unstable (non-zero) equilibrium points collide (named QSS). It has also been reported that, for values below QSS, the system goes to extinction. In this paper, we use a suitable Poincare map associated to the hypercycle system to analyze the dynamics in the bistability regime, where both oscillatory dynamics and extinction are possible. The stable periodic orbit is identified, together with an unstable periodic orbit. In particular, we are able to unveil the vanishing mechanism of the oscillatory dynamics: a saddle-node bifurcation of periodic orbits as the replication quality factor, Q, undergoes a critical fidelity threshold, QPO. The identified bifurcation involves the asymptotic extinction of all hypercycle members, since the attractor placed at the origin becomes globally stable for values Q0.056) except the mean of C. polykomos (p<0.05). The mean, SD, High5 of CB DBM at M2 of C. atys was significantly higher than those of C. polykomos and P. badius (p<0.006). CONCLUSIONS: The durophagous C. atys had higher CB DBM value at the M2 region than C. polykomos and P. badius, which supports the hypothesis that materially stiffer mandibular bone in C. atys can develop in response to the generation of high bite forces during hard object feeding. PMID- 26431829 TI - The evaluation of 7 commercial real-time PCR kits for Zaire ebolavirus using virus-like particle-encapsulated EBOV RNA. AB - Several Chinese commercial real-time PCR kits for Zaire ebolavirus have been developed after the Ebola outbreak and used by Chinese medical teams in West Africa. In order to know the essential performance indicators of these kits, analytical sensitivity and precision were evaluated with virus-like particle (VLP)-encapsulated EBOV RNA. The limit of detection (LOD) and the precision were completed with a series of VLPs. The maximum and minimum of LOD was acquired by ZJ BioTech and Daan gene, respectively. For precision, all of the detection results were <5% except the maximum 5.17%. Among them, Puruikang, Daan gene, Sansure, ZJ BioTech, and Huada demonstrated superior reproducibility. Overall, the requirements of LOD <1000 copies/mL and coefficient of variation <5% could be satisfied by all kits except Kehua. Meanwhile, it is feasible for VLPs as a substitute of positive samples in assay evaluation. PMID- 26431830 TI - Molecular characterization of Staphylococcus aureus isolates carrying the Panton Valentine leukocidin genes from Rio de Janeiro hospitals. AB - In a collection of 50 pvl-positive Staphylococcus aureus isolates from 10 Rio de Janeiro hospitals, 18 (36%) were from bloodstream infections, and 31 (62%) carried the SCCmec IV. Among 25 (50%) isolates of the USA1100/ST30/CC30 lineage present in 8 hospitals, 1 isolate was characterized as vancomycin-intermediate S. aureus. PMID- 26431831 TI - Leisure-time, occupational, and commuting physical activity and risk of type 2 diabetes in Japanese workers: a cohort study. AB - BACKGROUND: Physical activity has been suggested to reduce the risk of type 2 diabetes. However, evidence is limited regarding whether vigorous-intensity activity yields the same benefits in preventing type 2 diabetes compared with an equivalent dose of moderate-intensity activity as well as other type of physical activity. We examined the risk of type 2 diabetes associated with exercise intensity during leisure and occupational and commuting physical activity among Japanese individuals. METHODS: Participants included 26,628 workers (23,207 men and 3,421 women) aged 30 to 64 years without diabetes at baseline. There was 6 years of follow-up maximum. Leisure-time exercise, occupational physical activity, and duration of walking to and from work were self-reported. Diabetes was diagnosed by using HbA1c, fasting or random blood glucose, and self-report. We used Cox regression analysis to estimate the hazard ratio (HR) and the 95% confidence interval (CI) of incident diabetes. RESULTS: During a mean follow-up of 5.2 years, 1,770 participants developed type 2 diabetes. Compared with individuals who engaged in no exercise, the HRs (95% CIs) for <7.5, 7.5 to <15.0, and >=15.0 MET-hours per week of exercise were 0.94 (0.81, 1.08), 1.07 (0.88, 1.30), and 0.90 (0.67, 1.21), respectively, among individuals who engaged in moderate-intensity exercise alone; 0.68 (0.44, 1.06), 0.86 (0.54, 1.34), and 0.89 (0.56, 1.41), respectively, among individuals who engaged in vigorous-intensity exercise alone; and 0.70 (0.44, 1.11), 0.57 (0.37, 0.90), and 0.76 (0.52, 1.11), respectively, among individuals who engaged in the two intensities, with adjustments for potential confounders and the total volume of exercise. Occupational physical activity and walking to and from work were not associated with diabetes. CONCLUSIONS: The results suggest that vigorous-intensity exercise can reduce the risk of type 2 diabetes among Japanese workers. PMID- 26431832 TI - Guanosine inhibits LPS-induced pro-inflammatory response and oxidative stress in hippocampal astrocytes through the heme oxygenase-1 pathway. AB - Guanosine, a guanine-based purine, is an extracellular signaling molecule that is released from astrocytes and has been shown to promote central nervous system defenses in several in vivo and in vitro injury models. Our group recently demonstrated that guanosine exhibits glioprotective effects in the C6 astroglial cell line by associating the heme oxygenase-1 (HO-1) signaling pathway with protection against azide-induced oxidative stress. Astrocyte overactivation contributes to the triggering of brain inflammation, a condition that is closely related to the development of many neurological disorders. These cells sense and amplify inflammatory signals from microglia and/or initiate the release of inflammatory mediators that are strictly related to transcriptional factors, such as nuclear factor kappa B (NFkappaB), that are modulated by HO-1. Astrocytes also express toll-like receptors (TLRs); TLRs specifically recognize lipopolysaccharide (LPS), which has been widely used to experimentally study inflammatory response. This study was designed to understand the glioprotective mechanism of guanosine against the inflammatory and oxidative damage induced by LPS exposure in primary cultures of hippocampal astrocytes. Treatment of astrocytes with LPS resulted in deleterious effects, including the augmentation of pro-inflammatory cytokine levels, NFkappaB activation, mitochondrial dysfunction, increased levels of oxygen/nitrogen species, and decreased levels of antioxidative defenses. Guanosine was able to prevent these effects, protecting the hippocampal astrocytes against LPS-induced cytotoxicity through activation of the HO-1 pathway. Additionally, the anti-inflammatory effects of guanosine were independent of the adenosinergic system. These results highlight the potential role of guanosine against neuroinflammatory-related diseases. PMID- 26431834 TI - [Unilateral visual impairment and conspicuous optical coherence tomography in a 23-year-old woman]. PMID- 26431833 TI - ATP release, generation and hydrolysis in exocrine pancreatic duct cells. AB - Extracellular adenosine triphosphate (ATP) regulates pancreatic duct function via P2Y and P2X receptors. It is well known that ATP is released from upstream pancreatic acinar cells. The ATP homeostasis in pancreatic ducts, which secrete bicarbonate-rich fluid, has not yet been examined. First, our aim was to reveal whether pancreatic duct cells release ATP locally and whether they enzymatically modify extracellular nucleotides/sides. Second, we wished to explore which physiological and pathophysiological factors may be important in these processes. Using a human pancreatic duct cell line, Capan-1, and online luminescence measurement, we detected fast ATP release in response to pH changes, bile acid, mechanical stress and hypo-osmotic stress. ATP release following hypo-osmotic stress was sensitive to drugs affecting exocytosis, pannexin-1, connexins, maxi anion channels and transient receptor potential cation channel subfamily V member 4 (TRPV4) channels, and corresponding transcripts were expressed in duct cells. Direct stimulation of intracellular Ca(2+) and cAMP signalling and ethanol application had negligible effects on ATP release. The released ATP was sequentially dephosphorylated through ecto-nucleoside triphosphate diphosphohydrolase (NTPDase2) and ecto-5'-nucleotidase/CD73 reactions, with respective generation of adenosine diphosphate (ADP) and adenosine and their maintenance in the extracellular medium at basal levels. In addition, Capan-1 cells express counteracting adenylate kinase (AK1) and nucleoside diphosphate kinase (NDPK) enzymes (NME1, 2), which contribute to metabolism and regeneration of extracellular ATP and other nucleotides (ADP, uridine diphosphate (UDP) and uridine triphosphate (UTP)). In conclusion, we illustrate a complex regulation of extracellular purine homeostasis in a pancreatic duct cell model involving: ATP release by several mechanisms and subsequent nucleotide breakdown and ATP regeneration via counteracting nucleotide-inactivating and nucleotide phosphorylating ecto-enzymes. We suggest that extracellular ATP homeostasis in pancreatic ducts may be important in pancreas physiology and potentially in pancreas pathophysiology. PMID- 26431835 TI - What Do Molecular Tests Add to Prognostic Stratification in MF: Is It Time to Add These to Our Clinical Practice? AB - The molecular landscape of patients with myelofibrosis (MF) includes "phenotypic driver" and "subclonal" mutations. The three driver (JAK2, MPL and CALR)-mutated genes currently represent major diagnostic criteria, unlike subclonal mutations that are not specific for the disease and occur in other myeloid neoplasms. Recent data indicate that selected mutations deserve prognostic significance allowing to identify categories of patients with different survival and risk of leukemia. This review focuses on current knowledge regarding genotype-prognostic correlates in MF, however, with the understanding that this is a rapid moving field and no definite recommendations for the clinicians can be done yet. PMID- 26431837 TI - [Update on extracorporeal photopheresis]. AB - Extracorporeal photopheresis (ECP) is a treatment approach that combines leukapheresis with photochemotherapy and is derived from PUVA; with this procedure, nucleated cells such as lymphocytes and monocytes are extracorporeally irradiated with UVA light after photosensitization. ECP is an effective treatment modality with few side effects that in recent years has been expanded to treat a range of indications. It has been proven effective in the treatment of cutaneous T cell lymphoma and is being increasing used in other lymphocyte-mediated, autoimmune and inflammatory diseases that are associated with proliferation of autoreactive T cells. PMID- 26431836 TI - Molecular Pathogenesis of Peripheral T Cell Lymphoma. AB - Understanding the molecular pathogenesis of peripheral T cell lymphomas (PTCLs) has lagged behind that of B cell lymphomas due to disease rarity. However, novel approaches are gradually clarifying these mechanisms, and gene profiling has identified specific signaling pathways governing PTCL cell survival and growth. For example, genetic alterations have been discovered, including signal transducer and activator of transcription (STAT)3 and STAT5b mutations in several PTCLs, disease-specific ras homolog family member A (RHOA) mutations in angioimmunoblastic T cell lymphoma (AITL), and recurrent translocations at the dual specificity phosphatase 22 (DUSP22) locus in anaplastic lymphoma receptor tyrosine kinase (ALK)-negative anaplastic large cell lymphomas (ALCLs). Intriguingly, some PTCL-relevant mutations are seen in apparently normal blood cells as well as tumor cells, while others are confined to tumor cells. These data have dramatically changed our understanding of PTCL origins: once considered to originate from mature T lymphocytes, some PTCLs are now believed to emerge from immature hematopoietic progenitor cells. PMID- 26431838 TI - [Pigmented macule on the neck, red nodules on the trunk. Diagnosis: neck left: Melanoma. Pectoral right: Breast cancer]. PMID- 26431839 TI - Alpha-Lipoic Acid Attenuates Oxidative Damage in Organs After Sepsis. AB - Sepsis progression is linked with the imbalance between reactive oxygen species and antioxidant enzymes. Thus, the aim of this study was to evaluate the effect of alpha-lipoic acid (ALA), a powerful antioxidant, in organs of rats submitted to sepsis. Male Wistar rats were subjected to sepsis by cecal ligation puncture (CLP) and treated with ALA or vehicle. After CLP (12 and 24 h), the myeloperoxidase (MPO) activity, protein and lipid oxidative damage, and antioxidant enzymes in the liver, kidney, heart, and lung were evaluated. ALA was effective in reducing MPO activity, lipid peroxidation in the liver, and protein carbonylation only in the kidney in 12 h after CLP. In 12 h, SOD activity increased in the kidney and CAT activity in the liver and kidney with ALA treatment. Thus, ALA was able to reduce the inflammation and oxidative stress in the liver and kidney after sepsis in rats. PMID- 26431840 TI - Tafluprost/Timolol: A Review in Open-Angle Glaucoma or Ocular Hypertension. AB - A once-daily preservative-free fixed combination ophthalmic solution containing tafluprost 0.0015 % and timolol 0.5 % (hereafter referred to as tafluprost/timolol) [Taptiqom((r))] has been developed to lower intraocular pressure (IOP) whilst avoiding damage to the ocular surface associated with preservatives such as benzalkonium chloride. Tafluprost/timolol is available in various EU countries for the reduction of IOP in adults with open-angle glaucoma or ocular hypertension who are insufficiently responsive to topical monotherapy with beta-adrenergic receptor antagonists or prostaglandin analogues and require a combination therapy, and who would benefit from preservative-free eye drops. In two multinational, phase III studies, tafluprost/timolol was superior to monotherapy with either preservative-free tafluprost 0.0015 % once daily or preservative-free timolol 0.5 % twice daily, and noninferior to concomitant therapy with preservative-free tafluprost 0.0015 % once daily plus preservative free timolol 0.5 % twice daily in lowering IOP in adults with open-angle glaucoma or ocular hypertension. Tafluprost/timolol was well tolerated in these studies, with a tolerability profile consistent with that of its individual components and with no new adverse reactions observed. Thus, preservative-free fixed combination tafluprost/timolol is an effective treatment option for the reduction of IOP in adults with open-angle glaucoma or ocular hypertension, providing a useful alternative for those patients who would benefit from preservative-free eye drops. PMID- 26431841 TI - Artificial urinary sphincter implantation in women with stress urinary incontinence: preliminary comparison of robot-assisted and open approaches. AB - INTRODUCTION AND HYPOTHESIS: We aimed to compare outcomes of open and robot assisted artificial urinary sphincter (AUS) implantation in female patients. METHODS: The charts of all female patients who underwent an AUS implantation between 2008 and 2014 in a single center were retrospectively reviewed. From 2008 to 2012, AUS were implanted using an open approach and from 2013 to 2014 using a robot-assisted approach. Perioperative and functional parameters were compared between groups. The primary endpoint was continence status. RESULTS: Twenty-four women were assessed: 16 in the open group and eight in the robot-assisted group. Three patients had neurogenic stress urinary incontinence. Most patients had undergone previous procedures for urinary incontinence (15 in the open group and seven in the robotic group). Mean operative time was similar in both groups (214 vs. 211 min; p = 0.90). Postoperative complicationsrate was lower in the robot assisted group (25 vs. 75 %; p = 0.02). There was a trend toward a lower intraoperative complication rate (37.5 vs. 62.5 %; p = 0.25), decreased blood loss (17 ml vs. 275 ml; p = 0.22), and shorter length of stay (3.5 vs. 9.3 days; p = 0.09) in the robot-assisted group. Continence rates were comparable in both groups (75 vs. 68.8 %; p = 0.75). Three AUS explantations were needed in the open group (18.8 %) compared with one in the robot-assisted group (12.5 %; p = 0.70). CONCLUSIONS: In female patients, the robot-assisted approach compared with open AUS implantation could decrease intraoperative and postoperative complication rates, length of hospital stay, and blood loss. PMID- 26431842 TI - The "learning curve" for retropubic mid-urethral sling procedures: a retrospective cohort study. AB - INTRODUCTION AND HYPOTHESIS: Mid-urethral tape procedures brought a paradigm shift in surgery for stress incontinence; little research into the development and maintenance of surgical competence for the procedure exists. The hypothesis behind this study is that the "learning curve" for retropubic mid-urethral sling procedures, judged by the surrogate of bladder perforation, is longer than previously thought. METHODS: This was a retrospective single-centre database and case note review of retropubic mid-urethral tape procedures. Unadjusted rates of bladder perforation, operating time, postoperative voiding difficulty, tape extrusion, and patient reported outcome were calculated; progress was evaluated using the cumulative sum method. Outcomes were assessed for 1 consultant, 2 subspecialty trainees (fellows), 7 advanced training skills module (ATSM) trainees (senior residents) and 6 core specialty trainees (residents) in years 4 7 of training. RESULTS: A total of 1,568 women were identified as having mid urethral tape procedures; 568 (36 %) had additional procedures concurrently; 259 (20 %) were secondary procedures. The overall perforation rate for individual surgeons varied between 0 and 31 % and averaged 10.3 % amongst the core and ATSM trainees (a mean of 11 procedures), 4.5 % amongst the subspecialty trainees (a mean of 66 procedures) and 1.3 % for the consultant (1,284 procedures). The number of perforations for individual surgeons peaked at between 10 and 30 procedures undertaken. The number of cases performed to reach a target level of <= 5 % perforations varied between 20 and 80. CONCLUSIONS: Whilst seductively simple in concept, mid-urethral tape procedures are not without risk; their inherently "blind" nature makes them difficult to teach. The "learning curve" to independent practice may be longer than previously considered. PMID- 26431843 TI - [Not Available]. PMID- 26431844 TI - Smoking rates in UK continue to fall. PMID- 26431845 TI - Using subscales when scoring the Cushing's quality of life questionnaire. AB - CONTEXT: Patients in long-term remission of Cushing's syndrome (CS) commonly report impaired quality of life (QoL). The CushingQoL questionnaire is a disease specific QoL questionnaire for patients diagnosed with CS. The developers of the CushingQoL recommend using a global (total) score to assess QoL. However, the global score does not capture all aspects of QoL as outlined by the World Health Organization (WHO). OBJECTIVE: The aim of the study was to compare the performance of different scoring options to determine the optimal method for the CushingQoL. DESIGN AND PATIENTS: Patients in remission from CS (n=341) were recruited from the Cushing's Syndrome Research Foundation's email listserv and Facebook page, and asked to complete the CushingQoL and a short demographics survey. RESULTS: Using an exploratory analysis, adequate model fit was obtained for the global score, as well as a 2-subscale (psychosocial issues and physical problems) scoring solution. Confirmatory methods were performed to identify the optimal scoring solution. Both the global score and the 2-subscale scoring solution showed adequate model fit. However, a chi(2) difference test indicated that the 2-subscale scoring solution was a significantly better fit than the global score (P<0.05). CONCLUSION: If doctors or researchers would like to tease apart physical and psychosocial issues, the 2-subscale scoring solution would be recommended, since this solution showed to be optimal in scoring the CushingQoL. Regardless of the scoring solution used, the CushingQoL has proven to be a valuable resource for assessing health-related QoL in patients with CS. PMID- 26431846 TI - Guideline recommended treatments in complex patients with multimorbidity. PMID- 26431847 TI - Effectiveness of evidence-based medicine on knowledge, attitudes, and practices of family planning providers: a randomized experiment in Jordan. AB - BACKGROUND: Provider misconceptions and biases about contraceptive methods are major barriers to family planning access for women in low- and middle-income countries, including Jordan. Evidence-Based Medicine (EBM) programs aim to reduce biases and misconceptions by providing doctors with the most up-to-date scientific evidence on contraceptive methods. METHODS: We evaluate the effects of an EBM program conducted in Jordan on private providers' knowledge, attitudes, and practices. Family planning providers randomly assigned to a treatment group were invited to attend a roundtable seminar on the injectable contraceptive Depot Medroxy Progesterone Acetate (DMPA), and to receive two 15 min one-on-one educational visits that reinforce the messages from the seminar. RESULTS: There was low compliance with the EBM program. The study fails to detect an impact on providers' knowledge of DMPA's side effects or on reported clinical practices. There is suggestive evidence of a positive impact on providers' attitudes toward and confidence in prescribing the contraceptive to their patients. There is also evidence of positive selection into program participation. CONCLUSIONS: We conclude that EBM may not be effective as a stand-alone program targeting a family planning method with a high level of provider and consumer bias. Evidence of positive selection into program participation underscores the importance of randomization to avoid overestimating the true effects of interventions. TRIAL REGISTRATION: AEA RCT Registry, AEARCTR0000539 , 11/3/2014. PMID- 26431848 TI - Prevalence of pregnancy induced hypertension and pregnancy outcomes among women seeking maternity services in Harare, Zimbabwe. AB - BACKGROUND: Pregnancy induced hypertension (PIH) is one of the most common causes of both maternal and neonatal morbidity, affecting about 5 - 8 % of pregnant women. It is associated with adverse pregnancy outcomes as well as maternal morbidity and mortality. Harare City experienced an increase in referrals due to PIH to central hospitals from 2009 to 2011. We conducted a study to determine the prevalence of PIH and pregnancy outcomes among women with PIH. METHODS: An analytic cross sectional study was conducted. Interviewer administered questionnaires were used to capture demographic data, obstetric history and knowledge on PIH management. Records were reviewed for pregnancy outcomes while key informants were also interviewed on patient management. RESULTS: PIH prevalence was 19.4 %. Women with PIH were three times more likely to deliver a low birth weight baby (OR 3.00, p = 0.0115), 4.3 times more likely to have still birth (OR 4.34, p = 0.0517) and four times more likely to have a baby with low Apgar score at 5 minutes (OR 4.47, p = 0.0155) compared to women without PIH. There was no statistically significant difference in delivery before 37 weeks gestation between women with PIH and those without (OR 1.70, p = 0.1251). 12,5 % of the women delivered by caesarean section. Methyldopa was the drug of choice for management of PIH. Less than half of the health workers had sufficient knowledge on definition or management of PIH. Delay in seeking care and shortage of resources were the major reported challenges in the proper management of PIH. CONCLUSION: PIH prevalence was high. Women with PIH were at higher risk of adverse pregnancy outcomes than those without. Poor knowledge of management of PIH and inadequate resources are a threat to the proper management of PIH. This underscores the need for increased human resources and capacity building as well as resource mobilisation for proper management of pregnant women. Urinalysis must be routinely done for all pregnant women regardless of their blood pressure. PMID- 26431849 TI - Nitroreductase gene-directed enzyme prodrug therapy: insights and advances toward clinical utility. AB - This review examines the vast catalytic and therapeutic potential offered by type I (i.e. oxygen-insensitive) nitroreductase enzymes in partnership with nitroaromatic prodrugs, with particular focus on gene-directed enzyme prodrug therapy (GDEPT; a form of cancer gene therapy). Important first indications of this potential were demonstrated over 20 years ago, for the enzyme-prodrug pairing of Escherichia coli NfsB and CB1954 [5-(aziridin-1-yl)-2,4 dinitrobenzamide]. However, it has become apparent that both the enzyme and the prodrug in this prototypical pairing have limitations that have impeded their clinical progression. Recently, substantial advances have been made in the biodiscovery and engineering of superior nitroreductase variants, in particular development of elegant high-throughput screening capabilities to enable optimization of desirable activities via directed evolution. These advances in enzymology have been paralleled by advances in medicinal chemistry, leading to the development of second- and third-generation nitroaromatic prodrugs that offer substantial advantages over CB1954 for nitroreductase GDEPT, including greater dose-potency and enhanced ability of the activated metabolite(s) to exhibit a local bystander effect. In addition to forging substantial progress towards future clinical trials, this research is supporting other fields, most notably the development and improvement of targeted cellular ablation capabilities in small animal models, such as zebrafish, to enable cell-specific physiology or regeneration studies. PMID- 26431850 TI - miR-429 regulates alveolar macrophage inflammatory cytokine production and is involved in LPS-induced acute lung injury. AB - p38 MAPK (mitogen-activated protein kinase) is a critical regulator in lung inflammation. It can be inactivated by DUSP1 (dual-specificity phosphatase 1) which was identified as a putative target of miR-429. miR-429 mimics directly targeted to the 3'-UTR of the gene encoding DUSP1 may result in the translational attenuation of DUSP1. Moreover, the phosphorylation of p38 MAPK was prolonged after miR-429 mimic treatment. Additionally, miR-429 expression was sensitive to LPS (lipopolysaccharide) stimulation and the miR-429 mimics increased the production of pro-inflammatory cytokines. However, anti-miR-429 reduced the LPS induced production of pro-inflammatory cytokines. These results provide direct evidence that miR-429 is involved in the LPS-induced inflammatory response. In parallel with miR-429, miR-200b and miR-200c, but not miR-200a or miR-141, shared similar effects. In vivo, LPS induced the expression of miR-429, miR-200b and miR 200c in lung. At the same time, inhibiting these miRNAs by anti-miRNAs attenuated the LPS-induced pulmonary inflammatory response and injury. These findings reveal that miR-429 possesses pro-inflammatory activities and may be a potential therapy target for LPS-induced lung injury. PMID- 26431851 TI - Preoperative pulse and thermal radiofrequency facilitates prehabilitation and subsequent rehabilitation of a patient scheduled for total knee arthroplasty. PMID- 26431852 TI - Opioid information pamphlet increases postoperative opioid disposal rates: a before versus after quality improvement study. AB - PURPOSE: Half of postoperative patients are prescribed an opioid, but a majority do not store or dispose of them properly thus risking diversion. We examined the efficacy of an opioid educational pamphlet addressing opioid weaning, storage, and disposal. We hypothesized that the pamphlet would increase the rate of proper opioid disposal, storage, and weaning. METHODS: This prospective before and after study was conducted at UBC Hospital in primary total hip or knee arthroplasty patients. Adults with American Society of Anesthesiologists physical class I-III, with no addiction history and consuming <= 30 mg of morphine equivalents daily were enrolled in the study. Two groups received similar standard management, except the intervention group additionally received the opioid education pamphlet. Patients were contacted four weeks postoperatively to complete a survey. The primary endpoint was to evaluate proper opioid disposal rates. Secondary endpoints were to evaluate opioid storage and weaning rates. RESULTS: Two hundred twenty-six patients were enrolled and 172 (76%) completed the survey. Among patients who had discontinued opioids, rates of proper disposal increased from 2/42 (5%) to 12/45 (27%) in those receiving the pamphlet (difference in proportions, 22%; 95% confidence interval (CI), 5 to 38; P = 0.005). Secure opioid storage did not improve in those receiving the opioid pamphlet [before, 18/86 (21%) vs after, 20/86 (23%); difference in proportions, 3%; 95% CI, -11 to 15; P = 0.713]. The proportion of patients weaned from opioids was unchanged by the pamphlet [before, 42/86 (49%) vs after, 45/86 (52%); P = 0.735]. CONCLUSION: The introduction of an education pamphlet significantly improved self-reported proper opioid disposal rates in postoperative patients. PMID- 26431853 TI - Antithrombin activity and heparin response in neonates and infants undergoing congenital cardiac surgery: a retrospective cohort study. AB - PURPOSE: The immature coagulation system during infancy has age-related physiological differences in proteins that contribute to significant variation in heparin responsiveness through alterations in heparin-enhanced thrombin inhibition. The primary aim of this study was to evaluate the relationship between preoperative antithrombin (AT) activity and heparin responsiveness in neonates and infants undergoing congenital cardiac surgery. METHODS: In this retrospective cohort study, neonates (aged 0-28 days) and infants (aged 29-365 days) undergoing congenital cardiac surgery in the 12-month period from October 2013 to 2014 were studied. The two age groups were compared for the primary endpoint of heparin response measured by the heparin sensitivity index (HSI), with heparin loading doses and heparin resistance being secondary endpoints. Multivariable linear regression analyses were used to explore the relationship between AT activity and heparin response measured by HSI. RESULTS: There were 122 infants and 19 neonates included in the study. After adjusting for low-molecular weight heparin, unfractionated heparin, and platelet count, there was a significant relationship between AT activity and HSI (r = 0.44; P = 0.009). The median [interquartile range] HSI did not differ between neonates and infants (0.76 [0.69- 0.98] vs 0.89 [0.70-1.10] sec.unit(-1).kg(-1), respectively; median difference, 0.08; 95% confidence interval [CI], -0.01 to 0.17; P = 0.182), despite the mean (standard deviation) AT activity differing between age groups [60 (16)% vs 84 (18)%, respectively; mean difference, 24; 95% CI, 15 to 32; P < 0.001]. CONCLUSIONS: There was a moderate relationship between AT activity and heparin response measured by HSI. Comparing neonates and infants, there was similar heparin responsiveness measured by HSI despite differing AT activity levels. These findings should help guide the perioperative administration of exogenous AT to neonates and infants and suggest that, outside the neonatal period, preoperative AT activity may be used to identify children at risk of decreased heparin responsiveness. PMID- 26431854 TI - A randomized trial comparing axillary block versus targeted intracluster injection supraclavicular block for upper limb surgery. AB - PURPOSE: This randomized trial aimed to validate a new method for brachial plexus blockade, i.e., targeted intracluster injection supraclavicular block (TII SCB), by comparing it with ultrasound-guided axillary block (AXB). We hypothesized that TII SCB would result in a shorter total anesthesia-related time. METHODS: Forty patients undergoing upper limb surgery were randomized to ultrasound-guided TII SCB (n = 20) or AXB (n = 20). In the TII SCB group, we deposited 16 mL of lidocaine 1.5% with epinephrine 5 ug.mL(-1) into the largest neural cluster (i.e., brachial plexus trunks/divisions). Subsequently, an additional 16 mL was divided into equal aliquots and injected inside each satellite cluster. In the AXB group, 5.5 mL were deposited around the musculocutaneous nerve and 23.5 mL were injected at the 6 o'clock position of the axillary artery. The main outcome for comparison between the two groups was the total anesthesia-related time (defined as the sum of block performance and onset times). We also recorded the number of needle passes, procedural pain, and complications (vascular puncture, paresthesia). RESULTS: The TII SCB method provided a quicker mean (SD) onset time compared with the AXB group [9.5 (5.8) min vs 18.9 (6.1) min; mean difference, 9.5 min; 99% CI, -14.7 to -4.2; P < 0.001] and a shorter mean (SD) total anesthesia-related time [20.1 (5.0) min vs 27.2 (6.5) min; mean difference, -7.0 min; 95% CI, -10.9 to -3.1; P = 0.001]. There were no intergroup differences in terms of success rate (95%), procedural pain, vascular puncture and paresthesia. The AXB group displayed a faster performance time [8.2 (1.6) min vs 10.6 (2.6) min; P = 0.001] with fewer median [interquartile range] needle passes (3 [2-6] vs 5 [4-8]; P < 0.001). CONCLUSION: Ultrasound-guided TII SCB provides a quicker onset and a shorter total anesthesia-related time than ultrasound-guided AXB. PMID- 26431855 TI - Determination of ciprofloxacin and levofloxacin in human sputum collected from cystic fibrosis patients using microextraction by packed sorbent-high performance liquid chromatography photodiode array detector. AB - This paper reports a new, easy, cheap, and fast MEPS-HPLC-PDA method for the simultaneous analysis of ciprofloxacin and levofloxacin, two fluoroquinolones (FLQs) commonly used for the treatment of pulmonary infections in cystic fibrosis (CF) patients. The FLQs were resolved on a Discovery C8 column (250mm*4.6mm; 5MUm particle size) using an isocratic elution with a run time of 15min, without further purification. The method was validated over concentrations ranging from 0.05 to 2MUg/mL for both analytes in human sputum, and enrofloxacin was used as internal standard. This method was successfully tested to detect FLQs in sputum collected from CF patients. The MEPS-HPLC-PDA method was validated using biological samples collected from CF patients orally or intravenously injected with FLQs. The resultant data showed that the method is selective, sensitive and robust over range of concentrations for both FLQs. The limit of quantification of the method was 0.05MUg/mL for both analytes (comparable to more complex and expensive instrument configurations), weighted-matrix-matched standard curves showed a good linearity up to 2MUg/mL, and parallelism tests were also successfully assessed. The intra- and inter-day precision (RSD%) values were <=10.4% and <=11.1%, respectively, for all range of analysis. The intra- and inter-day trueness (Bias%) values are ranged from -11.8% to 7.25% for both antibiotic drugs. At the best of our knowledge, this is the first MEPS-HPLC-PDA based method that uses MEPS procedure for simultaneous determination of ciprofloxacin and levofloxacin in human sputum. The method was tested successfully on real sputum samples by following a conventional drug administration. Furthermore, the MEPS-HPLC-PDA based method provides more advantages to detect and analyze quickly the antibiotic drugs in biological matrices than other analytical procedures reported in literature. PMID- 26431856 TI - Rapid and sensitive multiresidue analysis of pesticides in tobacco using low pressure and traditional gas chromatography tandem mass spectrometry. AB - Public exposure to pesticide residues through the main/side-stream smoke of tobacco (Nicotiana tabacum L.) is an international concern. This article reports optimization and validation of large-scale multiresidue analysis methods involving low pressure and traditional gas chromatography tandem mass spectrometry in compliance with the guidance residue levels (GRLs) of Cooperative Centre for Scientific Research Relative to Tobacco (CORESTA). Analysis by low pressure GC-MS/MS offered three times rapid turn around time over the traditional GC-MS/MS with limits of quantifications (LOQs) less than 2MUg/L for all the 259 test compounds and the recoveries in the range of 70-118% (+/-20%) at 10 and 20MUg/kg levels of fortification. PMID- 26431857 TI - Development and validation of a high performance liquid chromatographic-mass spectrometry method for the simultaneous quantification of 10 trichothecenes in ultra-high temperature processed cow milk. AB - An LC-MS/MS (QqQ) method has been developed and validated for simultaneous determination of the following trichothecenes in UHT cow milk: nivalenol (NIV), deoxynivalenol (DON), deepoxy-deoxynivalenol (DOM-1), 3-acetyldeoxynivalenol (3 ADON), 15-acetyldeoxynivalenol (15-ADON), neosolaniol (NEO), diacetoxyscirpenol (DAS), fusarenon X (FUS-X), T-2 and HT-2 toxins. Sample treatment is simple and based on the extraction with acetonitrile (ACN), acidified with 0.2% formic acid, followed by a purification process, adding sodium acetate to the ACN/water extract in order to separate aqueous phase and, consequently, polar components of the milk. Validation of the method for all the 10 mycotoxins was successful; validation parameters taken into account were as follows: limits of detection (LOD) and quantification (LOQ), linearity, precision (within-day and between-day variability), recovery, matrix effect and stability. The LODs were 10.1, 2.5, 1.5, 1.9, 0.1, 0.5, 1.0, 0.08, 0.4 and 0.05ng/mL for NIV, DON, DOM-1, FUS-X, NEO, 3-ADON, 15-ADON, DAS, HT-2 and T-2, respectively. Mean recovery values (obtained in intermediate precision conditions) were between 63.5 and 75.8 (RSDR<=15%) for all the mycotoxins. All the mycotoxins suffered from matrix effects, especially DON. PMID- 26431858 TI - Solvent modulated linear pH gradient elution for the purification of conventional and bispecific antibodies: Modeling and application. AB - Classical ion-exchange chromatography using a linear salt gradient to elute the adsorbed protein at fixed pH is the most common method to separate product related impurities during downstream processing of biopharmaceuticals. Linear pH gradient elution provides a useful alternative by separating proteins in a linear pH gradient at fixed salt concentration. Although linear pH gradient elution provides excellent selectivity, it is rarely encountered in industrial purification processes. Here, a stoichiometric displacement model is used to characterize pH gradient elution based on simple linear gradient elution experiments. Protein retention behavior is described with respect to the pH dependencies of the characteristic binding charge and the equilibrium constant of the ion exchange reaction. Furthermore, the influence of solvent composition using PEG as a mobile phase modifier is investigated. Validity and applicability of the model are demonstrated for the purification of a conventional monoclonal antibody from soluble aggregates and for a novel bispecific antibody format containing a unique product-related impurity profile. pH step elution protocols are derived from model calculations without further optimization experiments necessary. PMID- 26431859 TI - Automated harvesting and 2-step purification of unclarified mammalian cell culture broths containing antibodies. AB - Therapeutic monoclonal antibodies represent one of the fastest growing segments in the pharmaceutical market. The growth of the segment has necessitated development of new efficient and cost saving platforms for the preparation and analysis of early candidates for faster and better antibody selection and characterization. We report on a new integrated platform for automated harvesting of whole unclarified cell-culture broths, followed by in-line tandem affinity capture, pH neutralization and size-exclusion chromatography of recombinant antibodies expressed transiently in mammalian human embryonic kidney 293T-cells at the 1-L scale. The system consists of two bench-top chromatography instruments connected to a central unit with eight disposable filtration devices used for loading and filtering the cell cultures. The staggered parallel multi-step configuration of the system allows unattended processing of eight samples in less than 24h. The system was validated with a random panel of 45 whole-cell culture broths containing recombinant antibodies in the early profiling phase. The results showed that the overall performances of the preparative automated system were higher compared to the conventional downstream process including manual harvesting and purification. The mean recovery of purified material from the culture-broth was 66.7%, representing a 20% increase compared to that of the manual process. Moreover, the automated process reduced by 3-fold the amount of residual aggregates in the purified antibody fractions, indicating that the automated system allows the cost-efficient and timely preparation of antibodies in the 20-200mg range, and covers the requirements for early in vitro and in vivo profiling and formulation of these drug candidates. PMID- 26431860 TI - Environmental friendly method for urban wastewater monitoring of micropollutants defined in the Directive 2013/39/EU and Decision 2015/495/EU. AB - The fate and removal of organic micropollutants in the environment is a demanding issue evidenced by the recent European policy. This work presents an analytical method for the trace quantification of 37 micropollutants including Priority Substances (Directive 2013/39/EU), substances of the recent watch list (Decision 2015/495/EU) and contaminants of emerging concern: pesticides, multi-class pharmaceuticals and a metabolite, estrogens and one industrial compound. The analytical method was based on solid phase extraction (SPE) followed by ultra high performance liquid chromatography with tandem mass spectrometry (UHPLC MS/MS), using eco-friendly solvents (ethanol and ultrapure water) both in the SPE and UHPLC, according to green analytical chemistry principles. Briefly, Oasis((r)) HLB cartridges were used to preconcentrate 100mL of water samples and the reconstituted extracts were analyzed with a KinetexTM column under reversed mode, the linear ranges extended to 200ngL(-1) (R(2)>0.99) for all the analytes. The method detection limits were between 0.04 and 2.26ngL(-1) and the method quantification limits were between 0.13 and 6.85ngL(-1). The identity of the compounds was confirmed using two MS/MS transitions and its ion ratios, according to Decision 2002/657/EC. The validated method was applied to wastewater treatment plant samples, assessing the concentration of micropollutants after secondary biological and tertiary UV treatments. Lab-scale photolysis and ozonation experiments were also performed with the secondary effluents, with ozonation showing the best performance for the removal of most of the determined micropollutants. PMID- 26431861 TI - Primary care and cancer: integration is key. PMID- 26431862 TI - Primary care in cancer control: towards mature cancer care. PMID- 26431863 TI - Chinese perspective of the role of primary care in cancer control. PMID- 26431864 TI - Paying for the expanding role of primary care in cancer control. PMID- 26431865 TI - Referral of suspected cancers: the NICE approach. PMID- 26431866 TI - The expanding role of primary care in cancer control. AB - The nature of cancer control is changing, with an increasing emphasis, fuelled by public and political demand, on prevention, early diagnosis, and patient experience during and after treatment. At the same time, primary care is increasingly promoted, by governments and health funders worldwide, as the preferred setting for most health care for reasons of increasing need, to stabilise health-care costs, and to accommodate patient preference for care close to home. It is timely, then, to consider how this expanding role for primary care can work for cancer control, which has long been dominated by highly technical interventions centred on treatment, and in which the contribution of primary care has been largely perceived as marginal. In this Commission, expert opinion from primary care and public health professionals with academic and clinical cancer expertise-from epidemiologists, psychologists, policy makers, and cancer specialists-has contributed to a detailed consideration of the evidence for cancer control provided in primary care and community care settings. Ranging from primary prevention to end-of-life care, the scope for new models of care is explored, and the actions needed to effect change are outlined. The strengths of primary care-its continuous, coordinated, and comprehensive care for individuals and families-are particularly evident in prevention and diagnosis, in shared follow-up and survivorship care, and in end-of-life care. A strong theme of integration of care runs throughout, and its elements (clinical, vertical, and functional) and the tools needed for integrated working are described in detail. All of this change, as it evolves, will need to be underpinned by new research and by continuing and shared multiprofessional development. PMID- 26431867 TI - Intranasal exposure to silica nanoparticles induces alterations in pro inflammatory environment of rat brain. AB - Silica nanoparticles (SiNPs) are being used increasingly in biomedical and industrial fields; however, their adverse effects on human health have not been fully investigated. In this study, we focused on some of the toxicological aspects of SiNPs by studying oxidative stress and pro-inflammatory responses in the frontal cortex, corpus striatum and hippocampus regions of rat brain. Wistar rats were exposed to SiNPs of size 80 nm and 10 nm at a dose of 150 ug/50 uL phosphate-buffered saline/rat for 30 days. The results indicated a significant increase of lipid peroxide levels and hydrogen peroxide content in various regions of the treated rat brain. Moreover, these changes were accompanied with a significant decrease in the activities of manganese superoxide dismutase, glutathione reductase, catalase and reduced glutathione in different brain regions, suggesting impaired antioxidant defence system. Furthermore, SiNPs exposure not only increased messenger RNA (mRNA) and protein expression of nuclear factor-kappaB (NF-kappaB) but also significantly increased the mRNA and protein levels of tumour necrosis factor alpha (TNF-alpha), interleukin 1beta (IL 1beta) and monocyte chemoattractant protein 1 (MCP-1) in different regions of rat brain. Cumulatively, these data suggest that SiNPs induced the activation of NF kappaB and increased the expression of TNF-alpha, IL-1beta and MCP-1 in rat brain, possibly via redox-sensitive cellular signalling pathways. PMID- 26431868 TI - The Sixth International Water and Health Seminar, Cannes, France, June 16-18, 2014. PMID- 26431869 TI - Reducing pathogens in combined sewer overflows using ozonation or UV irradiation. AB - Fecal contamination of water resources is a major public health concern in densely populated areas since these water bodies are used for drinking water production or recreational purposes. A main source of this contamination originates from combined sewer overflows (CSOs) in regions with combined sewer systems. Thus, the treatment of CSO discharges is urgent. In this study, we explored whether ozonation or UV irradiation can efficiently reduce pathogenic bacteria, viruses, and protozoan parasites in CSOs. Experiments were carried out in parallel settings at the outflow of a stormwater settling tank in the Ruhr area, Germany. The results showed that both techniques reduce most hygienically relevant bacteria, parasites and viruses. Under the conditions tested, ozonation yielded lower outflow values for the majority of the tested parameters. PMID- 26431870 TI - Characterization of modified proteins in plasma from a subtype of schizophrenia based on carbonyl stress: Protein carbonyl is a possible biomarker of psychiatric disorders. AB - Although it's well known that protein carbonyl (PCO) and advanced glycation end products (AGEs) levels are elevated in plasma from patients with renal dysfunction, we recently identified patients who had no renal dysfunction but possessed high levels of plasma pentosidine (PEN), which is an AGEs, and low vitamin B6 levels in serum. In this study, we investigated the status of carbonyl stress to characterize the subtype of schizophrenia. When plasma samples were subjected to Western blot analysis for various AGEs, clear differences were only observed with the anti-PEN antibody in the plasma from schizophrenic patients. Moreover, we determined the formation of protein carbonyl (PCO), a typical indicator of carbonyl stress, occurred prior to the accumulation of PEN in the plasma of schizophrenic patients. PCO levels in the plasma from schizophrenic patients were significantly higher than that from healthy subjects. Western blots analysis clearly showed that albumin and IgG were markedly carbonylated in the plasma of some patients. Thus, PCOs may be a novel marker of carbonyl stress-type schizophrenia in addition to albumin containing PEN structure. PMID- 26431871 TI - Selective enhancement of wnt4 expression by cyclic AMP-associated cooperation between rat central astrocytes and microglia. AB - The wnt protein family has important members involved in cell differentiation, proliferation and plasticity expression; however, little is known about its biosynthesis processes. On the other hand, an increase in the intracerebral cyclic adenosine 3', 5'-monophosphate (cAMP) level leads to synaptic plasticity via the de novo synthesis of any protein. Here, the effect of dibutyryl cAMP (dbcAMP), a membrane permeability cAMP analog, on the wnt family was investigated in rat primary-cultured glial cells containing astrocytes and microglia. Among wnt3a, 4, 5a, 7a and 11 mRNA, only wnt4 expression was increased by longer treatment (24 h), compared with short treatment (2 h), with dbcAMP in a concentration-dependent manner, and its effect reached statistical significance at 1 mM. In cultures of isolated astrocytes or microglia, wnt4 expression was not affected by 1 mM dbcAMP for 24 h, and microglial wnt4 protein was undetectable even when cells were treated with the drug. Mixed glial cells treated for 24 h with 1 mM dbcAMP showed significantly increased wnt4 protein, as well as mRNA. Immunofluorescence manifested that cells that expressed wnt4 protein were astrocytes, but not microglia. Intraperitoneal injection of 1.25 mg/kg rolipram, a phosphodiesterase (PDE) IV inhibitor that can pass through the blood brain barrier and inhibits cAMP degradation specifically, showed a tendency to increase wnt4 expression in the adult rat brain after 24 h, and the increases in wnt4 mRNA and protein levels reached statistical significance in the hippocampus and striatum, respectively. This is the first finding to help elucidate the selective biosynthesis of central wnt4 through cAMP-stimulated microglia and astrocytes interaction. PMID- 26431872 TI - Glyceraldehyde-3-phosphate dehydrogenase aggregation inhibitor peptide: A potential therapeutic strategy against oxidative stress-induced cell death. AB - The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has multiple functions, including mediating oxidative stress-induced neuronal cell death. This process is associated with disulfide-bonded GAPDH aggregation. Some reports suggest a link between GAPDH and the pathogenesis of several oxidative stress-related diseases. However, the pathological significance of GAPDH aggregation in disease pathogenesis remains unclear due to the lack of an effective GAPDH aggregation inhibitor. In this study, we identified a GAPDH aggregation inhibitor (GAI) peptide and evaluated its biological profile. The decapeptide GAI specifically inhibited GAPDH aggregation in a concentration dependent manner. Additionally, the GAI peptide did not affect GAPDH glycolytic activity or cell viability. The GAI peptide also exerted a protective effect against oxidative stress-induced cell death in SH-SY5Y cells. This peptide could potentially serve as a tool to investigate GAPDH aggregation-related neurodegenerative and neuropsychiatric disorders and as a possible therapy for diseases associated with oxidative stress-induced cell death. PMID- 26431873 TI - Ubiquitous versus restricted expression of the two mouse dendritic cell C-type lectin receptors, DCIR1 and DCAR2, among myeloid cells. AB - Dendritic cell inhibitory receptor 1 (DCIR1, also known as DCIR and Clec4a2) and dendritic cell activating receptor 2 (DCAR2, also known as DCAR and Clec4b1) are mouse lectin receptors expressed on antigen presenting cells. They have structurally similar C-type lectin domains, of which amino acid sequences show 90.5% identity, and commercially available antibodies against them cross-react each other. Here we have established novel antibodies against DCIR1 and DCAR2 that can unambiguously discriminate DCIR1 and DCAR2 and examined their distribution among various immune cells. While DCIR1 was ubiquitously expressed on myeloid cells, including conventional DCs (cDCs), macrophages, neutrophils and eosinophils, in various immune organs, significant expression of DCAR2 was detected only on subpopulations of cDCs from bone marrow and skin-draining lymph nodes. Interestingly, in FITC-painted mice, DCAR2 was expressed on all of the FITC(+) cDCs, which had migrated from the skin after FITC painting, suggesting that DCAR2 can be a marker of migratory cDCs in skin-draining lymph nodes. Our findings provide a basis to investigate in vivo function of DCIR1 and DCAR2. PMID- 26431874 TI - KDM3A interacted with p53K372me1 and regulated p53 binding to PUMA in gastric cancer. AB - Chemoresistance remains a major problem in the treatment of gastric cancer patients, leading to the serious limitation of efficacy of chemotherapeutic regime. However, the underlying mechanism remains largely unknown. In our present study, we for the first time found that knock down of KDM3A can promote apoptosis induced by chemoreagent Cisplatin and Paclitaxel through p53. Mechanistically, through promoting p53 binding to the promoter of PUMA. However, knock down of KDM3A as such doesn't affect p53 level. In addition, KDM3A can interact with p53K372me1 in protein-protein interaction fashion, leading to the inactivation of p53, may eventually leading to chemoresistance of gastric cancer. PMID- 26431875 TI - Intracellular Ca(2+) oscillations generated via the extracellular Ca(2+)-sensing receptor (CaSR) in response to extracellular Ca(2+) or L-phenylalanine: Impact of the highly conservative mutation Ser170Thr. AB - The extracellular Ca(2+)-sensing receptor (CaSR) is an allosteric protein that responds to changes in the extracellular concentration of Ca(2+) ([Ca(2+)]e) and aromatic amino acids with the production of different patterns of oscillations in intracellular Ca(2+) concentration ([Ca(2+)]i). An increase in [Ca(2+)]e stimulates sinusoidal oscillations in [Ca(2+)]i whereas aromatic amino acid induced CaR activation in the presence of a threshold [Ca(2+)]e promotes transient oscillations in [Ca(2+)]i. Here, we examined spontaneous and ligand evoked [Ca(2+)]i oscillations in single HEK-293 cells transfected with the wild type CaSR or with a mutant CaSR in which Ser170 was converted to Thr (CaSRS170T). Our analysis demonstrates that cells expressing CaSRS170T display [Ca(2+)]i oscillations in the presence of low concentrations of extracellular Ca(2+) and respond to L-Phe with robust transient [Ca(2+)]i oscillations. Our results indicate that the S170T mutation induces a marked increase in CaSR sensitivity to [Ca(2+)]e and imply that the allosteric regulation of the CaSR by aromatic amino acids is not only mediated by an heterotropic positive effect on Ca(2+) binding cooperativity but, as biased agonists, aromatic amino acids stabilize a CaSR conformation that couples to a different signaling pathway leading to transient [Ca(2+)]i oscillations. PMID- 26431877 TI - Urotensin II contributes to collagen synthesis and up-regulates Egr-1 expression in cultured pulmonary arterial smooth muscle cells through the ERK1/2 pathway. AB - AIM: The objective of this study was to investigate the effects of urotensin II (UII) treatment on the proliferation and collagen synthesis of cultured rat pulmonary arterial smooth muscle cells (PASMCs) and to explore whether these effects are mediated by mitogen-activated protein kinase (MAPK) signaling pathways and early growth response 1 (Egr-1). METHODS: The proliferation of cultured PASMCs stimulated with different doses of UII was detected by BrdU incorporation. The mRNA expression levels of procollagen I (procol I), procollagen III (procol III), extracellular regulated protein kinase 1/2 (ERK1/2), stress-stimulated protein kinase (Sapk), p38 MAPK (p38), and Egr-1 mRNA in cultured PASMCs after treatment with UII, the UII-specific antagonist urantide, and the ERK1/2 inhibitor PD98059 were detected by real-time polymerase chain reaction (PCR), and the protein expression levels of procol I, procol III, phosphorylated (p)-ERK1/2, p-Sapk, p-p38, and Egr-1 were detected by Western blotting. RESULTS: Treatment with UII increased the proliferation of cultured PASMCs in a dose-dependent manner (P<0.05). However, treatment with urantide and PD98059 inhibited the promoting effect of UII on PASMC proliferation (P<0.05). Real-time PCR analysis showed that UII up-regulated the expression of procol I, procol III, ERK1/2, Sapk, and Egr-1 mRNA (P<0.05), but not p38 mRNA. However, the up-regulating effect of UII was inhibited by PD98059 and urantide. Western blotting analysis showed that UII increased the synthesis of collagen I, collagen III, p-ERK1/2, p-Sapk, and Egr-1, and these effects also were inhibited by PD98059 and urantide (P<0.05). CONCLUSIONS: Egr-1 participates in the UII mediated proliferation and collagen synthesis of cultured rat PASMCs via activation of the ERK1/2 signaling pathway. PMID- 26431876 TI - Hepatic scavenger receptor BI is associated with type 2 diabetes but unrelated to human and murine non-alcoholic fatty liver disease. AB - Scavenger receptor, class B type I (SR-BI) is a physiologically relevant regulator of high density lipoprotein (HDL) metabolism. Low HDL is a common feature of patients with non-alcoholic fatty liver disease (NAFLD). Here, hepatic SR-BI expression was analyzed in human and murine NAFLD. In primary human hepatocytes NAFLD relevant factors like inflammatory cytokines, lipopolysaccharide and TGF-beta did not affect SR-BI protein. Similarly, oleate and palmitate had no effect. The adipokines chemerin, adiponectin, leptin and omentin did not regulate SR-BI expression. Accordingly, hepatic SR-BI was not changed in human and murine fatty liver and non-alcoholic steatohepatits. SR-BI was higher in type 2 diabetes patients but not in those with hypercholesterolemia. The current study indicates a minor if any role of SR-BI in human and murine NAFLD. PMID- 26431879 TI - O-GlcNAc modification of Sp3 and Sp4 transcription factors negatively regulates their transcriptional activities. AB - The addition of O-linked N-acetylglucosamine (O-GlcNAc) on serine or threonine modifies a myriad of proteins and regulates their function, stability and localization. O-GlcNAc modification is common among chromosome-associated proteins, such as transcription factors, suggesting its extensive involvement in gene expression regulation. In this study, we demonstrate the O-GlcNAc status of the Sp family members of transcription factors and the functional impact on their transcriptional activities. We highlight the presence of O-GlcNAc residues in Sp3 and Sp4, but not Sp2, as demonstrated by their enrichment in GlcNAc positive protein fractions and by detection of O-GlcNAc residues on Sp3 and Sp4 co expressed in Escherichia coli together with O-GlcNAc transferase (OGT) using an O GlcNAc-specific antibody. Deletion mutants of Sp3 and Sp4 indicate that the majority of O-GlcNAc sites reside in their N-terminal transactivation domain. Overall, using reporter gene assays and co-immunoprecipitations, we demonstrate a functional inhibitory role of O-GlcNAc modifications in Sp3 and Sp4 transcription factors. Thereby, our study strengthens the current notion that O-GlcNAc modification is an important regulator of protein interactome. PMID- 26431878 TI - Angelica sinensis polysaccharides promotes apoptosis in human breast cancer cells via CREB-regulated caspase-3 activation. AB - Angelica sinensis polysaccharide (ASP) is purified from the fresh roots of Angelica sinensis (AS). This traditional Chinese medicine has been used for thousands of years for treating gynecological diseases and used in functional foods for the prevention and treatment of various diseases, such as inflammation and cancer. The antitumor activity of ASP is related to its biological activities, because it suppresses a variety of pro-proliferative or anti apoptotic factors that are dramatically expressed in cancer cells of given types. In this study, we show that angelica sinensis polysaccharide induced apoptosis in breast cancer cells of T47D over-expressing the Cyclic AMP response element binding protein (CREB), inducing apoptosis-related signaling pathway activity. The result also found that ASP caused cell death was linked to caspase activity, accompanied by the loss of mitochondrial membrane potential, cytochrome c release, and Bax translocation from the cytosol to the mitochondria. We found that ASP significantly affected the poly-ADP-ribose polymerase (PARP), Bcl-2 Associated X Protein (Bax), Bcl-2, Bcl-xL and apoptotic protease activating facter-1 (Apaf1) protein expression in a dose- and time-dependent manner. DAPI staining and Flow cytometry were used to analyze apoptosis. The nude mice xenograft model was used to evaluate the antitumor effect of ASP in vivo. ASP has profound antitumor effect on T47D cells, probably by inducing apoptosis through CREB signaling pathway. Thus, these results suggest that ASP would be a promising therapeutic agent for breast cancer. PMID- 26431880 TI - Smaller Amygdala Volumes in Patients With Chronic Low Back Pain Compared With Healthy Control Individuals. AB - Although preclinical and clinical data strongly support an association between the amygdala and chronic pain by the presence of mood and cognitive disturbances in affected individuals, little attention has been paid to morphometric measurement of the structure in patients with chronic low back pain (CLBP). In the present study, magnetic resonance volumetric and surface analysis, using FMRIB's integrated registration and segmentation tool (FIRST), were performed to compare structural magnetic resonance imaging data obtained from 33 patients with CLBP with those obtained from 33 demographically similar healthy control individuals. Our results indicated that the normalized volumes of the left and right amygdala were significantly smaller in the CLBP group than in the control group. Detailed surface analyses further localized these differences. The degree of volume reduction was different between the left and right amygdala, with a greater involvement of the left side. Both groups exhibited similar significant hemispheric asymmetry for the amygdala (left > right). Similar asymmetry was suggested in the subgroup of 24 unmedicated patients. No significant correlations were found between amygdala volumes and pain characteristics or depressive symptoms. Our study provides in vivo imaging evidence of abnormal morphology of the amygdala in patients with CLBP using a fully automated segmentation method. PERSPECTIVE: Our study found that patients with CLBP had statistically significantly smaller normalized volumes of the bilateral amygdala, compared with healthy control individuals, with a greater involvement of the left side. These results may help to characterize the impaired affective-cognitive dimension in patients with chronic pain. PMID- 26431881 TI - My Brain Reads Pain in Your Face, Before Knowing Your Gender. AB - Humans are expert at recognizing facial features whether they are variable (emotions) or unchangeable (gender). Because of its huge communicative value, pain might be detected faster in faces than unchangeable features. Based on this assumption, we aimed to find a presentation time that enables subliminal discrimination of pain facial expression without permitting gender discrimination. For 80 individuals, we compared the time needed (50, 100, 150, or 200 milliseconds) to discriminate masked static pain faces among anger and neutral faces with the time needed to discriminate male from female faces. Whether these discriminations were associated with conscious reportability was tested with confidence measures on 40 other individuals. The results showed that, at 100 milliseconds, 75% of participants discriminated pain above chance level, whereas only 20% of participants discriminated the gender. Moreover, this pain discrimination appeared to be subliminal. This priority of pain over gender might exist because, even if pain faces are complex stimuli encoding both the sensory and the affective component of pain, they signal a danger. This supports the evolution theory relating to the necessity of quickly reading aversive emotions to ensure survival but might also be at the basis of altruistic behavior such as help and compassion. PERSPECTIVE: This study shows that pain facial expression can be processed subliminally after brief presentation times, which might be helpful for critical emergency situations in clinical settings. PMID- 26431882 TI - Concordance of Phantom and Residual Limb Pain Phenotypes in Double Amputees: Evidence for the Contribution of Distinct and Common Individual Factors. AB - Most, but not all, limb amputees develop phantom limb pain (PLP) or residual limb pain (RLP), and large interindividual differences in pain intensity and course are apparent. The present cross-sectional study of 122 double amputees investigated the possible role of genetic factors in PLP and RLP, assuming that strong individual predisposition results in high intraindividual concordance in pain phenotype. Intraindividual concordance was observed in 116 (95%) patients for development of PLP and in 110 patients (90%) for development of RLP. For both pain types, high intraindividual concordance was also observed for remission and current intensity. Moderate association for lifetime history and current intensity of PLP and RLP was observed both within and between limbs. The high intraindividual concordance in pain phenotypes suggests strong individual predisposition for PLP and RLP development. However, the finding of only moderate association between PLP and RLP suggests that susceptibility to these pain phenomena involves distinct, as well as common, risk factors. Genome-wide studies in large samples of single amputees may facilitate the dissection of these phenotypes and their underlying mechanisms. PERSPECTIVE: The observation of high intraindividual concordance for PLP and RLP in 122 double amputees suggests that individual factors contribute to post-amputation pain. The relatively low intraindividual association between PLP and RLP suggests that these factors are at least partially specific for each pain type. PMID- 26431883 TI - Associations of birth outcomes with maternal polybrominated diphenyl ethers and thyroid hormones during pregnancy. AB - BACKGROUND: Previous research has linked polybrominated diphenyl ether (PBDE) exposure to poor birth outcomes and altered thyroid hormone levels. OBJECTIVES: We examined whether maternal PBDE serum levels were associated with infant birth weight (g), head circumference (cm), birth length (cm), and birth weight percentile for gestational age. We explored the potential for a mediating role of thyroid hormone levels. METHODS: During 2008-2010, we recruited 140 pregnant women in their third trimester as part of a larger clinical obstetrics study known as Healthy Pregnancy, Healthy Baby. Blood samples were collected during a routine prenatal clinic visit. Serum was analyzed for PBDEs, phenolic metabolites, and thyroid hormones. Birth outcome information was abstracted from medical records. RESULTS: In unadjusted models, a two-fold increase in maternal BDE 153 was associated with an average decrease in head circumference of 0.32cm (95% CI: -0.53, -0.12); however, this association was attenuated after control for maternal risk factors. BDE 47 and 99 were similarly negatively associated but with 95% confidence intervals crossing the null. Associations were unchanged in the presence of thyroid hormones. CONCLUSIONS: Our data suggest a potential deleterious association between maternal PBDE levels and infant head circumference; however, confirmatory studies are needed in larger sample sizes. A mediating role of thyroid hormones was not apparent. PMID- 26431884 TI - Morphology and molecular phylogeny of Pleuronema orientale spec. nov. and Pleuronema paucisaetosum spec. nov. (Ciliophora, Scuticociliata) from Hangzhou Bay, China. AB - Two novel species, Pleuronema orientale spec. nov. and Pleuronema paucisaetosum spec. nov., isolated from coastal waters of Hangzhou Bay, China, were investigated with standard methods. Pleuronema orientale is characterized as follows: size in vivo 95-135 * 50-85 MUm; usually one spherical macronucleus; 12 15 prolonged caudal cilia; two or three preoral kineties and 42-50 somatic kineties; membranelle 1 (M1) about 20 % of the anterior fragment of membranelle 2 (M2a) in length, consisting of three longitudinal rows of kinetosomes; posterior end of M2a hook-like; membranelle 3 (M3) three-rowed. Pleuronema paucisaetosum is characterized as follows: size in vivo about 55-85 * 25-55 MUm; four or five preoral kineties and 21-23 somatic kineties; posterior end of M2a hook-like; M3 three-rowed. The small-subunit rRNA gene was sequenced for both species. Phylogenetic analyses revealed that P. orientale is most closely related to Pleuronema puytoraci and that P. paucisaetosum is sister to Pleuronema grolierei and Pleuronema setigerum (GenBank accession no. JX310015). With the inclusion of the two new sequences, the monophyly of the genus Pleuronema is not supported. PMID- 26431886 TI - Promoting protein self-association in non-glycosylated Thermomyces lanuginosus lipase based on crystal lattice contacts. AB - We have used the crystal structure of Thermomyces lanuginosus lipase (TlL) to identify and strengthen potential protein-protein interaction sites in solution. As wildtype we used a deglycosylated mutant of TlL (N33Q). We designed a number of TlL mutants to promote interactions via interfaces detected in the crystal lattice structure, through strengthening of hydrophobic, polar or electrostatic contacts or truncation of sterically blocking residues. We identify a mutant predicted to lead to increased interfacial hydrophobic contacts (N92F) that shows markedly increased self-association properties on native gradient gels. While wildtype TlL mainly forms monomer and <5% dimers, N92F forms stable trimers and dimers according to Size-Exclusion Chromatography and Small-Angle X-ray Scattering. These oligomers account for ~25% of the population and their enzymatic activity is comparable to that of the monomer. Self-association stabilizes TlL against thermal denaturation. Furthermore, the trimer is stable to dilution and requires high concentrations (>2M) of urea to dissociate. We conclude that crystal lattice contacts are a good starting point for design strategies to promote protein self-association. PMID- 26431887 TI - Neoadjuvant Chemotherapy With Gemcitabine and Cisplatin for Plasmacytoid Urothelial Bladder Cancer: A Case Report and Review of the Literature. PMID- 26431885 TI - Bendavia restores mitochondrial energy metabolism gene expression and suppresses cardiac fibrosis in the border zone of the infarcted heart. AB - AIMS: We have observed that Bendavia, a mitochondrial-targeting peptide that binds the phospholipid cardiolipin and stabilizes the components of electron transport and ATP generation, improves cardiac function and prevents left ventricular remodeling in a 6week rat myocardial infarction (MI) model. We hypothesized that Bendavia restores mitochondrial biogenesis and gene expression, suppresses cardiac fibrosis, and preserves sarco/endoplasmic reticulum (SERCA2a) level in the noninfarcted border zone of infarcted hearts. MAIN METHODS: Starting 2h after left coronary artery ligation, rats were randomized to receive Bendavia (3mg/kg/day), water or sham operation. At 6weeks, PCR array and qRT-PCR was performed to detect gene expression. Picrosirius red staining was used to analyze collagen deposition. KEY FINDINGS: There was decreased expression of 70 out of 84 genes related to mitochondrial energy metabolism in the border zone of untreated hearts. This down-regulation was largely reversed by Bendavia treatment. Downregulated mitochondrial biogenesis and glucose & fatty acid (FA) oxidation related genes were restored by administration of Bendavia. Matrix metalloproteinase (MMP9) and tissue inhibitor of metalloproteinase (TIMP1) gene expression were significantly increased in the border zone of untreated hearts. Bendavia completely prevented up-regulation of MMP9, but maintained TIMP1 gene expression. Picrosirius red staining demonstrated that Bendavia suppressed collagen deposition within border zone. In addition, Bendavia showed a trend toward restoring SERCA2a expression. SIGNIFICANCE: Bendavia restored expression of mitochondrial energy metabolism related genes, prevented myocardial matrix remodeling and preserved SERCA2a expression in the noninfarcted border, which may have contributed to the preservation of cardiac structure and function. PMID- 26431888 TI - Elevated IL-35 in bone marrow of the patients with acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is the most common hematological malignancy in adults, but the etiology of it remains poorly understood. IL-35 is a recently described cytokine composed of an IL-12 subunit p35 and an IL-27 subunit Epstein Barr virus induced gene 3 (EBI3), and has an immunosuppressive effect on inflammation through induction of regulatory T cells (Tregs) and suppression of Th1 and Th17. Recently, we have illustrated that concentrations of IL-35 in peripheral blood are up-regulated in newly diagnosed (ND) AML patients. However, whether IL-35 in bone marrow is increased in AML patients is not clear. In this study, we examined IL-35 in bone marrow by various methods including RT-PCR, ELISA, FCM and IHC, and found that IL-35 levels are also increased significantly in bone marrow of adult AML patients. Furthermore, we investigated that concentrations of bone marrow IL-35 in ND group were higher than that in complete remission (CR) group and control group, but there was no significant difference compared to that in relapse group. In conclusion, IL-35 was elevated in bone marrow of adult AML patients and this increase was correlated with the clinical stages of malignancy, suggesting that IL-35 is involved in pathogenesis of AML. PMID- 26431889 TI - HLA-frequencies of Austrian umbilical cord blood samples. AB - We investigated HLA-A, HLA-B, and HLA-DRB1 gene frequencies in 1368 unrelated Austrian umbilical cord blood samples. HLA-C gene frequencies were investigated in a subgroup of 503 samples. HLA typing was performed via sequenced-based typing (SBT). The aim of this study was to examine the HLA diversity in a large Austrian population sample. In addition we present results of a subsample of 100 samples at a subtype level. This study is the first systematic investigation of donated umbilical cord blood samples in the Austrian population. PMID- 26431890 TI - Identification and localization of a Novel Invasin of Plasmodium falciparum. AB - Plasmodium falciparum is the causative organism for the most severe form of malaria among humans. The clinical symptoms are accredited to the asexual stage of parasite life cycle, involving merozoite invasion of erythrocyte, development and re-invasion into the new erythrocyte. Interaction of parasite proteins present on the surface or secreted from apical organelles with the host receptors is indispensable for the invasion process. Identification and elucidation of precise localization and function of these proteins will not only enhance our understanding of this process but will also aid in the progress of development of treatment strategies against malaria. Here we report the identification and localization of a novel protein, PfAEP (P. falciparum Apical Exonemal Protein) (PF3D7_1137200/ PF11_0383) which is conserved across Plasmodium species. Transcription and translation analysis have confirmed its expression in the schizont stage of P. falciparum. Super-resolution microscopy in schizonts and merozoites revealed its localization in the exonemes of P. falciparum. PMID- 26431891 TI - Renal Collision and Composite Tumors: Imaging and Pathophysiology. AB - OBJECTIVE: To illustrate the imaging appearances of a spectrum of renal collision and composite tumors. Occurrence of collision and composite tumors in the genitourinary tract is rare compared to the usual occurrence of synchronous tumors. METHODS: Case studies were chosen that represent the different tumors. Analysis was made on both the imaging and the pathology if excision was performed. RESULTS: Presence of 2 different cell types can lead to confusing imaging findings, and biopsy or excision is typically needed for final diagnosis. Some composite tumors have a characteristic appearance on imaging based on their pathologic features. CONCLUSION: Familiarity with imaging findings may help radiologists include these tumors in their differential diagnosis. PMID- 26431892 TI - Prevention of Ischemic Priapism in Sickle Cell Disease: Sildenafil: Commentary on: Randomized Controlled Trial of Sildenafil for Preventing Recurrent Ischemic Priapism in Sickle Cell Disease. PMID- 26431893 TI - Colocalization properties of elementary Ca(2+) release signals with structures specific to the contractile filaments and the tubular system of intact mouse skeletal muscle fibers. AB - Ca(2+) regulates several important intracellular processes. We combined second harmonic generation (SHG) and two photon excited fluorescence microscopy (2PFM) to simultaneously record the SHG signal of the myosin filaments and localized elementary Ca(2+) release signals (LCSs). We found LCSs associated with Y-shaped structures of the myosin filament pattern (YMs), so called verniers, in intact mouse skeletal muscle fibers under hypertonic treatment. Ion channels crucial for the Ca(2+) regulation are located in the tubular system, a system that is important for Ca(2+) regulation and excitation-contraction coupling. We investigated the tubular system of intact, living mouse skeletal muscle fibers using 2PFM and the fluorescent Ca(2+) indicator Fluo-4 dissolved in the external solution or the membrane dye di-8-ANEPPS. We simultaneously measured the SHG signal from the myosin filaments of the skeletal muscle fibers. We found that at least a subset of the YMs observed in SHG images are closely juxtaposed with Y shaped structures of the transverse tubules (YTs). The distances of corresponding YMs and YTs yield values between 1.3 MUm and 4.1 MUm including pixel uncertainty with a mean distance of 2.52+/-0.10 MUm (S.E.M., n=41). Additionally, we observed that some of the linear-shaped areas in the tubular system are colocalized with linear-shaped areas in the SHG images. PMID- 26431894 TI - Protein domain mapping by internal labeling and single particle electron microscopy. AB - In recent years, electron microscopy (EM) and single particle analysis have emerged as essential tools for investigating the architecture of large biological complexes. When high resolution is achievable, crystal structure docking and de novo modeling allows for precise assignment of individual protein domain sequences. However, the achievable resolution may limit the ability to do so, especially when small or flexible complexes are under study. In such cases, protein labeling has emerged as an important complementary tool to characterize domain architecture and elucidate functional mechanistic details. All labeling strategies proposed to date are either focused on the identification of the position of protein termini or require multi-step labeling strategies, potentially interfering with the final labeling efficiency. Here we describe a strategy for determining the position of internal protein domains within EM maps using a recombinant one-step labeling approach named Efficient Mapping by Internal Labeling (EMIL). EMIL takes advantage of the close spatial proximity of the GFP's N- and C-termini to generate protein chimeras containing an internal GFP at desired locations along the main protein chain. We apply this method to characterize the subunit domain localization of the human Polycomb Repressive Complex 2. PMID- 26431895 TI - FEI's direct electron detector developments: Embarking on a revolution in cryo TEM. AB - In early 2011 FEI Company launched the "Falcon", its first commercial direct electron detector product intended for application in 3-D electron microscopy in the life sciences. In this paper we discuss the principle of direct electron detection and its implementation in Falcon cameras. We describe the signal formation in the sensor and its impact on the detection quantum efficiency (DQE) of the sensor. Insights into the signal formation led us to improved camera designs. Three significant improvements are discussed. (1) Back thinning of the sensor. This is implemented in the second-generation Falcon (Falcon 2), where the sensor thickness is reduced to 50 MUm, and in the latest generation Falcon 3 detector with further back-thinning down to 30 MUm. (2) The introduction of electron counting, a signal processing technology implemented in Falcon 3. (3) Dose fractionation mode, which allows the user to access intermediate results during the illumination of the sample. PMID- 26431896 TI - Mineral-bearing vesicle transport in sea urchin embryos. AB - Sea urchin embryos sequester calcium from the sea water. This calcium is deposited in a concentrated form in granule bearing vesicles both in the epithelium and in mesenchymal cells. Here we use in vivo calcein labeling and confocal Raman spectroscopy, as well as cryo-FIB-SEM 3D structural reconstructions, to investigate the processes occurring in the internal cavity of the embryo, the blastocoel. We demonstrate that calcein stained granules are also present in the filopodial network within the blastocoel. Simultaneous fluorescence imaging and Raman spectroscopy show that these granules do contain a calcium mineral. By tracking the movements of these granules, we show that the granules in the epithelium and primary mesenchymal cells barely move, but those in the filopodial network move long distances. We could however not detect any unidirectional movement of the filopodial granules. We also show the presence of mineral containing multivesicular vesicles that also move in the filopodial network. We conclude that the filopodial network is an integral part of the mineral transport process, and possibly also for sequestering calcium and other ions. Although much of the sequestered calcium is deposited in the mineralized skeleton, a significant amount is used for other purposes, and this may be temporarily stored in these membrane-delineated intracellular deposits. PMID- 26431897 TI - Functional Mapping in Pediatric Epilepsy Surgical Candidates: Functional Magnetic Resonance Imaging Under Sedation With Chloral Hydrate. AB - OBJECTIVES: Functional magnetic resonance imaging is a useful tool to lateralize and localize language in presurgical patients, as well as to localize other functionally salient cortex. The procedure is typically reserved for older children and adults, since it necessitates cooperation and participation in tasks. We have explored the applicability of functional magnetic resonance imaging for language and motor mapping at our epilepsy surgical center in younger children under sedation with chloral hydrate. METHODS: A series of 24 consecutive patients undergoing magnetic resonance imaging, between ages 16 months and 11 years, were scanned under sedation. Assisted finger-tapping and foot-tapping tasks were conducted for the purpose of motor mapping in nine patients, and a speech-based auditory task was conducted in 23 of the 24 patients for the purpose of lateralizing and localizing language. RESULTS: Significant blood oxygen level dependent signal increases in hand and foot regions of the primary motor cortex were generated in all but one patient who underwent the motor mapping tasks. Signal increases in receptive language cortex were convincingly generated in 12 of the 23 (52%) patients who underwent the speech-based auditory task. CONCLUSIONS: These results suggest that functional magnetic resonance imaging can help to localize motor and/or somatosensory cortex and language cortex in young children under sedation with chloral hydrate. This procedure may be used to assist in presurgical planning. The findings also imply that a sedating agent may be used in pediatric neuroimaging as an alternative to general anesthesia. PMID- 26431899 TI - Microalgae-microbial fuel cell: A mini review. AB - Microalgae-microbial fuel cells (mMFCs) are a device that can convert solar energy to electrical energy via biological pathways. This mini-review lists new research and development works on microalgae processes, microbial fuel cell (MFC) processes, and their combined version, mMFC. The substantial improvement and technological advancement are highlighted, with a discussion on the challenges and prospects for possible commercialization of mMFC technologies. PMID- 26431898 TI - Encephalitis Lethargica With Isolated Substantia Nigra Lesions Followed by a Second Encephalitis in a Child With Humoral Immunodeficiency. AB - BACKGROUND: Encephalitis lethargica is an encephalitic illness with multiple nervous system symptoms. Lesions only involving substantia nigra on magnetic resonance imaging are uncommon, especially in children. A second encephalitis illness after encephalitis lethargica has never been reported before. PATIENT DESCRIPTION: We describe a 7-year-old boy with humoral immunity deficiency who developed encephalitis lethargica associated with bilateral substantia nigra lesions on magnetic resonance imaging. After a nearly complete recovery, he developed encephalitis once again. He was diagnosed with encephalitis lethargica with somnolence, akinetic mutism, and ophthalmoplegia after intermittent fever. Cerebrospinal fluid pleocytosis and positive oligoclonal bands were documented. Symmetrical substantia nigra lesions on high-intensity magnetic resonance imaging gradually evolved into a liquid signal. He had almost recovered when he developed fatigue and hypersomnia and was diagnosed with encephalitis again, supported by mild pleocytosis in cerebrospinal fluid and subcortical white matter lesions in the frontal lobes. His symptoms resolved following administration of corticosteroids and immunoglobulins. CONCLUSION: This is the first report of an immune-deficient child to develop encephalitis lethargica with isolated substantia nigra lesions on magnetic resonance imaging and a second encephalitis illness after recovery from encephalitis lethargica. PMID- 26431900 TI - Early postnatal handling and environmental enrichment improve the behavioral responses of 17-month-old 3xTg-AD and non-transgenic mice in the Forced Swim Test in a gender-dependent manner. AB - Forced Swimming Test (FST) models behavioural despair in animals by loss of motivation to respond or the refusal to escape. The present study was aimed at characterizing genetic (genotype and gender) and environmental factors (age/stage of disease and rearing conditions: C, standard; H, early postnatal handling; EE, environmental enrichment consisting in physical exercise as well as social and object enrichment) that may modulate the poor behavioural and cognitive flexibility response we have recently described in 12-month-old male 3xTg-AD mice in the FST. The comprehensive analysis of the ethogram shown in the FST considered the intervals of the test (0-2 and 2-6min), all the elicited behavioural responses (immobility, swimming and climbing) and their features (total duration and frequency of episodes). The long persistence of behaviours found in 17-month-old (late-stages of disease) 3xTg-AD mice was comparable to that recently described in males at 12 months of age (beginning of advanced stages) but also suggested increased age-dependent frailty in both genotypes. The poor behavioral flexibility of 3xTg-AD mice to elicit the behavioural despair shown by the NTg mice, was also found in the female gender. Finally, the present work demonstrates that early-life interventions were able to improve the time and frequency of episodes of immobility, being more evident in the female gender of both old NTg and 3xTg-AD mice. Ontogenic modulation by early-postnatal handling resulted in a more effective long-term improvement of the elicited behaviours in the FST than that achieved by environmental enrichment. The results talk in favor of the beneficence of early-life interventions on ageing in both healthy and disease conditions. PMID- 26431902 TI - From state dissociation to status dissociatus. AB - The states of being are conventionally defined by the simultaneous occurrence of behavioral, neurophysiological and autonomic descriptors. State dissociation disorders are due to the intrusion of features typical of a different state into an ongoing state. Disorders related to these conditions are classified according to the ongoing main state and comprise: 1) Dissociation from prevailing wakefulness as seen in hypnagogic or hypnopompic hallucinations, automatic behaviors, sleep drunkenness, cataplexy and sleep paralysis 2) Dissociation from rapid eye movement (REM) sleep as seen in REM sleep behavior disorder and lucid dreaming and 3) Dissociation from NREM sleep as seen in the disorders of arousal. The extreme expression of states dissociation is characterized by the asynchronous occurrence of the various components of the different states that prevents the recognition of any state of being. This condition has been named status dissociatus. According to the underlying disorders/diseases and to their severity, among status dissociatus we may recognize disorders in which such an extreme dissociation occurs only at night time or intermittently (i.e., autoimmune encephalopathies, narcolepsy type 1 and IgLON5 parasomnia), and others in which it occurs nearly continuously with complete loss of any conventionally defined state of being, and of the circadian pattern (agrypnia excitata). Here, we render a comprehensive review of all diseases/disorders associated with state dissociation and status dissociatus and propose a critical classification of this complex scenario. PMID- 26431901 TI - Genetic polymorphisms in TNFSF13 and FDX1 are associated with IgA nephropathy in the Han Chinese population. AB - IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, and its pathogenesis is influenced by both genetic and environmental factors. In this study, we evaluated 23 tag single-nucleotide polymorphisms (tSNPs) in 21 IgAN-associated genes, in 200 subjects with IgAN and 310 healthy gender- and age matched unrelated control subjects with no history of renal disease or hypertension. Using the co-dominant model, we found that two genotypes of rs3803800 in TNFSF13 were associated with an increased risk of IgAN: "GA" (OR = 1.03, 95% CI = 0.71-1.51, p = 0.018) and "AA" (OR = 2.45, 95% CI = 1.29-4.65, p = 0.018). The "AA" genotype was also associated with an increased risk of IgAN in the recessive model (OR = 2.41, 95% CI = 1.30-4.46, p = 0.018), as was the genotype "AA" rs10488764 in FDX1 (OR = 1.88, 95% CI = 1.01-3.53, p = 0.048). Interestingly, we found that the allele "A" of rs3803800 in TNFSF13 is associated with a decreased risk of IgAN in females (OR = 0.43, 95% CI = 0.20-0.95, p = 0.009), but with an increased risk in males (OR = 1.78, 95% CI = 0.86-3.66, p = 0.009). Our findings, combined with previously reported results, suggest that TNFSF13 and FDX1 have potential roles in IgAN in the Han Chinese population. This information may be useful in the development of early prognostics for IgAN. PMID- 26431903 TI - Maternal mortality among women with sickle-cell disease in France, 1996-2009. AB - OBJECTIVE: To describe maternal mortality among women with sickle-cell disease in France. STUDY DESIGN: Data from the national confidential enquiry into maternal deaths and from reference centres for sickle-cell disease were examined to identify women with this disease who died in France during 1996-2009. The maternal mortality ratio among women with sickle-cell disease was estimated and compared with the ratio in the general population. Characteristics of these women and their pregnancies and circumstances of their deaths were examined in detail. RESULTS: Fifteen maternal deaths occurred among an estimated 3300 live births to women with sickle-cell disease, for a maternal mortality ratio of 454 per 100000 live births (95% CI [254; 750]), versus 9.4/100000 in the general population. Ten women were homozygous (SS) for sickle-cell disease, and five were composite heterozygotes. The episode leading to death appeared in the antepartum period for seven women (47%). Two women died of septic shock during pregnancy, one at 6 weeks, the other at 24 weeks. The other 13 women (87%) died postpartum. Thirteen deaths were directly attributable to sickle-cell disease. The other two maternal deaths, both considered direct obstetric causes, were due to amniotic fluid embolism and septic shock after post-amniocentesis chorioamnionitis. The expert committee on maternal mortality judged seven of these 15 deaths (47%) to be avoidable. CONCLUSION: Sickle-cell disease is responsible for a major excess risk of maternal death in France, due mainly to direct complications of the disease. PMID- 26431904 TI - Does short-term fasting promote pathological eating patterns? AB - Fasting, or going a significant amount of time without eating, has been identified as a risk factor for the development of pathological eating patterns. Findings from several studies examining the impact of fasting on subsequent eating behaviors have been mixed. The current study recruited college students to record food intake, episodes of binge eating, and use of compensatory behaviors before, throughout, and following a 24-hour fast. Participants attended an initial appointment in which they completed measures of dietary restraint and disinhibition and received instructions on self-monitoring and fasting. Participants (N=122) self-monitored their eating behaviors for 96 h, including a 24-hour fasting period. Participants did not demonstrate significant increases in disordered eating behaviors following the fast (e.g., objective binge episodes, self-defined excessive eating or compensatory behavior use). Baseline disinhibition predicted excessive eating as well as objective binge episodes both before and after fasting. Altogether, findings have implications for research seeking to further understand how fasting may contribute to the development of pathological eating patterns; specifically, it seems that the ED risk associated with fasting is derived from the behavior's interaction with other individual difference variables. PMID- 26431906 TI - Testing the antidepressant properties of the peptide ARA290 in a human neuropsychological model of drug action. AB - Studies on the neural effects of Erythropoietin (EPO) indicate that EPO may have antidepressant effects. Due to its hematopoietic effects, EPO may cause serious side-effects with repeated administration if patients are not monitored extensively. ARA290 is an EPO-analog peptide without such hematopoietic side effects but may have neurotrophic and antidepressant effects. The aim of this study was to investigate the possible antidepressant effects of ARA290 in a neuropsychological model of drug action. Healthy participants (N=36) received ARA290 (2mg) or placebo in a double-blind, randomized, parallel-group design. Neural and cognitive effects were assessed one week after administration. Primary outcome measures were the neural processing of fearful vs happy faces and the behavioral recognition of emotional facial expressions. ARA290-treated individuals displayed lower neural responses to happy faces in the fusiform gyrus. ARA290 tended to lower the recognition of happy and disgust facial expressions. Although ARA290 was not associated with a better memory for positive words, it was associated with faster categorization of positive vs negative words. Finally, ARA290 increased attention towards positive emotional pictures. No effects were observed on mood and affective symptoms. ARA290 may modulate some aspects of emotional processing, however, the direction and the strength of its effects do not unequivocally support an antidepressant-like profile for ARA290. Future studies may investigate the effects of different timing and dose. PMID- 26431905 TI - Fluoride induces oxidative damage and SIRT1/autophagy through ROS-mediated JNK signaling. AB - Fluoride is an effective caries prophylactic, but at high doses can also be an environmental health hazard. Acute or chronic exposure to high fluoride doses can result in dental enamel and skeletal and soft tissue fluorosis. Dental fluorosis is manifested as mottled, discolored, porous enamel that is susceptible to dental caries. Fluoride induces cell stress, including endoplasmic reticulum stress and oxidative stress, which leads to impairment of ameloblasts responsible for dental enamel formation. Recently we reported that fluoride activates SIRT1 and autophagy as an adaptive response to protect cells from stress. However, it still remains unclear how SIRT1/autophagy is regulated in dental fluorosis. In this study, we demonstrate that fluoride exposure generates reactive oxygen species (ROS) and the resulting oxidative damage is counteracted by SIRT1/autophagy induction through c-Jun N-terminal kinase (JNK) signaling in ameloblasts. In the mouse-ameloblast-derived cell line LS8, fluoride induced ROS, mitochondrial damage including cytochrome-c release, up-regulation of UCP2, attenuation of ATP synthesis, and H2AX phosphorylation (gammaH2AX), which is a marker of DNA damage. We evaluated the effects of the ROS inhibitor N-acetylcysteine (NAC) and the JNK inhibitor SP600125 on fluoride-induced SIRT1/autophagy activation. NAC decreased fluoride-induced ROS generation and attenuated JNK and c-Jun phosphorylation. NAC decreased SIRT1 phosphorylation and formation of the autophagy marker LC3II, which resulted in an increase in the apoptosis mediators gammaH2AX and cleaved/activated caspase-3. SP600125 attenuated fluoride-induced SIRT1 phosphorylation, indicating that fluoride activates SIRT1/autophagy via the ROS mediated JNK pathway. In enamel organs from rats or mice treated with 50, 100, or 125 ppm fluoride for 6 weeks, cytochrome-c release and the DNA damage markers 8 oxoguanine, p-ATM, and gammaH2AX were increased compared to those in controls (0 ppm fluoride). These results suggest that fluoride-induced ROS generation causes mitochondrial damage and DNA damage, which may lead to impairment of ameloblast function. To counteract this impairment, SIRT1/autophagy is induced via JNK signaling to protect cells/ameloblasts from fluoride-induced oxidative damage that may cause dental fluorosis. PMID- 26431907 TI - Rapid anti-depressant and anxiolytic actions following dopamine D1-D2 receptor heteromer inactivation. AB - A role for the mesolimbic dopaminergic system in the pathophysiology of depression has become increasingly evident. Specifically, brain-derived neurotrophic factor (BDNF) has been shown to be elevated in the nucleus accumbens of depressed patients and to positively contribute to depression-like behaviour in rodents. The dopamine D1-D2 receptor heteromer exhibits significant expression in NAc and has also been shown to enhance BDNF expression and signalling in this region. We therefore examined the effects of D1-D2 heteromer stimulation in rats by SKF 83959, or its inactivation by a selective heteromer-disrupting TAT-D1 peptide on depression- and anxiety-like behaviours in non-stressed animals and in animals exposed to chronic unpredictable stress. SKF 83959 treatment significantly enhanced the latency to immobility in the forced swim test, increased the latency to drink condensed milk and reduced total milk consumption in the novelty-induced hypophagia test, and additionally reduced the total time spent in the open arms in the elevated plus maze test. These pro-depressant and anxiogenic effects of SKF 83959 were consistently abolished or attenuated by TAT D1 peptide pre-treatment, signifying the behaviours were mediated by the D1-D2 heteromer. More importantly, in animals exposed to chronic unpredictable stress (CUS), TAT-D1 peptide treatment alone induced significant and rapid anxiolytic and antidepressant-like effects in two tests for CUS-induced anhedonia-like reactivity and in the novelty-suppressed feeding test. Together these findings indicate a positive role for the D1-D2 heteromer in mediating depression- and anxiety-like behaviours and suggest its possible value as a novel therapeutic target. PMID- 26431908 TI - Preoperative High-Resolution Ultrasound for the Assessment of Malignant Central Compartment Lymph Nodes in Papillary Thyroid Cancer. AB - BACKGROUND: The identification and removal of malignant central compartment lymph nodes (MCLN) is important to minimize the risk of persistent or recurrent local disease in patients with papillary thyroid cancer (PTC). While the diagnostic accuracy of preoperative ultrasound for the assessment of lateral compartment node metastases is well recognized, its role in the identification of central compartment node metastases in patients with PTC is less established. This study delineates the utility of high-resolution ultrasound (HUS) for the assessment of MCLN in patients with PTC. METHODS: A retrospective chart review was performed of 227 consecutive patients who underwent total thyroidectomy for biopsy-proven PTC by a single endocrine surgeon in an academic tertiary care center between 2004 and 2014. Preoperative sonographic results were compared to postoperative pathology reports to determine the accuracy of HUS for the assessment of MCLN. Statistical analysis also included sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: HUS identified abnormal central compartment nodes in 51 (22.5%) patients. All 227 patients underwent a careful central compartment node exploration. One hundred and four (45.8%) patients had MCLN identified by surgery, of whom 65 (62.5%) had a negative preoperative central compartment HUS. The sensitivity and specificity of preoperative HUS for the assessment of MCLN were 0.38 and 0.90, respectively. The PPV and NPV were 0.76 and 0.63, with an accuracy of 0.66. CONCLUSION: Preoperative HUS is quite specific for the identification of MCLN in patients with PTC. The present findings emphasize, however, that a negative HUS does not obviate the need for careful exploration of the central compartment to minimize the risk of persistent or recurrent local disease. PMID- 26431909 TI - Insoluble elastin reduces collagen scaffold stiffness, improves viscoelastic properties, and induces a contractile phenotype in smooth muscle cells. AB - Biomaterials with the capacity to innately guide cell behaviour while also displaying suitable mechanical properties remain a challenge in tissue engineering. Our approach to this has been to utilise insoluble elastin in combination with collagen as the basis of a biomimetic scaffold for cardiovascular tissue engineering. Elastin was found to markedly alter the mechanical and biological response of these collagen-based scaffolds. Specifically, during extensive mechanical assessment elastin was found to reduce the specific tensile and compressive moduli of the scaffolds in a concentration dependant manner while having minimal effect on scaffold microarchitecture with both scaffold porosity and pore size still within the ideal ranges for tissue engineering applications. However, the viscoelastic properties were significantly improved with elastin addition with a 3.5-fold decrease in induced creep strain, a 6-fold increase in cyclical strain recovery, and with a four-parameter viscoelastic model confirming the ability of elastin to confer resistance to long term deformation/creep. Furthermore, elastin was found to result in the modulation of SMC phenotype towards a contractile state which was determined via reduced proliferation and significantly enhanced expression of early (alpha-SMA), mid (calponin), and late stage (SM-MHC) contractile proteins. This allows the ability to utilise extracellular matrix proteins alone to modulate SMC phenotype without any exogenous factors added. Taken together, the ability of elastin to alter the mechanical and biological response of collagen scaffolds has led to the development of a biomimetic biomaterial highly suitable for cardiovascular tissue engineering. PMID- 26431910 TI - Gender-specific protective effect of the -463G>A polymorphism of myeloperoxidase gene against the risk of essential hypertension in Russians. AB - The purpose of this study was to investigate whether a common polymorphism 463G>A (rs2333227) in the promoter of myeloperoxidase (MPO) gene, an oxidant enzyme producing hypohalogenic radicals, is associated with the risk of essential hypertension (EH) in Russian population. A total of 2044 unrelated subjects including 1256 EH patients and 788 normotensive controls were recruited for this study. Genotyping of the MPO gene polymorphism was done using TaqMan-based assay. A genotype -463GA was associated with decreased risk of EH (odds ratio = 0.82; 95% confidence interval: 0.68-1.00) at a borderline significance level (P = .05). The gender-stratified analysis showed that a carriage of the -463GA and -463AA genotypes is associated with decreased EH risk only in females (odds ratio = 0.74, 95% confidence interval: 0.56-0.96; P = .02). To the best of our knowledge, this is the first study reporting a negative association between the -463G>A polymorphism of the MPO gene and EH risk. Molecular mechanisms by which MPO gene is involved in the pathogenesis of EH are discussed. PMID- 26431911 TI - Effect of sulfide, osmotic, and thermal stresses on taurine transporter mRNA levels in the gills of the hydrothermal vent-specific mussel Bathymodiolus septemdierum. AB - Hydrothermal vent environmental conditions are characterized by high sulfide concentrations, fluctuating osmolality, and irregular temperature elevations caused by vent effluents. These parameters represent potential stressors for organisms that inhabit the area around hydrothermal vents. Here, we aimed to obtain a better understanding of the adaptation mechanisms of marine species to hydrothermal vent environments. Specifically, we examined the effect of sulfide, osmolality, and thermal stress on the expression of taurine transporter (TAUT) mRNA in the gill of the deep-sea mussel Bathymodiolus septemdierum, which is a dominant species around hydrothermal vent sites. We analyzed TAUT mRNA levels by quantitative real-time polymerase chain reaction (PCR) in the gill of mussels exposed to sulfide (0.1 or 1mg/L Na2S.9H2O), hyper- (115% seawater) and hypo- (97.5%, 95.5%, and 85% seawater) osmotic conditions, and thermal stresses (12 degrees C and 20 degrees C) for 24 and 48h. The results showed that mussels exposed to relatively low levels of sulfide (0.1mg/L) and moderate heat stress (12 degrees C) exhibited higher TAUT mRNA levels than the control. Although hyper and hypo-osmotic stress did not significantly change TAUT mRNA levels, slight induction was observed in mussels exposed to low osmolality. Our results indicate that TAUT is involved in the coping mechanism of mussels to various hydrothermal vent stresses. PMID- 26431912 TI - The Tale of Two Hypoxia-Inducible Factors in Renal Cell Carcinoma. PMID- 26431913 TI - Three-dimensional Printed Model of Prostate Anatomy and Targeted Biopsy-proven Index Tumor to Facilitate Nerve-sparing Prostatectomy. PMID- 26431914 TI - Re: Idir Ouzaid and Karim Bensalah. Results of the First Trial Assessing Adjuvant Tyrosine Kinase Inhibitors in Renal Cell Carcinoma Do Not reASSURE. Eur Urol 2015;68:542-3. PMID- 26431915 TI - Teaching, caring, and altruistic behaviors in toddlers. AB - Peer-directed behaviors of toddlers were longitudinally recorded in a naturalistic preschool setting. An observer (O, the first author) recorded children's behaviors during play sessions with an IC recorder. One-year-old children (N=13) and children under the age of 12 months (N=8) were observed for 15 min, 6 times in a year. Their teaching, caring, and altruistic behaviors were analyzed in detail. Results indicated that peer-directed behaviors of one-year olds increased dramatically. It is concluded that toddlers are sophisticated social being. PMID- 26431917 TI - Evaluation of extrashort 4-mm implants in mandibular edentulous patients with reduced bone height in comparison with standard implants: a 12-month results. AB - OBJECTIVE: The aim of this research was to evaluate the primary stability, the marginal bone loss, the survival, and the success criteria, of 4-mm-length implants compared with implants of conventional length supporting fixed prostheses. MATERIALS AND METHODS: Ten patients were selected for treatment of their atrophic edentulous jaws. Each patient received the following treatment: six dental implants were inserted, two anterior implants of conventional length (10-mm) in the interforaminal area and four posterior short implants of 4-mm length (Standard Plus, Roxolid, SLActive, Institut Straumann AG). The implants supported screw-retained fixed complete dentures. Examinations were conducted at day 0, three, six, and twelve months after surgery for the evaluation of the implant primary stability, secondary stability, crestal bone loss and survival by clinical evaluations, insertion torque values, resonance frequency analysis (RFA), and periapical radiography, respectively. RESULTS: Sixty implants were inserted in ten patients. Mean insertion torque was slightly lower for 4-mm implants than 10-mm implants (38.1 Ncm vs. 42.2 Ncm) but without statistically significant difference. Implant stability was similar for extrashort and conventional implants. Marginal bone loss was similar for both groups for all the time periods. One short implant was lost before loading. The survival rates twelve months after implant placement were of 97.5% and 100% for short and conventional implants, respectively. Similarly, implant stability as measured by RFA was nonsignificantly lower for the 4-mm implants compared to the 10-mm implants. The marginal bone loss was lower for short implants three, six, and twelve months after the surgery without statistical significant difference. CONCLUSIONS: Within the limitations of this study, we conclude that short dental implants (8 mm or less in length) supporting single crowns or fixed bridges are a feasible treatment option with radiographic and clinical success rates similar to longer implants for patients with compromised ridges. Long-term data with larger number of implants and subjects are needed to confirm these preliminary results. PMID- 26431916 TI - Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma. AB - OBJECTIVES: Malignant mesothelioma (MM) is a highly aggressive tumor with poor prognosis. A major challenge is the development and application of early and highly reliable diagnostic marker(s). Serum biomarkers, such as 'soluble mesothelin-related proteins' (SMRPs), is the most studied and frequently used in MM. However, the low sensitivity of SMRPs for early MM limits its value; therefore, additional biomarkers are required. In this study, two epigenetically regulated markers in MM (microRNA-126, miR-126, and methylated thrombomodulin promoter, Met-TM) were combined with SMRPs and evaluated as a potential strategy to detect MM at an early stage. MATERIALS AND METHODS: A total of 188 subjects, including 45 MM patients, 99 asbestos-exposed subjects, and 44 healthy controls were prospectively enrolled, serum samples collected, and serum levels of SMRPs, miR-126 and Met-TM evaluated. Logistic regression analysis was performed to evaluate the diagnostic value of the three biomarkers. Using this approach, the performance of the '3-biomarker classifier' was tested by calculating the overall probability score of the MM and control samples, respectively, and the ROC curve was generated. RESULTS AND CONCLUSION: The combination of the three biomarkers was the best predictor to differentiate MM patients from asbestos-exposed subjects and healthy controls. The accuracy and cancer specificity was confirmed in a second validation cohort and lung cancer population. We propose that the combination of the two epigenetic biomarkers with SMRPs as a diagnosis for early MM overcomes the limitations of using SMRPs alone. PMID- 26431918 TI - Low bone mineral density is associated with intracranial posterior circulation atherosclerosis in women. AB - Low bone mineral density (BMD) is associated with carotid atherosclerosis and the incidence of stroke. However, there are no data on the association of BMD with intracranial atherosclerosis. The study population consisted of 357 participants who underwent dual energy x-ray absorptiometric scanning of the lumbar spine and brain 3D time of flight magnetic resonance angiography as part of their voluntary health checks. The basilar, middle cerebral, intracranial internal carotid and intracranial vertebral arteries were evaluated. Low BMD was defined as a T-score of less than -1. All analyses were stratified by sex and intracranial atherosclerosis location. One hundred seventy-six women (53 years; 66.9% postmenopausal; 33.5% low BMD; 60.2% intracranial atherosclerosis in the anterior circulation (AC); 60.2% intracranial atherosclerosis in the posterior circulation (PC)) and 181 men (51 years; 28.7% low BMD; 61.9% intracranial atherosclerosis in the AC; 55.8% intracranial atherosclerosis in the PC) were included. In women, low BMD was significantly associated with intracranial atherosclerosis in the PC with the odds ratio of 2.57 (95% confidence interval 1.11-5.99). However, intracranial atherosclerosis in the AC was not associated with BMD in women. In men, there were no significant associations between BMD and intracranial atherosclerosis. In conclusion, this study shows that low BMD is associated with subclinical intracranial PC atherosclerosis in women but not in men. PMID- 26431919 TI - Midterm Outcomes of Open Descending Thoracic Aortic Repair in More Than 5,000 Medicare Patients. AB - BACKGROUND: Diseases involving the descending thoracic aorta (DTA) represent a heterogeneous substrate with a variety of therapeutic options. Although thoracic endovascular aortic repair has been increasingly applied to DTA disease, open surgical repair is ostensibly more durable. METHODS: A total of 5,578 patients who underwent open DTA repair (Current Procedural Terminology code 33875) from 1999 to 2010 were identified from the Medicare database; 5,489 patients had complete data. Survival was assessed with Kaplan-Meier analysis. Cox regression determined predictors of death. Hospital and surgeon volume and variability were modeled, and their association with survival assessed. RESULTS: Median survival after open DTA repair was only 4.3 years (95% confidence interval: 4.0 to 4.6). The likelihood of death varied significantly by certain aortic diseases: aortic rupture and acute aortic dissection patients had the highest early mortality. Survival beyond 180 days was best for patients with acute aortic dissection and isolated thoracic aortic aneurysm, and lowest for patients with thoracoabdominal aneurysm and aortic rupture. Hospital and surgeon volume, as well as interhospital and intersurgeon variability, had associations with overall survival. CONCLUSIONS: Open DTA repair has treated a spectrum of aortic diseases in Medicare beneficiaries. Overall mortality was high, predominately confined to the initial postoperative hazard phase. Independent hospital and surgeon effects, hospital and surgeon volume, and a more recent date of surgery correlated with improved survival, while increased operative urgency and complexity correlated with worse outcomes. These observations argue for regionalization of DTA treatment for Medicare patients in specialized centers to concentrate expertise, which should translate into better outcomes. PMID- 26431920 TI - Effect of Hospital Volume on Prosthesis Use and Mortality in Aortic Valve Operations in the Elderly. AB - BACKGROUND: This study was designed to examine the effect of hospital procedural volume on outcomes in aortic valve replacement (AVR) in the elderly. METHODS: The study included 277,928 Medicare beneficiaries who underwent AVR from 2000 through 2009 at one of 1,255 participating hospitals. Operative mortality and the use of mechanical prostheses were analyzed according to hospital annual procedural volume. Annual AVR volume was divided into 5 different categories: the smallest volume group with less than 10 AVRs per year to the largest group averaging more than 70 AVRs per year. RESULTS: The overall observed operative mortality rate was 7.3%; for isolated AVR it was 5.5%. Lower-volume hospitals exhibited increased adjusted operative mortality: 10 cases or fewer per year--odds ratio (OR), 1.55; 95% confidence interval (CI), 1.39 to 1.72; 11 to 20 cases per year--OR, 1.35; 95% CI, 1.23 to 1.47; 21 to 40 cases per year--OR, 1.15; 95% CI, 1.06 to 1.25; 41 to 70 cases per year--OR, 1.10; 95% CI, 1.01 to 1.20 relative to those hospitals performing more than 70 cases per year. The discrepancy in operative mortality between low- and high-volume hospitals diverged during the study. Mechanical valve use decreased with increasing hospital volume (p = 0.0001). Mechanical valves were used in 64.5% of AVRs in hospitals with an annual AVR volume less than 10 in contrast to only 25.4% in hospitals with an annual AVR volume more than 70. After adjustment, the use of mechanical valves was independently associated with increased operative mortality (OR, 1.15; 95% CI, 1.11-1.19). CONCLUSIONS: Low-volume centers were characterized by increased adjusted operative mortality and greater use of mechanical prostheses, a trend that persisted during the 10-year course of the study. These data would support the center-of-excellence concept for AVR and may be particularly relevant in the elderly population. PMID- 26431921 TI - Survival After Extracorporeal Cardiopulmonary Resuscitation on Weekends in Comparison With Weekdays. AB - BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) requires urgent decision-making and high-quality skills, which may not be uniformly available throughout the week. Few data exist on the outcomes of patients with cardiac arrest who receive in-hospital ECPR on the weekday versus weekend. Therefore, we investigated whether the outcome differed when patients with in-hospital cardiac arrest received ECPR during the weekend compared with a weekday. METHODS: Two hundred patients underwent extracorporeal membrane oxygenation after in-hospital cardiac arrest between January 2004 and December 2013. Patients treated between 0800 on Monday to 1759 on Friday were considered to receive weekday care and patients treated between 1800 on Friday through 0759 on Monday were considered to receive weekend care. RESULTS: A total of 135 cases of ECPR for in-hospital cardiac arrest occurred during the weekday (64 during daytime hours and 71 during nighttime hours), and 65 cases occurred during the weekend (39 during daytime/evening hours and 26 during nighttime hours). Rates of survival to discharge were higher with weekday care than with weekend care (35.8% versus 21.5%, p = 0.041). Cannulation failure was more frequent in the weekend group (1.5% versus 7.7%, p = 0.038). Complication rates were higher on the weekend than on the weekday, including cannulation site bleeding (3.0% versus 10.8%, p = 0.041), limb ischemia (5.9% versus 15.6%, p = 0.026), and procedure-related infections (0.7% versus 9.2%, p = 0.005). CONCLUSIONS: ECPR on the weekend was associated with a lower survival rate and lower resuscitation quality, including higher cannulation failure and higher complication rate. PMID- 26431922 TI - Adequacy Criteria of Rapid On-Site Evaluation for Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration: A Simple Algorithm to Assess the Adequacy of ROSE. AB - BACKGROUND: Rapid on-site evaluation (ROSE) for endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been advocated to qualitatively diagnose biopsy samples. However, adequate ROSE criteria during EBUS-TBNA are unclear. The aim of this study was to determine adequacy criteria of ROSE in EBUS TBNA samples and suggest an appropriate algorithm. METHODS: Patients who underwent EBUS-TBNA for nodal evaluation between March and July 2013 at Seoul National University Hospital were included prospectively. The ROSE slides were reviewed independently by two pathologists, and the results were compared to the final pathologic results. Diagnostic yields, sensitivity, specificity, and accuracy were calculated in order to make nodal evaluations. RESULTS: EBUS-TBNA was performed on 300 lymph nodes in 133 patients. Samples were nondiagnostic in 7.7%, 6.3%, and 1.7% of the cytologic, histologic, and overall pathologic results, respectively. On the ROSE slides, a large tissue core size (>=2 cm), microscopic anthracotic pigment (MAP), and increased lymphocyte density (LD; >=40 cells/field [40*, mean of 10 fields]) were significantly associated with adequate final cytologic or histologic results. Malignant cells were not statistically associated with adequacy but were considered a parameter indicating an adequate diagnosis. Using four sequential criteria, tissue core size, the presence of malignant cell, MAP, and LD >=40 cells/field, the sensitivity and accuracy rates of ROSE increased from 64.4% to 98.6% and from 64.7% to 97.3%, respectively. CONCLUSIONS: A high adequacy rate of ROSE in EBUS-TBNA can be achieved by sequentially applying four criteria: tissue core size, malignant cells, MAP, and increased LD. PMID- 26431923 TI - Resected Tracheal Adenoid Cystic Carcinoma: Improvements in Outcome at a Single Institution. AB - BACKGROUND: Primary tracheal cancer comprises a heterogeneous and rare group of neoplasms. Management of patients with primary tracheal carcinoma at our institution has improved in recent years. METHODS: This retrospective review included patients with localized primary tracheal adenoid cystic carcinoma treated surgically at our institution between January 1995 and December 2014. Patients were classified according to the timing of first operation: "early years" operation was performed between January 1995 and December 2002, and subsequent "recent years" operation was associated with improved management and a focus on early diagnosis. RESULTS: The proportion of patients with tracheal malignancy who underwent operation for adenoid cystic carcinoma increased with time. Patients in the recent group were significantly younger than those in the early group at diagnosis (49.3 +/- 7.8 years versus 45.7 +/- 9.4 years; p = 0.042), and the resected tumor size and tracheal lengths tended to be smaller (28.2 +/- 7.6 mm versus 30.3 +/- 7.0 mm; p = 0.161) and shorter (32.1 +/- 7.7 mm versus 34.4 +/- 6.7 mm; p = 0.123). The use of postoperative radiotherapy in patients with R1 resection was also managed more effectively in the recent group compared with the early group (90.6% versus 65.0%; p = 0.009). Five- and 10-year overall survival rates in the early and recent groups were 86.4% and 90.8%, and 31.8% and 61.2%, respectively (p = 0.084), and the corresponding 5- and 10-year disease-free survival rates were 39.7% and 75.3%, and 9.9% and 21.2%, respectively (p = 0.025). CONCLUSIONS: There have been improved outcomes of adenoid cystic carcinomas. Early diagnosis, experienced surgical treatments, and postoperative adjuvant radiotherapy for patients with positive margins may contribute to the improved survival of patients with primary tracheal adenoid cystic carcinoma. PMID- 26431924 TI - Long-Term Outcome and Predictors of Noninstitutionalized Survival Subsequent to Prolonged Intensive Care Unit Stay After Cardiac Surgical Procedures. AB - BACKGROUND: There are minimal data on long-term functional survival (alive and not institutionalized) in patients undergoing cardiac operations who require a prolonged intensive care unit length of stay (prICULOS). We sought to describe 1- and 5-year functional survival in patients who had a prICULOS (ICULOS >= 5 days) and determine predictors of functional survival at 1 year. METHODS: Data were obtained from linked clinical and administrative databases from January 1, 2000 to December 31, 2011 to conduct this retrospective single-region analysis. Logistic regression was used to develop a model predicting functional survival at 1 year for patients who had a prICULOS after cardiac operations. RESULTS: There were 9,545 admissions to the ICU after cardiac operations; of these patients, 728 (7.6%) experienced a prICULOS. There was an increasing trend in patients who had a prICULOS over this study period. The functional survival at 1 and 5 years from the surgical procedure for the non-prICULOS versus the prICULOS cohort was 1 year (94.9% versus 73.9%) and 5 years (84.9% versus 53.8%) (p < 0.001). Factors associated with lower rates of functional survival at 1 year were age 80 years or older, female sex, peripheral vascular disease, preoperative renal dysfunction, cerebrovascular disease, preoperative infection, need for extracorporeal membrane oxygenation/ventricular assist device (ECMO/VAD) after cardiotomy, number of days on mechanical ventilation, and number of days in the ICU beyond 5 days (area under the receiver operating characteristic [ROC] curve = 0.766). CONCLUSIONS: The majority of patients who had a prICULOS experienced successful functional survival up to 5 years after cardiac operations. Identification of risk factors for poor functional survival may be of assistance to clinicians, patients, and families for prognostication and decision making. PMID- 26431925 TI - Hemodynamic Impact of Superior Vena Cava Placement in the Y-Graft Fontan Connection. AB - BACKGROUND: A Fontan Y-shaped graft using a commercially available aortoiliac graft has been used to connect the inferior vena cava (IVC) to the pulmonary arteries. This modification of the Fontan procedure seeks to improve hepatic flow distribution (HFD) to the lungs. However, patient-specific anatomical restrictions might limit the space available for graft placement. Altering the superior vena cava (SVC) positioning is hypothesized to provide more space for an optimal connection, avoiding caval flow collision. Computational modeling tools were used to retrospectively study the effect of SVC placement on Y-graft hemodynamics. METHODS: Patient-specific anatomies (N = 10 patients) and vessel flows were reconstructed from retrospective cardiac magnetic resonance (CMR) images after Fontan Y-graft completion. Alternative geometries were created using a virtual surgery environment, altering the SVC position and the offset in relation to the Y-graft branches. Geometric characterization and computational fluid dynamics simulations were performed. Hemodynamic factors (power loss and HFD) were computed. RESULTS: Patients with a higher IVC return showed less sensitivity to SVC positioning. Patients with low IVC flow showed varied HFD results, depending on SVC location. Balanced HFD values (50% to each lung) were obtained when the SVC lay completely between the Y-graft branches. The effect on power loss was patient specific. CONCLUSIONS: SVC positioning with respect to the Y-graft affects HFD, especially in patients with lower IVC flow. Careful positioning of the SVC at the time of a bidirectional Glenn (BDG) procedure based on patient-specific anatomy can optimize the hemodynamics of the eventual Fontan completion. PMID- 26431926 TI - Sero-surveillance and risk factors for avian influenza and Newcastle disease virus in backyard poultry in Oman. AB - Avian Influenza (AI) and Newcastle disease (ND) are the most important reportable poultry diseases worldwide. Low pathogenic AI (H9N2) and ND viruses are known to have been circulating in the Middle East, including in Oman, for many decades. However, detailed information on the occurrence of these pathogens is almost completely lacking in Oman. As backyard poultry are not vaccinated against either virus in Oman, this sector is likely to be the most affected poultry production sector for both diseases. Here, in the first survey of AI and ND viruses in backyard poultry in Oman, we report high flock-level seroprevalences of both viruses. Serum and oropharyngeal swabs were taken from 2350 birds in 243 backyard flocks from all regions and governorates of Oman. Information was recorded on location, type of bird and housing type for each sampled farm. Individual bird serum samples were tested using commercial indirect antibody detection ELISA kits. Pooled oropharyngeal samples from each flock were inoculated onto FTA cards and tested by RT-PCR. Samples came from chickens (90.5%), turkeys (2.1%), ducks (6.2%), guinea fowl (0.8%) and geese (0.4%). The bird-level seroprevalence of antibody to AI and ND viruses was 37.5% and 42.1% respectively, and at the flock level it was 84% and 90% respectively. There were statistically significant differences between some different regions of Oman in the seroprevalence of both viruses. Flock-level NDV seropositivity in chickens was significantly associated with AIV seropositivity, and marginally negatively associated with flock size. AIV seropositivity in chickens was marginally negatively associated with altitude. All oropharyngeal samples were negative for both viruses by RT-PCR, consistent with a short duration of infection. This study demonstrates that eight or nine out of ten backyard poultry flocks in Oman are exposed to AI and ND viruses, and may present a risk for infection for the commercial poultry sector in Oman, or wild birds which could carry infection further afield. PMID- 26431928 TI - Spondyloarthritis: Criteria, limitations, and perspectives throughout history. PMID- 26431927 TI - Role of mitochondrial oxidative stress on lymphocyte homeostasis in patients diagnosed with extra-pulmonary tuberculosis. AB - Extra-pulmonary tuberculosis is often an underrated illness. Recent clinical studies have pointed out that lymphocyte homeostasis is dramatically disturbed as revealed through a series of signs and symptoms. Lymphocytes, the known effector cells of our immune system, play an important role in providing immunologic resistance against Mycobacterium infection. It is important to have quantitative insights into the lifespan of these cells; therefore, we aimed to study the precise effect of gastrointestinal tuberculosis infection on peripheral blood lymphocyte subpopulations and function. Our results indicated that gastrointestinal tuberculosis could increase mitochondrial oxidative stress, lower mitochondrial DNA copy number, promote nuclear DNA damage and repair response, decrease mitochondrial respiratory chain enzyme activities, and upregulate Bcl-2 and caspase-3 gene expression in lymphocytes. We further revealed that Mycobacterium infection induces autophagy for selective sequestration and subsequent degradation of the dysfunctional mitochondrion before activating cellular apoptosis in the peripheral lymphocyte pool. Together, these observations uncover a new role of mitochondrial-nuclear crosstalk that apparently contributes to lymphocyte homeostasis in gastrointestinal tuberculosis infection. PMID- 26431929 TI - The impact of chronic low back pain is partly related to loss of social role: A qualitative study. AB - OBJECTIVES: Chronic low back pain (LBP) has an important impact on quality of life, through pain and functional incapacity, but also psychosocial distress. The social participation consequences of LBP have been less explored. The objective was to better understand experiences of patients living with chronic LBP, with a focus on impact on relationships with family, friends and work colleagues. METHODS: Monocentric qualitative study in a tertiary-referral centre in Paris, France. Participants had chronic mechanical LBP. Semi-structured interviews were conducted during 4 focus groups discussions focusing on living with LBP. Verbatim was categorized and coded using thematic content analysis. RESULTS: Twenty-five persons (11 men, 14 women) participated; ages ranged 25-81 years. Participants often reported a negative self-perception in social interactions, with shame and frustration regarding their difficulties to perform activities of daily living. They often felt misunderstood and unsupported, partly due to the absence of visible signs of the condition. Participants suffered from the negative collective image attached to LBP ("benign/psychological disease"). LBP resulted in some patients in a significant loss of social identity with perceived impossibility to perform one's social role at home and at work. In contrast, family and friends were sometimes a support and helped in pain management. CONCLUSION: A systematic assessment of social role is needed in LBP care. PMID- 26431931 TI - Enthesitis: The clue to the pathogenesis of spondyloarthritis? AB - The term "spondyloarthritis" designates a group of conditions whose shared characteristic is inflammation at the interface between the bone and either the tendons and ligaments or the joint capsule. This interface, known as the enthesis, can be the site of ossification in spondyloarthritis. The advent of high-performance imaging techniques such as magnetic resonance imaging has rekindled interest in the enthesis by providing new insights into the sequence that leads to entheseal ossification. These techniques have established initial inflammation and fatty metaplasia as key events that precede ossification. The pathophysiological mechanisms that trigger the initial inflammation probably involve multiple factors such as mechanical stress and the presence of resident cells responsive to interleukin-23 and capable of releasing proinflammatory cytokines. Research into the triggers of entheseal inflammation and ossification may thus provide the clue to the pathophysiology of spondyloarthritis. PMID- 26431930 TI - Sodium (18)F-sodium fluoride PET failed to predict responses to TNFalpha antagonist therapy in 31 patients with possible spondyloarthritis not meeting ASAS criteria. AB - OBJECTIVES: To determine whether (18)F-NaF positron-emission tomography (PET) contributes to the diagnosis of spondyloarthritis and whether observed uptakes predict the response to TNFalpha antagonist therapy. METHODS: We studied patients who had suspected spondyloarthritis but did not meet ASAS criteria and who were referred for an assessment of eligibility for TNFalpha antagonist therapy. (18)F NaF PET was offered instead of bone scintigraphy. TNFalpha antagonist therapy was given if the clinician's level of confidence in the diagnosis of spondyloarthritis based on (18)F-NaF PET findings was >=50/100. RESULTS: Thirty one patients accepted to undergo (18)F-NaF PET. Their mean age was 39.9+/-11.7 years; 22% were HLA-B27-positive and none had evidence of sacroiliitis by magnetic resonance imaging. Of the 31 patients, 30 had abnormal (18)F-NaF PET findings. However, of the 312 high-uptake foci, only 123 (39.4%) matched sites of pain. TNFalpha antagonist therapy was given to 16 patients. The treated group and untreated group (n=15) were not significantly different for the mean number of high-uptake foci per patient (11.7+/-8.1 vs. 8.3+/-5.1, respectively) or for the proportion of patients with high uptake by the sacroiliac joints (13/16 [81%] vs. 8/15 [53%], respectively). In the treated group, 5 patients met ASAS response criteria after 3 months. These 5 patients were among the 9 treated patients who met Amor's modified criteria (arthritis instead of asymmetrical oligoarthritis). In the 5 responders, the (18)F-NaF uptake scores were nonsignificantly lower than in the 11 nonresponders (9.0+/-8.5 vs. 13.0+/-6.4, respectively). In the patients for whom the (18)F-NaF PET findings increased the level of confidence in the diagnosis of spondyloarthritis, this effect was short-lived. DISCUSSION: The positive predictive value of (18)F-NaF PET for diagnosing spondyloarthritis or predicting a response to TNFalpha antagonist therapy seems very low. This finding is probably ascribable to poor specificity. PMID- 26431932 TI - The role of the neuropeptide Y (NPY) family in the pathophysiology of inflammatory bowel disease (IBD). AB - Inflammatory bowel disease (IBD) includes three main disorders: ulcerative colitis, Crohn's disease, and microscopic colitis. The etiology of IBD is unknown and the current treatments are not completely satisfactory. Interactions between the gut neurohormones and the immune system are thought to play a pivot role in inflammation, especially in IBD. These neurohormones are believed to include members of the neuropeptide YY (NPY) family, which comprises NPY, peptide YY (PYY), and pancreatic polypeptide (PP). Understanding the role of these peptides may shed light on the pathophysiology of IBD and potentially yield an effective treatment tool. Intestinal NPY, PYY, and PP are abnormal in both patients with IBD and animal models of human IBD. The abnormality in NPY appears to be primarily caused by an interaction between immune cells and the NPY neurons in the enteric nervous system; the abnormalities in PYY and PP appear to be secondary to the changes caused by the abnormalities in other gut neurohormonal peptides/amines that occur during inflammation. NPY is the member of the NPY family that can be targeted in order to decrease the inflammation present in IBD. PMID- 26431934 TI - Trends Form Follows Function: New Ways to Inform and Inspire. PMID- 26431933 TI - Elevated levels of neuropeptide Y in preeclampsia: A pilot study implicating a role for stress in pathogenesis of the disease. AB - OBJECTIVE: To determine if preeclampsia (PE) is associated with dysregulation of the neuropeptide Y (NPY) system. METHODS: The study enrolled 114 subjects either with normal pregnancy (NP) or with PE. Systolic blood pressure (SBP) was collected from patients using a standard sphygmomanometer. The PE patients were divided into two groups based on the gestational age (GA) at delivery - placental PE (PLPE, GA <34 weeks) or maternal PE (MTPE, GA >=34 weeks). NPY was measured in platelet rich plasma (PRP), platelet poor plasma (PPP) and in the serum of NP and PE patients utilizing radioimmunoassay. Serum levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) were measured in NP and PE subjects by ELISA. RESULTS: SBP was higher in PE compared to NP. Circulating NPY in serum and PRP, as well as NPY content per 100,000 platelets, but not its concentrations in PPP, were elevated in PE, as compared to NP. The highest NPY concentrations were observed in sera and PRP of patients with MTPE. PE patients had also elevated levels of sFlt-1, as compared to NP, although no difference between PLPE and MTPL groups were observed. There was no increase in P1GF in PE patients. CONCLUSION: Systemic NPY is elevated in PE patients, as compared to NP. This increase is observed in blood fractions containing platelets, suggesting accumulation of the peptide in these cells. NPY concentrations are particularly high in patients with MTPE, underlying differences in etiology between PLPE and MTPE. Our study implicates NPY as a potential target in antihypertensive therapies for PE patients. PMID- 26431935 TI - A Learning Experience. PMID- 26431936 TI - Revisiting the Mechanisms of CNS Immune Privilege. AB - Whereas the study of the interactions between the immune system and the central nervous system (CNS) has often focused on pathological conditions, the importance of neuroimmune communication in CNS homeostasis and function has become clear over that last two decades. Here we discuss the progression of our understanding of the interaction between the peripheral immune system and the CNS. We examine the notion of immune privilege of the CNS in light of both earlier findings and recent studies revealing a functional meningeal lymphatic system that drains cerebrospinal fluid (CSF) to the deep cervical lymph nodes, and consider the implications of a revised perspective on the immune privilege of the CNS on the etiology and pathology of different neurological disorders. PMID- 26431939 TI - Microglia Plasticity During Health and Disease: An Immunological Perspective. AB - Microglia are macrophages of the central nervous system (CNS) that continuously scrutinize their environment for damage. They colonize the cephalic mesenchyme during embryogenesis and actively shape the developing neuronal network by immune mediated mechanisms. Upon CNS maturation, microglia drastically change phenotype and function. During health, adult microglia contribute to homeostasis, but also the establishment and resolution of inflammatory conditions. Fulfillment of these distinct tasks requires these long-lived cells to accurately adjust to their changing environment. Deciphering microglia responsiveness to divergent stimuli is central to understanding this cell type and for eventual microglia manipulation to potentially reduce disease burden. Here we discuss new aspects of myeloid cell biology in general with special emphasis on the shifting role of microglia during establishment and protection of CNS integrity. PMID- 26431938 TI - Microglia: Dynamic Mediators of Synapse Development and Plasticity. AB - Neuronal communication underlies all brain activity and the genesis of complex behavior. Emerging research has revealed an unexpected role for immune molecules in the development and plasticity of neuronal synapses. Moreover microglia, the resident immune cells of the brain, express and secrete immune-related signaling molecules that alter synaptic transmission and plasticity in the absence of inflammation. When inflammation does occur, microglia modify synaptic connections and synaptic plasticity required for learning and memory. Here we review recent findings demonstrating how the dynamic interactions between neurons and microglia shape the circuitry of the nervous system in the healthy brain and how altered neuron-microglia signaling could contribute to disease. PMID- 26431940 TI - Homeostasis of Microglia in the Adult Brain: Review of Novel Microglia Depletion Systems. AB - Microglia are brain macrophages that emerge from early erythro-myeloid precursors in the embryonic yolk sac and migrate to the brain mesenchyme before the blood brain barrier is formed. They seed the brain, and proliferate until they have formed a grid-like distribution in the central nervous system that is maintained throughout lifespan. The mechanisms through which these embryonic-derived cells contribute to microglia homoeostasis at steady state and upon inflammation are still not entirely clear. Here we review recent studies that provided insight into the contribution of embryonically-derived microglia and of adult 'microglia like' cells derived from monocytes during inflammation. We examine different microglia depletion models, and discuss the origin of their rapid repopulation after depletion and outline important areas of future research. PMID- 26431937 TI - The Regulation of Immunological Processes by Peripheral Neurons in Homeostasis and Disease. AB - The nervous system and the immune system are the principal sensory interfaces between the internal and external environment. They are responsible for recognizing, integrating, and responding to varied stimuli, and have the capacity to form memories of these encounters leading to learned or 'adaptive' future responses. We review current understanding of the cross-regulation between these systems. The autonomic and somatosensory nervous systems regulate both the development and deployment of immune cells, with broad functions that impact on hematopoiesis as well as on priming, migration, and cytokine production. In turn, specific immune cell subsets contribute to homeostatic neural circuits such as those controlling metabolism, hypertension, and the inflammatory reflex. We examine the contribution of the somatosensory system to autoimmune, autoinflammatory, allergic, and infectious processes in barrier tissues and, in this context, discuss opportunities for therapeutic manipulation of neuro-immune interactions. PMID- 26431942 TI - GM-CSF in Neuroinflammation: Licensing Myeloid Cells for Tissue Damage. AB - Multiple sclerosis (MS) is the prototypical inflammatory disease of the central nervous system (CNS). MS lesions harbor different immune cells, but the contribution of individual cell types to disease etiology and progression is not well understood. In experimental autoimmune encephalomyelitis (EAE), auto reactive helper T (Th) cells instigate CNS inflammation by acting on myeloid cells via the production of granulocyte-macrophage colony-stimulating factor (GM CSF). Recent reports have implicated myeloid cells in both the inflammatory process and as executers of tissue damage in the CNS. We review these findings here, and integrate them into a model wherein GM-CSF produced by Th cells coordinates monocyte recruitment to the CNS, and differentiation into pathogenic effectors. We discuss the implications of this model to current therapies for MS, and outline important areas of further inquiry. PMID- 26431943 TI - First Detection of Antibodies Against African Swine Fever Virus in Faeces Samples. AB - African swine fever (ASF) is a viral, highly lethal haemorrhagic disease of swine with no available vaccine or effective treatment. Introduction of ASF into a country triggers immediate restriction measures that cause significant economic losses and threatens spread to neighbouring countries. Wild boar populations have been recently assigned an essential role in the spread of African swine fever virus (ASFV) to European countries. Therefore, effective surveillance and monitoring of wild boar populations is required, but sampling wild boar is logistically challenging and expensive. This study assessed the feasibility of detecting antibodies against ASFV in faeces for later implementation in surveillance and control programmes. Two groups of pigs were experimentally infected with an attenuated ASFV isolate Ken05, and blood, oral fluid and faecal samples were tested for the presence of viral DNA using quantitative real-time polymerase chain reaction (qPCR) to monitor infection progress. Faecal samples were analysed using two indirect enzyme-linked immunosorbent assays (ELISAs) based on semipurified viral protein (vp) 72 or purified recombinant vp30 expressed in mammalian cells. Faecal samples from 9 of 10 pigs with non haemorrhagic diarrhoea tested positive for antibodies against ASFV using the two ELISA tests that showed a positive correlation. The serum sample results from the two indirect ELISAs were compared against results from the reference ELISA technique and the immunoperoxidase test. Our findings indicate the feasibility of faecal sampling for detecting anti-ASFV antibodies, which may provide a practical non-invasive alternative for sampling wild boar populations. In conclusion, the application of these ELISA tests to faecal field samples could be particularly useful to screen for the presence of ASF in field conditions. PMID- 26431944 TI - Meningoencephalitis caused by septic arthritis of a lumbar facet joint in a patient without fever or risk factors. PMID- 26431941 TI - Immune Surveillance of the CNS following Infection and Injury. AB - The central nervous system (CNS) contains a sophisticated neural network that must be constantly surveyed in order to detect and mitigate a diverse array of challenges. The innate and adaptive immune systems actively participate in this surveillance, which is critical for the maintenance of CNS homeostasis and can facilitate the resolution of infections, degeneration, and tissue damage. Infections and sterile injuries represent two common challenges imposed on the CNS that require a prompt immune response. While the inducers of these two challenges differ in origin, the resultant responses orchestrated by the CNS share some overlapping features. Here, we review how the CNS immunologically discriminates between pathogens and sterile injuries, mobilizes an immune reaction, and, ultimately, regulates local and peripherally-derived immune cells to provide a supportive milieu for tissue repair. PMID- 26431945 TI - Rescuer factors predict high-quality CPR--a manikin-based study of health care providers. AB - BACKGROUND: In the provision of high-quality cardiopulmonary resuscitation (CPR) by health care providers, factors associated with high-quality CPR should be explored. METHODS: This is a post hoc analysis using data from a manikin-based survey of CPR quality among volunteer emergency medical technicians (EMTs) from 2 county fire departments in northern Taiwan. RESULTS: Among the 95 enrolled EMTs, 36 (37.9%) performed high-quality CPR on a manikin. The baseline characteristics that differed significantly between groups were board-certified EMT levels (P = .010), body mass index (BMI, P = .029), average exercise frequency (P = .001), and average exercise duration (P = .005). Average total exercise time per week, which uses frequency times exercise duration, was independently associated with high-quality CPR performance after adjusting for variables via logistic regression analysis (odds ratio, 1.004; P = .044). An index was developed (BMI * ExeTime) based on the product of BMI and average total exercise time per week. A comparison of the area under curve for the different indices showed that BMI * ExeTime was a significant predictor of high-quality CPR, with an area under curve of 0.718 (95% confidence interval, 0.613-0.824; P < .001; Fig. 2) and a cutoff value of 4136.7 kg.min/m(2) (sensitivity, 0.722; specificity, 0.678). CONCLUSIONS: This study identified factors associated with the performance by health care providers of high-quality CPR, including BMI and exercise habits. To optimize CPR quality, a program of exercise frequency and duration adjusted according to individual's BMI should be considered in such populations. PMID- 26431946 TI - Establishing diversity in the dopaminergic system. AB - Midbrain dopaminergic neurons (MbDNs) modulate cognitive processes, regulate voluntary movement, and encode reward prediction errors and aversive stimuli. While the degeneration of MbDNs underlies the motor defects in Parkinson's disease, imbalances in dopamine levels are associated with neuropsychiatric disorders such as depression, schizophrenia and substance abuse. In recent years, progress has been made in understanding how MbDNs, which constitute a relatively small neuronal population in the brain, can contribute to such diverse functions and dysfunctions. In particular, important insights have been gained regarding the distinct molecular, neurochemical and network properties of MbDNs. How this diversity of MbDNs is established during brain development is only starting to be unraveled. In this review, we summarize the current knowledge on the diversity in MbDN progenitors and differentiated MbDNs in the developing rodent brain. We discuss the signaling pathways, transcription factors and transmembrane receptors that contribute to setting up these diverse MbDN subpopulations. A better insight into the processes that establish diversity in MbDNs will ultimately improve the understanding of the architecture and function of the dopaminergic system in the adult brain. PMID- 26431947 TI - Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation. AB - Interleukin-23 (IL-23) and IL-17 are cytokines currently being targeted in clinical trials. Although inhibition of both of these cytokines is effective for treating psoriasis, IL-12 and IL-23 p40 inhibition attenuates Crohn's disease, whereas IL-17A or IL-17 receptor A (IL-17RA) inhibition exacerbates Crohn's disease. This dichotomy between IL-23 and IL-17 was effectively modeled in the multidrug resistance-1a-ablated (Abcb1a(-/-)) mouse model of colitis. IL-23 inhibition attenuated disease by decreasing colonic inflammation while enhancing regulatory T (Treg) cell accumulation. Exacerbation of colitis by IL-17A or IL 17RA inhibition was associated with severe weakening of the intestinal epithelial barrier, culminating in increased colonic inflammation and accelerated mortality. These data show that IL-17A acts on intestinal epithelium to promote barrier function and provide insight into mechanisms underlying exacerbation of Crohn's disease when IL-17A or IL-17RA is inhibited. PMID- 26431948 TI - Interleukin-23-Independent IL-17 Production Regulates Intestinal Epithelial Permeability. AB - Whether interleukin-17A (IL-17A) has pathogenic and/or protective roles in the gut mucosa is controversial and few studies have analyzed specific cell populations for protective functions within the inflamed colonic tissue. Here we have provided evidence for IL-17A-dependent regulation of the tight junction protein occludin during epithelial injury that limits excessive permeability and maintains barrier integrity. Analysis of epithelial cells showed that in the absence of signaling via the IL-17 receptor adaptor protein Act-1, the protective effect of IL-17A was abrogated and inflammation was enhanced. We have demonstrated that after acute intestinal injury, IL-23R(+) gammadelta T cells in the colonic lamina propria were the primary producers of early, gut-protective IL 17A, and this production of IL-17A was IL-23 independent, leaving protective IL 17 intact in the absence of IL-23. These results suggest that IL-17-producing gammadelta T cells are important for the maintenance and protection of epithelial barriers in the intestinal mucosa. PMID- 26431950 TI - Impact of maternal nutritional status before and during pregnancy on neonatal body composition: A cross-sectional study. AB - BACKGROUND: The existence of early factors which, acting during critical periods of intrauterine or immediate postnatal development, determine long-term health has become increasingly recognized. Both high and low birth weight have been associated with cardiovascular risk factors in adulthood. Therefore, body composition at birth rather than birth weight may be a marker to predict future diseases. Maternal weight previous to and gained during pregnancy is associated with intrauterine fetal growth. OBJECTIVE: To evaluate the correlation between maternal nutritional status before and during pregnancy and neonatal body composition. MATERIAL AND METHODS: We studied consecutive mother-child pairs at delivery at an Argentinean public hospital during 5 months period, evaluating maternal and neonatal anthropometry before 24h of life as well as the history of the mother before and during pregnancy. Neonatal body composition was calculated according to a mathematical formula based on skinfold thickness measurement validated in newborns. RESULTS: Mothers of newborns with high body fat mass were more frequently obese (72.7% versus 35.1%, p 0.005), and more frequently showed weight gain above 18kg during pregnancy (76.4% versus 31%, p 0.03). CONCLUSIONS: Our findings confirm the hypothesis that maternal obesity before pregnancy is highly correlated with neonatal fat mass in the first hours of life. PMID- 26431949 TI - T Follicular Helper Cell-Dependent Clearance of a Persistent Virus Infection Requires T Cell Expression of the Histone Demethylase UTX. AB - Epigenetic changes, including histone methylation, control T cell differentiation and memory formation, though the enzymes that mediate these processes are not clear. We show that UTX, a histone H3 lysine 27 (H3K27) demethylase, supports T follicular helper (Tfh) cell responses that are essential for B cell antibody generation and the resolution of chronic viral infections. Mice with a T cell specific UTX deletion had fewer Tfh cells, reduced germinal center responses, lacked virus-specific immunoglobulin G (IgG), and were unable to resolve chronic lymphocytic choriomeningitis virus infections. UTX-deficient T cells showed decreased expression of interleukin-6 receptor-alpha and other Tfh cell-related genes that were associated with increased H3K27 methylation. Additionally, Turner Syndrome subjects, who are predisposed to chronic ear infections, had reduced UTX expression in immune cells and decreased circulating CD4(+) CXCR5(+) T cell frequency. Thus, we identify a critical link between UTX in T cells and immunity to infection. PMID- 26431951 TI - Perioperative stroke in patients undergoing elective spinal surgery: a retrospective analysis using the Japanese diagnosis procedure combination database. AB - BACKGROUND: Although a few studies on perioperative stroke following spinal surgery have been reported, differences in the incidence of perioperative stroke among various surgical procedures have not been determined. The purpose of this retrospective analysis was to investigate the incidence of perioperative stroke during hospitalization in patients undergoing elective spinal surgery, and to examine whether the incidence varied according to the surgical procedure. METHODS: A retrospective analysis of data from the Diagnosis Procedure Combination database, a nationwide administrative impatient database in Japan, identified 167,106 patients who underwent elective spinal surgery during 2007 2012. Patient information extracted included age, sex, preoperative comorbidity, administration of blood transfusion, length of hospitalization, and type of hospital. Clinical outcomes included perioperative stroke during hospitalization, and in-hospital death. RESULTS: The overall incidence of perioperative stroke was 0.22 % (371/167,106) during hospitalization. A logistic regression model fitted with a generalized estimating equation showed perioperative stroke was associated with advanced age, a history of cardiac disease, an academic institution, and resection of a spinal tumor. Patients who underwent resection of a spinal cord tumor (reference) had a higher risk of stroke compared with those undergoing discectomy (odds ratio (OR), 0.29; 95 % confidence interval (CI), 0.14-0.58; p = 0.001), decompression surgery (OR, 0.44; 95 % CI, 0.26-0.73; p = 0.001), or arthrodesis surgery (OR, 0.55; 95 % CI, 0.34-0.90); p = 0.02). Advanced age (>=80 years; OR, 5.66; 95 % CI, 3.10-10.34; p <= 0.001), history of cardiac disease (OR, 1.58; 95 % CI, 1.10-2.26; p = 0.01), diabetes (OR, 1.73; 95 % CI, 1.36-2.20; p <= 0.001), hypertension (OR, 1.53; 95 % CI, 1.18-1.98; p = 0.001), cervical spine surgery (OR, 1.44; 95 % CI, 1.09-1.90; p = 0.01), a teaching hospital (OR, 1.36; 95 % CI, 1.01-1.82; p = 0.04), and length of stay (OR, 1.008; 95 % CI, 1.005-1.010; p <= 0.001) were also risk factors for perioperative stroke. CONCLUSIONS: Perioperative stroke occurred in 0.22 % of patients undergoing spinal surgery. Resection of a spinal cord tumor was associated with increased risk of perioperative stroke as well as advanced age, comorbidities at admission, cervical spine surgery, surgery in a teaching hospital, and length of stay. PMID- 26431952 TI - Feasibility of Using an Enzymatically Activatable Fluorescence Probe for the Rapid Evaluation of Pancreatic Tissue Obtained Using Endoscopic Ultrasound-Guided Fine Needle Aspiration: a Pilot Study. AB - PURPOSE: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is the most reliable method for the histological diagnosis of pancreatic tumors. Rapid on-site fluorescence-guided histological diagnosis was evaluated by topically applying an enzymatically activatable probe onto the EUS-FNA samples; the probe fluoresces in the presence of gamma-glutamyltranspeptidase (GGT). PROCEDURES: We evaluated GGT expression in pancreatic cancer cell lines in vitro. EUS-FNA was performed in 10 pancreatic tumors. After topical application of the probe, signal intensity was measured using a fluorescence imaging system for 13 min. RESULTS: GGT was expressed in Panc-1, AsPC-1, and AR42J, but not in KP4 cells. In samples from six cases, several regions of the specimens fluoresced and contained adequate tissue for pathological diagnosis. The remaining four non-fluorescent samples contained very small amounts of carcinoma, normal epithelial cells, or no epithelial cells. The signal intensity at 5 min was 25.5 +/- 7.7 and 7.7 +/- 0.5 in fluorescent and non-fluorescent regions, respectively (p < 0.05). CONCLUSIONS: Application of enzymatically activatable probe onto EUS-FNA samples would be feasible for the rapid evaluation of tissues suitable for histological diagnosis. PMID- 26431954 TI - The impact of Alpha/ESHRE consensus regarding oocytes with aggregates of smooth endoplasmic reticulum (SERa) on in vitro fertilization outcome. AB - PURPOSE: The present study aimed to gather information on the impact of Alpha/European Society of Human Reproduction and Embryology (ESHRE) consensus regarding oocytes with aggregates of smooth endoplasmic reticulum (SERa) on in vitro fertilization outcome. In particular, we investigated if patients undergoing intracytoplasmic sperm injection (ICSI) and whose oocytes are discarded due to SERa have a higher chance of embryo transfer cancellation compared to patients without SERa oocytes. METHODS: This is a nested case-control study drawn from the cohort of women referring for in vitro fertilization with ICSI. Cases were patients showing at least one oocyte with SERa at the time of injection. Controls were subsequent patients showing no SERa oocytes and matched ratio 1:1 for age, clinical indication to in vitro fertilization (IVF), and body mass index. The main outcome was the rate of embryo transfer cancellation. RESULTS: The percentage of women experiencing a transfer cancellation (absence of suitable oocytes or viable embryos) in their ICSI cycle were significantly higher in cases (18 %) compared to controls (8 %) (p = 0.02); however, adjusted odds ratio for FSH and number of SERa oocytes, of follicles, of retrieved oocytes, and of inseminated oocytes were not statistically significant. CONCLUSIONS: We have shown that the exclusion of SERa oocytes from ICSI cycles causes an increased frequency of transfer cancellation. This effect is mostly due to the reduced number of available oocytes after exclusion of SERa oocytes. PMID- 26431953 TI - [Injection treatment with hyaluronic acid]. AB - This article presents the spectrum of indications for the use of hyaluronic acid (HA) based on the recommendations of the European League Against Rheumatism (EULAR), the American College of Rheumatology (ACR), the Osteoarthritis Research Society International (OARSI), the International Institute for Health and Clinical Excellence (NICE) and the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) taking the reality of patient care in Europe into account. PMID- 26431955 TI - Reference values of reactive oxygen species in seminal ejaculates using chemiluminescence assay. AB - PURPOSE: A physiological balance exists between seminal reactive oxygen species (ROS) and antioxidant capacity. An overproduction of ROS which exceeds the seminal plasma antioxidant capacity results in oxidative stress (OS). The aim of the present study was to describe a detailed protocol to measure ROS in a diagnostic laboratory and revise our previous cutoff value of ROS in seminal ejaculates in a larger cohort of infertile men and controls with proven and unproven fertility. METHODS: A total of 258 infertile men and 92 controls were enrolled in the study. Following initial semen analysis, ROS measurement in whole ejaculates was carried out using luminol-based chemiluminescence assay. Chemiluminescence was measured for 15 min with a Berthold luminometer. Results were expressed as relative light units (RLU/s/10(6) sperm). The test's specificity, sensitivity, and cutoff values were calculated using the receiver operating characteristic (ROC) curve. RESULTS: Significantly higher ROS levels were seen in infertile men compared to controls (p < 0.001). The optimal cutoff value to differentiate between controls and infertile men was 102.2 RLU/s/10(6) sperm. At this cutoff value, the test was 76.4% sensitive and 53.3% specific. The positive and negative predictive values of the test were 82.1% and 44.5%, respectively. A total of 76.4% infertile population was above this cutoff value compared to 46.7% of controls. CONCLUSIONS: The luminol-based chemiluminescence assay can be used in routine diagnostic screening to test for male infertility diagnosis in a clinical setting. The current ROS cutoff value substantially distinguishes infertile from normal controls. Patients with elevated ROS must be evaluated for the underlying cause of ROS production. PMID- 26431957 TI - Juice Boxes. PMID- 26431956 TI - Clostridial Infections in Children: Spectrum and Management. AB - Clostridia can cause unique histotoxic syndromes produced by specific toxins (e.g., gas gangrene and food poisoning) as well as non-syndromic infections (e.g., abscess, local infections, and blood born infection). Clostridia can also be recovered from various body sites as part of polymicrobial aerobic-anaerobic infection. These include intra-abdominal (peritonitis and abscess), biliary tract, female genital tract, abscess (rectal area and oropharyngeal), pleuropulmonary, central nervous system, and skin and soft-tissue infections. Clostridia were recovered from children with bacteremia of gastrointestinal origin, necrotizing enterocolitis, and sickle cell disease. They have also been isolated in acute and chronic otitis media, chronic sinusitis and mastoiditis, peritonsillar abscesses, and neonatal conjunctivitis. Early and aggressive surgical debridement, decompression, and drainage of affected tissues are critical to successful outcome of histotoxic infections. Effective antimicrobials include penicillin, clindamycin, chloramphenicol, third-generation cephalosporins, carbapenems, and vancomycin. PMID- 26431958 TI - Analgesia-free flexible ureteroscopic treatment and laser lithotripsy for removal of a large urinary stone: a case report. AB - INTRODUCTION: Urinary stone formation is a frequent complication after continent urinary tract diversion and can require complex surgical management. Therapy options include open, percutaneous, transurethral, or transstomal stone fragmentation and extraction. The transstomal approach is considered to be one of the more complex treatment modalities. The patient's individual anatomy, minor stoma diameter, and the existing continence mechanism in the majority of cases cause substantial technical challenges for the surgeon. We present here what we believe to be the first description of an analgesia-free flexible endoscopic removal of a large pouch stone in an out-patient care setting. Additionally, we provide a brief overview of competing techniques. CASE PRESENTATION: A 30-year old Caucasian woman with a history of lower urinary tract reconstruction with an ileal pouch and a continent umbilical stoma was admitted to our department with pouch urolithiasis in the urinary reservoir. We employed a minimally invasive approach to extract the stone using flexible ureteroscopy via a modified access sheath and laser lithotripsy. No analgesia is needed with this procedure and it can be performed in an out-patient setting. CONCLUSION: The described clinical case highlights the difficulties of treating this high-incidence problem in patients with continent urinary diversions. Our presented technique is of particular interest to urologists and family doctors, and could improve the treatment of such patients by lowering the morbidity of the intervention. PMID- 26431959 TI - Validation of the Dutch version of the quick mild cognitive impairment screen (Qmci-D). AB - BACKGROUND: Differentiating mild cognitive impairment (MCI) from dementia is important, as treatment options differ. There are few short (<5 min) but accurate screening tools that discriminate between MCI, normal cognition (NC) and dementia, in the Dutch language. The Quick Mild Cognitive Impairment (Qmci) screen is sensitive and specific in differentiating MCI from NC and mild dementia. Given this, we adapted the Qmci for use in Dutch-language countries and validated the Dutch version, the Qmci-D, against the Dutch translation of the Standardised Mini-Mental State Examination (SMMSE-D). METHOD: The Qmci was translated into Dutch with a combined qualitative and quantitative approach. In all, 90 participants were recruited from a hospital geriatric clinic (25 with dementia, 30 with MCI, 35 with NC). The Qmci-D and SMMSE-D were administered sequentially but randomly by the same trained rater, blind to the diagnosis. RESULTS: The Qmci-D was more sensitive than the SMMSE-D in discriminating MCI from dementia, with a significant difference in the area under the curve (AUC), 0.73 compared to 0.60 (p = 0.024), respectively, and in discriminating dementia from NC, with an AUC of 0.95 compared to 0.89 (p = 0.006). Both screening instruments discriminated MCI from NC with an AUC of 0.86 (Qmci-D) and 0.84 (SMMSE-D). CONCLUSION: The Qmci-D shows similar,(good) accuracy as the SMMSE-D in separating NC from MCI; greater,(albeit fair), accuracy differentiating MCI from dementia, and significantly greater accuracy in separating dementia from NC. Given its brevity and ease of administration, the Qmci-D seems a useful cognitive screen in a Dutch population. Further study with a suitably powered sample against more sensitive screens is now required. PMID- 26431960 TI - SIADH-related hyponatremia in hospital day care units: clinical experience and management with tolvaptan. AB - Hyponatremia (Na ? 135 mmol/l) is the most frequent electrolyte disorder in clinical practice, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the commonest cause of hyponatremia in cancer patients. Correcting hyponatremia in these patients can reduce morbidity and mortality, increase the response to anti-cancer agents, and help reduce hospital length of stay and costs. Tolvaptan is an oral medication used to treat SIADH-related hyponatremia patients that needs to be initiated at hospital so patients can have their serum sodium monitored. If tolvaptan could be initiated in hospital day care units (DCUs), performing the same tests, hospitalization could be avoided, quality of life improved, and costs reduced. This is the first publication where a panel of oncologists are sharing their experience and making some recommendations with the use of tolvaptan to treat SIADH-related hyponatremia in DCU after collecting and examining 35 clinical cases with these type of patients. The conclusion from this retrospective observational analysis is that the use of tolvaptan in DCU is safe and effective in the therapeutic management of SIADH related hyponatremia. PMID- 26431961 TI - How effective are common medications: a perspective based on meta-analyses of major drugs. AB - The vastness of clinical data and the progressing specialization of medical knowledge may lead to misinterpretation of medication efficacy. To show a realistic perspective on drug efficacy we present meta-analyses on some of the most commonly used pharmacological interventions. For each pharmacological intervention we present statistical indexes (absolute risk or response difference, percentage response ratio, mean difference, standardized mean difference) that are often used to represent efficacy. We found that some of the medications have relatively low effect sizes with only 11 out of 17 of them showing a minimal clinically important difference. Efficacy was often established based on surrogate outcomes and not the more relevant patient-oriented outcomes. As the interpretation of the efficacy of medication is complex, more training for physicians might be needed to get a more realistic view of drug efficacy. That could help prevent harmful overtreatment and reinforce an evidence-based, but personalized medicine. PMID- 26431962 TI - Older people are not a burden, says WHO. PMID- 26431964 TI - Avian migrants facilitate invasions of neotropical ticks and tick-borne pathogens into the United States. AB - Migratory birds have the potential to transport exotic vectors and pathogens of human and animal health importance across vast distances. We systematically examined birds that recently migrated to the United States from the Neotropics for ticks. We screened both ticks and birds for tick-borne pathogens, including Rickettsia species and Borrelia burgdorferi. Over two spring seasons (2013 and 2014), 3.56% of birds (n = 3,844) representing 42.35% of the species examined (n = 85) were infested by ticks. Ground-foraging birds with reduced fuel stores were most commonly infested. Eight tick species were identified, including seven in the genus Amblyomma, of which only Amblyomma maculatum/Amblyomma triste is known to be established in the United States. Most ticks on birds (67%) were neotropical species with ranges in Central and South America. Additionally, a single Ixodes genus tick was detected. A total of 29% of the ticks (n = 137) and no avian blood samples (n = 100) were positive for infection with Rickettsia species, including Rickettsia parkeri, an emerging cause of spotted fever in humans in the southern United States, a species in the group of Rickettsia monacensis, and uncharacterized species and endosymbionts of unknown pathogenicity. No avian tick or blood samples tested positive for B. burgdorferi, the etiologic agent of Lyme disease. An extrapolation of our findings suggests that anywhere from 4 to 39 million exotic neotropical ticks are transported to the United States annually on migratory songbirds, with uncertain consequences for human and animal health if the current barriers to their establishment and spread are overcome. PMID- 26431963 TI - MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells. AB - Maternal embryonic leucine zipper kinase (MELK), a serine/threonine protein kinase, has oncogenic properties and is overexpressed in many cancer cells. The oncogenic function of MELK is attributed to its capacity to disable critical cell cycle checkpoints and reduce replication stress. Most functional studies have relied on the use of siRNA/shRNA-mediated gene silencing. In the present study, we have explored the biological function of MELK using MELK-T1, a novel and selective small-molecule inhibitor. Strikingly, MELK-T1 triggered a rapid and proteasome-dependent degradation of the MELK protein. Treatment of MCF-7 (Michigan Cancer Foundation-7) breast adenocarcinoma cells with MELK-T1 induced the accumulation of stalled replication forks and double-strand breaks that culminated in a replicative senescence phenotype. This phenotype correlated with a rapid and long-lasting ataxia telangiectasia-mutated (ATM) activation and phosphorylation of checkpoint kinase 2 (CHK2). Furthermore, MELK-T1 induced a strong phosphorylation of p53 (cellular tumour antigen p53), a prolonged up regulation of p21 (cyclin-dependent kinase inhibitor 1) and a down-regulation of FOXM1 (Forkhead Box M1) target genes. Our data indicate that MELK is a key stimulator of proliferation by its ability to increase the threshold for DNA damage tolerance (DDT). Thus, targeting MELK by the inhibition of both its catalytic activity and its protein stability might sensitize tumours to DNA damaging agents or radiation therapy by lowering the DNA-damage threshold. PMID- 26431965 TI - Facultative control of matrix production optimizes competitive fitness in Pseudomonas aeruginosa PA14 biofilm models. AB - As biofilms grow, resident cells inevitably face the challenge of resource limitation. In the opportunistic pathogen Pseudomonas aeruginosa PA14, electron acceptor availability affects matrix production and, as a result, biofilm morphogenesis. The secreted matrix polysaccharide Pel is required for pellicle formation and for colony wrinkling, two activities that promote access to O2. We examined the exploitability and evolvability of Pel production at the air-liquid interface (during pellicle formation) and on solid surfaces (during colony formation). Although Pel contributes to the developmental response to electron acceptor limitation in both biofilm formation regimes, we found variation in the exploitability of its production and necessity for competitive fitness between the two systems. The wild type showed a competitive advantage against a non-Pel producing mutant in pellicles but no advantage in colonies. Adaptation to the pellicle environment selected for mutants with a competitive advantage against the wild type in pellicles but also caused a severe disadvantage in colonies, even in wrinkled colony centers. Evolution in the colony center produced divergent phenotypes, while adaptation to the colony edge produced mutants with clear competitive advantages against the wild type in this O2-replete niche. In general, the structurally heterogeneous colony environment promoted more diversification than the more homogeneous pellicle. These results suggest that the role of Pel in community structure formation in response to electron acceptor limitation is unique to specific biofilm models and that the facultative control of Pel production is required for PA14 to maintain optimum benefit in different types of communities. PMID- 26431966 TI - Two pathways for glutamate biosynthesis in the syntrophic bacterium Syntrophus aciditrophicus. AB - The anaerobic metabolism of crotonate, benzoate, and cyclohexane carboxylate by Syntrophus aciditrophicus grown syntrophically with Methanospirillum hungatei provides a model to study syntrophic cooperation. Recent studies revealed that S. aciditrophicus contains Re-citrate synthase but lacks the common Si-citrate synthase. To establish whether the Re-citrate synthase is involved in glutamate synthesis via the oxidative branch of the Krebs cycle, we have used [1 (13)C]acetate and [1-(14)C]acetate as well as [(13)C]bicarbonate as additional carbon sources during axenic growth of S. aciditrophicus on crotonate. Our analyses showed that labeled carbons were detected in at least 14 amino acids, indicating the global utilization of acetate and bicarbonate. The labeling patterns of alanine and aspartate verified that pyruvate and oxaloacetate were synthesized by consecutive carboxylations of acetyl coenzyme A (acetyl-CoA). The isotopomer profile and (13)C nuclear magnetic resonance (NMR) spectroscopy of the obtained [(13)C]glutamate, as well as decarboxylation of [(14)C]glutamate, revealed that this amino acid was synthesized by two pathways. Unexpectedly, only the minor route used Re-citrate synthase (30 to 40%), whereas the majority of glutamate was synthesized via the reductive carboxylation of succinate. This symmetrical intermediate could have been formed from two acetates via hydration of crotonyl-CoA to 4-hydroxybutyryl-CoA. 4-Hydroxybutyrate was detected in the medium of S. aciditrophicus when grown on crotonate, but an active hydratase could not be measured in cell extracts, and the annotated 4-hydroxybutyryl-CoA dehydratase (SYN_02445) lacks key amino acids needed to catalyze the hydration of crotonyl-CoA. Besides Clostridium kluyveri, this study reveals the second example of a microbial species to employ two pathways for glutamate synthesis. PMID- 26431967 TI - Improvement of glucose uptake rate and production of target chemicals by overexpressing hexose transporters and transcriptional activator Gcr1 in Saccharomyces cerevisiae. AB - Metabolic engineering to increase the glucose uptake rate might be beneficial to improve microbial production of various fuels and chemicals. In this study, we enhanced the glucose uptake rate in Saccharomyces cerevisiae by overexpressing hexose transporters (HXTs). Among the 5 tested HXTs (Hxt1, Hxt2, Hxt3, Hxt4, and Hxt7), overexpression of high-affinity transporter Hxt7 was the most effective in increasing the glucose uptake rate, followed by moderate-affinity transporters Hxt2 and Hxt4. Deletion of STD1 and MTH1, encoding corepressors of HXT genes, exerted differential effects on the glucose uptake rate, depending on the culture conditions. In addition, improved cell growth and glucose uptake rates could be achieved by overexpression of GCR1, which led to increased transcription levels of HXT1 and ribosomal protein genes. All genetic modifications enhancing the glucose uptake rate also increased the ethanol production rate in wild-type S. cerevisiae. Furthermore, the growth-promoting effect of GCR1 overexpression was successfully applied to lactic acid production in an engineered lactic acid producing strain, resulting in a significant improvement of productivity and titers of lactic acid production under acidic fermentation conditions. PMID- 26431968 TI - Involutin is an Fe3+ reductant secreted by the ectomycorrhizal fungus Paxillus involutus during Fenton-based decomposition of organic matter. AB - Ectomycorrhizal fungi play a key role in mobilizing nutrients embedded in recalcitrant organic matter complexes, thereby increasing nutrient accessibility to the host plant. Recent studies have shown that during the assimilation of nutrients, the ectomycorrhizal fungus Paxillus involutus decomposes organic matter using an oxidative mechanism involving Fenton chemistry (Fe(2+) + H2O2 + H(+) -> Fe(3+) + OH + H2O), similar to that of brown rot wood-decaying fungi. In such fungi, secreted metabolites are one of the components that drive one electron reductions of Fe(3+) and O2, generating Fenton chemistry reagents. Here we investigated whether such a mechanism is also implemented by P. involutus during organic matter decomposition. Activity-guided purification was performed to isolate the Fe(3+)-reducing principle secreted by P. involutus during growth on a maize compost extract. The Fe(3+)-reducing activity correlated with the presence of one compound. Mass spectrometry and nuclear magnetic resonance (NMR) identified this compound as the diarylcyclopentenone involutin. A major part of the involutin produced by P. involutus during organic matter decomposition was secreted into the medium, and the metabolite was not detected when the fungus was grown on a mineral nutrient medium. We also demonstrated that in the presence of H2O2, involutin has the capacity to drive an in vitro Fenton reaction via Fe(3+) reduction. Our results show that the mechanism for the reduction of Fe(3+) and the generation of hydroxyl radicals via Fenton chemistry by ectomycorrhizal fungi during organic matter decomposition is similar to that employed by the evolutionarily related brown rot saprotrophs during wood decay. PMID- 26431969 TI - Interactions between closely related bacterial strains are revealed by deep transcriptome sequencing. AB - Comparative genomics, metagenomics, and single-cell technologies have shown that populations of microbial species encompass assemblages of closely related strains. This raises the question of whether individual bacterial lineages respond to the presence of their close relatives by modifying their gene expression or, instead, whether assemblages simply act as the arithmetic addition of their individual components. Here, we took advantage of transcriptome sequencing to address this question. For this, we analyzed the transcriptomes of two closely related strains of the extremely halophilic bacterium Salinibacter ruber grown axenically and in coculture. These organisms dominate bacterial assemblages in hypersaline environments worldwide. The strains used here cooccurred in the natural environment and are 100% identical in their 16S rRNA genes, and each strain harbors an accessory genome representing 10% of its complete genome. Overall, transcriptomic patterns from pure cultures were very similar for both strains. Expression was detected along practically the whole genome albeit with some genes at low levels. A subset of genes was very highly expressed in both strains, including genes coding for the light-driven proton pump xanthorhodopsin, genes involved in the stress response, and genes coding for transcriptional regulators. Expression differences between pure cultures affected mainly genes involved in environmental sensing. When the strains were grown in coculture, there was a modest but significant change in their individual transcription patterns compared to those in pure culture. Each strain sensed the presence of the other and responded in a specific manner, which points to fine intraspecific transcriptomic modulation. PMID- 26431970 TI - Multiplexed integrating plasmids for engineering of the erythromycin gene cluster for expression in Streptomyces spp. and combinatorial biosynthesis. AB - Bacteria in the genus Streptomyces and its close relatives are prolific producers of secondary metabolites with antibiotic activity. Genome sequencing of these bacteria has revealed a rich source of potentially new antibiotic pathways, whose products have never been observed. Moreover, these new pathways can provide novel genes that could be used in combinatorial biosynthesis approaches to generate unnatural analogues of existing antibiotics. We explore here the use of multiple orthologous integrating plasmid systems, based on the int/attP loci from phages TG1, SV1, and phiBT1, to express the polyketide synthase (PKS) for erythromycin in a heterologous Streptomyces host. Streptomyces strains containing the three polyketide synthase genes eryAI, eryAII, and eryAIII expressed from three different integrated plasmids produced the aglycone intermediate, 6 deoxyerythronolide B (6-dEB). A further pair of integrating plasmids, both derived from the phiC31 int/attP locus, were constructed carrying a gene cassette for glycosylation of the aglycone intermediates, with or without the tailoring gene, eryF, required for the synthesis of erythronolide B (EB). Liquid chromatography-mass spectrometry of the metabolites indicated the production of angolosaminyl-6-dEB and angolosaminyl-EB. The advantages of using multiplexed integrating plasmids for engineering expression and for combinatorial biosynthesis were demonstrated. PMID- 26431971 TI - Landscape position influences microbial composition and function via redistribution of soil water across a watershed. AB - Subalpine forest ecosystems influence global carbon cycling. However, little is known about the compositions of their soil microbial communities and how these may vary with soil environmental conditions. The goal of this study was to characterize the soil microbial communities in a subalpine forest watershed in central Montana (Stringer Creek Watershed within the Tenderfoot Creek Experimental Forest) and to investigate their relationships with environmental conditions and soil carbonaceous gases. As assessed by tagged Illumina sequencing of the 16S rRNA gene, community composition and structure differed significantly among three landscape positions: high upland zones (HUZ), low upland zones (LUZ), and riparian zones (RZ). Soil depth effects on phylogenetic diversity and beta diversity varied across landscape positions, being more evident in RZ than in HUZ. Mantel tests revealed significant correlations between microbial community assembly patterns and the soil environmental factors tested (water content, temperature, oxygen, and pH) and soil carbonaceous gases (carbon dioxide concentration and efflux and methane concentration). With one exception, methanogens were detected only in RZ soils. In contrast, methanotrophs were detected in all three landscape positions. Type I methanotrophs dominated RZ soils, while type II methanotrophs dominated LUZ and HUZ soils. The relative abundances of methanotroph populations correlated positively with soil water content (R = 0.72, P < 0.001) and negatively with soil oxygen (R = -0.53, P = 0.008). Our results suggest the coherence of soil microbial communities within and differences in communities between landscape positions in a subalpine forested watershed that reflect historical and contemporary environmental conditions. PMID- 26431972 TI - Protein engineering of a nitrilase from Burkholderia cenocepacia J2315 for efficient and enantioselective production of (R)-o-chloromandelic acid. AB - The nitrilase-mediated pathway has significant advantages in the production of optically pure aromatic alpha-hydroxy carboxylic acids. However, low enantioselectivity and activity are observed on hydrolyzing o chloromandelonitrile to produce optically pure (R)-o-chloromandelic acid. In the present study, a protein engineering approach was successfully used to enhance the performance of nitrilase obtained from Burkholderia cenocepacia strain J2315 (BCJ2315) in hydrolyzing o-chloromandelonitrile. Four hot spots (T49, I113, Y199, and T310) responsible for the enantioselectivity and activity of BCJ2315 were identified by random mutagenesis. An effective double mutant (I113M/Y199G [encoding the replacement of I with M at position 113 and Y with G at position 199]), which demonstrated remarkably enhanced enantioselectivity (99.1% enantiomeric excess [ee] compared to 89.2% ee for the wild type) and relative activity (360% of the wild type), was created by two rounds of site saturation mutagenesis, first at each of the four hot spots and subsequently at position 199 for combination with the selected beneficial mutation I113M. Notably, this mutant also demonstrated dramatically enhanced enantioselectivity and activity toward other mandelonitrile derivatives and, thus, broadened the substrate scope of this nitrilase. Using an ethyl acetate-water (1:9) biphasic system, o chloromandelonitrile (500 mM) was completely hydrolyzed in 3 h by this mutant with a small amount of biocatalyst (10 g/liter wet cells), resulting in a high concentration of (R)-o-chloromandelic acid with 98.7% ee, to our knowledge the highest ever reported. This result highlights a promising method for industrial production of optically pure (R)-o-chloromandelic acid. Insight into the source of enantioselectivity and activity was gained by homology modeling and molecular docking experiments. PMID- 26431973 TI - Adaptation of the cecal bacterial microbiome of growing pigs in response to resistant starch type 4. AB - Resistant starch (RS) exacerbates health benefits on the host via modulation of the gut bacterial community. By far, these effects have been less well explored for RS of type 4. This study aimed at gaining a community-wide insight into the impact of enzymatically modified starch (EMS) on the cecal microbiota and hindgut fermentation in growing pigs. Castrated male pigs (n = 12/diet; 29-kg body weight) were fed diets with either 70% EMS or control starch for 10 days. The bacterial profile of each cecal sample was determined by sequencing of the V345 region of the 16S rRNA gene using the Illumina MiSeq platform. EMS diet reduced short-chain fatty acid concentrations in cecum and proximal colon compared to the control diet. Linear discriminant analyses and K means clustering indicated diet specific cecal community profiles, whereby diversity and species richness were not different among diets. Pigs showed host-specific variation in their most abundant phyla, Firmicutes (55%), Proteobacteria (35%), and Bacteroidetes (10%). The EMS diet decreased abundance of Ruminococcus, Parasutterella, Bilophila, Enterococcus, and Lactobacillus operational taxonomic units (OTU), whereas Meniscus and Actinobacillus OTU were increased compared to those with the control diet (P < 0.05). Quantitative PCR confirmed results for host effect on Enterobacteriaceae and diet effect on members of the Lactobacillus group. The presence of less cecal short-chain fatty acids and the imputed metabolic functions of the cecal microbiome suggested that EMS was less degradable for cecal bacteria than the control starch. The present EMS effects on the bacterial community profiles were different than the previously reported RS effects and can be linked to the chemical structure of EMS. PMID- 26431974 TI - Microbiological oxidation of antimony(III) with oxygen or nitrate by bacteria isolated from contaminated mine sediments. AB - Bacterial oxidation of arsenite [As(III)] is a well-studied and important biogeochemical pathway that directly influences the mobility and toxicity of arsenic in the environment. In contrast, little is known about microbiological oxidation of the chemically similar anion antimonite [Sb(III)]. In this study, two bacterial strains, designated IDSBO-1 and IDSBO-4, which grow on tartrate compounds and oxidize Sb(III) using either oxygen or nitrate, respectively, as a terminal electron acceptor, were isolated from contaminated mine sediments. Both isolates belonged to the Comamonadaceae family and were 99% similar to previously described species. We identify these novel strains as Hydrogenophaga taeniospiralis strain IDSBO-1 and Variovorax paradoxus strain IDSBO-4. Both strains possess a gene with homology to the aioA gene, which encodes an As(III) oxidase, and both oxidize As(III) aerobically, but only IDSBO-4 oxidized Sb(III) in the presence of air, while strain IDSBO-1 could achieve this via nitrate respiration. Our results suggest that expression of aioA is not induced by Sb(III) but may be involved in Sb(III) oxidation along with an Sb(III)-specific pathway. Phylogenetic analysis of proteins encoded by the aioA genes revealed a close sequence similarity (90%) among the two isolates and other known As(III) oxidizing bacteria, particularly Acidovorax sp. strain NO1. Both isolates were capable of chemolithoautotrophic growth using As(III) as a primary electron donor, and strain IDSBO-4 exhibited incorporation of radiolabeled [(14)C]bicarbonate while oxidizing Sb(III) from Sb(III)-tartrate, suggesting possible Sb(III)-dependent autotrophy. Enrichment cultures produced the Sb(V) oxide mineral mopungite and lesser amounts of Sb(III)-bearing senarmontite as precipitates. PMID- 26431976 TI - Characterization of mesenchymal stem cells in sheep naturally infected with scrapie. AB - Mesenchymal stem cells (MSCs) can be infected with prions and have been proposed as in vitro cell-based models for prion replication. In addition, autologous MSCs are of interest for cell therapy in neurodegenerative diseases. To the best of our knowledge, the effect of prion diseases on the characteristics of these cells has never been investigated. Here, we analysed the properties of MSCs obtained from bone marrow (BM-MSCs) and peripheral blood (PB-MSCs) of sheep naturally infected with scrapie - a large mammal model for the study of prion diseases. After three passages of expansion, MSCs derived from scrapie animals displayed similar adipogenic, chondrogenic and osteogenic differentiation ability as cells from healthy controls, although a subtle decrease in the proliferation potential was observed. Exceptionally, mesenchymal markers such as CD29 were significantly upregulated at the transcript level compared with controls. Scrapie MSCs were able to transdifferentiate into neuron-like cells, but displayed lower levels of neurogenic markers at basal conditions, which could limit this potential .The expression levels of cellular prion protein (PrPC) were highly variable between cultures, and no significant differences were observed between control and scrapie-derived MSCs. However, during neurogenic differentiation the expression of PrPC was upregulated in MSCs. This characteristic could be useful for developing in vitro models for prion replication. Despite the infectivity reported for MSCs obtained from scrapie-infected mice and Creutzfeldt-Jakob disease patients, protein misfolding cyclic amplification did not detect PrPSc in BM- or PB-MSCs from scrapie-infected sheep, which limits their use for in vivo diagnosis for scrapie. PMID- 26431975 TI - Metabolic response of Clostridium ljungdahlii to oxygen exposure. AB - Clostridium ljungdahlii is an important synthesis gas-fermenting bacterium used in the biofuels industry, and a preliminary investigation showed that it has some tolerance to oxygen when cultured in rich mixotrophic medium. Batch cultures not only continue to grow and consume H2, CO, and fructose after 8% O2 exposure, but fermentation product analysis revealed an increase in ethanol concentration and decreased acetate concentration compared to non-oxygen-exposed cultures. In this study, the mechanisms for higher ethanol production and oxygen/reactive oxygen species (ROS) detoxification were identified using a combination of fermentation, transcriptome sequencing (RNA-seq) differential expression, and enzyme activity analyses. The results indicate that the higher ethanol and lower acetate concentrations were due to the carboxylic acid reductase activity of a more highly expressed predicted aldehyde oxidoreductase (CLJU_c24130) and that C. ljungdahlii's primary defense upon oxygen exposure is a predicted rubrerythrin (CLJU_c39340). The metabolic responses of higher ethanol production and oxygen/ROS detoxification were found to be linked by cofactor management and substrate and energy metabolism. This study contributes new insights into the physiology and metabolism of C. ljungdahlii and provides new genetic targets to generate C. ljungdahlii strains that produce more ethanol and are more tolerant to syngas contaminants. PMID- 26431979 TI - Preface. PMID- 26431977 TI - Photodynamic antimicrobial chemotherapy and ultraconservative caries removal linked for management of deep caries lesions. AB - BACKGROUND: Ultraconservative removal of carious tissue is becoming increasingly highlighted for management of deep caries lesions, and combined with an antimicrobial photochemistry-based treatment modality (PACT), this approach can be enhanced favoring dental tissue repair and preservation. The aim was to investigate the effectiveness of PACT using a light emitting diode (LED) associated with a photosensitizer toluidine blue ortho (TBO) on deep caries lesions. METHODS: For that, a single blind, randomized, controlled, split-mouth clinical trial where 45 patients with at least two deep carious lesions on permanent posterior teeth was performed. The primary intervention was deep caries lesion management with disinfection of remaining dentin tissue using PACT. Bacterial counts were measured following treatments as the main outcome. The remaining dentinal samples of each lesion were treated with either non-PACT control or PACT. The PACT procedure were characterized by 100 MUg mL(-1) TBO followed by 94J cm(-2) LED irradiation. Samples of dentin were collected before and immediately after treatments for microbiological analysis of total viable bacteria, mutans streptococci and Lactobacillus spp. counts. Microbial reduction was data were submitted to unpaired t test (alpha=5%). RESULTS: PACT led to statistically significant reductions in mutans streptococci (1.08 +/- 1.20 log), Lactobacillus spp. (1.69 +/- 1.37 log), and total viable bacteria (1.07 +/- 1.01 log) compared to the control, which showed log reductions respectively of 0.05 +/ 0.49, 0.52 +/- 0.89, and 0.47 +/- 0.77 for the same microorganisms. CONCLUSION: Dentin from deep carious lesions treated with PACT showed a decrease in cariogenic microbial load. PMID- 26431980 TI - CT and D-dimer testing are overused in patients with suspected pulmonary embolism, US college says. PMID- 26431981 TI - Impact of quadrivalent human papillomavirus vaccine in women at increased risk of genital warts burden: Population-based cross-sectional survey of Czech women aged 16 to 40 years. AB - BACKGROUND: To assess the impact of a quadrivalent human papillomavirus vaccine (4HPV) in women at increased risk of genital warts (GWs) acquisition. METHODS: The study was conducted using a population-based cross-sectional survey of 19,199 women aged 16 to 40 years randomly chosen from the general population in the Czech Republic between January 2013 and March 2014. A total of 1086 women reported having received the 4HPV vaccine. The vaccine's effectiveness was estimated not only in the general population of women but also in those at increased risk due to having a sexual partner with GWs or prior GWs history. RESULTS: The acquisition of GWs was dramatically reduced by 90.6% (80.1-95.6%) in immunised women at least one year after the completion of the 4HPV vaccination in comparison with unimmunised women. Recurrent GWs prevalences of 1.1% (95% CI, 0.0 5.9) and 10.9% (95% CI, 9.1-12.9) in immunised and unimmunised women with prior GWs history, respectively, resulted in a vaccine effectiveness of 89.0% (38.6 98.0%). The notably strong protective effect of 4HPV immunisation in women who had a sexual partner with GWs was demonstrated by a very low age-adjusted odds ratio of 0.02 (95% CI 0.01-0.10) in contrast to unimmunised women. CONCLUSIONS: To lower the chance of genital warts acquisition in the general population and in populations at increased risk, only current 4HPV or incoming 9HPV vaccination should be recommended to provide effective protection. PMID- 26431978 TI - Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies. AB - Mutations within the gene encoding for the chloride ion channel cystic fibrosis transmembrane conductance regulator (CFTR) results in cystic fibrosis (CF), the most common lethal autosomal recessive genetic disease that causes a number of long-term health problems, as the bone disease. Osteoporosis and increased vertebral fracture risk associated with CF disease are becoming more important as the life expectancy of patients continues to improve. The etiology of low bone density is multifactorial, most probably a combination of inadequate peak bone mass during puberty and increased bone losses in adults. Body mass index, male sex, advanced pulmonary disease, malnutrition and chronic therapies are established additional risk factors for CF-related bone disease (CFBD). Consistently, recent evidence has confirmed that CFTR plays a major role in the osteoprotegerin (OPG) and COX-2 metabolite prostaglandin E2 (PGE2) production, two key regulators in the bone formation and regeneration. Several others mechanisms were also recognized from animal and cell models contributing to malfunctions of osteoblast (cell that form bone) and indirectly of bone resorpting osteoclasts. Understanding such mechanisms is crucial for the development of therapies in CFBD. Innovative therapeutic approaches using CFTR modulators such as C18 have recently shown in vitro capacity to enhance PGE2 production and normalized the RANKL-to-OPG ratio in human osteoblasts bearing the mutation F508del-CFTR and therefore potential clinical utility in CFBD. This review focuses on the recently identified pathogenic mechanisms leading to CFBD and potential future therapies for treating CFBD. PMID- 26431982 TI - RTS,S: Toward a first landmark on the Malaria Vaccine Technology Roadmap. AB - The Malaria Vaccine Technology Roadmap calls for a 2015 landmark goal of a first generation malaria vaccine that has protective efficacy against severe disease and death, lasting longer than one year. This review focuses on product development efforts over the last five years of RTS,S, a pre-erythrocytic, recombinant subunit, adjuvanted, candidate malaria vaccine designed with this goal of a first-generation malaria vaccine in mind. RTS,S recently completed a successful pivotal Phase III safety, efficacy and immunogenicity study. Although vaccine efficacy was found to be modest, a substantial number of cases of clinical malaria were averted over a 3-4 years period, particularly in settings of significant disease burden. European regulators have subsequently adopted a positive opinion under the Article 58 procedure for an indication of active immunization of children aged 6 weeks up to 17 months against malaria caused by Plasmodium falciparum and against hepatitis B. Further evaluations of the benefit, risk, feasibility and cost-effectiveness of RTS,S are now anticipated through policy and financing reviews at the global and national levels. PMID- 26431983 TI - Immunogenicity and safety of the new intradermal influenza vaccine in adults and elderly: A randomized phase 1/2 clinical trial. AB - BACKGROUND: Recent clinical evidence indicates that an intradermal (ID) delivery of vaccines confers superior immunogenicity as compared to a standard intramuscular or subcutaneous (SC) delivery. METHODS: In this exploratory study, 600 healthy adults were randomized to 6 study groups with subgroups of young adults (20-64 years old) and older adults (65 years and older). The subjects were either injected by a novel ID injection system with a single dose of 6, 9, or 15 MUg HA or two doses (21 days apart) of 15 MUg HA per strain or injected by an SC injection method with a single or two doses (21 days apart) of 15 MUg HA per strain. Immunogenicity was assessed using hemagglutination inhibition (HAI) titer and microneutralization titer on Days 0, 10, 21, and 42. Solicited and unsolicited adverse events were recorded for 7 and 21 days post-vaccination, respectively. RESULTS: In both young adults and older adults groups, the geometric titer (GMT) ratios of HAI in the ID 15 MUg HA group were higher than those in the SC 15 MUg HA group on both Day 10 and Day 21, while those in the ID 6 and ID 9 MUg HA groups were comparable with those in the SC 15 MUg HA group. The kinetics of GMTs of HAI suggested that the ID vaccine has the potential to induce the prompt immune response, which is rather hampered in older adults as seen in the SC vaccine groups. The injection-site AEs were generally mild and transient, and did not occur in a dose or dosage-dependent manner. CONCLUSIONS: The results of this study clearly suggest that the immunologic profile of the ID vaccine is better than that of the SC vaccine, while the safety profile of the ID vaccine is similar to that of the SC vaccine. In this exploratory study with almost 100 subjects per each group, single or two-dose administration of the ID vaccine containing 15 MUg HA was suggested to be an appropriate regimen in order to prevent influenza and to reduce the associated disease burden. TRIAL REGISTRATION: JAPIC Clinical Trials Information (JapicCTI-132096). PMID- 26431984 TI - HPV vaccination series completion and co-vaccination: Pairing vaccines may matter for adolescents. AB - Very little is known about the effect of concurrent co-vaccination on HPV series completion. This study utilized a retrospective review of a Clinical Data Repository to assess whether concurrent vaccination had an impact on HPV vaccination series completion, and whether there were differences based on age. 3371 patients who received the HPV vaccine at a single academic medical center between the years 2009-2013 were included in this analysis. The adjusted odds ratio (aOR) for effect of concurrent vaccination on series completion for the age group 9-18 was 1.32 (95% CI 1.09, 1.60). Although not statistically significant, the aOR for effect of concurrent vaccination on completion changed direction for the 19-25 age group and was 0.44 (95% CI 0.17, 1.12). This study provides preliminary evidence that pairing the HPV vaccine with one or more co-vaccines may yield a higher HPV vaccination completion rate among adolescents age 9-18. PMID- 26431985 TI - Hepatitis B virus infection in northern Uganda: Impact of pentavalent hepatitis B vaccination. AB - Chronic hepatitis B virus infection (CHBI) is effectively prevented by vaccination starting at birth. Beginning in 2002 Uganda adopted a policy of providing the pentavalent hepatitis B vaccine starting at 6 weeks of age. However, there is concern that this delay may leave the infant vulnerable to infection during the first 6 weeks of life. We assessed whether vaccination at 6 weeks was an effective strategy by HBV serologic study. Of 656 persons tested for HBV, 9.4% were chronically infected; among children aged 5-9 years the prevalence was 7.6%. Of all tested, 73 were born (i.e., aged <= 4 years) after the introduction of the pentavalent vaccine; none were infected with HBV (p = 0.003). In this study, vaccination with the pentavalent vaccine at 6 weeks did not result in CHBI, but rather provides an opportunity to prevent mother-to-infant transmission of HBV infection where there is no access to birth-dose vaccine. PMID- 26431986 TI - Workshop report: Malaria vaccine development in Europe--preparing for the future. AB - The deployment of a safe and effective malaria vaccine will be an important tool for the control of malaria and the reduction in malaria deaths. With the launch of the 2030 Malaria Vaccine Technology Roadmap, the malaria community has updated the goals and priorities for the development of such a vaccine and is now paving the way for a second phase of malaria vaccine development. During a workshop in Brussels in November 2014, hosted by the European Vaccine Initiative, key players from the European, North American and African malaria vaccine community discussed European strategies for future malaria vaccine development in the global context. The recommendations of the European malaria community should guide researchers, policy makers and funders of global health research and development in fulfilling the ambitious goals set in the updated Malaria Vaccine Technology Roadmap. PMID- 26431987 TI - Effect of age on the incidence of aseptic meningitis following immunization with monovalent mumps vaccine. AB - OBJECTIVE: The purpose of this study was to determine the risk of aseptic meningitis after mumps vaccination in younger children compared with older children. METHODS: This prospective cohort study included a total of 21,465 children under 18 years of age who had received the first dose of three of the Japanese mumps monovalent vaccine. We compared the cumulative incidence of aseptic meningitis for 30 days after vaccination among the following age groups: <= 1, 2, 3-4, and >= 5 years old. We also investigated the cumulative incidence of salivary gland swelling, a fever (>= 38 degrees C) lasting at least 3 days during the 10 to 25 days following immunization, vomiting of 3 times or more, headache, and seizure. RESULTS: A total of 10 aseptic meningitis, 551 salivary gland swelling, 844 fevers, 669 vomiting, 757 headaches, and 29 seizure cases were identified. The cumulative incidence of aseptic meningitis increased with age (0.016%, 0.021%, 0.066%, and 0.096%, respectively). Statistical significance was observed between children >= 3 years old and those < 3 years of age [0.078% vs. 0.018%, RR 4.35 (95% CI 1.05-18.2), p=0.04]. The cumulative incidence of salivary gland swelling also increased with age (1.8%, 3.0%, 3.5%, and 4.5%, respectively). For non-specific adverse events, the cumulative incidence of fever or seizure decreased with age. In contrast, the cumulative incidence of headache increased with age. The cumulative incidence of vomiting was similar among children <= 4 years of age; however, that in those children >= 5 years old was significantly lower. CONCLUSIONS: The first dose of mumps vaccine that is currently available for use in Japan may be administered in children less than 3 years of age in order to complicate a less aseptic meningitis after immunization. PMID- 26431988 TI - Symposium report of the 17th annual meeting of the Japanese Society for Vaccinology, 2013: Bacterial vaccines: Effectiveness and issues. PMID- 26431989 TI - Assessment of a novel recombinant vesicular stomatitis virus with triple mutations in its matrix protein as a vaccine for pigs. AB - Vesicular stomatitis virus (VSV) causes a serious vesicular disease responsible for economic losses in the livestock industry. Currently, there are no suitable vaccines to prevent VSV infection. Although the structural matrix (M) protein of VSV has been shown to be a virulence factor in rodent models, its role in the pathogenicity of VSV infection in livestock species is unknown. We hypothesized that VSV with mutations in the M protein represents a novel live attenuated vaccine candidate. To test this, we introduced mutations into VSV M protein using reverse genetics and assessed their attenuation both in vitro and in pigs, an important natural host of VSV. A recombinant VSV with a triple amino acid mutation in M protein (VSVMT) demonstrated a significantly reduced ability to inhibit the type I interferon (IFN) signaling pathway and to shutoff host gene expression compared to WT-VSV and a mutant virus with a single amino acid deletion (VSVDeltaM51). Inoculation of pigs with VSVMT induced no apparent vesicular lesions but stimulated virus-neutralizing antibodies and animals were protected against virulent VSV challenge infection. These data demonstrate that the M protein is an important virulence factor for VSV in swine and VSVMT represents a novel vaccine candidate for VSV infections in pigs. PMID- 26431990 TI - Cross-protective efficacy of engineering serotype A foot-and-mouth disease virus vaccine against the two pandemic strains in swine. AB - Foot-and-mouth disease (FMD) is a highly contagious vesicular disease that affects domestic and wild cloven-hoofed animals worldwide. Recently, a series of outbreaks of type A FMDV occurred in Southeast Asian countries, China, the Russia Federation, Mongolia, Kazakhstan and South Korea. The FMD virus (A/GDMM/CHA/2013) from China's Guangdong province (2013) is representative of those responsible for the latest epidemic, and has low amino acid identity (93.9%) in VP1 protein with the epidemic strain A/WH/CHA/09 from Wuhan, China in 2009. Both of isolates belong to the Sea-97 genotype of ASIA topotype. Therefore, the application of a new vaccine strain with cross-protective efficacy is of fundamental importance to control the spread of the two described pandemic strains. A chimeric strain rA/P1 FMDV constructed by our lab previously through replacing the P1 gene in the vaccine strain O/CHA/99 with that from the epidemic stain A/WH/CHA/09, has been demonstrated to exhibit good growth characteristics in culture, and the rA/P1 FMDV inactivated vaccine can provide protection against epidemic strain A/WH/CHA/09 in cattle. However, it is still unclear whether the vaccine produces efficient protection against the new pandemic strain (A/GDMM/CHA/2013). Here, vaccine matching and pig 50% protective dose (PD50) tests were performed to assess the vaccine potency. The vaccine matching test showed cross-reactivity of sera from full dose vaccine vaccinated pigs with A/WH/CHA/09 and A/GDMM/CHA/2013 isolates, with average r1 values of 0.94+/-0.12 and 0.68+/-0.06 (r1>=0.3), which indicates that the rA/P1-FMDV vaccine is likely to confer good cross-protection against the two isolates. When challenged with two pandemic isolates A/WH/CHA/09 and A/GDMM/CHA/2013 strain, the vaccine achieved 12.51 PD50 and 10.05 PD50 per dose (2.8MUg), respectively. The results indicated that the rA/P1-FMDV inactivated vaccine could protect pigs against both A/WH/CHA/09 and A/GDMM/CHA/2013 pandemic isolates. PMID- 26431992 TI - Functional hyperspectral imaging captures subtle details of cell metabolism in olfactory neurosphere cells, disease-specific models of neurodegenerative disorders. AB - Hyperspectral imaging uses spectral and spatial image information for target detection and classification. In this work hyperspectral autofluorescence imaging was applied to patient olfactory neurosphere-derived cells, a cell model of a human metabolic disease MELAS (mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like syndrome). By using an endogenous source of contrast subtle metabolic variations have been detected between living cells in their full morphological context which made it possible to distinguish healthy from diseased cells before and after therapy. Cellular maps of native fluorophores, flavins, bound and free NADH and retinoids unveiled subtle metabolic signatures and helped uncover significant cell subpopulations, in particular a subpopulation with compromised mitochondrial function. Taken together, our results demonstrate that multispectral spectral imaging provides a new non-invasive method to investigate neurodegenerative and other disease models, and it paves the way for novel cellular characterisation in health, disease and during treatment, with proper account of intrinsic cellular heterogeneity. PMID- 26431991 TI - MMR vaccination status of children exempted from school-entry immunization mandates. AB - BACKGROUND: Child immunizations are one of the most successful public health interventions of the past century. Still, parental vaccine hesitancy is widespread and increasing. One manifestation of this are rising rates of nonmedical or "personal beliefs" exemptions (PBEs) from school-entry immunization mandates. Exemptions have been shown to be associated with increased risk of disease outbreak, but the strength of this association depends critically on the true vaccination status of exempted children, which has not been assessed. OBJECTIVE: To estimate the true measles-mumps-rubella (MMR) vaccination status of children with PBEs. METHODS: We use administrative data collected by the California Department of Public Health in 2009 and imputation to estimate the MMR vaccination status of children with PBEs under varying scenarios. RESULTS: Results from 2009 surveillance data indicate MMR1/MMR2 coverage of 18-47% among children with PBEs at typical schools and 11-34% among children with PBEs at schools with high PBE rates. Imputation scenarios point to much higher coverage (64-92% for MMR1 and 25-58% for MMR2 at typical schools; 49-90% for MMR1 and 16 63% for MMR2 at high PBE schools) but still below levels needed to maintain herd immunity against measles. CONCLUSIONS: These coverage estimates suggest that prior analyses of the relative risk of measles associated with vaccine refusal underestimate that risk by an order of magnitude of 2-10 times. PMID- 26431993 TI - The impact of cognitive load on reward evaluation. AB - The neural systems that afford our ability to evaluate rewards and punishments are impacted by a variety of external factors. Here, we demonstrate that increased cognitive load reduces the functional efficacy of a reward processing system within the human medial-frontal cortex. In our paradigm, two groups of participants used performance feedback to estimate the exact duration of one second while electroencephalographic (EEG) data was recorded. Prior to performing the time estimation task, both groups were instructed to keep their eyes still and avoid blinking in line with well established EEG protocol. However, during performance of the time-estimation task, one of the two groups was provided with trial-to-trial-feedback about their performance on the time-estimation task and their eye movements to induce a higher level of cognitive load relative to participants in the other group who were solely provided with feedback about the accuracy of their temporal estimates. In line with previous work, we found that the higher level of cognitive load reduced the amplitude of the feedback-related negativity, a component of the human event-related brain potential associated with reward evaluation within the medial-frontal cortex. Importantly, our results provide further support that increased cognitive load reduces the functional efficacy of a neural system associated with reward processing. PMID- 26431994 TI - Microcirculatory alterations during continuous renal replacement therapy in ICU: A novel view on the 'dialysis trauma' concept. AB - OBJECTIVE: The purpose of this study was to evaluate microcirculation over 24 h renal replacement therapy (CRRT) in critically ill patients. METHODS: We conducted a single-center, prospective, observational study, measuring microcirculation parameters, monitored by near infrared spectroscopy (NIRS) before hemodiafiltration onset (H0), and at six (H6) and 24 h (H24) during CRRT in critically ill patients. Serum Cystatin C (sCysC) and soluble (s)E-selectin levels were measured at the same time points. Twenty-eight patients [19 men (68%)] were included in the study. RESULTS: Tissue oxygen saturation (StO2, %) [76.5 +/- 12.5 (H0) vs 75 +/- 11 (H6) vs 70 +/- 16 (H24), p = 0.04], reperfusion rate, indicating endothelial function (EF, %/sec) [2.25 +/- 1.44 (H0) vs 2.1 +/- 1.8 (H6) vs 1.6 +/- 1.4 (H24), p = 0.02] and sCysC (mg/L) [2.7 +/- 0.8 (H0) vs 2.2 +/- 0.6 (H6) vs 1.8 +/- 0.8 (H24), p < 0.0001] significantly decreased within the 24 h CRRT. Change of EF positively correlated with changes of sCysC within 24 h CRRT (r = 0.464, p = 0.013) while in patients with diabetes the change of StO2 correlated with dose (r = - 0.8, p = 0.01). No correlation existed between hemoglobin and temperature changes with the deteriorated microcirculation indices. sE-Selectin levels in serum were elevated; no difference was established over the 24 h CRRT period. A strong correlation existed between the sE-Selectin concentration change at H6 and H24 and the mean arterial pressure change in the same period (r = 0.77, p < 0.001). CONCLUSIONS: During the first 24 h of CRRT implementation in critically ill patients, deterioration of microcirculation parameters was noted. Microcirculatory alterations correlated with sCysC changes and with dose in patients with diabetes. PMID- 26431995 TI - Clear cell ependymoma with late leptomeningeal and supratentorial metastases. PMID- 26431996 TI - Multiple posttraumatic cervical pseudomeningoceles. PMID- 26431997 TI - Association between compensation status and outcomes in spine surgery: a meta analysis of 31 studies. AB - BACKGROUND CONTEXT: Numerous studies have demonstrated poorer outcomes in patients with Workers' compensation (WC) when compared with those without WC following treatment of various of health conditions, including spine disorders. It is thus important to consider compensation status when assessing treatment outcomes in spine surgery. However, reported strengths of association have varied significantly (1.31-7.22). PURPOSE: The objective of this study was to evaluate the association of unsatisfactory outcomes on compensation status in spine surgery patients. STUDY DESIGN/SETTING: A meta-analysis was performed. PATIENT SAMPLE: Patient sample is not applicable in this study. OUTCOME MEASURE: Demographics, type of surgery, country, follow-up time, patient satisfaction, return to work and non-union events were the outcome measures. METHODS: Both prospective and retrospective studies that compared outcomes between compensated and non-compensated patients in spine surgery were included. Two independent investigators extracted outcome data. The meta-analysis was performed using Revman software. Random effects model was used to calculate risk ratio (RR, 95% confidence interval [CI]) for dichotomous variables. RESULTS: Thirty-one studies (13 prospective; 18 retrospective) with a total of 3,567 patients were included in the analysis. Follow-up time varied from 4 months to 10 years. Twelve studies involved only decompression; the rest were fusion. Overall RR of an unsatisfactory outcome was 2.12 [1.74, 2.58; p<.001] in patients with WC when compared with those without WC after surgery. The RR of an unsatisfactory outcome in patients with WC, compared with those without, was 2.09 [1.38, 3.17]; p<.01 among studies from Europe and Australia, and 2.14 [1.48, 2.60]; p<.01 among US studies. The RR of decompression-only procedures was 2.53 [1.85, 3.47]; p<.01,and 1.79 [1.45, 2.21]; p<.01 for fusion. Forty-three percent (209 of 491) of patients with WC did not return to work versus 17% (214 of 1250) of those without WC (RR 2.07 [1.43, 2.98]; p<.001). Twenty-five percent (74 of 292) and 13.5% (39 of 287) of patients had non-union in the compensated and non-compensated groups, respectively. This was not statistically significant (RR 1.33 [0.92, 1.91]; p=.07). CONCLUSIONS: Workers' compensation patients have a two-fold increased risk of an unsatisfactory outcome compared with non-compensated patients after surgery. This association was consistent when studies were grouped by country or procedure. Compensation status must be considered in all surgical intervention studies. PMID- 26431998 TI - Identification, classification, and expression profiles of heat shock transcription factors in tea plant (Camellia sinensis) under temperature stress. AB - In vascular plants, heat shock transcription factors (Hsfs) regulate heat stress response by regulating the expression of heat shock proteins. This study systematically and comprehensively analyzed the Hsf family in tea plant [Camellia sinensis (L.) O. Kuntze]. A total of 16 CsHsfs were identified from the transcriptome database of tea plant and analyzed for their phylogenetic relationships, motifs, and physicochemical characteristics. On the basis of the phylogenetic comparison of tea plant with Arabidopsis thaliana, Populus trichocarpa, Theobroma cacao, and Oryza sativa, the CsHsfs were classified into three classes, namely, A (56.25%), B (37.50%), and C (6.25%). Heat mapping showed that the expression profiles of CsHsf genes under non-stress conditions varied among four tea plant cultivars, namely, 'Yunnanshilixiang', 'Chawansanhao', 'Ruchengmaoyecha', and 'Anjibaicha'. Six CsHsf genes (CsHsfA1a, CsHsfA1b, CsHsfA6, CsHsfB1, CsHsfB2b, and CsHsfC1) were selected from classes A, B, and C to analyze the expression profiles of CsHsf genes through quantitative real-time PCR in 'Yingshuang', 'Anjibaicha', and 'Yunnanshilixiang' under high (38 degrees C) or low (4 degrees C) temperature stress. Temperature stress positively or negatively regulated all of the selected CsHsf genes, and the expression levels evidently varied even among CsHsf genes belonging to the same class. This study provided a relatively detailed summary of Hsfs in tea plant and may serve as a reference for further studies on the mechanism of temperature stress regulation by CsHsfs. PMID- 26431999 TI - Detection of genetic diversity and selection at the coding region of the melanocortin receptor 1 (MC1R) gene in Tibetan pigs and Landrace pigs. AB - Domestication and subsequent selective pressures have produced a large variety of pig coat colors in different regions and breeds. The melanocortin 1 receptor (MC1R) gene plays a crucial role in determining coat color of mammals. Here, we investigated genetic diversity and selection at the coding region of the porcine melanocortin receptor 1 (MC1R) in Tibetan pigs and Landrace pigs. By contrast, genetic variability was much lower in Landrace pigs than in Tibetan pigs. Meanwhile, haplotype analysis showed that Tibetan pigs possessed shared haplotypes, suggesting a possibility of recent introgression event by way of crossbreeding with neighboring domestic pigs or shared ancestral polymorphism. Additionally, we detected positive selection at the MC1R in both Tibetan pigs and Landrace pigs through the dN/dS analysis. These findings suggested that novel phenotypic change (dark coat color) caused by novel mutations may help Tibetan pigs against intensive solar ultraviolet (UV) radiation and camouflage in wild environment, whereas white coat color in Landrace were intentionally selected by human after domestication. Furthermore, both the phylogenetic analysis and the network analysis provided clues that MC1R in Asian and European wild boars may have initially experienced different selective pressures, and MC1R alleles diversified in modern domesticated pigs. PMID- 26432000 TI - Prediction of sumoylation sites in proteins using linear discriminant analysis. AB - Sumoylation is a multifunctional post-translation modification (PTM) in proteins by the small ubiquitin-related modifiers (SUMOs), which have relations to ubiquitin in molecular structure. Sumoylation has been found to be involved in some cellular processes. It is very significant to identify the exact sumoylation sites in proteins for not only basic researches but also drug developments. Comparing with time exhausting experiment methods, it is highly desired to develop computational methods for prediction of sumoylation sites as a complement to experiment in the post-genomic age. In this work, three feature constructions (AAIndex, position-specific amino acid propensity and modification of composition of k-space amino acid pairs) and five different combinations of them were used to construct features. At last, 178 features were selected as the optimal features according to the Mathew's correlation coefficient values in 10-fold cross validation based on linear discriminant analysis. In 10-fold cross-validation on the benchmark dataset, the accuracy and Mathew's correlation coefficient were 86.92% and 0.6845. Comparing with those existing predictors, SUMO_LDA showed its better performance. PMID- 26432001 TI - Overexpression of SOS genes in ciprofloxacin resistant Escherichia coli mutants. AB - INTRODUCTION: Fluoroquinolones are important antibiotics for the treatment of urinary tract infections caused by Escherichia coli. Mutational studies have shown that ciprofloxacin, a member of fluoroquinolones induces SOS response and mutagenesis in pathogenic bacteria which in turn develop antibiotic resistance. However, inhibition of SOS response can increase recombination activity which in turn leads to genetic variation. OBJECTIVE: The aim of this study was to measure 5 SOS genes expressions in nine E. coli mutants with different MICs for ciprofloxacin following exposure to ciprofloxacin. METHODS: Gene expression was assessed by quantitative real time PCR. Gene alteration assessment was conducted by PCR amplification and DNA sequencing. RESULTS: Results showed that the expression of recA was increased in 5 mutants. This overexpression is not related to gene alteration, and enhances the expression of polB and umuCD genes encoding nonmutagenic and mutagenic polymerases, respectively. The direct relationship between the level of SOS expression and the level of resistance to ciprofloxacin was also indicated. CONCLUSION: It was concluded that novel therapeutic strategy that inhibits RecA activity would enhance the efficiency of common antibiotics against pathogenic bacteria. PMID- 26432002 TI - A comparison of virus genome sequences with their host silkworm, Bombyx mori. AB - With the recent availability of the genomes of many viruses and the silkworm, Bombyx mori, as well as a variety of Basic Local Alignment Search Tool (BLAST) programs, a new opportunity to gain insight into the interaction of viruses with the silkworm is possible. This study aims to determine the possible existence of sequence identities between the genomes of viruses and the silkworm and attempts to explain this phenomenon. BLAST searches of the genomes of viruses against the silkworm genome were performed using the resources of the National Center for Biotechnology Information. All studied viruses contained variable numbers of short regions with sequence identity to the genome of the silkworm. The short regions of sequence identity in the genome of the silkworm may be derived from the genomes of viruses in the long history of silkworm-virus interaction. This study is the first to compare these genomes, and may contribute to research on the interaction between viruses and the silkworm. PMID- 26432003 TI - Lysosomal localization of Japanese medaka (Oryzias latipes) Neu1 sialidase and its highly conserved enzymatic profiles with human. AB - Desialylation in the lysosome is a crucial step for glycoprotein degradation. The abnormality of lysosomal desialylation by NEU1 sialidase is involved in diseases of mammals such as sialidosis and galactosialidosis. Mammalian Neu1 sialidase is also localized at plasma membrane where it regulates several signaling pathways through glycoprotein desialylation. In fish, on the other hand, the mechanism of desialylation in the lysosome and functions of Neu1 sialidase are still unclear. Here, to understand the significance of fish Neu1 sialidase, neu1 gene was cloned from medaka brain and the profiles of its polypeptides were analyzed. Open reading frame of medaka neu1 consisted 1,182 bp and the similarity of its deduced amino acids with human NEU1 was 57%. As this recombinant polypeptide did not show significant sialidase activity, medaka cathepsin A, known in mammals as protective protein activating Neu1, was cloned and then co-expressed with medaka Neu1 to examine whether medaka cathepsin A activates Neu1 activity. As a result, Neu1/cathepsin A showed a drastic increase of sialidase activity toward MU-NANA. Major substrate of medaka Neu1 was 3-sialyllactose and its optimal pH was 4.0. With immunofluorescence analysis, signal of overexpressed medaka Neu1 was found to coincide with Lysotracker signals (organelle marker of lysosome) and co localized with medaka cathepsin A in fish hepatic Hepa-T1 cells. Furthermore, part of medaka Neu1 was also detected at plasma membrane. Medaka Neu1 possessed signal peptide sequence at N-terminal and incomplete lysosomal targeting sequence at C-terminus. Medaka neu1 gene was ubiquitously expressed in various medaka tissues, and its expression level was significantly higher than other sialidase genes such as neu3a, neu3b and neu4. The present study revealed the profiles of fish Neu1 sialidase and indicated its high conservation with human NEU1 for the first time, suggesting the presence of similar desialylation system in the medaka lysosome to human. Moreover, the present study showed the possibility of medaka as a model animal of human NEU1 sialidase. PMID- 26432004 TI - Genetic analysis of 15 mtDNA SNP loci in Chinese Yi ethnic group using SNaPshot minisequencing. AB - SNaPshot minisequencing is a rapid and robust methodology based on a single base extension with a labeled ddNTP. The present study detected 15 selected SNPs in the mitochondrial DNA (mtDNA) control and coding regions by minisequencing methodology using SNaPshot for forensic purpose. The samples were collected from 99 unrelated individuals of the Yi ethnic minority group in Yunnan Province. We have predominantly found high-frequency transitions (91.7%) and a significantly lower frequency of transversions (8.3%). The nt152, 489, 8701, 10,398, 16,183, and 16,362 loci were highly polymorphic, while the nt231, 473 and 581 loci were not polymorphic in the studied population. Based on these 15 SNPs, a total of 28 mtDNA haplotypes were defined in 99 individuals with the haplotype diversity of 0.9136. Also, we compared the mtDNA sequences of Yi group and other 9 populations worldwide and drew a Neighbor-Joining tree based on the shared 12 mtDNA SNP loci, which demonstrated a close relationship between Yi and Bai groups. In conclusion, the analysis of the 15 selected SNPs increases considerably the discrimination power of mtDNA. Moreover, the SNaPshot minisequencing method could quickly detect mtDNA SNPs, and is economical and sensitive. The set of selected 15 SNPs is highly informative and is capable for anthropology genetic analysis. PMID- 26432005 TI - HMGCR positively regulated the growth and migration of glioblastoma cells. AB - The metabolic program of cancer cells is significant different from the normal cells, which makes it possible to develop novel strategies targeting cancer cells. Mevalonate pathway and its rate-limiting enzyme HMG-CoA reductase (HMGCR) have shown important roles in the progression of several cancer types. However, their roles in glioblastoma cells remain unknown. In this study, up-regulation of HMGCR in the clinical glioblastoma samples was observed. Forced expression of HMGCR promoted the growth and migration of U251 and U373 cells, while knocking down the expression of HMGCR inhibited the growth, migration and metastasis of glioblastoma cells. Molecular mechanism studies revealed that HMGCR positively regulated the expression of TAZ, an important mediator of Hippo pathway, and the downstream target gene connective tissue growth factor (CTGF), suggesting HMGCR might activate Hippo pathway in glioblastoma cells. Taken together, our study demonstrated the oncogenic roles of HMGCR in glioblastoma cells and HMGCR might be a promising therapeutic target. PMID- 26432006 TI - Molecular modeling, mutational analysis and conformational switching in IL27: An in silico structural insight towards AIDS research. AB - The advancement in proteomics and bioinformatics provokes to discern the molecular-level probe for HIV inhibitor; human interleukin-27 (IL27). Documentation documents that tyrosine residues in IL27 play a pivotal role for interacting with HIV, causing apoptosis of the HIV+ cells. Primarily, 3D structure of human wild-type (WT) IL27 was built through manifold molecular modeling techniques after the satisfaction of stereo-chemical properties. Its essential tyrosine residues were identified. Two mutant models for IL27 were prepared following the similar protocol by first substituting the tyrosine residues with glycine (MT_G) and then with alanine (MT_A) in the WT protein. Molecular dynamics (MD) simulation was performed to obtain a stable conformation. Conformational alterations in WT, MT_G and MT_A (before and after MD simulation) disclosed that MT_A was the steadiest one with the best secondary structure conformation supported by statistical significances. Though huge RMSD variations were observed on superimposing the MT structures on WT individually, the MTs were examined to share similar SCOP/CATH fold with TM-score=0.8, indicating that they retained their functionality even after mutation. Electrostatic surface potential again unveiled MT_A to be the most stable one. MT_A was thereby revealed to be the potent peptide inhibitor for HIV. This probe presents a pathway to investigate and compare the bio-molecular interaction of WT IL27 and MT_A IL27 (strongest model) with HIV in the future. This is the first report regarding the structural biology of IL27 accompanied by alteration at its genetic level and delving into the unknown residue-level and functional biochemistry for bringing about an annihilation towards AIDS. PMID- 26432007 TI - Ultrasound as a tool for fluid status assessment in the trauma and critically ill patient. AB - Resuscitation to euvolemia in trauma as well as in the critically ill patient, continues to be a challenge. Focused cardiac ultrasound has been shown to be a reliable tool to evaluate fluid status and to guide therapy. The present manuscript reviews the evidence supporting the use of this tool and describes the clinical applications for image-based resuscitation using echocardiogram. PMID- 26432008 TI - An open-label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam. AB - We evaluated nonpsychotic behavioral adverse events (BAEs) in patients receiving levetiracetam (LEV) who switched to brivaracetam (BRV). Patients >=16 years of age, receiving 2-3 antiepileptic drugs (AEDs), including LEV 1-3g/day, and experiencing BAEs within 16 weeks of LEV treatment initiation, enrolled in an open-label Phase 3b study (NCT01653262) comprising a <=1-week screening period, an immediate switch from LEV to BRV 200mg/day (without titration), and a 12-week treatment period. The percentages of patients with investigator-assessed clinically meaningful reduction in BAEs, shift in maximum BAE intensity, and change in health-related quality of life (HRQoL) (Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31 [QOLIE-31-P]) were assessed. Of 29 patients enrolled, 26 (89.7%) completed the study. At the end of the treatment period, 27/29 (93.1%) patients switched to BRV had clinically meaningful reductions in BAEs. Physicians reported a reduction in the maximum intensity of primary BAEs in 27/29 (93.1%) patients. Mean change from baseline to Week 12 in QOLIE-31-P total score was 12.1, indicating improved HRQoL. During the treatment period, 23/29 (79.3%) patients reported treatment-emergent adverse events (TEAEs). One patient reported a serious TEAE (suicidal ideation and suicide attempt). Two patients discontinued BRV because of TEAEs. Findings from this small study suggest that patients experiencing BAEs associated with LEV may benefit from switching to BRV. PMID- 26432009 TI - Childhood trauma and psychogenic nonepileptic seizures: A review of findings with speculations on the underlying mechanisms. AB - OBJECTIVE: The objective of this review was to examine the possible link between psychological trauma in a patient's medical history and the onset of psychogenic nonepileptic seizures (PNES). METHODOLOGY: An electronic search of published reports was made using the search engines PubMed-MedLine, EBSCO, PsycINFO, SFX, and Embase and the keywords "PNES", "psychogenic seizures", "sexual abuse", and "trauma". RESULTS: A correlation emerged between history of childhood trauma and the presence of PNES. Antecedent trauma was more frequent in females than in males and in patients exhibiting psychiatric disorders but was inversely correlated with cognitive impairment. CONCLUSIONS: In the presence of PNES, it is important to accurately investigate the patient's medical history in search of psychological trauma, particularly in women and in patients with psychiatric disorders. PMID- 26432010 TI - Safety assessment of Guibi-tang: Subchronic toxicity study in Crl:CD SD rats. AB - Guibi-tang (Kihi-To in Japanese and Qui-Pi-Tang in Chinese) is a multiherbal traditional Korean medicinal formula used for treatment of amnesia, fatigue, poor memory or forgetfulness, anemia, insomnia, and necrosis. The aim of the present study was to investigate potential safety, if any, of subchronic administration of Guibi-tang aqueous extract (GBT) in laboratory animals. For this study, 0, 1000, 2000, and 5000 mg/kg/day of GBT was administered to Crl:CD Sprague Dawley rats (10/sex/group) for 13 weeks via oral gavage. Administration of the GBT did not result in any mortality, body weight, food consumption, hematology, serum biochemistry, clinical or ophthalmological signs or changes in urinalysis, gross findings, or organ weight. However, histopathology revealed forestomach hyperplasia and duodenum mucosal hyperplasia in rats of both sexes at the highest dose of GBT, 5000 mg/kg/day. Therefore, the no-observed-adverse-effect level in rats was established for GBT at 2000 mg/kg/day under the conditions of this study. PMID- 26432012 TI - Missouri K-12 school disaster and biological event preparedness and seasonal influenza vaccination among school nurses. AB - BACKGROUND: School preparedness for bioevents, such as emerging infectious diseases, bioterrorism, and pandemics, is imperative, but historically has been low. METHODS: The Missouri Association of School Nurses members were sent an online survey during the 2013-2014 school year to assess current bioevent readiness. There were 15 and 35 indicators of school disaster and bioevent preparedness, respectively. Multivariate linear regressions were conducted to delineate factors associated with higher school disaster and bioevent preparedness scores. RESULTS: In total, 133 school nurses participated, with a 33.6% response rate. On average, schools had fewer than half of the disaster or bioevent indicators. Disaster and bioevent preparedness scores ranged from 1-12.5 (mean, 6.0) and 5-25 (mean, 13.8), respectively. The least frequently reported plan components included bioterrorism-specific psychological needs addressed (1.5%, n = 2), having a foodservice biosecurity plan (8.3%, n = 11), and having a liberal sick leave policy for bioevents (22.6%, n = 30). Determinants of better bioevent preparedness include perception that the school is well prepared for a pandemic (P = .001) or natural disaster (P < .05), nurse being on the disaster planning committee (P = .001), and school being a closed point of dispensing (P < .05). CONCLUSION: Schools are underprepared for biological events and are not on track to meet state and national biological preparedness goals. PMID- 26432013 TI - Vector representation and its application of DNA sequences based on nucleotide triplet codons. AB - Compared with single nucleotide, nucleotide triplet appears to contain more biological and genetic information, so it has been applied widely. We propose a new 3D-vector representation method of DNA sequences, namely use molecular weight of nucleotide triplet to define the '0' molecular plane, then make the 3-D coordinate transformation to map a DNA sequence into a curve by the coordinate accumulation, and then extract the D/D matrix's eigenvalues to describe, compare and analyze the DNA sequences as the numerical characterization. It is a new idea for comparison and phylogenetic trees' reconstruction of biological sequences. PMID- 26432014 TI - Comparative investigation of thermal and mechanical properties of cross-linked epoxy polymers with different curing agents by molecular dynamics simulation. AB - Molecular dynamics (MD) simulations were carried out to predict the thermal and mechanical properties of the cross-linked epoxy system composed of DGEBA resin and the curing agent TETA. To investigate the effects of curing agents, a comprehensive and comparative study was also performed on the thermal and mechanical properties of DGEBA/TETA and DGEBA/DETDA epoxy systems such as density, glass transition temperature (Tg), coefficient of thermal expansion (CTE) and elastic properties of different cross-linking densities and different temperatures. The results indicated that the glass transition temperature of DGEBA/TETA system calculated through density-temperature data, ~ 385-395 degrees K, for the epoxy system with the cross-linking density of 62.5% has a better agreement with the experimental value (Tg, ~ 400 degrees K) in comparison to the value calculated through the variation of cell volume in terms of temperature, 430-440 degrees K. They also indicated that CTE related parameters and elastic properties including Young, Bulk, and shear's moduli, and Poisson's ratio have a relative agreement with the experimental results. Comparison between the thermal and mechanical properties of epoxy systems of DGEBA/TETA and DGEBA/DETDA showed that the DGEBA/DETDA has a higher Tg in all cross linking densities than that of DGEBA/TETA, while higher mechanical properties was observed in the case of DGEBA/TETA in almost all cross linking densities. PMID- 26432016 TI - Modulation of Glucokinase Regulatory Protein: A Double-Edged Sword? AB - 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. PMID- 26432017 TI - Intercellular Transfer of Cancer Drug Resistance Traits by Extracellular Vesicles. AB - Extracellular vesicles (EVs) are nanosized particles (100-1000 nm) enclosed by a phospholipid bilayer that have been described as important mediators of intercellular communication. The role of EVs in oncobiology has been extensively studied, including their contribution to the horizontal transfer of drug resistance from drug-resistant to drug-sensitive cancer cells. This review focuses on the EVs cargo responsible for this intercellular transfer of drug resistance; namely, drug-efflux pumps, miRNAs, long noncoding RNAs (lncRNAs), and other mediators. Additionally, the known molecular mechanisms and features of this transfer are discussed. This is an emerging area of research and we highlight topics that need to be further studied to fully understand and counteract the intercellular transfer of drug resistance mediated by EVs. PMID- 26432018 TI - Modeling Disease In Vivo With CRISPR/Cas9. AB - The recent advent of CRISPR/Cas9-mediated genome editing has created a wave of excitement across the scientific research community, carrying the promise of simple and effective genomic manipulation of nearly any cell type. CRISPR has quickly become the preferred tool for genetic manipulation, and shows incredible promise as a platform for studying gene function in vivo. I discuss the current application of CRISPR technology to create new in vivo disease models, with a particular focus on how these tools, derived from an adaptive bacterial immune system, are helping us to better model the complexity of human cancer. PMID- 26432020 TI - Exhaled Molecular Fingerprinting in Diagnosis and Monitoring: Validating Volatile Promises. AB - Medical diagnosis and phenotyping increasingly incorporate information from complex biological samples. This has promoted the development and clinical application of non-invasive metabolomics in exhaled air (breathomics). In respiratory medicine, expired volatile organic compounds (VOCs) are associated with inflammatory, oxidative, microbial, and neoplastic processes. After recent proof of concept studies demonstrating moderate to good diagnostic accuracies, the latest efforts in breathomics are focused on optimization of sensor technologies and analytical algorithms, as well as on independent validation of clinical classification and prediction. Current research strategies are revealing the underlying pathophysiological pathways as well as clinically-acceptable levels of diagnostic accuracy. Implementing recent guidelines on validating molecular signatures in medicine will enhance the clinical potential of breathomics and the development of point-of-care technologies. PMID- 26432019 TI - UBA1: At the Crossroads of Ubiquitin Homeostasis and Neurodegeneration. AB - Neurodegenerative diseases are a leading cause of disability and early death. A common feature of these conditions is disruption of protein homeostasis. Ubiquitin-like modifier activating enzyme 1 (UBA1), the E1 ubiquitin-activating enzyme, sits at the apex of the ubiquitin cascade and represents an important regulator of cellular protein homeostasis. Critical contributions of UBA1 dependent pathways to the regulation of homeostasis and degeneration in the nervous system are emerging, including specific disruption of UBA1 in spinal muscular atrophy (SMA) and Huntington's disease (HD). In this review we discuss recent findings that put UBA1 at the centre of cellular homeostasis and neurodegeneration, highlighting the potential for UBA1 to act as a promising therapeutic target for a range of neurodegenerative diseases. PMID- 26432021 TI - Emerging Liver-Kidney Interactions in Nonalcoholic Fatty Liver Disease. AB - Mounting evidence connects non-alcoholic fatty liver disease (NAFLD) to chronic kidney disease (CKD). We review emerging mechanistic links between NAFLD and CKD, including altered activation of angiotensin converting enzyme (ACE)-2, nutrient/energy sensors sirtuin-1 and AMP-activated kinase, as well as impaired antioxidant defense mediated by nuclear factor erythroid 2-related factor-2 (Nrf2). Dietary fructose excess may also contribute to NAFLD and CKD. NAFLD affects renal injury through lipoprotein dysmetabolism and altered secretion of the hepatokines fibroblast growth factor-21, fetuin-A, insulin-like growth factor 1, and syndecan-1. CKD may mutually aggravate NAFLD and associated metabolic disturbances through altered intestinal barrier function and microbiota composition, the accumulation of uremic toxic metabolites, and alterations in pre receptor glucocorticoid metabolism. We conclude by discussing the implications of these findings for the treatment of NAFLD and CKD. PMID- 26432022 TI - G3BP1 restricts HIV-1 replication in macrophages and T-cells by sequestering viral RNA. AB - HIV-1 exploits the cellular machinery for replication and therefore several interactions with cellular factors take place, some of which are yet unknown. We identified GTPase-activating protein-(SH3 domain)-binding protein 1 (G3BP1) as a cellular factor that restricts HIV-1, by analyzing transcriptome profiles of in vitro-cytokine-activated macrophages that are non-permissive to HIV-1 replication. Silencing of G3BP1 by RNA interference resulted in increased HIV-1 replication in primary T-cells and macrophages, but did not affect replication of other retroviruses. G3BP1 specifically interacted with HIV-1 RNA in the cytoplasm, suggesting that it sequesters viral transcripts, thus preventing translation or packaging. G3BP1 was highly expressed in resting naive or memory T cells from healthy donors and HIV-1 infected patients, but significantly lower in IL-2-activated T-cells. These results strongly suggest that G3BP1 captures HIV-1 RNA transcripts and thereby restricts mRNA translation, viral protein production and virus particle formation. PMID- 26432023 TI - Isolation and characterization of a virus infecting the freshwater algae Chrysochromulina parva. AB - Water samples from Lake Ontario, Canada were tested for lytic activity against the freshwater haptophyte algae Chrysochromulina parva. A filterable lytic agent was isolated and identified as a virus via transmission electron microscopy and molecular methods. The virus, CpV-BQ1, is icosahedral, ca. 145nm in diameter, assembled within the cytoplasm, and has a genome size of ca. 485kb. Sequences obtained through PCR-amplification of DNA polymerase (polB) genes clustered among sequences from the family Phycodnaviridae, whereas major capsid protein (MCP) sequences clustered among sequences from either the Phycodnaviridae or Mimiviridae. Based on quantitative molecular assays, C. parva's abundance in Lake Ontario was relatively stable, yet CpV-BQ1's abundance was variable suggesting complex virus-host dynamics. This study demonstrates that CpV-BQ1 is a member of the proposed order Megavirales with characteristics of both phycodnaviruses and mimiviruses indicating that, in addition to its complex ecological dynamics, it also has a complex evolutionary history. PMID- 26432024 TI - Cryo-electron microscopy and single molecule fluorescent microscopy detect CD4 receptor induced HIV size expansion prior to cell entry. AB - Viruses are often thought to have static structure, and they only remodel after the viruses have entered target cells. Here, we detected a size expansion of virus particles prior to viral entry using cryo-electron microscopy (cryo-EM) and single molecule fluorescence imaging. HIV expanded both under cell-free conditions with soluble receptor CD4 (sCD4) targeting the CD4 binding site on the HIV-1 envelope protein (Env) and when HIV binds to receptor on cellular membrane. We have shown that the HIV Env is needed to facilitate receptor induced virus size expansions, showing that the 'lynchpin' for size expansion is highly specific. We demonstrate that the size expansion required maturation of HIV and an internal capsid core with wild type stability, suggesting that different HIV compartments are linked and are involved in remodelling. Our work reveals a previously unknown event in HIV entry, and we propose that this pre-entry priming process enables HIV particles to facilitate the subsequent steps in infection. PMID- 26432025 TI - Visual evoked potential latencies of three-year-old children prenatally exposed to buprenorphine or methadone compared with non-opioid exposed children: The results of a longitudinal study. AB - This study compared the latency of pattern reversal visual evoked potentials (VEP) of 36-month old children exposed to opioid pharmacotherapy in utero to that of a group of non-exposed children. Pregnant women were enrolled as part of an open-label non-randomised flexible dosing longitudinal study. Participants were 21 children whose mothers were treated with buprenorphine- (n=11) or methadone pharmacotherapy (n=10) during pregnancy, and 15 children not exposed to opioids in pregnancy. One-way between groups analyses of variance (ANOVA) were conducted to test the statistical significance of differences between the mean latencies of the peak response to two different sized checkerboard patterns (48' and 69' of retinal arc). Standard multiple regression analyses were conducted to determine whether there was a significant relationship between group status and VEP latencies after adjusting for the effect of covariates. VEP latencies ranged from 98 to 112 milliseconds (ms) for checks of 48' arc, and from 95 to 113ms for checks of 69' arc. Latencies were comparable across groups. After adjusting for covariates children prenatally exposed to methadone or buprenorphine did not differ significantly from non-opioid exposed children in their responses to either check size. Nor were there any significant differences in VEP latencies between children prenatally exposed to methadone and children prenatally exposed to buprenorphine. Head circumference (HC) was significantly associated with P100 latencies for both check sizes. Data from this controlled, non-randomised study suggest that neither buprenorphine nor methadone appear to have any long-term effects on visual maturity assessed at 36months of age. PMID- 26432026 TI - Combined exposure to nano-silica and lead induced potentiation of oxidative stress and DNA damage in human lung epithelial cells. AB - Growing evidence has confirmed that exposure to ambient particulate matters (PM) is associated with increased morbidity and mortality of cardiovascular and pulmonary diseases. Ambient PM is a complex mixture of particles and air pollutants. Harmful effects of PM are specifically associated with ultrafine particles (UFPs) that can adsorb high concentrations of toxic air pollutants and are easily inhaled into the lungs. However, combined effects of UFPs and air pollutants on human health remain unclear. In the present study, we elucidated the combined toxicity of silica nanoparticles (nano-SiO2), a typical UFP, and lead acetate (Pb), a typical air pollutant. Lung adenocarcinoma A549 cells were exposed to nano-SiO2 and Pb alone or their combination, and their combined toxicity was investigated by focusing on cellular oxidative stress and DNA damage. Factorial analyses were performed to determine the potential interactions between nano-SiO2 and Pb. Our results showed that exposure of A549 cells to a modest cytotoxic concentration of Pb alone induced oxidative stress, as evidenced by elevated reactive oxygen species generation and lipid peroxidation, and reduced glutathione content and superoxide dismutase and glutathione peroxidase activities. In addition, exposure of A549 cells to Pb alone induced DNA damage, as evaluated by alkaline comet assay. Exposure of A549 cells to non-cytotoxic concentration of nano-SiO2 did not induce cellular oxidative stress and DNA damage. However, exposure to the combination of nano-SiO2 and Pb potentiated oxidative stress and DNA damage in A549 cells. Factorial analyses indicated that the potentiation of combined toxicity of nano-SiO2 and Pb was induced by additive or synergistic interactions. PMID- 26432027 TI - Abatement of toxicity of effluents containing Cr(VI) by heterogeneous photocatalysis. Toxicity assessment by AMPHITOX assay. AB - Toxicity of a Cr(VI) solution before and after treatment by TiO2 heterogeneous photocatalysis (HP) was performed with AMPHITOX bioassay. Changes in toxicity on Rhinella arenarum larvae for 10-d were monitored after exposure to an untreated Cr(VI) solution and to the same solution after HP treatment. The HP treatment of a 41.60 mg L(-1) Cr(VI) solution reduced to 37.5% the concentration of the metal ion. A 10-fold reduction in toxicity at acute exposure (72 h) and 150-fold reduction in toxicity after 240 h was found. Further, the LOEC value increased from 0.001% for the untreated solution to 0.153% after HP treatment. Moreover, the safe concentration in untreated solution corresponded to 0.0001% sample, and it was 0.01% after the treatment, i.e., 100 times higher. A saving of water of about 100,000 L per L of effluent would be possible through dilution to allow safer concentrations for discharge; the saving would reach the highest value (1,000,000 L per L) at 240 h. Sub-lethal effects were completely absent in larvae exposed to the treated solution. The AMPHITOX test allowed to detect chronic effects at low Cr concentrations, i.e. at environmentally relevant levels. PMID- 26432028 TI - Host-parasite relationships as determinants of heavy metal concentrations in perch (Perca fluviatilis) and its intestinal parasite infection. AB - The concentrations of As, Cd, Cr, Cu, Hg, Mn, Ni, Pb, and Zn and their bioconcentration factors (BCFs) were determined in two intestinal parasites, an acanthocephalan, Acanthocephalus lucii, a tapeworm, Proteocephalus percae, present in the same host, the European perch (Perca fluviatilis, L.), in the heavily polluted Ruzin reservoir in eastern Slovakia. The bioaccumulation of heavy metals in the fish organs and parasites was studied for acanthocephalan and tapeworm monoinfections or mixed infections by the two parasites and for the size of their parasitic infrapopulations. Bioconcentration factors (c[parasite]/c[muscle tissue]) showed that the concentrations of As, Ni, Pb and Zn were higher in mixed infections than in monoinfections. Negative correlations between heavy metal concentrations in perch organs and the parasites were found. For example, higher concentrations of Ni and Zn in both parasite species corresponded with lower metal concentrations in perch and hard roe. Likewise, significant negative relationships between metal concentrations in fish organs and number of parasites were noticed with lower levels of Pb in fish harbouring higher numbers of tapeworms. Similarly, in both parasite species the concentrations of some essential elements (Cr, Mn) were lower at high infection intensities compared to low intensities. Our study revealed that the differential concentration of heavy metals in perch organs was affected by the type of infection (mono- or mixed-infection), and needs to be considered in field ecotoxicological and parasitological studies as a potentially important factor influencing the pollutant concentrations in fish. PMID- 26432029 TI - Accumulation properties of inorganic mercury and organic mercury in the red crowned crane Grus japonensis in east Hokkaido, Japan. AB - The red-crowned (Japanese) crane Grus japonensis is native to east Hokkaido, Japan, in contrast to the East Asia mainland. Previously, we reported that red crowned cranes in Hokkaido were highly contaminated with mercury in the 1990s and that the contamination rapidly decreased to a moderate level in the 2000s. In the present study, we determined levels of organic mercury (O-Hg) in the liver and kidney of cranes in east Hokkaido in comparison with levels of total mercury (T Hg). T-Hg levels in the kidneys were higher than those in the livers in adults but not in subadults and juveniles; however, the reverse was the case for O-Hg even for adults. The ratio of O-Hg to T-Hg in both the liver and kidney decreased as T-Hg increased in the three developmental stages. While the ratios of O-Hg to T-Hg in the liver and kidney of adults were significantly lower than those of juveniles, the ratios were similar for adults and juveniles in a lower range of T Hg. The ratio of selenium (Se) to T-Hg decreased as T-Hg increased in both the liver and kidney, irrespective of stages. Mercury burdens in feathers were about 59% and 67% of the total body burdens for juveniles and adults, respectively. Furthermore, ratios of carbon and nitrogen stable isotopes to T-Hg varied greatly, with no relation to mercury level in the liver. The results suggest slow accumulation of inorganic mercury in the kidney of red-crowned cranes in east Hokkaido, Japan. PMID- 26432030 TI - Generation of a de novo transcriptome from equine lamellar tissue. AB - BACKGROUND: Laminitis, the structural failure of interdigitated tissue that suspends the distal skeleton within the hoof capsule, is a devastating disease that is the second leading cause of both lameness and euthanasia in the horse. Current transcriptomic research focuses on the expression of known genes. However, as this tissue is quite unique and equine gene annotation is largely derived from computational predictions, there are likely yet uncharacterized transcripts that may be involved in the etiology of laminitis. In order to create a novel annotation resource, we performed whole transcriptome sequencing of sagittal lamellar sections from one control and two laminitis affected horses. RESULTS: Whole transcriptome sequencing of the three samples resulted in 113 million reads. Overall, 88 % of the reads mapped to the equCab2 reference genome, allowing for the identification of 119,430 SNPs. The de novo assembly generated around 75,000 transcripts, of which 36,000 corresponded to known annotations. Annotated transcript models are hosted in a public data repository and thus can be easily accessed or loaded into genome browsers. RT-PCR of 12 selected assemblies confirmed structure and expression in lamellar tissue. CONCLUSIONS: Transcriptome sequencing represents a powerful tool to expand on equine annotation and identify novel targets for further laminitis research. PMID- 26432031 TI - Is interpersonal counselling (IPC) sufficient treatment for depression in primary care patients? A pilot study comparing IPC and interpersonal psychotherapy (IPT). AB - BACKGROUND: Psychotherapeutic treatment is underused in primary care, where even short-term psychotherapy can be perceived as too lengthy and labour-intensive. We tested here for the first time the preliminary efficacy of seven sessions of interpersonal counselling (IPC) by comparison with sixteen sessions of interpersonal psychotherapy (IPT) in regular clinical settings. METHODS: Patients seeking treatment for the first time who met the DSM-IV criteria for major depressive disorder (MDD, mild/moderate) were randomized to either IPC (n=20) or IPT (n=20). The efficacy of the treatments was assessed using the 34-item Clinical Outcomes in Routine Evaluation (CORE-OM) scale and the Beck Depression Inventory (BDI) scale. RESULTS: 90% of the patients completed all the treatment sessions. IPC delivered by psychiatric nurses in primary care proved equally as effective as IPT delivered by psychotherapists/psychologists in secondary care. The pre-treatment to 12-month follow-up within-group effect sizes were large: 1.52 (CORE-OM) and 1.41 (BDI) in the IPC group and 1.58 (CORE-OM) and 1.40 (BDI) in the IPT group. At the 12-month follow-up 59% of the patients in the IPC group and 63% in the IPT group were classified as recovered on the CORE-OM scale, with corresponding remission rates of 61% for both groups on the BDI scale. LIMITATIONS: The small sample size limited the power to detect differences between the groups and the naturalistic settings may have confounded the results. CONCLUSIONS: This clinical trial suggests that IPC is an appropriate and even sufficient first-phase intervention for handling previously untreated mild to moderate depression in primary health care. PMID- 26432032 TI - Interaction between BDNF rs6265 Met allele and low family cohesion is associated with smaller left hippocampal volume in pediatric bipolar disorder. AB - BACKGROUND: Genetic and environmental factors are implicated in the onset and evolution of pediatric bipolar disorder, and may be associated to structural brain abnormalities. The aim of our study was to assess the impact of the interaction between the Brain-Derived Neurotrophic Factor (BDNF) rs6265 polymorphism and family functioning on hippocampal volumes of children and adolescents with bipolar disorder, and typically-developing controls. METHODS: We evaluated the family functioning cohesion subscale using the Family Environment Scale-Revised, genotyped the BDNF rs6265 polymorphism, and performed structural brain imaging in 29 children and adolescents with bipolar disorder, and 22 healthy controls. RESULTS: We did not find significant differences between patients with BD or controls in left or right hippocampus volume (p=0.44, and p=0.71, respectively). However, we detected a significant interaction between low scores on the cohesion subscale and the presence of the Met allele at BNDF on left hippocampal volume of patients with bipolar disorder (F=3.4, p=0.043). None of the factors independently (BDNF Val66Met, cohesion scores) was significantly associated with hippocampal volume differences. LIMITATIONS: small sample size, cross-sectional study. CONCLUSIONS: These results may lead to a better understanding of the impact of the interaction between genes and environment factors on brain structures associated to bipolar disorder and its manifestations. PMID- 26432033 TI - Association of asthma and anxiety: A nationwide population-based study in Taiwan. AB - BACKGROUND: Few studies have investigated the bidirectional relationship between asthma and anxiety; we sought to investigate asthma and anxiety in a large national sample. METHODS: Cases were identified from Taiwan's National Health Insurance Research Database with a new primary diagnosis of asthma (ICD-9:493) aged more than 15 years between 2000 and 2007. Case status required the presence of any inpatient diagnosis of asthma and/or at least one year diagnosis of asthma in outpatient service. These 22,797 cases were compared to 22,797 sex-, age-, residence- and insurance premium-matched controls and both groups were followed until the end of 2008 for instances of anxiety, defined as ICD-9 codes 300.0, 300.01, 300.02, 300.2, 300.21, 300.23, 300.3. Competing risk adjusted Cox regression analyses were applied, adjusting for sex, age, residence, insurance premium, prednisone use, Charlson comorbidity index, cardiovascular disease, diabetes, depression disorder, and hospital admission days for any disorder. The effect of asthma on the risk of panic disorder and the effect of anxiety disorder on the risk of later asthma were also examined as competing risk adjusted Cox regression analyses RESULTS: Of the 45,594 subjects, 2792 were ascertained as having anxiety during a mean (SD) follow-up period of 5.3 (2.5) years. Asthma, females, older age, rural residence, depression disorder, and prednisone use were independent risks on anxiety in the fully adjusted model. Anxiety, older age, rural residence, and prednisone use were independent risks on asthma in the fully adjusted model. LIMITATIONS: The severity of asthma and anxiety disorder, the duration of prednisone treatment and adherence, stressful life events, smoking, family history and relationship were not evaluated. CONCLUSIONS: Bidirectional relationship between asthma and anxiety disorder was confirmed in this population, in dependent of a number of potential confounding factors. PMID- 26432034 TI - Prior suicide attempts are less common in suicide decedents who died by firearms relative to those who died by other means. AB - BACKGROUND: Suicide prevention efforts often center on the identification of risk factors (e.g., prior suicide attempts); however, lists of risk factors without consideration of context may prove incapable of impacting suicide rates. One contextual variable worth considering is attempt method. METHODS: Utilizing data from the National Violent Death Reporting System (2005-2012), I examined suicide deaths (n=71,775) by firearms and other means to determine whether prior suicide attempts were more common in one group versus the other. RESULTS: Significantly fewer suicide decedents who died by firearms reported a prior history of suicide attempts (12.10%) than did decedents who died by other means (28.66%). This result was further replicated within each state that contributed data to the NVDRS. LIMITATIONS: Only 17 states have contributed to the NVDRS thus far and, within those states, not all suicide deaths were reported. Due to the nature of the data, I was unable to test proposed mediators within our model. CONCLUSIONS: Suicide decedents who die by firearms may die on their first attempt more often than other decedents due to a capability and willingness to utilize a highly lethal means. Current risk assessment protocols may be ill equipped to identify such individuals prospectively on their own. Broader methods of implementing means restriction (e.g., legislation) may thus be pivotal in suicide prevention efforts. PMID- 26432035 TI - Effects of alkyl side chains and terminal hydrophilicity on vitamin D receptor (VDR) agonistic activity based on the diphenylpentane skeleton. AB - Vitamin D receptor (VDR) is a family of nuclear receptors (NR) that regulates physiological effects such as the immune system, calcium homeostasis, and cell proliferation. We synthesized non-secosteroidal VDR ligands bearing a long alkyl chain based on the diphenylpentane skeleton. The VDR-mediated transcriptional activities of the synthesized compounds were evaluated using a reporter gene assay and HL-60 cell differentiation-inducing assay. We herein described the structure-activity relationship and effects of alkyl-chain length on VDR-mediated transcriptional activity. PMID- 26432036 TI - Synthesis, biological evaluation and structure-activity relationship studies of isoflavene based Mannich bases with potent anti-cancer activity. AB - Phenoxodiol, an analogue of the isoflavone natural product daidzein, is a potent anti-cancer agent that has been investigated for the treatment of hormone dependent cancers. This molecular scaffold was reacted with different primary amines and secondary amines under different Mannich conditions to yield either benzoxazine or aminomethyl substituted analogues. These processes enabled the generation of a diverse range of analogues that were required for structure activity relationship (SAR) studies. The resulting Mannich bases exhibited prominent anti-proliferative effects against SHEP neuroblastoma and MDA-MB-231 breast adenocarcinoma cell lines. Further cytotoxicity studies against MRC-5 normal lung fibroblast cells showed that the isoflavene analogues were selective towards cancer cells. PMID- 26432037 TI - Monoamine oxidase inhibitory activities of heterocyclic chalcones. AB - Studies have shown that natural and synthetic chalcones (1,3-diphenyl-2-propen-1 ones) possess monoamine oxidase (MAO) inhibition activities. Of particular importance to the present study is a report that a series of furanochalcones acts as MAO-B selective inhibitors. Since the effect of heterocyclic substitution, other than furan (and more recently thiophene, piperidine and quinoline) on the MAO inhibitory properties of the chalcone scaffold remains unexplored, the aim of this study was to synthesise and evaluate further heterocyclic chalcone analogues as inhibitors of the human MAOs. For this purpose, heterocyclic chalcone analogues that incorporate pyrrole, 5-methylthiophene, 5-chlorothiophene and 6 methoxypyridine substitution were examined. Seven of the nine synthesised compounds exhibited IC50 values <1 MUM for the inhibition of MAO-B, with all compounds exhibiting higher affinities for MAO-B compared to the MAO-A isoform. The most potent MAO-B inhibitor (4h) displays an IC50 value of 0.067 MUM while the most potent MAO-A inhibitor (4e) exhibits an IC50 value of 3.81 MUM. It was further established that selected heterocyclic chalcones are reversible and competitive MAO inhibitors. 4h, however, may exhibit tight-binding to MAO-B, a property linked to its thiophene moiety. We conclude that high potency chalcones such as 4h represent suitable leads for the development of MAO-B inhibitors for the treatment of Parkinson's disease and possibly other neurodegenerative disorders. PMID- 26432038 TI - A preoperative personalized risk assessment calculator for elderly ovarian cancer patients undergoing primary cytoreductive surgery. AB - OBJECTIVE: Cytoreductive surgery for ovarian cancer has higher rates of postoperative complication than neoadjuvant chemotherapy followed by surgery. If patients at high risk of postoperative complication were identified preoperatively, primary therapy could be tailored. Our objective was to develop a predictive model to estimate the risk of major postoperative complication after primary cytoreductive surgery among elderly ovarian cancer patients. METHODS: Patients who underwent primary surgery for ovarian cancer between 2005 and 2013 were identified from the National Surgical Quality Improvement Project. Patients were selected using primary procedure CPT codes. Major complications were defined as grade 3 or higher complications on the validated Claviden-Dindo scale. Using logistic regression, we identified demographic and clinical characteristics predictive of postoperative complication. RESULTS: We identified 2101 ovarian cancer patients of whom 35.9% were older than 65. Among women older than 65, the rate of major postoperative complication was 16.4%. Complications were directly associated with preoperative laboratory values (serum creatinine, platelets, white blood cell count, hematocrit), ascites, white race, and smoking status, and indirectly associated with albumin. Our predictive model had an area under receiver operating characteristic curve of 0.725. In order to not deny patients necessary surgery, we chose a 50% population rate of postoperative complication which produced model sensitivity of 9.8% and specificity of 98%. DISCUSSION: Our predictive model uses easily and routinely obtained objective preoperative factors to estimate the risk of postoperative complication among elderly ovarian cancer patients. This information can be used to assess risk, manage postoperative expectations, and make decisions regarding initial treatment. PMID- 26432040 TI - Emerging strategies for targeting PI3K in gynecologic cancer. AB - Ovarian, endometrial and cervical cancers are the most prevalent gynecologic cancers in the United States and account for significant mortality. Translational research into these cancers has highlighted the distinctive molecular and genomic profiles of these cancers finding that, even within a disease site, the landscapes and drivers of neoplasia are distinctive. Despite this molecular diversity, activation of the phosphatidylinositol-3-kinase (PI3K) pathway appears to be conserved in subsets of these tumors, suggesting that strategies that antagonize mediators in this signaling cascade could offer anti-tumor efficacy. Extensive pre-clinical and clinical data have demonstrated that single agent targeted therapies lead to modest single agent activity of generally limited duration, even in the setting of innate PI3K pathway activation via mutation or amplification. These findings in the laboratory and clinic have prompted investigations into resistance pathways following PI3K pathway inhibition in order to understand escape pathways and restore tumor cell sensitivity. A next generation of clinical trial investigations will focus on novel combinations in order to define how these important therapeutics can be used in the clinic. This review will present preclinical data that supports the role of the PI3K pathway in ovarian, endometrial and cervical cancers, in addition to discussing the reported clinical trial experience with PI3K pathway inhibition. A specific focus will be on the rationale behind ongoing clinical trials utilizing novel agents in concert with PI3K pathway inhibitors to reverse resistance in populations with and without gain of function alterations in this oncogenic signaling cascade. PMID- 26432039 TI - Groin surgery and risk of recurrence in lymph node positive patients with vulvar squamous cell carcinoma. AB - OBJECTIVES: Treatment of groin metastasis in vulvar squamous cell carcinoma (VSCC) patients consists of surgery, often combined with (chemo)radiotherapy, and is associated with significant morbidity. Our aim was to compare the risk of groin recurrence and morbidity in patients with lymph node positive VSCC after standard full inguinofemoral lymphadenectomy (IFL) versus less radical debulking of clinically involved lymph nodes or removal of sentinel nodes only followed by radiotherapy. METHODS: A retrospective cohort study of 68 patients with primary VSCC and proven lymph node metastasis to the groin(s) was conducted. Patients were divided into three subgroups by type of initial groin surgery (84 groins): sentinel node (SN), IFL, and debulking of clinically involved nodes. Most patients (82%) received adjuvant radiotherapy. Overall survival was analyzed using time dependent cox regression. Analysis of morbidity and groin recurrence free time was performed per groin with the generalized estimating equation model and Kaplan Meier method. RESULTS: There was no significant difference in the risk of developing a groin recurrence (SN 25%, debulking 16%, IFL 13%, p=0.495). Despite the fact that more patients received radiotherapy after debulking (90% vs 67%), the complication rate was significantly lower (p=0.003) compared to IFL, especially regarding lymphocysts and lymphedema (p=0.032 and p=0.002 respectively). CONCLUSIONS: The risk of groin recurrence was similar in all treatment groups. Debulking of clinically involved lymph nodes was related to a significant lower risk of complications compared to IFL. These findings support that the preferred treatment of patients with clinically involved lymph nodes is debulking followed by radiotherapy. PMID- 26432041 TI - Pros and cons of vaginal brachytherapy after external beam radiation therapy in endometrial cancer. AB - A large number of studies have looked at the role of radiation therapy in the treatment of endometrial cancer. One particular radiation strategy in common practice is the use of adjuvant external beam (EB) radiotherapy followed by vaginal brachytherapy (VB). While the addition of VB to EB provides a theoretical benefit of a localized boost with higher focused dose to an area of potentially high recurrence risk, a randomized clinical trial to compare outcomes and toxicities of EB+VB vs. EB alone is lacking. The goal of this review is to present the current data for and against the use of this combined radiation modality and to provide some preliminary evidence regarding which patient populations may be most likely to benefit. PMID- 26432042 TI - Wnt signalling in gynaecological cancers: A future target for personalised medicine? AB - The three major gynaecological cancers, ovarian, uterine and cervical, contribute a significant burden to global cancer mortality, and affect women in both developed and developing countries. However, unlike other cancer types that have seen rapid advances and incorporation of targeted treatments in recent years, personalised medicine is not yet a reality in the treatment of gynaecological cancers. Advances in sequencing technology and international collaborations and initiatives such as The Cancer Genome Atlas are now revealing the molecular basis of these cancers, and highlighting key signalling pathways involved. One pathway which plays a role in all three cancer types, is the Wnt signalling pathway. This complex developmental pathway is altered in most human malignancies, and members of this pathway, particularly the recently linked ROR receptor tyrosine kinases may be attractive future therapeutic targets. This review provides an up-to-date summary of research into Wnt signalling and ovarian, uterine and cervical cancers, and discusses the potential of the Wnt pathway as a future target for personalised medicine in gynaecological cancers. PMID- 26432043 TI - Retrospective review of symptoms and palliative care interventions in women with advanced cervical cancer. AB - OBJECTIVE: The objective of this study was to delineate and measure the symptom distress experienced by patients with advanced cervical cancer at the time of palliative care (PC) referral. METHODS: A total of 156 patients with advanced cervical cancer were referred to PC from 2010 to 2012. Of these, 88 patients had completed the Edmonton Symptom Assessment System (ESAS) and were included in the analysis. RESULTS: The mean age was 45years (25-76), 47% were white, 18% were African American, and 33% were Hispanic. Fifty-one percent were married, 64% had no advance directives, and 75% had recurrent disease. Clinically significant symptoms recorded by patient reported outcome measurement (defined as ESAS scores >=4) were pain (81%), anorexia (72%), a poor feeling of well-being (70%), fatigue (69%), and insomnia (54%). The chief complaint recorded for the visit was pain in 94% of patients. According to the PC specialists' assessment, pain (96%), emotional distress (77%), and constipation (50%) were predominant symptoms. Various PC interventions including opioids, laxatives, and expressive supportive counseling were provided. Clinically significant symptoms including nausea, depression, anxiety, and feeling of well-being were significantly improved at follow-up visits. CONCLUSION: More than half of patients with advanced cervical cancer were significantly burdened with pain, anorexia, a poor feeling of well being, fatigue, insomnia, and constipation at the time of PC referral. This research is an integral step towards developing a standardized tool for assessing symptoms in women diagnosed with cervical cancer and thus maximizing effectiveness of patient centered care. PMID- 26432044 TI - PIAS3, SHP2 and SOCS3 Expression patterns in Cervical Cancers: Relevance with activation and resveratrol-caused inactivation of STAT3 signaling. AB - OBJECTIVE: Resveratrol inhibits cervical cancer (CC) cells by blocking STAT3 signaling. However, the mechanism of resveratrol-induced STAT3 inactivation remains largely unknown. SHP2, PIAS3, and SOCS3 are STAT3 negative regulators; therefore, their statuses in cervical adenocarcinoma (HeLa) and squamous cell carcinoma (SiHa and C33A) cell lines without and with resveratrol treatment and their correlation with STAT3 activation in CC specimens were investigated. METHODS: MTT and TUNEL assays were used to check the resveratrol sensitivity of CC cells, and immunocytochemical staining, Western blotting, and RT-PCR were used to analyze SHP2, PIAS3, and SOCS3 expression and the intracellular distribution of STAT3. Tissue microarray based immunohistochemical staining was performed to investigate potential correlations between SHP2, PIAS3, and SOCS3 expression and STAT3 activation. RESULTS: PIAS3 and SOCS3 were found to be weakly expressed in CC cells and upregulated by resveratrol; this was accompanied by inhibition of STAT3 signaling. The SHP2 level remained unchanged in all three cell lines after resveratrol treatment. STAT3 nuclear translocation was more frequent in adenocarcinomas and squamous cell carcinomas than that of their noncancerous counterparts. The SOCS3 level and detection rate were higher in noncancerous squamous cells (but not in glandular epithelia) compared with their cancerous counterparts. The phospho-SHP2 detection rate was similar in noncancerous and tumor tissues of squamous and glandular origins; however, PIAS3 levels were distinct. CONCLUSIONS: Of the three STAT3 negative regulators, PIAS3 correlated most negatively with STAT3 nuclear translocation and may inhibit STAT3 signaling in both histological CC subtypes. PIAS3 responsiveness may reflect greater resveratrol sensitivity and improved therapeutic outcome in CCs. PMID- 26432045 TI - Eating with our eyes: From visual hunger to digital satiation. AB - One of the brain's key roles is to facilitate foraging and feeding. It is presumably no coincidence, then, that the mouth is situated close to the brain in most animal species. However, the environments in which our brains evolved were far less plentiful in terms of the availability of food resources (i.e., nutriments) than is the case for those of us living in the Western world today. The growing obesity crisis is but one of the signs that humankind is not doing such a great job in terms of optimizing the contemporary food landscape. While the blame here is often put at the doors of the global food companies - offering addictive foods, designed to hit 'the bliss point' in terms of the pleasurable ingredients (sugar, salt, fat, etc.), and the ease of access to calorie-rich foods - we wonder whether there aren't other implicit cues in our environments that might be triggering hunger more often than is perhaps good for us. Here, we take a closer look at the potential role of vision; Specifically, we question the impact that our increasing exposure to images of desirable foods (what is often labelled 'food porn', or 'gastroporn') via digital interfaces might be having, and ask whether it might not inadvertently be exacerbating our desire for food (what we call 'visual hunger'). We review the growing body of cognitive neuroscience research demonstrating the profound effect that viewing such images can have on neural activity, physiological and psychological responses, and visual attention, especially in the 'hungry' brain. PMID- 26432047 TI - Chemotherapy plus ponatinib: a new standard for Ph-positive ALL? PMID- 26432046 TI - Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study. AB - BACKGROUND: Combination of chemotherapy with a tyrosine-kinase inhibitor is effective in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia. Ponatinib is a more potent BCR-ABL1 inhibitor than all other tyrosine-kinase inhibitors and selectively suppresses the resistant T315I clones. We examined the activity and safety of combining chemotherapy with ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia in this continuing phase 2 trial. METHODS: In this single-centre, phase 2, single-arm trial, adult patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia were sequentially enrolled. Patients who had received fewer than two courses of previous chemotherapy with or without tyrosine-kinase inhibitors were also eligible. Patients had to be aged 18 years or older, have an Eastern Cooperative Oncology Group performance status of 2 or less, have normal cardiac function (defined by ejection fraction above 50%), and have adequate organ function (serum bilirubin <=3.0 mg/dL and serum creatinine <=3.0 mg/dL, unless higher concentrations were believed to be due to a tumour). Patients received eight cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternating with high dose methotrexate and cytarabine every 21 days. Ponatinib 45 mg was given daily for the first 14 days of cycle 1 then continuously for the subsequent cycles. Patients in complete remission received maintenance with ponatinib 45 mg daily with vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. The primary endpoint for this study was event-free survival. The trial is registered at ClinicalTrials.gov, number NCT01424982. FINDINGS: 37 patients were enrolled and treated from Nov 1, 2011, to Sept 1, 2013. 2-year event-free survival rate was 81% (95% CI 64-90). Grade 3 or more toxic effects included infections during induction (20 [54%] patients), increased aspartate aminotransferase and alanine aminotransferase concentration (14 [38%] patients), thrombotic events (three [8%]), myocardial infarction (three [8%]), hypertension (six [16%]), skin rash (eight [22%]), and pancreatitis (six [16%] patients). Two patients died from from myocardial infarction potentially related to treatment; another patient also died from myocardial infarction related to sepsis. Two further patients died, one from bleeding and another from infection, both deemed unrelated to treatment. INTERPRETATION: The first results of this ongoing trial indicate that the combination of chemotherapy with ponatinib is effective in achieving early sustained remissions in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia. New strategies, including dosing titration of ponatinib and optimised control of vascular risk factors, might further improve outcomes. FUNDING: ARIAD Pharmaceuticals Inc. PMID- 26432048 TI - Dietary pantothenic acid depressed the gill immune and physical barrier function via NF-kappaB, TOR, Nrf2, p38MAPK and MLCK signaling pathways in grass carp (Ctenopharyngodon idella). AB - This study explored the effects of pantothenic acid (PA) on the immune and physical barrier function, and relative mRNA levels of signaling molecules in the gill of grass carp (Ctenopharyngodon idella). The results indicated that compared with optimal PA supplementation, PA deficiency (1.31 mg/kg diet) decreased gill interleukin 10, transforming growth factor beta1, inhibitor of kappaBalpha (IkappaBalpha), eIF4E-binding protein 2, Claudin b and ZO-1 mRNA levels; anti superoxide anion activity, and activities and mRNA levels of copper/zinc superoxide dismutase, manganese superoxide dismutase, glutathione peroxidase, glutathione reductase and NF-E2-related factor (P < 0.05). Additionally, PA deficiency and excess (75.08 mg/kg diet) decreased gill complement 3 and glutathione contents, lysozyme and acid phosphatase, anti-hydroxy radical, catalase and glutathione S-transferases activities, and liver-expression antimicrobial peptide 2, hepcidin, Claudin 3, Claudin c and Occludin mRNA levels (P < 0.05). Conversely, PA deficiency increased gill reactive oxygen species and protein carbonyl contents, and interferon gamma2, interleukin 8, nuclear factor kappa B P65, Claudin 15a, Kelch-like ECH-associating protein 1a and Kelch-like ECH-associating protein 1b mRNA levels (P<0.05). Moreover, PA deficiency and excess increased gill malondialdehyde content, and tumor necrosis factor alpha, interleukin 1beta, IkappaB kinase alpha, IkappaB kinase beta, IkappaB kinase gamma, target of rapamycin and ribosomal S6 protein kinase1 p38 mitogen-activated protein kinases and myosin light-chain kinase mRNA levels (P<0.05). In conclusion, PA deficiency decreased immune and physical barrier function, and regulated relative mRNA levels of signaling molecules in fish gill. Based on the quadratic regression analysis of gill lysozyme activity, the optimal PA levels in grass carp (253.44-745.25 g) were estimated to be 36.97 mg/kg diet. PMID- 26432049 TI - Lvserpin3 is involved in shrimp innate immunity via the inhibition of bacterial proteases and proteases involved in prophenoloxidase system. AB - Serine protease inhibitor, represented by serpin, plays an important inhibitory role on proteases involved in the immune responses. To clarify the immune characterizations of serpin, a novel serpin (Lvserpin3) encoding for 410 amino acids with a 23-amino acid signal peptide and a serpin domain was identified from the Pacific white shrimp Litopenaeus vannamei. Lvserpin3 expressed strongest in hepatopancreas, and was significantly up-regulated in the early stage upon Vibrio anguillarum, Micrococcus lysodeikticus or White Spot Syndrome Virus (WSSV) infection. Suppression of Lvserpin3 by dsRNA led to a significant increase in the transcripts of LvPPAF, LvproPO and phenoloxidase (PO) activity, and also led to the high cumulative mortality. The recombinant Lvserpin3 protein (rLvserpin3) inhibited the proteases secreted by M. lysodeikticus and Bacillus subtilis, and further exhibited inhibitory role on the growth of B. subtilis and M. lysodeikticu. Moreover, rLvserpin3 was found to be able to block the activation of prophenoloxidase system. Taken together, the results imply that Lvserpin3 may be involved in shrimp innate immunity via the inhibition of bacterial proteases and proteases involved in prophenoloxidase system. PMID- 26432050 TI - Comment on arterial flow waveforms, vascular tone, and chronic fatigue by Zundel et al. PMID- 26432051 TI - Diversity of group A rotavirus on a UK pig farm. AB - Group A rotaviruses (GARV) are a significant cause of enteritis in young pigs. The aim of this study was to extend our understanding of the molecular epidemiology of porcine GARV in the UK by investigating the genetic diversity of GARV on a conventional farrow-to-finish farm. Faecal samples were obtained from six batches of pigs in 2009 and 8 batches in 2010, when the pigs were 2, 3 (time point omitted in 2009), 4, 5, 6 and 8 weeks of age. Presence of rotavirus was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in 89% and 80% of samples from 2009 and 2010, respectively. A combination of multiplex PCRs and sequencing identified four VP7 genotypes (G2, G3, G4 and G5) and three VP4 genotypes (P[6], P[7] and P[32]) present in almost every combination over the 2 years. The predominant genotype combination was G5P[32] in 2009 and G4P[32] in 2010. Conservation among the P[32] sequences between 2009 and 2010 suggests that reassortment may have led to the different genotype combinations. There were significant changes in the predominant VP7 genotype prior to weaning at 4 weeks, and post weaning when pigs were moved to a different building. Phylogenetic analysis indicated that introduction of new viruses onto the farm was limited. Taken together, these findings suggest that genetically diverse GARV strains persist within the farm environment. PMID- 26432052 TI - Screening young athletes for prevention of sudden cardiac death: Practical recommendations for sports physicians. AB - Regular intensive exercise in athletes increases the relative risk of sudden cardiac death (SCD) compared with the relatively sedentary population. Most cases of SCD are due to silent cardiovascular diseases, and pre-participation screening of athletes at risk of SCD is thus of major importance. However, medical guidelines and recommendations differ widely between countries. In Italy, the National Health System recommends pre-participation screening for all competitive athletes including personal and family history, a physical examination, and a resting 12-lead electrocardiogram (ECG). In the United States, the American College of Cardiology and the American Heart Association recommend a pre participation screening program limited to the use of specific questionnaires and a clinical examination. The value of a 12-lead ECG is debated based on issues surrounding cost-efficiency and feasibility. The aim of this review was to focus on (i) the incidence rate of cardiac diseases in relation to SCD; (ii) the value of conducting a questionnaire and a physical examination; (iii) the value of a 12 lead resting ECG; (iv) the importance of other cardiac evaluations in the prevention of SCD; and (v) the best practice for pre-participation screening. PMID- 26432053 TI - A process for energy-efficient high-solids fed-batch enzymatic liquefaction of cellulosic biomass. AB - The enzymatic hydrolysis of cellulosic biomass is a key step in the biochemical production of fuels and chemicals. Economically feasible large-scale implementation of the process requires operation at high solids loadings, i.e., biomass concentrations >15% (w/w). At increasing solids loadings, however, biomass forms a high viscosity slurry that becomes increasingly challenging to mix and severely mass transfer limited, which limits further addition of solids. To overcome these limitations, we developed a fed-batch process controlled by the yield stress and its changes during liquefaction of the reaction mixture. The process control relies on an in-line, non-invasive magnetic resonance imaging (MRI) rheometer to monitor real-time evolution of yield stress during liquefaction. Additionally, we demonstrate that timing of enzyme addition relative to biomass addition influences process efficiency, and the upper limit of solids loading is ultimately limited by end-product inhibition as soluble glucose and cellobiose accumulate in the liquid phase. PMID- 26432054 TI - Production of bioactive chitosan oligosaccharides using the hypertransglycosylating chitinase-D from Serratia proteamaculans. AB - The biological activities of chitosan and its oligosaccharides are greatly influenced by properties such as the degree of polymerization (DP), degree of acetylation (DA) and pattern of acetylation (PA). Here, structurally diverse chitosan oligosaccharides from chitosan polymers (DA=35% or 61%) were generated using Serratia proteamaculans wild-type chitinase D (SpChiD) and the W114A mutant which lacks transglycosylase activity. The crude oligosaccharide mixtures and purified fractions with specific DP and DA ranges were tested for their ability to induce an oxidative burst in rice cell suspension cultures. The crude mixtures were more active when produced by the W114A mutant whereas the purified fractions were more active when produced by wild-type SpChiD. Neither hydrolysis nor transglycosylation by SpChiD was inhibited in the presence of fully-deacetylated oligosaccharides, suggesting that SpChiD could be exploited to generate oligosaccharides with defined DA and PA values. PMID- 26432055 TI - A novel configuration for an anaerobic submerged membrane bioreactor (AnSMBR). Long-term treatment of municipal wastewater under psychrophilic conditions. AB - A novel design for a pilot scale anaerobic submerged membrane bioreactor (AnSMBR) equipped with an ultrafiltration unit, treating municipal wastewater at 18 +/- 2 degrees C, and inoculated with a mesophilic inoculum without acclimation, was implemented and evaluated over 3 years of stable operation. The AnSMBR operated with a volumetric loading rate between 1.6 to 2.0 kg COD/m(3)UASBd, 12.8 to 14.2h hydraulic retention time, and reached a tCOD removal efficiency of around 90%. Biosolid production was between 0.05 and 0.083 g VS/g CODremoved. Dissolved methane oversaturation in the effluent was observed, reaching average values of 19.1 +/- 0.84 mg CH4/L. The permeate flow rate ranged from 10 to 14L/m(2)h with trans-membrane pressure (TMP) values of 400-550 mbar, using cycles of 30s backwash, 7.5 min filtration, and continuous biogas sparging (9-16 m/h). During the three years of continuous operation, the membrane was not physically or chemically cleaned. PMID- 26432056 TI - Physico-chemical and biological characteristics of compost from decentralised composting programmes. AB - Composts that originated from small-scale composting programmes including home, community and canteen waste composters were studied. Heavy metals concentration indicated compliance with current regulations for conventional and organic agriculture. Compost from canteen waste showed high organic matter content (74% VS), while community (44 +/- 20% VS) and home composts (31 +/- 16% VS) had moderate levels. N content increased from home compost (1.3 +/- 0.9% dm) to community (2.0 +/- 0.9%) and canteen compost (2.5-3.0%) while P content ranged from 0.4% to 0.6% dm. C/N, absorbance E4/E6 and N-NH4(+)/N-NO3(-) ratios as well as respiration index indicated well-stabilized final products. Culturable bacterial and fungal cfu linkage to composting dynamics were identified and higher diversity of invertebrates was found in the smaller scale static systems. With similar process evolution indicators to industrial systems, overall results support the sustainability of these small-scale, self-managed composting systems. PMID- 26432057 TI - Fermentation of sweet sorghum derived sugars to butyric acid at high titer and productivity by a moderate thermophile Clostridium thermobutyricum at 50 degrees C. AB - In this study, a moderate thermophile Clostridium thermobutyricum is shown to ferment the sugars in sweet sorghum juice treated with invertase and supplemented with tryptone (10 g L(-1)) and yeast extract (10 g L(-1)) at 50 degrees C to 44 g L(-1) butyrate at a calculated highest volumetric productivity of 1.45 g L(-1)h( 1) (molar butyrate yield of 0.85 based on sugars fermented). This volumetric productivity is among the highest reported for batch fermentations. Sugars from acid and enzyme-treated sweet sorghum bagasse were also fermented to butyrate by this organism with a molar yield of 0.81 (based on the amount of cellulose and hemicellulose). By combining the results from juice and bagasse, the calculated yield of butyric acid is approximately 90 kg per tonne of fresh sweet sorghum stalk. This study demonstrates that C. thermobutyricum can be an effective microbial biocatalyst for production of bio-based butyrate from renewable feedstocks at 50 degrees C. PMID- 26432058 TI - Essential Thrombocythemia: The Dermatologic Point of View. AB - Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by an increase in blood platelets and dominated by a predisposition to vascular events. Cutaneous manifestations can complicate its course. itching has been the most common symptom reported; however, the percentage has ranged from 3% to 46%, depending on the survey. Erythromelalgia is found in 6% of cases, and livedo reticularis, minor bleeding, acrocyanosis, and Raynaud's phenomenon are rare manifestations. It is important to recognize and treat these events, because they can affect patients' quality of life and could worsen the prognosis. In addition to skin involvement as a possible sign of ET, the treatment of ET can be associated with cutaneous complications. Hydroxycarbamide, interferon-alfa, and anagrelide can induce different skin lesions. Hydroxycarbamide has been associated with major complications, including painful leg ulcers and actinic keratoses. Minor events include alopecia and hyperpigmentation. Xerosis, pruritus, and photosensitivity are some of the complications reported by patients treated with interferon-alfa. Anagrelide has proved to be associated with fewer dermatologic effects, only detected in single cases. Knowledge of the ET cutaneous manifestations, together with the clinical examination findings, can result in an earlier diagnosis and the start of effective treatment. PMID- 26432059 TI - Facial lesions in frontal fibrosing alopecia (FFA): Clinicopathological features in a series of 12 cases. AB - BACKGROUND: Facial lesions in frontal fibrosing alopecia (FFA) have been poorly described in published series. OBJECTIVE: We sought to describe facial lesions in FFA. METHODS: We reviewed our series of 55 cases of FFA, selecting 12 cases with clinically significant facial lesions. We performed a histologic study of these lesions. RESULTS: In addition to the observations already described in the literature such as facial papules or follicular red dots, we observed perifollicular and diffuse erythema, sometimes with a reticular pattern, and the gradual appearance of pigmented macules on facial skin. Biopsy specimens from the areas with facial erythema showed perifollicular and interfollicular lymphocytic infiltrate and fibrosis around vellus hair follicles. Histologic evaluation of pigmented macules sometimes exhibited an increased epidermal pigmentation and on occasions, pigmentary incontinence. LIMITATIONS: More patients are needed to determine the prevalence of these lesions in FFA. CONCLUSION: On facial skin of patients with FFA, we can observe papules or perifollicular erythema secondary to vellus hair follicle involvement. We describe diffuse erythema, owing to follicular and interfollicular lichenoid infiltrate, and the gradual appearance of pigmented macules, which could be secondary to an increased epidermal pigmentation or to pigmentary incontinence. PMID- 26432060 TI - Quantification of bovine oxylipids during intramammary Streptococcus uberis infection. AB - Streptococcus uberis mastitis results in severe mammary tissue damage in dairy cows due to uncontrolled inflammation. Oxylipids are potent lipid mediators that orchestrate pathogen-induced inflammatory responses, however, changes in oxylipid biosynthesis during S. uberis mastitis are unknown. Thus, the current objective was to determine how oxylipid concentrations change in milk and mammary tissues during different stages of S. uberis mastitis. Increased arachidonic acid and linoleic acid-derived oxylipids were significantly increased in S. uberis infected bovine mammary tissue. Linoleic acid metabolites, hydroxyoctadecadienoic acid (HODE) and oxooctadecadienoic acid, predominated in tissue and milk. Furthermore, in vitro exposure of bovine mammary endothelial cells to 13 hydroperoxyoctadecadienoic acid, upstream metabolite of HODE, significantly increased cyclooxygenase-2 expression, but 13-HODE exposure had no effect. The findings in the current study indicate lipidomic profiling may explain some of the dynamics of inflammation during bacterial challenge, however continued research is necessary to determine sample compartments which best reflect disease pathogenesis. PMID- 26432061 TI - Robotic stereotactic radioablation of breast tumors: Influence of beam size on the absorbed dose distributions. AB - Robotic stereotactic radioablation (RSR) therapy for breast tumors has been shown to be an effective treatment strategy when applied concomitantly with chemotherapy, with the purpose of reducing the tumor volume thus making it more amenable for breast conserving surgery. In this paper we used Monte Carlo simulation within a realistic patient model to determine the influence that the variation in beam collimation radius has on the resultant absorbed dose distributions for this type of treatment. Separate optimized plans were obtained for treatments using 300 circular beams with radii of 0.5 cm, 0.75 cm, 1.0 cm and 1.5 cm. Cumulative dose volume histograms were obtained for the gross, clinical and planning target volumes as well as for eight organs and structures at risk. Target coverage improves as the collimator size is increased, at the expense of increasing the volume of healthy tissue receiving mid-level absorbed doses. Interestingly, it is found that the maximum dose imparted to the skin is highly dependent on collimator size, while the dosimetry of other structures, such as both the ipsilateral and contralateral lung tissue are basically unaffected by a change in beam size. PMID- 26432062 TI - Characteristics of initial deposition and behavior of radiocesium in forest ecosystems of different locations and species affected by the Fukushima Daiichi Nuclear Power Plant accident. AB - After the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident, information about stand-level spatial patterns of radiocesium initially deposited in the surrounding forests was essential for predicting the future dynamics of radiocesium and suggesting a management plan for contaminated forests. In the first summer (approximately 6 months after the accident), we separately estimated the amounts of radiocesium ((134)Cs and (137)Cs; Bq m(-2)) in the major components (trees, organic layers, and soils) in forests of three sites with different contamination levels. For a Japanese cedar (Cryptomeria japonica) forest studied at each of the three sites, the radiocesium concentration greatly differed among the components, with the needle and organic layer having the highest concentrations. For these cedar forests, the proportion of the (137)Cs stock in the aboveground tree biomass varied from 22% to 44% of the total (137)Cs stock; it was 44% in highly contaminated sites (7.0 * 10(5) Bq m(-2)) but reduced to 22% in less contaminated sites (1.1 * 10(4) Bq m(-2)). In the intermediate contaminated site (5.0-5.8 * 10(4) Bq m(-2)), 34% of radiocesium was observed in the aboveground tree biomass of the Japanese cedar stand. However, this proportion was considerably smaller (18-19%) in the nearby mixed forests of the Japanese red pine (Pinus densiflora) and deciduous broad-leaved trees. Non negligible amounts of (134)Cs and (137)Cs were detected in both the sapwood and heartwood of all the studied tree species. This finding suggested that the uptake or translocation of radiocesium had already started within 6 months after the accident. The belowground compartments were mostly present in the organic layer and the uppermost (0-5 cm deep) mineral soil layer at all the study sites. We discussed the initial transfer process of radiocesium deposited in the forest and inferred that the type of initial deposition (i.e., dry versus wet radiocesium deposition), the amount of rainfall after the accident, and the leaf biomass by the tree species may influence differences in the spatial pattern of radiocesium by study plots. The results of the present study and further studies of the spatial pattern of radiocesium are important for modeling future radiocesium distribution in contaminated forest ecosystems. PMID- 26432063 TI - A longitudinal study of accommodative changes in biometry during incipient presbyopia. AB - PURPOSE: To profile accommodative biometric changes longitudinally and to determine the influence of age-related ocular structural changes on the accommodative response prior to the onset of presbyopia. METHODS: Twenty participants (aged 34-41 years) were reviewed at six-monthly intervals over two and a half years. At each visit, ocular biometry was measured with the LenStar biometer (www.Haag-Streit.com) in response to 0.00, 3.00 and 4.50 D stimuli. Accommodative responses were measured by the WAM 5500 Auto Ref/Keratometer (www.grandseiko.com). RESULTS: During accommodation, anterior chamber depth reduced (F = 29, p < 0.001), whereas crystalline lens thickness (F = 39, p < 0.001) and axial length (F = 5.4, p = 0.009) increased. The accommodative response (F = 5.5, p = 0.001) and the change in anterior chamber depth (F = 3.1, p = 0.039), crystalline lens thickness (F = 3.0, p = 0.042) and axial length (F = 2.5, p = 0.038) in response to the 4.50 D accommodative target reduced after 2.5 years. However, the change in anterior chamber depth (F = 2.2, p = 0.097), crystalline lens thickness (F = 1.7, p = 0.18) and axial length (F = 1.0, p = 0.40) per dioptre of accommodation exerted remained invariant after 2.5 years. The increase in disaccommodated crystalline lens thickness with age was not significantly associated with the reduction in accommodative response (R = 0.32, p = 0.17). CONCLUSION: Despite significant age-related structural changes in disaccommodated biometry, the change in biometry per dioptre of accommodation exerted remained invariant with age. The present study supports the Helmholtz theory of accommodation and suggests an increase in lenticular stiffness is primarily responsible for the onset of presbyopia. PMID- 26432064 TI - Long term mortality in a population-based cohort of adolescents, and young and middle-aged adults with burn injury in Western Australia: A 33-year study. AB - BACKGROUND: Advances in the treatment and management of burn patients over the past decades have resulted in a decline of in-hospital mortality rates. Current estimates of burn-related mortality are usually in the context of deaths occurring during the admission or within a short time period after the incident burn. Limited data are available that examine long term mortality after burn injury. This study aimed to assess the impact of burn injury on long-term mortality and quantify any increased risk of death attributable to burn injury. METHODS: A population-based cohort study of persons 15-44 years of age hospitalised for burn injury (n=14,559) in Western Australia (1980-2012) and a matched non-injured comparison group (n=56,822) using linked health administrative data was used. Hospital morbidity and death data were obtained from the Western Australian Hospital Morbidity Data System and Death Register. De identified extraction of all linked hospital morbidity and death records for the period 1980-2012 were provided by the Western Australian Data Linkage System. Survival analysis was conducted using the Kaplan-Meier method and Cox proportional hazards modelling. RESULTS: The adjusted all-cause Mortality Rate Ratio (MRR) for burn injury was 1.8 (95%CI: 1.7-2.0); those with burn injury had a 1.8 times greater rate of mortality than those with no injury. The index burn injury was estimated to account for 44% of all recorded deaths in the burn injury cohort during the study period after discharge. Increased risk of mortality was observed for both severe (MRR, 95%CI: 1.9, 1.3-2.9) and minor (MRR, 95%CI: 2.5, 2.2-3.0) burns. CONCLUSIONS: An increased risk of long-term all-cause mortality is associated with both minor and severe burn injury. Estimates of total mortality burden based on the early in-patient period alone, significantly underestimates the true burden of burn injury in adolescents, and young and middle aged adults. These results have significant implications for burn injury prevention. PMID- 26432065 TI - Finite element comparison of human and Hybrid III responses in a frontal impact. AB - The improvement of finite element (FE) Human Body Models (HBMs) has made them valuable tools for investigating restraint interactions compared to anthropomorphic test devices (ATDs). The objective of this study was to evaluate the effect of various combinations of safety restraint systems on the sensitivity of thoracic injury criteria using matched ATD and Human Body Model (HBM) simulations at two crash severities. A total of seven (7) variables were investigated: 3-point belt with two (2) load limits, frontal airbag, knee bolster airbag, a buckle pretensioner, and two (2) delta-v's - 40kph and 50kph. Twenty four (24) simulations were conducted for the Hybrid III ATD FE model and repeated with a validated HBM for 48 total simulations. Metrics tested in these conditions included sternum deflection, chest acceleration, chest excursion, Viscous Criteria (V*C) criteria, pelvis acceleration, pelvis excursion, and femur forces. Additionally, chest band deflection and rib strain distribution were measured in the HBM for additional restraint condition discrimination. The addition of a frontal airbag had the largest effect on the occupant chest metrics with an increase in chest compression and acceleration but a decrease in excursion. While the THUMS and Hybrid III occupants demonstrated the same trend in the chest compression measurements, there were conflicting results in the V*C, acceleration, and displacement metrics. Similarly, the knee bolster airbag had the largest effect on the pelvis with a decrease in acceleration and excursion. With a knee bolster airbag the simulated occupants gave conflicting results, the THUMS had a decrease in femur force and the ATD had an increase. Preferential use of dummies or HBM's is not debated; however, this study highlights the ability of HBM metrics to capture additional chest response metrics. PMID- 26432066 TI - Failure mode and effective analysis ameliorate awareness of medical errors: a 4 year prospective observational study in critically ill children. AB - BACKGROUND: Errors in are estimated to occur with an incidence of 3.7-16.6% in hospitalized patients. The application of systems for detection of adverse events is becoming a widespread reality in healthcare. Incident reporting (IR) and failure mode and effective analysis (FMEA) are strategies widely used to detect errors, but no studies have combined them in the setting of a pediatric intensive care unit (PICU). AIM: The aim of our study was to describe the trend of IR in a PICU and evaluate the effect of FMEA application on the number and severity of the errors detected. METHODS: With this prospective observational study, we evaluated the frequency IR documented in standard IR forms completed from January 2009 to December 2012 in the PICU of Woman's and Child's Health Department of Padova. On the basis of their severity, errors were classified as: without outcome (55%), with minor outcome (16%), with moderate outcome (10%), and with major outcome (3%); 16% of reported incidents were 'near misses'. We compared the data before and after the introduction of FMEA. RESULTS: Sixty-nine errors were registered, 59 (86%) concerning drug therapy (83% during prescription). Compared to 2009-2010, in 2011-2012, we noted an increase of reported errors (43 vs 26) with a reduction of their severity (21% vs 8% 'near misses' and 65% vs 38% errors with no outcome). CONCLUSION: With the introduction of FMEA, we obtained an increased awareness in error reporting. Application of these systems will improve the quality of healthcare services. PMID- 26432067 TI - Serial [18F]-fluoromisonidazole PET during radiochemotherapy for locally advanced head and neck cancer and its correlation with outcome. AB - PURPOSE: The aim was to assess changes of tumour hypoxia during primary radiochemotherapy (RCT) for head and neck cancer (HNC) and to evaluate their relationship with treatment outcome. MATERIAL AND METHODS: Hypoxia was assessed by FMISO-PET in weeks 0, 2 and 5 of RCT. The tumour volume (TV) was determined using FDG-PET/MRI/CT co-registered images. The level of hypoxia was quantified on FMISO-PET as TBRmax (SUVmaxTV/SUVmean background). The hypoxic subvolume (HSV) was defined as TV that showed FMISO uptake ?1.4 times blood pool activity. RESULTS: Sixteen consecutive patients (T3-4, N+, M0) were included (mean follow up 31, median 44months). Mean TBRmax decreased significantly (p<0.05) from 1.94 to 1.57 (week 2) and 1.27 (week 5). Mean HSV in week 2 and week 5 (HSV2=5.8ml, HSV3=0.3ml) were significantly (p<0.05) smaller than at baseline (HSV1=15.8ml). Kaplan-Meier plots of local recurrence free survival stratified at the median TBRmax showed superior local control for less hypoxic tumours, the difference being significant at baseline and after 2weeks (p=0.031, p=0.016). CONCLUSIONS: FMISO-PET documented that in most HNC reoxygenation starts early during RCT and is correlated with better outcome. PMID- 26432068 TI - Experimental Transmission of African Swine Fever (ASF) Low Virulent Isolate NH/P68 by Surviving Pigs. AB - African swine fever (ASF) has persisted in Eastern Europe since 2007, and two endemic zones have been identified in the central and southern parts of the Russian Federation. Moderate- to low-virulent ASF virus isolates are known to circulate in endemic ASF-affected regions. To improve our knowledge of virus transmission in animals recovered from ASF virus infection, an experimental in vivo study was carried out. Four domestic pigs were inoculated with the NH/P68 ASF virus, previously characterized to develop a chronic form of ASF. Two additional in-contact pigs were introduced at 72 days post-inoculation (dpi) in the same box for virus exposure. The inoculated pigs developed a mild form of the disease, and the virus was isolated from tissues in the inoculated pigs up to 99 dpi (pigs were euthanized at 36, 65, 99 and 134 dpi). In-contact pigs showed mild or no clinical signs, but did become seropositive, and a transient viraemia was detected at 28 days post-exposure (dpe), thereby confirming late virus transmission from the inoculated pigs. Virus transmission to in-contact pigs occurred at four weeks post-exposure, over three months after the primary infection. These results highlight the potential role of survivor pigs in disease maintenance and dissemination in areas where moderate- to low-virulent viruses may be circulating undetected. This study will help design better and more effective control programmes to fight against this disease. PMID- 26432069 TI - Erratum to: The effect of vitamin D supplements on the severity of restless legs syndrome. PMID- 26432071 TI - A case of a perforated obturator hernia with a femoral abscess treated a pectineus muscle flap. AB - BACKGROUND: An obturator hernia accompanied with a femoral abscess is rare, and leads to severe infection. Repeated draining is often required due to remnant abscess. CASE PRESENTATION: We herein reported a case of a perforated obturator hernia with a femoral abscess that was successfully treated via repair using the pectineus muscle. An 84-year-old Japanese woman was referred to our hospital with appetite loss and right femoral pain. Abdominal computed tomography (CT) revealed a right obturator hernia and abscess spreading to the right thigh. Emergency surgery was performed. Intraoperative findings revealed that the abscess had formed because of a perforation in the small intestine by an incarcerated obturator hernia. We performed partial resection of the small intestine, repaired the hernial orifice, drained the right femoral abscess, and filled the cavity using the pectineus muscle. A residual abscess was not detectable following surgery, and the patient was discharged on postoperative day 63. CONCLUSION: Some patients with a perforated obturator hernia and femoral abscess have a residual abscess following surgery that requires redrainage. Nevertheless, we consider it possible to successfully treat a perforated obturator hernia with a femoral abscess via repair using the pectineus muscle. PMID- 26432070 TI - Improved long-term autonomic function following resolution of sleep-disordered breathing in preschool-aged children. AB - PURPOSE: Sleep-disordered breathing (SDB) prevalence peaks in preschool children and is associated with deficits in cardiovascular functioning during sleep. No long-term studies have investigated the effects of SDB resolution in mitigating these outcomes. We hypothesized that following 3 years, normalization of alterations to heart rate (HR), pulse transit time (PTT), heart rate variability (HRV), and urinary catecholamines identified at the initial diagnosis would be associated with resolution of SDB. METHODS: Forty-five children with SDB and 28 non-snoring controls underwent polysomnography at baseline (3-5 years) and follow up (6-9 years). Children were classified into control, resolved, and unresolved SDB. Resolution was defined as an obstructive apnea-hypopnea index (OAHI) <=1 event/h, no snoring on polysomnography (PSG), or indicated by parents. PTT is an inverse surrogate measure of blood pressure change. HRV was assessed using power spectral analysis. RESULTS: There was no change in PTT or HR between studies for any group. Our HRV data suggest reduced parasympathetic activity in children whose SDB resolved and increased parasympathetic activity in children whose SDB remained the same or worsened at follow-up. We identified a significant correlation between low frequency power and urinary dopamine and adrenaline levels at follow-up in the unresolved group, suggesting increased sympathetic activity in children with unresolved SDB. CONCLUSION: Our findings suggest an association between resolution of SDB and normalization of HRV in the long term in these preschool children and an augmented sympathetic activity in the children with residual SDB. This highlights the autonomic impact of SDB in young children and the importance of detection and treatment. PMID- 26432072 TI - Clinical and Imaging Follow-up Practices after Transarterial Therapy for Primary and Secondary Hepatic Malignancies: Results of an Online Survey. AB - RATIONALE AND OBJECTIVES: To characterize practices and quantify variation in longitudinal follow-up approaches among interventional radiologists (IRs) after liver transarterial locoregional therapy (LRT) in contemporary Interventional Oncology practice. MATERIALS AND METHODS: In November/December 2014, Society of Interventional Radiology members were invited to participate in a survey regarding clinical and imaging follow-up of liver cancer patients treated with transarterial LRT. On survey closure, responses were compiled and analyzed. RESULTS: The 30-item survey response rate was 11% (361 of 3290). Respondents were predominantly American IRs (311 of 355, 88%) who perform 1-5 LRTs monthly (196 of 354, 55%). Most (305 of 336, 91%) IRs reported longitudinal follow-up, with patient encounters within 1-month (73%, 211 of 290) postprocedure and every 3 months (68%, 196 of 287) thereafter and involvement in imaging (up to 80%, 235 of 290) ordering and evaluation. Preferred timing of first follow-up imaging (1 month vs. 3 months) and response criteria used (mRECIST favored) varied. CONCLUSIONS: Although IRs are actively involved in clinical and imaging follow-up of patients with liver malignancies treated with transarterial LRTs, there are differences in imaging frequency and response assessment. These data may serve as a starting point for standardization of LRT follow-up. PMID- 26432073 TI - 70-kVp High-pitch Computed Tomography Pulmonary Angiography with 40 mL Contrast Agent: Initial Experience. AB - RATIONALE AND OBJECTIVES: To assess image quality, radiation dose, and diagnostic accuracy of 70-kVp high-pitch computed tomography pulmonary angiography (CTPA) using 40 mL contrast agent and sinogram affirmed iterative reconstruction (SAFIRE) compared to 100-kVp CTPA using 60 mL contrast agent and filtered back projection. MATERIALS AND METHODS: Eighty patients underwent CTPA at either 70 kVp (group A, n = 40; 3.2 pitch, 40 mL contrast medium, and SAFIRE) or 100 kVp (group B, n = 40; 1.2 pitch, 60 mL contrast medium, and filtered back projection). Signal-to-noise ratio and contrast-to-noise ratio were calculated. Subjective image quality was evaluated using a five-grade scale, and diagnostic accuracy was assessed. Radiation doses were compared. RESULTS: Computed tomography values, signal-to-noise ratio, and contrast-to-noise ratio of pulmonary arteries were higher in group A compared to group B (all P < 0.001). Subjective image quality showed no difference between the two groups (P = 0.559) with good interobserver agreement (kappa = 0.647). No difference was found regarding diagnostic accuracy between the two groups (P > 0.05). The effective dose for group A was lower by 80% compared to group B (P < 0.001). CONCLUSIONS: 70-kVp high-pitch CTPA with reduced contrast media and SAFIRE provides comparable image quality and substantial radiation dose savings compared to a routine CTPA protocol. PMID- 26432074 TI - Increasing aclarubicin dosage of the conventional CAG (low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor) regimen is more efficacious as a salvage therapy than CAG for relapsed/refractory acute myeloid leukemia. AB - The efficacy and safety of a modified CAG (low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor) regimen with an increased aclarubicin dosage [high-dose (HD)-CAG] were observed in 145 patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and compared to the results of 172 patients treated with a conventional CAG regimen. The HD-CAG regimen showed both a higher complete remission (CR) rate (60.7% vs. 46.5%, P=0.013) and overall response (OR) rate (74.5% vs. 63.4%, P=0.039) than CAG. For patients aged <60 years, HD-CAG manifested an efficacy advantage over the CAG regimen (62.6% vs. 47.4%, P=0.015). The 4-year overall survival (OS) rate was 30.3%+/-13.2% with a median survival time of 19.0+/-5.4 months for patients re induced with the HD-CAG regimen, which showed no significant difference compared to the CAG regimen (with a 4-year OS rate of 18.2%+/-5.3% and a median survival time of 16.0+/-3.6 months, P=0.485). The main adverse effect was myelosuppression; platelet recovery over 50*10(9)/L was extended by the HD-CAG regimen (15 days vs. 10 days of the CAG regimen, P=0.003), which was tolerable and manageable. HD-CAG can safely improve efficacy compared to the CAG regimen and thus serves as an alternative treatment for R/R AML. PMID- 26432075 TI - Dissecting estimation of conductances in subthreshold regimes. AB - We study the influence of subthreshold activity in the estimation of synaptic conductances. It is known that differences between actual conductances and the estimated ones using linear regression methods can be huge in spiking regimes, so caution has been taken to remove spiking activity from experimental data before proceeding to linear estimation. However, not much attention has been paid to the influence of ionic currents active in the non-spiking regime where such linear methods are still profusely used. In this paper, we use conductance-based models to test this influence using several representative mechanisms to induce ionic subthreshold activity. In all the cases, we show that the currents activated during subthreshold activity can lead to significant errors when estimating synaptic conductance linearly. Thus, our results add a new warning message when extracting conductance traces from intracellular recordings and the conclusions concerning neuronal activity that can be drawn from them. Additionally, we present, as a proof of concept, an alternative method that takes into account the main nonlinear effects of specific ionic subthreshold currents. This method, based on the quadratization of the subthreshold dynamics, allows us to reduce the relative errors of the estimated conductances by more than one order of magnitude. In experimental conditions, under appropriate fitting to canonical models, it could be useful to obtain better estimations as well even under the presence of noise. PMID- 26432076 TI - Combination therapy for multidrug-resistant cytomegalovirus disease. AB - Multidrug-resistant (MDR) cytomegalovirus (CMV) emerged after transient responses to ganciclovir, foscarnet, and cidofovir in a CMV-seropositive recipient who underwent allogeneic hematopoietic stem cell transplantation from a CMV seronegative donor. Experimental treatments using leflunomide and artesunate failed. Re-transplantation from a CMV-seropositive donor supported by adoptive transfer of pp65-specific T cells and maribavir was followed by lasting suppression. This case illustrates that successful MDR CMV therapy may require individualized multidisciplinary approaches. PMID- 26432077 TI - Meaning is Not a Reflex: Context Dependence of Spatial Congruity Effects. AB - In two experiments, Brookshire, Ivry, and Casasanto (2010) showed that words with positive and negative emotional valence can activate spatial representations with a high degree of automaticity, but also that this activation is highly context dependent. Lebois, Wilson-Mendenhall, and Barsalou (2015) reported that they "aimed to replicate" our study but found only null results in the "Brookshire et al. replication" conditions. Here we express concerns about three aspects of this paper. First, the study was not an attempt to replicate ours; it was a different study that adapted our method. Second, Lebois et al. did not accurately represent our theoretical position. Third, Lebois et al.'s main conclusion, that spatial congruity effects depend on the task context, was not supported by their data. Despite these concerns, we agree with Lebois et al.'s overall message that spatial aspects of words' meanings are activated differently in different contexts. This was a main conclusion of our study as well. PMID- 26432078 TI - Capybara Bites: Report of Human Injury Caused by a Hydrochoerus hydrochaeris. AB - BACKGROUND: Health care demand due to animal bites is frequent, especially in the emergency department (ED). In addition to the physical trauma caused by bites, one should be concerned with infectious diseases that can be transmitted. The range of the lesions depends on the animal species. Bites of Hydrochoerus hydrochaeris (capybaras) in humans are relatively uncommon. Capybaras are docile animals; however, their large rodent incisive teeth could cause serious injury. Localized care, antibiotic therapy when necessary, careful examination of the structures, tetanus and rabies immunization as indicated, and follow-up are recommended for wild animal bites. The authors hereby describe and discuss the medical management of a case of multiple lesions from capybara bites on the right thigh of a man. CASE REPORT: A 54-year-old male patient was admitted to the ED with a compression bandage soaked with blood after being bitten by a capybara. At the clinical examination, the patient had two lacerating wounds and multiple abrasions on the anterior face of the right thigh. Rabies prophylaxis was administered and the wounds were irrigated and closed with sterile dressings. Oral amoxicillin/clavulanate potassium for 7 days was administered to the patient. The patient was followed up; 3 months after the attack he returned to his previous level of activity without any complication. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: We recommend that practitioners and physicians should provide prompt attention due to potentially significant morbidities, particularly rabies. The adequate care of the wound will allow better aesthetic and functional results to victims of wild animal bites. PMID- 26432079 TI - Diabetic Ketoacidosis Precipitated by Urachal Cyst Infection. PMID- 26432080 TI - Tracheal Intubation with a McGrath(r) Series 5 Video Laryngoscope by Novice Personnel in a Cervical-immobilized Manikin. AB - BACKGROUND: Prehospital tracheal intubation may be performed by novice intubators in cervical immobilized patients. However, most indirect laryngoscopes require special training. The McGrath(r) Series 5 video laryngoscope is similar to the Macintosh laryngoscope in shape and usage, yet still confers the advantages of having indirect laryngoscopes. OBJECTIVE: This study compared tracheal intubation by novice users, using the McGrath(r) Series 5 video laryngoscope vs. the Macintosh laryngoscope in a cervical immobilized manikin. METHODS: Thirty-eight nurses intubated the trachea of a manikin using a McGrath(r) Series 5 video laryngoscope and a Macintosh laryngoscope, in random order. Then they repeated the procedure in a manikin with a cervical collar. Success rate, time to success, number of intubation attempts, dental clicks, and difficulty score were compared between the two laryngoscopes. RESULTS: First-attempt success rate was higher for the McGrath(r) Series 5 compared to the Macintosh laryngoscope in cervical immobilizations (84.2% vs. 47.7%, respectively; p = 0.019). However, overall intubation success rate with and without the cervical collar was no different. Tracheal intubation using the McGrath(r) Series 5 was faster than the Macintosh laryngoscope regardless of the presence of a cervical collar. McGrath(r) Series 5 required fewer trials, had fewer dental clicks, and was easier to use than the Macintosh laryngoscope. CONCLUSIONS: McGrath(r) Series 5 video laryngoscope may be better than a standard Macintosh laryngoscope for novice intubators intubating the trachea in cervical immobilization, due to the higher first-attempt success rate, faster intubation time, fewer dental clicks, lower number of intubation attempts, and overall ease of use. PMID- 26432081 TI - High Body Mass Index is Strongly Correlated with Decreased Image Quality in Focused Bedside Echocardiography. AB - BACKGROUND: There is a well-established relationship between obesity, as measured by body mass index (BMI), and overall health risk. The presence of body fat is a known limitation to ultrasound, but it is unknown whether any decrease in quality due to obesity limits the interpretability of focused bedside echocardiography (FBE). OBJECTIVES: To correlate obesity, as measured by BMI, with image quality and interpretability of (FBE) performed by an emergency physician. METHODS: We conducted a prospective observational study in a convenience sample of adults presenting to two academic emergency departments (EDs) and a bariatric surgery outpatient clinic. Twenty patients were enrolled in each of three BMI categories, <30, 30-39, and >=40 kg/m(2). FBE was performed in multiple views in two positions. Images were rated for ability to discern the pericardial myocardial interface (PMI) and the endocardial border of the left ventricle (ELV). RESULTS: There were 23 males and 37 females enrolled. The median age was 49 years and the median BMI was 35.6 kg/m(2). There was a significant difference in the percentage of technically limited examinations between BMI categories for both PMI and ELV. There was an overall negative linear correlation between BMI and image quality for both PMI and ELV. CONCLUSION: There is an overall decrease in the quality of focused bedside echocardiographic images as BMI increases. This relationship exists for visualization of both the PMI and the ELV. Emergency physicians should be aware of the potential limitations of focused bedside echocardiography in this patient population. PMID- 26432082 TI - Giant Right Coronary Artery Aneurysm Masquerading as a Pulmonary Embolus. PMID- 26432083 TI - Identification of Peroneal Tenosynovitis by Point-of-Care Ultrasonography. AB - BACKGROUND: Ankle pain is a frequent chief complaint, and although peroneal tendon disorders are relatively uncommon, if treated inappropriately they may cause persistent pain and dysfunction. Peroneal tendon disorders, including the tendon sheath inflammatory condition tenosynovitis, are a major cause of chronic lateral ankle pain. Although magnetic resonance imaging has emerged as the modality of choice to assess the majority of these injuries, dynamic ultrasonography detects tendon pathology such as tenosynovitis. CASE REPORT: A 69 year-old woman presented to the Emergency Department (ED) after several months of atraumatic, progressive right foot and ankle pain. On physical examination, she had swelling and point tenderness posterior and inferior to the lateral malleolus, which was exacerbated by eversion. Plain radiography of the foot and ankle showed only soft tissue swelling. Bedside ultrasonography performed by the emergency physician quickly identified findings consistent with peroneal tenosynovitis without tears. Management with a walking boot and nonsteroidal antiinflammatory drugs was initiated prior to discharge. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: In this case of peroneal tenosynovitis, point-of care ultrasonography was used to promptly and accurately identify hyperemia, synovial thickening, and a marked effusion within the right peroneal tendon sheath. Nonoperative treatment of tenosynovitis was initiated in the ED while findings were subsequently confirmed with magnetic resonance imaging. Emergency physicians should be aware of the utility of identifying tenosynovitis by point of-care ultrasonography, which can expedite nonoperative management and prevent long-term complications. PMID- 26432084 TI - Ventriculoperitoneal Shunt Failure Presenting as Isolated Unilateral Abducens Nerve Palsy. PMID- 26432085 TI - Unusual Complication of a Central Venous Catheter in a Thoracoabdominal Trauma. PMID- 26432086 TI - In Reply to: Unusual Complication of a Central Venous Catheter in a Thoracoabdominal Trauma. PMID- 26432087 TI - The impact of glutathione S-transferase genotype and phenotype on the adverse drug reactions to azathioprine in patients with inflammatory bowel diseases. AB - Azathioprine (AZA) is a thiopurine prodrug which is widely used in patients with inflammatory bowel disease (IBD). However, the use is limited in one-third of patients because of adverse drug reactions (ADRs) or a lack of clinical response. It has been considered that the polymorphic enzyme thiopurine S-methyltransferase (TPMT) plays an important role in the in vivo process of AZA and the occurrence of its myelotoxicity. Glutathione S-transferase (GST) mutation is another pharmacogenetic polymorphism which is probably involved in AZA metabolism and tolerance. The aim of this study was to investigate the association among GST polymorphism, enzyme activity and AZA-related ADRs in Chinese Han patients with IBD. We found that the patients who became neutropenic had a significantly higher GSTs activity when compared with of the patients who did not develop ADRs (analysis of variance, P < 0.001). There was also a significant underrepresentation of GSTP1*-105V allele among patients developing ADRs (odds ratio [OR] = 0.125, 95% confidence interval [CI] = 0.022-0.709, P = 0.0012). The patients with higher GST activity constituted a pharmacogenetic high risk group for leucopenia during AZA treatment. GST-P1 Ile105/Ile105 genotype appeared to be a promising marker indicating predisposition to AZA-related ADRs. PMID- 26432088 TI - Spontaneous baroreceptor reflex sensitivity for risk stratification of heart failure patients: optimal cut-off and age effects. AB - Baroreceptor reflex sensitivity (BRS) is an important prognostic factor because a reduced BRS has been associated with an adverse cardiovascular outcome. The threshold for a 'reduced' BRS was established by the ATRAMI study at BRS <3 ms/mmHg in patients with a previous myocardial infarction, and has been shown to improve risk assessment in many other cardiac dysfunctions. The successful application of this cut-off to other populations suggests that it may reflect an inherent property of baroreflex functioning, so our goal is to investigate whether it represents a 'natural' partition of BRS values. As reduced baroreflex responsiveness is also associated with ageing, we investigated whether a BRS estimate <3 ms/mmHg could be the result of a process of physiological senescence as well as a sign of BRS dysfunction. This study involved 228 chronic heart failure patients and 60 age-matched controls. Our novel method combined transfer function BRS estimation and automatic clustering of BRS probability distributions, to define indicative levels of different BRS activities. The analysis produced a fit clustering (cophenetic correlation coefficient 0.9 out of 1) and identified one group of homogeneous patients (well separated from the others by 3 ms/mmHg) with an increased BRS-based mortality risk [hazard ratio (HR): 3.19 (1.73, 5.89), P<0.001]. The age-dependent BRS cut-off, estimated by 5% quantile regression of log (BRS) with age (considering the age-matched controls), provides a similar mortality value [HR: 2.44 (1.37, 4.43), P=0.003]. In conclusion, the 3 ms/mmHg cut-off identifies two large clusters of homogeneous heart failure (HF) patients, thus supporting the hypothesis of a natural cut-off in the HF population. Furthermore, age was found to have no statistical impact on risk assessment, suggesting that there is no need to establish age-based cut-offs because 3 ms/mmHg optimally identifies patients at high mortality risk. PMID- 26432089 TI - [Resistant fungi]. AB - Particularly in the area of hematology/oncology and intensive care medicine, infections due to resistant fungi are to be expected. Emergence of resistance in fungi is a less dynamic process than in bacteria; it can, however, have an equally important impact on treatment strategies. In the following article, the most important resistance patterns of yeasts and molds (Candida albicans , Aspergillus fumigatus, the order Mucorales and the genus Fusarium) will be presented and discussed. Their diagnosis mostly being based on blood cultures, resistance testing for yeasts is usually readily available. Culture-based therapeutic adjustments in mold infections are, however, only rarely possible, as most antifungal therapies for these infections are initiated on an empirical basis after identification of typical infiltrates on a CT scan. Response to therapy is then evaluated on the basis of clinical signs and symptoms in combination with follow-up CT scans. In case of therapeutic failure or appearance of suspicious infiltrates under antifungal prophylaxis, an open or CT-guided biopsy is recommended to allow efficient adaptation of antifungal treatment. In individual cases, particularly in patients diagnosed with mucormycosis, resection of the focus of infection may be necessary to achieve a satisfactory treatment response. PMID- 26432090 TI - Employing transposon mutagenesis to investigate foot-and-mouth disease virus replication. AB - Probing the molecular interactions within the foot-and-mouth disease virus (FMDV) RNA replication complex has been restricted in part by the lack of suitable reagents. Random insertional mutagenesis has proven an excellent method to reveal domains of proteins essential for virus replication as well as locations that can tolerate small genetic insertions. Such insertion sites can subsequently be adapted by the incorporation of commonly used epitope tags, facilitating their detection with commercially available reagents. In this study, we used random transposon-mediated mutagenesis to produce a library of 15 nt insertions in the FMDV nonstructural polyprotein. Using a replicon-based assay, we isolated multiple replication-competent as well as replication-defective insertions. We adapted the replication-competent insertion sites for the successful incorporation of epitope tags within FMDV non-structural proteins for use in a variety of downstream assays. Additionally, we showed that replication of some of the replication-defective insertion mutants could be rescued by co-transfection of a 'helper' replicon, demonstrating a novel use of random mutagenesis to identify intergenomic trans-complementation. Both the epitope tags and replication-defective insertions identified here will be valuable tools for probing interactions within picornavirus replication complexes. PMID- 26432091 TI - Efficacy of skin closure with subcuticular sutures for preventing wound infection after resection of colorectal cancer: a propensity score-matched analysis. AB - PURPOSE: The purpose of this study was to examine the efficacy of skin closure with subcuticular sutures for the prevention of wound infection after colorectal cancer resection. METHODS: Medical records of 1008 patients with colorectal cancer who underwent resection between 2006 and 2013 were reviewed. Patients were divided into two groups based on skin closure method: the subcuticular suture group (n = 323) and the staple group (n = 685). The incidence of wound infection was compared with and without propensity score matching, and multivariate analysis was performed to identify risk factors for wound infection. RESULTS: The incidence of wound infection was 3.1 % (10/323) in the subcuticular suture group and 10.4 % (71/685) in the staple group. After propensity score matching, the incidence of wound infection was significantly lower in the subcuticular suture group (4.6 %, 9/197) than in the staple group (12.2 %, 24/197) (p = 0.004). In the propensity score-matched cohort, multivariate analysis identified advanced age (odds ratio [OR], 1.07; 95 % confidence interval [CI], 1.03-1.12), higher preoperative body mass index (OR, 1.19; 95 % CI, 1.07-1.33), lower preoperative serum albumin (OR, 0.45; 95 % CI, 0.22-0.91), open surgery (OR, 3.28; 95 % CI, 1.38-8.49), and skin closure with staples (OR, 3.21; 95 % CI, 1.43-7.81) as independent risk factors for wound infection. CONCLUSIONS: Our results suggest that subcuticular suturing could be beneficial after colorectal cancer surgery. PMID- 26432092 TI - Novel Therapies in IBS-D Treatment. AB - OPINION STATEMENT: Irritable bowel syndrome (IBS) is a common gastrointestinal disease characterized by abdominal pain and change in bowel habits. IBS diarrhea predominant (IBS-D), which is arguably the most common subset of IBS, is also associated with rectal urgency, increased frequency, abdominal bloating, and loose to watery stools. Current treatments for diarrhea include mu-opioid agonists (i.e., loperamide, lomotil) and bile acid sequestrants (i.e., cholestyramine) while treatments for abdominal pain include antispasmodics (i.e., hyoscyamine, dicyclomine) and tricyclic antidepressants (i.e., amitriptyline). There are currently 3 FDA-approved treatments for IBS-D, which have been shown to improve both abdominal pain and diarrhea. Alosetron was initially approved by FDA 2000; however, its use is now limited to women with severe IBS-D symptoms refractory to other treatment. Eluxadoline, a mixed mu-opioid agonist, and rifaximin, a broad spectrum gut specific antibiotic, were both FDA approved in 2015. Eluxadoline has been shown to relieve abdominal pain and stool consistency in appropriate candidates. While large trials already showed the efficacy of rifaximin in treating non-constipated IBS for bloating, stool consistency, and abdominal pain, the recent TARGET 3 trial demonstrates that retreatment is also effective. While these new treatments significantly expand options for patients suffering from IBS-D, there is likely to remain a need for additional safe and effective therapies. PMID- 26432093 TI - Development and psychometric evaluation of a new patient -reported outcome measure for stroke self -management: The Southampton Stroke Self - Management Questionnaire (SSSMQ). AB - BACKGROUND: Self-management is important to the recovery and quality of life of people following stroke. Many interventions to support self-management following stroke have been developed, however to date no reliable and valid outcome measure exists to support their evaluation. This study outlines the development and preliminary investigation of the psychometric performance of a newly developed patient-reported outcome measure (PROM) of self-management competency following stroke; the Southampton Stroke Self-Management Questionnaire (SSSMQ). METHODS: A convenience sample of 87 people who had had a stroke completed responses to the SSSMQ, the Stroke Self-Efficacy Questionnaire and the Stroke Impact Scale. Scaling properties were assessed using Mokken Scale Analysis. Reliability and construct validity were assessed using intra-class correlation coefficient (ICC), Mokken and Cronbach's reliability coefficients and Spearman rank order correlations with relevant measures. RESULTS: Mokken scaling refined the SSSMQ to 28 scalable items. Internal consistency reliability (Mokken r = 0.89) and test retest reliability (ICC = 0.928) were excellent. Hypotheses of expected correlations with additional measures held, demonstrating good evidence for construct validity. CONCLUSIONS: Early findings suggest the Southampton Stroke Self-Management Questionnaire is a reliable and valid scale of self-management competency. The SSSMQ represents a potentially valid PROM for the evaluation of self-management following stroke. PMID- 26432095 TI - Metagenome-wide Association Studies Potentiate Precision Medicine for Rheumatoid Arthritis. PMID- 26432094 TI - Applications of Next-generation Sequencing in Systemic Autoimmune Diseases. AB - Systemic autoimmune diseases are a group of heterogeneous disorders caused by both genetic and environmental factors. Although numerous causal genes have been identified by genome-wide association studies (GWAS), these susceptibility genes are correlated to a relatively low disease risk, indicating that environmental factors also play an important role in the pathogenesis of disease. The intestinal microbiome, as the main symbiotic ecosystem between the host and host associated microorganisms, has been demonstrated to regulate the development of the body's immune system and is likely related to genetic mutations in systemic autoimmune diseases. Next-generation sequencing (NGS) technology, with high throughput capacity and accuracy, provides a powerful tool to discover genomic mutations, abnormal transcription and intestinal microbiome identification for autoimmune diseases. In this review, we briefly outlined the applications of NGS in systemic autoimmune diseases. This review may provide a reference for future studies in the pathogenesis of systemic autoimmune diseases. PMID- 26432096 TI - Modulation of risk/reward decision making by dopaminergic transmission within the basolateral amygdala. AB - RATIONALE: Dopamine (DA) transmission within cortico-limbic-striatal circuitry is integral in modulating decisions involving reward uncertainty. The basolateral amygdala (BLA) also plays a role in these processes, yet how DA transmission within this nucleus regulates cost/benefit decision making is unknown. OBJECTIVES: We investigated the contribution of DA transmission within the BLA to risk/reward decision making assessed with a probabilistic discounting task. METHODS: Rats were well-trained to choose between a small/certain reward and a large/risky reward, with the probability of obtaining the larger reward decreasing (100-12.5 %) or increasing (12.5-100 %) over a session. We examined the effects of antagonizing BLA D1 (SCH 23390, 0.1-1 MUg) or D2 (eticlopride, 0.1 1 MUg) receptors, as well as intra-BLA infusions of agonists for D1 (SKF 81297, 0.1-1 MUg) and D2 (quinpirole, 1-10 MUg) receptors. We also assessed how DA receptor stimulation may induce differential effects related to baseline levels of risky choice. RESULTS: BLA D1 receptor antagonism reduced risky choice by decreasing reward sensitivity, whereas D2 antagonism did not affect overall choice patterns. Stimulation of BLA D1 receptors optimized decision making in a baseline-dependent manner: in risk-averse rats, infusions of a lower dose of SKF81297 increased risky choice when reward probabilities were high (50 %), whereas in risk-prone rats, this drug reduced risky choice when probabilities were low (12.5 %). Quinpirole reduced risky choice in risk-prone rats, enhancing lose-shift behavior. CONCLUSIONS: These data highlight previously uncharacterized roles for BLA DA D1 and D2 receptors in biasing choice during risk/reward decision making through mediation of reward/negative feedback sensitivity. PMID- 26432097 TI - Transplantation of human Wharton's jelly-derived mesenchymal stem cells highly expressing TGFbeta receptors in a rabbit model of disc degeneration. AB - INTRODUCTION: Mesenchymal stem cells (MSCs) are widely considered to hold promise for the treatment of intervertebral disc (IVD) degeneration. However, variation in the therapeutic efficacy of MSCs is a major problem and the derivation of MSCs for use in IVD regeneration has not been optimized. Additionally, no data are available on the efficacy of Wharton's Jelly-derived MSC (WJ-MSC) transplantation in an animal model of IVD degeneration. METHODS: This study evaluated the effectiveness of a cross-linked hyaluronic acid (XHA) scaffold loaded with human WJ-MSCs, according to their expression levels of transforming growth factor-beta receptor I/activin-like kinase receptor 5 (TbetaRI/ALK5) and TbetaRII, for IVD regeneration in a rabbit model. We compared the degree of IVD regeneration between rabbits transplanted with a XHA scaffold loaded with WJ-MSCs highly and lowly expressing TbetaRI/ALK5 and TbetaRII (MSC-highTR and MSC-lowTR, respectively) using magnetic resonance imaging (MRI) and histological analysis. RESULTS: At 12 weeks after transplantation, T2-weighted MRI analysis showed significant restoration of the disc water content in rabbits treated with a MSC highTR-loaded XHA scaffold in comparison to rabbits treated with the scaffold alone or a MSC-lowTR-loaded XHA scaffold. In addition, morphological and histological analyses revealed that IVD regeneration was highest in rabbits transplanted with a MSC-highTR-loaded XHA scaffold. CONCLUSION: Taken together, our results suggest that a MSC-highTR-loaded XHA scaffold supports IVD regeneration more effectively than a MSC-lowTR-loaded XHA scaffold. This study supports the potential clinical use of MSC-highTR-loaded XHA scaffolds to halt IVD degeneration or to enhance IVD regeneration. PMID- 26432098 TI - Imaging of lumbar spinal surgery complications. AB - Lumbar spine surgery for spinal stenosis is a frequently performed procedure and was the fastest growing type of surgery in the US from 1980 to 2000. With increasing surgical invasiveness, postoperative complications also tend to be higher. Cross-sectional imaging techniques (CT and MRI) are more sensitive than radiographs and play an increasingly important role in evaluation of patients with lumbar spine surgery. Their use in patients with metallic implants is somewhat limited by artefacts, which can obscure pathology and decrease accuracy and reader confidence. Metal artefact reduction techniques have been developed, which can significantly improve image quality and enable early detection of postoperative complications. Complications can occur throughout postoperative course. Early complications include hardware displacement, incidental durotomy, postoperative collections-most commonly seroma, and less likely haematoma and/or infection. Incidental durotomy with CSF leak causing intracranial hypotension has characteristic MR brain findings and diagnosis of occult leak sites have been improved with use of dynamic CT myelography. Haematomas, even when compressing the thecal sac, are usually asymptomatic. Early infection, with nonspecific MR findings, can be diagnosed accurately using dual radiotracer studies. Delayed complications include loosening, hardware failure, symptomatic new or recurrent disc herniation, peri-/epidural fibrosis, arachnoiditis, and radiculitis. TEACHING POINTS: * CT and MRI play an increasingly important role in evaluation of patients with lumbar spine surgery * Complications can occur throughout the postoperative course and early detection is critical * Artefact reduction techniques can improve image quality for early and improved detection of complications. PMID- 26432099 TI - Differentiating the bipolar disorders from borderline personality disorder. AB - OBJECTIVE: To identify features differentiating bipolar disorder (BP) from borderline personality disorder (BPD) and with each condition variably defined. METHOD: Participants were assigned a BP or BPD diagnosis on the basis of DSM criteria and, separately, by clinical judgment, and undertook a diagnostic interview and completed self-report measures. RESULTS: Predictors of BPD status varied according to diagnostic decisions, but with the most consistent items being childhood sexual abuse, childhood depersonalization, personality variables relating to relationship difficulties and sensitivity to criticism, and the absence of any BP family history. Across diagnostic groups, personality measure items alone predicted diagnostic allocation with an accuracy of 81-84%, the refined study variables other than hypo/manic features improved the classification rates to 88%, and when the presence or absence of hypo/manic features was added, classification rates increased to 92-95%. CONCLUSION: Study findings indicate that BPD can be differentiated from BP with a high degree of accuracy. PMID- 26432100 TI - Neurosteroids; potential underpinning roles in maintaining homeostasis. AB - The neuroactive steroids which are synthesized in the brain and nervous system are known as "Neurosteroids". These steroids have crucial functions such as contributing to the myelination and organization of the brain connectivity. Under the stressful circumstances, the concentrations of neurosteroid products such as allopregnanolone (ALLO) and allotetrahydrodeoxycorticosterone (THDOC) alter. It has been suggested that these stress-derived neurosteroids modulate the physiological response to stress. Moreover, it has been demonstrated that the hypothalamic-pituitary-adrenal (HPA) axis mediates the physiological adaptation following stress in order to maintain homeostasis. Although several regulatory pathways have been introduced, the exact role of neurosteroids in controlling HPA axis is not clear to date. In this review, we intend to discern specific pathways associated with regulation of HPA axis in which neuroactive steroids have the main role. In this respect, we propose pathways that may be initiated after neurosteroidogenesis in different brain subregions following acute stress which are potentially capable of activating or inhibiting the HPA axis. PMID- 26432102 TI - Monitor launches inquiry after NHS trust ran up L29.5m deficit in five months. PMID- 26432101 TI - Characterization and expression analysis of adipokinetic hormone and its receptor in eusocial aphid Pseudoregma bambucicola. AB - Aphids display an extraordinary phenotypic plasticity ranging from widespread reproductive and wing polyphenisms to the occurrence of sterile or subfertile soldier morphs restricted to eusocial species of the subfamilies Eriosomatinae and Hormaphidinae. Individual morphs are specialized by their behavior, anatomy, and physiology to perform different roles in aphid societies at different stages of the life cycle. The capacity of the insects to cope with environmental stressors is under the control of a group of neuropeptides of the adipokinetic hormone/red pigment-concentrating hormone family (AKH/RPCH) that bind to a specific receptor (AKHR). Here, we describe the molecular characteristics of AKH and AKHR in the eusocial aphid Pseudoregma bambucicola. The sequence of the bioactive AKH decapeptide and the intron position in P. bambucicola AKH preprohormone were found to be identical to those in a phylogenetically distant aphid Dreyfusia spp. (Adelgidae). We detected four transcript variants of AKHR that are translated into three protein isoforms. Further, we analyzed AKH/AKHR expression in different tissues and insects of different castes. In wingless females, a remarkable amount of AKH mRNA was only expressed in the heads. In contrast, AKHR transcript levels increased in the order gutCT) in intron 13 of the albumin gene. The second patient had an acquired alteration with a drift of albumin mobility to the anode. This severely ill patient was on intra venous antibiotics and electrospray TOF MS showed a stuttered repetition of the 66,439/66,558Da albumin isoforms at multiples of 455 459Da corresponding to the covalent attachment of 1, 2, 3 and 4 molecules of flucloxacillin. This modification of +455Da was also detected in a control on a 1g/day oral dose of flucloxacillin. CONCLUSION: Both aberrations were associated with diminished albumin concentrations. The C-terminal truncation of Rugby Park (albumin, 29g/l) likely interferes with receptor binding and albumin scavenging, while the 20g/l albumin in the second patient was mostly due to renal disease. In both cases electrospray TOF MS proved a rapid (5min) sensitive (0.2MUl plasma) and highly informative way of analysing whole plasma or serum. PMID- 26432107 TI - Desmoplastic Melanoma Carries High Mutation Burden. AB - The first thorough sequencing of desmoplastic melanoma samples has shown that these tumors carry a median of 62 mutations per megabase-among the highest known for all cancers. The results suggest that patients may respond well to immunotherapy, which relies on detecting differences between normal and cancerous cells. PMID- 26432109 TI - Surgical diversity and evolution in cataract and refractive surgery. PMID- 26432108 TI - Molecular Heterogeneity and Receptor Coamplification Drive Resistance to Targeted Therapy in MET-Amplified Esophagogastric Cancer. AB - MET inhibition is effective in some patients with MET-amplified esophagogastric cancer (EGC), but understanding acquired and de novo resistance mechanisms will be critical to improving therapy. We identified KRAS mutation as a novel cause of acquired resistance in a patient after a 2-year response to a MET inhibitor. We also observed that 40% to 50% of patients with MET-amplified EGC harbor coamplification of HER2 and/or EGFR concurrently in the same tumor cells, which can drive de novo resistance. One patient with concurrent MET and HER2 amplification was refractory to HER2 blockade, but responded to combined MET/HER2 inhibition. We also found striking heterogeneity in MET amplification between distinct metastatic lesions and primary tumors in individual patients with EGC. In these patients, MET inhibition led to mixed responses and disease progression through outgrowth of non-MET-amplified clones, which could be monitored in circulating tumor DNA. Thus, receptor coamplification and molecular heterogeneity may be key drivers of clinical resistance in MET-amplified EGC. SIGNIFICANCE: Coamplification of driver oncogenes occurs frequently in EGC and can drive therapeutic resistance, supporting a role for comprehensive molecular analysis prior to targeted therapy. EGCs can also exhibit extensive heterogeneity in gene amplification between distinct tumor lesions within the same patient, suggesting that molecular profiling of a single-lesion biopsy may be insufficient to guide targeted therapy selection. PMID- 26432110 TI - New add-on intraocular lens for patients with age-related macular degeneration. AB - We present a new option for visual rehabilitation of patients with advanced macular degeneration and evaluate the outcomes in the first 8 patients who had implantation of the ciliary sulcus-fixated macular add-on intraocular lens (IOL) (Scharioth Macula Lens) at our institute. The surgical technique for implantation of the add-on IOL is described. Near vision improved in 7 eyes and was stable in 1 eye. The corrected near visual acuity improved by 4.4 lines with the macular add-on IOL at 15 cm versus with glasses at 40 cm; it improved by 2.1 lines with the macular add-on IOL at 15 cm versus with glasses at 15 cm. Distance vision was stable in all eyes. No intraoperative or postoperative complication occurred. The macular add-on IOL has the potential of improving near vision and reading ability in patients with advanced age-related macular degeneration. FINANCIAL DISCLOSURE: Dr. Scharioth is a consultant to Alcon Laboratories, Inc., and Medicontur Ltd. He is the inventor of the Scharioth Macula Lens and receives royalties. PMID- 26432111 TI - Suture-guided capsular tension ring insertion to reduce risk for iatrogenic zonular damage. AB - The capsular tension ring (CTR) is a useful device for managing a zonular dialysis. However, insertion of the CTR has potential complications. The CTR can damage zonular fibers during deployment into the capsular bag. Also, the angle and point of initial contact of the CTR with the capsular bag relative to the orientation of the dialysis must be considered to avoid damage to the zonular fibers. Adequate fill of the capsular bag with an ophthalmic viscosurgical device is important to minimize the risk for capsule entanglement with the leading eyelet of the CTR. A simple technique is described to prevent these complications. The technique can be used with both standard and modified CTRs. FINANCIAL DISCLOSURE: Dr. Page is a consultant to Bausch & Lomb, Inc. and Abbott Medical Optics, Inc. He has no financial or proprietary interest in any material or method mentioned. PMID- 26432112 TI - Range of refractive independence and mechanism of action of a corneal shape changing hydrogel inlay: results and theory. AB - PURPOSE: To demonstrate the independence of visual performance over a range of preoperative refraction and age in presbyopes implanted with a corneal shape changing inlay (Raindrop Near Vision Inlay). SETTING: Two multispecialty clinics, Monterrey and Tijuana, Mexico. DESIGN: Prospective case series. METHODS: The nondominant eyes of patients were implanted with the hydrogel corneal inlay beneath a femtosecond flap, centered on the pupil. Clinical outcomes included uncorrected near, intermediate, and distance visual acuity (UNVA, UIVA, and UDVA) and patient-assessed task performance in good light and dim light. Statistical analyses assessed the dependencies on preoperative age (45 to 60 years) and preoperative manifest refraction spherical equivalent (MRSE) (-0.5 to +1.5 diopters [D]). Using the inlay effect derived from wavefront measurements, an eye model was created through which letter charts were simulated. RESULTS: The study evaluated eyes of 188 patients. Postoperative UNVA, UIVA, and task performance at these distances in good light was independent of age and preoperative MRSE (P > .05). Postoperative UDVA was weakly dependent on preoperative MRSE, but distance task performance in good light was not (P > .05). In the treated eye, the mean postoperative UNVA was 20/25, UIVA was 20/25, and UDVA was 20/32. The clinical outcomes are explained by consideration of zones within the pupil generating good near, intermediate, and distance image quality. This was confirmed by visual acuity simulations. CONCLUSIONS: The continuous center-near power profile induced by the corneal shape-changing inlay provides good visual acuity and performance from distance through near over a 2.0 D range of preoperative refraction and presbyopic age. FINANCIAL DISCLOSURE: Drs. Steinert, Schwiegerling, Barragan Garza, and Chayet are consultants to Revision Optics, Inc. Drs. Lang and Holliday and Mr. Roy are employees of Revision Optics, Inc. Drs. Steinert, Schwiegerling, Barragan-Garza, and Chayet have no financial or proprietary interest in any material or method mentioned. PMID- 26432113 TI - Corneal sensitivity after small-incision lenticule extraction and laser in situ keratomileusis. AB - PURPOSE: To longitudinally evaluate corneal sensitivity after small-incision lenticule extraction and compare the results with those in previous studies. SETTING: London Vision Clinic, London, United Kingdom. DESIGN: Retrospective case series. METHODS: Consecutive myopic eyes treated with small-incision lenticule extraction using the Visumax femtosecond laser were studied. Corneal sensitivity was measured centrally and at 4 paracentral locations using a Cochet-Bonnet esthesiometer preoperatively and 1 day, 1 week, and 1, 3, 6, and 12 months postoperatively. Results were compared with averaged results from previous laser in situ keratomileusis (LASIK) and small-incision lenticule extraction studies. RESULTS: The mean spherical equivalent was -6.85 diopters (D) +/- 2.57 (SD). The mean age was 36 +/- 11 years. After small-incision lenticule extraction, the preoperative mean central corneal sensitivity dropped from 54 mm preoperatively to 33 mm 1 day postoperatively, rising to 40 mm, 45 mm, 48 mm, 54 mm, and 55 mm over 12 months; it reached baseline at 6 months (P > .05). For 21 LASIK studies, the mean central corneal sensitivity dropped from 56 mm preoperatively to 6 mm at 1 day, rising to 14 mm, 23 mm, 34 mm, 45 mm, and 51 mm over 12 months. For 8 small-incision lenticule extraction studies, central corneal sensitivity dropped from 57 mm preoperatively to 39 mm at 1 week, then rose to 39 mm, 42 mm, 49 mm, 52 mm, and 54 mm over 12 months; it was higher than after LASIK at 1 week and 1, 3, and 6 months (P < .05). CONCLUSION: Recovery of central corneal sensitivity to baseline was reached by 6 months after small-incision lenticule extraction and was higher than after LASIK for the first 6 months after surgery. FINANCIAL DISCLOSURE: Dr. Reinstein is a consultant to Carl Zeiss Meditec AG, has a proprietary interest in the Artemis technology (Arcscan, Inc.), and is an author of patents related to very high-frequency digital ultrasound administered by the Center for Technology Licensing at Cornell University, Ithaca, New York, USA. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 26432114 TI - Safety and efficacy of wavefront-guided myopic laser in situ keratomileusis using a new wavefront sensor technology: first 100 cases. AB - PURPOSE: To evaluate the safety and efficacy of wavefront-guided laser in situ keratomileusis (LASIK) for the correction of low to high myopia and myopic astigmatism using data derived from a new-generation Hartmann-Shack aberrometer. SETTING: Refractive Surgery Unit, Bordeaux Hospital University, France. DESIGN: Retrospective case series. METHODS: This retrospective study analyzed the initial group of eyes treated with wavefront-guided LASIK for myopia and myopic astigmatism using the Visx S4IR excimer laser and wavefront data derived from a new Hartmann-Shack aberrometer (iDesign Advanced Wavescan aberrometer). Refractive (refraction and refractive accuracy) and visual outcomes (uncorrected [UDVA] and corrected [CDVA] distance visual acuities) were recorded 3 months postoperatively. RESULTS: The study included 100 eyes of 50 consecutively treated patients. The mean decimal UDVA improved from 0.1 +/- 0.1 (SD) preoperatively to 1.1 +/- 0.15 postoperatively (P < .01). A monocular UDVA of 20/16, 20/20, and 20/25 were achieved in 76.6%, 94.4%, and 96.6% of eyes, respectively. The postoperative manifest spherical equivalent was within +/-0.5 diopter in all eyes. No eye lost 2 or more lines of CDVA, and 29.2% of the eyes gained 1 or more lines of CDVA. CONCLUSION: Wavefront-guided LASIK performed using data derived from the new Hartmann-Shack aberrometer was safe, effective, and predictable for treating myopia and myopic astigmatism. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26432115 TI - Femtosecond-assisted laser in situ keratomileusis for consecutive hyperopia after radial keratotomy. AB - PURPOSE: To evaluate femtosecond-assisted laser in situ keratomileusis (LASIK) for the treatment of hyperopic shift after radial keratotomy (RK). SETTING: Private practice, Siena, Italy. DESIGN: Prospective case series. METHODS: Eyes with a spherical equivalent (SE) of +1.0 diopters (D) to +4.0 D after RK with 6 or 8 incisions had LASIK. The flap (nominal thickness 130 MUm) was created with a femtosecond laser (LDV Z2); the refractive ablation was performed with an excimer laser (217P). The flap was dissected in a centrifugal fashion along previous RK cuts. RESULTS: Eighteen eyes of 10 patients were treated. Preoperatively, the mean defocus equivalent was 3.13 diopters (D) +/- 0.71 (SD); the corrected distance visual acuity (CDVA) was 0.09 +/- 0.06 logMAR. At 9 months, the mean defocus equivalent was 0.51 +/- 0.47 D (P < .05), with 13 eyes (72%) having 0.50 D or less of defocus equivalent and 16 eyes (89%) having 1.0 D or less of defocus equivalent. The mean CDVA was 0.04 +/- 0.06 logMAR (P < .05). No lines of logMAR CDVA were lost. The mean uncorrected distance visual acuity was 0.11 +/- 0.10 logMAR. The safety index was 1.11; the efficacy index was 0.97. No retreatments were performed. Flap complications were limited to an RK incision opening larger than 2 mm in 3 eyes and 1 case of a small, self-limiting epithelial ingrowth. CONCLUSION: Laser in situ keratomileusis with a low-energy femtosecond laser was a safe and effective approach to treat post-RK hyperopia, causing no relevant inflammation. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 26432116 TI - Hyperopic laser in situ keratomileusis: comparison of femtosecond laser and mechanical microkeratome flap creation. AB - PURPOSE: To evaluate and compare the refractive predictability and stability of laser in situ keratomileusis (LASIK) flap creation performed with a femtosecond laser and with a mechanical microkeratome to correct mild to moderate hyperopia. SETTING: American University of Beirut Medical Center, Beirut, Lebanon. DESIGN: Retrospective case series. METHODS: Patients who had hyperopic LASIK treatment using the Amaris excimer laser were included. Eyes in which the LDV femtosecond laser was used for flap creation were compared with eyes in which the Moria M2 microkeratome was used. RESULTS: The microkeratome group comprised 53 eyes and the femtosecond laser group, 72 eyes. Baseline characteristics were similar between groups (P > .05). The mean spherical equivalent (SE) deviation from target 1 week postoperatively was -0.08 diopter (D) +/- 0.58 (SD) in the femtosecond laser group and -0.06 +/- 0.87 D in the microkeratome group (P = .92). Thereafter, the mean SE deviation from target increased gradually and by 6 months postoperatively was +0.30 +/- 0.50 D and +0.70 +/- 0.71 D, respectively (P = .001). The correlation between the achieved and the attempted SE refraction was better in the femtosecond laser group (R(2) = 0.806) than the microkeratome group (R(2) = 0.671). CONCLUSIONS: Using the same nomogram, the short-term refractive outcomes of hyperopic LASIK with flap creation performed with the femtosecond laser were comparable to those for the microkeratome; however, the femtosecond group showed significantly better stability over the 6-month follow-up and better predictability, as reflected by a lower standard deviation and stronger Pearson correlation. FINANCIAL DISCLOSURE: Dr. Arba Mosquera is an employee of Schwind eye-tech-solutions GmbH and Co. KG. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 26432117 TI - New posterior chamber phakic intraocular lens for high myopia: three-year results. AB - PURPOSE: To present the 3-year results regarding the safety and efficacy of the Epi.Lens N, a new posterior chamber phakic intraocular lens (PC pIOL). SETTING: Eye Center, University Hospital Freiburg, Freiburg, Germany. DESIGN: Prospective clinical study. METHODS: A PC pIOL was implanted in highly myopic eyes of consecutive patients. Standardized follow-up examinations including uncorrected (UDVA) and corrected (CDVA) distance visual acuities and refractions were performed 1, 3, and 6 months and 1, 2, and 3 years postoperatively. RESULTS: The patient cohort consisted of 30 eyes of 16 patients. The study eyes had a mean manifest refraction spherical equivalent of -10.1 diopters (D) +/- 3.4 (SD), which decreased to -0.3 +/- 0.8 D postoperatively. After 3 years, all eyes achieved (47%) or exceeded (53%) their preoperative CDVA, thus improving the mean CDVA from 20/21 (0.94) preoperatively to 20/18 (1.14) postoperatively. The mean postoperative UDVA (20/20 [0.98]) resembled the preoperative CDVA (20/21 [0.94]). When analyzing all eyes with good visual potential (preoperative CDVA 20/20 or better; n = 18), 94% achieved a postoperative UDVA of 20/20 or better. One small diameter PC pIOL contacted the crystalline lens, which led to slight anterior subcapsular lens opacification. Despite this, the patient achieved a CDVA of 20/20. CONCLUSION: The 3-year results of this pilot study of a new PC pIOL showed good efficacy and safety. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26432118 TI - Posterior chamber phakic intraocular lens sizing based on iris pigment layer measurements by anterior segment optical coherence tomography. AB - PURPOSE: To use anterior segment optical coherence tomography (AS-OCT) to evaluate the clinical effectiveness of Implantable Collamer Lens posterior chamber phakic intraocular lens (PC pIOL) sizing based on measurement of the distance from the iris pigment end to the iris pigment end. SETTING: S. Fyodorov Eye Microsurgery Federal State Institution, Moscow, Russia. DESIGN: Evaluation of diagnostic test or technology. METHODS: Stage 1 was a prospective study. The sulcus-to-sulcus (STS) distance was measured using ultrasound biomicroscopy (UBM) (Vumax 2), and the distance from iris pigment end to iris pigment end was assessed using a proposed AS-OCT algorithm. Part 2 used retrospective data from patients after implantation of a PC pIOL with the size selected according to AS OCT (Visante) measurements of the distance from iris pigment end to iris pigment end. The PC pIOL vault was measured by AS-OCT, and adverse events were assessed. RESULTS: Stage 1 comprised 32 eyes of 32 myopic patients (mean age 28.4 years +/- 6.3 [SD]; mean spherical equivalent [SE] -13.11 +/- 4.28 diopters [D]). Stage 2 comprised 29 eyes of 16 patients (mean age 27.7 +/- 4.7 years; mean SE -16.55 +/- 3.65 D). The mean STS distance (12.35 +/- 0.47 mm) was similar to the mean distance from iris pigment end to iris pigment end distance (examiner 1: 12.36 +/ 0.51 mm; examiner 2: 12.37 +/- 0.53 mm). The PC pIOL sized using the new AS-OCT algorithm had a mean vault of 0.53 +/- 0.18 mm and did not produce adverse events during the 12-month follow-up. In 16 of 29 eyes, the PC pIOL vault was within an optimum interval (0.35 to 0.70 mm). CONCLUSION: The new measurement algorithm can be effectively used for PC pIOL sizing. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26432119 TI - Implantation of a diffractive trifocal intraocular lens: one-year follow-up. AB - PURPOSE: To evaluate the visual, refractive, contrast-sensitivity, and aberrometric outcomes during a 1-year follow-up after implantation of a trifocal intraocular lens (IOL). SETTING: Premium Clinic, Teplice, Czech Republic. DESIGN: Prospective case series. METHODS: This study included eyes of patients having cataract surgery with implantation of the trifocal IOL model AT Lisa tri 839MP. Distance, intermediate (66 and 80 cm), and near (33 and 40 cm) vision; contrast sensitivity; aberrometric outcomes; and the defocus curve were evaluated during a 12-month follow-up. The level of posterior capsule opacification (PCO) was also evaluated. RESULTS: In 120 eyes (60 patients), 1 month postoperatively, an improvement was observed in all visual parameters (P <= .03) except corrected near and intermediate visual acuities (both P >= .05). From 1 month to 12 months postoperatively, small but statistically significant changes were observed in uncorrected and corrected distance and near visual acuities (all P <= .03) and in uncorrected intermediate visual acuity (P = .01). In the defocus curve, no significant differences were found between visual acuities corresponding to defocus levels of -1.0 diopter (D) and -2.0 D (P = .22). The level of ocular spherical aberration decreased statistically significantly at 6 months (P < .001). Ocular and internal higher-order aberrations increased minimally but significantly from 6 to 12 months postoperatively (P < .001). The mean 12-month PCO score was 0.32 +/- 0.44 (SD). Four eyes (3.3%) required neodymium:YAG capsulotomy. CONCLUSION: The trifocal IOL provided complete and stable visual restoration after cataract surgery during a 12-month follow-up, with good levels of visual quality. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26432120 TI - Comparison of a trifocal intraocular lens with a +3.0 D bifocal IOL: results of a prospective randomized clinical trial. AB - PURPOSE: To compare visual outcomes in patients with cataract surgery and bilateral implantation of a trifocal or bifocal intraocular lens (IOL). SETTING: University Eye Clinic Maastricht, the Netherlands. DESIGN: Prospective randomized clinical trial. METHODS: Eyes with cataract and less than 1.0 diopter (D) of corneal astigmatism were randomized to receive bilateral implantation of Finevision Micro F trifocal IOLs or Acrysof IQ Restor +3.0 bifocal IOLs. Outcome measures were monocular and binocular uncorrected distance (UDVA), uncorrected intermediate (UIVA), and uncorrected near (UNVA) visual acuities; refractive outcomes; binocular defocus curve; contrast sensitivity; reading speed; patient satisfaction; and spectacle independence. RESULTS: Six months postoperatively, the mean binocular UDVA, UIVA, and UNVA in 56 eyes of 28 patients were 0.01 logMAR +/- 0.11 (SD), 0.32 +/- 0.15 logMAR, and 0.15 +/- 0.13 logMAR in the trifocal group (n = 15) and 0.00 +/- 0.09 logMAR, 0.28 +/- 0.08 logMAR, and 0.12 +/- 0.08 logMAR in the bifocal group (n = 13), respectively. The trifocal group showed a more continuous defocus curve and better results at -1.0 D of defocus (P < .01). The mean mesopic contrast sensitivity was higher in the bifocal group (P = .02). Complete spectacle independence was reported by 80% of trifocal patients and 50% of bifocal patients. There were no significant differences in refractive outcomes, reading speed, or patient satisfaction. CONCLUSION: This study showed noninferiority of visual outcomes with the trifocal IOL compared with the bifocal IOL, although the defocus curve was better at an intermediate distance with the trifocal IOL. FINANCIAL DISCLOSURE: Dr. Bauer received study grants from Alcon Laboratories, Inc., Carl Zeiss Meditec AG, and Physiol S.A. and a lecture fee from Alcon Surgical, Inc. Dr. Nuijts is a consultant to Alcon Surgical, Inc., Thea Pharma GmbH, and ASICO LLC; he has received study grants from Acufocus, Inc., Alcon Surgical, Inc., Carl Zeiss Meditec AG, Ophtec BV, and Physiol S.A. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 26432121 TI - Correction of low levels of astigmatism. AB - PURPOSE: To reevaluate the analysis of the correction of astigmatism. SETTING: Academia, industry, and private practice. DESIGN: Evaluation of diagnostic test or technology. METHODS: Astigmatic refractive surgery outcomes are based on vector methods, including the correction index (also known as the correction ratio), which is the ratio of the surgically induced astigmatism to the target induced astigmatism (TIA). Mean correction indices substantially greater than 1 have been reported for astigmatic corrections less than 1.00 diopter (D) and as representing systematic overcorrection. We hypothesize that this reflects a limitation of the correction index rather than systematic flaws in treatments. The theoretical mathematic behavior of the correction index was analyzed, accounting for variability in astigmatism measurement. Then, the impact of cylinder measurement variability on the mean correction index was modeled. A Monte Carlo simulation was performed and calculated 10 000 values of correction index for various values of TIA. Finally, correction indices from published and unpublished studies of refractive lasers were compared with the simulations. RESULTS: The mean correction index is always greater than 1 for the case of a perfect refractive correction; however, for astigmatic corrections less than 1.00 D, the mean correction index increases sharply because the measurement variability is similar in magnitude to TIA. Almost all previous studies show the predicted increase in the correction index for low astigmatic corrections. CONCLUSION: The correction index is a useful vector-based metric for the evaluation of refractive procedures, but mean values greater than 1 should be anticipated for lower astigmatic treatments and do not necessarily represent systematic overcorrection. FINANCIAL DISCLOSURE: Dr. Bullimore is a consultant to Alcon Surgical, Inc., Carl Zeiss Meditec AG, Digital Vision Systems, Essilor, Innovega, Inc., and Paragon Vision Sciences, Inc. Dr. Spooner is a consultant to Alcon Surgical, Inc., Carl Zeiss Meditec AG, Digital Vision Systems, Thru-Focus Optics LLC, and i2eyediagnostics, Ltd. Dr. Dishler is a consultant to Carl Zeiss Meditec AG and Revision Optics, Inc. Dr. Sluyterman is an employee of Carl Zeiss Meditec AG. PMID- 26432122 TI - Comparison of SRK/T and Haigis formulas for predicting corneal astigmatism correction with toric intraocular lenses. AB - PURPOSE: To compare the accuracy of the SRK/T and Haigis formulas for predicting corneal astigmatism correction with a toric intraocular lens (IOL). SETTING: Department of Ophthalmology, Korea University College of Medicine, Seoul, South Korea. DESIGN: Retrospective cross-sectional study. METHODS: Eyes with an Acrysof toric IOL were enrolled in the study. The corneal plane effective cylinder power of toric IOLs (target induced astigmatism vector [TIA]) predicted by the SRK/T and Haigis formulas were compared with the cylindrical correction achieved postoperatively (surgically induced astigmatism vector [SIA]). The magnitude of error was defined as the difference between the magnitudes of the SIA and TIA. The median absolute magnitudes of error predicted by the SRK/T and Haigis formulas were compared. The median absolute errors predicted by the 2 formulas were also compared. RESULTS: The mean postoperative SIA was 1.80 diopters (D) +/- 0.55 (SD). The magnitude of error predicted by the SRK/T and Haigis formulas was 0.31 +/- 0.40 D and 0.23 +/- 0.40 D, respectively. The median absolute magnitude of error predicted by the Haigis formula was statistically significantly smaller than that predicted by the SRK/T formula (P < .001). The median absolute error predicted by the Haigis formula (0.35 D) was also statistically significantly smaller than that predicted by the SRK/T formula (0.43 D) (P = .003). CONCLUSION: The Haigis formula was more accurate than the SRK/T formula not only in predicting the refractive outcome but also in predicting corneal astigmatism correction by toric IOLs. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26432123 TI - Comparison of corneal power, astigmatism, and wavefront aberration measurements obtained by a point-source color light-emitting diode-based topographer, a Placido-disk topographer, and a combined Placido and dual Scheimpflug device. AB - PURPOSE: To evaluate and compare the performance of a point-source color light emitting diode (LED)-based topographer (color-LED) in measuring anterior corneal power and aberrations with that of a Placido-disk topographer and a combined Placido and dual Scheimpflug device. SETTING: Cullen Eye Institute, Baylor College of Medicine, Houston, Texas USA. DESIGN: Retrospective observational case series. METHODS: Normal eyes and post-refractive-surgery eyes were consecutively measured using color-LED, Placido, and dual-Scheimpflug devices. The main outcome measures were anterior corneal power, astigmatism, and higher-order aberrations (HOAs) (6.0 mm pupil), which were compared using the t test. RESULTS: There were no statistically significant differences in corneal power measurements in normal and post-refractive surgery eyes and in astigmatism magnitude in post-refractive surgery eyes between the color-LED device and Placido or dual Scheimpflug devices (all P > .05). In normal eyes, there were no statistically significant differences in 3rd-order coma and 4th-order spherical aberration between the color-LED and Placido devices and in HOA root mean square, 3rd-order coma, 3rd order trefoil, 4th-order spherical aberration, and 4th-order secondary astigmatism between the color-LED and dual Scheimpflug devices (all P > .05). In post-refractive surgery eyes, the color-LED device agreed with the Placido and dual-Scheimpflug devices regarding 3rd-order coma and 4th-order spherical aberration (all P > .05). CONCLUSIONS: In normal and post-refractive surgery eyes, all 3 devices were comparable with respect to corneal power. The agreement in corneal aberrations varied. FINANCIAL DISCLOSURE: Drs. Wang, Koch, and Weikert are consultants to Ziemer Ophthalmic Systems AG. Dr. Koch is a consultant to Abbott Medical Optics, Inc., Alcon Surgical, Inc., and i-Optics Corp. PMID- 26432124 TI - Effect of tear osmolarity on repeatability of keratometry for cataract surgery planning. AB - PURPOSE: To evaluate the effects of tear osmolarity on the repeatability of keratometry (K) measurements in patients presenting for cataract surgery. SETTING: Three clinical practices. DESIGN: Observational prospective nonrandomized study. METHODS: Subjects were prospectively recruited based on tear osmolarity (Tearlab Osmolarity System); that is, osmolarity more than 316 mOsm/L in at least 1 eye (hyperosmolar) and osmolarity less than 308 mOsm/L in both eyes (normal). The baseline K value was measured, and a second measurement was taken on the same instrument (IOLMaster) within 3 weeks of the first. Variability in average K, calculated corneal astigmatism using vector analysis, and intraocular lens (IOL) sphere power calculations were compared between groups. RESULTS: The hyperosmolar group (50 subjects) had a statistically significantly higher variability in the average K reading (P = .05) than the normal group (25 subjects) and a statistically significantly higher percentage of eyes with a 1.0 diopter (D) or greater difference in the measured corneal astigmatism (P = .02). A statistically significantly higher percentage of eyes in the hyperosmolar group had an IOL power difference of more than 0.5 D (P = .02). No statistically significant differences were present when the subjects were grouped by self reported dry eye. CONCLUSIONS: Significantly more variability in average K and anterior corneal astigmatism was observed in the hyperosmolar group, with significant resultant differences in IOL power calculations. Variability was not significantly different when subjects were grouped by self-reported dry eye. Measurement of tear osmolarity at the time of cataract surgery planning can effectively identify patients with a higher likelihood of high unexpected refractive error resulting from inaccurate keratometry. FINANCIAL DISCLOSURE: Drs. Epitropoulos, Matossian, Berdy, and Malhotra received compensation from Tearlab for participating in the study. No author has a financial or proprietary interest in any material or method mentioned. PMID- 26432125 TI - Comparability of anterior chamber depth measurements with partial coherence interferometry and optical low-coherence reflectometry in pseudophakic eyes. AB - PURPOSE: To assess whether anterior chamber depth (ACD) measurements in pseudophakic eyes obtained with partial coherence interferometry (PCI) and optical low-coherence reflectometry (OLCR) devices can be used interchangeably. SETTING: Vienna Institute for Research in Ocular Surgery, A Karl Landsteiner Institute, Hanusch Hospital, Vienna, Austria. DESIGN: Prospective case series. METHODS: The ACD measurements in 1 eye of each pseudophakic patient were performed with the PCI-based ACMaster device and the OLCR-based Lenstar LS900 device at least 1 day postoperatively. RESULTS: The study comprised 65 eyes of 65 patients with a mean age of 71.7 years +/- 9.0 (SD) (range 39 to 91 years). In 15 eyes, no valid ACD readings could be obtained with the OLCR device. No obvious reason for these measurement failures was identified; however, tear-film alterations shortly after surgery were suspected. No significant difference in the mean ACD in the remaining 50 eyes was found between PCI measurements (5019 +/ 660 MUm; range 4008 to 6181 MUm) and OLCR measurements (5015 +/- 663 MUm; range 4017 to 6163 MUm) (P = .06). Three (6%) of 50 measurements were not within the 95% limits of agreement in the Bland-Altman analysis. CONCLUSIONS: Pseudophakic ACD measurements with the PCI and OLCR devices can be used interchangeably. The OLCR device proved to be more user-friendly and faster; however, in a substantial number of eyes, no usable values were obtainable. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26432126 TI - Pediatric bag-in-the-lens intraocular lens implantation: long-term follow-up. AB - PURPOSE: To evaluate long-term follow-up results of pediatric cataract surgery using the bag-in-the-lens (BIL) intraocular lens (IOL) implantation technique. SETTING: Antwerp University Hospital, Edegem, Antwerp, Belgium. DESIGN: Prospective case series. METHODS: All pediatric cataract surgeries with BIL IOL implantation performed at the Antwerp University Hospital were evaluated. Only cases that completed a follow-up of 5 years at the hospital's Department of Ophthalmology were included in this study. RESULTS: Forty-six eyes of 31 children had a complete follow-up of 5 years or more after BIL IOL implantation. Sixteen cases were unilateral and 15 were bilateral. Patient age at time of surgery ranged from 2 months to 14 years. The mean refraction at the end of follow-up was -1.99 diopters (D) +/- 3.70 (SD). In bilateral cases, a corrected distance visual acuity (CDVA) of better than 0.5 was attained in 86.7% and a CDVA of 1.0 was achieved in 56.7%. In unilateral cases, 31.2% achieved a CDVA of better than 0.5 but none obtained a CDVA of 1.0. A clear visual axis was maintained in 91.3% of cases during follow-up. Visual axis reopacification was detected in 4 eyes of 3 cases, all due to inadequate BIL IOL positioning. None of these eyes needed more than 1 intervention to maintain visual axis clarity. Other than 1 case of glaucoma, no severe complications were detected. CONCLUSION: Long-term follow-up results show that BIL IOL implantation is a safe, well-tolerated approach for treating pediatric cataract with a very low rate of visual axis reopacification and a low rate of secondary interventions for other postoperative complications. FINANCIAL DISCLOSURE: Dr. Tassignon has intellectual property rights to the bag in-the-lens intraocular lens (U.S. patent 6 027 531; EU patent 009406794.PCT/120268), which is licensed to Morcher GmbH, Stuttgart, Germany. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 26432127 TI - Traumatic cataracts secondary to combat ocular trauma. AB - PURPOSE: To describe the characteristics, visual outcomes, and predictive value of the Ocular Trauma Score (OTS) in eyes with traumatic cataract from combat ocular trauma. SETTING: Walter Reed Army Medical Center, Washington, DC, USA. DESIGN: Retrospective case series. METHODS: Records of service members with traumatic cataract from combat ocular trauma over a 7-year period were reviewed. Visual acuity at initial presentation and visual acuity at the final follow-up were compared in addition to outcomes in closed versus open globes, by final lens status, and in eyes receiving primary versus secondary intraocular lenses (IOLs). Visual outcomes were predicted using the OTS and compared to the achieved corrected distance visual acuity (CDVA). RESULTS: A total of 181 eyes of 167 patients were included in the final analysis. Twenty-six percent of all eye injuries sustained traumatic cataract. The mean final visual outcome was 0.86 logMAR +/- 1.01 (SD) with 44 no light perception (NLP) eyes and 26 light perception (LP) eyes compared with an initial visual acuity of 2.41 +/- 0.88 logMAR with 27 no NLP eyes and 64 LP eyes (P <= .001, 2-tailed Student t test). Final CDVAs in eyes receiving primary IOLs were 0.72 +/- 0.84 logMAR with 1 NLP and 1 LP eye versus 0.51 +/- 0.78 logMAR with 2 LP eyes in eyes receiving a secondary IOL (P = .37, Student t test). CONCLUSION: Traumatic cataracts are frequently associated with ocular trauma. The OTS is a reliable means of predicting visual outcome. There was no difference in eyes receiving primary IOLs versus secondary IOLs. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26432128 TI - Effect of a hyaluronic acid and carboxymethylcellulose ophthalmic solution on ocular comfort and tear-film instability after cataract surgery. AB - PURPOSE: To evaluate the efficacy and safety of using sodium hyaluronate 0.1% and carboxymethylcellulose 0.5% artificial tears for ocular discomfort and tear-film stability in eyes after cataract surgery. SETTING: Twenty ophthalmic centers in Italy. DESIGN: Prospective randomized case series. METHODS: This study enrolled patients scheduled for unilateral cataract surgery. After surgery, patients received artificial tears and a topical steroid-antibiotic (study group) or topical steroid-antibiotic alone (control group) and were assessed postoperatively at 1 and 5 weeks. Outcome measures were tear breakup time (TBUT), ocular surface disease index (OSDI), frequency of dry-eye symptoms evaluated using a visual analog scale (VAS), and corneal fluorescein staining. RESULTS: The study comprised 282 patients. At 5 weeks, the mean TBUT was statistically significantly higher in the study group than in the control group (P = .0003). The mean OSDI score statistically significantly improved in both groups from 1 to 5 weeks (P < .0001 for both groups); however, there was no statistically significant difference between the groups at these timepoints. The artificial tears statistically significantly improved VAS-assessed dry-eye symptoms in the study group compared with the control group at 5 weeks (P < .001). The mean corneal fluorescein staining was significantly reduced in the study group compared with the control group at 5 weeks (P = .002 versus P = .05, respectively). No treatment-related adverse events were reported. CONCLUSION: Sodium hyaluronate 0.1% and carboxymethylcellulose 0.5% ophthalmic solution was effective and well tolerated in reducing dry-eye disease symptoms and improving the clinical outcome after cataract surgery. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26432129 TI - Association between serum 25-hydroxyvitamin D levels and age-related cataracts. AB - PURPOSE: To investigate associations between serum 25-hydroxyvitamin D levels and age-related cataracts. SETTING: Department of Ophthalmology, College of Medicine, Catholic University of Korea, South Korea. DESIGN: Observational cross-sectional study. METHODS: Participants aged 40 years or older in the fourth (2008 to 2009) and fifth (2010 to 2012) Korea National Health and Nutrition Examination Survey (KNHANES) had evaluation of their serum 25-hydroxyvitamin D levels and ophthalmic slitlamp examinations to identify cataract. An age-related cataract was defined as the presence of a cortical, nuclear, anterior subcapsular, posterior subcapsular, or mixed cataract or a history of cataract surgery. RESULTS: The study evaluated eyes of 18 804 patients. The mean levels of serum 25 hydroxyvitamin D were 20.0 ng/mL in men and 17.5 ng/mL in women. In men, but not in women, the odds ratio (OR) for age-related cataracts decreased statistically significantly when the serum 25-hydroxyvitamin D levels were in the highest quintile than when they were in the lowest quintile (OR, 0.76; 95% confidence interval, 0.59-0.99) after adjusting for potentially confounding factors including age, sex, smoking status, diabetes, hypertension, and sunlight exposure. However, trend analysis did not show a significant declining trend in the cataract risk associated with higher serum 25-hydroxyvitamin D quintiles (P = .084). In women, serum 25-hydroxyvitamin D levels were not associated with age related cataracts. CONCLUSIONS: The age-related cataract risk decreased in men with higher serum 25-hydroxyvitamin D levels than in those with lower serum 25 hydroxyvitamin D levels after adjusting for potential confounding factors. In light of previous research indicating an antioxidative effect of vitamin D, the connection between vitamin D and age-related cataract warrants further study. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 26432130 TI - Efficacy and safety of combined cataract surgery with 2 trabecular microbypass stents versus ab interno trabeculotomy. AB - PURPOSE: To compare the outcomes of combined cataract surgery with trabecular microbypass stents and ab interno trabeculotomy in patients with open-angle glaucoma. SETTING: University of Toronto, Toronto, Ontario, and University of Montreal, Montreal, Quebec, Canada, and Glaucoma Associates of Texas, Dallas, Texas, USA. DESIGN: Retrospective case series. METHODS: Patients with primary open-angle, pseudoexfoliative, or pigmentary dispersion glaucoma were included. Primary outcome measures were intraocular pressure (IOP), postoperative medications, success (IOP <=18 mm Hg, no glaucoma medications or reoperations), and postoperative adverse events. RESULTS: The average patient age was 76.5 years +/- 12 [SD]. Forty-nine eyes had phacoemulsification and 2 had stent implantations; 52 eyes had phacoemulsification and trabeculotomy surgery with a 12-month postoperative follow-up. The analysis of variance indicated a significant reduction in mean IOP from baseline to 12 months for stent (19.6 +/- 5.3 mm Hg to 14.3 +/- 3.1 mm Hg; P < .001) and trabeculotomy (20.6 +/- 6.8 mm Hg to 17.3 +/- 6.5 mm Hg; P < .001) and lower mean IOP at 12 months in the stent group (P = .01). The median number of glaucoma medications decreased from baseline to 12 months in both groups and was lower in the stent group at 3, 6, and 12 months. Thirty-nine percent (19 eyes) in the stent group and 14% (7 eyes) in the trabeculotomy group achieved success at 12 months (P = .006). The incidence of hyphema was lower in the stent group (P = .008). CONCLUSIONS: Both types of surgery achieved a significant reduction in IOP and medication use at 12 months, with the stent group achieving higher success and a reduced incidence of postoperative hyphema. FINANCIAL DISCLOSURE: Dr. Ahmed is a consultant to and investigator for Glaukos Corp., Ivantis, Inc., Transcend Medical, Inc., and Aquesys, Inc., and has received speaker honoraria from Neomedix, Inc. Dr. Saheb has received travel funding from Glaukos Corp., Ivantis, Inc., and Transcend Medical, Inc., and a research grant from Ivantis, Inc. Dr. Harasymowycz has received a research grant from Ivantis, Inc. Dr. Fellman is a consultant to Endo Optiks, Inc., and has received honoraria from Optous and research funds from Ivantis, Inc., Glaukos Corp., and Transcend Medical, Inc. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 26432131 TI - Changes in intraocular pressure after cataract surgery: analysis of the Swedish National Cataract Register Data. AB - PURPOSE: To analyze changes in intraocular pressure (IOP) after cataract surgery based on data from the Swedish National Cataract Register (NCR). SETTING: Ophthalmic surgery units in Sweden. DESIGN: Prospective database study. METHODS: Data for 2012 through 2014 were obtained prospectively from the NCR. The outcome register of the NCR has collected data on IOP before and a mean of 37.7 days +/- 29.1 (SD) after cataract surgery since 2012. RESULTS: The analyses were based on 20 437 cataract extractions reported during 1 month each year to the outcome registry of the NCR. Cataract surgery was found to reduce IOP by a mean of 1.46 mm Hg, which was statistically significant (P < .001). A larger IOP reduction was seen in cases with a higher preoperative IOP (r = 0.557, P < .001). Older patients and shorter eyes had a greater IOP reduction after surgery (P < .001 and P = .001, respectively). Women had a greater IOP reduction than men (P = .04) When high IOP was given as an indication for surgery, the IOP reduction after cataract surgery was 5.50 mm Hg compared with a reduction of 1.40 mm Hg in patients for whom this indication was not given (P < .001). Patients with glaucoma or pseudoexfoliation (PXF) had a more pronounced IOP reduction than patients without these diagnoses (P < .001). CONCLUSION: Cataract surgery had an IOP-lowering effect, in particular in older patients, women, short eyes, eyes with high preoperative IOP, and eyes with glaucoma or PXF. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26432132 TI - Mechanical epithelial removal followed by corneal collagen crosslinking in progressive keratoconus: short-term complications. AB - PURPOSE: To compare the complications occurring within the first 3 months of corneal collagen crosslinking (CXL) performed with mechanical or transepithelial phototherapeutic keratectomy (PTK) epithelial removal in keratoconus patients. SETTING: Yildirim Beyazit University Ataturk Training and Research Hospital, Ankara, Turkey. DESIGN: Nonrandomized retrospective clinical study. METHODS: Eyes of consecutive progressive keratoconus patients who had PTK or mechanical epithelial removal followed by CXL were included. All patients were examined regularly until epithelial healing. Detailed ophthalmologic examinations were performed preoperatively and 1 and 3 months postoperatively. RESULTS: The study comprised 499 eyes (302 patients) that had transepithelial PTK (Group 1, 153 eyes) or mechanical epithelial removal (Group 2, 256 eyes) followed by CXL. Delayed epithelial healing occurred in 15.0% of eyes in Group 1 and 3.5% of eyes in Group 2 (P = .001). Epithelial hypertrophy occurred in 24.8% of eyes and 3.5% of eyes, respectively (P = .001). Salzmann-like epithelial nodules (2.6%), epithelial herpetic keratitis (1.9%), anterior uveitis (1.9%), and elevated intraocular pressure (1.9%) occurred in Group 1 only and infective keratitis (0.8%) in Group 2 only. Marked stromal edema and peripheral sterile infiltrates occurred at similar rates in both groups (P = .567 and P = .479, respectively). Grade 1+ corneal haze was significantly high in Group 2. Grade 2+ and 3+ haze was significantly high in Group 1 (P = .001). CONCLUSIONS: Ocular surface healing disorders were the most common early complications of CXL. Short-term complications were higher with the transepithelial PTK epithelial removal technique than with mechanical epithelial removal. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26432133 TI - Evaluation of stability and capsular bag opacification with a foldable intraocular lens coupled with a protective membrane in the rabbit model. AB - PURPOSE: To evaluate the stability and capsular bag opacification of a smooth or a patterned silicone protective membrane implanted in the bag with secondary placement of an intraocular lens (IOL). SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Twelve New Zealand rabbits had bilateral implantation of a protective membrane and an IOL or an IOL alone. Three groups of 8 eyes each received the IOL and the smooth protective membrane, the IOL and the patterned membrane, or the IOL alone. Slitlamp examination was performed weekly for 4 weeks. The rabbits were then humanely killed and their globes enucleated. Capsular bag opacification was scored based on the Miyake-Apple view, and the eyes underwent histopathology. RESULTS: At 4 weeks, the mean central posterior capsule opacification (PCO) score was 0.28 +/- 0.32 (SD) in all eyes with a protective membrane and 2.08 +/- 1.28 in eyes with the IOL alone (P < .00001, Student t test). Peripheral PCO and Soemmerring ring formation were also significantly less in eyes with the protective membrane. Histopathologically, the posterior capsules were relatively clear in most IOLs with the protective membrane. The smooth and patterned protective membranes showed a significant difference in overall capsular bag opacification formation compared with the IOLs without the membrane. CONCLUSIONS: The circular geometry of the protective membrane led to expansion of the capsular bag and appeared to prevent capsular bag opacification. Further studies are warranted to assess whether the pattern on the device's posterior surface further enhances this effect. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26432134 TI - Resistance force for intraocular lens insertion through lens cartridges and syringe-type injectors. AB - PURPOSE: To measure and compare the resistance force for intraocular lens (IOL) insertion using 5 syringe-type injector systems. SETTING: Tokyo Medical University and laboratory in Kowa Co., Tokyo, Japan. DESIGN: Experimental study. METHODS: Intraocular lenses were inserted into the lens capsular bag of porcine eyes after phacoemulsification using 5 implantation systems (Groups A, B, C, D, and E). For each system, the resistance force for IOL insertion to the lens capsular bag of porcine eyes was measured using an automated force gauge system. For control, the resistance force for IOL delivery into a plastic dish was measured. Changes in the resistance force and its curve and maximum value were evaluated. The mean total area under the curve (AUC) was compared. Data were statistically analyzed. RESULTS: For all groups, the mean resistance forces were 17.2, 6.3, 4.2, 20.7, and 2.3 newtons (N), respectively, in porcine eyes, and 14.4, 5.8, 4.5, 12.6, and 2.2 N in controls. The mean sizes of the total AUC were 43 371, 8465, 6771, 30 306, and 2334 pixels in porcine eyes and 40 940, 7080, 6876, 20 710, and 2215 pixels in controls; the correlation coefficients between the resistance forces and the sizes of the total area were 0.576, 0.113, 0.346, 0.726, and 0.933 in porcine eyes and 0.707, 0.557, 0.914, 0.951, and 0.893 in controls. CONCLUSION: Resistance force and its curve were clarified in 5 IOL implantation systems. Appropriate IOL and injector selection may be achieved after clarifying resistance force and its waveform during IOL insertion. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 26432135 TI - Effects of torsional movements in refractive procedures. AB - Using PubMed and our internal database, we extensively reviewed the literature on the history of measurement of torsional movements of the eye from 1963 to the present, focusing specifically on the implications of torsional measurement and compensation in corneal refractive and ocular surgery. Mean cyclotorsional movements observed in refractive surgery procedures have been reported to be around 3 degrees, which can be well controlled by the currently used technology. Torsional movements affect aberrations with a vectorial component (astigmatic procedures) more adversely. Currently available eye-registration technology provides an accuracy of +/-1.5 degrees. The vectorial components of residual aberrations can be minimized by intentionally underplanning the refractive treatments. The gaps in our knowledge limit the precision in current surgical procedures due to imperfect cyclotorsion compensation. This review summarizes about the explored aspects of torsional movements in surgical applications and raises questions about the unexplored implications. FINANCIAL DISCLOSURE: Dr. Arba Mosquera and Mr. Verma are employees of Schwind eye-tech-solutions GmbH and Co. KG. PMID- 26432136 TI - Femtosecond laser-assisted primary posterior capsulotomy for toric intraocular lens fixation and stabilization. AB - We describe 2 cases in which a spontaneously rotated toric intraocular lens (IOL) was fixated and stabilized using the femtosecond laser to create a primary posterior capsulotomy for posterior optic capture. We also review the literature on previous techniques that have been used to prevent or stabilize recurrent toric IOL rotation. The design of toric IOLs must be evaluated further to determine the risk for rotation in myopic eyes. FINANCIAL DISCLOSURE: Dr. Scott is a consultant to Abbott Medical Optics, Inc. Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 26432137 TI - Early-onset methicillin-resistant Staphylococcus aureus keratitis and late-onset infectious keratitis in astigmatic keratotomy incision following femtosecond laser-assisted cataract surgery. AB - A 79-year-old woman had uneventful femtosecond laser-assisted cataract surgery including paired laser astigmatic keratotomies (AKs) in the right eye. Three weeks postoperatively, a corneal infiltrate developed in the superotemporal AK incision. Cultures grew methicillin-resistant Staphylococcus aureus. The infection was treated with topical fortified vancomycin and tobramycin; full resolution required several months of therapy. Five months after cataract surgery, the patient presented with a second stromal infiltrate, also in the superotemporal AK incision. Despite negative cultures, the infiltrate resolved quickly on a short course of broad-spectrum fortified antibiotics. At 6 months, the corrected distance visual acuity was 20/30. This case demonstrates that infectious keratitis can occur following uneventful femtosecond laser-assisted AK performed concurrently with cataract surgery. We reviewed the literature on infectious keratitis following refractive keratotomy and femtosecond laser assisted procedures. Several recommendations to prevent these infections are proposed. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26432138 TI - Massilia timonae as cause of chronic endophthalmitis following cataract surgery. AB - This is the first report of chronic postoperative endophthalmitis caused by Massilia timonae. The gram-negative bacillus was isolated from a patient who developed chronic endophthalmitis after cataract extraction. The microorganism was cultured on brain-heart infusion broth and identified using the 16S rRNA sequence analysis. Biochemically, the organism was positive for catalase and oxidase and negative for arginine dihydrolase. It was pansensitive to beta lactams, fluoroquinolones, aminoglycosides, and trimethoprim-sulfamethoxazole but resistant to aztreonam. Massilia timonae is a new bacterium implicated in postoperative chronic endophthalmitis. Eubacterial polymerase chain reaction was useful in identifying M timonae because phenotyping testing and conventional algorithms could not identify it. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26432139 TI - Bibliometric analysis of literature on cataract research in PubMed (2001-2013). PMID- 26432140 TI - Association between age and incidence of posterior capsule rupture during cataract surgery: cross-sectional study. PMID- 26432141 TI - Structural changes of the anterior chamber following cataract surgery during infancy. PMID- 26432142 TI - Peaked Pupil One Day After Cataract Surgery: August consultation #1. PMID- 26432143 TI - August consultation #2. PMID- 26432144 TI - August consultation #3. PMID- 26432145 TI - August consultation #4. PMID- 26432146 TI - August consultation #5. PMID- 26432147 TI - August consultation #6. PMID- 26432148 TI - August consultation #7. PMID- 26432149 TI - August consultation #8. PMID- 26432150 TI - Potential confounding factors in a comparison of femtosecond laser-assisted cataract surgery versus standard phacoemulsification. PMID- 26432151 TI - Reply: To PMID 25466483. PMID- 26432152 TI - Other comparators for outcomes in treatment of astigmatism with toric intraocular lenses. PMID- 26432153 TI - Pain during phacoemulsification with and without cryoanalgesia. PMID- 26432154 TI - Reply: To PMID 25936681. PMID- 26432155 TI - Reply: To PMID 25840296. PMID- 26432156 TI - Influence of corneal asphericity on refractive outcomes after cataract surgery. PMID- 26432157 TI - Reply: To PMID 25840302. PMID- 26432158 TI - Generation of iPSC line MU011.A-hiPS from homozygous alpha-thalassemia fetal skin fibroblasts. AB - Human iPSC line MU011.A-hiPS was generated from homozygous alpha-thalassemia ( (SEA)/-(SEA)) fetal skin fibroblasts using a non-integrative reprogramming method. Reprogramming factors OCT3/4, SOX2, KLF4, L-MYC, LIN28, and shRNA of TP53 contained in three episomal vectors were delivered using electroporation. PMID- 26432159 TI - Roles of oxidative stress and the ERK1/2, PTEN and p70S6K signaling pathways in arsenite-induced autophagy. AB - Studies show that arsenite induces oxidative stress and modifies cellular function via phosphorylation of proteins and inhibition of DNA repair enzymes. Autophagy, which has multiple physiological and pathological roles in cellular function, is initiated by oxidative stress and is regulated by the signaling pathways of phosphatidylinositol 3-phosphate kinase (PI3K)/mammalian target of rapamycin (mTOR)/p70S6 kinase (p70S6K) and extracellular signaling-regulated protein kinase 1/2 (ERK1/2) that play important roles in oncogenesis. However, the effects of arsenite-induced oxidative stress on autophagy and on expression of related proteins are not fully understood. This study found that cells treated with sodium arsenite had reduced 8-oxoguanine DNA glycosylase 1 (OGG1) and increased 8-hydroxy-2'-deoxyguanosine (8-OHdG) and activating transcription factor (ATF) 3 in SV-40 immortalized human uroepithelial (SV-HUC-1) cells. Arsenite also increased the number of autophagosomes and increased levels of the autophagy markers Beclin-1 and microtubule-associated protein 1 light chain 3B. Reactive oxygen species scavenger decreased arsenite-induced autophagy in SV-HUC 1 cells. Our previous work showed that arsenite induced phosphorylation of the ERK1/2 signaling pathway. The current study further showed that arsenite decreased phosphatase and tensin homologue (PTEN) levels and increased phospho p70S6 kinase (p-p70S6K) in SV-HUC-1 cells. However, both kinase inhibitor U0126 and the DNA (cytosine-5-)-methyltransferase 1 (DNMT1) inhibitor 5-aza deoxycytidine abolished the effect of arsenite on expressions of PTEN and p p70S6K. These results show that autophagy induced by arsenite exposure is mediated by oxidative stress, which regulates activation of the PTEN, p70S6K and ERK1/2 signaling pathways. Thus, this study clarifies the role of autophagy in arsenite-induced urothelial carcinogenesis. PMID- 26432160 TI - Expression and functionality of transient receptor potential melastatin 4 (TRPM4) like channels during development of the zebrafish. AB - Calcium signaling, from localized spikes to coordinated waves, are linked to cleavage, patterning, differentiation, and growth during embryonic development. The basis for control of these Ca(2+) signals is poorly defined. In this study, the expression and functionality of the transient receptor potential melastatin 4 protein (TRPM4), an ion channel that controls Ca(2+) entry into cells, was examined in the zebrafish embryo and adult. Originating with the human TRPM4 gene, Ensembl ortholog, NCBI BLAST, and Homologene searches identified a zebrafish TRPM4 "like" gene encoding a predicted protein of 1199 amino acids and sharing a 42-43% sequence identity with the mouse, rat, and human. Custom designed zebrafish primers identified TRPM4 transcripts throughout the 0-123h period of embryonic development with greatest and lowest relative expression at 12 and 123h post-fertilization, respectively. Perforated patch clamp recordings in 27h embryonic cells revealed Ca(2+)-activated currents with the characteristics of those described for mammalian TRPM4. Similarly, TRPM4-like expression and functionality was observed in brain and liver cells from adult fish. These findings suggest that a TRPM4-like channel is available for Ca(2+) regulation during early development of the zebrafish. PMID- 26432161 TI - Gemfibrozil disrupts the metabolism of circulating lipids in bobwhite quails. AB - The circulating lipids of birds play essential roles for egg production and as an energy source for flight and thermogenesis. How lipid-lowering pharmaceuticals geared to prevent heart disease in humans and that are routinely released in the environment affect their metabolism is unknown. This study assesses the impact of the popular drug gemfibrozil (GEM) on the plasma phospholipids (PL), neutral lipids (NL), and nonesterified fatty acids (NEFA) of bobwhite quails (Colinus virginianus). Results show that bird lipoproteins are rapidly altered by GEM, even at environmentally-relevant doses. After 4 days of exposure, pharmacological amounts cause an 83% increase in circulating PL levels, a major decrease in average lipoprotein size measured as a 56% drop in the NL/PL ratio, and important changes in the fatty acid composition of PL and NEFA (increases in fatty acid unsaturation). The levels of PL carrying all individual fatty acids except arachidonate are strongly stimulated. The large decrease in bird lipoprotein size may reflect the effects seen in humans: lowering of LDL that can cause atherosclerosis and stimulation of HDL that promote cholesterol disposal. Lower (environmental) doses of GEM cause a reduction of %palmitate in all the plasma lipid fractions of quails, but particularly in the core triacylglycerol of lipoproteins (NL). No changes in mRNA levels of bird peroxisome proliferator activated receptor (PPAR) could be demonstrated. The disrupting effects of GEM on circulating lipids reported here suggest that the pervasive presence of this drug in the environment could jeopardize reproduction and migratory behaviours in wild birds. PMID- 26432162 TI - Comparison of the occurrence and survival of fecal indicator bacteria in recreational sand between urban beach, playground and sandbox settings in Toronto, Ontario. AB - While beach sands are increasingly being studied as a reservoir of fecal indicator bacteria (FIB), less is known about the occurrence of FIB in other recreational sands (i.e., sandboxes and playgrounds). In this study, different culture-based FIB enumeration techniques were compared and microbial source tracking assays were conducted on recreational sand samples from beaches, playgrounds and sandboxes around Toronto, ON. FIB were detected in every sand sample (n=104) with concentrations not changing significantly over the five month sampling period. Concentrations of FIB and a gull-specific DNA marker were significantly higher in foreshore beach sands, and indicated these were a more significant reservoir of FIB contamination than sandbox or playground sands. Human- and dog-specific contamination markers were not detected. All culture based FIB enumeration techniques were consistent in identifying the elevated FIB concentrations associated with foreshore beach sands. However, significant differences between differential agar media, IDEXX and Aquagenx Compartment Bag Test were observed, with DC media and Enterolert being the most sensitive methods to detect Escherichia coli and enterococci, respectively. To better understand the elevated occurrence of E. coli in foreshore sands, microcosm survival experiments were conducted at two different temperatures (15 degrees C and 28 degrees C) using non-sterile saturated foreshore beach sands collected from two urban freshwater beaches with different sand type (fine grain and sand-cobble). Microcosms were inoculated with a mixture of eight sand-derived E. coli strains and sampled over a 28-day period. E. coli levels were found to decline in all microcosms, although survival was significantly greater in the finer sand and at the cooler temperature (15 degrees C). These results indicate that FIB can be widespread in any type of recreational sand and, while E. coli can survive for many weeks, it is most likely to accumulate in cooler fine-grain sand as occurs below the foreshore sand surface. PMID- 26432163 TI - Clinical Practice Guidelines for the Management of Gastroesophageal Reflux and Gastroesophageal Reflux Disease: 1 Year to 18 Years of Age. PMID- 26432164 TI - The regulatory roles of non-coding RNAs in nerve injury and regeneration. AB - Non-coding RNAs (ncRNAs), especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have attracted much attention since their regulatory roles in diverse cell processes were recognized. Emerging studies demonstrate that many ncRNAs are differentially expressed after injury to the nervous system, significantly affecting nerve regeneration. In this review, we compile the miRNAs and lncRNAs that have been reported to be dysregulated following a variety of central and peripheral nerve injuries, including acquired brain injury, spinal cord injury, and peripheral nerve injury. We also list investigations on how these miRNAs and lncRNAs exert the regulatory actions in neurodegenerative and neuroregenerative processes through different mechanisms involving their interaction with target coding genes. We believe that comprehension of the expression profiles and the possible functions of ncRNAs during the processes of nerve injury and regeneration will help understand the molecular mechanisms responsible for post nerve-injury changes, and may contribute to the potential use of ncRNAs as a diagnostic marker and therapeutic target for nerve injury. PMID- 26432165 TI - Atypical presentation of Charcot-Marie-Tooth disease 1A: A case report. AB - Charcot-Marie-Tooth (CMT) 1A is the most common form of CMT disease and is characterized by duplication of Peripheral myelin protein 22 (PMP22) gene. We report a boy with genetically confirmed CMT1A disease having clinical involvement of hypoglossal and glossopharyngeal nerves, as well as asymmetrical and primarily upper limb involvement. These atypical features widen the clinical spectrum of CMT1A, leading to interesting observations about PMP22 gene related disorders and varied clinical expression of similar genetic mutations. PMID- 26432166 TI - Tebuconazole disrupts steroidogenesis in Xenopus laevis. AB - A 27-day controlled exposure study of adult male African clawed frogs (Xenopus laevis) was conducted to examine the mechanism by which tebuconazole may disrupt steroidogenesis. The fungicide was measured by LC-MS/MS in tank water and in target tissues (adipose, kidney, liver, and brain), and we observed tissue specific bioconcentration with BCF up to 238. Up to 10 different steroid hormones were quantified in gonads using LC-MS/MS and in plasma using GC-MS/MS and a radioimmunoassay was performed for further measurement of androgens. In order to assess whether effects increased with exposure or animals adapted to the xenobiotic, blood samples were collected 12 days into the study and at termination (day 27). After 12 days of exposure to 100 and 500MUgL(-1) tebuconazole, plasma levels of testosterone (T) and dihydrotestosterone (DHT) were increased, while plasma 17beta-estradiol (E2) concentrations were greatly reduced. Exposure to 0.1MUgL(-1), on the other hand, resulted in decreased levels of T and DHT, with no effects observed for E2. After 27 days of exposure, effects were no longer observed in circulating androgen levels while the suppressive effect on E2 persisted in the two high-exposure groups (100 and 500MUgL(-1)). Furthermore, tebuconazole increased gonadal concentrations of T and DHT as well as expression of the enzyme CYP17 (500MUgL(-1), 27 days). These results suggest that tebuconazole exposure may supress the action of CYP17 at the lowest exposure (0.1MUgL(-1)), while CYP19 suppression dominates at higher exposure concentrations (increased androgens and decreased E2). Increased androgen levels in plasma half-way into the study and in gonads at termination may thus be explained by compensatory mechanisms, mediated through increased enzymatic expression, as prolonged exposure had no effect on circulating androgen levels. PMID- 26432167 TI - Associations between the neighbourhood built environment and out of school physical activity and active travel: An examination from the Kids in the City study. AB - This study's aim was to examine selected objectively-measured and child specific built environment attributes in relation to proportion of out-of-school time spent in moderate-to-vigorous physical activity (%MVPA) and active travel in a group of ethnically and socio-economically diverse children (n=236) living in Auckland, New Zealand. Street connectivity and distance to school were related to the proportion of trips made by active modes. Ratio of high speed to low speed roads and improved streetscape for active travel were related to %MVPA on weekdays only. Inconsistent results were found for destination accessibility. Local destinations (particularly schools) along a safe street network may be important for encouraging children's activity behaviours. PMID- 26432168 TI - Uncovering the function of Disrupted in Schizophrenia 1 through interactions with the cAMP phosphodiesterase PDE4: Contributions of the Houslay lab to molecular psychiatry. AB - Nearly 10years ago the laboratory of Miles Houslay was part of a collaboration which identified and characterized the interaction between Disrupted in Schizophrenia 1 and phosphodiesterase type 4. This work has had significant impact on our thinking of psychiatric illness causation and the potential for therapeutics. PMID- 26432169 TI - Phosphoinositide-dependent kinase-1 inhibits TRAF6 ubiquitination by interrupting the formation of TAK1-TAB2 complex in TLR4 signaling. AB - Phosphoinositide-dependent protein kinase 1 (PDK1) plays a key role in the phosphoinositide 3-kinase (PI3K)-PDK1-Akt pathway that induces cell survival and cardiovascular protections through anti-apoptosis, vasodilation, anti inflammation, and anti-oxidative stress activities. Although several reports have proposed the negative role of PDK1 in Toll-like receptor 4 (TLR4) signaling, the molecular mechanism is still unknown. Here we show that PDK1 inhibits tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) ubiquitination by interrupting the complex between transforming growth factor beta-activated kinase 1 (TAK1) and TAK1 binding protein 2 (TAB2), which negatively regulates TAK1 activity. The overexpression of PDK1 in 293/TLR4 cells resulted in suppressions of nuclear factor kappa B (NF-kappaB) activation and production of proinflammatory cytokines including interleukin (IL)-6 and TNF-alpha in response to lipopolysaccharide stimulation. Conversely, THP-1 human monocytes transiently cultured in low glucose medium displayed down-regulated PDK1 expression, and significantly enhanced TLR4-mediated signaling for the activation of NF-kappaB, demonstrating a negative role of PDK1. Biochemical studies revealed that PDK1 significantly interacted with TAK1, resulting in the inhibition of the association of TAB2 with TAK1, which led to the attenuation of TRAF6 ubiquitination. Moreover, PDK1-knockdown THP-1 cells displayed enhancement of downstream signals, activation of NF-kappaB, and increased production of pro inflammatory cytokines IL-6, IL-1beta, and TNF-alpha, which potentially led to the up-regulation of NF-kappaB-dependent genes in response to TLR4 stimulation. Collectively, the results demonstrate that PDK1 inhibits the formation of the TAK1-TAB2-TRAF6 complex and leads to the inhibition of TRAF6 ubiquitination, which negatively regulates the TLR4-mediated signaling for NF-kappaB activation. PMID- 26432170 TI - Distinct biological activity of threonine monophosphorylated MAPK isoforms during the stress response in fission yeast. AB - Mitogen-activated protein kinases (MAPKs) define a specific group of eukaryotic protein kinases which regulate a number of cellular functions by transducing extracellular signals to intracellular responses. Unlike other protein kinases, catalytic activation of MAPKs by MAPKKs depends on dual phosphorylation at two tyrosine and threonine residues within the conserved TXY motif, and this has been proposed to occur in an ordered fashion, where the initial phosphorylation on tyrosine is followed by phosphorylation at the threonine residue. However, monophosphorylated MAPKs also exist in vivo, and although threonine phosphorylated isoforms retain some catalytic activity, their functional significance remains to be further elucidated. In the fission yeast Schizosaccharomyces pombe MAPKs Sty1 and Pmk1 control multiple aspects of fission yeast life cycle, including morphogenesis, cell cycle, and cellular response to a variety of stressful situations. In this work we show that a trapping mechanism increases MAPKK binding and tyrosine phosphorylation of both Sty1 and Pmk1 when subsequent phosphorylation at threonine is hampered, indicating that a sequential and likely processive mechanism might be responsible for MAPK activation in this simple organism. Whereas threonine-monophosphorylated Sty1 showed a limited biological activity particularly at the transcriptional level, threonine monophosphorylated Pmk1 was able to execute most of the biological functions of the dually phosphorylated kinase. Thus, threonine monophosphorylated MAPKs might display distinct functional relevance among eukaryotes. PMID- 26432171 TI - p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. AB - p62/SQSTM1 is a stress-inducible cellular protein that is conserved among metazoans but not in plants and fungi. p62/SQSTM1 has multiple domains that mediate its interactions with various binding partners and it serves as a signaling hub for diverse cellular events such as amino acid sensing and the oxidative stress response. In addition, p62/SQSTM1 functions as a selective autophagy receptor for degradation of ubiqutinated substrates. In the present review, we describe the current knowledge about p62 with regard to mammalian target of rapamycin complex 1 activation, the Keap1-Nrf2 pathway and selective autophagy. PMID- 26432172 TI - Prediction of treatment discontinuation and recovery from Borderline Personality Disorder: Results from an RCT comparing Schema Therapy and Transference Focused Psychotherapy. AB - Knowing what predicts discontinuation or success of psychotherapies for Borderline Personality Disorder (BPD) is important to improve treatments. Many variables have been reported in the literature, but replication is needed and investigating what therapy process underlies the findings is necessary to understand why variables predict outcome. Using data of an RCT comparing Schema Therapy and Transference Focused Psychotherapy as treatments for BPD, variables derived from the literature were tested as predictors of discontinuation and treatment success. Participants were 86 adult outpatients (80 women, mean age 30.5 years) with a primary diagnosis of BPD who had on average received 3 previous treatment modalities. First, single predictors were tested with logistic regression, controlling for treatment type (and medication use in case of treatment success). Next, with multivariate backward logistic regression essential predictors were detected. Baseline hostility and childhood physical abuse predicted treatment discontinuation. Baseline subjective burden of dissociation predicted a smaller chance of recovery. A second study demonstrated that in-session dissociation, assessed from session audiotapes, mediated the observed effects of baseline dissociation on recovery, indicating that dissociation during sessions interferes with treatment effectiveness. The results suggest that specifically addressing high hostility, childhood abuse, and in session dissociation might reduce dropout and lack of effectiveness of treatment. PMID- 26432173 TI - Predictors of response to CBT and IPT for depression; the contribution of therapy process. AB - Little is known about the factors that contribute to a positive psychotherapy outcome. There is still considerable debate as to whether specific factors (e.g. severity of symptoms, comorbidity) or nonspecific factors (e.g. alliance, therapy process) are most important in influencing outcome. This study examined the additional contribution that therapeutic process and alliance made to previously identified specific predictors of response to CBT and IPT for depression over the course of therapy. The previously identified specific factors were belief that childhood reasons caused the depression, recurrent depression, perceptions about how logical therapy was and comorbid personality disorder symptoms. One hundred and sixty five adult outpatients with major depression were treated for depression in a randomised clinical trial examining predictors of response to Cognitive Behavior Therapy and Interpersonal Psychotherapy. All therapy sessions were audiorecorded to enable objective ratings of therapeutic process and alliance. Process factors - patient psychic distress, patient participation and patient alliance had the strongest associations with outcome. The early and middle stage of therapy process did not account for any additional variance other than that previously identified by the patient predictors, however, at the end stage of therapy process contributed a further 14%. PMID- 26432175 TI - Commitment questions targeting patients promotes uptake of under-used health services: Findings from a national quality improvement program in Australia. AB - RATIONALE: Interventions asking patients to commit to speaking with their doctor about a health-related issue could be used to improve quality of care. OBJECTIVE: To evaluate the impact of commitment questions targeting patients on the uptake of recommended health services within a national quality improvement program (Veterans' MATES). METHODS: Patients targeted in the home medicines reviews (HMRs), dose administration aids (DAAs), renal function testing and diabetes interventions were posted educational information and response forms which asked whether they intended to talk to their general practitioner (GP) about the targeted service. Uptake of the service after each intervention was determined using health claims data. Log binomial regression models compared the monthly rate of service use in the nine months post-intervention among patients answering 'yes' to a commitment question with non-responders and patients answering 'no' or 'unsure'. RESULTS: Each intervention targeted up to 58,000 patients. The average response rate was 28%. Positive responses were associated with increased uptake of HMRs (rate ratio (RR) 2.64, 95% CI 2.39-2.92; p < 0.0001), dose administration aids (RR 2.53, 95% CI 2.29-2.79; p < 0.0001), renal function tests (RR 1.18, 95% CI 1.13-1.24; p < 0.0001), GP management plans (RR 1.30, 95% CI 1.14-1.48; p < 0.0001) and diabetes care plans (RR 1.47, 95% CI 1.24-1.75; p < 0.0001) compared to non-responders. Similar increases in uptake were also observed among positive responders when compared to patients responding 'no' or 'unsure' to the commitment question. CONCLUSION: Positive responses to commitment questions distributed as part of national, multifaceted interventions were consistently associated with increased uptake of targeted services. PMID- 26432176 TI - Controlled but not cured: Structural processes and explanatory models of Chagas disease in tropical Bolivia. AB - Dressler (2001:456) characterizes medical anthropology as divided between two poles: the constructivist, which focuses on the "meaning and significance that events have for people," and the structuralist, which emphasizes socioeconomic processes and relationships. This study synthesizes structuralist and constructivist perspectives by investigating how structural processes impact explanatory models of Chagas disease in a highly endemic area. The research took place from March-June 2013 through the Centro Medico Humberto Parra, a non-profit clinic servicing low income populations in Palacios, Bolivia and surrounding communities. Semistructured interviews (n = 68) and consensus analysis questionnaires (n = 48) were administered to people dealing with Chagas disease. In the interview narratives, respondents link Chagas disease with experiences of marginalization and rural poverty, and describe multilayered impediments to accessing treatment. They often view the disease as incurable, but this reflects inconsistent messages from the biomedical system. The consensus analysis results show strong agreement on knowledge of the vector, ethnomedical treatment, and structural factors related to Chagas disease. In interpreting Chagas disease, respondents account for the structural factors which place them at risk and impede access to care. PMID- 26432174 TI - Cocaine choice procedures in animals, humans, and treatment-seekers: Can we bridge the divide? AB - Individuals with cocaine use disorder chronically self-administer cocaine to the detriment of other rewarding activities, a phenomenon best modeled in laboratory drug-choice procedures. These procedures can evaluate the reinforcing effects of drugs versus comparably valuable alternatives under multiple behavioral arrangements and schedules of reinforcement. However, assessing drug-choice in treatment-seeking or abstaining humans poses unique challenges: for ethical reasons, these populations typically cannot receive active drugs during research studies. Researchers have thus needed to rely on alternative approaches that approximate drug-choice behavior or assess more general forms of decision-making, but whether these alternatives have relevance to real-world drug-taking that can inform clinical trials is not well-understood. In this mini-review, we (A) summarize several important modulatory variables that influence cocaine choice in nonhuman animals and non-treatment seeking humans; (B) discuss some of the ethical considerations that could arise if treatment-seekers are enrolled in drug choice studies; (C) consider the efficacy of alternative procedures, including non-drug-related decision-making and 'simulated' drug-choice (a choice is made, but no drug is administered) to approximate drug choice; and (D) suggest opportunities for new translational work to bridge the current divide between preclinical and clinical research. PMID- 26432177 TI - [Facial palsy sequel and botulinum toxin]. AB - Medical treatment of facial paralysis sequel is an essential part of the overall management of this pathology. The use of botulinum toxin has revolutionized results in greatly improving facial symmetry. The toxin can be used either the healthy side of the face by treating the compensatory hyperactivity of non paralyzed side of the face or the paralyzed side (in the spastic forms) to treat synkinesis and spasms of the face on the pathologic side. This treatment course will be complemented by the rest of the therapeutic, i.e. rehabilitation and surgical treatment. PMID- 26432178 TI - Diethylcarbamazine citrate ameliorates insulin resistance in high-fat diet induced obese mice via modulation of adipose tissue inflammation. AB - Diethylcarbamazine citrate (DEC) had been known as anti-inflammatory drug but its effect on obesity-induced insulin resistance as a result of released inflammatory mediators from adipose tissue (AT) was not known. White male albino mice were fed with high fat diet (HFD) for 18weeks to induce obesity. DEC at different three doses (12, 50 and 200mg/kg) was orally administered twice a week starting at week 6. Body, liver and adipose tissue weights were taken, while glucose tolerance, insulin resistance, blood triglycerides and levels of adipokines (leptin, TNF alpha, IL-6 and MCP-1) were tested. The activity of cyclooxygenase (COX) in the liver tissue homogenate was also tested. In addition, NF-kappaBp65 localization in liver cell cytoplasmic and nuclear fractions was detected using Western blotting. The only effective anti-inflammatory dose was 50mg/kg to reduce (p<0.05) the high levels of glucose, insulin and triglycerides in serum. DEC was not anti-obesity drug because the weights of body, liver and adipose tissues were not changed. Hyperleptinemia was decreased (p<0.001) and associated with a reduction in serum levels of TNF-alpha, IL-6 and MCP-1 (p<0.001). In addition, the activity of COX in DEC treatment decreased significantly (p<0.01), while NF kappaBp65 localization in nuclear extracts was obviously inhibited in 50mg/kg treated group. It could be concluded that DEC was the only effective dose against mouse insulin resistance but not lipid accumulation. PMID- 26432179 TI - Linalool inhibits cigarette smoke-induced lung inflammation by inhibiting NF kappaB activation. AB - Linalool, a natural compound that exists in the essential oils of several aromatic plants species, has been reported to have anti-inflammatory effects. However, the effects of linalool on cigarette smoke (CS)-induced acute lung inflammation have not been reported. In the present study, we investigated the protective effects of linalool on CS-induced acute lung inflammation in mice. Linalool was given i.p. to mice 2h before CS exposure daily for five consecutive days. The numbers of macrophages and neutrophils in bronchoalveolar lavage fluid (BALF) were measured. The production of TNF-alpha, IL-6, IL-1beta, IL-8 and MCP-1 were detected by ELISA. The expression of NF-kappaB was detected by Western blotting. Our results showed that treatment of linalool significantly attenuated CS-induced lung inflammation, coupled with inhibited the infiltration of inflammatory cells and TNF-alpha, IL-6, IL-1beta, IL-8 and MCP-1 production. Meanwhile, treatment of linalool inhibited CS-induced lung MPO activity and pathological changes. Furthermore, linalool suppressed CS-induced NF-kappaB activation in a dose-dependent manner. In conclusion, our results demonstrated that linalool protected against CS-induced lung inflammation through inhibiting CS-induced NF-kappaB activation. PMID- 26432180 TI - Attention capacities of preterm and term born toddlers: A multi-method approach. AB - OBJECTIVE: Many preterm children show difficulties in attention at (pre)school age. The development of attention capacities of preterm and term toddlers was compared using a longitudinal and multi-method approach at 12, 18 and 24months. METHOD: Attention was measured for 123 preterm (32-36weeks gestation) and 101 term born children, using eye tracking (18months), observations during mother child interaction (18months), and mother-reports (12, 18, and 24months). RESULTS: Preterm toddlers had lower scores than term children on the eye-tracking measures of orienting and alerting. No group differences were found with observations, mother-reports, and the eye-tracking measure of executive attention. More preterm than term children had suboptimal scores on measures of the alerting system at 18months, possibly indicating difficulties in attention development. CONCLUSION: Preterm children showed an increased risk for suboptimal functioning in alerting attention capacities, as early as at a toddler age. PMID- 26432181 TI - Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. AB - BACKGROUND: Benefits of calcitonin-gene related peptide (CGRP) inhibition have not been established in chronic migraine. Here we assess the safety, tolerability, and efficacy of two doses of TEV-48125, a monoclonal anti-CGRP antibody, in the preventive treatment of chronic migraine. METHODS: In this multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel group phase 2b study, we enrolled men and women (aged 18-65 years) from 62 sites in the USA who had chronic migraine. Using a randomisation list generated by a central computerised system and an interactive web response system, we randomly assigned patients (1:1:1, stratified by sex and use of concomitant preventive drugs) to three 28-day treatment cycles of subcutaneous TEV-48125 675/225 mg (675 mg in the first treatment cycle and 225 mg in the second and third treatment cycles), TEV-48125 900 mg (900 mg in all three treatment cycles), or placebo. Investigators, patients, and the funder were blinded to treatment allocation. Daily headache information was captured using an electronic diary. Primary endpoints were change from baseline in the number of headache-hours during the third treatment cycle (weeks 9-12) and safety and tolerability during the study. Secondary endpoint was change in the number of moderate or severe headache-days in weeks 9-12 relative to baseline. Efficacy endpoints were analysed for the intention-to-treat population. Safety and tolerability were analysed using descriptive statistics. This trial is registered with ClinicalTrials.gov, number, NCT02021773. FINDINGS: Between Jan 8, 2014, and Aug 27, 2014, we enrolled 264 participants: 89 were randomly assigned to receive placebo, 88 to receive 675/225 mg TEV-48125, and 87 to receive 900 mg TEV-48125. The mean change from baseline in number of headache-hours during weeks 9-12 was -59.84 h (SD 80.38) in the 675/225 mg group and -67.51 h (79.37) in the 900 mg group, compared with -37.10 h (79.44) in the placebo group. The least square mean difference in the reduction of headache-hours between the placebo and 675/225 mg dose groups was -22.74 h (95% CI -44.28 to -1.21; p=0.0386), whereas the difference between placebo and 900 mg dose groups was -30.41 h (-51.88 to -8.95; p=0.0057). Adverse events were reported by 36 (40%) patients in the placebo group, 47 (53%) patients in the 675/225 mg dose group, and 41 (47%) patients in the 900 mg dose group, whereas treatment-related adverse events were recorded in 15 (17%) patients, 25 (29%) patients, and 28 (32%) patients, respectively. The most common adverse events were mild injection-site pain and pruritus. Four (1%) patients had serious non treatment-related adverse events (one patient in the placebo group, one patient in the 675/225 mg group, and two patients in the 900 mg group); no treatment related adverse events were serious and there were no relevant changes in blood pressure or other vital signs. INTERPRETATION: TEV-48125 given by subcutaneous injection every 28 days seems to be tolerable and effective, thus supporting the further development of TEV-48125 for the preventive treatment of chronic migraine in a phase 3 trial. FUNDING: Teva Pharmaceuticals. PMID- 26432183 TI - CGRP antibodies: the Holy Grail for migraine prevention? PMID- 26432184 TI - Recurrent Clostridium difficile infection in intensive care unit patients. AB - BACKGROUND: The purpose of this study was to assess the 12-week cumulative incidence of recurrent Clostridium difficile infection (rCDI) and identify risk factors for rCDI in patients that acquired index C difficile infection (CDI) while in the intensive care unit (ICU). METHODS: This retrospective single-center cohort study reviewed adult patients from 6 different ICUs who developed a CDI between February 2010 and September 2013. RESULTS: Out of 162 included ICU patients, 34 experienced rCDI. Risk of rCDI was higher in the ICU versus non-ICU group (21% vs 17%, P = .03). The incidence of rCDI was highest in the surgical intensive care unit (SICU) at 43.8%. A multivariable logistic regression model was constructed and identified 5 significant risk factors for rCDI: previous CDI (odds ratio [OR], 8.03; 95% confidence interval [CI], 1.90-34.02; P = .005), log10 ICU length of stay in days (OR, 3.67; 95% CI, 1.13-11.85; P = .03), acquisition of CDI in the medical intensive care unit (MICU) (OR, 5.35; 95% CI, 1.60-17.85; P = .006) or SICU (OR, 15.30; 95% CI, 4.09-57.23; P < .001), and chronic obstructive pulmonary disease (COPD) (OR, 3.55; 95% CI, 1.41-8.94; P = .007). CONCLUSION: ICU adults had a significantly higher 12-week incidence of rCDI than non-ICU patients. Risk factors for rCDI after acquisition of infection in an ICU include MICU and SICU patients, previous CDI, COPD, and length of stay. PMID- 26432182 TI - Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high frequency episodic migraine: a multicentre, randomised, double-blind, placebo controlled, phase 2b study. AB - BACKGROUND: Calcitonin gene-related peptide (CGRP) is a validated target for the treatment of episodic migraine. Here we assess the safety, tolerability, and efficacy of TEV-48125, a monoclonal anti-CGRP antibody, in the preventive treatment of high-frequency episodic migraine. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 2b study, we enrolled men and women (aged 18-65 years) from 62 sites in the USA who had migraine headaches 8-14 days per month. Using a randomisation list generated by a central computerised system and an interactive web response system, we randomly assigned patients (1:1:1; stratified by sex and use of concomitant preventive drugs) after a 28 day run-in period to three 28 day treatment cycles of subcutaneous 225 mg TEV-48125, 675 mg TEV-48125, or placebo. Investigators, patients, and the funder were blinded to treatment allocation. Patients reported headache information daily using an electronic diary. Primary endpoints were change from baseline in migraine days during the third treatment cycle (weeks 9-12) and safety and tolerability. The secondary endpoint was change relative to baseline in headache days during weeks 9-12. Efficacy endpoints were analysed for the intention-to treat population. Safety and tolerability were analysed using descriptive statistics. This trial is registered at ClinicalTrials.gov, number NCT02025556. FINDINGS: Between Jan 8, 2014, and Oct 15, 2014, we enrolled 297 participants: 104 were randomly assigned to receive placebo, 95 to receive 225 mg TEV-48125, and 96 to receive 675 mg TEV-48125. The least square mean (LSM) change in number of migraine-days from baseline to weeks 9-12 was -3.46 days (SD 5.40) in the placebo group, -6.27 days (5.38) in the 225 mg dose group, and -6.09 days (5.22) in the 675 mg dose group. The LSM difference in the reduction of migraine-days between the placebo and 225 mg dose groups was -2.81 days (95% CI -4.07 to -1.55; p<0.0001), whereas the difference between the placebo and 675 mg dose group was 2.64 days (-3.90 to -1.38; p<0.0001). LSM differences in the reduction of headache-days were -2.63 days (-3.91 to -1.34; p<0.0001) between the placebo group and 225 mg dose group and -2.58 days (-3.87 to 1.30; p <0.0001) between the placebo group and the 675 mg dose group. Adverse events occurred in 58 (56%) patients in the placebo group, 44 (46%) patients in the 225 mg dose group, and 57 (59%) patients in the 675 mg dose group; moderate or severe adverse events were reported for 29 (27%) patients, 24 (25%) patients, and 26 (27%) patients, respectively. INTERPRETATION: TEV-48125, at doses of 225 mg and 675 mg given once every 28 days for 12 weeks, was safe, well tolerated, and effective as a preventive treatment of high-frequency episodic migraine, thus supporting advancement of the clinical development programme to phase 3 clinical trials. FUNDING: Teva Pharmaceuticals. PMID- 26432185 TI - Cost-effectiveness of a hand hygiene program on health care-associated infections in intensive care patients at a tertiary care hospital in Vietnam. AB - BACKGROUND: The cost-effectiveness of a hand hygiene (HH) program in low- and middle-income countries (LMICs) is largely unknown. We assessed the cost effectiveness of a HH program in a large tertiary Vietnamese hospital. METHODS: This was a before and after study of a hand hygiene program where HH compliance, incidence of hospital-acquired infections (HAIs), and costs were analyzed.The HH program was implemented in 2 intensive care and 15 critical care units. The program included upgrading HH facilities, providing alcohol-based handrub at point of care, HH campaigns, and continuous HH education. RESULTS: The HH compliance rate increased from 25.7% to 57.5% (P < .001). The incidence of patients with HAI decreased from 31.7% to 20.3% (P < .001) after the intervention. The mean cost for patients with HAI was $1,908, which was 2.5 times higher than the costs for patients without an HAI. The mean attributable cost of an HAI was $1,131. The total cost of the HH program was $12,570, which equates to a per-patient cost of $6.5. The cost-effectiveness was estimated at -$1,074 or $1,074 saved per HAI prevented. The intervention remained cost savings under various scenarios with lower HAI rates. CONCLUSION: The HH program is an effective strategy in reducing the incidence of HAIs in intensive care units and is cost-effective in Vietnam. HH programs need to be encouraged across Vietnam and other LMICs. PMID- 26432186 TI - Responses of peripheral blood mononuclear cells to moderate exercise and hypoxia. AB - The purpose of this study was to analyze the physiological features of peripheral blood mononuclear cells (PBMCs) isolated from healthy female trekkers before and after physical activity carried out under both normoxia (low altitude, < 2000 m a.s.l.) and hypobaric hypoxia (high altitude, > 3700 m a.s.l.). The experimental design was to differentiate effects induced by exercise and those related to external environmental conditions. PBMCs were isolated from seven female subjects before and after each training period. The PBMCs were phenotypically and functionally characterized using fluorimetric and densitometric analyses, to determine cellular activation, and their intracellular Ca(2+) levels and oxidative status. After a period of normoxic physical exercise, the PBMCs showed an increase in fully activated T lymphocytes (CD3(+) CD69(+) ) and a reduction in intracellular Ca(2+) levels. On the other hand, with physical exercise performed under hypobaric hypoxia, there was a reduction in T lymphocytes and an increase in nonactivated B lymphocytes, accompanied by a reduction in O2 (-) levels in the mitochondria. These outcomes reveal that in women, low- to moderate-intensity aerobic trekking induces CD69 T cell activation and promotes anti-stress effects on the high-altitude-induced impairment of the immune responses and the oxidative balance. PMID- 26432188 TI - Variation in Lung Tumour Breathing Motion between Planning Four-dimensional Computed Tomography and Stereotactic Ablative Radiotherapy Delivery and its Dosimetric Implications: Any Role for Four-dimensional Set-up Verification? AB - AIMS: To investigate variation in tumour breathing motion (TBM) between the planning four-dimensional computed tomograph (4DCT) and treatment itself for primary or secondary lung tumours undergoing stereotactic ablative radiotherapy (SABR). MATERIALS AND METHODS: Sixteen consecutive patients underwent planning 4DCT at least 1 week after implantation of a fiducial marker. The maximal extent of breathing motion of the intra-tumoural fiducial was measured at 4DCT and again at delivery of each SABR fraction on the linac using stereoscopic kilovoltage imaging. Displacements of the fiducial beyond planned limits were measured in three dimensions and represented as vectors. Variation in breathing motion between the planning 4DCT and treatment, and between individual SABR fractions was analysed. RESULTS: Although TBM at treatment exceeded planned tumour motion limits for at least part of the course for all patients, 31% of patients remained consistently within 1 mm, 50% within 2 mm and 69% consistently within 3 mm of planned parameters. However, 19% of patients experienced TBM variation 5 mm or more beyond planned limits for at least one fraction. For all patients, the median displacement vector at treatment beyond the planned motion envelope was 1.0 mm (mean 2.0 mm, range 0-12.7 mm). Variation in TBM at treatment from 4DCT correlated neither with the magnitude of TBM at 4DCT nor with planning target volume size (rs = 0.13, P = 0.62; rs = 0.02, P = 0.94, respectively). Nor was TBM variation related to tumour type or lobar position (P = 0.35, P = 0.06, respectively). Inter-fraction TBM variation was modest, with an average standard deviation of 1.7 mm (0.3-8.7 mm). CONCLUSIONS: TBM variation between 4DCT and treatment and between SABR fractions was modest for most patients. However, 19% of patients experienced significant TBM variation that could be clinically relevant for those most severely affected. It seems prudent to carry out on-couch assessment of TBM at each SABR fraction to identify such patients who might benefit from respiratory gating or adaptive radiotherapy to maintain tumour motion within the planned limits. PMID- 26432187 TI - Fiber ball imaging. AB - By modeling axons as thin cylinders, it is shown that the inverse Funk transform of the diffusion MRI (dMRI) signal intensity obtained on a spherical shell in q space gives an estimate for a fiber orientation density function (fODF), where the accuracy improves with increasing b-value provided the signal-to-noise ratio is sufficient. The method is similar to q-ball imaging, except that the Funk transform of q-ball imaging is replaced by its inverse. We call this new approach fiber ball imaging. The fiber ball method is demonstrated for healthy human brain, and fODF estimates are compared to diffusion orientation distribution function (dODF) approximations obtained with q-ball imaging. The fODFs are seen to have sharper features than the dODFs, reflecting an enhancement of the higher degree angular frequencies. The inverse Funk transform of the dMRI signal intensity data provides a simple and direct method of estimating a fODF. In addition, fiber ball imaging leads to an estimate for the ratio of the fraction of MRI visible water confined to the intra-axonal space divided by the square root of the intra-axonal diffusivity. This technique may be useful for white matter fiber tractography, as well as other types of microstructural modeling of brain tissue. PMID- 26432189 TI - Prescribed journeys through life: Cultural differences in mental time travel between Middle Easterners and Scandinavians. AB - Mental time travel is the ability to remember past events and imagine future events. Here, 124 Middle Easterners and 128 Scandinavians generated important past and future events. These different societies present a unique opportunity to examine effects of culture. Findings indicate stronger influence of normative schemas and greater use of mental time travel to teach, inform and direct behaviour in the Middle East compared with Scandinavia. The Middle Easterners generated more events that corresponded to their cultural life script and that contained religious words, whereas the Scandinavians reported events with a more positive mood impact. Effects of gender were mainly found in the Middle East. Main effects of time orientation largely replicated recent findings showing that simulation of future and past events are not necessarily parallel processes. In accordance with the notion that future simulations rely on schema-based construction, important future events showed a higher overlap with life script events than past events in both cultures. In general, cross-cultural discrepancies were larger in future compared with past events. Notably, the high focus in the Middle East on sharing future events to give cultural guidance is consistent with the increased adherence to normative scripts found in this culture. PMID- 26432190 TI - Optimized ultrasonic attenuation measures for non-homogeneous materials. AB - In this paper the study of frequency-dependent ultrasonic attenuation in strongly heterogeneous materials is addressed. To determine the attenuation accurately over a wide frequency range, it is necessary to have suitable excitation techniques. Three kinds of transmitted signals have been analysed, grouped according to their bandwidth: narrowband and broadband signals. The mathematical formulation has revealed the relation between the distribution of energy in their spectra and their immunity to noise. Sinusoidal and burst signals have higher signal-to-noise ratios (SNRs) but need many measurements to cover their frequency range. However, linear swept-frequency signals (chirp) improve the effective bandwidth covering a wide frequency range with a single measurement and equivalent accuracy, at the expense of a lower SNR. In the case of highly attenuating materials, it is proposed to use different configurations of chirp signals, enabling injecting more energy, and therefore, improving the sensitivity of the technique without a high time cost. Thus, if the attenuation of the material and the sensitivity of the measuring equipment allows the use of broadband signals, the combination of this kind of signal and suitable signal processing results in an optimal estimate of frequency-dependent attenuation with a minimum measurement time. PMID- 26432191 TI - LAMTOR1-PRKCD and NUMA1-SFMBT1 fusion genes identified by RNA sequencing in aneurysmal benign fibrous histiocytoma with t(3;11)(p21;q13). AB - RNA sequencing of an aneurysmal benign fibrous histiocytoma with the karyotype 46,XY,t(3;11)(p21;q13),del(6)(p23)[17]/46,XY[2] showed that the t(3;11) generated two fusion genes: LAMTOR1-PRKCD and NUMA1-SFMBT1. RT-PCR together with Sanger sequencing verified the presence of fusion transcripts from both fusion genes. In the LAMTOR1-PRKCD fusion, the part of the PRKCD gene coding for the catalytic domain of the serine/threonine kinase is under control of the LAMTOR1 promoter. In the NUMA1-SFMBT1 fusion, the part of the SFMBT1 gene coding for two of four malignant brain tumor domains and the sterile alpha motif domain is controlled by the NUMA1 promoter. The data support a neoplastic genesis of aneurysmal benign fibrous histiocytoma and indicate a pathogenetic role for LAMTOR1-PRKCD and NUMA1 SFMBT1. PMID- 26432192 TI - Biofilm formation is a risk factor for mortality in patients with Candida albicans bloodstream infection-Scotland, 2012-2013. AB - Bloodstream infections caused by Candida species remain a significant cause of morbidity and mortality in hospitalized patients. Biofilm formation by Candida species is an important virulence factor for disease pathogenesis. A prospective analysis of patients with Candida bloodstream infection (n = 217) in Scotland (2012-2013) was performed to assess the risk factors associated with patient mortality, in particular the impact of biofilm formation. Candida bloodstream isolates (n = 280) and clinical records for 157 patients were collected through 11 different health boards across Scotland. Biofilm formation by clinical isolates was assessed in vitro with standard biomass assays. The role of biofilm phenotype on treatment efficacy was also evaluated in vitro by treating preformed biofilms with fixed concentrations of different classes of antifungal. Available mortality data for 134 patients showed that the 30-day candidaemia case mortality rate was 41%, with predisposing factors including patient age and catheter removal. Multivariate Cox regression survival analysis for 42 patients showed a significantly higher mortality rate for Candida albicans infection than for Candida glabrata infection. Biofilm-forming ability was significantly associated with C. albicans mortality (34 patients). Finally, in vitro antifungal sensitivity testing showed that low biofilm formers and high biofilm formers were differentially affected by azoles and echinocandins, but not by polyenes. This study provides further evidence that the biofilm phenotype represents a significant clinical entity, and that isolates with this phenotype differentially respond to antifungal therapy in vitro. Collectively, these findings show that greater clinical understanding is required with respect to Candida biofilm infections, and the implications of isolate heterogeneity. PMID- 26432193 TI - A virus-based nanoplasmonic structure as a surface-enhanced Raman biosensor. AB - Fabrication of nanoscale structures with localized surface plasmons allows for substantial increase in sensitivity of chem/bio sensors. The main challenge for realizing complex nanoplasmonic structures in solution is the high level of precision required at the nanoscale to position metal nanoparticles in 3D. In this study, we report a virus-like particle (VLP) for building a 3D plasmonic nanostructure in solution in which gold nanoparticles are precisely positioned on the VLP by directed self-assembly techniques. These structures allow for concentration of electromagnetic fields in the desired locations between the gold nanoparticles or "hot spots". We measure the efficiency of the optical field spatial concentration for the first time, which results in a ten-fold enhancement of the capsid Raman peaks. Our experimental results agree with our 3D finite element simulations. Furthermore, we demonstrate as a proof-of-principle that the plasmonic nanostructures can be utilized in DNA detection down to 0.25 ng/MUl (lowest concentration tested), while the protein peaks from the interior of the nanoplasmonic structures, potentially, can serve as an internal tracer for the biosensors. PMID- 26432194 TI - Small biomolecule immunosensing with plasmonic optical fiber grating sensor. AB - This study reports on the development of a surface plasmon resonance (SPR) optical fiber biosensor based on tilted fiber Bragg grating technology for direct detection of small biomarkers of interest for lung cancer diagnosis. Since SPR principle relies on the refractive index modifications to sensitively detect mass changes at the gold coated surface, we have proposed here a comparative study in relation to the target size. Two cytokeratin 7 (CK7) samples with a molecular weight ranging from 78 kDa to 2.6 kDa, respectively CK7 full protein and CK7 peptide, have been used for label-free monitoring. This work has first consisted in the elaboration and the characterization of a robust and reproducible bioreceptor, based on antibody/antigen cross-linking. Immobilized antibodies were then utilized as binding agents to investigate the sensitivity of the biosensor towards the two CK7 antigens. Results have highlighted a very good sensitivity of the biosensor response for both samples diluted in phosphate buffer with a higher limit of detection for the larger CK7 full protein. The most groundbreaking nature of this study relies on the detection of small biomolecule CK7 peptides in buffer and in the presence of complex media such as serum, achieving a limit of detection of 0.4 nM. PMID- 26432195 TI - Photoelectrochemical detection of enzymatically generated CdS nanoparticles: Application to development of immunoassay. AB - We report an innovative photoelectrochemical process (PEC) based on graphite electrode modified with electroactive polyvinylpyridine bearing osmium complex (Os-PVP). The system relies on the in situ enzymatic generation of CdS quantum dots (QDs). Alkaline phosphatase (ALP) catalyzes the hydrolisis of sodium thiophosphate (TP) to hydrogen sulfide (H2S) which in the presence Cd(2+) ions yields CdS semiconductor nanoparticles (SNPs). Irradiation of SNPs with the standard laboratory UV-illuminator (wavelength of 365 nm) results in photooxidation of 1-thioglycerol (TG) mediated by Os-PVP complex on the surface of graphite electrode at applied potential of 0.31 V vs. Ag/AgCl. A novel immunoassay based on specific enzyme linked immunosorbent assay (ELISA) combined with the PEC methodology was developed. Having selected the affinity interaction between bovine serum albumine (BSA) with anti-BSA antibody (AB) as a model system, we built the PEC immunoassay for AB. The new assay displays a linear range up to 20 ngmL(-1) and a detection limit (DL) of 2 ngmL(-1) (S/N=3) which is lower 5 times that of the traditional chromogenic ELISA test employing p-nitro phenyl phosphate (pNPP). PMID- 26432196 TI - Wrapping a facial nerve graft in a superficial temporofascial flap to optimise vascularisation: technical note. PMID- 26432197 TI - Current surgical management of metastases in the neck from mucosal squamous cell carcinoma of the head and neck. AB - Neck dissection, which is an important method of treatment for metastases from mucosal (and other) squamous cell carcinomas (SCC) of the head and neck, is also useful for staging disease. Since its inception it has changed from a radical to a more conservative procedure, and vital structures are preserved wherever possible. Refinements in methods of imaging to assess involvement in the neck have encouraged alternative approaches that can improve outcomes and reduce morbidity. We look at the reported evidence for the surgical management of metastases in the neck from mucosal SCC. PMID- 26432198 TI - Influence of education and diagnostic modes on glaucoma assessment by optometrists. AB - PURPOSE: To evaluate the influence of different clinical examination techniques, including optic nerve head (ONH) photography, visual field tests, and adjunct imaging on the diagnosis of glaucoma by Australian and New Zealand optometrists. The effect of a short-term, didactic teaching module on these is also explored. METHODS: Clinical data of 30 patients previously seen at the Centre for Eye Health was collected and compiled into glaucoma diagnostic assessment modules. Each of six modules contained different combinations of clinical examination results and required a classification of the cases as normal, suspicious or glaucoma. A cohort of 54 Australian and New Zealand optometrists were recruited for the study and allocated into two cohorts. The intervention group completed a glaucoma training course prior to the assessment while the control group completed the assessment without additional training. Diagnostic accuracy was compared between modules and optometrist groups. RESULTS: High false negative rates were observed with ONH photography, which were drastically reduced with the addition of visual field, albeit at the cost of increased false positive rates. Addition of adjunct imaging techniques partially compensated for the increase in the false positive rate from the visual field, but had limited effect on false negative rate. Educational intervention resulted in larger improvement in the diagnostic ability when multiple imaging modalities were provided. CONCLUSION: The study highlighted the importance of combining both structural and functional assessments in glaucoma. Current imaging technology demonstrated limited usefulness for event diagnosis due to the persistent difficulties of defining structural and functional loss in glaucoma, thus highlighting the need for new glaucoma assessment techniques. Short-term didactic teaching programs may only result in limited improvement of glaucoma diagnostic ability in optometrists, and hence, it may need to be combined with long-term and/or non-didactic training components to obtain a greater effect. PMID- 26432199 TI - Paperless anesthesia: uses and abuses of these data. AB - Demonstrably accurate records facilitate clinical decision making, improve patient safety, provide better defense against frivolous lawsuits, and enable better medical policy decisions. Anesthesia Information Management Systems (AIMS) have the potential to improve on the accuracy and reliability of handwritten records. Interfaces with electronic recording systems within the hospital or wider community allow correlation of anesthesia relevant data with biochemistry laboratory results, billing sections, radiological units, pharmacy, earlier patient records, and other systems. Electronic storage of large and accurate datasets has lent itself to quality assurance, enhancement of patient safety, research, cost containment, scheduling, anesthesia training initiatives, and has even stimulated organizational change. The time for record making may be increased by AIMS, but in some cases has been reduced. The question of impact on vigilance is not entirely settled, but substantial negative effects seem to be unlikely. The usefulness of these large databases depends on the accuracy of data and they may be incorrect or incomplete. Consequent biases are threats to the validity of research results. Data mining of biomedical databases makes it easier for individuals with political, social, or economic agendas to generate misleading research findings for the purpose of manipulating public opinion and swaying policymakers. There remains a fear that accessibility of data may have undesirable regulatory or legal consequences. Increasing regulation of treatment options during the perioperative period through regulated policies could reduce autonomy for clinicians. These fears are as yet unsubstantiated. PMID- 26432200 TI - Segmentation of retinal vessels by means of directional response vector similarity and region growing. AB - This paper presents a novel retinal vessel segmentation method. Opposed to the general approach in similar directional methods, where only the maximal or summed responses of a pixel are used, here, the directional responses of a pixel are considered as a vector. The segmentation method is a unique region growing procedure which combines a hysteresis thresholding scheme with the response vector similarity of adjacent pixels. A vessel score map is constructed as the combination of the statistical measures of the response vectors and its local maxima to provide the seeds for the region growing procedure. A nearest neighbor classifier based on a rotation invariant response vector similarity measure is used to filter the seed points. Many techniques in the literature that capture the Gaussian-like cross-section of vessels suffer from the drawback of giving false high responses to the steep intensity transitions at the boundary of the optic disc and bright lesions. To overcome this issue, we also propose a symmetry constrained multiscale matched filtering technique. The proposed vessel segmentation method has been tested on three publicly available image sets, where its performance proved to be competitive with the state-of-the-art and comparable to the accuracy of a human observer, as well. PMID- 26432201 TI - Testing times. PMID- 26432202 TI - Variety of life. PMID- 26432203 TI - Goals galore. PMID- 26432204 TI - Science must prepare for impact. PMID- 26432216 TI - China to launch cap-and-trade system. PMID- 26432217 TI - California faces arid future. PMID- 26432218 TI - Brazilian science paralysed by economic slump. PMID- 26432219 TI - Bacteria yield new gene cutter. PMID- 26432220 TI - Gene-edited 'micropigs' to be sold as pets at Chinese institute. PMID- 26432222 TI - Maths whizz solves a master's riddle. PMID- 26432221 TI - Archimedes' legendary sphere brought to life. PMID- 26432223 TI - The future of cryptocurrencies: Bitcoin and beyond. PMID- 26432224 TI - Mountain battle. PMID- 26432225 TI - Human Genome Project: Twenty-five years of big biology. PMID- 26432226 TI - Modelling: Build imprecise supercomputers. PMID- 26432234 TI - China: Ban unfair pricing of equipment imports. PMID- 26432235 TI - Climate modelling: Community initiative tackles urban heat. PMID- 26432236 TI - Plate tectonics: Continental-drift opus turns 100. PMID- 26432237 TI - Global emissions: New oil investments boost carbon lock-in. PMID- 26432238 TI - Environmental protection: US 'openness' bill is counterproductive. PMID- 26432239 TI - Astrophysics: Primordial stars brought to light. PMID- 26432241 TI - Neurodevelopmental disease: A molecular tightrope. PMID- 26432242 TI - Condensed-matter Physics: Flat transistor defies the limit. PMID- 26432243 TI - Human genomics: The end of the start for population sequencing. PMID- 26432244 TI - CRISPR-Cas immunity in prokaryotes. AB - Prokaryotic organisms are threatened by a large array of viruses and have developed numerous defence strategies. Among these, only clustered, regularly interspaced short palindromic repeat (CRISPR)-Cas systems provide adaptive immunity against foreign elements. Upon viral injection, a small sequence of the viral genome, known as a spacer, is integrated into the CRISPR locus to immunize the host cell. Spacers are transcribed into small RNA guides that direct the cleavage of the viral DNA by Cas nucleases. Immunization through spacer acquisition enables a unique form of evolution whereby a population not only rapidly acquires resistance to its predators but also passes this resistance mechanism vertically to its progeny. PMID- 26432247 TI - A subthermionic tunnel field-effect transistor with an atomically thin channel. AB - The fast growth of information technology has been sustained by continuous scaling down of the silicon-based metal-oxide field-effect transistor. However, such technology faces two major challenges to further scaling. First, the device electrostatics (the ability of the transistor's gate electrode to control its channel potential) are degraded when the channel length is decreased, using conventional bulk materials such as silicon as the channel. Recently, two dimensional semiconducting materials have emerged as promising candidates to replace silicon, as they can maintain excellent device electrostatics even at much reduced channel lengths. The second, more severe, challenge is that the supply voltage can no longer be scaled down by the same factor as the transistor dimensions because of the fundamental thermionic limitation of the steepness of turn-on characteristics, or subthreshold swing. To enable scaling to continue without a power penalty, a different transistor mechanism is required to obtain subthermionic subthreshold swing, such as band-to-band tunnelling. Here we demonstrate band-to-band tunnel field-effect transistors (tunnel-FETs), based on a two-dimensional semiconductor, that exhibit steep turn-on; subthreshold swing is a minimum of 3.9 millivolts per decade and an average of 31.1 millivolts per decade for four decades of drain current at room temperature. By using highly doped germanium as the source and atomically thin molybdenum disulfide as the channel, a vertical heterostructure is built with excellent electrostatics, a strain-free heterointerface, a low tunnelling barrier, and a large tunnelling area. Our atomically thin and layered semiconducting-channel tunnel-FET (ATLAS TFET) is the only planar architecture tunnel-FET to achieve subthermionic subthreshold swing over four decades of drain current, as recommended in ref. 17, and is also the only tunnel-FET (in any architecture) to achieve this at a low power-supply voltage of 0.1 volts. Our device is at present the thinnest-channel subthermionic transistor, and has the potential to open up new avenues for ultra dense and low-power integrated circuits, as well as for ultra-sensitive biosensors and gas sensors. PMID- 26432248 TI - Observed latitudinal variations in erosion as a function of glacier dynamics. AB - Glacial erosion is fundamental to our understanding of the role of Cenozoic-era climate change in the development of topography worldwide, yet the factors that control the rate of erosion by ice remain poorly understood. In many tectonically active mountain ranges, glaciers have been inferred to be highly erosive, and conditions of glaciation are used to explain both the marked relief typical of alpine settings and the limit on mountain heights above the snowline, that is, the glacial buzzsaw. In other high-latitude regions, glacial erosion is presumed to be minimal, where a mantle of cold ice effectively protects landscapes from erosion. Glacial erosion rates are expected to increase with decreasing latitude, owing to the climatic control on basal temperature and the production of meltwater, which promotes glacial sliding, erosion and sediment transfer. This relationship between climate, glacier dynamics and erosion rate is the focus of recent numerical modelling, yet it is qualitative and lacks an empirical database. Here we present a comprehensive data set that permits explicit examination of the factors controlling glacier erosion across climatic regimes. We report contemporary ice fluxes, sliding speeds and erosion rates inferred from sediment yields from 15 outlet glaciers spanning 19 degrees of latitude from Patagonia to the Antarctic Peninsula. Although this broad region has a relatively uniform tectonic and geologic history, the thermal regimes of its glaciers range from temperate to polar. We find that basin-averaged erosion rates vary by three orders of magnitude over this latitudinal transect. Our findings imply that climate and the glacier thermal regime control erosion rates more than do extent of ice cover, ice flux or sliding speeds. PMID- 26432250 TI - Correction. PMID- 26432249 TI - Badges of distinction. PMID- 26432246 TI - An integrated map of structural variation in 2,504 human genomes. AB - Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association. PMID- 26432251 TI - Publishing: The journal that publishes no papers. PMID- 26432252 TI - Neuroscience: Connectomes make the map. PMID- 26432254 TI - Testing the mid-latitude hydrologic seesaw. PMID- 26432255 TI - Woo et al. reply. PMID- 26432256 TI - Outcomes of both abbreviated hyper-CVAD induction followed by autologous hematopoietic cell transplantation and conventional chemotherapy for mantle cell lymphoma: a 10-year single-centre experience with literature review. AB - We retrospectively evaluated consecutive patients diagnosed with Mantle cell lymphoma (MCL) between 01 January 2000 and 31 December 2009. Eighty eight patients with MCL were included in the analysis of whom 46 (52%) received abbreviated Hyper-CVAD (a total of two cycles; with addition of Rituximab since 2005) with an intention of proceeding to autologous hematopoietic cell transplantation (auto-HCT), with a median age of 58 years. Response rate to induction at auto-HCT time was 89% and complete response was 61%. Forty four patients received an auto-HCT with a 5-year progression-free survival (PFS) and overall survival (OS) were 31.2% and 62.5%, respectively. There were 42 nontransplant eligible patients with a median age of 72 years, and 5-year PFS and OS were 0.0% and 39.9%, respectively. The median survival and PFS in the auto-HCT eligible group were 68 and 33 months, compared to 32 and 12 months in nontransplant eligible group, without a plateauing of the survival curves in either group. Treatment-related mortality in the auto-HCT eligible group was 10.9% (n = 5); two patients died during R-Hyper-CVAD and 3 (6.8%) experienced transplant-related mortality. An abbreviated R-Hyper-CVAD-based induction strategy followed by consolidative auto-HCT is feasible and provides moderate potential of long-term survival. Further research to define risk-adapted strategies; to optimize disease control, is required. PMID- 26432257 TI - Notch signaling induces cell proliferation in the labrum in a regulatory network different from the thoracic legs. AB - The insect head is composed of several segments and an anterior non-segmental region. While patterning of the segmental region relies - at least in part - on the known trunk patterning mechanisms, development of the anterior most region remains poorly understood. The labrum is an enigmatic structure of the anterior median region (AMR) of the insect head. Based on similar development and gene expression patterns it has been suggested to be a serial homolog of trunk appendages. However, its position in the non-segmental region indicated an independent origin. In order to learn more about development of the AMR including the labrum, we screened the results of the large scale RNAi screen iBeetle to identify novel genes. We found the Notch ligand Tc-Serrate and the ubiquitin ligase Tc-mind bomb1 to be required for labrum formation. Further studies showed that Notch signaling is acting upstream of the genetic hierarchy and is required for regulating cell proliferation. We combined our work with previous data to compare the regulatory gene networks of labrum and trunk appendage formation. This reveals that despite the involvement of a similar set of genes, the genetic interactions are quite different. PMID- 26432258 TI - Integrin beta4 regulation of PTHrP underlies its contribution to mammary gland development. AB - The integrin alpha6beta4 (referred to as beta4) is expressed in epithelial cells where it functions as a laminin receptor. Although in vitro studies have implicated beta4 in the biology of mammary epithelial cells, its contribution to mammary gland development has not been settled. To address this problem, we generated and analyzed itgb4(flox/flox)MMTV-Cre(-) and itgb4(flox/flox)MMTV Cre(+) mice. The salient features of embryonic mammary tissue from itgb4(flox/flox)MMTV-Cre(+) mice were significantly smaller mammary buds and increased apoptosis in the surrounding mesenchyme. Also, compared to control glands, the itgb4-deleted mammary buds lacked expression of the progenitor cell marker CK14 and they were unable to generate mammary glands upon transplantation into cleared fat pads of recipient mice. Analysis of mammary glands at puberty and during pregnancy revealed that itgb4-diminished mammary tissue was unable to elongate and undergo branching morphogenesis. Micro-dissection of epithelial cells in the mammary bud and of the surrounding mesenchyme revealed that loss of beta4 resulted in a significant decrease in the expression of parathyroid hormone related protein (PTHrP) in epithelial cells and of target genes of the PTHrP receptor in mesenchymal cells. Given that the phenotype of the itgb4-deleted mammary tissue mimicked that of the PTHrP knockout, we hypothesized that beta4 contributes to mammary gland development by sustaining PTHrP expression and enabling PTHrP signaling. Indeed, the inability of itgb4-deleted mammary buds to elongate was rescued by exogenous PTHrP. These data implicate a critical role for the beta4 integrin in mammary gland development and provide a mechanism for this role. PMID- 26432259 TI - Operative Factors Associated with the Development of New Brain Lesions During Awake Carotid Endarterectomy. AB - OBJECTIVES: The aim was to analyse a prospective, consecutive series of awake carotid endarterectomy (CEA) patients undergoing, when possible, pre- and postoperative diffusion-weighted magnetic resonance imaging brain scans (DWI). METHODS: All CEA patients from June 23, 2006, to January 13, 2012, were prospectively entered in the study. CEA was performed under regional cervical block. Only patients demonstrating shunt dependence were shunted. Before August 7, 2008, all longitudinal endarterectomy had been performed with a vein patch. From that date all CEA were eversions without a patch, except shunted patients who were vein patched. DWI was performed 2 days before and 5 days after (3 Tesla). Scans were reported by MRI-trained radiologists. Logistic regression analysis (LRA) identified predictive variables for MRI changes using backward stepwise elimination of variables with p > .05. RESULTS: There was a total of 295 consecutive CEA. There were no deaths but four clinical strokes (1.4 %); 89 excluded from DWI leaving 206; of these 27 (13%) developed new DWI lesions including four of 57 (7%) in the asymptomatic group and 23 of 149 (15%) symptomatic patients. Nineteen of the 206 (9.2%) were shunted. LRA showed that shunt dependence was highly associated with new DWI lesions: odds ratio (OR) 6.43; 95% confidence interval (CI) 2.3-17.9; p < .001. Both the vein patched, non shunted group (OR .25; CI 0.09-0.72; p = .010) and the eversion (all non-shunted and all non-patched) group (OR 0.05; CI 0.01-0.22; p < .001) were associated with a low risk of new lesions, with the eversion group a lower risk than the patched group. CONCLUSIONS: One in every eight CEA patients developed new DWI lesions (rate doubled in symptomatic patients). Shunt dependence in conscious CEA patients is highly associated with the development of new DWI lesions compared with non-shunted patients. For non-shunted patients the new lesion risk is low, and in those patients the risk in the eversion group is lower than in the patched group. PMID- 26432260 TI - Unfit for Repair After Screening for Abdominal Aortic Aneurysm: Do We Fail to Fulfil the Basic WHO Criterion of an Available Treatment? PMID- 26432261 TI - Sonic hedgehog-responsive lipoxygenases and cyclooxygenase-2 modulate Dectin-1 induced inflammatory cytokines. AB - Immune responses during fungal infections are predominately mediated by 5/15 lipoxygenases (LO)- or cyclooxygenase (COX)-2-catalysed bioactive eicosanoid metabolites like leukotrienes, lipoxins and prostaglandins. Although few host mediators of fungi-triggered eicosanoid production have been established, the molecular mechanism of expression and regulation of 5-LO, 15-LO and COX-2 are not well-defined. Here, we demonstrate that, macrophages infected with representative fungi Candida albicans, Aspergillus flavus or Aspergillus fumigatus or those treated with Curdlan, a selective agonist of pattern recognition receptor for fungi Dectin-1, displays increased expression of 5-LO, 15-LO and COX-2. Interestingly, Dectin-1-responsive Syk pathway activates mTOR-sonic hedgehog (SHH) signaling cascade to stimulate the expression of these lipid metabolizing enzymes. Loss-of-function analysis of the identified intermediaries indicates that while Syk-mTOR-SHH pathway-induced 5-LO and 15-LO suppressed the Dectin-1 responsive pro-inflammatory signature cytokines like TNF-alpha, IL-1beta and IL 12, Syk-mTOR-SHH-induced COX-2 positively regulated these cytokines. Dectin-1 stimulated IL-6, however, is dependent on 5-LO, 15-LO and COX-2 activity. Together, the current study establishes Dectin-1-arbitrated host mediators that direct the differential regulation of immune responses during fungal infections and thus are potential candidates of therapeutic intervention. PMID- 26432262 TI - Cytotoxicity and mutagenicity of sidestream cigarette smoke particulate matter of different particle sizes. AB - Sidestream cigarette smoke, the major component of environmental tobacco smoke, is a complex and reactive aerosol. The particulate matter (PM) in sidestream smoke is one of the carriers of chemical constituents. However, particle size dependent toxicological effects of PM are poorly understood. In this study, we evaluated the relationship between the PM size and in vitro cytotoxicity and mutagenicity of sidestream cigarette smoke. A NanoMoudi-II(TM) 125A was used to collect PM samples ranging from 10 nm to 10 MUm. The in vitro toxicity of PM was evaluated using a neutral red cytotoxicity assay and Salmonella mutagenicity assay. The results showed that the cytotoxicity and mutagenicity of PM larger than 1 MUm was significantly lower than PM sized 10 nm-1 MUm. Furthermore, there was a noticeable trend that the smaller the size of the PM of sidestream cigarette smoke, the greater the toxicity. This study suggests that the toxicity of PM in sidestream cigarette smoke is size-dependent. PMID- 26432263 TI - Contributions of a compost-biochar mixture to the metal sorption capacity of a mine tailing. AB - One technique applied to restore degraded or contaminated soils is to use amendments made of different types of waste materials, which in turn may contain metals such as Cu, Pb and Zn. For this reason, it is important to determine the capacity of the soil to retain these materials, and to compare the sorption capacity between an amended soil and another unamended soil. The aim of this study was to determine the mobility and availability of these metals in the soil after applying the amendment, and how it affected the soil's sorption capacity. Sorption isotherms were compared with the empirical models of Langmuir and Freundlich to estimate the sorption capacity. The overall capacity of the soils to sorb Cu, Pb or Zn was evaluated as the slope Kr. The amendments used in this study were a mixture made of compost and biochar in different proportions (20, 40, 60, 100 %), which were applied to the mine tailing from a settling pond from a copper mine. The mine tailing that were amended with the mixture of compost and biochar had a higher sorption capacity than the mine tailing from the unamended pond, and their sorption isotherms had a greater affinity towards Cu, Pb and Zn than the mine tailing that was studied. Therefore, the results obtained show that adding a mixture of compost and biochar favours the retention of Cu, Pb and Zn in mine tailing. PMID- 26432264 TI - Sources and potential health risk of gas phase PAHs in Hexi Corridor, Northwest China. AB - Gas phase polycyclic aromatic hydrocarbons (PAHs) in Hexi Corridor, Northwest China were determined during heating and non-heating seasons, respectively, using passive air samplers. Polyurethane foam (PUF) disks were chosen as the sampling medium. Fifteen PAHs out of the 16 PAHs classified by the United States Environmental Protection Agency (U.S. EPA) were detected in this field sampling investigation. The atmospheric levels of sampled PAHs were higher at urban sites than that at rural sites among 14 sampling sites and increased during heating season. The highest concentration (11.34 ng m(-3)) was observed in Lanzhou during the heating season, the capital and largest industrial city of Gansu Province. PAH contamination in air was dominated by three aromatic ring congeners. Possible sources of PAHs were apportioned using PAH species ratios and the principle component analysis (PCA) combined with a multiple linear regression (MLR) method. Fossil fuel consumption was identified to be the predominant source of PAHs over Hexi Corridor, accounting for 43 % of the concentration of total (15) PAHs. Backward and forward trajectory and cluster analysis were also carried out to identify potential origins of PAHs monitored at several urban and rural sites. Lung cancer risk of local residents to gas phase PAHs via inhalation exposure throughout the province was found to be around a critical value of the lung cancer risk level at 10(-6) recommended by the U.S. EPA risk assessment guideline. PMID- 26432265 TI - Effects of artemisinin sustained-release granules on mixed alga growth and microcystins production and release. AB - To safely and effectively apply artemisinin sustained-release granules to control and prevent algal water-blooms, the effects of artemisinin and its sustained release granules on freshwater alga (Scenedesmus obliquus (S. obliquus) and Microcystis aeruginosa (M. aeruginosa)), as well as the production and release of microcystins (MCs) were studied. The results showed that artemisinin sustained release granules inhibited the growth of M. aeruginosa (above 95% IR) and S. obliquus (about 90% IR), with M. aeruginosa more sensitive. The artemisinin sustained-release granules had a longer inhibition effect on growth of pure algae and algal coexistence than direct artemisinin dosing. The artemisinin sustained release granules could decrease the production and release of algal toxins due to the continued stress of artemisinin released from artemisinin sustained-release granules. There was no increase in the total amount of MC-LR in the algal cell culture medium. PMID- 26432266 TI - A comparative study with biologically and chemically synthesized nZVI: applications in Cr (VI) removal and ecotoxicity assessment using indigenous microorganisms from chromium-contaminated site. AB - In the present communication, we report a comparative study of Cr (VI) removal using biologically synthesized nano zero valent iron (BS-nZVI) and chemically synthesized nZVI (CS-nZVI), both immobilized in calcium alginate beads. The parameters like initial Cr (VI) concentration, nZVI concentration, and the contact time for Cr (VI) removal were optimized based on Box-Behnken design (BBD) by response surface modeling at a constant pH 7. Under the optimized conditions (concentration of nZVI = 1000 mg L(-1), contact time = ~ 80 min, and initial concentration of Cr (VI) = 10 mg L(-1)), the Cr (VI) removal by the immobilized BS-nZVI and CS-nZVI alginate beads was 80.04 and 81.08 %, respectively. The adsorption of Cr (VI) onto the surface of alginate beads was confirmed by scanning electron microscopy with energy-dispersive x-ray spectroscopy (SEM-EDX), Fourier transform infrared spectroscopy (FT-IR), and Brunauer-Emmett-Teller (BET) analysis. The applicability of the process using both the sorbents was successfully test medium Cr (VI) spiked environmental water samples. In order to assess the ecotoxic effects of nZVI, the decline in cell viability, generation of intracellular reactive oxygen species (ROS), cell membrane damage, and biouptake was studied at 1000 mg L(-1) concentration, with five indigenous bacterial isolates from chromium-contaminated lake sediments and their consortium. PMID- 26432267 TI - Characteristics of simultaneous ammonium and phosphate adsorption from hydrolysis urine onto natural loess. AB - Nutrient recovery from human urine is a promising pretreatment of domestic wastewater and provides a sustainable recyclability of N and P. In this study, batch experiments were conducted to identify the characteristics of natural loess (NL) for the adsorption and recovery of ammonium and phosphate from hydrolysis urine (HU). The adsorption mechanisms, the adsorption kinetics and isotherms, as well as the major influencing factors, such as pH and temperature, were investigated. Results revealed that adsorption of ammonium occurred by means of ion exchange and molecule adsorption with the = Si-OH groups, while phosphate adsorption was based on the calcium phosphate precipitation reaction and formation of inner-sphere complexes with = M-OH groups. The adsorption processes of ammonium and phosphate were well described by the pseudo-second-order kinetic model and the Freundlich isotherm model. Adsorption of phosphate was endothermic, while ammonium adsorption was exothermic. Furthermore, the maximum ammonium and phosphate adsorption capacities of NL was 23.24 mg N g(-1) and 4.01 mg P g(-1) at an initial pH of 9 and 10, respectively. Results demonstrated that nutrient adsorbed NL used as compound fertilizer or conventional fertilizer superaddition was feasible for its high contents of N and P as well as its environmental friendliness. PMID- 26432245 TI - A global reference for human genetic variation. AB - The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies. PMID- 26432269 TI - The use of food wastes as feed ingredients for culturing grass carp (Ctenopharyngodon idellus) in Hong Kong. AB - Different types of food wastes, e.g., meats, bones, cereals, fruits, and vegetables, were collected from hotels in Hong Kong, mixed in different ratio, and processed into feed pellets (food wastes (FWs) A, B, and C) for feeding trials in aquaculture species. Grass carp fed with cereal-dominant feed (FW A) showed the best growth (in terms of specific growth rate, relative weight gain, and protein efficiency ratio), among all food waste feeds. However, the growth rates of food waste groups especially the meat product-contained feeds (FW B and FW C) were lower than the commercial feed, Jinfeng((r)) 613 formulation (control). The results indicated that grass carp utilized plant proteins better than animal proteins and preferred carbohydrate as a major energy source than lipid. The high-lipid content in feed containing meat products was also a possible reason for hindering growth and resulted high body lipid. It is suggested that lipid should be removed in the preparation of food waste feed or further investigations by implementing supplements, e.g., enzymes in feed to enhance lipid or protein utilization by fish. This utilization of food waste could be an effective and practical way to deal with these wastes in this densely populated city. PMID- 26432268 TI - Comparative study of diethyl phthalate degradation by UV/H2O2 and UV/TiO2: kinetics, mechanism, and effects of operational parameters. AB - The photodegradation of diethyl phthalate (DEP) by UV/H2O2 and UV/TiO2 is studied. The DEP degradation kinetics and multiple crucial factors effecting the clearance of DEP are investigated, including initial DEP concentration ([DEP]0), initial pH values (pH0), UV light intensity, anions (Cl(-), NO(3-), SO4 (2-), HCO3 (-), and CO3 (2-)), cations (Mg(2+), Ca(2+), Mn(2+), and Fe(3+)), and humic acid (HA). Total organic carbon (TOC) removal is tested by two treatments. And, cytotoxicity evolution of DEP degradation intermediates is detected. The relationship between molar ratio ([H2O2]/[DEP] or [TiO2]/[DEP]) and degradation kinetic constant (K) is also studied. And, the cytotoxicity tests of DEP and its degradation intermediates in UV/H2O2 and UV/TiO2 treatments are researched. The DEP removal efficiency of UV/H2O2 treatment is higher than UV/TiO2 treatment. The DEP degradation fitted a pseudo-first-order kinetic pattern under experimental conditions. The K linearly related with molar ratio in UV/H2O2 treatment while nature exponential relationship is observed in the case of UV/TiO2. However, K fitted corresponding trends better in H2O2 treatment than in TiO2 treatment. The Cl(-) is in favor of the DEP degradation in UV/H2O2 treatment; in contrast, it is disadvantageous to the DEP degradation in UV/TiO2 treatment. Other anions are all disadvantageous to the DEP degradation in two treatments. Fe(3+) promotes the degradation rates significantly. And, all other cations in question inhibit the degradation of DEP. HA hinders DEP degradation in two treatments. The intermediates of DEP degradation in UV/TiO2 treatment are less toxic to biological cell than that in UV/H2O2 treatment. PMID- 26432271 TI - Chemical element accumulation in tree bark grown in volcanic soils of Cape Verde a first biomonitoring of Fogo Island. AB - Barks from Prosopis juliflora (acacia) were collected in 12 sites of different geological contexts over the volcanic Fogo Island (Cape Verde). Elemental contents of Ba, Br, Co, Cr, Fe, K, Na, Zn and some rare earth elements (REE)-La, Ce, Sm, Eu, Tb, Yb, and Lu, were obtained for biological samples and topsoils by using k 0-standardized and comparative method of instrumental neutron activation analysis (INAA), aiming the evaluation of chemical elements uptake by acacia bark. This first biomonitoring study of Fogo Island showed that, in general, significant accumulations of trace elements present in high amounts in these soils occur. This can be partially explained by the semi-arid climate with a consequent bioavailability of chemical elements when rain drops fall in this non polluted environment. REE enrichment factors (EFs) increase with the decrease of ionic radius. Heavy REE (HREE) are significantly enriched in bark, which agrees with their release after the primary minerals breakdown and the formation of more soluble compounds than the other REE, and uptake by plants. Among the potential harmful chemical elements, Cr appears to be partially retained in nanoparticles of iron oxides. The high EFs found in tree barks of Fogo Island are certainly of geogenic origin rather than anthropogenic input since industry and the use of fertilizers is scarce. PMID- 26432270 TI - Lead toxicity in rice: effects, mechanisms, and mitigation strategies--a mini review. AB - Lead (Pb) is a major environmental pollutant that affects plant morpho physiological and biochemical attributes. Its higher levels in the environment are not only toxic to human beings but also harmful for plants and soil microbes. We have reviewed the uptake, translocation, and accumulation mechanisms of Pb and its toxic effects on germination, growth, yield, nutrient relation, photosynthesis, respiration, oxidative damage, and antioxidant defense system of rice. Lead toxicity hampers rice germination, root/shoot length, growth, and final yield. It reduces nutrient uptake through roots, disrupts chloroplastic ultrastructure and cell membrane permeability, induces alterations in leaves respiratory activities, produces reactive oxygen species (ROS), and triggers some enzyme and non-enzymatic antioxidants (as defense to oxidative damage). In the end, biochar amendments and phytoremediation technologies have been proposed as soil remediation approaches for Pb tainted soils. PMID- 26432272 TI - Supplemental exogenous NPK application alters biochemical processes to improve yield and drought tolerance in wheat (Triticum aestivum L.). AB - The recent food security issues, combined with the threats from climate change, demand future farming systems to be more precise and accurate to fulfill the ever increasing global food requirements. The role of nutrients such as nitrogen (N), phosphorous (P), and potassium (K) in stimulating plant growth and development is well established; however, little is known about their function, if applied in combination, in improving crop yields under environmental stresses like drought. The aim of this study was to evaluate the effects of combined foliar spray of supplemental NPK (NPKc) on physiological and biochemical mechanisms that enhance the drought tolerance potential of wheat for improved yield. Foliar NPKc markedly influenced the accumulation of osmoprotectants and activity of both nitrogen assimilation and antioxidant enzymes. It significantly improved the concentration of proline (66 %), total soluble sugars (37 %), and total soluble proteins (10 %) and enhanced the activity of nitrate reductase, nitrite reductase, catalase, and peroxidase by 47, 45, 19, and 8 %, respectively, with respect to no spray under water-deficit conditions which, in turn, improve the yield and yield components. The accumulation of osmolytes and activity of antioxidant machinery were more pronounced in drought tolerant (Bhakkar-02) than sensitive genotype (Shafaq-06). PMID- 26432273 TI - Surface microstructural features of scales in relation to toxic stress of Basic Violet-1. AB - The present work deals with scanning electron microscopic (SEM) studies of the scales of Labeo rohita on exposure to lethal and sublethal doses of Basic Violet 1 (an important textile and hair colorant). The dye induced loosening of the scales and caused breakage and disorganization of lepidonts. Erosion of lepidonts occurred mostly in the fish exposed to 0.20 and 0.40 mg/L dye, during acute exposure and to 0.0225 and 0.045 mg/L dye, during the subchronic exposure. However, lepidonts were sloughed off from their sockets in 0.60 and 0.80 mg/L dye during acute exposure and in 0.09 mg/L dye during the subchronic exposure. Circuli, the base that provides anchorage to the lepidonts, got damaged, and tubercles responsible for coloration of a fish became atrophied with an increase in the duration of exposure. The results of the present investigation clearly indicated that exposure to Basic Violet-1 (BV-1) even at a concentration as low as 0.0225 mg was responsible for deleterious changes in the scale morphology of the test fish after 150 days of exposure. Similar changes were observed in the scales of the dead fish also. It can thus be suggested that this noninvasive technique is very helpful for evaluating the health status of an aquatic body. At the same time, the changes in ultramorphology of scales can act as an early indicator of the stress of very minute doses of dyes and even the scales of a dead fish can act as indicators of the untoward changes that would have occurred in the environment of the fish before death. PMID- 26432274 TI - The saga of the duration of dual antiplatelet therapy after drug-eluting stent placement. PMID- 26432275 TI - Echocardiographic measurement of left atrial volume: Does the method matter? AB - BACKGROUND: Four two-dimensional echocardiographic methods (cube, ellipsoid, Simpson's and area-length) can be used to assess left atrial volume (LAV). AIMS: To compare absolute LAV measurements and evaluate agreement regarding the semiquantitative assessment of degree of left atrial (LA) enlargement, between methods. METHODS: We prospectively measured LAV in 51 healthy volunteers using the four methods, and defined thresholds for moderate (mean+2 standard deviations [SDs]) and severe (mean+4 SDs) LA enlargement for each method. In 372 patients referred for echocardiography, we compared absolute LAV measurements and agreement between methods. RESULTS: LAV was significantly different between methods in the healthy volunteer group (11 +/- 4, 17 +/- 3, 26 +/- 6 and 28 +/- 7 mL/m(2), respectively; P<0.0001), resulting in different thresholds for moderate and severe LA enlargement. LAV was also significantly different in the 372 patients (30 +/- 20, 47 +/- 27, 61 +/- 34 and 65 +/- 36 mL/m(2), respectively; P<0.0001). Agreement regarding degree of LA enlargement (none, moderate, severe), using the area-length method as reference, was modest with the cube method (kappa=0.41), correct with the ellipsoid method (kappa=0.60) and excellent with Simpson's method (kappa=0.83). CONCLUSION: The choice of the method had a major effect on assessment of degree of LA enlargement. Our results suggest that the cube and ellipsoid methods, which significantly underestimated LAV and provided modest agreement, should be disregarded. In contrast, Simpson's method and the area-length method were slightly different, but showed close agreement, and should be preferred, using dedicated thresholds (50 and 56 mL/m(2) respectively). PMID- 26432276 TI - Effect of the aqueous extract of the aerial parts of Monsonia angustifolia E. Mey. Ex A. Rich., on the sexual behaviour of male Wistar rats. AB - BACKGROUND: Monsonia angustifolia (Geraniaceae) is a medicinal plant traditionally used in South Africa to increase libido and to treat erectile dysfunction. METHODS: In-vivo aphrodisiac activities of the crude extracts of the plant prepared in water at 3, 30 and 300 mg/kg body weight were evaluated for 7 days using sildenafil citrate (Viagra) and 1% ethanol in distilled water as positive and negative controls respectively. Male rats were selected and monitored in each group for sexual behaviour by exposing them to sexually receptive females on days 1, 3 and 7 for 60 minutes each between 7:00 pm and 3:00 am. The following male sexual parameters were observed: Mount Frequency (MF), Intromission Frequency (IF), Mount Latency (ML), Intromission Latency (IL), Ejaculation Frequency (EF), Ejaculatory Latency (EL) and Post-Ejaculatory Interval (PEI). RESULTS: The administration of the extract resulted in significant increase (p < 0.05) in mount frequency, intromission frequency, ejaculation frequency, ejaculation latency and serum hormone concentrations. The computed indices of sexual behaviour such as erection, quick flips, long flips and total penile reflexes were also increased. However, the mount latency, intromission latency and post ejaculation interval were significantly decreased throughout the experimental period. The administration of 300 mg/kg body weight of the aqueous extract produced the best effects in all the parameters. CONCLUSION: Generally, the extract of Monsonia angustifolia produced pro-sexual stimulatory effects in the male rats especially when administered at 300 mg/kg body weight. The results validate the use of the plant by the indigenous people to increase libido and treat premature ejaculation and erectile dysfunction in males. PMID- 26432277 TI - How Distractor Objects Trigger Referential Overspecification: Testing the Effects of Visual Clutter and Distractor Distance. AB - In two experiments, we investigate to what extent various visual saliency cues in realistic visual scenes cause speakers to overspecify their definite object descriptions with a redundant color attribute. The results of the first experiment demonstrate that speakers are more likely to redundantly mention color when visual clutter is present in a scene as compared to when this is not the case. In the second experiment, we found that distractor type and distractor color affect redundant color use: Speakers are most likely to overspecify if there is at least one distractor object present that has the same type, but a different color than the target referent. Reliable effects of distractor distance were not found. Taken together, our results suggest that certain visual saliency cues guide speakers in determining which objects in a visual scene are relevant distractors, and which not. We argue that this is problematic for algorithms that aim to generate human-like descriptions of objects (such as the Incremental Algorithm), since these generally select properties that help to distinguish a target from all objects that are present in a scene. PMID- 26432278 TI - Why do women invest in pre-pregnancy health and care? A qualitative investigation with women attending maternity services. AB - BACKGROUND: Despite the importance attributed to good pre-pregnancy care and its potential to improve pregnancy and child health outcomes, relatively little is known about why women invest in pre-pregnancy health and care. We sought to gain insight into why women invested in pre-pregnancy health and care. METHODS: We carried out 20 qualitative in-depth interviews with pregnant or recently pregnant women who were drawn from a survey of antenatal clinic attendees in London, UK. Interviewees were purposively sampled to include high and low investors in pre pregnancy health and care, with variation in age, partnership status, ethnicity and pre-existing medical conditions. Data analysis was conducted using the Framework method. RESULTS: We identified three groups in relation to pre pregnancy health and care: 1) The "prepared" group, who had high levels of pregnancy planning and mostly positive attitudes to micronutrient supplementation outside of pregnancy, carried out pre-pregnancy activities such as taking folic acid and making changes to diet and lifestyle. 2) The "poor knowledge" group, who also had high levels of pregnancy planning, did not carry out pre-pregnancy activities and described themselves as having poor knowledge. Elsewhere in their interviews they expressed a strong dislike of micronutrient supplementation. 3) The "absent pre-pregnancy period" group, had the lowest levels of pregnancy planning and also expressed anti-supplement views. Even discussing the pre pregnancy period with this group was difficult as responses to questions quickly shifted to focus on pregnancy itself. Knowledge of folic acid was poor in all groups. CONCLUSION: Different pre-pregnancy care approaches are likely to be needed for each of the groups. Among the "prepared" group, who were proactive and receptive to health messages, greater availability of information and better response from health professionals could improve the range of pre-pregnancy activities carried out. Among the "poor knowledge" group, better response from health professionals might yield greater uptake of pre-pregnancy information. A different, general health strategy might be more appropriate for the "absent pre pregnancy period" group. The fact that general attitudes to micronutrient supplementation were closely related to whether or not women invested in pre pregnancy health and care was an unanticipated finding and warrants further investigation. PMID- 26432279 TI - Invasive Vespula Wasps Utilize Kairomones to Exploit Honeydew Produced by Sooty Scale Insects, Ultracoelostoma. AB - Vespula wasps are widely distributed invasive alien species that are able to reach high population densities in the 1.2 M ha of beech forests (Fuscospora spp.) of New Zealand's South Island. These endemic temperate forests have an abundance of carbohydrate-rich honeydew produced by native scale insects (Ultracoelostoma spp.). A characteristic aroma is associated with the honeydew in beech forests, which we hypothesized is the signal used by wasps to harvest the vast resources previously exploited by birds and other insects. Volatile collections were taken of black beech tree trunks with honeydew and sooty mold present, and analyzed with a gas chromatograph-mass spectrometer. Eleven compounds (benzaldehyde, benzyl alcohol, 2-phenylethyl acetate, 2-phenylethanol, phenylacetaldehyde, methyl 2-phenylacetate, ethyl 2-phenylacetate, methyl salicylate, n-octanol, octan-3-ol, and 1-octen-3-ol) were positively identified from the headspace, and were shown to elicit an electrophysiological response from Vespula vulgaris worker antennae by using electroantennography (EAG). Field trials with delta traps individually baited with these compounds confirmed wasp attraction to 8 of the 11 compounds tested, with 2-phenylethyl acetate, methyl salicylate, and octan-3-ol capturing the same numbers of wasps as the control. In later trials, attraction to a 1:1 blend of benzaldehyde and n-octanol was significantly higher (45%) than to any other treatment. Many of the chemicals identified are known to be associated with fermenting sugars, or with fungal aroma. Benzaldehyde and n-octanol are common compounds produced by many different species in nature. The ability to respond to generic signals emanating from sugar resources is likely to contribute to the success of V. vulgaris as an invasive species. PMID- 26432280 TI - Growth factors and experimental arterial grafts. AB - BACKGROUND: The production of growth factors from several experimental arterial conduits was determined. METHODS: We implanted 105 experimental arterial grafts that were 1 cm long in the abdominal aorta of Lewis rats (average weight, 250 g). Five different types of grafts were analyzed: arterial isografts, vein grafts, arterial allografts, and polytetrafluoroethylene (PTFE) grafts with normal or decreased compliance. Animals were killed humanely 4 weeks after surgery and the production of platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), transforming growth factor-beta, tumor necrosis factor-alpha, and interleukin-1 was analyzed. RESULTS: Myointimal hyperplasia (MH) was evident in vein grafts, arterial allografts, and PTFE grafts, but not in arterial isografts. Growth factor production was increased for grafts prone to develop MH like vein, PTFE grafts, and arterial allografts. PDGF and bFGF were increased significantly for PTFE and vein grafts, but not for arterial allografts. The importance of bFGF and PGDF was confirmed by the capability of antibody to PDGF and to bFGF to reduce the mitogenic activity of smooth muscle cells, in vivo and in vitro, for PTFE and vein grafts, but not for arterial allografts, in which a predominant role was played by interleukin-1 and tumor necrosis factor-alpha. CONCLUSIONS: Agents able to neutralize this increased production of growth factors, either directly or by competition with their receptors, can prevent MH formation. PMID- 26432281 TI - Physician specialty and variation in carotid revascularization technique selected for Medicare patients. AB - OBJECTIVE: Carotid artery stenting (CAS) has become an alternative to carotid endarterectomy (CEA) for select patients with carotid atherosclerosis. We hypothesized that the choice of CAS vs CEA varies as a function of treating physician specialty, which would result in regional variation in the relative use of these treatment types. METHODS: We used Medicare claims (2002-2010) to calculate annual rates of CAS and CEA and examined changes by procedure type over time. To assess regional preferences surrounding CAS, we calculated the proportion of revascularizations by CAS, across hospital referral regions, defined according to the Dartmouth Atlas of Healthcare. We then examined relationships between patient factors, physician specialty, and regional use of CAS. RESULTS: The annual number of all carotid revascularization procedures decreased by 30% from 2002 to 2010 (3.2 to 2.3 per 1000; P = .005). Whereas rates of CEA declined by 35% during these 8 years (3.0 to 1.9 per 1000; P < .001), CAS utilization increased by 5% during the same interval (0.30 to 0.32 per 1000; P = .014). Variation in utilization of carotid revascularization varied across the Unites States, with some regions performing as few as 0.7 carotid procedure per 1000 beneficiaries (Honolulu, Hawaii) and others performing nearly 8 times as many (5.3 per 1000 in Houma, La). Variation in procedure type (CEA vs CAS) was evident as well, as the proportion of carotid revascularization procedures that were constituted by CAS varied from 0% (Casper, Wyo, and Meridian, Miss) to 53% (Bend, Ore). The majority of CAS procedures were performed by cardiologists (49% of all CAS cases), who doubled their rates of CAS during the study period from 0.07 per 1000 in 2002 to 0.15 per 1000 in 2010. CONCLUSIONS: Variation in rates of carotid revascularization exists. Whereas rates of carotid revascularization have declined by more than 30% in recent years, utilization of CAS has increased. The proportion of all carotid revascularization procedures performed as CAS varies markedly by geographic region, and regions with the highest proportion of cardiologists perform the most CAS procedures. Evidence-based guidelines for carotid revascularization will require a multidisciplinary approach to ensure uniform adoption across specialties that care for patients with carotid artery disease. PMID- 26432282 TI - Predicting outcomes for infrapopliteal limb-threatening ischemia using the Society for Vascular Surgery Vascular Quality Initiative. AB - OBJECTIVE: The outcomes of open surgical or endovascular intervention for limb threatening ischemia (LTI) involving the infrapopliteal vessels are dependent on complex anatomic, demographic, and disease factors. To assist in decision-making, we used the Vascular Quality Initiative (VQI) to derive a model using only preoperatively available factors to predict important outcomes for open or endovascular revascularization. METHODS: National VQI data for the infrainguinal bypass and peripheral vascular intervention (PVI) modules were reviewed in a blinded fashion for patients who underwent intervention for LTI of the infrapopliteal vessels. Primary outcomes consisted of major adverse limb event (MALE) and amputation-free survival (AFS). Generalized linear modeling was used for the multivariate analyses, with entry of variables dependent on results of univariate analysis. RESULTS: From January 2003 through August 2014 a total of 19,053 infrainguinal open bypass and 48,739 PVI procedures were identified, among which 5264 and 5252, respectively, represented infrapopliteal (tibial-peroneal pedal) revascularization for LTI. From these, 3036 infrapopliteal open bypass patients and 1319 infrapopliteal PVI patients had sufficient follow-up data for study inclusion. For open surgery, the reduced generalized linear model revealed that American Society of Anesthesiologists class 4 or 5, previous major amputation, living at home, and female sex had the greatest adverse effect on MALE, and dialysis dependence, low body mass index, and lack of great saphenous vein as a conduit had the greatest negative effect on AFS. For PVI, lesion length from 10 to 15 cm, treatment of three or more arteries, and classification other than A on the Trans-Atlantic Inter-Society Consensus demonstrated the largest adverse effects on MALE, and dialysis dependence, low body mass index, and congestive heart failure most negatively affected AFS. CONCLUSIONS: This study on a cross-section of patients selected for intervention in academic and community hospitals offers a "real world" glimpse of factors predictive of outcome. The VQI can be used to derive models that predict the outcomes of open surgical bypass or PVI for LTI involving the infrapopliteal vessels. PMID- 26432283 TI - Staged hybrid repair of extensive thoracoabdominal aortic aneurysms secondary to chronic aortic dissection. AB - OBJECTIVE: Many patients with aortic dissection develop Crawford extent I or II thoracoabdominal aortic aneurysms (TAAA). Because open repair is associated with a high morbidity and mortality, hybrid approaches to TAAA repair are emerging. In this study, we evaluated the midterm outcomes and aortic remodeling of a hybrid technique that combines proximal thoracic endovascular aneurysm repair (TEVAR), followed by staged distal open thoracoabdominal repair for patients with Crawford extent I or II TAAAs secondary to chronic aortic dissection. METHODS: We identified 19 patients with Crawford extent I (n = 1) or extent II (n = 18) TAAAs secondary to chronic aortic dissection who underwent a staged hybrid repair from 2007 to 2014 at our institution. Nine patients had previous open ascending aortic surgery for type I aortic dissection. Stage 1 TEVAR was performed via percutaneous (n = 8), femoral cutdown (n = 8), or iliac exposure (n = 3). The left subclavian artery was covered in nine patients and revascularized in eight patients using carotid-subclavian bypass (n = 7) or laser fenestration (n = 1). Stage 2 open repair was performed a median of 18 weeks later with partial cardiopulmonary bypass via left femoral arterial and venous cannulation for visceral and lower body perfusion. The open thoracoabdominal graft was anastomosed proximally in an end to end fashion with the endograft. We then assessed surgical morbidity and mortality, midterm survival, and freedom from reintervention. Aortic remodeling was measured and change in maximum aortic and false lumen diameter at last follow-up (median, 3 years) from baseline was assessed. RESULTS: There were no deaths, strokes, or chronic renal failure in this cohort. After stage 1 TEVAR, three patients required repeat intervention for endoleak (type Ia, n = 1; type Ib, n = 1; type II, n = 1) before open repair. After stage 2 open repair, there was a single delayed permanent paralysis 2 weeks after discharge. At a median 3-year follow-up (range, 6 months-6.2 years), there were no deaths, neurologic events, endoleaks, or TAAA reinterventions. Complete false lumen thrombosis occurred in 100% of the patients, with maximum false lumen diameter decreasing from 34.3 +/- 15.3 mm to 13.2 +/- 12.0 mm (P < .01) and total aortic diameter decreasing from 60.2 +/- 9.0 mm to 49.4 +/- 9.6 mm (P < .01). CONCLUSIONS: Staged hybrid TAAA repair, using a combination of proximal TEVAR with open distal repair, can be performed using established endovascular skills and technology coupled with traditional open aortic surgical techniques, with low surgical morbidity and mortality. In the midterm, staged hybrid TAAA repair was associated favorable survival, aortic remodeling, and freedom from reintervention. PMID- 26432284 TI - A ruptured abdominal aortic aneurysm that requires preoperative cardiopulmonary resuscitation is not necessarily lethal. AB - OBJECTIVE: A ruptured abdominal aortic aneurysm (RAAA) is associated with a high mortality rate. If cardiopulmonary resuscitation (CPR) is required before surgical repair, mortality rates are said to approach 100%. The aim of this multicenter, retrospective study was to study outcome in RAAA patients who required CPR before a surgical (endovascular or open) repair (CPR group). RAAA patients who did not need CPR served as controls (non-CPR group). METHODS: Over a 5-year time period, demographic and clinical characteristics and specifics of preoperative CPR if necessary were studied in all patients who were treated for a RAAA in three large, nonacademic hospitals. RESULTS: A total of 199 consecutive RAAA patients were available for analysis; 176 patients were surgically treated. Thirteen of these 176 patients (7.4%) needed CPR, and 163 (92.6%) did not. A 38.5% (5 of 13) survival rate was observed in the CPR group. Thirty-day mortality was almost three times greater in the CPR group compared with the non-CPR group (61.5% vs 22.7%; P = .005). Both CPR patients who received endovascular aortic repair survived. In contrast, survival in 11 CPR patients who underwent open RAAA repair was 27% (3 of 11; P = .128). A trend for higher Hardman index was found in patients who received CPR compared with patients who did not receive CPR (P = .052). The 30-day mortality in patients with a 0, 1, 2, or 3 Hardman index was 16.1%, 31.0%, 37.9%, and 33.3%, respectively (P = .093). CONCLUSIONS: An RAAA that requires preoperative CPR is not necessarily a lethal combination. Patient selection must be tailored before surgery is denied. PMID- 26432285 TI - Outcomes of endovascular aneurysm repair with contemporary volume-dependent sac embolization in patients at risk for type II endoleak. AB - OBJECTIVE: The aim of this study was to evaluate outcomes of intraoperative aneurysm sac embolization during endovascular aneurysm repair (EVAR) in patients considered at risk for type II endoleak (EII), using a sac volume-dependent dose of fibrin glue and coils. METHODS: Between January 2012 and December 2014, 126 patients underwent EVAR. Based on preoperative computed tomography evaluation of anatomic criteria, 107 patients (85%) were defined as at risk for EII and assigned to randomization for standard EVAR (group A; n = 55, 44%) or EVAR with intraoperative sac embolization (group B; n = 52, 42%); the remaining 19 patients (15%) were defined as at low risk for EII and excluded from the randomization (group C). Computed tomography scans were evaluated with OsiriX Pro 4.0 software to obtain aneurysm sac volume. Freedom from EII, freedom from EII-related reintervention, and aneurysm sac volume shrinkage at 6, 12, and 24 months were compared by Kaplan-Meier estimates. Patients in group C underwent the same follow up protocol as groups A and B. RESULTS: Patient characteristics, Society for Vascular Surgery comorbidity scores (0.99 +/- 0.50 vs 0.95 +/- 0.55; P = .70), and operative time (149 +/- 50 minutes vs 157 +/- 39 minutes; P = .63) were similar for groups A and B. Freedom from EII was significantly lower for group A compared with group B at 3 months (58% vs 80%; P = .002), 6 months (68% vs 85%; P = .04), and 12 months (70% vs 87%; P = .04) but not statistically significant at 24 months (85% vs 87%; P = .57). Freedom from EII-related reintervention at 24 months was significantly lower for group A compared with group B (82% vs 96%; P = .04). Patients in group B showed a significantly overall mean difference in aneurysm sac volume shrinkage compared with group A at 6 months (-11 +/- 17 cm(3) vs -2 +/- 14 cm(3); P < .01), 12 months (-18 +/- 26 cm(3) vs -3 +/- 32 cm(3); P = .02), and 24 months (-27 +/- 25 cm(3) vs -5 +/- 26 cm(3); P < .01). Patients in group C had the lowest EII rate compared with groups A and B (6 months, 5%; 12 months, 6%; 24 months, 0%) and no EII-related reintervention. CONCLUSIONS: This randomized study confirms that sac embolization during EVAR, using a sac volume dependent dose of fibrin glue and coils, is a valid method to significantly reduce EII and its complications during early and midterm follow-up in patients considered at risk. Although further confirmatory studies are needed, the faster aneurysm sac volume shrinkage over time in patients who underwent embolization compared with standard EVAR may be a positive aspect influencing the lower EII rate also during long-term follow-up. PMID- 26432286 TI - A technique for developing CAD geometry of long bones using clinical CT data. AB - Computed tomography scans are a valuable tool for developing computational models of bones. The objective of this study is to present a method to generate CAD representations of long bones from clinically based CT scans. A secondary aim is to apply the method to six long bones from a sample of three individuals. Periosteal and endosteal bone surfaces were segmented and used to calculate the characteristic cortical thickness, Tc, at 1 mm increments along the bone axis. In the epiphyses where the value of Tc fell below the scanner threshold, the endosteal bone layer was replaced using literature values projected inward from the periosteal surface. On average, 74.7 +/- 7.4% of the bone geometry was above the scanner cut-off and was therefore derived from the CT scan data. The thickness measurement was also compared to experimental measurements of cadaveric bone and was found to predict Tc with an error of 3.1%. This method presents a possible solution for the characterization of characteristic thickness along the length of the bone and may also aid in the development of orthopedic implant design and subject specific finite element models. PMID- 26432287 TI - Oligomerization between BSU1 Family Members Potentiates Brassinosteroid Signaling in Arabidopsis. PMID- 26432288 TI - Earlier diagnosis of neurodevelopmental disability can only help infants in neonatal intensive care units. PMID- 26432289 TI - No crucial amino acid changes in the predicted histo blood group antigen-binding sites of norovirus genotype GII.4 capsid between non-secretors and secretors origin might suggest an alternative route of infection or existence of coincidental molecules. PMID- 26432290 TI - TGF-beta induces miR-30d down-regulation and podocyte injury through Smad2/3 and HDAC3-associated transcriptional repression. AB - The microRNA-30 family plays important roles in maintaining kidney homeostasis. Patients with focal segmental glomerulosclerosis (FSGS) have reduced miR-30 levels in glomerulus. TGF-beta represses miR-30s in kidney podocytes, which leads to cytoskeleton damage and podocyte apoptosis. In this study, we investigated the mechanism by which TGF-beta represses miR-30d in vitro. The human miR-30d promoter contains multiple copies of Smad binding element-like sequences. A fragment of 150 base pairs close to the transcription start site was negatively regulated by TGF-beta to a similar extent as the 1.8 kb promoter, which was blocked by histone-deacetylase inhibition. TGF-beta specifically enhanced HDAC3 expression. Knockdown of HDAC3 by shRNA or a selective inhibitor RGFP966 significantly relieved the repression of miR-30d mRNA and the promoter transcription. TGF-beta promoted HDAC3 association with Smad2/3 and NCoR and caused their accumulation at the putative Smad binding site on the miR-30d promoter, which was prohibited by TSA or RGFP966. Furthermore, TSA or RGFP966 treatment reversed TGF-beta-induced up-regulation of miR-30d targets Notch1 and p53 and alleviated the podocyte cytoskeleton damage and apoptosis. Taken together, these findings pinpoint that TGF-beta represses miR-30d through a Smad2/3-HDAC3-NCoR repression complex and provide novel insights into a potential target for the treatment of podocyte injury-associated glomerulopathies. Key message: MiR-30d promoter is negatively regulated by TGF-beta. TGF-beta down regulates miR-30 through Smad signaling pathway. HDAC3 and NCoR are recruited by Smad2/3 to mediate miR-30d repression by TGF-beta. HDAC3 acts as a critical player in TGF-beta-induced miR-30d repression and podocyte injuries. PMID- 26432291 TI - RNA Interference of Odorant-Binding Protein 2 (OBP2) of the Cotton Aphid, Aphis gossypii (Glover), Resulted in Altered Electrophysiological Responses. AB - Aphis gossypii (Glover) (Hemiptera: Aphididae) is a highly invasive pest that feeds primarily on phloem resulting in severe economic loss to growers. A. gossypii has cosmopolitan distribution with broad host range, polyphenism, parthenogenetic mode of reproduction, vectoring abilities, and host alteration which has profound influence on its management. Odorant-binding proteins (OBPs) in insects are involved in olfaction, playing a key role in orienting the insect for feeding or oviposition. Recent studies revealed that OBP2 is found in both sensilla trichodea and sensilla basiconica and is preferentially binds to plant volatiles, thus playing crucial roles in host-seeking, detection of oviposition attractants, etc., However, information about the role of OBP2 in A. gossypii (AgOBP2) is still unavailable. In this study, we cloned and characterized OBP2, ortholog from A. gossypii, and the full-length AgOBP2 complementary DNA (cDNA) consisted of 859 bp with an open reading frame of 732 bp. Phylogenetic analysis resulted in grouping of AgOBP2 protein with members of the tribe Aphidini. Further, diet-mediated delivery of double-stranded RNA for AgOBP2 induced silencing, which was evaluated at 48 and 96 h. The reverse transcriptase real time quantitative polymerase chain reaction (RTq-PCR) results revealed that the level of AgOBP2 messenger RNA (mRNA) was significantly reduced (55-77 %) in dsAgOBP2 treatment after 96 h as compared to the untreated control. The same was reiterated by the electrophysiological responses in the aphids which was reduced (>50 % at 0.25 MUg/MUl concentration) as compared to the untreated control. Thus, our results showed the potential of gene silencing, possibly to interfere with the odorant perception of A. gossypii for RNAi-mediated pest management. The results from our study provided the first evidence that AgOBP2 play crucial roles in host-seeking, detection of oviposition attractants, etc.; as a result, we suggests that OBP2 could potentially serve as a practicable target for RNAi mediated gene silencing in hemipteran insect pest control. PMID- 26432292 TI - Glycoproteins and Gal-GalNAc cause Cryptosporidium to switch from an invasive sporozoite to a replicative trophozoite. AB - The apicomplexan parasite Cryptosporidium causes cryptosporidiosis, a diarrheal disease that can become chronic and life threatening in immunocompromised and malnourished people. There is no effective drug treatment for those most at risk of severe cryptosporidiosis. The disease pathology is due to a repeated cycle of host cell invasion and parasite replication that amplifies parasite numbers and destroys the intestinal epithelium. This study aimed to better understand the Cryptosporidium replication cycle by identifying molecules that trigger the switch from invasive sporozoite to replicative trophozoite. Our approach was to treat sporozoites of Cryptosporidium parvum and Cryptosporidium hominis, the species causing most human cryptosporidiosis, with various media under axenic conditions and examine the parasites for rounding and nuclear division as markers of trophozoite development and replication, respectively. FBS had a concentration dependent effect on trophozoite development in both species. Trophozoite development in C. parvum, but not C. hominis, was enhanced when RPMI supplemented with 10% FBS (RPMI-FBS) was conditioned by HCT-8 cells for 3h. The effect of non conditioned and HCT-8 conditioned RPMI-FBS on trophozoite development was abrogated by proteinase K and sodium metaperiodate pretreatment, indicating a glycoprotein trigger. Cryptosporidium parvum and C. hominis trophozoite development also was triggered by Gal-GalNAc in a concentration-dependent manner. Cryptosporidium parvum replication was greatest following treatments with Gal GalNAc, followed by conditioned RPMI-FBS and non-conditioned RPMI-FBS (P<0.05). Cryptosporidium hominis replication was significantly less than that in C. parvum for all treatments (P<0.05), and was greatest at the highest tested concentration of Gal-GalNAc (1mM). PMID- 26432293 TI - Intestinal microbes influence the survival, reproduction and protein profile of Trichinella spiralis in vitro. AB - The interactions between intestinal microbes and parasitic worms play an essential role in the development of the host immune system. However, the effects of gut microbes on Trichinella spiralis are unknown. The aim of this work was to explore microbe-induced alterations in the survival and reproduction of T. spiralis in vitro. To further identify the proteins and genes involved in the response of nematodes to microbes, quantitative proteomic analysis of T. spiralis was conducted by iTRAQ-coupled LCMS/MS technology and quantitative real-time-PCR was used to measure changes in mRNA expression. The results showed Lactobacillus acidophilus, and especially Lactobacillus bulgaricus, significantly enhanced the survival and reproductive rates of nematodes. Salmonella enterica, and especially Escherichia coli O157:H7 (EHEC), had opposite effects. Genetic responses were activated mainly by EHEC. A total of 514 proteins were identified and quantified, and carbohydrate metabolism-related proteins existed in a higher proportion. These findings indicated that some gut bacteria are friendly or harmful to humans and in addition they may have similar beneficial or detrimental effects on parasites. This may be due to the regulation of expression of specific genes and proteins. Our studies provide a basis for developing therapies against parasitic infections from knowledge generated by studying the gut microbes of mammals. PMID- 26432294 TI - Estimates of coextinction risk: how anuran parasites respond to the extinction of their hosts. AB - Amphibians are known as the most threatened vertebrate group. One of the outcomes of a species' extinction is the coextinction of its dependents. Here, we estimate the extinction risk of helminth parasites of South America anurans. Parasite coextinction probabilities were modeled, assuming parasite specificity and host vulnerability to extinction as determinants. Parasite species associated with few hosts were the most prone to extinction, and extinction risk varied amongst helminth species of different taxonomic groups and life cycle complexity. Considering host vulnerability in the model decreased the extinction probability of most parasites species. However, parasite specificity and host vulnerability combined to increase the extinction probabilities of 44% of the helminth species reported in a single anuran species. PMID- 26432295 TI - Vasoconstriction induced by salivary gland extracts from ixodid ticks. AB - In their quest for blood, most haematophagous parasites secrete vasodilators in their saliva to counter the host haemostatic response of vasoconstriction. Surprisingly, salivary gland extracts from adult female Dermacentor reticulatus and Rhipicephalus appendiculatus ticks induced constriction in a rat femoral artery model; males induced vasoconstriction or vasodilation depending on the time of feeding. Based on comparative HPLC fractionation, the active compounds inducing vasoconstriction do not appear to be prostaglandins (which ticks normally use as vasodilators). Vasoconstriction may be unique to ixodid ticks, helping them control blood flow during their prolonged blood-feeding of up to 10 days or more. PMID- 26432296 TI - The miRnome of Fasciola hepatica juveniles endorses the existence of a reduced set of highly divergent micro RNAs in parasitic flatworms. AB - The liver fluke Fasciola hepatica is a foodborne zoonotic parasite affecting livestock worldwide, with increasing relevance in human health. The first developmental stage that the host meets after ingestion of the parasite is the newly excysted juvenile, that actively transverses the gut wall and migrates to its final location in the liver. The regulation of the early developmental events in newly excysted juveniles is still poorly understood and a relevant target for control strategies. Here we investigated the putative involvement of small regulatory RNAs in the invasion process. The small RNA population of the newly excysted juvenile fall into two classes, one represented by micro (mi)RNAs and a secondary group of larger (32-33 nucleotides) tRNA-derived sequences. We identified 40 different miRNAs, most of those belonging to ancient miRNAs conserved in protostomes and metazoans, notably with a highly predominant miR 125b variant. Remarkably, several protostomian and metazoan conserved families were not detected in consonance with previous reports of drastic miRnome reduction in parasitic flatworms. Additionally, a set of five novel miRNAs was identified, probably associated with specific gene regulation expression needs in F. hepatica. While sequence conservation in mature miRNA is high across the metazoan tree, we observed that flatworm miRNAs are more divergent, suggesting that mutation rates in parasitic flatworms could be high. Finally, the distinctive presence of tRNA-derived sequences, mostly 5' tRNA halves of selected tRNAs in the small RNA population of newly excysted juveniles, raises the possibility that both miRNA and tRNA fragments participate in the regulation of gene expression in this parasite. PMID- 26432297 TI - Effect of angiotensin II-induced arterial hypertension on the voltage-dependent contractions of mouse arteries. AB - Arterial hypertension (AHT) affects the voltage dependency of L-type Ca(2+) channels in cardiomyocytes. We analyzed the effect of angiotensin II (AngII) induced AHT on L-type Ca(2+) channel-mediated isometric contractions in conduit arteries. AHT was induced in C57Bl6 mice with AngII-filled osmotic mini-pumps (4 weeks). Normotensive mice treated with saline-filled osmotic mini-pumps were used for comparison. Voltage-dependent contractions mediated by L-type Ca(2+) channels were studied in vaso-reactive studies in vitro in isolated aortic and femoral arteries by using extracellular K(+) concentration-response (KDR) experiments. In aortic segments, AngII-induced AHT significantly sensitized isometric contractions induced by elevated extracellular K(+) and depolarization. This sensitization was partly prevented by normalizing blood pressure with hydralazine, suggesting that it was caused by AHT rather than by direct AngII effects on aortic smooth muscle cells. The EC50 for extracellular K(+) obtained in vitro correlated significantly with the rise in arterial blood pressure induced by AngII in vivo. The AHT-induced sensitization persisted when aortic segments were exposed to levcromakalim or to inhibitors of basal nitric oxide release. Consistent with these observations, AngII-treatment also sensitized the vaso-relaxing effects of the L-type Ca(2+) channel blocker diltiazem during K(+) induced contractions. Unlike aorta, AngII-treatment desensitized the isometric contractions to depolarization in femoral arteries pointing to vascular bed specific responses of arteries to hypertension. AHT affects the voltage-dependent L-type Ca(2+) channel-mediated contraction of conduit arteries. This effect may contribute to the decreased vascular compliance in AHT and explain the efficacy of Ca(2+) channel blockers to reduce vascular stiffness and central blood pressure in AHT. PMID- 26432299 TI - Dr Edgar R. R. Parker: his time and now. PMID- 26432298 TI - Determinants of utilisation of antenatal care and skilled birth attendant at delivery in South West Shoa Zone, Ethiopia: a cross sectional study. AB - BACKGROUND: Ethiopia has high maternal mortality ratio and poor access to maternal health services. Attendance of at least four antenatal care (ANC) visits and delivery by a skilled birth attendant (SBA) are important in preventing maternal deaths. Understanding the reasons behind the poor use of these services is important in designing strategies to address the problem. This study aimed to determine the coverage of at least four ANC visits and delivery by a SBA and to identify determinants of utilisation of these services in three districts in South West Shoa Zone, Ethiopia. METHODS: A cross-sectional survey of 500 women aged 15-49 years with a delivery in two years prior to the survey was conducted in Wolisso, Wonchi and Goro districts in February 2013. Data were collected using an interviewer administered questionnaire. Logistic regression models were used to explore determinants of ANC attendance and SBA at delivery. RESULTS: Coverage of at least four ANC visits and SBA at delivery were 45.5 and 28.6 %, respectively. Most institutional deliveries (69 %) occurred at the single hospital that serves the study districts. Attendance of at least four ANC visits was positively associated with wealth status, knowledge of the recommended number of ANC visits, and attitude towards maternal health care, but was negatively associated with woman's age. SBA at delivery was negatively associated with parity and time to the health facility, but was positively associated with urban residence, wealth, knowledge of the recommended number of ANC visits, perceived good quality of maternal health services, experience of a pregnancy/delivery related problem, involvement of the partner/family in decision making on delivery place, and birth preparedness. CONCLUSIONS: Raising awareness about the minimum recommended number of ANC visits, tackling geographical inaccessibility, improving the quality of care, encouraging pregnant women to have a birth and complication readiness plan and community mobilisation targeting women, husbands, and families for their involvement in maternal health care have the potential to increase use of maternal health services in this setting. Furthermore, supporting health centres to increase uptake of institutional delivery services may rapidly increase coverage of delivery by SBA and reduce inequity. PMID- 26432300 TI - The cleft child. PMID- 26432301 TI - Matched, equal, equipoise. PMID- 26432302 TI - Postsurgical volumetric airway changes in 2-jaw orthognathic surgery patients. PMID- 26432303 TI - Authors' response. PMID- 26432304 TI - The 101st man of influence. PMID- 26432305 TI - Diversified rapid maxillary expander or utility maxillary expander? PMID- 26432307 TI - Without undue influence. PMID- 26432308 TI - T.M. "Tom" Graber: a passion for orthodontics. PMID- 26432309 TI - Viken Sassouni: scientist, teacher, and mentor. PMID- 26432310 TI - Overview of orthodontic care for children with cleft lip and palate, 1915-2015. AB - The purpose of this article is to review and discuss the advances in the management of children born with cleft lip and palate (CLP) as it has evolved over the past 100 years. This overview is based on articles published in the American Journal of Orthodontics, which frequently changed its name, over the past century. Additionally, other journals will be cited as craniofacial anomalies became recognized during the 20th century and the biologic basis became refined, with the new discipline of genetics replacing the term hereditary and its connotations of eugenics. The Human Genome Project, completed in 2003, has now provided an understanding of syndromic and nonsyndromic CLP that has led to advances in the diagnosis and treatment of CLP in the 21st century. These evolving concepts will be discussed in an overview of the types of procedures published from 1915 to 2015 and the major transition in the mid-20th century from multiple uncoordinated interventions from various specialists to a coordinated team approach in which the orthodontist has a specific role in the timing and sequencing of interdisciplinary treatment goals. Major technologic advancements in treatment modalities and the contemporary approach to the health-related quality of life of the patient and the caregiver have resulted in their participation in treatment options and decisions. The requirement of informed consent reflects the legal doctrine that now emphasizes the ethical imperative of greater respect for patient autonomy in the decision-making process. The orthodontist no longer makes decisions alone, but rather with the team and the patient or the caregiver. PMID- 26432311 TI - Etiology of maxillary canine impaction: a review. AB - This article is a review that enumerates the causes of impaction of the maxillary permanent canines, including hard tissue obstructions, soft tissue lesions, and anomalies of neighboring teeth, and discusses the much-argued relationship between environmental and genetic factors. These phenomena have been shown in many investigations to accompany the diagnosis of canine impaction and have been presented as unrelated anomalous features, each of which is etiologically construed as genetic, including the aberrant canine itself. While in general the influence of genetics pervades the wider picture, a guidance theory proposes an alternative etiologic line of reasoning and interpretation of these studies, in which the same genetically determined anomalous features provide an abnormal milieu in which the canine is reared and from which it is guided in its misdirected and often abortive path of eruption. PMID- 26432312 TI - Oral health-related quality of life changes in standard, cleft, and surgery patients after orthodontic treatment. AB - INTRODUCTION: The purpose of this study was to investigate the effect of orthodontic treatment on oral health-related quality of life (OHRQoL) in groups of standard patients with severe malocclusions; cleft lip, cleft palate, or cleft lip and palate patients; and orthognathic surgery patients. METHODS: The study sample consisted of 83 consecutive patients undergoing treatment at the orthodontic unit of Christchurch Hospital, Christchurch, New Zealand, divided into 3 groups: 30 adolescents with severe malocclusions; 24 adolescents with cleft lip, cleft palate, or cleft lip and palate; and 29 adults with severe skeletal discrepancies requiring both orthognathic surgery and orthodontic treatment. Each patient completed the Short Form of the Oral Health Impact Profile (OHIP-14) questionnaire before and after orthodontic treatment. RESULTS: The baseline OHIP-14 subscale scores among the 3 study groups were significantly different, with the surgery patients having nearly twice the OHIP-14 scores of the other 2 groups for nearly half of the items (P <0.05). The surgery patients experienced the greatest reduction in OHIP-14 scores (ie, improvement in OHRQoL), with the largest effect sizes reported for the psychological discomfort (+2.73) and disability (+2.65) domains. The group with clefts experienced the smallest changes in OHIP-14 scores across all 7 domains (-0.03 to +0.63). After adjusting for age and sex, the surgical patients had a significantly greater reduction in pretreatment OHIP-14 scores than did the standard and the cleft patients (P <0.01). CONCLUSIONS: The effect of orthodontic treatment on OHRQoL varies for different patient groups even after adjusting for age and sex. The greatest improvement in OHRQoL occurred in adults with a need for orthognathic surgery, whereas the least improvement seemed to occur in adolescents with cleft lip, cleft palate, or cleft lip and palate. PMID- 26432313 TI - Growth-related changes of skeletal and upper-airway features in bilateral cleft lip and palate patients. AB - INTRODUCTION: The craniofacial morphology of subjects with cleft lip and palate differs from that of subjects without clefts. Subjects with bilateral cleft lip and palate tend to have maxillary retrognathism, a smaller mandible with an obtuse gonial angle, greater anterior upper and lower facial heights, and retroclined maxillary incisors. The purposes of this research were to compare the skeletal and upper-airway features of subjects with bilateral cleft lip and palate with the same features in control subjects without clefts and to determine the growth-related changes at different growth stages. METHODS: The sample comprised 212 subjects divided into 2 groups: 68 with bilateral cleft lip and palate, and 144 controls without clefts; each group was further divided into 4 subgroups according to growth stage using the cervical vertebral maturation stage method. The subgroups were defined as early childhood (stage 1), prepubertal (stage 2), pubertal (stage 3), and postpubertal (stage 4). The cephalometric variables were evaluated with 2-way analysis of variance and the Bonferroni test. RESULTS: Maxillary position showed no significant differences between the male groups. The maxilla was more prognathic at stage 2 and became more retrognathic at stages 3 and 4 in the females. The mandible was more retrusive in the bilateral cleft lip and palate subjects at stage 1 in males and at stages 3 and 4 in females. ANB was larger at stages 1 and 2, and it became similar to the controls at stages 3 and 4 in male and female bilateral cleft lip and palate subjects. Vertical growth was seen in the bilateral cleft lip and palate subjects regardless of sex, and no change was observed with age. Posterior airway space was narrower in all stages (except for stage 1 in females). Middle airway space was wider after stage 1 in the male and female bilateral cleft lip and palate subjects. Inferior airway space was narrower in the male bilateral cleft lip and palate patients at the early childhood and pubertal stages. CONCLUSIONS: Age- and sex-dependent differences in skeletal morphology and upper-airway widths of the bilateral cleft lip and palate subjects were identified when compared with the control subjects without clefts. PMID- 26432314 TI - Evaluation of root and alveolar bone development of unilateral osseous impacted immature maxillary central incisors after the closed-eruption technique. AB - INTRODUCTION: In this study, we evaluated root and alveolar bone development in unilateral osseous impacted immature maxillary central incisors by cone-beam computed tomography before and after closed-eruption treatment, in comparison with naturally erupted contralateral immature maxillary central incisors. METHODS AND RESULTS: The study included 30 patients, 20 boys and 10 girls, with a mean age of 8.44 +/- 1.20 years (range, 6.5-11.2 years). After treatment, the root lengths of both the impacted maxillary central incisors (10.66 +/- 2.10 mm) and the contralateral maxillary central incisors (11.04 +/- 1.76 mm) were significantly greater than their pretreatment values (6.67 +/- 1.94 and 9.02 +/- 2.13 mm, respectively). The root canal widths of the incisors decreased significantly after treatment. From the posttreatment cone-beam computed tomography images, the ratio of exposed root length to total root length and the thickness of the alveolar bone at 1 mm under the alveolar crest and at the apex were calculated to evaluate alveolar bone development. Impacted immature maxillary central incisors differed significantly from contralateral immature maxillary central incisors in labial exposed root length, labial ratio to total root length, and lingual alveolar crest. Clinical crown height was higher (statistically but not clinically) for the impacted incisors (9.87 mm) than for the contralateral incisors (9.37 mm). CONCLUSIONS: Impacted immature incisors grew to the same stage as did erupted contralateral incisors after closed eruption treatment. Both incisor types had some alveolar bone loss, and thin alveolar bone surrounded the roots. PMID- 26432315 TI - Comparison of transverse changes during maxillary expansion with 4-point bone borne and tooth-borne maxillary expanders. AB - INTRODUCTION: The purposes of this study were to evaluate and compare the dentoskeletal changes concurrent with 4-point bone-borne and tooth-borne rapid maxillary expanders in growing children. METHODS: The study was conducted with 20 growing girls (ages, 12 +/- 0.6 years) with posterior crossbite. They were divided into 2 equal groups; patients in one group were treated with a tooth borne maxillary hyrax expander (TBME), and those in the other group received a bone-borne maxillary hyrax expander (BBME) anchored directly to the palatal bone. Changes were assessed using cone-beam computed tomography. Images were taken before and immediately after expansion. RESULTS: Superimpositions of the 3 dimensional palatal images showed significant increases in skeletal widths at the canine, first premolar, and first molar areas in both groups. The TBME group had greater nasal width expansion. Regarding the transverse dentolinear measurements, significant increases were seen in both groups, whereas the TBME group showed a greater increase than the BBME group. Significant increases in the dentoangular measurements were seen in the TBME group only and were significantly greater than in the BBME group at the first premolars. CONCLUSIONS: There were significant increases in facial and maxillary widths for the BBME group and in nasal width for the TBME group. Both expanders produced basal bone expansion at the level of the hard palate. The TBMEs produced more dental expansion, buccal rolling, and a greater increase in nasal width than did the BBMEs. PMID- 26432316 TI - Effect of low-level laser therapy on orthodontic tooth movement into bone-grafted alveolar defects. AB - INTRODUCTION: The objective of this study was to investigate the effect of low level laser therapy (LLLT) on the rate of orthodontic tooth movement (OTM) into bone-grafted alveolar defects based on different healing states. METHODS: Ten male beagles were randomly allocated to 3 groups: group C, OTM alone as a control; group G, OTM into the grafted defects; group GL, OTM into the grafted defects with LLLT. The maxillary second premolars were protracted into the defects for 6 weeks, immediately (G-0 and GL-0) and at 2 weeks (G-2 and GL-2) after surgery. The defects were irradiated with a diode laser (dose, 4.5 J/cm(2)) every other day for 2 weeks. The rates of OTM and alveolar bone apposition, and maturational states of the defects were analyzed by histomorphometry, microcomputed tomography, and histology. RESULTS: The total amounts of OTM and new bone apposition rates were decreased by LLLT, with increased bone mineral density and trabecular maturation in the defects. Group GL-2 had the slowest movement with root resorption in relation to less woven bone in the hypermatured defect. CONCLUSIONS: LLLT significantly decreased the rate of OTM into the bone grafted surgical defects by accelerating defect healing and maturation, particularly when the start of postoperative OTM was delayed. PMID- 26432317 TI - Effect of physical activity level on orthodontic pain perception and analgesic consumption in adolescents. AB - INTRODUCTION: The objective of this study was to assess the effect of baseline physical activity level on orthodontic pain perception and analgesic consumption after orthodontic separator placement in adolescents. METHODS: One hundred fifty participants (mean age, 14.5 years; SD, 1.7 years; 73 girls, 77 boys) were included in this longitudinal study. The physical activity questionnaire was used to assess their baseline physical activity levels. Once participants completed the questionnaire, orthodontic separators were placed at the mesial and distal contact points of the maxillary and mandibular first molars. A 100-mm visual analog scale was used for pain assessment. Analgesic consumption was recorded as a binary response (yes/no). Both outcomes were assessed at 1 baseline time point and 7 follow-up time points (bedtime on days 1 to 7). A multilevel mixed-effect model analysis approach was used to analyze the longitudinal data. RESULTS: Of the 150 participants in the study, data from 137 were included in the analysis (mean age, 14.4 years; SD, 1.7 years; 65 girls, 72 boys). Compared with the low activity group (84 participants; 61.3%), the high-activity group (53 participants; 38.7%) experienced significantly less pain (mean estimate, -8.958; P = 0.0114; 95% confidence interval, -15.868 to -2.049) and consumed fewer analgesics (odds ratio, 0.443; P <0.0318; 95% confidence interval, 0.199 to 0.786) during the study period. CONCLUSIONS: Physical activity has a significant influence on orthodontic pain perception and analgesic consumption in adolescents undergoing orthodontic treatment. Further research is needed on this topic to elucidate the association between physical activity and orthodontic pain. PMID- 26432318 TI - Compliance by state-subsidized and self-pay orthodontic patients. AB - INTRODUCTION: Medicaid is a needs-based program in the United States that subsidizes medical and dental care for minors. The purpose of this study was to test for compliance differences between self-pay and Medicaid-supported patients. METHODS: Medicaid patient records (n = 88) were perused retrospectively for characteristics that distract from an orthodontist's workflow (missed appointments, broken brackets, treatment duration, and so on) and compared with a sample (n = 145) of self-pay patients from the same teaching clinic. Differences in treatment difficulty were adjusted by subject selection and statistically (analysis of covariance). RESULTS: Medicaid patients were younger (mean age, 14.1 vs 14.9 years) and significantly more likely to be dismissed from treatment (19% vs 4%), generally for noncompliance. Broken brackets and missed appointments were more common in the Medicaid sample. There was no difference in the number of appointments in those completing treatment, but treatment duration was significantly longer for the Medicaid patients who completed treatment (29 vs 25 months). Commute distance and estimated driving time were significantly shorter for the Medicaid-assisted group. CONCLUSIONS: Greater difficulty in managing Medicaid patients may partly explain why they are underserved. Prospective studies are needed to clarify the causes of the differences. PMID- 26432319 TI - Mandibular changes secondary to serial extractions compared with late premolar extractions and controls. AB - INTRODUCTION: Variations in treatment times for serial extraction and late premolar extraction patients may be due to differences in the time needed to flatten the occlusal curves. In this study, we compared tooth tipping and occlusal curves in patients treated by serial extractions or late premolar extractions with untreated controls. METHODS: Mandibular dental casts and cephalometric radiographs were collected from 90 subjects (30 Class I control subjects, 30 patients with serial extractions, and 30 with late premolar extractions) at 3 time points: T0, baseline for the controls and serial extraction patients; T1, after natural drift and preorthodontics for the controls and the serial extraction patients, and pretreatment for the late premolar extraction patients; and T2, after comprehensive orthodontic treatment for the serial extraction and the late premolar extraction groups. The long axes of the central incisor, canine, and first molar to the palatal plane were measured on digitized headfilms to determine the direction and the amount of tipping between the time points. Three occlusal curves were measured by sphere fitting cusp-tip landmarks on digitized mandibular casts. RESULTS: From T0 to T1, incisors and canines in the patients with serial extractions tipped distally. Molars at T1 in the patients with serial extractions were tipped forward more than in the late premolar extraction patients and the controls. From T1 to T2, canines and molars in the patients with serial extractions were uprighted. CONCLUSIONS: Serial extractions produce steeper occlusal curves and distal tipping of the incisors and canines after drift (T1). Posttreatment (T2) occlusal curves in the patients with serial extractions are steeper than in the late premolar extraction patients and controls (except for the curve of Spee). After the serial extractions, orthodontic treatment included incisor and canine proclination, with molar uprighting and occlusal curve flattening. PMID- 26432320 TI - Effect of maxillary protraction with alternating rapid palatal expansion and constriction vs expansion alone in maxillary retrusive patients: a single-center, randomized controlled trial. AB - INTRODUCTION: The objective of this randomized controlled trial was to investigate the effects of facemask protraction combined with alternating rapid palatal expansion and constriction (RPE/C) vs rapid palatal expansion (RPE) alone in the early treatment of maxillary retrusive patients. METHODS: Patients with a midface deficiency were recruited and randomly allocated into either the control group (RPE) or the intervention group (RPE/C). Eligibility criteria included the following: age 7 to 13 years old, Class III malocclusion, anterior crossbite, ANB less than 0 degrees , Wits appraisal less than -2 mm, A-Np less than 0 mm, and no cleft of lip or palate. The primary outcome was the degree of maxillary forward movement after treatment. The secondary outcomes were the changes of the other cephalometric variables after treatment and the treatment time. Simple randomization was carried out using a random number table at the beginning of the study. Envelopes containing the grouping information were used to ensure allocation concealment from the researchers. Blinding was applicable for cephalometric analysis only. Hyrax palatal expanders and facemask maxillary protraction were used in all patients. Patients in the RPE group were treated with rapid palatal expansion for 1 week. Patients in the RPE/C group were treated with RPE/C for 7 weeks. The expansion or constriction rate was 1 mm per day. Cephalometric analysis with traditional cephalometric measurements and an x-y coordinate system were used to compare the pretreatment and posttreatment cephalometric radiographs. Independent t tests were used to compare the data between the 2 groups. RESULTS: A total of 44 patients were randomized to either the RPE group or the RPE/C group in a 1:1 ratio. One subject in the RPE group was lost to follow-up during the treatment. Per-protocol analysis was used. All the other 43 patients reached the treatment completion criteria and were analyzed (RPE group: n = 21; RPE/C group: n = 22). The average protraction time was 10.84 months in the RPE group, which was significantly longer than that in the RPE/C group (9.06 months) (effect size [ES], 1.78 [95% CI, 0.15, 3.42; P = 0.033]). Maxillary forward movement increased by 3.04 mm in the RPE/C group, which was significantly greater than that in the RPE group (2.11 mm) (ES, -0.93 [95% CI, 1.65, -0.20; P = 0.013]). The counterclockwise rotation of the palatal plane was 1.73 degrees in the RPE/C group, which was significantly greater than that in the RPE group (0.83 degrees ) (ES, 0.90 [95% CI, 0.08, 1.73; P = 0.033]). The degree of mandibular downward and backward rotation was significantly smaller in the RPE/C group (P <0.05). No serious harm was observed during treatment and research. CONCLUSIONS: Facemask maxillary protraction with RPE/C might positively affect the forward movement of the maxilla compared with facemask protraction with RPE alone in the early treatment of maxillary retrusive patients. Although the differences between the groups were statistically significant for forward movement of the maxilla and rotation of the palatal and mandibular planes, these may not be clinically relevant, since the differences were less than 1 mm and 1 degrees , respectively. REGISTRATION: This trial was not registered. PROTOCOL: The protocol was not published before trial commencement. FUNDING: This research was supported by Peking University Research Fund. No conflict of interest is declared. PMID- 26432321 TI - Factors associated with patient and parent satisfaction after orthodontic treatment: a systematic review. AB - INTRODUCTION: Our objective was to identify factors associated with orthodontic treatment satisfaction of patients and their caregivers, when applicable. METHODS: MEDLINE via Ovid, PubMed, EBM Reviews and EMBASE via OVIDSP, LILACS, Web of Science, and Google Scholar were searched electronically. Reference lists of included articles were also screened for potential relevant studies missed during the electronic searches. Studies evaluating the satisfaction levels of patients or caregivers after orthodontic treatment were considered. Methodologic quality of the included studies was assessed using a modified Newcastle-Ottawa scale. RESULTS: Eighteen studies satisfied the inclusion criteria, representing 2891 patients and 464 parents. The risk of bias was moderate in 13 and low in 4 of the included articles. The studies used different questionnaires and timings to assess postorthodontic treatment satisfaction. Based on the available limited evidence, satisfaction was associated with perceived esthetic outcomes, psychological benefits, and quality of care. The latter was specifically linked to dentist-staff-patient interactions. Dissatisfaction was associated with treatment duration, pain levels and discomfort, and the use of retention appliances. When both assessments were available, the patient's and the parent's satisfaction levels were strongly correlated. CONCLUSIONS: Based on the limited available evidence with moderate risk of bias, we identified factors that appear to be more commonly associated with a high or low level of satisfaction. Consideration of these factors could be important for practitioners attempting to set realistic expectations of their patients and caregivers regarding orthodontic treatment outcomes. PMID- 26432322 TI - Treatment of a mandibular functional shift in an adolescent boy with temporomandibular disorder and crossbites. AB - A mandibular functional shift usually poses a challenge for orthodontists, especially when it is accompanied by a temporomandibular disorder (TMD). Accurate diagnosis and complete elimination of the etiologic factors are the keys to an esthetic and stable outcome. This article describes the treatment of a teenager with a mandibular functional shift, TMD symptoms, and facial asymmetry resulting from an asymmetric maxillary arch form and multiple crossbites as occlusal interferences. The treatment alternatives and effective orthodontic techniques are described. To optimize the treatment results and prevent the recurrence of the TMD after treatment, the displaced mandible was repositioned by full-time wearing of a splint for 10 months. Adhesive bite-blocks were used to maintain the newly acquired mandibular position during fixed appliance treatment. A series of nickel-titanium and stainless steel rectangular archwires was placed in the maxillary arch to reshape it for 8 months after alignment. Finally, the displaced mandible was steadily seated into its physiologic position with fine occlusion. The TMD symptoms disappeared and never relapsed after treatment. At 2 years 3 months of retention, there was good stability. The combined splint and fixed appliance approach resolved an intractable clinical problem and avoided using additional appliances. An esthetic, functional, and stable outcome was achieved that satisfied both the patient and his parents. PMID- 26432323 TI - Sagittal correction of adolescent patients with modified palatal anchorage plate appliances. AB - The palate has been reported to be a suitable skeletal anchorage site in adolescents and adults. This article introduces new treatment modalities for correction of sagittal discrepancies by molar protraction and distalization with a modified palatal anchorage plate appliance. The effectiveness and versatility of this method are demonstrated in 2 adolescent patients. PMID- 26432324 TI - Impact on perceived root resorption based on the amount of incisal inclination as determined from conventional panoramic radiography. AB - INTRODUCTION: Our objective was to measure the impact on perceived root resorption based on the amount of anteroposterior incisal inclination as determined in vitro from conventional panoramic radiography. METHODS: A rapid prototyping model was created to mimic different maxillary and mandibular incisal anteroposterior inclinations. Two titanium beads were placed on the incisors at the apical and incisal edges. Panoramic radiographs were obtained, with the incisors changing relative inclination by 10 degrees increments. The length was measured from the midpoint of the bead on the incisal edge to the midpoint of the bead on the apical edge. By using a length of wire of known size, this value was compared in all images to correct for image magnification. RESULTS: Changes to mandibular incisor anteroposterior inclinations, as either a theoretical proclination or retroclination, resulted in an increase of "apparent" root resorption on a panoramic radiograph. When the maxillary incisors were significantly and severely retroclined, they appeared larger than expected. When the maxillary incisors were mildly retroclined, the length was roughly similar to the theoretical model. When the maxillary incisors were mildly proclined, they appeared shorter than expected. CONCLUSIONS: The foreshortening or forelengthening of incisor root lengths because of incisor inclination vs root resorption cannot be reliably evaluated from panoramic images. The proposed theoretical model helps to understand the direction of the changes produced by the magnification factor. More severe scenarios where either the maxillary or the mandibular teeth are outside the focal trough have not been fully evaluated. The clinical impact of these changes is likely to be questionable. PMID- 26432325 TI - Litigation and Legislation. Heeding the advice of others. PMID- 26432326 TI - Nonparametric methods. PMID- 26432327 TI - International Day of Radiology 2015. PMID- 26432328 TI - Hsp90 regulates autophagy and plays a role in cancer therapy. AB - Nowadays, heat shock protein 90 (Hsp90), a highly conserved molecular chaperone, has become the target of antitumor drugs as a result of its close relationship with the occurrence and development, biological behavior, and prognosis of a tumor. Autophagy has attracted big attention recently for its paradoxical roles in cell survival and cell death, especially in the pathogenesis and treatment of cancer. Moreover, it has been verified that Hsp90 plays a role in autophagy via regulating the stability and activity of signaling proteins, and some Hsp90 inhibitors can induce autophagy. However, the underlying mechanisms for these important processes have not been clarified so far. In this study, we focus on the roles of Hsp90 in the regulation of autophagy, such as toll-like receptor (TLR)-mediated autophagy, Ulk1-mediated mitophagy, and chaperone-mediated autophagy (CMA). The roles of Hsp90 inhibitors in cancer therapy will also be elucidated. PMID- 26432330 TI - Authentication of newly established human esophageal squamous cell carcinoma cell line (YM-1) using short tandem repeat (STR) profiling method. AB - Cross-contamination during or early after establishment of a new cell line could result in the worldwide spread of a misidentified cell line. Therefore, newly established cell lines need to be authenticated by a reference standard method. This study was conducted to investigate the authenticity of a newly established epithelial cell line of human esophageal squamous cell carcinoma (ESCC) called YM 1 using short tandem repeat (STR) DNA profiling method. Primary human ESCC epithelial cells were cultured from the fresh tumor tissue of an adult female patient. Growth characteristics and epithelial originality of YM-1 cells were studied. Genomic DNA was isolated from YM-1 cells harvested at passage 22 and ESCC donor tumor sample on two different days to prevent probable DNA contamination. STR profiling was performed using AmpFlSTR(r) Identifiler(r) Plus PCR Amplification Kit. To address whether YM-1 cells undergo genetic alteration as the passage number increases, STR profiling was performed again on harvested cells at passage 51. YM-1 cells grew as a monolayer with a population doubling time of 40.66 h. Epithelial originality of YM-1 cells was confirmed using ICC/IF staining of cytokeratins AE1/AE3. The STR profile of the ESCC donor tumor sample was the same with YM-1 cells at passage 22. However, STR profile of the donor tumor sample showed an off-ladder (OL) allele in their D7S820 locus. Also, re profiling of YM-1 cells at passage 51 showed a loss of heterozygosity (LOH) at D18S51 locus. This suggests that long-term culture of cell lines may alter their DNA profile. Comparison of the DNA fingerprinting results in DSMZ, and ATCC STR profiling databases confirmed unique identity of YM-1 cell line. This study provides an easy, fast, and reliable procedure for authentication of newly established cell lines, which helps in preventing the spread of misidentified cells and improving the reproducibility and validity of experiments, consequently. PMID- 26432329 TI - Silencing of FGFR4 could influence the biological features of gastric cancer cells and its therapeutic value in gastric cancer. AB - To clarify the role of fibroblast growth factor receptor 4 (FGFR4) in gastric cancer (GC) and explore the therapeutic value of BGJ398 targeted to FGFR4. We constructed lentivirus vectors to stably knockdown FGFR4 expression in GC cells. Function assays in vitro and in vivo, treated with 5-fluorouracil (5-Fu) and BGJ398, were performed to study the change of biological behaviors of GC cells and related mechanism. The proliferation and invasive ability of HGC27 and MKN45 significantly decreased while the apoptosis rate of GC cells obviously increased in shRNA group (P < 0.05). The expressions of Bcl-xl, FLIP, PCNA, vimentin, p erk, and p-STAT3 significantly reduced while the expressions of caspase-3 and E cadherin markly enhanced in shRNA group. The proliferation abilities of GC cells were more significantly inhibited by the combination of BGJ398 and 5-Fu in shRNA group (P < 0.05). Compared to negative control (NC), the single and combination of 5-Fu and BGJ398 all significantly increased the apoptosis rate of GC cells, especially in the combination group (P < 0.01). The single and combination of 5 Fu and BGJ398 decreased the expressions of PCNA, Bcl-xl, and FLIP while increased the expression of caspase-3 in GC cells, especially in shRNA groups. Furthermore, knockdown of FGFR4 expression might prevent the growth of GC in vivo. Silencing of FGFR4 expression could weaken the invasive ability, increase the apoptosis rate, and decrease the proliferation ability of GC cells in vitro and in vivo. Furthermore, the combination of 5-Fu and BGJ398 had synergy in inhibiting the proliferation ability and increasing apoptosis rate of GC cells, directing a new target drug in GC. PMID- 26432331 TI - Prognostic impact of cytological fluid tumor markers in non-small cell lung cancer. AB - The serum tumor markers CYFRA 21-1, carcinoembryonic antigen (CEA), and squamous cell carcinoma antigen (SCCA) are useful in diagnosis and prognosis of non-small cell lung cancer (NSCLC). Cytologic tumor markers obtained during needle aspiration biopsies (NAB) of lung lesions are useful for NSCLC diagnosis. This study investigated the incremental prognostic value of cytologic tumor markers compared to serum tumor markers. This prospective study included 253 patients diagnosed with NSCLC by NAB with cytologic tumor marker analysis. Levels of cytologic CYFRA 21-1, CEA, SCCA, and their serum counterparts were followed up for survival analysis. Optimal cutoff values for each tumor marker were obtained for overall survival (OS) and progression-free survival (PFS) analyses. All patients were followed up for a median of 22.8 months. Using cutoff values of 0.44 ng/ml for C-SCCA, 2.0 ng/ml for S-SCCA, and 3.3 ng/ml for S-CYFRA, a multivariate analysis revealed that high S-SCCA (hazard ratio, HR, 1.84) and high C-SCCA (HR, 1.63) were independent predictive factors of OS. The 3-year overall survival rate was 55 vs. 80 % for high and low C-SCCA, respectively. Cytologic tumor marker level detection is easily obtainable and provides prognostic information for NSCLC. Cytologic tumor markers provide comparable prognostic information relative to serum tumor markers, with C-SCCA acting as a strong prognostic factor of overall survival and PFS. PMID- 26432332 TI - MicroRNA-92a promotes growth, metastasis, and chemoresistance in non-small cell lung cancer cells by targeting PTEN. AB - MicroRNA-92a (miR-92a) has been reported to play important roles in tumorigenesis of human various cancers. However, the roles and underlying molecular mechanism of miR-92a in non-small cell lung cancer (NSCLC) have not been totally elucidated. Therefore, the aims of this study were to determine the role of miR 92a and to elucidate its regulatory mechanism in NSCLC. We found that miR-92a was significantly upregulated in NSCLC tissues compared to matched adjacent normal lung tissues, and its expression is significantly associated with clinical characteristics of patients, including tumor, node, and metastasis (TNM) stage; tumor size; and lymph node metastasis (all P < 0.01). Function assays demonstrated that upregulation of miR-92a in NSCLC cells promoted cell proliferation, migration, and invasion, decreased apoptosis and caspase-3 activity, and enhanced chemoresistance of NSCLC cells, whereas downregulation of miR-92a showed the opposite effects. Moreover, phosphatase and tensin homolog (PTEN), a unique tumor suppressor gene, was confirmed as a direct target of miR 92a, and PTEN messenger RNA (mRNA) expression was decreased in NSCLC tissues and was inversely correlated with miR-92a. Downregulation of PTEN could mimic the same effects of miR-92a mimic in NSCLC cells and rescue the effects on NSCLC cells induced by miR-92a inhibitor. Taken together, these findings suggested that miR-92a could promote growth, metastasis, and chemoresistance in NSCLC cells at least partially by targeting PTEN. PMID- 26432333 TI - Exosomes from adriamycin-resistant breast cancer cells transmit drug resistance partly by delivering miR-222. AB - Breast cancer (BCa) is one of the major deadly cancers in women. However, treatment of BCa is still hindered by the acquired-drug resistance. It is increasingly reported that exosomes take part in the development, metastasis, and drug resistance of BCa. However, the specific role of exosomes in drug resistance of BCa is poorly understood. In this study, we investigate whether exosomes transmit drug resistance through delivering miR-222. We established an adriamycin resistant variant of Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line (MCF-7/Adr) from a drug-sensitive variant (MCF-7/S). Exosomes were isolated from cell supernatant by ultracentrifugation. Cell viability was assessed by MTT assay and apoptosis assay. Individual miR-222 molecules in BCa cells were detected by fluorescence in situ hybridization (FISH). Then, FISH was combined with locked nucleic acid probes and enzyme-labeled fluorescence (LNA-ELF-FISH). Individual miR-222 could be detected as bright photostable fluorescent spots and then the quantity of miR-222 per cell could be counted. Stained exosomes were taken in by the receipt cells. MCF-7/S acquired drug resistance after co-culture with exosomes from MCF-7/Adr (A/exo) but did not after co-culture with exosomes from MCF-7/S (S/exo). The quantity of miR-222 in A/exo-treated MCF-7/S was significantly greater than in S/exo-treated MCF-7/S. MCF-7/S transfected with miR 222 mimics acquired adriamycin resistance while MCF-7/S transfected with miR-222 inhibitors lost resistance. In conclusion, exosomes are effective in transmitting drug resistance and the delivery of miR-222 via exosomes may be a mechanism. PMID- 26432334 TI - Note of the methodological flaws in the paper entitled "Association between the G870A polymorphism of cyclin D1 gene and glioma risk". PMID- 26432335 TI - Enantiomeric CopA3 dimer peptide suppresses cell viability and tumor xenograft growth of human gastric cancer cells. AB - The CopA3 dimer peptide is a coprisin analog that has an anticancer effect against human cancer cells in vitro. In this study, we investigated the anticancer activity of the enantiomeric CopA3 dimer peptide in human gastric cancer cell lines as well as in an in vivo tumor xenograft model. Enantiomeric CopA3 reduced gastric cancer cell viability and exhibited cytotoxicity against cancer cells. Enantiomeric CopA3-induced cell death was mediated by specific interactions with phosphatidylserine and phosphatidylcholine, membrane components that are enriched in cancer cells, in a calcein leakage assay. Moreover, acridine orange/ethidium bromide staining, flow cytometric analysis, and Western blot analysis showed that enantiomeric CopA3 induced apoptotic and necrotic gastric cancer cell death. The antitumor effect was also observed in a mouse tumor xenograft model in which intratumoral inoculation of the peptide resulted in a significant decrease in the SNU-668 gastric cancer tumor volume. In addition, periodic acid-Schiff and hematoxylin staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay revealed apoptotic and necrotic cell death in tumor masses treated with greater than 150 MUg CopA3. Collectively, these results indicate that the enantiomeric CopA3 dimer peptide induces apoptosis and necrosis of gastric cancer cells in vitro and in vivo, indicating that the peptide is a potential candidate for the treatment of gastric cancer, which is a common cause of cancer and cancer deaths worldwide. PMID- 26432336 TI - Recovery patterns, histological observations and genetic integrity in Malus shoot tips cryopreserved using droplet-vitrification and encapsulation-dehydration procedures. AB - A droplet-vitrification procedure is described for cryopreservation of Malus shoot tips. Survival patterns, recovery types, histological observations, and genetic integrity were compared for Malus shoot tips cryopreserved using this droplet-vitrification procedure and an encapsulation-dehydration procedure that was previously reported by us. In both procedures, three types of shoot tip recovery were observed following cryopreservation: callus formation without shoot regrowth, leaf formation without shoot regrowth, and shoot regrowth. Three categories of histological observations were also identified in cross-sections of shoot tips recovered after cryopreservation using the two cryogenic procedures. In category 1, almost all of the cells (94-95%) in the apical dome (AD) were damaged or killed and only some cells (30-32%) in the leaf primordia (LPs) survived. In category 2, only a few cells (18-20%) in the AD and some cells (30 31%) in the LPs survived. In category 3, majority of the cells (60-62%) in the AD and some cells (30-33%) in the LPs survived. These data suggest that shoot regrowth is correlated to the presence of a majority of surviving cells in the AD after liquid nitrogen exposure. No polymorphic bands were detected by inter simple sequence repeats or by random amplified polymorphic DNA assessments, and ploidy levels analyzed by flow cytometry were unchanged when plants recovered after cryoexposure were compared to controls. The droplet-vitrification procedure appears to be robust since seven genotypes representing four Malus species and one hybrid recovered shoots following cryopreservation. Mean shoot regrowth levels of these seven genotypes were 48% in the droplet-vitrification method, which were lower than those (61%) in the encapsulation-dehydration procedure reported in our previous study, suggesting the latter may be preferred for routine cryobanking applications for Malus shoot tips. PMID- 26432337 TI - Complete genome sequence of Lactobacillus heilongjiangensis DSM 28069(T): Insight into its probiotic potential. AB - Lactobacillus heilongjiangensis DSM 28069(T) is a potential probiotic isolated from traditional Chinese pickle. Here we report the complete genome sequence of this strain. The complete genome is 2,790,548bp with the GC content of 37.5% and devoid of plasmids. Sets of genes involved in the biosynthesis of riboflavin and folate were identified in the genome, which revealed its potential application in biotechnological industry. The genome sequence of L. heilongjiangensis DSM 28069(T) now provides the fundamental information for future studies. PMID- 26432338 TI - Construction and immunological evaluation of recombinant Lactobacillus plantarum expressing HN of Newcastle disease virus and DC- targeting peptide fusion protein. AB - Newcastle disease virus (NDV) has been considered as one of the most severe threats to poultry industry. In this study, we constructed a series of food grade recombinant Lactobacillus plantarum (L. plantarum) strains (RLP) synthesizing either virus hemagglutinin-neuraminidase protein (HN) alone or HN fused with DC cells targeting peptides (DCpep), named RLP(pSIP409-HN) and RLP (pSIP409-HN DCpep), respectively. The immune responses and protective efficacy were then evaluated in chickens. Results showed that the presence of DCpep in RLP (pSIP409 HN-DCpep) group significantly increased the production of secretory immunoglobulin A (SIgA) in intestines and the percentages of CD3(+)CD4(+) T cells in spleen and peripheral blood leukocytes (P<0.05) compared to chickens immunized with RLP (pSIP409-HN). In addition, the similar enhancement effects were also observed with regard to trachea SIgA, T lymphocytes proliferation and survival rates after NDV challenge, even without significant statics differences. The results demonstrated the possibility to take use of DCpep as an immune adjuvant in the design of NDV vaccine. PMID- 26432339 TI - DNA microarray analysis of the cyanotroph Pseudomonas pseudoalcaligenes CECT5344 in response to nitrogen starvation, cyanide and a jewelry wastewater. AB - Pseudomonas pseudoalcaligenes CECT5344 is an alkaliphilic bacterium that can use cyanide as nitrogen source for growth, becoming a suitable candidate to be applied in biological treatment of cyanide-containing wastewaters. The assessment of the whole genome sequence of the strain CECT5344 has allowed the generation of DNA microarrays to analyze the response to different nitrogen sources. The mRNA of P. pseudoalcaligenes CECT5344 cells grown under nitrogen limiting conditions showed considerable changes when compared against the transcripts from cells grown with ammonium; up-regulated genes were, among others, the glnK gene encoding the nitrogen regulatory protein PII, the two-component ntrBC system involved in global nitrogen regulation, and the ammonium transporter-encoding amtB gene. The protein coding transcripts of P. pseudoalcaligenes CECT5344 cells grown with sodium cyanide or an industrial jewelry wastewater that contains high concentration of cyanide and metals like iron, copper and zinc, were also compared against the transcripts of cells grown with ammonium as nitrogen source. This analysis revealed the induction by cyanide and the cyanide-rich wastewater of four nitrilase-encoding genes, including the nitC gene that is essential for cyanide assimilation, the cyanase cynS gene involved in cyanate assimilation, the cioAB genes required for the cyanide-insensitive respiration, and the ahpC gene coding for an alkyl-hydroperoxide reductase that could be related with iron homeostasis and oxidative stress. The nitC and cynS genes were also induced in cells grown under nitrogen starvation conditions. In cells grown with the jewelry wastewater, a malate quinone:oxidoreductase mqoB gene and several genes coding for metal extrusion systems were specifically induced. PMID- 26432340 TI - Seasonality in physical activity and walking of healthy older adults. AB - BACKGROUND: An increasing number of older adults require improvements in their quality of life. Physical activities, particularly walking ability, are of primary importance for older adults. The influence of season on physical activity has not been sufficiently studied among older adults. Therefore, this report compared the physical activity and walking of older individuals between summer and winter seasons using a longitudinal study design in a community in a mid latitude area. METHODS: Participants in the study comprised 39 healthy community dwelling adults ranging in age from 65 to 80 years. Physical parameters and activities as well as the preferred speed of walking were measured at half-year intervals. RESULTS: Significant seasonal differences from summer to winter and from winter to summer were detected. Specifically, body fat percentage, single leg stance, walking speed, cadence, stride length, and trunk and head-trunk pitch ranges were greater in winter than in summer, whereas grip strength and steps per day were greater in summer. Temperature and total activity level were considered to be related to body fat percentage. Grip strength was thought to be affected by outdoor temperature. The possibility of relationships between increased activity per unit time in older adults and increased preferred walking speed, cadence, and stride length in winter temperatures was discussed. CONCLUSION: The seasonal climatic environment of the geographic area of this study affected the activity level of the participants. These results indicate that seasonality should be considered when analyzing physical activity and walking in older adults. PMID- 26432342 TI - Event-related potentials indicate that fluency can be interpreted as familiarity. AB - Recent evidence suggests that fluency may be capable of supporting recognition independently of familiarity. This hypothesis was further tested in the present study. 29 participants encoded name-brand and off-brand products in an incidental task. Participants then judged whether the product was old or new during two tests with products from one category (i.e., only name-brand or only off-brand products) and a mixed test (where both name-brand and off-brand products were shown). The ERP data elicited by off-brand products varied as a function of test format. During the mixed test, off-brand products were correlated with a FN400 effect, whereas a fluency ERP (old ERPs were more negative than new at parietal electrodes 225-400ms) was observed during the other test. Importantly, no FN400 was detected during this test. The ERP results suggest that viewing the off-brand products during the mixed test produced a familiarity experience; however, fluency supported recognition when viewing off-brand products on the other test. The results are strong evidence that top-down processing of visual features during recognition interprets the information relative to the context. This process results in either fluency or, in other contexts, it is interpreted as familiarity as the Discrepancy-Attribution Hypothesis (Whittlesea and Williams, 2001a, 2001b) contends. PMID- 26432341 TI - An investigation of care-based vs. rule-based morality in frontotemporal dementia, Alzheimer's disease, and healthy controls. AB - Behavioral changes in dementia, especially behavioral variant frontotemporal dementia (bvFTD), may result in alterations in moral reasoning. Investigators have not clarified whether these alterations reflect differential impairment of care-based vs. rule-based moral behavior. This study investigated 18 bvFTD patients, 22 early onset Alzheimer's disease (eAD) patients, and 20 healthy age matched controls on care-based and rule-based items from the Moral Behavioral Inventory and the Social Norms Questionnaire, neuropsychological measures, and magnetic resonance imaging (MRI) regions of interest. There were significant group differences with the bvFTD patients rating care-based morality transgressions less severely than the eAD group and rule-based moral behavioral transgressions more severely than controls. Across groups, higher care-based morality ratings correlated with phonemic fluency on neuropsychological tests, whereas higher rule-based morality ratings correlated with increased difficulty set-shifting and learning new rules to tasks. On neuroimaging, severe care-based reasoning correlated with cortical volume in right anterior temporal lobe, and rule-based reasoning correlated with decreased cortical volume in the right orbitofrontal cortex. Together, these findings suggest that frontotemporal disease decreases care-based morality and facilitates rule-based morality possibly from disturbed contextual abstraction and set-shifting. Future research can examine whether frontal lobe disorders and bvFTD result in a shift from empathic morality to the strong adherence to conventional rules. PMID- 26432344 TI - Water purifier cannot claim to be endorsed by doctors, India's advertising regulator says. PMID- 26432343 TI - Intact action segmentation in Parkinson's disease: Hypothesis testing using a novel computational approach. AB - Action observation is known to trigger predictions of the ongoing course of action and thus considered a hallmark example for predictive perception. A related task, which explicitly taps into the ability to predict actions based on their internal representations, is action segmentation; the task requires participants to demarcate where one action step is completed and another one begins. It thus benefits from a temporally precise prediction of the current action. Formation and exploitation of these temporal predictions of external events is now closely associated with a network including the basal ganglia and prefrontal cortex. Because decline of dopaminergic innervation leads to impaired function of the basal ganglia and prefrontal cortex in Parkinson's disease (PD), we hypothesised that PD patients would show increased temporal variability in the action segmentation task, especially under medication withdrawal (hypothesis 1). Another crucial aspect of action segmentation is its reliance on a semantic representation of actions. There is no evidence to suggest that action representations are substantially altered, or cannot be accessed, in non-demented PD patients. We therefore expected action segmentation judgments to follow the same overall patterns in PD patients and healthy controls (hypothesis 2), resulting in comparable segmentation profiles. Both hypotheses were tested with a novel classification approach. We present evidence for both hypotheses in the present study: classifier performance was slightly decreased when it was tested for its ability to predict the identity of movies segmented by PD patients, and a measure of normativity of response behaviour was decreased when patients segmented movies under medication-withdrawal without access to an episodic memory of the sequence. This pattern of results is consistent with hypothesis 1. However, the classifier analysis also revealed that responses given by patients and controls create very similar action-specific patterns, thus delivering evidence in favour hypothesis 2. In terms of methodology, the use of classifiers in the present study allowed us to establish similarity of behaviour across groups (hypothesis 2). The approach opens up a new avenue that standard statistical methods often fail to provide and is discussed in terms of its merits to measure hypothesised similarities across study populations. PMID- 26432345 TI - Medicaid and Women's Health Coverage Two Years into the Affordable Care Act. PMID- 26432347 TI - Pressure limited vesico-amniotic shunt allows normal lung growth in a fetal lamb model of obstructive uropathy. AB - BACKGROUND: In our fetal lamb model of lower urinary tract obstruction, a pressure limited shunt preserves bladder function and renal development. This study investigates the effects on pulmonary histology. METHODS: We created obstructive uropathy (OU) in 60-day gestation fetal lambs, ligating the urethra and urachus, and delivering them at term (130-145days). We compared pulmonary histology in 4 groups: group A, OU without shunt; group B, pressure limited shunt; group C, non-valved shunt. Shunts were inserted 3weeks post-obstruction. Group D were normal controls. RESULTS: We compared 27 fetuses: 7 fetuses in group A, 4 fetuses in group B, 2 fetuses in group C, and 14 fetuses in group D. There was no significant difference in lung volume in any group. In group A, there were some areas of atelectasis and incomplete alveolar formation histologically. The alveoli in group A lambs lungs had a predominance of type II cells, whereas group B lambs lungs were lined by type I epithelial cells and were essentially indistinguishable from controls. CONCLUSIONS: This study suggests that using a pressure-limited vesico-amniotic shunt in OU may preserve the renal tract and the lungs. PMID- 26432346 TI - Prospective Analysis of Health and Mortality Risk in Veteran and Non-Veteran Participants in the Women's Health Initiative. AB - BACKGROUND: The health of postmenopausal women veterans is a neglected area of study. A stronger empirical evidence base is needed, and would inform the provision of health care for the nearly 1 million U.S. women veterans currently 50 years of age or older. To this end, the present work compares salient health outcomes and risk of all-cause mortality among veteran and non-veteran participants of the Women's Health Initiative (WHI). METHODS: This study features prospective analysis of long-term health outcomes and mortality risk (average follow-up, 8 years) among the 3,706 women veterans and 141,009 non-veterans who participated in the WHI Observational Study or Clinical Trials. Outcome measurements included confirmed incident cases of cardiovascular disease (CVD), cancer, diabetes, hip fractures, and all-cause mortality. RESULTS: We identified 17,968 cases of CVD, 19,152 cases of cancer, 18,718 cases of diabetes, 2,817 cases of hip fracture, and 13,747 deaths. In Cox regression models adjusted for age, sociodemographic variables, and health risk factors, veteran status was associated with significantly increased risk of all-cause mortality (hazard ratio [HR], 1.13; 95% CI, 1.03-1.23), but not with risk of CVD (HR, 1.00; 95% CI, 0.90 1.11), cancer (HR, 1.04; 95% CI, 0.95-1.14), hip fracture (HR, 1.16; 95% CI, 0.94 1.43), or diabetes (HR, 1.00; 95% CI, 0.89-1.1). CONCLUSIONS: Women veterans' postmenopausal health, particularly risk for all-cause mortality, warrants further consideration. In particular, efforts to identify and address modifiable risk factors associated with all-cause mortality are needed. PMID- 26432348 TI - Adverse effects of perinatal nicotine exposure on reproductive outcomes. AB - Nicotine exposure during pregnancy through cigarette smoking, nicotine replacement therapies or e-cigarette use continues to be a widespread public health problem, impacting both fetal and postnatal health. Yet, at this time, there remains limited data regarding the safety and efficacy in using these nicotine products during pregnancy. Notably, reports assessing the effect of nicotine exposure on postnatal health outcomes in humans, including reproductive health, are severely lacking. Our current understanding regarding the consequences of nicotine exposure during pregnancy is limited to a few animal studies, which do not comprehensively address the underlying cellular mechanisms involved. This paper aims to critically review the current knowledge from human and animal studies regarding the direct and indirect effects (e.g. obesity) of maternal nicotine exposure, regardless of its source, on reproductive outcomes in pregnancy and postnatal life. Furthermore, this review highlights several key cellular mechanisms involved in these adverse reproductive deficits including oxidative stress, inflammation, and endoplasmic reticulum (ER) stress. By understanding the interplay of the cellular mechanisms involved, further strategies could be developed to prevent the reproductive abnormalities resulting from exposure to nicotine in utero and influence informed clinical guidelines for pregnant women. PMID- 26432349 TI - Estradiol promotes cells invasion by activating beta-catenin signaling pathway in endometriosis. AB - Endometriosis is an estrogen-dependent disease that involves the adhesion, invasion, and angiogenesis of endometrial tissues outside of the uterine cavity. We hypothesized that a link exists between estrogen and beta-catenin (beta catenin) signaling in the pathogenesis of endometriosis. Human endometrial stromal cells (HESCs) were separated from eutopic endometrial tissues that were obtained from patients with endometriosis. beta-catenin expression and cells invasiveness ability were up-regulated by 17beta-estradiol (E2) in an estrogen receptor (ESR)-dependent manner, whereas beta-catenin siRNA abrogated this phenomenon. Moreover, co-immunoprecipitation and dual immunofluorescence studies confirmed ESR1, beta-catenin, and lymphoid enhancer factor 1/T cell factor 3 co localization in the nucleus in HESCs after E2 treatment. To determine the role of beta-catenin signaling in the implantation of ectopic endometrium, we xenotransplanted eutopic endometrium from endometriosis patients into ovariectomized severe combined immunodeficiency mice. The implantation of the endometrium was suppressed by beta-catenin siRNA. Collectively, studies regarding beta-catenin signaling are critical for improving our understanding of the pathogenesis of estrogen-induced endometriosis, which can translate into the development of treatments and therapeutic strategies for endometriosis. PMID- 26432350 TI - Role of cysteine-58 and cysteine-95 residues in the thiol di-sulfide oxidoreductase activity of Macrophage Migration Inhibitory Factor-2 of Wuchereria bancrofti. AB - Macrophage Migration Inhibitory Factor (MIF) is the first human cytokine reported and was thought to have a central role in the regulation of inflammatory responses. Homologs of this molecule have been reported in bacteria, invertebrates and plants. Apart from cytokine activity, it also has two catalytic activities viz., tautomerase and di-sulfide oxidoreductase, which appear to be involved in immunological functions. The CXXC catalytic site is responsible for di-sulfide oxidoreductase activity of MIF. We have recently reported thiol disulfide oxidoreductase activity of Macrophage Migration Inhibitory Factor-2 of Wuchereria bancrofti (Wba-MIF-2), although it lacks the CXXC motif. We hypothesized that three conserved cysteine residues might be involved in the formation of di-sulfide oxidoreductase catalytic site. Homology modeling of Wba MIF-2 showed that among the three cysteine residues, Cys58 and Cys95 residues came in close proximity (3.23A) in the tertiary structure with pKa value 9, indicating that these residues might play a role in the di-sulfide oxidoreductase catalytic activity. We carried out site directed mutagenesis of these residues (Cys58Ser & Cys95Ser) and expressed mutant proteins in Escherichia coli. The mutant proteins did not show any oxidoreductase activity in the insulin reduction assay, thus indicating that these two cysteine residues are vital for the catalytic activity of Wba-MIF-2. PMID- 26432351 TI - Medicinal plants of the genus Anthocleista--A review of their ethnobotany, phytochemistry and pharmacology. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The genus Anthocleista of the Gentianaceae family contains 14 species of trees and shrub-like plants distributed in tropical Africa, in Madagascar and on the Comoros. Traditionally, they are commonly used in the treatment of diabetes, hypertension, malaria, typhoid fever, obesity, diarrhea, dysentery, hyperprolactinemia, abdominal pain, ulcer, jaundice, asthma, hemorrhoids, hernia, cancer, wounds, chest pains, inflammations, rheumatism, STDs, infertility and skin diseases. They serve as an anthelmintic, laxative, diuretic and contraceptive. This review aims to provide for the first time a repository of ethnopharmacological information while critically evaluating the relation between the traditional medicinal uses, chemical constituents and pharmacological activities of the Anthocleista species so as to unveil opportunities for future research. MATERIALS AND METHODS: A search for relevant information on Anthocleista species was performed on scientific databases (Pubmed, Google Scholar, SciFinder, Web of Science, Scopus, PubChem and other web sources such as The Plant List, Kew Botanical Garden and PROTA) and books, PhD and MSc dissertations for un-published resources. RESULTS: Out of the 14 species of Anthocleista, 6 have been reported in literature to be widely used in traditional medicine for the treatment of various ailments. The six species include: A. djalonensis, A. vogelii, A. nobilis, A. grandiflora, A. schweinfurthii, and A. liebrechtsiana. The chemical compounds isolated from Anthocleista species fall into the class of phytochemicals such as secoiridoids, nor-secoiridoids, xanthones, phytosterols, triterpenes, alkaloids, and others of which majority of the compounds were isolated from A. djalonensis and A. vogelii. The in vitro and in vivo pharmacological studies on the crude extracts, fractions and few isolated compounds of Anthocleista species showed antidiabetic, antiplasmodial, antimicrobial, hypotensive, spasmogenic, anti-obesity, antiulcerogenic, analgesic, anti-inflammatory, antioxidant, antitrypanosomal, anthelmintic, fertility, diuretic and laxative activities which supports most of their uses in traditional medicine. However, the bulk of the studies where centered on the antidiabetic, antiplasmodial and antimicrobial activities of Anthocleista species, although the evidence of its antiplasmodial effect was not convincing enough due to the discrepancies between the in vitro and in vivo results. CONCLUSION: A. djalonensis and A. vogelii are potential antidiabetic and antibacterial agents. The antibacterial potency relates to infections or diseases caused by E. coli, S. typhi and S. aureus such as urinary tract infections, typhoid, diarrhea, skin diseases, and food poisoning. Pharmacological research on this genus is quite elementary and limited, thus, more advanced research is necessary to isolate and determine the activities of bioactive compounds in vitro and in vivo, establish their mechanisms of action and commence the process of clinical research. PMID- 26432352 TI - Central European medicinal bryophytes in the 16th-century work by Caspar Schwenckfeld, and their ethnopharmacological origin. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ubiquitous bryophyte species are reported from European, American and Asian ethnopharmacies. Some of their traditional medicinal uses are similar in distant and isolated cultures, and moreover, medicinal properties of some bryophytes are currently confirmed as justified by their chemical constituents. Aims of the work: we identify bryophytes listed in a medicinal and botanical work from 1600, and compare their medicinal applications (known in Europe between 1530-1600) with other ethnopharmacological data about these species and with modern pharmacological knowledge. This way we attempt to display origins of medicinal usage of bryophytes in Central Europe. MATERIALS AND METHODS: Bryophyte species in bibliographical sources printed in Central Europe (starting from O. Brunfels' Herbarum vivae Eicones... Argentorati, 1530) were identified according to old and recent taxonomical references. Caspar Schwenckfeld's scientific output from 1600 was treated here as a summary of 16th century knowledge about medicinal bryophytes. RESULTS: Central European pharmacy about the year 1600 was familiar with the following bryophytes: Marchantia polymorpha L., Polytrichum commune Hedw., P. formosum Hedw. and Funaria hygrometrica Hedw. CONCLUSIONS: Between 1530-1600 in Central Europe the number of medicinal bryophytes increased from 2 (Lichen sive Hepatica and Polytrichon) to 4. Pharmaceutical usage of them was similar as in other, distant ethnopharmacies. Further 2-4 mosses (Rhytidiadelphus loreus and Rh. squarrosus; Thuidium tamariscinum and Th. delicatulum) were recognised as non-medicinal. PMID- 26432353 TI - Text mining for pharmacovigilance: Using machine learning for drug name recognition and drug-drug interaction extraction and classification. AB - Pharmacovigilance (PV) is defined by the World Health Organization as the science and activities related to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem. An essential aspect in PV is to acquire knowledge about Drug-Drug Interactions (DDIs). The shared tasks on DDI-Extraction organized in 2011 and 2013 have pointed out the importance of this issue and provided benchmarks for: Drug Name Recognition, DDI extraction and DDI classification. In this paper, we present our text mining systems for these tasks and evaluate their results on the DDI-Extraction benchmarks. Our systems rely on machine learning techniques using both feature-based and kernel-based methods. The obtained results for drug name recognition are encouraging. For DDI Extraction, our hybrid system combining a feature-based method and a kernel-based method was ranked second in the DDI-Extraction-2011 challenge, and our two-step system for DDI detection and classification was ranked first in the DDI Extraction-2013 task at SemEval. We discuss our methods and results and give pointers to future work. PMID- 26432354 TI - Exploring methods for identifying related patient safety events using structured and unstructured data. AB - Most healthcare systems have implemented patient safety event reporting systems to identify safety hazards. Searching the safety event data to find related patient safety reports and identify trends is challenging given the complexity and quantity of these reports. Structured data elements selected by the event reporter may be inaccurate and the free-text narrative descriptions are difficult to analyze. In this paper we present and explore methods for utilizing both the unstructured free-text and structured data elements in safety event reports to identify and rank similar events. We evaluate the results of three different free text search methods, including a unique topic modeling adaptation, and structured element weights, using a patient fall use case. The various search techniques and weight combinations tended to prioritize different aspects of the event reports leading to different search and ranking results. These search and prioritization methods have the potential to greatly improve patient safety officers, and other healthcare workers, understanding of which safety event reports are related. PMID- 26432355 TI - A context-aware approach for progression tracking of medical concepts in electronic medical records. AB - Electronic medical records (EMRs) for diabetic patients contain information about heart disease risk factors such as high blood pressure, cholesterol levels, and smoking status. Discovering the described risk factors and tracking their progression over time may support medical personnel in making clinical decisions, as well as facilitate data modeling and biomedical research. Such highly patient specific knowledge is essential to driving the advancement of evidence-based practice, and can also help improve personalized medicine and care. One general approach for tracking the progression of diseases and their risk factors described in EMRs is to first recognize all temporal expressions, and then assign each of them to the nearest target medical concept. However, this method may not always provide the correct associations. In light of this, this work introduces a context-aware approach to assign the time attributes of the recognized risk factors by reconstructing contexts that contain more reliable temporal expressions. The evaluation results on the i2b2 test set demonstrate the efficacy of the proposed approach, which achieved an F-score of 0.897. To boost the approach's ability to process unstructured clinical text and to allow for the reproduction of the demonstrated results, a set of developed .NET libraries used to develop the system is available at https://sites.google.com/site/hongjiedai/projects/nttmuclinicalnet. PMID- 26432357 TI - The Human Vocal Fold Layers. Their Delineation Inside Vocal Fold as a Background to Create 3D Digital and Synthetic Glottal Model. AB - OBJECTIVES: To distinguish the layers of the vocal fold at the submacroscopic level and determine their boundaries, thereby creating a basis for the construction of a digital 3D model of the human vocal folds. STUDY DESIGN: The submacroscopic delineation of individual layers of fixed vocal ligaments based on their structural differences. METHODS: Following tasks were performed: (1) Submicroscopic dissection of the vocal folds fixed in a solution with a low concentration of fixation substance (in this case, the muscular parts of the vocal folds were removed); (2) Using the CT and micro-MRI methods, we determined the position of the dense parts of the vocal folds; and (3) Using a modified plastination method, we preserved macroscopically natural appearance of all ligamentous and muscular layers. RESULTS: The vocal ligament is composed of several volumes of connective tissue. It is surrounded by layers of fibrous material permeated by liquid. Individual fibers stretch all the way to the fibrous casing (fascia) of the vocal muscle. The vocal fold layer surrounding the ligament externally has a stratified character. CONCLUSIONS: According to our findings, we infer that this ligament is a complex of several fibrous bundles which are surrounded by a thin layer of connective tissue. Below the surface of epithelium of the vocal fold run several separate bands which are closely adjacent to it. Therefore, we propose using the term ligamentous complex involving closely adjacent structures, instead of the vocal ligament only. We feel that it better reflects the functional and structural character of the whole formation. PMID- 26432356 TI - Renal proximal tubule Na,K-ATPase is controlled by CREB-regulated transcriptional coactivators as well as salt-inducible kinase 1. AB - Sodium reabsorption by the kidney is regulated by locally produced natriuretic and anti-natriuretic factors, including dopamine and norepinephrine, respectively. Previous studies indicated that signaling events initiated by these natriuretic and anti-natriuretic factors achieve their effects by altering the phosphorylation of Na,K-ATPase in the renal proximal tubule, and that protein kinase A (PKA) and calcium-mediated signaling pathways are involved. The same signaling pathways also control the transcription of the Na,K-ATPase beta subunit gene atp1b1 in renal proximal tubule cells. In this report, evidence is presented that (1) both the recently discovered cAMP-regulated transcriptional coactivators (CRTCs) and salt-inducible kinase 1 (SIK1) contribute to the transcriptional regulation of atp1b1 in renal proximal tubule (RPT) cells and (2) renal effectors, including norepinephrine, dopamine, prostaglandins, and sodium, play a role. Exogenously expressed CRTCs stimulate atp1b1 transcription. Evidence for a role of endogenous CRTCs includes the loss of transcriptional regulation of atp1b1 by a dominant-negative CRTC, as well as by a CREB mutant, with an altered CRTC binding site. In a number of experimental systems, SIK phosphorylates CRTCs, which are then sequestered in the cytoplasm, preventing their nuclear effects. Consistent with such a role of SIK in primary RPT cells, atp1b1 transcription increased in the presence of a dominant-negative SIK1, and in addition, regulation by dopamine, norepinephrine, and monensin was disrupted by a dominant negative SIK1. These latter observations can be explained if SIK1 is phosphorylated and inactivated in the presence of these renal effectors. Our results support the hypothesis that Na,K-ATPase in the renal proximal tubule is regulated at the transcriptional level via SIK1 and CRTCs by renal effectors, in addition to the previously reported control of the phosphorylation of Na,K ATPase. PMID- 26432358 TI - Estrogen suppresses breast cancer proliferation through GPER / p38 MAPK axis during hypoxia. AB - Breast cancer cells frequently experience hypoxia which is associated with resistance to hormonal therapy and poor clinical prognosis, making it important to understand the function of estrogen under hypoxic condition. Here, we demonstrate that estrogen suppresses breast cancer cell growth under hypoxia, through inhibition at G1/S phase of cell cycle, by elevation of p21 expression. The involvement of GPER in estrogen mediated growth arrest was elucidated using specific ligands and siRNA. Although, estrogen was observed to activate both p44/42 and p38 MAPK signaling, pharmacological inhibition and silencing of p38 MAPK abrogated the induction of p21 expression and growth arrest, during hypoxia. The involvement of estrogen induced ROS in the p38 MAPK mediated p21 expression and cell growth arrest was established by observing that scavenging of ROS by NAC abrogated p38 MAPK activation and p21 expression during hypoxia. In conclusion, Estrogen suppresses breast cancer growth by inhibiting G1/S phase transition through GPER/ROS/p38 MAPK/p21 mediated signaling during hypoxic condition. PMID- 26432359 TI - Breast conservative surgery and local recurrence. AB - INTRODUCTION: Breast conservation is a legacy of Umberto Veronesi who laid the groundwork for the preservation of the body image of women affected by breast cancer (BC) with the Milan I study in the late 70ies of the last millennium. Breast conservative surgery (BCS) has two aspects: oncological safety of tumour resection with free margins and aesthetic preservation of the breast. Determinants of local control used to be T-size, nodal status and receptor status until biologically driven concepts defined risk of recurrence on the basis of molecular portraits. We explored whether these concepts of intrinsic subtypes prove at a large scale in the context of BCS and which surgical techniques procure best oncological and aesthetic outcomes, avoiding re-excision and necessity of conversion to mastectomy. PATIENTS AND METHODS: We analyzed 1035 BCS patients with primary unilateral breast cancer (2004-2009) with regards to the local recurrence as a function of tumour location, surgical technique, resection volume, T-size, nodal status, grading, histopathological and intrinsic subtype and margins. RESULTS: Five surgical techniques were applied to 944 eligible patients at a median follow-up of 5.2 years with the following frequency: Glandular rotation mammoplasty (63.8%), tumour-adapted rotation mammoplasty (20.9%), dermoglandular rotation mammoplasty (6.7%), 4.4% (lateral thoracic wall advancement), 0.7% latissimus dorsi flap (0.7%) and others (13.5%). Tumour-free margins were achieved in 88.6% of all patients at first surgery. Recurrence was independent of the surgical technique used, resection volume, T-size (in a T1/T2 cohort), nodal status (in low N-stages: NO/N1) and histopathology (inv.-ductal vs. lobular), however non-invasive subtype (DCIS), high grading (G3 vs. G1), non luminal Her2 positive BC and triple-negative breast cancer (TNBC) were significantly associated with local recurrence. CONCLUSIONS: Five defined oncoplastic principles presented in our nomogramme (targeted breast surgery) allow the reconstruction of major segmental resection defects during breast conserving therapy with high clinical applicability and result in favorable oncological and aesthetic outcome. Recurrence was not a function of traditional prognostic factors like T-size or nodal status (in a T1/T2, N0/N1 cohort), but of grading, intrinsic subtypes and non-invasive breast cancer components. Lobular histology, multi-centricity and DCIS were predictive for breast preservation failure and conversion to mastectomy. PMID- 26432360 TI - Optimal surgical management for high-risk populations. AB - The recognition that breast cancer is a group of genetically distinct diseases with differing responses to treatment and varying patterns of both local and systemic failure has led to many questions regarding optimal therapy for those considered to be high risk. Young patients, patients with triple-negative breast cancer (TNBC), and those who harbor a deleterious mutation in BRCA1 or BRCA2 are frequently considered to be at highest risk of local failure, leading to speculation that more-aggressive surgical treatment is warranted in these patients. For both age and the triple-negative subtype, it appears that the intrinsic biology which imparts inferior outcomes is not overcome with mastectomy; therefore, a recommendation for more extensive surgical therapy among these higher-risk groups is not warranted. For those at inherited risk, a more aggressive surgical approach may be preferable, however; patient age, ER status, stage of the index lesion, and individual patient preferences should all be considered in the surgical decision-making process. PMID- 26432361 TI - Direct injection human plasma analysis for the quantification of antihypertensive drugs for therapeutic drug monitoring using hydrophilic interaction liquid chromatography/electrospray ionization mass spectrometry. AB - The concept of personalized medicine is related to the development of new sensitive, precise and accurate analytical methods for therapeutic drug monitoring. In this article a rapid, sensitive and specific method was developed for the quantification of aliskiren, losartan, valsartan and hydrochlorothiazide in human plasma. Sample preparation was performed by protein precipitation with acetonitrile followed by filtration. All analytes and the internal standard (tiamulin) were separated by hydrophilic interaction liquid chromatography using an X-Bridge-HILIC analytical column (150.0*2.1mm i.d., particle size 3.5MUm) under isocratic elution. The mobile phase was composed of a 10% 5mM ammonium formate water solution pH 4.5, adjusted with formic acid, in acetonitrile and pumped at a flow rate of 0.25mLmin(-1). The assay was linear over the concentration range of 5-500ngmL(-1) for all the analytes. Intermediate precision was less than 5.2% over the tested concentration ranges. The method is the first reported application of HILIC in the analysis antihypertensives in human plasma. With a small sample size (50MUL human plasma) and a run time less than 6.0min for each sample the method can be used to support a wide range of clinical studies and therapeutic drug monitoring. PMID- 26432363 TI - Understanding the dissolution of cellulose in 1-butyl-3-methylimidazolium acetate+DMAc solvent. AB - Cellulose solvent ([C4mim][CH3COO]/DMAc) could be obtained by adding N,N dimethylacetamide (DMAc) in 1-butyl-3-methylimidazolium acetate ([C4mim][CH3COO]). The solubilities of cellulose in [C4mim][CH3COO]/DMAc solvents were determined at 25 degrees C. The effects of molar ratio of DMAc to [C4mim][CH3COO] on cellulose solubility and the possible dissolution mechanism of cellulose in [C4mim][CH3COO]/DMAc solvent have been studied. Moreover, the regenerated cellulose from [C4mim][CH3COO]/DMAc solvent were characterized by X ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA). It was found that, cellulose was more readily dissolved in [C4mim][CH3COO]/DMAc solvent than in a neat [C4mim][CH3COO], which mainly attributed to the increased "free" [CH3COO](-) anions and [C4mim](+) cations which result from the dissociation of [C4mim][CH3COO] by DMAc. Moreover, the regenerated cellulose from [C4mim][CH3COO]/DMAc solvent displayed good thermostability and similar molecular structure to the original cellulose. PMID- 26432364 TI - Effect of chemical modification on molecular structure and functional properties of Musa AAB starch. AB - Starch extracted from Musa AAB (poovan banana) was subjected to acetylation, acid thinning and oxidation. The effect of the treatments on molecular structure and functional properties of starch were analysed. Chemical composition revealed that non-starch components were reduced after chemical treatment. Amylose content of starch decreased on acetylation from 24.16% to 20.90%, whereas it increased to 24.50% and 25.5% on oxidation and acid-thinning, respectively. X-ray diffraction pattern of modified starches showed B-type crystalline structure with peaks at 2theta=5.5 degrees , 15.0 degrees , 17.1 degrees and 23.5 degrees ; which were parallel with the pattern observed in case of native starch. Swelling capacity of starch granules was found to reduce by acid-thinning and oxidation but acetylation induced to increase it. The percentage of colour (L*, a* and b*), solubility and water absorption capacities varied significantly from native starch after chemical modification. Changes in gelatinisation temperatures and enthalpy value of starches were observed in modified starches and it is varied according to reaction conditions. Pasting properties of the starches was increased by acetylation and oxidation while acid-thinning reduced it (P<0.05). PMID- 26432362 TI - The C4 region as a target for HIV entry inhibitors--NMR mapping of the interacting segments of T20 and gp120. AB - The peptide T20, which corresponds to a sequence in the C-terminal segment of the HIV-1 transmembrane glycoprotein gp41, is a strong entry inhibitor of HIV-1. It has been assumed that T20 inhibits HIV-1 infection by binding to the trimer formed by the N-terminal helical region (HR1) of gp41, preventing the formation of a six helix bundle by the N- and C-terminal helical regions of gp41. In addition to binding to gp41, T20 was found to bind to gp120 of X4 viruses and this binding was suggested to be responsible for an alternative mechanism of HIV 1 inhibition by this peptide. In the present study, T20 also was found to bind R5 gp120. Using NMR spectroscopy, the segments of T20 that interact with both gp120 and a gp120/CD4M33 complex were mapped. A peptide corresponding to the fourth constant region of gp120, sC4, was found to partially recapitulate gp120 binding to T20 and the segment of this peptide interacting with T20 was mapped. The present study concludes that an amphiphilic helix on the T20 C-terminus binds through mostly hydrophobic interactions to a nonpolar gp120 surface formed primarily by the C4 region. The ten- to thousand-fold difference between the EC50 of T20 against viral fusion and the affinity of T20 to gp120 implies that binding to gp120 is not a major factor in T20 inhibition of HIV-1 fusion. Nevertheless, this hydrophobic gp120 surface could be a target for anti-HIV therapeutics. PMID- 26432365 TI - Development of grafted xyloglucan micelles for pulmonary delivery of curcumin: In vitro and in vivo studies. AB - A novel grafted copolymer consisting of l-lactide grafted xyloglucan was synthesized by polymerization reaction and characterized. The grafted copolymers were analyzed by Fourier-transform infrared spectrometry (FTIR) and (1)H nuclear magnetic resonance ((1)H NMR) was performed to confirm the grafting of l-poly lactic acid on xyloglucan. The grafted polymer forms micelles at the critical micelle concentration of 0.0150 wt% with the average particle size of 102 nm, as determined by particle size analyzer. The zeta potential of the curcumin loaded micelles was -18.2 mV, an acceptable drug loading efficiency of 68.9 +/- 0.02% and the entrapment efficiency of 96.38 +/- 0.2%. The release study for 5h showed a sustained release property. In vitro assessment demonstrates suitability of micelles as dry powder for inhalation. In vivo studies showed significant improvement in bioavailability on pulmonary administration of curcumin micelles as DPI formulation. The potential for pulmonary delivery curcumin loaded in micelles was evaluated. In conclusion, polymeric micelle based on a newly synthesized grafted xyloglucan could be suitable carrier for pulmonary delivery of curcumin. PMID- 26432367 TI - Purification and antibiofilm activity of AHL-lactonase from endophytic Enterobacter aerogenes VT66. AB - The opportunistic pathogen Pseudomonas aeruginosa uses biofilm lifestyle to resist antibiotic treatment. In our study, endophytic bacterium Enterobacter aerogenes VT66 quenched the N-acyl homoserine lactone (AHL) molecules produced by P. aeruginosa PAO1. The quorum quenching activity was attributed to the presence of AHL-lactonase. The AHL-lactonase was purified using column chromatography and purified AHL-lactonase was applied for the control of biofilm formation in P. aeruginosa PAO1. The results showed that purified AHL-lactonase obtained with a molecular weight about 30kDa was able to inhibit more than 70% of biofilm in P. aeruginosa PAO1 (P<0.001). Antibiofilm activity of AHL-lactonase was correlated well with results from staining technique used to determine inhibition of biomass and viable cell activity. Therefore, results unambiguously confirm that the AHL lactonase from E. aerogenes VT66 could be used as antibiofilm therapeutics in P. aeruginosa associated biomedical applications. PMID- 26432366 TI - Preparation of lignosulfonate-acrylamide-chitosan ternary graft copolymer and its flocculation performance. AB - As flocculant plays an important role in wastewater treatment, searching for high efficient and cost-effective flocculants has always become the challenge in chemical industry. In the current work, lignosulfonate-acrylamide-chitosan ternary copolymer was designed and prepared as a new kind of flocculant. The elemental analysis and structure characterization of FTIR and XRD showed that acrylamide successfully grafted onto the two natural polymers and amorphous macromolecules were formed. The natural polymers-based flocculant was water soluble and pH independent. As it had multiple functional groups from the raw materials, the amphoteric flocculant showed high color removal efficiency to anionic (acid blue 113, >95%), neutral (reactive black 5, >95%) and cationic dyes (methyl orange, >50%) in a wide range of flocculant dosage and pH windows. The ternary flocculant, based on lignosulfonate, chitosan, and acrylamide, might be a promising material in practical applications from the perspective of cost, source and performance. PMID- 26432368 TI - Isolation, purification, and antioxidant activities of degraded polysaccharides from Enteromorpha prolifera. AB - In the present study, purification and characterization of enzymatic hydrolysates of polysaccharide from Enteromorpha prolifera (HPE) are described. HPE was sequentially purified by DEAE Cellulose-52 chromatography and Sephadex G-100 chromatography to afford three fractions, namely, PHPE1, PHPE2, and PHPE3. Molecular weights of these three fractions were measured to be 103, 45.4, and 9.8kDa, respectively, using high performance gel permeation chromatography (HPGPC). The three fractions were evaluated for their antioxidant activities by determining their ability to scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH), hydroxyl, and superoxide anion radicals. PHPE2 was found to possess the strongest scavenging ability. GC-MS analysis indicates that PHPE2 is mainly composed of mannose, xylose, and glucose. PMID- 26432369 TI - Effect of ultrasonication, pH and heating on stability of apricot gum lactoglobuline two layer nanoemulsions. AB - The objectives of this study were to evaluate the effect of apricot gum lactoglobuline (AG/LgC) ratio, thermal treatment, sonication with different times and amplitudes and pH, on double layer sunflower oil in water emulsion stability. The emulsion stability was determined by the evaluation of emulsion performance indices including particle size, zeta potential, creaming and emulsion volume stability during 10 days of storage. Applying AG and LgC with the ratio of 12.5:1 AG:LgC, in order to obtain double layer oil in water emulsion, could result in a completely stable nano-emulsions during 10 days storage in room temperature. The ultrasound treatment significantly increased the emulsion stability. A 10min ultrasound treatment with the amplitude of 25% was the optimum conditions for ultra-sonication. The best temperature for thermal treatment and the best pH, in order to improve the emulsion's stability, was 50 degrees C and 3, respectively. PMID- 26432370 TI - Synthesis of magnetic graphene nanocomposites decorated with ionic liquids for fast lead ion removal. AB - Seeking highly-efficient, low-cost and robust methods to remove metal ions from aqueous solutions is very much in demand. Here, we developed a novel magnetic composite bio-adsorbent, graphene oxide and magnetic chitosan-ionic liquids (GOMCS-ILs), for removing Pb(II) from water. This was the first time to combine ionic liquids and graphene oxide and magnetic chitosan, and apply to the adsorption of metal ions. The addition of ionic liquids can not only improve the dispersivity of the adsorbent, but also increase the adsorption sites. The characteristic result of FTIR, SEM, and XRD showed that GOMCS-ILs were prepared with large surface area and good magnetic responsiveness. The influence of various analytical parameters on the adsorption of Pb(II) such as pH, contact time, and initial ion concentration were studied in detail. The adsorption followed a pseudo second order kinetics. The equilibrium adsorption was well described by the Langmuir isotherm model and the maximum adsorption capacity was to be 85mgg(-1). Moreover, the GOMCS-ILs could be repeatedly used by simple treatment without obvious structure and performance degradation. These results demonstrated the potential applications of GOMCS-ILs microspheres in efficient removal of Pb(II) from wastewater and deep-purification of polluted water. PMID- 26432371 TI - Biodegradable polymer based ternary blends for removal of trace metals from simulated industrial wastewater. AB - The ternary blends consisting of Chitosan (CS), Nylon 6 (Ny 6) and Montmorillonite clay (MM clay) were prepared by the solution blending method with glutaraldehyde. The prepared ternary blends were characterization by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Thermo gravimetric analysis (TGA), Differential scanning calorimetry (DSC) and Scanning electron microscope (SEM). The FTIR results showed that the strong intermolecular hydrogen bondings were established between chitosan, nylon 6 and montmorillonite clay. TGA showed the thermal stability of the blend is enhanced by glutaraldehyde as Crosslink agent. Results of XRD indicated that the relative crystalline of the pure chitosan film was reduced when the polymeric network was reticulated by glutaraldehyde. Finally, the results of scanning electron microscopy (SEM) indicated that the morphology of the blend was rough and heterogenous. Further, it confirms the interaction between the functional groups of the blend components. The extent of removal of the trace metals was found to be almost the same. The removal of these metals at different pH was also done and the maximum removal of the metals was observed at pH 4.5 for both trace metals. Adsorption studies and kinetic analysis have also been made. Moreover, the protonation of amine groups is induced an electrostatic repulsion of cations. When the pH of the solution was more than 5.5, the sorption rate began to decrease. Besides, the quantity of adsorbate on absorbent was fitted as a function in Langmuir and Freundlich isotherm. The sorption kinetics was tested for pseudo first order and pseudo second order reaction. The kinetic experimental data correlated with the second order kinetic model and rate constants of sorption for kinetic models were calculated and accordingly, the correlation coefficients were obtained. PMID- 26432372 TI - Schiff base - Chitosan grafted L-monoguluronic acid as a novel solid-phase adsorbent for removal of congo red. AB - A novel modified chitosan adsorbent (GL-SBCS) was synthesized by covalently grafting a Schiff base-chitosan (SBCS) onto the surface of l-monoguluronic acid. Physico-chemical investigation on the adsorption of congo red, an anionic azo dye by GL-SBCS has been carried out. The effect of different weight contents of chitosan in GL-SBCS composite, adsorbent dosage, initial pH and contract time were studied in detail using batch adsorption. Results showed that GL-SBCS exhibited better than normal CS and l-monoguluronic acid. Further investigation demonstrated that the adsorption pattern fitted well with the Langmuir model (R(2)>0.99) but less-satisfied the Freundlich model. Both ionic interaction as well as physical forces is responsible for binding of congo red with GL-SBCS as determined by zeta potential measurement Both sodium chloride and sodium dodecyl sulfate significantly influenced the adsorption process. SBCS would be a good method and resource to increase absorption efficiency for the removal of anionic dyes in a wastewater treatment process. PMID- 26432373 TI - Optimization of rhamnolipid production by biodegrading bacterial isolates using Plackett-Burman design. AB - Biosurfactants are biological surfactants produced by microorganisms. Pseudomonas species are well known for the production of the rhamnolipid biosurfactant. In this work, the production of rhamnolipid biosurfactant by Pseudomonas spp. was investigated and further optimized. Two Plackett-Burman designs to study the effect of carbon source, nitrogen source, C/N ratio, iron concentration, magnesium concentration, phenol toxicity, pH, temperature, agitation and sampling time were tested. The first design revealed an optimization that increased biosurfactant productivity by almost two to fivefolds for the tested isolates. However, using the second design showed no remarkable increase in biosurfactant productivity. An additional validation run was adopted using the predicted optimal medium with predicted optimal conditions. The validation run showed remarkable increase in the productivity of the tested isolates. The use of microorganisms with biodegradation ability coupled with optimization of the parameters affecting productivity provides an efficient strategy for biosurfactant production. PMID- 26432375 TI - Thoracic outlet syndrome. PMID- 26432374 TI - Therapeutic efficacy of a polysaccharide isolated from Cordyceps sinensis on hypertensive rats. AB - This study was aimed to investigate the antihypertensive effect of a polysaccharide fraction from Cordyceps sinensis on spontaneously hypertensive rats (SHR). The CSP1, one component of Cordyceps sinensis polysaccharides (CSP), was obtained after water extraction, deproteinization, de-colorization and purification with DEAE-cellulose 52. And a more homogeneous component CSP1-2 was obtained using Sepharose CL-6B chromatography. CSP1-2 mainly consisted of mannose, glucose and galactose in a molar ratio of about 2:2:1 and its average molecular weight was approximately 2.70*10(4)Da. Pharmacological tests showed that CSP1, in which the CSP1-2 was its main component, had antihypertensive effect by stimulating the secretion of vasodilator NO, decreasing the level of ET 1, epinephrine, noradrenaline and angiotensin II, inhibiting the increase of transforming growth factor beta1 (TGF-beta1) and lowering the level of inflammatory mediator of C-reactive protein (CRP). These results suggested that CSP1 may possess high potential in treating hypertension. PMID- 26432377 TI - Observation of interactive behavior increases corticospinal excitability in humans: A transcranial magnetic stimulation study. AB - In humans, observation of others' behaviors increases corticospinal excitability (CSE), which is interpreted in the contexts of motor resonance and the "mirror neuron system" (MNS). It has been suggested that observation of another individual's behavior manifests an embodied simulation of his/her mental state through the MNS. Thus, the MNS may involve understanding others' intentions of behaviors, thoughts, and emotions (i.e., social cognition), and may therefore exhibit a greater response when observing human-interactive behaviors that require a more varied and complex understanding of others. In the present study, transcranial magnetic stimulation was applied to the primary motor cortex of participants observing human-interactive behaviors between two individuals (c.f. one person reaching toward an object in another person's hand) and non interactive individual behavior (c.f. one person reaching toward an object on a dish). We carefully controlled the kinematics of behaviors in these two conditions to exclude potential effects of MNS activity changes associated with kinematic differences between visual stimuli. Notably, motor evoked potentials, that reflect CSE, from the first dorsal interosseous muscle exhibited greater amplitude when the participants observed interactive behaviors than when they observed non-interactive behavior. These results provide neurophysiological evidence that the MNS is activated to a greater degree during observation of human-interactive behaviors that contain additional information about the individuals' mental states, supporting the view that the MNS plays a critical role in social cognition in humans. PMID- 26432378 TI - Transition from reactive control to proactive control across conflict adaptation: An sLORETA study. AB - In a flanker task, behavioral performance is modulated by previous trial compatibility (i.e., conflict adaptation); a longer response time (RT) is found for a compatible stimulus preceded by an incompatible stimulus than by a compatible stimulus, whereas a shorter RT is found for an incompatible stimulus preceded by an incompatible stimulus than by a compatible stimulus. We examined the temporal characteristics of cognitive control across conflict adaptation using prestimulus electroencephalogram oscillatory activity and an event-related potential component, N1. Prestimulus frontal (Fz) and posterior (O1 and O2) alpha1 (7-9 Hz) and alpha2 (10-13 Hz) activities were enhanced in trials preceded by incompatible stimuli more than those preceded by compatible stimuli. Furthermore, there were significant differences of alpha2 current densities between previous trial compatibilities in the superior/medial frontal cortex. We suggested that the modulation of alpha activity by previous trial compatibility was associated with proactive attentional control. N1 amplitude was decreased in trials preceded by incompatible stimuli more than in those preceded by compatible stimuli. N1 current densities in the right inferior frontal cortex were smaller for an incompatible stimulus preceded by an incompatible stimulus than those preceded by a compatible stimulus, suggesting that demands of transient cognitive control induced by an incompatible stimulus were decreased by the proactive control. Moreover, correlational analysis showed that participants with a larger increase in alpha2 activity tended to have a larger decrease in N1 in trials preceded by incompatible stimulus. These findings revealed that the manner of cognitive control for the incompatible stimulus was transited from reactive control to proactive control across conflict adaptation. PMID- 26432379 TI - Reduced sensitivity to neutral feedback versus negative feedback in subjects with mild depression: Evidence from event-related potentials study. AB - Many previous event-related potential (ERP) studies have linked the feedback related negativity (FRN) component with medial frontal cortex processing and associated this component with depression. Few if any studies have investigated the processing of neutral feedback in mildly depressive subjects in the normal population. Two experiments compared brain responses to neutral feedback with behavioral performance in mildly depressed subjects who scored highly on the Beck Depression Inventory (high BDI) and a control group with lower BDI scores (low BDI). In the first study, the FRN component was recorded when neutral, negative or positive feedback was pseudo-randomly delivered to the two groups in a time estimation task. In the second study, real feedback was provided to the two groups in the same task in order to measure their actual accuracy of performance. The results of experiment one (Exp. 1) revealed that a larger FRN effect was elicited by neutral feedback than by negative feedback in the low BDI group, but no significant difference was found between neutral condition and negative condition in the High BDI group. The present findings demonstrated that depressive tendencies influence the processing of neutral feedback in medial frontal cortex. The FRN effect may work as a helpful index for investigating cognitive bias in depression in future studies. PMID- 26432380 TI - Chemical and biological assessment of Jujube (Ziziphus jujuba)-containing herbal decoctions: Induction of erythropoietin expression in cultures. AB - Jujubae Fructus, known as jujube or Chinese date, is the fruit of Ziziphus jujuba (Mill.), which not only serves as daily food, but acts as tonic medicine and health supplement for blood nourishment and sedation. According to Chinese medicine, jujube is commonly included in herbal mixtures, as to prolong, enhance and harmonize the efficiency of herbal decoction, as well as to minimize the toxicity. Here, we aim to compare the chemical and pharmacological properties of three commonly used jujube-containing decoctions, including Guizhi Tang (GZT), Neibu Dangguijianzhong Tang (NDT) and Zao Tang (ZOT). These decoctions share common herbs, i.e. Glycyrrhizae Radix et Rhizoma Praeparata cum Melle, Zingiberis Rhizoma Recens and Jujube, and they have the same proposed hematopoietic functions. The amount of twelve marker biomolecules deriving from different herbs in the decoctions were determined by LC-MS, and which served as parameters for chemical standardization. In general, three decoctions showed common chemical profiles but with variations in solubilities of known active ingredients. The chemical standardized decoctions were tested in cultured Hep3B cells. The herbal treatment stimulated the amount of mRNA and protein expressions of erythropoietin (EPO) via the activation of hypoxia response elements: the three herbal decoctions showed different activation. The results therefore demonstrated the hematopoietic function of decoctions and explained the enhancement of jujube function within a herbal mixture. PMID- 26432381 TI - A novel mouse model provides insights into the neutropenia associated with the ribosomopathy Shwachman-Diamond syndrome. PMID- 26432384 TI - Comment on "acute lymphoblastic leukemia and adiponcosis" by M. Bifilco and AM Malfitano. PMID- 26432382 TI - JAK kinase targeting in hematologic malignancies: a sinuous pathway from identification of genetic alterations towards clinical indications. AB - Constitutive JAK-STAT pathway activation occurs in most myeloproliferative neoplasms as well as in a significant proportion of other hematologic malignancies, and is frequently a marker of poor prognosis. The underlying molecular alterations are heterogeneous as they include activating mutations in distinct components (cytokine receptor, JAK, STAT), overexpression (cytokine receptor, JAK) or rare JAK2 fusion proteins. In some cases, concomitant loss of negative regulators contributes to pathogenesis by further boosting the activation of the cascade. Exploiting the signaling bottleneck provided by the limited number of JAK kinases is an attractive therapeutic strategy for hematologic neoplasms driven by constitutive JAK-STAT pathway activation. However, given the conserved nature of the kinase domain among family members and the interrelated roles of JAK kinases in many physiological processes, including hematopoiesis and immunity, broad usage of JAK inhibitors in hematology is challenged by their narrow therapeutic window. Novel therapies are, therefore, needed. The development of more selective inhibitors is a questionable strategy as such inhibitors might abrogate the beneficial contribution of alleviating the cancer-related pro-inflammatory microenvironment and raise selective pressure to a threshold that allows the emergence of malignant subclones harboring drug resistant mutations. In contrast, synergistic combinations of JAK inhibitors with drugs targeting cascades that work in concert with JAK-STAT pathway appear to be promising therapeutic alternatives to JAK inhibitors as monotherapies. PMID- 26432383 TI - European Myeloma Network guidelines for the management of multiple myeloma related complications. AB - The European Myeloma Network provides recommendations for the management of the most common complications of multiple myeloma. Whole body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus we recommend it as the novel standard for the detection of lytic lesions in myeloma (grade 1A). Myeloma patients with adequate renal function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate (grade 1A). Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid (grade 1B), but its advantage is not clear for patients with no bone involvement on computed tomography or magnetic resonance imaging. In asymptomatic myeloma, bisphosphonates are not recommended (grade 1A). Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use (grade 1B). Treatment with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemoglobin <10g/dL) in whom other causes of anemia have been excluded (grade 1B). Erythropoietic agents should be stopped after 6-8 weeks if no adequate hemoglobin response is achieved. For renal impairment, bortezomib based regimens are the current standard of care (grade 1A). For the management of treatment-induced peripheral neuropathy, drug modification is needed (grade 1C). Vaccination against influenza is recommended; vaccination against streptococcus pneumonia and hemophilus influenza is appropriate, but efficacy is not guaranteed due to suboptimal immune response (grade 1C). Prophylactic aciclovir (or valacyclovir) is recommended for patients receiving proteasome inhibitors, autologous or allogeneic transplantation (grade 1A). PMID- 26432385 TI - Comparison of five Lonicera flowers by simultaneous determination of multi components with single reference standard method and principal component analysis. AB - The flowers of Lonicera japonica Thunb. were extensively used to treat many diseases. As the demands for L. japonica increased, some related Lonicera plants were often confused or misused. Caffeoylquinic acids were always regarded as chemical markers in the quality control of L. japonica, but they could be found in all Lonicera species. Thus, a simple and reliable method for the evaluation of different Lonicera flowers is necessary to be established. In this work a method based on single standard to determine multi-components (SSDMC) combined with principal component analysis (PCA) for control and distinguish of Lonicera species flowers have been developed. Six components including three caffeoylquinic acids and three iridoid glycosides were assayed simultaneously using chlorogenic acid as the reference standard. The credibility and feasibility of the SSDMC method were carefully validated and the results demonstrated that there were no remarkable differences compared with external standard method. Finally, a total of fifty-one batches covering five Lonicera species were analyzed and PCA was successfully applied to distinguish the Lonicera species. This strategy simplifies the processes in the quality control of multiple componential herbal medicine which effectively adapted for improving the quality control of those herbs belonging to closely related species. PMID- 26432386 TI - Dereplication of antioxidant compounds in Bene (Pistacia atlantica subsp. mutica) hull using a multiplex approach of HPLC-DAD, LC-MS and (1)H NMR techniques. AB - Bene is an edible fruit from the tree Pistacia atlantica subsp. mutica, and is of steadily growing interest in recent years due to its significant antioxidant properties and potential health benefits. An antioxidant activity-guided fractionation of the methanol extract from Bene hull together with an integrated approach of HPLC-DAD, LC-MS and (1)H NMR techniques led to the identification of main antioxidant phenolic compounds for the first time. Radical scavenging activity of each fraction/compound was tested using DPPH and FRAP assays. The phenolic content of the fractions was also determined by Folin-Ciocalteu's method. The main identified antioxidant compounds were luteolin (46.53% w/w of total extract), gallic acid (9.84% w/w), 2"-O-galloylisoquercitrin (0.53% w/w), quercetin 3-rutinoside (0.34% w/w) and 2"-O-cis-caffeoylquercitrin (0.26% w/w). The minor antioxidant compounds were also identified by liquid chromatography positive/negative electrospray ionization tandem mass spectrometry. The structure antioxidant activity relationship of identified phenolics are also discussed in this paper. PMID- 26432388 TI - Identification of proteins from human permanent erupted enamel. AB - Proteins from the extracellular matrix of enamel are highly specific and necessary for proper enamel formation. Most proteins are removed from the matrix by enamel proteases before complete mineralization is achieved; however, some residual protein fragments persist in the mineralized matrix of erupted enamel. So far, only amelogenin peptides obtained by traditional bottom-up proteomics have been recovered and identified in human permanent erupted enamel. In this study, we hypothesize that other enamel-specific proteins are also found in human permanent enamel, by analysing human erupted third molars. Pulverized enamel was used to extract proteins, and the protein extract was subjected directly to liquid-chromatography coupled to tandem mass spectrometry (LC-MS/MS) without a previous trypsin-digestion step. Amelogenin and non-amelogenin proteins (ameloblastin and enamelin) were succesfully identified. The sequences of the naturally occurring peptides of these proteins are reported, finding in particular that most of the peptides from the amelogenin X-isoform come from the tyrosine-rich amelogenin peptide (TRAP) and that some were identified in all specimens. In conclusion, our LC-MS/MS method without trypsin digestion increased the coverage of identification of the enamel proteome from a few amelogenin peptides to a higher number of peptides from three enamel-specific proteins. PMID- 26432389 TI - Greater rhea (Rhea americana) external morphology at different stages of embryonic and fetal development. AB - Knowledge of wild species embryonic development is important for their maintenance in captivity or the wild. The objective of the present study was to characterize the external morphology and define the biometry of greater rhea embryos and fetuses at different stages of development. A total of 41 embryos and fetuses were analyzed to describe their external morphology using a stereoscopic microscope. The crown-rump (CR), total length (TL), cephalocaudal length (CCL), biparietal diameter (BPD), beak, humerus and tibio-tarsal lengths were measured by digital pachymeter, millimetric scale ruler and cotton thread. The weight of the embryos and fetuses was measured on digital scales. The greater rhea embryos at 5, 6 and 7 days incubation presented a "C" shape. At 9, 10 and 11 days the eyes were big and pigmented. At 11, 12 and 13 days the eyelid covered more than half the eye, resulting in an oval slit. In 14 and 15 day-old embryos, the skin was still thin and the ribs evident, but at 18 days this structure was thicker. In embryos at 21 and 27 days of development closed eyelids were observed forming an eyelid slit, and the eye ball was less pronounced at 27 days. Weight gain presented an exponential growth curve, while measurements such as TL, DBP, beak, humerus and tibio-tarsal length had linear growth over time. Thus it was possible to characterize the greater rhea embryos and fetuses at several incubation ages using their external morphology and morphometric analyses. PMID- 26432387 TI - Genetics and physiology of cell wall polysaccharides in the model C4 grass, Setaria viridis spp. AB - BACKGROUND: Setaria viridis has emerged as a model species for the larger C4 grasses. Here the cellulose synthase (CesA) superfamily has been defined, with an emphasis on the amounts and distribution of (1,3;1,4)-beta-glucan, a cell wall polysaccharide that is characteristic of the grasses and is of considerable value for human health. METHODS: Orthologous relationship of the CesA and Poales specific cellulose synthase-like (Csl) genes among Setaria italica (Si), Sorghum bicolor (Sb), Oryza sativa (Os), Brachypodium distachyon (Bradi) and Hordeum vulgare (Hv) were compared using bioinformatics analysis. Transcription profiling of Csl gene families, which are involved in (1,3;1,4)-beta-glucan synthesis, was performed using real-time quantitative PCR (Q-PCR). The amount of (1,3;1,4)-beta glucan was measured using a modified Megazyme assay. The fine structures of the (1,3;1,4)-beta-glucan, as denoted by the ratio of cellotriosyl to cellotetraosyl residues (DP3:DP4 ratio) was assessed by chromatography (HPLC and HPAEC-PAD). The distribution and deposition of the MLG was examined using the specific antibody BG-1 and captured using fluorescence and transmission electron microscopy (TEM). RESULTS: The cellulose synthase gene superfamily contains 13 CesA and 35 Csl genes in Setaria. Transcript profiling of CslF, CslH and CslJ gene families across a vegetative tissue series indicated that SvCslF6 transcripts were the most abundant relative to all other Csl transcripts. The amounts of (1,3;1,4) beta-glucan in Setaria vegetative tissues ranged from 0.2% to 2.9% w/w with much smaller amounts in developing grain (0.003% to 0.013% w/w). In general, the amount of (1,3;1,4)-beta-glucan was greater in younger than in older tissues. The DP3:DP4 ratios varied between tissue types and across developmental stages, and ranged from 2.4 to 3.0:1. The DP3:DP4 ratios in developing grain ranged from 2.5 to 2.8:1. Micrographs revealing the distribution of (1,3;1,4)-beta-glucan in walls of different cell types and the data were consistent with the quantitative (1,3;1,4)-beta-glucan assays. CONCLUSION: The characteristics of the cellulose synthase gene superfamily and the accumulation and distribution of (1,3;1,4)-beta glucans in Setaria are similar to those in other C4 grasses, including sorghum. This suggests that Setaria is a suitable model plant for cell wall polysaccharide biology in C4 grasses. PMID- 26432390 TI - Sugar-Sweetened Beverages: Children's Perceptions, Factors of Influence, and Suggestions for Reducing Intake. AB - OBJECTIVES: This study aimed to gain an in-depth understanding of children's perceptions of sugar-sweetened beverages (SSBs). DESIGN: Nine focus groups were conducted in grade 5 and 6 elementary schoolchildren. SETTING: Nine urban and rural elementary schools in London, Ontario, Canada. PARTICIPANTS: Fifty-one children, 58% of which were male, 52% of whom were in grade 5, and 84% of whom were Caucasian. PHENOMENON OF INTEREST: Children's views on sugar-sweetened beverages. ANALYSIS: Three researchers conducted inductive content analysis on the data independently using the principles of the immersion-crystallization method. RESULTS: Participants had a high level of awareness of beverages and their health effects, which was primarily targeted at the sugar content. Dominant factors that influenced children's beverage choices and consumption patterns included taste, parental control practices, accessibility, and advertising. Participants identified a wide array of strategies to reduce SSB consumption in children, including educational strategies for both children and parents and policy-level changes at both the government and school levels. CONCLUSIONS AND IMPLICATIONS: Despite a high level of awareness of SSBs, children believed that further education and policies regarding SSBs were warranted. These data may prove helpful in designing effective interventions targeted at children and parents to reduce SSB consumption by children. PMID- 26432391 TI - TCEANC2 rs10788972 and rs12046178 variants in the PARK10 region in Chinese Han patients with sporadic Parkinson's disease. AB - Parkinson's disease (PD) is the second most common chronic neuronal degeneration disorder with motor and nonmotor clinical features. The rs10788972 variant of the transcription elongation factor A (SII) N-terminal and central domain containing 2 (TCEANC2) gene in the PARK10 region was recently identified to be strongly related to sporadic PD in the American population. To evaluate whether the same variant is associated with sporadic PD in Chinese Han population, we researched 513 sporadic PD patients and 512 normal controls of Chinese Han ethnicity in Mainland China. No significant difference in genotypic and allelic distributions between patients and control groups for either rs10788972 (for genotypic distribution, chi(2) = 0.412, p = 0.814, and for allelic distribution, chi(2) = 0.280, p = 0.597) or its neighbor marker rs12046178 (for genotypic distribution, chi(2) = 1.500, p = 0.472, and for allelic distribution, chi(2) = 1.339, p = 0.247) was found. Our data suggest that neither variant is related to sporadic PD in Chinese Han population. PMID- 26432392 TI - Origin of the hungry caterpillar: Evolution of fasting in slug moths (Insecta: Lepidoptera: Limacodidae). AB - Studies of caterpillar defense strategy evolution typically focus on aposematic coloration, gregarious behavior, and/or chemical defense. In the slug moth family Limacodidae, the evolution of chemical defense is coupled to the life history trait of first instar feeding behaviors. In nettle caterpillars, the first instars fast and molt into a second instar that feeds. In contrast, gelatines and monkey slug larval forms feed in the first instar. This study focused on whether the evolution of fasting associated with the nettle morphology was a derived trait of single or multiple origins. Twenty-nine species of Limacodidae (including one Chrysopolominae) representing 27 genera and four outgroup species with known first and final instar morphologies and behaviors were included. Four out-group species representing Megalopygidae (1 sp), Dalceridae (1 sp) and Aididae (2 sp) were included. These were sequenced for three molecular markers for a total of 4073 bp, mitochondrial COI (~1500 bp), 18S (~1900 bp) and the D2 region of 28S (approximately 670 bp). Maximum likelihood and Bayesian analyses were conducted. The resulting phylogeny and comparative analysis of feeding strategy revealed that the nettle caterpillar morphology and behavior of larval fasting may have a single origin. PMID- 26432393 TI - Biogeography of the Malagasy Celastraceae: Multiple independent origins followed by widespread dispersal of genera from Madagascar. AB - Of the 97 currently recognized genera of Celastraceae, 19 are native to Madagascar, including six endemics. In this study we conducted the most thorough phylogenetic analysis of Celastraceae yet completed with respect to both character and taxon sampling, and include representatives of five new endemic genera. Fifty-one new accessions, together with 328 previously used accessions of Celastrales, were sampled for morphological characters, two rDNA gene regions, and two plastid gene regions. The endemic Malagasy genera are resolved in two separate lineages-Xenodrys by itself and all other endemic genera in a clade that also includes four lineages inferred to have dispersed from Madagascar: Brexia madagascariensis (Mascarene Islands, coastal Africa), Elaeodendron (West Indies, Africa to New Caledonia), and Pleurostylia (Africa to New Caledonia). Of the 12 extant Malagasy Celastraceae lineages identified, eight are clearly of African origin. The origins of the remaining four lineages are less clear, but reasonable possibilities include America, Eurasia, Africa, southern India, Malesia, and Australia. Based on 95% credible age intervals from fossil-calibrated molecular dating, all 12 extant Malagasy Celastraceae lineages appear to have arisen following dispersal after the separation of Madagascar from other landmasses within the last 70 million years. PMID- 26432394 TI - Molecular data reveal spatial and temporal patterns of diversification and a cryptic new species of lowland Stenocercus Dumeril & Bibron, 1837 (Squamata: Tropiduridae). AB - Phylogenetic studies have uncovered biogeographic patterns and the associated diversification processes of Neotropical wet forest taxa, yet the extensive open and drier biomes have received much less attention. In the Stenocercus lizard radiation, restricted sampling and phylogenetic information have limited inferences about the timing, spatial context, and environmental drivers of diversification in the open and dry lowland settings of eastern and southern South America. Based on new DNA sequence data of previously unsampled species, we provide an updated historical biogeographic hypothesis of Stenocercus. We infer phylogenetic relationships, estimate divergence times, and track ancestral distributions, asking whether cladogenetic events within the genus correlate to reported shifts in South American landscapes during the past 30millionyears, focusing in the open and drier areas. To examine correlations between genetic and ecological divergence, we extracted environmental data from occurrence records and estimated climatic envelopes occupied by lowland taxa. Our results suggest that Stenocercus began to diversify around the South American Midwest by the late Oligocene. We recovered two main lowland and two main Andean clades within the genus; within both Andean clades, most cladogenetic events date back to the Miocene, synchronously with the most intense phase of Andean uplift. In the western clade of lowland Stenocercus, species ranges and divergence times are consistent with major landscape shifts at the upper Guapore and Paraguay River basins as a result of Andean orogeny, suggesting vicariant speciation. By contrast, in the 'horned' lowland clade, we find evidence that dispersal and ecological differentiation have shaped species divergences and current ranges in the Brazilian Cerrado, Caatinga, Pampas and Atlantic Forest, possibly under a vanishing refuge scenario. Lastly, our phylogenetic results indicate two divergent clades within the formerly recognized taxon S. sinesaccus, and further evaluation of morphological data corroborates the existence of a distinct, new species of Stenocercus, here described. The new taxon occurs in the Chapada dos Parecis massif in the Brazilian states of Mato Grosso and Rondonia. PMID- 26432396 TI - Canine degenerative myelopathy: a model of human amyotrophic lateral sclerosis. AB - Canine degenerative myelopathy (CDM) represents a unique naturally occurring animal model for human amyotrophic lateral sclerosis (ALS) because of similar clinical signs, neuropathologic findings, and involvement of the superoxide dismutase 1 (SOD1) mutation. A definitive diagnosis can only be made postmortem through microscopic detection of axonal degeneration, demyelination and astroglial proliferation, which is more severe in the dorsal columns of the thoracic spinal cord and in the dorsal portion of the lateral funiculus. Interestingly, the muscle acetylcholine receptor complexes are intact in CDM prior to functional impairment, thus suggesting that muscle atrophy in CDM does not result from physical denervation. Moreover, since sensory involvement seems to play an important role in CDM progression, a more careful investigation of the sensory pathology in ALS is also warranted. The importance of SOD1 expression remains unclear, while oxidative stress and denatured ubiquinated proteins appear to play a crucial role in the pathogenesis of CDM. In this updated narrative review we performed a systematic search of the published studies on CDM that may shed light on the pathophysiological mechanisms of human ALS. A better understanding of the factors that determine the disease progression in CDM may be beneficial for the development of effective treatments for ALS. PMID- 26432395 TI - Genetic and structural analyses of cytochrome P450 hydroxylases in sex hormone biosynthesis: Sequential origin and subsequent coevolution. AB - Biosynthesis of steroid hormones in vertebrates involves three cytochrome P450 hydroxylases, CYP11A1, CYP17A1 and CYP19A1, which catalyze sequential steps in steroidogenesis. These enzymes are conserved in the vertebrates, but their origin and existence in other chordate subphyla (Tunicata and Cephalochordata) have not been clearly established. In this study, selected protein sequences of CYP11A1, CYP17A1 and CYP19A1 were compiled and analyzed using multiple sequence alignment and phylogenetic analysis. Our analyses show that cephalochordates have sequences orthologous to vertebrate CYP11A1, CYP17A1 or CYP19A1, and that echinoderms and hemichordates possess CYP11-like but not CYP19 genes. While the cephalochordate sequences have low identity with the vertebrate sequences, reflecting evolutionary distance, the data show apparent origin of CYP11 prior to the evolution of CYP19 and possibly CYP17, thus indicating a sequential origin of these functionally related steroidogenic CYPs. Co-occurrence of the three CYPs in early chordates suggests that the three genes may have coevolved thereafter, and that functional conservation should be reflected in functionally important residues in the proteins. CYP19A1 has the largest number of conserved residues while CYP11A1 sequences are less conserved. Structural analyses of human CYP11A1, CYP17A1 and CYP19A1 show that critical substrate binding site residues are highly conserved in each enzyme family. The results emphasize that the steroidogenic pathways producing glucocorticoids and reproductive steroids are several hundred million years old and that the catalytic structural elements of the enzymes have been conserved over the same period of time. Analysis of these elements may help to identify when precursor functions linked to these enzymes first arose. PMID- 26432397 TI - Effortless assignment with 4D covariance sequential correlation maps. AB - Traditional Nuclear Magnetic Resonance (NMR) assignment procedures for proteins rely on preliminary peak-picking to identify and label NMR signals. However, such an approach has severe limitations when signals are erroneously labeled or completely neglected. The consequences are especially grave for proteins with substantial peak overlap, and mistakes can often thwart entire projects. To overcome these limitations, we previously introduced an assignment technique that bypasses traditional pick peaking altogether. Covariance Sequential Correlation Maps (COSCOMs) transform the indirect connectivity information provided by multiple 3D backbone spectra into direct (H, N) to (H, N) correlations. Here, we present an updated method that utilizes a single four-dimensional spectrum rather than a suite of three-dimensional spectra. We demonstrate the advantages of 4D COSCOMs relative to their 3D counterparts. We introduce improvements accelerating their calculation. We discuss practical considerations affecting their quality. And finally we showcase their utility in the context of a 52 kDa cyclization domain from a non-ribosomal peptide synthetase. PMID- 26432398 TI - The use of a selective saturation pulse to suppress t1 noise in two-dimensional (1)H fast magic angle spinning solid-state NMR spectroscopy. AB - A selective saturation pulse at fast magic angle spinning (MAS) frequencies (60+kHz) suppresses t1 noise in the indirect dimension of two-dimensional (1)H MAS NMR spectra. The method is applied to a synthetic nucleoside with an intense methyl (1)H signal due to triisopropylsilyl (TIPS) protecting groups. Enhanced performance in terms of suppressing the methyl signal while minimising the loss of signal intensity of nearby resonances of interest relies on reducing spin diffusion--this is quantified by comparing two-dimensional (1)H NOESY-like spin diffusion spectra recorded at 30-70 kHz MAS. For a saturation pulse centred at the methyl resonance, the effect of changing the nutation frequency at different MAS frequencies as well as the effect of changing the pulse duration is investigated. By applying a pulse of duration 30 ms and nutation frequency 725 Hz at 70 kHz MAS, a good compromise of significant suppression of the methyl resonance combined with the signal intensity of resonances greater than 5 ppm away from the methyl resonance being largely unaffected is achieved. The effectiveness of using a selective saturation pulse is demonstrated for both homonuclear (1)H-(1)H double quantum (DQ)/single quantum (SQ) MAS and (14)N-(1)H heteronuclear multiple quantum coherence (HMQC) two-dimensional solid-state NMR experiments. PMID- 26432399 TI - Localized 2D COSY sequences: Method and experimental evaluation for a whole metabolite quantification approach. AB - Two-dimensional spectroscopy offers the possibility to unambiguously distinguish metabolites by spreading out the multiplet structure of J-coupled spin systems into a second dimension. Quantification methods that perform parametric fitting of the 2D MRS signal have recently been proposed for resolved PRESS (JPRESS) but not explicitly for Localized Correlation Spectroscopy (LCOSY). Here, through a whole metabolite quantification approach, correlation spectroscopy quantification performances are studied. The ability to quantify metabolite relaxation constant times is studied for three localized 2D MRS sequences (LCOSY, LCTCOSY and the JPRESS) in vitro on preclinical MR systems. The issues encountered during implementation and quantification strategies are discussed with the help of the Fisher matrix formalism. The described parameterized models enable the computation of the lower bound for error variance--generally known as the Cramer Rao bounds (CRBs), a standard of precision--on the parameters estimated from these 2D MRS signal fittings. LCOSY has a theoretical net signal loss of two per unit of acquisition time compared to JPRESS. A rapid analysis could point that the relative CRBs of LCOSY compared to JPRESS (expressed as a percentage of the concentration values) should be doubled but we show that this is not necessarily true. Finally, the LCOSY quantification procedure has been applied on data acquired in vivo on a mouse brain. PMID- 26432400 TI - Optimizing low impact development (LID) for stormwater runoff treatment in urban area, Korea: Experimental and modeling approach. AB - Currently, continued urbanization and development result in an increase of impervious areas and surface runoff including pollutants. Also one of the greatest issues in pollutant emissions is the first flush effect (FFE), which implies a greater discharge rate of pollutant mass in the early part in the storm. Low impact development (LID) practices have been mentioned as a promising strategy to control urban stormwater runoff and pollution in the urban ecosystem. However, this requires many experimental and modeling efforts to test LID characteristics and propose an adequate guideline for optimizing LID management. In this study, we propose a novel methodology to optimize the sizes of different types of LID by conducting intensive stormwater monitoring and numerical modeling in a commercial site in Korea. The methodology proposed optimizes LID size in an attempt to moderate FFE on a receiving waterbody. Thereby, the main objective of the optimization is to minimize mass first flush (MFF), which is an indicator for quantifying FFE. The optimal sizes of 6 different LIDs ranged from 1.2 mm to 3.0 mm in terms of runoff depths, which significantly moderate the FFE. We hope that the new proposed methodology can be instructive for establishing LID strategies to mitigate FFE. PMID- 26432401 TI - Combined application of ultrasound and SPECT/CT has incremental value in detecting parathyroid tissue in SHPT patients. AB - PURPOSE: The goal of this study is to investigate whether combined application of ultrasound and 99mTc-sestamibi SPECT/CT had the incremental value in accurately detecting parathyroid tissue in patients with SHPT over either method alone. PATIENTS AND METHODS: Sixty patients with SHPT on hemodialysis were evaluated preoperatively with parathyroid 99mTc-sestamibi SPECT/CT scintigraphy and ultrasound prior to parathyroidectomy. The sensitivity, specificity and accuracy of 99mTc-sestamibi SPECT/CT scintigraphy, ultrasound and combined application were determined respectively. RESULTS: The sensitivity, specificity and accuracy of ultrasound were 81% (155/192), 47% (17/36) and 82% (172/228), respectively. The sensitivity, specificity and accuracy of 99mTc-sestamibi SPECT/CT were 85% (163/192), 58% (21/36) and 89% (184/228) respectively. The accuracy of 99mTc sestamibi SPECT/CT in the diagnosis of parathyroid tissue in patients with SHPT is significantly higher than that of ultrasound. The sensitivity, specificity and accuracy of combined application of ultrasound and 99mTc-sestamibi SPECT/CT were 93% (178/192), 61% (22/36) and 97% (200/228). The sensitivity, specificity and accuracy of combined application of ultrasound and 99mTc-sestamibi SPECT/CT were higher than those of either ultrasound or 99mTc-sestamibi SPECT/CT. CONCLUSIONS: The combined application of ultrasound and 99mTc-sestamibi SPECT/CT had incremental value in accurately detecting parathyroid tissue in patients with SHPT over either method alone. PMID- 26432402 TI - Retraction: Meeting Report: Inaugural Chemotherapy-Induced Peripheral Neuropathy Symposium, Santa Barbara, CA, February 2015. PMID- 26432403 TI - Suppression of intratumoral CCL22 by type i interferon inhibits migration of regulatory T cells and blocks cancer progression. AB - The chemokine CCL22 is abundantly expressed in many types of cancer and is instrumental for intratumoral recruitment of regulatory T cells (Treg), an important subset of immunosuppressive and tumor-promoting lymphocytes. In this study, we offer evidence for a generalized strategy to blunt Treg activity that can limit immune escape and promote tumor rejection. Activation of innate immunity with Toll-like receptor (TLR) or RIG-I-like receptor (RLR) ligands prevented accumulation of Treg in tumors by blocking their immigration. Mechanistic investigations indicated that Treg blockade was a consequence of reduced intratumoral CCL22 levels caused by type I IFN. Notably, stable expression of CCL22 abrogated the antitumor effects of treatment with RLR or TLR ligands. Taken together, our findings argue that type I IFN blocks the Treg attracting chemokine CCL22 and thus helps limit the recruitment of Treg to tumors, a finding with implications for cancer immunotherapy. PMID- 26432404 TI - Androgen Receptor Upregulation Mediates Radioresistance after Ionizing Radiation. AB - Clinical trials have established the benefit of androgen deprivation therapy (ADT) combined with radiotherapy in prostate cancer. ADT sensitizes prostate cancer to radiotherapy-induced death at least in part through inhibition of DNA repair machinery, but for unknown reasons, adjuvant ADT provides further survival benefits. Here, we show that androgen receptor (AR) expression and activity are durably upregulated following radiotherapy in multiple human prostate cancer models in vitro and in vivo. Moreover, the degree of AR upregulation correlates with survival in vitro and time to tumor progression in animal models. We also provide evidence of AR pathway upregulation, measured by a rise in serum levels of AR-regulated hK2 protein, in nearly 20% of patients after radiotherapy. Furthermore, these men were three-fold more likely to experience subsequent biochemical failure. Collectively, these data demonstrate that radiotherapy can upregulate AR signaling after therapy to an extent that negatively affects disease progression and/or survival. PMID- 26432405 TI - PI3K-mTORC2 but not PI3K-mTORC1 regulates transcription of HIF2A/EPAS1 and vascularization in neuroblastoma. AB - Hypoxia-inducible factor (HIF) is a master regulator of cellular responses to oxygen deprival with a critical role in mediating the angiogenic switch in solid tumors. Differential expression of the HIF subunits HIF1alpha and HIF2alpha occurs in many human tumor types, suggesting selective implications to biologic context. For example, high expression of HIF2alpha that occurs in neuroblastoma is associated with stem cell-like features, disseminated disease, and poor clinical outcomes, suggesting pivotal significance for HIF2 control in neuroblastoma biology. In this study, we provide novel insights into how HIF2alpha expression is transcriptionally controlled by hypoxia and how this control is abrogated by inhibition of insulin-like growth factor-1R/INSR-driven phosphoinositide 3-kinase (PI3K) signaling. Reducing PI3K activity was sufficient to decrease HIF2alpha mRNA and protein expression in a manner with smaller and less vascularized tumors in vivo. PI3K-regulated HIF2A mRNA expression was independent of Akt or mTORC1 signaling but relied upon mTORC2 signaling. HIF2A mRNA was induced by hypoxia in neuroblastoma cells isolated from metastatic patient-derived tumor xenografts, where HIF2A levels could be reduced by treatment with PI3K and mTORC2 inhibitors. Our results suggest that targeting PI3K and mTORC2 in aggressive neuroblastomas with an immature phenotype may improve therapeutic efficacy. PMID- 26432406 TI - The impact of GABA in harpin-elicited biotic stress responses in Nicotiana tabaccum. AB - Harpin is a bacterial elicitor protein that was first isolated from Erwinia amylovora. Infiltration of this elicitor into the leaves of plants activates systemic acquired resistance against a variety of plant pathogens via the salicyclic acid defense pathway. The non-protein amino acid, neurotransmission inhibitor molecule of mammals-GABA- is found in all organisms and is known to be an important component of stress responses in plants. We hypothesized a possible interaction between harpin-induced defense responses and GABA shunt. Therefore, we conducted experiments on harpin-infiltrated tobacco and analyzed the components of GABA shunt in relation to growth, photosynthesis and H2O2 levels. RGR, RWC and photosynthetic efficiency were all affected in harpin-infiltrated tobacco leaves, but the rate of decline was more remarkable on RGR. H2O2 levels showed significant difference on 7 days after harpin infiltration when the necrotic lesions were also visible. GABA accumulation was increased and glutamate levels were decreased parallel to the differences in GDH and GAD enzyme activities, especially on days 5 and 7 of harpin infiltration. Transcript abundance of GDH and GAD encoding genes were differentially regulated in harpin infiltrated leaves as compared to that of control and mock groups. In the present study, for the first time we showed a relationship between harpin-elicited responses and GABA in tobacco that was not mediated by H2O2 accumulation. Harpin infiltration significantly induced the first components of the GABA shunt such as GDH, GAD, glutamate and GABA in tobacco. PMID- 26432407 TI - Effect of blue LED light intensity on carotenoid accumulation in citrus juice sacs. AB - In the present study, the effects of blue LED light intensity on carotenoid accumulation and expression of genes related to carotenoid biosynthesis were investigated in the juice sacs of Satsuma mandarin (Citrus unshiu Marc.) and Valencia orange (Citrus sinensis Osbeck) in vitro. The results showed that 100 MUmol m(-2)s(-1) blue LED light (100B) was effective for increasing carotenoid content, especially beta-cryptoxanthin, in Satsuma mandarin after cultured in vitro for four weeks. In Valencia orange, in contrast, 50 MUmol m(-2)s(-1) blue LED light (50B) treatment was effective for inducing carotenoid accumulation through increasing the contents of two major carotenoids, all-trans-violaxanthin and 9-cis-violaxanthin. In addition, gene expression results showed that the simultaneous increases in the expression of genes (CitPSY, CitPDS, CitZDS, CitLCYb2, and CitHYb) involved in producing beta,beta-xanthophylls were well consistent with the accumulation of beta-cryptoxanthin in Satsuma mandarin under 100B, and violaxanthin in Valencia orange under 50B. The results presented herein contribute to further elucidating the regulatory mechanism of carotenoid accumulation by blue LED light. PMID- 26432408 TI - A large and unusual lung abscess with positive culture to Slackia exigua. PMID- 26432409 TI - Assessing cyber-user awareness of an emerging infectious disease: evidence from human infections with avian influenza A H7N9 in Zhejiang, China. AB - OBJECTIVES: The aim of this study was to assess cyber-user awareness of human infections with avian influenza A H7N9 in Zhejiang, China. METHODS: Daily Baidu index values were compared for different keywords, different periods (epidemic and non-epidemic), different levels of epidemic publicity (whether new cases were publicized), and different cities (divided into high, medium, low, and zero groups according to the number of cases). Furthermore, the correlation between the daily Baidu index values and the daily number of new cases was analyzed. RESULTS: Three epidemic periods (periods A/C/E) and three non-epidemic periods (periods B/D/F) were identified from April 2013 to May 2015 according to the curves of daily new cases. Each epidemic period was followed by a non-epidemic period. Baidu index values using 'H7N9' as a keyword were higher than the values using the keyword '' (avian influenza in Chinese) in earlier periods, but the situation reversed in later periods. Index values for 'H7N9' in the epidemic periods were higher than in the non-epidemic periods. In the first epidemic period (period A), the Baidu index values for 'H7N9' showed no difference between the different levels of epidemic publicity and had no correlation with the daily number of new cases. The index values in cities without reported cases showed no difference from the values recorded in the medium and low groups. However, a difference and a correlation were found in a later epidemic period. CONCLUSIONS: The Baidu index would be a useful tool for assessing cyber-user awareness of an emerging infectious disease. PMID- 26432410 TI - Conservation of nucleotide sequences for molecular diagnosis of Middle East respiratory syndrome coronavirus, 2015. AB - Infection due to the Middle East respiratory syndrome coronavirus (MERS-CoV) is widespread. The present study was performed to assess the protocols used for the molecular diagnosis of MERS-CoV by analyzing the nucleotide sequences of viruses detected between 2012 and 2015, including sequences from the large outbreak in eastern Asia in 2015. Although the diagnostic protocols were established only 2 years ago, mismatches between the sequences of primers/probes and viruses were found for several of the assays. Such mismatches could lead to a lower sensitivity of the assay, thereby leading to false-negative diagnosis. A slight modification in the primer design is suggested. Protocols for the molecular diagnosis of viral infections should be reviewed regularly after they are established, particularly for viruses that pose a great threat to public health such as MERS-CoV. PMID- 26432411 TI - Prevalence of type 2 diabetes and its association with measures of body composition among African residents in the Netherlands--The HELIUS study. AB - AIMS: To compare type 2 diabetes prevalence among three ethnic groups resident in the Netherlands: Ghanaians, African Surinamese and Dutch origin. Secondly, to determine the contribution of measures of body composition to ethnic differences in type 2 diabetes. METHODS: Baseline data from Ghanaian (n=1873), African Surinamese (n=2189) and Dutch (n=2151) origin participants of the HELIUS study (aged 18-70 years) were analyzed. Type 2 diabetes was determined according to the WHO criteria. Logistic regression tested ethnic differences in type 2 diabetes and the contribution of body fat percentage and waist-to-hip ratio. RESULTS: Among men, type 2 diabetes prevalence was higher in Ghanaians (14.9%) than in African Surinamese (10.4%) and Dutch (5.0%). Among women, type 2 diabetes prevalence in Ghanaian (11.1%) was higher than in Dutch (2.3%), but similar to African Surinamese (11.5%). After adjusting for age, body fat percentage and waist-to-hip ratio, the odds ratios for having type 2 diabetes were 1.55 (95% CI: 1.12-2.15) for Ghanaian men compared with African Surinamese and 4.19 (95% CI: 2.86-6.12) compared with Dutch. Among women these odds ratios were 0.94 (95% CI: 0.70-1.26) and 4.78 (95% CI: 2.82-8.11). CONCLUSIONS: The higher prevalence of type 2 diabetes among Ghanaian compared with African Surinamese men suggests a need to distinguish between African descent populations when assessing their type 2 diabetes risk. The higher odds for type 2 diabetes among Ghanaians cannot be attributed to differences in body composition. Further research on the contribution of lifestyle factors as well as genetic and epigenetic factors is needed to identify the reasons for the observed disparities. PMID- 26432414 TI - Technique determinants of knee abduction moments during pivoting in female soccer players. AB - BACKGROUND: No previous studies have investigated the optimal technique for pivoting with regard to reducing peak knee abduction moments and potential knee injury risk. The aim of this study was to investigate the relationships between technique characteristics and peak knee abduction moments during pivoting. METHODS: Twenty-seven female soccer players [mean (SD); age: 21 (3.8) years, height: 1.67 (0.07) m, and mass: 60.0 (7.2) kg] participated in the study. Three dimensional motion analyses of pivots on the right leg were performed using 10 Qualysis 'Pro reflex' infrared cameras (240Hz). Ground reaction forces were collected from two AMTI force platforms (1200Hz) embedded into the running track to examine penultimate and final contact. Pearson's correlation coefficients, co efficients of determination and stepwise multiple regression were used to explore relationships between a range of technique parameters and peak knee abduction moments. Significance was set at P<0.05. FINDINGS: Stepwise multiple regression found that initial foot progression and initial knee abduction angles together could explain 35% (30% adjusted) of the variation in peak knee abduction moments (F(2,26)=6.499, P=0.006). INTERPRETATION: The results of the present study suggest that initial-foot progression and knee abduction angles are potential technique factors to lower knee abduction moments during pivoting. PMID- 26432413 TI - Crystallographic phasing from weak anomalous signals. AB - The exploitation of anomalous signals for biological structural solution is maturing. Single-wavelength anomalous diffraction (SAD) is dominant in de novo structure analysis. Nevertheless, for challenging structures where the resolution is low (dmin>=3.5A) or where only lighter atoms (Z<=20) are present, as for native macromolecules, solved SAD structures are still scarce. With the recent rapid development in crystal handling, beamline instrumentation, optimization of data collection strategies, use of multiple crystals and structure determination technologies, the weak anomalous diffraction signals are now robustly measured and should be used for routine SAD structure determination. The review covers these recent advances on weak anomalous signals measurement, analysis and utilization. PMID- 26432415 TI - Hip kinematics and kinetics in persons with and without cam femoroacetabular impingement during a deep squat task. AB - BACKGROUND: Previous studies have indicated that hip and pelvis kinematics may be altered during functional tasks in persons with femoroacetabular impingement. The purpose of this study was to compare hip and pelvis kinematics and kinetics during a deep squat task between persons with cam femoroacetabular impingement and pain-free controls. METHODS: Fifteen persons with cam femoroacetabular impingement and 15 persons without cam femoroacetabular impingement performed a deep squat task. Peak hip flexion, abduction, and internal rotation, and mean hip extensor, adductor, and external rotator moments were quantified. Independent t tests (alpha<0.05) were used to evaluate between group differences. FINDINGS: Compared to the control group, persons with cam femoroacetabular impingement demonstrated decreased peak hip internal rotation (15.2 degrees (SD 9.5 degrees ) vs. 9.4 degrees (SD 7.8 degrees ); P=0.041) and decreased mean hip extensor moments (0.56 (SD 0.12) Nm/kg vs. 0.45 (SD 0.15) Nm/kg; P=0.018). In addition persons in the cam femoroacetabular impingement group demonstrated decreased posterior pelvis tilt during squat descent compared to the control group, resulting in a more anteriorly tilted pelvis at the time peak hip flexion (12.5 degrees (SD 17.1 degrees ) vs. 23.0 degrees (SD 12.4 degrees ); P=0.024). INTERPRETATION: The decreased hip internal rotation observed in persons with cam femoroacetabular impingement may be the result of bony impingement. Furthermore, the decrease in posterior pelvis tilt may contribute to impingement by further approximating the femoral head-neck junction with the acetabulum. Additionally, decreased hip extensor moments suggest that diminished hip extensor muscle activity may contribute to decreased posterior pelvis tilt. PMID- 26432412 TI - High burden of prediabetes and diabetes in three large cities in South Asia: The Center for cArdio-metabolic Risk Reduction in South Asia (CARRS) Study. AB - AIM: To estimate the prevalence of, and assess factors associated with, diabetes and prediabetes in three South Asian cities. METHODS: Using a multi-stage cluster random sample representative of each city, 16,288 subjects aged >=20 years (Chennai: 6906, Delhi: 5365 and Karachi: 4017) were recruited to the Centre for cArdio-metabolic Risk Reduction in South-Asia (CARRS) Study. Fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) were measured in 13720 subjects. Prediabetes was defined as FPG 100-125 mg/dl (5.6-6.9 mmol/l) and/or HbA1c 5.7-6.4% (39-46 mmol/mol) and diabetes as self-report and/or drug treatment for diabetes and/or FPG>=126 mg/dl (>=7.0 mmol/l) and/or HbA1c>=6.5% (48 mmol/mol). We assessed factors associated with diabetes and prediabetes using polytomous logistic regression models. RESULTS: Overall 47.3-73.1% of the population had either diabetes or prediabetes: Chennai 60.7% [95%CI: 59.0-62.4%] (diabetes - 22.8% [21.5-24.1%], prediabetes - 37.9% [36.1-39.7%]); Delhi 72.7% [70.6-74.9%] (diabetes - 25.2% [23.6-26.8%], prediabetes - 47.6% [45.6-49.5%]); and Karachi 47.4% [45.7-49.1%]; (diabetes - 16.3% [15.2-17.3%], prediabetes - 31.1% [29.5-32.8%], respectively). Proportions of self-reported diabetes were 55.1%, 39.0%, and 48.0% in Chennai, Delhi, and Karachi, respectively. City, age, family history of diabetes, generalized obesity, abdominal obesity, body fat, high cholesterol, high triglyceride, and low HDL cholesterol levels were each independently associated with prediabetes, while the same factors plus waist-to height ratio and hypertension were associated with diabetes. CONCLUSION: Six in ten adults in large South Asian cities have either diabetes or prediabetes. These data call for urgent action to prevent diabetes in South Asia. PMID- 26432416 TI - Variations in trunk muscle activities and spinal loads following posterior lumbar surgery: A combined in vivo and modeling investigation. AB - BACKGROUND: Iatrogenic injuries to paraspinal muscles during posterior lumbar surgery cause a reduction in their contractile cross-sectional area and thus presumably their postoperative activation. This study investigates the effect of such intraoperative injuries on postoperative patterns of muscle activations and spinal loads during various activities using a combined modeling and in vivo MR imaging approach. METHODS: A three-dimensional, multi-joint, musculoskeletal model was used to estimate pre- and postoperative muscle forces and spinal loads under various activities in upright and flexed postures. According to our in vivo pre- and postoperative (~6 months) measurements in six patients using a 3-Tesla MR scanner, physiological cross-sectional areas of multifidus and erector spinae were reduced in the postoperative model by 26 and 11%, respectively. FINDINGS: Postoperative trunk extension strength was predicted to decrease by ~23% from 215 Nm in the intact model to 165 Nm in the postoperative model. Postoperative force in multifidus fascicles decreased by ~21-40% in flexion tasks and by ~14-35% in upright tasks. In contrast, the sum of the forces in all other intact and less injured extensor muscles slightly increased (by <6%) in the postoperative model. Postoperative L5-S1 compressive and shear loads varied slightly (by ~3%). INTERPRETATION: Intraoperative injuries induced a shift in load-sharing from the most injured muscle (multifidus) toward other less injured and intact muscles during all simulated activities. Postoperative rehabilitation programs should therefore strengthen and facilitate (while avoiding muscle imbalance) not only the injured multifidus but also other intact and less injured trunk muscles that play a compensatory role after the operation. PMID- 26432417 TI - Prevalence and causes of reduced visual acuity among children aged three to six years in a metropolis in China. AB - PURPOSE: To determine the prevalence and possible causes for reduced visual acuity (VA) in preschool children in a metropolis in China. METHODS: A school based paediatric eye survey including 5862 preschool children aged three to 6 years was conducted from 2011 to 2012 in Yuhuatai District, Nanjing, China, using an age-stratified random sampling procedure. Clinical examinations including ocular alignment, ocular motility, visual acuity, prism cover test, cycloplegic refraction, stereopsis screening, slit lamp examination and fundus examination were performed by trained study ophthalmologists and optometrists. Reduced VA was defined as presenting VA of worse than 0.30 logMAR (Snellen 6/12 or 20/40), for both better and worse eyes. RESULTS: 5667 (94.8%) children with complete VA data were included in the data analyses. Among them, 208 and 93 had reduced VA in the worse and better eye, respectively. Reduced VA was detected in 3.7% (95% confidence interval [CI] 3.2%-4.2%) in the worse eye and 1.6% (95% CI 1.3%-2.0%) in the better eye. No significant age and gender differences in reduced VA were observed (p > 0.05). Refractive errors and amblyopia were the principal causes for reduced VA in the worse eye which accounted for 66.8% and 32.7% of the total cases with reduced VA, respectively. Astigmatism and hyperopia were the major types of refractive errors causing reduced VA. CONCLUSIONS: The burden of reduced VA in preschool children in China was similar to that of Asian children of similar ages in the United States. Uncorrected refractive error and amblyopia were the principal causes for reduced VA among preschoolers (aged three to 6 years) in China. PMID- 26432418 TI - Combining C6 and C5 sugar metabolism for enhancing microbial bioconversion. AB - Mixed sugars, which are often obtained from renewable biomass, can be converted into biofuels and chemicals by microbial conversion. This sustainable production process can also mitigate man-made climate change when used to petroleum-based fuel and chemical production. In contrast to single sugar fermentations, such as corn-based or sugarcane-based ethanol fermentations, mixed sugar fermentations present significant challenges for cost-effective production of the target products. In particular, inefficient and slow microbial fermentation of non glucose sugars, such as galactose and xylose from the depolymerization of marine and terrestrial biomass has been a major obstacle. Nonetheless, simultaneous utilization of mixed sugars has recently been demonstrated through innovative metabolic engineering strategies and the discovery of transporters, and metabolic pathways which are necessary for co-fermenting glucose and non-glucose sugars. PMID- 26432419 TI - Transforming somatic mutations of mammalian target of rapamycin kinase in human cancer. AB - Mammalian target of rapamycin (mTOR) is a serine-threonine kinase that acts downstream of the phosphatidylinositol 3-kinase signaling pathway and regulates a wide range of cellular functions including transcription, translation, proliferation, apoptosis, and autophagy. Whereas genetic alterations that result in mTOR activation are frequently present in human cancers, whether the mTOR gene itself becomes an oncogene through somatic mutation has remained unclear. We have now identified a somatic non-synonymous mutation of mTOR that results in a leucine-to-valine substitution at amino acid position 2209 in a specimen of large cell neuroendocrine carcinoma. The mTOR(L2209V) mutant manifested marked transforming potential in a focus formation assay with mouse 3T3 fibroblasts, and it induced the phosphorylation of p70 S6 kinase, S6 ribosomal protein, and eukaryotic translation initiation factor 4E-binding protein 1 in these cells. Examination of additional tumor specimens as well as public and in-house databases of cancer genome mutations identified another 28 independent non synonymous mutations of mTOR in various cancer types, with 12 of these mutations also showing transforming ability. Most of these oncogenic mutations cluster at the interface between the kinase domain and the FAT (FRAP, ATM, TRRAP) domain in the 3-D structure of mTOR. Transforming mTOR mutants were also found to promote 3T3 cell survival, and their oncogenic activity was sensitive to rapamycin. Our data thus show that mTOR acquires transforming activity through genetic changes in cancer, and they suggest that such tumors may be candidates for molecularly targeted therapy with mTOR inhibitors. PMID- 26432422 TI - The importance of teaching neuroscience to psychiatric residents in the context of psychological formulations. PMID- 26432420 TI - Reduced Brain Cannabinoid Receptor Availability in Schizophrenia. AB - BACKGROUND: Several lines of evidence suggest the presence of abnormalities in the endocannabinoid (eCB) system in schizophrenia (SCZ). However, there are limited in vivo measures of the eCB system in SCZ. METHODS: Twenty five male SCZ subjects (SCZs) (18 antipsychotic treated and 7 antipsychotic free) were compared with 18 age-matched male healthy control subjects (HCs). Subjects underwent one positron emission tomography scan each with the cannabinoid receptor-1 (CB1R) selective radiotracer [(11)C]OMAR on the high resolution research tomography scanner. Regional volume of distribution (VT) values were determined using kinetic modeling of positron emission tomography data as a measure of CB1R availability. Group differences in mean composite [(11)C]OMAR VT values were compared between SCZs and HCs. Exploratory comparisons of CB1R availability within 15 brain regions were also conducted. All analyses were covaried for age and body mass index. RESULTS: SCZs showed significantly (p = .02) lower composite [(11)C]OMAR VT relative to HCs (~12% difference, effect size d = .73). [(11)C]OMAR VT was significantly (all ps < .05) lower in SCZs in the amygdala, caudate, posterior cingulate cortex, hippocampus, hypothalamus, and insula. Composite [11]OMAR VT was HCs > antipsychotic treated SZCs > antipsychotic free SZCs. Furthermore, composite [(11)C]OMAR VT was greater in HCs than SCZ smokers (n = 11) and SCZ nonsmokers (n = 14). CONCLUSIONS: CB1R availability is lower in male SCZ subjects compared with HCs. Furthermore, antipsychotics and tobacco use may increase CB1R availability in this population. The findings of the study provide further evidence supporting the hypothesis that alterations in the eCB system might contribute to the pathophysiology of SCZ. PMID- 26432421 TI - Whole-exome sequencing of breast cancer, malignant peripheral nerve sheath tumor and neurofibroma from a patient with neurofibromatosis type 1. AB - Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by the development of multiple neurofibromas, cafe-au-lait spots, and Lisch nodules. Individuals with NF1 are at increased risk of developing various tumors, such as malignant peripheral nerve sheath tumor (MPNST), pheochromocytoma, leukemia, glioma, rhabdomyosarcoma, and breast cancer. Here, we describe the exome sequencing of breast cancer, MPNST, and neurofibroma from a patient with NF1. We identified a germline mutation in the NF1 gene which resulted in conversion of leucine to proline at amino acid position 847. In addition, we showed independent somatic NF1 mutations in all the three tumors (frameshift insertion in breast cancer (p.A985fs), missense mutation in MPNST (p.G23R), and inframe deletion in dermal neurofibroma (p.L1876del-Inf)), indicating that a second hit in NF1 resulting in the loss of function could be important for tumor formation. Each tumor had a distinct genomic profile with mutually exclusive mutations in different genes. Copy number analysis revealed multiple copy number alterations in the breast cancer and the MPNST, but not the benign neurofibroma. Germline loss of chromosome 6q22.33, which harbors two potential tumor suppressor genes, PTPRK and LAMA2, was also identified; this may increase tumor predisposition further. In the background of NF1 syndrome, although second-hit NF1 mutation is critical in tumorigenesis, different additional mutations are required to drive the formation of different tumors. PMID- 26432423 TI - An Elderly Man from Solukhumbu, Nepal, with a Rash. PMID- 26432424 TI - In Reply to Dr Lankford. PMID- 26432425 TI - Marked Hypofibrinogenemia and Gastrointestinal Bleeding After Copperhead (Agkistrodon contortrix) Envenomation. AB - Compared with other crotaline envenomations, copperhead envenomations have historically been reported as having less severe hematologic venom effects and rarely hemorrhage. We report a case of clinically significant gastrointestinal bleeding after a copperhead (Agkistrodon contortrix) envenomation. A 52-year-old woman with a history of systemic lupus erythematosus was bitten on her right medial ankle after which hypofibrinogenemia and hematochezia developed. The symptoms resolved after repeated administration of Crotalidae polyvalent immune Fab (ovine) antivenom. She was discharged without further complications 2 days later. Although copperhead envenomations are classically considered less severe than other crotaline envenomations, this case demonstrates the potential of the venom to produce clinically significant hematologic effects. PMID- 26432426 TI - Predictive Factors for Determining the Clinical Severity of Pediatric Scorpion Envenomation Cases in Southeastern Turkey. AB - OBJECTIVE: The aim of this study was to define the epidemiological, clinical, and laboratory manifestations of scorpion envenomation and to identify factors that are predictive of severe cases. METHODS: The medical files of 41 scorpion envenomation cases were reviewed retrospectively. The cases were classified as mild-moderate or severe. The epidemiological, clinical, and laboratory findings of patients were recorded. RESULTS: There were 27 patients (65.9%) in the mild moderate group and 14 patients (34.1%) in the severe group. The median age of all patients was 48 months. The most common systemic finding was cold extremities (41.5%). In all patients, the most commonly observed dysrhythmia was sinus tachycardia (34.1%). Two patients (4.9%) had pulseless ventricular tachycardia and died. Pulmonary edema and myocarditis were observed in 9 patients (22%). Median values of leukocyte and glucose levels were markedly increased in the severe group. Additionally, the mean thrombocyte level (540,857 +/- 115,261 cells/mm(3)) in the severe group was significantly increased compared with the mild-moderate group (391,365 +/- 150,017 cells/mm(3)). Thrombocyte levels exhibited a positive correlation with leukocyte and glucose values and a negative correlation with patient left ventricular ejection fraction. Multivariate analysis of laboratory parameters indicated that the most predictive factor for clinical severity is thrombocytosis (odds ratio 23.9; 95% CI: 1.6-353.5, P = .021). CONCLUSIONS: Although our results share some similarities with those of other reports, thrombocytosis was markedly increased in the severe group and served as the most predictive laboratory factor of clinical severity. PMID- 26432427 TI - Brown Bear Attacks in a Nepalese Scenario: A Brief Review. PMID- 26432428 TI - In Response to Snakebite Rebound Coagulopathy by Witham et al. PMID- 26432429 TI - New aspects of the clinicopathological features and treatment of mycosis fungoides and Sezary syndrome. AB - Mycosis fungoides and Sezary syndrome are T-helper (Th)2-skewed cutaneous lymphomas. The clinical course of mycosis fungoides is classically indolent, manifesting as patches, plaques and tumors. Along with their progression, Th2 dominance tends to be accelerated. In this review, we discuss the epidemiology, clinicopathogenetic features and therapeutic approaches in mycosis fungoides and Sezary syndrome. PMID- 26432430 TI - Efficacy of Intra-articular Platelet-Rich Plasma Injections in Knee Osteoarthritis: A Systematic Review. AB - PURPOSE: To determine (1) whether platelet-rich plasma (PRP) injection significantly improves validated patient-reported outcomes in patients with symptomatic knee osteoarthritis (OA) at 6 and 12 months postinjection, (2) differences in outcomes between PRP and corticosteroid injections or viscosupplementation or placebo injections at 6 and 12 months postinjection, and (3) similarities and differences in outcomes based on the PRP formulations used in the analyzed studies. METHODS: PubMed, Cochrane Central Register of Controlled Trials, SCOPUS, and Sport Discus were searched for English-language, level I evidence, human in vivo studies on the treatment of symptomatic knee OA with intra-articular PRP compared with other options, with a minimum of 6 months of follow-up. A quality assessment of all articles was performed using the Modified Coleman Methodology Score (average, 83.3/100), and outcomes were analyzed using 2 proportion z-tests. RESULTS: Six articles (739 patients, 817 knees, 39% males, mean age of 59.9 years, with 38 weeks average follow-up) were analyzed. All studies met minimal clinical important difference criteria and showed significant improvements in statistical and clinical outcomes, including pain, physical function, and stiffness, with PRP. All but one study showed significant differences in clinical outcomes between PRP and hyaluronic acid (HA) or PRP and placebo in pain and function. Average pretreatment Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were 52.36 and 52.05 for the PRP and HA groups, respectively (P = .420). Mean post-treatment WOMAC scores for PRP were significantly better than for HA at 3 to 6 months (28.5 and 43.4, respectively; P = .0008) and at 6 to 12 months (22.8 and 38.1, respectively; P = .0062). None of the included studies used corticosteroids. CONCLUSIONS: In patients with symptomatic knee OA, PRP injection results in significant clinical improvements up to 12 months postinjection. Clinical outcomes and WOMAC scores are significantly better after PRP versus HA at 3 to 12 months postinjection. There is limited evidence for comparing leukocyte-rich versus leukocyte-poor PRP or PRP versus steroids in this study. LEVEL OF EVIDENCE: Level I, systematic review of Level I studies. PMID- 26432431 TI - Poor Agreement on Classification and Treatment of Subscapularis Tendon Tears. AB - PURPOSE: To assess the inter- and intraobserver agreement for classification and management of subscapularis tendon pathology based on arthroscopy and magnetic resonance imaging (MRI). METHODS: Twenty-two orthopaedic surgeons from the Multicenter Orthopaedic Outcomes Network (MOON) shoulder group reviewed still arthroscopic and MRI images of the subscapularis tendon from patients with a random assortment of subscapularis morphology. The surgeons were asked to classify the pathology based on 2 systems (Lafosse and Lyons) and choose whether they would repair the tendon and, if so, the method of repair (open or arthroscopic). The survey was administered 3 times to each surgeon. Inter- and intraobserver reliability between testing rounds was determined by kappa analysis. RESULTS: Interobserver reliability on classification of tears was poor based on MRI (k = 0.18 to 0.19) and fair based on arthroscopy (k = 0.26 to 0.29). Interobserver agreement on whether surgical treatment was indicated was fair for both MRI (k = 0.28) and arthroscopy (k = 0.38), while the agreement for type of surgery was poor based on MRI (k = 0.18) and fair based on arthroscopy (k = 0.28). Interobserver agreement did not improve when both MRI and arthroscopy were provided simultaneously (k = 0.24 to 0.30). Intraobserver reliability for classification and treatment was fair to moderate for both MRI (k = 0.32 to 0.50) and arthroscopic imaging (k = 0.39 to 0.56). When considering just those patients with normal tendons, surgeon agreement improved. For all questions, the arthroscopic images had a higher level of agreement among surgeons than the MRI (P < .001). CONCLUSIONS: Although surgeons tended to have higher reliability when presented with arthroscopic images compared with MRI, there was very little agreement on the classification and management of subscapularis tendon tears. PMID- 26432432 TI - Efficacy of Nonsteroidal Anti-inflammatory Drug Prophylaxis for Heterotrophic Ossification in Hip Arthroscopy: A Systematic Review. AB - PURPOSE: The purpose of this systematic review was to investigate the efficacy of nonsteroidal anti-inflammatory drug (NSAID) prophylaxis for preventing heterotopic ossification (HO) in the setting of hip arthroscopy. METHODS: A systematic search was performed in duplicate for studies comparing the use of NSAID prophylaxis for HO in the setting of hip arthroscopy until March 2015. Study parameters--including sample size, incidence of HO, adverse effects, and level of symptoms--were obtained. Furthermore, the level of evidence of studies was collected and quality assessment was performed. The difference in incidence as well as pooled odds ratios were calculated and analyzed to compare no prophylaxis versus NSAID prophylaxis. RESULTS: This systematic review identified 5 studies, consisting of 1,662 patients, investigating NSAID prophylaxis in hip arthroscopy. HO was diagnosed with the use of postoperative hip radiographs at follow-up, with 95% of cases classified using the Brooker classification. The incidence of HO was 13.4% without NSAID prophylaxis and 3.3% with NSAID prophylaxis. Pooled odds ratios from the prospective studies were 0.07 (95% confidence interval [CI], 0.02 to 0.28; P = .0002; I(2) = 0%), showing with statistical significance that NSAID prophylaxis decreased the incidence of HO. The retrospective data similarly showed pooled odds ratios of 0.03 (95% CI, 0.00 to 1.43); P = .08; I(2) = 84%), although it was not statistically significant. Most of the patients who experienced HO in both groups were not reported to be symptomatic. Adverse effects and compliance were not consistently reported. CONCLUSIONS: The available orthopaedic literature suggests that the incidence of postoperative HO may be decreased with the use of NSAID prophylaxis in hip arthroscopy. However, the evidence is unclear regarding NSAID drug regimen choice, drug compliance, and adverse effects. LEVEL OF EVIDENCE: Level III, systematic review of Level I, Level II, and Level III studies. PMID- 26432433 TI - Preoperative platelet-lymphocyte ratio is superior to neutrophil-lymphocyte ratio as a prognostic factor for soft-tissue sarcoma. AB - BACKGROUND: Inflammation can promote tumor growth, invasion, angiogenesis and even metastasis. Inflammatory markers have been identified as prognostic indicators in various malignances. This study compared the usefulness of platelet lymphocyte ratio (PLR) with that of neutrophil-lymphocyte ratio (NLR) for predicting outcomes of patients who underwent radical resection for soft tissue sarcoma (STS). METHODS: We included 222 STS patients in this retrospective study. Kaplan-Meier curves and multivariate Cox proportional models were used to calculate overall survival (OS) and disease free survival (DFS). RESULTS: In univariate analysis, elevated PLR and NLR were both significantly associated with decreased OS. In multivariate analysis, PLR (HR: 2.60; 95 % CI: 1.17-5.74, P = 0.019) but not NLR was still identified as independent predictors of outcome. Median OS was 62 and 76 months for the high PLR and low PLR groups, respectively. High PLR and NLR were both significantly associated with shorter DFS in univariate analysis, with median DFS of 18 and 57 months in the high PLR and low PLR groups. In multivariate analysis, elevated PLR (HR: 1.77; 95 % CI: 1.05-2.97, P = 0.032) was also related to decreased DFS. DISCUSSION: Our findings provide a new and valuable clue for diagnosing and monitoring STS. Prediction of disease progression is not only determined by the use of clinical or histopathological factors including tumor grade, tumor size, and tumor site but also by host response factors such as performance status, weight loss, and systemic inflammatory response. They also significantly affect clinical outcomes. Thus, PLR can be used to enhance clinical prognostication. Furthermore, the PLR can be assessed from peripheral blood tests that are routinely available without any other complicated expenditure, thus providing lower cost and greater convenience for the prognostication. CONCLUSION: Elevated preoperative PLR as an independent prognostic factor is superior to NLR in predicting clinical outcome in patients with STS. PMID- 26432434 TI - Primary side control of load voltage for transcutaneous energy transmission. AB - Transcutaneous energy transmission (TET) is considered as a good way to wirelessly power the implanted devices in human bodies. The load voltage provided from the TET to the implanted device should be kept stable to ensure the device working well, which however, is easily affected by the required power variation for different body movements and coil-couple malposition accompanying skin peristalsis. Commonly, the load voltage applied onto the device should be measured and feedback for power is regulated by implanting sensing and communication units into the body, which causes additional energy cost, increased size and weight of the implanted device. This paper takes the TET for artificial heart as an example to propose a novel primary side control method of the load voltage for TET, which does not require any additional implanted components. In the method, sensing coils are used to measure the malposition between the transmitter coil (TC) and receiver coil, and the magnitude of the TC current outside the human body. The measurement results are used to estimate the load voltage inside the body through calculation, whose value provide a base to develop a PI control system to regulate the input power of TET for the load voltage stability. The proposed method is experimentally validated on an actual TET for artificial heart by varying its load in a wide range under serious coil couple malposition. With applying the primary side control, the variation of the load voltage is reduced to only 25 % of that without the control. PMID- 26432435 TI - The structure and mechanical properties of articular cartilage are highly resilient towards transient dehydration. AB - Articular cartilage is a mechanically highly challenged material with very limited regenerative ability. In contrast to elastic cartilage, articular cartilage is exposed to recurring partial dehydration owing to ongoing compression but maintains its functionality over decades. To extend our current understanding of the material properties of articular cartilage, specifically the interaction between the fluid and solid phase, we here analyze the reversibility of tissue dehydration. We perform an artificial dehydration that extends beyond naturally occurring levels and quantify material recovery as a function of the ionic strength of the rehydration buffer. Mechanical (indentation, compression, shear, and friction) measurements are used to evaluate the influence of de- and rehydration on the viscoelastic properties of cartilage. The structure and composition of native and de/rehydrated cartilage are analyzed using histology, scanning electron microscopy, and atomic force microscopy along with a 1,9 dimethylmethylene blue (DMMB) assay. A broad range of mechanical and structural properties of cartilage can be restored after de- and rehydration provided that a physiological salt solution is used for rehydration. We detect only minor alterations in the microarchitecture of rehydrated cartilage in the superficial zone and find that these alterations do not interfere with the viscoelastic and tribological properties of the tissue. STATEMENT OF SIGNIFICANCE: We here demonstrate the sturdiness of articular cartilage towards changes in fluid content and show that articular cartilage recovers a broad range of its material properties after dehydration. We analyze the reversibility of tissue dehydration to extend our current understanding of how the material properties of cartilage are established, focusing on the interaction between the fluid and solid phase. Our findings suggest that the high resilience of the tissue minimizes the risk of irreversible material failure and thus compensates, at least in part, its poor regenerative abilities. Tissue engineering approaches should thus not only reproduce the correct tissue mechanics but also its pronounced sturdiness to guarantee a similar longevity. PMID- 26432437 TI - Modulation of the gene expression of annulus fibrosus-derived stem cells using poly(ether carbonate urethane)urea scaffolds of tunable elasticity. AB - Annulus fibrosus (AF) injuries commonly lead to substantial deterioration of the intervertebral disc (IVD). While tissue engineering has recently evolved into a promising approach for AF regeneration, it remains challenging due to the cellular, biochemical, and mechanical heterogeneity of AF tissue. In this study, we explored the use of AF-derived stem cells (AFSCs) to achieve diversified differentiation of cells for AF tissue engineering. Since the differentiation of stem cells relies significantly on the elasticity of the substrate, we synthesized a series of biodegradable poly(ether carbonate urethane)urea (PECUU) materials whose elasticity approximated that of native AF tissue. When AFSCs were cultured on electrospun PECUU fibrous scaffolds, the gene expression of collagen I in the cells increased with the elasticity of scaffold material, whereas the expression of collagen-II and aggrecan genes showed an opposite trend. At the protein level, the content of collagen-I gradually increased with substrate elasticity, while collagen-II and GAG contents decreased. In addition, the cell traction forces (CTFs) of AFSCs gradually decreased with scaffold elasticity. Such substrate elasticity-dependent changes of AFSCs were similar to the gradual transition in the genetic, biochemical, and biomechanical characteristics of cells from inner to outer regions of native AF tissue. Together, findings from this study indicate that AFSCs, depending on the substrate elasticity, have strong tendencies to differentiate into various types of AF-like cells, thereby providing a solid foundation for the tissue engineering applications of AFSCs. STATEMENT OF SIGNIFICANCE: Repairing the annulus fibrosus (AF) of intervertebral disc (IVD) is critical for the treatment of disc degeneration disease, but remains challenging due to the significant heterogeneity of AF tissue. Previously, we have identified rabbit AF-derived stem cells (AFSCs), which are AF tissue-specific and hold promise for AF regeneration. In this study, we synthesized a series of poly(ether carbonate urethane)ureas of various elasticity (or stiffness) and explored the potential of induced differentiation of AFSCs using electrospun PECUU scaffolds. This work has, for the first time, found that AFSCs are able to present different gene expression patterns simply as a result of the elasticity of scaffold material. Therefore, our findings will help supplement current knowledge of AF tissue regeneration and may benefit a diversified readership from scientific, engineering, and clinical settings whose work involves the biology and tissue engineering of IVD. PMID- 26432436 TI - Tumor mitochondria-targeted photodynamic therapy with a translocator protein (TSPO)-specific photosensitizer. AB - Photodynamic therapy (PDT) has been proven to be a minimally invasive and effective therapeutic strategy for cancer treatment. It can be used alone or as a complement to conventional cancer treatments, such as surgical debulking and chemotherapy. The mitochondrion is an attractive target for developing novel PDT agents, as it produces energy for cells and regulates apoptosis. Current strategy of mitochondria targeting is mainly focused on utilizing cationic photosensitizers that bind to the negatively charged mitochondria membrane. However, such an approach is lack of selectivity of tumor cells. To minimize the damage on healthy tissues and improve therapeutic efficacy, an alternative targeting strategy with high tumor specificity is in critical need. Herein, we report a tumor mitochondria-specific PDT agent, IR700DX-6T, which targets the 18kDa mitochondrial translocator protein (TSPO). IR700DX-6T induced apoptotic cell death in TSPO-positive breast cancer cells (MDA-MB-231) but not TSPO negative breast cancer cells (MCF-7). In vivo PDT study suggested that IR700DX-6T mediated PDT significantly inhibited the growth of MDA-MB-231 tumors in a target specific manner. These combined data suggest that this new TSPO-targeted photosensitizer has great potential in cancer treatment. STATEMENT OF SIGNIFICANCE: Photodynamic therapy (PDT) is an effective and minimally invasive therapeutic technique for treating cancers. Mitochondrion is an attractive target for developing novel PDT agents, as it produces energy to cells and regulates apoptosis. Current mitochondria targeted photosensitizers (PSs) are based on cationic molecules, which interact with the negatively charged mitochondria membrane. However, such PSs are not specific for cancerous cells, which may result in unwanted side effects. In this study, we developed a tumor mitochondria targeted PS, IR700DX-6T, which binds to translocator protein (TSPO). This agent effectively induced apoptosis in TSPO-positive cancer cells and significantly inhibited tumor growth in TSPO-positive tumor-bearing mice. These combined data suggest that IR700DX-6T could become a powerful tool in the treatment of multiple cancers that upregulate TSPO. PMID- 26432438 TI - A smart, phase transitional and injectable DOX/PLGA-Fe implant for magnetic hyperthermia-induced synergistic tumor eradication. AB - Magnetic hyperthermia ablation is a new and minimally invasive modality for localized tumor removal. However, an inadequate ablation dosage can leave a residual tumor or cause a variety of complications. In addition, commonly used magnetic nanoparticles can easily escape from the tumor tissue, which present potential safety problems. In this study, a smart phase transitional and injectable implant based on biocompatible poly lactic-co-glycolic acid (PLGA) implant incorporating magnetic material (Fe powder) and anti-cancer drug (doxorubicin (DOX)) was developed. The magnetic-induced hyperthermia and release efficiency of DOX were evaluated in vitro. Drug release can be controlled under external alternating current magnetic field (AMF). The results of the in vivo tumor therapeutic efficacy showed that when exposed to external AMF, this smart injectable DOX/PLGA-Fe implant could converse magnetic energy into heat and accelerate the release of DOX, which leads to increasing the temperature to achieve tumor coagulative necrosis and accelerating the release of DOX to enhance residual tumor apoptosis. Furthermore, there was no leakage of magnetic material, as demonstrated using real-time ultrasound (US) and computerized tomography (CT) imaging, realizing the guidance and monitoring of tumor therapy. In conclusion, this smart phase transitional and injectable implant DOX/PLGA-Fe has the ability to improve the efficiency of this newly developed minimally invasive magnetic ablation of tumor treatment technique, and will provide a new avenue of developing minimally invasive synergistic tumor therapy. PMID- 26432439 TI - Inhibition of osteoclastogenesis through siRNA delivery with tunable mesoporous bioactive nanocarriers. AB - Gene silencing through siRNA delivery has shown great promise for treating diseases and repairing damaged tissues, including bone. This report is the first to develop siRNA delivery system in the inhibition of osteoclastic functions which in turn can help turn-over bone mass increase in the diseases like osteoporosis. For this reason, biocompatible and degradable nanocarriers that can effectively load and deliver genetic molecules to target cells and tissues are being actively sought by researchers. In this study, mesoporous bioactive glass nanospheres (MBG), a novel unique biocompatible degradable inorganic nanocarrier, is introduced. Furthermore, siRNA was designed to function by inhibiting the expression of the receptor activator of nuclear factor kappa B (RANK) in order to suppress osteoclastogenesis. Amine-functionalized MBG were synthesized with tunable mesoporosities, showing a strong complexation with siRNA. An in vitro release profile indicated that the siRNA from the MBG was able to achieve a highly sustainable liberation for up to 4 days, confirming a temporary delivery system can be designed to function for that period of time. The intracellular uptake capacity of the complex siRNA(RANK)-MBG was recorded to be around 70%. Furthermore, the RANK-expressing cell population declined down to 29% due to the delivery of siRNA(RANK)-MBG (vs. 86% in control). The expression of osteoclastogenesis-related genes, including c-fos, cathepsin-K, tartrate resistant acid phosphatase (TRAP), and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), was substantially down-regulated by the siRNA delivery system. This study reports for the first time on the use of a novel MBG delivery system for siRNA that aims to suppress osteoclastic actions. MBGs may be a potential gene delivery platform for hard tissue repair and disease treatment due to the collective results which indicate a high loading capacity, temporary release kinetics, high intracellular uptake rate, and sufficient gene silencing effects, together with the intrinsic beneficial properties like bone-bioactivity and degradability. STATEMENT OF SIGNIFICANCE: This report is the first to develop siRNA delivery system of biocompatible and degradable nanocarriers made from a unique composition, i.e., mesoporous bioactive glass that can effectively load and deliver genetic molecules to osteoclastic cells. We proved through a series of studies that the biocompatible nanocarriers are effective for the delivery of siRNA in the inhibition of osteoclastic functions which thus might be considered as a nanocarrier platform to help turn-over bone mass increase in the diseases like osteoporosis. PMID- 26432440 TI - Osteogenic differentiation of human mesenchymal stem cells in the absence of osteogenic supplements: A surface-roughness gradient study. AB - The use of biomaterials to direct osteogenic differentiation of human mesenchymal stem cells (hMSCs) in the absence of osteogenic supplements is thought to be part of the next generation of orthopedic implants. We previously engineered surface roughness gradients of average roughness (Ra) varying from the sub-micron to the micrometer range (~0.5-4.7 MUm), and mean distance between peaks (RSm) gradually varying from ~214 MUm to 33 MUm. Here we have screened the ability of such surface-gradients of polycaprolactone to influence the expression of alkaline phosphatase (ALP), collagen type 1 (COL1) and mineralization by hMSCs cultured in dexamethasone (Dex)-deprived osteogenic induction medium (OIM) and in basal growth medium (BGM). Ra~1.53 MUm/RSm~79 MUm in Dex-deprived OI medium, and Ra~0.93 MUm/RSm~135 MUm in BGM consistently showed higher effectiveness at supporting the expression of the osteogenic markers ALP, COL1 and mineralization, compared to the tissue culture polystyrene (TCP) control in complete OIM. The superior effectiveness of specific surface-roughness revealed that this strategy may be used as a compelling alternative to soluble osteogenic inducers in orthopedic applications featuring the clinically relevant biodegradable polymer polycaprolactone. STATEMENT OF SIGNIFICANCE: Biodegradable polymers, such as polycaprolactone (PCL), are promising materials in the field of tissue engineering and regenerative medicine, which aims at creating viable options to replace permanent orthopedic implants. The material, cells, and growth stimulating factors are often referred to as the key components of engineered tissues. In this article, we studied the hypothesis of specific surface modification of PCL being capable of inducing mesenchymal stem cell differentiation in bone cells in the absence of cell-differentiating factors. The systematic investigation of the linearly varying surface-roughness gradient showed that an average PCL roughness of 0.93 MUm alone can serve as a compelling alternative to soluble osteogenic inducers in orthopedic applications featuring the clinically relevant biodegradable polymer polycaprolactone. PMID- 26432441 TI - Preparation, characterization, in vitro drug release, and cellular interactions of tailored paclitaxel releasing polyethylene oxide films for drug-coated balloons. AB - Drug-coated balloons (DCBs) are used to treat various cardiovascular diseases. Currently available DCBs carry drug on the balloon surface either solely or using different carriers. Several studies have shown that a significant amount of drug is lost in the blood stream during balloon tracking to deliver only a sub therapeutic level of drug at the treatment site. This research is focused on developing paclitaxel (PAT) loaded polyethylene oxide (PEO) films (PAT-PEO) as a controlled drug delivery carrier for DCBs. An array of PAT-PEO films were developed in this study to provide tailored release of >90% of drug only at specific time intervals, which is the time frame required for carrying out balloon-based therapy. The characterizations of PAT-PEO films using SEM, FTIR, and DSC showed that the films developed were homogenous and the PAT was molecularly dispersed in the PEO matrix. Mechanical tests showed that most PAT PEO films developed were flexible and ductile, with yield and tensile strengths not affected after PAT incorporation. The viability, proliferation, morphology, and phenotype of smooth muscle cells (SMCs) interacted with control-PEO and PAT PEO films were investigated. All control-PEO and PAT-PEO films showed a significant inhibitory effect on the growth of SMCs, with the degree of inhibition strongly dependent on the w/v% of the polymer used. The PAT-PEO coating was produced on the balloons. The integrity of PAT-PEO coating was well maintained without any mechanical defects occurring during balloon inflation or deflation. The drug release studies showed that only 15% of the total PAT loaded was released from the balloons within the initial 1min (typical balloon tracking time), whereas 80% of the PAT was released between 1min and 4min (typical balloon treatment time). Thus, this study demonstrated the use of PEO as an alternate drug delivery system for the balloons. STATEMENT OF SIGNIFICANCE: Atherosclerosis is primarily responsible for cardiovascular diseases (CVDs) in millions of patients every year. Drug-coated balloons (DCBs) are commonly used to treat various CVDs. However, in several currently used DCBs, a significant amount of drug is lost in the blood stream during balloon tracking to deliver only a sub therapeutic level of drug at the treatment site. In this study, paclitaxel containing polyethylene oxide (PEO) films were developed to provide unique advantages including drug release profiles specifically tailored for balloon based therapy, homogeneous films with molecularly dispersed drug, flexible and ductile films, and exhibits significant inhibitory effect on smooth muscle cell growth. Thus, this study demonstrated the use of PEO as an alternate drug delivery platform for DCBs to improve its efficacy. PMID- 26432442 TI - Decellularized human placenta chorion matrix as a favorable source of small diameter vascular grafts. AB - Biomaterials based on decellularized tissues are increasingly attracting attention as functional alternatives to other natural or synthetic materials. However, a source of non-cadaver human allograft material would be favorable. Here we establish a decellularization method of vascular tissue from cryopreserved human placenta chorionic plate starting with an initial freeze-thaw step followed by a series of chemical treatments applied with a custom-made perfusion system. This novel pulsatile perfusion set-up enabled us to successfully decellularize the vascular tissue with lower concentrations of chemicals and shorter exposure times compared to a non-perfusion process. The decellularization procedure described here lead to the preservation of the native extracellular matrix architecture and the removal of cells. Quantitative analysis revealed no significant changes in collagen content and a retained glycosaminoglycan content of approximately 29%. In strain-to-failure tests, the decellularized grafts showed similar mechanical behavior compared to native controls. In addition, the mechanical values for ultimate tensile strength and stiffness were in an acceptable range for in vivo applications. Furthermore, biocompatibility of the decellularized tissue and its recellularizationability to serve as an adequate substratum for upcoming recellularization strategies using primary human umbilical vein endothelial cells (HUVECs) was demonstrated. HUVECs cultured on the decellularized placenta vessel matrix performed endothelialization and maintained phenotypical characteristics and cell specific expression patterns. Overall, the decellularized human placenta vessels can be a versatile tool for experimental studies on vascularization and as potent graft material for future in vivo applications. STATEMENT OF SIGNIFICANCE: In the US alone more than 1million vascular grafts are needed in clinical practice every year. Despite severe disadvantages, such as donor site morbidity, autologous grafting from the patient's own arteries or veins is regarded as the gold standard for vascular tissue repair. Besides, strategies based on synthetic or natural materials have shown limited success. Tissue engineering approaches based on decellularized tissues are regarded as a promising alternative to clinically used treatments to overcome the observed limitations. However, a source for supply of non-cadaver human allograft material would be favorable. Here, we established a decellularization method of vascular tissue from the human placenta chorionic plate, a suitable human tissue source of consistent quality. The decellularized human placenta vessels can be a potent graft material for future in vivo applications and furthermore might be a versatile tool for experimental studies on vascularization. PMID- 26432443 TI - Gingival epithelial cells support osteoclastogenesis by producing receptor activator of nuclear factor kappa B ligand via protein kinase A signaling. AB - BACKGROUND AND OBJECTIVE: Periodontal disease is dental plaque-induced inflammatory disease of the periodontal tissues that results in bone loss in the affected teeth. During bone resorption, receptor activator of nuclear factor kappa B ligand (RANKL) is an essential factor that regulates osteoclastogenesis. Recently, we found that gingival epithelial cells (GECs) in periodontal tissue produce RANKL, the expression of which is regulated by tumor necrosis factor alpha and protein kinase A signaling. In this study, we asked whether RANKL producing GECs induce bone marrow macrophages (BMMs) to form osteoclasts in a co culture system. MATERIAL AND METHODS: Ca9-22 GECs and osteoclast precursor BMMs were co-cultured with or without the protein kinase A signaling activator forskolin or inhibitor H89 to examine whether the RANKL-producing GECs could be induced to form osteoclasts, as determined using a pit formation assay. RESULTS: Osteoclasts formed spontaneously in co-cultures of Ca9-22 cells and BMMs, even in the absence of RANKL. The cells were cultured on bone slices for 14 d, at which time resorption pits were observed. Forskolin treatment significantly increased osteoclast numbers in these co-cultures, but forskolin alone did not induce osteoclast formation by BMMs. CONCLUSION: GECs producing RANKL are able to support osteoclastogenesis in an in vitro co-culture system using GECs and BMMs, in a process promoted by forskolin. PMID- 26432444 TI - A novel method for murine intrahepatic islet transplantation via cecal vein. AB - Islet transplantation is one of the most beneficial treatment modality to treat type 1 diabetic patients with frequent hypoglycemic unawareness. In clinical setting, human islets are infused via portal vein and are settled in the end portal venules in the liver. However, mouse islets are transplanted into kidney subcapsule or liver through direct portal vein. These conventional transplantation methods have several drawbacks such as different physiological environments around the transplanted islets in kidney subcapsule from the liver and high mortality rate in direct portal vein approach. In this study, we introduced murine intrahepatic islet transplantation method via cecal vein to have the same surgical operation route in humans as well as guaranteeing low mortality rate after islet transplantation. With this protocol, consistent normoglycemia can be obtained in diabetic mice, while keeping operation-related mortality extremely low. This approach with easier accessibility and low mortality will make murine intrahepatic islet transplantation a useful model for studying immunological mechanisms such as strong innate and adaptive immune responses that occur in human islet transplantation. PMID- 26432445 TI - Efficacy of the FilmArray blood culture identification panel for direct molecular diagnosis of infectious diseases from samples other than blood. AB - Molecular-based techniques reduce the delay in diagnosing infectious diseases and therefore contribute to better patient outcomes. We assessed the FilmArray blood culture identification (BCID) panel (Biofire Diagnostics/bioMerieux) directly on clinical specimens other than blood: cerebrospinal, joint, pleural and ascitic fluids, bronchoscopy samples and abscesses. We compared the results from 88 samples obtained by culture-based techniques. The percentage of agreement between the two methods was 75 % with a Cohen kappa value of 0.51. Global sensitivity and specificity using the FilmArray BCID panel were 71 and 97 %, respectively. Sensitivity was poorer in samples with a low bacterial load, such as ascitic and pleural fluids (25 %), whereas the sensitivity for abscess samples was high (89 %). These findings suggest that the FilmArray BCID panel could be useful to perform microbiological diagnosis directly from samples other than positive blood cultures, as it offers acceptable sensitivity and moderate agreement with conventional microbiological methods. Nevertheless, cost-benefit studies should be performed before introducing this method into algorithms for microbiological diagnostics. PMID- 26432446 TI - Genetic structure of populations of sugarcane streak mosaic virus in China: Comparison with the populations in India. AB - Sugarcane streak mosaic virus (SCSMV) causes mosaic and streak symptoms on sugarcane and sorghum crops, and has a broad host range. SCSMV is a member of the genus Poacevirus in the family Potyviridae.Ten SCSMV isolates were collected from sugarcane plants showing mosaic and streaking in Southern China from 2009-2011. Sequence-based phylogenetic and population genetic analyses were conducted using four partial genomic sequences covering the full genomes. These analyses were used to estimate the subpopulation differentiation and divergence within the Chinese virus population, and were compared with isolates from India. SCSMV infected sugarcane plants in the field commonly harbor virus quasispecies (mutant cloud), and often have mixed infections with the same virus isolates. Inter- and intra-lineage recombination sites were identified in the protein 1, helper component proteinase, coat protein and 3' non-coding regions of the Chinese isolates. All the Chinese non-recombinant isolates fell into at least nine lineages, and many clustered with Indian isolates. However, estimates of genetic differentiation and gene flow indicated that the SCSMV populations in China and India are genetically independent. Our genetic study of a poacevirus population in South Asia regions indicates the importance of the evolutionary-based design to control viruses. PMID- 26432447 TI - Comparison of small RNA profiles in Nicotiana benthamiana and Solanum lycopersicum infected by polygonum ringspot tospovirus reveals host-specific responses to viral infection. AB - Viral small RNAs (vsRNAs) are one of the key elements involved in RNA silencing based defense against viruses in plants. We analyzed the vsRNA profiles in Nicotiana benthamiana and Solanum lycopersicum infected by polygonum ringspot virus (PolRSV) (Tospovirus, Bunyaviridae). VsRNAs were abundant in both hosts, but a different size profile was observed, with an abundance peak at 21 in N. benthamiana and at 22 nt in tomato. VsRNAs mapping to the PolRSV L genomic segment were under-represented in both hosts, while S and M segments were differentially and highly targeted in N. benthamiana and tomato, respectively. Differences in preferential targeting of single ORFs were observed, with over representation of NSs ORF-derived reads in N. benthamiana. Intergenic regions (IGRs)-mapping vsRNAs were under-represented, while enrichment of vsRNAs reads mapping to the NSs positive sense strand was observed in both hosts. Comparison with a previous study on tomato spotted wilt virus (TSWV) under the same experimental conditions, showed that the relative accumulation of PolRSV-specific and endogenous sRNAs was similar to the one observed for silencing suppressor deficient TSWV strains, suggesting possible different properties of PolRSV NSs silencing suppressor compared to that of TSWV. PMID- 26432448 TI - Intestinal Alterations, Basal Hematology, and Biochemical Parameters in Adolescent Rats Fed Different Sources of Dietary Copper. AB - Copper (Cu) is required for basically all biochemical and physiological processes in the body. The aim was to evaluate the effects of different sources of dietary copper on jejunal epithelium histomorphometry in adolescent rats. Male rats at the age of 5 weeks were used in the 12-week experiment. The control group was fed with standard diet providing the required Cu level (5 mg/kg body weight (bw) per day) in an inorganic form (sulfate) covered 100 % of daily demand, and the other three groups were supplemented with Cu-glycine complex covered 50, 75, and 100 % daily demand. Basal hematological and plasma biochemical analyses as well as histomorphometric examinations of the jejunal epithelium and liver were performed. Cu given in the organic form in 100 % of daily demand depressed the muscular and submucosa layer and the crypt depth (P < 0.05) without an influence of the innervation of the jejunum. In turn, organic Cu given in 75 % of daily demand did not influence the intestinal morphology in adult rats. Dietary organic Cu given to rats covering the daily demand in 50 or 75 % appears to be less harmful with regard to the intestinal epithelium than when administered in 100 % of daily demand. PMID- 26432449 TI - The Effects of High Dietary Doses of Chromium(III) Complex with Propionic Acid on Nutritional and Selected Blood Indices in Healthy Female Rats. AB - People taking dietary supplements are usually determined to lose weight, supplement nutrition or reduce the risk of illness and negative effects of their state of health. Chromium(III) supplementation influence body composition and mass, glucose and lipid metabolism and it enhance insulin action. This fact could be of general interest because diabetes mellitus is an increasing health problem in many countries. The study describes the effects of high dietary doses of chromium(III) complex with propionic acid [Cr3] (from 100 to 1000 mg Cr . kg(-1) diet) on the organisms of healthy female rats, with special regard to overall nutritional, carbohydrate, lipid and blood biochemical and morphological and haematological indices. The study was carried out on 30 10-week-old female Wistar rats, which were divided into five equal groups (six animals in each): the control group and four groups of tested animals which had free access to the diet supplemented with 100, 200, 500 and 1000 mg Cr . kg(-1) (equivalent of 10, 20, 50 and 100 mg Cr . kg body weight (b.w.) . day(-1)), given as [Cr3O(O2CCH2CH3)6(H2O)3]?NO3, also known as Cr3, for 4 weeks. There were no significant differences in body mass gains, feeding efficiency ratio, internal organ masses or blood serum glucose concentrations, except for some changes in the serum triglycerides concentration, which decreased in the rats that received 500 and 1000 mg Cr . kg(-1) diet, as opposed to the group treated with 200 mg Cr . kg(-1) diet. The dietary supplementation of Cr3 for 4 weeks at doses of 100 to 1000 mg Cr . kg(-1) diet did not affect overall nutritional indices and most blood biochemical, morphological and haematological indices. PMID- 26432450 TI - The Selenylation Modification of Epimedium Polysaccharide and Isatis Root Polysaccharide and the Immune-enhancing Activity Comparison of Their Modifiers. AB - Epimedium polysaccharide (EPS) and isatis root polysaccharide (IRPS) were extracted, purified, and selenizingly modified by nitric acid-sodium selenite method to obtain nine selenizing EPSs (sEPSs), sEPS1-sEPS9 and nine selenizing IRPSs (sIRPSs), sIRPS1-sIRPS9, respectively. Their effects on chicken peripheral lymphocyte proliferation in vitro were compared by MTT assay. The results showed that selenium polysaccharides at appropriate concentration could promote lymphocyte proliferation more significantly than unmodified polysaccharides, sEPS5 and sIRPS5 with stronger actions were picked out and injected into the chickens vaccinated with Newcastle disease vaccine in vivo tests. The peripheral lymphocyte proliferation and serum antibody titer were determined. The results showed that sEPS5 and sIRPS5 could elevate serum antibody titer and promote lymphocyte proliferation more significantly than unmodified polysaccharides, sEPS5 possessed the strongest efficacy. These results indicate that selenylation modification can significantly enhance the immune-enhancing activity of EPS and IRPS, and sEPS5 can be as a new-type immunopotentiator of chickens. PMID- 26432451 TI - Proteomic Analysis to Elucidate the Antibacterial Action of Silver Ions Against Bovine Mastitis Pathogens. AB - Silver ions act as a powerful, broad-spectrum antimicrobial agent and are known to kill over 650 different kinds of pathogens. We investigated the protein expression pattern and identity after silver ion treatment in Escherichia coli and Staphylococcus aureus, which are primarily responsible for the majority of bovine mastitis cases using proteomics. Two-dimensional electrophoresis showed that silver ion treatment significantly reduced 5 spot's density in E. coli and S. aureus, respectively. We identified 10 proteins (alkyl hydroperoxide reductase C22 subunit, phosphoglucomutase, fructose-1-phosphate kinase, putative carbamoyl transferase, alpha-galactosidase, carbamate kinase, ornithine transcarbamoylase, fumarate hydratase class II, alcohol dehydrogenase, and conserved hypothetical protein) by matrix-assisted laser desorption ionization time of flight (MALDI TOF). These results demonstrated that silver ions have bactericidal effects through energy deprivation, inhibition of DNA replication, and accumulation of oxidants in bovine mastitis pathogens and suggested that silver ions can be applied for the treatment of bovine mastitis. PMID- 26432452 TI - T-lymphocyte populations following a period of high volume training in female soccer players. AB - PURPOSE: To investigate the T-lymphocyte response to a period of increased training volume in trained females compared to habitual activity in female controls. METHODS: Thirteen trained female (19.8 +/- 1.9 yrs) soccer players were monitored during a two-week long high volume training period (increased by 39%) and thirteen female untrained (20.5 +/- 2.2 yrs) controls were monitored during two-weeks of habitual activity. Blood lymphocytes, collected at rest, were isolated before and after the two-week period. Isolated lymphocytes were assessed for the cell surface expression of the co-receptor CD28, a marker of T-lymphocyte naivety, and CD57 a marker used to identify highly-differentiated T-lymphocytes. Co-expression of these markers was identified on helper CD4(+) and cytotoxic CD8(+) T-lymphocytes. In addition a further population of gammadelta(+) T lymphocytes were identified. Plasma was used to determine Cytomegalovirus (CMV) serostatus. RESULTS: No difference was observed in the T-lymphocyte populations following the two-week period of increased volume training. At baseline the number of total CD3(+), cytotoxic CD8(+), naive (CD8(+) CD28(+) CD57(-)), intermediate (CD8(+) CD28(+) CD57(+)) T-lymphocytes and the number and proportion of gammadelta(+) T-lymphocytes were greater in the trained compared to the untrained females (p<0.05). The proportion of CD4(+)T-lymphocytes was greater in the untrained compared to the trained (p<0.05), in turn the CD4(+):CD8(+) ratio was also greater in the untrained females (p<0.05). Inclusion of percentage body fat as a covariate removed the main effect of training status in all T-lymphocyte sub-populations, with the exception of the gammadelta(+) T-lymphocyte population. 8% of the untrained group was defined as positive for CMV whereas 23% of the trained group was positive for CMV. However, CMV was not a significant covariate in the analysis of T-lymphocyte proportions. CONCLUSION: The period of high volume training had no effect on T-lymphocyte populations in trained females. However, baseline training status differences were evident between groups. This indicates that long-term exercise training, as opposed to short-term changes in exercise volume, appears to elicit discernible changes in the composition of the blood T-lymphocyte pool. PMID- 26432453 TI - The capacity for volitional control of pharyngeal swallowing in healthy adults. AB - INTRODUCTION: Previous research has documented that pressure and duration of brainstem-generated pharyngeal swallowing can be cortically modulated. But there is a commonly held belief that the sequence of pharyngeal pressure remains constant. However, Huckabee et al. [19] reported a patient cohort who demonstrated reduced latency of peak pressure in the proximal and distal pharynx, disproportionate and sometimes inversely correlated with overall swallowing duration, suggesting independent timing of underlying muscle contraction within the overall pharyngeal response. This study examined if healthy adults can volitionally produce altered latency of pharyngeal closure in isolation following intensive training, thereby evaluating the capacity for pharyngeal adaptation in a healthy system. METHOD: Six healthy participants were seen for intensive training, consisting of daily one-hour sessions over two weeks (10 days) using pharyngeal manometry as a visual biofeedback modality. The participants were instructed to produce simultaneous pressure in the pharyngeal sensors when swallowing. The temporal separation of peak proximal and distal pharyngeal pressure was measured with discrete-sensor pharyngeal manometry at baseline, during training with biofeedback, and following training without biofeedback. RESULTS: Following intensive training, participants were able to reduce temporal separation of peak pressure between the proximal and distal pharyngeal sensors from a baseline median of 188 ms (IQR=231 ms) to 68 ms (IQR=92 ms; p=0.002). In contrast, there was no significant change in overall swallowing duration during training (p=0.41). However, change in pharyngeal pressure latency was moderately correlated with both change in swallowing duration (r=0.444) and amplitude (r=0.571) during training, and there was a reduction in swallowing duration post training (p=0.03). CONCLUSION: Given intensive manometric biofeedback training, participants substantially reduced temporal separation of peak proximal and distal pharyngeal pressure when volitionally swallowing. However, correlation with overall pressure and duration measures suggest the adaptation was one of modulating the cumulative pharyngeal response rather than altering discrete components of timing of pharyngeal pressure in isolation. This is inconsistent with the pattern of behaviour documented by Huckabee et al. [19] in the patient population. Further research on modulatory control over targeted aspects of the pharyngeal swallow is needed, and may provide avenues for rehabilitative treatment of patients with dysphagia. PMID- 26432454 TI - Indiscernible Benefit of Double-Unit Umbilical Cord Blood Transplantation in Children: A Single-Center Experience From Hong Kong. AB - Double-unit umbilical cord blood (DU-UCB) may extend the use of UCB transplantation and improve clinical outcomes. Data in the literature show that single-unit dominance happened in a vast majority of recipients, and the mechanism is unknown. We examined the clinical relevance and engraftment kinetics of DU-UCB transplant in 65 consecutive children who underwent unrelated single unit (n = 25) and double-unit (n = 40) UCB transplantation for various hematological malignancies (n = 45) and nonmalignant disorders (n = 20). Our result showed no discernible benefit to children receiving double-unit transplant over those receiving single-unit transplant when the total nucleated cell (TNC) doses are >=2.5 * 10(7)/kg, in terms of the hastening of the engraftment of neutrophils and platelets, reduction of nonengraftment, disease recurrence, early mortality, and graft-versus-host disease, despite significantly higher numbers of TNCs in double units. Further analyses demonstrated that the phenomena were not associated with underlying disease, duration of UCB storage, postthaw viability, HLA disparity, ABO incompatibility, gender, or doses of TNCs, CD34(+) cells, CD3(+) cells, or colony-forming units. Engrafting units in DU-UCB transplants were notably associated with higher CD34(+) cell dose. Chimerism studies demonstrated that single-unit dominance started before neutrophil engraftment in DU-UCB transplants. Data from the study suggested no advantage of infusing double unit UCB, if an adequately dosed single-unit UCB is available. Successful prediction of the dominant graft would optimize algorithms of UCB selection and maximize the long-term engraftment of chosen units. PMID- 26432456 TI - Erratum to: Use of porous high-density polyethylene grafts in open rhinoplasty: no infectious complication seen in spreader and dorsal grafts. PMID- 26432455 TI - Molecular phylogeny of four homeobox genes from the purple sea star Pisaster ochraceus. AB - Homeobox genes cloned from the purple sea star Pisaster ochraceus (Phylum Echinodermata/Class Asteroidea) were used along with related sequences available from members of other representative animal phyla to generate molecular phylogenies for Distal-less/Dlx, Hox5, Hox7, and Hox9/10 homeobox genes. Phylogenetic relationships were inferred based on the predicted 60 amino acid homeodomain, using amino acid (AA) and nucleotide (NT) models as well as the recently developed codon substitution models of sequence evolution. The resulting phylogenetic trees were mostly congruent with the consensus species-tree, grouping these newly identified genes with those isolated from other Asteroidea. This analysis also allowed a preliminary comparison of the performance of codon models with that of NT and AA evolutionary models in the inference of homeobox phylogeny. We found that, overall, the NT models displayed low reliability in recovering major clades at the Superphylum/Phylum level, and that codon models were slightly more dependable than AA models. Remarkably, in the majority of cases, codon substitution models seemed to outperform both AA and NT models at both the Class level and homeobox paralogy-group level of classification. PMID- 26432457 TI - The effects of cryopreservation on angiogenesis modulation activity of human amniotic membrane. AB - Amniotic membrane (AM), as the innermost layer of placenta, has side dependent effects on the angiogenesis. Cryopreservation is a necessary process to avoid the challenging problems of fresh tissues; a procedure which makes the AM ready-to use. Since the cryopreservation can influence the AM characteristics for experimental and clinical purposes, in this study the effects of cryopreservation were evaluated on angiogenesis modulation activity of the AM compared to fresh tissues in an animal model. The AM was implanted mesenchymal side up or epithelial side up in a rat dorsal skinfold chamber. The length and number of branches of formed capillaries were measured via intravital microscopy after 7 days. The amount of IL-8 (interleukin-8) and TIMP-2 (Tissue Inhibitor of Matrix Metalloproteinase-2) as two factors in amniotic cells which have great impacts on angiogenesis were evaluated using ELISA assay. The epithelial surface of cryopreserved AM had inhibitory effects on vessel formation. The cryopreserved amniotic mesenchymal side increased the vessel length and sprout. The result of cryopreserved AM on angiogenesis was similar to that of fresh tissues. The levels of IL-8 and TIMP-2 in cryopreserved samples were significantly less than fresh AMs which shows that angio-modulatory properties are not limited to the effects of amnion epithelial and mesenchymal stem cells and the other components such as extracellular matrix may contribute in angio-modulatory effects. These promising results show that inducing and inhibitory effects of the AM, which make it an appropriate candidate for different clinical situations, were maintained after cryopreservation. PMID- 26432458 TI - Role of Oxidative Stress in Modulating Unfolded Protein Response Activity in Chronic Myeloid Leukemia Cell Line. AB - Recently, it has been revealed that tyrosine kinase inhibitors (TKIs) act through inducing both oxidative and endoplasmic reticulum (ER) stress in chronic myeloid leukemia cells. However, ER stress signaling triggers both apoptotic and survival processes within cells. Nevertheless, mechanisms by which TKIs avoid the pro survival effects are not clear. The aim of this study was to evaluate the potential role of oxidative stress in activity of unfolded protein response (UPR) survival pathway within K562 cell line. METHODS: The expression of UPR survival target genes, Xbp1, and Grp94 (glucose requiring protein 94) was studied in single and combined exposure to oxidative and ER stress in K562 cell line by quantitative and qualitative PCR. RESULTS: The expression of UPR-related survival gene Grp94 was hampered by exposing to oxidative stress in cell induced with ER stress. CONCLUSION: Interaction of oxidative and ER stress may role as a mediator influencing UPR signaling activity. PMID- 26432459 TI - Process limitations of a whole-cell P450 catalyzed reaction using a CYP153A-CPR fusion construct expressed in Escherichia coli. AB - Cytochrome P450s are interesting biocatalysts due to their ability to hydroxylate non-activated hydrocarbons in a selective manner. However, to date only a few P450-catalyzed processes have been implemented in industry due to the difficulty of developing economically feasible processes. In this study, we have used the CYP153A heme domain from Marinobacter aquaeolei fused to the reductase domain of CYP102A1 from Bacillus megaterium (BM3) expressed in Escherichia coli. This self sufficient protein chimera CYP153A-CPRBM3 G307A mutant is able to selectively hydroxylate medium and long chain length fatty acids at the terminal position. omega-Hydroxylated fatty acids can be used in the field of high-end polymers and in the cosmetic and fragrance industry. Here, we have identified the limitations for implementation of a whole-cell P450-catalyzed reaction by characterizing the chosen biocatalyst as well as the reaction system. Despite a well-studied whole cell P450 catalyst, low activity and poor stability of the artificial fusion construct are the main identified limitations to reach sufficient biocatalyst yield (mass of product/mass of biocatalyst) and space-time yield (volumetric productivity) essential for an economically feasible process. Substrate and product inhibition are also challenges that need to be addressed, and the application of solid substrate is shown to be a promising option to improve the process. PMID- 26432461 TI - Transosseous Route for CT Fluoroscopy-Guided Radiofrequency Ablation of Lung Tumors. AB - PURPOSE: To retrospectively evaluate radiofrequency (RF) ablation of lung tumors performed via the transosseous approach. MATERIALS AND METHODS: Twelve lung tumors (mean diameter, 1.0 cm; range, 0.4-1.6 cm) in 12 patients were treated by RF ablation via a transscapular and/or transrib route with the use of a bone biopsy needle under computed tomographic fluoroscopy guidance. Therapeutic outcomes evaluated included feasibility, safety, and local efficacy. Complications were assessed based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: The transosseous route was successfully employed in all patients, and the electrode was successfully advanced into all tumors with this approach. The mean distance of penetrated bone was 0.57 cm (range, 0.19-1.16 cm). Complications occurred in eight RF ablation sessions, including six grade 1 events (two cases of pneumothorax and one case each of asymptomatic rib fracture 6 mo after treatment, neuralgia, pulmonary hemorrhage, and hemothorax), two grade 2 events (pneumonia and high fever), and one grade 3 event (pneumothorax requiring pleurodesis). No adverse events of grade >= 4 occurred. The mean and median tumor follow-up periods were 19.5 and 15.2 mo (range, 3.0-41.5 mo). Local progression occurred in two cases at 3 and 12 mo after treatment and was successfully treated with a second RF ablation procedure. The technique efficacy rates were 91.7% at 6 mo, 81.5% at 1 y, and 81.5% at 2 y. CONCLUSIONS: The transosseous approach was feasible in computed tomographic fluoroscopy-guided RF ablation of select lung tumors when no other option was available. PMID- 26432460 TI - Production of the polyketide 6-deoxyerythronolide B in the heterologous host Bacillus subtilis. AB - Polyketides, such as erythromycin, are complex natural products with diverse therapeutic applications. They are synthesized by multi-modular megaenzymes, so called polyketide synthases (PKSs). The macrolide core of erythromycin, 6 deoxyerythronolide B (6dEB), is produced by the deoxyerythronolide B synthase (DEBS) that consists of three proteins each with a size of 330-370 kDa. We cloned and investigated the expression of the corresponding gene cluster from Saccharopolyspora erythraea, which comprises more than 30 kb, in Bacillus subtilis. It is shown that the DEBS genes are functionally expressed in B. subtilis when the native eryAI-III operon was separated into three individual expression cassettes with optimized ribosomal binding sites. A synthesis of 6dEB could be detected by using the acetoin-inducible acoA promoter and a fed-batch simulating EnBase-cultivation strategy. B. subtilis was capable of the secretion of 6dEB into the medium. In order to improve the 6dEB production, several genomic modifications of this production strain were tested. This included the knockout of the native secondary metabolite clusters of B. subtilis for the synthesis of surfactin (26 kb), bacillaene (76 kb), and plipastatin (38 kb). It is revealed that the deletion of the prpBD operon, responsible for propionyl-CoA utilization, resulted in a significant increase of the 6dEB product yield when exogenous propionate is provided. Although the presented B. subtilis 6dEB production strain is not competitive with established Escherichia coli 6dEB production strains, the results of this study indicate that B. subtilis is a suitable heterologous host for the secretory production of a complex polyketide. PMID- 26432462 TI - Novel sporadic and recurrent mutations in KRT5 and KRT14 genes in Polish epidermolysis bullosa simplex patients: further insights into epidemiology and genotype-phenotype correlation. AB - Epidermolysis bullosa simplex (EBS) is a hereditary genodermatosis characterised by trauma-induced intraepidermal blistering of the skin. EBS is mostly caused by mutations in the KRT5 and KRT14 genes. Disease severity partially depends on the affected keratin type and may be modulated by mutation type and location. The aim of our study was to identify the molecular defects in KRT5 and KRT14 in a cohort of 46 Polish and one Belarusian probands with clinical suspicion of EBS and to determine the genotype-phenotype correlation. The group of 47 patients with clinical recognition of EBS was enrolled in the study. We analysed all coding exons of KRT5 and KRT14 using Sanger sequencing. The pathogenic status of novel variants was evaluated using bioinformatical tools, control group analysis (DNA from 100 healthy population-matched subjects) and probands' parents testing. We identified mutations in 80 % of patients and found 29 different mutations, 11 of which were novel and six were found in more than one family. All novel mutations were ascertained as pathogenic. In the majority of cases, the most severe genotype was associated with mutations in highly conserved regions. In some cases, different inheritance mode and clinical significance, than previously reported by others, was observed. We report 11 novel variants and show novel genotype-phenotype correlations. Our data give further insight into the natural history of EBS molecular pathology, epidemiology and mutation origin. PMID- 26432463 TI - Angiogenic factor imbalance early in pregnancy predicts adverse outcomes in patients with lupus and antiphospholipid antibodies: results of the PROMISSE study. AB - BACKGROUND: Over 20% of pregnancies in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (APL) result in an adverse pregnancy outcome (APO) related to abnormal placentation. The ability to identify, early in pregnancy, patients who are destined for poor outcomes would significantly impact care of this high-risk population. In nonautoimmune patients, circulating angiogenic factors are dysregulated in disorders of placentation, such as preeclampsia (PE) and fetal growth restriction. OBJECTIVE: We sought to determine whether early dysregulation of circulating angiogenic factors can predict APO in high-risk SLE and/or APL pregnancies. STUDY DESIGN: We used data and samples from the Predictors of Pregnancy Outcome: Biomarkers in APL Syndrome and SLE (PROMISSE), a multicenter prospective study that enrolled 492 pregnant women with SLE and/or APL from September 2003 through August 2013. Patients were followed through pregnancy from <12 weeks gestation. Circulating levels of soluble fms like tyrosine kinase-1 (sFlt1), placental growth factor (PlGF), and soluble endoglin were measured monthly and subjects followed up for APO, classified as severe (PE <34 weeks, fetal/neonatal death, indicated preterm delivery <30 weeks) or moderate (PE >=34 weeks, indicated preterm delivery 30-36 weeks, growth restriction without PE). RESULTS: Severe APOs occurred in 12% and moderate APOs in 10% of patients. By 12-15 weeks, sFlt1, PlGF, and soluble endoglin levels were markedly altered in women who developed severe APO. After adjusting for clinical risk factors, sFlt1 was the strongest predictor of severe APO among 12-15 week measures (odds ratio, 17.3 comparing highest and lowest quartiles; 95% confidence interval [CI], 3.5-84.8; positive predictive value [PPV], 61%; negative predictive value [NPV], 93%). At 16-19 weeks, the combination of sFlt1 and PlGF was most predictive of severe APO, with risk greatest for subjects with both PlGF in lowest quartile (<70.3 pg/mL) and sFlt1 in highest quartile (>1872 pg/mL; odds ratio, 31.1; 95% CI, 8.0-121.9; PPV, 58%; NPV, 95%). Severe APO rate in this high risk subgroup was 94% (95% CI, 70-99.8%), if lupus anticoagulant or history of high blood pressure was additionally present. In contrast, among patients with both sFlt1 <1872 pg/mL and PlGF >70.3 pg/mL, rate of severe APO was only 4.6% (95% CI, 2.1-8.6%). CONCLUSION: Circulating angiogenic factors measured during early gestation have a high NPV in ruling out the development of severe adverse outcomes among patients with SLE and/or APL syndrome. Timely risk stratification of patients is important for effective clinical care and optimal allocation of health care resources. PMID- 26432465 TI - Fetal tissue research: an ongoing story of professionally responsible success. AB - Therapies derived from fetal tissue research are some of the greatest success stories in medicine. Research using fetal tissue has allowed for development of vaccines for numerous diseases including polio, rubella, and measles. These vaccines have saved countless lives, improved quality of life, and decreased the need for induced abortion secondary to congenital infection. Research using cell lines derived from fetal tissue has assisted in better understanding disease pathogenesis and has served to produce human proteins as research reagents and therapies. Ongoing research points to the potential for fetal tissue to be used to cure debilitating diseases such as Parkinson disease. These scientific and medical advances are dependent on the use of fetal tissue from aborted fetuses. While the practice of induced abortion despite societal benefit may be theologically objectionable to some, these practices are professionally responsible. Federal regulations exist to discourage patients from being influenced by the societal benefit of fetal research in arriving at the decision to terminate as well as to prevent researchers from influencing a patient's decision. After a patient has chosen termination of pregnancy, it is consistent with professional responsibility to allow her to choose the disposition of the cadaveric fetal tissue. While some may view induced abortion and societal benefit from this practice as an ethical burden, the principle of justice makes it ethically obligatory to bear this ethical burden. The success story of cadaveric fetal tissue research and treatment should continue unhindered, to fulfill professional responsibility to current and future patients. PMID- 26432464 TI - Celiac disease and obstetric complications: a systematic review and metaanalysis. AB - The aim of this metaanalysis was to evaluate the risk of the development of obstetric complications in women with celiac disease. We searched electronic databases from their inception until February 2015. We included all cohort studies that reported the incidence of obstetric complications in women with celiac disease compared with women without celiac disease (ie, control group). Studies without a control group and case-control studies were excluded. The primary outcome was defined a priori and was the incidence of a composite of obstetric complications that included intrauterine growth restriction, small for gestational age, low birthweight, preeclampsia and preterm birth. Secondary outcomes included the incidence of preterm birth, intrauterine growth restriction, stillbirth, preeclampsia, small for gestational age, and low birthweight. The review was registered with PROSPERO (CRD42015017263) before data extraction. All authors were contacted to obtain the original databases and perform individual participant data metaanalysis. Primary and secondary outcomes were assessed in the aggregate data analysis and in the individual participant data metaanalysis. We included 10 cohort studies (4,844,555 women) in this metaanalysis. Four authors provided the entire databases for the individual participant data analysis. Because none of the included studies stratified data for the primary outcome (ie, composite outcome), the assessment of this outcome for the aggregate analysis was not feasible. Aggregate data analysis showed that, compared with women in the control group, women with celiac disease (both treated and untreated) had a significantly higher risk of the development of preterm birth (adjusted odds ratio, 1.35; 95% confidence interval, 1.09-1.66), intrauterine growth restriction (odds ratio, 2.48; 95% confidence interval, 1.32 4.67), stillbirth (odds ratio, 4.84; 95% confidence interval, 1.08-21.75), low birthweight (odds ratio, 1.63; 95% confidence interval, 1.06-2.51), and small for gestational age (odds ratio, 4.52; 95% confidence interval, 1.02-20.08); no statistically significant difference was found in the incidence of preeclampsia (odds ratio, 2.45; 95% confidence interval, 0.90-6.70). The risk of preterm birth was still significantly higher both in the subgroup analysis of only women with diagnosed and treated celiac disease (odds ratio, 1.26; 95% confidence interval, 1.06-1.48) and in the subgroup analysis of only women with undiagnosed and untreated celiac disease (odds ratio, 2.50; 95% confidence interval; 1.06-5.87). Women with diagnosed and treated celiac disease had a significantly lower risk of the development of preterm birth, compared with undiagnosed and untreated celiac disease (odds ratio, 0.80; 95% confidence interval, 0.64-0.99). The individual participant data metaanalysis showed that women with celiac disease had a significantly higher risk of composite obstetric complications compared with control subjects (odds ratio, 1.51; 95% confidence interval, 1.17-1.94). Our individual participant data concurs with the aggregate analysis for all the secondary outcomes. In summary, women with celiac disease had a significantly higher risk of the development of obstetric complications that included preterm birth, intrauterine growth restriction, stillbirth, low birthweight, and small for gestational age. Since the treatment with gluten-free diet leads to a significant decrease of preterm delivery, physicians should warn these women about the importance of a strict diet to improve obstetric outcomes. Future studies calculating cost-effectiveness of screening for celiac disease during pregnancy, which could be easily performed, economically and noninvasively, are needed. In addition, further studies are required to determine whether women with adverse pregnancy outcomes should be screened for celiac disease, particularly in countries where the prevalence is high. PMID- 26432467 TI - Perinatal risks of planned home births in the United States. PMID- 26432468 TI - Association between guideline recommended drugs and death in older adults with multiple chronic conditions: population based cohort study. AB - OBJECTIVE: To estimate the association between guideline recommended drugs and death in older adults with multiple chronic conditions. DESIGN: Population based cohort study. SETTING: Medicare Current Beneficiary Survey cohort, a nationally representative sample of Americans aged 65 years or more. PARTICIPANTS: 8578 older adults with two or more study chronic conditions (atrial fibrillation, coronary artery disease, chronic kidney disease, depression, diabetes, heart failure, hyperlipidemia, hypertension, and thromboembolic disease), followed through 2011. EXPOSURES: Drugs included beta blockers, calcium channel blockers, clopidogrel, metformin, renin-angiotensin system (RAS) blockers; selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs); statins; thiazides; and warfarin. MAIN OUTCOME MEASURE: Adjusted hazard ratios for death among participants with a condition and taking a guideline recommended drug relative to participants with the condition not taking the drug and among participants with the most common combinations of four conditions. RESULTS: Over 50% of participants with each condition received the recommended drugs regardless of coexisting conditions; 1287/8578 (15%) participants died during the three years of follow-up. Among cardiovascular drugs, beta blockers, calcium channel blockers, RAS blockers, and statins were associated with reduced mortality for indicated conditions. For example, the adjusted hazard ratio for beta blockers was 0.59 (95% confidence interval 0.48 to 0.72) for people with atrial fibrillation and 0.68 (0.57 to 0.81) for those with heart failure. The adjusted hazard ratios for cardiovascular drugs were similar to those with common combinations of four coexisting conditions, with trends toward variable effects for beta blockers. None of clopidogrel, metformin, or SSRIs/SNRIs was associated with reduced mortality. Warfarin was associated with a reduced risk of death among those with atrial fibrillation (adjusted hazard ratio 0.69, 95% confidence interval 0.56 to 0.85) and thromboembolic disease (0.44, 0.30 to 0.62). Attenuation in the association with reduced risk of death was found with warfarin in participants with some combinations of coexisting conditions. CONCLUSIONS: Average effects on survival, particularly for cardiovascular study drugs, were comparable to those reported in randomized controlled trials but varied for some drugs according to coexisting conditions. Determining treatment effects in combinations of conditions may guide prescribing in people with multiple chronic conditions. PMID- 26432466 TI - New development of the yolk sac theory in diabetic embryopathy: molecular mechanism and link to structural birth defects. AB - Maternal diabetes mellitus is a significant risk factor for structural birth defects, including congenital heart defects and neural tube defects. With the rising prevalence of type 2 diabetes mellitus and obesity in women of childbearing age, diabetes mellitus-induced birth defects have become an increasingly significant public health problem. Maternal diabetes mellitus in vivo and high glucose in vitro induce yolk sac injuries by damaging the morphologic condition of cells and altering the dynamics of organelles. The yolk sac vascular system is the first system to develop during embryogenesis; therefore, it is the most sensitive to hyperglycemia. The consequences of yolk sac injuries include impairment of nutrient transportation because of vasculopathy. Although the functional relationship between yolk sac vasculopathy and structural birth defects has not yet been established, a recent study reveals that the quality of yolk sac vasculature is related inversely to embryonic malformation rates. Studies in animal models have uncovered key molecular intermediates of diabetic yolk sac vasculopathy, which include hypoxia-inducible factor-1alpha, apoptosis signal-regulating kinase 1, and its inhibitor thioredoxin-1, c-Jun-N-terminal kinases, nitric oxide, and nitric oxide synthase. Yolk sac vasculopathy is also associated with abnormalities in arachidonic acid and myo-inositol. Dietary supplementation with fatty acids that restore lipid levels in the yolk sac lead to a reduction in diabetes mellitus-induced malformations. Although the role of the human yolk in embryogenesis is less extensive than in rodents, nevertheless, human embryonic vasculogenesis is affected negatively by maternal diabetes mellitus. Mechanistic studies have identified potential therapeutic targets for future intervention against yolk sac vasculopathy, birth defects, and other complications associated with diabetic pregnancies. PMID- 26432469 TI - A-kinase anchoring protein 2 is required for calcitonin-mediated invasion of cancer cells. AB - Expression of neuropeptide calcitonin (CT) and its receptor (CTR) is frequently elevated in prostate cancers (PCs) and activation of CT-CTR axis in non-invasive PC cells induces an invasive phenotype. Specific, cell-permeable inhibitors of protein kinase A abolish CTR-stimulated invasion of PC cells. Since PKA is ubiquitously distributed in cells, the present study examined the mechanism(s) by which CTR-stimulated PKA activity is regulated in time and space. CT reduced cell adhesion but increased invasion of PC cells. Both these actions were abolished by st-Ht31 inhibitory peptide suggesting the involvement of an A-kinase anchoring protein (AKAP) in CT action. Next, we identified the AKAP associated with CT action by the subtraction of potential AKAP candidates using siRNAs. Knock-down of membrane-associated AKAP2, but not other AKAPs, abolished CT-stimulated invasion. Stable knock-down of AKAP2 in PC3-CTR cells remarkably decreased their cell proliferation, invasion, clonogenicity and ability to form orthotopic tumors and distant metastases in nude mice. Re-expression of AKAP2-wt restored these characteristics. Primary PC specimens displayed remarkable upregulation of CTR/AKAP2 expression as compared to benign prostates. Metastatic cancers displayed significantly higher CTR/AKAP2 expression than localized cancers. These results for the first time demonstrate that AKAP2 is expressed in human prostates, its expression is elevated in metastatic prostate cancer, and the knock-down of its expression remarkably decreased tumorigenicity and metastatic ability of prostate cancer cells. AKAP2 may serve as a critical component of CTR mediated oncogenic actions. PMID- 26432470 TI - Targeting muscle signaling pathways to minimize adverse effects of androgen deprivation. AB - Androgen deprivation therapy (ADT) is a highly effective treatment used in ~30% of men with prostate cancer. Adverse effects of ADT on muscle are significant with consistent losses in muscle mass. However, effects of ADT on muscle strength and physical function, of most relevance to the patient, are less well understood. This is in part due to the fact that muscle effects of ADT at the cellular, genetic and protein level, critical to the understanding of the pathophysiology of sarcopenia, have come into focus only recently. This review highlights the complexity of androgen-dependent signaling in muscle with an emphasis on recent findings in the regulation of muscle growth and muscle atrophy pathways. Furthermore, the effects of ADT and testosterone on skeletal muscle histology, gene expression and protein transcription are discussed. A better mechanistic understanding of the regulation of muscle mass and function by androgens should not only pave the way for developing targeted promyogenic interventions for men with prostate cancer receiving ADT but also may have wider implications for age-associated sarcopenia in the general population. PMID- 26432471 TI - BML-111 attenuates acute lung injury in endotoxemic mice. AB - BACKGROUND: BML-111 is a lipoxin receptor agonist that has protective effects in various lung injury models. We tried to elucidate whether BML-111 could mitigate lung injury in a mouse model of endotoxemia and endothelial hyperpermeability in vitro. METHODS: The effect of BML-111 on lung injury was evaluated using C57BL/6 mice and human umbilical vein endothelial cells (HUVECs). Male C57BL/6 mice were intraperitoneally injected with normal saline, BML-111, and/or the lipoxin receptor antagonist Boc-2. Then, either lipopolysaccharide (LPS) or normal saline was given intraperitoneally. Lung injury was assessed by a pathohistologic examination for neutrophil infiltration, pulmonary endothelial permeability, and inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid. HUVECs were treated with or without BML-111 before incubation with LPS for 24 h. Boc-2 was also tested as a novel inhibitor of BML-111. A Transwell assay was used to evaluate the permeability of HUVECs. Junction protein expression was also assessed. RESULTS: BML-111 significantly improved the mouse survival rate, reduced body weight loss, attenuated the pulmonary pathologic changes, inhibited neutrophil infiltration and proinflammatory cytokine production, and mitigated endothelial hyperpermeability. The decreased expression of junction proteins induced by LPS in lung tissue and endothelial cells were upregulated by BML-111. In addition, BML-111 inhibited the activation of the Akt, ERK1/2, and p38 MAPK signaling pathways. However, the beneficial effects of BML-111 were abolished by Boc-2. CONCLUSIONS: BML-111 attenuated lung injury in endotoxemic mice and mitigated endothelial hyperpermeability by upregulating the expression of junction proteins. PMID- 26432472 TI - Evaluation of QSAR models for predicting the partition coefficient (log P) of chemicals under the REACH regulation. AB - The partition coefficient (log P) is a physicochemical parameter widely used in environmental and health sciences and is important in REACH and CLP regulations. In this regulatory context, the number of existing experimental data on log P is negligible compared to the number of chemicals for which it is necessary. There are many models to predict log P and we have selected a number of free programs to examine how they predict the log P of chemicals registered for REACH and to evaluate wheter they can be used in place of experimental data. Some results are good, especially if the information on the applicability domain of the models is considered, with R(2) values from 0.7 to 0.8 and root mean square error (RMSE) from 0.8 to 1.5. PMID- 26432473 TI - Examining confounding by diet in the association between perfluoroalkyl acids and serum cholesterol in pregnancy. AB - BACKGROUND: Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) have consistently been associated with higher cholesterol levels in cross sectional studies. Concerns have, however, been raised about potential confounding by diet and clinical relevance. OBJECTIVE: To examine the association between concentrations of PFOS and PFOA and total cholesterol in serum during pregnancy taking into considerations confounding by diet. METHODS: 854 Danish women who gave birth in 1988-89 and provided a blood sample and reported their diet in week 30 of gestation. RESULTS: Mean serum PFOS, PFOA and total cholesterol concentrations were 22.3 ng/mL, 4.1 ng/mL and 7.3 mmol/L, respectively. Maternal diet was a significant predictor of serum PFOS and PFOA concentrations. In particular intake of meat and meat products was positively associated while intake of vegetables was inversely associated (P for trend <0.01) with relative difference between the highest and lowest quartile in PFOS and PFOA concentrations ranging between 6% and 25% of mean values. After adjustment for dietary factors both PFOA and PFOS were positively and similarly associated with serum cholesterol (P for trend <=0.01). For example, the mean increase in serum cholesterol was 0.39 mmol/L (95%CI: 0.09, 0.68) when comparing women in the highest to lowest quintile of PFOA concentrations. In comparison the mean increase in serum cholesterol was 0.61 mmol/L (95%CI: 0.17, 1.05) when comparing women in the highest to lowest quintile of saturated fat intake. CONCLUSION: In this study associations between PFOS and PFOA with serum cholesterol appeared unrelated to dietary intake and were similar in magnitude as the associations between saturated fat intake and serum cholesterol. PMID- 26432474 TI - Reply. PMID- 26432475 TI - Reply. PMID- 26432476 TI - Subcutaneous Ustekinumab Provides Clinical Benefit for Two-Thirds of Patients With Crohn's Disease Refractory to Anti-Tumor Necrosis Factor Agents. AB - BACKGROUND & AIMS: Ustekinumab, a human monoclonal antibody against the p40 subunit of interleukins-12 and -23, is effective in inducing and maintaining remission in patients with luminal Crohn's disease (CD). We assessed the efficacy and safety of subcutaneous ustekinumab in patients with anti-tumor necrosis factor (anti-TNF) refractory CD. METHODS: We performed a retrospective observational study, collecting data from the Groupe d'Etude Therapeutique des Affections Inflammatoires du tube Digestif on 122 consecutive patients with active CD refractory to anti-TNF therapy who received at least 1 subcutaneous injection of ustekinumab from March 2011 to December 2014, in 20 tertiary centers in Europe. Subjects were followed for at least 3 months. The primary outcome was clinical benefit, defined as reductions in symptoms and biochemical markers of CD and complete weaning from steroids, without surgery or immunosuppressant therapies. RESULTS: Seventy-nine patients (65%) had a clinical benefit within 3 months of receiving ustekinumab. Concomitant immunosuppressant therapy at study inclusion increased the odds for a clinical benefit from ustekinumab (odds ratio, 5.43; 95% confidence interval, 1.14-25.77; P = .03). Over a median follow-up period of 9.8 months (interquartile range, 5.3-14.5 months), the cumulative probabilities that patients maintained the clinical benefit for 6 and 12 months after introduction of ustekinumab were 93% and 68%, respectively. CONCLUSIONS: Almost two-thirds of patients with CD refractory to at least 1 anti-TNF agent receive clinical benefit from ustekinumab therapy, not requiring steroids for up to 12 months afterward. While awaiting results from ongoing trials, ustekinumab can be considered for use in these patients. PMID- 26432477 TI - Reply. PMID- 26432478 TI - Reply. PMID- 26432479 TI - Genetic manipulation of microglia during brain development and disease. PMID- 26432480 TI - Bone marrow-derived macrophages and the CNS: An update on the use of experimental chimeric mouse models and bone marrow transplantation in neurological disorders. AB - The central nervous system (CNS) is a very unique system with multiple features that differentiate it from systemic tissues. One of the most captivating aspects of its distinctive nature is the presence of the blood brain barrier (BBB), which seals it from the periphery. Therefore, to preserve tissue homeostasis, the CNS has to rely heavily on resident cells such as microglia. These pivotal cells of the mononuclear lineage have important and dichotomous roles according to various neurological disorders. However, certain insults can overwhelm microglia as well as compromising the integrity of the BBB, thus allowing the infiltration of bone marrow-derived macrophages (BMDMs). The use of myeloablation and bone marrow transplantation allowed the generation of chimeric mice to study resident microglia and infiltrated BMDM separately. This breakthrough completely revolutionized the way we captured these 2 types of mononuclear phagocytic cells. We now realize that microglia and BMDM exhibit distinct features and appear to perform different tasks. Since these cells are central in several pathologies, it is crucial to use chimeric mice to analyze their functions and mechanisms to possibly harness them for therapeutic purpose. This review will shed light on the advent of this methodology and how it allowed deciphering the ontology of microglia and its maintenance during adulthood. We will also compare the different strategies used to perform myeloablation. Finally, we will discuss the landmark studies that used chimeric mice to characterize the roles of microglia and BMDM in several neurological disorders. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. PMID- 26432481 TI - Oxidative stress and its impact on neurons and glia in multiple sclerosis lesions. PMID- 26432483 TI - Diabetes mellitus and Takotsubo syndrome in two Spanish cohorts. PMID- 26432482 TI - Exosomes as new diagnostic tools in CNS diseases. PMID- 26432484 TI - Comparative effect on platelet function of a fixed-dose aspirin and clopidogrel combination versus separate formulations in patients with coronary artery disease: A phase IV, multicenter, prospective, 4-week non-inferiority trial. AB - BACKGROUND/OBJECTIVES: The effect of aspirin and clopidogrel in a fixed-dose combination (FDC) on platelet function was compared with separate formulations in patients that had undergone percutaneous coronary intervention (PCI) with drug eluting stent (DES). METHODS: This was a phase IV, prospective, multicenter, single-arm, non-inferiority study. Patients that had taken aspirin 100 mg and clopidogrel 75 mg once daily as separate formulations for >6 months after PCI with DES were enrolled, and then switched to an aspirin/clopidogrel FDC once daily for 4 weeks. Platelet reactivity was determined using the VerifyNow(r) P2Y12 assay at baseline (immediately prior to switching) and 4 weeks later. RESULTS: A total of 648 patients (the full-analysis population; age, 63.6+/-9.0 years; male, 76.5%) finished the study, and 565 (the per-protocol population) completed without protocol violations. In the per-protocol population, the % inhibitions of P2Y12 and ARU were not significantly different between baseline and after 4 weeks of FDC treatment (29.2+/-20.0% to 29.0+/-19.9%, P=0.708; 445.1+/-69.2 to 446.2+/-63.0, P=0.799, respectively) and the difference in P2Y12 inhibition observed did not exceed the predetermined limit of non-inferiority (95% CI, -0.9 to 1.3). In the full-analysis population, the % inhibitions of P2Y12, PRU, and ARU were not significantly changed after 4 weeks of FDC treatment. CONCLUSIONS: This study demonstrates that the efficacy of platelet inhibition by an aspirin/clopidogrel FDC was not inferior to that of separate aspirin and clopidogrel formulations in patients that had undergone PCI with DES. PMID- 26432485 TI - Giant aneurysmal evolution of a spontaneous coronary artery dissection in the postpartum. PMID- 26432486 TI - Remote monitoring of implantable devices: Should we continue to ignore it? AB - The number of patients with implantable cardioverter defibrillators (ICDs) is increasing. In addition to improve survival, ICD can collect data related to device function and physiological parameters. Remote monitoring (RM) of these data allows early detection of technical or clinical problems and a prompt intervention (reprogramming device or therapy adjustment) before the patient require hospitalization. RM is not a substitute for emergency service and its consultation is now limited during working hours. Thus, a consent form is required to inform patients about benefits and limitations. The available studies indicate that remote monitoring is more effective than traditional calendar face to face based encounters. RM is safe, highly reliable, cost efficient, allows quick reply to failures, and reduces the number of scheduled visits and the incidence of inappropriate shocks with a positive impact on survival. It follows that RM has the credentials to be the standard of care for ICD management; however, unfortunately, there is a delay in physician acceptance and implementation. The recent observations from randomized IN-TIME study that showed a clear survival benefit with RM in heart failure patients have encouraged us to review both the negative and positive aspects of RM collected in a little more than a decade. PMID- 26432487 TI - Circulating microparticle signature in coronary and peripheral blood of ST elevation myocardial infarction patients in relation to pain-to-PCI elapsed time. AB - BACKGROUND: Circulating microparticle (cMP) levels are increased in the acute phase of ST-elevation myocardial infarction (STEMI) and associate with microvascular obstruction; however, the precise cMP-parental cell signature and activation level are not elucidated. Here, we aimed to study the cMP signature in STEMI-patients and whether cMP phenotype changes in relation to onset of pain-to PCI [ischemic time (IT)]-elapsed time. METHODS: Blood was taken at PCI from the culprit coronary and the peripheral circulation in STEMI-patients (N=40). Two control groups were included: peripheral blood of age-matched patients recovering from STEMI [after 72 h] and of control individuals (N=20/group). cMP-parental origin and activation level were characterized by triple-labeling flow cytometry. RESULTS: Procoagulant annexin V-positive cMPs bearing parental cell markers as well as markers of activated cells displayed a significantly different profile in STEMI-patients, in control individuals and in patients recovering from STEMI. cMPs derived from monocytes, endothelium, and activated vascular cells were higher in the culprit coronary artery than in peripheral blood in STEMI-patients, especially in patients intervened at short IT. Indeed, cMP levels in coronary blood were inversely related to IT duration (more abundant in thrombi with pain to-PCI time<180 min). CONCLUSIONS: A characteristic [CD66b+/CD62E+/CD142+] cMP signature in the systemic circulation reflects the formation of coronary thrombotic occlusions in STEMI-patients. Changes in the cMP signature in the culprit coronary artery blood reveal the sensitivity of MPs to detect the ischemia-elapsed time. Interestingly, cMPs in peripheral blood may be sensitive markers of the thrombo-occlusive vascular process developing in the coronary arteries of STEMI-patients. PMID- 26432488 TI - Renal artery anatomy affects the blood pressure response to renal denervation in patients with resistant hypertension. AB - BACKGROUND: Renal denervation (RDN) has been shown to reduce blood pressure (BP), muscle sympathetic nerve activity (MSNA) and target organ damage in patients with resistant hypertension (RH) and bilateral single renal arteries. The safety and efficacy of RDN in patients with multiple renal arteries remains unclear. METHODS: We measured office and 24-hour BP at baseline, 3 and 6 months following RDN in 91 patients with RH, including 65 patients with single renal arteries bilaterally (group 1), 16 patients with dual renal arteries on either one or both sides (group 2) and 10 patients with other anatomical constellations or structural abnormalities (group 3). Thirty nine out of 91 patients completed MSNA at baseline and follow-up. RESULTS: RDN significantly reduced office and daytime SBP in group 1 at both 3 and 6 months follow-up (P<0.001) but not in groups 2 and 3. Similarly, a significant reduction in resting baseline MSNA was only observed in group 1 (P<0.05). There was no deterioration in kidney function in any group. CONCLUSION: While RDN can be performed safely irrespective of the underlying renal anatomy, the presence of single renal arteries with or without structural abnormalities is associated with a more pronounced BP and MSNA lowering effect than the presence of dual renal arteries in patients with RH. However, when patients with dual renal arteries received renal nerve ablation in all arteries there was trend towards a greater BP reduction. Insufficient renal sympathetic nerve ablation may account for these differences. PMID- 26432490 TI - Prognostic implications of pericardial effusion: The importance of underlying etiology. PMID- 26432491 TI - Electrocardiogram T-wave inversions in asymptomatic, "asymptomatic", and symptomatic patients: A need for exploration for underlying Takotsubo syndrome. PMID- 26432489 TI - Ryanodine receptor phosphorylation by CaMKII promotes spontaneous Ca(2+) release events in a rodent model of early stage diabetes: The arrhythmogenic substrate. AB - BACKGROUND: Heart failure and arrhythmias occur more frequently in patients with type 2 diabetes (T2DM) than in the general population. T2DM is preceded by a prediabetic condition marked by elevated reactive oxygen species (ROS) and subclinical cardiovascular defects. Although multifunctional Ca2+ calmodulin dependent protein kinase II (CaMKII) is ROS-activated and CaMKII hyperactivity promotes cardiac diseases, a link between prediabetes and CaMKII in the heart is unprecedented. OBJECTIVES: To prove the hypothesis that increased ROS and CaMKII activity contribute to heart failure and arrhythmogenic mechanisms in early stage diabetes. METHODS-RESULTS: Echocardiography, electrocardiography, biochemical and intracellular Ca2+ (Ca2+i) determinations were performed in fructose-rich diet induced impaired glucose tolerance, a prediabetes model, in rodents. Fructose rich diet rats showed decreased contractility and hypertrophy associated with increased CaMKII activity, ROS production, oxidized CaMKII and enhanced CaMKII dependent ryanodine receptor (RyR2) phosphorylation compared to rats fed with control diet. Isolated cardiomyocytes from fructose-rich diet showed increased spontaneous Ca2+i release events associated with spontaneous contractions, which were prevented by KN-93, a CaMKII inhibitor, or addition of Tempol, a ROS scavenger, to the diet. Moreover, fructose-rich diet myocytes showed increased diastolic Ca2+ during the burst of spontaneous Ca2+i release events. Mice treated with Tempol or with sarcoplasmic reticulum-targeted CaMKII-inhibition by transgenic expression of the CaMKII inhibitory peptide AIP, were protected from fructose-rich diet-induced spontaneous Ca2+i release events, spontaneous contractions and arrhythmogenesis in vivo, despite ROS increases. CONCLUSIONS: RyR2 phosphorylation by ROS-activated CaMKII, contributes to impaired glucose tolerance-induced arrhythmogenic mechanisms, suggesting that CaMKII inhibition could prevent prediabetic cardiovascular complications and/or evolution. PMID- 26432492 TI - Can electrical shock provide ST-segment resolution in patients with ST-segment elevation myocardial infarction? PMID- 26432493 TI - Dipeptidyl peptidase-4 inhibitors and the ischemic heart: Additional benefits beyond glycemic control. AB - Obese-insulin resistance and type 2 diabetes mellitus (T2DM) have become global health problems, and they are both associated with a higher risk of ischemic heart disease. Although reperfusion therapy is the treatment to increase blood supply to the ischemic myocardium, this intervention potentially causes cardiac tissue damage and instigates arrhythmias, processes known as reperfusion injury. Dipeptidyl peptidase 4 (DPP-4) inhibitors are glycemic control drugs commonly used in T2DM patients. Growing evidence from basic and clinical studies demonstrates that a DPP-4 inhibitor could exert cardioprotection and improve left ventricular function by reducing oxidative stress, apoptosis, and increasing reperfusion injury salvage kinase (RISK) activity. However, recent reports also showed potentially adverse cardiac events due to the use of a DPP-4 inhibitor. To investigate this disparity, future large clinical trials are essential in verifying whether DPP-4 inhibitors are beneficial beyond their glycemic control particularly for the ischemic heart in obese-insulin resistant subjects and T2DM patients. PMID- 26432494 TI - Accelerometer-determined physical activity and mortality in a national prospective cohort study of adults at high risk of a first atherosclerotic cardiovascular disease event. PMID- 26432495 TI - Regulation of neuropathic pain behavior by amygdaloid TRPC4/C5 channels. AB - Pain per se may increase anxiety and conversely, anxiety may increase pain. Therefore, a positive feedback loop between anxiety and pain possibly contributes to pain and suffering in some pathophysiological pain conditions, such as that induced by peripheral nerve injury. Recent results indicate that transient receptor channels 4 and 5 (TRPC4/C5) in the amygdala have anxiogenic effects in rodents, while their role in chronic pain conditions is not known. Here, we studied whether the amygdaloid TRPC4/C5 that are known to have anxiogenic properties contribute to the maintenance of sensory or affective aspects of pain in an experimental model of peripheral neuropathy. Rats with a spared nerve injury (SNI) model of neuropathy in the left hind limb had a chronic cannula for microinjections of drugs into the right amygdala or the internal capsule (a control site). Sensory pain was assessed by determining mechanical hypersensitivity with calibrated monofilaments and affective pain by determining aversive place-conditioning. Amygdaloid treatment with ML-204, a TRPC4/C5 antagonist, produced a dose-related (5-10 MUg) antihypersensitivity effect, without obvious side-effects. Additionally, amygdaloid administration of ML-204 reduced affective-like pain behavior. In the internal capsule, ML-204 had no effect on hypersensitivity or affective-like pain in SNI animals. In healthy controls, amygdaloid administration of ML-204 failed to influence pain behavior induced by mechanical stimulation or noxious heat. The results indicate that the amygdaloid TRPC4/C5 contribute to maintenance of pain hypersensitivity and pain affect in neuropathy. PMID- 26432496 TI - Pigmented ganglioglioma in a patient with chronic epilepsy and cortical dysplasia. AB - We report a rare case of a 22-year-old woman with biopsy-proven pigmented ganglioglioma. The patient initially underwent a right temporal lobectomy for intractable seizures at the age of 9 and remained seizure free for several years but subsequently developed complex partial seizures. Due to enhancement of a left mesial occipital lesion on preoperative MRI of the brain, the patient underwent a left subdural electrode placement and simultaneous biopsy of the left mesial occipital lesion. Biopsy results revealed a rare pigmented ganglioglioma, World Health Organization Grade I. The seizure focus was identified in the left mesial occipital lobe and the patient underwent tumor resection. An extensive literature search revealed that our patient is the fourth case of pigmented ganglioglioma described in the literature and was positive for BRAF V600E mutation by molecular studies. PMID- 26432497 TI - Rapid access point of care clinic for transient ischemic attacks and minor strokes. AB - We present 24months of prospective data from a new model of care for transient ischemic attacks (TIA) and minor stroke, established at the Royal North Shore Hospital, a tertiary teaching hospital in Sydney, Australia. Prior to 2011, approximately 200 patients were admitted to our emergency department (ED) annually, following presentation with a suspected TIA. These patients had an average length of stay of 5.3days. Following the establishment of a twice weekly multidisciplinary, one stop, stroke prevention and hospital avoidance clinic, all patients with suspected TIA were investigated and treated as outpatients. There was an average time to clinic from the initial presentation in the ED of 3.9days. Symptoms that were highly suggestive of TIA were seen in 47% of patients, and an additional 14% had MRI-confirmed acute stroke. In total, 405 patients were referred to the clinic, saving 2146.5 inpatient bed days and approximately AUD$1,180,575. Our model of care for patients with suspected TIA provides early access for investigation, treatment and management of the risk factors. The rapid access TIA clinic is highly cost effective and provides a transferable model of care for other health districts with similar patient loads and cost structures. PMID- 26432498 TI - Running in the family: A rare diagnosis of familial papillary thyroid cancer. AB - INTRODUCTION: Whilst inherited medullary thyroid cancer has been extensively reported, familial non-medullary thyroid cancer is a rare and less well described clinical entity. Familial forms of the disease demonstrate more aggressive features than sporadic non-medullary thyroid cancer. PRESENTATION OF CASE: A 54 year old lady was referred with globus on a background of a longstanding goitre. Three first degree relatives had a history of non-medullary thyroid carcinoma. Investigations revealed a papillary thyroid carcinoma and the patient proceeded to total thyroidectomy and ipsilateral Level VI neck dissection, followed by adjuvant radioiodine ablation. DISCUSSION: Familial papillary thyroid carcinoma syndrome is defined as three or more first degree relatives diagnosed with the disease in the absence of other known associated syndromes. It is often associated with the presence of benign thyroid disorders, and is characterised by the early onset of multi-focal bilateral locally advanced tumours. CONCLUSION: Familial papillary thyroid cancer is a rare clinical entity but should be considered where >=3 first degree relatives are diagnosed with non-medullary thyroid cancer. It is necessary to exclude other familial tumour syndromes to make the diagnosis. It demonstrates more aggressive features with higher rates of local recurrence than its sporadic counterpart, and therefore mandates more aggressive management than might otherwise be indicated. Screening of first degree relatives should be considered. SUMMARY: The case of a 54 year old female diagnosed with familial non-medullary thyroid carcinoma is reported. PMID- 26432499 TI - Clinical Weighting of Drug-Drug Interactions in Hospitalized Elderly. AB - Adverse drug reactions impact on patient health, effectiveness of pharmacological therapy and increased health care costs. This investigation intended to detect the most critical drug-drug interactions in hospitalized elderly patients, weighting clinical risk. We conducted a cross-sectional study between January and April 2014; all patients 70 years or older, hospitalized for >24 hr and prescribed at least one medication were included in the study. Drug-drug interactions were estimated by combining Stockley's, Hansten and Tatro drug interactions. Drug-drug interactions were weighted using a risk-analysis method based on failure modes, effects and criticality analysis. We calculated a criticality index for each drug involved in the drug-drug interactions based on the severity of the interaction mechanism, the frequency the drug was involved in drug-drug interactions and the risk of drug-drug interactions in patients with impaired renal function. The average number of drugs consumed in the hospital was 6 +/- 2.69, involving 160 active ingredients. The most frequent were as follows: Furosemide, followed by Enalapril. Of drug-drug interactions, 2% were classified as contraindicated, 14% advised against and 83% advised caution during the hospital stay. Thirty-four drug-drug interactions were assessed, of which 23 were pharmacodynamic drug-drug interactions and 12 were pharmacokinetic drug-drug interactions (1 was both). The clinical risk calculated for each drug-drug interaction included heparins + non-steroidal anti-inflammatory drugs (NSAIDs) or Digoxin + Calcium Gluconate, cases which are pharmacodynamic drug-drug interactions with agonist effect and clinical risk of bleeding, one of the most common clinical risks in the hospital. An index of clinical risk for drug-drug interactions can be calculated based on severity by the interaction mechanism, the frequency that the drug is involved in drug-drug interactions and the risk of drug-drug interactions in an elderly patient with impaired renal function. PMID- 26432500 TI - Single substitution in bacteriophage T4 RNase H alters the ratio between its exo- and endonuclease activities. AB - The article describes substitutions in bacteriophage T4 RNase H which provide so called das-effect. Phage T4 DNA arrest suppression (das) mutations have been described to be capable of partially suppressing the phage DNA arrest phenotype caused by a dysfunction in genes 46 and/or 47 (also known as Mre11/Rad50 complex). Genetic mapping of das13 (one of the das mutations) has shown it to be in the region of the rnh gene encoding RNase H. Here we report that Das13 mutant of RNase H has substitutions of valine 43 and leucine 242 with isoleucines. To investigate the influence of these mutations on RNase H nuclease properties we have designed a novel in vitro assay that allows us to separate and quantify exo- or endonuclease activities of flap endonuclease. The nuclease assay in vitro showed that V43I substitution increased the ratio between exonuclease/endonuclease activities of RNase H whereas L242I substitution did not affect the nuclease activity of RNase H in vitro. However, both mutations were necessary for the full das effect in vivo. Molecular modelling of the nuclease structure suggests that V43I substitution may lead to disposition of H4 helix, responsible for the interaction with the first base pairs of 5'end of branched DNA. These structural changes may affect unwinding of the first base pairs of gapped or nicked DNA generating a short flap and therefore may stabilize the DNA enzyme complex. L242I substitution did not affect the structure of RNase H and its role in providing das-effect remains unclear. PMID- 26432501 TI - An integrated network model of psychotic symptoms. AB - The full body of research on the nature of psychosis and its determinants indicates that a considerable number of factors are relevant to the development of hallucinations, delusions, and other positive symptoms, ranging from neurodevelopmental parameters and altered connectivity of brain regions to impaired cognitive functioning and social factors. We aimed to integrate these factors in a single mathematical model based on network theory. At the microscopic level this model explains positive symptoms of psychosis in terms of experiential equivalents of robust, high-frequency attractor states of neural networks. At the mesoscopic level it explains them in relation to global brain states, and at the macroscopic level in relation to social-network structures and dynamics. Due to the scale-free nature of biological networks, all three levels are governed by the same general laws, thereby allowing for an integrated model of biological, psychological, and social phenomena involved in the mediation of positive symptoms of psychosis. This integrated network model of psychotic symptoms (INMOPS) is described together with various possibilities for application in clinical practice. PMID- 26432502 TI - Computational modeling of psychiatric illnesses via well-defined neurophysiological and neurocognitive biomarkers. AB - A good deal of recent research has centered on the identification of biomarkers and endophenotypic measures of psychiatric illnesses using in vivo and in vitro studies. This is understandable, as these measures-as opposed to complex clinical phenotypes-may be more closely related to neurobiological and genetic vulnerabilities. However, instantiation of such biomarkers using computational models-in silico studies-has received less attention. This approach could become increasingly important, given the wealth of detailed information produced by recent basic neuroscience research, and increasing availability of high capacity computing platforms. The purpose of this review is to survey the current state of the art of research in this area. We discuss computational approaches to schizophrenia, bipolar disorder, Alzheimer's disease, fragile X syndrome and autism, and argue that it represents a promising and underappreciated research modality. In conclusion, we outline specific avenues for future research; also, potential uses of in silico models to conduct "virtual experiments" and to generate novel hypotheses, and as an aid in neuropsychiatric drug development are discussed. PMID- 26432503 TI - Implicit measures of "wanting" and "liking" in humans. AB - Incentive Sensitization Theory (IST; e.g., Robinson and Berridge, 1993. Brain Res. Rev., 18, 291; Robinson and Berridge, 2003 Trends Neurosci., 26, 507) suggests that a common dopamine system that deals with incentive salience attribution is affected by different types of drugs. Repeated drug use will sensitize this neural system, which means that drugs increasingly trigger the experience of incentive salience or "wanting". Importantly, Robinson and Berridge stress that there is a dissociation between drug "wanting" (the unconscious attribution of incentive salience) and drug "liking" (the unconscious hedonic experience when one consumes drugs). Whereas the former plays an essential role in the development and maintenance of drug addiction, the latter does not. Although this model was based mainly on research with non-human animals, more recently the dissociation between "wanting" and "liking" has been examined in humans as well. A widely used and promising means of studying these processes are behavioral implicit measures such as the Implicit Association Test (IAT), the Approach-Avoidance Task (AAT), different types of Stimulus-Response Compatibility (SRC) tasks, and Affective Simon Tasks (AST). IST makes the clear prediction that (1) there should be a positive correlation between indices of "wanting" (e.g., drug consumption) and implicit "wanting" scores. Similarly, there should be a positive correlation between indices of "liking" (e.g., various expressions of subjective pleasure) and implicit "liking" scores; (2) there should be higher "wanting" scores in substance abusers or frequent substance users compared to non users or infrequent users, and there should be no differences in "liking" between these groups (or even less "liking" in frequent substance users); (3) manipulations of "wanting" should affect implicit "wanting" scores whereas manipulations of "liking" should affect implicit "liking" scores. However, studies that tested these hypotheses did not produce equivocal results. To shed light on these discrepancies, we first discuss the different definitions of "wanting" and "liking" and the different tests that have been used to assess these processes. Then, we discuss whether it is reasonable to assume that these tests are valid measures of "wanting" and "liking" and we review correlational, quasi-experimental, and experimental studies that inform us about this issue. Finally, we discuss the future potential of implicit measures in research on IST and make several recommendations to improve both theory and methodology. PMID- 26432504 TI - The mechanisms of spatial and temporal patterning of cell-edge dynamics. AB - Adherent cells migrate and change their shape by means of protrusion and retraction at their edges. When and where these activities occur defines the shape of the cell and the way it moves. Despite a great deal of knowledge about the structural organization, components, and biochemical reactions involved in protrusion and retraction, the origins of their spatial and temporal patterns are still poorly understood. Chemical signaling circuitry is believed to be an important source of patterning, but recent studies highlighted mechanisms based on physical forces, motion, and mechanical feedback. PMID- 26432505 TI - Prior stress exposure increases pain behaviors in a rat model of full thickness thermal injury. AB - Thermal burns among individuals working in highly stressful environments, such as firefighters and military Service Members, are common. Evidence suggests that pre injury stress may exaggerate pain following thermal injury; however current animal models of burn have not evaluated the potential influence of pre-burn stress. This sham-controlled study evaluated the influence of prior stress exposure on post-burn thermal and mechanical sensitivity in male Sprague-Dawley rats. Rats were exposed to 20 min of inescapable swim stress or sham stress once per day for three days. Exposure to inescapable swim stress (1) increased the intensity and duration of thermal hyperalgesia after subsequent burn and (2) accelerated the onset of thermal hyperalgesia and mechanical allodynia after subsequent burn. This stress-induced exacerbation of pain sensitivity was reversed by pretreatment and concurrent treatment with the serotonin norepinephrine reuptake inhibitor (SNRI) duloxetine. These data suggest a better understanding of mechanisms by which prior stress augments pain after thermal burn may lead to improved pain treatments for burn survivors. PMID- 26432506 TI - Pessimism and the risk for coronary heart disease among middle-aged and older Finnish men and women: a ten-year follow-up study. AB - BACKGROUND: Despite the growth in knowledge about coronary heart disease (CHD) risk factors, and the advances made in preventing and treating them, the incidence of CHD is still notably quite high. Research has concentrated on the physiological factors that present risks for CHD, but there is an increasing amount of evidence for the connection of mental health, personal traits and CHD. Data on the connection of disposition (optimism or pessimism) and CHD are relatively scarce. The aim of this study was to investigate the long-term connection between optimism, pessimism and the risk for having CHD. METHODS: This was a ten-year prospective cohort study on a regional sample of three cohorts aged 52-56, 62-66 and 72-76 years at baseline (N = 2815). The study groups were personally interviewed four times (in 2002, 2005, 2008 and 2012). The revised Life Orientation Test (LOT-R) was completed at the first appointment to determine the level of dispositional optimism or pessimism. During the ten-year follow-up, the incidence of new cases of coronary heart diseases was measured. The association between dispositional optimism/pessimism and the incidence of CHD during the follow-up was studied with logistic regression. RESULTS: Those who developed coronary heart disease during the ten-year follow-up were significantly more pessimistic at baseline than the other subjects. Using multivariate logistic regression models separately for men and women, we noticed no elevated risk for CHD in the pessimistic women compared to the non-pessimistic women. However, among men in the highest quartile of pessimism, the risk for CHD was approximately four-fold (OR 4.11, 95 % CI 1.68-11.04) that of the men in the lowest quartile. Optimism did not seem to have any role in the risk for developing CHD. DISCUSSION: Our main finding is that pessimism seemed to be a clear risk factor for coronary heart disease in men even after adjusting for classical well-known risk factors while optimism did not seem to be a protective factor. Connection between pessimism and coronary heart disease was not detectable among women. Similar gender differences between psychosocial factors and overall well-being have been noticed in some earlier studies, too. The mechanism of this gender difference is not fully understood. Differences between men and women in somatic responses to stress found in earlier studies may at least partly explain this phenomenon. The impact of optimism and pessimism on cardiovascular disease has been studied earlier and several possible mechanisms have been discovered but it seems clear that they cannot fully explain the association. For example, optimists have healthier lifestyles which lowers the risk for coronary heart disease, but pessimism was established to be a risk factor for cardiovascular disease in our study even in logistic regressions including the best known classical risk factors, e.g. smoking and high level of blood glucose. According to our study it is important to pay attention also to the psychosocial components in addition to the well-known risk factors when planning the prevention of coronary heart disease. Measuring pessimism is quite easy and it consumes very little time. Once the amount of pessimism is ascertained, it is easier to define who is in the greatest need of preventive actions concerning coronary heart disease. CONCLUSIONS: Pessimism seems to be a substantial risk factor for CHD, and as an easily measured variable it might be a very useful tool together with the well-known physiological risk factors to determine the risk for developing CHD, at least among men. PMID- 26432507 TI - Predictors and outcomes of delayed graft function after living-donor kidney transplantation. AB - Delayed graft function (DGF) following deceased donor kidney transplantation is associated with inferior outcomes. Delayed graft function following living-donor kidney transplantation is less common, but its impact on graft survival unknown. We therefore sought to determine risk factors for DGF following living-donor kidney transplantation and DGF's effect on living-donor kidney graft survival. We analyzed living-donor kidney transplants performed between 2000 and 2014 in the UNOS dataset. A total of 64 024 living-donor kidney transplant recipients were identified, 3.6% developed DGF. Cold ischemic time, human leukocyte antigen mismatch, donor age, panel reactive antibody, recipient diabetes, donor and recipient body mass index, recipient race and gender, right nephrectomy, open nephrectomy, dialysis status, ABO incompatibility, and previous transplants were independent predictors of DGF in living-donor kidney transplants. Five-year graft survival among living-donor kidney transplant recipients with DGF was significantly lower compared with graft survival in those without DGF (65% and 85%, respectively, P < 0.001). DGF more than doubled the risk of subsequent graft failure (hazard ratio = 2.3, 95% confidence interval: 2.1-2.6; P < 0.001). DGF after living-donor kidney transplantation is associated with inferior allograft outcomes. Minimizing modifiable risk factors may improve outcomes in living-donor kidney transplantation. PMID- 26432508 TI - Treatment Rationale and Study Design for the JUNIPER Study: A Randomized Phase III Study of Abemaciclib With Best Supportive Care Versus Erlotinib With Best Supportive Care in Patients With Stage IV Non-Small-Cell Lung Cancer With a Detectable KRAS Mutation Whose Disease Has Progressed After Platinum-Based Chemotherapy. AB - This clinical trial summary provides the background and rationale for the JUNIPER study (NCT02152631). JUNIPER is a randomized study of abemaciclib (200 mg orally every 12 hours) with best supportive care (BSC) versus erlotinib (150 mg orally every 24 hours) with BSC in patients with stage IV non-small-cell lung cancer (NSCLC) whose tumors have detectable Kirsten rat sarcoma (KRAS) mutations and whose disease has progressed after platinum-based chemotherapy and 1 other previous therapy, or who are not eligible for further chemotherapy. Approximately 550 patients will be randomized in a 3:2 ratio and stratified according to number of previous chemotherapy regimens (1 vs. 2), Eastern Cooperative Oncology Group performance status (0 vs. 1), sex (male vs. female), and KRAS mutation (G12C vs. others). Erlotinib was chosen as the control arm, because it is the only agent indicated for second- and third-line therapy in advanced NSCLC. Treatment will continue until disease progression or unacceptable toxicity occurs, with assessments every 28 days, followed by short-term and long-term follow-up. The coprimary efficacy objectives of this study are progression-free survival (PFS) and overall survival (OS); secondary objectives are overall response rate, changes in patient-reported pain and disease-related symptoms, changes in health status, resource utilization, safety and tolerability, and pharmacokinetics/pharmacodynamics. This design has 80% power to detect OS hazard ratio (HR) of 0.75 (type I error 0.045) and PFS HR of 0.67 (type I error 0.005). If the coprimary objectives (OS and PFS) are achieved, this study will provide a new alternative third-line treatment option for patients with NSCLC whose tumors have detectable KRAS mutations. PMID- 26432509 TI - The European Food Safety Authority recommendation for polyunsaturated fatty acid composition of infant formula overrules breast milk, puts infants at risk, and should be revised. AB - The European Food Safety Authority (EFSA) has concluded from a limited review of the literature that although docosahexaenoic acid (DHA) is required for infant formula, arachidonic acid is not required "even in the presence of DHA" (EFSA Journal, 12 (2014) 3760). This flawed opinion is grounded in human trials which tested functionality of DHA in neural outcomes and included arachidonic acid ostensibly to support growth. The EFSA report mistakes a nutrient ubiquitous in the diets of newborn infants, through breast milk and with wide-ranging health and neurodevelopmental effects, for an optional drug targeted to a particular outcome that is properly excluded when no benefit is found for that particular outcome. Arachidonic acid has very different biological functions compared to DHA, for example, arachidonic acid has unique functions in the vasculature and in specific aspects of immunity. Indeed, the overwhelming majority of trials include both DHA and arachidonic acid, and test development specific to DHA such as neural and visual development. DHA suppresses membrane arachidonic acid concentrations and its function. An infant formula with DHA and no arachidonic acid runs the risk of cardio and cerebrovascular morbidity and even mortality through suppression of the favorable oxylipin derivatives of arachidonic acid. The EFSA recommendation overruling breast milk composition should be revised forthwith, otherwise being unsafe, ungrounded in most of the evidence, and risking lifelong disability. PMID- 26432510 TI - Analysis of hospital cost outcome of DHA-rich fish-oil supplementation in pregnancy: Evidence from a randomized controlled trial. AB - OBJECTIVE: Recent research emphasized the nutritional benefits of omega-3 long chain polyunsaturated fatty acids (LCPUFAs) during pregnancy. Based on a double blind randomised controlled trial named "DHA to Optimize Mother and Infant Outcome" (DOMInO), we examined how omega 3 DHA supplementation during pregnancy may affect pregnancy related in-patient hospital costs. METHOD: We conducted an econometric analysis based on ordinary least square and quantile regressions with bootstrapped standard errors. Using these approaches, we also examined whether smoking, drinking, maternal age and BMI could influence the effect of DHA supplementation during pregnancy on hospital costs. RESULTS: Our regressions showed that in-patient hospital costs could decrease by AUD92 (P<0.05) on average per singleton pregnancy when DHA supplements were consumed during pregnancy. Our regression results also showed that the cost savings to the Australian public hospital system could be between AUD15 - AUD51 million / year. CONCLUSION: Given that a simple intervention like DHA-rich fish-oil supplementation could generate savings to the public, it may be worthwhile from a policy perspective to encourage DHA supplementation among pregnant women. PMID- 26432511 TI - Association between hospital procedure volume and risk of revision after total hip arthroplasty: a population-based study within the Nordic Arthroplasty Register Association database. AB - OBJECTIVE: Outcome after total hip arthroplasty (THA) depends on several factors related to the patient, the surgeon and the implant. It has been suggested that the annual number of procedures per hospital affects the prognosis. We aimed to examine if hospital procedure volume was associated with the risk of revision after primary THA in the Nordic countries from 1995 to 2011. DESIGN: The Nordic Arthroplasty Register Association database provided information about primary THA, revision and annual hospital volume. Hospitals were divided into five volume groups (1-50, 51-100, 101-200, 201-300, >300). The outcome of interest was risk of revision 1, 2, 5, 10 and 15 years after primary THA. Multivariable regression was used to assess the relative risk (RR) of revision. RESULTS: 417,687 THAs were included. For the 263,176 cemented THAs no differences were seen 1 year after primary procedure. At 2, 5, 10 and 15 years the four largest hospital volume groups had a reduced risk of revision compared to group 1-50. After 10 years RR was for volume group 51-100 0.79 (CI 0.65-0.95), group 101-200 0.76 (CI 0.61 0.95), group 201-300 0.74 (CI 0.57-0.96) and group >300 0.57 (CI 0.46-0.71). For the uncemented THAs an association between hospital volume and risk of revision were only present for hospitals producing 201-300 THAs per year, beginning at years 2 through 5 and in all subsequent time intervals to 15 years. CONCLUSION: Hospital procedure volume was associated with a long term risk of revision after primary cemented THA. Hospitals operating 50 procedures or less per year had an increased risk of revision after 2, 5, 10 and 15 years follow up. PMID- 26432513 TI - Temporal changes in soil water repellency after a forest fire in a Mediterranean calcareous soil: Influence of ash and different vegetation type. AB - Forest fires usually modify soil water repellency (SWR), and its persistence and intensity show a high variability both in space and time. This research studies the evolution of SWR in a Mediterranean calcareous soil affected by a forest fire, which occurred in Gorga (SE Spain) in July 2011, comparing the effect of the main vegetation cover between pine (Pinus halepensis) and shrubs species (Quercus coccifera, Rosmarinus officinalis, Cistus albidus, Erica arborea and Brachypodium retusum) and the relationship with soil moisture content (SMC). Also the study analyzed the effect of ash on SWR dynamics under field conditions. Six plots were established on the fire-affected area and the unburned-control adjacent area to monitoring SWR with the water drop penetration time (WDPT) test, SMC through moist sensors (5cm depth) and three different ash treatments: ash presence, ash absence and incorporation of ash into the soil. An immediate increase of SWR was observed in the fire-affected area, mainly in pine plots. SWR changes in control (unburned) plots were quite similar between different types of vegetation influence, despite higher SWR values being observed on pine plots during the study period. A noticeable decrease of SWR was observed during the first months after fire in the affected areas, especially after the first rainy period, both in pine and shrubs plots. SWR increase was registered in all plots, and the highest levels were in March 2012 in burned pine plots. SWR decrease was higher in plots where ash was removed. Fire-affected soils became wettable 1year and a half after the fire. PMID- 26432512 TI - Synovitis and the risk of knee osteoarthritis: the MOST Study. AB - OBJECTIVE: To identify the independent relation of synovitis with incident radiographic knee osteoarthritis (OA) after adjusting for other structural factors known to cause synovitis. DESIGN: We examined MRIs from knees that developed incident radiographic OA from the Multicenter Osteoarthritis Study (MOST) and compared these case knees with controls that did not develop OA. We examined baseline MRIs for knees developing OA at any time up to 84 months follow up. We scored lesions in cartilage, meniscus, bone marrow and synovitis. Synovitis scores were summed (0-9) across three regions, suprapatellar, infrapatellar and intercondylar region, each of which was scored 0-3. After bivariate analyses examining each factor's association with incidence, we carried out multivariable regression analyses adjusting for age, sex, BMI, alignment and cartilage and meniscal damage. RESULTS: We studied 239 case and 731 control knees. In bivariate analyses, cartilage lesions, meniscal damage, synovitis and bone marrow lesions were all risk factors for OA. After multivariable analyses, synovitis was associated with incident OA. A higher synovitis score increased the risk of incident OA (adjusted OR per unit increase 1.1; (95% CI 1.0, 1.2, P = .02)), but increased risk was associated only with synovitis scores of >=3 (adjusted OR 1.6; 95% CI 1.2, 2.1, P = .003). CONCLUSIONS: Synovitis, especially when there is a substantial volume within the knee, is an independent cause of OA. PMID- 26432514 TI - Skin Testing in the Evaluation and Management of Carboplatin-Related Hypersensitivity Reactions. AB - Carboplatin-induced hypersensitivity reactions (HSRs) are a frequent occurrence in patients being retreated for malignancy. The most common and severe reactions are thought to be IgE mediated. Currently, skin testing is the only method used clinically to identify individuals sensitized to carboplatin. Despite almost 20 years of clinical use, a standardized approach to skin testing and its use in the management of carboplatin HSRs has not been well established. We review the utility of carboplatin skin testing and discuss factors that influence the interpretation of skin testing results. A risk stratification strategy using skin testing and desensitization to manage patients with carboplatin HSRs is proposed. PMID- 26432515 TI - Meta-xylene: identification of a new antigenic entity in hypersensitivity reactions to local anesthetics. PMID- 26432516 TI - Waddlia: An emerging pathogen and a model organism to study the biology of chlamydiae. AB - Waddlia chondrophila is an emerging pathogen associated with abortion in cattle. In humans, a growing body of evidence supports its pathogenic role in miscarriage and in respiratory tract infection. The human pathogenicity of W. chondrophila is further supported by the presence of several virulence factors including a catalase, a functional T3SS and several adhesins. Despite this medical importance, no commercial tests are available and diagnostic of this strict intracellular bacterium mainly relies on serology, PCR and immunohistochemistry. So far, the epidemiology of W. chondrophila remains largely unexplored and zoonotic, waterborne or interhuman transmission has been considered. Apart from its pathogenic role, chlamydiologists are also interested in W. chondrophila in order to better understand biological mechanisms conserved and shared with Chlamydia spp. Indeed, W. chondrophila proved to be a useful model organism to study the pathobiology of chlamydiae thanks to its rapid replication, its large size allowing precise subcellular protein localization, as well as its growth in Dictyostelium amoebae. PMID- 26432517 TI - Development of dual fluorescent stage specific reporter strain of Toxoplasma gondii to follow tachyzoite and bradyzoite development in vitro and in vivo. AB - Toxoplasma gondii is a protozoan that infects 30% of humans as intermediate hosts. T Sexual reproduction can occur only within the intestinal tract of felines, however, infection in other mammals and birds is associated with asexual replication and interconversion between the tachyzoite and bradyzoite stages. Bradyzoites are slow growing forms found in tissue cysts in latent infection. Recently, our group described the biological behavior of the EGS strain that forms thick walled cysts spontaneously in tissue culture, constituting a useful tool for examining the developmental biology of T. gondii. To further improve the usefulness of this model, we constructed genetically modified EGS parasites that express fluorescent tags under the control of stage specific promoters. The promoter regions for SAG-1 (tachyzoite specific), BAG-1 and LDH-2 (bradyzoite specific) were amplified by PCR and plasmids were constructed with mCherry (redT) and sfGFP (greenB) sequences, respectively. Strains of parasites were selected using FACS to arrive at single fluorescent and dual fluorescent strains of EGS expressing tags in a stage specific manner. In cell cultures, vacuoles labeled by immunofluorescence assay using anti-CST-1 a marker for T. gondii cyst wall contained parasites that were positive for BAG1-GFP and negative for SAG1 mCherry. Tachyzoites and bradyzoites harvested from the mice expressed stage specific mCherry and GFP proteins, respectively. These new dual fluorescent transgenic EGS strains are a promising tool to elucidate the mechanisms of T. gondii differentiation both in vitro and in vivo. PMID- 26432518 TI - Evaluation of a new serological test for the detection of anti-Coxiella and anti Rickettsia antibodies. AB - Coxiella burnetii and members of the genus Rickettsia are obligate intracellular bacteria. Since cultivation of these organisms requires dedicated techniques, their diagnosis usually relies on serological or molecular biology methods. Immunofluorescence is considered the gold standard to detect antibody-reactivity towards these organisms. Here, we assessed the performance of a new automated epifluorescence immunoassay (InoDiag) to detect IgM and IgG against C. burnetii, Rickettsia typhi and Rickettsia conorii. Samples were tested with the InoDiag assay. A total of 213 sera were tested, of which 63 samples from Q fever, 20 from spotted fever rickettsiosis, 6 from murine typhus and 124 controls. InoDiag results were compared to micro-immunofluorescence. For acute Q fever, the sensitivity of phase 2 IgG was only of 30% with a cutoff of 1 arbitrary unit (AU). In patients with acute Q fever with positive IF IgM, sensitivity reached 83% with the same cutoff. Sensitivity for chronic Q fever was 100% whereas sensitivity for past Q fever was 65%. Sensitivity for spotted Mediterranean fever and murine typhus were 91% and 100%, respectively. Both assays exhibited a good specificity in control groups, ranging from 79% in sera from patients with unrelated diseases or EBV positivity to 100% in sera from healthy patients. In conclusion, the InoDiag assay exhibits an excellent performance for the diagnosis of chronic Q fever but a very low IgG sensitivity for acute Q fever likely due to low reactivity of phase 2 antigens present on the glass slide. This defect is partially compensated by the detection of IgM. Because it exhibits a good negative predictive value, the InoDiag assay is valuable to rule out a chronic Q fever. For the diagnosis of rickettsial diseases, the sensitivity of the InoDiag method is similar to conventional immunofluorescence. PMID- 26432519 TI - Comparison of clinical and laboratory characteristics of patients fulfilling criteria for proven and probable human granulocytic anaplasmosis. AB - To assess the value of clinical definitions for human granulocytic anaplasmosis (HGA) epidemiological, clinical and laboratory findings in 50 adult patients with proven HGA (Anaplasma phagocytophilum isolated from blood, and/or positive PCR result, and/or seroconversion or >=4-fold change in serum IFA antibody titres to A. phagocytophilum) and 46 patients with probable HGA (demonstration of serum antibodies to A. phagocytophilum in titres >=1:256) were compared. Patients with proven HGA were older (55 versus 43.5 years; p = 0.001), were more often treated with doxycycline (31/50, 62% versus 11/46, 23.9%; p < 0.001), more frequently reported chills (40/50, 80% versus 17/46, 36.9%; p < 0.001), myalgia (37/50, 74% versus 21/46, 45.7%; p = 0.005) and cough (10/50, 20% versus 2/46, 4.4%; p = 0.02), and had more often abnormal laboratory findings such as thrombocytopenia (45/50, 90% versus 22/46, 47.8%; p < 0.001), abnormal liver function test results (45/50, 87% versus 22/46, 47.8%; p < 0.001), leukopenia (38/50, 76% versus 21/46, 45.7%; p = 0.002) and elevated serum CRP concentration (48/50, 96% versus 31/46, 67.4%; p < 0.001). The dissimilarities imply that in some patients fulfilling criteria for probable HGA the signs and symptoms most likely are not the result of a recent infection with A. phagocytophilum and indicate that clinical definitions used in the present study have a distinctive value. PMID- 26432520 TI - Genomic signatures in B-cell lymphoma: How can these improve precision in diagnosis and inform prognosis? AB - Current genomic technologies have immensely improved disease classification and prognostication of major subtypes of B-cell lymphomas. This novel genetic information has not only aided in diagnosis, but has also revealed a landscape of critical molecular events that determine the biological and clinical behavior of a lymphoma. In this review, we summarized the genetic characteristics of major subtypes of B-cell lymphomas, including diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL), and mantle cell lymphoma (MCL). We illustrated how genomic profiling had identified molecular subgroups in DLBCL with varied clinical outcomes, and how a subset of genes defined prognosis in MCL and aided in BL diagnoses. We also highlighted some Phase II/III clinical trials using new therapeutic agents to determine clinical efficacy in novel molecular subgroups with distinct gene expression patterns. We believe that refinement of genomic signatures will require more intensive efforts from the biomedical research community to improve targeted therapy designs and bring a substantial change in the treatment decisions. In the next era of genomic medicine, we anticipate that a clinically and biologically relevant molecular profile of each tumor will be obtained at diagnosis to guide therapy. PMID- 26432521 TI - An examination of factors related to aspiration and silent aspiration in older adults requiring long-term care in rural Japan. AB - Swallowing disorders are a growing problem among the elderly in long-term care (LTC), and they can cause aspiration pneumonia. In order to detect swallowing disorders early, simple tools are needed to assess aspiration and silent aspiration (SA). To compile a sample of elderly people requiring LTC, and categorise them as having suspected aspiration and/or SA using simple screening tools. In addition, oral ability, severity of dementia, vital functions and nutritional status were compared in these groups. A total of 393 elderly people in LTC (89 men and 304 women; age ranging from 65 to 100 years) were included in the study. The modified water swallow test, cervical auscultation and cough test were used to assess swallowing function. The participants were categorised as having suspected aspiration and/or SA, and the following assessments were performed: (i) oral ability (lips function, tongue function, rinsing and gargling ability), (ii) dementia severity, (iii) vital functions and (iv) nutritional status. Suspected aspiration was apparent in 50.5% of patients, of which 24.0% had suspected SA. Those with suspected aspiration showed worsened oral ability, dementia severity, vital functions and nutritional status. Similarly, those with suspected SA showed worsened dementia severity, vital functions and nutritional status. Logistic regression analysis revealed that lip closure, lingual movement and rinsing ability were significantly associated with suspected aspiration. Dementia severity was the best predictor of suspected SA. Simple screening tools can be used to identify suspected aspiration and SA, which may facilitate early detection of aspiration pneumonia or swallowing disorder risk. PMID- 26432522 TI - Erratum for Gjessing et al., Salmon Gill Poxvirus, the Deepest Representative of the Chordopoxvirinae. PMID- 26432525 TI - Monitoring Dynamics of DNA Methylation at Single-Cell Resolution during Development and Disease. AB - DNA methylation is a broadly studied epigenetic modification that is essential for normal mammalian development. Over the years, numerous methodologies were developed trying to cope with the intrinsic challenge of reading the "second dimension" epigenetic code. The recent rapid expansion of sequencing technologies has made it possible to fully chart the methylation landscape of different cell types at single-base resolution. Surprisingly, accumulating data suggest that, in addition to the massive epigenome remodeling during early development, cell type and tissue specification is associated with high levels of DNA methylation dynamics at distal regulatory elements. However, current methods provide only a static "snapshot" of DNA methylation, thus precluding the study of real-time methylation dynamics during cell fate changes. Here we review the principles of a new approach that enables monitoring loci-specific DNA methylation dynamics at single-cell resolution. We also discuss potential applications and promises for implementing this methodology to study DNA methylation changes during development and disease. PMID- 26432526 TI - Modulating the Genomic Programming of Adipocytes. AB - The ability to modify the transcriptional program in response to external signals provides a way for mammalian cells to alter their biological fate and properties, thereby adapting to changes in the environment. Adipocytes are excellent examples of differentiated cells that possess a striking transcriptional plasticity when exposed to physiological and metabolic stimuli. In our work, we have focused on understanding the processes responsible for modulating the genomic programming in response to different external signals. Thus, we have shown that browning of human adipocytes with rosiglitazone, an antidiabetic agonist of the key adipocyte transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma), involves redistribution of PPARgamma binding to form browning selective PPARgamma super-enhancers that drive expression of key browning genes. These include genes encoding transcriptional regulators, such as Kruppel-like factor 11 (KLF11) that are essential for modulating the genomic program in white adipocytes to induce browning. Furthermore, we have shown that acute suppression of adipocyte genes by the proinflammatory cytokine, tumor necrosis factor (TNF), involves redistribution of cofactors to enhancers activated by the master inflammatory regulator, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB). Interestingly, this redistribution occurs selectively from enhancers with high-cofactor occupancies, thereby predominantly affecting super enhancers and their associated genes. We propose that this is a general mechanism contributing to transcriptional repression associated with activation of signal dependent transcription factors. PMID- 26432527 TI - ACC/AHA/STS Statement on the Future of Registries and the Performance Measurement Enterprise: A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures and The Society of Thoracic Surgeons. PMID- 26432528 TI - Mortality reduction from gastric cancer by endoscopic and radiographic screening. AB - To evaluate mortality reduction from gastric cancer by endoscopic screening, we undertook a population-based cohort study in which both radiographic and endoscopic screenings for gastric cancer have been carried out. The subjects were selected from the participants of gastric cancer screening in two cities in Japan, Tottori and Yonago, from 2007 to 2008. The subjects were defined as participants aged 40-79 years who had no gastric cancer screening in the previous year. Follow-up of mortality was continued from the date of the first screening to the date of death or up to December 31, 2013. A Cox proportional hazards model was used to estimate the relative risk (RR) of gastric cancer incidence, gastric cancer death, all cancer deaths except gastric cancer death, and all-causes death except gastric cancer death. The number of subjects selected for endoscopic screening was 9950 and that for radiographic screening was 4324. The subjects screened by endoscopy showed a 67% reduction of gastric cancer compared with the subjects screened by radiography (adjusted RR by sex, age group, and resident city = 0.327; 95% confidence interval [CI], 0.118-0.908). The adjusted RR of endoscopic screening was 0.968 (95%CI, 0.675-1.387) for all cancer deaths except gastric cancer death, and 0.929 (95%CI, 0.740-1.168) for all-causes death except gastric cancer death. This study indicates that endoscopic screening can reduce gastric cancer mortality by 67% compared with radiographic screening. This is consistent with previous studies showing that endoscopic screening reduces gastric cancer mortality. PMID- 26432529 TI - Introduction: Ejaculatory problems and male infertility. AB - There are a variety of dysfunctions of the ejaculatory process which may negatively impact male fertility but are not commonly discussed. The meanings of the terms used to describe these conditions are often unclear. This month's Views and Reviews define the commonly used and confused terms. The initial article explains normal male function with an emphasis on the ejaculatory process. Following articles discuss the causes, evaluation and management of the male with ejaculatory dysfunction. PMID- 26432530 TI - Management of the dry ejaculate: a systematic review of aspermia and retrograde ejaculation. AB - A dry ejaculate (aspermia), may occur either because of an inability to transport semen (anejaculation) or because of an inability to ejaculate in an antegrade direction (retrograde ejaculation). The treatment of aspermia varies with underlying etiology and includes medical therapy with sympathomimetics, urinary sperm retrieval, bladder neck reconstruction, prostatic massage, penile vibratory stimulation, electroejaculation, and surgical sperm retrieval. A systematic review of the current literature was performed for articles on ejaculatory dysfunction related to dry ejaculate. However, the data are insufficient to allow firm comparisons between treatment options. Treatments must be tailored to the individual patient, and treatment decisions should involve consideration of ease of administration, degree of invasiveness, and anticipated success. PMID- 26432531 TI - Reducing capacities and redox potentials of humic substances extracted from sewage sludge. AB - Humic substances (HS) are redox active organic materials that can be extracted from sewage sludge generated in wastewater treatment processes. Due to the poor understanding of reducing capacity, redox potentials and redox active functional groups of HS in sewage sludge, the potential contribution of sludge HS in transformation of wastewater contaminants is unclear. In the present study, the number of electrons donated or accepted by sewage sludge HS were quantified before and after reduction by iron compounds that possess different redox potentials and defined as the reducing capacity of the sewage sludge. In contrast to previous studies of soil and commercial humic acids (HA), reduced sludge HA showed a lower reducing capacity than that of native HA, which implies formation of semiquinone radicals since the semiquinone radical/hydroquinone pair has a much higher redox potential than the quinone/hydroquinone pair. It is novel that reducing capacities of sludge HA were determined in the redox potential range from -314 to 430 mV. The formation of semiquinone radicals formed during the reduction of quinone moieties in sludge HA is shown by three-dimensional excitation/emission matrix fluorescence spectroscopies information, increasing fluorescence intensities and blue-shifting of the excitation/emission peak of reduced sludge HA. Knowledge of sludge HS redox potentials and corresponding reducing capacities makes it possible to predict the transformation of redox active pollutants and facilitate manipulation and optimization of sludge loading wastewater treatment processes. PMID- 26432532 TI - High resistance of Tetrahymena thermophila to paraquat: Mitochondrial alterations, oxidative stress and antioxidant genes expression. PMID- 26432533 TI - Effects of kaolin particle films on the life span of an orb-weaver spider. AB - Araniella cucurbitina (Araneae: Araneidae) is a widespread orb-weaver spider commonly found in agroecosystems. Mineral particle films such as kaolin, due to their protective or anti-feeding action, can represent an alternative to pesticides, especially in organic farming systems, but little is known about its effects on A. cucurbitina. Therefore, we tested the effect of kaolin sprays on the life span of A. cucurbitina under laboratory conditions. Four treatments were tested encompassing different exposure routes. Thus, kaolin sprays were applied on (i) the surface, (ii) the prey (fly), (iii) the spider and (iv) both spider & prey. A control group was tested with water in each treatment. Results showed that sprays of kaolin significantly affected the survival of A. curcubitina when applications were done on the surface and on both spider & prey registering a reduction of 48% and 56%, respectively. Spiders in control obtained higher probability of reaching alive at the end of the assay than those treated with kaolin. Differences observed can be explained by the feeding behavior of the species and may depend on the consumption of the web by the spider and the ratio spider/fly for body size. PMID- 26432534 TI - Responses of the CYP1A biomarker in Jenynsia multidentata and Phalloceros caudimaculatus and evaluation of a CYP1A refractory phenotype. AB - The level of cytochrome P450 1A (CYP1A) in fish is used as a typical environmental biomarker for the presence of organic contaminants. We used RT-qPCR to investigate CYP1A mRNA levels in the liver, gill and gonopodium of guppies Jenynsia multidentata and Phalloceros caudimaculatus in wetlands within the Rio Grande city (RG) which is under the influence of the Patos Lagoon Estuary (RS, Brazil). The CYP1A mRNA levels evaluated in fish liver from two locations that receive non-treated wastewater effluents (S3 and S4) and another locations near an oil refinery (S6) and an industrial complex (S7), were higher than in locations remote from those sites (S1, S2 and S5). The sum of 16 priority PAHs in sediment confirmed high levels in S4 and S6 (3914.0 and 4414.0 ng g(-1) dw, respectively) comparing to S7>S2>S3>S5>S1 (119.3, 66.3, 62.8, 16.4 and 1.7 ng g( 1) dw). J. multidentata from sites S1 to S4 that were transferred to the laboratory exhibited CYP1A induction after 24 h waterborne exposure to 1 uM betanaphtoflavone (BNF) in all organs compared to controls, except in the liver of fish from site S4. This lack of CYP1A induction by BNF indicates a CYP1A refractory phenotype in guppy. Although this characteristic possibly involves the alteration in AHR signaling or control, the mechanism of resistance is unknown. The present study provides information about the use of the use of CYP1A in South American guppies as an useful biomarker tool for environmental contamination studies. PMID- 26432535 TI - The effect of feed water dissolved organic carbon concentration and composition on organic micropollutant removal and microbial diversity in soil columns simulating river bank filtration. AB - This study investigated organic micropollutant (OMP) biodegradation rates in laboratory-scale soil columns simulating river bank filtration (RBF) processes. The dosed OMP mixture consisted of 11 pharmaceuticals, 6 herbicides, 2 insecticides and 1 solvent. Columns were filled with soil from a RBF site and were fed with four different organic carbon fractions (hydrophilic, hydrophobic, transphilic and river water organic matter (RWOM)). Additionally, the effect of a short-term OMP/dissolved organic carbon (DOC) shock-load (e.g. quadrupling the OMP concentrations and doubling the DOC concentration) on OMP biodegradation rates was investigated to assess the resilience of RBF systems. The results obtained in this study imply that - in contrast to what is observed for managed aquifer recharge systems operating on wastewater effluent - OMP biodegradation rates are not affected by the type of organic carbon fraction fed to the soil column, in case of stable operation. No effect of a short-term DOC shock-load on OMP biodegradation rates between the different organic carbon fractions was observed. This means that the RBF site simulated in this study is resilient towards transient higher DOC concentrations in the river water. However, a temporary OMP shock-load affected OMP biodegradation rates observed for the columns fed with the river water organic matter (RWOM) and the hydrophilic fraction of the river water organic matter. These different biodegradation rates did not correlate with any of the parameters investigated in this study (cellular adenosine triphosphate (cATP), DOC removal, specific ultraviolet absorbance (SUVA), richness/evenness of the soil microbial population or OMP category (hydrophobicity/charge). PMID- 26432536 TI - Effect of UV irradiation on the proportion of organic chloramines in total chlorine in subsequent chlorination. AB - This study investigated the changes of chlorine species and proportion of organic chloramines during the chlorination process after UV irradiation pretreatment in drinking water. It was found that the UV pretreatment could enhance the percentage of organic chloramines by increasing free chlorine consumption in the chlorination of raw waters. The percentage of organic chloramines in total chlorine increased with UV intensity and irradiation time in raw waters. However, for the humic acid synthesized water, the percentage of organic chloramines increased first and then decreased with the increase of UV irradiation time. The value of SUVA declined in both raw and humic acid synthesized waters over the UV irradiation time, which indicated that the decomposition of aromatic organic matter by UV could be a contributor to the increase of free chlorine consumption and organic chloramine proportion. The percentage of organic chloramines during chlorination of raw waters after 30-min UV irradiation pretreatment varied from 20.2% to 41.8%. Total chlorine decreased obviously with the increase of nitrate concentration, but the percentage of organic chloramines increased and was linearly correlated to nitrate concentration. PMID- 26432537 TI - Placental transfer of and infantile exposure to perchlorate. AB - Fetuses and infants are vulnerable to perchlorate toxicity. We assessed fetal and infantile exposure to perchlorate in two Chinese cities (Nanchang and Tianjin). Perchlorate was widely found (82%-100%) in breast milk, dissolved infant formula, infants' urine, maternal and cord blood samples. Perchlorate levels in infants' urine (mean +/- standard deviation: 22.4 +/- 35.6 ng mL(-1)), breast milk (36.6 +/- 48.1 ng mL(-1)), and cord blood (3.18 +/- 3.83 ng mL(-1)) samples collected from Nanchang and Tianjin were approximately an order of magnitude higher than those reported for the U.S. Perchlorate concentrations in cord blood were comparable to that in maternal blood, indicating that perchlorate is transferred from mother to fetus through placenta. Among all infants providing urine samples, the average daily intake of perchlorate (DOSEU) was estimated to be 1.17 +/- 1.57 MUg kg(-1) bw d(-1), and 40% of these infants had DOSEU exceeding the RfD (0.7 MUg kg(-1) bw d(-1)) recommended by U.S. EPA. However, approximately 70% of exclusively breast-fed infants had perchlorate exposure dose via breast milk exceeding the RfD. For breast-fed infants, breast milk was the overwhelmingly predominant exposure pathway; while infant formula and indoor dust ingestion were major perchlorate exposure sources for formula-fed infants. To our knowledge, this is the first report to assess the fetal and infantile exposure to perchlorate in China. PMID- 26432538 TI - Simulating CO2 leakages from CCS to determine Zn toxicity using the marine microalgae Pleurochrysis roscoffensis. AB - Due to the current climate change and ocean acidification, a new technology for CO2 mitigation has been proposed, the Carbon dioxide Capture and Storage (CCS). However, there is an ecological risk associated with potential CO2 leakages from the sub-seabed storages sites. To evaluate the effects related to CO2 leakages, laboratory-scales experiments were performed using the marine microalgae Pleurochrysis roscoffensis. Five Zn concentrations were tested at different pHs to study Zn toxicity under acidified conditions. Seawater was collected and submitted to acidification by means of CO2 injection and by HCl addition. Results showed differences between both acidification techniques: while microalgae growth was enhanced by CO2 supply, reaching the optimal growth at pH 6.5 and full inhibition at pH 5.5, HCl acidification growth was inhibited at pH 6.5. Although small concentrations of Zn were positive for P. roscoffensis growth, Zn toxicity increased at lower pHs, and more severely on samples acidified with HCl. The conclusions obtained in this work are useful to address the potential effects on the marine ecosystem related to changes in metal bioavailability during CO2 leakages scenarios. PMID- 26432539 TI - Interleukin-17, oxidative stress, and inflammation: role of melatonin during Trypanosoma cruzi infection. AB - Although the exact etiology of Chagas' disease remains unknown, the inflammatory process and oxidative stress are believed to be the main contributors to the dysfunction and pathogenesis during chronic Trypanosoma cruzi infection. Our hypothesis is that melatonin administered for 2 months daily could modulate the oxidative stress and the inflammatory response during the chronic infection. Flow cytometric analysis of macrophages and antigen-presenting cells (APC), expression of RT1B as well as LFA-1 and MCP-1 in CD4(+) and CD8(+) T cells and levels of interleukin-17A were assessed. The oxidative stress was evaluated through lipid peroxidation (LPO) analysis on the plasma of thiobarbituric acid-reactive substances (TBARS) and nitric oxide production. Decreased concentrations of nitrite and TBARS were found in infected and melatonin-treated animals, as well as a rising trend in the production of IL-17A as compared to infected and untreated counterparts. A significant decrease was found in the percentages of CD4(+) and CD8(+) T lymphocytes MCP-1 producers for infected and melatonin treated rats. Reduced percentage of CD8(+) T cells producing LFA-1 was observed in control and melatonin-treated animals as compared to untreated rats. The cellular response of peritoneal APC cells and macrophages significantly dropped in infected and treated animals. As an endpoint, the use of antioxidant compounds such as melatonin emerges as a new and promising approach to control the oxidative stress during the chronic Chagas' disease partially mediated through the abrogation of LPO and the prevention of the inflammatory response and can be used for further investigation on treatment trials for other infectious diseases. PMID- 26432540 TI - Auditory interference control in children with learning disability: An exploratory study. AB - OBJECTIVES: The current study aimed to compare the auditory interference control of participants with Learning Disability (LD) to a control group on two versions of an auditory Stroop task. METHODS: A group of eight children with LD (clinical group) and another group of eight typically developing children (control group) served as participants. All the participants were involved in a semantic and a gender identification-based auditory Stroop task. Each participant was presented with eight different words (10 times) that were pre-recorded by a male and a female speaker. The semantic task required the participants to ignore the speaker's gender and attend to the meaning of the word, and vice-versa for the gender identification task. The participants' performance accuracy and reaction time (RT) was measured on both the tasks. RESULTS: Control group participants significantly outperformed the clinical group participants on both the tasks with regard to performance accuracy as well as RT. CONCLUSION: The results suggest that children with LD have problems in suppressing irrelevant auditory stimuli and focusing on the relevant auditory stimuli. This can be attributed to the auditory processing problems in these children. PMID- 26432541 TI - Cost-benefit analysis of targeted hearing directed early testing for congenital cytomegalovirus infection. AB - OBJECTIVES: In this study, we estimate an ex ante cost-benefit analysis of a Utah law directed at improving early cytomegalovirus (CMV) detection. STUDY DESIGN: We use a differential cost of treatment analysis for publicly insured CMV-infected infants detected by a statewide hearing-directed CMV screening program. METHODS: Utah government administrative data and multi-hospital accounting data are used to estimate and compare costs and benefits for the Utah infant population. RESULTS: If antiviral treatment succeeds in mitigating hearing loss for one infant per year, the public savings will offset the public costs incurred by screening and treatment. If antiviral treatment is not successful, the program represents a net cost, but may still have non-monetary benefits such as accelerated achievement of diagnostic milestones. CONCLUSIONS: The CMV education and treatment program costs are modest and show potential for significant cost savings. PMID- 26432543 TI - Hypoparathyroidism in Children. PMID- 26432544 TI - Current concepts of shockwave therapy in chronic patellar tendinopathy. PMID- 26432545 TI - Effects of shock wave therapy on glycosaminoglycan expression during bone healing. AB - BACKGROUND: Several cases of delayed bone consolidation have been treated with extracorporeal shock wave therapy (ESWT) to improve bone healing and a key role of the extracellular matrix glycosaminoglycans in osteogenesis has been suggested. OBJECTIVE: In this study, we aimed to identify and quantify the amount of sulfated glycosaminoglycans (GAG) and hyaluronic acid (HA) within rat femurs following bone drilling and treatment with shock waves. METHODS: To identify and quantify the sulfated glycosaminoglycans (GAG) and hyaluronic acid (HA) within rat femurs following bone drilling and ESWT, 50 male Wistar rats were evaluated. The animals were divided into two groups, both of which were subjected to bone drilling. One of the groups was treated with ESWT. The rats were sacrificed on the 3rd, 7th, 14th, 21st, and 28th day. GAG presence was analyzed by agarose gel electrophoresis with subsequent densitometry and ELISA. RESULTS AND DISCUSSION: The content of sulfated GAGs increased significantly from the 3rd to the 28th day (p = 0.002). Chondroitin sulfate was expressed more highly than the other GAGs. HA content increased significantly at the 3rd day in animals treated with ESWT compared to the control group (p = 0.003). CONCLUSION: ESWT stimulates of sulfated glycosaminoglycans during bone healing and enhanced early expression of HA compared to the control group. PMID- 26432542 TI - Regulation of skeletal growth and mineral acquisition by the GH/IGF-1 axis: Lessons from mouse models. AB - The growth hormone (GH) and its downstream mediator, the insulin-like growth factor-1 (IGF-1), construct a pleotropic axis affecting growth, metabolism, and organ function. Serum levels of GH/IGF-1 rise during pubertal growth and associate with peak bone acquisition, while during aging their levels decline and associate with bone loss. The GH/IGF-1 axis was extensively studied in numerous biological systems including rodent models and cell cultures. Both hormones act in an endocrine and autocrine/paracrine fashion and understanding their distinct and overlapping contributions to skeletal acquisition is still a matter of debate. GH and IGF-1 exert their effects on osteogenic cells via binding to their cognate receptor, leading to activation of an array of genes that mediate cellular differentiation and function. Both hormones interact with other skeletal regulators, such as sex-steroids, thyroid hormone, and parathyroid hormone, to facilitate skeletal growth and metabolism. In this review we summarized several rodent models of the GH/IGF-1 axis and described key experiments that shed new light on the regulation of skeletal growth by the GH/IGF-1 axis. PMID- 26432546 TI - A Cochrane systematic review and network meta-analysis comparing treatment strategies aiming to decrease blood loss during liver resection. AB - INTRODUCTION: Intraoperative haemorrhage remains one of the major risks during liver resection, and perioperative blood loss and blood transfusion are important factors affecting perioperative morbidity and mortality. The aim of this study is to compare treatment strategies aiming to decrease blood loss during hepatectomy. METHODS: A systematic review of the literature was performed to identify randomised controlled trials reporting on the method of vascular occlusion, parenchymal transection, and management of the cut surface during liver resection. A Bayesian network meta-analysis was performed using WinBUGS. RESULTS: Seven trials reporting on 496 participants randomised to seven treatment strategies were analysed. Continuous vascular occlusion resulted in lower blood loss compared to no vascular occlusion when parenchymal transection was performed with clamp-crush and no fibrin sealant was used for the cut surface. People undergoing liver resection by continuous vascular occlusion had decreased amounts of blood transfused than people with intermittent vascular occlusion when parenchymal transection was performed with clamp-crush and no fibrin sealant. There was no significant difference in proportion of people transfused, mortality, or hospital stay between the different strategies. There were significantly more serious adverse events when surgery was performed using radiofrequency dissecting sealer compared with standard clamp-crush method in the absence of vascular occlusion and fibrin sealant. CONCLUSIONS: Continuous vascular occlusion during hepatectomy results in decreased blood loss and decreased blood transfusion requirements. Further studies are needed to compare treatment strategies aiming to decrease blood loss, defined by their method of vascular occlusion, parenchymal transection, and management of the cut surface. PMID- 26432547 TI - The association between loss of ankle dorsiflexion range of movement, and hip adduction and internal rotation during a step down test. AB - A pattern of excessive hip adduction and internal rotation with medial deviation of the knee has been associated with numerous musculo-skeletal dysfunctions. Research into the role that ankle dorsiflexion (DF) range of motion (ROM) play in lower limb kinematics is lacking. The objective of this cross-sectional, observational study was to investigate the relationship between ankle DF ROM, and hip adduction and hip internal rotation during a step-down test with and without heel elevation in a healthy female population. Hip and ankle ROM was measured kinematically using a ten-camera Optitrack motion analysis system. Thirty healthy female participants (mean age = 20.4 years; SD = 0.9 years) first performed a step-down test with the heel of the weight bearing foot flat on the step and then with the heel elevated on a platform. Ankle DF, hip adduction and hip internal rotation were measured kinematically for the supporting leg. Participants who had 17 degrees or less of ankle DF ROM displayed significantly more hip adduction ROM (p = 0.001; Cohen's d effect size = 1.2) than the participants with more than 17 degrees of DF during the step-down test. Participants with limited DF ROM showed a significant reduction in hip adduction ROM during the elevated-heel step down test (p = 0.008). Hip internal rotation increased in both groups during the EHSD compared to the step-down test (p > 0.05) Reduced ankle DF ROM is associated with increased hip adduction utilised during the step-down test. Ankle DF should be taken into account when assessing patients with aberrant frontal plane lower limb alignment. PMID- 26432548 TI - Reproductive management through integration of PGD and MPS-based noninvasive prenatal screening/diagnosis for a family with GJB2-associated hearing impairment. AB - A couple with a proband child of GJB2 (encoding the gap junction protein connexin 26)-associated hearing impairment and a previous pregnancy miscarriage sought for a reproductive solution to bear a healthy child. Our study aimed to develop a customized preconception-to-neonate care trajectory to fulfill this clinical demand by integrating preimplantation genetic diagnosis (PGD), noninvasive prenatal testing (NIPT), and noninvasive prenatal diagnosis (NIPD) into the strategy. Auditory and genetic diagnosis of the proband child was carried out to identify the disease causative mutations. The couple then received in-vitro fertilization treatment, and eight embryos were obtained for day 5 biopsy. PGD was performed by short-tandem-repeat linkage analysis and Sanger sequencing of GJB2 gene. Transfer of a GJB2c.235delC heterozygous embryo resulted in a singleton pregnancy. At the 13th week of gestation, genomic DNA (gDNA) from the trio family and cell-free DNA (cfDNA) from maternal plasma were obtained for assessment of fetal chromosomal aneuploidy and GJB2 mutations. NIPT and NIPD showed the absence of chromosomal aneuploidy and GJB2-associated disease in the fetus, which was later confirmed by invasive procedures and postnatal genetic/auditory diagnosis. This strategy successfully prevented the transmission of hearing impairment in the newborn, thus providing a valuable experience in reproductive management of similar cases and potentially other monogenic disorders. PMID- 26432549 TI - Secretion of Na(+), K(+) and fluid by the Malpighian (renal) tubule of the larval cabbage looper Trichoplusia ni (Lepidoptera: Noctuidae). AB - The Malpighian (renal) tubules play important roles in ionic and osmotic homeostasis in insects. In Lepidoptera, the Malpighian tubules are structurally regionalized and the concentration of Na(+) and K(+) in the secreted fluid varies depending on the segment of tubule analyzed. In this work, we have characterized fluid and ion (Na(+), K(+), H(+)) transport by tubules of the larval stage of the cabbage looper Trichoplusia ni; we have also evaluated the effects of fluid secretion inhibitors and stimulants on fluid and ion transport. Ramsay assays showed that fluid was secreted by the iliac plexus but not by the yellow and white regions of the tubule. K(+) and Na(+) were secreted by the distal iliac plexus (DIP) and K(+) was reabsorbed in downstream regions. The fluid secretion rate decreased>50% after 25MUM bafilomycin A1, 500MUM amiloride or 50MUM bumetanide was added to the bath. The concentration of K(+) in the secreted fluid did not change, whereas the concentration of Na(+) in the secreted fluid decreased significantly when tubules were exposed to bafilomycin A1 or amiloride. Addition of 500MUM cAMP or 1MUM 5-HT to the bath stimulated fluid secretion and resulted in a decrease in K(+) concentration in the secreted fluid. An increase in Na(+) concentration in the secreted fluid was observed only in cAMP-stimulated tubules. Secreted fluid pH and the transepithelial electrical potential (TEP) did not change when tubules were stimulated. Taken together, our results show that the secretion of fluid is carried out by the upper regions (DIP) in T. ni Malpighian tubules. Upper regions of the tubules secrete K(+), whereas lower regions reabsorb it. Stimulation of fluid secretion is correlated with a decrease in the K(+)/Na(+) ratio. PMID- 26432550 TI - Modified technique for transscleral fixation of posterior chamber intraocular lenses. AB - BACKGROUND: Suture exposure remains to be a potential problem of transscleral fixated posterior chamber intraocular lens (PCIOL). We report a modified technique to minimize the risk of suture exposure for the transscleral fixation of PCIOL. METHODS: The modified surgical technique is as following: at first, two 3 mm * 4 mm square scleral pockets were created from groove incisions at opposite positions. A straight needle attached to a 10-0 polypropylene suture was passed through one incision groove. Then, a 27-Gauge hollow needle passed through the opposite sclera incision bed was used to retrieve the straight fine needle via its barrel. The sutures were tied to themselves after one more bite on the scleral bed. At last, the suture ends were left long (about 4 mm) and laid flat into corresponding laminar scleral pockets. This modified technique of PCIOL was performed in 48 post-traumatic aphakic vitrectomized eyes from 48 patients (47 male, one female) with mean age of 34.8 +/- 14.8 years. Main outcome measures included best corrective visual acuity (BCVA), IOL decentration, IOL tilt, and postoperative complications. RESULTS: The mean follow-up was 32.3 +/- 10.8 months (3-67 months). The LogMAR BCVA remained stable, from a preoperative value of 0.46 +/- 0.34 to postoperative 0.44 +/- 0.34 (p = 0.69). Mild IOL tilt (5-10 degrees ) was observed in five eyes, and slight IOL decentration (0.5-1.0 mm) was seen in three cases. No case of suture exposure, suture breakage, IOL dislocation, or endophthalmitis was observed during the follow up period. CONCLUSION: The modified technique allowed stable placement of PCIOLs in post-traumatic aphakic eyes with a wide range of follow-up. Our procedure might have the potential benefit to avoid suture exposure in scleral-fixated IOL implantation. PMID- 26432551 TI - Validation of the Physician Teaching Motivation Questionnaire (PTMQ). AB - BACKGROUND: Physicians play a major role as teachers in undergraduate medical education. Studies indicate that different forms and degrees of motivation can influence work performance in general and that teachers' motivation to teach can influence students' academic achievements in particular. Therefore, the aim of this study was to develop and to validate an instrument measuring teaching motivations in hospital-based physicians. METHODS: We chose self-determination theory as a theoretical framework for item and scale development. It distinguishes between different dimensions of motivation depending on the amount of self-regulation and autonomy involved and its empirical evidence has been demonstrated in other areas of research. To validate the new instrument (PTMQ = Physician Teaching Motivation Questionnaire), we used data from a sample of 247 physicians from internal medicine and surgery at six German medical faculties. Structural equation modelling was conducted to confirm the factorial structure, correlation analyses and linear regressions were performed to examine concurrent and incremental validity. RESULTS: Structural equation modelling confirmed a good global fit for the factorial structure of the final instrument (RMSEA = .050, TLI = .957, SRMR = .055, CFI = .966). Cronbach's alphas indicated good internal consistencies for all scales (alpha = .75 - .89) except for the identified teaching motivation subscale with an acceptable internal consistency (alpha = .65). Tests of concurrent validity with global work motivation, perceived teaching competence, perceived teaching involvement and voluntariness of lesson allocation delivered theory-consistent results with slight deviations for some scales. Incremental validity over global work motivation in predicting perceived teaching involvement was also confirmed. CONCLUSIONS: Our results indicate that the PTMQ is a reliable, valid and therefore suitable instrument for assessing physicians' teaching motivation. PMID- 26432553 TI - Synthesis and Fluorescence Properties of Novel indol-3yl-thiazolo[3,2 a][1,3,5]triazines and indole-3-carbaldehyde Schiff Bases. AB - Novel photoactive 4-(4-chlorophenyl)-2-(1H-indol-3-yl)-6-substituted phenyl-2H thiazolo[3,2-a][1,3,5]triazines were synthesized by the conjugate addition of ammonia to the indole-3-carbaldehyde Schiff bases followed by the condensation with 4-chlorobenzaldehyde. All the synthesized compounds were characterized by FT IR, NMR, mass spectra and elemental analyses. Their antioxidant property, electrochemical and photophysical properties in different organic solvents were investigated. Comparative discussion on the photophysical properties of indole-3 carbaldehyde Schiff bases and 4-(4-chlorophenyl)-2-(1H-indol-3-yl)-6-substituted phenyl-2H-thiazolo[3,2-a][1,3,5]triazines has been described. The fluorescence quantum yield of Schiff bases (Phif = 0.66-0.70 in DMSO) found to be interestingly higher. High fluorescence quantum yield, large molar extinction coefficient, high stokes shift and smaller optical band gap positioning these new derivatives as an efficient metal free organic fluorescent and semiconductor material. Graphical Abstract ?. PMID- 26432552 TI - Triclosan-coated sutures and sternal wound infections: a prospective randomized clinical trial. AB - Surgical site infection is a common complication following cardiac surgery. Triclosan-coated sutures have been shown to reduce the rate of infections in various surgical wounds, including wounds after vein harvesting in coronary artery bypass grafting patients. Our purpose was to compare the rate of infections in sternotomy wounds closed with triclosan-coated or conventional sutures. A total of 357 patients that underwent coronary artery bypass grafting were included in a prospective randomized double-blind single-center study. The patients were randomized to closure of the sternal wound with either triclosan coated sutures (Vicryl Plus and Monocryl Plus, Ethicon, Inc., Somerville, NJ, USA) (n = 179) or identical sutures without triclosan (n = 178). Patients were followed up after 30 days (clinical visit) and 60 days (telephone interview). The primary endpoint was the prevalence of sternal wound infection according to the Centers for Disease Control and Prevention (CDC) criteria. The demographics in both groups were comparable, including age, gender, body mass index, and rate of diabetes and smoking. Sternal wound infection was diagnosed in 43 patients; 23 (12.8%) sutured with triclosan-coated sutures compared to 20 (11.2%) sutured without triclosan (p = 0.640). Most infections were superficial (n = 36, 10.1%), while 7 (2.0%) were deep sternal wound infections. There were 16 positive cultures in the triclosan group and 17 in the non-coated suture group (p = 0.842). The most commonly identified main pathogens were Staphylococcus aureus (45.4%) and coagulase-negative staphylococci (36.4%). Skin closure with triclosan coated sutures did not reduce the rate of sternal wound infection after coronary artery bypass grafting. (clinicaltrials.gov: NCT01212315). PMID- 26432554 TI - Multifunctional theranostic contrast agent for photoacoustics- and ultrasound based tumor diagnosis and ultrasound-stimulated local tumor therapy. AB - Biomedical imaging-guided cancer therapy should have capabilities of both accurate tumor diagnosis and high therapeutic efficacy for the personalized treatment. Various biomedical imaging-guided cancer therapies are currently being investigated to overcome current limitations that include low sensitivity of diagnosis and poor drug delivery to the tumor site. Here, we report the development of a multifunctional theranostic contrast agent demonstrating high sensitive photoacoustic and ultrasound imaging and effective local delivery of anticancer drug to a tumor site. A microbubble (porphyrin-MB) was developed using phospholipid-porphyrin conjugates to enhance ultrasound and photoacoustic signal intensities simultaneously. Paclitaxel-loaded human serum albumin nanoparticles (PTX-HSA-NPs) were then conjugated onto the surface of the microbubble. The developed PTX-HSA-NPs conjugated porphyrin-MB (porphyrin-MB-NPs) provided sensitive, dual modal images of a tumor at 700 nm optimal laser wavelength for photoacoustic imaging and 5-14 MHz operating frequency for the ultrasound imaging. In addition, porphyrin-MB-NPs efficiently suppressed tumor growth by ultrasound exposure. Exposure to the focused ultrasound triggered the collapse of porphyrin-MB-NPs, resulting in the local release of PTX-HSA-NPs and enhanced penetration into the tumor site. The increased preferential accumulation and penetration of PTX-HSA-NPs suppressed tumor growth 10-fold more than without exposure to ultrasound. In conclusion, the developed porphyrin-MB-NPs establish a new paradigm in simultaneous bi-functional ultrasound/photoacoustic imaging diagnosis and locally triggered release of nanomedicine and enhanced chemotherapy efficiency. PMID- 26432555 TI - Nanoparticulate immunotherapy for cancer. AB - Although surgery, radiation therapy, and chemotherapy have significantly improved as treatments for cancer, they can rarely control metastatic disease and cures remain scarce. Promising recent developments suggest that cancer immunotherapy may become a powerful new therapy that clinicians can offer cancer patients. The opportunity to orchestrate the body's own immune system to target, fight, and eradicate cancer cells without destroying healthy cells makes this an extremely attractive treatment modality. Our increased knowledge in anti-tumor immunity and the immunosuppressive tumor microenvironment (TME) has provided many therapeutic strategies to battle cancer. That combined with advancements in the field of particulate delivery systems provide a mechanism to deliver these immunotherapeutics to their specific targeted cells and the TME. In this review we will focus on the current status of immunotherapy and the potential advantages of utilizing nanocarriers within the field. PMID- 26432557 TI - The respiratory chain provides salt stress tolerance by maintaining a low NADH/NAD+ ratio in Zymomonas mobilis. AB - The respiratory chain of ethanol-producing Zymomonas mobilis shows an unusual physiological property in that it is not involved in energy conservation, even though this organism has a complete electron transport system. We reported previously that respiratory-deficient mutants (RDMs) of Z. mobilis exhibit higher growth rates and enhanced ethanol productivity under aerobic and high-temperature conditions. Here, we demonstrated that the salt tolerance of RDM strains was drastically decreased compared with the wild-type strain. We found that the NADH/NAD+ ratio was maintained at low levels in both the wild-type and the RDM strains under non-stress conditions. However, the ratio substantially increased in the RDM strains in response to salt stress. Complementation of the deficient respiratory-chain genes in the RDM strains resulted in a decrease in the NADH/NAD+ ratio and an increase in the growth rate. In contrast, expression of malate dehydrogenase, activity of which increases the supply of NADH, in the RDM strains led to an increased NADH/NAD+ ratio and resulted in poor growth. Taken together, these results suggest that the respiratory chain of Z. mobilis functions to maintain a low NADH/NAD+ ratio when the cells are exposed to environmental stresses, such as salinity. PMID- 26432556 TI - The Prevention of Hospital Readmissions in Heart Failure. AB - Heart failure (HF) is a growing healthcare burden and one of the leading causes of hospitalizations and readmission. Preventing readmissions for HF patients is an increasing priority for clinicians, researchers, and various stakeholders. The following review will discuss the interventions found to reduce readmissions for patients and improve hospital performance on the 30-day readmission process measure. While evidence-based therapies for HF management have proliferated, the consistent implementation of these therapies and development of new strategies to more effectively prevent readmissions remain areas for continued improvement. PMID- 26432558 TI - Serum-free process development: improving the yield and consistency of human mesenchymal stromal cell production. AB - BACKGROUND AIMS: The cost-effective production of human mesenchymal stromal cells (hMSCs) for off-the-shelf and patient specific therapies will require an increasing focus on improving product yield and driving manufacturing consistency. METHODS: Bone marrow-derived hMSCs (BM-hMSCs) from two donors were expanded for 36 days in monolayer with medium supplemented with either fetal bovine serum (FBS) or PRIME-XV serum-free medium (SFM). Cells were assessed throughout culture for proliferation, mean cell diameter, colony-forming potential, osteogenic potential, gene expression and metabolites. RESULTS: Expansion of BM-hMSCs in PRIME-XV SFM resulted in a significantly higher growth rate (P < 0.001) and increased consistency between donors compared with FBS-based culture. FBS-based culture showed an inter-batch production range of 0.9 and 5 days per dose compared with 0.5 and 0.6 days in SFM for each BM-hMSC donor line. The consistency between donors was also improved by the use of PRIME-XV SFM, with a production range of 0.9 days compared with 19.4 days in FBS-based culture. Mean cell diameter has also been demonstrated as a process metric for BM-hMSC growth rate and senescence through a correlation (R(2) = 0.8705) across all conditions. PRIME-XV SFM has also shown increased consistency in BM-hMSC characteristics such as per cell metabolite utilization, in vitro colony-forming potential and osteogenic potential despite the higher number of population doublings. CONCLUSIONS: We have increased the yield and consistency of BM-hMSC expansion between donors, demonstrating a level of control over the product, which has the potential to increase the cost-effectiveness and reduce the risk in these manufacturing processes. PMID- 26432559 TI - Interferon-gamma and tumor necrosis factor-alpha promote the ability of human placenta-derived mesenchymal stromal cells to express programmed death ligand-2 and induce the differentiation of CD4(+)interleukin-10(+) and CD8(+)interleukin 10(+)Treg subsets. AB - BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) and regulatory T cells (Treg) have been successfully used in treating autoimmune diseases accompanied by abundant inflammatory cytokines such as interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha. Therefore, this work investigated the effects of IFN-gamma and TNF-alpha on the ability of human placenta-derived mesenchymal stromal cells (hPMSCs) on inducing the differentiation of CD4(+)interleukin (IL)-10(+)and CD8(+)IL-10(+)Treg subsets. METHODS: Human PMSCs were co-cultured with T cells in the presence or absence of a trans-well system or anti- programmed death ligand-2 (PDL2) monoclonal antibody (mAb), respectively. CD4(+)IL-10(+)and CD8(+)IL 10(+)Treg subsets, as well as the levels of IL-10 in the supernatants, were detected on this basis. Examinations were conducted to explore the impact of IFN gamma and TNF-alpha on the expression of PDL2 in hPMSCs. In this process, flow cytometry, Western blot and reverse-transcriptase-polymerase chain reaction were used. RESULTS: CD4(+)IL-10(+)and CD8(+)IL-10(+)Treg subsets from T cells either non-activated or activated by use of phytohaemagglutinin (PHA) or CD3/CD28mAb significantly increased in the presence of hPMSCs. However, these levels markedly decreased after blocking the expression of PDL2 in hPMSCs. IL-10 followed the same pattern. Furthermore, the percentages of CD4(+)IL-10(+) and CD8(+)IL-10(+)T cells also sharply declined under the trans-well system, whereas the percentages as well as the expression of PDL2 in hPMSCs oppositely raised after hPMSCs pre stimulated by IFN-gamma and TNF-alpha. IFN-gamma could promote the expression of PDL2 partly through the JAK/STAT signaling pathway. CONCLUSIONS: IFN-gamma and TNF-alpha could promote the ability of hPMSCs in inducing the differentiation of CD4(+)IL-10(+)and CD8(+)IL-10(+)Treg subsets and enhance the expression of PDL2 in hPMSCs. These would benefit the application of hPMSCs in clinical trials. PMID- 26432560 TI - A novel method to expand large numbers of CD56(+) natural killer cells from a minute fraction of selectively accessed cryopreserved cord blood for immunotherapy after transplantation. AB - BACKGROUND AIMS: Umbilical cord blood transplantation (UCBT) is increasingly used to treat acute leukemias. UCB units are thawed and infused in their entirety at transplant, precluding later use as immunotherapy to prevent or treat leukemia relapse. METHODS: We developed a device that selectively thaws only 1 mL of the UCB unit, leaving the remaining UCB unit cryopreserved for subsequent transplantation. We also show that large numbers of CD56(+) natural killer (NK) cells can be expanded from these 1-mL fractions of selectively accessed UCB. Immunomagnetic depletion of CD3(+) cells of the 1-mL fraction was performed, and the cells were subsequently stimulated with irradiated Epstein-Barr virus transformed lymphoblastoid cell lines (EBV-LCLs) and set to culture in media containing interleukin (IL)-2. RESULTS: When a 1:20 ratio of total nucleated cells to EBV-LCL feeder cells was used, day-21 and day-35 NK cell cultures initiated from 1 mL of UCB contained a median of 430 * 10(6) (range: 44-4321 * 10(6)) and 6092 * 10(6) (range: 165-20947 * 10(6)) CD3(-)CD56(+) NK cells. These cells expressed high levels of CD161, LFA-1, CD69, NKG2D, NKp30, NKp44, NKp80 and NKp46. UCB-derived NK cells were highly cytotoxic against K562 leukemia cells, although cytotoxicity was slightly lower than in expanded PBMC-derived NK cells. CONCLUSIONS: We have developed and optimized a strategy to selectively access a small fraction from cryopreserved UCB and show that large numbers of CD56(+) cells can be expanded from this selectively accessed fraction. This strategy presents a method to explore whether early adoptive transfer of NK cells expanded from the same UCB unit used for transplantation can prevent leukemic relapse and decrease graft-versus-host disease after UCBT. PMID- 26432561 TI - Biodistribution of in vitro-derived microglia applied intranasally and intravenously to mice: effects of aging. AB - BACKGROUND AIMS: The age of both the donor and the recipient has a potential influence on the efficacy of various cell therapies, but the underlying mechanisms are still being charted. We studied the effect of donor and recipient age in the context of microglia migration. METHODS: Microglia were in vitro- differentiated from bone marrow of young (3 months) and aged (12 months) mice and transplanted into young (~ 3 months) and aged (~ 17 months) C57BL/6 mice (n = 25) through intravenous and intranasal application routes. Recipients were not immune suppressed or irradiated. Transplanted microglia were tracked through the use of a sex-mismatched setup or histologically with the use of cells from enhanced green fluorescent protein enhanced green fluorescent protein transgenic mice. RESULTS: No acute rejections or transplant-associated toxicity was observed. After 10 days, both intravenously and intranasally transplanted cells were detected in the brain. Transplanted cells were also found in the blood and the lymph system. The applied cells were also tracked in lungs and kidney but only after intravenous injection subjected to a "pulmonary first-pass effect." After 28 days, intravenously delivered cells were also found in the bone marrow and other organs, especially in aged recipients. Whereas in young recipients the transplanted microglia did not appear to persist, in aged brains the transplanted cells could still be identified up to 28 days after transplantation. However, when cells from aged donors were used, no signals of transplanted cells could be detected in the recipients. CONCLUSIONS: This study establishes proof of principle that in vitro--derived microglia from young but not from aged donors, intravenously or intranasally transplanted, migrate to the brain in young and aged recipients. PMID- 26432562 TI - A Case of Recurrent Ischemic Stroke Involving Subacute, Progressive Intracranial Cerebral Arterial Sclerosis Prior to Diagnosis with JAK2-mutated Polycythemia Vera. AB - CASE REPORT: A 58-year-old man presenting with no vascular risk factors visited our hospital with right hemiparesis and total aphasia. Diffusion-weighted magnetic resonance imaging of the brain showed multiple hyperintensities in watershed distributions in the left hemisphere. Magnetic resonance angiography (MRA) revealed stenosis of the middle cerebral artery, despite normal MRA findings 2 months prior. One year after the first stroke, the patient experienced a recurrent ischemic stroke involving the left anterior choroidal artery, pulmonary embolism, and deep venous thrombosis. After the recurrent stroke event, hemoglobin levels increased gradually. Two years after the first stroke, a JAK2V 617F mutation was detected. CONCLUSION: Our report suggests that progressive intracranial arterial sclerosis and venous thrombosis of undetermined etiologies could be several initial symptoms of polycythemia vera. PMID- 26432563 TI - Regional Gray Matter Atrophy in Vascular Mild Cognitive Impairment. AB - BACKGROUND: The aim of this study was to explore the neuroanatomical bases of vascular mild cognitive impairment (VaMCI) with respect to attention/executive function, memory, language, and visuospatial function. METHODS: We used voxel based morphometric analysis to identify brain regions that significantly differed in terms of gray matter volumes (GMVs) between 43 patients with VaMCI and 55 healthy controls. Then, we compared the individual GMVs of the selected regions with the neuropsychological profiles of the VaMCI patients. RESULTS: The delayed recall component of the Rey-Osterrieth Complex Figure Test (CFT) (74.4%), the Symbol Digit Modalities Test (74.4%), the Boston Naming Test (51.2%), and the CFT copy (81.4%) shared the highest incidence of impairment in the 4 cognitive domains, respectively. Compared with controls, patients with VaMCI exhibited significantly reduced GMVs. This effect was mainly present in the frontal regions, including the bilateral dorsolateral prefrontal cortex (DLPFC), the orbital portion of the superior frontal gyrus (SFG), and the left supplemental motor area, and was also observed in the bilateral posterior cingulated cortex (PCC). GMVs were significantly correlated with performance in the Trail Making Test, part B, in the bilateral DLPFC and PCC, the clock drawing test in the right orbital portion of the SFG, and CFT-delayed recall in the right PCC. CONCLUSIONS: These results, from the perspective of brain morphology, uniquely explored the specific cerebral structural changes of VaMCI, thus providing a deeper understanding of the pathophysiology of the disease. PMID- 26432564 TI - Actinoplanes rhizophilus sp. nov., an actinomycete isolated from the rhizosphere of Sansevieria trifasciata Prain. AB - A novel actinomycete, designated strain NEAU-A-2T, was isolated from the rhizosphere soil of Sansevieria trifasciata Prain collected from Heilongjiang province, north-east China. The taxonomic status of this organism was established using a polyphasic approach. The isolate formed irregular sporangia containing motile spores on the substrate mycelium. The whole-cell sugars were xylose and galactose. The predominant menaquinones were MK-9(H10), MK-9(H2), MK-10(H2) and MK-10(H4). The major fatty acids were iso-C15 : 0, iso-C16 : 0 and anteiso-C15 : 0. The polar lipids were diphosphatidylglycerol, phosphatidylmonomethylethanolamine, phosphatidylethanolamine, phosphatidylinositol, three unidentified phospholipids and an unidentified glycolipid. 16S rRNA gene sequence similarity studies showed that strain NEAU-A 2T belongs to the genus Actinoplanes with the highest sequence similarities to Actinoplanes globisporus NBRC 13912T (97.7 % 16S rRNA gene sequence similarity), Actinoplanes ferrugineus IMSNU 22125T (97.5 %), Actinoplanes toevensis MN07 A0368T (97.2 %) and Actinoplanes rishiriensis NBRC 108556T (97.2 %); similarities to type strains of other species of this genus were < 97 %. Two tree-making algorithms showed that strain NEAU-A-2T formed a distinct clade with A. globisporus NBRC 13912T and A. rishiriensis NBRC 108556T. However, low DNA-DNA relatedness values allowed the isolate to be differentiated from the above mentioned two species of the genus Actinoplanes. Moreover, strain NEAU-A-2T could also be distinguished from the most closely related species by morphological and physiological characteristics. Therefore, in conclusion, isolate NEAU-A-2T represents a novel species of the genus Actinoplanes, for which the name Actinoplanes rhizophilus sp. nov. is proposed. The type strain is NEAU-A-2T ( = CGMCC 4.7133T = DSM 46672T). PMID- 26432565 TI - Trifocal Intraocular Lens Implantation to Treat Visual Demands in Various Distances Following Lens Removal. AB - PURPOSE: To evaluate visual and refractive outcomes after implantation of a trifocal intraocular lens (IOL). DESIGN: Prospective, nonrandomized noncomparative case series. METHODS: setting: Department of Ophthalmology, Goethe University, Frankfurt/Germany. patient or study population: Twenty-seven patients (54 eyes) who had bilateral implantation of the AT LISA trifocal IOL (AT LISA tri839MP; Carl Zeiss Meditec, Jena, Germany) pre-enrollment. Exclusion criteria were previous ocular surgeries excluding cataract surgery and refractive lens exchange, irregular corneal astigmatism of >1.5 diopter, and ocular pathologies or corneal abnormalities. Intervention or Observation Procedure(s): Postoperative examination at 1 and 3 months included manifest refraction; monocular and binocular uncorrected (UCVA) and distance-corrected (DCVA) visual acuity in 4 m, 80 cm, and 40 cm; slit-lamp examination; and tomography. At 3 months defocus testing, binocular contrast sensitivity (CS) under photopic and mesopic conditions, and a questionnaire on subjective quality of vision, optical phenomena, and spectacle independence were performed. MAIN OUTCOME MEASURE(S): Three-months-postoperative monocular and binocular UCVA and DCVA in 4 m, 80 cm, and 40 cm (logMAR); defocus curve; CS; and quality-of-vision questionnaire results. RESULTS: Mean spherical equivalent was 0.05 +/- 0.32 D 3 months postoperatively. Binocular UCVA at distance, intermediate, and near was -0.1 +/- 0.1 logMAR, 0.0 +/- 0.1 logMAR, and 0.0 +/- 0.1 logMAR, respectively. Despite some optical phenomena, 92% of patients would choose the same IOL again. CONCLUSION: Evaluation of a trifocal IOL showed good VA (0.1 logMAR or better) at far, intermediate, and near distance; high patient satisfaction despite some optical phenomena; and high spectacle independence 3 months postoperatively. PMID- 26432566 TI - How Big Data Informs Us About Cataract Surgery: The LXXII Edward Jackson Memorial Lecture. AB - PURPOSE: To characterize the role of Big Data in evaluating quality of care in ophthalmology, to highlight opportunities for studying quality improvement using data available in the American Academy of Ophthalmology Intelligent Research in Sight (IRIS) Registry, and to show how Big Data informs us about rare events such as endophthalmitis after cataract surgery. DESIGN: Review of published studies, analysis of public-use Medicare claims files from 2010 to 2013, and analysis of IRIS Registry from 2013 to 2014. METHODS: Statistical analysis of observational data. RESULTS: The overall rate of endophthalmitis after cataract surgery was 0.14% in 216 703 individuals in the Medicare database. In the IRIS Registry the endophthalmitis rate after cataract surgery was 0.08% among 511 182 individuals. Endophthalmitis rates tended to be higher in eyes with combined cataract surgery and anterior vitrectomy (P = .051), although only 0.08% of eyes had this combined procedure. Visual acuity (VA) in the IRIS Registry in eyes with and without postoperative endophthalmitis measured 1-7 days postoperatively were logMAR 0.58 (standard deviation [SD]: 0.84) (approximately Snellen acuity of 20/80) and logMAR 0.31 (SD: 0.34) (approximately Snellen acuity of 20/40), respectively. In 33 547 eyes with postoperative VA after cataract surgery, 18.3% had 1-month postoperative VA worse than 20/40. CONCLUSIONS: Big Data drawing on Medicare claims and IRIS Registry records can help identify additional areas for quality improvement, such as in the 18.3% of eyes in the IRIS Registry having 1-month postoperative VA worse than 20/40. The ability to track patient outcomes in Big Data sets provides opportunities for further research on rare complications such as postoperative endophthalmitis and outcomes from uncommon procedures such as cataract surgery combined with anterior vitrectomy. But privacy and data-security concerns associated with Big Data should not be taken lightly. PMID- 26432567 TI - Corneal Deformation Response and Ocular Geometry: A Noninvasive Diagnostic Strategy in Marfan Syndrome. AB - PURPOSE: To evaluate corneal air-puff deformation responses and ocular geometry as predictors of Marfan syndrome. DESIGN: Prospective observational clinical study. METHODS: Sixteen investigator-derived, 4 standard Ocular Response Analyzer (ORA), and geometric variables from corneal tomography and optical biometry using Oculus Pentacam and IOL Master were assessed for discriminative value in Marfan syndrome, measuring right eyes of 24 control and 13 Marfan syndrome subjects. Area under the receiver operating characteristic (AUROC) curve was assessed in univariate and multivariate analyses. RESULTS: Six investigator-derived ORA variables successfully discriminated Marfan syndrome. The best lone disease predictor was Concavity Min (Marfan syndrome 47.5 +/- 20, control 69 +/- 14, P = .003; AUROC = 0.80). Corneal hysteresis (CH) and corneal resistance factor (CRF) were decreased (Marfan syndrome CH 9.45 +/- 1.62, control CH 11.24 +/- 1.21, P = .01; Marfan syndrome CRF 9.77 +/- 1.65, control CRF 11.03 +/- 1.72, P = .01) and corneas were flatter in Marfan syndrome (Marfan syndrome Kmean 41.25 +/- 2.09 diopter, control Kmean 42.70 +/- 1.81 diopter, P = .046). No significant differences were observed in central corneal thickness, axial eye length, or intraocular pressure. A multivariate regression model incorporating corneal curvature and hysteresis loop area (HLA) provided the best predictive value for Marfan syndrome (AUROC = 0.85). CONCLUSIONS: This study describes novel biodynamic features of corneal deformation responses in Marfan syndrome, including increased deformation, decreased bending resistance, and decreased energy dissipation capacity. A predictive model incorporating HLA and corneal curvature shows greatest potential for noninvasive clinical diagnosis of Marfan syndrome. PMID- 26432568 TI - Effect of Serial Intrasilicone Oil Bevacizumab Injections in Eyes With Recurrent Proliferative Vitreoretinopathy Retinal Detachment. AB - PURPOSE: To investigate the effect of serial intrasilicone oil bevacizumab injections (1.25 mg/0.05 mL) on visual acuity (VA) and anatomic outcomes in eyes undergoing proliferative vitreoretinopathy (PVR)-related retinal detachment (RD) repair. DESIGN: Prospective, nonrandomized, historical-control pilot study. METHODS: setting: Tertiary care center. STUDY POPULATION: Nondiabetic eyes undergoing pars plana vitrectomy (PPV) and silicone oil tamponade with or without scleral buckling procedure (SBP) for recurrent RD due to PVR. INTERVENTION: Intrasilicone oil injection of 1.25 mg bevacizumab was performed intraoperatively and at postoperative months 1, 2, and 3. OUTCOMES: Retinal reattachment rate, final VA, and rate of epiretinal membrane (ERM) formation at month 6. RESULTS: Twenty eyes of 20 patients were enrolled and compared to a historical control group composed of 35 age- and sex-matched controls. In the study group, logMAR VA improved from mean 1.78 +/- 0.43 (Snellen 20/1205) to 1.43 +/- 0.70 (Snellen 20/538, P = .04), retinal reattachment was achieved in 14 of 20 eyes (70%), and ERM formation was observed in 7 of 20 eyes (35%) at 6 months. In the control group, logMAR VA improved from mean 1.50 +/- 0.74 (Snellen 20/632) to 1.43 +/- 0.58 (Snellen 20/538, P = .64), retinal reattachment was achieved in 25 of 35 eyes (71%), and ERM formation was observed in 7 of 35 eyes (20%) at 6 months. No significant difference in final VA (P = .96), retinal reattachment rate (P = .75), or ERM formation (P = .33) was observed between groups. No intrasilicone oil injection-related adverse events occurred. CONCLUSIONS: Serial intrasilicone oil injections of bevacizumab did not improve retinal reattachment rate, improve final VA, or reduce ERM formation in patients undergoing PVR-related RD surgery. PMID- 26432569 TI - Secretory IgA from submucosal glands does not compensate for its airway surface deficiency in chronic obstructive pulmonary disease. AB - Secretory immunoglobulin A (SIgA) reaches the airway lumen by local transcytosis across airway epithelial cells or with tracheobronchial submucosal gland secretions. In chronic obstructive pulmonary disease (COPD), deficiency of SIgA on the airway surface has been reported. However, reduction of SIgA levels in sputum and bronchoalveolar lavage (BAL) fluid has not been consistently observed. To explain this discrepancy, we analyzed BAL fluid and lung tissue from patients with COPD and control subjects. Immunohistochemical analysis of large and small airways of COPD patients showed that MUC5AC is the predominant mucin expressed by airway epithelial cells, whereas MUC5B is expressed in submucosal glands of large airways. Dual immunostaining with anti-IgA and anti-MUC5B antibodies showed reduction of IgA on the airway surface as well as accumulation of IgA within MUC5B-positive luminal mucus plugs, suggesting that luminal SIgA originates from submucosal glands in COPD patients. We found that the concentration of SIgA in BAL is inversely correlated with forced expiratory volume in 1 s (FEV1) in COPD, but that the ratio of SIgA/MUC5B is a better predictor of FEV1, particularly in patients with moderate COPD. Together, these findings suggest that SIgA production by submucosal glands, which are expanded in COPD, is insufficient to compensate for reduced SIgA transcytosis by airway epithelial cells. Localized SIgA deficiency on the surface of small airways is associated with COPD progression and represents a potential new therapeutic target in COPD. PMID- 26432570 TI - Epidemiological investigation of caries prevalence in first grade school children in Rhineland-Palatinate, Germany. AB - INTRODUCTION: The annual examination of first graders' oral health as stipulated by law aimed to reach every child in Rhineland-Palatinate (Germany) in their first year of school. We intended to evaluate the first graders' oral health based on the examination data for 2013/2014. METHODS: Instructed examiners measured the d3mft(deciduous)/D3MFT(permanent) index according to World Health Organization criteria in 25,020 predominantly 6-7 year-old first-grade school children. Only caries affecting dentin was diagnosed; no radiography or fiber transillumination was used. Out of the d3mft value, the "Significant Caries Index" (SiC) was calculated. This index identifies the dmft score of the third of the population with the highest caries experience. Descriptive analysis was performed. RESULTS: Out of the the examined children, 60.9% were caries free. Mean d3mft score was 1.28 +/- 2.27 while the mean SiC was 3.73 +/- 2.51. A distinctly higher d3mft was found in the decidous molars compared to the front teeth. Boys were significantly more caries-experienced than girls (p < 0.001). CONCLUSION: The results of this study confirm the lasting trend towards decreasing caries prevalence in children starting school found in previous cross sectional studies. This trend was observed in the high-risk group (obtained by SiC) as well as in the entire study population. Particular attention in caries prophylaxis should be paid to the primary molars. PMID- 26432571 TI - The Burden of Polypharmacy in Patients Near the End of Life. AB - CONTEXT: Patients with advanced illness are prescribed multiple medications in the last year of life, intensifying the risk of negative consequences related to polypharmacy. OBJECTIVES: To describe the medication burden of patients near the end of life and identify potential areas for improvement in clinician prescribing practices. METHODS: This was a prespecified secondary analysis of data from a prospective trial. Eligible participants were adults with less than 12 months estimated prognosis taking a statin medication for primary prevention of cardiovascular disease. Participants were enrolled from 15 sites, randomized to continue or discontinue statin medications, and followed for up to a year. Concomitant medications were recorded at least monthly from study enrollment through death. Prescribed medications were categorized by class and subclass. Descriptive statistics were calculated. RESULTS: On average, participants (n = 244) were 74.3 years old (SD 11.5) and lived 264 days (SD 128); 47.5% of the patients had a primary diagnosis of malignant tumor. This population was exposed to medications across 51 classes, 192 subclasses, and 423 individual medications. Patients took an average of 11.5 (SD 5) medications at the time of enrollment and 10.7 (SD 5) medications at death or study termination. The five most common classes of medications prescribed near the end of life were antihypertensives, broncholytics/bronchodilators, laxatives, antidepressants, and gastric protection agents. CONCLUSION: There is a significant medication burden placed on patients with advanced illness. Although most medications were prescribed for supportive care, we observed a high prevalence of medications for managing non-life threatening comorbidities. PMID- 26432572 TI - Rifampin (INN Rifampicin). AB - Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles (hq@palliativedrugs.com). PMID- 26432573 TI - Chronic Aerobic Exercise Decreases Lectin-Like Low Density Lipoprotein (LOX-1) Receptor Expression in Heart of Diabetic Rat. AB - BACKGROUND: Overexpression of lectin-like low density lipoprotein (LOX-1) receptor plays an important role in hyperglycemia-induced vascular complications such as atherosclerosis. Based on the beneficial effects of exercise on preventing cardiovascular complications of diabetes, we aimed to examine the protective effects of aerobic exercise on expression of LOX-1 receptor and production of free radicals in the heart of diabetic rats. METHODS: Four groups of rats were used: (n = 5 per group): sedentary normal, trained normal, sedentary diabetes and trained diabetes. Diabetes was induced by a single intraperitoneal injection of streptozotocin (50 mg/kg). The exercise protocol was consisted of swimming 30 min/day, 5 days/week for eight weeks. Plasma glucose was evaluated at initiation, weeks 4 and 8 of experiment. At the end of experiment, rats were sacrificed and the heart was removed for determination of nitrate, malondialdehyde, and LOX-1 gene expression. RESULTS: In normal non-diabetic rats, the blood glucose level was <150 mg/dl; however, the induction of diabetes resulted in levels more than >400 mg/dl. Gene expression of LOX-1 was increased in the heart of diabetic rats. Exercise reduced the gene expression of this protein in diabetic states without reducing the blood glucose. Finally, swimming exercise decreased the malondialdehyde and nitrate levels in heart tissue both in control and diabetic rats. CONCLUSION: Swimming exercise reduces heart expression of the LOX-1 receptor in accompany with reduction of free radicals production. Since these parameters are important in generation of diabetic complications, swimming exercise is a good candidate for reducing these complications. PMID- 26432574 TI - The impact of hypoxia on mesenchymal progenitor cells of human skeletal tissue in the pathogenesis of heterotopic ossification. AB - PURPOSE: Mesenchymal progenitor cells (MPCs) are capable of differentiating into osteo/chondrogenic cells to contribute substantially to heterotopic ossification (HO). This study aimed to examine the impact of hypoxia on MPCs in the aetiology of HO. METHODS: MPCs from human normal and HO skeletal tissue were cultivated under normoxia and hypoxia. Gene expression of factors which have a key role in HO aetiology (BMPs, COX-1 and COX-2, etc.) were examined by real-time PCR. Tissue of both groups was analysed by immunohistochemistry. RESULTS: Under hypoxia, COX 1, -2 and SOX-9 gene expression was elevated in HO MPCs, whereas in normal muscle tissue only COX-2 was upregulated. MPCs from HO had a significantly elevated gene expression of BMP-4 and decreased expression of BMP-1 and HIF-1 under hypoxia compared to normal MPCs. Immunohistochemistry detected no significant differences between normal and HO tissue. CONCLUSIONS: Hypoxia causes an enhanced gene expression of factors, which have a key role in HO pathophysiology. A better understanding of this entity will possibly allow reducing HO rates in orthopaedic and trauma surgery. PMID- 26432576 TI - Ectopic germinoma involving multiple midline and paramedian structures outside the pineal gland or hypophyseal region of the brain prior to tumor development. PMID- 26432575 TI - Biomechanical evaluation of different surgical techniques for treating patellar tendon ruptures. AB - PURPOSE: The aim of this study was to biomechanically assess patellar tendon repair techniques with additional cable wire or polydioxanone suture (PDS) cord augmentation in comparison with a suture-anchor repair technique. METHODS: Patellar tendon repair was performed in 60 specimens using a porcine bone model. Yield load, maximum load, stiffness and elongation of patellar tendon reconstructions with (1) cable wire augmentation, (2) PDS cord augmentation or (3) suture anchor repair were evaluated using a cyclic loading and load-to failure test setup. RESULTS: In comparison with suture anchor repair, augmentation of the reconstruction with either cable wires or PDS cords provides significantly higher maximum loads (527 and 460 N vs. 301 N; p < 0.01 and p = 0,012, respectively) under load-to-failure testing and less elongation (8.81 mm +/- 1.55 mm and 10.56 mm +/- 3.1 mm vs. 18.38 mm +/- 7.51 mm; p = 0.037 and p = 0.033, respectively) under cyclic loading conditions. CONCLUSION: Augmentation of a patellar tendon repair with either a cable wire or a PDS cord provides higher primary stability than suture anchor repair in patellar tendon ruptures. The study supports the use of additional augmentation of a tendon repair in the clinical setting in order to prevent loss of reduction and allow for early post operative mobilisation. PMID- 26432577 TI - Quantitative muscle ultrasound measures rapid declines over time in children with SMA type 1. AB - Muscles are small in spinal muscular atrophy (SMA). It is not known if muscle size changes over time in SMA type 1. We quantified changes over time in muscle size and echointensity during two repeated ultrasound examinations of unilateral proximal (biceps brachii/brachialis and quadriceps) and distal (anterior forearm flexors and tibialis anterior) muscles in three children with SMA type 1. We compared muscle thickness (MT) to body weight-dependent normal reference values. Children were 1, 6, and 11months old at baseline and had 2, 2 and 4 months between ultrasound examinations, respectively. At baseline, MT was normal for weight in all muscles except an atrophic quadriceps in the oldest child. MT decreased and echointensity increased (worsened) over time. At follow up, MT was below normal for weight in the quadriceps in all three children, in the biceps/brachioradialis in two, and in the anterior forearm in one. Tibialis anterior MT remained normal for weight in all three children. Muscle echointensity increased over time in all muscles and, on average, more than doubled in two children. In children with SMA type 1, muscle atrophies and becomes hyperechoic over time. Quantitative muscle ultrasound measures disease progression in SMA type 1 that warrants additional study in more children. PMID- 26432578 TI - Recurrent cerebral infarction synchronous with menorrhagia caused by endometrial stromal sarcoma. PMID- 26432579 TI - Petroleomics by Direct Analysis in Real Time-Mass Spectrometry. AB - The analysis of crude oil and its fractions by applying ambient ionization techniques remains underexplored in mass spectrometry (MS). Direct analysis in real time (DART) in the positive-ion mode was coupled to a linear quadrupole ion trap Orbitrap mass spectrometer (LTQ Orbitrap) to analyze crude oil, paraffin samples, and porphyrin standard compounds. The ionization parameters of DART-MS were optimized for crude oil analysis. DART-MS rendered the optimum conditions of the operation using paper as the substrate, T = 400 degrees C, helium as the carrier gas, and a sample concentration >=6 mg mL(-1). In the crude oils analysis, the DART(+)-Orbitrap mass spectra detected the typical N, NO, and O containing compounds. In the paraffin samples, oxidized hydrocarbon species (Ox classes, where x = 1-4) with double-bond equivalent of 1-4 were detected, and their structures and connectivity were confirmed by collision-induced dissociation (CID) experiments. DART(+)-MS has identified the porphyrin standard compounds as [M + H](+) ions of m/z 615.2502 and 680.1763, where M = C44H30N4 and C44H28N4OV, respectively, based on the formula assignment and by phenyl losses observed on CID experiments. PMID- 26432580 TI - Mechanistic Study on Electronic Excitation Dissociation of the Cellobiose-Na(+) Complex. AB - The recent development of electron activated dissociation (ExD) techniques has opened the door for high-throughput, detailed glycan structural elucidation. Among them, ExD methods employing higher-energy electrons offer several advantages over low-energy electron capture dissociation (ECD), owing to their applicability towards chromophore-labeled glycans and singly charged ions, and ability to provide more extensive structural information. However, a lack of understanding of these processes has hindered rational optimization of the experimental conditions for more efficient fragmentation as well as the development of informatics tools for interpretation of the complex glycan ExD spectra. Here, cellobiose-Na(+) was used as the model system to investigate the fragmentation behavior of metal-adducted glycans under irradiation of electrons with energy exceeding their ionization potential, and served as the basis on which a novel electronic excitation dissociation (EED) mechanism was proposed. It was found that ionization of the glycan produces a mixture of radical cations and ring-opened distonic ions. These distonic ions then capture a low-energy electron to produce diradicals with trivial singlet-triplet splitting, and subsequently undergo radical-induced dissociation to produce a variety of fragment ions, the abundances of which are influenced by the stability of the distonic ions from which they originate. Graphical Abstract ?. PMID- 26432582 TI - Bipolar voltage amplitude: What does it really mean? PMID- 26432581 TI - Enhanced cardiac device management utilizing the random EGM: A neglected feature of remote monitoring. PMID- 26432583 TI - Elderly man with ICD shocks. PMID- 26432584 TI - Nadolol decreases the incidence and severity of ventricular arrhythmias during exercise stress testing compared with beta1-selective beta-blockers in patients with catecholaminergic polymorphic ventricular tachycardia. AB - BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inheritable cardiac disease predisposing to malignant ventricular arrhythmias. OBJECTIVE: We aimed to explore the incidence and severity of ventricular arrhythmias in patients with CPVT before the initiation of beta-blocker treatment, when treated with beta1-selective beta-blockers, and when treated with nadolol. METHODS: In this study, 34 patients with CPVT were included (mean age 34 +/- 19 years; 15 (44%) women; 30 (88%) ryanodine receptor 2 variant positive). We performed 3 bicycle exercise stress tests in each patient: (1) before the initiation of beta-blocker treatment, (2) after >6 weeks of treatment with beta1 selective beta-blockers and (3) after >6 weeks of treatment with nadolol. We recorded resting and maximum heart rates and the most severe ventricular arrhythmia occurring. Severity of arrhythmias was scored as 1 point for no arrhythmias or only single ventricular extrasystoles, 2 points for >10 ventricular extrasystoles per minute or bigeminy, 3 points for couplets, and 4 points for nonsustained ventricular tachycardia or sustained ventricular tachycardia. RESULTS: Resting heart rate was similar during treatment with nadolol and beta1-selective beta-blockers (54 +/- 10 beats/min vs 56 +/- 14 beats/min; P = .50), while maximum heart rate was lower during treatment with nadolol compared with beta1-selective beta-blockers (122 +/- 21 beats/min vs 139 +/- 24 beats/min; P = .001). Arrhythmias during exercise stress testing were less severe during treatment with nadolol compared with during treatment with beta1 selective beta-blockers (arrhythmic score 1.6 +/- 0.9 vs 2.5 +/- 0.8; P < .001) and before the initiation of beta-blocker treatment (arrhythmic score 1.6 +/- 0.9 vs 2.7 +/- 0.9; P = .001); however, no differences were observed during treatment with beta1-selective beta-blockers compared with before the initiation of beta blocker treatment (arrhythmic score 2.5 +/- 0.8 vs 2.7 +/- 0.9; P = .46). CONCLUSION: The incidence and severity of ventricular arrhythmias decreased during treatment with nadolol compared with during treatment with beta1-selective beta-blockers. beta1-Selective beta-blockers did not change the occurrence or severity of arrhythmias compared with no medication. PMID- 26432585 TI - Right-to-left frequency gradient during atrial fibrillation initiated by right atrial ectopies and its augmentation by adenosine triphosphate: Implications of right atrial fibrillation. AB - BACKGROUND: A left-to-right dominant frequency (DF) gradient commonly exists in paroxysmal atrial fibrillation (AF). AF initiated by right atrial (RA) ectopy (AF RAE) is rare. OBJECTIVE: This study aimed to investigate characteristics of AF RAE using pharmacological maneuvers and spectral analysis. METHODS: Seventy-nine consecutive patients referred for catheter ablation of paroxysmal AF were enrolled. Infusions of isoproterenol and adenosine triphosphate (ATP) were used to induce AF. Patients with AF-RAE and patients with AF initiated only by pulmonary vein (PV) ectopies were classified into the RA-ectopy group (n = 7[9%]) and PV-ectopy group (n = 32[41%]), respectively. ATP was also injected during ongoing AF to unmask the driver of AF. High RA, coronary sinus, and PV-left atrial junction electrograms and electrocardiogram lead V1 underwent spectral analyses. RESULTS: Patients in the RA-ectopy group were younger (51 +/- 13 years vs 63 +/- 7 years; P = .01) and more commonly had a family history of AF (71% vs 9%; P < .001) than patients in the PV-ectopy group. There was a baseline right-to left DF gradient in the RA-ectopy group (PV-left atrial junction: 6.0 +/- 0.4 Hz; coronary sinus: 5.7 +/- 0.6 Hz; RA: 7.3 +/- 0.8 Hz; P < .05) in contrast to a left-to-right DF gradient in the PV-ectopy group (5.9 +/- 0.8, 5.3 +/- 0.7, 5.2 +/- 0.8 Hz; P < .01). ATP injection predominantly increased the DF of the high RA in the RA-ectopy group and augmented a right-to-left DF gradient (7.9 +/- 1.8, 7.6 +/- 1.0, 10.7 +/- 0.7 Hz; P < .001), whereas it augmented a left-to-right DF gradient in the PV-ectopy group (7.9 +/- 1.0, 6.4 +/- 0.5, 6.6 +/- 1.2 Hz; P < .05). CONCLUSION: A rare type of paroxysmal AF initiated by RA ectopy may be maintained by a reentrant driver localized in the RA (so-called RA fibrillation). PMID- 26432586 TI - From the desk of the Editor-in-Chief. PMID- 26432587 TI - Space radiation protection: Destination Mars. AB - National space agencies are planning a human mission to Mars in the XXI century. Space radiation is generally acknowledged as a potential showstopper for this mission for two reasons: a) high uncertainty on the risk of radiation-induced morbidity, and b) lack of simple countermeasures to reduce the exposure. The need for radiation exposure mitigation tools in a mission to Mars is supported by the recent measurements of the radiation field on the Mars Science Laboratory. Shielding is the simplest physical countermeasure, but the current materials provide poor reduction of the dose deposited by high-energy cosmic rays. Accelerator-based tests of new materials can be used to assess additional protection in the spacecraft. Active shielding is very promising, but as yet not applicable in practical cases. Several studies are developing technologies based on superconducting magnetic fields in space. Reducing the transit time to Mars is arguably the best solution but novel nuclear thermal-electric propulsion systems also seem to be far from practical realization. It is likely that the first mission to Mars will employ a combination of these options to reduce radiation exposure. PMID- 26432588 TI - Changes in miRNA expression profile of space-flown Caenorhabditis elegans during Shenzhou-8 mission. AB - Recent advances in the field of molecular biology have demonstrated that small non-coding microRNAs (miRNAs) have a broad effect on gene expression networks and play a key role in biological responses to environmental stressors. However, little is known about how space radiation exposure and altered gravity affect miRNA expression. The "International Space Biological Experiments" project was carried out in November 2011 by an international collaboration between China and Germany during the Shenzhou-8 (SZ-8) mission. To study the effects of spaceflight on Caenorhabditis elegans (C. elegans), we explored the expression profile miRNA changes in space-flown C. elegans. Dauer C. elegans larvae were taken by SZ-8 spacecraft and experienced the 16.5-day shuttle spaceflight. We performed miRNA microarray analysis, and the results showed that 23 miRNAs were altered in a complex space environment and different expression patterns were observed in the space synthetic and radiation environments. Most putative target genes of the altered miRNAs in the space synthetic environment were predicted to be involved in developmental processes instead of in the regulation of transcription, and the enrichment of these genes was due to space radiation. Furthermore, integration analysis of the miRNA and mRNA expression profiles confirmed that twelve genes were differently regulated by seven miRNAs. These genes may be involved in embryonic development, reproduction, transcription factor activity, oviposition in a space synthetic environment, positive regulation of growth and body morphogenesis in a space radiation environment. Specifically, we found that cel miR-52, -55, and -56 of the miR-51 family were sensitive to space environmental stressors and could regulate biological behavioural responses and neprilysin activity through the different isoforms of T01C4.1 and F18A12.8. These findings suggest that C. elegans responded to spaceflight by altering the expression of miRNAs and some target genes that function in diverse regulatory pathways. PMID- 26432589 TI - Differential effects of p53 on bystander phenotypes induced by gamma ray and high LET heavy ion radiation. AB - High LET particle irradiation has several potential advantages over gamma-rays such as p53-independent response. The purpose of this work is to disclose the effect of p53 on the bystander effect induced by different LET irradiations and underlying mechanism. Lymphocyte cells of TK6 (wild type p53) and HMy2.CIR (mutated p53) were exposed to either low or high LET irradiation, then their mitochondrial dysfunction and ROS generation were detected. The micronuclei (MN) induction in HL-7702 hepatocytes co-cultured with irradiated lymphocytes was also measured. It was found that the mitochondrial dysfunction, p66(Shc) activation, and intracellular ROS were enhanced in TK6 but not in HMy2.CIR cells after gamma ray irradiation, but all of them were increased in both cell lines after carbon and iron irradiation. Consistently, the bystander effect of MN formation in HL 7702 cells was only triggered by gamma-irradiated TK6 cells but not by gamma irradiated HMy2.CIR cells. But this bystander effect was induced by both lymphocyte cell lines after heavy ion irradiation. PFT-MU, an inhibitor of p53, only partly inhibited ROS generation and bystander effect induced by 30 keV/MUm carbon-irradiated TK6 cells but failed to suppress the bystander effect induced by the TK6 cells irradiated with either 70 keV/MUm carbon or 180 keV/MUm iron. The mitochondrial inhibitors of rotenone and oligomycin eliminated heavy ion induced ROS generation in TK6 and HMy2.CIR cells and hence diminished the bystander effect on HL-7702 cells. These results clearly demonstrate that the bystander effect is p53-dependent for low LET irradiation, but it is p53 independent for high LET irradiation which may be because of p53-independent ROS generation due to mitochondrial dysfunction. PMID- 26432590 TI - The evaluation of upper body muscle activity during the performance of external chest compressions in simulated hypogravity. AB - BACKGROUND: This original study evaluated the electromyograph (EMG) activity of four upper body muscles: triceps brachii, erector spinae, upper rectus abdominis, and pectoralis major, while external chest compressions (ECCs) were performed in simulated Martian hypogravity using a Body Suspension Device, counterweight system, and standard full body cardiopulmonary resuscitation (CPR) mannequin. METHOD: 20 young, healthy male subjects were recruited. One hundred compressions divided into four sets, with roughly six seconds between each set to indicate 'ventilation', were performed within approximately a 1.5 minute protocol. Chest compression rate, depth and number were measured along with the subject's heart rate (HR) and rating of perceived exertion (RPE). RESULTS: All mean values were used in two-tailed t-tests using SPSS to compare +1 Gz values (control) versus simulated hypogravity values. The AHA (2005) compression standards were maintained in hypogravity. RPE and HR increased by 32% (p<0.001) and 44% (p=0.002), respectively, when ECCs were performed during Mars simulation, in comparison to +1 Gz. In hypogravity, the triceps brachii showed significantly less activity (p<0.001) when compared with the other three muscles studied. The comparison of all the other muscles showed no difference at +1 Gz or in hypogravity. CONCLUSIONS: This study was among the first of its kind, however several limitations were faced which hopefully will not exist in future studies. Evaluation of a great number of muscles will allow space crews to focus on specific strengthening exercises within their current training regimes in case of a serious cardiac event in hypogravity. PMID- 26432591 TI - Inhibition of microRNA-31-5p protects human colonic epithelial cells against ionizing radiation. AB - MicroRNAs (miRNAs), endogenous non-coding small RNAs, are sensitive to environmental changes, and their differential expression is important for adaptation to the environment. However, application of miRNAs as a clinical prognostic or diagnostic tool remains unproven. In this study we demonstrate a chronic/persistent change of miRNAs from the plasma of a colorectal cancer susceptible mouse model (CPC;Apc) about 250 days after exposure to a simulated solar particle event (SPE). Differentially expressed miRNAs were identified compared to unirradiated control mice, including miR-31-5p, which we investigated further. To address the cellular function of miR-31-5p, we transfected a miR-31 5p mimic (sense) or inhibitor (antisense) into immortalized human colonic epithelial cells followed by gamma-irradiation. A miR-31-5p mimic sensitized but a miR-31-5p inhibitor protected colonic epithelial cells against radiation induced killing. We found that the miR-31-5p mimic inhibited the induction of hMLH1 expression after irradiation, whereas the miR-31-5p inhibitor increased the basal level of hMLH1 expression. The miR-31-5p inhibitor failed to modulate radiosensitivity in an hMLH1-deficient HCT116 colon cancer cell line but protected HCT116 3-6 and DLD-1 (both hMLH1-positive) colon cancer cell lines. Our findings demonstrate that miR-31-5p has an important role in radiation responses through regulation of hMLH1 expression. Targeting this pathway could be a promising therapeutic strategy for future personalized anti-cancer radiotherapy. PMID- 26432592 TI - Comparison of space flight and heavy ion radiation induced genomic/epigenomic mutations in rice (Oryza sativa). AB - Rice seeds, after space flight and low dose heavy ion radiation treatment were cultured on ground. Leaves of the mature plants were obtained for examination of genomic/epigenomic mutations by using amplified fragment length polymorphism (AFLP) and methylation sensitive amplification polymorphism (MSAP) method, respectively. The mutation sites were identified by fragment recovery and sequencing. The heritability of the mutations was detected in the next generation. Results showed that both space flight and low dose heavy ion radiation can induce significant alterations on rice genome and epigenome (P<0.05). For both genetic and epigenetic assays, while there was no significant difference in mutation rates and their ability to be inherited to the next generation, the site of mutations differed between the space flight and radiation treated groups. More than 50% of the mutation sites were shared by two radiation treated groups, radiated with different LET value and dose, while only about 20% of the mutation sites were shared by space flight group and radiation treated group. Moreover, in space flight group, we found that DNA methylation changes were more prone to occur on CNG sequence than CG sequence. Sequencing results proved that both space flight and heavy ion radiation induced mutations were widely spread on rice genome including coding region and repeated region. Our study described and compared the characters of space flight and low dose heavy ion radiation induced genomic/epigenomic mutations. Our data revealed the mechanisms of application of space environment for mutagenesis and crop breeding. Furthermore, this work implicated that the nature of mutations induced under space flight conditions may involve factors beyond ion radiation. PMID- 26432593 TI - Biological filter capable of simultaneous nitrification and denitrification for Aquatic Habitat in International Space Station. AB - The biological filter capable of simultaneous nitrification and denitrification was constructed for aquatic animal experiments in the International Space Station (ISS). The biological filter will be used to remove harmful ammonia excreted from aquatic animals in a closed water circulation system (Aquatic Habitat). The biological filter is a cylindrical tank packed with porous glass beads for nitrification and dual plastic bags for denitrification. The porous beads are supporting media for Nitrosomonas europaea and Nitrobacter winogradskyi. The N. europaea cells and N. winogradskyi cells on the porous beads, oxidize the excreted ammonia to nitrate via nitrite. On the other hand, the dual bag is composed of an outer non-woven fabric bag and an inner non-porous polyethylene film bag. The outer bag is supporting media for Paracoccus pantotrophus. The inner bag, in which 99.5% ethanol is packed, releases the ethanol slowly, since ethanol can permeate through the non-porous polyethylene film. The P. pantotrophus cells on the outer bag reduce the produced nitrate to nitrogen gas by using the released ethanol as an electron donor for denitrification. The biological filter constructed in this study consequently removed the ammonia without accumulating nitrate. Most of the excess ethanol was consumed and did not affect the nitrification activity of the N. europaea cells and N. winogradskyi cells severely. In accordance with the aquatic animal experiments in the ISS, small freshwater fish had been bred in the closed water circulation system equipped with the biological filter for 90 days. Ammonia concentration daily excreted from fish is assumed to be 1.7 mg-N/L in the recirculation water. Under such conditions, the harmful ammonia and nitrite concentrations were kept below 0.1 mg-N/L in the recirculation water. Nitrate and total organic carbon concentrations in the recirculation water were kept below 5 mg-N/L and 3 mg-C/L, respectively. All breeding fish were alive and ate the feed well. The results show that the nitrification and denitrification abilities of the biological filter sufficed to keep water quality for aquatic animal experiments in the ISS. This simple and effective system is certainly applicable to aquarium systems and aquaculture systems. PMID- 26432594 TI - Quality factors for space radiation: A new approach. AB - NASA has derived new models for radiological risk assessment based on epidemiological data and radiation biology including differences in Relative Biological Effectiveness for leukemia and solid tumors. Comprehensive approaches were used to develop new risk cross sections and the extension of these into recommendations for risk assessment during space missions. The methodology relies on published data generated and the extensive research initiative managed by the NASA Human Research Program (HRP) and reviewed by the National Academy of Sciences. This resulted in recommendations for revised specifications of quality factors, QNASA(Z,beta) in terms of track structure concepts that extend beyond LET alone. The new paradigm for quality factors placed demands on radiation monitoring procedures that are not satisfied by existing dosimetry systems or particle spectrometers that are practical for space exploration where mass, volume, band width and power consumption are highly constrained. We have proposed a new definition of quality factors that relaxes the requirements for identifying charge, Z, and velocity, beta, of the incident radiation while still preserving the functional form of the inherent risk functions. The departure from the exact description of QNASA(Z,beta) is that the revised values are new functions of LET for solid cancers and leukemia. We present the motivation and process for developing the revised quality factors. We describe results of extensive simulations using GCR distributions in free space as well as the resulting spectra of primary and secondary particles behind aluminum shields and penetration through water. In all cases the revised dose averaged quality factors agreed with those based on the values obtained using QNASA(Z,beta). This provides confidence that emerging technologies for space radiation dosimetry can provide real time measurements of dose and dose equivalent while satisfying constraints on size, mass, power and bandwidth. The revised quality factors are sufficiently generalized to be applicable to radiation protection practices beyond space exploration. PMID- 26432595 TI - Chlorpromazine transformation by exposure to ultraviolet laser beams in droplet and bulk. AB - Multiple drug resistance requires a flexible approach to find medicines able to overcome it. One method could be the exposure of existing medicines to ultraviolet laser beams to generate photoproducts that are efficient against bacteria and/or malignant tumors. This can be done in droplets or bulk volumes. In the present work are reported results about the interaction of 266nm and 355nm pulsed laser radiation with microdroplets and bulk containing solutions of 10mg/ml Chlorpromazine Hydrochloride (CPZ) in ultrapure water. The irradiation effects on CPZ solution at larger time intervals (more than 30min) are similar in terms of generated photoproducts if the two ultraviolet wavelengths are utilized. The understanding of the CPZ parent compound transformation may be better evidenced, as shown in this paper, if studies at shorter than 30minute exposure times are made coupled with properly chosen volumes to irradiate. We show that at exposure to a 355nm laser beam faster molecular modifications of CPZ in ultrapure water solution are produced than at irradiation with 266nm, for both microdroplet and bulk volume samples. These effects are evidenced by thin layer chromatography technique and laser induced fluorescence measurements. PMID- 26432596 TI - Histological features of oral epithelium in seven animal species: As a reference for selecting animal models. AB - Several animals have been used as models for basic and clinical research on oral mucosa. Few studies have focused on the selection of an appropriate animal model. This study aimed to provide histological references for selecting a potential model. Histological features were assessed by exploring 6 morphological characteristics and 2 immunohistochemical markers. The morphological characteristics included keratinization, basal membrane appearance, epithelial thickness, rete ridge length, adjacent rete ridge distance, and regional variation; the immunohistochemical markers included Ki67 (a proliferative marker) and Cytokeratin 19 (CK19; a stemness marker). The histological similarity of each species compared to humans was calculated according to the designated scoring criteria. The results showed that the buccal mucosae from dog and pig were non keratinized, with similar rete ridge length and distance, compared to that of humans. The dog, rat, and cavy mucosae had analogous gross appearances in the basal membrane. The dog oral mucosae shared similar epithelial thickness with human oral mucosae. Compared to the human mucosa, the dog, pig, rat, and rabbit mucosae exhibited corresponding regional variations. The Ki67-positive cells in human and canine mucosae were predominantly localized in the suprabasal layers, whereas most of the proliferative cells were in the basal layer in other species. CK19 immunoreactivities were detected only in human and canine mucosae. The canine mucosae gained the highest point value (14), whereas the scores for the pig, rat, rabbit, cavy, sheep, and buffalo mucosae were 8, 6, 5, 5, 5, and 2, respectively. The histological variations in the oral epithelium of diverse animal species are considerable; the mucosae from dogs are most similar to human mucosae, implicating its histological basis as an animal model. PMID- 26432599 TI - Characteristic sign of a colonic submucosal lesion. PMID- 26432597 TI - Targeting downstream transcription factors and epigenetic modifications following Toll-like receptor 7/8 ligation to forestall tissue injury in anti-Ro60 associated heart block. AB - Based on the consistent demonstration of fibrosis of the atrioventricular node surrounded by macrophages and multinucleated giant cells in anti-Ro antibody exposed fetuses dying with heart block, this study focuses on macrophage signaling stimulated by ssRNA associated with the Ro60 protein and the impact of antagonizing innate cell drivers such as TLR7/8. Transcriptome and epigenetic modifications which affect transcription factors, NF-kappaB and STAT1, were selected to evaluate the phenotype of macrophages in which TLR7/8 was ligated following treatment with either anti-Ro60/Ro60/hY3 RNA immune complexes or transfection with hY3. Based on microarray, TNF and IL6 were among the most highly upregulated genes in both stimulated conditions, each of which was significantly inhibited by preincubation with hydroxychloroquine (HCQ). In contrast, following stimulation of macrophages with either TNF-alpha or IFN alpha, which do not signal through TLR, the resultant gene expression was refractory to HCQ. Ligation of TLR7/8 resulted in increased histone methylation as measured by increased H3K4me2, a requirement for binding of NF-kappaB at certain promoters, specifically the kB1 region in the TNF promoter (ChIP-qPCR), which was significantly decreased by HCQ. In summary, these results support that the HCQ-sensitive phenotype of hY3 stimulated macrophages reflects the bifurcation of TLR downstream signals involving NF-kappaB and STAT 1 pathways and for the former dimethylation of H3K4. Accordingly, HCQ may act more as a preventive measure in downregulating the initial production of IFN-alpha or TNF alpha and not affect the resultant autocoid stimulation reflected in TNF-alpha and IFN-alpha responsive genes. The beneficial scope of antimalarials in the prevention of organ damage, inclusive of heart block in an anti-Ro offspring or more broadly SLE, may include in part, a mechanism targeting TLR-dependent epigenetic modification. PMID- 26432598 TI - Successful treatment of murine autoimmune cholangitis by parabiosis: Implications for hematopoietic therapy. AB - There is a significant unmet need in the treatment of primary biliary cirrhosis (PBC) despite significant data on the effector pathways that lead to biliary duct damage. We focused attention on a murine model of PBC, the dominant negative transforming growth factor beta receptor II (Tg) mice. To further define the pathways that lead to biliary pathology in these mice, we developed Tg mice deleted of CD4 cells (CD4(-/-)Tg). Interestingly, these mice developed more severe cholangitis than control Tg mice. These mice, which lack CD4 cells, manifested increased levels of IFN-gamma produced by effector CD8 cells. It appears that increased cholangitis is due to the absence of CD4 Treg cells. Based on these data, we parabiosed CD4(-/-)Tg mice with established disease at 8-9 weeks of age with C57BL/6 control mice. Such parabiotic "twins" had a significant reduction in autoimmune cholangitis, even though they had established pathology at the time of surgery. We prepared mixed bone marrow chimera mice constructed from CD4(-/-)Tg and CD8(-/-) mice and not only was cholangitis improved, but a decrease in terminally differentiated CD8(+) T effector cells in the presence of wild type CD4 cells was noted. In conclusion, "correcting" the CD4 T cell subset, even in the presence of pathogenic CD8 T cells, is effective in treating autoimmune cholangitis. PMID- 26432600 TI - MicroRNA expression and protein acetylation pattern in respiratory and limb muscles of Parp-1(-/-) and Parp-2(-/-) mice with lung cancer cachexia. AB - BACKGROUND: Current treatment options for cachexia, which impairs disease prognosis, are limited. Muscle-enriched microRNAs and protein acetylation are involved in muscle wasting including lung cancer (LC) cachexia. Poly(ADP-ribose) polymerases (PARP) are involved in muscle metabolism. We hypothesized that muscle enriched microRNA, protein hyperacetylation, and expression levels of myogenic transcription factors (MTFs) and downstream targets, muscle loss and function improve in LC cachectic Parp-1(-/-) and Parp-2(-/-) mice. METHODS: Body and muscle weights, grip strength, muscle phenotype, muscle-enriched microRNAs (miR 1, -133, -206, and -486), protein acetylation, acetylated levels of FoxO1, FoxO3, and PGC-1alpha, histone deacetylases (HDACs) including SIRT1, MTFs, and downstream targets (alpha-actin, PGC-1alpha, and creatine kinase) were evaluated in diaphragm and gastrocnemius of LC (LP07 adenocarcinoma) wild type (WT), Parp 1(-/-) and Parp-2-/- mice. RESULTS: Compared to WT cachectic animals, in both respiratory and limb muscles of Parp-1(-/-) and Parp-2(-/-) cachectic mice: downregulation of muscle-specific microRNAs was counterbalanced especially in gastrocnemius of Parp-1(-/-) mice; increased protein acetylation was attenuated (improvement in HDAC3, SIRT-1, and acetylated FoxO3 levels in both muscles, acetylated FoxO1 levels in the diaphragm); reduced MTFs and creatine kinase levels were mitigated; body and muscle weights, strength, and muscle fiber sizes improved, while tumor weight and growth decreased. CONCLUSIONS: These molecular findings may explain the improvements seen in body and muscle weights, limb muscle force and fiber sizes in both Parp-1(-/-) and Parp-2(-/-) cachectic mice. GENERAL SIGNIFICANCE: PARP-1 and -2 play a role in cancer-induced cachexia, thus selective pharmacological inhibition of PARP-1 and -2 may be of interest in clinical settings. PMID- 26432601 TI - Production of 4-hydroxybutyrate from succinate semialdehyde in butyrate biosynthesis in Porphyromonas gingivalis. AB - BACKGROUND: Despite evidence demonstrating the importance of butyrate-producing bacteria in host health and disease, the characterization of enzymes responsible for butyrate production has not been fully elucidated in the periodontopathogen, Porphyromonas gingivalis. METHODS: LC-MS/MS and colorimetric analyses were employed to enzymatically characterize recombinant PGN_0724 in P. gingivalis as a succinate semialdehyde reductase. The concentration of short chain fatty acids in the culture supernatant of the wild-type bacteria and a mutant strain lacking the PGN_0724 gene were quantified using GC-MS. RESULTS: Incubation of recombinant PGN_0724 with succinate semialdehyde and NADH resulted in the production of 4 hydroxybutyrate as well as consumption of succinate semialdehyde. Double reciprocal plots showed that the reaction catalyzed by the PGN_0724 protein was associated with a ternary complex mechanism. The growth speed and final turbidity of the mutant strain were much lower than those of the wild-type cells. The capacity of the mutant strain to produce butyrate, isobutyrate, and isovalerate was 30%, 15%, and 45%, respectively, of that of the wild-type strain, while the mutant strain produced approximately 3.9-fold more propionate than the wild type. CONCLUSIONS: The pathway responsible for butyrate production is important for the growth of P. gingivalis and appears to be associated with production of the other short chain fatty acids. GENERAL SIGNIFICANCE: The aim of this study was to delineate the mechanisms involved in the production of 4-hydroxybutyrate, which is an intermediate in the biosynthetic pathway for production of butyrate, which is a virulence factor in P. gingivalis. PMID- 26432602 TI - Microbial diversity and dynamics throughout manufacturing and ripening of surface ripened semi-hard Danish Danbo cheeses investigated by culture-independent techniques. AB - Microbial successions on the surface and in the interior of surface ripened semi hard Danish Danbo cheeses were investigated by culture-dependent and -independent techniques. Culture-independent detection of microorganisms was obtained by denaturing gradient gel electrophoresis (DGGE) and pyrosequencing, using amplicons of 16S and 26S rRNA genes for prokaryotes and eukaryotes, respectively. With minor exceptions, the results from the culture-independent analyses correlated to the culture-dependent plating results. Even though the predominant microorganisms detected with the two culture-independent techniques correlated, a higher number of genera were detected by pyrosequencing compared to DGGE. Additionally, minor parts of the microbiota, i.e. comprising <10.0% of the operational taxonomic units (OTUs), were detected by pyrosequencing, resulting in more detailed information on the microbial succession. As expected, microbial profiles of the surface and the interior of the cheeses diverged. During cheese production pyrosequencing determined Lactococcus as the dominating genus on cheese surfaces, representing on average 94.7%+/-2.1% of the OTUs. At day 6 Lactococcus spp. declined to 10.0% of the OTUs, whereas Staphylococcus spp. went from 0.0% during cheese production to 75.5% of the OTUs at smearing. During ripening, i.e. from 4 to 18 weeks, Corynebacterium was the dominant genus on the cheese surface (55.1%+/-9.8% of the OTUs), with Staphylococcus (17.9%+/-11.2% of the OTUs) and Brevibacterium (10.4%+/-8.3% of the OTUs) being the second and third most abundant genera. Other detected bacterial genera included Clostridiisalibacter (5.0%+/-4.0% of the OTUs), as well as Pseudoclavibacter, Alkalibacterium and Marinilactibacillus, which represented <2% of the OTUs. At smearing, yeast counts were low with Debaryomyces being the dominant genus accounting for 46.5% of the OTUs. During ripening the yeast counts increased significantly with Debaryomyces being the predominant genus, on average accounting for 96.7%+/-4.1% of the OTUs. The interior of the cheeses was dominated by Lactococcus spp. comprising on average 93.9%+/-7.8% of the OTUs throughout the cheese processing. The microbial dynamics described at genus level in this study add to a comprehensive understanding of the complex microbiota existing especially on surface ripened semi-hard cheeses. PMID- 26432603 TI - Design, synthesis and structure-activity relationship of novel diphenylamine derivatives. AB - Diphenylamine derivatives have been reported with good fungicidal, insecticidal, acaricidal, rodenticidal and/or herbicidal activities. To find new lead compound of this kind, a series of novel diphenylamine derivatives were designed and synthesized by the approach of Intermediate Derivatization Methods. All compounds were identified by (1)H NMR and elemental analysis. Bioassays demonstrated that some compounds substituted at 2,4,6-positions or 2,4,5-positions of phenyl ring B exhibited excellent fungicidal activities. The optimal compounds P30 and P33 showed 80% and 85% control respectively against cucumber downy mildew at 12.5mgL( 1), both 100% control against rice blast at 0.3mgL(-1) and both 100% control against cucumber gray mold at 0.9mgL(-1). The relationship between structure and fungicidal activities was discussed as well. PMID- 26432604 TI - Evaluation of small molecule SecA inhibitors against methicillin-resistant Staphylococcus aureus. AB - Due to the emergence and rapid spread of drug resistance in bacteria, there is an urgent need for the development of novel antimicrobials. SecA, a key component of the general bacterial secretion system required for viability and virulence, is an attractive antimicrobial target. Earlier we reported that systematical dissection of a SecA inhibitor, Rose Bengal (RB), led to the development of novel small molecule SecA inhibitors active against Escherichia coli and Bacillus subtilis. In this study, two potent RB analogs were further evaluated for activities against methicillin-resistant Staphylococcus aureus (MRSA) strains and for their mechanism of actions. These analogs showed inhibition on the ATPase activities of S. aureus SecA1 (SaSecA1) and SecA2 (SaSecA2), and inhibition of SaSecA1-dependent protein-conducting channel. Moreover, these inhibitors reduce the secretion of three toxins from S. aureus and exert potent bacteriostatic effects against three MRSA strains. Our best inhibitor SCA-50 showed potent concentration-dependent bactericidal activity against MRSA Mu50 strain and very importantly, 2-60 fold more potent inhibitory effect on MRSA Mu50 than all the commonly used antibiotics including vancomycin, which is considered the last resort option in treating MRSA-related infections. Protein pull down experiments further confirmed SaSecA1 as a target. Deletion or overexpression of NorA and MepA efflux pumps had minimal effect on the antimicrobial activities against S. aureus, indicating that the effects of SecA inhibitors were not affected by the presence of these efflux pumps. Our studies show that these small molecule analogs target SecA functions, have potent antimicrobial activities, reduce the secretion of toxins, and have the ability to overcome the effect efflux pumps, which are responsible for multi-drug resistance. Thus, targeting SecA is an attractive antimicrobial strategy against MRSA. PMID- 26432605 TI - 5-Lipoxygenase inhibitors suppress RANKL-induced osteoclast formation via NFATc1 expression. AB - 5-Lipoxygenase synthesizes leukotrienes from arachidonic acid. We developed three novel 5-LO inhibitors having a benzoxazole scaffold as a potential anti osteoclastogenics. They significantly suppressed RANKL-induced osteoclast formation in mouse bone marrow-derived macrophages. Furthermore, one compound, K7, inhibited the bone resorptive activity of osteoclasts. The anti osteoclastogenic effect of K7 was mainly attributable to reduction in the expression of NFATc1, an essential transcription factor for osteoclast differentiation. K7 inhibited osteoclast formation via ERK and p38 MAPK, as well as NF-kappaB signaling pathways. K7 reduced lipopolysaccharide (LPS)-induced osteoclast formation in vivo, corroborating the in vitro data. Thus, K7 exerted an inhibitory effect on osteoclast formation in vitro and in vivo, properties that make it a potential candidate for the treatment of bone diseases associated with excessive bone resorption. PMID- 26432606 TI - Design, synthesis and insecticidal evaluation of aryloxy dihalopropene derivatives. AB - Plutella xylostella (P. xylostella) is a highly migratory, cosmopolitan species and one of the most important pest of cruciferous crops worldwide. Pyridalyl as a novel class of insecticides has good efficacy against P. xylostella. On the basis of the commercial insecticide pyridalyl, a series of new aryloxy dihalopropene derivatives were designed and synthesized by using Intermediate Derivatization Methods. Their chemical structures were confirmed by (1)H NMR, high-resolution mass spectrum (HRMS), and single-crystal X-ray diffraction analysis. The insecticidal activities of the new compounds against P. xylostella were evaluated. The results of bioassays indicated that most of the compounds showed moderate to high activities at the tested concentration, especially compounds 10e and 10g displayed more than 75% insecticidal activity against P. xylostella at 6.25mg/L, while pyridalyl showed 50% insecticidal activity at the same concentration. The field trials result of the insecticidal activities showed that compound 10e as a 10% emulsifiable concentrate (EC) was effective in the control of P. xylostella at 75-150g a.i./ha, and the mortality of P. xylostella for treatment with compound 10e at 75g a.i./ha was equivalent to pyridalyl at 105g a.i./ha. PMID- 26432607 TI - Click-tailed coumarins with potent and selective inhibitory action against the tumor-associated carbonic anhydrases IX and XII. AB - Coumarins behave as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) with a mechanism of inhibition distinct from other classes of inhibitors. A series of 7-substituted coumarins incorporating aryl-triazole moieties were prepared by click chemistry procedures starting from 7 hydroxycoumarin or 4-methyl-7-aminocoumarin. The panel of new compounds was assayed for the inhibition of the cytosolic, widespread human (h) isoforms hCA I and II, and the transmembrane, tumor-associated ones hCA IX and XII. Most of the coumarins were weak inhibitors or did not inhibit significantly hCA I and II, but showed low nanomolar inhibitory action against the transmembrane isoforms (K(I) of 14.3-34.4 nM against hCA IX and of 4.7-37.8 nM against hCA XII). Since many hypoxic tumors overexpress hCA IX/XII, and as these targets were recently validated for obtaining antitumor/antimetastatic agents, with one inhibitor in Phase I clinical trials, the present findings constitute an interesting extension to the knowledge of non-sulfonamide, selective inhibitors of CA isoforms involved in serious pathologies. PMID- 26432608 TI - Development of novel dipeptide-like rhodesain inhibitors containing the 3 bromoisoxazoline warhead in a constrained conformation. AB - Novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation were developed; some of them possess K(i) values in the micromolar range. We studied the structure-activity relationship of these derivatives and we performed docking studies, which allowed us to find out the key interactions established by the inhibitors with the target enzyme. Biological results indicate that the nature of the P2 and P3 substituents and their binding to the S2/S3 pockets is strictly interdependent. PMID- 26432609 TI - Antimicrobial and cytotoxic activities of 1,2,3-triazole-sucrose derivatives. AB - A library of 1-(1',2,3,3',4,4',6-hepta-O-acetyl-6'-deoxy-sucros-6'-yl)-1,2,3 triazoles have been investigated for their antibacterial, antifungal and cytotoxic activities. Most of the target compounds showed good inhibitory activity against a variety of clinically and food contaminant important microbial pathogens. In particular, 1-(1',2,3,3',4,4',6-hepta-O-acetyl-6'-deoxy-sucros-6' yl)-4-(4-pentylphenyl)-1,2,3-triazole (5) was highly active against all the tested bacteria with minimal inhibitory concentrations (MICs) ranging between 1.1 and 4.4 uM and bactericidal concentrations (MBCs) from 2.2 and 8.4 uM. The compound 1-(1',2,3,3',4,4',6-hepta-O-acetyl-6'-deoxy-sucros-6'-yl)-4-(4 bromophenyl)-1,2,3-triazole (3) showed antifungal activity with MICs from 0.6 to 4.8 uM and minimal fungicidal concentrations (MFCs) ranging between 1.2 and 8.9 uM. Furthermore, some of the compounds possessed moderate cytotoxicity against human breast, lung, cervical and hepatocellular carcinoma cell lines, without showing toxicity for non-tumor liver cells. The above mentioned derivatives represent promising leads for the development of new generation of sugar-triazole antifungal agents. PMID- 26432610 TI - Ab initio studies on the structure of and atomic interactions in cellulose III(I) crystals. AB - The crystal structure of cellulose III(I)was analyzed using first-principles density functional theory (DFT). The geometry was optimized using variable-cell relaxation, as implemented in Quantum ESPRESSO. The Perdew-Burke-Ernzerhof (PBE) functional with a correction term for long-range van der Waals interactions (PBE D) reproduced the experimental structure well. By using the optimized crystal structure, the interactions existed among the cellulose chains in the crystal were precisely investigated using the NBO analysis. The results showed that the weak bonding nature of CH/O and the hydrogen bonding occur among glucose molecules in the optimized crystal structure. To investigate the strength of interaction, dimeric and trimeric glucose units were extracted from the crystal, and analyzed using MP2 ab initio counterpoise methods with BSSE correction. The results estimated the strength of the interactions. That is, the packed chains along with a-axis interacts with weak bonding nature of CH/O and dispersion interactions by -7.50 kcal/mol, and two hydrogen bonds of O2HO2...O6 and O6HO6...O2 connect the neighboring packed chains with -11.9 kcal/mol. Moreover, FMO4 calculation was also applied to the optimized crystal structure to estimate the strength of the interactions. These methods can well estimate the interactions existed in the crystal structure of cellulose III(I). PMID- 26432611 TI - Synthesis of glycosyl fluorides from (phenylthio)glycosides using IF5-pyridine HF. AB - IF5-pyridine-HF, an air- and moisture-stable fluorinating reagent, was applied to the synthesis of glycosyl fluorides from (phenylthio)glycosides. Common protecting groups of alcohol and diol can tolerate the reaction conditions performed, and therefore, the present method is applicable to the synthesis of various glycosyl fluorides. PMID- 26432612 TI - Structures of three different neutral polysaccharides of Acinetobacter baumannii, NIPH190, NIPH201, and NIPH615, assigned to K30, K45, and K48 capsule types, respectively, based on capsule biosynthesis gene clusters. AB - Neutral capsular polysaccharides (CPSs) were isolated from Acinetobacter baumannii NIPH190, NIPH201, and NIPH615. The CPSs were found to contain common monosaccharides only and to be branched with a side-chain 1->3-linked beta-d glucopyranose residue. Structures of the oligosaccharide repeat units (K units) of the CPSs were elucidated by 1D and 2D (1)H and (13)C NMR spectroscopy. Novel CPS biosynthesis gene clusters, designated KL30, KL45, and KL48, were found at the K locus in the genome sequences of NIPH190, NIPH201, and NIPH615, respectively. The genetic content of each gene cluster correlated with the structure of the CPS unit established, and therefore, the capsular types of the strains studied were designated as K30, K45, and K48, respectively. The initiating sugar of each K unit was predicted, and glycosyltransferases encoded by each gene cluster were assigned to the formation of the linkages between sugars in the corresponding K unit. PMID- 26432613 TI - Biochemical and Histological Effects of Thiamine Pyrophosphate against Acetaminophen-Induced Hepatotoxicity. AB - The aim of this study was to investigate whether thiamine pyrophosphate (TPP) has biochemical and histological preventive effects on oxidative liver damage induced by paracetamol (APAP). Rats were divided into the following groups: healthy control (HG), APAP (AG, 1500 mg/kg, orally), thiamine pyrophosphate (TPPG, 100 mg/kg, intraperitoneally), APAP+NAC (ANAC, 100 mg/kg, intraperitoneally), APAP+TPP (ATPG) and APAP+NAC+TPP (ANTG). Oxidant, antioxidant parameters, liver function tests and histological assessment were performed between groups. Malondialdehyde levels in the AG, HG, TPPG, ANAC, ATPG and ANTG groups were 0.470 +/- 0.210, 0.213 +/- 0.004, 0.194 +/- 0.001, 0.197 +/- 0.06, 0.199 +/- 0.008 and 0.173 +/- 0.010 MUmol/g protein, respectively. Total glutathione levels were 7.787 +/- 0.395, 14.925 +/- 0.932, 13.200 +/- 0.984, 13.162 +/- 0.486, 13.287 +/- 0.787 and 13.500 +/- 0.891 MUm/g protein, respectively. In the AG group, marked liver damage occurred with the elevation of liver function tests and oxidative stress markers, such as malondialdehyde, myeloperoxidase and nitric oxide (p < 0.05). Biochemical results were congruent with the histological changes of oxidative damage. Compared to the AG group (p < 0.05), TPP significantly reduced oxidant parameter levels in the ATPG group and simultaneously increased the antioxidant parameter levels of catalase and glutathione. The histological changes were improved to almost normal hepatic structure. Moreover, TPP had nearly the same hepatoprotective effect as NAC, and there was statistically no additional benefit with NAC co-treatment. There was no statistically significant difference (p > 0.05) among the ANAC, ANTG and ATPG groups in terms of oxidant/antioxidant levels. TPP proved to be as efficacious as standard therapy and may be beneficial in APAP-induced hepatotoxicity. PMID- 26432614 TI - Synthesis, in vitro evaluation and molecular docking studies of biscoumarin thiourea as a new inhibitor of alpha-glucosidases. AB - Biscoumarin analogs 1-18 have been synthesized, characterized by EI-MS and (1)H NMR and evaluated for alpha-glucosidase inhibitory potential. All compounds showed variety of alpha-glucosidase inhibitory potential ranging in between 13.5+/-0.39 and 104.62+/-0.3MUM when compared with standard acarbose having IC50 value 774.5+/-1.94MUM. The binding interactions of the most active analogs were confirmed through molecular docking. The compounds showed very good interactions with enzyme. All synthesized compounds 1-18 are new. Our synthesized compounds can further be studied to developed lead compounds. PMID- 26432615 TI - Synthesis, characterization, anti-inflammatory and anti-proliferative activity against MCF-7 cells of O-alkyl and O-acyl flavonoid derivatives. AB - A series of O-alkyl and O-acyl flavonoid derivatives was synthesized in high efficiency. Alkylation and acylation of 5-hydroxyflavonoids showed that the low reactivity hydroxyl group, 5-OH, well reacted with strong reagents whereas with weaker reagents, the different products were obtained dependently on structural characteristic of ring C of respective flavonoid. In order to evaluate anti inflammatory activity, all compounds were tested for in vitro inhibition of bovine serum albumin denaturation and in vivo inhibition of carrageenan-induced mouse paw edema. Among them, the compounds 3, 3b, 4b and 4c demonstrated more effective anti-inflammatory activity than standard drugs (diclofenac sodium and ketoprofen) in both tests. Meanwhile, the flavonoids 2, 2c, 3a and 4b displayed anti-proliferative activity against MCF-7 cell lines. Triacetyl derivative of hesperetin 4b inducing degradation of DNA in MCF-7 cells was observed. PMID- 26432616 TI - Research and development of bronchodilators for asthma and COPD with a focus on G protein/KCa channel linkage and beta2-adrenergic intrinsic efficacy. AB - Bronchodilators are used to improve symptoms and lung function in asthma and COPD. Airway smooth muscle tone is regulated by both muscarinic and beta2 adrenergic receptor activity. Large-conductance Ca(2+)-activated K(+) (KCa) channels are activated by beta2-adrenergic receptor agonists, via Gs, and suppressed by muscarinic receptor antagonists via Gi. This functional antagonism converges on the G protein/KCa channel linkages. Membrane potential regulated by KCa channels contributes to airway smooth muscle tension via Ca(2+) influx passing through voltage-dependent Ca(2+) (VDC) channels. The Gs/KCa/VDC channel linkage is a key process in not only physiological effects, but also in dysfunction of beta2-adrenergic receptors and airway remodeling. Moreover, this pathway is involved in the synergistic effects between beta2-adrenergic receptor agonists and muscarinic receptor antagonists. Intrinsic efficacy is also an important characteristic for both maintenance and loss of beta2-adrenergic action. Allosteric modulators of G protein-coupled receptors contribute not only to this synergistic effect between beta2-adrenergic and muscarinic M2 receptors, but also to intrinsic efficacy. The effects of weak partial agonists are suppressed by lowering receptor number, disordering receptor function, and enhancing functional antagonism; in contrast, those of full or strong partial agonists are not suppressed. Excessive exposure to full agonists causes beta2 adrenergic desensitization; in contrast, exposure to partial agonists does not cause desensitization. Intrinsic efficacy may provide the rationale for the clinical use of beta2-adrenergic receptor agonists in asthma and COPD. In conclusion, the G protein/KCa linkage and intrinsic efficacy (allosteric effects) may be therapeutic targets for research and development of novel agents against both airway obstruction and airway remodeling. PMID- 26432617 TI - Activation of endogenous antioxidants as a common therapeutic strategy against cancer, neurodegeneration and cardiovascular diseases: A lesson learnt from DJ-1. AB - This review aims at presenting a new concept pertaining to the development of antioxidants, namely, to evolve from disease-oriented therapy to mechanism oriented therapy. Using as our illustrative example is DJ-1, a homodimeric protein that is ubiquitously expressed in a variety of mammalian tissues, including the brain, and is found in the matrix and the intermembrane space of the mitochondria. DJ-1 is known to be an endogenous antioxidant against cancer, neurodegeneration and cardiovascular diseases, of which oxidative stress plays a causal role. Interestingly, the mechanistic targets of DJ-1 as an antioxidant, including Daxx, Nrf2, thioredoxin, glutathione, alpha-synuclein, PTEN/PI3K/Akt, and Pink/Parkin are also associated with those oxidative stress-related diseases. Furthermore, activators of DJ-1 are available in the form of mortalin, phenylbutyrate and NAD(P)H: quinone oxidoreductase 1. It follows that activation of DJ-1 as a common endogenous antioxidant provides a new strategy against cancer, neurodegeneration and cardiovascular diseases. Since clinical trials on exogenous application of the known antioxidants have basically failed, an alternative approach would logically be to activate the endogenous antioxidants that are already present in the appropriate cellular locale where elevated oxidative stress is the culprit for the disease. At the same time, since oxidative stress is a common denominator among cancer, neurodegeneration and cardiovascular diseases, development of antioxidant therapy should target the reduction in reactive oxygen species. Instead of focusing on disease-oriented therapy, pharmaceutical companies should concentrate on developing agents and dosing schemes for effective activation of the endogenous antioxidants that are associated with a multitude of oxidative stress-related diseases (mechanism oriented therapy). PMID- 26432618 TI - Enhancement of indocyanine green stability and cellular uptake by incorporating cationic lipid into indocyanine green-loaded nanoemulsions. AB - Indocyanine green (ICG) is a near-infrared optical dye approved by the Food and Drug Administration. ICG has been investigated as a simultaneous color and fluorescence-imaging tracer for the intraoperative identification of sentinel lymph nodes, but its use has recently expanded to include application as a photosensitizer for the local photodynamic/thermal treatment of identified lymph node metastases. The current study was designed to develop an ICG-loaded nanoemulsion as an effective agent for both the diagnosis and treatment of lymph node metastases. Incorporating the cationic lipid stearylamine (SA) together with ICG in the shell of nanoemulsions did not affect the loaded ICG concentration, but changed the surface charge of nanoemulsions from a negative to a positive value and improved the physical stability of nanoemulsions. Loading ICG into SA incorporated nanoemulsions more effectively blocked the aggregation and degradation of ICG compared to loading in SA-free nanoemulsions. SA incorporation also enhanced tumor cell uptake of ICG-loaded nanoemulsions, resulting in greater cell killing upon light irradiation. After subcutaneous injection into the footpad of mice, SA-incorporated nanoemulsions increased the concentration of ICG accumulated in popliteal lymph nodes to a greater extent than SA-free nanoemulsions without affecting the kinetics of lymph node uptake of nanoemulsions. These multiple beneficial effects of incorporating SA in nanoemulsions are likely attributable to the electrostatic interaction between anionic ICG and cationic SA, as well as the change in the nanoemulsion surface charge from negative to positive. Our findings indicate that SA-incorporated nanoemulsions are promising ICG carriers for combined diagnosis and treatment of lymph node metastases. PMID- 26432619 TI - Silica nanowire conjugated with loop-shaped oligonucleotides: A new structure to silence cysteine proteinase gene in Leishmania tropica. AB - The main aim of this study was to evaluate the capability of silica nanowire conjugated with loop-shaped oligonucleotides (SNWCLSOs) to silence cysteine proteinase b (Cpb) gene in Leishmania (L) tropica. On the other hand, its toxicity on amastigotes and mouse peritoneal macrophages was evaluated by 5 diphenyl-tetrazolium bromide (MTT) assay. For control, two loop-shaped oligonucleotides (LSO) were considered. LSO1 and LSO2 were 5'-NH2 cccccaaaaaaaaaaaaaaaaaaaaaaaaaggggg-COOH-3' and LSO2: 5'-NH2 cccccttttttttttttttttttttttttttttttttttttttggggg-COOH-3', respectively. After 72 h incubation at 37 degrees C, AMSNW, LSO1, and LSO2 had no remarkable toxicity on L. tropica amastigote (2 * 10(5)/mL) and mouse peritoneal macrophages (2 * 10(5)/mL). In case of SNWCLSOs, they had high toxicity on L. tropica amastigote, but they had no effect on mouse peritoneal macrophages. At concentrations of 1, 10, and 25 MUg/mL, AMSNW, LSO1 and LSO2 had no effect on the gene expression. But, at concentration of 50 and 100 MUg/mL, decrease of gene expression was observed. In case of SNWCLSOs, they could dramatically decrease the gene expression. It could be concluded that since SNWCLSOs could silence Cpb gene with no remarkable toxicity, they are good choice for treat cutaneous leishmaniasis in future. As a new agent, it must be checked in vivo. PMID- 26432620 TI - A novel infant milk formula concept: Mimicking the human milk fat globule structure. AB - Human milk (HM) provides all nutrients to support an optimal growth and development of the neonate. The composition and structure of HM lipids, the most important energy provider, have an impact on the digestion, uptake and metabolism of lipids. In HM, the lipids are present in the form of dispersed fat globules: large fat droplets enveloped by a phospholipid membrane. Currently, infant milk formula (Control IMF) contains small fat droplets primarily coated by proteins. Recently, a novel IMF concept (Concept IMF) was developed with a different lipid architecture, Nuturis((r)), comprising large fat droplets with a phospholipid coating. Confocal laser scanning microscopy (CLSM), with appropriate fluorescent probes, and transmission electron microscopy were used to determine and compare the interfacial composition and structure of HM fat globules, Concept IMF fat droplets and Control IMF fat droplets. The presence of a trilayer-structured HM fat globule membrane, composed of phospholipids, proteins, glycoproteins and cholesterol, was confirmed; in addition exosome-like vesicles are observed within cytoplasmic crescents. The Control IMF fat droplets had a thick protein-only interface. The Concept IMF fat droplets showed a very thin interface composed of a mixture of phospholipids, proteins and cholesterol. Furthermore, the Concept IMF contained fragments of milk fat globule membrane, which has been suggested to have potential biological functions in infants. By mimicking more closely the structure and composition of HM fat globules, this novel IMF concept with Nuturis((r)) may have metabolic and digestive properties that are more similar to HM compared to Control IMF. PMID- 26432621 TI - Contrast and response gain control depend on cortical map architecture. AB - Visual cortical neurons are sensitive to visual stimulus contrast and most cells adapt their sensitivity to the prevailing visual environment. Specifically, they match the steepest region of their contrast response function to the prevailing contrast (contrast gain control), and reduce spike rates to limit saturation (response gain control). Most neurons are also tuned for stimulus orientation, and neurons with similar orientation preference are clustered together into iso orientation zones arranged around pinwheels, i.e. points where all orientations are represented. Here we investigated the relationship between the contrast adaptation properties of neurons and their location relative to pinwheels in the orientation preference map. We measured orientation preference maps in cat cortex using optical intrinsic signal imaging. We then characterized the contrast adaptation properties of single neurons located close to pinwheels, in iso orientation zones, and at regions in between. We found little evidence of differential contrast sensitivity of neurons adapted to zero contrast. However, after adaptation to their preferred orientation at high contrast, changes in both contrast and response gain were greater for neurons near pinwheels compared with other map regions. Therefore, in the adapted state, which is probably typical during natural viewing, there is a spatial map of contrast sensitivity that is associated with the orientation preference map. This differential adaptation revealed a new dimension of cortical functional organization, linking the contrast adaptation of cells with the orientation preference of their nearest neighbours. PMID- 26432622 TI - Effects of Physical Exercise on Health and Well-Being of Individuals Living With a Dementia in Nursing Homes: A Systematic Review. AB - BACKGROUND: Physical exercise interventions have benefits for older individuals and improve the health and well-being of individuals living with a dementia, specifically those living in nursing homes. PURPOSE: Report evidence from randomized controlled trials and cluster randomized control trials that evaluated the effects of physical exercise interventions on individuals living with a dementia in nursing homes. DATA SOURCES: Web of Science, Scopus, Science Direct, Academic Search Complete, Proquest Central, British Medical Journal Database, PubMed, Cochrane Library, PEDro, Informit, Informa, and Nursing Consult were searched for relevant clinical trials and snowballing of recommended studies. STUDY SELECTION: One reviewer screened articles on inclusion criteria and identified relevant studies. DATA EXTRACTION: Data extraction was performed by 1 reviewer and checked by second and third reviewers. Two authors assessed the methodological quality and risk of bias of the relevant studies. DATA SYNTHESIS: Twelve study populations consisting of individuals living with a dementia in nursing homes were included (n = 901). Different types of physical exercises were undertaken: multimodal (n = 6), walking (n = 5), music and movement (n = 2), and hand exercises (n = 1). The parameters of the interventions varied across the studies. Most of the studies reported significant positive effects of physical exercise on cognition, agitation, mood, mobility, and functional ability for individuals living with dementia in nursing homes. LIMITATIONS: The main limitations were the heterogeneity of design, small samples, and short interventions. CONCLUSIONS: There is emerging evidence that physical exercise significantly benefits individuals living with a dementia in nursing homes. Higher quality research is required adopting more rigorous methods, including longer interventions and larger samples to determine optimum parameters of the physical exercise interventions evaluated. PMID- 26432623 TI - Sliding Scale Insulin vs Basal-Bolus Insulin Therapy in Long-Term Care: A 21-Day Randomized Controlled Trial Comparing Efficacy, Safety and Feasibility. AB - INTRODUCTION: Sliding scale insulin (SSI) therapy remains a common means of insulin therapy in long-term care (LTC) for the management of type 2 diabetes mellitus, despite current recommendations not supportive of the form of therapy today. Lack of randomized trial data on the efficacy and safety of basal-bolus insulin (B-BI) therapy in nursing home residents may have precluded this form of insulin administration in the LTC setting. Our study is a comparison of the efficacy of SSI (control) and B-BI (intervention) therapies during a 21-day intervention trial in older nursing home residents. METHODS: Fourteen LTC facilities in the US participated; 110 residents with type 2 diabetes volunteered to participate; 35 failed inclusion criteria, 75 signed informed written consent, and 11 were discharged to home/hospital or withdrew consent; data from 64 participants are reported. Recent fasting blood glucose (FBG), hemoglobin A1c, and chemistries were obtained. Four glucose readings (prior to breakfast, lunch, dinner, and bedtime), oral antiglycemic drug, and insulin doses and changes, and all adverse events/serious adverse events, both those related to glucose control [hypoglycemic (<70 mg/dL) and hyperglycemic (>200 mg/dL) episodes] and those unrelated, were recorded daily. Patients were randomized to either remain on SSI or be shifted to the B-BI group. RESULTS: Nursing home residents 80 +/- 8 (standard deviation) years, 66% female participated; Control and Intervention participants had similar age, gender, race distributions, comorbidity, and 3-day average pretrial FBG levels (all P > .05). At study end, B-BI volunteers had significantly lower 3-day average FBG levels vs pretrial (P = .0231) while SSI participants had no change in 3-day average FBG (P > .05). During the trial, participants from both groups had similar rates of hypoglycemia, hyperglycemia, other adverse events, and hospitalizations (serious adverse events) unrelated to glucose control (all P > .05). CONCLUSIONS: B-BI therapy produced significantly lower average FBG levels after 21 days compared with SSI therapy; both groups had similar rates of hypo- and hyperglycemia. Switching to B-BI therapy is feasible, safe, and effective in the LTC setting. PMID- 26432624 TI - Differences in Case Conferences in Dementia Specific vs Traditional Care Units in German Nursing Homes: Results from a Cross-Sectional Study. AB - OBJECTIVES: To investigate differences in the provision and performance of case conferences for people with dementia between dementia special care units (DSCUs) and traditional care units (TCUs) in nursing homes. Because DSCUs employ more staff, we expect the likelihood of the provision of case conferences to be higher in DSCUs. DESIGN: Observational cross-sectional study. Residents from DSCUs and TCUs were compared using genetic propensity score matching over all of the observed potential covariates, including the characteristics that served as admission criteria for DSCUs. Because of the multisite structure of the data, clustering was accounted for with a generalized mixed model. SETTING: DSCUs are defined as units within nursing homes that offer care exclusively to residents with dementia and that charge higher rates for the specialized care provided. TCUs are defined as care units for residents with and without dementia. PARTICIPANTS: A matched sample was drawn out of a convenience sample of 1808 residents from 51 nursing homes. It consisted of 264 residents from 16 DSCUs and 264 residents from 48 TCUs. INTERVENTIONS: None. MEASUREMENTS: Data regarding the provision of case conferences were collected by the nurses using the Dementia Care Questionnaire. Other collected data included challenging behavior (Neuropsychiatric Inventory Questionnaire), mobility (Physical Self-Maintenance Scale), cognitive impairment (Dementia Screening Scale), and sociodemographic information. RESULTS: In the DSCU group, case conferences were provided to 91% (n = 224) of the residents; in the TCU group, 82.5% (n = 203) received a case conference. After adjusting for clustering, no significant difference between DSCUs and non-DSCUs was found. The topic "challenging behaviors" was discussed more often in case conferences in TCUs. CONCLUSIONS: Case conferences are a widespread intervention in German nursing homes, including both DSCUs and TCUs. The provision of a case conference is not a special feature of DSCUs. PMID- 26432625 TI - An Administrator's Perspective on the Organization of Physical Activity for Older Adults in Long-Term Care Facilities. AB - BACKGROUND: The positive influence of physical activity (PA) on health is well documented. Even at old age, PA remains useful but participation in PA decreases with age. In long-term care facilities (LTCFs), PA appears to be reduced to a bare minimum. Because administrators have a key role in developing the care policy of LTCFs, it is important that they support the organization of PA in LTCFs. OBJECTIVE: The main objective of this mixed-method study was to identify motivators and barriers for organizing PA in LTCFs according to administrators. A secondary goal was to examine the knowledge of the World Health Organization (WHO) guidelines regarding PA and to reveal potential motivators and barriers for the implementation of the guidelines. METHODS: First, 24 administrators completed semistructured interviews. Data were analyzed using the deductive approach of qualitative content analysis. The obtained motivators and barriers were categorized on 3 different levels (intrapersonal, interpersonal, and community) according to the socioecological model by 2 independent reviewers; conflicts were resolved with a third researcher. Next, 127 administrators of Flemish (Belgium) LTCFs completed an online questionnaire survey containing open-ended, unique, and multiple choice questions regarding the LTCFs, PA, and the WHO guidelines, as well as statements (scored on a 5-point Likert scale) regarding perceived motivators and barriers for organizing PA sessions in the LTCF. RESULTS: In the qualitative component, the administrators reported 31 motivators and 24 barriers for organizing PA in the LTCF. In the survey, maintaining or enhancing general health of the residents (98%) and improving the psychological well-being of the residents were marked as key motivators at the intrapersonal level. The administrators (97%) were convinced that PA is a useful way to spend time for LTCF residents. Encouraging social contact (94%) and countering loneliness (86%) are the motivators cited at the interpersonal level. At the community level, the infrastructure of the facility (91%) and adequate and sufficient material (88%) are the main motivators. The barriers that were presented to the participants were scored as less important. The majority of the administrators (83%) are not familiar with the WHO guidelines for PA; 70% of the participants believe that the guidelines are useful, but only 40% is convinced that it is realistic to implement the guidelines in an LTCF. CONCLUSIONS: This study described different motivators and barriers for administrators to organize PA in LTCFs. Contrary to other studies, lack of staff, lack of adequate equipment, and lack of financial resources were rejected as potential barriers for organizing PA. Despite the fact that administrators were not familiar with the WHO guidelines for PA, they believed that the guidelines are useful. The participants reported several barriers for implementation of the guidelines. Administrators of LTCFs are motivated to implement the guidelines if PA can be integrated in daily activities and education of LTCF staff regarding PA is provided. PMID- 26432626 TI - Psychoimmunology and Aging: A Tribute to George Freeman Solomon. PMID- 26432627 TI - Update on a proper use of systemic fluoroquinolones in adult patients (ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin. SPILF.). PMID- 26432628 TI - Extracorporeal CO2 removal: Technical and physiological fundaments and principal indications. AB - In recent years, technological improvements have reduced the complexity of extracorporeal membrane oxygenation devices. This have enabled the development of specific devices for the extracorporeal removal of CO2. These devices have a simpler configuration than extracorporeal membrane oxygenation devices and uses lower blood flows which could reduce the potential complications. Experimental studies have demonstrated the feasibility, efficacy and safety of extracorporeal removal of CO2 and some of its effects in humans. This technique was initially conceived as an adjunct therapy in patients with severe acute respiratory distress syndrome, as a tool to optimize protective ventilation. More recently, the use of this technique has allowed the emergence of a relatively new concept called "tra-protective ventilation"whose effects are still to be determined. In addition, the extracorporeal removal of CO2 has been used in patients with exacerbated hypercapnic respiratory failure with promising results. In this review we will describe the physiological and technical fundamentals of this therapy and its variants as well as an overview of the available clinical evidence, focused on its current potential. PMID- 26432629 TI - The Hruska postulate of Crohn's disease. AB - Crohn's disease is due to the loss of immunological tolerance within the gastrointestinal tract to the antigenic array of Mycobacterium avium subspecies paratuberculosis (MAP) and closely related polymorphic variants. The loss of immune tolerance results in an effector cytokine responsive upon re-exposure to MAP. For immune tolerance to MAP to be induced, infection must occur when acquired immunity is markedly underdeveloped. PMID- 26432630 TI - A hypothesis on the conflicting results of angiotensin converting enzyme inhibitor in the prevention of contrast-induced nephropathy. AB - Contrast-induced nephropathy (CIN) is regarded as acute tubular necrosis resulting from the cytotoxicity of contrast media and the medullary hypoxia linking to the interplay of vasoconstriction and vasodilatation. Saline infusion may prevent CIN by inhibiting renin release and thus production of angiotensin II (ANG II), a vasoconstrictor, from angiotensin I (ANG I). Yet the use of angiotensin converting enzyme inhibitor (ACEI) yields conflicting results in the prevention of CIN. We hypothesise that ACEI will be useful for CIN prevention when the saline infusion is insufficient, useless when the saline infusion is sufficient, and counterproductive when the saline infusion is excessive, respectively. When the production of ANG I and thus ANG II is insufficiently inhibited by insufficient saline infusion, ACEI may help prevent CIN by conferring extra inhibition on the production of ANG II from ANG I. The counterproductive effect may result from ACEI blocking the generation of angiotensin 1-7, a potent vasodilator, from angiotensin 1-9 whose precursor, ANG I, is excessively diminished by excessive saline infusion. Clinical data suggest that normal saline infusion at a rate of 1 ml/kg/h for 12 h, 1 ml/kg/h for 6 h, and 2 ml/kg/h for 6 h before and after contrast injection provide sufficient, insufficient, and excessive hydration in the prevention of CIN, respectively. The mainstream guideline is to stop ACEI and provide sufficient hydration for CIN prevention. Alternatively one may continue to have ACEI but the use of normal saline infusion must be limited to 1 ml/kg/h for 6 h before and after contrast injection. PMID- 26432631 TI - Cutis Marmorata skin decompression sickness is a manifestation of brainstem bubble embolization, not of local skin bubbles. AB - "Cutis Marmorata" skin symptoms after diving, most frequently in the form of an itching or painful cutaneous red-bluish discoloration are commonly regarded as a mild form of decompression sickness (DCS), and treated with oxygen inhalation without reverting to hyperbaric recompression treatment. It has been observed that the occurrence of Cutis Marmorata is frequently associated with the presence of a Patent Foramen Ovale (PFO) of the heart, and indeed, with a properly executed contrast echocardiographic technique, these patients have an almost 100% prevalence of PFO. Only occasionally, Cutis Marmorata is accompanied by other symptoms of DCS. These symptoms usually are in the form of visual distortions, vertigo, or mild, vague but generalized cerebral dysfunction (such as abnormal fatigue, clumsiness, concentration problems). The pathogenesis of these other manifestations is clearly emboligenic, and we hypothesize that Cutis Marmorata is also a manifestation of gas bubbles embolizing the brain stem: the site of autonomic nervous system regulation of skin blood vessel dilation and constriction. The consequences of this hypothesis are that Cutis Marmorata skin decompression sickness should no longer be considered a mild, innocuous form but rather a serious, neurological form and treated accordingly. PMID- 26432632 TI - Comparison of Switching and Biofilm Formation between MTL-Homozygous Strains of Candida albicans and Candida dubliniensis. AB - Candida albicans and Candida dubliniensis are highly related species that share the same main developmental programs. In C. albicans, it has been demonstrated that the biofilms formed by strains heterozygous and homozygous at the mating type locus (MTL) differ functionally, but studies rarely identify the MTL configuration. This becomes a particular problem in studies of C. dubliniensis, given that one-third of natural strains are MTL homozygous. For that reason, we have analyzed MTL-homozygous strains of C. dubliniensis for their capacity to switch from white to opaque, the stability of the opaque phenotype, CO2 induction of switching, pheromone induction of adhesion, the effects of minority opaque cells on biofilm thickness and dry weight, and biofilm architecture in comparison with C. albicans. Our results reveal that C. dubliniensis strains switch to opaque at lower average frequencies, exhibit a far lower level of opaque phase stability, are not stimulated to switch by high CO2, exhibit more variability in biofilm architecture, and most notably, form mature biofilms composed predominately of pseudohyphae rather than true hyphae. Therefore, while several traits of MTL-homozygous strains of C. dubliniensis appear to be degenerating or have been lost, others, most notably several related to biofilm formation, have been conserved. Within this context, the possibility is considered that C. dubliniensis is transitioning from a hypha-dominated to a pseudohypha-dominated biofilm and that aspects of C. dubliniensis colonization may provide insights into the selective pressures that are involved. PMID- 26432633 TI - Saccharomyces cerevisiae Is Dependent on Vesicular Traffic between the Golgi Apparatus and the Vacuole When Inositolphosphorylceramide Synthase Aur1 Is Inactivated. AB - Inositolphosphorylceramide (IPC) and its mannosylated derivatives are the only complex sphingolipids of yeast. Their synthesis can be reduced by aureobasidin A (AbA), which specifically inhibits the IPC synthase Aur1. AbA reportedly, by diminishing IPC levels, causes endoplasmic reticulum (ER) stress, an increase in cytosolic calcium, reactive oxygen production, and mitochondrial damage leading to apoptosis. We found that when Aur1 is gradually depleted by transcriptional downregulation, the accumulation of ceramides becomes a major hindrance to cell survival. Overexpression of the alkaline ceramidase YPC1 rescues cells under this condition. We established hydroxylated C26 fatty acids as a reliable hallmark of ceramide hydrolysis. Such hydrolysis occurs only when YPC1 is overexpressed. In contrast, overexpression of YPC1 has no beneficial effect when Aur1 is acutely repressed by AbA. A high-throughput genetic screen revealed that vesicle-mediated transport between Golgi apparatus, endosomes, and vacuole becomes crucial for survival when Aur1 is repressed, irrespective of the mode of repression. In addition, vacuolar acidification becomes essential when cells are acutely stressed by AbA, and quinacrine uptake into vacuoles shows that AbA activates vacuolar acidification. The antioxidant N-acetylcysteine does not improve cell growth on AbA, indicating that reactive oxygen radicals induced by AbA play a minor role in its toxicity. AbA strongly induces the cell wall integrity pathway, but osmotic support does not improve the viability of wild-type cells on AbA. Altogether, the data support and refine current models of AbA-mediated cell death and add vacuolar protein transport and acidification as novel critical elements of stress resistance. PMID- 26432634 TI - Yeast Integral Membrane Proteins Apq12, Brl1, and Brr6 Form a Complex Important for Regulation of Membrane Homeostasis and Nuclear Pore Complex Biogenesis. AB - Proper functioning of intracellular membranes is critical for many cellular processes. A key feature of membranes is their ability to adapt to changes in environmental conditions by adjusting their composition so as to maintain constant biophysical properties, including fluidity and flexibility. Similar changes in the biophysical properties of membranes likely occur when intracellular processes, such as vesicle formation and fusion, require dramatic changes in membrane curvature. Similar modifications must also be made when nuclear pore complexes (NPCs) are constructed within the existing nuclear membrane, as occurs during interphase in all eukaryotes. Here we report on the role of the essential nuclear envelope/endoplasmic reticulum (NE/ER) protein Brl1 in regulating the membrane composition of the NE/ER. We show that Brl1 and two other proteins characterized previously-Brr6, which is closely related to Brl1, and Apq12-function together and are required for lipid homeostasis. All three transmembrane proteins are localized to the NE and can be coprecipitated. As has been shown for mutations affecting Brr6 and Apq12, mutations in Brl1 lead to defects in lipid metabolism, increased sensitivity to drugs that inhibit enzymes involved in lipid synthesis, and strong genetic interactions with mutations affecting lipid metabolism. Mutations affecting Brl1 or Brr6 or the absence of Apq12 leads to hyperfluid membranes, because mutant cells are hypersensitive to agents that increase membrane fluidity. We suggest that the defects in nuclear pore complex biogenesis and mRNA export seen in these mutants are consequences of defects in maintaining the biophysical properties of the NE. PMID- 26432635 TI - Incidence of postoperative shivering comparing remifentanil with other opioids: a meta-analysis. AB - STUDY OBJECTIVE: To determine whether the administration of remifentanil increases the incidence of postoperative shivering in comparison with the administration of alfentanil, fentanyl, or sufentanil. DESIGN: Meta-analysis. SETTING: Operating room and postanesthesia care unit. MEASUREMENTS: We performed a computerized search of articles on PubMed, MEDLINE, and Scopus. Meta-analysis was performed using Review Manager and the DerSimonian and Laird random-effects model. The pooled effect estimates for binary variables were calculated as relative risk (RR) values with 95% confidence intervals (CIs). MAIN RESULTS: Eighteen randomized controlled trials met our inclusion criteria. Remifentanil was associated with a significantly increased incidence of postoperative shivering compared with other opioids (RR=2.17; CI, 1.76-2.68; P<.00001; I(2)=0.00%). A subgroup analysis of remifentanil compared with alfentanil, fentanyl, or sufentanil showed that only sufentanil had a similar rate of postoperative shivering incidence (RR=2.13; CI, 0.67-6.74; P=.20; I(2)=0.00%). Remifentanil administration was associated with a significant increase in the incidence of postoperative shivering compared with the administration of other opioids when both propofol (RR=2.44; CI, 1.52-3.92; P=.0002; I(2)=0.00%) and inhalation anesthesia drugs (RR=2.45; CI, 1.46-4.11; P=.0007; I(2)=0.00%) were used for anesthesia maintenance. In addition, the administration of remifentanil at both low (RR=2.06; CI, 1.63-2.60; P<.00001; I(2)=0.00%) and high dosages (RR=2.77; CI, 1.67-4.57; P<.0001; I(2)=0.00%) was associated with a significant increase in the incidence of postoperative shivering compared with the administration of other opioids. CONCLUSIONS: Our meta-analysis showed that remifentanil was associated with an increased incidence of postoperative shivering compared with alfentanil or fentanyl, but no significant difference was seen when compared with sufentanil. PMID- 26432636 TI - The Phytosiderophore Efflux Transporter TOM2 Is Involved in Metal Transport in Rice. AB - Iron is an essential metal element for all living organisms. Graminaceous plants produce and secrete mugineic acid family phytosiderophores from their roots to acquire iron in the soil. Phytosiderophores chelate and solubilize insoluble iron hydroxide in the soil. Subsequently, plants take up iron-phytosiderophore complexes through specific transporters on the root cell membrane. Phytosiderophores are also thought to be important for the internal transport of various transition metals, including iron. In this study, we analyzed TOM2 and TOM3, rice homologs of transporter of mugineic acid family phytosiderophores 1 (TOM1), a crucial efflux transporter directly involved in phytosiderophore secretion into the soil. Transgenic rice analysis using promoter-beta glucuronidase revealed that TOM2 was expressed in tissues involved in metal translocation, whereas TOM3 was expressed only in restricted parts of the plant. Strong TOM2 expression was observed in developing tissues during seed maturation and germination, whereas TOM3 expression was weak during seed maturation. Transgenic rice in which TOM2 expression was repressed by RNA interference showed growth defects compared with non-transformants and TOM3-repressed rice. Xenopus laevis oocytes expressing TOM2 released (14)C-labeled deoxymugineic acid, the initial phytosiderophore compound in the biosynthetic pathway in rice. In onion epidermal and rice root cells, the TOM2-GFP fusion protein localized to the cell membrane, indicating that the TOM2 protein is a transporter for phytosiderophore efflux to the cell exterior. Our results indicate that TOM2 is involved in the internal transport of deoxymugineic acid, which is required for normal plant growth. PMID- 26432637 TI - Procollagen Lysyl Hydroxylase 2 Expression Is Regulated by an Alternative Downstream Transforming Growth Factor beta-1 Activation Mechanism. AB - PLOD2 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2) hydroxylates lysine residues in collagen telopeptides and is essential for collagen pyridinoline cross-link formation. PLOD2 expression and subsequent pyridinoline cross-links are increased in fibrotic pathologies by transforming growth factor beta-1 (TGFbeta1). In this report we examined the molecular processes underlying TGFbeta1-induced PLOD2 expression. We found that binding of the TGFbeta1 pathway related transcription factors SMAD3 and SP1-mediated TGFbeta1 enhanced PLOD2 expression and could be correlated to an increase of acetylated histone H3 and H4 at the PLOD2 promoter. Interestingly, the classical co-activators of SMAD3 complexes, p300 and CBP, were not responsible for the enhanced H3 and H4 acetylation. Depletion of SMAD3 reduced PLOD2 acetylated H3 and H4, indicating that another as of yet unidentified histone acetyltransferase binds to SMAD3 at PLOD2. Assessing histone methylation marks at the PLOD2 promoter depicted an increase of the active histone mark H3K79me2, a decrease of the repressive H4K20me3 mark, but no role for the generally strong transcription-related modifications: H3K4me3, H3K9me3 and H3K27me3. Collectively, our findings reveal that TGFbeta1 induces a SP1- and SMAD3-dependent recruitment of histone modifying enzymes to the PLOD2 promoter other than the currently known TGFbeta1 downstream co-activators and epigenetic modifications. This also suggests that additional activation strategies are used downstream of the TGFbeta1 pathway, and hence their unraveling could be of great importance to fully understand TGFbeta1 activation of genes. PMID- 26432638 TI - The Regulatory and Kinase Domains but Not the Interdomain Linker Determine Human Double-stranded RNA-activated Kinase (PKR) Sensitivity to Inhibition by Viral Non coding RNAs. AB - Double-stranded RNA (dsRNA)-activated protein kinase (PKR) is an important component of the innate immune system that presents a crucial first line of defense against viral infection. PKR has a modular architecture comprising a regulatory N-terminal dsRNA binding domain and a C-terminal kinase domain interposed by an unstructured ~80-residue interdomain linker (IDL). Guided by sequence alignment, we created IDL deletions in human PKR (hPKR) and regulatory/kinase domain swap human-rat chimeric PKRs to assess the contributions of each domain and the IDL to regulation of the kinase activity by RNA. Using circular dichroism spectroscopy, limited proteolysis, kinase assays, and isothermal titration calorimetry, we show that each PKR protein is properly folded with similar domain boundaries and that each exhibits comparable polyinosinic-cytidylic (poly(rI:rC)) dsRNA activation profiles and binding affinities for adenoviral virus-associated RNA I (VA RNAI) and HIV-1 trans activation response (TAR) RNA. From these results we conclude that the IDL of PKR is not required for RNA binding or mediating changes in protein conformation or domain interactions necessary for PKR regulation by RNA. In contrast, inhibition of rat PKR by VA RNAI and TAR RNA was found to be weaker than for hPKR by 7- and >300-fold, respectively, and each human-rat chimeric domain-swapped protein showed intermediate levels of inhibition. These findings indicate that PKR sequence or structural elements in the kinase domain, present in hPKR but absent in rat PKR, are exploited by viral non-coding RNAs to accomplish efficient inhibition of PKR. PMID- 26432639 TI - TAZ Protein Accumulation Is Negatively Regulated by YAP Abundance in Mammalian Cells. AB - The mammalian Hippo signaling pathway regulates cell growth and survival and is frequently dysregulated in cancer. YAP and TAZ are transcriptional coactivators that function as effectors of this signaling pathway. Aberrant YAP and TAZ activity is reported in several human cancers, and normally the expression and nuclear localization of these proteins is tightly regulated. We sought to establish whether a direct relationship exists between YAP and TAZ. Using knockdown and overexpression experiments we show YAP inversely regulates the abundance of TAZ protein by proteasomal degradation. Interestingly this phenomenon was uni-directional since TAZ expression did not affect YAP abundance. Structure/function analyses suggest that YAP-induced TAZ degradation is a consequence of YAP-targeted gene transcription involving TEAD factors. Subsequent investigation of known regulators of TAZ degradation using specific inhibitors revealed a role for heat shock protein 90 and glycogen synthase kinase 3 but not casein kinase 1 nor LATS in YAP-mediated TAZ loss. Importantly, this phenomenon is conserved from mouse to human; however, interestingly, different YAP isoforms varied in their ability to degrade TAZ. Since shRNA-mediated TAZ depletion in HeLa and D645 cells caused apoptotic cell death, we propose that isoform-specific YAP-mediated TAZ degradation may contribute to the contradicting roles reported for YAP overexpression. This study identifies a novel mechanism of TAZ regulation by YAP, which has significant implications for our understanding of Hippo pathway regulation, YAP-isoform specific signaling, and the role of these proteins in cell proliferation, apoptosis, and tumorigenesis. PMID- 26432641 TI - Crystal Structure of the Human Cytomegalovirus pUL50-pUL53 Core Nuclear Egress Complex Provides Insight into a Unique Assembly Scaffold for Virus-Host Protein Interactions. AB - Nuclear replication of cytomegalovirus relies on elaborate mechanisms of nucleocytoplasmic egress of viral particles. Thus, the role of two essential and conserved viral nuclear egress proteins, pUL50 and pUL53, is pivotal. pUL50 and pUL53 heterodimerize and form a core nuclear egress complex (NEC), which is anchored to the inner nuclear membrane and provides a scaffold for the assembly of a multimeric viral-cellular NEC. Here, we report the crystal structure of the pUL50-pUL53 heterodimer (amino acids 1-175 and 50-292, respectively) at 2.44 A resolution. Both proteins adopt a globular fold with mixed alpha and beta secondary structure elements. pUL53-specific features include a zinc-binding site and a hook-like N-terminal extension, the latter representing a hallmark element of the pUL50-pUL53 interaction. The hook-like extension (amino acids 59-87) embraces pUL50 and contributes 1510 A(2) to the total interface area (1880 A(2)). The pUL50 structure overall resembles the recently published NMR structure of the murine cytomegalovirus homolog pM50 but reveals a considerable repositioning of the very C-terminal alpha-helix of pUL50 upon pUL53 binding. pUL53 shows structural resemblance with the GHKL domain of bacterial sensory histidine kinases. A close examination of the crystal structure indicates partial assembly of pUL50-pUL53 heterodimers to hexameric ring-like structures possibly providing additional scaffolding opportunities for NEC. In combination, the structural information on pUL50-pUL53 considerably improves our understanding of the mechanism of HCMV nuclear egress. It may also accelerate the validation of the NEC as a unique target for developing a novel type of antiviral drug and improved options of broad-spectrum antiherpesviral therapy. PMID- 26432640 TI - Finding Channels. PMID- 26432642 TI - A Novel alpha2/alpha4 Subtype-selective Positive Allosteric Modulator of Nicotinic Acetylcholine Receptors Acting from the C-tail of an alpha Subunit. AB - Positive allosteric modulators (PAMs) of nicotinic acetylcholine receptors (nAChR) are important therapeutic candidates as well as valuable research tools. We identified a novel type II PAM, (R)-7-bromo-N-(piperidin-3 yl)benzo[b]thiophene-2-carboxamide (Br-PBTC), which both increases activation and reactivates desensitized nAChRs. This compound increases acetylcholine-evoked responses of alpha2* and alpha4* nAChRs but is without effect on alpha3* or alpha6* nAChRs (* indicates the presence of other nAChR subunits). Br-BPTC acts from the C-terminal extracellular sequences of alpha4 subunits, which is also a PAM site for steroid hormone estrogens such as 17beta-estradiol. Br-PBTC is much more potent than estrogens. Like 17beta-estradiol, the non-steroid Br-PBTC only requires one alpha4 subunit to potentiate nAChR function, and its potentiation is stronger with more alpha4 subunits. This feature enables Br-BPTC to potentiate activation of (alpha4beta2)(alpha6beta2)beta3 but not (alpha6beta2)2beta3 nAChRs. Therefore, this compound is potentially useful in vivo for determining functions of different alpha6* nAChR subtypes. Besides activation, Br-BPTC affects desensitization of nAChRs induced by sustained exposure to agonists. After minutes of exposure to agonists, Br-PBTC reactivated short term desensitized nAChRs that have at least two alpha4 subunits but not those with only one. Three alpha4 subunits were required for Br-BPTC to reactivate long term desensitized nAChRs. These data suggest that higher PAM occupancy promotes channel opening more efficiently and overcomes short and long term desensitization. This C terminal extracellular domain could be a target for developing subtype or state selective drugs for nAChRs. PMID- 26432643 TI - Subcellular Distribution of NAD+ between Cytosol and Mitochondria Determines the Metabolic Profile of Human Cells. AB - The mitochondrial NAD pool is particularly important for the maintenance of vital cellular functions. Although at least in some fungi and plants, mitochondrial NAD is imported from the cytosol by carrier proteins, in mammals, the mechanism of how this organellar pool is generated has remained obscure. A transporter mediating NAD import into mammalian mitochondria has not been identified. In contrast, human recombinant NMNAT3 localizes to the mitochondrial matrix and is able to catalyze NAD(+) biosynthesis in vitro. However, whether the endogenous NMNAT3 protein is functionally effective at generating NAD(+) in mitochondria of intact human cells still remains to be demonstrated. To modulate mitochondrial NAD(+) content, we have expressed plant and yeast mitochondrial NAD(+) carriers in human cells and observed a profound increase in mitochondrial NAD(+). None of the closest human homologs of these carriers had any detectable effect on mitochondrial NAD(+) content. Surprisingly, constitutive redistribution of NAD(+) from the cytosol to the mitochondria by stable expression of the Arabidopsis thaliana mitochondrial NAD(+) transporter NDT2 in HEK293 cells resulted in dramatic growth retardation and a metabolic shift from oxidative phosphorylation to glycolysis, despite the elevated mitochondrial NAD(+) levels. These results suggest that a mitochondrial NAD(+) transporter, similar to the known one from A. thaliana, is likely absent and could even be harmful in human cells. We provide further support for the alternative possibility, namely intramitochondrial NAD(+) synthesis, by demonstrating the presence of endogenous NMNAT3 in the mitochondria of human cells. PMID- 26432645 TI - Functions of plant-specific myosin XI: from intracellular motility to plant postures. AB - The plant-specific protein motor class myosin XI is known to function in rapid bulk flow of the cytoplasm (cytoplasmic streaming) and in organellar movements. Recent studies unveiled a wide range of physiological functions of myosin XI motors, from intracellular motility to organ movements. Arabidopsis thaliana has 13 members of myosin XI class. In vegetative organs, myosins XIk, XI1, and XI2 primarily contribute to dynamics and spatial configurations of endoplasmic reticulum that develops a tubular network in the cell periphery and thick strand like structures in the inner cell regions. Myosin XI-i forms a nucleocytoplasmic linker and is responsible for nuclear movement and shape. In addition to these intracellular functions, myosin XIf together with myosin XIk is involved in the fundamental nature of plants; the actin-myosin XI cytoskeleton regulates organ straightening to adjust plant posture. PMID- 26432644 TI - Phospholipase Ceta2 Activation Redirects Vesicle Trafficking by Regulating F actin. AB - PI(4,5)P2 localizes to sites of dense core vesicle exocytosis in neuroendocrine cells and is required for Ca(2+)-triggered vesicle exocytosis, but the impact of local PI(4,5)P2 hydrolysis on exocytosis is poorly understood. Previously, we reported that Ca(2+)-dependent activation of phospholipase Ceta2 (PLCeta2) catalyzes PI(4,5)P2 hydrolysis, which affected vesicle exocytosis by regulating the activities of the lipid-dependent priming factors CAPS (also known as CADPS) and ubiquitous Munc13-2 in PC12 cells. Here we describe an additional role for PLCeta2 in vesicle exocytosis as a Ca(2+)-dependent regulator of the actin cytoskeleton. Depolarization of neuroendocrine PC12 cells with 56 or 95 mm KCl buffers increased peak Ca(2+) levels to ~400 or ~800 nm, respectively, but elicited similar numbers of vesicle exocytic events. However, 56 mm K(+) preferentially elicited the exocytosis of plasma membrane-resident vesicles, whereas 95 mm K(+) preferentially elicited the exocytosis of cytoplasmic vesicles arriving during stimulation. Depolarization with 95 mm K(+) but not with 56 mm K(+) activated PLCeta2 to catalyze PI(4,5)P2 hydrolysis. The decrease in PI(4,5)P2 promoted F-actin disassembly, which increased exocytosis of newly arriving vesicles. Consistent with its role as a Ca(2+)-dependent regulator of the cortical actin cytoskeleton, PLCeta2 localized with F-actin filaments. The results highlight the importance of PI(4,5)P2 for coordinating cytoskeletal dynamics with vesicle exocytosis and reveal a new role for PLCeta2 as a Ca(2+) dependent regulator of F-actin dynamics and vesicle trafficking. PMID- 26432647 TI - Design of the remede System Pivotal Trial: A Prospective, Randomized Study in the Use of Respiratory Rhythm Management to Treat Central Sleep Apnea. AB - BACKGROUND: Central sleep apnea is common in patients with cardiovascular disease and worsens outcomes. There is a lack of established therapies for central sleep apnea, and those available are limited by poor patient adherence and potentially adverse cardiovascular effects, at least in a subset of patients. The remede System (Respicardia, Minnetonka, Minnesota) is a new physiologic treatment that uses transvenous phrenic nerve stimulation to contract the diaphragm, thereby stabilizing gas exchange and restoring normal breathing throughout the sleep period. METHODS: This is a prospective multicenter randomized trial with blinded end points evaluating the safety and efficacy of the remede System. Up to 173 patients with central sleep apnea will be randomized 1:1 to remede System therapy initiated at 1 month after implantation (treatment) or to an implanted remede System that will remain inactive for 6 months (control). Primary efficacy end point is the percentage of patients who experience a reduction in apnea-hypopnea index by a >= 50% at 6 months (responder analysis). Primary safety end point is freedom from serious adverse events through 12 months. Secondary end points include sleep-disordered breathing parameters, sleep architecture, Epworth Sleepiness Scale score, and Patient Global Assessment. CONCLUSIONS: This is the 1st randomized controlled trial of the safety and efficacy of the remede System for the treatment of central sleep apnea. PMID- 26432646 TI - Outcomes of Adult Patients With Congenital Heart Disease After Heart Transplantation: Impact of Disease Type, Previous Thoracic Surgeries, and Bystander Organ Dysfunction. AB - BACKGROUND: Adults with congenital heart disease (CHD) are at increased risk for adverse outcomes after heart transplantation (HT). However, small cohorts have constrained the identification of factors associated with poor prognosis. We hypothesized that number of sternotomies and bystander organ dysfunction would be associated with an increased risk for early death after HT. METHODS AND RESULTS: We performed a retrospective observational study of all adult CHD patients who underwent HT at our institution from January 1997 to January 2014. Forty-eight adult CHD patients were followed for a mean of 5 years. Diagnoses included tetralogy of Fallot/pulmonary atresia/double-outlet right ventricle in 15 (31%), D-transposition of the great arteries (TGA) in 10 (21%), tricuspid atresia/double inlet left ventricle in 9 (19%), ventricular or atrial septal defect in 4 (8%), heterotaxy in 3 (6%), congenitally corrected TGA in 2 (4%), and other diagnoses in 5 (10%). Survival at both 1 and 5 years was 77%. According to multivariate analysis, >=3 sternotomies (hazard ratio [HR] 8.5; P = .02) and Model for End Stage Liver Disease Excluding International Normalized Ratio (MELD-XI) score >18 (HR 6.2; P = .01) were significant predictors of mortality. Failed Fontan surgery was not a significant predictor of death (P = .19). CONCLUSIONS: In our cohort of adult CHD patients undergoing HT, >=3 sternotomies and MELD-XI score >18 were significantly associated with death. These findings may be important in patient selection and decision regarding tolerable number of CHD surgeries before considering HT. PMID- 26432648 TI - [Delayed endoscopic reconstruction of the anterior wall of the frontal sinus: Technical note]. AB - INTRODUCTION: Reconstruction of the anterior wall of the frontal sinus usually requires a coronal incision. This extended approach may lead to paresthesia, unsightly scars, bruises and cicatricial alopecia. These complications encouraged several authors to endoscopic management of this kind of fractures. We present a delayed technique of reconstruction of the anterior wall of the frontal sinus by means of endoscopic hydroxyapatite filling. TECHNICAL NOTE: Two incisions were performed behind the hair line. Subperiosteal dissection using a periosteal elevator was performed. A 30 degrees angled endoscope was used to visualize the depression. The latter was filled by Hydroset(r) (Stryker, USA) as a bone substitute. DISCUSSION: In the absence of contra-indication, the reconstruction of the anterior wall of the frontal sinus by means of endoscopic hydroxyapatite filling has many advantages including uneventful outcome, reduction of the hospital stay and a fast learning curve. PMID- 26432649 TI - Improving the performance of factor VIII inhibitor tests in hemophilia A. PMID- 26432650 TI - Clinical outcomes of venous thromboembolism with dalteparin therapy in multiple myeloma patients. AB - This study focused on the clinical outcomes in multiple myeloma (MM) patients with venous thromboembolism (VTE) who received low-molecular-weight heparin (dalteparin) therapy. Changes in D-dimer levels before and after VTE were also evaluated. Among 549 patients treated with various chemotherapeutic agents, a total of 52 (9.47%) patients including 32 newly diagnosed with MM and 16 with relapsed/refractory MM developed VTE, 48 of whom received dalteparin. Among the 48 treated patients, 37 (77%) had proximal deep vein thrombosis (DVT), four had (8%) pulmonary embolism (PE), and seven (15%) had both DVT and PE. In 32 patients with available paired samples (at baseline and VTE occurrence), significant conversion of D-dimer levels from 2.2 +/- 0.4 mg/L to 11.8 +/- 1.6 mg/L (P < 0.001) was observed, which decreased from 10.9 +/- 0.4 mg/L to 1.9 +/- 0.6 mg/L one month after initiating dalteparin therapy. A total of 44 patients received dalteparin with a median duration of 4.2 months (range, 2.7-9.4), and four patients were discontinued early due to death (n = 3) and major bleeding (n = 1). After a median follow-up of 9.0 months (range, 0.7-35.8) since the first VTE episode, five patients showed recurrence of VTE with a cumulative incidence of 17.5 +/- 7.9%. Major bleeding occurred in three patients. In summary, dalteparin seems to be a promising drug for the treatment of VTE in MM. In addition, the significant difference in D-dimer levels observed before occurrence of VTE and after dalteparin treatment may suggest the usefulness of D-dimer testing as a surrogate marker for VTE in MM patients. PMID- 26432651 TI - The plasma levels of protein Z-dependent protease inhibitor increase after gynecological surgery independently of estrogen. AB - INTRODUCTION: Protein Z (PZ)-dependent protease inhibitor (ZPI) is a serine protease inhibitor that efficiently inhibits activated factor X when ZPI is in complex with PZ. We previously reported significantly higher concentrations of plasma ZPI (and PZ) in women during normal pregnancy than in non-pregnant women. METHODS: We explored the possible contribution of estrogen to the ZPI levels in patients with or without bilateral oophorectomy (OVX), which induces artificial menopause where blood estrogen levels drastically decrease. One hundred ninety one pre-menopausal Japanese women who underwent open hysterectomy owing to neoplasms participated in this study and were divided into two groups: 98 OVX and 93 Non-OVX cases. Plasma ZPI was measured by ELISA. RESULTS AND CONCLUSION: Contrary to our working hypothesis, plasma ZPI levels increased significantly in the OVX group after surgery when compared with the pre-operation levels. When these patients were individually analyzed, their ZPI value also rose significantly from pre-operation to post-operation levels. In contrast, plasma PZ levels remained unchanged. The significantly increased ZPI and unchanged PZ levels were also observed in the Non-OVX group. The increased ZPI levels were not significantly related to 17beta-estradiol, luteinizing hormone or follicular stimulating hormone levels, clearly indicating that estrogen did not contribute to the plasma ZPI concentrations. Typical acute phase reactants fibrinogen and C reactive protein (CRP) were also significantly elevated after surgery in both OVX and Non-OVX groups. However, only weakly significant linear relationships were observed between ZPI and fibrinogen or CRP, indicating the presence of alternative regulatory mechanisms underlying their plasma concentrations. PMID- 26432652 TI - A collaborative approach to improve the assessment of physical health in adult consumers with schizophrenia in Queensland mental health services. AB - OBJECTIVE: The objective of this study was to apply a quality improvement collaborative to increase the number of physical health assessments conducted with consumers diagnosed with schizophrenia in adult community mental health services across Queensland. METHOD: Sixteen adult mental health service organisations voluntarily took part in the statewide collaborative initiative to increase the number of physical health assessments completed on persons with a diagnosis of schizophrenia spectrum disorders managed through the community mental health service. RESULTS: Improvement in the physical health assessment clinical indicator was demonstrated across the state over a 3-year period with an increase in the number of physical health assessments recorded from 12% to 58%. CONCLUSIONS: Significant improvements were made over a 3-year period by all mental health services involved in the collaborative, supporting the application of a quality improvement methodology to drive change across mental health services. PMID- 26432653 TI - Towards culturally appropriate assessment of Aboriginal and Torres Strait Islander social and emotional well-being. AB - OBJECTIVE: Identification of need for specialist assessment and the use of relevant cultural information to inform mental health assessment and care are two key factors in improving Aboriginal and Torres Strait Islander access to and experience of mental health care. This paper describes the Here and Now Aboriginal Assessment tool (HANAA) and the Cultural Information Gathering Tool (CIGT), two instruments developed to be used respectively by non-mental health clinicians and Aboriginal and Torres Strait Islander mental health workers. METHOD: Following widespread consultations and feedback, two independent groups of mental health clinicians based in Western Australia and Queensland were involved in developing the HANAA and CIGT. RESULTS: Both the HANAA and CIGT fill unmet needs in terms of instruments that can be used by non-specialists working with Aboriginal and Torres Strait Islander people. CONCLUSIONS: Preliminary use of the HANAA and CIGT suggests that they are well received, easy to deploy and effective instruments that promote cultural security and communication with Aboriginal and Torres Strait Islander people. PMID- 26432654 TI - Mental health consequences of stress and trauma: allostatic load markers for practice and policy with a focus on Indigenous health. AB - OBJECTIVE: Mental health, well-being, and social life are intimately related as is evident from the higher incidence of psychiatric illness in individuals exposed to social stress and adversity. Several biological pathways linking social adversity to health outcomes are heavily investigated in the aims of facilitating early identification and prevention of adverse health outcomes. We provide a practice-orientated overview of the allostatic load model and how it relates to metabolic and cardiovascular comorbidity in psychiatric disorders. CONCLUSIONS: Allostatic load brings together a set of neuroendocrine, metabolic, immune and cardiovascular biomarkers that are elevated in individuals with adverse early life experiences and are predictive of cardiovascular and metabolic risk in psychiatric illness of critical importance for Indigenous Australians. PMID- 26432655 TI - Determinants of the cost of capital for privately financed hospital projects in the UK. AB - Many governments make use of private finance contracts to deliver healthcare infrastructure. Previous work has shown that the rate of return to investors in these markets often exceeds the efficient level. Our focus is on the factors that influence that return. We examine the effect of macroeconomic, project- and firm level variables using a detailed sample of 84 UK private finance initiative (PFI) contracts signed between 1997 and 2010. Of the above variables, macroeconomic conditions and lead sponsor size are related to the investor return. However, our results show a remarkable degree of stability in the return to investors over the 14-year period. We find evidence of a 'prevailing norm' that is robust to project and firm-level variation. The sustainability of excess returns over a long period is indicative of a concentrated market structure. We argue that policymakers should consider new mechanisms for increasing competition in the equity market, while ensuring that authorities have the specialist resources required to negotiate efficient contract prices. PMID- 26432656 TI - Prognostic factors in spinal chordoma: A systematic review. AB - OBJECTIVE: Discovering reliable prognostic factors for spinal chordoma remains a challenge. We attempted to identify evidence-based prognostic factors in the literature since its inception and to establish pooled relative risks (RR) of such factors. METHODS: MEDLINE and Embase search (inception to December 2014). Two reviewers independently selected papers involving spinal chordoma prognostic factors, and studied them for methodological quality and valuable new factors. Subsequently, we attempted to pool the results. RESULTS: Of 1465 citations, we studied 65 papers closely, and found several "new" prognostic factors. However, only eight papers were of adequate quality for analysis. Location in the upper cervical spine (pooled RR=5.46, 95% confidence interval [CI]: 2.23-13.34), worse preoperative Frankel score (pooled RR=2.77, 95% CI: 1.73-4.42), intralesional surgery (pooled RR=2.68, 95% CI: 1.66-4.32), greater extent of invasion (pooled RR=5.09, 95% CI: 1.49-17.41), and revision surgery (pooled RR=2.42, 95% CI: 1.34 4.36) appeared to be independent factors for worse outcome. CONCLUSIONS: Despite the wealth of literature available, disappointingly few papers are of sufficient quality for drawing valid conclusions related to spinal chordoma prognostic factors. The heterogeneity of the studies renders results pooling almost impossible. More accurate individual prognostication requires methodologically high-quality studies with more uniform study design and data reporting. PMID- 26432657 TI - Connexin43 in retinal injury and disease. AB - Gap junctions are specialized cell-to-cell contacts that allow the direct transfer of small molecules between cells. A single gap junction channel consists of two hemichannels, or connexons, each of which is composed of six connexin protein subunits. Connexin43 is the most ubiquitously expressed isoform of the connexin family and in the retina it is prevalent in astrocytes, Muller cells, microglia, retinal pigment epithelium and endothelial cells. Prior to docking with a neighboring cell, Connexin43 hemichannels have a low open probability as open channels constitute a large, relatively non-specific membrane pore. However, with injury and disease Connexin43 upregulation and hemichannel opening has been implicated in all aspects of secondary damage, especially glial cell activation, edema and loss of vascular integrity, leading to neuronal death. We here review gap junctions and their roles in the retina, and then focus in on Connexin43 gap junction channels in injury and disease. In particular, the effect of pathological opening of gap junction hemichannels is described, and hemichannel mediated loss of vascular integrity explained. This latter phenomenon underlies retinal pigment epithelium loss and is a common feature in several retinal diseases. Finally, Connexin43 channel roles in a number of retinal diseases including macular degeneration, glaucoma and diabetic retinopathy are considered, along with results from related animal models. A final section describes gap junction channel modulation and the ocular delivery of potential therapeutic molecules. PMID- 26432658 TI - Letter to the Editor. PMID- 26432661 TI - Pre-hospital pelvic girdle injury: Improving diagnostic accuracy in a physician led trauma service. AB - BACKGROUND: Examination of missed injuries in our physician-led pre-hospital trauma service indicated that the significant injuries missed were often pelvic fractures. We therefore conducted a study whose aim was to evaluate the pre hospital diagnostic accuracy of pelvic girdle injuries, and how this would be affected by implementing the pelvic injury treatment guidelines recently published by the Faculty of Pre-Hospital Care. STUDY DESIGN: All blunt trauma patients attended in a 5-month period were included in the study. The presence or absence of pelvic girdle injury on computed tomography (CT) or, if unavailable, pelvic X-ray was used as a primary outcome measure. A retrospective database and case note review was conducted to identify patients who had pelvic binder applied in the study period. For the purposes of the study, pelvic ring and acetabular fractures were grouped together as patients with suspected pelvic girdle injury that should be fitted with a pelvic binder in the pre-hospital setting. The sensitivity and specificity, relating to the presence of pelvic girdle injury in patients with pelvic binders, was calculated in order to determine pre-hospital diagnostic accuracy. RESULTS: 785 patients were attended during the study period. 170 met the study inclusion criteria. 26 (15.3%) sustained a pelvic girdle injury. 45 (26.5%) had a pelvic binder applied. There were eight missed fractures (31%), of which the majority (six) sustained less severe injuries that were managed non-operatively. Two patients required operative fixation. Radiological images and/or reports were available on 169 (99.4%) patients. As a test of the presence of pelvic fracture, pelvic binder application had a sensitivity of 0.69 (95% CI 0.50-0.85) and a specificity of 0.81 (95% CI 0.74-0.87). CONCLUSIONS: Even with a careful clinical assessment and a low threshold for binder application, this study highlights the problems of distracting injury when trying to diagnose and manage pelvic fractures. By implementing the pelvic treatment guidelines published by the Faculty of Pre-hospital Care, the missed injury rate could be reduced from 31% to 8%. PMID- 26432662 TI - Commentary on "Ten years of imaging for pulmonary embolism: too many scans or the tip of an iceberg?". PMID- 26432659 TI - Reactive oxygen species and mitochondria: A nexus of cellular homeostasis. AB - Reactive oxygen species (ROS) are integral components of multiple cellular pathways even though excessive or inappropriately localized ROS damage cells. ROS function as anti-microbial effector molecules and as signaling molecules that regulate such processes as NF-kB transcriptional activity, the production of DNA based neutrophil extracellular traps (NETs), and autophagy. The main sources of cellular ROS are mitochondria and NADPH oxidases (NOXs). In contrast to NOX generated ROS, ROS produced in the mitochondria (mtROS) were initially considered to be unwanted by-products of oxidative metabolism. Increasing evidence indicates that mtROS have been incorporated into signaling pathways including those regulating immune responses and autophagy. As metabolic hubs, mitochondria facilitate crosstalk between the metabolic state of the cell with these pathways. Mitochondria and ROS are thus a nexus of multiple pathways that determine the response of cells to disruptions in cellular homeostasis such as infection, sterile damage, and metabolic imbalance. In this review, we discuss the roles of mitochondria in the generation of ROS-derived anti-microbial effectors, the interplay of mitochondria and ROS with autophagy and the formation of DNA extracellular traps, and activation of the NLRP3 inflammasome by ROS and mitochondria. PMID- 26432660 TI - Nitric oxide-mediated sensitization of resistant tumor cells to apoptosis by chemo-immunotherapeutics. AB - The generation of NO by the various NO synthases in normal and malignant tissues is manifested by various biological effects that are involved in the regulation of cell survival, differentiation and cell death. The role of NO in the cytotoxic immune response was first revealed by demonstrating the induction of iNOS in target cells by immune cytokines (e.g. IFN-gamma, IL-1, TNF-alpha, etc.) and resulting in the sensitization of resistant tumor cells to death ligands-induced apoptosis. Endogenous/exogenous NO mediated its immune sensitizing effect by inhibiting NF-kappaBeta activity and downstream, inactivating the repressor transcription factor YY1, which inhibited both Fas and DR5 expressions. In addition, NO-mediated inhibition of NF-kappaBeta activity and inhibition downstream of its anti-apoptotic gene targets sensitized the tumor cells to apoptosis by chemotherapeutic drugs. We have identified in tumor cells a dysregulated pro-survival/anti-apoptotic loop consisting of NF kappaB/Snail/YY1/RKIP/PTEN and its modification by NO was responsible, in large, for the reversal of chemo and immune resistance and sensitization to apoptotic mechanisms by cytotoxic agents. Moreover, tumor cells treated with exogenous NO donors resulted in the inhibition of NF-kappaBeta activity via S-nitrosylation of p50 and p65, inhibition of Snail (NF-kappaBeta target gene), inhibition of transcription repression by S-nitrosylation of YY1 and subsequent inhibition of epithelial-mesenchymal transition (EMT), induction of RKIP (inhibition of the transcription repressor Snail), and induction of PTEN (inhibition of the repressors Snail and YY1). Further, each gene product modified by NO in the loop was involved in chemo-immunosensitization. These above findings demonstrated that NO donors interference in the regulatory circuitry result in chemo immunosensitization and inhibition of EMT. Overall, these observations suggest the potential anti-tumor therapeutic effect of NO donors in combination with subtoxic chemo-immuno drugs. This combination acts on multiple facets including reversal of chemo-immune resistance, and inhibition of both EMT and metastasis. PMID- 26432663 TI - Aberrant Expression of Dynein light chain 1 (DYNLT1) is Associated with Human Male Factor Infertility. AB - DYNLT1 is a member of a gene family identified within the t-complex of the mouse, which has been linked with male germ cell development and function in the mouse and the fly. Though defects in the expression of this gene are associated with male sterility in both these models, there has been no study examining its association with spermatogenic defects in human males. In this study, we evaluated the levels of DYNLT1 and its expression product in the germ cells of fertile human males and males suffering from spermatogenic defects. We screened fertile (n = 14), asthenozoospermic (n = 15), oligozoospermic (n = 20) and teratozoospermic (n = 23) males using PCR and Western blot analysis. Semiquantitative PCR indicated either undetectable or significantly lower levels of expression of DYNLT1 in the germ cells from several patients from across the three infertility syndrome groups, when compared with that of fertile controls. DYNLT1 was localized on head, mid-piece, and tail segments of spermatozoa from fertile males. Spermatozoa from infertile males presented either a total absence of DYNLT1 or its absence in the tail region. Majority of the infertile individuals showed negligible levels of localization of DYNLT1 on the spermatozoa. Overexpression of DYNLT1 in GC1-spg cell line resulted in the up regulation of several cytoskeletal proteins and molecular chaperones involved in cell cycle regulation. Defective expression of DYNLT1 was associated with male factor infertility syndromes in our study population. Proteome level changes in GC1-spg cells overexpressing DYNLT1 were suggestive of its possible function in germ cell development. We have discussed the implications of these observations in the light of the known functions of DYNLT1, which included protein trafficking, membrane vesiculation, cell cycle regulation, and stem cell differentiation. PMID- 26432664 TI - Central obesity early in adulthood may affect outcomes of hepatocellular carcinoma. PMID- 26432666 TI - Velocity of temperature and flowering time in wheat - assisting breeders to keep pace with climate change. AB - By accelerating crop development, warming climates may result in mismatches between key sensitive growth stages and extreme climate events, with severe consequences for crop yield and food security. Using recent estimates of gene responses to vernalization and photoperiod in wheat, we modelled the flowering times of all 'potential' genotypes as influenced by the velocity of climate change across the Australian wheatbelt. In the period 1957-2010, seasonal increases in temperature of 0.012 degrees C yr(-1) were recorded and changed flowering time of a mid-season wheat genotype by an average -0.074 day yr(-1) , with flowering 'velocity' of up to 0.95 km yr(-1) towards the coastal edges of the wheatbelt; this is an estimate of how quickly the given genotype would have to be 'moved' across the landscape to maintain its original flowering time. By 2030, these national changes are projected to accelerate by up to 3-fold for seasonal temperature and by up to 5-fold for flowering time between now and 2030, with average national shifts in flowering time of 0.33 and 0.41 day yr(-1) between baseline and the worst climate scenario tested for 2030 and 2050, respectively. Without new flowering alleles in commercial germplasm, the life cycle of wheat crops is predicted to shorten by 2 weeks by 2030 across the wheatbelt for the most pessimistic climate scenario. While current cultivars may be otherwise suitable for future conditions, they will flower earlier due to warmer temperatures. To allow earlier sowing to escape frost, heat and terminal drought, and to maintain current growing period of early-sown wheat crops in the future, breeders will need to develop and/or introduce new genetic sources for later flowering, more so in the eastern part of the wheatbelt. PMID- 26432667 TI - Cytogenetics in multiple myeloma patients progressing into extramedullary disease. AB - BACKGROUND: Extramedullary disease in multiple myeloma patients is an uncommon event occurring either at the time of diagnosis, or during disease progression/relapse. This manifestation is frequently associated with poor outcome and resistance to treatment. We evaluated chromosomal alterations of plasma cells of multiple myeloma patients with extramedullary relapse, either in the bone marrow (BM) or at extramedullary sites, and in previous BM collection by interphase fluorescence in situ hybridization. MATERIAL AND METHODS: Thirty-one patients [25 BM plasma cells (BMPCs), 18 extramedullary tumor plasma cells], of which 12 had paired samples of BM and extramedullary plasma cells and 14 had previous collection of BM, were investigated for the presence of chromosomal aberrations (CHAs): del(17)(p13), del(13)(q14), 14q32 disruption, t(4;14)(p16;q32), t(14;16)(q32;q23), gain(1)(q21), and hyperdiploidy status. RESULTS: Overall, in unrelated samples, t(4;14) was more prevalent in extramedullary plasma cells, and hyperdiploidy was more frequent in BMPCs. In paired samples, there was a higher frequency of del(13)(q14) and 14q32 disruption in BMPCs. Frequency of all studied CHAs was higher in BMPCs of extramedullary patients than in their previous sample collection. CONCLUSION: These data show that plasma cells harbor more aberrations during their transformation into extramedullary form. PMID- 26432668 TI - Smoothened Regulation: A Tale of Two Signals. AB - The G protein-coupled receptor (GPCR) Smoothened (Smo) is the signal transducer of the developmentally and therapeutically relevant Hedgehog (Hh) pathway. Although recent structural analyses have advanced our understanding of Smo biology, several questions remain. Chief among them are the identity of its natural ligand, the regulatory processes controlling its activation, and the mechanisms by which it signals to downstream effectors. In this review, we discuss recent discoveries from multiple model systems that have set the stage for solving these mysteries. We focus on the roles of distinct Smo functional domains, post-translational modifications, and trafficking, and conclude by discussing their contributions to signal output. PMID- 26432669 TI - Obstructive airway in Morquio A syndrome, the past, the present and the future. AB - Patients with severe tracheal obstruction in Morquio A syndrome are at risk of dying of sleep apnea and related complications. Tracheal obstruction also leads to life-threatening complications during anesthesia as a result of the difficulty in managing the upper airway due to factors inherent to the Morquio A syndrome, compounded by the difficulty in intubating the trachea. A detailed description of the obstructive pathology of the trachea is not available in the literature probably due to lack of a homogenous group of Morquio A patients to study at any one particular center. We present a series of cases with significant tracheal obstruction who were unrecognized due to the difficulty in interpreting tracheal narrowing airway symptoms. Our goal is to provide the guidelines in the management of these patients that allow earlier recognition and intervention of tracheal obstruction. Sagittal MRI images of the cervical spine of 28 Morquio A patients (12+/-8.14years) showed that19/28 (67.9%) patients had at least 25% tracheal narrowing and that narrowing worsened with age (all 8 patients over 15years had greater than 50% narrowing). Eight out of 28 patients were categorized as severe (>75%) tracheal narrowing when images were evaluated in neutral head and neck position. Of the 19 patients with tracheal narrowing, compression by the tortuous brachiocephalic artery was the most common cause (n=15). Evidence of such tracheal narrowing was evident as early as at 2years of age. The etiology of tracheal impingement by the brachiocephalic artery in Morquio A appears to be due to a combination of the narrow thoracic inlet crowding structures and the disproportionate growth of trachea and brachiocephalic artery in relationship to the chest cavity leading to tracheal tortuosity. In conclusion, tracheal narrowing, often due to impression from the crossing tortuous brachiocephalic artery, increases with age in Morquio A patients. Greater attention to the trachea is needed when evaluating cervical spine MRIs as well as other imaging and clinical investigations, with the goal of establishing a timely treatment protocol to reduce the mortality rate in this patient population. PMID- 26432670 TI - Molecular diagnosis of hypophosphatasia and differential diagnosis by targeted Next Generation Sequencing. AB - Hypophosphatasia (HPP) is a rare inherited skeletal dysplasia due to loss of function mutations in the ALPL gene. The disease is subject to an extremely high clinical heterogeneity ranging from a perinatal lethal form to odontohypophosphatasia affecting only teeth. Up to now genetic diagnosis of HPP is performed by sequencing the ALPL gene by Sanger methodology. Osteogenesis imperfecta (OI) and campomelic dysplasia (CD) are the main differential diagnoses of severe HPP, so that in case of negative result for ALPL mutations, OI and CD genes had often to be analyzed, lengthening the time before diagnosis. We report here our 18-month experience in testing 46 patients for HPP and differential diagnosis by targeted NGS and show that this strategy is efficient and useful. We used an array including ALPL gene, genes of differential diagnosis COL1A1 and COL1A2 that represent 90% of OI cases, SOX9, responsible for CD, and 8 potentially modifier genes of HPP. Seventeen patients were found to carry a mutation in one of these genes. Among them, only 10 out of 15 cases referred for HPP carried a mutation in ALPL and 5 carried a mutation in COL1A1 or COL1A2. Interestingly, three of these patients were adults with fractures and/or low BMD. Our results indicate that HPP and OI may be easily misdiagnosed in the prenatal stage but also in adults with mild symptoms for these diseases. PMID- 26432672 TI - Lipophilic Statins and Aldosterone Secretion: A Bridge Too Far? PMID- 26432671 TI - Statin Use and Adrenal Aldosterone Production in Hypertensive and Diabetic Subjects. AB - BACKGROUND: Statins substantially reduce cardiovascular mortality and appear to have beneficial effects independent of their lipid-lowering properties. We evaluated the hypothesis that statin use may modulate the secretion of aldosterone, a well-known contributor to cardiovascular disease. METHODS AND RESULTS: We measured adrenal hormones in 2 intervention studies. In study 1 in hypertensive subjects, aldosterone was analyzed at baseline and after angiotensin II stimulation on both high- and low-sodium diets (1122 observations, 15% on statins for >3 months). Statin users had 33% lower aldosterone levels in adjusted models (P<0.001). Cortisol was not modified by statins. In secondary analyses, the lowest aldosterone levels were seen with lipophilic statins and with higher doses. Statin users had lower blood pressure and reduced salt sensitivity of blood pressure (both P<0.001). In study 2, aldosterone was measured in diabetic patients on a high-sodium diet, before and after angiotensin II stimulation (143 observations, 79% statin users). Again, statin users had 26% lower aldosterone levels (P=0.006), particularly those using lipophilic statins. Ex vivo studies in rat adrenal glomerulosa cells confirmed that lipophilic statins acutely inhibited aldosterone, but not corticosterone, in response to different secretagogues. CONCLUSIONS: Statin use among hypertensive and diabetic subjects was associated with lower aldosterone secretion in response to angiotensin II and a low-sodium diet in 2 human intervention studies. This effect appeared to be most pronounced with lipophilic statins and higher doses. Future studies to evaluate whether aldosterone inhibition may partially explain the robust cardioprotective effects of statins are warranted. PMID- 26432673 TI - The Effect of Implementing a Multimodal Approach on the Rates of Periprosthetic Joint Infection After Total Joint Arthroplasty. AB - INTRODUCTION: We examined the efficacy of implementing a multimodal program aimed at reducing the incidence of periprosthetic joint infection (PJI) after total joint arthroplasty (TJA) in a mid-size community hospital. METHODS: An infection reduction committee (IRC) was formed at our hospital in November 2010. The IRC consisted of two orthopaedic surgeons, an infectious disease specialist, an internist with extensive experience in perioperative medical management of TJA patients, an anesthesiologist, the hospital infection control nurse, and two additional nurses. Their goals were to 1) evaluate the current incidence of PJI at our institution, compare it with the reported national data, and consider measures already in place directed at preventing PJI; 2) review and routinely evaluate recently published studies or information obtained from continuing medical education events related to PJI to determine if practice changes were warranted (based on intervention efficacy, cost, and safety) and then develop a plan to implement appropriate alterations in perioperative protocols using a multimodal strategy; and 3) evaluate the effect and safety of newly-introduced infection reduction strategies on the incidence of PJI. RESULTS: In 2008, the incidence of PJI at our hospital was 1.0%. By 2013, this rate had reduced to 0.4%. In absolute numbers, in 2009, 20 of 1,150 TJAs developed a PJI in the 12 month period following partial, primary, or revision TJA. In 2013, PJI occurred in only 4 of 1,053 TJA patients. CONCLUSION: We found that formation of an IRC focused on evaluating and implementing strategies to reduce PJI following TJA can be effective. PMID- 26432674 TI - Midterm Outcomes of Revision Total Hip Arthroplasty Using a Modular Revision Hip System. AB - BACKGROUND: The growth in hip arthroplasty surgery has meant a corresponding escalating revision burden with increasing challenges for the orthopaedic surgeon. The purpose of this study was to review clinical outcomes of a modular revision hip system within a single institution. METHODS: We retrospectively reviewed a cohort of modular revision hip system stems performed in our institution between January 2005 and October 2012 giving a potential minimum follow-up of 2 years. Clinical outcomes data on complications, Oxford Hip Score (OHS, 0-48) and patient satisfaction were collected. Radiographic outcomes including subsidence were assessed. Implant survival was estimated using Kaplan Meier analysis. RESULTS: 115 stems in 106 patients were identified. All cause survival was 82% (95%CIs: 73%-89%) at 6.1 years; survival excluding infection being 99% (95%CIs: 93%-100%). There was a low incidence of subsidence (seven stems) and no peri-prosthetic fractures. Primary cause of re-revision in this series was re-infection with only one re-revision for mechanical failure. Median Oxford Hip Score at mean follow up 4.1 years (2-9) was 40 (14-48) and 93% of patients reported being satisfied with their revision surgery. CONCLUSION: This study showed good clinical outcomes and survival using a modular revision stem with low mechanical failure and subsidence. Recurrence of infection remains a challenge in revision surgery. PMID- 26432675 TI - The Risk of a Deep Infection Associated With Intraarticular Injections Before a Total Knee Arthroplasty. AB - The aim of the study is to identify the risks associated with an intraarticular injection before a total knee arthroplasty (TKA). A total of 1628 patients were retrospectively studied over a 7-year period. The patients were divided into 2 groups: patient who received an intraarticular injection before a TKA and patients who did not receive an injection before a TKA. There were 16 deep infections identified (0.98%). Ten deep infections were identified in the patients who did not receive an injection before a TKA (1.18%), and 6 deep infections were identified in patients who received an injection before a TKA (0.77%). There does not appear to be a correlation with the timing of the injection before surgery and increased risk of infection. PMID- 26432676 TI - Impact of dynamic changes to a bone metastases pathway in a large, integrated, National Cancer Institute-designated comprehensive cancer center network. AB - PURPOSE: Studies suggest equivalent pain relief from bone metastases after radiation therapy with >10-fraction regimens and shorter courses. Although American Society for Radiation Oncology evidence-based guidelines and the Choosing Wisely campaign endorse single-fraction treatments and caution against the use of extended courses, publications report single-fraction utilization rates below 5%. We evaluated the impact of our bone metastasis clinical pathway on the adoption of short-course palliative radiation in a large, integrated radiation oncology network. METHODS AND MATERIALS: We implemented a clinical pathway for the management of bone metastases in 2003 that required the entry of management decisions into an online tool that subjected off-pathway choices to peer review beginning in 2009. In 2014, the pathway was modified to encourage single-fraction treatments, and the use of >10 fractions was considered off pathway. Data were obtained from 16 integrated sites (4 academic, 12 community) from 2003 through 2014. Multivariate logistic regression was conducted to establish factors associated with treatment with a single fraction and with >10 fractions. RESULTS: In this study, 12,678 unique courses were delivered. From 2003 to 2008, the single-fraction utilization rate was 7.6%. This increased to 10.9% from 2009 to 2013 and to 15.8% in 2014. The odds ratios for single-fraction use were 1.59 (95% confidence interval [CI], 1.39-1.81) and 2.58 (95% CI, 2.11 3.15) for 2009-2013 and 2014, respectively. Academic physicians were more likely to treat with a single fraction (odds ratio, 5.00; 95% CI, 4.38-5.71). Use of >10 fraction regimens significantly decreased from 18.6% in 2003-2008 to 15.2% in 2009-2013 and 9.7% in 2014. CONCLUSIONS: Although our single-fraction utilization rate was initially in line with national rates (7.6%), the adoption rate increased to >15%. The use of >10-fraction regimens decreased significantly, predominantly among community practices. By 2014, >90% of courses were delivered with <10 fractions. This study demonstrates that provider-driven clinical pathways are able to standardize practice patterns and promote change consistent with evidence-based guidelines. PMID- 26432677 TI - Tomotherapy improves local control and changes failure patterns in locally advanced malignant pleural mesothelioma. AB - PURPOSE: The purpose of the study was to determine whether intensity modulated radiation therapy delivered via helical tomotherapy improves local control (LC) after pleurectomy/decortication (P/D) for malignant pleural mesothelioma compared with 3-dimensional conformal radiation therapy (3D-CRT). METHODS AND MATERIALS: Forty-five consecutive patients were treated with adjuvant radiation to 45 Gy in 1.8 Gy fractions after P/D between 2006 and 2014; 23 received 3D-CRT, and 22 received tomotherapy. Kaplan-Meier analysis was used to calculate overall survival, time to in-field or local failure (LF), and time to out-of-field failure. The Student t test and Fisher exact test were used to detect between group differences. RESULTS: Median follow-up time was 19.4 months and 12.7 months for the 3D-CRT and tomotherapy groups, respectively. Eighty-two percent of patients had T3/T4 disease, and 64% had positive nodes; 17.4% and 41% of patients in the 3D-CRT and tomotherapy groups had nonepithelioid histology, respectively. Mean planning target volume dose, percentage of planning target volume receiving 100% of the prescription dose, and lung doses were significantly greater with tomotherapy (P < .05), but toxicity rates (including radiation pneumonitis rates) were equivalent. LC was significantly improved with tomotherapy on Kaplan-Meier analysis with outcomes censored at 2 years (P < .05); uncensored, this became a trend (P = .06). Median time to LF was 19 months with tomotherapy and 10.9 months in 3D-CRT (the latter interval being less than the median follow-up in the tomotherapy group). On univariate analysis, treatment modality was the only significant predictor of LC (P < .05). Isolated LF was significantly more frequent with 3D-CRT (P < .05). Conversely, isolated out-of-field failure was significantly more frequent with tomotherapy (P < .05). Overall survival and out of-field control were not significantly different. CONCLUSION: Tomotherapy after P/D for malignant pleural mesothelioma is associated with improved target coverage that translates into improved LC compared with 3D-CRT. This is related to a change in failure patterns, with isolated LF being more common in the 3D-CRT group and isolated out-of-field failures predominating in the tomotherapy group. PMID- 26432678 TI - A framework for quality improvement and patient safety education in radiation oncology residency programs. AB - In training future radiation oncologists, we must begin to focus on training future QI specialists. Our patients are demanding better quality and safer care, and accrediting bodies are requiring it. We must equip radiation oncology trainees to be leaders in this new world. To that end, a QI/PS educational program should contain 2 components: a didactic portion focused on teaching basic QI tools as well as an overview of the quality and safety goals of the institution, and an experiential component, ideally a resident-led QI project mentored by an expert faculty member and that is linked to the department's and institution's goals. PMID- 26432679 TI - Variability in clinical target volume delineation for intensity modulated radiation therapy in 3 challenging cervix cancer scenarios. AB - PURPOSE: The purpose of this study was to assess variability in contouring the gross tumor volume (GTV) and clinical target volume (CTV) of 3 clinical cervix cancer cases by a cohort of international experts in the field in preparation for the development of an online teaching atlas. METHODS AND MATERIALS: Twelve international experts participated. Three clinical scenarios: node positivity (PLN), retroverted uterus (RV), and parametrial invasion (PI) were used. Sagittal and axial magnetic resonance images of the clinical cases were downloaded to participants' treatment planning systems for contouring. The GTV/cervix/uterus/parametria/vagina and nodal CTV were contoured. Contour consensus was assessed for sensitivity/specificity using an expectation maximization algorithm called Simultaneous Truth and Performance Level Estimation and experts' overall agreement was summarized by kappa statistics. RESULTS: Agreement for GTV in the 3 clinical cases was high (Simultaneous Truth and Performance Level Estimation sensitivity, 0.54-0.92; specificity, 0.97-0.98; and kappa measure for PLN, RV, and PI was 0.86, 0.76, and 0.42; P < .0001). Moderate to substantial agreement was seen for nodal CTV (kappa statistics for PLN, RV, and PI was 0.65, 0.58, and 0.62; P < .0001), uterus (kappa for PLN, RV, and PI was 0.45, 0.74, and 0.77; P < .0001), and parametria (kappa for PLN, RV, and PI was 0.49, 0.62, and 0.50; P < .0001). Contouring heterogeneity was greatest for the cervix (kappa measure for PLN, RV, and PI was 0.15, 0.4, and 0.24; P < .0001) and vagina (kappa for PLN, RV, and PI was 0.47, 0.36 and 0.46; P < .0001), reflecting difficulties in determining the interface between GTV and these tissues. CONCLUSION: Kappa statistics of the different CTV components generally demonstrated moderate to substantial agreement among international experts in the field of gynecological radiation therapy. Further planning target volume margins accounting for organ motion and setup errors are a necessary addition to the CTV. PMID- 26432680 TI - Clinical and cosmetic outcomes in patients treated with high-dose-rate electronic brachytherapy for nonmelanoma skin cancer. AB - PURPOSE: To retrospectively analyze clinical and cosmetic outcomes in patients treated for nonmelanoma skin cancer (NMSC) with high-dose-rate (HDR) electronic brachytherapy (EBT) using surface applicators. METHODS AND MATERIALS: We identified 127 patients who had 154 NMSC lesions, 149 of which were basal cell carcinoma, treated with HDR EBT at our institution between July 2012 and March 2014. Lesions were treated to 40 Gy in 8 fractions. Local control, acute toxicity, late toxicity, and cosmetic outcomes were analyzed retrospectively. Acute and late toxicities were graded using the Common Terminology Criteria for Adverse Events, version 4.0. Cosmetic outcomes were graded using a standard scale based on the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring Schema. RESULTS: Median (range) follow-up from completion of treatment was 16.1 (3.4-34.8 months). The overall crude recurrence rate was 1.3% (n = 2). Grade 0 to 1 acute radiation dermatitis was observed in 52.6% of treated lesions (n = 81), grade 2 in 34.4% (n = 53), and grade 3 in 13.0% (n = 20). No acute toxicity greater than grade 3 was observed and all acute toxic events resolved after treatment. Grade 0 to 1 late toxicity was observed in 94.2% of cases (n = 145), and grade 2 in 5.8% (n = 9). No late toxicity greater than grade 2 was observed. Across the 152 controlled lesions, cosmetic results were excellent in 94.2% of treated lesions (n = 145), good in 3.3% (n = 5), fair in 0.7% (n = 1), and poor in 0.7% (n = 1). CONCLUSIONS: HDR EBT confers promising local control, minimal toxicity, and excellent cosmesis in our institutional experience. It should be considered ideal for NMSC of the head and neck, particularly for basal cell carcinoma involving central facial locations where surgical cosmesis may be inferior. PMID- 26432681 TI - Can the Neighborhood Built Environment Make a Difference in Children's Development? Building the Research Agenda to Create Evidence for Place-Based Children's Policy. AB - Healthy child development is determined by a combination of physical, social, family, individual, and environmental factors. Thus far, the majority of child development research has focused on the influence of individual, family, and school environments and has largely ignored the neighborhood context despite the increasing policy interest. Yet given that neighborhoods are the locations where children spend large periods of time outside of home and school, it is plausible the physical design of neighborhoods (built environment), including access to local amenities, can affect child development. The relatively few studies exploring this relationship support associations between child development and neighborhood destinations, green spaces, interaction with nature, traffic exposure, and housing density. These studies emphasize the need to more deeply understand how child development outcomes might be influenced by the neighborhood built environment. Pursuing this research space is well aligned with the current global movements on livable and child-friendly cities. It has direct public policy impact by informing planning policies across a range of sectors (urban design and planning, transport, public health, and pediatrics) to implement place based interventions and initiatives that target children's health and development at the community level. We argue for the importance of exploring the effect of the neighborhood built environment on child development as a crucial first step toward informing urban design principles to help reduce developmental vulnerability in children and to set optimal child development trajectories early. PMID- 26432682 TI - Bacillus thuringiensis impacts on primary and secondary baculovirus transmission dynamics in Lepidoptera. AB - Synergistic interactions between entomopathogenic micro-organisms can potentially be exploited to improve biological control of invertebrate pests but empirical data at the population level describing multiple-pathogen transmission dynamics is lacking. We examined how co-inoculation of Bacillus thuringiensis subsp. kurstaki (Btk) and the baculovirus Panolis flammea nucleopolyhedrovirus (PaflNPV) in an experimental field population of Lepidopteran Mamestra brassicae larvae impacted on viral transmission dynamics. We determined how the presence of Btk influenced primary and secondary PaflNPV transmission. When Btk was co-inoculated with PaflNPV, there was increased proportional viral mortality in primary transmission studies compared to plots with virus alone. A delay of up to 4days between applications of Btk and PaflNPV did not impact on primary viral mortality, indicating that a lag between inoculations was unlikely to affect the biocontrol potential of the two pathogens. Viral yields from cadavers in plots with Btk present were significantly lower than those from plots with virus only, and secondary cycling to introduced secondary transmission larvae was significantly reduced. Baculovirus transmission (in terms of the proportion of uninfected larvae in different treatments) was described by a 'refuge' model that allowed for heterogeneity in susceptibility and pathogen exposure. We discuss how transmission may be potentially affected by factors such as host feeding rate, spatial distribution of virus and interactions between pathogens within the insect host. This study improves understanding of the impact of pathogens within host populations and how mixtures of pathogens may be exploited for biocontrol of insect pests. PMID- 26432683 TI - The EHR and building the patient's story: A qualitative investigation of how EHR use obstructs a vital clinical activity. AB - BACKGROUND: Recent research has suggested that using electronic health records (EHRs) can negatively impact clinical reasoning (CR) and interprofessional collaborative practices (ICPs). Understanding the benefits and obstacles that EHR use introduces into clinical activities is essential for improving medical documentation, while also supporting CR and ICP. METHODS: This qualitative study was a longitudinal pre/post investigation of the impact of EHR implementation on CR and ICP at a large pediatric hospital. We collected data via observations, interviews, document analysis, and think-aloud/-after sessions. Using constructivist Grounded Theory's iterative cycles of data collection and analysis, we identified and explored an emerging theme that clinicians described as central to their CR and ICP activities: building the patient's story. We studied how building the patient's story was impacted by the introduction and implementation of an EHR. RESULTS: Clinicians described the patient's story as a cognitive awareness and overview understanding of the patient's (1) current status, (2) relevant history, (3) data patterns that emerged during care, and (4) the future-oriented care plan. Constructed by consolidating and interpreting a wide array of patient data, building the patient's story was described as a vitally important skill that was required to provide patient-centered care, within an interprofessional team, that safeguards patient safety and clinicians' professional credibility. Our data revealed that EHR use obstructed clinicians' ability to build the patient's story by fragmenting data interconnections. Further, the EHR limited the number and size of free-text spaces available for narrative notes. This constraint inhibited clinicians' ability to read the why and how interpretations of clinical activities from other team members. This resulted in the loss of shared interprofessional understanding of the patient's story, and the increased time required to build the patient's story. CONCLUSIONS: We discuss these findings in relation to research on the role of narratives for enabling CR and ICP. We conclude that EHRs have yet to truly fulfill their promise to support clinicians in their patient care activities, including the essential work of building the patient's story. PMID- 26432684 TI - Is single portal vein approach sufficient for hypothermic machine perfusion of DCD liver grafts? PMID- 26432685 TI - Age-dependent changes in extracellular matrix turnover: An under evaluated issue in the approach to chronic liver diseases. PMID- 26432686 TI - Microwave-assisted extraction and a new determination method for total steroid saponins from Dioscorea zingiberensis C.H. Wright. AB - An efficient microwave-assisted extraction (MAE) technique was applied to isolate total steroid saponins from Dioscorea zingiberensis C.H. Wright (DZW). The optimal extracting conditions were established as 75% ethanol as solvent, ratio of solid/liquid 1:20 (g/ml), temperature 75 degrees C, irradiation power 600 W and three extraction cycles of 6 min each. Scanning electron microscopy (SEM) images of DZW processed by four different extractions provided visual evidence of the disruption effect on DZW. Diosgenin was quantified by HPLC and examined further by LC-ESI/MS after acid hydrolysis. Total steroid saponins were calculated using diosgenin from total steroid saponins. The MAE procedure was optimized, validated and compared with other conventional extraction processes. This report provides a convenient technology for the extraction and quantification of total saponins of DZW combining MAE with HPLC and LC-ESI/MS for the first time. PMID- 26432687 TI - Crystallographic and spectroscopic study on a known orally active progestin. AB - 6,17alpha-Dimethyl-4,6-pregnadiene-3,20-dione (medrogestone, 2) is for a long time known steroid endowed with progestational activity. In order to study its crystallographic and NMR spectroscopic properties with the aim to fill the literature gap, we prepared medrogestone following a traditional procedure. A careful NMR study allowed the complete assignment of the (1)H and (13)C NMR signals not only of medrogestone but also of its synthetic intermediates. The structural and stereochemical characterizations of medrogestone together with its precursor 17alpha-methyl-3-ethoxy-pregna-3,5-dien-20-one were described by means of X-ray analysis, allowing a deepened conformational investigation. PMID- 26432688 TI - Epoetin beta pegol prevents endothelial dysfunction as evaluated by flow-mediated dilation in chronic kidney disease rats. AB - Chronic kidney disease (CKD) patients have a poor prognosis due to cardiovascular disease. Anemia and endothelial dysfunction are important risk factors for cardiovascular events in CKD patients, and treatment with erythropoiesis stimulating agent (ESA) has been reported to improve the quality of life in CKD patients. In this study, we evaluated the effect of anemia correcting dose of epoetin beta pegol (continuous erythropoietin receptor activator; C.E.R.A.) on endothelial function in 5/6 nephrectomized rats (Nx rats). C.E.R.A. was subcutaneously administered once a fortnight, 5 times in total, from 1 week after nephrectomy. Twenty-four hours after last administration, endothelial function was evaluated by measuring flow-mediated dilation (FMD) in the femoral arteries of anesthetized Nx rats by ultrasound system. Femoral arteries were harvested for western blot analysis. C.E.R.A. significantly increased FMD of Nx rats. Endothelium-independent vasodilation induced by nitroglycerin injection was not influenced by C.E.R.A treatment. Nox4 expression and nitrotyrosine accumulation were significantly decreased, and phosphorylation of eNOS was significantly enhanced in the femoral arteries of C.E.R.A.-treated rats. C.E.R.A. normalized hemoglobin levels but did not affect body weight, systolic blood pressure, heart rate, urinary protein excretion and plasma creatinine. These results indicate that C.E.R.A. prevented endothelial dysfunction in Nx rats, possibly through reduction of local oxidative stress and enhancement of eNOS phosphorylation in the arteries. This study provides the first evidence that C.E.R.A. prevented endothelial dysfunction in CKD model rats under conditions of amelioration of anemia. PMID- 26432689 TI - The effects of caffeic, coumaric and ferulic acids on proliferation, superoxide production, adhesion and migration of human tumor cells in vitro. AB - Reactive oxygen species are well-known mediators of various biological responses. In this study, we examined the effect of three phenolic acids, caffeic, coumaric and ferulic acids, on superoxide anion production, adhesion and migration of human lung (A549) and colon adenocarcinoma (HT29-D4) cancer cell lines. Proliferation of both tumor cells was inhibited by phenolic acids. Caffeic, coumaric and ferulic acids also significantly inhibited superoxide production in A549 and HT29-D4 cells. Superoxide anion production decreased by 92% and 77% at the highest tested concentration (200 uM) of caffeic acid in A549 and HT29-D4 cell lines respectively. Furthermore, A549 and HT29-D4 cell adhesion was reduced by 77.9% and 79.8% respectively at the higher tested concentration of ferulic acid (200 uM). Migration assay performed towards A549 cell line, revealed that tested compounds reduced significantly cell migration. At the highest concentration tested (200 uM), the covered surface was 7.7%, 9.5% and 35% for caffeic, coumaric or ferulic acids, respectively. These results demonstrate that caffeic, coumaric and ferulic acids may participate as active ingredients in anticancer agents against lung and colon cancer development, at adhesion and migration steps of tumor progression. PMID- 26432690 TI - Tailoring in risk communication by linking risk profiles and communication preferences: The case of speeding of young car drivers. AB - Speeding is one of the most relevant risk behaviors for serious and fatal accidents, particularly among young drivers. This study presents a tailoring strategy for anti-speeding communication. By referring to their motivational dispositions toward speeding derived from motivational models of health behavior, young car drivers were segmented into different risk groups. In order to ensure that risk communication efforts would actually be capable to target these groups, the linkage between the risk profiles and communication preferences were explored. The study was conducted on the basis of survey data of 1168 German car drivers aged between 17 and 24 years. The data reveal four types of risk drivers significantly differing in their motivational profiles. Moreover, the findings show significant differences in communication habits and media use between these risk groups. By linking the risk profiles and communication preferences, implications for tailoring strategies of road safety communication campaigns are derived. Promising segmentation and targeting strategies are discussed also beyond the current case of anti-speeding campaigns. PMID- 26432691 TI - The Danish High Risk and Resilience Study--VIA 7--a cohort study of 520 7-year old children born of parents diagnosed with either schizophrenia, bipolar disorder or neither of these two mental disorders. AB - BACKGROUND: Severe mental illnesses like schizophrenia and bipolar disorder are known to be diseases that to some extent, but not entirely can be understood genetically. The dominating hypothesis is that these disorders should be understood in a neurodevelopmental perspective where genes and environment as well as gene-environment-interactions contribute to the risk of developing the disease. We aim to analyse the influences of genetic risk and environmental factors in a population of 520 7-year-old children with either 0, 1 or 2 parents diagnosed with schizophrenia spectrum psychosis or bipolar disorder on mental health and level of functioning. We hypothesize that a larger proportion of children growing up with an ill parent will display abnormal or delayed development, behavioural problems or psychiatric symptoms compared to the healthy controls. METHODS/DESIGN: We are establishing a cohort of 5207 year old children and both their parents for a comprehensive investigation with main outcome measures being neurocognition, behaviour, psychopathology and neuromotor development of the child. Parents and children are examined with a comprehensive battery of instruments and are asked for genetic material (saliva or blood) for genetic analyses. The participants are recruited via Danish registers to ensure representativity. Data from registers concerning social status, birth complications, somatic illnesses and hospitalization are included in the database. Psychological and relational factors like emotional climate in the family, degree of stimulation and support in the home and attachment style are also investigated. DISCUSSION: Data collection started January 1, 2013, and is successfully ongoing. By Aug 2015 424 families are included. About 20% of the invited families decline to participate, equal for all groups. PMID- 26432692 TI - Adiponectin, leptin and IL-1 beta in elderly diabetic patients with mild cognitive impairment. AB - The aim of the study was to determine the serum levels of adiponectin, leptin and IL-1 beta in elderly diabetic patients with and without mild cognitive impairment (MCI) and to examine the associations of these markers with clinical and cognitive parameters. A biochemical evaluation was performed of 62 seniors with type 2 diabetes (T2DM) and MCI, and 132 seniors with T2DM but without MCI (controls). Serum leptin and IL-1 beta levels were higher and adiponectin concentration was lower in MCI patients than controls. In MCI subjects, adiponectin level was negatively correlated with leptin, IL-1 beta levels and BMI. Leptin concentration was correlated with IL-1 beta level. Univariate logistic regression models revealed that the factors which increased the likelihood of diagnosis of MCI in elderly patients with T2DM were higher levels of HbA1c, leptin, IL-1 beta and triglycerides, as well as lower levels of adiponectin and HDL cholesterol. Similarly, previous CVD, hypertension, hyperlipidemia, retinopathy, nephropathy, hypoglycemia, longer duration of diabetes, increased number of co-morbidities, older age, fewer years of formal education were found to be associated with MCI. The multivariable model indicated fewer years of formal education, previous CVD, hypertension, increased number of co-morbidities, higher HbA1c and IL-1 beta levels and lower adiponectin level. Elderly diabetic patients with MCI have higher levels of leptin and IL-1 beta and lower levels of adiponectin. Further prospective studies are needed to determine the role of these markers in the progression to dementia. PMID- 26432694 TI - Prevalence of exclusively and concomitant pelvic fractures at magnetic resonance imaging of suspect and occult hip fractures. AB - Pelvic fractures may occur together with hip fractures as a result of low energy trauma. It is unclear whether they do require special attention. There are conflicting results in the literature about the prevalence of both concomitant hip and pelvic fractures as well as exclusive pelvic fractures. It has been reported that hip fractures and obturator ring fractures are mutually exclusive. To retrospectively analyze the prevalence of exclusively pelvic as well as concomitant hip and pelvic fractures in patients examined with MRI after low energy trauma in elderly. During 9 years, 316 elderly patients had been examined with MRI for suspected or occult hip fracture after a fall. A fracture was diagnosed when MRI showed focal signal abnormalities in the subcortical bone marrow, with or without disruption of adjacent cortices. One observer reviewed all studies. A second observer verified all studies with hip fractures. Follow-up was available for all but two patients that died prior to hip surgery. The prevalence of concomitant pelvic and femoral neck or trochanteric fractures was statistically compared using chi-squared test for categorical variables. Hip fractures were found in 161 (51 %) patients of which 29 (9 %) had concomitant pelvic fractures. There were exclusively pelvic fractures in 82 (26 %) patients of which 65 (79 %) were on the traumatized side only. In 73 patients, there were no fractures. Occult or suspected hip fractures are not infrequently associated with pelvic fractures. Exclusively pelvic fractures are not uncommon. PMID- 26432693 TI - Multimorbidity, Depression, and Mortality in Primary Care: Randomized Clinical Trial of an Evidence-Based Depression Care Management Program on Mortality Risk. AB - BACKGROUND: Two-thirds of older adults have two or more medical conditions that often take precedence over depression in primary care. OBJECTIVE: We evaluated whether evidence-based depression care management would improve the long-term mortality risk among older adults with increasing levels of medical comorbidity. DESIGN: Longitudinal analyses of the practice-randomized Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT). Twenty primary care practices randomized to intervention or usual care. PATIENTS: The sample included 1204 older primary care patients completing the Charlson Comorbidity Index (CCI) and other interview questions at baseline. INTERVENTION: For 2 years, a depression care manager worked with primary care physicians to provide algorithm based care for depression, offering psychotherapy, increasing the antidepressant dose if indicated, and monitoring symptoms, medication adverse effects, and treatment adherence. MAIN MEASURES: Depression status based on clinical interview, CCI to evaluate medical comorbidity, and vital status at 8 years (National Death Index). KEY RESULTS: In the usual care condition, patients with the highest levels of medical comorbidity and depression were at increased risk of mortality over the course of the follow-up compared to depressed patients with minimal medical comorbidity [hazard ratio 3.02 (95% CI, 1.32 to 8.72)]. In contrast, in intervention practices, patients with the highest level of medical comorbidity and depression compared to depressed patients with minimal medical comorbidity were not at significantly increased risk [hazard ratio 1.73 (95% CI, 0.86 to 3.96)]. Nondepressed patients in intervention and usual care practices had similar mortality risk. CONCLUSIONS: Depression management mitigated the combined effect of multimorbidity and depression on mortality. Depression management should be integral to optimal patient care, not a secondary focus. PMID- 26432695 TI - Peer learning in the UNSW Medicine program. AB - BACKGROUND: The UNSW Australia Medicine program explicitly structures peer learning in program wide mixing of students where students from two adjoining cohorts complete the same course together, including all learning activities and assessment. The purpose of this evaluation is to explore the student experience of peer learning and determine benefits and concerns for junior and senior students. METHODS: All medical students at UNSW Australia in 2012 (n = 1608) were invited to complete the Peer Learning Questionnaire consisting of 26 fixed response items and 2 open-ended items exploring vertical integration and near peer teaching. Assessment data from vertically integrated and non-vertically integrated courses were compared for the period 2011-2013. RESULTS: We received valid responses from 20 % of medical students (n = 328). Eighty percent of respondents were positive about their experience of vertical integration. Year 1 students reported that second year students provided guidance and reassurance (87.8 %), whilst year 2 students reported that the senior role helped them to improve their own understanding, communication and confidence (84 %). Vertical integration had little effect on examination performance and failure rates. CONCLUSIONS: This evaluation demonstrates that vertical integration of students who are one year apart and completing the same course leads to positive outcomes for the student experience of learning. Students benefit through deeper learning and the development of leadership qualities within teams. These results are relevant not only for medical education, but also for other professional higher education programs. PMID- 26432696 TI - Preoperative Prevalence of J-Wave Syndrome Electrocardiographic Patterns and Their Association With Perioperative Cardiac Events. AB - OBJECTIVE: To evaluate the preoperative prevalence of each type of J-wave syndrome electrocardiographic pattern and its association with perioperative cardiac events. DESIGN: Retrospective study. SETTING: Single hospital university study. PARTICIPANTS: The study evaluated 930 patients who underwent gynecologic, abdominal, neurosurgical, orthopedic, and urologic surgeries. INTERVENTIONS: Preoperative standard 12-lead electrocardiogram (ECG) monitoring was performed, and each type of J-wave syndrome ECG pattern-types 1, 2, and 3 and Brugada syndrome-type-was evaluated. Incidence of perioperative cardiac events was investigated up to 1 year postoperatively using an electronic medical record system. MEASUREMENTS AND MAIN RESULTS: Data from 789 patients were included in the final study. Of these, 16 patients (2.0%) had J-wave syndrome: 7 patients (0.9%) had type-1 patterns; 5 patients (0.6%) had type-2 patterns; 2 patients (0.3%) had type-3 patterns; and 2 patients (0.3%) had Brugada syndrome-type ECG patterns. A J-point elevation>=0.2 mV, which is considered to be more dangerous, was found in only 2 patients with Brugada syndrome-type ECG patterns, both of whom suffered perioperative lethal arrhythmias. CONCLUSION: Patients with J-wave syndrome ECG patterns, even dangerous patterns, are not necessarily associated with a higher risk of perioperative cardiac events. However, Brugada syndrome type ECG patterns should be carefully monitored. PMID- 26432697 TI - Combined Lung and Liver Transplantation With Extracorporeal Membrane Oxygenation Instead of Cardiopulmonary Bypass. PMID- 26432698 TI - Predictors of Failure in Fast-Track Cardiac Surgery. AB - OBJECTIVES: Fast-track (FT) management of cardiac surgery patients is associated with early extubation and reduced length of intensive care unit (ICU) stay, with potential benefit of reduced hospital costs. The authors examined perioperative factors and their influence on failure of FT and what implications this failure had. DESIGN: Prospective data collection from all adult cardiac surgeries between 2011 and 2013. SETTING: Single-institution study. PARTICIPANTS: The study included 2,770 consecutive adult cardiac surgery patients. INTERVENTIONS: All participants underwent adult cardiac surgeries. Of those, 451 (16.3%) patients were selected to undergo FT management. MEASUREMENTS AND MAIN RESULTS: Failure of FT was defined as early (admission to ICU on day of surgery) or late (patients later admitted to the ICU from the ward). Univariate and multivariate regression analyses were used to identify which variables predicted FT failure. Of the 451 patients included in this study, 138 (30.6%) failed the FT, with 115 (83.3%) early failures and 23 (16.7%) late failures. Predictors of failure were reduced renal function, hypertension, age, EuroSCORE, cardiopulmonary bypass time, first lactate or base deficit after surgery (all p<0.01), and cross-clamp time (p<0.05). Multivariate analysis showed that the strongest predictor of failure was glomerular filtration rate (GFR)<65 mL/min/BSA (sensitivity, 54%; specificity, 61%; likelihood ratio, 1.39; area under receiver operating characteristics curve, 0.59; 95% confidence interval, 0.53-0.64). Median length of hospital stay was longer for the failed group (5 v 7 days, p<0.001). There were no mortalities in any of the patients selected for FT. CONCLUSIONS: A number of perioperative factors are associated with failure to FT, the strongest predictor being GFR. Failure to FT can lead to significantly longer hospital stay. PMID- 26432699 TI - Toxic shock syndrome toxin-1, not alpha-toxin, mediated Bundaberg fatalities. AB - The 1928 Bundaberg disaster is one of the greatest vaccine tragedies in history. Of 21 children immunized with a diphtheria toxin-antitoxin preparation contaminated with Staphylococcus aureus, 18 developed life-threatening disease and 12 died within 48 h. Historically, the deaths have been attributed to alpha toxin, a secreted cytotoxin produced by most S. aureus strains, yet the ability of the Bundaberg contaminant microbe to produce the toxin has never been verified. For the first time, the ability of the original strain to produce alpha toxin and other virulence factors is investigated. The study investigates the genetic and regulatory loci mediating alpha-toxin expression by PCR and assesses production of the cytotoxin in vitro using an erythrocyte haemolysis assay. This analysis is extended to other secreted virulence factors produced by the strain, and their sufficiency to cause lethality in New Zealand white rabbits is determined. Although the strain possesses a wild-type allele for alpha-toxin, it must have a defective regulatory system, which is responsible for the strain's minimal alpha-toxin production. The strain encodes and produces staphylococcal superantigens, including toxic shock syndrome toxin-1 (TSST-1), which is sufficient to cause lethality in patients. The findings cast doubt on the belief that alpha-toxin is the major virulence factor responsible for the Bundaberg fatalities and point to the superantigen TSST-1 as the cause of the disaster. PMID- 26432700 TI - [Interventions on the spine]. PMID- 26432701 TI - Biochemical insights from population studies with genetics and metabolomics. AB - Genome-wide association studies with concentrations of hundreds of small molecules in samples collected from thousands of individuals (mGWAS) access otherwise inaccessible natural genetic experiments and their influence on the metabolic capacities of the human body. By sampling the natural metabolic and genetic variability that is present in the general population, mGWAS identified over 150 associations between genetic variants and variation in the metabolic composition of human body fluids. Many of these genetic variants were found to be located in enzyme or transporter coding genes, whose functions match the biochemical nature of the associated metabolites. Associations identified by mGWAS can reveal novel biochemical knowledge, such as the function of uncharacterized genes, the biochemical identity of small molecules, and the structure of entire biochemical pathways. Here we review findings of recent mGWAS and discuss concrete examples of how their results can be interpreted in a biochemical context. We describe online resources that are available for mining mGWAS results. In this context, we present two concepts that also find more general applications in the field of metabolomics: strengthening of associations by looking at ratios between metabolite pairs and reconstruction of metabolic pathways by Gaussian graphical modeling. PMID- 26432702 TI - Stepping Into and Out of the Void: Funding Dynamics of Human Embryonic Stem Cell Research in California, Sweden, and South Korea. AB - Nonprofit organizations and philanthropists stepped into a funding void caused by controversies over public funding of human embryonic stem cell (hESC) research. Based on interviews of 83 representatives of 53 funders, we examine the motivations and accountability structures of public agencies, corporations, fundraising dependent nonprofit organizations and philanthropic organizations that funded hESC research in three jurisdictions: California, Sweden, and South Korea. While non-traditional forms of funding are essential in the early stages of research advancement, they are unreliable for the long timeframes necessary to advance cell therapies. Such funding sources may enter the field based on high expectations, but may exit just as rapidly based on disappointing rates of progress. PMID- 26432703 TI - Erratum to: Oxidative Stress and Adult Neurogenesis. PMID- 26432704 TI - Dissecting the taxonomic heterogeneity within Propionibacterium acnes: proposal for Propionibacterium acnes subsp. acnes subsp. nov. and Propionibacterium acnes subsp. elongatum subsp. nov. AB - Propionibacterium acnes subsp. acnes subsp. nov. and Propionibacterium acnes subsp. elongatum subsp. nov. are described. These emanate from the three known phylotypes of P. acnes, designated types I, II and III. Electron microscopy confirmed the filamentous cell shape of type III, showing a striking difference from types I/II, which were short rods. Biochemical tests indicated that, in types I/II, either the pyruvate, l-pyrrolidonyl arylamidase or d-ribose 2 test was positive, whereas all of these were negative among type III strains. Matrix assisted laser-desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) spectra, which profile mainly their ribosomal proteins, were different between these two groups. Surface-enhanced laser-desorption/ionization time-of flight mass spectrometry (SELDI-TOF MS) spectra of all phylotypes revealed a specific protein biomarker that was overexpressed in type III strains compared with types I/II only when grown aerobically. Reference strains had high whole genome similarity between types I (>91 %) and II (>75 %), but a considerably lower level of 72 % similarity with type III. recA and gyrB sequence dendrograms confirmed the distant relatedness of type III, indicating the presence of two distinct centres of variation within the species P. acnes. On the other hand, cellular fatty acid profiles and 16S rRNA gene sequence relatedness (>99.3 %) circumscribed the species. Thus, we propose two subspecies, Propionibacterium acnes subsp. acnes subsp. nov. for types I/II and Propionibacterium acnes subsp. elongatum subsp. nov. for type III. The type strain of Propionibacterium acnes subsp. acnes is NCTC 737T ( = ATCC 6919T = JCM 6425T = DSM 1897T = CCUG 1794T), while the type strain of Propionibacterium acnes subsp. elongatum is K124T ( = NCTC 13655T = JCM 18919T). PMID- 26432705 TI - Laparoscopic versus open peritoneal dialysis catheter insertion for the management of pediatric acute kidney injury. AB - BACKGROUND: Acute pediatric dialysis is provided by a single center in New Zealand. Most acute dialysis in our center is performed in the under 5 age group. The advantage of using peritoneal dialysis (PD) in these children is the ability to perform continuous renal replacement therapy without always requiring an ICU setting, avoiding central venous access and promoting greater cardiovascular stability. The disadvantage of PD in the acute setting includes the requirement for immediate use and the potential for early leaks due to peritoneal disruption with resulting delayed use and restricted volumes. There is a growing trend toward minimally invasive surgery and the laparoscopic method allows this. Surgeons at this center have been using a laparoscopic technique since 2005. METHODS: We performed a 10-year review of acute PD at the Starship Hospital from 2003 to 2013. Data on 102 children who met the criteria were collected. RESULTS: These 102 children had 113 acute PD catheters. The two groups were comparable in terms of age and reason for presentation. The median age of the laparoscopic group was 2 years (interquartile range [IQR] 6) and the open group was 3 years (IQR 3.2). The predominant diagnosis for both groups was hemolytic uremic syndrome (HUS) accounting for 71% of laparoscopic cases, and 72% of open cases. The incidence of infection was 0% versus 7% in the laparoscopic versus open approach. Ten percent of patients required further manipulation of the catheter after initial insertion in the laparoscopic group, compared with 11% in the open approach. Conversion to hemodialysis (HD) due to catheter-related complications was seen in 10% of laparoscopic cases and 9% of the open cases. Dialysate fluid leak was noted in 26% in the laparoscopic group compared with 11% in the open group (p = 0.08). Anesthesia time is longer in the laparoscopic group (p = 0.008). CONCLUSION: We found no significant differences in complication rates between laparoscopic and open surgical approaches regarding acute PD catheter insertion. We saw a trend in increased leakage with laparoscopic procedures and a significantly longer operative time. We concluded that the laparoscopic approach in the acute situation for emergency dialysis is safe and effective. PMID- 26432706 TI - Effect of cholecalciferol on local arterial stiffness and endothelial dysfunction in children with chronic kidney disease. AB - BACKGROUND: As cardiovascular factors are the leading cause of mortality in chronic kidney disease (CKD) and as vitamin D deficiency is prevalent in this population, we aimed to examine the effect of oral cholecalciferol on cardiac parameters and biomarkers for endothelial cell activation in children with CKD. METHODS: Forty-one children with CKD and 24 healthy subjects free of any underlying cardiac or renal disease with low 25-hydroxyvitamin D3 (25OHD) levels were evaluated using echocardiography basally and following Stoss vitamin D supplementation. The local vascular stiffness and endothelial dysfunction markers were compared among the groups. RESULTS: Initial flow-mediated dilatation (FMD) measurements were lower and local arterial stiffness was significantly higher in patients. After vitamin D supplementation, these improved significantly in patients, while no significant change was observed for the healthy group. Homocysteine showed inverse correlation with baseline vitamin D level in CKD children and von Willebrand factor emerged as an independent risk factor for FMD impairment. CONCLUSIONS: Our interventional study revealed the favorable effects of high-dose cholecalciferol on cardiovascular and endothelial parameters, implying the importance of vitamin D supplementation in children with CKD. PMID- 26432707 TI - Characterisation and cytotoxic screening of metal oxide nanoparticles putative of interest to oral healthcare formulations in non-keratinised human oral mucosa cells in vitro. AB - Nanoparticles are increasingly being utilised in the innovation of consumer product formulations to improve their characteristics; however, established links between their properties, dose and cytotoxicity are not well defined. The purpose of this study was to screen four different nanomaterials of interest to oral care product development in the absence of stabilisers, alongside their respective bulk equivalents, within a non-keratinised oral epithelial cell model (H376). Particle morphology and size were characterised using scanning electron microscopy (SEM) and dynamic light scattering (DLS). The H376 model showed that zinc oxide (ZnO) was the most cytotoxic material at concentrations exceeding 0.031% w/v, as assessed using the lactate dehydrogenase (LDH) and dimethylthiazolyl-diphenyl-tetrazolium-bromide (MTT) assays. ZnO cytotoxicity does not appear to be dependent upon size of the particle; a result supported by SEM of cell-particle interactions. Differences in cytotoxicity were observed between the bulk and nanomaterial forms of hydroxyapatite and silica (SiO2); titanium dioxide (TiO2) was well tolerated in both forms at the doses tested. Overall, nano-size effects have some impact on the cytotoxicity of a material; however, these may not be as significant as chemical composition or surface properties. Our data highlights the complexities involved at the nano-scale, in both the characterisation of materials and in relation to cytotoxic properties exerted on oral epithelial cells. PMID- 26432708 TI - Cystic Endosalpingiosis or Multicystic Mesothelioma? PMID- 26432709 TI - Response: Cystic Endosalpingiosis or Multicystic Mesothelioma? PMID- 26432710 TI - Power Morcellator Features Affecting Tissue Spill in Gynecologic Laparoscopy: An In-Vitro Study. AB - STUDY OBJECTIVE: To assess features of power morcellators (blade diameter, circular vs oscillating cutting, blade rotation speed, experience level) regarding their effect on the amount of tissue spill. In addition, the amount of tissue spill after the initial two-thirds and final one-third of the morcellated specimen was evaluated. DESIGN: In vitro study (Canadian Task Force classification II-2). SETTING: Laparoscopic skills lab of an academic hospital. PATIENTS: Not applicable. INTERVENTION: Power morcellation of beef tongue specimens. MEASUREMENTS AND MAIN RESULTS: Twenty-four trials were performed. Morcellation was performed in 2 phases (phase 1: initial two-thirds of the total tissue; phase 2: last one-third of the tissue). With larger blade diameter a decline was observed in both the weight of the spilled particles (phase 1) and the number of spilled particles (phases 1 and 2 and both combined) (weight phase 1: 6.5 g vs 6.3 g vs 2.2 g for 12.5 mm vs 15 mm vs 20 mm, respectively, p = .04; number particles: phase 1, 10.2 vs 7.2 vs 2.7, p = .01; phase 2, 22.9 vs 19.0 vs 8.9, p = .02; total, 34.7 vs 26.2 vs 11.6, p = .01). Also, spinning of the tissue mass due to torque applied by the rotating blade occurred later when blade size increased, and the size of the spilled particles was larger (weight of morcellated tissue at onset of torque: 136 g vs 198 g vs 222 g, p = .07; size: .6 g vs .9 g vs .8 g, p = .1). In the oscillation mode there was less total spill (6.8 g/100 g vs 21.3 g/100 g, p = .01, for oscillation and circular cutting, respectively). CONCLUSION: The present study demonstrates that less spill is created by power morcellators with an oscillating blade and/or a large diameter (>=20 mm). Furthermore, when using a large-diameter blade the spilled particles are larger, and less morcellation repetitions are needed. By combining these features with currently introduced contained morcellation, the safety of the morcellation process with respect to tissue spill can be further improved. PMID- 26432711 TI - Characteristics of elastofibroma dorsi on PET/CT imaging with (18)F-FDG. AB - PURPOSE: To assess the characteristics of 18F-FDG uptake in elastofibroma dorsi (EFD). METHODS: Seventeen patients with EFD were retrospectively studied. RESULTS: The mean+/-S.D. of SUV was 2.29+/-0.60 (range, 1.2-4.3), and the uptake were Grade 0 in 6, Grade 1 in 12, Grade 2 in 7, and Grade 3 in 1. There is no correlation between lesion volume, SUVmax, and computer tomography value. All EFD lesions showed soft tissue density with low or moderate diffused and homogeneous uptake of 18F-FDG. CONCLUSIONS: Mild and moderate uptake of 18F-FDG is frequently observed in EFD, which should be known to avoid making wrong diagnosis. PMID- 26432713 TI - Severe peripheral neuropathy following carfilzomib, rituximab, and dexamethasone for initial treatment of Waldenstrom's macroglobulinemia. PMID- 26432712 TI - [Update peripheral arterial occlusive disease]. AB - Due to demographic changes, peripheral arterial occlusive disease (PAD) has become one of the most prevalent diseases in western industrial nations. In recent years the trend towards initial endovascular treatment approaches has further continued. Because of the high primary success and low complication rates, intervention-based revascularization strategies are the method of choice in the majority of cases. The treatment strategy should always be assessed in a multidisciplinary setting and if possible, within a designated vascular center. One of the main limitations of interventions is the occurrence of restenosis, in particular in infrapopliteal arterial lesions. A major progress arose from drug eluting balloons, which dramatically reduced restenosis rates particular for femoropopliteal lesions. A potential alternative strategy could be the use of a combination therapy, such as plaque removal followed by insertion of drug-eluting balloons; however, economic issues have to be kept in mind for such approaches. PMID- 26432714 TI - Comparing perceptual and preferential decision making. AB - Perceptual and preferential decision making have been studied largely in isolation. Perceptual decisions are considered to be at a non-deliberative cognitive level and have an outside criterion that defines the quality of decisions. Preferential decisions are considered to be at a higher cognitive level and the quality of decisions depend on the decision maker's subjective goals. Besides these crucial differences, both types of decisions also have in common that uncertain information about the choice situation has to be processed before a decision can be made. The present work aims to acknowledge the commonalities of both types of decision making to lay bare the crucial differences. For this aim we examine perceptual and preferential decisions with a novel choice paradigm that uses the identical stimulus material for both types of decisions. This paradigm allows us to model the decisions and response times of both types of decisions with the same sequential sampling model, the drift diffusion model. The results illustrate that the different incentive structure in both types of tasks changes people's behavior so that they process information more efficiently and respond more cautiously in the perceptual as compared to the preferential task. These findings set out a perspective for further integration of perceptual and preferential decision making in a single ramework. PMID- 26432716 TI - Discussion. PMID- 26432715 TI - Is limiting transfusion safe? The devil is in the details. PMID- 26432717 TI - The impact of 6 weeks of atrial fibrillation on left atrial and ventricular structure and function. AB - OBJECTIVE: The impact of prolonged episodes of atrial fibrillation on atrial and ventricular function has been incompletely characterized. The purpose of this study was to investigate the influence of atrial fibrillation on left atrial and ventricular function in a rapid paced porcine model of atrial fibrillation. METHODS: A control group of pigs (group 1, n = 8) underwent left atrial and left ventricular conductance catheter studies and fibrosis analysis. A second group (group 2, n = 8) received a baseline cardiac magnetic resonance imaging to characterize left atrial and left ventricular function. The atria were rapidly paced into atrial fibrillation for 6 weeks followed by cardioversion and cardiac magnetic resonance imaging. RESULTS: After 6 weeks of atrial fibrillation, left atrial contractility defined by atrial end-systolic pressure-volume relationship slope was significantly lower in group 2 than in group 1 (1.1 +/- 0.5 vs 1.7 +/- 1.0; P = .041), whereas compliance from the end-diastolic pressure-volume relationship was unchanged (1.5 +/- 0.9 vs 1.6 +/- 1.3; P = .733). Compared with baseline, atrial fibrillation resulted in a significantly higher contribution of left atrial reservoir volume to stroke volume (32% vs 17%; P = .005) and lower left atrial booster pump volume contribution to stroke volume (19% vs 28%; P = .029). Atrial fibrillation also significantly increased maximum left atrial volume (206 +/- 41 mL vs 90 +/- 21 mL; P < .001). Left atrial fibrosis in group 2 was significantly higher than in group 1. Atrial fibrillation decreased left ventricular ejection fraction (29% +/- 9% vs 58 +/- 8%; P < .001), but left ventricular stroke volume was unchanged. CONCLUSIONS: In a chronic model of atrial fibrillation, the left atrium demonstrated significant structural remodeling and decreased contractility. These data suggest that early intervention in patients with persistent atrial fibrillation might mitigate against adverse atrial and ventricular structural remodeling. PMID- 26432718 TI - Expert opinion is often hot air: It is not the air; it is the clinical evidence. PMID- 26432719 TI - Late outcomes after the Cox maze IV procedure for atrial fibrillation. AB - OBJECTIVE: The Cox maze IV procedure (CMPIV) has been established as the gold standard for surgical ablation; however, late outcomes using current consensus definitions of treatment failure have not been well described. To compare to reported outcomes of catheter-based ablation, we report our institutional outcomes of patients who underwent a left-sided or biatrial CMPIV at 5 years of follow-up. METHODS: Between January 2002 and September 2014, data were collected prospectively on 576 patients with AF who underwent a CMPIV (n = 532) or left sided CMPIV (n = 44). Perioperative variables and long-term freedom from AF, with and without AADs, were compared in multiple subgroups. RESULTS: Follow-up at any time point was 89%. At 5 years, overall freedom from AF was 93 of 119 (78%), and freedom from AF off AADs was 77 of 177 (66%). No differences were found in freedom from AF, with or without AADs, at 1, 2, 3, 4, and 5 years for patients with paroxysmal AF (n = 204) versus with persistent/longstanding persistent AF (n = 305), or for those who underwent standalone versus a concomitant CMP. Duration of preoperative AF and hospital length of stay were the best predictors of failure at 5 years. CONCLUSIONS: The outcomes of the CMPIV remain good at late follow-up. The type of preoperative AF or the addition of a concomitant procedure did not affect late success. The results of the CMPIV remain superior to those reported for catheter ablation and other forms of surgical AF ablation, especially for patients with persistent or longstanding AF. PMID- 26432720 TI - Large clinical databases for the study of lung cancer: Making up for the failure of randomized trials. PMID- 26432721 TI - One-year clinical and angiographic results of hybrid coronary revascularization. AB - OBJECTIVE: To evaluate 1-year clinical and angiographic results after hybrid coronary revascularization (HCR) combining off-pump left internal mammary artery (LIMA) grafting through an inferior J-hemisternotomy with percutaneous coronary intervention (PCI). METHODS: Prospective, single-arm clinical feasibility study including 100 consecutive patients with multivessel disease undergoing staged HCR. The primary endpoint was the major adverse cardiac and cerebrovascular event rate at 1 year. Secondary endpoints included 1-year all-cause death, stroke, myocardial infarction, repeat revascularization, and angiographic graft and stent patency. RESULTS: One-year clinical follow-up data were available in all patients. The primary endpoint was met by 20 patients (20%). Individual endpoints were as follows: 1 death due to heart failure; 1 stroke, 2 procedure-related myocardial infarctions; and 1 spontaneous myocardial infarction during follow-up. A total of 16 patients underwent repeat revascularization: 5 surgical reinterventions during the index hospitalization for angiographically suspected internal mammary artery graft dysfunction, and 3 repeat PCIs. Only 1 patient had evidence of ischemia. After discharge, PCI was performed in 6 patients who had recurrent angina, and in 2 asymptomatic patients who had angiographic restenosis. At the 1-year angiographic follow-up, 87 of 89 (98%) patients had patent internal mammary artery grafts. Angiographic restenosis was present in 10 of 100 lesions treated by PCI. CONCLUSIONS: Angiographically controlled HCR was associated with a high repeat revascularization rate. The 1-year 98% LIMA-graft patency rate, and low risk of death and stroke, seem promising for the long-term outcome. Non-left anterior descending coronary artery lesion revascularization remains a challenge. PMID- 26432722 TI - Minimally invasive mitral valve surgery is associated with equivalent cost and shorter hospital stay when compared with traditional sternotomy. AB - OBJECTIVE: Mitral valve surgery is increasingly performed through minimally invasive approaches. There are limited data regarding the cost of minimally invasive mitral valve surgery. Moreover, there are no data on the specific costs associated with mitral valve surgery. We undertook this study to compare the costs (total and subcomponent) of minimally invasive mitral valve surgery relative to traditional sternotomy. METHODS: All isolated mitral valve repairs performed in our health system from March 2012 through September 2013 were analyzed. To ensure like sets of patients, only those patients who underwent isolated mitral valve repairs with preoperative Society of Thoracic Surgeons scores of less than 4 were included in this study. A total of 159 patients were identified (sternotomy, 68; mini, 91). Total incurred direct cost was obtained from hospital financial records. RESULTS: Analysis demonstrated no difference in total cost (operative and postoperative) of mitral valve repair between mini and sternotomy ($25,515 +/- $7598 vs $26,049 +/- $11,737; P = .74). Operative costs were higher for the mini cohort, whereas postoperative costs were significantly lower. Postoperative intensive care unit and total hospital stays were both significantly shorter for the mini cohort. There were no differences in postoperative complications or survival between groups. CONCLUSIONS: Minimally invasive mitral valve surgery can be performed with overall equivalent cost and shorter hospital stay relative to traditional sternotomy. There is greater operative cost associated with minimally invasive mitral valve surgery that is offset by shorter intensive care unit and hospital stays. PMID- 26432724 TI - Respect for nursing professional: silence must be heard. AB - The value of care giving seems to be at an all-time low. whether it is clinical (bedside) or for children and elderly at home (homemakers). Currently, individuals who pass away any opportunity (for themselves) to care for another individual instead are considered weak and/or unmotivated. Thus, it is not surprising that modern society often fails to respect the nursing professionals to the extent of underplaying their strengths, skills, and even clinical abilities. While qualities such as kindness, team spirit, and willingness to get their hands dirty are the core of this profession, nursing professionals have a complex variety of set duties, involving drug dosage, trouble-shooting, ongoing patient monitoring, and providing holistic comfort and support to the sick and needy. Beyond classical role, the nursing professional has currently ventured into other roles as well, as a nurse practitioner, administrator, researcher, or even an educator. Thus, considering the wide spectrum of duties performed by nursing professionals, they do deserve more status and power rather than be treated like "ward housewives." PMID- 26432725 TI - Subvalvular disease in patients undergoing balloon mitral valvotomy: a strong base is not always good. PMID- 26432723 TI - Signaling pathway and dysregulation of PD1 and its ligands in lymphoid malignancies. AB - Tumor cells evade immune destruction, at least partially, by upregulating inhibitory signals to limit effector T cell activation. Programmed death 1 (PD-1) is one of the most critical co-inhibitory molecules limiting the T-cell antitumor response. PD-1 and its ligands, PD-L1 and PD-L2, are overexpressed by various types of tumors as well as reactive cells in the tumor microenvironment. A growing body of evidence has shown the clinical efficiency and minimal toxicity of PD-1 pathway inhibitors in patients with solid tumors, but the role of these inhibitors in lymphoid malignancies is much less well studied. In this review, we analyze the pathologic role of the PD-1 pathway in most common lymphoid malignancies and we organize the clinical data from clinical trials of PD-1 pathway inhibitors. Several anti-PD-1 regimens have shown encouraging therapeutic effects in patients with relapsed or refractory Hodgkin lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. Additional progress is needed to foster an improved understanding of the role of anti-PD-1 therapy in reconstituting antitumor immunity in patients with lymphoid malignancies. Upcoming trials will explore the clinical efficiency of combining PD-1 pathway inhibitors and various agents with diverse mechanisms of action and create more therapeutic possibilities for afflicted patients. PMID- 26432727 TI - Doctors at cross road. PMID- 26432726 TI - LDL cholesterol, statins and PCSK 9 inhibitors. AB - Reduction of low density lipoprotein cholesterol (LDLc) is of vital importance for the prevention of atherosclerotic cardiovascular disease (ASCVD). Statin is the most effective therapy today to lower LDLc by inhibiting HMG-CoA-reductase. However despite intensive statin therapy, there remains a residual risk of recurrent myocardial infarction in about 20-30% cases. Moreover a few patients develop statin intolerance. For severe hypercholesterolemia, statins alone or in combination of ezetimibe, niacin and fenofibrate have been advocated. For homozygous familial hypercholesterolemia (HOFH), a microsomal triglyceride transfer protein MTP inhibitor (Lopitamide) and antisense oligonucleotide (ASO) (Mipomersen) have recently been approved by FDA, USA through 'Risk evaluation and Mitigation Strategy (REMS)'. Possible future therapies include PCSK-9 inhibitors which have excellent lipid lowering properties. Three monoclonal antibodies (PCSK 9 Inhibitors) alirocumab, evolocumab and Bococizumab are under advanced clinical stage IV trials and awaiting approval by FDA and European Medicines Agency. PMID- 26432728 TI - Rejuvenating practice of medicine. PMID- 26432729 TI - Subvalvular apparatus and adverse outcome of balloon valvotomy in rheumatic mitral stenosis. AB - BACKGROUND: Balloon mitral valvotomy (BMV) is a well-established therapeutic modality for rheumatic mitral stenosis (RMS). However, there are chances of procedural failure and the more ominous post-procedural severe mitral regurgitation. There are only a few prospective studies, which have evaluated the pathogenic mechanisms for these major complications of BMV, especially in relation to the subvalvular apparatus (SVA) pathology. METHODS: All symptomatic patients of RMS suitable for BMV by echocardiographic criteria in a span of 1 year were selected. In addition to the standard echocardiographic assessment of RMS (Wilkins score and score by Padial et al.), a separate grading and scoring system was assigned to evaluate the severity of the SVA pathology. The SVA score was 'I', when none of the two SVAs had severe disease, 'II' when one of the two SVAs has severe disease, and 'III' when both SVAs had severe disease. With these scoring systems, the outcomes of BMV (successful procedure, failure, and post procedural mitral regurgitation) were analyzed. Emergency valve replacement was performed depending on clinical situation, and in cases of replacement, the pathology of the excised mitral valves were compared with echocardiographic findings. RESULTS: Of the 356 BMVs performed in a year, 43 patients had adverse outcomes in the form of failed procedure (14 patients) and mitral regurgitation (29 patients). Forty-one among these had a SVA score of III. The sensitivity and specificity of the MR score was lesser than the SVA score (sensitivity 0.34 vs. 1.00, specificity 0.92 vs. 0.99, respectively). The mitral valvular morphology in 39 patients who underwent post-procedural valve replacements correlated well with echocardiography findings. CONCLUSION: It is important to assess the degree of SVA pathology in the conventional echocardiographic assessment for RMS, as BMV would have adverse events when both SVAs were severely diseased. PMID- 26432730 TI - Association of ST elevation with apical aneurysm in hypertrophic cardiomyopathy. AB - OBJECTIVES: Apical aneurysms in patients with hypertrophic cardiomyopathy (HCM) represent an underrecognized but clinically important subset of HCM patients. However it may be frequently missed by echocardiography because of poor image quality of left ventricular apex. We aimed to compare electrocardiographic STE in HCM patients with and without apical aneurysm. METHODS: We developed this clinical review using an extensive MEDLINE review of the literature and data from our laboratories; and some electrocardiographic parameters including STE were analysed in HCM patients with and without apical aneurysm. RESULTS: There were 29 HCM patients without apical aneurysm (Group 1; 52.6+/-17.7years, 69% male) and 28 HCM patients with apical aneurysm (Group 2; 59.6+/-13.2years, 57% male). The STE in V4-6 derivations were statistically more frequent in patients with apical aneurysm compared to those without aneurysm (93% vs 7%, p<0.001). There was a positive correlation between the presence of the STE in V4-6 derivations and the presence of the apical aneurysm (Spearman's rho=0.895, p<0.001). CONCLUSIONS: Clinicians and specifically echocardiographers must pay special attention on the electrocardiography to correctly detect the frequently overlooked apical aneurysm in HCM patients, and should be careful for apical aneurysm particularly in the presence of STE in V4-6 derivations. PMID- 26432731 TI - Periprocedural plasma fibrinogen levels and coronary stent outcome. AB - AIM: Percutaneous intervention is one of the treatment option for coronary artery disease. Reinfarction and restenosis is one of the complication of the procedure. So this study was conducted to assess plasma fibrinogen levels pre- and post coronary stenting and its relation with outcome. METHODS: After obtaining informed consent, venous blood samples were collected at three timed points in relation to stenting - 24h before, 24h after and 72h after stenting to assess fibrinogen levels. Patients were followed up for six months. Repeat revascularization, myocardial infarction and symptomatic angina were considered as major adverse clinical events. RESULTS: 57 patients who underwent successful stenting and followed up for six months up were included in the study. Mean age was 53 years and 87.7% were males and 29.8% were diabetics. Baseline plasma fibrinogen level was significantly high in patients who developed repeat angina and myocardial infarction after the stenting [288.64+/-59.43 vs 393.75+/ 32.97mg/dL, p=0.003] and it remained high during serial assessment [322.74+/ 63.92 vs 422.00+/-55.28mg/dL, 326.23+/-65.81 vs 419.50+/-45.82mg/dL, 0.008, 0.012 respectively]. Patients who developed adverse events denied any drug default. CONCLUSION: We conclude that plasma fibrinogen plays a significant role in the development of adverse events following stenting shown by high level of plasma fibrinogen in patients who developed adverse events. PMID- 26432734 TI - Device closure of pulmonary arteriovenous malformation using Amplatzer vascular plug II in hereditary hemorrhagic telangiectasia. AB - Pulmonary arteriovenous malformations (AVM) are very rare and carry the risk of cerebral thrombo-embolism, brain abscess or pulmonary hemorrhage. The Amplatzer vascular plug II (AVP II) is a new device, used for embolization of the pulmonary AVMs. We report a case of pulmonary AVM successfully managed by using AVP II in a patient with hereditary hemorrhagic telangiectasia (HHT). PMID- 26432732 TI - Do circulating blood cell types correlate with modifiable risk factors and outcomes in patients with acute coronary syndrome (ACS)? AB - AIMS: Atherosclerosis is an inflammatory process with different cardiovascular risk factors (CVRFs) contributing to its pathogenesis. We aimed to evaluate the specific relationship between circulating blood leukocytes, troponin I and CVRFs. METHODS: We prospectively enrolled 959 patients with evidence of acute coronary syndrome either in form of unstable angina or STEMI or NSTEMI. Details demographic characteristics, CVRF and biochemical parameters such as total white blood cells (WBC), neutrophil, lymphocytes, platelet, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and troponin I were collected. RESULTS: The results indicated that patients having either hypertension, diabetes or smoking habit had significantly higher levels of total WBC (p=0.013), neutrophil (p=0.029), NLR (p=0.029) and PLR (p=0.009). The level of troponin I was unaffected by these risk factors. Significant association of hypertension was found with total WBC (p=0.0392), lymphocytes (p=0.0384) and PLR (p=0.0027), whereas in diabetes and females all other leukocyte subtypes were significantly altered except for platelet and troponin I. Smokers had higher level of total WBC count (p=0.0033) and PLR (p=0.0464). No relationship between CVRFs and leukocytes was observed in males. The age independent effect was observed with PLR, whereas association with total WBC, lymphocytes, NLR, platelet was specific in older population. In younger patients NLR (p=0.0453) is more likely to be elevated. Mortality was significantly associated with changes in the leukocytes but not with the CVRF presence. CONCLUSION: We demonstrate that the neutrophils, lymphocytes and total WBC along with its ratios predict mortality and are more likely to be elevated in presence of CVRFs. PMID- 26432733 TI - Inadvertent transarterial pacemaker lead placement. AB - We present a case of a 73-year-old patient with acute left-sided hemiparesis four months after right ventricular pacemaker insertion. Post-procedural electrocardiogram revealed a paced RBBB complex and an abnormal lead path on chest X-ray. Subsequent echocardiography and computed tomography showed left ventricular pacemaker malposition with retrograde passage to the punctured subclavian artery. We also discuss the utility of routine cardiac investigations post-insertion to identify signal lead malposition as well as management strategies once identified. PMID- 26432735 TI - Isolated quadricuspid aortic valve referred with diagnosis of rheumatic carditis. AB - Quadricuspid aortic valve is a rare congenital malformation of the aortic valve. It appears often isolated or sometimes associated with other truncal anomalies, and approximately 50% of patients have aortic regurgitation. In this article we reported an eight-years-old boy referred with diagnose of rheumatic carditis from the outer medical center. PMID- 26432736 TI - Use of ADO II device in a large aorto-pulmonary collateral -an interesting case. AB - A 11month old girl was diagnosed to have a large aorto pulmonary collateral during evaluation for respiratory distress and seizures. Echocardiographic evaluation showed a large collateral from the descending aorta to left lung with ventricular dysfunction (left ventricular ejection fraction of 40%). This was confirmed on computed tomography angiogram (CT) scan. The collateral was closed with Amplatzer Ductal Occluder II device under fluoroscopic guidance. To the best of our knowledge, this is the first reported case of large aorto-pulmonary collateral closed successfully with an Amplatzer Ductal Occluder II device. PMID- 26432737 TI - Postoperative diffuse coronary spasm after two valve surgery - a rare phenomenon. AB - Postoperative coronary artery spasm is one of the grave complications of cardiac surgery and is usually seen in patients undergoing coronary artery bypass surgery. We describe the case of a 63 year old male patient developing postoperative spasm of the entire coronary tree after aortic & mitral valve replacement, manifesting as significant electrocardiographic changes. Urgent coronary angiography was performed which revealed diffuse spasm of the entire coronary tree. It resolved completely with intracoronary injection of Nitroglycerine. The present case highlights the likelihood of postoperative coronary spasm even after valve replacement surgery, and not just coronary bypass surgery. It also illustrated the usefulness of coronary angiography for both diagnosis and treatment of this entity. PMID- 26432738 TI - Wong's anomaly - a rare variant of cor triatriatum. AB - Cor triatriatum sinistrum is an extremely rare congenital heart disease. It is even more uncommon in adults, and clinically significant mitral valve lesion complicating cor triatriatum is distinctly rare. Wong et al reported for the first time the rare combination of cor triatriatum sinister associated with severe mitral regurgitation and abnormal tensor apparatus of the mitral valve. We report a similar case and used the term Wong's anomaly for the syndrome, having membranous type of cor triatriatum sinistrum, severe mitral regurgitation and hypoplasia of the papillary muscles and short chordae. Color Doppler Echocardiography showed peculiar 'helmet sign' of mitral regurgitation, wherein the mitral regurgitation color jet fills the distal atrial chamber and abruptly ends in a horizontal plane as it is halted by the intra-atrial membrane. PMID- 26432739 TI - 'Action potential-like' ST elevation following pseudo-Wellens' electrocardiogram. AB - Coronary artery vasospasm is an important cause of chest pain syndromes that can lead to myocardial infarction, ventricular arrhythmias, and sudden death. In 1959, Prinzmetal et al described a syndrome of nonexertional chest pain with ST segment elevation on electrocardiography. Persistent angina is challenging, and repeated coronary angioplasty may be required in this syndrome. Calcium antagonists are extremely effective in treating and preventing coronary spasm, and may provide long-lasting relief for the patient. Whereas the Wellens' syndrome is characterized by symmetrically inverted T-waves with preserved R waves in the precordial leads suggestive of impending myocardial infarction due to a critical proximal left anterior descending stenosis, the pseudo-Wellens' syndrome caused by coronary artery spasm has also rarely been reported in literature. We present a pseudo-Wellens syndrome as a cause of vasospastic angina, and a diffuse ST segment elavation on electrocardiogram resembling the Greek letter lambda, called also 'action potential-like' ECG in a patient with vasospastic-type Printzmetal angina. PMID- 26432740 TI - Challenges in coronary CTO intervention after TAVR: a case report and discussion. AB - Progression of coronary arteries after transcatheter aortic valve replacement is an important issue. Coronary revascularization in these patients can be challenging because of potential hindrance posed by the artificial valve structure in getting access to the coronary ostium. This gets even more difficult in chronic total occlusions (CTOs) that represent the most complex subset of coronary lesions. We report the first case of coronary CTO revascularization in a patient who underwent TAVR a few months prior and discuss the complexities involved in intervening such lesions. PMID- 26432741 TI - Apparently intact mitral valve repair complicated with hemolytic anemia. PMID- 26432742 TI - Systolic murmur in a young man who had previous ventricular septal defect repair: the double-chambered right ventricle. PMID- 26432743 TI - The evanescent right atrial mass. AB - An unusual cause of pulmonary emboli from an evanescent right atrial mass is described in this case report. The systematic approach from initial presentation to a definite diagnosis of a rare condition is described. PMID- 26432744 TI - Double chamber right ventricle and left ventricle: a rare association. PMID- 26432745 TI - Missing diagnosis: gingival hypertrophy due to amlodipine. AB - Gingival hypertrophy (GH) is a well-known physical manifestation due to inflammatory conditions, pregnancy, vitamin C deficiency, systemic diseases like leukemia, Wegners granulomatosis, and various drugs like anticonvulsants, immunosuppresant, and calcium channel blockers (CCBs).We present here a case of a 45-year-old woman, who has been taking Amlodipine 10mg once a day together with Atenelol 50mg per day for one and half years, and has subsequently developed gum hypertrophy. This manifestation was reversed after stopping of Amlodipine. Though this case presentation is described in literature, we hereby present it in a pictorial form, to sensitize the treating physician toward it. PMID- 26432746 TI - Successful coil embolization of a bleeding internal thoracic artery that caused severe hypotension immediately after permanent pacemaker placement. PMID- 26432747 TI - Dabigatran for left ventricular thrombus. AB - Male patient in dilated phase of hypertrophic cardiomyopathy had multiple hospitalizations during the past 2 years either due to congestive heart failure, stroke, scar epilepsy, or atrial fibrillation and ventricular tachycardia. Medication included evidence based therapy for heart failure, cordarone and warfarin. Anticoagulation had to be discontinued due to marked fluctuations in INR. Transthoracic Echocardiography (TTE) revealed a mobile mass in the left ventricle. He was treated with Dabigatran 110mg twice a day for 4 months without any bleeding or embolic episode and complete resolution of thrombus. Dabigatran is a reversible direct thrombin inhibitor and currently approved for the prevention of thromboembolic episodes in non-valvar atrial fibrillation. This case demonstrates possible thrombolytic properties of dabigatran in resolution of left ventricular thrombus. PMID- 26432749 TI - Calcific aortic valve disease: is it another face of atherosclerosis? AB - Calcific aortic valve disease (CAVD) is the most common valvular heart disease in the elderly. As life expectancy increases, prevalence of CAVD is expected to rise. CAVD is characterized by progressive dystrophic calcification of aortic cusps. In the initial stages, the pathogenesis is similar to atherosclerosis, characterized by basement membrane disruption, inflammation, cell infiltration, lipid deposition, and calcification. Presence of osteopontin in calcified aortic valves suggests pathological calcification and bone formation in these calcified valves. Historical, experimental, genetic, and clinical evidences suggest that CAVD and atherosclerosis share the same pathological sequences with common risk factors. Understanding the two faces of atherosclerosis, the vascular and valvular, will help us to prevent progression of aortic sclerosis to aortic stenosis, by controlling modifiable risk factors and by initiating statin therapy in them. However, the knowledge about these preventive measures and drugs is scanty. In this review article, an attempt is made to unfurl the relation between atherosclerosis and CAVD. PMID- 26432748 TI - Framework for a National STEMI Program: consensus document developed by STEMI INDIA, Cardiological Society of India and Association Physicians of India. AB - The health care burden of ST elevation myocardial infarction (STEMI) in India is enormous. Yet, many patients with STEMI can seldom avail timely and evidence based reperfusion treatments. This gap in care is a result of financial barriers, limited healthcare infrastructure, poor knowledge and accessibility of acute medical services for a majority of the population. Addressing some of these issues, STEMI India, a not-for-profit organization, Cardiological Society of India (CSI) and Association Physicians of India (API) have developed a protocol of "systems of care" for efficient management of STEMI, with integrated networks of facilities. Leveraging newly-developed ambulance and emergency medical services, incorporating recent state insurance schemes for vulnerable populations to broaden access, and combining innovative, "state-of-the-art" information technology platforms with existing hospital infrastructure, are the crucial aspects of this system. A pilot program was successfully employed in the state of Tamilnadu. The purpose of this article is to describe the framework and methods associated with this programme with an aim to improve delivery of reperfusion therapy for STEMI in India. This programme can serve as model STEMI systems of care for other low-and-middle income countries. PMID- 26432750 TI - Transradial approach for coronary angiogram: something not to be neglected. PMID- 26432752 TI - Atrazine triggers developmental abnormality of ovary and oviduct in quails (Coturnix Coturnix coturnix) via disruption of hypothalamo-pituitary-ovarian axis. AB - There has been a gradual increase in production and consumption of atrazine (ATR) in agriculture to meet the population rising demands. Female reproduction is necessary for growth and maintenance of population. However, ATR impact on females and particularly ovarian developmental toxicity is less clear. The aim of this study was to define the pathways by which ATR exerted toxic effects on ovarian development of ovary and hypothalamo-pituitary-ovarian (HPO) axis. Female quails were dosed by oral gavage from sexual immaturity to maturity with 0, 50, 250 and 500 mg ATR/kg/d for 45 days. ATR had no effect on mortality but depressed feed intake and growth and influenced the biochemical parameters. Notably, the arrested development of ovaries and oviducts were observed in ATR-exposed quails. The circulating concentrations of E2, P, LH and PRL were unregulated and FSH and T was downregulated in ATR-treated quails. The mRNA expression of GnRH in hypothalamo and LH in pituitary and FSH in ovary was downregulated significantly by ATR exposure and FSH and PRL in pituitary were upregulated. ATR exposure upregulated the level of P450scc, P450arom, 3beta-HSD and 17beta-HSD in ovary and downregulated ERbeta expression in female quails. However, ATR did not change ERalpha expression in ovary. This study provides new insights regarding female productive toxicology of ATR exposure. Ovary and oviduct in sexually maturing females were target organs of ATR-induced developmental toxicity. We propose that ATR-induced developmental abnormality of ovary and oviduct is associated with disruption of gonadal hormone balance and HPO axis in female quails. PMID- 26432754 TI - What went wrong at Addenbrooke's? PMID- 26432753 TI - Molecular imaging of aurora kinase A (AURKA) expression: Synthesis and preclinical evaluation of radiolabeled alisertib (MLN8237). AB - INTRODUCTION: Survival of patients after resection of colorectal cancer liver metastasis (CRCLM) is 36%-58%. Positron emission tomography (PET) tracers, imaging the expression of prognostic biomarkers, may contribute to assign appropriate management to individual patients. Aurora kinase A (AURKA) expression is associated with survival of patients after CRCLM resection. METHODS: We synthesized [(3)H]alisertib and [(11)C]alisertib, starting from [(3)H]methyl nosylate and [(11)C]methyl iodide, respectively. We measured in vitro uptake of [(3)H]alisertib in cancer cells with high (Caco2), moderate (A431, HCT116, SW480) and low (MKN45) AURKA expression, before and after siRNA-mediated AURKA downmodulation, as well as after inhibition of P-glycoprotein (P-gp) activity. We measured in vivo uptake and biodistribution of [(11)C]alisertib in nude mice, xenografted with A431, HCT116 or MKN45 cells, or P-gp knockout mice. RESULTS: [(3)H]Alisertib was synthesized with an overall yield of 42% and [(11)C]alisertib with an overall yield of 23%+/-9% (radiochemical purity >=99%). Uptake of [(3)H]alisertib in Caco2 cells was higher than in A431 cells (P=.02) and higher than in SW480, HCT116 and MKN45 cells (P<.01). Uptake in A431 cells was higher than in SW480, HCT116 and MKN45 cells (P<.01). Downmodulation of AURKA expression reduced [(3)H]alisertib uptake in Caco2 cells (P<.01). P-gp inhibition increased [(3)H]alisertib uptake in Caco2 (P<.01) and MKN45 (P<.01) cells. In vivo stability of [(11)C]alisertib 90min post-injection was 94.7%+/-1.3% and tumor-to background ratios were 2.3+/-0.8 (A431), 1.6+/-0.5 (HCT116) and 1.9+/-0.5 (MKN45). In brains of P-gp knockout mice [(11)C]alisertib uptake was increased compared to uptake in wild-type mice (P<.01) CONCLUSIONS: Radiolabeled alisertib can be synthesized and may have potential for the imaging of AURKA, particularly when AURKA expression is high. However, the exact mechanisms underlying alisertib accumulation need further investigation. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Radiolabeled alisertib may be used for non-invasively measuring AURKA protein expression and to stratify patients for treatment accordingly. PMID- 26432755 TI - Hemisynthesis, Antitumoral Effect, and Molecular Docking Studies of Ferutinin and Its Analogues. AB - The natural product ferutinin was shown to act as an agonist to estrogen receptor ERalpha and agonist/antagonist to ERbeta featuring a weak antiproliferative activity toward breast cancer cells. To enhance this activity, ferutinin analogues were synthesized by esterification of jaeschkenadiol with different acids. These compounds were assayed for their in vitro antiproliferative activity against estrogen-dependent (MCF-7) and estrogen-independent (MDA-MB-231) breast cancer cell lines. Among the compounds, 3c' exhibited a potent inhibitory selective activity against MCF-7 with IC50 value of 1 MUM. Docking simulation of 3c' in the ligand binding domain of the ERs indicated a potential antagonism interaction with both ER subtypes. Functional assay showed that 3c' binds as an antagonist to ERalpha protein while ferutinin acts as an agonist. PMID- 26432758 TI - Protein-caloric dietary restriction inhibits mossy fiber sprouting in the pilocarpine model of TLE without significantly altering seizure phenotype. AB - Given the known effects of undernutrition over protein synthesis, we promoted neonatal undernutrition to evaluate its effect over the neuroplasticity induced by the pilocarpine model of epilepsy and also over spontaneous seizure expression. A well-nourished group (WN), fed ad libitum rat chow diet, and an undernourished group (UN), fed 60% of the amount of diet consumed by a WN group, were submitted to status epilepticus (SE) through pilocarpine injection at 45 days of age. Thereafter, animals were behaviorally monitored for 6h daily to quantify seizures. On the 120th day, electroencephalography (EEG) was recorded and rats were sacrificed to measure proteins and glutamate release from hippocampus. Neo-Timm staining was used to detect mossy fiber sprouting. The results indicate no statistical difference in the latency for the first spontaneous recurrent seizure (SRS), in the number of daily SRS, or in EEG epileptiform activity duration between groups. However, PILO promoted more K(+) stimulated glutamate release in the hippocampus slices from WN animals when compared to the UN group. It was also found a lower degree of mossy fibers sprouting in UN group. Data from this work, thus, indicate that the decreased neuroplasticity as currently measured does not directly impact on the manifestation of spontaneous seizures. PMID- 26432751 TI - Deregulation of F-box proteins and its consequence on cancer development, progression and metastasis. AB - F-box proteins are substrate receptors of the SCF (SKP1-Cullin 1-F-box protein) E3 ubiquitin ligase that play important roles in a number of physiological processes and activities. Through their ability to assemble distinct E3 ubiquitin ligases and target key regulators of cellular activities for ubiquitylation and degradation, this versatile group of proteins is able to regulate the abundance of cellular proteins whose deregulated expression or activity contributes to disease. In this review, we describe the important roles of select F-box proteins in regulating cellular activities, the perturbation of which contributes to the initiation and progression of a number of human malignancies. PMID- 26432760 TI - Posttraumatic seizures and epilepsy in adult rats after controlled cortical impact. AB - Posttraumatic epilepsy (PTE) has been modeled with different techniques of experimental traumatic brain injury (TBI) using mice and rats at various ages. We hypothesized that the technique of controlled cortical impact (CCI) could be used to establish a model of PTE in young adult rats. A total of 156 male Sprague Dawley rats of 2-3 months of age (128 CCI-injured and 28 controls) was used for monitoring and/or anatomical studies. Provoked class 3-5 seizures were recorded by video monitoring in 7/57 (12.3%) animals in the week immediately following CCI of the right parietal cortex; none of the 7 animals demonstrated subsequent spontaneous convulsive seizures. Monitoring with video and/or video-EEG was performed on 128 animals at various time points 8-619 days beyond one week following CCI during which 26 (20.3%) demonstrated nonconvulsive or convulsive epileptic seizures. Nonconvulsive epileptic seizures of >10s were demonstrated in 7/40 (17.5%) animals implanted with 2 or 3 depth electrodes and usually characterized by an initial change in behavior (head raising or animal alerting) followed by motor arrest during an ictal discharge that consisted of high amplitude spikes or spike-waves with frequencies ranging between 1 and 2Hz class 3-5 epileptic seizures were recorded by video monitoring in 17/88 (19%) and by video-EEG in 2/40 (5%) CCI-injured animals. Ninety of 156 (58%) animals (79 CCI injured, 13 controls) underwent transcardial perfusion for gross and microscopic studies. CCI caused severe brain tissue loss and cavitation of the ipsilateral cerebral hemisphere associated with cell loss in the hippocampal CA1 and CA3 regions, hilus, and dentate granule cells, and thalamus. All Timm-stained CCI injured brains demonstrated ipsilateral hippocampal mossy fiber sprouting in the inner molecular layer. These results indicate that the CCI model of TBI in adult rats can be used to study the structure-function relationships that underlie epileptogenesis and PTE. PMID- 26432761 TI - [Influenza vaccination in risk groups. 2013-2014 season in the Community of Valencia]. PMID- 26432759 TI - Pilocarpine-induced status epilepticus in mice: A comparison of spectral analysis of electroencephalogram and behavioral grading using the Racine scale. AB - Pilocarpine-induced status epilepticus (SE) is a widely used seizure model in mice, and the Racine scale has been used to index seizure intensity. The goal of this study was to analyze electroencephalogram (EEG) quantitatively using fast Fourier transformation (FFT) and statistically evaluate the correlation of electrographic seizures with convulsive behaviors. Simultaneous EEG and video recordings in male mice in a mixed genetic background were conducted and pilocarpine was administered intraperitoneally to induce seizures. The videos were graded using the Racine scale and the root-mean-square (RMS) power analysis of EEG was performed with Sirenia Seizure Pro software. We found that the RMS power was very weakly correlated with convulsive behavior induced by pilocarpine. Convulsive behaviors appeared long before electrographic seizures and showed a strong negative correlation with theta frequency activity and a moderate positive correlation with gamma frequency activity. Racine scores showed moderate correlations with RMS power across multiple frequency bands during the transition from first electrographic seizure to SE. However, there was no correlation between Racine scores and RMS power during the SE phase except a weak correlation with RMS power in the theta frequency. Our analysis reveals limitations of the Racine scale as a primary index of seizure intensity in status epilepticus, and demonstrates a need for quantitative analysis of EEG for an accurate assessment of seizure onset and severity. PMID- 26432762 TI - [Co-existence of Crohn's disease and primary immune thrombocytopenia and its implications in treatment]. PMID- 26432763 TI - Targeting Treg signaling for the treatment of autoimmune diseases. AB - Regulatory T (Treg) cells are crucial players in the prevention of autoimmunity. Treg lineage commitment and functional stability are influenced by selected extracellular signals from the local environment, shaped by distinctive intracellular signaling network, and secured by their unique epigenetic profile. Recent advances in our understanding of the complex processes of Treg lineage differentiation, maintenance, and function has paved the way for developing strategies to manipulate these important cells for therapeutic benefit in many diseases. In this review, we will summarize recent advances in our understanding of Treg biology as well as Treg-targeted therapies in the context of autoimmune disease. PMID- 26432764 TI - Posttranscriptional T cell gene regulation to limit Tfh cells and autoimmunity. AB - T follicular helper (Tfh) cells are crucial to induce protective extrafollicular and germinal center antibody responses against protein antigens. Over the last decade, control of Tfh cell numbers has emerged as an important regulatory checkpoint which, when perturbed, may lead to production of autoantibodies. Recent progress in understanding how Tfh cells are kept limiting has revealed an important role for posttranscriptional control of gene expression mediated by microRNAs such as miR-17 ~ 92, miR-155 and miR-146a, and the RNA-binding proteins Roquin and Regnase. Additionally, T cell microRNAs dysregulated in patients with systemic lupus erythematosus have been shown to influence processes such as DNA hypomethylation, IL-2 and CCL5 secretion, and Treg function, which contribute to autoantibody formation and tissue damage. PMID- 26432766 TI - [Haematological toxicity during treatment with albendazole]. PMID- 26432767 TI - The Impact of Uninterrupted Warfarin on Hand and Wrist Surgery. AB - PURPOSE: To determine the impact of uninterrupted use of warfarin on hand and wrist surgery. METHODS: This single-center, prospective cohort trial enrolled adult patients undergoing hand and wrist surgery. Between May 2009 and August 2014, 47 surgical patients receiving uninterrupted warfarin (50 procedures) were enrolled and matched as a group by age and procedure type to 48 surgical patients (50 procedures) who were not prescribed warfarin. Complications, defined as bleeding, infection, or wound dehiscence requiring reoperation, were recorded for each group. Surgical outcome measures were composed of objective findings affected by surgical site bleeding (ie, ecchymosis extent, hematoma presence, 2 point discrimination) and standardized patient-rated assessments (Quick Disabilities of the Arm, Shoulder, and Hand, and visual analog scales: pain and swelling). We collected data preoperatively and at 2 and 4 weeks postoperatively. Statistical analyses contrasted complications and outcomes data between patient groups. RESULTS: One procedure (2%; 95% confidence interval, 0% to 11%) in a patient taking warfarin was complicated by hematoma requiring reoperation resulting from an elevated postoperative international normalized ratio of 5.4. There were no complications among controls (0%; 95% confidence interval, 0% to 7%). At 2 weeks postoperatively, patients receiving warfarin more frequently had hematomas (28% vs 10%) and demonstrated a greater extent of ecchymosis from the surgical incision (50 vs 19 mm). At 4 weeks, no differences existed in hematoma presence or extent of ecchymosis between groups. The incidence of transiently elevated 2-point discrimination was not different between groups (10% warfarin; 6% controls). Visual analog scores for pain and swelling were not significantly different between groups at any time. Differences in Quick-Disabilities of the Arm, Shoulder, and Hand scores between groups did not exceed a minimal clinically important difference. CONCLUSIONS: Uninterrupted use of warfarin in patients undergoing surgery of the hand and wrist was associated with an infrequent risk of bleeding complication requiring reoperation. Increased rates of hematoma and ecchymosis in patients taking warfarin normalized by 4 weeks postoperatively. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 26432768 TI - The Effect of Progressive Extensor Retinaculum Excision on Wrist Biomechanics and Bowstringing. AB - PURPOSE: To quantify the effect of the extensor retinaculum in preventing bowstringing and extensor lag. METHODS: The extensor carpi radialis brevis (ECRB) and extensor digitorum communis (EDC) tendons to the middle finger were isolated in 6 human cadaveric specimens. Extensor tendon excursion and bowstringing were measured as the extensor retinaculum was serially excised. RESULTS: For the second dorsal compartment, extensor lag averaged 7 degrees when the entire retinaculum over the ECRB was excised. Bowstringing did increase with sequential resections and was greater for distal resections than for proximal resections. When the entire retinaculum over the ECRB was removed, bowstringing averaged 12 mm. For the fourth dorsal compartment, excision of the distal retinaculum resulted in more bowstringing and extensor lag than excision of the proximal retinaculum. When the proximal two-thirds was excised, EDC extensor lag averaged 12 degrees and bowstringing averaged 9 mm; with the distal two-thirds excised, extensor lag averaged 18 degrees and bowstringing averaged 14 mm. Complete retinaculum excision resulted in EDC bowstringing of about 61 mm and extensor lag of 80 degrees . CONCLUSIONS: Resection of the entire extensor retinaculum over the second dorsal compartment results in minimal extensor lag and minimal bowstringing. Resection of the entire retinaculum over the fourth dorsal compartment results in massive extensor lag and bowstringing and should be avoided. The distal portion of the retinaculum is most important in preventing extensor lag and bowstringing for the fourth compartment. CLINICAL RELEVANCE: The findings inform the surgeon's handling of the extensor retinaculum during procedures on the dorsum of the wrist, especially when portions are to be excised, transposed, or repaired. PMID- 26432769 TI - Thyroid disrupting effects of polychlorinated biphenyls in ovariectomized rats: A benchmark dose analysis. AB - Polychlorinated biphenyls (PCBs) are proved endocrine disrupting potentials. Reference points (RP) for PCBs are derived from dose-response relationship analysis by using the traditional no observed adverse effect or lowest observed adverse effect level (NOAEL/LOAEL) methods, or a more advanced benchmark dose (BMD) method. In present study, toxicological RP for PCBs' thyroid disruption was established and compared between NOAEL/LOAEL and BMD method in an ovariectomized (OVX) rat model. Sham and OVX controls were given corn oil while other OVX groups were administered with 0.1, 1.0, 5.0, and 10.0mg/kg bw of PCBs (aroclor 1254) respectively by gavage. Body weight change, liver type I 5'-deiodinase (5'-DI) activity, serum total thyroxine (tT4), triiodothyroxine (tT3), thyroid stimulating hormones (TSH), and thyroid histopathological changes were measured and analyzed. In PCBs-treated groups, serum tT4, tT3, TSH, and histopathological examinations showed significant changes with a dose-dependent manner compared with those in OVX control (P<0.05). The toxicological RP for PCBs affecting thyroid function of OVX rats was 0.02 mg/kg'bw based on BMD analysis. PMID- 26432770 TI - In utero exposure of neonatal buffalo calves to pesticide residues and the alterations within their reproductive tract. AB - In utero exposure of neonates to pesticide residues could be damaging to the reproductive tract. Hence, the present study assessed the circulating concentrations of pesticide residues in buffalo and their neonatal calves as well as in the reproductive tract tissue samples of same calves. Also, histopathological alterations were revealed in the reproductive tract of calves. Pesticide residues were high (P<0.05) in the reproductive tract of calves (119.5 +/- 20.2 ng/g, 35% positive) in comparison to their blood (32.1 +/- 8.4 ng/ml, 15% positive) or blood of their dams (41.5 +/- 8.3 ng/ml, 25% positive). The number of histopathological alterations were high (P<0.05) in the reproductive tract of a calf contaminated with high concentrations of pesticide residues (3.43 +/- 1.29) in comparison to a tract positive for low residue concentrations (1.57 +/- 0.60) or pesticide negative tract (0.28 +/- 0.10). In conclusion, in utero exposure of neonatal buffalo calves to pesticide residues may be associated with damaging alterations in their reproductive tract. PMID- 26432771 TI - Prevention of cyclophosphamide-induced hepatotoxicity and genotoxicity: Effect of an L-cysteine based oxovanadium(IV) complex on oxidative stress and DNA damage. AB - Vanadium has been emerged as a promising agent owing to its ability to prevent several types of cancer. This study was aimed to investigate the protective role of an organovanadium complex, viz., oxovanadium(IV)-L-cysteine methyl ester (VC IV) against cyclophosphamide (CP)-induced hepatotoxicity and genotoxicity in mice. Oral administration of VC-IV quite effectively ameliorated CP-induced histopathological lesions and reduced levels of alanine transaminase, aspartate transaminase and alkaline phosphatase. In addition, VC-IV significantly attenuated CP-induced oxidative stress in the liver as evident from levels of reactive oxygen species, nitric oxide and lipid peroxidation. Restoration of glutathione level and activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase) were also observed upon VC-IV administration. Moreover, VC-IV significantly mitigated CP induced chromosomal aberrations, micronuclei formation, DNA fragmentation and apoptosis in bone marrow cells and DNA damage in lymphocytes. The present study showed that VC-IV could provide adequate protection against CP-induced hepatotoxicity and genotoxicity in vivo. PMID- 26432772 TI - Epigenetic modulation of Chlorella (Chlorella vulgaris) on exposure to polycyclic aromatic hydrocarbons. AB - DNA methylation in promoter region can be a new chemopreventive marker against polycyclic aromatic hydrocarbons (PAHs). We performed a randomized, double blind and cross-over trial (N=12 healthy females) to evaluate chlorella (Chlorella vulgaris)-induced epigenetic modulation on exposure to PAHs. The subjects consumed 4 tablets of placebo or chlorella supplement (total chlorophyll ~ 8.3mg/tablet) three times a day before meals for 2 weeks. When the subjects consumed chlorella, status of global hypermethylation (5-methylcytosine) was reduced, compared to placebo (p=0.04). However, DNA methylation at the DNMT1 or NQO1 was not modified by chlorella. We observed the reduced levels of urinary 1 hydroxypyrene (1-OHP), a typical metabolite of PAHs, by chlorella intake (p<0.1) and a positive association between chlorella-induced changes in global hypermethylation and urinary 1-OHP (p<0.01). Therefore, our study suggests chlorella works for PAH-detoxification through the epigenetic modulation, the interference of ADME of PAHs and the interaction of mechanisms. PMID- 26432773 TI - Quercetin induces hepatic gamma-glutamyl hydrolase expression in rats by suppressing hepatic microRNA rno-miR-125b-3p. AB - Exogenous factors such as food components including the flavonoid quercetin are suspected to influence micro RNA (miRNA) concentrations and thus possibly target enzymes involved in xenobiotic metabolism. This study therefore investigates the influence of orally administered quercetin on hepatic miRNA and the identification of enzyme target mRNAs relevant in drug metabolism. Male Wistar rats (n=16) were fed either a diet without (C) or with (Q) the addition of 100 ppm quercetin for 7 weeks and subsequently euthanized at the end of the dark phase. To avoid strong effects of food deprivation on hepatic metabolism, food was not removed until 5 h prior to the procedure. Liver was immediately dissected and snap-frozen in liquid nitrogen. Concentrations of 352 hepatic miRNA were measured in pool samples of each dietary group (n=8) using the RT(2) miRNA PCR Array System. Differential expression of miRNAs was assumed with fold changes >=3. Target genes of differentially expressed miRNAs were identified using the database TargetScan. Because rno-miR-125b-3p showed the most prominent fold change (-9) we further analyzed the expression of its top predicted target gene gamma-glutamyl hydrolase (GGH) by quantitative real-time PCR using hypoxanthine phosphoribosyltransferase 1 (hprt1) as endogenous control. Compared to controls, 23 miRNAs were differentially expressed in rats fed quercetin. A ninefold reduction in hepatic miRNA rno-miR-125b-3p was paralleled by significant induction of GGH mRNA in liver of quercetin fed rats. Because increased GGH expressions were repeatedly associated with resistance to methotrexate, concomitant intake with quercetin should be monitored carefully. PMID- 26432774 TI - Is the artificial pancreas coming to a home near you? PMID- 26432775 TI - 2 month evening and night closed-loop glucose control in patients with type 1 diabetes under free-living conditions: a randomised crossover trial. AB - BACKGROUND: An artificial pancreas (AP) that can be worn at home from dinner to waking up in the morning might be safe and efficient for first routine use in patients with type 1 diabetes. We assessed the effect on glucose control with use of an AP during the evening and night plus patient-managed sensor-augmented pump therapy (SAP) during the day, versus 24 h use of patient-managed SAP only, in free-living conditions. METHODS: In a crossover study done in medical centres in France, Italy, and the Netherlands, patients aged 18-69 years with type 1 diabetes who used insulin pumps for continuous subcutaneous insulin infusion were randomly assigned to 2 months of AP use from dinner to waking up plus SAP use during the day versus 2 months of SAP use only under free-living conditions. Randomisation was achieved with a computer-generated allocation sequence with random block sizes of two, four, or six, masked to the investigator. Patients and investigators were not masked to the type of intervention. The AP consisted of a continuous glucose monitor (CGM) and insulin pump connected to a modified smartphone with a model predictive control algorithm. The primary endpoint was the percentage of time spent in the target glucose concentration range (3.9-10.0 mmol/L) from 2000 to 0800 h. CGM data for weeks 3-8 of the interventions were analysed on a modified intention-to-treat basis including patients who completed at least 6 weeks of each intervention period. The 2 month study period also allowed us to asses HbA1c as one of the secondary outcomes. This trial is registered with ClinicalTrials.gov, number NCT02153190. FINDINGS: During 2000 0800 h, the mean time spent in the target range was higher with AP than with SAP use: 66.7% versus 58.1% (paired difference 8.6% [95% CI 5.8 to 11.4], p<0.0001), through a reduction in both mean time spent in hyperglycaemia (glucose concentration >10.0 mmol/L; 31.6% vs 38.5%; -6.9% [-9.8% to -3.9], p<0.0001) and in hypoglycaemia (glucose concentration <3.9 mmol/L; 1.7% vs 3.0%; -1.6% [-2.3 to -1.0], p<0.0001). Decrease in mean HbA1c during the AP period was significantly greater than during the control period (-0.3% vs -0.2%; paired difference -0.2 [95% CI -0.4 to -0.0], p=0.047), taking a period effect into account (p=0.0034). No serious adverse events occurred during this study, and none of the mild-to moderate adverse events was related to the study intervention. INTERPRETATION: Our results support the use of AP at home as a safe and beneficial option for patients with type 1 diabetes. The HbA1c results are encouraging but preliminary. FUNDING: European Commission. PMID- 26432776 TI - Evidence for a natural humoral response in dairy cattle affected by persistent botulism sustained by non-chimeric type C strains. AB - Bovine botulism is a sporadic acute disease that usually causes catastrophic losses in the herds. The unusual clinical evolution of a persistent mild outbreak in a dairy herd, prompted us to characterize the neurotoxin gene profile of the strain involved and to evaluate whether seroconversion had occurred. Diagnosis was based on mild classical symptoms and was supported by PCR and bacteriological findings, which revealed the involvement of a non-mosaic type C strain. An in house ELISA was developed to detect antibodies to botulinum neurotoxin type C and its performance was evaluated in a vaccination study. Fifty days after the index case, fecal and serum samples were collected from the 14 animals of the herd and screened for Clostridium botulinum and anti-botulinum neurotoxin antibodies type C, respectively. The in-house developed ELISA was also used to test 100 sera samples randomly collected from 20 herds. Strong ELISA reactions were observed in 3 convalescent and 5 asymptomatic animals involved in the studied outbreak. The ELISA-positive cows all tested positive for non-mosaic C. botulinum type C in the feces and the same strain was also detected in the alfalfa hay, suspected to be the carrier source. Ten out of the 100 randomly collected sera tested positive for anti-botulinum neurotoxin type C antibodies: 7 had borderline values and 3 from the same herd showed titers three times higher than the cut-off. We concluded that type C botulism in cattle may occur with variable severity and that prolonged exposure to sublethal doses of botulinum neurotoxin C may occur, resulting in detectable antibodies. PMID- 26432777 TI - Heterogeneous infectiousness in guinea pigs experimentally infected with Trypanosoma cruzi. AB - Guinea pigs are important reservoirs of Trypanosoma cruzi, the causative parasite of Chagas disease, and in the Southern Cone of South America, transmission is mediated mainly by the vector Triatoma infestans. Interestingly, colonies of Triatoma infestans captured from guinea pig corrals sporadically have infection prevalence rates above 80%. Such high values are not consistent with the relatively short 7-8 week parasitemic period that has been reported for guinea pigs in the literature. We experimentally measured the infectious periods of a group of T. cruzi-infected guinea pigs by performing xenodiagnosis and direct microscopy each week for one year. Another group of infected guinea pigs received only direct microscopy to control for the effect that inoculation by triatomine saliva may have on parasitemia in the host. We observed infectious periods longer than those previously reported in a number of guinea pigs from both the xenodiagnosis and control groups. While some guinea pigs were infectious for a short time, other "super-shedders" were parasitemic up to 22 weeks after infection, and/or positive by xenodiagnosis for a year after infection. This heterogeneity in infectiousness has strong implications for T. cruzi transmission dynamics and control, as super-shedder guinea pigs may play a disproportionate role in pathogen spread. PMID- 26432778 TI - Assessment of the calcification of the nuchal ligament and osteophytes of the cervical spine in obstructive sleep apnoea subjects and snorers. AB - The previous reports suggest that obstructive sleep apnoea (OSA) is related to metabolic syndrome, mineral metabolism disorders and cardiovascular disease. In addition, a possible relationship between obesity and the calcification of ligaments has been implied. However, the potential link between OSA and the calcification of ligaments has not been directly studied. In this present study, to investigate the potential link between OSA and the calcification of ligaments, we examined the prevalence of the calcification of ligaments in OSA patients and the relationship between these findings and OSA severity. Eighty consecutive patients (60 males, 20 females) diagnosed as OSA or a heavy snorer based on full night polyso-mnography were retrospectively recruited from May 2006 to July 2008. Each patient underwent cephalometric imaging examination before the arrangement of an oral appliance. One calibrated observer (YS) reviewed the cephalometric images for the presence of calcification of the nuchal ligament and osteophytes of the cervical spine. The prevalence of calcification of the nuchal ligament in OSA patients and snorers was 46.3% (males: 52%, females: 30%) There was a significant positive correlation between the severity of OSA (AHI) and the calcification of the nuchal ligament before and after adjusting for BMI. The prevalence of the calcification of the nuchal ligament in OSA subjects and snorers was higher than in previous studies with non-OSA subjects. In addition, it is suggested that the severity of OSA correlates with the presence of calcification of the nuchal ligament. PMID- 26432779 TI - Combination treatment with excimer laser and narrowband UVB light in vitiligo patients. AB - BACKGROUND: For the treatment of vitiligo, narrowband UVB (NBUVB) light is considered the most effective for nonsegmental vitiligo, while excimer laser treatment is commonly used for localized vitiligo. However, treatment areas may potentially be missed with excimer laser treatment. OBJECTIVE: We aimed to evaluate the effect of combinational treatment with NBUVB light and excimer laser on vitiligo. METHODS: All patients were first treated with NBUVB; excimer laser was then applied in conjunction with NBUVB phototherapy due to a slow response or no further improvement with continuous NBUVB treatment alone. To minimize adverse effects, a fixed dose of NBUVB was administered, and the dose of excimer laser was increased based on patient response. RESULTS: Among 80 patients, 54 patients showed responses after combination with excimer laser; however, 26 patients (32.5%) showed no remarkable change after combination therapy. Of the 26 patients who showed no further response, 12 patients (46.1%) presented with vitiligo on the acral areas, which are known to the least responsive sites. CONCLUSION: Our study suggests that combined treatment of NBUVB and excimer laser in vitiligo may enhance the treatment response without remarkable side effects, therefore might also increase the compliance of the patients to the treatment. PMID- 26432780 TI - Increased p53 protein expression as a potential predictor of early relapse after hematopoietic stem cell transplantation in children with acute myelogenous leukemia. AB - Dysregulation of genes involved in the cell cycle such as TP53, P21, P16, and PTEN plays a key role in oncogenesis. We have earlier reported increased expression of the TP53 encoded protein p53, in bone marrow samples from pediatric patients with more aggressive, rare chronic myeloid malignancies. The aim of this study was to investigate protein expression of p53, p21, p16, and PTEN before and after HSCT in pediatric patients with AML and evaluate whether any potential alterations could predict relapse after HSCT. Paraffin-embedded bone marrow samples from 34 pediatric patients with AML were collected retrospectively from time of diagnosis as well as pre- and post-HSCT. IHC was performed on tissue microarrays with antibodies against p53, p21, p16, and PTEN. Study material was analyzed by independent t-tests and nonlinear regression. t-Tests showed a statistical significant difference in p53 (p = 0.010) with overexpression in the group of patients who relapsed compared to the relapse-free patients at >3-6 months post-HSCT. Analysis of p53 protein expression by IHC may be a potential predictor for relapse after HSCT in children with AML. PMID- 26432781 TI - NHERF1 regulates actin cytoskeleton organization through modulation of alpha actinin-4 stability. AB - The actin cytoskeleton is composed of a highly dynamic network of filamentous proteins, yet the molecular mechanism that regulates its organization and remodeling remains elusive. In this study, Na(+)/H(+) exchanger regulatory factor (NHERF)-1 loss-of-function and gain-of-function experiments reveal that polymerized actin cytoskeleton (F-actin) in HeLa cells is disorganized by NHERF1, whereas actin protein expression levels exhibit no detectable change. To elucidate the molecular mechanism underlying actin cytoskeleton disorganization by NHERF1, a combined 2-dimensional electrophoresis-matrix-assisted laser desorption/ionization-time of flight mass spectrometry approach was used to screen for proteins regulated by NHERF1 in HeLa cells. alpha-Actinin-4, an actin cross-linking protein, was identified. Glutathione S-transferase pull-down and coimmunoprecipitation studies showed the alpha-actinin-4 carboxyl-terminal region specifically interacted with the NHERF1 postsynaptic density 95/disc-large/zona occludens-1 domain. The NHERF1/alpha-actinin-4 interaction increased alpha actinin-4 ubiquitination and decreased its expression levels, resulting in actin cytoskeleton disassembly. Our study identified alpha-actinin-4 as a novel NHERF1 interaction partner and provided new insights into the regulatory mechanism of the actin cytoskeleton by NHERF1. PMID- 26432782 TI - Drp1, Mff, Fis1, and MiD51 are coordinated to mediate mitochondrial fission during UV irradiation-induced apoptosis. AB - Mitochondrial fission and proteins vital to this process play essential roles in apoptosis. Several mitochondrial outer membrane proteins, including mitochondrial fission protein 1 (Fis1), mitochondrial fission factor (Mff) and mitochondrial dynamics of 51 kDa protein (MiD51), also known as mitochondrial elongation factor 1 (MEIF1), have been reported to promote mitochondrial fission by recruiting the GTPase dynamin-related protein 1 (Drp1). However, it remains unclear how these fission factors coordinate to control apoptotic mitochondrial fission. Molecular studies have suggested the existence of interaction between Mff and Drp1, but fundamental questions remain concerning their function. In the present study, we reported that the phosphorylation status of Drp1-Ser(637) was essential for its interaction with Mff. UV stimulation induced a decrease in cytoplasmic and mitochondrial Drp1 phosphorylation on Ser(637) and enhanced the interaction between Drp1 and Mff, resulting in mitochondrial fragmentation. Simultaneously, the interaction increased markedly between Fis1 and MiD51/MIEF1, whereas the interaction between Drp1 and MiD51/MIEF1 decreased significantly after UV irradiation, which suggests that Fis1 competitively binds to MiD51/MIEF1 to activate Drp1 indirectly. Moreover, Mff-Drp1 binding and Mff-mediated recruitment of Drp1 to mitochondria did not require Bax during UV stimulation. Our study revealed a novel role of Mff in regulation of mitochondrial fission and showed how the fission proteins are orchestrated to mediate the fission process during apoptosis. PMID- 26432783 TI - The origin and implementation of the Broadening Experiences in Scientific Training programs: an NIH common fund initiative. AB - Recent national reports and commentaries on the current status and needs of the U.S. biomedical research workforce have highlighted the limited career development opportunities for predoctoral and postdoctoral trainees in academia, yet little attention is paid to preparation for career pathways outside of the traditional faculty path. Recognizing this issue, in 2013, the U.S. National Institutes of Health (NIH) Common Fund issued a request for application titled "NIH Director's Biomedical Research Workforce Innovation Award: Broadening Experiences in Scientific Training (BEST)." These 5-yr 1-time grants, awarded to 17 single or partnering institutions, were designed to develop sustainable approaches to broaden graduate and postgraduate training, aimed at creating training programs that reflect the range of career options that trainees may ultimately pursue. These institutions have formed a consortium in order to work together to develop, evaluate, share, and disseminate best practices and challenges. This is a first report on the early experiences of the consortium and the scope of participating BEST programs. In this report, we describe the state of the U.S. biomedical workforce and development of the BEST award, variations of programmatic approaches to assist with program design without BEST funding, and novel approaches to engage faculty in career development programs. To test the effectiveness of these BEST programs, external evaluators will assess their outcomes not only over the 5 yr grant period but also for an additional 10 yr beyond award completion. PMID- 26432785 TI - Prevalence and social drivers of HIV among married and cohabitating heterosexual adults in south-eastern Tanzania: analysis of adult health community cohort data. AB - BACKGROUND: In sub-Saharan Africa, the prevalence of HIV among married and cohabiting couples is substantial. Information about the underlying social drivers of HIV transmission in couples is critical for the development of structural approaches to HIV prevention, but not readily available. We explored the association between social drivers, practices, and HIV status among stable couples in Ifakara, Tanzania. DESIGN: Using a cross-sectional design, we analyzed data from a sample of 3,988 married or cohabiting individuals, aged 15 years and older from the MZIMA adult health community cohort study of 2013. Sociodemographic factors (sex, income, age, and education), gender norms (perceived acceptability for a wife to ask her partner to use a condom when she knows he is HIV positive), marriage characteristics (being in a monogamous or a polygamous marriage, being remarried), sexual behavior practices (lifetime number of sexual partners and concurrent sexual partners), health system factors (ever used voluntary HIV counseling and testing), and lifestyle patterns (alcohol use) were used to explore the odds of being HIV positive, with 95% confidence intervals. RESULTS: Prevalence of HIV/AIDS was 6.7% (5.9% males and 7.1% females). Gender norms, that is, perception that a woman is not justified to ask her husband to use a condom even when she knows he has a disease (adjusted odds ratio AOR=1.51, 95% CI 1.06-2.17), marital characteristics, that is, being remarried (AOR=1.49, 95% CI 1.08-2.04), and sexual behavior characteristics, that is, lifetime number of sexual partners (2-4: AOR=1.47, 95% CI 1.02-2.11; 5+: AOR=1.61, 95% CI 1.05-2.47) were the main independent predictors of HIV prevalence. CONCLUSIONS: Among married or cohabiting individuals, the key social drivers/practices that appeared to make people more vulnerable for HIV are gender norms, marriage characteristics (being remarried), and sexual behavior practices (lifetime number of sexual partners). Married and cohabiting couples are an important target group for HIV prevention efforts in Tanzania. In addition to individual interventions, structural interventions are needed to address the gender norms, remarriage, and sexual practices that shape differential vulnerability to HIV in stable couples. PMID- 26432784 TI - Joint association of physical activity and overweight with subsequent psychotropic medication: a register-linked follow-up study among employees. AB - BACKGROUND: Physical activity level and overweight have shown associations with mental health problems but it is not known whether the risk of mental health problems due to overweight varies by physical activity. We examined joint association of physical activity and overweight with subsequent psychotropic medication among 40-60-year-old employees. METHODS: The questionnaire survey data were derived from Helsinki Health Study baseline postal questionnaires in 2000-02 among employees of the City of Helsinki aged 40-60 years (n = 8960, response rate 67%). Baseline survey data were linked with prospective register data on prescribed psychotropic medication (ATC-codes N05 and N06, except N06D) among those with written consent (74%) for such linkage. The analyses included 6169 responders (78% women, corresponding to the target population). We divided participants into six groups according to their baseline self-reported body mass index and leisure-time physical activity using physically highly active normal weight participants as a reference group. We used Cox regression analysis adjusted for age, gender, psychotropic medication prior to baseline, and socioeconomic position, marital status, working conditions, limiting long standing illness, alcohol use, and smoking. RESULTS: At baseline, 49% were overweight and 23% were physically inactive. After adjusting for age and gender, inactive normal-weight (hazard ratio (HR) 1.3, 95% CI 1.1-1.5), moderately active overweight (HR 1.3, 95% CI 1.1-1.5) and inactive overweight (HR 1.4, 95% CI 1.2 1.6) had higher risk for any psychotropic medication compared with group of highly active normal-weight. After adjusting for prior medication, only the inactive overweight group had higher risk (HR 1.4, 95% CI 1.2-1.6). Other covariates made but a minor contribution to the examined associations. For antidepressants the associations were somewhat stronger than for sedatives. CONCLUSIONS: Both normal-weight and physical activity help prevent psychotropic medication but physical activity dominates the association over normal-weight. PMID- 26432786 TI - Cabozantinib (XL184) Inhibits Growth and Invasion of Preclinical TNBC Models. AB - PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that is associated with poor clinical outcome. There is a vital need for effective targeted therapeutics for TNBC patients, yet treatment strategies are challenged by the significant intertumoral heterogeneity within the TNBC subtype and its surrounding microenvironment. Receptor tyrosine kinases (RTK) are highly expressed in several TNBC subtypes and are promising therapeutic targets. In this study, we targeted the MET receptor, which is highly expressed across several TNBC subtypes. EXPERIMENTAL DESIGN: Using the small-molecule inhibitor cabozantinib (XL184), we examined the efficacy of MET inhibition in preclinical models that recapitulate human TNBC and its microenvironment. To analyze the dynamic interactions between TNBC cells and fibroblasts over time, we utilized a 3D model referred to as MAME (Mammary Architecture and Microenvironment Engineering) with quantitative image analysis. To investigate cabozantinib inhibition in vivo, we used a novel xenograft model that expresses human HGF and supports paracrine MET signaling. RESULTS: XL184 treatment of MAME cultures of MDA-MB-231 and HCC70 cells (+/- HGF-expressing fibroblasts) was cytotoxic and significantly reduced multicellular invasive outgrowths, even in cultures with HGF-expressing fibroblasts. Treatment with XL184 had no significant effects on MET(neg) breast cancer cell growth. In vivo assays demonstrated that cabozantinib treatment significantly inhibited TNBC growth and metastasis. CONCLUSIONS: Using preclinical TNBC models that recapitulate the breast tumor microenvironment, we demonstrate that cabozantinib inhibition is an effective therapeutic strategy in several TNBC subtypes. PMID- 26432787 TI - Antimicrobial activity of Alcaligenes sp. HPC 1271 against multidrug resistant bacteria. AB - Alcaligenes sp. HPC 1271 demonstrated antibacterial activity against multidrug resistant bacteria, Enterobacter sp., resistant to sulfamethoxazole, ampicillin, azithromycin, and tetracycline, as well as against Serratia sp. GMX1, resistant to the same antibiotics with the addition of netilmicin. The cell-free culture supernatant was analyzed for possible antibacterials by HPLC, and the active fraction was further identified by LC-MS. Results suggest the production of tunicamycin, a nucleoside antibiotic. The draft genome of this bacterial isolate was analyzed, and the 4.2 Mb sequence data revealed six secondary metabolite producing clusters, identified using antiSMASH platform as ectoine, butyrolactone, phosphonate, terpene, polyketides, and nonribosomal peptide synthase (NRPS). Additionally, the draft genome demonstrated homology to the tunicamycin-producing gene cluster and also defined 30 ORFs linked to protein secretion that could also play a role in the antibacterial activity observed. Gene expression analysis demonstrated that both NRPS and dTDP-glucose 4,6 dehydratase gene clusters are functional and could be involved in antibacterial biosynthesis. PMID- 26432788 TI - Peri-articular lymphatic system and "Bi" theory of Chinese medicine in the pathogenesis and treatment of arthritis. AB - Rheumatoid arthritis (RA) and osteoarthritis (OA) are the two most common joint diseases, and they have characterization of synovial inflammation and cartilage destruction, associated with the accumulation of numerous catabolic mediators and inflammatory cells in the synovial space and surrounding soft tissues. How these factors are cleared and if the "clearance" process contributes to pathogenesis of arthritis are not known. Recently, we found the existence of the peri-articular lymphatic system in mouse joints. The blockade of lymphangiogenesis and lymphatic draining function accelerates while stimulation of lymphatic function attenuates the severity of joint tissue lesions in mouse models of RA and OA. More importantly, we noticed the similarity between the dysfunction of lymphatic drainage in arthritic joints and "Bi" theory of Chinese medicine (CM), and demonstrated that several Bi disease-treated herbal drugs directly affect the function of lymphatic endothelial cells. Here we review the advances about the interactions between joint inflammation and changes in the peri-articular lymphatic system and discuss our view of linking "Bi" theory of CM to lymphatic dysfunction in arthritis. PMID- 26432789 TI - Shen (Kidney)-tonifying principle for primary osteoporosis: to treat both the disease and the Chinese medicine syndrome. AB - Primary osteoporosis (POP) is one of the most common diseases in the elderly people resulting in high risk of fracture and poor quality of life. In addition to the pathological changes in bone mass, most of the POP patients also suffer from Chinese medicine (CM) syndromes of Shen (Kidney) essence deficiency. Shen essences are highly related to bone. Shen essence deficiency plays an important part in the development of POP and a better diagnosis of POP could be made by combining CM syndromes with Western medicine risk factors. Treatments of POP should aim at both increasing the bone mass and relieving the syndromes of Shen essence deficiency. Clinical study confirmed that treating POP patients with Shen tonifying herbs could increase the bone mass and relieve the CM syndromes of POP patients. Basic researches clarified the mechanism by which Shen-tonifying herbs increased bone mass in animal models. The mechanisms by which Shentonifying herbs relieve the CM syndromes are still in investigation. PMID- 26432790 TI - How personal and standardized coordination impact implementation of integrated care. AB - BACKGROUND: Integrating health care across specialized work units has the potential to lower costs and increase quality and access to mental health care. However, a key challenge for healthcare managers is how to develop policies, procedures, and practices that coordinate care across specialized units. The purpose of this study was to identify how organizational factors impacted coordination, and how to facilitate implementation of integrated care. METHODS: Semi-structured interviews were conducted in August 2009 with 30 clinic leaders and 35 frontline staff who were recruited from a convenience sample of 16 primary care and mental health clinics across eight medical centers. Data were drawn from a management evaluation of primary care-mental health integration in the US Department of Veterans Affairs. To protect informant confidentiality, the institutional review board did not allow quotations. RESULTS: Interviews identified antecedents of organizational coordination processes, and highlighted how these antecedents can impact the implementation of integrated care. Overall, implementing new workflow practices were reported to create conflicts with pre existing standardized coordination processes. Personal coordination (i.e., interpersonal communication processes) between primary care leaders and staff was reported to be effective in overcoming these barriers both by working around standardized coordination barriers and modifying standardized procedures. DISCUSSION: This study identifies challenges to integrated care that might be solved with attention to personal and standardized coordination. A key finding was that personal coordination both between primary care and mental health leaders and between frontline staff is important for resolving barriers related to integrated care implementation. CONCLUSION: Integrated care interventions can involve both new standardized procedures and adjustments to existing procedures. Aligning and integrating procedures between primary care and specialty care requires personal coordination amongst leaders. Interpersonal relationships should be strengthened between staff when personal connections are important for coordinating patient care across clinical settings. PMID- 26432791 TI - [Pavlik harness for the treatment of congenital hip dysplasia types D III and IV]. AB - BACKGROUND: Up to 4% of all neonates in Central Europe are born with congenital hip dysplasia (CHD), the most common congenital disease of the musculoskeletal system. However, in this retrospective analysis the outcomes of infants with CHD (type D, III or IV according to Graf) have been considered, with Pavlik therapy starting within the first 12 weeks of life. Connections between the start of therapy or the first finding according to Graf's classification and the ultrasound result achieved, as well as the X-rays taken after 1 and 2 years, were evaluated. No repositioning under Pavlik treatment or side effects and their relevance have been evaluated, especially with regard to avascular necrosis (AVN) of the femoral head. MATERIALS AND METHODS: All infants treated using Pavlik treatment for CHD between 2010 and 2012 in our clinic were determined. A total of 62 patients with 79 pathological hips were included. The infants were classified into three groups to evaluate the influence of the start of therapy on the result: group I with the first investigation and start of treatment within the first 10 days of life, group II between the 11th day and the end of week 3, group III within preventive general examinations (U3) after the 4th week. Clinical examinations and the usual ultrasound scans were performed at an average of 1, 3, and 6 months. Furthermore, after 1 and 2 years clinical and radiological investigations were carried out, as well as further examinations depending on the findings. RESULTS: A failure of repositioning of the Pavlik treatment occurred in group I in 1 case (2.2%), in group II in 1 case (7.1%), and in group III in 2 cases (10%). This occurs in hips type D and type III in 1 case each (3.3%) and type IV in 2 cases (10.5%). Maturation disorders of the hips were found in 1 case (2.2%) in group I, 1 case (7.1%) in group II, and 3 cases (15%) in group III. Avascular necrosis of the femoral head was proven in 2 cases (4.4%) in group I, 0% in group II, and in 1 case (5%) in group III. All patients initially had femoral head necrosis of Graf type IV . All necrosis and maturation disorders were no longer visible on subsequent examinations after 2 years at the most. CONCLUSIONS: In summary, the study shows that even with a late treatment start (U3) good results could be achieved, but with a rising number of repositioning failures and femoral necroses. Ultrasound screening on U3 seems to be sufficient; however, for high-risk groups an additional screening in the first week of life should be performed, which does not replace a second evaluation at U3 if there are normal findings. PMID- 26432792 TI - [Orthopaedic and trauma surgical care until 2050. Analysis of the utilization behavior for relevant diseases and derivation of the number of medical service providers]. AB - BACKGROUND: Due to current and prospective demographic developments, the provision of high-quality medical care is not guaranteed in Germany. OBJECTIVES: The aim of this study is to analyze the utilization of medical service providers for diseases related to orthopedic/trauma surgery and deduce the corresponding number of medical service providers until 2050. MATERIALS AND METHODS: Data provided by the Statistical Offices of the Federal Republic and the Federal States and the Scientific Institute of the AOK (2008-2012) were used to analyze the utilization behavior of four pre-determined orthopedic/trauma surgery disease groups (osteoarthritis, back pain, osteoporosis, trauma). Routine data of the current (2012) health care provision delivered by the compulsory health insurances (GKV) are the basis of the prognosis. Using population projections from the Federal Statistical Office, the health care demand until 2050 was predicted and using statistics from the German Medical Association, the number of required health care providers was determined. RESULTS: An increase in physician consultations until 2040 is expected for osteoarthritis (+ 21 %), osteoporosis (26 %), and trauma (+ 13 %). From 2040-2050 the health care utilization behavior of all examined diseases is expected to decrease. The increasing health care usage behavior until 2040 is associated with an increase in health care providers. CONCLUSIONS: Until 2030 a significant increase in the burden of orthopedic/trauma surgery diseases is expected. In 2050 the level of health care needs will be equivalent to that in 2030. Comprehensive needs assessment and planning are needed in order to create health care provision structures and processes that address potential changes in utilization behavior. PMID- 26432793 TI - Continuous EEG Monitoring for Early Detection of Delayed Cerebral Ischemia in Subarachnoid Hemorrhage: A Pilot Study. AB - INTRODUCTION: Early identification of delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH) is a major challenge. The aim of this study was to investigate whether quantitative EEG (qEEG) features can detect DCI prior to clinical or radiographic findings. METHODS: A prospective cohort study was performed in aSAH patients in whom continuous EEG (cEEG) was recorded. We studied 12 qEEG features. We compared the time point at which qEEG changed with the time point that clinical deterioration occurred or new ischemia was noted on CT scan. RESULTS: Twenty aSAH patients were included of whom 11 developed DCI. The alpha/delta ratio (ADR) was the most promising feature that showed a significant difference in change over time in the DCI group (median -62% with IQR -87 to -39%) compared to the control group (median +27% with IQR -32 to +104%, p = 0.013). Based on the ROC curve, a threshold was chosen for a combined measure of ADR and alpha variability (AUC: 91.7, 95% CI 74.2-100). The median time that elapsed between change of qEEG and clinical DCI diagnosis was seven hours (IQR -11-25). Delay between qEEG and CT scan changes was 44 h (median, IQR 14-117). CONCLUSION: In this study, ADR and alpha variability could detect DCI development before ischemic changes on CT scan was apparent and before clinical deterioration was noted. Implementation of cEEG in aSAH patients can probably improve early detection of DCI. PMID- 26432794 TI - Gibbsiella papilionis Kim et al. 2013 is a later heterotypic synonym of Gibbsiella dentisursi Saito et al. 2013. AB - Synonymy of Gibbsiella dentisursi DSM 23818T ( = NUM 1720T) and Gibbsiella papilionis JCM 18389T ( = LEN33T) was suspected following multilocus sequence analysis (MLSA) of both type strains in a previous classification study, where they were found to share >99.6 % gene sequence similarity. The taxonomic relationship between these two strains was re-examined here using a polyphasic approach. A DNA-DNA hybridization value of 98 % confirmed that the two type strains belong to a single taxon, while the phenotypic profiles were found to be nearly identical. Therefore we propose Gibbsiella papilionis as a later heterotypic synonym of Gibbsiella dentisursi, with the type strain as NUM 1720T ( = DSM 23818T = JCM 17201T). PMID- 26432796 TI - Erratum to: Dosimetrics of intracranial stereotactic radiosurgery : Only "an exercise of style"? PMID- 26432797 TI - War and Marriage: Assortative Mating and the World War II GI Bill. AB - World War II and its subsequent GI Bill have been widely credited with playing a transformative role in American society, but there have been few quantitative analyses of these historical events' broad social effects. We exploit between cohort variation in the probability of military service to investigate how WWII and the GI Bill altered the structure of marriage, and find that it had important spillover effects beyond its direct effect on men's educational attainment. Our results suggest that the additional education received by returning veterans caused them to "sort" into wives with significantly higher levels of education. This suggests an important mechanism by which socioeconomic status may be passed on to the next generation. PMID- 26432798 TI - [Communications of the Federal Association of German Pathologists: Further education (model) curriculum, status 29 April 2015]. PMID- 26432795 TI - Control of Proliferation and Cancer Growth by the Hippo Signaling Pathway. AB - The control of cell division is essential for normal development and the maintenance of cellular homeostasis. Abnormal cell proliferation is associated with multiple pathological states, including cancer. Although the Hippo/YAP signaling pathway was initially thought to control organ size and growth, increasing evidence indicates that this pathway also plays a major role in the control of proliferation independent of organ size control. In particular, accumulating evidence indicates that the Hippo/YAP signaling pathway functionally interacts with multiple other cellular pathways and serves as a central node in the regulation of cell division, especially in cancer cells. Here, recent observations are highlighted that connect Hippo/YAP signaling to transcription, the basic cell-cycle machinery, and the control of cell division. Furthermore, the oncogenic and tumor-suppressive attributes of YAP/TAZ are reviewed, which emphasizes the relevance of the Hippo pathway in cancer. PMID- 26432799 TI - [Cytopathology in the diagnostics of hematological diseases]. AB - Whereas in many fields of surgical pathology examination of cytological smears and analysis of histological tissue sections provide alternative methods which are chosen according to the clinical requirements, in hematopathology both types of morphological investigation are routinely applied in parallel and simultaneously. This procedure improves the diagnostic precision and safety. Unlike other European countries in Germany both procedures are performed by different specialties. Cytology is the responsibility of hematologists whereas histology is carried out by pathologists, which interferes with an integrative diagnostic approach unless intense communication takes place. Ideally, in the diagnosis of hematological disorders histology of bone marrow trephines should be studied in conjunction with smears of peripheral blood and bone marrow. In many instances, further complementary investigations, such as flow cytometry, cytogenetics and increasingly molecular pathological studies are necessary to guarantee an adequate modern state of diagnostics in hematopathology. PMID- 26432800 TI - David Oliver: Why I let some patients stay longer in hospital. PMID- 26432802 TI - DMSO Increases Mutation Scanning Detection Sensitivity of High-Resolution Melting in Clinical Samples. AB - BACKGROUND: Mutation scanning provides the simplest, lowest-cost method for identifying DNA variations on single PCR amplicons, and it may be performed before sequencing to avoid screening of noninformative wild-type samples. High resolution melting (HRM) is the most commonly used method for mutation scanning. With PCR-HRM, however, mutations less abundant than approximately 3%-10% that can still be clinically significant may often be missed. Therefore, enhancing HRM detection sensitivity is important for mutation scanning and its clinical application. METHODS: We used serial dilution of cell lines containing the TP53 exon 8 mutation to demonstrate the improvement in detection sensitivity for conventional-PCR-HRM in the presence of DMSO. We also conducted coamplification at lower denaturation temperature (COLD)-PCR with an extra step for cross hybridization, followed by preferential denaturation and amplification at optimized critical temperature (full-COLD-PCR), to further enrich low-level mutations before HRM with or without DMSO, and we used droplet-digital PCR to derive the optimal conditions for mutation enrichment. Both conventional PCR-HRM and full-COLD-PCR-HRM with and without DMSO were used for mutation scanning of TP53 exon 8 in cancer samples containing known mutations and myelodysplastic syndrome samples with unknown mutations. Mutations in other genes were also examined. RESULTS: The detection sensitivity of PCR-HRM scanning increases 2- to 5-fold in the presence of DMSO, depending on mutation type and sequence context, and can typically detect mutation abundance of approximately 1%. When mutation enrichment is applied during amplification with full-COLD-PCR followed by HRM in the presence of DMSO, mutations with 0.2%-0.3% abundance in TP53 exon 8 can be detected. CONCLUSIONS: DMSO improves HRM mutation scanning sensitivity with saturating dyes. When full-COLD-PCR is used, followed by DMSO-HRM, the overall improvement is about 20-fold compared with conventional PCR-HRM. PMID- 26432803 TI - Feeding on microbiomes: effects of detritivory on the taxonomic and phylogenetic bacterial composition of animal manures. AB - Earthworms play a key role in nutrient cycling by interacting with microorganisms thus accelerating organic matter turnover in soil systems. As detritivores, some earthworm types ingest and digest a mixture of dead organic matter and microorganisms, like animal manures (i.e. animal gut microbiomes). Here we described the earthworm cast microbiome and the role ingested bacteria play on its composition. We fed Eisenia andrei with cow, horse and pig manures and determined the taxonomic and phylogenetic composition of the these manures before and after passage through the earthworm gut. Earthworm cast microbiomes showed a smaller diversity than the manure they fed on. Manures strongly differed in their taxonomic and phylogenetic composition, but these differences were markedly reduced once transformed into earthworm cast microbiomes after passage through the earthworm gut. The core earthworm cast microbiome comprised 30 OTUs (2.6% of OTUs from cast samples), of which 10 are possibly native to the earthworm gut. Most of the core cast microbiome OTUs belonged to phyla Actinobacteria and Proteobacteria, as opposed to already described animal core gut microbiomes, which are composed mainly of Firmicutes and Bacteroidetes. Our results suggest that earthworms build up their cast microbiome by selecting from the pool of ingested bacteria. PMID- 26432801 TI - Menopausal Status and Abdominal Obesity Are Significant Determinants of Hepatic Lipid Metabolism in Women. AB - BACKGROUND: Android fat distribution (abdominal obesity) is associated with insulin resistance, hepatic steatosis, and greater secretion of large very low density lipoprotein (VLDL) particles in men. Since abdominal obesity is becoming increasingly prevalent in women, we aimed to investigate the relationship between android fat and hepatic lipid metabolism in pre- and postmenopausal women. METHODS AND RESULTS: We used a combination of stable isotope tracer techniques to investigate intrahepatic fatty acid synthesis and partitioning in 29 lean and 29 abdominally obese women (android fat/total fat 0.065 [0.02 to 0.08] and 0.095 [0.08 to 0.11], respectively). Thirty women were premenopausal aged 35 to 45 and they were matched for abdominal obesity with 28 postmenopausal women aged 55 to 65. As anticipated, abdominal obese women were more insulin resistant with enhanced hepatic secretion of large (404+/-30 versus 268+/-26 mg/kg lean mass, P<0.001) but not small VLDL (160+/-11 versus 142+/-13). However, postmenopausal status had a pronounced effect on the characteristics of small VLDL particles, which were considerably triglyceride-enriched (production ratio of VLDL2- triglyceride:apolipoprotein B 30+/-5.3 versus 19+/-1.6, P<0.05). In contrast to postmenopausal women, there was a tight control of hepatic fatty acid metabolism and triglyceride production in premenopausal women, whereby oxidation (rs=-0.49, P=0.006), de novo lipogenesis (rs=0.55, P=0.003), and desaturation (rs=0.48, P=0.012) were closely correlated with abdominal obesity-driven large VLDL triglyceride secretion rate. CONCLUSIONS: In women, abdominal obesity is a major driver of hepatic large VLDL particle secretion, whereas postmenopausal status was characterized by increased small VLDL particle size. These data provide a mechanistic basis for the hyperlipidemia observed in postmenopausal obesity. PMID- 26432804 TI - Exploiting the fungal highway: development of a novel tool for the in situ isolation of bacteria migrating along fungal mycelium. AB - Fungi and bacteria form various associations that are central to numerous environmental processes. In the so-called fungal highway, bacteria disperse along fungal mycelium. We developed a novel tool for the in situ isolation of bacteria moving along fungal hyphae as well as for the recovery of fungi potentially involved in dispersal, both of which are attracted towards a target culture medium. We present the validation and the results of the first in situ test. Couples of fungi and bacteria were isolated from soil. Amongst the enriched organisms, we identified several species of fast-growing fungi (Fusarium sp. and Chaetomium sp.), as well as various potentially associated bacterial groups, including Variovorax soli, Olivibacter soli, Acinetobacter calcoaceticus, and several species of the genera Stenotrophomonas, Achromobacter and Ochrobactrum. Migration of bacteria along fungal hyphae across a discontinuous medium was confirmed in most of the cases. Although the majority of the bacteria for which migration was confirmed were also positive for flagellar motility, not all motile bacteria dispersed using their potential fungal partner. In addition, the importance of hydrophobicity of the fungal mycelial surface was confirmed. Future applications of the columns include targeting different types of microorganisms and their interactions, either by enrichment or by state of the art molecular biological methods. PMID- 26432805 TI - Cercosporoid diseases of Citrus. AB - Citrus leaves and fruits exhibiting disease symptoms ranging from greasy spot, yellow spot, small or large brown spot, black dot, and brown dot were sampled from Fujian, Guangdong, Guizhou, Hunan, Jiangxi, Yunnan, Zhejiang provinces and the Guangxi Zhuang Autonomous Region in China. In total 82 isolates representing various cercosporoid genera were isolated from these disease symptoms, which were supplemented with eight Citrus cercosporoid isolates collected from other countries. Based on a morphological and phylogenetic study using sequence data from the nuclear ribosomal DNA's ITS1-5.8S-ITS2 regions (ITS), and partial actin (act), beta-tubulin (tub2), 28S nuclear ribosomal RNA (28S rDNA) and translation elongation factor 1-alpha (tef1) genes, these strains were placed in the following genera: Cercospora, Pallidocercospora, Passalora, Pseudocercospora, Verrucisporota and Zasmidium. All isolates tended to be sterile, except the Zasmidium isolates associated with citrus greasy spot-like symptoms, which subsequently were compared with phylogenetically similar isolates occurring on Citrus and other hosts elsewhere. From these results four Zasmidium species were recognized on Citrus, namely Z. indonesianum on Citrus in Indonesia, Z. fructicola and Z. fructigenum on Citrus in China and Z. citri-griseum, which appears to have a wide host range including Acacia, Citrus, Eucalyptus and Musa, as well as a global distribution. PMID- 26432806 TI - Phylogeny of Pluteus section Celluloderma including eight new species from Brazil. AB - A general phylogeny of Pluteus section Celluloderma based on nuc rITS1-5.8-ITS2 (ITS) barcode sequences is presented with description of eight new species from Brazil supported by morphological and molecular data: P. brunneocrinitus, P. cebolinhae, P. crinitus, P. halonatus, P. hispidulopsis, P. karstedtiae, P. necopinatus and P. paucicystidiatus. PMID- 26432807 TI - The importance of being NICE. PMID- 26432808 TI - Factors influencing junior doctors' choices of future specialty: trends over time and demographics based on results from UK national surveys. AB - OBJECTIVE: To study trends in factors influencing junior doctors' choice of future specialty. DESIGN: Respondents were asked whether each of 15 factors had a great deal of influence on their career choice, a little influence or no influence on it. Percentages are reported of those who specified that a factor had a great deal of influence on their career choice. SETTING: UK. PARTICIPANTS: A total of 15,765 UK-trained doctors who graduated between 1999 and 2012. MAIN OUTCOME MEASURES: Questions about career choices and factors which may have influenced those choices, in particular comparing doctors who qualified in 2008 2012 with those who qualified in 1999-2002. RESULTS: Enthusiasm for and commitment to the specialty was a greater influence on career choice in the 2008 2012 qualifiers (81%) than those of 1999-2002 (64%), as was consideration of their domestic circumstances (43% compared with 20%). Prospects for promotion were less important to recent cohorts (16%) than older cohorts (21%), as were financial prospects (respectively, 10% and 14%). Domestic circumstances and working hours were considered more important, and financial prospects less important, by women than men. Inclination before medical school was rated as important by 41% of doctors who were over 30 years old, compared with 13% of doctors who were under 21, at the time of starting medical school. CONCLUSIONS: The increasing importance of both domestic circumstances and enthusiasm for their specialty choice in recent cohorts suggest that today's young doctors prize both work-life balance and personal fulfilment at work more highly than did their predecessors. The differences in motivations of older and younger generations of doctors, men and women, and doctors who start medical school relatively late are worthy of note. PMID- 26432809 TI - Tuning the heart with music. PMID- 26432810 TI - Improving healthcare for people with dementia in England: good progress but more to do. PMID- 26432811 TI - Challenges of harmonising data from UK national health surveys: a case study of attempts to estimate the UK prevalence of asthma. PMID- 26432812 TI - Medicalisation in the UK: changing dynamics, but still ongoing. PMID- 26432813 TI - Climate change, conflict and health. AB - Future climate change is predicted to diminish essential natural resource availability in many regions and perhaps globally. The resulting scarcity of water, food and livelihoods could lead to increasingly desperate populations that challenge governments, enhancing the risk of intra- and interstate conflict. Defence establishments and some political scientists view climate change as a potential threat to peace. While the medical literature increasingly recognises climate change as a fundamental health risk, the dimension of climate change associated conflict has so far received little attention, despite its profound health implications. Many analysts link climate change with a heightened risk of conflict via causal pathways which involve diminishing or changing resource availability. Plausible consequences include: increased frequency of civil conflict in developing countries; terrorism, asymmetric warfare, state failure; and major regional conflicts. The medical understanding of these threats is inadequate, given the scale of health implications. The medical and public health communities have often been reluctant to interpret conflict as a health issue. However, at times, medical workers have proven powerful and effective peace advocates, most notably with regard to nuclear disarmament. The public is more motivated to mitigate climate change when it is framed as a health issue. Improved medical understanding of the association between climate change and conflict could strengthen mitigation efforts and increase cooperation to cope with the climate change that is now inevitable. PMID- 26432814 TI - Patient perceptions and recall of consent for regional anaesthesia compared with consent for surgery. AB - OBJECTIVE: In Britain, consent for surgery is documented using a Department of Health form signed by the surgeon and the patient. In contrast, anaesthetic procedures have no formalised consent process. Evidence on the process of consent for regional anaesthesia, and patient perceptions of this, is scarce outside obstetric practice. We aimed to determine patient recall and perceptions of consent for interscalene brachial plexus block and compared this to surgical consent for shoulder arthroplasty. DESIGN: Prospective observational survey. SETTING: A specialist musculoskeletal centre, UK. PARTICIPANTS: Forty-six patients (female:male 30:16, mean age 61 years) undergoing shoulder arthroplasty with interscalene brachial plexus block. MAIN OUTCOME MEASURES: Recall and understanding of consent for regional anaesthesia and surgery was examined using a semi-structured questionnaire 1-2 days after arthroplasty. Surgical consent forms and discussions recorded by the anaesthetist were examined in participants' medical notes to compare against the level of recall. Analysis to determine statistical significance was conducted using McNemar's test. RESULTS: Recall of surgical risks was overall significantly better than recall of brachial plexus block risks. Compared to their recollections of surgical risk, patients remembered fewer specific risks for brachial plexus block (p < 0.001). There were more patients unable to recall any risks when questioned about brachial plexus block than about their surgery (p < 0.05). One-third of patients did not regard the consent discussion about regional anaesthesia as important as consent for surgery and over one-quarter had not recognised the preoperative discussion about the brachial plexus block as a consent process similar to that conducted for surgery. CONCLUSIONS: Fundamental misunderstandings about the consent process are prevalent. Future work in this area should seek to investigate how documentation of the consent process and patients' understanding of consent for regional anaesthesia can be improved. PMID- 26432815 TI - Lessons from a modern review of the smallpox eradication files. PMID- 26432816 TI - International trials in middle-income countries: different local scenarios require different ethical approaches. PMID- 26432817 TI - Has NHS reorganisation saved lives? A CuSum study using 65 years of data. AB - OBJECTIVES: To determine if NHS reforms affect population mortality. DESIGN: Retrospective study using routinely published data. SETTING & PARTICIPANTS: Resident population of England and Wales 1948 to 2012 MAIN OUTCOME MEASURE: All cause age sex directly standardised mortality England and Wales 1948 to 2012. METHODS: Using the CuSum technique and Change-Point Analysis to identify sustained changes in the improving age-standardised mortality rates for the period 1948-2012, and comparing the time of these changes with periods of NHS reform. Where observed changes did not fit with NHS reform, changes external to the NHS were sought as a possible explanation of changes observed. RESULTS: CuSum plotting and CPA showed no significant changes in female mortality trend between 1948 and 2012. However, this analysis identified a sustained improvement in the male mortality trend, occurring in the mid-1970s. A further change in the rate of male mortality decline was found around the Millennium. CONCLUSION: The 1974 NHS reorganisation, changing service arrangements predominantly for women and children, is considered an unlikely explanation of the improved rate of male mortality decline. Thus, centrally led NHS reorganisation has never had any detectable effect on either male or female mortality and must be considered ineffective for this purpose. But some evidence supporting the view that increased funding improves outcomes is found. PMID- 26432819 TI - A tribute to Sjur: Sjur Olsnes, 1939-2014. PMID- 26432818 TI - Review of the neutrophil response to Bordetella pertussis infection. AB - The nature and timing of the neutrophil response to infection with Bordetella pertussis is influenced by multiple virulence factors expressed by the bacterium. After inoculation of the host airway, the recruitment of neutrophils signaled by B. pertussis lipooligosaccharide (LOS) is suppressed by pertussis toxin (PTX). Over the next week, the combined activities of PTX, LOS and adenylate cyclase toxin (ACT) result in production of cytokines that generate an IL-17 response, promoting neutrophil recruitment which peaks at 10-14 days after inoculation in mice. Arriving at the site of infection, neutrophils encounter the powerful local inhibitory activity of ACT, in conjunction with filamentous hemagglutinin. With the help of antibodies, neutrophils contribute to clearance of B. pertussis, but only after 28-35 days in a naive mouse. Studies of the lasting, antigen-specific IL-17 response to infection in mice and baboons has led to progress in vaccine development and understanding of pathogenesis. Questions remain about the mediators that coordinate neutrophil recruitment and the mechanisms by which neutrophils overcome B. pertussis virulence factors. PMID- 26432820 TI - Health Insurance-Related Disparities in Lymphoma Survival Are Partly Mediated by Baseline Clinical Factors. PMID- 26432821 TI - In Reply. PMID- 26432822 TI - Quorum quenching: role in nature and applied developments. AB - Quorum sensing (QS) refers to the capacity of bacteria to monitor their population density and regulate gene expression accordingly: the QS-regulated processes deal with multicellular behaviors (e.g. growth and development of biofilm), horizontal gene transfer and host-microbe (symbiosis and pathogenesis) and microbe-microbe interactions. QS signaling requires the synthesis, exchange and perception of bacterial compounds, called autoinducers or QS signals (e.g. N acylhomoserine lactones). The disruption of QS signaling, also termed quorum quenching (QQ), encompasses very diverse phenomena and mechanisms which are presented and discussed in this review. First, we surveyed the QS-signal diversity and QS-associated responses for a better understanding of the targets of the QQ phenomena that organisms have naturally evolved and are currently actively investigated in applied perspectives. Next the mechanisms, targets and molecular actors associated with QS interference are presented, with a special emphasis on the description of natural QQ enzymes and chemicals acting as QS inhibitors. Selected QQ paradigms are detailed to exemplify the mechanisms and biological roles of QS inhibition in microbe-microbe and host-microbe interactions. Finally, some QQ strategies are presented as promising tools in different fields such as medicine, aquaculture, crop production and anti biofouling area. PMID- 26432823 TI - Can Sonography Distinguish a Supraorbital Notch From a Foramen? AB - Diagnostic tools for evaluating the supraorbital rim in preparation for nerve decompression surgery in patients with chronic headaches are currently limited. We evaluated the use of sonography to diagnose the presence of a supraorbital notch or foramen in 11 cadaver orbits. Sonographic findings were assessed by dissecting cadaver orbits to determine whether a notch or foramen was present. Sonography correctly diagnosed the presence of a supraorbital notch in 7 of 7 cases and correctly diagnosed a supraorbital foramen in 4 of 4 cases. We found that sonography had 100% sensitivity in diagnosing a supraorbital notch and foramen. This tool may therefore be helpful in characterizing the supraorbital rim preoperatively and may influence the decision to use a transpalpebral or endoscopic approach for supraorbital nerve decompression as well as the decision to use local or general anesthesia. PMID- 26432824 TI - Wave Intensity Analysis Can Identify Eccentric Cardiac Hypertrophy in Hypertensive Patients With Varied Left Ventricular Configurations. AB - OBJECTIVES: The primary aim of this study was to determine whether wave intensity can discriminate cases of eccentric hypertrophy in patients with essential hypertension who have varied left ventricular configurations. METHODS: A total of 155 hypertensive patients with different ventricular configurations (27 normal configuration, 42 concentric remodeling, 62 concentric hypertrophy, and 24 eccentric hypertrophy) were recruited. We performed a noninvasive wave intensity analysis of the common carotid artery and conventional echocardiography. Blood pressure and flow velocity were measured in the right carotid artery of all patients. RESULTS: The left ventricular ejection fraction (LVEF) in the eccentric hypertrophy group was significantly lower than the values in the other groups (P < .05). The R-W1 interval/W1-W2 interval ratio (where W1 indicates the first positive peak and W2 the second positive peak) in the eccentric hypertrophy group was much higher than the values in the other groups (P < .05). However, there were no significant differences in W1, W2, and negative area among these groups. Pearson correlation analysis showed that R-W1/W1-W2, R-W1, and W1-W2were correlated with the LVEF, whereas there was no correlation between W1, W2, negative area, and the reflection coefficient with the LVEF. CONCLUSIONS: We propose that by using the R-W1/W1-W2 ratio, wave intensity analysis can identify hypertensive patients with eccentric hypertrophy without the need for echocardiography. PMID- 26432825 TI - Chronic Influences of Obstructive Sleep Apnea on Cerebral Venous Flow. AB - OBJECTIVES: Evidence reveals a pathophysiologic link between sleep apnea syndrome and cerebrovascular diseases. It is known that obstructive sleep apnea (OSA) may cause serial hemodynamic changes and structural abnormalities in the cerebral and cardiac arterial systems, but its effect on the cerebral venous system has remained unclear. The purpose of this study was to compare internal jugular vein hemodynamics between patients with OSA and healthy individuals. METHODS: Patients with OSA and age-, body mass index-, and sex-matched healthy control participants were recruited for a jugular venous duplex study and neurologic examination. The luminal area of the internal jugular vein, jugular venous flow volume, time averaged mean velocity, and presence of jugular venous reflux were recorded. These flow characteristics were obtained at different respiratory statuses, and we analyzed the differences between patients and controls. RESULTS: In the OSA group, there was an increasing flow volume in total internal jugular veins at rest. The frequency of venous reflux in patients compared with controls was significantly decreased (26.7% versus 53.3%, respectively; P < .05). The internal jugular vein drainage dominance was greater on the left side in the OSA group (right versus left: 48.8% versus 51.2%), whereas it was greater on the right side in the control group (right versus left: 61.7% versus 38.3%). CONCLUSIONS: Our data showed peculiar internal jugular vein hemodynamics at baseline and different respiratory statuses in patients with OSA. These characteristics imply that cerebral venous drainage conditions might be involved in the pathophysiologic mechanisms of OSA syndrome. PMID- 26432826 TI - Reliability of Doppler Assessment of the Middle Cerebral Artery in the Near and Far Fields in Healthy and Anemic Fetuses. AB - OBJECTIVES: The purpose of this study was to assess the reliability of the middle cerebral artery pulsatility index (PI) and peak systolic velocity (PSV) at the proximal portions of the near- and far-field vessel sites in healthy and anemic fetuses. METHODS: The middle cerebral artery PSV and PI were prospectively assessed in 50 normal singleton pregnancies. The Doppler waveforms for the middle cerebral artery PI and the PSV were recorded independently by 2 operators at the most proximal portions of the near- and far-field sites. Data for the PSV and PI at the proximal portions of both the near- and the far-field sites were also retrospectively collected in 7 anemic fetuses. RESULTS: No significant difference between the operators was detected for the middle cerebral artery PSV (P = .60) and PI (P = .88) measured in the conventionally used near-field proximal site in the 50 healthy fetuses. No significant difference between the proximal portions of the near- and far-field sites was detected for the PSV (P = .53) and PI (P = .23) in healthy or anemic fetuses. CONCLUSIONS: The findings of this study suggest that the use of the far-field vessel is an acceptable alternative for measurement of the middle cerebral artery PI and PSV when investigation of the near-field vessel is technically difficult. PMID- 26432827 TI - Ultrasound-Guided Fenestration of Tendons About the Hip and Pelvis: Clinical Outcomes. AB - OBJECTIVES: Percutaneous ultrasound-guided needle fenestration has been used to treat tendinopathy of the elbow, knee, and ankle with promising results. The purpose of this study was to evaluate the clinical outcome of ultrasound-guided fenestration of tendons about the hip and pelvis. METHODS: After Institutional Review Board approval, a retrospective search of imaging reports from January 1, 2005, to June 30, 2011, was completed to identify patients treated with ultrasound-guided tendon fenestration about the hip or pelvis. Subsequent clinic notes were retrospectively reviewed to determine whether the patient showed marked improvement, some improvement, no change, or worsening symptoms. RESULTS: The study group consisted of 22 tendons in 21 patients with an average age of 55.8 years (range, 26.7-77.0 years). The treated tendons included 11 gluteus medius (9 tendinosis and 2 partial tears), 2 gluteus minimus (both tendinosis), 8 hamstring (6 tendinosis and 2 partial tears), and 1 tensor fascia latae (tendinosis). The average interval to clinical follow-up was 70 days (range, 7 813 days). There was marked improvement in 45.5% (10 of 22), some improvement in 36.4% (8 of 22), no change in symptoms in 9.1% (2 of 22), and worsening symptoms in 9.1% (2 of 22). There were no patient variables (age, chronicity of symptoms, sex, tendon, tendinosis versus tear, prior physical therapy, and prior corticosteroid injection) that were significantly different between patients who improved and those who did not. There were no cases of a subsequent tendon tear or infection. CONCLUSIONS: Clinical follow-up after ultrasound-guided fenestration of the gluteus medius, gluteus minimus, proximal hamstring, and tensor fascia latae tendons showed that 82% of patients had improvement in their symptoms. PMID- 26432828 TI - MaizeGDB update: new tools, data and interface for the maize model organism database. AB - MaizeGDB is a highly curated, community-oriented database and informatics service to researchers focused on the crop plant and model organism Zea mays ssp. mays. Although some form of the maize community database has existed over the last 25 years, there have only been two major releases. In 1991, the original maize genetics database MaizeDB was created. In 2003, the combined contents of MaizeDB and the sequence data from ZmDB were made accessible as a single resource named MaizeGDB. Over the next decade, MaizeGDB became more sequence driven while still maintaining traditional maize genetics datasets. This enabled the project to meet the continued growing and evolving needs of the maize research community, yet the interface and underlying infrastructure remained unchanged. In 2015, the MaizeGDB team completed a multi-year effort to update the MaizeGDB resource by reorganizing existing data, upgrading hardware and infrastructure, creating new tools, incorporating new data types (including diversity data, expression data, gene models, and metabolic pathways), and developing and deploying a modern interface. In addition to coordinating a data resource, the MaizeGDB team coordinates activities and provides technical support to the maize research community. MaizeGDB is accessible online at http://www.maizegdb.org. PMID- 26432829 TI - Assembly and analysis of eukaryotic Argonaute-RNA complexes in microRNA-target recognition. AB - Experimental studies have uncovered a variety of microRNA (miRNA)-target duplex structures that include perfect, imperfect and seedless duplexes. However, non canonical binding modes from imperfect/seedless duplexes are not well predicted by computational approaches, which rely primarily on sequence and secondary structural features, nor have their tertiary structures been characterized because solved structures to date are limited to near perfect, straight duplexes in Argonautes (Agos). Here, we use structural modeling to examine the role of Ago dynamics in assembling viable eukaryotic miRNA-induced silencing complexes (miRISCs). We show that combinations of low-frequency, global modes of motion of Ago domains are required to accommodate RNA duplexes in model human and C. elegans Ago structures. Models of viable miRISCs imply that Ago adopts variable conformations at distinct target sites that generate distorted, imperfect miRNA target duplexes. Ago's ability to accommodate a duplex is dependent on the region where structural distortions occur: distortions in solvent-exposed seed and 3' end regions are less likely to produce steric clashes than those in the central duplex region. Energetic analyses of assembled miRISCs indicate that target recognition is also driven by favorable Ago-duplex interactions. Such structural insights into Ago loading and target recognition mechanisms may provide a more accurate assessment of miRNA function. PMID- 26432830 TI - MitoMiner v3.1, an update on the mitochondrial proteomics database. AB - Mitochondrial proteins remain the subject of intense research interest due to their implication in an increasing number of different conditions including mitochondrial and metabolic disease, cancer, and neuromuscular degenerative and age-related disorders. However, the mitochondrial proteome has yet to be accurately and comprehensively defined, despite many studies. To support mitochondrial research, we developed MitoMiner (http://mitominer.mrc mbu.cam.ac.uk), a freely accessible mitochondrial proteomics database. MitoMiner integrates different types of subcellular localisation evidence with protein information from public resources, and so provides a comprehensive central resource for data on mitochondrial protein localisation. Here we report important updates to the database including the addition of subcellular immunofluorescent staining results from the Human Protein Atlas, computational predictions of mitochondrial targeting sequences, and additional large-scale mass-spectrometry and GFP tagging data sets. This evidence is shared across the 12 species in MitoMiner (now including Schizosaccharomyces pombe) by homology mapping. MitoMiner provides multiple ways of querying the data including simple text searches, predefined queries and custom queries created using the interactive QueryBuilder. For remote programmatic access, API's are available for several programming languages. This combination of data and flexible querying makes MitoMiner a unique platform to investigate mitochondrial proteins, with application in mitochondrial research and prioritising candidate mitochondrial disease genes. PMID- 26432831 TI - New insights into the enzymatic role of EF-G in ribosome recycling. AB - During translation, elongation factor G (EF-G) plays a catalytic role in tRNA translocation and a facilitative role in ribosome recycling. By stabilizing the rotated ribosome and interacting with ribosome recycling factor (RRF), EF-G was hypothesized to induce the domain rotations of RRF, which subsequently performs the function of splitting the major intersubunit bridges and thus separates the ribosome into subunits for recycling. Here, with systematic mutagenesis, FRET analysis and cryo-EM single particle approach, we analyzed the interplay between EF-G/RRF and post termination complex (PoTC). Our data reveal that the two conserved loops (loop I and II) at the tip region of EF-G domain IV possess distinct roles in tRNA translocation and ribosome recycling. Specifically, loop II might be directly involved in disrupting the main intersubunit bridge B2a between helix 44 (h44 from the 30S subunit) and helix 69 (H69 from the 50S subunit) in PoTC. Therefore, our data suggest a new ribosome recycling mechanism which requires an active involvement of EF-G. In addition to supporting RRF, EF-G plays an enzymatic role in destabilizing B2a via its loop II. PMID- 26432832 TI - Quadruplex formation by both G-rich and C-rich DNA strands of the C9orf72 (GGGGCC)8*(GGCCCC)8 repeat: effect of CpG methylation. AB - Unusual DNA/RNA structures of the C9orf72 repeat may participate in repeat expansions or pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia. Expanded repeats are CpG methylated with unknown consequences. Typically, quadruplex structures form by G-rich but not complementary C-rich strands. Using CD, UV and electrophoresis, we characterized the structures formed by (GGGGCC)8 and (GGCCCC)8 strands with and without 5-methylcytosine (5mCpG) or 5 hydroxymethylcytosine (5hmCpG) methylation. All strands formed heterogenous mixtures of structures, with features of quadruplexes (at pH 7.5, in K(+), Na(+) or Li(+)), but no feature typical of i-motifs. C-rich strands formed quadruplexes, likely stabilized by G*C*G*C-tetrads and C*C*C*C-tetrads. Unlike G*G*G*G-tetrads, some G*C*G*C-tetrad conformations do not require the N7-Guanine position, hence C9orf72 quadruplexes still formed when N7-deazaGuanine replace all Guanines. 5mCpG and 5hmCpG increased and decreased the thermal stability of these structures. hnRNPK, through band-shift analysis, bound C-rich but not G rich strands, with a binding preference of unmethylated > 5hmCpG > 5mCpG, where methylated DNA-protein complexes were retained in the wells, distinct from unmethylated complexes. Our findings suggest that for C-rich sequences interspersed with G-residues, one must consider quadruplex formation and that methylation of quadruplexes may affect epigenetic processes. PMID- 26432833 TI - iPPI-DB: an online database of modulators of protein-protein interactions. AB - In order to boost the identification of low-molecular-weight drugs on protein protein interactions (PPI), it is essential to properly collect and annotate experimental data about successful examples. This provides the scientific community with the necessary information to derive trends about privileged physicochemical properties and chemotypes that maximize the likelihood of promoting a given chemical probe to the most advanced stages of development. To this end we have developed iPPI-DB (freely accessible at http://www.ippidb.cdithem.fr), a database that contains the structure, some physicochemical characteristics, the pharmacological data and the profile of the PPI targets of several hundreds modulators of protein-protein interactions. iPPI DB is accessible through a web application and can be queried according to two general approaches: using physicochemical/pharmacological criteria; or by chemical similarity to a user-defined structure input. In both cases the results are displayed as a sortable and exportable datasheet with links to external databases such as Uniprot, PubMed. Furthermore each compound in the table has a link to an individual ID card that contains its physicochemical and pharmacological profile derived from iPPI-DB data. This includes information about its binding data, ligand and lipophilic efficiencies, location in the PPI chemical space, and importantly similarity with known drugs, and links to external databases like PubChem, and ChEMBL. PMID- 26432834 TI - Dynamical features of the Plasmodium falciparum ribosome during translation. AB - Plasmodium falciparum, the mosquito-transmitted Apicomplexan parasite, causes the most severe form of human malaria. In the asexual blood-stage, the parasite resides within erythrocytes where it proliferates, multiplies and finally spreads to new erythrocytes. Development of drugs targeting the ribosome, the site of protein synthesis, requires specific knowledge of its structure and work cycle, and, critically, the ways they differ from those in the human host. Here, we present five cryo-electron microscopy (cryo-EM) reconstructions of ribosomes purified from P. falciparum blood-stage schizonts at sub-nanometer resolution. Atomic models were built from these density maps by flexible fitting. Significantly, our study has taken advantage of new capabilities of cryo-EM, in visualizing several structures co-existing in the sample at once, at a resolution sufficient for building atomic models. We have discovered structural and dynamic features that differentiate the ribosomes of P. falciparum from those of mammalian system. Prompted by the absence of RACK1 on the ribosome in our and an earlier study we confirmed that RACK1 does not specifically co-purify with the 80S fraction in schizonts. More extensive studies, using cryo-EM methodology, of translation in the parasite will provide structural knowledge that may lead to development of novel anti-malarials. PMID- 26432836 TI - Inhibition of BMK1 pathway suppresses cancer stem cells through BNIP3 and BNIP3L. AB - Cancer stem cells (CSCs) possess many characteristics associated with stem cells and are believed to drive tumor initiation. Although targeting of CSCs offers great promise for the new generation of therapeutics, lack of the effective drugable target and appropriate pharmacological reagents significantly impedes the development of chemotherapies. Here, we show that the phosphorylation of BMK1 was significantly correlated with not only embryonic and induced pluripotent stem (iPS) cells, but also the CSCs. It was showed that activation of BMK1 by the expression of MEK5D enhanced the self-renew (sphere formation), proliferation (clone formation) and tumorigenic capacity of CSCs. While BMK1 inhibitor, XMD8 92, suppressed these capacities. RNA-seq and microarray analysis revealed that inhibition of BMK1 significantly enhanced the expression of BNIP3 and BNIP3L, which play important roles in cell death. Further study indicated that shRNA mediated knock down of BNIP3 and BNIP3L impairs the BMK1 inhibitor, XMD8-92 induced suppression of sphere formation and clone formation of CSC. Collectively, these results not only indicate that BMK1 plays an important role in maintaining "stemness" of CSCs, but also implicate that BMK1 might be a potential drug target for CSCs. PMID- 26432837 TI - Cardiovascular response to thermoregulatory challenges. AB - A growing number of extreme climate events are occurring in the setting of ongoing climate change, with an increase in both the intensity and frequency. It has been shown that ambient temperature challenges have a direct and highly varied impact on cardiovascular health. With a rapidly growing amount of literature on this issue, we aim to review the recent publications regarding the impact of cold and heat on human populations with regard to cardiovascular disease (CVD) mortality/morbidity while also examining lag effects, vulnerable subgroups, and relevant mechanisms. Although the relative risk of morbidity/mortality associated with extreme temperature varied greatly across different studies, both cold and hot temperatures were associated with a positive mean excess of cardiovascular deaths or hospital admissions. Cause-specific study of CVD morbidity/mortality indicated that the sensitivity to temperature was disease-specific, with different patterns for acute and chronic ischemic heart disease. Vulnerability to temperature-related mortality was associated with some characteristics of the populations, including sex, age, location, socioeconomic condition, and comorbidities such as cardiac diseases, kidney diseases, diabetes, and hypertension. Temperature-induced damage is thought to be related to enhanced sympathetic reactivity followed by activation of the sympathetic nervous system, renin-angiotensin system, as well as dehydration and a systemic inflammatory response. Future research should focus on multidisciplinary adaptation strategies that incorporate epidemiology, climatology, indoor/building environments, energy usage, labor legislative perfection, and human thermal comfort models. Studies on the underlying mechanism by which temperature challenge induces pathophysiological response and CVD await profound and lasting investigation. PMID- 26432838 TI - Organic cation transporter 3 contributes to norepinephrine uptake into perivascular adipose tissue. AB - Perivascular adipose tissue (PVAT) reduces vasoconstriction to norepinephrine (NE). A mechanism by which PVAT could function to reduce vascular contraction is by decreasing the amount of NE to which the vessel is exposed. PVATs from male Sprague-Dawley rats were used to test the hypothesis that PVAT has a NE uptake mechanism. NE was detected by HPLC in mesenteric PVAT and isolated adipocytes. Uptake of NE (10 MUM) in mesenteric PVAT was reduced by the NE transporter (NET) inhibitor nisoxetine (1 MUM, 73.68 +/- 7.62%, all values reported as percentages of vehicle), the 5-hydroxytryptamine transporter (SERT) inhibitor citalopram (100 nM) with the organic cation transporter 3 (OCT3) inhibitor corticosterone (100 MUM, 56.18 +/- 5.21%), and the NET inhibitor desipramine (10 MUM) with corticosterone (100 MUM, 61.18 +/- 6.82%). Aortic PVAT NE uptake was reduced by corticosterone (100 MUM, 53.01 +/- 10.96%). Confocal imaging of mesenteric PVAT stained with 4-[4-(dimethylamino)-styrl]-N-methylpyridinium iodide (ASP(+)), a fluorescent substrate of cationic transporters, detected ASP(+) uptake into adipocytes. ASP(+) (2 MUM) uptake was reduced by citalopram (100 nM, 66.68 +/- 6.43%), corticosterone (100 MUM, 43.49 +/- 10.17%), nisoxetine (100 nM, 84.12 +/- 4.24%), citalopram with corticosterone (100 nM and 100 MUM, respectively, 35.75 +/- 4.21%), and desipramine with corticosterone (10 and 100 MUM, respectively, 50.47 +/- 5.78%). NET protein was not detected in mesenteric PVAT adipocytes. Expression of Slc22a3 (OCT3 gene) mRNA and protein in PVAT adipocytes was detected by RT-PCR and immunocytochemistry, respectively. These end points support the presence of a transporter-mediated NE uptake system within PVAT with a potential mediator being OCT3. PMID- 26432839 TI - A dilated cardiomyopathy mutation blunts adrenergic response and induces contractile dysfunction under chronic angiotensin II stress. AB - We investigated cardiac contractility in the ACTC E361G transgenic mouse model of dilated cardiomyopathy (DCM). No differences in cardiac dimensions or systolic function were observed in young mice, whereas young adult mice exhibited only mild diastolic abnormalities. Dobutamine had an inotropic and lusitropic effect on the mouse heart. In papillary muscle at 37 degrees C, dobutamine increased relaxation rates [~50% increase of peak rate of force decline normalized to force (dF/dtmin/F), 25% reduction of time to 90% relaxation (t90) in nontransgenic (NTG) mice], but in the ACTC E361G mouse, dF/dtmin/F was increased 20-30%, and t90 was only reduced 10% at 10 Hz. Pressure-volume measurements showed increases in maximum rate of pressure decline and decreases in time constant of left ventricular pressure decay in the ACTC E361G mouse that were 25-30% of the changes in the NTG mouse, consistent with blunting of the lusitropic response. The inotropic effect of dobutamine was also blunted in ACTC E361G mice, and the dobutamine-stimulated increase in cardiac output (CO) was reduced from 2,100 to 900 MUl/min. Mice were treated with high doses of ANG II for 4 wk. The chronic stress treatment evoked systolic dysfunction in ACTC E361G mice but not in NTG. There was a significant reduction in rates of pressure increase and decrease, as well as reduced end-systolic pressure and increased volume. Ejection fraction and CO were reduced in the ACTC E361G mouse, indicating DCM. In vitro DCM-causing mutations uncouple the relationship between Ca(2+) sensitivity and troponin I phosphorylation. We conclude that this leads to the observed, reduced response to beta1 agonists and reduced cardiac reserve that predisposes the heart to DCM under conditions of chronic stress. PMID- 26432840 TI - N-acetylcysteine reverses diastolic dysfunction and hypertrophy in familial hypertrophic cardiomyopathy. AB - S-glutathionylation of cardiac myosin-binding protein C (cMyBP-C) induces Ca(2+) sensitization and a slowing of cross-bridge kinetics as a result of increased oxidative signaling. Although there is evidence for a role of oxidative stress in disorders associated with hypertrophic cardiomyopathy (HCM), this mechanism is not well understood. We investigated whether oxidative myofilament modifications may be in part responsible for diastolic dysfunction in HCM. We administered N acetylcysteine (NAC) for 30 days to 1-mo-old wild-type mice and to transgenic mice expressing a mutant tropomyosin (Tm-E180G) and nontransgenic littermates. Tm E180G hearts demonstrate a phenotype similar to human HCM. After NAC administration, the morphology and diastolic function of Tm-E180G mice was not significantly different from controls, indicating that NAC had reversed baseline diastolic dysfunction and hypertrophy in our model. NAC administration also increased sarco(endo)plasmic reticulum Ca(2+) ATPase protein expression, reduced extracellular signal-related kinase 1/2 phosphorylation, and normalized phosphorylation of phospholamban, as assessed by Western blot. Detergent extracted fiber bundles from NAC-administered Tm-E180G mice showed nearly nontransgenic (NTG) myofilament Ca(2+) sensitivity. Additionally, we found that NAC increased tension cost and rate of cross-bridge reattachment. Tm-E180G myofilaments were found to have a significant increase in S-glutathionylation of cMyBP-C, which was returned to NTG levels upon NAC administration. Taken together, our results indicate that oxidative myofilament modifications are an important mediator in diastolic function, and by relieving this modification we were able to reverse established diastolic dysfunction and hypertrophy in HCM. PMID- 26432841 TI - Cardiomyocyte-specific Bmal1 deletion in mice triggers diastolic dysfunction, extracellular matrix response, and impaired resolution of inflammation. AB - The mammalian circadian clock consists of multiple transcriptional regulators that coordinate biological processes in a time-of-day-dependent manner. Cardiomyocyte-specific deletion of the circadian clock component, Bmal1 (aryl hydrocarbon receptor nuclear translocator-like protein 1), leads to age-dependent dilated cardiomyopathy and decreased lifespan in mice. We investigated whether cardiomyocyte-specific Bmal1 knockout (CBK) mice display early alterations in cardiac diastolic function, extracellular matrix (ECM) remodeling, and inflammation modulators by investigating CBK mice and littermate controls at 8 and 28 wk of age (i.e., prior to overt systolic dysfunction). Left ventricles of CBK mice exhibited (P < 0.05): 1) progressive abnormal diastolic septal annular wall motion and reduced pulmonary venous flow only at 28 wk of age; 2) progressive worsening of fibrosis in the interstitial and endocardial regions from 8 to 28 wk of age; 3) increased (>1.5 fold) expression of collagen I and III, as well as the matrix metalloproteinases MMP-9, MMP-13, and MMP-14 at 28 wk of age; 4) increased transcript levels of neutrophil chemotaxis and leukocyte migration genes (Ccl2, Ccl8, Cxcl2, Cxcl1, Cxcr2, Il1beta) with no change in Il 10 and Il-13 genes expression; and 5) decreased levels of 5-LOX, HO-1 and COX-2, enzymes indicating impaired resolution of inflammation. In conclusion, genetic disruption of the cardiomyocyte circadian clock results in diastolic dysfunction, adverse ECM remodeling, and proinflammatory gene expression profiles in the mouse heart, indicating signs of early cardiac aging in CBK mice. PMID- 26432842 TI - Effect of PDE5 inhibition on the modulation of sympathetic alpha-adrenergic vasoconstriction in contracting skeletal muscle of young and older recreationally active humans. AB - Aging is associated with an altered regulation of blood flow to contracting skeletal muscle; however, the precise mechanisms remain unclear. We recently demonstrated that inhibition of cGMP-binding phosphodiesterase 5 (PDE5) increased blood flow to contracting skeletal muscle of older but not young human subjects. Here we examined whether this effect of PDE5 inhibition was related to an improved ability to blunt alpha-adrenergic vasoconstriction (functional sympatholysis) and/or improved efficacy of local vasodilator pathways. A group of young (23 +/- 1 yr) and a group of older (72 +/- 1 yr) male subjects performed knee-extensor exercise in a control setting and following intake of the highly selective PDE5 inhibitor sildenafil. During both conditions, exercise was performed without and with arterial tyramine infusion to evoke endogenous norepinephrine release and consequently stimulation of alpha1- and alpha2 adrenergic receptors. The level of the sympatholytic compound ATP was measured in venous plasma by use of the microdialysis technique. Sildenafil increased (P < 0.05) vascular conductance during exercise in the older group, but tyramine infusion reduced (P < 0.05) this effect by 38 +/- 9%. Similarly, tyramine reduced (P < 0.05) the vasodilation induced by arterial infusion of a nitric oxide (NO) donor by 54 +/- 9% in the older group, and this effect was not altered by sildenafil. Venous plasma [ATP] did not change with PDE5 inhibition in the older subjects during exercise. Collectively, PDE5 inhibition in older humans was not associated with an improved ability for functional sympatholysis. An improved efficacy of the NO system may be one mechanism underlying the effect of PDE5 inhibition on exercise hyperemia in aging. PMID- 26432843 TI - MicroRNA-145 repairs infarcted myocardium by accelerating cardiomyocyte autophagy. AB - We investigated whether microRNA-145 (miR-145) has a cardioprotective effect in a rabbit model of myocardial infarction (MI) and in H9c2 rat cardiomyoblasts. Rabbits underwent 30 min of coronary occlusion, followed by 2 days or 2 wk of reperfusion. Control microRNA (control group; 2.5 nmol/kg, n = 10) or miR-145 (miR-145 group, 2.5 nmol/kg, n = 10) encapsulated in liposomes was intravenously administered immediately after the start of reperfusion. H9c2 rat cardiomyoblasts were transfected with miR-145. The MI size was significantly smaller in the miR 145 group than in the control group at 2 days and 2 wk post-MI. miR-145 had improved the cardiac function and remodeling at 2 wk post-MI. These effects were reversed by chloroquine. Western blot analysis showed that miR-145 accelerated the transition of LC3B I to II and downregulated p62/SQSTM1 at 2 days or 2 wk after MI, but not at 4 wk, and activated Akt in the ischemic area at 2 days after MI. miR-145 inhibited the growth of H9c2 cells, accelerated the transition of LC3B I to II, and increased phosphorylated Akt in the H9c2 cells at 2 days after miR-145 transfection. Antagomir-145 significantly abolished the morphological change, the transition of LC3B I to II, and the increased phosphorylated Akt induced by miR-145 in H9c2 cells. We determined fibroblast growth factor receptor substrate 2 mRNA to be a target of miR-145, both in an in vivo model and in H9c2 cells. In conclusion, post-MI treatment with miR-145 protected the heart through the induction of cardiomyocyte autophagy by targeting fibroblast growth factor receptor substrate 2. PMID- 26432844 TI - Depressor effect of chymase inhibitor in mice with high salt-induced moderate hypertension. AB - The aim of the present study was to determine whether long-term high salt intake in the drinking water induces hypertension in wild-type (WT) mice and whether a chymase inhibitor or other antihypertensive drugs could reverse the increase of blood pressure. Eight-week-old male WT mice were supplied with drinking water containing 2% salt for 12 wk (high-salt group) or high-salt drinking water plus an oral chymase inhibitor (TPC-806) at four different doses (25, 50, 75, or 100 mg/kg), captopril (75 mg/kg), losartan (100 mg/kg), hydrochlorothiazide (3 mg/kg), eplerenone (200 mg/kg), or amlodipine (6 mg/kg). Control groups were given normal water with or without the chymase inhibitor. Blood pressure and heart rate gradually showed a significant increase in the high-salt group, whereas a dose-dependent depressor effect of the chymase inhibitor was observed. There was also partial improvement of hypertension in the losartan- and eplerenone-treated groups but not in the captopril-, hydrochlorothiazide-, and amlodipine-treated groups. A high salt load significantly increased chymase dependent ANG II-forming activity in the alimentary tract. In addition, the relative contribution of chymase to ANG II formation, but not actual average activity, showed a significant increase in skin and skeletal muscle, whereas angiotensin-converting enzyme-dependent ANG II-forming activity and its relative contribution were reduced by high salt intake. Plasma and urinary renin angiotensin system components were significantly increased in the high-salt group but were significantly suppressed in the chymase inhibitor-treated group. In conclusion, 2% salt water drinking for 12 wk caused moderate hypertension and activated the renin-angiotensin system in WT mice. A chymase inhibitor suppressed both the elevation of blood pressure and heart rate, indicating a definite involvement of chymase in salt-sensitive hypertension. PMID- 26432845 TI - IFN-beta affects the angiogenic potential of circulating angiogenic cells by activating calpain 1. AB - Circulating angiogenic cells (CACs) are monocyte-derived cells with endothelial characteristics, which contribute to both angiogenesis and arteriogenesis in a paracrine way. Interferon-beta (IFN-beta) is known to inhibit these divergent processes in animals and patients. We hypothesized that IFN-beta might act by affecting the differentiation and function of CACs. CACs were cultured from peripheral blood mononuclear cells and phenotypically characterized by surface expression of monocytic and endothelial markers. IFN-beta significantly reduced the number of CACs by 18-64%. Apoptosis was not induced by IFN-beta, neither in mononuclear cells during differentiation, nor after maturation to CACs. Rather, IFN-beta impaired adhesion to, and spreading on, fibronectin, which was dependent on alpha5beta1 (VLA-5)-integrin. IFN-beta affected the function of VLA-5 in mature CACs, leading to rounding and detachment of cells, by induction of calpain 1 activity. Cell rounding and detachment was completely reversed by inhibition of calpain 1 activity in mature CACs. During in vitro capillary formation, CAC addition and calpain 1 inhibition enhanced sprouting of endothelial cells to a comparable extent, but were not sufficient to rescue tube formation in the presence of IFN-beta. We show that the IFN-beta-induced reduction of the numbers of in vitro differentiated CACs is based on activation of calpain 1, resulting in an attenuated adhesion to extracellular matrix proteins via VLA-5. In vivo, this could lead to inhibition of vessel formation due to reduction of the locally recruited CAC numbers and their paracrine angiogenic factors. PMID- 26432846 TI - Tubers are neither static nor discrete: Evidence from serial diffusion tensor imaging. AB - OBJECTIVE: To assess the extent and evolution of tissue abnormality of tubers, perituber tissue, and normal-appearing white matter (NAWM) in patients with tuberous sclerosis complex using serial diffusion tensor imaging. METHODS: We applied automatic segmentation based on a combined global-local intensity mixture model of 3T structural and 35 direction diffusion tensor MRIs (diffusion tensor imaging) to define 3 regions: tuber tissue, an equal volume perituber rim, and the remaining NAWM. For each patient, scan, lobe, and tissue type, we analyzed the averages of mean diffusivity (MD) and fractional anisotropy (FA) in a generalized additive mixed model. RESULTS: Twenty-five patients (mean age 5.9 years; range 0.5-24.5 years) underwent 2 to 6 scans each, totaling 70 scans. Average time between scans was 1.2 years (range 0.4-2.9). Patient scans were compared with those of 73 healthy controls. FA values were lowest, and MD values were highest in tubers, next in perituber tissue, then in NAWM. Longitudinal analysis showed a positive (FA) and negative (MD) correlation with age in tubers, perituber tissue, and NAWM. All 3 tissue types followed a biexponential developmental trajectory, similar to the white matter of controls. An additional qualitative analysis showed a gradual transition of diffusion values across the tissue type boundaries. CONCLUSIONS: Similar to NAWM, tuber and perituber tissues in tuberous sclerosis complex undergo microstructural evolution with age. The extent of diffusion abnormality decreases with distance to the tuber, in line with known extension of histologic, immunohistochemical, and molecular abnormalities beyond tuber pathology. PMID- 26432847 TI - Dynamic tubers in tuberous sclerosis complex: A window for intervention? PMID- 26432848 TI - Survival in synucleinopathies: A prospective cohort study. AB - OBJECTIVES: Parkinson disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) involve cytoplasmic deposition of alpha-synuclein and are considered to be synucleinopathies. Approximately 40% of patients with PD, most patients with MSA, and all patients with PAF have neurogenic orthostatic hypotension (OH). This study compared long-term survival in these synucleinopathies. METHODS: In this prospective cohort study, survival data were obtained for 97.6% of 206 referred patients evaluated between 1994 and 2014 (47 PD + OH, 54 PD no OH, 15 cerebellar MSA [MSA-C], 57 parkinsonian MSA [MSA-P], 28 PAF). Individual diagnoses were confirmed by clinical criteria and results of pharmacologic, neurochemical, and neuroimaging tests of sympathetic noradrenergic innervation. The Cox proportional hazard model was used to calculate hazard ratios (HRs) from symptom onset and from time of evaluation to death. RESULTS: Patients with MSA-C or MSA-P had shorter survival from symptom onset than did patients with PD + OH (age- and sex-adjusted HR = 6.1, 5.6; p < 0.0001 each), PAF (HR = 10.8, 9.9; p < 0.0001 each) or PD no OH (HR = 14.9, 13.6; p < 0.0001 each). Among parkinsonian patients who died, median times from motor onset to death were 7.5 years in MSA-P, 11.6 years in PD + OH, and 15.8 years in PD no OH. Probabilities of survival for 10 years from onset of relevant symptoms were 0.39 in MSA-C, 0.33 in MSA-P, 0.74 in PD + OH, 0.87 in PAF, and 0.93 in PD no OH. CONCLUSIONS: In synucleinopathies, survival depends on the particular disease, with the risk of death greater in MSA-P than in PD + OH and in PD + OH than in PD no OH. PMID- 26432849 TI - Genetics of frontotemporal dementia in Asia: Advancing knowledge through collaboration. PMID- 26432850 TI - Comment: Generalizability theory and assessment in medical training. PMID- 26432851 TI - Neurology objective structured clinical examination reliability using generalizability theory. AB - OBJECTIVES: This study examines factors affecting reliability, or consistency of assessment scores, from an objective structured clinical examination (OSCE) in neurology through generalizability theory (G theory). METHODS: Data include assessments from a multistation OSCE taken by 194 medical students at the completion of a neurology clerkship. Facets evaluated in this study include cases, domains, and items. Domains refer to areas of skill (or constructs) that the OSCE measures. G theory is used to estimate variance components associated with each facet, derive reliability, and project the number of cases required to obtain a reliable (consistent, precise) score. RESULTS: Reliability using G theory is moderate (Phi coefficient = 0.61, G coefficient = 0.64). Performance is similar across cases but differs by the particular domain, such that the majority of variance is attributed to the domain. Projections in reliability estimates reveal that students need to participate in 3 OSCE cases in order to increase reliability beyond the 0.70 threshold. CONCLUSIONS: This novel use of G theory in evaluating an OSCE in neurology provides meaningful measurement characteristics of the assessment. Differing from prior work in other medical specialties, the cases students were randomly assigned did not influence their OSCE score; rather, scores varied in expected fashion by domain assessed. PMID- 26432852 TI - Targeting semaphorins in MS as a treatment strategy to promote remyelination: A tale of mice, rats and men. PMID- 26432853 TI - Expression of semaphorin 3A, semaphorin 7A and their receptors in multiple sclerosis lesions. AB - BACKGROUND: Studies in multiple sclerosis (MS) and in experimental models point to a critical role of semaphorin (sema)3A and sema7A in MS pathogenesis. OBJECTIVE: The objective of this paper is to characterise the expression of sema3A, sema7A, and their receptors in MS lesions. METHODS: We included 44 demyelinating lesions from MS patients, 12 lesions with acute cerebral infarct, 11 lesions with progressive multifocal leucoencephalopathy and 10 non neurological control patients. MS lesions were classified according to inflammatory activity and all samples were immunostained for sema3A, sema7A, neuropilin 1 (Np-1), alpha1-integrin, and beta1-integrin. RESULTS: In MS-damaged white matter sema3A and Np-1 were both detected in microglia/macrophages, whereas reactive astrocytes expressed only sema3A. Otherwise, sema7A, alpha1-integrin and beta1-integrin were observed in reactive astrocytes, and microglia/macrophages only expressed beta1-integrin. The expression of sema3A, sema7A and their receptors is more relevant in MS than in other demyelinating diseases. Sema3A and sema7A expression correlated with the inflammatory activity of the MS lesions, suggesting their involvement in the immunological process that takes place in MS. CONCLUSIONS: The expression pattern of sema3A, sema7A and their receptors in MS lesions suggests that both molecules contribute to create a negative environment for tissue regeneration, influencing the ability to regenerate the damaged tissue. PMID- 26432854 TI - Grey matter involvement by focal cervical spinal cord lesions is associated with progressive multiple sclerosis. AB - BACKGROUND: The in vivo relationship of spinal cord lesion features with clinical course and function in multiple sclerosis (MS) is poorly defined. OBJECTIVE: The objective of this paper is to investigate the associations of spinal cord lesion features on MRI with MS subgroup and disability. METHODS: We recruited 120 people: 25 clinically isolated syndrome, 35 relapsing-remitting (RR), 30 secondary progressive (SP), and 30 primary progressive (PP) MS. Disability was measured using the Expanded Disability Status Scale. We performed 3T axial cervical cord MRI, using 3D-fast-field-echo and phase-sensitive-inversion recovery sequences. Both focal lesions and diffuse abnormalities were recorded. Focal lesions were classified according to the number of white matter (WM) columns involved and whether they extended to grey matter (GM). RESULTS: The proportion of patients with focal lesions involving at least two WM columns and extending to GM was higher in SPMS than in RRMS (p = 0.03) and PPMS (p = 0.015). Diffuse abnormalities were more common in both PPMS and SPMS, compared with RRMS (OR 6.1 (p = 0.002) and 5.7 (p = 0.003), respectively). The number of lesions per patient involving both the lateral column and extending to GM was independently associated with disability (p < 0.001). CONCLUSIONS: More extensive focal cord lesions, extension of lesions to GM, and diffuse abnormalities are associated with progressive MS and disability. PMID- 26432855 TI - No evidence of disease activity in multiple sclerosis: Implications on cognition and brain atrophy. AB - BACKGROUND: The concept of no evidence of disease activity (NEDA) has emerged as an important outcome measure for multiple sclerosis (MS). However, it is not known if maintaining NEDA has a positive impact on cognition or brain atrophy. OBJECTIVE: To evaluate NEDA status after two years, addressing its implications on cognition and brain atrophy. METHODS: Forty-two relapsing-remitting MS patients and 30 controls underwent MRI (3T) and cognitive evaluation (BRB-N). Forty patients performed additional evaluations, after 12 and 24 months. NEDA was defined as the absence of clinical (relapses/disability progression) and MRI activity (new T2/gadolinium-enhancing lesions). Repeated measures and multivariate analyses were performed to assess the contribution of NEDA criteria to GM atrophy. RESULTS: After two years, 30.8% of the cohort had NEDA. From these, 58.3% still had worsening in ?2 cognitive domains. Patients with MRI activity had more cortical thinning and slightly more thalamus volume decrease. Absence of new/enlarging T2 lesions was the only predictor of cortical thinning, subcortical GM and thalamic atrophy rates. CONCLUSIONS: NEDA status was achieved in a small proportion of our cohort, and did not preclude cognitive deterioration. Absence of MRI activity and especially of new/enlarging T2 lesions was associated with less cortical and subcortical GM atrophy. PMID- 26432856 TI - An investigation of the relationship between latitude and multiple sclerosis severity in New Zealand. PMID- 26432857 TI - Monthly oral methylprednisolone pulse treatment in progressive multiple sclerosis. AB - BACKGROUND: There is a large unmet need for treatments for patients with progressive multiple sclerosis (MS). Phase 2 studies with cerebrospinal fluid (CSF) biomarker outcomes may be well suited for the initial evaluation of efficacious treatments. OBJECTIVE: To evaluate the effect of monthly oral methylprednisolone pulse treatment on intrathecal inflammation in progressive MS. METHODS: In this open-label phase 2A study, 15 primary progressive and 15 secondary progressive MS patients received oral methylprednisolone pulse treatment for 60 weeks. Primary outcome was changes in CSF concentrations of osteopontin. Secondary outcomes were other CSF biomarkers of inflammation, axonal damage and demyelination; clinical scores; magnetic resonance imaging measures of disease activity, magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI); motor evoked potentials; and bone density scans. RESULTS: We found no change in the CSF concentration of osteopontin, but we observed significant improvement in clinical scores, MTR, DTI and some secondary CSF outcome measures. Adverse events were well-known side effects to methylprednisolone. CONCLUSION: Monthly methylprednisolone pulse treatment was safe, but had no effect on the primary outcome. However, improvements in secondary clinical and MRI outcome measures suggest that this treatment regimen may have a beneficial effect in progressive MS. PMID- 26432858 TI - PML risk stratification using anti-JCV antibody index and L-selectin. AB - BACKGROUND: Natalizumab treatment is associated with progressive multifocal leukoencephalopathy (PML) development. Treatment duration, prior immunosuppressant use, and JCV serostatus are currently used for risk stratification, but PML incidence stays high. Anti-JCV antibody index and L selectin (CD62L) have been proposed as additional risk stratification parameters. OBJECTIVE: This study aimed at verifying and integrating both parameters into one algorithm for risk stratification. METHODS: Multicentric, international cohorts of natalizumab-treated MS patients were assessed for JCV index (1921 control patients and nine pre-PML patients) and CD62L (1410 control patients and 17 pre PML patients). RESULTS: CD62L values correlate with JCV serostatus, as well as JCV index values. Low CD62L in natalizumab-treated patients was confirmed and validated as a biomarker for PML risk with the risk factor "CD62L low" increasing a patient's relative risk 55-fold (p < 0.0001). Validation efforts established 86% sensitivity/91% specificity for CD62L and 100% sensitivity/59% specificity for JCV index as predictors of PML. Using both parameters identified 1.9% of natalizumab-treated patients in the reference center as the risk group. CONCLUSIONS: Both JCV index and CD62L have merit for risk stratification and share a potential biological relationship with implications for general PML etiology. A risk algorithm incorporating both biomarkers could strongly reduce PML incidence. PMID- 26432859 TI - Regional cortical thinning in multiple sclerosis and its relation with cognitive impairment: A multicenter study. AB - OBJECTIVES: The objectives of this paper are to compare in a multicenter setting patterns of regional cortical thickness in patients with relapsing-remitting multiple sclerosis (RRMS) and cognitive impairment (CI) and those cognitively preserved (CP), and explore the relationship between cortical thinning and cognitive performance. METHODS: T1-weighted isotropic brain scans were collected at 3T from seven European centers in 60 RRMS patients and 65 healthy controls (HCs). Patients underwent clinical and neuropsychological examinations. Cortical thickness (CTh) measures were calculated using FreeSurfer (failing in four) and both lobar and vertex-based general linear model (GLM) analyses were compared between study groups. RESULTS: Twenty (36%) MS patients were classified as CI. Mean global CTh was smaller in RRMS patients compared to HCs (left 2.43 vs. 2.53 mm, right 2.44 vs. 2.54 mm, p < 0.001). Multivariate GLM regional analysis showed significantly more temporal thinning in CI compared to CP patients. Verbal memory scores correlated to regional cortical thinning in the insula whereas visual memory scores correlated to parietal thinning. CONCLUSIONS: This multicenter study showed mild global cortical thinning in RRMS. The extent of thinning is less pronounced than previously reported. Only subtle regional differences between CI and CP patients were observed, some of which related to specific cognitive domains. PMID- 26432860 TI - Proteomic Analysis of Microtubule Interacting Proteins over the Course of Xylem Tracheary Element Formation in Arabidopsis. AB - Plant vascular cells, or tracheary elements (TEs), rely on circumferential secondary cell wall thickenings to maintain sap flow. The patterns in which TE thickenings are organized vary according to the underlying microtubule bundles that guide wall deposition. To identify microtubule interacting proteins present at defined stages of TE differentiation, we exploited the synchronous differentiation of TEs in Arabidopsis thaliana suspension cultures. Quantitative proteomic analysis of microtubule pull-downs, using ratiometric (14)N/(15)N labeling, revealed 605 proteins exhibiting differential accumulation during TE differentiation. Microtubule interacting proteins associated with membrane trafficking, protein synthesis, DNA/RNA binding, and signal transduction peaked during secondary cell wall formation, while proteins associated with stress peaked when approaching TE cell death. In particular, CELLULOSE SYNTHASE INTERACTING PROTEIN1, already associated with primary wall synthesis, was enriched during secondary cell wall formation. RNAi knockdown of genes encoding several of the identified proteins showed that secondary wall formation depends on the coordinated presence of microtubule interacting proteins with nonoverlapping functions: cell wall thickness, cell wall homogeneity, and the pattern and cortical location of the wall are dependent on different proteins. Altogether, proteins linking microtubules to a range of metabolic compartments vary specifically during TE differentiation and regulate different aspects of wall patterning. PMID- 26432861 TI - Fibrillin 5 Is Essential for Plastoquinone-9 Biosynthesis by Binding to Solanesyl Diphosphate Synthases in Arabidopsis. AB - Fibrillins are lipid-associated proteins in plastids and are ubiquitous in plants. They accumulate in chromoplasts and sequester carotenoids during the development of flowers and fruits. However, little is known about the functions of fibrillins in leaf tissues. Here, we identified fibrillin 5 (FBN5), which is essential for plastoquinone-9 (PQ-9) biosynthesis in Arabidopsis thaliana. Homozygous fbn5-1 mutations were seedling-lethal, and XVE:FBN5-B transgenic plants expressing low levels of FBN5-B had a slower growth rate and were smaller than wild-type plants. In chloroplasts, FBN5-B specifically interacted with solanesyl diphosphate synthases (SPSs) 1 and 2, which biosynthesize the solanesyl moiety of PQ-9. Plants containing defective FBN5-B accumulated less PQ-9 and its cyclized product, plastochromanol-8, but the levels of tocopherols were not affected. The reduced PQ-9 content of XVE:FBN5-B transgenic plants was consistent with their lower photosynthetic performance and higher levels of hydrogen peroxide under cold stress. These results indicate that FBN5-B is required for PQ 9 biosynthesis through its interaction with SPS. Our study adds FBN5 as a structural component involved in the biosynthesis of PQ-9. FBN5 binding to the hydrophobic solanesyl moiety, which is generated by SPS1 and SPS2, in FBN5-B/SPS homodimeric complexes stimulates the enzyme activity of SPS1 and SPS2. PMID- 26432863 TI - Grasping at Straws: Unraveling the Proteome That Orchestrates Secondary Cell Wall Patterning in Tracheary Elements. PMID- 26432862 TI - High-Resolution Profiling of a Synchronized Diurnal Transcriptome from Chlamydomonas reinhardtii Reveals Continuous Cell and Metabolic Differentiation. AB - The green alga Chlamydomonas reinhardtii is a useful model organism for investigating diverse biological processes, such as photosynthesis and chloroplast biogenesis, flagella and basal body structure/function, cell growth and division, and many others. We combined a highly synchronous photobioreactor culture system with frequent temporal sampling to characterize genome-wide diurnal gene expression in Chlamydomonas. Over 80% of the measured transcriptome was expressed with strong periodicity, forming 18 major clusters. Genes associated with complex structures and processes, including cell cycle control, flagella and basal bodies, ribosome biogenesis, and energy metabolism, all had distinct signatures of coexpression with strong predictive value for assigning and temporally ordering function. Importantly, the frequent sampling regime allowed us to discern meaningful fine-scale phase differences between and within subgroups of genes and enabled the identification of a transiently expressed cluster of light stress genes. Coexpression was further used both as a data mining tool to classify and/or validate genes from other data sets related to the cell cycle and to flagella and basal bodies and to assign isoforms of duplicated enzymes to their cognate pathways of central carbon metabolism. Our diurnal coexpression data capture functional relationships established by dozens of prior studies and are a valuable new resource for investigating a variety of biological processes in Chlamydomonas and other eukaryotes. PMID- 26432865 TI - High-mobility group box 1 promotes extracellular matrix synthesis and wound repair in human bronchial epithelial cells. AB - High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) protein that binds Toll-like receptors (e.g., TLR4) and the receptor for advanced glycated end products (RAGE). The direct effects of HMGB1 on airway structural cells are not fully known. As epithelial cell responses are fundamental drivers of asthma, including abnormal repair-restitution linked to changes in extracellular matrix (ECM) synthesis, we tested the hypothesis that HMGB1 promotes bronchial epithelial cell wound repair via TLR4 and/or RAGE signaling that regulates ECM (fibronectin and the gamma2-chain of laminin-5) and integrin protein abundance. To assess impact of HMGB1 we used molecular and pharmacological inhibitors of RAGE or TLR4 signaling in scratch wound, immunofluorescence, and immunoblotting assays to assess wound repair, ECM synthesis, and phosphorylation of intracellular signaling. HMGB1 increased wound closure, and this effect was attenuated by blocking RAGE and TLR4 signaling. HMGB1-induced fibronectin and laminin-5 (gamma2 chain) was diminished by blocking RAGE and/or blunting TLR4 signaling. Similarly, induction of alpha3-integrin receptor for fibronectin and laminin-5 was also diminished by blocking TLR4 signaling and RAGE. Lastly, rapid and/or sustained phosphorylation of SMAD2, ERK1/2, and JNK signaling modulated HMGB1-induced wound closure. Our findings suggest a role for HMGB1 in human airway epithelial cell repair and restitution via multiple pathways mediated by TLR4 and RAGE that underpin increased ECM synthesis and modulation of cell-matrix adhesion. PMID- 26432864 TI - Imatinib attenuates inflammation and vascular leak in a clinically relevant two hit model of acute lung injury. AB - Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), an illness characterized by life-threatening vascular leak, is a significant cause of morbidity and mortality in critically ill patients. Recent preclinical studies and clinical observations have suggested a potential role for the chemotherapeutic agent imatinib in restoring vascular integrity. Our prior work demonstrates differential effects of imatinib in mouse models of ALI, namely attenuation of LPS-induced lung injury but exacerbation of ventilator-induced lung injury (VILI). Because of the critical role of mechanical ventilation in the care of patients with ARDS, in the present study we pursued an assessment of the effectiveness of imatinib in a "two-hit" model of ALI caused by combined LPS and VILI. Imatinib significantly decreased bronchoalveolar lavage protein, total cells, neutrophils, and TNF-alpha levels in mice exposed to LPS plus VILI, indicating that it attenuates ALI in this clinically relevant model. In subsequent experiments focusing on its protective role in LPS-induced lung injury, imatinib attenuated ALI when given 4 h after LPS, suggesting potential therapeutic effectiveness when given after the onset of injury. Mechanistic studies in mouse lung tissue and human lung endothelial cells revealed that imatinib inhibits LPS-induced NF-kappaB expression and activation. Overall, these results further characterize the therapeutic potential of imatinib against inflammatory vascular leak. PMID- 26432866 TI - Protective effects of surfactant protein D treatment in 1,3-beta-glucan-modulated allergic inflammation. AB - Surfactant protein D (SP-D) is a pulmonary collectin important in lung immunity. SP-D-deficient mice (Sftpd(-/-)) are reported to be susceptible to ovalbumin (OVA)- and fungal allergen-induced pulmonary inflammation, while treatment with exogenous SP-D has therapeutic effects in such disease models. beta-Glucans are a diverse group of polysaccharides previously suggested to serve as fungal ligands for SP-D. We set out to investigate if SP-D could interact with 1,3-beta-glucan and attenuate allergic pulmonary inflammation in the presence of 1,3-beta-glucan. Allergic airway disease was induced in Sftpd(-/-) and Sftpd(+/+) mice by OVA sensitization and subsequent challenge with OVA, 1,3-beta-glucan, or OVA/1,3-beta glucan together. Mice in the combined treatment group were further treated with a high dose of recombinant fragment of human SP-D (rfhSP-D). We demonstrated direct interaction between SP-D and 1,3-beta-glucan. OVA-induced mucous cell metaplasia was increased in Sftpd(-/-) mice, supporting previously reported protective effects of endogenous SP-D in allergy. OVA-induced parenchymal CCL11 levels and eosinophilic infiltration in bronchoalveolar lavage were unaffected by 1,3-beta glucan, but were reversed with rfhSP-D treatment. 1,3-beta-Glucan treatment did, however, induce pulmonary neutrophilic infiltration and increased TNF-alpha levels in bronchoalveolar lavage, independently of OVA-induced allergy. This infiltration was also reversed by treatment with rfhSP-D. 1,3-beta-Glucan reduced OVA-induced mucous cell metaplasia, T helper 2 cytokines, and IFN-gamma production. rfhSP-D treatment further reduced mucous metaplasia and T helper 2 cytokine secretion to background levels. In summary, rfhSP-D treatment resulted in attenuation of both allergic inflammation and 1,3-beta-glucan-mediated neutrophilic inflammation. Our data suggest that treatment with high-dose SP-D protects from mold-induced exacerbations of allergic asthma. PMID- 26432867 TI - Ecto-5'-nucleotidase CD73 modulates the innate immune response to influenza infection but is not required for development of influenza-induced acute lung injury. AB - Extracellular nucleotides and nucleosides are important signaling molecules in the lung. Nucleotide and nucleoside concentrations in alveolar lining fluid are controlled by a complex network of surface ectonucleotidases. Previously, we demonstrated that influenza A/WSN/33 (H1N1) virus resulted in increased levels of the nucleotide ATP and the nucleoside adenosine in bronchoalveolar lavage fluid (BALF) of wild-type (WT) C57BL/6 mice. Influenza-induced acute lung injury (ALI) was highly attenuated in A1-adenosine receptor-knockout mice. Because AMP hydrolysis by the ecto-5'-nucleotidase (CD73) plays a central role in and is rate limiting for generation of adenosine in the normal lung, we hypothesized that ALI would be attenuated in C57BL/6-congenic CD73-knockout (CD73-KO) mice. Infection induced hypoxemia, bradycardia, viral replication, and bronchoconstriction were moderately increased in CD73-KO mice relative to WT controls. However, postinfection weight loss, pulmonary edema, and parenchymal dysfunction were not altered. Treatment of WT mice with the CD73 inhibitor 5'-(alpha,beta-methylene) diphosphate (APCP) also had no effect on infection-induced pulmonary edema but modestly attenuated hypoxemia. BALF from CD73-KO and APCP-treated WT mice contained more IL-6 and CXCL-10/IFN-gamma-induced protein 10, less CXCL 1/keratinocyte chemoattractant, and fewer neutrophils than BALF from untreated WT controls. BALF from APCP-treated WT mice also contained fewer alveolar macrophages and more transforming growth factor-beta than BALF from untreated WT mice. These results indicate that CD73 is not necessary for development of ALI following influenza A virus infection and suggest that tissue-nonspecific alkaline phosphatase may be responsible for increased adenosine generation in the infected lung. However, they do suggest that CD73 has a previously unrecognized immunomodulatory role in influenza. PMID- 26432868 TI - An oxidative DNA "damage" and repair mechanism localized in the VEGF promoter is important for hypoxia-induced VEGF mRNA expression. AB - In hypoxia, mitochondria-generated reactive oxygen species not only stimulate accumulation of the transcriptional regulator of hypoxic gene expression, hypoxia inducible factor-1 (Hif-1), but also cause oxidative base modifications in hypoxic response elements (HREs) of hypoxia-inducible genes. When the hypoxia induced base modifications are suppressed, Hif-1 fails to associate with the HRE of the VEGF promoter, and VEGF mRNA accumulation is blunted. The mechanism linking base modifications to transcription is unknown. Here we determined whether recruitment of base excision DNA repair (BER) enzymes in response to hypoxia-induced promoter modifications was required for transcription complex assembly and VEGF mRNA expression. Using chromatin immunoprecipitation analyses in pulmonary artery endothelial cells, we found that hypoxia-mediated formation of the base oxidation product 8-oxoguanine (8-oxoG) in VEGF HREs was temporally associated with binding of Hif-1alpha and the BER enzymes 8-oxoguanine glycosylase 1 (Ogg1) and redox effector factor-1 (Ref-1)/apurinic/apyrimidinic endonuclease 1 (Ape1) and introduction of DNA strand breaks. Hif-1alpha colocalized with HRE sequences harboring Ref-1/Ape1, but not Ogg1. Inhibition of BER by small interfering RNA-mediated reduction in Ogg1 augmented hypoxia-induced 8-oxoG accumulation and attenuated Hif-1alpha and Ref-1/Ape1 binding to VEGF HRE sequences and blunted VEGF mRNA expression. Chromatin immunoprecipitation sequence analysis of 8-oxoG distribution in hypoxic pulmonary artery endothelial cells showed that most of the oxidized base was localized to promoters with virtually no overlap between normoxic and hypoxic data sets. Transcription of genes whose promoters lost 8-oxoG during hypoxia was reduced, while those gaining 8-oxoG was elevated. Collectively, these findings suggest that the BER pathway links hypoxia-induced introduction of oxidative DNA modifications in promoters of hypoxia-inducible genes to transcriptional activation. PMID- 26432869 TI - Pharmacological targeting of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis. AB - Pulmonary lymphangioleiomyomatosis (LAM), a rare progressive lung disease associated with mutations of the tuberous sclerosis complex 2 (Tsc2) tumor suppressor gene, manifests by neoplastic growth of LAM cells, induction of cystic lung destruction, and respiratory failure. LAM severity correlates with upregulation in serum of the prolymphangiogenic vascular endothelial growth factor D (VEGF-D) that distinguishes LAM from other cystic diseases. The goals of our study was to determine whether Tsc2 deficiency upregulates VEGF-D, and whether axitinib, the Food and Drug Administration-approved small-molecule inhibitor of VEGF receptor (VEGFR) signaling, will reduce Tsc2-null lung lesion growth in a mouse model of LAM. Our data demonstrate upregulation of VEGF-D in the serum and lung lining in mice with Tsc2-null lesions. Progressive growth of Tsc2-null lesions induces recruitment and activation of inflammatory cells and increased nitric oxide production. Recruited cells isolated from the lung lining of mice with Tsc2-null lesions demonstrate upregulated expression of provasculogenic Vegfa, prolymphangiogenic Figf, and proinflammatory Nos2, Il6, and Ccl2 genes. Importantly, axitinib is an effective inhibitor of Tsc2-null lesion growth and inflammatory cell recruitment, which correlates with reduced VEGF-D levels in serum and lung lining. Our data demonstrate that pharmacological inhibition of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth, attenuates recruitment and activation of inflammatory cells, and reduces VEGF-D levels systemically and in the lung lining. Our study suggests a potential therapeutic benefit of inhibition of VEGFR signaling for treatment of LAM. PMID- 26432870 TI - Homeostasis and its disruption in the lung microbiome. AB - The disciplines of physiology and ecology are united by the shared centrality of the concept of homeostasis: the stability of a complex system via internal mechanisms of self-regulation, resilient to external perturbation. In the past decade, these fields of study have been bridged by the discovery of the lung microbiome. The respiratory tract, long considered sterile, is in fact a dynamic ecosystem of microbiota, intimately associated with the host inflammatory response, altered in disease states. If the microbiome is a "newly discovered organ," ecology is the language we use to explain how it establishes, maintains, and loses homeostasis. In this essay, we review recent insights into the feedback mechanisms by which the lung microbiome and the host response are regulated in health and dysregulated in acute and chronic lung disease. We propose three explanatory models supported by recent studies: the adapted island model of lung biogeography, nutritional homeostasis at the host-microbiome interface, and interkingdom signaling and the community stress response. PMID- 26432873 TI - Therapeutic potential of soluble guanylate cyclase modulators in neonatal chronic lung disease. AB - Supplemental oxygen after premature birth results in aberrant airway, alveolar, and pulmonary vascular development with an increased risk for bronchopulmonary dysplasia, and development of wheeze and asthma, pulmonary hypertension, and chronic obstructive pulmonary disease in survivors. Although stimulation of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP signal transduction pathway has significant beneficial effects on disease development in animal models, so far this could not be translated to the clinic. Oxidative stress reduces the NO-sGC-cGMP pathway by oxidizing heme-bound sGC, resulting in inactivation or degradation of sGC. Reduced sGC activity and/or expression is associated with pathology due to premature birth, oxidative stress-induced lung injury, including impaired alveolar maturation, smooth muscle cell (SMC) proliferation and contraction, impaired airway relaxation and vasodilation, inflammation, pulmonary hypertension, right ventricular hypertrophy, and an aggravated response toward hyperoxia-induced neonatal lung injury. Recently, Britt et al. (10) demonstrated that histamine-induced Ca(2+) responses were significantly elevated in hyperoxia-exposed fetal human airway SMCs compared with normoxic controls and that this hyperoxia-induced increase in the response was strongly reduced by NO-independent stimulation and activation of sGC. These recent studies highlight the therapeutic potential of sGC modulators in the treatment of preterm infants for respiratory distress with supplemental oxygen. Such treatment is aimed at improving aberrant alveolar and vascular development of the neonatal lung and preventing the development of wheezing and asthma in survivors of premature birth. In addition, these studies highlight the suitability of fetal human airway SMCs as a translational model for pathological airway changes in the neonate. PMID- 26432871 TI - ncRNA-regulated immune response and its role in inflammatory lung diseases. AB - Despite the greatly expanded knowledge on the regulation of immune response by protein molecules, there is increasing understanding that noncoding RNAs (ncRNAs) are also an integral component of this regulatory network. Abnormal immune response serves a central role in the initiation, progression, and exacerbation of inflammatory lung diseases, such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, and acute respiratory distress syndrome/acute lung injury. Dysregulation of ncRNAs has been linked to various immunopathologies. In this review, we highlighted the role of ncRNAs in the regulation of innate and adaptive immunity and summarized recent findings that ncRNAs participate in the pathogenesis of inflammatory lung diseases via their regulation of pulmonary immunity. We also discussed therapeutic potentials for targeting ncRNAs to treat these lung disorders. PMID- 26432874 TI - Estimation of the number of alveolar capillaries by the Euler number (Euler Poincare characteristic). AB - The lung parenchyma provides a maximal surface area of blood-containing capillaries that are in close contact with a large surface area of the air containing alveoli. Volume and surface area of capillaries are the classic stereological parameters to characterize the alveolar capillary network (ACN) and have provided essential structure-function information of the lung. When loss (rarefaction) or gain (angiogenesis) of capillaries occurs, these parameters may not be sufficient to provide mechanistic insight. Therefore, it would be desirable to estimate the number of capillaries, as it contains more distinct and mechanistically oriented information. Here, we present a new stereological method to estimate the number of capillary loops in the ACN. One advantage of this method is that it is independent of the shape, size, or distribution of the capillaries. We used consecutive, 1 MUm-thick sections from epoxy resin-embedded material as a physical disector. The Euler-Poincare characteristic of capillary networks can be estimated by counting the easily recognizable topological constellations of "islands," "bridges," and "holes." The total number of capillary loops in the ACN can then be calculated from the Euler-Poincare characteristic. With the use of the established estimator of alveolar number, it is possible to obtain the mean number of capillary loops per alveolus. In conclusion, estimation of alveolar capillaries by design-based stereology is an efficient and unbiased method to characterize the ACN and may be particularly useful for studies on emphysema, pulmonary hypertension, or lung development. PMID- 26432872 TI - Role of epithelial sodium channels in the regulation of lung fluid homeostasis. AB - In utero, fetal lung epithelial cells actively secrete Cl(-) ions into the lung air spaces while Na(+) ions follow passively to maintain electroneutrality. This process, driven by an electrochemical gradient generated by the Na(+)-K(+) ATPase, is responsible for the secretion of fetal fluid that is essential for normal lung development. Shortly before birth, a significant upregulation of amiloride-sensitive epithelial channels (ENaCs) on the apical side of the lung epithelial cells results in upregulation of active Na(+) transport. This process is critical for the reabsorption of fetal lung fluid and the establishment of optimum gas exchange. In the adult lung, active Na(+) reabsorption across distal lung epithelial cells limits the degree of alveolar edema in patients with acute lung injury and cardiogenic edema. Cl(-) ions are transported either paracellularly or transcellularly to preserve electroneutrality. An increase in Cl(-) secretion across the distal lung epithelium has been reported following an acute increase in left atrial pressure and may result in pulmonary edema. In contrast, airway epithelial cells secrete Cl(-) through apical cystic fibrosis transmembrane conductance regulator and Ca(2+)-activated Cl(-) channels and absorb Na(+). Thus the coordinated action of Cl(-) secretion and Na(+) absorption is essential for maintenance of the volume of epithelial lining fluid that, in turn, maximizes mucociliary clearance and facilitates clearance of bacteria and debris from the lungs. Any factor that interferes with Na(+) or Cl(-) transport or dramatically upregulates ENaC activity in airway epithelial cells has been associated with lung diseases such as cystic fibrosis or chronic obstructive lung disease. In this review we focus on the role of the ENaC, the mechanisms involved in ENaC regulation, and how ENaC dysregulation can lead to lung pathology. PMID- 26432875 TI - PBL13 Is a Serine/Threonine Protein Kinase That Negatively Regulates Arabidopsis Immune Responses. AB - Receptor-like cytoplasmic kinases (RLCKs) are a subset of plant receptor-like kinases lacking both extracellular and transmembrane domains. Some of the 46 members in the Arabidopsis (Arabidopsis thaliana) RLCK subfamily VII have been linked to plant innate immunity; however, most remain uncharacterized. Thus, multiple subfamily VII members are expected to be involved in plant immune signaling. Here, we investigate the role of AvrPphB SUSCEPTIBLE1-LIKE13 (PBL13), a subfamily VII RLCK with unique domain architecture. Unlike other characterized RLCKs, PBL13 transfer DNA insertion lines exhibit enhanced disease resistance after inoculation with virulent Pseudomonas syringae. The pbl13-2 knockout also exhibits elevated basal-level expression of the PATHOGENESIS-RELATED GENE1 defense marker gene, enhanced reactive oxygen species (ROS) burst in response to perception of bacterial microbial patterns, and accelerated flagellin-induced activation of mitogen-activated protein kinases. Recombinant PBL13 is an active kinase, and its primary autophosphorylated sites map to a 15-amino acid repeat motif unique to PBL13. Complementation of pbl13-2 with PBL13-3xFLAG converts the enhanced resistance and elevated ROS phenotypes back to wild-type levels. In contrast, kinase-dead PBL13(K111A)-3xFLAG was unable to rescue pbl13-2 disease phenotypes. Consistent with the enhanced ROS burst in the pbl13-2 knockout, PBL13 is able to associate with the nicotinamide adenine dinucleotide phosphate, reduced oxidase RESPIRATORY BURST OXIDASE HOMOLOG PROTEIN D (RBOHD) by split luciferase complementation assay, and this association is disrupted by flagellin treatment. We conclude that the PBL13 kinase negatively regulates plant innate immunity to pathogenic bacteria and can associate with RBOHD before pathogen perception. These data are consistent with the hypothesis that PBL13 acts to prevent inappropriate activation of defense responses in the absence of pathogen challenge. PMID- 26432876 TI - Variability and Constancy in Cellular Growth of Arabidopsis Sepals. AB - Growth of tissues is highly reproducible; yet, growth of individual cells in a tissue is highly variable, and neighboring cells can grow at different rates. We analyzed the growth of epidermal cell lineages in the Arabidopsis (Arabidopsis thaliana) sepal to determine how the growth curves of individual cell lineages relate to one another in a developing tissue. To identify underlying growth trends, we developed a continuous displacement field to predict spatially averaged growth rates. We showed that this displacement field accurately describes the growth of sepal cell lineages and reveals underlying trends within the variability of in vivo cellular growth. We found that the tissue, individual cell lineages, and cell walls all exhibit growth rates that are initially low, accelerate to a maximum, and decrease again. Accordingly, these growth curves can be represented by sigmoid functions. We examined the relationships among the cell lineage growth curves and surprisingly found that all lineages reach the same maximum growth rate relative to their size. However, the cell lineages are not synchronized; each cell lineage reaches this same maximum relative growth rate but at different times. The heterogeneity in observed growth results from shifting the same underlying sigmoid curve in time and scaling by size. Thus, despite the variability in growth observed in our study and others, individual cell lineages in the developing sepal follow similarly shaped growth curves. PMID- 26432877 TI - GmEXPB2, a Cell Wall beta-Expansin, Affects Soybean Nodulation through Modifying Root Architecture and Promoting Nodule Formation and Development. AB - Nodulation is an essential process for biological nitrogen (N2) fixation in legumes, but its regulation remains poorly understood. Here, a beta-expansin gene, GmEXPB2, was found to be critical for soybean (Glycine max) nodulation. GmEXPB2 was preferentially expressed at the early stage of nodule development. beta-Glucuronidase staining further showed that GmEXPB2 was mainly localized to the nodule vascular trace and nodule vascular bundles, as well as nodule cortical and parenchyma cells, suggesting that GmEXPB2 might be involved in cell wall modification and extension during nodule formation and development. Overexpression of GmEXPB2 dramatically modified soybean root architecture, increasing the size and number of cortical cells in the root meristematic and elongation zones and expanding root hair density and size of the root hair zone. Confocal microscopy with green fluorescent protein-labeled rhizobium USDA110 cells showed that the infection events were significantly enhanced in the GmEXPB2 overexpressing lines. Moreover, nodule primordium development was earlier in overexpressing lines compared with wild-type plants. Thereby, overexpression of GmEXPB2 in either transgenic soybean hairy roots or whole plants resulted in increased nodule number, nodule mass, and nitrogenase activity and thus elevated plant N and phosphorus content as well as biomass. In contrast, suppression of GmEXPB2 in soybean transgenic composite plants led to smaller infected cells and thus reduced number of big nodules, nodule mass, and nitrogenase activity, thereby inhibiting soybean growth. Taken together, we conclude that GmEXPB2 critically affects soybean nodulation through modifying root architecture and promoting nodule formation and development and subsequently impacts biological N2 fixation and growth of soybean. PMID- 26432879 TI - Activated OCP unlocks nonphotochemical quenching in cyanobacteria. PMID- 26432878 TI - A Phylogenetically Conserved Group of Nuclear Factor-Y Transcription Factors Interact to Control Nodulation in Legumes. AB - The endosymbiotic association between legumes and soil bacteria called rhizobia leads to the formation of a new root-derived organ called the nodule in which differentiated bacteria convert atmospheric nitrogen into a form that can be assimilated by the host plant. Successful root infection by rhizobia and nodule organogenesis require the activation of symbiotic genes that are controlled by a set of transcription factors (TFs). We recently identified Medicago truncatula nuclear factor-YA1 (MtNF-YA1) and MtNF-YA2 as two M. truncatula TFs playing a central role during key steps of the Sinorhizobium meliloti-M. truncatula symbiotic interaction. NF-YA TFs interact with NF-YB and NF-YC subunits to regulate target genes containing the CCAAT box consensus sequence. In this study, using a yeast two-hybrid screen approach, we identified the NF-YB and NF-YC subunits able to interact with MtNF-YA1 and MtNF-YA2. In yeast (Saccharomyces cerevisiae) and in planta, we further demonstrated by both coimmunoprecipitation and bimolecular fluorescence complementation that these NF-YA, -B, and -C subunits interact and form a stable NF-Y heterotrimeric complex. Reverse genetic and chromatin immunoprecipitation-PCR approaches revealed the importance of these newly identified NF-YB and NF-YC subunits for rhizobial symbiosis and binding to the promoter of MtERN1 (for Ethylene Responsive factor required for Nodulation), a direct target gene of MtNF-YA1 and MtNF-YA2. Finally, we verified that a similar trimer is formed in planta by the common bean (Phaseolus vulgaris) NF-Y subunits, revealing the existence of evolutionary conserved NF-Y protein complexes to control nodulation in leguminous plants. This sheds light on the process whereby an ancient heterotrimeric TF mainly controlling cell division in animals has acquired specialized functions in plants. PMID- 26432880 TI - Control of cerebellar granule cell output by sensory-evoked Golgi cell inhibition. AB - Classical feed-forward inhibition involves an excitation-inhibition sequence that enhances the temporal precision of neuronal responses by narrowing the window for synaptic integration. In the input layer of the cerebellum, feed-forward inhibition is thought to preserve the temporal fidelity of granule cell spikes during mossy fiber stimulation. Although this classical feed-forward inhibitory circuit has been demonstrated in vitro, the extent to which inhibition shapes granule cell sensory responses in vivo remains unresolved. Here we combined whole cell patch-clamp recordings in vivo and dynamic clamp recordings in vitro to directly assess the impact of Golgi cell inhibition on sensory information transmission in the granule cell layer of the cerebellum. We show that the majority of granule cells in Crus II of the cerebrocerebellum receive sensory evoked phasic and spillover inhibition prior to mossy fiber excitation. This preceding inhibition reduces granule cell excitability and sensory-evoked spike precision, but enhances sensory response reproducibility across the granule cell population. Our findings suggest that neighboring granule cells and Golgi cells can receive segregated and functionally distinct mossy fiber inputs, enabling Golgi cells to regulate the size and reproducibility of sensory responses. PMID- 26432882 TI - Correction for Petersen et al., Effect of aging on muscle mitochondrial substrate utilization in humans. PMID- 26432883 TI - Reply to Berti: Relationship between production and consumption diversity remains small also with modified diversity measures. PMID- 26432881 TI - How grow-and-switch gravitropism generates root coiling and root waving growth responses in Medicago truncatula. AB - Experimental studies show that plant root morphologies can vary widely from straight gravity-aligned primary roots to fractal-like root architectures. However, the opaqueness of soil makes it difficult to observe how environmental factors modulate these patterns. Here, we combine a transparent hydrogel growth medium with a custom built 3D laser scanner to directly image the morphology of Medicago truncatula primary roots. In our experiments, root growth is obstructed by an inclined plane in the growth medium. As the tilt of this rigid barrier is varied, we find Medicago transitions between randomly directed root coiling, sinusoidal root waving, and normal gravity-aligned morphologies. Although these root phenotypes appear morphologically distinct, our analysis demonstrates the divisions are less well defined, and instead, can be viewed as a 2D biased random walk that seeks the path of steepest decent along the inclined plane. Features of this growth response are remarkably similar to the widely known run-and-tumble chemotactic behavior of Escherichia coli bacteria, where biased random walks are used as optimal strategies for nutrient uptake. PMID- 26432884 TI - Relationship between production diversity and dietary diversity depends on how number of foods is counted. PMID- 26432885 TI - Both ciliary and non-ciliary functions of Foxj1a confer Wnt/beta-catenin signaling in zebrafish left-right patterning. AB - The Wnt/beta-catenin pathway is implicated in left-right (LR) axis determination; however, the underlying mechanism remains elusive. Prompted by our recent discovery that Wnt signaling regulates ciliogenesis in the zebrafish Kupffer's vesicle (KV) via Foxj1a, a ciliogenic transcription factor, we decided to elucidate functions of Foxj1a in Wnt-regulated LR pattern formation. We showed that targeted injection of wnt8a mRNA into a single cell at the 128-cell stage is sufficient to induce ectopic foxj1a expression and ectopic cilia. By interrogating the transcription circuit of foxj1a regulation, we found that both Lef1 and Tcf7 bind to a consensus element in the foxj1a promoter region. Depletion of Lef1 and Tcf7 inhibits foxj1a transcription in the dorsal forerunner cells, downregulates cilia length and number in KV, and randomizes LR asymmetry. Targeted overexpression of a constitutively active form of Lef1 also induced an ectopic protrusion that contains ectopic transcripts for sox17, foxj1a, and charon, and ectopic monocilia. Further genetic studies using this ectopic expression platform revealed two distinct functions of Foxj1a; mediating Wnt governed monocilia length elongation as well as charon transcription. The novel Foxj1a-charon regulation is conserved in KV, and importantly, it is independent of the canonical role of Foxj1a in the biosynthesis of motile cilia. Together with the known function of motile cilia movement in generating asymmetric expression of charon, our data put forward a hypothesis that Foxj1a confers both ciliary and non-ciliary functions of Wnt signaling, which converge on charon to regulate LR pattern formation. PMID- 26432886 TI - Loss of arylformamidase with reduced thymidine kinase expression leads to impaired glucose tolerance. AB - Tryptophan metabolites have been linked in observational studies with type 2 diabetes, cognitive disorders, inflammation and immune system regulation. A rate limiting enzyme in tryptophan conversion is arylformamidase (Afmid), and a double knockout of this gene and thymidine kinase (Tk) has been reported to cause renal failure and abnormal immune system regulation. In order to further investigate possible links between abnormal tryptophan catabolism and diabetes and to examine the effect of single Afmid knockout, we have carried out metabolic phenotyping of an exon 2 Afmid gene knockout. These mice exhibit impaired glucose tolerance, although their insulin sensitivity is unchanged in comparison to wild-type animals. This phenotype results from a defect in glucose stimulated insulin secretion and these mice show reduced islet mass with age. No evidence of a renal phenotype was found, suggesting that this published phenotype resulted from loss of Tk expression in the double knockout. However, despite specifically removing only exon 2 of Afmid in our experiments we also observed some reduction of Tk expression, possibly due to a regulatory element in this region. In summary, our findings support a link between abnormal tryptophan metabolism and diabetes and highlight beta cell function for further mechanistic analysis. PMID- 26432887 TI - The zebrafish Kupffer's vesicle as a model system for the molecular mechanisms by which the lack of Polycystin-2 leads to stimulation of CFTR. AB - In autosomal dominant polycystic kidney disease (ADPKD), cyst inflation and continuous enlargement are associated with marked transepithelial ion and fluid secretion into the cyst lumen via cystic fibrosis transmembrane conductance regulator (CFTR). Indeed, the inhibition or degradation of CFTR prevents the fluid accumulation within cysts. The in vivo mechanisms by which the lack of Polycystin-2 leads to CFTR stimulation are an outstanding challenge in ADPKD research and may bring important biomarkers for the disease. However, hampering their study, the available ADPKD in vitro cellular models lack the three dimensional architecture of renal cysts and the ADPKD mouse models offer limited access for live-imaging experiments in embryonic kidneys. Here, we tested the zebrafish Kupffer's vesicle (KV) as an alternative model-organ. KV is a fluid filled vesicular organ, lined by epithelial cells that express both CFTR and Polycystin-2 endogenously, being each of them easily knocked-down. Our data on the intracellular distribution of Polycystin-2 support its involvement in the KV fluid-flow induced Ca(2+)-signalling. Mirroring kidney cysts, the KV lumen inflation is dependent on CFTR activity and, as we clearly show, the knockdown of Polycystin-2 results in larger KV lumens through overstimulation of CFTR. In conclusion, we propose the zebrafish KV as a model organ to study the renal cyst inflation. Favouring its use, KV volume can be easily determined by in vivo imaging offering a live readout for screening compounds and genes that may prevent cyst enlargement through CFTR inhibition. PMID- 26432888 TI - Targeting of ribosomal protein S6 to dendritic spines by in vivo high frequency stimulation to induce long-term potentiation in the dentate gyrus. AB - Late phase long-term potentiation (L-LTP) in the hippocampus is believed to be the cellular basis of long-term memory. Protein synthesis is required for persistent forms of synaptic plasticity, including L-LTP. Neural activity is thought to enhance local protein synthesis in dendrites, and one of the mechanisms required to induce or maintain the long-lasting synaptic plasticity is protein translation in the dendrites. One regulator of translational processes is ribosomal protein S6 (rpS6), a component of the small 40S ribosomal subunit. Although polyribosomes containing rpS6 are observed in dendritic spines, it remains unclear whether L-LTP induction triggers selective targeting of the translational machinery to activated synapses in vivo. Therefore, we investigated synaptic targeting of the translational machinery by observing rpS6 immunoreactivity during high frequency stimulation (HFS) for L-LTP induction in vivo. Immunoelectron microscopic analysis revealed a selective but transient increase in rpS6 immunoreactivity occurring as early as 15 min after the onset of HFS in dendritic spine heads at synaptic sites receiving HFS. Concurrently, levels of the rpS6 protein rapidly declined in somata of granule cells, as determined using immunofluorescence microscopy. These results suggest that the translational machinery is rapidly targeted to activated spines and that this targeting mechanism may contribute to the establishment of L-LTP. PMID- 26432889 TI - Genome-wide surveillance of mismatched alleles for graft-versus-host disease in stem cell transplantation. AB - Acute graft-versus-host disease (aGVHD) represents one of the major complications in allogeneic stem cell transplantation and is primarily caused by genetic disparity between the donor and recipient. In HLA-matched transplants, the disparity is thought to be determined by loci encoding minor histocompatibility antigens (minor H antigens), which are presented by specific HLA molecules. We performed a genome-wide association study (GWAS) to identify minor H antigen loci associated with aGVHD. A total of 500 568 single nucleotide polymorphisms (SNPs) were genotyped for donors and recipients from 1589 unrelated bone marrow transplants matched for HLA-A, -B, -C, -DRB1, and -DQB1, followed by the imputation of unobserved SNPs. We interrogated SNPs whose disparity between the donor and recipient was significantly associated with aGVHD development. Without assuming HLA unrestriction, we successfully captured a known association between HLA-DPB1 disparity (P = 4.50 * 10(-9)) and grade II-IV aGVHD development, providing proof of concept for the GWAS design aimed at discovering genetic disparity associated with aGVHD. In HLA-restricted analyses, whereby association tests were confined to major subgroups sharing common HLA alleles to identify putative minor H antigen loci, we identified 3 novel loci significantly associated with grade III-IV aGVHD. Among these, rs17473423 (P = 1.20 * 10(-11)) at 12p12.1 within the KRAS locus showed the most significant association in the subgroup, sharing HLA-DQB1*06:01. Our result suggested that a GWAS can be successfully applied to identify allele mismatch associated with aGVHD development, contributing to the understanding of the genetic basis of aGVHD. PMID- 26432890 TI - Cutting Edge: Inhibiting TBK1 by Compound II Ameliorates Autoimmune Disease in Mice. AB - TANK-binding kinase 1 (TBK1) is a serine/threonine protein kinase that plays a crucial role in innate immunity. Enhanced TBK1 function is associated with autoimmune diseases and cancer, implicating the potential benefit of therapeutically targeting TBK1. In this article, we examined a recently identified TBK1 inhibitor Compound II on treating autoimmune diseases. We found that Compound II is a potent and specific inhibitor of TBK1-mediated IFN response. Compound II inhibited polyinosinic-polycytidylic acid-induced immune activation in vitro and in vivo. Compound II treatment also ameliorated autoimmune disease phenotypes of Trex1(-/-) mice, increased mouse survival, and dampened the IFN gene signature in TREX1 mutant patient lymphoblasts. In addition, we found that TBK1 gene expression is elevated in systemic lupus erythematosus patient cells, and systemic lupus erythematosus cells with high IFN signature responded well to Compound II treatment. Together, our findings provided critical experimental evidence for inhibiting TBK1 with Compound II as an effective treatment for TREX1-associated autoimmune diseases and potentially other interferonopathies. PMID- 26432891 TI - Identification of the SLAM Adapter Molecule EAT-2 as a Lupus-Susceptibility Gene That Acts through Impaired Negative Regulation of Dendritic Cell Signaling. AB - We showed previously that C57BL/6 congenic mice with an introgressed homozygous 70 cM (125.6 Mb) to 100 cM (179.8 Mb) interval on c1 from the lupus-prone New Zealand Black (NZB) mouse develop high titers of antinuclear Abs and severe glomerulonephritis. Using subcongenic mice, we found that a genetic locus in the 88-96 cM region was associated with altered dendritic cell (DC) function and synergized with T cell functional defects to promote expansion of pathogenic proinflammatory T cell subsets. In this article, we show that the promoter region of the NZB gene encoding the SLAM signaling pathway adapter molecule EWS activated transcript 2 (EAT-2) is polymorphic, which results in an ~ 70% reduction in EAT-2 in DC. Silencing of the EAT-2 gene in DC that lacked this polymorphism led to increased production of IL-12 and enhanced differentiation of T cells to a Th1 phenotype in T cell-DC cocultures, reproducing the phenotype observed for DC from congenic mice with the NZB c1 70-100 cM interval. SLAM signaling was shown to inhibit production of IL-12 by CD40L-activated DCs. Consistent with a role for EAT-2 in this inhibition, knockdown of EAT-2 resulted in increased production of IL-12 by CD40-stimulated DC. Assessment of downstream signaling following CD40 cross-linking in the presence or absence of SLAM cross linking revealed that SLAM coengagement blocked activation of p38 MAPK and JNK signaling pathways in DC, which was reversed in DC with the NZB EAT-2 allele. We conclude that EAT-2 negatively regulates cytokine production in DC downstream of SLAM engagement and that a genetic polymorphism that disturbs this process promotes the development of lupus. PMID- 26432892 TI - Regulatory B Cells with a Partial Defect in CD40 Signaling and Overexpressing Granzyme B Transfer Allograft Tolerance in Rodents. AB - Emerging knowledge regarding B cells in organ transplantation has demonstrated that these cells can no longer be taken as mere generators of deleterious Abs but can also act as beneficial players. We previously demonstrated in a rat model of cardiac allograft tolerance induced by short-term immunosuppression an accumulation in the blood of B cells overexpressing inhibitory molecules, a phenotype also observed in the blood of patients that spontaneously develop graft tolerance. In this study, we demonstrated the presence in the spleen of regulatory B cells enriched in the CD24(int)CD38(+)CD27(+)IgD(-)IgM(+/low) subpopulation, which are able to transfer donor-specific tolerance via IL-10 and TGF-beta1-dependent mechanisms and to suppress in vitro TNF-alpha secretion. Following anti-CD40 stimulation, IgD(-)IgM(+/low) B cells were blocked in their plasma cell differentiation pathway, maintained high expression of the inhibitory molecules CD23 and Bank1, and upregulated Granzyme B and Irf4, two molecules described as highly expressed by regulatory B cells. Interestingly, these B cells recognized specifically a dominant donor Ag, suggesting restricted specificity that could lead to a particular B cell response. Regulatory B cells were not required for induction of tolerance and appeared following Foxp3(+)CD4(+)CD25(+) regulatory T cells, suggesting cooperation with regulatory T cells for their expansion. Nevertheless, following transfer to new recipients, these B cells migrated to the allograft, kept their regulatory profile, and promoted local accumulation of Foxp3(+)CD4(+)CD25(+) regulatory T cells. Mechanisms of regulatory B cells and their cell therapy potential are important to decipher in experimental models to pave the way for future developments in the clinic. PMID- 26432893 TI - Novel Role of TRPML2 in the Regulation of the Innate Immune Response. AB - TRPMLs (or mucolipins) constitute a family of endosomal cation channels with homology to the transient receptor potential superfamily. In mammals, the TRPML family includes three members: TRPML1-3. Although TRPML1 and TRPML3 have been well characterized, the cellular function of TRPML2 has remained elusive. To address TRPML2 function in a physiologically relevant cell type, we first analyzed TRPML2 expression in different mouse tissues and organs and found that it was predominantly expressed in lymphoid organs and kidney. Quantitative RT-PCR revealed tight regulation of TRPML2 at the transcriptional level. Although TRPML2 expression was negligible in resting macrophages, TRPML2 mRNA and protein levels dramatically increased in response to TLR activation both in vitro and in vivo. Conversely, TRPML1 and TRPML3 levels did not change upon TLR activation. Immunofluorescence analysis demonstrated that endogenous TRPML2 primarily localized to recycling endosomes both in culture and primary cells, in contrast with TRPML1 and TRPML3, which distribute to the late and early endosomal pathway, respectively. To better understand the in vivo function of TRPML2, we generated a TRPML2-knockout mouse. We found that the production of several chemokines, in particular CCL2, was severely reduced in TRPML2-knockout mice. Furthermore, TRPML2-knockout mice displayed impaired recruitment of peripheral macrophages in response to i.p. injections of LPS or live bacteria, suggesting a potential defect in the immune response. Overall, our study reveals interesting differences in the regulation and distribution of the members of the TRPML family and identifies a novel role for TRPML2 in the innate immune response. PMID- 26432894 TI - Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis. AB - In the intestinal tract, IL-22 activates STAT3 to promote intestinal epithelial cell (IEC) homeostasis and tissue healing. The mechanism has remained obscure, but we demonstrate that IL-22 acts via tyrosine kinase 2 (Tyk2), a member of the Jak family. Using a mouse model for colitis, we show that Tyk2 deficiency is associated with an altered composition of the gut microbiota and exacerbates inflammatory bowel disease. Colitic Tyk2(-/-) mice have less p-STAT3 in colon tissue and their IECs proliferate less efficiently. Tyk2-deficient primary IECs show reduced p-STAT3 in response to IL-22 stimulation, and expression of IL-22 STAT3 target genes is reduced in IECs from healthy and colitic Tyk2(-/-) mice. Experiments with conditional Tyk2(-/-) mice reveal that IEC-specific depletion of Tyk2 aggravates colitis. Disease symptoms can be alleviated by administering high doses of rIL-22-Fc, indicating that Tyk2 deficiency can be rescued via the IL-22 receptor complex. The pivotal function of Tyk2 in IL-22-dependent colitis was confirmed in Citrobacter rodentium-induced disease. Thus, Tyk2 protects against acute colitis in part by amplifying inflammation-induced epithelial IL-22 signaling to STAT3. PMID- 26432897 TI - Comment on "A Novel Thymoma-Associated Immunodeficiency with Increased Naive T Cells and Reduced CD247 Expression". PMID- 26432896 TI - Preferential Destruction of Interstitial Macrophages over Alveolar Macrophages as a Cause of Pulmonary Disease in Simian Immunodeficiency Virus-Infected Rhesus Macaques. AB - To our knowledge, this study demonstrates for the first time that the AIDS virus differentially impacts two distinct subsets of lung macrophages. The predominant macrophages harvested by bronchoalveolar lavage (BAL), alveolar macrophages (AMs), are routinely used in studies on human lung macrophages, are long-lived cells, and exhibit low turnover. Interstitial macrophages (IMs) inhabit the lung tissue, are not recovered with BAL, are shorter-lived, and exhibit higher baseline turnover rates distinct from AMs. We examined the effects of SIV infection on AMs in BAL fluid and IMs in lung tissue of rhesus macaques. SIV infection produced massive cell death of IMs that contributed to lung tissue damage. Conversely, SIV infection induced minimal cell death of AMs, and these cells maintained the lower turnover rate throughout the duration of infection. This indicates that SIV produces lung tissue damage through destruction of IMs, whereas the longer-lived AMs may serve as a virus reservoir to facilitate HIV persistence. PMID- 26432898 TI - Response to Comment on "A Novel Thymoma-Associated Immunodeficiency with Increased Naive T Cells and Reduced CD247 Expression". PMID- 26432895 TI - Targeting Anti-Insulin B Cell Receptors Improves Receptor Editing in Type 1 Diabetes-Prone Mice. AB - Autoreactive B lymphocytes that commonly arise in the developing repertoire can be salvaged by receptor editing, a central tolerance mechanism that alters BCR specificity through continued L chain rearrangement. It is unknown whether autoantigens with weak cross-linking potential, such as insulin, elicit receptor editing, or whether this process is dysregulated in related autoimmunity. To resolve these issues, we developed an editing-competent model in which anti insulin Vkappa125 was targeted to the Igkappa locus and paired with anti-insulin VH125Tg. Physiologic, circulating insulin increased RAG-2 expression and was associated with BCR replacement that eliminated autoantigen recognition in a proportion of developing anti-insulin B lymphocytes. The proportion of anti insulin B cells that underwent receptor editing was reduced in the type 1 diabetes-prone NOD strain relative to a nonautoimmune strain. Resistance to editing was associated with increased surface IgM expression on immature (but not transitional or mature) anti-insulin B cells in the NOD strain. The actions of mAb123 on central tolerance were also investigated, because selective targeting of insulin-occupied BCR by mAb123 eliminates anti-insulin B lymphocytes and prevents type 1 diabetes. Autoantigen targeting by mAb123 increased RAG-2 expression and dramatically enhanced BCR replacement in newly developed B lymphocytes. Administering F(ab')2123 induced IgM downregulation and reduced the frequency of anti-insulin B lymphocytes within the polyclonal repertoire of VH125Tg/NOD mice, suggesting enhanced central tolerance by direct BCR interaction. These findings indicate that weak or faulty checkpoints for central tolerance can be overcome by autoantigen-specific immunomodulatory therapy. PMID- 26432899 TI - Nucleic Acid-Sensing Receptors: Rheostats of Autoimmunity and Autoinflammation. AB - Distinct families of germline-encoded pattern recognition receptors can sense both microbial and endogenous nucleic acids. These DNA and RNA sensors include endosomal TLRs and cytosolic sensors upstream of stimulator of type I IFN genes (STING) and MAVS. The existence of overlapping specificities for both foreign and self nucleic acids suggests that, under optimal conditions, the activity of these receptors is finely tuned to effectively mediate host defense yet constrain pathogenic self-reactivity. This equilibrium becomes disrupted with the loss of either TLR9 or STING. To maintain immune protection, this loss can be counterbalanced by the elevated response of an alternative receptor(s). Unfortunately, this adjustment can lead to an increased risk for the development of systemic autoimmunity, as evidenced by the exacerbated clinical disease manifestations of TLR9-deficient and STING-deficient autoimmune-prone mice. These studies underscore the delicate balance normally maintained by tonic signals that prevent unchecked immune responses to nucleic acids released during infections and cellular duress or death. PMID- 26432900 TI - Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages. AB - The Fanconi anemia proteins participate in a canonical pathway that repairs cross linking agent-induced DNA damage. Cells with inactivated Fanconi anemia genes are universally hypersensitive to such agents. Fanconi anemia-deficient hematopoietic stem cells are also hypersensitive to inflammatory cytokines, and, as importantly, Fanconi anemia macrophages overproduce such cytokines in response to TLR4 and TLR7/8 agonists. We questioned whether TLR-induced DNA damage is the primary cause of aberrantly regulated cytokine production in Fanconi anemia macrophages by quantifying TLR agonist-induced TNF-alpha production, DNA strand breaks, crosslinker-induced chromosomal breakage, and Fanconi anemia core complex function in Fanconi anemia complementation group C-deficient human and murine macrophages. Although both M1 and M2 polarized Fanconi anemia cells were predictably hypersensitive to mitomycin C, only M1 macrophages overproduced TNF alpha in response to TLR-activating signals. DNA damaging agents alone did not induce TNF-alpha production in the absence of TLR agonists in wild-type or Fanconi anemia macrophages, and mitomycin C did not enhance TLR responses in either normal or Fanconi anemia cells. TLR4 and TLR7/8 activation induced cytokine overproduction in Fanconi anemia macrophages. Also, although TLR4 activation was associated with induced double strand breaks, TLR7/8 activation was not. That DNA strand breaks and chromosome breaks are neither necessary nor sufficient to account for the overproduction of inflammatory cytokines by Fanconi anemia cells suggests that noncanonical anti-inflammatory functions of Fanconi anemia complementation group C contribute to the aberrant macrophage phenotype and suggests that suppression of macrophage/TLR hyperreactivity might prevent cytokine-induced stem cell attrition in Fanconi anemia. PMID- 26432901 TI - At the Bench: Neutrophil extracellular traps (NETs) highlight novel aspects of innate immune system involvement in autoimmune diseases. AB - The putative role of neutrophils in host defense against pathogens is a well recognized aspect of neutrophil function. The discovery of neutrophil extracellular traps has expanded the known range of neutrophil defense mechanisms and catalyzed a discipline of research focused upon ways in which neutrophils can shape the immunologic landscape of certain autoimmune diseases, including systemic lupus erythematosus. Enhanced neutrophil extracellular trap formation and impaired neutrophil extracellular trap clearance may contribute to immunogenicity in systemic lupus erythematosus and other autoimmune diseases by promoting the externalization of modified autoantigens, inducing synthesis of type I IFNs, stimulating the inflammasome, and activating both the classic and alternative pathways of the complement system. Vasculopathy is a central feature of many autoimmune diseases, and neutrophil extracellular traps may contribute directly to endothelial cell dysfunction, atherosclerotic plaque burden, and thrombosis. The elucidation of the subcellular events of neutrophil extracellular trap formation may generate novel, therapeutic strategies that target the innate immune system in autoimmune and vascular diseases. PMID- 26432902 TI - The Choice of Hemodialysis Membrane Affects Bisphenol A Levels in Blood. AB - Bisphenol A (BPA), a component of some dialysis membranes, accumulates in CKD. Observational studies have linked BPA exposure to kidney and cardiovascular injury in humans, and animal studies have described a causative link. Normal kidneys rapidly excrete BPA, but insufficient excretion may sensitize patients with CKD to adverse the effects of BPA. Using a crossover design, we studied the effect of dialysis with BPA-containing polysulfone or BPA-free polynephron dialyzers on BPA levels in 69 prevalent patients on hemodialysis: 28 patients started on polysulfone dialyzers and were switched to polynephron dialyzers; 41 patients started on polynephron dialyzers and were switched to polysulfone dialyzers. Results were grouped for analysis. Mean BPA levels increased after one hemodialysis session with polysulfone dialyzers but not with polynephron dialyzers. Chronic (3-month) use of polysulfone dialyzers did not significantly increase predialysis serum BPA levels, although a trend toward increase was detected (from 48.8+/-6.8 to 69.1+/-10.1 ng/ml). Chronic use of polynephron dialyzers reduced predialysis serum BPA (from 70.6+/-8.4 to 47.1+/-7.5 ng/ml, P<0.05). Intracellular BPA in PBMCs increased after chronic hemodialysis with polysulfone dialyzers (from 0.039+/-0.002 to 0.043+/-0.001 ng/10(6) cells, P<0.01), but decreased with polynephron dialyzers (from 0.045+/-0.001 to 0.036+/ 0.001 ng/10(6) cells, P<0.01). Furthermore, chronic hemodialysis with polysulfone dialyzers increased oxidative stress in PBMCs and inflammatory marker concentrations in circulation. In vitro, polysulfone membranes released significantly more BPA into the culture medium and induced more cytokine production in cultured PBMCs than did polynephron membranes. In conclusion, dialyzer BPA content may contribute to BPA burden in patients on hemodialysis. PMID- 26432903 TI - Complement Factor H-Related 5-Hybrid Proteins Anchor Properdin and Activate Complement at Self-Surfaces. AB - C3 glomerulopathy (C3G) is a severe kidney disease for which no specific therapy exists. The causes of C3G are heterogeneous, and defective complement regulation is often linked to C3G pathogenesis. Copy number variations in the complement factor H-related (CFHR) gene cluster on chromosome 1q32 and CFHR5 mutant proteins associate with this disease. Here, we identified CFHR5 as a pattern recognition protein that binds to damaged human endothelial cell surfaces and to properdin, the human complement activator. We found the two N-terminal short consensus repeat domains of CFHR5 contact properdin and mediate dimer formation. These properdin-binding segments are duplicated in two mutant CFHR5 proteins, CFHR2 CFHR5Hyb from German patients with C3G and CFHR5Dup from Cypriot patients with C3G. Each of these mutated proteins assembled into large multimeric complexes and, compared to CFHR5, bound damaged human cell surfaces and properdin with greater intensity and exacerbated local complement activation. This enhanced surface binding and properdin recruitment was further evidenced in the mesangia of a transplanted and explanted kidney from a German patient with a CFHR2 CFHR5Hyb protein. Enhanced properdin staining correlated with local complement activation with C3b and C5b-9 deposition on the mesangial cell surface in vitro This gain of function in complement activation for two disease-associated CFHR5 mutants describes a new disease mechanism of C3G, which is relevant for defining appropriate treatment options for this disorder. PMID- 26432904 TI - Renal Deletion of 12 kDa FK506-Binding Protein Attenuates Tacrolimus-Induced Hypertension. AB - Tacrolimus is a widely used immunosuppressive drug that inhibits the phosphatase calcineurin when bound to the 12 kDa FK506-binding protein (FKBP12). When this binding occurs in T cells, it leads to immunosuppression. Tacrolimus also causes side effects, however, such as hypertension and hyperkalemia. Previously, we reported that tacrolimus stimulates the renal thiazide-sensitive sodium chloride cotransporter (NCC), which is necessary for the development of hypertension. However, it was unclear if tacrolimus-induced hypertension resulted from tacrolimus effects in renal epithelial cells directly or in extrarenal tissues, and whether inhibition of calcineurin was required. To address these questions, we developed a mouse model in which FKBP12 could be deleted along the nephron. FKBP12 disruption alone did not cause phenotypic effects. When treated with tacrolimus, however, BP and the renal abundance of phosphorylated NCC were lower in mice lacking FKBP12 along the nephron than in control mice. Mice lacking FKBP12 along the nephron also maintained a normal relationship between plasma potassium levels and the abundance of phosphorylated NCC with tacrolimus treatment. In cultured cells, tacrolimus inhibited dephosphorylation of NCC. Together, these results suggest that tacrolimus causes hypertension predominantly by inhibiting calcineurin directly in cells expressing NCC, indicating thiazide diuretics may be particularly effective for lowering BP in tacrolimus-treated patients with hypertension. PMID- 26432906 TI - Cracking the Egg: Potential of the Developing Chicken as a Model System for Nonclinical Safety Studies of Pharmaceuticals. AB - The advance of perinatal medicine has improved the survival of extremely premature babies, thereby creating a new and heterogeneous patient group with limited information on appropriate treatment regimens. The developing fetus and neonate have traditionally been ignored populations with regard to safety studies of drugs, making medication during pregnancy and in newborns a significant safety concern. Recent initiatives of the Food and Drug Administration and European Medicines Agency have been passed with the objective of expanding the safe pharmacological treatment options in these patients. There is a consensus that neonates should be included in clinical trials. Prior to these trials, drug leads are tested in toxicity and pharmacology studies, as governed by several guidelines summarized in the multidisciplinary International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use M3 (R2). Pharmacology studies must be performed in the major organ systems: cardiovascular, respiratory, and central nervous system. The chicken embryo and fetus have features that make the chicken a convenient animal model for nonclinical safety studies in which effects on all of these organ systems can be tested. The developing chicken is inexpensive, accessible, and nutritionally self-sufficient with a short incubation time and is ideal for drug-screening purposes. Other high-throughput models have been implemented. However, many of these have limitations, including difficulty in mimicking natural tissue architecture and function (human stem cells) and obvious differences from mammals regarding the respiratory organ system and certain aspects of central nervous system development (Caenorhabditis elegans, zebrafish).This minireview outlines the potential and limitations of the developing chicken as an additional model for the early exploratory phase of development of new pharmaceuticals. PMID- 26432907 TI - Cancer vaccines in the new era of cancer immunotherapy. PMID- 26432908 TI - Pertactin negative Bordetella pertussis demonstrates higher fitness under vaccine selection pressure in a mixed infection model. AB - Whooping cough or pertussis is a highly infectious respiratory disease in humans caused by Bordetella pertussis. The use of acellular vaccines (ACV) has been associated with the recent resurgence of pertussis in developed countries including Australia despite high vaccination coverage where B. pertussis strains that do not express pertactin (Prn), a key antigenic component of the ACV, have emerged and become prevalent. In this study, we used an in vivo competition assay in mice immunised with ACV and in naive (control) mice to compare the proportion of colonisation with recent clinical Prn positive and Prn negative B. pertussis strains from Australia. The Prn negative strain colonised the respiratory tract more effectively than the Prn positive strain in immunised mice, out-competing the Prn positive strain by day 3 of infection. However, in control mice, the Prn positive strain out-competed the Prn negative strain. Our findings of greater ability of Prn negative strains to colonise ACV-immunised mice are consistent with reports of selective advantage for these strains in ACV-immunised humans. PMID- 26432905 TI - Endocrine and other physiologic modulators of perinatal cardiomyocyte endowment. AB - Immature contractile cardiomyocytes proliferate to rapidly increase cell number, establishing cardiomyocyte endowment in the perinatal period. Developmental changes in cellular maturation, size and attrition further contribute to cardiac anatomy. These physiological processes occur concomitant with a changing hormonal environment as the fetus prepares itself for the transition to extrauterine life. There are complex interactions between endocrine, hemodynamic and nutritional regulators of cardiac development. Birth has been long assumed to be the trigger for major differences between the fetal and postnatal cardiomyocyte growth patterns, but investigations in normally growing sheep and rodents suggest this may not be entirely true; in sheep, these differences are initiated before birth, while in rodents they occur after birth. The aim of this review is to draw together our understanding of the temporal regulation of these signals and cardiomyocyte responses relative to birth. Further, we consider how these dynamics are altered in stressed and suboptimal intrauterine environments. PMID- 26432909 TI - Genetic stability of live attenuated vaccines against potentially pandemic influenza viruses. AB - BACKGROUND: Ensuring genetic stability is a prerequisite for live attenuated influenza vaccine (LAIV). This study describes the results of virus shedding and clinical isolates' testing of Phase I clinical trials of Russian LAIVs against potentially pandemic influenza viruses in healthy adults. METHODS: Three live attenuated vaccines against potentially pandemic influenza viruses, H2N2 LAIV, H5N2 LAIV and H7N3 LAIV, generated by classical reassortment in eggs, were studied. For each vaccine tested, subjects were randomly distributed into two groups to receive two doses of either LAIV or placebo at a 3:1 vaccine/placebo ratio. Nasal swabs were examined for vaccine virus shedding by culturing in eggs and by PCR. Vaccine isolates were tested for temperature sensitivity and cold adaptation (ts/ca phenotypes) and for nucleotide sequence. RESULTS: The majority of nasal wash positive specimens were detected on the first day following vaccination. PCR method demonstrated higher sensitivity than routine virus isolation in eggs. None of the placebo recipients had detectable vaccine virus replication. All viruses isolated from the immunized subjects retained the ts/ca phenotypic characteristics of the master donor virus (MDV) and were shown to preserve all attenuating mutations described for the MDV. These data suggest high level of vaccine virus genetic stability after replication in humans. During manufacture process, no additional mutations occurred in the genome of H2N2 LAIV. In contrast, one amino acid change in the HA of H7N3 LAIV and two additional mutations in the HA of H5N2 LAIV manufactured vaccine lot were detected, however, they did not affect their ts/ca phenotypes. CONCLUSIONS: Our clinical trials revealed phenotypic and genetic stability of the LAIV viruses recovered from the immunized volunteers. In addition, no vaccine virus was detected in the placebo groups indicating the lack of person-to-person transmission. LAIV TRIAL REGISTRATION at ClinicalTrials.gov: H7N3-NCT01511419; H5N2-NCT01719783; H2N2 NCT01982331. PMID- 26432910 TI - No evidence for priming response in Galleria mellonella larvae exposed to toxin protein PirA2B2 from Photorhabdus luminescens TT01: An association with the inhibition of the host cellular immunity. AB - There is accumulating evidence that many invertebrates including insects can acquire enhanced immune protection against subsequently pathogens infection through immune priming. However, whether the toxin protein from pathogenic bacteria can induce such priming response remains unclear. Here we cloned, expressed and purified the toxin Photorhabdus insect-related proteins A2B2 (PirA2B2) from Photorhabdus luminescens TT01. We primed Galleria mellonella with sublethal dose of PirA2B2 and then challenged the larvae with viable P. luminescens TT01 at 48 h after priming. We found no evidence for immune priming in G. mellonella larvae exposed to PirA2B2. Priming the larvae with PirA2B2 did not improve their resistance in a subsequent challenge with P. luminescens TT01. Whereas a robust priming response was observed when the larvae exposed to lipopolysaccharide (LPS) extracted from P. luminescens TT01. Because the larvae primed with LPS showed significant higher resistance against P. luminescens TT01 infection than those of the PBS and BSA controls. Furthermore, we investigated the changes of the cellular immune parameters, such as hemocyte counts, phagocytic activity and encapsulation ability of the hemocytes, after priming. We found that the toxin PirA2B2 significantly decreased the cellular immunity of the larvae, whereas the LPS significantly increased them. These results indicated that the degree of priming response in G. mellonella correlated positively to the levels of cellular immune parameters, and the underlying mechanism in regulating the immune priming of invertebrates was not homologous to that of the immunological memory of vertebrates. PMID- 26432911 TI - Is immunotherapy an opportunity for effective treatment of drug addiction? AB - Immunotherapy has a great potential of becoming a new therapeutic strategy in the treatment of addiction to psychoactive drugs. It may be used to treat addiction but also to prevent neurotoxic complications of drug overdose. In preclinical studies two immunological methods have been tested; active immunization, which relies on the administration of vaccines and passive immunization, which relies on the administration of monoclonal antibodies. Until now researchers have succeeded in developing vaccines and/or antibodies against addiction to heroin, cocaine, methamphetamine, nicotine and phencyclidine. Their effectiveness has been confirmed in preclinical studies. At present, clinical studies are being conducted for vaccines against nicotine and cocaine and also anti-methamphetamine monoclonal antibody. These preclinical and clinical studies suggest that immunotherapy may be useful in the treatment of addiction and drug overdose. However, there are a few problems to be solved. One of them is controlling the level of antibodies due to variability between subjects. But even obtaining a suitable antibody titer does not guarantee the effectiveness of the vaccine. Additionally, there is a risk of intentional or unintentional overdose. As vaccines prevent passing of drugs through the blood/brain barrier and thereby prevent their positive reinforcement, some addicted patients may erroneously seek higher doses of psychoactive substances to get "high". Consequently, vaccination should be targeted at persons who have a strong motivation to free themselves from drug dependency. It seems that immunotherapy may be an opportunity for effective treatment of drug addiction if directed to adequate candidates for treatment. For other addicts, immunotherapy may be a very important element supporting psycho- and pharmacotherapy. PMID- 26432912 TI - Env-2dCD4 S60C complexes act as super immunogens and elicit potent, broadly neutralizing antibodies against clinically relevant human immunodeficiency virus type 1 (HIV-1). AB - The ability to induce a broadly neutralizing antibody (bNAb) response following vaccination is regarded as a crucial aspect in developing an effective vaccine against human immunodeficiency virus type 1 (HIV-1). The bNAbs target the HIV-1 envelope glycoprotein (Env) which is exposed on the virus surface, thereby preventing cell entry. To date, conventional vaccine approaches such as the use of Env-based immunogens have been unsuccessful. We expressed, purified, characterized and evaluated the immunogenicity of several unique HIV-1 subtype C Env immunogens in small animals. Here we report that vaccine immunogens based on Env liganded to a two domain CD4 variant, 2dCD4(S60C) are capable of consistently eliciting potent, broadly neutralizing antibody responses in New Zealand white rabbits against a panel of clinically relevant HIV-1 pseudoviruses. This was irrespective of the Env protein subtype and context. Importantly, depletion of the anti-CD4 antibodies appeared to abrogate the neutralization activity in the rabbit sera. Taken together, this data suggests that the Env-2dCD4(S60C) complexes described here are "super" immunogens, and potentially immunofocus antibody responses to a unique epitope spanning the 2dCD4(60C). Recent data from the two available anti-CD4 monoclonal antibodies, Ibalizumab and CD4-Ig (and bispecific variants thereof) have highlighted that the use of these broad and potent entry inhibitors could circumvent the need for a conventional vaccine targeting HIV-1. Overall, the ability of the unique Env-2dCD4(S60C) complexes to elicit potent bNAb responses has not been described previously, reinforcing that further investigation for their utility in preventing and controlling HIV-1/SIV infection is warranted. PMID- 26432914 TI - Maternal Immunization: Current status and future prospects. PMID- 26432913 TI - Long-term immunogenicity and safety of an investigational herpes zoster subunit vaccine in older adults. AB - BACKGROUND: An investigational subunit vaccine containing the varicella-zoster virus (VZV) glycoprotein E (gE) and the AS01B adjuvant system is being evaluated for the prevention of herpes zoster (HZ) in older adults. A phase II trial evaluating different formulations of this vaccine (containing 25MUg, 50MUg, or 100MUg gE) was conducted in adults >=60 years of age and showed that all formulations elicited robust cellular and humoral immune responses for up to 3 years after vaccination. In this follow-up study in subjects who received two doses of the 50MUg gE/AS01B formulation (HZ/su), we assessed the persistence of the immune responses for up to 6 years after vaccination. METHODS: This phase II, open-label, multicenter, single-group trial conducted in the Czech Republic, Germany, Sweden, and the Netherlands followed 129 subjects who had received two doses (2 months apart) of HZ/su during the initial trial. Vaccine-induced immune responses (frequencies of gE-specific CD4(+) T cells expressing >=2 activation markers and serum anti-gE antibody concentrations) were evaluated at 48, 60, and 72 months after the first HZ/su dose. RESULTS: Six years after vaccination with HZ/su, gE-specific cell-mediated immune responses and anti-gE antibody concentrations had decreased by 20-25% from month 36, but remained higher than the prevaccination values. At month 72, the gE-specific cell-mediated immune response was 3.8 times higher than the prevaccination value (477.3 vs. 119.4 activated gE-specific CD4(+) T cells per 10(6) cells), and the anti-gE antibody concentration was 7.3 times higher than the prevaccination value (8159.0 vs. 1121.3mIU/mL). No vaccine-related serious adverse events were reported between months 36 and 72. CONCLUSIONS: gE-specific cellular and humoral immune responses persisted for 6 years after two-dose vaccination with HZ/su in healthy older adults. No safety concerns were identified. PMID- 26432916 TI - Protective antibody responses against A(H1N1)pdm09 primed by infection and recalled by intranasal vaccination. AB - This study investigated the effects of preceding infection and administration of whole inactivated virus (WIV) vaccine on immune responses against influenza virus challenge. Preceding infection alone provided minimal reduction in virus titer following viral challenge. Single administration of intranasal or subcutaneous WIV vaccine alone failed to reduce virus titers and induce antibody responses. Subcutaneous administration of A/Narita/1/09 (A/NRT)-WIV after A/NRT infection provided complete protection against infection and yielded low nasal IgA and high serum IgG antibody responses. Subcutaneous administration of A/NRT-WIV after A/Puerto Rico/8/34 (A/PR8) infection provided no protection. Conversely, intranasal administration of A/NRT-WIV after A/NRT infection provided complete protection and high nasal IgA and serum IgG antibody responses. While, intranasal administration of A/NRT-WIV after A/PR8 infection provided moderate reduction in viral titer with moderate increases in nasal IgA antibodies. These results indicate that intranasal vaccination is superior to subcutaneous vaccination in inducing protective immune responses after preceding heterologous infection. PMID- 26432917 TI - Human organotypic retinal cultures (HORCs) as a chronic experimental model for investigation of retinal ganglion cell degeneration. AB - There is a growing need for models of human diseases that utilise native, donated human tissue in order to model disease processes and develop novel therapeutic strategies. In this paper we assessed the suitability of adult human retinal explants as a potential model of chronic retinal ganglion cell (RGC) degeneration. Our results confirmed that RGC markers commonly used in rodent studies (NeuN, betaIII Tubulin and Thy-1) were appropriate for labelling human RGCs and followed the expected differential expression patterns across, as well as throughout, the macular and para-macular regions of the retina. Furthermore, we showed that neither donor age nor post-mortem time (within 24 h) significantly affected the initial expression levels of RGC markers. In addition, the feasibility of using human post mortem donor tissue as a long-term model of RGC degeneration was determined with RGC protein being detectable up to 4 weeks in culture with an associated decline in RGC mRNA and significant, progressive, apoptotic labelling of NeuN(+) cells. Differences in RGC apoptosis might have been influenced by medium compositions indicating that media constituents could play a role in supporting axotomised RGCs. We propose that using ex vivo human explants may prove to be a useful model for testing the effectiveness of neuroprotective strategies. PMID- 26432915 TI - Plant-derived H7 VLP vaccine elicits protective immune response against H7N9 influenza virus in mice and ferrets. AB - In March 2013, the Chinese Centre for Disease Control and Prevention confirmed the first reported case of human infection with an avian influenza A H7N9 virus. Infection with this virus often caused severe pneumonia and acute respiratory distress syndrome resulting in a case fatality rate >35%. The risk of pandemic highlighted, once again, the need for a more rapid and scalable vaccine response capability. Here, we describe the rapid (19 days) development of a plant-derived VLP vaccine based on the hemagglutinin sequence of influenza H7N9 A/Hangzhou/1/2013. The immunogenicity of the H7 VLP vaccine was assessed in mice and ferrets after one or two intramuscular dose(s) with and without adjuvant (alum or GLA-SETM). In ferrets, we also measured H7-specific cell-mediated immunity. The mice and ferrets were then challenged with H7N9 A/Anhui/1/2013 influenza virus. A single immunization with the adjuvanted vaccine elicited a strong humoral response and protected mice against an otherwise lethal challenge. Two doses of unadjuvanted vaccine significantly increased humoral response and resulted in 100% protection with significant reduction of clinical signs leading to nearly asymptomatic infections. In ferrets, a single immunization with the alum-adjuvanted H7 VLP vaccine induced strong humoral and CMI responses with antigen-specific activation of CD3(+) T cells. Compared to animals injected with placebo, ferrets vaccinated with alum-adjuvanted vaccine displayed no weight loss during the challenge. Moreover, the vaccination significantly reduced the viral load in lungs and nasal washes 3 days after the infection. This candidate plant made H7 vaccine therefore induced protective responses after either one adjuvanted or two unadjuvanted doses. Studies are currently ongoing to better characterize the immune response elicited by the plant-derived VLP vaccines. Regardless, these data are very promising for the rapid production of an immunogenic and protective vaccine against this potentially pandemic virus. PMID- 26432918 TI - Illumination from light-emitting diodes (LEDs) disrupts pathological cytokines expression and activates relevant signal pathways in primary human retinal pigment epithelial cells. AB - Age-related macular degeneration (AMD) is the leading cause of blindness in the aged people. The latest systemic review of epidemiological investigations revealed that excessive light exposure increases the risk of AMD. With the drastically increasing use of high-energy light-emitting diodes (LEDs) light in our domestic environment nowadays, it is supposed to pose a potential oxidative threat to ocular health. Retinal pigment epithelium (RPE) is the major ocular source of pathological cytokines, which regulate local inflammation and angiogenesis. We hypothesized that high-energy LED light might disrupt the pathological cytokine expression of retinal pigment epithelium (RPE), contributing to the pathogenesis of AMD. Primary human RPE cells were isolated from eyecups of normal eye donors and seeded into plate wells for growing to confluence. Two widely used multichromatic white light-emitting diodes (LEDs) with correlated color temperatures (CCTs) of 2954 and 7378 K were used in this experiment. The confluent primary RPE cells were under white LEDs light exposure until 24 h. VEGF-A, IL-6, IL-8 and MCP-1 proteins and mRNAs were measured using an ELISA kit and RT-PCR, respectively. Activation of mitogen-activated protein kinases (MAPKs), Akt, Janus kinase (JAK)2 and Nuclear factor (NF)-kappaB signal pathways after LEDs illumination were evaluated by western blotting analysis. The level of reactive oxygen species (ROS) using chloromethyl- 2',7' dichlorodihydrofluorescein diacetate. Inhibitors of relevant signal pathways and anti-oxidants were added to the primary RPE cells before LEDs illumination to evaluate their biological functions. We found that 7378 K light, but not 2954 K upregulated the VEGF-A, IL-6, IL-8 and downregulated MCP-1 proteins and mRNAs levels in a time-dependent manner. In parallel, initial activation of MAPKs and NF-kappaB signal pathways were also observed after 7378 K light exposure. Mechanistically, antioxidants for eliminating reactive oxygen species (ROS) and targeted inhibitors of MAPKs and NF-kappaB significantly blocked 7378 K light induced changes of specific cytokines, respectively. Our findings suggest that 7378 K light, not 2954 K induced upregulation of VEGF-A, IL-6, IL-8 and downregulation of MCP-1 via ROS accumulation, activating MAPKs and NF-kappaB signal pathways. PMID- 26432919 TI - Dysregulation of VEGF-induced proangiogenic Ca2+ oscillations in primary myelofibrosis-derived endothelial colony-forming cells. AB - Endothelial progenitor cells could be implicated in the aberrant neoangiogenesis that occurs in bone marrow and spleen in patients with primary myelofibrosis (PMF). However, antivascular endothelial growth factor (VEGF) monotherapy had only a modest and transient effect in these individuals. Recently it was found that VEGF-induced proangiogenic intracellular Ca(2+) oscillations could be impaired in endothelial progenitor cells of subjects with malignancies. Therefore, we employed Ca(2+) imaging, wavelet analysis, and functional assays to assess whether and how VEGF-induced Ca(2+) oscillations are altered in PMF derived endothelial progenitor cells. We focused on endothelial colony-forming cells (ECFCs), which are the only endothelial progenitor cell subtype capable of forming neovessels both in vivo and in vitro. VEGF triggers repetitive Ca(2+) spikes in both normal ECFCs (N-ECFCs) and ECFCs obtained from PMF patients (PMF ECFCs). However, the spiking response to VEGF is significantly weaker in PMF ECFCs. VEGF-elicited Ca(2+) oscillations are patterned by the interaction between inositol-1,4,5-trisphosphate-dependent Ca(2+) mobilization and store-operated Ca(2+) entry. However, in most PMF-ECFCs, Ca(2+) oscillations are triggered by a store-independent Ca(2+) entry pathway. We found that diacylglycerol gates transient receptor potential canonical 1 channel to trigger VEGF-dependent Ca(2+) spikes by recruiting the phospholipase C/inositol-1,4,5-trisphosphate signaling pathway, reflected as a decrease in endoplasmic reticulum Ca(2+) content. Finally, we found that, apart from being less robust and dysregulated as compared with N-ECFCs, VEGF-induced Ca(2+) oscillations modestly stimulate PMF-ECFC growth and in vitro angiogenesis. These results may explain the modest effect of anti VEGF therapies in PMF. PMID- 26432920 TI - Aerosol from a candidate modified risk tobacco product has reduced effects on chemotaxis and transendothelial migration compared to combustion of conventional cigarettes. AB - Reduction of harmful constituents by heating rather than combusting tobacco is a promising new approach to reduce harmful effects associated with cigarette smoking. We investigated the effect from a new candidate modified risk tobacco product, the tobacco heating system (THS) 2.2, on the migratory behavior of monocytes in comparison with combustible 3R4F reference cigarettes. The monocytic cell line (THP-1) and human coronary arterial endothelial cells (HCAECs) were used to analyze chemotaxis and transendothelial migration (TEM). To assess the influence of aerosol extract from THS2.2 and smoke extract from 3R4F on toxicity and inflammation, flow cytometry and ELISA assays were performed. The results show that treatment of THP-1 cells with extract from 3R4F or THS2.2 induced concentration-dependent increases in cytotoxicity and inflammation. The inhibitory effects of THS2.2 extract for chemotaxis and TEM were ~18 times less effective compared to 3R4F extract. Furthermore, extract from 3R4F or THS2.2 induced concentration-dependent decreases in the integrity of HCAEC monolayer. For all examined endpoints, the extract from 3R4F showed more than one order of magnitude stronger effects than that from THS2.2 extract. These data indicate the potential of a heat not burn tobacco product to reduce the risk for cardiovascular disease compared to combustible cigarettes. PMID- 26432922 TI - CD4(+) T cell surface alpha enolase is lower in older adults. AB - To identify novel cell ageing markers in order to gain insight into ageing mechanisms, we adopted membrane enrichment and comparison of the CD4(+) T cell membrane proteome (purified by cell surface labelling using Sulfo-NHS-SS-Biotin reagent) between healthy young (n=9, 20-25 years) and older (n=10; 50-70 years) male adults. Following two-dimensional gel electrophoresis (2DE) to separate pooled membrane proteins in triplicates, the identity of protein spots with age dependent differences (p<0.05 and >1.4 fold difference) was determined using liquid chromatography-mass spectrometry (LC-MS/MS). Seventeen protein spot density differences (ten increased and seven decreased in the older adult group) were observed between young and older adults. From spot intensity analysis, CD4(+) T cell surface alpha-enolase was decreased in expression by 1.5 fold in the older age group; this was verified by flow cytometry (n=22) and qPCR with significantly lower expression of cellular alpha-enolase mRNA and protein compared to young adult CD4(+) T cells (p<0.05). In an independent age-matched case-control study, lower CD4(+) T cell surface alpha-enolase expression was observed in age-matched patients with cardiovascular disease (p<0.05). An immune modulatory role has been proposed for surface alpha-enolase and our findings of decreased expression suggest that deficits in surface alpha-enolase merit investigation in the context of immune dysfunction during ageing and vascular disease. PMID- 26432924 TI - Therapeutics targeting innate immune/inflammatory responses through the interleukin-6/JAK/STAT signal transduction pathway in patients with cancer. AB - Over the last 15 years, there has been an evolution in the thinking of how tumors grow and disseminate: from the earlier work where it was considered that the intrinsic characteristics of the tumor largely determined the process to more recent work where local and systemic inflammatory responses play a key role in disease progression and survival in patients with cancer. Although the immune/inflammatory responses to cancer are complex, it is clear that targeting the host immune/inflammatory responses (in particular, innate/humoral responses) has considerable potential to improve outcomes in patients with a variety of common solid tumors. There are a wide variety of agents from the nonselective glucocorticoids to the selective Janus Activated Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) inhibitors that has considerable therapeutic potential. They may be considered to act through a main signal transduction mechanism, the interleukin-6/JAK/STAT pathway. This work heralds a new era in which it will be important not only to treat the tumor but also to treat the host, so called oncoimmunology. PMID- 26432921 TI - Cytoplasmic mRNA turnover and ageing. AB - Messenger RNA (mRNA) turnover that determines the lifetime of cytoplasmic mRNAs is a means to control gene expression under both normal and stress conditions, whereas its impact on ageing and age-related disorders has just become evident. Gene expression control is achieved at the level of the mRNA clearance as well as mRNA stability and accessibility to other molecules. All these processes are regulated by cis-acting motifs and trans-acting factors that determine the rates of translation and degradation of transcripts. Specific messenger RNA granules that harbor the mRNA decay machinery or various factors, involved in translational repression and transient storage of mRNAs, are also part of the mRNA fate regulation. Their assembly and function can be modulated to promote stress resistance to adverse conditions and over time affect the ageing process and the lifespan of the organism. Here, we provide insights into the complex relationships of ageing modulators and mRNA turnover mechanisms. PMID- 26432925 TI - Simultaneous quantitation of hexacosanoyl lysophosphatidylcholine, amino acids, acylcarnitines, and succinylacetone during FIA-ESI-MS/MS analysis of dried blood spot extracts for newborn screening. AB - OBJECTIVES: The goal of this study was to include the quantitation of hexacosanoyl lysophosphatidylcholine, a biomarker for X-linked adrenoleukodystrophy and other peroxisomal disorders, in the routine extraction and analysis procedure used to quantitate amino acids, acylcarnitines, and succinylacetone during newborn screening. Criteria for the method included use of a single punch from a dried blood spot, one simple extraction of the punch, no high-performance liquid chromatography, and utilizing tandem mass spectrometry to quantitate the analytes. DESIGN AND METHODS: Dried blood spot punches were extracted with a methanolic solution of stable-isotope labeled internal standards, formic acid, and hydrazine, followed by flow injection analysis electrospray ionization-tandem mass spectrometry. RESULTS: Quantitation of amino acids, acylcarnitines, and hexacosanoyl lysophosphatidylcholine using this combined method was similar to results obtained using two separate methods. CONCLUSIONS: A single dried blood spot punch extracted by a rapid (45min), simple procedure can be analyzed with high throughput (2min per sample) to quantitate amino acids, acylcarnitines, succinylacetone, and hexacosanoyl lysophosphatidylcholine. PMID- 26432926 TI - Translating depression biomarkers for improved targeted therapies. AB - Mood disorders are among the most common medical conditions and cause amongst the greatest disease burden. Currently approved antidepressants target monoamine pathways; these medicines take many weeks to relieve symptoms, and most patients do not have sustained responses. This review will highlight recent advances in translational science identifying dysfunctional biochemical processes and neuronal circuits associated with mood disorders. We will also summarize strategies for targeting these pathways and for enhancing synaptic plasticity to develop most effective and rapidly acting antidepressant therapies. PMID- 26432923 TI - Therapeutic benefits of young, but not old, adipose-derived mesenchymal stem cells in a chronic mouse model of bleomycin-induced pulmonary fibrosis. AB - The observation that pulmonary inflammatory lesions and bleomycin (BLM)-induced pulmonary fibrosis spontaneously resolve in young mice, whereas remaining irreversible in aged mice suggests that impairment of pulmonary regeneration and repair is associated with aging. Because mesenchymal stem cells (MSCs) may promote repair after injury, we postulated that differences in MSCs from aged mice may underlie postinjury fibrosis in aging. The potential for young-donor MSCs to inhibit BLM-induced pulmonary fibrosis in aged male mice (>22 months) has not been studied. Adipose-derived MSCs (ASCs) from young (4 months) and old (22 months) male mice were infused 1 day after intratracheal BLM administration. At 21-day sacrifice, aged BLM mice demonstrated lung fibrosis by Ashcroft score, collagen content, and alpha(v)-integrin messenger RNA (mRNA) expression. Lung tissue from aged BLM mice receiving young ASCs exhibited decreased fibrosis, matrix metalloproteinase (MMP)-2 activity, oxidative stress, and markers of apoptosis vs BLM controls. Lung mRNA expression of tumor necrosis factor-alpha was also decreased in aged BLM mice receiving young-donor ASCs vs BLM controls. In contrast, old-donor ASC treatment in aged BLM mice did not reduce fibrosis and related markers. On examination of the cells, young-donor ASCs had decreased mRNA expression of MMP-2, insulin-like growth factor (IGF) receptor, and protein kinase B (AKT) activation compared with old-donor ASCs. These results show that the BLM-induced pulmonary fibrosis in aged mice could be blocked by young-donor ASCs and that the mechanisms involve changes in collagen turnover and markers of inflammation. PMID- 26432927 TI - Retinal Pigment Epithelial Atrophy in Neovascular Age-Related Macular Degeneration After Ranibizumab Treatment. AB - PURPOSE: To investigate the risk factors for development and progression of retinal pigment epithelial (RPE) atrophy during ranibizumab treatment for neovascular age-related macular degeneration (AMD) in Japanese patients. DESIGN: Retrospective interventional case series. METHODS: This study included 195 eyes with treatment-naive subfoveal neovascular AMD. All patients were treated with an as-needed regimen after 3 monthly ranibizumab treatments. Color fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence were evaluated for RPE atrophy diagnosis. Baseline characteristics and ARMS2 A69S and CFH I62V polymorphisms were analyzed for their association with development and progression of RPE atrophy. RESULTS: Ten of 195 eyes (5.1%) had RPE atrophy at baseline; 3 had typical AMD and 7 had polypoidal choroidal vasculopathy (PCV). Among 185 eyes without preexisting RPE atrophy at baseline, 7 (3.8%) developed RPE atrophy at 12 months and 10 (5.4%) during the mean follow-up of 26.7 months. The incidence of newly developed RPE atrophy was lower in PCV than in typical AMD (P = .036), while the progression of the RPE atrophy area was faster in typical AMD than in PCV (0.57 +/- 0.35 and 0.31 +/- 0.13 mm/year, respectively; P = .018). The ARMS2 A69S and CFH I62V polymorphisms were significantly associated with the baseline RPE atrophy (P = .014 and P = .009, respectively). CONCLUSIONS: The RPE atrophy developed in 5.4% of eyes with neovascular AMD during the 26.7 months of ranibizumab treatment. When compared with white individuals, RPE atrophy developed less frequently in Japanese patients, but the progression rate was similar. The subtype of AMD thus affects the development of RPE atrophy. PMID- 26432928 TI - Photodynamic Therapy for Choroidal Metastasis. AB - PURPOSE: To evaluate the effectiveness of photodynamic therapy (PDT) in the management of choroidal metastasis. DESIGN: Retrospective, interventional case series. METHODS: Patients with choroidal metastasis treated with PDT at a single institution were reviewed. PDT was applied with verteporfin at a dose of 6 mg/m(2) body surface area and a 689 nm diode laser for 83 seconds. Visual acuity, tumor basal diameter, tumor thickness by ultrasonography, and enhanced depth imaging optical coherence tomography (EDI-OCT), as well as associated features including subretinal fluid, were recorded before PDT and during follow-up examinations. RESULTS: Twenty-one tumors in 13 eyes of 10 patients were included. Eight tumors were treated with a single session of PDT, 11 tumors received 2 sessions, 1 tumor received 3 sessions, and 1 tumor received 5 sessions. At the end of a mean follow-up of 12 months (range, 3-42 months), 9 eyes (69%) had stable or improved visual acuity, while 4 eyes (31%) had decreased visual acuity. Mean logMAR change in visual acuity was -0.09 (range, -1.3 to 0.8). Seventeen of 21 tumors (81%) were flat at last follow-up. The mean decrease in ultrasound measured thickness was 0.83 mm (range, 2.6 mm decrease to 1.4 mm increase), while the decrease in EDI-OCT-measured thickness was 400 MUm (range, 1280 MUm decrease to 280 MUm increase). Eighteen tumors (86%) had complete resolution of subretinal fluid. There were no PDT-related complications. CONCLUSIONS: Photodynamic therapy may be an effective therapeutic option for the management of choroidal metastasis in selected cases. PMID- 26432929 TI - Geo-Epidemiology of Age-Related Macular Degeneration: New Clues Into the Pathogenesis. AB - PURPOSE: To evaluate the demographic, geographic, and race-related variables that account for geographic variability in prevalence rates of age-related macular degeneration (AMD). DESIGN: Systematic review, meta-regression, and decision-tree analysis. METHODS: A systematic literature review of PubMed, Medline, Web of Science, and Embase databases identified population-based studies on the prevalence of AMD published before May 2014. Only population-based studies that took place in a spatially explicit geographic area that could be geolocalized, and used retinal photographs and standardized grading classifications, were included. Latitude and longitude data (geolocalization) and the mean annual insolation for the area where survey took place were obtained. Age-standardized prevalence rates across studies were estimated using the direct standardization method. Correlations between the prevalence of AMD and longitude and latitude were obtained by regression analysis. A hierarchical Bayesian meta-regression approach was used to assess the association between the prevalence of AMD and other relevant factors. We further investigated the interplay between location and these factors on the prevalence of AMD using regression based on conditional inference decision trees. RESULTS: We observed significant inverse correlations between latitude or longitude, and crude or age-standardized prevalence rates, of early and late AMD (P < .001). Metaregression analysis showed that insolation, latitude, longitude, age, and race have a significant effect on the prevalence rates of early and late AMD (P < .001). Decision-tree analysis identified that the most important predictive variable was race for early AMD (P = .002) and insolation for late AMD (P = .001). CONCLUSIONS: Geographic position and insolation are key factors in the prevalence of AMD. PMID- 26432930 TI - Huperzine A prophylaxis against pentylenetetrazole-induced seizures in rats is associated with increased cortical inhibition. AB - Huperzine A (HupA) is a naturally occurring compound found in the firmoss Huperzia serrata. While HupA is a potent acetylcholinesterase inhibitor, its full pharmacologic profile is incompletely described. Since previous works suggested a capacity for HupA to prophylax against seizures, we tested the HupA antiepileptic potential in pentylenetetrazole (PTZ) rat epilepsy model and explored its mechanism of action by spectral EEG analysis and by paired-pulse transcranial magnetic stimulation (ppTMS), a measure of GABA-mediated intracortical inhibition. We tested whether HupA suppresses seizures in the rat PTZ acute seizure model, and quantified latency to first myoclonus and to generalized tonic clonic seizure, and spike frequency on EEG. Additionally, we measured power in the EEG gamma frequency band which is associated with GABAergic cortical interneuron activation. Then, as a step toward further examining the HupA antiepileptic mechanism of action, we tested long-interval intracortical inhibition (LICI) using ppTMS coupled with electromyography to assess whether HupA augments GABA-mediated paired-pulse inhibition of the motor evoked potential. We also tested whether the HupA effect on paired-pulse inhibition was central or peripheral by comparison of outcomes following administration of HupA or the peripheral acetylcholinesterase inhibitor pyridostigmine. We also tested whether the HupA effect was dependent on central muscarinic or GABAA receptors by co-administration of HupA and atropine or PTZ, respectively. In tests of antiepileptic potential, HupA suppressed seizures and epileptic spikes on EEG. Spectral EEG analysis also revealed enhanced gamma frequency band power with HupA treatment. By ppTMS we found that HupA increases intracortical inhibition and blocks PTZ-induced cortical excitation. Atropine co-administration with HupA did not alter HupA-induced intracortical inhibition suggesting independent of muscarinic acetylcholine receptors mechanism in this model. Last, pyridostigmine did not affect the ppTMS-measured cortical inhibition suggesting that HupA induced effect is centrally-mediated. Our data support antiepileptic HupA applications, and suggest that such activity may be via enhancement of GABAergic intracortical inhibition. PMID- 26432931 TI - Voxel-based Gaussian naive Bayes classification of ischemic stroke lesions in individual T1-weighted MRI scans. AB - BACKGROUND: Manual lesion delineation by an expert is the standard for lesion identification in MRI scans, but it is time-consuming and can introduce subjective bias. Alternative methods often require multi-modal MRI data, user interaction, scans from a control population, and/or arbitrary statistical thresholding. NEW METHOD: We present an approach for automatically identifying stroke lesions in individual T1-weighted MRI scans using naive Bayes classification. Probabilistic tissue segmentation and image algebra were used to create feature maps encoding information about missing and abnormal tissue. Leave one-case-out training and cross-validation was used to obtain out-of-sample predictions for each of 30 cases with left hemisphere stroke lesions. RESULTS: Our method correctly predicted lesion locations for 30/30 un-trained cases. Post processing with smoothing (8mm FWHM) and cluster-extent thresholding (100 voxels) was found to improve performance. COMPARISON WITH EXISTING METHOD: Quantitative evaluations of post-processed out-of-sample predictions on 30 cases revealed high spatial overlap (mean Dice similarity coefficient=0.66) and volume agreement (mean percent volume difference=28.91; Pearson's r=0.97) with manual lesion delineations. CONCLUSIONS: Our automated approach agrees with manual tracing. It provides an alternative to automated methods that require multi-modal MRI data, additional control scans, or user interaction to achieve optimal performance. Our fully trained classifier has applications in neuroimaging and clinical contexts. PMID- 26432932 TI - Use of von Frey filaments to assess nociceptive sensitization in the hornworm, Manduca sexta. AB - BACKGROUND: The hornworm Manduca sexta exhibits a defensive strike to noxious assaults, a response that is robust and is easily observed by experimenters. Von Frey filaments and methods typical for studying nociception in other animals were used to assess the strike response in M. sexta. NEW METHODS: A series of von Frey filaments was applied to the body wall in ascending order and the data generated were used to determine the strike threshold by (i) the up-and-down method, (ii) the first response method, and (iii) the simplified up-and-down order method (SUDO). The effect of a noxious pinch on strike threshold was assessed. COMPARISON WITH EXISTING METHODS: To our knowledge none of these methods has been used on M. sexta previously, making the use of the up-and-down and SUDO methods the first in an invertebrate. The use of the first response method has been used in other invertebrates, and the method appears equally suited to M. sexta. RESULTS: All three methods were successful in monitoring the threshold sensitivity to touch, which was lowered (sensitized) by tissue damage induced with a pinch. Sensitization lasted 19h. CONCLUSIONS: All three methods of assessing nociception were successfully applied to quantify the defensive strike response in M. sexta, although the SUDO method required empirical assessment of which filament to start the test sequence with. The results revealed both short- and long-term sensitization. These methods should prove to be useful for quantifying sensitization in M. sexta. PMID- 26432933 TI - Isolating dividing neural and brain tumour cells for gene expression profiling. AB - BACKGROUND: The characterisation of dividing brain cells is fundamental for studies ranging from developmental and stem cell biology, to brain cancers. Whilst there is extensive anatomical data on these dividing cells, limited gene transcription data is available due to technical constraints. NEW METHOD: We focally isolated dividing cells whilst conserving RNA, from culture, primary neural tissue and xenografted glioma tumours, using a thymidine analogue that enables gene transcription analysis. RESULTS: 5-ethynyl-2-deoxyuridine labels the replicating DNA of dividing cells. Once labelled, cultured cells and tissues were dissociated, fluorescently tagged with a revised click chemistry technique and the dividing cells isolated using fluorescence-assisted cell sorting. RNA was extracted and analysed using real time PCR. Proliferation and maturation related gene expression in neurogenic tissues was demonstrated in acutely and 3 day old labelled cells, respectively. An elevated expression of marker and pathway genes was demonstrated in the dividing cells of xenografted brain tumours, with the non dividing cells showing relatively low levels of expression. COMPARISON WITH EXISTING METHOD: BrdU "immune-labelling", the most frequently used protocol for detecting cell proliferation, causes complete denaturation of RNA, precluding gene transcription analysis. This EdU labelling technique, maintained cell integrity during dissociation, minimized copper exposure during labelling and used a cell isolation protocol that avoided cell lysis, thus conserving RNA. CONCLUSIONS: The technique conserves RNA, enabling the definition of cell proliferation-related changes in gene transcription of neural and pathological brain cells in cells harvested immediately after division, or following a period of maturation. PMID- 26432934 TI - Growing neuronal islands on multi-electrode arrays using an accurate positioning MUCP device. AB - BACKGROUND: Multi-electrode arrays (MEAs) allow non-invasive multi-unit recording in-vitro from cultured neuronal networks. For sufficient neuronal growth and adhesion on such MEAs, substrate preparation is required. Plating of dissociated neurons on a uniformly prepared MEA's surface results in the formation of spatially extended random networks with substantial inter-sample variability. Such cultures are not optimally suited to study the relationship between defined structure and dynamics in neuronal networks. To overcome these shortcomings, neurons can be cultured with pre-defined topology by spatially structured surface modification. Spatially structuring a MEA surface accurately and reproducibly with the equipment of a typical cell-culture laboratory is challenging. NEW METHOD: In this paper, we present a novel approach utilizing micro-contact printing (MUCP) combined with a custom-made device to accurately position patterns on MEAs with high precision. We call this technique AP-MUCP (accurate positioning micro-contact printing). COMPARISON WITH EXISTING METHODS: Other approaches presented in the literature using MUCP for patterning either relied on facilities or techniques not readily available in a standard cell culture laboratory, or they did not specify means of precise pattern positioning. CONCLUSION: Here we present a relatively simple device for reproducible and precise patterning in a standard cell-culture laboratory setting. The patterned neuronal islands on MEAs provide a basis for high throughput electrophysiology to study the dynamics of single neurons and neuronal networks. PMID- 26432935 TI - Reply by Authors. PMID- 26432936 TI - Re: Tunneled Buccal Mucosa Tube Grafts for Repair of Proximal Hypospadias: R. Fine, E. F. Reda, P. Zelkovic, J. Gitlin, J. Freyle, I. Franco and L. S. Palmer J Urol, suppl., 2015;193:1813-1817. PMID- 26432937 TI - Reply by Authors. PMID- 26432938 TI - Re: Comparative Effectiveness of Targeted vs Empirical Antibiotic Prophylaxis to Prevent Sepsis from Transrectal Prostate Biopsy: A Retrospective Analysis: M. A. Liss, W. Kim, D. Moskowitz and R. J. Szabo J Urol 2015;194:397-402. PMID- 26432940 TI - Spontaneous esophageal perforation (Boerhaave syndrome) successfully treated with an over-the-scope clip and fully covered metal stent. PMID- 26432939 TI - Activation of serotonin 5-HT(2C) receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in morphine-dependent mice. AB - Opioid abuse and dependence have evolved into an international epidemic as a significant clinical and societal problem with devastating consequences. Repeated exposure to the opioid, for example morphine, can induce profound, long-lasting behavioral sensitization and physical dependence, which are thought to reflect neuroplasticity in neural circuitry. Central serotonin (5-HT) neurotransmission participates in the development of dependence on and the expression of withdrawal from morphine. Serotonin 5-HT(2C) receptor (5-HT(2C)R) agonists suppress psychostimulant nicotine or cocaine-induced behavioral sensitization and drug seeking behavior; however, the impact of 5-HT(2C)R agonists on behaviors relevant to opioid abuse and dependence has not been reported. In the present study, the effects of 5-HT(2C)R activation on the behavioral sensitization and naloxone precipitated withdrawal symptoms were examined in mice underwent repeated exposure to morphine. Male mice received morphine (10 mg/kg, s.c.) to develop behavioral sensitization. Lorcaserin, a 5-HT(2C)R agonist, prevented the induction and expression, but not the development, of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine-dependence. Pretreatment of lorcaserin, or the positive control clonidine (an alpha 2-adrenoceptor agonist), ameliorated the naloxone-precipitated withdrawal symptoms. SB 242084, a selective 5-HT(2C)R antagonist, prevented the lorcaserin-mediated suppression of behavioral sensitization and withdrawal. Chronic morphine treatment was associated with an increase in the expression of 5-HT(2C)R protein in the ventral tegmental area, locus coeruleus and nucleus accumbens. These findings suggest that 5-HT(2C)R can modulate behavioral sensitization and withdrawal in morphine-dependent mice, and the activation of 5-HT(2C)R may represent a new avenue for the treatment of opioid addiction. PMID- 26432941 TI - The "Moonsault" maneuver: retroflexed ileocecal valve insertion. PMID- 26432942 TI - Combined volume reduction with the loop-and-leave technique permits safe endoscopic management of high-risk giant gastric polyps. PMID- 26432943 TI - Type III choledochal cyst and anomalous pancreatobiliary junction. PMID- 26432944 TI - Peroral endoscopic myotomy with simultaneous submucosal and muscle dissection for achalasia with severe interlayer adhesions. PMID- 26432945 TI - convISA: A simple, convoluted method for isotopomer spectral analysis of fatty acids and cholesterol. AB - Isotopomer spectral analysis (ISA) is a simple approach for modelling the cellular synthesis of fatty acids and cholesterol in a stable isotope labelling experiment. In the simplest model, fatty acid biosynthesis is described by two key parameters: the fractional enrichment of acetyl-CoA from the labelled substrate, D, and the fractional de novo synthesis of the fatty acid during the exposure to the labelled substrate, g(t). The model can also be readily extended to include synthesis via elongation of unlabelled shorter fatty acids. This modelling strategy is less complex than metabolic flux analysis and only requires the measurement of the mass isotopologues of a single metabolite. However, software tools to perform these calculations are not freely available. We have developed an algorithm (convISA), implemented in MATLAB(TM), which employs the convolution (Cauchy product) of mass isotopologue distributions (MIDs) for ISA of fatty acids and cholesterol. In our method, the MIDs of each molecule are constructed as a single entity rather than deriving equations for individual isotopologues. The flexibility of this method allows the model to be applied to raw data as well as to data that has been corrected for natural isotope abundance. To test the algorithm, convISA was applied to 238 MIDs of methyl palmitate available from the literature, for which ISA parameters had been calculated via other methods. A very high correlation was observed between estimates of the D and g(t) parameters from convISA with both published values, and estimates generated by our own metabolic flux analysis using a simplified stoichiometric model (r=0.981 and 0.944, and 0.996 and 0.942). We also demonstrate the application of the convolution ISA approach to cholesterol biosynthesis; the model was applied to measurements made on MCF7 cells cultured in U-(13)C-glucose. In conclusion, we believe that convISA offers a convenient, flexible and transparent framework for metabolic modelling that will help facilitate the application of ISA to future experiments. PMID- 26432946 TI - Survival of rat cerebrocortical neurons after rickettsial infection. AB - Neuroinvasive microorganisms are suspected to play an important role in the etiopathogenesis of neurological diseases. However, direct evidence for the pathogenic function is still missing. The main aim of this study was to investigate biochemical and morphological changes that may occur as a result of an in vitro infection of rat cerebrocortical neurons by selected members of the genus Rickettsia. Our results showed that survival of the neurons is significantly reduced after the infection. Intracellular level of ATP is gradually decreased and inversely correlates with the load of rickettsiae. Immunofluorescence revealed that rickettsiae can enter the neurons and are localized in perinuclear space and also in neuronal processes. Data obtained in this study correspond to the idea of possible involvement of rickettsiae in the etiopathogenesis of various neuropathies. PMID- 26432948 TI - First report of a NDM-producing Providencia rettgeri strain in the state of Sao Paulo. PMID- 26432947 TI - Infection and characterization of Toxoplasma gondii in human induced neurons from patients with brain disorders and healthy controls. AB - Toxoplasma gondii is a protozoan parasite capable of establishing persistent infection within the brain. Serological studies in humans have linked exposure to Toxoplasma to neuropsychiatric disorders. However, serological studies have not elucidated the related molecular mechanisms within neuronal cells. To address this question, we used human induced neuronal cells derived from peripheral fibroblasts of healthy individuals and patients with genetically-defined brain disorders (i.e. childhood-onset schizophrenia with disease-associated copy number variations). Parasite infection was characterized by differential detection of tachyzoites and tissue cysts in induced neuronal cells. This approach may aid study of molecular mechanisms underlying individual predisposition to Toxoplasma infection linked to neuropathology of brain disorders. PMID- 26432950 TI - Establishment and validation of a 384-well antibacterial assay amenable for high throughput screening and combination testing. AB - A 384-well-based antibacterial assay amenable for high-throughput screening and combination testing is described. The assay uses 100-500nL of test compounds and tolerates up to 2.5% dimethyl sulfoxide concentrations. It can be used for screening compound libraries and testing combinatory/synergistic/antagonistic effects of antibiotics, small molecules, and natural product extracts. PMID- 26432949 TI - Recombinant expression, purification and preliminary biophysical and structural studies of C-terminal carbohydrate recognition domain from human galectin-4. AB - Galectin-4 (Gal4), a tandem-repeat type galectin, is expressed in healthy epithelium of the gastrointestinal tract. Altered levels of Gal4 expression are associated with different types of cancer, suggesting its usage as a diagnostic marker as well as target for drug development. The functional data available for this class of proteins suggest that the wide spectrum of cellular activities reported for Gal4 relies on distinct glycan specificity and structural characteristics of its two carbohydrate recognition domains. In the present work, two independent constructs for recombinant expression of the C-terminal domain of human galectin-4 (hGal4-CRD2) were developed. His6-tagged and untagged recombinant proteins were overexpressed in Escherichia coli, and purified by affinity chromatography followed by gel filtration. Correct folding and activity of hGal4-CRD2 were assessed by circular dichroism and fluorescence spectroscopies, respectively. Diffraction quality crystals were obtained by vapor diffusion sitting drop setup and the crystal structure of CRD2 was solved by molecular replacement techniques at 1.78 A resolution. Our work describes the development of important experimental tools that will allow further studies in order to correlate structure and binding properties of hGal4-CRD2 and human galectin-4 functional activities. PMID- 26432951 TI - Exenatide exerts a PKA-dependent positive inotropic effect in human atrial myocardium: GLP-1R mediated effects in human myocardium. AB - Glucagon-like peptide-1 receptor (GLP-1R) agonists are a rapidly growing class of drugs developed for treating type-2 diabetes mellitus. Patients with diabetes carry an up to 5-fold greater mortality risk compared to non-diabetic patients, mainly as a result of cardiovascular diseases. Although beneficial cardiovascular effects have been reported, exact mechanisms of GLP-1R-agonist action in the heart, especially in human myocardium, are poorly understood. The effects of GLP 1R-agonists (exenatide, GLP-1(7-36)NH2, PF-06446009, PF-06446667) on cardiac contractility were tested in non-failing atrial and ventricular trabeculae from 72 patients. The GLP-1(7-36)NH2 metabolite, GLP-1(9-36)NH2, was also examined. In electrically stimulated trabeculae, the effects of compounds on isometric force were measured in the absence and presence of pharmacological inhibitors of signal transduction pathways. The role of beta-arrestin signaling was examined using a beta-arrestin partial agonist, PF-06446667. Expression levels were tested by immunoblots. Translocation of GLP-1R downstream molecular targets, Epac2, GLUT-1 and GLUT-4, were assessed by fluorescence microscopy. All tested GLP-1R-agonists significantly increased developed force in human atrial trabeculae, whereas GLP 1(9-36)NH2 had no effect. Exendin(9-39)NH2, a GLP-1R-antagonist, and H-89 blunted the inotropic effect of exenatide. In addition, exenatide increased PKA-dependent phosphorylation of phospholamban (PLB), GLUT-1 and Epac2 translocation, but not GLUT-4 translocation. Exenatide failed to enhance contractility in ventricular myocardium. Quantitative real-time PCR (qRT-PCR) revealed a significant higher GLP-1R expression in the atrium compared to ventricle. Exenatide increased contractility in a dose-dependent manner via GLP-1R/cAMP/PKA pathway and induced GLUT-1 and Epac2 translocation in human atrial myocardium, but had no effect in ventricular myocardium. Therapeutic use of GLP-1R-agonists may therefore impart beneficial effects on myocardial function and remodelling. PMID- 26432952 TI - Early-life adversity and brain development: Is the microbiome a missing piece of the puzzle? AB - The prenatal and postnatal early-life periods are both dynamic and vulnerable windows for brain development. During these important neurodevelopmental phases, essential processes and structures are established. Exposure to adverse events that interfere with this critical sequence of events confers a high risk for the subsequent emergence of mental illness later in life. It is increasingly accepted that the gastrointestinal microbiota contributes substantially to shaping the development of the central nervous system. Conversely, several studies have shown that early-life events can also impact on this gut community. Due to the bidirectional communication between the gut and the brain, it is possible that aberrant situations affecting either organ in early life can impact on the other. Studies have now shown that deviations from the gold standard trajectory of gut microbiota establishment and development in early life can lead not only to disorders of the gastrointestinal tract but also complex metabolic and immune disorders. These are being extended to disorders of the central nervous system and understanding how the gut microbiome shapes brain and behavior during early life is an important new frontier in neuroscience. PMID- 26432953 TI - Bilateral retinal microglial response to unilateral optic nerve transection in rats. AB - When retinal ganglion cells undergo apoptosis after optic nerve (ON) injury, microglial cells proliferate and promptly clear the degenerated debris in the ipsilateral retina. However, microglial changes in the contralateral retina have not been fully elucidated. This study characterized the long-term bilateral retinal microglial responses after unilateral ON transection. We analyzed the time course of proliferation and morphology changes of microglial cells, between 3 days and 12 weeks post ON transection, of undisturbed and reactive microglia in bilateral retinas of adult Fischer rats with unilateral ON transection. Microglia in retinas without ON transection were distributed homogeneously and possessed a highly ramified morphology, as judged by immunohistochemistry for ionized calcium binding adapter molecule 1 (Iba1). After ON transection, microglia density in the ipsilateral retina increased gradually from 3 days to 2 weeks, and decreased from 3 weeks to 12 weeks, along with dramatic inverted alteration of process branch points of microglia in the ganglion cell layer (GCL). Transformation of ramified microglia into ameboid-like macrophages with few branching processes was observed in the ipsilateral retina from 1 week to 3 weeks. Though an increase in microglial density was weak in the contralateral retina and could only be statistically detected in the central retina, the morphological alteration over time was obvious and similar to that of the ipsilateral retina. In the inner plexiform layer (IPL), cell density and morphological changes of microglia in both the ipsilateral and contralateral retina were not prominent. These findings indicates that, though proliferation of microglial cells is weak in the contralateral retina after unilateral ON transection, conspicuous alterations in microglial morphology occur bilaterally. These suggest that using the contralateral retina as a control in studies of retinal degeneration should be considered with caution. PMID- 26432954 TI - Animal models for diabetes: Understanding the pathogenesis and finding new treatments. AB - Diabetes mellitus is a lifelong, metabolic disease that is characterised by an inability to maintain normal glucose homeostasis. There are several different forms of diabetes, however the two most common are Type 1 and Type 2 diabetes. Type 1 diabetes is caused by the autoimmune destruction of pancreatic beta cells and a subsequent lack of insulin production, whilst Type 2 diabetes is due to a combination of both insulin resistance and an inability of the beta cells to compensate adequately with increased insulin release. Animal models are increasingly being used to elucidate the mechanisms underlying both Type 1 and Type 2 diabetes as well as to identify and refine novel treatments. However, a wide range of different animal models are currently in use. The majority of these models are suited to addressing certain specific aspects of diabetes research, but may be of little use in other studies. All have pros and cons, and selecting an appropriate model for addressing a specific question is not always a trivial task and will influence the study results and their interpretation. Thus, as the number of available animal models increases it is important to consider the potential roles of these models in the many different aspects of diabetes research. This review gathers information on the currently used experimental animal models of both Type 1 and Type 2 diabetes and evaluates their advantages and disadvantages for research purposes and details the factors that should be taken into account in their use. PMID- 26432955 TI - How important is local food to organic-minded consumers? AB - The study deals with German consumers' attitudes towards organic food and local food, their food purchase behaviour and their personal characteristics. The purpose is to investigate the differences in attitudes and willingness-to-pay values between consumers who consider the organic production of food (very) important and those who consider it less important. This study combines a consumer survey with an in-store, discrete choice experiment. In the analysis, findings from the consumer survey were related to the choices made by consumers in the experiment. Consumers' preferences and willingness-to-pay values were estimated through random parameter logit modelling. Organic-minded consumers (i.e. those who regarded organic food production as (very) important in the survey) have stronger preferences and estimated willingness-to-pay values for organic as well as local products. Locally produced food, as opposed to food from neighbouring countries or non-EU countries, is preferred over organically produced food by both consumer groups which demonstrates that organic-minded consumers do not only consider organic food production as important, but also value local food production in a purchase situation. Hence, it can be assumed that local food production complements organic food production for the group of organic-minded consumers. This contribution is the first study dealing with local and organic food purchase behaviour in Germany that examines four different products and is carried out in rural as well as urban locations in four different regions. Due to the application of a choice experiment including no-choice options and binding purchase decisions, the results are expected to be closer to real purchase situations than results of direct questioning and choice experiments in online applications. PMID- 26432956 TI - Long-term smoking cessation and heart rate dynamics in an aging healthy cohort: Is it possible to fully recover? AB - AIM: To evaluate the long-term influence of smoking cessation on the regulation of the autonomic cardiovascular system in an aging general population, using the subpopulation of lifelong non-smokers as control group. METHODS: We analyzed 1481 participants aged >=50 years from the SAPALDIA cohort. In each participant, heart rate variability and heart rate dynamics were characterized by means of various quantitative analyzes of the inter-beat interval time series generated from 24 hour electrocardiogram recordings. Each parameter obtained was then used as the outcome variable in multivariable linear regression models in order to evaluate the association with smoking status and time elapsed since smoking cessation. The models were adjusted for known confounding factors and stratified by the time elapsed since smoking cessation. RESULTS: Our findings indicate that smoking triggers adverse changes in the regulation of the cardiovascular system, even at low levels of exposure since current light smokers exhibited significant changes as compared to lifelong non-smokers. Moreover, there was evidence for a dose response effect. Indeed, the changes observed in current heavy smokers were more marked as compared to current light smokers. Furthermore, full recovery was achieved in former smokers (i.e., normalization to the level of lifelong non smokers). However, while light smokers fully recovered within the 15 first years of cessation, heavy former smokers might need up to 15-25 years to fully recover. CONCLUSION: This study supports the substantial benefits of smoking cessation, but also warns of important long-term alterations caused by heavy smoking. PMID- 26432957 TI - Heme oxygenase-1, a novel target for the treatment of diabetic complications: focus on diabetic peripheral neuropathy. AB - Diabetic neuropathy is a complex disorder induced by long standing diabetes. Many signaling pathways and transcription factors have been proposed to be involved in the development and progression of related processes. Years of research points to critical role of oxidative stress, neuroinflammation and apoptosis in the pathogenesis of neuropathy in diabetes. Heme oxygenase-1 (HO-1) is heat-shock protein induced under conditions of different kinds of stress and has been implicated in cellular defense against oxidative stress. HO-1 degrades heme to biliverdin, carbon monoxide (CO) and free iron. Biliverdin and CO are gaining particular interest because these two have been found to mediate most of anti inflammatory, antioxidant and anti-apoptotic effects of HO-1. Although extensively studied in different kinds of cancers and cardiovascular conditions, role of HO-1 in diabetic neuropathy is still under investigation. In this paper, we review the unique therapeutic potential of HO-1 and its role in mitigating various pathological processes that lead to diabetic neuropathy. This review also highlights the therapeutic approaches such as pharmacological and natural inducers of HO-1, gene delivery of HO-1 or its reaction products that in future, could lead to progression of HO-1 activators through the preclinical stages of drug development to clinical trials. PMID- 26432958 TI - Reconstruction of the Nasoseptal L-Strut in Rhinoplasty. PMID- 26432959 TI - Binding studies of hydroxylated Multi-Walled Carbon Nanotubes to hemoglobin, gamma globulin and transferrin. AB - Biocompatibility of nanoparticles depends on their binding behavior with biomolecules. Herein, we have reported the interaction of three different biological macromolecules such as hemoglobin, gamma globulin and transferrin with hydroxyl group functionalized Multi-Walled Carbon Nanotubes (OH-MWCNTs). Multiple spectroscopic methods were utilized to identify the binding cum structural changes in biomolecules upon their interaction. Hyperchromic effect observed in the UV-visible spectra, and the quenching behavior from fluorescence emission evidences the existence of bio-nanotube complex formation. Synchronous and three dimensional fluorescence spectra of biomolecules, in correspondence with Trp and Tyr residues showed the possible disturbance towards their aromatic micro environment. Changes observed in the FTIR and FT-Raman amide bands, and amino acid residue position of biomolecules upon interaction with CNTs showed the possible effect towards their secondary structure. Further studies with CD spectroscopy indicated the loss of alpha-helical structures quantitatively. The study remains significant in evaluating the biosafety profile of functionalized MWCNTs for their in vivo biomedical applications. PMID- 26432960 TI - Palladium-Catalyzed Thioetherification of Quinolone Derivatives via Decarboxylative C-S Cross-Couplings. AB - A highly efficient and practical procedure for palladium-catalyzed direct thioetherification of quinolone derivatives with diaryl disulfides through decarboxylative C-S coupling has been established. The reaction could proceed smoothly under air in the presence of Pd(OAc)2 and Ag2 CO3 in DMSO. This protocol provides an appealing alternative to existing approaches to construct aryl sulfides of quinolone derivatives, which may be used as key intermediates in the synthesis of drug candidates. PMID- 26432961 TI - Robotic and Open Radical Prostatectomy: Celebrating Oncologic Equivalence. PMID- 26432962 TI - Legends in Urology. PMID- 26432963 TI - Epigenetics application in the diagnosis and treatment of bladder cancer. AB - INTRODUCTION: Bladder cancer is the sixth most common cancer in the Western world. Patients with bladder cancer require close monitoring, which may include frequent cystoscopy and urine cytology. Such monitoring results in significant health care cost. The application of epigenetics may allow for a risk adapted approach and more cost-effective method of monitoring. A number of epigenetic changes have been described for many cancer sites, including the urinary bladder. In this review, we discuss the use of epigenetics in bladder cancer and the potential diagnostic and therapeutic applications. MATERIALS AND METHODS: A comprehensive search of the English medical literature was conducted in PubMed using the terms microRNA regulation, DNA methylation, histone modification and bladder cancer. RESULTS: The most important epigenetic changes include DNA methylation, histone modification and microRNA regulation. Both DNA hypomethylation and hypermethylation have been associated with higher rate of cancer. The association of epigenetic changes with bladder cancer has led to the research of its diagnostic and prognostic implications as well as to the development of novel drugs to target these changes with the aim of achieving a survival benefit. CONCLUSIONS: Recently, epigenetics has been shown to play a much greater role than previously anticipated in the initiation and propagation of many tumors. The use of epigenetics for the diagnosis and treatment of bladder cancer is an evolving and promising field. The possibility of reversing epigenetic changes may facilitate additional cancer treatment options in the future. PMID- 26432964 TI - Validation of the lower urinary tract symptom score. AB - INTRODUCTION: To develop and validate a lower urinary tract symptom score (LUTSS) as a measure of lower urinary tract symptom (LUTS) severity and a treatment outcome tool in adults. MATERIALS AND METHODS: An expert panel was convened to develop the LUTSS questionnaire. Content validity was achieved by obtaining subject and expert feedback from two prospective drafts. Subjects were divided into three groups: normal, LUTS and overactive bladder (OAB). Questionnaire was administered on two separate occasions within 1-2 weeks. Test-retest reliability, internal consistency, discriminant validity, criterion validity and responsiveness to change were also assessed. RESULTS: The questionnaire contains 14 questions with answers scored on a 5-point Likert scale (0-4). It includes 9 storage, 4 voiding and 1 bother question. One hundred ninety-one patients completed it; 80 males and 111 females, mean age 65 years (range 22-91). Seventy two had OAB, 91 LUTS without OAB and 28 were normal. Test-retest intraclass correlation was 0.96 and Cronbach's-? was 0.77, indicating strong test-retest reliability and internal consistency, respectively. ANOVA and post-hoc bootstrap generated adjustments showed significant differences between the three groups (p < 0.001), demonstrating discriminant validity. Responsiveness to change was exhibited by the significant decrease between preop and postop scores and a concurrent patient global impression of improvement (PGI-I) score indicative of symptomatic improvement. CONCLUSION: The 14-question LUTSS is a validated questionnaire that assesses a full range of LUTS in men and women. The ordinal nature of the data with its highly specific description of symptoms makes it ideally suited as a nuanced and comprehensive symptom score and patient reported outcome (PRO) tool. PMID- 26432965 TI - Impact of remote monitoring and supervision on resident training using new ACGME milestone criteria. AB - INTRODUCTION: The study objective was to determine the impact of remote monitoring and supervision (RMS) in integrated endourology suites (IES) on residents achieving endoscopic training milestones. MATERIALS AND METHODS: Twenty one urology residents evaluated RMS in IES using a 25-question survey. IES provided audio-visual communication for faculty to supervise residents remotely. Questionnaire used a linear visual scale of 1-10 to assess acceptability (8 questions), impact on training (10 questions), supervision level (1 question), and pre- and post-training milestone self-assessments (6 questions). Improvements in Patient Care Milestone #7 (upper/lower tract endoscopic procedures) and Patient Care Milestone #9 (office-based procedures) were analyzed. RESULTS: Twenty-one urology residents (out of potential 23) evaluated RMS in IES using a 25-question survey (91.3% response rate). Overall RMS acceptability and satisfaction was high (mean score = 9.1/10) with a majority (95.2%) feeling comfortable being alone with the patient. Residents reported positively on the following parameters: autonomy without compromising safety (8.7), supervision level (8.6), achieving independence (8.4), education quality (8.3), learning rate (8.1), clinical decision-making (8.0), and reducing case numbers to achieve proficiency (7.6). Residents perceived no issues with under- or over-supervision, and a majority (76.2%) expressed that RMS should be standard of training in residency programs. Residents reported mean level increases of 2.5 and 2.8 (out of 5) in Patient Care Milestones for endoscopic procedures and office-based procedures, respectively (p < 0.0001). CONCLUSIONS: RMS in integrated endourology suites may enhance resident education and endoscopic training. The study demonstrated an increase in competency levels reported by residents trained using RMS. PMID- 26432966 TI - Association of quantitative magnetic resonance imaging parameters with histological findings from MRI/ultrasound fusion prostate biopsy. AB - INTRODUCTION: Purpose of this pilot study was to correlate quantitative parameters derived from the multiparametric magnetic resonance imaging (MP-MRI) of the prostate with results from MRI guided transrectal ultrasound (MRI/TRUS) fusion prostate biopsy in men with suspected prostate cancer. MATERIALS AND METHODS: Thirty-nine consecutive patients who had 3.0T MP-MRI and subsequent MRI/TRUS fusion prostate biopsy were included and 73 MRI-identified targets were sampled by 177 cores. The pre-biopsy MP-MRI consisted of T2-weighted, diffusion weighted (DWI), and dynamic contrast enhanced (DCE) images. The association of quantitative MRI measurements with biopsy histopathology findings was assessed by Mann-Whitney U- test and Kruskal-Wallis test. RESULTS: Of 73 targets, biopsy showed benign prostate tissue in 46 (63%), cancer in 23 (31.5%), and atypia/high grade prostatic intraepithelial neoplasia in four (5.5%) targets. The median volume of cancer-positive targets was 1.3 cm3. The cancer-positive targets were located in the peripheral zone (56.5%), transition zone (39.1%), and seminal vesicle (4.3%). Nine of 23 (39.1%) cancer-positive targets were higher grade cancer (Gleason grade > 6). Higher grade targets and cancer-positive targets compared to benign lesions exhibited lower mean apparent diffusion coefficient (ADC) value (952.7 < 1167.9 < 1278.9), and lower minimal extracellular volume fraction (ECF) (0.13 < 0.185 < 0.213), respectively. The difference in parameters was more pronounced between higher grade cancer and benign lesions. CONCLUSIONS: Our findings from a pilot study indicate that quantitative MRI parameters can predict malignant histology on MRI/TRUS fusion prostate biopsy, which is a valuable technique to ensure adequate sampling of MRI-visible suspicious lesions under TRUS guidance and may impact patient management. The DWI-based quantitative measurement exhibits a stronger association with biopsy findings than the other MRI parameters. PMID- 26432967 TI - Selling blood and gametes during tough economic times: insights from Google search. AB - INTRODUCTION: To use Google Insights search volume and publicly available economic indicators to test the hypothesis that sperm, egg, and blood donations increase during economic downturns and to demonstrate the feasibility of using Google search volume data to predict national trends in actual sperm, egg, and blood donations rates. MATERIALS AND METHODS: Cross-correlation statistical analysis comparing Google search data for terms relating to blood, egg, and sperm donations with various economic indicators including the S&P 500 closing values, gross domestic product (GDP), the U.S. Index of Leading Indicators (U.S. Leading Index), gross savings rate, mortgage interest rates, unemployment rate, and consumer price index (CPI) from 2004-2011. A secondary analysis determined the Pearson correlation coefficient between Google search data with actual sperm, egg, and blood donation volume in the U.S. as measured by California Cryobank, the National Assisted Reproductive Technology Surveillance System, and the National Blood Collection and Utilization Survey, respectively. Significance of cross-correlation and Pearson correlation analysis as indicated by p value. RESULTS: There were several highly significant cross-correlation relationships between search volume and various economic indicators. Correlation between Google search volume for the term 'sperm donation,' 'egg donation,' and 'blood donation' with actual number of sperm, egg and blood donations in the United States demonstrated Pearson correlation coefficients of 0.2 (p > 0.10), -0.1 (p > 0.10), and 0.07 (p > 0.10), respectively. Temporal analysis showed an improved correlation coefficient of 0.9 (p < 0.05) for blood donation when shifted 12 months later relative to Google search volume. CONCLUSION: Google search volume data for search terms relating to sperm, egg, and blood donation increase during economic downturns. This finding suggests gamete and bodily fluid donations are influenced by market forces like other commodities. Google search may be useful for predicting blood donation trends but is more limited in predicting actual semen and oocyte donation patterns. PMID- 26432968 TI - Renal track creation for percutaneous nephrolithotomy: the history and relevance of single stage dilation. AB - INTRODUCTION: Percutaneous nephrolithotomy (PCNL) was described in the 1980s and revolutionized the treatment of stone disease. The crucial component to this surgery is satisfactory track creation. We examine how the development and production in the 1980s of a single stage dilator (SSD) subsequently modified for pediatric PCNL has become the ideal access tool for mini percutaneous nephrolithotomy (mPCNL) today. MATERIALS AND METHODS: The conception, production, scientific and clinical development of the original SSD is described. The pitfalls of track dilation in general according to method of dilation are also discussed and outlined. RESULTS: This study provides evidence clarifying commonly held misconceptions about the origin of SSD which is the mainstay of the mPCNL technique. CONCLUSIONS: Percutaneous renal surgery continues to evolve. In less than 40 years stone surgery has transformed from a morbid open operation to a number of minimally invasive, routine techniques. The SSD has been an innovation that has played a crucial role in this change. PMID- 26432969 TI - Aspirin and clopidogrel during robotic partial nephrectomy, is it safe? AB - INTRODUCTION: Continuation of antiplatelet medications through major urologic surgery may increase the risk of intraoperative and postoperative bleeding complications. However, withdrawal of antiplatelet therapy may place some patients at high risk of serious cardiovascular or cerebrovascular complications. We assess the feasibility of performing robotic partial nephrectomy (RPN) in patients maintained on aspirin or dual antiplatelet therapy with aspirin and clopidogrel. MATERIAL AND METHODS: Perioperative data was collected prospectively on 230 subjects undergoing RPN enrolled in an IRB approved quality of life study. We analyzed subjects who were maintained on either aspirin alone or both aspirin and clopidogrel throughout the operative and perioperative period. RESULTS: Of the 230 patients, six were identified who continued antiplatelet medication throughout the perioperative period. Four patients were maintained on 81 mg of aspirin and two patients continued aspirin and clopidogrel. Average RENAL score was 7 with mean tumor size of 4.1 cm. There were no intraoperative complications and no conversions to open surgery. Average estimated blood loss was 242 mL. Ninety day complication rate was 33%. One patient had postoperative bleeding on day 14 after restarting coumadin in addition to their aspirin. CONCLUSIONS: We present a case series demonstrating that in carefully selected patients, RPN on aspirin and clopidogrel is feasible and safe. This is the first report of patients who underwent RPN while on both aspirin and clopidogrel. PMID- 26432970 TI - Safety of perioperative subcutaneous heparin for partial nephrectomy. AB - INTRODUCTION: The development of deep venous thrombosis (DVT) or pulmonary embolism (PE) following urologic surgery is a life threatening, but largely preventable complication. Patients undergoing partial nephrectomy are at increased risk for the development of DVT or PE as they often possess multiple risk factors including malignancy, advanced age, and prolonged surgical time. This risk can be significantly reduced by administration of perioperative subcutaneous heparin (SQH), however many surgeons feel this is contraindicated due to potential blood loss and related complications. MATERIALS AND METHODS: The medical records of 293 consecutive patients undergoing planned open, laparoscopic, or robotic assisted partial nephrectomy by a single surgeon over a 7 year period were reviewed. Approximately halfway through the period, the standard DVT prevention practice was changed from sequential compression stockings and early ambulation to include 5000 units of SQH administered 30-60 minutes prior to incision and continuing every 8 hours until discharge. RESULTS: A total of 158 patients received perioperative SQH. There was no significant difference in surgical blood loss, transfusions, operative time, change in pre to postoperative hemoglobin or creatinine, conversion to radical nephrectomy, or duration of stay between the groups. There were no DVTs in either group. There was one PE in the group receiving SQH which was incidentally discovered. CONCLUSIONS: Patients undergoing renal surgery for cancer are at increased risk for the development of DVT and PE. Prophylaxis against this serious complication with perioperative SQH is safe in patients undergoing partial nephrectomy despite common surgeon concerns regarding blood loss and related complications. PMID- 26432971 TI - Pediatric sutureless circumcision: an effective and cost efficient alternative. AB - INTRODUCTION: Circumcision is the most commonly performed surgical procedures in male children. Maine is one of 18 states in the United States which does not pay for neonatal circumcisions. The aim of this study was to perform outcomes and cost analysis of a sutureless circumcision technique versus circumcision using sutures. Specifically, we evaluated Dermaflex (2-octyl cyanoacrylate, 2-OCA) surgical glue circumcision as a cost effective, faster, and safe alternative to traditional suture circumcision. MATERIALS AND METHODS: Our study was a non randomized series. We collected the operative details prospectively, abstracted clinical outcomes retrospectively, and performed data analysis retrospectively. One hundred and twenty-six circumcisions were performed by two pediatric urologists over a 1 year period. Suture circumcisions were performed exclusively during the first 6 months, and 2-OCA glue circumcisions were performed during the second 6 months. Billing charges were analyzed to extrapolate variable costs between the two surgical procedures. The technique used to perform the sutureless circumcision was a modification of the standard sleeve technique, with the use of monopolar diathermy instead of scalpel, and application of 2-OCA glue to approximate tissue edges. RESULTS: From Jan 2013 to Jan 2014, 72 patients underwent circumcision with suture, and 54 patients underwent circumcision with 2 OCA glue. Mean age in the glue group was 61 months (range 8-202 months), and 50 months in the suture group (range 5-215 months), p = 0.19. All cases were performed under general anesthesia, as outpatient surgery. Mean operative cut time was 18.4 min for the glue group, and 28.6 min for the suture group (p < 0.01). The 10.2 min operative time difference translated to a $378 cost savings per glue circumcision case. Complication rates were not statistically significant between the two groups. CONCLUSION: The use of 2-OCA tissue adhesive for sutureless circumcision is an alternative to the standard technique. It results in faster operative times, with a significant cost savings, while maintaining comparable complication rates to the standard suture technique. This is a viable, less expensive surgical option for patients whose circumcisions are not covered by Medicaid. PMID- 26432972 TI - Retropubic prostatectomy for giant benign prostatic hyperplasia. AB - Giant benign prostatic hyperplasia is a rare pathology of the prostate gland. Here we report the successful removal of the ninth largest prostate ever reported. This 65-year-old patient presented with acute urinary retention secondary to a bulky left prostatic mass identified on pelvic magnetic resonance imaging (MRI). His preoperative prostate-specific antigen (PSA) value was 44 ng/mL; preoperative biopsies were negative for malignancy. Open radical retropubic prostatectomy was performed and the resulting prostatic mass was measured at 13.5 cm x 11.5 cm x 5.2 cm, weighing 708 g including the prostate. The patient tolerated the procedure well. Surgical pathology showed no evidence of malignancy. PMID- 26432973 TI - Not all penile cancers are created equal. AB - Warty carcinoma variant of squamous cell carcinoma of the penis is a rare condition, making up 7% to 10% of all penile carcinomas. We present a case of warty carcinoma variant of squamous cell carcinoma of the penis in a 43-year-old Caucasian. The tumor presented in a locally invasive manner, requiring a total penectomy. The primary lesion measured over 15 cm x 16 cm, covering the entire perineum. The clinical features, diagnosis, surgical treatment and pathology are reviewed. In light of the locally invasive nature of warty carcinoma of the penis and high recurrence rate, early diagnosis and aggressive treatment is necessary for this type of unique penile cancer. PMID- 26432974 TI - Multiple intra-renal artery aneurysms causing renal obstruction managed with radical nephrectomy. AB - A 46-year-old male with a history of hypertension presented with symptoms of persistent abdominal fullness and a non-pulsatile abdominal mass. Subsequent computed tomographic angiography studies revealed the presence multiple large renal aneurysms from the segmental branches of the renal artery and an enlarged hydronephrotic kidney with minimal parenchyma. The renal deterioration appeared to be as a result of an obstruction caused by the large intra-renal aneurysms at the level of the renal calyces. Since the right kidney had no function, an open radical nephrectomy was subsequently performed without complications at 3 months follow up. PMID- 26432975 TI - BK virus associated pronounced hemorrhagic cystoureteritis after bone marrow transplantation. AB - Ureteral stenosis due to reactivation of the BK virus (BKV) in a state of immunodeficiency is very rare. More common is the appearance of a hemorrhagic cystitis. This report not only shows bilateral ureteral stenosis after bone marrow transplantation, but also presents severe complications as chronic pelvic pain and impaired kidney function as well as irreparable damage to the whole urinary tract leading to nephroureterectomy, subtrigonal cystectomy and orthotopic ileal neobladder. Finally renal transplantation was required. To our knowledge this is the first case in the literature where such a severe course of BKV associated hemorrhagic cystoureteritis is described. PMID- 26432976 TI - Abstracts of the Mid-Atlantic and New England Sections of the American Urological Association Joint Annual Meeting. October 22-24, 2015, Paradise Island, Bahamas. PMID- 26432977 TI - Effect of Controlled Deposition of ZnS Shell on the Photostability of CdTe Quantum Dots as Studied by Conventional Fluorescence and FCS Techniques. AB - The effect of one and two monolayers of ZnS shells on the photostability of CdTe quantum dots (QDs) in aqueous and nonaqueous media has been studied by monitoring the fluorescence behavior of the QDs under ensemble and single-molecule conditions. ZnS capping of the CdTe QDs leads to significant enhancement of the fluorescence brightness of these QDs. Considerable enhancement of the photostability of the shell-protected QDs, including the suppression of photoactivation, is also observed. Fluorescence correlation spectroscopy measurements reveal an increase in the number of particles undergoing reversible fluorescent on-off transitions in the volume under observation with increasing excitation power; this effect is found to be more pronounced in the case of core only QDs than for core-shell QDs. PMID- 26432979 TI - Increasing severity of traumatic brain injury in early childhood is associated with a progressive reduction in long-term serum thyroid-stimulating hormone concentrations. PMID- 26432978 TI - Finding the gap: revealing local disparities in coverage of maternal, newborn and child health services in South Sudan using lot quality assurance sampling. AB - OBJECTIVES: We adapted a rapid monitoring method to South Sudan, a new nation with one of the world's highest maternal and child mortality rates, aiming to assess coverage of maternal, neonatal and child health (MNCH) services at the time of independence, and introducing a monitoring and evaluation system (M&E) for equity-sensitive tracking of progress related to Millennium Development Goals (MDG) 4 and 5 at national, state and county levels to detect local variability. METHODS: We conducted a national cross-sectional household survey among women from six client populations in all, but six of South Sudan's 79 counties. We used lot quality assurance sampling (LQAS) to measure coverage with diverse MNCH indicators to obtain information for national-, state- and county-level health system management decision-making. RESULTS: National coverage of MNCH services was low for all maternal and neonatal care, child immunisation, and child care indicators. However, results varied across states and counties. Central Equatoria State (CES), where the capital is located, showed the highest coverage for most indicators (e.g. >=4 antenatal care visits range: 4.5% in Jonglei to 40.1% in CES). Urban counties often outperformed rural ones. CONCLUSIONS: This adaptation of LQAS to South Sudan demonstrates how it can be used in the future as an M&E system to track progress of MDGs at national, state and county levels to detect local disparities. Overall, our data reveal a desperate need for improving MNCH service coverage in all states. PMID- 26432980 TI - Aldehyde-modified proteins as mediators of early inflammation in atherosclerotic disease. AB - Inflammation is widely accepted to play a major role in atherosclerosis and other cardiovascular diseases. However, the exact mechanism(s) by which inflammation exerts its pathogenic effect remains poorly understood. A number of oxidatively modified proteins have been associated with cardiovascular disease. Recently, attention has been given to the oxidative compound of malondialdehyde and acetaldehyde, two reactive aldehydes known to covalently bind and adduct macromolecules. These products have been shown to form stable malondialdehyde acetaldehyde (MAA) adducts that are reactive and induce immune responses. These adducts have been found in inflamed and diseased cardiovascular tissue of patients. Antibodies to these adducted proteins are measurable in the serum of diseased patients. The isotypes involved in the immune response to MAA (i.e., IgM, IgG, and IgA) are predictive of atherosclerotic disease progression and cardiovascular events such as an acute myocardial infarction or coronary artery bypass grafting. Therefore, it is the purpose of this article to review the past and current knowledge of aldehyde-modified proteins and their role in cardiovascular disease. PMID- 26432981 TI - Osthol attenuates neutrophilic oxidative stress and hemorrhagic shock-induced lung injury via inhibition of phosphodiesterase 4. AB - Oxidative stress caused by neutrophils is an important pathogenic factor in trauma/hemorrhagic (T/H)-induced acute lung injury (ALI). Osthol, a natural coumarin found in traditional medicinal plants, has therapeutic potential in various diseases. However, the pharmacological effects of osthol in human neutrophils and its molecular mechanism of action remain elusive. In this study, our data showed that osthol potently inhibited the production of superoxide anion (O2(*-)) and reactive oxidants derived therefrom as well as expression of CD11b in N-formylmethionylleucylphenylalanine (FMLP)-activated human neutrophils. However, osthol inhibited neutrophil degranulation only slightly and it failed to inhibit the activity of subcellular NADPH oxidase. FMLP-induced phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) was inhibited by osthol. Notably, osthol increased the cAMP concentration and protein kinase A (PKA) activity in activated neutrophils. PKA inhibitors reversed the inhibitory effects of osthol, suggesting that these are mediated through cAMP/PKA dependent inhibition of ERK and Akt activation. Furthermore, the activity of cAMP specific phosphodiesterase (PDE) 4, but not PDE3 or PDE7, was significantly reduced by osthol. In addition, osthol reduced myeloperoxidase activity and pulmonary edema in rats subjected to T/H shock. In conclusion, our data suggest that osthol has effective anti-inflammatory activity in human neutrophils through the suppression of PDE4 and protects significantly against T/H shock-induced ALI in rats. Osthol may have potential for future clinical application as a novel adjunct therapy to treat lung inflammation caused by adverse circulatory conditions. PMID- 26432983 TI - Symptoms of anxiety and depression in school-aged children with active epilepsy: A population-based study. AB - METHODS: Children (5-15 years) with active epilepsy were screened using the parent-report (n=69) and self-report (n=48) versions of the Spence Children's Anxiety Scale (SCAS) and the self-report version of the Children's Depression Inventory (CDI) (n=48) in a population-based sample. RESULTS: A total of 32.2% of children (self-report) and 15.2% of children (parent-report) scored >=1 SD above the mean on the SCAS total score. The subscales where most difficulty were reported on parent-report were Physical Injury and Separation Anxiety. There was less variation on self-report. On the CDI, 20.9% of young people scored >=1 SD above the mean. Children reported significantly more symptoms of anxiety on the SCAS total score and three of the subscales (p<.05). There was a significant effect on the SCAS total score of respondents by seizure type interaction, suggesting higher scores on SCAS for children with generalized seizures on self- but not parent-report. Higher CDI scores were significantly associated with generalized seizures (p>.05). SUMMARY: Symptoms of anxiety were more common based on self-report compared with parent-report. Children with generalized seizures reported more symptoms of depression and anxiety. PMID- 26432982 TI - Molecular weaponry: diverse effectors delivered by the Type VI secretion system. AB - The Type VI secretion system is a widespread bacterial nanomachine, used to deliver toxins directly into eukaryotic or prokaryotic target cells. These secreted toxins, or effectors, act on diverse cellular targets, and their action provides the attacking bacterial cell with a significant fitness advantage, either against rival bacteria or eukaryotic host organisms. In this review, we discuss the delivery of diverse effectors by the Type VI secretion system, the modes of action of the so-called 'anti-bacterial' and 'anti-eukaryotic' effectors, the mechanism of self-resistance against anti-bacterial effectors and the evolutionary implications of horizontal transfer of Type VI secretion system associated toxins. Whilst it is likely that many more effectors remain to be identified, it is already clear that toxins delivered by this secretion system represent efficient weapons against both bacteria and eukaryotes. PMID- 26432985 TI - Lateral wedge insoles for people with medial knee osteoarthritis: one size fits all, some or none? PMID- 26432984 TI - The relationship between smoking and knee osteoarthritis in the Osteoarthritis Initiative. AB - OBJECTIVE: To estimate the extent that smoking history is associated with symptoms and disease progression among individuals with radiographically confirmed knee Osteoarthritis (OA). METHOD: Both cross-sectional (baseline) and longitudinal studies employed data from the Osteoarthritis Initiative (OAI) (n = 2250 participants). Smoking history was assessed at baseline with 44% current or former smokers. The Western Ontario and McMaster Universities Arthritis Index (WOMAC) was used to measure knee pain, stiffness, and physical function. Disease progression was measured using joint space width (JSW). We used adjusted multivariable linear models to examine the relationship between smoking status and exposure in pack years (PY) with symptoms and JSW at baseline. Changes in symptoms and JSW over time were further assessed. RESULTS: In cross-sectional analyses, compared to never-smokers high PY (>=15 PY) was associated with slightly greater pain (beta 0.36, 95% CI: 0.01-0.71) and stiffness (beta 0.20, 95% CI: 0.03-0.37); and low PY (<15 PY) was associated with better JSW (beta 0.15, 95% CI: 0.02-0.28). Current smoking was associated with greater pain (beta 0.59, 95% CI: 0.04-1.15) compared to never-smokers. These associations were not confirmed in the longitudinal study. Longitudinally, no associations were found between high or low PY or baseline smoking status with changes in symptoms (at 72 months) or JSW (at 48 months). CONCLUSION: Cross-sectional findings are likely due residual confounding. The more robust longitudinal analysis found no associations between smoking status and symptoms or JSW. Long-term smoking provides no benefits to knee OA patients while exposing them to other well documented serious health risks. PMID- 26432986 TI - Primary care physicians' perceptions about and confidence in deciding which patients to refer for total joint arthroplasty of the hip and knee. AB - OBJECTIVE: The purpose of this study is to examine the perceptions of primary care physicians (PCPs) regarding indications, contraindications, risks and benefits of total joint arthroplasty (TJA) and their confidence in selecting patients for referral for TJA. DESIGN: PCPs recruited from among those providing care to participants in an established community cohort with hip or knee osteoarthritis (OA). Self-completed questionnaires were used to collect demographic and practice characteristics and perceptions about TJA. Confidence in referring appropriate patients for TJA was measured on a scale from 1 to 10; respondents scoring in the lowest tertile were considered to have 'low confidence'. Descriptive analyses were conducted and multiple logistic regression was used to determine key predictors of low confidence. RESULTS: 212 PCPs participated (58% response rate) (65% aged 50+ years, 45% female, 77% >15 years of practice). Perceptions about TJA were highly variable but on average, PCPs perceived that a typical surgical candidate would have moderate pain and disability, identified few absolute contraindications to TJA, and overestimated both the effectiveness and risks of TJA. On average, PCPs indicated moderate confidence in deciding who to refer. Independent predictors of low confidence were female physicians (OR = 2.18, 95% confidence interval (CI): 1.06-4.46) and reporting a 'lack of clarity about surgical indications' (OR = 3.54, 95% CI: 1.87 6.66). CONCLUSIONS: Variability in perceptions and lack of clarity about surgical indications underscore the need for decision support tools to inform PCP - patient decision making regarding referral for TJA. PMID- 26432987 TI - Focused electron beam induced deposition as a tool to create electron vortices. AB - Focused electron beam induced deposition (FEBID) is a microscopic technique that allows geometrically controlled material deposition with very high spatial resolution. This technique was used to create a spiral aperture capable of generating electron vortex beams in a transmission electron microscope (TEM). The vortex was then fully characterized using different TEM techniques, estimating the average orbital angular momentum to be ~0.8h per electron with almost 60% of the beam ending up in the l=1 state. PMID- 26432988 TI - Phosphoenolpyruvate carboxykinase and gluconeogenesis in grape pericarp. AB - Glycolysis from sugars is necessary at all stages of development of grape pericarp, and this raises the question as to why gluconeogenesis from malate occurs. Phosphoenolpyruvate carboxykinase (PEPCK) is required for gluconeogenesis in grape pericarp. In this study we determined the abundance of PEPCK protein and activity in different parts of grape pericarp during its development. Both PEPCK protein and activity were present throughout development, however, in both the skin and the flesh their abundance increased greatly at the start of ripening. This coincided with the onset of the decrease in the malate content of the berry. The location of PEPCK in the pericarp at different stages of development was determined using both immunohistochemistry and dissection. We provide a possible explanation for the occurrence of gluconeogenesis in grape pericarp. PMID- 26432989 TI - Fast detection of both O157 and non-O157 shiga-toxin producing Escherichia coli by real-time optical immunoassay. AB - Among bacterial pathogens involved in food-illnesses, seven serogroups (O26, O45, O103, O111, O121, O145 and O157) of Shiga-toxin producing Escherichia coli (STEC), are frequently identified. During such outbreak, and due to the perishable property of most foodstuff, the time laps for the identification of contaminated products and pathogens is thus critical to better circumvent their spread. Traditional detection methods using PCR or culture plating are time consuming and may present some limitations. In this study, we present a multiplexed immunoassay for the optical detection of most commonly enterohemorrhagic E. coli serogroups: O26, O45, O103, O111, O121, O145 and O157:H7 in a single device. The use of Surface Plasmon Resonance imaging not only enabled the label-free analysis of the samples but gave results in a real-time manner. A dedicated protocol was set up for the detection of both low contaminating bacterial concentrations of food samples (5 CFU per 25 g) and postenrichment aliquots. By combining one single device for the detection of O157 and non-O157 STEC in a label-free manner, this rapid approach may have an important economic and societal impact. SIGNIFICANCE AND IMPACT OF THE STUDY: This article presents a simple-to-operate immunoassay for the specific detection of Shiga-toxin producing Escherichia coli (STEC). This approach consists in the on-chip assay detection of viable cells on a specifically designed antibody microarray. By skipping any enrichment step and avoiding the use of labelling agent, this approach based on the Surface Plasmon Resonance imaging of the microarrays turns out to be much faster and more cost effective by comparison with standardized methods. PMID- 26432990 TI - Single and cartel effect of pesticides on biochemical and haematological status of Clarias batrachus: A long-term monitoring. AB - Pesticide mixtures are common in the streams of agricultural or urban catchments. Individual and cartel toxicity of four different pesticides, namely Endosulfan, Carbofuran, Methyl parathion and Cypermethrin were studied. Sub acute exposure (1/10th of LC50) for 1, 7, 15, 30 and 60 days in Clarias batrachus active tissues such as brain, gills, blood and liver were evaluated. Growth, hepatosomatic index and survival performance were decreased, inhibition of brain acetylcholinesterase, gills Na(+)/K(+) ATPase activities, and abnormal behavior are noticed. The characteristics of the blood respiratory burst activity, erythrocyte count, contents of hematocrit and hemoglobin are dwindled. Plasma total proteins and liver glycogen decreased whereas blood glucose and serum creatinine, triglycerides are elevated. The immunological attributes such as white blood cell count was elevated, whereas albumin, globulins and lysozyme activity significantly decreased. Hepatic superoxide dismutase, catalase and glutathione S-transferase activities and lipid peroxidation levels are elevated, whereas glutathione peroxidase and glutathione are reduced. Toxicity effect of pesticides reached to a crest on 30th day and showed a descent thereafter except in endosulfan which mounted its detrimental effect throughout the experimental period. Toxicity trends of the present study are determined to be highest in Mix group followed by cypermethrin, methyl parathion and carbofuran. Indiscriminate application of these chemicals pose a toxic threat to non-target organisms, damage the ecosystems and jeopardizes human health. PMID- 26432991 TI - What are the differences in driver injury outcomes at highway-rail grade crossings? Untangling the role of pre-crash behaviors. AB - Crashes at highway-rail grade crossings can result in severe injuries and fatalities to vehicle occupants. Using a crash database from the Federal Railroad Administration (N=15,639 for 2004-2013), this study explores differences in safety outcomes from crashes between passive controls (Crossbucks and STOP signs) and active controls (flashing lights, gates, audible warnings and highway signals). To address missing data, an imputation model is developed, creating a complete dataset for estimation. Path analysis is used to quantify the direct and indirect associations of passive and active controls with pre-crash behaviors and crash outcomes in terms of injury severity. The framework untangles direct and indirect associations of controls by estimating two models, one for pre-crash driving behaviors (e.g., driving around active controls), and another model for injury severity. The results show that while the presence of gates is not directly associated with injury severity, the indirect effect through stopping behavior is statistically significant (95% confidence level) and substantial. Drivers are more likely to stop at gates that also have flashing lights and audible warnings, and stopping at gates is associated with lower injury severity. This indirect association lowers the chances of injury by 16%, compared with crashes at crossings without gates. Similar relationships between other controls and injury severity are explored. Generally, crashes occurring at active controls are less severe than crashes at passive controls. The results of study can be used to modify Crash Modification Factors (CMFs) to account for crash injury severity. The study contributes to enhancing the understanding of safety by incorporating pre-crash behaviors in a broader framework that quantifies correlates of crash injury severity at active and passive crossings. PMID- 26432992 TI - Screening and modular design for metabolic pathway optimization. AB - Biological conversion of substrate sugars to a variety of products is an increasingly popular option for chemical transformation due to its high specificity and because of significant interest in the use of renewable feedstocks. However, pathway optimization through metabolic engineering is often needed to make such molecules economically at a relevant scale. Employing effective methods to search and narrow the immense pathway parameter space is essential to meet performance metrics such as high titer, yield and productivity with efficiency. This review focuses on two practices that increase the likelihood of finding a more advantageous pathway solution: implementing a screen to identify high producers and utilizing modular pathway design to streamline engineering efforts. While screens seek to couple product titer with a high throughput measurement output, modular design aims to rationally construct pathways to allow parallel optimization of various units. Both of these methodologies have proven widely successful in metabolic engineering, with combinations of them resulting in synergistic enhancements to pathway optimization. This review will particularly highlight their utility for microbially derived acid and alcohol products, which are of interest as fuels and value added products. PMID- 26432993 TI - Antioxidant treatment ameliorates experimental diabetes-induced depressive-like behaviour and reduces oxidative stress in brain and pancreas. AB - Studies have shown a relationship between diabetes mellitus (DM) and the development of major depressive disorder. Alterations in oxidative stress are associated with the pathophysiology of both diabetes mellitus and major depressive disorder. This study aimed to evaluate the effects of antioxidants N acetylcysteine and deferoxamine on behaviour and oxidative stress parameters in diabetic rats. To this aim, after induction of diabetes by a single dose of alloxan, Wistar rats were treated with N-acetylcysteine or deferoxamine for 14 days, and then depressive-like behaviour was evaluated. Oxidative stress parameters were assessed in the prefrontal cortex, hippocampus, amygdala, nucleus accumbens and pancreas. Diabetic rats displayed depressive-like behaviour, and treatment with N-acetylcysteine reversed this alteration. Carbonyl protein levels were increased in the prefrontal cortex, hippocampus and pancreas of diabetic rats, and both N-acetylcysteine and deferoxamine reversed these alterations. Lipid damage was increased in the prefrontal cortex, hippocampus, amygdala and pancreas; however, treatment with N-acetylcysteine or deferoxamine reversed lipid damage only in the hippocampus and pancreas. Superoxide dismutase activity was decreased in the amygdala, nucleus accumbens and pancreas of diabetic rats. In diabetic rats, there was a decrease in catalase enzyme activity in the prefrontal cortex, amygdala, nucleus accumbens and pancreas, but an increase in the hippocampus. Treatment with antioxidants did not have an effect on the activity of antioxidant enzymes. In conclusion, animal model of diabetes produced depressive-like behaviour and oxidative stress in the brain and periphery. Treatment with antioxidants could be a viable alternative to treat behavioural and biochemical alterations induced by diabetes. PMID- 26432994 TI - Correlation of diffusion tensor and dynamic susceptibility contrast MRI with DNA ploidy and cell cycle analysis of gliomas. AB - OBJECTIVES: Flow cytometry provides a powerful tool to assess cells in G0/G1, S and G2/M phase and ploidy. The purpose of the present study was to investigate the correlation between diffusion tensor (DTI) and dynamic susceptibility contrast (DSC) MRI metrics with cell cycle analysis findings in gliomas. PATIENTS AND METHODS: We studied thirty patients who were operated on for glioma. DTI and DSC MRI were performed within a week prior to surgical excision. Lesion/normal ratios were calculated for the ADC, FA and rCBV. In an excised tumour sample flow cytometric analysis was performed. RESULTS: There were 24 glioblastomas, 2 anaplastic astrocytomas, 1 oligoastrocytoma and 3 diffuse astrocytomas. There were significant differences between low and high-grade gliomas for rCBV and ADC values. Low grade tumours had higher G0/G1 phase fraction and lower S-phase, G2/M, S+G2/M and S+G2/M/G0/G1 fractions There was a significant negative correlation between rCBV and G0/G1 phase fraction and a positive correlation with G2/M, S+G2/M and the S+G2/M/G0/G1 fraction. Significant correlation was also observed between FA ratio and S+G2/M/G0/G1. There was a negative significant correlation between ADC and S+G2/M and the S+G2/M/G0/G1 fraction. There were 21 (70%) diploid and 9 (30%) aneuploid tumours. No significant difference was found between diploid and aneuploid tumours with respect to rCBV, ADC and FA values. CONCLUSION: Dynamic susceptibility contrast MRI and diffusion tensor imaging metrics are correlated to tumour aggressiveness as assessed by cell cycle analysis. PMID- 26432995 TI - Fluorescein sodium-guided surgery in cerebral lymphoma. AB - OBJECTIVES: Growth and progress of primary central nervous lymphoma (PCNSL) severely disrupt the blood brain barrier (BBB). Such disruptions can be intraoperatively visualized by injecting fluorescein sodium (FL) and applying a YELLOW 560 nm surgical microscope filter. Here, we report a small cohort of patients with PCNSL that mimicked high grade gliomas (HGG) or cerebral metastases (CM), who had been operated on with the use of FL. PATIENTS AND METHODS: Retrospectively, seven patients with PCNSL were identified, who had been operated on by means of microsurgery after intravenous FL injection. The surgical reports were screened for statements on the grade of fluorescent staining in the tumor area. One representative case was chosen to show the staining under white light as well as under filtered light at different distances to the tumor area. RESULTS: All patients had shown bright and homogenous fluorescent staining of the tumor (n=7. 100%). No adverse effects had been observed. CONCLUSION: Similar to patients with HGG or CM, patients with PCNSL may benefit from use of FL and the dedicated YELLOW 560 nm filter in open surgery. PMID- 26432996 TI - Targeted exome sequencing identified two novel truncation mutations in GPR98 causing Usher syndrome. PMID- 26432997 TI - Sarcoidosis mimicking metastatic papillary thyroid cancer. AB - INTRODUCTION: Sarcoidosis is a multisystemic, idiopathic disease. It has a highly variable clinical course. It has been reported to present in association with malignancy. Coexistence of sarcoidosis and thyroid cancer is rarely reported in the literature. PRESENTATIOIN OF THE CASE: We present a case with neck swelling for 3 months, and symmetrical painless thyroid enlargement without fixation to deep tissues of the neck. Multiple nodules on the both thyroid lobes, hard irregular, grade two goiter with lymphadenopathy all over anterior neck compartments. Fine needle aspiration cytology was done under ultrasound guide from right thyroid nodule and showed papillary thyroid carcinoma. Excisional biopsy of the neck lymphnode showed picture typical for sarcoidosis. DISCUSSION: Most researchers believe that patients with pulmonary sarcoidosis are predisposed to develop malignancies, less than a dozen of cases are reported in the literature to be associated with PTC with a very wide range of presentations and clincal coarses. An interesting finding of our case is that in contrast to what is reported, both diseases were not known by the physician until the time of presentation. CONCLUSION: Cervical lymphadenopathy in association with goiter could be metastasis, sarcoidosis or mixed, therefore should be seperately biopsied. PMID- 26432998 TI - A case of de Garengeot hernia: the feasibility of laparoscopic transabdominal preperitoneal hernia repair. AB - INTRODUCTION: de Garengeot hernia is described as the presence of an appendix in a femoral hernia. This rare hernia usually presents with both diagnostic and therapeutic dilemmas. PRESENTATION OF CASE: We report a case of a 59 year-old woman with a one-year history of a right irreducible femoral hernia. She underwent diagnostic laparoscopy with an intraoperative diagnosis of de Garengeot hernia. This was followed by a laparoscopic transabdominal preperitoneal (TAPP) approach for hernia repair. DISCUSSION: The long-standing presentation of de Garengeot hernia is seldomly reported in literature. There has been no standard approach of treatment for de Garengeot hernias described, possibly due to the rarity of this condition. The unusual presentation of the hernia prompted us to undergo a diagnostic laparoscopy first, during which the appendix was seen incarcerated in a femoral hernia sac. We were easily able to proceed for a laparoscopic TAPP approach for hernia repair without the need for conversion to an open repair. CONCLUSION: We were able to obtain an accurate diagnosis of an appendix within a long-standing irreducible femoral hernia through diagnostic laparoscopy followed by transabdominal preperitoneal (TAPP) approach for hernia repair. We would like to underline the usefulness of laparoscopy as a valuable tool in the diagnosis and treatment of this unusual presentation of groin hernias. PMID- 26432999 TI - Letrozole-induced necrotising leukocytoclastic small vessel vasculitis: First report of a case in the UK. AB - INTRODUCTION: Letrozole, an aromatase inhibitor, is a commonly used neo-adjuvant drug to treat hormone-sensitive breast cancer. There have been a few cases of aromatase inhibitor induced vasculitis but the first case of letrozole-induced vasculitis was reported from Switzerland in 2014 (Digklia et al.) [1]. PRESENTATION OF CASE: We report the case of a 72-year-old woman with a small breast cancer. She was started on pre-operative letrozole (2.5mg/d) whilst awaiting surgery. Ten days later she presented with burning pain and purpuric skin lesions which progressed to extensive ischaemic superficial necrosis of the lower limb skin, resolving over 3-4 months after local and systemic steroids. Histologically, it showed leucocytoclasis with evidence of eosinophilia consistent with a diagnosis of cutaneous leukocytoclastic small vessel vasculitis. DISCUSSION: The initial clinical presentation was severe burning pain around the ankles and a spreading violaceous rash. Letrozole was stopped. Wide local excision (lumpectomy) and sentinel node biopsy were postponed because of the accompanying pneumonitis and gastrointestinal upset, and were carried out 3.5 months later. Fortunately, the tumour size did not increase, but appeared to reduce, and axillary lymph nodes remained negative, i.e., this patient's cancer outcome does not seem to have been jeopardized. CONCLUSION: Leukocytoclastic vasculitis is a hypersensitivity reaction that is usually self-resolving, though our case needed systemic steroid treatment. Letrozole is a commonly used drug in clinical practice and prescribers should be aware of this rare side effect, which in our case delayed treatment without any apparent harm and possibly reduced tumour size. PMID- 26433000 TI - 15q11.2 microdeletion and hypoplastic left heart syndrome. PMID- 26433001 TI - Autoimmune Diseases in the Bioinformatics Paradigm. Preface. PMID- 26433002 TI - Comparison of a high-performance liquid chromatography method for quantification of carbamazepine with chemiluminescent microparticle immunoassay. AB - Carbamazepine is an antiepileptic drug widely used for the treatment of epilepsy. In the National Institute of Neurology, monitoring has been performed using the technique chemiluminescent microparticle immunoassay (CMIA) in an automated way during the last five years. The aim of this study was to develop a simple and rapid HPLC analytical method coupled to DAD-UV detection for the determination of plasma concentrations of carbamazepine and compare its feasibility with those used in routine analysis. The developed HPLC method was fully validated and the applicability of the proposed method was verified through the analysis of plasma samples of patients and later compared with the quantification of the same plasma samples with the CMIA method. The limit of quantification obtained was 0.5 MUg/mL. The mean value for recovery was 99.05% and the coefficient of variation (CV) was 5.6%. The precision and accuracy of this method were within the acceptable limits; inter- and intraday CV values were <10%. The correlation between the CMIA method and the developed HPLC method was very good (r ~ 0.999). A Bland-Altman plot showed no significant bias between the results. The HPLC-DAD method may be an alternative to determine and monitoring the carbamazepine levels in human plasma or serum. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26433003 TI - 2-Oxoglutarate levels control adenosine nucleotide binding by Herbaspirillum seropedicae PII proteins. AB - Nitrogen metabolism in Proteobacteria is controlled by the Ntr system, in which PII proteins play a pivotal role, controlling the activity of target proteins in response to the metabolic state of the cell. Characterization of the binding of molecular effectors to these proteins can provide information about their regulation. Here, the binding of ATP, ADP and 2-oxoglutarate (2-OG) to the Herbaspirillum seropedicae PII proteins, GlnB and GlnK, was characterized using isothermal titration calorimetry. Results show that these proteins can bind three molecules of ATP, ADP and 2-OG with homotropic negative cooperativity, and 2-OG binding stabilizes the binding of ATP. Results also show that the affinity of uridylylated forms of GlnB and GlnK for nucleotides is significantly lower than that of the nonuridylylated proteins. Furthermore, fluctuations in the intracellular concentration of 2-OG in response to nitrogen availability are shown. Results suggest that under nitrogen-limiting conditions, PII proteins tend to bind ATP and 2-OG. By contrast, after an ammonium shock, a decrease in the 2 OG concentration is observed causing a decrease in the affinity of PII proteins for ATP. This phenomenon may facilitate the exchange of ATP for ADP on the ligand binding pocket of PII proteins, thus it is likely that under low ammonium, low 2 OG levels would favor the ADP-bound state. PMID- 26433004 TI - Prevalence of depression in Type 1 diabetes and the problem of over-diagnosis. AB - AIMS: To determine the prevalence of depression and diabetes distress in adults with Type 1 diabetes and the rate of false-positives when compared with rates of major depressive disorder. METHODS: The sample consisted of 368 individuals with Type 1 diabetes, aged > 19 years. Individuals completed: the eight-item Patient Health Questionnaire depression scale (PHQ8), which was coded using four scoring criteria (scores > 10, >12 and >15, and Diagnostic and Statistical Manual of Mental Disorders 5 (DSM) algorithm scores); the Type 1 Diabetes Distress Scale; and the Structured Clinical Interview for DSM Disorders (SCID) to assess major depressive disorder. RESULTS: The prevalence rates of depression according to the eight-item Patient Health Questionnaire were: score >10, 11.4%; score >12, 7.1%; score >15, 3.8%; and positive algorithm result, 4.6%. The prevalence of major depressive disorder was 3.5%; and the prevalence of at least moderate diabetes distress was 42.1%. Depending on the criterion used, the false-positive rate when using the Patient Health Questionnaire compared with the results when using the SCID varied from 52 to 71%. Of those classified as depressed on the PHQ-8 or Structured Clinical Interview for DSM Disorders, between 92.3 and 96.2% also reported elevated diabetes distress. No significant association was found between any group classed as having depression according to the PHQ8 or the SCID and HbA1c concentration. Depression was significantly associated with more other life stress, more complications and a lower level of education. CONCLUSIONS: We found an unexpectedly low rate of current depression and major depressive disorder in this diverse sample of adults with Type 1 diabetes, and a very high rate of false positive results using the Patient Health Questionnaire. Considering the high prevalence of diabetes distress, much of what has been considered depression in adults with Type 1 diabetes may be attributed to the emotional distress associated with managing a demanding chronic disease and other life stressors and not necessarily to underlying psychopathology. PMID- 26433005 TI - Phosphorus removal performance and speciation in virgin and modified argon oxygen decarburisation slag designed for wastewater treatment. AB - Argon oxygen decarburisation (AOD) slag may be used for phosphorus (P) removal, as its high pH and weatherable calcium (Ca) minerals provide sufficient Ca(2+) and OH(-) for calcium phosphate (Ca-PO4) precipitation. This study examined the P removal performance of AOD slag for use as wastewater treatment material. Batch experiments were carried out using both synthetic P solution and real wastewater, followed by chemical modelling and X-ray absorption near edge structure (XANES) spectroscopy. The influences of initial P concentration, slag dose and modification by polyethylene glycol (PEG), an effective agent for generation of porous materials, were investigated to determine the optimal conditions for P removal by AOD slag. It was found that virgin AOD slag removed 94.8% of P from a synthetic P solution in 4 h and 97.8% in 10 h. This high P removal was accompanied by a rapid increase in pH from 7.0 to 10.74. The maximum P removal capacity (PRC) from synthetic P solution ranged from 1.3 to 27.5 mg P g(-1). The optimal AOD dose for P removal from wastewater, determined in 8-h batch experiments, was 25 g L(-1). PEG modification increased the reaction rate and resulted in higher final pH, increasing PRC by 47.9%. Combined Visual MINTEQ and XANES analysis for detailed examination of P removal mechanisms revealed that the main P removal mechanism was precipitation of calcium phosphate. According to the XANES analysis, the main Ca-PO4 precipitate formed on virgin AOD slag under low initial P concentration and high pH was apatite, while brushite was the dominant product at high initial P concentration and low pH. PMID- 26433006 TI - Interrogating chemical variation via layer-by-layer SERS during biofouling and cleaning of nanofiltration membranes with further investigations into cleaning efficiency. AB - Periodic chemical cleaning is an essential step to maintain nanofiltration (NF) membrane performance and mitigate biofouling, a major impediment in high-quality water reclamation from wastewater effluent. To target the important issue of how to clean and control biofouling more efficiently, this study developed surface enhanced Raman spectroscopy (SERS) as a layer-by-layer tool to interrogate the chemical variations during both biofouling and cleaning processes. The fact that SERS only reveals information on the surface composition of biofouling directly exposed to cleaning reagents makes it ideal for evaluating cleaning processes and efficiency. SERS features were highly distinct and consistent with different biofouling stages (bacterial adhesion, rapid growth, mature and aged biofilm). Cleaning was performed on two levels of biofouling after 18 h (rapid growth of biofilm) and 48 h (aged biofilm) development. An opposing profile of SERS bands between biofouling and cleaning was observed and this suggests a layer-by-layer cleaning mode. In addition, further dynamic biochemical and infrastructural changes were demonstrated to occur in the more severe 48-h biofouling, resulting in the easier removal of sessile cells from the NF membrane. Biofouling substance dependent cleaning efficiency was also evaluated using the surfactant sodium dodecyl sulfate (SDS). SDS appeared more efficient in cleaning lipid than polysaccharide and DNA. Protein and DNA were the predominant residual substances (irreversible fouling) on NF membrane leading to permanent flux loss. The chemical information revealed by layer-by-layer SERS will lend new insights into the optimization of cleaning reagents and protocols for practical membrane processes. PMID- 26433007 TI - Applying the polarity rapid assessment method to characterize nitrosamine precursors and to understand their removal by drinking water treatment processes. AB - Some N-nitrosamines (NAs) have been identified as emerging disinfection by products during water treatment. Thus, it is essential to understand the characteristics of the NA precursors. In this study, the polarity rapid assessment method (PRAM) and the classical resin fractionation method were studied as methods to fractionate the NA precursors during drinking water treatment. The results showed that PRAM has much higher selectivity for NA precursors than the resin approach. The normalized N-nitrosodimethylamine formation potential (NDMA FP) and N-nitrosodiethylamine (NDEA) FP of four resin fractions was at the same level as the average yield of the bulk organic matter whereas that of the cationic fraction by PRAM showed 50 times the average. Thus, the cationic fraction was shown to be the most important NDMA precursor contributor. The PRAM method also helped understand which portions of the NA precursor were removed by different water treatment processes. Activated carbon (AC) adsorption removed over 90% of the non-polar PRAM fraction (that sorbs onto the C18 solid phase extraction [SPE] cartridge) of NDMA and NDEA precursors. Bio treatment removed 80-90% of the cationic fraction of PRAM (that is retained on the cation exchange SPE cartridge) and 40-60% of the non-cationic fractions. Ozonation removed 50-60% of the non-polar PRAM fraction of NA precursors and transformed part of them into the polar fraction. Coagulation and sedimentation had very limited removal of various PRAM fractions of NA precursors. PMID- 26433008 TI - Economic evaluations of pharmacist-managed services in people with diabetes mellitus: a systematic review. AB - AIM: To review and evaluate the most recent literature on the economic outcomes of pharmacist-managed services in people with diabetes. BACKGROUND: The global prevalence of diabetes is increasing. Although pharmacist-managed services have been shown to improve people's health outcomes, the economic impact of these programmes remains unclear. METHODS: A systematic review was conducted of six databases. Study inclusion criteria were: (1) original research; (2) evaluation of pharmacist-managed services in people with diabetes; (3) an economic evaluation; (4) English-language publication; and (5) full-text, published between January 2006 and December 2014. The quality of the full economic evaluations reviewed was evaluated using the Consolidated Health Economic Evaluation Reporting Standards checklist. RESULTS: A total of 2204 articles were screened and 25 studies were selected. These studies were conducted in a community pharmacy (n = 10), a clinic- /hospital-based outpatient facility (n = 8), or others. Pharmacist-managed services included targeted education (n = 24), general pharmacotherapeutic monitoring (n = 21), health screening or laboratory testing services (n = 9), immunization services (n = 2) and pharmacokinetic monitoring (n = 1). Compared with usual care, pharmacist-managed services resulted in cost savings that varied from $7 to $65,000 ($8 to $85,000 in 2014 US dollars) per person per year, and generated higher quality-adjusted life years with lower costs. Benefit-to-cost ratios ranged from 1:1 to 8.5:1. Among the 25 studies reviewed, 11 were full economic evaluations of moderate quality. CONCLUSIONS: Pharmacist-managed services had a positive return in terms of economic viability. With the expanding role of pharmacists in the healthcare sector, alongside increasing health expenditure, future economic studies of high quality are needed to investigate the cost-effectiveness of these services. PMID- 26433009 TI - Dairy consumption and risk of metabolic syndrome: a meta-analysis. AB - AIMS: To conduct a systematic review and meta-analysis of epidemiological studies in order to assess quantitatively the effect of dairy consumption on risk of metabolic syndrome. METHODS: We searched for eligible studies published up to March 2015 through the PubMed and Embase databases and reviewed the references of relevant articles. Random-effects models were used to calculate the pooled relative risks with 95% CIs after adjusting for several confounders. RESULTS: We identified nine prospective cohort studies including a total of 35 379 subjects and 7322 incident cases of metabolic syndrome, and 12 cross-sectional studies including 37 706 subjects. In the meta-analysis of prospective cohort studies, the pooled relative risk of incidence of metabolic syndrome for the highest vs. the lowest category of dairy consumption was 0.85 (95% CI 0.73-0.98), and for a 1 serving/day increment of dairy consumption, the pooled relative risk was 0.88 (95% CI 0.82-0.95). In the meta-analysis of cross-sectional studies, the pooled relative risk of prevalence of metabolic syndrome for the highest vs. the lowest category of dairy consumption was 0.73 (95% CI 0.63-0.86). The association was not significantly different by geographical region, follow-up time and adjustment factors. CONCLUSION: Our findings indicate that dairy consumption is inversely associated with the incidence and prevalence of metabolic syndrome. Further well designed cohort studies and randomized controlled trials are warranted to provide definitive evidence. PMID- 26433010 TI - Recombination and horizontal transfer of nodulation and ACC deaminase (acdS) genes within Alpha- and Betaproteobacteria nodulating legumes of the Cape Fynbos biome. AB - The goal of this work is to study the evolution and the degree of horizontal gene transfer (HGT) within rhizobial genera of both Alphaproteobacteria (Mesorhizobium, Rhizobium) and Betaproteobacteria (Burkholderia), originating from South African Fynbos legumes. By using a phylogenetic approach and comparing multiple chromosomal and symbiosis genes, we revealed conclusive evidence of high degrees of horizontal transfer of nodulation genes among closely related species of both groups of rhizobia, but also among species with distant genetic backgrounds (Rhizobium and Mesorhizobium), underscoring the importance of lateral transfer of symbiosis traits as an important evolutionary force among rhizobia of the Cape Fynbos biome. The extensive exchange of symbiosis genes in the Fynbos is in contrast with a lack of significant events of HGT among Burkholderia symbionts from the South American Cerrado and Caatinga biome. Furthermore, homologous recombination among selected housekeeping genes had a substantial impact on sequence evolution within Burkholderia and Mesorhizobium. Finally, phylogenetic analyses of the non-symbiosis acdS gene in Mesorhizobium, a gene often located on symbiosis islands, revealed distinct relationships compared to the chromosomal and symbiosis genes, suggesting a different evolutionary history and independent events of gene transfer. The observed events of HGT and incongruence between different genes necessitate caution in interpreting topologies from individual data types. PMID- 26433012 TI - DOCTORS' LIABILITY TO THE PATIENT'S RELATIVES IN GENETIC MEDICINE: ABC V St George's Healthcare NHS trust[2015] EWHC 1394 (QB). AB - This comment analyses the recent High Court's decision in ABC v St George's Healthcare NHS Trust. In this case, the court struck out a claim brought by a patient's daughter against her father's doctors for their failure to warn her of his hereditary disease. The claimant argued that the doctors' failure caused her harm and violated her rights under the European Convention on Human Rights. It is argued in this comment that the judge should have accepted the claimant's application. PMID- 26433011 TI - The Role of Phospholipase D in Regulated Exocytosis. AB - There are a diversity of interpretations concerning the possible roles of phospholipase D and its biologically active product phosphatidic acid in the late, Ca(2+)-triggered steps of regulated exocytosis. To quantitatively address functional and molecular aspects of the involvement of phospholipase D-derived phosphatidic acid in regulated exocytosis, we used an array of phospholipase D inhibitors for ex vivo and in vitro treatments of sea urchin eggs and isolated cortices and cortical vesicles, respectively, to study late steps of exocytosis, including docking/priming and fusion. The experiments with fluorescent phosphatidylcholine reveal a low level of phospholipase D activity associated with cortical vesicles but a significantly higher activity on the plasma membrane. The effects of phospholipase D activity and its product phosphatidic acid on the Ca(2+) sensitivity and rate of fusion correlate with modulatory upstream roles in docking and priming rather than to direct effects on fusion per se. PMID- 26433013 TI - How computer science can help in understanding the 3D genome architecture. AB - Chromosome conformation capture techniques are producing a huge amount of data about the architecture of our genome. These data can provide us with a better understanding of the events that induce critical regulations of the cellular function from small changes in the three-dimensional genome architecture. Generating a unified view of spatial, temporal, genetic and epigenetic properties poses various challenges of data analysis, visualization, integration and mining, as well as of high performance computing and big data management. Here, we describe the critical issues of this new branch of bioinformatics, oriented at the comprehension of the three-dimensional genome architecture, which we call 'Nucleome Bioinformatics', looking beyond the currently available tools and methods, and highlight yet unaddressed challenges and the potential approaches that could be applied for tackling them. Our review provides a map for researchers interested in using computer science for studying 'Nucleome Bioinformatics', to achieve a better understanding of the biological processes that occur inside the nucleus. PMID- 26433014 TI - Caveolin-1 single-nucleotide polymorphism and arterial stiffness in non-dialysis chronic kidney disease. AB - BACKGROUND: Arteriosclerosis is an independent predictor of increased cardiovascular mortality in chronic kidney disease (CKD). Histologically it is characterized by hypertrophy and fibrosis of the arterial media wall leading to increased arterial stiffness and end-organ damage. Caveolin-1 acts as an intracellular signalling pathway chaperone in human fibrotic and vascular diseases. The purpose of this study was to assess the association between caveolin-1 (CAV1) single-nucleotide polymorphism (SNP) rs4730751 and arterial stiffness as measured by arterial pulse wave velocity (PWV) in an early-stage CKD cohort and in a cohort with more severe CKD. METHODS: Two prospectively maintained patient cohorts with non-dialysis CKD were studied: 144 patients in the Chronic Renal Impairment in Birmingham (CRIB) cohort and 147 patients in the Renal Impairment in Secondary Care (RIISC) cohort, with matched exclusion criteria and DNA sampling availability. At entry to each cohort database, each patient's initial arterial PWV was measured, as well as their anthropomorphic and biochemical data. CAV1 rs4730751 SNP genotyping was performed using Taqman technology. RESULTS: The CAV1 rs4730751 SNP CC genotype was associated with lower arterial PWV in both CRIB early stage CKD patients [8.1 versus 8.6 m/s; coefficient -0.780 (-1.412, -0.149); P = 0.016] and RIISC more advanced stage CKD patients [8.7 versus 9.4 m/s; coefficient -0.695 (-1.288, -0.102); P = 0.022]; these relationships held following adjustment for other important confounders. CONCLUSIONS: This replicated study suggests potential utility of the studied CAV1 SNP as a genetic biomarker in CKD and a role for CAV1 in the development of arteriosclerosis in this setting. Further studies are warranted to further explore the basic science driving these clinical observations. PMID- 26433016 TI - Possible role of trace elements in epilepsy and febrile seizures: a meta analysis. AB - Seizures are among the most common causes of apparent life-threatening events. There are discrepancies among the published reports on the correlation between epilepsy/febrile seizures and deficiency or overload of trace elements. The objective of this review and meta-analysis was to examine the present knowledge on the concentrations of the most investigated trace metals, including zinc, copper, selenium, and magnesium, in patients with epilepsy and febrile seizures. The PubMed and Scopus databases were searched to identify case-control studies that compared the concentration of zinc, copper, magnesium, and selenium in serum, hair, or cerebrospinal fluid between patients with epilepsy/febrile seizures and controls. A total of 60 articles were included in the present study (40 pertaining to epilepsy and 25 pertaining to febrile seizures). The serum concentration of zinc in nontreated patients with epilepsy was significantly higher than in controls (P = 0.034). There were significantly reduced serum concentrations of zinc (P = 0.018) and selenium (P = 0.012) in patients with febrile seizures compared with controls. The concentrations of copper, magnesium, and zinc were all significantly altered in patients with epilepsy who received antiepileptic drugs compared with untreated patients with epilepsy. Designing treatments to selectively restore zinc levels may be a strategy for treating patients with epilepsy. It is still unclear whether these ions are causal to, or a cofactor in, the development of epilepsy. Knowledge of the effects of various antiepileptic drugs on trace element homeostasis could potentially be used to effectively guide appropriate therapeutic strategies in the future. PMID- 26433015 TI - How complicated can it be? The link between APOL1 risk variants and lipoprotein heterogeneity in kidney and cardiovascular diseases. PMID- 26433017 TI - Evidence of the effectiveness of flour fortification programs on iron status and anemia: a systematic review. AB - CONTEXT: More than 80 countries fortify flour, yet the public health impact of this intervention on iron and anemia outcomes has not been reviewed. OBJECTIVE: The objective of this systematic review was to review published and gray literature pertaining to the impact of flour fortification on iron and anemia. DATA SOURCES: A systematic review was conducted by searching 17 databases and appealing for unpublished reports, yielding 1881 documents. STUDY SELECTION: Only studies of government-supported, widely implemented fortification programs in which anemia or iron status was measured prior to and >=12 months after initiation of fortification were included. DATA EXTRACTION: Details about the design, coverage, compliance with national standards, and evaluation (e.g., anemia prevalence before and after fortification) of flour fortification programs were extracted from the reports. DATA SYNTHESIS: Thirteen studies describing 26 subgroups (n = 14 for children <=15 y, n = 12 for women of reproductive age) were included. During the period from pre- to postfortification (and as difference-in difference for those studies that included a control group), there were statistically significant decreases in the prevalence of anemia in 4 of 13 subgroups of children and in 4 of 12 subgroups of women of reproductive age as well as significant decreases in the prevalence of low ferritin in 1 of 6 subgroups of children and in 3 of 3 subgroups of women of reproductive age. CONCLUSIONS: . Evidence of the effectiveness of flour fortification for reducing the prevalence of anemia is limited; however, evidence of effectiveness for reducing the prevalence of low ferritin in women is more consistent. PMID- 26433018 TI - The diameter growth-height growth relationship as related to the diameter-height relationship. PMID- 26433019 TI - The relationship between needle sugar carbon isotope ratios and tree rings of larch in Siberia. AB - Significant gaps still exist in our knowledge about post-photosynthetic leaf level and downstream metabolic processes and isotopic fractionations. This includes their impact on the isotopic climate signal stored in the carbon isotope composition (delta(13)C) of leaf assimilates and tree rings. For the first time, we compared the seasonal delta(13)C variability of leaf sucrose with intra annual, high-resolution delta(13)C signature of tree rings from larch (Larix gmelinii Rupr.). The trees were growing at two sites in the continuous permafrost zone of Siberia with different growth conditions. Our results indicate very similar low-frequency intra-seasonal trends of the sucrose and tree ring delta(13)C records with little or no indication for the use of 'old' photosynthates formed during the previous year(s). The comparison of leaf sucrose delta(13)C values with that in other leaf sugars and in tree rings elucidates the cause for the reported (13)C-enrichment of sink organs compared with leaves. We observed that while the average delta(13)C of all needle sugars was 1.20/00 more negative than delta(13)C value of wood, the delta(13)C value of the transport sugar sucrose was on an average 1.00/00 more positive than that of wood. Our study shows a high potential of the combined use of compound-specific isotope analysis of sugars (leaf and phloem) with intra-annual tree ring delta(13)C measurements for deepening our understanding about the mechanisms controlling the isotope variability in tree rings under different environmental conditions. PMID- 26433020 TI - Overexpression of gibberellin 20-oxidase1 from Pinus densiflora results in enhanced wood formation with gelatinous fiber development in a transgenic hybrid poplar. AB - Gibberellins (GAs) are important regulators of plant shoot biomass growth, and GA 20-oxidase (GA20ox) is one of the major regulatory enzymes in the GA biosynthetic pathway. Previously, we showed that the expression levels of a putative GA20ox1 (i.e., PdGA20ox1) in stem tissue of 3-month-old seedlings of 12 families of Pinus densiflora were positively correlated with stem diameter growth across those same families growing in an even-aged 32-year-old pine forest (Park EJ, Lee WY, Kurepin LV, Zhang R, Janzen L, Pharis RP (2015) Plant hormone-assisted early family selection in Pinus densiflora via a retrospective approach. Tree Physiol 35:86-94). To further investigate the molecular function of this gene in the stem wood growth of forest trees, we produced transgenic poplar lines expressing PdGA20ox1 under the control of the 35S promoter (designated as 35S::PdGA20ox1). By age 3 months, most of the 35S::PdGA20ox1 poplar trees were showing an exceptional enhancement of stem wood growth, i.e., up to fourfold increases in stem dry weight, compared with the nontransformed control poplar plants. Significant increases in endogenous GA1, its immediate precursor (GA20) and its catabolite (GA8) in elongating internode tissue accompanied the increased stem growth in the transgenic lines. Additionally, the development of gelatinous fibers occurred in vertically grown stems of the 35S::PdGA20ox1 poplars. An analysis of the cell wall monosaccharide composition of the 35S::PdGA20ox1 poplars showed significant increases in xylose and glucose contents, indicating a qualitative increase in secondary wall depositions. Microarray analyses led us to find a total of 276 probe sets that were upregulated (using threefold as a threshold) in the stem tissues of 35S::PdGA20ox1 poplars relative to the controls. 'Cell organization or biogenesis'- and 'cell wall'-related genes were overrepresented, including many of genes that are involved in cell wall modification. Several transcriptional regulators, which positively regulate cell elongation through GA signaling, were also upregulated. In contrast, genes involved in defense signaling were appreciably downregulated in the 35S::PdGA20ox1 stem tissues, suggesting a growth versus defense trade-off. Taken together, our results suggest that PdGA20ox1 functions to promote stem growth and wood formation in poplar, probably by activating GA signaling while coincidentally depressing defense signaling. PMID- 26433021 TI - Ponderosa pine resin defenses and growth: metrics matter. AB - Bark beetles (Coleoptera: Curculionidae, Scolytinae) cause widespread tree mortality in coniferous forests worldwide. Constitutive and induced host defenses are important factors in an individual tree's ability to survive an attack and in bottom-up regulation of bark beetle population dynamics, yet quantifying defense levels is often difficult. For example, in Pinus spp., resin flow is important for resistance to bark beetles but is extremely variable among individuals and within a season. While resin is produced and stored in resin ducts, the specific resin duct metrics that best correlate with resin flow remain unclear. The ability and timing of some pine species to produce induced resin is also not well understood. We investigated (i) the relationships between ponderosa pine (Pinus ponderosa Lawson & C. Lawson) resin flow and axial resin duct characteristics, tree growth and physiological variables, and (ii) if mechanical wounding induces ponderosa pine resin flow and resin ducts in the absence of bark beetles. Resin flow increased later in the growing season under moderate water stress and was highest in faster growing trees. The best predictors of resin flow were nonstandardized measures of resin ducts, resin duct size and total resin duct area, both of which increased with tree growth. However, while faster growing trees tended to produce more resin, models of resin flow using only tree growth were not statistically significant. Further, the standardized measures of resin ducts, density and duct area relative to xylem area, decreased with tree growth rate, indicating that slower growing trees invested more in resin duct defenses per unit area of radial growth, despite a tendency to produce less resin overall. We also found that mechanical wounding induced ponderosa pine defenses, but this response was slow. Resin flow increased after 28 days, and resin duct production did not increase until the following year. These slow induced responses may allow unsuccessfully attacked or wounded trees to resist future bark beetle attacks. Forest management that encourages healthy, vigorously growing trees will also favor larger resin ducts, thereby conferring increased constitutive resistance to bark beetle attacks. PMID- 26433022 TI - A quantitative framework for whole-body coordination reveals specific deficits in freely walking ataxic mice. AB - The coordination of movement across the body is a fundamental, yet poorly understood aspect of motor control. Mutant mice with cerebellar circuit defects exhibit characteristic impairments in locomotor coordination; however, the fundamental features of this gait ataxia have not been effectively isolated. Here we describe a novel system (LocoMouse) for analyzing limb, head, and tail kinematics of freely walking mice. Analysis of visibly ataxic Purkinje cell degeneration (pcd) mice reveals that while differences in the forward motion of individual paws are fully accounted for by changes in walking speed and body size, more complex 3D trajectories and, especially, inter-limb and whole-body coordination are specifically impaired. Moreover, the coordination deficits in pcd are consistent with a failure to predict and compensate for the consequences of movement across the body. These results isolate specific impairments in whole body coordination in mice and provide a quantitative framework for understanding cerebellar contributions to coordinated locomotion. PMID- 26433023 TI - Human observers have optimal introspective access to perceptual processes even for visually masked stimuli. AB - Many believe that humans can 'perceive unconsciously' - that for weak stimuli, briefly presented and masked, above-chance discrimination is possible without awareness. Interestingly, an online survey reveals that most experts in the field recognize the lack of convincing evidence for this phenomenon, and yet they persist in this belief. Using a recently developed bias-free experimental procedure for measuring subjective introspection (confidence), we found no evidence for unconscious perception; participants' behavior matched that of a Bayesian ideal observer, even though the stimuli were visually masked. This surprising finding suggests that the thresholds for subjective awareness and objective discrimination are effectively the same: if objective task performance is above chance, there is likely conscious experience. These findings shed new light on decades-old methodological issues regarding what it takes to consider a neurobiological or behavioral effect to be 'unconscious,' and provide a platform for rigorously investigating unconscious perception in future studies. PMID- 26433024 TI - What the [beep]? Six-month-olds link novel communicative signals to meaning. AB - Over the first year, infants tune into the signals of their native language and begin to link them to meaning. Here, we ask whether infants, like adults, can also infer the communicative function of otherwise arbitrary signals (here, tone sequences) and link these to meaning as well. We examined 6-month-olds' object categorization in the context of sine-wave tones, a signal that fails to support categorization at any point during their first year. However, before the categorization task, we exposed infants to tones in one of two vignettes. In one, the tones were produced by an actor in a rich communicative exchange; in the other, infants heard the very same tones, but these were uncoupled from the actors' activity. Infants exposed to the communicative vignette successfully formed object categories in the subsequent test; those exposed to the non communicative vignette failed, performing identically to infants with no prior exposure to this novel signal. This reveals in 6-month-old infants a remarkable flexibility in identifying which signals in the ambient environment are communicative and in linking these signals to core cognitive capacities including categorization. PMID- 26433025 TI - Open ventral hernia repair using ProGrip self-gripping mesh. AB - PURPOSE: Secure mesh fixation in incisional hernia repair is mandatory to prevent mesh dislocation and possible recurrence. Traditional fixation methods have been implicated as a source of chronic postoperative pain. We report 2-year outcomes with a self-gripping mesh for open tension-free repair of large incisional hernia. METHODS: This prospective case series enrolled 20 patients with large primary incisional hernia (mean defect size: 84 cm(2)). Patients were electively treated by a single surgeon using a macroporous polyester mesh with resorbable polylactic acid microgrips (ProGrip, Covidien, Mansfield, MA, USA) using open onlay technique. Main outcomes included pain severity, Carolinas Comfort Scale (CCS), complications, and hernia recurrence. Patients returned for follow-up at 1, 3, 6, 12, and 24 months. RESULTS: Median mesh fixation time was 2 min. Mean operative time was 38 min and blood loss was minimal (50 cc). Most patients (75%) were discharged same day. The only perioperative complication was a minor seroma in one patient. Patient follow-up compliance through 2 years was 100%. Mean pain score was 1.8 at discharge, 0.9 at 1 month, 0.7 at 1 year, and 0 at 2 years. At 2 years, all patients were "very satisfied" with treatment and hernia-specific quality of life was excellent (mean CCS score = 0). No infection, mesh removal, or hernia recurrence occurred during follow-up. CONCLUSIONS: Open repair using a self-gripping mesh is a viable treatment option in patients with large incisional hernia. Immediate mesh fixation facilitates a safe and durable tension-free repair. PMID- 26433026 TI - Hepatitis delta virus facilitates the selection of hepatitis B virus mutants in vivo and functionally impacts on their replicative capacity in vitro. AB - To identify molecular interactions between hepatitis B virus (HBV) and hepatitis delta virus (HDV), HBV sequences were analysed in HBV/HDV-infected patients. Characteristic amino acid substitutions were found in cytosolic domains of hepatitis B surface antigen (HBsAg), in contrast to HBV-mono-infected controls. The functional impact of HDV on the replication of wild-type and mutant HBV was assessed in vitro. HDV co-transfection significantly reduced the replication of HBV strains containing precore or basal core promoter mutations, and HBV polymerase or surface antigen mutants affected HDV replication in vitro. Conclusively, our study revealed distinct HBsAg mutational patterns in HBV/HDV infected patients and novel functional interactions between HBV and HDV. PMID- 26433027 TI - Simultaneous determination of sample thickness, tilt, and electron mean free path using tomographic tilt images based on Beer-Lambert law. AB - Cryo-electron tomography (cryo-ET) is an emerging technique that can elucidate the architecture of macromolecular complexes and cellular ultrastructure in a near-native state. Some important sample parameters, such as thickness and tilt, are needed for 3-D reconstruction. However, these parameters can currently only be determined using trial 3-D reconstructions. Accurate electron mean free path plays a significant role in modeling image formation process essential for simulation of electron microscopy images and model-based iterative 3-D reconstruction methods; however, their values are voltage and sample dependent and have only been experimentally measured for a limited number of sample conditions. Here, we report a computational method, tomoThickness, based on the Beer-Lambert law, to simultaneously determine the sample thickness, tilt and electron inelastic mean free path by solving an overdetermined nonlinear least square optimization problem utilizing the strong constraints of tilt relationships. The method has been extensively tested with both stained and cryo datasets. The fitted electron mean free paths are consistent with reported experimental measurements. The accurate thickness estimation eliminates the need for a generous assignment of Z-dimension size of the tomogram. Interestingly, we have also found that nearly all samples are a few degrees tilted relative to the electron beam. Compensation of the intrinsic sample tilt can result in horizontal structure and reduced Z-dimension of tomograms. Our fast, pre-reconstruction method can thus provide important sample parameters that can help improve performance of tomographic reconstruction of a wide range of samples. PMID- 26433028 TI - A novel fully automatic scheme for fiducial marker-based alignment in electron tomography. AB - Although the topic of fiducial marker-based alignment in electron tomography (ET) has been widely discussed for decades, alignment without human intervention remains a difficult problem. Specifically, the emergence of subtomogram averaging has increased the demand for batch processing during tomographic reconstruction; fully automatic fiducial marker-based alignment is the main technique in this process. However, the lack of an accurate method for detecting and tracking fiducial markers precludes fully automatic alignment. In this paper, we present a novel, fully automatic alignment scheme for ET. Our scheme has two main contributions: First, we present a series of algorithms to ensure a high recognition rate and precise localization during the detection of fiducial markers. Our proposed solution reduces fiducial marker detection to a sampling and classification problem and further introduces an algorithm to solve the parameter dependence of marker diameter and marker number. Second, we propose a novel algorithm to solve the tracking of fiducial markers by reducing the tracking problem to an incomplete point set registration problem. Because a global optimization of a point set registration occurs, the result of our tracking is independent of the initial image position in the tilt series, allowing for the robust tracking of fiducial markers without pre-alignment. The experimental results indicate that our method can achieve an accurate tracking, almost identical to the current best one in IMOD with half automatic scheme. Furthermore, our scheme is fully automatic, depends on fewer parameters (only requires a gross value of the marker diameter) and does not require any manual interaction, providing the possibility of automatic batch processing of electron tomographic reconstruction. PMID- 26433029 TI - The giant keyhole limpet radular teeth: A naturally-grown harvest machine. AB - The limpet radula is a feeding organ, which contains more than 100 rows of teeth. During their growth the teeth mature and advance in position along the radula. The simpler doccoglossan radulae operate by grinding rocky substrates, extracting the algae by rasping and scraping with the teeth functioning as shovels. Less is known about the rhipidoglossan radulae, used as rakes or brooms that brush and collect loose marine debris. This type of radula is found in the giant keyhole limpet (Megathura crenulata). The large size of this organism suggests that the rhipidoglossan radula entails a technological superiority for M. crenulata in its habitat. The structure and function of the radulae teeth have however not been reported in detail. Using a combination of 2D and 3D microscopy techniques coupled with amino acid analysis and X-ray scattering, we reveal the working components of M. crenulata's radula. It is characterized by numerous marginal teeth surrounding a pair of major hook-like lateral teeth, two pairs of minor lateral teeth and a large central tooth. The mature major lateral teeth show pronounced signs of wear, which gradually increase towards the very front end of the radula and are evidence for scraping. An abrupt change in the amino acid composition in the major lateral teeth and the concurrent formation of a chitinous fiber-network mark the onset of tooth maturation. In comparison to the simpler rock-scraping doccoglossate limpets, the radula of M. crenulata forms an elaborate feeding apparatus, which can be seen as a natural harvest machine. PMID- 26433030 TI - Molecular events during the early stages of aggregation of GNNQQNY: An all atom MD simulation study of randomly dispersed peptides. AB - This study probes the early events during lag phase of aggregation of GNNQQNY using all atom MD simulations in explicit solvent. Simulations were performed by varying system size, temperature and starting configuration. Peptides dispersed randomly in the simulation box come together early on in the simulation and form aggregates. These aggregates are dynamic implying the absence of stabilizing interactions. This facilitates the exploration of alternate arrangements. The constituent peptides sample a variety of conformations, frequently re-orient and re-arrange with respect to each other and dissociate from/re-associate with the aggregate. The size and lifetime of aggregates vary depending upon the number of inter-peptide backbone H-bonds. Most of the aggregates formed are amorphous but crystalline aggregates of smaller size (mainly 2-mers) do appear and sustain for varying durations of time. The peptides in crystalline 2-mers are mostly anti parallel. The largest crystalline aggregate that appears is a 4-mer in a single sheet and a 4-, 5-, or 6-mer in double layered arrangement. Crystalline aggregates grow either by the sequential addition of peptides, or by the head-on or lateral collision-adhesion of 2-mers. The formation of various smaller aggregates suggests the polymorphic nature of oligomers and heterogeneity in the lag phase. PMID- 26433031 TI - Structural and biochemical insights into the DNA-binding mode of MjSpt4p:Spt5 complex at the exit tunnel of RNAPII. AB - Spt5 (NusG in bacteria) is the only RNA polymerase-associated factor known to be conserved in all three domains of life. In archaea and eukaryotes, Spt5 associates with Spt4, an elongation factor that is absent in bacteria, to form a functional heterodimeric complex. Previous studies suggest that the Spt4:Spt5 complex interacts directly with DNA at the double-stranded DNA exit tunnel of RNA polymerase to regulate gene transcription. In this study, the DNA-binding ability of Spt4:Spt5 from the archaeon Methanocaldococcus jannaschii was confirmed via nuclear magnetic resonance chemical shift perturbation and fluorescence polarization assays. Crystallographic analysis of the full-length MjSpt4:Spt5 revealed two distinct conformations of the C-terminal KOW domain of Spt5. A similar alkaline region was found on the Spt4:Spt5 surface in both crystal forms, and identified as double-stranded DNA binding patch through mutagenesis fluorescence polarization assays. Based on these structural and biochemical data, the Spt4:Spt5-DNA binding model was built for the first time. PMID- 26433032 TI - Expression of the CD68 glycoprotein in the rat epididymis. AB - The 110 kDa trans-membrane glycoprotein CD68 is highly expressed by human monocytes and tissue macrophages. However, in addition to the monocyte/macrophage system, CD68 has been also found in normal and tumor cells with no macrophagic activity such as lymphocytes, fibroblasts, endothelial cells, small intestinal epithelial cells, and neoplastic cells of different origins. Here, for the first time we demonstrate the immunohistochemical localization of CD68 in the principal cells of the cranial and caudal segments of rat epididymis. These results were confirmed by biochemical analyses showing the expression of CD68 mRNA transcripts and the protein in the epididymis tissues. Our findings, while providing further evidence that CD68 expression is not restricted to the monocyte/macrophage system, suggest that the glycoprotein might be involved in the functions of epididymal principal cells that contribute to spermatozoa maturation process. PMID- 26433034 TI - Cervical flexion myelopathy causing distal upper limb amyotrophy. PMID- 26433033 TI - A conserved linkage group on chromosome 6, the 8.1 ancestral haplotype, is a predisposing factor of chronic rhinosinusitis associated with nasal polyposis in aspirin-sensitive Hungarians. AB - Inflammation plays a central role in the pathogenesis of chronic rhinosinusitis (CRS), and TNFalpha is a key pro-inflammatory cytokine in the pathogenesis of this disease. In our previous studies, we showed that the TNFA -308A allele is a genetic predisposition factor in a subgroup of aspirin-sensitive (ASA+) CRS patients suffering from nasal polyps (NP) in the Hungarian population. To determine whether the TNF -308A allele or the presence of a complex, extended ancestral haplotype (8.1AH) located on chromosome 6 is responsible for the previously observed genetic effect, we performed a case-control study for examining the frequency of 8.1AH carriers in controls and in subgroups of CRS patients. Our novel observations demonstrate that the presence of the 8.1AH may be responsible for the development of severe forms of CRS (CRSwNP, ASA+) and strengthen the clinical observation that CRS patients can be classified into clinically and genetically different subgroups. PMID- 26433035 TI - Spontaneous regression of a retro-odontoid cyst. PMID- 26433036 TI - Congenital odontoid process separation with atlantoaxial dislocation associated with Klipple-Feil syndrome and cervical angular kyphosis secondary to C6 wedging vertebra. PMID- 26433037 TI - Spinal cord injury enhances arterial expression and reactivity of alpha1 adrenergic receptors-mechanistic investigation into autonomic dysreflexia. AB - BACKGROUND CONTEXT: Autonomic dysreflexia (AD) usually presents with a significant increase in blood pressure, and uncontrollable autonomic response to stimuli below the level of spinal cord injury (SCI). PURPOSE: This study analyzed the vasomotor function and molecular changes in the peripheral arteries below the lesion of SCI to characterize the mechanism of autonomic dysreflexia. STUDY DESIGN: This was a randomized experimental study in rats. METHODS: Contusive SCI was induced using a force-calibrated weight-drop device at the T10 level in anesthetized rats. Two weeks after severe SCI, blood flow in the femoral arteries was measured, and the vasomotor function and expression of alpha1-adrenergic receptors were analyzed. RESULTS: Blood flow in the femoral artery was significantly reduced in rats with SCI (8.0+/-2 vs. 17.5+/-4 mL/min, SCI vs. control, respectively; p=.016). The contraction responses of femoral artery segments to cumulative addition of alpha1-adrenergic agonist phenylephrine were significantly enhanced in rats with SCI. Expression of alpha1-adrenergic receptor was upregulated in the medial layer of femoral artery vascular homogenates of these rats. CONCLUSION: Our study provides evidence demonstrating that prolonged denervation below the lesion level following SCI results in a compensatory increased expression of alpha1-adrenergic receptors in the arterial smooth muscle layer, thereby enhancing the responsiveness to alpha1-adrenergic agonist and potentiating the development of AD. PMID- 26433038 TI - Development of a Rat Model of Mechanically Induced Tunable Pain and Associated Temporomandibular Joint Responses. AB - PURPOSE: Although mechanical overloading of the temporomandibular joint (TMJ) is implicated in TMJ osteoarthritis (OA) and orofacial pain, most experimental models of TMJ-OA induce only acute and resolving pain, which do not meaningfully simulate the pathomechanisms of TMJ-OA in patients with chronic pain. The aim of this study was to adapt an existing rat model of mechanically induced TMJ-OA, to induce persistent orofacial pain by altering only the jaw-opening force, and to measure the expression of common proxies of TMJ-OA, including degradation and inflammatory proteins, in the joint. MATERIALS AND METHODS: TMJ-OA was mechanically induced in a randomized, prospective study using 2 magnitudes of opening loads in separate groups (ie.,. 2-N, 3.5-N and sham control [no load]). Steady mouth opening was imposed daily (60 minutes/day for 7 days) in female Holtzman rats, followed by 7 days of rest, and orofacial sensitivity was measured throughout the loading and rest periods. Joint structure and extent of degeneration were assessed at day 14 and expression of matrix metalloproteinase 13 (MMP-13), hypoxia-inducible factor-1alpha (HIF-1alpha), and tumor necrosis factor-alpha (TNF-alpha) in articular cartilage was evaluated by immunohistochemistry and quantitative densitometry methods at day 7 between the 2 loading and control groups. Statistical differences of orofacial sensitivity and chondrocyte expression between loading groups were computed and significance was set at a P value less than .05. RESULTS: Head-withdrawal thresholds for the 2 loading groups were significantly decreased during loading (P < .0001), but that decrease remained through day 14 only for the 3.5-N group (P < .00001). At day 14, TMJs from the 2-N and 3.5-N groups exhibited truncation of the condylar cartilage, typical of TMJ-OA. In addition, a 3.5-N loading force significantly upregulated MMP-13 (P < .0074), with nearly a 2-fold increase in HIF-1alpha (P < .001) and TNF-alpha (P < .0001) at day 7, in 3.5-N loaded joints over those loaded by 2 N. CONCLUSION: Unlike a 2-N loading force, mechanical overloading of the TMJ using a 3.5-N loading force induced constant and nonresolving pain and the upregulation of inflammatory markers only in the 3.5-N group, suggesting that these markers could predict the maintenance of persistent orofacial pain. As such, the development of a tunable experimental TMJ-OA model that can separately induce acute or persistent orofacial pain using similar approaches provides a platform to better understand the pathomechanisms involved and possibly to evaluate potential treatment strategies for patients with painful TMJ-OA. PMID- 26433039 TI - Primary Intraosseous Squamous Cell Carcinoma of the Jaws: 6 New Cases, Experience, and Literature Comparison. AB - PURPOSE: To analyze the clinical, histologic, radiologic, therapeutic, and prognostic aspects of 6 cases of an uncommon head and neck malignancy and compare these results with data in the literature. MATERIALS AND METHODS: The medical histories of all patients treated in the Maxillofacial Surgery Unit in San Gerardo Hospital (Monza, Italy) for primitive intraosseous squamous cell carcinoma (PIOSCC) of the jaw were reviewed. All patients were considered suitable for inclusion in the study, specifically those whose oral mucosa had not been compromised and who did not have distant metastases. RESULTS: Six patients were included (4 male, 2 female). The odontogenic origin was histologically shown in only 2 patients. The male-to-female ratio was 2:1, and the malignancy occurred in the posterior mandible in 50% of cases. The most common symptoms were swelling and pain, but no sensory disturbances were observed. Radiologic findings indicated considerable variation in presentation, including small cystic lesions, which might complicate a pathologic diagnosis. All patients in the study were treated with surgery, and 2 patients received adjuvant radiotherapy. Cervical node metastases were present in 33% of patients. All patients are currently alive and free of disease. CONCLUSION: PIOSCC is a rare malignancy of the head and neck. Diagnosis can be difficult during the early stages of disease owing to a lack of clinical symptoms or radiologic presentation. Treatment is surgical and, like every other cancer, must be adequate to cure the cancer. PMID- 26433040 TI - Effects of a Single-Dose of Pre-Emptive Pregabalin on Postoperative Pain and Opioid Consumption After Double-Jaw Surgery: A Randomized Controlled Trial. AB - PURPOSE: The effect of a single-dose of pre-emptive pregabalin is still unknown, although it is used as an adjuvant in controlling acute postoperative pain. The purpose of this study was to evaluate the effects of pre-emptive single-dose pregabalin on postoperative acute pain and 24-hour opioid consumption in patients who underwent double-jaw surgery. PATIENTS AND METHODS: Forty patients (18 to 45 yr old; American Society of Anesthesiologists status I to II) for whom elective double-jaw surgery was planned under general anesthesia were included in this study, which had been planned as a prospective, randomized, and double-blinded study. Patients were randomly divided into 2 groups: the pregabalin group (n = 20) was given pregabalin 150 mg orally 1 hour before general anesthesia and the placebo group (n = 20) was given an oral placebo capsule. The groups were administered the routine general anesthesia protocol. Postoperative analgesia was performed intravenously in the 2 groups twice a day with dexketoprofen trometamol 50 mg and patient-controlled analgesia with fentanyl. Postoperative analgesia was evaluated using the visual analog scale (VAS). Fentanyl consumption, additional analgesia requirement, and side-effects were recorded during the first 24 hours after surgery. Descriptive and bivariate statistics were computed, and significance was set at a P value less than .05. RESULTS: Compared with placebo, the VAS score was statistically lower in the pregabalin group during the early postoperative period (P < .05). The 24-hour opioid consumption was significantly higher in the placebo group compared with the pregabalin group (509.40 +/- 261.56 vs. 260.10 +/- 246.53 MUq, respectively; P = .004). In addition, the analgesia requirement was statistically lower in the pregabalin group (P < .05). Nausea or vomiting was observed more often in the placebo group, whereas other side-effects were similar for the 2 groups. CONCLUSION: A single 150-mg dose of pre-emptive pregabalin decreased postoperative opioid consumption in the first 24 hours after double-jaw surgery. Multimodal analgesia techniques that contain pre-emptive analgesia can be used successfully in preventing postoperative pain caused by orthognathic surgery. PMID- 26433041 TI - Adipose-Derived Stem Cells Decrease Bone Morphogenetic Protein Type 2-Induced Inflammation In Vivo. AB - PURPOSE: Recombinant human bone morphogenetic protein type 2 (rhBMP-2) has been used to promote bone regeneration. In contrast, some reports have suggested rhBMP 2 does not provide advantages over autogenous bone grafting owing to the undesirable postoperative symptoms of this growth factor. Because the undesirable symptoms of rhBMP-2 are usually promoted by inflammation, this study evaluated the in vivo effect of human adipose-derived stem cells (ASCs) incorporated into polylactic co-glycolic acid (PLGA) scaffolds in decreasing the inflammatory response induced by a low dose of rhBMP-2. MATERIALS AND METHODS: PLGA scaffolds were characterized and loaded with rhBMP-2 1, 2.5, or 5 MUg per scaffold (n = 6) and the in vitro released protein amounts were quantified at 7 hours and 1, 7, and 21 days after loading (n = 3). The muscle tissue of 6 beagles received the following treatments: PLGA, PLGA plus rhBMP-2 (2.5 MUg), and PLGA plus rhBMP-2 plus ASCs (1 * 10(6) ASCs). The samples were evaluated 45 days after surgery. Statistical analyses were performed and the P value was set at .05. RESULTS: PLGA plus rhBMP-2 plus ASCs yielded the smallest number of inflammatory foci (P < .001) and giant cells (P < .001) and the largest number of angiogenesis sites (P < .001). CONCLUSIONS: Human ASCs administered in vivo into PLGA scaffolds with a low dose of rhBMP-2 decrease tissue inflammation and increase angiogenesis in muscular sites. PMID- 26433042 TI - Epidural Tube: A Useful Device in Sialendoscopy Operations. AB - Salivary endoscopy, which was first described in 1991, is a safe technique with few complications. The sialendoscopy operation has been developed and successfully offered as a minimally invasive and gland-preserving approach for the treatment of chronic obstructive sialadenitis. For many surgeons, entering the duct lumen of the salivary gland is the most difficult and time-consuming step of the sialendoscopy operation. This report introduces a timesaving and straightforward method for entering the duct lumen using an epidural tube, which is a plastic tube with a blunt tip. PMID- 26433043 TI - Alterations in hippocampal myelin and oligodendrocyte precursor cells during epileptogenesis. AB - Recent reports have described damage to myelinated fibers in the central nervous system (CNS) in patients with temporal lobe epilepsy (TLE) and animal models. However, only limited data are available on the dynamic changes that occur in myelinated fibers, oligodendrocytes (which are myelin-forming cells), and oligodendrocyte precursor cells (OPCs), which are a reservoir of new oligodendrocytes, in the hippocampus throughout epileptogenesis. The current study was designed to examine this issue using a rat model of lithium-pilocarpine induced epilepsy. Electroencephalography (EEG), immunofluorescence, and Western blot analysis showed that the loss of myelin and oligodendrocytes in the rat hippocampus began during the acute stage of epileptogenesis, and the severity of this loss increased throughout epileptogenesis. Accompanying this loss of myelin and oligodendrocytes, OPCs in the rat hippocampus became activated and their populations increased during several phases of epileptogenesis (the acute, latent and chronic phases). The transcription factors olig1 and olig2, which play crucial roles in regulating OPC proliferation, differentiation and remyelination, were up-regulated during the early phases (the acute and latent phases) followed by a sharp decline in their expression during the chronic and late chronic phases. This study is the first to confirm the loss of myelin and oligodendrocytes during lithium-pilocarpine-induced epileptogenesis accompanied by a transient increase in the number of OPCs. Prevention of the loss of myelin and oligodendrocytes may provide a novel treatment strategy for epilepsy. PMID- 26433045 TI - At the Intersection of Poverty and Disability: Supplemental Security Income for Children With Disabilities Due to Mental Health Problems. PMID- 26433044 TI - The effects of repetitive vibration on sensorineural function: biomarkers of sensorineural injury in an animal model of metabolic syndrome. AB - Exposure to hand-transmitted vibration in the work-place can result in the loss of sensation and pain in workers. These effects may be exacerbated by pre existing conditions such as diabetes or the presence of primary Raynaud's phenomena. The goal of these studies was to use an established model of vibration induced injury in Zucker rats. Lean Zucker rats have a normal metabolic profile, while obese Zucker rats display symptoms of metabolic disorder or Type II diabetes. This study examined the effects of vibration in obese and lean rats. Zucker rats were exposed to 4h of vibration for 10 consecutive days at a frequency of 125 Hz and acceleration of 49 m/s(2) for 10 consecutive days. Sensory function was checked using transcutaneous electrical stimulation on days 1, 5 and 9 of the exposure. Once the study was complete the ventral tail nerves, dorsal root ganglia and spinal cord were dissected, and levels of various transcripts involved in sensorineural dysfunction were measured. Sensorineural dysfunction was assessed using transcutaneous electrical stimulation. Obese Zucker rats displayed very few changes in sensorineural function. However they did display significant changes in transcript levels for factors involved in synapse formation, peripheral nerve remodeling, and inflammation. The changes in transcript levels suggested that obese Zucker rats had some level of sensory nerve injury prior to exposure, and that exposure to vibration activated pathways involved in injury and re-innervation. PMID- 26433046 TI - Impact of Wheelchair Rugby on Body Composition of Subjects With Tetraplegia: A Pilot Study. AB - OBJECTIVE: To investigate the longitudinal effects of wheelchair rugby (WR) training on body composition of subjects with tetraplegia. DESIGN: Subjects were evaluated at baseline and after WR training. SETTING: Faculty of physical education settings. PARTICIPANTS: Individuals with tetraplegia (N=13; age, 26.6+/ 6.0y). INTERVENTIONS: Four sessions per week of WR training composed by aerobic and anaerobic activities and technical and tactical aspects of WR. The average time of intervention was 8.1+/-2.5 months. MAIN OUTCOME MEASURES: Body composition assessed by dual-energy x-ray absorptiometry. RESULTS: After training, fat mass was significantly reduced in the whole body (15,191+/-4603 vs 13,212+/-3318 g, P=.016), trunk (7058+/-2639 vs 5693+/-1498 g, P=.012), and legs (2847+/-817 vs 2534+/-742 g, P=.003). Conversely, increased bone mineral content (183+/-35 vs 195+/-32 g, P=.01) and fat-free mass (2991+/-549 vs 3332+/-602 g, P=.016) in the arms and reduced bone mineral content in the trunk (553+/-82 vs 521+/-86 g, P=.034) were observed after training. Furthermore, no significant correlation between the duration of training and changes in body composition was detected. CONCLUSIONS: Regular WR training increased lean mass and bone mineral content in the arms and decreased total body fat mass. Conversely, WR training was associated with decreased bone mineral content in the trunk. These results suggest that regular WR training improves body composition in subjects with tetraplegia. PMID- 26433047 TI - Nanobody-functionalized PEG-b-PCL polymersomes and their targeting study. AB - We prepared and characterized polymersomes functionalized with nanobodies (VHHs) on the basis of biocompatible, biodegradable and FDA-approved poly(ethylene glycol)-block-poly(epsilon-caprolactone) (PEG-b-PCL). Fluorescein isothiocyanate (FITC) and N-beta-maleimidopropyl-oxysuccinimide ester were allowed reacting with H2N-PEG-b-PCL to produce FITC and maleimide (Mal) functionalized copolymers, Mal PEG-b-PCL and FITC-PEG-b-PCL. A mixture of MeO-PEG-b-PCL, Mal-PEG-b-PCL and FITC PEG-b-PCL was used to prepare polymersomes by thin film hydration and nanoprecipitation methods. Morphological studies by cryogenic transmission electron microscopy (Cryo-TEM) showed that the nanoparticles exhibited predominantly vesicular structures (polymersomes). Their mean diameters measured by dynamic light scattering were around 150 nm and the zeta-potentials around -1 mV at pH 7.4. The nanoparticles were functionalized with either anti-HER2 (VHH1) or anti-GFP (VHH2) nanobodies using maleimide-cysteine chemistry. Their particle size and zeta-potential increased slightly after nanobody-functionalization. The specific binding of VHH-functionalized polymersomes and control nanoparticles towards HER2 positive breast cancer cells was analyzed by flow cytometry and confocal microscopy. The collected results represent the first report which experimentally demonstrates that VHH1-functionalized PEO-b-PCL polymersomes can target specifically breast cancer cells expressing HER2 receptors. The detailed morphological and cell-binding studies described herein pave the way for future in vivo studies to evaluate the feasibility to use such nanoparticles for targeted drug delivery. PMID- 26433049 TI - Budget constrained non-monotonic feature selection. AB - Feature selection is an important problem in machine learning and data mining. We consider the problem of selecting features under the budget constraint on the feature subset size. Traditional feature selection methods suffer from the "monotonic" property. That is, if a feature is selected when the number of specified features is set, it will always be chosen when the number of specified feature is larger than the previous setting. This sacrifices the effectiveness of the non-monotonic feature selection methods. Hence, in this paper, we develop an algorithm for non-monotonic feature selection that approximates the related combinatorial optimization problem by a Multiple Kernel Learning (MKL) problem. We justify the performance guarantee for the derived solution when compared to the global optimal solution for the related combinatorial optimization problem. Finally, we conduct a series of empirical evaluation on both synthetic and real world benchmark datasets for the classification and regression tasks to demonstrate the promising performance of the proposed framework compared with the baseline feature selection approaches. PMID- 26433048 TI - Total synthesis of biologically active 20S-hydroxyvitamin D3. AB - A total synthetic strategy of 20S-hydroxyvitamin D3 [20S-(OH)D3] involving modified synthesis of key intermediates 7 and 12, Grignard reaction to stereoselectively generate 20S-OH and Wittig-Horner coupling to establish D3 framework, was completed in 16 steps with an overall yield of 0.4%. The synthetic 20S-(OH)D3 activated vitamin D receptor (VDR) and initiated the expression of downstream genes. In addition, 20S-(OH)D3 showed similar inhibitory potency as calcitriol [1,25(OH)2D3] on proliferation of melanoma cells. PMID- 26433050 TI - Binding of inferred germline precursors of broadly neutralizing HIV-1 antibodies to native-like envelope trimers. AB - HIV-1 envelope glycoproteins (Env) and Env-based immunogens usually do not interact efficiently with the inferred germline precursors of known broadly neutralizing antibodies (bNAbs). This deficiency may be one reason why Env and Env-based immunogens are not efficient at inducing bNAbs. We evaluated the binding of 15 inferred germline precursors of bNAbs directed to different epitope clusters to three soluble native-like SOSIP.664 Env trimers. We found that native like SOSIP.664 trimers bind to some inferred germline precursors of bNAbs, particularly ones involving the V1/V2 loops at the apex of the trimer. The data imply that native-like SOSIP.664 trimers will be an appropriate platform for structure-guided design improvements intended to create immunogens able to target the germline precursors of bNAbs. PMID- 26433051 TI - Addition of N-glycosylation sites on the globular head of the H5 hemagglutinin induces the escape of highly pathogenic avian influenza A H5N1 viruses from vaccine-induced immunity. AB - Highly pathogenic avian influenza A H5N1 viruses remain endemic in poultry in several countries and still constitute a pandemic threat. Since the early 20th century, we experienced four influenza A pandemics. H3N2 and H1N1pdm09 viruses that respectively emerged during 1968 and 2009 pandemics are still responsible for seasonal epidemics. These viruses evolve regularly by substitutions in antigenic sites of the hemagglutinin (HA), which prevent neutralization by antibodies directed against previous strains (antigenic drift). For seasonal H3N2 viruses, an addition of N-glycosylation sites (glycosites) on H3 contributed to this drift. Here, we questioned whether additional glycosites on H5 could induce an escape of H5N1 virus from neutralization, as it was observed for seasonal H3N2 viruses. Seven H5N1 mutants were produced by adding glycosites on H5. The most glycosylated virus escaped from neutralizing antibodies, in vitro and in vivo. Furthermore, a single additional glycosite was responsible for this escape. PMID- 26433052 TI - Blind people are more sensitive than sighted people to binaural sound-location cues, particularly inter-aural level differences. AB - Blind people use auditory information to locate sound sources and sound reflecting objects (echolocation). Sound source localization benefits from the hearing system's ability to suppress distracting sound reflections, whereas echolocation would benefit from "unsuppressing" these reflections. To clarify how these potentially conflicting aspects of spatial hearing interact in blind versus sighted listeners, we measured discrimination thresholds for two binaural location cues: inter-aural level differences (ILDs) and inter-aural time differences (ITDs). The ILDs or ITDs were present in single clicks, in the leading component of click pairs, or in the lagging component of click pairs, exploiting processes related to both sound source localization and echolocation. We tested 23 blind (mean age = 54 y), 23 sighted-age-matched (mean age = 54 y), and 42 sighted-young (mean age = 26 y) listeners. The results suggested greater ILD sensitivity for blind than for sighted listeners. The blind group's superiority was particularly evident for ILD-lag-click discrimination, suggesting not only enhanced ILD sensitivity in general but also increased ability to unsuppress lagging clicks. This may be related to the blind person's experience of localizing reflected sounds, for which ILDs may be more efficient than ITDs. On the ITD-discrimination tasks, the blind listeners performed better than the sighted age-matched listeners, but not better than the sighted young listeners. ITD sensitivity declines with age, and the equal performance of the blind listeners compared to a group of substantially younger listeners is consistent with the notion that blind people's experience may offset age-related decline in ITD sensitivity. PMID- 26433053 TI - Cochlear implantation as a long-term treatment for ipsilateral incapacitating tinnitus in subjects with unilateral hearing loss up to 10 years. AB - INTRODUCTION: The authors previously demonstrated that tinnitus resulting from unilateral hearing loss (UHL) can be treated with electrical stimulation via a Cochlear Implant (CI). The study aimed to do a long-term (LT) evaluation of CI in subjects suffering from UHL and accompanied incapacitating tinnitus up to 10 years. The primary focus of the study is on LT tinnitus reduction. SUBJECTS: LT evaluation was derived from 23 subjects suffering from UHL and accompanied incapacitating tinnitus (Pre-operative Tinnitus Loudness Visual Analogue Scale (VAS) score >6/10). They were cochlear implanted at a median age of 55 years (22 71 yr) and had 8 years (3-10 yr) experience with their CI at the LT testing. The subjects were categorized into two groups: a Single-Sided Deaf Group (SSD) and an Asymmetric Hearing Loss Group (AHL). The SSD group comprises subjects with contralateral normal hearing (i.e. air conduction pure tone average (PTA0.5, 1, 2 and 4 kHz) <= 30 dB HL) and the AHL group subjects with contralateral mild to moderate hearing loss (i.e. air conduction PTA0.5, 1, 2 and 4 kHz > 30 dB HL). METHODS: In order to obtain a LT structural overview of the CI use in UHL subjects, a structured interview was conducted including questions about daily amount of CI use, residual inhibition of the tinnitus after switch off, tinnitus type, etc. The VAStinnitus loudness and the Tinnitus Questionnaire were obtained pre-operatively, one, three, six, 12, and 36-months post-operatively and at the long-term test interval (8 (3-10 years) post-operative). The Hyperacusis Questionnaire was administered in the CION and the CIOFF condition. RESULTS: The structural interview revealed that all patients (23/23) still wear their CI seven days a week, eight (3-10) years after cochlear implantation. It appeared that in all subjects but one CI switch-on is the first act when rising and CI switch-off is the last act before bedtime. In the SSD group, tinnitus suppression is still the primary benefit reported (83%), whereas in the AHL the majority of the subjects (55%) report that the primary benefit shifted to improved hearing. In the majority of the subjects the tinnitus reduction starts within 1 min (in 70% of the cases) and the residual inhibition after CI switch-off is less than a minute (in 65% of the cases). The VAS and TQ scores significantly improved up to three months after the first-fitting and remain stable up to the LT test interval. The median score on the Hyperacusis Questionnaire was 17 (7-36) in the CIOFF condition and improved to 23,5 (12-39) in the CION condition in the SSD group. CONCLUSION: This is the first study to report on LT results in a large number of UHL CI users, up to 10 years. Structured interviews shows that 100% of the subjects wears their CI seven days a week. The tinnitus reduces significantly up to three months after the first-fitting and the tinnitus reduction remain stable up to the LT test interval. The SSD group report tinnitus reduction as the primary benefit, whereas the majority of the AHL group report improved hearing as the primary benefit, eight (3-10) years after implantation. In addition to the tinnitus reduction, the CI provides also a benefit regarding reported. PMID- 26433054 TI - Cannabinoids, cannabinoid receptors and tinnitus. AB - One hypothesis suggests that tinnitus is a form of sensory epilepsy, arising partly from neuronal hyperactivity in auditory regions of the brain such as the cochlear nucleus and inferior colliculus. Although there is currently no effective drug treatment for tinnitus, anti-epileptic drugs are used in some cases as a potential treatment option. There is increasing evidence to suggest that cannabinoid drugs, i.e. cannabinoid receptor agonists, can also have anti epileptic effects, at least in some cases and in some parts of the brain. It has been reported that cannabinoid CB1 receptors and the endogenous cannabinoid, 2 arachidonylglycerol (2-AG), are expressed in the cochlear nucleus and that they are involved in the regulation of plasticity. This review explores the question of whether cannabinoid receptor agonists are likely to be pro- or anti-epileptic in the cochlear nucleus and therefore whether cannabinoids and Cannabis itself are likely to make tinnitus better or worse. PMID- 26433055 TI - PDCD5 functions as a regulator of p53 dynamics in the DNA damage response. AB - The tumor suppressor p53 plays a central role in cell fate decisions after DNA damage. Programmed Cell Death 5 (PDCD5) interacts with the p53 pathway to promote cell apoptosis. Recombinant human PDCD5 can significantly sensitize different cancers to chemotherapies. In the present paper, we construct a computational model that includes PDCD5 interactions in the p53 signaling network and study the effects of PDCD5 on p53-mediated cell fate decisions during the DNA damage response. Our results revealed that PDCD5 functions as a co-activator of p53 and regulates p53-dependent cell fate decisions via the mediation of p53 dynamics. The effects of PDCD5 are dose-dependent, such that p53 activity exhibits sustained low level, pulsed oscillations, or sustained high level dynamics depending on the PDCD5 level following DNA damage. Moreover, PDCD5 regulates caspase-3 activation via two mechanisms during the two phases of sustained and pulsed p53 dynamics. This study provides insights regarding how PDCD5 functions as a regulator of the p53 pathway and might be helpful for increasing our understanding of the molecular mechanisms by which PDCD5 can be used to treat cancers. PMID- 26433056 TI - Redox modulation of cellular stress response and lipoxin A4 expression by Coriolus versicolor in rat brain: Relevance to Alzheimer's disease pathogenesis. AB - Increasing evidence supports the notion that oxidative stress-driven neuroinflammation is an early pathological feature in neurodegenerative diseases. As a prominent intracellular redox system involved in neuroprotection, the vitagene system is emerging as a potential neurohormetic target for novel cytoprotective interventions. Vitagenes encode for cytoprotective heat shock proteins 70, heme oxygenase-1, thioredoxin and lipoxin A4. Emerging interest is now focusing on molecules capable of activating the vitagene system as novel therapeutic targets to minimize deleterious consequences associated with free radical-induced cell damage, such as in neurodegeneration. Mushroom-derived lipoxin A4 (LXA4) is an emerging endogenous eicosanoid able to promote resolution of inflammation, acting as an endogenous "braking signal" in the inflammatory process. Mushrooms have long been used in traditional medicine for thousands of years, being now increasingly recognized as rich source of polysaccharopeptides endowed with significant antitumor, antioxidant, antiviral, antibacterial and cytoprotective effects, thereby capable of stimulating host immune responses. Here we provide evidence of a neuroprotective action of the Coriolus mushroom when administered orally to rat. Expression of LXA4 was measured in different brain regions after oral administration of a Coriolus biomass preparation, given for 30 days. LXA4 up-regulation was associated with an increased content of redox sensitive proteins involved in cellular stress response, such as Hsp72, heme oxygenase-1 and thioredoxin. In the brain of rats receiving Coriolus, maximum induction of LXA4 was observed in cortex and hippocampus. Hsps induction was associated with no significant changes in IkBalpha, NFkB and COX-2 brain levels. Conceivably, activation of LXA4 signaling and modulation of stress-responsive vitagene proteins could serve as a potential therapeutic target for AD-related inflammation and neurodegenerative damage. PMID- 26433057 TI - Expression and function of toll-like receptors in human circulating endothelial colony forming cells. AB - Mature endothelial cells are known to sense microbial products through toll-like receptors (TLRs), a family of membrane proteins which serve as pathogen recognition and signaling elements; however, there are limited data in the literature about the expression and function of TLRs in human circulating endothelial colony forming cells (ECFCs), which are considered the most likely endothelial precursors. We expanded and differentiated in vitro umbilical cord blood (UCB) and adult peripheral blood (PB) ECFCs and studied the expression of TLR1 to TLR10 mRNA by qPCR analysis, and we further characterized TLR function in ECFCs through functional assays including in vitro ECFC growth and differentiation, assessment of cytokine production, and measurement of intracellular Ca(2+) signals. Both UCB- and PB-ECFCs had detectable mRNA levels of all the TLRs from 1 to 10; TLR4, a sensor of Gram-negative bacterial lipopolysaccharide (LPS), had a higher level compared to other TLRs. Exposure to LPS induced cytokine production, although with less efficiency compared to PB mononuclear cells. However, no effect of LPS was seen on ECFC growth and differentiation, and no increase in intracellular Ca(2+) concentrations, which is essential for ECFC proliferation, was observed after exposure to increasing amounts of LPS. Our data show that all TLRs from 1 to 10 are constitutively expressed in ECFCs, and suggest that TLR4 is functional in ECFCs, but its activation through its ligand LPS does not affect ECFC growth and differentiation. PMID- 26433058 TI - Characteristics of the peripheral T cell immune response of patients at different stages of vascular cognitive impairment. AB - AIM: To investigate the characteristics of the peripheral T cell immune response of patients at different stages of vascular cognitive impairment (VCI). METHODS: 61 Arterial atherosclerotic cerebral infarct induced VCI patients, including 28 vascular dementia (VaD) cases, 33 no dementia (VCI-ND) cases, and 25 atherosclerotic cerebral infarct patients with normal cognitive function (CI-NC) as controls were enrolled. Peripheral CD8(+)T, CD4(+)CD25(+) Treg, CD4(+)IL-17(+) Th17 cells proportion, and IL-1beta, IL-2, IL-6, IFN-gamma levels, and neuropsychological function were assessed. RESULTS: There was no difference in average age, gender ratio, years of education, and risk factors of infarct among the three groups. Peripheral CD4(+)CD25(+) Treg in VCI-ND and VaD groups were significantly lower than that in controls, and CD8(+) T cells were markedly elevated in VaD group. The IL-17(+) Th17 cell proportion did not differ significantly among three groups. IL-6 and IFN-gamma expression levels in VaD group were higher than those in other two groups. The VDAS-Cog executive function subscale score was negatively correlated with CD4(+)CD25(+) Treg proportion in VCI patients, and positively correlated with IL-6 levels. CONCLUSION: VCI patients demonstrated a decrease in peripheral CD4(+) Treg proportion and increased IL-6 expression, and both parameters were correlated with the decline of executive functions. PMID- 26433059 TI - Antibody profile in Indian severe haemophilia A patients with and without FVIII inhibitors. AB - Diagnosis and management of haemophilia patients with inhibitors is often tricky due to the heterogeneous nature of the antibodies with regard to their kinetics, as well as the co-existence of other interfering antibodies. Plasma samples from severe haemophilia A patients from India with and without FVIII inhibitors were analysed for the presence of possible co-existing antibodies such as lupus anticoagulants (LA), anti-cardiolipin antibodies (ACLA), anti-beta2-glycoprotein I (anti-beta2-GP-I) antibodies, viral transfusion transmitted disease (HIV, HBsAg, HCV) related antibodies, anti-cyclic citrullinated peptides (anti-CCP), and anti-nuclear antibodies. A high incidence of LA and anti-HCV antibodies was detected in Indian haemophilia A patients similar to earlier reports. More importantly, a relatively high incidence of autoantibodies to nuclear antigens (18.62%) and anti-CCP antibodies (1.38%) associated with autoimmune disorders was also seen in these congenital haemophilia A patients with and without inhibitors. Knowledge on the antibody profile in these haemophilia patients especially in those with FVIII inhibitors along with correlation with the clinical manifestations and other risk factors for inhibitor development could possibly shed more light on the complex immune response in these patients. PMID- 26433060 TI - Glucocorticoid receptor exhibits sexually dimorphic expression in the medaka brain. AB - The differential impact of stress on brain functions of males and females has been widely observed in vertebrates. Recent evidence suggests that stress-induced glucocorticoid signaling affects sexual differentiation and sex changes in teleost fish. These facts led us to postulate that there were sex differences in glucocorticoid signaling in the teleost brain that underlie some sex differences in their physiological and behavioral traits. Here we found sexually dimorphic expression of a glucocorticoid receptor gene (gr1) in the brain of medaka fish (Oryzias latipes), with females having greater expression in several preoptic and thalamic nuclei. Further, gr1 exhibits female-biased expression in neurons of the anterior parvocellular preoptic nucleus that produce the neuropeptides vasotocin and gonadotropin-releasing hormone 1 (these neuropeptides have been implicated in the regulation of neuroendocrine and behavioral functions). These findings suggest that glucocorticoids have a greater influence on physiology and behavior mediated by these neuropeptides in females than in males, which may contribute to sex differences in the brain's response to stress. PMID- 26433061 TI - Shaking the myth: Body mass, aggression, steroid hormones, and social dominance in wild house mouse. AB - In social mammals, the position of a male in the group's hierarchy strongly affects his reproductive success. Since a high social rank is often gained through competition with other males, selection should favour bigger males over smaller ones. We may therefore predict faster growth and/or delayed sexual maturity in dominant males. Likewise, dominants should have higher levels of testosterone, hormone important in many aspects of male dominance. Less obvious is the relationship between dominance and levels of corticosterone but generally higher concentrations are expected in subordinate individuals. We studied body growth, sexual maturation and endocrinal changes in males of two house mouse subspecies, raised in fraternal pairs. Since Mus musculus domesticus is the subspecies which dominates mutual encounters with Mus musculus musculus we predicted higher growth rate, delayed puberty and aggression, and higher testosterone and corticosterone levels in domesticus males compared to musculus. In all comparisons, no differences were found between dominant and subordinate musculus brothers. On the other hand, in M. m. domesticus, dominant males revealed a different growth trajectory and lower corticosterone levels than subordinate males but not delayed puberty and higher testosterone concentrations, thus contradicting our predictions. In inter-subspecific comparisons, musculus males matured earlier but became aggressive at the same time as domesticus males. The musculus testosterone ontogeny suggests that social positions in this subspecies remain unfixed for an extended period and that the increasing levels probably reflect prolonged hierarchy contests. It appears that the ontogeny of behaviour and physiological traits diverge cryptically between the two subspecies. PMID- 26433062 TI - Preventing Thrombosis to Improve Outcomes in Heart Failure Patients. AB - Heart failure (HF) is associated with an increased risk of thrombotic events, particularly if this condition is accompanied by atrial fibrillation (AF). Many HF patients have background coronary artery disease (CAD) making them prone to coronary thrombosis resulting in myocardial infarction or sudden death. Oral anticoagulation is essential in the vast majority of HF patients with AF with non vitamin K based anticoagulants being a suitable alternative to warfarin. In contrast, aspirin alone does not provide adequate stroke prevention in such patients. In HF without AF, oral anticoagulation should not be routinely used, and antiplatelet agents should be prescribed in patients with background CAD. This review provides an overview of prothrombotic factors and antithrombotic management of patients with HF. PMID- 26433063 TI - Loss of the Drosophila melanogaster DEAD box protein Ddx1 leads to reduced size and aberrant gametogenesis. AB - Mammalian DDX1 has been implicated in RNA trafficking, DNA double-strand break repair and RNA processing; however, little is known about its role during animal development. Here, we report phenotypes associated with a null Ddx1 (Ddx1(AX)) mutation generated in Drosophila melanogaster. Ddx1 null flies are viable but significantly smaller than control and Ddx1 heterozygous flies. Female Ddx1 null flies have reduced fertility with egg chambers undergoing autophagy, whereas males are sterile due to disrupted spermatogenesis. Comparative RNA sequencing of control and Ddx1 null third instars identified several transcripts affected by Ddx1 inactivation. One of these, Sirup mRNA, was previously shown to be overexpressed under starvation conditions and implicated in mitochondrial function. We demonstrate that Sirup is a direct binding target of Ddx1 and that Sirup mRNA is differentially spliced in the presence or absence of Ddx1. Combining Ddx1 null mutation with Sirup dsRNA-mediated knock-down causes epistatic lethality not observed in either single mutant. Our data suggest a role for Drosophila Ddx1 in stress-induced regulation of splicing. PMID- 26433065 TI - A photoelectrochemical biosensor for fibroblast-like synoviocyte cell using visible light-activated NCQDs sensitized-ZnO/CH3NH3PbI3 heterojunction. AB - Based on ZnO nanorods (NRs)/CH3NH3PbI3/nitrogen-doped carbon quantum dots (NCQDs) nanocomposites, the highly sensitive detection of fibroblast-like synoviocyte (FLS) cell was realized by a photoelectrochemical (PEC) biosensor. ZnO/CH3NH3PbI3/NCQDs nanocomposites were exploited as the photo-to-electron generator to produce the signal. CH3NH3PbI3 was spin-coated on ZnO surface after ZnO NRs grew on ITO electrode then by dropping on the modified electrode, NCQDs were diffused and adhered to the surface of ZnO and CH3NH3PbI3. In the presence of EDC/NHS, the combination of CH3NH3PbI3 and NCQDs was achieved by the carboxyl groups (-COOH) and amino groups (-NH2) in the preparation process. Furthermore, the capture probe of FLS cell, CD95 antibody, can be anchored by -COOH and -NH2 groups through EDC/NHS. The specific recognition between the antibody capture probes and cell targets gained high-sensitive detection for FLS cell for the first time. The developed biosensor showed a wide linear range from 1.0 * 10(4)cell/mL to 10 cell/mL and a low detection limit of 2 cell/mL. This kind of biosensor would provide a novel detection strategy for FLS cell. PMID- 26433064 TI - RNA sequences required for the noncoding function of oskar RNA also mediate regulation of Oskar protein expression by Bicoid Stability Factor. AB - The Drosophila oskar (osk) mRNA is unusual in having both coding and noncoding functions. As an mRNA, osk encodes a protein which is deployed specifically at the posterior of the oocyte. This spatially-restricted deployment relies on a program of mRNA localization and both repression and activation of translation, all dependent on regulatory elements located primarily in the 3' untranslated region (UTR) of the mRNA. The 3' UTR also mediates the noncoding function of osk, which is essential for progression through oogenesis. Mutations which most strongly disrupt the noncoding function are positioned in a short region (the C region) near the 3' end of the mRNA, in close proximity to elements required for activation of translation. We show that Bicoid Stability Factor (BSF) binds specifically to the C region of the mRNA. Both knockdown of bsf and mutation of BSF binding sites in osk mRNA have the same consequences: Osk expression is largely eliminated late in oogenesis, with both mRNA localization and translation disrupted. Although the C region of the osk 3' UTR is required for the noncoding function, BSF binding does not appear to be essential for that function. PMID- 26433066 TI - Ultrasensitive photoelectrochemical immunoassay for CA19-9 detection based on CdSe@ZnS quantum dots sensitized TiO2NWs/Au hybrid structure amplified by quenching effect of Ab2@V(2+) conjugates. AB - A novel, enhanced photoelectrochemical immunoassay was established for sensitive and specific detection of carbohydrate antigen 19-9 (CA19-9, Ag). In this protocol, TiO2 nanowires (TiO2NWs) were first decorated with Au nanoparticles to form TiO2NWs/Au hybrid structure, and then coated with CdSe@ZnS quantum dots (QDs) via the layer-by-layer method, producing TiO2NWs/Au/CdSe@ZnS sensitized structure, which was employed as the photoelectrochemical matrix to immobilize capture CA19-9 antibodies (Ab1); whereas, bipyridinium (V(2+)) molecules were labeled on signal CA19-9 antibodies (Ab2) to form Ab2@V(2+) conjugates, which were used as signal amplification elements. The TiO2NWs/Au/CdSe@ZnS sensitized structure could adequately absorb light energy and dramatically depress electron hole recombination, resulting in evidently enhanced photocurrent intensity of the immunosensing electrode. While target Ag were detected, the Ab2@V(2+) conjugates could significantly decrease the photocurrent detection signal because of strong electron-withdrawing property of V(2+) coupled with evident steric hindrance of Ab2. Thanks to synergy effect of TiO2NWs/Au/CdSe@ZnS sensitized structure and quenching effect of Ab2@V(2+) conjugates, the well-established photoelectrochemical immunoassay exhibited a low detection limit of 0.0039 U/mL with a wide linear range from 0.01 U/mL to 200 U/mL for target Ag detection. This proposed photoelectrochemical protocol also showed good reproducibility, specificity and stability, and might be applied to detect other important biomarkers. PMID- 26433067 TI - Label free electrochemical aptasensor for ultrasensitive detection of ractopamine. AB - A label free electrochemical (EC) aptasensor for ultrasensitive detection of ractopamine (RAC) was developed. A special immobilization media consisting of gold nanoparticles/poly dimethyl diallyl ammonium chloride-graphene composite (AuNPs/PDDA-GN) was utilized to improve conductivity and performance of the biosensor. The RAC aptamer was attached on AuNPs of the composite membrane via Au S bond. The fabrication process of the EC aptasensor was characterized by electrochemical impedance spectroscopy and cyclic voltammetry. The peak currents obtained by differential pulse voltammetry decreased linearly with the increasing of RAC concentrations and the sensor responds approximately logarithmically over a wide dynamic range of RAC concentration from 1.0 * 10(-12)mol/L to 1.0 * 10( 8)mol/L. The linear correlation coefficient of the developed aptasensor was 0.998, the limit of detection was 5.0 * 10(-13)mol/L. The proposed EC aptasensor displayed good stability, reproducibility and robust operation in animal urine. Particularly, the generality of the fabrication approach of electrochemical aptasensor is highlighted with a further example for illegal drugs detection via the aptamer identification. PMID- 26433068 TI - Highly sensitive and simultaneous electrochemical determination of 2-aminophenol and 4-aminophenol based on poly(l-arginine)-beta-cyclodextrin/carbon nanotubes@graphene nanoribbons modified electrode. AB - Owing to the similar characteristics and physiochemical property of 2-aminophenol (2-AP) and 4-aminophenol (4-AP), the highly sensitive simultaneous electrochemical determination of 2- and 4-AP is a great challenge. In this paper, by electropolymerizing beta-cyclodextrin (beta-CD) and l-arginine (l-Arg) on the surface of carbon nanotubes@graphene nanoribbons (CNTs@GNRs) core-shell heterostructure, a P-beta-CD-l-Arg/CNTs@GNRs nanohybrid modified electrode was prepared successfully, and it could exhibit the synergetic effects of beta-CD (high host-guest recognition and enrichment ability), l-Arg (excellent electrocatalytic activity) and CNTs@GNRs (prominent electrochemical properties and large surface area), the P-beta-CD-l-Arg/CNTs@GNRs modified electrode was used in the electrochemical determination of 2- and 4-AP, the results demonstrated that the highly sensitive and simultaneous determination of 2- and 4 AP is successfully achieved and the modified electrode has a linear response range of 25.0-1300.0 nM for both 2- and 4-AP, and the detection limits of 2- and 4-AP obtained in this work are 6.2 and 3.5 nM, respectively. PMID- 26433069 TI - Quantitative determination of uric acid using CdTe nanoparticles as fluorescence probes. AB - A convenient enzymatic optical method for uric acid detection was developed based on the fluorescence quenching of ligand-capped CdTe nanoparticles by H2O2 which was generated from the enzymatic reaction of uric acid. The interactions between the CdTe nanoparticles capped with different ligands (glutathione, 3 mercaptopropionic acid, and thioglycerol) and H2O2 were investigated. The fluorescence quenching studies of GSH-capped CdTe nanoparticles demonstrated an excellent sensitivity to H2O2. The effects of uric acid, uricase and H2O2 on the fluorescence intensity of CdTe nanoparticles were also explored. The detection conditions, reaction time, pH value, incubation period and the concentration of uricase and uric acid were optimized. The detection limit of uric acid was found to be 0.10 uM and the linear range was 0.22-6 uM under the optimized experimental conditions. These results typify that CdTe nanoparticles could be used as a fluorescent probe for uric acid detection. PMID- 26433070 TI - Sensitive and rapid detection of staphylococcus aureus in milk via cell binding domain of lysin. AB - Staphylococcus aureus (S. aureus) is an important food-borne pathogen in dairy products contaminated through raw ingredients or improper food handling. Rapid detection of S. aureus with high sensitivity is of significance for food quality and safety. In this study, a new method was developed for detecting S. aureus in milk by coupling immunomagnetic separation with enzyme linked cell wall binding domain (CBD) of lysin plyV12, which can bind to S. aureus with high affinity. There are millions of binding sites present on the cell surface of S. aureus for the CBD attachment, which greatly improves the detection sensitivity. The method has the overall testing time of only 1.5h with the detection limit of 4 * 10(3)CFU/mL in spiked milk. Because it is simple, rapid and sensitive, this method could be used for the detection of S. aureus in various food samples. PMID- 26433071 TI - Nickel/cobalt oxide-decorated 3D graphene nanocomposite electrode for enhanced electrochemical detection of urea. AB - A NiCo2O4 bimetallic electro-catalyst was synthesized on three-dimensional graphene (3D graphene) for the non-enzymatic detection of urea. The structural and morphological properties of the NiCo2O4/3D graphene nanocomposite were characterized by X-ray diffraction, Raman spectroscopy, and scanning electron microscopy. The NiCo2O4/3D graphene was deposited on an indium tin oxide (ITO) glass to fabricate a highly sensitive urea sensor. The electrochemical properties of the prepared electrode were studied by cyclic voltammetry. A high sensitivity of 166 MUAmM(-)(1)cm(-)(2) was obtained for the NiCo2O4/3D graphene/ITO sensor. The sensor exhibited a linear range of 0.06-0.30 mM (R(2)=0.998) and a fast response time of approximately 1.0 s with a detection limit of 5.0 uM. Additionally, the sensor exhibited high stability with a sensitivity decrease of only 5.5% after four months of storage in ambient conditions. The urea sensor demonstrates feasibility for urea analysis in urine samples. PMID- 26433072 TI - Role of bioactive lipid mediators in obese adipose tissue inflammation and endocrine dysfunction. AB - White adipose tissue is recognized as an active endocrine organ implicated in the maintenance of metabolic homeostasis. However, adipose tissue function, which has a crucial role in the development of obesity-related comorbidities including insulin resistance and non-alcoholic fatty liver disease, is dysregulated in obese individuals. This review explores the physiological functions and molecular actions of bioactive lipids biosynthesized in adipose tissue including sphingolipids and phospholipids, and in particular fatty acids derived from phospholipids of the cell membrane. Special emphasis is given to polyunsaturated fatty acids of the omega-6 and omega-3 families and their conversion to bioactive lipid mediators through the cyclooxygenase and lipoxygenase pathways. The participation of omega-3-derived lipid autacoids in the resolution of adipose tissue inflammation and in the prevention of obesity-associated hepatic complications is also thoroughly discussed. PMID- 26433074 TI - The relationship between wing length, blood meal volume, and fecundity for seven colonies of Anopheles species housed at the Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand. AB - Established colonies of Anopheles campestris, Anopheles cracens, Anopheles dirus, Anopheles kleini, Anopheles minimus, Anopheles sawadwongporni, and Anopheles sinensis are maintained at the Armed Forces Research Institute of Medical Sciences (AFRIMS). Females were provided blood meals on human blood containing citrate as an anticoagulant using an artificial membrane feeder. The mean wing length, used as an estimate of body size, for each species was compared to blood feeding duration (time), blood meal volume, and numbers of eggs oviposited. Except for An. campestris and An. cracens, there were significant interspecies differences in wing length. The mean blood meal volumes (mm(3)) of An. kleini and An. sinensis were significantly higher than the other 5 species. For all species, the ratios of unfed females weights/blood meal volumes were similar (range: 0.76 0.88), except for An. kleini (1.08) and An. cracens (0.52), that were significantly higher and lower, respectively. Adult females were allowed to feed undisturbed for 1, 3, and 5min intervals before blood feeding was interrupted. Except for An. campestris and An. sawadwongporni, the number of eggs oviposited were significantly higher for females that fed for 3min when compared to those that only fed for 1min. This information is critical to better understand the biology of colonized Anopheles spp. and their role in the transmission of malaria parasites as they relate to the relative size of adult females, mean volumes of blood of engorged females for each of the anopheline species, and the effect of blood feeding duration on specific blood meal volumes and fecundity. PMID- 26433073 TI - MicroRNA regulation of F-box proteins and its role in cancer. AB - MicroRNAs (miRNAs) are small endogenous non-coding RNAs, which play critical roles in cancer development by suppressing gene expression at the post transcriptional level. In general, oncogenic miRNAs are upregulated in cancer, while miRNAs that act as tumor suppressors are downregulated, leading to decreased expression of tumor suppressors and upregulated oncogene expression, respectively. F-box proteins function as the substrate-recognition components of the SKP1-CUL1-F-box (SCF)-ubiquitin ligase complex for the degradation of their protein targets by the ubiquitin-proteasome system. Therefore F-box proteins and miRNAs both negatively regulate target gene expression post-transcriptionally. Since each miRNA is capable of fine-tuning the expression of multiple target genes, multiple F-box proteins may be suppressed by the same miRNA. Meanwhile, one F-box proteins could be regulated by several miRNAs in different cancer types. In this review, we will focus on miRNA-mediated downregulation of various F-box proteins, the resulting stabilization of F-box protein substrates and the impact of these processes on human malignancies. We provide insight into how the miRNA: F-box protein axis may regulate cancer progression and metastasis. We also consider the broader role of F-box proteins in the regulation of pathways that are independent of the ubiquitin ligase complex and how that impacts on oncogenesis. The area of miRNAs and the F-box proteins that they regulate in cancer is an emerging field and will inform new strategies in cancer treatment. PMID- 26433075 TI - Mansonella ozzardi in Neotropical region of Argentina: Prevalence through time (1986-2010). AB - Human filariasis caused by Mansonella ozzardi is a parasitic infection of a controversial pathology and poorly studied in Argentina. The aim of this study was not only to obtain data of the prevalence of M. ozzardi in Northwestern Argentina through comparison of infection rates in relation to sex and age group determining the range of distribution of mansonelliasis in the region but also to investigate the prevalence of the cases over time. Through field work carried between 1986 and 2010 by technicians of the National Ministry of Health, aiming to detect active cases of malaria in the Northwestern Argentina, blood samples were taken for smear and thick blood. 417 blood samples were examined, 381 of them (91.4%) were positive for M. ozzardi. The highest prevalence was found in Salta province (92.3%) mainly affecting the male sex (92.6%) and the age groups comprised between 48-57 years (97.0%) and >= 68 (90.7%). The paired t-test and Spearman coefficients showed significant differences in prevalence according to sex (t=2.677; p=0.015), and according infection rates in males and females/age (r=0.994; p=0.001; r=0.994, p=0.001, respectively). The prevalence over time showed a general pattern with the highest cases in 1986, decreasing later during the following years. Aguas Blancas, El Oculto and San Ramon de la Nueva Oran, exhibited a pattern of prevalence according to the general trend but Salvador Mazza and Tartagal, which are also localities close to the border with Bolivia, showed peaks of cases up to 2010. These results provide relevant information about M. ozzardi in Argentina, demonstrating not only its presence and endemicity after almost 100 years from its discovery in the country, but also its wide range of distribution in the region. PMID- 26433076 TI - An epidemiological study of dengue in Delhi, India. AB - Delhi, the capital of India, is an important metropolitan hub for major financial and sociocultural exchanges, offering challenging threats to current public health infrastructure. In recent past, an upsurge of dengue cases in Delhi posed a significant menace to the existing dengue control policies. To reform the control strategies and take timely intervention to prevent future epidemics, an epidemiological study on the proportion of both asymptomatic and symptomatic dengue infections in selected population was conducted. The aim of the study was to investigate and assess the epidemiology of dengue infection and to estimate the proportion of asymptomatic and symptomatic dengue infections in Delhi. In this study, around 50 confirmed dengue cases, a total of 2125 individuals as household and neighbourhood contacts, with or without dengue febrile illness, were finger pricked and serologically detected as dengue positive or negative using SD Duo Bioline Rapid Diagnostic Test (SD Inc, Korea) with NS1, IgM & IgG combo test, which detected dengue virus antigen and antibodies to dengue virus in human blood. Out of 2125 individuals, 768 (36.1%) individuals showed positive dengue test with past (25.5%), primary (1.88%) or secondary (8.8%) dengue infections. Higher percentage of IgG was found in age groups 15-24 years and 25 50 years (36% each). Infants (<1 year) presented higher incidence of new infections (22% of NS1+IgM positives) as compared to adults. Further analysis revealed that out of the 226 newly infected cases (including NS1 and IgM positives), 142 (63%) were asymptomatic and 84 (37%) were symptomatic, as per WHO guidelines. Our findings also suggest that out of the total population screened, 10.6% dengue infection was either primary or secondary. On the basis of these results, it may be hypothesized that there are large number of asymptomatic dengue infections in the community as compared to reported symptomatic cases in Delhi. For the effective control of dengue transmission in such community like Delhi where dengue epidemics have frequently been encountered, it is essential to ascertain the proportion of asymptomatic dengue infections which may act as a reservoir for dengue transmission, as well as threat for developing dengue haemorrhagic fever (DHF). PMID- 26433077 TI - Evidence of selection on phenotypic plasticity and cost of plasticity in response to host-feeding sources in the major Chagas disease vector Triatoma infestans. AB - Phenotypic plasticity is the ability of a genotype to display alternative phenotypes in different environments. Understanding how plasticity evolves and the factors that favor and constrain its evolution have attracted great interest. We investigated whether selection on phenotypic plasticity and costs of plasticity affect head and wing morphology in response to host-feeding sources in the major Chagas disease vector Triatoma infestans. Full-sib families were assigned to blood-feeding on either live pigeons or guinea pigs throughout their lives. We measured diet-induced phenotypic plasticity on wing and head size and shape; characterized selection on phenotypic plasticity for female and male fecundity rates, and evaluated costs of plasticity. Wing size and shape variables exhibited significant differences in phenotypic plasticity associated with host feeding source in female and male bugs. Evidence of selection on phenotypic plasticity was detected in head size and shape for guinea pig-fed females. A lower female fecundity rate was detected in more plastic families for traits that showed selection on plasticity. These results provide insights into the morphological phenotypic plasticity of T. infestans, documenting fitness advantages of head size and shape for females fed on guinea pigs. This vector species showed measurable benefits of responding plastically to environmental variation rather than adopting a fixed development plan. The presence of cost of plasticity suggests constraints on the evolution of plasticity. Our study indicates that females fed on guinea pigs (and perhaps on other suitable mammalian hosts) have greater chances of evolving under selection on phenotypic plasticity subject to some constraints. PMID- 26433078 TI - A Petal-like Calyceal Diverticulum. AB - Calyceal diverticula are rare outpouchings of the upper collecting system that likely have a congenital origin. They are usually single cystic lesions accompanied by stones inside them and located in the upper pole calyces. We present a case containing a petal-like cystic lesion with multiple septa in the lower pole of the left kidney, which was confirmed as calyceal diverticulum by computed tomography urography and intraoperative findings. PMID- 26433079 TI - Medicinal Leech Therapy for Glans Penis Congestion After Primary Bladder Exstrophy-Epispadias Repair in an Infant: A Case Report. AB - Many postoperative complications have been reported after repair of classic bladder exstrophy. We present a case of medicinal leech therapy for glans penis congestion following exstrophy repair in an infant. A 2-week-old male with classic bladder exstrophy underwent complete primary repair. On postoperative day 1, he developed rapidly worsening glans penis venous congestion. Medicinal leech therapy was instituted with antibiotics and blood transfusions to maintain a hematocrit >30%. After 24 hours, venous congestion improved and therapy was discontinued. The patient's remaining hospital course was uncomplicated. Medicinal leeches are an effective therapy to relieve glans penis venous congestion. PMID- 26433080 TI - Quadruple Orchidopexy for Torsion Testis in an Adolescent With Polyorchidism: A Case Report. AB - We report a case of testicular torsion in an adolescent with polyorchidism, specifically quadorchidism. Sonographic and intraoperative images are provided to describe the presentation and management of this case, while the challenges and pitfalls with this clinical scenario are discussed. PMID- 26433081 TI - Dorsal Lumbotomy Incision for Partial Nephrectomy in Patients With Small Posterior Renal Masses. AB - OBJECTIVE: To describe our single-surgeon experience with dorsal lumbotomy, an uncommonly utilized muscle-sparing incision, for open partial nephrectomy. MATERIALS AND METHODS: We retrospectively identified patients who underwent partial nephrectomy through dorsal lumbotomy incision by a single surgeon from September 2012 through April 2014. Clinicopathologic characteristics were recorded along with early postoperative outcomes including hospital length of stay and narcotic requirement. RESULTS: Twenty-four patients were identified for analysis. Median operative time was 71 minutes (interquartile range [IQR]: 63-91 minutes), and median estimated blood loss was 250 mL (IQR: 100-438 mL). Median length of stay was 1.2 days (IQR: 0.94-2.0 days) and median narcotic requirement was 17 mg of oral morphine equivalents (IQR: 4.9-43 mg). Overall perioperative complication rate was 25% including 1 major (Clavien III-V) complication. CONCLUSION: Partial nephrectomy via dorsal lumbotomy incision is a safe and feasible option for small posterior renal masses when performed by an experienced surgeon. The drawbacks of this approach are limited access to the renal hilum and risk of injury to the iliohypogastric or subcostal nerves. Dorsal lumbotomy is associated with postoperative outcomes equivalent to or better than standard operative approaches and should be considered a viable surgical approach in selected cases. PMID- 26433082 TI - High Prevalence of Opaline Silica in Urinary Stones From Burkina Faso. AB - OBJECTIVE: To underline peculiar composition of kidney stones and to propose an epidemiologic study of urinary stones in West African countries, where epidemiologic studies are scarce. Only few data are available regarding stone composition in sub-Saharan countries. Recently, a set of 100 stones consecutively removed by surgery in the Department of Urology of the University Hospital of Ouagadougou in Burkina Faso were collected for physical analysis, which provided the opportunity to obtain an epidemiologic profile of stone composition in this country. MATERIALS AND METHODS: A total of 100 stones from 64 men, 22 women, 10 boys, and four girls were analyzed by morphologic examination, infrared spectroscopy, and electron microscopy in our laboratory. The results were considered by sex and separately for adults and children. RESULTS: Sixty-five percent of the 100 stones contained calcium oxalate as the main component. Interestingly, the second main component was opaline silica (18%). Furthermore, opaline silica was identified in any proportion in 48% of the stones. The prevalence was sex and age dependent. Opaline silica was detected as the main component in 42% of the nuclei, which underlines its role as one of the main components involved in the initiation of calculi in this country. CONCLUSION: For the first time, a dramatically high occurrence of a "scarce" urinary stone component, namely opaline silica, was reported in a series of consecutive calculi from a single country. We propose that a regular consumption of clay could be the origin of this phenomenon in these populations. PMID- 26433083 TI - Malignant Mesothelioma of Spermatic Cord in an Elderly Man With a History of Asbestos Exposure. AB - We report a case of malignant mesothelioma of the spermatic cord in 80-year-old man presented with retained testis, hydrocele, and right inguinal mass. The patient had a long history of asbestos exposure as a railway worker. The patient was submitted to inguinal radical orchiectomy. One year after surgery, the patient is alive without signs of disease. Malignant mesothelioma of spermatic cord is a very rare disease, but this diagnosis should be suspected in patient with a history of asbestos exposure. PMID- 26433084 TI - Universal dispersing agent for electrophoretic deposition of inorganic materials with improved adsorption, triggered by chelating monomers. AB - Poly[1-[4-(3-carboxy-4-hydroxyphenylazo)benzenesulfonamido]-1,2-ethanediyl, sodium salt] (PAZO) is a polymeric functional material with a number of unique physical properties, which attracted significant interest of different scientific communities. Films of PAZO were deposited by anodic electrophoretic deposition (EPD) under constant current and constant voltage conditions. The deposition kinetics was analyzed under different conditions and the deposition mechanism was discussed. New strategy was developed for the EPD of different inorganic materials and composites using PAZO as a dispersing, charging, binding and film forming agent. It was found that PAZO exhibits remarkable adsorption on various inorganic materials due to the presence of chelating salicylate ligands in its molecular structure. The salicylate ligands of PAZO monomers provide multiple adsorption sites by complexation of metal atoms on particle surfaces and allow for efficient electrosteric stabilization of particle suspensions. The remarkable performance of PAZO in its application in EPD have been exemplified by deposition of a wide variety of inorganic materials including the single element oxides (NiO, ZnO, Fe2O3) the complex oxides (Al2TiO5, BaTiO3, ZrSiO4, CoFe2O4) different nitrides (TiN, Si3N4, BN) as well as pure Ni metal and hydrotalcite clay. The use of PAZO can avoid limitation of other dispersing agents in deposition and co deposition of different materials. Composite films were obtained using PAZO as a co-dispersant for different inorganic materials. The deposit composition, microstructure and deposition yield can be varied. The EPD method offers the advantages of simplicity, high deposition rate, and ability to deposit thin or thick films. PMID- 26433085 TI - Preparation of flower-like ZnO architectures assembled with nanosheets for enhanced photocatalytic activity. AB - As an important semiconductor metal oxide, various methods have been developed for preparation of ZnO architectures owing to their excellent properties and extensive applications. In this paper, two kinds of 3D flower-like ZnO architectures assembled with numerous nanosheets were successfully synthesized by a simple hydrothermal route assisted by sodium dodecyl sulfate (SDS), origining from the different alkali environment created by urea and hexamine (HMT). SEM and TEM results revealed that the two products had hydrangea-like and rose-like nanostructures with uniform particle sizes, respectively. XRD results confirmed that the growth process of ZnO involved a phase transformation from intermediate compound basic zinc carbonate to ZnO. Base on the experimental results, the formation mechanisms of two kinds of flower-like ZnO undergoing nucleation, oriented growth and self-assembly processes were discussed. The photocatalytic results indicated that both samples exhibited high photocatalytic activities and good cycling stability for the degradation of rhodamine B (RhB), which was almost completely degraded within 25min, in comparison to those milled samples (above 45min). The excellent performances were mainly ascribed to their unique nanostructure, good stability, and uniform particle size. PMID- 26433086 TI - How B-Type Natriuretic Peptide (BNP) and Body Weight Changes Vary in Heart Failure With Preserved Ejection Fraction Compared With Reduced Ejection Fraction: Secondary Results of the HABIT (HF Assessment With BNP in the Home) Trial. AB - BACKGROUND: Heart failure is a common cause of hospitalization and can be divided into types with preserved and reduced ejection fraction (HFpEF and HFrEF, respectively). In this subanalysis of the HABIT (Heart Failure Assessment With BNP in the Home) trial, we examined the differences between home B-type natriuretic peptide (BNP) testing and weight monitoring in patients with HFpEF and with HFrEF before decompensation. METHODS AND RESULTS: This was a retrospective review of patients with HFpEF and HFrEF from the HABIT trial. The HFpEF patients compared with HFrEF patients were older and more obese and had lower baseline BNP values. Intra-individual BNP dispersion (spread of distribution over time) was greater in HFpEF than in HFrEF owing to rapid fluctuations (within 3 days). Slowly varying changes in BNP (estimated by a moving average) were equally predictive of ADHF risk in both HFpEF and HFrEF. However, in HFpEF, a rapid rise in BNP >200 pg/mL within 3 days was associated with an increased risk of acute decompensated heart failure (ADHF; hazard ratio 4.0), whereas a similar association was not observed in HFrEF. Weight gain >=5 lb in 3 days had a high specificity but low sensitivity for ADHF in both HFpEF and HFrEF, whereas a lower threshold of >=2 lb weight gain over 3 days in patients with HFpEF (but not HFrEF) was a moderately sensitive cutoff associated with decompensation (60% sensitivity). CONCLUSIONS: Patients with HFpEF and HFrEF have variations in their BNP and weight before decompensation. The rapid time scale behaves differently between the groups. In those with HFpEF, a 3-day period characterized by >=2 lb weight gain and/or >200 pg/mL BNP rise was significantly associated with decompensation. Future prospective studies investigating different weight and BNP cutoffs for home monitoring of HFpEF and HFrEF patients should be performed to fully learn the value of BNP changes before clinical deompensation. PMID- 26433087 TI - Cardiac Resynchronization in Different Age Groups: A MADIT-CRT Long-Term Follow Up Substudy. AB - BACKGROUND: Cardiac resynchronization with defibrillators (CRT-D) reduces heart failure and mortality compared with defibrillators alone. Whether this applies to all ages is unclear. METHODS AND RESULTS: We assessed the association of age on heart failure and death as a post hoc analysis of the MADIT-CRT follow-up study, in which 1,281 patients with class I/II heart failure (HF) were randomized to CRT D or implantable cardioverter-defibrillators alone. Different age groups (<60, 60 74, and >=75 years) were evaluated over 7 years for mortality and HF events. Among the 3 age groups, there were 399, 651, and 231 patients, respectively. We compared events with the use of a multivariate regression model. CRT-D compared with defibrillators alone significantly reduced the composite of HF or death across all age groups: <60 years: relative risk reduction (RRR) = 36%; 60-74 years: RRR = 61%; >=75 years: RRR = 56%. CRT-D significantly reduced HF in all age groups: <60 years: RRR = 49%; 60-74 years: RRR = 62%; >=75 years: RRR = 74%. CRT-D was associated with significant mortality reduction only in the 60-74 year age group: RRR = 59%. CONCLUSIONS: CRT-D reduced HF events and the composite of mortality or HF events during long-term follow-up in all age groups. CRT-D reduced mortality only in the 60-74 year age group. PMID- 26433088 TI - Mixed-mode I+II fracture characterization of human cortical bone using the Single Leg Bending test. AB - Mixed-mode I+II fracture characterization of human cortical bone was analyzed in this work. A miniaturized version of the Single Leg Bending test (SLB) was used owing to its simplicity. A power law criterion was verified to accurately describe the material fracture envelop under mixed-mode I+II loading. The crack tip opening displacements measured by digital image correlation were used in a direct method to determine the cohesive law mimicking fracture behavior of cortical bone. Cohesive zone modeling was used for the sake of validation. Several fracture quantities were compared with the experimental results and the good agreement observed proves the appropriateness of the proposed procedure for fracture characterization of human bone under mixed-mode I+II loading. PMID- 26433089 TI - Degradation and swelling issues of poly-(d,l-lactide)/beta-tricalcium phosphate/calcium carbonate composites for bone replacement. AB - Recently a tri-phase material consisting of poly-(d,l-lactide) (PDLLA), beta tricalcium phosphate (beta-TCP), and calcium carbonate (CC) was proposed as a novel bone substitute candidate. beta-TCP is suitable because of its bone-like mineral phase, PDLLA is introduced as a biodegradable adhesive phase, and CC is essential for buffering the acidic degradation of the lactate component. We hypothesize that the amounts of the three different components in the composite material must be carefully balanced in order to avoid issues such as accelerated degradation or pronounced volumetric swelling. To prove this, granulates made of different mixing ratios of the tri-phase compound were prepared by grinding. Specimens of the different compounds were manufactured by a hot pressing process. The bending strength of the specimens was determined before and after storing in demineralized water and phosphate buffered saline (PBS). The particle size of the compound granulates was smaller than 100um. A ratio of 60wt% of the PDLLA component indicated the best compromise between stability of test specimens based on a strong melting network and bone-like properties. The specimens exhibited a bending strength up to 90MPa. The strength increased with an increasing ratio of beta-TCP to calcium carbonate (based on 60wt% PDLLA). A vast volumetric swelling up to 40%, and thus a huge reduction of the bending strength, was observed during the storage of specimens in PBS. A swelling and thus a volume increase could be critical, especially for using the tri-phase bone substitute compound as 3D scaffold with defined dimensions. This must be considered with regard to the composition of the compound and the scaffold design. PMID- 26433091 TI - Modeling dynamical electron scattering with Bethe potentials and the scattering matrix. AB - Bethe potentials were introduced by Bethe in 1928 as a first order perturbation approach to reducing the number of diffracted beams in dynamical electron scattering problems. The approach starts from the Bloch wave representation, and uses a threshold criterion to split the diffracted beams into two subsets, namely strong and weak beams. Since the use of Bloch wave based Bethe potentials for defect simulations is somewhat tedious, this paper applies the perturbation approach to the scattering matrix formalism, which is more readily adaptable for defect image simulations. The size of the dynamical matrix, and hence the computation time, can be reduced significantly. A threshold criterion for the separation of scattered beams into strong and weak sets is introduced. A general guideline in setting the threshold for strong or weak beam selection is discussed along with several parameters that may influence the threshold values, such as atomic number, accelerating voltage, structure complexity, incident beam tilt and temperature. PMID- 26433090 TI - Transcriptional enhancers: functional insights and role in human disease. AB - In recent years, studies of cis-regulatory mechanisms have evolved from a predominant focus on promoter regions to the realization that spatial and temporal gene regulation is frequently driven by long-range enhancer clusters that operate within chromosomal compartments. This increased understanding of genome function, together with the emergence of technologies that enable whole genome sequencing of patients' DNAs, open the prospect of dissecting the role of cis-regulatory defects in human disease. In this review we discuss how recent epigenomic studies have provided insights into the function of transcriptional enhancers. We then present examples that illustrate how integrative genomics can help uncover enhancer sequence variants underlying Mendelian and common polygenic human disease. PMID- 26433092 TI - Involvement of the osrR gene in the hydrogen peroxide-mediated stress response of Corynebacterium glutamicum. AB - A transcriptional profile of the H2O2-adapted Corynebacterium glutamicum HA strain reveals a list of upregulated regulatory genes. Among them, we selected ORF NCgl2298, designated osrR and analyzed its role in H2O2 adaptation. The osrR deleted (DeltaosrR) mutant had defective growth in minimal medium, which was even more pronounced in an osrR deletion mutant of an HA strain. The DeltaosrR strain displayed increased sensitivity to H2O2. In addition to H2O2 sensitivity, the DeltaosrR strain was found to be temperature-sensitive at 37 degrees C. 2D-PAGE analysis of the DeltaosrR mutant found that MetE and several other proteins involved in redox metabolism were affected by the mutation. Accordingly, the NADPH/NADP(+) ratio of the DeltaosrR strain (0.85) was much lower than that of the wild-type strain (2.01). In contrast, the NADH/NAD(+) ratio of the mutant (0.54) was considerably higher than that of the wild-type (0.21). Based on these findings, we propose that H2O2-detoxifying metabolic systems, excluding those involving catalase, are present in C. glutamicum and are regulated, in part, by osrR. PMID- 26433093 TI - Profilin Regulates Apical Actin Polymerization to Control Polarized Pollen Tube Growth. AB - Pollen tube growth is an essential step during flowering plant reproduction, whose growth depends on a population of dynamic apical actin filaments. Apical actin filaments were thought to be involved in the regulation of vesicle fusion and targeting in the pollen tube. However, the molecular mechanisms that regulate the construction of apical actin structures in the pollen tube remain largely unclear. Here, we identify profilin as an important player in the regulation of actin polymerization at the apical membrane in the pollen tube. Downregulation of profilin decreased the amount of filamentous actin and induced disorganization of apical actin filaments, and reduced tip-directed vesicle transport and accumulation in the pollen tube. Direct visualization of actin dynamics revealed that the elongation of actin filaments originating at the apical membrane decreased in profilin mutant pollen tubes. Mutant profilin that is defective in binding poly-L-proline only partially rescues the actin polymerization defect in profilin mutant pollen tubes, although it fully rescues the actin turnover phenotype. We propose that profilin controls the construction of actin structures at the pollen tube tip, presumably by favoring formin-mediated actin polymerization at the apical membrane. PMID- 26433094 TI - Repetitive Plantar Flexion Test as an Adjunct Tool for the Diagnosis of Common Peroneal Nerve Entrapment Neuropathy. AB - OBJECTIVE: The diagnosis of common peroneal nerve entrapment neuropathy (CPNEN) is based on clinical symptoms and nerve conduction studies. However, nerve conduction studies may not detect abnormalities. Under the hypothesis that repetitive plantar flexion that loads the peroneal nerve (PN) at the entrapment point without lumbar loading would be a useful CPNEN provocation test, we evaluated the repetitive plantar flexion (RPF) test as an adjunct diagnostic tool for CPNEN. The study design was a retrospective analysis of prospectively collected data. METHODS: Our study population consisted of 18 consecutive patients whose ipsilateral CPNEN improved significantly after PN neurolysis. Using repetitive ankle plantar flexion as a CPNEN provocation test, results were recorded as positive when it elicited numbness and/or pain in the affected area of the PN. RESULTS: The RPF test induced symptoms on all affected sides in the course of 57.4 seconds (range, 14-120 seconds). In 3 patients it induced numbness in the affected area of the PN in the normal leg. Receiver operating characteristic analysis showed that the diagnostic sensitivity and accuracy of the test were 94.4% each. The suggested cutoff point was 110 seconds and the area under the receiver operating characteristic curve was 0.97 (95% confidence interval 0.93-1.02). The positive and the negative predictive values were 89.5% and 94.1%, respectively. CONCLUSIONS: Our simple RPF test elicited the symptoms of CPNEN and our provocation test helped to identify dynamic PN entrapment neuropathy as the origin of intermittent claudication. PMID- 26433095 TI - The Role of Therapeutic Hypothermia After Traumatic Spinal Cord Injury--A Systematic Review. AB - BACKGROUND: Traumatic spinal cord injury (SCI) is a devastating neurologic entity characterized by a primary insult followed by a secondary pathologic cascade that propagates further injury. Hypothermia has an established clinical role in preventing SCI after cardiac arrest and thoracoabdominal aortic aneurysm repair, yet its emergence as a potential neuroprotectant after spinal cord trauma remains experimental. There are currently no pharmacologic interventions available to prevent secondary mechanisms of injury after spinal cord trauma. METHODS: Systematic review of literature. RESULTS: Experimental studies demonstrated that hypothermia diminishes secondary pathomechanisms, such as ischemia, oxidative stress, apoptosis, inflammation, and edema. Early onset and longer durations of hypothermia as well as concomitant steroids or neural stem cell engraftment combined with hypothermia appear to improve functional and histologic outcomes in animal models of spinal cord trauma. Recent clinical studies provide evidence that localized and systemic hypothermia may be applied safely and efficaciously in patients with severe acute SCI. Randomized clinical trials are needed to better evaluate optimal cooling parameters and the effectiveness of hypothermia after traumatic SCI. CONCLUSION: Although variability exists in the literature, therapeutic hypothermia most likely confers neuroprotection after spinal cord trauma by diminishing the destructive secondary cascade. The available clinical data suggest that regional and systemic hypothermia is a relatively safe and feasible initial treatment modality for patients with acute SCI when combined with surgical decompression/stabilization with or without steroids. However, establishing a clinical role for therapeutic hypothermia after spinal cord trauma will invariably depend on future well-designed, multicentered, randomized, controlled clinical trial data. PMID- 26433096 TI - Analysis of Decompressive Craniectomies with Subsequent Cranioplasties in the Presence of Collagen Matrix Dural Substitute and Polytetrafluoroethylene as an Adhesion Preventative Material. AB - OBJECTIVE: Decompressive craniectomy is an established treatment for malignant intracranial hypertension. Cranioplasty is performed once cerebral swelling has resolved. Complications include infection, postoperative fluid collections, hematoma, reoperation, and seizures. Our experience using a double layer technique during craniectomy with a collagen matrix onlay dural substitute and expanded polytetrafluoroethylene for antiadhesive properties during cranioplasty was reviewed. METHODS: This is a retrospective chart review of 39 consecutive patients who underwent craniectomy with placement of collagen matrix dural onlay and expanded polytetrafluoroethylene and subsequent cranioplasty. Demographic data, size of craniectomy defect, estimated blood loss, operative time, time between operations, presence of dural tackups, and postoperative complications were analyzed. RESULTS: Mean operative time was 132 minutes and estimated blood loss was 112 mL. Overall complication rate was 25.6% and no mortality was encountered. Nine patients had postoperative fluid collections measuring >= 10 mm in thickness and/or 5 mm of midline shift. Two patients required reoperation for these collections. Two patients developed infections requiring bone flap removal. Three patients developed seizures after cranioplasty. Five patients required shunt placement for hydrocephalus. CONCLUSIONS: Our dual layer closure technique at time of decompressive craniectomy carries a similar reduction in operative time and estimated blood loss when compared with cranioplasty series with other antiadhesives present. The technique described enables easy dissection of the musculocutaneous flap from the dural plane during cranioplasty and increases the safety of the operation. PMID- 26433097 TI - Occipitocervical Fusions in Elderly Patients: Mortality and Reoperation Rates From a National Spine Registry. AB - BACKGROUND: Several studies have shown excellent fusion rates in occipitocervical (OC) fusions, but very little is reported on mortality and reoperation rates in elderly patients. Our article reports these rates in elderly patients from a national spine registry with a >2-year follow-up period. METHODS: Using data from a spine implant registry developed at a large integrated health care system (Kaiser Permanente), elderly patients (aged >= 65 years) with instrumented OC fusions between January 1, 2009 and September 30, 2013 were identified. Patients' demographics were extracted from the registry. From chart review, the types of hardware and bone graft used, as well as mortality and reoperations rates were noted. RESULTS: Forty-seven patients with OC fusions were identified. Six patients had reoperations related to their fusions. Two occurred in the same patient, which resulted in a 14.9% reoperation rate. There were a total of 13 deaths (27.7%), with 7 occurring within 3 months, but only 4 (8.5%) related to the procedure. Bone morphogenetic protein was used in 29 patients (85.3%, 29/34). All cases used occipital plates with rods and screws. There was 1 nonunion. CONCLUSIONS: Mortality rate was 27.7% and the reoperations rate was 14.9% for patients who underwent OC fusions with age >65 years and were observed for >2 years. These numbers are much higher than in younger patients, but reflect a higher mortality due to their comorbidities and from progression of their disease for cases of metastasis to the spine. PMID- 26433098 TI - The Incidence of Neurologic Susceptibility to a Skull Defect. AB - OBJECTIVE: To determine whether there is a measureable change in neurologic function after cranioplasty. METHODS: This is a prospective single-surgeon, single-center study. Fifty patients who required a cranioplasty procedure were assessed neurologically within 72 hours before and 7 days after surgery. The assessment tools were the Functional Independence Measure (FIM) and the Cognitive assessment report (Cognistat). The scores for both assessments were calculated and then compared before and after surgery. RESULTS: FIM assessment was performed on all fifty patients, and a Cognistat assessment was performed on 47 patients. Most improvements were seen in the Cognistat scores; however, there appeared to be no specific areas in which there was consistent improvement. There were substantial improvements in the Cognistat assessment in 9 patients. One patient had a much-improved FIM assessment (improved from 18 to 34), but a Cognistat assessment was not possible because of poor neurologic function. These results suggested that improvements after cranioplasty were more likely to occur in the domain of cognitive function than motor function, although overall these results did not reach statistically significance. Bifrontal (vs. unilateral) cranioplasty, timing between decompression and cranioplasty, and age of the patients did not appear to affect the postoperative FIM scores, after we adjusted for preoperative FIM scores and surgical complications. CONCLUSIONS: A small but significant number of patients appear to improve clinically after cranioplasty. Neurologic susceptibility to a skull defect may be more common than had been appreciated previously. PMID- 26433099 TI - China's Medical Education and INR Training. PMID- 26433100 TI - Gastroenterology training recruitment -- a UK perspective. PMID- 26433101 TI - Reply: To PMID 25921370. PMID- 26433102 TI - An unusual case of colonic hemorrhage. PMID- 26433103 TI - A rare case of gastric ulcerative mass. PMID- 26433104 TI - Research in gastroenterology fellowship training. PMID- 26433105 TI - A rare cause of postprandial abdominal pain and nausea. PMID- 26433106 TI - Was adjuvant immunotherapy really effective to reduce hepatocellular carcinoma recurrence? PMID- 26433107 TI - Multiple liver lesions after oxaliplatin-based chemotherapy for colorectal cancer. PMID- 26433108 TI - Reply: To PMID 25747273. PMID- 26433109 TI - An enlarging liver in a young diabetic male. PMID- 26433110 TI - Reply: To PMID 25836985. PMID- 26433111 TI - Adjuvant immunotherapy for postoperative hepatocellular carcinoma. PMID- 26433112 TI - An uncommon cause of infantile jaundice. PMID- 26433114 TI - Tackling extremes: challenges for ecological and evolutionary research on extreme climatic events. AB - Extreme climatic events (ECEs) are predicted to become more frequent as the climate changes. A rapidly increasing number of studies - though few on animals - suggest that the biological consequences of ECEs can be severe. However, ecological research on the impacts of ECEs has been limited by a lack of cohesiveness and structure. ECEs are often poorly defined and have often been confusingly equated with climatic variability, making comparison between studies difficult. In addition, a focus on short-term studies has provided us with little information on the long-term implications of ECEs, and the descriptive and anecdotal nature of many studies has meant it is still unclear what the key research questions are. Synthesizing the current state of work is essential to identify ways to make progress. We conduct a synthesis of the literature and discuss conceptual and practical challenges faced by research on ECEs. We consider three steps to advance research. First, we discuss the importance of choosing an ECE definition and identify the pros and cons of 'climatological' and 'biological' definitions of ECEs. Secondly, we advocate research beyond short term descriptive studies to address questions concerning the long-term implications of ECEs, focussing on selective pressures and phenotypically plastic responses and how they might differ from responses to a changing climatic mean. Finally, we encourage a greater focus on multi-event studies that help us understand the implications of changing patterns of ECEs, through the combined use of modelling, experimental and observational field studies. This study aims to open a discussion on the definitions, questions and methods currently used to study ECEs, which will lead to a more cohesive approach to future ECE research. PMID- 26433113 TI - Improved cardiovascular outcomes following temporal advances in lipid-lowering therapy in a genetically-characterised cohort of familial hypercholesterolaemia homozygotes. AB - BACKGROUND AND AIMS: There is a paucity of data concerning the influence of lipid lowering therapy on cardiovascular (CV) outcomes in patients with homozygous familial hypercholesterolaemia (FH). To redress this a retrospective analysis was undertaken of the demographic features, lipid levels, low density lipoprotein receptor and Autosomal Recessive Hypercholesterolaemia gene mutations, CV outcomes and vital status of 44 FH homozygotes referred to a single centre in the UK between 1964 and 2014. METHODS: Data were obtained from past publications, case records and death certificates. Differences in categorical and continuous variables between living and dead patients were analysed using Fisher's exact test and an independent t-test respectively. RESULTS: During the 50 years covered by this survey 13 patients have died, 30 are still alive and 1 was lost to follow up. The mean age of Alive patients was 32.6 +/- 11.5 versus 28.3 +/- 14.9 years in Dead ones (P = 0.31) and they were born 18 years later (P = 0.0001). Pre treatment serum total cholesterol (TC) was similar in Alive and Dead (20.2 +/- 5.1 v 21.3 +/- 4.4 mmol/l, P = 0.52) but on-treatment TC was lower in Alive than Dead (8.1 +/- 2.8 v 14.5 +/- 6.0 mmol/l, P = 0.0001) and CV adverse events were far less frequent (eg aortic stenosis, 33% v 77%, P = 0.02). CONCLUSIONS: The lower on-treatment TC and fewer CV adverse events in FH homozygotes still living reflect advances in apheresis and drug therapy since the 1990s. Further improvements in prognosis can be expected with the impending introduction of novel lipid-lowering agents. PMID- 26433115 TI - Elevated miR-155 expression induces immunosuppression via CD39(+) regulatory T cells in sepsis patient. AB - BACKGROUND: An altered microRNA profile exists in many infectious diseases, including sepsis. CD39(+) regulatory T-cells (Tregs) have a remarkable immunosuppressive effect and play an important role in the regulation of immune balance in sepsis. However, the correlation between microRNA changes and the ratio of CD39(+) Tregs in sepsis patients has not yet been reported. The altered microRNA expression profile in sepsis patients was analyzed in this study. Moreover, the correlation between microRNAs and disease severity and prognosis was investigated. Furthermore, the correlation between microRNAs and the percentage of peripheral blood CD39(+) Tregs was investigated and further verified in an animal model. METHODS: Sixty sepsis patients and 30 healthy controls were included. The difference in microRNA expression was investigated by microRNA microarray and was further confirmed by real-time quantitative PCR. The correlations between microRNA changes and the Sepsis-related Organ Failure Assessment (SOFA) score, severity of sepsis, and survival were analyzed. The percentage CD39(+) Tregs in the peripheral blood of sepsis patients was measured by flow cytometry. The correlation between microRNAs and the percentage CD39(+) Tregs was analyzed and further confirmed in a mouse sepsis model. RESULTS: Compared to healthy controls, sepsis patients exhibited a significantly elevated microRNA-155 (miR-155) level (p < 0.05), which was positively related to a higher SOFA score (r = 0.641, p < 0.05) and a greater severity of sepsis. The area under the receiver operating characteristic curve of miR-155 used for the prediction of 28-day survival was 0.763, with a cut-off point of 2.47. Patients with a miR-155 level >2.47 had a lower 28-day survival (p < 0.05). The miR-155 level of patients was proportional to the percentage of CD39(+) Tregs (r = 0.637, p < 0.05). After transfection with miR-155 inhibitor, the ratio of CD39(+) Tregs in mice with sepsis was significantly reduced (p < 0.05). CONCLUSIONS: A higher level of miR 155 indicated a more severe condition and poorer prognosis in sepsis patients. The possible underlying mechanism could be that miR-155 induces an increased percentage of CD39(+) Tregs and thus immunosuppression. PMID- 26433116 TI - Anxiety and depression among out-of-hospital cardiac arrest survivors. AB - AIM: Survivors of out-of-hospital cardiac arrest (OHCA) may experience psychological distress but the actual prevalence is unknown. The aim of this study was to investigate anxiety and depression within a large cohort of OHCA survivors. METHODS: OHCA-survivors randomized to targeted temperature of 33 degrees C or 36 degrees C within the Target Temperature Management trial (TTM trial) attended a follow-up after 6 months that included the questionnaire Hospital Anxiety and Depression Scale (HADS). A control group with ST-elevation myocardial infarction (STEMI) completed the same follow-up. Correlations to variables assumed to be associated with anxiety and depression in OHCA-survivors were tested. RESULTS: At follow-up 278 OHCA-survivors and 119 STEMI-controls completed the HADS where 24% of OHCA-survivors (28% in 33 degrees C group/22% in 36 degrees C group, p=0.83) and 19% of the STEMI-controls reported symptoms of anxiety (OR 1.32; 95% CI (0.78-2.25), p=0.30). Depressive symptoms were reported by 13% of OHCA-survivors (equal in both intervention groups, p=0.96) and 8% of STEMI-controls (OR 1.76; 95% CI (0.82-3.79), p=0.15). Anxiety and depression among OHCA-survivors correlated to Health-Related Quality-of-Life, and subjectively reported cognitive deterioration by patient or observer. In addition, depression was associated with a poor neurological outcome. CONCLUSION: One fourth of OHCA-survivors reported symptoms of anxiety and/or depression at 6 months which was similar to STEMI-controls and previous normative data. Subjective cognitive problems were associated with an increased risk for psychological distress. Since psychological distress affects long-term prognosis of cardiac patients in general it should be addressed during follow-up of survivors with OHCA due to a cardiac cause. ClinicalTrials.gov NCT01020916/NCT01946932. PMID- 26433117 TI - Electronic learning in advanced resuscitation training: The perspective of the candidate. AB - BACKGROUND: Studies have shown that blended approaches combining e-learning with face-to-face training reduces costs whilst maintaining similar learning outcomes. The preferences in learning approach for healthcare providers to this new style of learning have not been comprehensively studied. The aim of this study is to evaluate the acceptability of blended learning to advanced resuscitation training. METHODS: Participants taking part in the traditional and blended electronic advanced life support (e-ALS) courses were invited to complete a written evaluation of the course. Participants' views were captured on a 6-point Likert scale and in free text written comments covering the content, delivery and organisation of the course. Proportional-odds cumulative logit models were used to compare quantitative responses. Thematic analysis was used to synthesise qualitative feedback. RESULTS: 2848 participants from 31 course centres took part in the study (2008-2010). Candidates consistently scored content delivered face to-face over the same content delivered over the e-learning platform. Candidates valued practical hands on training which included simulation highly. Within the e ALS group, a common theme was a feeling of "time pressure" and they "preferred the face-to-face teaching". However, others felt that e-ALS "suited their learning style", was "good for those recertifying", and allowed candidates to "use the learning materials at their own pace". CONCLUSIONS: The e-ALS course was well received by most, but not all participants. The majority felt the e-learning module was beneficial. There was universal agreement that the face-to-face training was invaluable. Individual learning styles of the candidates affected their reaction to the course materials. PMID- 26433118 TI - Time to identify cardiac arrest and provide dispatch-assisted cardio-pulmonary resuscitation in a criteria-based dispatch system. AB - INTRODUCTION: Dispatch-assisted cardiopulmonary resuscitation (DA-CPR) plays a key role in out-of-hospital cardiac arrests. We sought to measure dispatchers' performances in a criteria-based system in recognizing cardiac arrest and delivering DA-CPR. Our secondary purpose was to identify the factors that hampered dispatchers' identification of cardiac arrests, the factors that prevented them from proposing DA-CPR, and the factors that prevented bystanders from performing CPR. METHODS AND RESULTS: We reviewed dispatch recordings for 1254 out-of-hospital cardiac arrests occurring between January 1, 2011 and December 31, 2013. Dispatchers correctly identified cardiac arrests in 71% of the reviewed cases and 84% of the cases in which they were able to assess for patient consciousness and breathing. The median time to recognition of the arrest was 60s. The median time to start chest compression was 220s. CONCLUSIONS: This study demonstrates that performances from a criteria-based dispatch system can be similar to those from a medical-priority dispatch system regarding out-of hospital cardiac arrest (OHCA) time recognition and DA-CPR delivery. Agonal breathing recognition remains the weakest link in this sensitive task in both systems. It is of prime importance that all dispatch centers tend not only to implement DA-CPR but also to have tools to help them reach this objective, as today it should be mandatory to offer this service to the community. In order to improve benchmarking opportunities, we completed previously proposed performance standards as propositions. PMID- 26433119 TI - Combined omega-3 fatty acids, aerobic exercise and cognitive stimulation prevents decline in gray matter volume of the frontal, parietal and cingulate cortex in patients with mild cognitive impairment. AB - Previous studies in older adults suggested beneficial effects of omega-3 fatty acid (FA) supplementation, aerobic exercise, or cognitive stimulation on brain structure and function. However, combined effects of these interventions in patients suffering from mild cognitive impairment (MCI) are unknown. Using a randomized interventional design, we evaluated the effect of combined omega-3 FA supplementation, aerobic exercise and cognitive stimulation (target intervention) versus omega-3 FA supplementation and non-aerobic exercise (control intervention) on cognitive function and gray matter volume in patients with MCI. Moreover, we analyzed potential vascular, metabolic or inflammatory mechanisms underlying these effects. Twenty-two MCI patients (8 females; 60-80years) successfully completed six months of omega-3 FA intake, aerobic cycling training and cognitive stimulation (n=13) or omega-3 FA intake and non-aerobic stretching and toning (n=9). Before and after the interventions, cognitive performance, magnetic resonance imaging of the brain at 3T (n=20), intima-media thickness of the internal carotid artery and serum markers of glucose control, lipid and B-vitamin metabolism, and inflammation were assessed. Intervention-related changes in gray matter volume of Alzheimer's disease (AD)-related brain regions, i.e., frontal, parietal, temporal and cingulate cortex were examined using voxel-based morphometry of high resolution T1-weighted images. After the intervention period, significant differences emerged in brain structure between groups: Gray matter volume decreased in the frontal, parietal and cingulate cortex of patients in the control intervention, while gray matter volume in these areas was preserved or even increased after the target intervention. Decreases in homocysteine levels in the target intervention group were associated with increases in gray matter volume in the middle frontal cortex (p=0.010). No significant differences in cognitive performance or other vascular, metabolic and inflammatory parameters were observed between groups. This pilot study provides preliminary evidence that omega-3 FA intake combined with aerobic exercise and cognitive stimulation prevents atrophy in AD-related brain regions in MCI patients, compared to omega-3 FA intake plus the control condition of stretching and toning. These promising findings should now be validated in a larger interventional trial. PMID- 26433120 TI - Dissociating temporal attention from spatial attention and motor response preparation: A high-density EEG study. AB - Engagement of various forms of attention and response preparation determines behavioral performance during stimulus-response tasks. Many studies explored the respective properties and neural signatures of each of these processes. However, very few experiments were conceived to explore their interaction. In the present work we used an auditory target detection task during which both temporal attention on the one side, and spatial attention and motor response preparation on the other side could be explicitly cued. Both cueing effects speeded response times, and showed strictly additive effects. Target ERP analysis revealed modulations of N1 and P3 responses by these two forms of cueing. Cue-target interval analysis revealed two main effects paralleling behavior. First, a typical contingent negative variation (CNV), induced by the cue and resolved immediately after target onset, was found larger for temporal attention cueing than for spatial and motor response cueing. Second, a posterior and late cue-P3 complex showed the reverse profile. Analyses of lateralized readiness potentials (LRP) revealed both patterns of motor response inhibition and activation. Taken together these results help to clarify and disentangle the respective effects of temporal attention on the one hand, and of the combination of spatial attention and motor response preparation on the other hand on brain activity and behavior. PMID- 26433121 TI - Fragrance sensitisers: Is inhalation an allergy risk? AB - It is well established that some fragrance substances have the potential to cause skin sensitisation associated with the development of allergic contact dermatitis (ACD). Fragrances are invariably relatively volatile leading to the consideration that inhalation of fragrances might be a relevant route for either the induction of allergic sensitisation or the elicitation of allergic reactions. Moreover, there has been increasing recognition that allergic sensitisation of the respiratory tract can be induced by topical exposure to certain chemical allergens. Here the central question addressed is whether inhalation exposure to fragrance allergens has the potential to cause skin and/or respiratory sensitisation via the respiratory tract, or elicit allergic symptoms in those already sensitised. In addressing those questions, the underlying immunobiology of skin and respiratory sensitisation to chemicals has been reviewed briefly, and the relevant experimental and clinical evidence considered. The essential mechanistic differences between skin and respiratory allergy appear consistent with other sources of information, including the phenomenon of ACD that can arise from topical exposure to airborne allergens, but in the absence of accompanying respiratory effects. The conclusion is that, in contrast to topical exposure (including topical exposure to airborne material), inhalation of fragrance sensitisers does not represent a health risk with respect to allergy. PMID- 26433122 TI - Creation of a new longitudinal corpus of clinical narratives. AB - The 2014 i2b2/UTHealth Natural Language Processing (NLP) shared task featured a new longitudinal corpus of 1304 records representing 296 diabetic patients. The corpus contains three cohorts: patients who have a diagnosis of coronary artery disease (CAD) in their first record, and continue to have it in subsequent records; patients who do not have a diagnosis of CAD in the first record, but develop it by the last record; patients who do not have a diagnosis of CAD in any record. This paper details the process used to select records for this corpus and provides an overview of novel research uses for this corpus. This corpus is the only annotated corpus of longitudinal clinical narratives currently available for research to the general research community. PMID- 26433123 TI - p53-dependent and p53-independent anticancer activity of a new indole derivative in human osteosarcoma cells. AB - Osteosarcoma (OS) is the most common primary malignant tumor of bone, occurring most frequently in children and adolescents. The mechanism of formation and development of OS have been studied for a long time. Tumor suppressor pathway governed by p53 gene are known to be involved in the pathogenesis of osteosarcoma. Moreover, loss of wild-type p53 activity is thought to be a major predictor of failure to respond to chemotherapy in various human cancers. In previous studies, we described the activity of a new indole derivative, NSC743420, belonging to the tubulin inhibitors family, capable to induce apoptosis and arrest of the cell cycle in the G2/M phase of various cancer cell lines. However, this molecule has never been tested on OS cell line. Here we address the activity of NSC743420 by examine whether differences in the p53 status could influence its effects on cell proliferation and death of OS cells. In particular, we compared the effect of the tested molecule on p53-wild type and p53-silenced U2OS cells, and on SaOS2 cell line, which is null for p53. Our results demonstrated that NSC743420 reduces OS cell proliferation by p53 dependent and p53-independent mechanisms. In particular, the molecule induces proliferative arrest that culminate to apoptosis in SaOS2 p53-null cells, while it brings a cytostatic and differentiating effect in U2OS cells, characterized by the cell cycle arrest in G0/G1 phase and increased alkaline phosphatase activity. PMID- 26433124 TI - Implication of a galactomannan-binding GH2 beta-mannosidase in mannan utilization by Caldicellulosiruptor bescii. AB - Many glycoside hydrolases involved in deconstruction of cellulose and xylan from the excellent plant cell wall polysaccharides-degrader Caldicellulosiruptor bescii have been cloned and analyzed. However, far less is known about the enzymatic breakdown of mannan, an important component of hemicellulose. We herein cloned, expressed and purified the first beta-mannosidase CbMan2A from C. bescii. CbMan2A is thermophilic, with an optimal temperature of 80 degrees C. CbMan2A hydrolyzes mannooligosaccharides with degrees of polymerization from 2 to 6 mainly into mannose and shows strong synergy with CbMan5A, an endo-mannanase from the same bacterium, in releasing mannose from beta-1,4-mannan. Thus CbMan2A forms the missing link in enzymatic conversion of mannan into the ready-to-use mannose by C. bescii. Based on these observations, a model illustrating how CbMan2A may assist C. bescii in mannan utilization is presented. In addition, CbMan2A appeared to bind to insoluble galactomannan in a pH-dependent fashion. Although the relation of this feature to mannan utilization remains elusive, CbMan2A represents an excellent model for investigation of the binding of GH2 beta mannosidases to galactomannan. PMID- 26433126 TI - Importance of corneal saturation time with riboflavin prior to collagen cross linking. PMID- 26433127 TI - A negative feedback loop between miR-200b and the nuclear factor-kappaB pathway via IKBKB/IKK-beta in breast cancer cells. AB - MicroRNAs (miRNAs) act as important post-transcriptional regulators of gene expression in diverse signalling pathways. However, the relationship between miR 200b and the nuclear factor-kappaB (NF-kappaB) signalling pathway remains poorly understood in breast cancer cells. In the current study, we show that IKBKB is a direct target of miR-200b, and that miR-200b downregulates IKBKB expression via directly binding to its 3'-UTR. miR-200b inhibits IkappaBalpha phosphorylation, nuclear p50/p65 expression, NF-kappaB-binding activity, and the translocation of p65 to the nucleus. In addition, miR-200b also suppresses tumour necrosis factor (TNF)-alpha-induced NF-kappaB activation and the expression of NF-kappaB target genes. Importantly, IKBKB overexpression attenuates the inhibitory roles of miR 200b in NF-kappaB expression, NF-kappaB-binding activity, and the nuclear translocation of p65. We also show that NF-kappaB p65 knockdown reduces the binding of NF-kappaB to the miR-200b promoter and miR-200b promoter activity. Furthermore, p65 knockdown or inhibition of IkappaBalpha phosphorylation suppresses miR-200b expression. Finally, functional studies show that IKBKB overexpression can restore the cell growth and migration that are suppressed by miR-200b. In conclusion, our results demonstrate that miR-200b, a transcriptional target of NF-kappaB, suppresses breast cancer cell growth and migration, and NF kappaB activation, through downregulation of IKBKB, indicating that miR-200b has potential as a therapeutic target in breast cancer patients. PMID- 26433125 TI - Exploring the role of polymer structure on intracellular nucleic acid delivery via polymeric nanoparticles. AB - Intracellular nucleic acid delivery has the potential to treat many genetically based diseases, however, gene delivery safety and efficacy remains a challenging obstacle. One promising approach is the use of polymers to form polymeric nanoparticles with nucleic acids that have led to exciting advances in non-viral gene delivery. Understanding the successes and failures of gene delivery polymers and structures is the key to engineering optimal polymers for gene delivery in the future. This article discusses the polymer structural features that enable effective intracellular delivery of DNA and RNA, including protection of nucleic acid cargo, cellular uptake, endosomal escape, vector unpacking, and delivery to the intracellular site of activity. The chemical properties that aid in each step of intracellular nucleic acid delivery are described and specific structures of note are highlighted. Understanding the chemical design parameters of polymeric nucleic acid delivery nanoparticles is important to achieving the goal of safe and effective non-viral genetic nanomedicine. PMID- 26433128 TI - Enhancement of solvent tolerance in Pseudomonas sp. BCNU 106 with trehalose. AB - As the solvent hyper-resistant Pseudomonas sp. BCNU 106 experiences limited growth with solvents, a strategy is therefore needed to allow better growth to broaden its performance in biotechnological applications. Pseudomonas sp. BCNU 106 was cultivated in a medium supplemented with 0.05 mol l(-1) trehalose, and the cell survival was observed during subsequent growth with 1% (v/v) toluene. Exogenously added trehalose was transported into the cells and conferred protection against toluene stress. BCNU 106 grown in the presence of exogenous trehalose showed higher solvent tolerance, it can thus have more potential for biotransformation and biodegradation. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows that exogenously supplemented trehalose confers protection against toluene stress and enhances the bacterial cell growth in the presence of toluene. This is of importance to the mass cultivation of solvent-tolerant bacteria, where some of the growth-related limitations of solvent-tolerant bacteria can be overcome, and their performance in biotechnological applications for biotransformation and biodegradation broadened. PMID- 26433130 TI - Outcomes from community-based diabetic eye disease screening: a 3-year review. PMID- 26433129 TI - GCKR and PPP1R3B identified as genome-wide significant loci for plasma lactate: the Atherosclerosis Risk in Communities (ARIC) study. AB - AIM: To investigate the genetic influence of circulating lactate level, a marker of oxidative capacity associated with diabetes. METHODS: We conducted a genome wide association study of log-transformed plasma lactate levels in 6901 European American participants in the Atherosclerosis Risk in Communities study. For regions that achieved genome-wide significance in European-American participants, we conducted candidate region analysis in African-American subjects and tested for interaction between metformin use and the index single nucleotide polymorphisms for plasma lactate in European-American subjects. RESULTS: The genome-wide association study in European-American subjects identified two genome wide significant loci, GCKR (rs1260326, T allele beta=0.08; P=1.8*10(-47) ) and PPP1R3B/LOC157273 (rs9987289, A allele beta=0.06; P=1.6*10(-9) ). The index single nucleotide polymorphisms in these two loci explain 3.3% of the variance in log-transformed plasma lactate levels among the European-American subjects. In the African-American subjects, based on a region-significant threshold, the index single nucleotide polymorphism at GCKR was associated with plasma lactate but that at PPP1R3B/LOC157273 was not. Metformin use appeared to strengthen the association between the index single nucleotide polymorphism at PPP1R3B/LOC157273 and plasma lactate in European-American subjects (P for interaction=0.01). CONCLUSIONS: We identified GCKR and PPP1R3B/LOC157273 as two genome-wide significant loci of plasma lactate. Both loci are associated with other diabetes related phenotypes. These findings increase our understanding of the genetic control of lactate metabolism. PMID- 26433131 TI - Improved simultaneous estimation of tracer kinetic models with artificial immune network based optimization method. AB - Tracer kinetic modeling (TKM) is a promising quantitative method for physiological and biochemical processes in vivo. In this paper, we investigated the applications of an immune-inspired method to better address the issues of Simultaneous Estimation (SIME) of TKM with multimodal optimization. Experiments of dynamic FDG PET imaging experiments and simulation studies were carried out. The proposed artificial immune network (TKM_AIN) shows more scalable and effective when compared with the gradient-based Marquardt-Levenberg algorithm and the scholastic-based simulated annealing method. PMID- 26433132 TI - Pseudotumoral presentation of fungating mycetoma caused by Phaeoacremonium fuscum in a renal transplant patient. AB - Eumycetoma is an unusual infection in immunocompromised patients outside the tropics, caused by a variety of fungal pathogens. We describe the case of a 51 year-old renal transplant recipient who presented with a large pseudotumoral foot lesion necessitating complete surgical excision of the lesion. Cultures and molecular diagnosis confirmed Phaeoacremonium fuscum. This is the first case, to our knowledge, of fungating mycetoma caused by this fungal species in a solid organ transplant recipient. PMID- 26433133 TI - Does exposure to hyperglycaemia in utero increase the risk of obesity and diabetes in the offspring? PMID- 26433134 TI - Physicians' Reflections on Death and Dying on Completion of a Palliative Medicine Fellowship. AB - CONTEXT: Patient and family dissatisfaction may result when they are not satisfied with the physician/patient interaction, although the physician may feel he/she worked hard to provide information to the patient and family. New approaches to visual analysis can (1) identify significant insights from physicians' personal and clinical experiences in providing compassionate palliative care and end-of-life care and (2) provide an effective and practical vehicle for communicating with patients, their families, and other professional caregivers. OBJECTIVES: To elucidate palliative physicians' core experiences with their patients' dying and death. METHODS: A qualitative visual analysis was conducted on 75 images created by physicians completing a one year palliative medicine fellowship. These images are part of a larger personal reflections narratives database of images, text, and auditory projects prepared by students, interns, and fellows completing training in palliative care at a large hospice provider. Participation in the personal reflections project is a required part of the training program, with the goal of blending clinical competencies with lived experiences of caring for the dying. RESULTS: Two categories of visual metaphors underlying the images were identified, with both expressing the relationship and transitional dynamics of life and death: portraits (n = 30, 40%) and nature (n = 45, 60%). Conventional images representing anxiety, pain, or other dimensions of suffering commonly associated with death and dying were virtually absent (n = 2, 0.03%). CONCLUSION: We propose the communication of positive, hopeful, even peaceful perceptions of death and dying was likely the result of effective personal and professional skills gained through physicians' clinical experiences during the fellowship. PMID- 26433135 TI - The Social Convoy for Family Caregivers Over the Course of Hospice. AB - CONTEXT: Family caregivers play a central role in the care of those in hospice care. Little is known about the social support networks for those providing this day-to-day care without training. OBJECTIVES: The purpose of this study was to explore changes in family and friend social networks among hospice caregivers over the course of the hospice stay. METHODS: Data on social support networks were collected as part of a multisite randomized controlled trial and analyzed using structural equation modeling. RESULTS: A statistically significant decline in the caregivers' family network subscale score was found over the four week period during which they received hospice services, reflecting a possible weakening of their family networks. CONCLUSION: This result illustrates the potential importance of ongoing comprehensive assessment of caregiver networks and attention to interventions that may assist in capitalizing on both the quantity of support (numbers of individuals asked to help) and the quality of social support (attending to issues of support burden). PMID- 26433136 TI - ACROSCORE: a new and simple tool for the diagnosis of acromegaly, a rare and underdiagnosed disease. AB - OBJECTIVE: Acromegaly, a disease caused by GH/IGF-I hypersecretion, is associated with a high mortality rate; early recognition is therefore necessary to ensure successful treatment and to avoid comorbidities. We have created a symptom/sign scoring tool (ACROSCORE) for physicians to use to identify acromegaly. DESIGN: To compare cases of acromegaly diagnosed between 1990 and 2014 against a control group affected by non-GH-secreting pituitary tumours to identify symptoms and signs that are most discriminative for acromegaly. PATIENTS: Confirmed acromegaly patients and patients affected by non-GH-secreting pituitary tumours. MEASUREMENTS: In all patients, signs, symptoms and comorbidities were recorded from medical records and collected using a specifically designed questionnaire. RESULTS: A total of 194 acromegaly patients [115 women; mean (SD) age 47.2 (14.2) years] and 243 patients affected by non-GH-secreting pituitary tumours [131 women; mean (SD) age 45.8 (15.8) years] were included. A strong association was observed for type 2/secondary diabetes [odds ratio (OR) 3.7], hyperhidrosis (OR 6.1), thyroid hyperplasia (OR 13.9), colorectal polyps (OR 10.4), spaced teeth (OR 25.4) and carpal tunnel syndrome (OR 4.3). Based on this information, a multivariable logistic model was built and a 14-point scoring system developed. A score of 0 excludes the risk of acromegaly [positive predictive value (PV(+)) = 0.6%]; scores 1-5 comprise a grey area; scores >5 indicate that a diagnosis of acromegaly cannot be excluded (PV(+) = 46.1%). CONCLUSIONS: Once validated in independent studies, ACROSCORE may represent a new tool for the clinical screening of acromegaly that can be used by general practitioners and nonendocrinology specialists. PMID- 26433137 TI - UPLC-HRMS based metabolomics reveals the sphingolipids with long fatty chains and olefinic bonds up-regulated in metabolic pathway for hypoxia preconditioning. AB - Hypoxia preconditioning (HPC) could protect cells, tissues, organs and systems from hypoxia injury, but the molecular mechanism still remained unclear. The ultra-high performance liquid chromatography coupled high resolution mass spectrometry (UPLC-HRMS) based metabolomics method was utilized to explore the key endogenous metabolites and metabolic pathways related to HPC. Our results clearly showed that the HPC mice model was established and refined, suggesting that there were significant differences between the control group and 6 * HPC group at the molecular levels. A serious of statistical analyses, including univariate analysis and multivariate analysis, were performed by the Progenesis QI software package and MetaboAnalyst web-server. The sphingolipid metabolic pathways were noticed due to the low p-value and high pathway impact calculated by the MetaboAnalyst and the pathways were altered under HPC condition. Especially, the sphingolipid compound sphingomyelin, ceramide, glucosylceramide, galactosylceramide and lactosylceramide were mapping in this metabolic pathway. Interestingly, these sphingolipid metabolites with olefinic bond in the long fatty chain were up-regulated, while those sphingolipids without olefinic bond were down-regulated. The results indicated that C24:1-Cers played a critical role in HPC and had potential in endogenous protective mechanism. Our data provided an insight to further reveal the protection mechanism of HPC. PMID- 26433138 TI - Relative hypoaldosteronism in a patient with Wolcott-Rallison syndrome. AB - BACKGROUND: Wolcott-Rallison syndrome is an autosomal recessive, multisystem disorder with onset of diabetes in the neonatal period or early infancy. CASE REPORT: A 9-year-old girl with diabetes and growth failure from 2 months of age presented with ketoacidosis and multiple organ failure. Evaluation for short stature revealed epiphyseal dysplasia. A homozygous mutation in the EIF2AK3 gene confirmed the clinical diagnosis of Wolcott-Rallison syndrome. She was euthyroid. Biochemical evaluation for potential adrenal dysfunction because of persistently elevated serum potassium (range 5.9-6.3 meq/l) and low serum sodium levels (range 128-130 meq/l) 2 weeks after resolution of ketoacidosis yielded normal findings with respect to basal corticotropin (31 pg/ml) and cortisol (18.7 MUg/dl) levels. Estimated GFR-Schwartz (36.9 ml/min/1.73 m(2) ) was consistent with stage 3 chronic renal failure. The transtubular potassium gradient was 1.39 (normal value in hyperkalemic states: > 4.1). The plasma aldosterone (upright: 241.3 pmol/l) was within normal ranges, and plasma renin [39 pg/ml (range 5.41-34.53 pg/ml)] was slightly elevated. The patient was diagnosed as having relative hypoaldosteronism and was started on a sodium-rich diet and low potassium. Failure to respond to the dietary intervention prompted a trial of oral fludrocortisone with subsequent normalization of electrolyte levels. CONCLUSIONS: This is the first case report of Wolcott-Rallison syndrome complicated with relative hypoaldosteronism. Further research is needed to probe the causal inference of relative hypoaldosteronism with chronic renal failure in patients with Wolcott-Rallison syndrome. PMID- 26433139 TI - Longitudinal circulating concentrations of long-chain polyunsaturated fatty acids in the third trimester of pregnancy in gestational diabetes. AB - AIM: Gestational diabetes mellitus is a common complication of pregnancy. Long chain polyunsaturated fatty acids (LCPUFA) are essential for fetal neurodevelopment. Docosahexaenoic acid (DHA) is the predominant n-3 LCPUFA in the brain and retina. Circulating absolute concentrations of total n-3 and n-6 LCPUFAs rise during normal pregnancy. It remains unclear whether gestational diabetes may affect the normal rise in circulating concentrations of LCPUFAs in the third trimester of pregnancy - a period of rapid fetal neurodevelopment. This study aimed to address this question. METHODS: In a prospective singleton pregnancy cohort, fatty acids in fasting plasma total lipids were measured at 24 28 and 32-35 weeks of gestation in women with (n = 24) and without gestational diabetes mellitus (n = 116). Fatty acid desaturase activity indices were estimated by relevant product-to-precursor fatty acid ratios. Dietary nutrient intakes were estimated by a food frequency questionnaire. RESULTS: Plasma absolute concentrations of total n-6 LCPUFAs rose significantly between 24-28 and 32-35 weeks of gestation in women with or without gestational diabetes, whereas total n-3 LCPUFAs and DHA concentrations rose significantly only in women without gestational diabetes (all P < 0.01). Delta-5 desaturase indices (20:4n-6/20:3n-6) were similar, but delta-6 desaturase indices (18:3n-6/18:2n-6) were significantly lower in women with gestational diabetes at 32-35 weeks of gestation. Dietary intakes of all fatty acids were comparable. CONCLUSION: The normal rise in circulating absolute concentrations of DHA and total n-3 LCPUFAs in the third trimester of pregnancy may be compromised in gestational diabetes, probably due to impaired synthesis or mobilization rather than dietary intake difference. PMID- 26433140 TI - Impact of Reduced Glomerular Filtration Rate and Proteinuria on Overall Survival of Patients with Renal Cancer. AB - PURPOSE: Although it is commonly staged according to glomerular filtration rate, an international work group recommended classifying chronic kidney disease by cause, glomerular filtration rate and albuminuria. Data on nonsurgical patients with chronic kidney disease indicate proteinuria to be an independent predictor of renal function decrease and mortality. We evaluated whether preoperative proteinuria impacted survival in patients undergoing nephrectomy. MATERIALS AND METHODS: An institutional registry was queried for information regarding preoperative creatinine/glomerular filtration rate and urinalysis in 900 patients, including 362 and 538 treated with partial and radical nephrectomy, respectively. Patients were grouped according to glomerular filtration rate level (G1 to G5), proteinuria level (A1 to A3) and chronic kidney disease risk classification (low to very high). Kaplan-Meier and Cox proportional hazards analyses of overall survival were performed. RESULTS: The preoperative glomerular filtration rate was less than 60 ml/minute/1.73 m(2) in 30% of patients (median 73, IQR 56-91) and 20% of patients had baseline proteinuria. According to the KDIGO (Kidney Disease Improving Global Outcomes) classification 23% of patients were at moderately increased, 11% were at high and 8% were at very high risk for chronic kidney disease progression. Kaplan-Meier analysis revealed that the preoperative glomerular filtration rate, proteinuria and chronic kidney disease risk group were associated with poor overall survival. In Cox proportional hazard models accounting for age, gender, race, tumor size, clinical stage and surgery type the glomerular filtration rate, proteinuria and chronic kidney disease risk group were highly significant predictors of overall survival (p <0.0001). CONCLUSIONS: Preoperative proteinuria is a significant predictor of overall survival in patients who undergo nephrectomy. Classification according to preoperative glomerular filtration rate and proteinuria more accurately predicts survival than using the glomerular filtration rate alone after accounting for cancer stage. This information supports routine evaluation of proteinuria in patients with kidney cancer. PMID- 26433141 TI - The introduction of the meningococcal B (MenB) vaccine (Bexsero(r)) into the national infant immunisation programme--New challenges for public health. AB - The United Kingdom is the first country to introduce Bexsero((r)) (GSK Biologicals), a multicomponent, protein-based vaccine against meningococcal group B (MenB), into the national infant immunisation programme. This vaccine is like no other licensed vaccine and poses a number of implementation and surveillance challenges in England. From 01 September 2015, UK infants were offered a reduced two dose primary immunisation schedule at 2 and 4 months followed by a booster at 12 months. Because of high rates of fever post-vaccination, parents were advised to give their infants three doses of prophylactic paracetamol, with the first dose given as soon as possible after the primary MenB vaccination dose. Since the vaccine only protects against 73-88% of MenB strains causing invasive disease in England, clinical isolates and PCR-positive samples will require extensive characterisation by the Meningococcal Reference Unit (MRU) at Public Health England (PHE) in order to monitor vaccine effectiveness and identify potential vaccine failures. PHE is also conducting detailed clinical and epidemiological surveillance to assess the impact of the MenB immunisation programme on the morbidity and mortality associated with invasive meningococcal disease in infants and young children. PMID- 26433142 TI - Whole spine imaging is justified in tuberculous spondylodiscitis but not pyogenic spondylodiscitis. PMID- 26433143 TI - Specialist enemies, generalist weapons and the potential spread of exotic pathogens: malaria parasites in a highly invasive bird. AB - Pathogens can influence the success of invaders. The Enemy Release Hypothesis predicts invaders encounter reduced pathogen abundance and diversity, while the Novel Weapons Hypothesis predicts invaders carry novel pathogens that spill over to competitors. We tested these hypotheses using avian malaria (haemosporidian) infections in the invasive myna (Acridotheres tristis), which was introduced to southeastern Australia from India and was secondarily expanded to the eastern Australian coast. Mynas and native Australian birds were screened in the secondary introduction range for haemosporidians (Plasmodium and Haemoproteus spp.) and results were combined with published data from the myna's primary introduction and native ranges. We compared malaria prevalence and diversity across myna populations to test for Enemy Release and used phylogeographic analyses to test for exotic strains acting as Novel Weapons. Introduced mynas carried significantly lower parasite diversity than native mynas and significantly lower Haemoproteus prevalence than native Australian birds. Despite commonly infecting native species that directly co-occur with mynas, Haemoproteus spp. were only recorded in introduced mynas in the primary introduction range and were apparently lost during secondary expansion. In contrast, Plasmodium infections were common in all ranges and prevalence was significantly higher in both introduced and native mynas than in native Australian birds. Introduced mynas carried several exotic Plasmodium lineages that were shared with native mynas, some of which also infected native Australian birds and two of which are highly invasive in other bioregions. Our results suggest that introduced mynas may benefit through escape from Haemoproteus spp. while acting as important reservoirs for Plasmodium spp., some of which are known exotic lineages. PMID- 26433144 TI - l-Scoulerine attenuates behavioural changes induced by methamphetamine in zebrafish and mice. AB - Methamphetamine (METH), a substance with a high potential for abuse and addiction, is a serious worldwide public health problem. METH addicts often show extreme paranoia, anxiety, and depression. Thus, there is no effective medication for the treatment of METH-induced abnormalities. In the present study, we investigated the effects of l-Scoulerine (l-SLR), a tetrahydroprotoberberine (THPBS) alkaloid, on METH-induced anxiety-like behaviour in zebrafish and METH induced addictive behavior in mice. In the novel tank test, acute administration of METH (2 mg/L) induced a significant decrease in the number of total vertical transitions and time spent in the upper zone. Moreover, METH produced significant avoidance behaviour showing increased swimming time in the central area and high speed movement in the mirror area in the mirror stimulation test; these anxiety like changes were attenuated by l-SLR. Chronic administration of METH (2 mg/kg) produced a steady increase in locomotor activity and conditioned place preference in mice. l-SLR (5 mg/kg) failed to reduce acute METH-induced hyperlocomotion, but attenuated chronic METH-induced behavioural sensitization and significantly blocked the expression of conditioned place preference induced by METH in mice. The present study suggests that l-SLR may be a promising agent for the treatment of addiction and anxiety induced by METH. PMID- 26433145 TI - Interpersonal stroking touch is targeted to C tactile afferent activation. AB - C tactile fibers are a specialized group of fibers innervating the non-glabrous skin that are tuned to light gentle stroking applied with velocities between 1 and 10 cm/s. Those fibers add to the sensation of interpersonal caressing and pleasant touch. It is unclear whether people spontaneously apply touch that is tuned to optimally activate those fibers. This was investigated in three studies. In study one, 45 participants (21.8 +/- 2.3 years, 24 women) were asked to stroke an artificial arm. In study two, 32 participants (28.3 +/- 8.7 years, 16 women) were asked to stroke their partner. In study three, 11 parents (29.4 +/- 5.7 years, 6 women) were asked to stroke their babies. Stroking velocity was tracked in all conditions. Stroking velocities were significantly slower in the partner touch and baby touch condition than in the artificial arm condition and all of the participants stroking their partner or baby used velocities that can activate C tactile fibers. We conclude that human social stroking is optimized for C tactile stimulation. PMID- 26433146 TI - Brain-derived neurotrophic factor into adult neocortex strengthens a taste aversion memory. AB - Nowadays, it is known that brain derived neurotrophic-factor (BDNF) is a protein critically involved in regulating long-term memory related mechanisms. Previous studies from our group in the insular cortex (IC), a brain structure of the temporal lobe implicated in acquisition, consolidation and retention of conditioned taste aversion (CTA), demonstrated that BDNF is essential for CTA consolidation. Recent studies show that BDNF-TrkB signaling is able to mediate the enhancement of memory. However, whether BDNF into neocortex is able to enhance aversive memories remains unexplored. In the present work, we administrated BDNF in a concentration capable of inducing in vivo neocortical LTP, into the IC immediately after CTA acquisition in two different conditions: a "strong-CTA" induced by 0.2M lithium chloride i.p. as unconditioned stimulus, and a "weak-CTA" induced by 0.1M lithium chloride i.p. Our results show that infusion of BDNF into the IC converts a weak CTA into a strong one, in a TrkB receptor dependent manner. The present data suggest that BDNF into the adult insular cortex is sufficient to increase an aversive memory-trace. PMID- 26433148 TI - Exocrine pancreas ER stress is differentially induced by different fatty acids. AB - Exocrine pancreas acinar cells have a highly developed endoplasmic reticulum (ER), accommodating their high protein production rate. Overload of dietary fat (typical to obesity) is a recognized risk factor in pancreatitis and pancreatic cancer. Dietary fat, especially saturated fat, has been suggested by others and us to induce an acinar lipotoxic effect. The effect of different dietary fatty acids on the ER stress response is unknown. We studied the effect of acute (24h) challenge with different fatty acids (saturated, mono and poly-unsaturated) at different concentrations (between 200 and 500uM, typical to normal and obese states, respectively), testing fat accumulation, ER stress indicators, X-box binding protein 1 (Xbp1) splicing and nuclear translocation, as well as unfolded protein response (UPR) transcripts and protein levels using exocrine pancreas acinar AR42J and primary cells. Acute exposure of AR42J cells to different fatty acids caused increased accumulation of triglycerides, dependent on the type of fat. Different FAs had different effects on ER stress: most notably, saturated palmitic acid significantly affected the UPR response, as demonstrated by altered Xbp1 splicing, elevation in transcript levels of UPR (Xbp, CHOP, Bip) and immune factors (Tnfalpha, Tgfbeta), and enhanced Xbp1 protein levels and Xbp1 time dependent nuclear translocation. Poly-unsaturated FAs caused milder elevation of ER stress markers, while mono-unsaturated oleic acid attenuated the ER stress response. Thus, various fatty acids differentially affect acinar cell fat accumulation and, apart from oleic acid, induce ER stress. The differential effect of the various fatty acids could have potential nutritional and therapeutic implications. PMID- 26433147 TI - Synthesis of new steroidal imidazo [1,2-a] pyridines: DNA binding studies, cleavage activity and in vitro cytotoxicity. AB - A one-pot strategy for the catalytic synthesis of series of new 5alpha-cholestan 6-spiro-5'-phenylamino-2H-imidazo [1',2'-a] pyridines (4-14) has been investigated. The synthesized products were obtained in good yields (85-90%) and the protocol uses Multi-component Reaction (MCR) involving steroidal ketones, 2 aminopyridines, isocyanides and propylphosphonic anhydride ((r)T3P) as a catalyst. After characterization by spectral and analytical data, the interaction studies of compounds (4-6) with DNA were studied by UV-vis, fluorescence spectroscopy, gel electrophoresis and molecular docking. The compounds bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb; 2.35*10(4), 3.71*10(4) and 3.24*10(4) M(-1), respectively, indicating the higher binding affinity of compound 5 towards DNA. Gel electrophoresis showed the concentration dependent cleavage activity of compounds 4-6 with DNA. Molecular docking studies suggested that compounds bind through minor groove to DNA. The 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay depicted promising anti-proliferative activity of compound 4-9 against different given cancer cells. In Western blotting, the expressions of relevant apoptotic markers depicted an apoptosis by steroidal imidazopyridines in A549 cells. Annexin V FITC/PI staining data indicated that compounds could effectively induce apoptosis in A549 cells in a dose-dependent manner. FACS analysis shows that the compound 6 bring about cell cycle arrest at 2.62 MUM concentration. PMID- 26433149 TI - The chemical properties and microbial community characterization of the thermophilic microaerobic pretreatment process. AB - Thermophilic microaerobic pretreatment (TMP) was recently reported as an efficient pretreatment method of anaerobic digestion (AD). In this study, the chemical properties and microbial community were characterized to reveal how TMP working. Compared with thermophilic treatment under anaerobic condition (TMP0), cellulase activity obviously improved under microaerobic condition (TMP1), which was 10.9-49.0% higher than that of TMP0. Reducing sugar, SCOD and VFAs concentrations of TMP1 were 2.6-8.9%, 1.8-4.8% and 13.8-24% higher than those of TMP0, respectively. TMP gave obvious rise to phylum Firmicutes, which associated with extracellular enzymes production. The proportion of class Bacilli (belongs to phylum Firmicutes and mainly acts during hydrolysis) in TMP1 was 124.89% higher than that of TMP0, which reflected the greater hydrolytic ability under microaerobic condition. The improved abundance of phylum Firmicutes (especially class Bacilli, order Bacillales) under microaerobic condition could be the fundamental reason for the improved AD performance of thermophilic microaerobic pretreated corn straw. PMID- 26433150 TI - End-product inhibition and acidification limit biowaste fermentation efficiency. AB - Converting waste to resource may mitigate environmental pollution and global resource limitation. The platform chemical lactic acid can be produced from biowaste and its liquid fraction after solid-liquid separation. A fermentation step for lactic acid production prior to the conversion of biowaste to methane and organic fertilizer would increase the biowaste's value. Despite the huge potential and promising results of the treatment procedure, the reasons for efficiency loss observed previously need to be addressed in order to pave the way for an up-scaling of the fermentation process. Therefore, biowaste was fermented applying pH control, acid extraction and glucose addition in order to counteract reasons such as acidification, end-product inhibition and carbon limitation, respectively. The fermentation was competitive compared to other renewable lactic acid production substrates and reached a maximum productivity of >5 g Clactic acidg(-1)Ch(-1) and a concentration exceeding 30 g L(-1). A combination of acidification and end-product inhibition was identified as major obstacle. Lactobacillus crispatus and its closest relatives were identified as key lactic acid producers within the process using Miseq Illumina sequencing. PMID- 26433151 TI - Optimization of continuous lipid extraction from Chlorella vulgaris by CO2 expanded methanol for biodiesel production. AB - CO2-expanded methanol (CXM) was used to extract lipids from the microalgae Chlorella vulgaris (a total lipid content of 20.7% was determined by Soxhlet extraction with methanol at 373 K for 96 h) in a continuous mode. The CXM was found to be a superior solvent to methanol, ethanol, pressurized methanol and ethanol, and CO2-expanded ethanol for lipid extraction. The effects of operation variables including temperature, pressure and CO2 flow rate on extraction performance were examined using the response surface and contour plot methodologies. The optimal operating conditions were at a pressure of 5.5 MPa, a temperature of 358 K, a methanol flow rate of 1 mL/min and a CO2 flow rate of 3.0 mL/min, providing an extracted lipid yield of 84.8 wt% over an extraction period of 30 min. Compared with propane methanol mixture, CXM was safer and more energy efficient for lipid extraction from C. vulgaris. PMID- 26433152 TI - Sequential Heterotrophy-Dilution-Photoinduction Cultivation of Haematococcus pluvialis for efficient production of astaxanthin. AB - A novel cultivation strategy called "Sequential Heterotrophy-Dilution Photoinduction" was successfully applied in the cultivation of Haematococcus pluvialis to produce astaxanthin effectively. Cells were first cultivated heterotrophically to achieve a high cell density, then were diluted to a suitable concentration and switched to a favorable environment for cells acclimation. Finally, the culture was transferred to high light environment for astaxanthin accumulation. By this strategy, the dry cell weight of 26 g/L and biomass productivity of 64.1mg/L/h were obtained in heterotrophy stage which surpassed ever before reported in literatures. Meanwhile, the cells could accumulate considerable astaxanthin up to 4.6% of dry cell weight after 10 days of photoinduction. Furthermore, the application prospects of the strategy were confirmed further by outdoor experiments. Therefore, this novel strategy provided a promising approach for high-efficient production of natural astaxanthin from H. pluvialis to meet the huge demand of this high value product. PMID- 26433153 TI - Thermophilic bio-hydrogen production from corn-bran residue pretreated by calcined-lime mud from papermaking process. AB - This study investigated the use of calcined-lime mud from papermaking process (CLMP) pretreatment to improve fermentative hydrogen yields from corn-bran residue (CBR). CBR samples were pretreated with different concentrations (0-15 g/L) of CLMP at 55 degrees C for 48 h, prior to the thermophilic fermentation with heat-treated anaerobic sludge inoculum. The maximum hydrogen yield (MHY) of 338.91 ml/g-VS was produced from the CBR pretreated with 10 g/L CLMP, with the corresponding lag-phase time of 8.24h. Hydrogen yield increments increased from 27.76% to 48.07%, compared to the control. The CLMP hydrolyzed more cellulose, which provided adequate substrates for hydrogen production. PMID- 26433154 TI - Exploring the inhibitory characteristics of acid hydrolysates upon butanol fermentation: A toxicological assessment. AB - This study aimed to quantitatively evaluate the inhibitor tolerance of butanol producing bacterium Clostridium acetobutylicum. The inhibitory effect of the inhibitors generated by acid pretreatment of biomass feedstock on butanol fermentation decreased in the order of formic acid>oxalic acid>furfural>5 HMF>Na2SO4. C. acetobutylicum has a small tolerance range for furfural (1.06 2.6g/L) and 5-HMF (1.99-2.3g/L). However, the inhibitory effect of Na2SO4 appears to have a wide range, with a chronic toxicity for C. acetobutylicum. All the results could explain, in quantitative manner, the instability of butanol fermentation with C. acetobutylicum from various acid-pretreated feedstocks caused by the fermentation inhibitors. PMID- 26433155 TI - Growth of mono- and mixed cultures of Nannochloropsis salina and Phaeodactylum tricornutum on struvite as a nutrient source. AB - The suitability of crude and purified struvite (MgNH4PO4), a major precipitate in wastewater streams, was investigated for renewable replacement of conventional nitrogen and phosphate resources for cultivation of microalgae. Bovine effluent wastewater stone, the source of crude struvite, was characterized for soluble N/P, trace metals, and biochemical components and compared to the purified mineral. Cultivation trials using struvite as a major nutrient source were conducted using two microalgae production strains, Nannochloropsis salina and Phaeodactylum tricornutum, in both lab and outdoor pilot-scale raceways in a variety of seasonal conditions. Both crude and purified struvite-based media were found to result in biomass productivities at least as high as established media formulations (maximum outdoor co-culture yield ~20+/-4gAFDW/m(2)/day). Analysis of nutrient uptake by the alga suggest that struvite provides increased nutrient utilization efficiency, and that crude struvite satisfies the trace metals requirement and results in increased pigment productivity for both microalgae strains. PMID- 26433156 TI - An integrated process for hydrogen-rich gas production from cotton stalks: The simultaneous gasification of pyrolysis gases and char in an entrained flow bed reactor. AB - An integrated process (pyrolysis, gas-solid simultaneous gasification and catalytic steam reforming) was utilized to produce hydrogen-rich gas from cotton stalks. The simultaneous conversion of the pyrolysis products (char and pyrolysis gases) was emphatically investigated using an entrained flow bed reactor. More carbon of char is converted into hydrogen-rich gas in the simultaneous conversion process and the carbon conversion is increased from 78.84% to 92.06% compared with the two stages process (pyrolysis and catalytic steam reforming). The distribution of tar components is also changed in this process. The polycyclic aromatic compounds (PACs) of tar are converted into low-ring compounds or even chain compounds due to the catalysis of char. In addition, the carbon deposition yield over NiO/MgO catalyst in the steam reforming process is approximately 4 times higher without the simultaneous process. The potential H2 yield increases from 47.71 to 78.19g/kg cotton stalks due to the simultaneous conversion process. PMID- 26433157 TI - Phosphate adsorption ability of biochar/Mg-Al assembled nanocomposites prepared by aluminum-electrode based electro-assisted modification method with MgCl2 as electrolyte. AB - In this work, the textural properties and phosphate adsorption capability of modified-biochar containing Mg-Al assembled nanocomposites prepared by an effective electro-assisted modification method with MgCl2 as an electrolyte have been determined. Structure and chemical analyses of the modified-biochar showed that nano-sized stonelike or flowerlike Mg-Al assembled composites, MgO, spinel MgAl2O4, AlOOH, and Al2O3, were densely grown and uniformly dispersed on the biochar surface. The adsorption isotherm and kinetics data suggested that the biochar/Mg-Al assembled nanocomposites have an energetically heterogeneous surface and that phosphate adsorption could be controlled by multiple processes. The maximum phosphate adsorption capacity was as high as 887 mg g(-1), as fitted by the Langmuir-Freundlich model, and is the highest value ever reported. It was concluded that this novel electro-assisted modification is a very attractive method and the biochar/Mg-Al assembled nanocomposites provide an excellent adsorbent that can effectively remove phosphate from aqueous solutions. PMID- 26433158 TI - Mining the coding and non-coding genome for cancer drivers. AB - Progress in next-generation sequencing provides unprecedented opportunities to fully characterize the spectrum of somatic mutations of cancer genomes. Given the large number of somatic mutations identified by such technologies, the prioritization of cancer-driving events is a consistent bottleneck. Most bioinformatics tools concentrate on driver mutations in the coding fraction of the genome, those causing changes in protein products. As more non-coding pathogenic variants are identified and characterized, the development of computational approaches to effectively prioritize cancer-driving variants within the non-coding fraction of human genome is becoming critical. After a short summary of methods for coding variant prioritization, we here review the highly diverse non-coding elements that may act as cancer drivers and describe recent methods that attempt to evaluate the deleteriousness of sequence variation in these elements. With such tools, the prioritization and identification of cancer implicated regulatory elements and non-coding RNAs is becoming a reality. PMID- 26433159 TI - TLR7/8 agonists promote NK-DC cross-talk to enhance NK cell anti-tumor effects in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a common cancer worldwide and the third leading cause of cancer death. Immunotherapy is considered a promising treatment with the aim to boost or arouse HCC-specific immune responses. TLR7 and TLR8 agonists are effective immunomodulators and have been applied topically for the treatment of certain skin tumors and viral infections. Here, we explored the role of TLR7 and TLR8 agonists on the activation of dendritic cells (DCs) and natural killer (NK) cells. We demonstrated that these agonists could directly activate NK cells, promoting the maturation of immature DCs. Meanwhile, DCs also assisted in the function of NK cells, resulting in enhanced anti-tumor immune responses to HCC. Importantly, the combination therapy with NK cells stimulated with DCs and TLR7/8 agonist Gardiquimod (GDQ) significantly suppresses the growth of human HepG2 liver carcinoma xenografts. This study provides a new immunotherapeutic approach for human HCC based on DC-NK cross-talk and also suggests that TLR7 and/or TLR8 agonists, particularly GDQ, may serve as potent innate and adaptive immune response immunomodulators in tumor therapy. PMID- 26433161 TI - Defects in 15-HETE Production and Control of Epithelial Permeability by Human Enteric Glial Cells From Patients With Crohn's Disease. AB - BACKGROUND & AIMS: Enteric glial cells (EGCs) produce soluble mediators that regulate homeostasis and permeability of the intestinal epithelial barrier (IEB). We investigated the profile of polyunsaturated fatty acid (PUFA) metabolites produced by EGCs from rats and from patients with Crohn's disease (CD), compared with controls, along with the ability of one of these metabolites, 15 hydroxyeicosatetraenoic acid (15-HETE), to regulate the permeability of the IEB. METHODS: We isolated EGCs from male Sprague-Dawley rats, intestinal resections of 6 patients with CD, and uninflamed healthy areas of intestinal tissue from 6 patients who underwent surgery for colorectal cancer (controls). EGC-conditioned media was analyzed by high-sensitivity liquid-chromatography tandem mass spectrometry to determine PUFA signatures. We used immunostaining to identify 15 HETE-producing enzymes in EGCs and tissues. The effects of human EGCs and 15-HETE on permeability and transepithelial electrical resistance of the IEB were measured using Caco-2 cells; effects on signal transduction proteins were measured with immunoblots. Levels of proteins were reduced in Caco-2 cells using short-hairpin RNAs or proteins were inhibited pharmacologically. Rats were given intraperitoneal injections of 15-HETE or an inhibitor of 15-lipoxygenase (the enzyme that produces 15-HETE); colons were collected and permeability was measured. RESULTS: EGCs expressed 15-lipoxygenase-2 and produced high levels of 15-HETE, which increased IEB resistance and reduced IEB permeability. 15-HETE production was reduced in EGCs from patients with CD compared with controls. EGCs from patients with CD were unable to reduce the permeability of the IEB; the addition of 15-HETE restored permeability to levels of control tissues. Inhibiting 15-HETE production in rats increased the permeability of the IEB in colon tissues. We found that 15-HETE regulates IEB permeability by inhibiting an adenosine monophosphate-activated protein kinase and increasing expression of zonula occludens-1. CONCLUSIONS: Enteric glial cells from patients with CD have reduced production of 15-HETE, which controls IEB permeability by inhibiting adenosine monophosphate-activated protein kinase and increasing expression of zonula occludens-1. PMID- 26433160 TI - Activation of signal transduction pathways during hepatic oncogenesis. AB - BACKGROUND AND AIMS: Understanding the molecular pathogenesis of hepatocellular carcinoma (HCC) is essential to identify therapeutic targets. A hepatitis B virus (HBV) related double transgenic murine model was developed. METHODS: Liver specific expression of HBV X protein (HBx) and insulin receptor substrate 1 (IRS1) was achieved and transgenic mice were followed from birth to age 21 months. Liver and tumor tissue were assessed for histologic changes as well as activation of signal transduction pathways by qRT-PCR and multiplex ELISA protein assays. RESULTS: Overexpression of HBx and IRS1 stimulates liver cell proliferation in the double transgenic mice. Only the male mice developed HCC starting at age 15-18 months. The IN/IGF1/IRS1/MAPK/ERK and IN/IGF1/IRS1/PI3K/AKT/GSK3beta cascades were activated early (6-9 months) in the liver followed by WNT/beta-catenin and Notch signaling. Aspartate beta hydroxylase (ASPH) was found to link these upstream growth factor signaling pathways to downstream Notch activation in tumor tissues. CONCLUSIONS: Sustained overexpression of HBx and IRS1 led to constitutive activation of a tripartite growth factor signal transduction cascade in the liver and was necessary and sufficient to promote HCC development and progression. PMID- 26433162 TI - Could Carlos Chagas' assumption on the relationship between goiter and chronic Chagas heart disease be correct? A historical reappraisal. AB - In 1910, Chagas divided the clinical manifestations of the chronic form of Chagas disease according to heart, Central Nervous System, and thyroid involvement, particularly the presence of goiter. Chagas emphasized the association of goiter with poor houses infested with kissing bugs, the similarity of the clinical picture with that of patients underwent partial thyroidectomy, and with the presence of thyroid sclerosis (inflammation) on histological examination. In addition, Chagas observed that all people living in poor houses infested by sucking bugs had goiter, contrasting with persons who lived in the same region, drinking the same water, but living in good houses, which did not have goiter. Furthermore, Chagas stressed the fact that people without any evidence of thyroid disease that migrated to live in poor houses in areas infested by sucking bugs developed thyroid disease some time later. Finally, and more importantly, Chagas emphasized the association of goiter with cardiac abnormalities in 80% of patients with chronic Chagas heart disease. Despite this, other authors working in different regions did not confirm such an association. A reappraisal of data from a work published in 1949 clearly shows that the presence of goiter was statistically associated with chronic Chagas heart disease and with chronic Chagas disease. Our paper highlights once more the grandiosity of Chagas' work, which has been proved to be correct even in the history of goiter, and justifies our claim for a posthumous Nobel Prize inasmuch as his work was not perceived by the Karolinska Institute. PMID- 26433163 TI - Comparison of transradial and transfemoral coronary intervention in octogenarians with acute myocardial infarction. AB - BACKGROUND: The transradial (TR) approach for percutaneous coronary intervention (PCI) is challenging and associated with failure in elderly patients. We compared the TR and transfemoral (TF) approaches in patients>80 years with acute myocardial infarction (MI) undergoing PCI. METHODS: A total of 1945 (7.2%) octogenarians were enrolled from among 27,129 patients in the Korea Acute Myocardial Infarction Registry. The TR group (n=336, 17.3%) was compared with the TF group (n=1609, 82.7%) in the overall and propensity-matched cohorts with respect to procedural success, complications, in-hospital mortality, and one-year mortality and total major adverse cardiac event (MACE; death, MI, and revascularization) rate. RESULTS: In the overall cohort, the TR group had lower incidence of Killip class III or IV compared to the TF group. The disease extent and lesion severity were similar between groups, as was the procedural success rate (97.7% vs. 98.3%); however, in-hospital complications were significantly lower in the TR group (8.1% vs. 20.3%). In-hospital mortality was significantly lower in the TR group than the TF group (3.4% vs. 11.4%), as were the one-year mortality and total MACE (9.8% vs. 18.4% and 13% vs. 21.9%, respectively). These outcomes were consistent in the propensity-matched cohort. The TR approach was found to be a significant predictor of low in-hospital mortality (OR 0.355, 95% CI 0.139-0.907), but not of one-year mortality (OR 0.644, 95% CI 0.334-1.240). CONCLUSIONS: In octogenarians with acute MI undergoing PCI, the TR approach was more effective than the TF approach as it had lower complication rate and better clinical outcomes with comparable procedural success. PMID- 26433164 TI - Targeted ablation of cardiac sympathetic neurons: A promising approach to prevent sudden cardiac death. PMID- 26433165 TI - Association between weekend admission for atrial fibrillation or flutter and in hospital mortality, procedure utilization, length-of-stay and treatment costs. PMID- 26433166 TI - The role of angioplasty in octogenarian patients with Acute Coronary Syndrome. PMID- 26433167 TI - Worldwide disparities in cardiovascular disease: Challenges and solutions. AB - The 20th century saw cardiovascular disease ascend as the leading cause of death in the world. In response to the new challenge that heart disease imposed, the cardiovascular community responded with ground breaking innovations in the form of evidence based medications that have improved survival, imaging modalities that allow for precise diagnosis and guide treatment; revascularization strategies that have not only reduced morbidity, but also improved survival following an acute myocardial infarction. However the benefits have not been distributed equitably and as a result disparities have arisen in cardiovascular care. There is tremendous data from the United States demonstrating the many phenotypical forms of disparities. This paper takes a global view of disparities and highlights that disparate care is not limited to the United States and it is another challenge that the medical community should rise and face head on. PMID- 26433168 TI - Identification of bioactive ingredients with immuno-enhancement and anti oxidative effects from Fufang-Ejiao-Syrup by LC-MS(n) combined with bioassays. AB - Fufang Ejiao Syrup (FES) is a widely used immune-boosting Traditional Chinese Medicine (TCM) in Eastern Asian countries. This study attempts to investigate the bioactive compounds in FES. First, FES extract was separated into fractions to facilitate the investigation and 72 compounds were identified using LC-MS(n). Subsequently, Immune-enhancement effects of FES and its components were investigated on bone marrow cells and neuroprotective effects against H2O2 induced oxidative damage were evaluated in SH-SY5Y neuroblastoma cells and bEnd.3. Our results indicated that fraction 3, 5, 6 and 8 showed significant improvements on immune function, while several fractions had cytoprotective effects against H2O2-induced oxidative injury. Jionoside A1 isolated from Radix Rehmanniae Praeparata displayed dose dependent immune-enhancement activity. 20(R) ginsenoside Rg3 could protect bEnd.3 against oxidative damage. Furthermore, echinacoside, jionoside A1, vitexin-2-O-rhamnoside, acteoside and isoacteoside possessed moderate protective activities on H2O2-treated SH-SY5Y cells. In conclusion, our study provided both chemical and biological evidences to support clinical application of FES. PMID- 26433169 TI - Simultaneous determination of four furostanol glycosides in rat plasma by UPLC MS/MS and its application to PK study after oral administration of Dioscorea nipponica extracts. AB - A novel, sensitive and rapid ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method for simultaneous quantification of four furostanol glycosides in rat plasma was established and validated. Ginsenoside Rb1 was used as an internal standard. Plasma samples were pretreated by liquid liquid extraction with n-butanol and chromatographed on a C18 column (2.1*50 mm i.d., 2.6 MUm) using a gradient elution program consisting of acetonitrile and water (containing 0.03% formic acid and 0.1 mM lithium acetate) at a flow rate of 0.4 mL/min. Lithium adduct ions were employed to enhance the response of the analytes in electrospray positive ionization mode and multiple reaction monitoring transitions were performed for detection. All calibration curves exhibited good linearity (r>0.999) over the range of 10-20,000 ng/mL for protodioscin and 2-4000 ng/mL for protogracillin, pseudoprotodioscin and pseudoprotogracillin. The recoveries of the whole analytes were more than 80.3% and exhibited no severe matrix effect. Meanwhile, the intra- and inter-day precisions were all less than 10.7% and accuracies were within the range of -8.1 12.9%. The four saponins showed rapid excretion and relative high plasma concentrations when the validated method was applied to the PK study of Dioscorea nipponica extracts by intragastric administration at low, medium and high dose to rats. Moreover, the T(1/2) and AUC(0-t) of each compound turned out to behave in a dose-dependent pattern by comparing them at different dose levels. PMID- 26433170 TI - Association of cervical precancer with human papillomavirus types other than 16 among HIV co-infected women. AB - BACKGROUND: HIV-seropositive women face high risk for infection with oncogenic human papillomavirus (oncHPV) types, abnormal Pap test results, and precancer, but cervical cancer risk is only modestly increased. Human papillomavirus (HPV)16 is highly oncogenic but only weakly associated with HIV status and immunosuppression, suggesting HPV16 may have a greater innate ability to evade host immune surveillance than other oncHPV types, which in turn should result in a greater relative increase in the prevalence of other oncHPV types among women with cervical precancer. OBJECTIVE: We sought to assess whether the underrepresentation of HPV16 among HIV-seropositive relative to HIV-seronegative women remains among those with cervical precancers. STUDY DESIGN: HIV seropositive and HIV-seronegative women in the Women's Interagency HIV Study were screened for cervical intraepithelial neoplasia (CIN) grade >=3 (CIN3(+)). DNA from >40 HPV types was detected by polymerase chain reaction in cervicovaginal lavage specimens obtained at the visit at which CIN3(+) was diagnosed. RESULTS: HPV16 was detected in 13 (62%) of 21 HIV-seronegative women with CIN3(+) but only 44 (29%) of 154 HIV-seropositive women with CIN3(+) (P = .01). The lower prevalence of HPV16 in CIN3(+) among HIV-seropositive women persisted after controlling for covariates (odds ratio [OR], 0.25; 95% confidence interval [CI], 0.08-0.78). The prevalence of other members of the HPV16-related alpha-9 oncHPV clade as a group was similar in HIV-infected and uninfected women with CIN3(+) (OR, 1.02; 95% CI, 0.53-1.94). The prevalence of non-alpha-9 oncHPV types was increased in HIV-seropositive vs HIV-seronegative women with CIN3(+) (OR, 3.9; 95% CI, 1.3-11.8). CONCLUSION: The previously demonstrated increase in CIN3(+) incidence among HIV-seropositive women is associated with lower HPV16 and higher non-alpha-9 oncHPV prevalence. This is consistent with prior reports that HIV has a weak effect on infection by HPV16 relative to other oncHPV and supports use of nonavalent HPV vaccine in HIV-seropositive women. PMID- 26433171 TI - Mortality rate of gestational trophoblastic neoplasia with a FIGO score of >=13. AB - BACKGROUND: Gestational trophoblastic diseases include premalignant (partial and complete hydatidiform moles) and malignant entities referred to as gestational trophoblastic neoplasia. Use of the International Federation of Gynecology and Obstetrics prognostic score is encouraged in cases of gestational trophoblastic neoplasia to predict the potential for the development of resistance to single agent chemotherapy. An International Federation of Gynecology and Obstetrics score of >=7 defines a high-risk patient and requires combination chemotherapy. Appropriate and rapid diagnosis, treatment by specialized centers, and reduction of early deaths at the time of chemotherapy initiation have led to significant improvements in survival for patients with high-risk gestational trophoblastic neoplasia. There is a crucial need for the early identification of high-risk patients with gestational trophoblastic neoplasia who have an increased death risk to organize their treatment in highly specialized centers. OBJECTIVES: The purpose of this study was to describe cases of gestational trophoblastic neoplasia that have resulted in death, particularly in a subgroup with an International Federation of Gynecology and Obstetrics prognostic score of >=13, for whom low-dose etoposide and cisplatin induction chemotherapy recently was shown to reduce early death rate. STUDY DESIGN: We identified 974 patients from the French Center for Trophoblastic Diseases who had a diagnosis of gestational trophoblastic neoplasia from November 1999 to March 2014. Among 140 patients who were at high risk of resistance to single-agent chemotherapy (International Federation of Gynecology and Obstetrics score, >=7), 29 patients (21%) had a score of >=13. Mortality rate was estimated with the use of the Kaplan-Meier method. RESULTS: The 5-year overall mortality rate, after the exclusion of placental site trophoblastic tumors and epithelioid trophoblastic tumors, was 2% for patients with gestational trophoblastic neoplasia (95% confidence interval, 1.25-3.13%). High-risk patients had a 5-year mortality rate of 12% (95% confidence interval, 7.49-18.9%). Patients with an International Federation of Gynecology and Obstetrics score of >=13 had a higher 5-year mortality rate (38.4%; 95% confidence interval, 23.4-58.6%) and accounted for 52% of the deaths in the entire cohort. Early deaths, defined as those that occur within 4 weeks after treatment initiation, occurred in 8 patients of the entire cohort. Six of them had an International Federation of Gynecology and Obstetrics score of >=13 at presentation, of whom 5 patients had brain and/or liver metastases. CONCLUSION: Gestational trophoblastic diseases with an International Federation of Gynecology and Obstetrics score of >=13 have an increased risk of early death. We suggest that an International Federation of Gynecology and Obstetrics score of >=13 becomes a consensual criterion for prediction of patients with gestational trophoblastic neoplasia with increased risk of death, particularly early death. These patients justify treatment in highly specialized gestational trophoblastic disease centers and may benefit from the use of induction low-dose etoposide and cisplatin. PMID- 26433172 TI - Accelerated acidosis in response to variable fetal heart rate decelerations in chronically hypoxic ovine fetuses. AB - BACKGROUND: Due to limitations of technology, clinicians are typically unable to determine if human fetuses are normoxic or moderately, chronically hypoxic. Risk factors for chronic hypoxia include fetal growth restriction, which is associated with an increased incidence of oligohydramnios and thus a risk for umbilical cord occlusion (UCO) and variable fetal heart rate (FHR) decelerations. At delivery, fetal growth restriction infants (<3rd percentile) have nearly twice the incidence of low Apgar scores and umbilical pH <7.0. Despite the risks of oligohydramnios and intermittent UCO, there is little understanding of the acid/base responses rates of chronically hypoxic fetuses to variable FHR decelerations as might occur during human labor. OBJECTIVE: We sought to compare the increase in base deficit (BD) among chronically hypoxic as compared to normoxic ovine fetuses in response to simulated mild, moderate, and severe variable FHR decelerations. STUDY DESIGN: Near-term ovine fetuses were chronically prepared with brachial artery catheters and an inflatable umbilical cuff occluder. Following a recovery period, normoxic (n = 9) and spontaneously hypoxic (n = 5) fetuses were identified (arterial O2 saturation <=55%). Both animal groups underwent graded, 1-minute occlusions every 2.5 minutes with 1 hour of mild (~30 beats/min [bpm] decrease from baseline), 1 hour of moderate (~60 bpm decrease from baseline), and up to 2 hours of severe (~90 bpm decrease from baseline) variable FHR decelerations until fetal arterial pH reached 7.00, when occlusions were stopped. RESULTS: Repetitive UCO resulted in development of acidosis (pH <7.0) in both groups. Hypoxic and normoxic fetuses demonstrated similar BD increases in response to both mild (0.39, interquartile range [IQR] 0.28-0.45 vs 0.26, IQR 0.01-0.30 mEq/L/10 min, P = .25) and severe (1.97, IQR 1.50-2.43 vs 1.51, IQR 0.97-2.45 mEq/L/10 min, P = .63) variable decelerations. However, moderate variable decelerations increased BD in hypoxic fetuses at 2.5 times the rate of normoxic fetuses (0.97, IQR 0.52-1.72 vs 0.39, IQR 0.23-0.47 mEq/L/10 min, P = .03). During the recovery period, hypoxic fetuses cleared BD slower than normoxic fetuses (0.08 +/- 0.02 vs 0.12 +/- 0.03 mEq/L/min, P = .02). CONCLUSION: In comparison to normoxic fetuses, hypoxic fetuses can more rapidly progress to significant metabolic acidosis in response to moderate FHR variable decelerations, and more slowly recover with in utero resuscitation, likely a consequence of impaired placental function and fetal physiologic responses. PMID- 26433173 TI - Comparative outcomes in older and younger women undergoing laparotomy or robotic surgical staging for endometrial cancer. AB - BACKGROUND: Older patients are at increased risk of perioperative morbidity and mortality. There are limited data on the safety of a robotic approach in the staging for endometrial cancer. OBJECTIVE: We compared outcomes in women undergoing laparotomy or robotic surgical staging for endometrial cancer. STUDY DESIGN: Using the Healthcare Cost and Utilization Project National Inpatient Sample database from 2008 through 2010, we abstracted records for patients who had surgery for endometrial cancer with either a robotic approach or laparotomy. Patients were categorized by age (<65 vs >=65 years and 5-year increments). Medical comorbidity scores were calculated using the Charlson Comorbidity Index. Outcomes included intraoperative/perioperative/medical complications, death, length of stay (LOS), and discharge disposition. Student t and chi(2) tests were used to compare groups and approach. Multiple analysis of variance models were used to compare differences between robotics and laparotomy and age groups. RESULTS: We identified 16,980 patients who had surgery for endometrial cancer with either a robotic approach (age >=65 years, n = 1228; age <65 years, n = 1574) or laparotomy (age >=65 years, n = 5914; age <65 years, n = 8264). Older patients had a higher Charlson Comorbidity Index score at the time of surgery (2.6 vs 2.5, P < .001). In laparotomy cases, intraoperative complication rates were similar (4.1% vs 3.7%, P = .17). Older patients had higher rates of perioperative surgical (20.5% vs 15.4%, P < .001) and medical (23.3% vs 15.5%, P < .001) complications, longer LOS (5.1 vs 4.2 days, P < .001), and lower rates of discharge to home (71.2% vs 90.1%, P < .001). In robotic cases, rates of intraoperative complications were similar (5.9% vs 6.8%, P = .32). Older patients had higher rates of perioperative surgical (8.3% vs 5.2%, P = .001) and medical (12.3% vs 6.7%, P = .001) complications, longer LOS (2.00 vs 1.67 days, P < .001), and lower rates of discharge to home (88.8% vs 96.8%, P < .001). With both approaches, as age increased, perioperative surgical and medical complications also increased in a linear fashion. In a subanalysis of older patients (n = 7142), there were lower rates of perioperative surgical (8.3% vs 20.5%, P < .001) and medical (12.3% vs 23.3%, P < .001) complications, death (0.0% vs 0.8%, P < .001), shorter LOS (2.00 vs 5.13 days, P < .001) and higher rate of discharge to home (88.8% vs 71.2%, P < .001) in robotic compared to laparotomy cases. CONCLUSION: Although the risks of surgery increase with age, in patients age >=65 years, a robotic approach for endometrial cancer appears to be safe given current selection criteria utilized in the United States. PMID- 26433174 TI - Single-step purification of chitosanases from Bacillus cereus using expanded bed chromatography. AB - A chitosanase-producing strain was isolated and identified as Bacillus cereus C 01. The purification and characterization of two chitosanases were studied. The purification assay was accomplished by ion exchange expanded-bed chromatography. Experiments were carried out in the presence and in the absence of cells through different expansion degree to evaluate the process performance. The adsorption experiments demonstrated that the biomass does not affect substantially the adsorption capacity of the matrix. The enzyme bound to the resin with the same extent using clarified and unclarified broth (0.32 and 0.30 U/g adsorbent, respectively). The fraction recovered exhibited 31% of the yield with a 1.26-fold increase on the specific activity concerned to the initial broth. Two chitosanases from different elution steps were recovery. Chit A and Chit B were stable at 30-60 degrees C, pH 5.5-8.0 and 5.5-7.5, respectively. The highest activity was found at 55 degrees C, pH 5.5 to Chit A and 50 degrees C, pH 6.5 to Chit B. The ions Cu(2+), Fe(2+) and Zn(2+) indicated inhibitory effect on chitosanases activities that were significantly activated by Mn(2+). The methodology applied in this study enables the partial purification of a stable chitosanase using a feedstock without any pre-treatment using a single-step purification. PMID- 26433175 TI - Interaction of a snake venom L-amino acid oxidase with different cell types membrane. AB - Snake venom l-amino acid oxidases are multifunctional enzymes that exhibited a wide range of pharmacological activities. Although it has been established that these activities are primarily caused by the H2O2 generated in the enzymatic reaction, the molecular mechanism, however, has not been fully investigated. In this work, LAAO interaction with cytoplasmic membranes using different cell types and Langmuir interfacial monolayers was evaluated. The Cerastes cerastes venom LAAO (CC-LAAO) did not exhibit cytotoxic activities against erythrocytes and peripheral blood mononuclear cells (PBMC). However, CC-LAAO caused cytotoxicity on several cancer cell lines and induced platelet aggregation in dose-dependent manner. Furthermore, the enzyme showed remarkable effect against Gram-positive and Gram-negative bacteria. These activities were inhibited on the addition of catalase or substrate analogs, suggesting that H2O2 liberation* is required for these effects. Binding studies revealed that CC-LAAO binds to the cell surface and enables the production of highly localized concentration of H2O2 in or near the binding interfaces. On another hand, the interaction of CC-LAAO with a mimetic phospholipid film was evaluated, for the first time, using a monomolecular film technique. Results indicated that phospholipid/CC-LAAO interactions are not involved in their binding to membrane and in their pharmacological activities. PMID- 26433176 TI - Yeast expressed ArtinM shares structure, carbohydrate recognition, and biological effects with native ArtinM. AB - Recent advances in glycobiology have revealed the essential role of lectins in deciphering the glycocodes at the cell surface to generate important biological signaling responses. ArtinM, a d-mannose-binding lectin isolated from the seeds of jackfruit (Artocarpus heterophyllus), is composed of 16 kDa subunits that are associated to form a homotetramer. Native ArtinM (n-ArtinM) exerts immunomodulatory and regenerative effects, but the potential pharmaceutical applicability of the lectin is highly limited by the fact that its production is expensive, laborious, and impossible to be scaled up. This led us to characterize a recombinant form of the lectin obtained by expression in Saccharomyces cerevisiae (y-ArtinM). In the present study, we demonstrated that y-ArtinM is similar to n-ArtinM in subunit arrangement, oligomerization and carbohydrate binding specificity. We showed that y-ArtinM can exert n-ArtinM biological activities such as erythrocyte agglutination, stimulation of neutrophil migration and degranulation, mast cell degranulation, and induction of interleukin-12 and interleukin-10 production by macrophages. In summary, the expression of ArtinM in yeast resulted in successful production of an active, recombinant form of ArtinM that is potentially useful for pharmaceutical application. PMID- 26433177 TI - Facile synthesis of chitosan/ZnO bio-nanocomposite hydrogel beads as drug delivery systems. AB - ZnO nanoparticles were synthesized in situ during the formation of physically cross-linked chitosan hydrogel beads using sodium tripolyphosphate as the cross linker. The aim of the study was to investigate whether these nanocomposite beads have the potential to be used in drug delivery applications. The formation of ZnO nanoparticles (ZnONPs) in the hydrogels was confirmed by X-ray diffraction and scanning electron microscopy studies. SEM micrographs revealed the formation of ZnONPs with size range of 10-25 nm within the hydrogel matrix. Furthermore, the swelling and drug release properties of the beads were studied. The prepared nanocomposite hydrogels showed a pH sensitive swelling behavior. The ZnO nanocomposite hydrogels have rather higher swelling ratio in different aqueous solutions in comparison with neat hydrogel. In vitro drug release test was carried out to prove the effectiveness of this novel type of nanocomposite beads as a controlled drug delivery system. A prolonged and more controlled drug releases were observed for ZnONPs containing chitosan beads, which increased by the increase in ZnONPs content. PMID- 26433179 TI - A comprehensive Y-STR portrait of Argentinean populations. AB - A study of 23 Y-STRs was conducted in 257 individuals living in urban areas from eight Argentinean provinces. The data were meta-analyzed together with 364 profiles obtained from the literature that represent other five provinces. A total of 255 different haplotypes were observed (253 singletons). Genetic structure estimated from analysis of molecular variance (AMOVA) and exploring different grouping scenarios, yielded high within population variance. Not surprisingly, analyses of genetic distances with respect to main ancestral continental populations indicated Argentinean haplotypes to be closely related to European ones. Overall, these results provide a quite complete picture of the patterns of Y chromosome variation in Argentina, notably contributing to increase the previous national database, and consequently allowing a better estimation of parameters of interest in forensic casework and parentage testing. PMID- 26433180 TI - Emerging issue of e-waste in Pakistan: A review of status, research needs and data gaps. AB - This review article focuses on the current situation of e-waste in Pakistan with the emphasis on defining the major e-waste recycling sites, current and future domestic generation of e-waste, hidden flows or import of e-waste and discusses various challenges for e-waste management. Needed policy interventions and possible measures to be taken at governmental level are discussed to avoid the increasing problem of e-waste in the country. Our findings highlight that there is still a general lack of reliable data, inventories and research studies addressing e-waste related issues in the context of environmental and human health in Pakistan. There is therefore a critical need to improve the current knowledge base, which should build upon the research experience from other countries which have experienced similar situations in the past. Further research into these issues in Pakistan is considered vital to help inform future policies/control strategies as already successfully implemented in other countries. PMID- 26433181 TI - The role of phytoplankton composition, biomass and cell volume in accumulation and transfer of endocrine disrupting compounds in the Southern Baltic Sea (The Gulf of Gdansk). AB - Endocrine disrupting compounds (EDCs) like bisphenol A (BPA), 4-tert-octylphenol (OP) and 4-nonylphenol (NP) are introduced to the trophic webs through among others phytoplankton. This paper describes BPA, OP and NP concentrations in phytoplankton in the Gulf of Gdansk (Southern Baltic Sea) in the years 2011-2012. The assays of BPA, OP and NP in samples were performed using HPLC with fluorescence detection. The concentrations of BPA, the most commonly used of the three compounds, were over ten times higher than OP and NP concentrations. The concentrations of the studied EDCs in phytoplankton from the Gulf of Gdansk depended on anthropogenic factors and on phytoplankton properties (species composition, biomass, volume). An increase in phytoplankton biomass did not always result in an increase of BPA, OP and NP concentrations. However, the load of the studied EDCs accumulated in phytoplankton biomass increase with a rise of biomass. An increase in BPA, OP and NP concentrations was effected by biomass growth and the proportions ofciliates, dinoflagellates, diatoms and green algae. A strong positive correlation between OP and NP concentrations and negative correlation between BPA concentrations and biomass of organisms with cells measuring <1000 MUm(3) in volume results from the differing properties of these compounds. PMID- 26433182 TI - THE CHALLENGE OF CIEMAT INTERNAL DOSIMETRY SERVICE FOR ACCREDITATION ACCORDING TO ISO/IEC 17025 STANDARD, FOR IN VIVO AND IN VITRO MONITORING AND DOSE ASSESSMENT OF INTERNAL EXPOSURES. AB - The accreditation of an Internal Dosimetry Service (IDS) according to ISO/IEC 17025 Standard is a challenge. The aim of this process is to guarantee the technical competence for the monitoring of radionuclides incorporated in the body and for the evaluation of the associated committed effective dose E(50). This publication describes the main accreditation issues addressed by CIEMAT IDS regarding all the procedures involving good practice in internal dosimetry, focussing in the difficulties to ensure the traceability in the whole process, the appropriate calculation of detection limit of measurement techniques, the validation of methods (monitoring and dose assessments), the description of all the uncertainty sources and the interpretation of monitoring data to evaluate the intake and the committed effective dose. PMID- 26433178 TI - Above the fray: Surface remodeling by secreted lysosomal enzymes leads to endocytosis-mediated plasma membrane repair. AB - The study of plasma membrane repair is coming of age. Mirroring human adolescence, the field shows at the same time signs of maturity and significant uncertainty, confusion and skepticism. Here we discuss concepts that emerged from experimental data over the years, some of which are solidly established while others are still subject to different interpretations. The firmly established concepts include the critical requirement for Ca(2+) in wound repair, and the role of rapid exocytosis of intracellular vesicles. Lysosomes are being increasingly recognized as the major vesicles involved in injury-induced exocytosis in many cell types, as a growing number of laboratories detect markers for these organelles on the cell surface and lysosomal hydrolases in the supernatant of wounded cells. The more recent observation of massive endocytosis following Ca(2+)-triggered exocytosis initially came as a surprise, but this finding is also being increasingly reported by different groups, shifting the discussion to the mechanisms by which endocytosis promotes repair, and whether it operates or not in parallel with the shedding of membrane blebs. We discuss how the abundant intracellular vesicles that undergo homotypic fusion close to wound sites, previously interpreted as exocytic membrane patches, actually acquire extracellular tracers demonstrating their endocytic origin. We also suggest that an initial, temporary patch that prevents cytosol loss until the bilayer is restored might result not from vesicular fusion, but from rapid Ca(2+)-dependent crosslinking and aggregation of cytosolic proteins. Finally, we propose that cell surface remodeling, orchestrated by the extracellular release of lysosomal hydrolases and perhaps also cytosolic molecules, may represent a key aspect of the plasma membrane repair mechanism that has received little attention so far. PMID- 26433183 TI - The effect of albendazole treatment on seizure outcomes in patients with symptomatic neurocysticercosis. AB - BACKGROUND: Randomized controlled trials have found an inconsistent effect of anthelmintic treatment on long-term seizure outcomes in neurocysticercosis. The objective of this study was to further explore the effect of albendazole treatment on long-term seizure outcomes and to determine if there is evidence for a differential effect by seizure type. METHODS: In this trial, 178 patients with active or transitional neurocysticercosis cysts and new-onset symptoms were randomized to 8 days of treatment with albendazole (n=88) or placebo (n=90), both with prednisone, and followed for 24 months. We used negative binomial regression and logistic regression models to determine the effect of albendazole on the number of seizures and probability of recurrent or new-onset seizures, respectively, over follow-up. RESULTS: Treatment with albendazole was associated with a reduction in the number of seizures during 24 months of follow-up, but this was only significant for generalized seizures during months 1-12 (unadjusted rate ratio [RR] 0.19; 95% CI: 0.04-0.91) and months 1-24 (unadjusted RR 0.06; 95% CI: 0.01-0.57). We did not detect a significant effect of albendazole on reducing the number of focal seizures or on the probability of having a seizure, regardless of seizure type or time period. CONCLUSIONS: Albendazole treatment may be associated with some symptomatic improvement; however, this association seems to be specific to generalized seizures. Future research is needed to identify strategies to better reduce long-term seizure burden in patients with neurocysticercosis. PMID- 26433184 TI - Autism spectrum disorder symptoms in children with ADHD: A community-based study. AB - This study examined the prevalence of autism spectrum disorder (ASD) symptoms in a community-based sample of children with attention-deficit/hyperactivity disorder (ADHD) and non-ADHD controls. We also examined the relationship between ASD symptoms and ADHD subtype, ADHD symptom severity and child gender. Participants were 6-10-year-old children (164 ADHD; 198 non-ADHD control) attending 43 schools in Melbourne, Australia, who were participating in the Children's Attention Project. ADHD was assessed in two stages using the parent and teacher Conners' 3 ADHD index and the Diagnostic Interview Schedule for Children IV (DISC-IV). ASD symptoms were identified using the Social Communication Questionnaire (SCQ). Unadjusted and adjusted linear and logistic regression examined continuous and categorical outcomes, respectively. Children with ADHD had more ASD symptoms than non-ADHD controls (adjusted mean difference=4.0, 95% confidence interval (CI) 2.8; 5.3, p<0.001, effect size=0.7). Boys with ADHD had greater ASD symptom severity than girls with ADHD (adjusted mean difference=2.9, 95% CI 0.8; 5.2, p=0.01, effect size=0.4). Greater ADHD symptom severity was associated with greater ASD symptom severity (regression co efficient=1.6, 95% CI 1.2; 2.0, p<0.001). No differences were observed by ADHD subtype. Greater hyperactive/impulsive symptoms were associated with greater ASD symptoms (regression coefficient=1.0; 95% CI 0.0; 2.0, p=0.04) however, this finding attenuated in adjusted analyses (p=0.45). ASD symptoms are common in children with ADHD. It is important for clinicians to assess for ASD symptoms to ensure appropriate intervention. PMID- 26433185 TI - History of preeclampsia is more predictive of cardiometabolic and cardiovascular risk factors than obesity. AB - OBJECTIVE: To determine to what extent a history of preeclampsia affects traditional cardiometabolic (insulin resistance and dyslipidemia) and cardiovascular (hypertension and micro-albuminuria) risk factors of the metabolic syndrome irrespective of BMI. STUDY DESIGN: In a retrospective case-control study we compared 90 formerly preeclamptic women, divided in 3 BMI-classes (BMI 19.5 24.9, 25.0-29.9, >=30.0kg/m(2)) to 30 controls, matched for BMI, age and parity. Cardiometabolic and cardiovascular risk factors (WHO-criteria) were tested 6-18 months post partum. Statistical analysis included unpaired t-tests, Mann-Whitney U test, or Chi square test and two-way ANOVA. RESULTS: Constituents of the metabolic syndrome (glucose, insulin, HOMAIR, HDL-cholesterol, triglycerides, blood pressure, micro-albuminuria) were higher in formerly preeclamptic women than in BMI-matched controls. Resultantly, traditional risk factors were more prevalent in formerly preeclamptic women than in controls (insulin resistance 80% vs 30%, dyslipidemia 52% vs 3%, hypertension 24% vs 0%, micro-albuminuria 30% vs 0%). Cardiometabolic risk factors increased with BMI, to the same extent in both groups. Formerly preeclamptic women had metabolic syndrome more often than their BMI-matched controls (38% vs 3%, p<0.001). CONCLUSION: Traditional risk factors of the metabolic syndrome are more prevalent in formerly preeclamptic women than in BMI-matched controls and increase with BMI to the same extent in both groups. A history of preeclampsia seems to be a stronger indicator of cardiovascular risk than obesity per se. PMID- 26433186 TI - Neurosteroids and potential therapeutics: Focus on pregnenolone. AB - Considerable evidence from preclinical and clinical studies shows that steroids and in particular neurosteroids are important endogenous modulators of several brain-related functions. In this context, it remains to be elucidated whether neurosteroids may serve as biomarkers in the diagnosis of disorders and might have therapeutic potential for the treatment of these disorders. Pregnenolone (PREG) is the main steroid synthesized from cholesterol in mammals and invertebrates. PREG has three main sources of synthesis, the gonads, adrenal glands and brain and is submitted to various metabolizing pathways which are modulated depending on various factors including species, steroidogenic tissues and steroidogenic enzymes. Looking at the whole picture of steroids, PREG is often known as the precursor to other steroids and not as an active steroid per se. Actually, physiological and brain functions have been studied mainly for steroids that are very active either binding to specific intracellular receptors, or modulating with high affinity the abundant membrane receptors, GABAA or NMDA receptors. However, when high sensitive and specific methodological approaches were available to analyze low concentrations of steroids and then match endogenous levels of different steroid metabolomes, several studies have reported more significant alterations in PREG than in other steroids in extraphysiological or pathological conditions, suggesting that PREG could play a functional role as well. Additionally, several molecular targets of PREG were revealed in the mammalian brain and beneficial effects of PREG have been demonstrated in preclinical and clinical studies. On this basis, this review will be divided into three parts. The first provides a brief overview of the molecular targets of PREG and the pharmacological effects observed in animal and human studies. The second will focus on the possible functional role of PREG with an outline of the modulation of PREG levels in animal and in human research. Finally, the review will highlight the possible therapeutic uses of PREG that point towards the development of pregnenolone-like molecules. PMID- 26433187 TI - Enhanced Recovery After Surgery (ERAS) multimodal programme as experienced by pancreatic surgery patients: Findings from an Italian qualitative study. AB - BACKGROUND: ERAS has recently been implemented in pancreatic surgery settings, but there is little evidence regarding the effects as perceived by patients. Given the lack of the knowledge in the field, the aim of this study was to capture the experience of patients undergoing pancreatic surgery who received perioperative care based on the ERAS programme. METHODS: We designed a qualitative study undertaken in the pancreatic surgery unit of San Raffaele Hospital in Milan, Italy. Twenty-two consecutive patients were invited to participate in the study and 13 patients were interviewed. Data was collected between March and December 2012 either through face-to-face or semi-structured telephone follow-up from three to six weeks after discharge. Data was analysed using the interpretative phenomenological approach. RESULTS: Patients who underwent surgical pancreatic procedures and treated with ERAS programme reported experiences based on four themes: (1) Feeling prepared to face surgery, (2) Being actively "inside" or "outside" the programme, (3) Healing at home: the best setting, and (4) "Perceiving the ordinary as extraordinary": reaching independence, once at home. CONCLUSION: According to the findings, uncomplicated pancreatic surgery patients may benefit from the ERAS programme. Preadmission counselling should help patients to assume an active role. Once the patient returns home, the availability of a caregiver should be thoroughly assessed to guarantee the support needed by patients to successfully complete the ERAS(programme. Surgery and nursing staff should carefully monitor patients and suggest whether they continue, interrupt, or individualise the scheduled ERAS interventions in accordance with a patient's clinical condition and preferred personal timing. PMID- 26433188 TI - Inhibitory effects of arabitol on caries-associated microbiologic parameters of oral Streptococci and Lactobacilli. AB - The aim of this study was to compare arabitol with its better studied isomer xylitol for their inhibitory effects on cell growth and acid production of oral bacteria. Streptococcus mutans, Streptococcus salivarius and Streptococcus sobrinus were used as representatives of oral streptococci and Lactobacillus acidophilus and Lactobacillus fermentum were used for oral lactobacilli. Growth was followed by measuring the absorbance at 660nm, acid production by pH change. Sensitivity of these oral bacteria to arabitol and xylitol was first compared at 1% (65mM) additive concentration with glucose as sugar substrate. For all bacteria tested, the inhibitory effects of the two polyols were comparable; both were significantly stronger on streptococci (with 20-60% inhibition) than on lactobacilli (with 5-10% inhibition). Effects of arabitol and xylitol were also compared for S. mutans and S. salivarius in media with 1% of different sugar substrates: glucose (55mM), fructose (55mM), galactose (55mM) and sucrose (30mM). Inhibition occurred for all sugars: stronger on glucose and galactose (60-65%) than on fructose and sucrose (40-45%). Inhibition dependency on the arabitol/xylitol concentration from 0.01% (0.65mM) to 2% (130mM) was further determined for S. mutans and S. salivarius. Regardless of the concentration, sugar substrate and bacterial species tested, arabitol showed very similar inhibition effects to its isomer xylitol. PMID- 26433189 TI - The effects of dental pulp stem cells on bone regeneration in rat calvarial defect model: micro-computed tomography and histomorphometric analysis. AB - OBJECTIVE: Stem cell therapies may be applicable to all fields of medicine, including craniomaxillofacial surgery. Dental pulp stem cells also have significant osteogenic properties. This study aimed to evaluate the influence of dental pulp stem cells on bone regeneration and to ascertain whether or not there was any superiority over traditional methods. DESIGN: In this study, 15 non immunodeficient Wistar albino rats were used. The rats were divided into three groups: (1) untreated control group; (2) hydroxyapatite tri-calcium-phosphate (HA/TCP) paste; (3) human dental pulp derived stem cells (DPSC) mixed with HA/TCP paste (HA/TCP+DSPC group, n=10). Two symmetrical full-thickness cranial defects were created on each parietal region (10 defects for each group). The animals were sacrificed 8 weeks post-surgery and samples were analyzed by microcomputer tomography (MU-CT) and histomorphometry. RESULTS: The calcification rate and bone mineral density (BMD) values in Group 3 were found to be significantly higher than in the other two groups. Radiographically, bone regeneration was greater in Group 2 compared with the control group. However, there was no significant difference between Groups 2 and 1 in respect of histological analysis. CONCLUSIONS: According to the results of the present study, DPSCs may be a suitable factor for bone tissue engineering because they can be easily obtained and differentiate into bone cells. PMID- 26433190 TI - Histologic features and fascicular arrangement of the inferior alveolar nerve. AB - OBJECTIVES: Knowledge of the various possible morphologies and courses of the inferior alveolar nerve and artery is important for successful and safe surgical procedures in the mandibular region. The purpose of this study was to verify the histologic features and fascicular arrangement of the inferior alveolar nerve and artery relative to tooth region. MATERIALS AND METHODS: Twenty embalmed dentulous hemimandibles were examined (eight males and two females; mean age, 58.2 years). The hemimandibles were prepared for routine histology and stained with hematoxylin-eosin and Masson's trichrome. The histologic features, fascicular arrangement, courses, and areas of the inferior alveolar nerve and artery were investigated with the aid of a light microscope. RESULTS: The inferior alveolar neurovascular bundle comprised the inferior alveolar nerve, which appeared as a large trunk comprising two major nerves (the mental and dental nerves), and the inferior alveolar artery, which occupied a relatively small portion of the bundle. The mental nerve was located inferolingually in the third molar region and turned to the buccal side in the first molar region, separating from the dental nerve before reaching the mental foramen. The mandibular incisive canal with a bony wall was not found in the lateral incisor region; instead, small dental nerve fascicles and arteries presented consistently in the intertrabecular spaces. The inferior alveolar artery traveled above the inferior alveolar nerve over the entire mandibular canal. CONCLUSIONS: These results provide data that are relevant to treatment planning for operative procedures such as implant placement, endodontic treatment, and osteotomy in the mandibular region. PMID- 26433192 TI - Head and neck cancer among marijuana users: a meta-analysis of matched case control studies. AB - OBJECTIVES: The scientific literature presents conflicting data on a possible causal relationship between marijuana users and the development of head and neck cancer. DESIGN: This study performed a systematic review with meta-analysis. Articles were selected from various electronic databases using keywords obtained from the Medical Subject Headings (MeSH). After reading by three reviewers and scoring of methodological quality, six articles (totaling nine case-control studies) were assessed with Comprehensive Meta-Analysis((r)) software. The value of effect (odds ratio) was calculated, which represented the chance of developing head and neck cancer between individuals who had smoked marijuana in their lifetime in models controlled for age, gender, race, and tobacco consumption. RESULTS: Approximately 12.6% of cases and 14.3% of controls were marijuana users. The meta-analysis found no association between exposure and disease (OR=1.021; IC 95%=0.912-1.14; p=0.718). CONCLUSION: No association between lifetime marijuana use and the development of head and neck cancer was found. The different methods of collection/presentation of results in the selected articles prevented other analyzes from being conducted. Additional studies are needed to assess for long term effects. PMID- 26433191 TI - FGF2 gene activated matrices promote proliferation of bone marrow stromal cells. AB - BACKGROUND: In this study, we report on the results from the development and early in vitro testing of a gene activated matrix encoding basic human fibroblast growth factor 2 (FGF2) in bone marrow stromal cells (BMSCs). METHODS: Polyethylenimine (PEI), a cationic polymer, was utilized as a gene delivery vector and collagen scaffolds were used as the carrier to deliver the PEI-pDNA nano-sized complexes (nanoplexes) encoding the FGF2 protein. Initially, the BMSCs were transfected in vitro with the PEI-pFGF2 nanoplexes, prepared at a N/P ratio of 10, with cells alone and naked DNA as controls. This was followed by transfection experiments using collagen scaffold containing complexes, with the scaffold alone as a control. The transfection efficacy of the nanoplexes was assessed using ELISA for the determination of FGF2 protein expressed by the transfected cells. The functionality of transfection was assessed by evaluating cellular recruitment, attachment, and proliferation of BMSCs on the scaffold using imaging techniques. RESULTS: BMSCs transfected with the PEI-pFGF2 nanoplexes (either alone or within the scaffold) led to higher expression of FGF2, compared to controls. Scanning electron microscopy and confocal imaging confirmed the recruitment and attachment of BMSCs to scaffolds containing the PEI pFGF2 nanoplexes. Confocal microscopy showed a significantly higher number of proliferating cells within PEI-pFGF2 nanoplex-loaded scaffolds than with empty scaffolds. CONCLUSIONS: This first in vitro evaluation in BMSCs provides evidence that gene activated matrices (GAMs) encoding the FGF2 protein may have strong translational potential for clinical applications that require enhanced osseous and periodontal tissue regeneration. PMID- 26433193 TI - Objective assessment of actual chewing side by measurement of bilateral masseter muscle electromyography. AB - OBJECTIVE: The aim of this study was to examine the validity of objective assessment of actual chewing side by measurement of electromyographic (EMG) activity of the bilateral masseter muscles upon chewing test foods. DESIGN: The sample consisted of 19 healthy, dentate individuals. The subjects were asked to chew three types of test foods (peanuts, beef jerky, and chewing gum) for 10 strokes on the right side and then on the left side, and instructed to perform maximum voluntary clenching for 3s, three times. EMG activity from the bilateral masseter muscles was recorded. The data were collected in three different days. The root mean square EMG amplitude obtained from the maximum clenching task was used as the maximum voluntary contraction (MVC). Then, the level of amplitude against the MVC (%MVC) was calculated for the right and left sides on each stroke. The side with the larger %MVC value was judged as the chewing side, and the concordance rates (CRs) for the instructed chewing side (ICS) and the judged chewing side (JCS) were calculated. Intraclass correlation coefficients (ICCs) of the CRs were calculated to evaluate the reproducibility of the method. RESULTS: High CRs between the ICS and JCS for each test food were recognized. There were significant ICCs for beef jerky (R=0.761, P<0.001) and chewing gum (R=0.785, P<0.001). CONCLUSIONS: The results suggested that the measurement of EMG activity from the bilateral masseter muscles may be a useful method for the objective determination of the actual chewing side during mastication. PMID- 26433194 TI - Coordination of AUF1 and miR-148a destabilizes DNA methyltransferase 1 mRNA under hypoxia in endometriosis. AB - STUDY HYPOTHESIS: DNA methylation is regulated by hypoxia in endometriosis. STUDY FINDING: Hypoxia causes global hypomethylation through AU-rich element binding factor 1 (AUF1)/microRNA-148a (miR-148a)-mediated destabilization of DNA methyltransferase 1 (DNMT1) mRNA. WHAT IS KNOWN ALREADY: Eutopic endometrial and ectopic endometriotic stromal cells have the same genetic background, but differ in several cellular and molecular responses. Both hypoxia and DNA methylation regulate several genes involved in the development of endometriosis. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: This laboratory study included 15 patients of reproductive age with endometriosis or normal menstrual cycles. Paired endometrial and endometriotic tissues were collected for assaying the levels of DNMT1, 3a and 3b using quantitative RT-PCR, western blot and immunohistochemical (IHC) staining. Primary cultured endometrial stromal cells maintained in normoxia/hypoxia (1% O2) or treated with hypoxia-mimetic compounds were also assayed. The levels of DNA 5-methylcytosine were assayed by using IHC in clinical specimens and murine tissues, and by ELISA in cultured stromal cells. The 3' untranslated region reporter assay was used to evaluate the effect of hypoxia, microRNAs (miRNAs) and human antigen R (HuR)/AUF1 on DNMT1 mRNA stability. RNA immunoprecipitation was used to assess the interaction of HuR/AUF1 and miR 148a/DNMT1 mRNA under hypoxia. Finally, a transplant-induced mouse model of endometriosis using 20 mice was used to elucidate the alteration of Dnmt1 levels and DNA methylation in the endometriotic tissues. MAIN RESULTS AND THE ROLE OF CHANCE: Levels of DNMT1 mRNA and protein and 5-methylcytosine were lower in the ectopic stromal cells (P < 0.05) than in the eutopic cells. Treatment with hypoxia and its mimetic compounds recapitulated the reduced levels of DNMT1 and 5 methylcytosine levels (P < 0.05 versus control). Hypoxia treatment destabilized DNMT1 mRNA through recruitment of miR-148a and AUF1. Mutations introduced to the miR-148a targeting site or AU-rich element (ARE) restored the hypoxia-suppressed DNMT1 3'-untranslated region (3'-UTR) reporter activity (P < 0.05 versus control). Levels of proteins of three hypermethylated genes in endometrial stroma cells, GATA6, HOXA3 and SLC16A5, were elevated after 72 h of hypoxia treatment (P < 0.05 versus control). Finally, a transplant-induced model of endometriosis demonstrated the down-regulation of DNMT1 and a decrease in 5-methylcytosine in the endometriotic tissues (P < 0.05, eutopic versus ectopic). LIMITATIONS, REASONS FOR CAUTION: Primary human cell cultures and a murine model were used in this study, and thus the results may not fully represent the situation in vivo. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to elucidate how microenvironmental hypoxia links to the epigenetic effects of DNA methylation in the endometriosis, and to delineate the molecular mechanism of hypoxia coordinated AUF1/miR-148a interaction and recruitment to DNMT1 mRNA during the pathogenesis of endometriosis. The development of future therapeutics in endometriosis may aim at disrupting this specific interaction and eventually restore the epigenetic regulation. STUDY FUNDING AND COMPETING INTERESTS: This work was supported by the National Science Council of Taiwan (NSC101-2320-B-006 030-MY3). The author declares that there are no conflicts of interest. PMID- 26433195 TI - Children With Mild Bilateral and Unilateral Hearing Loss: Parents' Reflections on Experiences and Outcomes. AB - Children with mild bilateral and unilateral hearing loss are now commonly identified early through newborn hearing screening initiatives. There remains considerable uncertainty about how to support parents and about which services to provide for children with mild bilateral and unilateral hearing loss. The goal of this study was to learn about parents' experiences and understand, from their perspectives, the impact of hearing loss in the mild range on the child's functioning. Parents of 20 children in Ontario, Canada, participated in the study. The median age of identification of hearing loss was 4.6 months (interquartile range: 3.6, 10.8). Parents appreciated learning early about hearing loss, but their experiences with the early process were mixed. Parents felt that professionals minimized the importance of milder hearing loss. There was substantial uncertainty about the need for hearing aids and the findings suggest that parents need specific guidance. Parents expressed concerns about the potential impact of hearing loss on their child's development, particularly at later ages. PMID- 26433196 TI - Expertise in unexpected places: Children's acceptance of information from gender counter-stereotypical experts. AB - The current study examined children's willingness to accept novel information from expert informants with nontraditional gender role interests. Four- to 8-year olds heard conflicting information about traditionally feminine or masculine domains from a gender counter-stereotypical expert (e.g., a boy with expertise in ballet) and a layperson of the other gender (e.g., a girl with little knowledge about ballet). Participants were asked which informant was correct, who they would prefer to learn from in the future, and to rate their liking of each informant. Overall, participants selected the gender counter-stereotypical expert as correct. Four- to 5-year-olds reported a preference to learn from same-gender participants in the future irrespective of expertise, whereas 6- to 8-year-olds reported wanting to learn from counter-stereotypical experts. Boys showed relatively greater acceptance of information from a male counter-stereotypical expert than from a female counter-stereotypical expert. Although participants reported greater liking of same-gender informants, liking evaluations were largely positive irrespective of gender norm deviations. Implications for children's acceptance of gender nonconforming activities are discussed. PMID- 26433197 TI - Thalamic segmentation based on improved fuzzy connectedness in structural MRI. AB - Thalamic segmentation serves an important function in localizing targets for deep brain stimulation (DBS). However, thalamic nuclei are still difficult to identify clearly from structural MRI. In this study, an improved algorithm based on the fuzzy connectedness framework was developed. Three-dimensional T1-weighted images in axial orientation were acquired through a 3D SPGR sequence by using a 1.5 T GE magnetic resonance scanner. Twenty-five normal images were analyzed using the proposed method, which involved adaptive fuzzy connectedness combined with confidence connectedness (AFCCC). After non-brain tissue removal and contrast enhancement, the seed point was selected manually, and confidence connectedness was used to perform an ROI update automatically. Both image intensity and local gradient were taken as image features in calculating the fuzzy affinity. Moreover, the weight of the features could be automatically adjusted. Thalamus, ventrointermedius (Vim), and subthalamic nucleus were successfully segmented. The results were evaluated with rules, such as similarity degree (SD), union overlap, and false positive. SD of thalamus segmentation reached values higher than 85%. The segmentation results were also compared with those achieved by the region growing and level set methods, respectively. Higher SD of the proposed method, especially in Vim, was achieved. The time cost using AFCCC was low, although it could achieve high accuracy. The proposed method is superior to the traditional fuzzy connectedness framework and involves reduced manual intervention in time saving. PMID- 26433198 TI - Retrovirus-based vectors for transient and permanent cell modification. AB - Retroviral vectors are commonly employed for long-term transgene expression via integrating vector technology. However, three alternative retrovirus-based platforms are currently available that allow transient cell modification. Gene expression can be mediated from either episomal DNA or RNA templates, or selected proteins can be directly transferred through retroviral nanoparticles. The different technologies are functionally graded with respect to safety, expression magnitude and expression duration. Improvement of the initial technologies, including modification of vector designs, targeted increase in expression strength and duration as well as improved safety characteristics, has allowed maturation of retroviral systems into efficient and promising tools that meet the technological demands of a wide variety of potential application areas. PMID- 26433200 TI - Within- and trans-generational effects of herbivores and detritivores on plant performance and reproduction. AB - Mutualistic and antagonistic above-ground and below-ground species have the potential to be involved in strong interactions that can either weaken or strengthen their individual impacts on plants. Their impacts can also have delayed effects on a plant's progeny by altering offspring traits and survival. Few studies have explored the effect of herbivore and detritivore interactions with parent plants on offspring vital life-cycle processes, such as seedling emergence rate, seedling establishment and offspring survival. In the field, I experimentally studied the combined effects of floral herbivores (FH), root herbivores (RH) and detritivores on plant growth and reproduction of Moricandia moricandioides (Brassicaceae). In particular, I analysed the trans-generational effects of herbivores and detritivores on seed and juvenile production as well as on vital life-cycle processes (i.e. seedling emergence rates, survival). Floral herbivores strongly reduced the number of flowers, fruits, seeds and juveniles. Detritivores had an impact on plant success by increasing seed quality (% N and N : C ratio), although the effect was altered by the presence of floral and RH. I found maternal effects (trans-generational effects) of FH, RH and detritivores. Floral herbivores reduced seedling emergence and establishment. Floral and RH in combination reduced seedling emergence timing, but the effect was counteracted by detritivores. Detritivores also reduced the negative effect of FH on offspring mortality rate. This study shows that the impact of above-ground and below-ground organisms on M. moricandioides plants go beyond seed production and were evident in the probability of establishment and survival of the following generation. Trans-generational effects were induced by all three groups of interacting organisms and the net consequences for plant offspring depended on the organisms interacting with the plant. PMID- 26433199 TI - Directly visualized glioblastoma-derived extracellular vesicles transfer RNA to microglia/macrophages in the brain. AB - BACKGROUND: To understand the ability of gliomas to manipulate their microenvironment, we visualized the transfer of vesicles and the effects of tumor released extracellular RNA on the phenotype of microglia in culture and in vivo. METHODS: Extracellular vesicles (EVs) released from primary human glioblastoma (GBM) cells were isolated and microRNAs (miRNAs) were analyzed. Primary mouse microglia were exposed to GBM-EVs, and their uptake and effect on proliferation and levels of specific miRNAs, mRNAs, and proteins were analyzed. For in vivo analysis, mouse glioma cells were implanted in the brains of mice, and EV release and uptake by microglia and monocytes/macrophages were monitored by intravital 2 photon microscopy, immunohistochemistry, and fluorescence activated cell sorting analysis, as well as RNA and protein levels. RESULTS: Microglia avidly took up GBM-EVs, leading to increased proliferation and shifting of their cytokine profile toward immune suppression. High levels of miR-451/miR-21 in GBM-EVs were transferred to microglia with a decrease in the miR-451/miR-21 target c-Myc mRNA. In in vivo analysis, we directly visualized release of EVs from glioma cells and their uptake by microglia and monocytes/macrophages in brain. Dissociated microglia and monocytes/macrophages from tumor-bearing brains revealed increased levels of miR-21 and reduced levels of c-Myc mRNA. CONCLUSIONS: Intravital microscopy confirms the release of EVs from gliomas and their uptake into microglia and monocytes/macrophages within the brain. Our studies also support functional effects of GBM-released EVs following uptake into microglia, associated in part with increased miRNA levels, decreased target mRNAs, and encoded proteins, presumably as a means for the tumor to manipulate its environs. PMID- 26433201 TI - Transcription factors WRKY70 and WRKY11 served as regulators in rhizobacterium Bacillus cereus AR156-induced systemic resistance to Pseudomonas syringae pv. tomato DC3000 in Arabidopsis. AB - The activation of both the SA and JA/ETsignalling pathways may lead to more efficient general and broad resistance to Pst DC3000 by non-pathogenic rhizobacteria. However, the mechanisms that govern this simultaneous activation are unclear. Using Arabidopsis as a model system, two transcription factors, WRKY11 and WRKY70, were identified as important regulators involved in Induced Systemic Resistance (ISR) triggered by Bacillus cereus AR156. The results revealed that AR156 treatment significantly stimulated the transcription of WRKY70, but suppressed that of WRKY11 in Arabidopsis leaves. Furthermore, they were shown to be required for AR156 enhancing the activation of cellular defence responses and the transcription level of the plant defence response gene. Overexpression of the two transcription factors in Arabidopsis also showed that they were essential for AR156 to elicit ISR. AR156-triggered ISR was completely abolished in the double mutant of the two transcription factors, but still partially retained in the single mutants, indicating that the regulation of the two transcription factors depend on two different pathways. The target genes of the two transcription factors and epistasis analysis suggested that WRKY11 regulated AR156-triggered ISR through activating the JA signalling pathway, and WRKY70 regulated the ISR through activating the SA signalling pathway. In addition, both WRKY11 and WRKY70 modulated AR156-triggered ISR in a NPR1 dependent manner. In conclusion, WRKY11 and WRKY70 played an important role in regulating the signalling transduction pathways involved in AR156-triggered ISR. This study is the first to illustrate the mechanism by which a single rhizobacterium elicits ISR by simultaneously activating both the SA and JA/ET signalling pathways. PMID- 26433203 TI - Streptococcal toxins: role in pathogenesis and disease. AB - Group A Streptococcus (Streptococcus pyogenes), group B Streptococcus (Streptococcus agalactiae) and Streptococcus pneumoniae (pneumococcus) are host adapted bacterial pathogens among the leading infectious causes of human morbidity and mortality. These microbes and related members of the genus Streptococcus produce an array of toxins that act against human cells or tissues, resulting in impaired immune responses and subversion of host physiological processes to benefit the invading microorganism. This toxin repertoire includes haemolysins, proteases, superantigens and other agents that ultimately enhance colonization and survival within the host and promote dissemination of the pathogen. PMID- 26433202 TI - Mutation in Brachypodium caffeic acid O-methyltransferase 6 alters stem and grain lignins and improves straw saccharification without deteriorating grain quality. AB - Cereal crop by-products are a promising source of renewable raw material for the production of biofuel from lignocellulose. However, their enzymatic conversion to fermentable sugars is detrimentally affected by lignins. Here the characterization of the Brachypodium Bd5139 mutant provided with a single nucleotide mutation in the caffeic acid O-methyltransferase BdCOMT6 gene is reported. This BdCOMT6-deficient mutant displayed a moderately altered lignification in mature stems. The lignin-related BdCOMT6 gene was also found to be expressed in grains, and the alterations of Bd5139 grain lignins were found to mirror nicely those evidenced in stem lignins. The Bd5139 grains displayed similar size and composition to the control. Complementation experiments carried out by introducing the mutated gene into the AtCOMT1-deficient Arabidopsis mutant demonstrated that the mutated BdCOMT6 protein was still functional. Such a moderate down-regulation of lignin-related COMT enzyme reduced the straw recalcitrance to saccharification, without compromising the vegetative or reproductive development of the plant. PMID- 26433204 TI - Characterization of antioxidant phenolics in Syringa vulgaris L. flowers and fruits by HPLC-DAD-ESI-MS. AB - In this study the polyphenolic composition of lilac flowers and fruits was determined for the first time. For the identification of compounds, accurate molecular masses and formulas, acquired by LC and ESI-TOF-MS and fragmentation pattern given by LC-ESI/MS/MS analyses, were used. Our chromatographic system in conjunction with tandem MS was found to be valuable in the rapid separation and determination of the multiple constituents in methanolic extracts of lilac flowers and fruits. Altogether 34 phenolics, comprising 18 secoiridoids, seven phenylpropanoids, four flavonoids and five low-molecular-weight phenols, were identified. As marker compounds two secoiridoids (oleuropein and nuzhenide), two phenylpropanoids (acteoside and echinacoside) and rutin were quantified by validated methods. As a result of quantitative analysis, it was confirmed that flowers contain significant amounts of phenylpropanoids (acteoside, 2.48%; echinacoside, 0.75%) and oleuropein (0.95%), while in fruits secoiridoid oleuropein (1.09%) and nuzhenide (0.42%) are the major secondary metabolites. The radical scavenging activities of the extracts and the constituents were investigated by DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS [2,2'-azino-bis-(3 ethylbenzothiazoline-6-sulfonic acid)] assays. Both extracts show remarkable antioxidant activities. Our results clearly show that lilac flowers and fruits are inexpensive, readily available natural sources of phenolic compounds with pharmacological and cosmetic applications. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26433205 TI - lincRNA-p21 inhibits hepatic stellate cell activation and liver fibrogenesis via p21. AB - Long non-coding RNAs are involved in various biological processes and diseases. The biological role of long intergenic non-coding RNA-p21 (lincRNA-p21) in liver fibrosis remains unknown before this study. In this study, we observed marked reduction of lincRNA-p21 expression in mice liver fibrosis models and human cirrhotic liver. Over-expression of lincRNA-p21 suppressed activation of hepatic stellate cells (HSCs) in vitro. Lentivirus-mediated lincRNA-p21 transfer into mice decreased the severity of liver fibrosis in vivo. Additionally, lincRNA-p21 reversed the activation of HSCs to their quiescent phenotype. The mRNA levels of lincRNA-p21 and p21 were positively correlated. Our results show that over expression of lincRNA-p21 promotes up-regulation of p21 at both the mRNA and protein levels. Furthermore, lincRNA-p21 inhibited cell-cycle progression and proliferation of primary HSCs through enhancement of p21 expression. Compared with healthy subjects, serum lincRNA-p21 levels were significantly lower in patients with liver cirrhosis, especially those with decompensation. These findings collectively indicate that lincRNA-p21 is a mediator of HSC activation, supporting its utility as a novel therapeutic target for liver fibrosis. PMID- 26433206 TI - Long-Term Follow-Up of the Edmonton Protocol of Islet Transplantation in the United States. AB - We report the long-term follow-up of the efficacy and safety of islet transplantation in seven type 1 diabetic subjects from the United States enrolled in the multicenter international Edmonton Protocol who had persistent islet function after completion of the Edmonton Protocol. Subjects were followed up to 12 years with serial testing for sustained islet allograft function as measured by C-peptide. All seven subjects demonstrated continued islet function longer than a decade from the time of first islet transplantation. One subject remained insulin independent without the need for diabetic medications or supplemental transplants. One subject who was insulin-independent for over 8 years experienced graft failure 10.9 years after the first islet transplant. The remaining six subjects demonstrated continued islet function upon trial completion, although three had received a supplemental islet transplant each. At trial completion, five subjects were receiving insulin and two remained insulin independent, although one was treated with liraglutide. The median hemoglobin A1c was 6.3% (45 mmol/mol). All subjects experienced progressive decline in the C-peptide/glucose ratio. No patients experienced severe hypoglycemia, opportunistic infection, or lymphoma. Thus, although the rate and duration of insulin independence was low, the Edmonton Protocol was safe in the long term. Alternative approaches to islet transplantation are under investigation. PMID- 26433207 TI - Low alanine aminotransferase levels and higher number of cardiovascular events in people with Type 2 diabetes: analysis of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. AB - AIMS: To determine whether alanine aminotransferase or gamma-glutamyltransferase levels, as markers of liver health and non-alcoholic fatty liver disease, might predict cardiovascular events in people with Type 2 diabetes. METHODS: Data from the Fenofibrate Intervention and Event Lowering in Diabetes study were analysed to examine the relationship between liver enzymes and incident cardiovascular events (non-fatal myocardial infarction, stroke, coronary and other cardiovascular death, coronary or carotid revascularization) over 5 years. RESULTS: Alanine aminotransferase measure had a linear inverse relationship with the first cardiovascular event occurring in participants during the study period. After adjustment, for every 1 sd higher baseline alanine aminotransferase measure (13.2 U/l), the risk of a cardiovascular event was 7% lower (95% CI 4-13; P = 0.02). Participants with alanine aminotransferase levels below and above the reference range 8-41 U/l for women and 9-59 U/l for men, had hazard ratios for a cardiovascular event of 1.86 (95% CI 1.12-3.09) and 0.65 (95% CI 0.49-0.87), respectively (P = 0.001). No relationship was found for gamma glutamyltransferase. CONCLUSIONS: The data may indicate that in people with Type 2 diabetes, which is associated with higher alanine aminotransferase levels because of prevalent non-alcoholic fatty liver disease, a low alanine aminotransferase level is a marker of hepatic or systemic frailty rather than health. PMID- 26433208 TI - Use of topical retinoic acid for limbal stem cell failure: a retrospective clinical case series. PMID- 26433209 TI - Phaeochromocytoma and ACTH-dependent cushing's syndrome: tumour crf secretion can mimic pituitary cushing's disease. AB - INTRODUCTION: 10% of corticotrophin (ACTH)-dependent Cushing's syndrome arises from secretion by extrapituitary tumours, with phaeochromocytoma implicated in a few cases. Ectopic secretion by phaeochromocytoma of corticotropin-releasing hormone (CRF), with secondary corticotroph hyperplasia, is even rarer, with only five cases in the literature hitherto. However, such cases may be classified as 'ectopic ACTH' due to incomplete verification. CLINICAL CASES: We describe three patients with phaeochromocytoma and ACTH-dependent Cushing's syndrome in whom biochemical cure was achieved following unilateral adrenalectomy. Although unable to access a validated CRF assay within the timeframe for sample storage, we nevertheless inferred CRF secretion in 2 of 3 cases by tumour immunostaining (positive for CRF; negative for ACTH), supported in one case by pre-operative inferior petrosal sinus sampling (IPSS) indicative of pituitary ACTH source. Both cases were characterized by rapid postoperative wean off glucocorticoids, presumed to reflect the pituitary stimulatory-effect of CRF outweighing central negative feedback inhibition by hypercortisolaemia. By contrast, the tumour excised in a third case exhibited positive immunostaining for ACTH - negative for CRF - and postoperative recovery of hypothalamic-pituitary-adrenal axis took significantly longer. DISCUSSION: Ectopic CRF production is biochemically indistinguishable from ectopic ACTH secretion, except that IPSS mimics pituitary Cushing's disease and cortisol dynamics may normalize rapidly postadrenalectomy. CRF secretion can be inferred through tumour immunohistochemistry, even if no CRF assay is available. Unrecognized phaeochromocytoma ACTH secretion may underpin some cases of cardiovascular collapse postadrenalectomy through acute hypocortisolaemia. Despite advances in phaeochromocytoma genetics since previous reports, we were unable to identify somatic DNA defects associated with either ACTH or CRF secretion. PMID- 26433210 TI - beta-Carotene Revisited by Transient Absorption and Stimulated Raman Spectroscopy. AB - beta-Carotene in n-hexane was examined by femtosecond transient absorption and stimulated Raman spectroscopy. Electronic change is separated from vibrational relaxation with the help of band integrals. Overlaid on the decay of S1 excited state absorption, a picosecond process is found that is absent when the C9 methyl group is replaced by ethyl or isopropyl. It is attributed to reorganization on the S1 potential energy surface, involving dihedral angles between C6 and C9 . In Raman studies, electronic states S2 or S1 were selected through resonance conditions. We observe a broad vibrational band at 1770 cm(-1) in S2 already. With 200 fs it decays and transforms into the well-known S1 Raman line for an asymmetric C=C stretching mode. Low-frequency activity (<800 cm(-1) ) in S2 and S1 is also seen. A dependence of solvent lines on solute dynamics implies intermolecular coupling between beta-carotene and nearby n-hexane molecules. PMID- 26433211 TI - Do dogs sense hypoglycaemia? AB - AIMS: To summarize the current knowledge on the phenomenon of dogs, both trained and untrained, sensing hypoglycaemia and alerting their owners to it. METHODS: Electronic databases were searched for all types of articles reporting on untrained or trained 'diabetes alert' dogs. Articles published up until December 2014 in the English or German language were included. RESULTS: Several case reports and observational studies provide evidence that animals can perform at a level above that attributable to chance, and may reliably detect low diurnal as well as nocturnal hypoglycaemic episodes. Behavioural changes in untrained dogs were reported during 38-100% of hypoglycaemic events experienced by their owners. The sensitivity and specificity of the performance of trained diabetes alert dogs sensing hypoglycaemia ranged from 22 to 100% and 71 to 90%, respectively. Additionally, 75-81% of patients with diabetes who owned a trained dog reported a subsequent improvement in their quality of life. Nevertheless, the available data are limited and heterogeneous because they rely on low patient numbers and survey based studies prone to recall bias. CONCLUSION: Further research is needed to confirm the preliminary data on the reliability and mechanism underlying the dogs' abilities to detect hypoglycaemia, and its impact on patient outcomes. PMID- 26433212 TI - Effect of a structured diabetes education programme in primary care on hospitalizations and emergency department visits among people with Type 2 diabetes mellitus: results from the Patient Empowerment Programme. AB - AIM: To assess whether a structured diabetes education programme, the Patient Empowerment Programme, was associated with a lower rate of all-cause hospitalization and emergency department visits in a population-based cohort of patients with Type 2 diabetes mellitus in primary care. METHODS: A cohort of 24 250 patients was evaluated using a linked administrative database during 2009 2013. We selected 12 125 patients with Type 2 diabetes who had at least one Patient Empowerment Programme session attendance. Patients who did not participate in the Patient Empowerment Programme were matched one-to-one with patients who did, using the propensity score method. Hospitalization events and emergency department visits were the events of interest. Cox proportional hazard and negative binomial regressions were performed to estimate the hazard ratios for the initial event, and incidence rate ratios for the number of events. RESULTS: During a median 30.5 months of follow-up, participants in the Patient Empowerment Programme had a lower incidence of an initial hospitalization event (22.1 vs 25.2%; hazard ratio 0.879; P < 0.001) and emergency department visit (40.5 vs 44%; hazard ratio 0.901; P < 0.001) than those who did not participate in the Patient Empowerment Programme. Participation in the Patient Empowerment Programme was associated with a significantly lower number of emergency department visits (incidence rate ratio 0.903; P < 0.001): 40.4 visits per 100 patients annually in those who did not participate in the Patient Empowerment Programme vs. 36.2 per 100 patients annually in those who did. There were significantly fewer hospitalization episodes (incidence rate ratio 0.854; P < 0.001): 20.0 hospitalizations per 100 patients annually in those who did not participate in the Patient Empowerment Programme vs. 16.9 hospitalizations per 100 patients annually in those who did. CONCLUSIONS: Among patients with Type 2 diabetes, the Patient Empowerment Programme was shown to be effective in delaying the initial hospitalization event and in reducing their frequency. PMID- 26433213 TI - Short-term and long-term effects of dipeptidyl peptidase-4 inhibitors in type 2 diabetes mellitus patients with renal impairment: a meta-analysis of randomized controlled trials. AB - To assess the short-term and long-term effects of dipeptidyl peptidase-4 (DPP-4) inhibitors in type 2 diabetes mellitus patients with renal impairment, a meta analysis of randomized clinical trials of DPP-4 inhibitor interventions in type 2 diabetes mellitus patients with renal impairment was performed. PubMed, Embase, Cochrane Library and ClinicalTrials.gov were searched through the end of March 2015. Randomized clinical trials were selected if (1) DPP-4 inhibitors were compared with a placebo or other active-comparators, (2) the treatment duration was >=12 weeks and (3) data regarding changes in haemoglobin A1c (HbA1c ), changes in fasting plasma glucose or hypoglycaemia and other adverse events were reported. Of 790 studies, ten studies on eight randomized clinical trials were included. Compared with the control group, DPP-4 inhibitors were associated with a greater HbA1c reduction in both the short-term [mean differences (MD) = -0.45, 95% confidence intervals (-0.57, -0.33), p < 0.0001] and long-term [MD = -0.33, 95% confidence intervals (-0.63, -0.03), p = 0.03] treatments. However, the long term greater reduction in HbA1c with DPP-4 inhibitor treatment was only significant when the control treatment comprised placebo plus stable background treatment, but not glipizide plus stable background treatment. DPP-4 inhibitors were associated with a greater fasting plasma glucose reduction [MD = -12.59, 95% confidence intervals (-22.01, -3.17), p = 0.009] over the short-term; however, this effect was not present over the long-term. Regarding the hypoglycaemia adverse events assessment, the long-term treatment data indicated there was no increased risk of hypoglycaemia compared with placebo or active-controlled anti diabetic drugs. The present meta-analysis confirms that DPP-4 inhibitors are effective and equivalent to other agents in type 2 diabetes mellitus patients with renal impairment. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26433215 TI - Transcutaneous Skin-Muscle Flap Suspension Lower-Eyelid Blepharoplasty. PMID- 26433214 TI - Response of colonic motility to dopaminergic stimulation is subverted in rats with nigrostriatal lesion: relevance to gastrointestinal dysfunctions in Parkinson's disease. AB - BACKGROUND: Constipation is extremely common in patients with Parkinson's disease (PD) and has been described in PD animal models. In this study, we investigated whether a PD-like degeneration of dopaminergic neurons of the substantia nigra can influence peristalsis in colonic segments of rats by impacting on enteric dopaminergic transmission. METHODS: Male, Sprague-Dawley rats received a unilateral injection of neurotoxin 6-hydroxydopamine (6-OHDA), or saline, into the medial-forebrain-bundle. Peristaltic activity was recorded in isolated colonic segments, in baseline conditions and following exposure to combinations of D2 receptor (DRD2) agonist sumanirole and antagonist L-741626. Dopamine levels and DRD2 expression were assessed in the ileum and colon of animals. We also investigated the involvement of the dorsal motor nucleus of the vagus (DMV) - a potential relay station between central dopaminergic denervation and gastrointestinal (GI) dysfunction - by analyzing cytochrome c oxidase activity and FosB/DeltaFosB expression in DMV neurons. KEY RESULTS: We observed profound alterations in the response of colonic segments of 6-OHDA lesioned animals to DRD2 stimulation. In fact, the inhibition of colonic peristalsis elicited by sumanirole in control rats was absent in 6-OHDA-lesioned animals. These animals also showed reduced DRD2 expression in the colon, along with elevation of dopamine levels. No significant changes were detected within the DMV. CONCLUSIONS & INFERENCES: Our results demonstrate that selective lesion of the nigrostriatal dopaminergic pathway subverts the physiological response of the colon to dopaminergic stimulation, opening new perspectives in the comprehension and treatment of GI dysfunctions associated with PD. PMID- 26433216 TI - Prevalence, Employment Rate, and Cost of Schizophrenia in a High-Income Welfare Society: A Population-Based Study Using Comprehensive Health and Welfare Registers. AB - Schizophrenia is associated with recurrent hospitalizations, need for long-term community support, poor social functioning, and low employment rates. Despite the wide- ranging financial and social burdens associated with the illness, there is great uncertainty regarding prevalence, employment rates, and the societal costs of schizophrenia. The current study investigates 12-month prevalence of patients treated for schizophrenia, employment rates, and cost of schizophrenia using a population-based top-down approach. Data were obtained from comprehensive and mandatory health and welfare registers in Norway. We identified a 12-month prevalence of 0.17% for the entire population. The employment rate among working age individuals was 10.24%. The societal costs for the 12-month period were USD 890 million. The average cost per individual with schizophrenia was USD 106 thousand. Inpatient care and lost productivity due to high unemployment represented 33% and 29%, respectively, of the total costs. The use of mandatory health and welfare registers enabled a unique and informative analysis on true population-based datasets. PMID- 26433217 TI - Cognitive Effects of High-Frequency rTMS in Schizophrenia Patients With Predominant Negative Symptoms: Results From a Multicenter Randomized Sham Controlled Trial. AB - Cognitive impairments are one of the main contributors to disability and poor long-term outcome in schizophrenia. Proof-of-concept trials indicate that repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (DLPFC) has the potential to improve cognitive functioning. We analyzed the effects of 10-Hz rTMS to the left DLPFC on cognitive deficits in schizophrenia in a large-scale and multicenter, sham-controlled study. A total of 156 schizophrenia patients with predominant negative symptoms were randomly assigned to a 3-week intervention (10-Hz rTMS, 15 sessions, 1000 stimuli per session) with either active or sham rTMS. The Rey Auditory Verbal Learning Test, Trail Making Test A and B, Wisconsin Card Sorting Test, Digit Span Test, and the Regensburg Word Fluency Test were administered before intervention and at day 21, 45, and 105 follow-up. From the test results, a neuropsychological composite score was computed. Both groups showed no differences in any of the outcome variables before and after intervention. Both groups improved markedly over time, but effect sizes indicate a numeric, but nonsignificant superiority of active rTMS in certain cognitive tests. Active 10-Hz rTMS applied to the left DLPFC for 3 weeks was not superior to sham rTMS in the improvement of various cognitive domains in schizophrenia patients with predominant negative symptoms. This is in contrast to previous preliminary proof-of-concept trials, but highlights the need for more multicenter randomized controlled trials in the field of noninvasive brain stimulation. PMID- 26433219 TI - Acacetin 7-O-alpha-l-rhamnopyranosyl (1-2) beta-D-xylopyranoside Elicits Life span Extension and Stress Resistance in Caenorhabditis elegans. AB - The advancements in the field of gerontology have unraveled the signaling pathways that regulate life span, suggesting that it might be feasible to modulate aging. To this end, we isolated a novel phytomolecule Acacetin 7-O-alpha l-rhamnopyranosyl (1-2) beta-D-xylopyranoside (ARX) from Premna integrifolia and evaluated its antiaging effects in Caenorhabditis elegans The spectral data analysis revealed the occurrence of a new compound ARX. Out of the three tested pharmacological doses of ARX, viz. 5, 25, and 50 uM, the 25-uM dose was able to extend life span in C. elegans by more than 39%. The present study suggests that ARX affects bacterial metabolism, which in turn leads to dietary restriction (DR) like effects in the worms. The effect of ARX on worms with mutations (mev-1, eat 2, sir-2.1, skn-1, daf-16, and hsf-1) indicates that ARX-mediated life-span extension involves mechanisms associated with DR and maintenance of cellular redox homeostasis. This study is the first time report on longevity-promoting activity of ARX in C. elegans mediated by stress and DR-regulating genes. This novel phytomolecule can contribute in designing therapeutics for managing aging and age-related diseases. PMID- 26433220 TI - Reproducibility of the assessment of the Frankel manoeuvre for the evaluation of sagittal skeletal discrepancies in Class II individuals. AB - OBJECTIVES: The Frankel manoeuvre is a procedure by which the mandible of Class II individuals is postured forward in dental Class I relationship. The evaluation of the resulting facial profile provides information concerning the components determining the sagittal discrepancy. Data concerning the reproducibility of its assessment are not available. This study aimed to evaluate the intra-observer and inter-observer reproducibility of the assessment of the manoeuvre and to assess whether the amount of clinical experience affects its reproducibility. METHODS: Two lateral photographs, one in centric occlusion, and the other with the mandible postured forward (Frankel manoeuvre) of 100 Angle Class II individuals aged between 9 and 13 years were evaluated by six orthodontists (T0). Each examiner was asked whether the facial profile worsen or not with the manoeuvre after being trained by an expert orthodontist. The test was repeated after 2 weeks interval (T1). Intra-observer and inter-observer agreement were evaluated by computing the Cohen's K. RESULTS: The agreement (K values) between observations (T0 versus T1) for each examiner ranged from 0.49 to 0.72. The overall agreement was 0.65 [95% confidence interval (CI) = 0.54-0.75]. The agreement in the group with less clinical experience was 0.61 (95% CI = 0.46 0.76), while it was 0.68 (95% CI = 0.53-0.83) in the more experienced group. The amount of clinical experience did not affect intra-observer agreement (P = 0.50). The overall agreement between the examiners and the trainer was 0.74 (95% CI = 0.65-0.83) and 0.73 (95% CI = 0.64-0.83) at T0 and T1 respectively. CONCLUSION: The assessment of the Frankel manoeuvre is reproducible and it is not influenced by the amount of clinical experience. PMID- 26433218 TI - Pain and Cognitive Function Among Older Adults Living in the Community. AB - BACKGROUND: Pain related to many age-related chronic conditions is a burdensome problem in elderly adults and may also interfere with cognitive functioning. The purpose of this study was to examine the cross-sectional relationship between measures of pain severity and pain interference and cognitive performance in community-living older adults. METHODS: We studied 765 participants in the Maintenance of Balance Independent Living Intellect and Zest (MOBILIZE) Boston Study, a population-based study of persons aged 70 and older. Global pain severity and interference were measured using the Brief Pain Inventory subscales. The neuropsychological battery included measures of attentional capacity (Trail Making Test A, WORLD Test), executive function (Trail Making Test B and Delta, Clock-in-a-Box, Letter Fluency), memory (Hopkins Verbal Learning Test), and a global composite measure of cognitive function. Multivariable linear regression models were used to analyze the relationship between pain and cognitive functioning. RESULTS: Elderly adults with more severe pain or more pain interference had poorer performance on memory tests and executive functioning compared to elders with none or less pain. Pain interference was also associated with impaired attentional capacity. Additional adjustment for chronic conditions, behaviors, and psychiatric medication resulted in attenuation of many of the observed associations. However, the association between pain interference and general cognitive function persisted. CONCLUSIONS: Our findings point to the need for further research to understand how chronic pain may contribute to decline in cognitive function and to determine strategies that may help in preventing or managing these potential consequences of pain on cognitive function in older adults. PMID- 26433221 TI - ORF8-Related Genetic Evidence for Chinese Horseshoe Bats as the Source of Human Severe Acute Respiratory Syndrome Coronavirus. AB - Several lineage B betacoronaviruses termed severe acute respiratory syndrome (SARS)-like CoVs (SL-CoVs) were identified from Rhinolophus bats in China. These viruses are characterized by a set of unique accessory open reading frames (ORFs) that are located between the M and N genes. Among unique accessory ORFs, ORF8 is most hypervariable. In this study, the ORF8s of all SL-CoVs were classified into 3 types, and, for the first time, it was found that very few SL-CoVs from Rhinolophus sinicus have ORF8s that are identical to that of human SARS-CoV. This finding provides new genetic evidence for Chinese horseshoe bats as the source of human SARS-CoV. PMID- 26433222 TI - Asymptomatic and Submicroscopic Carriage of Plasmodium knowlesi Malaria in Household and Community Members of Clinical Cases in Sabah, Malaysia. AB - Although asymptomatic carriage of human malaria species has been widely reported, the extent of asymptomatic, submicroscopic Plasmodium knowlesi parasitemia is unknown. In this study, samples were obtained from individuals residing in households or villages of symptomatic malaria cases with the aim of detecting submicroscopic P. knowlesi in this population. Four published molecular assays were used to confirm the presence of P. knowlesi. Latent class analysis revealed that the estimated proportion of asymptomatic individuals was 6.9% (95% confidence interval, 5.6%-8.4%). This study confirms the presence of a substantial number of asymptomatic monoinfections across all age groups; further work is needed to estimate prevalence in the wider community. PMID- 26433223 TI - Hairpins participating in folding of human telomeric sequence quadruplexes studied by standard and T-REMD simulations. AB - DNA G-hairpins are potential key structures participating in folding of human telomeric guanine quadruplexes (GQ). We examined their properties by standard MD simulations starting from the folded state and long T-REMD starting from the unfolded state, accumulating ~130 MUs of atomistic simulations. Antiparallel G hairpins should spontaneously form in all stages of the folding to support lateral and diagonal loops, with sub-MUs scale rearrangements between them. We found no clear predisposition for direct folding into specific GQ topologies with specific syn/anti patterns. Our key prediction stemming from the T-REMD is that an ideal unfolded ensemble of the full GQ sequence populates all 4096 syn/anti combinations of its four G-stretches. The simulations can propose idealized folding pathways but we explain that such few-state pathways may be misleading. In the context of the available experimental data, the simulations strongly suggest that the GQ folding could be best understood by the kinetic partitioning mechanism with a set of deep competing minima on the folding landscape, with only a small fraction of molecules directly folding to the native fold. The landscape should further include non-specific collapse processes where the molecules move via diffusion and consecutive random rare transitions, which could, e.g. structure the propeller loops. PMID- 26433224 TI - Acentric chromosome ends are prone to fusion with functional chromosome ends through a homology-directed rearrangement. AB - The centromeres of many eukaryotic chromosomes are established epigenetically on potentially variable tandem repeats; hence, these chromosomes are at risk of being acentric. We reported previously that artificially created acentric chromosomes in the fission yeast Schizosaccharomyces pombe can be rescued by end to-end fusion with functional chromosomes. Here, we show that most acentric/functional chromosome fusion events in S. pombe cells harbouring an acentric chromosome I differed from the non-homologous end-joining-mediated rearrangements that result in deleterious dicentric fusions in normal cells, and were elicited by a previously unidentified homologous recombination (HR) event between chromosome end-associated sequences. The subtelomere repeats associated with the non-fusogenic ends were also destabilized in the surviving cells, suggesting a causal link between general subtelomere destabilization and acentric/functional chromosome fusion. A mutational analysis indicated that a non canonical HR pathway was involved in the rearrangement. These findings are indicative of a latent mechanism that conditionally induces general subtelomere instability, presumably in the face of accidental centromere loss events, resulting in rescue of the fatal acentric chromosomes by interchromosomal HR. PMID- 26433225 TI - SubtiWiki 2.0--an integrated database for the model organism Bacillus subtilis. AB - To understand living cells, we need knowledge of each of their parts as well as about the interactions of these parts. To gain rapid and comprehensive access to this information, annotation databases are required. Here, we present SubtiWiki 2.0, the integrated database for the model bacterium Bacillus subtilis (http://subtiwiki.uni-goettingen.de/). SubtiWiki provides text-based access to published information about the genes and proteins of B. subtilis as well as presentations of metabolic and regulatory pathways. Moreover, manually curated protein-protein interactions diagrams are linked to the protein pages. Finally, expression data are shown with respect to gene expression under 104 different conditions as well as absolute protein quantification for cytoplasmic proteins. To facilitate the mobile use of SubtiWiki, we have now expanded it by Apps that are available for iOS and Android devices. Importantly, the App allows to link private notes and pictures to the gene/protein pages. Today, SubtiWiki has become one of the most complete collections of knowledge on a living organism in one single resource. PMID- 26433226 TI - BacWGSTdb, a database for genotyping and source tracking bacterial pathogens. AB - Whole genome sequencing has become one of the routine methods in molecular epidemiological practice. In this study, we present BacWGSTdb (http://bacdb.org/BacWGSTdb), a bacterial whole genome sequence typing database which is designed for clinicians, clinical microbiologists and hospital epidemiologists. This database borrows the population structure from the current multi-locus sequence typing (MLST) scheme and adopts a hierarchical data structure: species, clonal complex and isolates. When users upload the pre assembled genome sequences to BacWGSTdb, it offers the functionality of bacterial genotyping at both traditional MLST and whole-genome levels. More importantly, users are told which isolates in the public database are phylogenetically close to the query isolate, along with their clinical information such as host, isolation source, disease, collection time and geographical location. In this way, BacWGSTdb offers a rapid and convenient platform for worldwide users to address a variety of clinical microbiological issues such as source tracking bacterial pathogens. PMID- 26433227 TI - A cytoplasmic pathway for gapmer antisense oligonucleotide-mediated gene silencing in mammalian cells. AB - Antisense oligonucleotides (ASOs) are known to trigger mRNA degradation in the nucleus via an RNase H-dependent mechanism. We have now identified a putative cytoplasmic mechanism through which ASO gapmers silence their targets when transfected or delivered gymnotically (i.e. in the absence of any transfection reagent). We have shown that the ASO gapmers can interact with the Ago-2 PAZ domain and can localize into GW-182 mRNA-degradation bodies (GW-bodies). The degradation products of the targeted mRNA, however, are not generated by Ago-2 directed cleavage. The apparent identification of a cytoplasmic pathway complements the previously known nuclear activity of ASOs and concurrently suggests that nuclear localization is not an absolute requirement for gene silencing. PMID- 26433228 TI - RPFdb: a database for genome wide information of translated mRNA generated from ribosome profiling. AB - Translational control is crucial in the regulation of gene expression and deregulation of translation is associated with a wide range of cancers and human diseases. Ribosome profiling is a technique that provides genome wide information of mRNA in translation based on deep sequencing of ribosome protected mRNA fragments (RPF). RPFdb is a comprehensive resource for hosting, analyzing and visualizing RPF data, available at www.rpfdb.org or http://sysbio.sysu.edu.cn/rpfdb/index.html. The current version of database contains 777 samples from 82 studies in 8 species, processed and reanalyzed by a unified pipeline. There are two ways to query the database: by keywords of studies or by genes. The outputs are presented in three levels. (i) Study level: including meta information of studies and reprocessed data for gene expression of translated mRNAs; (ii) Sample level: including global perspective of translated mRNA and a list of the most translated mRNA of each sample from a study; (iii) Gene level: including normalized sequence counts of translated mRNA on different genomic location of a gene from multiple samples and studies. To explore rich information provided by RPF, RPFdb also provides a genome browser to query and visualize context-specific translated mRNA. Overall our database provides a simple way to search, analyze, compare, visualize and download RPF data sets. PMID- 26433229 TI - SerRS-tRNASec complex structures reveal mechanism of the first step in selenocysteine biosynthesis. AB - Selenocysteine (Sec) is found in the catalytic centers of many selenoproteins and plays important roles in living organisms. Malfunctions of selenoproteins lead to various human disorders including cancer. Known as the 21st amino acid, the biosynthesis of Sec involves unusual pathways consisting of several stages. While the later stages of the pathways are well elucidated, the molecular basis of the first stage-the serylation of Sec-specific tRNA (tRNA(Sec)) catalyzed by seryl tRNA synthetase (SerRS)-is unclear. Here we present two cocrystal structures of human SerRS bound with tRNA(Sec) in different stoichiometry and confirm the formation of both complexes in solution by various characterization techniques. We discovered that the enzyme mainly recognizes the backbone of the long variable arm of tRNA(Sec) with few base-specific contacts. The N-terminal coiled-coil region works like a long-range lever to precisely direct tRNA 3' end to the other protein subunit for aminoacylation in a conformation-dependent manner. Restraints of the flexibility of the coiled-coil greatly reduce serylation efficiencies. Lastly, modeling studies suggest that the local differences present in the D- and T-regions as well as the characteristic U20:G19:C56 base triple in tRNA(Sec) may allow SerRS to distinguish tRNA(Sec) from closely related tRNA(Ser) substrate. PMID- 26433230 TI - The International Federation of Gynecology and Obstetrics (FIGO) recommendations on adolescent, preconception, and maternal nutrition: "Think Nutrition First". PMID- 26433231 TI - Selecting cases for feedback to pre-hospital clinicians - a pilot study. AB - Background There are currently limited avenues for routine feedback from hospitals to pre-hospital clinicians aimed at improvements in clinical practice. Objective The aim of this study was to pilot a method for selectively identifying cases where there was a clinically significant difference between the pre hospital and in-hospital diagnoses that could have led to a difference in pre hospital patient care. Methods This was a single-centre retrospective study involving cases randomly selected through informatics extraction of final diagnoses at hospital discharge. Additional data on demographics, triage and diagnoses were extracted by explicit chart review. Blinded groups of pre-hospital and in-hospital clinicians assessed data to detect clinically significant differences between pre-hospital and in-hospital diagnoses. Results Most (96.9%) patients were of Australasian Triage Scale category 1-3 and in-hospital mortality rate was 32.9%. Of 353 cases, 32 (9.1%; 95% CI: 6.1-12.1) were determined by both groups of clinical assessors to have a clinically significant difference between the pre-hospital and final in-hospital diagnoses, with moderate inter-rater reliability (kappa score 0.6, 95% CI: 0.5-0.7). Conclusion A modest proportion of cases demonstrated discordance between the pre-hospital and in-hospital diagnoses. Selective case identification and feedback to pre-hospital services using a combination of informatics extraction and clinician consensus approach can be used to promote ongoing improvements to pre-hospital patient care. What is known about the topic? Highly trained pre-hospital clinicians perform patient assessments and early interventions while transporting patients to healthcare facilities for ongoing management. Feedback is necessary to allow for continual improvements; however, the provision of formal selective feedback regarding diagnostic accuracy from hospitals to pre-hospital clinicians is currently not routine. What does this paper add? For a significant proportion of patients, there is a clinically important difference in the diagnosis recorded by their pre hospital clinician compared with their final in-hospital diagnosis. These clinically significant differences in diagnoses between pre-hospital and in hospital clinicians were most notable among acute myocardial infarction and trauma subgroups of patients in this study. What are the implications for practitioners? Identification of patients who have a significant discrepancy between their pre-hospital and in-hospital diagnoses could lead to the development of feedback mechanisms to pre-hospital clinicians. Providing pre hospital clinicians with this selective feedback would be intended to promote ongoing improvements in pre-hospital assessments and thereby to improve service delivery. PMID- 26433232 TI - The Apprenticeship Model for Surgical Training Is Inferior. AB - While the apprenticeship model for surgical training is a long-standing gold standard worldwide, proficiency-based progression (PBP) training proves significantly superior. The combination of a metrics tool describing procedural steps and errors with a simulator model or cadaveric training, results in a measurement tool that not only judges but serves to improve surgeon skill. PMID- 26433233 TI - Value, Technology, and Our Role As Surgeons: It's Time for a Call to Action. PMID- 26433234 TI - Synthetic Grafts--Where is the Common Sense? PMID- 26433235 TI - Authors' Reply. PMID- 26433236 TI - Regarding "Efficacy of Magnetic Resonance Imaging and Clinical Tests in Diagnostics of Wrist Ligament Injuries: A Systematic Review". PMID- 26433237 TI - Author's Reply. PMID- 26433238 TI - Editorial Commentary: Wrist Ligament Injury Diagnosis. AB - As also noted regarding the knee, shoulder, and hip, wrist ligament pathology cannot be ruled out by a negative magnetic resonance imaging. However, while arthroscopic surgery could be a gold standard for wrist injury diagnosis, clinically relevant research could consider history, physical examination, and imaging data in aggregate, rather than focusing solely on an magnetic resonance imaging interpretation. PMID- 26433239 TI - Editorial Commentary: Knee Lateral Extra-articular Tenodesis. AB - Knee lateral extra-articular tenodesis (LET) can be combined with anterior cruciate ligament (ACL) reconstruction with a goal of reducing anterolateral rotatory instability. Like double-bundle ACL reconstruction, LET combined with ACL reconstruction reduces pivot-shift, a subjective test, but results in no significant difference in clinical outcome. PMID- 26433240 TI - Editorial Commentary: Knee Hyaluronic Acid Viscosupplementation Reduces Osteoarthritis Pain. AB - In contrast to the AAOS knee osteoarthritis guidelines, systematic review of overlapping meta-analyses shows that viscosupplementation with intra-articular hyaluronic acid injection reduces knee osteoarthritis pain and improves function according to the highest level of evidence. PMID- 26433241 TI - Editorial Commentary: Femoroacetabular Impingement Under-resection Is the Primary Indication for Revision Arthroscopy. AB - Complications indicating revision after hip arthroscopy generally manifest within 24 months. Femoroacetabular cam or pincher impingement deformity under-resection is the primary indication for revision arthroscopy. Revision results in decreased pain and improved function, and primary and revision hip femoroacetabular impingement arthroscopic surgeons must be mindful of femoral cam lesion over resection, which could result in iatrogenic femoral neck fracture. PMID- 26433242 TI - Editorial Commentary: Rotator Cuff Tears of the Hip. AB - Abductor muscle tears are the rotator cuff tears of the hip. Arthroscopic or endoscopic repair results in fewer complications and equal clinical outcomes to open repair. PMID- 26433243 TI - A Comparison of K-Wire Versus Screw Fixation on the Outcomes of Distal Phalanx Fractures. AB - PURPOSE: To compare K-wire and screw fixation of distal phalanx (DP) fractures with respect to union and functional outcome. METHODS: This retrospective study identified patients with DP fractures from a clinic registry taken from 2007 to 2013. Clinical data collected included patient demographics, range of motion (ROM), removal of implant (ROI), and complications. Radiographic data collected included fracture type, location, configuration, fracture displacement, and radiographic union. Statistical analysis was done using a chi-squared test for categorical variables and paired Student's t test for continuous variables. RESULTS: A total of 172 patients with DP fractures were seen in our clinic between 2007 and 2013. Of these, 141 patients were managed conservatively and 31 patients had surgery for 33 DP fractures, of which 12 had K-wire and 21 had screw fixation. Mean union incidence for screw was 100% compared with 83% for K-wire. Time to union was 2.4 months for screw fixation compared with 4.1 months for K wire fixation. ROM for screw fixation was significantly better (60 degrees ) compared with K-wire fixation (45 degrees ). ROM for non-transarticular K-wire (46 degrees ) was similar to transarticular K-wire (44 degrees ). ROI was performed in 52% of patients with screw fixation. Other than fingertip tenderness, which resolved after ROI, no other complications were noted. CONCLUSIONS: Our study showed that the union incidence and time to union for screw fixation were comparable to those for K-wire fixation. Screw fixation of DP fractures resulted in greater distal interphalangeal joint motion compared with K wire fixation but required removal in half of cases. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 26433244 TI - Transfer of a Terminal Motor Branch Nerve to the Flexor Carpi Ulnaris for Triceps Reinnervation: Anatomical Study and Clinical Cases. AB - PURPOSE: To analyze the anatomical feasibility of transferring a motor branch nerve to the flexor carpi ulnaris (FCU) to the triceps upper medial head motor branch (UMHM) and to report the resultant outcome of the restoration of elbow extension in 5 patients with extensive brachial plexus injury. METHODS: The ulnar and radial nerves were dissected in 10 cadavers. We measured the length and diameter of the branches to the FCU and the UMHM branch and counted the axons. Then, 5 male patients, mean age 30 years, underwent FCU nerve branch transfer for reconstruction of elbow extension. Elbow flexion was restored via a median nerve branch to biceps transfer. RESULTS: Mean UMHM nerve length and diameter were 86 and 1.5 mm, respectively. Mean number of branches to the FCU muscle was 2.9. Mean FCU nerve length and diameter were 50 and 1.0 mm, respectively. Mean number of myelinated fibers was 818 and 743 for the UMHM and the longest branch to the FCU, respectively. Coaptation between nerves was possible without tension. All patients recovered functional active elbow extension at a mean follow-up of 19 months with a British Medical Research Council score of M4. After surgery, all patients retained a functional FCU with a British Medical Research Council score of M4. CONCLUSIONS: Nonselective ulnar nerve fascicles at the root of the limb might not be adequate to restore elbow extension when combined with a median nerve branch transfer for elbow flexion. A selective distal ulnar motor fascicle such as a FCU motor branch could be harvested and connected to a triceps branch to restore elbow extension. Such a nerve transfer would also allow for later transfer of the still functional FCU tendon to the digital extensors. CLINICAL RELEVANCE: For patients with extensive brachial plexus injury and a preserved medial cord, transferring a motor branch nerve to the FCU is an effective technique for the reconstruction of elbow extension. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 26433245 TI - Operative Treatment of Unstable Long Oblique Proximal Phalanx Fractures. PMID- 26433246 TI - Clinical and dermoscopic features of combined cutaneous squamous cell carcinoma (SCC)/neuroendocrine [Merkel cell] carcinoma (MCC). AB - BACKGROUND: Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma, associated with Merkel cell polyomavirus. MCC admixed with squamous cell carcinoma (SCC) is unassociated with polyomavirus, and is genetically distinct. OBJECTIVE: We sought to distinguish clinically and dermoscopically between MCC and SCC/MCC. METHODS: We compared patient data for SCC/MCC (n = 26) and MCC (n = 20), and reviewed clinical and dermoscopic images (n = 9) of SCC/MCC. RESULTS: Patients with SCC/MCC were older (median 76.5 vs 69 years) and more often male (77% vs 60%), and had more nonmelanoma skin cancer (85% vs 25%), malignant extracutaneous tumors (25% vs 5%), lymphoproliferative disorders (23% vs 10%), and immunodeficient/proinflammatory states (77% vs 35%). In all, 58% of SCC/MCC versus 10% of MCC were clinically diagnosed nonmelanoma skin cancer. Patients with SCC/MCC had more metastases (77% vs 40%), more treatment failures (53% vs 45%), shorter survival (41 vs 54 months), and more death from disease (50% vs 40%). SCC/MCC demonstrated marked scale (7/9), and telangiectasia (1/9). Dermoscopically, small dotted and short linear irregular peripheral vessels and central milky-red areas with large-diameter arborizing vessels were seen. LIMITATIONS: The rarity of SCC/MCC limits available data. CONCLUSIONS: SCC/MCC is aggressive, arising within elderly patients' chronically ultraviolet-exposed skin, often in the setting of immunosuppression or inflammation. Dermoscopically, polymorphous vessels in lesions suspicious for nonmelanoma skin cancer are suggestive. PMID- 26433248 TI - Trends Form Follows Function: New Ways to Inform and Inspire. PMID- 26433247 TI - Can oral nonsteroidal antiinflammatory drugs play a role in the prevention of basal cell carcinoma? A systematic review and metaanalysis. AB - BACKGROUND: Evidence for an association between aspirin or other nonsteroidal antiinflammatory drug (NSAID) use and basal cell carcinoma (BCC) has been inconsistent. OBJECTIVE: We conducted a systematic review and metaanalysis to assess the effect of oral NSAIDs on BCC. METHODS: PubMed, Web of Science, and Embase databases were searched up to December 3, 2014. A random effects model metaanalysis was used to calculate summary estimates of the effects of aspirin, nonaspirin NSAIDs, or any (aspirin or nonaspirin) NSAID use in patients with BCC. RESULTS: The summary estimates from 11 studies (1 randomized controlled trial, 5 cohort studies, and 5 case control studies) found a 10% risk reduction of BCC among those using any NSAID (relative risk [RR], 0.90 [95% confidence interval {CI}, 0.84-0.97]). A similar but not statistically significant inverse association was observed for nonaspirin NSAIDs (RR, 0.93 [95% CI, 0.86-1.02]), while aspirin use was more weakly associated (RR, 0.95 [95% CI, 0.91-1.00]). The strongest inverse associations were noted among those with either a history of skin cancers or a high prevalence of actinic keratoses. LIMITATIONS: Dose-effect estimates could not be calculated because the available data were too heterogeneous to pool. CONCLUSION: The intake of NSAIDs may help prevent BCC, particularly in high-risk populations. A large randomized controlled trial is required to confirm these findings. PMID- 26433249 TI - New Approaches to Systematics of Trypanosomatidae: Criteria for Taxonomic (Re)description. AB - While dixenous trypanosomatids represent one of the most dangerous pathogens for humans and domestic animals, their monoxenous relatives have frequently become model organisms for studies of diversity of parasitic protists and host-parasite associations. Yet, the classification of the family Trypanosomatidae is not finalized and often confusing. Here we attempt to make a blueprint for future studies in this field. We would like to elicit a discussion about an updated procedure, as traditional taxonomy was not primarily designed to be used for protists, nor can molecular phylogenetics solve all the problems alone. The current status, specific cases, and examples of generalized solutions are presented under conditions where practicality is openly favored over rigid taxonomic codes or blind phylogenetic approach. PMID- 26433250 TI - Regulation of the Immune Response to alpha-Gal and Vector-borne Diseases. AB - Vector-borne diseases (VBD) challenge our understanding of emerging diseases. Recently, arthropod vectors have been involved in emerging anaphylactic diseases. In particular, the immunoglobulin E (IgE) antibody response to the carbohydrate Galalpha1-3Galbeta1-(3)4GlcNAc-R (alpha-gal) following a tick bite was associated with allergies to red meat, cetuximab, and gelatin. By contrast, an anti-alpha gal IgM antibody response was shown to protect against mosquito-borne malaria. Herein, we highlight the interplay between the gut microbiota, vectors, transmitted pathogens, and the regulation of the immune response as a model to understand the protective or allergic effect of alpha-gal. Establishing the source of alpha-gal in arthropod vectors and the immune response to vector bites and transmitted pathogens will be essential for diagnosing, treating, and ultimately preventing these emerging anaphylactic and other vector-borne diseases. PMID- 26433252 TI - The Social Life of African Trypanosomes. AB - The unicellular parasite Trypanosoma brucei shuttles between its definitive host, the tsetse fly, and various mammals including humans. In the fly digestive tract, T. brucei must first migrate to the ectoperitrophic space, establish a persistent infection of the midgut and then migrate to the salivary glands before being transmitted to a new mammalian host. In 2010, it was shown that insect stages of the parasite (procyclic forms) exhibit social motility (SoMo) when cultured on a semi-solid surface, and it was postulated that this behaviour might reflect a migration step in the tsetse fly. Now, almost 5 years after the initial report, several new publications shed some light on the biological function of SoMo and provide insights into the underlying signalling pathways. PMID- 26433251 TI - Exosomes and Other Extracellular Vesicles: The New Communicators in Parasite Infections. AB - Extracellular vesicles (EVs) have emerged as a ubiquitous mechanism for transferring information between cells and organisms across all three kingdoms of life. In addition to their roles in normal physiology, vesicles also transport molecules from pathogens to hosts and can spread antigens as well as infectious agents. Although initially described in the host-pathogen context for their functions in immune surveillance, vesicles enable multiple modes of communication by, and between, parasites. Here we review the literature demonstrating that EVs are secreted by intracellular and extracellular eukaryotic parasites, as well as their hosts, and detail the functional properties of these vesicles in maturation, pathogenicity and survival. We further describe the prospects for targeting or exploiting these complexes in therapeutic and vaccine strategies. PMID- 26433253 TI - Diverse Applications of Environmental DNA Methods in Parasitology. AB - Nucleic acid extraction and sequencing of genes from organisms within environmental samples encompasses a variety of techniques collectively referred to as environmental DNA or 'eDNA'. The key advantages of eDNA analysis include the detection of cryptic or otherwise elusive organisms, large-scale sampling with fewer biases than specimen-based methods, and generation of data for molecular systematics. These are particularly relevant for parasitology because parasites can be difficult to locate and are morphologically intractable and genetically divergent. However, parasites have rarely been the focus of eDNA studies. Focusing on eukaryote parasites, we review the increasing diversity of the 'eDNA toolbox'. Combining eDNA methods with complementary tools offers much potential to understand parasite communities, disease risk, and parasite roles in broader ecosystem processes such as food web structuring and community assembly. PMID- 26433254 TI - Critical Steps in Protein Export of Plasmodium falciparum Blood Stages. AB - Plasmodium falciparum blood stages export a large number of proteins into their host red blood cell, leading to changes to the infected cell that are pivotal for parasite survival and contribute to parasite virulence. To reach the host cell, exported proteins follow a multistep pathway that now has been revealed to be similar for different classes of exported proteins. Here we summarise the current understanding about the critical segments in protein export of P. falciparum blood stages and discuss recent findings highlighting protein export as a potential target for chemotherapeutic interventions. PMID- 26433255 TI - Temporal patterning of neural synchrony in the basal ganglia in Parkinson's disease. PMID- 26433256 TI - Nano-silymarin provides protection against gamma-radiation-induced oxidative stress in cultured human embryonic kidney cells. AB - Radiation can produce biological damage, mainly oxidative stress, via production of free radicals, including reactive oxygen species (ROS). Nanoparticles are of interest as radioprotective agents, particularly due to their high solubility and bioavailability. Silymarin is a hepatoprotective agent but has poor oral bioavailability. Silymarin was formulated as a nanoemulsion with the aim of improving its bioavailability and therapeutic efficacy. In the present study, we evaluated self-nanoemulsifying drug delivery systems (SNEDDS) formulated with surfactants and co-surfactants. Nano-silymarin was characterized by estimating % transmittance, globule size, and polydispersity index, and by transmission electron microscopy (TEM). The nano-silymarin obtained was in the range of 3-8nm diameter. With regard to DNA damage, measured by a plasmid relaxation assay, maximum protection was obtained at 10MUg/mL. Cytotoxicity of nano-silymarin to human embryonic kidney (HEK) cells was evaluated using the 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Protective efficacy against gamma-radiation was assessed by reduction in micronucleus frequency and ROS generation, using the 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) assay. Radiation-induced apoptosis was estimated by microscopic analysis and cell-cycle estimation. Nano-silymarin was radioprotective, supporting the possibility of developing new approaches to radiation protection via nanotechnology. PMID- 26433257 TI - Effects of soluble and particulate Cr(VI) on genome-wide DNA methylation in human B lymphoblastoid cells. AB - Several previous studies highlighted the potential epigenetic effects of Cr(VI), especially DNA methylation. However, few studies have compared the effects of Cr(VI) on DNA methylation profiles between soluble and particulate chromate in vitro. Accordingly, Illumina Infinium Human Methylation 450K BeadChip array was used to analyze DNA methylation profiles of human B lymphoblastoid cells exposed to potassium dichromate or lead chromate, and the cell viability was also studied. Array based DNA methylation analysis showed that the impacts of Cr(VI) on DNA methylation were limited, only about 40 differentially methylated CpG sites, with an overlap of 15CpG sites, were induced by both potassium dichromate and lead chromate. The results of mRNA expression showed that after Cr(VI) treatment, mRNA expression changes of four genes (TBL1Y, FZD5, IKZF2, and KIAA1949) were consistent with their DNA methylation alteration, but DNA methylation changes of other six genes did not correlate with mRNA expression. In conclusion, both of soluble and particulate Cr(VI) could induce a small amount of differentially methylated sites in human B lymphoblastoid cells, and the correlations between DNA methylation changes and mRNA expression varied between different genes. PMID- 26433258 TI - The effect of gamma radiation on the Common carp (Cyprinus carpio): In vivo genotoxicity assessment with the micronucleus and comet assays. AB - Radioactive wastes may be leached into freshwater, either accidentally or in industrial effluents. We have studied gamma radiation-induced DNA damage in the freshwater fish Cyprinus carpio. Fish were irradiated with 2-10Gy gamma radiation and genotoxic effects in blood cells were studied with the micronucleus (MN) and comet assays. Micronuclei and a dose-dependent increase in comet-tail DNA were seen in dose- and time-dependent studies. The highest % tail DNA was observed at 24h, declining until 72h, which may indicate the repair of radiation-induced DNA single-strand breaks after gamma radiation. However, double-stranded DNA damage may not have been repaired, as indicated by increased micronuclei at later periods. A positive correlation was observed between the comet and micronucleus assay results. This study confirms the mutagenic/genotoxic potential of gamma radiation in the Common carp, as well as the possible combined use of the micronucleus and comet assays for in vivo laboratory studies with fresh-water fish for screening the genotoxic potential of radioactive pollution. PMID- 26433259 TI - Radiation sensitivity of the gastrula-stage embryo: Chromosome aberrations and mutation induction in lacZ transgenic mice: The roles of DNA double-strand break repair systems. AB - At the gastrula phase of development, just after the onset of implantation, the embryo proper is characterized by extremely rapid cell proliferation. The importance of DNA repair is illustrated by embryonic lethality at this stage after ablation of the genes involved. Insight into mutation induction is called for by the fact that women often do not realize they are pregnant, shortly after implantation, a circumstance which may have important consequences when women are subjected to medical imaging using ionizing radiation. We screened gastrula embryos for DNA synthesis, nuclear morphology, growth, and chromosome aberrations (CA) shortly after irradiation with doses up to 2.5Gy. In order to obtain an insight into the importance of DNA repair for CA induction, we included mutants for the non-homologous end joining (NHEJ) and homologous recombination repair (HRR) pathways, as well as Parp1-/- and p53+/- embryos. With the pUR288 shuttle vector assay, we determined the radiation sensitivity for point mutations and small deletions detected in young adults. We found increased numbers of abnormal nuclei 5h after irradiation; an indication of disturbed development was also observed around this time. Chromosome aberrations 7h after irradiation arose in all genotypes and were mainly of the chromatid type, in agreement with a cell cycle dominated by S-phase. Increased frequencies of CA were found for NHEJ and HR mutants. Gastrula embryos are unusual in that they are low in exchange induction, even after compromised HR. Gastrula embryos were radiation sensitive in the pUR288 shuttle vector assay, giving the highest mutation induction ever reported for this genetic toxicology model. On theoretical grounds, a delayed radiation response must be involved. The compromised developmental profile after doses up to 2.5Gy likely is caused by both apoptosis and later cell death due to large deletions. Our data indicate a distinct radiation-sensitive profile of gastrula embryos, including some stage-specific aspects that are not as yet understood. PMID- 26433260 TI - Ameliorative effects of N-acetylcysteine on fluoride-induced oxidative stress and DNA damage in male rats' testis. AB - This study was to elucidate DNA damage in rats treated with sodium fluoride (NaF) by performing 8-Hydroxy-2-deoxyguanosine (8-OHdG) immunohistochemical staining assays on seminiferous tubules of rats' testis, and also to evaluate the protective effects of N-acetylcysteine (NAC) on spermatogenesis. Male Sprague Dawley (SD) rats were exposed to a single dose of NaF (25mg/kg/day) with or without NAC (150mg/kg/day) for 7 weeks (7W) by gastric gavage. Testicular fluorine content was detected by fluorine ion selective electrode method. Oxidative damage to DNA was evaluated by measuring the increase in 8-OHdG formation in testicular tissue through immunohistochemical staining assays and also the effects of NAC pretreatment. The biochemical indicators about oxidative stress were detected by colorimetric assays, sperm parameters and the morphological changes of testis were studied. NaF significantly increased serum levels of oxidative stress, markedly elevated testicular fluorine and 8-OHdG expression levels as well as the rate of sperm aberration compared to saline group. Testosterone in serum, sperm counts and the mobility of sperm were lower than those of the rats in control group. The pathological morphological changes in testicular seminiferous tubule were also obvious in the rats with NaF treatment. Pretreatment with NAC did not reduce the contents of fluoride content in testis, but significantly reduced 8-OHdG formation and lipid peroxidation. This study suggests that NAC may have certain antagonism on the reproductive damage induced by NaF. PMID- 26433261 TI - Does the crystal habit modulate the genotoxic potential of silica particles? A cytogenetic evaluation in human and murine cell lines. AB - Crystalline silica inhaled from occupational sources has been classified by IARC as carcinogenic to humans; in contrast, for amorphous silica, epidemiological and experimental evidence remains insufficient. The genotoxicity of crystalline silica is still debated because of the inconsistency of experimental results ("variability of silica hazard"), often related to the features of the particle surfaces. We have assessed the role of crystal habit in the genotoxicity of silica powders. Pure quartz (crystalline) and vitreous silica (amorphous), sharing the same surface features, were used in an in vitro study with human pulmonary epithelial (A549) and murine macrophage (RAW264.7) cell lines, representative of occupational and environmental exposures. Genotoxicity was evaluated by the comet and micronucleus assays, and cytotoxicity by the trypan blue method. Cells were treated with silica powders for 4 and 24h. Quartz but not vitreous silica caused cell death and DNA damage in RAW264.7 cells. A549 cells were relatively resistant to both powders. Our results support the view that crystal habit per se plays a pivotal role in modulating the biological responses to silica particles. PMID- 26433262 TI - Dominant lethal mutation test in male mice exposed to 900MHz radiofrequency fields. AB - Adult male ICR mice were exposed to continuous wave 900MHz radiofrequency fields (RF) at 1.6mW/cm(2) power intensity (whole body average specific absorption rate of 0.731W/kg) for 4 hour/day for 15 days. At the end of exposure, each mouse was caged with 3 mature virgin female mice for mating. After 7 days, each male mouse was transferred to a fresh cage and mated with a second batch of 3 females. This process was repeated for a total of 4 consecutive weeks. Sham exposed male mice and those subjected to an acute 2Gy gamma-irradiation (GR) were handled similarly and used as un-exposed and positive controls, respectively. All females were sacrificed on the 18th day of gestation and presumptive mating and, the contents in their uteri were examined. The overall observations during the 4 weeks of mating indicated that the un-exposed female mice mated to RF-exposed male mice showed no significant differences in the percentage of pregnancies, total implants, live implants and dead implants when compared with those mated with sham-exposed mice. In contrast, female mice mated with GR-exposed males showed a consistent pattern of significant differences in the above indices in each and all 4 weeks of mating. Thus, the data indicated an absence of mutagenic potential of RF exposure in the germ cells of male mice. PMID- 26433263 TI - Graphene oxide/polyethyleneglycol composite coated stir bar for sorptive extraction of fluoroquinolones from chicken muscle and liver. AB - Graphene oxide (GO) is an ideal adsorbent for polar and less polar compounds due to its hexagonal carbon network structure with oxygen-containing groups, while its strong hydrophilicity and water solubility limited its application in sample pretreatment techniques. Herein, GO was composited with polyethyleneglycol (PEG) or polyaniline (PAN) through intermolecular interactions to improve its stability, and the GO/PEG and GO/PAN composite coated stir bars were prepared by sol-gel technique. Compared with GO/PAN composite and polydimethylsiloxane (PDMS) coated stir bar, the prepared GO/PEG composite coated stir bar exhibited higher extraction efficiency for five fluoroquinolones (FQs). Based on it, a method of GO/PEG composite coated stir bar sorptive extraction (SBSE) combined with high performance liquid chromatography-fluorescence detector (HPLC-FLD) was proposed. The factors influencing SBSE, such as sample pH, salt effect, stirring rate, extraction time, desorption solvent and desorption time, were optimized, and the analytical performance of the developed SBSE-HPLC-FLD method was evaluated. The limits of detection (LODs) for five FQs were in the range of 0.0045-0.0079MUgL( 1), and the enrichment factors (EFs) were in the range of 41.5-65.5-fold (theoretical enrichment factor was 100-fold). The reproducibility was also investigated at concentrations of 0.05MUgL(-1) and the relative standard deviations (RSDs, n=6) were found to be in the range of 4.6-12.1%. The proposed method was successfully applied for the determination of FQs in chicken muscle and chicken liver samples. PMID- 26433264 TI - Comparison of nano and conventional liquid chromatographic methods for the separation of (+)-catechin-ethyl-malvidin-3-glucoside diastereoisomers. AB - Nano-liquid chromatography and conventional HPLC were used for the separation of diastereomers of (+)-catechin-ethyl-malvidin-3-glucoside. Those bridged anthocyanin dyes were obtained by reaction of (+)-catechin with malvidin-3 glucoside in the presence of acetaldehyde. Both diastereomers were isolated with semipreparative chromatography and their structures were confirmed by nuclear magnetic resonance and mass spectrometry. In-laboratory prepared capillary columns packed with fully porous particles Chromosphere C18, dp=3MUm, core-shell particles Kinetex C18, dp=2.6MUm (100MUm i.d.) and monolithic column Chromolith CapRod (100MUm i.d.) were used for the separation of (+)-catechin, malvidin-3 glucoside and both diastereomers. Chromosphere C18 stationary phase provided the best chromatographic performance. Mobile phase containing water:acetonitrile (80:20) acidified with trifluoroacetic acid (0.1%, v/v/v) was used in an isocratic elution mode with a flow rate of 360nLmin(-1). Separation of studied compounds was achieved in less than 7min under optimized conditions. The nano liquid chromatographic method and a conventional HPLC one using the same fully porous particles (Chromosphere C18, 3MUm, 100mm*4.6mm) were compared providing higher separation efficiency with the first analytical method and similar selectivity. A better peak symmetry and higher resolution of the studied diastereomers was achieved by conventional chromatography. Nevertheless, nano liquid chromatography appeared to be useful for the separation of complex anthocyanin dyes and can be utilized for their analysis in plant and food micro samples. The developed method was used for analysis of red wine grape pomace. PMID- 26433265 TI - Tadpole toxicity prediction using chromatographic systems. AB - Toxicity has been emulated in tadpole species through chromatographic systems. The parameter studied to evaluate the non-specific toxicity of a compound is the narcosis concentration (Cnar), which is defined as the concentration needed for the immobilization of the organism. Because experimental investigation with animals is lengthy, costly, technically difficult, and ethically questionable, there is a great interest in developing surrogate physicochemical systems able to emulate biological systems to obtain the same information in a faster, more economic, and easier manner. In order to see which chromatographic systems would be able to emulate tadpole narcosis, both, tadpole narcosis data and data in several chromatographic and electrophoretic systems, were fitted to a linear solvation energy relationship (LSER) model. Thus, by comparison of the models it was possible to see which of the chromatographic systems were more similar to the biological one. The physicochemical systems that best emulate tadpole narcosis were an HPLC system based on an immobilized artificial membrane (IAM) column, and two micellar electrokinetic chromatography (MEKC) systems based on sodium taurocholate (STC) and a mixture of sodium dodecylsulphate (SDS) and Brij 35 as surfactants. A system based on a RP18 HPLC column also was selected for comparison because it is a common column in most analytical laboratories. To establish the models, a set of compounds with known Cnar values were analyzed in the chromatographic, and electrophoretic selected systems and, then, the retention factor (k) was correlated to the concentration of narcosis. Statistics showed that the system based on STC micelles was the best to emulate toxicity in tadpoles. The robustness and predictive ability of the developed models were validated. PMID- 26433266 TI - Development of a subcritical water extraction approach for trace analysis of chloramphenicol, thiamphenicol, florfenicol, and florfenicol amine in poultry tissues. AB - Subcritical water extraction was investigated as a novel and alternative technology for the separation of trace amounts of chloramphenicol, thiamphenicol, florfenicol and its major metabolite florfenicol amine from poultry tissues and its results were compared with those of conventional shaking extraction, ultrasonic extraction, and pressurized liquid extraction. Decreasing the polarity of water by successively increasing the extraction temperature from 50 degrees C to 200 degrees C at the moderate pressure enabled selective, highly effective extractions to be performed. Rapid quantification of the target compounds was carried out by ultra-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS). The critical parameters of subcritical water extraction such as solvent modifier, temperature, pressure, extraction time, and static cycles were varied with control. The optimized extraction procedures using subcritical water as extraction solvent, were carried out on a pressurized liquid extractor operated at 150 degrees C and 100bar, applying two static cycles for 3min. Average recoveries of the four analytes from fortified samples ranged between 86.8% and 101.5%, with relative standard deviations (RSDs) lower than 7.7%. The limits of detection (LODs) and quantification (LOQs) for the target compounds were in the ranges of 0.03 0.5MUgkg(-1) and 0.1-2.0MUgkg(-1), respectively. The proposed method is fast, sensitive, water-based thus more environmental acceptable, making it a suitable replacement for conventional organic solvent extraction in veterinary drug residue analysis. PMID- 26433267 TI - Effect of gestational antiandrogen treatment on Dicer1 expression in the porcine fetal gonads. AB - Recently, we have demonstrated that flutamide-induced androgen deficiency during fetal life led to changes in gene expression that affected both testicular functions and follicular formation. It is known that microRNA-mediated genes regulation is essential for gonadal development and function. Thus, the aim of the present study was to examine whether prenatal flutamide exposure influences expression of Dicer1, an enzyme involved in microRNA maturation, in gonads of porcine fetuses during mid- and late gestation. Pregnant gilts were injected with flutamide (50mg/day/kg b.w.) or corn oil (controls) between days 43-49, 83-89 or 101-107 of gestation. The fetal gonads were obtained on gestational day 50 (GD50), 90 (GD90) or 108 (GD108). To assess Dicer1 mRNA expression real-time PCR were performed. Furthermore, immunohistochemical Dicer1 localization was conducted. In testes from flutamide treated fetuses, increased Dicer1 mRNA expression was observed in the GD50 and GD108 groups, but decreased in the GD90 group. Dicer1 was immunolocalized in the fetal Leydig cells in both control and flutamide-treated groups. In fetal ovaries, antiandrogen treatment increased Dicer1 mRNA level in the GD50 and GD90 groups. In control and flutamide-exposed groups, Dicer1 was localized in the germ cells within oogonia/oocyte nests as well as in the granulosa cells and oocytes of forming follicles. Concluding, diminished androgen action during gestation induces changes in Dicer1 mRNA expression, which may affect post-transcriptional gene regulation via miRNAs in porcine fetal gonads. However, it seems that androgens exert diverse biological effects depending on the gestational period. PMID- 26433268 TI - Chronic stress and antidepressant induced changes in Hdac5 and Sirt2 affect synaptic plasticity. AB - Changes in histone acetylation could contribute to the pathogenesis of depression and antidepressant therapy. Using the chronic social defeat stress (CSDS) model of depression and different antidepressant treatments we studied the regulation of histone deacetylases (Hdac's) and synaptic plasticity markers in the prefrontal cortex (PFC). Further, functional implication of identified Hdac's in brain plasticity was explored. Mice were exposed to CSDS (10 days) followed by saline or imipramine (4 weeks). PFC Hdac's mRNA abundance was studied and compared to human's. Further, protein expression of acetylated histones (AcH3 and AcH4), neuroplasticity markers (CREB and pro-BDNF) and selected Hdac's were analyzed. Moreover, other antidepressants (fluoxetine and reboxetine) and selective HDAC inhibitors were studied. CSDS increased Hdac5 and Sirt2 mRNA whereas repeated imipramine did the opposite. Accordingly, stress and imipramine induced opposite changes on AcH3, AcH4 and CREB expression. At protein level, CSDS upregulated nuclear fraction of Hdac5 and repeated imipramine and reboxetine increased its phosphorylated form (p-Hdac5), mainly located in the cytoplasm. Moreover, Sirt2 was downregulated by all monoaminergic antidepressants. Further, repeated treatment with the class IIa Hdac inhibitor MC1568 and the Sirt2 inhibitor 33i for three weeks increased synaptic plasticity in the prefrontal cortex. Our results suggest that Hdac5 and Sirt2 upregulation could constitute stable stress-induced neuronal adaptations. Noteworthy, the SIRT2 upregulation in depressed patients supports the interest of this target for therapeutic intervention. On the other hand, cytoplasmic Hdac5 export and Sirt2 downregulation induced by monoaminergic antidepressants could contribute to the well-known beneficial effects of antidepressants on brain plasticity. PMID- 26433269 TI - Familial Incidence of Cardiovascular Malformations in Hypoplastic Left Heart Syndrome. AB - Obstructive left-sided congenital heart lesions exhibit familial clustering, and familial echocardiographic screening for bicuspid aortic valve has become standard practice. Hypoplastic left heart syndrome (HLHS) is a severe left-sided obstructive lesion; however, familial screening is not universally recommended. The purpose of this study was to define the incidence of cardiovascular malformations (CVMs) in first-degree relatives of HLHS probands. First-degree relatives were screened for CVM by transthoracic echocardiography. Screening was completed in 152 family members (97 parents and 55 siblings) of 52 probands. Of these, 17 of 152 (11%) had CVM. Anomalies detected included: bicuspid aortic valve in 5 (3%), isolated dilated ascending aorta in 4 (3%), coarctation of the aorta in 1, partial anomalous pulmonary venous connection in 1, anomalous, intramural coronary artery in 1, bicuspid pulmonary valve in 1, and other anomalies in 4. Most were previously undiagnosed (11 of 17, 65%). Fourteen of 52 families (27%) had >=1 relative with CVM. Overall, 7 of 55 siblings (13%), 5 of 46 fathers (11%) and 5 of 51 mothers (10%) had CVM. Although the incidence of CVM in first-degree relatives of HLHS probands was lower in this cohort than previously reported, it remained substantial, with at least one additional member having CVM in 27% of families. The frequent occurrence of undiagnosed CVM highlights the importance of routine familial screening in HLHS. In fact, even if screening was done in childhood, it may be appropriate to screen again in the third or fourth decade to exclude isolated enlargement of the ascending aorta. PMID- 26433270 TI - Immediate and Long-Term Results of Drug-Eluting Stents in Mammary Artery Grafts. AB - Percutaneous intervention of a coronary graft is the treatment of choice when the graft fails. The objective is to report the long-term results of drug-eluting stents (DES) in mammary artery grafts (MAG). Patients who had been treated with DES for MAG in 27 centers were selected. The baseline and procedural clinical data were included prospectively, and the follow-up was performed with the patients, families, and medical records. Two hundred and sixty-eight patients were included: age 65.5 +/- 10.1 years, diabetes 47.8%, ejection fraction 55.5 +/ 14.9%. INDICATION: stable angina 28.4%, unstable angina 38.1%, non-ST-elevation myocardial infarction 21.6%, ST-elevation myocardial infarction 5.3%, and heart failure 6.7%; 1.19 +/- 0.59 stents/patient were implanted measuring 18.8 +/- 8.8 mm in length and 2.68 +/- 0.35 mm in diameter. Rapamycin was used in 78 cases (29.1%), paclitaxel in 77 (28.7%), everolimus in 70 (26.1%), zotarolimus in 34 (12.7%), and biolimus in 9 (3.4%). All cases were successful except for 1 in which the patient died 30 minutes after the procedure. There were no other inhospital events. After a follow-up of 41 months (Q25: 23.7 to Q75: 57.8), 24 patients (9%) died of heart-related causes and 20 (7.5%) of noncardiac causes. Repeat revascularization was necessary in 31 cases, and in 1 additional patient, there was total occlusion, which was not treated. These 32 patients represented 11.9% of the total. In conclusion, the implantation of DES in MAG shows very high procedural success and also low long-term event rates. PMID- 26433271 TI - What do grade school students and physicians have in common? PMID- 26433272 TI - Usefulness of the Left Anterior Descending Coronary Artery Wrapping Around the Left Ventricular Apex to Predict Adverse Clinical Outcomes in Patients With Anterior Wall ST-Segment Elevation Myocardial Infarction (from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction Trial). AB - The association between anatomic features of the left anterior descending artery (LAD) and outcomes in patients with anterior ST-segment elevation myocardial infarction (STEMI) has not been fully investigated. We sought to clarify the impact of an LAD coronary artery wrapping around the left ventricular (LV) apex on clinical outcomes in patients with anterior STEMI. Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction enrolled patients with STEMI presenting <12 hours after symptom onset who underwent primary percutaneous coronary intervention. Patients with a culprit lesion in the LAD were categorized as (1) LAD wrapping around the LV apex (wrap-around LAD, n = 871) versus (2) LAD not wrapping around the LV apex (non-wrap-around LAD, n = 224). Killip class >=II, dysrhythmia, and LV mural thrombi were more frequently observed in the wrap-around LAD group; LV ejection fraction was worse in the wrap around LAD group (54.5% vs 58.7%, p = 0.006). At 3 years of follow-up, major adverse cardiac events (death, stroke, or stent thrombosis, 12.7% vs 5.4%, p = 0.002), death (6.6% vs 3.2%, p = 0.052), stroke (1.9% vs 0.5%, p = 0.12), stent thrombosis (5.6% vs 2.3%, p = 0.047), and severe heart failure (4.5% vs 1.4%, p = 0.03) were more common in patients with a wrap-around LAD versus those with a non wrap-around LAD. Multivariate analysis indicated that a wrap-around LAD independently and significantly predicted major adverse cardiac events (hazard ratio 2.18, p = 0.02) and severe heart failure (odds ratio 3.31, p = 0.049) in patients with an anterior STEMI. In conclusion, a wrap-around LAD predicted adverse clinical outcomes at 3 years in patients with anterior STEMI who underwent primary percutaneous coronary intervention. PMID- 26433274 TI - Usefulness of Coronary Atheroma Burden to Predict Cardiovascular Events in Patients Presenting With Acute Coronary Syndromes (from the PROSPECT Study). AB - We investigated the relation between overall atheroma burden and clinical events in the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study. In PROSPECT, 660 patients (3,229 nonculprit lesions with a plaque burden >= 40% and complete intravascular ultrasound data) were divided into tertiles according to baseline percent atheroma volume (PAV: total plaque/vessel volume). Patients were followed for 3.4 years (median); major adverse cardiac events (MACE: death from cardiac causes, cardiac arrest, myocardial infarction, or rehospitalization because of unstable or progressive angina) were adjudicated to either culprit or nonculprit lesions. Compared with patients in low or intermediate PAV tertiles, patients in the high PAV tertile had the greatest prevalence of plaque rupture and radiofrequency thin-cap fibroatheroma (VH-TCFA) and the highest percentage of necrotic core volume; they were also more likely to have high-risk lesion characteristics: >= 1 lesion with minimal luminal area <= 4 mm(2), plaque burden >70%, and/or VH-TCFA. Three-year cumulative nonculprit lesion-related MACE was greater in the intermediate and high tertiles than in the low tertile (6.3% vs 14.7% vs 15.1%, low vs intermediate vs high tertiles, p = 0.009). On Cox multivariable analysis, insulin dependent diabetes (hazard ratio [HR] 3.98, p = 0.002), PAV (HR 1.06, p = 0.03), and the presence of >=1 VH-TCFA (HR 1.80, p = 0.02) were independent predictors of nonculprit MACE. In conclusion, increasing baseline overall atheroma burden was associated with more advanced, complex, and vulnerable intravascular ultrasound lesion morphology and independently predicted nonculprit lesion related MACE in patients with acute coronary syndromes after successful culprit lesion intervention. PMID- 26433273 TI - Relation of Pre-anthracycline Serum Bilirubin Levels to Left Ventricular Ejection Fraction After Chemotherapy. AB - Myocardial injury because of oxidative stress manifesting through reductions in left ventricular ejection fraction (LVEF) may occur after the administration of anthracycline-based chemotherapy (A-bC). We hypothesized that bilirubin, an effective endogenous antioxidant, may attenuate the reduction in LVEF that sometimes occurs after receipt of A-bC. We identified 751 consecutively treated patients with cancer who underwent a pre-A-bC LVEF measurement, exhibited a serum total bilirubin level <2 mg/dl, and then received a post-A-bC LVEF assessment because of symptomatology associated with heart failure. Analysis of variance, Tukey's Studentized range test, and chi-square tests were used to evaluate an association between bilirubin and LVEF changes. The LVEF decreased by 10.7 +/- 13.7%, 8.9 +/- 11.8%, and 7.7 +/- 11.5% in group 1 (bilirubin at baseline <=0.5 mg/dl), group 2 (bilirubin 0.6 to 0.8 mg/dl), and group 3 (bilirubin 0.9 to 1.9 mg/dl), respectively. More group 1 patients experienced >15% decrease in LVEF compared with those in group 3 (p = 0.039). After adjusting for age, coronary artery disease/myocardial infarction, diabetes mellitus, hematocrit, and the use of cardioactive medications, higher precancer treatment bilirubin levels and lesser total anthracycline doses were associated with LVEF preservation (p = 0.047 and 0.011, respectively). In patients treated with anthracyclines who subsequently develop symptoms associated with heart failure, pre-anthracycline treatment serum bilirubin levels inversely correlate with subsequent deterioration in post-cancer treatment LVEF. In conclusion, these results suggest that increased levels of circulating serum total bilirubin, an intrinsic antioxidant, may facilitate preservation of LVEF in patients receiving A-bC for cancer. PMID- 26433275 TI - Comparison of Outcomes of Transfemoral Transcatheter Aortic Valve Implantation Using a Minimally Invasive Versus Conventional Strategy. AB - Some centers, mostly in Europe, have demonstrated the feasibility of a minimally invasive strategy (MIS; i.e., local anesthesia and conscious sedation, performed in the cath laboratory without transesophageal echocardiography guidance). Nonetheless, the experience of MIS for TAVI using both commercially available valves is lacking in the United States. We, therefore, retrospectively studied all transfemoral TAVI cases performed at our institution between March 2011 and November 2014 to assess the safety and efficacy of MIS. Patients were dichotomized according to the strategy (MIS vs conventional strategy [CS]) used for the procedure. One hundred sixteen patients were included in the MIS group and 91 patients were included in the CS group. Baseline characteristics were similar, and procedural success was comparable (99.1% in MIS and 98.9% in CS, p = 1). One intraprocedural death occurred in each group, whereas conversion rates to general anesthesia were low (3.4%). Comparable device success was obtained. Rates of complications and >mild paravalvular leak before discharge were low and comparable. Length of hospital stay was significantly reduced in the MIS (median, 3.0 [2.0 to 5.0] days) compared with than that in CS group (median 6.0 days [3.5, 8.0]). At a median follow-up of 230 days, no significant difference in survival rate was detected (89% vs 88%, p = 0.9). On average, MIS was associated with remarkable cost saving compared with CS ($16,000/case). In conclusion, TAVI through MIS was associated with a shorter postprocedural hospital stay, lower costs, and similar safety profile while keeping procedural efficacy compared with CS. PMID- 26433276 TI - Prevalence of diabetes mellitus in patients With Takotsubo syndrome. PMID- 26433277 TI - Clinical Outcome and Cost Analysis of Sutureless Versus Transcatheter Aortic Valve Implantation With Propensity Score Matching Analysis. AB - Surgical sutureless and interventional transcatheter aortic valve prostheses are nowadays extensively adopted in high-risk elderly patients. An explorative analysis was carried out to compare the clinical outcome and costs associated to these approaches. Since 2010, a total of 626 patients were distributed between transcatheter aortic valve implantation (TAVI; n = 364) and sutureless (n = 262) groups. Patients of both groups were not comparable for clinical and surgical characteristics, but many patients were in a "gray zone"; therefore, a retrospective propensity score analysis was possible and performed. For the matched pair samples, postoperative, follow-up clinical data, and costs data were obtained. In-hospital death occurred in 5 patients in sutureless group and 3 patients in TAVI group (p = 0.36). Blood transfusions were higher in sutureless group (2.1 +/- 2.3 vs 0.4 +/- 1.0 U). TAVI group had a shorter intensive care unit and hospital stay (2.2 +/- 2.7 vs 3.2 +/- 3.5 days, p = 0.037; 12 +/- 6 vs 14 +/- 6 days, p = 0.017). No differences in postoperative neurologic (p = 0.361), renal (p = 0.106), or respiratory (p = 0.391) complications were observed between groups. At follow-up (24.5 +/- 13.8 months), 1 patient in sutureless group and 7 patients in TAVI group died (p = 0.032). Paravalvular leakage occurred more frequently in patients in TAVI group (35 [34%] vs 7 [6.9%]; p <0.001) with an impact on follow-up survival rate. The costs associated to the 2 procedures are similar when the cost of the device was excluded (p = 0.217). When included, the sutureless approach resulted a cost saving (?22,451 vs ?33,877, p <0.001). In conclusion, the patients in the "gray zone" record a satisfying clinical outcome after sutureless surgery and TAVI. Patients in the sutureless group endure more hospital complications, but TAVI entails a higher follow-up mortality. On the costs aspects, TAVI technologies are more expensive, and it reflects on higher overall hospital costs. PMID- 26433278 TI - Preface. PMID- 26433279 TI - Thirty years of progress in harmonizing and compiling food data as a result of the establishment of INFOODS. AB - The International Network of Foods Data Systems (INFOODS) has provided leadership on the development and use of food composition data for over 30years. The mission of INFOODS is the promotion of international participation, cooperation and harmonization in the generation, compilation and dissemination of adequate and reliable data on the composition of foods, beverages, and their ingredients in forms appropriate to meet the needs of various users. Achievements include the development of guidelines and standards, increased capacity development in generating and compiling food composition data, a food composition database management system, improvements in laboratory quality assurance, and development of several food composition databases and tables. Recently, INFOODS has led efforts to define and document food biodiversity. As new foods and food components come into prominence, and as analytical methods evolve, the activities of INFOODS will continue to advance the quality and quantity of food composition data globally into the future. PMID- 26433280 TI - FAO/INFOODS e-Learning Course on Food Composition Data. AB - The FAO/INFOODS e-Learning Course on Food Composition Data was developed to close existing knowledge gaps on food composition of professionals working with those data. It covers the important aspects of food composition, is based on instructional design, is highly interactive and comprises 14 lessons of approximate 10h duration. It was developed primarily for usage in universities, but also suits self-paced learning and blended learning programmes. It is available at: http://www.fao.org/infoods/infoods/training/en/ free-of-charge in English, as on-line version or CD-ROM. Feedback from users was very positive and universities start to incorporate it into their curricula. The translation into other languages and the implementation of a certification and assessment programme are envisaged. e-Learning is cost-effective and reaches a wide audience. The course is expected to contribute to the improved data quality, usage, generation, publication and appreciation of food composition data. PMID- 26433281 TI - Comparison of methods for iodine analysis in foods. AB - Spectrophotometric and ICP-MS methodology for iodine determination was compared. Samples were alkali dry-ashed, dissolved in water, and iodine assayed by spectrophotometry and by ICP-MS. Iodine content in the studied foods ranged from 3 to 1304MUg/100g. There was no significant difference (p>0.05) between iodine values determined spectrophotometrically using an external calibration curve and values determined using a standard addition. Foods containing low iodine concentrations (4-25MUg/100g) also showed no significant difference (p>0.05) between iodine concentrations determined spectrophotometrically and concentrations determined by ICP-MS. For food items with more than 25MUg/100g, the spectrophotometric methods yielded markedly higher (p<0.05) concentrations than the standard ICP-MS method (relative positive bias 25-122%), especially in foods with high sodium and/or iron contents. A catalytic effect of sodium and iron on the Sandell and Kolthoff reaction, leading to false high values in the spectrophotometric determination of iodine was demonstrated. ICP-MS is recommended for iodine determination in foods. PMID- 26433282 TI - Cholesterol determination in foods: Comparison between high performance and ultra high performance liquid chromatography. AB - Analytical methods for cholesterol evaluation in foods are crucial since this compound was closely related with cardiovascular disease. In the present study, two chromatographic methods were implemented and validated, in order to achieve the ideal analytical method for the quantification of cholesterol in food matrices. The developed methods were applied to different foodstuffs, sour cream, egg, egg yolk and chicken nuggets. Both HPLC and UHPLC methods are rapid, specific, sensitive, precise (RSD<2.5%) and accurate. The achieved LOD and LOQ for UHPLC were 0.7 and 2.4MUg/mL, respectively, while for HPLC were 3 and 11MUg/mL. UHPLC method allowed reduction of the organic solvents consumption (8 times lower) and decreased analysis time in 4min, being more eco-friendly, than conventional HPLC methods. Moreover, it will be very useful for the quality control of cholesterol content in food matrices and can be easily adopted by analytical laboratories. PMID- 26433283 TI - A simplified HPLC method for determination of tryptophan in some cereals and legumes. AB - In the present study, a simple analytical method is proposed for determining tryptophan, and method is validated on some cereal and legume samples. In the method alkaline hydrolysis of proteins was used due to the destruction of tryptophan structure during acid hydrolysis. Following alkaline hydrolysis (120 degrees C for 12h), hydrolysates are filtered through ashless filter paper and pH values are adjusted with hydrochloric acid solution. Separation and detection of tryptophan are performed on a reversed-phase column with fluorescence detection within 10min by using a mobile phase of acetonitrile and acetate buffer of pH 6.3 (1:9, v/v). For determination of tryptophan content, the procedure described in the study offers an alternative analysis method by enabling high speed analysis and the use of simple extraction process to the other available methods. PMID- 26433284 TI - Establishment and advances in the online Serbian food and recipe data base harmonized with EuroFIRTM standards. AB - Within the European Food Information Resource Network of Excellence (EuroFIR NoE; FP6) and EuroFIR Nexus (FP7) project paucity in food composition databases (FCDB) in the Central Eastern Europe/Balkan (CEE/B) region was identified. As a member of EuroFIR NoE, the Centre of Research Excellence in Nutrition and Metabolism, Serbia initiated creation of the 1st online Serbian FCDB employing EuroFIR quality framework and CEN Food Data Standard requirements, supporting capacity development and designing the web-based Food Composition Data Management (FCDM) software for FCDB building. The 1st online version of Serbian FCDB was launched in 2007, and then extended with food composition data from other Balkan countries (Balkan Food Platform-Regional FCDB). All foods are indexed using LanguaL Thesaurus and coded with EFSA FoodEx2 coding system. To date, upgraded Serbian FCDB with 1046 foods and 129 traditional/common Serbian composite dishes is a prerequisite for nutritional research in Serbia, CEE/B region and wider Europe. PMID- 26433285 TI - Review of food composition data for edible insects. AB - Edible insects are considered rich in protein and a variety of micronutrients, and are therefore seen as potential contributors to food security. However, the estimation of the insects' contribution to the nutrient intake is limited since data are absent in food composition tables and databases. Therefore, FAO/INFOODS collected and published analytical data from primary sources with sufficient quality in the Food Composition Database for Biodiversity (BioFoodComp). Data were compiled for 456 food entries on insects in different developmental stages. A total of 5734 data points were entered, most on minerals and trace elements (34.8%), proximates (24.5%), amino acids (15.3%) and (pro)vitamins (9.1%). Data analysis of Tenebrio molitor confirms its nutritive quality that can help to combat malnutrition. The collection of data will assist compilers to incorporate more insects into tables and databases, and to further improve nutrient intake estimations. PMID- 26433286 TI - Assessment of the nutritional composition of quinoa (Chenopodium quinoa Willd.). AB - Quinoa (Chenopodium quinoa Willd.) is an ancient crop which can play an important role for worldwide food security. The current review aimed at evaluating existing compositional data which were compiled according to international standards. A limited number of data were found that met the dataset quality criteria. In general, high variations in nutrient contents of quinoa were observed per 100g edible portion on fresh weight basis, for example: protein (9.1-15.7g), total fat (4.0-7.6g) and dietary fiber (8.8-14.1g). The variations of nutrient values among different varieties and among different data sources were considerable. The results show the nutritional potential of quinoa but they also demonstrate that more high-quality analytical data of quinoa are needed, especially for minerals and vitamins. PMID- 26433287 TI - Protein content and amino acids profile of pseudocereals. AB - Quinoa (Chenopodium quinoa), amaranth (Amaranthus caudatus) and buckwheat (Fagopyrum esculentum) represent the main protein source in several diets, although these pseudocereals are not currently present in the FCDB nutrient profile information. The aim of this work is to characterise the AA profile of these pseudocereals and compare them with rice. Total protein content revealed to vary from 16.3g/100g (quinoa Salta) to 13.1g/100g (buckwheat) and lower values were found in rice samples (6.7g/100g). For pseudocereals the most abundant essential AA was leucine. Quinoa-Salta evidences the highest leucine content (1013mg/100g) and the minor methionine content (199mg/100g). Buckwheat was the cereal with the highest phenylalanine content (862mg/100g). Rice (Oryza sativa) presents the lowest content for all AA. Results showed pseudocereals as the best source of AA. EuroFIR guidelines where strictly followed and proved to be a crucial tool to guarantee data interchangeability and comparability. PMID- 26433288 TI - Aibika (Abelmoschus manihot L.): Genetic variation, morphology and relationships to micronutrient composition. AB - Aibika (Abelmoschus manihot L.) is believed to be a good source of micronutrients. However, although many varieties of aibika are commonly consumed in Papua New Guinea, their micronutrient content is unknown. Therefore, the mineral (Ca, Fe, K, Mg, Mn, Na, Zn & Cu), folate composition and the genetic variation of 23 aibika accessions from the collection at the National Agricultural Research Institute were studied over a 3year period to provide data for nutritional studies and to inform breeding programs. The data showed that aibika is, potentially, a crop of high nutritional value with the potential to boost the micronutrient status of local PNG communities. However, there were substantial differences in the micronutrient concentrations of the accessions from year to year and accessions that had the highest concentration of a particular mineral in 1year did not have the high concentrations in other years. Clusters determined using unweighted pair group method with arithmetic mean analysis (UPGMA) of the micronutrient contents differed in each of the 3years. Genetic analysis made using random amplification of polymorphic DNA and directed amplification of mini satellite region DNA placed the accessions into five groups. There was no correlation between these groups and leaf morphology, nor were there correlations with the clusters determined from the UPGMA analyses. There appears to be considerable interaction between genotype and environmental factors determining micronutrient composition and environmental factors may play a greater role than genotype in influencing micronutrient composition. PMID- 26433289 TI - EuroFIR quality approach for managing food composition data; where are we in 2014? AB - A EuroFIR quality management framework was developed to assure data quality of food composition data, incorporating several recommendations developed or improved during the EuroFIR projects. A flow chart of the compilation process with standard operating procedures to assure critical steps was the starting point. Recommendations for food description, component identification, value documentation, recipe calculation, quality evaluation of values, guidelines to assess analytical methods, document and data repositories and training opportunities were harmonized as elements of the quality framework. European food composition database organizations reached consensus on the EuroFIR quality framework and started implementation. Peer reviews of the European compiler organizations were organized to evaluate the quality framework, focusing on what was achieved and on improvements needed. The reviews demonstrated that European food database compilers have made good use of standards and guidelines produced by EuroFIR, as well as a common understanding that a quality framework is essential to assure food composition data quality. PMID- 26433290 TI - Improving food composition data quality: Three new FAO/INFOODS guidelines on conversions, data evaluation and food matching. AB - Food composition data play a key role in many sectors and the availability of quality data is critically important. Since 1984, the International Network of Food Data Systems (INFOODS) has been working towards improving food composition data quality and availability, including the development and updating of standards, guidelines and tools for food composition. FAO/INFOODS has recently published three comprehensive guidelines to improve and harmonise the compilation of data: (1) Guidelines for Food Matching, (2) Guidelines for Checking Food Composition Data prior to Publication of a User Table/Database, and (3) Guidelines for Converting Units, Denominators and Expressions. This article describes their content and development processes. Their adoption, along with additional ones planned for the future by FAO/INFOODS, should further improve the quality of published food composition data, which in turn can lead to more accurate nutrient intake estimates and more precise food labels, as well as better-targeted programs and policies. PMID- 26433291 TI - EuroFIR guidelines for assessment of methods of analysis: GAMA. AB - Analytical methodology is a key factor in food composition databases and specific criteria, at the component level, is needed for comparison of analytical data from different sources. The aim of this work is to describe how EuroFIR guidelines for assessment of methods of analysis are created and made available to users. Comprehensive information for macronutrients, vitamins, minerals and trace elements addressing all aspects of analytical procedures was obtained from international standards, and scientific literature. Documentation was compiled in a confluence wiki format provided for each component: background information, description of reference methods of analysis and critical steps, available reference materials, proficiency testing schemes, other analytical methods and relevant references. The information for each nutrient was collated, edited and presented with hypertext links to additional pages where more detailed information can be accessed using full text searches. The wiki format is a useful tool for preparing information and disseminating to users. PMID- 26433292 TI - Implementing the EuroFIR Document and Data Repositories as accessible resources of food composition information. AB - The EuroFIR Document and Data Repositories are being developed as accessible collections of source documents, including grey literature, and the food composition data reported in them. These Repositories will contain source information available to food composition database compilers when selecting their nutritional data. The Document Repository was implemented as searchable bibliographic records in the Europe PubMed Central database, which links to the documents online. The Data Repository will contain original data from source documents in the Document Repository. Testing confirmed the FoodCASE food database management system as a suitable tool for the input, documentation and quality assessment of Data Repository information. Data management requirements for the input and documentation of reported analytical results were established, including record identification and method documentation specifications. Document access and data preparation using the Repositories will provide information resources for compilers, eliminating duplicated work and supporting unambiguous referencing of data contributing to their compiled data. PMID- 26433293 TI - Total and haem iron content lean meat cuts and the contribution to the diet. AB - This study provides data on the total and haem iron contents in raw lean beef, chicken, lamb and pork meat samples. Total iron, expressed as mg/100g edible portion on fresh weight basis in raw lean beef (A-age), lamb, pork and chicken average 1.58, 1.64, 0.81 and 0.78, respectively. The haem iron content in beef (A age), lamb, pork and chicken are 77%, 81%, 88% and 74% respectively of total iron. This has important dietary implications in calculating haem iron fractions of meat as this is higher than the common value used in the Monsen equation. PMID- 26433294 TI - Inulin content of fortified food products in Thailand. AB - This study examined inulin content in 266 samples. They were 126 dried, 105 liquid and 27 semi-solid of twelve commercial inulin fortified food products and 8 samples of natural dried sunchoke. For dried food products, inulin content ranged from 3.0 +/-0.8g/100g fresh weight (FW) in milk powder to 83.7+/- 17.8g/100g FW in inulin powder. The levels in a descending order are the powder of inulin, weight control diet, coffee mixed, instant beverage, supplemented food products for pregnant and milk. For liquid fortified foods, inulin at the level of 0.3+/- 0.1g/100mL FW was found in UHT milk, and up to 13.5+/- 4.1g/100mL FW in weight control diet beverage. The level of 2.0-2.3g/100g FW of inulin was found in beverage with different flavours, soybean milk and fruit juice. For semi-solid food, cream yoghurt, inulin at 3.9+/- 1.1g/100g FW was found. A serving of most products contributes inulin at 11-33% of the recommended daily intake of dietary fibre. PMID- 26433295 TI - Australian seafood compositional profiles: A pilot study. Vitamin D and mercury content. AB - Given the scarcity of comprehensive nutritional data for Australia's >400 commercially produced seafood species a pilot study was undertaken to collect and analyse 22 species of wild and aquaculture seafood in order to develop a model for future comprehensive surveys. The species analysed were: Atlantic salmon, Australian sardine, prawn (six species), barramundi, abalone (three species), blue sprat, burrowing blackfish, gummy shark, oyster (four species), ocean trout and yellowtail kingfish. The analyses undertaken in this pilot study were: moisture, protein, total fat, cholesterol, fatty acids, vitamin C, vitamins A and D, and 21 mineral elements (including total mercury and methyl mercury). The data reported here are for vitamin D and mercury only. Comprehensive data have already been published elsewhere. Issues identified that should be addressed prior to undertaking a more extensive and representative study of the remaining major edible commercial Australian seafood species include: choice of samples and nutrients for analysis, facilities for sample handling and storage, data management and scrutiny, and laboratory quality control. PMID- 26433296 TI - Report on the development of the FAO/INFOODS user database for fish and shellfish (uFiSh) - Challenges and possible solutions. AB - Reliable food composition data are required for virtually all nutrition-related programs and policies. In many food composition tables, fish are included to a limited extent. Therefore, FAO/INFOODS decided to compile and publish a user databases for fish and shellfish (uFiSh), considering the following main objectives: to develop a global database for fish, crustaceans and molluscs with raw, cooked and processed foods; to base the database preferable on analytical data; to include major as well as minor species consumed; and to capture intra species variation due to habitat, edible part, season or region. The development of the uFiSh is based on FAO/INFOODS international standards and guidelines. The paper describes challenges and possible solution of data compilation specific to fish and shellfish, as well as the uFiSh in terms of its structure, including coverage of nutrients, documentation and format of publication. The first edition is intended to be published in 2015. PMID- 26433298 TI - Impact of dietary fiber energy on the calculation of food total energy value in the Brazilian Food Composition Database. AB - Dietary fiber (DF) contributes to the energy value of foods and including it in the calculation of total food energy has been recommended for food composition databases. The present study aimed to investigate the impact of including energy provided by the DF fermentation in the calculation of food energy. Total energy values of 1753 foods from the Brazilian Food Composition Database were calculated with or without the inclusion of DF energy. The energy values were compared, through the use of percentage difference (D%), in individual foods and in daily menus. Appreciable energy D% (?10) was observed in 321 foods, mainly in the group of vegetables, legumes and fruits. However, in the Brazilian typical menus containing foods from all groups, only D%<3 was observed. In mixed diets, the DF energy may cause slight variations in total energy; on the other hand, there is appreciable energy D% for certain foods, when individually considered. PMID- 26433297 TI - ePlantLIBRA: A composition and biological activity database for bioactive compounds in plant food supplements. AB - The newly developed ePlantLIBRA database is a comprehensive and searchable database, with up-to-date coherent and validated scientific information on plant food supplement (PFS) bioactive compounds, with putative health benefits as well as adverse effects, and contaminants and residues. It is the only web-based database available compiling peer reviewed publications and case studies on PFS. A user-friendly, efficient and flexible interface has been developed for searching, extracting, and exporting the data, including links to the original references. Data from over 570 publications have been quality evaluated and entered covering 70 PFS or their botanical ingredients. PMID- 26433299 TI - Compilation of a standardised international folate database for EPIC. AB - This paper describes the methodology applied for compiling an "international end user" folate database. This work benefits from the unique dataset offered by the European Prospective Investigation into Cancer and Nutrition (EPIC) (N=520,000 subjects in 23 centres). Compilation was done in four steps: (1) identify folate free foods then find folate values for (2) folate-rich foods common across EPIC countries, (3) the remaining "common" foods, and (4) "country-specific" foods. Compiled folate values were concurrently standardised in terms of unit, mode of expression and chemical analysis, using information in national food composition tables (FCT). 43-70% total folate values were documented as measured by microbiological assay. Foods reported in EPIC were either matched directly to FCT foods, treated as recipes or weighted averages. This work has produced the first standardised folate dataset in Europe, which was used to calculate folate intakes in EPIC; a prerequisite to study the relation between folate intake and diseases. PMID- 26433300 TI - Validation of a sampling plan to generate food composition data. AB - A methodology to develop systematic plans for food sampling was proposed. Long life whole and skimmed milk, and sunflower oil were selected to validate the methodology in Argentina. Fatty acid profile in all foods, proximal composition, and calcium's content in milk were determined with AOAC methods. The number of samples (n) was calculated applying Cochran's formula with variation coefficients ?12% and an estimate error (r) maximum permissible ?5% for calcium content in milks and unsaturated fatty acids in oil. n were 9, 11 and 21 for long life whole and skimmed milk, and sunflower oil respectively. Sample units were randomly collected from production sites and sent to labs. Calculated r with experimental data was ?10%, indicating high accuracy in the determination of analyte content of greater variability and reliability of the proposed sampling plan. The methodology is an adequate and useful tool to develop sampling plans for food composition analysis. PMID- 26433301 TI - Voluntary fortification with folic acid in Spain: An updated food composition database. AB - Folic acid (FA) is a key vitamin in the prevention of many diseases including neural tube defects. In Spain, only voluntary FA food fortification is allowed and there is a lack of compositional data to assess the contribution of these products to population's dietary folate intakes. Since 2007, our group has been compiling and updating a FA fortified food composition database. FA levels were obtained from retailers in Madrid and information provided by manufacturers. FA was also quantified by an affinity chromatography-HPLC method. In the present study we recorded 375 products. Our results show a high variability in the declared FA levels amongst different products, and food groups, which is also dependant on the commercial brand. FA overages are commonly added by manufacturers to some fortified products. FA content label claims are missing in 64% of products. This database is a useful tool to manage FA fortified foods data but it is necessary to continuously update it for the sound evaluation and monitoring of population's FA dietary intakes. PMID- 26433302 TI - Nutrient and phytochemical composition of two varieties of Monkey kola (Cola parchycarpa and Cola lepidota): An underutilised fruit. AB - The nutrient and phytochemical composition of two varieties of Monkey kola: Cola parchycarpa and Cola lepidota were determined. The pulps were extracted, grated and dried using solar dryer. Dried pulps were milled into flour with attrition milling machine (0.5mm sieve size). The nutrient compositions were determined using standard AOAC methods. Gravimetric and spectrophotometric methods were used for phytochemical determinations. There were significant (p<0.05) differences in the proximate and some mineral and vitamin composition of the two varieties. Most abundant minerals were calcium (195-199mg for C. parchycarpa), potassium (204 209mg/100g for C. lepidota) and beta-carotene (2755-5028MUg/100g for C. parchycarpa). Calcium:phosphorus and sodium:potassium ratios were adequate (>1.0 and ?0.06, respectively). Monkey kola had substantial amounts of iron, zinc, and copper; the B-vitamins and vitamin C. The phytochemical contents were quiet high, the most abundant being flavonoids (415-494mg/100g). Monkey kola is a fruit that should be fully exploited for its potential health benefits. PMID- 26433303 TI - Effect of animal age and trimming practices on the physical composition of Bonsmara beef. AB - Increased economic incentive for producing young and leaner carcasses, as well as demand for lean meat from progressively health conscious consumers, are considered drivers for change in carcass composition over time. Furthermore, many retailers trim visible fat from meat to various degrees and consumers increasingly remove visible fat from meat prior to, or after, cooking. The objective of this study was to determine the composition of South African Bonsmara beef from four age groups from different production systems, as well as to extrapolate the effect of fat trimming on physical composition. Fat content of marketable beef has decreased notably since the 1930s, and beef from the South African Bonsmara breed contains less than 10g lipid per 100g after trimming of subcutaneous fat, irrespective of age. Removal of all visible fat reduces the lipid content to less than 5g per 100g, comparing favourably with other lean animal products. PMID- 26433304 TI - A scope classification of data quality requirements for food composition data. AB - Data quality is an important issue when managing food composition data since the usage of the data can have a significant influence on policy making and further research. Although several frameworks for data quality have been proposed, general tools and measures are still lacking. As a first step in this direction, we investigated data quality requirements for an information system to manage food composition data, called FoodCASE. The objective of our investigation was to find out if different requirements have different impacts on the intrinsic data quality that must be regarded during data quality assessment and how these impacts can be described. We refer to the resulting classification with its categories as the scope classification of data quality requirements. As proof of feasibility, the scope classification has been implemented in the FoodCASE system. PMID- 26433305 TI - Improving nutrition surveillance and public health research in Central and Eastern Europe/Balkan Countries using the Balkan Food Platform and dietary tools. AB - The objective of this paper is to share experience and provide updated information on Capacity Development in the Central and Eastern Europe/Balkan Countries (CEE/BC) region relevant to public health nutrition, particularly in creation of food composition databases (FCDBs), applying dietary intake assessment and monitoring tools, and harmonizing methodology for nutrition surveillance. Balkan Food Platform was established by a Memorandum of Understanding among EuroFIR AISBL, Institute for Medical Research, Belgrade, Capacity Development Network in Nutrition in CEE - CAPNUTRA and institutions from nine countries in the region. Inventory on FCDB status identified lack of harmonized and standardized research tools. To strengthen harmonization in CEE/BC in line with European research trends, the Network members collaborated in development of a Regional FCDB, using web-based food composition data base management software following EuroFIR standards. Comprehensive nutrition assessment and planning tool - DIET ASSESS & PLAN could enable synchronization of nutrition surveillance across countries. PMID- 26433306 TI - Nutrients and bioactive compounds in popular and indigenous durian (Durio zibethinus murr.). AB - This study identified nutrients, fatty acids, bioactive compounds and antioxidant activities of two popular varieties (Mon-thong, Cha-ni) and two indigenous varieties (Kra-dum and Kob-ta-kam) of durian. Each of variety was collected from 3 gardens in Nonthaburi province, Thailand. At optimal ripeness, the edible part was separated, homogenised or freeze dried, as fresh or dry samples for further analysis using standard methods. All durian varieties contained a considerable amount of dietary fibre (7.5-9.1g/100g dry matter, DM) and high amounts of carbohydrate and sugar (62.9-70.7g and 47.9-56.4g/100g DM respectively). Cha-ni, Kra-dum and Kob-ta-kam varieties had monounsaturated (MUFA) (6.1-7.8g/100g DM)>saturated (SFA) (4.2-5.7g/100g DM)>polyunsaturated fatty acid (PUFA) (0.8 1.5g/100g DM), whereas the Mon-thong variety had SFA>MUFA>PUFA (5.1, 4.0, 1.1g/100g DM, respectively). The Kob-ta-kam variety showed greater potential for health benefits in terms of carotenoids and beta-carotene (2248MUg and 1202MUg/100g DM respectively). Phenolic compounds and antioxidant capacity were not significantly different among each variety, though the Cha-ni variety had the lowest. This study provides data on nutrients, bioactive compounds and antioxidant activities of indigenous and popular durian varieties that could be used for consumer education as well as for incorporation into the food composition databases. PMID- 26433307 TI - Nutritional and phytochemical composition of Annona cherimola Mill. fruits and by products: Potential health benefits. AB - Annona cherimola Mill., commonly known as cherimoya, is a tropical fruit well known due to its tasty flavour. In the present study the antioxidant activity of pulp, peel and seeds of four cultivars from A. cherimola Mill. from Madeira Island (Madeira, Funchal, Perry Vidal and Mateus II) was analysed. Moreover, nutritional composition (proximates and vitamins) and bioactive compounds content were determined. The peel of Madeira cultivar showed the highest antioxidant capacity, with an EC50 of 0.97mg/mL, and total flavonoids (44.7 epicatechin equivalents/100g). The most abundant carotenoid was lutein, with values ranging from 129 to 232MUg/100g. The highest l-ascorbic acid content (4.41mg/100g) was found in the peel of Perry Vidal cultivar. These results highlight A. cherimola Mill. antioxidant properties, especially in its by-products and encourage their application in cosmetic, pharmaceutical and food processing industries, as added value natural extracts. PMID- 26433308 TI - The use of food composition data in the Choices International Programme. AB - Food composition data have extensively been used in the Choices International Programme: they formed the basis of both criteria development and nutrient intake modeling. Criteria were developed for key nutrients linked to non communicable diseases by an independent scientific committee. The criteria can be used for the logo assignment on food products, in order to stimulate producers to improve their products and to stimulate consumers to purchase these products. Insights in steps of development of the criteria for the Choices program illustrates the importance of food composition data in this process. Modeling studies with the criteria for the Dutch Choices program showed an improved nutrient intake profile if consumers would choose products fulfilling the criteria of the Dutch logo as part of their diets. The role and availability of food composition databases in the development of the criteria and the modeling studies is discussed. PMID- 26433309 TI - [Testosterone deficiency, metabolic syndrome and diabetes mellitus]. AB - Testosterone deficiency in adult age is associated with a decrease in libido, energy, hematocrit, muscle mass and bone mineral density, as well as with depression. More recently, testosterone deficiency has also been associated with various components of the metabolic syndrome, which in turn is associated with a five-fold increase in the risk of cardiovascular disease. Low testosterone levels are associated with increased insulin resistance, increase in fat mass, low HDL cholesterol, higher triglyceride levels and hypertension. Testosterone replacement therapy in patients with testosterone deficiency and type 2 diabetes mellitus and/or metabolic syndrome has shown reductions in insulin resistance, total cholesterol, LDL cholesterol and triglycerides and improvement in glycemic control and anthropometric parameters. PMID- 26433310 TI - [Post-thrombotic syndrome: A pending issue]. PMID- 26433311 TI - [Primary cutaneous amyloidosis of the external ear: A peculiar, unusual and benign entity]. PMID- 26433313 TI - Next-Generation Sequencing for Infectious Disease Diagnosis and Management: A Report of the Association for Molecular Pathology. AB - Next-generation sequencing (NGS) technologies are increasingly being used for diagnosis and monitoring of infectious diseases. Herein, we review the application of NGS in clinical microbiology, focusing on genotypic resistance testing, direct detection of unknown disease-associated pathogens in clinical specimens, investigation of microbial population diversity in the human host, and strain typing. We have organized the review into three main sections: i) applications in clinical virology, ii) applications in clinical bacteriology, mycobacteriology, and mycology, and iii) validation, quality control, and maintenance of proficiency. Although NGS holds enormous promise for clinical infectious disease testing, many challenges remain, including automation, standardizing technical protocols and bioinformatics pipelines, improving reference databases, establishing proficiency testing and quality control measures, and reducing cost and turnaround time, all of which would be necessary for widespread adoption of NGS in clinical microbiology laboratories. PMID- 26433312 TI - Aberrant Levels of miRNAs in Bone Marrow Microenvironment and Peripheral Blood of Myeloma Patients and Disease Progression. AB - The bone marrow (BM) microenvironment of multiple myeloma (MM) is reported to play a role in the biology of disease. In this study, we found that the extracellular BM microenvironment in MM contains a unique miRNA signature detectable by miRNA microarray and quantitative real-time PCR, which is partially represented in the peripheral blood. Eleven miRNAs were significantly decreased in both BM and serum of MM patients in comparison with controls. Evaluation of these miRNAs in plasma of a separate cohort of MM patients and controls confirmed significantly aberrant levels of let-7a, let-7b, let-7i, miR-15b, miR-16, and miR 20a in both serum and plasma. We then studied the myeloma precursor diseases and found that a subset of the MM miRNAs exhibited aberrant expression in monoclonal gammopathy of undetermined significance and smoldering myeloma. miRNA analysis of enriched CD138(+) plasma cells from MM and monoclonal gammopathy of undetermined significance found that most of the validated MM BM signature miRNAs were significantly decreased in MM plasma cells. Gene expression profiling indicated that multiple targets of the decreased miRNAs found increased expression in MM plasma cells, including ATF2, HRAS, HDAC4, TGFB1, TGFBR1, and mitogen-activated protein kinases. The findings suggest that these miRNAs are detectable in aberrant levels in the peripheral blood of patients with plasma cell proliferation and may play a role in aberrant plasma cell proliferation and disease progression. PMID- 26433315 TI - [Early epithelial lesions in prophylactic annexectomies in patients at high risk of ovarian cancer: Report of a series of 93 cases]. AB - OBJECTIVE: Tubal lesions detected in specimen of risk reducing salpingo oophorectomy (RRSO) for mutation BRCA1/2 seems to play a role in ovarian carcinogenesis. The main objective of this study is to evaluate the prevalence of occult neoplasia, of Serous Tubal Intraepithelial Carcinoma (STIC), and signature P53 in a cohort of patients who underwent a risk reducing salpingo oophorectomy. METHODS: From January 2010 to January 2014 unicentric, retrospective study on a consecutive cases cohort of RRSO for patients with a high risk of ovarian neoplasia (mutation BRCA 1/2 or family history). Pathological specimen should be analysed according to the SEE-FIM protocol. RESULTS: Ninety-three RRSO were recorded. Among them, 44% of the patients had the germ line mutation BRCA1, 30.1% BRAC2 and 18.2% had no identified mutation. In all, 33.3% of the RRSO reveal a signature P53, in the fimbria for 93.9%, 7.9% of them were bilateral. 1,10/00 (n=1) of the patients presented a unilateral STIC. We obtained 4.3% of occult neplasia: 3 ovarian high-grade serous carcinomas and 1 tubal high-grade serous carcinoma. Only the tubal carcinoma coexists with STIC. CONCLUSION: 5,4% of the patients who underwent RRSO had a diagnostic of occult neoplasia. One percent of the patients had an isolated STIC. These results agree with recent data of the literature. Extensive examination of the Fallopian tube opens up a new way to understand ovarian carcinogenesis. PMID- 26433316 TI - [Social inequalities in maternal health]. AB - Although medical literature on social inequalities in perinatal health is qualitatively heterogeneous, it is quantitatively important and reveals the existence of a social gradient in terms of perinatal risk. However, published data regarding maternal health, if also qualitatively heterogeneous, are relatively less numerous. Nevertheless, it appears that social inequalities also exist concerning severe maternal morbidity as well as maternal mortality. Analyses are still insufficient to understand the mechanisms involved and explain how the various dimensions of the women social condition interact with maternal health indicators. Inadequate prenatal care and suboptimal obstetric care may be intermediary factors, as they are related to both social status and maternal outcomes, in terms of maternal morbidity, its worsening or progression, and maternal mortality. PMID- 26433317 TI - Medial thighplasty: Current concepts and practices. AB - Medial thighplasty, also known as medial thigh lift, is a procedure that has been carried out for five decades. The original "Lewis" technique has undergone many changes, and thereby been rendered widely available to plastic surgeons. Given the increasingly high number of surgical reconstructions after massive weight loss, this technique is now an integral part of a surgeon's therapeutic arsenal as he strives to meet the evolving demands of patients. The objective of this article, which is based on a comprehensive review of the literature, is to summarize current knowledge on medial thighplasty and thereby allow plastic surgeons to adopt the operating technique best suited to the deformations presented by their patients and to the overall context. The different techniques, outcomes and complications are successively discussed. PMID- 26433319 TI - Is it time for treat to target in psoriatic arthritis? PMID- 26433318 TI - Effect of tight control of inflammation in early psoriatic arthritis (TICOPA): a UK multicentre, open-label, randomised controlled trial. AB - BACKGROUND: Early intervention and tight control of inflammation optimise outcomes in rheumatoid arthritis but these approaches have not yet been studied in psoriatic arthritis. We aimed to assess the effect of tight control on early psoriatic arthritis using a treat-to-target approach. METHODS: For this open label multicentre randomised controlled trial, adult patients (aged >=18 years) with early psoriatic arthritis (<24 months symptom duration), who had not previously received treatment with any disease-modifying anti-rheumatic drugs, were enrolled from eight secondary care rheumatology centres in the UK. Enrolled patients were randomly assigned in a 1:1 ratio to receive either tight control (with review every 4 weeks and with escalation of treatment if minimal disease activity criteria not met) or standard care (standard therapy according to the treating clinician, with review every 12 weeks) for 48 weeks. Randomisation was done by minimisation incorporating a random element, to ensure treatment groups were balanced for randomising centre and pattern of arthritis (oligoarticular vs polyarticular). The randomisation procedure was done through a central 24-h automated telephone system based at the Leeds Institute of Clinical Trials Research (Leeds, UK). This was an open-label study in which patients and clinicians were aware of treatment group assignment. Clinical outcomes were recorded by a masked assessor every 12 weeks. The primary outcome was the proportion of patients achieving an American College of Rheumatology (ACR) 20% (ACR20) response at 48 weeks, analysed by intention to treat with multiple imputation for missing ACR components. Cost-effectiveness was also assessed. This trial is registered with ClinicalTrials.gov, number NCT01106079, and the ISCRCTN registry, number ISCRCTN30147736. FINDINGS: Between May 28, 2008, and March 21, 2012, 206 eligible patients were enrolled and randomly assigned to receive tight control (n=101) or standard care (n=105). In the intention-to-treat patient population, the odds of achieving an ACR20 response at 48 weeks were higher in the tight control group than in the standard care group (odds ratio 1.91, 95% CI 1.03-3.55; p=0.0392). Serious adverse events were reported by 20 (10%) patients (25 events in 14 [14%] patients in the tight control group and eight events in six [6%] patients in the standard care group) during the course of the study. No unexpected serious adverse events or deaths occurred. INTERPRETATION: Tight control of psoriatic arthritis disease activity through a treat-to-target approach significantly improves joint outcomes for newly diagnosed patients, with no unexpected serious adverse events reported. FUNDING: Arthritis Research UK and Pfizer. PMID- 26433320 TI - Editorial overview: Protein design and evolution-new protein architectures, evolutionary fine-tuning and analysis. PMID- 26433321 TI - The International Conference on Radioecology and Environmental Radioactivity, 2014, (ICRER-2014). PMID- 26433322 TI - Nipple discharge: The role of imaging. AB - Nipple discharge is a common symptom in breast medicine. It is usually benign in origin (papillomas and galactophore duct ectasia) although it is essential not to miss the risk of an underlying malignant lesion (5%) mostly due to in situ carcinomas. Clinical examination is essential in the management, distinguishing benign "physiological" discharge from discharge suspected of being "pathological" in which further investigations with mammography and ultrasound are required. When the conventional imaging assessment for pathological nipple discharge is normal, breast MRI is gradually replacing galactography although this is still an emerging and invalidated indication. In this context and if the whole imaging assessment is normal, surgery is no longer the only solution for patients, who can now be offered regular monitoring. PMID- 26433323 TI - Image-guided percutaneous internal fixation of sacral fracture. AB - Percutaneous iliosacral screw placement is a technically challenging procedure with a significant complication profile for misplaced screws. The use of stereotactic image guidance has been shown to provide superior accuracy in the placement of spinal instrumentation. Here, the authors describe a novel application of O-arm technology (Medtronic Sofamor Danek, Memphis, TN, USA) to help safely place iliosacral screws for the treatment of a traumatic sacral fracture. PMID- 26433324 TI - The vagaries of proper imaging in diagnosing single-system ectopic ureter in children with continuous incontinence and outcomes of simple nephrectomy. AB - PURPOSE: To investigate the proper diagnostic modalities and failure cases of treatment in patients with single-system ectopic ureter (SSEU) who underwent nephrectomy for incontinence. METHODS: SSEU combined with dysplastic kidney is a rare cause of female incontinence. We retrospectively analyzed 45 pediatric SSEU patients that underwent simple nephrectomy at our institution during 1996-2013 for incontinence. We reviewed imaging studies to detect dysplastic kidney and ectopic ureter insertion, postoperative results, and urodynamic findings for remaining incontinence after nephrectomy. RESULTS: Median operative age was 59.3months. Both ultrasonography and magnetic resonance imaging (MRI) showed 50.0% dysplastic kidney detection rates respectively. Dimercaptosuccinic acid (DMSA) scanning and computerized tomography (CT) showed equal detection rates of 95.5%. Ectopic ureter insertion sites were determined by ultrasonography, CT, and MRI in 17.5%, 13.6%, and 33.3% of patients, respectively. Renal vascular structures were identified in 3/22 patients (13.6%) with CT. Post-nephrectomy, incontinence disappeared in 41 patients (91.1%), but remained in 4 patients (8.9%); urodynamics suggested bladder neck incompetence in these patients. CONCLUSIONS: DMSA is a highly sensitive diagnostic modality for detecting dysplastic kidney in SSEU patients with more than 95% detection rates. Once detected by DMSA, additional CT or MRI studies do not provide further information about ectopic ureter insertion or renal vascular structure. Although nephrectomy is successful in nearly 90% of SSEU patients with dysplastic kidneys, postoperative incontinence occasionally remains and requires additional treatment. PMID- 26433325 TI - The neuroendocrine response to stress under the effect of drugs: Negative synergy between amphetamine and stressors. AB - There have been numerous studies into the interaction between stress and addictive drugs, yet few have specifically addressed how the organism responds to stress when under the influence of psychostimulants. Thus, we studied the effects of different acute stressors (immobilization, interleukin-1beta and forced swimming) in young adult male rats simultaneously exposed to amphetamine (AMPH, 4 mg/kg SC), evaluating classic biological markers. AMPH administration itself augmented the plasma hypothalamic-pituitary-adrenal (HPA) hormones, adrenocorticotropin (ACTH) and corticosterone, without affecting plasma glucose levels. By contrast, this drug dampened the peripheral HPA axis, as well as the response of glucose to the three stressors. We also found that AMPH administration completely blocked the forced swim-induced expression of the corticotropin-releasing hormone (hnCRH) and it partially reduced c-fos expression in the paraventricular nucleus of the hypothalamus (PVN). Indeed, this negative synergy in the forced swim test could even be observed with a lower dose of AMPH (1mg/kg, SC), a dose that is usually received in self-administration experiments. In conclusion, when rats that receive AMPH are subjected to stress, a negative synergy occurs that dampens the prototypic peripheral physiological response to stress and activation of the PVN. PMID- 26433326 TI - An ultra-sensitive monoclonal antibody-based enzyme-linked immunosobent assay for dibutyl phthalate in human urinary. AB - Dibutyl phthalate (DBP) has been extensively used as a plasticizer in many daily products, which is highly toxic to human, notably affecting the reproductive and developmental function. As the previous method is expensive, time-consuming, low sensitivity and just focused on the environment. Present study was aimed to establish an ultra-sensitive and simple method based on good quality monoclonal antibody, applying to evaluate excretion level of DBP in urine samples of Chinese population directly. A monoclonal antibody was generated and characterized after fusion of myeloma cells with spleen cells isolated from BALB/c mouse. The mouse was previously immunized using a specially designed amino derivative of DBP conjugated with bovine serum albumin (BSA) as immunogen. Cross-reactivity values of the monoclonal antibody against DBP, di-isobutyl phthalate (DIBP) were observed 100% and 1.25%, while for dimethyl phthalate (DMP), butyl benzyl phthalate (BBP) and didecyl phthalate (DDP) the values were <0.06%. The standard curve was constructed at 0-50 ng mL(-1) and good linearity (R(2)=0.994) was achieved. The observed IC50 (7.34 ng mL(-1)) and LOD (0.06 ng mL(-1)) values was improved 1000-fold to polyclonal antibody and 5-fold to other monoclonal antibodies. A total 1246 urine samples were analyzed and the detection frequency of DBP was observed 72.87% by ic-ELISA. The 95th percentile and mean concentration of DBP were 12.07 and 3.00 ng mL(-1). Acceptable recovery rates of DBP were 97.8-114.3% and coefficients variation 5.93-11.09%. The concentrations of DBP in females were found significantly higher (p<0.05) than males. Similarly, the DBP in middle aged and low educated individuals was found higher (p<0.001) than the others. Considering the adverse health effects, DBP internal exposure in the Chinese population should be reduced. The ic-ELISA method has been proved as a cost effective, specific, and highly sensitive screening tool to detect DBP in urinary samples. PMID- 26433327 TI - Sources apportionment of PM2.5 in a background site in the North China Plain. AB - To better understand the sources and potential source regions of PM2.5, a field study was conducted from January 2011 to November 2011 at a background site, the Yellow River Delta National Nature Reserve (YRDNNR) in the North China Plain. Positive matrix factorisation (PMF) analysis and a potential source contribution function (PSCF) model were used to assess the data, which showed that YRDNNR experienced serious air pollution. Concentrations of PM2.5 at YRDNNR were 71.2, 92.7, 97.1 and 62.5 MUg m(-3) in spring, summer, autumn and winter, respectively, with 66.0% of the daily samples exhibiting higher concentrations of PM2.5 than the national air quality standard. PM2.5 mass closure showed remarkable seasonal variations. Sulphate, nitrate and ammonium were the dominant fractions of PM2.5 in summer (58.0%), whereas PM2.5 was characterized by a high load of organic aerosols (40.2%) in winter. PMF analysis indicated that secondary sulphate and nitrate (54.3%), biomass burning (15.8%), industry (10.7%), crustal matter (8.3%), vehicles (5.2%) and copper smelting (4.9%) were important sources of PM2.5 at YRDNNR on an annual average. The source of secondary sulphate and nitrate was probably industrial coal combustion. PSCF analysis indicated a significant regional impact on PM2.5 at YRDNNR all year round. Local emission may be non-negligible at YRDNNR in summer. The results of the present study provide a scientific basis for the development of PM2.5 control strategies on a regional scale. PMID- 26433328 TI - Monitoring changes in the structure and properties of humic substances following ozonation using UV-Vis, FTIR and (1)H NMR techniques. AB - The main objective of this work is to conduct a comprehensive structural characterization of humic substances using the following experimental techniques: FTIR, 1H NMR and several UV-Vis parameters (Specific UV Absorbance at 254 nm or SUVA254, SUVA280, A400, the absorbance ratios A210/254, A250/365, A254/203, A254/436, A265/465, A270/400, A280/350, A465/665, the Absorbance Slope Index (ASI), the spectral slopes S275-295, S350-400 and the slope ratio SR). These UV Vis parameters have also been correlated with key properties of humic substances such as aromaticity, molecular weight (MW) and trihalomethane formation potential (THMFP). An additional objective of this work is also to evaluate the usefulness of these techniques to monitor structural changes in humic substances produced by the ozonation treatment. Four humic substances were studied in this work: three of them were provided by the International Humic Substances Society (Suwannee River Fulvic Acid Standard: SRFA, Suwannee River Humic Acid Standard: SRHA and Nordic Reservoir Fulvic Acid Reference: NLFA) and the other one was a terrestrial humic acid widely used as a surrogate for aquatic humic substances in various studies (Aldrich Humic Acid: AHA). The UV-Vis parameters showing the best correlations with aromaticity in this study were SUVA254, SUVA280, A280/A350 ratio and A250/A364 ratio. The best correlations with molecular weight were for SUVA254, SUVA280 and A280/A350 ratio. Finally, in the case of the THMFP it was STHMFP-per mol HS the parameter showing good correlations with most of the UV-Vis parameters studied (especially with A280/A350 ratio, A265/A465 ratio and A270/A400 ratio) whereas STHMFP-per mg C showed poor correlations in most cases. On the whole, the UV-Vis parameter showing the best results was A280/A350 ratio as it showed excellent correlations for the three properties studied (aromaticity, MW and THMFP). A decrease in aromaticity following ozonation of humic substances can be readily monitored by 1H NMR and FTIR; the latter technique also allows to monitor an increase in carboxylic acidity with ozone dosage. This organic matter originated following ozonation (more aliphatic in character and more polar) is expected to be recalcitrant to further oxidation. The terrestrial humic acid (AHA) showed some structural differences with the aquatic humic substances and its behavior upon ozonation also differed in some extent from that shown by them. PMID- 26433329 TI - Application of IEUBK model in lead risk assessment of children aged 61-84 months old in central China. AB - Few studies have focused on the accuracy of using the Integrated Exposure Uptake Biokinetic (IEUBK) model in Chinese children with site- and age-specific exposure data. This study aimed to validate the accuracy and sensitivity of the IEUBK model in lead risk assessment of Chinese children aged 61-84 months old. A total of 760 children were enrolled from two respective counties in Central China by using random cluster sampling method. Blood lead levels (BLLs) of all subjects were determined using graphite furnace atomic absorption spectrometry, as well as that in the environmental media, such as air, drinking water, soil, dust and food. Age- and site-specific time-activity patterns and water consumption were evaluated by using questionnaires for children. Exposure parameters including outdoor and indoor activity time, ventilation rate and water consumption in this study were different from the default values of the IEUBK model. Statistical analysis revealed no significant differences between the predicted and observed BLLs. Diet and soil/dust lead intake contributed approximately 83.39% (57.40% 93.84% range) and 15.18% (3.25%-41.60% range) of total lead intake, respectively. These findings showed that the IEUBK model is suitable for lead risk assessment of Chinese children aged 61-84 months old and diet acts as an important lead source. PMID- 26433330 TI - A model-based analysis of SO2 and NO2 dynamics from coal-fired power plants under representative synoptic circulation types over the Iberian Peninsula. AB - Emissions of SO2 and NO2 from coal-fired power plants are a significant source of air pollution. In order to typify the power plants' plumes dynamics and quantify their contribution to air quality, a comprehensive characterisation of seven coal fired power plant plumes has been performed under six representative circulation types (CTs) identified by means of a synoptic classification over the Iberian Peninsula. The emission and the transport of SO2 and NO2 have been simulated with the CALIOPE air quality forecasting system that couples the HERMES emission model for Spain and WRF and CMAQ models. For the facilities located in continental and Atlantic areas (As Pontes, Abono, and Compostilla) the synoptic advection controls pollutant transport, however for power plants located along the Mediterranean or over complex-terrains (Guardo, Andorra, Carboneras, and Los Barrios), plume dynamics are driven by a combination of synoptic and mesoscale mountain-valley and sea-land breezes. The contribution of power plants to surface concentration occurs mainly close to the source (<20 km) related to a fumigation process when the emission injection takes place within the planetary boundary layer reaching up to 55 MUg SO2 m(-3) and 32 MUg NO2 m(-3). However, the SO2 and NO2 plumes can reach long distances (>250 km from the sources) especially for CTs characterised by Atlantic advection. PMID- 26433331 TI - Hexabromocyclododecanes, polybrominated diphenyl ethers, and polychlorinated biphenyls in radiometrically dated sediment cores from English lakes, ~1950 present. AB - This paper reports input fluxes between ~1950 and present, of polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and hexabromocyclododecanes (HBCDs) in radiometrically-dated sediment cores from 7 English lakes. Fluxes of PCBs at all but one location prone to significant sediment resuspension peaked in the late-1960s/early-1990s, before declining thereafter. Input fluxes of HBCDs at all sites increased from first emergence in the mid-1960s. Thereafter, fluxes peaked in the late-1980s/early-2000s, before declining through to the present, except at the most urban site where HBCD fluxes are still increasing. Trends of PBDEs predominant in the Penta-BDE and Octa-BDE formulations vary between sites. While at some locations, fluxes peaked in the late-1990s/early-2000s; at others, fluxes are still increasing. This suggests the full impact of EU restrictions on these formulations has yet to be felt. Fluxes of BDE-209 have yet to peak at all except one location, suggesting little discernible environmental response to recent EU restrictions on the Deca-BDE product. Strikingly, fluxes of BDE-209 in the most recent core slices either exceed or approach peak fluxes of SigmaPCBs, implying substantial UK use of Deca BDE. Excepting HBCDs, inventories of our target contaminants correlated significantly with local population density, implying substantial urban sources. PMID- 26433332 TI - Air pollution and fasting blood glucose: A longitudinal study in China. AB - Limited studies have examined the associations between air pollutants [particles with diameters of 10 MUm or less (PM10), sulphur dioxide (SO2), and nitrogen dioxide (NO2)] and fasting blood glucose (FBG). We collected data for 27,685 participants who were followed during 2006 and 2008. Generalized Estimating Equation models were used to examine the effects of air pollutants on FBG while controlling for potential confounders. We found that increased exposure to NO2, SO2 and PM10 was significantly associated with increased FBG levels in single pollutant models (p<0.001). For exposure to 4 days' average of concentrations, a 100 MUg/m(3) increase in SO2, NO2, and PM10 was associated with 0.17 mmol/L (95% CI: 0.15-0.19), 0.53 mmol/L (95% CI: 0.42-0.65), and 0.11 mmol/L (95% CI: 0.07 0.15) increase in FBG, respectively. In the multi-pollutant models, the effects of SO2 were enhanced, while the effects of NO2 and PM10 were alleviated. The effects of air pollutants on FBG were stronger in female, elderly, and overweight people than in male, young and underweight people. In conclusion, the findings suggest that air pollution increases the levels of FBG. Vulnerable people should pay more attention on highly polluted days to prevent air pollution-related health issues. PMID- 26433333 TI - Temporal variations in embryotoxicity of Lake Ontario American eel (Anguilla rostrata) extracts to developing Fundulus heteroclitus. AB - The recruitment of American eel (Anguilla rostrata) juveniles to Lake Ontario (LO), Canada has declined significantly since the 1980s. To investigate the possible contribution of maternally-transferred persistent organic pollutants (POPs) to this decline, this study measured temporal variations in the toxicity of complex organic mixtures extracted from LO American eels captured in 1988, 1998 and 2008 to developing Fundulus heteroclitus exposed by intravitelline (IVi) injection. The 1988 and 1998 eel extracts were most toxic, causing a pattern of sublethal embryotoxic responses similar to those previously reported in F. heteroclitus embryos exposed to single dioxin-like compounds (DLCs): stunted growth, craniofacial deformities, EROD activity induction, and reduced predatory capacities. The potency of extracts declined over time; the only significant effect of the 2008 eel extracts was EROD induction. The chemically-derived TCDD TEQs of eel extracts, calculated using measured concentrations of some DLCs and their relative potencies for F. heteroclitus, overestimated their potency to induce EROD activity possibly due to interactions among POPs. Other POPs measured in eel extracts (non-dioxin-like PCBs, PBDEs and organochlorinated pesticides) did not appear to be important agonistic contributors to the observed toxicity. The toxicity of the complex mixtures of POPs measured in LO eels may have been underestimated as a result of several factors, including the loss of POPs during extracts preparation and a focus only on short-term effects. Based on the model species examined, our results support the hypothesis that contamination of LO with DLCs may have represented a threat to the American eel population through ecologically-relevant effects such as altered larval prey capture ability. These results prioritize the need to assess early life stage (ELS) toxicity of DLCs in Anguilla species, to investigate long-term effects of complex eel extracts to ELS of fish, and to develop biomarkers for potential effects in eel ELS sampled in the field. PMID- 26433334 TI - Environmental fate of the fungicide metalaxyl in soil amended with composted olive-mill waste and its biochar: An enantioselective study. AB - A large number of pesticides are chiral and reach the environment as mixtures of optical isomers or enantiomers. Agricultural practices can affect differently the environmental fate of the individual enantiomers. We investigated how amending an agricultural soil with composted olive-mill waste (OMWc) or its biochar (BC) at 2% (w:w) affected the sorption, degradation, and leaching of each of the two enantiomers of the chiral fungicide metalaxyl. Sorption of metalaxyl enantiomers was higher on BC (Kd ~ 145 L kg(-1)) than on OMWc (Kd ~ 22 L kg(-1)) and was not enantioselective in either case, and followed the order BC-amended>OMWc amended>unamended soil. Both enantiomers showed greater resistance to desorption from BC-amended soil compared to unamended and OMWc-amended soil. Dissipation studies revealed that the degradation of metalaxyl was more enantioselective (R>S) in unamended and OMWc-amended soil than in BC-amended soil. The leaching of both S- and R-metalaxyl from soil columns was almost completely suppressed after amending the soil with BC and metalaxyl residues remaining in the soil columns were more racemic than those in soil column leachates. Our findings show that addition of BC affected the final enantioselective behavior of metalaxyl in soil indirectly by reducing its bioavailability through sorption, and to a greater extent than OMWc. BC showed high sorption capacity to remove metalaxyl enantiomers from water, immobilize metalaxyl enantiomers in soil, and mitigate the groundwater contamination problems particularly associated with the high leaching potential of the more persistent enantiomer. PMID- 26433335 TI - Environmental risk assessment of chemicals and nanomaterials--The best foundation for regulatory decision-making? AB - Environmental risk assessment (ERA) is often considered as the most transparent, objective and reliable decision-making tool for informing the risk management of chemicals and nanomaterials. ERAs are based on the assumption that it is possible to provide accurate estimates of hazard and exposure and, subsequently, to quantify risk. In this paper we argue that since the quantification of risk is dominated by uncertainties, ERAs do not provide a transparent or an objective foundation for decision-making and they should therefore not be considered as a "holy grail" for informing risk management. We build this thesis on the analysis of two case studies (of nonylphenol and nanomaterials) as well as a historical analysis in which we address the scientific foundation for ERAs. The analyses show that ERAs do not properly address all aspects of actual risk, such as the mixture effect and the environmentally realistic risk from nanomaterials. Uncertainties have been recognised for decades, and assessment factors are used to compensate for the lack of realism in ERAs. The assessment factors' values were pragmatically determined, thus lowering the scientific accuracy of the ERAs. Furthermore, the default choice of standard assay for assessing a hazard might not always be the most biologically relevant, so we therefore argue that an ERA should be viewed as a pragmatic decision-making tool among several, and it should not have a special status for informing risk management. In relation to other relevant decision-making tools we discuss the use of chemical alternative assessments (CAAs) and the precautionary principle. PMID- 26433336 TI - Tracking progress towards global drinking water and sanitation targets: A within and among country analysis. AB - INTRODUCTION: Global access to safe drinking water and sanitation has improved dramatically during the Millennium Development Goal (MDG) period. However, there is substantial heterogeneity in progress between countries and inequality within countries. METHODS: We assessed countries' temporal patterns in access to drinking water and sanitation using publicly available data. We then classified countries using non-linear modeling techniques as having one of the following trajectories: 100% coverage, linear growth, linear decline, no change, saturation, acceleration, deceleration, negative acceleration, or negative deceleration. We further assessed the degree to which temporal profiles follow a sigmoidal pattern and how these patterns might vary within a given country between rural and urban settings. RESULTS: Among countries with more than 10 data points, between 15% and 38% showed a non-linear trajectory, depending on the indicator. Overall, countries' progress followed a sigmoidal trend, but some countries are making better progress and some worse progress than would be expected. We highlight several countries that are not on track to meet the MDG for water or sanitation, but whose access is accelerating, suggesting better performance during the coming years. Conversely, we also highlight several countries that have made sufficient progress to meet the MDG target, but in which access is decelerating. DISCUSSION: Patterns were heterogeneous and non-linearity was common. Characterization of these heterogeneous patterns will help policy makers allocate resources more effectively. For example, policy makers can identify countries that could make use of additional resources or might be in need of additional institutional capacity development to properly manage resources; this will be essential to meet the forthcoming Sustainable Development Goals. PMID- 26433337 TI - Reply to the Letter to the Editor "High-sensitivity C-reactive protein in obese children: Too complex a marker to use?". PMID- 26433338 TI - The impact of response frequency on spatial stimulus-response correspondence effects. AB - The present study explored how response preparation, varied by relative response frequency, affects response conflict as expressed in the Simon effect. Previous studies showed that valid response cues, when presented before the imperative stimulus, increase rather than decrease the Simon effect. This finding was explained by the hypothesis that response cues trigger shifts of attention to the side of the prepared response, and that these attention shifts modulate processing of the imperative stimulus. We investigated whether cues are necessary for inducing shifts of attention and thereby modulating the Simon effect, or whether response preparation without cues is sufficient. In two experiments, participants performed a Simon task with one response being more frequent than the other. Results showed larger Simon effects for the more frequent (i.e. prepared) response than for the less frequent (i.e. unprepared) response. These results suggest that response preparation (rather than the cue that induces the preparation) triggers a shift of spatial attention which modulates the Simon effect. PMID- 26433339 TI - CdTe quantum dots@luminol as signal amplification system for chrysoidine with chemiluminescence-chitosan/graphene oxide-magnetite-molecularly imprinting sensor. AB - A sensitive chemiluminescence (CL) sensor based on chemiluminescence resonance energy transfer (CRET) in CdTe quantum dots@luminol (CdTe QDs@luminol) nanomaterials combined with chitosan/graphene oxide-magnetite-molecularly imprinted polymer (Cs/GM-MIP) for sensing chrysoidine was developed. CdTe QDs@luminol was designed to not only amplify the signal of CL but also reduce luminol consumption in the detection of chrysoidine. On the basis of the abundant hydroxy and amino, Cs and graphene oxide were introduced into the GM-MIP to improve the adsorption ability. The adsorption capacities of chrysoidine by both Cs/GM-MIP and non-imprinted polymer (Cs/GM-NIP) were investigated, and the CdTe QDs@luminol and Cs/GM-MIP were characterized by UV-vis, FTIR, SEM and TEM. The proposed sensor can detect chrysoidine within a linear range of 1.0*10(-7) - 1.0*10(-5) mol/L with a detection limit of 3.2*10(-8) mol/L (3delta) due to considerable chemiluminescence signal enhancement of the CdTe quantum dots@luminol detector and the high selectivity of the Cs/GM-MIP system. Under the optimal conditions of CL, the CdTe QDs@luminol-Cs/GM-MIP-CL sensor was used for chrysoidine determination in samples with satisfactory recoveries in the range of 90-107%. PMID- 26433340 TI - pH-dependent plasmonic catalysis of 4-nitrobenzenethiol in aqueous environment. AB - Plasmon-driven chemical reaction of 4-nitrobenzenethiol (4-NBT) dimerizing to p,p'-dimercaptoazobenzene (DMAB) has been successfully monitored under different pH solutions. The experimental results indicated that the chemical reactions were dependent on the pH values, and they proceeded more completely under acidic conditions than those under neutral and alkaline conditions. Furthermore, the rate of the chemical reactions was effectively controlled by exposure time and incident laser power. The stable pH dependence demonstrated the plasmon-driven chemical reactions of 4-NBT to DMAB are sensitive to the surrounding environment, and have wider applications. PMID- 26433341 TI - A comparison of antioxidative capacities of fruit juices, drinks and nectars, as determined by EPR and UV-vis spectroscopies. AB - The differences in the Trolox Equivalent Antioxidant Capacity (TEAC) values at the same incubation time obtained by two different techniques: electron paramagnetic resonance (EPR) spectroscopy and ultraviolet visible (UV-vis) spectroscopy, which use the same antioxidant-free radical reaction mechanism, were determined for fruit juices, nectars and drinks. For this study, the stable free radical 1,1-Diphenyl-2-picryl-hydrazyl (DPPH(*)) was used. The antioxidant capacity was presented in Trolox Equivalents, e.g., MUM trolox per 100 ml of sample. All of the studied fruit juices, drinks and nectars showed antioxidative properties. Dependencies between TEAC values and the percent fruit content and sample color were observed for the studied beverages. It was found that EPR spectroscopy is the more adequate method for determining TEAC values for these kinds of samples. PMID- 26433342 TI - Alteration of human serum albumin tertiary structure induced by glycation. Spectroscopic study. AB - The modification of human serum albumin (HSA) structure by non-enzymatic glycation is one of the underlying factors that contribute to the development of complications of diabetes and neurodegenerative diseases. The aim of the present work was to estimate how glycation of HSA altered its tertiary structure. Changes of albumin conformation were investigated by comparison of glycated (gHSA) and non-glycated human serum albumin (HSA) absorption spectra, red edge excitation shift (REES) and synchronous spectra. Effect of glycation on human serum albumin tertiary structure was also investigated by (1)H NMR spectroscopy. Formation of gHSA Advanced Glycation End-products (AGEs) caused absorption of UV-VIS light between 310 nm and 400 nm while for non-glycated HSA in this region no absorbance has been registered. Analysis of red edge excitation shift effect allowed for observation of structural changes of gHSA in the hydrophobic pocket containing the tryptophanyl residue. Moreover changes in the microenvironment of tryptophanyl and tyrosyl residues brought about AGEs on the basis of synchronous fluorescence spectroscopy have been confirmed. The influence of glycation process on serum albumin binding to 5-dimethylaminonaphthalene-1-sulfonamide (DNSA), 2-(p toluidino) naphthalene-6-sulfonic acid (TNS), has been studied. Fluorescence analysis showed that environment of both binding site I and II is modified by galactose glycation. PMID- 26433343 TI - Electrophoretic mobility of cell nuclei (EMN index) as a biomarker of the biological aging process: Considering the association between EMN index and age. AB - The present study examined whether a specific property of cell microstructures may be useful as a biomarker of aging. Specifically, the association between age and changes of cellular structures reflected in electrophoretic mobility of cell nuclei index (EMN index) values across the adult lifespan was examined. This report considers findings from cross sections of females (n=1273) aged 18-98 years, and males (n=506) aged 19-93 years. A Biotest apparatus was used to perform intracellular microelectrophoresis on buccal epithelial cells collected from each individual. EMN index was calculated on the basis of the number of epithelial cells with mobile nuclei in reference to the cells with immobile nuclei per 100cells. Regression analyses indicated a significant negative association between EMN index value and age for men (r=-0.71, p<0.001) and women (r=-0.60, p<0.001); demonstrating a key requirement that must be met by a biomarker of aging. The strength of association observed between EMN index and age for both men and women was encouraging and supports the potential use of EMN index for determining a biological age of an individual (or a group). In this study, a new attempt of complex explanation of cellular mechanisms contributing to age related changes of the EMN index was made. In this study, a new attempt of complex explanation of cellular mechanisms contributing to age related changes of the EMN index was made. EMN index has demonstrated potential to meet criteria proposed for biomarkers of aging and further investigations are necessary. PMID- 26433344 TI - Primary testicular lymphoma. PMID- 26433345 TI - Reply from Authors RE "Analysis of the safety profile of treatment with a large number of shock waves per session in extracorporeal lithotripsy". PMID- 26433346 TI - Biofilm formation on the surface of polylactide during its biodegradation in different environments. AB - The research was aimed at determining the abundance and viability of biofilm formed on the surface of polylactide (PLA) during its biodegradation in different environments. It was also aimed at isolating biofilm forming bacteria, determining their hydrolytic activity and taxonomic status. The first step was to evaluate PLA biodegradability in lake water, compost and soil, using OxiTop Control. The next step was to assess the ability of isolated bacteria to form biofilm in the investigated environments and to evaluate the biofilm structure. The results indicate that PLA is sensitive to biodegradation in any environment, particularly in compost. During this process biofilm of high viability was observed on the surface of PLA. Based on the 16S rRNA gene sequence, the biofilm forming bacteria were classified as the following species: Acidovorax sp. LW9, Chryseobacterium sp. LW2, Aeromonas veronii LW8, Arthrobacter aurescens LG2, Arthrobacter sp. LG12, A. aurescens LG9, Elizabethkingia meningoseptica LK3, A. aurescens LK9, A. aurescens and LK7. The results show that different bacterial species formed biofilm of different abundance and hydrolytic activitiy levels. PMID- 26433347 TI - Enhanced anti-hyperproliferative activity of human thymidylate synthase inhibitor peptide by solid lipid nanoparticle delivery. AB - Recently, octapeptide LSCQLYQR (LRp), reducing growth of cis-platinum (cDDP) resistant ovarian carcinoma cells by inhibiting the monomer-monomer interface of the human enzyme thymidylate synthase, has been identified. As the peptide is not able to cross the cell membrane it requires an appropriate delivery system. In this work the application of SLNs, biocompatible and efficient tools for the intracellular drug transport, applied especially for lipophilic drugs, was exploited for the delivery of the hydrophilic peptide LRp. SLNs formulated in the absence/presence of small amount of squalene showed dimensions below 150 nm, negative zeta potential and good stability to the freeze-drying process. Even though the particles formulated with squalene exhibited a less ordered crystal lattice and a lower surface hydrophobicity, a rapid drug release from these nanocarriers occurred as a result of the relevant expulsion of the drug from the lipid core during lipid crystallization. On the contrary, SLNs formulated in the absence of squalene were able to incorporate more stably the peptide showing considerable cytotoxic effect on cDDP resistant C13* ovarian carcinoma cell line at concentration 50 times lower than that used previously with a marketed delivery system. From the cell cycle analysis by the propidium iodide test in SLNs-peptide treated cancer cells an increase of apoptosis percentage was observed, indicating that SLNs were able to carry efficiently the peptide until its enzymatic target. PMID- 26433348 TI - Cellular delivery of shRNA using aptamer-conjugated PLL-alkyl-PEI nanoparticles. AB - Introduction of an efficient gene delivery vector is still the main challenge of gene therapy. Both polyethylenimine (PEI) and poly(l-lysine) (PLL) comprise disadvantages which limited their application. To explore whether their deficiencies could be compensated by preparing copolymers consisting of both PLL and PEI, we generated several combinations of PLL-alkyl-PEI copolymers conjugated to aptamer and evaluated their both gene delivery efficiency and down-regulation of Bcl-XL, an anti-apoptotic gene, in lung cancer cell line. PLL was conjugated to either 10% or 50% of PEI by grafting different percentages of PEI to alkylated PLL as core. The properties of modified polymers including size, surface charge density, DNA condensation ability, buffering capacity and cytotoxicity were evaluated. According to transfection results, aptamer conjugated PLL-alkyl-10% PEI (PLPE8%) was selected for further gene silencing study by plasmid shRNA. Decrease in Bcl-XL gene expression was estimated by both RT-PCR and western-blot experiments. The obtained results revealed that the new copolymers had appropriate nano-scale size (117-128 nm) even after aptamer conjugation (168-183 nm). Moreover, they exhibited increased transfection efficiencies by up to 1.8-5 folds and acceptable cytotoxicity. The apoptosis was induced in transfected cells by shRNA-aptamer-copolymer due to the down-regulation of mRNA and protein levels. This study suggested a new vector for targeted non-viral gene delivery with high transfection efficiency in lung cancer or pulmonary systems. PMID- 26433349 TI - Acid-responsive PEGylated doxorubicin prodrug nanoparticles for neuropilin-1 receptor-mediated targeted drug delivery. AB - Self-assembled prodrug nanoparticles have demonstrated great promise in cancer chemotherapy. In the present study, we developed a new kind of prodrug nanoparticles for targeted drug delivery. PEGylated doxorubicin conjugate with an acid-cleavable cis-aconityl spacer was prepared. Then it was functionalized with a tumor-penetrating peptide, Cys-Arg-Gly-Asp-Lys (CRGDK), providing the prodrug nanoparticles with the specific binding ability to neurophilin-1 receptor. In acid mediums, doxorubicin could be released from the prodrug nanoparticles with an accumulative release around 60% through the acid-triggered hydrolysis of cis aconityl bond and nanoparticle disassembly. Whereas, drug release was slow under a neutral pH and the accumulative drug release was less than 16%. In the cell culture tests, our prodrug nanoparticles showed enhanced endocytosis and cytotoxicity in cancer cells including HepG2, MCF-7 and MDA-MB-231 cells, but lower cytotoxicity in human cardiomyocyte H2C9. In the animal experiments, the prodrug nanoparticles were intravenously injected into Balb/c nude mice bearing MDA-MB-231 tumors. Enhanced drug penetration and accumulation in tumors, accompanying with a rapid early tumor-binding behavior, was observed after intravenous injection of the peptide modified prodrug nanoparticles. These data suggests that the acid-sensitive and tumor-targeting PEGylated doxorubicin prodrug nanoparticle may be an efficient drug delivery system for cancer chemotherapy. PMID- 26433350 TI - Infra-renal abdominal aortic calcification volume does not predict small abdominal aortic aneurysm growth. AB - BACKGROUND: Vascular calcification is a common finding in abdominal aortic aneurysms (AAA) however whether it predicts aneurysm expansion is controversial. OBJECTIVES: 1) To establish a reproducible method of assessing AAA calcification using computed tomography (CT); 2) To investigate the association between AAA calcification and growth. METHOD: Patients were identified from a prospectively maintained small AAA surveillance database. To be included patients required at least two CT scans a minimum of 6 months apart. All patients had a maximal AAA diameter of <=55 mm on their initial scan. Infra-renal aortic calcification volume, total infra-renal aortic volume and maximal AAA diameter were measured. Reproducibility was assessed from repeat scans performed on 31 patients. AAA growth, estimated by volume change per year, was compared between patients with baseline infra-renal aortic calcification volumes< and >=median. RESULTS: 95% agreement limits (lower, upper) for intra and inter-observer error in measuring infra-renal aortic calcification volume were 0.68, 97 mm(3) and -140, 5.8 mm(3), respectively. Concordance correlation coefficients for inter and intra-observer variability in measuring infra-renal aortic calcification volume were 0.99 and 0.99, respectively. Patients with infra-renal aortic calcification volume < median (n = 44) and >=median (n = 44) had an infra-renal aortic volume increase of 6.0 cm(3)/yr and 7.8 cm(3)/yr, respectively (p = 0.66). Mean percentage infra renal aortic volume increase/yr was found to be 4.2 +/- 6.4 and 8.9 +/- 6.2 for patients with and without diabetes, respectively (p = 0.003). CONCLUSION: Infra renal aortic calcification volume can be assessed reproducibly from CT images. Infra-renal aortic calcification volume did not predict small AAA growth. PMID- 26433352 TI - Electrochemical lateral flow immunosensor for detection and quantification of dengue NS1 protein. AB - An Electrochemical Lateral Flow Immunosensor (ELFI) is developed combining screen printed gold electrodes (SPGE) enabling quantification together with the convenience of a lateral flow test strip. A cellulose glassy fiber paper conjugate pad retains the marker immunoelectroactive nanobeads which will bind to the target analyte of interest. The specific immunorecognition event continues to occur along the lateral flow bed until reaching the SPGE-capture antibodies at the end of the cellulosic lateral flow strip. The rationale of the immunoassay consists in the analyte antigen NS1 protein being captured selectively and specifically by the dengue NS1 antibody conjugated onto the immunonanobeads thus forming an immunocomplex. With the aid of a running buffer, the immunocomplexes flow and reach the immuno-conjugated electrode surface and form specific sandwich type detection due to specific, molecular recognition, while unbound beads move along past the electrodes. The successful sandwich immunocomplex formation is then recorded electrochemically. Specific detection of NS1 is translated into an electrochemical signal contributed by a redox label present on the bead immobilized detection dengue NS1 antibody while a proportional increase of faradic current is observed with increase in analyte NS1 protein concentration. The first generation ELFI prototype is simply assembled in a cassette and successfully demonstrates wide linear range over a concentration range of 1-25 ng/mL with an ultrasensitive detection limit of 0.5 ng/mL for the qualitative and quantitative detection of analyte dengue NS1 protein. PMID- 26433353 TI - Colon-derived uremic biomarkers induced by the acute toxicity of Kansui radix: A metabolomics study of rat plasma and intestinal contents by UPLC-QTOF-MS(E). AB - Kansui radix (KR) is a poisonous Chinese herbal medicine recorded in the Chinese Pharmacopoeia, and the acute toxicity obstructs its clinical applications. To explore its acute toxicity mechanism to enhance clinical safety, a metabolomics study based on UPLC-ESI-QTOF-MS(E) was performed. Wistar rats were exposed for 4h to the aqueous and ethyl acetate extracts prepared from KR at a high dose (25g/kg). The contents of six different sections of rat intestine, including the duodenum, jejunum, ileum, cecum, colon, and rectum were collected as samples for the first time, as well as the rat plasma. The interesting results showed that only those rats exposed to the ethyl acetate extract showed a watery diarrhea, similar to the observed acute human toxicity. The identified biomarkers found in the plasma, such as phenol sulfate, indoxyl sulfate, and p-cresol sulfate were significantly perturbed in the rats. These biomarkers are known as colon-derived uremic compounds, which were first reported with respect to KR. The three essential amino acids which produced these biomarkers were only found in the contents of colon and rectum. A hypothesis was proposed that only the colon derived uremic compounds induced by KR might be responsible for the acute toxicity. Three traditional process methods to reduce the toxicity of KR were compared based on these biomarkers, and different levels of toxicity modulation were observed. These results may be helpful to further understand the mechanism of acute toxicity, and the relevance of the traditional process methods to ameliorate the adverse effects of KR. PMID- 26433351 TI - Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer's disease. AB - INTRODUCTION: We performed linkage analyses in Caribbean Hispanic families with multiple late-onset Alzheimer's disease (LOAD) cases to identify regions that may contain disease causative variants. METHODS: We selected 67 LOAD families to perform genome-wide linkage scan. Analysis of the linked regions was repeated using the entire sample of 282 families. Validated chromosomal regions were analyzed using joint linkage and association. RESULTS: We identified 26 regions linked to LOAD (HLOD >=3.6). We validated 13 of the regions (HLOD >=2.5) using the entire family sample. The strongest signal was at 11q12.3 (rs2232932: HLODmax = 4.7, Pjoint = 6.6 * 10(-6)), a locus located ~2 Mb upstream of the membrane spanning 4A gene cluster. We additionally identified a locus at 7p14.3 (rs10255835: HLODmax = 4.9, Pjoint = 1.2 * 10(-5)), a region harboring genes associated with the nervous system (GARS, GHRHR, and NEUROD6). DISCUSSION: Future sequencing efforts should focus on these regions because they may harbor familial LOAD causative mutations. PMID- 26433355 TI - Stability of saliva microbiota during moderate consumption of red wine. AB - OBJECTIVE: This study has evaluated the effect of regular and moderate red wine consumption on the diversity and occurrence of different groups of bacteria that are representative in human saliva. METHODS: Saliva from twenty-two healthy volunteers (age range 20-48 years) was analyzed in this study. Fourteen individuals consumed red wine (250mL/day) during 4 weeks, whereas 8 volunteers were included in the control group. The evolution and composition of the microbial community in saliva was evaluated by PCR-DGGE and quantitative PCR. RESULTS: The microbial inter-individual variability observed in the PCR-DGGE band patterns was higher than the differences observed after the 4-weeks period of red wine intake. Bifidobacterium dentium, Bifidobacterium spp. and Alloscardovia omnicolens were the most representative bifidobacterial species, whereas the Streptococcus mitis-Streptococcus oralis group predominated within Streptococcus. This genus was the most numerous of the bacterial groups assayed, reaching average counts above 8 log copy numbers/mL. On the other hand, the lowest counts were recorded for Actinomyces, Fusobacterium, Haemophilus, Neisseria and Veillonella, which showed average values of 5 log copy numbers/mL. The results showed no significant differences (P>0.5) in bacterial counts after the period of red wine intake. CONCLUSION: The overall diversity and stability of representative bacterial groups of the human saliva is not disturbed due to regular-moderate red wine consumption. PMID- 26433354 TI - Identifying genetic determinants of autoimmunity and immune dysregulation. AB - Common autoimmune diseases are relatively heterogeneous with both genetic and environmental factors influencing disease susceptibility and progression. As the populations in developed countries age, these chronic diseases will become an increasing burden in human suffering and health care costs. By contrast, rare immune diseases that are severe and develop early in childhood are frequently monogenic and fully penetrant, often with a Mendelian inheritance pattern. Although these may be incompatible with survival or cured by hematopoietic stem cell transplantation, we will argue that they constitute a rich source of genetic insights into immunological diseases. Here, we discuss five examples of well studied Mendelian disease-causing genes and their known or predicted roles in conferring susceptibility to common, polygenic diseases of autoimmunity. Mendelian disease mutations, as experiments of nature, reveal human loci that are indispensable for immune regulation and, therefore, most promising as therapeutic targets. PMID- 26433356 TI - Modelling contaminant transport for pumping wells in riverbank filtration systems. AB - Analytical study of the influence of both the pumping well discharge rate and pumping time on contaminant transport and attenuation is significant for hydrological and environmental science applications. This article provides an analytical solution for investigating the influence of both pumping time and travelling time together for one-dimensional contaminant transport in riverbank filtration systems by using the Green's function approach. The basic aim of the model is to understand how the pumping time and pumping rate, which control the travelling time, can affect the contaminant concentration in riverbank filtration systems. Results of analytical solutions are compared with the results obtained using a MODFLOW numerical model. Graphically, it is found that both analytical and numerical solutions have almost the same behaviour. Additionally, the graphs indicate that any increase in the pumping rate or simulation pumping time should increase the contamination in groundwater. The results from the proposed analytical model are well matched with the data collected from a riverbank filtration site in France. After this validation, the model is then applied to the first pilot project of a riverbank filtration system conducted in Malaysia. Sensitivity analysis results highlight the importance of degradation rates of contaminants on groundwater quality, for which higher utilization rates lead to the faster consumption of pollutants. PMID- 26433357 TI - A greenhouse trial to investigate the ameliorative properties of biosolids and plants on physicochemical conditions of iron ore tailings: Implications for an iron ore mine site remediation. AB - An iron ore mine site in Swaziland is currently (2015) in a derelict state as a consequence of past (1964-1988) and present (2011 - current) iron ore mining operations. In order to control problems associated with mine wastes, the Swaziland Water Services Corporation (SWSC) recently (2013) proposed the application of biosolids in sites degraded by mining operations. It is thought that this practice could generally improve soil conditions and enhance plant reestablishment. More importantly, the SWSC foresees this as a potential solution to the biosolids disposal problems. In order to investigate the effects of biosolids and plants in soil physicochemical conditions of iron mine soils, we conducted two plant growth trials. Trial 1 consisted of tailings that received biosolids and topsoil (TUSB mix) while in trial 2, tailings received biosolids only (TB mix). In the two trials, the application rates of 0 (control), 10, 25, 50, 75 and 100 t ha(-1) were used. After 30 days of equilibration, 25 seeds of Cynodon dactylon were sown in each pot and thinned to 10 plants after 4 weeks. Plants were watered twice weekly and remained under greenhouse conditions for 12 weeks, subsequent to which soils were subjected to chemical analysis. According to the results obtained, there were significant improvements in soil parameters related to fertility such as organic matter (OM), water holding capacity (WHC), cation exchange capacity (CEC), ammonium [Formula: see text] , magnesium (Mg(2+)), calcium (Ca(2+)) and phosphorus ( [Formula: see text] ). With regard to heavy metals, biosolids led to significant increases in soil total concentrations of Cu, Zn, Cd, Hg and Pb. The higher concentrations of Zn and Cu in treated tailings compared to undisturbed adjacent soils are a cause for concern because in the field, this might work against the broader objectives of mine soil remediation, which include the recolonization of reclaimed sites by soil-dwelling organisms. Therefore, while biosolids contain important nutrients that may greatly improve physicochemical conditions and enhance vegetation reestablishment in mined soils, the threat of the build-up of higher levels of trace elements in treated tailings compared to surrounding adjacent soils must not be underestimated. PMID- 26433358 TI - Recovery of Zn from acid mine water and electric arc furnace dust in an integrated process. AB - In this paper, the purification of acid mine water and the treatment of electric arc furnace dust (EAFD) are integrated into one process with the aim of recovering the Zn content of both effluent and waste. Zinc recovery can reduce the cost of their environmental management: purified acid mine water is discharged after removing all metals; EAFD ceases to be hazardous waste; and Zn is valorised. The process consists of the recovery of Zn as zinc oxide and its purification into commercial products. First, EAFD is leached with acid water and the dissolved metals are selectively precipitated as hydroxides. After EADF leaching, ferrous iron is bio-oxidized and Fe and Al are then precipitated; in the following stage, Cu, Ni, Co and Cd are cemented and finally Zn is precipitated as ZnO. In order to purify water that finally is discharged to a river, lime is used as the neutralizing agent, which results in a precipitate of mainly gypsum, MnO, and ZnO. From the impure zinc oxide produced, various alternatives for the attainment of commercial products, such as basic zinc carbonate and electrolytic zinc, are studied in this work. PMID- 26433359 TI - Evaluation of rhamnolipid (RL) as a biosurfactant for the removal of chromium from aqueous solutions by precipitate flotation. AB - Rhamnolipid (RL) is a biosurfactant which is produced by the bacterial species Pseudomonas aeruginosa. Although applications of this material have been examined in various fields, its applications in the flotation of heavy metals remain to be explored. In this research, rhamnolipid was applied as a collector in the flotation of Cr(III) from aqueous solutions. FeSO4 was used for the precipitation of Cr(VI) to Cr(III) which was subsequently removed by flotation. A two level full factorial design (with center points) was used to evaluate the effects of pH, air flow rate, RL/Cr and Fe/Cr molar ratios on the performance of the flotation system. The results showed that the biosurfactant was highly effective in the removal of chromium, and all of the factors had significant effects on the flotation performance. The chromium removal efficiencies of greater than 95% were obtained with the initial chromium concentration of 40 ppm within 5 min. Kinetic studies showed that a first order kinetic model was appropriate to describe the precipitate flotation of Cr(III) using rhamnolipid as a collector. The interference of NaCl, CaCl2, CaSO4, and CaCO3 on the Cr removal was also investigated, and it was demonstrated that CaSO4 and CaCO3 as sparingly water soluble salts, and CaCl2 as a contributor to water hardness had significant negative impacts on Cr removal efficiency of rhamnolipid. PMID- 26433360 TI - Shale gas wastewater management under uncertainty. AB - This work presents an optimization framework for evaluating different wastewater treatment/disposal options for water management during hydraulic fracturing (HF) operations. This framework takes into account both cost-effectiveness and system uncertainty. HF has enabled rapid development of shale gas resources. However, wastewater management has been one of the most contentious and widely publicized issues in shale gas production. The flowback and produced water (known as FP water) generated by HF may pose a serious risk to the surrounding environment and public health because this wastewater usually contains many toxic chemicals and high levels of total dissolved solids (TDS). Various treatment/disposal options are available for FP water management, such as underground injection, hazardous wastewater treatment plants, and/or reuse. In order to cost-effectively plan FP water management practices, including allocating FP water to different options and planning treatment facility capacity expansion, an optimization model named UO-FPW is developed in this study. The UO-FPW model can handle the uncertain information expressed in the form of fuzzy membership functions and probability density functions in the modeling parameters. The UO-FPW model is applied to a representative hypothetical case study to demonstrate its applicability in practice. The modeling results reflect the tradeoffs between economic objective (i.e., minimizing total-system cost) and system reliability (i.e., risk of violating fuzzy and/or random constraints, and meeting FP water treatment/disposal requirements). Using the developed optimization model, decision makers can make and adjust appropriate FP water management strategies through refining the values of feasibility degrees for fuzzy constraints and the probability levels for random constraints if the solutions are not satisfactory. The optimization model can be easily integrated into decision support systems for shale oil/gas lifecycle management. PMID- 26433361 TI - Risk analysis of emergent water pollution accidents based on a Bayesian Network. AB - To guarantee the security of water quality in water transfer channels, especially in open channels, analysis of potential emergent pollution sources in the water transfer process is critical. It is also indispensable for forewarnings and protection from emergent pollution accidents. Bridges above open channels with large amounts of truck traffic are the main locations where emergent accidents could occur. A Bayesian Network model, which consists of six root nodes and three middle layer nodes, was developed in this paper, and was employed to identify the possibility of potential pollution risk. Dianbei Bridge is reviewed as a typical bridge on an open channel of the Middle Route of the South to North Water Transfer Project where emergent traffic accidents could occur. Risk of water pollutions caused by leakage of pollutants into water is focused in this study. The risk for potential traffic accidents at the Dianbei Bridge implies a risk for water pollution in the canal. Based on survey data, statistical analysis, and domain specialist knowledge, a Bayesian Network model was established. The human factor of emergent accidents has been considered in this model. Additionally, this model has been employed to describe the probability of accidents and the risk level. The sensitive reasons for pollution accidents have been deduced. The case has also been simulated that sensitive factors are in a state of most likely to lead to accidents. PMID- 26433362 TI - Optimisation of sludge pretreatment by low frequency sonication under pressure. AB - This work aims at optimizing sludge pretreatment by non-isothermal sonication, varying frequency, US power (PUS) and intensity (IUS varied through probe size), as well as hydrostatic pressure and operation mode (continuous vs. sequential - or pulsed - process). Under non isothermal sonication sludge solubilization results from both ultrasound disintegration and thermal hydrolysis which are conversely depending on temperature. As found in isothermal operation: - For a given specific energy input, higher sludge disintegration is still achieved at higher PUS and lower sonication time. - US effects can be highly improved by applying a convenient pressure. - 12 kHz always performs better than 20 kHz. Nevertheless the optimum pressure depends not only on PUS and IUS, but also on temperature evolution during sonication. Under adiabatic mode, a sequential sonication using 5 min US-on at 360 W, 12 kHz, and 3.25 bar and 30 min US-off gives the best sludge disintegration, while maintaining temperature in a convenient range to prevent US damping. PMID- 26433363 TI - Pilot-scale study on the treatment of basal aquifer water using ultrafiltration, reverse osmosis and evaporation/crystallization to achieve zero-liquid discharge. AB - Basal aquifer water is deep groundwater found at the bottom of geological formations, underlying bitumen-saturated sands. Some of the concerns associated with basal aquifer water at the Athabasca oil sands are the high concentrations of hardness-causing compounds, alkalinity, and total dissolved solids. The objective of this pilot-scale study was to treat basal aquifer water to a quality suitable for its reuse in the production of synthetic oil. To achieve zero-liquid discharge (ZLD) conditions, the treatment train included chemical oxidation, polymeric ultrafiltration (UF), reverse osmosis (RO), and evaporation crystallization technologies. The results indicated that the UF unit was effective in removing solids, with UF filtrate turbidity averaging 2.0 NTU and silt density index averaging 0.9. Membrane autopsies indicated that iron was the primary foulant on the UF and RO membranes. Laboratory and pilot-scale tests on RO reject were conducted to determine the feasibility of ZLD crystallization. Due to the high amounts of calcium, magnesium, and bicarbonate in the RO reject, softening of the feed was required to avoid scaling in the evaporator. Crystals produced throughout the testing were mainly sodium chloride. The results of this study indicated that the ZLD approach was effective in both producing freshwater and minimizing brine discharges. PMID- 26433364 TI - Smoking, passive smoking and lung cancer cell types among women in Morocco: analysis of epidemiological profiling of 101 cases. AB - BACKGROUND: Recently women's lung cancer mortality rates have dramatically increased in developed countries, contrasting with a levelling off or decrease among men. Descriptive epidemiological data on primary lung cancer in women is scarce in Morocco. The aim of this study, conducted in the National Institute of Oncology in Rabat, was to describe the epidemiological profiling especially for the smoking status, to determine the most frequent type of lung cancer, and to analyse the survival of Moroccan women with lung cancer diagnosis. RESULTS: We found 101 women among 1680 (male and female) cases of lung cancer. The never smokers were estimated to 75 %. The proportion of adenocarcinoma among never and passive smokers was higher than that of squamous cell carcinoma (SCC) (69.4 versus 30.6 %), while among women who were smokers, the most frequent histological type was SCC (63.6 %). The Cox regression analysis showed that smoking and passive smoking were not significantly associated with survival [HR: 0.62 (95 % CI 0.31, 1.30); p = 0.19] [HR: 0.56 (95 % CI 0.29, 1.08); p = 0.08] respectively. Adenocarcinoma was significantly associated with shorter survival [HR: 1.73 (95 % CI 1.05, 2.85); p = 0.03]. CONCLUSIONS: The majority Moroccan women affected by lung cancer have never smoked (75 %). Environmental exposures, genetic predisposition, hormonal factors, and viral infection may all play a role in lung cancer in this category. The relation between histological type and tobacco found in our series concurred with those reported in the literature- adenocarcinoma appears to be the most frequent cell type affecting never and passive smokers. Adenocarcinoma is significantly associated with poorer survival. PMID- 26433365 TI - Development of nitric oxide catalytic coatings by conjugating 3,3 disulfodipropionic acid and 3,3-diselenodipropionic acid for improving hemocompatibility. AB - Nitric oxide (NO), discovered as an endothelium-derived relaxing factor, has been found to have multiple intracellular effects in vascular diseases including vasorelaxation regulation, endothelial regeneration, inhibition of leukocyte chemotaxis, and platelet activation. In the work described here, the authors have developed a NO-catalytic bioactive coating for improving hemocompatibility. The authors first prepared a dopamine and hexamethylendiamine (PDAM/HD) amine-rich adherent copolymer coating to introduce amine groups onto 316L stainless steel, followed by covalently conjugating 3,3-disulfodipropionic acid (S-S) and 3,3 diselenodipropionic acid (Se-Se), which mimic glutathione peroxidase-like catalytic production of NO. S-S and Se-Se were immobilized on the PDAM/HD surface via carbodiimide coupling chemistry. X-ray photoelectron spectroscopy analysis revealed clear S2p and Se3d signals, confirming the immobilization of S-S and Se Se on the PDAM/HD surface. The NO release behavior of different samples was investigated. In detail, two species of thionitrites (RSNO), S-nitrosoglutathione (GSNO, endogenous NO donors) and S-nitrosoacetylpenicillamine (SNAP) were chosen as NO donors to investigate the NO catalytic properties of S-S and Se-Se modified PDAM/HD surfaces. Not only Se-Se@PDAM/HD but also S-S@PDAM/HD coatings showed the ability to continuously catalyze RSNO to generate NO in the presence of proper thiol reducing agent. For the Se-Se@PDAM/HD coating, the NO release amount and rate were greater than S-S@PDAM/HD in both GSNO and SNAP conditions. The results showed that organosulfide species possesses NO catalytic ability as well as organoselenium species. The authors demonstrated that both S-S@PDAM/HD and Se Se@PDAM/HD coatings exhibited outstanding inhibition effect on platelet adhesion, aggregation and activation via the cyclic guanylate monophosphate signal pathway. Thus these results suggested that NO catalytic coatings based on organoselenium and organosulfide species immobilization can help to improve hemocompatibility. NO-catalytic strategies possess huge potential applications in blood-contacting devices. PMID- 26433366 TI - Modulation of cationicity of chitosan for tuning mesenchymal stem cell adhesion, proliferation, and differentiation. AB - The aim of this study was to modulate the cationicity of chitosan to influence the mesenchymal stem cell (MSC) responses in terms of cell adhesion, proliferation, and differentiation. The authors prepared water-soluble carboxymethyl chitosan hydrogels using genipin as the crosslinking agent. The chitosan cationicity was modulated by varying the genipin content from 0.5 to 10 wt. %. The results indicated that the cationicity exerted a striking modulation effect on various MSC responses. The increase of the genipin content, i.e., decrease of the free amino group content (cationicity), overall promoted the MSC adhesion, cytoskeleton organization, proliferation, and differentiation into the osteogenic lineage. A surprising cell alignment effect was also observed on chitosan samples with high genipin concentrations (>2.5%). The chitosan sample with the highest genipin concentrations (10%) exhibited the best MSC proliferation and highest protein expression levels toward osteogenic lineages. The genipin content also showed a strong modulation effect on MSC condensation, and cell-cell and cell-matrix interactions, as suggested by the expressions of the sry related HMG box9 (Sox9), intercellular adhesion molecule 1, and N Cadherin. Overall, the authors have demonstrated that modulation of cationicity (amino content) of chitosan is an effective and simple approach to tuning various MSC responses, including adhesion, proliferation, differentiation, as well as cell-cell interactions. Such findings might have important implications in biomaterial design for various biomedical applications. PMID- 26433367 TI - High-risk plaque features can be detected in non-stenotic carotid plaques of patients with ischaemic stroke classified as cryptogenic using combined (18)F-FDG PET/MR imaging. AB - PURPOSE: The aim of this study was to investigate in 18 patients with ischaemic stroke classified as cryptogenic and presenting non-stenotic carotid atherosclerotic plaques the morphological and biological aspects of these plaques with magnetic resonance imaging (MRI) and (18)F-fluoro-deoxyglucose positron emission tomography ((18)F-FDG PET) imaging. METHODS: Carotid arteries were imaged 150 min after injection of (18)F-FDG with a combined PET/MRI system. American Heart Association (AHA) lesion type and plaque composition were determined on consecutive MRI axial sections (n = 460) in both carotid arteries. (18)F-FDG uptake in carotid arteries was quantified using tissue to background ratio (TBR) on corresponding PET sections. RESULTS: The prevalence of complicated atherosclerotic plaques (AHA lesion type VI) detected with high-resolution MRI was significantly higher in the carotid artery ipsilateral to the ischaemic stroke as compared to the contralateral side (39 vs 0 %; p = 0.001). For all other AHA lesion types, no significant differences were found between ipsilateral and contralateral sides. In addition, atherosclerotic plaques classified as high risk lesions with MRI (AHA lesion type VI) were associated with higher (18)F-FDG uptake in comparison with other AHA lesions (TBR = 3.43 +/- 1.13 vs 2.41 +/- 0.84, respectively; p < 0.001). Furthermore, patients presenting at least one complicated lesion (AHA lesion type VI) with MRI showed significantly higher (18)F-FDG uptake in both carotid arteries (ipsilateral and contralateral to the stroke) in comparison with carotid arteries of patients showing no complicated lesion with MRI (mean TBR = 3.18 +/- 1.26 and 2.80 +/- 0.94 vs 2.19 +/- 0.57, respectively; p < 0.05) in favour of a diffuse inflammatory process along both carotid arteries associated with complicated plaques. CONCLUSION: Morphological and biological features of high-risk plaques can be detected with (18)F-FDG PET/MRI in non-stenotic atherosclerotic plaques ipsilateral to the stroke, suggesting a causal role for these plaques in stroke. Combined (18)F-FDG PET/MRI systems might help in the evaluation of patients with ischaemic stroke classified as cryptogenic. PMID- 26433368 TI - Changes in the activities of starch metabolism enzymes in rice grains in response to elevated CO2 concentration. AB - The global atmospheric CO(2) concentration is currently (2012) 393.1 MUmol mol( 1), an increase of approximately 42 % over pre-industrial levels. In order to understand the responses of metabolic enzymes to elevated CO(2) concentrations, an experiment was conducted using the Free Air CO(2) Enrichment (FACE )system. Two conventional japonica rice varieties (Oryza sativa L. ssp. japonica) grown in North China, Songjing 9 and Daohuaxiang 2, were used in this study. The activities of ADPG pyrophosphorylase, soluble and granule-bound starch synthases, and soluble and granule-bound starch branching enzymes were measured in rice grains, and the effects of elevated CO(2) on the amylose and protein contents of the grains were analyzed. The results showed that elevated CO(2) levels significantly increased the activity of ADPG pyrophosphorylase at day 8, 24, and 40 after flower, with maximum increases of 56.67 % for Songjing 9 and 21.31 % for Daohuaxiang 2. Similarly, the activities of starch synthesis enzymes increased significantly from the day 24 after flower to the day 40 after flower, with maximum increases of 36.81 % for Songjing 9 and 66.67 % for Daohuaxiang 2 in soluble starch synthase (SSS), and 25.00 % for Songjing 9 and 36.44 % for Daohuaxiang 2 in granule-bound starch synthase (GBSS), respectively. The elevated CO(2) concentration significantly increased the activity of soluble starch branching enzyme (SSBE) at day 16, 32, and 40 after flower, and also significantly increased the activity of granule-bound starch branching enzyme (GBSBE) at day 8, 32, and 40 after flower. The elevated CO(2) concentration increased the peak values of enzyme activity, and the timing of the activity peaks for SSS and GBSBE were earlier in Songjing 9 than in Daohuaxiang 2. There were obvious differences in developmental stages between the two varieties of rice, which indicated that the elevated CO(2) concentration increased enzyme activity expression and starch synthesis, affecting the final contents of starch and protein in the rice grains. Our results will provide a foundation for understanding the physiological mechanisms of rice yield under elevated atmospheric CO(2) concentrations. PMID- 26433369 TI - One-year follow-up of two novel CBTs for adolescents with ADHD. AB - Long-term effects of two CBTs for adolescents with ADHD are explored: One aimed at improving planning skills (Plan My Life; PML), the other a solution-focused therapy (SFT) without focusing on planning skills. In a RCT, adolescents with ADHD (n = 159) were assigned to PML or SFT and improved significantly between pre and posttest with large effect sizes Boyer et al (Eur Child Adolesc Psychiatry. doi: 10.1007/s00787-014-0661-5 ), with marginal differences in favor of PML. One year follow-up data were gathered. Initial improvements remained stable or continued to improve from posttest to 1-year follow-up. 25.9 % of adolescents showed normalized functioning. However, no treatment differences were found. These results are consistent with the finding that treatment of ADHD improves long-term outcomes, but not to the point of normalization. Earlier found differences at 3-month follow-up in favor of PML disappeared, indicating that focusing treatment on planning skills is not necessary for improvement or that a more prolonged planning-focused treatment is needed. PMID- 26433371 TI - A dynamic ambulance management model for rural areas : Computing redeployment actions for relevant performance measures. AB - We study the Dynamic Ambulance Management (DAM) problem in which one tries to retain the ability to respond to possible future requests quickly when ambulances become busy. To this end, we need models for relocation actions for idle ambulances that incorporate different performance measures related to response times. We focus on rural regions with a limited number of ambulances. We model the region of interest as an equidistant graph and we take into account the current status of both the system and the ambulances in a state. We do not require ambulances to return to a base station: they are allowed to idle at any node. This brings forth a high degree of complexity of the state space. Therefore, we present a heuristic approach to compute redeployment actions. We construct several scenarios that may occur one time-step later and combine these scenarios with each feasible action to obtain a classification of actions. We show that on most performance indicators, the heuristic policy significantly outperforms the classical compliance table policy often used in practice. PMID- 26433370 TI - Salivary oxytocin in adolescents with conduct problems and callous-unemotional traits. AB - Callous-unemotional (CU) traits correlate with the severity and prognosis of conduct disorder in youth. The neuropeptide oxytocin (OT) has been linked to prosocial behaviors, including empathy and collaboration with others. This study discusses a possible role for OT in the biology of delinquent behavior. We hypothesized that in delinquent youth OT secretion will correlate with the severity of conduct problems and specifically with the level of CU traits. The study group included 67 male adolescents (mean age 16.2 years) undergoing residential treatment, previously assessed by an open clinical interview and history for the psychiatric diagnosis. Staff based Inventory of Callous Unemotional traits for psychopathy and Strength and Difficulties Questionnaire were administered, and patients' medical and social personal files were systematically coded for previous history of antisocial acts using the Brown Goodwin Questionnaire. Salivary OT was assayed by ELISA. Salivary OT levels were inversely correlated with conduct problems severity on Strength and Difficulties Questionnaire (r = -0.27; p <= 0.01). Recorded history of antisocial acts did not correlate with current OT levels. Odds ratio (OR) for significant CU traits among subjects with conduct problems was increased in low-OT (OR = 14, p <= 0.05) but not in high-OT subjects (OR = 6, p >= 0.05). Children with conduct problems and low levels of salivary OT are at risk for significant CU traits. These results suggest a possible role for salivary OT as a biomarker for CU traits and conduct problems severity. PMID- 26433372 TI - Overutilization and underutilization of operating rooms - insights from behavioral health care operations management. AB - The planning of surgery durations is crucial for efficient usage of operating theaters. Both planning too long and too short durations for surgeries lead to undesirable consequences, e.g. idle time, overtime, or rescheduling of surgeries. We define these consequences as operating room inefficiency. The overall objective of planning surgery durations is to minimize expected operating room inefficiency, since surgery durations are stochastic. While most health care studies assume economically rational behavior of decision makers, experimental studies have shown that decision makers often do not act according to economic incentives. Based on insights from health care operations management, medical decision making, behavioral operations management, as well as empirical observations, we derive hypotheses that surgeons' behavior deviates from economically rational behavior. To investigate this, we undertake an experimental study where experienced surgeons are asked to plan surgeries with uncertain durations. We discover systematic deviations from optimal decision making and offer behavioral explanations for the observed biases. Our research provides new insights to tackle a major problem in hospitals, i.e. low operating room utilization going along with staff overtime. PMID- 26433373 TI - Long-Range Reduced Predictive Information Transfers of Autistic Youths in EEG Sensor-Space During Face Processing. AB - The majority of previous functional/effective connectivity studies conducted on the autistic patients converged to the underconnectivity theory of ASD: "long range underconnectivity and sometimes short-rang overconnectivity". However, to the best of our knowledge the total (linear and nonlinear) predictive information transfers (PITs) of autistic patients have not been investigated yet. Also, EEG data have rarely been used for exploring the information processing deficits in autistic subjects. This study is aimed at comparing the total (linear and nonlinear) PITs of autistic and typically developing healthy youths during human face processing by using EEG data. The ERPs of 12 autistic youths and 19 age matched healthy control (HC) subjects were recorded while they were watching upright and inverted human face images. The PITs among EEG channels were quantified using two measures separately: transfer entropy with self-prediction optimality (TESPO), and modified transfer entropy with self-prediction optimality (MTESPO). Afterwards, the directed differential connectivity graphs (dDCGs) were constructed to characterize the significant changes in the estimated PITs of autistic subjects compared with HC ones. By using both TESPO and MTESPO, long range reduction of PITs of ASD group during face processing was revealed (particularly from frontal channels to right temporal channels). Also, it seemed the orientation of face images (upright or upside down) did not modulate the binary pattern of PIT-based dDCGs, significantly. Moreover, compared with TESPO, the results of MTESPO were more compatible with the underconnectivity theory of ASD in the sense that MTESPO showed no long-range increase in PIT. It is also noteworthy that to the best of our knowledge it is the first time that a version of MTE is applied for patients (here ASD) and it is also its first use for EEG data analysis. PMID- 26433374 TI - Money and Mental Illness: A Study of the Relationship Between Poverty and Serious Psychological Problems. AB - Several studies have indicated a co-occurrence between mental problems, a bad economy, and social isolation. Medical treatments focus on reducing the extent of psychiatric problems. Recent research, however, has highlighted the possible effects of social initiatives. The aim of this study was to examine the relation between severe mental illness, economic status, and social relations. METHOD: a financial contribution per month was granted to 100 individuals with severe mental illnesses for a 9-month period. Assessments of the subjects were made before the start of the intervention and after 7 months' duration. A comparison group including treatment as usual only was followed using the same instruments. Significant improvements were found for depression and anxiety, social networks, and sense of self. No differences in functional level were found. Social initiatives may have treatment and other beneficial effects and should be integrated into working contextually with persons with severe mental illnesses. PMID- 26433375 TI - The Potential Roles of Aquaporin 4 in Alzheimer's Disease. AB - Aquaporin 4 (AQP4) is the major water channel expressed in the central nervous system (CNS), and it is primarily expressed in astrocytes. It has been studied in various brain pathological conditions. However, the potential for AQP4 to influence Alzheimer's disease (AD) is still unclear. Research regarding AQP4 functions related to AD can be traced back several years and has gradually progressed toward a better understanding of the potential mechanisms. Currently, it has been suggested that AQP4 influences synaptic plasticity, and AQP4 deficiency may impair learning and memory, in part, through glutamate transporter 1 (GLT-1). AQP4 may mediate the clearance of amyloid beta peptides (Abeta). In addition, AQP4 may influence potassium (K(+)) and calcium (Ca(2+)) ion transport, which could play decisive roles in the pathogenesis of AD. Furthermore, AQP4 knockout is involved in neuroinflammation and interferes with AD. To date, no specific therapeutic agents have been developed to inhibit or enhance AQP4. However, experimental results strongly emphasize the importance of this topic for future investigations. PMID- 26433376 TI - Sulforaphane Ameliorates Okadaic Acid-Induced Memory Impairment in Rats by Activating the Nrf2/HO-1 Antioxidant Pathway. AB - Okadaic acid (OKA) causes memory impairment and attenuates nuclear factor erythroid 2-related factor 2 (Nrf2) along with oxidative stress and neuroinflammation in rats. Sulforaphane (dietary isothiocyanate compound), an activator of Nrf2 signaling, exhibits neuroprotective effects. However, the protective effect of sulforaphane in OKA-induced neurotoxicity remains uninvestigated. Therefore, in the present study, the role of sulforaphane in OKA induced memory impairment in rats was explored. A significant increased Nrf2 expression in the hippocampus and cerebral cortex was observed in trained (Morris water maze) rats, and a significant decreased Nrf2 expression in memory-impaired (OKA, 200 ng icv) rats indicated its involvement in memory function. Sulforaphane administration (5 and 10 mg/kg, ip, days 1 and 2) ameliorates OKA-induced memory impairment in rats. The treatment also restored Nrf2 and its downstream antioxidant protein expression (GCLC, HO-1) and attenuated oxidative stress (ROS, nitrite, GSH), neuroinflammation (NF-kappaB, TNF-alpha, IL-10), and neuronal apoptosis in the cerebral cortex and hippocampus of OKA-treated rats. Further, to determine whether modulation of Nrf2 signaling is responsible for the protective effect of sulforaphane, in vitro, Nrf2 siRNA and its downstream HO-1 inhibition studies were carried out in a rat astrocytoma cell line (C6). The protective effects of sulforaphane were abolished with Nrf2 siRNA and HO-1 inhibition in astrocytes. The results suggest that Nrf2-dependent activation of cellular antioxidant machinery results in sulforaphane-mediated protection against OKA induced memory impairment in rats. Graphical Abstract ?. PMID- 26433377 TI - Dopamine Burden Triggers Neurodegeneration via Production and Release of TNF alpha from Astrocytes in Minimal Hepatic Encephalopathy. AB - Dopamine (DA)-induced learning and memory impairment is well documented in minimal hepatic encephalopathy (MHE), but the contribution of DA to neurodegeneration and the involved underlying mechanisms are not fully understood. In this study, the effect of DA on neuronal apoptosis was initially detected. The results showed that MHE/DA (10 MUg)-treated rats displayed neuronal apoptosis. However, we found that DA (10 MUM) treatment did not induce evident apoptosis in primary cultured neurons (PCNs) but did produce TNF-alpha in primary cultured astrocytes (PCAs). Furthermore, co-cultures between PCAs and PCNs exposed to DA exhibited increased astrocytic TNF-alpha levels and neuronal apoptosis compared with co-cultures exposed to the vehicle, indicating the attribution of the neuronal apoptosis to astrocytic TNF-alpha. We also demonstrated that DA enhanced TNF-alpha production from astrocytes by activation of the TLR4/MyD88/NF-kappaB pathway, and secreted astrocytic TNF-alpha potentiated neuronal apoptosis through inactivation of the PI3K/Akt/mTOR pathway. Overall, the findings from this study suggest that DA stimulates substantial production and secretion of astrocytic TNF-alpha, consequently and indirectly triggering progressive neurodegeneration, resulting in cognitive decline and memory loss in MHE. PMID- 26433378 TI - Neuroprotective and Functional Improvement Effects of Methylene Blue in Global Cerebral Ischemia. AB - Transient global cerebral ischemia (GCI) causes delayed neuronal cell death in the vulnerable hippocampus CA1 subfield, as well as behavioral deficits. Ischemia reperfusion (I/R) produces excessive reactive oxygen species and plays a key role in brain injury. The mitochondrial electron respiratory chain is the main cellular source of free radical generation, and dysfunction of mitochondria has a significant impact on the neuronal cell death in ischemic brain. The aim of the present study is to investigate the potential beneficial effects of methylene blue (MB) in a four-vessel occlusion (4VO) GCI model on adult male rats. MB was delivered at a dose of 0.5 mg/kg/day for 7 days, through a mini-pump implanted subcutaneously after GCI. We first found that MB significantly improved ischemic neuronal survival in the hippocampal CA1 region as measured by cresyl violet staining as well as NeuN staining. We also found that MB has the ability to rescue ischemia-induced decreases of cytochrome c oxidase activity and ATP generation in the CA1 region following I/R. Further analysis with labeling of MitoTracker(r) Red revealed that the depolarization of mitochondrial membrane potential (MMP) was markedly attenuated following MB treatment. In addition, the induction of caspase-3, caspase-8, and caspase-9 activities and the increased numbers of TUNEL-positive cells of the CA1 region were significantly reduced by MB application. Correspondingly, Barnes maze tests showed that the deterioration of spatial learning and memory performance following GCI was significantly improved in the MB-treatment group compared to the ischemic control group. In summary, our study suggests that MB may be a promising therapeutic agent targeting neuronal cell death and cognitive deficits following transient global cerebral ischemia. PMID- 26433379 TI - Help-seeking behaviours, barriers to care and self-efficacy for seeking mental health care: a population-based study in Rwanda. AB - PURPOSE: Mental disorders commonly affect young people but usually go unrecognized and untreated. This study aimed to investigate help-seeking behaviours, barriers to care and self-efficacy for seeking mental health care among young adults with current depression and/or suicidality in a low-income setting. METHODS: This cross-sectional study used two sub-populations: a sub sample of those suffering from current depression and/or suicidality (n = 247) and another of those not suffering from these conditions and not suffering from any other mental condition investigated (n = 502). Help-seeking behaviours, barriers to care and self-efficacy for mental health care seeking were measured among those suffering from current depression and/or suicidality (n, %). Logistic regression was used to identify risk factors for experiencing barriers to care. Self-efficacy for seeking mental health care was compared between men and women in the two sub-populations. RESULTS: Of the 247 men and women with current depression and/or suicidality, 36.0 % sought help at a health care unit and 64.0 % from trusted people in the community. Only six people received help from a mental health professional. The identified barriers were mainly related to accessibility and acceptability of health services. For the population suffering from current depression and/or suicidality, the self-efficacy scale for seeking mental health care suggested a low confidence in accessing mental health care but a high confidence in respondents' ability to successfully communicate with health care staff and to cope with consequences of seeking care. CONCLUSION: The current study clearly highlights young adults' poor access to mental health care services. To reach universal health coverage, substantial resources need to be allocated to mental health, coupled with initiatives to improve mental health literacy in the general population. PMID- 26433380 TI - The Antidiabetic Drug Metformin Stimulates Glycolytic Lactate Production in Cultured Primary Rat Astrocytes. AB - Metformin is the most frequently used drug for the treatment of type 2 diabetes in humans. However, only little is known about effects of metformin on brain metabolism. To investigate potential metabolic consequences of an exposure of brain cells to metformin, we incubated rat astrocyte-rich primary cultures with this compound. Metformin in concentrations of up to 30 mM did not acutely compromise the viability of astrocytes, but caused a time- and concentration dependent increase in cellular glucose consumption and lactate production. For acute incubations in the hour range, the presence of 10 mM metformin doubled the glycolytic flux, while already 1 mM metformin doubled glycolytic flux during incubation for 24 h. In addition to metformin, also other guanidino compounds increased astrocytic lactate production. After 4 h of incubation, half-maximal stimulation of glycolysis was observed for metformin, guanidine and phenformin at concentrations of around 3 mM, 3 mM and 30 uM, respectively. The acute stimulation of glycolytic lactate production by metformin was persistent after removal of extracellular metformin and was also observed, if glucose was absent from the incubation medium or replaced by other hexoses. The metformin-induced stimulation of glycolytic flux was not prevented by compound C, an inhibitor of AMP-dependent protein kinase, nor was it additive to the stimulation of glycolytic flux caused by respiratory chain inhibitors. These data demonstrate that the antidiabetic drug metformin has the potential to strongly activate glycolytic lactate production in brain astrocytes. PMID- 26433381 TI - Modification of Astrocyte Metabolism as an Approach to the Treatment of Epilepsy: Triheptanoin and Acetyl-L-Carnitine. AB - Epilepsy is a severe neurological disorder characterized by altered electrical activity in the brain. Important pathophysiological mechanisms include disturbed metabolism and homeostasis of major excitatory and inhibitory neurotransmitters, glutamate and GABA. Current drug treatments are largely aimed at decreasing neuronal excitability and thereby preventing the occurrence of seizures. However, many patients are refractory to treatment and side effects are frequent. Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy in adults. In rodents, the pilocarpine-status epilepticus model reflects the pathology and chronic spontaneous seizures of TLE and the pentylenetetrazole kindling model exhibits chronic induced limbic seizures. Accumulating evidence from studies on TLE points to alterations in astrocytes and neurons as key metabolic changes. The present review describes interventions which alleviate these disturbances in astrocyte-neuronal interactions by supporting mitochondrial metabolism. The compounds discussed are the endogenous transport molecule acetyl-L-carnitine and the triglyceride of heptanoate, triheptanoin. Both provide acetyl moieties for oxidation in the tricarboxylic acid cycle whereas heptanoate is also provides propionyl-CoA, which after carboxylation can produce succinyl-CoA, resulting in anaplerosis-the refilling of the tricarboxylic acid cycle. PMID- 26433382 TI - Improved validation of IDP ensembles by one-bond Calpha-Halpha scalar couplings. AB - Intrinsically disordered proteins (IDPs) are best described by ensembles of conformations and a variety of approaches have been developed to determine IDP ensembles. Because of the large number of conformations, however, cross validation of the determined ensembles by independent experimental data is crucial. The (1)JCalphaHalpha coupling constant is particularly suited for cross validation, because it has a large magnitude and mostly depends on the often less accessible dihedral angle psi. Here, we reinvestigated the connection between (1)JCalphaHalpha values and protein backbone dihedral angles. We show that accurate amino-acid specific random coil values of the (1)JCalphaHalpha coupling constant, in combination with a reparameterized empirical Karplus-type equation, allow for reliable cross-validation of molecular ensembles of IDPs. PMID- 26433383 TI - Identification and activation of novel biosynthetic gene clusters by genome mining in the kirromycin producer Streptomyces collinus Tu 365. AB - Streptomycetes are prolific sources of novel biologically active secondary metabolites with pharmaceutical potential. S. collinus Tu 365 is a Streptomyces strain, isolated 1972 from Kouroussa (Guinea). It is best known as producer of the antibiotic kirromycin, an inhibitor of the protein biosynthesis interacting with elongation factor EF-Tu. Genome Mining revealed 32 gene clusters encoding the biosynthesis of diverse secondary metabolites in the genome of Streptomyces collinus Tu 365, indicating an enormous biosynthetic potential of this strain. The structural diversity of secondary metabolisms predicted for S. collinus Tu 365 includes PKS, NRPS, PKS-NRPS hybrids, a lanthipeptide, terpenes and siderophores. While some of these gene clusters were found to contain genes related to known secondary metabolites, which also could be detected in HPLC-MS analyses, most of the uncharacterized gene clusters are not expressed under standard laboratory conditions. With this study we aimed to characterize the genome information of S. collinus Tu 365 to make use of gene clusters, which previously have not been described for this strain. We were able to connect the gene clusters of a lanthipeptide, a carotenoid, five terpenoid compounds, an ectoine, a siderophore and a spore pigment-associated gene cluster to their respective biosynthesis products. PMID- 26433384 TI - Microbial conversion of pyrolytic products to biofuels: a novel and sustainable approach toward second-generation biofuels. AB - This review highlights the potential of the pyrolysis-based biofuels production, bio-ethanol in particular, and lipid in general as an alternative and sustainable solution for the rising environmental concerns and rapidly depleting natural fuel resources. Levoglucosan (1,6-anhydrous-beta-D-glucopyranose) is the major anhydrosugar compound resulting from the degradation of cellulose during the fast pyrolysis process of biomass and thus the most attractive fermentation substrate in the bio-oil. The challenges for pyrolysis-based biorefineries are the inefficient detoxification strategies, and the lack of naturally available efficient and suitable fermentation organisms that could ferment the levoglucosan directly into bio-ethanol. In case of indirect fermentation, acid hydrolysis is used to convert levoglucosan into glucose and subsequently to ethanol and lipids via fermentation biocatalysts, however the presence of fermentation inhibitors poses a big hurdle to successful fermentation relative to pure glucose. Among the detoxification strategies studied so far, over-liming, extraction with solvents like (n-butanol, ethyl acetate), and activated carbon seem very promising, but still further research is required for the optimization of existing detoxification strategies as well as developing new ones. In order to make the pyrolysis-based biofuel production a more efficient as well as cost-effective process, direct fermentation of pyrolysis oil-associated fermentable sugars, especially levoglucosan is highlly desirable. This can be achieved either by expanding the search to identify naturally available direct levoglusoan utilizers or modify the existing fermentation biocatalysts (yeasts and bacteria) with direct levoglucosan pathway coupled with tolerance engineering could significantly improve the overall performance of these microorganisms. PMID- 26433386 TI - Overexpression of PTP4A3 is associated with metastasis and unfavorable prognosis in bladder cancer. AB - PURPOSE: Bladder cancer (BC) is the most common malignancy in urinary system. The prognosis of metastatic BC is poor, but there remains no reliable marker to early detect metastasis. Dysregulated prenylated protein tyrosine phosphatases (PTPs) are commonly associated with cancer metastasis. From a published BC transcriptome, we identified that PTP IVA3 (PTP4A3) was the most significantly upregulated gene implicated in tumor progression among genes related to prenylated PTPs. We therefore analyzed PTP4A3 expression in our well characterized cohort of BC. METHODS: By immunohistochemistry, PTP4A3 expression was determined using H-score. PTP4A3 expression of 295 BCs was compared with clinicopathological parameters, and the effect of PTP4A3 on cancer-specific survival (CSS) and metastasis-free survival (MFS) was also examined. Two independent sets of BCs were used to assess PTP4A3 protein and transcript expression in normal urothelium and different stage tumors. RESULTS: PTP4A3 overexpression was significantly associated with higher pT stage (P < 0.001), nodal metastasis (P < 0.001), vascular invasion (P < 0.001), and perineural invasion (P = 0.021). In multivariate analysis, PTP4A3 overexpression was an independent predictor for CSS (P < 0.001) and MFS (P = 0.007). Notably, the difference in CSS and MFS between high and low PTP4A3-expressing tumors was also significant in muscle-invasive BCs. PTP4A3 protein expression showed significant and stepwise increments from normal urothelium to noninvasive BC, invasive BC, and metastatic foci (P < 0.001). PTP4A3 transcript was also obviously upregulated in high-stage BC (P < 0.001). CONCLUSIONS: PTP4A3 may play a role in BC oncogenesis and is a predictive marker of metastasis. PTP4A3 overexpression represents an independent prognosticator for BC, suggesting its potential theranostic value. PMID- 26433387 TI - Robotic versus conventional laparoscopic pyeloplasty in children less than 20 kg by weight: single-center experience. AB - PURPOSE: To compare outcomes of robotic versus conventional laparoscopic pyeloplasty in children less than 20 kg by weight. METHODS: Nineteen patients undergoing RP and twenty-five LP under 20 kg by weight were compared retrospectively with respect to demographics and operative, postoperative, and follow-up data. For all cases, a lateral transperitoneal approach was used and all anastomoses were stented. Success was defined as the resolution of preoperative symptoms and hydronephrosis postoperatively. If either case is not fulfilled, a renogram was obtained postoperatively. Student's t test was used for statistical analysis. RESULTS: Forty-four patients underwent forty-seven pyeloplasties (19 RP and 25 LP), with three patients undergoing bilateral simultaneous laparoscopic procedure with mean age of 2.7 and 2.4 years in RP and LP, respectively. The robotic procedures were superior in terms of shorter mean hospital stay by one and half day on an average. Minimum time taken for RP was 60 min, while for LP it was 90 min. Both procedures were comparable in terms of complication rate, success rate as well as operating time. CONCLUSIONS: This comparative study confirms the feasibility, efficacy, and safety of robotic pyeloplasty in infants and toddlers. The obvious advantage is being shorter hospital stay. Further prospective studies will be needed to show its superiority over LP. PMID- 26433385 TI - David and Goliath: chemical perturbation of eukaryotes by bacteria. AB - Environmental microbes produce biologically active small molecules that have been mined extensively as antibiotics and a smaller number of drugs that act on eukaryotic cells. It is known that there are additional bioactives to be discovered from this source. While the discovery of new antibiotics is challenged by the frequent discovery of known compounds, we contend that the eukaryote active compounds may be less saturated. Indeed, despite there being far fewer eukaryotic-active natural products these molecules interact with a far richer diversity of molecular and cellular targets. PMID- 26433388 TI - Acute and Chronic Management of Neuromyelitis Optica Spectrum Disorder. AB - OPINION STATEMENT: Neuromyelitis optica and neuromyelitis optica spectrum disorder (NMO/NMOSD) is a rare but clinically aggressive demyelinating disease of the central nervous system (CNS) caused by antibodies against water channel protein aquaporin 4 (AQP4) in the astrocytic foot processes. Patients typically present with optic neuritis (ON) or longitudinally extensive transverse myelitis (LETM). The majority of patients with NMOSD show good response to treatment with steroids and plasmapheresis in the acute setting; however, 90 % of patients will eventually have clinical relapses and accrue permanent disability. Currently, immune modulation is the mainstay of maintenance therapy with anti CD-20 (rituximab, RituxanTM) having collectively the strongest evidence to support its use and mycophenolate mofetil having comparable reductions in absolute relapse rate (ARR) and expanded disability status scale (EDSS) scores. Azathioprine, mitoxantrone, and methotrexate also have retrospective case series data that demonstrate reduction in ARR and stabilization of EDSS but with higher relapse rates and exposure to greater risk of treatment toxicities. Excitingly, multiple novel therapies are under clinical study for patients who are refractory to these first-line therapies including monoclonal antibodies targeting interleukin-6 (IL 6), CD19, CD20, complement, and neutrophil elastase inhibitors which may provide additional options for patients with severe clinical presentations. Importantly, no randomized clinical trials have been published to date comparing clinical outcomes of different maintenance therapies in NMOSD. Several trials are currently underway, and results will help guide future management decisions as current evidence is from many small, retrospective case series and cohort studies with many potential confounds. PMID- 26433390 TI - How can the health situation and well-being of staff at German schools for the severely handicapped be improved? AB - PURPOSE: The aim of the study was to describe measures suggested by staff at German schools for the severely handicapped regarding possibilities to improve their health situation and well-being at work. We further wanted to analyze whether sociodemographic, occupation-related, and health-related characteristics influence the type of measures proposed. METHODS: The cross-sectional study was carried out between August 2010 and August 2012 at 13 schools for the handicapped focusing on motoric and/or holistic development of severely handicapped pupils. Data of teachers and educational staff were surveyed using written questionnaires. The analysis is based on free-text answers regarding the question: "What specific occupation-related measures would lead to an improvement of your well-being or health situation at the workplace?" RESULTS: A total of 395 persons (response proportion: 59.7 %) with a mean age of 45 years and predominantly female (86.8 %) participated in our survey. A total of 205 persons answered the study question providing 456 improvement suggestions, which were classified into 6 main and 13 subcategories. The main categories were professional education and supervision, organization of working tasks and time, work safety and work equipment, social aspects of work, human resources and contractual framework, and other. Measures proposed were influenced by gender, burden by nursing activities, teaching, and administrative tasks, and frequency of deterioration in working atmosphere. DISCUSSION: Proposed measures raise awareness for job-related health stressors and are a starting point to improve working conditions at these schools. Since suggestions vary widely by school and composition of staff, individual priorities have to be set and discussed with the school management. PMID- 26433389 TI - Elevated OCT1 participates in colon tumorigenesis and independently predicts poor prognoses of colorectal cancer patients. AB - Octamer transcription factor 1 (OCT1) was found to influence the genesis and progression of numerous cancers except for colorectal cancer (CRC). This study tried to explore the role of OCT1 in CRC and clarify the association between its expression and patients' clinical outcome. Transcriptional and post transcriptional expression of OCT1 was detected in CRC cancerous tissues and paired normal mucosae by real-time PCR as well as immunohistochemistry. Moreover, the effect of OCT1 knockdown on CRC cell proliferation was investigated both in vitro and in vivo using Cell Counting Kit-8 assay, colony-forming assay, and mouse tumorigenicity assay. Expression of OCT1 was found to be elevated in CRC. Suppression of OCT1 significantly inhibited CRC cell proliferation both in vitro and in vivo. Furthermore, upregulated level of OCT1 was significantly associated with N stage, M stage, and American Joint Committee on Cancer (AJCC) stage (P = 0.027, 0.014, and 0.002, respectively) as well as differential degree (P = 0.022). By using multivariate Cox hazard model, OCT1 was also shown to be a factor independently predicting overall survival (OS; P = 0.013, hazard ratio = 2.747, 95 % confidence interval 1.125 to 3.715) and disease-free survival (DFS; P = 0.004, hazard ratio = 2.756, 95 % confidence interval 1.191 to 4.589) for CRC patients. Our data indicate that OCT1 carries weight in colorectal carcinogenesis and functions as a novel prognostic indicator and a promising target of anti cancer therapy for CRC. PMID- 26433391 TI - Problematic recreational drug use: is there a role for outpatient sexual health clinics in identifying those not already engaged with treatment services? AB - Background There is an association between recreational drug use, high-risk sexual activity and sexually transmissible infections. Studies have shown a higher prevalence of drug use in those accessing sexual health services; however, there are minimal data on the proportion with problematic recreational drug use. We aimed to understand whether sexual health clinics could identify problematic drug and alcohol use as a novel referral pathway into treatment services. METHODS: Males attending two sexual health clinics in London completed questionnaires. Data were collected on demographics; gender of sexual partner; use of alcohol and recreational drugs; if they felt they had problematic use of drugs, alcohol or both; and if they had sought help for their problematic use. RESULTS: In total, 867 males completed the questionnaire; 387 (44.7%) were men who have sex with men (MSM). MSM had significantly higher lifetime use of any drug compared with non-MSM (80.6% vs. 62.5%; P<0.0001). Thirty-five (4.7%) self identified problematic drug or alcohol use, with no difference between MSM and non-MSM (6.3% vs. 3.5%; P=0.08). Of those with problematic drug or alcohol use, 20 were currently or had been engaged with a treatment service and 15 had never engaged with treatment services. MSM were more likely to have ever sought help for drug or alcohol problems compared with non-MSM (P=0.003). CONCLUSIONS: Some individuals attending sexual health clinics with problematic drug use have not engaged with treatment services. It is therefore appropriate to develop screening tools for sexual health clinics to identify these individuals and novel referral pathways to engage them in treatment services. PMID- 26433392 TI - Development and Validation of a High Pressure Liquid Chromatography-UV Method for the Determination of Treosulfan and Its Epoxy Metabolites in Human Plasma and Its Application in Pharmacokinetic Studies. AB - Treosulfan (l-threitol-1,4-di-methanesulfonate) is a prodrug of a bifunctional alkylating agent that is being used increasingly in pediatric bone marrow transplantation regimens. The activation pathway is a complex reaction, which consists of two consecutive reactions leading to epoxybutane derivatives which are responsible for DNA alkylation. A simple, sensitive high performance liquid chromatography method for the determination of the sum of treosulfan and its epoxy metabolites by UV detection after derivatization with sodium diethyldithiocarbamate in human plasma was developed and validated. Plasma samples containing treosulfan and epoxy metabolites were converted into thiocarbamate derivative with 10% sodium diethyldithiocarbamate. Dinitrobiphenyl was used as an internal standard. The analysis was carried out using a reversed phase C18 column with a mobile phase consisting of methanol-water (65:35, v/v) at a flow rate of 1 mL/min. The eluent was monitored at 254 nm. The standard calibration curve was established between 2.5 and 50 ug/mL, with a correlation coefficient of 0.9987. Intra- and interday precision and accuracy of the method was <8% and met the analytical criteria. Pharmacokinetic parameters were determined in six children who received intravenous treosulfan (dose range 12-24 g/m(2)) in combination with fludarabine prior to blood or marrow transplantation. PMID- 26433393 TI - Glutathione Deficit Affects the Integrity and Function of the Fimbria/Fornix and Anterior Commissure in Mice: Relevance for Schizophrenia. AB - BACKGROUND: Structural anomalies of white matter are found in various brain regions of patients with schizophrenia and bipolar and other psychiatric disorders, but the causes at the cellular and molecular levels remain unclear. Oxidative stress and redox dysregulation have been proposed to play a role in the pathophysiology of several psychiatric conditions, but their anatomical and functional consequences are poorly understood. The aim of this study was to investigate white matter throughout the brain in a preclinical model of redox dysregulation. METHODS: In a mouse model with impaired glutathione synthesis (Gclm KO), a state-of-the-art multimodal magnetic resonance protocol at high field (14.1 T) was used to assess longitudinally the white matter structure, prefrontal neurochemical profile, and ventricular volume. Electrophysiological recordings in the abnormal white matter tracts identified by diffusion tensor imaging were performed to characterize the functional consequences of fractional anisotropy alterations. RESULTS: Structural alterations observed at peri-pubertal age and adulthood in Gclm KO mice were restricted to the anterior commissure and fornix-fimbria. Reduced fractional anisotropy in the anterior commissure (-7.5% +/- 1.9, P<.01) and fornix-fimbria (-4.5% +/- 1.3, P<.05) were accompanied by reduced conduction velocity in fast-conducting fibers of the posterior limb of the anterior commissure (-14.3% +/- 5.1, P<.05) and slow-conducting fibers of the fornix-fimbria (-8.6% +/- 2.6, P<.05). Ventricular enlargement was found at peri puberty (+25% +/- 8 P<.05) but not in adult Gclm KO mice. CONCLUSIONS: Glutathione deficit in Gclm KO mice affects ventricular size and the integrity of the fornix-fimbria and anterior commissure. This suggests that redox dysregulation could contribute during neurodevelopment to the impaired white matter and ventricle enlargement observed in schizophrenia and other psychiatric disorders. PMID- 26433395 TI - Statistical controversies in clinical research: long-term follow-up of clinical trials in cancer. AB - Long-term follow-up is an important unmet need for the full analysis of new treatments for cancer. Earlier detection of cancer and more effective treatment have led to many more patients surviving for more than 5 and even 10 years, so that evaluating late recurrences and side-effects is an increasingly important issue. This is particularly relevant for oestrogen receptor-positive breast cancer, where the existence of late recurrences is well documented. However, survival for other cancers, notably prostate, colorectal and cervix cancer, has dramatically increased in recent years due to screening and better treatment of early lesions. Trials of preventive therapies have an even greater need for long follow-up. Here, we review these issues and suggest ways in which provision for long-term follow-up can be improved. PMID- 26433394 TI - Microbial ribonucleases (RNases): production and application potential. AB - Ribonuclease (RNase) is hydrolytic enzyme that catalyzes the cleavage of phosphodiester bonds in RNA. RNases play an important role in the metabolism of cellular RNAs, such as mRNA and rRNA or tRNA maturation. Besides their cellular roles, RNases possess biological activity, cell stimulating properties, cytotoxicity and genotoxicity. Cytotoxic effect of particular microbial RNases was comparable to that of animal derived counterparts. In this respect, microbial RNases have a therapeutic potential as anti-tumor drugs. The significant development of DNA vaccines and the progress of gene therapy trials increased the need for RNases in downstream processes. In addition, RNases are used in different fields, such as food industry for single cell protein preparations, and in some molecular biological studies for the synthesis of specific nucleotides, identifying RNA metabolism and the relationship between protein structure and function. In some cases, the use of bovine or other animal-derived RNases have increased the difficulties due to the safety and regulatory issues. Microbial RNases have promising potential mainly for pharmaceutical purposes as well as downstream processing. Therefore, an effort has been given to determination of optimum fermentation conditions to maximize RNase production from different bacterial and fungal producers. Also immobilization or strain development experiments have been carried out. PMID- 26433397 TI - IJGO at the FIGO 2015 Congress. PMID- 26433396 TI - Outcomes of prevention of mother to child transmission of the human immunodeficiency virus-1 in rural Kenya--a cohort study. AB - BACKGROUND: Success in prevention of mother-to-child transmission (PMTCT) raises the prospect of eliminating pediatric HIV infection. To achieve global elimination, however, strategies are needed to strengthen PMTCT interventions. This study aimed to determine PMTCT outcomes and identify challenges facing its successful implementation in a rural setting in Kenya. METHODS: A retrospective cohort design was used. Routine demographic and clinical data for infants and mothers enrolling for PMTCT care at a rural hospital in Kenya were analysed. Cox and logistic regression were used to determine factors associated with retention and vertical transmission respectively. RESULTS: Between 2006 and 2012, 1338 infants were enrolled and followed up for PMTCT care with earlier age of enrollment and improved retention observed over time. Mother to child transmission of HIV declined from 19.4 % in 2006 to 8.9 % in 2012 (non-parametric test for trend p = 0.024). From 2009 to 2012, enrolling for care after 6 months of age, adjusted Odds Ratio [aOR]: 23.3 [95 % confidence interval (CI): 8.3 65.4], presence of malnutrition ([aOR]: 2.3 [95 % CI: 1.1-5.2]) and lack of maternal use of highly active antiretroviral therapy (HAART) (aOR: 6.5 [95 % CI: 1.4-29.4]) was associated with increased risk of HIV infection. Infant's older age at enrollment, malnutrition and maternal HAART status, were also associated with drop out from care. Infants who were not actively followed up were more likely to drop out from care (adjusted Hazard Ratio: 6.6 [95 % CI: 2.9-14.6]). DISCUSSION: We report a temporal increase in the proportion of infants enrolling for PMTCT care before 3 months of age, improved retention in PMTCT and a significant reduction in the proportion of infants enrolled who became HIV infected, emphasizing the benefits of PMTCT. CONCLUSION: A simple set of risk factors at enrollment can identify mother-infant pairs most at risk of infection or drop out for targeted intervention. PMID- 26433398 TI - FIGO consensus guidelines on intrapartum fetal monitoring: Introduction. PMID- 26433399 TI - FIGO consensus guidelines on intrapartum fetal monitoring: Physiology of fetal oxygenation and the main goals of intrapartum fetal monitoring. PMID- 26433400 TI - FIGO consensus guidelines on intrapartum fetal monitoring: Intermittent auscultation. PMID- 26433401 TI - FIGO consensus guidelines on intrapartum fetal monitoring: Cardiotocography. PMID- 26433402 TI - FIGO consensus guidelines on intrapartum fetal monitoring: Adjunctive technologies. PMID- 26433403 TI - Dermoscopic insight into skin microcirculation--Burn depth assessment. AB - To investigate the effectiveness of dermoscopic observation of skin microcirculation, the dermal capillary integrity of burn wounds was evaluated by dermoscopy according to a proposed algorithm that is designed to distinguish burn wounds between superficial dermal burns: SDB, and deep dermal burns: DDB. As the gold standard for comparison, two widely accepted endpoints of primary healing within 21 days (SDB) or over 21 days after injury (DDB) were used. A number of dermatologists conducted diagnostic imaging by dermoscopy. Comparison among polarized noncontact dermoscopy (PNCD), polarized contact dermoscopy (PCD) and nonpolarized contact dermoscopy (NPD) was also conducted. Images from the three modalities were evaluated for color, pattern and qualitative differences among them. The results of dermoscopy measurements according to the proposed algorithm showed accuracy of 96.7%, sensitivity of 100.0% and specificity of 94.4%. Dermoscopy measurements were significantly more accurate than clinical assessment (p<0.05). The recognition of dots increased for NPD, vessels were most clearly observed under PCD and colours tended to be more distinctly recognized under polarized light. Dermoscopy is a useful and simple tool to evaluate not only epidermal and superficial dermal skin components but also the skin microcirculation. PMID- 26433404 TI - Paediatric burns with epilepsy or learning disabilities do not have increased risk of hospitalisation or increased length of hospital stay compared to the adult burns. PMID- 26433405 TI - Imaging morphological changes of intraductal papillary mucinous neoplasm of the pancreas was associated with its malignant transformation but not with development of pancreatic ductal adenocarcinoma. AB - BACKGROUND/OBJECTIVE: A considerable number of branch duct intraductal papillary mucinous neoplasm (BD-IPMN) developed not infrequently pancreatic malignancy, either as part of IPMN (malignant IPMN) or as concomitant pancreatic ductal adenocarcinoma (PDAC). To date, imaging morphological changes predicting occurrence of malignancy in BD-IPMN are not well-investigated. This study aimed to evaluate the relationships between occurrence of malignancy in BD-IPMN and imaging morphological changes of the tumors observed during follow-up. METHODS: 515 BD-IPMN patients with mural nodule <10 mm and negative cytology were included. 19 patients developed malignant IPMN and 8 patients developed concomitant PDAC during mean follow-up of 4.7 years. The following imaging morphological features were assessed: cyst/main pancreatic duct (MPD) diameter, occurrence of additional cyst/mural nodule. RESULTS: Growth rate of cyst/MPD diameter were significantly larger in patients who developed malignant IPMN compared to those in patients whose IPMN remained benign (p = 0.013, p = 0.01). Occurrence of additional cyst/mural nodule were more frequently observed in patients who developed malignant IPMN (p = 0.009, p = 0.04). In contrast, none of the factors associated with imaging morphological changes of IPMN were shown to be significantly different between patients who developed concomitant PDAC and patients whose IPMN remained benign. Growth rate of MPD diameter and occurrence of additional cyst were independent factors associated with development of malignant IPMN (odds ratio 21.5, and 5.62, respectively). CONCLUSIONS: Imaging morphological changes of IPMN, such as growth rate of MPD diameter and occurrence of additional cyst, could be indicators for development of malignant IPMN, but not for development of concomitant PDAC. PMID- 26433406 TI - Editorial. PMID- 26433407 TI - A novel approach to improving antibiotic selection in patients reporting penicillin allergy. PMID- 26433408 TI - Delayed red meat allergy: clinical ramifications of galactose-alpha-1,3-galactose sensitization. PMID- 26433409 TI - Allergen of the Month--Monk's Rhubarb. PMID- 26433410 TI - Effects of acute heat stress on lipid metabolism of bovine primary adipocytes. AB - Heat stress (HS) affects numerous physiological processes including nutrient partitioning and lipid metabolism. Objectives of this study were to evaluate how acute HS affects lipid metabolism in subcutaneous adipose tissue of dairy cattle. Adipose tissue biopsies were performed on Holstein cows for bovine primary adipocyte isolation and cultured at either 42 degrees C (HS) or 37 degrees C (thermal neutral, TN). Adipocytes were incubated with increasing isoproterenol (ISO), and with increasing concentrations of insulin in the presence of ISO to evaluate changes in lipolysis. Incorporation of radioactive acetate into lipids was measured as an indicator of lipogenesis. Abundance and phosphorylation of several lipolytic and lipogenic proteins were also measured. Adipocytes exposed to HS had an elevated maximal response to ISO and were more sensitive to lipolytic stimulation by ISO compared with cells cultured at TN. Thermal treatment did not affect the antilipolytic effects of insulin in the presence of ISO. Lipogenesis measured as acetate incorporation was not altered by HS, but a temperature by insulin interaction was observed for the regulation of acetyl CoA carboxylase, such that the presence of insulin resulted in a reduction in phosphorylation of acetyl CoA carboxylase in adipocytes cultured at TN but not HS conditions. Results of this study demonstrate that acute HS has a direct effect on the regulation of lipolysis and the rate-limiting enzyme of lipogenesis in isolated bovine adipocytes. PMID- 26433411 TI - Integration of external estimated breeding values and associated reliabilities using correlations among traits and effects. AB - Based on a Bayesian view of linear mixed models, several studies showed the possibilities to integrate estimated breeding values (EBV) and associated reliabilities (REL) provided by genetic evaluations performed outside a given evaluation system into this genetic evaluation. Hereafter, the term "internal" refers to this given genetic evaluation system, and the term "external" refers to all other genetic evaluations performed outside the internal evaluation system. Bayesian approaches integrate external information (i.e., external EBV and associated REL) by altering both the mean and (co)variance of the prior distributions of the additive genetic effects based on the knowledge of this external information. Extensions of the Bayesian approaches to multivariate settings are interesting because external information expressed on other scales, measurement units, or trait definitions, or associated with different heritabilities and genetic parameters than the internal traits, could be integrated into a multivariate genetic evaluation without the need to convert external information to the internal traits. Therefore, the aim of this study was to test the integration of external EBV and associated REL, expressed on a 305-d basis and genetically correlated with a trait of interest, into a multivariate genetic evaluation using a random regression test-day model for the trait of interest. The approach we used was a multivariate Bayesian approach. Results showed that the integration of external information led to a genetic evaluation for the trait of interest for, at least, animals associated with external information, as accurate as a bivariate evaluation including all available phenotypic information. In conclusion, the multivariate Bayesian approaches have the potential to integrate external information correlated with the internal phenotypic traits, and potentially to the different random regressions, into a multivariate genetic evaluation. This allows the use of different scales, heritabilities, variance components, measurement units, or trait definitions for external and internal traits. However, one possible issue for implementing multivariate Bayesian approaches could be the availability or estimation of genetic correlations between external and internal traits. PMID- 26433412 TI - Setup of a rapid method to distinguish among dead, alive, and viable but not cultivable cells of Pseudomonas spp. in mozzarella cheese. AB - Pseudomonas spp. is the main psychrotrophic genus involved in the spoilage of raw milk and more in general of dairy products, such as mozzarella cheese. The members of this bacterial species are able to produce heat-resistant proteolytic enzymes, determining the casein hydrolysis, and as a consequence, a reduction of the shelf life and sensory quality of the products. Therefore, the spoilage activity could be attributed not only to viable, but also to viable but noncultivable (VBNC) cells. For this reason, the setup of a non-culture-based method is useful for a rapid detection of cells that are still alive, but no longer cultivable, such as VBNC cells. Here we propose a method based on DNA or RNA content (or both) to reveal the presence of dead, alive, and VBNC cells belonging to the genus Pseudomonas. The obtained results clearly indicate the limits of the classical plating count overcome by molecular detection of Pseudomonas spp. through DNA and RNA analysis, enabling us to establish the presence of different states of the cells. PMID- 26433413 TI - Regulation of cell number in the mammary gland by controlling the exfoliation process in milk in ruminants. AB - Milk yield is partly influenced by the number of mammary epithelial cells (MEC) in the mammary gland. It is well known that variations in MEC number are due to cell proliferation and apoptosis. The exfoliation of MEC from the mammary epithelium into milk is another process that might influence MEC number in the mammary tissue. The rate of MEC exfoliation can be assessed by measuring the milk MEC content through light microscopy, flow cytometry analysis, or an immuno magnetic method for MEC purification. Various experimental models have been used to affect milk yield and study the rate of MEC exfoliation. Reducing milking frequency from twice to once daily did not seem to have any effect on MEC loss in goat and cow milk after 7 d, but increased MEC loss per day in goats when applied for a longer period. An increase in MEC exfoliation was also observed during short days as compared with long days, or in response to an endotoxin-induced mastitis in cows. Other animal models were designed to investigate the endocrine control of the exfoliation process and its link with milk production. Suppression of ovarian steroids by ovariectomy resulted in a greater persistency of lactation and a decrease in MEC exfoliation. Administering prolactin inhibitors during lactation or at dry-off enhanced MEC exfoliation, whereas exogenous prolactin during lactation tended to prevent the negative effect of prolactin inhibitors. These findings suggest that prolactin could regulate MEC exfoliation. In most of these studies, variations of MEC exfoliation were associated with variations in milk yield and changes in mammary epithelium integrity. Exfoliation of MEC could thus influence milk yield by regulating MEC number in mammary tissue. PMID- 26433414 TI - Effects of whey or maltodextrin addition during production on physical quality of white cheese powder during storage. AB - There is an increasing demand for cheese as a food ingredient, especially as a flavoring agent. One of the most important cheese flavoring agents is cheese powder. To obtain an intense cheese flavor, ripened cheese is used as a raw material in cheese powder but this increases production costs. Moreover, use of natural cheese decreases the physical quality of powder because of its high fat content. In this study, we evaluated opportunities to use whey or maltodextrin for improving the physical quality of powders in production of white cheese powder. We produced cheese powders with 3 different formulations-control (CON), whey-added (WACP), and maltodextrin-added (MACP)-and determined the effects of formulation on cheese powder quality. Physical quality parameters such as color, densities, reconstitution properties, free fat content, particle morphology, and sensory characteristics were investigated. The different cheese powders were stored for 12 mo at 20 degrees C and we evaluated the effect of storage on powder quality. Addition of maltodextrin to cheese powder formulations significantly improved their physical quality. The densities and reconstitution properties of cheese powder were increased and free fat content was decreased by use of maltodextrin. The MACP particles were spherical with a uniform distribution and larger particle sizes, whereas CON and WACP particles were wrinkled, irregular shaped with deep surface dents, and variable in size. Although caking was observed in scanning electron micrographs after 12 mo of storage, it was not detected by sensory panelists. The color of cheese powders changed very slowly during storage but browning was detected. The results of this study show that it is possible to use maltodextrin or whey in production of white cheese powder to reduce production costs and improve the physical quality of powders. PMID- 26433415 TI - Single-step genomic model improved reliability and reduced the bias of genomic predictions in Danish Jersey. AB - A bias in the trend of genomic estimated breeding values (GEBV) was observed in the Danish Jersey population where the trend of GEBV was smaller than the deregressed proofs for individuals in the validation population. This study attempted to improve the prediction reliability and reduce the bias of predicted genetic trend in Danish Jersey. The data consisted of 1,238 Danish Jersey bulls and 611,695 cows. All bulls were genotyped with the 54K chip, and 1,744 cows were genotyped with either 7K chips (1,157 individuals) or 54K chips (587 individuals). The trait used in the analysis was protein yield. All cows with EBV were used in a single-step approach. Deregressed proofs were used as the response variable. Four alternative approaches were compared with genomic best linear unbiased prediction (GBLUP) model with bulls in the reference data (GBLUPBull): (1) GBLUP with both bulls and genotyped cows in the reference data; (2) GBLUP including a year of birth effect; (3) GEBV from a GBLUP model that accounted for the difference of EBV between dams and maternal grandsires; and (4) using a single-step approach. The results indicated all 4 alternatives could reduce the bias of predicted genetic trend and that the single-step approach performed best. However, not all these approaches improved reliability or reduced inflation of GEBV. The reliability was 0.30 and regression coefficients of deregressed proofs on GEBV were 0.69 in the scenario GBLUPBull. When genotyped cows were included in the reference population, the regression coefficients decreased to 0.59 but the reliability increased to 0.35. If a year effect was included in the model, the prediction reliability decreased to 0.29 and the regression coefficient improved to 0.75. The method in which GEBV were adjusted for the difference between dam EBV and maternal grandsire EBV led to much lower regression coefficients though the reliability increased to 0.4. The single-step approach improved both the reliability, to 0.38 and regression coefficient to 0.78. Therefore, the bias in genetic trend was reduced. The results suggest that implementing the single-step approach is an effective way to improve genomic prediction in Danish Jersey cattle. PMID- 26433416 TI - Peripartal changes in reticuloruminal pH and temperature in dairy cows differing in the susceptibility to subacute rumen acidosis. AB - The present study aimed to investigate changes in the reticuloruminal pH and temperature dynamics in periparturient dairy cows. Reticuloruminal pH and temperature measurements were conducted from 7 d before until 8 d after parturition using indwelling sensors. Nine Simmental and 4 Brown Swiss dairy cows were fed a close-up total mixed ration (52.5% neutral detergent fiber, 5.68MJ of net energy for lactation per kg of dry matter) with additional 1kg/cow per d concentrate mixture (29.5% neutral detergent fiber and 6.25MJ of net energy for lactation per kg of dry matter), starting from 2 wk before the estimated calving date. Postpartum, all cows had free access to the same close-up diet and were gradually fed increasing amounts of a concentrate-rich total mixed ration for early-lactation cows (32.7% neutral detergent fiber, 7.22MJ of net energy for lactation per kg of dry matter). Data showed depressed reticuloruminal pH early postpartum, but only in the group of cows defined as subacute ruminal acidosis (SARA) susceptible (n=8), which had a higher duration time of pH <5.8 (753+/ 82min/d) compared with SARA-tolerant cows (n=5; 15+/-6min/d). Also, compared with SARA-tolerant cows (112+/-91min/d), the SARA-susceptible group showed longer (1,049+/-75min/d) duration time of pH <6.0. When compared by breed, mean reticuloruminal pH tended to be lower in Simmental (6.16+/-0.03) than in Brown Swiss cows (6.25+/-0.05), but no differences were observed in the duration of pH <5.8 between breeds. Simmental cows produced more milk (30.4+/-1.2kg/d) compared with Brown Swiss cows (27.9+/-1.3kg/d). Neither total dry matter intake nor milk yield were different between SARA-susceptible and SARA-tolerant groups. However, SARA-tolerant cows consumed greater amounts of the close-up total mixed ration than their SARA-susceptible counterparts, whereas no difference was observed in the intake of the early-lactating total mixed ration between the groups. Reticuloruminal temperature was not affected by breed or SARA susceptibility. Interestingly, the mean reticuloruminal temperature and the time duration of temperature >39.5 degrees C abruptly dropped from d 2 to 1 before calving by 0.35 degrees C and 430min/d, respectively. In conclusion, the strong inter-animal variation in reticuloruminal pH responses suggests the need for more careful monitoring and differentiated feeding management of cows during the transition period, whereby the SARA-susceptible cows may require particular attention regarding feeding management and diet composition. The abrupt decrease in reticuloruminal temperature the day before parturition may enable this noninvasive method as a management tool for prediction of parturition time. PMID- 26433417 TI - Effect of combined long-term starvation and gamma-irradiation on membrane fatty acids and cell surface hydrophobicity of Salmonella enterica serovar Typhimurium. AB - This study was carried out to explore the adaptive mechanisms of Salmonella enterica serovar Typhimurium, in particular the implication of fatty acids (FA) in the remodeling of membrane lipid composition to overcome the combined effects of long-term starvation and gamma-irradiation stresses. In addition, cell surface hydrophobicity was also evaluated. The bacterial strains (control and starved) were treated with a nonlethal gamma-irradiation dose of 0.5 kGy and sublethal doses of 1 kGy. Gas chromatography analysis showed that the FA composition of starved and gamma-irradiated cells was modified. However starvation combined with gamma-irradiation induced more modifications in the FA composition than gamma irradiation or starvation alone. Indeed, the unsaturated FA-to-saturated FA ratio decreased significantly for both strains compared with gamma-irradiated cells, as main consequence of the cyclic FA formation. Our results showed that starvation, irradiation, or combined stresses significantly influenced the hydrophobicity, and this may have affected the virulence state of Salmonella Typhimurium cells. This study represents one of the few to demonstrate the modifications on bacterial membrane as a cellular response to survive to the ionizing radiation combined with long-term starvation stress. PMID- 26433418 TI - Effect of a second treatment with prostaglandin F2alpha during the Ovsynch protocol on luteolysis and pregnancy in dairy cows. AB - The main objective of this study was to evaluate the effect of a second treatment with prostaglandin F2alpha (PGF) during Ovsynch on regression of the corpus luteum (CL) and on fertility to the timed artificial insemination. Two experiments were performed. In both experiments, cows were randomized to receive (1) no additional treatments with PGF=1 PGF, or (2) a second PGF treatment at 24h after the first PGF treatment=2 PGF. The first experiment (n=344 synchronized lactating dairy cows that received artificial insemination at 81+/-3d in milk) used the Double-Ovsynch protocol for synchronizing ovulation. Blood samples were collected at the PGF and final GnRH treatments (72 and 16h before timed artificial insemination) during the breeding Ovsynch protocol, to determine CL regression in response to the protocol. Treatment with 2 PGF increased CL regression from 83.0% with 1 PGF to 97.0% with 2 PGF. The effect of 2 PGF on CL regression was observed in both primiparous and multiparous cows. Cows with lower (2.0 to 4.8ng/mL) versus greater (4.9 to 12.0ng/mL) circulating progesterone at the time of PGF had lower percentage of cows with complete CL regression after 1 PGF (66.7 vs. 88.1%) but not after 2 PGF (95.1 vs. 97.6%). Experiment 2 used 2,148 lactating dairy cows on 11 dairy farms in 4 different regions of the United States. Cows were synchronized with Ovsynch and received timed artificial insemination at 60+/-3d in milk. Cows that received 2 PGF had a tendency for increased pregnancies per artificial insemination (P/AI) compared with cows with 1 PGF (36.1 vs. 33.3%). This tendency for improvement in P/AI was observed in multiparous but not in primiparous cows. Combining data from the 2 experiments indicated a 9.45% relative increase in P/AI for cows receiving 2 compared with 1 PGF (37.6 vs. 34.4%) with the increase in P/AI observed in multiparous but not in primiparous cows. Thus, a second PGF treatment in Ovsynch-type protocols can increase pregnancy success by about 10%, primarily due to enhanced fertility in multiparous cows. PMID- 26433419 TI - Including different groups of genotyped females for genomic prediction in a Nordic Jersey population. AB - Including genotyped females in a reference population (RP) is an obvious way to increase the RP in genomic selection, especially for dairy breeds of limited population size. However, the incorporation of these females must be conducted cautiously because of the potential preferential treatment of the genotyped cows and lower reliabilities of phenotypes compared with the proven pseudo-phenotypes of bulls. Breeding organizations in Denmark, Finland, and Sweden have implemented a female-genotyping project with the possibility of genotyping entire herds using the low-density (LD) chip. In the present study, 5 scenarios for building an RP were investigated in the Nordic Jersey population: (1) bulls only, (2) bulls with females from the LD project, (3) bulls with females from the LD project plus non LD project females genotyped before their first calving, (4) bulls with females from the LD project plus non-LD project females genotyped after their first calving, and (5) bulls with all genotyped females. The genomically enhanced breeding value (GEBV) was predicted for 8 traits in the Nordic total merit index through a genomic BLUP model using deregressed proof (DRP) as the response variable in all scenarios. In addition, (daughter) yield deviation and raw phenotypic data were studied as response variables for comparison with the DRP, using stature as a model trait. The validation population was formed using a cut off birth year of 2005 based on the genotyped Nordic Jersey bulls with DRP. The average increment in reliability of the GEBV across the 8 traits investigated was 1.9 to 4.5 percentage points compared with using only bulls in the RP (scenario 1). The addition of all the genotyped females to the RP resulted in the highest gain in reliability (scenario 5), followed by scenario 3, scenario 2, and scenario 4. All scenarios led to inflated GEBV because the regression coefficients are less than 1. However, scenario 2 and scenario 3 led to less bias of genomic predictions than scenario 5, with regression coefficients showing less deviation from scenario 1. For the study on stature, the daughter yield deviation/daughter yield deviation performed slightly better than the DRP as the response variable in the genomic BLUP (GBLUP) model. Therefore, adding unselected females in the RP could significantly improve the reliabilities and tended to reduce the prediction bias compared with adding selectively genotyped females. Although the DRP has performed robustly so far, the use of raw data is recommended with a single-step model as an optimal solution for future genomic evaluations. PMID- 26433420 TI - Modifications to Ovsynch improve fertility during resynchronization: Evaluation of presynchronization with gonadotropin-releasing hormone 6 d before initiation of Ovsynch and addition of a second prostaglandin F2alpha treatment. AB - Lactating Holstein cows (n=897) were randomly assigned to a 2*2 factorial arrangement of treatments to compare the main effects of presynchronization with GnRH 6 d before beginning an Ovsynch protocol (+/-GnRH) and a second PGF2alpha treatment 24h after the first (1 vs. 2 PGF2alpha) on pregnancies per artificial insemination (P/AI). This resulted in the following 4 treatments: (1) an Ovsynch protocol (GPG, control); (2) presynchronization with GnRH followed by an Ovsynch protocol (GGPG); (3) an Ovsynch protocol with a second PGF2alpha treatment (GPPG); and (4) presynchronization with GnRH followed by an Ovsynch protocol with a second PGF2alpha treatment (GGPPG). All cows were submitted for first timed artificial insemination (TAI) using a Presynch Ovsynch protocol, and cows detected in estrus after the second PGF2alpha treatment of the Presynch portion of the protocol were inseminated and removed from the experiment. Nonpregnant cows were resynchronized using an Ovsynch protocol initiated 32+/-3 d after artificial insemination. Blood samples were collected at the first GnRH treatment (G1), at the PGF2alpha treatment (PGF), and at the last GnRH treatment (G2) of the Ovsynch protocol and were assayed for progesterone (P4) concentrations. Overall, P/AI tended to be greater for cows receiving a second PGF2alpha treatment compared with cows not receiving the second PGF2alpha treatment (40 and 37% for GGPPG and GPPG treatments, respectively, vs. 33 and 32% for GGPG and GPG treatments, respectively). Interestingly, treatment effects on P/AI were detected only for resynchronized cows receiving second and greater TAI, but not for cows receiving first TAI. Fewer cows presynchronized with GnRH had low (<0.5ng/mL) P4 at G1 than cows not presynchronized (13 vs. 25%), and P4 was greater at PGF2alpha for cows presynchronized with GnRH (4.4 vs. 4.0ng/mL). Cows receiving 2 PGF2alpha treatments had lower P4 at G2 than cows receiving 1 PGF2alpha treatment (0.15 vs. 0.35ng/mL). Differences in P4 at PGF2alpha were detected only for resynchronized cows and not for cows submitted for first TAI. We conclude that presynchronization with GnRH 6 d before beginning an Ovsynch protocol tended to increase P4 at the first GnRH treatment of an Ovsynch protocol, and that a second PGF2alpha treatment 24h after the first decreased P4 at TAI, thereby increasing P/AI in cows resynchronized for second and greater TAI. PMID- 26433421 TI - Effect of ensiling time and exogenous protease addition to whole-plant corn silage of various hybrids, maturities, and chop lengths on nitrogen fractions and ruminal in vitro starch digestibility. AB - The objective of this study was to evaluate the effects of ensiling time and exogenous protease addition on soluble CP (% of CP), ammonia-N (% of N), and ruminal in vitro starch digestibility (ivSD) of whole-plant corn silage (WPCS) from 3 hybrids, 2 maturities, and 2 chop lengths. Samples from 3 nonisogenic hybrids [brown midrib containing the bm3 gene mutation (BM3), dual-purpose (DP), or floury-leafy (LFY)] at 2 harvest maturities [2/3 kernel milk line (early) or 7d later (late)] with 2 theoretical lengths of cut settings (0.64 or 1.95cm) on a forage harvester were collected at harvest, treated with or without exogenous protease, and ensiled in triplicate in vacuum heat-sealed plastic bags for 0, 30, 60, 120, and 240d. Thus, the experiment consisted of 120 treatments (3 hybrids * 2 maturities * 2 chop lengths * 2 protease treatments * 5 time points) and 360 mini-silos (3 replications per treatment). Vitreousness, measured by dissection on unfermented kernels on the day of harvest, averaged 66.8, 65.0, and 59.0% for BM3, DP, and LFY, respectively. A protease * maturity interaction was observed with protease increasing ivSD in late but not early maturity. Ensiling time * hybrid interactions were observed for ammonia-N and soluble CP concentrations with greater values for FLY than other hybrids only after 120d of ensiling. Ensiling time * hybrid or protease * hybrid interactions were not observed for ivSD. Measurements of ivSD were greatest for FLY and lowest for BM3. Length of the ensiling period did not attenuate negative effects of kernel vitreousness or maturity on ivSD in WPCS. Results suggest that the dosage of exogenous protease addition used in the present study may reduce but not overcome the negative effects of maturity on ivSD in WPCS. No interactions between chop length and ensiling time or exogenous protease addition were observed for ivSD. PMID- 26433422 TI - Prospective intervention study with a microarray-based, multiplexed, automated molecular diagnosis instrument (Verigene system) for the rapid diagnosis of bloodstream infections, and its impact on the clinical outcomes. AB - The Verigene Gram-positive blood culture test (BC-GP) and the Verigene Gram negative blood culture test (BC-GN) identify representative Gram-positive bacteria, Gram-negative bacteria and their antimicrobial resistance by detecting resistance genes within 3 h. Significant benefits are anticipated due to their rapidity and accuracy, however, their clinical utility is unproven in clinical studies. We performed a clinical trial between July 2014 and December 2014 for hospitalized bacteremia patients. During the intervention period (N = 88), Verigene BC-GP and BC-GN was used along with conventional microbiological diagnostic methods, while comparing the clinical data and outcomes with those during the control period (N = 147) (UMIN registration ID: UMIN000014399). The median duration between the initiation of blood culture incubation and the reporting time of the Verigene system results was 21.7 h (IQR 18.2-26.8) and the results were found in 88% of the cases by the next day after blood cultures were obtained without discordance. The hospital-onset infection rate was higher in the control period (24% vs. 44%, p = 0.002), however, no differences were seen in co morbidities and severity between the control and intervention periods. During the intervention period, the time of appropriate antimicrobial agents' initiation was significantly earlier than that in the control period (p = 0.001) and most cases (90%; 79/88) were treated with antimicrobial agents with in-vitro susceptibility for causative bacteria the day after the blood culture was obtained. The costs for antimicrobial agents were lower in the intervention period (3618 yen vs. 8505 yen, p = 0.001). The 30-day mortality was lower in the intervention period (3% vs. 13%, p = 0.019). PMID- 26433423 TI - Failed Attempts to Reduce Inappropriate Laboratory Utilization in an Emergency Department Setting in Cyprus: Lessons Learned. AB - BACKGROUND: Laboratory test ordering is a significant part of the diagnosis definition and disease treatment monitoring process. Inappropriate laboratory test ordering wastes scarce resources, places unnecessary burden on the health care delivery system, and exposes patients to unnecessary discomfort. Inappropriate ordering is caused by many factors, such as lack of guidelines, defensive medicine, thoughtless ordering, and lack of awareness of costs incurred to the system. OBJECTIVES: The purpose of this study is to assess two successive measures, which were introduced in a Cyprus emergency department (ED) for the purpose of synergistically reducing inappropriate laboratory ordering: the introduction of a copayment fee to reduce nonemergent visits, and the development of a Web-based protocol defining the tests emergency physicians could order. METHODS: An autoregressive integrated moving average model for interrupted time series analysis was constructed. Data include number and type of tests ordered, along with number of visits for a period of 4 years from an ED in Cyprus. RESULTS: Copayment fee and introduction of a revised Web-based protocol for a test ordering form did not reduce the number of ordered tests in the ED unit. Copayment fee alone resulted in a statistically significant reduction in ED visits. CONCLUSIONS: The implementation of two consecutive measures resulted in an increase of ordered tests per patient. Laboratory ordering is a multidimensional process that is primarily supplier induced, therefore, all underlying possible causes must be scrutinized by health authorities. These include lack of guidelines, defensive medicine and thoughtless prescribing. To attain significant gains, an integrated approach must be implemented. PMID- 26433424 TI - First-generation Antipsychotics Are Often Prescribed in the Emergency Department but Are Often Not Administered with Adjunctive Medications. AB - BACKGROUND: Although first-generation antipsychotics (FGAs) have long been used in the emergency department (ED) to treat acute agitation, little is known about how these medications are used in modern clinical practice. In particular, little work has been published about whether ED clinicians administer FGAs with adjunctive medications in accordance with expert guidelines or the prescribing practices of FGAs over time. OBJECTIVES: 1) To provide a comparison of the frequency with which FGAs are administered with adjunctive benzodiazepines or anticholinergic medications. 2) To analyze the prescribing trends for FGAs over time, particularly in the years after the U.S. Food and Drug Administration (FDA) black-box warning for droperidol. METHODS: This is a structured review of a retrospective cohort of patients receiving haloperidol or droperidol in two EDs over a 7-year period. RESULTS: Haloperidol or droperidol was administered on 2833 patient visits during the study period, with haloperidol being administered most often. Adjunctive medications are administered less than half of the time. The use of droperidol has remained relatively static, whereas the use of haloperidol has increased. CONCLUSIONS: First-generation antipsychotics are still widely utilized in the ED. When administered, these medications are used with adjunctive medications that may decrease side effects less than half of the time. Droperidol use has remained unchanged in the years after the FDA black-box warning, whereas use of haloperidol has continued to rise. PMID- 26433425 TI - Endocarditis With Fistulization and Rupture of Aortic Root Abscess to the Left Atrium. AB - BACKGROUND: Infective endocarditis (IE) is a difficult emergency department (ED) diagnosis to make. Symptoms are nonspecific and diverse and the classic triad of fever, anemia, and murmur is rare. Severe IE causes considerable morbidity and mortality and should be diagnosed early. However, echocardiogram is essential but not readily available in the ED and can cause diagnostic delay. CASE REPORT: This case describes severe IE and its unique presentation, diagnostic challenges, and the use of bedside cardiac ultrasonography. A 28-year-old previously healthy male presented with intermittent fevers, arthralgias, and myalgias for 2 weeks. He had twice been evaluated and diagnosed with lumbar back pain. Physical examination revealed moderate respiratory distress, pale skin with a cyanotic right lower extremity, and unequal extremity pulses. He became hypotensive and rapidly deteriorated. Chest x-ray study showed bilateral pulmonary infiltrates with subsequent imaging demonstrating worsening septic emboli. Bedside ultrasound revealed mitral and aortic valve vegetations and a presumed diagnosis of IE with septic embolization was made. Formal echocardiography (ECHO) confirmed IE with an aortic root abscess with rupture and fistulization into the left atrium. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Clinical criteria for IE include blood cultures and ECHO, however, these are often not available to an emergency physician, making IE a diagnostic challenge even in severe cases. The role of bedside ultrasound for IE continues to evolve and its utility in the diagnosis of severe IE is distinctly demonstrated in this case. PMID- 26433426 TI - Thorn Injury Osteomyelitis. PMID- 26433427 TI - Impact of Clinical Pharmacists on Initiation of Postintubation Analgesia in the Emergency Department. AB - BACKGROUND: Pain and anxiety are common in mechanically ventilated patients, and frequently undertreated in the emergency department (ED) setting. OBJECTIVE: We sought to compare the rate of initiation of postintubation analgesia in the ED before and after intervention by pharmacists specialized in emergency medicine. METHODS: This was a retrospective cohort study of patients who underwent rapid sequence intubation (RSI) in the ED. The primary endpoint was overall frequency of analgesia initiation, with subset analysis of RSI during the ED pharmacist (EDP) duty hours. Secondary endpoints included frequency of sedative or anxiolytic use without analgesia, time to initiation of postintubation analgesia, and adverse drug events (ADEs) resulting in analgesia discontinuation. RESULTS: Forty-one patients were included in each group. The overall rate of postintubation analgesia increased after pharmacist intervention, from 20% to 49% (p = 0.005). Analgesia initiation during EDP hours was 50% and 85% in the pre- and postintervention groups, respectively. In the preintervention group, more patients received sedation without analgesia (73% vs. 51%; p = 0.04), and a small percentage (7%) received neither sedation nor analgesia. Time to initiation of postintubation analgesia decreased from 98 min to 45 min. ADEs were rare: there were no discontinuations of analgesic therapy in the preintervention group and one temporary discontinuation because of hypotension in the postintervention group. CONCLUSION: Analgesic use after RSI in the ED significantly increased after the implementation of ED pharmacy services. The large proportion of patients receiving analgesia during the EDP duty hours suggest the increase may be related to direct pharmacist involvement in postintubation management. PMID- 26433428 TI - Evaluation of Warfarin Reversal with 4-Factor Prothrombin Complex Concentrate Compared to 3-Factor Prothrombin Complex Concentrate at a Tertiary Academic Medical Center. AB - BACKGROUND: The U.S. Food and Drug Administration recently approved a four-factor prothrombin complex concentrate (4-PCC) for warfarin reversal. The literature supporting its use over three-factor prothrombin complex concentrate (3-PCC) is limited. OBJECTIVE: Our objective was to retrospectively compare the efficacy of 3-PCC to 4-PCC in reversing warfarin in patients who were actively bleeding. METHODS: We conducted a single-center, retrospective cohort analysis of adult patients who received 3-PCC or 4-PCC for international normalized ratio (INR) reversal. Our study excluded patients not actively bleeding and not on warfarin. The main outcome was the percentage of patients who achieved warfarin reversal defined as INR <= 1.3 at first INR check post factor administration. We recorded baseline data including PCC dose, location of bleed, pre- and posttreatment INR, and time to INR reversal. RESULTS: We included a total of 53 patients. Intracranial hemorrhage was the most common site of bleeding (26 [74.3%] in 3-PCC vs. 12 [66.7%] in 4-PCC). The mean dose of 3-PCC was 25.5 units/kg, compared to 27.9 units/kg of 4-PCC. The mean baseline INR was 2.3 in the 3-PCC group and 3 in the 4-PCC group (p = 0.03), and the first posttreatment INRs were 1.4 and 1.2, respectively (p < 0.01). Warfarin reversal was achieved in 15 (42.9%) patients who received 3-PCC and 15 (83.3%) patients who received 4-PCC (p < 0.01). Faster time to INR reversal was noted in the 4-PCC group vs. the 3-PCC group (3.7 vs. 5 h, p = 0.48). CONCLUSION: A higher percentage of patients achieved warfarin reversal with 4-PCC compared to 3-PCC treatment. A prospective randomized control trial is necessary to confirm our results. PMID- 26433429 TI - Peripheral Intravenous Line Placement and Utilization in an Academic Emergency Department. AB - BACKGROUND: Rising health care costs and increased scrutiny concerning spending have prompted providers and hospitals to identify unnecessary procedures and waste. Peripheral intravenous line (pIV) placement is one of the most common medical procedures performed. A recent study reported that 50% of intravenous lines placed in the emergency department (ED) went unused. If half of all pIVs placed in EDs systemically go unused, the costs and complications associated with pIV placement are unacceptably high. OBJECTIVES: Our study aims to ascertain the frequency of pIV placement and usage in an urban ED. METHODS: This was a retrospective review of medical records for consecutive patients seen in an academic ED in June 2014. The following data points were recorded: age, sex, chief complaint, acuity level on admission, pIV placement both prehospital and in the ED, and pIV utilization (for fluids, medications, or contrast administration). RESULTS: There were 509 charts reviewed, with a median patient age of 40 years. Common chief complaint categories included neurologic, cardiac, and skin/soft tissue. Triage acuity was varied, with a mean of 3.3. A pIV was placed in 55% of subjects. Prehospital providers placed 19%. Of all pIVs placed, 72% were used for the administration of medications, 19% for contrast, and 67% for fluids. Eighty-five percent of pIVs were used; 51% of patients with a pIV were admitted from the ED. CONCLUSION: In this study's ED, 85% of pIVs were used prior to discharge. Strategies to lower pIV placement rates should focus on alternative routes of medication and fluid administration. PMID- 26433430 TI - Inferior Vena Cava Filter Migration. PMID- 26433431 TI - Randomized Controlled Noninferiority Trial Comparing Daptomycin to Vancomycin for the Treatment of Complicated Skin and Skin Structure Infections in an Observation Unit. AB - BACKGROUND: Incidence of methicillin-resistant Staphylococcus aureus (MRSA) is increasing in complicated skin and skin structure infection (cSSSI) presenting to emergency departments (EDs). Treatment is heterogeneous and can require inpatient admission to an observation unit (OU). Vancomycin is commonly used in the OU for treatment, but increasing MRSA resistance to vancomycin suggests the need for alternatives. Daptomycin is an alternative but it is not known how it compares with vancomycin. OBJECTIVE: This study tested the hypothesis that daptomycin is noninferior to vancomycin for the treatment of cSSSI in an OU, using a relative risk (RR) of 1.3 as the noninferiority limit. METHODS: Subjects admitted to an ED based OU with a diagnosis of cSSSI were eligible. Consenting subjects were randomized 1:1 to intravenous (i.v.) vancomycin at 15 mg/kg dosing every 12 h or i.v. daptomycin at 4 mg/kg once. Subjects were followed until they met objective criteria for discharge home or hospital admission. Discharged patients were prescribed 10-14 days of oral cephalexin and trimethoprim-sulfamethoxazole, or clindamycin if allergic to either of these medications. The primary endpoint was meeting objective discharge criteria with no change in antibiotic therapy or return to the ED for the same cellulitis within 30 days of OU discharge. RESULTS: There were 100 patients enrolled. RR for satisfying the endpoint was 1.07 (95% confidence interval 0.58-1.98) for daptomycin compared with vancomycin. Hospital admission rates were 36% and 32% for daptomycin and vancomycin treatment, respectively. CONCLUSION: Daptomycin was not inferior to vancomycin in the treatment of cSSSI in an OU. PMID- 26433432 TI - Fahr's Disease: A Rare Puzzle for an Emergent Neurological Presentation. PMID- 26433433 TI - A cylindrical traveling wave ultrasonic motor using bonded-type composite beam. AB - A cylindrical traveling wave ultrasonic motor using bonded-type composite beam is proposed in this work. In this new design, a new exciting mode for L-B (longitudinal-bending) hybrid vibrations using bonded-type is adopted, which requires only two pieces of PZT ceramic plates and a single metal beam. In the new motor, the traveling wave of a cylinder can be excited by the L-B vibrations of a bonded-type beam. When two alternating voltages with phase difference are applied, the longitudinal and bending vibrations of the beam can be generated synchronously based on the new exciting mode for L-B hybrid vibrations, and the temporal phase difference of the two vibrations is always 90 degrees . Finite element method is adopted to realize the modal degeneration in order to confirm the final structural parameters of the motor, and analyze the motion trajectory of the driving tip. After the fabrication of a prototype, the vibration characteristics and mechanical output ability are measured. The maximum no-load speed and maximum output torque of the prototype are 342 rpm and 6.26 mN m at a voltage of 100 Vrms. PMID- 26433434 TI - Targeted gene delivery to the synovial pannus in antigen-induced arthritis by ultrasound-targeted microbubble destruction in vivo. AB - The purpose of this study was to optimize an ultrasound-targeted microbubble destruction (UTMD) technique to improve the in vivo transfection efficiency of the gene encoding enhanced green fluorescent protein (EGFP) in the synovial pannus in an antigen-induced arthritis rabbit model. A mixture of microbubbles and plasmids was locally injected into the knee joints of an antigen-induced arthritis (AIA) rabbits. The plasmid concentrations and ultrasound conditions were varied in the experiments. We also tested local articular and intravenous injections. The rabbits were divided into five groups: (1) ultrasound+microbubbles+plasmid; (2) ultrasound+plasmid; (3) microbubble+plasmid; (4) plasmid only; (5) untreated controls. EGFP expression was observed by fluorescent microscope and immunohistochemical staining in the synovial pannus of each group. The optimal plasmid dosage and ultrasound parameter were determined based on the results of EGFP expression and the present and absent of tissue damage under light microscopy. The irradiation procedure was performed to observe the duration of the EGFP expression in the synovial pannus and other tissues and organs, as well as the damage to the normal cells. The optimal condition was determined to be a 1-MHz ultrasound pulse applied for 5 min with a power output of 2 W/cm(2) and a 20% duty cycle along with 300 MUg of plasmid. Under these conditions, the synovial pannus showed significant EGFP expression without significant damage to the surrounding normal tissue. The EGFP expression induced by the local intra-articular injection was significantly more increased than that induced by the intravenous injection. The EGFP expression in the synovial pannus of the ultrasound+microbubbles+plasmid group was significantly higher than that of the other four groups (P<0.05). The expression peaked on day 5, remained detectable on day 40 and disappeared on day 60. No EGFP expression was detected in the other tissues and organs. The UTMD technique can significantly enhance the in vivo gene transfection efficiency without significant tissue damage in the synovial pannus of an AIA model. Thus, this could become a safe and effective non viral gene transfection procedure for arthritis therapy. PMID- 26433435 TI - Forced vibrations of SC-cut quartz crystal rectangular plates with partial electrodes by the Lee plate equations. AB - Lee plate equations for high frequency vibrations of piezoelectric plates have been established and perfected over decades with the sole objective of obtaining accurate predictions of frequency and mode shapes to aid the analysis and design of quartz crystal resonators. The latest improvement includes extra terms related to derivatives of the flexural displacement to provide much accurate solutions for vibrations of the thickness-shear mode, which is the functioning mode of resonators and has much higher frequency than the flexural mode. The improved Lee plate equations have been used in the analysis of high frequency vibrations of quartz crystal plates as an essential step for analysis of AT- and SC-cut quartz crystal resonators after validations with fully electrode quartz crystal piezoelectric plates. In this study, closed-form solutions of free and forced vibrations of SC-cut quartz plates with partial electrodes are obtained. A procedure has been established for the calculation of dispersion relations, frequency spectra, selected vibration modes, and capacitance ratios of forced vibrations. The vibration solutions obtained with the first-order Lee plate equations are proven to be close to solutions from the Mindlin plate equations. It is now clear that both the Mindlin and Lee plate equations can be used in the analysis and design of quartz crystal resonators. PMID- 26433436 TI - Increased working memory related fMRI signal in children following Tick Borne Encephalitis. AB - OBJECTIVE: Tick Borne Encephalitis (TBE) is a viral infection in the central nervous system endemic in Europe and Asia. While pediatric infection may carry a lower risk for serious neurological sequelae compared to adults, a large proportion of children experience long term cognitive problems, most markedly decreased working memory capacity. We explored whether task related functional magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) could reveal a biological correlate of status-post TBE in children. METHODS: We examined 11 serologically verified pediatric TBE patients with central nervous system involvement with 55 healthy controls with working memory tests and MRI. RESULTS: The TBE patients showed a prominent deficit in working memory capacity and an increased task related functional MRI signal in working memory related cortical areas during a spatial working memory task performed without sedation. No diffusion differences could be found with DTI, in line with the reported paucity of anatomical abnormalities. CONCLUSION: This study is the first to demonstrate functional MRI abnormalities in TBE patients that bears similarity to other patient groups with diffuse neuronal damage. PMID- 26433437 TI - [Can we decrease cesarean rate at a university hospital treating high risk pregnancies?]. AB - OBJECTIVE: To determine which clinical practice changes were responsible for a decrease in cesarean rate from 19.2% in 2003 to 15.5% in 2012 at our university hospital treating high risk pregnancies, while verifying the absence of any increase in neonatal morbidity and death. MATERIALS AND METHODS: A descriptive retrospective study was undertaken at our labour ward including all patients delivering in 2003 and in 2012. Maternal, obstetrical and neonatal characteristics of the two populations were compared. Cesarean rates were analysed following : (1) Robson classification, (2) some maternal and obstetrical characteristics, and (3) indications for cesarean. RESULTS: Mean age, BMI and rate of scarred uterus significantly increased in 2012. The two populations remained comparable in terms of other criteria studied. The main cause responsible for decrease in cesarean rate was breech presentations (p<0.05). Furthermore, significantly less cesareans were performed after labour induction (p=0.04). We also significantly decreased our elective cesarean rate by more than 3% without increasing cesarean sections during labour, showing a rise in successful vaginal delivery trials. The impact of in utero transfers on the global rate of cesarean is highly significant since the latter has been divided by half in 10 years in this population considered to be of high risk for cesareans. DISCUSSION: These significant decreases reflect our experience in allowing vaginal deliveries in breech presentations, and also a better selection of patients for labour induction. Furthermore, it should be noted that increasing vaginal delivery trials in various obstetrical situations participated in this decrease. We clearly found that some indications for elective cesarean can be avoided, such as multiple pregnancies and scarred uterus, thus showing the importance of restricting the first indication for cesarean. Finally, the decrease in cesarean rate had no negative effect on neonatal outcome. CONCLUSION: Decreasing cesarean rate is possible in a university hospital treating high risk pregnancies. It requires daily obstetrical case by case critical analysis, allowing wide acceptance of vaginal delivery trials, and continuously evaluating clinical practices. PMID- 26433438 TI - Cumulative Brain Injury from Motor Vehicle-Induced Whole-Body Vibration and Prevention by Human Apolipoprotein A-I Molecule Mimetic (4F) Peptide (an Apo A-I Mimetic). AB - BACKGROUND: Insidious cumulative brain injury from motor vehicle-induced whole body vibration (MV-WBV) has not yet been studied. The objective of the present study is to validate whether whole-body vibration for long periods causes cumulative brain injury and impairment of the cerebral function. We also explored a preventive method for MV-WBV injury. METHODS: A study simulating whole-body vibration was conducted in 72 male Sprague-Dawley rats divided into 9 groups (N = 8): (1) 2-week normal control; (2) 2-week sham control (in the tube without vibration); (3) 2-week vibration (exposed to whole-body vibration at 30 Hz and .5 G acceleration for 4 hours/day, 5 days/week for 2 weeks; vibration parameters in the present study are similar to the most common driving conditions); (4) 4-week sham control; (5) 4-week vibration; (6) 4-week vibration with human apolipoprotein A-I molecule mimetic (4F)-preconditioning; (7) 8-week sham control; (8) 8-week vibration; and (9) 8-week 4F-preconditioning group. All the rats were evaluated by behavioral, physiological, and histological studies of the brain. RESULTS: Brain injury from vibration is a cumulative process starting with cerebral vasoconstriction, squeezing of the endothelial cells, increased free radicals, decreased nitric oxide, insufficient blood supply to the brain, and repeated reperfusion injury to brain neurons. In the 8-week vibration group, which indicated chronic brain edema, shrunken neuron numbers increased and whole neurons atrophied, which strongly correlated with neural functional impairment. There was no prominent brain neuronal injury in the 4F groups. CONCLUSIONS: The present study demonstrated cumulative brain injury from MV-WBV and validated the preventive effects of 4F preconditioning. PMID- 26433439 TI - Assessment of Left Atrial Appendage Morphology and Function in Patients with Non valvular Paroxysmal Atrial Fibrillation with Different Rhythms Using Real-Time 3D Transesophageal Echocardiography. AB - The aim of this study was to evaluate the morphology and function of the left atrial appendage (LAA) in different rhythms of paroxysmal atrial fibrillation (PaAF) patients using real-time 3D transesophageal echocardiography. This study included 46 patients with PaAF-24 with PaAF with sinus rhythm (PaAF-S) and 22 with PaAF with fibrillation (PaAF-F)-and 23 healthy volunteers. Real-time 3D transesophageal echocardiography images of the LAA were acquired in all patients. LAA end-diastolic volume increased in PaAF-S and PaAF-F, whereas LAA end-systolic volume increased only in PaAF-F. LAA emptying index, end-diastolic volume and end systolic volume were strongly negatively correlated. LAA emptying index was positively correlated with percentage changes in LAA area and diameter, as well as flow velocity. The co-occurrence of spontaneous echo contrast and thrombus gradually increased in the PaAF-F group, compared with the PaAF-S group. The morphology and change in function of the LAA in patients with paroxysmal PaAF can be evaluated with superior feasibility and reproducibility using real-time 3D transesophageal echocardiography. Morphologic changes in the LAA appeared earlier than changes in LAA function during the course of PaAF. Spontaneous echo contrast and thrombus co-occurred more often in PaAF-F than in PaAF-S. PMID- 26433440 TI - Changing nomenclature for PBC: From 'cirrhosis' to 'cholangitis'. PMID- 26433442 TI - Studying epilepsy to understand bipolar disorder? PMID- 26433441 TI - Unilateral or Bilateral Thoracocentesis for Bilateral Pleural Effusion. A Prospective Study. AB - INTRODUCTION: In the absence of firm recommendations, we analyzed whether unilateral thoracic puncture is sufficient for bilateral pleural effusion (PE), or if the procedure needs to be performed in both sides. MATERIALS AND METHODS: Prospective study of patients seen consecutively for bilateral PE during a period of 3 years and 9 months. All patients underwent simultaneous bilateral thoracocentesis. The standard protocol variables collected in our hospital served as study parameters. Size of PE, presence of chest pain or fever, or accompanying lung abnormalities, different attenuation values on chest computed tomography, presence of loculated pleural fluid, and radiological resolution in a single side were also evaluated. RESULTS: A total of 36 patients (19 men; mean age 68.5 +/- 16.5 years) were included. The etiology of the effusion was different in each side in only 2 patients (5.6%). In 6/32 cases (18.8%), the biological analysis of the pleural fluid (in terms of transudate/exudate) from both sides did not correspond with the etiological diagnosis of the effusion. Correlation between biochemical parameters analyzed in the fluid from both sides (Pearson's correlation coefficient) ranged between 0.74 (LDH) and 0.998 (NT-proBNP). As different diagnoses in each side were found in only 2 patients, the circumstances in which bilateral diagnostic thoracocentesis would be necessary could not be determined. CONCLUSIONS: Simultaneous bilateral thoracocentesis does not appear to be recommendable. Larger series are needed to establish which factors might suggest the need for simultaneous puncture of both PE. PMID- 26433444 TI - Management of Children with Mild, Moderate, and Moderately Severe Sensorineural Hearing Loss. AB - Any degree of hearing loss can have a negative impact on child development. The amount of impact is largely determined by the type, quality, and timeliness of intervention. Early identification and management of hearing loss is essential for minimizing the impact of hearing loss and ensuring that children can reach their cognitive, linguistic, educational, and social potential. Advances in hearing technology and broadening of candidacy for same, have resulted in improved outcomes for many children with hearing loss. Through ongoing hearing monitoring throughout childhood, children with congenital, late-onset, or progressive losses can receive timely management from interprofessional, collaborative teams. PMID- 26433443 TI - Prostate-specific antigen screening and prostate cancer treatment in renal transplantation candidates: A survey of U.S. transplantation centers. AB - INTRODUCTION: Renal transplantation candidates are a highly screened population. There are currently no guidelines or consensus on prostate cancer (CaP) screening in these patients. In light of the recent United States Preventive Services Task Force recommendations against prostate-specific antigen (PSA) screening, we conducted a survey of transplantation surgeons to gain a better understanding of practice patterns among U.S. centers. MATERIALS AND METHODS: A 14-question multiple-choice online survey was e-mailed to 195 U.S. renal transplantation centers. The questionnaire assessed CaP screening and treatment practices. The survey also evaluated characteristics of the respondent's institution. Descriptive statistics were used for each of the responses, and associations were made with program characterization using logistic or linear regression models. RESULTS: A total of 90 surgeons responded, representing 65 of 195 programs (33% response rate). Overall, 89% of respondents reported routinely screening for CaP in renal transplantation candidates and 71% had set guidelines for PSA screening. The most common age to start PSA screening was 50 years (51%) and 79% of respondents reported no age limit to stop PSA screening. Definitive treatment of CaP was required before proceeding to transplantation in 45% of respondents. Active surveillance was a viable option in 67% of responders. Most respondents (73%) replied that the waiting time for eligibility after treatment depended on the CaP stage and risk. CONCLUSIONS: Although most programs have guidelines on PSA screening in renal transplantation candidates, there is still variation nationwide in screening and treatment practices. AS is a viable treatment option in most of the programs. Our results suggest a benefit of a consensus panel to recommend guidelines in this population. PMID- 26433445 TI - Vitamins C and E (ascorbate/alpha-tocopherol) provide synergistic neuroprotection in the jejunum in experimental diabetes. AB - The present study evaluated the synergistic effects of the association of ascorbic acid and alpha-tocopherol on myenteric in the jejunum of diabetic rats. The rats were randomly divided into four equal groups: untreated normoglycemic (UC), untreated diabetic (UD), ascorbic acid and alpha-tocopherol-treated normoglycemic (CAE) and ascorbic acid and alpha-tocopherol-treated diabetic (DAE). The rats from the CAE and DAE group received supplementation with ascorbic acid (1g/L in water) and alpha-tocopherol (1% in chow). At 210-days-old, the animals were sacrified and their jejunum was collected and submitted to immunohistochemistry. Quantitative and/or morphometric analysis were performed. Supplementation with ascorbic acid and alpha-tocopherol prevented the cell loss of myenteric neurons expressing HuC/D and TrkA in an equivalent proportion. We also observed a reduction of the CGRP nerve fiber varicosities and the prevention of the increased cell body size of submucosal VIP neurons (p<0.05). The association of ascorbic acid and alpha-tocopherol reduced the deleterious effects of diabetes promoting protection on the enteric neurons. PMID- 26433446 TI - Case of osseous dysplasia with an unusual concentric, circular, radiological appearance. AB - Osseous dysplasia is an idiopathic process that is characterised by the replacement of normal bone with fibrous tissue and metaplastic bone. On radiographic images it may be predominantly radiolucent, predominantly radio opaque, or mixed. We present a focal osseous dysplastic lesion with an unusual concentric, circular, radiographic appearance. PMID- 26433447 TI - Complications and Failures of Office-Based Endoscopic Angiolytic Laser Surgery Treatment. AB - OBJECTIVES/HYPOTHESIS: Although office-based laser surgery applications for benign and premalignant lesions of the larynx are appealing, there are scant data on their complications and failures. We review office-based angiolytic laser surgery in patients with benign laryngeal pathology for rates of complication and failure. STUDY DESIGN: Retrospective chart review. METHODS: Two hundred fifty five patients who underwent in-office angiolytic laser surgery treatment over 4 years were reviewed. The criteria for complications and failures were based on postprocedure stroboscopy and clinical findings. RESULTS: The majority of patients had unilateral disease, which included polyps (46%), leukoplakia (14%), papilloma (13%), scar (12%), and varix (11%). There were 382 laser treatments, of which 56% were by pulsed potassium titanyl phosphate laser. Average energy delivery was lesion specific, with papilloma receiving the most (mean 351 J) and varices receiving the least (mean 53 J) energy. Most in-office treatments were tolerated well. Four percent of patients had complications including stiffness, atrophy, and transient but prolonged hyperemia. Twenty-seven percent of patients required multiple laser treatments. Multiple treatments were more likely in papilloma and leukoplakia. CONCLUSIONS: While in-office laser therapy for benign vocal fold lesions is appealing, repeated treatment due to incomplete resolution may be needed. Risks of transient and long-term complications are low but real. Patient selection and standardized laser energy parameters may help in decreasing complications and need for repeat procedures. PMID- 26433448 TI - A fragment of the Escherichia coli ClpB heat-shock protein is a micromolar melanocortin 1 receptor agonist. AB - The melanocortin system consists of five receptor subtypes (MC1-5R), endogenous agonists derived from the proopiomelanocortin gene transcript, and the antagonists agouti and agouti-related protein. The Escherichia coli heat shock protein ClpB has previously been described as an antigen mimetic to the endogenous melanocortin agonist alpha-MSH. Herein, we investigated if a fragment of the ClpB protein could directly signal through the melanocortin receptors. We synthesized a complementary fragment of the ClpB protein that partially aligned with alpha-MSH. Pharmacological assessment of this fragment resulted in no antagonist activity at the MC3R or the MC4R and no agonist activity at the MC4R. Partial receptor activation was observed for the MC3R and MC5R at 100 MUM concentrations. This fragment was shown to be a full micromolar MC1R agonist and may serve as a template for future research into selective MC1R ligands. PMID- 26433449 TI - Discovery of the oxazabicyclo[3.3.1]nonane derivatives as potent and orally active GPR119 agonists. AB - The design and synthesis of two conformationally restricted oxazabicyclo octane derivatives as GRP119 agonists is described. Derivatives of scaffold C, with syn configuration, have the best overall profiles with respect to solubility and in vivo efficacy. Compound 25a was found to have extremely potent agonistic activity and was orally active in lowering blood glucose levels in a mouse oral glucose tolerance test at a dose of 0.1 mg/kg. PMID- 26433450 TI - Anterior spreader flap technique: A new minimally invasive method for stabilising and widening the nasal valve. AB - BACKGROUND: The 'anterior spreader flap' is a new minimally invasive technique, for the treatment of nasal valve insufficiency or stenosis. The aim of this study was to present our experience with a series of patients with nasal valve dysfunction corrected by the minimally invasive spreader flap technique. METHODOLOGY: We performed a retrospective review of our patients with nasal valve malfunction who underwent the anterior spreader flap between June 2010 and June 2013. The patients had to judge their symptoms of nasal obstruction pre- and 12 months post-operatively by the Nasal Obstruction and Septoplasty Effectiveness (NOSE) quality-of-life assessment scale. The difference between the pre- and post operative evaluations of each group and between the groups was calculated, and it was statistically analysed. RESULTS: Forty-three patients were treated. In seven patients, the anterior spreader flap was performed as a single procedure (group F), in 15 patients the anterior spreader flap was combined with a septoplasty and a turbinoplasty (group FST), in 10 patients with a turbinoplasty (group FT) and in 11 with a septoplasty (group FS). All patients reported significant post operative improvement in nasal breathing (p < 0.05). The mean improvement (diffNOSE) of all patients was 54.2 points. The 'FS' group and the 'FST' group showed best post-operative results, but there were no significant differences between the groups (p > 0.8). CONCLUSIONS: The anterior spreader flap is an effective and safe method for minimally invasive improvement of nasal breathing in patients with nasal valve dysfunction. PMID- 26433451 TI - The DOT flap for nasal sidewall reconstruction. PMID- 26433452 TI - School Breakfast Policy Is Associated with Dietary Intake of Fourth- and Fifth Grade Students. AB - BACKGROUND: Breakfast skipping has been associated with obesity. Schools have adopted breakfast policies to increase breakfast participation. Recently, there have been concerns that students in schools where breakfast is served in the classroom may be eating two breakfasts--one at home and one at school--thereby increasing their risk of excessive energy intake and weight gain. OBJECTIVE: The study objective was to compare the prevalence of not eating breakfast, eating breakfast at home or school only, and eating double breakfasts (home and school) by students in schools with distinct breakfast policies and evaluate the relationship of breakfast policy to energy intake and diet quality. DESIGN: Baseline data were collected in 2011-2012 as part of a cluster randomized controlled trial to evaluate the effectiveness of a school-based intervention to promote fruit and vegetable intake and physical activity in low-resource elementary schools in California. PARTICIPANTS/SETTING: Participants were 3,944 fourth and fifth graders from 43 schools, 20 served breakfast in the cafeteria before school, 17 served breakfast in the classroom at the start of school, and 6 served "second chance" breakfast (in the cafeteria before school and again at first recess). STATISTICAL ANALYSIS: As part of a secondary data analysis, differences in school and individual characteristics by school breakfast policy were assessed by chi(2) test of independence or analysis of variance. Associations between school breakfast policy and breakfast eating patterns were assessed. Outcomes included calorie intake at breakfast, total daily calorie intake, and diet quality as measured by the Healthy Eating Index 2010. Control variables included student race/ethnicity, grade, and language spoken at home, and clustering of students by school. RESULTS: Breakfast in the classroom was associated with fewer students not eating breakfast (P<0.001), but more eating breakfast at both home and school (P<0.001). Students in the breakfast in the classroom group did not have higher mean energy intakes from breakfast or higher daily energy intakes that were higher than other breakfast policy groups. The breakfast in the classroom group had higher overall diet quality (P=0.01). CONCLUSIONS: No evidence was found to support discontinuation of breakfast in the classroom policy on the basis of concerns that children will eat excess calories. PMID- 26433453 TI - Racial and Ethnic Disparities in Dietary Intake among California Children. AB - BACKGROUND: The prevalence of childhood obesity among racial and ethnic minority groups is high. Multiple factors affect the development of childhood obesity, including dietary practices. OBJECTIVE: To examine the racial and ethnic differences in reported dietary practices among the largest minority groups of California children. METHODS: Data from the 2007 and 2009 California Health Interview Survey were analyzed using multivariate regression with survey weights to examine how race, ethnicity, sociodemographic characteristics, and child factors were associated with specific dietary practices. RESULTS: The sample included 15,902 children aged 2 to 11 years. In multivariate regressions, substantial differences in fruit juice, fruit, vegetable, sugar-sweetened beverages, sweets, and fast-food consumption were found among the major racial and ethnic groups of children. Asians regardless of interview language were more likely than whites to have low vegetable intake consumption (Asians English interview odds ratio [OR] 1.20, 95% CI 1.01 to 1.43; Asians non-English-interview OR 2.09, 95% CI 1.23 to 3.57) and low fruit consumption (Asians English interview OR 1.69, 95% CI 1.41 to 2.03; Asians non-English interview OR 3.04, 95% CI 2.00 to 4.6). Latinos regardless of interview language were also more likely than whites to have high fruit juice (Latinos English interview OR 1.54, 95% CI 1.28 to 1.84 and Latinos non-English interview OR 1.29, 95% CI 1.02 to 1.62) and fast food consumption (Latinos English interview OR 1.74, 95% CI 1.46 to 2.08 and Latinos non-English interview OR 1.48, 95% CI 1.16 to 1.91); but Latinos were less likely than whites to consume sweets (Latinos English interview OR 0.81, 95% CI 0.66 to 0.99 and Latinos non-English interview OR 0.56, 95% CI 1.16 to 1.91). CONCLUSIONS: Significant racial and ethnic differences exist in the dietary practices of California children. Increased fruit and vegetable consumption appears to be associated with parent education but not income. Our findings suggest that anticipatory guidance and dietary counseling might benefit from tailoring to specific ethnic groups to potentially address disparities in overweight and obesity. PMID- 26433455 TI - Biomechanical implications of excessive endograft protrusion into the aortic arch after thoracic endovascular repair. AB - Endografts placed in the aorta for thoracic endovascular aortic repair (TEVAR) may determine malappositioning to the lesser curvature of the aortic wall, thus resulting in a devastating complication known as endograft collapse. This premature device failure commonly occurs in young individuals after TEVAR for traumatic aortic injuries as a result of applications outside the physical conditions for which the endograft was designed. In this study, an experimentally calibrated fluid-structure interaction (FSI) model was developed to assess the hemodynamic and stress/strain distributions acting on the excessive protrusion extension (PE) of endografts deployed in four young patients underwent TEVAR. Endograft infolding was experimentally measured for different hemodynamic scenarios by perfusion testing and then used to numerically calibrate the mechanical behavior of endograft PE. Results evinced that the extent of endograft can severely alter the hemodynamic and structural loads exerted on the endograft PE. Specifically, PE determined a physiological aortic coarctation into the aortic arch characterized by a helical flow in the distal descending aorta. High device displacement and transmural pressure across the stent-graft wall were found for a PE longer than 21 mm. Finally, marked intramural stress and principal strain distributions on the protruded segment of the endograft wall may suggest failure due to material fatigue. These critical parameters may contribute to the endograft collapse observed clinically and can be used to design new devices more suitable for young individuals to be treated with an endoprosthesis for TEVAR of blunt traumatic aortic injuries. PMID- 26433456 TI - Changeability of tissue's magnetic remanence after galvanic-magnetostimulation in upper-back pain treatment. AB - OBJECTIVE: Research was conducted on parametric profiles of healthy subjects and patients with cervico-brachial pain syndrome resulting from C4/5 and/or C5/6 discopathy, including magnetic remanence of tissues in marker points 1-12 (L+R) and functional parameters, and their subsequent change after treatment in group A, using method of push-pull galvanic magnetostimulation (GMT 2.0). DESIGN: GMT 2.0 device, comprised of one air solenoid and three galvanic solenoids in electrolytic tubs, was designed for push-pull magnetostimulation of the head, coupled with simultaneous stimulation of the limbs. SETTING: Clinical trial was conducted in Outpatient Private Clinic "VIS" under the auspices of Silesian Higher Medical School in Katowice, Poland. PATIENTS: 55 subjects participated in the study: control group K consisted of 23 healthy individuals, whereas 33 patients in group A were treated using GMT 2.0. INTERVENTION: Only patients in group A were treated with GMT 2.0 during 40-min sessions over a period of 10 days. MAIN OUTCOME MEASURES: Parametric profile of the patients was defined using various measurements: electronic SFTR test (C-Th-shoulders), HR, RR, BDI and VAS tests, magnetic remanence in marker points 1-12 (L+R) and blood parameters: HB, ER, CREA, BIL, K(+), Na(+), Cl(-) Fe(2+), Ca(2+) and Mg(2+). RESULTS: There was a significant reduction in pain (VAS), increase in the range of motion (SFTR), lower depression symptoms (BDI), slower heart rate (HR), lower blood pressure (RR), greater concentration of Mg(2+), K(+), Ca(2+)ions and reduction in the concentration of BIL, CREA Fe(2+) after GMT 2.0 treatment in group A. Evaluation of magnetic remanence in marker points M1-12 (L+R) initially showed higher values in group K, which after treatment were normalized to values similar to those in group K. CONCLUSION: GMT 2.0 treatment in group A resulted in normalization of magnetic remanence, synergically with increased range of motion (SFTR test), decreased HR and RR parameters, smaller depressive trends (BDI test), as well as increased ion levels (K(+), Mg(2+), Ca(2+)) and better functional parameters of kidneys and liver. PMID- 26433457 TI - iTIS-PseKNC: Identification of Translation Initiation Site in human genes using pseudo k-tuple nucleotides composition. AB - Translation is an essential genetic process for understanding the mechanism of gene expression. Due to the large number of protein sequences generated in the post-genomic era, conventional methods are unable to identify Translation Initiation Site (TIS) in human genes timely and accurately. It is thus highly desirable to develop an automatic and accurate computational model for identification of TIS. Considerable improvements have been achieved in developing computational models; however, development of accurate and reliable automated systems for TIS identification in human genes is still a challenging task. In this connection, we propose iTIS-PseKNC, a novel protocol for identification of TIS. Three protein sequence representation methods including dinucleotide composition, pseudo-dinucleotide composition and Trinucleotide composition have been used in order to extract numerical descriptors. Support Vector Machine (SVM), K-nearest neighbor and Probabilistic Neural Network are assessed for their performance using the constructed descriptors. The proposed model iTIS-PseKNC has achieved 99.40% accuracy using jackknife test. The experimental results validated the superior performance of iTIS-PseKNC over the existing methods reported in the literature. It is highly anticipated that the iTIS-PseKNC predictor will be useful for basic research studies. PMID- 26433454 TI - Disruption of IP3R2-mediated Ca2+ signaling pathway in astrocytes ameliorates neuronal death and brain damage while reducing behavioral deficits after focal ischemic stroke. AB - Inositol trisphosphate receptor (IP3R)-mediated intracellular Ca(2+) increase is the major Ca(2+) signaling pathway in astrocytes in the central nervous system (CNS). Ca(2+) increases in astrocytes have been found to modulate neuronal function through gliotransmitter release. We previously demonstrated that astrocytes exhibit enhanced Ca(2+) signaling in vivo after photothrombosis (PT) induced ischemia, which is largely due to the activation of G-protein coupled receptors (GPCRs). The aim of this study is to investigate the role of astrocytic IP3R-mediated Ca(2+) signaling in neuronal death, brain damage and behavior outcomes after PT. For this purpose, we conducted experiments using homozygous type 2 IP3R (IP3R2) knockout (KO) mice. Histological and immunostaining studies showed that IP3R2 KO mice were indeed deficient in IP3R2 in astrocytes and exhibited normal brain cytoarchitecture. IP3R2 KO mice also had the same densities of S100beta+ astrocytes and NeuN+ neurons in the cortices, and exhibited the same glial fibrillary acidic protein (GFAP) and glial glutamate transporter (GLT-1) levels in the cortices and hippocampi as compared with wild type (WT) mice. Two-photon (2-P) imaging showed that IP3R2 KO mice did not exhibit ATP-induced Ca(2+) waves in vivo in the astrocytic network, which verified the disruption of IP3R-mediated Ca(2+) signaling in astrocytes of these mice. When subject to PT, IP3R2 KO mice had smaller infarction than WT mice in acute and chronic phases of ischemia. IP3R2 KO mice also exhibited less neuronal apoptosis, reactive astrogliosis, and tissue loss than WT mice. Behavioral tests, including cylinder, hanging wire, pole and adhesive tests, showed that IP3R2 KO mice exhibited reduced functional deficits after PT. Collectively, our study demonstrates that disruption of astrocytic Ca(2+) signaling by deleting IP3R2s has beneficial effects on neuronal and brain protection and functional deficits after stroke. These findings reveal a novel non-cell-autonomous neuronal and brain protective function of astrocytes in ischemic stroke, whereby suggest that the astrocytic IP3R2-mediated Ca(2+) signaling pathway might be a promising target for stroke therapy. PMID- 26433458 TI - Binary combination of epsilon-poly-L-lysine and isoeugenol affect progression of spoilage microbiota in fresh turkey meat, and delay onset of spoilage in Pseudomonas putida challenged meat. AB - Proliferation of microbial population on fresh poultry meat over time elicits spoilage when reaching unacceptable levels, during which process slime production, microorganism colony formation, negative organoleptic impact and meat structure change are observed. Spoilage organisms in raw meat, especially Gram negative bacteria can be difficult to combat due to their cell wall composition. In this study, the natural antimicrobial agents epsilon-poly-L-lysine (epsilon PL) and isoeugenol were tested individually and in combinations for their activities against a selection of Gram-negative strains in vitro. All combinations resulted in additive interactions between epsilon-PL and isoeugenol towards the bacteria tested. The killing efficiency of different ratios of the two antimicrobial agents was further evaluated in vitro against Pseudomonas putida. Subsequently, the most efficient ratio was applied to a raw turkey meat model system which was incubated for 96 h at spoilage temperature. Half of the samples were challenged with P. putida, and the bacterial load and microbial community composition was followed over time. CFU counts revealed that the antimicrobial blend was able to lower the amount of viable Pseudomonas spp. by one log compared to untreated samples of challenged turkey meat, while the single compounds had no effect on the population. However, the compounds had no effect on Pseudomonas spp. CFU in unchallenged meat. Next-generation sequencing offered culture-independent insight into population diversity and changes in microbial composition of the meat during spoilage and in response to antimicrobial treatment. Spoilage of unchallenged turkey meat resulted in decreasing species diversity over time, regardless of whether the samples received antimicrobial treatment. The microbiota composition of untreated unchallenged meat progressed from a Pseudomonas spp. to a Pseudomonas spp., Photobacterium spp., and Brochothrix thermosphacta dominated food matrix on the expense of low abundance species. We observed a similar shift among the dominant species in meat treated with epsilon-PL or the antimicrobial blend, but the samples differed markedly in the composition of less abundant species. In contrast, the overall species diversity was constant during incubation of turkey meat challenged with P. putida although the microbiota composition did change over time. Untreated or epsilon-PL treated samples progressed from a Pseudomonas spp. to a Pseudomonas spp. and Enterobacteriaceae dominated food matrix, while treatment with the antimicrobial blend resulted in increased relative abundance of Hafnia spp., Enterococcaceae, and Photobacterium spp. We conclude that the blend delayed the onset of spoilage of challenged meat, and that all antimicrobial treatments of unchallenged or challenged meat affect the progression of the microbial community composition. Our study confirms that the antimicrobial effects observed in vitro can be extrapolated to a food matrix such as turkey meat. However, it also underlines the consequence of species-to-species variation in susceptibility to antimicrobials, namely that the microbial community change while the CFU remains the same. Addition of antimicrobials may thus prevent the growth of some microorganisms, allowing others to proliferate in their place. PMID- 26433459 TI - Assessment of the effect of a Salmonella enterica ser. Typhimurium culture supernatant on the single-cell lag time of foodborne pathogens. AB - The objective of this study was the in vitro evaluation of the effect of a cell free microbial supernatant, produced by a luxS-positive Salmonella enterica ser. Typhimurium strain, on the single-cell growth kinetic behavior of two strains of S. enterica (serotypes Enteritidis and Typhimurium) and a methicillin-resistant Staphylococcus aureus strain. The single-cell lag time (lambda) of the pathogens was estimated in the absence and presence (20% v/v) of microbial supernatant based on optical density measurements. As demonstrated by the obtained results, the tested microbial supernatant had a strain-specific effect on the single-cell lambda and its variability. Although the mean lambda values were similar in the absence and presence of microbial supernatant in the case of Salmonella Enteritidis, a significant (P <= 0.05) reduction and increase in the mean value of this parameter in the presence of microbial supernatant were observed for Salmonella Typhimurium and St. aureus, respectively. With regard to the effect of the tested microbial supernatant on the single-cell variability of lambda, similar lambda distributions were obtained in its absence and presence for S. Enteritidis, while considerable differences were noted for the other two tested organisms; the coefficient of variation of lambda in the absence and presence of microbial supernatant was 41.6 and 69.8% for S. Typhimurium, respectively, with the corresponding values for St. aureus being 74.0 and 56.9%. As demonstrated by the results of bioassays, the tested microbial supernatant exhibited autoinducer 2 activity, indicating a potential association of such quorum sensing compounds with the observed effects. Although preliminary in nature, the collected data provide a good basis for future research on the role of quorum sensing in the single-cell growth behavior of foodborne pathogens. PMID- 26433460 TI - Detection of hepatitis E virus RNA in raw sausages and liver sausages from retail in Germany using an optimized method. AB - Hepatitis E virus (HEV) is a pathogen of increasing importance, which can be zoonotically transmitted from domestic pigs, wild boar, and deer to humans. Foodborne transmission by consumption of raw and undercooked liver, meat, or sausages prepared from infected animals has been documented. The aim of this study was to investigate the distribution of HEV in different types of sausages sold in Germany. As no standardized methods for HEV detection in food exist, several techniques of sample homogenization, virus concentration and nucleic acid extraction followed by real-time RT-PCR were compared using artificially contaminated sausages. A method using TRI Reagent(r) Solution showed the best efficacy of matrix disruption and a treatment with chloroform followed by a silica-based RNA extraction method resulted in the highest HEV detection rates. The detection limit of the method was 2.9 * 10(3) and 5.3 * 10(4) genome equivalents per 5 g raw sausage and 2 g liver sausage, respectively. Application of the method to raw and liver sausages from retail in Germany resulted in the HEV genome detection in 14 out of 70 (20%) raw sausages and in 11 out of 50 (22%) liver sausages. The detected HEV sequences showed a high diversity and belonged to different subtypes of HEV genotype 3. The results indicate a broad distribution of HEV-RNA in meat products sold in Germany; however, the infectivity of the detected virus remains to be assessed in future. PMID- 26433461 TI - Improvement of the antifungal activity of Litsea cubeba vapor by using a helium neon (He-Ne) laser against Aspergillus flavus on brown rice snack bars. AB - The aim of this study was to improve the antifungal activity of the volatile Litsea cubeba essential oil and its main components (citral and limonene) on brown rice snack bars by applying He-Ne laser treatment. Different volumes (50 200 MUL) of L. cubeba, citral or limonene were absorbed into a filter paper and placed inside an oven (18 L). Ten brown rice snack bars (2 cm wide * 4 cm long * 0.5 cm deep) were put in an oven and heated at 180 degrees C for 20 min. The shelf-life of the treated snack bars at 30 degrees C was assessed and sensory testing was carried out to investigate their consumer acceptability. A count of total phenolic content (TPC) and Fourier transform infrared spectroscopy (FTIR) on the properties of essential oil, citral, and limonene before and after the laser treatment was studied for possible modes of action. It was found that the laser treatment improved the antifungal activity of the examined volatile L. cubeba and citral with Aspergillus flavus inhibition by 80% in comparison with those of the control not treated with the laser. L. cubeba vapor at 100 MUL with the laser treatment was found to completely inhibit the growth of natural molds on the snack bars for at least 25 days; however, without essential oil vapor and laser treatment, naturally contaminating mold was observed in 3 days. Results from the sensory tests showed that the panelists were unable to detect flavor and aroma differences between essential oil treatment and the control. Laser treatment caused an increase in TPC of citral oil whereas the TPC in limonene showed a decrease after the laser treatment. These situations could result from the changing peak of the aliphatic hydrocarbons that was revealed by the FTIR spectra. PMID- 26433462 TI - Metabolites and hormones are involved in the intraspecific variability of drought hardening in radiata pine. AB - Studies of metabolic and physiological bases of plant tolerance and hardening against drought are essential to improve genetic breeding programs, especially in productive species such as Pinus radiata. The exposure to different drought cycles is a highly effective tool that improves plant conditioning, but limited information is available about the mechanisms that modulate this process. To clarify this issue, six P. radiata breeds with well-known differences in drought tolerance were analyzed after two consecutive drought cycles. Survival rate, concentration of several metabolites such as free soluble amino acids and polyamines, and main plant hormones varied between them after drought hardening, while relative growth ratio and water potential at both predawn and dawn did not. Hardening induced a strong increase in total soluble amino acids in all breeds, accumulating mainly those implicated in the glutamate metabolism (GM), especially L-proline, in the most tolerant breeds. Other amino acids from GM such as gamma aminobutyric acid (GABA) and L-arginine (Arg) were also strongly increased. GABA pathway could improve the response against drought, whereas Arg acts as precursor for the synthesis of spermidine. This polyamine showed a positive relationship with the survival capacity, probably due to its role as antioxidant under stress conditions. Finally, drought hardening also induced changes in phytohormone content, showing each breed a different profile. Although all of them accumulated indole-3-acetic acid and jasmonic acid and reduced zeatin content in needles, significant differences were observed regarding abscisic acid, salicylic acid and mainly zeatin riboside. These results confirm that hardening is not only species dependent but also an intraspecific processes controlled through metabolite changes. PMID- 26433464 TI - SCA38 is rare in Mainland China. AB - Spinocerebellar ataxias (SCAs) are a group of dominantly inherited neurodegenerative disorders distributed worldwide. Nearly 35 SCAs have been localized and 28 genes have been identified. Recently, mutations in the elongation of a very long chain fatty acids-5 gene (ELOVL5) were reported to cause a SCA38 subtype. To describe the epidemiology of SCA38 in Mainland China, we analyzed the coding sequence of ELOVL5 in 346 patients diagnosed as SCAs. Finally, we did not observe any disease-related gene mutations in ELOVL5. This suggests that the SCA38 subtype is very rare in Mainland China. PMID- 26433465 TI - Etiology, clinical characteristics and prognosis of spontaneous intracerebral hemorrhage in children: A prospective cohort study in China. AB - BACKGROUND AND OBJECTIVE: Much is known about spontaneous intracerebral hemorrhage (SICH) in adults, but few studies have examined pediatric SICH, especially in China. The aim of the present study was to describe the etiology, clinical characteristics and prognosis of SICH in children from southwest China. METHOD: Consecutive patients aged 1-18 years with SICH at our medical center were prospectively enrolled from January 2012 to June 2014. SICH was defined by WHO criteria and confirmed by CT or MRI findings. Demographic and clinical information was collected at baseline, and follow-up assessments were conducted at 3 and 6 months after SICH, when patients were scored on the modified Rankin Scale (mRS) and events of deaths and recurrent hemorrhagic stroke were recorded. RESULTS: Among the 70 children (43 males; median age, 12.0 years) in the final analysis, 44 patients (62.9%) had SICH due to arteriovenous malformation, and less frequent etiologies were cavernous malformation (n=4), aneurysm (n=2), tumors (n=2), moyamoya (n=2), hemophilia (n=1), hypertension (n=1), while 14 (20.0%) had SICH of unknown etiology. The mortality rate at 3 months and 6 months was equal, which was both 3%. The rate of disability was 12.1% at 3 months and 9.1% at 6 months. CONCLUSION: The most frequent etiology of pediatric SICH in this Chinese cohort was arteriovenous malformation. SICH of unknown etiology occurred much more often in our cohort than in previously published Caucasian patients in the US and Europe. PMID- 26433466 TI - Group cognitive behavioural therapy for insomnia: Effects on sleep and depressive symptomatology in a sample with comorbidity. AB - AIM: To investigate the effects of group CBT for insomnia (CBT-I) on insomnia and depressive symptomatology in a comorbid sample through a randomised controlled trial with a 6 month follow-up. METHODS: 64 participants were recruited through advertisements and randomised to receive CBT-I or an active control (relaxation training: RT) during four group sessions. Insomnia Severity Index and BDI-II were the primary outcome measures, assessed pre-treatment, post-treatment and at 6 month follow-up. Insomnia and depressive diagnoses, and functional impairment were assessed before and after treatment, whereas sleep diary data was gathered continuously from one week before treatment until after treatment. RESULTS: CBT-I was more efficient than RT in reducing insomnia severity and equally effective in reducing depressive symptoms, although CBT-I was associated with a higher proportion of remitted persons than RT, regarding both insomnia and depression diagnoses. Also, CBT-I was associated with less functional impairment, shorter sleep onset latency and wake after sleep onset but both treatments had equal improvements of sleep quality, early morning awakenings and total sleep time. CONCLUSION: Group CBT-I is an efficient form of insomnia-treatment for people with insomnia comorbid with depressive symptomatology. The mixed results regarding depression outcomes warrants replication and further studies into treatment mechanisms. PMID- 26433463 TI - Eliminating roles for T-bet and IL-2 but revealing superior activation and proliferation as mechanisms underpinning dominance of regulatory T cells in tumors. AB - Foxp3(+) regulatory T cells (Tregs) are often highly enriched within the tumor infiltrating T cell pool. Using a well-characterised model of carcinogen-induced fibrosarcomas we show that the enriched tumor-infiltrating Treg population comprises largely of CXCR3(+) T-bet(+) 'TH1-like' Tregs which are thymus-derived Helios(+) cells. Whilst IL-2 maintains homeostatic ratios of Tregs in lymphoid organs, we found that the perturbation in Treg frequencies in tumors is IL-2 independent. Moreover, we show that the TH1 phenotype of tumor-infiltrating Tregs is dispensable for their ability to influence tumor progression. We did however find that unlike Tconvs, the majority of intra-tumoral Tregs express the activation markers CD69, CD25, ICOS, CD103 and CTLA4 and are significantly more proliferative than Tconvs. Moreover, we have found that CD69(+) Tregs are more suppressive than their CD69- counterparts. Collectively, these data indicate superior activation of Tregs in the tumor microenvironment, promoting their suppressive ability and selective proliferation at this site. PMID- 26433467 TI - Unintended pregnancy among HIV-positive pregnant women in Enugu, southeast Nigeria. AB - OBJECTIVE: To determine the prevalence and factors associated with unintended pregnancy among HIV-positive pregnant women in Enugu, southeast Nigeria. METHODS: A questionnaire-based cross-sectional study was performed of HIV-positive pregnant women receiving prenatal care at two tertiary health institutions in Enugu between March 1 and August 31, 2012. The women were interviewed with a pretested questionnaire. RESULTS: Overall, 180 HIV-positive pregnant women were recruited, 67 (37.2%) of whom declared that their pregnancy was unintended. Overall, 174 (96.7%) patients were receiving antiretroviral therapy and 99 (55.0%) had future fertility intensions. Participants with regular partners (married or cohabiting) had a significantly higher rate of unintended pregnancy than those with unstable partners (40.3%, n=64/159 vs 14.3%, n=3/21 P=0.029). Age, parity, educational level, and current treatment with antiretroviral therapy did not significantly affect the prevalence of unintended pregnancy. CONCLUSION: A substantial number of HIV-positive pregnant women declared their pregnancies to be unintended. Modern contraceptives should be made readily available and accessible to HIV-positive women to help eliminate mother-to-child transmission of HIV and subsequent new pediatric HIV infections. PMID- 26433468 TI - Association between sonographic measurement of fetal head circumference and labor outcome. AB - OBJECTIVE: To evaluate the association between sonographically measured head circumference (HC) and labor outcome. METHODS: In a retrospective study at a tertiary medical center in Israel, data were reviewed for all term singleton deliveries between July 2007 and December 2012 with HC measurements up to 7days before delivery. HC was compared between women with operative vaginal delivery (OVD) or cesarean delivery for prolonged second stage and those with normal vaginal delivery. The impact of HC above the 75th percentile on pregnancy outcome was analyzed. RESULTS: The study included 2351 women, of whom 2045 (87.0%) had a normal vaginal delivery, 259 (11.0%) underwent OVD, and 47 (2.0%) cesarean. Each 10mm increase in HC was associated with increased risk for obstetric intervention because of a prolonged second stage (adjusted odds ratio [aOR] 1.26; 95% confidence interval [CI] 1.08-1.46). HC above the 75th percentile was independently associated with increased odds of OVD (aOR 1.77; 95% CI 1.30-2.41), 1-minute Apgar score less than 7 (aOR 2.91; 95% CI 1.50-5.66), and neonatal asphyxia (aOR 2.19; 95% CI 1.02-4.71). CONCLUSION: Term HC above the 75th percentile was associated with increased rates of obstetric interventions because of a prolonged second stage and might be associated with neonatal asphyxia. PMID- 26433469 TI - International Federation of Gynecology and Obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals. AB - Exposure to toxic environmental chemicals during pregnancy and breastfeeding is ubiquitous and is a threat to healthy human reproduction. There are tens of thousands of chemicals in global commerce, and even small exposures to toxic chemicals during pregnancy can trigger adverse health consequences. Exposure to toxic environmental chemicals and related health outcomes are inequitably distributed within and between countries; universally, the consequences of exposure are disproportionately borne by people with low incomes. Discrimination, other social factors, economic factors, and occupation impact risk of exposure and harm. Documented links between prenatal exposure to environmental chemicals and adverse health outcomes span the life course and include impacts on fertility and pregnancy, neurodevelopment, and cancer. The global health and economic burden related to toxic environmental chemicals is in excess of millions of deaths and billions of dollars every year. On the basis of accumulating robust evidence of exposures and adverse health impacts related to toxic environmental chemicals, the International Federation of Gynecology and Obstetrics (FIGO) joins other leading reproductive health professional societies in calling for timely action to prevent harm. FIGO recommends that reproductive and other health professionals advocate for policies to prevent exposure to toxic environmental chemicals, work to ensure a healthy food system for all, make environmental health part of health care, and champion environmental justice. PMID- 26433470 TI - Altered purinergic receptor-Ca2+ signaling associated with hypoxia-induced epithelial-mesenchymal transition in breast cancer cells. AB - Hypoxia is a feature of the microenvironment of many cancers and can trigger epithelial-mesenchymal transition (EMT), a process by which cells acquire a more invasive phenotype with enriched survival. A remodeling of adenosine 5' triphosphate (ATP)-induced Ca(2+) signaling via purinergic receptors is associated with epidermal growth factor (EGF)-induced EMT in MDA-MB-468 breast cancer cells. Here, we assessed ATP-mediated Ca(2+) signaling in a model of hypoxia-induced EMT in MDA-MB-468 cells. Like EGF, hypoxia treatment (1% O2) was also associated with a significant reduction in the sensitivity of MDA-MB-468 cells to ATP (EC50 of 0.5 MUM for normoxic cells versus EC50 of 5.8 MUM for hypoxic cells). Assessment of mRNA levels of a panel of P2X and P2Y purinergic receptors following hypoxia revealed a change in levels of a suite of purinergic receptors. P2X4, P2X5, P2X7, P2Y1 and P2Y11 mRNAs decreased with hypoxia, whereas P2Y6 mRNA increased. Up-regulation of P2Y6 was a common feature of both growth factor- and hypoxia-induced models of EMT. P2Y6 levels were also significantly increased in basal-like breast tumors compared to other subtypes and breast cancer patients with higher P2Y6 levels showed reduced overall survival rates. P2Y6 siRNA-mediated silencing and the P2Y6 pharmacological inhibitor MRS2578 reduced hypoxia-induced vimentin protein expression in MDA-MB-468 cells. P2Y6 inhibition also reduced the migration of mesenchymal-like MDA-MB-231 breast cancer cells. The up-regulation of P2Y6 appears to be a common feature of the mesenchymal phenotype of breast cancer cells and inhibition of this receptor may represent a novel therapeutic target in breast cancer metastasis. PMID- 26433472 TI - Neural dynamics of object noun, action verb and action noun production in picture naming. AB - The verb/noun dissociation has often involved the semantic/grammatical confound. We conducted two event-related potentials (ERPs) studies with the aim of minimizing this confound. In Experiment 1 participants named pictures depicting actions, with verbs or nouns and pictures depicting objects with nouns. In Experiment 2, participants named objects (nouns) or actions (verbs/nouns) from the same set of action pictures. Compatible with lexical-semantic processes, semantic category modulated waveform amplitudes and topographic patterns between 250 and 380 ms after picture-onset in Experiment 1. No such effects were observed in Experiment 2. No effects were found for grammatical class in both experiments suggesting that grammatical information is not mandatorily activated during lexical-semantic processes. Given the absence of dissociation when same pictures were used the results are described as feed-forward effects from visual to semantic processing, indicating differential neural networks for lexical selection of action and object words from their corresponding visual referents. PMID- 26433471 TI - Interleukin-33 predicts poor prognosis and promotes ovarian cancer cell growth and metastasis through regulating ERK and JNK signaling pathways. AB - Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer, it remains a huge challenge to understand the cellular and molecular mechanisms of the aggressive behavior of EOC cells. Here we investigated the role of an immunomodulatory cytokine IL-33 and its receptor ST2 in mediating the growth and metastasis of EOC. Our data show that both IL-33 and ST2 were highly up-regulated in EOC tumors compared with normal ovary and ovarian benign tumors, and the expression levels were further increased in tumor tissues at the metastatic site. The expression levels of IL-33 and ST2 were positively correlated with the Ki-67 expression, and negatively correlated with the patient survival time. Using EOC cell lines, we observed that cells knocked down of IL-33 gene by siRNA had reduced migratory and invasive potential, while full length human IL-33 (fl-hIL 33) promoted the invasive, migratory and proliferative capacity of EOC cells and this process could be inhibited by IL-33 decoy receptor sST2. Signaling pathway analysis suggested that IL-33 increased the phosphorylation of ERK and JNK which was blocked by sST2. Fl-hIL-33-induced increases in EOC cell migration, invasive potential and proliferation were specifically abrogated by treatment with the ERK inhibitor U0126 while JNK inhibitor SP600125 only disrupted IL-33-induced enhancement of cell viability. Taken together, our data suggest that IL-33/ST2 axis closely associates with poor prognosis of EOC patients, and it promotes ovarian cancer growth and metastasis through regulating ERK and JNK signaling pathways. Thus IL-33/ST2 might be potential prognosis markers and therapeutic targets for EOC patients. PMID- 26433473 TI - Spotlighted Brains: Optogenetic Activation and Silencing of Neurons. AB - Optogenetics is revolutionizing cell biology and neuroscience research by allowing precise biochemical control of neuronal activity through light-activated channels. Light-induced ion transporters have been used extensively for cellular activation, and now light-gated inhibitory channels have been discovered. These represent a key new tool to elucidate the molecular mechanisms underlying neurological and neuropsychiatric disorders. PMID- 26433474 TI - Enhancement of Localized Surface Plasmon Resonance polymer based biosensor chips using well-defined glycopolymers for lectin detection. AB - Poly(methyl methacrylate) polymer based Localized Surface Plasmon Resonance biosensor chips were successfully fabricated using glycopolymer brushes carrying glucose moieties for the detection of concanavalin A. Poly(pentafluorostyrene), with pre-determined polymer chain lengths, were synthesized via a reversible addition-fragmentation chain transfer polymerization technique. The synthesized poly(pentafluorostyrene), was subsequently converted into glycopolymers via a para-fluoro-thiol "click" reaction and grafted onto the surface of sensor chips. The "glycocluster effect" induced by pendent carbohydrate moieties enabled a stronger affinity for concanavalin A binding, which resulted in a dramatic expansion of the sensors' response range. It was discovered that the longer polymer brushes did not guarantee additional enhancements for the sensor chips. Instead, they could lead to higher detection limits. In this study, the limit of detection for the sensor chips was discovered to be 1.3nmolL(-1) with a saturated response at 1054.2nmolL(-1). In addition to the superior performance, the capabilities of the reported sensor chips can be easily manipulated to detect a diverse range of analytes by "clicking" various sensing elements onto the polymer brushes. PMID- 26433475 TI - In-situ preparation, characterization and anticorrosion property of polypropylene glycol/silver nanoparticles composite for mild steel corrosion in acid solution. AB - A novel polypropylene glycol/silver nanoparticles (PPG/AgNPs) composite was prepared in-situ using natural honey as the reducing and capping agent. Characterization of the composite was done by UV-Vis spectroscopy, FTIR, TEM, XRD, and EDS. The TEM results reveal that the nanoparticles are spherical in shape. XRD and EDS results confirm the presence of elemental silver in the polymer matrix. The influence of the prepared composite on the corrosion inhibition of mild steel in 0.5M H2SO4 solution was studied by weight loss, electrochemical, SEM, EDS, and water contact angle measurements. Results show that PPG/AgNPs is effective inhibitor for mild steel in 0.5M H2SO4 solution and adsorbs onto the metal surface via chemisorption mechanism. Maximum inhibition efficiency of 94% is afforded by the highest studied concentration of PPG/AgNPs at 333K from weight loss measurements. Potentiodynamic polarization results reveal that the composite acts as a mixed-type corrosion inhibitor. Adsorption of PPG/AgNPs composite onto the mild steel surface follows Temkin adsorption isotherm. The SEM, EDS, and water contact angle images confirm the formation of PPG/AgNPs protective film on the mild steel surface. PMID- 26433477 TI - A trimodal porous carbon as an effective catalyst for hydrogen production by methane decomposition. AB - A new type of porous carbon with an interconnected trimodal pore system is synthesized by a nanocasting method using nanoparticulated bimodal micro mesoporous silica particles as the template. The synthesized template and carbon material are characterized using transmission electron microscopy (TEM), field emission electron scanning microscopy (FESEM) and nitrogen adsorption-desorption test. The synthesized carbon material has an extremely high surface area, a large pore volume and an interconnected pore structure, which could provide abundant active sites and space for chemical reactions and minimize the diffusion resistance of the reactants. The resulting carbon is used as the catalyst for hydrogen production by the thermal decomposition of methane. The catalytic results show that the as-synthesized carbon in this study produces much higher methane conversion and hydrogen yield than the commercial carbon materials. PMID- 26433476 TI - A novel inorganic precipitation-peptization method for VO2 sol and VO2 nanoparticles preparation: Synthesis, characterization and mechanism. AB - In this paper, a simple, safe and cost-saving precipitation-peptization method was proposed to prepare VO2 sol by using inorganic VOSO4-NH3?H2O-H2O2 reactants system in air under room temperature. In this process, VOSO4 was firstly precipitated to form VO(OH)2, then monometallic species of VO(O2)(OH)(-) were formed through the coordination between VO(OH)2 and H2O2. The rearrangement of VO(O2)(OH)(-) in a nonplanar pattern and intermolecular condensation reactions result in multinuclear species. Finally, VO2 sol is prepared through the condensation reactions between the multinuclear species. After drying the obtained sol at 40 degrees C, VO2 xerogel exhibiting monoclinic crystal structure with the space group of C2/m was prepared. The crystal structure of VO2 nanoparticles was transferred to monoclinic crystal structure with the space group of P21/c (VO2(M)) by annealing the xerogel at 550 degrees C. Both XRD and TEM analysis indicated that the nanoparticles possess good crystallinity with crystallite size of 34.5nm as estimated by Scherrer's method. These results suggest that the VO2 sol has been prepared successfully through the proposed simple method. PMID- 26433478 TI - Stabilizing and destabilizing protein surfactant-based foams in the presence of a chemical surfactant: Effect of adsorption kinetics. AB - Stimuli-responsive protein surfactants promise alternative foaming materials that can be made from renewable sources. However, the cost of protein surfactants is still higher than their chemical counterparts. In order to reduce the required amount of protein surfactant for foaming, we investigated the foaming and adsorption properties of the protein surfactant, DAMP4, with addition of low concentrations of the chemical surfactant sodium dodecylsulfate (SDS). The results show that the small addition of SDS can enhance foaming functions of DAMP4 at a lowered protein concentration. Dynamic surface tension measurements suggest that there is a synergy between DAMP4 and SDS which enhances adsorption kinetics of DAMP4 at the initial stage of adsorption (first 60s), which in turn stabilizes protein foams. Further interfacial properties were revealed by X-ray reflectometry measurements, showing that there is a re-arrangement of adsorbed protein-surfactant layer over a long period of 1h. Importantly, the foaming switchability of DAMP4 by metal ions is not affected by the presence of SDS, and foams can be switched off by the addition of zinc ions at permissive pH. This work provides fundamental knowledge to guide formulation using a mixture of protein and chemical surfactants towards a high performance of foaming at a low cost. PMID- 26433479 TI - Tunable ZnO spheres with high anti-biofilm and antibacterial activity via a simple green hydrothermal route. AB - A family of distinct ZnO morphologies - hollow, compartmented, core-shell and full solid ZnO spheres, dispersed or interconnected - is obtained by a simple hydrothermal route, in the presence of the starch biopolymer. The zinc carbonaceous precursors were characterized by infrared spectroscopy, thermal analysis and scanning electron microscopy, while the ZnO spheres, obtained after the thermal processing, were investigated by X-ray diffraction, Raman spectroscopy, scanning electron microscopy, UV-VIS spectroscopy, photoluminescence measurements, antimicrobial, anti-biofilm and flow cytometry tests. The formation mechanism proposed for this versatile synthesis route is based on the gelling ability of amylose, one of the starch template constituents, responsible for the effective embedding of zinc cations into starch prior to its hydrothermal carbonization. The simple variation of the raw materials concentration dictates the type of ZnO spheres. The micro-sized ZnO spheres exhibit high antibacterial and anti-biofilm activity against Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa) reference and methicillin resistant clinical strains especially for Gram-negative biofilms (P. aeruginosa), demonstrating great potential for new ZnO anti-biofilm formulations. PMID- 26433480 TI - Transient Marangoni transport of colloidal particles at the liquid/liquid interface caused by surfactant convective-diffusion under radial flow. AB - HYPOTHESIS: Interfacial tension gradients at a liquid/liquid interface drive Marangoni flows. When colloidal particles are adsorbed to an interface in systems with spatial and temporal gradients of surfactant concentration, these interfacial flows can be potentially significant contributors to the direction and rate of particle transport. EXPERIMENTS: In this work, we use optical microscopy to measure the interfacial velocities of 5MUm diameter polystyrene latex particles adsorbed at an oil/water interface, using olive oil to represent polar oils often encountered in cleaning applications. FINDINGS: On surfactant adsorption the maximum interfacial velocity scales linearly with bulk surfactant concentration, even for concentrations exceeding the critical micelle concentration (CMC). The maximum interfacial velocity weakly decreases with increasing flow rate, but it varies non-monotonically with the radial distance from the inlet. Upon surfactant desorption into a rinse solution, the maximum velocity increases with increasing concentration of the original surfactant solution, but only up to a plateau near the CMC. These experimental trends are well-described by a convective-diffusion model for surfactant transport to or from the liquid/liquid interface coupled with Langmuir-type adsorption, using a constitutive relation between the interfacial tension gradient and interfacial velocity based on the interfacial tangential stress jump. PMID- 26433481 TI - Stability of a compound sessile drop at the axisymmetric configuration. AB - The equilibrium configuration of compound sessile drops has been calculated previously in the absence of gravity. Using the Laplace equations, we establish seven dimensionless parameters describing the axisymmetric configuration in the presence of gravity. The equilibrium axisymmetric configuration can be either stable or unstable depending on the fluid properties. A stability criterion is established by calculating forces on a perturbed Laplacian shape. In the zero Bond number limit, the stability criterion depends on the density ratio, two ratios of interfacial tensions, the volume ratio of the two drops, and the contact angle. We use Surface Evolver to examine the stability of compound sessile drops at small and large Bond numbers and compare with the zero Bond number approximation. Experimentally, we realize a stable axisymmetric compound sessile drop in air, where the buoyancy force exerted by the air is negligible. Finally, using a pair of fluids in which the density ratio can be tuned nearly independently of the interfacial tensions, the stability transition is verified for the axisymmetric configuration. Even though the perturbations are different for the theory, simulations and experiments, both simulations and experiments agree closely with the zero Bond number approximation, exhibiting a small discrepancy at large Bond number. PMID- 26433482 TI - Astragaloside IV attenuates apoptosis of hypertrophic cardiomyocyte through inhibiting oxidative stress and calpain-1 activation. AB - Calpain-1 activation and oxidative stress are two critical factors contributing to apoptosis of hypertrophic cardiomyocyte. Astragaloside IV (ASIV) exhibits protective effect against various heart diseases. The present study was designed to investigate whether the inhibitory effect of ASIV on isoproterenol (ISO) induced apoptosis of hypertrophic cardiomyocyte was associated with the anti oxidation and calpain-1 inhibition. Hypertrophy, apoptosis, mitochondrial oxidative stress and calpain-1 expression were measured in the heart tissue of Sprague-Dawley (SD) rats and H9C2 cells treated with ISO alone or combination with ASIV. The results showed that ASIV attenuated apoptotic rate, increased Bcl 2 expression, decreased Bax expression, ameliorated the integrity of mitochondrial structure and improved mitochondrial membrane potential (MMP). Moreover, ASIV combination reduced both calpain-1 protein expression and calpain activity, down-regulated mitochondrial NOX4 (mito-NOX4) expression, increased activity of mitochondrial superoxide dismutase (mito-SOD) and mitochondrial catalase (mito-CAT) compared to ISO treated alone. The results suggested that ASIV exerted anti-apoptosis effect on ISO-induced hypertrophic cardiomyocyte by attenuating oxidative stress and calpain-1 activation. PMID- 26433483 TI - Maximizing lipocalin prediction through balanced and diversified training set and decision fusion. AB - Lipocalins are short in sequence length and perform several important biological functions. These proteins are having less than 20% sequence similarity among paralogs. Experimentally identifying them is an expensive and time consuming process. The computational methods based on the sequence similarity for allocating putative members to this family are also far elusive due to the low sequence similarity existing among the members of this family. Consequently, the machine learning methods become a viable alternative for their prediction by using the underlying sequence/structurally derived features as the input. Ideally, any machine learning based prediction method must be trained with all possible variations in the input feature vector (all the sub-class input patterns) to achieve perfect learning. A near perfect learning can be achieved by training the model with diverse types of input instances belonging to the different regions of the entire input space. Furthermore, the prediction performance can be improved through balancing the training set as the imbalanced data sets will tend to produce the prediction bias towards majority class and its sub-classes. This paper is aimed to achieve (i) the high generalization ability without any classification bias through the diversified and balanced training sets as well as (ii) enhanced the prediction accuracy by combining the results of individual classifiers with an appropriate fusion scheme. Instead of creating the training set randomly, we have first used the unsupervised Kmeans clustering algorithm to create diversified clusters of input patterns and created the diversified and balanced training set by selecting an equal number of patterns from each of these clusters. Finally, probability based classifier fusion scheme was applied on boosted random forest algorithm (which produced greater sensitivity) and K nearest neighbour algorithm (which produced greater specificity) to achieve the enhanced predictive performance than that of individual base classifiers. The performance of the learned models trained on Kmeans preprocessed training set is far better than the randomly generated training sets. The proposed method achieved a sensitivity of 90.6%, specificity of 91.4% and accuracy of 91.0% on the first test set and sensitivity of 92.9%, specificity of 96.2% and accuracy of 94.7% on the second blind test set. These results have established that diversifying training set improves the performance of predictive models through superior generalization ability and balancing the training set improves prediction accuracy. For smaller data sets, unsupervised Kmeans based sampling can be an effective technique to increase generalization than that of the usual random splitting method. PMID- 26433484 TI - Validating multiplexes for use in conjunction with modern interpretation strategies. AB - In response to requests from the forensic community, commercial companies are generating larger, more sensitive, and more discriminating STR multiplexes. These multiplexes are now applied to a wider range of samples including complex multi person mixtures. In parallel there is an overdue reappraisal of profile interpretation methodology. Aspects of this reappraisal include 1. The need for a quantitative understanding of allele and stutter peak heights and their variability, 2. An interest in reassessing the utility of smaller peaks below the often used analytical threshold, 3. A need to understand not just the occurrence of peak drop-in but also the height distribution of such peaks, and 4. A need to understand the limitations of the multiplex-interpretation strategy pair implemented. In this work we present a full scheme for validation of a new multiplex that is suitable for informing modern interpretation practice. We predominantly use GlobalFilerTM as an example multiplex but we suggest that the aspects investigated here are fundamental to introducing any multiplex in the modern interpretation environment. PMID- 26433485 TI - Evaluation of the Illumina((r)) Beta Version ForenSeqTM DNA Signature Prep Kit for use in genetic profiling. AB - While capillary electrophoresis-based technologies have been the mainstay for human identity typing applications, there are limitations with this methodology's resolution, scalability, and throughput. Massively parallel sequencing (MPS) offers the capability to multiplex multiple types of forensically-relevant markers and multiple samples together in one run all at an overall lower cost per nucleotide than traditional capillary electrophoresis-based methods; thus, addressing some of these limitations. MPS also is poised to expand forensic typing capabilities by providing new strategies for mixture deconvolution with the identification of intra-STR allele sequence variants and the potential to generate new types of investigative leads with an increase in the overall number and types of genetic markers being analyzed. The beta version of the Illumina ForenSeq DNA Signature Prep Kit is a MPS library preparation method with a streamlined workflow that allows for targeted amplification and sequencing of 63 STRs and 95 identity SNPs, with the option to include an additional 56 ancestry SNPs and 22 phenotypic SNPs depending on the primer mix chosen for amplification, on the MiSeq desktop sequencer (Illumina). This study was divided into a series of experiments that evaluated reliability, sensitivity of detection, mixture analysis, concordance, and the ability to analyze challenged samples. Genotype accuracy, depth of coverage, and allele balance were used as informative metrics for the quality of the data produced. The ForenSeq DNA Signature Prep Kit produced reliable, reproducible results and obtained full profiles with DNA input amounts of 1ng. Data were found to be concordant with current capillary electrophoresis methods, and mixtures at a 1:19 ratio were resolved accurately. Data from the challenged samples showed concordant results with current DNA typing methods with markers in common and minimal allele drop out from the large number of markers typed on these samples. This set of experiments indicates the beta version of the ForenSeq DNA Signature Prep Kit is a valid tool for forensic DNA typing and warrants full validation studies of this MPS technology. PMID- 26433486 TI - High resource-capture and -use efficiency, and effective antioxidant protection contribute to the invasiveness of Alnus formosana plants. AB - To investigate the traits contributing to the invasiveness of Alnus formosana and the mechanisms underlying its invasiveness, we compared A. formosana with its native congener (Alnus cremastogyne) under three light treatments (13%, 56%, and 100%). The consistently higher plant height, total leaf area, light-saturated photosynthetic rate (A(max)), light saturation point (LSP), light compensation point (LCP), respiration efficiency (RE), and non-photochemical quenching coefficient (NPQ) but lower root mass fraction (RMF) and specific leaf area (SLA) of the invader than of its native congener contributed to the higher RGR and total biomass of A. formosana across light regimes. The total biomass and RGR of the invader increased markedly with increased RMF, A(max), LSP, LCP, RE, stomatal conductance (G(s)) and total leaf area. Furthermore, compared with the native species, the higher plasticity index in plant height, RMF, leaf mass fraction (LMF), SMF, SLA, A(max) and dark respiration rate (R(d)) within the range of total light contributed to the higher performance of the invader. In addition, the activities of antioxidant enzymes were higher in the invader compared to the native, contributing to its invasion success under high/low light via photoprotection. With a decrease in light level, superoxide dismutase (SOD) and catalase (CAT) activities increased significantly, whereas total carotenoid (Car) and total chlorophyll (Chl) decreased; ascorbate peroxidase (APX) and glutathione reductase (GR) activities remained unchanged. These responses may help the invader to spread and invade a wide range of habitats and form dense monocultures, displacing native plant species. The results suggest that both resource capture-related traits (morphological and photosynthetic) and adaptation related traits (antioxidant protection) contribute to the competitive advantage of the invader. PMID- 26433487 TI - Predictors of Pathologic Complete Response After Neoadjuvant Treatment for Rectal Cancer: A Multicenter Study. AB - BACKGROUND: Pathologic complete response (pCR) to neoadjuvant chemoradiation (CRT) for rectal cancer is associated with better long-term outcomes, and is used as an early indicator of response to novel agents. To assess the rate and predictors of pCR, we performed a retrospective multicenter study involving 5 Canadian cancer centers. PATIENTS AND METHODS: Cancer registries identified consecutive patients with locally advanced rectal adenocarcinoma from the Tom Baker Cancer Centre, Cross Cancer Institute, British Columbia Cancer Agency, Ottawa Hospital Cancer Centre, and the Dr H. Bliss Murphy Cancer Centre who received fluoropyrimidine-based CRT and had curative intent surgery from 2005 to 2012. Patient, tumor, and therapy characteristics were correlated with response. RESULTS: Of the 891 patients included, 885 patients had pCR data available. Of the included patients, 161 (18.2%) had a pCR to CRT, and 724 (81.8%) did not. Patients with a pCR had a lower pretreatment carcinoembryonic antigen (CEA) level, and higher hemoglobin level in univariate analysis. In multivariable analysis, statin use at baseline (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.02-2.92; P = .04), lower pretreatment CEA level (OR, 1.03; 95% CI, 1.01 1.06; P = .03), and distance closer to anal verge (OR, 1.07; 95% CI, 1.01-1.15; P = .04) were significant predictors of pCR. The 3-year disease-free survival was 86% in those with a pCR versus 62.5% in those without a pCR (P < .0001) and pCR was associated with improved overall survival (hazard ratio, 0.29; 95% CI, 0.17 0.51; P < .0001). CONCLUSION: Lower pretreatment CEA level, proximity to anal verge, and statin use are predictors of pCR in our large retrospective cohort. Clinical trials to investigate statins combined with neoadjuvant CRT might be warranted. PMID- 26433488 TI - Nanomedicine-mediated cancer stem cell therapy. AB - Circumstantial evidence suggests that most tumours are heterogeneous and contain a small population of cancer stem cells (CSCs) that exhibit distinctive self renewal, proliferation and differentiation capabilities, which are believed to play a crucial role in tumour progression, drug resistance, recurrence and metastasis in multiple malignancies. Given that the existence of CSCs is a primary obstacle to cancer therapy, a tremendous amount of effort has been put into the development of anti-CSC strategies, and several potential approaches to kill therapeutically-resistant CSCs have been explored, including inhibiting ATP binding cassette transporters, blocking essential signalling pathways involved in self-renewal and survival of CSCs, targeting CSCs surface markers and destroying the tumour microenvironment. Meanwhile, an increasing number of therapeutic agents (e.g. small molecule drugs, nucleic acids and antibodies) to selectively target CSCs have been screened or proposed in recent years. Drug delivery technology-based approaches hold great potential for tackling the limitations impeding clinical applications of CSC-specific agents, such as poor water solubility, short circulation time and inconsistent stability. Properly designed nanocarrier-based therapeutic agents (or nanomedicines) offer new possibilities of penetrating CSC niches and significantly increasing therapeutic drug accumulation in CSCs, which are difficult for free drug counterparts. In addition, intelligent nanomedicine holds great promise to overcome pump-mediated multidrug resistance which is driven by ATP and to decrease detrimental effects on normal somatic stem cells. In this review, we summarise the distinctive biological processes related to CSCs to highlight strategies against inherently drug-resistant CSCs. We then focus on some representative examples that give a glimpse into state-of-the-art nanomedicine approaches developed for CSCs elimination. A perspective on innovative therapeutic strategies and the potential direction of nanomedicine-based CSC therapy in the near future is also presented. PMID- 26433490 TI - Microarray analyses to quantify advantages of 2D and 3D hydrogel culture systems in maintaining the native valvular interstitial cell phenotype. AB - Valvular interstitial cells (VICs) actively maintain and repair heart valve tissue; however, persistent activation of VICs to a myofibroblast phenotype can lead to aortic stenosis. To better understand and quantify how microenvironmental cues influence VIC phenotype and myofibroblast activation, we compared expression profiles of VICs cultured on poly(ethylene glycol) (PEG) gels to those cultured on tissue culture polystyrene (TCPS), as well as fresh isolates. In general, VICs cultured in hydrogel matrices had lower levels of activation (<10%), similar to levels seen in healthy valve tissue, while VICs cultured on TCPS were ~75% activated myofibroblasts. VICs cultured on TCPS also exhibited a higher magnitude of perturbations in gene expression than soft hydrogel cultures when compared to the native phenotype. Using peptide-modified PEG gels, VICs were seeded on (2D), as well as encapsulated in (3D), matrices of the same composition and modulus. Despite similar levels of activation, VICs cultured in 2D had distinct variations in transcriptional profiles compared to those in 3D hydrogels. Genes related to cell structure and motility were particularly affected by the dimensionality of the culture platform, with higher expression levels in 2D than in 3D. These results indicate that dimensionality may play a significant role in dictating cell phenotype (e.g., through differences in polarity, diffusion of soluble signals), and emphasize the importance of using multiple metrics when characterizing cell phenotype. PMID- 26433491 TI - Vitamin D3 modulates the innate immune response through regulation of the hCAP 18/LL-37 gene expression and cytokine production. AB - INTRODUCTION: The steroid hormone metabolite of vitamin D3, 1alpha,25 dihydroxyvitamin D3 (1,25D3), promotes osteogenic activity and regulates calcium and phosphate metabolism, which are actions regarded as classical vitamin D regulated functions. Besides its role in these processes, 1,25D3 also seems implicated in the host defense against microbial/pro-inflammatory attacks. Low serum levels of vitamin D3 (vitamin D deficiency) are associated with osteoporosis and increased risk of fractures but also inflammatory diseases and their disease progression, presumably via mechanisms associated with 1,25D3 evoked modulation of the innate immune system. 1,25D3 has been reported to modulate many inflammatory responses, suggesting that it regulates multiple transcriptional targets within the inflammatory system. RESULTS: Experimental studies in various experimental systems show that 1,25D3 differentially regulates the production of pro-inflammatory cytokines and chemokines depending on cell type. Importantly, many reports show that 1,25D3 up-regulates expression of the human antimicrobial peptide hCAP-18/LL-37 gene. The hCAP-18/LL-37 gene seems indeed to be an important transcriptional target for 1,25D3. However, only limited evidence is presented showing that 1,25D3 consistently increases the amount of biologically active LL-37 peptide. CONCLUSION: In the present review, we discuss 1,25D3-induced down-regulation of cytokine/chemokine production and stimulation of hCAP-18/LL-37 gene expression which represent two very important pathways for 1,25D3-evoked regulation of the innate immune response. PMID- 26433489 TI - Cell surface glycoengineering improves selectin-mediated adhesion of mesenchymal stem cells (MSCs) and cardiosphere-derived cells (CDCs): Pilot validation in porcine ischemia-reperfusion model. AB - Promising results are emerging in clinical trials focused on stem cell therapy for cardiology applications. However, the low homing and engraftment of the injected cells to target tissue continues to be a problem. Cellular glycoengineering can address this limitation by enabling the targeting of stem cells to sites of vascular injury/inflammation. Two such glycoengineering methods are presented here: i. The non-covalent incorporation of a P-selectin glycoprotein ligand-1 (PSGL-1) mimetic 19Fc[FUT7(+)] via lipid-protein G fusion intermediates that intercalate onto the cell surface, and ii. Over-expression of the alpha(1,3)fucosyltransferse FUT7 in cells. Results demonstrate the efficient coupling of 19Fc[FUT7(+)] onto both cardiosphere-derived cells (CDCs) and mesenchymal stem cells (MSCs), with coupling being more efficient when using protein G fused to single-tailed palmitic acid rather than double-tailed DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine). This non-covalent cellular modification was mild since cell proliferation and stem-cell marker expression was unaltered. Whereas coupling using 19Fc[FUT7(+)] enhanced cell capture on recombinant P-selectin or CHO-P cell surfaces, alpha(1,3)fucosylation was necessary for robust binding to E-selectin and inflamed endothelial cells under shear. Pilot studies confirm the safety and homing efficacy of the modified stem cells to sites of ischemia-reperfusion in the porcine heart. Overall, glycoengineering with physiological selectin-ligands may enhance stem cell engraftment. PMID- 26433493 TI - Penises not required: a systematic review of the potential for human papillomavirus horizontal transmission that is non-sexual or does not include penile penetration. AB - The primary mode of human papillomavirus (HPV) transmission is through penetrative sex; however, there is evidence of other modes of transmission. No systematic review was found that focussed on HPV horizontal transmission that is not penocentric. A systematic review of the literature by searching Medline (Ovid), PubMed (NLM) and Embase (Ovid) was conducted to retrieve articles published from 1946 to March 2014. Studies that suggested evidence of non-sexual or non-penetrative sexual transmission of alpha-HPV genotypes were included. After review of 2061 titles and abstracts, 51 studies were abstracted. Fifteen studies examined HPV fomites from medical settings or public environments, and 36 examined HPV in humans. Human papillomavirus DNA was detected in the genital tract of female virgins, with prevalence estimates ranging from 0% to 51.1%. HPV transmission from hands to genitals or genitals to hands was reported for both sexes and heterosexual couples. Other studies commonly found HPV on surfaces in medical settings and public environments. Further studies on non-sexual and non penetrative sexual transmission are needed to understand the complexity of HPV transmission. Health-care policies may need to be reassessed/established to ensure the safety of medical instruments and to reduce the risk of HPV nosocomial infection. PMID- 26433492 TI - What makes health impact assessments successful? Factors contributing to effectiveness in Australia and New Zealand. AB - BACKGROUND: While many guidelines explain how to conduct Health Impact Assessments (HIAs), less is known about the factors that determine the extent to which HIAs affect health considerations in the decision making process. We investigated which factors are associated with increased or reduced effectiveness of HIAs in changing decisions and in the implementation of policies, programs or projects. This study builds on and tests the Harris and Harris-Roxas' conceptual framework for evaluating HIA effectiveness, which emphasises context, process and output as key domains. METHODS: We reviewed 55 HIA reports in Australia and New Zealand from 2005 to 2009 and conducted surveys and interviews for 48 of these HIAs. Eleven detailed case studies were undertaken using document review and stakeholder interviews. Case study participants were selected through purposeful and snowball sampling. The data were analysed by thematic content analysis. Findings were synthesised and mapped against the conceptual framework. A stakeholder forum was utilised to test face validity and practical adequacy of the findings. RESULTS: We found that some features of HIA are essential, such as the stepwise but flexible process, and evidence based approach. Non-essential features that can enhance the impact of HIAs include capacity and experience; 'right person right level'; involvement of decision-makers and communities; and relationships and partnerships. There are contextual factors outside of HIA such as fit with planning and decision making context, broader global context and unanticipated events, and shared values and goals that may influence a HIA. Crosscutting factors include proactive positioning, and time and timeliness. These all operate within complex open systems, involving multiple decision makers, levels of decision-making, and points of influence. The Harris and Harris Roxas framework was generally supported. CONCLUSION: We have confirmed previously identified factors influencing effectiveness of HIA and identified new factors such as proactive positioning. Our findings challenge some presumptions about 'right' timing for HIA and the rationality and linearity of decision-making processes. The influence of right timing on decision making needs to be seen within the context of other factors such as proactive positioning. This research can help HIA practitioners and researchers understand and identify what can be enhanced within the HIA process. Practitioners can adapt the flexible HIA process to accommodate the external contextual factors identified in this report. PMID- 26433494 TI - Maryland's Helicopter Emergency Medical Services Experience From 2001 to 2011: System Improvements and Patients' Outcomes. AB - STUDY OBJECTIVE: Helicopter emergency medical services (EMS) has become a well established component of modern trauma systems. It is an expensive, limited resource with potential safety concerns. Helicopter EMS activation criteria intended to increase efficiency and reduce inappropriate use remain elusive and difficult to measure. This study evaluates the effect of statewide field trauma triage changes on helicopter EMS use and patient outcomes. METHODS: Data were extracted from the helicopter EMS computer-aided dispatch database for in-state scene flights and from the state Trauma Registry for all trauma patients directly admitted from the scene or transferred to trauma centers from July 1, 2000, to June 30, 2011. Computer-aided dispatch flights were analyzed for periods corresponding to field triage protocol modifications intended to improve system efficiency. Outcomes were separately analyzed for trauma registry patients by mode of transport. RESULTS: The helicopter EMS computer-aided dispatch data set included 44,073 transports. There was a statewide decrease in helicopter EMS usage for trauma patients of 55.9%, differentially affecting counties closer to trauma centers. The Trauma Registry data set included 182,809 patients (37,407 helicopter transports, 128,129 ambulance transports, and 17,273 transfers). There was an increase of 21% in overall annual EMS scene trauma patients transported; ground transports increased by 33%, whereas helicopter EMS transports decreased by 49%. Helicopter EMS patient acuity increased, with an attendant increase in patient mortality. However, when standardized with W statistics, both helicopter EMS- and ground-transported trauma patients showed sustained improvement in mortality. CONCLUSION: Modifications to state protocols were associated with decreased helicopter EMS use and overall improved trauma patient outcomes. PMID- 26433495 TI - The unfinished agenda of women's reproductive health. PMID- 26433496 TI - Moving beyond silos: How do we provide distributed personalized medicine to pregnant women everywhere at scale? Insights from PRE-EMPT. AB - While we believe that pre-eclampsia matters-because it remains a leading cause of maternal and perinatal morbidity and mortality worldwide-we are convinced that the time has come to look beyond single clinical entities (e.g. pre-eclampsia, postpartum hemorrhage, obstetric sepsis) and to look for an integrated approach that will provide evidence-based personalized care to women wherever they encounter the health system. Accurate outcome prediction models are a powerful way to identify individuals at incrementally increased (and decreased) risks associated with a given condition. Integrating models with decision algorithms into mobile health (mHealth) applications could support community and first level facility healthcare providers to identify those women, fetuses, and newborns most at need of facility-based care, and to initiate lifesaving interventions in their communities prior to transportation. In our opinion, this offers the greatest opportunity to provide distributed individualized care at scale, and soon. PMID- 26433497 TI - Prevention of type 2 diabetes among women with prior gestational diabetes mellitus. AB - The morbidity and mortality rates related to diabetes are constantly rising, as well as those for other noncommunicable diseases. The epidemic is spreading throughout the world, in both low- and high-resource countries. Prevention is a key aspect in the battle against the disease and obstetricians play a critical role in the fight. Prevention starts in utero-for the diabetic mother, her infant, and future generations. The postpartum period should not be neglected because it provides another window of opportunity to address prevention. Data on the prevention of type 2 diabetes among women diagnosed with gestational diabetes are discussed. PMID- 26433498 TI - New drug regimens for HIV in pregnancy and a national strategic plan to manage HIV: A South African perspective. AB - In South Africa, new drug regimens (WHO treatment Option B) used to manage HIV infection in pregnancy and the national strategic plan on HIV have resulted in improved health outcomes. Among these outcomes are reductions in the following: mother-to-child transmission (MTCT) of HIV to 2.4%; maternal deaths attributable to HIV; and adverse reactions due to antiretroviral therapy (ART). The present article describes these new drug regimens and the national strategic HIV management plan, as well as their challenges and the implications of improved health outcomes. Such outcomes imply that further decreases in MTCT of HIV, and HIV attributable maternal deaths are possible if potential challenges are addressed and treatment option B+ offered. A confidential enquiry into each case of MTCT is advocated to reduce vertical transmission rates to zero levels. PMID- 26433499 TI - Quality assurance: The 10-Group Classification System (Robson classification), induction of labor, and cesarean delivery. AB - Quality assurance in labor and delivery is needed. The method must be simple and consistent, and be of universal value. It needs to be clinically relevant, robust, and prospective, and must incorporate epidemiological variables. The 10 Group Classification System (TGCS) is a simple method providing a common starting point for further detailed analysis within which all perinatal events and outcomes can be measured and compared. The system is demonstrated in the present paper using data for 2013 from the National Maternity Hospital in Dublin, Ireland. Interpretation of the classification can be easily taught. The standard table can provide much insight into the philosophy of care in the population of women studied and also provide information on data quality. With standardization of audit of events and outcomes, any differences in either sizes of groups, events or outcomes can be explained only by poor data collection, significant epidemiological variables, or differences in practice. In April 2015, WHO proposed that the TGCS (also known as the Robson classification) is used as a global standard for assessing, monitoring, and comparing cesarean delivery rates within and between healthcare facilities. PMID- 26433500 TI - Cancer of the cervix: Early detection and cost-effective solutions. AB - Cervical cancer is known to be a preventable disease through the detection of cervical cancer precursors, historically using cytology of the cervix as the primary screening test. Over 85% of cervical cancer cases and deaths occur in low resource countries. Alternatives to cytology have been investigated with the strongest possibilities being visual inspection with acetic acid (VIA) and HPV DNA testing. HPV DNA testing has been shown in randomized trials to be significantly more sensitive for the detection of cervical cancer precursors than either cytology or VIA. In this paper we argue that prevention really does cost less than cure, or that prevention and treatment of cancer costs less than no prevention, in effect just treatment, of cancer. The true cost savings of prevention will include a more difficult assessment of the socioeconomic savings associated with longer, healthier lives for women in their prime who have a major role in supporting their families. PMID- 26433501 TI - Strengthening accountability to end preventable maternal deaths. AB - The present paper describes the ongoing efforts to revitalize the accountability of national governments toward preventable maternal deaths. Maternal death reviews are included in the national health policies of the majority of countries contributing 95% of global maternal deaths. However in actual practice, the extent of implementation and follow-up of recommended actions on lessons learnt from maternal death reviews is inadequate. This paper describes and discusses the role of the Maternal Death Surveillance and Response (MDSR) system in strengthening accountability and ending preventable maternal deaths. MDSR provides a surveillance tool for timely information on where, when, and why maternal deaths occur, builds on maternal death reviews, and includes the missing "response" component for improving quality of care and preventing maternal deaths. PMID- 26433502 TI - HPV vaccination: The most pragmatic cervical cancer primary prevention strategy. AB - The evidence that high-risk HPV infections cause cervical cancers has led to two new approaches for cervical cancer control: vaccination to prevent HPV infections, and HPV screening to detect and treat cervical precancerous lesions. Two vaccines are currently available: quadrivalent vaccine targeting oncogenic HPV types 16, 18, 6, and 11, and bivalent vaccine targeting HPV 16 and 18. Both vaccines have demonstrated remarkable immunogenicity and substantial protection against persistent infection and high-grade cervical cancer precursors caused by HPV 16 and 18 in HPV-naive women, and have the potential to prevent 70% of cervical cancers in adequately vaccinated populations. HPV vaccination is now implemented in national programs in 62 countries, including some low- and middle income countries. The early findings from routine national programs in high income countries are instructive to encourage low- and middle-income countries with a high risk of cervical cancer to roll out HPV vaccination programs and to introduce resource-appropriate cervical screening programs. PMID- 26433503 TI - A historic and scientific review of breast cancer: The next global healthcare challenge. AB - Breast cancer is fast becoming the leading cause of oncologic morbidity and mortality among women worldwide. Demographic changes in Asia, Southeast Asia, and South America will further accelerate this trend. Different specialties are involved in the treatment of breast cancer patients: gynecology, surgery, pathology, hematology/oncology, radiology, radiation oncology, and nuclear medicine. Optimal results are seen in countries providing standardized breast cancer care in certified breast centers. The present article provides an overview of current state-of-the-art treatment strategies and explains the contributions of different specialties to optimal and individualized care for breast cancer patients. Breast cancer will be one of the most important health issues facing physicians involved with women's health and a basic understanding of current treatment objectives will be essential medical knowledge for everyone taking care of female patients. PMID- 26433504 TI - Adolescent sexual and reproductive health: The global challenges. AB - Adolescent sexual and reproductive health (ASRH) has been overlooked historically despite the high risks that countries face for its neglect. Some of the challenges faced by adolescents across the world include early pregnancy and parenthood, difficulties accessing contraception and safe abortion, and high rates of HIV and sexually transmitted infections. Various political, economic, and sociocultural factors restrict the delivery of information and services; healthcare workers often act as a barrier to care by failing to provide young people with supportive, nonjudgmental, youth-appropriate services. FIGO has been working with partners and its member associations to break some of these barriers enabling obstetricians and gynecologists to effect change in their countries and promote the ASRH agenda on a global scale. PMID- 26433505 TI - Ending preventable newborn deaths in a generation. AB - The end of the Millennium Development Goal (MDG) era was marked in 2015, and while maternal and child mortality have been halved, MGD 4 and MDG 5 are off track at the global level. Reductions in neonatal death rates (age <1 month) lag behind those for post-neonates (age 1-59 months), and stillbirth rates (omitted from the MDGs) have been virtually unchanged. Hence, almost half of under-five deaths are newborns, yet about 80% of these are preventable using cost-effective interventions. The Every Newborn Action Plan has been endorsed by the World Health Assembly and ratified by many stakeholders and donors to reduce neonatal deaths and stillbirths to 10 per 1000 births by 2035. The plan provides an evidence-based framework for scaling up of essential interventions across the continuum of care with the potential to prevent the deaths of approximately three million newborns, mothers, and stillbirths every year. Two million stillbirths and newborns could be saved by care at birth and care of small and sick newborns, giving a triple return on investment at this key time. Commitment, investment, and intentional leadership from global and national stakeholders, including all healthcare professionals, can make these ambitious goals attainable. PMID- 26433506 TI - The global epidemic of abuse and disrespect during childbirth: History, evidence, interventions, and FIGO's mother-baby friendly birthing facilities initiative. AB - Recent evidence indicates that disrespectful/abusive/coercive service delivery by skilled providers in facilities, which results in actual or perceived poor quality of care, is directly and indirectly associated with adverse maternal and newborn outcomes. The present article reviews the evidence for disrespectful/abusive care during childbirth in facilities (DACF), describes examples of DACF, discusses organizations active in a rights-based respectful maternity care movement, and enumerates some strategies and interventions that have been identified to decrease DACF. It concludes with a discussion of one strategy, which has been recently implemented by FIGO with global partners-the International Pediatrics Association, International Confederation of Midwives, the White Ribbon Alliance, and WHO. This strategy, the Mother and Baby Friendly Birth Facility (MBFBF) Initiative, is a criterion-based audit process based on human rights' doctrines, and modeled on WHO/UNICEF's Baby Friendly Facility Initiative. PMID- 26433507 TI - What can obstetrician/gynecologists do to support abortion access? AB - Unsafe abortion causes approximately 13% of all maternal deaths worldwide, with higher rates in areas where abortion access is restricted. Because safe abortion is so low risk, if all women who needed an abortion could access safe care, this rate would drop dramatically. As women's health providers and advocates, obstetrician/gynecologists can support abortion access. By delivering high quality, evidence-based care ourselves, supporting other providers who perform abortion, helping women who access abortion in the community, providing second trimester care, and improving contraceptive uptake, we can decrease morbidity and mortality from unsafe abortion. PMID- 26433508 TI - Evidence supporting broader access to safe legal abortion. AB - Unsafe abortion continues to be a major cause of maternal death; it accounts for 14.5% of all maternal deaths globally and almost all of these deaths occur in countries with restrictive abortion laws. A strong body of accumulated evidence shows that the simple means to drastically reduce unsafe abortion-related maternal deaths and morbidity is to make abortion legal and institutional termination of pregnancy broadly accessible. Despite this evidence, abortion is denied even when the legal condition for abortion is met. The present article aims to contribute to a better understanding that one can be in favor of greater access to safe abortion services, while at the same time not be "in favor of abortion," by reviewing the evidence that indicates that criminalization of abortion only increases mortality and morbidity without decreasing the incidence of induced abortion, and that decriminalization rapidly reduces abortion-related mortality and does not increase abortion rates. PMID- 26433509 TI - Emergency obstetric care: Making the impossible possible through task shifting. AB - Task shifting-moving tasks to healthcare workers with a shorter training-for emergency obstetric care (EmOC) can potentially improve access to lifesaving interventions and thereby contribute to reducing maternal and neonatal morbidity and mortality. The present paper reviews studies on task shifting for the provision of EmOC. Most studies were performed in Sub-Saharan Africa and South Asia and focused primarily on task shifting for the performance of cesarean deliveries. Cesarean delivery rates increased following EmOC training without significant increase in adverse outcomes. The paper discusses the advantages and disadvantages of task shifting in EmOC and the role of this approach in improving maternal and newborn health in the short and long term. PMID- 26433510 TI - Global trends in use of long-acting reversible and permanent methods of contraception: Seeking a balance. AB - The global trend shows that the use of permanent contraception to prevent unintended pregnancy is high. Although the trend also shows a rise in the use of long-acting reversible methods, these are still underutilized despite having contraceptive as well as non-contraceptive benefits. Lack of knowledge among women, dependence on the provider for information, and provider bias for permanent contraception are cited as reasons for this reduced uptake. Training of healthcare providers and increased patient awareness about the effectiveness of long-acting reversible contraceptive methods will increase their uptake and help prevent unintended pregnancies. PMID- 26433511 TI - Global efforts for effective training in fistula surgery. AB - Obstetric fistulas continue to be a problem in low- and middle-income nations, affecting women of childbearing age during pregnancy and labor and resulting in debilitating urinary and/or fecal incontinence. Historically, this predicament also affected women in high-income nations until the middle of the last century. This is not a "new world" crisis therefore, but simply one of economic and health development. In the last two decades, new global initiatives have been instituted to improve training and education in preventative and curative fistula treatment by developing a unified and competency-based learning tool by surgeons in the field in partnership with FIGO and its global partners. This modern approach to the management of a devastating condition can only serve to achieve the WHO objective of health security for women throughout their life span. PMID- 26433512 TI - Task shifting: A key strategy in the multipronged approach to reduce maternal mortality in India. AB - Task shifting from specialist to nonspecialist doctors (NSDs) is an important strategy that has been implemented in India to overcome the critical shortage of healthcare workers by using the human resources available to serve the vast population, particularly in rural areas. A competency-based training program in comprehensive emergency obstetric care was implemented to train and certify NSDs. Trained NSDs were able to provide key services in maternal health, which contribute toward reductions in maternal morbidity and mortality. The present article provides an overview of the maternal health challenges, shares important steps in program implementation, and shows how challenges can be overcome. The lessons learned from this experience contribute to understanding how task shifting can be used to address large-scale public health issues in low-resource countries and in particular solutions to address maternal health issues. PMID- 26433513 TI - The role of health professional organizations in improving maternal and newborn health: The FIGO LOGIC experience. AB - The FIGO Leadership in Obstetrics and Gynecology for Impact and Change (LOGIC) Initiative in Maternal and Newborn Health improved the internal and external capacity of eight national professional organizations of obstetrics and gynecology in six African and two Asian countries. The initiative was funded by a grant from the Bill and Melinda Gates Foundation and had three key objectives: to support the eight FIGO member associations to strengthen their capacity to work effectively; to influence national policies on maternal and newborn health; and to work toward improving clinical practice in this area. Through improved capacity, and underpinned by Memoranda of Understanding with their governments, the associations influenced national policy in maternal and newborn health, impacted clinical care through the development of over forty national clinical guidelines, delivered national curricula, trained clinical and management staff, and led the development of national maternal death and near-miss review programs. PMID- 26433514 TI - Targeting immune checkpoints: New opportunity for mesothelioma treatment? AB - Malignant pleural mesothelioma is an aggressive cancer linked to asbestos exposure in most patients. Due to the long latency between exposure and presentation, incidence is expected to further increase in the next decade, despite the ban on asbestos import which occurred at the end of last century in industrialized countries. Platinum-based palliative chemotherapy is the only treatment with proven benefit on outcome, resulting in selected patients in a median overall survival of about 1 year. Therefore, there is room for therapeutic improvement using a new strategy to prolong survival. Dealing with cancer cell induced immunosuppression is a promising approach. Reactivating immune responses that are silenced by immune checkpoints recently gained a lot of interest. Checkpoint blockade has already shown promising preclinical and clinical results in several cancer types and is currently also being investigated in mesothelioma. Here, we discuss the expression patterns and mechanisms of action of CTLA-4 and PD-1 as the two most studied and of TIM-3 and LAG-3 as two interesting upcoming immune checkpoints. Furthermore, we review the clinical results of molecules blocking these immune checkpoints and point out their future opportunities with a special focus on mesothelioma. PMID- 26433516 TI - The Clinical Application of Strain: Raising the Standard. PMID- 26433515 TI - Echocardiographic Identification of Acute Cellular Rejection in Heart Transplant Recipients. PMID- 26433517 TI - Celebrating Sonographers All Year. PMID- 26433518 TI - Injury prevention for sonographers. PMID- 26433519 TI - The Expanding Role of Peri-Procedural Echocardiography for Guidance of Transcatheter Structural Heart Interventions. PMID- 26433520 TI - Determinants of Operative Mortality in Patients With Ruptured Acute Type A Aortic Dissection. AB - BACKGROUND: Acute type A aortic dissection (ATAAD) is a surgical emergency associated with high mortality and morbidity. We analyzed our 15-year experience in the management of ruptured ATAAD (rATAAD) and non-rATAAD to determine the predictors of early and late mortality. METHODS: We reviewed all cases with ATAAD between 1999 and 2014. Patients were grouped into rATAAD and non-rATAAD based on intraoperative confirmation. Clinical data on preoperative characteristics and in hospital and long-term outcomes were analyzed to determine risk factors for early and long-term mortality. Survival was analyzed using Kaplan-Meier and log rank statistics. RESULTS: Of the 489 total ATAAD repairs, 75 patients (15.3%) had rATAAD. The rATAAD patients were older compared with non-rATAAD (64.4 +/- 16.2 versus 57.3 +/- 14.2 years, respectively; p = 0.0001) and commonly female (31 of 75 [41.3%] versus 107 of 414 [25.9%], respectively; p = 0.006). Early mortality was higher among rATAAD patients that among non-rATAAD patients (19 of 75 [25.3%] versus 48 of 414 [11.6%], respectively; p = 0.002); predictors included rupture, age, malperfusion syndrome, and coronary artery disease. Patients aged 70 years or more with malperfusion syndrome had a 7.7-fold risk of 24-hour mortality (p = 0.0003) that was augmented by rATAAD (p = 0.004). Long-term survival was lower among rATAAD than non-rATAAD (57.4% versus 78.2%, respectively, at 5 years; p < 0.0001); independent predictors included rupture (p = 0.01), low glomerular filtration rate (p = 0.001), and high-risk group (p = 0.004). These risk factors were used to construct a predictive model for estimating the probability of early mortality in ATAAD. CONCLUSIONS: Rupture is associated with significantly higher mortality in ATAAD. This predictive model provides surgical risk assessment for early mortality after rATAAD. For acceptable surgical candidates, immediate aortic repair can provide favorable outcomes. PMID- 26433521 TI - Contributory Role of Fluorine 18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in the Diagnosis and Clinical Management of Infections in Patients Supported With a Continuous-Flow Left Ventricular Assist Device. AB - BACKGROUND: The current study sought to demonstrate the advantages offered by fluorine 18-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) in patients supported with continuous-flow left ventricular assist devices (CF-LVADs) in detecting infection and the consequent effect on clinical decisions. METHODS: Between April 2009 and September 2013, 40 PET examinations were performed in 31 patients (78.1% men; mean age, 51.0 +/- 14.9 years) supported with a CF-LVAD. In group A (19 examinations in 14 patients), PET/CT was performed to detect infectious focus in patients without external signs of driveline involvement but with at least two of the following infection signs: recurrent fever, positive blood culture, or elevated infectious indicators. In group B (21 examinations in 17 patients), PET/CT aimed to assess the internal extension of infection in patients with external signs of driveline infection. RESULTS: In 50% of the cases of the patients in group A, abnormal (18)F-FDG uptake (9 patients) was related to VAD components. Matching the results with the final diagnosis, we reported 9 true-positive, 8 true-negative, no false negative, and 2 false-positive findings. New information unrelated to VAD was found in 9 patients (50%): pneumonia in 3, colon diverticulitis in 3, sternal dehiscence in 1, paravertebral abscess in 1, and erysipelas in 1. In group B, superficial abnormal (18)F-FDG uptake was found at the piercing site of the driveline in 2 patients, deeper extension of infection along the driveline in 10, initial involvement of the pump housing in 2, and full involvement of the device in 4. These findings contributed to changing the clinical management in 84.2% of group A patients and in 85.7% of group B patients: 16 patients were scheduled for urgent transplantation, 2 underwent surgical revision of the driveline, 7 required prolonged antibiotic therapy, and 3 underwent colonoscopy. CONCLUSIONS: This single-center experience highlights the diagnostic value of PET/CT in detecting the localization and internal extension of infection to internal VAD components. Moreover, this information notably influences the therapeutic management. PMID- 26433522 TI - Hybrid Procedure for Neonates With Hypoplastic Left Heart Syndrome at High-Risk for Norwood: Midterm Outcomes. AB - BACKGROUND: Hybrid procedure offers patients with severe congenital heart disease an alternative initial procedure to conventional surgical reconstruction. We report the midterm outcomes of a cohort of neonates who had a hybrid procedure for variants of hypoplastic left heart syndrome because they were at high risk for the Norwood procedure. METHODS: Between December 2005 and January 2013, 41 neonates underwent bilateral pulmonary artery banding followed by ductal stenting by means of a sternotomy at a median age of 6 days (range, 2 to 18 days) and weight of 2.6 kg (range, 1.5 to 3.7 kg). Thirty-five patients had hypoplastic left heart syndrome, and 6 patients had critical aortic stenosis with hypoplastic left ventricle. Primary indications for the hybrid procedure were low birth weight in 17 patients, hypoplastic left ventricle with the possibility of later biventricular repair in 6 patients, intact or near-intact atrial septum in 5 patients, and poor patient condition in 13 patients. Echocardiographic, angiographic, operative, and clinical data were reviewed. Outcomes were summarized with descriptive statistics and risk factors for mortality identified. RESULTS: All but 6 patients had an antenatal diagnosis, and 24 patients were from other congenital cardiac centers. Nine patients had perioperative balloon aortic valvuloplasty, 1 patient had fetal balloon aortic valvuloplasty, and 17 patients had intervention to their atrial septum (41.4%). There were 9 inpatient deaths (21.9%) and 4 interstage deaths (9.8%) after the hybrid procedure. Twenty-eight patients subsequently underwent either the Norwood procedure (11 patients), combined stage I and II (14 patients), or biventricular repair (3 patients). No patient had heart transplantation. Among the patients who had combined stage I and II as a second procedure after the hybrid procedure, there were 2 early deaths, 1 late death before the Fontan, and 1 late death after the Fontan completion after combined stage I and II. All patients who had subsequent Norwood procedure were midterm survivors. Three of the 4 patients who had biventricular repair were midterm survivors. Overall survival was 56.1% at a median follow-up of 32.0 months. By univariate analysis, patient factors, intact or near-intact atrial septum, and aortic atresia were associated with nonsurvival. CONCLUSIONS: Hybrid procedure as an alternative to the Norwood procedure offers good midterm survival in patients deemed at high risk for neonatal reconstruction. PMID- 26433524 TI - Allergens in modern society: Updated catalogs and future prospects. PMID- 26433523 TI - Transcatheter or Surgical Aortic Valve Replacement in Patients With Prior Coronary Artery Bypass Grafting. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) are treatment options for aortic stenosis in patients with prior coronary artery bypass graft surgery. We assessed the major clinical outcomes of such patients enrolled in the CoreValve High Risk (CHR) study. METHODS: Of the 795 CHR study patients, 226 had prior coronary artery bypass graft surgery; 115 underwent TAVR and 111 underwent SAVR. The primary endpoint was a comparison of all-cause mortality at 1 year. Important secondary clinical endpoints were assessed. RESULTS: At 1 year, all-cause mortality was 9.6% for TAVR versus 18.1% for SAVR (p = 0.06); cardiovascular mortality was 7.0% for TAVR versus 13.8% for SAVR (p = 0.09). A combination of The Society of Thoracic Surgeons risk score greater than 7 and age greater than 80 years was a significant predictor of mortality, with TAVR demonstrating a survival advantage (p = 0.03). No differences were seen for stroke. The SAVR group had longer intensive care unit and hospital stays, increased incidence of acute kidney injury, life-threatening or disabling bleeding, and major adverse cardiac and cerebrovascular events (p < 0.05). Pacemaker implantation and paravalvular regurgitation were greater with TAVR at all timepoints. CONCLUSIONS: For patients with prior coronary artery bypass graft surgery and aortic stenosis, TAVR offers a significant morbidity advantage and a strong trend toward improved survival over SAVR at 1 year. PMID- 26433526 TI - Hierarchy and molecular properties of house dust mite allergens. AB - The allergenic load of house dust mite allergy is largely constituted by a few proteins with a hierarchical pattern of allergenicity. The serodominant specificities are the group 1&2 and the group 23 faecal allergens. The collective IgE binding to the group 1&2 allergens can measure unequivocal HDM sensitisation better than HDM extracts although discrepancies have been found in regions with complex acarofauna suggesting a need to investigate the specificity with allergen components. The group 4, 5, 7&21 allergens that each induce responses in about 40% of subjects are mid-tier allergens accounting for most of the remaining IgE binding. Their titres are proportional to the concomitant responses to Der p1&2. Group 2 allergen variants have different antibody binding. Body proteins only occasionally induce sensitisation although a higher prevalence of binding by atopic dermatitis patients provides a new avenue of research. A broad spectrum of IgE binding has been associated with diverse symptoms but not with the severity of asthma which is associated with low IgG antibody. Some allergens such as the group 14 large lipid binding proteins and the recently described proteins Der f 24-33, need further investigation but with the cognoscence that other denominated allergens have been found to be minor sensitisers by comparative quantitative analyses. Scabies is a confounder for diagnosis with extracts, inducing cross reactive antibodies with Der p 4&20 as is seafood allergy with cross reactivity to Der p 10 a minor HDM allergen. The HDM genome sequence can now be used to verify allelic and paralogous variations. PMID- 26433527 TI - Spectrum of allergens for Japanese cedar pollinosis and impact of component resolved diagnosis on allergen-specific immunotherapy. AB - The high prevalence of Japanese cedar pollinosis in Japan is associated with a negative impact on the quality of life of patients, as well as significant loss of productivity among the workforce in early spring, thus representing a serious social problem. Furthermore, the prevalence is increasing, and has risen by more than 10% in this decade. Cry j 1 and Cry j 2 were identified as the major allergens in Japanese cedar pollen (JCP), and in 2004, the existence of other major and minor allergens were revealed by a combination of two-dimensional electrophoresis and immunoblotting analysis. Allergenome analysis identified a chitinase, a lipid transfer protein, a serine protease, and an aspartic protease as novel IgE-reactive allergens in patients with JCP allergy. Thaumatin-like protein (Cry j 3) was shown to be homologous to Jun a 3, a major allergen from mountain cedar pollen. Isoflavone reductase-like protein was also characterized in a study of a JCP cDNA library. The characterization of component allergens is required to clarify the sensitizer or cross-reactive elicitor allergens for component-resolved diagnosis (CRD). Increasing evidence from numerous clinical trials indicates that CRD can be used to design effective allergen-specific immunotherapy. In this review, we summarize the eight characterized JCP allergens and discuss the impact of CRD and characterization of novel allergens on allergen specific immunotherapy. PMID- 26433525 TI - Allergens, sources, particles, and molecules: Why do we make IgE responses? AB - Allergens are foreign proteins or glycoproteins that are the target of IgE antibody responses in humans. The relationship between subsequent exposure and the allergic symptoms is often or usually obvious; however, there is increasing evidence that in asthma, atopic dermatitis and some forms of food allergy the induction of symptoms is delayed or chronic. The primary exposure to inhaled allergens is to the particles, which are capable of carrying allergens in the air. Thus, the response reflects not only the properties of the proteins, but also the biological properties of the other constituents of the particle. This is best understood in relation to the mite fecal particles in which the contents include many different immunologically active substances. Allergic disease first became a major problem over 100 years ago, and for many years sensitization to pollens was the dominant form of these diseases. The rise in pediatric asthma correlates best with the move of children indoors, which started in 1960 and was primarily driven by indoor entertainment for children. While the causes of the increase are not simple they include both a major increase in sensitization to indoor allergens and the complex consequences of inactivity. Most recently, there has also been an increase in food allergy. Understanding this has required a reappraisal of the importance of the skin as a route for sensitization. Overall, understanding allergic diseases requires knowing about the sources, the particles and the routes of exposure as well as the properties of the individual allergens. PMID- 26433528 TI - Sensitization to fungal allergens: Resolved and unresolved issues. AB - Exposure and sensitization to fungal allergens can promote the development and worsening of allergic diseases. Although numerous species of fungi have been associated with allergic diseases in the literature, the significance of fungi from the genera Alternaria, Cladosporium, Penicillium, Aspergillus, and Malassezia has been well documented. However, it should be emphasized that the contribution of different fungal allergens to allergic diseases is not identical, but species-specific. Alternaria and Cladosporium species are considered to be important outdoor allergens, and sensitization and exposure to species of these genera is related to the development of asthma and rhinitis, as well as epidemics of asthma exacerbation, including life-threatening asthma exacerbation. In contrast, xerophilic species of Penicillium and Aspergillus, excluding Aspergillus fumigatus, are implicated in allergic diseases as indoor allergens. A. fumigatus has a high capacity to colonize the bronchial tract of asthmatic patients, causing severe persistent asthma and low lung function, and sometimes leading to allergic bronchopulmonary aspergillosis. Malassezia are common commensals of healthy skin, although they are also associated with atopic dermatitis, especially on the head and neck, but not with respiratory allergies. Despite its importance in the management of allergic diseases, precise recognition of species-specific IgE sensitization to fungal allergens is often challenging because the majority of fungal extracts exhibit broad cross reactivity with taxonomically unrelated fungi. Recent progress in gene technology has contributed to the identification of specific and cross-reactive allergen components from different fungal sources. However, data demonstrating the clinical relevance of IgE reactivity to these allergen components are still insufficient. PMID- 26433529 TI - Common food allergens and their IgE-binding epitopes. AB - Food allergy is an adverse immune response to certain kinds of food. Although any food can cause allergic reactions, chicken egg, cow's milk, wheat, shellfish, fruit, and buckwheat account for 75% of food allergies in Japan. Allergen specific immunoglobulin E (IgE) antibodies play a pivotal role in the development of food allergy. Recent advances in molecular biological techniques have enabled the efficient analysis of food allergens. As a result, many food allergens have been identified, and their molecular structure and IgE-binding epitopes have also been identified. Studies of allergens have demonstrated that IgE antibodies specific to allergen components and/or the peptide epitopes are good indicators for the identification of patients with food allergy, prediction of clinical severity and development of tolerance. In this review, we summarize our current knowledge regarding the allergens and IgE epitopes in the well-researched allergies to chicken egg, cow's milk, wheat, shrimp, and peanut. PMID- 26433530 TI - Indicators of violence and asthma: An ecological study. AB - BACKGROUND: Global studies on asthma point to socioeconomic status as one of the main variables in terms of prevalence and disease severity in various parts of the world. Social factors related to community violence have been linked to higher incidence of asthma in the current studies. This study investigates the relationship between indicators of both community violence and development and hospital admissions due to asthma. METHODS: This was an analytical ecological study of multiple groups, using public databases with information up until 2006. All Brazilian municipalities with more than 100,000 inhabitants were considered as units of analysis. The main index used as socioeconomic indicator was the FIRJAN Index of Municipal Development (FIMD). The Index of Youth Vulnerability to Violence (IYVV) was used as indicators of community violence. The rate of admissions due to asthma was used as the outcome. Pearson's correlation was used for multivariate analyses. The coefficient of determination (R(2)) was calculated and the simple linear regression model adjusted for significant correlations. RESULTS: There was an inverse correlation between asthma admissions and FIMD (r = -0.354, p < 0.001), with statistical significance for all dimensions of the index. Admissions due to asthma were associated with the IYVV (r = 0.240, p < 0.001) and its component related to school attendance and employment (r = 0.315, p < 0.001), homicides (r = 0.112, p = 0.034), and poverty (r = 0.303, p < 0.001). CONCLUSIONS: There was a direct correlation between indicators of violence and rates of admission due asthma, and an inverse correlation with indicators of development. These results suggest that social detriment can act as a risk factor for hospital admissions due to asthma. PMID- 26433531 TI - Expression of CysLT2 receptors in asthma lung, and their possible role in bronchoconstriction. AB - BACKGROUND: The expression and functional role of CysLT2 receptors in asthma have not been clarified. In this study, we evaluated CysLT2 receptors expression, and effects of CysLT2-and CysLT1/2-receptor antagonists on antigen-induced bronchoconstriction using isolated lung tissues from both asthma and non-asthma subjects. METHODS: CysLT1 and CysLT2 receptors expression in asthma and non asthma lung tissue preparations was examined in immunohistochemistry experiments, and their functional roles in antigen-induced bronchoconstriction were assessed using ONO-6950, a dual CysLT1/2-receptor antagonist, montelukast, a CysLT1 receptor antagonist, and BayCysLT2RA, a CysLT2 receptor-specific antagonist. RESULTS: CysLT1 receptors were expressed on the bronchial smooth muscle and epithelium, and on alveolar leukocytes in 5 in 5 non-asthma subjects and 2 in 2 asthma subjects. On the other hand, although degrees of CysLT2 receptors expression were variable among the 5 non-asthma subjects, the expression in the asthma lung was detected on bronchial smooth muscle, epithelium and alveolar leukocytes in 2 in 2 asthma subjects. In the non-asthma specimens, antagonism of CysLT2 receptors did not affect antigen-induced bronchial contractions, even after pretreatment with the CysLT1-receptor specific antagonist, montelukast. However, in the bronchus isolated from one of the 2 asthma subjects, antagonism of CysLT2 receptors suppressed contractions, and dual antagonism of CysLT1 and CysLT2 receptors resulted in additive inhibitory effect on anaphylactic contractions. CONCLUSIONS: CysLT2 receptors were expressed in lung specimens isolated from asthma subjects. Activation of CysLT2 receptors may contribute to antigen-induced bronchoconstriction in certain asthma population. PMID- 26433532 TI - Elevated exhaled nitric oxide in anaphylaxis with respiratory symptoms. AB - BACKGROUND: Anaphylaxis is a serious type I allergic reaction that occurs suddenly and can result in death, but it is sometimes difficult to differentiate from other diseases, and physicians must rely on symptoms alone for its diagnosis. Meanwhile, fractional exhaled nitric oxide (FeNO) concentration, used in assessing airway inflammation in bronchial asthma, is known to be affected by atopic disposition. The possible role of FeNO measurements was evaluated in patients with anaphylaxis. METHODS: FeNO was measured in 52 adult patients (17-78 years old, median age 41.5 years) in whom anaphylaxis occurred. These measurements were made within 24 h after onset and after about one month when the patients were symptom-free. In some of these patients, FeNO was measured a third time, two months or more after onset. RESULTS: The FeNO level in the 52 patients was not significantly different in measurement made within 24 h of onset of anaphylaxis and after one month. However, excluding 9 patients who also had asthma history, the FeNO level in the remaining 43 patients decreased significantly from within 24 h of onset (36.7 +/- 27.5 ppb) to one month later (28.8 +/- 19.5 ppb). Of these 43 patients, this phenomenon was evident in a group that had respiratory symptoms (31 patients), but it was not seen in a group that did not have respiratory symptoms (12 patients). CONCLUSIONS: Elevation of FeNO was related to respiratory symptoms observed in anaphylactic patients without asthma. Although the mechanism of increased FeNO level is unclear, its usefulness for diagnosis of anaphylaxis must be examined in prospective studies. PMID- 26433533 TI - Omalizumab in Japanese children with severe allergic asthma uncontrolled with standard therapy. AB - BACKGROUND: Omalizumab has demonstrated clinical benefits in children with moderate to severe allergic asthma. However, no studies have been performed in Japanese asthmatic children. The aim of this study was to evaluate the efficacy including free IgE suppression and safety of omalizumab in Japanese children with severe allergic asthma. The primary objective was to examine whether omalizumab decreases serum free IgE levels to less than 25 ng/ml (target level of suppression). METHODS: Thirty-eight Japanese children (6-15 years) with uncontrolled severe allergic asthma despite inhaled corticosteroids (>200 MUg/day fluticasone propionate or equivalent) and two or more controller therapies received add-on treatment with omalizumab in a 24-week, multicenter, uncontrolled, open-label study. RESULTS: The geometric mean serum free IgE level at 24 weeks was 15.6 ng/mL. Compared with baseline, total asthma symptom scores, daily activity scores and nocturnal sleep scores at 24 weeks were significantly improved. The rates of asthma exacerbation and hospitalization due to asthma were reduced by 69.2% and 78.2%, respectively (p < 0.001), versus baseline. Quality-of life scores were also significantly improved (p < 0.001). In addition, 11 (28.9%) patients reduced the dose of any asthma controller medications. Thirty-six (94.7%) patients experienced at least one adverse event during the treatment period. All adverse events were mild or moderate in severity and no new safety concerns were detected. No patients discontinued the study. CONCLUSIONS: In Japanese children with severe allergic asthma, omalizumab decreased free IgE levels to less than 25 ng/mL. Omalizumab improved asthma control and was well tolerated, as well. PMID- 26433535 TI - A case of fixed drug eruption caused by loxoprofen sodium hydrate. PMID- 26433534 TI - Caregiver treatment satisfaction is improved together with children's asthma control: Prospective study for budesonide monotherapy in school-aged children with uncontrolled asthma symptoms. AB - BACKGROUND: If asthmatic children cannot obtain sufficient control of their disease, not only do they suffer from asthma symptoms, but the daily life activities of their caregivers are also disrupted. We investigated the effectiveness of an inhaled corticosteroid (ICS) for symptom control in previously ICS-untreated school-aged asthmatic children as well as caregiver treatment satisfaction (CTS). METHODS: A multicenter, open-label, single-arm study on 12-week ICS (budesonide Turbuhaler(r)) monotherapy was undertaken in subjects aged 5-15 years with bronchial asthma not treated with ICS during the previous 3 months. At 0, 4, 8, and 12 weeks after start of ICS administration, Japanese Pediatric Asthma Control Program (JPAC) scores, and CTS scores were summated and lung function measured. At weeks 0 and 12, questionnaires on caregiver anxiety were also assessed. RESULTS: Seventy-five patients were enrolled, and 69 assessed. Ninety percent of subjects had been treated with asthma controller medication except ICS before study enrollment. JPAC score and CTS score were improved significantly at weeks 4, 8, and 12 (p < 0.001). With regard to CTS, more than half of caregivers showed a perfect score at weeks 8 and 12. There was a significant correlation between JPAC score and CTS score. Lung function and caregiver anxiety were also improved, and good compliance with treatment was observed during the intervention. CONCLUSIONS: If treating ICS untreated school-aged asthmatic children with uncontrolled symptoms, ICS monotherapy can improve CTS along with improving asthma control. PMID- 26433536 TI - Drugs causing severe ocular surface involvements in Japanese patients with Stevens-Johnson syndrome/toxic epidermal necrolysis. PMID- 26433537 TI - Atopic dermatitis exacerbated with ustekinumab in a psoriatic patient with childhood history of atopy. PMID- 26433538 TI - Par j 2 IgE measurement for distinguishing between sensitization and allergy. PMID- 26433539 TI - A case of an anaphylactic reaction due to oats in granola. PMID- 26433540 TI - Usefulness of rapid measurement of serum thymus and activation-regulated chemokine level in diagnosing drug-induced hypersensitivity syndrome. PMID- 26433541 TI - Comparison of the aerosol velocity of Respimat(r) soft mist inhaler and seven pressurized metered dose inhalers. PMID- 26433542 TI - A case of oral allergy syndrome due to star fruit sensitized from atopic hands. PMID- 26433543 TI - Diagnosis of IgE-mediated hypersensitivity to sesame seeds supplemented with lipid body proteins. PMID- 26433545 TI - Acute parkinsonism in alcohol withdrawal: A case report. PMID- 26433546 TI - A randomized phase II study of Xilonix, a targeted therapy against interleukin 1alpha, for the prevention of superficial femoral artery restenosis after percutaneous revascularization. AB - OBJECTIVE: The purpose of this study was to evaluate an anti-interleukin 1alpha antibody for its ability to reduce acute postprocedural inflammation, thereby reducing neointimal hyperplasia and restenosis after superficial femoral artery (SFA) angioplasty. Restenosis of the SFA after endovascular intervention is a common problem leading to 1-year primary patency as low as 40%. These failures are primarily due to the development of neointimal hyperplasia, resulting from arterial wall inflammation. METHODS: This was a randomized, phase II trial examining SFA restenosis in patients after percutaneous revascularization. Randomization occurred after successful revascularization, and patients were assigned to either the standard of care arm or the Xilonix (XBiotech USA, Inc, Austin, Tex) plus standard of care arm (N = 43). Xilonix was administered immediately after revascularization, every 2 weeks intravenously for four doses, and monthly subcutaneously until month 12. The major efficacy end points were target vessel event-free survival and incidence of major adverse cardiovascular events (MACEs). RESULTS: At 12 months of follow-up, MACE (43% vs 36%; P = .76) and target vessel restenosis (24% vs 27%; log-rank, P = .79) rates were not significantly different between the groups. At 3-month follow-up, which covers the intravenous dosing period, a trend toward lower incidence of restenosis (0 of 22 [0%] vs 2 of 21 [10%]; P = .14) and MACE (2 of 22 [9%] vs 5 of 21 [24%]; P = .22) was observed in the Xilonix cohort. Adverse events were equally distributed in both arms. CONCLUSIONS: Xilonix was well tolerated. Observed tendency to improved vessel patency with intravenous dosing suggests Xilonix could potentially represent a safe and effective therapeutic approach to preserving vessel patency. PMID- 26433544 TI - Information in pallidal neurons increases with parkinsonian severity. AB - INTRODUCTION: The motor symptoms of Parkinson's disease (PD) present with pathological neuronal activity in the basal ganglia. Although neuronal firing rate changes in the globus pallidus internus (GPi) and externus (GPe) are reported to underlie the development of PD motor signs, firing rates change inconsistently, vary confoundingly with some therapies, and are poor indicators of symptom severity. METHODS: We explored the relationship between parkinsonian symptom severity and the effectiveness with which pallidal neurons transmit information. We quantify neuronal entropy and information - alternatives to firing rate and correlations respectively - in and between GPe and GPi neurons using a progressive, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, non-human primate model of PD. RESULTS: Neuronal entropy and symptom severity were not linearly correlated: in both pallidal segments, entropy increased from naive to moderate parkinsonism, but decreased with further progression to the severely parkinsonian condition. In contrast, information transmitted from GPe to GPi increased consistently with symptom severity. Furthermore, antidromic information from GPi to GPe increased substantially with symptom severity. Together, these findings suggest that as parkinsonian severity increases, more and more information enters GPe and GPi from common sources, diminishing the relative importance of the orthodromic GPe to GPi connection. CONCLUSIONS: With parkinsonian progression, the direct and indirect pathways lose their independence and start to convey redundant information. We hypothesize that a loss of parallel processing impairs the ability of the network to select and implement motor commands, thus promoting the hypokinetic symptoms of PD. PMID- 26433547 TI - A meta-analysis of water quality and aquatic macrophyte responses in 18 lakes treated with lanthanum modified bentonite (Phoslock((r))). AB - Lanthanum (La) modified bentonite is being increasingly used as a geo-engineering tool for the control of phosphorus (P) release from lake bed sediments to overlying waters. However, little is known about its effectiveness in controlling P across a wide range of lake conditions or of its potential to promote rapid ecological recovery. We combined data from 18 treated lakes to examine the lake population responses in the 24 months following La-bentonite application (range of La-bentonite loads: 1.4-6.7 tonnes ha(-1)) in concentrations of surface water total phosphorus (TP; data available from 15 lakes), soluble reactive phosphorus (SRP; 14 lakes), and chlorophyll a (15 lakes), and in Secchi disk depths (15 lakes), aquatic macrophyte species numbers (6 lakes) and aquatic macrophyte maximum colonisation depths (4 lakes) across the treated lakes. Data availability varied across the lakes and variables, and in general monitoring was more frequent closer to the application dates. Median annual TP concentrations decreased significantly across the lakes, following the La-bentonite applications (from 0.08 mg L(-1) in the 24 months pre-application to 0.03 mg L(-1) in the 24 months post-application), particularly in autumn (0.08 mg L(-1) to 0.03 mg L(-1)) and winter (0.08 mg L(-1) to 0.02 mg L(-1)). Significant decreases in SRP concentrations over annual (0.019 mg L(-1) to 0.005 mg L(-1)), summer (0.018 mg L(-1) to 0.004 mg L(-1)), autumn (0.019 mg L(-1) to 0.005 mg L(-1)) and winter (0.033 mg L(-1) to 0.005 mg L(-1)) periods were also reported. P concentrations following La-bentonite application varied across the lakes and were correlated positively with dissolved organic carbon concentrations. Relatively weak, but significant responses were reported for summer chlorophyll a concentrations and Secchi disk depths following La-bentonite applications, the 75th percentile values decreasing from 119 MUg L(-1) to 74 MUg L(-1) and increasing from 398 cm to 506 cm, respectively. Aquatic macrophyte species numbers and maximum colonisation depths increased following La-bentonite application from a median of 5.5 species to 7.0 species and a median of 1.8 m to 2.5 m, respectively. The aquatic macrophyte responses varied significantly between lakes. La-bentonite application resulted in a general improvement in water quality leading to an improvement in the aquatic macrophyte community within 24 months. However, because, the responses were highly site-specific, we stress the need for comprehensive pre- and post-application assessments of processes driving ecological structure and function in candidate lakes to inform future use of this and similar products. PMID- 26433548 TI - Progress and Infrastructure for Improved Patient Outcomes of the National Cancer Institute Network Groups. PMID- 26433549 TI - Involving Advocates in Cancer Research. AB - Advocates can play an important role in cancer research. In 2010, the National Cancer Institute (NCI) Advocate in Research Working Group (ARWG) defined a "research advocate" as an individual who brings and can convey a nonscientific viewpoint to the research process and can communicate a collective patient perspective through knowledge of multiple disease experiences. Experiences cited in this review are related to publically funded research. They, exemplify challenges and successes of advocate engagement and involvement in the cancer research process. PMID- 26433550 TI - Cooperative Group Trials in the Community Setting. AB - Over the last 40 years the National Cancer Institute (NCI) has created a vibrant public-private partnership for the implementation of NCI-sponsored cooperative group (Network) clinical trials throughout the United States and Canada. Over these four decades, the cancer clinical trials process has become more complex more precise and more resource intensive. During this same time period, financial resources to support the NCI community research initiative have become more constrained. The newest manifestation of NCI-sponsored community based cancer clinical trial research, known as the National Community Oncology Research Program (NCORP) began initial operation August 1, 2014. We describe several key strategies that community sites may use to not only be successful but to thrive in this new financially austere research environment. PMID- 26433553 TI - The Master Protocol Concept. AB - During the past decade, biomedical technologies have undergone an explosive evolution-from the publication of the first complete human genome in 2003, after more than a decade of effort and at a cost of hundreds of millions of dollars-to the present time, where a complete genomic sequence can be available in less than a day and at a small fraction of the cost of the original sequence. The widespread availability of next-generation genomic sequencing has opened the door to the development of precision oncology. The need to test multiple new targeted agents both alone and in combination with other targeted therapies, as well as classic cytotoxic agents, demands the development of novel therapeutic platforms (particularly Master Protocols) capable of efficiently and effectively testing multiple targeted agents or targeted therapeutic strategies in relatively small patient subpopulations. Here, we describe the Master Protocol concept, with a focus on the expected gains and complexities of the use of this design. An overview of Master Protocols currently active or in development is provided along with a more extensive discussion of the Lung Master Protocol (Lung-MAP study). PMID- 26433552 TI - Genetic Testing and Tissue Banking for Personalized Oncology: Analytical and Institutional Factors. AB - Personalized oncology, or more aptly precision oncogenomics, refers to the identification and implementation of clinically actionable targets tailored to an individual patient's cancer genomic information. Banking of human tissue and other biospecimens establishes a framework to extract and collect the data essential to our understanding of disease pathogenesis and treatment. Cancer cooperative groups in the United States have led the way in establishing robust biospecimen collection mechanisms to facilitate translational research, and combined with technological advances in molecular testing, tissue banking has expanded from its traditional base in academic research and is assuming an increasingly pivotal role in directing the clinical care of cancer patients. Comprehensive screening of tumors by DNA sequencing and the ability to mine and interpret these large data sets from well-organized tissue banks have defined molecular subtypes of cancer. Such stratification by genomic criteria has revolutionized our perspectives on cancer diagnosis and treatment, offering insight into prognosis, progression, and susceptibility or resistance to known therapeutic agents. In turn, this has enabled clinicians to offer treatments tailored to patients that can greatly improve their chances of survival. Unique challenges and opportunities accompany the rapidly evolving interplay between tissue banking and genomic sequencing, and are the driving forces underlying the revolution in precision medicine. Molecular testing and precision medicine clinical trials are now becoming the major thrust behind the cooperative groups' clinical research efforts. PMID- 26433554 TI - The National Clinical Trials Network: Conducting Successful Clinical Trials of New Therapies for Rare Cancers. AB - Rare cancers account for 27% of neoplasms diagnosed each year, and 25% of cancer related deaths in the United States. However, rare cancers show some of the highest response rates to targeted therapies, probably due to identification of oncogenic drivers with little interpatient variability. Although the low incidence of rare cancers makes large-scale randomized trials involving single histologies difficult to perform, drugs have been successfully developed in rare cancers using clinical trial designs that combine microscopic histologies. Such trials are being pursued within the National Clinical Trials Network (NCTN), which possesses unique qualifications to perform widespread molecular screening of tumors for patient enrollment onto therapeutic clinical trials. When larger clinical trials are needed to determine optimum treatment strategies in rare cancers, the NCTN's broad reach in North America and internationally, and their ability to partner with both United States-based and international research organizations, can make these challenging studies feasible. PMID- 26433555 TI - Enhancing Adolescent and Young Adult Oncology Research Within the National Clinical Trials Network: Rationale, Progress, and Emerging Strategies. AB - Adolescent and Young Adult Oncology (AYAO, including patients 15-39 years of age) is an emerging discipline in the field of cancer treatment and research. Poorer survival outcomes for this population and characteristic age-related challenges in care have called attention to the need for increased AYAO research. This chapter outlines pressing questions and reviews recent progress in AYAO research within the current organizational structure of the federal clinical trials enterprise, emphasizing how the United States National Cancer Institute's National Clinical Trials Network (NCTN) has created novel opportunities for collaborative AYAO research among the pediatric and adult NCTN groups. Potential strategies for expanding AYAO research, both within the NCTN and with other partners in the federal and advocacy domains are identified. PMID- 26433557 TI - Social Media and Oncology: The Past, Present, and Future of Electronic Communication Between Physician and Patient. AB - The relationship between patient and physician is in flux with the advent of electronic media that are advancing and enhancing communication. We perform a retrospective, current, and forward-looking examination of the technologies by which information is exchanged within the healthcare community. The evolution from e-mail and listservs to blogs and the modern social networks is described, with emphasis on the advantages and pitfalls of each medium, especially in regard to maintaining the standards of privacy and professionalism to which doctors are held accountable. We support the use of contemporary platforms like Twitter and Facebook for physicians to establish themselves as trustworthy online sources of medical knowledge, and anticipate ongoing collaboration between researchers, patients, and their advocates in trial design and accrual. PMID- 26433558 TI - A 46-Year-Old Asian Woman With Liver Mass. PMID- 26433559 TI - Analyzing IVF laboratory error rates: highlight or hide? PMID- 26433551 TI - The Globalization of Cooperative Groups. AB - The National Cancer Institute (NCI)-supported adult cooperative oncology research groups (now officially Network groups) have a longstanding history of participating in international collaborations throughout the world. Most frequently, the US-based cooperative groups work reciprocally with the Canadian national adult cancer clinical trial group, NCIC CTG (previously the National Cancer Institute of Canada Clinical Trials Group). Thus, Canada is the largest contributor to cooperative groups based in the United States, and vice versa. Although international collaborations have many benefits, they are most frequently utilized to enhance patient accrual to large phase III trials originating in the United States or Canada. Within the cooperative group setting, adequate attention has not been given to the study of cancers that are unique to countries outside the United States and Canada, such as those frequently associated with infections in Latin America, Asia, and Africa. Global collaborations are limited by a number of barriers, some of which are unique to the countries involved, while others are related to financial support and to US policies that restrict drug distribution outside the United States. This article serves to detail the cooperative group experience in international research and describe how international collaboration in cancer clinical trials is a promising and important area that requires greater consideration in the future. PMID- 26433556 TI - Ongoing Use of Data and Specimens From National Cancer Institute-Sponsored Cancer Prevention Clinical Trials in the Community Clinical Oncology Program. AB - Large cancer prevention trials provide opportunities to collect a wide array of data and biospecimens at study entry and longitudinally, for a healthy, aging population without cancer. This provides an opportunity to use pre-diagnostic data and specimens to evaluate hypotheses about the initial development of cancer. We report on strides made by, and future possibilities for, the use of accessible biorepositories developed from precisely annotated samples obtained through large-scale National Cancer Institute (NCI)-sponsored cancer prevention clinical trials conducted by the NCI Cooperative Groups. These large cancer prevention studies, which have enrolled more than 80,000 volunteers, continue to contribute to our understanding of cancer development more than 10 years after they were closed. PMID- 26433560 TI - Extracellular vesicle-derived protein from Bifidobacterium longum alleviates food allergy through mast cell suppression. AB - BACKGROUND: The incidence of food allergies has increased dramatically during the last decade. Recently, probiotics have been studied for the prevention and treatment of allergic disease. OBJECTIVE: We examined whether Bifidobacterium longum KACC 91563 and Enterococcus faecalis KACC 91532 have the capacity to suppress food allergies. METHODS: B longum KACC 91563 and E faecalis KACC 91532 were administered to BALB/c wild-type mice, in which food allergy was induced by using ovalbumin and alum. Food allergy symptoms and various immune responses were assessed. RESULTS: B longum KACC 91563, but not E faecalis KACC 91532, alleviated food allergy symptoms. Extracellular vesicles of B longum KACC 91563 bound specifically to mast cells and induced apoptosis without affecting T-cell immune responses. Furthermore, injection of family 5 extracellular solute-binding protein, a main component of extracellular vesicles, into mice markedly reduced the occurrence of diarrhea in a mouse food allergy model. CONCLUSION: B longum KACC 91563 induces apoptosis of mast cells specifically and alleviates food allergy symptoms. Accordingly, B longum KACC 91563 and family 5 extracellular solute-binding protein exhibit potential as therapeutic approaches for food allergies. PMID- 26433561 TI - Wheel running exercise attenuates vulnerability to self-administer nicotine in rats. AB - BACKGROUND: Preventing or postponing tobacco use initiation could greatly reduce the number of tobacco-related deaths. While evidence suggests that exercise is a promising treatment for tobacco addiction, it is not clear whether exercise could prevent initial vulnerability to tobacco use. Thus, using an animal model, we examined whether exercise attenuates vulnerability to the use and reinforcing effects of nicotine, the primary addictive chemical in tobacco. METHODS: Initial vulnerability was assessed using an acquisition procedure wherein exercising (unlocked running wheel, n=10) and sedentary (locked or no wheel, n=12) male adolescent rats had access to nicotine infusions (0.01-mg/kg) during daily 21.5-h sessions beginning on postnatal day 30. Exercise/sedentary sessions (2-h/day) were conducted prior to each of the acquisition sessions. The effects of exercise on nicotine's reinforcing effects were further assessed in separate groups of exercising (unlocked wheel, n=7) and sedentary (no wheel, n=5) rats responding for nicotine under a progressive-ratio schedule with exercise/sedentary sessions (2-h/day) conducted before the daily progressive-ratio sessions. RESULTS: While high rates of acquisition of nicotine self-administration were observed among both groups of sedentary controls, acquisition was robustly attenuated in the exercise group with only 20% of exercising rats meeting the acquisition criterion within the 16-day testing period as compared to 67% of the sedentary controls. Exercise also decreased progressive-ratio responding for nicotine as compared to baseline and to sedentary controls. CONCLUSIONS: Exercise may effectively prevent the initiation of nicotine use in adolescents by reducing the reinforcing effects of nicotine. PMID- 26433564 TI - Who receives cannabis use offers: A general population study of adolescents. AB - BACKGROUND: Drug use is predicated on a combination of "willingness" and "opportunity". That is, independent of any desire to use drugs, a drug use opportunity is required; be it indirect (i.e., being in a drug-use setting) or direct (i.e., receiving a direct drug offer). However, whether some youth are more likely to encounter such direct drug use opportunities is not fully known. AIMS: We examined whether certain characteristics placed adolescents at greater risk for being offered cannabis, after accounting for a number of demographic-, contextual-, interpersonal-, and personal-level risk factors. METHODS: We utilized data from a Norwegian school survey (n=19,309) where the likelihood of receiving cannabis offer in the past year was estimated using logistic regression models. Substantive focus was on the individual and combined effects of personal (i.e., delinquency) and interpersonal (i.e., cannabis-using close friend) risk factors. Separate models were fit for middle- and high-school students. RESULTS: Delinquency was a significant risk factor for receiving cannabis offers, as was a cannabis-using best friend. In addition, peer cannabis use increased the risk of cannabis offers mostly for adolescents on the lower delinquency spectrum, but less so for highly delinquent adolescents. These interaction effects were primarily driven by the middle-school cohort. CONCLUSIONS: Cannabis offers were more likely to be extended to youth of certain high-risk profiles. Targeted prevention strategies can therefore be extended to a general profile of younger adolescents with externalizing problems and cannabis-using peers. PMID- 26433563 TI - Categorical perception of emotional facial expressions in alcohol-dependence. AB - BACKGROUND: Emotional deficits have been widely described in alcohol-dependence, but several subtle and critical emotional decoding abilities remain to be investigated. In particular, the ability of alcohol-dependent individuals to process emotionally ambiguous facial stimuli, which are more frequent in everyday life than full emotional facial expressions, remains poorly understood. The present study used a categorical perception paradigm to evaluate the identification of mixed emotional facial expressions among alcohol-dependent participants. METHOD: Nineteen recently detoxified participants with alcohol dependence and 19 healthy controls were presented with facial stimuli depicting four emotional facial expressions (happy, angry, sad, and neutral), morphed along continua between each possible pair of emotions. Participants had to indicate the predominant emotion within the randomly presented facial stimuli. For each emotional category, a logistic function that estimated the percentage of identification according to the morph steps was adjusted for each participant's data. RESULTS: While there was no significant group difference regarding the response slope (p=0.502, etap(2)=0.014), the identification threshold was significantly increased in alcohol-dependent participants compared to controls (p=0.007, etap(2)=0.204), independently of the emotional category. CONCLUSIONS: The categorical perception of emotional facial expression per se appeared preserved in alcohol-dependence, but alcohol-dependent participants exhibited a bias in emotional facial expression decoding characterized by a global under identification. This study is the first to evidence a deficit of alcohol dependent individuals in the processing of ambiguous emotional facial expressions by using this emotional continuum paradigm measuring the categorical perception effect. PMID- 26433562 TI - Predictors of outcome from computer-based treatment for substance use disorders: Results from a randomized clinical trial. AB - BACKGROUND: Although empirical evidence for the effectiveness of technology mediated interventions for substance use disorders is rapidly growing, the role of baseline characteristics of patients in predicting treatment outcomes of a technology-based therapy is largely unknown. METHOD: Participants were randomly assigned to either standard methadone maintenance treatment or reduced standard treatment combined with the computer-based therapeutic education system (TES). An array of demographic and behavioral characteristics of participants (N=160) was measured at baseline. Opioid abstinence and treatment retention were measured weekly for a 52-week intervention period. Generalized linear model and Cox regression were used to estimate the predictive roles of baseline characteristics in predicting treatment outcomes. RESULTS: We found significant predictors of opioid abstinence and treatment retention within and across conditions. Among 21 baseline characteristics of participants, employment status, anxiety, and ambivalent attitudes toward substance use predicted better opioid abstinence in the reduced-standard-plus-TES condition compared to standard treatment. Participants who had used cocaine/crack in the past 30 days at baseline showed lower dropout rates in standard treatment, whereas those who had not used exhibited lower dropout rates in the reduced-standard-plus-TES condition. CONCLUSIONS: This study is the first randomized controlled trial, evaluating over a 12-month period, how various aspects of participant characteristics impact outcomes for treatments that do or do not include technology-based therapy. Compared to standard alone treatment, including TES as part of the care was preferable for patients who were employed, highly anxious, and ambivalent about substance use and did not produce worse outcomes for any subgroups of participants. PMID- 26433565 TI - An evaluation of the Public Health Responsibility Deal: Informants' experiences and views of the development, implementation and achievements of a pledge-based, public-private partnership to improve population health in England. AB - OBJECTIVES: The Coalition Government's Public Health Responsibility Deal (RD) was launched in England in 2011 as a public-private partnership designed to improve public health in the areas of food, alcohol, health at work and physical activity. As part of a larger evaluation, we explored informants' experiences and views about the RD's development, implementation and achievements. METHODS: We conducted 44 semi-structured interviews with 50 interviewees, purposively sampled from: RD partners (businesses, public sector and non-governmental organisations); individuals with formal roles in implementing the RD; and non-partners and former partners. Data were analysed thematically: NVivo (10) software was employed to manage the data. RESULTS: Key motivations underpinning participation were corporate social responsibility and reputational enhancement. Being a partner often involved making pledges related to work already underway or planned before joining the RD, suggesting limited 'added value' from the RD, although some pledge achievements (e.g., food reformulation) were described. Benefits included access to government, while drawbacks included resource implications and the risk of an 'uneven playing field' between partners and non-partners. CONCLUSIONS: To ensure that voluntary agreements like the RD produce gains to public health that would not otherwise have occurred, government needs to: increase participation and compliance through incentives and sanctions, including those affecting organisational reputation; create greater visibility of voluntary agreements; and increase scrutiny and monitoring of partners' pledge activities. PMID- 26433566 TI - Development of a three-dimensional pre-vascularized scaffold-free contractile cardiac patch for treating heart disease. AB - BACKGROUND: The aim of our study was to develop a completely scaffold-free, viable, contractile cardiac tissue capable of being grafted into the damaged native heart. METHODS: Our technology is based on the fundamental characteristics of the self-assembling nature of cells. We created contractile cardiac spheroids by plating a mixture of rat neonatal ventricular cardiomyocytes, human dermal fibroblasts, and human coronary microartery endothelial cells in ultralow attachment plates. First, the optimal cell ratios for the 3 cell sources were determined. Next, approximately 1 * 10(4) optimal spheroids were fused into a patch-like construct, and the morphologic characteristics and mechanical functions of these patches were evaluated. Finally, the cardiac patches were grafted into the hearts of F344 nude rats, and histologic studies were performed after transplantation. RESULTS: Synchronous beating of the cardiac patch was confirmed electrophysiologically and mechanically. A micronetwork of endothelial cells was also demonstrated in the construct, and the histologic study performed 5 days after transplantation showed the grafts to be viable, with functioning microvascular structures inside the graft tissue. CONCLUSIONS: We consider the application of our scaffold-free 3-dimensional tissue engineering technology to cardiac regeneration therapy is feasible and expect that this technology will become a promising tool for the treatment of end-stage heart failure. PMID- 26433567 TI - Driver drowsiness detection based on non-intrusive metrics considering individual specifics. AB - OBJECTIVES: Drowsy driving is a serious highway safety problem. If drivers could be warned before they became too drowsy to drive safely, some drowsiness-related crashes could be prevented. The presentation of timely warnings, however, depends on reliable detection. To date, the effectiveness of drowsiness detection methods has been limited by their failure to consider individual differences. The present study sought to develop a drowsiness detection model that accommodates the varying individual effects of drowsiness on driving performance. METHODS: Nineteen driving behavior variables and four eye feature variables were measured as participants drove a fixed road course in a high fidelity motion-based driving simulator after having worked an 8-h night shift. During the test, participants were asked to report their drowsiness level using the Karolinska Sleepiness Scale at the midpoint of each of the six rounds through the road course. A multilevel ordered logit (MOL) model, an ordered logit model, and an artificial neural network model were used to determine drowsiness. RESULTS: The MOL had the highest drowsiness detection accuracy, which shows that consideration of individual differences improves the models' ability to detect drowsiness. According to the results, percentage of eyelid closure, average pupil diameter, standard deviation of lateral position and steering wheel reversals was the most important of the 23 variables. CONCLUSION: The consideration of individual differences on a drowsiness detection model would increase the accuracy of the model's detection accuracy. PMID- 26433568 TI - An extension of the theory of planned behavior to predict pedestrians' violating crossing behavior using structural equation modeling. AB - This paper aimed to examine pedestrians' self-reported violating crossing behavior intentions by applying the theory of planned behavior (TPB). We studied the behavior intentions regarding instrumental attitude, subjective norm, perceived behavioral control, the three basic components of TPB, and extended the theory by adding new factors including descriptive norm, perceived risk and conformity tendency to evaluate their respective impacts on pedestrians' behavior intentions. A questionnaire presented with a scenario that pedestrians crossed the road violating the pedestrian lights at an intersection was designed, and the survey was conducted in Dalian, China. Based on the 260 complete and valid responses, reliability and validity of the data for each question was evaluated. The data were then analyzed by using the structural equation modeling (SEM). The results showed that people had a negative attitude toward the behavior of violating road-crossing rules; they perceived social influences from their family and friends; and they believed that this kind of risky behavior would potentially harm them in a traffic accident. The results also showed that instrumental attitude and subjective norm were significant in the basic TPB model. After adding descriptive norm, subjective norm was no more significant. Other models showed that conformity tendency was a strong predictor, indicating that the presence of other pedestrians would influence behavioral intention. The findings could help to design more effective interventions and safety campaigns, such as changing people's attitude toward this violation behavior, correcting the social norms, increasing their safety awareness, etc. in order to reduce pedestrians' road crossing violations. PMID- 26433569 TI - Reply from Authors re: Jean-Nicolas Cornu, Stephan Madersbacher. Greenlight Photovaporisation of the Prostate: Now Ready for Prime Time. Eur Urol 2016;69:103 4. PMID- 26433570 TI - A Systematic Review of Virtual Reality Simulators for Robot-assisted Surgery. AB - CONTEXT: No single large published randomized controlled trial (RCT) has confirmed the efficacy of virtual simulators in the acquisition of skills to the standard required for safe clinical robotic surgery. This remains the main obstacle for the adoption of these virtual simulators in surgical residency curricula. OBJECTIVE: To evaluate the level of evidence in published studies on the efficacy of training on virtual simulators for robotic surgery. EVIDENCE ACQUISITION: In April 2015 a literature search was conducted on PubMed, Web of Science, Scopus, Cochrane Library, the Clinical Trials Database (US) and the Meta Register of Controlled Trials. All publications were scrutinized for relevance to the review and for assessment of the levels of evidence provided using the classification developed by the Oxford Centre for Evidence-Based Medicine. EVIDENCE SYNTHESIS: The publications included in the review consisted of one RCT and 28 cohort studies on validity, and seven RCTs and two cohort studies on skills transfer from virtual simulators to robot-assisted surgery. Simulators were rated good for realism (face validity) and for usefulness as a training tool (content validity). However, the studies included used various simulation training methodologies, limiting the assessment of construct validity. The review confirms the absence of any consensus on which tasks and metrics are the most effective for the da Vinci Skills Simulator and dV-Trainer, the most widely investigated systems. Although there is consensus for the RoSS simulator, this is based on only two studies on construct validity involving four exercises. One study on initial evaluation of an augmented reality module for partial nephrectomy using the dV-Trainer reported high correlation (r=0.8) between in vivo porcine nephrectomy and a virtual renorrhaphy task according to the overall Global Evaluation Assessment of Robotic Surgery (GEARS) score. In one RCT on skills transfer, the experimental group outperformed the control group, with a significant difference in overall GEARS score (p=0.012) during performance of urethrovesical anastomosis on an inanimate model. Only one study included assessment of a surgical procedure on real patients: subjects trained on a virtual simulator outperformed the control group following traditional training. However, besides the small numbers, this study was not randomized. CONCLUSIONS: There is an urgent need for a large, well-designed, preferably multicenter RCT to study the efficacy of virtual simulation for acquisition competence in and safe execution of clinical robotic-assisted surgery. PATIENT SUMMARY: We reviewed the literature on virtual simulators for robot-assisted surgery. Validity studies used various simulation training methodologies. It is not clear which exercises and metrics are the most effective in distinguishing different levels of experience on the da Vinci robot. There is no reported evidence of skills transfer from simulation to clinical surgery on real patients. PMID- 26433571 TI - Metabolic Modulation of Clear-cell Renal Cell Carcinoma with Dichloroacetate, an Inhibitor of Pyruvate Dehydrogenase Kinase. AB - BACKGROUND: Clear-cell renal cell carcinoma (ccRCC) exhibits suppressed mitochondrial function and preferential use of glycolysis even in normoxia, promoting proliferation and suppressing apoptosis. ccRCC resistance to therapy is driven by constitutive hypoxia-inducible factor (HIF) expression due to genetic loss of von Hippel-Lindau factor. In addition to promoting angiogenesis, HIF suppresses mitochondrial function by inducing pyruvate dehydrogenase kinase (PDK), a gatekeeping enzyme for mitochondrial glucose oxidation. OBJECTIVE: To reverse mitochondrial suppression of ccRCC using the PDK inhibitor dichloroacetate (DCA). DESIGN, SETTING, AND PARTICIPANTS: Radical nephrectomy specimens from patients with ccRCC were assessed for PDK expression. The 786-O ccRCC line and two animal models (chicken in ovo and murine xenografts) were used for mechanistic studies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Mitochondrial function, proliferation, apoptosis, HIF transcriptional activity, angiogenesis, and tumor size were measured in vitro and in vivo. Independent sample t-tests and analysis of variance were used for statistical analyses. RESULTS: PDK was elevated in 786-O cells and in ccRCC compared to normal kidney tissue from the same patient. DCA reactivated mitochondrial function (increased respiration, Krebs cycle metabolites such as alpha-ketoglutarate [cofactor of factor inhibiting HIF], and mitochondrial reactive oxygen species), increased p53 activity and apoptosis, and decreased proliferation in 786-O cells. DCA reduced HIF transcriptional activity in an FIH-dependent manner, inhibiting angiogenesis in vitro. DCA reduced tumor size and angiogenesis in vivo in both animal models. CONCLUSIONS: DCA can reverse the mitochondrial suppression of ccRCC and decrease HIF transcriptional activity, bypassing its constitutive expression. Its previous clinical use in humans makes it an attractive candidate for translation to ccRCC patients. PATIENT SUMMARY: We show that an energy-boosting drug decreases tumor growth and tumor blood vessels in animals carrying human kidney cancer cells. This generic drug has been used in patients for other conditions and thus could be tested in kidney cancer that remains incurable. PMID- 26433572 TI - Balanced Translocations Disrupting SMARCB1 Are Hallmark Recurrent Genetic Alterations in Renal Medullary Carcinomas. AB - BACKGROUND: Renal medullary carcinoma (RMC) is a rare and highly aggressive neoplasm that most often occurs in the setting of sickle cell trait or sickle cell disease (SCD). Most patients present with metastatic disease resistant to conventional chemotherapy, and therefore there is an urgent need for molecular insight to propose new therapies. OBJECTIVE: To determine the molecular alterations and oncogenic pathways that drive RMC development. DESIGN, SETTING, AND PARTICIPANTS: A series of five frozen samples of patients with RMC was investigated by means of gene expression profiling, array comparative genomic hybridization, and RNA and whole exome sequencing (WES). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: RNA and DNA sequencing read data were analyzed to detect gene fusions and somatic mutations. Gene fusions mutations were validated by real time polymerase chain reaction and fluorescence in situ hybridization. Gene expression profiling was analyzed by unsupervised hierarchical clustering and Gene Set Enrichment Analysis (Broad Institute, Cambridge, MA, USA). RESULTS AND LIMITATIONS: We observed inactivation of the tumor suppressor gene SMARCB1 in all tumors. In all four cases developed in patients with SCD, we identified an original mechanism of interchromosomal balanced translocations that disrupt the SMARCB1 sequence and thus contribute to its inactivation. Gene expression profiling revealed that RMC shares common oncogenic pathways with pediatric malignant rhabdoid tumors, another tumor subtype characterized by SMARCB1 deficiency. CONCLUSIONS: RMCs are characterized by an original mechanism of interchromosomal balanced translocations that disrupt the SMARCB1 sequence. WES reveals that RMCs show no other recurrent genetic alteration and an overall stable genome, underscoring the oncogenic potency of SMARCB1 inactivation. PATIENT SUMMARY: Our comprehensive molecular study supports a pivotal role of the tumor suppressor gene SMARCB1 in the development of renal medullary carcinoma. The use of therapeutic strategies based on the biologic effects of its inactivation should now open new perspectives for this typically lethal malignancy. PMID- 26433573 TI - Studying upper-limb kinematics using inertial sensors: a cross-sectional study. AB - BACKGROUND: In recent years, there has been a great interest in analyzing upper limb kinematics in order to investigate scapulohumeral rhythm, as its alteration has been associated with shoulder joint complex injuries. The use of inertial sensors is presented as a convenient and portable analysis method for studying kinematics in terms of angular mobility and linear acceleration. The aim of this study was to analyze upper-limbs kinematics in the three anatomical axes, obtained by inertial sensors. RESULTS: Descriptive graphics of analytical tasks performed were obtained. The main difference in mobility between the scapula and humerus was found in pitch axis for abduction ([Formula: see text] = 107.6 degrees , SD = 9.3 degrees ) and flexion ([Formula: see text] = 113.1 degrees , SD = 9.3 degrees ). CONCLUSION: The use of inertial sensors for human kinematics analysis is favorable. Although this study identified movement patterns, and supports inertial sensors as a useful device to analyze upper-limb kinematics, further studies with subjects with shoulder pathology to establish differences in movement patterns and scapulohumeral rhythm between healthy and pathological shoulders should be carried out. PMID- 26433574 TI - The supply of general practitioners across local areas: accounting for spatial heterogeneity. AB - BACKGROUND: The geographic distribution of general practitioners (GPs) remains persistently unequal in many countries despite notable increases in overall supply. This paper explores how the factors associated with the supply of general practitioners (GPs) are aligned with the arbitrary geographic boundaries imposed by the use of spatially referenced GP supply data. METHODS: Data on GP supply in postcodes within Australia are matched to data on the population characteristics and levels of amenities in postcodes. Tobit regression models are used that examine the associations between GP supply and postcode characteristics, whilst accounting for spatial heterogeneity. RESULTS: The results demonstrate that GPs do not consider space in a one-dimensional sense. Location choice is related to both neighbourhood-specific factors, such as hospitals, and broader area factors, such as area income and proximity to private schools. Although the proportion of females and elderly were related to GPs supply, mortality rate was not. CONCLUSIONS: This paper represents the first attempt to map the factors influencing GP supply to the appropriate geographic level at which GPs may be considering that factor. We suggest that both neighbourhood and broader regional characteristics can influence GPs' locational choices. This finding is highly relevant to the design and evaluation of relocation incentive programmes. PMID- 26433575 TI - [Prevalence and determinants of anemia in young children in French-speaking Africa. Role of iron deficiency]. AB - Anemia and iron deficiency are major public health issues worldwide and particularly in Africa. Reliable information about their prevalence and associated factors is required to allow for effective actions. In this study, we used data from recent (2006-2012) large population health surveys, carried out in 11 French-speaking African countries (Benin, Burkina Faso, Cameroon, Congo Brazzaville, Ivory Coast, Gabon, Guinea, Mali, Niger, Democratic Republic of Congo, and Senegal). Hemoglobin (Hb) was assessed and demographic and health related parameters were obtained from nation-representative samples of children aged 6-59 months. Anemia (Hb<11g/dL) was found in 72.4% of the children (60.2 87.8%), with no gender difference but a slightly lower incidence in older children (62% at age 4-5 years versus 85% at age 9 months), especially for the more severe forms (2.1% versus 8.7%, respectively). Anemia was only slightly but significantly affected by location (75.5% in rural areas versus 67.3% in towns), income (79.8% in lower quintile of income versus 62.3% in higher quintile), or maternal education (74.1% in children from non-educated mothers versus 62.4% in children whose mothers had secondary education). Nearly 50% of women of child bearing age had anemia. In the countries that report this information, less than 50% (17-65%) of children consumed iron-rich foods regularly and only 12% (7.4 20.5%) received iron supplementation. Infection and parasitism are known to affect some markers of iron status, because of the inflammatory reaction, thereby making the diagnosis of iron deficiency difficult. In the study countries, acute respiratory diseases and diarrhea affected 6.2 and 15.6% of children aged between 6 and 59 months, respectively; their distribution according to age and location is very different from the one of anemia, which is also the case for the distribution of malaria. It is thus likely that a large part of the anemia observed in young children is due to iron deficiency, although further research is needed to confirm this. This fully justifies the nationwide programs of iron fortification of flour, currently undergoing in most countries of French-speaking Africa. Their formal evaluation is still pending but the initial data suggest some efficacy, although far from optimal. It is thus likely that a more holistic approach, including iron fortification, actions against undernutrition and parasitism in children, and actions in favor of improving young women's iron and nutritional status, together with appropriate communication and education objectives, would be more effective. PMID- 26433576 TI - [Morgagni-Larrey diaphragmatic hernia in a 3-month-old child affected by Marfan syndrome]. AB - The authors report on a case of diaphragmatic hernia occurring in a 3-month-old child affected by Marfan syndrome. Diagnosis was made on a chest X-ray and cardiac ultrasounds, performed because of the association of poor general condition, failure to thrive, and signs of respiratory distress. As a reminder, we emphasize the association between Marfan disease and diaphragmatic hernias as well as the diagnostic approach to reach an appropriate diagnosis. PMID- 26433577 TI - [Hematologic abnormalities in infantile visceral leishmaniasis]. AB - The clinical and biological manifestations of visceral leishmaniasis are often confusing, most particularly because it can mimic and lead to a variety of hematological disorders. The aim of this study was to investigate the hematologic abnormalities observed in infantile visceral leishmaniasis from January 2000 and December 2013. The study included 35 children with a mean age of 3.5 years. Clinical manifestations were dominated by splenomegaly, fever, and paleness, defining the classic triad in 16% of our patients. Anemia was present in all patients. Leukopenia was found in 51% of the cases. Thrombocytopenia was observed in 48% of our patients and 36% had pancytopenia. All cases were confirmed by the presence of Leishman bodies (amastigotes) in the bone marrow smears. Quantitative and qualitative megakaryocyte abnormalities were found. Similarly, dysgranulopoiesis was observed in 31% of the cases, eosinophilia was present in 6%, erythroid hypoplasia in 3%, and erythroid hyperplasia in 34%. Different features of dyserythropoiesis were revealed in 71% of the patients with images of hemophagocytosis in 6% and multiple dysplasias in 9%. The knowledge of these hematological abnormalities associated with infantile visceral leishmaniasis can assist us in searching for Leishman bodies in the bone marrow smears to provide a diagnosis more quickly without necessarily resorting to more sophisticated tests. PMID- 26433578 TI - Anti-inflammatory and Anti-oxidative Activities of Paeonol and Its Metabolites Through Blocking MAPK/ERK/p38 Signaling Pathway. AB - The possible protective and curative effects of paeonol on carrageenan-induced acute hind paw edema in rats and dextran sulfate sodium (DSS)-induced colitis in mice have been evaluated. After oral administration, paeonol (20 and 40 mg/kg) reduced the edema increase in paw volumes and also the development of DSS-induced murine colitis. Furthermore, anti-inflammatory and anti-oxidant activities of paeonol (1) together with its 10 metabolites (M2~M11) were investigated by using in vitro anti-inflammatory and anti-oxidant assays. M3 and M11 exhibited significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities (with EC50 values of 93.44 and 23.24 MUM, respectively). All the metabolites except M8 showed hydroxyl radical scavenging activities, and M3 and M11 were the most potent agents (with EC50 values of 336.02 and 124.05 MUM, respectively). Inhibitory effects of paeonol, M2~M11 on the overproduction of nitric oxide (NO), and the release of TNF-alpha were also tested. M3 and M11 potently inhibited lipopolysaccharide (LPS)-induced overproduction of NO in macrophage RAW 264.7. Western blot results demonstrated that paeonol, M3, and M11 downregulated the high expression of inducible nitric oxide synthase (iNOS) and COX-2 proteins, and the effects of M3 and M11 were more potent when compared with paeonol. These findings indicated that paeonol may play anti-inflammatory and anti-oxidant roles by changing to its active metabolites after absorption. In addition, further investigations on the mechanism showed that paeonol, M3, and M11 blocked the phosphorylation of MAPK/ERK 1/2 and p38, whereas they showed no effect on the phosphorylation of JNK. The above results suggested that pre-treatment with paeonol might be an effective therapeutic intervention against inflammatory diseases including colitis. PMID- 26433579 TI - Activation of Neutrophils via IP3 Pathway Following Exposure to Demodex Associated Bacterial Proteins. AB - Rosacea is a chronic inflammatory condition that predominantly affects the skin of the face. Sera from rosacea patients display elevated reactivity to proteins from a bacterium (Bacillus oleronius) originally isolated from a Demodex mite from a rosacea patient suggesting a possible role for bacteria in the induction and persistence of this condition. This work investigated the ability of B. oleronius proteins to activate neutrophils and demonstrated activation via the IP3 pathway. Activated neutrophils displayed increased levels of IP1 production, F-actin formation, chemotaxis, and production of the pro-inflammatory cytokines IL-1beta and IL-6 following stimulation by pure and crude B. oleronius protein preparations (2 MUg/ml), respectively. In addition, neutrophils exposed to pure and crude B. oleronius proteins (2 MUg/ml) demonstrated increased release of internally stored calcium (Ca(2+)), a hallmark of the IP3 pathway of neutrophil activation. Neutrophils play a significant role in the inflammation associated with rosacea, and this work demonstrates how B. oleronius proteins can induce neutrophil recruitment and activation. PMID- 26433580 TI - Pharmacokinetics of eribulin mesylate in cancer patients with normal and impaired renal function. AB - PURPOSE: To evaluate the effect of renal impairment on eribulin mesylate pharmacokinetics following a single dose in adults with advanced solid tumors. METHODS: Patients were grouped by renal function: moderate impairment (creatinine clearance [CrCl] 30-50 mL/min), severe impairment (CrCl 15-29 mL/min), or normal (CrCl >=80 mL/min). During each 21-day cycle, eribulin mesylate doses (days 1 and 8) were administered intravenously: moderate, 1.1 mg/m(2) (except cycle 1 day 1, 1.4 mg/m(2)); severe, 0.7 mg/m(2); normal, 1.4 mg/m(2). RESULTS: Nineteen patients were enrolled (normal, n = 6; moderate, n = 7; severe, n = 6). Renal impairment was associated with an increased mean dose-normalized area under the concentration-time curve (ratios for moderate/normal and severe/normal: 1.49; 90 % confidence interval [CI] 0.9, 2.45). CrCl and renal function correlated positively, with a numerically small slope (0.0184; 90 % CI -0.00254, 0.0394). A simulated dose reduction to eribulin 1.1 mg/m(2) in patients with moderate or severe renal impairment achieved the same exposure as 1.4 mg/m(2) in those with normal renal function. All groups had similar toxicity profiles, with no unexpected adverse events. CONCLUSIONS: Renal impairment decreased eribulin clearance and increased exposure. Pharmacokinetic evaluation supports an eribulin dose reduction to 1.1 mg/m(2) in patients with moderate or severe renal impairment. CLINICALTRIALS. GOV IDENTIFIER: NCT01418677. PMID- 26433581 TI - A phase 1 study evaluating the pharmacokinetics and preliminary efficacy of veliparib (ABT-888) in combination with carboplatin/paclitaxel in Japanese subjects with non-small cell lung cancer (NSCLC). AB - INTRODUCTION: Veliparib is a potent, orally bioavailable PARP inhibitor that enhances efficacy of DNA-damaging chemotherapeutic agents. The study objectives were to determine the recommended phase 2 dose (RPTD) of veliparib plus carboplatin and paclitaxel, and assess pharmacokinetics (PK), tolerability, and preliminary efficacy in Japanese patients with solid tumors. METHODS: Carboplatin (AUC 6 mg/mL min) and paclitaxel (200 mg/m(2)) were administered on day 3 of a 21 day cycle. Oral veliparib (40, 80, or 120 mg BID) was administered on days 1-7. Patients received <=6 cycles. Adverse events (AEs) were reported using NCI-CTCAE version 4.03, PK parameters were analyzed using noncompartmental methods, and responses were measured by RECIST version 1.1. RESULTS: Twelve patients with non small cell lung cancer (NSCLC) were treated. Common treatment-emergent AEs, consistent with toxicities associated with carboplatin and paclitaxel, included leukopenia (100 %), neutropenia (100 %), anemia (83 %), thrombocytopenia (75 %), increased alanine aminotransferase (67 %), and increased aspartate aminotransferase (67 %). Grade 3/4 AEs (in >=2 patients) included neutropenia (100 %), leukopenia (33 %), anemia (25 %), and hyponatremia (17 %). No AEs led to veliparib, carboplatin, or paclitaxel interruption; no DLTs were observed. The RPTD was determined to be 120 mg BID. Veliparib C max and AUC were approximately dose proportional. Six partial responses were observed. CONCLUSIONS: Veliparib PK was not impacted by carboplatin and paclitaxel. The safety profile was manageable. The 120 mg BID RPTD confirmed in Japanese patients is the dose being evaluated in global studies of veliparib. Preliminary efficacy suggests veliparib may enhance carboplatin and paclitaxel activity, providing benefit to patients with NSCLC. PMID- 26433582 TI - The Arabidopsis thaliana NGATHA transcription factors negatively regulate cell proliferation of lateral organs. AB - The cell proliferation process of aerial lateral organs, such as leaves and flowers, is coordinated by complex genetic networks that, in general, converge on the cell cycle. The Arabidopsis thaliana NGATHA (AtNGA) family comprises four members that belong to the B3-type transcription factor superfamily, and has been suggested to be involved in growth and development of aerial lateral organs, although its role in the cell proliferation and expansion processes remains to be resolved in more detail. In order to clarify the role of AtNGAs in lateral organ growth, we took a systematic approach using both the loss- and gain-of-functional mutants of all four members. Our results showed that overexpressors of AtNGA1 to AtNGA4 developed small, narrow lateral organs, whereas the nga1 nga2 nga3 nga4 quadruple mutant produced large, wide lateral organs. We found that cell numbers of the lateral organs were significantly affected: a decrease in overexpressors and, inversely, an increase in the quadruple mutant. Kinematic analyses on leaf growth revealed that, compared with the wild type, the overexpressors displayed a lower activity of cell proliferation and yet the mutant a higher activity. Changes in expression of cell cycle-regulating genes were well in accordance with the cell proliferation activities, establishing that the AtNGA transcription factors act as bona fide negative regulators of the cell proliferation of aerial lateral organs. PMID- 26433583 TI - Delayed postoperative C5 root palsy and the use of neurophysiologic monitoring. AB - INTRODUCTION: Although advances have been made in surgical technique and intraoperative monitoring, the rate of postoperative C5 palsy remains the same. We attempt to define characteristics which may predict risk of developing postoperative C5 palsy. METHODS: Retrospective chart review identified 644 patients undergoing cervical procedures. Anterior cervical discectomy and fusion was performed in 456, anterior cervical corpectomy and fusion (ACCF) in 78, posterior laminectomy and fusion (PLF) in 106, and posterior open-door laminoplasty in 4 patients. All patients had neurophysiologic monitoring [somatosensory-evoked potentials (SSEP), spontaneous electromyogram (EMG), and/or motor-evoked potential (MEP)]. RESULTS: Postoperative C5 root palsy occurred in 5 (2 with ACCF and 3 with PLF) cases (1.4%). In all cases, there were no changes in intraoperative neurophysiologic monitoring. C5 palsy did not occur before postoperative day 2. CONCLUSIONS: Patients undergoing cervical decompression remain at risk for C5 root palsy despite use of monitoring. Given that all patients experienced delayed onset of C5 palsy, MEP, SSEP, and EMG may not be sensitive enough to assess the risk of developing C5 palsy. PMID- 26433584 TI - Interest of T1 parameters for sagittal alignment evaluation of adolescent idiopathic scoliosis patients. AB - PURPOSE: In the last few years several reports stressed the importance of sagittal alignment in adolescent idiopathic scoliosis (AIS) patients. It was recently reported that T1 slope, defined as the angle between the superior endplate of T1 and the horizontal, correlates strongly with overall sagittal parameters. The aim of this study was to assess the impact of T1 parameters (T1 slope and T1-tilt) on sagittal alignment of AIS hypokyphotic patients preoperatively and postoperatively. METHODS: Twenty-nine AIS patients with <20 degrees preoperative hypokyphosis were included in a retrospective study. Surgery systematically comprised hybrid construct with screws below T11, sublaminar bands at thoracic level and a lamino-laminar claw on the upper instrumented vertebra. Preoperative, postoperative and 2-year follow-up radiological assessment included Cobb angle, T1 slope, T1 sagittal tilt, regional sagittal parameters and pelvic parameters. RESULTS: In the series as a whole, coronal Cobb angle was significantly reduced postoperatively (58 degrees vs. 17 degrees ; p < 0.001), thoracic kyphosis significantly improved (12.4 degrees vs. 25.6 degrees ; p < 0.001) and cervical lordosis significantly restored (6.2 degrees kyphosis vs. 4.1 degrees lordosis; p < 0.001). There was a significant modification in T1-slope (10.2 degrees vs. 18.2 degrees ; p < 0.001). Preoperatively, T1 slope was significantly correlated with T1 tilt (r = 0.427; p = 0.029). Postoperatively, T1 slope was significantly correlated with T1 tilt (r = 0.549; p = 0.002), thoracic kyphosis (r = 0.535, p = 0.005) and cervical lordosis (r = -0.444, p = 0.03). Restoration of cervical lordosis was significantly correlated to changes of T1-slope (r = -0.393, p = 0.032), which was significantly correlated to postoperative thoracic kyphosis. CONCLUSION: According to these results, T1 seems to be of major interest in postoperative modifications of sagittal alignment. T1 slope and sagittal tilt are good indicators of postoperative changes for regional (cervical lordosis and thoracic kyphosis) and global parameters. We therefore consider these parameters as essential in the assessment of AIS patients. Further studies and correlation with clinical scores will, however, be necessary in order to confirm the present findings. PMID- 26433585 TI - Relationship between modic changes and facet joint degeneration in the cervical spine. AB - PURPOSE: Given that the disc moves simultaneously with facet joints, there would be a relationship between Modic changes and facet joint degeneration in the cervical spine. However, there is no literature investigating the relationship. The purpose is to evaluate the relationship between Modic changes and facet joint degeneration in the cervical spine. METHODS: Ninety-eight patients underwent both computed tomography (CT) and magnetic resonance images (MRI) of the cervical spine. They consisted of fifty-one males and forty-eight females and their mean age was 60.1 years (ranged from 40 years to 81 years). We compared the degree of facet joint degeneration based on CTs with Modic changes based on MRIs from C2-C3 to C6-C7. The degree of facet joint degeneration was classified into four categories and Modic changes were classified into four types. Disc degeneration was determined with Miyazaki's grading system. RESULTS: Facet joint degeneration was most common at C2-C3 and C4-C5 and rarest at C6-C7. Modic changes were most common at C2-C3 and rarest at C6-C7. However, there was no relationship between facet joint degeneration and any Modic changes at the same level. However, the presence of facet joint degeneration and the presence of Modic change are common in high grades of disc degeneration at the same level of the cervical spine. CONCLUSION: Modic changes and facet joint degeneration are most common at C2-C3 in the cervical spine. However, there were no relationships between the presence of Modic changes and facet joint degeneration at the same level of the cervical spine. PMID- 26433586 TI - A Computational Approach for the Prediction of Fatigue Behaviour in Peripheral Stents: Application to a Clinical Case. AB - Nickel-Titanium (NiTi) peripheral stents are commonly used for the treatment of diseased femoropopliteal arteries (FPA). However, cyclic deformations of the vessel, induced by limb movements affect device performance and fatigue failure may occur. Stent strut fracture has been described in the literature, and is implicated as a potential causative factor in vessel re-occlusion. In this paper, a numerical approach is proposed to predict the fatigue behaviour of peripheral NiTi stents within patient-specific arterial geometries, as additional information to aid clinician intervention planning. The procedure needs some patient-specific vessel features derived from routine clinical images but, when this information is not available, reference data from the literature may be used, obviously increasing the uncertainties of the results. In addition, specific stent material data are required and can be obtained from experimental tests. Several 3D finite element models resembling stented vessel segments are built and used for fatigue analyses. For each model, axial cyclic boundary conditions are obtained from a patient-specific lumped parameter model representing the entire artery as a series of suitable springs. This allows the simplification of stiffness changes along the vessel due to plaque and stent that affect local axial deformations. Imposed local cyclic bending values depend on the stent location along the FPA. The procedure is exemplified by its application to an actual clinical case that showed two strut fractures at 18 months follow up. Interestingly, despite the lack of some of patient-specific information and the use of data from the literature to inform the model, the numerical approach was able to interpret the in vivo fractures. PMID- 26433587 TI - Transportable data from non-target arthropod field studies for the environmental risk assessment of genetically modified maize expressing an insecticidal double stranded RNA. AB - As part of an environmental risk assessment, the potential impact of genetically modified (GM) maize MON 87411 on non-target arthropods (NTAs) was evaluated in the field. MON 87411 confers resistance to corn rootworm (CRW; Diabrotica spp.) by expressing an insecticidal double-stranded RNA (dsRNA) transcript and the Cry3Bb1 protein and tolerance to the herbicide glyphosate by producing the CP4 EPSPS protein. Field trials were conducted at 14 sites providing high geographic and environmental diversity within maize production areas from three geographic regions including the U.S., Argentina, and Brazil. MON 87411, the conventional control, and four commercial conventional reference hybrids were evaluated for NTA abundance and damage. Twenty arthropod taxa met minimum abundance criteria for valid statistical analysis. Nine of these taxa occurred in at least two of the three regions and in at least four sites across regions. These nine taxa included: aphid, predatory earwig, lacewing, ladybird beetle, leafhopper, minute pirate bug, parasitic wasp, sap beetle, and spider. In addition to wide regional distribution, these taxa encompass the ecological functions of herbivores, predators and parasitoids in maize agro-ecosystems. Thus, the nine arthropods may serve as representative taxa of maize agro-ecosystems, and thereby support that analysis of relevant data generated in one region can be transportable for the risk assessment of the same or similar GM crop products in another region. Across the 20 taxa analyzed, no statistically significant differences in abundance were detected between MON 87411 and the conventional control for 123 of the 128 individual-site comparisons (96.1%). For the nine widely distributed taxa, no statistically significant differences in abundance were detected between MON 87411 and the conventional control. Furthermore, no statistically significant differences were detected between MON 87411 and the conventional control for 53 out of 56 individual-site comparisons (94.6 %) of NTA pest damage to the crop. In each case where a significant difference was observed in arthropod abundance or damage, the mean value for MON 87411 was within the reference range and/or the difference was not consistently observed across collection methods and/or sites. Thus, the differences were not representative of an adverse effect unfamiliar to maize and/or were not indicative of a consistent plant response associated with the GM traits. Results from this study support a conclusion of no adverse environmental impact of MON 87411 on NTAs compared to conventional maize and demonstrate the utility of relevant transportable data across regions for the ERA of GM crops. PMID- 26433588 TI - Why Narrating Changes Memory: A Contribution to an Integrative Model of Memory and Narrative Processes. AB - This paper aims to reflect on the relation between autobiographical memory (ME) and autobiographical narrative (NA), examining studies on the effects of narrating on the narrator and showing how studying these relations can make more comprehensible both memory's and narrating's way of working. Studies that address explicitly on ME and NA are scarce and touch this issue indirectly. Authors consider different trends of studies of ME and NA: congruency vs incongruency hypotheses on retrieving, the way of organizing memories according to gist or verbatim format and their role in organizing positive and negative emotional experiences, the social roots of ME and NA, the rules of conversation based on narrating. Analysis of investigations leads the Authors to point out three basic results of their research. Firstly, NA transforms ME because it narrativizes memories according to a narrative format. This means that memories, when are narrated, are transformed in stories (verbal language) and socialised. Secondly, the narrativization process is determined by the act of telling something within a communicative situation. Thus, relational situation of narrating act, by modifying the story, modifies also memories. The Authors propose the RE.NA.ME model (RElation, NArration, MEmory) to understand and study ME and NA. Finally, this study claims that ME and NA refer to two different types of processes having a wide area of overlapping. This is due to common social, developmental and cultural roots that make NA to include part of ME (narrative of memory) and ME to include part of NA (memory of personal events that have been narrated). PMID- 26433589 TI - Cerebral Vasculitis in X-linked Lymphoproliferative Disease Cured by Matched Unrelated Cord Blood Transplant. AB - Vasculitis occurs rarely in association with X-linked lymphoproliferative disease (XLP). There are four published cases of non-EBV XLP-associated cerebral vasculitis reported, none of whom have survived without major cognitive impairment. CASE: A 9-year old boy initially presented aged 5 years with a restrictive joint disease. He subsequently developed dysgammaglobulinemia, episodic severe pneumonitis, aplastic anaemia, gastritis and cerebral vasculitis. A diagnosis of XLP was made, based on flow cytometric analysis and the identification of a novel mutation in SH2D1A, c.96G>C. No peripheral blood lymphocyte clonal proliferation was identified and he was EBV negative, although human herpes virus-7 (HHV7) was detected repeatedly in his cerebrospinal fluid. He underwent a reduced intensity unrelated umbilical cord blood transplant, but failed to engraft. A second 5/6 matched cord gave 100 % donor engraftment. Complications included BK virus-associated haemorrhagic cystitis, a possible NK cell mediated immune reconstitution syndrome and post-transplant anti-glomerular basement membrane disease, the latter treated with cyclophosphamide and rituximab. At +450 days post-transplant he is in remission from his vasculitis and anti-glomerular basement membrane disease, and HHV-7 has remained undetectable. CONCLUSION: This is the second published description of joint disease in XLP, and only the fourth case of non-EBV associated cerebral vasculitis in XLP, as well as being the first to be successfully treated for this manifestation. This case raises specific questions about vasculitis in XLP, in particular the potential relevance of HHV-7 to the pathogenesis. PMID- 26433590 TI - Sleeve Gastrectomy Reduces Body Weight and Improves Metabolic Profile also in Obesity-Prone Rats. AB - BACKGROUND: Susceptibility to obesity is associated with a notable inter individual variation. The aim of the present study was to compare the effectiveness of sleeve gastrectomy (SG) on weight loss and metabolic profile in obesity-prone (OP) rats vs animals that are non-susceptible to obesity (NSO). METHODS: Young male Wistar rats (n = 101) were put in a diet-induced obesity (DIO) programme with ad libitum access to a high-fed diet (HFD) during 12 months. Body weight and food intake were regularly registered. Thereafter, rats were ranked by final body weight to identify the obesity-prone (OP) (n = 13) and non susceptible to obesity (NSO) (n = 14) animals. OP and NSO rats were submitted to surgical interventions (sham operation, SG and pair-fed to the amount of food eaten by sleeve-gastrectomized rats). Body weight, food intake, energy expenditure, body temperature, fat pads weight, and metabolic profiling were analysed 4 weeks after surgical or dietary interventions. RESULTS: SG in both OP and NSO rats decreased body weight as compared to sham and pair-fed groups (P < 0.05), mainly due to reductions in subcutaneous and perirenal fat mass (P < 0.001). Total weight loss achieved in sleeve-gastrectomized OP and NSO rats was higher than that of pair-fed ones (P < 0.05), showing that the SG effect goes beyond caloric restriction. In this regard, sleeve-gastrectomized rats exhibited significantly (P < 0.05) increased basal rectal temperature together with upregulated brown adipose tissue Ucp-1 protein expression levels. A significant (P < 0.05) improvement in insulin sensitivity was also observed in both OP and NSO animals that underwent SG as compared with pair-fed counterparts. CONCLUSION: Our findings provide the first evidence that obesity-prone rats also benefit from surgery responding effectively to SG, as evidenced by the significant body weight reduction and the metabolic profile improvement. PMID- 26433591 TI - Predictors of Excess Weight Loss in Obese Patients After Gastric Bypass: a 60 Month Follow-up. AB - BACKGROUND: The objective of this study was to analyze the factors associated with change in body mass index (BMI) and with percentage of excess weight loss (%EWL) in patients undergoing Roux-en-Y gastric bypass (RYGB). The following factors were analyzed: sex, age, surgical access (laparotomy vs. laparoscopy), preoperative BMI, waist circumference (WC), type 2 diabetes mellitus (T2DM), high blood pressure, and dyslipidemia. METHODS: Retrospective cohort study using a convenience sample of 2070 patients of both sexes, aged 18 to 65 years, undergoing RYGB between 2000 and 2013. The outcomes of interest were BMI and %EWL at 0, 6, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months after RYGB. RESULTS: After 36, 48, and 60 months, approximately 50 % of patients had BMI >30 kg/m(2). As for %EWL, 60-month results were poor for 17 % of patients (%EWL <50 %), good for 40 % of patients (%EWL 50-75 %), very good for 24 % of patients (%EWL from >75-90 %), and excellent for 19 % of patients (%EWL >90 %). The four most significant predictors of BMI change 60 months after RYGB (in descending order of magnitude) were preoperative BMI, preoperative WC, surgical access, and age; and of %EWL, surgical access, preoperative BMI, preoperative WC, and age. CONCLUSIONS: After 60 months of follow-up, the most relevant predictors of weight loss after RYGB were lower preoperative BMI and WC, videolaparoscopy as surgical access, and younger age. Further studies must be carried out to elucidate the impact of these factors on RYGB outcomes. PMID- 26433592 TI - Imaging approaches to assess the therapeutic response of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): current perspectives and future trends of an exciting field in development. AB - Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a family of neoplasms with a complex spectrum of clinical behavior. Although generally more indolent than carcinomas, once they progress beyond surgical resectability, they are essentially incurable. Systemic treatment options have substantially expanded in recent years for the management of advanced disease. Imaging plays a major role in new drug development, as it is the main tool used to objectively evaluate response to novel agents. However, current standard response criteria have proven suboptimal for the assessment of the antiproliferative effect of many targeted agents, particularly in the context of slow-growing tumors such as well differentiated NETs. The aims of this article are to discuss the advantages and limitations of conventional radiological techniques and standard response assessment criteria and to review novel imaging modalities in development as well as alternative cancer- and therapy-specific criteria to assess drug efficacy in the field of GEP-NETs. PMID- 26433593 TI - Systematic review of factors influencing extracellular vesicle yield from cell cultures. AB - The potential therapeutic utility of extracellular vesicles (EVs) has spawned an interest into a scalable production, where the quantity and purity of EV samples is sufficient for clinical applications. EVs can be isolated using several different protocols; however, these isolation protocols and the subsequent methods of quantifying the resulting EV yield have not been sufficiently standardized. Therefore, the possibility of comparing different studies with respect to these parameters is limited. In this review, we have presented factors that might influence the yield and function of EVs from cell culture supernatants. The methods of isolation, downstream quantification, and culture conditions of the EV producing cells have been discussed. In order to examine the inter-study coherency of EV yields, 259 studies were initially screened, and 46 studies were included for extensive downstream analysis of EV yields where information pertaining to the isolation protocols and quantification methods was obtained from each study. Several other factors influencing yield were compared, such as cell type producing EVs, cell confluence level, and cell stimulation. In conclusion, various factors may impact the resulting EV yield, including technical aspects such as EV isolation and quantification procedures, and biological aspects such as cell type and culture conditions. The reflections presented in this review might aid in future standardization of the workflow in EV research. PMID- 26433594 TI - A Cost-effectiveness Analysis of Surgery, Endothermal Ablation, Ultrasound-guided Foam Sclerotherapy and Compression Stockings for Symptomatic Varicose Veins. AB - OBJECTIVE: The aim was to investigate the cost-effectiveness of interventional treatment for varicose veins (VV) in the UK NHS, and to inform the national clinical guideline on VV, published by the National Institute of Health and Care Excellence. DESIGN: An economic analysis was constructed to compare the cost effectiveness of surgery, endothermal ablation (ETA), ultrasound-guided foam sclerotherapy (UGFS), and compression stockings (CS). The analysis was based on a Markov decision model, which was developed in consultation with members of the NICE guideline development group (GDG). METHODS: The model had a 5-year time horizon, and took the perspective of the UK National Health Service. Clinical inputs were based on a network meta-analysis (NMA), informed by a systematic review of the clinical literature. Outcomes were expressed as costs and quality adjusted life years (QALYs). RESULTS: All interventional treatments were found to be cost-effective compared with CS at a cost-effectiveness threshold of L20,000 per QALY gained. ETA was found to be the most cost-effective strategy overall, with an incremental cost-effectiveness ratio of L3,161 per QALY gained compared with UGFS. Surgery and CS were dominated by ETA. CONCLUSIONS: Interventional treatment for VV is cost-effective in the UK NHS. Specifically, based on current data, ETA is the most cost-effective treatment in people for whom it is suitable. The results of this research were used to inform recommendations within the NICE guideline on VV. PMID- 26433595 TI - Commentary on "Male Sex Associated With Increased Long-term Cardiovascular Mortality After Peripheral Vascular Surgery for Atherosclerosis Despite Optimal Medical Treatment". PMID- 26433596 TI - Plasma and Synovial Fluid CXCL12 Levels Are Correlated With Disease Severity in Patients With Knee Osteoarthritis. AB - BACKGROUND: The aim is to determine whether CXC chemokine ligand-12 (CXCL12) levels in plasma and synovial fluid (SF) of patients with knee osteoarthritis (OA) are correlated with the disease severity. In addition, we set out to investigate whether a peripheral blood test can avoid aspirating patients to determine CXCL12 levels. METHODS: This study consisted of 244 patients with knee OA and 244 age- and gender-matched healthy controls. Osteoarthritis progression was classified based on Kellgren-Lawrence (KL) by evaluating radiographic changes observed in anteroposterior knee radiography. The CXCL12 levels in the plasma and SF were measured by a quantitative sandwich enzyme-linked immunosorbent assay. RESULTS: Plasma CXCL12 levels were higher in OA patients as compared with controls (P < .0001). There was a positive correlation between levels of CXCL12 and grade (P < .0001). Base on the receiver operating characteristic curve, the optimal cutoff value of plasma CXCL12 levels as an indicator for screening of OA was estimated to be 5.5 ng/mL, which yielded a sensitivity of 78.4% and a specificity of 80.2%, with the area under the curve at 0.850 (95% confidence interval [CI], 0.816-0.889; P < .0001). In multivariate analysis, there was an increased risk of active OA associated with plasma CXCL12 levels >=10.5 ng/mL (odds ratio, 6.76; 95% CI, 3.88-12.53; P < .0001) after adjusting for possible confounders. Similarly, there was an increased risk of active OA associated with SF CXCL12 levels >=15.0 ng/mL (odds ratio, 8.45; 95% CI, 3.23-18.22; P < .0001) after adjusting for possible confounders. CONCLUSION: The CXCL12 levels in the plasma and SF may serve as effective biomarkers for the severity of OA. PMID- 26433597 TI - Load knowledge reduces rapid force production and muscle activation during maximal-effort concentric lifts. AB - PURPOSE: Rapid force development is a key factor influencing performance and injury risk in movements where little time is available for force production; thus there is a need to develop interventions that enhance this ability. In the present study, the influence of load knowledge on mechanical output [rate of force development; (RFD) and power] and muscle activation [electromyographic (EMG) responses] in the concentric-only bench press throw exercise was studied. METHODS: Fifteen strength-trained individuals performed 6 sets of 6 maximal explosive repetitions in a single test session after extensive familiarization. In three of these sets the subjects were given knowledge about the load before each repetition (known condition; KC), whereas in the other three sets they were given no information (unknown condition; UC). In both conditions the loads were 30, 50 and 70 % of maximum, but condition and load orders were randomized. RESULTS: RFD (24-50 %) and power output (20-39 %) were significantly higher in UC in the early time intervals from movement onset (<150 ms). In addition, UC elicited greater EMG amplitudes in anterior deltoid both prior to movement onset (pre50-0 ms) and in the early time intervals (<100 ms) after movement onset, and in pectoralis major after movement onset (<100 ms). CONCLUSIONS: UC resulted in a greater initial activation of the muscles and both a higher RFD and mechanical power output in the early phase of the movement under all loading conditions (30 70 % of maximum). UC appears to offer a novel neuromuscular stimulus, and further research on the effects of continued exposure is warranted. PMID- 26433598 TI - Influence of acute passive stretching on the oxygen uptake vs work rate slope during an incremental cycle test. AB - PURPOSE: The aim of the study was to investigate the effects of acute passive stretching on O2 uptake (VO2) vs work rate slope during a continuous incremental ramp exercise. METHODS: On two different occasions, eight participants (age 23 +/ 3 years; stature 1.71 +/- 0.10 m; body mass 68 +/- 8 kg; mean +/- SD) performed two maximum incremental ramp tests on a cycle ergometer (25 W/min), with and without pre-exercise stretching. During tests, we measured VO2 and other metabolic and cardiorespiratory parameters on a breath-by-breath basis. The VO2 vs work rate slopes were calculated below (S 1) and above (S 2) the first ventilatory threshold (VET1). RESULTS: With stretching: (1) peak VO2 did not change, while peak work rate decreased (P < 0.05, ES = -0.41; CI -1.40/-0.58); (2) in spite of a similar S 1, S 2 was steeper by about 11 % (P < 0.05; ES = 0.62; CI -0.38/-1.62). CONCLUSIONS: Stretching reduced peak work rate and altered the [Formula: see text] vs work rate relationship above VET1 (S 2), without affecting peak VO2. The present findings have practical implications, questioning the use of stretching manoeuvres especially when peak work rate plays a key role in exercise performance. PMID- 26433600 TI - The Production of High Purity Phycocyanin by Spirulina platensis Using Light Emitting Diodes Based Two-Stage Cultivation. AB - Phycocyanin is a photosynthetic pigment found in photosynthetic cyanobacteria, cryptophytes, and red algae. In general, production of phycocyanin depends mainly on the light conditions during the cultivation period, and purification of phycocyanin requires expensive and complex procedures. In this study, we propose a new two-stage cultivation method to maximize the quantitative content and purity of phycocyanin obtained from Spirulina platensis using red and blue light emitting diodes (LEDs) under different light intensities. In the first stage, Spirulina was cultured under a combination of red and blue LEDs to obtain the fast growth rate until reaching an absorbance of 1.4-1.6 at 680 nm. Next, blue LEDs were used to enhance the concentration and purity of the phycocyanin in Spirulina. Two weeks of the two-stage cultivation of Spirulina yielded 1.28 mg mL(-1) phycocyanin with the purity of 2.7 (OD620/OD280). PMID- 26433599 TI - Characteristics of Recombinant Phytase (rSt-Phy) of the Thermophilic mold Sporotrichum thermophile and its applicability in dephytinizing foods. AB - Sporotrichum thermophile produces very low titres of phytase (St-Phy) extracellularly, which is acidstable, thermostable, and protease insensitive with broad substrate specificity, and therefore, the gene encoding phytase (St-Phy) has been cloned and expressed in E. coli. The purified recombinant phytase (rSt Phy) has the molecular mass of 55 kDa with Km and Vmax (calcium phytate), kcat and kcat/Km of 0.143 mM, 185.05 nmoles mg(-1) s(-1), 5.1 * 10(3) s(-1), and 3.5 * 10(7) M(-1) s(-1), respectively. Mg(2+) and Ba(2+) display slight stimulatory effect on the enzyme, while it is inhibited by other ions to a varied extent. The enzyme is also inhibited by chaotropic agents (guanidinium hydrochloride, potassium iodide, and urea), Woodward's reagent K, and 2,3-butanedione but resistant to both pepsin and trypsin. The rSt-Phy is useful in dephytinization of tandoori and naan (unleavened flat Indian breads), and bread, liberating soluble inorganic phosphate that mitigates anti-nutrient effects of phytic acid. PMID- 26433601 TI - Enhanced 3beta,7alpha,15alpha-Trihydroxy-5-Androsten-17-One Production from Dehydroepiandrosterone by Colletotrichum lini ST-1 Resting Cells with Tween-80. AB - 7alpha,15alpha-diOH-DHEA is a key precursor of the novel oral contraceptive Yasmin. Colletotrichum lini could catalyze dehydroepiandrosterone (DHEA) at the 7alpha and 15alpha positions. In this work, C. lini resting cells were applied in the bioconversion of DHEA to 7alpha,15alpha-diOH-DHEA. In the presence of 2 % (w/v) Tween-80, the conversion efficiency of DHEA increased drastically. The DHEA conversion and the 7alpha,15alpha-diOH-DHEA yield increased by 34.6 and 87.0 %, respectively, at the DHEA concentration of 10 g/L. Furthermore, the effects of Tween-80 on substrate solubility and C. lini physiological properties were studied. Results showed that the DHEA solubility with 2 % Tween-80 increased by 7.8 times. Meanwhile, the mycelia were integrated and full in the presence of 2 % Tween-80. The analysis on fatty acid profile of the C. lini cell membrane indicated that Tween-80 increases the content of unsaturated fatty acid. All above results suggested that the enhanced product yield caused by Tween-80 was mainly associated with easier substrate-molecule transportation across the cell membrane of C. lini. PMID- 26433602 TI - Mixed Substrate Fermentation for Enhanced Phytase Production by Thermophilic Mould Sporotrichum thermophile and Its Application in Beneficiation of Poultry Feed. AB - The optimum values of the critical variables determined by the central composite design of response surface methodology (RSM) for maximum phytase production (1881.26 U g(-1) dry mouldy residue (DMR)) by Sporotrichum thermophile are 2.5 % Tween 80, 1.0 % yeast extract and 48 h of incubation period. Phytase production in the mixed substrate (sugarcane bagasse and wheat bran) fermentation enhanced 11.6-fold over the initial production as a consequence of optimization. Phytase titres are sustainable in flasks, trays and column bioreactor (1796 to 2095 U g( 1) DMR), thus validating the model and the process for large-scale phytase production. When the yeast extract was replaced with corn steep liquor (2 % w/v), a sustained enzyme titre (1890 U g(-1) DMR) was attained, making the process cost effective. Among all the detergents, Tween 80 supported a higher phytase production than others. The enzyme efficiently liberated nutritional components from poultry feed (inorganic phosphate, soluble protein and reducing sugars) in a time-dependent manner. PMID- 26433603 TI - Evaluation of the fate and transport of chlorinated ethenes in a complex groundwater system discharging to a stream in Wonju, Korea. AB - Chlorinated ethenes such as trichloroethylene (TCE) are common and persistent groundwater contaminants. If contaminated groundwater discharges to a stream, then stream water pollution near the contamination site also becomes a problem. In this respect, the fate and transport of chlorinated ethenes around a stream in an industrial complex were evaluated using the concentration of each component, and hydrogeochemical, microbial, and compound-specific carbon isotope data. Temporal and spatial monitoring reveal that a TCE plume originating from main and local source zones continues to be discharged to a stream. Groundwater geochemical data indicate that aerobic conditions prevail in the upgradient area of the studied aquifer, whereas conditions become anaerobic in the downgradient. The TCE molar fraction is high at the main and local source zones, ranging from 87.4 to 99.2% of the total volatile organic compounds (VOCs). An increasing trend in the molar fraction of cis-1, 2-Dichloroethene (cis-DCE) and vinyl chloride (VC) was observed in the downgradient zone of the study area. The enriched delta(13)C values of TCE and depleted values of cis-DCE in the stream zone, compared to those of the source zone, also suggest biodegradation of VOCs. Microbial community structures in monitoring wells adjacent to the stream zone in the downgradient area were analyzed using 16S rRNA gene-based pyrosequencing to identify the microorganisms responsible for biodegradation. This was attributed to the high relative abundance of dechlorinating bacteria in monitoring wells under anaerobic conditions farthest from the stream in the downgradient area. The multilateral approaches adopted in this study, combining hydrogeochemical and biomolecular methods with compound-specific analyses, indicate that contaminants around the stream were naturally attenuated by active anaerobic biotransformation processes. PMID- 26433604 TI - Laterality as an indicator of emotional stress in ewes and lambs during a separation test. AB - We assessed motor laterality in sheep to explore species-specific brain hemi field dominance and how this could be affected by genetic or developmental factors. Further, we investigated whether directionality and strength of laterality could be linked to emotional stress in ewes and their lambs during partial separation. Forty-three ewes and their singleton lambs were scored on the (left/right) direction of turn in a y-maze to rejoin a conspecific (laterality test). Further, their behavioural response (i.e. time spent near the fence, vocalisations, and activity level) during forced separation by an open-mesh fence was assessed (separation test). Individual laterality was recorded for 44.2% ewes (significant right bias) and 81.4% lambs (equally biased to the left and the right). There was no significant association in side bias between dams and offspring. The Chi-squared test revealed a significant population bias for both groups (p < 0.05). Evolutionary adaptive strategies or stimuli-related visual laterality may provide explanation for this decision-making process. Absolute strength of laterality (irrespective of side) was high (Kolmogorov-Smirnov test, dams: D = 0.2; p < 0.001; lambs: D = 0.36, p < 0.0001). The Wilcoxon test showed that lateralised lambs and dams spent significantly more time near each other during separation than non-lateralised animals (p < 0.05), and that lateralised dams were also more active than non-lateralised ones. Arguably, the lateralised animals showed a greater attraction to their pair because they were more disturbed and thus required greater reassurance. The data show that measures of laterality offer a potential novel non-invasive indicator of separation stress. PMID- 26433605 TI - The effects of intervention on quality of telephone triage at an emergency unit in Finland: Nurses' perspective. AB - AIMS AND OBJECTIVES: The aim of this study was to investigate the effects of a nurse training intervention on the assessment of patients' care needs in telephone triage at an emergency unit. The objective of this study was to generate information about nurse training that can be utilized when developing telephone triage and health care education. BACKGROUND: With the growing number of patients coming into emergency departments and a lack of resources in healthcare, it would be valuable to determine an effective training intervention in telephone triage, particularly when assessing the training needs of nurses. DESIGN: The study was quasi-experimental, with a pre- and post-test design. METHODS: The data were collected from the nurses at the emergency department and joint emergency service of the Central Hospital in Northern Finland (baseline n = 28, post-test n = 26). The descriptive statistic, Fisher's chi(2) test and McNemar's test were used to analyse the data. RESULTS: The intervention improved nurses' skills to evaluate patients' needs and health condition via the telephone triage. There was a statistically significant difference in the resources, knowledge, skills and attitudes of the nurses between the baseline and post-test measurements. CONCLUSIONS: The nurse training intervention improved the quality of telephone triage. RELEVANCE TO CLINICAL PRACTICE: Nurses should receive continuous training in telephone triage in order to maintain and reinforce their professional competence. When planning the training, the age and relevant work experience of the nurses should be taken into consideration as well, since the results indicate that they lead to variation in the nurses' competence. PMID- 26433606 TI - Age-dependent variation in innate immune responses to porcine epidemic diarrhea virus infection in suckling versus weaned pigs. AB - Porcine epidemic diarrhea (PED) is an enteric coronaviral infection that causes severe morbidity and mortality in suckling pigs, but less severe disease in older pigs. Consequently, it causes significant economic losses to the pork industry. There are limited studies on the innate immune responses to PED virus (PEDV) in pigs. The aims of our study were to investigate differences in innate immune responses to PEDV infection in suckling and weaned pigs and to examine if disease severity coincides with reduced innate immune responses. Weaned 26-day-old pigs (n=20) and 9-day-old nursing pigs (n=20) were assigned to PEDV inoculated or uninoculated control groups. The pigs were observed daily for clinical signs, virus shedding and were euthanized at post-inoculation days (PIDs) 1 and 5 to assay immune responses. Blood samples were collected at PIDs 1, 3 and 5. The natural killer (NK) cell frequencies, NK cell activities (lysis of target K562 tumor cells in vitro), CD3+CD4+ T cell and CD3+CD8+ T cell frequencies were measured in blood and ileum at PIDs 1 and 5. The PEDV infected suckling pigs showed severe diarrhea and vomiting at PID 1, whereas the PEDV infected weaned pigs showed milder clinical signs starting at PID 3. PEDV infected suckling pigs had significantly higher diarrhea scores, earlier fecal PEDV RNA shedding and significantly higher viremia (viral RNA in serum) compared to weaned pigs. There was no mortality in either infected suckling or infected weaned pigs. The control pigs not inoculated with PEDV did not show any clinical signs and no detectable fecal or serum PEDV RNA. Strikingly, PEDV infected suckling pigs had significantly lower NK cell frequencies, undetectable NK cell activity and lower IFNgamma producing NK cells in blood and ileum compared to PEDV infected weaned pigs. Pro-inflammatory cytokine profiles of PEDV infected suckling pigs differed from those of PEDV infected weaned pigs and coincided with onset of fecal PEDV RNA shedding and serum PEDV RNA titers. The infected suckling pigs have higher and earlier increases in serum IFNalpha, but lower serum IL-8 and TNFalpha levels compared to infected weaned pigs. CD3+CD4+ T cell frequencies were significantly higher in ileum of suckling pigs than in weaned pigs, whereas there was no difference in CD3+CD8+ T cell frequencies. In conclusion, the observations of impaired lytic activity and IFN-gamma production by NK cells in suckling pigs coincided with the increased severity of PEDV infection in the suckling pigs compared with the weaned pigs. PMID- 26433607 TI - Not an Aspirin: No Evidence for Acute Anti-Nociception to Laser-Evoked Pain After Motor Cortex rTMS in Healthy Humans. AB - BACKGROUND: High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has shown efficacy in relieving neuropathic pain. Whether its analgesic effect also applies to acute physiological nociception remains unclear due to previous contradictory findings. OBJECTIVE: To provide an in-depth investigation of the effects of motor cortex HF-rTMS on acute laser-evoked pain and excitability of nociceptive networks in healthy subjects. METHODS: Randomized, placebo controlled, double-blind, cross-over study in 20 healthy participants. Laser heat stimuli at nociceptive threshold were delivered to the right hand, allowing assessment of: (a) subjective pain intensity and unpleasantness; (b) laser-evoked potentials (LEPs, 128 electrodes) and their source model; (c) sympathetic skin responses, and (d) spino-thalamic pathway excitability. Data were collected before and 20 minutes after a session of neuro-navigated 20 Hz rTMS to the contralateral motor cortex. RESULTS: Subjective pain reports to thermal laser pulses, amplitude of late cortical potentials and sympathetic skin responses were decreased after cortical stimulation, to a similar extent whether it was active or placebo. Early cortical potentials and nociceptive network excitability remained identical before and after rTMS, as did anatomical sources of LEPs. CONCLUSIONS: Our results do not provide evidence for a genuine anti-nociceptive effect of rTMS on acute physiological pain. We suggest that motor cortex rTMS may act upon high-order networks linked to the emotional and cognitive appraisal of chronic pain, and/or modulate pathologically sensitized networks, rather than change the physiological transmission within an intact nervous system. Such dichotomy is reminiscent of that observed with most drugs used for neuropathic pain. PMID- 26433608 TI - Trigeminal Nerve Stimulation (TNS) for the Treatment of Irritable Bowel Syndrome in an Elderly Patient with Major Depressive Disorder: A Case Study. PMID- 26433609 TI - Transcranial Direct Current Stimulation Post-Stroke Upper Extremity Motor Recovery Studies Exhibit a Dose-Response Relationship. AB - BACKGROUND AND PURPOSE: Transcranial direct current stimulation (tDCS) has shown mixed results in post-stroke motor recovery, possibly because of tDCS dose differences. The purpose of this meta-analysis was to explore whether the outcome has a dose-response relationship with various dose-related parameters. METHODS: The literature was searched for double-blind, randomized, sham-controlled clinical trials investigating the role of tDCS (>=5 sessions) in post-stroke motor recovery as measured by the Fugl-Meyer Upper Extremity (FM-UE) scale. Improvements in FM-UE scores were compared between active and sham groups by calculating standardized mean differences (Hedge's g) to derive a summary effect size. Inverse-variance-weighted linear meta-regression across individual studies was performed between various tDCS parameters and Hedge's g to test for dose response relationships. RESULTS: Eight studies with total of 213 stroke subjects were included. Summary Hedge's g was statistically significant in favor of the active group (Hedge's g = 0.61, p = 0.02) suggesting moderate effect. Specifically, studies that used bihemispheric tDCS montage (Hedge's g = 1.30, p = 0.08) or that recruited chronic stroke patients (Hedge's g = 1.23, p = 0.02) showed large improvements in the active group. A positive dose-response relationship was found with current density (p = 0.017) and charge density (p = 0.004), but not with current amplitude. Moreover, a negative dose-response relationship was found with electrode size (p < 0.001, smaller electrodes were more effective). CONCLUSIONS: Our meta-analysis and meta-regression results suggest superior motor recovery in the active group when compared to the sham group and dose-response relationships relating to electrode size, charge density and current density. These results need to be confirmed in future dedicated studies. PMID- 26433610 TI - Alcohol Intoxication by Binge Drinking Impairs Neuroplasticity. AB - BACKGROUND: Binge drinking, resulting in acute alcohol intoxication, is considered an initial step in developing alcohol use disorders (AUDs). It has been suggested that alcohol intoxication may act on mechanisms of neuroplasticity to produce brain changes that contribute to the pathophysiology of AUDs. However, the effect of binge drinking on neuroplasticity has not been evaluated in humans. OBJECTIVE: The current study was aimed at evaluating the effect of a binge drinking episode on LTP-like neuroplasticity. METHODS: In a within-subject randomized, cross-over design, fifteen otherwise healthy binge drinkers were administered paired associative stimulation (PAS) following consumption of alcohol or a placebo beverage. PAS is an experimental paradigm that allows for the induction of associative long-term potentiation (LTP)-like neuroplasticity. Subjects were administered alcohol at a dose of 1.5 g/l of body water, producing a peak blood alcohol concentration (BAC) of 26.1 mM (0.120% BAC). PAS induced neuroplasticity was measured at Post 0 (immediately following PAS), Post 15 (15 minutes following PAS), Post 30 (30 minutes following PAS), Post 60 (60 minutes following PAS) and Post Day 1 (the next day following PAS). RESULTS: The binge drinking episode inhibited LTP-like neuroplasticity, which was significantly different from placebo at 30 and 60 min following the PAS administration. Examination of longitudinal effects revealed no differences between beverages on LTP-like neuroplasticity the following day. CONCLUSIONS: Findings suggest that binge drinking impairs neuroplasticity and while these effects are no longer evident the day after a single binge session, repetitive binging may produce long lasting changes in neuroplasticity that contribute to the development of AUDs. PMID- 26433611 TI - Implementation of a multidisciplinary clinical pathway for the management of postpartum hemorrhage: a retrospective study. AB - OBJECTIVE: To compare the outcomes of postpartum hemorrhage (PPH) episodes before and after the introduction of a clinical pathway known as the Severance Protocol to save postpartum bleeding through Expeditious care Delivery (SPEED). DESIGN: This study was designed as a retrospective analysis. SETTING: The study was conducted in a hospital implementing SPEED. PARTICIPANTS: The non-SPEED group included 74 patients with PPH who were treated before the introduction of SPEED, whereas the SPEED group included 155 patients. METHODS: Differences in outcomes were compared between groups. MAIN OUTCOME MEASURES: Reduction in treatment duration was the primary outcome measure, whereas uterus preservation was the secondary. RESULTS: No significant intergroup differences were observed for hemoglobin levels, hematocrit values and vital signs upon patients' emergency room arrival. The turnaround time for hemoglobin, mean duration until treatment by obstetricians and gynecologists and duration between chest radiography ordering and performance significantly differed between the two groups (SPEED, 10.0 [1.0-30.0], 3.0 [0-25.0] and 23.0 [1.0-86.0] min, respectively; non-SPEED, 17.0 [1.0-37.0], 12.0 [0-62.0] and 46.0 [1.0-580.0] min, respectively; P < 0.001). Similarly, the mean duration until transfusion of cross-matched red blood cells (SPEED, 77.6 +/- 58.6 min; non-SPEED, 103.4 +/- 64.4 min; P = 0.015) and uterus preservation rate (SPEED, 90.1% [136/151]; non-SPEED, 81.7% [58/71]; P = 0.043) also differed significantly between the groups. CONCLUSIONS: Clinical pathways enable prompt and efficient care for patients experiencing PPH through faster evaluation and access to red blood cell transfusion, resulting in a decrease in maternal mortality. PMID- 26433612 TI - Estimating DNA methylation levels by joint modeling of multiple methylation profiles from microarray data. AB - DNA methylation studies have been revolutionized by the recent development of high throughput array-based platforms. Most of the existing methods analyze microarray methylation data on a probe-by-probe basis, ignoring probe-specific effects and correlations among methylation levels at neighboring genomic locations. These methods can potentially miss functionally relevant findings associated with genomic regions. In this article, we propose a statistical model that allows us to pool information on the same probe across multiple samples to estimate the probe affinity effect, and to borrow strength from the neighboring probe sites to better estimate the methylation values. Using a simulation study, we demonstrate that our method can provide accurate model-based estimates. We further use the proposed method to develop a new procedure for detecting differentially methylated regions, and compare it with a state-of-the-art approach via a data application. PMID- 26433613 TI - The R900S mutation in CACNA1S associated with hypokalemic periodic paralysis. AB - Primary hypokalemic periodic paralysis is an autosomal dominant skeletal muscle channelopathy. In the present study, we investigated the genotype and phenotype of a Chinese hypokalemic periodic paralysis family. We used whole-exome next generation sequencing to identify a mutation in the calcium channel, voltage dependent, L type, alpha subunit gene (CACNA1S), R900S, which is a rare mutation associated with hypokalemic periodic paralysis. We first present a clinical description of hypokalemic periodic paralysis patients harboring CACNA1SR900S mutations: they were non-responsive to acetazolamide, but combined treatment with triamterene and potassium supplements decreased the frequency of muscle weakness attacks. All male carriers of the R900S mutation experienced such attacks, but all three female carriers were asymptomatic. This study provides further evidence for the phenotypic variation and pharmacogenomics of hypokalemic periodic paralysis. PMID- 26433615 TI - A bifurcation identifier for IV-OCT using orthogonal least squares and supervised machine learning. AB - Intravascular optical coherence tomography (IV-OCT) is an in-vivo imaging modality based on the intravascular introduction of a catheter which provides a view of the inner wall of blood vessels with a spatial resolution of 10-20 MUm. Recent studies in IV-OCT have demonstrated the importance of the bifurcation regions. Therefore, the development of an automated tool to classify hundreds of coronary OCT frames as bifurcation or nonbifurcation can be an important step to improve automated methods for atherosclerotic plaques quantification, stent analysis and co-registration between different modalities. This paper describes a fully automated method to identify IV-OCT frames in bifurcation regions. The method is divided into lumen detection; feature extraction; and classification, providing a lumen area quantification, geometrical features of the cross sectional lumen and labeled slices. This classification method is a combination of supervised machine learning algorithms and feature selection using orthogonal least squares methods. Training and tests were performed in sets with a maximum of 1460 human coronary OCT frames. The lumen segmentation achieved a mean difference of lumen area of 0.11 mm(2) compared with manual segmentation, and the AdaBoost classifier presented the best result reaching a F-measure score of 97.5% using 104 features. PMID- 26433614 TI - Robust anatomical landmark detection with application to MR brain image registration. AB - Comparison of human brain MR images is often challenged by large inter-subject structural variability. To determine correspondences between MR brain images, most existing methods typically perform a local neighborhood search, based on certain morphological features. They are limited in two aspects: (1) pre-defined morphological features often have limited power in characterizing brain structures, thus leading to inaccurate correspondence detection, and (2) correspondence matching is often restricted within local small neighborhoods and fails to cater to images with large anatomical difference. To address these limitations, we propose a novel method to detect distinctive landmarks for effective correspondence matching. Specifically, we first annotate a group of landmarks in a large set of training MR brain images. Then, we use regression forest to simultaneously learn (1) the optimal sets of features to best characterize each landmark and (2) the non-linear mappings from the local patch appearances of image points to their 3D displacements towards each landmark. The learned regression forests are used as landmark detectors to predict the locations of these landmarks in new images. Because each detector is learned based on features that best distinguish the landmark from other points and also landmark detection is performed in the entire image domain, our method can address the limitations in conventional methods. The deformation field estimated based on the alignment of these detected landmarks can then be used as initialization for image registration. Experimental results show that our method is capable of providing good initialization even for the images with large deformation difference, thus improving registration accuracy. PMID- 26433616 TI - Synthesis and pharmacological evaluation of some new fluorine containing hydroxypyrazolines as potential anticancer and antioxidant agents. AB - Breast cancer is probably the most prevalent cancer in women. The development of resistance to therapeutic agents and lack of targeted therapy for breast cancer cells provide motivation to identify new compounds for the treatment. With this objective in mind, a new series of 3-fluoro-4-methoxyphenyl group based 1,3,5 trisubstituted aryl-5-hydroxypyrazoline analogues 4a-l was synthesized through multi-step reaction sequence. The structures of the newly synthesized compounds were confirmed by IR, (1)H NMR, (13)C NMR, LC-MS and elemental analysis. They were screened for their in vitro anticancer and in vitro antioxidant activities. Among the tested compounds 4h, 4c and particularly 4i displayed promising cytotoxic effect on breast cancer cell lines. The compounds were also found to possess antioxidant activity when tested against DPPH free radical. Overall, this work has contributed to the development of promising leads for anticancer and antioxidant activities. PMID- 26433617 TI - alpha-Halogenated oxaphosphinanes: Synthesis, unexpected reactions and evaluation as inhibitors of cancer cell proliferation. AB - This paper describes the preparation and the biological evaluation of alpha halogenated oxaphosphinanes. These halogen derivatives were synthetized from a short and stereoselective synthetic sequence starting by previously described hydroxy-precursors 1 and 2 with respectively a glucose and mannose-like configuration. The in vitro biological tests of these unnatural halogenated phosphinosugars, on several cell lines, highlighted, for some of them, their antiproliferative and anti migration and invasion properties at nanomolar concentration. PMID- 26433618 TI - Antiproliferative, DNA intercalation and redox cycling activities of dioxonaphtho[2,3-d]imidazolium analogs of YM155: A structure-activity relationship study. AB - The anticancer agent YM155 is widely investigated as a specific survivin suppressant. More recently, YM155 was found to induce DNA damage and this has raised doubts as to whether survivin is its primary target. In an effort to assess the contribution of DNA damage to the anticancer activity of YM155, several analogs were prepared and evaluated for antiproliferative activity on malignant cells, participation in DNA intercalation and free radical generation by redox cycling. The intact positively charged scaffold was found to be essential for antiproliferative activity and intercalation but was less critical for redox cycling where the minimal requirement was a pared down bicyclic quinone. Side chain requirements at the N(1) and N(3) positions of the scaffold were more alike for redox cycling and intercalation than antiproliferative activity, underscoring yet again, the limited structural overlaps for these activities. Furthermore, antiproliferative activities were poorly correlated to DNA intercalation and redox cycling. Potent antiproliferative activity (IC50 9-23 nM), exceeding that of YM155, was found for a minimally substituted methyl analog AB7. Like YM155 and other dioxonaphthoimidazoliums, AB7 was a modest DNA intercalator but with weak redox cycling activity. Thus, the capacity of this scaffold to inflict direct DNA damage leading to cell death may not be significant and YM155 should not be routinely classified as a DNA damaging agent. PMID- 26433620 TI - Application of genome editing technologies to the study and treatment of hematological disease. AB - Genome editing technologies have advanced significantly over the past few years, providing a fast and effective tool to precisely manipulate the genome at specific locations. The three commonly used genome editing technologies are Zinc Finger Nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs), and the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated Cas9 (CRISPR/Cas9) system. ZFNs and TALENs consist of endonucleases fused to a DNA-binding domain, while the CRISPR/Cas9 system uses guide RNAs to target the bacterial Cas9 endonuclease to the desired genomic location. The double-strand breaks made by these endonucleases are repaired in the cells either by non-homologous end joining, resulting in the introduction of insertions/deletions, or, if a repair template is provided, by homology directed repair. The ZFNs, TALENs and CRISPR/Cas9 systems take advantage of these repair mechanisms for targeted genome modification and have been successfully used to manipulate the genome in human cells. These genome editing tools can be used to investigate gene function, to discover new therapeutic targets, and to develop disease models. Moreover, these genome editing technologies have great potential in gene therapy. Here, we review the latest advances in the application of genome editing technology to the study and treatment of hematological disorders. PMID- 26433619 TI - Faecal microbiota transplantation in recurrent Clostridium difficile infection: Recommendations from the French Group of Faecal microbiota Transplantation. AB - Faecal microbiota transplantation is effective for treating recurrent forms of Clostridium difficile infection and its use in this indication is recommended in the most recent European and North American guidelines. In this context, faecal microbiota transplantation is beginning to be performed in France in clinical practice, while the rules governing this procedure have been defined in France only for clinical trials. To unify, secure, and evaluate practice in this field in France, the French Group of Faecal microbiota Transplantation (FGFT) was created in October 2014 with the support of the French National Society of Gastroenterology, the French Infectious Disease Society, and the National Academy of Pharmacy. We present here the deliberations of this group regarding the use of faecal microbiota transplantation for recurrent Clostridium difficile infection. The issues addressed are the indications, therapeutic sequence, delivery procedures, donor selection, methods and conditions of specimen preparation, and traceability. PMID- 26433621 TI - Response to Commentary: 'Retrospective study of the association between epidural analgesia during labour and complications for the newborn'. Authors: Herrera Gomez A, MsC; Garcia-Martinez O, PhD; Ramos-Torrecillas J, PhD; De Luna-Bertos E, PhD; Ruiz C, PhD; Ocana-Peinado FM, PhD. PMID- 26433622 TI - Women's help-seeking behaviours for depressive symptoms during the perinatal period: Socio-demographic and clinical correlates and perceived barriers to seeking professional help. AB - OBJECTIVE: This study aims to characterize the help-seeking behaviours of women who were screened positive for perinatal depression, to investigate its sociodemographic and clinical correlates, and to characterize the perceived barriers that prevent women from seeking professional help. DESIGN: Cross sectional internet survey. SETTING: Participants were recruited through advertisements published in pamphlets and posted on social media websites (e.g., Facebook) and websites and forums that focused on pregnancy and childbirth. PARTICIPANTS: 656 women (currently pregnant or who had a baby during the last 12 months) completed the survey. MEASUREMENTS: Participants were assessed with the Edinburgh Postpartum Depression Scale, and were questioned about sociodemographic and clinical data, help-seeking behaviours and perceived barriers to help seeking. FINDINGS: Different pathways of help-seeking were found, with only 13.6% of women with a perinatal depression seeking help for their emotional problems. Married women, currently pregnant women, and women without history of psychological problems had a higher likelihood of not engaging in any type of help-seeking behaviour. The majority of women who had not sought professional assistance identified several barriers to help-seeking, particularly knowledge barriers. KEY CONCLUSIONS: Strategies to increase women's help-seeking behaviours should be implemented, namely improving mental health literacy, introducing screening procedures for mental health problems in pre/postnatal health care settings, and offering women innovative opportunities (e.g., web-based tools) that allow them to overcome the practical barriers to help-seeking. PMID- 26433624 TI - Magnetic resonance imaging in the assessment of anomalous pulmonary venous connections. AB - OBJECTIVE: To illustrate the morphological and functional magnetic resonance findings for total and partial anomalous pulmonary venous connections as well as of the most common complications after surgery. CONCLUSION: The magnetic resonance findings are fundamental in defining the type of anomalous connection, deciding on the treatment, planning the surgery, and detecting postsurgical complications. PMID- 26433623 TI - [Imaging findings in cardiac masses. Part II: malignant tumors and pseudotumors]. AB - Malignant heart tumors are less common than benign ones. They can be primary or secondary. Secondary or metastatic heart tumors are 20 to 40 times more common than primary malignant heart tumors, which have an estimated incidence of 0.05%. Non-neoplastic pseudotumors can present as cardiac masses, with imaging characteristics than can suggest the diagnosis of a tumor. The aim of this article is to describe and illustrate malignant heart tumors and pseudotumors, stressing the CT and MRI findings that make it possible to differentiate them from benign cardiac tumors. PMID- 26433625 TI - Triple-negative breast carcinoma: heterogeneity in immunophenotypes and pharmacokinetic behavior. AB - OBJECTIVES: To evaluate the morphokinetic, pharmacokinetic, and diffusion characteristics of triple-negative breast cancers on magnetic resonance (MR) imaging and to analyze whether there is a relation between these parameters and the time to progression. MATERIAL AND METHODS: This was a retrospective observational study of a consecutive series of 100 patients with histologically confirmed triple-negative breast cancer studied at our center between January 2005 and December 2010. We reviewed the findings on MR locoregional extension studies, the histological findings, and the follow-up of patients until August 2014. RESULTS: The most common MR findings for these tumors were a rounded mass (47.3%), well-defined borders (53.7%), ring enhancement (46.2%), type 3 curves (50.5%), hyperintensity within the tumor on T2-weighted sequences, high ADC values (1.04 * 10(-3) mm2/s), and increased capillary permeability (Kep) (0.94 min(-1)). No significant association was observed between the morphokinetic or pharmacokinetic characteristics and the time to progression. The in situ component in the surgical specimens was high, although its expression was low. During follow-up, 25% of patients had metastases, with a predilection for the visceral organs, and survival was low. CONCLUSION: Tumors with the triple negative phenotype mostly presented in MR as rounded tumors with well-defined borders and ring enhancement. We found no significant association between the morphokinetic or pharmacokinetic characteristics and the time to progression. PMID- 26433626 TI - Interim (18)F-Fluorodeoxyglucose Positron Emission Tomography for Early Metabolic Assessment of Response to Cisplatin, Etoposide, and Bleomycin Chemotherapy for Metastatic Seminoma: Clinical Value and Future Directions. AB - BACKGROUND: In patients with metastatic seminoma, designing a risk-adapted strategy that may help personalize the burden of treatment and follow-up is required. PATIENTS AND METHODS: Patients who were administered cisplatin, etoposide, and bleomycin (PEB) were staged at baseline with computed tomography (CT), positron emission tomography (PET), and serum tumor markers. Restaging was then performed with PET after 2 cycles of PEB (PET2) and with CT after 3 to 4 cycles of treatment. The 20% cutoff of maximal standardized uptake value (SUVmax) changes and Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) criteria were applied to define the response. The Wilcoxon rank sum test was used to analyze the association between metabolic response and the shrinkage of target lesions. RESULTS: Between February 2009 and November 2013, 37 patients were enrolled. After 2 cycles of PEB, 27 patients (72.9%; 95% confidence interval [CI], 55.8-86.2) had a metabolic complete response (CR) and 10 patients had a partial response (PR; 27%; 95% CI, 13.8-44.1). A significant association was found between PET2 response and baseline (P = .003), final diameter (P < .001), and percentage of tumor shrinkage (P = .014) of target lesions. After 18 months' (interquartile range [IQR], 13-23) median follow-up, 2 patients with PET2 PR had relapsed disease; none of those with a CR had relapsed disease. CONCLUSIONS: A significant association was found between early metabolic response and tumor shrinkage in patients with advanced seminoma. Patients achieving a PET2 CR could be predicted not to need additional treatment after PEB, and simplifying their follow-up should be an end point. PET2 might also identify difficult to treat cases at an early stage. PMID- 26433628 TI - Vaccine monitoring systems: A potential model for medications in pregnancy. AB - Multiple vaccine safety systems contribute to monitor and assess the safety of vaccines given to pregnant women and their offspring. This article presents a review of the strengths and limitations of several national vaccine safety systems. The review concludes that the present framework of vaccine safety systems offers lessons to be learned toward the design of a system for monitoring and assessing the safety of medications administered to pregnant women in clinical practice and research. PMID- 26433627 TI - Effective and Safe Administration of Low-Dose Estramustine Phosphate for Castration-Resistant Prostate Cancer. AB - Despite the favorable toxicity profile at the standard dose of 560 mg daily, the tolerability and toxicology of estramustine phosphate (EMP) have been a cause for concern at administration. Moreover, we do not know whether a lower dose of 280 mg of EMP daily can be administered with some efficacy and fewer side effects. The results of our phase II study suggest that low-dose EMP is a safe treatment option with the same efficacy in patients with castration-resistant prostate cancer. BACKGROUND: We evaluated the efficacy and safety of low-dose estramustine phosphate (EMP) in Japanese patients with castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: The present study was a single-arm, nonrandomized prospective study in which all patients received EMP orally twice daily for a total dose of 280 mg/day. A total of 31 patients with CRPC were enrolled from December 2009 to December 2012 at 5 institutions in Japan. The primary endpoint was the prostate-specific antigen (PSA) response, defined as a 50% decline in the serum PSA level, confirmed >= 3 weeks later. The secondary endpoints included the objective response rate, interval to PSA progression, PSA response duration, progression-free survival, disease-specific survival, overall survival, safety, and quality-of-life assessment using the Functional Assessment of Cancer Therapy Prostate scores. RESULTS: Ten patients (32%) had a PSA response, and no patient had an objective response. The treatment was well tolerated, and the most frequent toxicities were grade 1 to 2 nausea/vomiting, anorexia, and gynecomastia. The median interval to PSA progression was 140 days (95% confidence interval [CI], 117-260 days). The PSA response duration was 119 days (95% CI, 49 219 days). The median progression-free survival was 213 days (95% CI, 167-422 days). The 3-year disease-specific survival and overall survival rates were 68.6% (median not reached; 95% CI, 33 months to not available) and 59.9% (median 42 months, 95% CI, 28 months to not available), respectively. CONCLUSION: Low-dose EMP seems to be a safe treatment option with some efficacy in patients with CRPC. PMID- 26433629 TI - Geographical variation in relative risks associated with heat: Update of Spain's Heat Wave Prevention Plan. AB - A decade after the implementation of prevention plans designed to minimise the impact of high temperatures on health, some countries have decided to update these plans in order to improve the weakness detected in these ten years of operation. In the case of Spain, this update has fundamentally consisted of changing the so-called "threshold" or "trigger" temperatures used to activate the plan, by switching from temperature values based on climatological criteria to others obtained by epidemiological studies conducted on a provincial scale. This study reports the results of these "trigger" temperatures for each of Spain's 52 provincial capitals, as well as the impact of heat on mortality by reference to the relative risks (RRs) and attributable risks (ARs) calculated for natural as well as circulatory and respiratory causes. The results obtained for threshold temperatures and RRs show a more uniform behaviour pattern than those obtained using temperature values based on climatological criteria; plus a clear decrease in RRs of heat-associated mortality due to the three causes considered, at both a provincial and regional level as well as for Spain as a whole. The updating of prevention plans is regarded as crucial for optimising the operation of these plans in terms of reducing the effect of high temperatures on population health. PMID- 26433630 TI - Design, synthesis and antibacterial study of new potent and selective coumarin chalcone derivatives for the treatment of tenacibaculosis. AB - With the aim of finding new chemical entities selective for fish pathogens to avoid drug resistance in humans, a series of coumarin-chalcone hybrid compounds with different patterns of substitution were designed and synthesized. Their antibacterial activity was evaluated against important types of human bacteria strains (Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa) and against a fourteen strains of the marine pathogen Tenacibaculum maritimum, responsible for tenacibaculosis in fish, which is an important disease that causes great economical loss in the aquaculture industry. All the amino derivatives 5-12 presented high activity against different strains of T. maritimum, no activity against any of the three human pathogenic bacteria strains and no toxicity. Compounds 6, 7 and 11 were the most promising molecules. The most sensitive strains to these compounds were LL01 8.3.8 and LL01 8.3.1, being compound 11 up to 20 times more active than enrofloxacin. Therefore these scaffolds are good candidates for aquaculture treatments, avoiding possible drug resistance problems in humans. PMID- 26433631 TI - Antihyperlipidemic morpholine derivatives with antioxidant activity: An investigation of the aromatic substitution. AB - Drugs affecting more than one target could result in a more efficient treatment of multifactorial diseases as well as fewer safety concerns, compared to a one drug one-target approach. Within our continued efforts towards the design of multifunctional molecules against atherosclerosis, we hereby report the synthesis of 17 new morpholine derivatives which structurally vary in terms of the aromatic substitution on the morpholine ring. These derivatives simultaneously suppress cholesterol biosynthesis through SQS inhibition (IC50 values of the most active compounds are between 0.7 and 5.5 MUM) while exhibiting a significant protection of hepatic microsomal membranes against lipid peroxidation (with IC50 values for the most active compounds being between 73 and 200 MUM). Further evaluation of these compounds was accomplished in vivo in an animal model of acute experimental hyperlipidemia, where it was observed that compounds reduced the examined lipidemic parameters (TC, TG and LDL) by 15-80%. In order to examine the mode of binding of these molecules in the active catalytic site of SQS, we also performed docking simulation studies. Our results indicate that some of the new compounds can be considered interesting structures in the search for new multifunctional agents of potential application in atherosclerosis. PMID- 26433632 TI - Still shimming or already measuring?--Quantitative reaction monitoring for small molecules on the sub minute timescale by NMR. AB - In order to enable monitoring of rapidly occurring reactions Wagner et al. recently presented a simple scheme for 1D NMR experiments with continuous data acquisition, without inter-scan delays, using a spatially-selective and frequency shifted excitation approach (Wagner et al., 2013). This scheme allows acquisition of proton spectra with temporal resolutions on the millisecond timescale. Such high temporal resolutions are desired in the case of reaction monitoring using stopped flow setups. In regular (1)H NMR-spectra without spatial selection the line width increases for a given shim setting with changes in sample volume, susceptibility, convection and temperature or concentration gradients due to the disturbance of magnetic field homogeneity. Concerning reaction monitoring this is unfortunate as shimming prior to acquisition becomes necessary to obtain narrow signals after injection of a reactant into an NMR sample. Even automatic shim routines may last up to minutes. Thus fast reactions can hardly be monitored online without large hardware dead times in a single stopped flow experiment. This problem is reduced in the spatially-selective and frequency-shifted continuous NMR experiment as magnetic field inhomogeneties are less pronounced and negative effects on the obtained line shapes are reduced as pointed out by Bax and Freeman (1980) [2] and demonstrated by Wagner et al. (2013). Here we present the utilization of this technique for observation of reactions in small molecule systems in which chemical conversion and longitudinal relaxation occur on the same timescale. By means of the alkaline ethyl acetate hydrolysis, a stoichiometric reaction, we show advantages of spatially-selective excitation on both temporal resolution and line shapes in stopped flow experiments. Results are compared to data obtained by non-selective small angle excitation experiments. PMID- 26433633 TI - Off-pump coronary artery bypass grafting improves short-term outcomes in high risk patients compared with on-pump coronary artery bypass grafting: Meta analysis. AB - OBJECTIVES: To assess the benefits and risks of off-pump coronary artery bypass (OPCAB) versus coronary artery bypass grafting (CABG) through a meta-analysis of randomized controlled trials (RCTs), and to investigate the relationship between outcomes and patient risk profile. METHODS: PubMed, Embase, the Cumulative Index of Nursing and Allied Health Literature, Scopus, Web of Science, Cochrane Library, and major conference proceedings databases were searched for RCTs comparing OPCAB and CABG and reporting short-term (<= 30 days) outcomes. Endpoints assessed were all-cause mortality, myocardial infarction (MI), and cerebral stroke. RESULTS: The meta-analysis included 100 studies, with a total of 19,192 subjects. There was no difference between the 2 techniques with respect to all-cause mortality and MI (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.71-1.09; P = .25; I(2) = 0% and OR, 0.90; 95% CI, 0.77-1.05; P = .19; I(2) = 0%, respectively). OPCAB was associated with a significant 28% reduction in the odds of cerebral stroke (OR, 0.72; 95% CI, 0.56-0.92; P = .009; I(2) = 0%). A significant relationship between patient risk profile and benefits from OPCAB was found in terms of all-cause mortality (P < .01), MI (P < .01), and cerebral stroke (P < .01). CONCLUSIONS: OPCAB is associated with a significant reduction in the odds of cerebral stroke compared with conventional CABG. In addition, benefits of OPCAB in terms of death, MI, and cerebral stroke are significantly related to patient risk profile, suggesting that OPCAB should be strongly considered in high-risk patients. PMID- 26433634 TI - Discussion. PMID- 26433635 TI - Prophylactic stage 1 elephant trunk for moderately dilated descending aorta in patients with predominantly proximal disease. AB - OBJECTIVE: Staged elephant trunk (ET) repair is a commonly performed procedure for extensive aortic disease. A significant proportion of patients with predominantly proximal aortic pathology often have in addition a moderately dilated descending aorta (<5 cm) that can progress over time. Objectives were to characterize patients, determine completion rate after prophylactic stage 1 ET, and assess outcomes. METHODS: From 1992 to 2012, a total of 572 patients underwent stage 1 ET for degenerative aneurysm and dissection at Cleveland Clinic. Prophylactic stage 1 ET was performed in 117 (20.5%) who had predominantly proximal disease (5.5 +/- 1 cm) with moderate dilation of the descending aorta (4 +/- 0.6 cm). Aortic pathology included: aneurysm (n = 56 [48%]); chronic dissection (n = 41 [35%]); pseudoaneurysm (n = 9 [7.7%]); penetrating ulcer (n = 9 [7.7%]); and intramural hematoma (n = 2 [1.7%]). Other diagnoses included connective tissue disorder (12 [10%]); aortitis (20 [17%]); bicuspid aortic valve (9 [7.6%]); and previous type A dissection repair (27 [23%]). RESULTS: Operative mortality was 0.8% (1 of 117). This patient suffered postoperative myocardial infarction and mesenteric ischemia, resulting in sepsis and death. Other complications included: stroke (n = 7 [6%]); tracheostomy (n = 6 [5%]); renal dialysis (n = 4 [3.3%]); and reoperation for bleeding (n = 7 [6%]). The mean follow-up time was 4 +/- 3 years. Fifty-three (45%) patients completed the stage 2 ET (open: 20 [38%]; endovascular: 33 [62%]) at a median interval of 6 months (9 days-10 years). The mean descending diameter increased from 4.1 +/- 0.6 cm to 5 +/- 1 cm at the time of stage 2 completion. In 11 patients, stage 2 was performed for acute aortic events. Estimated survival at 1, 5, and 8 years was 94%, 88%, and 74%, respectively. CONCLUSIONS: Prophylactic ET for moderately dilated descending aorta is an effective strategy for staged repair, especially in patients with chronic dissection, connective tissue disorder, and aortitis. In addition, this approach can be beneficial for emergency treatment of late distal aortic complications. PMID- 26433636 TI - Light response and potential interacting proteins of a grape flavonoid 3' hydroxylase gene promoter. AB - Flavonoid 3'-hydroxylase (F3'H), a member of cytochrome P450 protein family, introduces B-ring hydroxyl group in the 3' position of the flavonoid. In this study, the cDNA sequence of a F3'H gene (VviF3'H), which contains an open reading frame of 1530 bp encoding a polypeptide of 509 amino acids, was cloned and characterized from Vitis vinifera L. cv. Cabernet Sauvignon. VviF3'H showed high homology to known F3'H genes, especially F3'Hs from the V. vinifera reference genome (Pinot Noir) and lotus. Expression profiling analysis using real-time PCR revealed that VviF3'H was ubiquitously expressed in all tested tissues including berries, leaves, flowers, roots, stems and tendrils, suggesting its important physiological role in plant growth and development. Moreover, the transcript level of VviF3'H gene in grape berries was relatively higher at early developmental stages and gradually decreased during veraison, and then increased in the mature phase. In addition, the promoter of VviF3'H was isolated by using TAIL-PCR. Yeast one-hybrid screening of the Cabernet Sauvignon cDNA library and subsequent in vivo/vitro validations revealed the interaction between VviF3'H promoter and several transcription factors, including members of HD-Zip, NAC, MYB and EIN families. A transcriptional regulation mechanism of VviF3'H expression is proposed for the first time. PMID- 26433637 TI - The effect of cryptogein with changed abilities to transfer sterols and altered charge distribution on extracellular alkalinization, ROS and NO generation, lipid peroxidation and LOX gene transcription in Nicotiana tabacum. AB - Cryptogein, a protein from oomycete Phytophthora cryptogea, induces a hypersensitive cell death in Nicotiana tabacum. We prepared a new series of cryptogein mutant proteins with altered abilities to bind sterols and with altered charge distribution in the proteins. The effect of the mutations on the cryptogein ability to induce plant defence mechanisms associated with hypersensitive cell death were examined. Our results with new mutants support the previous findings that the sterol binding does not influence synthesis of ROS, cytosol acidification and development of leaf necrosis as these events seem to be more likely affected by the charge distribution and the overall protein structure. This hypothesis was also applicable on other mechanisms involved in the execution of plant cell death such as the NO generation, the stimulation of lipid peroxidation (determination of malondialdehyde and hydroxy fatty acids levels) and LOX gene transcription. In addition, the ability to bind sterols was found to serve not only for pathogen utilisation in its own metabolism but also to have an important function for the destabilization of plant membrane facilitating the pathogen spread inside the plant tissue as well as intensively contributing to the development of plant cell death. Considering the insertion of charged amino acid residues in the protein structure, the change localized in the protein surface affected its biological activity more effectively than that change inside the protein cavity. Moreover, the insertion of negative charged amino acids influenced mainly the events involved in the early phase of defence reaction, while the positive residues affected especially the necrotic activity of cryptogein. PMID- 26433638 TI - Visual field asymmetries in object individuation. AB - Repetition blindness (RB) is a failure to detect both instances of two identical stimuli presented in close temporal proximity. It is due to an inability to form separate episodic tokens for a repeated stimulus, resulting in a single conscious representation. In three experiments, participants identified two targets presented simultaneously in different spatial locations. These stimuli were either the same or different. In two experiments the targets occurred on either side of fixation, and in a third experiment both were in the same hemifield. In all experiments, RB was more pronounced for stimuli in the right hemifield. In addition, there was a left hemifield advantage for both repeated and non-repeated stimuli when the two stimuli occurred in opposite visual fields and, thus, were processed by different hemispheres. These findings suggest that the right hemisphere plays a dominant role in attentional selection and in creating conscious representations of visual events. PMID- 26433639 TI - Turning I into me: Imagining your future self. AB - A widely endorsed belief is that perceivers imagine their present selves using a different representational format than imagining their future selves (i.e., near future=first-person; distant future=third-person). But is this really the case? Responding to the paucity of work on this topic, here we considered how temporal distance influences the extent to which individuals direct their attention outward or inward during a brief imaginary episode. Using a non-verbal measure of visual perspective taking (i.e., letter-drawing task) our results confirmed the hypothesized relation between temporal distance and conceptions of the self. Whereas simulations of an event in the near future were dominated by a first person representation of the self, this switched to a third-person depiction when the event was located in the distant future. Critically, this switch in vantage point was restricted to self-related simulations. The theoretical and practical implications of these findings are considered. PMID- 26433640 TI - Reply to: Assessment of pouch and stoma size in weight loss failure after Roux-en Y gastric bypass. PMID- 26433641 TI - Internal hernia after revisional laparoscopic loop duodenal switch surgery. PMID- 26433642 TI - Lengthening of the biliopancreatic limb is a key step during revisional Roux-en-Y gastric bypass for weight regain and diabetes recurrence. PMID- 26433643 TI - Comment on: Comprehensive evaluation of the effect of bariatric surgery on pelvic floor disorders. PMID- 26433644 TI - Water-insoluble sericin/beta-cyclodextrin/PVA composite electrospun nanofibers as effective adsorbents towards methylene blue. AB - A novel water-insoluble sericin/beta-cyclodextrin/poly (vinyl alcohol) composite nanofiber adsorbent was prepared by electrospinning and followed by thermal crosslinking for removal of cationic dye methylene blue from aqueous solution. Fourier transform infrared spectroscopy and solubility experiments confirmed that sericin and beta-cyclodextrin were incorporated into the nanofibers and the crosslinking reaction occurred successfully. Kinetics, isotherms and thermodynamics analysis were studied for adsorption of methylene blue. The adsorption process is better fitted with the pseudo-second-order model and Langmuir isotherm model. The maximum adsorption capacities are 187.97, 229.89, and 261.10mg/g at the temperatures 293, 313 and 333 K, respectively. Thermodynamic parameters showed that methylene blue adsorption was endothermic and spontaneous. In addition, the fiber membrane adsorbent could be easily separated from dye solution and showed high recyclable removal efficiency. All these results suggest that crosslinked sericin/beta-cyclodextrin/poly(vinyl alcohol) composite nanofibers could be potential recyclable adsorbents in dye wastewater treatment. PMID- 26433645 TI - Enhanced toxicity and cellular uptake of methotrexate-conjugated nanoparticles in folate receptor-positive cancer cells by decorating with folic acid-conjugated d alpha-tocopheryl polyethylene glycol 1000 succinate. AB - Folic acid-conjugated d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS FOL) decorated methotrexate (MTX)-conjugated nanoparticles were developed for targeted delivery of MTX to folate receptor-expressed tumor cells. The synthesis of TPGS-FOL followed 3-step process. Firstly, the terminal hydroxyl group of TPGS was converted to sulfonyl chloride using mesyl chloride in comparison with nosyl and tosyl chlorides. The highest conversion efficiency and yield were obtained by mesyl chloride due to the formation of higher reactive intermediate in a presence of triethylamine. Secondly, the substitution of sulfonyl group by sodium azide produced considerably high yield with conversion efficiency of over 90%. Lastly, the coupling reaction of azido-substituted TPGS and propargyl folamide by click reaction resulted in 96% conjugation efficiency without polymer degradation. To fabricate the folate receptor-targeted nanoparticles, 10 and 20%mol MTX conjugated PEGylated poly(epsilon-caprolactone) nanoparticles were decorated with TPGS-FOL. The size and size distribution of MTX-conjugated nanoparticles relatively increased with %MTX. The MTX release from the nanoparticles was accelerated in acidic medium with an increase of %MTX but retarded in physiological pH medium. The decoration of TPGS-FOL onto the nanoparticles slightly enlarged the size and size distribution of the nanoparticles; however, it did not affect the surface charge. The cytotoxicity and cellular uptake of MCF 7 cells demonstrated that 10% MTX-conjugated nanoparticles and FOL-decorated nanoparticles possessed higher toxicity and uptake efficiency than 20% MTX conjugated nanoparticles and undecorated nanoparticles, respectively. The results indicated that FOL-10% MTX-conjugated nanoparticles exhibited potential targeted delivery of MTX to folate receptor-expressed cancer cells. PMID- 26433646 TI - Bioengineered neo-corneal endothelium using collagen type-I coated silk fibroin film. AB - Corneal transplantation, a common surgical protocol for visual acuity improvement, is limited owing to shortage of high quality donor corneas and/or lack of accurate replication of structural and biochemical composition of native cornea in a scaffold. Construction of neo-corneas utilizing novel, biocompatible and biodegradable scaffold/film source, could possibly address such formidable challenges. Herein, we designed optically transparent, micro-structurally stable silk films surface-coated with collagen type-I (Col-I/SF) as an alternative scaffold source for bioengineering of neo-cornea. Morphological, structural characteristics and in vitro biological studies were performed using primary rabbit corneal endothelial cells (rCEnCs) as models. The Col-I/SF films demonstrated higher Ra (nm) values compared to the bare SF surfaces. In vitro biological studies showed a significant increment in initial cell attachment and proliferation of cultured rCEnCs on the Col-I/SF films with well-maintained characteristic polygonal shape of rCEnCs. Although any remarkable changes regarding the morphology, expression of ZO-1 and Na(+)/K(+)-ATPase were absent, however the cells were found to be capable of well-expressing their functional proteins which regulates functions of corneal endothelium. Collectively, these results strongly suggest Col-I/SF film for future corneal transplantation therapy. PMID- 26433647 TI - Favourable attitudes towards serosorting are associated with overall less frequent condom use among young Black men having sex men. AB - This study determined whether YBMSM endorsing serosorting are less likely to use condoms. A questionnaire assessed men's attitudes towards serosorting with a three-item scale; various sexual risk behaviours were measured using a 90-day recall period. Favourable attitudes toward serosorting were associated with a greater likelihood of condomless sex as a top (P<0.001) and as a bottom (P<0.001), as well as a lower likelihood of using condoms with main partners (P=0.003). Findings suggest that YBMSM having favourable attitudes toward serosorting may be more likely to report condomless sex than their counterparts without favourable attitudes. PMID- 26433648 TI - DAC-EuCheMS Lecture Award presented to ABC Advisory Board Member Miguel Valcarcel. PMID- 26433651 TI - Diuretic and antioxidant activities of the aqueous extract of leaves of Cassia occidentalis (Linn.) in rats. AB - OBJECTIVE: To assess the putative diuretic and antioxidant properties of Cassia occidentalis (C. occidentalis) leaves' aqueous extract. METHODS: Adult rats were administered with C. occidentalis leaves aqueous extract acutely (24 h) and subchronically (7 d), at doses 80, 160, 240, 320, and 400 mg/kg (per os). Negative control group received only an equivalent volume of distilled water, while the two positive control groups received the diuretic drugs furosemide (20 mg/kg, ip.) and hydrochlorothiazide (HCTZ) (20 mg/kg, ip.). Urinary elimination of electrolytes in response to treatments was evaluated, together with changes in concentrations of creatinine, urea, aldosterone, glucose, and albumin in urine and plasma. Various urinary indicators of kidney function and plasmatic markers of oxidative stress were also assessed. RESULTS: The acute administration of C. occidentalis increased the urinary excretion of 107.58% at the higher dose tested, compared to negative control. The reference drugs furosemide and HCTZ induced increases of 84.27% and 48.05%, respectively. Acutely, the extract induced Na(+) and Cl(-) elimination, whereas subchronically an increase in K(+) elimination was also observed. The extract also improved the kidney function indexes and oxidative stress markers. These effects were dose-dependent and comparable with positive control observations. CONCLUSIONS: Our findings strongly suggest that C. occidentalis aqueous extract has diuretic and antioxidant activities, and deserves further studies considering the potential for the treatment of hypertension. PMID- 26433649 TI - Performing a hepatic timing signal: glucocorticoids induce gper1a and gper1b expression and repress gclock1a and gbmal1a in the liver of goldfish. AB - Glucocorticoids have been recently proposed as input signals of circadian system, although the underlying molecular mechanism remains unclear. This work investigates the role of glucocorticoids as modulators of clock genes expression in the liver of goldfish. In fish maintained under a 12L:12D photoperiod, an intraperitoneal injection at Zeitgeber Time 2 of a glucocorticoid analog, dexamethasone (1 MUg/g body weight) induced per1 genes while decreased gbmal1a and gclock1a expression in the liver at 8 h post-injection. A 4-h in vitro exposure of goldfish liver to cortisol (0.1-10 MUM) also induced gper1 genes in a concentration-dependent manner. Similarly, the exposure of the goldfish cultured liver to dexamethasone produced a concentration-dependent induction of gper1 genes. Moreover, this glucocorticoid analog led to a decrease in gbmal1a and gclock1a transcripts, while the other clock genes analyzed were unaffected. The induction of gper1a and gper1b by dexamethasone in vitro was observed at short times (2 h), whereas the reductions of gbmal1a and gclock1a transcripts needed longer exposure times (8 h) to the glucocorticoid to be significant. Additionally, a 2-h exposure to dexamethasone in the liver culture was enough to extend the induction of per genes for more than 12 h. Present results indicate that gper1 genes are targets for glucocorticoids in the regulation of goldfish hepatic oscillator, as previously reported in mammals, suggesting a conserved role of glucocorticoids in the functional organization of the peripheral circadian system in vertebrates. The repression of clock1a and bmal1a is not so well established, and suggests that other clock genes could be glucocorticoid targets in the goldfish liver. PMID- 26433650 TI - Peroxiredoxin 6 from the Antarctic emerald rockcod: molecular characterization of its response to warming. AB - In the present study, we describe the purification and molecular characterization of two peroxiredoxins (Prdxs), referred to as Prdx6A and Prdx6B, from Trematomus bernacchii, a teleost widely distributed in many areas of Antarctica, that plays a pivotal role in the Antarctic food chain. The two putative amino acid sequences were compared with Prdx6 orthologs from other fish, highlighting a high percentage of identity and similarity with the respective variant, in particular for the residues that are essential for the characteristic peroxidase and phospholipase activities of these enzymes. Phylogenetic analyses suggest the appearance of the two prdx6 genes through a duplication event before the speciation that led to the differentiation of fish families and that the evolution of the two gene variants seems to proceed together with the evolution of fish orders and families. The temporal expression of Prdx6 mRNA in response to short-term thermal stress showed a general upregulation of prdx6b and inhibition of prdx6a, suggesting that the latter is the variant most affected by temperature increase. The variations of mRNA accumulation are more conspicuous in heart than the liver, probably related to behavioral changes of the specimens in response to elevated temperature. These data, together with the peculiar differences between the molecular structures of the two Prdx6s in T. bernacchii as well as in the tropical species Stegastes partitus, suggest an adaptation that allowed these poikilothermic aquatic vertebrates to colonize very different environments, characterized by different temperature ranges. PMID- 26433652 TI - Chemical composition, mechanism of antibacterial action and antioxidant activity of leaf essential oil of Forsythia koreana deciduous shrub. AB - OBJECTIVE: To identify the chemical constituents of leaf essential oil of Forsythia koreana (F. koreana) and evaluate its effects on bacterial strains. METHODS: The essential oil of leaf of F. koreana was extracted by using hydrodistillation process and the volatile components investigated with the help of gas chromatography coupled with mass spectrometry. The antibacterial study was carried out with the help of agar disc diffusion method, MIC, MBC and viable count. The mode of action was determined with help of potassium ion flux, cellular material release and scanning electron microscopy. The antioxidant activity was determined with the help of 2, 3-diphenyl-2-picrylhydrazyl method, nitric oxide scavenging activity and superoxide anion radical scavenging assay. RESULTS: Total ten compounds were identified as trans-phytol (42.73%), cis-3 hexenol (12.95%), beta-linalool (10.68%), trans-2-hexenal (8.86%), trans-2 hexenol (8.86%), myrcenol (3.86%), 4-vinylphenyl acetate (3.86%), (4Z)-4,6 heptadien-1-ol (3.18%), lemonol (2.73%) and benzeneacetaldehyde (2.27%) by gas chromatography coupled with mass spectrometry. The antibacterial study was demonstrated that leaf essential oil of F. koreana act against foodborne and other pathogenic bacteria. The mode of action revealed that this essential oil acted on the cytoplasmic membrane, resulting in loss of integrity and increased permeability. In addition, leaf essential oil of F. koreana was shown to be rich in linalool, which contributes to improved antioxidant activity. CONCLUSIONS: These results show that leaf essential oil of F. koreana has great potential as a natural food preservative, antibacterial and antioxidant agent. PMID- 26433653 TI - A pilot study of antioxidant potential of endophytic fungi from some Sudanese medicinal plants. AB - OBJECTIVE: To evaluate the total phenolic content and total antioxidant capacity of ethyl acetate extracts of 21 endophytic fungi isolated from five Sudanese medicinal plants: Calotropis procera, Catharanthus roseus, Euphorbia prostrate, Vernonia amygdalina and Trigonella foenum-graecum. METHODS: Crude extracts of endophytic fungi and their host plants were tested by classical Folin-Ciocalteu colorimetric method to determine the total phenolic content, also total antioxidant capacity was estimated using 1,1-diphenyl-2-picrylhydrazyl free radical scavenging in vitro method. RESULTS: Among the endophytes, endophytic fungus Aspergillus sp. from Trigonella foenum-graecum seeds demonstrated the highest both total phenolic content in term of gallic acid equivalent [(89.9 +/- 7.1) mg GAE/g] and antioxidant activity for 1,1-diphenyl-2-picrylhydrazyl radical scavenging assay [IC50: (18.0 +/- 0.1) MUg/mL]. A high positive linear correlation (R(2) = 0.999 1) was found between total antioxidant capacity and total phenolic content of endophytic fungi isolated from Vernonia amygdalina. CONCLUSIONS: The present study revealed that some endophytic fungi from the five Sudanese medicinal plants could be a potential source of novel natural antioxidant compounds. PMID- 26433654 TI - Prevalence of filarial parasites in domestic and stray cats in Selangor State, Malaysia. AB - OBJECTIVE: To determine the prevalence of the filarial parasites,ie.,Brugia malayi, Brugia, Brugia pahangi(B. pahangi), Dirofilaria immitisandDirofilaria repens (D. repens) in domestic and stray cats. METHODS: A total of 170 blood sample were collected from domestic and stray cats and examined for filarial worm parasites in two localities, Pulau Carey and Bukit Gasing, Selangor State, Malaysia. RESULTS: The overall prevalence of infection was 23.5% (40/170; 95% CI = 17.4-30.6). Of this, 35% (14/40; 95% CI = 22.1-50.5) and 50% (20/40; 95% CI = 35.2-64.8) were positive for single B. pahangi nd D. repens, respectively. The remaining of 15% (6/40; 95% CI = 7.1-29.1) were positive for mixed B. pahangi and D. repens. In addition, 75% of the infected cats were domestic, and 25% were strays. No Brugia malayi and Dirofilaria immitis was detected. Eighty-four cats were captured at Pulau Carey, of which 35.7% (30/84) were infected. Among the cats determined to be infected, 93% (28/30; 95% CI = 78.7-98.2) were domestic, and only 6.7% (2/30; 95% CI = 19.0-21.3) were strays. Conversely, the number of infected cats was three times lower in Bukit Gasing than in Pulau Carey, and most of the cats were stray. CONCLUSIONS: B. pahangi and D. repens could be the major parasites underlying filariasis in the study area. Adequate prophylactic plans should be administrated in the cat population in study area. PMID- 26433655 TI - Genetic variation of Leptospira isolated from rats catched in Yogyakarta Indonesia. AB - OBJECTIVE: To detect genetic variations among pathogenic Leptospira isolated from rats using 16S rRNA gen as chronometer. METHODS: This is an observational study with cross sectional design. Rats samples were taken in Yogyakarta Special Region of Indonesia. Leptospira in the rats was detected by two methods i.e. real time PCR (qPCR) by using primers correspond to16S rRNA gene of Leptospira, and standard PCR by using different set of primer correspond to the 16S rRNA gene of Leptospira. The standard PCR amplicon then subjected for DNA sequencing. Analysis genetic variation was performed using MEGA 6.2. Software. RESULTS: There were 99 DNA samples from rats included in this study. Detection of Leptospira by using qPCR revealed 25 samples positive for pathogenic Leptospira, while only 6 samples were able to be detected using standard PCR. The new primer set correspond to 16S rRNA gene was able to detect specifically pathogenic Leptospira in the rats. Sequencing analysis of 6 PCR amplicons showed that the Leptospira which infect the rats catched in Yogyakarta genetically close related with pathogenic Leptospira which were isolated from human, animal, rodents, and environment. CONCLUSIONS: It can be considered that rats are the most important vector and reservoir of Leptospira. PMID- 26433657 TI - Epidemiology of influenza viruses from 2009 to 2013 - A sentinel surveillance report from Union territory of Puducherry, India. AB - OBJECTIVE: To report the findings of influenza surveillance programme from Union territory of Puducherry and to document the clinical and epidemiological data of influenza viruses over a five year period from 2009 to 2013. METHODS: Respiratory samples were collected from patients with influenza-like illness from 2009 to 2013 as part of routine diagnostic and surveillance activity. Detection of pandemic influenza A (H1N1) 2009, influenza A (H3N2) and influenza B was done using Real-time PCR. RESULTS: Of the total 2247 samples collected from patients with influenza-like illness during the study period 287 (12.7%) and 92 (4.0%) were positive for influenza A (H1N1) 2009 and influenza A (H3N2) respectively. A subset of 557 of these samples were also tested for influenza B and 24 (4.3%) were positive. Significantly higher positivity rate for both viruses was observed in adults when compared with children. The peak positivity of influenza A (H1N1) 2009 was observed in 2009 followed by 2012, while that of influenza A (H3N2) was more uniformly distributed with the exception of 2012. Overall mortality rate due to influenza A (H1N1) 2009 was 7.6% while it was 1% for influenza A (H3N2). Each year influenza-like illness and influenza virus activity coincided with period of high rainfall and low temperature except in the first half of 2012. CONCLUSIONS: As the sole referral laboratory in this region, the data provides a comprehensive picture of influenza activity. This information will be useful in future planning of the vaccine schedule and influenza pandemic preparedness. PMID- 26433656 TI - Molecular survey of tick-borne pathogens in Ixodid ticks collected from hunted wild animals in Tuscany, Italy. AB - OBJECTIVE: To determine the prevalence of zoonotic tick-borne bacteria in feeding ticks removed from hunted wild animals. METHODS: PCR was executed on DNA extracted from 77 tick pools to detect Anaplasma phagocytophilum, Bartonella spp., Borrelia burgdorferi sensu lato, Coxiella burnetii and Rickettsia spp. RESULTS: A total of 432 ticks were collected: 30 (6.94%) Haemaphysalis punctata, 72 (16.7%) Dermacentor marginatus and 330 (76.38%) Ixodes ricinus. For each animal one or two pools of 3 ticks of the same species was constituted. Seventy seven tick pools were examined by PCR: 58 (75.32%) resulted infected and among them 14 (18.18%) showed co-infections. In particular, 29 (37.66%) pools were positive for Bartonella spp., 23 (29.87%) for Anaplasma phagocytophilum, 16 (20.78%) for Rickettsia spp., and 5 (6.49%) for Borrelia burgdorferi s.l. All samples were negative for Coxiella burnetii. CONCLUSIONS: The results demonstrate the presence of several zoonotic tick-borne pathogens in the studied area, and underline the risk of exposure to infections for hunters not only during the outdoor activity, but also when they manipulate hunted animals infested by infected ticks. PMID- 26433658 TI - Effect of BRMS1 expression on proliferation, migration and adhesion of mouse forestomach carcinoma. AB - OBJECTIVE: To discuss the effect of BRMS1 on the proliferation, migration and adhesion of mouse forestomach carcinoma. METHODS: The constructed pCMV-myc-BRMS1 recombinant plasmid and blank plasmid were transfected into mouse forestomach carcinoma. MTT method was employed to measure the activity of gastric cancer cell; the scratch assay and Transwell assay to measure the migration and invasion of gastric cancer cell; the adhesion assay to measure the adhesion of gastric cancer cell; while the Western blot assay to measure the expression of The NF kappaB signal pathway, downstream matrix metalloproteinase (MMP)-2, MMP-9 and osteopontin and E-cadherin in the gastric cancer cell. Besides, the transplanted animal model of gastric cancer in mice was constructed to measure the size of tumor xenograft. RESULTS: Results of MTT assay showed that, compared with the empty vector control group, the activity of gastric cancer cell was not affected in the BRMS1 transfection group. The improved expression of BRMS1 could inhibit the adhesion, migration and invasion of gastric cancer cell (P < 0.01). Besides, compared with the empty vector control group, the phosphorylation of NF-kappaB p65 and IkappaBalpha was reduced in the BRMS1 transfection group, with the decreased expression of MMP-2, MMP-9 and osteopontin and the increased expression of E-cadherin (P < 0.01). Results of animal experiment also showed that the expression of BRMS1 did not affect the transplanted tumor. CONCLUSIONS: The expression of BRMS1 can significantly inhibit the adhesion, migration, invasion and metastasis of mouse forestomach carcinoma gastric cancer cell, which is related to The NF-kappaB signal pathway. PMID- 26433659 TI - Effect of PI3K-mediated autophagy in human osteosarcoma MG63 cells on sensitivity to chemotherapy with cisplatin. AB - OBJECTIVE: To investigate the influence of autophagy on sensitivity to the chemotherapy drug cisplatin (DDP) and the role of PI3K in autophagy. METHODS: MTT methods and flow cytometer, with rapamycin up-regulating the autophagy and 3-MA down-regulating the autophagy, were employed to measure the proliferation inhibition rate on DDP-treated osteosarcoma cells and the change in cell cycle. The expression of intracellular protein was detected by Western blot. The autophagy of MG63 cell was observed using fluorescence microscope and transmission electron microscope. RESULTS: Western blot showed that basic autophagy level of MG63 cell was significantly lower than that of hFOB cell. MTT test revealed that the cell proliferation inhibition rate in the group treated with rapamycin and DDP, group treated with 3-MA and DDP, and group only treated with DDP was significantly different. It was demonstrated by the flow cytometry that in group treated with DDP, inhibition on autophagy can increase the cell numbers in G1 phase and reduce the cell numbers in S phase of cell cycle. Increase of autophagosome in MG63 cytoplasm was observed under fluorescence microscope. CONCLUSIONS: Up-regulating the autophagy significantly reduced the sensitivity of MG63 cell to chemotherapy with DDP. DDP induced autophagy of MG63 cell and blocked the cell cycle at G1 phase. PMID- 26433660 TI - Comparative analysis of biological characteristics of adult mesenchymal stem cells with different tissue origins. AB - OBJECTIVE: To invest the differences among mesenchymal stem cells (MSCs) derived from different tissues and their impacts on clinical applications. METHODS: In this study, MSCs were isolated from adipose tissue (AD), umbilical cord tissue (UC), and menstrual blood (Men) and compared their biological characteristics in terms of proliferation capacity, passage capacity, colony formation, and surface markers were compared. RESULTS: The stem cells (SCs) obtained from different sources were all characterized as MSCs, but demonstrated some differences. Umbilical cord-derived MSCs (UCMSCs) were able to overcome density inhibition. The proliferation rate decreased in the order UCMSCs > MenSCs > ADSCs, while the colony-forming ability decreased in the order MenSCs > ADSCs > UCMSCs. Based on gene-expression data for MSCs from different sources within the same donor, 768 MenSC genes were found that were specifically upregulated or downregulated compared with bone marrow-derived MSCs and UCMSCs, most of which were involved in cell function-related pathways. In addition, MenSCs appeared to be superior in terms of immune inflammation, stress response, and neural differentiation potentials, but weaker in terms of osteogenic and chondrogenic differentiation capacities, compared with UCMSCs and bone marrow-derived MSCs. CONCLUSIONS: MenSCs have higher extraction efficiency, colony-forming ability, and long time passage capacity. Although the proliferation capacity is inferior to UCMSCs. PMID- 26433661 TI - Effect of microRNA-208a on mitochondrial apoptosis of cardiomyocytes of neonatal rats. AB - OBJECTIVE: To explore the effect and mechanism of microRNA-208a (miR-208a) in the mitochondrial apoptosis of cardiomyocytes of neonatal rats. METHODS: The primary cultured cardiomyocytes of neonatal rats were added into the hypoxia incubator for the hypoxia induction. The overexpression system for miR-208a of cardiomyocytes of neonatal rats was built. The flow cytometry assay was employed to detect the incidence of apoptosis in the over-expressed miR-208a. The mitochondrial staining technique was used to detect the change in the mitochondrial morphology of over-expressed miR-208a. The bioinformatic analysis was chosen to analyze and predict the target gene of miR-208a. RESULTS: Firstly, the primary culture system of cardiomyocytes of neonatal rats was successfully built. The miR-208a was over-expressed in cardiomyocytes of neonatal rats by miR 208a Mimics. Results of flow cytometry assay showed that the over-expressed miR 208a could significantly reduce the incidence of apoptosis; while results of mitochondrial staining indicated the change in the mitochondrial morphology of over-expressed miR-208a and the mitochondrial fission process was inhibited. In conclusion, it was supposed that miR-208a could inhibit the activation of mitochondrial fission process to keep the cardiomyocytes from apoptosis. CONCLUSIONS: The over-expressed miR-208a can reduce the incidence of apoptosis in the cardiomyocytes of neonatal rats, significantly change the mitochondrial morphology and inhibit the mitochondrial fission process. PMID- 26433662 TI - Clinical significance of microRNA-130b in osteosarcoma and in cell growth and invasion. AB - OBJECTIVE: To investigate clinical significance of microRNA-130b (miR-130b) in osteosarcoma and its role in cell growth and invasion. METHODS: miR-130b expression was detected in 68 samples of surgically resected osteosarcoma and matched normal tumor-adjacent tissues by qRT-PCR. The expression of miR-130b was altered by corresponding vectors in osteosarcoma cells, and then Western blot was used to detect the expression of PPARgamma. BrdU cell proliferation and Transwell assays were performed to determine cell proliferation and invasion. RESULTS: The expression of miR-130b in osteosarcoma tissues was significantly higher than that in normal tumor-adjacent tissues. Its expression in patients with metastasis was significantly higher than that in those without metastases. miR-130b expression in tumor tissues was significantly associated with tumor size, clinical stage and distant metastasis. And its expression was significantly correlated with overall survival and disease free survival. miR-130b overexpression obviously repressed the expression of PPARgamma, and resulted in significant increase of Saos-2 cell proliferation and invasion. On the contrast, repressing miR-130b expression with its inhibitor significantly increased PPARgamma expression, and inhibited MG-63 cell proliferation and invasion. CONCLUSIONS: The high-expression of miR-130b is correlated with the adverse clinicopathological features and poor prognosis in osteosarcoma. miR-130b may regulate proliferation and invasion of osteosarcoma cells by targeting PPARgamma, suggesting miR-130b may play a key role in the progression of osteosarcoma. PMID- 26433663 TI - Anti-proliferation and radiosensitization effects of chitooligosaccharides on human lung cancer line HepG2. AB - OBJECTIVE: To observe the anti-proliferation and radiosensitization effect of chitooligosaccharides (COS) on human lung cancer cell line HepG2. METHODS: CCK-8 assay was employed to obtain the inhibition ratio of COS on HepG2 cells at 24 h after treatment. The clonogenic assay was used to analyze the cell viability of RAY group and RAY + COS group with X-ray of 0, 1, 2, 4, 6 and 8 Gy, and the cell survival curve was used to analyze the sensitization ratio of COS. Flow cytometry was employed to detect cell cycle and apoptosis rate in control group, RAY group and RAY + COS group after 24 h treatment. RESULTS: COS inhibited the proliferation of HepG2 cells, and the inhibition rate positively correlated with the concentration of COS. The cell viability decreased with increasing exposure dose in RAY group and RAY + COS group. The cell viabilities of RAY + COS group were lower than those of RAY group at the dose of 4, 6 and 8 Gy (P < 0.05), and the sensitization ratio of COS was 1.19. There were higher percentage at G2/M phase and apoptosis rate, and lower percentage at S phase in RAY + COS group versus the other two groups (P < 0.01). CONCLUSIONS: COS can inhibit the proliferation of HepG2 cells, and enhance the radiosensitization of HepG2 cells, induce apoptosis and G2/M phase arrest. PMID- 26433664 TI - Correlation between microRNA-21 and expression of Th17 and Treg cells in microenvironment of rats with hepatocellular carcinoma. AB - OBJECTIVE: To study the correlation between miR-21 and Treg/Th17 ratio in the microenvironment of rats with hepatocellular carcinoma. METHODS: Diethylnitrosamine was used to build the hepatocellular carcinoma model of rats; the content of Treg cells and Th17 cells and the expression of miR-21 in the peripheral blood of rats with hepatocellular carcinoma were detected. The statistical analysis was performed on the correlation between miR-21 expression and Treg/Th17 ratio. RESULTS: Hepatocellular carcinoma model of rats was successfully constructed. The proportion of Th17 cells among all CD4(+)T cells in the peripheral blood of rats with hepatocellular carcinoma was 5.319%, which was higher than the control group; while the proportion of Treg cells was 9.472%, which was higher than the control group. Treg/Th17 ratio in the model group was 1.781, compared with 1.478 in the control group. The expression of miR-21 was increased in the peripheral blood of rats with hepatocellular carcinoma and it showed a positive correlation with the ratio of Treg/Th17. CONCLUSIONS: There is a positive correlation between the expression level of miR-21 and the ratio of Treg/Th17. PMID- 26433665 TI - Effect of CXCR4 pretreated with ultrasound-exposed microbubbles on accelerating homing of bone marrow mesenchymal stem cells to ischemic myocardium in AMI rats. AB - OBJECTIVE: To investigate the role and potential mechanism of CXCR4 in promoting targeted homing of bone marrow mesenchymal stem cells (BMSCs) with ultrasound exposed microbubbles (UM) pretreatment. METHODS: Third generation BMSCs were divided into four groups control group, ultrasound (US) group, UM group and ultrasound-exposed microbubbles plus catalase group. RT-PCR and western blot were performed to determine the levels of CXCR4 mRNA transcription and protein expression, respectively. Third generation BMSCs were labeled with Fluo-alpha/AM and divided into three groups: control group, US group and UM group, and fluorescence intensities in the cells were observed immediately, 5 min and 15 min after intervention under fluorescence microscope. The calcium iron levels in the cells were analyzed. BMSCs were divided into five group: group A without calcium in the medium, group B, group C, group D and group E containing calcium chloride with concentration of l mol, 2 mol, 4 mol, anti-calcium-sensing receptor antibody, respectively. RT-PCR and western blot were performed to determine the levels of CXCR4 mRNA transcription and proteins expression of the third generation BMSCs of each group, respectively. RESULTS: The levels of CXCR4 mRNA transcription and protein expression between US group and control group had no statistically significant difference (P > 0.05) shown by RT-PCR and western blot; the transcription level in the UM group was significantly higher than that in US group and control group (P < 0.05); and in the ultrasound-exposed microbubbles plus catalase group, the transcription level was much lower than that in UM group. Fluorescence intensify in the cells of US group had no significant difference compared with that in the cells of the control group (P > 0.05), which in the cells of UM group was significantly higher than that in the cells of both US group and control group (P < 0.05). Compared to group A, expressions of CXCR4 of group B to D were significantly increased in concentration-dependent manner showed by RT-PCR and western blot (P < 0.05). Compared to group C, expressions of CXCR4 of group E were significantly decreased (P < 0.05). CONCLUSIONS: UM can promote the influx of calcium in BMSCs and increase mRNA transcription and protein expression of CXCR4. The latter may partly be caused by influx of calcium. PMID- 26433666 TI - Uterine sarcomas. PMID- 26433667 TI - Cancer of the ovary, fallopian tube, and peritoneum. PMID- 26433668 TI - Update on the diagnosis and management of gestational trophoblastic disease. PMID- 26433669 TI - The future role of molecular staging in gynecologic cancer. PMID- 26433670 TI - Pathology of cancers of the female genital tract. PMID- 26433671 TI - Principles of chemotherapy. PMID- 26433672 TI - Targeted therapy in gynecologic cancers: Ready for prime time? PMID- 26433673 TI - Principles of radiation therapy in low-resource and well-developed settings, with particular reference to cervical cancer. PMID- 26433674 TI - Psychosexual health in gynecological cancer. PMID- 26433675 TI - Rehabilitation after gynecological cancer treatment. PMID- 26433676 TI - Palliative care in gynecological cancer. PMID- 26433677 TI - FIGO Cancer Report 2015. PMID- 26433678 TI - Cancer of the vulva. PMID- 26433679 TI - Cancer of the vagina. PMID- 26433680 TI - Cancer of the cervix uteri. PMID- 26433681 TI - Cancer of the corpus uteri. PMID- 26433682 TI - Aging causes morphological alterations in astrocytes and microglia in human substantia nigra pars compacta. AB - Age being a risk factor for Parkinson's disease, assessment of age-related changes in the human substantia nigra may elucidate its pathogenesis. Increase in Marinesco bodies, alpha-synuclein, free radicals and so forth in the aging nigral neurons are clear indicators of neurodegeneration. Here, we report the glial responses in aging human nigra. The glial numbers were determined on Nissl stained sections. The expression of glial fibrillary acidic protein, S100beta, 2', 3'-cyclic nucleotide 3' phosphodiesterase, and Iba1 was assessed on cryosections of autopsied midbrains by immunohistochemistry and densitometry. The glial counts showed a biphasic increase, of which, the first prominent phase from fetal age to birth could be physiological gliogenesis whereas the second one after middle age may reflect mild age-related gliosis. Astrocytic morphology was altered, but glial fibrillary acidic protein expression increased only mildly. Presence of type-4 microglia suggests possibility of neuroinflammation. Mild reduction in 2', 3'-cyclic nucleotide 3' phosphodiesterase-labeled area denotes subtle demyelination. Stable age-related S100beta expression indicates absence of calcium overload. Against the expected prominent gliosis, subtle age-related morphological alterations in human nigral glia attribute them a participatory role in aging. PMID- 26433684 TI - The importance of influenza diagnosis. PMID- 26433685 TI - Polio in Pakistan--A public health event of international concern with implications for travellers' vaccination. PMID- 26433686 TI - Early disruption of neurovascular units and microcirculatory dysfunction in the spinal cord in spinal muscular atrophy type I. AB - Spinal muscular atrophy type I (SMA-I) is characterized by progressive muscle weakness with onset in early infancy, usually resulting in mortality before two years of age. However, the processes underlying the pathophysiological progression of the disease remain unclear. Prior to the onset of muscle weakness, a regression of local capillaries is observed along with motor neuron loss. Local populations of neurons, astrocytes, and vascular endothelial cells constitute a neurovascular unit (NVU), in which neuronal and synaptic metabolism is tightly coupled to capillary blood flow by astrocyte-mediated vasodilatory control. We hypothesize that survival motor neuron protein deficiency and initial neuronal dysfunction leads to the regression of vascular beds and the disruption of NVU function. As a result, local capillary blood flow becomes insufficient, leading to metabolic stress in neurons, endothelial cells, pericytes, and astrocytes, ultimately disrupting the astrocytic regulation of capillaries. This pathogenic process may accelerate the loss of anterior horn motor neurons, leading to the further regression of capillaries and astroglial dysfunction. Hypocapnia, resulting from dehydration and hyperventilation during therapeutic manual ventilation, might further damage the NVU. Moreover, disruption of the microcirculation may affect sympathetic and sensory neurons in the spinal cord, contributing to sympathetic hyperactivity and sensory nerve degeneration, respectively. These mutually reinforcing processes may underlie the progression of muscle weakness during infancy in SMA-I. Therefore, disruption of the NVU and a stressful neurovascular environment in the anterior horn may play important roles in disease initiation and/or progression in SMA-I. The NVU is therefore a critical therapeutic target for treating SMA-I. Our hypothetical model may provide insight into why most neuroprotective strategies that do not address astroglial and vascular cell dysfunction have limited efficacy. PMID- 26433683 TI - The endoplasmic reticulum: structure, function and response to cellular signaling. AB - The endoplasmic reticulum (ER) is a large, dynamic structure that serves many roles in the cell including calcium storage, protein synthesis and lipid metabolism. The diverse functions of the ER are performed by distinct domains; consisting of tubules, sheets and the nuclear envelope. Several proteins that contribute to the overall architecture and dynamics of the ER have been identified, but many questions remain as to how the ER changes shape in response to cellular cues, cell type, cell cycle state and during development of the organism. Here we discuss what is known about the dynamics of the ER, what questions remain, and how coordinated responses add to the layers of regulation in this dynamic organelle. PMID- 26433687 TI - An evolutionary perspective on the immunomodulatory role of hydrogen sulphide. AB - Most preclinical studies on endogenous hydrogen sulphide signalling have given little consideration to the fact that the human body contains more bacterial cells than human cells, and that evolution provides the context for all biology. Whether hydrogen sulphide is pro or anti-inflammatory is heavily debated within the literature, yet researchers have not fully considered that invasive bacteria produce hydrogen sulphide, often at levels far above the endogenous levels of the host. Here I argue that if hydrogen sulphide is an endogenous signalling molecule with immunomodulatory functions, then it must have evolved in the presence of virulent bacteria which produce hydrogen sulphide. This context leads to two competing theories about the evolution of endogenous hydrogen sulphide signalling. The detectable emission theory proposes that bacteria produce hydrogen sulphide as part of normal metabolism and hosts which evolved to detect and respond to this hydrogen sulphide would gain a selective survival advantage. This predicts that the endogenous production of hydrogen sulphide is a mechanism which amplifies the bacterial hydrogen sulphide signal. The opposing protective agent theory predicts that bacterial hydrogen sulphide is an effective defence against the bactericidal mechanisms of the host's immune response. In this case, endogenous hydrogen sulphide production is either at inconsequential levels to alter the immune response, or is involved in the inflammation resolution process. Evidence suggests that the direct interactions of hydrogen sulphide with the bactericidal mechanisms of the innate immune system are most congruent with the protective agent theory. Therefore, I argue that if hydrogen sulphide is an immunomodulatory endogenous signalling molecule its effects are most likely anti inflammatory. PMID- 26433688 TI - Does perineural invasion of the myenteric plexus have a key role in annular rectal invasion and digestive system symptoms of prostate carcinoma patients? AB - Prostate carcinoma is one of the most common cancers globally. It relatively rarely invades the rectum, accounting for only about 4% of resected cases. About half of these cases of rectal invasion show an annular rectal stricture pattern. It has been hypothesized that anatomical structures, namely Denonvilliers fascia, may play an important role in annular rectal involvement of prostate carcinoma. Here, we propose another hypothesis: the reason for annular rectal invasion by prostate carcinoma is its extension along the myenteric plexus (Auerbach's plexus). We illustrate this using a case presentation and description of the symptoms of such cases. From a review of the literature, autonomic digestive system symptoms of rectal invasion of prostatic carcinoma, such as diarrhea, tenesmus, or fecal incontinence is seen in about half of cases, coinciding with the frequency of annular rectal invasion. Thus, by modifying the long-established hypothesis, our suggestion that prostate carcinoma spreads along the myenteric plexus when cancer cells invade beyond the Denonvilliers fascia to the rectum could explain the cause and frequency not only of the annular rectal invasion but also the digestive system symptoms related to this disease. The prognosis of prostate carcinoma invading the rectum is very poor; however, this new hypothesis might shed light on the digestive system symptoms associated with prostate carcinoma and might lead to recognition and treatment of these cases at a relatively early stage of rectal invasion. PMID- 26433690 TI - Trends Form Follows Function: New Ways to Inform and Inspire. PMID- 26433689 TI - Dietary diversity, meal frequency and associated factors among infant and young children in Northwest Ethiopia: a cross- sectional study. AB - BACKGROUND: Inappropriate feeding practice increases risk of under nutrition, illness, and mortality amongst children less than 2 years of age. The objective of this study is to assess minimum dietary diversity, meal frequency and its associated factors among infant and young children aged 6-23 months in Dangila Town, Northwest Ethiopia. METHODS: A community based cross sectional study was conducted. Simple random sampling technique was used to select study participants. Interviewer administered questionnaire were used. Bivariate and multivariable logistic regression analyses was employed to identify factors associated with minimum dietary diversity and meal frequency. RESULTS: A total of 920 children 6-23 months were included. Proportion of children who met the minimum dietary diversity and meal frequency was 12.6 and 50.4 %, respectively. Mothers education [AOR =2.52], age of a child [AOR = 2.05], birth order of index child [AOR = 2.08], living in urban area [AOR = 2.09], having home gardening [AOR = 2.03], and media exposure [AOR = 2.74] were positively associated with dietary diversity. Moreover, age of the child [AOR = 3.03], birth order of index child [AOR = 1.58], mothers involvement in decision making [AOR = 1.51], media exposure [AOR = 2.62], and having postnatal visit [AOR = 2.30] were positively associated with meal frequency. CONCLUSION: The proportion of children who received minimum dietary diversity and meal frequency was low. Being at younger age, first birth order, and lack of media exposure affect both dietary diversity and meal frequency. Increasing mother's education, home gardening, mass media promotion and empowering women in decision making are highly recommended to increase dietary diversity and meal frequency. PMID- 26433691 TI - Is There Sufficient Evidence to Consider Bacillus thuringiensis a Multihost Pathogen? Response to Loguercio and Argolo-Filho. PMID- 26433692 TI - The Tailocin Tale: Peeling off Phage Tails. AB - Bacteria produce a variety of particles resembling phage tails that are functional without an associated phage head. Acquired from diverse bacteriophage sources, these stand-alone units were sculpted to serve different ecological roles. Such tailocins mediate antagonism between related bacteria as well as interactions with eukaryotic cells. PMID- 26433693 TI - Rates of Lateral Gene Transfer in Prokaryotes: High but Why? AB - Lateral gene transfer is of fundamental importance to the evolution of prokaryote genomes and has important practical consequences, as evidenced by the rapid dissemination of antibiotic resistance and virulence determinants. Relatively little effort has so far been devoted to explicitly quantifying the rate at which accessory genes are taken up and lost, but it is possible that the combined rate of lateral gene transfer and gene loss is higher than that of point mutation. What evolutionary forces underlie the rate of lateral gene transfer are not well understood. We here use theory developed to explain the evolution of mutation rates to address this question and explore its consequences for the study of prokaryote evolution. PMID- 26433695 TI - Sweet Talk: Protein Glycosylation in Bacterial Interaction With the Host. AB - Pathogenic bacteria encode virulent glycosyltransferases that conjugate various glycans onto substrate proteins via the N- or O-linkage. The HMW system in nontypeable Haemophilus influenzae and the Pgl system in Campylobacter jejuni glycosylate bacterial surface or periplasmic proteins at the eukaryotic-like Asn X-Ser/Thr motif. The NleB effector from enterobacteria mediates arginine GlcNAcylation of host death-domain proteins to block inflammation, representing an atypical N-glycosylation. The large clostridial cytotoxins and related glucosyltransferase toxins from Legionella and Photorhabdus monoglycosylate a serine/threonine or tyrosine in host Rho GTPase or elongation factor 1A (eEF1A). The emerging bacterial autotransporter heptosyltransferase (BAHT) family of heptosyltransferases also catalyses O-glycosylation and modifies autotransporters for adhesion to the host. These glycosylations, diverse in linkages and glycan structures, determine appropriate functioning of bacterial virulence factors or hijack host cellular processes in pathogenesis. PMID- 26433694 TI - Roles of Lipoproteins and Apolipoproteins in Particle Formation of Hepatitis C Virus. AB - More than 160 million people worldwide are infected with hepatitis C virus (HCV), and cirrhosis and hepatocellular carcinoma induced by HCV infection are life threatening diseases. HCV takes advantage of many aspects of lipid metabolism for an efficient propagation in hepatocytes. Due to the morphological and physiological similarities of HCV particles to lipoproteins, lipid-associated HCV particles are named lipoviroparticles. Recent analyses have revealed that exchangeable apolipoproteins directly interact with the viral membrane to generate infectious HCV particles. In this review, we summarize the roles of lipid metabolism in the life cycle of HCV. PMID- 26433696 TI - Natural Product Biosynthetic Diversity and Comparative Genomics of the Cyanobacteria. AB - Cyanobacteria are an ancient lineage of slow-growing photosynthetic bacteria and a prolific source of natural products with intricate chemical structures and potent biological activities. The bulk of these natural products are known from just a handful of genera. Recent efforts have elucidated the mechanisms underpinning the biosynthesis of a diverse array of natural products from cyanobacteria. Many of the biosynthetic mechanisms are unique to cyanobacteria or rarely described from other organisms. Advances in genome sequence technology have precipitated a deluge of genome sequences for cyanobacteria. This makes it possible to link known natural products to biosynthetic gene clusters but also accelerates the discovery of new natural products through genome mining. These studies demonstrate that cyanobacteria encode a huge variety of cryptic gene clusters for the production of natural products, and the known chemical diversity is likely to be just a fraction of the true biosynthetic capabilities of this fascinating and ancient group of organisms. PMID- 26433697 TI - Antiviral Monoclonal Antibodies: Can They Be More Than Simple Neutralizing Agents? AB - Monoclonal antibodies (mAbs) are increasingly being considered as agents to fight severe viral diseases. So far, they have essentially been selected and used on the basis of their virus-neutralizing activity and/or cell-killing activity to blunt viral propagation via direct mechanisms. There is, however, accumulating evidence that they can also induce long-lasting protective antiviral immunity by recruiting the endogenous immune system of infected individuals during the period of immunotherapy. Exploiting this property may revolutionize antiviral mAb-based immunotherapies, with benefits for both patients and healthcare systems. PMID- 26433698 TI - [The competence of the family physician in the care of patients at the end of life. Reflections on the proposal of Specific Competence Area in Palliative Care]. PMID- 26433699 TI - [Cost-efficacy of new antiviral treatments for chronic hepatitis C]. PMID- 26433701 TI - Reassuringly calm? Self-reported patterns of responses to reassurance seeking in obsessive compulsive disorder. AB - BACKGROUND AND OBJECTIVES: The perception of threat and associated feelings of anxiety typically prompt people to seek safety; reassurance seeking is an interpersonal strategy almost universally used to reduce the immediate perception of risk. Excessive Reassurance Seeking (ERS) is considered to be particularly prominent and unequivocally counter-productive in people suffering from anxiety disorders in general and OCD in particular, producing short term relief but a longer term return and worsening of the original anxiety. We evaluated the extent and specificity of the effects of ERS in OCD and mechanisms involved in both anxiety relief and the hypothesized later return of anxiety.. METHOD: Self rated effects of reassurance seeking were investigated in 153 individuals with OCD, 50 with panic disorder, and 52 healthy controls, evaluating reactions to the provision and non-provision of reassurance. RESULTS: Reassurance is associated with short term relief then longer term return of both discomfort and the urge to seek further reassurance in both anxious groups; healthy controls do not experience significant resurgence. Greater return of anxiety and urge to seek more reassurance were associated with higher levels of overall reassurance seeking.. LIMITATIONS: The findings were based on retrospective self-report of naturally occurring episodes of ERS; prospective studies and induced behaviours are now needed. CONCLUSIONS: Not only is reassurance a quick fix for people experiencing OCD, but in the absence of treatment the only fix! The findings explain why reassurance seeking continues despite advice that it will worsen anxiety problems. Such advice is potentially harmful to patients and their loved ones.. PMID- 26433700 TI - The negativity bias predicts response rate to Behavioral Activation for depression. AB - BACKGROUND AND OBJECTIVES: This treatment study investigated the extent to which asymmetric dimensions of affective responding, specifically the positivity offset and the negativity bias, at pretreatment altered the rate of response to Behavioral Activation treatment for depression. METHOD: Forty-one depressed participants were enrolled into 16 weekly sessions of BA. An additional 36 lifetime healthy participants were evaluated prospectively for 16 weeks to compare affective responding between healthy and remitted patients at post treatment. All participants were assessed at Weeks 0, 8 and 16 using repeated measures, involving a structured clinical interview for DSM-IV Axis I disorders, questionnaires, and a computerized task designed to measure affective responses to unpleasant, neutral, and pleasant images. RESULTS: The negativity bias at pre treatment predicted the rate of response to BA, while the positivity offset did not. LIMITATIONS: Only one treatment condition was used in this study and untreated depressed participants were not enrolled, limiting our ability to compare the effect of BA. CONCLUSIONS: Baseline negativity bias may serve as a signal for patients to engage in and benefit from the goal-directed BA strategies, thereby accelerating rate of response. PMID- 26433702 TI - Simplified 2-tier histologic grading system accurately predicts outcomes in goblet cell carcinoid of the appendix. AB - Goblet cell carcinoid (GCC) is a rare appendiceal malignancy with both neuroendocrine and glandular features. Clinical outcomes of patients with GCC vary widely and a histology-based 3-tiered prognostic scheme has been previously suggested; however, this scheme is subjective and challenging to apply in day-to day practice. We sought to construct a simplified and prognostic grading system based on objective histologic features with specific criteria. A continuous population-based cohort of GCC with clinical outcome data and archival tissue available for review was extracted from regional databases. For the 78 patients with confirmed appendiceal GCC, specific histologic features, including cytologic atypia, peritumoral stromal desmoplasia, and solid growth pattern, were recorded, and a scoring system was devised, which separates patients with GCC into low grade (n = 55; 71%) or high-grade (n = 23; 29%) histology. Correspondingly, clinical follow-up data show good prognosis in those with low-grade histology with median and 10-year overall survival of 51.0 months and 80.5%, respectively, whereas those with high-grade histology have a poor prognosis with median and 10 year overall survival of 16.5 months (P = .006) and 0% (P < .001), respectively. Multivariate Cox proportional hazard modeling demonstrates that this 2-tier histologic system remains predictive of overall survival when controlled for TNM clinicopathological stage. These data show that a simple and objective histologic scoring system separates GCC into low- and high-grade histology with divergent clinical outcomes. PMID- 26433703 TI - FOXG1 expression shows correlation with neuronal differentiation in cerebellar development, aggressive phenotype in medulloblastomas, and survival in a xenograft model of medulloblastoma. AB - FOXG1 is a transcription factor that interacts with multiple signaling pathways and modulates neuronal differentiation in the telencephalon. Dysregulation of FOXG1 expression has been previously reported in medulloblastoma. In this study, we demonstrate a regional specific expression of FOXG1 and its colocalization with Nestin expression in the premigratory mitotically active (outer) layer of the external granular layer of the cerebellum. An inverse expression of the granular precursor cell markers, Math1 and Musashi1, in the inner nonmitotic migratory layer of the external granular layer and in the internal granular layer was observed. Furthermore, modulation of FOXG1 in the medulloblastoma cell line, DAOY, was associated with the induction of neuronal differentiation markers and significant changes in multiple signaling pathways regulating cell proliferation, differentiation, survival, and apoptosis. Additionally, we observed enhanced survival in intracerebellar mice xenografts injected with DAOY cells bearing shFOXG1 constructs versus shLuciferase construct. Overall, these findings suggest that down-modulation of FOXG1 is a prerequisite for the onset of neuronal differentiation during cerebellar development and that a decrease of FOXG1 in medulloblastoma cells offers a survival advantage in mice. We propose that the disruption of signaling pathways that promote mature neuronal differentiation by overexpressed FOXG1 is a contributing event in the neoplastic transformation of cerebellar stem cells. PMID- 26433704 TI - IL-18 is highly expressed in inflammatory infiltrates of submandibular glands in patients with immunoglobulin G4-related disease. AB - Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a new disease entity characterized by high serum IgG4 concentrations, infiltration of IgG4-positive plasmacytes, and fibrosis of various organs. Several groups have reported that IgG4-RD is a unique inflammatory disorder characterized by an immune reaction predominantly mediated by T helper (Th) 2 and regulatory T cells. Meanwhile, recent studies have demonstrated that interleukin (IL) 18 has a potential to trigger the production of Th2 cytokines by Th1 cells. We analyzed IL-18 expression in submandibular glands of patients with IgG4-RD (20 cases) and controls (19 cases) by immunohistochemical analysis and quantitative real-time reverse-transcription polymerase chain reaction. We found that IL-18 was highly expressed in submandibular glands of patients with IgG4-RD than in controls with both protein (P < .05, chi(2) test) and messenger RNA levels (P < .05, Mann Whitney U test). In addition, the expression of IL-18 and IL-13 was correlated in submandibular glands of patients with IgG4-RD. Moreover, by analyzing dual immunofluorescence staining, a few numbers of cells were double positive for IL 13 and interferon gamma at the inflammatory infiltrates of submandibular glands of patients with IgG4-RD. These data suggest a possibility that IL-13 is produced by Th1 cells. We speculated that IL-18 stimulates Th1 cells producing Th2 cytokines and enhances the immune reaction of Th2 cytokines in pathogenesis of IgG4-RD. PMID- 26433705 TI - An empirical model that uses light attenuation and plant nitrogen status to predict within-canopy nitrogen distribution and upscale photosynthesis from leaf to whole canopy. AB - Modelling the spatial and temporal distribution of leaf nitrogen (N) is central to specify photosynthetic parameters and simulate canopy photosynthesis. Leaf photosynthetic parameters depend on both local light availability and whole-plant N status. The interaction between these two levels of integration has generally been modelled by assuming optimal canopy functioning, which is not supported by experiments. During this study, we examined how a set of empirical relationships with measurable parameters could be used instead to predict photosynthesis at the leaf and whole-canopy levels. The distribution of leaf N per unit area (Na) within the canopy was related to leaf light irradiance and to the nitrogen nutrition index (NNI), a whole-plant variable accounting for plant N status. Na was then used to determine the photosynthetic parameters of a leaf gas exchange model. The model was assessed on alfalfa canopies under contrasting N nutrition and with N2-fixing and non-fixing plants. Three experiments were carried out to parameterize the relationships between Na, leaf irradiance, NNI and photosynthetic parameters. An additional independent data set was used for model evaluation. The N distribution model showed that it was able to predict leaf N on the set of leaves tested. The Na at the top of the canopy appeared to be related linearly to the NNI, whereas the coefficient accounting for N allocation remained constant. Photosynthetic parameters were related linearly to Na irrespective of N nutrition and the N acquisition mode. Daily patterns of gas exchange were simulated accurately at the leaf scale. When integrated at the whole-canopy scale, the model predicted that raising N availability above an NNI of 1 did not result in increased net photosynthesis. Overall, the model proposed offered a solution for a dynamic coupling of leaf photosynthesis and canopy N distribution without requiring any optimal functioning hypothesis. PMID- 26433706 TI - Growth habit and leaf economics determine gas exchange responses to high elevation in an evergreen tree, a deciduous shrub and a herbaceous annual. AB - Plant growth at high elevations necessitates physiological and morphological plasticity to enable photosynthesis (A) under conditions of reduced temperature, increased radiation and the lower partial pressure of atmospheric gases, in particular carbon dioxide (pCO2). Previous studies have observed a wide range of responses to elevation in plant species depending on their adaptation to temperature, elevational range and growth habit. Here, we investigated the effect of an increase in elevation from 2500 to 3500 m above sea level (a.s.l.) on three montane species with contrasting growth habits and leaf economic strategies. While all of the species showed identical increases in foliar delta(13)C, dark respiration and nitrogen concentration with elevation, contrasting leaf gas exchange and photosynthetic responses were observed between species with different leaf economic strategies. The deciduous shrub Salix atopantha and annual herb Rumex dentatus exhibited increased stomatal (Gs) and mesophyll (Gm) conductance and enhanced photosynthetic capacity at the higher elevation. However, evergreen Quercus spinosa displayed reduced conductance to CO2 that coincided with lower levels of photosynthetic carbon fixation at 3500 m a.s.l. The lower Gs and Gm values of evergreen species at higher elevations currently constrains their rates of A. Future rises in the atmospheric concentration of CO2 ([CO2]) will likely predominantly affect evergreen species with lower specific leaf areas (SLAs) and levels of Gm rather than deciduous species with higher SLA and Gm values. We argue that climate change may affect plant species that compose high-elevation ecosystems differently depending on phenotypic plasticity and adaptive traits affecting leaf economics, as rising [CO2] is likely to benefit evergreen species with thick sclerophyllous leaves. PMID- 26433707 TI - Genetic structure of coexisting wild and managed agave populations: implications for the evolution of plants under domestication. AB - Domestication is a continuous evolutionary process guided by humans. This process leads to divergence in characteristics such as behaviour, morphology or genetics, between wild and managed populations. Agaves have been important resources for Mesoamerican peoples since prehistory. Some species are domesticated and others vary in degree of domestication. Agave inaequidens Koch is used in central Mexico to produce mescal, and a management gradient from gathered wild and silvicultural populations, as well as cultivated plantations, has been documented. Significant morphological differences were reported among wild and managed populations, and a high phenotypic variation in cultivated populations composed of plants from different populations. We evaluated levels of genetic diversity and structure associated with management, hypothesizing that high morphological variation would be accompanied by high genetic diversity in populations with high gene flow and low genetic structure among managed and unmanaged populations. Wild, silvicultural and cultivated populations were studied, collecting tissue of 19-30 plants per population. Through 10 nuclear microsatellite loci, we compared population genetic parameters. We analysed partition of variation associated with management categories to estimate gene flow among populations. Agave inaequidens exhibits high levels of genetic diversity (He = 0.707) and moderate genetic structure (FST = 0.112). No differences were found in levels of genetic diversity among wild (He = 0.704), silviculturally managed (He = 0.733) and cultivated (He = 0.698) populations. Bayesian analysis indicated that five genetic clusters best fit the data, with genetic groups corresponding to habitats where populations grow rather than to management. Migration rates ranged from zero between two populations to markedly high among others (M = 0.73-35.25). Natural mechanisms of gene flow and the dynamic management of agave propagules among populations favour gene flow and the maintenance of high levels of variation within all populations. The slight differentiation associated with management indicates that domestication is in an incipient stage. PMID- 26433708 TI - Temperature monitoring during microwave ablation in ex vivo porcine livers. AB - OBJECTIVE: The aim of the present study was to assess the temperature map and its reproducibility while applying two different MWA systems (915 MHz vs 2.45 GHz) in ex vivo porcine livers. MATERIALS AND METHODS: Fifteen fresh pig livers were treated using the two antennae at three different settings: treatment time of 10 min and power of 45 W for both systems; 4 min and 100 W for the 2.45 GHz system. Trends of temperature were recorded during all procedures by means of fiber optic based probes located at five fixed distances from the antenna, ranging between 10 mm and 30 mm. Each trial was repeated twice to assess the reproducibility of temperature distribution. RESULTS: Temperature as function of distance from the antenna can be modeled by a decreasing exponential trend. At the same settings, temperature obtained with the 2.45 GHz system was higher than that obtained with the 915 MHz thus resulting into a wider area of ablation (diameter 17 mm vs 15 mm). Both systems showed good reproducibility in terms of temperature distribution (root mean squared difference for both systems ranged between 2.8 degrees C and 3.4 degrees C). CONCLUSIONS: When both MWA systems are applied, a decreasing exponential model can predict the temperature map. The 2.45 GHz antenna causes higher temperatures as compared to the 915 MHz thus, resulting into larger areas of ablation. Both systems showed good reproducibility although better results were achieved with the 2.45 GHz antenna. PMID- 26433709 TI - Robotic blue-dye sentinel lymph node detection for endometrial cancer - Factors predicting successful mapping. AB - OBJECTIVE: Sentinel lymph node (SLN) mapping has emerged as a viable option for the treatment of patients with endometrial cancer. We report our initial experience with SLN mapping algorithm, and examine the factors predicting successful SLN mapping. METHODS: We analyzed all data recorded in our institute on robotic blue-dye SLN detection mapping from the time it was first introduced to our department in January 2012-December 2014. Data included patient demographics, SLN allocation, operating room times, and pathology results. RESULTS: During the study period, 74 patients had robotic assisted surgery for endometrial cancer with attempted SLN mapping. SLN was found overall in 46 patients (62.1%). At first, SLN was detected in only 50% of cases, but after performing 30 cases, detection rates rose to 84.6% (OR = 3.34, CI 1.28-8.71; p = 0.003). Univariate analysis showed a higher detection rate with methylene blue than patent blue dye, 74.3% vs. 52.3% (OR = 2.744, 95% CI 1.026-7.344; p = 0.042). In multivariate analysis, high body mass index (BMI) was associated with failed mapping (OR = 0.899; 95% CI 0.808-1.00), as was the presence of lymph vascular space invasion (LVSI) (OR = 0.126; 95% CI 0.24-0.658) and few cases per surgeon (OR = 1.083, 95% CI 1.032-1.118). Factors related to uterine pathology itself, including tumor histology, grade, method of diagnosis, the presence of an endometrial polyp, and lower uterine segment involvement were not found to be associated with successful mapping. CONCLUSIONS: Surgeon experience, BMI and LVSI may affect the success rate of SLN mapping for endometrial cancer. These factors should be investigated further in future studies. PMID- 26433711 TI - Efficiency of an education program on the safety knowledge and skills of patients with rheumatoid arthritis treated by biologics. PMID- 26433712 TI - And the history goes on. PMID- 26433710 TI - Anti-pseudo-PCNA type 1 (anti-SG2NA) pattern: Track down Cancer, not SLE. AB - OBJECTIVE: Describe the clinical significance of anti-SG2NA antibodies also called anti-pseudo-PCNA type 1 (proliferating cell nuclear antigen auto antibodies) which are rare antinuclear antibodies (ANAs) staining distinctly S/G2 proliferative HEp-2 cells by indirect immunofluorescence. By analogy with anti PCNA antibodies, they have been suspected to be associated with systemic lupus erythematosus (SLE), cancers or viral diseases. METHODS: From May 2006 to February 2013, 16,827 patients were tested positive for ANAs in the Laboratory of Immunology, Strasbourg, France. We retrospectively analyzed clinical and biological data from 126 patients with anti-pseudo-PCNA type 1 antibodies. RESULTS: There was a 0.75% prevalence of anti-pseudo-PCNA type 1 Abs among ANAs(+) patients. Median age was 56.9 years (standard deviation [SD] 13.4 years) with a sex ratio female/male of 1.9. Compared to ANAs(+) patients, many more patients have been hospitalized in the Oncology and Hematology Department (23% vs. 6.3%, P < 0.05). Indeed, anti-pseudo-PCNA type 1 Abs were detected in 33 patients suffering from solid and hematological cancers (26%). Another group of patients presented various auto-immune diseases but surprisingly none of our patients was affected with SLE when 5 out of 8 patients in anti-PCNAs(+) Abs group (P < 5.10(-6)) were. Finally, the presence of anti-pseudo-PCNA type 1 Abs was associated in 30 cases with other auto-Abs reflecting a more general breakdown of B cell tolerance against other self-antigens. CONCLUSION: Considering our results, explorations for tumors should be at least recommended for patients with anti-pseudo-PCNA type 1 Abs. Lupus disease is not associated with these autoAbs. PMID- 26433713 TI - Evaluation and treatment of Sjogren's syndrome in focus. PMID- 26433714 TI - Characterization of alkaline phosphatase activity in seminal plasma and in fresh and frozen-thawed stallion spermatozoa. AB - Alkaline phosphatase (AP) has been studied in several situations to elucidate its role in reproductive biology of the male from different mammalian species; at present, its role in horse sperm physiology is not clear. The aim of the present work was to measure AP activity in seminal plasma and sperm extracts from freshly ejaculated as well as in frozen-thawed stallion spermatozoa and to verify whether relationship exists between AP activity and sperm quality parameters. Our data on 40 freshly ejaculated samples from 10 different stallions demonstrate that the main source of AP activity is seminal plasma, whereas sperm extracts contribution is very low. In addition, we found that AP activity at physiological pH (7.0) is significantly lower than that observed at pH 8.0, including the optimal AP pH (pH 10.0). Alkaline phosphatase did not exert any effect on sperm-oocyte interaction assessed by heterologous oocyte binding assay. Additionally, we observed a thermal stability of seminal plasma AP, concluding that it is similar to that of bone isoforms. Positive correlations were found between seminal plasma AP activity and sperm concentration, whereas a negative correlation was present between both spermatozoa extracts and seminal plasma AP activity and seminal plasma protein content. A significant decrease in sperm extract AP activity was found in frozen-thawed samples compared with freshly ejaculated ones (n = 21), concomitantly with the decrease in sperm quality parameters. The positive correlation between seminal plasma AP activity measured at pH 10 and viability of frozen-thawed spermatozoa suggests that seminal plasma AP activity could be used as an additional predictive parameter for stallion sperm freezability. In conclusion, we provide some insights into AP activity in both seminal plasma and sperm extracts and describe a decrease in AP after freezing and thawing. PMID- 26433715 TI - Verbal memory and menopause. AB - Midlife women frequently report memory problems during the menopausal transition. Recent studies validate those complaints by showing significant correlations between memory complaints and performance on validated memory tasks. Longitudinal studies demonstrate modest declines in verbal memory during the menopausal transition and a likely rebound during the postmenopausal stage. Clinical studies that examine changes in memory following hormonal withdrawal and add-back hormone therapy (HT) demonstrate that estradiol plays a critical role in memory. Although memory changes are frequently attributed to menopausal symptoms, studies show that the memory problems occur during the transition even after controlling for menopausal symptoms. It is well established that self-reported vasomotor symptoms (VMS) are unrelated to objective memory performance. However, emerging evidence suggests that objectively measured VMS significantly correlate with memory performance, brain activity during rest, and white matter hyperintensities. This evidence raises important questions about whether VMS and VMS treatments might affect memory during the menopausal transition. Unfortunately, there are no clinical trials to inform our understanding of how HT affects both memory and objectively measured VMS in women in whom HT is indicated for treatment of moderate to severe VMS. In clinical practice, it is helpful to normalize memory complaints, to note that evidence suggests that memory problems are temporary, and to counsel women with significant VMS that memory might improve with treatment. PMID- 26433716 TI - Wegener granulomatosis with supraglottic involvement. PMID- 26433717 TI - Effect of a mouthrinse containing rice peptide CL(14-25) on early dental plaque regrowth: a randomized crossover pilot study. AB - BACKGROUND: We aimed to evaluate clinically the effect of mouthrinse containing a rice peptide on early dental plaque regrowth. METHODS: The study was designed as a double-masked, two-group crossover randomized pilot trial, involving 10 periodontally healthy volunteers. After receiving a professional tooth cleaning at baseline, over the next 3 days each participant refrained from all oral hygiene measures and had two daily rinses with 20 ml of the test mouthrinse containing 0.4 % rice peptide CL(14-25) or placebo rinse. At the end of each experimental period, plaque score was assessed using the modified Volpe's method, and the participants filled out a questionnaire. Each participant underwent a 7 day washout period followed by a second allocation. The plaque score was the primary outcome of the study and participant perception was the secondary outcome. RESULTS: No adverse effects were observed in the participants during the study. Clinically, the mean plaque score of the examined teeth was significantly lower in the test group (2.44 +/- 0.74, CI: 1.91-2.96) than the placebo group (2.65 +/- 0.63, CI: 2.20-3.10) (P < 0.05). When analyzed according to the type of teeth, a significantly lower score of the premolars/molars was observed in the test group (2.39 +/- 0.68, CI: 2.08-2.71) than that in the placebo group (2.66 +/ 0.58, CI: 2.39-2.93) (P < 0.05). CONCLUSIONS: The mouthrinse containing 0.4 % rice peptide CL(14-25) was effective in reducing the early regrowth of dental plaque. However, clinical relevance of this efficacy needs to be validated in a future large-scale study. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN CTR) R000014000. Date of formal registration: November 1, 2013. PMID- 26433719 TI - Decreased Antibiotic Consumption in the Belgian Community: Is It Credible? PMID- 26433718 TI - Supply-side dimensions and dynamics of integrating HIV testing and counselling into routine antenatal care: a facility assessment from Morogoro Region, Tanzania. AB - BACKGROUND: Integration of HIV into RMNCH (reproductive, maternal, newborn and child health) services is an important process addressing the disproportionate burden of HIV among mothers and children in sub-Saharan Africa. We assess the structural inputs and processes of care that support HIV testing and counselling in routine antenatal care to understand supply-side dynamics critical to scaling up further integration of HIV into RMNCH services prior to recent changes in HIV policy in Tanzania. METHODS: This study, as a part of a maternal and newborn health program evaluation in Morogoro Region, Tanzania, drew from an assessment of health centers with 18 facility checklists, 65 quantitative and 57 qualitative provider interviews, and 203 antenatal care observations. Descriptive analyses were performed with quantitative data using Stata 12.0, and qualitative data were analyzed thematically with data managed by Atlas.ti. RESULTS: Limitations in structural inputs, such as infrastructure, supplies, and staffing, constrain the potential for integration of HIV testing and counselling into routine antenatal care services. While assessment of infrastructure, including waiting areas, appeared adequate, long queues and small rooms made private and confidential HIV testing and counselling difficult for individual women. Unreliable stocks of HIV test kits, essential medicines, and infection prevention equipment also had implications for provider-patient relationships, with reported decreases in women's care seeking at health centers. In addition, low staffing levels were reported to increase workloads and lower motivation for health workers. Despite adequate knowledge of counselling messages, antenatal counselling sessions were brief with incomplete messages conveyed to pregnant women. In addition, coping mechanisms, such as scheduling of clinical activities on different days, limited service availability. CONCLUSION: Antenatal care is a strategic entry point for the delivery of critical tests and counselling messages and the framing of patient-provider relations, which together underpin care seeking for the remaining continuum of care. Supply-side deficiencies in structural inputs and processes of delivering HIV testing and counselling during antenatal care indicate critical shortcomings in the quality of care provided. These must be addressed if integrating HIV testing and counselling into antenatal care is to result in improved maternal and newborn health outcomes. PMID- 26433720 TI - Epidemiology of Hepatitis B and Hepatitis C Infections and Benefits of Programs for Hepatitis Prevention in Northeastern China: A Cross-Sectional Study. AB - BACKGROUND: To investigate the epidemiology of hepatitis B and C infections and the benefits of programs aimed at hepatitis prevention and control in Northeastern China. METHODS: Individuals receiving health examinations were recruited to complete a questionnaire and undergo laboratory tests for hepatitis infection. Data on demographic characteristics, results of hepatitis B virus (HBV) and hepatitis C virus (HCV) serological tests, for HBV and HCV infection were analyzed. RESULTS: Among 227 808 study participants, the hepatitis B surface antigen (HBsAg) and anti-HCV-positive rates were 6.1% and 3.0%, respectively. Among HBsAg-positive participants, 63.8% tested positive for HBV DNA, 20.2% had an abnormal alanine aminotransferase (ALT) level, and 10.7% had cirrhosis. Among anti-HCV-positive participants, 57.2% tested positive for HCV RNA, 29.6% had an abnormal ALT level, and 8.4% had cirrhosis. Among HBsAg- or anti-HCV-positive participants, 47.1% and 32.0%, respectively, were aware of their infection. Among participants infected with HBV or HCV and suitable for antivirus treatment, 23.5% and 16.1%, respectively, had received antivirus treatment. The HBV plus HCV coinfection rate was 0.08%. CONCLUSIONS: The HBsAg-positive rate decreased significantly after implementation of recently introduced HBV control programs in China. However, the anti-HCV-positive rate showed only a slight decrease, indicating that programs for the prevention and control of hepatitis viruses require continued strengthening. CHINESE CLINICAL TRIALS REGISTRATION: ChiCTR-ECS 13004009. PMID- 26433721 TI - Swept source optical coherence tomography of a vitreal pocket entrapped in myelinated retinal nerve fibers. PMID- 26433723 TI - Effect of supplementation of beef cattle with different protein levels and degradation rates during transition from the dry to rainy season. AB - The objective of this study was to evaluate the effect of increasing the supply of protein with different degradation rates on the performance and metabolism of growing Nellore cattle reared on Brachiaria brizantha cv. Marandu pasture during the transition period from the dry to rainy season. The experiment was installed on an area of 34 ha, divided into 12 paddocks with an average area of 2.85 ha. In the performance evaluation were utilized 72 recently weaned, non-castrated Nellore cattle with an initial body weight (BW) of 199 kg (SEM = 16). The following supplements were used: energy protein supplement containing 25% crude protein (CP) (C-25) and energy protein supplements containing 40% CP with one third highly degradable CP and two thirds poorly degradable CP (40-1/3NPN), one half highly degradable CP and one half poorly degradable CP (40-1/2NPN), and two thirds highly degradable CP and one third poorly degradable CP (40-2/3NPN). Higher protein degradation rates reduced supplement intake (P < 0.01). In the first period, animals consuming supplement 40-1/3NPN exhibited higher average daily gain (ADG) (0.30 kg/day), similar to that of animals receiving supplement 40-1/2NPN (P = 0.04). In the second period, supplement 40-2/3NPN resulted in lower ADG (0.19 kg/day less than the other supplements). There was no effect of supplement on animal performance in the third period (P > 0.10), when ADG was 0.56 kg/day. In conclusion, the response to supplementation is associated with interactions with characteristics of the forage canopy. Supplementation with a true protein source will be beneficial only during the early stage of the dry rainy season transition period. PMID- 26433724 TI - Cross-Sectional Survey on Newborn Screening in Wisconsin Amish and Mennonite Communities. AB - Old Order Amish and Mennonites, or Plain populations, are a growing minority in North America with unique health care delivery and access challenges coupled with higher frequencies of genetic disorders. The objective of this study was to determine newborn screening use and attitudes from western Wisconsin Plain communities. A cross-sectional survey, with an overall response rate of 25 %, provided data representing 2010 children. In households with children (n = 297), the rate of newborn screening was 74 % and all children were screened in 40 % of these households. Lack of access to testing was the most common reason for not screening all children and parental age was inversely associated with testing. The majority of respondents reported some or more knowledge of screening, viewed screening as important, and had access to screening in their communities. Households with children who had never received newborn screening (26 %) reported lower frequencies of favorable responses in all categories compared to households that had at least one child screened. The difference in access to newborn screening was less marked between the groups compared to differences on knowledge and consideration of its importance. Moreover, 55 % of households who had never screened any of their children reported being unlikely or unsure of screening any future children. A focus on improving access to newborn screening alongside establishing approaches to change parental perceptions on the importance of newborn screening is necessary for increasing newborn screening in these Plain communities. PMID- 26433722 TI - Transcriptional regulators of GntR family in Streptomyces coelicolor A3(2): analysis in silico and in vivo of YtrA subfamily. AB - Transcriptional factors of the GntR family regulate numerous physiological and morphological processes in response to the nutrient state of bacterial cells. The number of GntR transcriptional factors in genomes of soil-dwelling actinomycetes is one of the highest among bacteria, reflecting both the large size of their chromosomes and the complex ecological niche that they occupy. However, very little is known about the roles of GntRs in actinomycete biology. Here, we analyzed the genome of model actinomycete, Streptomyces coelicolor A3(2), in an attempt to gain new insights into the function of GntR family. All 56 GntR proteins of M145 strain were classified into FadR, HutC, MocR, YtrA, and DevA subfamilies according to their secondary structure. We then checked for the presence of GntR orthologs in six other sequenced Streptomyces and one Kitasatospora genomes, revealing that 12 GntRs were conserved in all analyzed strains. Genomic analysis of the less studied YtrA type regulators revealed 160 sequences present in 88 members of Coriobacteridae, Rubrobacteridae, and Actinobacteridae subclasses. These proteins form seven dense clusters on the consensus phylogenetic tree and their genes are usually co-located with the genes for transport proteins. Probable operator sites were identified for orthologous groups of Sco0823 and Sco3812 proteins. All S. coelicolor YtrA-like regulatory genes (SCO0823, SCO1728, SCO3812) were analyzed at transcriptional level, knocked out, and introduced on moderate copy number plasmid in M145 strain. Also, gene SCO0824, a part of putative SCO0823 operon, was studied. Results of these experiments are discussed here. PMID- 26433725 TI - Community Stakeholders' Perceptions of Major Factors Influencing Childhood Obesity, the Feasibility of Programs Addressing Childhood Obesity, and Persisting Gaps. AB - Prior research has identified numerous factors contributing to increased rates of childhood obesity. However, few studies have focused explicitly on the experience of community stakeholders in low-income communities. This study sought to capture the perspectives of these on-the-ground experts regarding major factors contributing to childhood obesity as well as gaps in current prevention and control efforts. We conducted semi-structured interviews with 39 stakeholders from different community sectors (e.g., healthcare providers, childcare providers, teachers). Data were drawn from the Massachusetts Childhood Obesity Research Demonstration project, a multi-level, multi-sector intervention designed to reduce childhood obesity being implemented in two low-income communities in Massachusetts. Interviews were conducted at baseline, transcribed, coded using grounded theory approach, and analyzed in NVivo 10.0. The vast majority of stakeholders had recently participated in obesity prevention strategies, and nearly all of them identified gaps in prevention efforts either within their organizations or in the broader community. In addition to factors previously identified in the literature, several themes emerged including the need to change policies to increase physical activity during school, offer healthier snacks in schools and afterschool programs, and increase communication and collaboration within the community in prevention efforts. Community stakeholders can impact the success of interventions by bridging the gap between science and lived experience. The results of this study can guide future research by highlighting the importance of including stakeholders' frontline experiences with target populations, and using information on identified gaps to augment intervention planning efforts. PMID- 26433726 TI - Current status of nontuberculous mycobacterial surgery in Japan: analysis of data from the annual survey by the Japanese Association for Thoracic Surgery. AB - OBJECTIVE: The prevalence of pulmonary disease caused by nontuberculous mycobacteria (NTM) has been increasing in Japan. Adjuvant resectional surgery is often recommended to lessen disease progression when the response to drug therapy is poor. In all likelihood, as affected cases of NTM disease increase, so will the number of operations. The goal of this study was to determine the current status of NTM surgery in Japan by analyzing data from the annual survey of the Japanese Association for Thoracic Surgery (JATS). METHODS: Data were obtained from annual surveys conducted between 2008 and 2012. The annual number of operations for pulmonary NTM disease was tabulated nationwide and in each region (Hokkaido, Tohoku, Kanto, Tokyo, Chubu, Kinki, Chugoku/Shikoku, and Kyushu). For comparison, the numbers for pulmonary tuberculosis and tuberculoma operations were also obtained. RESULTS: The annual number of operations for pulmonary NTM disease nationwide increased each year between 2008 and 2012: 292 (2008), 323 (2009), 452 (2010), 440 (2011), and 514 (2012); an overall increase of 76%. Conversely, the annual numbers of operations for pulmonary tuberculosis were stable: 145 (2008), 181 (2009), 117 (2010), 113 (2011), and 107 (2012), as were the annual numbers of operations for tuberculoma: 386 (2008), 341 (2009), 320 (2010), 390 (2011), and 351 (2012). CONCLUSION: Data from the JATS annual survey demonstrate a steady increase in the number of NTM surgeries in Japan. General thoracic surgeons will continue to increasingly encounter NTM patients who are candidates for surgery until a magic bullet against NTM disease is available. PMID- 26433727 TI - Rapid Clozapine Titration in Patients with Treatment Refractory Schizophrenia. AB - The aim of this study is to evaluate the safety and effectiveness of rapid clozapine titration in patients with schizophrenia in hospital settings. We conducted a retrospective two-center cohort study to compare the safety and effectiveness of clozapine with different titration rates in treatment-refractory patients with schizophrenia. In the first center, clozapine was started at 25-50 mg followed by 50-100 mg as needed every 6 h on day 1, followed by increases of 50-100 mg/day. In the second center, titration was slower; clozapine initiated with 12.5-50 mg on day 1 followed by increases of 25-50 mg/day. The number of days between starting of clozapine until discharge was shorter in the rapid titration group (22.4 +/- 8.72 vs 27.0 +/- 10.5, p = 0.1). Number of days of total hospital stay were significantly shorter in the rapid titration group (29.6 +/- 10.6 vs 41.2 +/- 14.8, p = 0.002). Hypotension was more common in the rapid titration group and one patient had suspected myocarditis. Rapid clozapine titration appeared safe and effective. The length of stay following initiation of clozapine was shorter in the rapid-titration group, although this was not statistically significant. However starting clozapine earlier together with rapid titration has significantly shortened the length of hospital stay in patients with treatment refractory schizophrenia. PMID- 26433728 TI - Prognoses and treatment strategies for synchronous peritoneal dissemination of colorectal carcinoma. AB - PURPOSE: We devised a simple dichotomous classification system and showed sufficient reproducibility to indicate treatment strategies for peritoneal metastasis of colorectal cancer. METHODS: We included 67 patients with peritoneal metastasis of colorectal cancer and classified them according to the largest lesion size, number of lesions and number of regional peritoneal metastases. The oncological data were recorded and compared. RESULTS: According to the univariate analyses, the prognoses were significantly better in patients with <=3 disseminated lesions than in those with >=4, and in patients with disseminated lesions in only one region than in those with >=2 lesions. A multivariate analysis showed that primary tumor resection and the presence of peritoneal metastases in only one region were favorable factors for the patient survival. Patients with disseminated lesions in only one region (localized group) and those with nonlocalized lesions had three-year survival rates of 45.6 and 12.2 %, respectively. Finally, primary tumor resection improved the prognoses in both the localized and nonlocalized groups. CONCLUSIONS: Colorectal cancer patients were categorized into localized and nonlocalized groups according to the number of regions with peritoneal metastasis, and significant prognostic associations were demonstrated. Subsequent analyses of the oncological data suggested that primary tumor resection contributes to an improved prognosis in all patients with synchronous peritoneal metastases. PMID- 26433729 TI - Exploiting the ubiquitin and phosphoinositide pathways by the Legionella pneumophila effector, SidC. AB - Intracellular bacterial pathogens use secreted effector proteins to alter host cellular processes, with the goal of subverting host defenses and allowing the infection to progress. One such pathogen, Legionella pneumophila, secretes ~300 proteins into its host to alter a number of pathways including intracellular trafficking, phosphoinositide metabolism, and cell signaling. The Legionella effector SidC was previously found to bind to PI(4)P and was responsible for the enrichment of ER proteins and ubiquitinated species on the Legionella-containing vacuoles. Through our recent work, we have discovered that SidC contains a unique N-terminal E3 ubiquitin ligase domain and a C-terminal novel PI(4)P-binding domain. Our results demonstrate that SidC serves to link two distinct cellular pathways, ubiquitin and phosphoinositide. However, how the ubiquitin ligase activity regulates host membrane trafficking events remains to be investigated. PMID- 26433730 TI - An experimental study on the effects of a simulation game on students' clinical cognitive skills and motivation. AB - Simulation games are becoming increasingly popular in education, but more insight in their critical design features is needed. This study investigated the effects of fidelity of open patient cases in adjunct to an instructional e-module on students' cognitive skills and motivation. We set up a three-group randomized post-test-only design: a control group working on an e-module; a cases group, combining the e-module with low-fidelity text-based patient cases, and a game group, combining the e-module with a high-fidelity simulation game with the same cases. Participants completed questionnaires on cognitive load and motivation. After a 4-week study period, blinded assessors rated students' cognitive emergency care skills in two mannequin-based scenarios. In total 61 students participated and were assessed; 16 control group students, 20 cases students and 25 game students. Learning time was 2 h longer for the cases and game groups than for the control group. Acquired cognitive skills did not differ between groups. The game group experienced higher intrinsic and germane cognitive load than the cases group (p = 0.03 and 0.01) and felt more engaged (p < 0.001). Students did not profit from working on open cases (in adjunct to an e-module), which nonetheless challenged them to study longer. The e-module appeared to be very effective, while the high-fidelity game, although engaging, probably distracted students and impeded learning. Medical educators designing motivating and effective skills training for novices should align case complexity and fidelity with students' proficiency level. The relation between case-fidelity, motivation and skills development is an important field for further study. PMID- 26433731 TI - Wilderness Medical Society Practice Guidelines for the Treatment of Pitviper Envenomations in the United States and Canada. PMID- 26433732 TI - Intrathecal Administration of Tempol Reduces Chronic Constriction Injury-Induced Neuropathic Pain in Rats by Increasing SOD Activity and Inhibiting NGF Expression. AB - We investigate the antinociceptive effect of intrathecal and intraperitoneal tempol administration in a rat model of chronic constriction injury (CCI)-induced neuropathic pain and explore the underlying antinociceptive mechanisms of tempol. Rats were randomly assigned to four groups (n = 8 per group): sham group, CCI group, Tem1 group (intrathecal injection of tempol), and Tem2 group (intraperitoneal injection of tempol). Neuropathic pain was induced by CCI of the sciatic nerve. Tempol was intrathecally or intraperitoneally administered daily for 7 days beginning on postoperative day one. The mechanical withdrawal threshold and thermal withdrawal latency were tested on preoperative day 3 and postoperative days 1, 3, 5, 7, 10, 14, and 21. Structural changes were examined by hematoxylin and eosin staining, toluidine blue staining, and electron microscopy. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were determined using the thiobarbituric acid and nitroblue tetrazolium methods, respectively. Nerve growth factor (NGF) expression levels were determined by immunohistochemistry and Western blot. Intrathecal, but not intraperitoneal, injection of tempol produced a persistent antinociceptive effect. Intraperitoneal injection of tempol did not result in high enough concentration of tempol in the cerebrospinal fluid. Intrathecal, but not intraperitoneal, injection of tempol inhibited CCI-induced structural damage in the spinal cord reduced MDA levels, and increased SOD activities in the spinal cord. Furthermore, intrathecal, but not intraperitoneal, injection of tempol further downregulated the expression of NGF in the spinal cord following CCI, and this effect was blocked by p38MAPK inhibitor. Intrathecal injection of tempol produces antinociceptive effects and reduces CCI-induced structural damage in the spinal cord by increasing SOD activities and downregulating the expression of NGF via the p38MAPK pathway. Intraperitoneal administration of tempol does not exhibit antinociceptive effects. PMID- 26433733 TI - Annual cost of stable coronary artery disease in France: A modeling study. AB - BACKGROUND: Few studies have analyzed the cost of treatment of chronic angina pectoris, especially in European countries. AIM: To determine, using a modeling approach, the cost of care in 2012 for 1year of treatment of patients with stable angina, according to four therapeutic options: optimal medical therapy (OMT); percutaneous coronary intervention with bare-metal stent (PCI-BMS); PCI with drug eluting stent (PCI-DES); and coronary artery bypass graft (CABG). METHODS: Six different clinical scenarios that could occur over 1year were defined: clinical success; recurrence of symptoms without hospitalization; myocardial infarction (MI); subsequent revascularization; death from non-cardiac cause; and cardiac death. The probability of a patient being in one of the six clinical scenarios, according to the therapeutic options used, was determined from a literature search. A direct medical cost for each of the therapeutic options was calculated from the perspective of French statutory health insurance. RESULTS: The annual costs per patient for each strategy, according to their efficacy results, were, in our models, ?1567 with OMT, ?5908 with PCI-BMS, ?6623 with PCI-DES and ?16,612 with CABG. These costs were significantly different (P<0.05). A part of these costs was related to management of complications (recurrence of symptoms, MI and death) during the year (between 3% and 38% depending on the therapeutic options studied); this part of the expenditure was lowest with the CABG therapeutic option. CONCLUSION: OMT appears to be the least costly option, and, if reasonable from a clinical point of view, might achieve appreciable savings in health expenditure. PMID- 26433734 TI - The cost-effectiveness of the Olweus Bullying Prevention Program: Results from a modelling study. AB - Exposure to bullying affects around 3-5 percent of adolescents in secondary school and is related to various mental health problems. Many different anti bullying programmes are currently available, but economic evaluations are lacking. The aim of this study is to identify the cost effectiveness of the Olweus Bullying Prevention Program (OBPP). We constructed a decision-tree model for a Swedish secondary school, using a public payer perspective, and retrieved data on costs and effects from the published literature. Probabilistic sensitivity analysis to reflect the uncertainty in the model was conducted. The base-case analysis showed that using the OBPP to reduce the number of victims of bullying costs 131,250 Swedish kronor (?14,470) per victim spared. Compared to a relevant threshold of the societal value of bullying reduction, this indicates that the programme is cost-effective. Using a relevant willingness-to-pay threshold shows that the OBPP is a cost-effective intervention. PMID- 26433735 TI - Sunflower (Helianthus annuus) fatty acid synthase complex: beta-hydroxyacyl-[acyl carrier protein] dehydratase genes. AB - MAIN CONCLUSION: Two sunflower hydroxyacyl-[acyl carrier protein] dehydratases evolved into two different isoenzymes showing distinctive expression levels and kinetics' efficiencies. beta-Hydroxyacyl-[acyl carrier protein (ACP)]-dehydratase (HAD) is a component of the type II fatty acid synthase complex involved in 'de novo' fatty acid biosynthesis in plants. This complex, formed by four intraplastidial proteins, is responsible for the sequential condensation of two carbon units, leading to 16- and 18-C acyl-ACP. HAD dehydrates 3-hydroxyacyl-ACP generating trans-2-enoyl-ACP. With the aim of a further understanding of fatty acid biosynthesis in sunflower (Helianthus annuus) seeds, two beta-hydroxyacyl [ACP] dehydratase genes have been cloned from developing seeds, HaHAD1 (GenBank HM044767) and HaHAD2 (GenBank GU595454). Genomic DNA gel blot analyses suggest that both are single copy genes. Differences in their expression patterns across plant tissues were detected. Higher levels of HaHAD2 in the initial stages of seed development inferred its key role in seed storage fatty acid synthesis. That HaHAD1 expression levels remained constant across most tissues suggest a housekeeping function. Heterologous expression of these genes in E. coli confirmed both proteins were functional and able to interact with the bacterial complex 'in vivo'. The large increase of saturated fatty acids in cells expressing HaHAD1 and HaHAD2 supports the idea that these HAD genes are closely related to the E. coli FabZ gene. The proposed three-dimensional models of HaHAD1 and HaHAD2 revealed differences at the entrance to the catalytic tunnel attributable to Phe166/Val1159, respectively. HaHAD1 F166V was generated to study the function of this residue. The 'in vitro' enzymatic characterization of the three HAD proteins demonstrated all were active, with the mutant having intermediate K m and V max values to the wild-type proteins. PMID- 26433736 TI - Incidence of morphometric vertebral fractures in adult patients with growth hormone deficiency. AB - Cross-sectional studies showed an elevated prevalence of clinical and morphometric vertebral fractures (VFs) in adult patients with growth hormone deficiency (GHD). However, no data are available on incidence and determinants of radiological VFs in this clinical setting. In this prospective study, we investigated the incidence and risk factors of radiological VFs in adults with GHD. Forty patients with GHD (28 males, 12 females; median age 44 years, range 19 82) were studied for incident VFs using quantitative morphometric approach on spine X-ray at baseline and after 6 years of follow-up. GHD patients were also studied for bone mineral density (BMD) measured by DXA at lumbar spine. After 6 years of follow-up, 12 patients (30 %) experienced incident VFs. Patients with incident VFs had more frequently untreated GHD and prevalent VFs at baseline, as compared to patients who did not experience incident VFs. Untreated GHD patients were significantly older as compared to treated GHD (50 years, range 19-82 vs. 36 years, range 19-75; p = 0.003), but the correlation between high risk of VFs and untreated GHD remained significant even after adjustment for the age of patients (odds ratio 6.8, CI 95 % 1.1-41.8; p = 0.037). In GHD patients experiencing incident VFs, lumbar spine BMD decreased significantly whereas it did not change in patients not developing VFs. This is the first prospective study confirming the hypothesis suggested by cross-sectional studies that untreated GHD may cause high risk of VFs in adult patients and that recombinant human GH treatment may effectively decrease such a risk. PMID- 26433737 TI - Increased serum gamma-glutamyltransferase levels are associated with ventricular instability in type 2 diabetes. AB - The purpose of our study is to examine the association between serum GGT levels and ventricular instability in Chinese patients with T2DM. We conducted a cross sectional, community-based study in Nanjing, China from June to November 2011. Among 10,050 patients aged 40-79 years, we enrolled 2444 with pre-diabetes, 2496 with T2DM, and 4521 without diabetes (non-diabetes). Electrocardiograms were performed to measure the QT interval corrected for heart rate (QTc) and QT interval dispersion (QTd). Serum GGT levels, metabolic parameters, body mass index, and blood pressure were also measured. We found that there were no significant associations of increased QTc/QTd with serum GGT levels in participants with pre-existing T2DM and non-diabetes, after adjusting for age, duration of diabetes, and metabolic parameters. Even after adjustment, higher risks of QTc >= 440 ms/?s and QTd >= 58 ms were found in participants with serum GGT levels >=49 U/L compared with those with <15 U/L in the pre-diabetes (QTc: OR 1.96, 95 % CI 1.23-2.47; QTd: OR 1.34, 95 % CI 1.07-1.94) and newly diagnosed T2DM (QTc: OR 2.01, 95 % CI 1.39-2.51; QTd: OR 1.53, 95 % CI 1.03-1.99) groups. We conclude that Increased serum GGT levels are associated with some markers of ventricular repolarization abnormalities in the early stage of T2DM. PMID- 26433738 TI - Factors associated with 1,25-dihydroxyvitamin D3 concentrations in liver transplant recipients: a prospective observational longitudinal study. AB - The aim of the study was to identify factors associated with 1,25(OH)2D3 concentrations in liver transplant recipients with emphasis on the renal function and catabolism. We also tested the hypothesis that tacrolimus increases 1,25(OH)2D3 concentrations. Serum 25(OH)D3, 1,25(OH)2D3, and 24,25(OH)2D3 were measured in 41 patients before, at 2 weeks and 3 months after transplantation. Dose-adjusted tacrolimus concentration was used as a surrogate marker of CYP3A4 activity. Factors associated with 1,25(OH)2D3 were identified using multivariate linear regression analysis. The median 1,25(OH)2D3 levels remained stable: 55 versus 46 pg/ml (P = 0.36) despite an increase in 25(OH)D3 from 18 ng/ml at baseline to 26 ng/ml (P = 0.03), serum albumin (34 to 41 g/l, P = 0.02), and comparable eGFR at baseline and month 3 (94 and 92 ml/min, respectively, P = 0.15). At 3 months 19 % of patients had 1,25(OH)2D3 < 25 pg/ml. Low eGFR and a low dose-adjusted tacrolimus concentration were both independently associated with 1,25(OH)2D3 at 3 months. Liver transplant recipients with impaired renal function or a low dose-adjusted tacrolimus concentration suggesting a high CYP3A4 are at risk of low 1,25(OH)2D3 concentrations. The use of tacrolimus does not lead to an increase in 1,25(OH)2D3 concentrations in a clinical setting. PMID- 26433739 TI - Duration of anti-resorptive therapy for osteoporosis. AB - Osteoporotic fractures are common, and available medications reduce fracture risk by up to half. However, because the most commonly used drugs, bisphosphonates, have side effects that may be related to duration of therapy and because long term efficacy has not been established, the optimal length of treatment has not been determined. Based on two long-term studies and extensive clinical experience, a plan is provided to treat patients at risk for 5 years with re assessment every 2 years thereafter. Assessment tools are limited, but for each individual, the potential risks and benefits of continuing, discontinuing, re instituting, or changing therapy can be estimated. PMID- 26433740 TI - Low 25 (OH) vitamin D levels are associated with autoimmune thyroid disease in polycystic ovary syndrome. AB - Low 25(OH) vitamin D levels have been associated with several autoimmune diseases and recently with autoimmune thyroid disease (AITD). The aim of the study was to investigate the association of AITD with 25(OH) vitamin D levels in women with polycystic ovary syndrome (PCOS). Fifty women with PCOS were consecutively enrolled and underwent routine health checkups, which included measurements of 25(OH) vitamin D, anti-thyroid peroxidase (TPO-Ab), anti-thyreoglobulin (TG-Ab) antibodies, FT3, FT4, and TSH. Selecting 50 nmol/L as cut-off point, low 25(OH) vitamin D levels were detected in 23 of 50 patients (46 %). AITD was diagnosed when TPO-Ab levels exceeding 80 U/ml and/or TG-Ab levels exceeding 70 U/ml. AITD was detected in 12 of 50 patients (24 %). The levels of 25(OH) vitamin D were significantly lower in women with PCOS and AITD when compared with women with PCOS and without AITD (p = 0.02). In women with AITD no correlation was found between 25(OH) vitamin D and TG-Ab (r = 0.48; p = 0.16), TPO-Ab (r = 0.43; p = 0.21), TSH (r = 0.38; p = 0.27), FT3 (r = -0.40; p = 0.25) and FT4 levels (r = 0.54; p = 0.10). These findings suggest that low levels of 25(OH) vitamin D were significantly associated with AITD in women with PCOS. PMID- 26433741 TI - Health risk assessment of heavy metals via dietary intake of wheat grown in Tianjin sewage irrigation area. AB - The possible health risks from heavy metal (Zn, Cu, Cr, Ni, Pb, and Cd) contamination to the local population through the food chain were evaluated in Tianjin, China, a city with a long history of sewage irrigation. Results showed that the continuous application of wastewater has led to an accumulation of heavy metals in the soil, and 54.5 and 18.25% soil samples accumulated Cd and Zn in concentrations exceeding the permissible limits in China. Concentrations of heavy metals in wheat grain decreased in the order of Zn > Cu > Cr > Ni > Pb > Cd, and transfer factors for the six heavy metals showed the trend as Zn > Cd > Cu > Pb > Cr > Ni. The risk assessment for the six heavy metals through wheat consumption suggests that concentrations of Cr and Cd in some wheat samples exceed their reference oral dose for adults and children. In general, no target hazard quotient value of any individual element was greater than one, which means they are within the safe interval. However, 36.4 and 63.6% hazard index values for adults and children were greater than one, respectively. The health risk due to the added effects of heavy metals was significant for children and adults, and more attention should be paid tothe potential added threat fromheavy metals to the health of children via dietary intake of wheat in Tianjin. PMID- 26433742 TI - An investigation of classical swine fever virus seroprevalence and risk factors in pigs in Timor-Leste. AB - Classical swine fever virus (CSFV) is a highly infectious pathogen of pigs and believed to be a major constraint to pig production in Timor-Leste. The Ministry of Agriculture and Fisheries conducts vaccination campaigns in an attempt to control clinical disease, however, there is no empirical data available concerning the seroprevalence and distribution of CSFV in Timor-Leste. To help address this knowledge deficit, a cross-sectional study to determine seroprevalence was conducted in the three districts that border Indonesia. Data on farmer- and pig-level factors were also collected to look at their impact on CSFV serological status. Overall, true CSFV seroprevalence was estimated at 34.4%. Seroprevalence estimates varied widely between and within districts, subdistricts, and villages. Older pigs and pigs that had been vaccinated for CSFV were more likely to test positive for CSFV antibody. Pigs owned by farmers that experienced the sudden death of pigs in the 12 months prior to the survey were more likely to test positive for CSFV antibody, while pigs that had been sick in the previous three months were less likely to test positive for CSFV antibody. The final multivariable model accounted for a large amount of variation in the data, however, much of this variation was explained by the random effects with less than one percent of the variation explained by the fixed effects. This work further supports the need for a collaborative approach to whole-island CSFV control between West Timor, Indonesia and Timor-Leste. Further work is needed to better understand the risk factors for CSFV serological status in order to allocate resources for control. As CSFV is now endemic in Timor-Leste research involving a combination of serology, antigen detection and in-depth investigation of suspect cases over a period of time may be required. PMID- 26433743 TI - Medical information concerning an infant's congenital anomaly: Successful communication to support parental adjustment and transition. AB - BACKGROUND: When a diagnosis of congenital anomaly (CA) is made, parents are confronted with new and complex medical information, which may impact their parental adjustment. However, few studies have explored the role of information concerning the CA in parental adjustment, during the transition to parenthood. OBJECTIVE/HYPOTHESIS: This study aimed to characterize both parents' perceptions of information concerning the CA and to investigate their role in maternal and paternal adjustment, one month after the disclosure and six months post-birth. METHODS: Thirty six couples whose infants were prenatally- or postnatally diagnosed with a CA participated in this prospective longitudinal study. During both assessment times (Time 1: one-month after the disclosure; Time 2: six-month post-birth), they answered the Brief Symptom Inventory-18, the EUROHIS-QOL-8, and other specific questions to assess parents' information perceptions. RESULTS: Mothers were more satisfied than fathers (p < .01) with the amount of information that was received at the disclosure, although mothers and fathers reported similar levels of comprehension of information. Six-month post-birth, both parents were similarly satisfied with the information that was received, although mothers sought significantly more (p < .01) additional information. Both maternal and paternal adjustment were significantly associated with maternal perceptions of information concerning CA. CONCLUSION: Health professionals should recognize the important role of information concerning CA in parental adjustment and tailor their communication practices in order to promote parents' satisfaction and comprehension of the medical information. Despite the prominent influence of maternal perceptions on parental adjustment, both parents should be included in the communication process. PMID- 26433744 TI - Large-scale signal detection: A unified perspective. AB - There is an overwhelmingly large literature and algorithms already available on "large-scale inference problems" based on different modeling techniques and cultures. Our primary goal in this article is not to add one more new methodology to the existing toolbox but instead (i) to clarify the mystery how these different simultaneous inference methods are connected, (ii) to provide an alternative more intuitive derivation of the formulas that leads to simpler expressions in order (iii) to develop a unified algorithm for practitioners. A detailed discussion on representation, estimation, inference, and model selection is given. Applications to a variety of real and simulated datasets show promise. We end with several future research directions. PMID- 26433745 TI - Real-time polymerase chain reaction and culture in the diagnosis of invasive group B streptococcal disease in infants: a retrospective study. AB - Group B streptococcus (GBS) is a leading cause of invasive disease in infants. Accurate and rapid diagnosis is crucial to reduce morbidity and mortality. Real time polymerase chain reaction (PCR) targeting the dltR gene was utilised for the direct detection of GBS DNA in blood and cerebrospinal fluid (CSF) from infants at an Irish maternity hospital. A retrospective review of laboratory and patient records during the period 2011-2013 was performed in order to evaluate PCR and culture for the diagnosis of invasive GBS disease. A total of 3570 blood and 189 CSF samples from 3510 infants had corresponding culture and PCR results. Culture and PCR exhibited concordance in 3526 GBS-negative samples and 13 (25%) GBS positive samples (n = 53). Six (11%) and 34 (64%) GBS-positive samples were positive only in culture or PCR, respectively. Culture and PCR identified more GBS-positive infants (n = 47) than PCR (n = 43) or culture (n = 16) alone. Using culture as the reference standard, the sensitivity, specificity, and positive and negative predictive values for PCR on blood samples were 71.4%, 99.2%, 25% and 99.9%, and for CSF samples, they were 60%, 97.8%, 42.9% and 98.9%, respectively. The sensitivity and positive predictive values were improved (blood: 84.6% and 55%; CSF: 77.8% and 100%, respectively) when maternal risk factors and other laboratory test results were considered. The findings in this study recommend the use of direct GBS real-time PCR for the diagnosis of GBS infection in infants with a clinical suspicion of invasive disease and as a complement to culture, but should be interpreted in the light of other laboratory and clinical findings. PMID- 26433747 TI - A report on the consequences of the first implanted device for long-term analgesia in refractory cancer pain. AB - BACKGROUND: During the early 1970s, satisfactory long-term treatment of the severe pain associated with metastatic cancer was not available. Spinal cord stimulation introduced a few years earlier in 1967 had not proven to be effective in treating nociceptive pain. We describe our pioneering experience using an implanted device to infuse local anesthetics into the epidural space and provide pain relief to the patient. METHODS: Increasing doses of systemic opioids were unsuccessful in treating the intractable pain of spinal metastases in our patient. We devised an analgesic delivery system by modifying equipment usually used for ventriculoperitoneal shunts. A lumbar epidural catheter was inserted in the patient's spine, then tunneled subcutaneously across the flank to the anterior abdominal wall, and subsequently connected to a modified Ommaya reservoir with ventriculoperitoneal shunt tubing. This was filled with local anesthetic and injected into the patient's epidural space by manual compression. RESULTS: The system was used for several months with intermittent addition of local anesthetic to the reservoir with satisfactory control of the patient's pain. CONCLUSIONS: We describe the first use of an implanted epidural catheter system for long-term relief of pain due to terminal cancer that occurred at Peter Bent Brigham Hospital in Boston. We contend that this event played an important role in the cascade of devices that followed and connect it to the changes in the attitude of health care providers toward treatment of cancer pain. PMID- 26433746 TI - Activity of temocillin, mecillinam, ceftazidime, and ceftazidime/avibactam against carbapenem-non-susceptible Enterobacteriaceae without carbapenemase production. AB - Treatment options for multidrug-resistant Gram-negative infections are scarce and therefore alternatives with a narrow spectrum or new agents are sought. Antimicrobial susceptibility to temocillin, mecillinam, ceftazidime, and ceftazidime/avibactam was determined using Etest and disk diffusion according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodology. A total of 77 carbapenem-nonsusceptible Enterobacteriaceae were studied, including Klebsiella pneumoniae (26%), Escherichia coli (26%), Enterobacter cloacae (26%), and Enterobacter aerogenes (22%). Several phenotypic tests, PCRs followed by sequencing and a microbiological bioassay excluded carbapenemase production in all isolates. Antimicrobial susceptibility rates were low for temocillin (15.6%, minimum inhibitory concentration [MIC] range 2 to >1,024 MUg/ml), moderate for mecillinam (59.7%, MIC range 0.25 to >256 MUg/ml), and excellent for ceftazidime/avibactam (100%, zone diameter range 19 to 32 mm, median 25 mm). 5.2% of the isolates were susceptible to ceftazidime alone (zone diameter range 6 to 32 mm). In this study, mecillinam exhibited moderate and ceftazidime/avibactam excellent in vitro antimicrobial activity against carbapenem-nonsusceptible Enterobacteriaceae without carbapenemase production. Ceftazidime/avibactam was able to restore previously reduced susceptibility to ceftazidime in all isolates, thus potentiating its activity. Temocillin only exhibited low in vitro antimicrobial activity against the isolates. Further evaluation of mecillinam and ceftazidime/avibactam with regard to the potential clinical utility against infections caused by these pathogens has to be performed. PMID- 26433749 TI - Interactions involved in pH protection of the alphavirus fusion protein. AB - The alphavirus membrane protein E1 mediates low pH-triggered fusion of the viral and endosome membranes during virus entry. During virus biogenesis E1 associates as a heterodimer with the transmembrane protein p62. Late in the secretory pathway, cellular furin cleaves p62 to the mature E2 protein and a peripheral protein E3. E3 remains bound to E2 at low pH, stabilizing the heterodimer and thus protecting E1 from the acidic pH of the secretory pathway. Release of E3 at neutral pH then primes the virus for fusion during entry. Here we used site directed mutagenesis and revertant analysis to define residues important for the interactions at the E3-E2 interface. Our data identified a key residue, E2 W235, which was required for E1 pH protection and alphavirus production. Our data also suggest additional residues on E3 and E2 that affect their interacting surfaces and thus influence the pH protection of E1 during alphavirus exit. PMID- 26433748 TI - Mungbean yellow mosaic Indian virus encoded AC2 protein suppresses RNA silencing by inhibiting Arabidopsis RDR6 and AGO1 activities. AB - RNA silencing refers to a conserved RNA-directed gene regulatory mechanism in a wide range of eukaryotes. It plays an important role in many processes including growth, development, genome stability, and antiviral defense in the plants. Geminivirus encoded AC2 is identified as an RNA silencing suppressor protein, however, the mechanism of action has not been characterized. In this paper, we elucidate another mechanism of AC2-mediated suppression activity of Mungbean Yellow Mosaic India Virus (MYMIV). The AC2 protein, unlike many other suppressors, does not bind to siRNA or dsRNA species and its suppression activity is mediated through interaction with key components of the RNA silencing pathway, viz., RDR6 and AGO1. AC2 interaction inhibits the RDR6 activity, an essential component of siRNA and tasi-RNA biogenesis and AGO1, the major slicing factor of RISC. Thus the study identifies dual sites of MYMIV-AC2 interference and probably accounts for its strong RNA silencing suppression activity. PMID- 26433750 TI - Electrophysiological evaluation of nerve function in inferior alveolar nerve injury: relationship between nerve action potentials and histomorphometric observations. AB - The objective of this study was to improve the accuracy of diagnosis of inferior alveolar nerve (IAN) injury by determining degrees of nerve disturbance using the sensory nerve action potential (SNAP) and sensory nerve conduction velocity (SCV). Crush and partial and complete nerve amputation injuries were applied to the IAN of rabbits, then SNAPs and histomorphometric observations were recorded at 1, 5, and 10 weeks. For crush injury, most nerves were smaller in diameter at 5 weeks than at 1 week, however after 10 weeks, extensive nerve regeneration was observed. The SNAP showed a decrease in SCV at weeks 1 and 5, followed by an increase at week 10. For partial nerve amputation, small to medium-sized nerve fibres were observed at weeks 1 and 5, then larger nerves were seen at week 10. Minimal changes in SCV were observed at weeks 1 and 5, however SCV increased at week 10. For complete nerve amputation, nerve fibres were sparse at week 1, but gradual nerve regeneration was observed at weeks 5 and 10. SNAPs were detectable from week 10, however the SCV was extremely low. This study showed SCV to be an effective factor in the evaluation of nerve injury and regeneration. PMID- 26433751 TI - Radiologists' interpretive efficiency and variability in true- and false-positive detection when screen-reading with tomosynthesis (3D-mammography) relative to standard mammography in population screening. AB - We examined interpretive efficiency and variability in true- and false-positive detection (TP, FP) for radiologists screen-reading with digital breast tomosynthesis as adjunct to full-field digital mammography (2D/3D) relative to 2D alone in population-based screening studies. A systematic literature search was performed to identify screening studies that provided radiologist-specific data for TP and FP detection. Radiologist interpretive efficiency (trade-off between TPs and FPs) was calculated using the FP:TP ratio which expresses the number of FP recalls for each screen-detected breast cancer. We modeled a pooled FP:TP ratio to assess variability in radiologists' interpretive efficiency at study level using random effects logistic regression. FP:TP ratio improved (ratio decreased) for 2D/3D screen-reading (relative to 2D) for a majority of radiologists (18 of 22) across all studies. Variability in radiologists' FP:TP ratio was consistently lower in all studies for 2D/3D screen-reading, as suggested by lower variance in ratios. Study-level pooled FP:TP ratio for 2D- and 2D/3D-mammography respectively, were 5.96 (95%CI: 4.08 to 8.72) and 3.17 (95%CI: 2.25 to 4.47) for the STORM trial; 10.25 (95%CI: 6.42 to 16.35) and 7.07 (95%CI: 4.99 to 10.02) for the Oslo trial; and 20.84 (95%CI: 13.95 to 31.12) and 8.37 (95%CI: 5.87 to 11.93) for the Houston study. This transfers into study-level improved interpretative efficiencies of 48%, 30% and 55%, respectively, for 2D/3D screen-reading (relative to 2D). In summary, study-level FP:TP trade-off improved using 2D/3D-mammography for all studies, which was also seen for most individual radiologists. There was variability in the FP:TP trade-off between readers and studies for 2D-as well as for 2D/3D-interpretations but variability in radiologists' interpretive efficiency was relatively lower using 2D/3D mammography. PMID- 26433752 TI - Differences in Caregiver Food Allergy Quality of Life Between Tertiary Care, Specialty Clinic, and Caregiver-Reported Food Allergic Populations. AB - BACKGROUND: Food allergy is associated with diminished caregiver quality of life (QoL), but the heterogeneity of this effect is unknown. OBJECTIVE: The objective of this study was to explore potential differences in caregiver QoL between self selected caregivers reporting a child with food allergy (SS) and caregivers with children followed at a food allergy referral center clinic (RC). METHODS: The Food Allergy Quality of Life Parental Burden (FAQL-PB) index and screening questions regarding the child's most severe food reaction were administered to caregivers of milk, egg, peanut, or tree nut allergic children. SS were recruited via the email and/or social media networks of 2 large national food allergy advocacy groups, and RC from a tertiary referral center specialty clinic. RESULTS: Among 2003 SS and 305 RC, the mean total FAQL-PB QoL score was 2.67. Compared with SS, RC had a lower (better) mean total QoL score (1.84 vs 2.81, P < .001), individual FAQL-PB domain scores (mean difference range 0.51-1.93; all P < .001), and lower QoL scores for all allergens (mean difference range 0.89-1.32; peanut P < .001, tree nut P < .001, milk P = .006, egg P = .001). In an adjusted multiple linear regression model, RC were associated with a lower QoL score (-1.6 [95% CI, -1.91 to -1.29], P < .001). Factor analysis of the index revealed 2 dimensions. A minimal clinically important difference of 0.3 was calculated for the FAQL-PB using the standard error of measurement method. CONCLUSIONS: Caregiver food allergy QoL is heterogeneous, and worse among SS versus RC. Clinically and statistically significant differences were noted in the total, domain-specific, and allergen-specific QoL scores, which indicated that the food allergic population may be segmented and have different risk profiles and/or burdens of illness, despite a common diagnosis. PMID- 26433753 TI - Skeletal muscle electrical stimulation improves baroreflex sensitivity and heart rate variability in heart failure rats. AB - The goal of the current study was to evaluate the effects of electrical stimulation (ES) on the arterial baroreflex sensitivity (BRS) and cardiovascular autonomic control in rats with chronic heart failure (CHF). Male Wistar rats were designated to one of four groups: placebo sham (P-Sham, n=9), ES sham (ES-Sham, n=9), placebo CHF (P-CHF, n=9) or ES CHF (ES-CHF, n=9). The ES was adjusted at a low frequency (30 Hz), duration of 250 MUs, with hold and rest time of 8s (4 weeks, 30 min/day, 5 times/week). It was applied on the gastrocnemius muscle with intensity to produce a visible muscle contraction. The rats assigned to the placebo groups performed the same procedures with the equipment turned off. The two-way ANOVA and the post hoc Student-Newman-Keuls tests (P<0.05) were used to data comparison. The BRS was higher in ES-Sham group compared to the P-Sham group and the ES-CHF group compared to the P-CHF group. ES was able to decrease heart rate sympatho-vagal modulation and peripheral sympathetic modulation in ES-CHF compared to P-CHF group. Interestingly, heart rate sympatho-vagal modulation was similar between ES-CHF and P-Sham groups. Thus, ES enhances heart rate parasympathetic modulation on heart failure (ES-CHF) compared to placebo (P-CHF), with consequent decrease of sympatho-vagal balance in the ES-CHF group compared to the P-CHF. The results show that a 4 week ES protocol in CHF rats enhances arterial BRS and cardiovascular autonomic control. PMID- 26433754 TI - Evaluation of performance of human immunodeficiency virus antigen/antibody combination assays in Taiwan. AB - BACKGROUND: The fourth-generation human immunodeficiency virus (HIV) combination assay, which can simultaneously detect the presence of anti-HIV antibody and HIV antigen, has been shown to shorten the window period in HIV diagnosis compared with the third-generation HIV antibody immunoassay. This study was aimed to determine the performance of HIV combination assays in Taiwan, where the HIV-1 seroprevalence is 0.007% and HIV-2 infection has never been reported. METHODS: Performance of three fourth-generation HIV Ag/Ab combination assays (Dia.Pro, Wantai, and Bio-Rad) and one third-generation HIV Ab immunoassay (AxSYM HIV 1/2 gO) was assessed. RESULTS: A total of 152 specimens, including 86 confirmed HIV seropositive and 66 HIV-seronegative samples, were used in the study. The sensitivity of four assays varied from 98.8% to 100%, and specificity varied from 98.5% to 100%. Performance of the 75 equivocal samples, the HIV status of which was confirmed later, in terms of negative prediction varied from 81.8% to 87.5%. The Bio-Rad and Dia.Pro assays exhibited higher sensitivity for the detection of p24 antigen among the three fourth-generation HIV combination assays. CONCLUSION: The three fourth-generation HIV Ag/Ab combination assays exhibited better sensitivity, specificity, and negative prediction than the third-generation HIV Ab immunoassay. PMID- 26433755 TI - Virulence factors, antibiotic resistance phenotypes and O-serogroups of Escherichia coli strains isolated from community-acquired urinary tract infection patients in Mexico. AB - BACKGROUND/PURPOSE: Uropathogenic Escherichia coli (UPEC) strains isolated from patients with community-acquired urinary tract infections (UTIs) were assessed to determine the prevalence of virulence genes, antibiotic resistance, and the O serogroup of the strains. METHODS: Consenting patients with community-acquired UTI were enrolled at Unidad Medica Familiar Number 64 (Instituto Mexicano del Seguro Social, Estado de Mexico, Mexico) and 321 urine samples were collected. Polymerase chain reaction (PCR) was used to assess 24 virulence genes and 14 O serogroups. The Kirby-Bauer method was used to evaluate the antibiotic susceptibility of the isolated strains to 12 commonly used antibiotics. RESULTS: A total of 194 strains were identified as E. coli using standard biochemical tests, followed by PCR amplification of 16S ribosomal RNA gene. Only 58.2% of the strains belonged to the assessed 14 O-serogroups. The serogroups O25, O15, O8, and O75 were present in 20.6%, 17%, 6.1%, and 4.6% of strains, respectively. The most frequently occurring virulence genes among UPEC strains included kpsMT (92.2% strains), usp (87.1%), irp2 (79.3%), iha (64.9%), fim (61.3%), set (36%), astA (33.5%), pap (24.7%), and papGII (21.1%). In addition, 97% of the strains were multi-drug resistant (coresistance to 3-11 antibiotics). CONCLUSION: The isolated UPEC strains predominantly belonged to three serogroups (O25, O15, and O8), harboured numerous virulence genes, and are multiresistant to antibiotics. The findings of this study could be used to orient UTI treatment strategies and in epidemiological studies in Mexico. PMID- 26433756 TI - [Comparison of propofol and midazolam on patients undergoing spinal surgery with intraoperative wake-up test: randomized clinical trial]. AB - BACKGROUND AND OBJECTIVES: Instrumentation in correction operations for spinal deformities carries a 0.5-5% risk of injuring the spinal cord. The wake-up test is used for early detection of these injuries. In this study we compared the effects of propofol and midazolam during wake-up test in scoliosis surgery. METHODS: Thirty patients were randomly assigned as group P and group M. Anesthesia was induced with propofol 2.5mgkg(-1) for group P or midazolam 0.5mgkg(-1) for group M with remifentanil 0.5MUgkg(-1) and cisatracurium 0.15mgkg(-1) for both groups. At the maintenance of anesthesia O2/air and infusions of remifentanil and cisatracurium were used. In group P, propofol 6 10mgkg(-1)h(-1) and in group M, midazolam 0.5mgmgkg(-1) were preferred. Approximately 15min before the wake-up test, all drugs were discontinued. At the wake-up test, anesthesiologist asked the patients to open their eyes and squeeze his/her hand at every 30s until the patients responded. Then patients were told to wiggle their toes. Hemodynamic parameters, time of eye-opening, appropriate movement upon verbal command were evaluated. BIS frequency throughout the operation was recorded. RESULTS: The eye opening time was 9+/-2.15min in group P and 7+/-3.15min in group M. Motor movement time was 12+/-2.55min in group P and 21.25+/-3.93min in group M. CONCLUSION: Propofol provided better wake-up conditions and conducted a better neurologic assessment within the same BIS values than midazolam. PMID- 26433757 TI - Environmental noise and incident mental health problems: A prospective cohort study among school children in Germany. AB - BACKGROUND: Environmental noise is considered a threat to public health as 20% of the EU population is exposed to health influencing noise levels. An association of noise and mental health problems in children has been suggested by some studies, but results are not consistent and there are no longitudinal studies of this association. Our aim was to investigate the influence of different environmental noise sources at children's homes on incident mental health problems in school-aged children. METHOD: A cohort study of children from first (t0) to fourth grade (t1) of primary school was conducted. Different environmental noise sources (day/night separately) at children's home were assessed via parental annoyance reports. Increased noise exposure between t0 and t1 was the exposure variable. Incident mental health problems were assessed with the parental version of the Strengths and Difficulties Questionnaire (SDQ). RRs and 95% CIs were analysed to investigate the association between different noise sources and incident mental health problems. RESULTS: The study population consisted of 583 boys and 602 girls. The most common increase in noise exposure between t0 and t1 was road traffic noise day (26.38%). After adjusting for covariates exposure to road traffic night was significantly associated with the total difficulties score (RR=2.06; 95% CI=1.25-3.40), emotional symptoms (RR=1.69, 95% CI=1.04-2.72), and conduct problems (RR=1.57, 95% CI=1.04-2.38). Noise by neighbours during the day was associated with conduct problems (RR=1.62, 95% CI=1.11-2.40) and hyperactivity (RR=1.69, 95% CI=1.08-2.65). Aircraft noise day and construction work day were not associated with any of the SDQ categories at a significant level. CONCLUSION: Environmental noise is an important public health problem. This is the first study to investigate the association of a broad range of noise sources and incident mental health problems in children in a cohort study. Our results suggest that exposure to noise at children's home is associated with mental health problems such as emotional symptoms, conduct problems and hyperactivity. PMID- 26433758 TI - Attention-deficit hyperactivity disorder, its treatment with medication and the probability of developing a depressive disorder: A nationwide population-based study in Taiwan. AB - OBJECTIVE: The purpose of this study is to determine the risk of developing depressive disorders by evaluating children with attention-deficit/hyperactivity disorder (ADHD) in comparison to controls that do not have ADHD, as well as to analyze whether the medications used to treat ADHD, methylphenidate (MPH) and atomoxetine (ATX), influence the risk of depression. METHODS: A group of patients newly diagnosed with ADHD (n=71,080) and age- and gender-matching controls (n=71,080) were chosen from Taiwan's National Health Insurance database during the period of January 2000 to December 2011. Both the patients and controls were monitored through December 31, 2011. We also explore the potential influence of the length of MPH and ATX treatment on developing depressive disorders. RESULTS: The ADHD patients showed a significantly increased probability of developing a depressive disorder when compared to the control group (ADHD: 5.3% vs. CONTROLS: 0.7%; aHR, 7.16, 99% CI: 6.28-8.16). Regarding treatment with MPH, a longer MPH use demonstrates significant protective effects against developing a depressive disorder (aOR, 0.91, 99%CI: 0.88-0.94). However, the duration of ATX treatment could not be significantly correlated with the probability of developing a depressive disorder. LIMITATIONS: The database employed in this study lacks of comprehensive clinical information for the patients with ADHD. Potential moderating factors between ADHD and depression were not considered in-depth in this study. CONCLUSIONS: The results of this study reveal that youths diagnosed with ADHD have a greater risk of developing depressive disorders. Long-term treatment with MPH correlated to the reduced probability of developing a depressive disorder among youths with ADHD. PMID- 26433759 TI - Association of Type D personality with increased vulnerability to depression: Is there a role for inflammation or endothelial dysfunction? - The Maastricht Study. AB - BACKGROUND: Type D personality - the combination of negative affectivity (NA) and social inhibition (SI) - has been associated with depression but little is known about underlying mechanisms. We examined whether (1) Type D is a vulnerability factor for depression in general, (2) Type D is associated with inflammation or endothelial dysfunction, and (3) these biomarkers alter the possible association between Type D and depression. METHODS: In the Maastricht Study, 712 subjects underwent assessment of NA, SI and Type D personality (DS14), depressive disorder (Mini-International Neuropsychiatric Interview) and depressive symptoms (Patient Health Questionnaire-9). Plasma biomarkers of inflammation (hsCRP, SAA, sICAM-1, IL-6, IL-8, TNF-alpha) and endothelial dysfunction (sVCAM-1, sICAM-1, E-selectin, vWF) were measured with sandwich immunoassays or ELISA and combined into standardized sumscores. RESULTS: Regarding personality, 49% of the study population was low in NA and SI, 22% had SI only, 12% NA only and 17% had Type D. Depressive disorder and depressive symptoms were significantly more prevalent in Type D versus the other three personality subgroups. Multivariable regression analyses showed that Type D was associated with inflammation (beta=0.228, p=0.014) and endothelial dysfunction (beta=0.216, p=0.022). After adjustment for these biomarkers, Type D remained independently associated with increased vulnerability to depressive disorder (OR=13.20, p<0.001) and depressive symptoms (beta=3.87, p<0.001). LIMITATIONS: The cross-sectional design restrained us to draw any conclusions on causality. The relatively low prevalence of depressive disorder restrained us to adjust for more potential confounders. CONCLUSIONS: Type D personality may be a vulnerability factor for depression, irrespective of levels of inflammation or endothelial dysfunction. Future research should examine possible underlying mechanisms. PMID- 26433760 TI - Altered resting-state functional connectivity in late-life depression: A cross sectional study. AB - BACKGROUND: Disrupted brain connectivity is implicated in the pathophysiology of late-life depression (LLD). There are few studies in this area using resting state functional magnetic resonance imaging (rs-fMRI). In this pilot case-control study, we compare rs-fMRI data between age-matched depressed and non-depressed older adults. METHODS: Older participants (>=55 years) with current major depressive disorder (MDD) were recruited to participate in an ongoing study of LLD, and were compared to the age-matched, non-depressed controls. Rs-fMRI data were collected using a 3-Tesla MRI system. In this study, a data-driven approach was chosen and an independent component analysis (ICA) was performed. RESULTS: Seventeen subjects with MDD were compared to 31 controls. The depressed group showed increased connectivity in three main networks compared to the controls (p(corr)<0.05), including connectivity between the default mode network (DMN) and the posterior superior temporal sulcus (pSTS). Increased connectivity was also observed within the visual network in the medial, lateral and ventral regions of the occipital lobes, and within the auditory network throughout the right superior temporal cortex. CONCLUSION: This data-driven, pilot study finds patterns of increased connectivity that may be unique to LLD in the DMN, as well as visual and auditory networks. The functional implications of this aberrant connectivity remains to be determined. These findings should be further explored in larger samples. PMID- 26433761 TI - Psychometric properties of the rass scale in the Serbian population. PMID- 26433763 TI - Clinical effectiveness of cognitive behavioral therapy for depression in routine care: A propensity score based comparison between randomized controlled trials and clinical practice. AB - BACKGROUND: The efficacy of cognitive behavioral therapy (CBT) for the treatment of depressive disorders has been demonstrated in many randomized controlled trials (RCTs). This study investigated whether for CBT similar effects can be expected under routine care conditions when the patients are comparable to those examined in RCTs. METHOD: N=574 CBT patients from an outpatient clinic were stepwise matched to the patients undergoing CBT in the National Institute of Mental Health Treatment of Depression Collaborative Research Program (TDCRP). First, the exclusion criteria of the RCT were applied to the naturalistic sample of the outpatient clinic. Second, propensity score matching (PSM) was used to adjust the remaining naturalistic sample on the basis of baseline covariate distributions. Matched samples were then compared regarding treatment effects using effect sizes, average treatment effect on the treated (ATT) and recovery rates. RESULTS: CBT in the adjusted naturalistic subsample was as effective as in the RCT. However, treatments lasted significantly longer under routine care conditions. LIMITATIONS: The samples included only a limited amount of common predictor variables and stemmed from different countries. There might be additional covariates, which could potentially further improve the matching between the samples. CONCLUSIONS: CBT for depression in clinical practice might be equally effective as manual-based treatments in RCTs when they are applied to comparable patients. The fact that similar effects under routine conditions were reached with more sessions, however, points to the potential to optimize treatments in clinical practice with respect to their efficiency. PMID- 26433764 TI - Pilot trial of light therapy for depression in hospitalized patients with cystic fibrosis. AB - BACKGROUND: Depression is common in cystic fibrosis (CF) and linked with worse outcomes during hospitalization. Bright-light therapy during hospitalizations augments antidepressant regimens and reduces length of stay (LOS) in depressed non-CF patients, but has not been examined in CF METHODS: Thirty subjects used a light box emitting 10,000lx for 30min each day for 7 straight days following hospital admission for pulmonary exacerbation. Depressive symptom severity (QIDS C) and quality of life factors (CFQ-R) were recorded pre/post light therapy. RESULTS: Eighty percent of subjects had at least mild depressive symptoms upon admission. Hospitalized CF patients had a significantly lower mean LOS of 11.0+/ 3.6 days compared to a historical cohort from the year prior (13.3+/-4.4 days, p value=0.038). There was a significant decrease in depressive symptoms for all subjects receiving light therapy (p value<0.0001). There was no relation between depressive symptoms and lung function or vitamin D. Six out of twelve quality of life indicators improved with light therapy including the domains of vitality, emotion, and health perceptions. There were no adverse events reported. LIMITATIONS: As a pilot study, the design was limited by a lack of a control group and possible confounding effects of hospitalization treatment on systemic symptoms. CONCLUSIONS: Light therapy was well tolerated by hospitalized CF patients and resulted in improved depressive symptoms and quality of life. Light therapy was associated with a reduced length of stay. Large, randomized trials of light therapy may be indicated for hospitalized CF patients. PMID- 26433762 TI - A genome-wide association study of bipolar disorder with comorbid eating disorder replicates the SOX2-OT region. AB - BACKGROUND: Bipolar disorder is a heterogeneous mood disorder associated with several important clinical comorbidities, such as eating disorders. This clinical heterogeneity complicates the identification of genetic variants contributing to bipolar susceptibility. Here we investigate comorbidity of eating disorders as a subphenotype of bipolar disorder to identify genetic variation that is common and unique to both disorders. METHODS: We performed a genome-wide association analysis contrasting 184 bipolar subjects with eating disorder comorbidity against both 1370 controls and 2006 subjects with bipolar disorder only from the Bipolar Genome Study (BiGS). RESULTS: The most significant genome-wide finding was observed bipolar with comorbid eating disorder vs. controls within SOX2-OT (p=8.9*10(-8) for rs4854912) with a secondary peak in the adjacent FXR1 gene (p=1.2*10(-6) for rs1805576) on chromosome 3q26.33. This region was also the most prominent finding in the case-only analysis (p=3.5*10(-7) and 4.3*10(-6), respectively). Several regions of interest containing genes involved in neurodevelopment and neuroprotection processes were also identified. LIMITATIONS: While our primary finding did not quite reach genome-wide significance, likely due to the relatively limited sample size, these results can be viewed as a replication of a recent study of eating disorders in a large cohort. CONCLUSIONS: These findings replicate the prior association of SOX2-OT with eating disorders and broadly support the involvement of neurodevelopmental/neuroprotective mechanisms in the pathophysiology of both disorders. They further suggest that different clinical manifestations of bipolar disorder may reflect differential genetic contributions and argue for the utility of clinical subphenotypes in identifying additional molecular pathways leading to illness. PMID- 26433765 TI - Infectious thoracic disease in patients with neutropenia. PMID- 26433766 TI - A systematic review and meta-analysis of the impact of Spirulina supplementation on plasma lipid concentrations. AB - BACKGROUND & AIMS: The impact of Spirulina supplementation on plasma lipid concentrations has not been conclusively studied. Therefore the aim of the meta analysis was to assess the effect of Spirulina supplementation on plasma lipid concentrations. METHODS: We searched PubMed and Scopus (up to July 03, 2015) to identify randomized controlled trials (RCTs) that investigate the effect Spirulina supplementation on plasma lipid concentrations. Meta-analysis and meta regression were performed using random-effects models. RESULTS: Random-effect meta-analysis of data from 7 RCTs showed a significant effect of supplementation with spirulina in reducing plasma concentrations of total cholesterol (WMD: 46.76 mg/dL, 95% CI: -67.31 to -26.22, p < 0.001), LDL-C (WMD: -41.32 mg/dL, 95% CI: -60.62 to -22.03, p < 0.001) and triglycerides (WMD: -44.23 mg/dL, 95% CI: 50.22 to -38.24, p < 0.001), and elevating those of HDL-C (WMD: 6.06 mg/dL, 95% CI: 2.37-9.76, p = 0.001). The impact of spirulina on plasma concentrations of total cholesterol (slope: -1.32; 95% CI: -8.58 to 5.93; p = 0.720), LDL-C (slope: -1.01; 95% CI: -8.03 to 6.02; p = 0.778), triglycerides (slope: -1.39; 95% CI: 4.26 to 1.48; p = 0.342) and HDL-C (slope: 1.79, 95% CI: -0.48 to 4.05; p = 0.122) was independent of administered dose. Regarding duration of supplementation with Spirulina, significant associations were found with changes in plasma concentrations of total cholesterol (slope: -1.77; 95% CI: -3.48 to 0.07; p = 0.042), LDL-C (slope: -1.73; 95% CI: -3.40 to -0.06; p = 0.042) HDL-C (slope: 0.91; 95% CI: 0.68-1.14; p < 0.001) and triglycerides (slope: -1.39; 95% CI: -2.28 to -0.50; p = 0.002). CONCLUSIONS: This meta-analysis showed a significant effect of supplementation with Spirulina in reducing plasma concentrations of total cholesterol, LDL-C, triglycerides and elevating those of HDL-C. PMID- 26433767 TI - PURE muscle and more. PMID- 26433768 TI - Safety of prone positioning still in doubt. PMID- 26433769 TI - The fate of autogenous free fat grafts in the human temporomandibular joint using magnetic resonance imaging. AB - OBJECTIVE: Autologous fat grafts in the temporomandibular joint (TMJ) has achieved positive clinical effects in preventing adhesion after surgery. However it still remains indeterminate about the survival rate of grafted fat. The purpose of this study was to evaluate the long-term survival rate of free fat grafts in the TMJ using magnetic resonance imaging (MRI). MATERIALS AND METHODS: 89 patients (117 joints) with free fat grafts placed into TMJs following modified TMJ disc anchor were included in our study. They were divided into the following groups according to the time lapse between TMJ surgery and the latest MRI investigation: 1-3 months, 4-6 months, 7-12 months, 13-24 months, and >24 months. The signal intensity changes and volume retention were evaluated by MRI. RESULTS: The volume retention rate of grafted free fat showed that the size was hovering right around 50% although it reduced very slowly with a long-term follow-up. Nearly half joints showed lower signal intensity of the grafted fat on MRI within 6 months and it recovered to normal compared with that of the day after surgery 6 months later. CONCLUSIONS: Free fat grafted into TMJ cavity could be alive for a long time with the survival rate about 48.44%. However the survival mechanism has still been unknown, which need us to explore and study in the future. PMID- 26433770 TI - Quantifying the outcome of surgical treatment of temporomandibular joint ankylosis: A systematic review and meta-analysis. AB - INTRODUCTION: Temporomandibular joint ankylosis results in restricted mouth opening due to a fibrous or bony (non-neoplastic) union of the mandibular head to the glenoid fossa. Early surgical treatment is recommended, but the ideal surgical technique is debated. Our objective was to quantify the effect of different surgical interventions on maximal (interincisal) mouth opening. METHODS: The systematic literature search (1960-2015) was based on PubMed, Web of Science and the Cochrane Library. Pooled mean differences and 95% confidence intervals between pre-operative and post-operative maximal mouth opening (in mm) were calculated with random-effects meta-analyses. The surgical interventions were grouped according to increasing complexity: gap arthroplasty, interposition arthroplasty and reconstruction arthroplasty. RESULTS: Thirty-eight articles were identified (1993-2015), including 1215 patients who underwent operations; 84% of the cases were caused by trauma, and 8% by infection. Gap arthroplasty (n=463), interposition arthroplasty (n=409) and reconstruction arthroplasty (n=293) resulted in improved maximal mouth opening of 26.2 mm (95% CI, 24.1-28.2), 26.7 mm (95% CI, 24.6-28.8) and 30.6 mm (95% CI, 28.7-32.5), respectively, and 28.7 mm overall (95% CI, 26.7-29.2). The mean pooled post-operative maximal mouth opening ranged between 33.0 and 36.1 mm. CONCLUSIONS: The maximal mouth opening improved most after reconstruction arthroplasty, and least after gap arthroplasty. However, the post-operative maximal mouth opening was similar for all techniques. PMID- 26433771 TI - Development of mandibular osteoradionecrosis in rats: Importance of dental extraction. AB - OBJECTIVES: To develop an animal model of mandibular osteoradionecrosis (ORN) using a high-energy radiation source (as used in human therapeutics) and to assess the role of tooth extraction on ORN development. MATERIALS AND METHODS (STUDY DESIGN): Ten animals were irradiated with a single 35- or 50-Gy dose. Three weeks later, the second left mandibular molar was extracted from three animals in each group. Nine weeks after irradiation, the animals were euthanized, with an injection of contrast agent in the bloodstream to highlight vascularization. Mandibles were harvested and studied using micro-CT, histology, tartrate-resistant acid phosphatase activity and scanning electron microscopy. RESULTS: This study demonstrates that a single 50-Gy dose associated with molar extraction is necessary for ORN development. In these conditions, absence of healing of the mucosa and bone, dental effects, fibrosis, an increase in osteoclast activity and a decrease in vascularization were observed. We also determined that molar extraction increases the impact of the cellular effects of radiation. CONCLUSION: The mandibular ORN animal model was validated after 50-Gy irradiation and molar extraction. The results of this study therefore support an animal ORN model and tissue engineering strategies will now be developed to regenerate bone for patients with head and neck cancer. PMID- 26433772 TI - Human parvovirus B19 and autoimmune diseases. Review of the literature and pathophysiological hypotheses. AB - A number of arguments support the role played by PVB19 in autoimmunity, in the broad sense of the term essentially derived from numerous clinical case reports and/or small series over the past 20-30 years in the medical literature. PVB19 can induce a very broad spectrum of autoantibody production, especially including: anti-soluble nuclear antigen antibodies, antiphospholipid antibodies anti-native DNA antibodies, antilymphocyte antibody, anticardiolipin antibodies, antinuclear antibodies and rheumatoid factor. Notably acute PVB19 infection can mimic or stimulate autoimmune systemic diseases as rheumatoid arthritis or systemic lupus erythematosus. However, at the present time, there is no formal scientific evidence demonstrating a direct role of PVB19 in autoimmunity, bearing in mind that there are also no formal arguments against it. Further large studies are needed to understand the eventual role of PVB19 in autoimmune diseases. PMID- 26433774 TI - A quantitative analysis of microplastic pollution along the south-eastern coastline of South Africa. AB - The extent of microplastic pollution (<5mm) in the southern hemisphere, particularly southern Africa, is largely unknown. This study aimed to evaluate microplastic pollution along the south-eastern coastline of South Africa, looking at whether bays are characterised by higher microplastic densities than open stretches of coastline in both beach sediment and surf-zone water. Microplastic (mean +/- standard error) densities in the beach sediment ranged between 688.9 +/ 348.2 and 3308 +/- 1449 particles . m(-2), while those in the water column varied between 257.9 +/- 53.36 and 1215 +/- 276.7 particles . m(-3). With few exceptions there were no significant spatial patterns in either the sediment or water column microplastic densities; with little differences in density between bays and the open coast (P>0.05). These data indicate that the presence of microplastics were not associated with proximity to land-based sources or population density, but rather is governed by water circulation. PMID- 26433773 TI - Motivated to win: Relationship between anticipatory and outcome reward-related neural activity. AB - Reward-processing involves two temporal stages characterized by two distinct neural processes: reward-anticipation and reward-outcome. Intriguingly, very little research has examined the relationship between neural processes involved in reward-anticipation and reward-outcome. To investigate this, one needs to consider the heterogeneity of reward-processing within each stage. To identify different stages of reward processing, we adapted a reward time-estimation task. While EEG data were recorded, participants were instructed to button-press 3.5s after the onset of an Anticipation-Cue and received monetary reward for good time estimation on the Reward trials, but not on No-Reward trials. We first separated reward-anticipation into event related potentials (ERPs) occurring at three sub stages: reward/no-reward cue-evaluation, motor-preparation and feedback anticipation. During reward/no-reward cue-evaluation, the Reward-Anticipation Cue led to a smaller N2 and larger P3. During motor-preparation, we report, for the first time, that the Reward-Anticipation Cue enhanced the Readiness Potential (RP), starting approximately 1s before movement. At the subsequent feedback anticipation stage, the Reward-Anticipation Cue elevated the Stimulus-Preceding Negativity (SPN). We also separated reward-outcome ERPs into different components occurring at different time-windows: the Feedback-Related Negativity (FRN), Feedback-P3 (FB-P3) and Late-Positive Potentials (LPP). Lastly, we examined the relationship between reward-anticipation and reward-outcome ERPs. We report that individual-differences in specific reward-anticipation ERPs uniquely predicted specific reward-outcome ERPs. In particular, the reward-anticipation Early-RP (1 .8s before movement) predicted early reward-outcome ERPs (FRN and FB-P3), whereas, the reward-anticipation SPN most strongly predicted a later reward outcome ERP (LPP). Results have important implications for understanding the nature of the relationship between reward-anticipation and reward-outcome neural processes. PMID- 26433775 TI - Clam predator protection is effective and necessary for food production. AB - Shellfish aquaculture is a widely practiced way of producing food for human consumption in coastal areas. When farming intertidal clams, farmers commonly protect young seedling clams from predatory losses by covering farmed plots with netting or screening. Recent discussion of the effectiveness of protective nets or screens and their environmental effects has raised questions concerning the utility of the practice. We provide data based on a review of more than 35 peer reviewed articles, as well as our own research that demonstrates the efficacy of predator protection for clam farms in various habitats around the world. In addition, we evaluate the effects of screening on temperature, and comment on ancient practices of clam gardening as conducted in the Pacific Northwest. PMID- 26433777 TI - Sleep Violence. PMID- 26433776 TI - Measurement properties of patient-reported outcome measures (PROMs) in adults with obstructive sleep apnea (OSA): A systematic review. AB - This systematic review summarizes the evidence regarding the quality of patient reported outcome measures (PROMs) validated in patients with obstructive sleep apnea (OSA). We performed a systematic literature search of all PROMs validated in patients with OSA, and found 22 measures meeting our inclusion criteria. The quality of the studies was assessed using the consensus-based standards for the selection of health status measurement instruments (COSMIN) checklist. The results showed that most of the measurement properties of the PROMs were not, or not adequately, assessed. For many identified PROMs there was no involvement of patients with OSA during their development or before the PROM was tested in patients with OSA. Positive exceptions and the best current candidates for assessing health status in patients with OSA are the sleep apnea quality of life index (SAQLI), Maugeri obstructive sleep apnea syndrome (MOSAS) questionnaire, Quebec sleep questionnaire (QSQ) and the obstructive sleep apnea patient-oriented severity index (OSAPOSI). Even though there is not enough evidence to fully judge the quality of these PROMs as outcome measure, when interpreted with caution, they have the potential to add value to clinical research and clinical practice in evaluating aspects of health status that are important to patients. PMID- 26433778 TI - Experimental and numerical characterization of the water flow in spacer-filled channels of spiral-wound membranes. AB - Micro-scale flow distribution in spacer-filled flow channels of spiral-wound membrane modules was determined with a particle image velocimetry system (PIV), aiming to elucidate the flow behaviour in spacer-filled flow channels. Two dimensional water velocity fields were measured in a flow cell (representing the feed spacer-filled flow channel of a spiral wound reverse osmosis membrane module without permeate production) at several planes throughout the channel height. At linear flow velocities (volumetric flow rate per cross-section of the flow channel considering the channel porosity, also described as crossflow velocities) used in practice (0.074 and 0.163 m.s(-1)) the recorded flow was laminar with only slight unsteadiness in the upper velocity limit. At higher linear flow velocity (0.3 m.s(-1)) the flow was observed to be unsteady and with recirculation zones. Measurements made at different locations in the flow cell exhibited very similar flow patterns within all feed spacer mesh elements, thus revealing the same hydrodynamic conditions along the length of the flow channel. Three-dimensional (3-D) computational fluid dynamics simulations were performed using the same geometries and flow parameters as the experiments, based on steady laminar flow assumption. The numerical results were in good agreement (0.85-0.95 Bray-Curtis similarity) with the measured flow fields at linear velocities of 0.074 and 0.163 m.s(-1), thus supporting the use of model-based studies in the optimization of feed spacer geometries and operational conditions of spiral wound membrane systems. PMID- 26433779 TI - Using UV-vis absorbance spectral parameters to characterize the fouling propensity of humic substances during ultrafiltration. AB - Ultrafiltration (UF) can achieve excellent removal of natural organic matter (NOM), but the main challenge for this process is the limited understanding of membrane fouling. The objective of this study is to explore the potential of UV vis spectroscopic analysis for the detection of membrane fouling caused by humic acids (HA) at different solution chemistries (i.e., calcium ions (Ca(2+)) and pH). In the presence of Ca(2+), several spectral parameters, including the DSlope(325-375) (the slope of the log-transformed absorbance spectra over 325-375 nm), S(275-295) (the slope of the absorption coefficient over 257-295 nm) and S(R) (the ratio of S(275-295) to S(350-400)) of various HA solutions, were correlated with the molecule aggregation and the membrane fouling potential. Interestingly, increased DSlope(325-375) and decreased S(275-295) and S(R) were observed for the HA-Ca(2+) interaction under alkaline conditions (i.e., pH = 9) relative to those in lower pH environments (i.e., pH = 7 or 6), suggesting that spectral parameters were able to predict HA-Ca(2+) interactions under varying pH conditions. The strong correlations between the spectral parameters and the unified membrane fouling index (UMFI) obtained from UF experiments further corroborated that the spectral parameters were able to predict the membrane fouling potential. Moreover, the spectral parameters were also found to well reveal the fouling extent of the mixture of HA and Suwannee River NOM (SRNOM) or the pure SRNOM added with varying calcium concentrations, implying that the spectroscopic analysis was also available for the indication of practical NOM fouling. In addition, the measurement of S(275-295) and S(R) of the permeate solution suggests an increasing proportion of small-molecule HA in the permeate during the UF process. This study not only expands our knowledge of NOM-Ca(2+) aggregates as well as their role in membrane fouling behavior but also provides an approach for the in situ characterization of membrane performance. PMID- 26433780 TI - Database on natural polymorphisms and resistance-related non-synonymous mutations in thymidine kinase and DNA polymerase genes of herpes simplex virus types 1 and 2. AB - The use of genotypic resistance testing of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) is increasing because the rapid availability of results significantly improves the treatment of severe infections, especially in immunocompromised patients. However, an essential precondition is a broad knowledge of natural polymorphisms and resistance-associated mutations in the thymidine kinase (TK) and DNA polymerase (pol) genes, of which the DNA polymerase (Pol) enzyme is targeted by the highly effective antiviral drugs in clinical use. Thus, this review presents a database of all non-synonymous mutations of TK and DNA pol genes of HSV-1 and HSV-2 whose association with resistance or natural gene polymorphism has been clarified by phenotypic and/or functional assays. In addition, the laboratory methods for verifying natural polymorphisms or resistance mutations are summarized. This database can help considerably to facilitate the interpretation of genotypic resistance findings in clinical HSV-1 and HSV-2 strains. PMID- 26433782 TI - Susceptibility of Clostridium difficile isolates from a Phase 2 clinical trial of cadazolid and vancomycin in C. difficile infection. AB - OBJECTIVES: The aim of this study was to evaluate the susceptibilities of Clostridium difficile isolates to cadazolid, a novel antibiotic for the treatment of C. difficile infection. METHODS: Ribotyping and susceptibilities were determined for C. difficile isolates from a multicentre, double-blind, Phase 2 study of oral cadazolid in patients with C. difficile infection (NCT01222702, ClinicalTrials.gov; EudraCT 2010-020941-29, European Clinical Trials Database). Patients were randomized to receive 250, 500 or 1000 mg of cadazolid twice daily or 125 mg of vancomycin four times daily, for 10 days. MICs of cadazolid, vancomycin, fidaxomicin, linezolid and moxifloxacin were determined at baseline for all patients and post-baseline for patients with clinical failure or recurrence, using the agar dilution method. RESULTS: Seventy-eight of 84 patients had an evaluable toxigenic C. difficile isolate at baseline. The most frequent PCR ribotype was 027 (15.4%). Cadazolid MICs for baseline isolates (including epidemic strain 027) ranged from 0.06 to 0.25 mg/L. Baseline cadazolid MICs were similar to those of fidaxomicin and lower than those of vancomycin, linezolid and moxifloxacin. For each clinical outcome group (clinical cure, clinical failure, sustained clinical response and clinical failure or recurrence), the baseline cadazolid MIC range was 0.06-0.25 mg/L. Mean (min-max) cadazolid faecal concentration (MUg/g) on day 5 was 884 (101-2710), 1706 (204-4230) and 3226 (1481 12 600) for the doses 250, 500 and 1000 mg, respectively. CONCLUSIONS: For all cadazolid doses, the faecal concentration was in excess of several thousand-fold the MIC90 for C. difficile. The MIC of cadazolid for all C. difficile isolates, including epidemic strains, was low and in the same narrow range regardless of treatment outcome. PMID- 26433781 TI - Rhesus theta-defensin-1 (RTD-1) exhibits in vitro and in vivo activity against cystic fibrosis strains of Pseudomonas aeruginosa. AB - OBJECTIVES: Chronic endobronchial infections with Pseudomonas aeruginosa contribute to bronchiectasis and progressive loss of lung function in patients with cystic fibrosis. This study aimed to evaluate the therapeutic potential of a novel macrocyclic peptide, rhesus theta-defensin-1 (RTD-1), by characterizing its in vitro antipseudomonal activity and in vivo efficacy in a murine model of chronic Pseudomonas lung infection. METHODS: Antibacterial testing of RTD-1 was performed on 41 clinical isolates of P. aeruginosa obtained from cystic fibrosis patients. MIC, MBC, time-kill and post-antibiotic effects were evaluated following CLSI-recommended methodology, but using anion-depleted Mueller-Hinton broth. RTD-1 was nebulized daily for 7 days to cystic fibrosis transmembrane conductance regulator (CFTR) F508del-homozygous mice infected using the agar bead model of chronic P. aeruginosa lung infection. In vivo activity was evaluated by change in lung bacterial burden, airway leucocytes and body weight. RESULTS: RTD 1 exhibited potent in vitro bactericidal activity against mucoid and non-mucoid strains of P. aeruginosa (MIC90 = 8 mg/L). Cross-resistance was not observed when tested against MDR and colistin-resistant isolates. Time-kill studies indicated very rapid, concentration-dependent bactericidal activity of RTD-1 with >=3 log10 cfu/mL reductions at concentrations >=4* MIC. No post-antibiotic effect was observed. In vivo, nebulized treatment with RTD-1 significantly decreased lung P. aeruginosa burden (mean difference of -1.30 log10 cfu; P = 0.0061), airway leucocytes (mean difference of -0.37 log10; P = 0.0012) and weight loss (mean difference of -12.62% at day 7; P < 0.05) when compared with controls. CONCLUSIONS: This study suggests that RTD-1 is a promising potential therapeutic agent for cystic fibrosis airway disease. PMID- 26433784 TI - Comparative evaluation of the hydrogen production by mixed consortium, synthetic co-culture and pure culture using distillery effluent. AB - Wastewater comprises of various carbon sources. So, the use of microbial consortium may improve the hydrogen production and organic reduction. The present study deals with biohydrogen production by acidogenic mixed consortia (AMC), synthetic co-culture (Klebsiella pneumoniae IIT-BT 08 and Citrobacter freundii IIT-BT L139) and pure culture using distillery effluent (DE). Higher hydrogen yield was observed in case of AMC (9.17 mol/kg CODreduced) as compared to the synthetic co-culture and pure culture. PCR-DGGE analysis indicated that the consortium was predominated by species closely affiliated to Clostridium sp. The average hydrogen production rate was 267 mL/Lh. The maximum hydrogen production rate (Rm), hydrogen production potential (P) and lag time (lambda) by AMC using DE were 507.2 mL/Lh, 3729 m/L and 2.04 h, respectively. Maximum gaseous energy recovery by AMC was found to be higher by 21.9% and 45.4% than that of using co culture and pure culture respectively. PMID- 26433785 TI - Non-severe thermochemical hydrolysis of stover from white corn and sequential enzymatic saccharification and fermentation to ethanol. AB - A parametric study, with an initial load of 15%w/w of dry stover from white corn, was conducted to evaluate the sequential thermochemical hydrolysis (TH), enzymatic saccharification (ES) and fermentation of the whole slurry with ethanologenic Escherichia coli. The TH was designed to release the maximum amount of xylose with a concomitant formation of minimal amounts of furans. It was found that 29.0% or 93.2% of the xylan was recovered as free xylose at 130 degrees C after 8 min in the presence of 1% or 2%w/w H2SO4 and produced only 0.06 or 0.44 g/L of total furans, respectively. After 24h of ES, 76.14-77.18 g/L of monosaccharides (pentoses and hexoses) were obtained. These slurries, which contained 0.03-0.26 g/L of total furans and 5.14-5.91 g/L of acetate, were fermented with 3.7 g/L of ethanologenic E. coli to produce 24.5-23.5 g/L of ethanol. PMID- 26433786 TI - Cultivation of Chlorella vulgaris JSC-6 with swine wastewater for simultaneous nutrient/COD removal and carbohydrate production. AB - Swine wastewater, containing a high concentration of COD and ammonia nitrogen, is suitable for the growth of microalgae, leading to simultaneous COD/nutrients removal from the wastewater. In this study, an isolated carbohydrate-rich microalga Chlorella vulgaris JSC-6 was adopted to perform swine wastewater treatment. Nearly 60-70% COD removal and 40-90% NH3-N removal was achieved in the mixotrophic and heterotrophic culture, depending on the dilution ratio of the wastewater, while the highest removal percentage was obtained with 20-fold diluted wastewater. Mixotrophic cultivation by using fivefold diluted wastewater resulted in the highest biomass concentration of 3.96 g/L. The carbohydrate content of the microalga grown on the wastewater can reach up to 58% (per dry weight). The results indicated that the microalgae-based wastewater treatment can efficiently reduce the nutrients and COD level, and the resulting microalgal biomass had high carbohydrate content, thereby having potential applications for the fermentative production of biofuels or chemicals. PMID- 26433783 TI - Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort. AB - OBJECTIVES: We utilized the database of the Defining Antibiotic Levels in Intensive care unit patients (DALI) study to statistically compare the pharmacokinetic/pharmacodynamic and clinical outcomes between prolonged-infusion and intermittent-bolus dosing of piperacillin/tazobactam and meropenem in critically ill patients using inclusion criteria similar to those used in previous prospective studies. METHODS: This was a post hoc analysis of a prospective, multicentre pharmacokinetic point-prevalence study (DALI), which recruited a large cohort of critically ill patients from 68 ICUs across 10 countries. RESULTS: Of the 211 patients receiving piperacillin/tazobactam and meropenem in the DALI study, 182 met inclusion criteria. Overall, 89.0% (162/182) of patients achieved the most conservative target of 50% fT>MIC (time over which unbound or free drug concentration remains above the MIC). Decreasing creatinine clearance and the use of prolonged infusion significantly increased the PTA for most pharmacokinetic/pharmacodynamic targets. In the subgroup of patients who had respiratory infection, patients receiving beta-lactams via prolonged infusion demonstrated significantly better 30 day survival when compared with intermittent bolus patients [86.2% (25/29) versus 56.7% (17/30); P = 0.012]. Additionally, in patients with a SOFA score of >=9, administration by prolonged infusion compared with intermittent-bolus dosing demonstrated significantly better clinical cure [73.3% (11/15) versus 35.0% (7/20); P = 0.035] and survival rates [73.3% (11/15) versus 25.0% (5/20); P = 0.025]. CONCLUSIONS: Analysis of this large dataset has provided additional data on the niche benefits of administration of piperacillin/tazobactam and meropenem by prolonged infusion in critically ill patients, particularly for patients with respiratory infections. PMID- 26433787 TI - Biophotonic perception on Desmodesmus sp. VIT growth, lipid and carbohydrate content. AB - Constant and fluctuating light intensity significantly affects the growth and biochemical composition of microalgae and it is essential to identify suitable illumination conditions for commercial microalgae biofuel production. In the present study, effects of light intensities, light:dark cycles, incremental light intensity strategies and fluctuating light intensities simulating different sky conditions in indoor photobioreactor on Desmodesmus sp. VIT growth, lipid and carbohydrate content were analyzed in batch culture. The results revealed that Desmodesmus sp. VIT obtained maximum lipid content (22.5%) and biomass production (1.033 g/L) under incremental light intensity strategy. The highest carbohydrate content of 25.4% was observed under constant light intensity of 16,000 lx and 16:08 h light:dark cycle. The maximum biomass productivity of Desmodesmus sp. VIT (53.38 mg/L/d) was occurred under fluctuating light intensity simulating intermediate overcast sky condition. PMID- 26433789 TI - Kinetic analysis of two-phase enzymatic hydrolysis of hemicellulose of xylan type. AB - We present a coupled experimental and theoretical framework for quantifying the kinetics of two-phase enzymatic hydrolysis of hemicellulose. For xylan loading of 1-5mg/ml, the nature of inhibition by the product xylose (non-competitive), the kinetic constants (Km=3.93 mg/ml, Vmax=0.0252 mg/ml/min) and the xylose inhibition constant (Kx=0.122 mg/ml) are experimentally determined. Our multi step two-phase kinetic model incorporating enzyme adsorption to the solid substrate and non-competitive product inhibition is simulated using our kinetic data and validated against our experimentally measured temporal dynamics of xylose and reducing sugars. Further experiments show that higher substrate loading reduces the specific adsorption of the endoxylanase to the solid xylan and the enzyme's solid-liquid distribution ratio, which decelerates the solid hydrolysis and accelerates the liquid phase reactions. Thus, the xylose yield increases with substrate loading, which increases product inhibition and decreases reducing sugar yields. An operating cost analysis gives 3mg/ml as the optimal substrate loading. PMID- 26433788 TI - Thermogravimetric characterization and gasification of pecan nut shells. AB - This study focuses on the evaluation of pecan nut shells as an alternative source of energy through pyrolysis and gasification. The physicochemical characteristics of the selected biomass that can influence the process efficiency, consumption rates, and the product yield, as well as create operational problems, were determined. In addition, the thermal decomposition kinetics necessary for prediction of consumption rates and yields were determined. Finally, the performance of a downdraft gasifier fed with pecan nut shells was analyzed in terms of process efficiency and exit gas characteristics. It was found that the pyrolytic decomposition of the nut shells can be modeled adequately using a single equation considering two independent parallel reactions. The performance of the gasification process can be influenced by the particle size and air flow rate, requiring a proper combination of these parameters for reliable operation and production of a valuable syngas. PMID- 26433790 TI - Production of optically pure L-lactic acid from lignocellulosic hydrolysate by using a newly isolated and D-lactate dehydrogenase gene-deficient Lactobacillus paracasei strain. AB - The use of lignocellulosic feedstock for lactic acid production with a difficulty is that the release of inhibitory compounds during the pretreatment process which inhibit the growth of microorganism. Thus we report a novel lactic acid bacterium, Lactobacillus paracasei 7 BL, that has a high tolerance to inhibitors and produced optically pure l-lactic acid after the interruption of ldhD gene. The strain 7 BL fermented glucose efficiently and showed high titer of l-lactic acid (215 g/l) by fed-batch strategy. In addition, 99 g/l of l-lactic acid with high yield (0.96 g/g) and productivity (2.25-3.23 g/l/h) was obtained by using non-detoxified wood hydrolysate. Rice straw hydrolysate without detoxification was also tested and yielded a productivity rate as high as 5.27 g/l/h. Therefore, L. paracasei 7 BL represents a potential method of l-lactic acid production from lignocellulosic biomass and has attractive application for industries. PMID- 26433791 TI - Efficient magnesium lactate production with in situ product removal by crystallization. AB - In this paper, attempts were made to develop an in situ product removal process for magnesium lactate production based on crystallization. The crystallization was conducted at 42 degrees C without seed crystal addition. The product concentration, productivity and yield of fermentation coupled with in situ product removal (ISPR) reached 143 g L(-1), 2.41 g L(-1)h(-1) and 94.3%. In four cycles of crystallization, the average reuse rate of fermentation medium and removal rate of product reached 64.0% and 77.7%. At the same time, ISPR fermentation saved 40% water, 41% inorganic salts and 43% yeast extract (YE) as compared to fed-batch fermentation. The process introduces an effective way to reduce the amount of waste water and the raw material cost in magnesium lactate fermentation. PMID- 26433792 TI - Open fermentative production of L-lactic acid using white rice bran by simultaneous saccharification and fermentation. AB - To reduce raw material cost for lactic acid production, white rice bran as an important byproduct in rice milling, was used in l-lactic acid production by open simultaneous saccharification and fermentation (SSF). Although one thermotolerant strain was used at a temperature as high as 50 degrees C, the open fermentation was still inefficient due to the indigenous thermophilic bacteria from corn steep liquor powder. A stepwise controlled pH was proposed in open SSF process, and no complicated pretreatment or sterilization was needed before fermentation. In batch fermentation, 117 gL(-1) lactic acid was obtained, and the productivity and yield reached 2.79 gL(-1) h(-1) and 98.75%, respectively. These results showed an efficient way to develop high value-added products from white rice bran. PMID- 26433793 TI - Economic analysis and environmental impact assessment of three different fermentation processes for fructooligosaccharides production. AB - Three different fermentation processes for the production of fructooligosaccharides (FOS) were evaluated and compared in terms of economic aspects and environmental impact. The processes included: submerged fermentation of sucrose solution by Aspergillus japonicus using free cells or using the cells immobilized in corn cobs, and solid-state fermentation (SSF) using coffee silverskin as support material and nutrient source. The scale-up was designed using data obtained at laboratory scale and considering an annual productivity goal of 200 t. SSF was the most attractive process in both economic and environmental aspects since it is able to generate FOS with higher annual productivity (232.6 t) and purity (98.6%) than the other processes; reaches the highest annual profit (6.55 M?); presents the lowest payback time (2.27 years); and is more favourable environmentally causing a lower carbon footprint (0.728 kg/kg, expressed in mass of CO2 equivalent per mass of FOS) and the lowest wastewater generation. PMID- 26433794 TI - Synergistic action of recombinant accessory hemicellulolytic and pectinolytic enzymes to Trichoderma reesei cellulase on rice straw degradation. AB - Synergism between core cellulases and accessory hydrolytic/non-hydrolytic enzymes is the basis of efficient hydrolysis of lignocelluloses. In this study, the synergistic action of three recombinant accessory enzymes, namely GH62 alpha-l arabinofuranosidase (ARA), CE8 pectin esterase (PET), and GH10 endo-1,4-beta xylanase (XYL) from Aspergillus aculeatus expressed in Pichia pastoris to a commercial Trichoderma reesei cellulase (Accellerase(r) 1500; ACR) on hydrolysis of alkaline pretreated rice straw was studied using a mixture design approach. Applying the full cubic model, the optimal ratio of quaternary enzyme mixture was predicted to be ACR:ARA:PET:XYL of 0.171:0.079:0.100:0.150, which showed a glucose releasing efficiency of 0.173 gglc/FPU, higher than the binary ACR:XYL mixture (0.122 gglc/FPU) and ACR alone (0.081 gglc/FPU) leading to a 47.3% increase in glucose yield compared with that from ACR at the same cellulase dosage. The result demonstrates the varying degree of synergism of accessory enzymes to cellulases useful for developing tailor-made enzyme systems for bio industry. PMID- 26433795 TI - Move more and sit less: regular physical activity improves mobility in older age. PMID- 26433796 TI - Development of a self-administrated quality of life questionnaire for sarcopenia in elderly subjects: the SarQoL. AB - BACKGROUND: The impact of sarcopenia on quality of life is currently assessed by generic tools. However, these tools may not detect subtle effects of this specific condition on quality of life. OBJECTIVE: The aim of this study was to develop a sarcopenia-specific quality of life questionnaire (SarQoL, Sarcopenia Quality of Life) designed for community-dwelling elderly subjects aged 65 years and older. SETTINGS: Participants were recruited in an outpatient clinic in Liege, Belgium. SUBJECTS: Sarcopenic subjects aged 65 years or older. METHODS: The study was articulated in the following four stages: (i) Item generation-based on literature review, sarcopenic subjects' opinion, experts' opinion, focus groups; (ii) Item reduction-based on sarcopenic subjects' and experts' preferences; (iii) Questionnaire generation-developed during an expert meeting; (iv) Pretest of the questionnaire-based on sarcopenic subjects' opinion. RESULTS: The final version of the questionnaire consists of 55 items translated into 22 questions rated on a 4-point Likert scale. These items are organised into seven domains of dysfunction: Physical and mental health, Locomotion, Body composition, Functionality, Activities of daily living, Leisure activities and Fears. In view of the pretest, the SarQoL is easy to complete, independently, in ~10 min. CONCLUSIONS: The first version of the SarQoL, a specific quality of life questionnaire for sarcopenic subjects, has been developed and has been shown to be comprehensible by the target population. Investigations are now required to test the psychometric properties (internal consistency, test-retest reliability, divergent and convergent validity, discriminant validity, floor and ceiling effects) of this questionnaire. PMID- 26433797 TI - Evidence on Acupuncture and Pain: Reporting on a Work in Progress. PMID- 26433798 TI - As Acupressure Decreases Pain, Acupuncture May Improve Some Aspects of Quality of Life for Women with Primary Dysmenorrhea: A Systematic Review with Meta-Analysis. AB - Primary dysmenorrhea is the most common gynecological symptom reported by women and constitutes a high health, social, and economic burden. Chemotherapies, along with their side effects, have not yielded satisfactory outcomes. Alternative nonpharmacological interventions, including acupuncture and acupressure, have been advocated, but evidence regarding their beneficial effect is inconclusive. This study sought to obtain evidence on the effectiveness of acupuncture and acupressure interventions. Twelve electronic databases were searched by using menstrual pain intensity and quality of life as primary and secondary outcomes, respectively, with the PEDro guideline for quality appraisal. Data unsuitable for a meta-analysis were reported as descriptive data. The search yielded 38 citations, from which eight studies were systematically reviewed, four of the eight being eligible for meta-analysis. The systematic review showed moderate methodological quality with a mean of 6.1 out of 10 on the PEDro quality scale. Acupressure showed evidence of pain relief while acupuncture improved both the mental and the physical components of quality of life. In conclusion, physiotherapists should consider using acupuncture and acupressure to treat primary dysmenorrhea, but a need exists for higher quality, randomized, blinded, sham-controlled trials with adequate sample sizes to establish clearly the effects of these modalities. PMID- 26433799 TI - Efficacies of Acupuncture and Anti-inflammatory Treatment for Carpal Tunnel Syndrome. AB - This study compared the efficacies of acupuncture and anti-inflammatory treatment in patients with carpal tunnel syndrome (CTS). Fifty patients with mild to moderate CTS were randomly divided into two groups. Both groups received night wrist splints as the standard conservative treatment for 1 month. The acupuncture group also received eight sessions of acupuncture therapy (twice a week for 4 weeks). The control group received 400 mg of ibuprofen three times a day for 10 days. The visual analog scale (VAS) score, the score on the Boston Carpal Tunnel Questionnaire for Functional Status and Symptom Severity (BCTQ FUNCT and SYMPT), and the electrodiagnostic findings were evaluated at baseline and 1 month after treatment. At the final follow up, significant improvements were found in both groups (p < 0.05). Statistically significant improvements were observed in the VAS score, the score on the global BCTQ FUNCT and SYMPT, and the electrodiagnostic findings, but not in the distal motor latency (DML), in the acupuncture group (p < 0.05). Our findings indicate that acupuncture affected the score on the global BCTQ FUNCT and SYMPT, the VAS score, and the electrodiagnostic findings, except the DML, more than ibuprofen did and that acupuncture might be an effective treatment for CTS. PMID- 26433800 TI - Inhibitory Effects of Scolopendra Pharmacopuncture on the Development and Maintenance of Neuropathic Pain in Rats: Possible Involvement of Spinal Glial Cells. AB - Scolopendra extracts were used for pharmacopuncture at the Kidney 1 acupoint to investigate the role of Scolopendra pharmacopuncture (SPP) in both the development and maintenance of neuropathic pain induced by L5 spinal nerve ligation in rats and the contribution of spinal glial cells. A single treatment and five once-daily treatments with SPP were given to evaluate its effects on the development and maintenance stages of neuropathic pain, respectively, which was followed by behavioral tests. Immunohistochemistry and Western blotting tests were also carried out. A single treatment of SPP delayed spinal nerve ligation induced mechanical allodynia and thermal hyperalgesia and induced a profound decrease in the expression of ionized calcium binding adaptor protein in the lumbar spinal cord. Repeated SPP treatments reliably suppressed mechanical allodynia and thermal hyperalgesia at later time points, and these results correlated mainly with decreases in glial fibrillary acidic protein. Intriguingly, ionized calcium binding adaptor protein expression was also reduced after repeated SPP. These results illustrate that neuropathic pain in the development and maintenance stages is alleviated by SPP treatment, which may be ascribed principally to deactivations of microglia and astroglia, respectively. Additionally, microglial inactivation seems to be partially involved in preventing neuropathic pain in the maintenance stage. PMID- 26433801 TI - The Effects of Acupuncture on Peripheral Facial Palsy Sequelae after 20 Years via Electromyography. AB - OBJECTIVE: This research used electromyography to evaluate the effects of acupuncture on facial palsy peripheral sequelae. METHODS: The 44-year-old woman who participated in this study presented sequelae resulting from 20 years of peripheral facial nerve palsy (FNP) on the right side and synkinesis in the left eye. In electromyography, the electrodes were positioned on the motor points over the orbicularis oris and the orbicularis oculi muscles to establish myofunctional feedback prior to and after rehabilitation, which consisted of 20-minute sessions of acupuncture once per week for 20 weeks: using manual stimulation at acupoints Yintang, LR3, GB21, CV17, ST2, ST3, ST6, ST7, GB2, and SI19; and Tou-Kuang-Min and ST4 using electrical stimulation with a 4-Hz pulsed current. The subjective pain intensities were recorded. RESULTS: The root-mean-square (RMS) electromyographic comparative analysis showed greater activation and recruitment of muscle fibers on the right side and a reduced overload on the left side, which promoted a functional evolution of movements and a positive response in the stomatognathic system. CONCLUSION: Acupuncture associated with electrical stimulation reversed the peripheral facial paralysis in a short time. Severe sequelae were minimized due to the balance of muscle activation in response to the electrical stimulation provided by the acupuncture needles. PMID- 26433802 TI - Effects of LI-4 and SP-6 Acupuncture on Labor Pain, Cortisol Level and Duration of Labor. AB - Nowadays, acupuncture is widely used to manage pain, and childbirth is a condition requiring appropriate pain management interventions. The efficacy of acupuncture in the management of labor pain has recently been studied, but the results are not satisfactory and conflicts exist. In this study, we investigated the effects of acupuncture on labor pain, serum cortisol level, and duration of labor. We conducted a randomized, single-blind, controlled trial that included 63 nulliparous women: 32 in the study group and 31 in the control group. Acupuncture was performed at the SP-6 and the LI-4 points in the study group, and sham acupuncture was performed at the same points in the control group. Pain scores and serum cortisol levels were measured before and after the intervention. Changes in these measures and in the duration of labor were compared between the groups. No significant variations in pain scores or serum cortisol levels were observed between the two control groups. However, the duration of labor was significantly lower (p < 0.001) in the group receiving real acupuncture. Our results show that acupuncture is significantly associated with a decreased duration of labor, even though it was no better than a placebo for the treatment of labor pain. PMID- 26433803 TI - Acupuncture Treatment of Chronic Low Back Pain by Using the Jingjin (Meridian Sinews) Model. AB - This case report details the unexpected and sustained relief from chronic low back pain in a patient after a single acupuncture treatment. The treatment administered on that occasion was based on the jingjin (i.e., "meridian sinew") model of traditional acupuncture. Treatments based on the jingjin model involve needling the ah shi (i.e., locally tender) points in myofascial tissue along the jingjin pathway. Tight chains can be needled to treat symptoms that are either close to or at some distance from the site of the needling treatment. In this patient, the points were in the gastrocnemius muscle and the hamstring muscles, which are part of the Bladder jingjin pathway. The patient, a 69-year-old woman, had had back pain for more than 40 years. The relief from the pain occurred within a day after the treatment and, at the time of this report, the relief has persisted for 5 months. This report examines two possible mechanisms for such a result: (1) a local increase in the extensibility of the hamstrings could be responsible or (2) the complex interactions within the central nervous system that are involved in acupuncture treatment could be more important factors. PMID- 26433804 TI - Acupuncture Treatment of Pain along the Gall Bladder Meridian in 15 Horses. AB - This study reports on clinically significant relief of pain along the gall bladder meridian in 15 sport horses. Both local and distant points were needled in this study. Pain relief was marked not only locally but also in remote areas along the gall bladder meridian. Clinical improvement was observed in all 15 horses within 30 seconds to 2 minutes after the treatment had started. Twelve horses and three horses were rated as "cured" and "improved", respectively, when they were re-examined 1-8 days after the treatment. The relief of somatic pain was often associated with improved riding performance of the horses. These data are relevant in terms of equine clinical pain relief, as well as in terms of meridian therapy and the scientific theory of acupuncture. PMID- 26433805 TI - Narrative Review of Perioperative Acupuncture for Clinicians. AB - Acupuncture is one of the oldest forms of the natural healing arts. The exact mechanisms of action are unknown at this time; however, current theories to explain the benefits experienced after acupuncture include Traditional Chinese Medicine and Western medicine concepts. Acupuncture may improve the quality of perioperative care and reduce associated complications. Perioperative acupuncture is apparently effective in reducing preoperative anxiety, postoperative nausea and vomiting, and postoperative pain. The Pericardium-6 (P-6; Nei Guan), Yintang (Extra 1), and Shenmen acupuncture points are the most studied and effective acupuncture points in reducing preoperative anxiety, postoperative nausea and vomiting, and postoperative pain experiences. Intraoperatively administered acupuncture may reduce immunosuppression in patients and lessen intraoperative anesthetic requirements, although the clinical usefulness of acupuncture in the intraoperative period remains inconclusive. Perioperative acupuncture is a promising intervention, but additional studies are needed to further understand and define acupuncture's role throughout the perioperative period and determine its clinical usefulness. The purpose of this article is to provide a brief clinical review concerning acupuncture and its application for common issues that occur in the perioperative period. PMID- 26433806 TI - Acupuncture for Pain Management in Evidence-based Medicine. AB - Pain is an enormous and prevalent problem that troubles people of all ages worldwide. The effectiveness of acupuncture for pain management has been strongly verified by large randomized controlled trials (RCTs) and meta-analyses. Increasing numbers of patients with pain have accepted acupuncture treatment worldwide. However, some challenges exist in establishing evidence for the efficacy of acupuncture. A more applicable and innovative research methodology that can reflect the effect of acupuncture in the settings of daily clinical practice needs to be developed. PMID- 26433807 TI - The International Federation of Gynecology and Obstetrics (FIGO) Initiative on gestational diabetes mellitus: A pragmatic guide for diagnosis, management, and care. PMID- 26433808 TI - Factors Affecting Distribution of Estrogenicity in the Influents, Effluents, and Biosolids of Canadian Wastewater Treatment Plants. AB - Canadian wastewater treatment plants (WWTPs) release significant amounts of estrogenic chemicals to nearby surface waters. Environmental estrogens have been implicated as the causative agents of many developmental and reproductive problems in animals, including fish. The goals of this study were to assess the estrogenic activity in the influents, effluents, and biosolids of thirteen Canadian WWTPs using the yeast estrogen screen (YES) bioassay and to investigate whether factors, such as wastewater treatment method, sample storage, extraction efficiency, population, and summer/winter temperature had any effects on the distribution of estrogenicity in the WWTPs. Results of the study showed that estrogenicity from the influent to the effluent decreased in seven WWTPs, increased in two WWTPs, and did not change in four WWTPs during the winter. Estrogenic concentrations generally decreased in the order of biosolids > influents > effluents and ranged from 1.57 to 24.6, 1.25E-02 to 3.84E-01, and 9.46E-03 to 3.90E-01 ng estradiol equivalents/g or ml, respectively. The estrogenicity in the final effluents, but not those in the influents and biosolids, was significantly higher in the summer than the winter. Among the WWTP treatment methods, advanced, biological nutrient removal appeared to be the most effective method to remove estrogenic chemicals from wastewaters in Canada. Our studies help to identify factors or mechanisms that affect the distribution of estrogenicity in WWTPs, providing a better understanding on the discharges of estrogenic chemicals from WWTPs. PMID- 26433809 TI - Dust-Metal Sources in an Urbanized Arid Zone: Implications for Health-Risk Assessments. AB - The available information concerning metal pollution in different dust sources and the health effects in children remains limited in Mexico. This study focuses on Hermosillo, which is an urbanized area located in the Sonoran Desert in which soil resuspension and dust emission processes are common. The metal content of arsenic (As), chromium (Cr), manganese (Mn), and lead (Pb) were determined in three dust sources (playgrounds, roofs, and roads), each representing different exposure media (EM) for these elements. The metal levels in dust were found in the order of Mn > Cr > Pb > As with the highest metal content found in road dust. Despite the similar average metal distributions, principal component analysis shows a clear separation of the three EM with playground dust related to Cr and Mn and road dust to As and Pb. However, the geoaccumulation index results indicate that dust samples are uncontaminated to moderately polluted, except for Pb in road dust, which is considerably high. In addition, the enrichment factor suggests an anthropogenic origin for all of the studied metals except for Mn. In this context, the hazard index (HI) for noncarcinogenic risk is >1 in this population and thus represents a potential health risk. The spatial distribution for each metal on EM and the HI related to the marginality index could represent a more accurate decision-making tool in risk assessment studies. PMID- 26433810 TI - Surgeon-performed bedside ultrasound to assess volume status: a feasibility study. AB - PURPOSE: Rapid assessment of volume status in children is often difficult. The purpose of this study was to evaluate the feasibility of surgeon-performed ultrasound to assess volume status in patients with hypertrophic pyloric stenosis. METHODS: Ultrasounds were performed on admission and before operation. The diameters of the inferior vena cava (IVC) and aorta (Ao) were measured and IVC/Ao ratios were calculated. Electrolytes were measured on admission and repeated if warranted. Logistic regression was used to associate the clinical outcome, defined as CO2 <=30 mEq/L, with IVC/Ao ratios. Predictive capacity was estimated from the logistic regression for IVC/Ao ratios. Linear regression was used to estimate associations between CO2 values and IVC/Ao ratios. RESULTS: Thirty-one patients were enrolled. The IVC/Ao ratio is highly associated with actual CO2 values (P < 0.001) and the clinical outcome (P = 0.004). For every 0.05 unit increase in IVC/Ao ratio, predicted CO2 decreased 1.1 units. For every 0.05 unit increase in the IVC/Ao ratio, the odds of having a CO2 <=30 mEq/L increased 48% [OR = 1.48, 95% CI (1.13,1.94)]. Predictive capacity is maximized at an IVC/Ao ratio of 0.75 as 83.9 % of subjects were correctly classified and specificity and PPV = 100%. CONCLUSIONS: Surgeon-performed ultrasound to determine IVC/Ao ratio is feasible. An IVC/Ao ratio of 0.75 predicted adequate resuscitation. PMID- 26433811 TI - Migrant workers in Sabah, East Malaysia: The importance of legislation and policy to uphold equity on sexual and reproductive health and rights. AB - Sabah, located in Southeast Asia, hosts the highest number of non-Malaysian citizens (27.7%), predominantly the Indonesian and Filipino migrants in comparison to other states in Malaysia. Sabah has inadequate data on migrants' sexual and reproductive health and rights (SRHRs). Various migrant-related policies and laws are present, but they do not offer full protection and rights to legal migrants in terms of their SRHRs. The aim of the laws and policies appears to be controlling the migrants from having any negative impact on the locals, rather than protecting migrants' health and rights. This affected their rights to marriage, having children, increase their vulnerabilities to labour trafficking and sexual abuse and access to health-care services. Female migrant workers and undocumented migrants form the most vulnerable subgroups of migrants. This narrative review highlights the status of SRHRs of migrants in Sabah and the migrant-related Malaysian laws and policies affecting their SRHRs. PMID- 26433812 TI - Bands, Chords, Tendons, and Membranes in the Heart: An Imaging Overview. AB - Crests, bands, chords, and membranes can be seen within the different cardiac chambers, with variable clinical significance. They can be incidental or can have clinical implications by causing hemodynamic disturbance. It is crucial to know the morphology and orientation of normal structures, aberrant or accessory muscles, and abnormal membranes to diagnose the hemodynamic disturbance associated with them. Newer generation computed tomographic scanners and faster magnetic resonance imaging sequences offer high spatial and temporal resolution allowing for acquisition of high resolution images of the cardiac chambers improving identification of small internal structures, such as papillary muscles, muscular bands, chords, and membranes. They also help in identification of other associated complications, malformations, and provide a road map for treatment. In this article, we review cross-sectional cardiac imaging findings of normal anatomical variants and distinctive imaging features of pathologic bands, chords, or membranes, which may produce significant hemodynamic changes and clinical symptomatology. PMID- 26433813 TI - Is UK cancer care broken? PMID- 26433814 TI - Adjuvant sorafenib for liver cancer: wrong stage, wrong dose. PMID- 26433815 TI - PD-L1 expression as a potential predictive biomarker. PMID- 26433816 TI - Dose-limiting toxicity and maximum tolerated dose: still fit for purpose? PMID- 26433817 TI - Cannabis and cancer: reality or pipe dream? PMID- 26433818 TI - Hello. I have cancer. How are you? PMID- 26433820 TI - Discordance between the results and conclusions of ICON7 - Authors' reply. PMID- 26433821 TI - Discordance between the results and conclusions of ICON7. PMID- 26433822 TI - Evolving treatment options for melanoma brain metastases. AB - Melanoma is a leading cause of lost productivity due to premature cancer mortality. Melanoma frequently spreads to the brain and is associated with rapid deterioration in quality and quantity of life. Until now, treatment options have been restricted to surgery and radiotherapy, although neither modality has been well studied in clinical trials. However, the new immune checkpoint inhibitors and molecularly targeted agents that have been introduced for treatment of metastatic melanoma are active against brain metastases and offer new opportunities to improve disease outcomes. New challenges arise, including how to integrate or sequence multiple treatment modalities, and current practice varies widely. In this Review, we summarise evidence for the treatment of melanoma brain metastases, and discuss the rationale and evidence for combination modalities, highlighting areas for future research. PMID- 26433819 TI - Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. AB - BACKGROUND: In the COMBI-v trial, patients with previously untreated BRAF Val600Glu or Val600Lys mutant unresectable or metastatic melanoma who were treated with the combination of dabrafenib and trametinib had significantly longer overall and progression-free survival than those treated with vemurafenib alone. Here, we present the effects of treatments on health-related quality of life (HRQoL), an exploratory endpoint in the COMBI-v study. METHODS: COMBI-v was an open-label, randomised phase 3 study in which 704 patients with metastatic melanoma with a BRAF Val600 mutation were randomly assigned (1:1) by an interactive voice response system to receive either a combination of dabrafenib (150 mg twice-daily) and trametinib (2 mg once-daily) or vemurafenib monotherapy (960 mg twice-daily) orally as first-line therapy. The primary endpoint was overall survival. In this pre-specified exploratory analysis, we prospectively assessed HRQoL in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer quality of life (EORTC QLQ C30), EuroQoL-5D (EQ-5D), and Melanoma Subscale of the Functional Assessment of Cancer Therapy-Melanoma (FACT-M), completed at baseline, during study treatment, at disease progression, and after progression. We used a mixed-model, repeated measures ANCOVA to assess differences in mean scores between groups with baseline score as covariate; all p-values are descriptive. The COMBI-v trial is registered with ClinicalTrials.gov, number NCT01597908, and is ongoing for the primary endpoint, but is not recruiting patients. FINDINGS: From June 4, 2012, to Oct 7, 2013, 1645 patients at 193 centres worldwide were screened for eligibility, and 704 patients were randomly assigned to dabrafenib plus trametinib (n=352) or vemurafenib (n=352). Questionnaire completion rates for both groups were high (>95% at baseline, >80% at follow-up assessments, and >70% at disease progression) with similar HRQoL and symptom scores reported at baseline in both treatment groups for all questionnaires. Differences in mean scores between treatment groups were significant and clinically meaningful in favour of the combination compared with vemurafenib monotherapy for most domains across all three questionnaires during study treatment and at disease progression, including EORTC QLQ-C30 global health (7.92, 7.62, 6.86, 7.47, 5.16, 7.56, and 7.57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0.001 for all assessments except p=0.005 at week 40), EORTC QLQ-C30 pain (-13.20, -8.05, 8.82, -12.69, -12.46, -11.41, and -10.57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0.001), EQ-5D thermometer scores (7.96, 8.05, 6.83, 11.53, 7.41, 9.08, and 10.51 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0.001 for all assessments except p=0.006 at week 32), and FACT-M Melanoma Subscale score (3.62, 2.93, 2.45, 3.39, 2.85, 3.00, and 3.68 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0.001). INTERPRETATION: From the patient's perspective, which integrates not only survival advantage but also disease-associated and adverse-event associated symptoms, treatment with the combination of a BRAF inhibitor plus a MEK inhibitor (dabrafenib plus trametinib) adds a clear benefit over monotherapy with the BRAF inhibitor vemurafenib and supports the combination therapy as standard of care in this population. PMID- 26433823 TI - Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. AB - Checkpoint blockade immunotherapy has received mainstream attention as a result of striking and durable clinical responses in some patients with metastatic disease and a reasonable response rate in many tumour types. The activity of checkpoint blockade immunotherapy is not restricted to melanoma or lung cancer, and additional indications are expected in the future, with responses already reported in renal cancer, bladder cancer, and Hodgkin's lymphoma among many others. Additionally, the interactions between radiation and the immune system have been investigated, with several studies describing the synergistic effects on local and distant tumour control when radiation therapy is combined with immunotherapy. Clinical enthusiasm for this approach is strengthened by the many ongoing trials combining immunotherapy with definitive and palliative radiation. Herein, we discuss the biological and mechanistic rationale behind combining radiation with checkpoint blockade immunotherapy, with a focus on the preclinical data supporting this potentially synergistic combination. We explore potential hypotheses and important considerations for clinical trial designs. Finally, we reintroduce the notion of radiosensitising immunotherapy, akin to radiosensitising chemotherapy, as a potential definitive therapeutic modality. PMID- 26433825 TI - Disease kinetics for decision-making in advanced melanoma: a call for scenario driven strategy trials. AB - In the past 5 years, the treatment of metastatic melanoma has changed from almost no effective treatment to the use of targeted and immune therapies with proven improvements in survival. The time has now come to define the optimal drug combinations, sequence of treatment, and drug regimens (intermittent vs continuous dosing) in the treatment of patients with metastatic melanoma. In view of the prevalence of advanced melanoma, finite resources, and the heterogeneity of disease characteristics, not all possibilities can be tested in therapeutic trials starting from an unselected population of patients with metastatic melanoma. In practice, clinicians rely on a few clinically derived signals, especially dynamic signals, to categorise patients into scenarios, from fast disease kinetics to slow disease kinetics, which drive clinicians' therapeutic decision making. The realistic goals of therapy are different in each scenario. We recommend that these scenarios are incorporated into clinical trials as either patient inclusion criteria or stratification factors. This approach is not only feasible but is also the only way to generate evidence for more effective and individualised treatment strategies for patients with metastatic melanoma. PMID- 26433824 TI - Targeting brain metastases in ALK-rearranged non-small-cell lung cancer. AB - The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy. PMID- 26433826 TI - Map-based cloning reveals the complex organization of the BnRf locus and leads to the identification of BnRf(b), a male sterility gene, in Brassica napus. AB - KEY MESSAGE: Sequencing of BAC clones reveals the complex organization of the BnRf locus and allowed us to clone BnRf (b) , which encodes a nucleus-localized chimeric protein BnaA7.mtHSP70-1-like. The male sterility in an extensively used genic male sterility (GMS) line (9012A) in Brassica napus was regarded to be conferred by BnMs3/Bnms3 and the multiallelic BnRf locus including three alleles. We previously mapped BnRf to a 13.8 kb DNA fragment on the B. napus chromosome A7. In the present study, we isolated bacterial artificial chromosome clones individually covering the restorer allele BnRf (a) and the male-sterile allele BnRf (b) , and revealed that the candidate regions of BnRf (a) and BnRf (b) show complex structural variations relative to the maintainer allele BnRf (c). By analyzing the recombination events and the newly developed markers, we delimited BnRf (a) to a 35.9 kb DNA fragment that contained seven predicted open-reading frames (ORFs). However, genetic transformation of the ORF G14 from both the male sterile and restorer lines into wild-type Arabidopsis plants led to a stable male sterile phenotype matching a 9012A-derived GMS line (RG206A); moreover, the male sterility caused by G14 could be fully recovered by the restorer gene BnMs3. These facts indicate that BnRf (b) corresponds to G14 while BnRf (a) likely associates with another flanking ORF. G14 encodes a nucleus-localized chimeric protein designated as BnaA7.mtHSP70-1-like. Ectopic expression of G14 in Arabidopsis negatively regulates some vital genes responsible for tapetum degeneration, and delayed programmed cell death of tapetum and led to the developmental arrest of tetrads. Our work not only presents new insights on the hereditary model of sterility control but also lays a solid foundation for dissecting the molecular basis underlying male sterility and restoration in 9012A. PMID- 26433827 TI - Fine mapping for double podding gene in chickpea. AB - KEY MESSAGE: For the first time, fine mapping for sfl locus was carried out using a battery of new STMS and SNP markers. The target region was delimited to 92.6 Kb where seven annotated genes were found that could be candidate genes for the simple/double podding trait in chickpea. Four recombinant inbred populations (RIP 1, RIP-7, RIP-11, and CPR-01) were used to map the double podding gene (sfl) in chickpea. In RIP-1, the gene was initially mapped on linkage group (LG) 6 between the two sequence-tagged microsatellite site (STMS) markers TA120 and TR1. Eight new STMS markers were added onto LG6 in the target region and sfl locus was finally located between CAGM27819 and CAGM27777 markers within an interval of 2 cM. Seven out of the eight markers were mapped in RIP-7 and its reciprocal RIP-11 confirming the location of the sfl locus to a 4.8 cM interval flanked by TR44 and CAGM27705. Furthermore, using a high-density single nucleotide polymorphism (SNP) map of CPR-01, sfl was mapped to the same genomic region in a 5.1 cM interval between TR44 and the SNP scaffold1646p97220. Five pairs of near isogenic lines (NILs) and eight recombinant inbred lines (RILs) were used to refine this region in the chickpea physical map. Combining data from linkage analysis in four RIPs, marker physical positions and recombination events obtained in both pairs of NILs and selected RILs, sfl could be placed within a genomic window of 92.6 Kb. Seven annotated genes were extracted from this region. The regulator of axillary meristem-predicted gene could be a candidate gene for the simple/double podding gene. This study provides additional set of markers flanking and tightly linked to sfl locus that are useful for marker-assisted selection. PMID- 26433828 TI - Complementary resistance genes in wheat selection 'Avocet R' confer resistance to stripe rust. AB - KEY MESSAGE: Complementary genes for resistance to wheat stripe rust in an Avocet selection mapped to chromosome arms 3DL and 5BL. Susceptible Avocet selections lacked the 5BL gene due to a chromosomal deletion. This study reports the inheritance and genetic mapping of the YrA (temporary name of convenience to describe the specificity) seedling resistance to wheat stripe rust (caused by Puccinia striiformis f. sp. tritici; Pst) in a resistant selection of the Australian cv. Avocet [Avocet R (AvR)-AUS 90660]. Genetic analysis was performed on F2 populations and F3 generation families from crosses between wheats that carried and lacked the YrA resistance. Greenhouse seedling tests with two avirulent Pst pathotypes (104 E137 A- and 108 E141 A-) confirmed that the YrA resistance was inherited as two complementary dominant genes. Ninety-two doubled haploid (DH) lines from a cross between the Australian cv. Teal (Pst susceptible) and AvR were used for DArT-Seq genotypic analysis to map the seedling resistance. Marker-trait association analysis using 9035 DArT-Seq loci mapped the genes to the long arms of chromosomes 3D (3DL) and 5B (5BL), respectively. F2 populations from crosses between susceptible DH lines that carried either the 3DL or 5BL marker genotypes confirmed the complementary gene model. Fluorescence in situ hybridization (FISH) analysis determined that Teal carries a reciprocal T5B-7B translocation. FISH analysis also identified a 5BL chromosomal deletion in Avocet S relative to AvR that further validated the complementary gene model and possibly explained the heterogeneity of closely related wheats carrying the YrA resistance. The individual loci of the complementary YrA resistance were designated Yr73 (3DL) and Yr74 (5BL). Candidate single gene reference stocks will be permanently accessioned following cytological analysis to avoid the T5B-7B translocation. PMID- 26433830 TI - Editorial overview: Cell signalling and gene regulation-communication and control as the twin pillars of systems biology. PMID- 26433829 TI - A major quantitative trait locus conferring subgynoecy in cucumber. AB - KEY MESSAGE: A major QTL conditioning high degree of femaleness in cucumber was identified by marker analysis and next generation sequencing. Cucumber (Cucumis sativus L.) is a model species for sex determination studies, and its yield is associated with the degree of femaleness. Subgynoecy represents a sex form with a high degree of femaleness for which the genetic basis remains elusive. In this study, genetic analysis in the F2 and BC1 populations developed from a cross between subgynoecious S-2-98 and monoecious M95 suggested a quantitative nature of subgynoecy. Application of simple sequence repeat markers between subgynoecious and monoecious bulks constructed from BC1 plants identified three QTLs: sg3.1, sg6.1, and sg6.2. The major QTL sg3.1 contributed to 54.6% of the phenotypic variation, and its presence was confirmed by genome-wide comparison of SNP profiles between parental lines and a subgynoecious bulk constructed from BC6 plants. Using PCR-based markers developed from the SNP profile, sg3.1 was further delimited to a genomic region of 799 kb. The genetic basis of subgynoecy revealed here shall shed light on the development of elite cultivars with high yield potential. PMID- 26433831 TI - Crime and subjective well-being in the countries of the former Soviet Union. AB - BACKGROUND: Criminal victimisation and subjective well-being have both been linked to health outcomes, although as yet, comparatively little is known about the relationship between these two phenomena. In this study we used data from nine countries of the former Soviet Union (fSU) to examine the association between different types of crime and subjective well-being. METHODS: Data were obtained from 18,000 individuals aged 18 and above collected during the Health in Times of Transition (HITT) survey in 2010/11 in Armenia, Azerbaijan, Belarus, Georgia, Moldova, Kazakhstan, Kyrgyzstan, Russia and Ukraine. Information was obtained on respondents' experience of crime (violence and theft) and self reported affective (happiness) and cognitive (life satisfaction) well-being. Ordered probit and ordinary least squares (OLS) regression analyses were undertaken to examine the associations between these variables. RESULTS: In pooled country analyses, experiencing violence was associated with significantly lower happiness and life satisfaction. Theft victimisation was associated with significantly reduced life satisfaction but not happiness. Among the individual countries, there was a more pronounced association between violent victimisation and reduced happiness in Kazakhstan and Moldova. CONCLUSIONS: The finding that criminal victimisation is linked to lower levels of subjective well-being highlights the importance of reducing crime in the fSU, and also of having effective support services in place for victims of crime to reduce its detrimental effects on health and well-being. PMID- 26433832 TI - [Neuromuscular dynamic scapular winging: Clinical, electromyographic and magnetic resonance imaging diagnosis]. AB - Dyskinesia of the scapula is a clinical diagnosis and includes all disorders affecting scapula positioning and movement whatever its etiology. Scapular winging is a subtype of scapular dyskinesia due to a dynamic prominence of the medial border of the scapula (DSW) secondary to neuromuscular imbalance in the scapulothoracic stabilizer muscles. The two most common causes of DSW are microtraumatic or idiopathic lesions of the long thoracic nerve (that innerves the serratus anterior) or the accessory nerve (that innerves the trapezius). Diagnosis of DSW is clinical and electromyographic. Use of magnetic resonance imaging (MRI) could be of interest to distinguish lesion secondary to a long thoracic nerve from accessory nerve and to rule out scapular dyskinesia related to other shoulder disorders. Causal neuromuscular lesion diagnosis in DSW is challenging. Clinical examinations, combined with scapular MRI, could help to their specific diagnosis, determining their stage, ruling out differential diagnosis and thus give raise to more targeted treatment. PMID- 26433833 TI - [Prevalence and impact of post-traumatic stress disorder in a disordered eating population sample]. AB - OBJECTIVE: Eating disorders (ED) are associated with a higher prevalence of post traumatic stress disorder (PTSD). However, the impact they may have on the clinical features and severity of the ED remains unknown. In this study, we assessed the prevalence and the impact of PTSD in a disordered eating population sample. METHODS: We recruited patients with eating disorders during a period of 6 months, in 2014. The patients underwent a semistructured diagnostic interview by trained psychiatrists. The severity of eating behaviours and PTSD was assessed using the Eating Disorder Inventory 2 and the Impact of Event Scale - Revised. RESULTS: One hundred and thirty patients (57 patients with anorexia nervosa, 26 with bulimia nervosa, 18 with eating disorder not otherwise specified and 29 with binge eating disorder) were included. Our analyses revealed a PTSD rate of 33.9% in patients with ED. No difference was observed between the ED subtypes. Severity of ED was significantly higher among patients suffering from PTSD. Specific clinical characteristics of the ED-PTSD association have been found. Analyses revealed a significantly higher level of insecurity, interpersonal distrust, impulsivity and a decrease of interoceptive awareness. DISCUSSION: The frequency and negative impact of PTSD on ED reinforce the need for a systematic clinical evaluation and the implementation of specific care. PMID- 26433834 TI - Influenza prevention in nursing homes: Great significance of seasonal variability and spatio-temporal pattern. AB - OBJECTIVE: This work evaluated seasonal variations and spatio-temporal pattern of respiratory tract infections (RTI) in geriatric nursing homes in order to improve effective surveillance, prevention, control and management of RTI. METHODS: Prospective surveillance of RTI (Low Respiratory Tract infections and Influenza Like Illnesses) was conducted in 11 sites in Alsace over a 10-year period with clinical case definitions and rapid tests (Immunoassay) to identify influenza virus. RESULTS: Influenza national epidemic was a period at high risk of RTI in nursing homes with variable impacts depending on the seasonal period. 2004-2005, 2008-2009, 2011-2012 and 2012-2013 were the periods with the highest impacts. The higher risk was not well understood during these four influenza epidemics and outbreaks occurred in numerous nursing homes despite the alerts and surveillance. CONCLUSION: Information about seasonal variability and spatio-temporal patterns of the RTI during the national epidemic periods is essential for the nursing homes in order to help the health care workers and the visitors to understand the risk for the residents and then to improve the implementation of the control and prevention measures. PMID- 26433835 TI - [Pseudotumoral thoracic splenosis in a patient with adult-onset Still disease and reactive hemophagocytic syndrome]. PMID- 26433836 TI - Severe dizziness following rivaroxaban introduction in a parkinsonian patient: Drug-drug interaction? PMID- 26433837 TI - The influence of VKORC1 gene polymorphism on warfarin maintenance dosage in pediatric patients: A systematic review and meta-analysis. AB - INTRODUCTION: Warfarin is the most commonly used oral anticoagulant, however, there are large interindividual variations in dose responses. Genetic polymorphisms in CYP2C9, VKORC1 and CYP4F2 have been shown to play an important role in variations in the warfarin maintenance dose in adults, but their effects in children remain unclear. We aimed to investigate the effect of VKORC1 polymorphism on warfarin dosage in pediatric patients by meta-analysis. MATERIALS AND METHODS: Using strict inclusion and exclusion criteria, we searched PubMed, EMBASE, Cochrane library, Chinese Biomedical Literature Database, CNKI and ChainInfo from 2004 to Mach 17th, 2015. The relationship between warfarin dose and two single nucleotide polymorphisms of the VKORC1 gene (at positions -1639 and 1173) were analyzed using Revman version 5.2.3 software. RESULTS AND CONCLUSIONS: Eight studies were included in the meta-analysis, involving 610 pediatric patients. Patients that were VKORC1 -1639 GA, AA or A carriers required significantly lower warfarin dosage than GG carriers (the weighted mean difference in warfarin dose ranged from -26% to -50%). Additionally, the age of the patient and indication of warfarin (i.e. Fontan procedure) significantly affected warfarin dosage, but changes in the target international normalized ratio range had no effect. On the other hand, VKORC1 1173 polymorphisms showed no significant effect on warfarin dosage, which differs from adult patients. In conclusion, we found that VKORC1 -1639 gene polymorphisms have a moderate effect on warfarin dosage in pediatric patients, but clinical characteristics such as age and indication of warfarin also play an important role. PMID- 26433838 TI - Primary hyperparathyroidism associated with a giant cell tumor: One case in the distal radius. AB - Hyperparathyroidism can present itself as brown tumors (or osteolytic expansive lesions) that usually disappear after normalization of calcium and phosphate levels. It rarely occurs simultaneously with a giant cell tumor. The authors report one case of a localized form at the distal radius in a patient being followed for primary hyperparathyroidism. The diagnostic challenges related to the clinical and radiological similarities of these two pathological entities are discussed, as they can lead to delays in therapeutic management. PMID- 26433839 TI - Evaluation, Diagnosis, and Staging of Cutaneous Lymphoma. AB - Primary cutaneous lymphomas (PCLs) are an extremely heterogeneous group of non Hodgkin lymphomas that manifest in the skin. Their diagnosis is complex and based on clinical lesion type and evaluation of findings on light microscopic examination, immunohistochemistry and molecular analysis of representative skin biopsies. The evaluation, classification, and staging system is unique for mycosis fungoides (MF) and Sezary syndrome (SS), the most common subtypes of cutaneous T-cell lymphoma (CTCL) versus the other subtypes of Non-MF/Non-SS CTCL and the subtypes of cutaneous B-cell lymphoma (CBCL). Since current treatment is stage-based, it is particularly important that the correct diagnosis and stage be ascertained initially. The purpose of this article is to review the current evaluation, diagnosis, classification, staging, assessment techniques, and response criteria for the various types of both T-cell and B-cell PCLs. PMID- 26433840 TI - Pathologic Diagnosis of Cutaneous Lymphomas. AB - Primary cutaneous lymphomas comprise a prognostically heterogeneous group of lymphocytic skin neoplasms, which display a broad spectrum of clinical, histologic, immunophenotypic, and genetic features. The histopathological examination plays an essential role and is often the starting point in the diagnostic workup of cutaneous lymphomas. In most cases, the histopathological and the phenotypic analysis alone are limited to provide a list of differential diagnoses. As a consequence of overlapping clinical, histologic, phenotypic, and genetic features among several entities of cutaneous lymphomas, the clinicopathological correlation is of utmost importance to achieve the final diagnosis. PMID- 26433842 TI - Phototherapy of Mycosis Fungoides. AB - Therapies based on ultraviolet light have long been established in mycosis fungoides (MF). They have traditionally included whole-body ultraviolet light B, both broad-band and narrow-band, and psoralen plus ultraviolet A. Phototherapy may be applied alone in early stage MF or in combination with systemic therapy in refractory early stage MF and advanced MF. This article reviews the most frequently used forms of phototherapy for MF with emphasis on efficacy, safety, and practical considerations. PMID- 26433841 TI - Skin-Directed Therapies in Cutaneous T-Cell Lymphoma. AB - Early stage mycosis fungoides represents the most common clinical presentation of cutaneous lymphoma, with skin-directed therapies long established in its treatment. These therapies continue to change as new treatment regimens emerge. Other skin-directed treatments include light and radiation therapy. Therapies with higher levels of evidence and less systemic toxicity are usually preferred as first-line treatment. However, even these established therapies, like topical corticosteroids and carmustine, lack randomized clinical trials to establish their efficacy. Research is also needed to further define the role of combination topical therapies and how skin-directed therapies can be used as adjuvants to systemic medications. PMID- 26433843 TI - Radiation Therapy for Cutaneous T-Cell Lymphomas. AB - Radiation therapy is an extraordinarily effective skin-directed therapy for cutaneous T-cell lymphomas. Lymphocytes are extremely sensitive to radiation and a complete response is generally achieved even with low doses. Radiation therapy has several important roles in the management of mycosis fungoides. For the rare patient with unilesional disease, radiation therapy alone is potentially curative. For patients with more advanced cutaneous disease, radiation therapy to local lesions or to the entire skin can effectively palliate symptomatic disease and provide local disease control. Compared with other skin-directed therapies, radiation therapy is particularly advantageous because it can effectively penetrate and treat thicker plaques and tumors. PMID- 26433844 TI - The Role of Systemic Retinoids in the Treatment of Cutaneous T-Cell Lymphoma. AB - Retinoids are natural and synthetic vitamin A analogs with effects on cell proliferation, differentiation, and apoptosis. They have significant activity in hematologic malignancies and have been studied extensively in cutaneous T-cell lymphoma. Retinoids bind to nuclear receptors and exert their effects through moderation of gene expression. Retinoic acid receptor and retinoic X receptor exert regulatory activity in vivo, binding to distinct ligands. Studies investigating systemic retinoids as monotherapy and in combination with other agents active against cutaneous lymphoma are reviewed. Side effects associated with retinoids include teratogenicity, dyslipidemias, and hypothyroidism, which should be carefully monitored in patients receiving treatment. PMID- 26433845 TI - The Use of Interferons in the Treatment of Cutaneous T-Cell Lymphoma. AB - Interferons are polypeptides that naturally occur in the human body as a part of the innate immune response. By harnessing these immunomodulatory functions, synthetic interferons have shown efficacy in combating various diseases including cutaneous T-cell lymphoma. This article closely examines the qualities of interferon alfa and interferon gamma and the evidence behind their use in the 2 most common types of cutaneous T-cell lymphomas, namely, mycosis fungoides and Sezary syndrome. PMID- 26433847 TI - Histone Deacetylase Inhibitors for Cutaneous T-Cell Lymphoma. AB - Cutaneous T-cell lymphomas (CTCLs) are non-Hodgkin's T-cell lymphomas that present as skin lesions. Mycosis fungoides with large cell transformation has a 5 year overall survival of 32% with involved skin and 7% with extracutaneous involvement. Failure to cure advanced MF with large cell transformation and peripheral T-cell lymphoma has resulted in a search for novel targeted agents including antibodies and gene modulators. Histone deacetylase inhibitors are small molecules that seem to be particularly active for T-cell lymphoma. PMID- 26433846 TI - Methotrexate and Pralatrexate. AB - This article reviews methotrexate and the more potent, related compound, pralatrexate, for the treatment of cutaneous T-cell lymphomas, including mycosis fungoides, Sezary syndrome, and CD30+ lymphoproliferative disorders. Although these folate antagonists are traditionally viewed as antiproliferative cell cycle inhibitors, it is recognized that they inhibit DNA methylation, providing a rationale for their use as epigenetic regulators and cell proliferation inhibitors. The underlying mechanisms are outlined, key supporting data presented, followed by brief mention of recent mathematical modeling supporting the general superiority of combination therapy. Several novel examples involving folate antagonists are proposed. PMID- 26433848 TI - Extracorporeal Photopheresis in the Treatment of Mycosis Fungoides and Sezary Syndrome. AB - Extracorporeal photopheresis (ECP) is an immunomodulating procedure that leads to an expansion of peripheral blood dendritic cell populations and an enhanced TH1 immune response in cutaneous T-cell lymphoma (CTCL). Because of its excellent side effect profile and moderate efficacy, ECP is considered first-line therapy for erythrodermic mycosis fungoides (MF) and Sezary syndrome. Patients with a measurable but low blood tumor burden are most likely to respond to ECP, and the addition of adjunctive immunostimulatory agents may also increase response rates. There may be a role for ECP in the treatment of refractory early stage MF, but data are limited. PMID- 26433849 TI - Monoclonal Antibodies. AB - Use of monoclonal antibodies (mAbs) has revolutionized cancer therapy. Approaches targeting specific cellular targets on the malignant cells and in tumor microenvironment have been proved to be successful in hematologic malignancies, including cutaneous lymphomas. mAb-based therapy for cutaneous T-cell lymphoma has demonstrated high response rates and a favorable toxicity profile in clinical trials. Several antibodies and antibody-based conjugates are approved for use in clinical practice, and many more are in ongoing and planned clinical trials. In addition, these safe and effective drugs can be used as pillars for sequential therapies in a rational stepwise manner. PMID- 26433850 TI - Other Chemotherapeutic Agents in Cutaneous T-Cell Lymphoma. AB - Traditional chemotherapies, interleukins, phosphorylase inhibitors, and proteasome inhibitors are important therapies available to patients with cutaneous T-cell lymphoma (CTCL). Traditional chemotherapies, both in combination and as single agents, are commonly used in relapsed, refractory CTCLs that behave in an aggressive manner. Interleukins, phosphorylase inhibitors, and proteasome inhibitors are less commonly used but data support a role in patients with more refractory disease. PMID- 26433851 TI - Hematopoietic Stem Cell Transplant for Mycosis Fungoides and Sezary Syndrome. AB - Mycosis fungoides (MF) and Sezary syndrome (SS) are common types of primary cutaneous T-cell lymphoma. Early-stage MF has a favorable prognosis and responds well to skin-directed regimens. Patients with advanced-stage MF, transformed MF, and SS are treated with combined systemic and skin-directed therapies. However, the disease is incurable with standard regimens, and frequent relapses are common. Owing to the lack of improvement in overall survival with standard regimens, hematopoietic stem cell transplant (HSCT) has been explored as a potential curative option. This article reviews the role of HSCT in MF/SS and discusses data regarding conditioning regimens, treatment-related complications, and outcomes. PMID- 26433853 TI - Diagnosis and Management of Cutaneous B-cell Lymphoma. AB - The diagnosis of primary cutaneous B-cell lymphoma (CBCL) requires that the search for a more widespread lymphoma has been negative. The clinical presentation, outlook, and treatment options of the common types of CBCLs, with emphasis on differences or similarities to their nodal counterparts, are discussed. Treatment may range from observation to topical therapies to systemic therapies, depending on the histology, degree and area of skin involvement, patient performance, and comorbidities. Rare lymphomas, such as intravascular large B-cell lymphoma and Epstein-Barr virus-positive cutaneous lymphoproliferations that are associated with immunodeficiency, are also briefly described. PMID- 26433852 TI - Practical Management of CD30+ Lymphoproliferative Disorders. AB - Primary cutaneous CD30+ lymphoproliferative disorders (LPDs) account for approximately 25% of cutaneous lymphomas. Although these LPDs are clinically heterogeneous, they can be indistinguishable histologically. Lymphomatoid papulosis rarely requires systemic treatment; however, multifocal primary cutaneous anaplastic large cell cutaneous lymphoma and large cell transformation of mycosis fungoides are typically treated systemically. As CD30+ LPDs are rare, there is little published evidence to support a specific treatment algorithm. Most studies are case reports, small case series, or retrospective reviews. This article discusses various treatment choices for each of the CD30+ disorders and offers practical pearls to aid in choosing an appropriate regimen. PMID- 26433854 TI - Cutaneous Lymphoma. PMID- 26433856 TI - Dental Pulp Status of Posterior Teeth in Patients with Oral and Oropharyngeal Cancer Treated with Concurrent Chemoradiotherapy. AB - INTRODUCTION: The absence of tooth sensitivity has been observed in patients who have undergone radiotherapy. The aim of this investigation was to evaluate the effects of concurrent chemoradiotherapy on the pulp status of posterior teeth in patients with malignant oral and oropharyngeal cancer. METHODS: Twenty-one patients diagnosed with malignant oral and oropharyngeal cancer undergoing concurrent chemoradiotherapy underwent cold thermal pulp sensitivity testing and electric pulp testing of 4 teeth, 1 from each quadrant, at 4 points in time (PT): before radiotherapy (PT1), after 30-35 Gy (PT2), at the end of radiotherapy at 66 70 Gy (PT3), and 4 months (PT4) after beginning radiotherapy. RESULTS: All 84 teeth tested positive to cold thermal pulp sensitivity testing at PT1 (100%) and 25 teeth at PT2. No tooth responded at PT3 and PT4 (100%). A statistically significant difference (P < .05) existed in the number of positive responses between different points in time. CONCLUSIONS: Radiotherapy decreased the number of teeth responding to pulp sensitivity testing after doses greater than 30-35 Gy. PMID- 26433855 TI - Effect of Intracanal Cryotherapy on Reducing Root Surface Temperature. AB - INTRODUCTION: The positive effect of cryotherapy has been widely described in medicine. The aim of the present study was to validate a new methodology to reduce and maintain external root surface temperature for at least 4 minutes. METHODS: Twenty extracted single-rooted teeth were instrumented to size 35/.06 and subjected to 2 different irrigation interventions with a repeated-measures design using 5% sodium hypochlorite first (control) and 2.5 degrees C cold saline solution later (experimental). In both, 20 mL of the irrigant solution was delivered for a total time of 5 minutes with a microcannula attached to the EndoVac system (Kerr Endo, Orange County, CA) inserted to the working length. The initial and lowest temperatures were recorded in the apical 4 mm with a digital thermometer for both irrigants. Data were analyzed with the repeated measure analysis of variance (Greenhouse-Geisser correction) and Bonferroni post hoc tests. Differences in maintaining a -10 degrees C temperature reduction over 4 minutes were assessed with the Fisher exact test. RESULTS: Although significant differences were found between the initial and lowest temperatures in both the control and experimental irrigation procedures (P < .001), the experimental intervention reduced it almost 10 times that of the control. When maintaining a 10 degrees C temperature reduction over 4 minutes, the teeth in the experimental group also sustained significantly better results (P = 3.047 * 10(-10)). CONCLUSIONS: Using cold saline solution as the final irrigant reduced the external root surface temperature more than 10 degrees C and maintained it for 4 minutes, which may be enough to produce a local anti-inflammatory effect in the periradicular tissues. PMID- 26433858 TI - Requiring On-Site Evaluation in the Nursing Home Before Hospital Transfer: Is This Proposed CMS Rule Change Feasible and Safe? PMID- 26433857 TI - Micro-Computed Tomographic Evaluation of the Influence of Root Canal System Landmarks on Access Outline Forms and Canal Curvatures in Mandibular Molars. AB - INTRODUCTION: This study investigated the influence of anatomic root canal system landmarks on access outline forms of mandibular molars and correlated these to the theoretical distance of orifice relocation and changes in canal primary curvature. METHODS: Thirty relatively calcified human mandibular molars were selected and examined by micro-computed tomographic imaging. Three-dimensional volume reconstructions were made, root canal system landmarks identified, and plotted: canal orifices, canal position at the furcation level, and pulp horn location. Each landmark was separately projected onto the occlusal surface, and 3 access designs were respectively proposed: (1) minimally invasive, (2) straight line furcation, and (3) straight-line radicular. For each access design, the theoretical distance of orifice relocation and canal primary curvature were determined. Data were submitted to 2-way repeated measures analysis of variance (alpha < 0.05). RESULTS: The orifice relocation distance required to obtain each type of access outline was greater for radicular-based accesses (0.97 +/- 0.32 mm) than for furcation accesses (0.52 +/- 0.30 mm, P < .001) and resulted in a greater change in canal primary curvature (P < .001; 15.9 degrees +/- 4.6 degrees and 9.4 degrees +/- 4.3 degrees , respectively). The canal primary curvature for each access outline type was statistically different from each other (P < .0001), whereas the minimally invasive access showed the highest mean angle (40.1 degrees +/- 8.4 degrees ) followed by the straight-line furcation (30.7 degrees +/- 7.5 degrees ) and the straight-line radicular accesses (24.2 degrees +/- 8.4 degrees ). CONCLUSIONS: The use of different landmarks to establish access outline designs affected the primary angle of curvature in relatively calcified mandibular molars. PMID- 26433860 TI - Rapid Geriatric Assessment. PMID- 26433861 TI - How Should Cognitive Impairment Be Recognized? PMID- 26433862 TI - Hospitalization and Mortality Rates in Long-Term Care Facilities: Does For-Profit Status Matter? AB - OBJECTIVES: To establish if proprietary status (ie, for-profit or not-for-profit) is associated with mortality and hospitalizations among publicly funded long-term care (nursing) homes. METHODS: We conducted a retrospective cohort study of new admissions in 640 publicly funded long-term care facilities in Ontario, Canada (384 for-profit, 256 not-for-profit). A population-based cohort of 53,739 incident admissions into long-term care facilities between January 1, 2010, and March 1, 2012, was observed. We measured adjusted rates of hospital admissions and mortality, per 1000 person-years (PY) of follow-up, among for-profit and not for-profit facilities at 3, 6, and 12 months postadmission. Rates were measured postadmission and until discharge or death, whichever came first. RESULTS: One year after admission and before discharge, 11.7% of residents died and 25.7% had at least one hospitalization. After 12 months of follow-up, residents in for profit facilities had a hospitalization rate of 462 per 1000 PY versus 358 per 1000 PY in not-for-profit facilities. During this period, the crude mortality rate in for-profit facilities was 208 per 1000 PY versus 185 per 1000 PY in not for-profit facilities. At 3, 6, and 1 year after admission, for-profit facilities had an adjusted hazard ratio of 1.36 (95% confidence interval [CI] 1.28-1.43), 1.33 (95% CI 1.27-1.39), and 1.25 (95% CI 1.21-1.30) for hospitalizations and hazards of 1.20 (95% CI 1.11-1.29), 1.16 (95% CI 1.09-1.24), and 1.10 (95% CI 1.05-1.16) for mortality, respectively. CONCLUSIONS: Publicly funded for-profit facilities have significantly higher rates of both mortality and hospital admissions. PMID- 26433863 TI - Reply to the Letter to Editor by Maeda et al. PMID- 26433864 TI - Intensity and Types of Physical Exercise in Relation to Dementia Risk Reduction in Community-Living Older Adults. AB - OBJECTIVE: To systematically examine the amount and type of physical exercise that might reduce the future risk of dementia in community-living older people. DESIGN: Six-year observational study. SETTING: All the Elderly Health Centers (EHCs) of the Department of Health in Hong Kong. PARTICIPANTS: A total of 15,589 community-living Chinese aged 65 years and older with no history of stroke, clinical dementia, or Parkinson disease when they completed health assessment at the EHCs in the first 6 months of 2005. MEASUREMENTS: Self-reported habitual physical exercise patterns, including the frequency, duration, and type of exercise, at baseline and Year 3 were analyzed. The study outcome was incident dementia in 6 years. Dementia was defined by presence of clinical dementia in accordance with the 10th revision of the International Statistical Classification of Diseases and Related Health Problems or Clinical Dementia Rating of 1 to 3. RESULTS: Both the cognitively stable and incident groups reported exercising a median of 7 days per week and 45 minutes per day at baseline and Year 3. The former practiced aerobic and mind-body exercises more at baseline and Year 3, whereas the latter practiced stretching and toning exercises more. The odds ratio for dementia remained significant for aerobic (0.81; 95% confidence interval 0.68 0.95; P = .01) and mind-body exercises (0.76; 0.63-0.92; P = .004) after excluding participants who developed dementia within 3 years after baseline and adjusting for important potential confounders, such as age, gender, educational level, and physical and psychiatric comorbidities. CONCLUSION: Although physical exercise is widely promoted as a nonpharmacological intervention for dementia prevention, not all types of exercise appear to be useful in reducing risk of dementia in older people. Our findings suggest that daily participation in aerobic and mind-body but not stretching and toning exercises might protect community-living older adults from developing dementia. PMID- 26433865 TI - Is Aging in Place Delaying Nursing Home Admission? AB - OBJECTIVES: This study examines whether aging in place (community-based living before admission to a nursing home) delays nursing home admission among New York State home health care recipients. DESIGN: Retrospective cohort study (January 2007-December 2012). SETTING: New York State. PARTICIPANTS: Adults age 65+ who received home health services for at least 2 months before permanent nursing home admission. MEASUREMENT AND ANALYSIS: Permanent transition is defined as home care patients who are discharged to and stay at a nursing home for more than 3 months. Data were abstracted from the Minimum Data Set (MDS) and Outcome and Assessment Information Set (OASIS). Descriptive and bivariate Kruskal-Wallis and chi(2) tests were performed. RESULTS: The average age of nursing home residents at admission remained steady at 83 years between 2007 and 2012. The proportion of minority populations (Asian, black, Hispanic/Latino) increased, whereas the white population declined (P < .0001). The average length of stay at home increased 8 months, from 17 months in 2007 to 25 months in 2012 (P < .0001). Chronic conditions with significant increases in prevalence during the study period were hypertension (P < .0009), dementia (P < .0001), heart failure (P = .05), urinary incontinence (P < .0001), and bowel incontinence (P < .0001). Increases in functional disabilities requiring extensive human assistance included toileting, dressing, personal hygiene, and transferring (all P < .001). CONCLUSION: Home health services enabled recipients to remain at home 8 months longer, thus delaying nursing home entry. Given the increase in prevalence of comorbidities and disability, we anticipate a concomitant increase in support services at the nursing home. These results may inform policy and staffing decisions regarding adjustments in required caregivers' credentials and nurse-patient ratios. PMID- 26433866 TI - Pain management in pigs undergoing experimental surgery; a literature review (2012-4). AB - Failure to provide effective analgesia to animals in noxious studies contravenes the obligation to refine animal experimentation and, by increasing 'noise' in physiological data sets, may decrease the scientific validity of results. Pig models of surgical conditions are becoming increasingly important and used for translational work. This review aimed to determine the extent to which the recent biomedical literature describes pain assessment and alleviation in pigs recovering from experimental surgery. Three databases (Medline, Web of Knowledge, and Google Scholar) were searched to find relevant studies published from January 2012 to March 2014. Information on pain assessment and peri- and postoperative analgesia was extracted. The review identified 233 papers meeting selection criteria. Most articles (193/233, 83%) described use of drugs with analgesic properties, but only 87/233 (37%) described postoperative analgesia. No article provided justification for the analgesic chosen, despite the lack of guidelines for analgesia in porcine surgical models and the lack of formal studies on this subject. Postoperative pain assessment was reported in only 23/233 (10%) articles. It was found that the reporting of postoperative pain management in the studies was remarkably low, reflecting either under-reporting or under-use. Analgesic description, when given, was frequently too limited to enable reproducibility. Development of a pain-scoring system in pigs, together with the mandatory description of pain management in submitted articles, would contribute to improved laboratory pig welfare. PMID- 26433867 TI - ABO (histo) blood group phenotype development and human reproduction as they relate to ancestral IgM formation: A hypothesis. AB - The formation of a histo (blood) group) ABO phenotype and the exclusion of an autoreactive IgM or isoagglutinin activity arise apparently in identical glycosylation of complementary domains on cell surfaces and plasma proteins. The fundamental O-glycan emptiness of the circulating IgM, which during the neonatal amino acid sequencing of the variable regions is exerting germline-specific O GalNAc glycan-reactive serine/threonine residues that in the plasma of the adult human blood group O individuals apparently remain associated with the open glycosidic sites on the ABOH convertible red cell surface, must raise suggestions on a transient expression of developmental glycans, which have been "lost" over the course of maturation. In fact, while the mammalian non-somatic, embryogenic stem cell (ESC)- germ cell (GC) transformation is characterized by a transient and genetically as-yet-undefined trans-species-functional O-GalNAc glycan expression, in the C57BL/10 mouse such expression was potentially identified in growth-dependent, blood group A-like GalNAc glycan-bearing, ovarian glycolipids complementary with the syngeneic anti-A reactive IgM, which does not appear in early ovariectomized animals. This non-somatically encoded, polyreactive, ancestral IgM molecule has not undergone clonal selection and does primarily not differentiate between self and non-self and might, due to amino acid hydroxyl groups, highly suggest substrate competition with subsequent O-glycosylations in ongoing ESC-GC transformations and affecting GC maturation. However, the membrane bound somatic N/O-glycotransferases, which initiate, after formation of the zygote, the complex construction of the human ABO phenotypes in the trans cisternae of the Golgi apparatus, are associated and/or completed with soluble enzyme versions exerting identical specificities in plasma and likely competing vice versa by glycosylation of neonatal IgM amino acids, where they suggest to accomplish the clearance of anti-A autoreactivity at germline serine and threonine residues. Sustaining the lineage-maintaining position of the classic A allele and the discovery of the OA hybrid alleles at the normal ABO locus and in heterozygous ESC lines have, together with clinical observations, raised discussions about a silent A-allelic support within blood group O reproduction. However, the question of whether a fictional "continued blood group O inbreeding" ultimately occurs without the A-allelic or somatic function remains unanswered because the genetic relationship between non-somatic O-GalNAc-glycosylations that operate before sperm-egg recognition and somatic O-GalNAc-glycosylations that arise after the formation of the zygote remains to be elucidated. PMID- 26433868 TI - Noduler an immune protein augments infection-induced cell proliferation through cross-talking with p38 MAPK. AB - Noduler, an immune protein that mediates nodule formation by binding to specific bacteria and hemocytes was previously reported in the wild tasar silkworm, Antheraea mylitta. However, the molecular mechanism underlying nodulation in lepidopterans remains unclear. The present study is performed to investigate the functional connection between Noduler with various signalling pathways. It was observed that Noduler is an upstream factor in the phenoloxidase cascade and its knockdown has no direct effect on Toll/Imd pathway inducible genes. Additionally, Noduler was shown to stimulate cell proliferation via activation of p38 mitogen activated protein kinase (MAPK). Inhibition of p38 in the infected hemocytes cultured in vitro resulted in reduced cell proliferation and melanization. These results suggest that Noduler mediates nodulation via p38/MAPK signalling. This is the first report implicating the p38 MAPK signalling pathway in the nodulation response of insects. PMID- 26433869 TI - Lateral Sesamoid Position Relative to the Second Metatarsal in Feet With and Without Hallux Valgus: A Prospective Study. AB - We sought to determine whether hallux valgus displaces the sesamoid bones laterally away from a stationary first metatarsal or whether the first metatarsal head is displaced medially from the stationary sesamoids, which remain in position relative to the rest of the forefoot. We reviewed weightbearing radiographs in the dorsal plantar view of 128 consecutive patients (149 feet) seen over 2 months in 2014. Of these, 82 feet (55%) had a hallux valgus angle of >15 degrees (hallux valgus group) and 67 feet (45%) had an angle of no more than 15 degrees (control group). We measured the absolute distances from the center of the lateral sesamoid and the first metatarsal head to the long axis of the second metatarsal. Next, the relative distances, defined as the ratio of these 2 absolute distances to the length of the second metatarsal, were calculated to adjust for foot size. Both the absolute and the relative distances from the center of the first metatarsal head to the second metatarsal differed significantly between the 2 groups and correlated positively with the hallux valgus angle and first intermetatarsal angle. However, neither the absolute nor the relative distance to the lateral sesamoid bone differed significantly between the groups, nor did they correlate with either of the 2 angles. Thus, despite medial shifting of the first metatarsal in hallux valgus, the lateral sesamoid retains its relationship to the second metatarsal in transverse plane. Its apparent lateral movement is a radiographic misinterpretation. Awareness of this misinterpretation should improve the success of corrective surgery. PMID- 26433870 TI - Effect of Preoperative Stress Radiographic Findings on Radiographic and Clinical Outcomes of the Modified Brostrom Procedure for Chronic Ankle Instability. AB - The purpose of the present study is to evaluate whether findings of instability on preoperative stress radiographs of patients with chronic ankle instability affects the radiographic and clinical outcomes after a modified Brostrom procedure. A total of 45 consecutive patients (45 ankles) who had undergone the modified Brostrom procedure for unilateral ankle joint instability and were followed up for >=2 years were selected. The patients were classified into 2 groups according to the results of the preoperative stress radiographs: 1 group with positive findings (35 [77.8%] patients; stress-positive group) and 1 group with negative findings (10 [22.2%] patients; stress-negative group). The radiographic and clinical outcomes were compared between the 2 groups. The mean preoperative talar tilt measured on the stress radiograph was 14.4 degrees +/- 4.2 degrees and 4.8 degrees +/- 2.6 degrees in the stress-positive and stress negative groups, respectively, a statistically significant difference. Postoperative talar tilt improved in both groups, with a mean final talar tilt of 5.4 degrees +/- 3.4 degrees in the stress-positive group (p < .001) and 3.0 degrees +/- 1.5 degrees in the stress-negative group (p = .038). The average American Orthopaedic Foot and Ankle Society ankle-hindfoot score in the stress positive and stress-negative groups improved from 65.1 +/- 14.6 to 90.0 +/- 6.3 (p < .001) and 72.5 +/- 9.3 to 92.6 +/- 7.8 (p = .007), respectively. The mean postoperative satisfaction rate was 83.9 +/- 11.9 and 85.0 +/- 11.8 in the 2 groups. No statistically significant differences were seen in the preoperative and postoperative American Orthopaedic Foot and Ankle Society ankle-hindfoot scores or in postoperative satisfaction rates between the 2 groups. PMID- 26433871 TI - Positron emission tomography to diagnose chronic Q fever. PMID- 26433872 TI - Prevalence of extended-spectrum beta-lactamase-producing Enterobacteriaceae isolated from blood cultures in Africa. AB - Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae have been isolated from many regions of the world. Epidemiological studies are being conducted in Europe, North America, and Asia. No study has however been conducted in Africa to determine the prevalence and distribution of ESBLs on the continent. This literature review aimed at describing the prevalence of ESBL-producing Enterobacteriaceae isolated from blood cultures, as well as the ESBL genes involved at the international level. Our focus was mainly on Africa. We conducted a literature review on PubMed. Articles related to our study field and published between 1996 and 2014 were reviewed and entirely read for most of them, while we only focused on the abstracts of some other articles. Relevant articles to our study were then carefully reviewed and included in the review. The prevalence of ESBL-producing Enterobacteriaceae differs from one country to another. The results of our literature review however indicate that class A ESBLs prevail over the other types. We took into consideration articles focusing on various types of samples to assess the prevalence of ESBL-producing Enterobacteriaceae, but information on isolates from blood cultures is limited. The worldwide prevalence of ESBL-producing Enterobacteriaceae has increased over time. Evidence of ESBL producing Enterobacteriaceae can be found in all regions of the world. Studies conducted in Africa mainly focused on the Northern and Eastern parts of the continent, while only rare studies were carried out in the rest of the continent. PMID- 26433873 TI - An express sexual health service: in and out in a jiffy. AB - Objectives The aims of the present study were to assess client satisfaction with existing services, gauge the interest in an express service option and to compare waiting times before and after the introduction of an express service. Methods A survey evaluating satisfaction with existing services, waiting times and interest in an express service was offered to all clients attending the Western Sydney Sexual Health Centre in May 2013. A pilot of the express service ran from May to December 2013, and a follow-up survey was conducted in December 2013. Results There was a high level of interest in the express service. Median waiting times and satisfaction with waiting times improved following introduction of the express clinic. A high level of satisfaction was reported in those who had used the express service. Conclusions The express service was well received by clients and has the potential to improve client waiting times, increase clinic capacity and improve the overall client journey through the clinic. What is known about the topic? Express service options for testing for sexually transmitted infections (STIs) are being introduced both in Australia and overseas. Express services have been shown to increase clinic capacity and can create cost savings. They appear to be acceptable to clients. What does this paper add? This paper demonstrates that an express service option can be successfully introduced in an at-risk multicultural population. What are the implications for practitioners? The present study helps show that new models can be successfully introduced into long-standing traditional service models. Such models can help improve efficiency, clinic capacity and may produce cost savings. An express clinic is an option for screening asymptomatic clients for STIs. Clients complete a self collected history and take self-collected specimens, and clinician-collected blood tests and throat swabs are advised accordingly. PMID- 26433874 TI - Abdominal Wall Angiosarcoma in a Patient With Drug-Induced Immunosuppression Following Renal Transplantation. PMID- 26433875 TI - Factors associated with antenatal and delivery care in Sudan: analysis of the 2010 Sudan household survey. AB - BACKGROUND: Every day, globally approximately a thousand women and girls needlessly die as a result of complications during pregnancy, childbirth or the 6 weeks following delivery. The majority of maternal deaths are avoidable and could be prevented with proven interventions to prevent or manage complications during pregnancy and child birth. The aim of this study was to examine factors associated with underutilization of maternal health services in Sudan. METHODS: Data was obtained from the Sudan Household Health Survey 2010(SHHS). The SHHS collected data from 5730 women, aged 15-49 years and who were pregnant in the last 2 years preceding the survey. The selection of the respondents was through a multi-stage cluster sampling technique. Interviews were conducted with respondents to collect data about their demographic characteristics, reproductive history, pregnancy and child delivery. Univariate analysis and logistic regression were used to analyze the data. RESULTS: The factors associated with receiving antenatal care were, higher educational level (odds ratio (OR) = 3.428, 95% CI 2.473-4.751 - p value 0.001), higher household wealth (OR 1.656, 95% CI: 1.484-1.855 - p value 0.001) and low parity (OR =1.214, 95% CI: 1.035-1.423 - p value 0.017). The factors associated with institutional delivery were higher educational level (OR = 1.929, 95% CI: 1.380-2.697 - p value 0.001), high household wealth (OR = 2.293, 95% CI: 1.988-2.644 p value 0.001), urban residence (OR = 1.364, 95% CI: 1.081-1.721 p value 0.009), low parity (OR = 2.222, 95% CI: 1/786-2.765 p value 0.001), receiving ANC (OR = 3.342, 95% CI: 2.306-4.844 p value 0.001) and complications during pregnancy (OR = 1.606, 95% CI: 1.319-1.957 p value 0.001). CONCLUSIONS: The factors associated with both antenatal care use and institutional delivery are similar and interventions to target these include expanding female education and improving coverage and affordability of health services. PMID- 26433877 TI - The Generality of Interview-Informed Functional Analyses: Systematic Replications in School and Home. AB - Behavioral interventions preceded by a functional analysis have been proven efficacious in treating severe problem behavior associated with autism. There is, however, a lack of research showing socially validated outcomes when assessment and treatment procedures are conducted by ecologically relevant individuals in typical settings. In this study, interview-informed functional analyses and skill based treatments (Hanley et al. in J Appl Behav Anal 47:16-36, 2014) were applied by a teacher and home-based provider in the classroom and home of two children with autism. The function-based treatments resulted in socially validated reductions in severe problem behavior (self-injury, aggression, property destruction). Furthermore, skills lacking in baseline-functional communication, denial and delay tolerance, and compliance with adult instructions-occurred with regularity following intervention. The generality and costs of the process are discussed. PMID- 26433876 TI - Phase II, Multicenter, Single-Arm, Feasibility Study of Eribulin Combined With Capecitabine for Adjuvant Treatment in Estrogen Receptor-Positive, Early-Stage Breast Cancer. AB - BACKGROUND: The present phase II, open-label, multicenter study explored the feasibility, safety, and tolerability of eribulin, a novel non-taxane microtubule inhibitor, plus capecitabine as adjuvant therapy. PATIENTS AND METHODS: Postmenopausal women with early-stage, human epidermal growth factor receptor 2 (HER2)-negative, estrogen-receptor (ER)-positive breast cancer received four 21 day cycles of treatment with eribulin mesylate (1.4 mg/m(2) intravenously on days 1 and 8 of each cycle) combined with capecitabine (900 mg/m(2) orally twice daily on days 1-14 of each cycle [standard schedule] or 1500 mg orally twice daily using a 7-days on/7-days off schedule [weekly schedule]). Feasibility was determined by the relative dose intensity (RDI) of the combination using prespecified criteria for 80% of patients achieving an RDI of >= 85%, with a lower 95% confidence boundary > 70%. RESULTS: The mean RDI was 90.6%, and the feasibility rate was 81.3% among women (n = 67, mean age, 61.3 years) receiving the standard schedule and 95.6% and 100% among women (n = 10, mean age 62.3 years) receiving the weekly schedule. Dose reductions, missed doses, and withdrawals due to adverse events (most commonly hand-foot syndrome) ascribed to capecitabine led to a higher RDI (93.5% vs. 87.8%) and feasibility rate (82.8% vs. 71.9%) for eribulin than for capecitabine using the standard dosing schedule. The most common adverse events were alopecia and fatigue. CONCLUSION: Eribulin plus capecitabine with standard or weekly dosing schedules is feasible in patients with early-stage, HER2-negative, ER-positive breast cancer. Full-dose eribulin (1.4 mg/m(2) on days 1 and 8) with capecitabine (1500 mg orally twice daily, 7 days on/7 days off) is recommended as a regimen for further evaluation. PMID- 26433878 TI - Evaluation of Classroom Active Engagement in Elementary Students with Autism Spectrum Disorder. AB - This study evaluated the classroom measure of active engagement (CMAE), an observational tool designed to measure active engagement in students with autism spectrum disorder (ASD). Participants included 196 students with ASD and their educators (n = 126) who were video-recorded at the beginning of the school year. Findings documented limited active engagement overall, with students spending less than half of the observation well-regulated, productive, or independent and infrequently directing eye gaze and communicating. Confirmatory factor analysis indicated that the structure of the CMAE was represented by a 5-factor model. These findings underscore the need for improved active engagement in students with ASD and show promise for a tool to measure behaviors associated with positive educational outcomes in students with ASD. PMID- 26433879 TI - The role of mannose binding lectin on fever episodes in pediatric oncology patients. AB - Despite significant changes in pediatric oncological therapy, mortality is still high, mainly due to infections. Complement system as an ancient immune defense against microorganisms plays a significant role in surmounting infections, therefore, deficiency of its components may have particular importance in malignancies. The present paper assesses the effect of promoter (X/Y) and exon 1 (A/0) polymorphisms of the MBL2 gene altering mannose binding lectin (MBL) serum level in pediatric oncological patients with febrile neutropenia. Furthermore, frequency distribution of MBL2 alleles in children with malignancies and age matched controls was analysed. Fifty-four oncohematological patients and 53 children who had undergone pediatric surgery were enrolled into this retrospective study. No significant differences were found in the frequency of MBL2 alleles between the hemato-oncologic and control group. The average duration of fever episodes was significantly shorter (p = 0.035) in patients carrying genotypes (AY/AY and AY/AX) that encode normal MBL level, compared to individuals with genotypes associated with lower functional MBL level (AX/AX, AY/0, AX/0, or 0/0) (days, median (IQ range) 3.7(0-5.4) vs. 5.0(3.8-6.6), respectively). In conclusion, our data suggest that MBL2 genotypes may influence the course of febrile neutropenia in pediatric patients with malignancies, and may contribute to clarification of the importance of MBL in infections. PMID- 26433880 TI - Absence of KNSTRN Mutation, a Cutaneous Squamous Carcinoma-Specific Mutation, in Other Solid Tumors and Leukemias. PMID- 26433881 TI - Upper limb DVT after an optical urethrotomy in a patient with a permanent pacemaker: a case for continuing anticoagulation during low-risk urological surgery. PMID- 26433883 TI - The safety and efficiency of onabotulinumtoxinA for the treatment of overactive bladder: a systematic review and meta-analysis. AB - PURPOSE: To assess the impact on safety and efficiency of onabotulinumtoxinA (BOTOX1, Allergan, Inc.) treatment in patients with an overactive bladder. MATERIALS AND METHODS: We searched the PubMed((r)), Embase((r)), and Cochrane Library Databases to identify all randomized controlled trials comparing the outcomes of onabotulinumtoxinA and placebo for overactive bladder. The outcomes included reductions in overactive bladder symptoms or improvements in the function of bladder and the side effects of two treatments. The Cochrane Collaboration Review Manager software (RevMan 5.1.4) was used for statistical analysis. RESULTS: The study inclusion criteria were met by eight randomized controlled trials involving 1875 patients. The synthesized data from these randomized controlled trials indicated that onabotulinumtoxinA was better than placebo in decreasing most overactive bladder symptoms (p < 0.00001, p < 0.00001, p < 0.00001, p < 0.00001, p = 0.0003) in the micturition, urgency, urinary incontinence, urgency urinary incontinence (UUI), and nocturia per day change, respectively; however, the maximum cystometric capacity change from the baseline appeared not to be significantly different between two methods (p = 0.05). In addition, the side effects in the onabotulinumtoxinA group were more serious than the placebo group (p < 0.00001, p = 0.009, p = 0.07, p < 0.0001, p = 0.03 in the UTI, bacteriuria, dysuria, urinary retention, residual urine volume, respectively). CONCLUSIONS: Compared with the placebo, onabotulinumtoxinA had significantly and clinically relevant reductions in overactive bladder symptoms, but it also leaded to more side effects. PMID- 26433882 TI - Role of Smad signaling in kidney disease. AB - Smads are the key intermediates of canonical transforming growth factor-beta (TGF beta) signaling. These intermediates are divided into three distinct subgroups based on their role in TGF-beta family signal transduction: Receptor-regulated Smads (R-Smads) 1, 2, 3, 5 and 8, common Smad4, and inhibitory Smads6 and 7. TGF beta signaling through Smad pathway involves phosphorylation, ubiquitination, sumoylation, acetylation, and protein-protein interactions with mitogen-activated protein kinases, PI3K-Akt/PKB, and Wnt/GSK-3. Several studies have suggested that upregulation or downregulation of TGF-beta/Smad signaling pathways may be a pathogenic mechanism in the progression of chronic kidney disease. Smad2 and 3 are the two major downstream R-Smads in TGF-beta-mediated renal fibrosis, while Smad7 also controls renal inflammation. In this review, we characterize the role of Smads in kidney disease, describe the molecular mechanisms, and discuss the potential of Smads as a therapeutic target in chronic kidney disease. PMID- 26433884 TI - Comparison of immunosuppressive therapies for IgA nephropathy after tonsillectomy: three-course versus one-course steroid pulse combined with mizoribine. AB - PURPOSE: It has been reported that steroid pulse therapy for IgA nephropathy improves renal prognosis. However, because of the side effects, steroid dose must be restricted to some cases. Treatment effects of steroid on cases already presenting with reduced renal function are unknown. In this study, we performed tonsillectomy in patients with IgA nephropathy and conducted a comparative study about subsequent immunosuppressive therapy. METHODS: Subjects were patients younger than 70 years of age diagnosed with IgA nephropathy by renal biopsy. Treatment protocols were a single-course steroid pulse combined with mizoribine during a period from August 2006 to June 2010 (Group A; n = 34) and a three course steroid pulse during a period from July 2010 to March 2013 (Group B; n = 32). Primary end points were excretory amounts of proteinuria, disappearance of proteinuria and hematuria, and exacerbation of renal function. RESULTS: In both the groups, proteinuria decreased significantly 12 months after treatment, and no significant difference in alleviation effects on proteinuria was found between groups. eGFR increased significantly 12 months after treatment in Group A, whereas it tended to decrease in Group B. As for the preservation effect on eGFR, Group A showed significantly higher preservation of eGFR. Similar results were shown in the patients whose eGFR at the start of the treatment was less than 60 mL/min/1.73 m(2). CONCLUSIONS: Single-course steroid pulse therapy combined with mizoribine was considered to have a protective effect on the renal function in IgA nephropathy, especially accompanying renal dysfunction. PMID- 26433885 TI - Effect of bevacizumab, a vascular endothelial growth factor inhibitor, on a rat model of peritoneal sclerosis. AB - PURPOSE: Peritoneal fibrosis is almost uniform feature encountered in peritoneal dialysis patients. The transition of epithelial cells to mesenchymal phenotype, neovascularization, and consequently development of peritoneal fibrosis occur due to the involvement of peritoneal membrane by various insults such as uremia itself, peritonitis attacks, and exposure to bio-incompatible peritoneal dialysis fluids. Bevacizumab is a monoclonal antihuman antibody developed against vascular endothelial growth factor and can reduce fibrosis by preventing neovascularization. There has been no study so far that demonstrates the effect of bevacizumab on peritoneal fibrosis in a rat model. METHODS: A total of 41 female Wistar albino rats were divided into six groups. The control group (C) received 0.9 % isotonic saline (2 ml/day) intraperitoneally (i.p) for 21 days. Chlorhexidine group (CH) received 15 % ethyl alcohol and 0.1 % chlorhexidine gluconate (CG) in saline (2 ml/day) i.p for 21 days. The resting group (R) received CG 2 ml/day i.p for 21 days. The bevacizumab-1 group (B1) received CG 2 ml/day i.p for 21 days and bevacizumab 2.5 mg/kg i.p as a single dose on day 21. The bevacizumab-2 group (B2) received CG 2 ml/day for 21 days and bevacizumab 2.5 mg/kg i.p on day 0 and day 21. The bevacizumab-3 group (B3) received bevacizumab 2.5 mg/kg i.p on day 0 and day 21. Peritoneal samples were taken from the left anterior abdominal wall. The thickness, vascularization, and fibrosis scores in the peritoneal samples were assessed using a light microscope. RESULTS: On histopathological evaluations, peritoneum thicknesses, vascularization scores, and fibrosis significantly decreased in bevacizumab groups B1 and B2. CONCLUSION: Histopathologically, bevacizumab was proven to attenuate fibrotic process in experimental peritoneal sclerosis model. PMID- 26433886 TI - A neurophysiological study of large- and small-diameter nerve fibers in the hands of hemodialysis patients. AB - PURPOSE: Polyneuropathy in patients with advanced clinical kidney disease is a very disabling condition. The aim of this study was to evaluate neurophysiological abnormalities of large- and small-diameter nerve fibers in the hands of hemodialysis patients. METHODS: A total of 38 hemodialysis patients and 38 healthy control subjects underwent a conventional electrophysiological examination. The function of small nerve fibers was assessed using cutaneous silent period (CSP) measurement. RESULTS: Slower median nerve motor conduction velocities were recorded in patients with fistula (p < 0.0001) and without fistula (p < 0.001). Sensory median and ulnar nerve conduction velocities were slower in both patient groups compared with the control group (p = 0.001). Median sensory nerve action potential amplitudes were lower in patients with fistulas (p = 0.009) and without fistulas (p = 0.005) compared with the control group. Significantly prolonged F-wave latencies of the median (p = 0.002) and ulnar nerves (p = 0.023) in patients with fistulas hands were observed. In 12/38 (32 %) patients, the onset latencies of CSPs were significantly delayed (p = 0.001). There was an inverse correlation of beta2-microglobulin and decreased conduction velocities of the median nerves, while Kt/V was associated with improved sensory nerve conduction velocity of the median nerve. An inverse correlation between motor velocity of both nerves and hemodialysis duration was observed in the patient groups. CONCLUSIONS: The measurement of CSPs provides a useful method for assessing small nerve fibers. The role of A-delta fibers is often overlooked. PMID- 26433887 TI - The association of high sCD163/sTWEAK ratio with cardiovascular disease in hemodialysis patients. AB - PURPOSE: Cardiovascular disease (CVD) is the most common cause of death in hemodialysis (HD) patients. Transmembrane proteins that circulate as soluble form such as tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and CD163 have been proposed in previous studies as CVD biomarkers in chronic kidney disease patients. In HD patients, since studies are scarce, the role of these proteins is not completely understood. We tested the hypothesis that sTWEAK, sCD163 or sCD163/sTWEAK ratio could be associated with cardiovascular disease in HD patients. METHODS: We recorded current clinical and biological data, and we measured sTWEAK and sCD163 serum levels by ELISA in 70 hemodialysis patients. Univariate analysis and multivariate (logistic regression) analysis were used to identify the relation between sTWEAK, sCD163 and sCD163/sTWEAK ratio and CVD. RESULTS: In univariate analysis, CVD in HD patients is associated with higher sCD163/sTWEAK ratio (p = 0.04), sCD163 (p = 0.07), CRP (p = 0.04), age (p = 0.07), smoking (p = 0.09) and vascular calcifications (p = 0.10). In multivariate analysis, only logarithm of sCD163/sTWEAK ratio (p = 0.04) and smoking (p = 0.03) was significantly associated with CVD. The levels of these molecules and their ratio were correlated with atherosclerosis risk factors: diabetes mellitus, high fasting glucose, tricipital skinfold thickness and CRP as well as (for sCD163/sTWEAK) intravenous iron therapy. CONCLUSIONS: Cardiovascular disease is associated with increased sCD163/sTWEAK ratio. To our knowledge, this is the first report about this relationship in HD patients. PMID- 26433888 TI - Impact of Elicitation on Antioxidant and Potential Antihypertensive Properties of Lentil Sprouts. AB - The aim of this study was to investigate the application of elicitors (500 MUM ascorbic acid, 50 MUM folic acid, 5 mM glutamic acid and 50 ppm chitosan in 5 mM glutamic acid) during lentil germination up to 8 days as a strategy to increase germination rate and to enhance the accumulation of gamma-aminobutyric acid (GABA) and phenolic compounds. The effect of elicitation on the protein profile and antioxidant and angiotensin I converting enzyme (ACE) inhibitory activities of sprouted lentils was also evaluated. The application of elicitors did not negatively affect the germination yield of lentils and no significant changes on the protein pattern of lentils germinated in the presence of elicitors were observed. Chitosan/glutamic acid increased by 1.6-fold the GABA content in lentil sprouts, whilst ascorbic and folic acids as well as chitosan/glutamic acid were highly effective to enhance the total content of phenolic compounds and the antioxidant activity of sprouted lentils. All elicited lentil sprouts showed ability to inhibit ACE activity (IC50: 9.5-11.9 MUg peptides/mL). Therefore, elicitation can be considered a promising approach to improve the content of compounds with antioxidant and potential antihypertensive activities in lentil sprouts. PMID- 26433889 TI - An Efficient and Practical Smart Card Based Anonymity Preserving User Authentication Scheme for TMIS using Elliptic Curve Cryptography. AB - In the last few years, numerous remote user authentication and session key agreement schemes have been put forwarded for Telecare Medical Information System, where the patient and medical server exchange medical information using Internet. We have found that most of the schemes are not usable for practical applications due to known security weaknesses. It is also worth to note that unrestricted number of patients login to the single medical server across the globe. Therefore, the computation and maintenance overhead would be high and the server may fail to provide services. In this article, we have designed a medical system architecture and a standard mutual authentication scheme for single medical server, where the patient can securely exchange medical data with the doctor(s) via trusted central medical server over any insecure network. We then explored the security of the scheme with its resilience to attacks. Moreover, we formally validated the proposed scheme through the simulation using Automated Validation of Internet Security Schemes and Applications software whose outcomes confirm that the scheme is protected against active and passive attacks. The performance comparison demonstrated that the proposed scheme has lower communication cost than the existing schemes in literature. In addition, the computation cost of the proposed scheme is nearly equal to the exiting schemes. The proposed scheme not only efficient in terms of different security attacks, but it also provides an efficient login, mutual authentication, session key agreement and verification and password update phases along with password recovery. PMID- 26433890 TI - Targets, Toxins, and T Cells--a Review of New Monoclonal Antibodies in the Treatment of Peripheral T Cell Lymphomas. AB - The peripheral T cell lymphomas (PTCLs) are a heterogeneous group of neoplasms for which standardized treatment approaches remain elusive. A number of new therapeutic agents have become available, of which monoclonal antibodies (MAbs) represent a powerful tool for targeted treatment of PTCLs. Therapeutic MAbs vary in their structure, targets, and mechanisms of action. Common mechanisms of action include antibody-dependent cell-mediated cytotoxicity, complement dependent cytotoxicity, direct apoptosis, blocking of receptors or signaling pathways, delivery of cytotoxic agents to tumor cells, and binding to and blocking biologically active molecules. This review will focus on recent published evidence for the various MAbs used in the treatment of PTCLs. The results overall have been very promising, and the future will see more trials with these antibodies alone and in various therapy combinations, as well as newer ones with novel modifications, conjugates, and targets. PMID- 26433891 TI - Mature T-cell leukemias: Molecular and Clinical Aspects. AB - Mature T-cell leukemias are a group of uncommon lymphoid neoplasms. These disorders have widely variable clinical features, ranging from indolent, slowly progressive processes to diseases with rapidly progressive courses, leading to death. Cytogenetic aberrations have long been identified in some of these diseases, and recent studies have found recurrent genetic mutations that contribute to their pathogenesis. Conventional multiagent chemotherapy lacks significant efficacy in this group of diseases and therapies vary from immunosuppression to treatment with monoclonal antibodies, antiviral agents, and hematopoietic stem cell transplantation. The recent expansion of knowledge regarding the underlying genetic basis of these disorders raises hope that new, more targeted therapeutic approaches will be available to patients in the near future. PMID- 26433892 TI - N-acetylcysteine stimulates protein synthesis in enterocytes independently of glutathione synthesis. AB - Dietary supplementation with N-acetylcysteine (NAC) has been reported to improve intestinal health and treat gastrointestinal diseases. However, the underlying mechanisms are not fully understood. According to previous reports, NAC was thought to exert its effect through glutathione synthesis. This study tested the hypothesis that NAC enhances enterocyte growth and protein synthesis independently of cellular glutathione synthesis. Intestinal porcine epithelial cells were cultured for 3 days in Dulbecco's modified Eagle medium containing 0 or 100 MUM NAC. To determine a possible role for GSH (the reduced form of glutathione) in mediating the effect of NAC on cell growth and protein synthesis, additional experiments were conducted using culture medium containing 100 MUM GSH, 100 MUM GSH ethyl ester (GSHee), diethylmaleate (a GSH-depletion agent; 10 MUM), or a GSH-synthesis inhibitor (buthionine sulfoximine, BSO; 20 MUM). NAC increased cell proliferation, GSH concentration, and protein synthesis, while inhibiting proteolysis. GSHee enhanced cell proliferation and GSH concentration without affecting protein synthesis but inhibited proteolysis. Conversely, BSO or diethylmaleate reduced cell proliferation and GSH concentration without affecting protein synthesis, while promoting protein degradation. At the signaling level, NAC augmented the protein abundance of total mTOR, phosphorylated mTOR, and phosphorylated 70S6 kinase as well as mRNA levels for mTOR and p70S6 kinase in IPEC-1 cells. Collectively, these results indicate that NAC upregulates expression of mTOR signaling proteins to stimulate protein synthesis in enterocytes independently of GSH generation. Our findings provide a hitherto unrecognized biochemical mechanism for beneficial effects of NAC in intestinal cells. PMID- 26433893 TI - Implications of a pre-exercise alkalosis-mediated attenuation of HSP72 on its response to a subsequent bout of exercise. AB - The aim of this study was to investigate if a pre-exercise alkalosis-mediated attenuation of HSP72 had any effect on the response of the same stress protein after a subsequent exercise. Seven physically active males [25.0 +/- 6.5 years, 182.1 +/- 6.0 cm, 74.0 +/- 8.3 kg, peak aerobic power (PPO) 316 +/- 46 W] performed a repeated sprint exercise (EXB1) following a dose of 0.3 g kg(-1) body mass of sodium bicarbonate (BICARB), or a placebo of 0.045 g kg(-1) body mass of sodium chloride (PLAC). Participants then completed a 90-min intermittent cycling protocol (EXB2). Monocyte expressed HSP72 was significantly attenuated after EXB1 in BICARB compared to PLAC, however, there was no difference in the HSP72 response to the subsequent EXB2 between conditions. Furthermore there was no difference between conditions for measures of oxidative stress (protein carbonyl and HSP32). These findings confirm the sensitivity of the HSP72 response to exercise-induced changes in acid-base status in vivo, but suggest that the attenuated response has little effect upon subsequent stress in the same day. PMID- 26433894 TI - Psychiatric disorders in Ehlers-Danlos syndrome are frequent, diverse and strongly associated with pain. AB - Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary connective tissue disorders characterized by joint hypermobility, widespread musculoskeletal pain and tissue fragility. Psychiatric disorders and psychosocial impairment are common, yet poorly characterized, findings in EDS patients. We investigated the frequency and types of psychiatric disorders and their relationship to systemic manifestations in a cohort of 106 classic and hypermobility type EDS patients. In this retrospective study, extensive medical chart review was performed for patients referred at two genetics clinics who were diagnosed with EDS. Statistical analysis was undertaken to determine the frequency of psychiatric disorders and association with systemic findings. Psychiatric disorders were found in 42.5% of the EDS cohort, with 22.7% of patients affected with 2 or more psychiatric diagnoses. Anxiety and depression were most commonly reported, with frequencies of 23.6 and 25.5%, respectively. A variety of other psychiatric diagnoses were also identified. Abdominal pain [odds ratio (OR) 7.38], neuropathic pain (OR 4.07), migraines (OR 5.21), joint pain (OR 2.85) and fatigue (OR 5.55) were significantly associated with the presence of a psychiatric disorder. The presence of any pain symptom was significantly associated with having a psychiatric disorder (OR 9.68). Muscle pain (OR 2.79), abdominal pain (OR 5.78), neuropathic pain (OR 3.91), migraines (OR 2.63) and fatigue (OR 3.78) were significantly associated with having an anxiety or mood disorder. Joint hypermobility and the classic dermatological features of EDS showed no significant association with having a psychiatric disorder. Our findings demonstrate a high frequency of psychiatric disorders and an association with pain symptoms in EDS. PMID- 26433895 TI - The validity of a non-radiologist reader in identifying cam and pincer femoroacetabular impingement (FAI) using plain radiography. AB - The purpose of this study was to evaluate the validity and reliability of a radiographic diagnosis of femoroacetabular impingement (FAI) by a non radiologist. Symptomatic FAI is prevalent and thought to be a cause of hip osteoarthritis. However, the diagnosis is often delayed by 1-2 years, in large part because radiographic findings are often subtle and clinicians have been unaware of their significance. The purpose of this study was to evaluate the validity of a radiographic diagnosis of FAI by a non-radiologist. A population based sample of 701 subjects was recruited in Vancouver, Canada. For the current study, 50 subjects were selected-40 randomly from the population sample and 10 from an orthopedic practice with confirmed FAI. An anterior-posterior pelvis and bilateral Dunn radiographs were acquired and read by a fellowship-trained musculoskeletal radiologist and a third-year medical student who received basic training in radiographic signs of FAI. Three radiographic signs were evaluated: the lateral center edge angle, alpha angle and crossover sign. Validity was assessed using sensitivity and specificity, Bland-Altman limits of agreement and kappa. The sample contained 65% women (n = 31), was 62% Caucasian and 38% Chinese and had a mean age of 38.3 years. For correctly diagnosing FAI, the non radiologist reader had a sensitivity of 0.83 and specificity of 0.87. Intra-rater kappa value was 0.72, and prevalence-adjusted bias-adjusted kappa was 0.76. This study provides evidence that a non-radiologist can accurately and reliably identify FAI on plain films. PMID- 26433896 TI - Aluminium stress disrupts metabolic performance of Plantago almogravensis plantlets transiently. AB - Little is known about how tolerant plants cope with internalized aluminium (Al). Tolerant plants are known to deploy efficient detoxification mechanisms, however it is not known to what extent the primary and secondary metabolism is affected by Al. The aim of this work was to study the metabolic repercussions of Al stress in the tolerant plant Plantago almogravensis. P. almogravensis is well adapted to acid soils where high concentrations of free Al are found and has been classified as a hyperaccumulator. In vitro reared plantlets were used for this purpose in order to control Al exposure rigorously. The metabolome of P. almogravensis plantlets as well as its metabolic response to the supply of sucrose was characterized. The supply of sucrose leads to an accumulation of amino acids and secondary metabolites and consumption of carbohydrates that result from increased metabolic activity. In Al-treated plantlets the synthesis of amino acids and secondary metabolites is transiently impaired, suggesting that P. almogravensis is able to recover from the Al treatment within the duration of the trials. In the presence of Al the consumption of carbohydrate resources is accelerated. The content of some metabolic stress markers also demonstrates that P. almogravensis is highly adapted to Al stress. PMID- 26433897 TI - Effect of manganese treatment on the accumulation on biologically relevant metals in rat cochlea and brain by inductively coupled plasma mass spectrometry. AB - Manganese (Mn), iron (Fe), zinc (Zn), and copper (Cu) are essential transitions metals that are required in trace amounts, however chronic exposure to high concentrations can cause severe and irreversible neurotoxicity. Since prolonged exposure to Mn leads to manganism, a disorder exhibiting a diverse array of neurological impairments progressing to a debilitating and irreversible extrapyramidal condition symptomatically similar to Parkinson's disease, we measured the concentration of Mn as well as Fe, Zn and Cu in three region of the brain (globus pallidus, striatum and inferior colliculus) and three regions in the cochlea (stria vascularis, basilar membrane and modiolus) under normal conditions or after 30 or 60 days of oral administration of Mn (10 mg/ml ad libitum). Under normal conditions, Mn, Zn and Fe were typically higher in the cochlea than in the three brain regions whereas Cu was equal to or lower. Oral treatment with Mn for 30 or 60 days resulted in 20-75 % increases in Mn concentrations in both cochlea and brain samples, but had little effect on Cu and Fe levels. In contrast, Zn levels decreased (20-80 %) with Mn exposure. Our results show for the first time how prolonged oral Mn-ingestion affects the concentration of Mn, Cu, Zn and Fe, in the three regions of the cochlea, the inferior colliculus in auditory midbrain and the striatum and globus pallidus, two regions implicated in Parkinson's disorder. The Mn-induced changes in the concentration of Mn, Cu, Zn and Fe may provide new insights relevant to the neurotoxicity of Mn and the transport and accumulation of these metals in cochlea and brain. PMID- 26433898 TI - Are Callous-Unemotional Traits Associated with Conflict Adaptation in Childhood? AB - This study examined associations between childhood callous-unemotional (CU) traits and cognitive control using a conflict adaptation paradigm. Participants were (N = 158) children aged 9 to 12 years (M = 10.42, SD = 1.05; 57 % boys), who completed a modified color-word Stroop task. CU traits and conduct problems were indexed via self-reports on the Strengths and Difficulties Questionnaire and the Inventory of Callous-Unemotional Traits. CU traits were found to be uniquely associated with reduced conflict adaptation, however, this significant association was specific to boys. Conversely, conduct problems were associated with increased conflict adaptation, but among girls only. These findings contribute to evidence of atypical goal directed behavior in boys with CU traits by providing preliminary evidence that the specific impairments in cognitive control that characterize these boys include those concerning dynamic adjustments in cognitive control. Findings are discussed in relation to accounts of childhood CU traits based on the Response Modulation hypothesis. PMID- 26433899 TI - Connectivity-Based Brain Parcellation: A Connectivity-Based Atlas for Schizophrenia Research. AB - Defining brain structures of interest is an important preliminary step in brain connectivity analysis. Researchers interested in connectivity patterns among brain structures typically employ manually delineated volumes of interest, or regions in a readily available atlas, to limit the scope of connectivity analysis to relevant regions. However, most structural brain atlases, and manually delineated volumes of interest, do not take voxel-wise connectivity patterns into consideration, and therefore may not be ideal for anatomic connectivity analysis. We herein propose a method to parcellate the brain into regions of interest based on connectivity. We formulate connectivity-based parcellation as a graph-cut problem, which we solve approximately using a novel multi-class Hopfield network algorithm. We demonstrate the application of this approach using diffusion tensor imaging data from an ongoing study of schizophrenia. Compared to a standard anatomic atlas, the connectivity-based atlas supports better classification performance when distinguishing schizophrenic from normal subjects. Comparing connectivity patterns averaged across the normal and schizophrenic subjects, we note significant systematic differences between the two atlases. PMID- 26433900 TI - Effects of soil contamination by trace elements on white poplar progeny: seed germination and seedling vigour. AB - Seed germination is considered a critical phase in plant development and relatively sensitive to heavy metals. White poplar (Populus alba) trees tend to accumulate Cd and Zn in their tissues. We tested if soil contamination can affect P. alba progeny, reduced seed germination and explored the distribution of mineral elements in the seed. For this purpose, fruits and seeds from female P. alba trees were selected from two contaminated and one non-contaminated areas. Seeds from all the sites were germinated using only water or a nutritive solution (in vitro). Concentrations of nutrients and trace elements in the fruits and seeds were analysed. Seedling growth in vitro was also analysed. Finally, a mapping of different elements within the poplar seed was obtained by particle induced X-ray emission (PIXE). Germination was similar between different progenies, refuting our hypothesis that seeds from a contaminated origin would have reduced germination capacity compared to those from a non-contaminated site. Seedling growth was not affected by the contaminated origin. Cadmium and Zn concentrations in fruits produced by P. alba trees in the contaminated sites were higher than by those from the non-contaminated site. However, the nutritional status of the trees was adequate in both cases. Cd in seedlings was higher in those from contaminated soils although lower than in fruits, indicating a certain exclusion from seeds. Preliminary results of the PIXE technique showed that Al and Zn were distributed uniformly in the seeds (Cd was not detected with this technique), while the nutrients P and S were concentrated in the cotyledons. PMID- 26433901 TI - Microalgal diversity in relation to the physicochemical parameters of some Industrial sites in Mangalore, South India. AB - This study is undertaken to understand the microalgal species composition, diversity, abundance and their association with the polluted sites of an industrial area. The microalgae and the wastewater samples collected from these sites were preserved and analysed using standard methods. One hundred and eight species of the microalgae, belonging to Cyanophyceae, Chlorophyceae, Euglenophyceae, Bacillariophyceace and Desmidaceae, were identified. Of these, the members of Cyanophyceae formed the dominant flora. It was observed that the family Oscillatoriaceae was the most diverse family. In this family, the most diverse genus was found to be the Oscillatoria, with 13 species. Further, the abundance of Oscillatoria princeps indicated that these species are tolerant to the pollution and therefore considered as the 'marker species' of the habitat. The abundance of the Cyanophyceae in these sites was found to be due to the favourable contents of the oxidizable organic matter and the presence of the nutrients, such as the nitrates and the phosphates, in abundance, with less dissolved oxygen. The lesser percentage of the Bacillariophyceae (14%), and the negligible number of the euglenoids (2%) indicated that the sites were rich in the inorganic pollutants and poor in the organic pollutants. The range of Shannon diversity indices was found between 2.10 and 3.50, while the dominance index was found between 0.03 and 0.14, the species evenness between 0.73 and 0.93 and the Margalef index between 1.8 and 6.3. The diversity indices indicated that there is light to moderate level of pollution in the studied sites, with moderate diversity level. The principal component analysis (PCA) of the physicochemical parameters identified the four possible groups, which were responsible for the data structure, explaining the 74% of the total variance of the data set. In the PCA performed using all the variables, the first principal component showed the positive correlation with the total dissolved solids (TDS), salinity, conductivity, temperature, biochemical oxygen demand (BOD) and the sulphates and the negative correlation with the dissolved oxygen (DO) and Pb2+. The second principal component showed the positive correlation with the pH, dissolved oxygen, chemical oxygen demand (COD), nitrates and phosphates, and the negative correlation with the TDS, salinity, conductivity, temperature and BOD. The canonical correspondence analysis (CCA) showed that there were significant (p<0.05) positive and negative relationships between some of the physicochemical parameters and the microalgal species at these sites. The results showed that Calonies bacillum and Pseudanabaena amphigranulata were in close positive association with the pH, DO, COD, chlorides, nitrates and Cu+2 at the third and the fifth sites; the Navicula sphaerophora, Stigonema minutum and Chlamydomonas sphagnicola were in close positive association with the phosphates and the lead at the first, second and the fifth sites; the Anabaena spiroides, Anabaena constricta, Oscillatoria curviceps, Oscillatoria princeps, Spirogyra pratensis, Spirogyra crassa, Aulosira laxa and Micrasterias foliacea were in close positive association with the conductivity and the BOD levels at the fourth site, while the Phormidium acutum, Oedogonium decipiens, Oscillatoria trichoides and Parapediastrum biradiatum were in close positive association with the TDS, salinity, temperature, sulphate and Cr+6 levels at the first and the second sites. Therefore, the variations in the physicochemical parameters in the waters of these habitats are attributed to be the reasons for the differences in the diversity and the distribution of the species. Further, the significant correlations observed between the microalgal species and the physicochemical parameters studied here suggest that the type of pollution can be predicted, based on the structure of the microalgal community. PMID- 26433902 TI - Groundwater-induced alterations in elemental concentration and interactions in semi-arid soils of the Southern High Plains, USA. AB - This study examined and compared arsenic (As) and other element [copper (Cu), iron (Fe), potassium (K), manganese (Mn), rubidium (Rb), and zinc (Zn)] distribution, as well as their interactions in historically irrigated and non irrigated semi-arid agricultural soils of the Southern High Plains (SHP) in the USA, using findings from a portable X-ray fluorescence spectrometer. The portable X-ray fluorescence (PXRF) findings revealed that the concentrations of As (5.1 vs. 3.1 mg kg(-1)), Cu (7.2 vs. 6.2), Fe (7398 vs. 5677), K (8638 vs. 7061), Mn (80 vs. 68), Rb (36 vs. 27), and Zn (19.3 vs. 13.8) were higher in the historically irrigated field compared to the non-irrigated and, when examined within depths, were consistently and significantly higher (P<0.001) in the subsurface soils of the non-irrigated field, a trend not evident in the irrigated field. The strengths of the correlation among elements were higher in the non irrigated field compared to the irrigated (average R of 0.60 vs. 0.54), suggesting a possible external input of these pollutants in the historically irrigated field which could have altered the natural background concentration and association among them. Furthermore, findings from principal component analysis (PCA) indicated that As, Mn, Rb, Fe, Zn, and K were more closely associated in the non-irrigated field and likely of lithogenic origin. The observed differences in elemental concentration and interaction between the irrigated and non irrigated soils support the hypothesis that water from the local aquifer could be a potential source of pollutant addition to these semi-arid alkaline soils. PMID- 26433903 TI - Prediction of blast-induced air overpressure: a hybrid AI-based predictive model. AB - Blast operations in the vicinity of residential areas usually produce significant environmental problems which may cause severe damage to the nearby areas. Blast induced air overpressure (AOp) is one of the most important environmental impacts of blast operations which needs to be predicted to minimize the potential risk of damage. This paper presents an artificial neural network (ANN) optimized by the imperialist competitive algorithm (ICA) for the prediction of AOp induced by quarry blasting. For this purpose, 95 blasting operations were precisely monitored in a granite quarry site in Malaysia and AOp values were recorded in each operation. Furthermore, the most influential parameters on AOp, including the maximum charge per delay and the distance between the blast-face and monitoring point, were measured and used to train the ICA-ANN model. Based on the generalized predictor equation and considering the measured data from the granite quarry site, a new empirical equation was developed to predict AOp. For comparison purposes, conventional ANN models were developed and compared with the ICA-ANN results. The results demonstrated that the proposed ICA-ANN model is able to predict blast-induced AOp more accurately than other presented techniques. PMID- 26433904 TI - Synthesis and biological evaluation of strained unusual amino acid containing tetrapeptides as potential antidepressant agents. AB - Strained unusual amino acid derived tetrapeptides were synthesized as mimics of GLYX-13, a clinical candidate for neuroprotective and anti-depressant properties, were studied. The synthesized compounds were screened for neurite growth and anti depressant properties in vitro and in vivo respectively comparing with the parent GLYX-13 compound. Neurite growth property was assessed by neurite length and anti depressant property by percentage of immobility in forced swim test, a behavioural assay. Mechanistic insights about protein-ligand interactions were obtained using molecular docking study. Based on the in vitro and in vivo screening data and molecular docking study, a new analogue of GLYX-13, Compound 11a has been found to be as good as the parent compound in all respects. PMID- 26433905 TI - Quantification of renal and diaphragmatic interfractional motion in pediatric image-guided radiation therapy: A multicenter study. AB - BACKGROUND AND PURPOSE: To quantify renal and diaphragmatic interfractional motion in order to estimate systematic and random errors, and to investigate the correlation between interfractional motion and patient-specific factors. MATERIAL AND METHODS: We used 527 retrospective abdominal-thoracic cone beam CT scans of 39 childhood cancer patients (<18 years) to quantify renal motion relative to bony anatomy in the left-right (LR), cranio-caudal (CC) and anterior-posterior (AP) directions, and diaphragmatic motion in the CC direction only. Interfractional motion was quantified by distributions of systematic and random errors in each direction (standard deviations Sigma and sigma, respectively). Also, correlation between organ motion and height was analyzed. RESULTS: Inter patient organ motion varied widely, with the largest movements in the CC direction. Values of Sigma in LR, CC, and AP directions were 1.1, 3.8, 2.1 mm for the right, and 1.3, 3.0, 1.5 mm for the left kidney, respectively. The sigma in these three directions was 1.1, 3.1, 1.7 mm for the right, and 1.2, 2.9, 2.1 mm for the left kidney, respectively. For the diaphragm we estimated Sigma=5.2 mm and sigma=4.0 mm. No correlations were found between organ motion and height. CONCLUSIONS: The large inter-patient organ motion variations and the lack of correlation between motion and patient-related factors, suggest that individualized margin approaches might be required. PMID- 26433906 TI - Evolving Therapeutic Options for Polycythemia Vera: Perspectives of the Canadian Myeloproliferative Neoplasms Group. AB - Polycythemia vera (PV) is a clonal stem cell disorder characterized by erythrocytosis and associated with burdensome symptoms, reduced quality of life, risk of thrombohemorrhagic complications, and risk of transformation to myelofibrosis and acute myeloid leukemia. The discovery of the JAK2 V617 mutation marked a significant milestone in understanding the pathophysiology of the disease and subsequently the diagnostic and therapeutic approaches. The current diagnostic criteria for PV are based on hemoglobin level and presence of the JAK2 V617 mutation. The treatment is geared toward prevention of thrombotic events, normalization of blood counts, control of disease-related symptoms, and potential prolongation of survival. Cytoreductive therapy is indicated in patients at increased risk of thrombosis. Hydroxyurea (HU) remains the most commonly used first-line cytoreductive therapy and is superior to phlebotomy in reducing risk of arterial and venous thrombosis. Interferon (IFN) is used either at failure of HU or in selected patients as first-line therapy. The results of pegylated IFN in phase 2 studies appear encouraging, with molecular responses occurring in some patients. Ongoing phase 3 studies of HU versus pegylated IFN will define the optimal first-line cytoreductive therapy for PV. A recent phase 3 trial has shown the superiority of the JAK1/2 inhibitor ruxolitinib in comparison to best available treatment in HU-intolerant or -resistant patients. The therapeutic landscape of PV is likely to change in the near future. In this report, we assess the potential impact of the changing landscape of PV management on daily practice. PMID- 26433907 TI - Monitoring Chronic Myeloid Leukemia in the Real World: Gaps and Opportunities. AB - In clinical trials, in which treatment algorithms and monitoring schedules are tightly prescribed by research protocols, outcomes for patients with chronic myeloid leukemia (CML) have been excellent, with > 90% 5-year survival rates. However, outside of clinical trials in the so-called real world, monitoring schedules are more variable, with < 40% of patients undergoing quantitative polymerase chain reaction (qPCR) molecular testing 3 to 4 times during the first year after diagnosis as recommended by National Comprehensive Cancer Network/European Leukemia Net (NCCN/ELN) evidence-based guidelines. Results from chart reviews, claims-based databases, and observational databases suggest that carefully monitored patients with CML are more likely to be adherent to medications, incur fewer hospitalizations, experience lower overall treatment costs, and have better progression-free survival and overall survival compared with patients who are not monitored. Regular monitoring provides valuable early information on treatment responses that physicians can use to modify treatment. Unfortunately, physician-perceived resource barriers, lack of familiarity, and lack of agreement have restricted monitoring guideline adoptions. Multifaceted approaches to encourage appropriate monitoring are needed to improve clinical outcomes and reduce costs in the real world. PMID- 26433908 TI - More on Scylla and Charybdis. PMID- 26433910 TI - Assessing cardiac and kidney protective effects by remote ischemic preconditioning in cardiac surgery patients. PMID- 26433909 TI - Sitagliptin use and risk of acute pancreatitis in type 2 diabetes mellitus: A population-based case-control study in Taiwan. AB - BACKGROUND: There is still lack of definite evidence to establish the association between sitagliptin use and acute pancreatitis. The study aimed to test this issue in Taiwan. METHODS: This case-control study was designed to analyze the database of the Taiwan National Health Insurance Program. There were 349 subjects with type 2 diabetes mellitus aged 20-84 with a first-attack of acute pancreatitis from 2009 to 2011 as the case group and 1116 randomly selected subjects with type 2 diabetes mellitus without acute pancreatitis as the control group. Both groups were matched with sex, age, comorbidities, and index year of diagnosing acute pancreatitis. Current use of sitagliptin was defined as subjects who had their last tablet of sitagliptin <=7 days before the date of diagnosing acute pancreatitis. Late use of sitagliptin was defined as subjects who had their last tablet of sitagliptin between 8 and 30 days before the date of diagnosing acute pancreatitis. Never use of sitagliptin was defined as subjects who never had a sitagliptin prescription. The risk of acute pancreatitis associated with sitagliptin use was estimated by the odds ratio (OR) and 95% confidence interval (CI) using the multivariable logistic regression model. RESULTS: After statistical correction for potential confounders, the adjusted OR of acute pancreatitis was 2.47 for subjects with current use of sitagliptin (95% CI 0.84, 7.28), when compared with those never using sitagliptin, but without statistical significance. The adjusted OR decreased to 1.14 for subjects with late use of sitagliptin (95% CI 0.66, 1.98), but without statistical significance. CONCLUSIONS: No significant association is detected between sitagliptin use and acute pancreatitis in type 2 diabetes mellitus. PMID- 26433911 TI - Resistance to conventional cardiopulmonary resuscitation in witnessed out-of hospital cardiac arrest patients with shockable initial cardiac rhythm. AB - BACKGROUND: Shockable initial cardiac rhythm is a key predictor of survival after out-of-hospital cardiac arrest (OHCA). However, not all patients with shockable OHCA achieve return of spontaneous circulation (ROSC) via conventional cardiopulmonary resuscitation (CPR). Therefore, we retrospectively analyzed patients with witnessed OHCA and shockable initial cardiac rhythm to identify the resistance factors for conventional CPR. METHODS: We retrospectively analyzed consecutive patients with witnessed OHCA and shockable initial cardiac rhythm who were admitted to our hospital between October 2009 and October 2014. We then compared the baseline characteristics, pre-hospital clinical course, and causes of the cardiopulmonary arrest among patients who achieved ROSC via conventional CPR and patients who did not achieve ROSC via conventional CPR and underwent extracorporeal CPR (ECPR). RESULTS: A total of 85 patients achieved ROSC via conventional CPR (non-ECPR group) and 40 patients did not achieve ROSC via conventional CPR and underwent ECPR (ECPR group). Among these 125 patients, 113 had known causes for their cardiopulmonary arrest, including 66 cases (53%) of acute myocardial infarction (AMI). There were no significant differences in the causes of arrest between the non-ECPR and ECPR cases. However, among the 66 cases of AMI (43 non-ECPR and 23 ECPR), the rate of non-recanalization during the initial coronary angiography was significantly higher among the ECPR cases (non ECPR: 58% vs. ECPR: 87%; p=0.03). CONCLUSIONS: The major cause of witnessed OHCA with shockable initial cardiac rhythm was AMI, and resistance to conventional CPR was related to continuous myocardial ischemia. PMID- 26433912 TI - Subclinical elevation of high-sensitive troponin T levels at the convalescent stage is associated with increased 5-year mortality after ST-elevation myocardial infarction. AB - BACKGROUND: It is unclear whether serum high-sensitive troponin T (hs-TnT) levels at the convalescent stage of ST-elevation myocardial infarction (STEMI) are associated with long-term mortality. METHODS: This study enrolled a total of 2944 consecutive STEMI patients who were registered in the Osaka Acute Coronary Insufficiency Study between 2000 and 2009, and whose hs-TnT levels were evaluated at the convalescent stage. Patients were divided into four hs-TnT category groups according to the results of survival classification and regression tree (CART) analysis. The impact of hs-TnT levels on 5-year mortality was evaluated using multivariate Cox regression analysis. RESULTS: Only one patient had hs-TnT level below the detection limit of the assay (<0.003ng/mL). The median hs-TnT level was 0.025 (quartile 0.011-0.083)ng/mL. During the median follow-up period of 1782 days, 188 patients died. Survival CART analysis revealed that the 1st, 2nd, and 3rd discriminating hs-TnT levels to discern 5-year mortality were 0.028, 0.008, and 1.340ng/mL, respectively. The adjusted hazard ratios for the medium-low (0.009-0.028ng/mL), medium-high (0.029-1.340ng/mL), and high-risk (>=1.341ng/mL) groups were 3.03 (95% confidence interval 1.18-7.77, p=0.021), 4.29 (1.63-11.28, p=0.003), and 8.68 (2.20-34.27, p=0.002), respectively. Integrated discrimination improvement (IDI) analysis revealed that incorporation of this hs-TnT classification scheme with other clinical variables statistically improved the discriminatory accuracy for 5-year mortality, with a time-dependent IDI of 0.0076 (p=0.033). CONCLUSIONS: hs-TnT levels at the convalescent stage were associated with long-term mortality in STEMI patients. Even subclinical elevation of hs-TnT levels was associated with increased 5-year mortality. PMID- 26433914 TI - Medical frontiers in an ancient desert. PMID- 26433913 TI - Validity and reliability of an IMU-based method to detect APAs prior to gait initiation. AB - Anticipatory postural adjustments (APAs) prior to gait initiation have been largely studied in traditional, laboratory settings using force plates under the feet to characterize the displacement of the center of pressure. However clinical trials and clinical practice would benefit from a portable, inexpensive method for characterizing APAs. Therefore, the main objectives of this study were (1) to develop a novel, automatic IMU-based method to detect and characterize APAs during gait initiation and (2) to measure its test-retest reliability. Experiment I was carried out in the laboratory to determine the validity of the IMU-based method in 10 subjects with PD (OFF medication) and 12 control subjects. Experiment II was carried out in the clinic, to determine test-retest reliability of the IMU-based method in a different set of 17 early-to-moderate, treated subjects with PD (tested ON medication) and 17 age-matched control subjects. Results showed that gait initiation characteristics (both APAs and 1st step) detected with our novel method were significantly correlated to the characteristics calculated with a force plate and motion analysis system. The size of APAs measured with either inertial sensors or force plate was significantly smaller in subjects with PD than in control subjects (p<0.05). Test retest reliability for the gait initiation characteristics measured with inertial sensors was moderate-to-excellent (0.56= 3 months). Almost 50 % of the patients who presented to the ED for evaluation of abscess were diagnosed with abscess while the remaining patients were diagnosed with mastitis. Appropriate clinical and/or imaging follow-up occurred in 77 %. Long-term follow-up (>= 3 months) occurred more frequently in patients older than 30 years of age. Appropriate follow-up does not occur in approximately one fourth of cases, suggesting that additional clinician and patient education is warranted. PMID- 26433917 TI - Group B streptococci screening. PMID- 26433918 TI - Did self-sampling improve the adherence to group B streptococci screening in pregnant women? PMID- 26433920 TI - Characterising skeletal muscle under large strain using eccentric and Fourier Transform-rheology. AB - Characterising the passive anisotropic properties of soft tissues has been largely limited to the linear viscoelastic regime and shear loading is rarely done in the large deformation regime, despite the physiological significance of such properties. This paper demonstrates the use of eccentric rheology, which allows the anisotropy of skeletal muscle to be investigated. The large amplitude oscillatory strain properties of skeletal muscle were also investigated using Fourier Transform-rheology. Histology was used to qualitatively assess the microstructure changes induced by large strain. Results showed that skeletal muscle was strongly anisotropic in the linear regime. The storage and loss moduli were found to be significantly different (p<0.05) between the three fibre alignment groups; for the group tested with fibres perpendicular to plane of shear was 12.3+/-1.3 kPa and 3.0+/-0.35 kPa, parallel to shear direction was 10.6+/-1.2 kPa and 2.4+/-0.23 kPa, and perpendicular to shear direction was 5.5+/ 0.90 kPa and 1.3+/-0.21 kPa. The appearance and growth of higher order harmonics at large strain was different in the three testing directions indicating that the anisotropy of muscle affects skeletal muscle behaviour in the nonlinear regime. Histological analysis showed an increasing destruction of extracellular matrix and the rearrangement of fibres with increasing strain indicating mechanical damage at strains of larger than 10%. These microstructural changes could contribute to the complex nonlinear behaviour in skeletal muscle. This paper demonstrates a method of characterising the anisotropic properties in skeletal muscle under large strain whilst giving meaningful information on the physical response of tissue at various strains. PMID- 26433919 TI - Developmental toxicity of the PBDE metabolite 6-OH-BDE-47 in zebrafish and the potential role of thyroid receptor beta. AB - 6-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (6-OH-BDE-47) is both a polybrominated diphenyl ether (PBDE) flame retardant metabolite and a marine natural product. It has been identified both as a neurotoxicant in cell-based studies and as a developmental toxicant in zebrafish. However, hydroxylated PBDE metabolites are also considered thyroid hormone disruptors due to their structural similarity to endogenous thyroid hormones. The purpose of this study was to evaluate the effects of 6-OH-BDE-47 on a developmental pathway regulated by thyroid hormones in zebrafish. Morphological measurements of development (head trunk angle, otic vesicle length, and eye pigmentation) were recorded in embryos at 30h post fertilization (hpf) and detailed craniofacial morphology was examined in 4 day old larvae using cartilage staining. Exposure to 6-OH-BDE-47 resulted in severe developmental delays. A 100nM concentration resulted in a 26% decrease in head trunk angle, a 54% increase in otic vesicle length, and a 42% decrease in eye pigmentation. Similarly, altered developmental morphology was observed following thyroid receptor beta morpholino knockdown, exposure to the thyroid hormone triiodothyronine (T3) or to thyroid disrupting chemicals (TDC; iopanoic acid and propylthiouracil). The threshold for lower jaw deformities and craniofacial cartilage malformations was at doses greater than 50nM. Of interest, these developmental delays and effects were rescued by microinjection of TRbeta mRNA during the 1-2 cell stage. These data indicate that OH-BDEs can adversely affect early life development of zebrafish and suggest they may be impacting thyroid hormone regulation in vivo through downregulation of the thyroid hormone receptor. PMID- 26433921 TI - Kinematic hand parameters in front crawl at different paces of swimming. AB - The aim of this study was to investigate the evolution of kinematic hand parameters (sweepback angle, angle of attack, velocity, acceleration and orientation of the hand relative to the absolute coordinate system) throughout an aquatic stroke and to study the possible modifications caused by a variation of the swimming pace. Seventeen competitive swimmers swam at long distance, middle distance and sprint paces. Parameters were calculated from the trajectory of seven markers on the hand measured with an optoelectronic system. Results showed that kinematic hand parameters evolve differently depending on the pace. Angle of attack, sweepback angle, acceleration and orientation of the hand do not vary significantly. The velocity of the hand increases when the pace increases, but only during the less propulsive phases (entry and stretch and downsweep to catch). The more the pace increases and the more the absolute durations of the entry and stretch and downsweep to catch phases decrease. Absolute durations of the insweep and upsweep phases remain constant. During these phases, the propulsive hand forces calculated do not vary significantly when the pace increases. The increase of swimming pace is then explained by the swimmer's capacity to maintain propulsive phases rather than increasing the force generation within each cycle. PMID- 26433923 TI - Fitts's Law using lower extremity movement: Performance driven outcomes for degenerative lumbar spinal stenosis. AB - A paucity of objective outcome measures exists for assessing movement disorders, including degenerative lumbar spinal stenosis (LSS). Fitts's Law provides a novel approach to clinical outcome measurement since performance is resistant to learning, and task difficulty can be altered. The objective of the present study was to compare, using a Fitts's task, movement performance of individuals with and without LSS to determine if motor difficulties that arise with LSS impede the planning, initiation, or execution of deliberate lower limb movements. Twelve pre surgical LSS patients and twelve control participants from the community performed a Fitts's Law (foot reaching) task, while LSS participants also completed pain and disability questionnaires. Fitts's Law was evident for both groups, however the LSS group's movements were more adversely impacted as task difficulty increased. Specifically, the LSS group's movement time and time to peak velocity (ttPV) increased as task index of difficulty increased, while peak velocity decreased. Correlations between ttPV and leg pain, and with stenosis impairment severity respectively, provided evidence that less support leg pain and less stenosis impairment severity yield faster ttPV in the moving leg at the highest index of difficulty. Therefore a lower extremity Fitts's Law task captured differences in the planning and execution of leg movements between healthy and LSS populations. PMID- 26433924 TI - Pediatric aggressive giant cell granuloma of nasal cavity. AB - INTRODUCTION: Giant cell granuloma (GCG) is a non-neoplastic osseous proliferative lesion of unknown etiology. Although a benign disease process, GCG can be locally destructive. It is extremely rare to have a pediatric case of GCG occurring in the nasal cavity with intracranial invasion. PRESENTATION OF CASE: We report a case of an aggressive and recurrent giant cell granuloma with intracranial invasion in a 10 years old female patient which was completely excised with endoscopic craniofacial resection. DISCUSSION: A literature review on pathogenesis, diagnosis and management is also performed. CONCLUSION: The most common treatment for giant cell granuloma is surgery, ranging from simple curettage to resection. However, it must be completely excised in cases of aggressive and extensive lesion because of the high recurrence rate after incomplete removal. PMID- 26433922 TI - Enhancing vaccine safety capacity globally: A lifecycle perspective. AB - Major vaccine safety controversies have arisen in several countries beginning in the last decades of 20th century. Such periodic vaccine safety controversies are unlikely to go away in the near future as more national immunization programs mature with near elimination of target vaccine-preventable diseases that result in relative greater prominence of adverse events following immunizations, both true reactions and temporally coincidental events. There are several ways in which vaccine safety capacity can be improved to potentially mitigate the impact of future vaccine safety controversies. This paper aims to take a "lifecycle" approach, examining some potential pre- and post-licensure opportunities to improve vaccine safety, in both developed (specifically U.S. and Europe) and low- and middle-income countries. PMID- 26433926 TI - A pre-pubertal girl with giant juvenile fibroadenoma: A rare case report. AB - INTRODUCTION: Fibroadenomas are benign neoplasms usually arising between the ages of 15-25 years. Approximately 0.4% fibroadenomas arise in juvenile age group. Usually the diagnosis is straightforward by clinical examination and FNAC. But sometimes rapid growth and giant size may pose difficulty in clinical approach. CASE PRESENTATION: In this paper we are presenting a rare case of giant juvenile fibroadenoma in a 10 years old girl which was diagnosed by FNAC and treated by excision. Diagnosis was confirmed by histopathology. DISCUSSION: Giant juvenile fibroadenomas are over 5cm in diameter and tend to show rapid growth mimicking a carcinoma. But histological features are similar to smaller fibroadenomas and can be enucleated. CONCLUSION: Through this case we want to emphasize that these giant benign neoplasms should be suspected in any pre-pubertal girl with breast lump and should always be treated with breast conserving surgery. PMID- 26433925 TI - Intradiploic epidermoid cyst with intracranial hypertension syndrome: Report of two cases and literature review. AB - INTRODUCTION: Intradiploic epidermoid intracranial cysts (IEIC) derive from ectodermal cells and are covered with stratified squamous epithelium. They are extremely rare, and most common locations are in the occipital, frontal and parietal bones. They have a very slow growth and can be asymptomatic until becoming evident by the deformation produced. The treatment is based on the removal of the lesion, and subsequent histopathological confirmation. PRESENTATION OF CASE: Two cases are reported, with intracranial hypertension syndrome, which is very uncommon because of the slow growth of this type of pathology; however, decompensations occurring in the space-occupying lesions at intracranial level explain this type of clinical presentation. DISCUSSION: The most common presentation of intracranial intradiploic epidermoid cysts (IEIC) is asymptomatically, which is made evident by the prominence at the level of the soft tissues and then presenting less frequently local pain and cephalea; rarely the size of the lesion can cause focal neurological signs. CONCLUSION: These benign lesions, although they are of low incidence, are seen very rarely in intradiploic locations and above all, of significant size, may produce significant mass effect in patients, which was initially tolerated because of its slow growth, however, they may become decompensate and cause intracranial hypertension syndrome. PMID- 26433927 TI - A rare cause of root-compression: Subaxial cervical synovial cyst in association with congenital fusion. AB - INTRODUCTION: Synovial cyst in the cervical spine is a very rare pathology that develops from the facet joint. When a synovial cyst emerges into the surrounding space, it can compress the nervous tissue and cause neurological symptoms. In the cervical area there is additionally the risk of spinal cord compression comparing to the more common presentation of synovial cysts in the lumbar spine. PRESENTATION OF CASE: Here, a cervical synovial cysts from the left facet joint grew into the spinal canal and compressed the C8 nerve root which led to root compressing symptoms. Interestingly we found this synovial cyst with congenital fusion. We identified only nine similar cases in the literature. The cyst was removed surgically and the patient discharged without complications. DISCUSSION: Numerous theories have been established to explain the pathogenesis of synovial cyst. Biomechanical alterations of the spine play a significant role in the development of synovial cyst. However, the etiology is still unclear. CONCLUSION: Surgical treatment should be considered in cervical synovial cysts with neurologic deficit or with cord compression or when the conservative treatment is ineffective. PMID- 26433928 TI - Extending Shelf Life Just Makes Sense. PMID- 26433930 TI - Ontogenetic patterns in the dreams of women across the lifespan. AB - The present study supports and extends previous research on the developmental differences in women's dreams across the lifespan. The participants included 75 Canadian women in each of 5 age groups from adolescence to old age including 12 17, 18-24, 25-39, 40-64, and 65-85, totaling 375 women. One dream per participant was scored by two independent judges using the method of content analysis. Trend analysis was used to determine the ontogenetic pattern of the dream content categories. Results demonstrated significant ontogenetic decreases (linear trends) for female and familiar characters, activities, aggression, and friendliness. These patterns of dream imagery reflect the waking developmental patterns as proposed by social theories and recognized features of aging as postulated by the continuity hypothesis. Limitations and suggestions for future research including the examining of developmental patterns in the dreams of males are discussed. PMID- 26433929 TI - Voxelwise atlas rating for computer assisted diagnosis: Application to congenital heart diseases of the great arteries. AB - Atlas-based analysis methods rely on the morphological similarity between the atlas and target images, and on the availability of labelled images. Problems can arise when the deformations introduced by pathologies affect the similarity between the atlas and a patient's image. The aim of this work is to exploit the morphological dissimilarities between atlas databases and pathological images to diagnose the underlying clinical condition, while avoiding the dependence on labelled images. We propose a voxelwise atlas rating approach (VoxAR) relying on multiple atlas databases, each representing a particular condition. Using a local image similarity measure to assess the morphological similarity between the atlas and target images, a rating map displaying for each voxel the condition of the atlases most similar to the target is defined. The final diagnosis is established by assigning the condition of the database the most represented in the rating map. We applied the method to diagnose three different conditions associated with dextro-transposition of the great arteries, a congenital heart disease. The proposed approach outperforms other state-of-the-art methods using annotated images, with an accuracy of 97.3% when evaluated on a set of 60 whole heart MR images containing healthy and pathological subjects using cross validation. PMID- 26433931 TI - Cytopathology of the trachea of Bombyx mori (Lepidoptera: Bombycidae) to Bombyx mori nucleopolyhedrovirus. AB - Bombyx mori is a holometabolous insect found only in germplasm banks and morphological data related of resistance and susceptibility to diseases is important when selecting hybrids for commercial and scientific interest. This study analyzed the cytopathology of B. mori trachea to BmNPV, isolated geographically in Parana state, Brazil. Fifth instar larvae were divided into two groups, control and inoculated; the viral suspension used was 2.4*10(7) polyhedral occlusion bodies/mL. From the second to the ninth day post inoculation, segments of silkworm organs, containing the trachea, were processed for transmission electron microscopy. Analyses of fresh hemolymph were also performed to verify the susceptibility of the hemocytes. Signs of infection were initially detected in the hemocytes and in the tracheal cells on the second and fourth post-inoculation days, respectively. The cytopathology of the trachea showed all stages of the viral cycle, which was the same as in other tissues. Virions were detected in the basal lamina, which showed structural disorganization. So, the infection time of the hemocytes prior to trachea and the presence of virus in basal lamina, suggests that the trachea was a secondary target, infected by budded virus coming from the hemolymph. PMID- 26433933 TI - Age-dependent gait abnormalities in mice lacking the Rnf170 gene linked to human autosomal-dominant sensory ataxia. AB - Really interesting new gene (RING) finger protein 170 (RNF170) is an E3 ubiquitin ligase known to mediate ubiquitination-dependent degradation of type-I inositol 1,4,5-trisphosphate receptors (ITPR1). It has recently been demonstrated that a point mutation of RNF170 gene is linked with autosomal-dominant sensory ataxia (ADSA), which is characterized by an age-dependent increase of walking abnormalities, a rare genetic disorder reported in only two families. Although this mutant allele is known to be dominant, the functional identity thereof has not been clearly established. Here, we generated mice lacking Rnf170 (Rnf170(-/ )) to evaluate the effect of its loss of function in vivo. Remarkably, Rnf170(-/ ) mice began to develop gait abnormalities in old age (12 months) in the form of asynchronous stepping between diagonal limb pairs with a fixed step sequence during locomotion, while age-matched wild-type mice showed stable gait patterns using several step sequence repertoires. As reported in ADSA patients, they also showed a reduced sensitivity for proprioception and thermal nociception. Protein blot analysis revealed that the amount of Itpr1 protein was significantly elevated in the cerebellum and spinal cord but intact in the cerebral cortex in Rnf170(-/-) mice. These results suggest that the loss of Rnf170 gene function mediates ADSA-associated phenotypes and this gives insights on the cure of patients with ADSA and other age-dependent walking abnormalities. PMID- 26433932 TI - APP overexpression in the absence of NPC1 exacerbates metabolism of amyloidogenic proteins of Alzheimer's disease. AB - Amyloid-beta (Abeta) peptides originating from beta-amyloid precursor protein (APP) are critical in Alzheimer's disease (AD). Cellular cholesterol levels/distribution can regulate production and clearance of Abeta peptides, albeit with contradictory outcomes. To better understand the relationship between cholesterol homeostasis and APP/Abeta metabolism, we have recently generated a bigenic ANPC mouse line overexpressing mutant human APP in the absence of Niemann Pick type C-1 protein required for intracellular cholesterol transport. Using this unique bigenic ANPC mice and complementary stable N2a cells, we have examined the functional consequences of cellular cholesterol sequestration in the endosomal-lysosomal system, a major site of Abeta production, on APP/Abeta metabolism and its relation to neuronal viability. Levels of APP C-terminal fragments (alpha-CTF/beta-CTF) and Abeta peptides, but not APP mRNA/protein or soluble APPalpha/APPbeta, were increased in ANPC mouse brains and N2a-ANPC cells. These changes were accompanied by reduced clearance of peptides and an increased level/activity of gamma-secretase, suggesting that accumulation of APP-CTFs is due to decreased turnover, whereas increased Abeta levels may result from a combination of increased production and decreased turnover. APP-CTFs and Abeta peptides were localized primarily in early-/late-endosomes and to some extent in lysosomes/autophagosomes. Cholesterol sequestration impaired endocytic-autophagic lysosomal, but not proteasomal, clearance of APP-CTFs/Abeta peptides. Moreover, markers of oxidative stress were increased in vulnerable brain regions of ANPC mice and enhanced beta-CTF/Abeta levels increased susceptibility of N2a-ANPC cells to H2O2-induced toxicity. Collectively, our results show that cellular cholesterol sequestration plays a key role in APP/Abeta metabolism and increasing neuronal vulnerability to oxidative stress in AD-related pathology. PMID- 26433935 TI - Synthesis and optimization of Fe2O3 nanofibers for chromate adsorption from contaminated water sources. AB - In this work, alpha-Fe2O3 nanofibers were synthesized via electrospinning and characterized to observe optimal morphological and dimensional properties towards chromate removal. The Fe2O3 nanofiber samples were tested in aqueous solutions containing chromate (CrO4(2-)) to analyze their adsorption capabilities and compare them with commercially-available Fe2O3 nanoparticles. Synthesized Fe2O3 nanofibers were observed with a variety of different average diameters, ranging from 23 to 63 nm, while having a constant average grain size at 34 nm, point zero charge at pH 7.1, and band gap at 2.2 eV. BET analysis showed an increase in specific surface area with decreasing average diameter, from 7.2 to 59.2 m(2)/g, due to the increased surface area-to-volume ratio with decreasing nanofiber size. Based on CrO4(2-) adsorption isotherms at pH 6, adsorption capacity of the Fe2O3 nanofibers increased with decreasing diameter, with the 23 nm sized nanofibers having an adsorption capacity of 90.9 mg/g, outperforming the commercially available Fe2O3 nanoparticles by nearly 2-fold. Additionally, adsorption kinetics was also analyzed, increasing with decreasing nanofiber diameter. The enhanced performance of the nanofiber is suggested to be caused solely due to the increased surface area, in part by its size and morphology. Electrospun Fe2O3 nanofibers provide a promising solution for effective heavy metal removal through nanotechnology-integrated treatment systems. PMID- 26433934 TI - A non-synonymous single-nucleotide polymorphism associated with multiple sclerosis risk affects the EVI5 interactome. AB - Despite recent progress in the characterization of genetic loci associated with multiple sclerosis (MS) risk, the ubiquitous linkage disequilibrium operating across the genome has stalled efforts to distinguish causative variants from proxy single-nucleotide polymorphisms (SNPs). Here, we have identified through fine mapping and meta-analysis EVI5 as the most plausible disease risk gene within the 1p22.1 locus. We further show that an exonic SNP associated with risk induces changes in superficial hydrophobicity patterns of the coiled-coil domain of EVI5, which, in turns, affects the EVI5 interactome. Immunoprecipitation of wild-type and mutated EVI5 followed by mass spectrometry generated a roster of disease-specific interactors functionally linked to lipid metabolism. Among the exclusive binding partners of the risk variant, we describe the novel interaction with sphingosine 1-phosphate lyase (SGPL1)-a key enzyme for the creation of the sphingosine-1 phosphate gradient, which is relevant to the pathogenic process and therapeutic management of MS. PMID- 26433936 TI - Enhanced removal of 8-quinolinecarboxylic acid in an activated carbon cloth by electroadsorption in aqueous solution. AB - The effect of the electrochemical treatment (potentiostatic treatment in a filter press electrochemical cell) on the adsorption capacity of an activated carbon cloth (ACC) was analyzed in relation with the removal of 8-quinolinecarboxylic acid pollutant from water. The adsorption capacity of an ACC is quantitatively improved in the presence of an electric field (electroadsorption process) reaching values of 96% in comparison to 55% in absence of applied potential. In addition, the cathodic treatment results in higher removal efficiencies than the anodic treatment. The enhanced adsorption capacity has been proved to be irreversible, since the removed compound remains adsorbed after switching the applied potential. The kinetics of the adsorption processes is also improved by the presence of an applied potential. PMID- 26433937 TI - Biodegradability of iopromide products after UV/H2O2 advanced oxidation. AB - Iopromide is an X-ray and MRI contrast agent that is virtually non-biodegradable and persistent through typical wastewater treatment processes. This study determined whether molecular transformation of iopromide in a UV/H2O2 advanced oxidation process (AOP) can result in biodegradable products. The experiments used iopromide labeled with carbon-14 on the aromatic ring to trace degradation of iopromide through UV/H2O2 advanced oxidation and subsequent biodegradation. The biotransformation assay tracked the formation of radiolabeled (14)CO2 which indicated full mineralization of the molecule. The results indicated that AOP formed biodegradable iopromide products. There was no (14)C released from the pre AOP samples, but up to 20% of all radiolabeled carbon transformed into (14)CO2 over the course of 42 days of biodegradation after iopromide was exposed to advanced oxidation (compared to 10% transformation in inactivated post-AOP controls). In addition, the quantum yield of photolysis of iopromide was determined using low pressure (LP) and medium pressure (MP) mercury lamps as 0.069 +/- 0.005 and 0.080 +/- 0.007 respectively. The difference in the quantum yields for the two UV sources was not statistically significant at the 95% confidence interval (p = 0.08), which indicates the equivalency of using LP or MP UV sources for iopromide treatment. The reaction rate between iopromide and hydroxyl radicals was measured to be (2.5 +/- 0.2) * 10(9) M(-1) s(-1). These results indicate that direct photolysis is a dominant degradation pathway in UV/H2O2 AOP treatment of iopromide. Other iodinated contrast media may also become biodegradable after exposure to UV or UV/H2O2. PMID- 26433938 TI - Individual Pulmonary Veins Outgrow Somatic Growth After Primary Sutureless Repair for Total Anomalous Pulmonary Venous Drainage. AB - Indications of sutureless repair (SR) for pulmonary vein anomalies have evolved from re-operational SR for pulmonary vein stenosis after the repair of total anomalous pulmonary venous drainage (TAPVD) to primary SR for TAPVD associated with right atrial isomerism or isolated TAPVD with small individual pulmonary veins (IPVs) and an unfavorable pulmonary vein anatomy. We sought to determine whether small IPVs outgrow somatic growth after primary SR. Between 2004 and 2013, 21 children underwent primary SR for TAPVD: 13 with a functionally single ventricle, 11 with right atrial isomerism, six with isolated TAPVD, and 13 with a pulmonary venous obstruction. TAPVD types were supracardiac in nine, infracardiac in 10, and mixed in two. Utilizing cardiac computed tomography (CT), the maximal diameter of each IPV was measured, and pulmonary vein index (PVI, summation of cross-sectional areas of all four IPVs divided by body surface area) was calculated. There were five early deaths after SR. Among survivors, 10 had both preoperative and postoperative cardiac CT at a 3.6-month median interval. On postoperative cardiac CT, IPVs were patent in all patients except one who developed a left lower pulmonary vein obstruction. There was a 71 +/- 48 % postoperative increase in the actual diameter of all four IPVs, and PVI increased significantly from 215 +/- 55 to 402 +/- 117 mm(2)/m(2) (P value = 0.005). IPVs outgrew somatic growth after primary SR of TAPVD. Primary SR may be a useful measure in TAPVD patients whose IPVs are small. PMID- 26433939 TI - Exploring the Discussion of Risk of Sudden Cardiac Death. AB - Sudden arrhythmic death syndrome (SADS), where death is secondary to cardiac arrhythmia, is associated with several cardiac ion channelopathies, including long QT syndrome and Brugada syndrome, as well as cardiomyopathies such as hypertrophic cardiomyopathy and dilated cardiomyopathy. Many of these conditions often present in childhood or adolescence. This study investigates how diagnoses of cardiac diseases associated with SADS are communicated within families. A questionnaire was distributed through cardiac disease-focused support groups and organizations. Data from 114 parents who have a child with a SADS condition were used for analysis. Based on the responses, parents explained the risk of SADS in a straightforward manner and related the risk to the importance of compliance with the prescribed treatment. Participants also found it difficult to determine and enforce lifestyle modifications, manage individuals' emotional reactions, convey the seriousness of the information without scaring their children, and discuss the risk of SADS during these conversations. Concerns regarding disease progression, length and quality of life, and treatment failures were also expressed. Healthcare providers, the Internet, other affected people, visual aids, and personal experience were all reported to be helpful for facilitating these discussions. Services and resources requested by participants included children's support groups, a counselor or psychologist, and child-oriented materials. Increased understanding of how families discuss children's diagnosis of SADS conditions will equip healthcare providers with the information to address parental concerns and help facilitate meaningful and informative discussions within families. PMID- 26433941 TI - Type 2 diabetes and leucocyte DNA methylation: an epigenome-wide association study in over 1,500 older adults. AB - AIMS/HYPOTHESIS: Development of type 2 diabetes depends on environmental and genetic factors. We investigated the epigenome-wide association of prevalent diabetes with DNA methylation (DNAm) in peripheral blood. METHODS: DNAm was measured in whole blood with the Illumina Infinium HumanMethylation450 BeadChip in two subsamples of participants from the ESTHER cohort study. Cohort 1 included 988 participants, who were consecutively recruited between July and October 2000 and cohort 2 included 527 randomly selected participants. The association of DNAm with prevalent type 2 diabetes at recruitment was estimated using median regression analysis adjusting for sex, age, BMI, smoking behaviour, cell composition and batch at 361,922 CpG sites. RESULTS: Type 2 diabetes was prevalent in 16% of the participants, and diabetes was poorly controlled in 45% of the diabetic patients. In cohort 1 (discovery) DNAm at 39 CpGs was significantly associated with prevalent diabetes after correction for multiple testing. In cohort 2 (replication) at one of these CpGs, DNAm was still significantly associated. Decreasing methylation levels at cg19693031 with increasing fasting glucose and HbA1c concentrations were observed using restricted cubic spline analysis. In diabetic patients with poorly controlled diabetes, the decrease in estimated DNAm levels was approximately 5% in comparison with participants free of diagnosed diabetes. CONCLUSIONS/INTERPRETATION: Cg19693031, which is located within the 3' untranslated region of TXNIP, might play a role in the pathophysiology of type 2 diabetes. This result appears biologically plausible given that thioredoxin interacting protein is overexpressed in diabetic animals and humans and 3' untranslated regions are known to play a regulatory role in gene expression. PMID- 26433940 TI - Fructose-enriched diet induces inflammation and reduces antioxidative defense in visceral adipose tissue of young female rats. AB - PURPOSE: The consumption of refined, fructose-enriched food continuously increases and has been linked to development of obesity, especially in young population. Low-grade inflammation and increased oxidative stress have been implicated in the pathogenesis of obesity-related disorders including type 2 diabetes. In this study, we examined alterations in inflammation and antioxidative defense system in the visceral adipose tissue (VAT) of fructose-fed young female rats, and related them to changes in adiposity and insulin sensitivity. METHODS: We examined the effects of 9-week fructose-enriched diet applied immediately after weaning on nuclear factor kappaB (NF-kappaB) intracellular distribution, and on the expression of pro-inflammatory cytokines (IL-1beta and TNFalpha) and key antioxidative enzymes in the VAT of female rats. Insulin signaling in the VAT was evaluated at the level of insulin receptor substrate-1 (IRS-1) protein and its inhibitory phosphorylation on Ser307. RESULTS: Fructose-fed rats had increased VAT mass along with increased NF-kappaB nuclear accumulation and elevated IL-1beta, but not TNFalpha expression. The protein levels of antioxidative defense enzymes, mitochondrial manganese superoxide dismutase 2, and glutathione peroxidase, were reduced, while the protein content of IRS-1 and its inhibitory phosphorylation were not altered by fructose diet. CONCLUSIONS: The results suggest that fructose overconsumption related alterations in pro-inflammatory markers and antioxidative capacity in the VAT of young female rats can be implicated in the development of adiposity, but do not affect inhibitory phosphorylation of IRS-1. PMID- 26433943 TI - Report on the 4-h rule and National Emergency Access Target (NEAT) in Australia: time to review. AB - Objective The aim of the present study was to provide a summary of a systematic review of literature reporting benefits and limitations of implementing National Emergency Access Target (NEAT), a target stipulating that a certain proportion of patients presenting to hospital emergency departments are admitted or discharged within 4h of presentation. Methods A systematic review of published literature using specific search terms, snowballing techniques applied to retrieved references and Google searches was performed. Results are presented as a narrative synthesis given the heterogeneity of included studies. Results Benefits of a time-based target for emergency care are improved timeliness of emergency care and reduced in-hospital mortality for emergency admissions to hospital. Limitations centre on using a process measure (time) alone devoid of any monitoring of patient outcomes, the threshold nature of a time target and the fact that currently NEAT combines the measurement of clinical management of two very different patient cohorts seeking emergency care: less acute patients discharged home and more acute patients admitted to hospital. Conclusions Time based access targets for emergency presentations are associated with significant improvements in in-hospital mortality for emergency admissions. However, other patient-important outcomes are deserving of attention, choice of targets needs to be validated by empirical evidence of patient benefit and single targets need to be partitioned into separate targets pertaining to admitted and discharged patients. What is known about the topic? Time targets for emergency care originated in the UK. The introduction of NEAT in Australia has been controversial. NEAT directs that a certain proportion of patients will be admitted or discharged from an emergency department (ED) within 4h. Recent dissolution of the Australian National Partnership Agreement (which provided hospitals with financial incentives for achieving NEAT compliance) has prompted a re-examination of the 4-h rule, the evidence underpinning its introduction and its benefits and risks to patients What does this paper add? This paper is executive summary of key findings from a systematic literature review on the benefits and limitations of NEAT (the 4-h rule) commissioned by the Queensland Clinical Senate to inform future policy and targets. What are the implications for practitioners? There is evidence that a time-based target has been associated with a reduction in in-hospital mortality for emergency admissions to Australian hospitals. Concerns remain regarding a time-based target alone being used to drive redesign efforts at improving access to emergency care. A time-based target should be coupled with close monitoring of patient outcomes of emergency care. Target thresholds need to be evidence based and separate targets should be reported for admitted, discharged and all patients presenting to the ED. PMID- 26433942 TI - netCare, a new collaborative primary health care service based in Swiss community pharmacies. AB - BACKGROUND: The Swiss Pharmacists Association has launched a new collaborative project, netCare. Community pharmacists provide a standard form with structured triage based on decision trees and document findings. As a backup, they can collaborate with physicians via video consultation. OBJECTIVE: The aim of the study was to evaluate the impact of this service on the Swiss health care system. METHOD: All pharmacists offering netCare completed two training courses, a course covering the most common medical conditions observed in primary health care and a specific course on all of the decision trees. The pharmacists were free to decide whether they would provide the usual care or offer netCare triage. The patient was also free to accept or refuse netCare. Pharmacists reported the type of ailment, procedure of the consultation, treatment, patient information and outcomes of the follow-up call on a standardized form submitted to the study center. RESULTS: Pharmacists from 162 pharmacies performed 4118 triages over a period of 21 months. A backup consultation was needed for 17% of the cases. In follow-up calls, 84% of the patients who were seen only by pharmacists reported complete relief or symptom reduction. CONCLUSIONS: netCare is a low-threshold service by which pharmacists can manage common medical conditions with physician backup, if needed. This study showed that a pharmacist could resolve a large proportion of the cases. However, to be efficient and sustainable, this service must be fully integrated into the health care system. PMID- 26433945 TI - Prevalence of Hazardous Drinking Among UK 18-35 Year Olds; the Impact of a Revision to the AUDIT Cut Score. AB - AIM: Most published research utilizes an AUDIT score of >8 as the threshold for hazardous drinking. Recent research suggests that this limit should be amended for younger drinkers (aged 18-35 years). This study aimed to explore the effect of a revision to AUDIT cut scores. METHOD: Applying Foxcroft et al.'s [(2015) Accuracy of Alcohol Use Disorders Identification Test for detecting problem drinking in 18-35 year-olds in England: method comparison study. Alcohol Alcohol 50, 244-50] suggested cut off scores of nine for males and four for females to the most recent Adult Psychiatric Morbidity Survey (2007) data. RESULTS: This more than doubles the prevalence of female hazardous drinkers, and significantly increases the overall rate for that age group when compared with the standard threshold of >8. CONCLUSION: The prevalence of hazardous drinking among females ages 18-30 may be significantly higher than current estimates. PMID- 26433944 TI - Impaired mitochondrial network excitability in failing guinea-pig cardiomyocytes. AB - AIMS: Studies in guinea-pig cardiomyocytes show that reactive oxygen species (ROS) produced by a few mitochondria can propagate to their neighbours, triggering synchronized, cell-wide network oscillations via an ROS-induced ROS release (RIRR) mechanism. How mitochondria in cardiomyocytes from failing hearts (HF) respond to local oxidative stress perturbations has not been investigated. Since mitochondrial ultrastructure is reportedly disrupted in HF, and propagation of ROS signals depends on mitochondrial network integrity, we hypothesized that the laser flash-induced RIRR is altered in HF. METHODS AND RESULTS: To test the hypothesis, pressure-overload HF was induced in guinea pigs by ascending aortic constriction leading to left ventricular dilatation and decreased ejection fraction after 8 weeks. Isolated cardiomyocytes were studied with two photon/confocal microscopy to determine their basal oxidative stress and propensity to undergo mitochondrial depolarization/oscillations in response to local laser flash stimulations. The expression of mitofusin proteins and mitochondrial network structure were also analysed. Results showed that HF cardiomyocytes had higher baseline ROS levels and less reduced glutathione, and were more prone to laser flash-induced mitochondrial depolarization. In contrast, the delay between the laser flash and synchronized cell-wide network oscillations was prolonged in HF myocytes compared with shams, and the spatial extent of coupling was diminished, suggesting dampened RIRR and ROS signal propagation. In addition, the expressions of mitofusin proteins in HF myocardium were down regulated compared with these from sham-operated animals, and the mitochondrial network structure altered. CONCLUSION: The disrupted inter-mitochondrial tethering and loss of structural organization may underlie decreased ROS dependent mitochondrial coupling in HF. PMID- 26433946 TI - The Benefits of Administering Folic Acid in Order to Combat the Oxidative Damage Caused by Binge Drinking in Adolescent Rats. AB - AIMS: An important mechanism in alcohol-induced injury is biomolecular oxidative damage. Folic acid is supplied to chronic alcoholic patients in order to prevent this situation, as this is the main vitamin deficiency that they suffer from. Acute alcohol exposure, such as binge drinking, is one of the most widespread ethanol consumption models practiced by adolescents. However, there is no evidence of folic acid body profiles after this pattern of consumption. METHODS: Four groups of adolescent rats were used: control, alcohol (exposed to intraperitoneal binge drinking), control folic acid-supplemented group and alcohol folic acid-supplemented group. Folic acid levels, protein, lipid and DNA oxidative damage in serum, and liver glutathione (GSH) and reduced/oxidized glutathione ratio (GSH/GSSG) were measured. RESULTS: Binge-drinking rats had higher lipids and DNA oxidation levels. They also had lower hepatic GSH levels and GSH/GSSG ratio. Folic acid supplementation to binge-drinking rats does not change the serum protein oxidation but decreases lipid and DNA oxidation. Finally, GSH increased to control levels with folic acid supplementation. CONCLUSION: Folic acid supplementation is an economic and efficient therapy against the oxidative damage in lipids and mainly in DNA stability caused by binge drinking during adolescence. It has also been demonstrated that folic acid increases GSH levels, improving the antioxidant status and revealing a hepatoprotective effect during binge drinking. PMID- 26433947 TI - Socioeconomic Disparities in Alcohol-Related Mortality in Sweden, 1991-2006: A Register-Based Follow-Up Study. AB - AIM: To examine whether apparent stability of overall alcohol-related mortality in Sweden during a period when traditionally strict alcohol policies went through a series of liberalizations and overall alcohol mortality remained stable, concealed a heterogeneity across socioeconomic groups (defined by educational level); and whether an increase occurred in the contribution of alcohol-related mortality to overall mortality differentials. METHODS: Drawing on cause of death data linked to census records for the period 1991-2006, we computed annual age standardized and sex-specific rates of alcohol-related mortality for groups with low, intermediate and high education. RESULTS: Alcohol-related mortality was considerably higher in lower educational groups for both men and women. For men, the trends in alcohol-related mortality were roughly stable for all education groups, and there were no signs of increasing inequalities by education. For women, alcohol-related mortality increased significantly for the low-education group whereas the two higher education groups showed no significant time trends, thus resulting in a widened educational gap in alcohol mortality for women. Alcohol's contribution to the overall mortality differentials declined for men and was basically unchanged for women. CONCLUSIONS: The findings provide only partial support to the hypothesis that the liberalizations of Swedish alcohol policy have been followed by a general increase in socioeconomic disparities in alcohol-related mortality. PMID- 26433950 TI - Editorial. PMID- 26433948 TI - Next generation sequencing of triple negative breast cancer to find predictors for chemotherapy response. AB - INTRODUCTION: In triple negative breast cancers (TNBC) the initial response to chemotherapy is often favorable, but relapse and chemotherapy resistance frequently occur in advanced disease. Hence there is an urgent need for targeted treatments in this breast cancer subtype. In the current study we deep sequenced DNA of tumors prior to chemotherapy to search for predictors of response or resistance. METHODS: Next generation sequencing (NGS) was performed for 1,977 genes involved in tumorigenesis. DNA from 56 pre-treatment TNBC-biopsies was sequenced, as well as matched normal DNA. Following their tumor biopsy, patients started neoadjuvant chemotherapy with doxorubicin and cyclophosphamide. We studied associations between genetic alterations and three clinical variables: chemotherapy response, relapse-free survival and BRCA proficiency. RESULTS: The mutations observed were diverse and few recurrent mutations were detected. Most mutations were in TP53, TTN, and PIK3CA (55 %, 14 %, and 9 %, respectively). The mutation rates were similar between responders and non-responders (average mutation rate 9 vs 8 mutations). No recurrent mutations were associated with chemotherapy response or relapse. Interestingly, PIK3CA mutations were exclusively observed in patients proficient for BRCA1. Samples with a relapse had a higher copy number alteration rate, and amplifications of TTK and TP53BP2 were associated with a poor chemotherapy response. CONCLUSIONS: In this homogenous cohort of TNBCs few recurrent mutations were found. However, PIK3CA mutations were associated with BRCA proficiency, which can have clinical consequences in the near future. PMID- 26433951 TI - Analysis of watermelon chlorotic stunt virus and tomato leaf curl Palampur virus mixed and pseudo-recombination infections. AB - Watermelon chlorotic stunt virus (WmCSV) and tomato leaf curl Palampur virus (ToLCPMV) are limiting factors for cucurbit production in south and southeastern Iran. ToLCPMV infects all cucurbit crops (except watermelons) whereas WmCSV is somewhat limited to watermelon, causing detrimental effects on fruit production. In a survey, we detected WmCSV in all watermelon growing farms in Fars province (southern Iran). Given that WmCSV and ToLCPMV are present in the same geographical location in Iran, we studied the interaction of two viruses. Co infection using agroinfectious clones of WmCSV and ToLCPMV caused severe symptoms in watermelon and zucchini in comparison to symptoms observed from individual infections. Interestingly, inoculation of zucchini with WmCSV DNA-A and ToLCPMV DNA-B agroinfectious clones or vice versa produced a viable pseudo-recombinant and induced systemic symptoms. This demonstrates that replication-associated protein of DNA-A of each virus is able to bind to cis elements of the DNA-B molecules of another virus. PMID- 26433952 TI - Patient-relevant needs and treatment goals in nail psoriasis. AB - PURPOSE: Patient-centered health care implies that medical decisions are made jointly by physician and patient, based on patient needs. Aims were to (a) identify treatment goals for a new questionnaire on patient needs and benefits in nail psoriasis treatment; (b) analyze the importance of treatment goals in patients with nail psoriasis in general and in defined subgroups; and (c) determine the association between overall treatment goal importance and quality of life. METHODS: The study comprised the following steps: qualitative survey on needs and burdens in 120 patients; development of items by an interdisciplinary expert group; item testing in 55 patients in four countries; revision of the questionnaire and assessment in 203 patients in six countries (Germany, Denmark, Italy, Spain, USA, Japan). The percentage of patients rating the goals as 'quite/very important' was compared between various patient subgroups. RESULTS: Based on 692 free-text statements, 26 items were developed which were reduced to 24 items after pilot testing. Each of these treatment goals applied to the majority of patients in the multi-center study. Goal importance increased with severity of nail psoriasis, but not with age or disease duration. Manual dexterity and social interaction were of particular importance. Goal importance and quality of life were associated, but not redundant (r = 0.612, p < 0.001). CONCLUSIONS: Patients with nail psoriasis have manifold and specific treatment goals. Goal importance is a construct different from disease-specific quality of life and should be assessed separately. The new questionnaire can support goal setting in clinical practice. PMID- 26433953 TI - Validation of an innovative instrument of Positive Oral Health and Well-Being (POHW). AB - INTRODUCTION: Most existing measures of oral health focus solely on negative oral health, illness, and deficiencies and ignore positive oral health. In an attempt to commence exploration of this challenging field, an innovative instrument was developed, the "Positive Oral Health and Well-Being" (POHW) index. This study aimed to validate this instrument and to explore an initial model of the pathway between oral health attributes and positive oral health. METHODS: A cross sectional, multicenter study (Israel, USA, and Germany), was conducted. Our conceptual model suggests that positive oral health attributes, which integrate with positive unawareness or positive awareness on the one hand and with positive perception on the other hand, may result via appropriate oral health behavior on positive oral health. The 17-item self-administered index was built on a theoretical concept by four experts from Israel and Germany. Reliability, factor, and correlation analyses were performed. For external correlations and to measure construct validity of the instrument, we utilized the oral health impact profile 14, self-perceived oral impairment, life satisfaction, self-perceived well-being, sociodemographic and behavioral data, and oral health status indices. RESULTS: Four hundred and seventy participants took part in our three-center study. The combined data set reliability analyses detected two items which were not contributing to the index reliability. Thus, we tested a 15-item construct, and a Cronbach's alpha value of 0.933 was revealed. Primary factor analysis of the whole sample indicated three subconstructs which could explain 60 % of variance. Correlation analyses demonstrated that the POHW and OHIP-14 were strongly and negatively associated. The POHW correlated strongly and positively with general well-being, moderately with life satisfaction, and weakly with the perceived importance of regular dental checkups. It correlated moderately and negatively with perceived oral impairment, and marginally and negatively with dental caries experience (DMFT) and periodontal health status (CPI) scores. When DMFT and CPI clinical measurements were categorized, a higher score of POHW was revealed for better oral health. DISCUSSION: Our study introduced a new instrument with good reliability and sound correlations with external measures. This instrument is the first to allow measurability of positive instead of impaired oral health. We utilized subjective-psychological and functional-social measures. The current results indicate that by further exploring our conceptual model, POHW may be of importance for identifying patients with good and poor oral health, and building an effective and inexpensive strategy for prevention, by being able to evaluate the effect of interventions in a standardized way. PMID- 26433954 TI - Managing CAP in the ICU. AB - Despite remarkable progress in diagnosis and antibiotic therapy, mortality due to pneumonia has not changed significantly and ICU admissions are increasing. The management includes early evaluation of severity, collection of microbiological cultures, and appropriate antibiotic administration. The prognostic scores as the ATS/IDSA rule, the PIRO, or SCAP system are valuable in timely recognition of critically ill patients with community-acquired pneumonia (CAP) requiring admission to ICU. Implementation of guidelines for CAP treatment should be emphasized in order to increase survival. Guidelines for antibiotic management for severe CAP are based on illness severity, covering most likely bacterial and atypical pathogens and the level of ICU antibiotic resistance. Combination therapy suggested in patients with nonrefractory septic shock and severe sepsis pneumococcal bacteremia also. Recent studies suggest that steroid therapy may be valuable in nonrefractory septic shock from sCAP. PMID- 26433955 TI - Increased synthesis of folate transporters regulates folate transport in conditions of ethanol exposure and folate deficiency. AB - Excessive alcohol consumption and dietary folate inadequacy are the main contributors leading to folate deficiency (FD). The present study was planned to study regulation of folate transport in conditions of FD and ethanol exposure in human embryonic kidney cell line. Also, the reversible nature of effects mediated by ethanol exposure and FD was determined by folate repletion and ethanol removal. For ethanol treatment, HEK293 cells were grown in medium containing 100 mM ethanol, and after treatment, one group of cells was shifted on medium that was free from ethanol. For FD treatment, cells were grown in folate-deficient medium followed by shifting of one group of cells on folate containing medium. FD as well as ethanol exposure resulted in an increase in folate uptake which was due to an increase in expression of folate transporters, i.e., reduced folate carrier, proton-coupled folate transporter, and folate receptor, both at the mRNA and protein level. The effects mediated by ethanol exposure and FD were reversible on removal of treatment. Promoter region methylation of folate transporters remained unaffected after FD and ethanol exposure. As far as transcription rate of folate transporters is concerned, an increase in rate of synthesis was observed in both ethanol exposure and FD conditions. Additionally, mRNA life of folate transporters was observed to be reduced by FD. An increased expression of folate transporters under ethanol exposure and FD conditions can be attributed to enhanced rate of synthesis of folate transporters. PMID- 26433956 TI - Monitoring Crohn's disease during anti-TNF-alpha therapy: validation of the magnetic resonance enterography global score (MEGS) against a combined clinical reference standard. AB - OBJECTIVES: To assess the ability of magnetic resonance enterography global score (MEGS) to characterise Crohn's disease (CD) response to anti-TNF-alpha therapy. METHODS: Thirty-six CD patients (median age 26 years, 20 males) commencing anti TNF-alpha therapy with concomitant baseline MRI enterography (MRE) were identified retrospectively. Patients' clinical course was followed and correlated with subsequent MREs. Scan order was randomised and MEGS (a global activity score) was applied by two blinded radiologists. A physician's global assessment of the disease activity (remission, mild, moderate or severe) at the time of MRE was assigned. The cohort was divided into clinical responders and non-responders and MEGS compared according to activity status and treatment response. Interobserver agreement was assessed. RESULTS: Median MEGS decreased significantly between baseline and first follow-up in responders (28 versus 6, P < 0.001) but was unchanged in non-responders (26 versus 18, P = 0.28). The median MEGS was significantly lower in clinical remission (9) than in moderate (14) or severe (29) activity (P < 0.001). MEGS correlated significantly with clinical activity (r = 0.53; P < 0.001). Interobserver Bland-Altman limits of agreement (BA LoA) were -19.7 to 18.5. CONCLUSIONS: MEGS decreases significantly in clinical responders to anti-TNF-alpha therapy but not in non-responders, demonstrates good interobserver agreement and moderate correlation with clinical disease activity. KEY POINTS: * MRI scores of Crohn's activity are used increasingly in clinical practice and therapeutic trials. * Such scores have been advocated as biomarkers of therapeutic response. * MEGS reflects clinical response to anti-TNF-alpha therapy and the clinical classification of disease activity. * MEGS demonstrates good interobserver agreement. PMID- 26433957 TI - Radiation dose reduction in paediatric coronary computed tomography: assessment of effective dose and image quality. AB - OBJECTIVES: To assess the impact of different protocols on radiation dose and image quality for paediatric coronary computed tomography (cCT). MATERIALS AND METHODS: From January-2012 to June-2014, 140 children who underwent cCT on a 64 slice scanner were included. Two consecutive changes in imaging protocols were performed: 1) the use of adaptive statistical iterative reconstruction (ASIR); 2) the optimization of acquisition parameters. Effective dose (ED) was calculated by conversion of the dose-length product. Image quality was assessed as excellent, good or with significant artefacts. RESULTS: Patients were divided in three age groups: 0-4, 5-7 and 8-18 years. The use of ASIR combined to the adjustment of scan settings allowed a reduction in the median ED of 58 %, 82 % and 85 % in 0-4, 5-7 and 8-18 years group, respectively (7.3 +/- 1.4 vs 3.1 +/- 0.7 mSv, 5.5 +/- 1.6 vs 1 +/- 1.9 mSv and 5.3 +/- 5.0 vs 0.8 +/- 2.0 mSv, all p < 0,05). Prospective protocol was used in 51 % of children. The reduction in radiation dose was not associated with reduction in diagnostic image quality as assessed by the frequency of coronary segments with excellent or good image quality (88 %). CONCLUSIONS: cCT can be obtained at very low radiation doses in children using ASIR, and prospective acquisition with optimized imaging parameters. KEY POINTS: * Using ASIR allows 25 % to 41 % reduction in the ED. * Prospective protocol is used up to 51 % of children after premedication. * Low dose is possible using ASIR and optimized prospective paediatric cCT. PMID- 26433958 TI - Loss of heterozygosity for chromosomal regions 15q14-21.1, 17q21.31, and 13q12.3 13.1 and its relevance for prostate cancer. AB - Although prostate cancer is one of the most common cancers in men, the genetic defects underlying its pathogenesis remain poorly understood. DNA damage repair mechanisms have been implicated in human cancer. Accumulating evidence indicates that the fidelity of the response to DNA double-strand breaks is critical for maintaining genome integrity. RAD51 is a central player in double-strand break repair via homologous recombination, and its alterations may confer and increase the risk of cancer. RAD51 functioning depends on the indirect or direct interactions with BRCA1 and BRCA2. To evaluate the contribution of RAD51 to sporadic prostate cancer, loss of heterozygosity (LOH) for chromosomal region 15q14-21.1 (RAD51 locus) was determined and compared to LOH in 17q21.31 (BRCA1 locus) and 13q12.3-13.1 (BRCA2 region). DNA was isolated from prostate biopsies and matched peripheral blood of 50 patients. The regions 15q14-21.1, 17q21.31, and 13q12.3-13.1 were examined using microsatellite markers on chromosome 15 (D15S118, D15S214, D15S1006), chromosome 17 (D17S855, D17S1323), and chromosome 13 (D13S260, D13S290), respectively. The LOH in tumors was analyzed by PCR with fluorescently labeled primers and an ABI PRISM 377 DNA Sequencer. Allele sizing was determined by GeneScan version 3.1.2 and Genotyper version 2.5 software (Applied Biosystems, USA). LOH was identified in 57.5, 23, and 40 % for chromosomal regions 15q14-21.1, 17q21.31, and 13q12.3-13.1, respectively. Twenty six percent of studied cases manifested LOH for at least one marker in 15q14-21.1 exclusively. A significant correlation was found between LOH for studied region and PSAD (prostate-specific antigen density). The findings suggest that RAD51 may be considered as a prostate cancer susceptibility gene. PMID- 26433960 TI - Adult survival selection in relation to multilocus heterozygosity and body size in a tropical bird species, the Zenaida dove, Zenaida aurita. AB - Both phenotypic and genetic quality can influence the survival of individuals through time, although their relative influences are rarely addressed simultaneously. Here we used capture-mark-recapture modelling to assess the influence of both multilocus heterozygosity (MLH) and body size on apparent adult survival in a tropical bird species, the Zenaida dove, Zenaida aurita, using a sample of 391 individuals genotyped at 11 microsatellites, while controlling for the effects of sex. No effect of body size on either adult survival or capture rate was found. In the best model, survival was a logit linear function of MLH, whereas detection probability was a sex-dependent logit linear function of the logarithm of field effort, increasing with time and affected by a random individual effect. Using a Bayesian approach, we found that MLH explained 1.14% of the total deviance, as expected from theory and previous studies of heterozygosity-fitness correlations, with no evidence for local effects. However, results from capture-mark-recapture modelling indicated that expected longevity varied from 4.8 years in the least heterozygous individuals (MLH = 0.37) to 10.6 years in the most heterozygous ones (MLH = 1), thus suggesting that MLH had potentially a substantial effect on survival. We discuss our results in relation to current hypotheses about the origin of heterozygosity-fitness correlations. PMID- 26433959 TI - A phase I study of adjuvant intensity-modulated radiotherapy with concurrent paclitaxel and cisplatin for cervical cancer patients with high risk factors. AB - The aim of the study is to determine the maximum tolerated dose (MTD) and acute dose-limiting toxicities (DLTs) of adjuvant concurrent paclitaxel and cisplatin (TP) with pelvic intensity-modulated radiotherapy (IMRT) for early-stage cervical cancer patients with high risk factors. Women who underwent radical hysterectomy and pelvic lymphadenectomy for stages IB-IIA cervical cancer and had high risk factors were enrolled. One cycle of TP was delivered before and after concurrent chemoradiotherapy, respectively. Then 3 weeks after the start of the initial cycle of the chemotherapy, patients received IMRT in a total dose of 50-50.4 Gy in 25-28 fractions with two cycles of concurrent TP, which was administered with escalating doses. Eighteen patients were enrolled at three dose levels. At dose level 1 (paclitaxel 90 mg/m(2), cisplatin 40 mg/m(2)) and level 2 (paclitaxel 90 mg/m(2), cisplatin 50 mg/m(2)), DLT (grade 3 leukopenia) was observed in one patient, respectively. At level 3 (paclitaxel 105 mg/m(2), cisplatin 50 mg/m(2)), two DLTs (grade 3 leukopenia) were observed in two patients. The MTD of paclitaxel and cisplatin was then defined as 90 and 50 mg/m(2), respectively. Pelvic IMRT and concurrent TP is a safe and tolerable adjuvant treatment regimen for cervical cancer patients with high risk factors. The MTD of concurrent chemotherapy is paclitaxel 90 mg/m(2) and cisplatin 50 mg/m(2). Trial registration Current controlled trials ChiECRCT-2014025. PMID- 26433961 TI - Environmental drivers of carbon and nitrogen isotopic signatures in peatland vascular plants along an altitude gradient. AB - Peatlands are important sinks of atmospheric carbon (C) that, in response to climate warming, are undergoing dynamic vegetation succession. Here we examined the hypothesis that the uptake of nutrients by different plant growth forms (PGFs) is one key mechanism driving changes in species abundance in peatlands. Along an altitude gradient representing a natural climate experiment, we compared the variability of the stable C isotope composition (delta(13)C) and stable nitrogen (N) isotope composition (delta(15)N) in current-year leaves of two major PGFs, i.e. ericoids and graminoids. The climate gradient was associated with a gradient of vascular plant cover, which was parallelled by different concentrations of organic and inorganic N as well as the fungal/bacterial ratio in peat. In both PGFs the (13)C natural abundance showed a marginal spatial decrease with altitude and a temporal decrease with progression of the growing season. Our data highlight a primary physical control of foliar delta(13)C signature, which is independent from the PGFs. Natural abundance of foliar (15)N did not show any seasonal pattern and only in the ericoids showed depletion at lower elevation. This decreasing delta(15)N pattern was primarily controlled by the higher relative availability of organic versus inorganic N and, only for the ericoids, by an increased proportion of fungi to bacteria in soil. Our space-for time approach demonstrates that a change in abundance of PGFs is associated with a different strategy of nutrient acquisition (i.e. transfer via mycorrhizal symbiosis versus direct fine-root uptake), which could likely promote observed and predicted dwarf shrub expansion under climate change. PMID- 26433962 TI - Germline TERT promoter mutations are rare in familial melanoma. AB - Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP, POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.-57 T>G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated in carriers. The c.-57 T>G TERT promoter variant was identified in one 7-case family with multiple primaries and early age of onset (earliest, 15 years) but not among population cases or controls. One family member had multiple primary melanomas, basal cell carcinomas and a bladder tumour. The blood leukocyte telomere length of a carrier was similar to wild-type cases. We provide evidence confirming that a rare promoter variant of TERT (c.-57 T>G) is associated with high penetrance, early onset melanoma and potentially other cancers, and explains <1 % of UK melanoma multicase families. The identification of POT1 and TERT germline mutations highlights the importance of telomere integrity in melanoma biology. PMID- 26433963 TI - Senescent peritoneal mesothelium induces a pro-angiogenic phenotype in ovarian cancer cells in vitro and in a mouse xenograft model in vivo. AB - It is believed that senescent cells contribute to the progression of primary and metastatic tumors, however, the exact mechanisms of this activity remain elusive. In this report we show that senescent human peritoneal mesothelial cells (HPMCs) alter the secretory profile of ovarian cancer cells (A2780, OVCAR-3, SKOV-3) by increasing the release of four angiogenic agents: CXCL1, CXCL8, HGF, and VEGF. Proliferation and migration of endothelial cells subjected to conditioned medium generated by: cancer cells modified by senescent HPMCs; cancer cells co-cultured with senescent HPMCs; and by early-passage HPMCs from aged donors, were markedly intensified. The same was the case for the vascularization, size and number of tumors that developed in the mouse peritoneum upon injection of ovarian cancer cells with senescent HPMCs. When the identified pro-angiogenic proteins were neutralized in conditioned medium from the cancer cells, both aspects of endothelial cell behavior intensified in vitro in response to senescent HPMCs were markedly reduced. The search for mediators of senescent HPMC activity using specific neutralizing antibodies and recombinant exogenous proteins showed that the intensified angiogenic potential of cancer cells was elicited by IL-6 and TGF beta1. At the transcriptional level, increased proliferation and migration of endothelial cells exposed to cancer cells modified by senescent HPMCs was regulated by HIF-1alpha, NF-kappaB/p50 and AP-1/c-Jun. Collectively, our findings indicate that senescent HPMCs may promote the progression of ovarian cancer cells by reprogramming their secretory phenotype towards increased production of pro angiogenic agents and subsequent increase in the angiogenic capabilities of the vascular endothelium. PMID- 26433965 TI - Should a detailed ultrasound examination of the complete urinary tract be routinely performed in women with suspected pelvic endometriosis? AB - STUDY QUESTION: Is there any benefit to including the routine examination by ultrasound of the bladder, ureters and kidneys of women with endometriosis? SUMMARY ANSWER: The benefit of examination of the complete urinary tract of women with suspected endometriosis is that ureteric endometriosis, with or without hydronephrosis, can be detected which facilitates early intervention to prevent nephropathy. WHAT IS ALREADY KNOWN: Women with endometriosis can get ureteric obstruction but there is no clear consensus on the correct diagnostic technique. Ultrasound is accurate at detecting women with bladder endometriosis but ureteric involvement has not been assessed previously. STUDY DESIGN, SIZE, DURATION: This was a prospective observational study, conducted at a teaching hospital over a period of 14 months. A total of 848 women presenting with chronic pelvic pain were included into the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: All women with chronic pelvic pain underwent a detailed transvaginal and transabdominal pelvic ultrasound examination to investigate possible causes of their symptoms. This included a systematic assessment of the urinary bladder, pelvic sections of the ureters and kidneys. The ultrasound findings were compared with findings at surgery and the results of targeted urological imaging and interventions. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 848 women presenting with chronic pelvic pain were included into the study. 28/848 women (3.3% 95% CI 2.1-4.5) had evidence of urinary tract abnormalities on initial ultrasound scan. Among these 17/848 (2.0% 95% CI 1.06-2.94) had evidence of urinary tract endometriosis, whilst 11/848 (1.3% 95% CI 0.54-2.06) women had other urinary tract abnormalities. Among women with urinary tract endometriosis 11/17 (65%) had evidence of ureteric involvement, 3/17 (18%) had both ureteric and bladder disease and 3/17 (18%) had bladder disease only. 12/17 (59%) women with urinary tract endometriosis also had evidence of hydronephrosis. The diagnosis of ureteral endometriosis had a sensitivity of 12/13 (92%) (95% CI 63.9-99.8), specificity 151/151 100% (95% CI 97.6-100), PPV 100% (95% CI 73.5-100), NPV 99.3% (95% CI 96.3-99.9%) LR- 0.08 (95% CI 0.01-0.39). LIMITATIONS, REASONS FOR CAUTION: The routine examination of the complete urinary tract including the distal ureters is a novel technique that should be evaluated in different populations. WIDER IMPLICATIONS OF THE FINDINGS: Ultrasound is an accurate test to diagnose urinary tract involvement in women with suspected pelvic endometriosis and examination of the complete urinary tract should become an integral part of ultrasound assessment of women with suspected endometriosis. PMID- 26433966 TI - Substrate preference of citrus naringenin rhamnosyltransferases and their application to flavonoid glycoside production in fission yeast. AB - Flavonoids, which comprise a large family of secondary plant metabolites, have received increased attention in recent years due to their wide range of features beneficial to human health. One of the most abundant flavonoid skeletons in citrus species is the flavanone naringenin, which is accumulated as glycosides containing terminal rhamnose (Rha) after serial glycosylation steps. The linkage type of Rha residues is a determining factor in the bitterness of the citrus fruit. Such Rha residues are attached by either an alpha1,2- or an alpha1,6 rhamnosyltransferase (1,2RhaT or 1,6RhaT). Although the genes encoding these RhaTs from pummelo (Citrus maxima) and orange (Citrus sinensis) have been functionally characterized, the details of the biochemical characterization, including the substrate preference, remain elusive due to the lack of availability of the UDP-Rha required as substrate. In this study, an efficient UDP-Rha in vivo production system using the engineered fission yeast expressing Arabidopsis thaliana rhamnose synthase 2 (AtRHM2) gene was constructed. The in vitro RhaT assay using the constructed UDP-Rha revealed that recombinant RhaT proteins (Cm1,2RhaT; Cs1,6RhaT; or Cm1,6RhaT), which were heterologously produced in fission yeast, catalyzed the rhamnosyl transfer to naringenin-7-O-glucoside as an acceptor. The substrate preference analysis showed that Cm1,2RhaT had glycosyl transfer activity toward UDP-xylose as well as UDP-Rha. On the other hand, Cs1,6RhaT and Cm1,6RhaT showed rhamnosyltransfer activity toward quercetin-3-O glucoside in addition to naringenin-7-O-glucoside, indicating weak specificity toward acceptor substrates. Finally, naringin and narirutin from naringenin-7-O glucoside were produced using the engineered fission yeast expressing the AtRHM2 and the Cm1,2RhaT or the Cs1,6RhaT genes as a whole-cell-biocatalyst. PMID- 26433964 TI - Long non-coding RNA CARLo-5 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients. AB - Recently, many studies show that long non-coding RNAs (lncRNAs) play important roles in cancer biology. Although its expression was reported dysregulated during tumorigenesis, the contributions of lncRNAs to hepatocellular carcinoma (HCC) are still largely unknown. In particular, the lncRNA CARLo-5 has a functional role in cell-cycle regulation in colon cancer, while the clinical significance and biological function of CARLo-5 in HCC remain unelucidated. In order to fill those study blanks, the expression level of CARLo-5 in human HCC specimens was tested, and its correlation with clinicopathologic features as well as the prognosis for patients with HCC was analyzed. Additionally, MTT, wound healing and transwell assays were employed to investigate the biological function of CARLo-5. The results showed that CARLo-5 levels were significantly overexpressed in HCC tissues compared to ANLT. Besides, high expression of CARLo-5 was associated with liver cirrhosis (P = 0.001), tumor number (P < 0.001), vascular invasion (P = 0.001), capsular formation (P = 0.014) and Edmondson-Steiner grade (P < 0.001), which proved that CARLo-5 was an independent risk factor for overall survival and disease-free survival. In addition, in highly metastatic HCC cell lines (HCCLM3 and MHCC97-L), CARLo-5 was up-regulated, but in lowly metastatic HCC cell lines (HepG2, SNU387), it showed down-regulated. Besides, by using gain and loss of function experiments in HCC cell lines (HCCLM3 and HepG2), the results showed that CARLo-5 overexpression significantly enhanced cell proliferation, migration and invasion in vitro. Our study also revealed that CARLo-5 was prominently up regulated in HCC specimens and its high expression was associated with poor prognosis of HCC patients. Totally, those findings together indicate that CARLo-5 promotes proliferation and metastasis of HCC and potentially emerged as a novel therapeutic target. PMID- 26433967 TI - Metagenomic analysis of microbial community in uranium-contaminated soil. AB - Uranium tailing is a serious pollution challenge for the environment. Based on metagenomic sequencing analysis, we explored the functional and structural diversity of the microbial community in six soil samples taken at different soil depths from uranium-contaminated and uncontaminated areas. Kyoto Encyclopedia of Genes and Genomes Orthology (KO) groups were obtained using a Basic Local Alignment Search Tool search based on the universal protein resource database. The KO-pathway network was then constructed using the selected KOs. Finally, alpha and beta diversity analyses were performed to explore the differences in soil bacterial diversity between the radioactive soil and uncontaminated soil. In total, 30-68 million high-quality reads were obtained. Sequence assembly yielded 286,615 contigs; and these contigs mostly annotated to 1699 KOs. The KO distributions were similar among the six soil samples. Moreover, the proportion of the metabolism of other amino acids (e.g., beta-alanine, taurine, and hypotaurine) and signal transduction was significantly lower in radioactive soil than in uncontaminated soil, whereas the proportion of membrane transport and carbohydrate metabolism was higher. Additionally, KOs were mostly enriched in ATP binding cassette transporters and two-component systems. According to diversity analyses, Actinobacteria and Proteobacteria were the dominant phyla in radioactive and uncontaminated soil, and Robiginitalea, Microlunatus, and Alicyclobacillus were the dominant genera in radioactive soil. Taken together, these results demonstrate that soil microbial community, structure, and functions show significant changes in uranium-contaminated soil. The dominant categories such as Actinobacteria and Proteobacteria may be applied in environmental governance for uranium-contaminated soil in southern China. PMID- 26433968 TI - Responses of photosystems I and II of Acutodesmus obliquus to chemical stress caused by the use of recycled nutrients. AB - Nutrients derived from hydrothermal gasification of Acutodesmus obliquus were tested on its biological compatibility to support growth of the same microalgae. Photosynthetic parameters of photosystems I and II (PS I and PS II) were investigated to study physiological effects on the microalgal cell. The nutrients were collected as liquid residues. Dilutions of 1:500 showed no effect on both photosystems. Lower dilutions affected PS II initially and later also PS I. Cyclic electron flow around PS I compensated for loss of electrons due to partially inhibited PS II. The highest tested concentration of liquid residue erased any photosynthetic activity of PS II after 28 min and onwards. In contrast, PS I remained active. The results suggest that PS I is less susceptible than PS II and that the mixture of chemicals in the liquid residue did not directly affect PS I but PS II. The toxicants in the residues seemed to interfere with linear electron flow of PS II even though light-driven formation of radicals and subsequent damage to one of the photosystems can be excluded as demonstrated in darkness. Lowered photosynthetic activity of PS I during actinic irradiation was caused due to lack of supply of electrons from PS II. The cyclic electron flow might play a key role in delivering the energy needed to restore PS II activity and to biodegrade the toxicants when linear electron flow failed. These negative effects of liquid residue towards microalgal cells require a remediation step for direct application of the liquid residue to substitute commercial fertilizers in microalgal mass cultures. PMID- 26433969 TI - Expression and immunogenic characterization of recombinant gp350 for developing a subunit vaccine against Epstein-Barr virus. AB - Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that is linked to the development of various malignancies. There is an urgent need for effective vaccines against EBV. EBV envelope glycoprotein gp350 is an attractive candidate for a prophylactic vaccine. This study was undertaken to produce the truncated (codons 1-443) gp350 protein (gp350(1-443)) in Pichia pastoris and evaluate its immunogenicity. The gp350(1-443) protein was expressed as a secretory protein with an N-terminal His-tag in P. pastoris and purified through Ni-NTA chromatography. Immunization with the recombinant gp350(1-443) could elicit high levels of gp350(1-443)-specific antibodies in mice. Moreover, gp350(1-443) immunized mice developed strong lymphoproliferative and Th1/Th2 cytokine responses. Furthermore, the recombinant gp350(1-443) could stimulate CD4(+) and CD8(+) T cell responses in vaccinated mice. Collectively, these findings demonstrated that the yeast-expressed gp350(1-443) retained strong immunogenicity. This study will provide a useful source for developing EBV subunit vaccine candidates. PMID- 26433970 TI - Enhanced D-lactic acid production from renewable resources using engineered Lactobacillus plantarum. AB - D-lactic acid is used as a monomer in the production of poly-D-lactic acid (PDLA), which is used to form heat-resistant stereocomplex poly-lactic acid. To produce cost-effective D-lactic acid by using all sugars derived from biomass efficiently, xylose-assimilating genes encoding xylose isomerase and xylulokinase were cloned into an L-lactate-deficient strain, Lactobacillus plantarum. The resulting recombinant strain, namely L. plantarum NCIMB 8826 ?ldhL1-pLEM-xylAB, was able to produce D-lactic acid (at optical purity >99 %) from xylose at a yield of 0.53 g g(-1). Simultaneous utilization of glucose and xylose to produce D-lactic acid was also achieved by this strain, and 47.2 g L(-1) of D-lactic acid was produced from 37.5 g L(-1) glucose and 19.7 g L(-1) xylose. Corn stover and soybean meal extract (SBME) were evaluated as cost-effective medium components for D-lactic acid production. Optimization of medium composition using response surface methodology resulted in 30 % reduction in enzyme loading and 70 % reduction in peptone concentration. In addition, we successfully demonstrated D lactic acid fermentation from corn stover and SBME in a fed-batch fermentation, which yielded 61.4 g L(-1) D-lactic acid with an overall yield of 0.77 g g(-1). All these approaches are geared to attaining high D-lactic acid production from biomass sugars to produce low-cost, highly thermostable biodegradable plastics. PMID- 26433971 TI - Comparing the efficacy and neuroinflammatory potential of three anti-abeta antibodies. AB - Immunotherapy is a promising strategy for the treatment of Alzheimer's disease (AD). Antibodies directed against Amyloid Beta (Abeta) are able to successfully clear plaques and reverse cognitive deficits in mouse models. Excitement towards this approach has been tempered by high profile failures in the clinic, one key issue has been the development of inflammatory side effects in the brain (ARIAs). New antibodies are entering the clinic for Alzheimer's disease; therefore, it is important to learn all we can from the current generation. In this study, we directly compared 3 clinical candidates in the same pre-clinical model, with the same effector function, for their ability to clear plaques and induce inflammation in the brain. We produced murine versions of the antibodies: Bapineuzumab (3D6), Crenezumab (mC2) and Gantenerumab (chGantenerumab) with an IgG2a constant region. 18-month transgenic APP mice (Tg2576) were injected bilaterally into the hippocampus with 2 ug of each antibody or control. After 7 days, the mice tissue was analysed for clearance of plaques and neuroinflammation by histology and biochemical analysis. 3D6 was the best binder to plaques and in vitro, whilst mC2 bound the least strongly. This translated into 3D6 effectively clearing plaques and reducing the levels of insoluble Abeta, whilst chGantenerumab and mC2 did not. 3D6 caused a significant increase in the levels of pro-inflammatory cytokines IL-1beta and TNFalpha, and an associated increase in microglial expression of CD11B and CD68. chGantenerumab increased pro inflammatory cytokines and microglial activation, but minimal changes in CD68, as an indicator of phagocytosis. Injection of mC2 did not cause any significant inflammatory changes. Our results demonstrate that the ability of an antibody to clear plaques and induce inflammation is dependent on the epitope and affinity of the antibody. PMID- 26433972 TI - Evidence and Counterevidence in Motion Perception. AB - Sensory neurons gather evidence in favor of the specific stimuli to which they are tuned, but they could improve their sensitivity by also taking counterevidence into account. The Bours-Lankheet model for motion detection uses counterevidence that relies on a specific combination of the ON and OFF channels in the early visual system. Specifically, the model detects pairs of flashes that occur separated in space and time. If the flashes have the same contrast polarity, they are interpreted as evidence in favor of the corresponding motion. But if they have opposite contrasts, they are interpreted as evidence against it. This mechanism provides an explanation for reverse-phi (the perceived reversal of an apparent motion stimulus due to periodic contrast-inversions) that is a conceptual departure from the standard explanations of the effect. Here, we investigate this counterevidence mechanism by measuring directional tuning curves of neurons in the primary visual and middle temporal cortex areas of awake, behaving macaques using constant-contrast and inverting-contrast moving dot stimuli. Our electrophysiological data support the Bours-Lankheet model and suggest that the counterevidence computation occurs at an early stage of neural processing not captured by the standard models. PMID- 26433973 TI - Risk factors and consequences of anastomotic leakage after Ivor Lewis oesophagectomy?. AB - OBJECTIVES: Oesophageal carcinoma (EC) remains an aggressive disease. Despite extensive changes in therapeutic modalities, surgical resection remains the first choice therapy for curable oesophageal cancer patients. Anastomotic sites are prone to serious complications such as leakage, fistula, bleeding and stricture. Leakage of the anastomosis (AL) remains one of the main causes of postoperative morbidity and mortality. The purpose of this study was to identify predictors associated with postoperative leakage after Ivor Lewis oesophagectomy and its consequences in a single centre. METHODS: We performed a retrospective analysis of 412 Ivor Lewis oesophageal resections in a single institute between 2005 and 2014. Univariable and multivariable logistic regression have been used to identify predictors of AL and its impact on postoperative outcome and overall survival. Kaplan-Meier curve was used to analyse overall survival and log-rank analysis to determine odds ratio. RESULTS: A total of 412 patients were evaluated. Mean age was 62 +/- 11 years (77% male). Overall leak rate was 2.9%. In-hospital or 30-day mortality was 4.4%. Mean intensive care unit (ICU) stay was 1 day and mean hospital stay was 19 days. A history of renal failure, diabetes, higher American Society of Anaesthesiologists score and current cigarette and corticosteroid use were identified as predictors of AL on univariable analysis. Multivariable analysis identified active smoking [P = 0.05, odds ratio (OR) 4.34, 95% confidence interval (CI): 0.98-19.28] and active corticosteroid use (P < 0.001, OR 15.8, 95% CI: 3.25-76.7) as independent significant predictors. A history of diabetes tended to be associated with a higher leakage rate but failed to reach statistical significance. AL was associated with a longer ICU and hospital stay and a significantly higher mortality (42% in the AL group vs 3% in the control group, P < 0.0001). CONCLUSIONS: Anastomotic leakage after oesophagectomy is a major cause of postoperative morbidity and mortality. Identifying risk factors preoperatively can contribute to the prevention of postoperative complications. PMID- 26433974 TI - Is a minimally invasive approach for mitral valve surgery more cost-effective than median sternotomy? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: is a minimally invasive approach for mitral valve surgery more cost-effective than median sternotomy? Altogether, 51 studies were found using the reported search, of which 7 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated. No randomized controlled trials have assessed the cost-effectiveness of less invasive mitral valve surgery compared with median sternotomy, with the best evidence coming from retrospective and propensity matched analyses. Five studies compared minithoracotomy versus sternotomy, one compared minimally invasive port-access surgery versus sternotomy and one compared video-assisted minithoracotomy versus sternotomy. The use of a minithoracotomy or a minimally invasive port-access approach for mitral valve surgery resulted in significant reductions in costs of cardiac imaging and laboratory tests, lower use of blood products, fewer perioperative infections, faster recovery, shorter hospital length of stay, fewer requirements for rehabilitation and lower readmission rates in the following postoperative year. We conclude that a minimally invasive approach for mitral valve surgery is safe, effective and significantly more cost-effective than median sternotomy. PMID- 26433975 TI - POLICY AND PROCEDURE CONSIDERATIONS FOR HEALTH INFORMATION EXCHANGE ORGANIZATIONS. PMID- 26433977 TI - Catherine Smrcina, PhD, RN, ONC: 1952-2015. PMID- 26433976 TI - [Update on Current Care Guidelines. Rheumatoid Arthritis (RA)]. AB - Patients with signs and symptoms of early rheumatoid arthritis (RA) should be referred to a multidisciplinary rheumatology clinic. The ACR-EULAR criteria help in identification of patients with risk for erosive RA. Treatment should aim at early remission. Start with the combination of methotrexate, hydroxychloroquine, sulfasalazine, and low-dose glucocorticoid is recommended if contraindications exist. Methotrexate has better bioavailability as injection. Glucocorticoids are injected into active joints. Patient education with shared decision is essential. Exercise training is recommended. If treatment target is not achieved by the DMARD combination, a biological drug is added. PMID- 26433978 TI - Opinion Paper: Post-surgical Delirium, Consciousness, and Therapy. PMID- 26433979 TI - Cholera, 2014. PMID- 26433980 TI - Revitalizing control efforts for cholera. PMID- 26433981 TI - Innovative WASH interventions to prevent cholera. PMID- 26433982 TI - Cholera surveillance, rapid diagnostics and laboratory networks. PMID- 26433983 TI - Cholera in Bangladesh. PMID- 26433984 TI - Cholera in Haiti: successes and challenges in a low income country. PMID- 26433985 TI - Editorial note: cholera a public health priority. PMID- 26433989 TI - MouthHealthy--Increasing the Public's Oral Health Literacy. PMID- 26433988 TI - A Time For Every Purpose. PMID- 26433990 TI - Missing a Mentor. PMID- 26433991 TI - Outreach, Prevention, and the "Urgent Chair". PMID- 26433992 TI - The Pain Puzzle: Q's, A's, and Mapping the Maze. PMID- 26433993 TI - Differential Diagnoses for Persistent Pain Following Root Canal Treatment: A Study in the National Dental PBRN. AB - INTRODUCTION: Pain present six months following root canal treatment (RCT) may be either of odontogenic or non-odontogenic origin. This is important because treatments and prognoses are different; therefore, the aim of this study was to provide specific diagnoses of patients reporting pain six months after receiving initial orthograde RCT. METHODS: We enrolled patients from the Midwest region of an existing prospective observational study of pain after RCT. Pain at six months was defined as >= 1 day of pain and average pain intensity of at least 1/10 over the preceding month. An endodontist and an orofacial pain practitioner independently performed clinical evaluations, which included periapical and cone beam computed tomograph (CT) radiographs, to determine diagnoses. RESULTS: Thirty eight out of the 354 eligible patients in the geographic area (11%) met the pain criteria, with 19 (50%) consenting to be clinically evaluated. As the sole reason for pain, 7 patients (37%) were given odontogenic diagnoses (4 involving the RCT tooth, 3 involving an adjacent tooth). Eight patients (42%) were given non odontogenic pain diagnoses (7 from referred temporomandibular disorder [TMD] pain, 1 from persistent dentoalveolar pain disorder [PDAP]). Two patients (11%) had both odontogenic and non-odontogenic diagnoses, while 2 (11%) no longer fit the pain criteria at the time of the clinical evaluation. CONCLUSION: Patients reporting "tooth" pain 6 months following RCT had a non-odontogenic pain diagnosis accounting for some of this pain, with TMD being the most frequent non odontogenic diagnosis. Dentists should have the necessary knowledge to differentiate between these diagnoses to adequately manage their patients. PMID- 26433995 TI - I Have Something to Say--But No One Is Listening! PMID- 26433994 TI - Improve Your Practice and Engage Your Patients: Participate in the NDPBRN. PMID- 26433997 TI - The Future of Dental Board Structure and Regulation. PMID- 26433998 TI - President's Address. PMID- 26433999 TI - Amelogenesis Imperfecta, Facial Esthetics and Snap-On Smile. AB - Amelogenesis imperfecta is a hereditary enamel protein disorder affecting deciduous and secondary crown formation. The prevalence ranges from 1:700 to 1:14,000 depending on the population. These teeth may be hypoplastic, hypomineralized, or hypermineralized and are often discolored, sensitive and caries vulnerable. Patients often present with psychosocial issues due to appearance. Primary teeth are often treated with stainless steel crowns while secondary teeth are treated with full coverage esthetic crowns. The presenting preteen male here was fitted with Snap-On Smile? (www.snaponsmile.com). This treatment option provided cosmetic enhancement of the patient's appearance besides stabilization without altering the primary and secondary dentition during adolescent development. PMID- 26434000 TI - Oral Complications of Cancer Therapy: A Summary Guide for the Clinician. AB - Oral complications of cancer therapy can be so severe that they can lead to the discontinuation of cancer treatment. This can affect prognosis, patient survival, and alter patient quality of life. Early recognition and management of oral complications in cancer patients is a very important part of the overall treatment. Currently, a large number of cancers are treated at the ambulatory level, and when patients develop oral problems they may seek care from their private dentist. The goal of this manuscript is to discuss common oral complications of cancer therapy, and the role the general dentist can play in diagnosis and management. PMID- 26434001 TI - Combination PROP: A Case Report of a Hybrid Flexible and Traditional Partial Removable Dental Prosthesis. AB - The need for partial removable dental prostheses (PRDP) is increasing as the over 65 partially edentulous population grows. The use of flexible materials in the fabrication of these prostheses has captured a large portion of the market once occupied by traditional cast metal PRDPs. While there are some clinical advantages to the use of flexible PRDPs, there are also disadvantages and contraindications that must be considered. This paper describes a clinical case in which a patient's dentition is restored with a hybrid partial removable dental prosthesis consisting of a traditional metal framework and flexible denture base and clasps. This design can result in achieving the benefits of each type of prosthesis in an effort to satisfy the needs of the patient. PMID- 26434002 TI - Seeking to Understand the Reader of Interest-Your Patient-Health Literacy and Adherence Concerns for the Dentist and the Dental/Medical Team. AB - The overall health of the United States' (U.S.) population has been surveyed and reported for several decades in a quest by healthcare professionals to understand the etiology for healthcare disparities and seek to lessen its effects on individuals and, ultimately, eliminate them. Many of these surveys and reports have illuminated disparities, of access to healthcare by focusing on measures to address health literacy deficiencies. A plethora of information concerning patients' health literacy skills and printed information has been made available for dentists and their staff. The printed information is in the format of published patient- centered educational guidelines and readable dental and medical limited reach media (LRM), such as information sheets and prescription drug leaflets. LRM has great potential to enhance access to healthcare information for the reader of interest--your patient--at a readable and comprehensible level. Printed materials are an effective means to enhance health promotion and education for the lay populace. Tailored LRM protocol and the Patient Introduction Form (PIF) are excellent educational instruments for dentists and the dental/medical team (The Team). These instruments are valuable assets for The Team to assist its patients in monitoring and maintaining dental and medical adherence protocols in their daily lives. PMID- 26434004 TI - Health, Growth and Development, and Kinesiology. PMID- 26434003 TI - Changes in the Clinical Training of Dental Students at the University of Tennessee College of Dentistry. AB - Dental education is an ever evolving process due to continual advancements in patient treatment. This article provides the reader with a look into an educational process that affords the student with better clinical experience without an increase in clinical training hours. When a comprehensive care model of education is introduced into a traditional care setting, the comparison of procedures completed with the previous 5 years results indicate an increase in the number of amalgam and composite restorations placed of 26% and an increase in crowns placed of 32.9%. Integration of the dental hygiene program and additional remote sites afford new populations of patients where clinical skills can be developed which will result in a graduate more able to go directly into private practice. PMID- 26434005 TI - Trend of Growth and Level of Nutrition in Children from 7 to 14 Years. AB - The research was conducted with the aim of determining the trend of development of morphological characteristics in female and male students aged seven (7) to fourteen (14) years. The sample of examinees was drawn from the population of female and male students from first (1) to eighth (8) grade of elementary schools in Split. In total, 771 female students and 840 male students were measured. Height, weight and upper arm and dorsal skin folds were measured, and used in calculation of fat tissue percentage. The results indicate the increase of body height and mass, what is in concordance with the secular trend. The increased percentage of fat tissue, especially in first four grades of elementary school, is a characteristic of this population, especially boys. The characteristic of this population is obesity, caused by the inadequate nutrition and lack of kinesiological activity. In later age, the trend of height growth and gaining weight continues, but the weight increase occurs due to fat tissue increase, not increase of muscle tissue. PMID- 26434006 TI - Correlation between Balance Ability and Speech-Language Development in Children. AB - The longitudinal study was conducted in order to establish whether the success rate of reflexes related to maintaining balance at birth is in correlation with the success rate of maintaining balance in early childhood, as well as to examine the correlation of a certain level of speech and language development with the ability of maintaining balance at birth and at the age of 5. The main study group included 54 children of both genders, aged 5.0 to 5.4, whose balance ability and speech and language status were evaluated based on the battery of standardized tests, whereas the group of reflexes related to the function of the vestibular sense was clinically tested on the 3rd day upon birth, within the same sample of children. The data at birth and at the age of 5 were recorded by means of a digital camera, then scored and statistically and descriptively processed. The research results indicated a statistically significant correlation between the achieved level of balance ability in the newborns and five-year-olds, as well as between balance skills and a certain level of speech and language development in children at the age of 5. The importance of this research lies in new knowledge in the domain of maturation of vestubular function immediately after birth, given that this segment of physiology of a newborn has not so far been processed in such a way, as well as in the recognition of function of the vestibular sense as another parametre of a child's maturation. PMID- 26434007 TI - The Percentage of Body Fat in Children and the Level of their Motor Skills. AB - The aim of this study was to determine the prevalence of overweight and obesity among primary education pupils and to identify differences in motor skills between normal weight, excessive and obese pupils. Partial aim was to determine differences in motor status of girls and boys and their anthropometric characteristics (Body Mass Index, body fat percentage). The study was conducted in two primary schools in Zagreb, Ivan Goran Kovacic and Davorin Trstenjak. Total of 333 pupils, aged 7-11, were measured (178 boys and 155 girls). Four anthropometric and seven motor variables were used to analyze differences in motor abilities of children. Children were divided into three groups within gender based on their body fat measures. We established a statistically significant difference in motor abilities between groups of subjects in three subsamples (1st-2nd class girls and 3rd-4th boys and girls). Children with normal weight have better results in explosive strength, coordination, static strength of arm and shoulder than children who are overweight and obese. The differences are not observed in motor variables where body weight is not a requisite for efficient execution of movement. Differences in motor skills by gender showed that boys are better in coordination, speed of the simple movements, explosive and repetitive strength, and girls are better in flexibility. The conclusion of this study confirmed the existence of differences in the development of motor skills in children with normal body weight compared to children who are overweight or obese. These facts prove that excessive body weight has negative repercussions on motor performance. PMID- 26434008 TI - Effects of Acute Physical Exercise on Mathematical Computation Depending on the Parts of the Training in Young Children. AB - The aim of this study was to determine whether acute physical exercise may increase the ability to quickly solve basic mathematical operations in young children. In this way, the children acquired the means to activate a larger area of the brain when necessary. The research sample of 38 preschool and 18 schoolchildren was tested in basic mathematical operations before and after physical exercise. The results showed that children's computational performance was enhanced significantly during exercise and remained stable after relaxation part of their physical training. PMID- 26434009 TI - Can Kinesiological Activities Change "Pure" Motor Development in Preschool Children during One School Year? AB - The purpose of this study was to evaluate the effects of an additional, organized, and more intensive kinesiological treatment on "pure" motor abilities in preschool children. In the present study an experimental treatment was carried out on a sample of 37 preschool boys by applying kinesiological activities. The 60 minute treatment was applied over a period of one school year (9 months), twice a week. A control group of 31 boys were trained according to the regular program for preschool institutions. Treatment effects were assessed by 8 motor ability tests and 5 anthropometric measures. The significant differences between the groups, which were observed after the final measurement and compared to the initial one, proved that the kinesiological treatment had a positive impact on the general development of "pure" motor abilities. The most significant effect of experimental kinesiological treatment was the improvement in whole body force, flexibility and coordination of preschool boys. These findings, obtained only in one school year, point to the importance of physical exercise and the application of additional kinesiological activities with various modalities, to improve motor development, even morphological growth and development in preschool children. The effects of the perennial application of kinesiological activities, under the supervision of kinesiological professionals, could be beneficial and could form the basis for a better biological and motor development in older age. PMID- 26434010 TI - Differences in Some Kinematic Parameters between Two Qualitatively Different Groups of Pole Vaulters. AB - The basic aim of this research was to determine the differences of kinematic parameters in two qualitatively different groups of young pole vaulters. With this purpose, a research was conducted in which the video records from a competition were acquired. The sample of entities (N = 71) consisted of successful vaults of 30 pole vaulters, whose attempts were recorded at the European Junior Championship in Novi Sad, held on 23-26th July 2009. The examinees performed the vaults as a part of the elimination competition for the finals, and during the final part of the competition. The age of examinees was from 17 to 19 years, and the span of their best results was from 4.70 to 5.30 meters. The kinematic analysis was conducted according to the standards of APAS procedure (Ariel Performance Analysis System, USA), determining 25 kinematic variables necessary for further analysis. The entities (vaults) were divided into two categories (qualitative classes) based on the expert knowledge. Group 1 consisted of successful vaults up to 4.90 m (N = 46), while group 2 consisted of successful vaults whose height was more than 4.90 m (N = 25). The discrimination analysis determined the parameters differentiating the vaults of different quantitative classes. Also, it was confirmed that the result efficiency in pole vault was primarily determined by the variables defined by motor abilities, as well as the indicators determining the vault performance technique. PMID- 26434011 TI - Relation between Anthropometric Characteristics and Kinematic Parameters which Influence Standing Long Jump Efficiency in Boys and Adolescents. AB - The aim of this research was to determine the relation between the anthropometrical variables and kinematic parameters that influence the standing long jump efficiency in boys and adolescents aged 4 to 18, as well as students of second year of Faculty of Kinesiology. With this aim, a sample of 120 examinees has been selected and divided into 5 experimental groups consisting of 20 boys and adolescents (aged 4 to 6, 7 to 9, 10 to 12, 13 to 15, 16 to 18), and one control group consisting of 20 second year students of Faculty of Kinesiology. The sample of variables consisted of 21 kinematic parameters relevant for efficient standing long jump performance, followed by battery of 13 morphological characteristics, as well as the age of the examinees. This research determined the relation between certain morphological characteristics and kinematic parameters relevant for standing long jump performance. It can be concluded that in adults, the jump length was primarily influenced by body mass, subcutaneous fat tissue and body fat percentage, while in younger age groups, besides the mentioned measures, the examinees who were taller, had longer arms and legs achieved better results. PMID- 26434013 TI - The Relationship between 200 m Performance and Selected Anthropometric Variables and Motor Abilities in Male Sprinters. AB - The goal of this study was the investigation of the relationship between 200 m performance and motor abilities and anthropometric characteristics of different level of male sprinters (200 m performance 23.80 +/- 2.16 s--the best results 21.40 s). The physical fitness measures included: 50 m from standing and flying start, standing long jump (SLJ) standing five jump (SFJ), double and single leg countermovement jumps CMJ), flexibility (sit and reach) and 4 kg shot put throwing (over head). The Spearman correlation coefficient was applied to verify the association. The results demonstrated strong relationships (p < 0.05) between 200 m performance and experience (age) and body mass (r = 0.85, r = -0.80 respectively) As for the motor abilities strong relationship exists between 200 m and time of 150 m, 50 m from standing and flying start and CMJ on single leg. Vertical jumping displayed stronger relationship with 200 m performance that horizontal one. From a practical point of view this is very important notice. PMID- 26434012 TI - The Influence of Anthropometric Characteristics on Kinematic Parameters of Children's Sprinter's Running. AB - Children's sprinters running differs from the adults' one primarily in their motoric abilities, anthropometric characteristics, physiological and biochemical characteristics, as well as psychological and sociological characteristics. This research's aim was to examine the influence of anthropometric characteristics on kinematic parameters of children's sprinter's running. The sample of variables consisted of variables which determine anthropometric characteristics (14 anthropometric characteristics) and of 5 kinematic parameters'variables of sprinter's running. Kinematic parameters of sprinter's running in the phase of maximal speed have been collected by applying the Optojump technology (Microgate, Italy) and the sprinter's running times were measured every 5 meters on a 50 m lap. The results obtained from the multiple regression analysis between the group of anthropometric characteristics and the 50 m running results indicate that the percentage of fatty tissue is a statistically significant variable with boys, while the same variable with girls is near the limit of statistical significance. In the factor structure of anthropometric characteristics two factors have been set apart with boys and three with girls. The first factor set apart with both boys and girls is the factor of body voluminosity, the second factor with boys is the factor of longitudinal dimensionality, while with girls it is the factor of fatty tissue quantity. The factor of longitudinal dimensionality is the third girls' factor. For most variables a negative correlation has been determined with a higher percentage of fat or a higher quantity of subcutaneous fatty tissue with both boys and girls. Boys having a lower quantity of subcutaneous fatty tissue achieve better results in 50 m running, they have a shorter duration of contact with the pad, a longer duration of the flight phase and a longer step length when compared to boys with a higher quantity of subcutaneous fatty tissue. Boys with a bigger body muscular mass achieve a shorter duration of the contact, a longer duration of the flight and a longer step length. Girls who have a lower quantity of subcutaneous fatty tissue achieve a better 50 m running time, have a shorter duration of contact with the pad and a longer step length. It has been established that taller boys have a longer step length, and longer feet significantly influence the longer duration of contact with the pad and the lowering of the step frequency. PMID- 26434014 TI - Success in Adopting Technique of Alpine Skiing with Respect to Motor Abilities of the Children Aged 7-8 Years. AB - The aim of this research was to determine relations between estimated motor abilities and efficiency of alpine ski learning in children ski beginners. It included 54 children between 7 and 8 years of age (average 7.44 +/- 0.52 years). Children were tested for balance, agility, strength, coordination and frequency of movement on ten motor ability tests. After motor abilities were assessed, participants learned alpine skiing during six-day alpine ski school and upon completion of ski school program, were tested on three elements of alpine ski technique (stopping in a snow-plough, uphill turn and turns around the posted marks) by three independent judges. According to achieved level of ski knowledge, they were allocated to three groups differing by the level of success; less successful (N = 18; 26-44 points), moderately successful (N = 11; 45-48 points) and successful (N = 25; 49-55 points). Significant differences in success of adopting basic ski technique were noticed with respect to the results achieved in the task polygon backwards (F = 6.162, p = 0.004), foot tapping (F = 6.337, p = 0.003) and crossed arm sit-ups (F = 3.099, p = 0.053). The participants who successfully adopted the basic ski technique also achieved good results in tests: polygon backwards, foot tapping, crossed arm sit-ups, side steps, balancing on left leg perpendicular on balance board, vertical jump and medium results in tests 20m dash and balancing on right leg perpendicular on balance board. Our results suggest that successful participants have better developed coordination, frequency of movement, strength and agility. PMID- 26434015 TI - Gender Differentiations of Some Anthropological Characteristics of Karate Players -Cadets. AB - The research was conducted with the aim of determining gender differentiations of some anthropological characteristics of male and female cadet karate players. To achieve this aim, a group of 10 morphological variables, ten motor tests, five situation motor test and six technical performance evaluation tests was applied. Two hundred and six competing players were measured, of which 105 male and 101 female. The examinees were divided according to weight categories (lower and higher weight categories). Based on the variance analysis and canon discrimination analysis a conclusion can be made: gender differentiations are most strongly expressed in morphological and basic motor area, and significantly less in the area of specific motor abilities and motor knowledge (technical efficiency). PMID- 26434016 TI - Technical and Tactical Aspects that Differentiate Winning and Losing Performances in Elite Male Karate Fighters. AB - The purpose of this research was to identify the fighters' technical and tactical activity indicators in order to determine indicator significance regarding situational efficiency and designation between winning and losing performances in a karate match. We scientifically observed a sample of 274 male contesters of 137 karate matches during the 2008 World Karate Championship in Tokyo. Each individual competitor was observed in maximum of three matches. The matches were recorded using a DVD camera in order to collect data for further analysis, and the sample was further described using 48 technical and tactical indicators of situational efficiency and match outcome variables. The obtained results indicate that a karate match is composed of 91% of non-scoring techniques and 9% of scoring techniques in the total technique frequency. On this basis a significant difference in the situational efficiency between the match winners and the losing contesters has been discovered. Those two groups of fighters exhibit a statistically significant difference (p<0.05) in 11 out of 21 observed variables of situational efficiency in the table of derived situational indicators. A prevalence of non-scoring techniques suggests that energy demand and technical and tactical requirements of a karate match are in the largest extent defined by non-scoring techniques. Therefore, it would be a grave mistake to disregard non scoring karate techniques in any future situational efficiency studies. It has been discovered that the winners differ from the defeated contesters by a higher level of situational efficiency in their executed techniques, which incorporate versatility, biomechanical and structural complexity, topological diversity and a specific tactical concept of technique use in the attack phase. PMID- 26434017 TI - Importance of Hierarchical Structure Determining Tennis Performance for Modern Defensive Baseliner. AB - Hierarchies are present everywhere (physics, medicine, nature, human needs, etc.) and tennis is no exception. Is counterpuncher's goal just to chase down every ball and force the opponents into long rallies? The aim of this first empirical study is integrate theory and practice about overall quality evaluation and accurately analyze offensive and defensive tennis priorities for counterpunchers. Weight of each criterion was obtained using AHP technique in Expert Choice software. The results indicate that this model is able to provide important training variables in order to control and manipulate training process. Also, issues prior to research indicate that sports scientists and expert coaches need to learn from each other in order to help players maximizing their performance. PMID- 26434018 TI - Relationship of Speed, Agility, Neuromuscular Power, and Selected Anthropometrical Variables and Performance Results of Male and Female Junior Tennis Players. AB - The aim of the study was to analyses the relation between the selected speed, agility, and neuromuscular power test items. The sample of subjects consisted of 154 male and 152 female young tennis players. Using six motor and three anthropometrical tests we investigate differences between males and females and between two age categories. Finally, we analyzed the relation between motor and anthropometrical tests and a player's tennis performance. The correlation between the two agility test items and 5-m sprint is very large in male players, while only moderate with 20-m sprint in female category. Male tennis players have higher correlations between speed test items and neuromuscular test items. The speed test item (5-m sprint) has large correlation with a player's tennis performance. One-way analysis of variance results indicated that young male tennis players performed significantly better than females in all motor test items. Significant differences between genders have not been revealed only in the body mass index. Differences between the males aged 18& under and 16& under have been noted as significant in all test items, except the vertical jump, while differences between the females have been noted as significant in three anthropometrical tests, quarter jump, and the fan-drill test. Regression analyses have shown that the system of prediction variables explains a relatively small part of variance (46%--males and 40%--females). In both genders, it has been revealed that test items measuring speed significantly influence a player's tennis performance. PMID- 26434019 TI - Non-Linear Approach in Kinesiology Should Be Preferred to the Linear--A Case of Basketball. AB - In kinesiology, medicine, biology and psychology, in which research focus is on dynamical self-organized systems, complex connections exist between variables. Non-linear nature of complex systems has been discussed and explained by the example of non-linear anthropometric predictors of performance in basketball. Previous studies interpreted relations between anthropometric features and measures of effectiveness in basketball by (a) using linear correlation models, and by (b) including all basketball athletes in the same sample of participants regardless of their playing position. In this paper the significance and character of linear and non-linear relations between simple anthropometric predictors (AP) and performance criteria consisting of situation-related measures of effectiveness (SE) in basketball were determined and evaluated. The sample of participants consisted of top-level junior basketball players divided in three groups according to their playing time (8 minutes and more per game) and playing position: guards (N = 42), forwards (N = 26) and centers (N = 40). Linear (general model) and non-linear (general model) regression models were calculated simultaneously and separately for each group. The conclusion is viable: non linear regressions are frequently superior to linear correlations when interpreting actual association logic among research variables. PMID- 26434020 TI - Differences in Basic Non-Standard Situational Efficiency Indicators between Winning and Defeated European Senior Basketball Teams. AB - The aim of the conducted research was to identify and explain the differences in basic non-standard situational efficiency indicators between winning and defeated European senior basketball teams. Discriminant analysis and Mann-Whitney U-test were used with the purpose of investigating the differences between winning and defeated teams in the domain of basic non-standard situational variables. The grouping variable distinguished 24 defeated teams from 24 winning teams participating in 2009/2010 season of Euroleague Top 16. The research clearly reveals the differences between the winning and defeated European senior basketball teams in the domain of non-standard situational variables of position and transition offense and defense. Eight situational efficiency indicators were used which include the overall number of successful and unsuccessful position and transition defenses and offenses. Based on the results obtained by parametric and non-parametric methods, it has been noticed that successful position defense is crucial for winning, and unsuccessful position offense is an indicator of defeat prediction. Therefore, practical aims in situational training must involve balanced development of relevant abilities and skills which determine successful simultaneous performance of multiple tasks in all the phases of game flow. Such process of sport preparation improves the overall actual quality of players and whole team performance. In conclusion, it is important to emphasize that the process of improving position and transition defense stimulates the development of position and transition offense, and vice versa. PMID- 26434021 TI - Morphological Profiles of Playing Positions in Defense and Offense in Professional Men's Handball. AB - The main scope of the study is concerned with the morphological profiles of playing positions in defense, offense and the combinations of these two phases of the game. Furthermore, study attempted to identify the difference between the morphological profiles of the individual playing positions. Entity sample of the study consist of the 148 players that participated in 45 matches of the World Men's Handball Championship which took place in Croatia in 2009. The study dealt with the differences between playing positions concerning basic morphological characteristics which are due to the selection based on roles and tasks that need to be carried out in each position. Moreover, morphological similarity of playing positions in offense and defense was noticed. It was determined that wing players play dominantly in the position of left back, external players in the position of right and center back whereas pivots participate in the positions of center, back and center forward positions in defense. Morphological profiles of playing positions in defense, offense and in the combination of these two phases of the game were determined. Identical positions on different sides in offense (left right wing player, left-right back player) have shown that these positions are quite similar when it comes to morphological profile and playing position in defense. It can be concluded that some playing positions in offense are accompanied by the respective positions in defense. All positions are characterized by one or two morphological profiles. PMID- 26434023 TI - An Explanation of the Influence on Deciding which Type of Foot Strike to Use when Running Barefoot or in Minimalistic Shoes. AB - Buying minimalistic shoes does not mean that you know how to use them. Salespersons are rarely competent to give adequate advice how to transition to new shoes. The same happens when someone chooses to run barefoot. So, the aim of the present experiment was to find out whether giving or not giving an explanation of the correct technique of foot placement in barefoot running and running in a minimalistic shoe influences the frequency of rear-foot strikes in natural, rear foot strikers when running barefoot or in minimalistic shoes. Thirty-nine subjects (age =34.9 +/- 6.9 years, height = 174 +/- 9 cm, mass = 73.1 +/- 13.8 kg), randomly divided into four groups participated in this experiment. Subjects in groups 1 and 3 did not receive an explanation, while groups 2 and 4 did. Besides the difference in explanation, there was also a difference in the shoes worn during the intervention. Subjects in the groups 1 and 2 ran barefoot, while subjects in groups 3 and 4 ran in minimalistic shoes. The initial state of the foot strike patterns was measured in classic running shoes. During the intervention subjects ran according to the group they were in. 80% of the subjects in groups 1 and 3 took the most steps in a rear-foot strike pattern (Median =100) while only 21% of the subjects in groups 2 and 4 took the most steps in a rear-foot strike pattern (Median = 15.7), U = 64, z = 3.619, p (0.00) < 0.05, r = -0.58. The results show that an explanation and dem-onstration of the correct technique of foot placement in barefoot running and running in a minimalistic shoe is important when someone decides to switch from classic running shoes to minimalistic shoes or to go barefoot. PMID- 26434022 TI - The Relationship between Selected Motor Ability Determinants and Anthropometric Characteristics in Adolescent Athletes from Various Sport. AB - The main purpose of this study was to examine the relationship between speed, lower extremities explosive power, simple, and complex responses in adolescent athletes from various disciplines. Thirty nine athletes of 16.5 years old, N = 13 sprinters and jumpers, N = 13 soccer players, and N = 13 judokas participated in the experiment. Pearson correlations, a one-way ANOVA and an independent t-test for establishing differences between those three groups of athletes was applied. Additionally the Ward method of hierarchical cluster analysis also was applied. The strong correlation occurred between complex responses and speed; 20 m from standing and 20 m flying start (r = 0.62 and r = 0.65 respectively). In other cases, no strong association was found. The substantial differences between groups occurred in the 20 m run from flying start (t = 5.92) and standing triple jump (t = 4.16). The study indicates that adolescent athletes may need to be assessed differently to a certain extent, including sport specialization. PMID- 26434024 TI - Effects of Neuromuscular Electrical Stimulation and Resistance Training on Knee Extensor/Flexor Muscles. AB - Neuromuscular electrical stimulation (NMES) has recently drawn a lot of attention as means for strengthening of voluntary muscle contraction both in sport and rehabilitation. NMES training increases maximal voluntary contraction (MVC) force output through neural adaptations. On the other hand, positive effects of resistance training (RT) on muscle strength are well known. The aim of this study was to investigate effects of a 5-week program of NMES compared to RT program of same duration. Sample of 15 students' of faculty of sport and physical education (age 22 +/- 2) were randomized in two groups: NMES (N = 7) and RT (N = 8). NMES group performed NMES superimposed over voluntary muscle contraction, RT group performed resistance training with submaximal loads. Subjects were evaluated for knee isokinetic dynamometry on both sides (60 degrees and 180 degrees s). After intervention no significant difference between groups were observed in isokinetic dynamometry (p = 0.177). However, applying pair sample t test within each group revealed that peak torque increased in NMES-group (p = 0.002 for right knee extensors muscles, p = 0.003 for left, respectively, at 60 degrees and p = 0.004 for left knee extensors muscles, at angular velocity 180 degrees ). In RT group (p = 0.033 for right knee extensors muscles, p = 0.029 for right knee flexor muscles, at angular velocity 60 degrees ). Our results indicate that NMES has equal potential if not in some way better than classical RT having in mind that overload on locomotor apparatus during NMES is minimal and force of muscle contraction is equal on both sides, for enhancement of knee muscles concentric peak torque. PMID- 26434025 TI - Kinematic, Dynamic and EMG Analysis of Drop Jumps in Female Elite Triple Jump Athletes. AB - The purpose of the study was a biodynamic analysis of the kinematic, dynamic and EMG parameters of two types of drop jumps (heights of 25 cm and 45 cm). The sample of measured subjects included four female elite triple jump athletes, with their best results varying from 13.33 to 15.06 meters. The kinematic and dynamic parameters were calculated with the use of a bipedal tensiometric force plate, which was synchronized with nine CCD cameras. A 16-channel electromyography (BTS Pocket, Myolab) was used to analyze the EMG activation of the following muscles: m. erector spinae, m. gluteus, m. rectus femoris, m. vastus medialis, m. vastus lateralis, m. biceps femoris, m. soleus and m. gastrocnemius medialis. In the drop jump from a 25 cm height, the measured subjects achieved the following results: height of jump 43.37 +/- 5.39 cm and ground reaction force 2770 +/- 411 N. In comparison, results for the drop jump from a 45 cm height were: height of jump 45.22 +/- 4.65 cm and ground reaction force 2947 +/- 366 N. Vertical velocity of the take-off in the 25 cm drop jump was 2.77 +/- 0.19 ms(-1) and in the 45 cm drop jump it was 2.86 +/- 0.15 ms(-1). Observation of the EMG activation revealed the proximal to distal principle of muscle activation at work in both types of drop jumps. In the first phase of the concentric phase the most active muscles were m. gluteus maximus and m. rectus femoris. The greatest activity of m. gastrocnemius medialis and m. soleus was noticed in the last third of the take-off action. Significantly high EMG activation of m. vastus medialis and m. vastus lateralis was already shown in the flight phase prior to the feet making contact with the ground. PMID- 26434026 TI - Activation Pattern of Lower Leg Muscles in Running on Asphalt, Gravel and Grass. AB - Running is performed on different natural surfaces (outdoor) and artificial surfaces (indoor). Different surface characteristics cause modification of the lower leg muscle activation pattern to adopt ankle stiffness to these characteristics. So the purpose of our investigation was to study changes of lower leg muscles activation pattern in running on different natural running surfaces. Six male and two female runners participated. The participants ran at a freely chosen velocity in trials on asphalt while in trials on gravel, and grass surfaces they were attempting to reach similar velocities as in the trials on asphalt. Muscle activation of the peroneus brevis, tibialis anterior, soleus, and gastrocnemius medialis of the right leg was recorded. Running on asphalt increased average EMG amplitude of the m. tibialis anterior in the pre-activation phase and the m. gastrocnemius medialis in the entire contact phase compared to running on grass from 0.222 +/- 0.113 V to 0.276 +/- 0.136 V and from 0.214 +/- 0.084 V to 0.238 +/- 0.088 V, respectively. The average EMG of m. peroneus brevis in pre-activation phase increased from 0.156 +/- 0.026 V to 0.184 +/- 0.455 V in running on grass in comparison to running on gravel. Running on different surfaces is connected with different activation patterns of lower leg muscles. Running on asphalt requires stiff ankle joints, running on gravel requires greater stability in ankle joints, while running on grass is the least demanding on lower leg muscles. PMID- 26434028 TI - Environmental Success Factors or the Justification for the Prohibition of High Tech Swimsuits in Swimming. AB - The scope of the study was to elaborate and represent different aspects of high tech suits which influence the swimming results and to justify the change of swimming rules in 2009. Impact of environmental factors on the result should not be greater than the athlete's impact. Impact of high-tech suits greatly contributes to the development of technology, new materials and modern design of sports equipment. The paper describes the genesis of the high-tech swimsuits and provides an analysis of causes and consequences of its prohibition. The arguments against the suits have an effect on prohibition of different sports requisites and equipment in all sports. This prohibition directly affects the modern swimmers who will have difficulties in breaking the world records swimming in high-tech suits. PMID- 26434027 TI - Motor Skills in Hearing Impaired Children with or without Cochlear Implant--A Systematic Review. AB - Hearing impairment is a major limitation in communication, and it can obstruct psychological development, development of social skills and motor development. Hearing impairment is the third most common contemporary chronic health condition, and it has become a public health problem. The effectiveness of problem solving in everyday life and in emergency situations depends greatly on the amount and quality of the motor programs. Therefore, it is evident that the normal motor development in persons with hearing impairment is essential for everyday life. The aim of this research is to analyze the available information pertaining to motor skills of hearing impaired children both with and without a cochlear implant (CI) and to analyze possibilities of influencing their motor skills. The relevant studies on motor skills of hearing impaired children both with and without CI were obtained by an extensive computer search of various databases using special keywords and extraction with respect to certain criteria, resulting in 22 studies. The overall results of this systematic review indicate that the children with hearing impairment exhibit suboptimal levels of motor skills especially balance. Very few studies compared children with hearing impairment with CI units and without CI units and the results of those studies are quite contradictory. Numerous studies have confirmed that the regular and appropriate physical exercise can improve motor skills of children with hearing impairment, especially balance. The fact that the development of motor skills is crucial for the child's interaction with the outside world, action, perception and acquisition of academic skills and other skills necessary for life shows the importance of motor skills development for children with hearing impairment. PMID- 26434029 TI - Physical Activity as a Function of Women's Health. AB - Physical activity means any form of body movement that is associated with certain metabolic demands. At the same time, physical activity is one of the most important steps in the maintenance, protection and improvement of health. There is strong evidence to suggest that higher levels of physical activity are associated with numerous preventive effects and therapeutic effects in the treatment of many diseases. Although they account for a larger portion of the population, physical inactivity is more often registered in women, which can be attributed to a variety of reasons--ranging from anatomical and physiological to the socio-psychological. The present paper discusses some of the most important benefits associated with physical activity in women, to encourage their greater participation in various forms of physical activity. PMID- 26434030 TI - Evidence-Based Practice: Share the Spirit of Inquiry. PMID- 26434031 TI - It's Time to Recognize APRN Practice Nationally. PMID- 26434032 TI - The Gluten-Free Frenzy: Fad or Fitting? AB - Although the gluten-free diet has been recognized as therapeutic for individuals suffering from celiac disease, it has been promoted recently for other indications, such as autism, chronic fatigue syn- drome, and irritable bowel syndrome, or simply as a healthy dietary choice for anyone. The basics of the gluten-free diet are explored, with evidence-based indications and nursing implications when patients choose gluten-free. PMID- 26434033 TI - Sensitivity and Specificity of a Nurse Dysphagia Screen in Stroke Patients. AB - PURPOSE: To determine how well an institutionally developed nurse dysphagia screening tool correctly identified the presence (sensitivity) or absence (specificity) of dysphagia in patients following acute stroke. METHODS: A method comparison design was used to compare results of the Nurse Dysphagia Screen to the dysphagia evaluation by a speech and language pathologist (SLP). Each newly diagnosed participant served as his or her control, with both dysphagia evaluations (nurse, SLP) occurring within 2 hours of each other. Sensitivity and specificity of the Nurse Dysphagia Screen was calculated using standard formulas. RESULTS: For 49 patients evaluated following stroke, average age was 71.7 (SD +/- 13.5). Twenty-five subjects were female and 24 were male. The majority of the participants had strokes identified as ischemic in origin (n=35). The SLP found 18 (37%) participants had a positive dysphagia assessment. The Nurse Dysphagia Screen was positive in 16 of 18 participants screened positive by SLP, resulting in some type of dietary restriction. The Nurse Dysphagia Screen was negative in 28 of the 31 patients screened as negative by SLP. Sensitivity and specificity of the Nurse Dysphagia Screen were 89% and 90%, respectively. CONCLUSIONS: An easy to-use, institutionally developed nurse dysphagia screening tool successfully identified patients with swallowing difficulties after stroke later diagnosed by SLP. PMID- 26434034 TI - 'I'm Not Calling Him!': Disruptive Physician Behavior in the Acute Care Setting. AB - Results of a qualitative study of the experience of 15 acute care nurses with disruptive physician behavior and its impact on communication are reported. Findings will help educators and leaders prepare nurses by coaching and educating them on the importance of communication and patient advocacy. PMID- 26434035 TI - Is Nursing Care Missed? A Comparative Study of Three North Carolina Hospitals. AB - Results of a survey measuring frequency, types, and reasons for missed care at three acute care hospitals in North Carolina are described. Results also are compared to those of a previous, similar study in the midwestern United States. PMID- 26434036 TI - Use of a Soft Silicone Foam Dressing to Change the Trajectory of Destruction Associated with Suspected Deep Tissue Pressure Ulcers. AB - PURPOSE: To explore the evolution of suspected deep tissue injury (sDTI) pressure ulcers and identify the role of early identification and intervention in hindering tissue destruction. In contrast to previously published evidence, the foundational research identified a significant trend of sDTI recovery which warranted further analysis. SUBJECTS AND SETTINGS: A single-site, 24-month retrospective, IRB-approved study evaluated 77 adult (age 18 or older) hospitalized subjects with 128 wound care nurse-identified sDTIs over the course of 1 day to 14 weeks for 377 encounters. METHODS: Data from a 24-month period (2010-2012) were analyzed during the primary study. In addition to demographics, the evolution process including site, initial presentation, measurements, tissue consistency, and treatment, were assessed. In response to findings of significant sDTI recovery, a secondary in-depth analysis focused on commonalities and variables for clarity of their contribution to the isolated improved patient outcomes. RESULTS: In addition to clearer delineation of demographics, co-morbid conditions, and evolutionary patterns, the researcher identified patient outcomes in stark contrast to those previously published in the literature. A significant outcome of resolution of sDTI pressure ulcers was observed. Upon further review, the role of absorbent soft silicone, multi-layer, self-adherent bordered foam (Mepilex) in these outcomes was elucidated clearly. PMID- 26434037 TI - Postoperative Complications and Emergency Care for Patients Following Bariatric Surgery. AB - Evidence-based practice for multiple types of bariatric surgeries is addressed, along with complications, signs and symptoms of a postoperative emergency with the correct course of action, and general postoperative care. PMID- 26434038 TI - Exploration of Nurse Practices and Attitudes Related to Postoperative Vital Signs. AB - Analysis of surgical nurses' attitudes toward postoperative vital sign (VS) assessment found tradition and ritual rather than research continue to drive postoperative VS assessment practices. Recommendations for practice, education, and research are made based on these findings. PMID- 26434039 TI - Postoperative Delirium Prevention in the Older Adult: An Evidence-Based Process Improvement Project. AB - Postoperative delirium is a major complication in hospitalized older adults. Implementation of a screening tool and evidence-based delirium-prevention protocol on a surgical unit increased nurses' knowledge regarding delirium, increased identification of delirium, and produced medical treatment alterations leading to positive patient outcomes. PMID- 26434041 TI - Nursing Implications of Research. PMID- 26434040 TI - Coping with Death and Dying in Afghanistan: A Reflection. PMID- 26434042 TI - The New 'Code of Ethics for Nurses With Interpretive Statements' (2015): Practical Clinical Application, Part I. PMID- 26434043 TI - Inflammatory Bowel Disease: Caring for a Patient with Crohn's Disease. AB - The Medical-Surgical Nursing Certification Board (MSNCB) encourages certification for all registered nurses who provide care in a medical-surgical setting. Initial certification is achieved through successful testing by written examination. The certification examination is based on Benner's Nursing Model. Questions on the examination fall within the seven domains of nursing practice: Helping Role, Teaching-Coaching Function, Diagnostic and Patient Monitoring, Effective Management of Rapidly Changing Situations, Administering and Monitoring Therapeutic Interventions and Regimens, Monitoring and Ensuring the Quality of Health Care Practices, and Organizational and Work Role Competencies. The examination is designed to assess comprehensive knowledge of medical-surgical nursing. The medical-surgical practitioner must understand diseases, diagnoses, and treatment modalities to function as a caregiver and educator. The topic of this article is a part of the comprehensive examination given by MSNCB. The following scenario and questions offer an example that potential certificants may use to test their knowledge. For more information about MSNCB, visit www.amsn.org/certification. PMID- 26434044 TI - Nursing Care Considerations: The Epidural Catheter. PMID- 26434045 TI - The Voice--of Email. PMID- 26434046 TI - Promoting Success in Self-Injection: Listening to Patients. PMID- 26434048 TI - HealthyNurse Healthy Work Environment = Your Health, Safety, and Wellness. PMID- 26434047 TI - The Influence of Health Care Literacy on the Use of PHRs among Older Adults. PMID- 26434049 TI - Ohio's Safe Nurse Staffing Law. PMID- 26434050 TI - Social Media in Healthcare: Safeguarding Healthcare Staff. PMID- 26434052 TI - HSDM Awarded Major NIH Grant in Pain-Management Education. PMID- 26434053 TI - A New Way to Learn Clinical Skills. PMID- 26434054 TI - HSDM at the National Oral Health Conference. PMID- 26434055 TI - FROM THE DEAN. PMID- 26434056 TI - Class of '44 Members Studied Together, Went to War Together. PMID- 26434057 TI - Mortimer Lorber, DMD '50, MD '52. PMID- 26434058 TI - History of Oral and Maxillofacial Surgery. PMID- 26434059 TI - Making Stem Cells from Mature Cells. PMID- 26434060 TI - HSDM Research Targets Osteoarthritis. PMID- 26434061 TI - The Electronic Health Record as Research Tool. PMID- 26434062 TI - Enhancing Advanced Graduate Education. PMID- 26434063 TI - To Give and Receive. PMID- 26434064 TI - Operation Mouthguard. PMID- 26434066 TI - From the Dean. PMID- 26434065 TI - Biotechnology in Developing-Country Health Care. PMID- 26434067 TI - The Goodman Family Embodies Philanthropy. PMID- 26434068 TI - John and Peggy Rusnock Give Back. PMID- 26434069 TI - Aleksander Iofin, DMD '01: Gratitude for a "Second Life". PMID- 26434070 TI - Lorne Golub, PD '68, Brings Dental Research into Medicine. PMID- 26434071 TI - HSDM Students Protect Young Athletes' Mouths. PMID- 26434072 TI - Delivering Oral Health Care in Colombia. PMID- 26434073 TI - Providing Care in Ecuador. PMID- 26434074 TI - Research Toward a "Fat-Busting Pill". PMID- 26434075 TI - President's Message. PMID- 26434076 TI - Rapidly Progressive Seeding of a Community Acquired Pathogen in an Immune competent Host--End Organ Damage from Head to Bone. AB - This report describes a 64-years-old male patient that presented to our hospital with a chief complaint of acute worsening of his usual chronic lower back pain, progressive weakness in lower extremities and subjective fevers at home. Spine CT failed to demonstrate any infectious foci but showed partially visualized lung cavitary lesion and renal pole abnormalities. Blood cultures grew methicillin sensitive Staphylococcus Aureus (MSSA). Transthoracic echocardiogram (TTE) showed no signs of infective endocarditis (IE). Later, the patient experienced an acute deterioration on clinical status and examination showed development of a new murmur. He also developed new hemiparesis with up-going babinski reflex. A head MRI showed multiple infarcts. MRI spine displayed osteomyelitis at T12-L1. Cerebro-spinal fluid was positive for meningitis. A transesophageal echocardiogram (TEE) was performed demonstrating new severe mitral and mild tricuspid regurgitations with a definitive 1.5 cm mobile vegetation on posterior mitral leaflet. We present is a very interesting case of a rapidly progressive MSSA infection. MSSA meningitis is a rare disease; there are only few reported cases in the literature to date. We describe a case of MSSA bacteremia, of questionable source, that resulted in MSSA endocarditis affecting right and left heart in a patient who did not have a history of intravenous drug use (IVDU) or immunosuppression. The case was complicated by septic emboli to systemic circulation involving the kidneys, vertebral spine (osteomyelitis), lungs and brain with consequent meningitis and stroke. Even when MSSA infections are well known, to our knowledge there are no previous case reports describing such an acute-simultaneous-manifestation of multi-end-organ failure, including meningitis and stroke. These latter are rarely reported, even individually. PMID- 26434077 TI - Knee avascular necrosis in HIV patient. PMID- 26434078 TI - Endoscopic- Assisted Trephination approach for repair of Frontal Sinus posterior wall fracture in a Child. AB - A 9 year-old male sustained multiple maxillofacial fractures after falling from a two-store building. Frontal sinuses suffered a bilateral non-displaced linear fractures extending into the anterior and posterior walls. Magnetic resonance imaging (MRI) at this time showed a small encephalocele extending into the right frontal sinus. Operative repair was performed using an Endoscopic-Assisted Trephination approach. PMID- 26434079 TI - Endoscopic Resection of a Posterior Nasal Septum Pleomorphic Adenoma. AB - A 60 year-old female presented to our clinic with a two-year history of progressive nasal obstruction and one isolated episode of epistaxis that did not respond to medical treatment. Endoscopic evaluation revealed roundish, dumbbell shape, smooth-surfaced, submucosal mass with prominent vessels of approximately 2 cm in the posterior nasal septum,. A paranasal CT scan revealed a well circumscribed oval shape mass (1.7 cm x 1.6 x 1.5 cm) arising from the posterior border of the bony nasal septum. The tumor was removed en-bloc with 1-centimeter free margins confirmed by intra-operative frozen sections through a completely endoscopic approach. Pathology results confirmed the diagnosis of a pleomorphic adenoma. PMID- 26434080 TI - Isolated Xanthoma Of The Sphenoid Sinus: A Rare Presentation. AB - OBJECTIVE: To present the first case in the English literature of a sphenoid xanthoma. METHODS: Case Report DISCUSSION: A 36 year-old Hispanic female with past medical history of Hashimoto's hypothyroidism and family history of hyperlipidemia that presented with a 1-year history of sporadic left sided epistaxis. A paranasal sinus Computed Tomography (CT) was performed revealing a soft tissue lesion infiltrating the left sphenoid sinus. Patient underwent endoscopic sinus sphenoidotomy with intraoperative findings of a yellow-tan, friable soft tissue mass filling the left sphenoid sinus. Biopsies were taken which exhibited histologically findings consistent with a xanthoma. CONCLUSION: In a patient with hyperlipidemia isolated lesions on paransasal sinuses can be related to xanthoma formation. PMID- 26434082 TI - Case Report: Prothesis-patient mismatch after aortic valve replacement. AB - Valve replacement is the standard surgical treatment of diseased valves that cannot be repaired. The main goal of replacement is to exchange the diseased valve with one that has the engineering and hemodynamics as close as possible to the disease free native valve. However due to mechanical and fluid dynamic constraints all prosthetic heart valves (PHVs) are smaller than normal and thus are inherently stenotic. This represents a challenge when it comes time to replace a valve. The correct valve with the correct and matching profile has to be selected before the procedure to avoid possible complications. It is well recognized that patients are also prone to patient-prosthesis mismatch at long term which could have consequences in the clinical outcomes (1). The evaluation of patient-prosthesis mismatch (PPM) has not been sufficiently emphasized in common practice. Failure to recognize this fact may lead to significant hemodynamic impairment and worsening of the clinical status over the time. Making efforts to identifying patients at risk may decrease the prevalence of PPM, the economic impact to our health system, the morbidity and mortality involved in these cases as well as creates efforts to standardized pre-operative protocols to minimized risk of PPM. We present a case of a 78 years old male patient who underwent aortic valve replacement due severe aortic stenosis, afterwards his clinical course got complicated with several admissions for shortness of breath and decompensated congestive heart failure (CHF). PMID- 26434081 TI - Manati Medical Center Sepsis Management Epidemiological Study. AB - Sepsis is the combination of infection and physiological changes known as the systemic inflammatory response syndrome. There have been improvements in mortality rates and outcomes of septic patients based on "Surviving Sepsis Campaign" guidelines. Current management of sepsis at our Institution follows no specific mandatory protocols. This study aimed to verify the incidence and outcome of sepsis in Manati Medical Center, Puerto Rico. An observational retrospective study was conducted. All the Emergency Department admissions from May 1/ to October 31/ 2013 were screened for sepsis per ICD-9 code. For all included patients, demographic and clinical data at ED admission were collected. During this period 8931 patients were admitted and 148 met criteria for sepsis and related conditions. The overall mortality rate was 43.91%. Mortality increased with age, from 10.52% among <= 44 years old to 68.75% in those >= 85 years old. The main infection sources were respiratory (32.66%) and urinary tract (24.62%). Mean age among non-survivors was 10.8 years higher than the survivor group (95% Cl 5.2-1 6.5, p < 0.05). Multivariate analysis showed an increased fatality rate associated to severity of sepsis (HR 1.33; 95% Cl; 1.03-1.72, p = 0.02) and the APACHE2 score (HR 1.05; 95% Cl, 1.01-1.09 p = 0.03). Our data suggests that sepsis is an important problem to consider. We strongly encourage an institutional standardized protocol to diminish the mortality impact. Our results will allow adequate preventive strategies to improve early diagnosis, mortality rates and outcomes of septic patients. PMID- 26434083 TI - Surviving Sepsis Puerto Rico: A Call For Action. AB - There are 1.7 million sepsis-related hospitalizations each year making it the sixth most common cause for hospitalization in the United States. Not only are this hospitalizations common, they are expensive to our medical system with $15.3 billion spent yearly (3) and hospitalizations lasting 75% longer than for other conditions. In 2001, Rivers et al published in the NEJM the results of his study "Early Goal Directed Therapy (EGDT) in The Treatment of Severe Sepsis and Septic Shock". EGDT demonstrated a 16.5% decrease in mortality in septic patients (4). In 2002 the Surviving Sepsis Campaign began as a collaboration between the Society of Critical Care Medicine and European Society of Intensive Care Medicine with goals of reducing worldwide sepsis related mortality by 25% in the next 5 years. Despite the proven benefit of early identification and management, knowledge regarding the topic in Puerto Rico remains scarce. In a study performed in PR by Fernandez et al. in 2006, only an alarming 31.4% of doctors from different specialties correctly identified SIRS criteria. Our goal is to educate physicians about the importance of early identification and treatment of the septic patient. A campaign to increase awareness and improve care is essential and we propose treatment protocols for our Puerto Rican hospitals to help reduce morbidity, mortality, length of stay and costs. PMID- 26434084 TI - Dengue Fever: A Rare Cause Of Immune Thrombocytopenia. AB - Immune thrombocytopenia (ITP) is a rare autoimmune disorder characterized by low platelet count and skin-mucosal bleeding. In adults it is usually idiopathic and may have a chronic onset, while in children it is usually acute following a viral illness. Dengue has been rarely reported as a cause of ITP. We report a case of a young adult woman that presented with acute ITP following a dengue virus infection. PMID- 26434085 TI - Metabolic Correction as a tool to improve diabetes type 2 management. AB - Diabetes Mellitus type 2 (DM2) is a metabolic disease that develops by a decrease in sensitivity of insulin receptors as an effect of the disruption certain metabolic functions in the processing of glucose. DM2 patients have, uncontrolled glucose levels, and commonly have problems with obesity and cardiovascular disease. Patients are treated with standard diet, insulin, diabetic oral agents and antihypertensive drugs, but this approach does not completely stops tissue deterioration since it does not address the metabolic root of the disease. Metabolic correction is proposed as a suitable adjunct treatment to improve clinical outcomes. Metabolic correction is based on diet modification, proper hydration and scientific supplementation directed to improve cellular biochemistry and metabolic efficiency. In addition, other possible benefits may include reduction in medication use, disease complications and medical costs. To test the results of a metabolic correction program, 25 patients with DM2 participated in an education program about adequate food consumption that promoted control of blood glucose levels. Anthropometric measurements and blood tests were performed during a 13 week program based on a low carbohydrate diet, proper hydration and magnesium supplementation. The metabolic correction program implemented by a proprietary educational system resulted in significant reductions in glucose, triglycerides, cholesterol, weight and waist circumference. Improvements in these values could represent an important reduction of coronary heart disease risk factors as well as other chronic degenerative diseases. In addition there was medication dosage reduction in one or more medications in 21 of the 25 participating patients, which suggest that the program has the potential to improve health outcomes and reduce health care costs. PMID- 26434086 TI - [Metabolic correction: a biochemical option against diseases]. AB - Human development and its physiology depends on a number of complex biochemical body processes, many of which are interactive and codependent. The speed and the degree in which many physiological reactions are completed depend on enzyme activity, which in turn depends on the bioavailability of co-factors and micronutrients such as vitamins and minerals. To achieve a healthy physiological state, organism need that biochemical reactions occur in a controlled and specific way at a particular speed and level or grade fully completed. To achieve this, is required an optimal metabolic balance. Factors such as, a particular genetic composition, inadequate dietary consumption patterns, traumas, diseases, toxins and environmental stress all of these factors rising demands for nutrients in order to obtain optimal metabolic balance. Metabolic correction is a biochemical and physiological concept that explains how improvements in cellular biochemistry of an organism can help the body achieve metabolic and physiological optimization. We summarize the contribution of several pioneers in understanding the role of micronutrients in health management. The concept of metabolic correction is becoming a significant term due to the presence of genetic variants that affect the speed of reactions of enzymes, causing metabolic alterations that enhance or promote the state/development of multiple diseases. Decline in the nutritional value of the food we eat, the increase in demand for certain nutrients caused by normal development, diseases and medications induce, usually, nutrients consumption. These nutritional deficiencies and insufficiencies are causing massive economic costs due to increased morbidity and mortality in our society. In summary, metabolic correction improves the enzymatic function, which favors the physiological normal functions, thus, contributing to improving health and the welfare of the human being. The purpose of this paper is to describe and introduce the concept of optimal metabolic correction as a functional cost effective mechanism against disease, in addition, to contribute to diseases prevention and regeneration of the body and health. PMID- 26434087 TI - Brugada Syndrome in Puerto Rico: a Case Series. AB - Brugada syndrome (BrS) is characterized by ST-segment changes in the right precordial ECG leads and a high incidence of sudden death in patients with structurally normal hearts. Life-threatening ventricular arrhythmias are the hallmark of Brugada syndrome. The incidence and prevalence of BrS in Puerto Rico, to our knowledge, has never been studied and there is only one case report of BrS in Puerto Rico in the literature [1]. We present 3 cases of BrS in Puerto Rican patients who presented to our institution with syncope and review the literature. PMID- 26434088 TI - 23 y/o female with dysphagia--Evaluation, intervention and resolution of symptoms in the Psychiatry consultation setting. AB - Dysphagia is a symptom shared by many medical and psychiatric conditions. A thorough Psychiatric evaluation could rule in a functional or psychological etiology. If a Psychological etiology is identified, a psychodynamic formulation could help the consultation psychiatrist clarify the origin of the symptom and provide a better explanation to the patient and medical team, resulting in improved care by prevention of unnecessary medical interventions, improvement of symptoms and individualization of the treatment. PMID- 26434089 TI - Functional Brain Imaging in Cornelia de Lange Syndrome: Case Report and Literature review. AB - Functional brain imaging with brain single photon emission computer tomography (Brain SPECT) has been used for many years in the evaluation of multiple neuro degenerative and neuro-developmental disorders. Brain SPECT is a nuclear medicine tomographic study performed with a lipophilic radiopharmaceutical labeled with 99mTc-pertechnetate. It is a cerebral perfusion agent that depicts the global and regional perfusion patterns in the cortical gray matter and subcortical structures. Cornelia de Lange syndrome (CdLS) is a rare neuro-developmental and genetic condition, associated to several malformations. There are a limited number of cases reported in the medical literature and few of them report neuro radiological and/or neuro-pathologic abnormalities. We report a case of a 15 year old patient, clinically diagnosed at birth with CdLS, who presents limited anatomical findings on Computed Tomography and Magnetic Resonance Imaging. To the best of our knowledge, this is the first report of the Brain SPECT findings in this syndrome. PMID- 26434090 TI - Does Injection Site Matter? A Randomized Controlled Trial to Evaluate Different Entry Site Efficacy of Knee Intra-articular Injections. AB - BACKGROUND: Complaints of knee pain secondary to early osteoarthritis may account for up to 30% of visits to primary care physicians. Due to the proposed inflammatory changes in early osteoarthritis, intra-articular injections of corticosteroids (IACS) have been considered as an option for disease progression modification, pain control, and improvement of function. However, some studies have suggested poor accuracy rates of IA injections depending on the entry site chosen. It is therefore the aim of this study to evaluate the efficacy of IA knee corticosteroid injection in reducing pain and improving function in patients with early osteoarthritis and whether the low accuracy rates reported with the Anterolateral joint line injection site translate to worse functional and pain outcome measures as compared to Suprapatellar lateral injections. MATERIALS AND METHODS: The study was carried out as an open-label, randomized controlled trial with 60 sequential patients recruited. Simple randomization separated groups into anterolateral joint line or suprapatellar lateral injection sites. Improvements were measured with WOMAC and VAS scores after injection of Lidocaine and steroid solution. RESULTS: Patients receiving IACS injections had a measurable improvement in self-reported outcomes as evidenced by standard deviation change in WOMAC and VAS scores. The majority of patients had a clinically significant improvement in VAS scores as compared to their initial measures with a notable amount of patients improving significantly as well on their WOMAC scores, irrespective of the injection site chosen. CONCLUSIONS: We have therefore continued the use of palpation-guided intra-articular knee injections in an effort to reduce costs as compared to other injection modalities with positive results in our osteoarthritis patients. PMID- 26434092 TI - Acquired Von Willebrand Syndrome In Aortic Stenosis: Case Report And Review. AB - We present a case of a 61 year old man who presented with a 3 week history of easy bruising and ecchymoses in both thighs and right arm without significant trauma. Physical exam was remarkable for oozing gums, diminished second heart sound, a systolic ejection murmur at the aortic position with radiation to carotids, and delayed pulses. Laboratories were remarkable for iron deficiency anemia. Echocardiogram was consistent with severe aortic stenosis. Colonoscopy revealed several arteriovenous malformations throughout the colon. There is an association between severe aortic stenosis and gastrointestinal bleeding. The pathogenesis of Heyde's Syndrome involves iron deficiency anemia due to acquired von Willebrand factor (vWF) deficiency and ultimately gastrointestinal angiodysplasia. Correct diagnosis and management warrants a multidisciplinary approach. PMID- 26434091 TI - Use of Screening Tests for Colorectal Cancer Among Gynecologists in Puerto Rico. AB - OBJECTIVE: To determine the use of screening tests for colorectal cancer (CRC) among Gynecologists in Puerto Rico. This study evaluates the screening practices used by Gynecologists in PR to diagnose CRC and adherence to screening guidelines. METHODS: A self-administered anonymous questionnaire was mailed to 440 practicing gynecologists through the College of Physicians and Surgeons of PR. The questionnaire included general and specific questions. RESULTS: Response rate was 23.2% (102/440). Of this group of gynecologists, 77.5% referred screening patients, while 22.5% did not. The majority (28.4%) use Fecal Occult Blood Test (FOBT) as a first screening test, while 27.5% use Colonoscopy. Screening is started by 49% at age 50. Only 7% stop screening at 75 years and 31% never stop screening. CRC Screening performed by participants were: 35% screen annually, 6% screen 2-3 years, 10% screen every 5 years, 6% screen every 10 years and 6% screen 5-10 years. Data for CRC Screening reveals 7% gynecologists comply with all the guidelines; 49% comply with the recommendations regarding the start screening age and 7% stop screening as per guidelines. CONCLUSION: The recommendations are not followed by most of the gynecologists in PR that participated in the study, Further research should be directed towards the reasons for not complying and how to educatethemedical population to achieve adequate screening in the PR female population. PMID- 26434093 TI - Do We Need Hormonal Screening In Patients With Subcentimeter Pituitary Microadenomas? AB - A 54-year-old woman came to our endocrinology clinics presenting with upper and lower extremity paresthesia, salt cravings, episodes of hypotension, fatigue and a long term history of depression. Physical exam was unremarkable. Cervical and brain MRI ordered by her neurologist three years ago revealed sella and pituitary normal in size, stable very small 3 mm pituitary incidentaloma and mild disc bulging. Basal pituitary hormonal screening showed low cortisol and ACTH levels. Insulin Tolerance Test and Glucagon Stimulation Test confirmed secondary ACTH deficiency with concomitant GH deficiency. In spite of medical counseling the patient refused glucocorticoid replacement. Due to the non-specific symptoms of this condition it remains a challenge to be diagnosed by clinicians. In conclusion: Our case shows that hormonal deficiencies may occur in small tumors less than 6 mm. PMID- 26434094 TI - Lack of training and Comfort level with Provision of Palliative Care in Puerto Rican Emergency Departments. AB - OBJECTIVE: Although many institutions in the United States have incorporated palliative care practices in their emergency departments, very little has occurred in Puerto Rico. Information regarding palliative care training of emergency medicine physicians in Puerto Rico is unclear and most physicians have poor or no access to palliative care services for their patients. This study explores the perceptions and barriers encountered by practicing emergency physicians in providing palliative care in Puerto Rican Emergency Departments. METHODS: A survey was administered to physicians attending the American College of Emergency Physicians Puerto Rico Chapter annual Convention Attending physicians and residents from the University of Puerto Rico School of Medicine validated the survey tool via a "content validity" approach. Participants were asked to respond to Likert scaled statements with options that ranged from "Strongly Agree" to "Strongly Disagree". The statements addressed physician comfort level with provision of palliative care and discussion of end of life issues, as well as barriers encountered by providers such as time constraints, fear of lawsuits, and lack of access to specialists among others. RESULTS: Of the 85 physicians at the convention 59 provided surveys available for review for a response rate of 70%. Of those surveyed, 35% reported feeling some level of discomfort at providing palliative care in the ED and 39.6% agreed or strongly agreed that their lack of training in palliative care affects their ability to provide this service. In addition, 81% lack access to palliative care specialists/teams in the emergency department. However, 82.8% agreed or strongly agreed that palliative care is an important competence for emergency physicians. CONCLUSIONS: Despite recognizing palliative care as an important competence, emergency physicians in Puerto Rico reported insufficiencies in training, decreased level of comfort, and lack of access to specialists in palliative care. Efforts to enhance physician training and provide palliative care resources must be pursued in order to improve the quality of care given to patients visiting Puerto Rican Emergency departments. PMID- 26434095 TI - Are Young Adults with ADHD Undertreated? PMID- 26434096 TI - [Glutamic acid as a universal extracellular signal]. AB - The prevailing view is that both glutamic (Glu) and gamma-aminobutyric (GABA) acids play a role as an amino acid neurotransmitter released from neurons. However, little attention has been paid to the possible expression and functionality of signaling machineries required for amino acidergic neurotransmission in cells other than central neurons. In line with our first demonstration of the presence of Glu receptors outside the brain, in this review I will outline our recent findings accumulated since then on the physiological and pathological significance of neuronal amino acids as an extracellular signal essential for homeostasis in a variety of phenotypic cells. In undifferentiated neural progenitor cells, for instance, functional expression is seen with different signaling machineries used for glutamatergic and GABAergic neurotransmission in neurons. Moreover, Glu plays a role in mechanisms underlying suppression of proliferation for self-replication in undifferentiated mesenchymal stem cells. There is more accumulating evidence for neuronal amino acids playing a role as an extracellular autocrine or paracrine signal commonly used in different phenotypic cells. Evaluation of drugs currently used could be thus beneficial for the efficient prophylaxis and/or the therapy of a variety of diseases relevant to disturbance of amino acid signaling in diverse organs. PMID- 26434097 TI - [Pain and emotional dysregulation: Cellular memory due to pain]. AB - Genetic factors are involved in determinants for the risk of psychiatric disorders, and neurological and neurodegenerative diseases. Chronic pain stimuli and intense pain have effects at a cellular and/or gene expression level, and will eventually induce "cellular memory due to pain", which means that tissue damage, even if only transient, can elicit epigenetically abnormal transcription/translation and post-translational modification in related cells depending on the degree or kind of injury or associated conditions. Such cell memory/transformation due to pain can cause an abnormality in a fundamental intracellular response, such as a change in the three-dimensional structure of DNA, transcription, or translation. On the other hand, pain is a multidimensional experience with sensory-discriminative and motivational-affective components. Recent human brain imaging studies have examined differences in activity in the nucleus accumbens between controls and patients with chronic pain, and have revealed that the nucleus accumbens plays a role in predicting the value of a noxious stimulus and its offset, and in the consequent changes in the motivational state. In this review, we provide a very brief overview of a comprehensive understanding of chronic pain associated with emotional dysregulation due to transcriptional regulation, epigenetic modification and miRNA regulation. PMID- 26434098 TI - [Controlling sleep/wakefulness using optogenetics]. AB - Optogenetics is a recently developed experimental technique to control the activity of neurons using light. Optogenetics shows its power to reveal the physiological role of specific neural circuits in the brain. In particular, manipulation of a specific type of neurons using optogenetics with high accuracy timing enables us to analyze causality between neural activity and initiation of animal behaviors. However, to manipulate the activity of specific neurons in vivo, there are two critical steps to succeed in manipulation of the neural activity and control of the behavior of individual animals. The first step is an adequate number of molecules of light-activated protein that has to be expressed in the cell membrane of the neurons of interest. The second step is the optical system to illuminate the targeted neurons with enough intensity of light to activate the light-activated protein. We applied optogenetics to hypothalamic peptidergic neurons such as orexin/hypocretin neurons or melanin concentrating hormone (MCH) neurons. These neurons are implicated in sleep/wakefulness regulation. In this mini review, I will show the regulatory mechanism of sleep/wakefulness by these neurons using optogenetics. PMID- 26434099 TI - [Animals' clever adaptation strategy for seasonal changes in environment]. AB - Organisms living outside of tropical zones experience seasonal changes in environment. Organisms are using day length as a calendar to change their physiology and behavior such as seasonal breeding, hibernation, migration, and molting. A comparative biology approach revealed underlying mechanisms of vertebrate seasonal reproduction. Here we review the current understanding of vertebrate seasonal reproduction. We Aso describe the involvement of tissue specific post-translational modification in functional diversification of a hormone. PMID- 26434100 TI - Mid-term Results of Endovascular Treatment for Infrarenal Aortic Stenosis and Occlusion. AB - BACKGROUND: Focal stenosis or occlusion of the infrarenal aorta is rare, and treatment is usually conventional bypass or endarterectomy. However, endovascular treatment has advanced in recent years. The purpose of this retrospective study is to report the results of primary stenting for focal infrarenal aortic occlusive disease and clarify the usefulness of endovascular treatment. METHODS: This study includes 6 consecutive patients (3 men, 3 women; mean age, 59.3 years) with infrarenal aortic stenosis or occlusion who underwent endovascular intervention at our hospital between April 2009 and February 2014. All patients had bilateral intermittent claudication. The mean preoperative ankle-brachial index (ABI) showed a slight to moderate decrease: right 0.668 and left 0.636. The mean lesion site length was 12.5 mm, the percent stenosis was 90.7%, and calcification was present in 3 patients. Primary stenting was performed in all patients. The stent selected was generally a self-expanding stent (SES). For patients with severe calcification, the stent selected was a balloon-expandable stent (BES). RESULTS: Four patients received an SES and two patients received a BES. The technical success rate was 100%, no complications occurred, and the mean pressure gradient disappeared or decreased. Symptoms resolved in all patients and the postoperative ABI improved: right 0.923 and left 0.968. During a mean follow up period of 27 months, there were no recurrent symptoms and no restenosis on CT angiography. CONCLUSIONS: Endovascular treatment should be considered as a first line treatment for focal infrarenal aortic stenosis and occlusion. PMID- 26434101 TI - Clinical Characteristics of Late Gadolinium Enhancement in Patients with Cardiac Sarcoidosis. AB - BACKGROUND: The presence of cardiac involvement in sarcoidosis, a multisystem granulomatous disease of unknown etiology, is associated with very poor prognosis. Therefore, early detection of cardiac sarcoidosis (C-sar) is very important for effective treatment. Recently, the value of late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR), which allows visualization of even minute amounts of myocardial damage, has been emphasized in diagnosing C sar. Although the presence of LGE has been added as a minor criterion for diagnosing C-sar in the most recent Japan Ministry of Health and Welfare (JMHW) guidelines, its clinical utility remains unknown. METHODS: A total of 17 patients with biopsy-proven extracardiac sarcoidosis, who underwent CMR and examinations using a sufficient number of modalities to diagnose or exclude C-sar in accordance with the JMHW diagnostic criteria, were retrospectively enrolled in this study. Among these 17 patients, 7 patients were diagnosed with C-sar and 10 with non-C-sar. We investigated the clinical performance of LGE in the detection of cardiac involvement, compared the distribution of LGE with perfusion defects of iodine-123-labeled 15-(p-iodophenyl)-3R,S-methyl pentadecanoic acid (BMIPP) or thallium-201 (201Tl) scintigraphy, and evaluated the prognostic value of LGE on CMR in identifying adverse clinical events. RESULTS: All patients diagnosed with C-sar were positive for LGE and all diagnosed with non-C-sar patients were negative. Evaluation of LGE revealed a broader range of abnormalities than the evaluation of the defects shown by either BMIPP or 201Tl scintigraphy. All adverse events occurred in the C-sar patients with LGE. CONCLUSIONS: This study showed that LGE is useful for the detection of cardiac involvement, and it might be a promising tool for determining the prognosis of patients with biopsy-proven extracardiac sarcoidosis. PMID- 26434102 TI - Vascular Functional and Morphological Alterations in Smokers during Varenicline Therapy. AB - BACKGROUND: Varenicline has been reported to achieve high rates of smoking cessation. It remains undetermined whether varenicline therapy improves vascular function in smokers. METHODS: Consecutive Seventy-two smokers (age 57 +/- 12 years) who succeeded in complete smoking cessation and 46 normal healthy volunteers (age 24 +/- 3 years) with no cardiovascular risk factors were enrolled into this study. Vascular function and structure were assessed by flow-mediated dilation (FMD), nitroglycerin-induced vasodilation, and brachial artery intima media thickness (baIMT) at baseline and 20 weeks after the initiation of varenicline therapy in smokers. FMD and baIMT were measured simultaneously using a semi-automatic vessel wall-tracking software program. 75 MUg dose of a nitroglycerin tablet were sublingually administered for the nitroglycerin-induced vasodilation measurement. RESULTS: Exhaled-carbon monoxide concentration decreased significantly (20.0 +/- 11.1 ppm at baseline vs 1.9 +/- 1.5 ppm after 20 weeks, p < 0.001). FMD was significantly improved after 20 weeks (4.09% +/- 1.83% at baseline vs 4.77% +/- 2.33% after 20 weeks, p = 0.010), whereas nitroglycerin-induced vasodilation and baIMT were not significantly changed. CONCLUSIONS: Smoking cessation with varenicline therapy significantly increased FMD without significant changes of nitroglycerin-induced vasodilation or baIMT from baseline to 20 weeks. It appears to improve vascular function in smokers, which depends on endothelial function rather than on vascular smooth muscle function or changes in vascular structure. PMID- 26434103 TI - Percutaneous Carbon Dioxide Treatment Using a Gas Mist Generator Attenuates the Development of Right Ventricular Dysfunction in Monocrotaline-induced Pulmonary Hypertensive Rats. AB - BACKGROUND: Highly concentrated carbon dioxide (GO2) is useful for treating ischemic diseases. Therefore, we investigated whether treatment with a few micrometers of CO2 molecules, atomized by two fluid nozzles (CO2 mist), could attenuate the development of right ventricular (RV) dysfunction in pulmonary hypertensive rats. METHODS: Six-week-old male Wistar rats were divided into three groups: one that received injected saline; a second that received subcutaneous monocrotaline (MCT; 60 mg/kg) without treatment (PH-UT) group; and a third that received MCT with CO2 mist treatment (PH-CM) after MCT administration. The lower body of each rat was encased in a polyethylene bag, filled with the designated gaseous agent via a gas mist generator, for 30 minutes daily. Hemodynamics and cardiac function were measured at 28 days after beginning MCT administration. Protein levels were measured by western blotting. RESULTS: Rats that received MCT without treatment began to die within 3-4 weeks of the initial administration. However, treatment with CO2 mist extended the survival period of rats in that group. At 28 days after MCT administration, the hemodynamic status, such as the blood pressure and heart rate, involved with left ventricular function, of rats in the PH-UT group were similar to those of rats in the PH-CM group. However, MCT induced RV weight and RV dysfunction were significantly attenuated by treatment with CO2 mist. Both RV phosphorylated endothelial nitric oxide synthase and heat shock protein 72 levels increased significantly in the PH-CM group, compared to the PH-UT group. CONCLUSIONS: Percutaneous CO2 mist therapy may alleviate RV dysfunction in patients with pulmonary hypertension. PMID- 26434104 TI - Pentraxin-3 as a Biomarker for Febrile Neutropenia in Patients with Lung Cancer. AB - BACKGROUND: Pentraxin-3 (PTX3) is a newly discovered biomarker for various inflammatory conditions. We measured plasma PTX3 levels in patients with febrile neutropenic lung cancer and examined the utility of PTX3 levels as a biomarker for febrile neutropenia. METHODS: Fourteen patients with febrile neutropenic lung cancer were enrolled in the study. In addition, 10 untreated lung cancer patients and 12 healthy adults were enrolled as a disease control group and a healthy control group, respectively. On the day of onset of febrile neutropenia (day 1) and days 3 and 7, PTX3 and C-reactive protein (CRP) levels were measured. In the control groups, PTX3 and CRP levels were measured once. RESULTS: On day 1, plasma CRP levels in febrile neutropenia during chemotherapy or chemoradiotherapy for lung cancer (FN/LC) patients (8.11 +/- 6.42 mg/dL) were significantly higher than those in healthy controls (HC) and chemotherapy/chemoradiotherapy-naive lung cancer (CN/LC) patients (p < 0.05). However, CRP levels of the CN/LC group (0.33 +/- 0.02 mg/dL) were also significantly higher than those of the HC group (0.07 +/- 0.09 mg/dL) (p < 0.05). In contrast, plasma PTX3 levels of the FN/LC group (6.14 +/- 5.28 ng/mL) were significantly higher than those of the HC and CN/LC groups on day 1 (p < 0.05), but PTX3 levels of the CN/LC group (1.60 +/- 0.64 ng/mL) were not significantly higher than those of the HC group (1.05 +/- 0.25 ng/mL). In the FN/LC group, PTX3 levels peaked immediately on day 1. CONCLUSIONS: PTX3 may be a useful biomarker for diagnosis of FN in patients with LC. PMID- 26434105 TI - C-reactive Protein is a Useful Marker for Early Prediction of Anastomotic Leakage after Esophageal Reconstruction. AB - BACKGROUND: Esophageal anastomotic leakage is one of the most fatal complications after esophagectomy and increases the hospitalization length. We aimed to identify a convenient clinical marker of anastomotic leakage in the early postoperative period. METHODS: In total, 108 patients who underwent esophagectomy were retrospectively screened, and 96 were used to validate the overall results. All 108 patients underwent physical examinations and determination of their white blood cell count, C-reactive protein level, platelet count, fibrinogen level, fibrin degradation product level, and antithrombin III level until postoperative day 6. RESULTS: Anastomotic leakage occurred in 21 of the 108 patients (median detection, 8 days). The C-reactive protein level on postoperative day 3 and fibrinogen level on postoperative day 4 in the leakage group were significantly higher than those in the nonleakage group. Receiver operating characteristic curves for detection of anastomotic leakage were constructed; the cutoff value of C-reactive protein on postoperative day 3 was 8.62 mg/dL, and that of fibrinogen on postoperative day 4 was 712 mg/dL. Anastomotic leakage occurred in 23 of the 96 patients in the validation group. There was a significant difference between the leakage and nonleakage groups when the C-reactive protein threshold on postoperative day 3 was set at 8.62 mg/dL. However, there was no difference between the groups when the fibrinogen threshold on postoperative day 4 was set at 712 mg/dL. CONCLUSIONS: The C-reactive protein level on postoperative day 3 is a valuable predictor of anastomotic leakage after esophagectomy and might allow for earlier management of this complication. PMID- 26434106 TI - Isolation of Monovalerianester A, an Inhibitor of Fat Accumulation, from Valeriana fauriei. AB - The rhizomes and roots of Valeriana fauriei were extracted with 80% aqueous ethanol. This extract was found to exhibit potent inhibitory effects on fat accumulation in 3T3-LI murine adipocytes. After several steps of chromatographic purification, we succeeded in identifying monovalerianester A as an inhibitor of fat accumulation. Thus, monovalerianester A and the crude extract of the rhizomes and roots of V. fauriei may have therapeutic potential for the treatment of obesity. PMID- 26434107 TI - Arthropod Deterrents from Artemisia pallens (Davana Oil) Components. AB - Davanone, a key sesquiterpene component of davana oil, has been synthesized in five convenient steps. Oxygenated sesquiterpenes have been linked to insect deterrent properties. Based on initial screening of davana oil, davanone and its hydroxy precursors have been generated and are being evaluated as arthropod deterrents against disease vectors. PMID- 26434108 TI - Stereoselective Synthesis of 2,15-Dihydroxycalamenene and 2-Methoxycalamenene. Determination of the Configuration of Natural 2,15-Dihydroxycalamenene. AB - The enantioselective preparation of the two diastereoisomeric forms of 2,15 dihydroxycalamelene and 2-methoxycalamenene is here described. The (7S,10R) and (7R,10R) isomers of these natural products were synthesized starting from (5R,8S) methyl-4-hydroxy-8-isopropyl-5-methyl-5,6,7,8-tetrahydronaphthalene-2-carboxylate and (5R,8R)-methyl-4-hydroxy-8-isopropyl-5-methyl-5,6,7,8-tetrahydronaphthalene-2 carboxylate, respectively, in turn preparable from (-)-menthone and (+) isomenthone. The NMR analysis of the obtained sesquiterpenes allow assigning (7R,10S) absolute configuration to the natural occurring 2,15 dihydroxycalamelene. PMID- 26434109 TI - Sesquiterpenes from the Vietnamese Marine Sponge Dysidea fragilis. AB - Two new sesquiterpenes, named dysinidins A-B (3, 4) along with two known sesquiterpenes, furodysinin lactone (1) and O-methyl urodysinin lactone (2), were isolated from the Vietnamese marine sponge Dysidea fragilis. Their structures were determined by ID- and 2D-NMR spectroscopies and HR ESI MS, as well as by comparison with reported literature data. None of compounds showed inhibitory growth of human lung cancer cell lines, A-549 and H-1975 (IC50 > 30 MUM). PMID- 26434110 TI - Vibrational Circular Dichroism Absolute Configuration of 9,12-Cyclomulin-13-ol, a Diterpene from Azorella and Laretia Species. AB - The absolute configuration of the diterpenoid 9,12-cyclomulin-13-ol (1), a constituent of Azorella and Laretia species, has been established by vibrational circular dichroism spectroscopy in combination with density functional theory calculations. The obtained normal diterpene absolute configuration confirms that of azorellanol (2), which was determined by single crystal X-ray diffraction. PMID- 26434111 TI - Ultrafine Betulin Formulation with Biocompatible Carriers Exhibiting Improved Dissolution Rate. AB - The purpose of this research was to develop new methods of increasing dissolution rate and solubility of betulin extracted from birch bark. The ultrafine formulation of betulin with polyethylene glycol and beta-glycine was obtained by freeze-drying. The rate of release of betulin from the formulation into water was significantly higher in comparison with the initial betulin sample and its composite with polyethylene glycol obtained by ball-milling. PMID- 26434112 TI - Bio-assay Guided Isolation of Anti-cancer Compounds from Anthocephalus cadamba Bark. AB - Anthocephalus cadamba, an important plant in the traditional system of medicine in India, is reported to possess anticancer activity. Guided by bio-assay tests using human colorectal (HCT116) and hepatocellular carcinoma (HepG2) cell lines, it has been shown to contain three active constituents, the triterpenoid saponins 3-O-[alpha-L-rhamnopyranosyl]-quinovic acid (1) and 3-O-[alpha-L-rhamnopyranosyl] quinovic acid 28-O-[beta-D-glucopyranosyl] ester (2), and the alkaloid cadambine (3). The structures of the isolated compounds were established using spectroscopic techniques. The isolated compounds demonstrated concentration dependent inhibition of both the cell lines, where compound 3 proved to be the most potent inhibitor of cell line HCT116 (IC50 45 +/- 4 MUg/mL) and compound 2 demonstrated maximum inhibitory activity against HepG2 cell line with an IC50 value of 89 +/- 7 MUg/mL. PMID- 26434113 TI - Damarane-type Saponins from Gynostemma longipes and their Cytotoxic Activity. AB - Two new damarane-type saponins, named gylongiposides II-III (1 and 2), along with one known compound, (23S)-3beta,20xi,21xi-trihydroxy-19-oxo-21,23-epoxydammar-24 ene 3-O-alpha-L-rhamnopyranosyl-(1-->2)-[-D-xylopyranosyl-(1-->3)]-alpha-L arabinopyranoside, were isolated from the leaves of Gynostemma longipes C.Y.Wu. Their structures were determined by 1D- and 2D-NMR and HR-ESI-MS spectra. Compounds 1-3 exhibited moderate activity against four human cancer cell lines, A 549, HT-29, OVCAR, and MCF-7, with IC50 values ranging from 9.8 +/- 2.1 to 49.6 +/- 2.6 MUM. PMID- 26434114 TI - A New C23 Steroid from the Venom of Bufo bufo gargarizans. AB - A new C23 steroid, (3beta,5beta,14beta)-methyl (3-hydroxy-14,15-epoxy-20-oxo-21 norcholan-24-oate) (1), together with four known ones (2-5), were isolated from the venom of Bufo bufo gargarizans. Their structures were elucidated on the basis of extensive spectroscopic analysis. The cytotoxicity of these compounds was also evaluated against human hepatocarcinoma HepG2 cells. Compound 3 showed significant cytotoxicity with an IC50 value of 16.8 +/- 0.7 MUM. PMID- 26434115 TI - (-)-Pentylsedinine, a New Alkaloid from the Leaves of Lobelia tupa with Agonist Activity at Nicotinic Acetylcholine Receptor. AB - Lobelia tupa, also called devil's tobacco, is a native plant from the center south of Chile which has been used by the native people of Chile as a hallucinogenic and anesthetic plant. A new piperidine alkaloid, called pentylsedinine, which comprises five carbons in the side chain, was isolated from the aerial part of L. tupa, along with lobeline and lobelanidine. The structure was established on the basis of 1D and 2D NMR spectroscopy. While lobeline is a neutral antagonist at alpha3beta2/alpha3beta4 nAChR and alpha7 nAChR, both lobelanidine and pentylsedinine act as partial agonists at nAChR. PMID- 26434116 TI - Furoquinoline Alkaloids from the Leaves of Evodia lepta as Potential Cholinesterase Inhibitors and their Molecular Docking. AB - Nine furoquinoline alkaloids (1-9) were isolated from the leaves of Evodia lepta based on bioassay-guided fractionation and chromatographic techniques. All isolates were evaluated for their cholinesterase (ChEs) inhibitory activities, in which kokusaginine (7) and melineurine (5) exhibited the highest activity toward AChE and BChE, respectively. Lineweaver-Burk plots indicated that 5 and 7 were mixed mode inhibitors of both ChE enzymes. Molecular docking studies on the binding sites of AChE and BChE were performed in order to afford a molecular insight into the mode of action of these active compounds. From this study these compounds have emerged as promising molecules for Alzheimer's disease therapy. PMID- 26434117 TI - Asperginine, an Unprecedented Alkaloid from the Marine-derived Fungus Aspergillus sp. AB - Asperginine (1), an alkaloid possessing a rare skeleton, was isolated from the cultural broth of the marine fungus Aspergillus sp. (Z-4) isolated from the gut of the marine isopod Ligia oceanica. The planar structure and relative configuration of 1 was determined by analysis of NMR and mass spectral data. Its absolute configuration was elucidated by Marfey's method, together with NOESY correlations of key hydrogen atoms. The cytotoxicity against prostate cancer PC3 and human HCT116 was assayed by the MTT method. Unfortunately, asperginine did not show any activity. PMID- 26434118 TI - Effect of Quercetin on Cell Cycle and Cyclin Expression in Ovarian Carcinoma and Osteosarcoma Cell Lines. AB - Resistance to chemotherapeutic drugs is a major problem in cancer treatment. The search for new interventions able to overcome this resistance may involve compounds of natural origin, such as flavonoids, ubiquitously present in many foods. In the present study, the cytotoxic effects and cell cycle modulation of the flavonoid quercetin were investigated in ovarian carcinoma (SKOV3) and osteosarcoma (U2OS) human cell lines and in their cisplatin (CDDP)-resistant counterparts (SKOV3/CDDP and U2OSPt cells, respectively). Quercetin (10-50 MUM) caused evident changes in the distribution of cell cycle phases in the CDDP resistant SKOV3/CDDP ovarian cell line. The levels of cyclin D1 and cyclin B1 were determined by means of Western blot in all cell lines incubated with quercetin (50 MUM) for 48 hours. The cyclin D1 expression was significantly decreased following the treatment with quercetin in SKOV3 and U2OSPt cells, but not in SKOV3/CDDP and U2OS cells. The reduction of cyclin D1 level could be linked to the G1/S phase alteration found in quercetin-treated cells. Although cyclin B1 is required for G2/M phase, and despite our observation that quercetin influenced the G2/M phase of cell cycle, the flavonoid did not affect cyclin B1 levels in all cell lines, indicating the involvement of other possible mechanisms. These results suggest that quercetin, exceeding the resistance to CDDP, might become an interesting tool to evaluate cytotoxic activity in combination with chemotherapy drugs. PMID- 26434119 TI - Anti-Helicobacter pylori Activity of Four Alchemilla Species (Rosaceae). AB - The present study evaluated the anti-Helicobacterpylori activity of Alchemilla glabra Neygenf. (A. sect. Alchemilla), A. monticola Opiz (A. sect. Plicatae S.E. Frohner), A. fissa Gunther & Schummel (A. sect. Calycinae (Buser) Buser) and A. viridiflora Rothm. (A. sect. Calycinae), and identified ellagic acid and quercetin-3-O-beta-glucoside. Anti-H. pylori activity was tested against ten clinical isolates and one reference strain (ATCC 43504). The methanol extracts were more active than the dichloromethane and cyclohexane extracts. The ranges of concentrations were between 4 MUg/mL for methanol extracts of A. viridiflora, A. glabra and A. monticola, and 256 MUg/mL for cyclohexane extracts of A. viridiflora, A. glabra and A. fissa. The best overall activity was obtained with A. monticola extracts. No significant difference was found in the ellagic acid contents of the methanol extracts of the tested Alchemilla species (0.2-0.3 mg/mL), and anti-H. pylori activity was similar (4-32 MUg/mL). Ellagic acid exhibited strong activity at very low concentrations (0.125-0.5 MUg/mL), while the second identified compound, quercetin-3-O-beta-D-glucoside, was also very active in concentration of 2-16 MUg/mL. PMID- 26434120 TI - Peracylated Glucosyl Kaempferols from Pasania dodonfifolia Leaf. AB - Phytochemical investigation of the ethanolic extract of Pasania dodoniifolia leaf led to the isolation of four kaempferol 3-0-peracylated glucosides (1-4), together with four flavonoid glucosides (5-8), epicatechin (9), and (7S, 7'S, 8R, 8'R)-icariol A2 (10). Of these, kaempferol-3-O-(3",4"-di-O-acetyl-2"-O-(Z)-p- coumaroyl)-6"-O-(E)-p-coumaroyl)-beta-glucopyranoside (3) and 3-O-(3",4"-di-O acetyl-2",6"-di-O-(Z)-p-coumaroyl)-beta-glucopyranoside (4) are new and their structures were elucidated by 2D NMR spectroscopic analyses and MS data. PMID- 26434121 TI - 6-Methoxyflavonol Glycosides with In Vitro Hepatoprotective Activity from Chenopodium bonus-henricus Roots. AB - One new, namely 6-methoxykaempferol 3-O-[beta-apiofuranosyl(l-->2)]-f glucopyranosyl(l->6)-fl-glucopyranoside (2), and two known flavonoid glycosides, spinacetin 3-O-[beta-apiofuranosyl(1-->2)]-beta-glucopyranosyl(1-->6)-beta glucopyranoside (1) and spinacetin 3-O-gentiobioside (3), were isolated from the roots of Chenopodium bonus-henricus L. Their structures were determined by means of spectroscopic methods (ID, 2D NMR, UV, IR) and HR-ESI-MS. Radical scavenging and anti-oxidant activities of 1 and 3 were established using DPPH and ABTS free radicals, FRAP assay and inhibition of lipid peroxidation (LP) in a linoleic acid system by the ferric thiocyanate method. Compound 3 was found to possess stronger DPPH and ABTS radical scavenging activity (IC50 0.44 +/- 0.008 mM and 0.089 +/- 0.002 mM, respectively) compared with 1 (IC50 1.22 +/- 0.0 10 mM and 0.11 +/- 0.004 mM, respectively). Both flavonoids inhibited the lipid peroxidation of linoleic acid significantly. Additionally, 1 and 3 significantly reduced the cellular damage caused by the hepatotoxic agent CCI4 in rat hepatocytes and preserved cell viability and GSH level, decreased LDH leakage and reduced lipid damage. Effects were similar to those of the positive control silymarin. Control of self-toxic effects made in a MTT based assay using HepG2 cells revealed statistically significant cytotoxic effects only in very high concentrations (exceeding mM) and an incubation time of 72 h, making flavonoid glycosides with a 6-methoxykaempferol skeleton a promising and safe class of hepatoprotective compounds. PMID- 26434122 TI - Flavonol Glycosides from the Leaves of Allium macrostemon. AB - Twelve flavonoids were isolated from Allium macrostemon leaves. Five compounds were identified as kaempferol 3,7-di-O-glucoside (1), kaempferol 3,4'-di-O glucoside (2), quercetin 3-O-glucoside (3), kaempferol 3-0-glucoside (4) and isorhamnetin 3-O-glucoside (5) by UV spectra, LC-MS, acid hydrolysis and HPLC comparisons with authentic standards. Other flavonoids were characterized as kaempferol glycosides (6-8, 10 and 11) and quercetin glycosides (9 and 12). Other compounds, such as steroidal saponins, have been already found from the bulbs of A. macrostemon. However, flavonoids were reported for the first time from the leaves. PMID- 26434123 TI - HPLC Plasma Assay of a Novel Anti-MRSA Compound, Kaempferol-3-O-Alpha-L-(2",3"-di p-coumaroyl)rhamnoside, from Sycamore Leaves. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a serious pathogen that is resistant to current antibiotic therapy. Thus, there is an urgent need for novel antimicrobial agents that can effectively combat these new strains of drug resistant "superbugs". Recently, fractionation of an extract from Platanus occidentalis (American sycamore) leaves produced an active kaempferol molecule, 3 O-alpha-L-(2",3"-di-p-coumaroyl)rhamnoside (KCR), in four isomeric forms; all four isomers exhibit potent anti-MRSA activity. In order to further the preclinical development of KCR as a new antibiotic class, we developed and validated a simple analytical method for assaying KCR plasma concentration. Because KCR will be developed as a new drug, although comprising four stereoisomers, the analytical method was devised to assay the total amount of all four isomers. In the present work, both a plasma processing procedure and an HPLC method have been developed and validated. Mouse plasma containing KCR was first treated with ethanol and then centrifuged. The supernatant was dried, suspended in ethanol, centrifuged, and the supernatant was injected into an HPLC system comprising a Waters C18, a mobile phase composing methanol, acetonitrile, and trifluoroacetic acid and monitored at 313 nm. The method was validated by parameters including a good linear correlation, a limit of quantification of 0.27 microg/mL, and high accuracy. In summary, this method allows a rapid analysis of KCR in the plasma samples for pharmacokinetics studies. PMID- 26434125 TI - Prenylhydroquinone-Derived Secondary Metabolites from Cultures of the Basidiomycete Lentinus similis BCC 52578. AB - Two new prenylhydroquinone-derived compounds, Ientinospirol (1) and 1-(2,5 dihydroxyphenyl)-4-hydroxy-3-methyl-l-butanone (2), were isolated from cultures of the basidiomycete Lentinus similis BCC 52578, together with the known compounds panepoxydone (3), panepoxydione (4), isopanepoxydone (5), 2,2-dimethyl 6-hydroxy-2H-chromene (6), and (3R,4S)-3,4-dihydroxy-2,2-dimethyl-6 methoxychroman (7). Compounds 3 and 4 exhibited cytotoxicity against all cell lines tested, while the other compounds were inactive. PMID- 26434124 TI - Biological Activity of Dolichandrone serrulata Flowers and Their Active Components. AB - Dolichandrone serrulata (DC.) Seem flowers are widely used as vegetables in northern and eastern Thailand. Biological studies of the methanolic extract of these flowers have shown promising antioxidant activity. Biological-guided separation of D. serrulata flowers yielded six compounds, identified as hallerone, protocatechuic acid, rengyolone, cleroindicin B, ixoside, and isomaltose. This is the first report on hallerone, protocatechuic acid, rengyolone, cleroindicin B, and isomaltose in D. serrulata. Protocatechuic acid was the most potent scavenger of 2,2-diphenyl-l-picrylhydrazyl and hydroxyl radicals with IC50 values of 25.6 +/- 0.6 and 29.6 +/- 0.4 microM, respectively. Hallerone and rengyolone showed moderate scavenging action on superoxide radicals and inhibited H202 induced reactive oxygen species production in HEK-293 cell. In addition, the other isolated compounds showed weak activity. PMID- 26434126 TI - Effects of Thymoquinone on the Pharmacokinetics and Pharmacodynamics of Glibenclamide in a Rat Model. AB - Glibenclamide and thymoquinone plasma concentrations were analysed using a sensitive RP-HPLC method, and non-compartmental model pharmacokinetic parameters were calculated. The maximum reduction in blood glucose level was observed 3 hours following glibenclamide administration, which reached 47.4% of baseline, whereas it was reduced by 53.0% to 56.2% when co-administrated with thymoquinone. Plasma concentration of glibenclamide was increased by 13.4% and 21.8% by the co administration of thymoquinone as single and multiple doses, respectively (P<0.05). The AUC and TI/2 of glibenclamide were also increased respectively by 32.0% and 17.4% with a thymoquinone single dose, and by 52.5% and 92.8% after chronic treatment. Furthermore, diabetic rats treated with thymoquinone demonstrated a marked decrease in hepatic protein expressions of CYP3A2 and CYP2C 11 enzymes that are responsible for the metabolism of glibenclamide. The current data suggest that thymoquinone exhibits a synergistic effect with glibenclamide on glucose level, which could be explained by reducing CYP450 activity at the protein level. PMID- 26434127 TI - Antioxidant and Antiinflammatory Compounds in Nutmeg (Myristicafragrans) Pericarp as Determined by in vitro Assays. AB - Nutmeg, Myristicafragrans, is known for its culinary and medicinal values. The nutmeg pericarp, abundant during the production of the seed, is also used in food and beverage preparations. In this study, the pericarp of M. fragrans was evaluated for its bioactive components using in vitro antioxidant and antiinflammatory assays. The hexane, ethyl acetate and methanolic extracts inhibited lipid peroxidation (LPO) by 82.5, 70.1 and 73.2%, and cyclooxygenase enzymes COX-1 by 44, 44 and 42% and COX-2 by 47, 41 and 36%, respectively, at 100 microg/mL. The bioassay-guided purifications of extracts yielded 20 compounds belonged to neolignans (0.13%), phenylpropanoids (0.28%), phenolic aldehyde (0.35%), triterpenoids (0.06%), triglycerides (0.20%), sugars (10.2%) and steroids (0.49%). Pure isolates 1-5 inhibited LPO by 70-99% and 3-12 inhibited COX-1 and -2 enzymes by 37-49%. This is the first report on the bioassay-guided characterization of constituents in nutmeg pericarp. Our results support the medicinal claims of nutmeg pericarp. PMID- 26434128 TI - In Vitro Safety/Protection Assessment of Resveratrol and Pterostilbene in a Human Hepatoma Cell Line (HepG2). AB - The aim of this work was to evaluate in vitro the genotoxic and/or antigenotoxic effects of resveratrol (RESV) and pterostilbene (PTER) on HepG2 cells. Moreover, additional tests were performed to evaluate early and late apoptosis events induced by the tested stilbenes. RESV and PTER did not show any genotoxic activity. As regards antigenotoxicity testing, RESV and PTER showed a typical, U shaped hormetic dose-response relationship characterized by a biphasic trend with small quantities having opposite effects to large ones. HepG2 cells treated with PTER exhibited a marked increase in early apoptosis (40.1%) at 250 microM; whereas, the highest concentration tested for both RESV and PTER significantly increased the proportion of HepG2 cells undergoing late apoptosis (32.5 and 51.2%, respectively). The observed pro-apoptotic activity could, at least in part, explain the hormetic response observed when the compounds were tested for antigenotoxicity (i.e., in the presence of induced DNA damage). PMID- 26434129 TI - Red Maple (Acer rubrum) Aerial Parts as a Source of Bioactive Phenolics. AB - The bark and stems of red maple (Acer rubrum) are reported to contain bioactive phenolics but its aerial parts, namely, flowers and leaves, remain largely unexplored. This is unfortunate considering that various parts of the red maple were used for traditional medicinal purposes by the indigenous peoples of eastern North America, where this species is found. Herein, we report the identification of twenty-five (1-25) phenolics, including two new galloyl derivatives (1 and 2), from red maple flowers and leaves. Of these, ten compounds (1-10), including the new compounds, were isolated and identified by NMR and HRESIMS data while the remaining fifteen compounds (11-25) were identified by HPLC-DAD analyses (by comparison with chemical standards). The isolates (1-10), along with the clinical drug, acarbose, were evaluated for their alpha-glucosidase enzyme inhibitory activities. PMID- 26434130 TI - Changes in the Content of the Glycosides, Aglycons and their Possible Precursors of Rhodiola rosea during the Vegetation Period. AB - Phytochemical participants in the biosynthetic pathway of salidroside and cinnamyl alcohol glycosides were studied from seven Rhodiola rosea L. individuals originating from a wild population. Plants were grown in a phytotron and samples were taken at 3 weekly intervals during the vegetation period. Based on HPLC analysis, all the key compounds to which roseroot medicinal property is attributed were detected, with salidrosde being the most dominant, followed by its aglycone, tyrosol. The contents of all compounds were 2-3 times more in the rhizomes than in roots. The highest content of salidroside, tyrosol, rosarin, rosavin and cinnamyl alcohol was recorded in rhizomes and at the beginning of shoot elongation. The seven roseroot individuals showed a very high deviation in their chemical content at each sampling time. Our statistical analysis showed that the trend of salidroside accumulation in the rhizome was the most similar in all studied plants. These results have important implications for choosing a reasonable harvest time to obtain the maximum phytochemical content and a better understanding of active compounds formation in R. rosea L. PMID- 26434131 TI - Biocompounds Attenuating the Development of Obesity and Insulin Resistance Produced by a High-fat Sucrose Diet. AB - The use of biocompounds as agents with potential anti-obesity effects might be a feasible alternative to the prescription of traditional drugs in the near future. The goal of the present study was to screen five different compounds in relation to their ability to prevent body weight gain and ameliorate obesity-associated metabolic impairments, namely insulin resistance. For this purpose, seventy Wistar rats were randomly assigned into seven experimental groups. A standard diet-fed control group (control, n=10); a high-fat, high-sucrose diet-fed group (HFS, n=10) and five experimental groups which were fed the HFS diet supplemented with one of the following biocompounds; curcumin (100 mg/kg bw, n=10), chlorogenic acid (50 mg/kg bw, n=10), coumaric acid (100 mg/kg bw, n=10), naringin (100 mg/kg bw, n=10) and leucine (1% of diet, n=10). These results confirm the effectiveness of all the compounds to reduce significantly food efficiency, despite the significant higher food intake. Moreover, visceral fat mass percentage was significantly decreased after naringin and coumaric acid supplementation. In fact, this finding might be related to the considerable amelioration of HOMA-IR index detected in naringin-treated animals. A significant reduction in serum insulin levels and an improvement in the intraperitoneal glucose tolerance test and AUC were found in leucine- and coumaric acid-treated rats, respectively. In summary, the tested biocompounds, particularly naringin, coumaric acid and leucine, showed potential benefits in the prevention of obesity related complications in rats, at least at the proved doses. PMID- 26434132 TI - A Novel C21 Cyclopentenone Derivative from Cipadessa cinerascens. AB - A new C21 cyclopentenone derivative, Cipacyclonone (1), was isolated from the leaves of Cipadessa cinerascens. Its structure was elucidated on the basis of spectroscopic analysis, including extensive 1D- and 2D-NMR techniques. Compound 1 showed strong cytotoxicity activity against HL-60 and A-549 cell lines, with IC50 values of 1.2 and 3.0 microM, respectively. PMID- 26434133 TI - Effects on MC3T3-E1 Cells and In silico Toxicological Study of Two 6-(Propan-2 yl)-4-methyl-morpholine-2,5-diones. AB - Recently, we found that two cyclodidepsipeptides, 3,6-di-(propan-2-yl)-4-methyl morpholine-2,5-dione (1) and 3-(2-methylpropyl)-6-(propan-2-yl)-4-methyl- morpholine-2,5-dione (2), are excellent inhibitors of xanthine oxidase. In order to obtain more information about the toxicological potential of compounds 1 and 2 on bone cells, the current study was designed to evaluate the effect of these compounds on viability and proliferation of MC3T3-E1 cells. Compound 1 showed neither cytotoxic nor stimulatory effect on cell viability, while compound 2 showed a slight stimulatory effect on cell viability. Both studied compounds showed slight stimulatory effects on proliferation of MC3T3-E1 cells, in a dose dependent manner. Additionally, an in silico toxicological study of compounds 1 and 2 was performed, and the results indicate that they have a good probability of safe biological intake. PMID- 26434134 TI - Release of Antioxidant Peptides from the Body Wall Proteins of the Sea Cucumber Isostichopus fuscus. AB - Proteases from the tentacles of the sea cucumber Isostichopusfuscus were partially purified and used to produce antioxidant peptides from body wall proteins of this marine species. Three proteins (105, 68, and 39 kDa) were identified by SDS-PAGE in the proteolytic extract of the tentacles. Protein hydrolyzates were generated with gelatin and crude protein substrates from body wall, and peptidic fractions lower and higher than 3 kDa were obtained to evaluate their oxygen radical scavenging capacity (ORAC). The 3 kDa-fraction obtained from the crude protein hydrolyzate showed the highest ORAC value (0.92 +/- 0.04 micromol Trolox equivalent/mg protein). This fraction was selected to purify peptides potentially responsible for the activity that might be used as ingredients for development of functional foods. PMID- 26434135 TI - Bioactivity-guided Separation of the Active Compounds in Acacia pennata Responsible for the Prevention of Alzheimer's Disease. AB - The objective of this study was to evaluate the health benefits of plants used in Thai food, specifically Acacia pennata Willd., in Alzheimer's prevention. A. pennata twigs strongly inhibited beta-amyloid aggregation. Bioactivity-guided separation of the active fractions yielded six known compounds, tetracosane (1), 1-(heptyloxy)-octadecane (2), methyl tridecanoate (3), arborinone (4), confertamide A (5) and 4-hydroxy-1-methyl-pyrrolidin-2-carboxylic acid (6). The structures were determined by spectroscopic analysis. Biological testing revealed that tetracosane (1) was the most potent inhibitor of beta-amyloid aggregation, followed by 1-(heptyloxy)-octadecane (2) with IC50 values of 0.4 and 12.3 MUM. Methyl tridecanoate (3), arborinone (4) and 4-hydroxy-1-methyl-pyrrolidin-2 carboxylic acid (6) moderately inhibited beta-amyloid aggregation. In addition, tetracosane (1) and methyl tridecanoate (3) weakly inhibited acetylcholinesterase (AChE). These results suggested that the effect of A. pennata on Alzheimer's disease was likely due to the inhibition of beta-amyloid aggregation. Thus A. pennata may be beneficial for Alzheimer's prevention. PMID- 26434136 TI - Development and Validation of LC-MS/MS Method for Quantitative Determination of Adenosine, Guanosine, Xanthine and Uric acid in Widely Consumed Vegetables in Thailand. AB - In this study, a triple quadrupole LC-MS/MS electrospray ionization method was developed and validated for quantitative determination of adenosine, guanosine, xanthine and uric acid in fifteen widely consumed Thai vegetables. The method was successively developed by using caffeine as internal standard. The lower limit of quantitation (LLOQ) was 0.2 MUg/g for adenosine and guanosine, and 1.0 MUg/g for uric acid and xanthine. The method was fully validated according to USFDA guidelines and all performance characteristics were found acceptable. Subsequently, the developed and validated LC-MS/MS method was applied to determine the four interest substances in fifteen widely consumed vegetables in Thailand. The results showed that all vegetables included in the study could be classified as low adenosine, guanosine, xanthine and uric acid containing foods since the concentrations of these substances were less than 50 mg per 100 g. This finding was enormously valuable information for hyperuricemia and gouty patients. PMID- 26434137 TI - Chemical Composition of the Essential Oil from Chaerophyllum temulum (Apiaceae). AB - The present study reports the chemical composition on the essential oil obtained from fresh roots, stems, inflorescences and fruits of Chaerophyllum temulum. In all samples, except the roots, the most dominant components were sesquiterpene hydrocarbons. (Z)-Falcarinol was the principal constituent of the root essential oils (61.7% at the flowering stage and 62.3% at the fruiting stage). The blossom oil was dominated by (Z,E)-alpha-famesene (23.4%), (E)-beta-farnesene (9.0%) and germacrene D-4-ol (9%), whereas the oil from the fruit had germacrene D-4-ol (27.6%) as its main compound, accompanied by (Z,E)-alpha-famesene (13.4%). Germacrene D was the most abundant component of the stem essential oil (38.4% at the flowering stage and 32.5% at the fruiting stage). The obtained results show that the qualitative composition of the oil depends on the part of the plant which is analyzed, while the quantitative composition of the main components depends on the growing stage of the plant. PMID- 26434138 TI - Comparison of Essential Oils Obtained from Different Extraction Techniques as an Aid in Identifying Aroma Significant Compounds of Nutmeg (Myristica fragrans). AB - Distribution of volatile constituents in the essential oil of nutmeg obtained by simultaneous distillation extraction (SDE), high vacuum distillation (HVD) and super critical fluid extraction (SFE) was compared with reduced pressure distillation (RPD) and head space (HS) analysis. HS and RPD volatiles were characterized by a high content of sabinene, followed by alpha-pinene and beta pinene. Interestingly, unlike the SDE, HVD and SFE oils, distillates from HS and RPD were marked by the absence of phenolic ethers namely myristicin, elemicin and safrole. The HS and RPD volatiles possessed a pleasant nutmeg aroma indicating a significant role of terpenic constituents in contributing to the top aroma note. GC-olfactometry (GC-O) of the oils aided in establishing the role of sabinene, alpha-pinene and beta-pinene in contributing to the distinctive note of the spice. A high odor activity value (OAV) of sabinene and alpha-pinene established the role of these two constituents in imparting the characteristic nutmeg odor. PMID- 26434139 TI - Chemical Variability of the Essential Oil Isolated from Aerial Parts of Tetraclinis articulata from North-Western Algeria. AB - The objective was to investigate the yield and chemical composition of 50 essential oil samples isolated from leaves and flowers of Tetraclinis articulata harvested in eight locations (coastal township and highlands) of Tlemcen Province (North-Western Algeria). Essential oil yields varied drastically from sample to sample (0.03 to 0.86%, w/w). No direct correlation was observed between the yield and the altitude of the harvest areas. The oils consisted mainly of monoterpenes: alpha-pinene (9.2-56.5%), bornyl acetate (1.2-45.1%), camphor (0.5-40.3%), borneol (0.2-12.9%), limonene (3.6-12.5%), and myrcene (1.6-9.7%). Sesquiterpenes were represented by germacrene D (up to 14.2%) and (E)-beta-caryophyllene (up to 13.3%). PCA analysis of the data allowed the distinction of two groups within the samples. The composition of group I (9 samples) was dominated by camphor, (Mean = 30.9%) followed by alpha-pinene (M = 19.1%) and bornyl acetate (M = 11.4%). Group II was divided into two sub-groups. Samples of sub-group IIA (8 samples) contained mainly alpha-pinene (M = 45.4%). Samples of the largest group IIB (33 samples) were characterized by similar contents of alpha-pinene (M = 28.2%) and bornyl acetate (M = 24.5%) and the occurrence of camphor to a lesser extent (M = 10.0%). PMID- 26434140 TI - Composition and Bioactivities of an (E)-beta-Farnesene Chemotype of Chamomile (Matricaria chamomilla) Essential Oil from Nepal. AB - The essential oil of Matricaria chamomilla, collected from Nepal, was obtained by hydrodistillation and analyzed by gas chromatography-mass spectrometry. The major components in Nepalese chamomile oil were (E)-beta-famesene (42.2%), alpha bisabolol oxide A (22.3%), (E,E)-alpha-famesene (8.3%), cis-bicycloether (5.0%), alpha-bisabolol oxide B (4.5%), and alpha-bisabolone oxide A (4.0%). A cluster analysis based on the chemical compositions of 48 samples of chamomile oil reported in the literature has revealed seven chemotypes, and the oil from Nepal represents the (E)-beta-farnesene chemotype. The chamomile oil was screened for antimicrobial activity against Bacillus cereus, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger, and toxicity toward MCF-7 breast tumor cells, Artemia salina, Chaoborus plumicornis, Caenorhabditis elegans, and Drosophila melanogaster. PMID- 26434141 TI - Chemical Composition of the Essential Oil from Croton oblongifolius and its Antibacterial Activity against Propionibacterium acnes. AB - The essential oil of C. oblongifolius Roxb. stem bark was obtained by hydrodistillation. Chemical analysis by GC-MS identified 29 compounds. Terpinen-4 ol (17.8%) was a major component, together with alpha-guaiene (7.9%), E caryophyllene (7.0%), myrcene (6.7%), (+)-cyclosativene (5.1%), sabinene (4.8%), aciphyllene (4.7%), pogostol (4.6%), gamma-terpinene (3.4%), alpha-muurolol (3.2%) and germecrene D (3.2%). The essential oil exhibited antibacterial activity against Propionibacterium acnes ATCC 6919 with an MIC of 0.125%, v/v. PMID- 26434142 TI - Composition, in vitro Anti-inflammatory, Antioxidant and Antimicrobial Activities of Essential Oils from Leaf and Twig Parts of Cupressus cashmeriana. AB - The chemical composition and in vitro anti-inflammatory, antioxidant and antimicrobial activities of the essential oils isolated from the leaf and twig of Cupressus cashmeriana have been investigated. The essential oils were isolated using hydrodistillation in a Clevenger-type apparatus, and characterized by GC FID and GC-MS, respectively. The leaf oil mainly consisted of alpha-pinene (21.8%), epizonarene (8.0%), sabinene (7.9%), limonene (7.6%), gamma-terpinene (7.0%), and allo-aromadendrene (7.0%); the twig oil was mostly carvacrol methyl ether (35.4%), manool (16.1%), carvacrol (14.2%), and (2Z,6E)-farnesol (6.9%). Twig oil, but not leaf oil, was able to reduce nitric oxide production by lipopolysaccharide-activated murine macrophages RAW 264.7 without reducing the cell viability. In addition, twig oil showed better antioxidant and antimicrobial activities than leaf oil. The major ingredient of the twig oil that was responsible for the anti-inflammatory, antioxidant and antimicrobial activities was carvacrol. PMID- 26434143 TI - Antioxidant and Anticholinesterase Activities of Essential Oils of Cinnamomum griffithii and C. macrocarpum. AB - The essential oils of Cinnamomum griffithii and C. macrocarpum were analyzed by GC and GC-MS and evaluated for their antioxidant and anticholinesterase activities. The essential oils of leaf and bark of C. grffithii were characterized by the presence of 30 components, with methyl eugenol (38.5-43.8%) as the major component. A total of 11 components were characterized in.the leaf and bark of C. macrocarpum essential oil with the most abundant component was safrole (54.5-59.5%). The bark oil of C. griffithii demonstrated significant activity on DPPH (IC50 73.4 microg/mL) and a high phenolic content (192.0%), while the leaf oil inhibited oxidation of beta-carotene/linoleic acid with an inhibition value of 65.5 MUg/mL. Acetylcholinesterase and butyrylcholinesterase inhibition were assessed and the results showed that C. macrocarpun bark oil exhibited significant activity with inhibition values of 55.8% and 66.1%, respectively at a concentration of 1 mg/mL. PMID- 26434144 TI - Essential Oil Composition and Antigermination Activity of Artemisia dracunculus (Tarragon). AB - The chemical composition of an Italian oil of tarragon (Artemisia dracunculus L.) was analyzed by GC/EIMS. The major compound of the oil was estragole (73.3%), followed by limonene (5.4%), (E)-beta-ocimene (5.3%), beta-pinene (3.4%) and (Z) beta-ocimene (3.0%). The essential oil was tested "in vitro" for its antigermination activity against Raphanus sativus L., Lepidium sativum L, Papaver rhoeas L. and Avena fatua L. seeds and demonstrating a good inhibitory activity in a dose-dependent way. PMID- 26434145 TI - In Vitro Activity of Twenty Commercially Available, Plant-Derived Essential Oils against Selected Dermatophyte Species. AB - The in vitro activity of twenty chemically defined essential oils (EOs) obtained from Boswellia sacra, Citrus bergamia, C. limon, C. medica, Cinnamomum zeylanicum, Eucalyptus globulus, Foeniculum vulgare, Helichrysum italicum, Illicium verum, Litsea cubeba, Mentha spicata, Myrtus communis, Ocimum basilicum, Origanum majorana, O. vulgare, Pelargonium graveolens, Rosmarinus officinalis, Santalum album, Satureja montana, and Thymus serpyllum was assayed against clinical animal isolates of Microsporum canis, Trichophyton mentagrophytes, T. erinacei, T. terrestre and Microsporum gypseum, main causative agents of zoonotic and/or environmental dermatophytoses in humans. Single main components present in high amounts in such EOs were also tested. Different dermatophyte species showed remarkable differences in sensitivity. In general, more effective EOs were T. serpyllum (MIC range 0.025%-0.25%), O. vulgare (MIC range 0.025%-0.5%) and L. cubeba (MIC range 0.025%-1.5%). F. vulgare showed a moderate efficacy against geophilic species such as M gypseum and T terrestre. Among single main components tested, neral was the most active (MIC and MFC values 5 0.25%). The results of the present study seem to be promising for an in vivo use of some assayed EOs. PMID- 26434146 TI - Intracerebral Distribution of a-Pinene and the Anxiolytic-like Effect in Mice Following Inhaled Administration of Essential Oil from Chamaecyparis obtuse. AB - The anxiolytic-like and stress reduction effects following inhaled administration of essential oil from Chamaecyparis obtusa (EOCO) have been reported. Volatile components are thought to produce these effects of EOCO by neurological transfer and pharmacological transfer. The regions of the brain in which inhaled compounds are found due to pharmacological transfer of EOCO are not known. This research was undertaken to clarify the relationship between the intracerebral distribution of alpha-pinene, which is the main component of EOCO, and emotional behavior. alpha-Pinene was detected as the main component of volatile EOCO. The amount of alpha-pinene in each region of the brain was measured following inhaled administration of EOCO. The amount of alpha-pinene was different in each region of the brain. With inhaled administration of 32 MUL/L air EOCO, a high concentration of alpha-pinene was observed. However, no significant differences in the concentration of alpha-pinene among brain regions were found. A therapeutic concentration of alpha-pinene (8 MUL/L air EOCO) in each region of the brain may induce an anxiolytic-like effect, and a high concentration of alpha pinene (32 MUL/L air EOCO) in each region of the brain may induce an excitatory like effect. The increases in the concentration of alpha-pinene from 8 to 32 MUL/L air EOCO in the striatum and the hippocampus were significantly lower compared with the increases in other brain regions. These results indicate that regions besides the striatum and the hippocampus participated in the increase in locomotor activity due to the high concentration of alpha-pinene in the brain. PMID- 26434147 TI - A Comprehensive Review of the Cosmeceutical Benefits of Vanda Species (Orchidaceae). AB - Orchidaceae is the largest family of flowering plants with over 35,000 species and 850 genera. About 3300 species of orchids are found in Malaysia and the diversity is highest in the Main, Keledang, Bintang and Tahan Ranges. Apart from being prized for their beauty, orchids have long been used by humans for medicinal purposes. Today the uses of orchids have been expanded to the food and cosmetics industries. Many cosmeceutical companies use orchid extracts as an active ingredient in their products. Previous studies provide riveting insights into the potential uses of orchid extracts as an active agent in cosmetics. This paper describes the cosmeceutical potential of orchids as an anti-aging, and skin moisturizing agent. Orchid extracts from Vanda coerulea and V. teres delay aging caused by reactive oxygen species (ROS) following LV irradiation through their antioxidant and anti-inflammatory activity. These extracts also show anti-aging properties by stimulating cytochrome c oxidase (complex IV), which is part of the electron transport chain in mitochondria. Stimulation of cytochrome c oxidase improves the respiratory function of mitochondria in keratinocytes. The presence of mucilage in orchids enables them to maintain skin hydration. Mucilage functions as a moisturizer and emollient due to its high water binding capacity. Additionally, orchid extracts provide skin hydration by stimulating aquaporin 3 (AQP3) and LEKTI protein expression. The presence of AQP3 leads to a five-fold increase in water permeability, which subsequently increases stratum corneum hydration. Increased LEKTI protein expression mediated by orchid extracts reduces the degradation of desmoglein-1 and enhances the structural function of desmosomes, which play important roles in preventing water evaporation. PMID- 26434148 TI - Genotoxicity and Antigenotoxicity Studies of Traditional Medicinal Plants: How Informative and Accurate are the Results? AB - Genotoxicity and antigenotoxicity studies of (traditional medicinal) plants are important from a risk assessment point of view and in the search for new medication against, for example, cancer. It is clear yet that attention should be paid to a number of aspects that may influence the outcome of a study and to which often no or insufficient attention is paid. A short overview is given of such aspects that deserve more attention. PMID- 26434149 TI - Bodil Schmidt-Nielson (1918-2015) 48th APS President. PMID- 26434150 TI - How Diversity is Becoming a Reality in the American Physiological Society. PMID- 26434151 TI - Off the Grid. PMID- 26434153 TI - Cuban and American Physiological Societies Sign Historic Agreement for Research Collaboration. PMID- 26434154 TI - APS, FASEB Highlight Role of Professional Societies in Annual Postdoc Meeting. PMID- 26434155 TI - Serving Our Society. PMID- 26434156 TI - APSselect: Year One a Success! PMID- 26434157 TI - APS Suggests Ways for USDA to Reduce Regulatory Burden. PMID- 26434158 TI - Congress Introduces Authorizing Legislation for NIH, NSF. PMID- 26434159 TI - The W's of Networking in Physiology. PMID- 26434160 TI - Response to "Bias is Stagnating Physiology". PMID- 26434161 TI - Impact Factors. PMID- 26434162 TI - FOREWORD. Ninety years ago, Raymond Pearl, a professor of biology at Johns Hopkins University. PMID- 26434163 TI - HEALTH SELECTION THEORY: AN EXPLANATION FOR THE PARADOX BETWEEN PERCEIVED MALE WELL-BEING AND MORTALITY. AB - Paradoxically, men report better health and quality of life than women, but men experience higher mortality rates than women at most ages. One conclusion from these findings is that men have been selected to disregard signs of ill health, or even to deceive themselves about their health, to their detriment because presenting themselves as healthy has fitness benefits. We hypothesize that men have been sexually selected to present themselves to women as healthy but that the cost of not attending to their minor health problems results in earlier mortality than women. We present a review of the human and primate literature that supports health selection theory, the hypothesis that females have preferentially selected males who present themselves as healthy. PMID- 26434164 TI - ECOLOGICAL AND EVOLUTIONARY APPLICATIONS FOR ENVIRONMENTAL SEX REVERSAL OF FISH. AB - Environmental sex reversal (ESR), which results in a mismatch between genotypic and phenotypic sex, is well documented in numerous fish species and may be induced by chemical exposure. Historically, research involving piscine ESR has been carried out with a view to improving profitability in aquaculture or to elucidate the processes governing sex determination and sexual differentiation. However, recent studies in evolution and ecology suggest research on ESR now has much wider applications and ramifications. We begin with an overview of ESR in fish and a brief review of the traditional applications thereof. We then discuss ESR and its potential demographic consequences in wild populations. Theory even suggests sex-reversed fish may be purposefully released to manipulate population dynamics. We suggest new research directions that may prove fruitful in understanding how ESR at the individual level translates to population-level processes. In the latter portion of the review we focus on evolutionary applications of ESR. Sex-reversal studies from the aquaculture literature provide insight in to the evolvability of determinants of sexual phenotype. Additionally, induced sex reversal can provide information about the evolution of sex chromosomes and sex-linked traits. Recently, naturally occurring ESR has been implicated as a mechanism contributing to the evolution of sex chromosomes. PMID- 26434165 TI - REWRITING ECOLOGICAL SUCCESSION HISTORY: DID CARRION ECOLOGISTS GET THERE FIRST? AB - Ecological succession is arguably the most enduring contribution of plant ecologists and its origins have never been contested. However, we show that French entomologist Pierre Megnin, while collaborating with medical examiners in the late 1800s, advanced the first formal definition and testable mechanism of ecological succession. This discovery gave birth to the twin disciplines of carrion ecology and forensic entomology. As a novel case of multiple independent discovery, we chronicle how the disciplines of plant and carrion ecology (including forensic entomology) accumulated strikingly similar parallel histories and contributions. In the 1900s, the two groups diverged in methodology and purpose, with carrion ecologists and forensic entomologists focusing mostly on case reports and observational studies instead of hypothesis testing. Momentum is currently growing, however, to develop the ecological framework of forensic entomology and advance carrion ecology theory. Researchers are recognizing the potential of carcasses as subjects for testing not only succession mechanisms (without assuming space-for-time substitution), but also aggregation and coexistence models, diversity-ecosystem function relationships, and the dynamics of pulsed resources. By comparing the contributions of plant and carrion ecologists, we hope to stimulate future crossover research that leads to a general theory of ecological succession. PMID- 26434166 TI - Telemedicine: The Physician's Double-Edged Sword. PMID- 26434167 TI - Indigenous Cases of Leprosy (Hansen's Disease) in Southern Mississippi. AB - Hansen's disease or leprosy is a chronic infection of the skin and peripheral nerves caused by Mycobacterium leprae. In the U.S., leprosy is mainly reported in immigrants, but indigenous leprosy cases have been also reported in this country, especially in semitropical southern states (i.e., Texas, Louisiana). The objective of this series of cases is to describe indigenous leprosy cases reported in southern Mississippi (MS) during the period 2012-2014. Information was collected from medical records at Hattiesburg Clinic and the MS Department of Health. Four cases were reported during the period of study (3 Caucasian males, 1 African-American woman). Non of visited endemic leprosy country. The age ranged from 60 to 83 years (median: 75.5 years). Of the four cases, three presented with a slowly progressive erythematous rash disseminated mainly on the thorax and abdomen, with a lesser degree on the extremities. The time between onset of rash until the diagnosis ranged from 5 to 16 months (median: 7 months). Only one case had direct contact with armadillos (blood exposure). Non of these patients had a history of immunosuppression. The most common symptoms were neuropathic pain (n=2), generalized pruritus (n=2) and loss of sensation in extremities (n=2). One case had severe peripheral neuropathy with muscle weakness, atrophy in left arm, and wasting on left hand. Skin biopsies showed diffuse granulomatous infiltrate with foamy histiocytes along with acid fast bacilli by Fite stain. By Ridley Jopling classification system, three cases were diagnosis as lepromatous leprosy, and one, borderline lepromatous. Treatment included clofazimine, dapsone and rifampin that was offered free of charge by the National Hansen's Diseases Program, Baton Rouge, L.A. One patient did not tolerate therapy. In conclusion, a slowly progressive disseminated erythematous skin rash on the trunk should raise suspicion for leprosy in the elderly population in south MS. PMID- 26434168 TI - Beyond Respiratory Depression and Constipation: Adverse Effects of Opioids. AB - The numbers of opioid presciptions have skyrocketed over the last two decades. Adverse effects of opioids are difficult to diagnose because the usual presenting complaints is persistence of severe pain and decreases function leading to chronic usage of medication with minimal benefit to patients. This concise review discusses the adverse effects of opioids to appropriately diagnose and treat patients on opioid therapy. We emphasize less commonly known adverse effects and the controversial use of opioids in non-cancer pain. PMID- 26434169 TI - Top Ten Facts You Need to Know about Medical Emergencies While Flying. PMID- 26434170 TI - Two New Members Appointed to the State Board of Health. PMID- 26434172 TI - On Match Day, Suspense Reigns as Med Students Reveal Residency Fates. PMID- 26434171 TI - Let's Measure It in Dollars and Cents. PMID- 26434173 TI - Carey Medical College Graduates Second Class. PMID- 26434174 TI - Gulfport Veterans' Hospital 1935-8. PMID- 26434175 TI - Spotlight on: Physician Leadership Academy. PMID- 26434176 TI - Physicians mean business. Physicians create jobs everywhere they go. PMID- 26434178 TI - Uncertain future for school nurses. PMID- 26434177 TI - "Trusts and universities need more cooperation". PMID- 26434180 TI - NICE guidelines on treatment of diabetic ulcers. PMID- 26434179 TI - Education inadequate for future care needs, warn nurse directors. PMID- 26434181 TI - Meningitis vaccine should be followed up with paracetamol. PMID- 26434182 TI - Important role of nursing needs more recognition, says crash nurse. PMID- 26434183 TI - Open visiting leads to drop in complaints. PMID- 26434184 TI - Community hospital research will look at nurse staffing levels. PMID- 26434186 TI - "We must all be confident using evidence to shape our practice". PMID- 26434185 TI - "Nurses are key to ensuring all patients are discharged safely". PMID- 26434187 TI - Using hospital at home to reduce admissions. AB - In the UK at present there is a constant pressure for inpatient beds; with this comes a need to develop services so that patients can be managed in their own homes. Although community nursing has historically been synonymous with district nursing, with the ageing population and the need to manage the increasing numbers of patients who have long-term conditions, community nursing is changing. This article describes a hospital in the home service, developed by one NHS trust; it not only delivers care traditionally provided in hospitals, but is also an effective setting for student nurses to undertake practice placements. PMID- 26434188 TI - Vital signs monitoring in hospitals at night. AB - Vital signs are important indicators of patients' clinical condition and inform required interventions. This article reports on a review of the literature on current practice, which showed that nurses' compliance with monitoring protocols is poor, particularly at night. This has important implications for patient safety and outcomes. PMID- 26434189 TI - Assessing the pulse rate in adult patients. AB - Assessing the pulse is a common procedure and an important aspect of many nursing interventions; it should always be done with care and reassessed as needed. Assessment should always be taken seriously, with any deviations from the norm reported to a senior clinician, and pulse rate, rhythm and strength must always be documented. Pulses indicate numerous patient characteristics including the degree of relaxation, regularity of cardiac contractions and sufficiency of cardiac output. This article considers the relevant anatomy, physiology and practice of pulse assessment and recording. PMID- 26434191 TI - 60 seconds with Sam Foster. PMID- 26434190 TI - Setting standards for high-quality placements. AB - As part of a project undertaken by a local education and training board, a wide range of stakeholders across South London were asked what makes a high-quality practice placement for student nurses, and how that quality could be effectively measured. This article outlines the drafting and testing of a set of quality standards in a mix of provider settings. Although further refinement is required, the standards enabled placement sites to question themselves about their own education and training processes, strengthened their partnership with the training and education board and facilitated the assurance that student nurses receive safe, effective and compassionate preparation when they are on placement. PMID- 26434192 TI - The hand that feeds. PMID- 26434193 TI - [Help! Accumulation of manuscripts!]. PMID- 26434194 TI - [TERIFLUNOMIDE: A NEW ORAL IMMUNOMODULATING AGENT FOR MULTIPLE SCLEROSIS]. AB - Multiple sclerosis (MS) is the autoimmune, demyelinating, neurodegenerative disorder of the central nervous system (CNS). There are nine drugs available in Hungary reimbursed by the National Health Insurance Fund of Hungary (OEP) to reduce the activity of the disease, from which seven can be used as first line therapies. We have approximately 20 years of experience with the interferon beta 1a/1b and glatiramer-acetate products. Though in case of approximately 30% of the patients using one of the first line drugs, the disease remains active, that we call break-through disease. The reasons for breakthrough disease could be the insufficient adherence and compliance, the appearance of neutralizing antibodies or the high activity of the disease. One of the oral immunomodulating drugs for MS, teriflunomide, was registered in Europe in 2013. Because of the anti proliferative and anti-inflammatory effect of teriflunomide, it can be used for the reduction of the disease activity in the relapsing-remitting course of MS. The effect of teriflunomide was proved in one Phase II. and four Phase III. (TEMSO, TOWER, TENERE, TOPIC) studies. Teriflunomide 14 mg once daily was able to demonstrate in two consecutive placebo-controlled phase 3 clinical trials that significantly reduces the relapse rate (31.5% and 36.3%) and in both studies significantly reduces the sustained disability progression (29.8% and 31.5%) moreover delays the appearance of the clinically definitive MS in patients with clinically isolated syndrome (CIS). According to the TENERE study there were no significant differences observed between teriflunomide 14 mg and IFNbeta-alpha a s.c. in time to failure and annualized relapse rate but the treatment satisfaction domains of global satisfaction, side-effects and convenience were significantly improved with teriflunomide compared with s.c. IFNbeta-alpha. PMID- 26434195 TI - [CONVULSIVE EFFECTS OF ANTIEPILEPTIC AGENTS]. AB - Antiepileptic drugs can provoke and worsen seizures, what is called paradoxical effect. Paradoxical seizure worsening can occur as a nonspecific manifestation of drug intoxication in number of antiepileptic drugs. The other type is a specific type, when antiepileptic drugs with pure GABAergic and sodium channel blocker mechanism of action provoke myoclonic, absence and atonic seizures in specific epilepsy syndromes, mainly in idiopathic generalized epilepsies. Antiepileptic drug-induced exacerbation of seizures is a common, often unrecognized clinical problem, which can be avoided by a careful syndromic diagnosis and by using broad spectrum antiepileptic drugs. PMID- 26434196 TI - [DRUG THERAPY OF NEUROPATHIC PAIN BASED ON THE LATEST RECOMMENDATIONS]. AB - Neuropathic pain is considered as a special type of different pain conditions. It's pathophysiological basis and treatment is completely different from the nociceptive pain. The first comprehensive therapeutic guidelines published approximately a decade ago recommended tricyclic antidepressants, anticonvulsants and opioids. The recent summary presents and evaluates national and international guidelines issued in the last five years. The most frequently suggested drugs by all guidelines are amitriptyline, duloxetine, gabapentin and pregabalin. Pregabalin is the only drug that is recommended first line in all guidelines referred. Opioids are in the second or third line. There seems to be no major development in the pharmacological treatment of the neuropathic pain compared to the earlier recommendations. High quality studies of head to head comparisons and effectiveness of combination therapy are still lacking. PMID- 26434197 TI - DO PREVIOUS OFFENCES PREDICT VIOLENT ACTS IN PSYCHIATRIC PATIENTS? A RETROSPECTIVE STUDY IN HUNGARY. AB - AIM: To investigate the presence of offences in the previous past history of perpetrators of violent acts who have undergone forced medical treatment. METHODS: The documentation of all patients released over a 10-year period from the National Institute of Forensic Psychiatry (IMEI) was reviewed. A comparison was drawn between patients who were convicted of any type of offense before the violent act (patients with previous offences-PPO) and those who were not (patients with no previous offences-PNO). RESULTS: Eighty-six (29%) and 208 (71%) patients formed the PPO and PNO groups, respectively. Prior contact with psychiatric services was significantly higher in the PPO group (p=0.038) and this group was also more likely to offend under the influence of a psychoactive substance (p<0.001). Exceptional brutality and other qualifying factors were more frequent in the PNO group (p=0.019). CONCLUSION: As IMEI is the only forensic institution in Hungary, the picture presented here reflects the situation in the entire country. A recidivism rate of 29% is within the internationally published range. PMID- 26434198 TI - EFFECTS OF MATERNAL EPILEPSY AND ANTIEPILEPTIC THERAPY IN WOMEN DURING PREGNANCY. AB - OBJECTIVE: The aim of this study was to analyse the effects of epilepsy and antiepileptic drug (AED) treatment on pregnancy and the perinatal outcome, retrospectively. METHODS: We examined the obstetric and fetal outcomes among women with epilepsy (WWE), who were followed-up at the Department of Neurology, and who delivered at the Department of Obstetrics and Gynaecology (n=91) between 31th December 2000 and 31th March 2014. Statistical comparisons of different obstetric and fetal parameters on a sample of 91 WWE and 182 non-WWE were assessed by the chi-square-test, the independent sample t-test. RESULTS: The rate of major congenital malformations (MCMS) among the newborns of all AEDs exposed mothers was 7.69%. There were three peaks of seizures: during the third trimester, during delivery and in the puerperium. The prevalence of miscarriages, post-term birth and the rate of caesarean section were significantly higher among the WWE than among the non-WWE (p=0.001; p<0.001; p=0.02). Parameters of neonates (birth weight, birth length, head-, and chest circumference) were significantly different between the WWE group and the non-WWE group (p=0.003, p<0.001, p<0.001, p<0.001) CONCLUSIONS: In contrast with recent publications, there were significant differences in the parameters of neonates between the two groups. Our results are in accordance with those of previous studies from the aspect of AED related MCM, the elevated risk of miscarriages and pre-existing hypertension. PMID- 26434199 TI - LACK OF ASSOCIATIONS BETWEEN CLU AND PICALM GENE POLYMORPHISMS AND ALZHEIMER'S DISEASE IN A TURKISH POPULATION. AB - BACKGROUND AND PURPOSE: To investigate the association between the rs11136000 single nucleotide polymorphism (SNP) of the clusterin (CLU) gene, the rs541458 and rs3851179 SNPs of the phosphatidylinositol-binding clathrin assembly protein (PICALM) gene and Alzheimer's disease (AD) in a Turkish population, and to determine whether there are any relationships between the CLU and the PICALM genotypes and behavioral and psychological symptoms of dementia (BPSD) in the Turkish population. METHODS: One-hundred and twelve AD patients and 106 controls were included in this study. BPSD were evaluated by the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). SNPs in the CLU and the PICALM gene were genotyped by Real-Time PCR. Genotype distributions were assessed for the groups of patients and controls, for the patient groups with and without each BPSD, and "No BPSD" and "BPSD". RESULTS: The CLU and the PICALM genotypes were similar in the AD and control subjects, and the groups with and without each BPSD. There were also no significant differences between the "No BPSD" and the "BPSD" groups for the PICALM genotypes, but even without a statistical significance, it is notable that none of the "No BPSD" patients had genotype pattern CLU-rs11136000-TT, and the female subjects with genotype pattern CLU rs11136000-TT had higher mean score of BEHAVE-AD. CONCLUSION: This study claims that investigated SNPs are not genetic risk factors for AD in a Turkish population. In addition, the rs541458 and rs3851179 of PICALM SNPs are not related to development of BPSD, but the rs11136000 of CLU SNP might be related to development of BPSD in AD female Turkish subpopulation. PMID- 26434200 TI - [SHIFTING FUNCTION OF WORKING MEMORY IN PSYCHOTIC DISORDERS]. AB - BACKGROUND AND AIMS: Mental disorders with psychotic features are overlapping in many ways and there are a growing number of comparative studies in the last decades regarding this. Cognitive deficit is well underpinned in schizophrenia, but fewer studies are conducted in this area including patients with bipolar affective disorder. Therefore the aim of the present study was to investigate the cognitive performance of these two patient groups and healthy controls. The Wisconsin Card Sorting Task is a very sensitive measure of the shifting function. Schizophrenic patients perform consistently poorer on this task than healthy controls, while there are not much data about individuals with bipolar affective disorder. METHODS: The Wisconsin Card Sorting Task and clinical symptom rating scales were administered to 26 patients with schizophrenia, 24 with bipolar affective disorder and 21 healthy controls. RESULTS: Significant differences were found among the performance of the three groups using four different dimensions of the Wisconsin Card Sorting Task. The schizophrenic group made more perseverative errors and achieved less conceptual level responses and completed fewer categories compared to healthy controls. Patients with schizophrenia were able to complete fewer categories and had fewer conceptual level responses than the bipolar group. No significant differences were observed between patients with bipolar disorder and healthy controls. CONCLUSIONS: According to these results, patients with schizophrenia and bipolar affective disorder showed no similarities on the Wisconsin Card Sorting Task. Bipolar patients performed the task on the same level as healthy individuals did. The two mental disorders influence cognitive performance differently. PMID- 26434201 TI - GENETIC POLYMORPHISMS OF HUMAN beta-DEFENSINS IN PATIENTS WITH MULTIPLE SCLEROSIS. AB - AIMS: Recent studies have started to elucidate the contribution of microbiome to the pathogenesis of multiple sclerosis (MS). It is also supposed, that neuropathological alterations might be associated with abnormal expression and regulatory function of antimicrobial peptides (AMPs), including defensins. It is in our interest to investigate the relevance of the single nucleotide polymorphisms (SNPs) of the DEFB1 gene and the copy number polymorphism of the DEFB4 genes in MS. METHODS: DEFBI polymorphisms: c.-20G > A (rsl 1362), DEFB1 c. 44C > G (rsI 800972), DEFB1 c.-52G>A (rsl 799946), and the DEFB4 gene copy number were investigated in 250 MS patients The control patients comprised 232 age- and gender-matched healthy blood donors. The occurrence of the human beta-defensin 2 peptide (hBD2) in the plasma of controls and patients-was determined by ELISA. RESULTS: The DEFB1 c.-44C>G polymorphism the GG protective genotype was much less frequent among patients than among the controls. A higher frequency of a lower (<4) copy number of the DEFB4 gene was observed in the patients with MS as compared with the controls (43% vs. 28%, respectively). The median levels of the circulating hBD2 in the patients were 150.6 +/- 12.71 pg/ml vs. 262.1 +/- 23.82 pg/mI in the control group (p<0.0001). Our results suggest that beta-defensins play role in the development of MS. PMID- 26434202 TI - [MEASURING THE FUNCTIONAL IMPAIRMENT OF THE LUMBAR SPINE]. AB - BACKGROUND AND PURPOSE: The purpose of our study was to outline the Hungarian validation process of the Oswestry Disability Index, the Quebec Back Pain Disability Scale, the Roland-Morris Disability Questionnaire and the Core Outcome Measurement Index, as well as to draw up recommendations regarding their future applications. METHODS: The Hungarian versions were created after a cultural and linguistic adaptation. Next to the above-mentioned questionnaires, the questionnaire booklet used for validation also contained the WHOQoL-BREF general quality of life questionnaire and a pain measuring Visual Analog Scale. The data of low-back pain patients were registered twice in two weeks. We determined the internal homogeneity (Cronbach alpha), reproducibility, standard error of measurement and the minimal detectable change of the questionnaires. Patients were assigned into different two subgroups (surgical / non-surgical, with/without affection of nerve roots) and differences between the subgroups were examined with the help of the questionnaires. We determined the physical subscale of the WHOQoL-BREF and the correlation between the pain and the studied questionnaires. RESULTS: The value of Cronbach alpha was between 0.85 and 0.95. All four questionnaires showed significant differences (p<0.001) between the subgroups. The correlation studies brought strong and significant results (p<0.001, r>0.5) in every case. The values of reproducibility were between 0.93-0.92. The results of standard measurement error: 4.8 (Oswestry), 5.2 (Quebec), 1.6 (Roland-Morris), 0.59 (Core Index). The minimal detectable change was 13; 14; 4, and 2 points, respectively. CONCLUSION: The Hungarian versions of all four questionnaires are valid. They can be applied with scientific certainty to measure low back pain patients. From the studied questionnaires, we especially recommend the wide raging application of the Oswestry Disability Index and the Core Outcome Measurement Index based on their psychometric and application features. PMID- 26434203 TI - [Position Statement of Hungarian Epilepsy League: The use of valproate preparations for epilepsy in pregnancy and in women of childbearing age]. PMID- 26434204 TI - [Dr. Pal Fejerdy receives the Eotvos-Jozsef Award]. PMID- 26434205 TI - [Experience with the use of short dental implants in the literature]. AB - According to the literature short dental implants have often been used for the replacement of teeth in the daily praxis. The implantation of short dental implants raise a lot of questions. The autors's aim is to collect the most important experiences of current literature on the mentioned theme to oral implantologists. In the article 33 reviews and clinical studies have been overviewed. The analysis of the different studies suggest that the use of short implants--taking into account of indications and contraindications--decreases the incidence of complications and the patient's discomfort as well as the cost of treatment. The use of short dental implants is proposed as an alternative method in the daily dental praxis. PMID- 26434206 TI - [Report form the symposium in honor of Professor Bob ten Cate -- Amsterdam, April 17, 2015]. PMID- 26434207 TI - [Surgery on virtual model and 3-dimensional printing of a surgical wafer for the correction of a severe mandibular asymmetry]. AB - Correction of a severe facial asymmetry presents a challenge due to the geometric complexity of the dentition, the bony structures and the soft tissues. In most asymmetric cases two-jaw surgery is recommended. Manual model surgery is an essential part of treatment planning but it can be complicated, time-consuming and may contain potential errors. We present a case of a 26-year-old male with a severe right-sided hemimandibular elongation when computerized simulation surgery was performed instead of manual model surgery. High-resolution computer tomography scan was done following presurgical orthodontics and the stack images were reformatted into a three-dimensional structure. The symmetry of the maxilla was corrected via a virtual Le Fort I osteotomy with the help of a three dimensional planning software. A virtual intermediate surgical wafer was designed and fabricated with a three-dimensional printer. Virtual bilateral sagittal split osteotomy was performed and the mandible was rotated into the correct position to visualize the movements of the osteotomized segments. Real surgery was accomplished according to the virtual plan. The splint fitted well. There is a significant improvement in the facial symmetry; the occlusion is good and stable. This case supports the usage of computer-aided surgical planning and three dimensional rapid prototyping for the correction of facial asymmetries. PMID- 26434208 TI - [Difficulties in differential diagnosis of dentin dysplasia. Case report]. AB - In cases of periapical lesions of unknown origin we have to keep in mind the possibility of dentin dysplasia. From the differential diagnostic point of view of differential diagnosis it is important to recognize this disease as it significantly influences the treatment modality. It is an anomaly of unknown etiology that could affect both deciduous and permanent dentition. Dentin dysplasia presentation varies clinically and radiologically. A rare manifestation which affects 1: 100000 patients is spontaneously occurring either as periapical abscess or odontogenic cyst. The affected teeth could become mobile and eventually lost. Dentin dysplasia is a genetic disease which shows autosomal dominant inheritance and characterized by abnormal formation of dentin structure which occurs during tooth development. For this article we have reviewed available literature and PubMed database. Dentin dysplasia increases the risk of early tooth loss and associated with it esthetic and functional disturbances. As a result it can influence the psychological and social status of the patients and affect their quality of life. PMID- 26434209 TI - [Dental management of hemorrhage-prone patients]. AB - The authors present a proposal of dental treatment and management of anticoagulated patients and of patients on antiplatelet therapy, with the approval by the Hungarian Association of Oral and Maxillofacial Surgeons and by the Dental Implantology Association of Hungarian Dentists. This current guide was based on recent Hungarian and on several foreign national guidelines and considers significant publications from international literature. PMID- 26434210 TI - [Dental and oral surgical treatment of a B haemophilic patient with high inhibitor level. Case report]. AB - More than 1000 hemophilic male patients are registered in Hungary, from which only a trace number suffers from factor IX inhibitory hemophilia. For correct dental and oral surgical treatment of these patients mandatory cooperation is required among medical specialties, exerting multi-staged haemostatic principles. Authors represent in this case report the dental and oral surgical treatment of a B hemophilic patient with high inhibitor level and describe possible local haemostatic measures. PMID- 26434211 TI - [Dr. Ferenc Konrad lived 70 years and few more days]. PMID- 26434213 TI - [80 years of dentistry education at Debrecen University, Hungary]. PMID- 26434212 TI - [In memory of Professor Dezso Kovacs]. PMID- 26434214 TI - Nurse entrepreneur recognized. PMID- 26434215 TI - Retirement is a dream at 55, but not a reality. Can nurses work until 70? PMID- 26434216 TI - Workforce shortages and retention of older nurses. PMID- 26434217 TI - AUSTRALIA'S HEALTH CUTS. PAYING THE PRICE FOR AUSTERITY MEASURES. PMID- 26434218 TI - Poor communication leads to poor outcomes. PMID- 26434219 TI - Ageing with HIV. PMID- 26434220 TI - Engaging with people with dementia in subacute care. PMID- 26434221 TI - Challenges in self-care in older adults with diabetes. PMID- 26434222 TI - Malnutrition and depression in older adults: Are these health issues too hard to tackle? PMID- 26434223 TI - A partnership approach to evaluating evidence-based practice project in aged care. PMID- 26434224 TI - Passion--the DNA that binds nursing. PMID- 26434225 TI - The deteriorating diabetic client in residential aged care facilities. PMID- 26434226 TI - Alcohol and drug screening for older Australians. PMID- 26434227 TI - What do you do well? Positive questions improve life for older people living in residential care. PMID- 26434228 TI - Developing a conceptual understanding of 'quality continence care'. PMID- 26434229 TI - Rapid Access Service. PMID- 26434230 TI - Aged mental health--innovation in developing a specialist workforce. PMID- 26434231 TI - Change of attitude to males involvement in childbirth. PMID- 26434232 TI - Can feeling good strengthen relationships? PMID- 26434233 TI - Annie. PMID- 26434234 TI - Retention Mechanism for Ion-Pair Chromatography with Chaotropic Reagents. From Ion-Pair Chromatography toward a Unified Salt Chromatography. AB - The breakthrough of chaotropic mobile phase modifiers in reversed-phase high performance liquid chromatography (RP-HPLC) is due to their strong potential to provide adequate retention of ionic analytes without the blamed semipermanent modification of the chromatographic packing often connected to the use of classical ion-pair reagents. The lack of a physicochemical framework that is able to unify eclectic experimental evidence concerning the use of a wide gamut of ionic additives in RP-HPLC is the primary motive force for recent theoretical efforts to model their behavior. The time-honored solvophobic theory cannot properly explain salt effects. Its theoretical basis was recently questioned by breaking experimental evidence at variance with the textbook knowledge of ionic solutions interfaces; meanwhile, a recently proved extended thermodynamic approach to ion-pair chromatography (IPC) is challenged by the breakthrough of neoteric ionic additives whose behavior questions the rigidity of previous retention schemes and bridges salting chromatographic phenomena to IPC. Building on these research needs, the aims of this review are (1) to illustrate a comprehensive theory of analyte retention in the presence of any kind of electrolytes (hydrophobic ions, chaotropes, kosmotropes, ionic liquids [ILs]) to capture and rationalize the main salting effects and to support their strong practical impact for the separation of organic and inorganic ions, ionogenic, neutral, and zwitterionic analytes; (2) to explain why ion-specific salting chromatographic effects that represent a diachronic scientific consideration were not satisfactorily explained in the rubric of the solvophobic theory; and (3) to highlight the eligibility of chromatography as a basic technique that is able to clarify the currently hotly debated behavior of ions at water interfaces. The practical impact of chaotropic chromatography will also be detailed, and urgent research needs and suggestions will be illustrated. PMID- 26434235 TI - Mechanistic Aspects of Chiral Recognition on Protein-Based Stationary Phases. PMID- 26434236 TI - Mechanistic Aspects and Applications of Chiral Ligand-Exchange Chromatography. PMID- 26434237 TI - Glycosylation Analysis of Proteins, Proteoglycans, and Glycolipids Using Capillary Electrophoresis and Mass Spectrometry. PMID- 26434238 TI - Oligonucleotide Adducts as Biomarkers for DNA Damages. Analysis by Mass Spectrometry Coupled to Separation Methods. PMID- 26434239 TI - Quantitative in Silico Analysis of the Specificity of Graphitized (Graphitic) Carbons. PMID- 26434240 TI - Application of Column-Switching Methods in HPLC for Evaluating Pharmacokinetic Parameters. PMID- 26434241 TI - Chromatographic Procedures in a Regulated Environment. PMID- 26434242 TI - The Use of Novel Materials as Solid-Phase Extractors for Chromatographic Analysis. PMID- 26434243 TI - Thin-Layer and High-Performance Thin-Layer Chromatographic Analysis of Biological Samples. PMID- 26434244 TI - Development of the Model for Local Drowning Surveillance System in Northeastern Thailand. AB - BACKGROUND AND OBJECTIVE: There is growing evidence that the drowning fatality rate in Thailand has been increasing, particularly among children. The use of public health surveillance system in accident injury, specifically from drowning, at a community level is limited. This study aimed to develop a surveillance system to reduce risk of drowning in a rural area of Thailand. MATERIAL AND METHOD: A 7-step process was used to develop a model for local drowning surveillance system based on community participation. The target population consisted of 182 informants, 562 participating surveillance networks, and 21,234 villagers in two sub-districts of Ubon Ratchathani Province, northeastern Thailand. Two similar sub-districts were chosen as comparison areas. RESULTS: Fifteen months after implementation of the model for local drowning surveillance system (MLDSS) was introduced, improvements were found in all identified risk factors, and the incidence rate ratio of injury in the comparison areas was 23.36 times higher than in the target areas. CONCLUSION: In the developing world where community bonds remain strong, governments need to encourage local officials, the private sector and the wider community to work together in solving the problem of drowning in their local areas. Such schemes will require national promotion and basic funding. PMID- 26434245 TI - Developing a Substance Literacy Scale for Thai Population. AB - OBJECTIVE: To develop a substance literacy scale for Thai population. MATERIAL AND METHOD: The research design was divided into 8 steps as follows: 1) devising the items, 2) exploring construct validity of each factor 3) validating reliability of each factor, 4) generating construct validity of scale, 5) testing conceptual construct ofthe scale, 6) constructing alternated rating scales, 7) conducting cognitive test, and 8) conducting pilot test. There were 15 experts involved in the content validation of scale. The research was conducted with 3,824 samples of Thai population aged between 12-65 years old from all over the country using the Stratified Three Stages Cluster sampling technique. RESULTS: Two substance literacy scales were developed. A standard has questionnaire of 37 items. The scale content validity index was 0.65, concurrent validity was 0.648. A short has questionnaire of 32 items. The scale content validity index was 0.86, concurrent validity was 0.667. CONCLUSION: Both scales are simple and easy to use. Scale characteristics are appropriate to assess the substance literacy of population. It can be beneficial to planners for strategic development to respond to the problem more accurately. PMID- 26434246 TI - Size Estimation of Injecting Drug Users through the Network Scale-Up Method in Thailand. AB - BACKGROUND AND OBJECTIVE: Hard to reach populations such as injecting drug users (IDU) is one, among the most at risk, for HIV infection in Thailand. This study examined an indirect methodfor estimating the size of IDU population in Thailand. MATERIAL AND METHOD: A household survey was conducted among 3,790 individuals who were 12-65 years old, stayed at least 3 months in the sample households. Through, reference groups and summation procedure, personal network size was estimated. The participants were asked to identify the number of their acquaintances whom they perceived to be IDU. Using the survey results with the network scale-up method, the IDU population size was estimated. RESULTS: The personal network size was estimated to be 71,000 ID Us. The estimated prevalence of total population in Thailand was 110 IDUs in 100,000 population. CONCLUSION: Estimating population sizes through the network scale-up method appeared to be an effective method in terms of time, simplicity, and low cost as compared with more-conventional methods. PMID- 26434247 TI - Using Population Based Data on Drugs Abuse to Estimate the Relative Need for Medical Services in Thailand. AB - BACKGROUND AND OBJECTIVE: Epidemiological background shows a trend in drug abuse and essential need for revising its strategic plans, allocating resources, and advocating services for populations. The relative need for drug abuse prevention and medical services across different geographic areas of Thailand, which has been examined through an analysis of existing population-based datasets and reported routinely. The objective was to develop an indicator of relative need for drug abuse prevention and medical services. MATERIAL AND METHOD: Qualitative data were collected as primary data sources from 10 focus group discussions throughout Thailand. The primary data were integrated into study framework with the result from literature review. Data sets in 2011 were retrieved from the national databank to obtain variables regarding drug abuse. Multiple regression and factor analysis were undertaken using the district as the unit of analysis. RESULTS: A factor analysis, which revealed six factors that explained 64% of the variance in the data set. Factors identified in the analysis were taken as indicators of variation in the need for services as all of the drugs-related variables loaded strongly on these factors. The distribution of ranks for factor scores (determined through regression) obtained for these factors across districts in Thailand showed that scores were highest in urban and suburban areas. CONCLUSION: In terms of practical implications, the study results could be used for resource allocation in medical service plans for community drug abuse. PMID- 26434248 TI - The Prevalence and Associated Factors of Alcohol Consumption: A Cross-Sectional Study in Khon Kaen, Thailand. AB - BACKGROUND AND OBJECTIVE: Knowledge of the situation and risk factors associated with alcohol consumption are essential for prevention and control measures of health consequences. This study aims to explore the prevalence of alcohol consumption and the factors associated with alcohol consumption in the population aged 12-65 years. MATERIAL AND METHOD: This was a descriptive study. This survey used multi-stage sampling and face-to-face interviews, carried out in both urban and rural areas. Those interviewed were a representative sample of 876 people in the ratio ofone male and one female to represent the household. Data were collected by interviewers between 1 January and 28 February 2012. The data were analyzed by frequency, percentage, mean, standard deviation, Chi-square, multiple logistic regression, OR and 95% CI of OR. This study was approved by the ethics and research institutional review board of Khon Kaen University No. HE53121. RESULTS: The mean age of the respondents was 41.7 years (SD 13.6). The majority of the respondents were the head of the family (33.9%), those educated to primary school level (44.6%), living in rural areas (55.9%), who were married (70.7%), and who were farmers (35.3%). The prevalence of alcohol consumption during the previous week was 6.3% (95% CI: 4.7 to 7.9), during the previous month was 35.2% (95% CI: 32.0 to 38.3), and during the previous year was 41.0% (95% CI: 37.7 to 44.2). The factors associated with alcohol consumption were gender (male/female) AOR 6.5 (95% CI 4.4 to 8.9, p-value < 0.001) age group (25-44/45-65) AOR 1.6 (95% CI 1.1 to 2.4, p-value = 0.011) location (rural/urban) AOR 1.7 (95% C1 1.3 to 2.4, p-value < 0.001) educational attainment (bachelor or master degree/primary school) AOR 1.7 (95% CI 1.1 to 2.8, p-value = 0.031) and the occupation (laborer) AOR 1.6 (95% CI 1.1 to 2.4, p-value = 0.015). CONCLUSION: Knowing the prevalence and factors associated with alcohol consumption are essential to understanding the situation, solving related problems and using the information in the campaign for the prevention and control of alcohol consumption PMID- 26434249 TI - Effect of Andrographis paniculata Extract on Triglyceride Levels of the Patients with Hypertriglyceridemia: A Randomized Controlled Trial. AB - BACKGROUND: Hypertriglyceridemia is one of the risk factors for cardiovascular disease, and reduction oftriglyceride (TG) level is recommended in clinical practice guidelines for the treatment. Recently, andrographolide, a main active compound of Andrographispaniculata has been shown to possess hypolipidemic effects in animals. OBJECTIVE: To investigate the TG-lowering effects of A. paniculata extract (APE) in patients with hypertriglyceridemia (TG >= 150 mg/dL) using gemfibrozil treatment as the reference. MATERIAL AND METHOD: A randomized controlled clinical trial was carried out in sixty subjects with hypertriglyceridemia. They were divided into three groups and treated with low dose of APE (APE-L, andrographolide 71.64-72.36 mg/day), high dose of APE (APE-H, andrographolide 119.64-120.36 mg/day), and gemfibrozil 300 mg/day. The treatments were conducted for 8 weeks. Guidance on lifestyle modifications was provided. RESULTS: The primary endpoint was the mean difference +/- SD (95% CI) in TG levels (baseline from the end of treatment), which were -3 +/- 125.6 (-59.1, 58.5), 41.6 +/- 86.3 (1.2, 82), and 57.1 +/- 94.9 (12.7, 101.6) in the APE-L, APE H, and gemfibrozil groups, respectively. APE-H 120 mg/day and gemfibrozil 300 mg/day caused a significant reduction of TG level (P = 0.0442 and 0.0145, respectively) when compared to the baseline. There was no notable difference in the safety or tolerability among the treatment groups. CONCLUSION: In patients with modest hypertriglyceridemia with lifestyle intervention, APE-H reduced the TG level comparable to the effect of gemfibrozil 300 mg/day. APE treatment was as tolerable as gemfibrozil treatment. Hence, Andrographis paniculata might be used as an alternative medicine in treating hypertriglyceridemic patients. PMID- 26434250 TI - The Development of a Readiness Scale for Changing Farmers' Behaviors of Using Pesticides. AB - BACKGROUND AND OBJECTIVE: Inappropriate pesticide-using behaviors impose significant negative impacts on health and environment. Developmentalprograms to change such behaviors offarmers should target those who are ready to change in order to achieve efficiency. The objective was to develop a readiness scale in changing behavior ofusing pesticides offarmers. The scale of this study is expected to be used in recruiting targetfarmers in developmental programs. MATERIAL AND METHOD: A cross-sectional study was divided into two phases. The first phase, qualitative method, performed on 17farmers participated to seek factors related to the farmers' safe use of pesticides. The second phase, quantitative method to develop the readiness scale, an exploratoryfactor analysis (EFA) was analyzed on 230farmers and was randomly selected to measure the scale's construct validity, internal consistency (reliability), one-dimensionality and the appropriate cut-off point, respectively. RESULTS: Farmers' pesticide use, safety behaviors involved several factors, and are applied to create a set ofquestions on the readiness scale; there were 33 main items (with 40 sub-items), which could be grouped into 8 factors associated with farmers using pesticide safety, the scale, the best way to predict farmers who are ready to change. Finally, they were reduced to 23 main questions with 30 sub-questions in the scale. CONCLUSION: The development of a readiness scale application of changing behaviors as a guide, to assess content validity using index of item-objective congruence measurement (IOC), the exploratory factor analysis was used to determine an item and to test reliability on the scale. The scale can be a useful tool for recruiting farmers into intervention program in changing pesticide use, safety behaviors. PMID- 26434251 TI - Disability-Adjusted Life Years among Drug Users in Khon Kaen: An Evidence-Based Approach. AB - OBJECTIVE: To examine the Disability Adjusted Life Years (DALYs) among drug users in Khon Kaen. MATERIAL AND METHOD: A cross-sectional descriptive study was conducted between January 2014 and February 2015. Patients' medical records, supported by the Khon Kaen Provincial Public Health Office, were used for data regarding the treatment ofthe drug users between October 2013 and September 2014. SPSS version 19.0 for windows was used to analyze descriptive statistics and Pearson's correlations. RESULTS: A review of medical records revealed a total number of drug users were 3,605 males (92.25%) and 303 females (7.75%). A total of 2,195 cases (56.17%) were drug dependence. 20 drug users died due to drug related causes. A total DALYs were 6,772.26 and a prevalence rate of DALYs was 3.76/1,000 populations. The correlation analyses showed significantly factors related to the DALYs among drug users were age, occupation, pattern of drug use, levels of severity, drug-related death and treatment services. CONCLUSION: The DALYs were apparently high among male drug users, who completed primay school education, were drug-dependent and being treated in group therapy. The health authorities may use these associated factors in order to develop or improve programs related to prevention, harm reduction and treatment services effectively. PMID- 26434252 TI - Effectiveness of Culturally Appropriate Initiative on Drug-Related Harm Reduction for Sex Workers on the Thai/Malaysian Border. AB - BACKGROUND AND OBJECTIVE: Drug use can harm to sex workers. Abstinence intervention, however, may not be appropriate since drug use fosters their career performance. The objective was to develop the culturally appropriate model for sex workers participation on drug demand reduction at the Thailand/Malaysian border MATERIAL AND METHOD: This study was a pre-post quasi-experimental design. Tripartite participation was used to develop the model aiming to reduce harm regarding drug use. The study carried out during June 2010-May 2011. Data were collected from 150 key informant interviews, 56 focus group discussions, 22 participant observations in various situations, and numerous related materials. Descriptive statistics, survival analysis and 95% confidence interval were utilizedfor quantitative data. Qualitative data were analyzed by content analysis. RESULTS: Drug related harm reduction was evaluated at two-week time along implementation period of 12 months. 89.5% of all sessions introduced could decrease drug related harm. Of all sex workers participated in the study, intended to treat analysis showed 86.9% success rate (95% CI; 77.1, 96.7). Of these, 32.6% became abstinence, 39.1% reduced most of drug related harm. 13.0% reduced partial drug related harm either lessfrequency, less quantity, less concentration, decrease types of drugs/switch to safe drugs or safer method of administration. 2.2% was infancy stage, which needed further support. CONCLUSION: Key success ofthe model was tripartite participation. With active leaders and strong support, sex workers were continually motivated to reduce harm regarding drug use. PMID- 26434253 TI - Prevalence and Factors Associated with the Utilization of Dental Care Services among Factory Workers in Nava Nakorn Industrial Estate, Pathumthani Province, Thailand. AB - OBJECTIVE: The present study aimed to find out the utilization prevalence of dental care services among factory workers over a period of one year and factors associated with utilization of dental care services. MATERIAL AND METHOD: This was a cross-sectional analytic study. The study population was factory workers in Nava Nakorn Industrial Estate randomly sampled using Probability Proportion to Size Cluster Sampling Method. The tool was a questionnaire about utilization of dental care services. RESULTS: Among the sample group of 1,500 workers from 16 factories, almost 2/3 (63.9%) had never used any dental care services in the previous year while only 36.1% did. A multivariable logistic regression analysis showed that workplace, accommodation, tooth decay, toothache history, transportation, experience in using social security fund for dental care services, availability and accessibility of dental care services, brushing teeth regularly after meals, using dental care services regularly in a dental clinic, and agreement with the idea that a tooth extraction and medication by a dentist could reduce the risk of progression of disease, statistical significance (p value < 0.05), were factors associated with the utilization of dental care services at R2 (The Nagelkerke R Square) 0.38. CONCLUSION: That the prevalence of the factory workers who did not use dental care services during the last one year was 63.9 percent. This study identified three groups of factors associated with the utilization of dental care services as: 1) Predisposing factors, 2) Enabling factors, and 3) Need factors. PMID- 26434254 TI - A Fluorescence Polarization Assay To Detect Steroid Hormone Traces in Milk. AB - Steroids are a class of hormones improperly used in livestock as growth-promoting agents. Due to their high risk for human health, the European Union (EU) has strictly forbidden the administration of all natural and synthetic steroid hormones to food-producing animals, and the development of new rapid detection methods are greatly encouraged. This work reports a novel fluorescence polarization assay, ready to use, capable of detecting 17beta-estradiol directly in milk samples with a low limit of detection of <10 pmol. It is based on the coupling of monospecific antibodies against 17beta-estradiol and fluorophores, capable of modulating the fluorescence polarization emission on the basis of the specific binding of antibodies to fluorescence-labeled 17beta-estradiol derivative. The successful detection of 17beta-estradiol has disclosed the development of an efficient method, easily extensible to any food matrix and having the potential to become a milestone in food quality and safety. PMID- 26434255 TI - SELF-REPORTED MORBIDITY AND BURDEN OF DISEASE IN UTTAR PRADESH, INDIA: EVIDENCE FROM A NATIONAL SAMPLE SURVEY AND THE MILLION DEATHS STUDY. AB - Uttar Pradesh is India's most populous state with a population of 200 million. Any change in its fertility and mortality is bound to bring change at the national level. This study analysed the burden of disease in the state by calculating the disability-adjusted life year (DALY) for infectious and non communicable diseases. Data were from two rounds (52nd and 60th) of the National Sample Survey Organization (NSSO) survey conducted in 1995-96 and 2004, respectively, and the Million Deaths Study (MDS) of 2001-03. Descriptive and multivariate analyses were carried out to identify the determinants of different types of self-reported morbidity and DALY. The results show that in Uttar Pradesh the prevalence of all selected self-reported infectious and non-communicable diseases increased over the study period from 1995 to 2004, and in most cases by more than two times. The highest observed increase in prevalence was in non communicable diseases excluding CVDs, which increased from 7% in 1995 to 19% in 2004. The prevalence was higher for those aged 60 and above, females, those who were illiterate and rich across the time period and for all selected morbidities. The results were significant at p<0.001. The estimation of the DALY revealed that the burden of infectious diseases was higher during infancy, noticeably among males than females in 2002. However, females aged 1-5 years were more likely to report infectious diseases than corresponding males. The age distribution of the DALY indicated that individuals aged below 5 years and above 60 years were more susceptible to ill health. The growing incidence of non-communicable diseases, especially among the older generation, puts an additional burden on the health system in the state. Uttar Pradesh has to grapple with the unresolved problem of preventable infectious diseases on the one hand and the growth in non communicable disease on the other. PMID- 26434256 TI - Antioxidant activities of chestnut nut of Castanea sativa Mill. (cultivar 'Judia') as function of origin ecosystem. AB - The antioxidant properties of different ecotypes of chestnut nut (cv. Judia) were studied. Total phenolics and flavonoids were also determinated. Total phenolics amount ranged from 9.6mg/g of GAE (hottest ecotype, Murca) to 19.4mg/g of GAE (coldest ecotype, Valpacos). Gallic and ellagic acid were the predominant compounds and Valpacos had the highest values while, Murca had the lowest ones. The antioxidant capacity of ethanolic extracts were evaluated through several biochemical essays: ABTS (2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonic acid)) and DPPH (2,2-diphenyl-1-picrylhydrazyl) radical-scavenging activity, FRAP (ferric reducing/antioxidant power) and inhibition of oxidative haemolysis in erythrocytes. In order to evaluate the antioxidant efficiency of each ecotype, the EC50 values were calculated. Once again Valpacos revealed the best antioxidant properties, presenting much lower EC50 values. Climatic conditions influence seems to be a limiting factor for production of phenolic compounds and consequently for the antioxidant properties of chestnut nuts. PMID- 26434257 TI - Relevance of calpain and calpastatin activity for texture in super-chilled and ice-stored Atlantic salmon (Salmo salar L.) fillets. AB - The aim of the present experiment was to measure the protease activities in ice stored and super-chilled Atlantic salmon (Salmo salar) fillets, and the effect on texture. Pre-rigour fillets of Atlantic salmon were either super-chilled to a core temperature of -1.5 degrees C or directly chilled on ice prior to 144h of ice storage. A significantly higher calpain activity was detected in the super chilled fillets at 6h post-treatment compared to the ice-stored fillets and followed by a significant decrease below its initial level, while the calpastatin activity was significantly lower for the super-chilled fillets at all time points. The cathepsin B+L and B activities increased significantly with time post treatment; however, no significant differences were observed at any time points between the two treatments. For the ice stored fillets, the cathepsin L activity decreased significantly from 6 to 24h post-treatment and thereafter increased significantly to 144h post-treatment. There was also a significantly lower cathepsin L activity in the super-chilled fillets at 0h post-treatment. No significant difference in breaking force was detected; however, a significant difference in maximum compression (Fmax) was detected at 24h post-treatment with lower Fmax in the super-chilled fillets. This experiment showed that super chilling had a significant effect on the protease activities and the ATP degradation in salmon fillets. The observed difference in Fmax may be a result of these observed differences, and may indicate a softening of the super-chilled salmon muscle at 24h post-treatment. PMID- 26434258 TI - Volatile compounds in low-acid fermented sausage "espetec" and sliced cooked pork shoulder subjected to high pressure processing. A comparison of dynamic headspace and solid-phase microextraction. AB - Two extraction techniques, dynamic headspace extraction (DHE) and solid-phase microextraction (SPME), were compared to assess the effect of high-pressure treatment (400MPa, 10min, 12 degrees C) on the volatile compounds of low-acid fermented sausage "espetec" and sliced cooked pork shoulder stored at 4 degrees C. DHE was more efficient at extracting low-boiling compounds such as ethanal, 2,3-butanedione and alcohols, while SPME extracted more efficiently a higher number of chemical families, especially fatty acids. The effect of pressurisation on the volatile fraction of "espetec" was better categorized by DHE, whereas SPME was more appropriate for cooked pork shoulder. The volatile fraction of "espetec" changed slightly after pressurisation, mainly showing a decrease in the levels of lipid-derived compounds, like linear alkanes, aldehydes, or 1-alcohols in pressurised samples. The volatile profile of cooked pork shoulder underwent substantial changes during refrigerated storage, mainly due to microbial metabolism, most of these changes being limited by HPP. PMID- 26434259 TI - Differential inhibition of human colon cancer cells by structurally similar flavonoids of citrus. AB - A number of studies in the recent years have evaluated the anti-proliferative activity of flavonoids. Although certain studies investigated the structure activity based on the phenotypic assays, no study has correlated the flavonoids structure with the ability to alter gene/protein expression. Present study was focused to understand the structure-function relationship of citrus flavonoids in terms of their ability to alter the gene expression in the colon adenocarcinoma cells. Eight structurally related flavonoids found in citrus were evaluated for their ability to inhibit colon cancer (SW480) cells, as well as change the expression of apoptosis related genes/proteins. Apigenin and quercetagetin demonstrated most significant inhibition of cell proliferation with 63.6% and 45.7% inhibition of cell growth at 200MUM after 48h of incubation, respectively. The cell death was also confirmed by images of fluorescently tagged cells. Furthermore, up-regulation of Bax/Bcl2 protein ratio as well as activation of Caspase3 at 200MUM at 48h confirmed the induction of apoptosis by apigenin and quercetagetin. In addition, results suggest that the change in Bax/Bcl2 ratio by apigenin and quercetagetin seems to be due to their ability to alter the expression of bax and bcl2 transcription. Results of the currents study suggest that among the citrus flavonoids, double bond between C2 and C3 and hydroxyl group at C3, C6 are highly decisive for the proliferation inhibition and apoptosis induction ability. Taken together, these results demonstrate that among the major flavonoids of citrus, apigenin and quercetagetin have potent anti cancer activity through inducing apoptosis in SW480 human colon cancer cells. PMID- 26434260 TI - Co-occurrence of aflatoxins, ochratoxin A and zearalenone in barley from a northern region of Spain. AB - One-hundred and twenty-three barley samples from a region of Spain (Navarra) were analysed in order to evaluate the possible co-occurrence of aflatoxins (AFB1, AFG1, AFB2 and AFG2), ochratoxin A (OTA) and zearalenone (ZEA). The results indicated that 80% of the samples presented detectable, although very low levels, of two or more mycotoxins. The most frequent combinations were AFB1 and OTA; AFB1, ZEA and OTA; and AFB1 and ZEA. In general, the statistical study did not show significant differences between levels or incidence for the mycotoxins in different years of harvest, variety of barley, farming or origin. The calculated values for daily intake were low and the risk to consumers could be assumed to be very low. However, the co-occurrence of several mycotoxins, and therefore synergic or additive effects, should be taken into account when determining permitted levels or risk assessment. PMID- 26434261 TI - The mechanism underlying proliferation-inhibitory and apoptosis-inducing effects of curcumin on papillary thyroid cancer cells. AB - Recently, many studies on health benefits associated with curcumin have been reported. In this study, the effects of curcumin on apoptosis of papillary thyroid cancer cell line K1 and its potential mechanisms were investigated. Curcumin was found to significantly inhibit cell viability and promoted cell apoptosis in a dose-dependent manner. Moreover, curcumin-induced cell apoptosis was characterized with a rapid stimulation of reactive oxygen species (ROS) production. Furthermore, curcumin-induced ROS generation led to the loss of mitochondrial membrane potential (MMP) and the disturbance of intracellular Ca(2+) concentration. A decrease in expression of Bcl-2 and the cleavage of poly ADP-ribose polymerase (PARP) were observed after exposure to curcumin. Results of this study may elucidate the curcumin-induced apoptosis effects on K1 cells. Thus, our results indicate a role of curcumin as health-promoting food ingredient, as well as a potential chemotherapeutic agent which is able to fight against papillary thyroid cancer. PMID- 26434262 TI - Effect of temperature and air velocity on drying kinetics, antioxidant capacity, total phenolic content, colour, texture and microstructure of apple (var. Granny Smith) slices. AB - The aim of this work was to study the effect of temperature and air velocity on the drying kinetics and quality attributes of apple (var. Granny Smith) slices during drying. Experiments were conducted at 40, 60 and 80 degrees C, as well as at air velocities of 0.5, 1.0 and 1.5ms(-1). Effective moisture diffusivity increased with temperature and air velocity, reaching a value of 15.30*10( 9)m(2)s(-1) at maximum temperature and air velocity under study. The rehydration ratio changed with varying both air velocity and temperature indicating tissue damage due to processing. The colour difference, DeltaE, showed the best results at 80 degrees C. The DPPH-radical scavenging activity at 40 degrees C and 0.5ms( 1) showed the highest antioxidant activity, closest to that of the fresh sample. Although DeltaE decreased with temperature, antioxidant activity barely varied and even increased at high air velocities, revealing an antioxidant capacity of the browning products. The total phenolics decreased with temperature, but at high air velocity retardation of thermal degradation was observed. Firmness was also determined and explained using glass transition concept and microstructure analysis. PMID- 26434263 TI - Preparation and properties of rutin-hydrolyzing enzyme from tartary buckwheat seeds. AB - A rutin hydrolyzing enzyme (RHE) was isolated from Fagopyrum tataricum Moench seeds by using ammonium sulphate fractionation, anion exchange and size exclusion chromatography. The purified RHE has an apparent molecular weight of about 70kDa determined by SDS-PAGE, with an isoelectric point (pI) (determined by isoelectric focusing) of 6.7. RHE has a specific catalytic activity toward rutin when incubated together with rutin at 37 degrees C for 30min in the presence of 20% ethanol, and its Km value for rutin is 1.04*10(-3)M. The RHE catalytic product analyzed by HPLC displayed high similarity with quercetin and this is confirmed by (1)H NMR spectroscopy and LC-ESI-MS/MS, suggesting that the RHE hydrolysis product is quercetin. These results suggest that the RHE from tartary buckwheat seeds is a specific rutin-hydrolyzing enzyme, providing a new enzymatic preparation method for quercetin. PMID- 26434264 TI - Nutritional and functional properties of Vicia faba protein isolates and related fractions. AB - The goal of this research was the characterisation of Vicia faba (broadbean) protein isolates and related fractions in order to determine whether this grain legume could be used for production of high quality protein products and other fractions rich in functional components. Alkaline extraction of the defatted seed flour, followed by precipitation at the isoelectric pH, yielded a 92% protein isolate with a high oil absorption capacity. The contents of the favism-inducing glycosides, vicine and convicine, in the isolate were reduced by more than 99% as compared to the original flour, although the amino acid composition was similar to that of the flour. Some of the by-products of protein isolate production may also be of interest from a nutritional and functional point of view. Thus, the oil resulting from hexane extraction of the flour is rich in unsaturated fatty acids, and polyphenols (resulting from extraction of the defatted flour with acetone) showed a high ABTS radical-scavenging activity. In addition, the solid residue (resulting from protein solubilisation) was high in fibre and showed good water absorption. These results show good nutritional and functional properties in V. faba protein isolates and related fractions, which may favour the revalorisation of this traditional bean crop. PMID- 26434265 TI - Glycidyl esters in refined palm (Elaeis guineensis) oil and related fractions. Part II: practical recommendations for effective mitigation. AB - In a previous work, it was shown that at high temperatures (up to 280 degrees C) glycidyl esters (GE) are formed from diacylglycerols (DAG) via elimination of free fatty acid (FFA). In the present study, the impact of DAG content and temperature on the formation of GE using a model vacuum system mimicking industrial edible oil deodorization is investigated. These deodorization experiments confirmed that the formation of GE from DAG is extensive at temperatures above 230-240 degrees C, and therefore, this value should be considered as an upper limit for refining operations. Furthermore, experimental data suggest that the formation of GE accelerates in particular when the DAG levels in refined oils exceed 3-4% of total lipids. Analysis of the lipid composition of crude palm oil (CPO) samples allowed the estimation that this critical DAG content corresponds to about 1.9-2.5% of FFA, which is the conventional quality marker of CPO. Moreover, high levels (>100ppm) of GE were also found in palm fatty acid distillate samples, which may indicate that the level of GE in fully refined palm oils also depends on the elimination rate of GE into the fatty acid distillate. PMID- 26434266 TI - Effect of cooking method on carnosine and its homologues, pentosidine and thiobarbituric acid-reactive substance contents in beef and turkey meat. AB - Commercial samples of beef and turkey meat were prepared by commonly used cooking methods with standard cooking times: (1) broiled at 200 degrees C for 10min, (2) broiled at a medium temperature (140 degrees C) for 10min, (3) cooked by microwave (MW) for 3min and then grilled (MW/grill) for 7min, (4) cooked in a domestic microwave oven for 10min, and (5) boiled in water for 10min. The raw and cooked meats were then analysed to determine the carnosine, anserine, homocarnosine, pentosidine, and thiobarbituric acid-reactive substance (TBARS) contents. It was observed that boiling beef caused a loss of approximately 50% of the carnosine, probably because of the high water solubility of carnosine and its homologues; cooking by microwave caused a medium loss of the anti-oxidants of approximately 20%; cooking by MW/grill led to a reduction in carnosine of approximately 10%. As far as the anserine and homocarnosine contents were concerned, a greater loss was observed for the boiling method (approximately 70%) while, for the other cooking methods, the value ranged from 30% to 70%. The data oscillate more for the turkey meat: the minimum carnosine decrease was observed in the cases of MW/grill and broiling at high temperature (25%). Analogously, the anserine and homocarnosine contents decreased slightly in the case of MW/grill and broiling at a high temperature (2-7%) and by 10-30% in the other cases. No analysed meat sample showed any traces of pentosidine above the instrumental determination limits. The cooked beef showed an increased TBARS value compared to the raw meat, and the highest values were found when the beef was broiled at a high temperature, cooked by microwave or boiled in water. The TBARS value of the turkey meat decreased for all the cooking methods in comparison to the TBARS value of the fresh meat. PMID- 26434267 TI - Phenolic compounds in strawberry (Fragaria x ananassa Duch.) fruits: Composition in 27 cultivars and changes during ripening. AB - Phenolic compounds in fruits of 27 cultivars of strawberry (Fragaria x ananassa Duch.) grown in Norway were characterised and quantified by HPLC-DAD-MS(n). Total phenolic content, calculated as the sum of the individual compounds, varied 2.3 fold among cultivars, i.e., from 57 to 133mg/100g of fw. There were significant differences among cultivars in concentration of all phenolic compounds. The highest variation between cultivars was found for cinnamoyl glucose (0.6 24.9mg/100g of fw). Concentration of anthocyanins, the most abundant class of phenolic compounds in the majority of the cultivars, varied from 8.5 to 65.9mg/100g of fw. Flavan-3-ols (11-45mg/100g of fw) and ellagitannins (7.7 18.2mg/100g of fw) contributed on average 28% and 14% to total phenolic contents in the strawberry cultivars, respectively. In three cultivars harvested at three stages of ripeness, anthocyanins and cinnamic acid conjugates were the compounds most affected by ripening. The anthocyanin profile for the individual cultivars was only slightly affected by ripening and growing conditions. PMID- 26434268 TI - Influence of filtration on volatile compounds and sensory profile of virgin olive oils. AB - The influence of filtration through a hydrophilic cotton layer on volatile compounds, sensory characteristics and colour of two monovarietal oils was investigated in this study. Volatiles were evaluated using headspace solid-phase microextraction-gas chromatography. After the filtration of Buza oils only a slight increase in total alcohols was noticed. In filtered Crna oils a significant decrease of total alcohols and slight changes in total aldehydes, total ketones and total C5 volatile compounds concentration were detected. No significant influence on the sensory scores of oils, but some slight changes in sensorial profiles were noted (slightly higher intensities of sensory characteristics apple and grass, and higher values of the lightness L(*) in filtered samples). The results point to unequal filtration impact on different monovarietal oils and could be useful in developing targeted technologies for specific monovarietal oils quality improvement. PMID- 26434269 TI - Antioxidant activity of protein hydrolysates derived from threadfin bream surimi byproducts. AB - Antioxidant activities of protein hydrolysates from threadfin bream surimi wastes, including frame, bone and skin (FBS) and refiner discharge (RD), were investigated. FBS and RD were rich in Lys, Glu, Gly, Pro, Asp, Leu, His, Tyr and Phe. FBS was hydrolysed to a greater extent than RD regardless of proteinases tested (Virgibacillus sp. SK33 proteinase, Alcalase, pepsin and trypsin). Pepsin hydrolysed FBS, at a 5% degree of hydrolysis (DH), showed the highest antioxidant activity based on 2,2'-azinobis (3-ethyl-benzothiazoline-6-sulphonate) (ABTS) radical (0.455+/-0.054mg Trolox equivalents/mg leucine equivalents), ferric reducing antioxidant power (FRAP) (0.221+/-0.005mM Trolox equivalents) and inhibition of beta-carotene bleaching assays. FBS hydrolysates showed higher antioxidant activity based on chemical assays than their RD counterparts. However, FBS and RD hydrolysates protected HepG2 cells against tert-butyl hydroperoxide-induced oxidative damage to a similar extent. Therefore, FBS and RD hydrolysates have a potential as antioxidative neutraceutical ingredients. PMID- 26434270 TI - Aroma potential of Brancellao grapes from different cluster positions. AB - In this study the presence of aroma compounds in grapes of Brancellao (Vitis vinifera L.) was investigated in order to obtain its aroma potential fingerprint. It is well known that differences exist in aromatic compounds amongst grapevine varieties at ripening stages. Within the framework of an increasingly competitive market, the chance of obtaining different wines from vines of the same variety grown at the same vineyard is becoming of increasing importance. This can be done through the managing of the vineyard, but also some wineries have assayed the separation of the tip and shoulder berries of the clusters of a specific variety with this objective. In this work it is evaluated that, in the final stages of maturation, differences exist in the probable alcoholic degree, total acidity of the must, as well as in the aromatic composition of skin and flesh of berries coming from the tips and shoulders of the clusters. Gas chromatography coupled to mass spectrometry (GC-MS) was used to determine the aromatic composition, in the skin and flesh of each sample, either tip or shoulder berries from the clusters. The obtained results showed that there was not variability for the probable alcoholic degree and total acidity between the shoulders and tips, whereas there was variability for their aromatic composition. For the berries from the tips of the clusters most of volatiles were found in the flesh (except aldehydes) and spicy and floral nuances (with the only exception of beta-ionone) were in higher proportions. For the berries from the shoulders of the clusters, most of volatiles were found in the skin (monoterpenes, norisoprenoids, aldehydes, and C6 alcohols), where the flesh was slightly richer in aromatic alcohols, volatile phenols and pantolactone; beta-ionone and herbaceous nuances were in higher proportions. These results are promising for those wineries that are considering the chance of separating berries from tips and shoulders of the clusters for the elaboration of different quality wines. PMID- 26434271 TI - Chemical composition and anti-proliferative and anti-inflammatory effects of the leaf and whole-plant samples of diploid and tetraploid Gynostemma pentaphyllum (Thunb.) Makino. AB - Leaf and whole-plant samples of the diploid and tetraploid Gynostemma pentaphyllum (GP) were investigated and compared for their chemical compositions, and their potential anti-proliferative and anti-inflammatory effects. The highest levels of total flavonoids and phenolics were observed in the diploid leaf botanical (2L3) at 36.84mg rutin equiv/g and 41.15mg gallic acid equiv/g, respectively. The diploid leaf sample (2L2) had the highest amount of rutin and quercetin contents of 77.7MUmol quercetin equiv/g. The tetraploid whole-plant botanical (4L3) had the highest total saponin content of 227.1mg gypenoside equiv/g. Extracts from all tested GP samples showed time- and dose-dependent antiproliferative effects in HT-29 cells, and the diploid leaf samples had the overall highest inhibitory activity. These extracts had different order of antiproliferative properties in the LNCaP cells, suggesting the potential selective inhibition of GP extracts against different types of cancer cells and the effect of the cell model in screening and evaluation of antiproliferative components. In addition, the diploid leaf extracts showed the strongest inhibitory effects on the expression of TNF-alpha, IL-6 and COX-2 mRNA at final concentrations of 0.2 and 1mg botanical equiv/ml media. The results from this study will be used to develop new nutraceutical products from G. pentaphyllum. PMID- 26434272 TI - Possible causes of variation in acrylamide concentration in French fries prepared in food service establishments: an observational study. AB - Acrylamide is a probable human carcinogen, and its presence in a range of fried and oven-cooked foods has raised considerable health concern world-wide. Dietary intake studies observed significant variations in acrylamide concentrations, which complicate risk assessment and the establishment of effective control measures. The objective of this study was to obtain an insight into the actual variation in acrylamide concentrations in French fries prepared under typical conditions in a food service establishment (FSE). Besides acrylamide, frying time, frying temperature, and reducing sugars were measured and the actual practices at receiving, thawing and frying during French fries preparation were observed and recorded. The variation in the actual frying temperature contributed most to the variation in acrylamide concentrations, followed by the variation in actual frying time; no obvious effect of reducing sugars was found. The lack of standardised control of frying temperature and frying time (due to inadequate frying equipment) and the variable practices of food handlers seem to contribute most to the large variation and high acrylamide concentrations in French fries prepared in a restaurant type of FSE as compared to chain fast-food services, and institutional caterers. The obtained insights in this study can be used to develop dedicated control measures in FSE, which may contribute to a sustainable reduction in the acrylamide intake. PMID- 26434273 TI - Determination of catechins and flavonol glycosides in Chinese tea varieties. AB - A standardised profiling method based on high performance liquid chromatography combined with ultraviolet (UV) and mass spectrometric detection (MS) was established to analyse the phenolic compounds of selected tea varieties used for manufacturing of green, black and oolong teas. The composition and content of 24 tea constituents were analysed, including catechins, flavonol and flavones glycosides, phenolic acids and purine alkaloids. Each tea variety had a unique chemical profile. The compositions of catechins were lower in the tea varieties for green tea manufacturing, while the content of myricetin glycosides was the lowest in the tea variety for oolong tea manufacturing. The content of individual phenolic compounds in the selected tea varieties is highly variable. However, the content of total catechins is proposed to be helpful to classify tea according to the future application as non fermented green and fermented oolong or black tea. PMID- 26434274 TI - Alterations in antioxidant enzyme activities and oxidative damage in alcoholic rat tissues: protective role of Thespesia populnea. AB - Recent advances in our understanding of the pathogenesis of alcohol-induced hepato-renal injury and the development of new approaches to its treatment have been reported in various works. This study involves alcohol-induced oxidative stress linked to the metabolism of ethanol involving both mitochondrial and peroxisomal fractions of liver and kidney. Alcohol treatment resulted in the depletion of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), Glutathione-S-Transferase (GST) activities, and reduced glutathione (GSH) content, higher level of malondialdehyde (MDA) and lower levels of protein carbonyls (PC) causing malfunction of hepatic and renal tissues, when compared to control rats. Thespesia populnea (TP) leaf extracts, administered to chronic alcohol ingested rats, were envisaged to possess significant antioxidant defence properties and help in the recovery of tissues from alcohol-induced oxidative damage. The results showed that degenerative changes in hepatic and renal cells of alcoholic groups were minimized by the administration of TP leaf extracts as also revealed by histopathological examination. The current findings indicate that treatment with TP extracts reduces alcohol-induced oxidative stress, thereby protecting the hepatic and renal tissue from alcohol-induced damage. PMID- 26434275 TI - Vibrational spectroscopic analysis of hake (Merluccius merluccius L.) lipids during frozen storage. AB - Vibrational spectroscopy (mid FTIR and FT-Raman) was used to monitor lipids extracted from hake fillets during frozen storage. Kramer shear resistance was used as a marker of texture changes and lipid damage was also investigated by following the development of conjugated dienes and free fatty acids by spectrophotometric methods. Results show that the intensity of the free fatty acid carboxylic nu(CO) band measured by ATR-FTIR spectroscopy can be used for monitoring the development of lipid hydrolysis in hake lipids. Changes in the Raman nu(CC) stretching region (1658cm(-1) band), partially attributed to conjugated dienes development, were the only observed spectroscopic alterations related to lipid oxidation of hake lipids during frozen storage at -10 degrees C. The high correlation of free fatty acids with instrumental texture and the disappearance of the nuas(PO2(-)) band are consistent with membrane lipid hydrolysis being one of the factors directly related with toughening of lean fish flesh. PMID- 26434276 TI - Model studies on the role of 5-hydroxymethyl-2-furfural in acrylamide formation from asparagine. AB - This study aimed to investigate the mechanism of acrylamide formation during heating asparagine (ASN) at elevated temperatures with glucose (GLC), and 5 hydroxymethyl-2-furfural (HMF). The results revealed that HMF rapidly reacted with ASN, leading to acrylamide formation. The ASN-HMF model system generated acrylamide more efficiently than the ASN-GLC model system during heating at 180 degrees C. A significantly higher amount of 3-aminopropionamide (3-APA) was formed in the ASN-HMF model system than in the ASN-GLC model system within 5min at 180 degrees C. The amount of 3-APA decreased after 5min of heating in both model systems while the amount of acrylamide continued to increase in the ASN-HMF model system. In-depth high resolution mass spectrometry analyses of reaction products formed in the model systems together with the kinetic data suggested that HMF is a potent carbonyl accelerating acrylamide formation during heating. 3 APA was found as one of the key intermediates leading to acrylamide formation. PMID- 26434277 TI - Use of monoglyceride hydrogel for the production of low fat short dough pastry. AB - The influence of palm oil replacement with a monoglyceride-palm oil-water gel (hydrogel) on physical properties and acrylamide content of a low fat short dough pastry was studied. The effect of the incorporation of the hydrogel was monitored during storage by assessing moisture, firmness, proton density/mobility using magnetic resonance imaging (MRI) and acrylamide content. The use of hydrogel allowed the lipid content of pastries to be reduced with minor effects on their quality characteristics. However, the hydrogel-containing pastries showed a crunchier crust, higher acrylamide content and a higher tendency to staling. As assessed by MRI, these results were ascribable to the development of a peculiar system morphology promoted by hydrogel incorporation in the food matrix. PMID- 26434278 TI - Antithrombotic activity of fractions and components obtained from raspberry leaves (Rubus chingii). AB - The 70% ethanol fraction from an aqueous extract of raspberry leaves was shown to be the most antithrombotic fraction in in vitro and in vivo tests. The total flavonoids and phenolics in this fraction were 0.286g/g and 0.518g/g by colorimetry. Six compounds, including salicylic acid, kaempferol, quercetin, tiliroside, quercetin 3-O-beta-d-glucopyranoside and kaempferol 3-O-beta-d glucopyranoside, were isolated from the active fraction. Among them, kaempferol, quercetin and tiliroside obviously delayed plasma recalcification time (PRT) in blood. PMID- 26434279 TI - Antidiabetic effect of Ficus racemosa Linn. stem bark in high-fat diet and low dose streptozotocin-induced type 2 diabetic rats: a mechanistic study. AB - The present study was designed to investigate the effects of the ethanol extract of Ficus racemosa (FRE) on biochemical parameters in type 2-like diabetes, induced by a combination of standardised high-fat diet and low-dose streptozotocin (25mgkg(-1), i.p.) in rats. To elucidate the mode of action of FRE, its effects on a battery of targets involved in glucose homeostasis was evaluated. FRE (200 and 400mgkg(-1), p.o.), in a dose-dependent manner, altered the biochemical parameters and significantly improved glucose tolerance and HDL-c levels. In different bioassays, FRE showed inhibition of PTP-1B (IC50 12.1MUg/mL) and DPP-IV (42.5%). FRE exhibited 82.6% binding to PPAR-gamma. Furthermore FRE exhibited stimulation of glucose uptake by skeletal muscles (hemi-diaphragm). Bergenin was quantified in bioactive-FRE by high-performance liquid chromatography (0.15%w/w). This is the first report demonstrating the effectiveness of F. racemosa stem bark in type 2 diabetes and targets involved in it. PMID- 26434280 TI - Rice alpha-globulin decreases serum cholesterol concentrations in rats fed a hypercholesterolemic diet and ameliorates atherosclerotic lesions in apolipoprotein E-deficient mice. AB - The hypocholesterolemic and antiatherogenic effects of rice alpha-globulin remain unclear. We investigated the hypocholesterolemic effect of rice alpha-globulin in rats fed a hypercholesterolemic diet. The rats were divided into 4 groups and were orally administrated the following three proteins or a vehicle for 4weeks: rice protein, rice alpha-globulin, or soy beta-conglycinin at a dose of 100mg/kg body weight or carboxymethylcellulose to the control rats. In the rice alpha globulin group, serum cholesterol concentrations were 28% lower than the control group and fecal neutral steroid excretion was increased by 30%. The hypocholesterolemic effect of rice alpha-globulin was equal to soy beta conglycinin in SD rats fed the hypercholesterolemic diet. However, the serum cholesterol concentrations in the rice protein group did not change compared to the control group. To investigate the antiatherogenic effects of rice alpha globulin, male apolipoprotein E-deficient mice were orally administered the same dose of rice alpha-globulin for 9weeks. The en face lesion area in the aorta was 46% lower than in the control group. In conclusion, administration of rice alpha globulin improves hypercholesterolemia in rats fed a hypercholesterolemic diet by increasing the fecal excretion of neutral sterols, and inhibits atherosclerosis development in apolipoprotein E-deficient mice. The anti-atherosclerotic effect exerts by mechanism(s) other than the regulation of serum MCP-1 and NO concentrations. PMID- 26434281 TI - Anti-angiogenic effects and mechanisms of zerumin A from Alpinia caerulea. AB - Alpinia caerulea (R.Br.) Bentham, a perennial herb growing in tropical and subtropical Australia, is used as a flavouring spice and a ginger substitute. Its fruit has been used as indigenous food among the aboriginal Australians; 95% ethanol extracts of the dried fruits, leaves, rhizomes and roots of this plant were investigated in a zebrafish model by quantitative endogenous alkaline phosphatase assay. Only the fruit extract showed potential anti-angiogenic effect, inhibiting vessel formation by 25% at 20MUg/ml. Two diterpenoids were isolated and identified as zerumin A and (E)-8(17),12-labdadiene-15,16-dial. Zerumin A, which had mainly accumulated in the fruits and bearing a carboxylic group, could dose-dependently inhibit vessel formation, in both wild-type and Tg(fli1a:EGFP)y1 zebrafish embryos. The semi-quantitative reverse transcription polymerase chain reaction assay on wild type zebrafish embryos suggested that zerumin A affected multiple molecular targets related to angiogenesis. Further investigation, by human umbilical vein endothelial cell assays, revealed that zerumin A specifically inhibited the proliferation and migration steps, to prevent angiogenesis progress. PMID- 26434282 TI - Properties of Calanus finmarchicus biomass during frozen storage after heat inactivation of autolytic enzymes. AB - Calanus finmarchicus is a marine zooplankton of interest for the aquaculture industry, as well as for nutraceuticals and the cosmetic industry. The chemical composition of C. finmarchicus rapidly changes postmortem due to autolytic processes; in particular phospholipids rapidly degrade to give free fatty acids. The aim of this study was to inactivate autolytic enzymes in C. finmarchicus by applying heat (72 degrees C, 5-30min) through mixing with boiling, fresh water, and further to explore the effects of heat (70 degrees C, 15min) combined with long time storage (-20 degrees C, 12months) of treated and untreated material. Heat treatment (5min) inactivated all tested enzymes and maintained the initial amount of phospholipids, total lipids and crude protein. Storage of untreated material led to complete degradation of all phospholipids, whereas heat treatment resulted in a stable product containing the initial amount of phospholipids and astaxanthin. PMID- 26434283 TI - Preparation of palm olein enriched with medium chain fatty acids by lipase acidolysis. AB - Medium chain (MC) fatty acids, caprylic (C8:0) and capric (C10:0) were incorporated into palm olein by 1,3-specific lipase acidolysis, up to 36% and 43%, respectively, when added as mixtures or individually after 24h. It was found that these acids were incorporated into palm olein at the expense of palmitic and oleic acids, the former being larger in quantity and reduction of 18:2 was negligible. The modified palm olein products showed reduction in higher molecular weight triacylglycerols (TGs) and increase in concentration of lower molecular weight TGs compared to those of palm olein. Fatty acids at sn-2 position in modified products were: C10:0, 4%; C16:0, 13%; C18:1, 66%; and C18:2, 15.4%. DSC results showed that the onset of melting and solids fat content were considerably reduced in modified palm olein products and no solids were found even at and below 10 degrees C and also the onset of crystallisation was considerably lowered. The cloud point was reduced and iodine value dropped from 55.4 to 38 in modified palm olein. Thus, nutritionally superior palm olein was prepared by introducing MC fatty acids with reduced palmitic acid through lipase acidolysis. PMID- 26434284 TI - Bioprospecting traditional Pakistani medicinal plants for potent antioxidants. AB - Antioxidant potential of four methanol extracts from three selected plant species, namely Salvia nubicola (Lamiaceae), Acer oblongifolium (Aceraceae) and Hedera nepalensis (Araliaceae) was measured using assays in aqueous and lipid systems. Antioxidant activities were investigated in aqueous systems by using DPPH radical-scavenging assay, ABTS radical-scavenging assay and DNA protection assay, while antioxidant activity in a lipid system was determined by using the thiobarbituric acid-reactive substances (TBARS) assay. Additionally, the Folin Ciocalteu method was used to measure total phenolic content. Methanol extracts of leaves and flowers of S. nubicola showed the highest Trolox equivalent (TE) values in the case of the DPPH assay, 2484+/-4.9mmol TE/g extract, as well as total phenolic content, 139+/-0.2mg gallic acid equivalents/g extract. Three fractions (A-C) of the methanol extract of S. nubicola leaves and flowers were produced by semi-preparative HPLC. Fraction B was found to be the most active in the DPPH radical-scavenging assay and had the highest total phenol content. HPLC DAD and LC-MS revealed rosmarinic acid in S. nubicola extracts and chlorogenic acid and rutin in H. nepalensis extracts as the main phenolic antioxidants. PMID- 26434285 TI - Identification of ethyl 2-hydroxy-4-methylpentanoate in red wines, a compound involved in blackberry aroma. AB - The aroma profile of Bordeaux red wines is known to be marked by blackberry and blackcurrant flavours; this study focused on the fresh blackberry aroma in Bordeaux red wines, using sensory gas chromatography-olfactometry (GC-O) and two dimensional gas chromatography analysis (GC-GC-MS). A previous HPLC fractionation of red wine extracts on a C18 column produced four fractions with blackberry aromas that were then analysed by GC-O, GC-GC-MS and GC-MS. From these fractions, 10 esters, corresponding to red- or black-berry fruit descriptors, were characterised by GC-MS. Ethyl 2-hydroxy-4-methylpentanoate (ethyl leucate, EL) was identified for the first time in red and white table wines as a compound directly associated with a "fresh blackberry" aroma. Its perception thresholds were 900 and 300MUg/l, respectively, in dearomatized red wine and model wine solution (alcohol 12%, pH 3.5), and the average concentration in the various wines was ~400MUg/l. Sensory omission tests highlighted the importance of this compound and identified a perceptive interaction with ethyl butanoate. PMID- 26434286 TI - Losses of nitrogen fractions from herring to brine during marinating. AB - Fish meat is characterized by a high content of valuable nutrients. During the marinating process, however, the process of proteins diffusion and other nitrogen fractions from fish to the surrounding brine is commonly observed. It was determined that the total nitrogen loss from herring meat of industrial maturity (4-5day) amounted to 6-19% of raw material nitrogen. Extension of the marinating time to 16-18days increases nitrogen losses even to 18-27%. Less loss was observed during marinating of fresh than of frozen herring and during marinating of carcasses, as opposite to fillets. Higher nitrogen content in fish was not proved to influence higher nitrogen losses in a brine. The majority of loss consisted of nitrogen fractions soluble in TCA, of which one third was formed by alpha-amine nitrogen. Nitrogen contained in brine suspension accounted for only 1.5-4% of total nitrogen losses. With increasing salt or acid concentration the amount of total nitrogen loss was lower from fresh herring and higher from frozen one. Higher salt concentration significantly reduced the amount of non-protein nitrogen and all its fractions during marinating of fresh and frozen herring. In case of acetic acid, the influence of its concentration was diverse and depended on type of herring and its dressing. PMID- 26434287 TI - Antioxidant activity of a new phenolic glycoside from Lagenaria siceraria Stand. fruits. AB - The antioxidant properties of different extracts of Lagenaria siceraria (bottle gourd) fruit were evaluated. In the process, a new phenolic glycoside (E)-4 hydroxymethyl-phenyl-6-O-caffeoyl-beta-d-glucopyranoside (1) was isolated and identified together with 1-(2-hydroxy-4-hydroxymethyl)-phenyl-6-O-caffeoyl-beta-d gluco-pyranoside (2), protocatechuic acid (3), gallic acid (4), caffeic acid (5) and 3,4-dimethoxy cinnamic acid (6). Their structures were elucidated by extensive NMR experiments including (1)H-(1)H (COSY) and (1)H-(13)C (HMQC and HMBC) spectroscopy and chemical evidences. The antioxidant potential of the compound 1 and 2 was tested in different in vitro assay systems such as free radical scavenging assay, 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay, superoxide scavenging activity, reducing power assay and linoleic acid peroxidation assay. PMID- 26434288 TI - Berberine, an isoquinoline alkaloid, inhibits streptozotocin-induced apoptosis in mouse pancreatic islets through down-regulating Bax/Bcl-2 gene expression ratio. AB - Diabetes may cause apoptosis in pancreatic islets. Berberine is an isoquinoline alkaloid used for its pharmacological functions including anti-inflammation. However, the berberine effect on pancreatic islets is still not clear. This study is aimed at clarifying the protective mechanism in berberine against islet cell apoptosis. This study established in vitro experimental models using streptozotocin (STZ)-treated primary pancreatic islet cells from ICR mice to unravel the protective mechanism of berberine on islets. The Bax/Bcl-2 (pro-/anti apoptotic) genes expression in the islets was determined using real-time quantitative polymerase chain reaction assay. The results showed that berberine administration at one time or before STZ-stimulation significantly (P<0.05) down regulated the Bax/Bcl-2 genes expression ratio, compared to those in STZ treatment alone group. Our results suggest that berberine's anti-apoptotic effect on pancreatic primary islets is through down-regulating the Bax/Bcl-2 genes expression ratio in both concurrent and preventive manners. PMID- 26434289 TI - The anticarcinogenic potential of essential oil and aqueous infusion from caper (Capparis spinosa L.). AB - The present study assessed the influence of essential oil and aqueous infusion from wild-grown caper (Capparis spinosa L.) on cell growth, NF-kappaB activation, apoptosis and cell cycle in the human colon carcinoma cell line, HT-29. Methyl isothiocyanate (92.06%), a degradation product of glucosinolate glucocapparin, was detected as major component of essential oil from caper leaves and flower buds. Aqueous infusion of caper showed an interesting and variegate compositional pattern containing several phenolic compounds, among which a flavonol glycoside, rutin (quercetin 3-O-rutinoside, 50.7%) and 5-caffeoyl-quinic acid (chlorogenic acid, 17.5%) were detected as dominant. Caper essential oil and aqueous infusion showed time- and dose-dependent high inhibitory effect on HT-29 cell proliferation. In addition, they induced the inhibition on nuclear factor kappaB (NF-kappaB) activity in a dose-dependent manner, while they did not show any effect on apoptosis in HT-29 cells. Flow cytometric analysis indicated that treatment with caper essential oil and aqueous infusion resulted in G2/M cell cycle arrest in a dose-dependent manner. Presented results suggest that caper contains volatile and non-volatile compounds which potentially can play an important role in colon cancer prevention. PMID- 26434290 TI - Preparative separation and purification of Rebaudioside A from Stevia rebaudiana Bertoni crude extracts by mixed bed of macroporous adsorption resins. AB - The separation and purification of Rebaudioside A (RA) from Stevia rebaudiana Bertoni crude extracts (Steviosides) by macroporous adsorption resin (MAR) mixed bed were systematically investigated. MAR mixed bed of HPD750-LSA40-LSA30-DS401 was selected due to its better separation degree. Based on the kinetics/thermodynamics experiment of the mixed bed, it was found that the experimental data fitted better to the pseudo-second-order model, and intra particle diffusion was rate-limiting step. The adsorption isotherm was consistent with IV equilibrium adsorption isotherm classified by Brunauer. Furthermore, the influencing factors for the separation of RA based on HPLC were also investigated. Under the optimal conditions, the separation degree for RA (DAS) increased from 0.771 to 1.54. Moreover, the experimental results showed that the purity of the obtained product increased from 60% to 97%. PMID- 26434291 TI - Effect of fermentation time and drying temperature on volatile compounds in cocoa. AB - The effects of fermentation time and drying temperature on the profile of volatile compounds were evaluated after 2, 4, 6, and 8 fermentation days followed by drying at 60, 70 and 80 degrees C. These treatments were compared with dry cocoa controls produced in a Samoa drier and by a sun-drying process. A total of 58 volatile compounds were identified by SPME-HS/GC-MS and classified as: esters (20), alcohols (12), acids (11), aldehydes and ketones (8), pyrazines (4) and other compounds (3). Six days of fermentation were enough to produce volatile compounds with flavour notes desirable in cocoa beans, as well as to avoid the production of compounds with off-flavour notes. Drying at 70 and 80 degrees C after six fermentation days presented a volatile profile similar to the one obtained by sun drying. However, drying at 70 degrees C represents a lower cost. Given the above results, in the present study the optimal conditions for fermentation and drying of cocoa beans were 6days of fermentation, followed by drying at 70 degrees C. PMID- 26434292 TI - Pharmacokinetic study of mangiferin in human plasma after oral administration. AB - Mangiferin, an active component of traditional Chinese herbal medicine, although it is reported to have various pharmacological effects, the limited number of pharmacokinetic studies limit its wide application. To evaluate the pharmacokinetics of mangiferin in human, a sensitive high performance liquid chromatography-mass spectrometry (HPLC-MS) method for the determination of mangiferin in human plasma was developed. The proposed HPLC-MS method is selective, precise and accurate enough and enables the identification and quantification of mangiferin for the use in clinical studies. After single oral administration of 0.1, 0.3 and 0.9g mangiferin, respectively, the method was successfully applied for the pharmacokinetics of mangiferin in 21 healthy male Chinese volunteers. The pharmacokinetic of mangiferin was fit to the non compartmental model. The pharmacokinetics parameters were calculated. Mangiferin concentration in plasma reached 38.64+/-6.75ng/mL about 1h after oral administration of 0.9g mangiferin and the the apparent elimination half-life (t1/2) was 7.85+/-1.72h. The absorption of mangiferin was increased with the administration of a large dose and it was concluded that the pharmacokinetics of mangiferin in human was nonlinear. PMID- 26434293 TI - Antifungal nortriterpene and triterpene glycosides from the sea cucumber Apostichopus japonicus Selenka. AB - A nortriterpene glycoside, 26-nor-25-oxo-holotoxin A1 (1), four triterpene glycosides, including both holostane and non-holostane types analogues, holotoxins D-G (2-5), together with three known triterpene glycosides, holotoxins A1 and B (6, 7), and cladoloside B (8), were isolated from the warty sea cucumber Apostichopus japonicus Selenka, a traditional tonic with high economic value in China. The structures of the new compounds were elucidated by a combination of detailed spectroscopic analysis and chemical methods. This is the first report of a nortriterpene glycoside isolated from sea cucumbers. These compounds showed potent antifungal activities in the in vitro biotest. A preliminary structure activity analysis suggests that the 18(20) lactone group and the Delta(25) terminal double bond may increase the activity. The component of the carbohydrate chain seems play an important role whereas the double bond transformation from Delta(9(11)) to Delta(7) in the aglycone moiety contributes little to the bioactivity. PMID- 26434294 TI - A taste of sweet pepper: Volatile and non-volatile chemical composition of fresh sweet pepper (Capsicum annuum) in relation to sensory evaluation of taste. AB - In this study volatile and non-volatile compounds, as well as some breeding parameters, were measured in mature fruits of elite sweet pepper (Capsicum annuum) lines and hybrids from a commercial breeding program, several cultivated genotypes and one gene bank accession. In addition, all genotypes were evaluated for taste by a trained descriptive sensory expert panel. Metabolic contrasts between genotypes were caused by clusters of volatile and non-volatile compounds, which could be related to metabolic pathways and common biochemical precursors. Clusters of phenolic derivatives, higher alkanes, sesquiterpenes and lipid derived volatiles formed the major determinants of the genotypic differences. Flavour was described with the use of 14 taste attributes, of which the texture related attributes and the sweet-sour contrast were the most discriminatory factors. The attributes juiciness, toughness, crunchiness, stickiness, sweetness, aroma, sourness and fruity/apple taste could be significantly predicted with combined volatile and non-volatile data. Fructose and (E)-2-hexen-1-ol were highly correlated with aroma, fruity/apple taste and sweetness. New relations were found for fruity/apple taste and sweetness with the compounds p-menth-1-en-9 al, (E)-beta-ocimene, (Z)-2-penten-1-ol and (E)-geranylacetone. Based on the overall biochemical and sensory results, the perspectives for flavour improvement by breeding are discussed. PMID- 26434295 TI - Effect of cholestin on toxicity of vitamin A in rats. AB - A study was undertaken to investigate the effect of cholestin on the toxicity of vitamin A in male wistar rats. The rats were divided into six groups and fed different diets with or without supplement of 1% cholestin and 25,000-50,000 (IU) vitamin A for 2 months. Hence, the symptoms of vitamin A toxicity in rats included loss of body weight, hepatotoxicity and nephrotoxicity. However, these toxic effects of vitamin A were significantly reduced when the rats fed a diet supplemented with cholestin. Furthermore, the level of vitamin A in the serum of rats treated with cholestin and vitamin A was higher than that of the rats treated with vitamin A alone. It indicated that cholestin might play a role in reducing the toxic effect of vitamin A in rats. PMID- 26434296 TI - Physicochemical properties and oral bioavailability of ursolic acid nanoparticles using supercritical anti-solvent (SAS) process. AB - The objective of the study was to prepare ursolic acid (UA) nanoparticles using the supercritical anti-solvent (SAS) process and evaluate its physicochemical properties and oral bioavailability. The effects of four process variables, pressure, temperature, drug concentration and drug solution flow rate, on drug particle formation during SAS process, were investigated. Particles with mean particle size ranging from 139.2+/-19.7 to 1039.8+/-65.2nm were obtained by varying the process parameters. The UA was characterised by scanning electron microscopy, X-ray diffraction, Fourier-transform infrared spectroscopy, thermal gravimetric analysis, specific surface area, dissolution test and bioavailability test. It was concluded that physicochemical properties and bioavailability of crystalline UA could be improved by physical modification, such as particle size reduction and generation of amorphous state using SAS process. Further, SAS process was a powerful methodology for improving the physicochemical properties and bioavailability of UA. PMID- 26434297 TI - One-step separation of beta-galactosidase from beta-lactoglobulin using water-in oil microemulsions. AB - Solubilisation of beta-galactosidase from Kluyveromyces lactis in Aerosol-OT water-in-isooctane microemulsions was measured as a function of buffer type and concentration, pH, and protein concentration. For buffer concentrations above ~40mM, the enzyme was largely excluded from the droplets. Based on these results, a one-step separation was developed. A protein-containing aqueous feed was injected into an AOT/isooctane solution, with the feed volume slightly in excess of the predicted water solubility. Impurity proteins were entrapped inside the microemulsion droplets that then formed in the organic phase, while the high MW target protein was excluded and entered a newly formed, excess aqueous phase. The separation of beta-galactosidase from the test protein beta-lactoglobulin was most complete at 100mM KCl salt concentration, where the droplets were large enough to carry beta-lactoglobulin but too small for beta-galactosidase. At 100mM [KCl], 92% of the total enzyme activity was recovered in a concentrated and virtually pure form. PMID- 26434298 TI - Evaluation of the total oxidant scavenging capacity of saponins isolated from Platycodon grandiflorum. AB - The antioxidant activity of saponins isolated from Platycodon grandiflorum (PG; Balloon flower) was determined using the total oxidant-scavenging capacity (TOSC) assay. Platycodigenin, polygalacic acid, platycodin D, platycoside E and deapioplatycoside E were isolated and their structures were characterised based on their physical and spectral properties and by comparison of these results with similar data in the literature. Platycodin D showed the greatest TOSC value against peroxyl radicals, followed (in decreasing order) by polygalacic acid, platycodigenin, deapioplatycosides E and platycoside E. Although the TOSC value of the saponins against peroxyl radicals was less than that of glutathione (GSH) and Trolox used as positive controls. However, TOSC value of platycodigenin, deapioplatycoside E, platycodin D or platycoside E against peroxynitrite was 2.35 , 1.27-, 1.02- or 0.75-fold of GSH, respectively, while polygalacic acid exhibited no scavenging capacity of peroxynitrites. These results suggest importance of the presence of hydroxyl group at carbon 24 in platycodigenin in peroxynitrite scavenging. As the number of attached sugar residues in the saponin glycosides is increased, the scavenging capacity of peroxyl radical, but not peroxynitrite was significantly decreased. These results showed that PG saponins have potent antioxidant activities, which is different according to the structure of aglycones and the number of attached sugar residues. PMID- 26434299 TI - Structural characterisation and anti-ageing activity of extracellular polysaccharide from a strain of Lachnum sp. AB - A homogeneous extracellular polysaccharide of Lachnum YM261(LEPS-1) with a molecular weight of 21670Da was characterised. According to HPGPC, IR, periodate oxidation and Smith degradation, GC-MS and (1)H NMR analysis, the results indicated that LEPS-1 was a glucan linked by the beta-(1->3)-d-pyran glycosidic bond. The effect of LEPS-1 on anti-ageing in d-gal model mice was also studied. It was found that LEPS-1 significantly increased the activities of antioxidant enzymes (i.e. SOD superoxide dismutase, CAT catalase, GSH-PX glutathione peroxidase) and decreased malondialdehyde (MDA) content in liver, brain and serum of d-gal model mice. These results showed that LEPS-1 had a strong anti-ageing activity. PMID- 26434300 TI - Development of oxidised and heat-moisture treated potato starch film. AB - This study investigated the effects of sodium hypochlorite oxidation and a heat moisture treatment of potato starch on the physicochemical, pasting and textural properties of potato starches in addition to the water vapour permeability (WVP) and mechanical properties of potato starch films produced from these starches. The carbonyl contents, carboxyl contents, swelling power, solubility, pasting properties and gel texture of the native, oxidised and heat-moisture treated (HMT) starches were evaluated. The films made of native, oxidised and HMT starches were characterised by thickness, water solubility, colour, opacity, mechanical properties and WVP. The oxidised and HMT starches had lower viscosity and swelling power compared to the native starch. The films produced from oxidised potato starch had decreased solubility, elongation and WVP values in addition to increased tensile strength compared to the native starch films. The HMT starch increased the tensile strength and WVP of the starch films compared to the native starch. PMID- 26434301 TI - Implementation of response surface methodology to assess the antiradical behaviour in mixtures of ascorbic acid and alpha-tocopherol with grape (Vitis vinifera) stem extracts. AB - The efficiency of grape stem extracts to express antiradical activity was assessed using two different approaches and DPPH as the radical probe. In addition, the mixture effects when the extracts were combined with ascorbic acid (AA) and alpha-tocopherol (alpha-Tcp) were also evaluated. The approaches included a simple linear regression analysis between the response (antiradical activity) and concentration, but also a response surface methodology, which permitted the monitoring of the response upon simultaneous variation of both the concentration of the total polyphenols of the extracts and either of the antioxidants (AA and alpha-Tcp). The deployment of linear regression poses important constraints with regard to concentration ranges, whereas response surface methodology might be a valuable statistical tool for similar assessments and credible modelling of binary mixtures of antioxidants. In all combinations tested it was found that an antagonism was manifested, presumably as a result of AA and alpha-Tcp regeneration by the extract polyphenols, at the expense of the latter. PMID- 26434302 TI - Heat and pressure treatments effects on peanut allergenicity. AB - Peanut allergy is recognized as one of the most severe food allergies. The aim of this study was to investigate the changes in IgE binding capacity of peanut proteins produced by thermal-processing methods, including autoclaving. Immunoreactivity to raw and thermally processed peanut extracts was evaluated by IgE immunoblot and skin prick test in patients with clinical allergy to peanut. Roasted peanut and autoclaved roasted peanut were selected for IgE ELISA experiments with individual sera, immunoblot experiments with antibodies against peanut allergens (Ara h 1, Ara h 2 and Ara h 3), digestion experiments, and circular dichroism spectroscopy. In vitro and in vivo experiments showed IgE immunoreactivity of roasted peanut proteins decreased significantly at extreme conditions of autoclaving. Circular dichroism experiments showed unfolding of proteins in autoclave treated samples, which makes them more susceptible to digestion. Autoclaving at 2.56atm, for 30min, produces a significant decrease of IgE-binding capacity of peanut allergens. PMID- 26434303 TI - Effect of low-dose irradiation on biogenic amines formation in vacuum-packed trout flesh (Oncorhynchus mykiss). AB - The effects of vacuum packaging followed by high-energy electron beam irradiation on the shelf-life of fillets of rainbow trout (Oncorhynchus mykiss) were examined. Samples were irradiated at doses of 0.25, 0.50, 0.75, 1.0 and 2.0kGy. The control and treated packs were stored at 3.5 degrees C for up to 28, 42, 70 and 98days (control - 0, 0.25, 0.50 and >0.50kGy respectively). The content of seven biogenic amines (putrescine, cadaverine, spermidine, spermine, histamine, tyramine and tryptamine) were determined. Putrescine, cadaverine and tyramine showed very good correspondence with the irradiation dose and organoleptic properties. Samples of good quality contained less than 10mg/kg of each of these amines. The polyamines spermidine and spermine did not show statistically significant changes with the irradiation dose and the time of storage. With few exceptions, histamine was not detected in the samples treated with radiation. Tryptamine was not detected in any of the samples. PMID- 26434304 TI - Effect of moisture content on selected physicochemical properties of two commercial hen egg white powders. AB - After short-term storage at 23 degrees C, selected physicochemical properties of two hen egg white powders (with and without hydrolysis) were studied. Overall, the effect of moisture content on physicochemical properties of Hydrolysed Egg White powder (HEW) was more severe than those of Dried Egg White powder (DEW). The denaturation temperature (Td) and its enthalpy change (DeltaHd) of ovalbumin in DEW followed an exponential model, as well as the Td of HEW. The Gordon-Taylor equation modelled well the glass transition temperatures (Tg) of HEW and DEW. The Guggenheim-Anderson-de Boer (GAB) model fitted well to the type II moisture sorption isotherm. At the critical moisture content (12.0%, dry basis), compared with DEW, the colour of HEW began to darken dramatically and its hardness started to change significantly. These changes were closely related to the inherent characteristics of the two products. The mechanisms relevant to these physicochemical changes were discussed. PMID- 26434305 TI - Inhibition of aldose reductase and anti-cataract action of trans-anethole isolated from Foeniculum vulgare Mill. fruits. AB - Foeniculum vulgare fruits are routinely consumed for their carminative and mouth freshening effect. The plant was evaluated for aldose reductase inhibition and anti-diabetic action. Bioguided fractionation using silica gel column chromatography, HPLC, and GC-MS analysis revealed trans-anethole as the bioactive constituent possessing potent aldose reductase inhibitory action, with an IC50 value of 3.8MUg/ml. Prolonged treatment with the pet ether fraction of the F. vulgare distillate demonstrated improvement in blood glucose, lipid profile, glycated haemoglobin and other parameters in streptozotocin-induced diabetic rats. Trans-anethole could effectively show anti-cataract activity through the increase in soluble lens protein, reduced glutathione, catalase and SOD activity on in vitro incubation of the eye lens with 55mM glucose. Trans-anethole demonstrated noncompetitive to mixed type of inhibition of lens aldose reductase using Lineweaver Burk plot. PMID- 26434306 TI - Binding of divalent metal ions to 1-25 beta-caseinophosphopeptide: an isothermal titration calorimetry study. AB - To better understand the mechanism of metal ion transport through the gastrointestinal tract to their absorption sites, isothermal titration calorimetry (ITC) was used to investigate the binding of dicationic metals to beta-CN(1-25)4P, a beta-casein tetraphosphorylated peptide. ITC technology was found suitable for studying weak bonds between metal ions and phosphopeptides and provided a direct means of thermodynamic and stoichiometric characterisation of complex formation. Thus, one mole of beta-CN(1-25)4P binds two moles of Ca(2+), Mg(2+) or Zn(2+) under experimental conditions close to those of the ileum (pH 8, 37 degrees C), with rather low binding affinity constants (K=4900-11,200M(-1)). These low affinities should facilitate the release of metal ions during intestinal absorption. By contrast, Cu(2+) did not bind to beta-CN(1-25)4P at pH 8, despite its reported significant affinity towards beta-casein and the 1-25 peptide at near-neutral pH. PMID- 26434307 TI - Effect of cultural system and essential oil treatment on antioxidant capacity in raspberries. AB - The effects of cultural system and essential oil treatment on antioxidant capacities in raspberries were evaluated. Raspberries were hand-harvested from organic and conventional farms in Maryland, USA, and were treated with essential oil including carvacrol, anethole, cinnamic acid, perillaldehyde, cinnamaldehyde, and linalool. Results from this study showed that raspberries grown from organic culture exhibited higher value of antioxidant capacities and individual flavonoids contents. Moreover, the organic culture also enhanced the activities of antioxidant enzymes. In addition, essential oil treatments promoted the antioxidant enzymes activities and antioxidant capacities of raspberries, and the most effective compound was perillaldehyde. In conclusion, raspberries produced from organic culture contained significantly higher antioxidant capacities than those produce from conventional culture. Postharvest essential oil treatments have positive effect on enhancing antioxidant capacities in raspberries from both organic and conventional cultures. PMID- 26434308 TI - Phenolic profile and antioxidant activities of olive mill wastewater. AB - Olive trees play an important role in the Moroccan agro-economy, providing both employment and export revenue. However, the olive oil industry generates large amounts of wastes and wastewaters. The disposal of these polluting by-products is a significant environmental problem that needs an adequate solution. On one hand, the phytotoxic and antimicrobial effects of olive mill wastewaters are mainly due to their phenolic content. The hydrophilic character of the polyphenols results in the major proportion of natural phenols being separated into the water phase during the olive processing. On other hand, the health benefits arising from a diet containing olive oil have been attributed to its richness in phenolic compounds that act as natural antioxidants and are thought to contribute to the prevention of heart diseases and cancers. Olive mill wastewater (OMW) samples have been analysed in terms of their phenolic constituents and antioxidant activities. The total phenolic content, flavonoids, flavanols, and proanthocyanidins were determined. The antioxidant and radical scavenging activity of phenolic extracts and microfiltred samples was evaluated using different tests (iron(II) chelating activity, total antioxidant capacity, DPPH assays and lipid peroxidation test). The obtained results reveal the considerable antioxidant capacity of the OMW, that can be considered as an inexpensive potential source of high added value powerful natural antioxidants comparable to some synthetic antioxidants commonly used in the food industry. PMID- 26434309 TI - Role of carbohydrases on the release of reducing sugar, total phenolics and on antioxidant properties of oat bran. AB - Aqueous solutions of medium oat bran flour were treated with four carbohydrases viscozyme, celluclast, alpha-amylase, and amyloglucosidase, and then extracted with equal volume of methanol. The resulting extracts were examined for their reducing sugar content, total phenolic content (TPC), oxygen radical scavenging absorbance capacity (ORAC), hydroxyl radical scavenging effect, superoxide scavenging activity, and ferrous ion chelating potential. The amount of reducing sugar increased form 2.0% in the control sample to 21.4% in the sample treated with four fungal beta-glucanase units/g of bran. The increase in reducing sugar was also associated with subsequent increase of other extractable compounds. The total phenolic content as measured by Folin-Ciocalteu's method ranged from 0.50 to 4.80mg of gallic acid equivalents/g of bran, whereas the ORAC values were 14.4 25.4MUM of Trolox equivalents/g of bran. All the samples treated with carbohydrases had higher TPC content and higher ORAC values than the control sample (no enzyme treatment). In the hydroxyl radical scavenging assay, except for the alpha-amylase treated sample, all other samples demonstrated a greater inhibition power than the control. These results indicated that pre-treatment of oat bran with cell wall degrading enzymes (i.e. carbohydrases) is a way to increase the amount of extracted phenols as well as the antioxidant properties of oat bran samples. PMID- 26434310 TI - Characterisation and cooperative antimicrobial properties of chitosan/nano-ZnO composite nanofibrous membranes. AB - Chitosan was combined with nano-ZnO to increase its antimicrobial activity, using polyvinyl alcohol as a support, and then were electronspun to form composite nanofibres. Through SEM, EDX and XRD observations, chitosan was seen to be able to incorporate nano-ZnO in the composite nanofibres. Escherichia coli, expressing recombinant enhanced green fluorescent protein, and Candida albicans were used to test the antimicrobial efficacy of the newly synthesised chitosan/nano-ZnO antimicrobial composite. The CdTe quantum dots were used to rapidly detect the residual changes of C. albicans and determine the end point of using antimicrobial agents. Minimal minimum inhibitory concentration (MIC), post antibiotic effect and continuous agent effect of the composite were determined. The MIC of chitosan/nano-ZnO against C. albicans was 160MUg/ml, close to the concentration of the treated composite with the lowest fluorescence intensity. The cell damage was observed by SEM, which indicated that nano-ZnO in the nanofibrous membranes played a cooperative role in the antimicrobial process of chitosan. PMID- 26434312 TI - Cytotoxic phenylpropanoid glycosides from Fagopyrum tataricum (L.) Gaertn. AB - Fagopyrum tataricum (L.) Gaertn (tartary buckwheat) is an ancient dicotyledonous crop belonging to Polygonaceae family. Besides its benefits for human consumption, tartary buckwheat is also an important folk medicine in China for its antioxidant, antitumour, hypotensive, hypoglycaemic and hypolipidaemic activities. Phytochemical investigation of the ethyl acetate fraction of tartary buckwheat roots led to the isolation of seven new phenylpropanoid glycosides, tatarisides A-G (1-7), together with a known phenylpropanoid glycoside, diboside A (8). Their structures were elucidated by means of spectroscopic methods. All compounds (1-8) were evaluated for their cytotoxic activity against four human cancer cell lines (A-549, HCT116, ZR-75-30 and HL-60). Tatariside C (3) was the most active compound with IC50 values of 6.44-7.49MUg/ml against the four tested cell lines. PMID- 26434311 TI - Prebiotic effect of diosgenin, an immunoactive steroidal sapogenin of the Chinese yam. AB - This study investigated the effect of diosgenin, a yam-derived phytochemical, on the growth of enteric lactic acid bacteria (LAB). The in vivo effect of diosgenin on the density of intestinal flora was examined in a murine model of food allergy. Oral administration with diosgenin markedly restored the diminished density of faecal LAB associated with allergic reactions. The direct effect of diosgenin and several structure-related steroidal compounds on the growth of faecal anaerobes isolated from diosgenin-administered mice was also investigated. The presence of diosgenin significantly enhanced the growth of Lactobacillus murinus and Lactobacillus reuteri, but not enterococci. Structure-activity relationship analysis showed that the prebiotic activity of steroidal sapogenins might require structural elements of the C5-C6 double bond and intact E- and F rings. Collectively, these results indicate that steroidal sapogenins may be a novel class of prebiotics to LAB. PMID- 26434313 TI - Stability of avocado oil during heating: comparative study to olive oil. AB - The stability of the saponifiable and unsaponifiable fractions of avocado oil, under a drastic heating treatment, was studied and compared to that of olive oil. Avocado and olive oil were characterised and compared at time 0h and after different times of heating process (180 degrees C). PUFA/SFA (0.61 at t=0) and omega-6/omega-3 (14.05 at t=0) were higher in avocado oil than in olive oil during the whole experiment. Avocado oil was richer than olive oil in total phytosterols at time 0h (339.64; 228.27mg/100g) and at 9h (270.44; 210.30mg/100g) of heating. TBARs was higher in olive oil after 3h, reaching the maximum values in both oils at 6h of heating treatment. Vitamin E was higher in olive oil (35.52 vs. 24.5mg/100g) and it disappeared earlier in avocado oil (at 4 vs. 5h). The stability of avocado oil was similar to that of olive oil. PMID- 26434314 TI - Temperature and water loss affect ADH activity and gene expression in grape berry during postharvest dehydration. AB - Clusters of Aleatico wine grape were picked at 18 degrees Brix and placed at 10, 20, or 30 degrees C, 45% relative humidity (RH) and 1.5m/s of air flow to dehydrate the berries up to 40% of loss of initial fresh weight. Sampling was done at 0%, 10%, 20%, 30%, and 40% weight loss (wl). ADH (alcohol dehydrogenase) gene expression, enzyme activity, and related metabolites were analysed. At 10 degrees C, acetaldehyde increased rapidly and then declined, while ethanol continued to rise. At 20 degrees C, acetaldehyde and ethanol increased significantly with the same pattern and declined at 40%wl. At 30 degrees C, acetaldehyde did not increase but ethanol increased rapidly already at 10%wl. At the latter temperature, a significant increase in acetic acid and ethyl acetate occurred, while at 10 degrees C their values were low. At 30 degrees C, the ADH activity (ethanol to acetaldehyde direction), increased rapidly but acetaldehyde did not rise because of its oxidation to acetic acid, which increased together with ethyl acetate. At 10 degrees C, the ADH activity increased at 20%wl and continued to rise even at 40%wl, meaning that ethanol oxidation was delayed. At 20 degrees C, the behaviour was intermediate to the other temperatures. The relative expression of the VvAdh2 gene was the highest at 10 degrees C already at 10%wl in a synchrony with the ADH activity, indicating a rapid response likely due to low temperature. The expression subsequently declined. At 20 and 30 degrees C, the expression was lower and increased slightly during dehydration in combination with the ADH activity. This imbalance between gene expression and ADH activity at 10 degrees C, as well as the unexpected expression of the carotenoid cleavage dioxygenase 1 (CCD1) gene, opens the discussion on the stress sensitivity and transcription event during postharvest dehydration, and the importance of carefully monitoring temperature during dehydration. PMID- 26434315 TI - Analysis of indole compounds in edible Basidiomycota species after thermal processing. AB - Methanolic extracts of processed fruiting bodies of six edible mushroom species (Basidiomycota) -Armillaria mellea, Boletus badius, Boletus edulis, Cantharellus cibarius, Lactarius deliciosus collected from natural habitats and Pleurotus ostreatus of commercial origin - were analysed for the presence of non hallucinogenic indole compounds. Thermal processing was designed in such a way that it mimicked conditions used for cooking of mushroom dishes, since only a narrow group of mushrooms can be eaten raw, while indole compounds are thermolabile. All processed extracts were shown to contain l-tryptophan (up to 8.92mg/100g dw). The contents of the remaining compounds, 5-methyltryptophan, tryptamine, melatonin, indoleacetonitrile and indole, varied in different species (from 0.71 to 6.55mg/100g dw). Extract of processed C. cibarius fruiting bodies contained l-tryptophan, 5-methyltryptophan, tryptamine, melatonin, indoleacetonitrile and indole (1.96-4.94mg/100g dw) whereas l-tryptophan (2.78mg/100g dw) and tryptamine (2.77mg/100g dw) were the only indole compounds identified in the processed fruiting bodies of A. mellea. PMID- 26434316 TI - Regulation of lipid disorders by ethanol extracts from Zingiber zerumbet in high fat diet-induced rats. AB - The aim of this study was to investigate the antihyperlipidaemic effects of the ethanol extract of Zingiber zerumbet (L) Smith (EEZZ). After being fed a high-fat diet (HFD) for 2weeks, rats were dosed orally with EEZZ (100, 200 or 300mg/kg) or fenofibrate (100mg/kg) once daily for 8weeks. EEZZ (300mg/kg/day) produced effects similar to fenofibrate in reducing body weight gain, visceral fat-pad weights and plasma lipid levels. EEZZ caused reductions in hepatic triglyceride and cholesterol content, and lowered hepatic lipid droplet accumulation and the size of epididymal adipocytes. HFD-induced reductions in the hepatic proteins of peroxisome proliferator-activated receptor (PPAR) alpha, acyl-CoA oxidase (ACO) and cytochrome P450 isoform 4A1 (CYP4A1) were reversed by EEZZ. These results suggest that EEZZ reduced the accumulation of visceral fat and improved hyperlipidaemia in HFD-fed rats by increasing fatty acid oxidation, an effect which is likely to be mediated via up-regulation of hepatic PPARalpha. PMID- 26434318 TI - Malting revisited: Germination of barley (Hordeum vulgare L.) is inhibited by both oxygen deficiency and high carbon dioxide concentrations. AB - During malting, barley (Hordeum vulgare L.) seeds are germinated to promote the mobilisation of storage compounds. Germination is strongly influenced by O2 and CO2; however, any distinction between the particular effects is missing. Since, in this study, the ambient O2 concentration was maintained when high CO2 concentrations were applied, for the first time the impacts of CO2 and of O2 deficiency could be distinguished unambiguously. Germination was inhibited by both O2 deficiency and high CO2 (80%) concentrations, documented by the lack of any growth of coleoptiles and any increase of alpha-amylase and beta-glucanase activity. In contrast, the related impacts of O2 starvation and high CO2 on fermentation differ strongly, demonstrated by quite different patterns of ethanol emission. Additionally, the stress metabolism - monitored by the means of GABA accumulation - was also differently impacted. The elucidation of the underlying, so far unknown, mechanisms will provide novel opportunities to improve malting. PMID- 26434317 TI - Low molecular weight flaxseed protein-derived arginine-containing peptides reduced blood pressure of spontaneously hypertensive rats faster than amino acid form of arginine and native flaxseed protein. AB - Flaxseed protein isolate (FPI) contains high amount of arginine, which plays important physiological roles especially as nitric oxide precursor in the vascular endothelium. Arginine-rich peptides can be generated from FPI and used as a source of nitric oxide, which can produce in vivo vasodilatory effects during hypertension. Enzymatic hydrolysis of FPI with trypsin and pronase resulted in a hydrolysate that was fractionated using electrodialysis ultrafiltration (EDUF). EDUF experiment resulted in migration of peptides to the anionic and cationic recovery compartments. Compared to FPI with 11% arginine, about one-third of the cationic fraction was composed of arginine. Thirteen potential peptide sequences were identified to be present in the cationic compartment of which 12 contained at least one arginine residue. None of the peptides identified from the anionic compartment contained arginine. Oral administration of the cationic peptides (200mg/kgbodywt.) to spontaneously hypertensive rats resulted in a more rapid decrease in systolic blood pressure when compared to similar amounts of FPI or the amino acid form of arginine. It was concluded that the rapid effect of the arginine-rich peptide product suggests faster rate of peptide absorption than amino acids and this may be exploited to provide fast relief from hypertension. PMID- 26434319 TI - Clitocybe alexandri extract induces cell cycle arrest and apoptosis in a lung cancer cell line: Identification of phenolic acids with cytotoxic potential. AB - Mushrooms are a possible rich source of biologically active compounds with the potential for drug discovery. The aim of this work was to gain further insight into the cytotoxicity mechanism of action of Clitocybe alexandri ethanolic extract against a lung cancer cell line (NCI-H460 cells). The effects on cell cycle profile and levels of apoptosis were evaluated by flow cytometry, and the effect on the expression levels of proteins related to cellular apoptosis was also investigated by Western blot. The extract was characterised regarding its phenolic composition by HPLC-DAD, and the identified compounds were studied regarding their growth inhibitory activity, by sulforhodamine B (SRB) assay. The effect of individual or combined compounds on viable cell number was also evaluated using the Trypan blue exclusion assay. It was observed that the C. alexandri extract induced an S-phase cell cycle arrest and increased the percentage of apoptotic cells. In addition, treatment with the GI50 concentration (concentration that was able to cause 50% of cell growth inhibition; 24.8MUg/ml) for 48h caused an increase in the levels of wt. p53, cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP). The main components identified in this extract were protocatechuic, p-hydroxybenzoic and cinnamic acids. Cinnamic acid was found to be the most potent compound regarding cell growth inhibition. Nevertheless, it was verified that the concomitant use of the individual compounds provided the strongest decrease in viable cell number. Overall, evidence was found for alterations in cell cycle and apoptosis, involving p53 and caspase-3. Furthermore, our data suggests that the phenolic acids identified in the extract are at least partially responsible for the cytotoxicity induced by this mushroom extract. PMID- 26434320 TI - Pepsin-solubilised collagen (PSC) from Red Sea cucumber (Stichopus japonicus) regulates cell cycle and the fibronectin synthesis in HaCaT cell migration. AB - Pepsin-solubilised collagen (PSC) from Red Sea cucumber (Stichopus japonicus) was studied with respect to its wound-healing effects on a human keratinocyte (HaCaT) cell line. Disaggregated collagen fibres were treated with 0.1M NaOH for 24h and digested with pepsin for 72h to reach maximum yield of 26.6%. The results of an in vitro wound-healing test showed that migration of HaCaT cells was 1.5-fold faster on PSC-coated plates than on untreated plates. The migration rate of sea cucumber PSC was similar to that of rat PSC, but five times higher than that of bovine gelatin. HaCaT cells grown on PSC-coated plates revealed increased fibronectin synthesis (6-fold and 3-fold compared to gelatin and rat PSC, respectively). Additionally, sea cucumber PSCs induced HaCaT cell proliferation by decreasing the G1 phase by 5% and maintaining a larger population (8%) of cells in mitosis. Collagen from Red Sea cucumber might be useful as an alternative to mammalian collagen in the nutraceutical and pharmaceutical industries. PMID- 26434321 TI - Antioxidant, antifungal and antiviral activities of chitosan from the larvae of housefly, Musca domestica L. AB - Antioxidant activity of the chitosan from the larvae of Musca domestica L. was evaluated in two different reactive oxygen species assays, and inhibitory effects against seven fungi were also tested. The results showed that the chitosan had scavenging activity for hydroxyl and superoxide radicals which were similar to that of ascorbic acid. Also the chitosan exhibited excellent antifungal activity, especially in the low concentration, it could significantly inhibit the growth of Rhizopus stolonifer. Besides, antiviral results demonstrated that the chitosan could effectively inhibit the infection of AcMNPV and BmNPV. These results suggested that the chitosan from the larvae of housefly could be effectively used as a natural antioxidant to protect the human body from free radicals and retard the progress of many chronic diseases. Furthermore, the chitosan with antiviral and antifungal activity might provide useful information for antiviral breeding technology of economic insect and development of plant pathological control. PMID- 26434322 TI - Differential partitioning of antioxidants, including hydroxytyrosol, in human plasma and LDL: implications for their antioxidant activity in vivo. AB - In vivo studies of LDL oxidation following consumption of natural phenolic compounds have yielded mixed results. It is reported that the amphiphilic hydroxytyrosol, after addition to human plasma, does not accumulate in LDL but protects plasma lipids, which are extracted together with hydroxytyrosol, from chemically-induced oxidation. Thus, a novel methodology was proposed, which does not rely on LDL separation and subsequent oxidation but is based on the oxidation of total lipids - simultaneously extracted from plasma with antioxidants - to evaluate the effects of micronutrients that do not partition into LDL, after in vivo supplementation. PMID- 26434323 TI - Determination of nonylphenol ethoxylate metabolites in vegetables and crops by high performance liquid chromatography-tandem mass spectrometry. AB - A method has been developed for the simultaneous determination of the concentration of nonylphenol (4-NP), nonylphenol monoethoxylates (NP1EO) and nonylphenol diethoxylates (NP2EO) in vegetables and crops by liquid chromatography-tandem quadrupole mass spectrometry (HPLC-MS/MS). These target compounds were extracted from vegetable and crop samples with acetonitrile, and then the extracts were cleaned using solid phase extraction with graphitised carbon black tandem primary secondary amine (PSA) cartridges. The MS method enabled highly reliable identification by monitoring the corresponding ammonium adduct [M+NH4](+) in the positive mode for NP1EO and NP2EO, and the deprotonated molecule [M-H](-) in the negative mode for 4-NP. Recoveries for the spiked samples ranged from 65% to 118%. The limit of detection (LOD) of 4-NP, NP1EO and NP2EO was 3, 5 and 0.1MUgkg(-1), respectively. This method would be useful for the quick and routine detection of the residues of 4-NP, NP1EO and NP2EO in vegetables and crops. PMID- 26434324 TI - Ultra-performance liquid chromatographic separation of geometric isomers of carotenoids and antioxidant activities of 20 tomato cultivars and breeding lines. AB - All-trans-lutein, lycopene, beta-carotene and their 22 cis-isomers in 20 tomato breeding were separated and identified by a rapid and sensitive UPLC method using a 1.7MUm C18 column and a new gradient mobile phase based on methanol-MTBE-water in 15 min. All-trans-carotenoids were predominant, but 9-cis, 13-cis-lutein, 5 cis, 9-cis, 13-cis, 15-cis, di-cis-lycopene, 9-cis, 13-cis, 15-cis and di-cis beta-carotene were also found. The cis-isomers were identified using absorption around 330nm and the Q-ratio. The total antioxidant activities as evaluated by PCL and DPPH assays were found to correlate well with the total carotenoid content, but not with the individual carotenoid or its different isomers. This paper provides an efficient analytical method for obtaining a complete picture of carotenoids in tomatoes. It can be a valuable tool for plant breeders, food processors and researchers in developing designer tomatoes and tomato-products with unique carotenoid compositions, and functional properties. PMID- 26434325 TI - Utility of solid phase spectrophotometry for the modified determination of trace amounts of cadmium in food samples. AB - A modified selective, highly sensitive and accurate procedure for the determination of trace amounts of cadmium which reacts with 1-(2 benzothiazolylazo)-2-hydroxy-3-naphthoic acid (BTAHNA) to give a deep violet complex with high molar absorptivity (7.05*10(6)Lmol(-1) cm(-1), 3.92*10(7)Lmol( 1)cm(-1), 1.78*10(8)Lmol(-1)cm(-1), and 4.10*10(8)Lmol(-1)cm(-1)), fixed on a Dowex 1-X8 type anion-exchange resin for 10mL, 100mL, 500mL, and 1000mL, respectively. Calibration is linear over the range 0.2-3.5MUgL(-1) with RSD of ?1.14% (n=10). The detection and quantification limits were calculated. Increasing the sample volume can enhance the sensitivity. The method has been successfully applied for the determination of Cd(II) in food samples, water samples and some salts samples without interfering effect of various cations and anions. PMID- 26434326 TI - Profiling of bioactive compounds in cultivars of Runner and Valencia peanut market-types using liquid chromatography/APCI mass spectrometry. AB - Peanuts are classified into four market-types (Runners, Spanish, Virginia and Valencia). Studies on their phytochemical composition have focused mainly on market-types other than Valencia. The objectives of this study are to evaluate the phytochemical composition of cultivars of Valencia and Runner market-types. Extracts of 25 peanut cultivars of Runner and Valencia market-types were analysed using HPLC-DAD-MS analysis. Results showed major differences in UV profile of the market-types. A major peak with m/z 317 identified as isorhamnetin was present only in Valencia cultivars while its glycoside (isorhamnetin-3-O-rutinoside) having m/z 625 was identified in both market-types. Genistein, daidzein, rutin, quercetin and trans-resveratrol were also identified and quantified. Genistein and daidzein concentrations (0.03mg/100g) were similar in both market-types. trans-Resveratrol and rutin were significantly (p<0.05) higher in Runner cultivars while quercetin was 10-fold higher (0.60+/-0.04mg/100g) in Valencia cultivars making them a better source of this phytochemical. PMID- 26434327 TI - Selective cloud point extraction for the determination of cadmium in food samples by flame atomic absorption spectrometry. AB - A new cloud point extraction (CPE) procedure for preconcentration of cadmium prior to the determination by flame atomic absorption spectrometry (FAAS) was developed. The method is based on the fact that cadmium could form hydrophobic ion-associated complex in the presence of iodide and methyl green (MG), and the hydrophobic ion-associated complex could be extracted into surfactant-rich phase. The main factors affecting CPE procedure, such as pH, concentration of KI, MG and surfactant, equilibrium temperature and incubation time, sample volume were investigated. Potential interference from co-existing ions was largely eliminated as most of co-existing ions can not form extractable ion-associated complex with iodide and MG. Under the optimum conditions, the limit of detection (3sigma) and limit of quantity (10sigma) were 0.90ngmL(-1) and 3.0ngmL(-1) for cadmium, respectively, and relative standard deviation was 4.2% (c=50ngmL(-1), n=7). The proposed method was successfully applied to determination of cadmium in the certified reference rice sample (GBW08510) and food samples with satisfactory results. PMID- 26434328 TI - Simultaneous determination of eight underivatised biogenic amines in fish by solid phase extraction and liquid chromatography-tandem mass spectrometry. AB - Biogenic amines on fish tissue are formed as a result of bacterial contamination and spoilage during storage. A new method based on liquid chromatography (LC) and tandem mass spectrometry (MS/MS) using a triple quadrupole (QqQ) analyser was developed for the analysis of eight biogenic amines (cadaverine, histamine, phenylethylamine, putrescine, spermine, spermidine, tyramine and tryptamine) in fish tissues. Sample preparation was performed by extraction with trichloroacetic acid 5% and solid phase extraction clean up with STRATA X cartridge. The MS/MS method was validated and compared with a method based on the analysis of dansyl derivatives by LC and fluorescence detector (FD). MS/MS achieved higher sensitivity (from 0.02mgkg(-1) for spermidine and phenylethylamine to 0.2mgkg(-1) for spermine) when compared to FD (from 1mgkg(-1) for putrescine and tyramine to 4mgkg(-1) for histamine); MS/MS method showed higher precision too, with intraday relative standard deviations (RSDs) from 1% to 4% with respect to those obtained with FD method (from 3% to 17%). Recovery study was conducted at two different fortification levels and the average ranged from 71% to 93% for all of the studied compounds with RSDs lower than 18%. Matrix-matched standards were used to counteract matrix effect observed in MS/MS determination. The applicability of the method was demonstrated by the analysis of biogenic amines in fish obtained from commercials of Valencia. PMID- 26434329 TI - Rapid antioxidant capacity screening in herbal extracts using a simple flow injection-spectrophotometric system. AB - A simple flow injection (FI)-spectrophotometric system for the screening of antioxidant capacity in herbal extracts was developed. The analysis was based on the color disappearance due to the scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical by antioxidant compounds. DPPH and ascorbic acid were used as reagent and antioxidant standard, respectively. Effects of the DPPH concentration, DPPH flow rate, and reaction coil length on sensitivity were studied. The optimized condition provided the linear range of 0.010-0.300mM ascorbic acid with less than 5%RSD(n=10). Detection limit and quantitation limit were 0.004 and 0.013mM, respectively. Comparison of antioxidant capacity in some herbal extracts determined by the FI system and a standard method was carried out and no significant difference was obtained. PMID- 26434330 TI - Investigation of antiradical activity of plant material by thin-layer chromatography with image processing. AB - A novel, easy, and cheap technique for preliminary quantitative evaluation of antiradical activity, based on HPTLC, has been proposed. This method combines chromatographic separation of polar compounds, present in plant extracts, with data analysis by means of image processing software. Bleaching of the purple DPPH colour, caused by substances with antiradical activity, was observed and recorded using a photo camera. ImageJ, a free and open source image processing program was used for quantitative measurements. For evaluation of assay efficiency, the antiradical activity of rose flower extracts (from Rosa rugosa Thunb.) was expressed as Standard Activity Coefficients (SACs), which are relative measures of the activity to the four well known antioxidants; i.e., quercetin, gallic acid, protocatechuic acid, and Trolox. The method uses small amounts of free radical and is easily applicable - only a digital camera with freely available open source software is required. PMID- 26434331 TI - Comparison of chemical modifiers for direct determination of Cd, Cu and Zn in food stuffs by solid-sampling-ETAAS. AB - In this work, the capability of different chemical modifiers (Pd, Pd/Mg(NO3)2, Pd/NH4NO3, NH4H2PO4, NH4H2PO4/Mg(NO3)2) to eliminate the matrix effects in the direct determination of Cd, Cu and Zn in food-stuffs by solid sampling electrothermal atomic absorption spectrometry was compared. The alternative analytical lines were used for determination of Cu (327.4nm) and Zn (307.6nm) in order to allow the introduction of reasonably high sample mass into the furnace. Mixed modifiers containing palladium were useful to eliminate the matrix effect in Cd determination. For Cu and Zn determination the application of Pd shows satisfactory analytical performance. In the determinations of Cd and Zn the phosphate containing modifiers shows elimination of matrix effects only when applying them to a partially pyrolysed sample (at 400 degrees C). The achievable limits of detection for Cd, Cu and Zn in solid samples were 0.279ngg(-1); 0.020MUgg(-1) and 2.04MUgg(-1), respectively. PMID- 26434332 TI - Classification of 'Chemlali' accessions according to the geographical area using chemometric methods of phenolic profiles analysed by HPLC-ESI-TOF-MS. AB - The present work describes a classification method of Tunisian 'Chemlali' olive oils based on their phenolic composition and geographical area. For this purpose, the data obtained by HPLC-ESI-TOF-MS from 13 samples of extra virgin olive oils, obtained from different production area throughout the country, were used for this study focusing in 23 phenolics compounds detected. The quantitative results showed a significant variability among the analysed oil samples. Factor analysis method using principal component was applied to the data in order to reduce the number of factors which explain the variability of the selected compounds. The data matrix constructed was subjected to a canonical discriminant analysis (CDA) in order to classify the oil samples. These results showed that 100% of cross validated original group cases were correctly classified, which proves the usefulness of the selected variables. PMID- 26434333 TI - Feasibility study for producing a carrot/potato matrix reference material for 11 selected pesticides at EU MRL level: material processing, homogeneity and stability assessment. AB - The feasibility for producing a matrix reference material for selected pesticides in a carrot/potato matrix was investigated. A commercially available baby food (carrot/potato-based mash) was spiked with 11 pesticides at the respective EU maximum residue limits (MRLs), and further processed by either freezing or freeze drying. Batches of some 150 units were produced per material type. First, the materials were assessed for the relative amount of pesticide recovered after processing (ratio of pesticide concentration in the processed material to the initially spiked pesticide concentration). In addition, the materials' homogeneity (bottle-to-bottle variation), and the short-term (1 month) and mid term (5 months) stability at different temperatures were assessed. For this, an in-house validated GC-EI-MS method operated in the SIM mode with a sample preparation procedure based on the QuEChERS ("quick, easy, cheap, effective, rugged, and safe") principle was applied. Measurements on the frozen material provided the most promising results (smallest analyte losses during production), and also freeze-drying proved to be a suitable alternative processing technique for most of the investigated pesticides. Both the frozen and the freeze-dried material showed to be sufficiently homogeneous for the intended use, and storage at -20 degrees C for 5 months did not reveal any detectable material degradation. The results constitute an important step towards the development of a pesticide matrix reference material. PMID- 26434334 TI - Validation of a gas chromatography-electron capture detection of T-2 and HT-2 toxins in Chinese herbal medicines and related products after immunoaffinity column clean-up and pre-column derivatization. AB - A sensitive, reproducible and accurate gas chromatography-electron capture detection (GC-ECD) method was developed for simultaneous determination of T-2 and HT-2 toxins in Chinese herbal medicines (CHMs) and related products after immunoaffinity column (IAC) clean-up and pre-column derivatization with N heptafluoro-butyryl imidazole (HFBI). Then, gas chromatography-spectrometry spectrometer (GC-MS) was applied to confirm the positive results and interfering peaks. The limits of detection (LODs) for T-2 and HT-2 toxins were 1.88 and 0.47ng/g, and the recoveries for different CHMs ranged from 89.2% to 99.1% with relative standard deviation (RSD) <6.0% for T-2 and from 85.9% to 99.0% with RSD <8.8% for HT-2 toxin, respectively. The validated method was successfully applied for the determination of T-2 and HT-2 toxins in 89 Chinese herbal medicines and 10 related products from various sources, where it was found that T-2 and HT-2 toxins were not detected in any of the tested samples. These results were reliable by confirmation using GC-MS. Some unknown peaks were interfering peaks not the target toxins. PMID- 26434335 TI - Application of response surface methodology to optimise supercritical carbon dioxide extraction of essential oil from Cyperus rotundus Linn. AB - Supercritical fluid extraction with carbon dioxide (SC-CO2 extraction) was performed to isolate essential oils from the rhizomes of Cyperus rotundus Linn. Effects of temperature, pressure, extraction time, and CO2 flow rate on the yield of essential oils were investigated by response surface methodology (RSM). The oil yield was represented by a second-order polynomial model using central composite rotatable design (CCRD). The oil yield increased significantly with pressure (p<0.0001) and CO2 flow rate (p<0.01). The maximum oil yield from the response surface equation was predicted to be 1.82% using an extraction temperature of 37.6 degrees C, pressure of 294.4bar, extraction time of 119.8 min, and CO2 flow rate of 20.9L/h. PMID- 26434336 TI - Elemental analysis of nutritional preparations by inductively coupled plasma mass and optical emission spectrometry. AB - This paper reports the development and using of ICP-MS and ICP-OES methods for determination of major, minor and trace elements in multivitamin preparations and dietary supplements and, based on results, their classification using multivariate statistical methods. The method was optimised and evaluated with the use of "in-house" reference material, commercial reference materials and spiked samples. Macroelements (Na, K, Ca, Mg, P), microelements (Cu, Fe, Mn, Zn, Se, Cr), toxic elements (As, Cd, Pb, Ni, V) and a whole series of other elements (e.g. REEs, Ti, Au, Pt, Pd, etc.) were detected with excellent limits of detection as well as other procedure parameters suitable for the purpose of the elemental analysis. As for physiologically significant elements, contents were found as follows (mgkg(-1)): Ca 560-196,000, Mg 308-70,300, Na 289-74,000, K from undetectable to 28,200, Cu 28-1460, P from undetectable to 217,000, Zn 2.1 25,000, Fe 115-39,400, Mn 28-1860, Cr 0.486-26.6, Mo 0.0418-9.88, and Se 0.395 161. It was found out, if compared with recommended daily intakes, that maximally 50% Ca, 37% Mg, 3% K, 20% P, 14% Na, 100% Cu, 160% Mn, 190% Fe, 120% Zn, 24% Cr, 29% Mo and 79% Se can be obtained from one dose. Extreme samples presenting a possible health risk (Ni content nearly 200mgkg(-1)) were indicated. Most of the remaining elements (e.g. REEs) were analysed in order to get reference values for nutritional preparation. PMID- 26434337 TI - Chromium determination in food by slurry sampling graphite furnace atomic absorption spectrometry using classical and permanent modifiers. AB - A simple method, using permanent modifiers, has been developed for chromium (Cr) determination in food of plant origin by the slurry sampling graphite furnace atomic absorption spectrometry. In particular comparison of the action of Mg(NO3)2, iridium (Ir)/niobium (Nb) and iridium (Ir)/tungsten (W) was examined. Finally, for chromium determination in food, the mixture of 2MUg of Ir with 10MUg of Nb was used as permanent modifier. The analytical procedure was optimised carefully on the basis of the data from pyrolysis and atomisation temperature curves studies. The results obtained for four certified reference materials using external calibration with aqueous standards were in good agreement with the certified values. The precision and accuracy of Cr determination by the described method were also acceptable: the RSD were lower than 10% and recoveries for CRMs were in the range of 95-103%. The characteristic mass for chromium was determined to be 3.9pg and the detection limit for the optimised procedure at the 0.75% (w/v) slurry concentration - 86.6ngg(-1). PMID- 26434338 TI - Application of differential scanning calorimetry (DSC), HPLC and pNMR for interpretation primary crystallisation caused by combined low and high melting TAGs. AB - The main goal of the present work was to assess the mechanism of crystallisation, more precisely the dominant component responsible for primary crystal formations and fat agglomerations. Therefore, DSC results exhibited significant effect on temperature transition; peak sharpness and enthalpy at palm stearin (PS) levels more than 40wt.%. HPLC data demonstrated slight reduction in the content of POO/OPO at PS levels less than 40wt.%, while the excessive addition of PS more than 40wt.% increased significantly PPO/POP content. The pNMR results showed significant drop in SFC for blends containing PS less than 40wt.%, resulting in low SFC less than 15% at body temperature (37 degrees C). Moreover, the values of viscosity (eta) and shear stress (tau) at PS levels over 40wt.% expressed excellent internal friction of the admixtures. All the data reported indicate that PPO/POP was the major component of primary nucleus developed. In part, the levels of PS should be less than 40wt.%, if these blends are designed to be used for margarine production. PMID- 26434339 TI - Rapid screening of phytosterols in orange juice by solid-phase microextraction on polyacrylate fibre derivatisation and gas chromatographic-mass spectrometric. AB - The potential of solid-phase microextraction on polyacrylate coated fibre, with sequential or simultaneous trimethylsilyl derivatisation followed by gas chromatographic-mass spectrometric analysis, was evaluated for a rapid determination of the distribution of the phytosterols in aqueous food matrixes. Influences of different parameters (bis(trimethylsilyl)trifluoro-acetamide and sterol exposure time, sterol concentration and experimental protocol) on the recovery of sterols were investigated to determine optimum conditions which were tested for sterol extraction and analysis from orange juice. Best selectivity, sterol recovery and derivatisation yields were obtained by extraction and simultaneous derivatisation through immersion of the SPME-PA fibre in the orange juice (10min, 65 degrees C) after headspace absorption of BSTFA (30min, 65 degrees C) on the fibre. Nevertheless the method developed cannot be used for quantitative analysis. But the possibility to effect rapid screen of phytosterol containing in complex media have been shown. PMID- 26434340 TI - Preparative isolation and purification of xanthohumol from hops (Humulus lupulus L.) by high-speed counter-current chromatography. AB - Xanthohumol (XN) and related prenylflavonoids are the main bioactive components of hops (Humulus lupulus L.). The current work is to investigate the use of high speed counter-current chromatography (HSCCC) in search for high isolation of xanthohumol from hops. A solvent system consisted of n-hexane-ethyl acetate methanol-water at a volume ratio of 5:5:4:3 was employed. The results demonstrated that the constructed method could be well applied for the isolation of xanthohumol from hops extract. After HSCCC isolation procedure, the purity of xanthohumol was over 95% assayed by HPLC and the yield of extraction was 93.60%. The chemical structure identification of xanthohumol was carried out by UV, (1)H NMR and (13)C NMR. The present results demonstrated that xanthohumol could be efficiently obtained using a single HSCCC step from H. lupulus L. extract. PMID- 26434341 TI - Flow injection spectrophotometry using natural reagent from Morinda citrifolia root for determination of aluminium in tea. AB - A flow injection (FI) spectrophotometric method with using natural reagent extracted from Morinda citrifolia root has been developed for determination of aluminium. The extract contained anthraquinone compounds which could react with Al(3+) to form reddish complexes which had maximum absorption wavelength at 499.0nm. The extract could be used as a reagent in FI system without further purification to obtain pure compound. A sensitive method for determination of aluminium in concentration range of 0.1-1.0mgL(-1), with detection limit of 0.05mgL(-1) was achieved. Relative standard deviations of 1.2% and 1.7% were obtained for the determination of 0.1 and 0.6mgL(-1) Al(3+) (n=11). Sample throughput of 35h(-1) was achieved with the consumption of 3mL each of carrier and reagent solutions per injection. The developed method was successfully applied to tea samples, validated by the FAAS standard method. The method is simple, fast, economical and could be classified as a greener analytical method. PMID- 26434342 TI - Analysis of six fungicides and one acaricide in still and fortified wines using solid-phase microextraction-gas chromatography/tandem mass spectrometry. AB - A multiresidue gas chromatographic method for the determination of six fungicides (captan, chlorthalonil, folpet, iprodione, procymidone and vinclozolin) and one acaricide (dicofol) in still and fortified wines was developed. Solid-phase microextraction (SPME) was chosen for the extraction of the compounds from the studied matrices and tandem mass spectrometry (MS/MS) detection was used. The extraction consists in a solvent free and automated procedure and the detection is highly sensitive and selective. Good linearity was obtained with correlation coefficients of regression (R(2))>0.99 for all the compounds. Satisfactory results of repeatability and intermediate precision were obtained for most of the analytes (RSD?20%). Recoveries from spiked wine ranged from 80.1% to 112.0%. Limits of quantification (LOQs) were considerably below the proposed maximum residue limits (MRLs) for these compounds in grapes and below the suggested limits for wine (MRLs/10), with the exception of captan. PMID- 26434343 TI - Simultaneous determination of Sunset yellow and Tartrazine in soft drinks using gold nanoparticles carbon paste electrode. AB - The monitoring of synthetic dyes in foods is very important due to their potential harmfulness to human beings. Herein, a carbon-paste electrode (CPE) that is chemically modified with gold nanoparticles (nAu) was fabricated and used for the determination of Sunset yellow (SY) and Tartrazine (Tz). Cyclic and differential pulse voltammetry (CV and DPV) results revealed two well-resolved anodic peaks for SY and Tz with remarkably increase in oxidation signals of these colourants. Based on this, a novel electrochemical method was developed for the simultaneous determination of SY and Tz. High sensitivity and selectivity, sub micromolar detection limit, high reproducibility and regeneration of the electrode surface by simple polishing make the nAu-CPE electrode very suitable for the determination of SY and Tz in commercially available soft drinks. The detection limits was 3.0*10(-8) and 2.0*10(-9)moll(-1) for SY and Tz, respectively, which are remarkably lower than those reported previously for SY and Tz using other modified electrodes. PMID- 26434345 TI - Molecularly imprinted solid-phase extraction coupled to liquid chromatography for determination of Sudan dyes in preserved beancurds. AB - New molecularly imprinted microspheres synthesized by suspension polymerisation using phenylamine and naphthol as mimic template were successfully applied as selective sorbents for the solid-phase extraction used for the simultaneous determination of four Sudan dyes from preserved beancurd products. The obtained imprinted microspheres showed good recognition and selectivity to the four Sudan dyes in aqueous solution and the affinity could be easily controlled by adjusting the property of the solution. Under the selected experimental condition, the recoveries of the Sudan dyes in preserved beancurds at three spiked levels were ranged between 90.2-104.5% with the relative standard deviation of less than 6.8%. The limit of detection (LOD) and limit of quantification (LOQ) based on a signal-to-noise of 3 and 10 were in the range of 0.005-0.009MUgg(-1) and 0.015 0.030MUgg(-1), respectively. Comparing with alumina and C18-based extraction, the selectivity and repeatability of molecularly imprinted solid-phase extraction (MISPE) were obviously improved. This method could be potentially applied for the determination of Sudan dyes in complicated food samples. PMID- 26434344 TI - Detection of adulterated commercial Spanish beeswax. AB - The physical and chemical parameters (melting point and saponification number), and the fraction of hydrocarbons, monoesters, acids and alcohols have been determined in 90 samples of Spanish commercial beeswax from Apis mellifera L. The adulteration with paraffins of different melting point, cow tallow, stearic acid, and carnauba wax were determined by HTGC-FID/MS detection, and the research was focussed mainly on paraffins and microcrystallines waxes. In general, the added adulterant can be identified by the presence of non-naturally beeswax components, and by the differences of values of selected components between pure and adulterated beeswax. The detection limits were determined using pure and adulterated beeswax with different amounts of added waxes (5%, 10%, 20% and 30%). Percentages higher than 1-5% of each adulterant can be detected in the mixtures. Paraffin waxes were confirmed in 33 of the 90 samples analysed at concentrations between 5% and 30%. PMID- 26434346 TI - A proteomic approach to detect lactosylation and other chemical changes in stored milk protein concentrate. AB - Milk proteins undergo chemical changes such as lactosylation, deamidation and protein cross-linking during processing and storage of milk products. A proteomic technique combining two-dimensional gel electrophoresis and mass spectrometry was used to investigate chemical modifications to proteins, in milk protein concentrate (MPC80), during storage. Lactosylation, deamidation and protein cross linking were observed on 2-DE gels. They were storage temperature-, humidity- and time-dependent. Lactosylated whey proteins were well separated on 2-DE in vertical stacks of spots. The masses of the spots varied by multiples of 324, indicating the attachment of lactose to lysine residues in the proteins. The trypsin-digested spots of alpha-lactalbumin were analysed by MALDI-TOF mass spectrometry, which indicated multiple lactosylation sites. The lactose adducts on gels were quantified by image analysis, allowing development of adducts over time to be monitored. The results show that proteomics can be used for the detection and quantification of chemical modifications to proteins in stored MPC80. PMID- 26434347 TI - Spectroscopic investigation on the interaction of 3,7-dihydroxyflavone with different isomers of human serum albumin. AB - The interaction mechanism of 3,7-dihydroxyflavone (3,7-diHF) and human serum albumin (HSA) was investigated by fluorescence quenching, fluorescence enhancement, steady-state and time-resolved fluorescence emission and UV-vis absorption spectrometry. The binding site of 3,7-diHF on protein was determined by investigating the spectroscopic properties of 3,7-diHF-HSA complex at pH 7.4 and pH 3.5 individually, and confirmed by the site marker competitive experiments. The binding parameters of 3,7-diHF-HSA complex were estimated by fluorescence quenching experiments, and the data were in good agreement with the results obtained from fluorescence enhancement measurements. A remarkable increase in the fluorescence anisotropy values suggested that 3,7-diHF bound at a motional restricted pocket on HSA. The results indicated that 3,7-diHF, in anionic form, was bound within the hydrophobic pockets of the subdomain IIA of HSA (site I), and stabilised mainly by electrostatic force and ionic interactions. The binding mode of drug-protein was discussed based on above experimental results. PMID- 26434348 TI - An improved method for thin layer chromatographic analysis of saponins. AB - Analysis of saponins by thin layer chromatography (TLC) is reported. The solvent system was n-butanol:water:acetic acid (84:14:7). Detection of saponins on the TLC plates after development and air-drying was done by immersion in a suspension of sheep erythrocytes, followed by washing off the excess blood on the plate surface. Saponins appeared as white spots against a pink background. The protocol provided specific detection of saponins in the saponins enriched extracts from Aesculusindica (Wall. ex Camb.) Hook.f., Lonicera japonica Thunb., Silene inflata Sm., Sapindusmukorossi Gaertn., Chlorophytum borivilianum Santapau & Fernandes, Asparagusadscendens Roxb., Asparagus racemosus Willd., Agave americana L., Camellia sinensis [L.] O. Kuntze. The protocol is convenient, inexpensive, does not require any corrosive chemicals and provides specific detection of saponins. PMID- 26434351 TI - Shot Noise of Charge and Spin Current of a Quantum Dot Coupled to Semiconductor Electrodes. AB - On the basis of the scattering matrix theory and nonequilibrium green function method, we have investigated the fluctuations of charge and spin current of the systems that consist of a quantum dot (QD) with a resonant level coupled to two semiconductor contacts within in alternative site (AS) and alternative bond (AB) framework, where two transverse (Bx) and longitudinal (Bz) magnetic fields are applied to the QD. It is only necessary to use the autocorrelation function to characterize the fluctuations of charge current for a twoterminal system because of the relation that is defined as Sigmaalpha e Salphabeta = Sigmabeta e Salphabeta = 0. Our result shows that both auto-shot noise (SLL) and cross-shot noise (SLR) are essential to characterize the fluctuations of spin current when Bx is present. Moreover, our model calculations show that the sign of the cross shot noise of spin current is negative for all surface states of AS/QD/AS junctions, whereas it oscillates between positive and negative values for two surface states of AB/QD/AB junctions as we sweep the gate voltage. PMID- 26434352 TI - Equilibrium cluster fluids: pair interactions via inverse design. AB - Inverse methods of statistical mechanics are becoming productive tools in the design of materials with specific microstructures or properties. While initial studies have focused on solid-state design targets (e.g., assembly of colloidal superlattices), one can alternatively design fluid states with desired morphologies. This work addresses the latter and demonstrates how a simple iterative Boltzmann inversion strategy can be used to determine the isotropic pair potential that reproduces the radial distribution function of a fluid of amorphous clusters with prescribed size. The inverse designed pair potential of this "ideal" cluster fluid, with its broad attractive well and narrow repulsive barrier at larger separations, is qualitatively different from the so-called SALR form most commonly associated with equilibrium cluster formation in colloids, which features short-range attractive (SA) and long-range repulsive (LR) contributions. These differences reflect alternative mechanisms for promoting cluster formation with an isotropic pair potential, and they in turn produce structured fluids with qualitatively different static and dynamic properties. Specifically, equilibrium simulations show that the amorphous clusters resulting from the inverse designed potentials display more uniformity in size and shape, and they also show greater spatial and temporal resolution than those resulting from SALR interactions. PMID- 26434353 TI - Mapping the trajectory of the stria terminalis of the human limbic system using high spatial resolution diffusion tensor tractography. AB - The human limbic system is composed of gray and white matter structures which have been known to have a role in core processes such as motivation, memory, emotion, social behavior, self-awareness as well as certain primitive instincts. Multiple functional studies investigated some of these brain tasks in human brain limbic system. However, the underlying fine fiber pathways of the limbic system including the trajectory of the stria terminalis have not been delineated separately by prior diffusion weighted imaging. The ability to trace the underlying fiber anatomy noninvasively using diffusion tensor tractography (DTT) would be helpful to study the neurophysiology of these tracts in different functions in future functional studies. Few studies have focused on the stria terminalis using diffusion tensor tractography. Yet, the trajectory of the stria terminalis and some fine subtrajectories of the fornix have not been elucidated by prior DTT studies. We decided to further investigate these fine neuronal trajectory using tractography and high spatial resolution diffusion tensor imaging on 3T. Fifteen healthy right-handed men (age range 24-37 years) were studied. We delineated the detailed trajectories of the stria terminalis and fornix bilaterally in fifteen normal adult human brains. Using a high resolution DTT technique, we demonstrate for the first time, the trajectory of stria terminalis as well as detailed precommissural and postcommissural connectivity of the forniceal columns. PMID- 26434355 TI - Understanding death, extending life. PMID- 26434354 TI - A molecular marker of disease activity in autoimmune liver diseases with histopathological correlation; FoXp3/RORgammat ratio. AB - Autoimmune liver diseases (AILDs) encompass a group of diseases with variable clinicopathological manifestations. Th17 and Treg cells have roles in the pathogenesis of AILDs with a balance shifted towards a relative increase in activity of the Th17 cells. In this study, the balance between the transcription factors of Treg and Th17 cells (FoXp3 and RORgammat) was sought as a molecular marker of disease activity and to highlight the pathogenesis. The peripheral blood samples of 46 treatment-naive patients were collected and RNA was extracted. Real time PCR was performed and the ratio of gene expression was calculated. Histopathology of 18 patients was obtained and the activity score of these biopsies were also corroborated with their respective molecular (FoXp3/RORgammat) (FRGT=FoXp3-ROR Gamma T) ratio. The FRGT ratio in healthy individuals was close to 1 and in disease the ratio changed significantly. This ratio (FRGT) was not significantly different in different varieties of AILD or in adult or paediatric form of the disease. However, the ratio remained consistently below 1 (mean 0.3) in acute disease and high (mean 224.7) in chronic or asymptomatic form of the disease (p < 0.001). The histopathological activity score also significantly correlated with the ratio. This signified the relative excess of Th17 (RORgammat) in active disease as compared to Treg (FoXp3) and the reverse in chronic form. This ratio can be an important peripheral molecular marker to assess the disease activity without the necessity of performing a liver biopsy. PMID- 26434356 TI - BGA66 and BGA71 facilitate complement resistance of Borrelia bavariensis by inhibiting assembly of the membrane attack complex. AB - Borrelia (B.) bavariensis exhibits a marked tropism for nervous tissues and frequently causes neurological manifestations in humans. The molecular mechanism by which B. bavariensis overcomes innate immunity, in particular, complement remains elusive. In contrast to other serum-resistant spirochetes, none of the B. bavariensis isolates investigated bound complement regulators of the alternative (AP) and classical pathway (CP) or proteolytically inactivated complement components. Focusing on outer surface proteins BGA66 and BGA71, we demonstrated that both molecules either inhibit AP, CP and terminal pathway (TP) activation, or block activation of the CP and TP respectively. Both molecules bind complement components C7, C8 and C9, and thereby prevent assembly of the terminal complement complex. This inhibitory activity was confirmed by the introduction of the BGA66 and BGA71 encoding genes into a serum-sensitive B. garinii strain. Transformed spirochetes producing either BGA66 or BGA71 overcome complement-mediated killing, thus indicating that both proteins independently facilitate serum resistance of B. bavariensis. The generation of C-terminally truncated proteins as well as a chimeric BGA71 protein lead to the localization of the complement-interacting binding site within the N-terminus. Collectively, our data reveal a novel immune evasion strategy of B. bavariensis that is directed against the activation of the TP. PMID- 26434357 TI - Understanding the nutrition care needs of patients newly diagnosed with type 2 diabetes: a need for open communication and patient-focussed consultations. AB - Patients who are newly diagnosed with type 2 diabetes mellitus (T2DM) commonly attempt to modify their dietary intake after receiving nutrition care from primary health professionals. Yet, adherence to dietary recommendations is rarely sustained and factors influencing adherence are poorly understood. This study explored T2DM patients' experiences of dietary change and their views on how primary health professionals can best support long-term maintenance of dietary change. A purposive sample of 10 individuals recently diagnosed with T2DM participated in three individual semi-structured qualitative telephone interviews: at baseline, then at 3 and 6 months after recruitment. Interview questions were modified from the initial interview in order to investigate emerging findings. A two-step data analysis process occurred through content analysis of individual interviews and meta-synthesis of findings over time. Participants initially made wide-ranging attempts to improve dietary behaviours, but most experienced negative emotions from the restraint required to maintain a healthy diet. Participants felt confused by the conflicting advice received from health professionals and other sources such as friends, family, internet and diabetes organisations. Participants frequently reported feeling rushed and not heard in consultations, resulting in limited ongoing engagement with primary healthcare services. These findings suggest that there is opportunity for primary health professionals to enhance the dietary support provided to patients by: acknowledging the challenges of sustained improvements in dietary intake; open communication; and investing in patient relationships through more patient focussed consultations. PMID- 26434358 TI - Framework and optimisation procedure for flexible parametric survival models. PMID- 26434359 TI - Reply to Letter to the Editor by Remontet et al. PMID- 26434364 TI - Total Synthesis of Atisane-Type Diterpenoids: Application of Diels-Alder Cycloadditions of Podocarpane-Type Unmasked ortho-Benzoquinones. AB - Few examples of [4 + 2] cycloaddition with unmasked ortho-benzoquinones (UMOBs) as carbodiene have been reported in complex molecule synthesis. Herein we report that this cycloaddition with podocarpane-type UMOB was developed and applied to construct fully functionalized bicyclo[2.2.2]octanes. Based on this methodology, divergent total syntheses of atisane-type diterpenoids, including (+/-) crotobarin, crotogoudin, atisane-3beta,16alpha-diol, and 16S,17-dihydroxy-atisan 3-one, were accomplished in 14, 14, 12, and 16 steps, respectively. Key elements in these total syntheses include: (1) FeCl3-catalyzed cationic cascade cyclization to construct podocarpane-type skeleton; (2) Mn(III)/Co(II)-catalyzed radical hydroxylation of alkene with high regio-, diastereo-, and chemoselectivities; (3) and a ketal-deprotection/lactone opening/deprotonation/lactonization cascade. Additionally, the synthetic utility of the fully functionalized bicyclo[2.2.2]octane framework was further elucidated by applying ring distortion strategy to afford different skeleton-rearranged natural product-like compounds. PMID- 26434365 TI - Body mass index, diabetes and survival after diagnosis of endometrial cancer: A report from the HUNT-Survey. AB - OBJECTIVE: We studied the association of body mass index (BMI) and diabetes with all-cause death and endometrial cancer-specific death among women with endometrial cancer (EC). METHODS: Included were 337 women in the Health Surveys in North-Trondelag, Norway who were followed from EC diagnosis to death or end of follow-up, 30th June 2012. Risks of death associated with BMI and diabetes were estimated as hazard ratios (HRs) with 95% confidence intervals (95% CI). The risks of EC-specific death were estimated as sub-HRs, after adjustment for competing causes of death. We also studied the risk of death associated with diabetes in women with BMI<25kg/m(2) and in women with BMI>=25kg/m(2). RESULTS: During the median follow-up time of 6.7years, 166 women (49.3%) died. Diabetes increased the risk of all-cause death (HR 2.14, 95% CI: 1.26-3.63) and endometrial cancer-specific death (SHR, 2.62, 95% CI: 1.07-6.43) after adjustment for age, histological type and stage of EC. BMI was not associated with risk of all-cause or EC-specific death. The increased risk of both all-cause death and EC specific death in diabetic women seemed to be more pronounced in women with BMI<25kg/m(2) (HR 6.35, 95% CI: 1.90-21.14) compared to women with BMI>25kg/m(2) (HR 1.80, 95% CI: 0.98-3.33). CONCLUSIONS: Diabetes, but not BMI, was associated with increased risk of all-cause death and death from EC. The increased risk of death associated with diabetes seemed to be most pronounced in women with BMI<25kg/m(2). PMID- 26434366 TI - Magnetic ionic liquids as PCR-compatible solvents for DNA extraction from biological samples. AB - A polymerase chain reaction (PCR) buffer was systematically designed to relieve the inhibition caused by hydrophobic magnetic ionic liquids (MILs). We describe a simple, rapid method for MIL-based plasmid DNA extraction from crude bacterial cell lysate in which DNA-enriched MIL is transferred directly to a PCR tube for analysis. PMID- 26434368 TI - Gingipain-dependent augmentation by Porphyromonas gingivalis of phagocytosis of Tannerella forsythia. AB - In the pathogenesis of periodontitis, Porphyromonas gingivalis plays a role as a keystone pathogen that manipulates host immune responses leading to dysbiotic oral microbial communities. Arg-gingipains (RgpA and RgpB) and Lys-gingipain (Kgp) are responsible for the majority of bacterial proteolytic activity and play essential roles in bacterial virulence. Therefore, gingipains are often considered as therapeutic targets. This study investigated the role of gingipains in the modulation by P. gingivalis of phagocytosis of Tannerella forsythia by macrophages. Phagocytosis of T. forsythia was significantly enhanced by coinfection with P. gingivalis in a multiplicity of infection-dependent and gingipain-dependent manner. Mutation of either Kgp or Rgp in the coinfecting P. gingivalis resulted in attenuated enhancement of T. forsythia phagocytosis. Inhibition of coaggregation between the two bacterial species reduced phagocytosis of T. forsythia in mixed infection, and this coaggregation was dependent on gingipains. Inhibition of gingipain protease activities in coinfecting P. gingivalis abated the coaggregation and the enhancement of T. forsythia phagocytosis. However, the direct effect of protease activities of gingipains on T. forsythia seemed to be minimal. Although most of the phagocytosed T. forsythia were cleared in infected macrophages, more T. forsythia remained in cells coinfected with gingipain-expressing P. gingivalis than in cells coinfected with the gingipain-null mutant or infected only with T. forsythia at 24 and 48 h post-infection. Collectively, these results suggest that P. gingivalis, mainly via its gingipains, alters the clearance of T. forsythia, and provide some insights into the role of P. gingivalis as a keystone pathogen. PMID- 26434369 TI - Synthetic cannabinoid (K2) use in pediatric patients and cardiovascular events: A place for pericarditis and myopericarditis? PMID- 26434367 TI - Inflammation-associated alterations to the intestinal microbiota reduce colonization resistance against non-typhoidal Salmonella during concurrent malaria parasite infection. AB - Childhood malaria is a risk factor for disseminated infections with non-typhoidal Salmonella (NTS) in sub-Saharan Africa. While hemolytic anemia and an altered cytokine environment have been implicated in increased susceptibility to NTS, it is not known whether malaria affects resistance to intestinal colonization with NTS. To address this question, we utilized a murine model of co-infection. Infection of mice with Plasmodium yoelii elicited infiltration of inflammatory macrophages and T cells into the intestinal mucosa and increased expression of inflammatory cytokines. These mucosal responses were also observed in germ-free mice, showing that they are independent of the resident microbiota. Remarkably, P. yoelii infection reduced colonization resistance of mice against S. enterica serotype Typhimurium. Further, 16S rRNA sequence analysis of the intestinal microbiota revealed marked changes in the community structure. Shifts in the microbiota increased susceptibility to intestinal colonization by S. Typhimurium, as demonstrated by microbiota reconstitution of germ-free mice. These results show that P. yoelii infection, via alterations to the microbial community in the intestine, decreases resistance to intestinal colonization with NTS. Further they raise the possibility that decreased colonization resistance may synergize with effects of malaria on systemic immunity to increase susceptibility to disseminated NTS infections. PMID- 26434370 TI - Prostaglandin E2 Mediates Cardiorespiratory Disturbances during Infection in Neonates. AB - OBJECTIVE: To determine whether infection, with associated eicosanoid release, is a main cause of respiratory disruption in neonates, by measuring levels of prostaglandin E2 (PGE2) and its metabolite (PGEM) in cerebrospinal fluid (CSF). STUDY DESIGN: Of 59 eligible infants, 25 preterm infants (mean gestational age, 28 +/- 0.5 weeks) and 22 full-term infants (mean gestational age, 40 +/- 0.5 weeks) from a level 3 neonatal intensive care unit and the general maternity neonatal ward were enrolled prospectively. Infants with a condition that can cause secondary apnea were excluded. Cardiorespiratory disturbances, such as apnea, bradycardia, and desaturation (ABD) events, were quantified. All infants were subjected to standard laboratory analysis of blood and CSF concentrations of biomarkers, including PGE2 and PGEM, within 24 hours of lumbar puncture, which were correlated with ABD events and culture-verified infections. RESULTS: PGEM levels were highest in infants with culture-verified sepsis and meningitis (P < .01). In infants without culture-verified bacterial infections, PGEM levels were higher in preterm infants compared with term infants (P < .05). The numbers of desaturation events and apnea events in neonates were positively associated with PGE2 levels in CSF (P < .05). CONCLUSION: PGE2 and PGEM are rapidly elevated in CSF during an infectious event and may explain cardiorespiratory disturbances, which are the major presenting symptoms of neonatal infections. PGE2 and PGEM are released during bacterial infections and could serve as biomarkers for sepsis and autonomic dysfunction in neonates. PMID- 26434371 TI - Reply: To PMID 26165442. PMID- 26434372 TI - Screen-Based Behaviors of Children and Cardiovascular Risk Factors. AB - OBJECTIVE: To determine whether the amount of time spent in screen-based behaviors (SBBs; television viewing, computer use, and playing electronic games) is independently associated with individual and clustered cardiovascular disease (CVD) risk factors among elementary school children. STUDY DESIGN: Baseline data were used from 264 children (age 7-10 years) participating in the Transform-Us! cluster-randomized controlled trial. Time (h/d) spent in SBBs was obtained using a parent proxy-report questionnaire. Anthropometrics, blood pressure (BP), and lipids were measured using standard techniques. A clustered CVD risk score was calculated as the average of the standardized values of the subcomponents (waist circumference [WC], systolic BP, diastolic BP, and lipids). RESULTS: After adjusting for sex, parent education, physical activity (accelerometry), diet, and WC (when adiposity was not the outcome), television viewing time was positively associated with body mass index z-score (P = .002), WC (P = .02), and systolic BP (P = .05). Electronic games was positively associated with low density lipoprotein levels (P = .05), and total screen-time was positively associated with body mass index (P = .02). CONCLUSIONS: Differential associations were observed between types of SBBs and CVD risk factors, indicating that not all SBBs are adversely associated with obesity and CVD risk. There is a need to differentiate between types of SBBs when evaluating the CVD risk associated with screen behaviors in children. TRIAL REGISTRATION: International Standard Randomized Controlled Trial: ISRCTN83725066; Australian New Zealand Clinical Trials Registry: ACTRN12609000715279. PMID- 26434373 TI - Temperature measurement in human fat with T2 imaging. AB - PURPOSE: To develop a method for noninvasive T2 -based thermometry that enables estimation of the in vivo temperature in adipose tissues at both 1.5T and 3T field strengths. MATERIALS AND METHODS: A total of 27 apparent T2 -temperature measurement sets were performed on 13 human abdominal adipose tissue samples using an inversion prepared dual-echo single-slice sequence for apparent T2 estimation. The measurements were performed on Ingenia 1.5T and 3.0T scanners and Achieva 1.5T and 3.0T scanners. The apparent T2 -values were measured at 4 degrees C temperature intervals during heating from 21 to 45 degrees C and cooling to 21 degrees C. A two-parameter exponential fit was used to estimate the apparent T2 to temperature dependency on a scanner-to-scanner basis. RESULTS: In the temperature range evaluated (21-45 degrees C), the apparent T2 relaxation times increased from an average of ~100 msec to 190 msec at 1.5T and an average of ~130 msec to 220 msec at 3T. The measured T2 -relaxation times followed the calibration curve with a median absolute error of 0.37 degrees C and maximum error of 1.7 degrees C in 12 of the 13 samples, with the outlier having a notably different appearance upon visual inspection prior to measurement. CONCLUSION: Changes in apparent T2 relaxation time has the potential to be used for accurately estimating local temperature within in vivo subcutaneous fat. PMID- 26434375 TI - Fifth International Symposium on Childhood, Adolescent and Young Adult Non Hodgkin Lymphoma Abstracts, 22 October 2015, Varese, Italy. PMID- 26434374 TI - Health promotion and intellectual disability: listening to men. AB - Taking responsibility for your own health has been a central tenet of public health policy internationally for a number of decades. Governments in the UK and internationally continue to promote a plethora of health promotion strategies, encouraging individuals and communities to adopt healthy lifestyle choices. Although it is widely recognised that men are not as proactive in seeking out medical help or taking on health promotion advice as women, limited gender sensitive research exists in the field of intellectual disability. Despite many health promotion policy and practice strategies targeted at this population, little research exists exploring whether men with intellectual disability acknowledge health promotion advice. The study aimed to explore how men with mild to-moderate intellectual disability understood and perceived their health and what health promotion messages they acted upon. The study was based on a participatory approach which enabled 11 men with intellectual disability to contribute as steering group members and as participants through one-to-one interviews. Data were collected between September 2011 and July 2012. Thematic analysis was undertaken. The participants demonstrated a capacity to understand their own health. This was inclusive of a concern about associating being obese with being unhealthy. The participants reported good relationships with their general practitioners (GPs) and felt valued, in particular when the GP was prepared to offer specific intellectual disability and health promotion advice. More gendered research inclusive of the views of this male population is required and the study reiterates the importance of promoting the health of men and women with intellectual disability. PMID- 26434376 TI - Conformational analysis of an acyclic tetrapeptide: ab-initio structure determination from X-ray powder diffraction, Hirshfeld surface analysis and electronic structure. AB - A terminally protected acyclic tetrapeptide has been synthesized, and the crystal structure of its hydrated form, Boc-Tyr-Aib-Tyr-Ile-OMe.2H2O (1), has been determined directly from powder X-ray diffraction data. The backbone conformation of tetrapeptide (1) exhibiting two consecutive beta-turns is stabilized by two 4 > 1 intramolecular N-H . . . O hydrogen bonds. In the crystalline state, the tetrapeptide molecules are assembled through water-mediated O-H . . . O hydrogen bonds to form two-dimensional molecular sheets, which are further linked by intermolecular C-H . . . O hydrogen bonds into a three-dimensional supramolecular framework. The molecular electrostatic potential (MEP) surface of (1) has been used to supplement the crystallographic observations. The nature of intermolecular interactions in (1) has been analyzed quantitatively through the Hirshfeld surface and two-dimensional fingerprint plot. The DFT optimized molecular geometry of (1) agrees closely with that obtained from the X-ray structure analysis. The present structure analysis of Boc-Tyr-Aib-Tyr-Ile-OMe.2H2 O (1) represents a case where ab-initio crystal structure of an acyclic tetrapeptide with considerable molecular flexibility has been accomplished from laboratory X-ray powder diffraction data. PMID- 26434377 TI - Irradiated Graphene Loaded with SnO2 Quantum Dots for Energy Storage. AB - Tin dioxide (SnO2) and graphene are unique strategic functional materials with widespread technological applications, particularly in the areas of solar batteries, optoelectronic devices, and solid-state gas sensors owing to advances in optical and electronic properties. Versatile strategies for microstructural evolution and related performance of SnO2 and graphene composites are of fundamental importance in the development of electrode materials. Here we report that a novel composite, SnO2 quantum dots (QDs) supported by graphene nanosheets (GNSs), has been prepared successfully by a simple hydrothermal method and electron-beam irradiation (EBI) strategies. Microstructure analysis indicates that the EBI technique can induce the exfoliation of GNSs and increase their interlayer spacing, resulting in the increase of GNS amorphization, disorder, and defects and the removal of partial oxygen-containing functional groups on the surface of GNSs. The investigation of SnO2 nanoparticles supported by GNSs (SnO2/GNSs) reveals that the GNSs are loaded with SnO2 QDs, which are dispersed uniformly on both sides of GNSs. Interestingly, the electrochemical performance of SnO2/GNSs indicates that SnO2 QDs supported by a 210 kGy irradiated GNS shows excellent cycle response, high specific capacity, and high reversible capacity. This novel SnO2/GNS composite has potential practical applications in SnO2 electrode materials during Li(+) insertion/extraction. PMID- 26434378 TI - Prognostic Value of Ambulatory Blood Pressure Monitoring in Obese Patients. PMID- 26434379 TI - Systematic differences in time of cerebellar-neuron origin derived from bromodeoxyuridine immunoperoxidase staining protocols and tritiated thymidine autoradiography: A comparative study. AB - As exogenous markers of DNA synthesis, 5-bromo-2'-deoxyuridine (BrdU) and tritiated thymidine ([(3)H]TdR) have revolutionized our ability to identify proliferating neuroblasts and follow their fate during the development of the central nervous system. The effect of the incorporation of these molecules into DNA on cell proliferation, migration and differentiation is frequently neglected (Duque and Rakic, 2011. J. Neurosci. 31, 15205-15217). By a progressively delayed cumulative labeling method, the current paper analyzes the development of the cerebellum in mice exposed to either BrdU or [(3)H]TdR as embryos and collected at postnatal day 90. We observed that, in comparison to the saline group, several parameters of the cerebellum such as length of the cerebellar cortex, the area of the molecular layer, Purkinje cell (PCs) number, the areas of the cerebellar nuclei, and the number of the deep cerebellar nuclei (DCN) neurons were lower in the BrdU injected group. No consequence of [(3)H]TdR administration was observed. On the other hand, we also studied whether immunohistochemical methods, including BrdU antibodies from different vendors (Sigma and Dako), partial DNA denaturation procedures and trypsin pretreatments, alter the neurogenetic timetables of PC and DCN neurons that resulted from analysis of these tissue specimens. Our analysis revealed that the generative programs of these macroneurons were unrelated to differences in the sensibility of BrdU antibodies but were dependent on the partial denaturation of DNA and trypsin digestion protocols. Finally, we also compare the generation and spatial distribution of PC and DCN neurons in mice exposed to either BrdU or [(3)H]TdR to assess whether the results obtained by these two markers are quantitatively similar. The data presented here show that systematic differences exist in the pattern of neurogenesis and the spatial location of cerebellar neurons between mice injected with BrdU or [(3)H]TdR. These findings have implications for the interpretation of results obtained by both exogenous makers as an index of the production, migration and settling of neurons in the developing central nervous system. PMID- 26434380 TI - Invasive pneumococcal disease among children younger than 5 years of age before and after introduction of pneumococcal conjugate vaccine in Casablanca, Morocco. AB - OBJECTIVES: The purpose of this study was to compare the incidence rate of invasive pneumococcal disease, the rates of antibiotic resistance and serotype distribution among children <=5 years old before and after PCVs introduction in Casablanca, Morocco. METHODS: This study was conducted at the Ibn Rochd University Hospital Centre of Casablanca during two periods encompassing pre-and post-implementation of PCVs, respectively from January 2007 to October 2010 and from January 2011 to December 2014. All the non-duplicate invasive S. pneumoniae isolates recovered during the study periods were included. RESULTS: There were 136 cases of IPD, 91 before and 45 after PCVs introduction. The greatest decrease in incidence rate of IPD occurred in children <= 2 years of age declining from 34.6 to 13.5 per 100,000 populations (p<0.0001) before and after vaccination, respectively. The incidence rate of PCV-7, PCV-10 non-PCV-7 and PCV-13 non-PCV-10 serotypes decrease significantly from 18.0 to 4.6, from 5.7 to 1.3 and from 5.7 to 0.8/100,000 population (p<0.001) in the same age, respectively. CONCLUSION: Shifts in the distribution of IPD serotypes and reductions in the incidence rate of disease suggest an effective reduction of the burden of IPD in children, but continued high quality surveillance is critical to assess the changes in serotype distributions. PMID- 26434381 TI - Nutrition for homeless populations: shelters and soup kitchens as opportunities for intervention. AB - Nutrition is a daily challenge for the homeless population in America. Homeless individuals suffer from a high prevalence of diseases related to poor diet, yet there has been little public health effort to improve nutrition in this population. Shelters and soup kitchens may have an untapped potential to impact food access, choice and quality. We offer ideas for intervention and lessons learned from ten shelters and soup kitchens around Greater Boston, MA, USA. By advancing food quality, education and policies in shelters and soup kitchens, the homeless population can be given an opportunity to restore its nutrition and health. PMID- 26434382 TI - Randomized, controlled, double-blind trial of topical lidocaine gel and intrauterine lidocaine infusion for pain relief during saline contrast sonohysterography. AB - OBJECTIVES: To evaluate the efficacy of topical lidocaine gel and intrauterine lidocaine infusion administered prior to saline contrast sonohysterography (SCSH) in reducing pain level during the procedure. METHODS: This was a randomized, double-blind, placebo controlled trial. We recruited 120 women scheduled to undergo SCSH and randomized them into one of three groups according to administration of gel and intrauterine infusion immediately prior to the procedure: (1) the 'lidocaine gel' group received 3 mL 2% lidocaine gel applied to the cervix and intrauterine infusion, using an infant feeding tube without balloon, of 5 mL normal saline; (2) the 'lidocaine infusion' group received 3 mL gel lubricant applied to the cervix and intrauterine infusion of 5 mL 2% lidocaine; (3) the placebo group received 3 mL gel lubricant applied to the cervix and intrauterine infusion of 5 mL normal saline. The tube was left in place for the SCSH procedure. The primary outcome measure was the overall pain level (on a scale of 0-100) reported by the women during the SCSH procedure. Women also rated their pain levels at various other time points and an observer assessed visible signs of the women's discomfort during the procedure, producing a distress score. RESULTS: There were no significant differences among the three groups in baseline characteristics, volume of saline solution infused, tenaculum use and duration and difficulty level of the SCSH procedure. The median (range) pain scores during normal saline infusion for the SCSH procedure were 0 (0-65) in the placebo group, 2.5 (0-80) in the lidocaine gel group, and 0 (0-70) in the lidocaine infusion group. The pain scores at other time points, the overall pain score and the distress score were also comparable for the three groups. No significant adverse events were reported. CONCLUSIONS: SCSH performed with an infant feeding tube without balloon is associated with very low pain levels. Topical lidocaine gel application and intrauterine lidocaine infusion do not further reduce pain levels during SCSH. PMID- 26434385 TI - Tropical Medicine & International Health. PMID- 26434383 TI - Magnetic bead fluorescent immunoassay for the rapid detection of the novel inflammation marker YKL40 at the point-of-care. AB - Pneumonia is one of the leading causes of death worldwide.We present a magnetic bead fluorescent sandwich immunoassay that allows rapid serum measurement of the novel inflammation marker YKL40 (CHI3L1) at the point of care (POC) that could aid pneumonia diagnosis. The magnetic beads serve as the solid phase for separation of YKL40 from serum. The readout is performed using a small and robust fluorescence reader,which detects the turnover of a fluorescent substrate. The assay procedure, from sample addition to data retrieval, consists of three steps and is performed in less than 20 min. The presented assay has a linear range from 3 to 111 ng/mL, with a limit of detection of 2.9 ng/mL. The average recoveries were found between 101 and 111%. The developed method was applied in sera from healthy subjects (n= 14; c(YKL40)= 50 +/- 49 ng/mL) and from pneumonia patients (n = 14; c(YKL40) = 333.6 +/- 225 ng/mL). The elevated YKL40 concentrations in pneumonia-diseased patients are in good agreement with previously published data. The POC-ready device provides a simple immunoassay that could help to optimize pneumonia inflammation diagnostics in low-resource settings. PMID- 26434386 TI - Redesign of a Fluorogenic Labeling System To Improve Surface Charge, Brightness, and Binding Kinetics for Imaging the Functional Localization of Bromodomains. AB - Protein labeling with fluorogenic probes is a powerful method for the imaging of cellular proteins. The labeling time and fluorescence contrast of the fluorogenic probes are critical factors for the precise spatiotemporal imaging of protein dynamics in living cells. To address these issues, we took mutational and chemical approaches to increase the labeling kinetics and fluorescence intensity of fluorogenic PYP-tag probes. Because of charge-reversal mutations in PYP-tag and probe redesign, the labeling reaction was accelerated by a factor of 18 in vitro, and intracellular proteins were detected with an incubation period of only 1 min. The brightness of the probe both in vitro and in living cells was enhanced by the mutant tag. Furthermore, we applied this system to the imaging analysis of bromodomains. The labeled mutant tag successfully detected the localization of bromodomains to acetylhistone and the disruption of the bromodomain-acetylhistone interaction by a bromodomain inhibitor. PMID- 26434384 TI - Immunodominant epitope-specific Th1 but not Th17 responses mediate protection against Helicobacter pylori infection following UreB vaccination of BALB/c mice. AB - Helicobacter pylori (H. pylori) infects more than half of the world's population, causing chronic gastritis, peptic ulcers and gastric cancer. Urease B subunit (UreB), a conserved protein of H. pylori, is capable of inducing specific CD4(+) T-cell responses and provides protection against this infection. Previous studies have confirmed the effectiveness of rUreB subunit vaccines in generating CD4(+) T cell-mediated protection, but less is known regarding the roles of different subtypes of T-cell immunity, such as Th1, Th2 and Th17, particularly the immunodominant epitopes inducing specific CD4(+) T-cell responses, in vaccine mediated protection. In this study, we demonstrated that the vaccination of BALB/c mice with rUreB resulted in significant antigen-specific Th1 and Th17 immune responses. Importantly, two novel Th epitopes, UreB317-329 and UreB409 421, which are recognized by a major population of CD4(+) T cells, were identified in immunized mice. Our results demonstrated that two novel epitopes can simultaneously induce Th1 and Th17 immune responses; however, only the epitope vaccine-induced CD4(+) T-cells secreting IFN-gamma mediated the protection against H. pylori; cells secreting IL-17A did not. Taken together, our results suggest that two novel immunodominant epitopes can induce Th1 and Th17 immune responses, but only the induced Th1 lymphocytes mediate protection against H. pylori. PMID- 26434387 TI - Smart gating membranes with in situ self-assembled responsive nanogels as functional gates. AB - Smart gating membranes, inspired by the gating function of ion channels across cell membranes, are artificial membranes composed of non-responsive porous membrane substrates and responsive gates in the membrane pores that are able to dramatically regulate the trans-membrane transport of substances in response to environmental stimuli. Easy fabrication, high flux, significant response and strong mechanical strength are critical for the versatility of such smart gating membranes. Here we show a novel and simple strategy for one-step fabrication of smart gating membranes with three-dimensionally interconnected networks of functional gates, by self-assembling responsive nanogels on membrane pore surfaces in situ during a vapor-induced phase separation process for membrane formation. The smart gating membranes with in situ self-assembled responsive nanogels as functional gates show large flux, significant response and excellent mechanical property simultaneously. Because of the easy fabrication method as well as the concurrent enhancement of flux, response and mechanical property, the proposed smart gating membranes will expand the scope of membrane applications, and provide ever better performances in their applications. PMID- 26434388 TI - Can we beat the biotin-avidin pair?: cucurbit[7]uril-based ultrahigh affinity host-guest complexes and their applications. AB - The design of synthetic, monovalent host-guest molecular recognition pairs is still challenging and of particular interest to inquire into the limits of the affinity that can be achieved with designed systems. In this regard, cucurbit[7]uril (CB[7]), an important member of the host family cucurbit[n]uril (CB[n], n = 5-8, 10, 14), has attracted much attention because of its ability to form ultra-stable complexes with multiple guests. The strong hydrophobic effect between the host cavity and guests, ion-dipole and dipole-dipole interactions of guests with CB portals helps in cooperative and multiple noncovalent interactions that are essential for realizing such strong complexations. These highly selective, strong yet dynamic interactions can be exploited in many applications including affinity chromatography, biomolecule immobilization, protein isolation, biological catalysis, and sensor technologies. In this review, we summarize the progress in the development of high affinity guests for CB[7], factors affecting the stability of complexes, theoretical insights, and the utility of these high affinity pairs in different challenging applications. PMID- 26434389 TI - Terminal hepatic venule injury in liver biopsies of allogeneic haematopoietic stem cell recipients-a study of 63 cases. AB - AIMS: Subtle lesions of terminal hepatic venules (THVs) may be overlooked in liver biopsies from haematopoietic stem cell transplant (HSCT) receipients when graft-versus-host disease is the clinical concern. The aim of this study was to evaluate the frequency of THV injury resembling sinusoidal obstruction syndrome (SOS). METHODS AND RESULTS: Sixty-three consecutive biopsies from allogeneic HSCT recipients were scored for injured THVs. Forty-nine (78%) biopsies had injured THVs, and 10 (16%) were diagnosed with SOS (mean +/- standard deviation of injured THVs/biopsy: 90 +/- 9%). Biopsies diagnosed with other diseases also had injured THVs (36 +/- 33%). Biopsies from patients with cyclophosphamide plus fractionated total body irradiation conditioning and biopsies taken within 100 days post-HSCT had significantly more occluded THVs (respectively: 40 +/- 38%, P = 0.0188; and 35 +/- 35%, P = 0.0076) than those with other conditioning regimens or in biopsies taken >100 days post-HSCT. All biopsies taken at any time in the 6 year post-HSCT period had similar amounts of THV phlebosclerosis (23 +/- 25%). CONCLUSIONS: Our results demonstrate a high incidence of THV injuries resembling SOS in post-HSCT liver biopsies. THV injuries were detectable for several years post-HSCT, and were concurrent with other diagnoses. Our results also suggest that SOS may be underdiagnosed. PMID- 26434390 TI - Isolation and crystal structure of a dithiophene dication: controlling covalent connection and disconnection with temperature and phase. AB - A dithienylethene (1o) undergoes a two-electron chemical oxidation to a singlet diradical as an open-isomer (1o(2+)) in solution, which cyclizes to a closed-form (1c(2+)) upon cooling. The latter crystallizes out and its structure is analyzed by single crystal X-ray diffraction. Equilibrium between 1o(2+) and 1c(2+) in solution is observed by NMR and UV spectroscopy at various temperatures and is further supported by reduction reactions with Zn powder. PMID- 26434391 TI - Case of auricular herpes zoster associated with contralateral facial paralysis. PMID- 26434392 TI - Protein function annotation using protein domain family resources. AB - As a result of the genome sequencing and structural genomics initiatives, we have a wealth of protein sequence and structural data. However, only about 1% of these proteins have experimental functional annotations. As a result, computational approaches that can predict protein functions are essential in bridging this widening annotation gap. This article reviews the current approaches of protein function prediction using structure and sequence based classification of protein domain family resources with a special focus on functional families in the CATH Gene3D resource. PMID- 26434393 TI - Early-life characteristics and educational disparities in smoking. AB - Health inequalities pose an important public health challenge in European countries, for which increased social mobility has been suggested as a cause. We sought to describe how the relationship between health inequalities and social mobility varies among welfare regime types in the European region. Data from six rounds of the European Social Survey was analyzed using multilevel statistical techniques,stratified by welfare regime type, including 237,535 individuals from 136 countries. Social mobility among individuals was defined according to the discrepancy between parental and offspring educational attainment. For each welfare regime type, the association between social mobility and self-rated health was examined using odds ratios and risk differences, controlling for parental education. Upwardly mobile individuals had between 23 and 44% lower odds of reporting bad or very bad self-rated health when compared to those who remained stable. On an absolute scale, former USSR countries showed the biggest and only significant differences for upward movement,while Scandinavian countries showed the smallest. Downward social mobility tended to be associated with worse health, but the results were less consistent. Upward social mobility is associated with better health in all European welfare regime types. However, in Scandinavian countries the association of upward mobility was smaller, suggesting that the Nordic model is more effective in mitigating the impact of social mobility on health and/or of health on mobility [corrected]. PMID- 26434394 TI - Global investigation of potential energy surfaces for the pyrolysis of C(1)-C(3) hydrocarbons: toward the development of detailed kinetic models from first principles. AB - Detailed kinetic models (DKMs) are the most fundamental "bottom-up" approaches to computational investigation of the pyrolysis and oxidation of fuels. The weakest points of existing DKMs are incomplete information about the reaction types that can be involved in the potential energy surfaces (PESs) in pyrolysis and oxidation processes. Also, the computational thermodynamic parameters available in the literature vary widely with the level of theory employed. More sophisticated models require improvement both in our knowledge of the type of the reactions involved and the consistency of thermodynamic and kinetic parameters. In this paper, we aim to address these issues by developing ab initio models that can be used to describe early stages of pyrolysis of C1-C3 hydrocarbons. We applied a recently developed global reaction route mapping (GRRM) strategy to systematically investigate the PES of the pyrolysis of C1-C3 hydrocarbons at a consistent level of theory. The reactions are classified into 14 reaction types. The critical points on the PES for all reactions in the network are calculated at the highly accurate UCCSD(T)-F12b/cc-pVTZ//UM06-2X/cc-pVTZ level of theory. The data reported in this paper can be used for first principle calculations of kinetic constants and for a subsequent study on modeling the evolution of the species from the reaction network of the pyrolysis and oxidation of C1-C3 hydrocarbons. PMID- 26434395 TI - Thrombophilic genetic risk factors for liver fibrosis: To screen or not to screen? PMID- 26434396 TI - MRP2 in cholestasis: Putting down the anchor. PMID- 26434397 TI - An evaluation of physician predictions of discharge on a general medicine service. AB - The goal of this study was to evaluate general medicine physicians' ability to predict hospital discharge. We prospectively asked study subjects to predict whether each patient under their care would be discharged on the next day, on the same day, or neither. Discharge predictions were recorded at 3 time points: mornings (7-9 am), midday (12-2 pm), or afternoons (5-7 pm), for a total of 2641 predictions. For predictions of next-day discharge, the sensitivity (SN) and positive predictive value (PPV) were lowest in the morning (27% and 33%, respectively), but increased by the afternoon (SN 67%, PPV 69%). Similarly, for same-day discharge predictions, SN and PPV were highest at midday (88% and 79%, respectively). We found that although physicians have difficulty predicting next day discharges in the morning prior to the day of expected discharge, their ability to correctly predict discharges continually improved as the time to actual discharge decreased. Journal of Hospital Medicine 2015;10:808-810. (c) 2015 Society of Hospital Medicine. PMID- 26434398 TI - Childhood-onset epilepsy five decades later. A prospective population-based cohort study. AB - OBJECTIVE: To study the impact of childhood-onset epilepsy on a variety of outcomes across the life span. METHODS: A population-based cohort of 245 subjects with childhood-onset epilepsy was assessed for outcomes at 45 years. In addition, 51 of 78 surviving subjects with uncomplicated epilepsy and 52 of 99 originally matched controls participated in a detailed evaluation including electroencephalography (EEG), imaging, and laboratory studies at 50 years. RESULTS: Of 179 surviving subjects, 61% were in terminal 10-year remission and 43% in remission off medications. At 45 years, 95% of the idiopathic group, 72% of the cryptogenic group, and 47% of the remote symptomatic group were in terminal remission (p < 0.001). Abnormal neurologic signs were significantly more common in subjects with uncomplicated epilepsy than in controls. Mortality during period 1992-2012 was higher in subjects than in controls (9% vs. 1%, p = 0.02). The rate of 3T MRI abnormalities was higher in subjects than in controls (risk ratio [RR] 2.0; 1.3-3.1) specifically including findings considered markers of cerebrovascular disease (RR 2.5; 1.04-5.9). Even subjects with idiopathic epilepsy had higher rates of imaging abnormalities than controls (73% vs. 34%, p = 0.002). SIGNIFICANCE: Long-term seizure outcomes are excellent and a function of etiology. The presence of imaging abnormalities suggestive of vascular disease may put these subjects at higher risk for clinically evident stroke and cognitive changes as they age. PMID- 26434399 TI - Recent advances in amino acid analysis by capillary electromigration methods, 2013-2015. AB - We describe the most important research articles published on amino acid analysis using CE during the period from June 2013 to May 2015, and follows the format of the previous articles published in electrophoresis the new developments in amino acid analysis with CE are mainly describing improvements in detection means and injection methods. Enantiomeric separation developments are still important. Focusing the applications, we describe the neurochemical and clinical works, but also the metabolomic studies for which the publication number increase greatly. Finally, works focused on amino acids in food and agricultural applications are described. PMID- 26434400 TI - A path to practical Solar Pumped Lasers via Radiative Energy Transfer. AB - The optical conversion of incoherent solar radiation into a bright, coherent laser beam enables the application of nonlinear optics to solar energy conversion and storage. Here, we present an architecture for solar pumped lasers that uses a luminescent solar concentrator to decouple the conventional trade-off between solar absorption efficiency and the mode volume of the optical gain material. We report a 750-MUm-thick Nd(3+)-doped YAG planar waveguide sensitized by a luminescent CdSe/CdZnS (core/shell) colloidal nanocrystal, yielding a peak cascade energy transfer of 14%, a broad spectral response in the visible portion of the solar spectrum, and an equivalent quasi-CW solar lasing threshold of 23 W cm(-2), or approximately 230 suns. The efficient coupling of incoherent, spectrally broad sunlight in small gain volumes should allow the generation of coherent laser light from intensities of less than 100 suns. PMID- 26434401 TI - Hypertension: PATHWAY to improving the treatment of drug-resistant hypertension. PMID- 26434403 TI - Infection: Efficacy of chlorhexidine against catheter-related infections. PMID- 26434404 TI - Effect of high-dose atorvastatin on the cardiovascular risk associated with individual components of metabolic syndrome: a subanalysis of the Treating to New Targets (TNT) study. AB - AIMS: To investigate the impact of intensive lipid-lowering with high-dose atorvastatin on the cardiovascular risk associated with individual metabolic syndrome components [high body mass index (BMI), elevated triglycerides, low high density lipoprotein (HDL) cholesterol, hypertension and elevated fasting glucose] in patients with coronary heart disease (CHD). METHODS: Patients with clinically evident, stable CHD and low-density lipoprotein (LDL) cholesterol <3.4 mmol/l (130 mg/dl) were randomized to double-blind therapy with atorvastatin 10 mg/day (n = 5006) or 80 mg/day (n = 4995) after an 8-week open-label run-in with atorvastatin 10 mg. The median follow-up was 4.9 years. The impact of individual metabolic syndrome risk factors was tested on the primary endpoint, which was the occurrence of a first major cardiovascular event. RESULTS: On-treatment LDL cholesterol was 2.6 mmol/l (101 mg/dl) with atorvastatin 10 mg and 2.0 mmol/l (77 mg/dl) with atorvastatin 80 mg. Among patients receiving atorvastatin 10 mg, the presence of each individual metabolic syndrome component significantly increased the risk of major cardiovascular events compared with the absence of each (BMI, p = 0.014; triglycerides, p = 0.006; HDL cholesterol, p = 0.0006; hypertension, p < 0.0001; and fasting glucose p < 0.0001). In patients receiving atorvastatin 80 mg, elevated triglycerides and fasting glucose were no longer significant predictors of major cardiovascular events. The predictive power of hypertension on the risk of major cardiovascular events was reduced in patients treated with atorvastatin 80 mg, although it remained a significant predictor. CONCLUSIONS: Treatment with high-dose atorvastatin to a mean LDL cholesterol level of 2.0 mmol/l (77 mg/dl) considerably attenuated the predictive power associated with three metabolic syndrome components. PMID- 26434402 TI - Mechanisms and mediators of lung injury after acute kidney injury. AB - Acute kidney injury (AKI) is a common complication in hospitalized patients, associated with >50% mortality in those in intensive care who require renal replacement therapy. Data suggest that AKI is a systemic disease that adversely affects the immune system and organ function, and in this way contributes to the high mortality observed in affected patients. Data from patients and animal models indicate that AKI adversely affects the lungs. Respiratory complications are common in patients with AKI and include pulmonary oedema, respiratory failure requiring mechanical ventilation, prolonged duration of mechanical ventilation, and prolonged weaning from mechanical ventilation. The development of respiratory failure in patients with AKI greatly increases the risk of death. Data from animal models support the notion that cardiogenic pulmonary oedema (from volume overload) and non-cardiogenic pulmonary oedema (from endothelial injury due to inflammation and apoptosis) can occur in AKI. In this Review we discuss the clinical, epidemiologic, and animal data that provide insights into the mechanisms by which AKI can lead to lung injury and respiratory complications. Elucidation of the mechanisms of lung injury and respiratory complications after AKI is essential to develop effective therapies and reduce the high mortality associated with AKI and respiratory failure. PMID- 26434405 TI - A pH-mediated enhancement of the graphene carbocatalyst activity for the reduction of 4-nitrophenol. AB - Using alkaline pH adjustment, the reaction between graphene oxide and L-ascorbic acid led to the formation of a carbocatalyst film with numerous graphene edges protruding out of basal planes, which had a markedly enhanced carbocatalytic activity for conversion of 4-nitrophenol to 4-aminophenol, as compared to that of the carbocatalyst counterpart without involving pH mediation. PMID- 26434407 TI - Pauli Spin Blockade of Heavy Holes in a Silicon Double Quantum Dot. AB - In this work, we study hole transport in a planar silicon metal-oxide semiconductor based double quantum dot. We demonstrate Pauli spin blockade in the few hole regime and map the spin relaxation induced leakage current as a function of interdot level spacing and magnetic field. With varied interdot tunnel coupling, we can identify different dominant spin relaxation mechanisms. Application of a strong out-of-plane magnetic field causes an avoided singlet triplet level crossing, from which the heavy hole g-factor ~0.93 and the strength of spin-orbit interaction ~110 MUeV can be obtained. The demonstrated strong spin orbit interaction of heavy holes promises fast local spin manipulation using only electric fields, which is of great interest for quantum information processing. PMID- 26434408 TI - Right hippocampus size is negatively correlated with leptin serum levels in bipolar disorder. AB - Obesity is more frequent in bipolar disorder. Adipokines are associated with depression and obesity via the inflammatory process. Twenty-six DSM-IV patients with BD and 39 controls were enrolled to assess the relationship between serum leptin and adiponectin with hippocampal volumes. Among patients, there was a significant negative correlation between right hippocampal volume and serum leptin levels. This result sum for the hypothesis of a pro-inflammatory state associated with BD and the prevalent co-morbid obesity. PMID- 26434409 TI - Silibinin suppresses astroglial activation in a mouse model of acute Parkinson's disease by modulating the ERK and JNK signaling pathways. AB - Parkinson's disease (PD) is the second-most common neurodegenerative disease after Alzheimer's disease, and is characterized by dopaminergic neuronal loss in midbrain. The MPTP-induced PD model has been well characterized by motor deficits and selective dopaminergic neuronal death accompanied by glial activation. Silibinin is a constituent of silymarin, an extract of milk thistle seeds, and has been proposed to have hepatoprotective, anti-cancer, anti-oxidative, and neuroprotective effects. In the present study, the authors studied the neuroprotective effects of silibinin in an acute MPTP model of PD. Silibinin was administered for 2 weeks, and then MPTP was administered to mice over 1 day (acute MPTP induced PD). Silibinin pretreatment effectively ameliorated motor dysfunction, dopaminergic neuronal loss, and glial activations caused by MPTP. In addition, an in vitro study demonstrated that silibinin suppressed astroglial activation and ERK and JNK phosphorylation in primary astrocytes in response to MPP(+) treatment. These findings show silibinin protected dopaminergic neurons in an acute MPTP-induced mouse model of PD, and suggest its neuroprotective effects might be mediated by the suppression of astrocyte activation via the inhibition of ERK and JNK phosphorylation. In conclusion, the study indicates silibinin should be viewed as a potential treatment for PD and other neurodegenerative diseases associated with neuroinflammation. PMID- 26434410 TI - Outcomes of living donor renal transplantation in children with lower urinary tract dysfunction: a comparative retrospective study. AB - OBJECTIVES: To compare outcomes of renal transplantation (RTx) in children with end-stage renal disease (ESRD) resulting from lower urinary tract dysfunction (LUTD) vs other causes. PATIENTS AND METHODS: A database of children (<18 years old) who underwent RTx between May 2008 and April 2012 was reviewed. Patients were divided into those with LUTD (group A, n = 29) and those with other causes of ESRD (group B, n = 74). RTx was performed after achieving low intravesical pressure (<30 cmH2 O) with adequate bladder capacity and drainage. The groups were compared using Student's t-test, Mann-Whitney, chi-squared or exact tests. Graft survival rates (GSRs) were evaluated using Kaplan-Meier curves and the log rank test. RESULTS: The mean +/- sd (range) age of the study cohort was 5.05 +/- 12.4 (2.2-18) years. Causes of LUTD were posterior urethral valve (PUV; 41.4%), vesico-ureteric reflux (VUR; 37.9%), neurogenic bladder (10.3%), prune belly syndrome (3.4%), obstructive megaureter (3.4%) and urethral stricture disease (3.4%). There was no significant difference in age, dialysis duration or donor type. In group A, 25 of the 29 patients (86.2%) underwent >=1 surgery to optimize the urinary tract for allograft. Pretransplant nephrectomy was performed in 15 of the 29 patients (51.7%), PUV ablation in nine patients (31%) and ileocystoplasty in four patients (13.7%). The mean +/- sd follow-up was 4.52 +/- 1.55 and 4.07 +/ 1.27 years in groups A and B, respectively. There was no significant difference in creatinine and eGFR between the groups at different points of follow-up. The GSRs at the end of the study were 93.1 and 91.1% in groups A and B, respectively (P = 1.00). According to Kaplan-Meier survival curves, there was no significant difference in the GSR between the groups using the log-rank test (P = 0.503). No graft was lost as a result of urological complications. In group B, one child died from septicaemia. The rate of urinary tract infections was 24 and 12% in groups A and B, respectively, but was not significant. No significant difference was found between the groups with regard to the incidence of post-transplantation hydronephrosis. Of the 22 patients who had hydronephrosis after transplantation, three were complicated by UTI. Injection of bulking agents was required in two patients for treatment of grade 3 VUR. In the third patient, augmentation cystoplasty was needed. CONCLUSION: Acceptable graft function, survival and UTI rates can be achieved in children with ESRD attributable to LUTD. Thorough assessment and optimization of LUT, together with close follow-up, are key for successful RTx. PMID- 26434412 TI - MALAT1 long non-coding RNA in cancer. AB - A recent massive parallel sequencing analysis has shown the fact that more than 80% of the human genome is transcribed into RNA. Among many kinds of the non protein coding RNAs, we focus on the metastasis associated lung adenocarcinoma transcript 1 (MALAT1) that is a long non-coding RNA upregulated in metastatic carcinoma cells. Two molecular functions of MALAT1 have been proposed, one is the control of alternative splicing and the other is the transcriptional regulation. In this review, we document the molecular characteristics and functions of MALAT1 and shed light on the implication in the molecular pathology of various cancers. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa. PMID- 26434411 TI - Linkage and regional association analysis reveal two new tightly-linked major QTLs for pod number and seed number per pod in rapeseed (Brassica napus L.). AB - To facilitate the pseudochromosomes assembly and gene cloning in rapeseed, we developed a reference genetic population/map (named BnaZNF2) from two sequenced cultivars, Zhongshuang11 and No.73290, those exhibit significant differences in many traits, particularly yield components. The BnaZNF2 genetic map exhibited perfect collinearity with the physical map of B. napus, indicating its high quality. Comparative mapping revealed several genomic rearrangements between B. napus and B. rapa or B. oleracea. A total of eight and 16 QTLs were identified for pod number and seed number per pod, respectively, and of which three and five QTLs are identical to previously identified ones, whereas the other five and 11 are novel. Two new major QTL respectively for pod number and seed number per pod, qPN.A06-1 and qSN.A06-1 (R(2 )= 22.8% and 32.1%), were colocalised with opposite effects, and only qPN.A06-1 was confirmed and narrowed by regional association analysis to 180 kb including only 33 annotated genes. Conditional QTL analysis and subsequent NILs test indicated that tight linkage, rather than pleiotropy, was the genetic causation of their colocalisation. Our study demonstrates potential of this reference genetic population/map for precise QTL mapping and as a base for positional gene cloning in rapeseed. PMID- 26434413 TI - Untangling reaction pathways through modern approaches to high-throughput single molecule force-spectroscopy experiments. AB - Single-molecule experiments provide a unique means for real-time observation of the activity of individual biomolecular machines. Through such techniques, insights into the mechanics of for example, polymerases, helicases, and packaging motors have been gleaned. Here we describe the recent advances in single-molecule force spectroscopy instrumentation that have facilitated high-throughput acquisition at high spatiotemporal resolution. The large datasets attained by such methods can capture rare but important events, and contain information regarding stochastic behaviors covering many orders of magnitude in time. We further discuss analysis of such data sets, and with a special focus on the pause states described in the general literature on RNA polymerase pausing we compare and contrast the signatures of different reaction pathways. PMID- 26434414 TI - Current harmonics elimination control method for six-phase PM synchronous motor drives. AB - To reduce the undesired 5th and 7th stator harmonic current in the six-phase permanent magnet synchronous motor (PMSM), an improved vector control algorithm was proposed based on vector space decomposition (VSD) transformation method, which can control the fundamental and harmonic subspace separately. To improve the traditional VSD technology, a novel synchronous rotating coordinate transformation matrix was presented in this paper, and only using the traditional PI controller in d-q subspace can meet the non-static difference adjustment, the controller parameter design method is given by employing internal model principle. Moreover, the current PI controller parallel with resonant controller is employed in x-y subspace to realize the specific 5th and 7th harmonic component compensation. In addition, a new six-phase SVPWM algorithm based on VSD transformation theory is also proposed. Simulation and experimental results verify the effectiveness of current decoupling vector controller. PMID- 26434415 TI - New passivity criteria for memristive uncertain neural networks with leakage and time-varying delays. AB - In this paper, the problem of passivity analysis is studied for memristor-based uncertain neural networks with leakage and time-varying delays. By combining differential inclusions with set-valued maps, the system of memristive neural networks is changed into the conventional one. By adding a triple quadratic integral and relaxing the requirement for the positive definiteness of some matrices, a proper Lyapunov-Krasovskii functional is constructed. Based on the establishment of the novel Lyapunov-Krasovskii functional, the new passivity criteria are derived by mainly applying Wirtinger-based double integral inequality, S-procedure and so on. Moreover, the conservatism of passivity conditions can be reduced. Finally, four numerical examples are given to show the effectiveness and less conservatism of the proposed criteria. PMID- 26434416 TI - Colorimetric detection of hazardous gases using a remotely operated capturing and processing system. AB - This paper presents an electronic system for the automatic detection of hazardous gases. The proposed system implements colorimetric sensing algorithms, thus providing a low-cost solution to the problem of gas sensing. It is remotely operated and it performs the tasks of image capturing and processing, hence obtaining colour measurements in RGB (Red-Green-Blue) space that are subsequently sent to a remote operator via the internet. A prototype of the system has been built to test its performance. Specifically, experiments have been carried out aimed at the detection of CO, CO2, NO, NO2, SO2 and formaldehyde at diverse concentrations by using a chromogenic array composed by 13 active and 2 inert compounds. Statistical analyses of the results reveal a good performance of the electronic system and the feasibility of remote hazardous gas detection using colorimetric sensor arrays. PMID- 26434418 TI - A composite control method based on the adaptive RBFNN feedback control and the ESO for two-axis inertially stabilized platforms. AB - Due to the nonlinearity and time variation of a two-axis inertially stabilized platform (ISP) system, the conventional feedback control cannot be utilized directly. To realize the control performance with fast dynamic response and high stabilization precision, the dynamic model of the ISP system is expected to match the ideal model which satisfies the desired control performance. Therefore, a composite control method based on the adaptive radial basis function neural network (RBFNN) feedback control and the extended state observer (ESO), is proposed for ISP. The adaptive RBFNN is proposed to generate the feedback control parameters online. Based on the state error information in the working process, the adaptive RBFNN can be constructed and optimized directly. Therefore, no priori training data is needed for the construction of the RBFNN. Furthermore, a linear second-order ESO is constructed to compensate for the composite disturbance. The asymptotic stability of the proposed control method has been proven by the Lyapunov stability theory. The applicability of the proposed method is validated by a series of simulations and flight tests. PMID- 26434417 TI - Finite-time stabilization of uncertain nonholonomic systems in feedforward-like form by output feedback. AB - This paper investigates the problem of finite-time stabilization by output feedback for a class of nonholonomic systems in chained form with uncertainties. Comparing with the existing relevant literature, a distinguishing feature of the systems under investigation is that the x-subsystem is a feedforward-like rather than feedback-like system. This renders the existing control methods inapplicable to the control problems of the systems. A constructive design procedure for output feedback control is given. The designed controller renders that the states of closed-loop system are regulated to zero in a finite time. Two simulation examples are provided to illustrate the effectiveness of the proposed approach. PMID- 26434419 TI - Causal role of oxidative stress in unfolded protein response development in the hyperthyroid state. AB - L-3,3',5-Triiodothyronine (T3)-induced liver oxidative stress underlies significant protein oxidation, which may trigger the unfolded protein response (UPR). Administration of daily doses of 0.1mg T3 for three consecutive days significantly increased the rectal temperature of rats and liver O2 consumption rate, with higher protein carbonyl and 8-isoprostane levels, glutathione depletion, and absence of morphological changes in liver parenchyma. Concomitantly, liver protein kinase RNA-like endoplasmic reticulum (ER) kinase and eukaryotic translation initiator factor 2alpha were phosphorylated in T3 treated rats compared to controls, with increased protein levels of binding immunoglobulin protein and activating transcription factor 4. In addition, higher mRNA levels of C/EBP homologous protein, growth arrest and DNA damage 34, protein disulfide isomerase, and ER oxidoreductin 1alpha were observed, changes that were suppressed by N-acetylcysteine (0.5 g/kg) given before each dose of T3. In conclusion, T3-induced liver oxidative stress involving higher protein oxidation status has a causal role in UPR development, a response that is aimed to alleviate ER stress and promote cell survival. PMID- 26434420 TI - A review of case-control studies on the risk factors for the development of autoimmune blistering diseases. AB - Autoimmune blistering diseases (AIBD) are a group of rare but potentially fatal diseases characterized by the production of autoantibodies directed against the structural proteins of the skin. Much has been published on the clinical manifestation and interventional options for AIBD, especially on the more common subtypes such as bullous pemphigoid, pemphigus vulgaris (PV) and pemphigus foliaceus (PF). However, the aetiology of AIBD remains unknown. We aim to provide an overview of published case-control studies focussing on the non-genetic aetiological factors of bullous pemphigoid, PV and/or PF. The relevant studies were appraised for their validity and results. Our results showed that a large proportion of the studies had inconclusive results due to compromised study methodologies. Moreover, there were no identified case-control studies that investigated the possible associations between bullous pemphigoid and patient environment, or the potential links between pemphigus and drugs. Hence, a case control study with a higher quality design addressing these shortcomings would contribute greatly to our knowledge of AIBD. PMID- 26434421 TI - A population-based analysis of Head and Neck hemangiopericytoma. AB - OBJECTIVES/HYPOTHESIS: Hemangiopericytomas (HPC) are tumors that arise from pericytes. Hemangiopericytomas of the head and neck are rare and occur both extracranially and intracranially. This study analyzes the demographic, clinicopathologic, treatment modalities, and survival characteristics of extracranial head and neck hemangiopericytomas (HN-HPC) and compares them to HPCs at other body sites (Other-HPC). METHODS: The Surveillance, Epidemiology, and End Results (SEER) database (1973-2012) was queried for HN-HPC (121 cases) and Other HPC (510 cases). Data were analyzed comparatively with respect to various demographic and clinicopathologic factors. Disease-specific survival (DSS) was analyzed using the Kaplan-Meier model. RESULTS: There was no significant difference in age at time of diagnosis between HN-HPC and Other-HPC. Head and neck HPC was most commonly located in the connective and soft tissue (18.4%), followed by the nasal cavity and paranasal sinuses (8.5%). Head and neck HPCs were smaller than Other-HPC (P < 0.0001) and more likely to be a lower histologic grade (P < 0.0097). The primary treatment modality for HN-HPC was surgery alone, used in 55.8% of cases. The 5-, 10-, and 20-year DSS for HN-HPC were 84.0%, 79.4%, and 69.4%, respectfully. Higher histologic grade and the presence of distant metastases were poor prognostic factors for HN-HPC. CONCLUSION: Head and neck HPCs are rare tumors. This study represents the largest series of HN-HPCs to date. Surgery alone is the primary treatment modality for HN-HPC, with a favorable prognosis. Adjuvant radiotherapy does not appear to confer a survival benefit for any body site. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:643-650, 2016. PMID- 26434423 TI - SGR Repeal: Reprieve or Pyrrhic Victory? AB - The United States Congress recently passed the bill titled H.R.2: the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) to repeal the Sustainable Growth Rate (SGR). The SGR, part of the Balanced Budget Act of 1997, was passed to attempt to control the rate of growth for Medicare spending for physician services. As a result, all physicians were annually subject to the aggregate cuts in compensation depending on rate of economic growth in the country, requiring Congress to pass legislation each year to defer the scheduled pay cuts. Will MACRA, however, truly be a reprieve to providers from the threat of annual cuts in reimbursement of between 21% and 30%, or will it result in a Pyrrhic victory for both providers and patients after the financial impact of the repeal has been realized and the quality of health care delivery and true access to care for our seniors have been evaluated? This article from The Society of Thoracic Surgeons Workforce on Health Policy, Advocacy, and Reform attempts to summarize MACRA and considers its impact on the specialty of cardiothoracic surgery. PMID- 26434422 TI - Introducing Policy Perspectives. PMID- 26434424 TI - 50th Anniversary Perspective on Volume 1: Urschel HC, Paulson DL. Mesotheliomas of the Pleura. Ann Thorac Surg 1965;1:559-73. PMID- 26434425 TI - 50th Anniversary Landmark Commentary on Griffith BP, Hardesty RL, Trento A, et al. Heart-lung transplantation: lessons learned and future hopes. Ann Thorac Surg 1987;43:6-16. PMID- 26434426 TI - 50th Anniversary Landmark Commentary on Bender HW Jr, Stewart JR, Merrill WH, Hammon JW Jr, Graham TP Jr. Ten years' experience with the Senning operation for transposition of the great arteries: physiological results and late follow-up. Ann Thorac Surg 1989;47:218-23. PMID- 26434427 TI - 50th Anniversary Landmark Commentary on Ginsberg RJ, Pearson FG, Cooper JD, et al. Closure of chronic postpneumonectomy bronchopleural fistula using the transsternal transpericardial approach. Ann Thorac Surg 1989;47:231-5. PMID- 26434428 TI - Invited Commentary. PMID- 26434429 TI - Invited Commentary. PMID- 26434430 TI - Invited Commentary. PMID- 26434431 TI - Invited Commentary. PMID- 26434432 TI - Invited Commentary. PMID- 26434433 TI - Invited Commentary. PMID- 26434434 TI - Invited Commentary. PMID- 26434435 TI - Invited Commentary. PMID- 26434436 TI - Invited Commentary. PMID- 26434437 TI - Invited Commentary. PMID- 26434438 TI - Anomalous Origin of the Circumflex Artery: An Underestimated Threat During Mitral Valve Operation. AB - Ischemic iatrogenic lesions can complicate surgical procedures on the mitral valve. One of the causative mechanisms is direct injury to or distortion of the circumflex coronary artery. The risk of damaging the circumflex coronary artery depends mainly on the proximity of that vessel to the posterior segment of the mitral annulus, and this varies from patient to patient. Herein, we report the case of an iatrogenic circumflex coronary artery lesion after mitral annuloplasty in a patient with an anomalous origin of the circumflex artery. PMID- 26434439 TI - Aortic and Mitral Valve Replacement Due to Extensive Inflammatory Immunoglobulin G4-Related Pseudotumor. AB - A 64-year-old woman with extensive tumorous infiltration of the mitral and aortic valves underwent partial resection of a tumor of the left ventricular outflow tract and replacement of both affected valves. Histology revealed an inflammatory pseudotumor with a significant number of immunoglobulin-G4-positive plasma cells. The histologic and clinical findings suggested immunoglobulin-G4-related disease of the heart. PMID- 26434440 TI - Severely Thrombosed Transcatheter Aortic Valve 9 Months After Implantation. AB - Bioprosthetic aortic valve thrombosis is a rare complication after transcatheter aortic valve implantation; however, one with a high mortality. We describe the case of a patient with a completely thrombosed transcatheter aortic valve prosthesis 9 months after implantation and review the diagnosis and management of this complication. PMID- 26434441 TI - Endovascular Repair for Type A Aortic Dissection After Transcatheter Aortic Valve Replacement With a Medtronic CoreValve. AB - Transcatheter aortic valve replacement is being used with increasing frequency in patients with severe aortic stenosis who are otherwise deemed to be at high surgical risk. Aortic dissection is a rare complication of transcatheter aortic valve replacement and poses a unique management dilemma. We describe the treatment of an acute Stanford type A aortic dissection after transcatheter aortic valve replacement with a modified thoracic endovascular stent graft in a 95-year-old woman. PMID- 26434442 TI - Modified Senning Procedure for Correction of Atrioventricular Discordance With Total Anomalous Pulmonary Venous Return, Atrial Situs Inversus, Dextrocardia, and Bilateral Superior Venae Cavae. AB - The Senning and Mustard baffles remain important techniques for the treatment of congenitally corrected transposition (cc-TGA), isolated ventricular inversion, and D-transposition of the great arteries with delayed presentation. We describe the treatment of an 8-month old infant with atrioventricular discordance, ventriculoarterial concordance, and dextrocardia with atrial situs inversus. A modified Senning procedure was performed through the "left-sided" atrium. Modifications of the Senning and Mustard baffles remain important tools in the treatment of rare conditions like isolated ventricular inversion. PMID- 26434443 TI - Metastatic Ocular Melanoma Presenting as a Heart-Compressing Mediastinal Mass. AB - Ocular malignant melanoma is characterized by an unpredictable course, and metastases may develop, after a long disease-free interval, anywhere in the body. The mediastinum, however, is a rare site of these metastases, and metastatic melanoma presenting as a large mediastinal mass is quite unusual. We report herein a peculiar case of a solitary, late metastasis of malignant ocular melanoma, manifesting as a sizable posterior mediastinal mass and presenting with paroxysmal atrial fibrillation. Transthoracic echocardiography, computed tomography scan findings, and surgical treatment and pathologic examination are described. PMID- 26434444 TI - Congenital Absence of One Pulmonary Valve Cusp With Other Hypoplastic Cusps. AB - Congenital absence of a single pulmonary valve cusp is extremely rare. We report a case of a 38-year-old woman with a confirmed congenital absence of a single pulmonary valve cusp associated with dextrocardia. The other 2 leaflets were moderately hypoplastic, and transthoracic echocardiography showed severe pulmonary regurgitation. This combination of lesions has not been reported previously. Pulmonary valve replacement using a composite biologic valved conduit was performed with an excellent outcome. PMID- 26434445 TI - Novel Cannulation Strategy for Repair of an Ascending Aortic Pseudoaneurysm in a 2.8-kg Infant. AB - Pseudoaneurysm of the ascending aorta is rare in infants, with few cases reported in the literature. These aneurysms are usually mycotic, occurring after cardiac surgery, or caused by mediastinitis. They have high risk of spontaneous rupture. Surgery is usually complex because of the need for peripheral cannulation in small infants. We report an ascending aortic pseudoaneurysm in a less than 3 month-old infant that occurred within a month after repair of type 2 truncus arteriosus and was managed successfully with a modified cardiopulmonary bypass strategy. PMID- 26434446 TI - Endobronchial Primitive Neuroectodermal Tumor With Pneumothorax Ex Vacuo. AB - We experienced a rare case of an endobronchial primitive neuroectodermal tumor of the left main bronchus. Initially we suspected pneumothorax caused by a collapsed left upper lobe and an air-entrapped lower lobe. After tube thoracostomy, the pneumothorax persisted without air leakage. A tumor was detected at the left main bronchus on computed tomography and bronchoscopy, and diagnosed pathologically as small cell lung cancer. Under the presumed diagnosis of limited-stage small cell lung cancer, we performed a left pneumonectomy. The tumor was eventually identified pathologically as a primitive neuroectodermal tumor. Although adjuvant chemoradiotherapy was not performed, no recurrence was observed. PMID- 26434447 TI - Severe Pulmonary Valve Regurgitation 40 Years After Blunt Chest Trauma. AB - Severe pulmonary valve regurgitation caused by a pulmonary valve tear is a rare complication to a blunt chest trauma. In this case report, we present a patient with pulmonary regurgitation originating from a chest trauma 40 years ago. Possible mechanisms are osseous pinch of the pulmonary valve between the anterior chest wall and the vertebral column, and retrograde blowout from severe compression of the lungs. PMID- 26434448 TI - Successful Primary Repair of a Colopericardial Fistula: A Late Complication of Esophageal Replacement. AB - Colopericardial fistula after colonic interposition is a rare complication, with few prior reported cases. Management of such cases has usually consisted of resection of the colonic segment with cervical diversion. Here we present a case of successful primary repair of a colopericardial fistula in a 73-year-old woman who had initially undergone a colonic interposition graft 30 years before presentation. PMID- 26434449 TI - Thoracoscopic Excision of Migrated Kirschner Wire to Right Pulmonary Hilum. AB - Kirschner wires are often used for the stabilization of complex fractures. Wire migration is a rare but still recognized complication of its use. A 56-year-old man suffered a clavicle fracture at age 26 that was stabilized with one Kirschner wire, and for 30 years he was asymptomatic. Recently, he presented with cough and right thoracic pain. Chest radiographs revealed migration of the Kirschner wire, and thoracoscopic visualization revealed that the Kirschner wire had penetrated the middle lobe parenchyma and was in close contact with the right auricle. This case study reports the successful thoracoscopic treatment of a rare complication of Kirschner wire migration. PMID- 26434450 TI - Arteriovenous Fistula: A Rare Complication After Nuss Procedure for Pectus Excavatum. AB - We report a case of a 13-year-old female patient who underwent the Nuss procedure for surgical correction of pectus excavatum. As a result of the procedure, the patient developed an arteriovenous fistula between the left internal mammary artery and the pulmonary venous system. PMID- 26434451 TI - Spontaneous Regression of Metastatic Extraskeletal Myxoid Chondrosarcoma. AB - Spontaneous regression of tumors is very unusual and is defined as a partial or complete disappearance of metastatic tumors without any treatment. This phenomenon has been reported in almost all types of cancer. The patient was a 25 year-old woman who presented with multiple pulmonary nodules on her bilateral lungs on the annual chest roentgenograph. Simultaneously, a swelling mass on her subcutaneous inguinal region was observed. The diagnosis of the inguinal mass was extraskeletal myxoid chondrosarcoma. The inguinal mass and pulmonary nodules spontaneously regressed without any treatment after biopsy. The patient was doing well without evidence of recurrence at 1 year after the operation without any additional therapy. Our case is the first clinical one that indicated a possibility of histologic regression of extraskeletal myxoid chondrosarcoma. PMID- 26434452 TI - Surgical Treatment in a Case of Cogan's Syndrome Complicated With Proximal Aortic Vasculitis. AB - Cogan's syndrome is a rare idiopathic inflammatory disease with involvement of the eye and inner ear. This syndrome can be associated with aortic root vasculitis. We report the case of a young man with a history of uveitis and bilateral hearing loss who presented with proximal aortic vasculitis and dilatation after aortic valve replacement. Cogan's syndrome was diagnosed on the basis of large artery vasculitis with typical vestibuloauditory and ocular involvement. The patient underwent successful a Bentall operation after aortic valve replacement. PMID- 26434453 TI - Acute Aortic Dissection Associated With Pregnancy. PMID- 26434454 TI - Right Ventricular Perforation Caused by a Pacing Catheter Two Weeks After Insertion in a Neonate With Congenital Atrioventricular Block. PMID- 26434455 TI - Mobile Thoracolithiasis in a Patient With Lung Cancer. PMID- 26434456 TI - Skeletonization of the Recurrent Laryngeal Nerve During Norwood Procedure and Aortic Arch Repair. AB - Recurrent laryngeal nerve injury is a frequent adverse event of aortic arch repair. We hereby present a technique of skeletonization of the recurrent nerve to preserve its function during the Norwood procedure and aortic arch repair. PMID- 26434457 TI - Easy and Safe Total Debranching of Arch Aneurysms Using Axilloaxillary Arterial Bypass. AB - Techniques used in hybrid repair of proximal aortic arch diseases are associated with perioperative complications such as cerebrovascular emboli. We present an easy and safe technique of total debranching thoracic endovascular aortic repair for arch diseases using axilloaxillary arterial bypass. The placement of the axilloaxillary arterial bypass enables perfusion of the brachiocephalic artery even when the artery is clamped. After reconstruction of the brachiocephalic artery and the left common carotid artery, the left subclavian artery is proximally ligated, and it is perfused through the bypass. This procedure is simple, safe, and useful for the prevention of neurologic complications. PMID- 26434458 TI - Arena Roof Technique for Complex Reconstruction After Extensive Chest Wall Resection. AB - Extensive primary resections or redos may produce significant chest wall defects requiring creative reconstructions in order to avoid reduction of the intrathoracic volume. We describe the successful use of an innovative technique for chest wall reconstruction based on the concept of roof coverage of sport arenas. In fact, titanium plates are anchored to the residual rib stumps along the parasternal and paravertebral lines. The acellular collagen matrix prosthesis was sutured to the free edges of the same titanium plates to create a roof, reproducing the chest wall dome geometric configuration. A 36-year-old female patient was diagnosed with an extensive desmoid tumor involving the lateral segments of second to fifth ribs on the right side. The arena roof technique allowed for adequate expansion of the uninvolved lung and optimal chest wall functional recovery. PMID- 26434459 TI - An Easy Modification of Tube Graft Interposition During Fenestration in Borderline Fontan Circulation. AB - One of the options for the management of borderline/failing extracardiac Fontan circulation is surgical creation of an atrial fenestration to decompress the systemic venous compartment and improve cardiac output. Depending on the body surface area of the patient, a 5- to 10-mm polytetrafluoroethylene (PTFE) tube graft can be used. When fenestration is required in a patient with failing Fontan circulation, particularly in redo cases, application of a side-biting clamp may be challenging because of adhesions and a thickened atrial wall. In this article, we present our off-pump technique of atrial-side anastomosis of PTFE graft interposition between an extracardiac Fontan conduit and the atrium without using a side-biting clamp. PMID- 26434460 TI - Chest Wall Surgery: Less Arbitrium, More Science. PMID- 26434461 TI - Antegrade Cerebral Perfusion. PMID- 26434462 TI - What Really Affects Synchronous Pulmonary Adenocarcinoma Management? PMID- 26434463 TI - Severity of Angina Is a Predictor of Long-Term Improvement of Quality of Life After Coronary Artery Bypass Grafting. PMID- 26434464 TI - Reply: To PMID 25443005. PMID- 26434465 TI - Regarding Freestyle Pseudoaneurysms. PMID- 26434466 TI - Extrapleural Pneumonectomy and Pleurectomy Decortication: Can We Really Compare Their Survival? PMID- 26434467 TI - Reply: To PMID 25301369. PMID- 26434468 TI - Personalized Aortic Root Support With Mesh Provides Optimal Valve Conservation. PMID- 26434469 TI - Reply: To PMID 25534527. PMID- 26434470 TI - What Can We Do to Reduce Hospital Readmission After Lung Lobectomy? PMID- 26434471 TI - Reply: To PMID 25662437. PMID- 26434472 TI - Reply: To PMID 25497070. PMID- 26434473 TI - Reply: To PMID 25499482. PMID- 26434474 TI - Should We Discontinue Intraaortic Balloon During Cardioplegic Arrest? Our Old But Still Open Question. PMID- 26434475 TI - Reply: To PMID 25633461. PMID- 26434476 TI - Is TNM Alone Enough to Predict Prognosis in Lung Adenocarcinomas? PMID- 26434477 TI - Simultaneous Carotid Artery Stenting Combined With Open Heart Surgery: Another Indication. PMID- 26434478 TI - Reply: To PMID 25661578. PMID- 26434479 TI - The Left Thoracotomy Approach for Oncologic Esophageal Resection Is Still Relevant for the Modern Surgical Trainee. PMID- 26434480 TI - Reply: To PMID 24650587. PMID- 26434481 TI - Percutaneous SAPIEN S3 Transcatheter Valve Implantation for Post-Left Ventricular Assist Device Aortic Regurgitation. AB - Aortic regurgitation was found to develop in a considerable share of patients supported with continuous flow left ventricular assist devices (LVADs). The resulting circulatory loop renders LVAD operation inefficient so that symptoms of heart failure develop in spite of high LVAD flows. In patients with a high reoperative risk, transcatheter aortic valve implantation may be considered as an alternative to reoperative valve surgical procedures. We report a case of percutaneous transcatheter aortic valve implantation using the SAPIEN S3 (Edwards Lifesciences, Inc, Irvine, CA) valve for post-LVAD aortic regurgitation. PMID- 26434482 TI - Primary Endoscopic Repair of a Large Tracheal Rupture Through Tracheal Stoma. AB - We describe the case of an 83-year-old man who presented with a large trauma to the membranous wall of the trachea and was treated with endoscopic primary repair of the tracheal wall through a preexisting tracheal stoma. Assessment with an optical telescope through the tracheal stoma revealed a 5-cm laceration in the membranous wall of the trachea starting immediately above the carina. The laceration was closed using continuous 4-0 monofilament polydioxanone sutures with direct visualization of tissues through a fiberoptic telescope. This approach is particularly effective in cases of traumatic rupture of the membranous trachea. PMID- 26434483 TI - A Case Series of Biventricular Circulatory Support Using Two Ventricular Assist Devices: A Novel Operative Approach. AB - Increased use of continuous-flow left ventricular assist devices (LVADs) to treat advanced heart failure has heightened concern for right ventricular failure after LVAD implantation, which is associated with increased morbidity and mortality. Biventricular support is required in up to 30% of LVAD recipients. Currently, no durable long-term right ventricular assist device (RVAD) has been approved other than the Syncardia (Tucson, AZ) total artificial heart. A recent publication reported the placement of continuous flow LVAD in the heavily trabeculated right ventricle; however, this orientation may jeopardize both assist device and right ventricle function. We describe three cases of right-sided mechanical circulatory support with durable RVAD implanted in the right atrium, allowing long-term support with fewer anatomic limitations as compared with right ventricular cannulation. PMID- 26434484 TI - Mediastinal Bronchogenic Cyst With Acute Cardiac Dysfunction: Two-Stage Surgical Approach. AB - We describe a two-stage surgical approach in a patient with cardiac dysfunction and hemodynamic compromise resulting from a massive and compressive mediastinal bronchogenic cyst. To drain this cyst, video-assisted mediastinoscopy was performed as an emergency procedure, which immediately improved the patient's cardiac function. Five days later and under video thoracoscopy, resection of the cyst margins was impossible because the cyst was tightly adherent to the left atrium. We performed deroofing of this cyst through a right thoracotomy. The patient had an uncomplicated postoperative recovery, and no recurrence was observed at the long-term follow-up visit. PMID- 26434485 TI - Novel Use of External Tissue Expander for Management of Sternal Wound Dehiscence. AB - Sternal wound dehiscence and its associated complications contribute to significant morbidity and mortality after coronary bypass operations. We present the novel use of continuous external tissue expansion to achieve delayed primary closure of a previously dehisced sternal wound. PMID- 26434486 TI - Primary Sternal Osteomyelitis With Extensive Mediastinal Abscess in a Neonate. AB - Sternal osteomyelitis is extremely rare in neonates. We present the first report of a neonate with primary sternal osteomyelitis and an extensive mediastinal collection. Magnetic resonance imaging was used to delineate the extent of bony and soft tissue involvement. Serial ultrasound imaging proved useful for monitoring the response to treatment. The patient was successfully treated with antibiotics, surgical debridement, vacuum-assisted dressings, and delayed primary closure. PMID- 26434487 TI - Idiopathic Pseudoaneurysm of the Mitral-Aortic Intervalvular Fibrosa. AB - The mitral-aortic intervalvular fibrosa is an avascular fibrous structure between the anterior mitral leaflet and the aortic annulus. Pseudoaneurysm formation of the mitral-aortic intervalvular fibrosa is a rare but known entity most commonly caused by infective endocarditis or valve surgery. We present a 29-year-old patient with a mitral-aortic intervalvular fibrosa pseudoaneurysm of no evident cause who was successfully managed surgically. PMID- 26434488 TI - Left Ventricular Assist Device End-to-End Connection to the Left Subclavian Artery: An Alternative Technique. AB - We describe a modified implantation technique for the HeartWare ventricular assist device. We access the apex through a left minithoracotomy. The outflow graft is tunneled through a small incision in the fourth intercostal space and then subcutaneously to the subclavian region. After division of the left axillary artery, an end-to-end anastomosis is performed to the proximal part, and the distal vessel is connected end-to-side through a fenestration in the outflow graft. We believe that this technique, particularly suitable for redo scenarios or severely calcified aorta, achieves a more direct blood flow into the aorta and reduces cerebrovascular events while avoiding excessive flow to the arm. PMID- 26434489 TI - Brugia malayi soluble and excretory-secretory proteins attenuate development of streptozotocin-induced type 1 diabetes in mice. AB - Understanding the modulation of the host-immune system by pathogens-like filarial parasites offers an alternate approach to prevent autoimmune diseases. In this study, we have shown that treatment with filarial proteins prior to or after the clinical onset of streptozotocin-induced type-1 diabetes (T1D) can ameliorate the severity of disease in BALB/c mice. Pre-treatment with Brugia malayi adult soluble (Bm A S) or microfilarial excretory-secretory (Bm mf ES) or microfilarial soluble (Bm mf S) antigens followed by induction of diabetes led to lowering of fasting blood glucose levels with as many as 57.5-62.5% of mice remaining nondiabetic. These proteins were more effective when they were used to treat the mice with established T1D as 62.5-71.5% of the mice turned to be nondiabetic. Histopathological examination of pancreas of treated mice showed minor inflammatory changes in pancreatic islet cell architecture. The therapeutic effect was found to be associated with the decreased production of cytokines TNF alpha & IFN-gamma and increased production of IL-10 in the culture supernatants of splenocytes of treated mice. A switch in the production of anti-insulin antibodies from IgG2a to IgG1 isotype was also seen. Together these results provide a proof towards utilizing the filarial derived proteins as novel anti diabetic therapeutics. PMID- 26434490 TI - The impact of perioperative dexamethasone on swallowing impairment score after thyroidectomy: a retrospective study of 118 total thyroidectomies. PMID- 26434493 TI - Difference of concentration of placental soluble fms-like tyrosine kinase-1(sFlt 1), placental growth factor (PlGF), and sFlt-1/PlGF ratio in severe preeclampsia and normal pregnancy. AB - BACKGROUND: Placental soluble fms-like tyrosine kinase-1 (sFlt-1) which is an antagonist of vascular endothelial growth factor and placental growth factor (PIGF), is considered as one of etiology factors cause endothelial damage in preeclampsia due to increase of sFlt-1 level that change vascular endothelial integrity. This study aims to analyze the difference of sFlt-1 and PlGF concentration in severe preeclampsia and normal pregnancy, and the correlation between both in occurrence of severe preeclampsia. METHOD: This is case control study involving 18 subjects with severe preeclampsia and 19 subjects with normal pregnancy as controls who met inclusion and exclusion criteria. Concentration of sFlt-1 and PlGF are measured with ELISA. Statistical analysis is performed with Chi square test, Fisher's exact test, T test, Mann-Whitney test, and Spearman's rank correlation test. RESULTS: This study results in no significant difference in characteristics of gestational age, and parity in both study groups. Median concentration of sFlt-1 in severe preeclampsia is higher (20,524.75 pg/mL) compared with normal pregnancy (6820.4 pg/mL). Concentration of PlGF is lower in severe preeclampsia (47 pg/mL) compared with normal pregnancy (337 pg/mL). sFlt-1 concentration is higher in severe preeclampsia compared to normal pregnancy. PlGF concentration is lower in severe preeclampsia compared to normal pregnancy. Ratio of sFlt-1 and PlGF concentration is significantly correlated in both severe preeclampsia and normal pregnancy. CONCLUSIONS: There is a significant negative correlation between the concentration of sFLt-1 and PlGF in normal pregnancy. PMID- 26434492 TI - Enhanced Production of Adenosine Triphosphate by Pharmacological Activation of Adenosine Monophosphate-Activated Protein Kinase Ameliorates Acetaminophen Induced Liver Injury. AB - The hepatic cell death induced by acetaminophen (APAP) is closely related to cellular adenosine triphosphate (ATP) depletion, which is mainly caused by mitochondrial dysfunction. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of low energy status. AMPK regulates metabolic homeostasis by stimulating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. We found that the decrease in active phosphorylation of AMPK in response to APAP correlates with decreased ATP levels, in vivo. Therefore, we hypothesized that the enhanced production of ATP via AMPK stimulation can lead to amelioration of APAP-induced liver failure. A769662, an allosteric activator of AMPK, produced a strong synergistic effect on AMPK Thr172 phosphorylation with APAP in primary hepatocytes and liver tissue. Interestingly, activation of AMPK by A769662 ameliorated the APAP-induced hepatotoxicity in C57BL/6N mice treated with APAP at a dose of 400 mg/kg intraperitoneally. However, mice treated with APAP alone developed massive centrilobular necrosis, and APAP increased their serum alanine aminotransferase and aspartate aminotransferase levels. Furthermore, A769662 administration prevented the loss of intracellular ATP without interfering with the APAP-mediated reduction of mitochondrial dysfunction. In contrast, inhibition of glycolysis by 2-deoxy glucose eliminated the beneficial effects of A769662 on APAP-mediated liver injury. In conclusion, A769662 can effectively protect mice against APAP-induced liver injury through ATP synthesis by anaerobic glycolysis. Furthermore, stimulation of AMPK may have potential therapeutic application for APAP overdose. PMID- 26434491 TI - Physiological Functions of the COPI Complex in Higher Plants. AB - COPI vesicles are essential to the retrograde transport of proteins in the early secretory pathway. The COPI coatomer complex consists of seven subunits, termed alpha-, beta-, beta'-, gamma-, delta-, epsilon-, and zeta-COP, in yeast and mammals. Plant genomes have homologs of these subunits, but the essentiality of their cellular functions has hampered the functional characterization of the subunit genes in plants. Here we have employed virus-induced gene silencing (VIGS) and dexamethasone (DEX)-inducible RNAi of the COPI subunit genes to study the in vivo functions of the COPI coatomer complex in plants. The beta'-, gamma-, and delta-COP subunits localized to the Golgi as GFP-fusion proteins and interacted with each other in the Golgi. Silencing of beta'-, gamma-, and delta COP by VIGS resulted in growth arrest and acute plant death in Nicotiana benthamiana, with the affected leaf cells exhibiting morphological markers of programmed cell death. Depletion of the COPI subunits resulted in disruption of the Golgi structure and accumulation of autolysosome-like structures in earlier stages of gene silencing. In tobacco BY-2 cells, DEX-inducible RNAi of beta'-COP caused aberrant cell plate formation during cytokinesis. Collectively, these results suggest that COPI vesicles are essential to plant growth and survival by maintaining the Golgi apparatus and modulating cell plate formation. PMID- 26434494 TI - Blood Cadmium Level Associates with Lower Testosterone and Sex Hormone-Binding Globulin in Chinese men: from SPECT-China Study, 2014. AB - Cadmium is a widespread environmental pollutant. We aimed to determine whether blood cadmium level (BCL) associates with reproductive hormones in a cross sectional study. Our data were from SPECT-China. We selected 5690 participants (2286 men and 3404 women), aged 18 years and older, among whom 1589 were postmenopausal women. BCL, blood lead level, total testosterone (TT), estradiol (E2), sex hormone-binding globulin (SHBG), luteinizing hormone, and follicle stimulating hormone were measured. Results showed that BCL was significantly higher in men (median 1.90 MUg/L) than that in women (median 1.56 MUg/L). The median level of cadmium in postmenopausal women was 1.40 MUg/L. In men, BCL was negatively correlated with TT (Spearmen coefficient = -0.057, P < 0.01) and SHBG (Spearmen coefficient = -0.098, P < 0.01), but in postmenopausal women, this correlation was not observed. In linear regression, after full adjustment for blood lead level, age, body mass index, residence area, economic status, and smoking, TT and SHBG were still negatively associated with BCL in men. Additionally, the association between BCL and TT levels was modified by BMI group (P for interaction = 0.041). However, from base model to fully adjusted model, BCL was not associated with TT and E2 in postmenopausal women. In conclusion, men had higher BCL than women in China, and BCL was associated with TT and SHBG in Chinese men, which may have important implications for male reproductive health. Concerted efforts are warranted to reduce adult cadmium exposure. PMID- 26434495 TI - Temperature Management After Cardiac Arrest: An Advisory Statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation and the American Heart Association Emergency Cardiovascular Care Committee and the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation. AB - For more than a decade, mild induced hypothermia (32 degrees C-34 degrees C) has been standard of care for patients remaining comatose after resuscitation from out-of-hospital cardiac arrest with an initial shockable rhythm, and this has been extrapolated to survivors of cardiac arrest with initially nonshockable rhythms and to patients with in-hospital cardiac arrest. Two randomized trials published in 2002 reported a survival and neurological benefit with mild induced hypothermia. One recent randomized trial reported similar outcomes in patients treated with targeted temperature management at either 33 degrees C or 36 degrees C. In response to these new data, the International Liaison Committee on Resuscitation Advanced Life Support Task Force performed a systematic review to evaluate 3 key questions: (1) Should mild induced hypothermia (or some form of targeted temperature management) be used in comatose post-cardiac arrest patients? (2) If used, what is the ideal timing of the intervention? (3) If used, what is the ideal duration of the intervention? The task force used Grading of Recommendations Assessment, Development and Evaluation methodology to assess and summarize the evidence and to provide a consensus on science statement and treatment recommendations. The task force recommends targeted temperature management for adults with out-of-hospital cardiac arrest with an initial shockable rhythm at a constant temperature between 32 degrees C and 36 degrees C for at least 24 hours. Similar suggestions are made for out-of-hospital cardiac arrest with a nonshockable rhythm and in-hospital cardiac arrest. The task force recommends against prehospital cooling with rapid infusion of large volumes of cold intravenous fluid. Additional and specific recommendations are provided in the document. PMID- 26434496 TI - Australian general practitioner attitudes to clinical practice guidelines and some implications for translating osteoarthritis care into practice. AB - Clinical practice guidelines (CPGs) have been shown to improve processes of care and health outcomes, but there is often a discrepancy between recommendations for care and clinical practice. This study sought to explore general practitioner (GP) attitudes towards CPGs, in general and specifically for osteoarthritis (OA), with the implications for translating OA care into practice. A self-administered questionnaire was conducted in January 2013 with a sample of 228 GPs in New South Wales and South Australia. Seventy-nine GPs returned questionnaires (response rate 35%). Nearly all GPs considered that CPGs support decision-making in practice (94%) and medical education (92%). Very few respondents regarded CPGs as a threat to clinical autonomy, and most recognised that individual patient circumstances must be taken into account. Shorter CPG formats were preferred over longer and more comprehensive formats, with preferences being evenly divided among respondents for short, 2-3-page summaries, flowcharts or algorithms and single page checklists. GPs considered accessibility to CPGs to be important, and electronic formats were popular. Familiarity and use of The Royal Australian College of General Practitioners OA Guideline was poor, with most respondents either not aware of it (30%; 95% confidence interval (CI) 27 - 41%), had never used it (19%; 95% CI 12 - 29%) or rarely used it (34%; 95% CI 25-45%). If CPGs are to assist with the translation of evidence into practice, they must be easily accessible and in a format that encourages use. PMID- 26434497 TI - Relative Binding Free Energies of Adenine and Guanine to Damaged and Undamaged DNA in Human DNA Polymerase eta: Clues for Fidelity and Overall Efficiency. AB - Human DNA polymerase eta (Pol eta) plays an essential protective role against skin cancer caused by cyclobutane thymine-thymine dimers (TTDs), a frequent form of DNA damage arising from exposure to the sun. This enzyme rescues stalled replication forks at the TTDs by inserting bases opposite these DNA defects. Herein we calculate binding free energies for a free deoxyribose nucleotide triphosphate, dATP or dGTP, to Pol eta complexed with undamaged or damaged DNA. The calculations indicate that the binding of dATP to the enzyme-DNA complex is thermodynamically favored for TTD-containing DNA over undamaged DNA, most likely because of more extensive hydrogen-bonding interactions between the TTD and the enzyme that hold the TTD more rigidly in place. The calculations also illustrate that dATP binding is thermodynamically favored over dGTP binding at both thymine positions of the TTD, most likely due to more persistent and stable hydrogen bonding interactions between the TTD and dATP than between the TTD and dGTP. This free energy difference is slightly greater for binding at the 5' thymine position than at the 3' thymine position, presumably because of stabilization arising from the A:T base pair formed at the 3' position of the TTD in the previous step of Pol eta function. All of these trends in binding free energies are consistent with experimental measurements of binding strength, fidelity, processivity, and overall efficiency. The insights gained from this analysis have implications for drug design efforts aimed at modifying the binding properties of this enzyme for improving cancer chemotherapy treatments. PMID- 26434498 TI - Core/Shell Face-Centered Tetragonal FePd/Pd Nanoparticles as an Efficient Non-Pt Catalyst for the Oxygen Reduction Reaction. AB - We report the synthesis of core/shell face-centered tetragonal (fct)-FePd/Pd nanoparticles (NPs) via reductive annealing of core/shell Pd/Fe3O4 NPs followed by temperature-controlled Fe etching in acetic acid. Among three different kinds of core/shell FePd/Pd NPs studied (FePd core at ~8 nm and Pd shell at 0.27, 0.65, or 0.81 nm), the fct-FePd/Pd-0.65 NPs are the most efficient catalyst for the oxygen reduction reaction (ORR) in 0.1 M HClO4 with Pt-like activity and durability. This enhanced ORR catalysis arises from the desired Pd lattice compression in the 0.65 nm Pd shell induced by the fct-FePd core. Our study offers a general approach to enhance Pd catalysis in acid for ORR. PMID- 26434499 TI - Gesture, sign, and language: The coming of age of sign language and gesture studies. AB - How does sign language compare with gesture, on the one hand, and spoken language on the other? Sign was once viewed as nothing more than a system of pictorial gestures without linguistic structure. More recently, researchers have argued that sign is no different from spoken language, with all of the same linguistic structures. The pendulum is currently swinging back toward the view that sign is gestural, or at least has gestural components. The goal of this review is to elucidate the relationships among sign language, gesture, and spoken language. We do so by taking a close look not only at how sign has been studied over the past 50 years, but also at how the spontaneous gestures that accompany speech have been studied. We conclude that signers gesture just as speakers do. Both produce imagistic gestures along with more categorical signs or words. Because at present it is difficult to tell where sign stops and gesture begins, we suggest that sign should not be compared with speech alone but should be compared with speech-plus gesture. Although it might be easier (and, in some cases, preferable) to blur the distinction between sign and gesture, we argue that distinguishing between sign (or speech) and gesture is essential to predict certain types of learning and allows us to understand the conditions under which gesture takes on properties of sign, and speech takes on properties of gesture. We end by calling for new technology that may help us better calibrate the borders between sign and gesture. PMID- 26434500 TI - Effect of Intestinal Tapeworm Clestobothrium crassiceps on Concentrations of Toxic Elements and Selenium in European Hake Merluccius merluccius from the Gulf of Lion (Northwestern Mediterranean Sea). AB - The capacity for heavy metal bioaccumulation by some fish parasites has been demonstrated, and their contribution to decreasing metal concentrations in tissues of parasitized fish has been hypothesized. The present study evaluated the effect of the cestode Clestobothrium crassiceps on the accumulation of trace elements in 30 European hake, Merluccius merluccius, in Spain (half of them infested by C. crassiceps). Tissue samples from all M. merluccius and specimens of C. crassiceps from the infected hakes were collected and stored until element analysis by inductively coupled plasma mass spectrometry (ICP-MS). Arsenic, mercury, and selenium were generally present in lower levels in the cestode than in all hake tissues. The mean value of the muscular Se:Hg molar ratio in the infested subsample was higher than that in hakes without cestodes. Values indicate that the edible part of infested hakes presents a lower amount of Cd and Pb in relation to noninfested hakes. PMID- 26434501 TI - Relative validity and reproducibility of a parent-administered semi-quantitative FFQ for assessing food intake in Danish children aged 3-9 years. AB - OBJECTIVE: To assess the relative validity and reproducibility of the semi quantitative FFQ (SFFQ) applied in the evaluation of a community intervention study, SoL-Bornholm, for estimating food intakes. DESIGN: The reference measure was a 4 d estimated food record. The SFFQ was completed two times separated by a 1-month period in order to test reproducibility. SETTING: The Capital Region and the Regional Municipality of Bornholm, Denmark. SUBJECTS: A total of fifty-four children aged 3-9 years were enrolled in the study. RESULTS: In terms of validity, the SFFQ generally overestimated intakes compared with the food records, especially for vegetables. For most intakes, the mean difference increased with increasing intake. Gross misclassification was on average higher for energy and nutrients (17%) than for foods (8%). Spearman correlation coefficients were significant for twelve out of fourteen intakes, ranging from 0.29 to 0.63 for foods and from 0.12 to 0.48 for energy and nutrients. Comparing the repeated SFFQ administrations, the intakes of the first SFFQ were slightly higher than those of the second SFFQ. Gross misclassification was low for most intakes; on average 6% for foods and 8% for energy and nutrients. Intra-class correlations were significant for all intakes, ranging from 0.30 to 0.82 for foods and from 0.46 to 0.81 for energy and nutrients. CONCLUSIONS: The results indicate that the SFFQ gives reproducible estimates. The relative validity of the SFFQ was low to moderate for most intakes but comparable to other studies among children. PMID- 26434502 TI - Mitofusin 2 ameliorates hypoxia-induced apoptosis via mitochondrial function and signaling pathways. AB - Mitochondrial dynamics play a critical role in mitochondrial function and signaling. Although mitochondria play a critical role in hypoxia/ischemia, the further mechanisms between mitochondrial dynamics and ischemia are still unclear. The current study aimed to determine the role of mitofusin 2, a key regulator of mitochondrial fusion, in a hypoxic model and to explore a novel strategy for cerebral ischemia via modulation of mitochondrial dynamics. To the best of our knowledge, this is the first study to investigate both mitochondrial function and molecular pathways to determine the role of mitofusin 2 in hypoxia-induced neuronal apoptosis. In vivo, C57BL/6 mice (male, 19-25g) underwent a permanent middle cerebral artery occlusion for 12 or 24h (n=6 per group). In vitro, cobalt chloride was used to mimic hypoxia in immortalized hippocampal neurons. Down- or up-regulation of Mfn2 was induced to investigate the role of Mfn2 in hypoxia, especially in mitochondrial function and signaling pathways. The findings demonstrated that decreased mitofusin 2 occurred both in vivo and in vitro hypoxic models; second, the anti-apoptotic effect of Mfn2 may work via restoration of mitochondrial function; third, the modulation of the B Cell Leukemia 2/Bcl-2 Associated X protein and extracellular signal-regulated kinase 1/2 signaling pathways highlight the role of Mfn2 in signaling pathways beyond fusion. In summary, depletion of mitofusin 2 would lead to apoptosis both in normal or hypoxic conditions; however, mitofusin 2 overexpression could attenuate hypoxia-induced apoptosis, which represents a potential novel strategy for neuroprotection against ischemic brain damage. PMID- 26434503 TI - Conventional protein kinase C isoforms differentially regulate ADP- and thrombin evoked Ca2+ signalling in human platelets. AB - Rises in cytosolic Ca(2+) concentration ([Ca(2+)]cyt) are central in platelet activation, yet many aspects of the underlying mechanisms are poorly understood. Most studies examine how experimental manipulations affect agonist-evoked rises in [Ca(2+)]cyt, but these only monitor the net effect of manipulations on the processes controlling [Ca(2+)]cyt (Ca(2+) buffering, sequestration, release, entry and removal), and cannot resolve the source of the Ca(2+) or the transporters or channels affected. To investigate the effects of protein kinase C (PKC) on platelet Ca(2+) signalling, we here monitor Ca(2+) flux around the platelet by measuring net Ca(2+) fluxes to or from the extracellular space and the intracellular Ca(2+) stores, which act as the major sources and sinks for Ca(2+) influx into and efflux from the cytosol, as well as monitoring the cytosolic Na(+) concentration ([Na(+)]cyt), which influences platelet Ca(2+) fluxes via Na(+)/Ca(2+) exchange. The intracellular store Ca(2+) concentration ([Ca(2+)]st) was monitored using Fluo-5N, the extracellular Ca(2+) concentration ([Ca(2+)]ext) was monitored using Fluo-4 whilst [Ca(2+)]cyt and [Na(+)]cyt were monitored using Fura-2 and SFBI, respectively. PKC inhibition using Ro-31-8220 or bisindolylmaleimide I potentiated ADP- and thrombin-evoked rises in [Ca(2+)]cyt in the absence of extracellular Ca(2+). PKC inhibition potentiated ADP-evoked but reduced thrombin-evoked intracellular Ca(2+) release and Ca(2+) removal into the extracellular medium. SERCA inhibition using thapsigargin and 2,5-di(tert-butyl) l,4-benzohydroquinone abolished the effect of PKC inhibitors on ADP-evoked changes in [Ca(2+)]cyt but only reduced the effect on thrombin-evoked responses. Thrombin evokes substantial rises in [Na(+)]cyt which would be expected to reduce Ca(2+) removal via the Na(+)/Ca(2+) exchanger (NCX). Thrombin-evoked rises in [Na(+)]cyt were potentiated by PKC inhibition, an effect which was not due to altered changes in non-selective cation permeability of the plasma membrane as assessed by Mn(2+) quench of Fura-2 fluorescence. PKC inhibition was without effect on thrombin-evoked rises in [Ca(2+)]cyt following SERCA inhibition and either removal of extracellular Na(+) or inhibition of Na(+)/K(+)-ATPase activity by removal of extracellular K(+) or treatment with digoxin. These data suggest that PKC limits ADP-evoked rises in [Ca(2+)]cyt by acceleration of SERCA activity, whilst rises in [Ca(2+)]cyt evoked by the stronger platelet activator thrombin are limited by PKC through acceleration of both SERCA and Na(+)/K(+) ATPase activity, with the latter limiting the effect of thrombin on rises in [Na(+)]cyt and so forward mode NCX activity. The use of selective PKC inhibitors indicated that conventional and not novel PKC isoforms are responsible for the inhibition of agonist-evoked Ca(2+) signalling. PMID- 26434504 TI - A scoring system to predict the severity of appendicitis in children. AB - BACKGROUND: It appears that two forms of appendicitis exist. Preoperative distinction between the two is essential to optimize treatment outcome. This study aimed to develop a scoring system to accurately determine the severity of appendicitis in children. MATERIALS AND METHODS: Historical cohort study of pediatric patients (aged 0-17 y old) with appendicitis treated between January 2010 and December 2012. Division into simple, complex appendicitis, or another condition based on preset criteria. Multiple logistic regression analysis was used to build the prediction model with subsequent validation. RESULTS: There were 64 patients with simple and 66 with complex appendicitis. Five variables explained 64% of the variation. Independent validation of the derived prediction model in a second cohort (55 simple and 10 complex appendicitis patients) demonstrated 90% sensitivity (54-99), 91% specificity (79-97), a positive predictive value of 64% (36-86), and an negative predictive value of 98% (88 100). The likelihood ratio+ was 10 (4.19-23.42), and likelihood ratio- was 0.11 (0.02-0.71). Diagnostic accuracy was 91% (84-98). CONCLUSIONS: Our scoring system consisting of five variables can be used to exclude complex appendicitis in clinical practice if the score is <4. PMID- 26434505 TI - Inhibition of peptidylarginine deiminase attenuates inflammation and improves survival in a rat model of hemorrhagic shock. AB - BACKGROUND: We have recently shown that inhibition of peptidylarginine deiminase (PAD) improves survival in a rodent model of lethal cecal ligation and puncture. The roles of PAD inhibitors in hemorrhagic shock (HS), however, are largely unknown. The goal of this study was to investigate the effects of YW3-56, a novel PAD inhibitor, on survival after severe HS. METHODS: Mouse macrophages were exposed to hypoxic conditions followed by reoxygenation in the presence or absence of YW3-56. Enzyme-linked immunosorbent assay (ELISA) was performed to measure levels of secreted tumor necrosis factor alpha and interleukin-6 in the culture medium. Cell viability was determined by methyl thiazolyl tetrazolium assay. In the survival experiment, anesthetized male Wistar-Kyoto rats (n = 10/group) were subjected to 55% blood loss, and treated with or without YW3-56 (10 mg/kg, intraperitoneally). Survival was monitored for 12 h. In the nonsurvival experiment, morphologic changes of the lungs were examined. Levels of circulating cytokine-induced neutrophil chemoattractant 1 (CINC-1) and myeloperoxidase (MPO) in the lungs were measured by ELISA. Expression of lung intercellular adhesion molecules-1 (ICAM-1) was also determined by Western blotting. RESULTS: Hypoxia/reoxygenation (H/R) insult induced tumor necrosis factor alpha and interleukin-6 secretion from macrophages, which was significantly attenuated by YW3-56 treatment. YW3-56 treatment also increased cell viability when macrophages were exposed to H/R up to 6/15 h and improved survival rate from 20% to 60% in lethal HS rat model. Compared to the sham groups, pulmonary MPO activity and ICAM-1 expression in the HS group were significantly increased, and acute lung injury was associated with a higher degree of CINC-1 levels in serum. Intraperitoneal delivery of YW3-56 significantly reduced pulmonary MPO and ICAM-1 expression and attenuated acute lung injury. CONCLUSIONS: Our results demonstrate for the first time that administration of YW3-56, a novel PAD inhibitor, can improve survival in a rat model of HS and in a cell culture model of H/R. The survival advantage is associated with an attenuation of local and systemic pro-inflammatory cytokines and the protection against acute lung injury after hemorrhage. Thus, PAD inhibition may represent a novel and promising therapeutic strategy for severe HS. PMID- 26434506 TI - Sequence-Structure-Function Classification of a Catalytically Diverse Oxidoreductase Superfamily in Mycobacteria. AB - The deazaflavin cofactor F420 enhances the persistence of mycobacteria during hypoxia, oxidative stress, and antibiotic treatment. However, the identities and functions of the mycobacterial enzymes that utilize F420 under these conditions have yet to be resolved. In this work, we used sequence similarity networks to analyze the distribution of the largest F420-dependent protein family in mycobacteria. We show that these enzymes are part of a larger split beta-barrel enzyme superfamily (flavin/deazaflavin oxidoreductases, FDORs) that include previously characterized pyridoxamine/pyridoxine-5'-phosphate oxidases and heme oxygenases. We show that these proteins variously utilize F420, flavin mononucleotide, flavin adenine dinucleotide, and heme cofactors. Functional annotation using phylogenetic, structural, and spectroscopic methods revealed their involvement in heme degradation, biliverdin reduction, fatty acid modification, and quinone reduction. Four novel crystal structures show that plasticity in substrate binding pockets and modifications to cofactor binding motifs enabled FDORs to carry out a variety of functions. This systematic classification and analysis provides a framework for further functional analysis of the roles of FDORs in mycobacterial pathogenesis and persistence. PMID- 26434507 TI - Bacterial danger sensing. AB - Here we propose that bacteria detect and respond to threats posed by other bacteria via an innate immune-like process that we term danger sensing. We find support for this contention by reexamining existing literature from the perspective that intermicrobial antagonism, not opportunistic pathogenesis, is the major evolutionary force shaping the defensive behaviors of most bacteria. We conclude that many bacteria possess danger sensing pathways composed of a danger signal receptor and corresponding signal transduction mechanism that regulate pathways important for survival in the presence of the perceived competitor. PMID- 26434508 TI - ExoCarta: A Web-Based Compendium of Exosomal Cargo. AB - Exosomes are membranous vesicles that are released by a variety of cells into the extracellular microenvironment and are implicated in intercellular communication. As exosomes contain RNA, proteins and lipids, there is a significant interest in characterizing the molecular cargo of exosomes. Here, we describe ExoCarta (http://www.exocarta.org), a manually curated Web-based compendium of exosomal proteins, RNAs and lipids. Since its inception, the database has been highly accessed (>54,000 visitors from 135 countries). The current version of ExoCarta hosts 41,860 proteins, >7540 RNA and 1116 lipid molecules from more than 286 exosomal studies annotated with International Society for Extracellular Vesicles minimal experimental requirements for definition of extracellular vesicles. Besides, ExoCarta features dynamic protein-protein interaction networks and biological pathways of exosomal proteins. Users can download most often identified exosomal proteins based on the number of studies. The downloaded files can further be imported directly into FunRich (http://www.funrich.org) tool for additional functional enrichment and interaction network analysis. PMID- 26434509 TI - Nucleocytoplasmic Transport of RNAs and RNA-Protein Complexes. AB - RNAs and ribonucleoprotein complexes (RNPs) play key roles in mediating and regulating gene expression. In eukaryotes, most RNAs are transcribed, processed and assembled with proteins in the nucleus and then either function in the cytoplasm or also undergo a cytoplasmic phase in their biogenesis. This compartmentalization ensures that sequential steps in gene expression and RNP production are performed in the correct order and it allows important quality control mechanisms that prevent the involvement of aberrant RNAs/RNPs in these cellular pathways. The selective exchange of RNAs/RNPs between the nucleus and cytoplasm is enabled by nuclear pore complexes, which function as gateways between these compartments. RNA/RNP transport is facilitated by a range of nuclear transport receptors and adaptors, which are specifically recruited to their cargos and mediate interactions with nucleoporins to allow directional translocation through nuclear pore complexes. While some transport factors are only responsible for the export/import of a certain class of RNA/RNP, others are multifunctional and, in the case of large RNPs, several export factors appear to work together to bring about export. Recent structural studies have revealed aspects of the mechanisms employed by transport receptors to enable specific cargo recognition, and genome-wide approaches have provided the first insights into the diverse composition of pre-mRNPs during export. Furthermore, the regulation of RNA/RNP export is emerging as an important means to modulate gene expression under stress conditions and in disease. PMID- 26434510 TI - Myths to Debunk to Improve Management, Referral, and Outcomes in Patients With Chronic Total Occlusion of an Epicardial Coronary Artery. AB - A chronic total occlusion (CTO) is defined as an occlusive (100% stenosis) coronary lesion with anterograde Thrombolysis In Myocardial Infarction 0 flow for at least 3 months. CTOs are common in patients referred for coronary angiography (up to 33%) and are associated with angina, impaired quality of life, and reduced survival. Unfortunately, CTO percutaneous coronary intervention continues to be underperformed worldwide (10% to 15% at most institutions, ~30% where expert operators are available). The aim of this study was to address common fallacies pertaining to CTOs among cardiologists by providing a concise review of pertinent previously published reports along with an update on safety and efficacy of state of-the-art CTO percutaneous coronary intervention techniques. PMID- 26434511 TI - Identification by ultrasound evaluation of the carotid and femoral arteries of high-risk subjects missed by three validated cardiovascular disease risk algorithms. AB - Atherosclerotic cardiovascular disease (ASCVD) events are the leading cause of death in the United States and globally. Traditional global risk algorithms may miss 50% of patients who experience ASCVD events. Noninvasive ultrasound evaluation of the carotid and femoral arteries can identify subjects at high risk for ASCVD events. We examined the ability of different global risk algorithms to identify subjects with femoral and/or carotid plaques found by ultrasound. The study population consisted of 1,464 asymptomatic adults (39.8% women) aged 23 to 87 years without previous evidence of ASCVD who had ultrasound evaluation of the carotid and femoral arteries. Three ASCVD risk algorithms (10-year Framingham Risk Score [FRS], 30-year FRS, and lifetime risk) were compared for the 939 subjects who met the algorithm age criteria. The frequency of femoral plaque as the only plaque was 18.3% in the total group and 14.8% in the risk algorithm groups (n = 939) without a significant difference between genders in frequency of femoral plaque as the only plaque. Those identified as high risk by the lifetime risk algorithm included the most men and women who had plaques either femoral or carotid (59% and 55%) but had lower specificity because the proportion of subjects who actually had plaques in the high-risk group was lower (50% and 35%) than in those at high risk defined by the FRS algorithms. In conclusion, ultrasound evaluation of the carotid and femoral arteries can identify subjects at risk of ASCVD events missed by traditional risk-predicting algorithms. The large proportion of subjects with femoral plaque only supports the use of including both femoral and carotid arteries in ultrasound evaluation. PMID- 26434512 TI - Mechanical circulatory support devices and transcatheter aortic valve implantation (from the National Inpatient Sample). AB - High-risk surgical patients undergoing transcatheter aortic valve implantation (TAVI) represent an emerging population, which may benefit from short-term use of mechanical circulatory support (MCS) devices. The aim of this study was to determine the practice and inhospital outcomes of MCS utilization in patients undergoing TAVI. We analyzed data from Nationwide Inpatient Sample (2011 and 2012) using the International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes. A total of 1,794 TAVI procedures (375 hospitals in the United States) were identified of which 190 (10.6%) used an MCS device (MCS group) and 1,604 (89.4%) did not (non-MCS group). The use of MCS devices with TAVI was associated with significant increase in the inhospital mortality (14.9% vs 3.5%, p <0.01). The mean length (11.8 +/- 0.8 vs 8.1 +/- 0.2 days, p <0.01) and cost ($68,997 +/- 3,656 vs $55,878 +/- 653, p = 0.03) of hospitalization were also significantly greater in the MCS group. Ventricular fibrillation arrest, transapical access for TAVI, and cardiogenic shock were the most significant predictors of MCS use during TAVI. In the multivariate model, use of any MCS device was found to be an independent predictor of increased mortality (odds ratio 3.5, 95% confidence interval 2.6 to 4.6, p <0.0001) and complications (odds ratio 3.3, 95% confidence interval 2.8 to 3.9, p <0.0001). The propensity score-matched analysis also showed a similar result. In conclusion, the unacceptably high rates of mortality and complications coupled with a significant increase in the length and cost of hospitalization should raise concerns about utility of MCS devices during TAVI in this prohibitive surgical risk population. PMID- 26434513 TI - Impact of an Empiric Isolation of the Superior Vena Cava in Addition to Circumferential Pulmonary Vein Isolation on the Outcome of Paroxysmal Atrial Fibrillation Ablation. AB - The safety and efficacy of an empiric superior vena cava isolation (SVCI) in addition to circumferential pulmonary vein isolation (CPVI) in patients with paroxysmal atrial fibrillation (PAF) have not been clarified. A total of 186 consecutive patients who underwent catheter ablation of PAF were included. All patients underwent a CPVI. Patients in the first half underwent an additional SVCI only if SVC-triggered AF or rapid SVC activity was observed during the procedure (n = 93, as-needed SVCI, group I), and those in the second half underwent an empirical SVCI after the CPVI (n = 93, empiric SVCI, group II). The CPVI was successfully performed in all patients. An SVCI was performed in 8 of 93 patients (9%) in group I and 81 of the 93 patients (87%) in group II. In the remaining 12 patients in group II, an SVCI was not performed because of the lack of SVC potentials. During a mean follow-up of 27 +/- 12 months, the atrial tachyarrhythmia recurrence rate after a single ablation procedure in the patients in group II was lower than that in group I (44% vs 23%, p = 0.035). A Cox regression multivariate analysis demonstrated that an empiric SVCI was an independent predictor of an atrial tachyarrhythmia recurrence after a single ablation procedure (odds ratio: 0.57, 95% confidence interval 0.31 to 0.999; p = 0.049). Neither sinus node injury nor any injury to the phrenic nerve was observed. In conclusion, an empiric SVCI in addition to the CPVI improved the outcome of AF ablation in patients with PAF without any additional adverse effects. PMID- 26434514 TI - Significance and Determinants of Cardiac Troponin I in Patients With Obstructive Hypertrophic Cardiomyopathy. AB - Serum cardiac troponins have been demonstrated to have important clinical implications in patients with hypertrophic cardiomyopathy (HC). However, little is known about their roles in patients with obstructive HC. The aim of this study was to explore the clinical significance and determinants of serum cardiac troponin I (cTnI) in patients with obstructive HC using cardiovascular magnetic resonance imaging. We investigated the relations between serum cTnI levels and clinical, echocardiographic, and cardiovascular magnetic resonance parameters and assessed the determinants of serum cTnI in 149 consecutive patients with obstructive HC. The median level of serum cTnI was 0.019 ng/ml (interquartile range 0.009 to 0.044). CTnI was elevated (>=0.04 ng/ml) in 42 (28%) of the overall cohort. Patients with elevated cTnI had greater maximum wall thickness (p <0.001), larger left ventricular mass index (LVMI, p <0.001), more frequency of left atrium diameter >=50 mm (p = 0.020), higher plasma values of N-terminal pro B-type natriuretic peptide (p <0.001), and less hypertension (p = 0.014). Serum cTnI levels were positively correlated with maximum wall thickness (r = 0.444, p <0.001), LVMI (r = 0.556, p <0.001), N-terminal pro-B-type natriuretic peptide (r = 0.305, p <0.001), left ventricular end-diastolic volume index (r = 0.246, p = 0.002), and left ventricular end-systolic volume index (r = 0.272, p = 0.001) but negatively with left ventricular ejection fraction (r = -0.180, p = 0.028). On multivariate analysis, LVMI was independently associated with both elevated cTnI (odds ratio 1.032, p = 0.001) and increasing serum cTnI levels (beta = 0.556, p <0.001). In addition, the presence of hypertension was independently related to less likely elevated cTnI (odds ratio 0.307, p = 0.029) and decreasing levels of serum cTnI (beta = -0.165, p = 0.015). In conclusion, levels of serum cTnI are elevated in a significant proportion of our patients. Serum cTnI is associated with multiple parameters of disease severity, suggesting its great significance in assessing cardiac remodeling in patients with obstructive HC. Left ventricular hypertrophy, as indicated by LVMI, is the major determinant of serum cTnI levels. PMID- 26434515 TI - Relation Between Monocyte to High-Density Lipoprotein Cholesterol Ratio With Presence and Severity of Isolated Coronary Artery Ectasia. AB - The aim of this study was to investigate an easily available inflammatory and oxidative stress marker and monocyte to high-density lipoprotein cholesterol ratio (MHR) in patients with coronary artery ectasia (CAE). The study population included 405 patients of which 135 patients had isolated CAE, 135 patients had obstructive coronary artery disease (CAD), and 135 patients had normal coronary angiograms (NCAs). The severity of isolated CAE was determined according to the Markis classification. The MHR was significantly greater in patients with isolated CAE than those with obstructive CAD and NCAs: 14.8 (11.6 to 19.8), 11.4 (9.6 to 13.5), 9.8 (7.5 to 11.9), respectively. Linear regression analyses showed that MHR and C-reactive protein were significantly related with the severity of isolated CAE. In conclusion, the MHR is significantly greater in patients with CAE compared to controls with obstructive CAD and NCAs, and MHR is associated with the severity of CAE. PMID- 26434516 TI - Stroke Risk Factors Beyond the CHA2DS2-VASc Score: Can We Improve Our Identification of "High Stroke Risk" Patients With Atrial Fibrillation? AB - The prevention of stroke and other thromboembolic events plays a crucial role in the management of patients with atrial fibrillation. Not all patients with atrial fibrillation are equal in terms of thromboembolic risk; therefore, not all will benefit from oral anticoagulation treatment. The general principle is that the expected benefit of anticoagulation in reduction of thromboembolic risk must exceed the expected harm caused by possible bleeding. Some guidelines have focused on a categorical approach to stroke prevention, with a focus on identifying patients at high risk for oral anticoagulation. Various current guidelines recommend assessment of stroke risk using the CHADS2 or CHA2DS2-VASc scores to initially detect patients at low risk who require no antithrombotic therapy. However, the scores do not incorporate all possible risk factors causing a high thromboembolic risk. Factors such as impaired renal function, obstructive sleep apnea, and echocardiographic and biochemical or coagulation parameters can also predict adverse thromboembolic events. The present review aims to describe biomarkers whether blood, urine, imaging (cardiac or cerebral), or clinical that go beyond the CHA2DS2-VASc score and potentially aid stroke risk assessment. Although useful in some cases, the presented parameters should be perhaps used to further refine initial identification of patients at low risk, after which effective stroke prevention can be offered to those with >=1 additional stroke risk factors. PMID- 26434517 TI - Protective effect of Astragalus polysaccharide on endothelial progenitor cells injured by thrombin. AB - Several studies have demonstrated that Astragalus polysaccharide (APS) has a protective effect on endothelial cells damaged by various factors. To examine the role of APS in the endothelial inflammatory response, rat bone marrow endothelial progenitor cells (EPCs) were isolated by density gradient centrifugation and identified by immunohistochemistry, then we established a model of inflammatory injury induced by thrombin and measured the effects of APS on EPC viability and proliferation by MTT assays. We also assayed the effect APS had on the inflammatory response, by examining the nuclear factor kappa B (NF-kappaB) signaling pathway, as well as the expression of intercellular adhesion molecule-1 (ICAM-1), vascular endothelial growth factor (VEGF) and its receptors Flt-1 and KDR. Results demonstrated that EPCs were damaged by thrombin, and APS appeared to inhibit this damage. APS suppressed thrombin-induced ICAM-1 expression by blocking NF-kappaB signaling in rat bone marrow EPCs, and up-regulating expression of VEGF and its receptors. We believed that APS may be used to treat and prevent EPC injury-related diseases. PMID- 26434518 TI - Hydrogen peroxide sensing and cytotoxicity activity of Acacia lignin stabilized silver nanoparticles. AB - The study is aimed at detection of hydrogen peroxide (H2O2) using Acacia lignin mediated silver nanoparticles (AGNPs). The synthesis of AGNPs was achieved at conditions optimized as, 3 ml of 0.02% lignin and 1mM silver nitrate incubated for 30 min at 80 degrees C and pH 9. Initial screening of AGNPs was performed by measuring the surface plasmon resonance peak at 410-430 nm using UV-vis spectrophotometer. Transmission electron microscopy, atomic force microscopy, X ray diffraction and particle size analysis confirmed the spherical shaped face centered cubic structure and 10-50 nm size of AGNPs. The infrared spectroscopy study further revealed that the active functional groups present in lignin were responsible for the reduction of silver ions (Ag(+)) to metallic silver (Ag(0)). Lignin stabilized silver nanoparticles showed good sensitivity and a linear response over wide concentrations of H2O2 (10(-1) to 10(-6)M). Further, the in vitrocytotoxicity activity of the lignin mediated AGNPs (5-500 MUg/ml) demonstrated toxicity effects in MCF-7 and A375 cell lines. Thus, lignin stabilized silver nanoparticles based optical sensor for H2O2 could be potentially applied in the determination of reactive oxygen species and toxic chemicals which further expands the importance of lignin stabilized silver nanoparticles. PMID- 26434519 TI - Covalent immobilization of Enterococcus faecalis Esawy dextransucrase and dextran synthesis. AB - Enterococcus faecalis Esawy dextransucrase was immobilized in Fe(3+)-cross-linked alginate/carboxymethyl cellulose (AC) beads. The gel beads were modified with polyethylenimine (PEI) followed by glutaraldehyde (GA) to form Fe(3+) (ACPG) beads. Fe(3+) (ACPG) was characterized using FTIR and DSC techniques. GA activated beads showed new two peaks. The first was at 1,717 cm(-1) which refers to (CO) group of a free aldehyde end of glutaraldehyde, and another peak was at 1,660 cm(-1) referring to (CN) group. The immobilization process improved the optimum temperature from 35 to 45 degrees C. The immobilized enzyme showed its optimum activity in wide pH range (4.5-5.4) compared to pH 5.4 in case of free form. Also, the immobilization process improved the thermal and pH enzyme stability to great extent. Reusability test proved that the enzyme activity retained 60% after 15 batch reactions. Immobilized enzyme was applied successfully in the synthesis of oligosaccharides and different molecular weights of dextran. PMID- 26434520 TI - Some physico-chemical properties of Prunus armeniaca L. gum exudates. AB - The objectives of this paper were to investigate some physicochemical properties of Prunus armeniaca L. gum exudates (PAGE). PAGE had, on average, 66.89% carbohydrate, 10.47% uronic acids, 6.9% moisture (w.b.), 2.91% protein, 4% ash and 1.59% fat. PAGE was composed of monosaccharides including l-arabinose, d galactose, xylose, mannose and rhamnose in molar percentages of 41.52%, 23.72%, 17.82%, 14.40% and 2.54%, respectively. Elemental analysis showed that PAGE had high values of nutrients. FTIR analysis demonstrated the presence of carboxyl, hydroxyl and methyl groups and glycoside bonds. The weight average molecular weight, number average molecular weight and polydispersity index were found to be approximately 5.69 * 10(5)g/mol, 4.33 g/mol and 1.31, respectively. Rheological measurement of PAGE solutions as a function of concentration (8, 10 and 12% (w/w)) and temperature (10, 20, 30 and 40 degrees C) demonstrated that the gum solutions had a non Newtonian shear thinning behaviour. Intrinsic viscosity for PAGE in deionized water was 3.438 dl/g based on Kramer equation. PMID- 26434521 TI - Evaluation of selected properties of biocompatible chitosan/poly(vinyl alcohol) blends. AB - Selected properties of chitosan (CS) and poly(vinyl alcohol) (PVA) blends crosslinked by tetraethoxysilane (TEOS) were studied. XRD analysis showed characteristics peak at 22.5 degrees attributed to the crystalline structure of CS and PVA. DSC thermograms unveiled the quantitative determination of free, intermediate and bound water in the blends. Tensile strength and fracture strain of blends were observed due to the combined effect of physically and chemically crosslinked network structures. The decrease in water contact angle indorsed the hydrophilic performance while the storage modulus G' and loss modulus G" was decreased as the temperature was increased exhibited the viscoelastic property of the blends. The fabricated blends can be employed for drug delivery systems, tissue engineering and other biomedical applications. PMID- 26434522 TI - Production of pullulan from raw potato starch hydrolysates by a new strain of Auerobasidium pullulans. AB - In the present study, hydrolysis of potato starch with marine cold-adapted alpha amylase and pullulan production from the hydrolysates by a new strain of Auerobasidium pullulans isolated from sea mud were conducted. The hydrolysis conditions were optimized as follows: reaction time 2h, pH 6.5, temperature 20 degrees C, and alpha-amylase amount 12 U/g. Under these optimum hydrolysis conditions, the DE value of the potato starch hydrolysates reached to 49.56. The potato starch hydrolysates consist of glucose, maltose, isomaltose, maltotriose, and trace of other maltooligosaccharides with degree of polymerization ranged 4 7. The maximum production of pullulan at 96 h from the hydrolysate of potato starch was 36.17 g/L, which was higher than those obtained from glucose (22.07 g/L, p<0.05) and sucrose (31.42 g/L, p<0.05). Analysis of the high performance liquid chromatography of the hydrolysates of the pullulan product with pullulanase indicated that the main composition is maltotriose, thus confirming the pullulan structure of this pullulan product. PMID- 26434523 TI - Silver nanoparticle synthesis using lignin as reducing and capping agents: A kinetic and mechanistic study. AB - Silver nanoparticles (AgNPs) were robustly synthesized from aqueous AgNO3 with alkali lignin (low sulfonate) (ALls) severing as dual reducing and capping agent. The AgNP synthesis mechanisms were highly pH dependent. Under neutral and acidic conditions, polydispersed AgNPs were synthesized via the self-catalyzed reduction of Ag(+) on instantaneously formed Ag2O surfaces followed by the slower pseudo first order reduction. The Ag2O nanoparticles functioned as the nucleating sites for the reduction of remaining silver cations to form AgNPs whose size and size distribution strongly dependent of lignin concentrations. AgNPs were optimally synthesized by reducing 2 mmol/L AgNO3 with 0.16 wt% ALls at pH 10 and 85 degrees C in 30 min to near 100% yield in bimodal distributed sizes with 23% and 77% in feret diameters of 7.3 (+/- 2.2)nm and 14.3 (+/- 1.8)nm, respectively. PMID- 26434524 TI - Synthesis of nanohydrogels based on tragacanth gum biopolymer and investigation of swelling and drug delivery. AB - The present article deals with preparation of pH responsive nanohydrogels based on tragacanth gum (TG) biopolymer for drug delivery. The nanohydrogels were prepared using different chemical reagents such as 3-aminopropyltriethoxysilane (APTES) modifier and glyceroldiglycidylether (GDE), polyvinyl alcohol (PVA), and glutaraldehyde (GA) as cross-linkers. The obtained nanohydrogels were characterized using different techniques such as scanning electron microscope (SEM), elemental analysis, FT-IR, zeta sizer and thermogravimetric analysis (TGA). The gel content increased with increasing the cross-linkers contents and reached to a maximum of 90%. The swelling behavior of nanohydrogels was investigated in terms of the effect of pH (2.2, 7.4 and 9), temperature (27, 37 and 60 degrees C), and reaction time (2-24h). Loading of Indomethacin (IND) as a model drug showed dependence on the network structure of nanohydrogels. The total in vitro IND release showed dependence on the network structure of nanohydrogels and was in the range of 50-80% at pH 9 after 24h. PMID- 26434525 TI - Removal of copper(II) from aqueous solution using nanochitosan/sodium alginate/microcrystalline cellulose beads. AB - The present study was aimed to prepare the novel ternary biopolymeric beads of nanochitosan (NCS)/sodium alginate (SA)/microcrystalline cellulose (MC) for the removal of heavy metal copper from aqueous solution through batch adsorption mode. The polymeric beads were characterized before and after adsorption using FTIR, XRD and EDX-SEM studies. The efficiency of the adsorbent was analyzed by varying the parameters such as initial metal ion concentration, contact time, adsorbent dose and pH. The experimental data obtained were fitted in the isotherm models such as Langmuir, Freundlich and Tempkin models and in pseudo first and second order kinetics studies. The isotherm and kinetics models revealed that the adsorption was found to fit well with Freundlich isotherm and follows pseudo second-order kinetics. PMID- 26434526 TI - Synthesis and in vitro antifungal efficacy of oleoyl-chitosan nanoparticles against plant pathogenic fungi. AB - An antifungal dispersion system was prepared by oleoyl-chitosan (O-chitosan) nanoparticles, and the antifungal activity against several plant pathogenic fungi was investigated. Under scanning electron microscopy, the nanoparticles formulation appeared to be uniform with almost spherical shape. The particle size of nanoparticles was around 296.962 nm. Transmission electron microscopy observation showed that nanoparticles could be well distributed in potato dextrose agar medium. Mycelium growth experiment demonstrated that Nigrospora sphaerica, Botryosphaeria dothidea, Nigrospora oryzae and Alternaria tenuissima were chitosan-sensitive, while Gibberella zeae and Fusarium culmorum were chitosan-resistant. The antifungal index was increased as the concentration of nanoparticles increased for chitosan-sensitive fungi. Fatty acid analyses revealed that plasma membranes of chitosan-sensitive fungi were shown to have lower levels of unsaturated fatty acid than chitosan-resistant fungi. Phylogenetic analysis based on ITS gene sequences indicated that two chitosan resistant fungi had a near phylogenetic relationship. Results showed that O chitosan nanoparticles could be a useful alternative for controlling pathogenic fungi in agriculture. PMID- 26434527 TI - A detailed study of homogeneous agarose/hydroxyapatite nanocomposites for load bearing bone tissue. AB - Agarose/hydroxyapatite (agar/HA) nanocomposites for load-bearing bone substitutes were successfully fabricated via a novel in situ precipitation method. Observation via SEM and TEM revealed that the spherical inorganic nanoparticles of approximately 50 nm were well dispersed in the organic matrix, and the crystallographic area combined closely with the amorphous area. The uniform dispersion of HA nanoparticles had prominent effect on improving the mechanical properties of the agar/HA nanocomposites (the highest elastic modulus: 1104.42 MPa; the highest compressive strength: 400.039 MPa), which proved to be potential load-bearing bone substitutes. The thermal stability of agarose and nanocomposites was also studied. The MG63 osteoblast-like cells on the composite disks displayed fusiform and polygonal morphology in the presence of HA, suggesting that the cell maturation was promoted. The results of cell proliferation and cell differentiation indicated that the cells cultured on the agar/HA composite disks significantly increased the alkaline phosphatase activity and calcium deposition. The structural role of agarose in the composite system was investigated to better understand the effect of biopolymer on structure and properties of the composites. The optimal properties were the result of a comprehensive synergy of the components. PMID- 26434528 TI - The simultaneous production of sphingan Ss and poly(R-3-hydroxybutyrate) in Sphingomonas sanxanigenens NX02. AB - Sphingans and poly(R-3-hydroxybutyrate) (PHB) are both widely used biopolymers produced by bacteria. In the batch fermentation of Sphingomonas sanxanigenens NX02 in a 5L fermenter using glucose as carbon source, ivory colored sphingan Ss production was a growth-associated process with a maximum purified production of 14.88 +/- 0.83 g/L, while 6.08 +/- 0.23 g/L PHB was simultaneously produced. Sphingan Ss and PHB were separated by a simple dilution, heating and centrifugation or filtration process, and sphingan Ss can be cost-effectively extracted using a small amount of acid rather than multi-fold volumes of alcohols. From ultrathin sections of S. sanxanigenens NX02, we found that the interior space of the cells was filled with PHB granules, and the outside was surrounded by abundant Ss. The purified sphingan Ss can be used as an excellent gelling and emulsifying agent in biotechnology applications such as food, personal care and production processes. Proposed pathways of Ss and PHB biosynthesis from glucose are also presented. PMID- 26434529 TI - Cardiovascular protective effect of polysaccharide from Ophiopogon japonicus in diabetic rats. AB - Ophiopogon japonicus (Thunb.) Ker-Gawl is a well known traditional Chinese medicine used to treat cardiovascular and chronic inflammatory diseases for thousands of years. The present study was set up to investigate the protective effects of O. japonicus polysaccharide (OJP1) on cardiovascular injuries in diabetic rats. Results showed that OJP1 significantly reduced the MDA concentration and increased the activities of GPx, CAT and SOD in heart of diabetic rats. The levels of AGE, hs-CRP, sICAM-1, NO and ET-1 in diabetic rats were significantly reversed by OJP1 treatment. In addition, the level of ET-1 mRNA was decreased significantly, whereas eNOS mRNA level was increased after administration of OJP1. Meanwhile, the histopathological analysis showed that OJP1 alleviates the heart injury in diabetic rats. Together, these results suggest that OJP1 maintains the antioxidant enzyme levels and improves cardiovascular performance in diabetic rats. PMID- 26434530 TI - Comparative safety evaluation of silica-based particles. AB - PURPOSE: Silica nanoparticles (SNPs) are increasingly used as drug delivery systems (DDS) and for biomedical imaging. Therapeutic and diagnostic agents can be incorporated into the silica matrix to improve the stability and dissolution of drug substances in biological systems. However, the safety of SNPs as drug carriers remains controversial. To date, no validated and accepted nano-specific tests exist to predict the potentially harmful impact of these materials on the human body. METHODS: We synthesized by a systematic approach 12 different types of SNPs with varying size, surface topology (porous vs non-porous), and surface modifications. We characterized these particles in terms of dry state and hydrodynamic diameter, specific surface area, and net surface charge (zeta potential). For cellular studies, we exposed non-phagocytic (HepG2) cells, phagocytic (THP-1) cells, and erythrocytes to SNPs. Cellular uptake and stability of fluorescently labeled SNPs were analyzed by confocal microscopy and flow cytometry. RESULTS: SNPs with a porous surface and negative net surface charge had the strongest impact on cell viability. This is in contrast to non-porous SNPs. None of the studied particles induced oxidative stress in either cell lines. Particles with a negative surface charge induced hemolysis in a concentration-dependent manner. CONCLUSIONS: Physico-chemical properties promoting cytotoxicity and hemolysis were investigated. Our study revealed potential hazards of spherical amorphous SNPs. PMID- 26434531 TI - Transcriptional regulation of human paraoxonase 1 by PXR and GR in human hepatoma cells. AB - Human paraoxonase 1 (PON1) is A-esterase synthesized in the liver and secreted into the plasma, where it associates with HDL. PON1 acts as an antioxidant preventing lipid oxidation and detoxifies a wide range of substrates, including organophosphate compounds. The variability of PON1 (enzyme activity/serum levels) has been attributed to internal and external factors. However, the molecular mechanisms involved in the transcriptional regulation of PON1 have not been well studied. The aim of this study was to evaluate and characterize the transcriptional activation of PON1 by nuclear receptors (NR) in human hepatoma cells. In silico analysis was performed on the promoter region of PON1 to determine the response elements of NR. Real-time PCR was used to evaluate the effect of specific NR ligands on the mRNA levels of genes regulated by NR and PON1. The results indicated that NR response elements had 95% homology to pregnenolone (PXR), glucocorticoids (GR), retinoic acid (RXR) and peroxisomes proliferator-activated receptor alpha (PPARalpha). Treatments with Dexamethasone (GR ligand), Rifampicin (PXR ligand) and TCDD (AhR ligand) increased the mRNA levels of PON1 at 24 and 48 h. We showed that the activation of GR by Dexamethasone results in PON1 gene induction accompanied by an increase in activity levels. In conclusion, these results demonstrate that GR regulates PON1 gene transcription through directly binding to NR response elements at -95 to 628 bp of the PON1 promoter. This study suggests new molecular mechanisms for the transcriptional regulation of PON1 through a process involving the activation of PXR. PMID- 26434532 TI - Antigenotoxic, anti-photogenotoxic and antioxidant activities of natural naphthoquinone shikonin and acetylshikonin and Arnebia euchroma callus extracts evaluated by the umu-test and EPR method. AB - The aim of this study was to evaluate the antigenotoxic and antioxidant potential of shikonin (SH), acetylshikonin (ACS) and Arnebia euchroma callus extract (EXT). The antigenotoxic activity was investigated by the umu-test as the inhibition of the SOS system induction caused by genotoxic chemical agents - 4-nitroquinoline oxide and 2-aminoanthracene. Moreover the ability of SH, ACS and EXT to prevent photogenotoxicity triggered by chlorpromazine under UVA irradiation was measured. The cytotoxicity of EXT toward V79 Chinese hamster cell line was additionally assessed. Shikonin and acetylshikonin had no effect on 4-NQO induced genotoxicity whereas EXT demonstrated an unclear effect. The protection against 2AA induced genotoxicity was observed for all tested substances. The highest protection was demonstrated for EXT with inhibition of 66%. SH and ACS reduced 2AA genotoxicity with inhibition of about 60%. Under UVA the strongest and dose-dependent activity was observed for EXT. Acetylshikonin was a weak anti-photogenotoxin whereas shikonin had no clear effect. EXT was highly cytotoxic toward the V79 cell line - the cells' morphology was affected seriously and apoptosis was impacted. The antioxidant activity of SH, ACS and EXT was studied by means of electron paramagnetic resonance spectroscopy using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical. All three samples exhibited radical scavenging properties. PMID- 26434533 TI - Speciation change and redistribution of arsenic in soil under anaerobic microbial activities. AB - Arsenic speciation and behavior in soil are strongly affected by redox conditions. This work investigated speciation transformation and redistribution of arsenic in soil under anaerobic conditions. The effect of microbial sulfidogenesis on these processes was examined by addition of sulfate to the incubation systems. As(III) was found to be the dominant arsenic species in solution during the process of anaerobic incubation. The change of dissolved As concentration with incubation time showed "M" shaped profiles, e.g. the curves displaying two peaks at approximately 24 h and 240 h for the system with added sulfate. Arsenic was released and reduced to As(III) in the early stage of the incubation, and then resequestered into the solid phase. After excess sulfide was generated, the resequestered arsenic was released again (probably due to the dissolution of arsenic sulfide by dissolved sulfide ions) via the formation of thioarsenite. At the end of the incubation process, most of the dissolved arsenic was removed again from solution. The findings may have important implications to the fate of arsenic in flooded sulfur-rich soils. PMID- 26434534 TI - Evaluation of Ag nanoparticle coated air filter against aerosolized virus: Anti viral efficiency with dust loading. AB - In this study, the effect of dust loading on the anti-viral ability of an anti viral air filter was investigated. Silver nanoparticles approximately 11 nm in diameter were synthesized via a spark discharge generation system and were used as anti-viral agents coated onto a medium air filter. The pressure drop, filtration efficiency, and anti-viral ability of the filter against aerosolized bacteriophage MS2 virus particles were tested with dust loading. The filtration efficiency and pressure drop increased with dust loading, while the anti-viral ability decreased. Theoretical analysis of anti-viral ability with dust loading was carried out using a mathematical model based on that presented by Joe et al. (J. Hazard. Mater.; 280: 356-363, 2014). Our model can be used to compare anti viral abilities of various anti-viral agents, determine appropriate coating areal density of anti-viral agent on a filter, and predict the life cycle of an anti viral filter. PMID- 26434535 TI - CdTe quantum dots as fluorescent probes to study transferrin receptors in glioblastoma cells. AB - BACKGROUND: Overexpression of transferrin receptors (TfRs), which are responsible for the intracellular uptake of ferric transferrin (Tf), has been described in various cancers. Although molecular biology methods allow the identification of different types of receptors in cancer cells, they do not provide features about TfRs internalization, quantification and distribution on cell surface. This information can, however, be accessed by fluorescence techniques. In this work, the quantum dots (QDs)' unique properties were explored to strengthen our understanding of TfRs in cancer cells. METHODS: QDs were conjugated to Tf by covalent coupling and QDs-(Tf) bioconjugates were applied to quantify and evaluate the distribution of TfRs in two human glioblastoma cells lines, U87 and DBTRG-05MG, and also in HeLa cells by using flow cytometry and confocal microscopy. RESULTS: HeLa and DBTRG-05MG cells showed practically the same TfR labeling profile by QDs-(Tf), while U87 cells were less labeled by bioconjugates. Furthermore, inhibition studies demonstrated that QDs-(Tf) were able to label cells with high specificity. CONCLUSIONS: HeLa and DBTRG-05MG cells presented a similar and a higher amount of TfR than U87 cells. Moreover, DBTRG-05MG cells are more efficient in recycling the TfR than the other two cells types. GENERAL SIGNIFICANCE: This is the first study about TfRs in human glioblastoma cells using QDs. This new fluorescent tool can contribute to our understanding of the cancer cell biology and can help in the development of new therapies targeting these receptors. PMID- 26434536 TI - Functional expression and purification of Anabaena PCC 7120 XisA protein. AB - Anabaena PCC 7120 xisA gene product mediates the site-specific excision of 11,278 bp nifD element in heterocysts formed under nitrogen starvation conditions. Although XisA protein possesses both site-specific recombinase and endonuclease activities, till date neither xisA transcript nor XisA protein has been detected. Gene encoding XisA protein was isolated from plasmid pMX25 and overexpressed in Escherichia coli BL21 DE3 yielding 7.7 mg enzyme per L of growth culture in soluble fraction. His-tagged XisA was purified using Ni-NTA affinity chromatography with 95% recovery. The purified XisA showed a single band on SDS PAGE with molecular mass of 52 kDa. Identity of XisA was confirmed by MALDI-TOF analysis and functionality of enzyme was confirmed using restriction digestion. A PCR based method was developed to monitor excision by XisA, which displayed near 100% activity in E. coli within 1 h at 37 ( degrees )C on LB under static condition. PMID- 26434538 TI - Life-threatening hematuria in a hemodialysis patient with systemic light-chain amyloidosis. AB - BACKGROUND: Direct amyloid invasion of prostate tissue resulting in massive bleeding may be fatal, and rapid diagnosis is difficult. CASE REPORT: A 71-y-old male undergoing regular hemodialysis with primary light-chain (AL) amyloidosis was admitted due to gross hematuria for 2 days. Cystoscopy revealed oozing from the prostatic urethra. Therefore, electrocauterization was performed, and his symptoms resolved. Unfortunately, he experienced recurrent massive hematuria 3 months later. Tests for serum D-dimer and fibrin degradation products were both positive. Followed serum factor X level was low at 5.4%. Gross hematuria persisted despite of blood transfusions, desmopressin, and vitamin K therapy. Emergent cystoscopy revealed oozing from the prostatic urethra, as was found previously. Therefore, electrocauterization and transurethral resection of the prostate were performed. Analysis of a biopsy specimen of prostate demonstrated strong amyloid deposition in the vascular and perivascular regions. Electron microscopy showed relatively straight fibrils with diameters of 7-10nm in the perivascular region. Gross hematuria subsided then, and no recurrence was noted at a 6-month follow-up. CONCLUSIONS: Systemic AL amyloidosis can cause potentially life-threatening hemorrhage. Hemostatic defects and direct invasion with amyloid angiopathy are main pathogenic factors. Timely surgical intervention may be imperative. PMID- 26434539 TI - Palladium-catalyzed dearomative cyclization by a norbornene-mediated sequence: a route to spiroindolenine derivatives. AB - The first palladium-catalyzed dearomative cyclization via a modified Catellani type C-H functionalization has been realized. The new strategy led to a series of spiroindolenine derivatives bearing an all-carbon quaternary spirocenter from simple aryl halides and substituted indoles. PMID- 26434537 TI - Development of mesoporous silica-based nanoparticles with controlled release capability for cancer therapy. AB - Nanoparticles that respond to internal and external stimuli to carry out controlled release of anticancer drugs have been developed. In this review, we focus on the development of mesoporous silica based nanoparticles, as this type of materials provides a relatively stable material that is amenable to various chemical modifications. We first provide an overview of various designs employed to construct MSN-based controlled release systems. These systems respond to internal stimuli such as pH, redox state and the presence of biomolecules as well as to external stimuli such as light and magnetic field. They are at a different stage of development; depending on the system, their operation has been demonstrated in aqueous solution, in cancer cells or in animal models. Efforts to develop MSNs with multi-functionality will be discussed. Safety and biodegradation of MSNs, issues that need to be overcome for clinical development of MSNs, will be discussed. Advances in the synthesis of mechanized theranostic nanoparticles open up the possibility to start envisioning future needs for medical equipment. PMID- 26434540 TI - CO2 capture and electrochemical conversion using superbasic [P66614][124Triz]. AB - The ionic liquid trihexyltetradecylphosphonium 1,2,4-triazolide, [P66614][124Triz], has been shown to chemisorb CO2 through equimolar binding of the carbon dioxide with the 1,2,4-triazolide anion. This leads to a possible new, low energy pathway for the electrochemical reduction of carbon dioxide to formate and syngas at low overpotentials, utilizing this reactive ionic liquid media. Herein, an electrochemical investigation of water and carbon dioxide addition to the [P66614][124Triz] on gold and platinum working electrodes is reported. Electrolysis measurements have been performed using CO2 saturated [P66614][124Triz] based solutions at -0.9 V and -1.9 V on gold and platinum electrodes. The effects of the electrode material on the formation of formate and syngas using these solutions are presented and discussed. PMID- 26434541 TI - The effect of nanoclay on the rheology and dynamics of polychlorinated biphenyl. AB - The thermal, rheological, and mechanical and dielectric relaxation properties of exfoliated dispersions of montmorillonite clay in a molecular liquid, polychlorobiphenyl (PCB), were studied. The viscosity enhancement at low concentrations of clay (<=5%) exceeded by a factor of 50 the increase obtainable with conventional fillers. However, the effect of the nanoclay on the local dynamics, including the glass transition temperature, was quite small. All materials herein conformed to density-scaling of the reorientation relaxation time of the PCB for a common value of the scaling exponent. A new relaxation process was observed in the mixtures, associated with PCB molecules in proximity to the clay surface. This process has an anomalously high dielectric strength, suggesting a means to exploit nanoparticles to achieve large electrical energy absorption. This lower frequency dispersion has a weaker dependence on pressure and density, consistent with dynamics constrained by interactions with the particle surface. PMID- 26434542 TI - Spontaneous growth of ultra-thin titanium oxides shell on Ag nanowires: an electron energy loss spectroscope observation. AB - Ag nanowires with a spontaneous ultra-thin TiO2 shell (~0.5 nm) can be grown on TiO2 substrate. STEM/EELS results demonstrate that this oxygen-deficient TiO2 layer is formed through the oxidation of Ti which is released from the substrate and segregated to the nanowire surface simultaneously with crystal growth of the nanowires. PMID- 26434543 TI - Mechanical properties of monolayer sulphides: a comparative study between MoS2, HfS2 and TiS3. AB - The in-plane stiffness (C), Poisson's ratio (nu), Young's modulus and ultimate strength (sigma) along two different crystallographic orientations are calculated for the single layer crystals: MoS2, HfS2 and TiS3 in 1H, 1T and monoclinic phases. We find that MoS2 and HfS2 have isotropic in-plane stiffnesses of 124.24 N m(-1) and 79.86 N m(-1), respectively. While for TiS3 the in-plane stiffness is highly anisotropic due to its monoclinic structure, with Cx = 83.33 N m(-1) and Cy = 133.56 N m(-1) (x and y are parallel to its longer and shorter in-plane lattice vectors.). HfS2 which is in the 1T phase has the smallest anisotropy in its ultimate strength, whereas TiS3 in the monoclinic phase has the largest. Along the armchair direction MoS2 has the largest sigma of 23.48 GPa, whereas along y TiS3 has the largest sigma of 18.32 GPa. We have further analyzed the band gap response of these materials under uniaxial tensile strain, and find that they exhibit different behavior. Along both armchair and zigzag directions, the band gap of MoS2 (HfS2) decreases (increases) as strain increases, and the response is almost isotropic. For TiS3, the band gap decreases when strain is along x, while if strain is along y, the band gap increases first and then decreases beyond a threshold strain value. The different characteristics observed in these sulphides with different structures shed light on the relationship between the structure and properties, which is useful for applications in nanotechnology. PMID- 26434544 TI - A sensitive SERS detection of miRNA using a label-free multifunctional probe. AB - A novel surface enhanced Raman scattering (SERS) detection method is fabricated for miRNA based on a smart multifunctional probe for dual cyclical nucleic acid strand-displacement polymerization (CNDP), achieving high sensitivity, universality, rapid analysis, and good performance in real cell samples. PMID- 26434545 TI - IR-Driven Photocatalytic Water Splitting with WO2-NaxWO3 Hybrid Conductor Material. AB - An IR-driven photocatalytic water splitting system based on WO2-NaxWO3 (x > 0.25) hybrid conductor materials was established for the first time; this system can be directly applied in seawater. The WO2-NaxWO3 (x > 0.25) hybrid conductor material was readily prepared by a high-temperature reduction process of semiconductor NaxWO3 (x < 0.25) nanowire bundles. A novel ladder-type carrier transfer process is suggested for the established IR-driven photocatalytic water splitting system. PMID- 26434546 TI - Quercetine attenuates the gentamicin-induced ototoxicity in a rat model. AB - OBJECTIVES: The aim of this study is to evaluate the protective role of quercetin in gentamicin-induced ototoxicity through an auditory brainstem response (ABR) test and a histopathological evaluation of the cochlea. METHODS: In this study, 48 female adult Sprague-Dawley rats aged 20-22 weeks and weighing 200-250g were used. An ABR test was carried out on all rats prior to drug administration, after which, the rats were divided into four groups of 12 animals each. Drug administration was gentamicin 120mg/kg plus ethanol in group one; gentamicin 120mg/kg plus quercetin 15mg/kg in group two; quercetin 15mg/kg in group three; and ethanol in group four. The drugs were administered intraperitoneally once a day for two weeks, and the ABR test was repeated after drug administration. Subsequently, the rats were sacrificed and their cochleae were dissected and examined histopathologically. RESULTS: There was no significant difference between the pre-treatment ABR measurement values of the groups. However, a significant increase was detected in the ABR values in the group of rats that were administered gentamicin plus ethanol, while no statistically significant increase was found in the ABR values in the groups administered with gentamicin plus quercetin; quercetin alone; and ethanol alone. The number of TUNEL positive cells in the inner and outer hair cells in the Corti organ was found to be fewer, and Caspase 3 and 9 expressions were found to be weaker in the group receiving gentamicin plus quercetin than in the group receiving gentamicin plus ethanol. CONCLUSIONS: Auditory function was detected to be significantly protected and apoptotic cells were found to be decreased when quercetin was administered together with gentamicin. From these results it was concluded that quercetin, a powerful antioxidant, attenuates ABR thresholds and histopathological lesions in the cochlea in gentamicin-induced ototoxicity in rats. PMID- 26434547 TI - Peripheral vestibular loss detected in pediatric patients using a smartphone based test of the subjective visual vertical. AB - INTRODUCTION: Detection of peripheral vestibular loss (PVL) in children with dizziness is an important and challenging task. The static subjective visual vertical (SVV) test can effectively detect PVL, but requires specialized equipment. OBJECTIVE: The goal of this study was to determine the efficacy of a smartphone-based SVV test at detecting PVL in pediatric patients. METHODS: Thirty nine patients between 7 and 18 years old (mean=14.0+/-2.70) underwent conventional SVV (conv-SVV) and smartphone-based SVV (ip-SVV) testing. Subjects included 6 with PVL (based on clinical history and other vestibular tests), 6 with benign paroxysmal positioning vertigo (BPPV), 11 with central causes of vertigo (CV), 8 with non-vestibular dizziness (NVD), and 8 controls. RESULTS: Mean ip-SVV score in the PVL group (2.77+/-1.45) was significantly higher than in each of the other groups (BPPV=0.89+/-0.55; CV=1.08+/-0.68; NVD=1.45+/-1.19; Control=1.08+/-0.73; one-way analysis of variance, p=0.008), and remained significant after adjusting for age and gender by multiple linear regression analysis. Receiver operating characteristic analysis predicted an optimal ip-SVV cut-off score of >2.13 degrees with a sensitivity of 66.7%, specificity of 97.0%, positive predictive value (PPV) of 80%, and negative predictive value of 94.1% for detecting PVL. Sensitivity and PPV improved to 75% and 100%, respectively, when subjects tested >1 month after symptom onset (n=24) were excluded. CONCLUSION: Smartphone-based SVV testing is a simple and useful office based method for detecting PVL in children with dizziness. PMID- 26434548 TI - Procalcitonin and community-acquired pneumonia (CAP) in children. AB - The role of procalcitonin (PCT) as a biomarker for sepsis in adults is well documented, while its role in infections affecting neonatal children remains controversial. Among these infections, Community-Acquired pneumonia (CAP) has been studied extensively, because it's the second cause of death in children in developing countries, and one of the most frequent causes of hospitalization in industrialized countries. The PubMed database and the Cochrane Library were used to search for the following keywords: CAP, procalcitonin, and children. Thirteen articles were studied to determine the role of PCT in CAP management, specifically its usefulness for distinguishing pneumococcal infections from viral and unknown infections, for predicting severity and the correct antibiotic treatment. This paper focuses on the studies performed to identify the best inflammatory biomarker for CAP management. Although there is an increase in studies confirming the usefulness of PCT in CAP management in children, further studies are needed to have better understanding of its role for pediatric CAP management. PMID- 26434549 TI - Negative interference of N-acetyl cysteine (NAC) on selected chemistries on the Abbott architect platform. PMID- 26434550 TI - WITHDRAWN: Dual display bacteriophage as a platform for high sensitive detection of serum p53 antibodies in breast cancer patients. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26434551 TI - Circadian time structure of circulating plasma lipid peroxides, antioxidant enzymes and other small molecules in peptic ulcers. AB - BACKGROUND: The circadian rhythm, as part of a broad time structure (chronome) of lipid peroxides and antioxidant defense mechanisms may relate to prevention, efficacy and management of preventive and curative chronotherapy. METHODS: Fifty newly diagnosed patients with peptic ulcers, 30-45 years of age, and 60 age matched clinically healthy volunteers were synchronized for one week with diurnal activity from about 06:00 to about 22:00 and nocturnal rest. Breakfast was served around 08:30, lunch around 13:30 and dinner around 20:30. Drugs known to affect the free-radical systems were not taken. Blood samples were collected at 6-hour intervals for 24h under standardized, presumably 24-hour synchronized conditions. Plasma lipid peroxides, in the form of malondialdehyde (MDA), blood superoxide dismutase (SOD), glutathione peroxide (GPx), glutathione reductase (GR), catalase (CAT) activities, and serum total protein, albumin, ascorbic acid, total serum cholesterol, and HDL-cholesterol concentrations were determined. RESULTS: By population-mean cosinor analysis, a marked circadian variation was demonstrated for all variables in healthy subjects and in ulcer patients (p<0.001). As compared to controls, patients had a lower MESOR of MDA, SOD, GPx, GR, ascorbic acid, and HDL-C. They also had smaller circadian amplitude of SOD, CAT, GPx, GR, ascorbic acid, T-C, and HDL-C, but larger circadian amplitude of MDA and albumin. As compared to healthy subjects, the circadian acrophase of ulcer patients occurred later for MDA and GR and earlier for GPx. CONCLUSION: Mapping circadian rhythms, important chronome components that include trends with age and extra circadian components characterizing antioxidants and pro-oxidants, is needed for exploring their putative role as markers in the treatment and management of peptic ulcers. PMID- 26434552 TI - Mass spectrometric phosphoproteome analysis of small-sized samples of human neutrophils. AB - BACKGROUND: Global analysis of stimulus-dependent changes in the neutrophil phosphoproteome will improve the understanding of neutrophil signal transduction and function in diverse disease settings. However, gel-free phosphoproteomics of neutrophils in clinical studies is hampered by limited sample amounts and requires protein extract stability, efficient tryptic digestion and sensitive phosphopeptide enrichment in a protease-rich environment. For development of an appropriate workflow, we assessed neutrophil protein stability in urea-based lysis buffers and determined feasibility of gel-free phosphoproteomic analyses using polymer-based metal ion affinity capture (PolyMAC). METHODS: Western blotting, phosphopeptide enrichment and mass spectrometric analyses of samples of neutrophils were performed. RESULTS: Degradation of proteins in neutrophil extracts was observed after preparation with a urea-containing lysis buffer and could be prevented by addition of highly concentrated protease inhibitors. Subsequent tryptic digestion and PolyMAC-based phosphopeptide enrichment proved efficient with accordingly prepared neutrophil samples. Applying the new workflow, formyl-methionyl-leucyl-phenylalanine-induced phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) was detected after gel free and gel-based phosphoproteomic analyses as proof of principle from 20 ml of whole blood. Furthermore, phosphorylation of other ERK1/2 pathway-associated proteins was monitored. CONCLUSION: We provide a workflow for efficient, gel-free phosphoproteome analyses with small-sized neutrophil samples, suitable for application in clinical studies. PMID- 26434554 TI - Bayesian approach for assessing non-inferiority in a three-arm trial with pre specified margin. AB - Non-inferiority trials are becoming increasingly popular for comparative effectiveness research. However, inclusion of the placebo arm, whenever possible, gives rise to a three-arm trial which has lesser burdensome assumptions than a standard two-arm non-inferiority trial. Most of the past developments in a three arm trial consider defining a pre-specified fraction of unknown effect size of reference drug, that is, without directly specifying a fixed non-inferiority margin. However, in some recent developments, a more direct approach is being considered with pre-specified fixed margin albeit in the frequentist setup. Bayesian paradigm provides a natural path to integrate historical and current trials' information via sequential learning. In this paper, we propose a Bayesian approach for simultaneous testing of non-inferiority and assay sensitivity in a three-arm trial with normal responses. For the experimental arm, in absence of historical information, non-informative priors are assumed under two situations, namely when (i) variance is known and (ii) variance is unknown. A Bayesian decision criteria is derived and compared with the frequentist method using simulation studies. Finally, several published clinical trial examples are reanalyzed to demonstrate the benefit of the proposed procedure. PMID- 26434553 TI - Biofilm formation by Bacillus subtilis requires an endoribonuclease-containing multisubunit complex that controls mRNA levels for the matrix gene repressor SinR. AB - Biofilm formation by Bacillus subtilis is largely governed by a circuit in which the response regulator Spo0A turns on the gene for the anti-repressor SinI. SinI, in turn, binds to and inactivates SinR, a dedicated repressor of genes for matrix production. Mutants of the genes ylbF, ymcA and yaaT are blocked in biofilm formation, but the mechanism by which they act has been mysterious. A recent report attributed their role in biofilm formation to stimulating Spo0A activity. However, we detect no measurable effect on the transcription of sinI. Instead, we find that the block in biofilm formation is caused by an increase in the levels of SinR and of its mRNA. Evidence is presented that YlbF, YmcA and YaaT interact with, and control the activity of, RNase Y, which is known to destabilize sinR mRNA. We also show that the processing of another target of RNase Y, cggR-gapA mRNA, similarly depends on YlbF and YmcA. Our work suggests that sinR mRNA stability is an additional posttranscriptional control mechanism governing the switch to multicellularity and raises the possibility that YlbF, YmcA and YaaT broadly regulate mRNA stability as part of an RNase Y-containing, multi-subunit complex. PMID- 26434555 TI - An Epitope-Specific Respiratory Syncytial Virus Vaccine Based on an Antibody Scaffold. AB - Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in children. We have generated an epitope-specific RSV vaccine by grafting a neutralizing epitope (F-epitope) in its native conformation into an immunoglobulin scaffold. The resulting antibody fusion exhibited strong binding affinity to Motavizumab, an RSV neutralizing antibody, and effectively induced potent neutralizing antibodies in mice. This work illustrates the potential of the immunoglobulin molecule as a scaffold to present conformationally constrained B-cell epitopes. PMID- 26434556 TI - Reversible skin and hair depigmentation during chemotherapy with dasatinib for chronic myeloid leukemia. PMID- 26434557 TI - The Value of Genetic Risk Scores to Predict Hypertension. PMID- 26434558 TI - Physical Activity Engagement in Young People with Down Syndrome: Investigating Parental Beliefs. AB - BACKGROUND: Despite the wide documentation of the physical/psychological benefits derived from regular physical activity (PA), high levels of inactivity are reported among people with Down syndrome. This study aims to explore parental beliefs concerning involvement, facilitators/barriers and benefits of PA in young people. METHOD: Semi-structured interviews were conducted with 13 parents of young people with Down syndrome. RESULTS: Three facilitation themes were identified: (i) the support derived from family; (ii) the availability of APA (Adapted Physical Activity) expert instructors and coaches; (iii) the challenging nature of sport activities. Three barrier themes were identified: (i) the lack of APA expert coaches and specialized gyms; (ii) the characteristics of Down syndrome; and (iii) the parental beliefs and worries. CONCLUSIONS: Family plays a key role, as facilitator and barrier, to the participation of their children with Down syndrome in PA. Crucial is the implementation of evidence-based exercise programmes involving people with Down syndrome and their families. PMID- 26434559 TI - Quality of life and late-effects among childhood brain tumor survivors: a mixed method analysis. AB - BACKGROUND: Reports on the quality of life (QOL) of childhood brain tumor (BT) survivors have been inconsistent. As cognitive limitations may restrict their participation in questionnaire-based studies, our aim was to evaluate in depth the QOL with a mixed-method analysis. METHODS: The 5-year survivors of childhood BTs born in 1975-2000 and alive in 2010 were identified via the Finnish Cancer Registry and treating clinics. Twenty-one survivors (32%) participated in a mixed method analysis including 15D (a general health-related QOL questionnaire), the Beck Depression Inventory, and a qualitative semi-structured interview. RESULTS: Based on the 15D-questionnaire, the BT survivors had an impaired health-related QOL in several dimensions such as speech and usual activities. On the other hand, no difference was found in other dimensions such as distress or vitality. A majority (95%) of the survivors showed no increased risk for depression. The qualitative interview revealed that the most important aspects affecting the QOL of the survivors were positive mental growth, negative conceptions concerning illness, living one day at a time, age at diagnosis, time since diagnosis, social relationships, learning disabilities and limitations in vocational opportunities, limitations in independent life, and changed understanding of the term 'health'. CONCLUSIONS: Childhood BT survivors have heterogeneous attitudes on QOL. The survivors assess social aspects to be more important than functionality for their QOL. Social concerns should actively be brought up to offer support for those with significant social difficulties. Interventions for social difficulties should be more actively developed. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26434560 TI - Three-dimensional HDlive rendering of fetal perineum in anorectal atresia. PMID- 26434561 TI - Sesame indicum, a nutritional supplement, elicits antiamnesic effect via cholinergic pathway in scopolamine intoxicated mice. AB - PURPOSE: Present study was undertaken to evaluate the antiamnesic effect of Sesamum indicum (S. indicum) seeds (standardized for sesamin, a lignan, content) in scopolamine, a muscarinic antagonist intoxicated mice. METHODS: Male Swiss albino mice (18-22 g bw) were pretreated with methanolic extract of sesame seeds (MSSE) (100 and 200 mg/kg/day, p.o) for a period of 14 days. Scopolamine (0.3 mg/kg, i.p.) was injected on day 14, 45 +/- 10 min after MSSE administration. Antiamnesic effect of MSSE was evaluated using step-down latency (SDL) on passive avoidance apparatus and transfer latency (TL) on an elevated plus maze. To unravel the mechanism of action, we examined the effects of MSSE on the genes such as acetyl cholinesterase (AChE), muscarinic receptor M1 subtype (mAChRM1 ), and brain derived neurotrophic factor (BDNF) expression within hippocampus of experimental mice. Further, its effects on bax and bcl-2 were also evaluated. Histopathological examination of hippocampal CA1 region was performed using cresyl violet staining. RESULTS: MSSE treatment produced a significant and dose dependent increase in step down latency in passive avoidance test and decrease in transfer latency in elevated plus maze in scopolamine intoxicated injected mice. MSSE down-regulated AChE and mAChRM1 and up-regulated BDNF mRNA expression. Further, it significantly down-regulated the bax and caspase 3 and up-regulated bcl-2 expression in scopolamine intoxicated mice brains. Mice treated with MSSE showed increased neuronal counts in hippocampal CA1 region when compared with scopolamine-vehicle treated mice. CONCLUSION: Sesame seeds have the ability to interact with cholinergic components involved in memory function/restoration and also an interesting candidate to be considered for future cognitive research. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1955-1963, 2016. PMID- 26434562 TI - Calcium silicate-based cements: composition, properties, and clinical applications. AB - Mineral trioxide aggregate (MTA) is a calcium silicate-based cement (CSC) commonly used in endodontic procedures involving pulpal regeneration and hard tissue repair, such as pulp capping, pulpotomy, apexogenesis, apexification, perforation repair, and root-end filling. Despite the superior laboratory and clinical performance of MTA in comparison with previous endodontic repair cements, such as Ca(OH)2 , MTA has poor handling properties and a long setting time. New CSC have been commercially launched and marketed to overcome the limitations of MTA. The aim of the present review was to explore the available literature on new CSC products, and to give evidence-based recommendations for the clinical use of these materials. Within the limitations of the available data in the literature regarding the properties and performance of the new CSC, the newer products could be promising alternatives to MTA; however, further research is required to support this assumption. PMID- 26434563 TI - A mixed-method synthesis of knowledge, experiences and attitudes of health professionals to Female Genital Mutilation. AB - AIM: To synthesize knowledge, attitudes and experiences of health professionals about Female Genital Mutilation. BACKGROUND: Despite the World Health Organization campaigning to stop FGM, and it being illegal in many countries, the practice remains common in some countries and cultures. Migration has contributed to the growth of this practice in countries where it was not previously carried out. DESIGN: Mixed-method synthesis. DATA SOURCES: Search of ten electronic databases: 2006-2014. Manual scanning of reference lists and summary feeds from international organizations such as WHO, UN and UNICEF. REVIEW METHODS: Thematic synthesis comparing country of origin where the practice was common with country of residence where migrant women affected by the practice reside. 17 included descriptive, quantitative, qualitative studies and grey literature studies in English or Spanish. RESULTS: Seven themes were developed: Ignorance of FGM practice and its consequences; Lack of adherence to FGM protocols and guidelines; Socially constructed acceptance of FGM; Ignorance of legislation and legal status of FGM; Condoning, sanctioning or supporting FGM; Lack of information and training; Nurses and Midwives as key to protecting and supporting girls and women CONCLUSIONS: Although some nurses and midwives are in the forefront of eradicating FGM this is counterbalanced by health professionals (including nurses and midwives) who condone, sanction or support the practice with some calling for medicalization of FGM as a legitimate procedure. Girls at risk need better protection and women affected need more competent and cultural care from health professionals. Health and legal systems, professional regulation and governance, and professional training require strengthening to eradicate FGM, prevent the medicalization of FGM as an acceptable procedure, and to better manage the lifelong consequences for affected girls and women. PMID- 26434564 TI - Early renin-angiotensin system intervention is more beneficial than late intervention in delaying end-stage renal disease in patients with type 2 diabetes. AB - AIMS: To develop and validate a model to simulate progression of diabetic kidney disease (DKD) from early onset until end-stage renal disease (ESRD), and to assess the effect of renin-angiotensin system (RAS) intervention in early, intermediate and advanced stages of DKD. METHODS: We used data from the BENEDICT, IRMA-2, RENAAL and IDNT trials that assessed effects of RAS intervention in patients with type 2 diabetes. We built a model with discrete disease stages based on albuminuria and estimated glomerular filtration rate (eGFR). Using survival analyses, we assessed the effect of RAS intervention on delaying ESRD in early [eGFR>60 ml/min/1.73 m(2) and albumin:creatinine ratio (ACR) <30 mg/g], intermediate (eGFR 30-60 ml/min/1.73 m(2) or ACR 30-300 mg/g) and advanced (eGFR <30 ml/min/1.73 m(2) or ACR >300 mg/g) stages of DKD for patients in different age groups. RESULTS: For patients at early, intermediate and advanced stage of disease, whose mean age was 60 years and who received placebo, the median time to ESRD was 21.4, 10.8 and 4.7 years, respectively. RAS intervention delayed the predicted time to ESRD by 4.2, 3.6 and 1.4 years, respectively. The benefit of early RAS intervention was more pronounced in younger patients; for example, for patients with a mean age of 45 years, RAS intervention at early, intermediate or advanced stage delayed ESRD by 5.9, 4.0 and 1.1 years versus placebo. CONCLUSIONS: RAS intervention early in the course of proteinuric DKD is more beneficial than late intervention in delaying ESRD. PMID- 26434566 TI - Improving the sensitivity in chiral capillary electrophoresis. AB - CE is known for being one of the most powerful analytical techniques when performing enantioseparations due to its numerous advantages such as excellent separation efficiency and extremely low solvents and reagents consumption, all of them derived from the capillary small dimensions. Moreover, it is worth highlighting that unlike in chromatographic techniques, in CE the chiral selector is generally within the separation medium instead of being attached to the separation column which makes the method optimization a more versatile task. Despite its numerous advantages, when using UV-Vis detection, CE lacks of sensitivity detection due to its short optical path length derived from the narrow separation capillary. This issue can be overcome by means of different approaches, either by sample treatment procedures or by in-capillary preconcentration techniques or even by employing detection systems more sensitive than UV-Vis, such as LIF or MS. The present review assembles the latest contributions regarding improvements of sensitivity in chiral CE published from June 2013 until May 2015, which follows the works included in a previous review reported by Sanchez-Hernandez et al. [Electrophoresis 2014, 35, 12-27]. PMID- 26434565 TI - Diagnostic methods and treatment options for focal cortical dysplasia. AB - Our inability to adequately treat many patients with refractory epilepsy caused by focal cortical dysplasia (FCD), surgical inaccessibility and failures are significant clinical drawbacks. The targeting of physiologic features of epileptogenesis in FCD and colocalizing functionality has enhanced completeness of surgical resection, the main determinant of outcome. Electroencephalography (EEG)-functional magnetic resonance imaging (fMRI) and magnetoencephalography are helpful in guiding electrode implantation and surgical treatment, and high frequency oscillations help defining the extent of the epileptogenic dysplasia. Ultra high-field MRI has a role in understanding the laminar organization of the cortex, and fluorodeoxyglucose-positron emission tomography (FDG-PET) is highly sensitive for detecting FCD in MRI-negative cases. Multimodal imaging is clinically valuable, either by improving the rate of postoperative seizure freedom or by reducing postoperative deficits. However, there is no level 1 evidence that it improves outcomes. Proof for a specific effect of antiepileptic drugs (AEDs) in FCD is lacking. Pathogenic mutations recently described in mammalian target of rapamycin (mTOR) genes in FCD have yielded important insights into novel treatment options with mTOR inhibitors, which might represent an example of personalized treatment of epilepsy based on the known mechanisms of disease. The ketogenic diet (KD) has been demonstrated to be particularly effective in children with epilepsy caused by structural abnormalities, especially FCD. It attenuates epigenetic chromatin modifications, a master regulator for gene expression and functional adaptation of the cell, thereby modifying disease progression. This could imply lasting benefit of dietary manipulation. Neurostimulation techniques have produced variable clinical outcomes in FCD. In widespread dysplasias, vagus nerve stimulation (VNS) has achieved responder rates >50%; however, the efficacy of noninvasive cranial nerve stimulation modalities such as transcutaneous VNS (tVNS) and noninvasive (nVNS) requires further study. Although review of current strategies underscores the serious shortcomings of treatment-resistant cases, initial evidence from novel approaches suggests that future success is possible. PMID- 26434567 TI - Effects of Aspergillus niger fermented rapeseed meal on nutrient digestibility, growth performance and serum parameters in growing pigs. AB - The aim of the present study was to investigate the influences of Aspergillus niger fermented rapeseed meal (FRSM) on growth performance and nutrient digestibility of growing pigs. A total of 72 growing pigs (body weight = 40.8 +/- 2.1 kg) were used in feeding trials, lasting for up to 42 days, and were randomly allotted to one of three diets, including a corn-soybean meal control diet as well as two experimental diets containing 10% unfermented rapeseed meal (RSM) or 10% FRSM. The results showed that average daily gain and feed conversion ratio of pigs fed FRSM were superior (P < 0.05) to that of pigs fed unfermented RSM and did not differ from the control. Pigs fed control diet had higher (P < 0.05) total tract apparent digestibility for dry matter, protein, calcium and phosphorus than pigs fed unfermented RSM diet and did not differ from the FRSM diet. Pigs fed FRSM had lower levels (P < 0.05) of serum aspartate transaminase compared to unfermented RSM. In conclusion, solid state fermentation using Aspergillus niger may improve the growth performance and nutrient digestibility of RSM for pigs and FRSM is a promising alternative protein for pig production. PMID- 26434568 TI - Demystifying discharge: Assessing discharge readiness to predict day of discharge. PMID- 26434569 TI - Efficacy of Flow-Diverting Devices for Cerebral Aneurysms: A Systematic Review and Meta-analysis. AB - BACKGROUND: To evaluate the efficacy of flow-diverting devices (FDDs) used in the treatment for intracranial aneurysms (IAs), we performed a meta-analysis of published literature on FDDs. METHODS: A systematic electronic database search was conducted using MEDLINE, PubMed, Springer, and EBSCO for all accessible articles on FDDs published until December 2014. Abstracts, full-text manuscripts, and the reference lists of retrieved articles were analyzed. Random effects meta analysis was used to pool the occlusion rate outcomes across studies. RESULTS: Fifty-nine studies containing efficacy data on 2263 patients with more than 2493 treated aneurysms were included in the analysis. The overall complete occlusion rate was 82.5% (95% CI, 78.8%-86%) across studies. The success rate of FDD implantation was 97.4% (95% CI, 95.4%-99.4%). The occlusion rate for anterior circulation aneurysms was 83.3% (95% CI, 71.2%-95.4%); with regard to complete occlusion, the odds ratio for anterior circulation aneurysms was significantly higher than that of posterior circulation IAs (odds ratio, 1.93; 95% CI, 1.00 3.73). CONCLUSIONS: FDDs have high technical success rates in the management of IAs. Additional studies on well-designed, multicenter, randomized controlled trials will be required to validate the findings of the present study and to identify the best therapeutic strategy for IAs depending on their size, location, and characteristics. PMID- 26434570 TI - Need of the Hour: Stimulating Medical and Nonmedical Students to Choose a Career in Neuro and Spinal Surgery: A Perspective. PMID- 26434571 TI - Importance of Continued Support for Microsurgical Anatomical Studies. PMID- 26434572 TI - Poor-Grade Subarachnoid Hemorrhage Patients: Do We All Know the Best Way to Manage? PMID- 26434573 TI - A new signal characterization and signal-based Chou's PseAAC representation of protein sequences. AB - Most of the algorithms used for information extraction and for processing the amino acid chains that make up proteins treat them as symbolic chains. Fewer algorithms exploit signal processing techniques that require a numerical representation of amino acid chains. However, these algorithms are very powerful for extracting regularities that cannot be detected when working with a symbolic chain, which may be important for understanding the biological meaning of a sequence or in classification tasks. In this study, a new mathematical representation of amino acid chains is proposed, which is derived using a similarity measure based on the PAM250 amino acid substitution matrix and that generates 20 signals for each protein sequence. Using this representation 20 consensus spectra for a protein family are determined and the relevance of the frequency peaks is established, obtaining a group of significant frequency peaks that manifest common periodicities of the amino acid sequences that belong to a protein family. We also show that the proposed representation in 20 signals can be integrated into Chou's pseudo amino acid composition (PseAAC) and constitute a useful alternative to amino acid physicochemical properties in Chou's PseAAC. PMID- 26434574 TI - Consistency of QSAR models: Correct split of training and test sets, ranking of models and performance parameters. AB - Recent implementations of QSAR modelling software provide the user with numerous models and a wealth of information. In this work, we provide some guidance on how one should interpret the results of QSAR modelling, compare and assess the resulting models, and select the best and most consistent ones. Two QSAR datasets are applied as case studies for the comparison of model performance parameters and model selection methods. We demonstrate the capabilities of sum of ranking differences (SRD) in model selection and ranking, and identify the best performance indicators and models. While the exchange of the original training and (external) test sets does not affect the ranking of performance parameters, it provides improved models in certain cases (despite the lower number of molecules in the training set). Performance parameters for external validation are substantially separated from the other merits in SRD analyses, highlighting their value in data fusion. PMID- 26434575 TI - A snapshot of circulation failure following acute traumatic injury: The expansion of computed tomography beyond injury diagnosis. AB - OBJECTIVE: CT scans with a flat Inferior Vena Cava (IVC) suggest hypovolemia, and the presence of shock bowel implies hypoperfusion. The purpose of this study is to correlate injury severity, resuscitation needs, and clinical outcomes with CT indices of hypovolemia and hypoperfusion. DESIGN: Retrospective cohort study. SETTING: Level II trauma centre in Central California. PATIENTS: Adult patients imaged with abdominal and pelvic CT scans, from January 2010-January 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Circulatory derangements on CT scans were defined as an IVC (AP) diameter measurement of <9 mm, flat IVC (FIVC), hypovolemia. The presence of small intestine hypoperfusion was shock bowel (SB). The absence of these findings was a normal CT scan (NCT). Comparisons of acid-base status, fluids, morbidity and mortality were made based on CT findings. Subgroups were: FIVC (n=20), FIVC+SB (n=19), SB (n=4) only versus normal CT scans, NCT (n=47). RESULTS: Overall ISS was 19 (SD) 14. The lowest ISS was in NCT 14 (SD) 10 and there was an incremental increase in ISS based on circulatory derangements, p=0.001. ICU admission was lowest in NCT and highest in the presence of hyovolemia and hypoperfusion, p=0.03. Similarly ED crystalloid requirements and the activation of a massive transfusion protocol (MTP), was lowest in NCT group and gradually increased significantly as hypovolemia and hypoperfusion was demonstrated on CT scans. Additional parameters such as metabolic acidosis, nosocomial infections and mortality were associated with acute CT findings of circulatory failure. CONCLUSIONS: Hypovolemia and hypoperfusion, markers of abnormal circulation, were demonstrated on CT scans for trauma evaluation. The presence of these findings alone or in combination showed strong correlation with high injury severity, and the need for aggressive resuscitation. PMID- 26434576 TI - Estimating pre-traumatic quality of life in patients with surgically treated acetabular fractures and pelvic ring injuries: Does timing matter? AB - BACKGROUND AND PURPOSE: Evaluation of patient-assessed functional outcome in traumatic conditions has specific challenges. To obtain pre-traumatic data to allow for comparison during follow-up, retrospective assessments are needed. How such data is affected by posttraumatic time-point chosen for evaluation is unknown. The primary purpose of this study was to investigate how the time-point chosen for retrospective assessment of pre-traumatic quality of life (QoL) in patients with surgically treated acetabular fractures and pelvic ring injuries influenced the results. A secondary purpose was to examine the pre-traumatic QoL profile in patients with these injuries. PATIENTS AND METHODS: 73 patients were included, where 50 had an acetabular fracture and 23 a pelvic ring injury. Pre traumatic QoL was evaluated using the generic instruments SF-36 and EQ5D in conjunction with the condition-specific Pelvic Trauma Questionnaire (PTQ). Questionnaires were completed at three time points: 0, 1 and 2 months post surgery. RESULTS: Number of responders were 73 patients at 0 months, 61 patients at 1 month and 53 patients at 2 months. 50 patients answered the questionnaires at all three time-points. A trend was observed with all instruments where patients estimated a better pre-traumatic status with narrower distributions when assessment was delayed. At 2 months, scores for 4 out of 8 SF-36 domains where significantly higher compared to 0 months. For EQ5D, EQ VAS improved at 1 and 2 months compared to month 0 results but no other significant differences between time-points were found. Results from the PTQ demonstrated no significant differences over time. Pre-traumatic quality of life was high and for SF-36 comparable to a population norm. A very low level of pre-existing discomfort from the pelvic region was reported through the PTQ. CONCLUSION: Patients with surgically treated acetabular fractures and pelvic ring injuries estimate a higher pre-traumatic functional status when assessment is carried out at 1 or 2 months post-surgery compared to perioperative measurements. The SF-36 seems to be more sensitive than the EQ5D in this respect. Pre-traumatic QoL in patients with surgically treated acetabular fractures and pelvic ring injuries is generally high and pre-existing discomfort from the pelvic region is uncommon. PMID- 26434580 TI - Uncovering the sources of DNA found on the Turin Shroud. AB - The Turin Shroud is traditionally considered to be the burial cloth in which the body of Jesus Christ was wrapped after his death approximately 2000 years ago. Here, we report the main findings from the analysis of genomic DNA extracted from dust particles vacuumed from parts of the body image and the lateral edge used for radiocarbon dating. Several plant taxa native to the Mediterranean area were identified as well as species with a primary center of origin in Asia, the Middle East or the Americas but introduced in a historical interval later than the Medieval period. Regarding human mitogenome lineages, our analyses detected sequences from multiple subjects of different ethnic origins, which clustered into a number of Western Eurasian haplogroups, including some known to be typical of Western Europe, the Near East, the Arabian Peninsula and the Indian sub continent. Such diversity does not exclude a Medieval origin in Europe but it would be also compatible with the historic path followed by the Turin Shroud during its presumed journey from the Near East. Furthermore, the results raise the possibility of an Indian manufacture of the linen cloth. PMID- 26434582 TI - Enhancement of the Si p-n diode NIR photoresponse by embedding beta-FeSi2 nanocrystallites. AB - By using solid phase epitaxy of thin Fe films and molecular beam epitaxy of Si, a p(+)-Si/p-Si/beta-FeSi2 nanocrystallites/n-Si(111) diode structure was fabricated. Transmission electron microscopy data confirmed a well-defined multilayered structure with embedded nanocrystallites of two typical sizes: 3-4 and 15-20 nm, and almost coherent epitaxy of the nanocrystallites with the Si matrix. The diode at zero bias conditions exhibited a current responsivity of 1.7 mA/W, an external quantum efficiency of about 0.2%, and a specific detectivity of 1.2 * 10(9) cm * Hz(1/2)/W at a wavelength of 1300 nm at room temperature. In the avalanche mode, the responsivity reached up to 20 mA/W (2% in terms of efficiency) with a value of avalanche gain equal to 5. The data obtained indicate that embedding of beta-FeSi2 nanocrystallites into the depletion region of the Si p-n junction results in expansion of the spectral sensitivity up to 1600 nm and an increase of the photoresponse by more than two orders of magnitude in comparison with a conventional Si p-n junction. Thereby, fabricated structure combines advantage of the silicon photodiode functionality and simplicity with near infrared light detection capability of beta-FeSi2. PMID- 26434581 TI - mirPRo-a novel standalone program for differential expression and variation analysis of miRNAs. AB - Being involved in many important biological processes, miRNAs can regulate gene expression by targeting mRNAs to facilitate their degradation or translational inhibition. Many miRNA sequencing studies reveal that miRNA variations such as isomiRs and "arm switching" are biologically relevant. However, existing standalone tools usually do not provide comprehensive, detailed information on miRNA variations. To deepen our understanding of miRNA variability, we developed a new standalone tool called "mirPRo" to quantify known miRNAs and predict novel miRNAs. Compared with the most widely used standalone program, miRDeep2, mirPRo offers several new functions including read cataloging based on genome annotation, optional seed region check, miRNA family expression quantification, isomiR identification and categorization, and "arm switching" detection. Our comparative data analyses using three datasets from mouse, human and chicken demonstrate that mirPRo is more accurate than miRDeep2 by avoiding over-counting of sequence reads and by implementing different approaches in adapter trimming, mapping and quantification. mirPRo is an open-source standalone program (https://sourceforge.net/projects/mirpro/). PMID- 26434583 TI - Atypical role of sprouty in colorectal cancer: sprouty repression inhibits epithelial-mesenchymal transition. AB - Sprouty (SPRY) appears to act as a tumor suppressor in cancer, whereas we demonstrated that SPRY2 functions as a putative oncogene in colorectal cancer (CRC) (Oncogene, 2010, 29: 5241-5253). We investigated the mechanisms by which SPRY regulates epithelial-mesenchymal transition (EMT) in CRC. SPRY1 and SPRY2 mRNA transcripts were significantly upregulated in human CRC. Suppression of SPRY2 repressed AKT2 and EMT-inducing transcription factors and significantly increased E-cadherin expression. Concurrent downregulation of SPRY1 and SPRY2 also increased E-cadherin and suppressed mesenchymal markers in colon cancer cells. An inverse expression pattern between AKT2 and E-cadherin was established in a human CRC tissue microarray. SPRY2 negatively regulated miR-194-5p that interacts with AKT2 3' untranslated region. Mir-194 mimics increased E-cadherin expression and suppressed cancer cell migration and invasion. By confocal microscopy, we demonstrated redistribution of E-cadherin to plasma membrane in colon cancer cells transfected with miR-194. Spry1(-/-) and Spry2(-/-) double mutant mouse embryonic fibroblasts exhibited decreased cell migration while acquiring several epithelial markers. In CRC, SPRY drive EMT and may serve as a biomarker of poor prognosis. PMID- 26434584 TI - Hepatitis C virus upregulates B-cell receptor signaling: a novel mechanism for HCV-associated B-cell lymphoproliferative disorders. AB - B-cell receptor (BCR) signaling is essential for the development of B cells and has a critical role in B-cell neoplasia. Increasing evidence indicates an association between chronic hepatitis C virus (HCV) infection and B-cell lymphoma, however, the mechanisms by which HCV causes B-cell lymphoproliferative disorder are still unclear. Herein, we demonstrate the expression of HCV viral proteins in B cells of HCV-infected patients and show that HCV upregulates BCR signaling in human primary B cells. HCV nonstructural protein NS3/4A interacts with CHK2 and downregulates its activity, modulating HuR posttranscriptional regulation of a network of target mRNAs associated with B-cell lymphoproliferative disorders. Interestingly, the BCR signaling pathway was found to have the largest number of transcripts with increased association with HuR and was upregulated by NS3/4A. Our study reveals a previously unidentified role of NS3/4A in regulation of host BCR signaling during HCV infection, contributing to a better understanding of the molecular mechanisms underlying HCV-associated B cell lymphoproliferative disorders. PMID- 26434587 TI - Negative regulation of RNA-binding protein HuR by tumor-suppressor ECRG2. AB - Esophageal cancer-related gene 2 (ECRG2) is a newer tumor suppressor whose function in the regulation of cell growth and apoptosis remains to be elucidated. Here we show that ECRG2 expression was upregulated in response to DNA damage, and increased ECRG2 expression induced growth suppression in cancer cells but not in non-cancerous epithelial cells. ECRG2-mediated growth suppression was associated with activation of caspases and marked reduction in the levels of apoptosis inhibitor, X chromosome-linked inhibitor of apoptosis protein (XIAP). ECRG2, via RNA-binding protein human antigen R (HuR), regulated XIAP mRNA stability and expression. Furthermore, ECRG2 increased HuR ubiquitination and degradation but was unable to modulate the non-ubiquitinable mutant form of HuR. We also identified missense and frame-shift ECRG2 mutations in various human malignancies and noted that, unlike wild-type ECRG2, one cancer-derived ECRG2 mutant harboring glutamic acid instead of valine at position 30 (V30E) failed to induce cell death and activation of caspases. This naturally occurring V30E mutant also did not suppress XIAP and HuR. Importantly, the V30E mutant overexpressing cancer cells acquired resistance against multiple anticancer drugs, thus suggesting that ECRG2 mutations appear to have an important role in the acquisition of anticancer drug resistance in a subset of human malignancies. PMID- 26434586 TI - Nestin regulates proliferation and invasion of gastrointestinal stromal tumor cells by altering mitochondrial dynamics. AB - Nestin is widely expressed in numerous tumors and has become a diagnostic and prognostic indicator. However, the exact mechanism by which nestin contributes to tumor malignancy remains poorly understood. Here, we found marked upregulation of nestin expression in highly proliferative and invasive gastrointestinal stromal tumor (GIST) specimens. Nestin knockdown in GIST cells reduced the proliferative and invasive activity owing to a decrease of mitochondrial intracellular reactive oxygen species (ROS) generation. Furthermore, nestin was co-localized with mitochondria, and knockdown of nestin increased mitochondrial elongation and influenced the mitochondrial function, including oxygen consumption rates, ATP generation and mitochondrial membrane potential and so on. In exploring the underlying mechanism, we demonstrated nestin knockdown inhibited the mitochondrial recruitment of Dynamin-related protein1 and induced the change of mitochondrial dynamics. Thus, nestin may have an important role in GIST malignancy by regulating mitochondrial dynamics and altering intracellular ROS levels. The findings provide new clues to reveal mechanisms by which nestin mediates the proliferation and invasion of GISTs. PMID- 26434585 TI - The EGFR-HER2 module: a stem cell approach to understanding a prime target and driver of solid tumors. AB - The epidermal growth factor receptor (EGFR) and a coreceptor denoted HER2/ERBB2 are frequently overexpressed or mutated in solid tumors, such as carcinomas and gliomas. In line with driver roles, cancer drugs intercepting EGFR or HER2 currently outnumber therapies targeting other hubs of signal transduction. To explain the roles for EGFR and HER2 as prime drivers and targets, we take lessons from invertebrates and refer to homeostatic regulation of several mammalian tissues. The model we infer ascribes to the EGFR-HER2 module pivotal functions in rapid clonal expansion of progenitors called transient amplifying cells (TACs). Accordingly, TACs of tumors suffer from replication stress, and hence accumulate mutations. In addition, several lines of evidence propose that in response to EGF and related mitogens, TACs might undergo dedifferentiation into tissue stem cells, which might enable entry of oncogenic mutations into the stem cell compartment. According to this view, antibodies or kinase inhibitors targeting EGFR-HER2 effectively retard some solid tumors because they arrest mutation enriched TACs and possibly inhibit their dedifferentiation. Deeper understanding of the EGFR-HER2 module and relations between cancer stem cells and TACs will enhance our ability to control a broad spectrum of human malignancies. PMID- 26434588 TI - Exosomes mediate the acquisition of the disease phenotypes by cells with normal genome in tuberous sclerosis complex. AB - Functions of extracellular vesicles including exosomes in the pathogenesis of tuberous sclerosis complex (TSC) have not yet been studied. We report that the extracellular vesicles such as exosomes derived from tuberous sclerosis 1 (Tsc1) null cells transform phenotypes of neighboring wild-type cells in vivo in such manner that they become functionally similar to Tsc1-null cells. The loss of Tsc1 in the mouse neural tube increases the number of the wild-type neuronal progenitors, which is followed by the precocious and transient acceleration of neuronal differentiation of these cells. The mechanisms regulating these changes involve the exosomal delivery of exosomal shuttle Notch1 and Rheb esRNA and component of gamma-secretase complex presenilin 1 from Tsc1-null cells to wild type cells leading to the activation of Notch and Rheb signaling in the recipient cells. The exosome-mediated mechanisms may also operate in the cells of angiomyolipoma (AML), which develops as a result of mutations in TSC1/TSC2 genes in TSC patients, because we observed the reactivation of mammalian target of rapamycin and Notch pathways, driven by the delivery of Rheb and Notch1 esRNA, in AML cells depleted of Rheb that were treated with the exosomes purified from AML cells with the constitutively high Rheb levels. PMID- 26434589 TI - DNMT3A mutations mediate the epigenetic reactivation of the leukemogenic factor MEIS1 in acute myeloid leukemia. AB - Close to half of de novo acute myeloid leukemia (AML) cases do not exhibit any cytogenetic aberrations. In this regard, distortion of the DNA methylation setting and the presence of mutations in epigenetic modifier genes can also be molecular drivers of the disease. In recent years, somatic missense mutations of the DNA methyltransferase 3A (DNMT3A) have been reported in ~20% of AML patients; however, no obvious critical downstream gene has been identified that could explain the role of DNMT3A in the natural history of AML. Herein, using whole genome bisulfite sequencing and DNA methylation microarrays, we have identified a key gene undergoing promoter hypomethylation-associated transcriptional reactivation in DNMT3 mutant patients, the leukemogenic HOX cofactor MEIS1. Our results indicate that, in the absence of mixed lineage leukemia fusions, an alternative pathway for engaging an oncogenic MEIS1-dependent transcriptional program can be mediated by DNMT3A mutations. PMID- 26434590 TI - AP2alpha controls the dynamic balance between miR-126&126* and miR-221&222 during melanoma progression. AB - Accumulating evidences have shown the association between aberrantly expressed microRNAs (miRs) and cancer, where these small regulatory RNAs appear to dictate the cell fate by regulating all the main biological processes. We demonstrated the responsibility of the circuitry connecting the oncomiR-221&222 with the tumor suppressors miR-126&126* in melanoma development and progression. According to the inverse correlation between endogenous miR-221&222 and miR-126&126*, respectively increasing or decreasing with malignancy, their enforced expression or silencing was sufficient for a reciprocal regulation. In line with the opposite roles of these miRs, protein analyses confirmed the reverse expression pattern of miR-126&126*-targeted genes that were induced by miR-221&222. Looking for a central player in this complex network, we revealed the dual regulation of AP2alpha, on one side directly targeted by miR-221&222 and on the other a transcriptional activator of miR-126&126*. We showed the chance of restoring miR 126&126* expression in metastatic melanoma to reduce the amount of mature intracellular heparin-binding EGF like growth factor, thus preventing promyelocytic leukemia zinc finger delocalization and maintaining its repression on miR-221&222 promoter. Thus, the low-residual quantity of these two miRs assures the release of AP2alpha expression, which in turn binds to and induces miR-126&126* transcription. All together these results point to an unbalanced ratio functional to melanoma malignancy between these two couples of miRs. During progression this balance gradually moves from miR-126&126* toward miR-221&222. This circuitry, besides confirming the central role of AP2alpha in orchestrating melanoma development and/or progression, further displays the significance of these miRs in cancer and the option of utilizing them for novel therapeutics. PMID- 26434591 TI - Metabolic targeting of oncogene MYC by selective activation of the proton-coupled monocarboxylate family of transporters. AB - Deregulation of the MYC oncogene produces Myc protein that regulates multiple aspects of cancer cell metabolism, contributing to the acquisition of building blocks essential for cancer cell growth and proliferation. Therefore, disabling Myc function represents an attractive therapeutic option for cancer treatment. However, pharmacological strategies capable of directly targeting Myc remain elusive. Here, we identified that 3-bromopyruvate (3-BrPA), a drug candidate that primarily inhibits glycolysis, preferentially induced massive cell death in human cancer cells overexpressing the MYC oncogene, in vitro and in vivo, without appreciable effects on those exhibiting low MYC levels. Importantly, pharmacological inhibition of glutamine metabolism synergistically potentiated the synthetic lethal targeting of MYC by 3-BrPA due in part to the metabolic disturbance caused by this combination. Mechanistically, we identified that the proton-coupled monocarboxylate transporter 1 (MCT1) and MCT2, which enable efficient 3-BrPA uptake by cancer cells, were selectively activated by Myc. Two regulatory mechanisms were involved: first, Myc directly activated MCT1 and MCT2 transcription by binding to specific recognition sites of both genes; second, Myc transcriptionally repressed miR29a and miR29c, resulting in enhanced expression of their target protein MCT1. Of note, expressions of MCT1 and MCT2 were each significantly elevated in MYCN-amplified neuroblastomas and C-MYC-overexpressing lymphomas than in tumors without MYC overexpression, correlating with poor prognosis and unfavorable patient survival. These results identify a novel mechanism by which Myc sensitizes cells to metabolic inhibitors and validate 3 BrPA as potential Myc-selective cancer therapeutics. PMID- 26434592 TI - Oxidative pentose phosphate pathway inhibition is a key determinant of antimalarial induced cancer cell death. AB - Despite immense interest in using antimalarials as autophagy inhibitors to treat cancer, it remains unclear whether these agents act predominantly via autophagy inhibition or whether other pathways direct their anti-cancer properties. By comparing the treatment effects of the antimalarials chloroquine (CQ) and quinacrine (Q) on KRAS mutant lung cancer cells, we demonstrate that inhibition of the oxidative arm of the pentose phosphate pathway (oxPPP) is required for antimalarial induced apoptosis. Despite inhibiting autophagy, neither CQ treatment nor RNAi against autophagy regulators (ATGs) promote cell death. In contrast, Q triggers high levels of apoptosis, both in vitro and in vivo, and this phenotype requires both autophagy inhibition and p53-dependent inhibition of the oxPPP. Simultaneous genetic targeting of the oxPPP and autophagy is sufficient to trigger apoptosis in lung cancer cells, including cells lacking p53. Thus, in addition to reduced autophagy, oxPPP inhibition serves as an important determinant of antimalarial cytotoxicity in cancer cells. PMID- 26434593 TI - More complex transcriptional regulation and stress response by MOF. AB - MOF (males absent on the first) was initially discovered as a dosage compensation factor that regulates the epigenetic acetylation of histone H4 lysine 16. In this issue, Sheikh et al. demonstrate that MOF expression is not required for normal kidney tissue function but is required for maintaining transcriptional regulation under conditions of stress. This work along with results from previous investigators highlights the importance of the cell lineage-chromatin modification interaction in determining transcriptional programs and physiological outcomes under normal and stress conditions. PMID- 26434595 TI - TAMing resistance to multi-targeted kinase inhibitors through Axl and Met inhibition. AB - TAM (Tyro3-Axl-Mer) receptor tyrosine kinases and Met are implicated in several hallmarks of cancer progression including sustained angiogenesis, enhanced motility, tissue invasion and acquisition of metastatic potential through the upregulation of epithelial-to-mesenchymal transition. Increasing evidence has confirmed Axl and Met as emerging central drivers of adaptive resistance to targeted therapies across a wide variety of cancers. In this issue of Oncogene, Zhou et al. describe the mechanisms linking Axl and Met activation to acquired resistance to sunitinib in renal cell carcinoma (RCC), providing a pre-clinical rationale for the development of Axl and Met inhibitors including cabozantinib in anti-angiogenic resistant RCC. PMID- 26434594 TI - PAT4 levels control amino-acid sensitivity of rapamycin-resistant mTORC1 from the Golgi and affect clinical outcome in colorectal cancer. AB - Tumour cells can use strategies that make them resistant to nutrient deprivation to outcompete their neighbours. A key integrator of the cell's responses to starvation and other stresses is amino-acid-dependent mechanistic target of rapamycin complex 1 (mTORC1). Activation of mTORC1 on late endosomes and lysosomes is facilitated by amino-acid transporters within the solute-linked carrier 36 (SLC36) and SLC38 families. Here, we analyse the functions of SLC36 family member, SLC36A4, otherwise known as proton-assisted amino-acid transporter 4 (PAT4), in colorectal cancer. We show that independent of other major pathological factors, high PAT4 expression is associated with reduced relapse free survival after colorectal cancer surgery. Consistent with this, PAT4 promotes HCT116 human colorectal cancer cell proliferation in culture and tumour growth in xenograft models. Inducible knockdown in HCT116 cells reveals that PAT4 regulates a form of mTORC1 with two distinct properties: first, it preferentially targets eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), and second, it is resistant to rapamycin treatment. Furthermore, in HCT116 cells two non-essential amino acids, glutamine and serine, which are often rapidly metabolised by tumour cells, regulate rapamycin-resistant mTORC1 in a PAT4 dependent manner. Overexpressed PAT4 is also able to promote rapamycin resistance in human embryonic kidney-293 cells. PAT4 is predominantly associated with the Golgi apparatus in a range of cell types, and in situ proximity ligation analysis shows that PAT4 interacts with both mTORC1 and its regulator Rab1A on the Golgi. These findings, together with other studies, suggest that differentially localised intracellular amino-acid transporters contribute to the activation of alternate forms of mTORC1. Furthermore, our data predict that colorectal cancer cells with high PAT4 expression will be more resistant to depletion of serine and glutamine, allowing them to survive and outgrow neighbouring normal and tumorigenic cells, and potentially providing a new route for pharmacological intervention. PMID- 26434596 TI - Histopathological features of sinonasal inverted papillomas in chinese patients. AB - OBJECTIVES/HYPOTHESIS: Nasal inverted papilloma (IP) is a benign tumor with high recurrence rates. Evidence of inflammation has been reported in IP in Caucasian studies. This study aimed to investigate the histopathological patterns and their associations with clinical characteristics in Chinese patients with IP. STUDY DESIGN: Basic science study. METHODS: IP tissues were obtained from 50 Chinese patients with unilateral IPs. Biopsies of inferior turbinate mucosa from 17 healthy subjects were used as controls. The histological patterns and severity of epithelial remodeling and inflammatory cell infiltration were evaluated and analyzed for associations with clinical characteristics. RESULTS: Thirty-one percent of IP specimens were classified as grade I (mild remodeling) and 49% as grade II (moderate and severe remodeling). Concomitant inflammatory nasal polyps were found in 14 patients (28%). Recurrent IP was strongly associated with grade II (odds ratio: 5.81, 95% confidence interval: 1.34-25.18). Except CD4(+) T cells, quantities of neutrophils, macrophages, eosinophils, CD8(+) T cells, and FoxP3(+) T-reg cells were significantly elevated in IP. Of these, neutrophils were the predominant cell type in IP. CONCLUSIONS: Inflammation may have potential roles in IPs and the higher grade of epithelial remodeling was associated with the recurrence of IPs. LEVEL OF EVIDENCE: NA. PMID- 26434597 TI - Determination of the hyperfine magnetic field in magnetic carbon-based materials: DFT calculations and NMR experiments. AB - The prospect of carbon-based magnetic materials is of immense fundamental and practical importance, and information on atomic-scale features is required for a better understanding of the mechanisms leading to carbon magnetism. Here we report the first direct detection of the microscopic magnetic field produced at (13)C nuclei in a ferromagnetic carbon material by zero-field nuclear magnetic resonance (NMR). Electronic structure calculations carried out in nanosized model systems with different classes of structural defects show a similar range of magnetic field values (18-21 T) for all investigated systems, in agreement with the NMR experiments. Our results are strong evidence of the intrinsic nature of defect-induced magnetism in magnetic carbons and establish the magnitude of the hyperfine magnetic field created in the neighbourhood of the defects that lead to magnetic order in these materials. PMID- 26434598 TI - Time-of-Flight Microwave Camera. AB - Microwaves can penetrate many obstructions that are opaque at visible wavelengths, however microwave imaging is challenging due to resolution limits associated with relatively small apertures and unrecoverable "stealth" regions due to the specularity of most objects at microwave frequencies. We demonstrate a multispectral time-of-flight microwave imaging system which overcomes these challenges with a large passive aperture to improve lateral resolution, multiple illumination points with a data fusion method to reduce stealth regions, and a frequency modulated continuous wave (FMCW) receiver to achieve depth resolution. The camera captures images with a resolution of 1.5 degrees, multispectral images across the X frequency band (8 GHz-12 GHz), and a time resolution of 200 ps (6 cm optical path in free space). Images are taken of objects in free space as well as behind drywall and plywood. This architecture allows "camera-like" behavior from a microwave imaging system and is practical for imaging everyday objects in the microwave spectrum. PMID- 26434599 TI - Repertory of eukaryotes (eukaryome) in the human gastrointestinal tract: taxonomy and detection methods. AB - Eukaryotes are an important component of the human gut, and their relationship with the human host varies from parasitic to commensal. Understanding the diversity of human intestinal eukaryotes has important significance for human health. In the past few decades, most of the multitudes of techniques that are involved in the diagnosis of the eukaryotic population in the human intestinal tract were confined to pathological and parasitological aspects that mainly rely on traditionally based methods. However, development of culture-independent molecular techniques comprised of direct DNA extraction from faeces followed by sequencing, offer new opportunities to estimate the occurrence of eukaryotes in the human gut by providing data on the entire eukaryotic community, particularly not-yet-cultured or fastidious organisms. Further broad surveys of the eukaryotic communities in the gut based on high throughput tools such as next generation sequencing might lead to uncovering the real diversity of these ubiquitous organisms in the human intestinal tract and discovering the unrecognized roles of these eukaryotes in modulating the host immune system and inducing changes in host gut physiology and ecosystem. PMID- 26434600 TI - Awake Flexible Fiberoptic Laryngoscopy to diagnose glossoptosis in Robin Sequence patients. AB - BACKGROUND: Robin Sequence (RS) is usually defined as the combination of micrognathia, glossoptosis and upper airway obstruction. No objective criteria to diagnose RS exist. To compare management strategy results, a single RS definition using objective criteria is needed. The most frequently used primary diagnostic tool for glossoptosis is awake Flexible Fiberoptic Laryngoscopy (aFFL). OBJECTIVES: To determine the reliability of the aFFL videos as an independent diagnostic tool itself, rather than on the complete evaluation of a patient. DESIGN, SETTING, PARTICIPANTS: All RS individuals from an existing cohort with an available aFFL video were included retrospectively. Thirty age-matched patients without pathologic findings on aFFL were used as controls. aFFL videos were scored by six otolaryngologists as: a. Marked glossoptosis, b. Mild glossoptosis, c. Severity unknown, d. No glossoptosis, e. Insufficient video quality. Videos were anonymised and rated twice, in altered sequences, after a washout period of minimally 2 weeks. MAIN OUTCOME MEASURES: Inter-rater and intrarater agreement. RESULTS: Twenty-six videos of 16 RS patients and 30 videos of controls were included. Inter-rater agreement was fair in the whole group (kappa: 0.320) and RS group (kappa: 0.226), and fair to moderate in determining presence of glossoptosis (total group kappa: 0.430; RS kappa: 0.302; controls kappa: 0.212). The intrarater agreement for the presence of glossoptosis in RS was moderate (kappa: 0.541). CONCLUSIONS: aFFL offers fair to moderate inter-rater agreement, with moderate intrarater agreement, in evaluating glossoptosis in RS. Using aFFL as the single tool in choosing management strategies in RS seems insufficient. There is need for a more reliable, patient friendly diagnostic tool or an internationally accepted aFFL scoring system, to diagnose glossoptosis in RS. PMID- 26434601 TI - Expression of Heat Shock Protein 27 in Benign Prostatic Hyperplasia with Chronic Inflammation. AB - BACKGROUND: Heat shock protein 27 (HSP 27) is known as a mediator in immune response and has been recently found to be expressed in prostate cancer. This study aimed to investigate the role of HSP27 in inflammatory BPH. MATERIAL AND METHODS: Hospitalized BPH patients who received TURP were divided into 4 groups by the presence and degrees of chronic inflammation: non-inflammatory BPH (NI BPH), mild-inflammatory BPH (MI BPH), moderate-inflammatory BPH (MOI BPH), and severe-inflammatory BPH (SI BPH). Expressions of HSP 27, TNF-alpha, IL-6, and CD3 in prostate tissues and serum of patients were detected by immunohistochemistry and ELISA. RESULTS: Expression of HSP27 in BPH with histological inflammation was significantly higher than in non-inflammatory BPH. In inflammatory BPH groups, HSP27 expression gradually increased along with increasing inflammation. There was a significant correlation between the expression of TNF-alpha, IL-6, CD3 and HSP27 among different inflammatory BPH groups. CONCLUSIONS: HSP27 expression level is associated with the degree of chronic inflammation in BPH and may participate in the pathological process in inflammatory BPH. PMID- 26434602 TI - Modulation of embryonic development due to mating with immunised males. AB - The modification of pre- and postnatal development conferred by immunogenic stimulation of mothers provides a population-level adaptation mechanism for non genetic transfer of maternal experiences to progeny. However little is known about the transmission of paternal immune experiences to offspring. Here, we show that immune priming of males 3-9 days before mating affects the growth and humoral environment of developing embryos of outbred (ICR) and inbred (C57BL and BALB/c) mice. Antigenic stimulation of fathers caused a significant increase in embryonic bodyweight as measured on Day 16 of pregnancy and altered other gestation parameters, such as feto-placental ratio. Pregnant females mated with immunised males were also characterised by changes in humoral conditions as shown by measurements of blood and amniotic progesterone, testosterone and granulocyte macrophage colony-stimulating factor (GM-CSF) cytokine concentrations. These results emphasise the role of paternal effects of immune priming on the in utero environment and fetal growth. PMID- 26434603 TI - A Hafnium-Based Metal-Organic Framework as a Nature-Inspired Tandem Reaction Catalyst. AB - Tandem catalytic systems, often inspired by biological systems, offer many advantages in the formation of highly functionalized small molecules. Herein, a new metal-organic framework (MOF) with porphyrinic struts and Hf6 nodes is reported. This MOF demonstrates catalytic efficacy in the tandem oxidation and functionalization of styrene utilizing molecular oxygen as a terminal oxidant. The product, a protected 1,2-aminoalcohol, is formed selectively and with high efficiency using this recyclable heterogeneous catalyst. Significantly, the unusual regioselective transformation occurs only when an Fe-decorated Hf6 node and the Fe-porphyrin strut work in concert. This report is an example of concurrent orthogonal tandem catalysis. PMID- 26434604 TI - Patterned Poly(acrylic acid) Brushes Containing Gold Nanoparticles for Peptide Detection by Surface-Assisted Laser Desorption/Ionization Mass Spectrometry. AB - Patterned poly(acrylic acid) (PAA) brushes was successfully generated via photolithography and surface-initiated reversible addition-fragmentation chain transfer (RAFT) polymerization of acrylic acid as verified by water contact angle measurements and FT-IR analysis. The carboxyl groups of PAA brushes can act as reducing moieties for in situ synthesis of gold nanoparticles (AuNPs), without the use of additional reducing agent. The formation of AuNPs was confirmed by transmission electron microscopy and X-ray photoelectron spectroscopy. The glass surface-modified by PAA brushes and immobilized with AuNPs (AuNPs-PAA) can be used as a substrate for SALDI-MS analysis, which is capable of detecting both small peptides having m/z <= 600 (glutathione) and large peptides having m/z >= 1000 (bradykinin, ICNKQDCPILE) without the interference from matrix signal suggesting that AuNPs were stably trapped within the PAA brushes and the carboxyl groups of PAA can serve as internal proton source. By employing AuNPs as the capture probe, the AuNPs-PAA substrate can selectively identify thiol-containing peptides from the peptide mixtures with LOD as low as 0.1 and 0.05 nM for glutathione and ICNKQDCPILE, respectively. An ability to selectively detect ICNKQDCPILE in a diluted human serum is also demonstrated. The patterned format together with its high sensitivity and selectivity render this newly developed substrate a potential platform for high-throughput analysis of other biomarkers, especially those with low molecular weight in complex biological samples. PMID- 26434605 TI - Bioinspired Hierarchical Surface Structures with Tunable Wettability for Regulating Bacteria Adhesion. AB - To circumvent the influence from varied topographies, the systematic study of wettability regulated Gram-positive bacteria adhesion is carried out on bioinspired hierarchical structures duplicated from rose petal structures. With the process of tuning the interfacial chemical composition of the self-assembled films from supramolecular gelators, the varied wettable surfaces from superhydrophilicity to superhydrophobicity can be obtained. The investigation of Gram-positive bacteria adhesion on the hierarchical surfaces reveals that Gram positive bacteria adhesion is crucially mediated by peptidoglycan due to its different interaction mechanisms with wettable surfaces. The study makes it possible to systematically study the influence mechanism of wettability regulated bacteria adhesion and provides a sight to make the bioinspired topographies in order to investigate wettability regulated bioadhesion. PMID- 26434606 TI - Quantum Chemical Study of the Thermochemical Properties of Organophosphorous Compounds. AB - Organophosphorous compounds are involved in many toxic compounds such as fungicides, pesticides, or chemical warfare nerve agents. The understanding of the decomposition chemistry of these compounds in the environment is largely limited by the scarcity of thermochemical data. Because of the high toxicity of many of these molecules, experimental determination of their thermochemical properties is very difficult. In this work, standard gas-phase thermodynamic data, i.e., enthalpies of formation (DeltafH298 degrees ), standard entropies (S298 degrees ), and heat capacities (Cp degrees (T)), were determined using quantum chemical calculations and more specifically the CBS-QB3 composite method, which was found to be the best compromise between precision and calculation time among high accuracy composite methods. A large number of molecules was theoretically investigated, involving trivalent and pentavalent phosphorus atoms, and C, H, O, N, S, and F atoms. These data were used to propose 83 original groups, used in the semiempirical group contribution method proposed by Benson. Thanks to these latter group values, thermochemical properties of several nerve agents, common pesticides and herbicides have been evaluated. Bond dissociations energies (BDE), useful for the analysis the thermal stability of the compounds, were also determined in several molecules of interest. PMID- 26434607 TI - Efficient, Solvent-Free, Multicomponent Method for Organic-Base-Catalyzed Synthesis of beta-Phosphonomalonates. AB - An efficient, one-pot, di-n-butylamine-catalyzed, three-component synthesis of beta-phosphonomalonates has been developed. A wide range of substrates, including aromatic and fused aromatic aldehydes, were condensed with enolizable C-H activated compounds and dialkylphosphites to give the desired products in excellent yields. This method provides an eco-friendly alternative approach to rapid construction of a diversity-oriented library of beta-phosphonomalonates. PMID- 26434608 TI - One-Pot Synthesis of Monodisperse Noble Metal @ Resorcinol-Formaldehyde (M@RF) and M@Carbon Core-Shell Nanostructure and Their Catalytic Applications. AB - We demonstrate that noble metal @ RF core-shell nanostructures can be obtained through a facile one-pot synthesis approach in the absence of any additional surfactants. Monodisperse metal@RF core-shell nanostructures can be produced within 1 h on a large scale. Both the core size and shell thickness can be readily tuned by altering the reaction parameters. Systematic studies reveal that resorcinol could have several functions: it could act as a reactant to form RF resin, and it also could passivate the surface of metallic nanoparticles to prevent them from aggregating. Additionally, for the first time, our results suggest that resorcinol may act as a reducing agent that can reduce metal salts to form metal nanoparticles. The core-shell nanoparticles can be carbonized into M@carbon nanostructures, which have shown great performance in the catalytic hydrogenation of chlorobenzene. This work not only will help to achieve the controllable synthesis of noble metal@RF resin and M@carbon core-shell nanostructures but also will promote research into other RF-based nanostructures and their catalytic applications. PMID- 26434609 TI - VRE and VSE Bacteremia Outcomes in the Era of Effective VRE Therapy: A Systematic Review and Meta-analysis. AB - BACKGROUND Prior data suggest that vancomycin-resistant Enterococcus (VRE) bacteremia is associated with worse outcomes than vancomycin-sensitive Enterococcus (VSE) bacteremia. However, many studies evaluating such outcomes were conducted prior to the availability of effective VRE therapies. OBJECTIVE To systematically review VRE and VSE bacteremia outcomes among hospital patients in the era of effective VRE therapy. METHODS Electronic databases and grey literature published between January 1997 and December 2014 were searched to identify all primary research studies comparing outcomes of VRE and VSE bacteremias among hospital patients, following the availability of effective VRE therapies. The primary outcome was all-cause, in-hospital mortality, while total hospital length of stay (LOS) was a secondary outcome. All meta-analyses were conducted in Review Manager 5.3 using random-effects, inverse variance modeling. RESULTS Among all the studies reviewed, 12 cohort studies and 1 case control study met inclusion criteria. Similar study designs were combined in meta analyses for mortality and LOS. VRE bacteremia was associated with increased mortality compared with VSE bacteremia among cohort studies (odds ratio [OR], 1.80; 95% confidence interval [CI], 1.38-2.35; I2=0%; n=11); the case-control study estimate was similar, but not significant (OR, 1.93; 95% CI, 0.97-3.82). LOS was greater for VRE bacteremia patients than for VSE bacteremia patients (mean difference, 5.01 days; 95% CI, 0.58-9.44]; I2=0%; n=5). CONCLUSIONS Despite the availability of effective VRE therapy, VRE bacteremia remains associated with an increased risk of in-hospital mortality and LOS when compared to VSE bacteremia. Infect. Control Hosp. Epidemiol. 2015;37(1):26-35. PMID- 26434610 TI - Current Approaches to the Diagnosis of Classical form of Congenital Adrenal Hyperplasia. AB - Congenital adrenal hyperplasia (CAH) is one of the most common diseases transmitted in an autosomal recessive manner and is caused by mutations of enzymes which are responsible for the process of adrenal steroidogenesis. According to the impairment of enzymes involved in steroidogenesis, several types of CAH can be distinguished. The most common type is associated with mutations in the CYP21A2 gene, encoding 21-hydroxylase enzyme and has different clinical forms: Classical (in which there are two types: salt wasting and simple virilization) and non-classical, characterized by less severe symptoms and late onset. CAH is characterized by a strong correlation between the genotype and the phenotype. Mutations in the CYP21A2 gene can cause different degrees of loss of 21-hydroxylase enzyme activity which result in a wide spectrum of clinical pictures. Several methods used to diagnose CAH (such as determining steroids in serum or urine) have been known from the 70's. Modern diagnosis of CAH is based primarily on the use of genetic testing, which is the subject of numerous constantly updated patents. In this paper the most recent patents on the diagnosis of CAH were assessed. PMID- 26434611 TI - Cassia tora Seed Extract and Its Active Compound Aurantio-obtusin Inhibit Allergic Responses in IgE-Mediated Mast Cells and Anaphylactic Models. AB - Cassia tora seed is widely used due to its various biological properties including anticancer, antidiabetic, and anti-inflammatory effects. However, there has been no report of the effects of C. tora seed extract (CTE) on immunoglobulin E (IgE)-mediated allergic responses. In this research, we demonstrated the effects of CTE and its active compound aurantio-obtusin on IgE-sensitized allergic reactions in mast cells and passive cutaneous anaphylaxis (PCA). CTE and aurantio-obtusin suppressed degranulation, histamine production, and reactive oxygen species generation and inhibited the production and mRNA expression of tumor necrosis factor-alpha and interleukin-4. CTE and aurantio-obtusin also suppressed the prostaglandin E2 production and expression of cyclooxygenase 2. Furthermore, CTE and aurantio-obtusin suppressed IgE-mediated FcepsilonRI signaling such as phosphorylation of Syk, protein kinase CMU, phospholipase Cgamma, and extracellular signal-regulated kinases. CTE and aurantio-obtusin blocked mast cell-dependent PCA in IgE-mediated mice. These results suggest that CTE and aurantio-obtusin are a beneficial treatment for allergy-related diseases. PMID- 26434612 TI - Decline in the prevalence of anaemia among children of pre-school age after implementation of wheat flour fortification with multiple micronutrients in Jordan. AB - OBJECTIVE: To examine changes in the prevalence of anaemia and its correlates among children of pre-school age after implementation of wheat flour fortification with multiple micronutrients in Jordan. DESIGN: Retrospective analysis of the data from two repeated national cross-sectional panels of pre school children. SETTING: The two surveys were conducted in 2007 and 2009, 16-20 months and 34-36 months, respectively, after implementation of wheat flour fortification with multiple micronutrients in Jordan. Anaemia was considered if Hb level was <11 g/dl. An anaemia prevalence of >=40 % was considered a severe public health problem, while that of 20-39.9 % was considered a moderate public health problem. SUBJECTS: A total of 3789 and 3447 children aged 6-59 months tested in 2007 and 2009, respectively. RESULTS: The prevalence of anaemia in pre school children declined from 40.4 % in 2007 to 33.9 % in 2009 (adjusted OR=0.74; P24 months (-13.7 points), children living in urban areas (-8.0 points), children from rich households (-9.0 points), children who had never been breast-fed (-17.0 points) and well-nourished children (-6.8 points). In both surveys, presence of childhood anaemia was strongly associated with child age <=24 months, living in poor households, breast-feeding for >=6 months, malnourishment, poor maternal education and maternal anaemia. CONCLUSIONS: The public health problem of childhood anaemia declined from severe in 2007 to moderate in 2009, after the implementation of wheat flour fortification with multiple micronutrients in Jordan. PMID- 26434613 TI - Induction of labor--pharmacology methods. AB - Pharmacologic methods for induction of labor have been used for many decades. Pharmacologic agents have an advantage over mechanical methods in that they can be used during both the initial cervical ripening stage of induction and throughout the second stage of labor. Pharmacologic induction agents such as prostaglandins and oxytocin are commonly used for labor and delivery floors and are well established for use in cervical ripening. Nitric oxide donors and mifepristone are known agents in medicine but are new and actively studied in the area of cervical ripening. These agents are introduced and analyzed in this review. PMID- 26434614 TI - Intracranial and extracranial arterial dissection presenting with ischemic stroke: Lesion location and stroke mechanism. AB - Background and purpose Although cervicocranial artery dissections (CADs) are common causes of ischemic stroke in young individuals, anatomical locations and mechanisms of ischemic strokes are still unclear. We evaluate the prevalence, location, and pathogenic mechanisms of ischemic stroke caused by CADs. METHODS: We reviewed CAD patients who presented with acute (<7days) ischemic events and who had undergone diffusion weighted magnetic resonance imaging (MRI) and appropriate vascular imagings (MR angiography, computed tomography angiography, digital subtraction angiography, and high-resolution MRI). Stroke mechanisms were categorized as artery-to-artery (AA) embolism, local branch occlusion, in situ thrombotic occlusion and hemodynamic impairment. RESULTS: One hundred and thirty five patients with cerebral infarcts (n=125) or transient ischemic attacks (n=10) were included. The locations of 159 dissected vessels were: 77 vertebral, 29 internal carotid, 24 middle cerebral, 12 basilar, eight posterior inferior cerebellar, five anterior cerebral, and four posterior cerebral arteries. Among stroke mechanisms, A-A embolism (n=70, 55.5%) was the most common followed by local branch occlusions (n=40, 31.7%) and in situ thrombotic occlusions (n=8, 6.3%). Intracranial CADs were more common (89 vs. 44), less often associated with trauma (21.3% vs. 40.9%, p=0.018) and A-A embolism (32.9% vs. 97.6%, p<0.001), and more often treated with intravenous thrombolysis (15.7% vs. 2.3%. p=0.021) than extracranial CADs. CONCLUSIONS: In our cohort, intracranial CADs are more common than extracranial CADs, and the vertebral artery is the most frequently involved site. Although A-A embolism is the main stroke mechanism, local branch occlusion is another important stroke mechanism. PMID- 26434615 TI - Chronic kidney disease and intravenous thrombolysis in acute stroke: A systematic review and meta-analysis. AB - BACKGROUND: The association between chronic kidney disease (CKD) and hemorrhagic complications or clinical outcomes in patients treated with intravenous (IV) thrombolytic agents is controversial. METHODS: We searched multiple databases for studies on the association between CKD and symptomatic intracerebral hemorrhage (ICH) and/or clinical outcomes in acute stroke patients treated with IV tissue plasminogen activator (tPA). Observational studies that evaluated the association between CKD and outcomes after adjusting for other confounding factors were eligible. We assessed study quality and performed a meta-analysis. The main outcome was symptomatic ICH. The secondary outcomes were poor functional status at 3 months using the modified Rankin Scale, mortality at 3 months, and any ICH. RESULTS: Seven studies were selected based on our eligibility criteria. Of 7168 patients treated with IV tPA, 2001 (27.9%) had CKD. Patients with CKD had a higher risk of symptomatic ICH and mortality [pooled odds ratio (OR) 1.56, 95% confidence interval (CI) 1.05-2.33 and pooled OR 1.70, 95% CI 1.03-2.81, respectively]. Patients with CKD were likely to have an increased risk of poor outcome at 3 months. There was no significant association between CKD and any ICH. CONCLUSIONS: Chronic kidney disease may significantly affect symptomatic hemorrhagic complications and poor clinical outcomes following administration of IV tPA. PMID- 26434616 TI - Transient reduction in venous susceptibility during posterior reversible encephalopathy syndrome. AB - We report a case of posterior reversible encephalopathy syndrome (PRES) in which followed-up MRI demonstrated a transient reduction in venous signal on initial SWAN images. The progressive normalization of venous signal on D10 and D40 imaging paralleled the progressive decrease of hyperperfusion on CBF images. Decreased venous susceptibility has never been reported in PRES; it relates most likely to a transient BOLD effect induced by brain hyperperfusion. PMID- 26434617 TI - Stabilization of protein-protein interaction complexes through small molecules. AB - Most of the small molecules that have been identified thus far to modulate protein-protein interactions (PPIs) are inhibitors. Another promising way to interfere with PPI-associated biological processes is to promote PPI stabilization. Even though PPI stabilizers are still scarce, stabilization of PPIs by small molecules is gaining momentum and offers new pharmacological options. Therefore, we have performed a literature survey of PPI stabilization using small molecules. From this, we propose a classification of PPI stabilizers based on their binding mode and the architecture of the complex to facilitate the structure-based design of stabilizers. PMID- 26434618 TI - On a stochastic gene expression with pre-mRNA, mRNA and protein contribution. AB - In this paper we develop a model of stochastic gene expression, which is an extension of the model investigated in the paper [T. Lipniacki, P. Paszek, A. Marciniak-Czochra, A.R. Brasier, M. Kimmel, Transcriptional stochasticity in gene expression, J. Theor. Biol. 238 (2006) 348-367]. In our model, stochastic effects still originate from random fluctuations in gene activity status, but we precede mRNA production by the formation of pre-mRNA, which enriches classical transcription phase. We obtain a stochastically regulated system of ordinary differential equations (ODEs) describing evolution of pre-mRNA, mRNA and protein levels. We perform mathematical analysis of a long-time behavior of this stochastic process, identified as a piece-wise deterministic Markov process (PDMP). We check exact results using numerical simulations for the distributions of all three types of particles. Moreover, we investigate the deterministic (adiabatic) limit state of the process, when depending on parameters it can exhibit two specific types of behavior: bistability and the existence of the limit cycle. The latter one is not present when only two kinds of gene expression products are considered. PMID- 26434619 TI - Transition from grant funding to a self-supporting burn telemedicine program in the western United States. AB - BACKGROUND: Many Americans have limited access to specialty burn care, and telemedicine has been proposed as a means to address this disparity. However, many telemedicine programs have been founded on grant support and then fail once the grant support expires. Our objective was to demonstrate that a burn telemedicine program can be financially viable. METHODS: This retrospective review from 2005 to 2014 evaluated burn telemedicine visits and financial reimbursement during and after a Technology Opportunities Program grant to a regional burn center. RESULTS: In 2005, we had 12 telemedicine visits, which increased to 458 in 2014. In terms of how this compares to in-person clinic visits, we saw a consistent increase in telemedicine visits as a percentage of total clinic visits from .26% in 2005 to 14% in 2014. Median telemedicine reimbursement has been equivalent to in-person visits. CONCLUSIONS: Specialty telemedicine programs can successfully transition from grant-funded enterprises to self-sustaining. The availability of telemedicine services allows access to specialty expertise in a large and sparsely populated region without imposing an undue financial burden. PMID- 26434620 TI - A novel junctional adhesion molecule A (CgJAM-A-L) from oyster (Crassostrea gigas) functions as pattern recognition receptor and opsonin. AB - Junctional adhesion molecule (JAM), a subfamily of immunoglobulin superfamily (IgSF) with a couple of immunoglobulin domains, can act as regulator in homeostasis and inflammation of vertebrates. In the present study, a structural homolog of JAM-A (designated CgJAM-A-L) was screened out from oyster, Crassostrea gigas, through a search of JAM-A D1 domain (N-terminal Ig domain in JAM-A). The cDNA of CgJAM-A-L was of 1188 bp encoding a predicted polypeptide of 395 amino acids. The immunoreactive area of CgJAM-A-L mainly distributed over the plasma membrane of hemocytes. After Vibro splendidus or tumor necrosis factor (CgTNF-1) stimulation, the mRNA transcripts of CgJAM-A-L in hemocytes increased significantly by 4.46-fold and 9.00-fold (p < 0.01) of those in control group, respectively. The recombinant CgJAM-A-L protein (rCgJAM-A-L) could bind multiple PAMPs including lipopolysaccharides (LPS), peptidoglycan (PGN), lipoteichoic acid (LTA), mannose (MAN), beta-glucan (GLU) and poly(I:C), and various microorganisms including Micrococcus luteus, Staphylococcus aureus, Escherichia coli, Vibro anguillarum, V. splendidus, Pastoris pastoris and Yarrowia lipolytica. The phagocytic rates of oyster hemocytes towards Gram-negative bacteria V. anguillarum and yeast P. pastoris were significantly enhanced after the incubation of rCgJAM-A-L, and even increased more significantly after the pre incubation of rCgJAM-A-L with microbes (p < 0.01). The results collectively indicated that CgJAM-A-L functioned as an important pattern recognition receptor (PRR) and opsonin in the immune defense against invading pathogen in oyster. Moreover, as the most primitive specie with homolog of JAMs, the information of CgJAM-A-L in oyster would provide useful clues for the evolutionary study of JAMs and immunoglobulins. PMID- 26434621 TI - Chronic glucocorticoids exposure enhances neurodegeneration in the frontal cortex and hippocampus via NLRP-1 inflammasome activation in male mice. AB - Neuroinflammation plays an important role in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD) and depression. Chronic glucocorticoids (GCs) exposure has deleterious effects on the structure and function of neurons and is associated with development and progression of AD. However, little is known about the proinflammatory effects of chronic GCs exposure on neurodegeneration in brain. Therefore, the aim of this study was to evaluate the effects of chronic dexamethasone (DEX) treatment (5mg/kg, s.c. for 7, 14, 21 and 28 days) on behavior, neurodegeneration and neuroinflammatory parameters of nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 1 (NLRP-1) inflammasome in male mice. The results showed that DEX treatment for 21 and 28 days significantly reduced the spontaneous motor activity and exploratory behavior of the mice. In addition, these mice showed significant neurodegeneration and a decrease of microtubule-associated protein 2 (MAP2) in the frontal cortex and hippocampus CA3. DEX treatment for 7, 14, 21 and 28 days significantly decreased the mRNA and protein expression of glucocorticoid receptor (GR). Moreover, DEX treatment for 21 and 28 days significantly increased the proteins expression of NLRP-1, Caspase-1, Caspase-5, apoptosis associated speck-like protein (ASC), nuclear factor-kappaB (NF-kappaB), p-NF-kappaB, interleukin-1beta (IL-1beta), IL-18 and IL-6 in the frontal cortex and hippocampus brain tissue. DEX treatment for 28 days also significantly increased the mRNA expression levels of NLRP-1, Caspase-1, ASC and IL-1beta. These results suggest that chronic GCs exposure may increase brain inflammation via NLRP-1 inflammasome activation and induce neurodegeneration. PMID- 26434622 TI - The expression of Toll-like receptor 4, 7 and co-receptors in neurochemical sub populations of rat trigeminal ganglion sensory neurons. AB - The recent discovery that mammalian nociceptors express Toll-like receptors (TLRs) has raised the possibility that these cells directly detect and respond to pathogens with implications for either direct nociceptor activation or sensitization. A range of neuronal TLRs have been identified, however a detailed description regarding the distribution of expression of these receptors within sub-populations of sensory neurons is lacking. There is also some debate as to the composition of the TLR4 receptor complex on sensory neurons. Here we use a range of techniques to quantify the expression of TLR4, TLR7 and some associated molecules within neurochemically-identified sub-populations of trigeminal (TG) and dorsal root (DRG) ganglion sensory neurons. We also detail the pattern of expression and co-expression of two isoforms of lysophosphatidylcholine acyltransferase (LPCAT), a phospholipid remodeling enzyme previously shown to be involved in the lipopolysaccharide-dependent TLR4 response in monocytes, within sensory ganglia. Immunohistochemistry shows that both TLR4 and TLR7 preferentially co-localize with transient receptor potential vallinoid 1 (TRPV1) and purinergic receptor P2X ligand-gated ion channel 3 (P2X3), markers of nociceptor populations, within both TG and DRG. A gene expression profile shows that TG sensory neurons express a range of TLR-associated molecules. LPCAT1 is expressed by a proportion of both nociceptors and non-nociceptive neurons. LPCAT2 immunostaining is absent from neuronal profiles within both TG and DRG and is confined to non-neuronal cell types under naive conditions. Together, our results show that nociceptors express the molecular machinery required to directly respond to pathogenic challenge independently from the innate immune system. PMID- 26434623 TI - Task-specific stability of abundant systems: Structure of variance and motor equivalence. AB - Our main goal was to test a hypothesis that transient changes in performance of a steady-state task would result in motor equivalence. We also estimated effects of visual feedback on the amount of reorganization of motor elements. Healthy subjects performed two variations of a four-finger pressing task requiring accurate production of total pressing force (F TOT) and total moment of force (M TOT). In the Jumping-Target task, a sequence of target jumps required transient changes in either F TOT or M TOT. In the Step-Perturbation task, the index finger was lifted by 1cm for 0.5s leading to a change in both F TOT and M TOT. Visual feedback could have been frozen for one of these two variables in both tasks. Deviations in the space of finger modes (hypothetical commands to individual fingers) were quantified in directions of unchanged F TOT and M TOT (motor equivalent - ME) and in directions that changed F TOT and M TOT (non-motor equivalence - nME). Both the ME and nME components increased when the performance changed. After transient target jumps leading to the same combination of F TOT and M TOT, the changes in finger modes had a large residual ME component with only a very small nME component. Without visual feedback, an increase in the nME component was observed without consistent changes in the ME component. Results from the Step-Perturbation task were qualitatively similar. These findings suggest that both external perturbations and purposeful changes in performance trigger a reorganization of elements of an abundant system, leading to large ME change. These results are consistent with the principle of motor abundance corroborating the idea that a family of solutions is facilitated to stabilize values of important performance variables. PMID- 26434625 TI - Altered crosstalk in the dipeptidyl peptidase-4-incretin-immune system in type 1 diabetes: A hypothesis generating pilot study. AB - Both GLP1(7)(-)(36) (via GLP1 receptor) and the dipeptidyl peptidase-4 (DPP4) cleaved form of GLP1 (GLP1(9)(-)(36), independently of GLP1R) may modulate the response of lymphocytes to cytokine stimuli. The incretin axis, CXCR3 (receptor of DPP4 ligand cytokines CXCL9-11) expression on T(reg)s and hematologic parameters were assessed in 34 patients with long standing type 1 diabetes (T1DM) and in 35 healthy controls. Serum DPP4 (sDPP4) activity, plasma total GLP1 and GLP1(7)(-)(36) concentrations were determined. GLP1(9)(-)(36) concentrations were calculated. CXCR3 expression (flow cytometry) was higher on the CD25( /)(low)Foxp3(+) than on the CD25(+)Foxp3(+) T(reg)s independently from T1DM, suggesting that CD25(-/)(low)Foxp3(+) T(reg)s are possibly waiting for orientational chemotactic stimuli in a "standby mode". The higher sDPP4 activities in T1DM were inversely correlated with GLP1(7)(-)(36) levels and GLP1(9)(-)(36) levels directly with lymphocyte counts in controls. Our results might indicate an altered DPP4-incretin system and altered immunoregulation including a potentially dysfunctional GLP1(9)(-)(36) signaling in T1DM. PMID- 26434626 TI - Analysis of distinct molecular assembly complexes of keratin K8 and K18 by hydrogen-deuterium exchange. AB - Keratins are intermediate filament (IF) proteins that form complex filament systems in epithelial cells, thus serving as scaffolding elements and mechanical stress absorbers. The building blocks of keratin IFs are parallel coiled-coil dimers of two distinct sequence-related proteins distinguished as type I and type II keratins. To gain more insight into their structural dynamics, we resorted to hydrogen-deuterium exchange mass spectrometry of keratins K8 and K18, which are characteristic for simple epithelial cells. Using this powerful technique not employed with IFs before, we mapped patterns of protected versus unprotected regions in keratin complexes at various assembly levels. In particular, we localized protein segments exhibiting different hydrogen exchange patterns in tetramers versus filaments. We observed a general pattern of precisely positioned regions of stability intertwining with flexible regions, mostly represented by the non-alpha-helical segments. Notably, some regions within the coiled-coil domains are significantly more dynamic than others, while the IF-consensus motifs at the end domains of the central alpha-helical "rod" segment, which mediate the "head-to-tail" dimer-dimer interaction in the filament elongation process, become distinctly more protected upon formation of filaments. Moreover, to gain more insight into the dynamics of the individual keratins, we investigated the properties of homomeric preparations of K8 and K18. The physiological importance of keratins without a partner is encountered in both pathological and experimental situations when one of the two species is present in robust excess or completely absent, such as in gene-targeted mice. PMID- 26434627 TI - Reward Processing, Functional Connectivity, Psychopathy, and Research Domain Criteria. PMID- 26434628 TI - Dysfunctional Connectivity in the Depressed Adolescent Brain. PMID- 26434629 TI - Consequences of Adolescent Smoking: Cognitive Performance, Brain Function, and Policy Implications. PMID- 26434624 TI - Influence of maternal thyroid hormones during gestation on fetal brain development. AB - Thyroid hormones (THs) play an obligatory role in many fundamental processes underlying brain development and maturation. The developing embryo/fetus is dependent on maternal supply of TH. The fetal thyroid gland does not commence TH synthesis until mid gestation, and the adverse consequences of severe maternal TH deficiency on offspring neurodevelopment are well established. Recent evidence suggests that even more moderate forms of maternal thyroid dysfunction, particularly during early gestation, may have a long-lasting influence on child cognitive development and risk of neurodevelopmental disorders. Moreover, these observed alterations appear to be largely irreversible after birth. It is, therefore, important to gain a better understanding of the role of maternal thyroid dysfunction on offspring neurodevelopment in terms of the nature, magnitude, time-specificity, and context-specificity of its effects. With respect to the issue of context specificity, it is possible that maternal stress and stress-related biological processes during pregnancy may modulate maternal thyroid function. The possibility of an interaction between the thyroid and stress systems in the context of fetal brain development has, however, not been addressed to date. We begin this review with a brief overview of TH biology during pregnancy and a summary of the literature on its effect on the developing brain. Next, we consider and discuss whether and how processes related to maternal stress and stress biology may interact with and modify the effects of maternal thyroid function on offspring brain development. We synthesize several research areas and identify important knowledge gaps that may warrant further study. The scientific and public health relevance of this review relates to achieving a better understanding of the timing, mechanisms and contexts of thyroid programing of brain development, with implications for early identification of risk, primary prevention and intervention. PMID- 26434630 TI - Overexpression of the chemokine receptor CXCR3 and its correlation with favorable prognosis in gastric cancer. AB - Chemokine receptor, CXCR3, has been increasingly reported to be involved in tumorigenesis and tumor progression, but limited data are available regarding the expression of CXCR3 in gastric cancer (GC). In the present study, the expressions of CXCR3 and its variants were detected in 96 GC and corresponding nontumor gastric tissues by immunohistochemical staining, in 40 freshly frozen GC and nontumor gastric tissues by reverse-transcription polymerase chain reaction and quantitative real-time polymerase chain reaction, and in 10 freshly frozen GC and nontumor gastric tissues by Western blotting. Results revealed that an overexpression of CXCR3 occurs in GC tissues as compared to the nontumor gastric tissues. High level of CXCR3 expression was found to be inversely associated with invasion depth and metastasis (P = .030 and P = .019, respectively) and directly associated with improved overall survival (log-rank test, P < .001). Furthermore, multivariate analysis showed that high CXCR3 expression acts an independent prognostic factor for GC patients (hazard ratio, 0.379 [0.196-0.734]; P = .004). The messenger RNA expression of both the CXCR3 variants, CXCR3-A and CXCR3-B, were up-regulated in GC tissues (P = .006 and P = .002, respectively), although CXCR3-B messenger RNA expression was significantly higher than CXCR3-A, with an average CXCR3-B to CXCR3-A ratio of 1.80. CXCR3-B protein expression was also up regulated in GC tissues (P = .023). In conclusion, our study suggested a potential use of CXCR3 overexpression as a prognostic marker for GC and involvement of the up-regulation of CXCR3-B in favorable prognosis of GC patients. PMID- 26434631 TI - Molecular characteristics of colorectal neuroendocrine carcinoma; similarities with adenocarcinoma rather than neuroendocrine tumor. AB - To further clarify the molecular features of colorectal neuroendocrine carcinomas (NECs), we immunohistochemically examined tumor samples from 25 NECs, including 9 small cell NECs (SCNECs) and 16 large cell NECs (LCNECs), 20 neuroendocrine tumors (NETs), and 21 poorly differentiated adenocarcinomas (PDCs) for the expression of several biomarkers (p53, beta-catenin, Bcl-2, Rb, p16, p21, cyclin D1, and cyclin E) and used sequencing analysis to identify gene alterations of TP53, APC, CTNNB1, KRAS, and BRAF. The frequencies of aberrant p53 expression (88%), beta-catenin nuclear expression (48%), and high expression of cyclin E (84%) were significantly higher in NECs than in NETs (0%, 5%, and 5%, P < .01, respectively). The immunohistochemical results of NECs and PDCs were similar. TP53, APC, KRAS, and BRAF gene mutations were variously detected in NECs and PDCs but not in any NETs. The frequencies of decreased expression of Rb (56%) and high expression of p16 (56%) and Bcl-2 (64%) were significantly higher in NECs than in PDCs (5%, 19%, and 5%, P < .05, respectively) or NETs (10%, 5%, and 5%, P < .01, respectively). Such immunohistochemical characteristics of NECs were more evident in SCNECs than in large cell NECs (P < .01). In conclusion, the molecular features of colorectal NECs are similar to those of adenocarcinomas and not to those of NETs. Decreased expression of Rb and high expression of p16 and Bcl-2 are characteristics of NECs, suggesting that Rb-p16 pathway disruption may contribute to the promotion of proliferative activity in colorectal NECs. SCNECs may be a prototype of NECs. PMID- 26434632 TI - Self-selecting homochiral quadruple-stranded helicates and control of supramolecular chirality. AB - Enantiomeric M4L4 helical cages have been prepared whose supramolecular chirality is induced by the chemical chirality of the self-sorting amino acid-derived ligands that are used. Using scrambled diastereomeric ligands or achiral glycine derived ligands yields analogous complexes yet 'turns off' the supramolecular chirality by producing centrosymmetric cages. PMID- 26434633 TI - Nitronyl nitroxide based 2p-3d-4f chains with the magnetocaloric effect and slow magnetic relaxation. AB - Four new nitronyl nitroxide radical based hetero-tri-spin one-dimensional compounds, namely [{Ln(hfac)3}3{Cu(hfac)2}{NIT-Ph(OMe)2}4]n (Ln = Gd (1), Tb (2), Dy (3), Er (4); hfac = hexafluoroacetylacetonate; NIT-Ph(OMe)2 = 2-(2',4' dimethoxyphenyl)-4,4,5,5-tetramethyl-imidazolyl-1-oxyl-3-oxide) have been successfully prepared. Single crystal X-ray crystallographic analysis reveals that complexes 1-4 possess a 1D chain structure with a repeating [Cu-Rad-Ln-Rad Ln-Rad-Ln-Rad] moiety in which Ln(hfac)3 and Cu(hfac)2 units are bridged by nitronyl nitroxide radicals through the NO groups. DC magnetic studies found that ferromagnetic interactions between metals and the coordinated NO groups are active in all four compounds. The Tb derivative displays frequency dependent ac magnetic susceptibilities, indicating slow magnetic relaxation behavior. The Gd complex shows an important cryogenic magnetocaloric effect with the entropy change (-DeltaSm) of 13.5 J kg(-1) K(-1) at 2 K and a magnetic field of 7 T, representing the first example of Gd-radical molecular species exhibiting the magnetocaloric effect. PMID- 26434634 TI - Backbone circularization of Bacillus subtilis family 11 xylanase increases its thermostability and its resistance against aggregation. AB - The activity of proteins is dictated by their three-dimensional structure, the native state, and is influenced by their ability to remain in or return to the folded native state under physiological conditions. Backbone circularization is thought to increase protein stability by decreasing the conformational entropy in the unfolded state. A positive effect of circularization on stability has been shown for several proteins. Here, we report the development of a cloning standard that facilitates implementing the SICLOPPS technology to circularize proteins of interest using split inteins. To exemplify the usage of the cloning standard we constructed two circularization vectors based on the Npu DnaE and gp41-1 split inteins, respectively. We use these vectors to overexpress in Escherichia coli circular forms of the Bacillus subtilis enzyme family 11 xylanase that differ in the identity and number of additional amino acids used for circularization (exteins). We found that the variant circularized with only one additional serine has increased thermostability of 7 degrees C compared to native xylanase. The variant circularized with six additional amino acids has only a mild increase in thermostability compared to the corresponding exteins-bearing linear xylanase, but is less stable than native xylanase. However, this circular xylanase retains more than 50% of its activity after heat shock at elevated temperatures, while native xylanase and the corresponding exteins-bearing linear xylanase are largely inactivated. We correlate this residual activity to the fewer protein aggregates found in the test tubes of circular xylanase after heat shock, suggesting that circularization protects the protein from aggregation under these conditions. Taken together, these data indicate that backbone circularization has a positive effect on xylanase and can lead to increased thermostability, provided the appropriate exteins are selected. We believe that our cloning standard and circularization vectors will facilitate testing the effects of circularization on other proteins. PMID- 26434636 TI - The synthesis and structure of a carbene-stabilized iminocarboranyl-boron(I) compound. AB - A carbene-stabilized iminocarboranylboron(I) compound has been synthesized and structurally characterized. Single-crystal X-ray analyses and DFT calculations show that the pi back donation of the lone pair of electrons on the boron(I) center onto the pi* orbital of the imine unit is crucial for removing the electron density of the boron center thereby stabilizing such species, in which the carbene serves solely as a sigma donor. This work also demonstrates that imines play a similar role to that of carbenes in the stabilization of low valent boron compounds. PMID- 26434637 TI - Microstructure and rheology of microfibril-polymer networks. AB - By using an adsorbing polymer in combination with mechanical de-agglomeration, the microstructure and rheological properties of networks of microfibrils could be controlled. By the addition of sodium carboxymethyl cellulose during de agglomeration of networks of bacterial cellulose, the microstructure could be changed from an inhomogeneous network with bundles of microfibrils and voids to a more homogeneous spread and alignment of the particles. As a result the macroscopic rheological properties were altered. Although still elastic and gel like in nature, the elasticity and viscous behavior of the network as a function of microfibril concentration is altered. The microstructure is thus changed by changing the surface properties of the building blocks leading to a direct influence on the materials macroscopic behavior. PMID- 26434635 TI - Cerebrospinal fluid levels of IL-6 are decreased and correlate with cognitive status in DLB patients. AB - INTRODUCTION: Inflammatory processes have previously been shown to influence cognition and progression of dementia. An involvement of interleukin (IL)-6 has in particular been suggested as altered levels of IL-6 in cerebrospinal fluid (CSF) have been found in patients with Alzheimer's disease (AD). Also, an association between cognitive decline and levels of IL-6 in CSF have been reported. The aim of the present study was to investigate whether patients clinically diagnosed with dementia with Lewy bodies (DLB) display altered CSF IL 6 levels in comparison with patients with AD and control subjects without dementia and whether the IL-6 levels are correlated with cognitive status and biomarkers for AD and synucleinopathy. METHODS: To analyse CSF of patients with AD (n = 45), patients with DLB (n = 29) and control subjects without dementia (n = 36), we used immunoassays to measure levels of IL-6 (multiplex electrochemiluminescence); AD markers phosphorylated tau, total tau and amyloid beta1-42 (enzyme-linked immunosorbent assay [ELISA]); and alpha-synuclein (ELISA). Cognitive status was evaluated using the Mini Mental State Examination (MMSE). RESULTS: Our analysis showed significantly lower levels of IL-6 in CSF from patients with DLB than in CSF from patients with AD and control subjects without dementia. The IL-6 levels were also negatively correlated with MMSE and positively correlated with alpha-synuclein CSF levels. CONCLUSIONS: Our findings support previous studies by demonstrating a link between inflammatory processes and dementia progression and further strengthen the hypothesis that IL-6 is involved in dementia pathology and cognitive decline. PMID- 26434638 TI - Gas sorption in solid surfaces: a computational study using rigid and Einstein solid models. AB - The reactive Monte Carlo (RxMC) method was proposed to describe the sorption of gases in solid materials due to the chemical reaction A + B ? C. Two models were used to simulate the solid; the first model considered simulations with rigid particles in the solid whereas in the second model the particles were allowed to vibrate inside the solid with a given spring constant, i.e. an Einstein solid was used to simulate the substrate. In both models not only physisorption but also chemisorption of the fluid was observed. Sorption curves, at different spring constants, were simulated and it was noted that sorption was always enhanced with the Einstein solid model. Moreover, an inverse dependent function of the spring constant with the temperature was found. Finally, the second model might be used to explain the unusual sorption behavior observed in actual experimental reactions such as CO2 + Li2O ? Li2CO3. PMID- 26434639 TI - Solid phase polymerization of phenylenediamine toward a self-supported FeN(x)/C catalyst with high oxygen reduction activity. AB - Solid phase polymerization of phenylenediamine with a template toward a self supported FeNx/C catalyst was introduced. Using ZnO nanoparticles as the hard template could increase the surface area of the catalyst, thus the oxygen reduction activity was radically enhanced, to 21.9 A g(-1) at 0.80 V (vs. RHE) in acid medium. PMID- 26434640 TI - Synthesis and Structural Reassignment of Plakinidone. AB - In connection with its first synthesis, plakinidone was structurally revised to a five-membered lactone. The key evidence for the previous assignment of this natural product as a perlactone was proven to be a misinterpretation of the MS data because of unawareness of a facile air oxidation. The synthetic samples also allowed for detection of differences in (13)C NMR for diastereomers of remote stereogenic centers, along with the influence of the air oxidation on the optical rotation. PMID- 26434641 TI - Novel Cardioprotective Agents: Fact or Fiction? PMID- 26434642 TI - Interview with Ira Lurie. PMID- 26434643 TI - Polypharmacology Shakes Hands with Complex Aetiopathology. AB - Chronic diseases are due to deviations of fundamental physiological systems, with different pathologies being characterised by similar malfunctioning biological networks. The ensuing compensatory mechanisms may weaken the body's dynamic ability to respond to further insults and reduce the efficacy of conventional single target treatments. The multitarget, systemic, and prohomeostatic actions emerging for plant cannabinoids exemplify what might be needed for future medicines. Indeed, two combined cannabis extracts were approved as a single medicine (Sativex((r))), while pure cannabidiol, a multitarget cannabinoid, is emerging as a treatment for paediatric drug-resistant epilepsy. Using emerging cannabinoid medicines as an example, we revisit the concept of polypharmacology and describe a new empirical model, the 'therapeutic handshake', to predict efficacy/safety of compound combinations of either natural or synthetic origin. PMID- 26434645 TI - Bone response to collagenized xenografts of porcine origin (mp3((r)) ) and a bovine bone mineral grafting (4BONE(TM) XBM) grafts in tibia defects: experimental study in rabbits. AB - OBJECTIVES: This study aimed to carry out the evaluation of bone response of new bone formation to two different xenografts (bovine and porcine) biomaterials inserted in rabbit tibiae. MATERIALS AND METHODS: The study used a total of 20 male New Zealand albino rabbits. They received a total of 40 grafts in the proximal metaphyseal areas of both tibiae. Two biomaterials were evaluated: 20 porcine xenografts, as a bone granulate (OsteoBiol((r)) MP3((r)) ; Tecnoss srl, Giaveno, Italy), were placed in the proximal metaphyseal area of the right tibia, 20 anorganic bovine bone mineral grafting (4BONE(TM) XBM, MIS Implants Inc., BARLEV, Israel) were placed in the left tibia. Following graft insertion, the animals were sacrificed in two groups of 10 animals, after 1 and 4 months, respectively. For each group, biomaterials were analyzed: newly formed bone, residual graft materials and the connective tissue. Histomorphometric, EDX analysis and element mapping were performed at 1 and 4 months after graft insertion. RESULTS: At 4 months after treatment, the bone defects displayed radiological images that showed complete repair of osseous defects. Histomorphometric evaluation showed that for the porcine xenograft, the study averages for newly formed bone represented 84.23 +/- 2.9%, while bovine matrix was 79.34 +/- 2.1%. For residual graft material, the porcine biomaterial had 11.23 +/- 1.7% and the bovine graft 31.56 +/- 2.3%. Finally, the connective tissue for MP3 was 10.33 +/- 1.8%, while for the 4BONE(TM) XBM we obtained 14.34 +/- 2.9%. Element analysis revealed higher percentages of Ca (54 +/- 9%) and P (35 +/- 6%) in the group B than group A and control group (P < 0.05). CONCLUSIONS: Defects of a critical size in a rabbit tibia model can be sealed using a bovine porous biphasic calcium phosphate and MP3 material; this supports new bone formation, creates a bridge between borders, and facilitates bone ingrowth in both biomaterials. Furthermore, this study observed partial dissolution of the mineral phase of four bone graft and complete resorption of porcine MP3 biomaterial and its incorporation into the surrounding bone. Depending on clinical needs, each biomaterial could be useful in daily clinical practice. PMID- 26434644 TI - Pharmacological Modulation of the N-End Rule Pathway and Its Therapeutic Implications. AB - The N-end rule pathway is a proteolytic system in which single N-terminal amino acids of short-lived substrates determine their metabolic half-lives. Substrates of this pathway have been implicated in the pathogenesis of many diseases, including malignancies, neurodegeneration, and cardiovascular disorders. This review provides a comprehensive overview of current knowledge about the mechanism and functions of the N-end rule pathway. Pharmacological strategies for the modulation of target substrate degradation are also reviewed, with emphasis on their in vivo implications. Given the rapid advances in structural and biochemical understanding of the recognition components (N-recognins) of the N end rule pathway, small-molecule inhibitors and activating ligands of N-recognins emerge as therapeutic agents with novel mechanisms of action. PMID- 26434646 TI - Contraceptive care at the time of medical abortion: experiences of women and health professionals in a hospital or community sexual and reproductive health context. AB - OBJECTIVE: To examine experiences of contraceptive care from the perspective of health professionals and women seeking abortion, in the contexts of hospital gynaecology departments and a specialist sexual and reproductive health centre (SRHC). MATERIALS AND METHODS: We conducted in-depth semistructured interviews with 46 women who had received contraceptive care at the time of medical abortion (gestation <=9weeks) from one SRHC and two hospital gynaecology-department-based abortion clinics in Scotland. We also interviewed 25 health professionals (nurses and doctors) involved in abortion and contraceptive care at the same research sites. We analysed interview data thematically using an approach informed by the Framework method, and comparison was made between the two clinical contexts. RESULTS: Most women and health professionals felt that contraceptive counselling at abortion was acceptable and appropriate, if provided in a sensitive, nonjudgmental way. Participants framed contraceptive provision at abortion as significant primarily as a means of preventing subsequent unintended conceptions. Accounts of contraceptive decision making also presented tensions between the priorities of women and health professionals, around 'manoeuvring' women towards contraceptive uptake. Comparison between clinical contexts suggests that women's experiences may have been more positive in the SRHC setting. CONCLUSIONS: Whilst abortion may be a theoretically and practically convenient time to address contraception, it is by no means an easy time to do so and requires considerable effort and expertise to be managed effectively. Training for those providing contraceptive care at abortion should explicitly address potential conflicts between the priorities of health professionals and women seeking abortion. IMPLICATIONS: This paper offers unique insight into the detail of women and health professionals' experiences of addressing contraception at the time of medical abortion. The comparison between hospital and community SRHC contexts highlights best practise and areas for improvement relevant to a range of settings. PMID- 26434647 TI - Anti-Arthritic and Antiinflammatory Effects of the Traditional Uighur Formula Kursi Caper In Vivo. AB - Kursi Caper (KC) is a Uighur medicine based on caper which is widely used to treat arthritis and rheumatism, and preliminary studies in our laboratory showed that this traditional formula may possess potent antiinflammatory effects. This study confirms the antiinflammatory effect of KC in the adjuvant induced arthritis (AIA) model, the carrageenan and cotton-pellet induced granuloma rat models, and further investigates in vivo the mechanism of action by measuring relevant indicators of anti-arthritic activity. KC showed significant and dose dependent anti-arthritic and antiinflammatory effects, demonstrated by reduced paw edema and arthritic scores in all animal models. Histopathological examination showed that KC reduced levels of synovial inflammatory factors in AIA rats. The overproduction of TNF-alpha and IL-1beta was attenuated, and CAT, MDA and SOD levels were restored to normal in KC-treated rats. KC also significantly reduced LPS-induced proliferation of B lymphocytes and ConA induced proliferation of T lymphocytes in a dose-dependent manner. Flow cytometry showed that the high dose KC-treated group had a significantly decreased frequency of Th17 cells. This study indicates that KC can significantly attenuate arthritis and inflammation in rats by decreasing the levels of inflammatory cytokines, regulating oxidative stress, reducing lymphocyte proliferation and decreasing Th17. This supports the traditional use of KC as a potential modern therapeutic agent for the treatment of arthritis and related conditions. PMID- 26434648 TI - Preface for small-molecule activation: from biological principles to energy applications. part 2: small molecules related to the global nitrogen cycle. PMID- 26434649 TI - Centile estimation for a proportion response variable. AB - This paper introduces two general models for computing centiles when the response variable Y can take values between 0 and 1, inclusive of 0 or 1. The models developed are more flexible alternatives to the beta inflated distribution. The first proposed model employs a flexible four parameter logit skew Student t (logitSST) distribution to model the response variable Y on the unit interval (0, 1), excluding 0 and 1. This model is then extended to the inflated logitSST distribution for Y on the unit interval, including 1. The second model developed in this paper is a generalised Tobit model for Y on the unit interval, including 1. Applying these two models to (1-Y) rather than Y enables modelling of Y on the unit interval including 0 rather than 1. An application of the new models to real data shows that they can provide superior fits. PMID- 26434650 TI - The influence of various rehydration protocols on biomechanical properties of different acellular tissue matrices. AB - OBJECTIVES: This study evaluated the influence of different rehydration media and time periods on biomechanical and structural properties of different acellular collagen matrices (ACMs). MATERIALS AND METHODS: Specimens of three ACMs (mucoderm(r), Mucograft(r), Dynamatrix(r)) were rehydrated in saline solution (SS) or human blood for different time periods (5-60 min). ACMs under dry condition served as controls. Biomechanical properties of the ACMs after different rehydration periods were determined by means of tensile testing. ACMs' properties were further characterized using Fourier-transform-infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). RESULTS: At dry conditions, mucoderm(r) presented the highest tensile strength (TS) and Dynamatrix(r) showed the maximum elastic modulus (EM; p each <=0.036). Rehydration in SS and blood resulted in significant TS changes of mucoderm(r) (p each <=0.05). Concering EM, mucograft(r) showed significantly decreased values after rehydration in SS compared to Dynamatrix(r) and mucoderm(r) after 10 min (p each <=0.024). mucoderm(r) hydrated for 5 min in blood displayed nearly double TS and a significantly increased EM after 60 min (p = 0.043) compared to rehydration in SS. TS and EM values of Dynamatrix(r) and Mucograft(r) were not altered following rehydration in blood versus SS (p each >=0.053). FTIR analysis confirmed the recovery of the graft protein backbone with increased rehydration in all samples. DSC measurements revealed that tissue hydration decreased thermal stability of the investigated ACMs. CONCLUSION: Our findings demonstrated that the rehydration protocol affects the biomechanical properties of ACMs. CLINICAL RELEVANCE: Clinicians should be aware of altered handling and mechanical properties of ACMs following different rehydration protocols. PMID- 26434651 TI - Effects of periodontal therapy on serum lipid profile and proinflammatory cytokines in patients with hyperlipidemia: a randomized controlled trial. AB - OBJECTIVE: The aim of this study was to evaluate whether periodontal treatment in patients with periodontitis and hyperlipidemia may have any influence on plasma lipids and pro-inflammatory cytokine levels. MATERIAL AND METHODS: We randomly assigned 109 patients with hyperlipidemia and chronic periodontitis into group 1 (n = 55) and group 2 (n = 54). Patients in group 1 underwent a standard cycle of supragingival mechanical scaling and polishing. Patients in group 2 underwent the adjunctive full-mouth intensive removal of subgingival dental plaque biofilms with the use of scaling and root planning. Periodontal parameters, total cholesterol (TC), triglyceride (TRG), high-density lipoprotein cholesterol (HDL C), low-density lipoprotein cholesterol (LDL-C), tumor necrosis factor-alpha (TNF alpha), interleukin(IL)-1beta(IL-1beta), and IL-6 were evaluated before treatment and 2 and 6 months after treatment. RESULTS: Two and 6 months after treatment, TRG levels were significantly lower in group 2 than in group 1 (P < 0.05), and the levels of HDL-C were significantly higher (P < 0.05). Two and 6 months after therapy, the levels of TNF-alpha were significantly lower in group 2 than in group 1 (P < 0.05), as were the levels of IL-1beta (P < 0.001) and IL-6 (P < 0.001). CONCLUSIONS: Intensive periodontal treatment of participants with hyperlipidemia and chronic periodontitis improved serum lipid levels and decreased circulating pro-inflammatory cytokine levels. CLINICAL RELEVANCE: This study showed that intensive treatment of periodontitis results in an improvement in serum lipid levels and a decrease in serum proinflammatory cytokine levels in patients with periodontitis and hyperlipidemia. These findings may contribute to present knowledge that periodontal therapy may be beneficial for individuals with hyperlipidemia. PMID- 26434652 TI - Investigation of dental materials as skin simulants for forensic skin/skull/brain model impact testing. AB - PURPOSE: The purpose of this study was to measure the tear strength and hardness of four different dental silicones in comparison to that of porcine skin. METHODS: Specimens were prepared (n = 20/group) according to ASTM D624-00, using three hydrophilic vinyl polysiloxane impression materials, one duplication silicone, and fresh porcine skin. A universal testing machine was used to strain each test specimen until complete rupture and calculate its tear strength (kNm( 1)). Failure analysis was then conducted using a stereoscopic zoom light microscope, as well as a scanning electron microscope (SEM). A shore A-type durometer was used to measure the hardness of all specimens. RESULTS: The tear strength for the silicones ranged from 1.75 to 9.58 kNm(-1) and the pigskin from 3.65 to 56.40 kNm(-1). The mean shore hardness for the silicones ranged from 16.275 to 62.65DU and the pigskin had a mean shore hardness of 22.65DU, with p values <0.0125 (0.05/4). Failure analysis of the silicone materials showed the origin of failure being in the tension side of the specimens and typical failure patterns were observed. Examining the materials under a SEM revealed that materials with higher viscosity presented with a larger amount of filler particle content than silicones with low viscosity, with the duplication silicone having no filler content. CONCLUSION: Dental silicones are a good alternative for skin in studies that require a skin simulant. PMID- 26434653 TI - A fatal case of electrocution with unique forensic radiological postmortem findings. AB - PURPOSE: Documentation of forensic radiological observations in postmortem imaging of electrical injuries is not common yet and is less prevalent compared to other forms of burn injuries. However, electrical injuries have high morbidity and mortality. The objective of this case report was the visualization and evaluation of unique electrocution-related injuries by postmortem contrast and non-contrast enhanced imaging compared to a forensic autopsy. METHODS: Forensic imaging included whole-body postmortem computed tomography (PMCT), PMCT angiography (PMCTA), postmortem magnetic resonance tomography (PMMR), and PMMR angiography (PMMRA). Initial external inspection and subsequent autopsy were performed. RESULTS: Imaging results revealed intestinal mucosal pathologies, particularly of the gastric vascular integrity and remarkable rhabdomyolysis of the striated muscles of the extremities. Furthermore, PMCT and PMCTA revealed a hepatic lesion with perihepatic free fluid. The results from external inspection and autopsy correlated to the well-known pathologies of electrocution in the course of a high-voltage incident. CONCLUSION: Postmortem imaging visualized electrocution-related injuries and aided substantially in the medico-legal investigation. These findings, particularly of the rhabdomyolysis in magnetic resonance tomography, may support the future image interpretation of cases with electrical injuries-in the living and the deceased. PMID- 26434655 TI - Ultimate concerns in late modernity: Archer, Bourdieu and reflexivity. AB - Through a critique of Margaret Archer's theory of reflexivity, this paper explores the theoretical contribution of a Bourdieusian sociology of the subject for understanding social change. Archer's theory of reflexivity holds that conscious 'internal conversations' are the motor of society, central both to human subjectivity and to the 'reflexive imperative' of late modernity. This is established through critiques of Bourdieu, who is held to erase creativity and meaningful personal investments from subjectivity, and late modernity is depicted as a time when a 'situational logic of opportunity' renders embodied dispositions and the reproduction of symbolic advantages obsolete. Maintaining Archer's focus on 'ultimate concerns' in a context of social change, this paper argues that her theory of reflexivity is established through a narrow misreading and rejection of Bourdieu's work, which ultimately creates problems for her own approach. Archer's rejection of any pre-reflexive dimensions to subjectivity and social action leaves her unable to sociologically explain the genesis of 'ultimate concerns', and creates an empirically dubious narrative of the consequences of social change. Through a focus on Archer's concept of 'fractured reflexivity', the paper explores the theoretical necessity of habitus and illusio for understanding the social changes that Archer is grappling with. In late modernity, reflexivity is valorized just as the conditions for its successful operation are increasingly foreclosed, creating 'fractured reflexivity' emblematic of the complex contemporary interaction between habitus, illusio, and accelerating social change. PMID- 26434654 TI - Validation of adequate endogenous reference genes for reverse transcription-qPCR studies in human post-mortem brain tissue of SIDS cases. AB - Sudden infant death syndrome (SIDS) is the main cause of post-neonatal infant death in most developed countries. It is still of ambiguous etiology. Gene expression studies of relevant target genes using reverse transcription quantitative real-time PCR (RT-qPCR) in SIDS cases, and comparing them with age matched controls, could help in understanding the pathogenesis of SIDS. However, selecting inadequate reference genes used for normalization of the RT-qPCR gene expression data can give misleading results. The aim of the present study was to identify reference genes with the most stable expression in post-mortem brainstem samples of SIDS and control cases. Among the five candidate reference genes (GAPDH, GUSB, HMBS, SDHA, UBXN6) studied in both groups, SDHA and UBXN6 were identified as the most stable. To further demonstrate the importance of using validated genes for RT-qPCR data normalization, the expression of a potential gene of interest in SIDS, the RPS27A gene, was evaluated using validated versus non-validated reference genes for normalization. This gene encodes the ubiquitin protein that has been shown in other pathological studies to be induced in SIDS. Using the identified most stable genes for normalization of RPS27A gene expression data revealed, as expected, a statistically significant up-regulation in SIDS as compared to the controls. However, using a single unstable reference gene for normalization resulted in no significant differences in transcript abundance of RPS27A between SIDS and the controls. This emphasizes the need for validation of the suitability of reference genes used in a given tissue type under certain experimental conditions. PMID- 26434656 TI - Silica Nanowires Templated by Amyloid-like Fibrils. AB - Many peptides self-assemble to form amyloid fibrils. We previously explored the sequence propensity to form amyloid using variants of a designed peptide with sequence KFFEAAAKKFFE. These variant peptides form highly stable amyloid fibrils with varied lateral assembly and are ideal to template further assembly of non proteinaceous material. Herein, we show that the fibrils formed by peptide variants can be coated with a layer of silica to produce silica nanowires using tetraethyl-orthosilicate. The resulting nanowires were characterized using electron microscopy (TEM), X-ray fiber diffraction, FTIR and cross-section EM to reveal a nanostructure with peptidic core. Lysine residues play a role in templating the formation of silica on the fibril surface and, using this library of peptides, we have explored the contributions of lysine as well as arginine to silica templating, and find that sequence plays an important role in determining the physical nature and structure of the resulting nanowires. PMID- 26434657 TI - Dermoscopic observation of acquired digital fibrokeratoma developed on the dorsum of the fourth left toe. PMID- 26434658 TI - Left Ventricular Hypertrophy Phenotype in Childhood-Onset Essential Hypertension. AB - The aim of this study was to determine the risk factors associated with left ventricular (LV) hypertrophy (LVH) among 89 untreated children with primary hypertension. Clinic hypertension was confirmed by 24-hour ambulatory blood pressure (BP) monitoring. LV mass (LVM) index was calculated as LVM (g)/height (m)(2.7) and LVH was defined as LVM index >95th percentile. Children with (n=32) and without (n=57) LVH were compared. Both obesity and systolic BP were independently associated with LVH, with a higher contribution by body mass index. Obesity contributed significantly, with a nearly nine-fold increased risk of LVH. There was evidence of effect modification by the presence or absence of obesity on the relationship between systolic BP and LVH, whereby the relationship existed mainly in nonobese rather than obese children. Hence, to achieve reversal of LVH, clinicians should take into account both BP control and weight management. PMID- 26434660 TI - Zebrafish epiboly: Spreading thin over the yolk. AB - Tissue thinning and spreading, a morphogenetic movement termed epiboly, is used widely during animal development. In zebrafish, epiboly is a prominent cell movement during gastrulation, whereby a squamous epithelium (the enveloping layer), a multi-layer of loosely packed cells (the deep cells), and a yolk nuclear syncytium (the yolk syncytial layer) undergo coordinated expansion to engulf the yolk and close the blastopore. Elucidating the mechanisms that underlie epiboly is important not only for understanding animal development in general, but also for providing insights into fundamental cell behaviors including cell intercalation, cell adhesion, cell signaling, and epithelial morphogenesis. Here, recent work is reviewed with a focus on findings that advance our understanding of (1) the role of actomyosin motors in the yolk cell to drive epiboly, (2) the mechanisms that underlie the spreading of the epithelial enveloping layer, and (3) the regulation of deep cell movements by E cadherin based adhesion. A discussion of how these new insights add to the current view of epiboly and future prospects is also presented. Overall, the study of zebrafish epiboly can provide general and broadly applicable insights into the genetic, molecular, and cellular control of morphogenesis. PMID- 26434659 TI - Characterization of Mycobacterium smegmatis sigF mutant and its regulon: overexpression of SigF antagonist (MSMEG_1803) in M. smegmatis mimics sigF mutant phenotype, loss of pigmentation, and sensitivity to oxidative stress. AB - In Mycobacterium smegmatis, sigF is widely expressed during different growth stages and plays role in adaptation to stationary phase and oxidative stress. Using a sigF deletion mutant of M. smegmatis mc(2) 155, we demonstrate that SigF is not essential for growth of bacterium. Deletion of sigF results in loss of carotenoid pigmentation which rendered increased susceptibility to H2 O2 induced oxidative stress in M. smegmatis. SigF modulates the cell surface architecture and lipid biosynthesis extending the repertoire of SigF function in this species. M. smegmatis SigF regulon included variety of genes expressed during exponential and stationary phases of growth and those responsible for oxidative stress, lipid biosynthesis, energy, and central intermediary metabolism. Furthermore, we report the identification of a SigF antagonist, an anti-sigma factor (RsbW), which upon overexpression in M. smegmatis wild type strain produced a phenotype similar to M. smegmatis mc(2) 155 DeltasigF strain. The SigF-anti-SigF interaction is duly validated using bacterial two-hybrid and pull down assays. In addition, anti sigma factor antagonists, RsfA and RsfB were identified and their interactions with anti-sigma factor were experimentally validated. Identification of these proteins will help decode regulatory circuit of this alternate sigma factor. PMID- 26434661 TI - Semi-automatic outlining of levator hiatus. AB - OBJECTIVE: To create a semi-automated outlining tool for the levator hiatus, to reduce interobserver variability and and speed up analysis. METHODS: The proposed automated hiatus segmentation (AHS) algorithm takes a C-plane image, in the plane of minimal hiatal dimensions, and manually defined vertical hiatal limits as input. The AHS then creates an initial outline by fitting predefined templates on an intensity-invariant edge map, which is further refined using the B-spline explicit active surfaces framework. The AHS was tested using 91 representative C plane images. Reference hiatal outlines were obtained manually and compared with the AHS outlines by three independent observers. The mean absolute distance (MAD), Hausdorff distance and Dice and Jaccard coefficients were used to quantify segmentation accuracy. Each of these metrics was calculated both for computer observer differences (COD) and for interobserver differences. The Williams index was used to test the null hypothesis that the automated method would agree with the operators at least as well as the operators agreed with each other. Agreement between the two methods was assessed using the intraclass correlation coefficient (ICC) and Bland-Altman plots. RESULTS: The AHS contours matched well with the manual ones (median COD, 2.10 (interquartile range (IQR), 1.54) mm for MAD). The Williams index was greater than or close to 1 for all quality metrics, indicating that the algorithm performed at least as well as did the manual references in terms of interrater variability. The interobserver differences using each of the metrics were significantly lower, and a higher ICC was achieved (0.93), when obtaining outlines using the AHS compared with manually. The Bland-Altman plots showed negligible bias between the two methods. Using the AHS took a median time of 7.07 (IQR, 3.49) s, while manual outlining took 21.31 (IQR, 5.43) s, thus being almost three-fold faster. Using the AHS, in general, the hiatus could be outlined completely using only three points, two for initialization and one for manual adjustment. CONCLUSIONS: We present a method for tracing the levator hiatal outline with minimal user input. The AHS is fast, robust and reliable and improves interrater agreement. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26434662 TI - Thiamethoxam induces oxidative stress and antioxidant response in zebrafish (Danio Rerio) livers. AB - Thiamethoxam, a second-generation neonicotinoid insecticide, was found to be toxic to nontarget aquatic organisms. The purpose of this study was to investigate the toxicity of thiamethoxam (0.30, 1.25, and 5.00 mg/L) on zebrafish (Danio rerio) livers at the 7th, 14th, 21st, and 28th days. The reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), glutathione-s transferase (GST), malondialdehyde (MDA) content, and DNA damage were used to evaluate the toxic effects of thiamethoxam on zebrafish. Compared to control groups, ROS levels were ascended in the exposure period; SOD and CAT activities were dramatically increased during early exposure and then inhibited. GST activity only increased on days 28. MDA content was slightly elevated on days 21 and 28. Additionally, a clear dose-response relationship was found for DNA damage. In conclusion, thiamethoxam could induce oxidative stress and DNA damage on the exposed zebrafish. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 2006-2015, 2016. PMID- 26434663 TI - Cytogenetic and oxidative status of human lymphocytes after exposure to clinically relevant concentrations of antimalarial drugs atovaquone and proguanil hydrochloride in vitro. AB - Atovaquone (ATO) and proguanil hydrochloride (PROG) is the fixed combination for the prevention and treatment of Plasmodium falciparum malaria. As safe and effective antimalarial drugs are needed in both the treatment and the prophylaxis of malaria, this study was performed to investigate their possible cyto/genotoxic potential towards human lymphocytes and the possible mechanism responsible for it. Two different concentrations of ATO and PROG were used with and without S9 metabolic activation. The concentrations used were those found in human plasma when a fixed-dose combination of ATO and PROG was used: 2950/130 ng/mL after prophylactic treatment and 11 800/520 ng/mL after treatment of malaria, respectively. Possible cellular and DNA-damaging effects were evaluated by cell viability and alkaline comet assays, while oxidative stress potential was evaluated by formamidopyrimidine-DNA glycosylase (Fpg)-modified comet assay, in addition to measuring malondialdehyde and glutathione levels. According to our results, the ATO/PROG combination displayed only weak cyto/genotoxic potential towards human lymphocytes with no impact on oxidative stress parameters, suggesting that oxidative stress is not implicated in their mechanism of action towards human lymphocytes. Given that the key portion of the damaging effects was induced after S9 metabolic activation, it is to presume that the principal metabolite of PROG, cycloguanil, had the greatest impact. The obtained results indicate that the ATO/PROG combination is relatively safe for the consumption from the aspect of cyto/genotoxicity, especially if used for prophylactic treatment. Nevertheless, further cytogenetic research and regular patient monitoring are needed to minimize the risk of adverse events especially among frequent travellers. PMID- 26434664 TI - Prioritisation of citizen-centric information for disaster response. AB - In the aftermath of a disaster event, and in the absence of trained professionals, many responsibilities are assumed by uninjured citizens who are willing and able to help, such as care of the injured or search and rescue. These citizens are constrained by communications and logistics problems but are less equipped to deal with them as most often they are cut off from any coordinated assistance. The method proposed in this study would increase the survivability of those injured or trapped by a disaster event by providing a facility to allow citizens to coordinate and share information among themselves. This is facilitated by the proposed deployment and the autonomous management of an ad hoc infrastructure that liaises directly with survivors without central control. Furthermore, as energy concerns present critical constraints to these networks, this research proposes a system of categorising information elements within the network to ensure efficient information exchange. PMID- 26434665 TI - Evaluation of immunogenicity of LY2963016 insulin glargine compared with Lantus(r) insulin glargine in patients with type 1 or type 2 diabetes mellitus. AB - AIMS: To compare the immunogenicity profiles and the potential effects on clinical outcomes of LY2963016 insulin glargine (LY IGlar) and Lantus(r) insulin glargine (IGlar), products with identical primary amino acid sequences, in patients with type 1 or type 2 diabetes mellitus (T1DM or T2DM). METHODS: To assess immunogenicity, anti-insulin glargine antibodies (measured as percent binding) were compared between treatments in 52-week (open-label) and 24-week (double-blind) randomized studies in total study populations of patients with T1DM (N = 535) and T2DM (N = 756), respectively, and two subgroups of patients with T2DM: insulin-naive patients and those reporting prestudy IGlar treatment (prior IGlar). Relationships between insulin antibody levels and clinical outcomes were assessed using analysis of covariance and partial correlations. Insulin antibody levels were assessed using Wilcoxon rank sum. Treatment comparisons for treatment-emergent antibody response (TEAR) and incidence of detectable antibodies were analysed using Fisher's exact test. RESULTS: No significant treatment differences were observed for insulin antibody levels, incidence of detectable anti-insulin glargine antibodies, or incidence of TEAR [overall and endpoint, by last-observation-carried-forward (LOCF)] in patients with T1DM or patients with T2DM, including the insulin-naive subgroup. A statistically significant difference was noted in the overall incidence of detectable antibodies but not at endpoint (LOCF) nor in TEAR for the prior IGlar subgroup of patients with T2DM. Insulin antibody levels were low (<5%) in both treatment groups. Insulin antibody levels or developing TEAR was not associated with clinical outcomes. CONCLUSIONS: LY IGlar and IGlar have similar immunogenicity profiles; anti-insulin glargine antibody levels were low for both treatments, with no observed effect on efficacy and safety outcomes. PMID- 26434666 TI - Proteomic responses of human intestinal Caco-2 cells exposed to silver nanoparticles and ionic silver. AB - Even although quite a number of studies have been performed so far to demonstrate nanoparticle-specific effects of substances in living systems, clear evidence of these effects is still under debate. The present study was designed as a comparative proteomic analysis of human intestinal cells exposed to a commercial silver nanoparticle reference material and ions from AgNO3. A two-dimensional gel electrophoresis/MALDI mass spectrometry (MS)-based proteomic analysis was conducted after 24-h incubation of differentiated Caco-2 cells with non-cytotoxic and low cytotoxic silver concentrations (2.5 and 25 ug ml(-1) nanosilver, 0.5 and 5 ug ml(-1) AgNO3). Out of an overall number of 316 protein spots differentially expressed at a fold change of >= 1.4 or <= -1.4 in all treatments, 169 proteins could be identified. In total, 231 spots were specifically deregulated in particle-treated groups compared with 41 spots, which were limited to AgNO3 treatments. Forty-four spots (14 %) were commonly deregulated by both types of treatment. A considerable fraction of the proteins differentially expressed after treatment with nanoparticles is related to protein folding, synthesis or modification of proteins as well as cellular assembly and organization. Overlays of networks obtained for particulate and ionic treatments showed matches, indicating common mechanisms of combined particle and ionic silver exposure and exclusive ionic silver treatment. However, proteomic responses of Caco-2 cells treated with higher concentrations of silver species also showed some differences, for example regarding proteins related to fatty acid and energy metabolism, suggesting an induction of also some different molecular mechanisms for particle exposure and ionic treatment. PMID- 26434667 TI - Porcine circovirus type 2 detection in in vitro produced porcine blastocysts after virus sperm exposure. AB - This study was aimed at assessing the capability of semen experimentally infected with porcine circovirus type 2 (PCV2) to produce porcine blastocysts PCR positive for PCV2. Embryos were obtained from in vitro maturation (IVM) and in vitro fertilization (IVF) of porcine oocytes or by parthenogenesis. Sperm suspension was exposed to PCV2b and utilized for IVF. PCV2 spiked semen did not reveal any reduction in sperm viability or motility but its ability to produce infected blastocysts was irrelevant as only one out of 15 blastocysts obtained by IVF were PCV2b; however two blastocysts were PCV2a positive. Furthermore, the presence of PCV2 was demonstrated also in embryos obtained by parthenogenesis (one out of 17 was PCV2b and one PCV2a positive). Even if PCV2 firmly attaches to the surface of spermatozoa, experimentally spiked sperm were not effective in infecting oocytes during IVF and in producing PCR positive embryos. The infected blastocysts we obtained derived most probably from infected oocytes recovered at the abattoir. PMID- 26434668 TI - Zoledronic acid suppresses callus remodeling but enhances callus strength in an osteoporotic rat model of fracture healing. AB - MINI-ABSTRACT: In this study, we demonstrated that the use of zoledronic acid does not impair fracture healing, but results in superior callus size and resistance at the fracture site, which could be the consequence of a lower rate of bone turnover due to its anti-catabolic effect. OBJECTIVE: To investigate the effect of inhibition of bone remodeling by the bisphosphonate, zoledronic acid, on callus properties in an osteoporotic rat model of fracture healing. METHODS: Ovariectomized (OVX) rats were randomly divided into four treatment groups (n=24 per group): saline control (CNT); and three systemic zoledronic acid-injected groups (0.1mg/kg), administered 1 day (ZOLD1), 1 week (ZOLW1), and 2 weeks (ZOLW2) after fracture. Rats were killed at either 6 or 12 weeks postoperatively. Postmortem analyses included radiography, microcomputed tomography, histology, histomorphometry, biomechanical tests, and nanoindentation tests. RESULTS: Treatment with zoledronic acid led to a significant increase in trabecular bone volume within the callus, as well as in callus resistance, compared to those in the saline control rats; delayed administration (ZOLW2) reduced intrinsic material properties, including ultimate stress and elastic modulus, and microarchitecture parameters, including bone volume/total volume (BV/TV), trabecular thickness (Tb.Th), and connectivity density (Conn.D), compared with ZOLD1 at 12 weeks after surgery. OVX had a negative effect on the progression of endochondral ossification at 6 weeks. Zoledronic acid administration at an early stage following fracture may bind to early callus, and thus not affect subsequent callus formation and endochondral ossification, while delayed administration (ZOLW2) mildly suppresses bony callus remodeling. CONCLUSION: The superior results obtained with zoledronic acid (ZOLD1, ZOLW1, and ZOLW2) compared to CNT in terms of callus size and resistance could be the consequence of a lower rate of bone turnover at the fracture site due to the anti-catabolic effect of zoledronic acid. Mild suppression of callus remodeling by delayed administration did not impair the initial phase of the fracture healing process. PMID- 26434669 TI - Retrospective comparison of laparoscopic versus open radical hysterectomy after neoadjuvant chemotherapy for locally advanced cervical cancer. AB - OBJECTIVE: To compare outcomes after laparoscopic radical hysterectomy (LRH) and abdominal radical hysterectomy (ARH) for locally advanced cervical cancer (LACC)after neoadjuvant chemotherapy (NACT). METHODS: In a retrospective study, data were analyzed from patients with FIGO stage IB2-IIB cervical cancer who underwent LRH or ARH after NACT at Union Hospital, Wuhan, China, between January 2007 and August 2013.Perioperative outcomes and survival were compared. RESULTS: Overall, 99 patients who underwent LRH and 30 who underwent ARH were included. Compared with ARH patients, LRH patients presented with lower-stage tumors (P=0.013). Median operative time, number of harvested lymph nodes, and rate of positive surgical margins did not differ significantly between the groups, but LRH resulted in less blood loss (median 300mL [range 20-1100] vs 375mL [100 1200]; P=0.027). There were two intraoperative complications and 23 postoperative complications in the LRH group, and 12 postoperative complications in the ARH group. No conversions occurred in the LRH group; all complications were managed without severe sequelae. As of March 2014, recurrence had been noted for 6(6.1%) LRH patients and 2 (6.7%) ARH patients. CONCLUSION: LRH was similar to ARH in terms of safety, feasibility, and morbidity, with less blood loss among women with LACC undergoing NACT. Long-term outcomes need to be documented. PMID- 26434670 TI - Organization and evaluation of a pilot cervical cancer screening program in Morocco. AB - OBJECTIVE: To evaluate a pilot program for early detection of cervical cancer using visual inspection with acetic acid (VIA) and the loop electrosurgical excision procedure (LEEP) in one region of Morocco. METHODS: A descriptive analysis of the screening outcome measures of 43 participating primary care units and one reference center for LEEP was conducted in Meknes-Tafilalet between January 1, 2011, and December 31, 2013. Data on the number of participants, VIA results, colposcopy, and treatment were used in analyses. RESULTS: Of the 308 197 women in the target age group (30-49 years), 18 586 (6.0%) were screened by VIA. Positive screening test results were recorded for 1628 (8.8%) women, of whom 1144 (70.3%) received diagnostic confirmation by colposcopy. Of the 87 (7.6%) women with cervical intraepithelial neoplasia, only 16 (18.4%) underwent LEEP; three cases of invasive cervical cancer were diagnosed. CONCLUSION: Issues with implementation of the screening program were found, including low compliance and a low treatment rate of cervical intraepithelial neoplasia by LEEP. By contrast, high rates of colposcopy referral were observed. Screen-and-treat by ablative methods (e.g. thermocoagulation) should be considered to increase treatment rates at national scale-up. PMID- 26434671 TI - Socio-structural and behavioral risk factors associated with trafficked history of female bar/spa entertainers in the sex trade in the Philippines. AB - OBJECTIVE: To explore factors associated with trafficking (deceptive/coercive entry to sex trade) among female bar/spa entertainers who traded sex in the Philippines. METHOD: Female bar/spa entertainers who traded sex in the past 6months were recruited from 25bar/spa venues in Metro Manila (April 2009-January 2010) and assessed via cross-sectional survey data collection for HIV-risk related socio-structural factors associated with deceptive/coercive entry into the sex trade. The study employed hierarchical linear modeling. RESULTS: Of 166bar/spa entertainers assessed, 19 (11.4%) reported being deceived/coerced (i.e. trafficked) into their first jobs. Trafficking history was independently associated with current drug use (adjusted odds ratio [AOR] 2.05; 95% confidence interval [CI] 1.00-3.97) decreased availability of condoms at venues for entertainers (AOR 0.18; 95% CI 0.05-0.71) and, conversely, increased peer support for practicing safer sex behaviors (AOR 3.08; 95% CI 1.63-5.09). Those deceived/coerced into their positions were more likely than non-trafficked women to have been recruited by an agency who came to their rural province (AOR 12.07; 95% CI 1.77-82.25) as opposed to getting the job from advertisement (AOR 0.10; 95% CI 0.02-0.65) or a friend/acquaintance (AOR 0.02; 95% CI 0.00-0.48). CONCLUSION: The findings have implications for designing interventions to prevent and target trafficked women in the Philippines who may be more vulnerable to substance use and, potentially, HIV infection. PMID- 26434672 TI - Emil Kraepelin's concepts of the phenomenology and physiology of sleep: The first systematic description of chronotypes. AB - Emil Kraepelin is considered one of the most influential psychiatrists ever. His research on sleep, however, has received little attention to date. Therefore, Kraepelin's published work was reviewed, statements on the topic "sleep" identified, historically contextualized and compared with current knowledge. His assumptions on the "physiology of sleep" are rather speculative and not substantiated by own research. The opposite is true for his findings on the "phenomenology of sleep". For example, his results on sleep depth and sleep stages are not only in overall good agreement with current concepts, but also based on sleep studies. Of special relevance are his findings on chronotypes: Based on empirical clinical studies, neuropsychological experiments and sleep studies, Kraepelin systematically described a morning and evening disposition and intermediate types on the basis of the maximum physical capacity, cognitive ability and alertness/sleepiness during the day as well as sleeping habits. In fact, this concept is basically still valid and these aspects are being captured in morningness-eveningness scales. Our findings challenge the common notion that Nathaniel Kleitman was the first to systematically describe the morningness eveningness dimension. Overall, we deem Kraepelin's contributions to sleep research, compiled here for the first time, well worth being acknowledged by modern sleep research. PMID- 26434673 TI - A systematic review and meta-analysis of randomized controlled trials of cognitive behavior therapy for insomnia (CBT-I) in cancer survivors. AB - This review examined the efficacy of cognitive behavior therapy for insomnia (CBT I) in people diagnosed with cancer. Studies were identified through November 2014 using multiple databases, clinical trial records, and bibliography searches. Inclusion was limited to randomized controlled trials of CBT-I conducted in individuals with a cancer diagnosis who had clinically relevant insomnia. The primary outcome variable was sleep efficiency (SE) as measured by sleep diary. Eight studies including data from 752 cancer survivors met inclusion criteria. CBT-I resulted in a 15.5% improvement in SE relative to control conditions (6.1%) from pre- to post-intervention, with a medium effect size (ES: d = 0.53). Overall, sleep latency was reduced by 22 min with an ES of d = 0.43, compared to a reduction of 8 min in the control conditions. Wake after sleep onset was reduced by 30 min with an ES of d = 0.41, compared to 13 min in the control conditions. Large effect sizes were observed for self-reported insomnia severity (d = 0.77) for those patients who received CBT-I, representing a clinically relevant eight point reduction. Effects were durable up to 6 mo. The quality of the evidence supports a strong recommendation for the use of CBT-I among cancer survivors. PMID- 26434674 TI - The etiology of delayed sleep phase disorder. AB - According to classification manuals for sleep disorders, nine disorders are directly related to biological clock timing misalignments. Of all, delayed sleep phase disorder (DSPD) is the most commonly diagnosed, predominantly affecting adolescents, young adults, and insomnia patients. It is a persistent inability to fall asleep at earlier, more desirable and socially conventional times, coupled with extreme difficulty awakening in the morning. Considerable evidence shows a delay in the circadian clock to be associated with DSPD. Therefore, treatments have mainly focused on advancing the biological clock and sleep timing through pharmacotherapy, phototherapy and behavioral therapies. The clinical evidence indicates that these treatments are efficacious, at least in the short term. However, follow up studies show frequent patient relapse, leading researchers to speculate that alternative etiologies may be contributing to sleep and circadian clock delays in DSPD. The aim of the present paper is to review and collate current literature related to DSPD etiology in order to outline gaps in current knowledge and suggest future research. PMID- 26434678 TI - Phonon transport control by nanoarchitecture including epitaxial Ge nanodots for Si-based thermoelectric materials. AB - Phonon transport in Si films was controlled using epitaxially-grown ultrasmall Ge nanodots (NDs) with ultrahigh density for the purpose of developing Si-based thermoelectric materials. The Si/Ge ND stacked structures, which were formed by the ultrathin SiO2 film technique, exhibited lower thermal conductivities than those of the conventional nanostructured SiGe bulk alloys, despite the stacked structures having a smaller Ge fraction. This came from the large thermal resistance caused by phonon scattering at the Si/Ge ND interfaces. The phonon scattering can be controlled by the Ge ND structure, which was independent of Si layer structure for carrier transport. These results demonstrate the effectiveness of ultrasmall epitaxial Ge NDs as phonon scattering sources, opening up a route for the realisation of Si-based thermoelectric materials. PMID- 26434679 TI - Control of a chemical reaction (photodegradation of the p3ht polymer) with nonlocal dielectric environments. AB - Proximity to metallic surfaces, plasmonic structures, cavities and other inhomogeneous dielectric environments is known to control spontaneous emission, energy transfer, scattering, and many other phenomena of practical importance. The aim of the present study was to demonstrate that, in spirit of the Marcus theory, the rates of chemical reactions can, too, be influenced by nonlocal dielectric environments, such as metallic films and metal/dielectric bilayer or multilayer structures. We have experimentally shown that metallic, composite metal/dielectric substrates can, indeed, control ordering as well as photodegradation of thin poly-3-hexylthiophene (p3ht) films. In many particular experiments, p3ht films were separated from metal by a dielectric spacer, excluding conventional catalysis facilitated by metals and making modification of the nonlocal dielectric environment a plausible explanation for the observed phenomena. This first step toward understanding of a complex relationship between chemical reactions and nonlocal dielectric environments is to be followed by the theory development and a broader scope of thorough experimental studies. PMID- 26434680 TI - The importance of spatial heterogeneity and self-restraint on mutualism stability - a quantitative review. AB - Understanding the factors that enable mutualisms to evolve and to subsequently remain stable over time, is essential to fully understand patterns of global biodiversity and for evidence based conservation policy. Theoretically, spatial heterogeneity of mutualists, through increased likelihood of fidelity between cooperative partners in structured populations, and 'self-restraint' of symbionts, due to selection against high levels of virulence leading to short term host overexploitation, will result in either a positive correlation between the reproductive success of both mutualists prior to the total exploitation of any host resource or no correlation after any host resource has been fully exploited. A quantitative review by meta-analysis on the results of 96 studies from 35 papers, showed no evidence of a significant fitness correlation between mutualists across a range of systems that captured much taxonomic diversity. However, when the data were split according to four categories of host: 1) cnidarian corals, 2) woody plants, 3) herbaceous plants, and 4) insects, a significantly positive effect in corals was revealed. The trends for the remaining three categories did not significantly differ to zero. Our results suggest that stability in mutualisms requires alternative processes, or mechanisms in addition to, spatial heterogeneity of hosts and/or 'self-restraint' of symbionts. PMID- 26434681 TI - Azobenzene Modified Imidacloprid Derivatives as Photoswitchable Insecticides: Steering Molecular Activity in a Controllable Manner. AB - Incorporating the photoisomerizable azobenzene into imidacloprid produced a photoswitchable insecticidal molecule as the first neonicotinoid example of remote control insecticide performance with spatiotemporal resolution. The designed photoswitchable insecticides showed distinguishable activity against Musca both in vivo and in vitro upon irradiation. Molecular docking study further suggested the binding difference of the two photoisomers. The generation of these photomediated insecticides provides novel insight into the insecticidal activity facilitating further investigation on the functions of insect nicotinic acetylcholine receptors and opens a novel way to control and study insect behavior on insecticide poisoning using light. PMID- 26434684 TI - Blood-brain barrier disruption during spontaneous canine visceral leishmaniasis. AB - Visceral leishmaniasis is a complex disease caused by Leishmania infantum, and in dogs, besides the classical symptoms, there are descriptions of inflammatory alterations in the brain. Brain inflammation is a strictly controlled process, and as the brain counts on the efficiency of the blood-brain barrier (BBB), we aimed to assess BBB integrity in dogs with spontaneous visceral leishmaniasis. Therefore, we evaluated markers in the cerebrospinal fluid (CSF) and in brain tissue related to BBB disruption and brain inflammation. Elevated albumin quota revealed BBB breakdown, corroborated by increased concentrations of anti Leishmania antibodies in the CSF. In the brain, albumin and IgG staining formed halos around blood vessels, a classical indicator of BBB leakage. Soluble IgG was also detected in the choroid plexus and ependyma, and in these structures, IgG stained random resident cells. IgG(+) cells and Fcgamma-RI(+) cells were identified in the choroid plexus, ependyma and perivascular in the brain parenchyma. The data support the occurrence of BBB disruption in dogs with spontaneous visceral leishmaniasis, and IgG as a key molecule that is capable of initiating and/or maintaining the inflammatory stimuli in the nervous milieu and the CSF as an important disseminator of inflammatory stimuli within the CNS. PMID- 26434682 TI - Genetic variants in PLCB4/PLCB1 as susceptibility loci for coronary artery aneurysm formation in Kawasaki disease in Han Chinese in Taiwan. AB - Kawasaki disease (KD) is an acute, inflammatory, and self-limited vasculitis affecting infants and young children. Coronary artery aneurysm (CAA) formation is the major complication of KD and the leading cause of acquired cardiovascular disease among children. To identify susceptible loci that might predispose patients with KD to CAA formation, a genome-wide association screen was performed in a Taiwanese KD cohort. Patients with both KD and CAA had longer fever duration and delayed intravenous immunoglobulin treatment time. After adjusting for these factors, 100 susceptibility loci were identified. Four genes were identified from a single cluster of 35 using the Ingenuity Pathway Analysis (IPA) Knowledge Base. Silencing KCNQ5, PLCB1, PLCB4, and PLCL1 inhibited the effect of lipopolysaccharide-induced endothelial cell inflammation with varying degrees of proinflammatory cytokine expression. PLCB1 showed the most significant inhibition. Endothelial cell inflammation was also inhibited by using a phospholipase C (PLC) inhibitor. The single nucleotide polymorphism rs6140791 was identified between PLCB4 and PLCB1. Plasma PLC levels were higher in patients with KD and CC+CG rs6140791genotypes, and these genotypes were more prevalent in patients with KD who also had CAA. Our results suggest that polymorphism of the PLCB4/B1 genes might be involved in the CAA pathogenesis of KD. PMID- 26434683 TI - Prenatal ethanol exposure increases osteoarthritis susceptibility in female rat offspring by programming a low-functioning IGF-1 signaling pathway. AB - Epidemiological evidence indicates that osteoarthritis (OA) and prenatal ethanol exposure (PEE) are both associated with low birth weight but possible causal interrelationships have not been investigated. To investigate the effects of PEE on the susceptibility to OA in adult rats that experienced intrauterine growth retardation (IUGR), and to explore potential intrauterine mechanisms, we established the rat model of IUGR by PEE and dexamethasone, and the female fetus and 24-week-old adult offspring subjected to strenuous running for 6 weeks were sacrificed. Knee joints were collected from fetuses and adult offspring for histochemistry, immunohistochemistry and qPCR assays. Histological analyses and the Mankin score revealed increased cartilage destruction and accelerated OA progression in adult offspring from the PEE group compared to the control group. Immunohistochemistry showed reduced expression of insulin-like growth factor-1 (IGF-1) signaling pathway components. Furthermore, fetuses in the PEE group experienced IUGR but exhibited a higher postnatal growth rate. The expression of many IGF-1 signaling components was downregulated, which coincided with reduced amounts of type II collagen in the epiphyseal cartilage of fetuses in the PEE group. These results suggest that PEE enhances the susceptibility to OA in female adult rat offspring by down-regulating IGF-1 signaling and retarding articular cartilage development. PMID- 26434685 TI - Total lesion glycolysis by 18F-FDG PET/CT is independent prognostic factor in patients with advanced non-small cell lung cancer. AB - BACKGROUND AND AIMS: To determine whether the primary tumor SUVmax and total lesion glycolysis (TLG) measured on 18 F-FDG PET/CT have prognostic significance in patients with non-small-cell lung cancer (NSCLC). METHODS: A retrospective review identified 142 patients NSCLC who underwent 18 F-FDG PET/CT at the time of diagnosis. The affect of the SUVmax and TLG of the primary tumor on survival were examined. RESULTS: Total 142 patients were included the study. Thirty-two patients were at early stage (stage I and II) and 110 patients were at advanced stage (stage III and IV). Both early and advanced stage patients were divided into two groups according to SUVmax 12 as low and high SUVmax groups. Overall survival (OS) of the low SUVmax group was significantly longer than higher SUVmax group for early-stage patients (35.8 +/- 15.3 vs 21.8 +/- 13.3, P = 0.013). But there was no differences in advanced stage patients for OS (16.1 +/- 14.8 vs 17.0 +/- 15.1, P = 0.862). Primary lesion TLG of the 99 patients were calculated. For advanced stage, the patients with the lower TLG had significantly longer survival time (P < 0.001). In multivariate analysis only TLG remained significant predictor of OS in advanced stage patients (HR and 95% confidence interval = 7.716 and 1.664-4.342, respectively). CONCLUSION: High SUVmax is related to poor OS in patients with surgically resected early stage (stage I and II) NSCLC, but it is not an independent prognostic factor. TLG is a prognostic measurement and it is independent predictor factor of survival for advanced stage NSCLC. PMID- 26434687 TI - Visible-Light Photoreduction of CO2 in a Metal-Organic Framework: Boosting Electron-Hole Separation via Electron Trap States. AB - It is highly desirable to convert CO2 to valuable fuels or chemicals by means of solar energy, which requires CO2 enrichment around photocatalysts from the atmosphere. Here we demonstrate that a porphyrin-involved metal-organic framework (MOF), PCN-222, can selectively capture and further photoreduce CO2 with high efficiency under visible-light irradiation. Mechanistic information gleaned from ultrafast transient absorption spectroscopy (combined with time-resolved photoluminescence spectroscopy) has elucidated the relationship between the photocatalytic activity and the electron-hole separation efficiency. The presence of a deep electron trap state in PCN-222 effectively inhibits the detrimental, radiative electron-hole recombination. As a direct result, PCN-222 significantly enhances photocatalytic conversion of CO2 into formate anion compared to the corresponding porphyrin ligand itself. This work provides important insights into the design of MOF-based materials for CO2 capture and photoreduction. PMID- 26434686 TI - Effectiveness of Polyvalent Bacterial Lysate and Autovaccines Against Upper Respiratory Tract Bacterial Colonization by Potential Pathogens: A Randomized Study. AB - BACKGROUND: Polyvalent bacterial lysate (PBL) is an oral immunostimulating vaccine consisting of bacterial standardized lysates obtained by lysis of different strains of bacteria. Autovaccines are individually prepared based on the results of smears obtained from the patient. Both types of vaccine can be used to treat an ongoing chronic infection. This study sought to determine which method is more effective against nasal colonization by potential respiratory tract pathogens. MATERIAL AND METHODS: We enrolled 150 patients with aerobic Gram stain culture and count results indicating bacterial colonization of the nose and/or throat by potential pathogens. The participants were randomly assigned to each of the following groups: 1. administration of PBL, 2. administration of autovaccine, and 3. no intervention (controls). RESULTS: Reduction of the bacterial count in Streptococcus pneumoniae-colonized participants was significant after the autovaccine (p<0.001) and PBL (p<0.01). Reduction of the bacterial count of other beta-hemolytic streptococcal strains after treatment with the autovaccine was significant (p<0.01) and was non-significant after PBL. In Haemophilus influenzae colonization, significant reduction in the bacterial count was noted in the PBL group (p<0.01). Methicillin-resistant Staphylococcus aureus colonization did not respond to either treatment. CONCLUSIONS: The autovaccine is more effective than PBL for reducing bacterial count of Streptococcus pneumoniae and beta-hemolytic streptococci, while PBL was more effective against Haemophilus influenzae colonization. PMID- 26434688 TI - CMAP decrement as a potential diagnostic marker for ALS. AB - OBJECTIVE: We previously reported that decrement of compound muscle action potential (CMAP) by repetitive nerve stimulation (RNS) was greater in the median nerves than in the ulnar nerves of patients with amyotrophic lateral sclerosis (ALS). The aim of this study was to evaluate whether CMAP decrement by RNS is a feasible marker for the differentiation of ALS from other diseases. MATERIALS & METHODS: We performed RNS in the median and ulnar nerves of 51 patients with ALS and 40 patients with other diseases. RESULTS: The CMAP decrement was significantly greater in the median nerves of patients with ALS, compared to the disease control patients. In the median nerves of patients with ALS, CMAP decrement was significantly greater in the cervical region-onset group than in the other region-onset group. CONCLUSIONS: The finding of CMAP decrement in the median nerves can be useful for differentiating ALS patients with cervical region onset from other controls with active neuropathic diseases. PMID- 26434689 TI - Thermal Degradation of Small Molecules: A Global Metabolomic Investigation. AB - Thermal processes are widely used in small molecule chemical analysis and metabolomics for derivatization, vaporization, chromatography, and ionization, especially in gas chromatography mass spectrometry (GC/MS). In this study the effect of heating was examined on a set of 64 small molecule standards and, separately, on human plasma metabolite extracts. The samples, either derivatized or underivatized, were heated at three different temperatures (60, 100, and 250 degrees C) at different exposure times (30 s, 60 s, and 300 s). All the samples were analyzed by liquid chromatography coupled to electrospray ionization mass spectrometry (LC/MS) and the data processed by XCMS Online ( xcmsonline.scripps.edu ). The results showed that heating at an elevated temperature of 100 degrees C had an appreciable effect on both the underivatized and derivatized molecules, and heating at 250 degrees C created substantial changes in the profile. For example, over 40% of the molecular peaks were altered in the plasma metabolite analysis after heating (250 degrees C, 300s) with a significant formation of degradation and transformation products. The analysis of 64 small molecule standards validated the temperature-induced changes observed on the plasma metabolites, where most of the small molecules degraded at elevated temperatures even after minimal exposure times (30 s). For example, tri- and diorganophosphates (e.g., adenosine triphosphate and adenosine diphosphate) were readily degraded into a mono-organophosphate (e.g., adenosine monophosphate) during heating. Nucleosides and nucleotides (e.g., inosine and inosine monophosphate) were also found to be transformed into purine derivatives (e.g., hypoxanthine). A newly formed transformation product, oleoyl ethyl amide, was identified in both the underivatized and derivatized forms of the plasma extracts and small molecule standard mixture, and was likely generated from oleic acid. Overall these analyses show that small molecules and metabolites undergo significant time-sensitive alterations when exposed to elevated temperatures, especially those conditions that mimic sample preparation and analysis in GC/MS experiments. PMID- 26434690 TI - Knowledge, attitude, and practices with respect to disease surveillance among urban private practitioners in Pune, India. AB - BACKGROUND: Participation of private practitioners in routine disease surveillance in India is minimal despite the fact that they account for over 70% of the primary healthcare provision. We aimed to investigate the knowledge, attitudes, and practices of private practitioners in the city of Pune toward disease surveillance. Our goal was to identify what barriers and facilitators determine their participation in current and future surveillance efforts. DESIGN: A questionnaire-based survey was conducted among 258 practitioners (response rate 86%). Data were processed using SPSSTM Inc., Chicago, IL, USA, version 17.0.1. RESULTS: Knowledge regarding surveillance, although limited, was better among allopathy practitioners. Surveillance practices did not differ significantly between allopathy and alternate medicine practitioners. Multivariable logistic regression suggested practicing allopathy [odds ratio (OR) 3.125, 95% confidence interval (CI) 1.234-7.915, p=0.016] and availability of a computer (OR 3.670, 95% CI 1.237-10.889, p=0.019) as significant determinants and the presence of a laboratory (OR 3.792, 95% CI 0.998-14.557, p=0.052) as a marginal determinant of the practitioner's willingness to participate in routine disease surveillance systems. Lack of time (137, 55%) was identified as the main barrier at the individual level alongside inadequately trained subordinate staff (14, 6%). Main extrinsic barriers included lack of cooperation between government and the private sector (27, 11%) and legal issues involved in reporting data (15, 6%). There was a general agreement among respondents (239, 94%) that current surveillance efforts need strengthening. Over a third suggested that availability of detailed information and training about surveillance processes (70, 33%) would facilitate reporting. CONCLUSIONS: The high response rate and the practitioners' willingness to participate in a proposed pilot non-communicable disease surveillance system indicate that there is a general interest from the private sector in cooperating. Keeping reporting systems simple, preferably in electronic formats that minimize infrastructure and time requirements on behalf of the private practitioners, will go a long way in consolidating disease surveillance efforts in the state. Organizing training sessions, providing timely feedback, and awarding continuing medical education points for routine data reporting seem feasible options and should be piloted. PMID- 26434691 TI - 'You must carry your wheelchair'--barriers to accessing healthcare in a South African rural area. AB - BACKGROUND: There is international evidence that people with disabilities face barriers when accessing primary healthcare services and that there is inadequate information about effective interventions that work to improve the lives of people with disabilities, especially in low-income and middle-income countries. Poor rural residents generally experience barriers to accessing primary healthcare, and these problems are further exacerbated for people with disabilities. OBJECTIVE: In this study, we explore the challenges faced by people with disabilities in accessing healthcare in Madwaleni, a poor rural Xhosa community in South Africa. DESIGN: Purposive sampling was done with 26 participants, using semi-structured interviews and content analysis to identify major themes. RESULTS: This study showed a number of barriers to healthcare for people with disabilities. These included practical barriers, including geographical and staffing issues, and attitudinal barriers. CONCLUSIONS: It is suggested that although there are practical barriers that need to be addressed, attitudinal barriers could potentially be addressed more easily and cost effectively. PMID- 26434692 TI - A Colorimetric Plasmonic Nanosensor for Dosimetry of Therapeutic Levels of Ionizing Radiation. AB - Modern radiation therapy using highly automated linear accelerators is a complex process that maximizes doses to tumors and minimizes incident dose to normal tissues. Dosimeters can help determine the radiation dose delivered to target diseased tissue while minimizing damage to surrounding healthy tissue. However, existing dosimeters can be complex to fabricate, expensive, and cumbersome to operate. Here, we demonstrate studies of a liquid phase, visually evaluated plasmonic nanosensor that detects radiation doses commonly employed in fractionated radiotherapy (1-10 Gy) for tumor ablation. We accomplished this by employing ionizing radiation, in concert with templating lipid surfactant micelles, in order to convert colorless salt solutions of univalent gold ions (Au(1)) to maroon-colored dispersions of plasmonic gold nanoparticles. Differences in color intensities of nanoparticle dispersions were employed as quantitative indicators of the radiation dose. The nanoparticles thus formed were characterized using UV-vis absorbance spectroscopy, dynamic light scattering, and transmission electron microscopy. The role of lipid surfactants on nanoparticle formation was investigated by varying the chain lengths while maintaining the same headgroup and counterion; the effect of surfactant concentration on detection efficacy was also investigated. The plasmonic nanosensor was able to detect doses as low as 0.5 Gy and demonstrated a linear detection range of 0.5-2 Gy or 5-37 Gy depending on the concentration of the lipid surfactant employed. The plasmonic nanosensor was also able to detect radiation levels in anthropomorphic prostate phantoms when administered together with endorectal balloons, indicating its potential utility as a dosimeter in fractionated radiotherapy for prostate cancer. Taken together, our results indicate that this simple visible nanosensor has strong potential to be used as a dosimeter for validating delivered radiation doses in fractionated radiotherapies in a variety of clinical settings. PMID- 26434693 TI - Contrasting the Role of Mg and Ba Doping on the Microstructure and Thermoelectric Properties of p-Type AgSbSe2. AB - Microstructure has a critical influence on the mechanical and functional properties. For thermoelectric materials, deep understanding of the relationship of microstructure and thermoelectric properties will enable the rational optimization of the ZT value and efficiency. Herein, taking AgSbSe2 as an example, we first report a different role of alkaline-earth metal ions (Mg(2+) and Ba(2+)) doping in the microstructure and thermoelectric properties of p-type AgSbSe2. For Mg doping, it monotonously increases the carrier concentration and then reduces the electrical resistivity, leading to a substantially enhanced power factor in comparison to those of other dopant elements (Bi(3+), Pb(2+), Zn(2+), Na(+), and Cd(2+)) in the AgSbSe2 system. Meanwhile, the lattice thermal conductivity is gradually suppressed by point defects scattering. In contrast, the electrical resistivity first decreases and then slightly rises with the increased Ba-doping concentrations due to the presence of BaSe3 nanoprecipitates, exhibiting a different variation tendency compared with the corresponding Mg doped samples. More significantly, the total thermal conductivity is obviously reduced with the increased Ba-doping concentrations partially because of the strong scattering of medium and long wavelength phonons via the nanoprecipitates, consistent with the theoretical calculation and analysis. Collectively, ZT value ~1 at 673 K and calculated leg efficiency ~8.5% with Tc = 300 K and Th = 673 K are obtained for both AgSb0.98Mg0.02Se2 and AgSb0.98Ba0.02Se2 samples. PMID- 26434694 TI - Selective Access to Heterocyclic Sulfonamides and Sulfonyl Fluorides via a Parallel Medicinal Chemistry Enabled Method. AB - A sulfur-functionalized aminoacrolein derivative is used for the efficient and selective synthesis of heterocyclic sulfonyl chlorides, sulfonyl fluorides, and sulfonamides. The development of a 3-step parallel medicinal chemistry (PMC) protocol for the synthesis of pyrazole-4-sulfonamides effectively demonstrates the utility of this reagent. This reactivity was expanded to provide rapid access to other heterocyclic sulfonyl fluorides, including pyrimidines and pyridines, whose corresponding sulfonyl chlorides lack suitable chemical stability. PMID- 26434695 TI - Probing Anisotropic Surface Properties of Molybdenite by Direct Force Measurements. AB - Probing anisotropic surface properties of layer-type mineral is fundamentally important in understanding its surface charge and wettability for a variety of applications. In this study, the surface properties of the face and the edge surfaces of natural molybdenite (MoS2) were investigated by direct surface force measurements using atomic force microscope (AFM). The interaction forces between the AFM tip (Si3N4) and face or edge surface of molybdenite were measured in 10 mM NaCl solutions at various pHs. The force profiles were well-fitted with classical DLVO (Derjaguin-Landau-Verwey-Overbeek) theory to determine the surface potentials of the face and the edge surfaces of molybdenite. The surface potentials of both the face and edge surfaces become more negative with increasing pH. At neutral and alkaline conditions, the edge surface exhibits more negative surface potential than the face surface, which is possibly due to molybdate and hydromolybdate ions on the edge surface. The point of zero charge (PZC) of the edge surface was determined around pH 3 while PZC of the face surface was not observed in the range of pH 3-11. The interaction forces between octadecyltrichlorosilane-treated AFM tip (OTS-tip) and face or edge surface of molybdenite were also measured at various pHs to study the wettability of molybdenite surfaces. An attractive force between the OTS-tip and the face surface was detected. The force profiles were well-fitted by considering DLVO forces and additional hydrophobic force. Our results suggest the hydrophobic feature of the face surface of molybdenite. In contrast, no attractive force between the OTS-tip and the edge surface was detected. This is the first study in directly measuring surface charge and wettability of the pristine face and edge surfaces of molybdenite through surface force measurements. PMID- 26434696 TI - Surgical Procedure Characteristics and Risk of Sharps-Related Blood and Body Fluid Exposure. AB - OBJECTIVE To use a unique multicomponent administrative data set assembled at a large academic teaching hospital to examine the risk of percutaneous blood and body fluid (BBF) exposures occurring in operating rooms. DESIGN A 10-year retrospective cohort design. SETTING A single large academic teaching hospital. PARTICIPANTS All surgical procedures (n=333,073) performed in 2001-2010 as well as 2,113 reported BBF exposures were analyzed. METHODS Crude exposure rates were calculated; Poisson regression was used to analyze risk factors and account for procedure duration. BBF exposures involving suture needles were examined separately from those involving other device types to examine possible differences in risk factors. RESULTS The overall rate of reported BBF exposures was 6.3 per 1,000 surgical procedures (2.9 per 1,000 surgical hours). BBF exposure rates increased with estimated patient blood loss (17.7 exposures per 1,000 procedures with 501-1,000 cc blood loss and 26.4 exposures per 1,000 procedures with >1,000 cc blood loss), number of personnel working in the surgical field during the procedure (34.4 exposures per 1,000 procedures having >=15 personnel ever in the field), and procedure duration (14.3 exposures per 1,000 procedures lasting 4 to <6 hours, 27.1 exposures per 1,000 procedures lasting >=6 hours). Regression results showed associations were generally stronger for suture needle-related exposures. CONCLUSIONS Results largely support other studies found in the literature. However, additional research should investigate differences in risk factors for BBF exposures associated with suture needles and those associated with all other device types. Infect. Control Hosp. Epidemiol. 2015;37(1):80-87. PMID- 26434697 TI - Destabilization of the torsioned conformation of a ligand side chain inverts the LXRbeta activity. AB - BACKGROUND: Liver X receptors (LXRs) are transcription factors activated by cholesterol metabolites containing an oxidized side chain. Due to their ability to regulate lipid metabolism and cholesterol transport, they have become attractive pharmacological targets. LXRs are closely related to DAF-12, a nuclear receptor involved in nematode lifespan and regulated by the binding of C-27 steroidal acids. Based on our recent finding that the lack of the C-25 methyl group does not abolish their DAF-12 activity, we evaluated the effect of removing it from the (25R)-cholestenoic acid, a LXR agonist. METHODS: The binding mode and the molecular basis of action of 27-nor-5-cholestenoic acid were evaluated using molecular dynamics simulations. The biological activity was investigated using reporter gene expression assays and determining the expression levels of endogenous target genes. The in vitro MARCoNI assay was used to analyze the interaction with cofactors. RESULTS: 27-Nor-5-cholestenoic acid behaves as an inverse agonist. This correlates with the capacity of the complex to better bind corepressors rather than coactivators. The C-25 methyl moiety would be necessary for the maintenance of a torsioned conformation of the steroid side chain that stabilizes an active LXRbeta state. CONCLUSION: We found that a 27-nor analog is able to act as a LXR ligand. Interestingly, this minimal structural change on the steroid triggered a drastic change in the LXR response. GENERAL SIGNIFICANCE: Results contribute to improve our understanding on the molecular basis of LXRbeta mechanisms of action and provide a new scaffold in the quest for selective LXR modulators. PMID- 26434698 TI - Experimental evidence of heparanase, Hsp70 and NF-kappaB gene expression on the response of anti-inflammatory drugs in TNBS-induced colonic inflammation. AB - AIM: Etiopathogenesis of inflammatory bowel disease is unclear and results from a complex interplay of genetic, microbial, environmental and immune factors. Elucidating the mechanisms that drive IBD depends on the detailed characterization of human inflammatory mediators in animal models. Therefore, we studied how intestinal inflammation affects heparanase, NF-kappaB and Hsp70 gene expression in rats, and if current intestinal anti-inflammatory drugs (sulphasalazine, prednisolone and azathioprine) act on these expressions. Moreover, we investigated the relationships among these genes with colonic cytokines levels (IL-1beta, TNF-alpha, IL-6, INF-gamma and IL-10) and oxidative stress that have fundamental role in IBD. MATERIAL AND METHODS: Macroscopic parameters (diarrhea, extension of lesion, colonic weight/length ratio and damage score), biochemical markers (myeloperoxidase and alkaline phosphatase activities, and glutathione, IL-1beta, TNF-alpha, IL-6, INF-gamma and IL-10 levels), gene expressions (heparanase, NF-kappaB and Hsp70), and microscopic evaluations (optic, electronic scanning and transmission microscopic) were performed in rats. KEY FINDINGS: Expression of heparanase, Hsp70 and NF-kappaB and oxidative stress were increased by inflammatory process and differentially modulated by sulphasalazine, prednisolone and azathioprine treatments. Protective effects of drugs were also related to differential modulation of cytokine changes induced by inflammatory process, showing different mechanisms to control inflammation. SIGNIFICANCE: Heparanase, NF-kappaB and Hsp70 gene expression participate in the inflammatory response induced by TNBS and represent pharmacological targets of the intestinal anti-inflammatory drugs. In addition, current drugs used to treat IBD (sulphasalazine, prednisolone and azathioprine) differentially modulate heparanase, NF-kappaB and Hsp70 gene expression, cytokine production and oxidative stress. PMID- 26434699 TI - Linoleic acid and breast cancer risk: a meta-analysis. AB - OBJECTIVE: Prior studies on linoleic acid, the predominant n-6 fatty acid, and breast cancer risk have generated inconsistent results. We performed a meta analysis to summarize the evidence regarding the relationship of dietary and serum linoleic acid with breast cancer risk. DESIGN: Pertinent studies were identified by a search of PubMed and EMBASE. The fixed- or random-effect pooled measure was selected based on between-study heterogeneity. RESULTS: Eight prospective cohort studies and four prospective nested case-control studies, involving 10 410 breast cancer events from 358 955 adult females across different countries, were included in present study. Compared with the lowest level of linoleic acid, the pooled relative risk (RR; 95 % CI) of breast cancer was 0.98 (0.93, 1.04) for the highest level of linoleic acid. The pooled RR (95 % CI) for dietary and serum linoleic acid were 0.99 (0.92, 1.06) and 0.98 (0.88, 1.08), respectively. The RR (95 % CI) of breast cancer was 0.97 (0.91, 1.04), 0.95 (0.85, 1.07), 0.96 (0.86, 1.07), 0.98 (0.87, 1.10) and 0.99 (0.85, 1.14) for linoleic acid intake of 5, 10, 15, 20 and 25 g/d, respectively. The risk of breast cancer decreased by 1 % (RR=0.99; 95 % CI 0.93, 1.05) for every 10 g/d increment in linoleic acid intake. CONCLUSIONS: This meta-analysis indicated that both dietary linoleic acid intake and serum linoleic acid level were associated with decreased risk of breast cancer, although none of the associations were statistically significant. Further investigations are warranted. PMID- 26434701 TI - The real root-cause analysis: Optimizing surgical options in the current era. PMID- 26434700 TI - 7-prenyloxi-6-methoxycoumarin from Polygala sabulosa A.W. Bennett Regulates p38 MAPK and NF-kB Pathways Inhibiting the Inflammation Induced by Carrageenan in the Mouse Model of Pleurisy. AB - CONTEXT: Polygala sabulosa, popularly known as "timutu-pinheirinho," has been used in Brazilian folk medicine for the treatment of bowel and kidney disorders and as an expectorant. OBJECTIVE: Evaluate the anti-inflammatory effects of the crude extract (CE), acetonic fraction (Ac), and the main compound, 7-prenyloxi-6 methoxycoumarin (PC) on a mouse model of carrageenan-induced pleurisy. MATERIALS AND METHODS: A mouse model of carrageenan-induced pleurisy was used to investigate the effects of P. sabulosa CE, Ac and PC on leukocyte migration, exudate formation, activities of myeloperoxidase (MPO), and adenosine-deaminase (ADA), levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL 1beta) and nitric oxide (NO). In addition, the effect of the plant material on lung histology was also evaluated. The effects of PC on the TNF-alpha, IL-1beta and NO synthase 2 (NOS2) mRNA expression, were also investigated. Finally, the effect of PC on the nuclear factor-kappa B (NF-kappaB) and p38 mitogen-activated protein kinase (p38 MAPK) was also evaluated. RESULTS: CE, Ac and PC reduced inflammation in the pleural cavity and lungs. This effect was evidenced by reduction on all inflammatory parameters evaluated; the exception being the inability of the CE to inhibit exudate formation. In isolation, PC showed reduction on mRNA levels of TNF-alpha, IL-1beta and NOS2, and on activation of the NF-kappaB and p38 MAPK pathways. CONCLUSION: The presented results show that P. sabulosa has significant anti-inflammatory activity, as does its main compound, PC. Moreover, the results suggest that PC exerts its effects mainly by inhibited the NF-kappaB and p38 MAPK pathways. PMID- 26434702 TI - Bleeding and cerebral injury following aortic arch repair: Two chinks in the armor. PMID- 26434703 TI - Gibbons of the world, dream on. PMID- 26434704 TI - A reliability assessment of constrained spherical deconvolution-based diffusion weighted magnetic resonance imaging in individuals with chronic stroke. AB - BACKGROUND: Diffusion-weighted magnetic resonance imaging (DW-MRI) is commonly used to assess white matter properties after stroke. Novel work is utilizing constrained spherical deconvolution (CSD) to estimate complex intra-voxel fiber architecture unaccounted for with tensor-based fiber tractography. However, the reliability of CSD-based tractography has not been established in people with chronic stroke. NEW METHOD: Establishing the reliability of CSD-based DW-MRI in chronic stroke. High-resolution DW-MRI was performed in ten adults with chronic stroke during two separate sessions. Deterministic region of interest-based fiber tractography using CSD was performed by two raters. Mean fractional anisotropy (FA), apparent diffusion coefficient (ADC), tract number, and tract volume were extracted from reconstructed fiber pathways in the corticospinal tract (CST) and superior longitudinal fasciculus (SLF). Callosal fiber pathways connecting the primary motor cortices were also evaluated. Inter-rater and test-retest reliability were determined by intra-class correlation coefficients (ICCs). RESULTS: ICCs revealed excellent reliability for FA and ADC in ipsilesional (0.86 1.00; p<0.05) and contralesional hemispheres (0.94-1.00; p<0.0001), for CST and SLF fibers; and excellent reliability for all metrics in callosal fibers (0.85 1.00; p<0.05). ICC ranged from poor to excellent for tract number and tract volume in ipsilesional (-0.11 to 0.92; p<=0.57) and contralesional hemispheres ( 0.27 to 0.93; p<=0.64), for CST and SLF fibers. COMPARISON WITH EXISTING METHOD: Like other select DW-MRI approaches, CSD-based tractography is a reliable approach to evaluate FA and ADC in major white matter pathways, in chronic stroke. CONCLUSION: Future work should address the reproducibility and utility of CSD-based metrics of tract number and tract volume. PMID- 26434705 TI - Models of hypoxia and ischemia-induced seizures. AB - Despite greater understanding and improved management, seizures continue to be a major problem in childhood. Neonatal seizures are often refractory to conventional antiepileptic drugs, and can result in later life epilepsy and cognitive deficits, conditions for which there are no specific treatments. Hypoxic and/or ischemic encephalopathy (HIE) is the most common cause for neonatal seizures, and accounts for more than two-thirds of neonatal seizure cases. A better understanding of the cellular and molecular mechanisms is essential for identifying new therapeutic strategies that control the neonatal seizures and its cognitive consequences. This heavily relies on animal models that play a critical role in discovering novel mechanisms underlying both epileptogenesis and associated cognitive impairments. To date, a number of animal models have provided a tremendous amount of information regarding the pathophysiology of HIE-induced neonatal seizures. This review provides an overview on the most important features of the main animal models of HIE-induced seizures. In particular, we focus on the methodology of seizure induction and the characterizations of post-HIE injury consequences. These aspects of HIE-induced seizure models are discussed in the light of the suitability of these models in studying human HIE-induced seizures. PMID- 26434706 TI - Human brain slices for epilepsy research: Pitfalls, solutions and future challenges. AB - Increasingly, neuroscientists are taking the opportunity to use live human tissue obtained from elective neurosurgical procedures for electrophysiological studies in vitro. Access to this valuable resource permits unique studies into the network dynamics that contribute to the generation of pathological electrical activity in the human epileptic brain. Whilst this approach has provided insights into the mechanistic features of electrophysiological patterns associated with human epilepsy, it is not without technical and methodological challenges. This review outlines the main difficulties associated with working with epileptic human brain slices from the point of collection, through the stages of preparation, storage and recording. Moreover, it outlines the limitations, in terms of the nature of epileptic activity that can be observed in such tissue, in particular, the rarity of spontaneous ictal discharges, we discuss manipulations that can be utilised to induce such activity. In addition to discussing conventional electrophysiological techniques that are routinely employed in epileptic human brain slices, we review how imaging and multielectrode array recordings could provide novel insights into the network dynamics of human epileptogenesis. Acute studies in human brain slices are ultimately limited by the lifetime of the tissue so overcoming this issue provides increased opportunity for information gain. We review the literature with respect to organotypic culture techniques that may hold the key to prolonging the viability of this material. A combination of long-term culture techniques, viral transduction approaches and electrophysiology in human brain slices promotes the possibility of large scale monitoring and manipulation of neuronal activity in epileptic microcircuits. PMID- 26434707 TI - Spatially Structured Sparse Morphological Component Separation for voltage sensitive dye optical imaging. AB - BACKGROUND: Voltage-sensitive dye optical imaging is a promising technique for studying in vivo neural assemblies dynamics where functional clustering can be visualized in the imaging plane. Its practical potential is however limited by many artifacts. NEW METHOD: We present a novel method, that we call "SMCS" (Spatially Structured Sparse Morphological Component Separation), to separate the relevant biological signal from noise and artifacts. It extends Generalized Linear Models (GLM) by using a set of convex non-smooth regularization priors adapted to the morphology of the sources and artifacts to capture. RESULTS: We make use of first order proximal splitting algorithms to solve the corresponding large scale optimization problem. We also propose an automatic parameters selection procedure based on statistical risk estimation methods. COMPARISON WITH EXISTING METHODS: We compare this method with blank subtraction and GLM methods on both synthetic and real data. It shows encouraging perspectives for the observation of complex cortical dynamics. CONCLUSIONS: This work shows how recent advances in source separation can be integrated into a biophysical model of VSDOI. Going beyond GLM methods is important to capture transient cortical events such as propagating waves. PMID- 26434708 TI - Energy production through organic fraction of municipal solid waste-A multiple regression modeling approach. AB - In the 21st century, people migrated from rural to urban areas for several reasons. As a result, the populations of Indian cities are increasing day by day. On one hand, the country is developing in the field of science and technology and on the other hand, it is encountering a serious problem called 'Environmental degradation'. Due to increase in population, the generation of solid waste is also increased and is being disposed in open dumps and landfills which lead to air and land pollution. This study is attempted to generate energy out of organic solid waste by the bio- fermentation process. The study was conducted for a period of 7 months at Erode, Tamilnadu and the reading on various parameters like Hydraulic retention time, organic loading rate, sludge loading rate, influent pH, effluent pH, inlet volatile acids, out let volatile fatty acids, inlet VSS/TS ratio, outlet VSS/TS ratio, influent COD, effluent COD and % of COD removal are recorded for every 10 days. The aim of the present study is to develop a model through multiple linear regression analysis with COD as dependent variable and various parameters like HRT, OLR, SLR, influent, effluent, VSS/TS ratio, influent COD, effluent COD, etc as independent variables and to analyze the impact of these parameters on COD. The results of the model developed through step-wise regression method revealed that only four parameters Influent COD, effluent COD, VSS/TS and Influent/pH were main influencers of COD removal. The parameters influent COD and VSS/TS have positive impact on COD removal and the parameters effluent COD and Influent/pH have negative impact. The parameter Influent COD has the highest order of impact, followed by effluent COD, VSS/TS and influent pH. The other parameters HRT, OLR, SLR, INLET VFA and OUTLET VFA were not significantly contributing to the removal of COD. The implementation of the process suggested through this study might bring in dual benefit to the community, viz treatment of solid waste and creation of energy. PMID- 26434709 TI - The spinal antinociceptive mechanism determined by systemic administration of BD1047 in zymosan-induced hyperalgesia in rats. AB - Although sigma-1 receptor (Sig-1R) antagonists have a potential antinociceptive effect in inflammatory diseases, the precise mechanism is not fully understood. The present study was aimed to elucidate the role of spinal neurons and microglia in the anti-nociceptive mechanism of BD1047 (a prototypical Sig-1R antagonist) using an inflammatory pain model based on intraplantar injection of zymosan. Oral pretreatment with BD1047 dose-dependently reduced zymosan-induced thermal and mechanical hyperalgesia as well as spinal neuronal activation including increased immunoreactivity of Fos, protein kinase C (PKC) and 'PKC-dependent phosphorylation of the NMDA receptor subunit 1' (pNR1). Zymosan also led to increased CD11b immunoreactivity (a marker of microglia) accompanied by 'phosphorylated p38 mitogen activated protein kinase' (p-p38MAPK) and interleukin 1betaimmunoreactivity in the spinal dorsal horn. Intrathecal injection of a microglia modulator (minocycline), p38MAPK inhibitor (SB203580) or interleukin 1betaneutralizing antibody significantly attenuated zymosan-induced hyperalgesia. Specifically, oral pretreatment with BD1047 reduced the immunoreactivity of CD11b, p-p38MAPK and interleukin-1beta. In the spinal cord section, Sig-1R immunoreactivity was exclusively distributed in both spinal dorsal horn neurons and central endings of unmyelinated primary afferent fibers but not in glia. Intrathecal injection of BD1047 alleviated zymosan-induced hyperalgesia up to the level of oral administration. Taken together, our data imply that antinociceptive effect induced by oral treatment with BD1047 may be mediated, at least in part, by the inhibition of neuronal and microglial activation in the spinal cord triggered by inflammatory conditions. PMID- 26434710 TI - Developmental toxicity studies with 6 forms of titanium dioxide test materials (3 pigment-different grade & 3 nanoscale) demonstrate an absence of effects in orally-exposed rats. AB - Six different commercial forms and sizes of titanium dioxide particles were tested in separate developmental toxicity assays. The three pigment-grade (pg) or 3 ultrafine (uf)/nanoscale (anatase and/or rutile) titanium dioxide (TiO2) particle-types were evaluated for potential maternal and developmental toxicity in pregnant rats by two different laboratories. All studies were conducted according to OECD Guideline 414 (Prenatal Developmental Toxicity Study). In addition, all test materials were robustly characterized. The BET surface areas of the pg and uf samples ranged from 7 to 17 m(2)/g and 50-82 m(2)/g respectively (see Table 1). The test substances were formulated in sterile water. In all of the studies, the formulations were administered by oral gavage to time-mated rats daily beginning around the time of implantation and continuing until the day prior to expected parturition. In 3 of the studies (uf-1, uf-3, & pg-1), the formulations were administered to Crl:CD(SD) rats beginning on gestation day (GD) 6 through GD 20. In 3 additional studies (uf-2, and pg-2, pg-3 TiO2 particles), the formulations were administered to Wistar rats beginning on GD 5 through 19. The dose levels used in all studies were 0, 100, 300, or 1000 mg/kg/day; control group animals were administered the vehicle. During the in-life portions of the studies, body weights, food consumption, and clinical observations before and after dosing were collected on a daily basis. All dams were euthanized just prior to expected parturition (GD 21 for Crl:CD(SD) rats and GD 20 for Wistar rats). The gross necropsies included an examination and description of uterine contents including counts of corpora lutea, implantation sites, resorptions, and live and dead fetuses. All live fetuses were sexed, weighed, and examined externally and euthanized. Following euthanasia, fresh visceral and head examinations were performed on selected fetuses. The fetal carcasses were then processed and examined for skeletal alterations. There was no evidence of maternal or developmental toxicity at any dose level tested in any of the six studies. Based on these results, the no-observed-adverse-effect level (NOAEL) for titanium dioxide was 1000 mg/kg/day, the highest administered dose, in both the Sprague Dawley (Crl:CD(SD) and Wistar rat strains. PMID- 26434711 TI - A first insight into temperature stress-induced neuroendocrine and immunological changes in giant freshwater prawn, Macrobrachium rosenbergii. AB - Haemolymph norepinephrine (NE); total haemocyte count (THC); respiratory bursts (RBs); superoxide dismutase (SOD), phenoloxidase (PO), and phagocytic activity; and prophenoloxidase (proPO)-system-related genes (lipopolysaccharide- and beta 1,3-glucan-binding protein: LGBP, proPO, peroxinectin: PE, and alpha2 macroglobulin: alpha2-M) in haemocytes of Macrobrachium rosenbergii were investigated after transferring them from 28 degrees C to 22 degrees C, 28 degrees C, and 34 degrees C respectively. The results revealed that haemolymph NE, hyaline cells (HCs), and PO activity per granulocyte increased from 30 to 120 min of exposure, and however, RBs and phagocytic activity significantly decreased from 30 to 120 min of exposure as well as granular cells (GCs), semigranular cells (SGCs), and SOD activity decreased from 60 to 120 min of exposure for the prawns subjected to temperature stress. The proPO-system-related gene expression markedly increased with 60-120 min of exposure for the prawns transferred from 28 degrees C to 22 degrees C and 34 degrees C, except alpha2M at 120 min. These results provide a first insight into the effects of temperature stress on haemolymph NE level and immune functions in prawns and suggest that temperature stress-induced acute modulation in immunity is associated with the release of haemolymph NE in M. rosenbergii. PMID- 26434712 TI - Occurrence of immune cells in the intestinal wall of Squalius cephalus infected with Pomphorhynchus laevis. AB - A sub-population of 34 specimens of chub, Squalius cephalus, was sampled from the River Brenta (Northern Italy) and examined for ecto- and endo-parasites. Pomphorhynchus laevis (Acanthocephala) was the only enteric helminth encountered. Immunofluorescence and ultrastructural studies were conducted on the intestines of chub. Near the site of parasite's attachment, mucous cells, mast cells (MCs), neutrophils and rodlet cells (RCs) were found to co-occur within the intestinal epithelium. The numbers of mucous cells, MCs and neutrophils were significantly higher in infected fish (Mann-Whitney U test, p < 0.05). Dual immunofluorescence staining with the lectin Dolichos Biflorus Agglutinin (DBA) and the macrophage specific MAC387 monoclonal antibody, with parallel transmission electron microscopy, revealed that epithelial MCs often made intimate contact with the mucous cells. Degranulation of a large number of MCs around the site of the acanthocephalan's attachment and in proximity to mucous cells was also documented. MCs and neutrophils were abundant in the submucosa. Immune cells of the intestinal epithelium have been described at the ultrastructural level and their possible functions and interactions are discussed. PMID- 26434713 TI - Uncaria tomentosa increases growth and immune activity in Oreochromis niloticus challenged with Streptococcus agalactiae. AB - Cat's claw (Uncaria tomentosa) is an Amazon herb using in native cultures in Peru. In mammals, it has been described several effects of this herb. However, this is the first report of its use on the diet of fish. The aim of this study was to determinate the effect of this plant on the growth and immune activity in Oreochromis niloticus. Nile tilapia (81.3 +/- 4.5 g) were distributed into 5 groups and supplemented with 0 (non-supplement fish), 75, 150, 300, and 450 mg of U. tomentosa.kg(-1) of diet for a period of 28 days. Fish were inoculated in the swim bladder with inactivated Streptococcus agalactiae and samples were taken at 6, 24, and 48 h post inoculation (HPI). Dose dependent increases were noted in some of the evaluated times of thrombocytes and white blood cells counts (WBC) in blood and exudate, burst respiratory activity, lysozyme activity, melanomacrophage centers count (MMCs), villi length, IgM by immunohistochemistry in splenic tissue, and unexpectedly on growth parameters. However, dietary supplementation of this herb did not affect red blood cells count (RBC), hemoglobin, and there were no observed histological lesions in gills, intestine, spleen, and liver. The current results demonstrate for the first time that U. tomentosa can stimulate fish immunity and improve growth performance in Nile tilapia. PMID- 26434714 TI - YHV-responsive gene expression under the influence of PmRelish regulation. AB - In animals, infection by Gram-negative bacteria and certain viruses activates the Imd signaling pathway wherein the a NF-kappaB transcription factor, Relish, is a key regulatory protein for the synthesis of antimicrobial proteins. Infection by yellow head virus (YHV) activates the Imd pathway. To investigate the expression of genes involved in YHV infection and under the influence of PmRelish regulation, RNA interference and suppression subtractive hybridization (SSH) are employed. The genes in forward library expressed in shrimp after YHV infection and under the activity of PmRelish were obtained by subtracting the cDNAs from YHV-infected and PmRelish-knockdown shrimp with cDNAs from YHV-infected shrimp. Opposite subtraction gave a reverse library whereby an alternative set of genes under YHV infection and no PmRelish expression were obtained. Nucleotide sequences of 252 and 99 cDNA clones from the forward and reverse libraries, respectively, were obtained and annotated through blast search against the GenBank sequences. Genes involved in defense and homeostasis were abundant in both libraries, 31% and 23% in the forward and reverse libraries, respectively. They were predominantly antimicrobial proteins, proteinases and proteinase inhibitors. The expression of antimicrobial protein genes, ALFPm3, crustinPm1, penaeidin3 and penaeidin5 were tested under PmRelish silencing and Gram-negative bacterium Vibrio harveyi infection. Together with the results using YHV infection previously reported, the expression of penaeidin5 and also penaeidin3 but not ALFPm3 and crustinPm1 were under the regulation of PmRelish in the Imd pathway. PMID- 26434715 TI - Genome-wide identification and characterization of TRAF genes in the Yesso scallop (Patinopecten yessoensis) and their distinct expression patterns in response to bacterial challenge. AB - The tumor necrosis factor (TNF) receptor associated factors (TRAFs) are the major signal transducers for the TNF receptor superfamily and the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) superfamily, which regulate a variety of cellular activities and innate immune responses. TRAF genes have been extensively studied in various species, including vertebrates and invertebrates. However, as one of the key component of NF-kappaB pathway, TRAF genes have not been systematically characterized in marine invertebrates. In this study, we identified and characterized five TRAF genes, PyTRAF2, PyTRAF3, PyTRAF4, PyTRAF6 and PyTRAF7, in the Yesso scallop (Patinopecten yessoensis). Phylogenetic and protein structural analyses were conducted to determine their identities and evolutionary relationships. In comparison with the TRAF genes from vertebrate species, the structural features were all relatively conserved in the PyTRAF genes. To gain insights into the roles of TRAF genes during scallop innate immune responses, quantitative real-time PCR was used to investigate the expression profiles in the different stages of scallop development, in the healthy adult tissues, and in the hemocytes after bacterial infection with Micrococcus luteus and Vibrio anguillarum. Based on the qRT-PCR analysis, the expression of most of the PyTRAFs was significantly induced in the acute phases (3-6 h) after infection with Gram-positive (M. luteus) and Gram-negative (V. anguillarum) bacteria, and many more dramatic changes in PyTRAFs expression were observed after V. anguillarum challenge. Notably, the strong response in the up-regulation of PyTRAF6 post-bacterial challenge was distinct from that previously reported in scallops and crabs but was similar to that of other shellfish, Echinodermata and even teleost fish. The high level expressions of PyTRAFs in the hemocytes and the gill, and their specific expression patterns after challenges provide insights into the versatile roles and responses of TRAFs in the innate immune system against Gram-negative bacterial pathogens in bivalves. PMID- 26434716 TI - Mucosal expression signatures of two Cathepsin L in channel catfish (Ictalurus punctatus) following bacterial challenge. AB - The mucosal surfaces of fish are the first line of host defense against various pathogens. The mucosal immune responses are the most critical events to prevent pathogen attachment and invasion. Cathepsins are a group of peptidases that involved in different levels of immune responses, but the knowledge of the roles of Cathepsin in mucosal immune responses against bacterial infection are still lacking. Therefore, in the present study we characterized the Cathepsin L gene family in channel catfish, and profiled their expression levels after challenging with two different Gram-negative bacterial pathogens. Here, two Cathepsin L genes were identified from channel catfish and were designated CTSL1a and CTSL.1. Comparing to other fish species, the catfish CTSL genes are highly conserved in their structural features. Phylogenetic analysis was conducted to confirm the identification of CTSL genes. Expression analysis revealed that the CTSL genes were ubiquitously expressed in all tested tissues. Following infection, the CTSL genes were significantly induced at most timepoints in mucosal tissues. But the expression patterns varied depending on both pathogen and tissue types, suggesting that CTSL genes may exert disparate functions or exhibit distinct tissue-selective roles in mucosal immune responses. Our findings here, clearly revealed the key roles of CTSL in catfish mucosal immunity; however, further studies are needed to expand functional characterization and examine whether CTSL may also play additional physiological roles in catfish mucosal tissues. PMID- 26434718 TI - Ganglioside GM3 as a gatekeeper of obesity-associated insulin resistance: Evidence and mechanisms. AB - Gangliosides constitute a large family of sialic acid-containing glycosphingolipids which play a key regulatory role in a diverse array of cellular processes, including receptor-associated signalling. Accordingly, the aberrant production of the ganglioside GM3 has been linked to pathophysiological changes associated with obesity, which in turn can lead to metabolic disorders such as insulin resistance and type 2 diabetes mellitus. This review examines the role of GM3 in mediating obesity-induced perturbations in metabolic function, including impaired insulin action. By doing so, we highlight the potential use of therapies targeting GM3 biosynthesis in order to counteract obesity-related metabolic disorders. PMID- 26434717 TI - High pressure promotes alpha-synuclein aggregation in cultured neuronal cells. AB - alpha-Synuclein is found in plaques associated with Parkinson's and other neurodegenerative diseases. Changes in alpha-synuclein oligomerization are thought to give rise to nucleation of neurodegenerative plaques. Here, we investigated the effect of hydrostatic pressure on the aggregation of alpha synuclein in cultured neuronal cells. We found that hydrostatic pressure is associated with a transition from monomeric to higher order alpha-synuclein aggregates. We then tested whether this aggregation is associated with the loss of binding partners, such as phospholipase Cbeta. We found that increased pressure reduces the level of PLCbeta1 and the amount of alpha-synuclein/PLCbeta1 complexes. These studies suggest that pressure promotes release of alpha synuclein from protein partners promoting its oligomerization. PMID- 26434719 TI - Alternative Transposition Generates New Chimeric Genes and Segmental Duplications at the Maize p1 Locus. AB - The maize Ac/Ds transposon family was the first transposable element system identified and characterized by Barbara McClintock. Ac/Ds transposons belong to the hAT family of class II DNA transposons. We and others have shown that Ac/Ds elements can undergo a process of alternative transposition in which the Ac/Ds transposase acts on the termini of two separate, nearby transposons. Because these termini are present in different elements, alternative transposition can generate a variety of genome alterations such as inversions, duplications, deletions, and translocations. Moreover, Ac/Ds elements transpose preferentially into genic regions, suggesting that structural changes arising from alternative transposition may potentially generate chimeric genes at the rearrangement breakpoints. Here we identified and characterized 11 independent cases of gene fusion induced by Ac alternative transposition. In each case, a functional chimeric gene was created by fusion of two linked, paralogous genes; moreover, each event was associated with duplication of the ~70-kb segment located between the two paralogs. An extant gene in the maize B73 genome that contains an internal duplication apparently generated by an alternative transposition event was also identified. Our study demonstrates that alternative transposition induced duplications may be a source for spontaneous creation of diverse genome structures and novel genes in maize. PMID- 26434720 TI - The Effects of Background and Interference Selection on Patterns of Genetic Variation in Subdivided Populations. AB - It is well known that most new mutations that affect fitness exert deleterious effects and that natural populations are often composed of subpopulations (demes) connected by gene flow. To gain a better understanding of the joint effects of purifying selection and population structure, we focus on a scenario where an ancestral population splits into multiple demes and study neutral diversity patterns in regions linked to selected sites. In the background selection regime of strong selection, we first derive analytic equations for pairwise coalescent times and FST as a function of time after the ancestral population splits into two demes and then construct a flexible coalescent simulator that can generate samples under complex models such as those involving multiple demes or nonconservative migration. We have carried out extensive forward simulations to show that the new methods can accurately predict diversity patterns both in the nonequilibrium phase following the split of the ancestral population and in the equilibrium between mutation, migration, drift, and selection. In the interference selection regime of many tightly linked selected sites, forward simulations provide evidence that neutral diversity patterns obtained from both the nonequilibrium and equilibrium phases may be virtually indistinguishable for models that have identical variance in fitness, but are nonetheless different with respect to the number of selected sites and the strength of purifying selection. This equivalence in neutral diversity patterns suggests that data collected from subdivided populations may have limited power for differentiating among the selective pressures to which closely linked selected sites are subject. PMID- 26434721 TI - Simple Biophysical Model Predicts Faster Accumulation of Hybrid Incompatibilities in Small Populations Under Stabilizing Selection. AB - Speciation is fundamental to the process of generating the huge diversity of life on Earth. However, we are yet to have a clear understanding of its molecular genetic basis. Here, we examine a computational model of reproductive isolation that explicitly incorporates a map from genotype to phenotype based on the biophysics of protein-DNA binding. In particular, we model the binding of a protein transcription factor to a DNA binding site and how their independent coevolution, in a stabilizing fitness landscape, of two allopatric lineages leads to incompatibilities. Complementing our previous coarse-grained theoretical results, our simulations give a new prediction for the monomorphic regime of evolution that smaller populations should develop incompatibilities more quickly. This arises as (1) smaller populations have a greater initial drift load, as there are more sequences that bind poorly than well, so fewer substitutions are needed to reach incompatible regions of phenotype space, and (2) slower divergence when the population size is larger than the inverse of discrete differences in fitness. Further, we find longer sequences develop incompatibilities more quickly at small population sizes, but more slowly at large population sizes. The biophysical model thus represents a robust mechanism of rapid reproductive isolation for small populations and large sequences that does not require peak shifts or positive selection. Finally, we show that the growth of DMIs with time is quadratic for small populations, agreeing with Orr's model, but nonpower law for large populations, with a form consistent with our previous theoretical results. PMID- 26434725 TI - Reaction of diazocompounds with C70: unprecedented synthesis and characterization of isomeric [5,6]-fulleroids. AB - The synthesis of a variety of PCBM-type [5,6]-fulleroids and their further highly selective photoisomerization to the respective [6,6]-methanofullerenes is presented. Interestingly, the chemical reactivity of [5,6]-fulleroids reveals the same trend (a > b > c > d) to that observed for pristine C70 (alpha > beta > gamma > delta). PMID- 26434722 TI - Identifying Regulators of Morphogenesis Common to Vertebrate Neural Tube Closure and Caenorhabditis elegans Gastrulation. AB - Neural tube defects including spina bifida are common and severe congenital disorders. In mice, mutations in more than 200 genes can result in neural tube defects. We hypothesized that this large gene set might include genes whose homologs contribute to morphogenesis in diverse animals. To test this hypothesis, we screened a set of Caenorhabditis elegans homologs for roles in gastrulation, a topologically similar process to vertebrate neural tube closure. Both C. elegans gastrulation and vertebrate neural tube closure involve the internalization of surface cells, requiring tissue-specific gene regulation, actomyosin-driven apical constriction, and establishment and maintenance of adhesions between specific cells. Our screen identified several neural tube defect gene homologs that are required for gastrulation in C. elegans, including the transcription factor sptf-3. Disruption of sptf-3 in C. elegans reduced the expression of early endodermally expressed genes as well as genes expressed in other early cell lineages, establishing sptf-3 as a key contributor to multiple well-studied C. elegans cell fate specification pathways. We also identified members of the actin regulatory WAVE complex (wve-1, gex-2, gex-3, abi-1, and nuo-3a). Disruption of WAVE complex members reduced the narrowing of endodermal cells' apical surfaces. Although WAVE complex members are expressed broadly in C. elegans, we found that expression of a vertebrate WAVE complex member, nckap1, is enriched in the developing neural tube of Xenopus. We show that nckap1 contributes to neural tube closure in Xenopus. This work identifies in vivo roles for homologs of mammalian neural tube defect genes in two manipulable genetic model systems. PMID- 26434723 TI - The Importance of cGMP Signaling in Sensory Cilia for Body Size Regulation in Caenorhabditis elegans. AB - The body size of Caenorhabditis elegans is thought to be controlled by sensory inputs because many mutants with sensory cilium structure defects exhibit small body size. The EGL-4 cGMP-dependent protein kinase acts in sensory neurons to reduce body size when animals fail to perceive sensory signals. In addition to body size control, EGL-4 regulates various other behavioral and developmental pathways, including those involved in the regulation of egg laying and chemotaxis behavior. Here we have identified gcy-12, which encodes a receptor-type guanylyl cyclase, as a gene involved in the sensory regulation of body size. Analyses with GFP fusion constructs showed that gcy-12 is expressed in several sensory neurons and localizes to sensory cilia. Genetic analyses indicated that GCY-12 acts upstream of EGL-4 in body size control but does not affect other EGL-4 functions. Our studies indicate that the function of the GCY-12 guanylyl cyclase is to provide cGMP to the EGL-4 cGMP-dependent kinase only for limited tasks including body size regulation. We also found that the PDE-2 cyclic nucleotide phosphodiesterase negatively regulates EGL-4 in controlling body size. Thus, the cGMP level is precisely controlled by GCY-12 and PDE-2 to determine body size through EGL-4, and the defects in the sensory cilium structure may disturb the balanced control of the cGMP level. The large number of guanylyl cyclases encoded in the C. elegans genome suggests that EGL-4 exerts pleiotropic effects by partnering with different guanylyl cyclases for different downstream functions. PMID- 26434724 TI - Natural Variations in SLG7 Regulate Grain Shape in Rice. AB - Rice (Oryza sativa) grain shape, which is controlled by quantitative trait loci (QTL), has a strong effect on yield production and quality. However, the molecular basis for grain development remains largely unknown. In this study, we identified a novel QTL, Slender grain on chromosome 7 (SLG7), that is responsible for grain shape, using backcross introgression lines derived from 9311 and Azucena. The SLG7 allele from Azucena produces longer and thinner grains, although it has no influence on grain weight and yield production. SLG7 encodes a protein homologous to LONGIFOLIA 1 and LONGIFOLIA 2, both of which increase organ length in Arabidopsis. SLG7 is constitutively expressed in various tissues in rice, and the SLG7 protein is located in plasma membrane. Morphological and cellular analyses suggested that SLG7 produces slender grains by longitudinally increasing cell length, while transversely decreasing cell width, which is independent from cell division. Our findings show that the functions of SLG7 family members are conserved across monocots and dicots and that the SLG7 allele could be applied in breeding to modify rice grain appearance. PMID- 26434726 TI - Zinc is a transmembrane agonist that induces platelet activation in a tyrosine phosphorylation-dependent manner. AB - Following platelet adhesion and primary activation at sites of vascular injury, secondary platelet activation is induced by soluble platelet agonists, such as ADP, ATP, thrombin and thromboxane. Zinc ions are also released from platelets and damaged cells and have been shown to act as a platelet agonist. However, the mechanism of zinc-induced platelet activation is not well understood. Here we show that exogenous zinc gains access to the platelet cytosol and induces full platelet aggregation that is dependent on platelet protein tyrosine phosphorylation, PKC and integrin alphaIIbbeta3 activity and is mediated by granule release and secondary signalling. ZnSO4 increased the binding affinity of GpVI, but not integrin alpha2beta1. Low concentrations of ZnSO4 potentiated platelet aggregation by collagen-related peptide (CRP-XL), thrombin and adrenaline. Chelation of intracellular zinc reduced platelet aggregation induced by a number of different agonists, inhibited zinc-induced tyrosine phosphorylation and inhibited platelet activation in whole blood under physiologically relevant flow conditions. Our data are consistent with a transmembrane signalling role for zinc in platelet activation during thrombus formation. PMID- 26434727 TI - Polyvinylpyrrolidone (PVP) in nanoparticle synthesis. AB - Colloidal synthesis offers a route to nanoparticles (NPs) with controlled composition and structural features. This Perspective describes the use of polyvinylpyrrolidone (PVP) to obtain such nanostructures. PVP can serve as a surface stabilizer, growth modifier, nanoparticle dispersant, and reducing agent. As shown with examples, its role depends on the synthetic conditions. This dependence arises from the amphiphilic nature of PVP along with the molecular weight of the selected PVP. These characteristics can affect nanoparticle growth and morphology by providing solubility in diverse solvents, selective surface stabilization, and even access to kinetically controlled growth conditions. This Perspective includes discussions of the properties of PVP-capped NPs for surface enhanced Raman spectroscopy (SERS), assembly, catalysis, and more. The contribution of PVP to these properties as well as its removal is considered. Ultimately, the NPs accessed through the use of PVP in colloidal syntheses are opening new applications, and the concluding guidelines provided herein should enable new nanostructures to be accessed facilely. PMID- 26434728 TI - A multifunctional transparent superhydrophobic gel nanocoating with self-healing properties. AB - Inspired by mussels we designed a novel green superhydrophobic gel nanocoating with good transparency and stability through a facile copolymerization reaction at room temperature and a subsequent trimethyl silyl modified process, which is applicable to various substrates via a simple spray process without requiring toxic substances. Importantly, this well-designed nanocoating has rapid self healing superhydrophobicity induced by usual organic solvents to face complicated work conditions, which satisfies the need of daily life and can be applied in industry as well. PMID- 26434729 TI - Remarks on energetic conditions for positronium formation in non-polar solids. Coupled dipole method application. AB - A numerical program calculating the energy of a positron or/and an electron near the free volume in solid n-alkanes has been built. The theory of the interaction of e(+) or/and e(-) with this non-polar medium based on polarizability has been introduced. The energy of the e(+)-e(-) pair in the bulk was compared to that calculated when the pair forms a positronium (Ps) inside the free volume. The calculations are based on the coupled dipole method and the dipole-dipole interaction energy for induced dipoles is taken into account. Furthermore, a correction for the local permittivity for the e(+)-e(-) interaction is calculated taking into account the non-isotropic medium between them. The method is a step toward more accurate calculations of energetic conditions during Ps formation in matter. The possibility of the emission of the excess energy of the Ps formation as electromagnetic radiation is discussed. It is argued that if this radiation is observed, it can be used as a new spectroscopic tool providing information about the microscopic properties of media. PMID- 26434731 TI - On-surface derivatisation of aromatic molecules on graphene: the importance of packing density. AB - An efficient, high-throughput method for the formation of densely packed molecular films on graphene is reported. The films exhibit high stability and remain intact during a subsequent derivatisation reaction, offering a versatile route for the non-covalent functionalisation of graphene. PMID- 26434732 TI - One-Pot Relay Gold(I) and Bronsted Acid Catalysis: Cyclopenta[b]annulation of Indoles via Hydroamination/Nazarov-Type Cyclization Cascade of Enynols. AB - An expedient relay gold(I) and Bronsted acid catalyzed hydroamination/Nazarov cyclization of 1-(2-aminophenyl)pent-4-en-2-ynols for the synthesis of various polyfunctionalized cyclopenta[b]indoles is described. The synthetic utility of this method has been demonstrated by the synthesis of a few unprecedented pentacyclic indoles and indole-steroidal hybrids. Further, the new methodology has been successfully applied to the enantioselective synthesis of core carbon structure of the polyveoline family of natural products. PMID- 26434730 TI - Improved OTU-picking using long-read 16S rRNA gene amplicon sequencing and generic hierarchical clustering. AB - BACKGROUND: High-throughput bacterial 16S rRNA gene sequencing followed by clustering of short sequences into operational taxonomic units (OTUs) is widely used for microbiome profiling. However, clustering of short 16S rRNA gene reads into biologically meaningful OTUs is challenging, in part because nucleotide variation along the 16S rRNA gene is only partially captured by short reads. The recent emergence of long-read platforms, such as single-molecule real-time (SMRT) sequencing from Pacific Biosciences, offers the potential for improved taxonomic and phylogenetic profiling. Here, we evaluate the performance of long- and short read 16S rRNA gene sequencing using simulated and experimental data, followed by OTU inference using computational pipelines based on heuristic and complete linkage hierarchical clustering. RESULTS: In simulated data, long-read sequencing was shown to improve OTU quality and decrease variance. We then profiled 40 human gut microbiome samples using a combination of Illumina MiSeq and Blautia-specific SMRT sequencing, further supporting the notion that long reads can identify additional OTUs. We implemented a complete-linkage hierarchical clustering strategy using a flexible computational pipeline, tailored specifically for PacBio circular consensus sequencing (CCS) data that outperforms heuristic methods in most settings: https://github.com/oscar-franzen/oclust/ . CONCLUSION: Our data demonstrate that long reads can improve OTU inference; however, the choice of clustering algorithm and associated clustering thresholds has significant impact on performance. PMID- 26434733 TI - Unique features of human cathelicidin LL-37. AB - Cathelicidins are antimicrobial peptides produced by humans and animals in response to various pathogenic microbes. This review intends to provide a brief overview of the expression, structure, properties and function of human cathelicidin LL-37 which may be a therapeutic agent against a variety of bacterial and viral diseases, cancers, and hard-to-heal wounds. Cathelicidins act as a primary defense against bacteria and other pathogens in the case of inflammation. They are able to kill bacteria and fungi, inhibit and destroy bacterial biofilms, and possess antiviral and antiparasitics properties. They can also play a role in angiogenesis, wound healing, and the regulation of apoptosis. The host defense peptide LL-37 has emerged as a novel modulator of tumor growth and metastasis in carcinogenesis of various types of cancers. LL-37 is an antimicrobial peptide able of inducing various effects. It acts as an anti- and pro- inflammatory factor. Cathelicidins are able to directly and selectively destroy membranes of various microbes and cancer cells, but they do not attack normal cells. The role of cathelicidins in cancer is double-sided. They play an important role in killing cancer cells and may provide a new possibility for the development of cancer therapeutics. However, they also can participate in carcinogenesis. Due to its activity spectrum LL-37 could be applied in pharmacotherapy. Cathelicidin peptides could serve as a template for the development of modern anti-microbial and anti-viral drugs. LL-37 is an excellent candidate to develop into therapeutics for infected wounds. PMID- 26434734 TI - Retrospective volume analysis of bone remodeling after tooth extraction with and without deproteinized bovine bone mineral insertion. AB - OBJECTIVES: The aim of the study was to analyze volume changes of post-extractive sockets grafted with or without deproteinized bovine bone mineral (DBBM) and a resorbable barrier. MATERIALS AND METHODS: This retrospective analysis utilized patients who had undergone tooth extraction. Sites, one per patient, were allocated to two groups: post-extractive non-grafted sockets (NG) and post extractive grafted sockets with DBBM and resorbable barrier insertion (G). Maximal primary soft tissue closure was sought for both procedures. Before extraction and 6 months later, three-dimensional features of the sockets (linear indexes, areas, and volumes) and outcome variables at 6 months (volume- and surface changes) were acquired through computer tomography scans. Intra- and inter-group comparisons of the outcome variables were performed. Nonparametric tests were applied with a level of significance set at P < 0.01. RESULTS: Twenty four sites, 9 grafted and 15 ungrafted, were enrolled. Between baseline and the 6 month evaluation, significant bone volume loss, superior surface shrinkage, and height reduction were registered for the G (72 mm(3) , 76 mm(2) , and 0.5 mm, respectively) and the NG group (274 mm(3) , 87 mm(2) , and 1.8 mm, respectively) with all P-values <= 0.0039. A significant difference, regarding the percentage of the volume change, was registered between the two procedures with a volume loss of 9.9% for the grafted sockets and 34.8% for the ungrafted ones (P-value = 0.0073). CONCLUSION: Grafting of the sockets with DBBM and a resorbable barrier insertion seemed to reduce negative osseous remodeling in the short term when compared to that of the ungrafted sockets. PMID- 26434735 TI - Assessment of the cryoprotectant concentration inside a bulky organ for cryopreservation using X-ray computed tomography. AB - Cryoprotection of bulky organs is crucial for their storage and for subsequent transplantation. In this work we demonstrate the capability of the X-ray computed tomography (CT) as a non-invasive method to measure the cryoprotectant (cpa) concentration inside a tissue or an organ, specifically for the case of dymethil sulfoxide (Me2SO). It is remarkable that the use of Me2SO has been leader in techniques of cells and tissues cryopreservation. Although CT technologies are mainly based in density differences, and many cpas are alcohols with densities similar to water, the use of very low energies as acceleration voltage (~70 kV) and the sulfur atom in the molecule of Me2SO makes possible the visualization of this cpa inside tissues. As result we obtain a CT signal proportional to the Me2SO concentration with a spatial resolution up to 50 MUm in the case of our device. PMID- 26434736 TI - On reflexivity and the conduct of the self in everyday life: reflections on Bourdieu and Archer. AB - This article provides a critique of the concept of reflexivity in social theory today and argues against the tendency to define agency exclusively in terms of reflexivity. Margaret Archer, in particular, is highlighted as a key proponent of this thesis. Archer argues that late modernity is characterized by reflexivity but, in our view, this position neglects the impact of more enduring aspects of agency, such as the routinization of social life and the role of the taken-for granted. These concepts were pivotal to Bourdieu and Giddens' theorization of everyday life and action and to Foucault's understanding of technologies of the self. We offer Bourdieu's habitus as a more nuanced approach to theorizing agency, and provide an alternative account of reflexivity. Whilst accepting that reflexivity is a core aspect of agency, we argue that it operates to a backdrop of the routinization of social life and operates from within and not outside of habitus. We highlight the role of the breach in reflexivity, suggesting that it opens up a critical window for agents to initiate change. The article suggests caution in over-ascribing reflexivity to agency, instead arguing that achieving reflexivity and change is a difficult and fraught process, which has emotional and moral consequences. The effect of this is that people often prefer the status quo, rather than to risk change and uncertainty. PMID- 26434737 TI - Regrowth patterns and rosette attributes contribute to the differential compensatory responses of Arabidopsis thaliana genotypes to apical damage. AB - A plant's compensatory performance refers to its ability to maintain or increase its reproductive output following damage. The ability of a plant to compensate depends on numerous factors including the type, severity, frequency and timing of damage, the environmental conditions and the plant's genotype. Upon apical damage, a cascade of hormonal and genetic responses often produces dramatic changes in a plant's growth, development, architecture and physiology. All else being equal, this response is largely dependent on a plant's genotype, with different regrowth patterns displayed by different genotypes of a given species. In this study, we compare the architectural and growth patterns of two Arabidopsis thaliana genotypes following apical damage. Specifically, we characterise regrowth patterns of the genotypes Columbia-4 and Landsberg erecta, which typically differ in their compensation to apical meristem removal. We report that Landsberg erecta suffered reductions in the number of stems produced, maximum elongation rate, a delay in reaching this rate, lower average rosette quality throughout the growing period, and ultimately, less aboveground dry biomass and seed production when damaged compared to undamaged control plants. Columbia-4 had no reductions in any of these measures and maintained larger rosette area when clipped relative to when unclipped. Based on the apparent influence of the rosette on these genotypes' compensatory performances, we performed a rosette removal experiment, which confirmed that the rosette contributes to compensatory performance. This study provides a novel characterisation of regrowth patterns following apical damage, with insights into those measures having the largest effect on plant performance. PMID- 26434738 TI - Proactive treatment with calcipotriol reduces recurrence of plaque psoriasis. AB - Topical calcipotriol is a widely used treatment for plaque-type psoriasis worldwide, and has been shown to improve psoriatic plaques as well as very potent corticosteroids. However, there remains the practical question of whether calcipotriol application should continue on healed pigmentation/depigmentation associated with psoriatic plaques. Therefore, we conducted a pilot clinical study to answer this question. Plaque-type psoriatic patients not receiving systemic treatment were enrolled and treated with calcipotriol for 8 weeks (stage I) to achieve maximum effect. The patients were then divided into two groups: group A continued to apply calcipotriol to the entirety of the previous lesion (including pigmentation/depigmentation) regardless of whether skin was healed or not, while group B applied calcipotriol to the remaining lesion only. Patients were followed for 12 weeks (stage II) and dates of plaque recurrence were recorded. A total of 29 patients (13 men, 16 women) were enrolled. During stage I, reductions in scores for redness, induration and scale occurred in 40%, 47% and 55% of patients, respectively. After stage II was completed, group A (n = 19) showed a significantly better Kaplan-Meier curve of non-recurrence than group B (n = 8, P < 0.01). The mean non-recurrence duration was 76.8 +/- 11.8 in group A and 35.0 +/- 12.0 in group B. Our study showed that applying topical calcipotriol on seemingly healed psoriatic plaque lesions suppresses recurrence better than applying it only on remaining plaques. This finding may be important for instructing psoriatic patients on topical calcipotriol treatment. PMID- 26434739 TI - Renal Denervation in Patients With Uncontrolled Hypertension and Confirmed Adherence to Antihypertensive Medications. AB - Renal denervation (RDN) has emerged as a potential device-based treatment for resistant hypertension. The authors present their experience of the use of catheter-based RDN as part of routine clinical care in two specialist hypertension clinics. Thirty-four patients with uncontrolled hypertension underwent RDN. All patients had ambulatory blood pressure (BP) monitoring and directly observed medication administration prior to the procedure to exclude white-coat hypertension and nonadherence, respectively. Overall, there was a significant change in clinic systolic BP of -15.1 mm Hg (95% confidence interval, -23.4 to -6.8; P=.001) and clinic diastolic BP of -6.2 mm Hg (95% confidence interval, -11.5 to -0.9; P=.02) 6 months postprocedure, and a nonsignificant change in daytime ambulatory BP of -5.4/-2.9 mm Hg. Eighteen patients (51.4%) showed a significant reduction in their clinic systolic BP (>=10 mm Hg) and 16 (47%) had a significant reduction in their daytime ambulatory systolic BP (>=5 mm Hg) at 6 months. PMID- 26434740 TI - Enhanced Pain Sensitivity Among Individuals With Symptomatic Knee Osteoarthritis: Potential Sex Differences in Central Sensitization. AB - OBJECTIVE: Symptomatic knee osteoarthritis (OA) is a condition commonly associated with increased pain, disability, and functional limitations. Given the poor correspondence between radiographic evidence and clinical pain, central sensitization has been implicated as a potential mechanism underlying pain facilitation in knee OA. Sex may be a moderator of centrally mediated changes in knee OA pain; however, few studies have systematically assessed this. Therefore, the aim of this study was to examine differences in peripheral and central sensitization in men and women with symptomatic knee OA, as well as to determine whether these differences vary across age (middle age versus older age). METHODS: Participants (n = 288) between the ages of 45 and 85 years completed a battery of quantitative sensory pain procedures assessing sensitivity to contact heat, cold pressor, mechanical pressure, and punctate stimuli. Differences in temporal summation (TS) were examined, as well as measures of clinical pain and functional performance. RESULTS: When compared to men, women exhibited greater sensitivity to multiple pain modalities (i.e., lower heat, cold, pressure thresholds/tolerances, greater TS of pain); however, there were no sex differences in clinical pain, with the exception of greater widespread pain observed in women. Although there were select age-related differences in pain sensitivity, sex differences in pain varied minimally across the age cohort. CONCLUSION: Overall, these findings provide evidence for greater overall sensitivity to experimental pain in women with symptomatic knee OA compared to men, suggesting that enhanced central sensitivity may be an important contributor to pain in this group. PMID- 26434741 TI - Esco2 regulates cx43 expression during skeletal regeneration in the zebrafish fin. AB - BACKGROUND: Roberts syndrome (RBS) is a rare genetic disorder characterized by craniofacial abnormalities, limb malformation, and often severe mental retardation. RBS arises from mutations in ESCO2 that encodes an acetyltransferase and modifies the cohesin subunit SMC3. Mutations in SCC2/NIPBL (encodes a cohesin loader), SMC3 or other cohesin genes (SMC1, RAD21/MCD1) give rise to a related developmental malady termed Cornelia de Lange syndrome (CdLS). RBS and CdLS exhibit overlapping phenotypes, but RBS is thought to arise through mitotic failure and limited progenitor cell proliferation while CdLS arises through transcriptional dysregulation. Here, we use the zebrafish regenerating fin model to test the mechanism through which RBS-type phenotypes arise. RESULTS: esco2 is up-regulated during fin regeneration and specifically within the blastema. esco2 knockdown adversely affects both tissue and bone growth in regenerating fins consistent with a role in skeletal morphogenesis. esco2-knockdown significantly diminishes cx43/gja1 expression which encodes the gap junction connexin subunit required for cell-cell communication. cx43 mutations cause the short fin (sof(b123) ) phenotype in zebrafish and oculodentodigital dysplasia (ODDD) in humans. Importantly, miR-133-dependent cx43 overexpression rescues esco2 dependent growth defects. CONCLUSIONS: These results conceptually link ODDD to cohesinopathies and provide evidence that ESCO2 may play a transcriptional role critical for human development. PMID- 26434743 TI - Bacillus thuringiensis subsp. israelensis producing endochitinase ChiA74Deltasp inclusions and its improved activity against Aedes aegypti. AB - AIMS: The objective of this study was to produce stable inclusions of chitinase ChiA74Deltasp in Bacillus thuringiensis subsp. israelensis (Bti) and to assay its insecticidal activity against Aedes aegypti larvae. METHODS AND RESULTS: Bti was transformed with chiA74Deltasp regulated by its own promoter or by the strong chimeric cytAp/STAB-SD promoter system to generate two recombinant Bti strains. These recombinants produced their native parasporal bodies composed of Cry4Aa, Cry4Ba, Cry11Aa and Cyt1Aa and ChiA74Deltasp inclusions, and showed a approx. threefold increase in both endochitinase activity and viable spore count when compared with the parental strain. Both recombinants were approximately twofold more toxic (LC50s 8.02, 9.6 ng ml(-1) ) than parental Bti (19.8 ng ml(-1) ) against 4(th) instars of A. aegypti larvae. CONCLUSIONS: ChiA74Deltasp inclusions, together with the insecticidal crystals and spores of Bti increased the toxicity against A. aegypti larvae by at least twofold. SIGNIFICANCE AND IMPACT OF THE STUDY: We report for the first time the engineering of Bti to produce spore-parasporal body-ChiA74?sp inclusions in the same sporangium, which are released together following autolysis. Our work lays a foundation for engineering Bti to produce more efficacious combinations of Cry4Aa, Cry4Ba, Cry11Aa, Cyt1Aa and chitinase inclusions. PMID- 26434744 TI - Highlighting the problematic reliance on CD18 for diagnosing leukocyte adhesion deficiency type 1. AB - Leukocyte adhesion deficiency type 1 (LAD-1) is an autosomal recessive primary immunodeficiency, hallmarked by defective polymorphonuclear transmigration. It is caused by mutations in the gene encoding CD18, which interfere with the CD18/CD11 heterodimerization and expression on leukocyte cell surface. LAD-1 diagnosis rests primarily on the measurement of CD18 expression. However, CD18 measurement entails its pitfalls. Here we present a cohort of ten LAD patients and a review of the relevant literature illustrating the difficulties in sole reliance on CD18 measurement for initial diagnosis. These include normal range expression in some mutations, great variability between patients with the same mutation and subjective interpretation of results. We think there is a need for additional markers as part of the initial LAD diagnostic algorithm. We suggest CD11a expression, which was near absent in all patients in our cohort. The dual use of CD18 and CD11a can increase testing sensitivity and prevent delayed diagnosis of LAD-1. PMID- 26434745 TI - In Vivo Evaluation of Two-Piece Implants Placed Following One-Stage and Two-Stage Surgical Protocol in Posterior Mandibular Region. Assessment of Alterations in Crestal Bone Level. AB - BACKGROUND: Endosseous implants can be placed following either two-stage technique requiring second-stage surgery or one-stage technique, which does not involve a second surgical intervention. PURPOSE: The present study was undertaken to evaluate and compare the changes in crestal bone level when two-piece implants were placed in posterior mandibular region following one-stage and two-stage surgical protocol. MATERIALS AND METHODS: A parallel group randomized prospective study was designed in which 20 two-piece implants were placed in the posterior mandibular region of 16 partially edentulous healthy patients following either one-stage (Group I) or a two-stage surgical protocol (Group II). Alterations in crestal bone level were assessed with the help of DentaScan at baseline, that is, at the time of implant placement, third month and sixth month. RESULTS: Nonsignificant differences were seen in both groups in terms of changes in crestal bone level at the final evaluation. CONCLUSIONS: Hence, it could be concluded that two-piece implants can be placed following one-stage surgical protocol as predictably as when two-stage surgical technique is followed. PMID- 26434742 TI - Leveraging ecological theory to guide natural product discovery. AB - Technological improvements have accelerated natural product (NP) discovery and engineering to the point that systematic genome mining for new molecules is on the horizon. NP biosynthetic potential is not equally distributed across organisms, environments, or microbial life histories, but instead is enriched in a number of prolific clades. Also, NPs are not equally abundant in nature; some are quite common and others markedly rare. Armed with this knowledge, random 'fishing expeditions' for new NPs are increasingly harder to justify. Understanding the ecological and evolutionary pressures that drive the non uniform distribution of NP biosynthesis provides a rational framework for the targeted isolation of strains enriched in new NP potential. Additionally, ecological theory leads to testable hypotheses regarding the roles of NPs in shaping ecosystems. Here we review several recent strain prioritization practices and discuss the ecological and evolutionary underpinnings for each. Finally, we offer perspectives on leveraging microbial ecology and evolutionary biology for future NP discovery. PMID- 26434746 TI - Sutureless 3F Enable Valve Replacement for Pure Aortic Regurgitation. AB - BACKGROUND AND AIM: We present our experience in the use of the sutureless valve in patients undergoing aortic valve replacement for pure aortic regurgitation. METHODS: Out of 167 patients who underwent sutureless aortic valve implantation with a Medtronic 3f Enable prosthesis in our unit between March 2011 and February 2014, 12 (7.1%) received a sutureless valve for pure aortic regurgitation. RESULTS: Mean age, logistic EuroSCORE, and left ventricular ejection fraction were 72 +/- 5 years, 6.3 +/- 2.9%, and 52.5 +/- 15.3%, respectively. The sutureless valve could be successfully implanted in all cases; nine patients had a full sternotomy (associated coronary artery bypass graft in four cases and associated mitral surgery in five), one patient had a ministernotomy, and two had a thoracoscopic approach. Average cross-clamping and cardiopulmonary bypass times were 90 +/- 30 and 127 +/- 51 minutes, respectively. At the outpatient echocardiography, average mean gradient was 10.54 +/- 4.99 mmHg and a grade I-II paravalvular leakage (PVL) was detected in the first patient of the cohort (ministernotomy approach). At a mean follow-up of 11.1 +/- 5.5 months, average mean gradient was 9.75 +/- 2.87 mmHg, no new PVL was detected, and the known PVL was stable. No pacemaker implantation was required. CONCLUSIONS: Implantation of the 3f Enable sutureless valve is technically possible with pure aortic regurgitation in selected patients. Multicenter investigations are necessary to assess the mid-term benefits of such a device in this subset of patients. PMID- 26434747 TI - As I recall the beginning of the American journal of hematology forty years ago. PMID- 26434749 TI - Melanosomes and ancient coloration re-examined: A response to Vinther 2015 (DOI 10.1002/bies.201500018). AB - Round to elongate microbodies associated with fossil vertebrate soft tissues were interpreted as microbial traces until 2008, when they were re-described as remnant melanosomes - intracellular, pigment-containing eukaryotic organelles. Since then, multiple claims for melanosome preservation and inferences of organismal color, behavior, and physiology have been advanced, based upon the shape and size of these microstructures. Here, we re-examine evidence for ancient melanosomes in light of information reviewed in Vinther (2015), and literature regarding the preservation potential of microorganisms and their exopolymeric secretions. We: (i) address statements in Vinther's recent (2015) review that are incorrect or which misrepresent published data; (ii) discuss the need for caution in interpreting "voids" and microbodies associated with degraded fossil soft tissues; (iii) present evidence that microorganisms are in many cases an equally parsimonious source for these "voids" as are remnant melanosomes; and (iv) suggest methods/criteria for differentiating melanosomes from microbial traces in the fossil record. PMID- 26434748 TI - Glucagon increases energy expenditure independently of brown adipose tissue activation in humans. AB - AIMS: To investigate, for a given energy expenditure (EE) rise, the differential effects of glucagon infusion and cold exposure on brown adipose tissue (BAT) activation in humans. METHODS: Indirect calorimetry and supraclavicular thermography was performed in 11 healthy male volunteers before and after: cold exposure; glucagon infusion (at 23 degrees C); and vehicle infusion (at 23 degrees C). All volunteers underwent (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET)/CT scanning with cold exposure. Subjects with cold-induced BAT activation on (18)F-FDG PET/CT (n = 8) underwent a randomly allocated second (18)F-FDG PET/CT scan (at 23 degrees C), either with glucagon infusion (n = 4) or vehicle infusion (n = 4). RESULTS: We observed that EE increased by 14% after cold exposure and by 15% after glucagon infusion (50 ng/kg/min; p < 0.05 vs control for both). Cold exposure produced an increase in neck temperature (+0.44 degrees C; p < 0.001 vs control), but glucagon infusion did not alter neck temperature. In subjects with a cold-induced increase in the metabolic activity of supraclavicular BAT on (18)F-FDG PET/CT, a significant rise in the metabolic activity of BAT after glucagon infusion was not detected. Cold exposure increased sympathetic activation, as measured by circulating norepinephrine levels, but glucagon infusion did not. CONCLUSIONS: Glucagon increases EE by a similar magnitude compared with cold activation, but independently of BAT thermogenesis. This finding is of importance for the development of safe treatments for obesity through upregulation of EE. PMID- 26434750 TI - Lactobacillus rhamnosus GG SpaC pilin subunit binds to the carbohydrate moieties of intestinal glycoconjugates. AB - Lactobacillus rhamnosus GG (LGG) is a well-established probiotic strain. The beneficial properties of this strain are partially dependent on its prolonged residence in the gastrointestinal tract, and are likely influenced by its adhesion to the intestinal mucosa. The pilin SpaC subunit, located within the Spa pili structure, is the most well studied LGG adhesion factor. However, the binding epitopes of SpaC remain largely unknown. The aim of this study was to evaluate the binding properties of SpaC to the carbohydrate moieties of intestinal glycoconjugates using a recombinant SpaC protein. In a competitive enzyme-linked immunosorbent assay, SpaC binding was markedly reduced by addition of purified mucin and the mucin oligosaccharide fraction. Histochemical staining revealed that the binding of SpaC was drastically reduced by periodic acid treatment. Moreover, in the surface plasmon resonance-based Biacore assay, SpaC bound strongly to the carbohydrate moieties containing beta-galactoside at the non-reducing terminus of glycolipids. We here provide the first demonstration that SpaC binds to the oligosaccharide chains of mucins, and that the carbohydrate moieties containing beta-galactoside at the non-reducing termini of glycoconjugates play a crucial role in this binding. Our results demonstrate the importance of carbohydrates of SpaC for mucus interactions. PMID- 26434751 TI - Funnel compression suture: a conservative procedure to control postpartum bleeding from the lower uterine segment. AB - Bleeding from the lower uterine segment (LUS) during caesarean section remains a life-threatening obstetric problem, particularly in women with placenta praevia or partial placenta accreta in the LUS. Various conservative measures for the surgical treatment of postpartum haemorrhage have been studied for decades. In this paper we describe a funnel compression suture to staunch intractable bleeding from LUS for placenta praevia accreta. The suture brings the anterior and posterior walls of the LUS together using absorbable thread and was successful in the overwhelming majority of women. It is an easy, safe and effective conservative surgical treatment to stop severe bleeding of the LUS. PMID- 26434752 TI - Impact of pharmacist involvement in the transitional care of high-risk patients through medication reconciliation, medication education, and postdischarge call backs (IPITCH Study). AB - BACKGROUND: Previous data suggest that direct pharmacist interaction with patients through medication reconciliation, discharge counseling, and postdischarge phone calls decreases the number of adverse drug events (ADEs) and plays an overall positive role in transitional care. Previous studies have evaluated pharmacist involvement in improving transitional care, but these studies did not include multiple postdischarge follow-up phone calls. OBJECTIVES: The objectives of this study were to assess the impact of pharmacist involvement in transitions of care as measured by decreased medication errors (MEs) and ADEs, patients' knowledge related to communication about their medications as measured by improvement in the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores, and 30-day all-cause inpatient readmissions and emergency department (ED) visits. METHODS: This was a prospective, randomized, single-period longitudinal study that occurred from November 2012 through June 2013 at an urban, tertiary, academic medical center. Patients admitted to 2 designated internal medicine units on high-risk medications or with greater than 3 prescription medications upon discharge were included for randomization. The control group received the usual hospital standard of care. The study group received face-to-face medication reconciliation, a patient-specific pharmaceutical care plan, discharge counseling, and postdischarge phone calls on days 3, 14, and 30 to provide education and assess study endpoints. RESULTS: A total of 278 patients were included in the final analysis, with 141 in the control group and 137 in the study group. Fifty-five patients (39%) in the control arm experienced an inpatient readmission or ED visit within 30-days postdischarge compared to 34 patients (24.8%) in the study arm (P = 0.01). Eighteen patients (12.8%) in the control group experienced an ADEs or MEs compared to 11 patients (8%) in the study group (P > 0.05). The HCAHPS scores during the study period showed a 9% improvement for the assessed questionnaire domain (P > 0.05). CONCLUSIONS: This study demonstrated that pharmacist involvement in hospital discharge transitions of care had a positive impact on decreasing composite inpatient readmissions and ED visits. Statistically significant difference in medication-related events and HCAHPS scores were not observed. Patients with moderately complex medication regimens benefited from a continuity of care involving a pharmacy team during transitions in care. PMID- 26434753 TI - Droplet digital polymerase chain reaction assay for screening of ESR1 mutations in 325 breast cancer specimens. AB - Droplet digital polymerase chain reaction (ddPCR), which could perform thousands of PCRs on a nanoliter scale simultaneously, would be an attractive method to massive parallel sequencing for identifying and studying the significance of low frequency rare mutations. Recent evidence has shown that the key potential mechanisms of the failure of aromatase inhibitors-based therapy involve identifying activating mutations affecting the ligand-binding domain of the ESR1 gene. Therefore, the detection of ESR1 mutations may be useful as a biomarker predicting an effect of the treatment. We aimed to develop a ddPCR-based method for the sensitive detection of ESR1 mutations in 325 breast cancer specimens, in which 270 primary and 55 estrogen receptor-positive (ER+) metastatic breast cancer (MBC) specimens. Our ddPCR assay could detect the ESR1 mutant molecules with low concentration of 0.25 copies/MUL. According to the selected cutoff, ESR1 mutations occurred in 7 (2.5%) of 270 primary breast cancer specimens and in 11 (20%) of 55 ER+ MBC specimens. Among the 11 MBC specimens, 5 specimens (45.5%) had the most common ESR1 mutation, Y537S, 4 specimens (36.3%) each had D538G, Y537N, and Y537C. Interestingly, 2 patients had 2 ESR1 mutations, Y537N/D538G and Y537S/Y537C, and 2 patients had 3 ESR1 mutations, Y537S/Y537N/D538G. Biopsy was performed in heterochrony in 8 women twice. In 8 women, 4 women had primary breast cancer and MBC specimens and 4 women had 2 specimens when treatment was failure. Four of these 8 women acquired ESR1 mutation, whereas no ESR1 mutation could be identified at first biopsy. ddPCR technique could be a promising tool for the next-generation sequencing-free precise detection of ESR1 mutations in endocrine therapy resistant cases and may assist in determining the treatment strategy. PMID- 26434754 TI - The association between total leukocyte count and longevity: Evidence from longitudinal and cross-sectional data. AB - The aim of the study was to evaluate the relationship between age-dependent changes in total leukocyte count (TLC) and certain selected differential counts expressed as frequencies (granulocytes, band cells, eosinophils, lymphocytes, and monocytes) and longevity in physically healthy men and women aged 45+. Longitudinal data on cell counts from 142 subjects (68 men and 74 women; all aged 45-70 and examined for 25 years) were compared with cross-sectional data from 225 subjects (113 men and 112 women; this group was divided into four categories of average lifespan; i.e.: 53, 63, 68, and 76+ years of age). ANOVA, t-test, and regression analysis were employed. Secular changes in leukocyte count were controlled. Men had continuously higher TLC compared with women. Moreover, sex differences in patterns of changes with age were found. The longitudinal assessment revealed a U-shaped pattern of changes in TLC in men (y=0.0026x(2) 0.2866x+14.4374; R(2)=0.852) and women (y=0.0048x(2)-0.5386x+20.922; R(2)=0.938), whereas the cross-sectional comparison showed an inverted U-shaped pattern in men (y=-0.0021x(2)+0.2421x; R(2)=0.417) and women (y=-0.0017x(2)+0.2061x; R(2)=0.888). In general, the comparison of longitudinal and cross-sectional data on changes with age in TLC indicates that longevity favors individuals with lower yet normal TLC and this correlation is more pronounced in men. In conclusion, our findings are in line with previous longitudinal studies of aging and suggest that lower TLC within the normal range (4.0-10.0 * 10(3)MUL(-1)) can be a useful predictor of longevity in physically healthy individuals. PMID- 26434755 TI - Changes in collagens and chondrocytes in the temporomandibular joint cartilage in growing rats fed a liquid diet. AB - The temporomandibular joint (TMJ) of growing rats fed a soft diet is reported to be smaller in size and to have thinner condyle and glenoid fossa cartilage than rats fed a solid diet. The aim of this study was to determine the effect of a soft diet on the collagens and chondrocytes in the growing TMJ cartilage. Forty eight male Wistar rats were divided into a control group fed a solid diet and an experimental group fed a liquid diet for 1-8 weeks. After the experimental period, the TMJs were harvested and examined histologically, immunohistochemically for collagen types I, II, and X, and with transmission electron microscopy. The condylar cartilage in the experimental rats showed weak immunoreactions for three types of collagens compared with the controls. The ultrastructure had fewer fine collagen fibrils in the experimental rats compared with that of the controls. The glenoid fossa cartilage in the experimental rats showed narrower Alcian blue-positive areas than the control staining. The immunoreactions for three types of collagen in the experimental rats were also weaker than those of the controls. The chondrocytes in the experimental rats appeared dark, had extended thin cytoplasmic processes, and had formed gap junctions, as assessed by transmission electron microscopy. Fewer fine collagen fibrils, but thick bands of collagen fibrils were observed in the glenoid fossa of the experimental cartilage. The results of the present study showed that a liquid diet had deleterious effects on the quality and quantity of collagens and chondrocytes in the TMJ cartilage in growing rats. PMID- 26434756 TI - Morphological aspects and physical properties of enamel and dentine of Sus domesticus: A tooth model in laboratory research. AB - This study aims to describe and analyze morphological and physical properties of deciduous teeth of Sus domesticus. Ultrastructural analysis, mineral composition and microhardness of enamel and dentine tissues were performed on 10 skulls of S. domesticus. External anatomic characteristics and the internal anatomy of the teeth were also described. Data regarding microhardness and ultrastructural analysis were subjected to statistical tests. For ultrastructural analysis, we used the analysis of variance (ANOVA) with Tukey's post hoc (p<=0.05) test. In the analysis of microhardness, the difference between the enamel and dentine tissues was analyzed by a Student's t test. Values were expressed as mean with standard error. The results of ultrastructural analysis showed the presence of an enamel prism pattern. A dentinal tubule pattern was also observed, with a larger diameter in the pulp chamber and the cervical third, in comparison to middle and apical thirds. We observed an average microhardness of 259.2kgf/mm(2) for enamel and 55.17kgf/mm(2) for dentine. In porcine enamel and dentine, the chemical elements Ca and P showed the highest concentration. The analysis of internal anatomy revealed the presence of a simple root canal system and the occurrence of main canals in the roots. The observed features are compatible with the functional demand of these animals, following a pattern very similar to that seen in other groups of mammals, which can encourage the development of research using dental elements from the pig as a substitute for human teeth in laboratory research. PMID- 26434757 TI - Centric slide in different Angle's classes of occlusion. AB - The purpose of this study was to test the possible differences in centric slide values between different Angle's classes of occlusion. The study included 98 participants divided into four groups: Angle's class I, Angle's class II, subdivision 1, Angle's class II, subdivision 2 and Angle's class III. All recordings were obtained using an ultrasound jaw tracking device with six degrees of freedom. The distance between the maximum intercuspation (reference position) and the centric occlusion was recorded at the condylar level. Anteroposterior, superoinferior and transversal distance of the centric slide were calculated for each participant, and the data were statistically analyzed (analysis of variance and Newman-Keuls post hoc test). No statistically significant difference was found in the anteroposterior and transversal distance of the centric slide between tested groups, while Angle's class II, subdivision 2 showed smaller vertical amount of the centric slide compared to Angle's class I and class II, subdivision 1. None of the 98 participants showed coincidence of centric occlusion and maximum intercuspation. Our results suggest that coincidence of the maximum intercuspation with the centric occlusion should not be expected. Smaller extent of the vertical distance of the centric slide could be morphological and a functional expression characteristic of the Angle's class II, subdivision 2. PMID- 26434758 TI - Uptake of ferromagnetic carbon-encapsulated metal nanoparticles in endothelial cells: influence of shear stress and endothelial activation. AB - AIM: Magnetic field guided drug targeting holds promise for more effective cancer treatment. Intravascular application of magnetic nanoparticles, however, bears the risk of potentially important, yet poorly understood side effects, such as off-target accumulation in endothelial cells. MATERIALS & METHODS: Here, we investigated the influence of shear stress (0-3.22 dyn/cm(2)), exposure time (5 30 min) and endothelial activation on the uptake of ferromagnetic carbon encapsulated iron carbide nanomagnets into endothelial cells in an in vitro flow cell model. RESULTS: We found that even moderate shear stresses typically encountered in the venous system strongly reduce particle uptake compared with static conditions. Interestingly, a pronounced particle uptake was observed in inflamed endothelial cells. CONCLUSION: This study highlights the importance of relevant exposure scenarios accounting for physiological conditions when studying particle-cell interactions as, for example, shear stress and endothelial activation are major determinants of particle uptake. Such considerations are of particular importance with regard to successful translation of in vitro findings into (pre-)clinical end points. PMID- 26434759 TI - The association of serum sodium and chloride levels with blood pressure and estimated glomerular filtration rate. AB - BACKGROUND: High serum sodium (sNa) concentrations may be associated with hypertension, which deteriorates kidney function. However, it is equivocal whether high sNa concentrations are associated with impaired kidney function independently of blood pressure (BP) or serum chloride (sCl). Therefore, we addressed this issue in an apparently healthy population. METHODS: Clinical variables including estimated glomerular filtration rate (eGFR) were examined in 3603 men and women (aged 25-75 years) who underwent health-screening check-ups. sNa concentrations were classified into five categories. RESULTS: Most parameters, including age and BP, increased with increasing sNa, whereas eGFR decreased. Logistic regression analysis showed that, compared with low-normal sNa (<= 140 mEq/l), high sNa (>= 144 mEq/l) was significantly associated with elevated BP (>= 130/85 mmHg) even after adjustment for blood hematocrit, eGFR, serum potassium (sK) concentration and sCl. The highest sNa category was significantly associated with reduced eGFR (< 60 ml/min/1.73 m(2)) independently of elevated BP. Unlike adjustment for sK, adjustment for sCl strengthened the association between high sNa and elevated BP but attenuated the association between high sNa and reduced eGFR. CONCLUSIONS: These results suggest that high sNa concentrations, even within the normal range, are independently associated with elevated BP and impaired kidney function. These associations may be substantially modified by sCl. PMID- 26434760 TI - Site Covalent Modification of Methionyl Peptides for the Production of FRET Complexes. AB - Flax cyclic peptides (orbitides, linusorbs (LOs)) [1-8-NalphaC],[1-MetO2] linusorb B1 ([MetO2]-LO1) and [1-9-NalphaC],[1-MetO2]-linusorb B2 ([MetO2]-LO2) are biologically active. These LOs lack active nuclei commonly used in peptide modification. We have developed reactions to activate methionine methyl sulphide to produce stable derivatives. In these reactions, LOs are converted to sulfonium intermediates and subsequently to derivatives containing active nuclei while preserving their fundamental structures. The reaction conditions preserved cyclic peptide fundamental structure and organic solvent solubility. [Met]-LO1 and [Met] LO2 analogues containing activated groups (-CN, -COOEt, and -NH2 ) in the form of methionine, methionine (S)-oxide, and methionine (S,S)-dioxide amino acids were synthesized and characterized by LCMS and 1D and 2D NMR spectroscopy. Coumarin orbitide complexes produced in this manner bind Eu(3+) yielding FRET compounds that absorb energy through coumarin antennae and emit photons at lanthanide wavelengths. PMID- 26434766 TI - Design and fabrication of a metastable beta-type titanium alloy with ultralow elastic modulus and high strength. AB - Titanium and its alloys have become the most attractive implant materials due to their high corrosion resistance, excellent biocompatibility and relatively low elastic modulus. However, the current Ti materials used for implant applications exhibit much higher Young's modulus (50 ~ 120 GPa) than human bone (~30 GPa). This large mismatch in the elastic modulus between implant and human bone can lead to so-called "stress shielding effect" and eventual implant failure. Therefore, the development of beta-type Ti alloys with modulus comparable to that of human bone has become an ever more pressing subject in the area of advanced biomedical materials. In this study, an attempt was made to produce a bone compatible metastable beta-type Ti alloy. By alloying and thermo-mechanical treatment, a metastable beta-type Ti-33Nb-4Sn (wt. %) alloy with ultralow Young's modulus (36 GPa, versus ~30 GPa for human bone) and high ultimate strength (853 MPa) was fabricated. We believe that this method can be applied to developing advanced metastable beta-type titanium alloys for implant applications. Also, this approach can shed light on design and development of novel beta-type titanium alloys with large elastic limit due to their high strength and low elastic modulus. PMID- 26434764 TI - Extensive weight loss reveals distinct gene expression changes in human subcutaneous and visceral adipose tissue. AB - Weight loss has been shown to significantly improve Adipose tissue (AT) function, however changes in AT gene expression profiles particularly in visceral AT (VAT) have not been systematically studied. Here, we tested the hypothesis that extensive weight loss in response to bariatric surgery (BS) causes AT gene expression changes, which may affect energy and lipid metabolism, inflammation and secretory function of AT. We assessed gene expression changes by whole genome expression chips in AT samples obtained from six morbidly obese individuals, who underwent a two step BS strategy with sleeve gastrectomy as initial and a Roux-en Y gastric bypass as second step surgery after 12 +/- 2 months. Global gene expression differences in VAT and subcutaneous (S)AT were analyzed through the use of genome-scale metabolic model (GEM) for adipocytes. Significantly altered gene expressions were PCR-validated in 16 individuals, which also underwent a two step surgery intervention. We found increased expression of cell death-inducing DFFA-like effector a (CIDEA), involved in formation of lipid droplets in both fat depots in response to significant weight loss. We observed that expression of the genes associated with metabolic reactions involved in NAD+, glutathione and branched chain amino acid metabolism are significantly increased in AT depots after surgery-induced weight loss. PMID- 26434765 TI - Real-time Detection of Breast Cancer Cells Using Peptide-functionalized Microcantilever Arrays. AB - Ligand-directed targeting and capturing of cancer cells is a new approach for detecting circulating tumor cells (CTCs). Ligands such as antibodies have been successfully used for capturing cancer cells and an antibody based system (CellSearch((r))) is currently used clinically to enumerate CTCs. Here we report the use of a peptide moiety in conjunction with a microcantilever array system to selectively detect CTCs resulting from cancer, specifically breast cancer. A sensing microcantilever, functionalized with a breast cancer specific peptide 18 4 (WxEAAYQrFL), showed significant deflection on cancer cell (MCF7 and MDA-MB 231) binding compared to when exposed to noncancerous (MCF10A and HUVEC) cells. The peptide-functionalized microcantilever allowed efficient capture and detection of cancer cells in MCF7 spiked human blood samples emulating CTCs in human blood. A detection limit of 50-100 cancer cells mL(-1) from blood samples was achieved with a capture yield of 80% from spiked whole blood samples. The results emphasize the potential of peptide 18-4 as a novel peptide for capturing and detecting cancer cells in conjunction with nanomechanical cantilever platform. The reported peptide-based cantilever platform represents a new analytical approach that can lead to an alternative to the various detection platforms and can be leveraged to further study CTCs. PMID- 26434767 TI - Rapid low dose electron tomography using a direct electron detection camera. AB - We demonstrate the ability to record a tomographic tilt series containing 3487 images in only 3.5 s by using a direct electron detector in a transmission electron microscope. The electron dose is lower by at least one order of magnitude when compared with that used to record a conventional tilt series of fewer than 100 images in 15-60 minutes and the overall signal-to-noise ratio is greater than 4. Our results, which are illustrated for an inorganic nanotube, are important for ultra-low-dose electron tomography of electron-beam-sensitive specimens and real-time dynamic electron tomography of nanoscale objects with sub ms temporal resolution. PMID- 26434768 TI - Extended storage and glucose exhaustion are associated with apoptotic changes in platelets stored in additive solution. AB - BACKGROUND: The storage of platelets (PLTs) in additive solution (AS) may facilitate improved PLT quality and possibly extension of the PLT shelf life. A minimum amount of plasma is required when PLTs are stored in AS, as a source of glucose. The aim of this study was to assess the effect of reducing the plasma carryover to 20% on PLT quality when stored in SSP+ for an extended period. STUDY DESIGN AND METHODS: Using a pool-and-split design, buffy coat-derived PLTs were stored in either 30% plasma/SSP+ or 20% plasma/SSP+. In vitro analyses were carried out to Day 10. Metabolites and markers of PLT activation and apoptosis were measured using a blood gas analyzer and flow cytometry. PLT apoptotic protein expression was investigated by Western blotting. RESULTS: Glucose exhaustion occurred in the 20% plasma group between Day 7 and Day 10. The surface expression of P-selectin and PAC-1 was comparable on Day 10 in both groups, suggesting that the PLTs were not activated. However, the exposure of phosphatidylserine and the number of phosphatidylserine-positive microparticles were significantly higher in the 20% group on Day 10. The expression of the proapoptotic proteins Bak, Bax, and cleaved caspase-3 were higher in the 20% plasma group by Day 7 of storage, compared to the 30% plasma group. CONCLUSION: Exhaustion of glucose was associated with a proapoptotic phenotype. Results such as these should be considered before extending the PLT shelf life beyond 7 days, particularly when stored in ASs lacking glucose with low plasma carryover. PMID- 26434769 TI - The enhanced information flow from visual cortex to frontal area facilitates SSVEP response: evidence from model-driven and data-driven causality analysis. AB - The neural mechanism of steady-state visual evoked potentials (SSVEP) is still not clearly understood. Especially, only certain frequency stimuli can evoke SSVEP. Our previous network study reveals that 8 Hz stimulus that can evoke strong SSVEP response shows the enhanced linkage strength between frontal and visual cortex. To further probe the directed information flow between the two cortex areas for various frequency stimuli, this paper develops a causality analysis based on the inversion of double columns model using particle swarm optimization (PSO) to characterize the directed information flow between visual and frontal cortices with the intracranial rat electroencephalograph (EEG). The estimated model parameters demonstrate that the 8 Hz stimulus shows the enhanced directional information flow from visual cortex to frontal lobe facilitates SSVEP response, which may account for the strong SSVEP response for 8 Hz stimulus. Furthermore, the similar finding is replicated by data-driven causality analysis. The inversion of neural mass model proposed in this study may be helpful to provide the new causality analysis to link the physiological model and the observed datasets in neuroscience and clinical researches. PMID- 26434770 TI - An assessment of the amount of untapped fold level novelty in under-sampled areas of the tree of life. AB - Previous studies of protein fold space suggest that fold coverage is plateauing. However, sequence sampling has been -and remains to a large extent- heavily biased, focusing on culturable phyla. Sustained technological developments have fuelled the advent of metagenomics and single-cell sequencing, which might correct the current sequencing bias. The extent to which these efforts affect structural diversity remains unclear, although preliminary results suggest that uncultured organisms could constitute a source of new folds. We investigate to what extent genomes from uncultured and under-sampled phyla accessed through single cell sequencing, metagenomics and high-throughput culturing efforts have the potential to increase protein fold space, and conclude that i) genomes from under-sampled phyla appear enriched in sequences not covered by current protein family and fold profile libraries, ii) this enrichment is linked to an excess of short (and possibly partly spurious) sequences in some of the datasets, iii) the discovery rate of novel folds among sequences uncovered by current fold and family profile libraries may be as high as 36%, but would ultimately translate into a marginal increase in global discovery of novel folds. Thus, genomes from under-sampled phyla should have a rather limited impact on increasing coarse grained tertiary structure level novelty. PMID- 26434771 TI - Advice, authority and autonomy in shared decision-making in antenatal screening: the importance of context. AB - Shared decision-making (SDM) has been widely advocated across many branches of healthcare, yet there is considerable debate over both its practical application and how it should be examined or assessed. More recent discussions of SDM have highlighted the important of context, both internal and external to the consultation, with a recognition that decisions cannot be understood in isolation. This paper uses conversation analysis (CA) to examine how decision making is enacted in the context of antenatal screening consultations in Hong Kong. Building on previous CA work (Collins et al. , Toerien et al. 2013), we show that, whilst previously identified formats are used here to present the need for a decision, the overriding basis professionals suggest for actually making a decision in this context is the level of worry or concern a pregnant woman holds about potential foetal abnormality. Professionals take an unknowing 'epistemic stance' (Heritage ) towards this worry, and hence step back from involvement in decision-making. We argue that this is linked to the non-directive ethos that prevails in antenatal screening services, and suggest that more research is needed to understand how the enactment of SDM is affected by wider professional contexts and parameters. PMID- 26434772 TI - Molecular Anion Hydrogen Bonding Dynamics in Aqueous Solution. AB - The dynamic nature of hydrogen bonding between a molecular anion, selenocyanate (SeCN(-)), and water in aqueous solution (D2O) is addressed using FT-IR spectroscopy, two-dimensional infrared (2D IR) vibrational echo spectroscopy, and polarization selective IR pump-probe (PSPP) experiments performed on the CN stretching mode. The CN absorption spectrum is asymmetric with a wing on the low frequency (red) side of the line in contrast to the spectrum in the absence of hydrogen bonding. It is shown that the red wing is the result of an increase in the CN stretch transition dipole moment due to the effect of hydrogen bonding (non-Condon effect). This non-Condon effect is similar in nature to observations on pure water and other nonionic systems where hydrogen bonding enhances the extinction coefficient. The 2D IR measurements of spectral diffusion (solvent structural evolution) yield a time constant of 1.5 ps, which is within error the same as that of the OH stretch of HOD in D2O (1.4 ps). The orientational relaxation of SeCN(-) measured by PSPP experiments is long (4.04 ps) compared to the spectral diffusion time. The population decay at or near the absorption line center is a single-exponential decay of 37.4 +/- 0.3 ps, the vibrational lifetime. However, on the red side of the line the decay is biexponential with a low amplitude, fast component; on the blue side of the line there is a low amplitude, fast growth followed by the lifetime decay. Both of the fast components have 1.5 ps time constants, which is the spectral diffusion time. The fast components of the population decays are the results of the non-Condon effect that causes the red side of the line to be over pumped by the pump pulse. Spectral diffusion then produces the fast decay component on the red side of the line and the growth on the blue side of the line as the excess initial population on the red side produces a net population flow from red to blue. PMID- 26434773 TI - Maternal morbid obesity: financial implications of weight management. AB - The objective of this study was to evaluate health outcomes and costs of pregnancies complicated by extreme maternal obesity (class III obesity, body mass index >= 40). We conducted a retrospective case-control descriptive study comparing extremely obese women (cases) and their infants with randomly selected controls. Health outcomes were obtained from the medical records and costs from billing data. Total costs for each mother-infant dyad were calculated. Compared with 85 controls, the 82 cases experienced higher morbidity, higher costs and prolonged hospital stay. However, 26% of cases maintained or lost weight during pregnancy, whereas none of the controls maintained or lost weight during pregnancy. When mother/infant dyads were compared on costs, case subjects who maintained or lost weight experienced lower costs than those who gained weight. Neonatal intensive care consumed 78% of total hospital costs for infants of the obese women who gained weight, but only 48% of costs for infants of obese women who maintained or lost weight. For extremely obese women, weight management during pregnancy was achievable, resulted in healthier neonatal outcomes and reduced perinatal healthcare costs. PMID- 26434774 TI - Highly Stable and Tunable Chemical Doping of Multilayer WS2 Field Effect Transistor: Reduction in Contact Resistance. AB - The development of low resistance contacts to 2D transition-metal dichalcogenides (TMDs) is still a big challenge for the future generation field effect transistors (FETs) and optoelectronic devices. Here, we report a chemical doping technique to achieve low contact resistance by keeping the intrinsic properties of few layers WS2. The transfer length method has been used to investigate the effect of chemical doping on contact resistance. After doping, the contact resistance (Rc) of multilayer (ML) WS2 has been reduced to 0.9 kOmega.MUm. The significant reduction of the Rc is mainly due to the high electron doping density, thus a reduction in Schottky barrier height, which limits the device performance. The threshold voltage of ML-WS2 FETs confirms a negative shift upon the chemical doping, as further confirmed from the positions of E(1)2g and A1g peaks in Raman spectra. The n-doped samples possess a high drain current of 65 MUA/MUm, with an on/off ratio of 1.05 * 10(6) and a field effect mobility of 34.7 cm(2)/(V.s) at room temperature. Furthermore, the photoelectric properties of doped WS2 flakes were also measured under deep ultraviolet light. The potential of using LiF doping in contact engineering of TMDs opens new ways to improve the device performance. PMID- 26434775 TI - The Many Faces of Heterogeneous Ice Nucleation: Interplay Between Surface Morphology and Hydrophobicity. AB - What makes a material a good ice nucleating agent? Despite the importance of heterogeneous ice nucleation to a variety of fields, from cloud science to microbiology, major gaps in our understanding of this ubiquitous process still prevent us from answering this question. In this work, we have examined the ability of generic crystalline substrates to promote ice nucleation as a function of the hydrophobicity and the morphology of the surface. Nucleation rates have been obtained by brute-force molecular dynamics simulations of coarse-grained water on top of different surfaces of a model fcc crystal, varying the water surface interaction and the surface lattice parameter. It turns out that the lattice mismatch of the surface with respect to ice, customarily regarded as the most important requirement for a good ice nucleating agent, is at most desirable but not a requirement. On the other hand, the balance between the morphology of the surface and its hydrophobicity can significantly alter the ice nucleation rate and can also lead to the formation of up to three different faces of ice on the same substrate. We have pinpointed three circumstances where heterogeneous ice nucleation can be promoted by the crystalline surface: (i) the formation of a water overlayer that acts as an in-plane template; (ii) the emergence of a contact layer buckled in an ice-like manner; and (iii) nucleation on compact surfaces with very high interaction strength. We hope that this extensive systematic study will foster future experimental work aimed at testing the physiochemical understanding presented herein. PMID- 26434777 TI - Crystal Perfection of Particle Monolayer at the Air-Water Interface. AB - Crystal growth in colloidal particle monolayers fabricated by Langmuir-Blodgett method on 4 in. sapphire wafers was investigated under the condition of two techniques, that is, ultrasonic annealing at 1.2 to 1.5 MHz and barrier-sway process at 0.2 to 0.5 Hz. Significant increases of the ordered area were obtained by the both techniques and more than 60 times growth was confirmed. The remaining crystal defects after the growth were categorized as grain boundary, vacancy, and line defect. Both techniques exhibited different features regarding the component ratio of the defects, and different mechanisms for the reorientation of particles are discussed. The driving force of these re-orientations is thought to be associated with the 2D Ostwald ripening of colloidal crystals. PMID- 26434776 TI - Triomics Analysis of Imatinib-Treated Myeloma Cells Connects Kinase Inhibition to RNA Processing and Decreased Lipid Biosynthesis. AB - The combination of metabolomics, lipidomics, and phosphoproteomics that incorporates triple stable isotope labeling by amino acids in cell culture (SILAC) protein labeling, as well as (13)C in vivo metabolite labeling, was demonstrated on BCR-ABL-positive H929 multiple myeloma cells. From 11 880 phosphorylation sites, we confirm that H929 cells are primarily signaling through the BCR-ABL-ERK pathway, and we show that imatinib treatment not only downregulates phosphosites in this pathway but also upregulates phosphosites on proteins involved in RNA expression. Metabolomics analyses reveal that BCR-ABL ERK signaling in H929 cells drives the pentose phosphate pathway (PPP) and RNA biosynthesis, where pathway inhibition via imatinib results in marked PPP impairment and an accumulation of RNA nucleotides and negative regulation of mRNA. Lipidomics data also show an overall reduction in lipid biosynthesis and fatty acid incorporation with a significant decrease in lysophospholipids. RNA immunoprecipitation studies confirm that RNA degradation is inhibited with short imatinib treatment and transcription is inhibited upon long imatinib treatment, validating the triomics results. These data show the utility of combining mass spectrometry-based "-omics" technologies and reveals that kinase inhibitors may not only downregulate phosphorylation of their targets but also induce metabolic events via increased phosphorylation of other cellular components. PMID- 26434779 TI - Cellulose Nanocrystal Microcapsules as Tunable Cages for Nano- and Microparticles. AB - We demonstrate the fabrication of highly open spherical cages with large through pores using high aspect ratio cellulose nanocrystals with "haystack" shell morphology. In contrast to traditional ultrathin shell polymer microcapsules with random porous morphology and pore sizes below 10 nm with limited molecular permeability of individual macromolecules, the resilient cage-like microcapsules show a remarkable open network morphology that facilitates across-shell transport of large solid particles with a diameter from 30 to 100 nm. Moreover, the transport properties of solid nanoparticles through these shells can be pH triggered without disassembly of these shells. Such behavior allows for the controlled loading and unloading of solid nanoparticles with much larger dimensions than molecular objects reported for conventional polymeric microcapsules. PMID- 26434778 TI - Association Between ESR1 PvuII, XbaI, and P325P Polymorphisms and Breast Cancer Susceptibility: A Meta-Analysis. AB - BACKGROUND: Breast cancer is one of the leading causes of cancer-related deaths for women. Numerous studies have shown that single-nucleotide polymorphisms (SNPs) on the ESR1 gene are associated to this disease. However, data and conclusions are inconsistent and controversial. MATERIAL AND METHODS: To investigate the association between PvuII (rs2234693), XbaI (rs9340799) and P325P (rs1801132) polymorphisms of ESR1 gene with the risk of breast cancer under different population categorizations, we searched multiple databases for data collection, and performed the meta-analysis on a total of 25 case-control studies. Three different comparison models - dominant model, recessive model, and homozygote comparison model - were applied to evaluate the association. RESULTS: Our results indicated that people with TT+TC or TT genotype were at a greater risk of developing breast cancer than those with CC genotype in the PvuII polymorphism. While for XbaI and P325P polymorphisms, no significance was found using any of the 3 models. Furthermore, the data were also stratified into different subgroups according to the ethnicity (white or Asian) and source of controls (hospital-based or population-based), and separate analyses were conducted to assess the association. The ethnicity subgroup assessment showed that the higher risk of breast cancer for TT genotype of PvuII polymorphism than CC genotype only occurred in Asian people, but not in white populations. For the source-stratified subgroup analysis, significant association suggested that people with TT + TC genotype were at a greater risk of developing breast cancer than those with CC genotype in the hospital-based subgroup. CONCLUSIONS: Thus, this meta-analysis clarified the inconsistent conclusions from previous studies, conducted analyses for the entire population as well as for different subgroups using diverse population categorization strategies, and has the potential to help provide a personalized risk estimate for breast cancer susceptibility. PMID- 26434781 TI - Indwelling Urinary Catheter Insertion Practices in the Emergency Department: An Observational Study. PMID- 26434780 TI - Economic and epidemiological impact of early antiretroviral therapy initiation in India. AB - INTRODUCTION: Recent WHO guidance advocates for early antiretroviral therapy (ART) initiation at higher CD4 counts to improve survival and reduce HIV transmission. We sought to quantify how the cost-effectiveness and epidemiological impact of early ART strategies in India are affected by attrition throughout the HIV care continuum. METHODS: We constructed a dynamic compartmental model replicating HIV transmission, disease progression and health system engagement among Indian adults. Our model of the Indian HIV epidemic compared implementation of early ART initiation (i.e. initiation above CD4 >=350 cells/mm(3)) with delayed initiation at CD4 <=350 cells/mm(3); primary outcomes were incident cases, deaths, quality-adjusted-life-years (QALYs) and costs over 20 years. We assessed how costs and effects of early ART initiation were impacted by suboptimal engagement at each stage in the HIV care continuum. RESULTS: Assuming "idealistic" engagement in HIV care, early ART initiation is highly cost effective ($442/QALY-gained) compared to delayed initiation at CD4 <=350 cells/mm(3) and could reduce new HIV infections to <15,000 per year within 20 years. However, when accounting for realistic gaps in care, early ART initiation loses nearly half of potential epidemiological benefits and is less cost effective ($530/QALY-gained). We project 1,285,000 new HIV infections and 973,000 AIDS-related deaths with deferred ART initiation with current levels of care engagement in India. Early ART initiation in this continuum resulted in 1,050,000 new HIV infections and 883,000 AIDS-related deaths, or 18% and 9% reductions (respectively), compared to current guidelines. Strengthening HIV screening increases benefits of earlier treatment modestly (1,001,000 new infections; 22% reduction), while improving retention in care has a larger modulatory impact (676,000 new infections; 47% reduction). CONCLUSIONS: Early ART initiation is highly cost-effective in India but only has modest epidemiological benefits at current levels of care-engagement. Improved retention in care is needed to realize the full potential of earlier treatment. PMID- 26434782 TI - pROC-Chemotype Plots Enhance the Interpretability of Benchmarking Results in Structure-Based Virtual Screening. AB - Recently, we have reported a systematic comparison of molecular preparation protocols (using MOE or Maestro) in combination with two docking tools (GOLD or Glide), employing our DEKOIS 2.0 benchmark sets. Herein, we demonstrate how comparable settings of data preparation protocols can affect the profile and AUC of pROC curves based on variations in chemotype enrichment. We show how the recognition of different classes of chemotypes can affect the docking performance, particularly in the early enrichment, and monitor changes in this recognition behavior based on score normalization and rescoring strategies. For this, we have developed "pROC-Chemotype", which is an automated protocol that matches and visualizes ligand chemotype information together with potency classes in the pROC profiles obtained by docking. This tool enhances the understanding of the influence of chemotype recognition in early enrichment, but also reveals trends of impaired recognition of chemotype classes at the end of the score ordered rank. Identifying such issues helps to devise score-normalization strategies to overcome this potential bias in an intuitive manner. Furthermore, strong perturbations in chemotype ranking between different methods can help to identify the underlying reasons (e.g., changes in the protonation/tautomerization state). It also assists in the selection of appropriate scoring functions that are capable to retrieve more potent and diverse hits. In summary, we demonstrate how this new tool can be utilized to identify and highlight chemotype-specific behavior, e.g., in dataset preparation. This can help to overcome some chemistry related bias in virtual screening campaigns. pROC-Chemotype is made freely available at www.dekois.com. PMID- 26434783 TI - Comparing Counterconditioning and Extinction as Methods to Reduce Fear of Movement-Related Pain. AB - Cognitive-behavioral treatments for chronic pain typically target pain-related fear; exposure in vivo is a common treatment focusing on disconfirming harm expectancy of feared movements. Exposure therapy is tailored on Pavlovian extinction; an alternative fear reduction technique that also alters stimulus valence is counterconditioning. We compared both procedures to reduce pain related fear using a voluntary joystick movement paradigm. Participants were randomly allocated to the counterconditioning or extinction group. During fear acquisition, moving the joystick in 2 directions (conditioned stimulus [CS+]) was followed by a painful electrocutaneous stimulus (pain-unconditioned stimulus [US]), whereas moving the joystick in 2 other directions was not (CS-). During fear reduction, 1 CS+ was extinguished, but another CS+ was still followed by pain in the extinction group; in the counterconditioning group, 1 CS+ was extinguished and followed by a monetary reward-US, and another CS+ was followed by both USs (pain-US and reward-US). The results indicate that counterconditioning effectively reduces pain-related fear but that it does not produce deeper fear reduction than extinction. Adding a reward-US to a painful movement attenuated neither fear nor the intensity/unpleasantness of the pain. Both procedures changed stimulus valence. We contend that changing the affective valence of feared movements might improve fear reduction and may prevent relapse. PERSPECTIVE: This article reports no immediate differences between counterconditioning and extinction in reducing pain-related fear in the laboratory. Unexpectedly, both methods also altered stimulus valence. However, we cautiously suggest that methods explicitly focusing on altering the affective valence of feared movements may improve the long-term effectiveness of fear reduction and prevent relapse. PMID- 26434784 TI - 2015 Distinguished career award: Reflections on a career in science. AB - I was very pleased to receive the 2015 Distinguished Career Award from SSIB. This brief manuscript contains reminisces that might stir up pleasant memories in the older members of SSIB and also some general thoughts that I hope will be of value to the younger investigators who are closer to the beginning of their scientific careers. Although the organization has chosen to honor me with this special award, my own career was shaped by a great many people who have influenced my scientific career and I want to acknowledge them. They include Neal Miller, my doctoral mentor at Yale; Joe Holmes and Alan Epstein, my postdoctoral mentors; George Wolf and Reed Hainsworth, graduate student colleagues; John Brobeck, Paul Rozin, and Phil Teitelbaum, Michael Zigmond, Joe Verbalis, Jim Smith, and Alan Sved, faculty colleagues; Derek Denton, Paul McHugh, and James Fitzsimons, scientific role models; John Bruno, Steve Fluharty, and Linda Rinaman, post doctoral trainees at Pitt; and Lori Flanagan, Kath Curtis, Michael Bushey, Mike Bykowski, Reza Manesh, Carrie Smith, Jennifer Vaughan, and Myriam Stricker, student trainees at Pitt. I thank them all and also my colleagues in SSIB not only for the honor of this award but for providing an abundant supply of insights and discoveries that have stimulated me throughout my adult life, in addition to being an attentive community in supporting my own work. PMID- 26434785 TI - Skin temperature reveals the intensity of acute stress. AB - Acute stress triggers peripheral vasoconstriction, causing a rapid, short-term drop in skin temperature in homeotherms. We tested, for the first time, whether this response has the potential to quantify stress, by exhibiting proportionality with stressor intensity. We used established behavioural and hormonal markers: activity level and corticosterone level, to validate a mild and more severe form of an acute restraint stressor in hens (Gallus gallus domesticus). We then used infrared thermography (IRT) to non-invasively collect continuous temperature measurements following exposure to these two intensities of acute handling stress. In the comb and wattle, two skin regions with a known thermoregulatory role, stressor intensity predicted the extent of initial skin cooling, and also the occurrence of a more delayed skin warming, providing two opportunities to quantify stress. With the present, cost-effective availability of IRT technology, this non-invasive and continuous method of stress assessment in unrestrained animals has the potential to become common practice in pure and applied research. PMID- 26434786 TI - Cardiovascular activity and chronic pain severity. AB - OBJECTIVE: Objective markers of chronic pain severity are needed when examining and treating patients with chronic pain whose suffering may be overstated or underestimated. This study tested a hypothesis that the strength of cardiovascular (CV) reactivity in response to a social evaluative threat and orthostatic challenge is a reliable index of severity of pain-related complaints. METHODS: Measurement of CV reactivity and response styles in 34 men and 16 women with chronic pain from different bodily injuries, were retrieved from a larger database of patients. Measurement of CV reactivity in response to a postural challenge was repeated twice (sessions 1 and 2) on the same day of a medical examination which includes a psychosocial evaluation . RESULTS: A decrease in systolic blood pressure (SBP) from session 1 to session 2 was found in subjects with low pain severity scores, but not in those with high pain severity scores. High scores for pain catastrophizing/ magnification and pain-related emotional distress were independently associated respectively with a SBP increase at an early-point in time and a SBP decrease at a mid-point in time after standing up from lying down. Stronger heart rate reactivity responses to orthostatic challenge indicated greater protection against the presence of these chronic pain symptoms. CONCLUSIONS: This biobehavioral protocol enables measurement of chronic pain suffering and protection in three dimensions: physical, emotional, and cognitive. PMID- 26434787 TI - The influence of cancer on endocrine, immune, and behavioral stress responses. AB - Tumors perturb various physiological systems beyond their local microenvironment, including the immune, nervous, and metabolic systems. Given the involvement of these systems in physiological stress responses, the goal of this review is to compile evidence regarding whether or not cancer alters acute stress responses. Here, we focus on stress responses that are endocrine, immune, or behavioral. This question is clinically relevant as cancer patients are exposed to many stressors throughout diagnosis and treatment, and then later as survivors. Alterations in their stress responses may specifically affect how they respond to advice, treatments, and surgery under duress. To determine whether tumors alone alter stress responses, the relevant literature using rodent cancer models is first reviewed. Next, the more complicated clinical literature in cancer patients is integrated into the discussion. Based on the results of this analysis, goals for future basic and clinical research are proposed. This work aims to advance our understanding of the most effective methods for treating cancer patients and supporting their long-term survival. PMID- 26434788 TI - Invited review: Improving neonatal survival in small ruminants: science into practice. AB - Neonatal mortality in small ruminant livestock has remained stubbornly unchanging over the past 40 years, and represents a significant loss of farm income, contributes to wastage and affects animal welfare. Scientific knowledge about the biology of neonatal adaptation after birth has been accumulating but does not appear to have had an impact in improving survival. In this paper, we ask what might be the reasons for the lack of impact of the scientific studies of lamb and kid mortality, and suggest strategies to move forward. Biologically, it is clear that achieving a good intake of colostrum, as soon as possible after birth, is crucial for neonatal survival. This provides fuel for thermoregulation, passive immunological protection and is involved in the development of attachment between the ewe and lamb. The behaviour of the lamb in finding the udder and sucking rapidly after birth is a key component in ensuring sufficient colostrum is ingested. In experimental studies, the main risk factors for lamb mortality are low birthweight, particularly owing to poor maternal nutrition during gestation, birth difficulty, litter size and genetics, which can all be partly attributed to their effect on the speed with which the lamb reaches the udder and sucks. Similarly, on commercial farms, low birthweight and issues with sucking were identified as important contributors to mortality. In epidemiological studies, management factors such as providing assistance with difficult births, were found to be more important than risk factors associated with housing. Social science studies suggest that farmers generally have a positive attitude to improving neonatal mortality but may differ in beliefs about how this can be achieved, with some farmers believing they had no control over early lamb mortality. Facilitative approaches, where farmers and advisors work together to develop neonatal survival strategies, have been shown to be effective in achieving management goals, such as optimising ewe nutrition, that lead to reductions in lamb mortality. We conclude that scientific research is providing useful information on the biology underpinning neonatal survival, such as optimal birthweights, lamb vigour and understanding the importance of sufficient colostrum intake, but the transfer of that knowledge would benefit from an improved understanding of the psychology of management change on farm. Developing tailored solutions, on the basis of adequate farm records, that make use of the now substantial body of scientific literature on neonatal mortality will help to achieve lower neonatal mortality. PMID- 26434789 TI - A standardized approach to estimating survival statistics for population-based cystic fibrosis registry cohorts. AB - OBJECTIVES: Our objective was to quantify the effect of different statistical techniques, inclusion/exclusion criteria, and missing data on the predicted median survival age. STUDY DESIGN AND SETTING: Using the Canadian cystic fibrosis registry (CCFR), the median age of survival was calculated using both the Cox proportional hazards (PH) and the life-table methods. Through simulations, we examined how the median age of survival would change when: (1) patients were excluded, (2) death dates were inaccurate, (3) patients were lost to follow-up, (4) entire years with no clinic visits were excluded even if the patient had a visit in subsequent years, and (5) censoring patients at their date of transplant. Simulations were run assuming 5-35% of data were affected by each scenario. RESULTS: Over the period 2009-2013, there were 4,666 individuals in the CCFR with 240 deaths. The observed median age of survival calculated by the Cox PH method was 50.9 [95% confidence interval (CI): 47.4, 54.3] and 50.5 from the life-table method (95% CI: 47.5, 53.5). Censoring patients at their transplant date overestimated the median age of survival by 7.2 years (58.1; 95% CI: 53.3, 64.7). Simulations determined that by missing just 15% of deaths, the median age of survival can be overestimated by 3.5 years (54.4; 95% CI: 54.2, 56.1), and having 25% of patients lost to follow-up can underestimate the median age of survival by 3.3 years (47.6; 95% CI: 46.8, 47.7). CONCLUSION: We present several recommendations to assist national cystic fibrosis registries in calculating and reporting the median age of survival in a standardized fashion. It is imperative to state the statistical method used as well as the proportion lost to follow-up and the treatment of missing data and transplanted patients. Registries must be diligent in their data collection as incomplete data can lead to overestimation and underestimation of survival. PMID- 26434790 TI - Are not good practice statements necessarily based on evidence? Are their grades always strong? PMID- 26434791 TI - Klebsiella sp. FIRD 2, a TBT-resistant bacterium isolated from contaminated surface sediment along Strait of Johor Malaysia. AB - A possible tributyltin (TBT)-degrading bacterium isolated from contaminated surface sediment was successfully identified as Klebsiella sp. FIRD 2. It was found to be the best isolate capable of resisting TBT at a concentration of 1000 MUg L(-1). This was a concentration above the reported contaminated level at the sampling station, 790 MUg L(-1). Further studies revealed that the isolate was Gram negative and resisted TBT concentrations of up to 1500 MUg L(-1) in a Minimal Salt Broth without the addition of any carbon source within the first 48 h of incubation. It is expected that additional work could be conducted to check the degradation activity of this new isolate and possibly improve the degradation capacity in order to contribute to finding a safe and sustainable remediation solution of TBT contamination. PMID- 26434792 TI - Differential clearance mechanisms, neutrophil extracellular trap degradation and phagocytosis, are operative in systemic lupus erythematosus patients with distinct autoantibody specificities. AB - Systemic lupus erythematosus (SLE) patients are generally presented with autoantibodies against either dsDNA or RNA-associated antigens (also known as extractable nuclear antigens, ENA) or both. However, the mechanisms and processes that lead to this distinctive autoantibody profile are not well understood. Defects in clearance mechanism i.e. phagocytosis may lead to enhanced microbial and cellular debris of immunogenic potential. In addition to defective phagocytosis, impaired neutrophil extracellular trap (NET) degradation has been recently reported in SLE patients. However, the extent to which both these clearance processes (NET-degradation and phagocytosis) are operative in serologically distinguished subsets of SLE patients is not established. Therefore, in this report, we evaluated NET-degradation and phagocytosis efficiency among SLE patients with different autoantibody specificities. SLE patients were classified into three subsets based on their autoantibody profile (anti-dsDNA, anti-ENA or both) as determined by ELISA. NET-degradation by SLE and control sera was assessed by sytox orange-based fluorescence assay. Neutrophil mediated phagocytosis in the presence of SLE and control sera was determined by flowcytometry. The segregation of SLE patients revealed significant differences in NET-degradation and phagocytosis in SLE patients with autoantibodies against dsDNA and ENA. We report that NET-degradation efficiency was significantly impaired in SLE patients with anti-dsDNA autoantibodies and not in those with anti-ENA autoantibodies. In contrast to NET-degradation, neutrophil-mediated phagocytosis was impaired in all three subsets independent of autoantibody specificity. These observations suggest that varying clearance mechanisms are operative in SLE subsets with anti-dsDNA or anti-ENA autoantibodies. The results outlined in this manuscript also suggest that sub-grouping of SLE patients could be useful in delineating the molecular and pathological processes that are often missed when SLE patients are studied as a single group. Further, it will be imperative to propose that therapies targeted at improving NET clearance can be effective in anti-dsDNA(+) SLE patients. PMID- 26434793 TI - Increasing Incidence of Thyroid Nodules and Thyroid Cancer: Does Increased Detection of a Subclinical Reservoir Justify the Associated Anxiety and Treatment? AB - The incidence of thyroid cancer has been increasing over the last few decades, and it is subject to debate regarding whether the incidence is reflective of better diagnostic techniques and therefore better detection or if it is a reflection of a true increase in incidence. This increase in incidence has been most clearly manifested by an exponential increase in the diagnosis of micropapillary thyroid carcinomas. This article reviews the diagnosis of thyroid cancers, the dilemmas facing clinicians in the management of these micropapillary thyroid carcinomas, and the advances in molecular diagnostics that are being used to assist in the decision-making process. We consider the possibility of overtreatment of a relatively indolent disease and propose a less aggressive management plan in the appropriate clinical scenario. PMID- 26434794 TI - Twice the negativity bias and half the positivity offset: Evaluative responses to emotional information in depression. AB - BACKGROUND AND OBJECTIVES: Humans have the dual capacity to assign a slightly pleasant valence to neutral stimuli (the positivity offset) to encourage approach behaviors, as well as to assign a higher negative valence to unpleasant images relative to the positive valence to equally arousing and extreme pleasant images (the negativity bias) to facilitate defensive strategies. We conducted an experimental psychopathology study to examine the extent to which the negativity bias and the positivity offset differ in participants with and without major depression.. METHOD: Forty-one depressed and thirty-six healthy participants were evaluated using a structured clinical interview for DSM-IV Axis I disorders, questionnaires, and a computerized task designed to measure implicit affective responses to unpleasant, neutral, and pleasant stimuli. RESULTS: The negativity bias was significantly higher and the positivity offset was significantly lower in depressed relative to healthy participants.. LIMITATIONS: Entry criteria enrolling medication-free participants with minimal DSM-IV comorbidity may limit generalizability of the findings. CONCLUSIONS: This study advances our understanding of the positive and negative valence systems in depression, highlighting the irregularities in the positive valence system.. PMID- 26434795 TI - Cloning and analysis of DnaJ family members in the silkworm, Bombyx mori. AB - Heat shock proteins (Hsps) are involved in a variety of critical biological functions, including protein folding, degradation, and translocation and macromolecule assembly, act as molecular chaperones during periods of stress by binding to other proteins. Using expressed sequence tag (EST) and silkworm (Bombyx mori) transcriptome databases, we identified 27 cDNA sequences encoding the conserved J domain, which is found in DnaJ-type Hsps. Of the 27 J domain containing sequences, 25 were complete cDNA sequences. We divided them into three types according to the number and presence of conserved domains. By analyzing the gene structures, intron numbers, and conserved domains and constructing a phylogenetic tree, we found that the DnaJ family had undergone convergent evolution, obtaining new domains to expand the diversity of its family members. The acquisition of the new DnaJ domains most likely occurred prior to the evolutionary divergence of prokaryotes and eukaryotes. The expression of DnaJ genes in the silkworm was generally higher in the fat body. The tissue distribution of DnaJ1 proteins was detected by western blotting, demonstrating that in the fifth-instar larvae, the DnaJ1 proteins were expressed at their highest levels in hemocytes, followed by the fat body and head. We also found that the DnaJ1 transcripts were likely differentially translated in different tissues. Using immunofluorescence cytochemistry, we revealed that in the blood cells, DnaJ1 was mainly localized in the cytoplasm. PMID- 26434796 TI - Sequencing and characterization of the complete mitochondrial genome from the pancreatic fluke Eurytrema pancreaticum (Trematoda: Dicrocoeliidae). AB - The trematode Eurytrema pancreaticum is a parasite of ruminant pancreatic and bile ducts, and also occasionally infects humans, causing eurytremiasis. In spite of it being a common fluke of cattle and sheep in endemic regions, little is known about the genomic resources of the parasite. We sequenced the complete mitochondrial (mt) genome of E. pancreaticum. It is 15,031 bp in size, and encodes 36 genes: 12 protein-coding genes, two ribosomal RNA genes, and 22 transfer RNA genes. The E. pancreaticum mt gene order is the same as that of Dicrocoelium chinensis and Dicrocoelium dendriticum, and all genes are transcribed in the same direction. Phylogenetic analysis based on the concatenated amino acid sequences of 12 protein-coding genes by Bayesian inference shows that E. pancreaticum is closely related to D. chinensis and other members of the family Dicrocoeliidae with strong posterior probability support. The E. pancreaticum mt genome should prove to be a useful resource for comparative mt genomic studies of digenetic trematodes, and will provide a rich source of DNA markers for studies into the systematics, epidemiology, and population genetics of this parasite and other digenean trematodes. PMID- 26434797 TI - A 28-day oral gavage toxicity study of 3-monochloropropane-1,2-diol (3-MCPD) in CB6F1-non-Tg rasH2 mice. AB - 3-Monochloro-1,2-propanediol (3-MCPD) is a well-known contaminant of foods containing hydrolyzed vegetable protein. However, limited toxicity data are available for the risk assessment of 3-MCPD and its carcinogenic potential is controversial. To evaluate the potential toxicity and determine the dose levels for a 26-week carcinogenicity test using Tg rasH2 mice, 3-MCPD was administered once daily by oral gavage at doses of 0, 25, 50, and 100 mg/kg body weight (b.w.)/day for 28 days to male and female CB6F1-non-Tg rasH2 mice (N = 5 males and females per dose). The standard toxicological evaluations were conducted during the in-life and post-mortem phase. In the 100 mg/kg b.w./day group, 3 males and 1 female died during the study and showed clinical signs such as thin appearance and subdued behavior accompanied by significant decreases in mean b.w. Microscopy revealed tubular basophilia in the kidneys, exfoliated degenerative germ cells in the lumen of the seminiferous tubule of the testes, vacuolation in the brain, axonal degeneration of the sciatic nerve, and cardiomyopathy in the 100, >=25, >=50, 100, and 100 mg/kg b.w./day groups, respectively. In conclusion, 3-MCPD's target organs were the kidneys, testes, brain, sciatic nerve, and heart. The "no-observed-adverse-effect level" (NOAEL) of 3-MCPD was <=25 and 25 mg/kg b.w./day in males and females, respectively. PMID- 26434798 TI - The Brain Protective Effect of rTMS (Repetitive Transcranial Magnetic Stimulation) in Depression: A Mini-Review in Animal Studies. AB - There are rapidly replicating human data suggesting the therapeutic and neurorestorative role of repetitive transcranial magnetic stimulation (rTMS) in clinical depression. However there are only limited experimental studies in the literature and the neurobiological mechanisms of the technique are still unclear. Studies have suggested that modulating of either excitatory or inhibitory neural circuitry may be responsible for the mechanism of action of rTMS while it is still unclear whether rTMS exerts a neuroprotective effect. In the light of these findings, we aimed to review the neuroprotective effect of rTMS in animal models of depression. We have shown that rTMS may exert significant neuroprotective effect through acting on the oxidative injury, stress hormones, dopamine and serotonin levels, Brain Derived Neurotrophic Factor expression, neuroinflamation and hippocampal cell proliferation. PMID- 26434799 TI - Robust Modeling and Scaffold Hopping: Case Study Based on HIV Reverse Transcriptase Inhibitors Type-1 Data. AB - BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) is the causative agent of AIDS occurs across mucosal surfaces or by direct inoculation. OBJECTIVE: The objective of this study was to consider chemically diverse scaffold sets of HIV-1 Reverse Transcriptase Inhibitors (HIV-1 RTI) subjected to ideal oriented QSAR with large descriptor space. METHOD: We generated a four-parameter QSAR model based on 111 data points, which provided an optimum prediction of HIV-1 RTI for overall 367 experimentally measured compounds. RESULTS: The robustness of the model is demonstrated by its statistical validation (Ntraining = 111, R2 = 0.85, Q2lmo = 0.84) and by the prediction of HIV-1 inhibition activity for experimentally measured compounds. CONCLUSION: Finally, 5 novel hit compounds were designed in silico by using a virtual screening approach. The new hits met all the pharmacophore constraints and predicted pIC50 values within the binding ability of HIV-1 RT protein targets. PMID- 26434800 TI - Identification of Bostrycin Derivatives as Potential Inhibitors of Mycobacterium tuberculosis Protein Tyrosine Phosphatase (MptpB). AB - BACKGROUND: As a virulence factor secreted into host cells, the Mycobacterium tuberculosis protein tyrosine phosphatase (MptpB) mediates the intracellular survival of M. tuberculosis. MptpB has become an attractive target for the development of new anti-tuberculosis drugs. OBJECTIVE: In the present study, we assessed the inhibitory activity of marine fungus-derived bostrycin and its derivatives against MptpB in vitro. METHOD: The compounds were tested for their inhibitory effects on MptpB in vitro and the inhibition mode. The binding characteristics of inhibitors and MptpB were determined by microscale thermophoresis (MST). RESULTS: Our data showed that one of the derivatives, compound 25 (IC50 = 64.6 +/- 9.1 uM), possessed a greater inhibitory activity compared with bostrycin (IC50 = 327.6 +/- 60.4 uM) and behaved as a non competitive inhibitor. The binding characteristic of MptpB and compound 25 was determined by MST, exhibiting a moderate affinity with a KD constant of 5200 +/- 1020 nM. CONCLUSION: We, for the first time, reported that bostrycin and one of its analogues exhibited inhibitory activity against MptpB, which possessed potential as novel agents against tuberculosis. PMID- 26434801 TI - Cytotoxic Effects of Salvinorin A, A Major Constituent of Salvia divinorum. AB - S. divinorum is a psychoactive plant that has been consumed as a recreational drug of abuse in the last years. Salvinorin A is its main constituent, and is responsible for the observed psychoactive effects. Both S. divinorum and salvinorin A have become controlled drugs in several countries, but they are not listed in the Schedules of the United Nations Drug Conventions. Regarding the effects of S. divinorum consumption, almost all studies are based on in vivo or on surveys, and there are no studies in vitro on its toxicity. Furthermore, all studies are focused on the acute toxicological effects of the plant. So, it is of utmost importance to further investigate the effects of S. divinorum and salvinorin A, particularly using in vitro models, after prolonged exposures. In this context, the present work evaluated the in vitro toxicity induced by S. divinorum or salvinorin A in six cell lines, through MTT assays and LC50 determination. Overall, results showed that both S. divinorum and salvinorin A are cytotoxic, dose- and time-dependent. Also, Hep G2 and Caco 2 (to a lesser extent) cells showed lower sensitivity to S. divinorum and salvinorin A when compared to the other studied cell lines. To our knowledge, this is the first work focused on the in vitro toxicity of S. divinorum and salvinorin A using a variety of cell lines, which are extensively described in literature and have been widely used in several in vitro studies. PMID- 26434802 TI - Disrupted prefrontal activity during emotion processing in complicated grief: An fMRI investigation. AB - Complicated Grief, marked by a persistent and intrusive grief lasting beyond the expected period of adaptation, is associated with a relative inability to disengage from idiographic loss-relevant stimuli (O'Connor and Arizmendi, 2014). In other populations, functional magnetic resonance imaging (fMRI) studies investigating the neural networks associated with this bias consistently implicate the anterior cingulate cortex (ACC) during emotion regulation. In the present study, twenty-eight older adults were categorized into three groups based on grief severity: Complicated Grief (n=8), Non-Complicated Grief (n=9), and Nonbereaved, married controls (n=11). Using a block design, all participants completed 8 blocks (20 stimuli per block) of the ecStroop task during fMRI data acquisition. Differences in neural activity during grief-related (as opposed to neutral) stimuli across groups were examined. Those with Complicated Grief showed an absence of increased rostral ACC (rACC) and fronto-cortical recruitment relative to Nonbereaved controls. Activity in the orbitofrontal cortex (x=6, y=54, z=-10) was significantly elevated in the Non-Complicated Grief group when compared to Nonbereaved controls. Post hoc analysis evidenced activity in the dorsal ACC in the Complicated Grief and Nonbereaved groups late in the task. These findings, supported by behavioral data, suggest a relative inability to recruit the regions necessary for successful completion of this emotional task in those with Complicated Grief. This deficit was not observed in recruitment of the orbitofrontal cortex and the rACC during processing of idiographic semantic stimuli in Non-Complicated Grief. PMID- 26434804 TI - Obesity and reproduction: a committee opinion. AB - The purpose of this ASRM Practice Committee report is to provide clinicians with principles and strategies for the evaluation and treatment of couples with infertility associated with obesity. This revised document replaces the Practice Committee document titled, "Obesity and reproduction: an educational bulletin," last published in 2008 (Fertil Steril 2008;90:S21-9). PMID- 26434803 TI - Adolescent neurodevelopment of cognitive control and risk-taking in negative family contexts. AB - Adolescents have an increased need to regulate their behavior as they gain access to opportunities for risky behavior; however, cognitive control systems necessary for this regulation remain relatively immature. Parents can impact their adolescent child's abilities to regulate their behavior and engagement in risk taking. Since adolescents undergo significant neural change, negative parent child relationship quality may impede or alter development in prefrontal regions subserving cognitive control. To test this hypothesis, 20 adolescents completed a Go/NoGo task during two fMRI scans occurring 1year apart. Adolescents reporting greater family conflict and lower family cohesion showed longitudinal increases in risk-taking behavior, which was mediated by longitudinal increases in left VLPFC activation during cognitive control. These results underscore the importance of parent-child relationships during early adolescence, and the neural processes by which cognitive control may be derailed and may lead to increased risk taking. PMID- 26434805 TI - Transitioning through AIDS epidemics - gender and temporality. AB - OBJECTIVE: To understand the evolution of AIDS over time in Mato Grosso do Sul, Brazil, using incidence, lethality, and mortality coefficients. METHODS: A descriptive epidemiological study based on time series analysis of secondary data from the Notifiable Diseases Information System reported between 1985 and 2012. RESULTS: The prevalence of AIDS was higher among men, with evidence of feminization during the first 14 years of the epidemic. There was no statistically significant sex difference in AIDS lethality. Women were 1.3 times more likely to survive than men. CONCLUSIONS: Gender differences must be considered when designing new HIV/AIDS prevention strategies. PMID- 26434808 TI - Synthetic multivalency for biological applications. AB - Current directions and emerging possibilities under investigation for the integration of synthetic and semi-synthetic multivalent architectures with biology are discussed. Attention is focussed around multivalent interactions, their fundamental role in biology, and current and potential approaches in emulating them in terms of structure and functionality using synthetic architectures. PMID- 26434807 TI - Passive dust collectors for assessing airborne microbial material. AB - BACKGROUND: Settled airborne dust is used as a surrogate for airborne exposure in studies that explore indoor microbes. In order to determine whether detecting differences in dust environments would depend on the sampler type, we compared different passive, settled dust sampling approaches with respect to displaying qualitative and quantitative aspects of the bacterial and fungal indoor microbiota. RESULTS: Settled dust sampling approaches-utilizing plastic petri dishes, TefTex material, and electrostatic dustfall collectors (EDCs)-were evaluated in indoor spaces in the USA and Finland and in an experimental chamber study. The microbial content was analyzed with quantitative PCR (qPCR) to quantify total bacterial and fungal biomass and through high-throughput sequencing to examine bacterial community composition. Bacterial composition and diversity were similar within a sampling environment regardless of the sampler type. The sampling environment was the single largest predictor of microbial community composition within a study, while sampler type was found to have much less predictive power. Quantitative analyses in indoor spaces indicated highest yields using a petri dish approach, followed by sampling with EDCs and TefTex. The highest correlations between duplicate samples were observed for EDC and petri dish approaches, indicating greater experimental repeatability for these sampler types. For the EDC samples, it became apparent that, due to the fibrous nature of the material, a rigorous extraction protocol is crucial to obtain optimal yields and stable, repeatable results. CONCLUSIONS: Correlations between sampler types were strong both in compositional and quantitative terms, and thus, the particular choice of passive settled dust sampler is not likely to strongly alter the overall conclusion of a study that aims to characterize dust across different environments. Microbial cell abundances determined from settled dust varied with the use of different sampling approaches, and thus, consistency in the method is necessary to allow for absolute comparisons within and among studies. Considering practical aspects, petri dishes were found to be an inexpensive, simple, and feasible approach that showed the highest quantitative determinations under typical building conditions, though the choice of sampler will ultimately depend on study logistics and characteristics such as low- or high-exposure settings. PMID- 26434806 TI - The Regulatory Domain of Squalene Monooxygenase Contains a Re-entrant Loop and Senses Cholesterol via a Conformational Change. AB - Squalene monooxygenase (SM) is an important control point in cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase. Although it is known to associate with the endoplasmic reticulum, its topology has not been determined. We have elucidated the membrane topology of the sterol-responsive domain of SM comprising the first 100 amino acids fused to GFP (SM N100-GFP) by determining the accessibility of 16 introduced cysteines to the cysteine reactive, membrane-impermeable reagent PEG-maleimide. We have identified a region integrally associated with the endoplasmic reticulum membrane that is likely to interact with cholesterol or respond to cholesterol-induced membrane effects. By comparing cysteine accessibility with and without cholesterol treatment, we further present evidence to suggest that cholesterol induces a conformational change in SM N100-GFP. This change is likely to lead to its targeted degradation by the ubiquitin-proteasome system because degradation is blunted by treatment with the chemical chaperone glycerol, which retains SM N100-GFP in its native conformation. Furthermore, degradation can be disrupted by insertion of two N terminal myc tags, implicating the N terminus in this process. Together, this information provides new molecular insights into the regulation of this critical control point in cholesterol synthesis. PMID- 26434809 TI - [Advanced heart failure due to endomyocardial fibroelastosis]. PMID- 26434810 TI - A systematic review of the clinical validity of the CologuardTM genetic test for screening colorectal cancer. AB - OBJECTIVES: The aim of this study was to assess the available evidence on the validity, diagnostic accuracy and clinical utility of the multitarget DNA test in faeces (CologuardTM) for screening for colorectal cancer (CRC). MATERIAL AND METHODS: A systematic review was performed by consulting MedLine, EMBASE and Web of Science to July 2014. Studies on diagnostic tests were selected that evaluated the test in asymptomatic adults who underwent CRC screening. The quality and risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. The level of evidence was defined according to the National Institute for Health and Clinical Excellence. A qualitative synthesis was conducted. RESULTS: A total of 299 literature references were identified, including 1 synthesis report and 5 diagnostic test studies. Three of the 5 studies had a case-control design in Sackett phase II and were of moderate quality, and 2 had a prospective design in Sacket phase III and were of high quality. The sensitivity for detecting CRC was greater than 90%, but only 40% for detecting advanced adenomas. The test provided conclusive diagnostic evidence to rule out CRC (negative likelihood ratio, LR-: 0.02-0.09), although it was not useful for ruling out advanced adenoma (LR-: 0.5-0.7). CONCLUSIONS: The CologuardTM test is a valid screening test for ruling out cancerous lesions but is suboptimal for ruling out precancerous lesions. There is no evidence in terms of mortality, survival or cost-effectiveness. PMID- 26434811 TI - Clinical practice guidelines for posmenopausal, glucocorticoid-induced and male osteoporosis. Spanish Society for Research on Bone and Mineral Metabolism (3rd updated version 2014). AB - These guidelines update issues covered in previous versions and introduce new ones that have arisen in recent years. The former refer mainly to the therapeutic developments that have been made during this time (zoledronate, denosumab, bazedoxifene), which have led to a change in the drug selection algorithm. The latter deal with therapeutic management, the description of new adverse effects (which have led to changes in therapeutic behaviour patterns, as is the case with atypical fracture of the femur), treatment duration (with consideration for the so-called "therapeutic holidays"), the so-called sequential treatment and changes in treatment imposed by certain circumstances. A new algorithm has been introduced for sequential treatment. Attention has also been paid to vertebroplasty and kyphoplasty. PMID- 26434813 TI - Investigation of Fickian diffusion in the ternary mixtures of water-ethanol triethylene glycol and its binary pairs. AB - We present a comprehensive experimental study of isothermal Fickian diffusion in the ternary and binary liquid mixtures of water, ethanol, and triethylene glycol over the entire ternary composition space. 21 ternary mixtures inside the composition triangle have been investigated by means of the Taylor dispersion technique and 30 binary mixtures by Taylor dispersion and/or optical beam deflection in a Soret cell. The scalar binary diffusion coefficient has been determined along all three binary boundaries of the composition space and compared with estimations based on the Stokes-Einstein relation using stick or slip boundary conditions. The four elements of the ternary diffusion matrix and the diffusion eigenvalues were determined over a large portion of the composition triangle. The pseudo-binary diffusion coefficients obtained in Taylor dispersion experiments with either one of the two independent concentrations kept constant are comparable to the two diffusion eigenvalues. One of the two off-diagonal elements of the diffusion matrix is of the same order as the diagonal ones and, hence, not negligible, whereas the other one is approximately one order of magnitude smaller. Where available, our results compare well with literature data. The investigated compositions also comprise the five compositions that are scheduled for microgravity experiments in the ESA DCMIX3 project. PMID- 26434812 TI - Detecting compartmental non-Gaussian diffusion with symmetrized double-PFG MRI. AB - Diffusion in tissue and porous media is known to be non-Gaussian and has been used for clinical indications of stroke and other tissue pathologies. However, when conventional NMR techniques are applied to biological tissues and other heterogeneous materials, the presence of multiple compartments (pores) with different Gaussian diffusivities will also contribute to the measurement of non Gaussian behavior. Here we present symmetrized double PFG (sd-PFG), which can separate these two contributions to non-Gaussian signal decay as having distinct angular modulation frequencies. In contrast to prior angular d-PFG methods, sd PFG can unambiguously extract kurtosis as an oscillation from samples with isotropic or uniformly oriented anisotropic pores, and can generally extract a combination of compartmental anisotropy and kurtosis. The method further fixes its sensitivity with respect to the time dependence of the apparent diffusion coefficient. We experimentally demonstrate the measurement of the fourth cumulant (kurtosis) of diffusion and find it consistent with theoretical predictions. By enabling the unambiguous identification of contributions of compartmental kurtosis to the signal, sd-PFG has the potential to help identify the underlying micro-structural changes corresponding to current kurtosis based diagnostics, and act as a novel source of contrast to better resolve tissue micro-structure. PMID- 26434814 TI - Comparative Efficacy of Four Imaging Instruments for Breast Cancer Screening. AB - Sensitivity and specificity are the two most important indicators in selection of medical imaging devices for cancer screening. Breast images taken by conventional or digital mammography, ultrasound, MRI and optical mammography were collected from 2,143,852 patients. They were then studied and compared for sensitivity and specificity results. Optical mammography had the highest sensitivity (p<0.001 and p<0.006) except with MRI. Digital mammography had the highest specificity for breast cancer imaging. A comparison of specificity between digital mammography and optical mammography was significant (p<0.021). If two or more breast diagnostic imaging tests are requested the overall sensitivity and specificity will increase. In this literature review study patients at high-risk of breast cancer were studied beside normal or sensitive women. The image modality performance of each breast test was compared for each. PMID- 26434815 TI - Survivin as a Potential Target for Cancer Therapy. AB - In 1997 for the first time, survivin was described by Amborsini et al. as an anti apoptotic protein. Subsequent studies revealed that survivin is a multifunctional protein that plays critical roles in several crucial cell processes such as apoptosis, cell cycle, chromosome movement, mitosis and cellular stress responses. Moreover, it's over- expression in cancer cells versus normal cells is associated with chemotherapy resistance, increased tumor recurrence, and shorter patient survival. All of these features make survivin a promising target for cancer therapy. Here, we review the potential characteristics of survivin as a tumor marker. PMID- 26434816 TI - Roles of Human Papillomaviruses and p16 in Oral Cancer. AB - Head and neck cancer, including oral cancer, is the sixth most common cancer in humans worldwide. More than 90% of oral cancers are of squamous cell carcinoma type. Recent studies have shown a strong relationship between human papillomavirus (HPV) infection and head and neck cancer, especially oropharyngeal squamous cell carcinoma (OPSCC) and oral squamous cell carcinoma (OSCC). Moreover, the incidence of HPV-related OSCC appears to be on the rise while HPV unrelated OSCC tends to have stabilized in the past decades. p16, a tumor suppressor gene, normally functions as a regulator of the cell cycle. Upon infection with high-risk types of HPV (HR-HPV), particularly types 16, 18, 31, 33, 34, 35, 39, 51, 52, 56, 58, 59, 66, 68, and 70, the expression of p16 is aberrantly overexpressed. Therefore, the expression of p16 is widely used as a surrogate marker for HPV infection in head and neck cancer. PMID- 26434817 TI - Roles of Signaling Pathways in the Epithelial-Mesenchymal Transition in Cancer. AB - The epithelial-mesenchymal transition (EMT) is a cellular process though which an epithelial phenotype can be converted into a phenotype of mesenchymal cells. Under physiological conditions EMT is important for embryogenesis, organ development, wound repair and tissue remodeling. However, EMT may also be activated under pathologic conditions, especially in carcinogenesis and metastatic progression. Major signaling pathways involved in EMT include transforming growth factor beta(TGF-beta), Wnt, Notch, Hedgehog and other signaling pathways. These pathways are related to several transcription factors, including Twist, Smads and zinc finger proteins snail and slug. These interact with each other to provide crosstalk between the relevant signaling pathways. This review lays emphasis on studying the relationship between EMT and signaling pathways in carcinogenesis and metastatic progression. PMID- 26434818 TI - Prevention of Chemotherapy-Induced Nausea and Vomiting in Cancer Patients. AB - The supportive care of patients receiving antineoplastic treatment has dramatically improved over the past few years and development of effective measures to prevent nausea and vomiting after chemotherapy serves as one of the most important examples of this progress. A patient who starts cancer treatment with chemotherapy lists chemotherapy-induced nausea and vomiting as among their greatest fears. Inadequately controlled emesis impairs functional activity and quality of life, increases the use of health care resources, and may occasionally compromise adherence to treatment. New insights into the pathophysiology of chemotherapy-induced nausea and vomiting, a better understanding of the risk factors for these effects, and the availability of new antiemetic agents have all contributed to substantial improvements in emetic control. This review focuses on current understanding of chemotherapy-induced nausea and vomiting and the status of pharmacological interventions for their prevention and treatment. PMID- 26434819 TI - Tumor-Suppression Mechanisms of Protein Tyrosine Phosphatase O and Clinical Applications. AB - Tyrosine phosphorylation plays an important role in regulating human physiological and pathological processes. Functional stabilization of tyrosine phosphorylation largely contributes to the balanced, coordinated regulation of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Research has revealed PTPs play an important suppressive role in carcinogenesis and progression by reversing oncoprotein functions. Receptor-type protein tyrosine phosphatase O (PTPRO) as one member of the PTPs family has also been identified to have some roles in tumor development. Some reports have shown PTPRO over-expression in tumors can not only inhibit the frequency of tumor cell division and induce tumor cell death, but also suppress migration. However, the tumor-suppression mechanisms are very complex and understanding is incomplete, which in some degree blocks the further development of PTPRO. Hence, in order to resolve this problem, we here have summarized research findings to draw meaningful conclusions. We found tumor-suppression mechanisms of PTPRO to be diverse, such as controlling G0/G1 of the tumor cell proliferation cycle, inhibiting substrate phosphorylation, down-regulating transcription activators and other activities. In clinical anticancer efforts, expression level of PTPRO in tumors can not only serve as a biomarker to monitor the prognosis of patients, but act as an epigenetic biomarker for noninvasive diagnosis. In addition, the re activation of PTPRO in tumor tissues, not only can induce tumor volume reduction, but also enhance the susceptibility to chemotherapy drugs. So, we can propose that these research findings of PTPRO will not only support new study ideas and directions for other tumor- suppressors, importantly, but also supply a theoretical basis for researching new molecular targeting agents in the future. PMID- 26434820 TI - Effects of Two Traditional Chinese Cooking Oils, Canola and Pork, on pH and Cholic Acid Content of Faeces and Colon Tumorigenesis in Kunming Mice. AB - Faecal pH and cholate are two important factors that can affect colon tumorigenesis, and can be modified by diet. In this study, the effects of two Chinese traditional cooking oils (pork oil and canola/rapeseed oil) on the pH and the cholic acid content in feces, in addition to colon tumorigenesis, were studied in mice. Kunming mice were randomized into various groups; negative control group (NCG), azoxymethane control group (ACG), pork oil group (POG), and canola oil Ggroup (COG). Mice in the ACG were fed a basic rodent chow; mice in POG and COG were given 10% cooking oil rodent chow with the respective oil type. All mice were given four weekly AOM (azoxymethane) i.p. injections (10 mg/kg). The pH and cholic acid of the feces were examined every two weeks. Colon tumors, aberrant crypt foci and organ weights were examined 32 weeks following the final AOM injection. The results showed that canola oil significantly decreased faecal pH in female mice (P<0.05), but had no influence on feces pH in male mice (P>0.05). Pork oil significantly increased the feces pH in both male and female mice (P<0.05). No significant change was found in feces cholic acid content when mice were fed 10% pork oil or canola oil compared with the ACG. Although Kunming mice were not susceptible to AOM-induced tumorigenesis in terms of colon tumor incidence, pork oil significantly increased the ACF number in male mice. Canola oil showed no influence on ACF in either male or female mice. Our results indicate that cooking oil effects faecal pH, but does not affect the faecal cholic acid content and thus AOM-induced colon neoplastic ACF is modified by dietary fat. PMID- 26434821 TI - Knowledge of Female Undergraduate Students on Breast Cancer and Breast Self examination in Klang Valley, Malaysia. AB - BACKGROUND: In Malaysia, breast cancer is the first cancer among females regardness of race. AIM: The purpose of this study was to identify the knowledge and BSE practice among undergraduate female students at four public universities in Klang Valley, Malaysia. MATERIALS AND METHODS: This cross-sectional study was conducted among 820 undergraduate female students using a self-administered questionnaire covering socio-demographic data, knowledge of breast cancer and BSE practice. RESULTS: The mean age of the respondents was 21.7+/-1.2 years. The majority of them were single (96.8%), Malay (91.9%) and 16.5% of respondents had a family history of breast cancer. This study showed low level of knowledge on breast cancer and breast self-examination among participants. Only 19.6% participants were performing BSE regularly. Knowledge of breast self-examination was significantly associated with BSE practice (p=0.00). Also, there were significant associations between performing BSE with age, marital status and being trained by a doctor for doing BSE (p<0.05). CONCLUSIONS: Our findings showed that the rate of BSE practice and knowledge of breast cancer is inadequate among young Malaysian females. A public health education program is essential to improve breast cancer prevention among this group. PMID- 26434822 TI - An Empirical Study on Traditional, Complementary and Alternative Medicine Usage among Malaysian Cancer Patients. AB - Usage of traditional, complementary and alternative medicine (TCAM) has gained popularity over the past few years. However, very little is known about TCAM use among Malaysian cancer patients. This study aimed to identify the determinants of TCAM usage among cancer patients with determination of relationships between demographic factors, patient satisfaction with conventional treatment, knowledge on TCAM and healthcare professional influence. Patient's perceptions towards TCAM were also determined. A simple random convenient sampling method was used to recruit 354 patients from Hospital Kuala Lumpur between February to April 2013. All were directly interviewed with a structured questionnaire. In this study, 172 respondents were TCAM users. There was no significant differences between demographic background of respondents in the usage of TCAM. Minimal correlation was found between patient satisfaction with the conventional treatment and usage of TCAM (r=0.091). A poor correlation was found between healthcare professional's influence and TCAM usage (r=-0.213) but the results suggested that increase in influence would decrease TCAM usage. Patient TCAM knowledge correlated negatively with the TCAM usage (r=-0.555) indicated that cancer patients are less likely to use TCAM when they have more TCAM knowledge. Healthcare professionals should be fully equipped with the necessary TCAM knowledge while maintaining patient satisfaction with the conventional treatment. They should also intervene on patient TCAM usage where a potential drug interaction or a harmful adverse event can occur. PMID- 26434823 TI - Risk Factors for Thyroid Cancer in Females Using a Logit Model in Lahore, Pakistan. AB - BACKGROUND: Thyroid cancer (TC) is a more common endocrine malignancy in females and is a major cause of death in developing countries. Therefore the aim of this study was to explore possible risk factors of thyroid cancer in females of Pakistan. MATERIALS AND METHODS: This study covered 232 females, including 127 (54.7%) cases and 105 (45.2%) controls, from the INMOL Hospital and Sheikh Zayed Hospital, Lahore. Different risk factors were explored by the descriptive and inferentially statistics. Odds ratios and 95% confidence intervals for different risk factors were computed using logistic regression. RESULTS: The results showed six risk factors, marital status, family history of thyroid cancer, iodine in the diet, oxidative stress, fast food and fried food, to demonstrate positive significant links to thyroid cancer (odds ratios and 95% confidence intervals of :2.152, 1.104-4.198; 2.630, 1.416-4.887; 2.391, 1.282-4.458; 4.115, 2.185-7.750; 3.656, 1.851-7.223; 2.357, 1.268-4.382; and 2.360, 1.199-4.643, respectively). CONCLUSIONS: The Oxidative stress, marital status, family history of cancer, fast food, use of iodine diet and fried food are the risk factors of thyroid cancer in females. PMID- 26434824 TI - Breast Cancer Awareness among Middle Class Urban Women--a Community-Based Study from Mumbai, India. AB - Targeting breast cancer awareness along with comprehensive cancer care is appropriate in low and middle income countries like India, where there are no organized and affordable screening services. It is essential to identify the existing awareness about breast cancer in the community prior to launching an organized effort. This study assessed the existing awareness about breast cancer amongst women and their health seeking practices in an urban community in Mumbai, India. A postal survey was undertaken with low or no cost options for returning the completed questionnaires. The majority of the women were aware about cancer but awareness about symptoms and signs was poor. Women were willing to accept more information about cancer and those with higher awareness scores were more likely to seek medical help. They were also more likely to have undergone breast examination in the past and less likely to use alternative medicines. High income was associated with better awareness but this did not translate into better health seeking behaviour. Organized programmes giving detailed information about breast cancer and its symptoms are needed and women from all income categories need to be encouraged for positive change towards health seeking. Further detailed studies regarding barriers to health seeking in India are necessary. PMID- 26434825 TI - Model Based on Alkaline Phosphatase and Gamma-Glutamyltransferase for Gallbladder Cancer Prognosis. AB - PURPOSE: To evaluate the prognostic value of alkaline phosphatase (ALP) and gamma glutamyltransferase (GGT) in gallbladder cancer (GBC). MATERIALS AND METHODS: Serum ALP and GGT levels and clinicopathological parameters were retrospectively evaluated in 199 GBC patients. Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off values of ALP and GGT. Then, associations with overall survival were assessed by multivariate analysis. Based on the significant factors, a prognostic score model was established. RESULTS: By ROC curve analysis, ALP>=210 U/L and GGT>=43 U/L were considered elevated. Overall survival for patients with elevated ALP and GGT was significantly worse than for patients within the normal range. Multivariate analysis showed that the elevated ALP, GGT and tumor stage were independent prognostic factors. Giving each positive factor a score of 1, we established a preoperative prognostic score model. Varied outcomes would be significantly distinguished by the different score groups. By further ROC curve analysis, the simple score showed great superiority compared with the widely used TNM staging, each of the ALP or GGT alone, or traditional tumor markers such as CEA, AFP, CA125 and CA199. CONCLUSIONS: Elevated ALP and GGT levels were risk predictors in GBC patients. Our prognostic model provides infomration on varied outcomes of patients from different score groups. PMID- 26434826 TI - Clinicopathology Profile and Bone Involvement of Multiple Myeloma Patients in Dharmais National Cancer Hospital, Indonesia. AB - BACKGROUND: Even though rarely found in Indonesia, the incidence of multiple myeloma (MM) is increasing every year. Bone involvement of MM is the most often a clinical disorder which leads to worsening clinical conditions and low quality of life of patients. PURPOSE: To determine the clinicopathology profile of bone involvement of MM patients in Indonesia. MATERIALS AND METHODS: The cross sectional study of MM conducted at Dharmais National Cancer Hospital (DNCH) by collecting data from medical records of MM patients who came to DNCH in period 2008-2012. RESULTS: There were 39 MM patients all with age above 60 years. There were 56.4% male and 43.6% female patients. Most were diagnosed at stage III (32.4%), and 41% had obesity. The comorbid conditions were anemia (82.9%), hypoalbuminemia (60%), increased creatinine level (38.5%), increased beta2 microglobulin level (94.1%), increased LDH level (23.1%) and plasmocytes above 30% (65%), but only 4.2% patients presented with hypercalcemia. Meanwhile, bone involvement occurred in 76.9% of MM patients with 4 lesions on average and a maximum of 16 lesions. The locations of bone lesions were spine (70%), skull (70%), pelvis (33.3%), humerus (30%), and femur (30%). CONCLUSIONS: The incidence of MM in Indonesia is increasing annually with bone involvement in more than three-fourths, but interestingly without hypercalcemia. PMID- 26434827 TI - Head and neck extra nodal NHL (HNENL)--Treatment Outcome and Pattern of failure- A Single Institution Experience. AB - BACKGROUND: Extra nodal lymphoma (ENL) constitutes about 33 % of all non Hodgkin's lymphoma. 18-28% develops in the head and neck region. A multimodality treatment with multi-agent chemotherapy (CT) and radiotherapy (RT) is considered optimum. MATERIALS AND METHODS: We retrieved the treatment charts of patients of HNENL treated in our institute from 2001-2012. The charts were reviewed and the demographic, treatment details and outcome of HNENL patients were retrieved using predesigned pro-forma. RESULTS: We retrieved data of 75 consecutive patients HNENL. Median age was 47 years (Range: 8-76 years). Of the 75 patients 51 were male and 24 were female. 55 patients were evaluable. The patient and tumor characteristics are summarized in Table 1. All patients were staged comprehensively with contrast enhanced computed tomography of head, neck, thorax, abdomen, pelvis and bone marrow aspiration and biopsy 66 patients received a combination multi-agent CT with CHOP being the commonest regimen. 42 patients received 4 or lesser number of cycles of chemotherapy whereas 24 received more than 4 cycles chemotherapy. Post radiotherapy, 41 out of 42 patients had a complete response at 3 months. Only 21 patients had a complete response after chemotherapy. All patients received radiation (mostly involved field radiation) as a part of the treatment. The median radiation dose was 45 Gray (Range: 36 Gray 50 Gray). The radiation was planned by 2D fluoro simulation based technique in 37 cases and by 3 Dimensional conformal radiation therapy (3DCRT) in 36 cases. Two patients were planned by the intensity modulated radiation therapy (IMRT) technique. IMRT was planned for one thyroid and one nasal cavity primary. 5 patients experienced relapse after a median follow up of 19 months. The median survival was not reached. The estimated two and three year survival were 92.9% (95%CI-68.6-95.35) and 88% (95%CI-60.82-92.66) respectively. Univariate analysis revealed higher stage and poorer baseline performance status to be significantly associated with worse progression free survival. 5 patients progressed (relapse or primary disease progression) after treatment. Of the 5 patients, two patients were primary orbital NHL, two patients had NHL nasal cavity and one was NHL thyroid. CONCLUSIONS: Combined modality treatment in HNENL confers excellent disease control with acceptable side effects. PMID- 26434828 TI - Relationships between Body Image, Body Mass Index, and Smoking in Korean Adolescents: Results of a Nationwide Korea Youth Risk Behavior Web-based Survey. AB - OBJECTIVE: This study assessed the association between subjective body image or objective body mass index (BMI) and the risk of daily smoking in Korean adolescents, with a purpose of identifying the most suitable models. MATERIALS AND METHODS: Using the 2013 9th Korea Youth Risk Behavior Web-based Survey data for 72,435 students, odds ratios were calculated for daily smoking in the past month, according to the subjective body image and calculated BMI using a respective multiple logistic regression model. The combined effect of these two factors was also analyzed by pairing a BMI category with a subjective body image category, using odds ratios for the same event within each sex group. RESULTS: Among the surveyed students, 7.2% of boys and 1.8% of girls were classified as daily smokers. Students who perceived themselves as being very obese tended to be at lower risk of daily smoking (OR=0.61 in boys with 95% CI=0.47 to 0.79; OR=0.66 in women with 95% CI=0.47 to 0.93). In addition, boys within the obese or overweight BMI category showed a lower risk of daily smoking (OR=0.86, 95% CI: 0.77-0.96). Lean BMI was significantly associated with higher odds ratios for daily smoking only in female students (OR=1.24, 95% CI: 1.02-1.52). When pairing these two objective and subjective factors, results suggested that subjective body image has a greater effect on daily smoking than BMI in both boys and girls. CONCLUSIONS: In both male and female students, subjective body image had a greater effect on daily smoking than body mass index. A model using the combination of BMI and subjective body image was the best fit in girls, in contrast to the model using subjective body image only best suitable in boys, for the prediction of daily smoking. These results including several factors associated with daily smoking in Korean students, provide useful data for the development and implementation of smoking intervention and cessation programs for adolescents. PMID- 26434829 TI - Anticancer Activity of Atractylodes lancea (Thunb.) DC in a Hamster Model and Application of PET-CT for Early Detection and Monitoring Progression of Cholangiocarcinoma. AB - Opisthorchis viverrini (OV)-induced cholangiocarcinoma (CCA) is an important cancer in the Great Mekong region, particularly in Thailand. Limitations of treatment options and the lack of an effective diagnostic tool for early detection of CCA are major concerns for the control of this type of cancer. The aim of the study was to investigate anti-CCA activity of the ethanolic extract of Atractylodes lancea (Thunb.) DC., and the applicability of positron emission tomography-computed tomography (PET-CT) as a tool for detection and monitoring the progression of CCA in Opisthorchis viverrini (OV)/dimethylnitrosamine (DMN) induced CCA hamsters. Male Syrian hamsters were used for toxicity tests and anti CCA activity evaluation. Development of CCA was induced by initial feeding of 50 metacercariae of OV, followed by drinking water containing 12.5 ppm of DMN in hamsters. The ethanolic extract of A. lancea (Thunb.) DC. was administered orally for 30 days. PET-CT was performed every 4 weeks after initiation of CCA using 18F fluorodeoxyglucose (18F-FDG). Results from the present study suggest that the ethanolic extract of A. lancea (Thunb.) DC. rhizome exhibited promising anti-CCA activity and safety profile in the OV/DMN-induced hamster model. To successfully apply PET-CT as a tool for early detection of tumor development and progression, modification of radiolabeling approach is required to improve its specificity for CCA cells. PMID- 26434830 TI - Breast Cancer Screening in Morocco: Performance Indicators During Two Years of an Organized Programme. AB - BACKGROUND: Breast cancer is commonly diagnosed at late stages in countries with limited resources. In Morocco, breast cancer is ranked the first female cancer (36.1%) and screening methods could reduce the proportion presenting with a late diagnosis. Morocco is currently adopting a breast cancer screening program based on clinical examination at primary health facilities, diagnosis at secondary level and treatment at tertiary level. So far, there is no systematic information on the performance of the screening program for breast cancer in Morocco. The aim of this study was to analyze early performance indicators. MATERIALS AND METHODS: A retrospective evaluative study conducted in Temara city. The target population was the entire female population aged between 45-70 years. The study was based on process and performance indicators collected at the individual level from the various health structures in Tamara between 2009 and 2011. RESULTS: A total of 2,350 women participated in the screening program; the participation rate was 35.7%. Of these, 76.8% (1,806) were married and 5.2% (106) of this group had a family history of breast cancer. Of the women who attended screening, 9.3% (190) were found to have an abnormal physical examination findings. A total of 260 (12.7%) were referred for a specialist consultation. The positive predictive value of clinical breast examination versus mammography was 23.0%. Forty four (35.5%) of the lesions found on the mammograms were classified as BI-RADs 3; 4 or 5 category. Cancer was found in 4 (1.95%) of the total number of screened women and benign cases represented 0.58%. CONCLUSIONS: These first results of the programme are very encouraging, but there is a need to closely monitor performance and to improve programme procedures with the aim of increasing both the participation rate and the proportion of women eligible to attend screening. PMID- 26434831 TI - Expression of Bcl-2 in Primary and Recurrent Odontogenic Keratocysts in Comparison with Other Odontogenic Lesions. AB - PURPOSE: To determine the biological behaviour of common odontogenic cystic lesions by analysing and comparing bcl-2 expression amongst them. MATERIALS AND METHODS: Our study covered 90 formalin fixed paraffin embedded tissue samples: 26 primary cases each of radicular cysts (RC), dentigerous cysts (DC) and odontogenic keratocysts (OKC) and 12 of recurrent OKCs. Bcl-2 expression was analysed immunohistochemically and data analysis was accomplished using SPSS version 17.0. Means were taken for age while for gender and site of the lesions frequencies and percentages were determined. The Chi-square test was applied to evaluate any statistically significant difference of bcl-2 expression in these lesions and p value of <=0.05 was taken as significant. RESULTS: All the recurrent OKCs showed a strong positivity for bcl-2 that was absent in all of its primary cases (p value<0.05). Although variation in expression of bcl-2 was not found to be statistically significant between RC and DC, however, it became significant when all primary cases of these common odontogenic lesions were compared. CONCLUSIONS: Recurrent OKC showed comparatively a more aggressive behaviour than their primary counterparts and also from RC and DC. Bcl-2 proved to be a valuable adjunct in determining aggressive biological behaviour of odontogenic lesions. PMID- 26434832 TI - Intentions to Undergo Lung Cancer Screening among Korean Men. AB - Opportunistic screening for lung cancer is commonly conducted in Korea in accordance with physician recommendations and screenee's preferences. However, studies have yet to thoroughly examine the public's understanding of the risks posed by lung cancer screening. This study was conducted to assess changes in intentions to undergo lung cancer screening in response to being informed about exposure to radiation during low-dose computed tomography (LDCT) tests and to identify factors with the greatest influence thereon among Korean men. We conducted sub-group interviews among men chosen from the 2013 Korea National Cancer Screening Survey (KNCSS), a nationwide, population-based, cross-sectional survey of men aged 40 to 74 years and women aged 30 to 74 years. From 4100 participants in the KNCSS, 414 men who underwent any cancer screening test within the last 2 years were randomly selected for inclusion in this study. Via face-to face interviews, their intentions to undergo lung cancer screening were assessed before and after being informed about exposure to radiation during LDCT testing. Of the 414 participants, 50% were current smokers. After receiving information on the benefits of the test, 95.1% stated an intention to undergo screening; this decreased to 81.6% after they received information on the harms of the test. The average decrease in intention rate was 35.3%. Smoking status, household income, and education level were not associated with lowered intentions to undergo lung cancer screening. Participants who were older than 60 years old (OR=0.56; 95% CI=0.33-0.96) and those with less concern for radiation exposure (OR=0.56; 95% CI=0.36-0.89) were less likely to lower their screening intentions. The results of this study suggest that there is a need to educate both non-smokers and former smokers on the harms of lung cancer screening. PMID- 26434833 TI - Is Exposure to Tobacco Advertising, Promotion and Sponsorship Associated with Initiation of Tobacco Use among Current Tobacco Users in Youth in India? AB - BACKGROUND: The rise in consumption of tobacco products among youth is a public health concern in India. Several studies have shown that advertisements promoting tobacco products influence decisions and behaviour of youth towards smoking. OBJECTIVE: To ascertain which method of Tobacco Advertising, Promotion and Sponsorship (TAPS) was more influential for initiating tobacco use in youth in India. MATERIALS AND METHODS: The secondary data of youth (15-24 years) from nationally representative Global Adult Tobacco Survey (GATS) conducted in 2009 2010 was analyzed. Odds ratio and p-value were used to know the association between TAPS and initiation of use of tobacco products among youth. Logistic regression was used to determine the most significant means of TAPS altering the youth's behaviour towards tobacco products. RESULTS: Out of 13,383 youths, 1,982 (14.7%) used smokeless forms of tobacco and 860 (6.38%) used smoke forms. Logistic regression reveals that promotional activities mainly through cinemas (p<0.05) and providing free samples of tobacco products (p<=.001) were most influential means of initiating consumption of tobacco products among youth. CONCLUSIONS: The smoking in youth is associated with watching advertisements particularly in cinema and promotional activities like distribution of free samples, coupons and sales on the price of tobacco products. Stronger legislative measures should be enforced to curb promotional advertisements in cinemas and distribution of free samples. PMID- 26434834 TI - Addressing Factors Associated with Arab Women's Socioeconomic Status May Reduce Breast Cancer Mortality: Report from a Well Resourced Middle Eastern Country. AB - Differences in socioeconomic status (SES) such as income levels may partly explain why breast cancer screening (BCS) disparities exist in countries where health care services are free or heavily subsidized. However, factors that contribute to such differences in SES among women living in well resourced Middle East countries are not fully understood. This quantitative study investigated factors that influence SES and BCS of Arab women. Understanding of such factors can be useful for the development of effective intervention strategies that aim to increase BCS uptake among Arab women. Using data from a cross-sectional survey among 1,063 Arabic-speaking women in Qatar, age 35+, additional data analysis was performed to determine the relationship between socioeconomic indicators such as income and other factors in relation to BCS activities. This study found that income is determined and influenced by education level, occupation, nationality, years of residence in the country, level of social activity, self-perceived health status, and living area. Financial stress, unemployment, and unfavorable social conditions may impede women's participation in BCS activities in well resourced Middle East countries. PMID- 26434835 TI - Staged Improvement in Awareness of Disease for Elderly Cancer Patients in Southern China. AB - BACKGROUND: In mainland China, awareness of disease of elderly cancer patients largely relies on the patients' families. We developed a staged procedure to improve their awareness of disease. MATERIALS AND METHODS: Participants were 224 elderly cancer patients from 9 leading hospitals across Southern China. A questionnaire was given to the oncologists in charge of each patient to evaluate the interaction between family and patients, patient awareness of their disease and participation in medical decision-making. After first cycles of treatment, increased information of disease was given to patients with cooperation of the family. Then patient awareness of their disease and participation in medical decision-making was documented. RESULTS: Among the 224 cancer elderly patients, 26 (11.6%) made decisions by themselves and 125 (55.8%) delegated their rights of decision- making to their family. Subordinate family members tended to play a passive role in decision-making significantly. Patients participating more in medical decision-making tended to know more about their disease. However, in contrast to the awareness of disease, patient awareness of violation of medical recommendations was reversely associated with their participation in medical decision-making. Improvement in awareness of diagnosis, stages and prognosis was achieved in about 20% elderly cancer patients. About 5% participated more actively in medical decision-making. CONCLUSIONS: Chinese elderly cancer patient awareness of disease and participation in medical decision-making is limited and relies on their family status. The staged procedure we developed to improve patient awareness of disease proved effective. PMID- 26434836 TI - Inhibitory Aromatase Effects of Flavonoids from Ginkgo Biloba Extracts on Estrogen Biosynthesis. AB - Ginkgo biloba extract (GBE) is a popular phytomedicine and has been used for disorders of the central nervous system, cardiovascular, renal, respiratory, and circulatory diseases. Although GBE is a complex mixture of over 300 compounds, its major components are 24% flavonoids and 6% terpene lactones. In this study, we tested the inhibitory effects of the three major flavonoids (kaempferol, quercetin, and isorhamnetin) from GBE, independently and as mixtures, on aromatase activity using JEG-3 cells (human placental cells) and recombinant proteins (human placental microsome). In both systems, kaempferol showed the strongest inhibitory effects among the three flavonoids; the flavanoid mixtures exerted increased inhibitory effects. The results of exon I.1-driven luciferase reporter gene assays supported the increased inhibitory effects of flavonoid mixtures, accompanied by suppression of estrogen biosynthesis. In the RT-PCR analysis, decreased patterns of aromatase promoter I.1 mRNA expressions were observed, which were similar to the aromatase inhibition patterns of flavonoids and their mixtures. The present study demonstrated that three flavonoids synergistically inhibit estrogen biosynthesis through aromatase inhibition, decrease CYP19 mRNA, and induce transcriptional suppression. Our results support the usefulness of flavonoids in adjuvant therapy for breast cancer by reducing estrogen levels with reduced adverse effects due to estrogen depletion. PMID- 26434837 TI - 4G/5G and A-844G Polymorphisms of Plasminogen Activator Inhibitor-1 Associated with Glioblastoma in Iran--a Case-Control Study. AB - BACKGROUND: Glioblastoma is a highly aggressive and malignant brain tumor. Risk factors are largely unknown however, although several biomarkers have been identified which may support development, angiogenesis and invasion of tumor cells. One of these biomarkers is PAI-1. 4G/5G and A-844G are two common polymorphisms in the gene promotor of PAI 1 that may be related to high transcription and expression of this gene. Studies have shown that the prevalence of the 4G and 844G allele is significantly higher in patients with some cancers and genetic disorders. MATERIALS AND METHODS: We here assessed the association of 4G/5G and A-844G polymorphisms with glioblastoma cancer risk in Iranians in a case-control study. All 71 patients with clinically confirmed and 140 volunteers with no history and symptoms of glioblastoma as control group were screened for 4G/5G and A-844G polymorphisms of PAI-1, using ARMS-PCR. Genotype and allele frequencies of case and control groups were analyzed using the DeFinetti program. RESULTS: Our results showed significant associations between 4G/5G (p=0.01824) and A-844G (p=0.02012) polymorphisms of the PAI-1 gene with glioblastoma cancer risk in our Iranian population. CONCLUSIONS: The results of this study supporting an association of the PAI-1 4G/5G (p=0.01824) and A-844G (p=0.02012) polymorphisms with increasing glioblastoma cancer risk in Iranian patients. PMID- 26434838 TI - Palliative Care Education in Gynecologic Oncology: a Survey of Gynecologic Oncologists and Gynecologic Oncology Fellows in Thailand. AB - BACKGROUND: The main purpose of this study was to survey the education and training of certified gynecologic oncologists and fellows in Thailand. A secondary objective was to study the problems in fellowship training regarding palliative care for gynecologic cancer patients. MATERIALS AND METHODS: A descriptive study was conducted by sending a questionnaire regarding palliative care education to all certified gynecologic oncologists and gynecologic oncology fellows in Thailand. The contents of the survey included fellowship training experience, caring for the dying, patient preparation, attitudes and respondent characteristics. Statistics were analyzed by percentage, mean and standard deviation and chi-square. RESULTS: One hundred seventy completed questionnaires were returned; the response rate was 66%. Most certified gynecologic oncologists and fellows in gynecologic oncology have a positive attitude towards palliative care education, and agree that "psychological distress can result in severe physical suffering". It was found that the curriculum of gynecologic oncology fellowship training equally emphasizes three aspects, namely managing post operative complications, managing a patient at the end of life and managing a patient with gynecologic oncology. As for experiential training during the fellowship of gynecologic oncology, education regarding breaking bad news, discussion about goals of care and procedures for symptoms control were mostly on the-job training without explicit teaching. In addition, only 42.9% of respondents were explicitly taught the coping skill for managing their own stress when caring for palliative patients during fellowship training. Most of respondents rated their clinical competency for palliative care in the "moderately well prepared" level, and the lowest score of the competency was the issue of spiritual care. CONCLUSIONS: Almost all certified gynecologic oncologists and fellows in gynecologic oncology have a positive attitude towards learning and teaching in palliative care. In this study, some issues were identified for improving palliative care education such as proper training under the supervision of a mentor, teaching how to deal with work stress, competency in spiritual care and attitudes on responsibility for bereavement care. PMID- 26434839 TI - Expression of Cytoplasmic 8-oxo-Gsn and MTH1 Correlates with Pathological Grading in Human Gastric Cancer. AB - BACKGROUND: Cancers have dysfunctional redox regulation resulting in production of reactive oxygen species (ROS), damaging DNA, RNA and free NTPs, and causing the accumulation of oxidative nucleic acids in cytoplasm. The major types are 8 oxo-7,8-dihydroguanine(8-oxoGsn) in RNA and 8-oxo-7,8-dihydro-2' deoxyguanosine(8 oxodGsn) in Mt-DNA. The MTH1 protein sanitizes oxidized nucleotide pools from NTPs to monophosphates, preventing the occurrence of transversion mutations. This study concerned cytoplasmic 8-oxodGsn/Gsn and MTH1 expression in gastric cancer and para-cancer tissues and elucidated roles of nucleic-acid oxidation and anti oxidation. MATERIALS AND METHODS: A polymer HRP detection system was used to detect 8-oxo-Gsn/dGsn and MTH1 expression in 51 gastric cancer and para-cancer tissue samples. Analyses of patient clinical and pathological data were also performed. RESULTS: The expression of MTH1 and the 8-oxo-dGsn/Gsn ratio were significantly higher in cancer tissues than para-cancer tissues (P<0.05). Cytoplasmic 8-oxo-Gsn and MTH1 were both found to positively correlate (P<0.05) with tumor differentiation, while no significant associations were found with gender, age, invasion depth, lymph node metastasis and clinical stage (P>0.05). CONCLUSIONS: We found 8-oxo-dGsn/Gsn and MTH1 are both highly expressed in gastric cancer tissues, especially in well differentiated lesions. In addition, oxidated mtDNA is prevalently expressed in gastric cancers, while 8-oxo-Gsn expression in cytoplasmic RNA is a bit lower, but more selectively. PMID- 26434840 TI - Supportive Care Needs of Iranian Cancer Survivors and Relationships with Social Support. AB - BACKGROUND: Assessment of supportive care needs of cancer survivors and identifying factors affecting such needs is important for implementation of any supportive care programs. So, the aims of present study were to investigate the supportive care needs of Iranian cancer survivors and relationships with social support. MATERIALS AND METHODS: In this descriptive-correlational study two hundred and fifty cancer survivors participated via convenient sampling methods. The Supportive Care Needs Survey (SCNS-SF34) and Multidimensional Scale of Perceived Social Support (MSPSS) were used for data collection. SPSS software was applied and univariate regression was used for examine relationships of supportive care needs with social support. RESULTS: Participants demonstrated many unmet supportive care needs, especially in health system and information and psychological domains. In addition, participants reported that family members and significant others were their main source of support. Also, social support has a significant correlation with all domains of supportive care needs. CONCLUSIONS: There is an indispensable need for establishment of supportive care programs for Iranian cancer survivors. In addition, family members of family members of such survivors are an important resource to help develop such programs. PMID- 26434841 TI - Evaluation of Common Risk Factors for Breast Carcinoma in Females: a Hospital Based Study in Karachi, Pakistan. AB - BACKGROUND: Breast malignancies are one of the leading causes of deaths in females worldwide. There are a number of risk factors associated with breast cancer but in Karachi Pakistan there are insufficient data available. MATERIALS AND METHODS: A case control study was conducted on females in age group between 30-80 years. This study was accomplished by retrospective data collection in Aga Khan University Hospital Karachi, Pakistan. A total of 108 females with primary malignancy of breast were included along with 108 matched controls. Relationship of various factors with disease was studied using logistic regression to calculate odds ratios with 95 % confidence intervals. RESULTS: A total of 14 variables were analyzed and based on and 7 were found to be risk factors: old age, family history of breast cancer, family history of other carcinomas, personal history of breast carcinoma, early age of menarche, older age of mother at first delivery and lower number of children. Five factors, parity, breast feeding, history of oral contraceptive pills intake, past history of oophorectomy and hysterectomy showed protective associations. One variable, use of hormonal replacement therapy, showed a controversial link and one other, marital status, was not significant in this study. CONCLUSIONS: It is concluded that most of the well-known risk factors for breast cancer are also associated with the disease in the female population of Karachi, Pakistan. High risk patients should be the focus with the help of this study so that screening can be more effective for early diagnosis before clinically evident breast malignancy. PMID- 26434842 TI - Laparoscopic Versus Open Radical Cystectomy for Patients Older than 75 Years: a Single-Center Comparative Analysis. AB - BACKGROUND: To explore the safety, efficacy, and oncological outcome of 3-port laparoscopic radical cystectomy (LRC) compared to open radical cystectomy (ORC) in patients older than 75 years. MATERIALS AND METHODS: From June 2010 to July 2014, we analyzed 16 radical cystectomies in patients older than 75 years (LRC group=8; ORC group=8). Demographic parameters, operative variables, and perioperative outcome in the 2 groups were retrospectively collected, analyzed, and compared. RESULTS: Patients in both groups had comparable preoperative characteristics. A significantly longer operating time (476 vs. 303 min, P=0.0002) and less estimated blood loss (627 vs. 2,106 mL, P=0.021) were observed in the LRC group compared to the ORC group. Infection and ileus were the most common early complications after surgery. Patients who underwent ORC suffered from more postoperative infection (22.2% vs. 0.0%, P=0.054) and ileus (25.0% vs. 12.5%, P=0.521) than the LRC group, but the difference was not significant. CONCLUSIONS: Judging from this initial trial, 3-port LRC can be safely carried out in elderly patients. We suggest 3-port LRC as the primary intervention to treat muscle-invasive or high-risk nonmuscle-invasive bladder cancer in elderly patients with an otherwise relatively long life expectancy. PMID- 26434843 TI - Aromatase Inhibition and Capecitabine Combination as 1st or 2nd Line Treatment for Metastatic Breast Cancer - a Retrospective Analysis. AB - BACKGROUND: Preclinical studies have shown that the combination of an aromatase inhibitor (AI) and capecitabine in estrogen receptor (ER)-positive cell lines enhance antitumor efficacy. This retrospective analysis of a group of patients with metastatic breast cancer (MBC) evaluated the efficacy and safety of combined AI with capecitabine. MATERIALS AND METHODS: Patients with hormone receptor positive metastatic breast cancer treated between 1st January 2005 and 31st December 2010 with a combination of capecitabine and AI were evaluated and outcomes were compared with those of women treated with capecitabine in conventional dose or AI as a monotherapy. RESULTS: Of 72 patients evaluated, 31 received the combination treatment, 22 AI and 19 capecitabine. The combination was used in 20 patients as first-line and 11 as second-line treatment. Mean age was 46.2 years with a range of 28-72 years. At the time of progression, 97% had a performance status of <2 and 55% had visceral disease. No significant difference was observed between the three groups according to clinical and pathological features. Mean follow up was 38 months with a range of 16-66 months. The median PFS of first-line treatment was significantly better for the combination (PFS 21 months vs 8.0 months for capecitabine and 15.0 months for AI). For second-line treatment, the PFS was longer in the combination compared with capecitabine and Al groups (18 months vs. 5.0 months vs. 11.0 months, respectively). Median 2 year and 5 year survival did not show any significant differences among combination and monotherapy groups. The most common adverse events for the combination group were grade 1 and 2 hand-for syndrome (69%), grade 1 fatigue (64%) and grade 1 diarrhoea (29%). Three grade 3 hand-foot syndrome events were reported. CONCLUSIONS: Combination treatment with capecitabine and AI used as a first line or second line treatment was safe with much lowered toxicity. Prospective randomized clinical trials should evaluate the use of combination therapy in advanced breast cancer to confirm these findings. PMID- 26434844 TI - Women and Tobacco Use: Discrepancy in the Knowledge, Belief and Behavior towards Tobacco Consumption among Urban and Rural Women in Chhattisgarh, Central India. AB - BACKGROUND: Tobacco consumption has become pandemic, and is estimated to have killed 100 million people in the 20th century worldwide. Some 700,000 out of 5.4 million deaths due to tobacco use were from India. The era of global modernization has led to an increase in the involvement of women in tobacco consumption in the low income and middle-income countries. Tobacco consumption by females is known to have grave consequences. OBJECTIVES: To assess: (1) the tobacco use among urban and rural women; (2) the discrepancy in the knowledge, belief and behavior towards tobacco consumption among urban and rural women in Durg-Bhilai Metropolitan, Chhattisgarh, Central India. MATERIALS AND METHODS: The study population consisted of 2,000 18-25 year old young women from Durg-Bhilai Metropolitan, Chhattisgarh, Central India, from both urban and rural areas. Data were collected using a pretested, anonymous, extensive face to face interview by a female investigator to assess the tobacco use among women and the discrepancy in the knowledge, belief and behavior towards tobacco consumption among urban and rural individuals. RESULTS: The prevalence of tobacco use was found to be 47.2%. Tobacco consumption among rural women was 54.4% and in urban women was 40%. The majority of the women from urban areas (62.8%) were smokers whilst rural women (77.4%) showed preponderance toward smokeless tobacco use. Urban women had a better knowledge and attitude towards harms from tobacco and its use than the rural women. Women in rural areas had higher odds (1.335) of developing tobacco habit than the urban women. CONCLUSIONS: Increased tobacco use by women poses very severe hazards to their health, maternal and child health, and their family health and economic well-being. Due to the remarkably complex Indian picture of female tobacco use, an immediate and compulsory implementation of tobacco control policies laid down by the WHO FCTC is the need of the hour. PMID- 26434845 TI - Age Specific Cytological Abnormalities in Women Screened for Cervical Cancer in the Emirate of Abu Dhabi. AB - BACKGROUND: Cervical cancer is the second most common cancer in women worldwide, with about 500,000 new cases and 270,000 deaths each year. Globally, it is estimated that over one million women currently have cervical cancer, most of whom have not been diagnosed, or have no access to treatment that could cure them or prolong their lives. In the United Arab Emirates (UAE) cervical cancer is the third most common cancer in women. MATERIALS AND METHODS: A population-based cross-sectional retrospective survey of cervical smear abnormalities was conducted in the Emirate of Abu Dhabi, UAE, from January 2013 to December 2013 by collecting consecutive liquid-based cytology samples from the Department of Pathology at the SKMC Hospital in Abu Dhabi city. RESULTS: The total number of women screened for cervical cancer for the year 2013 at SKMC was 4,593, with 225 (4.89%) abnormal smears. The majority of the abnormal smear results were atypical squamous cells of undetermined significance (ASCUS) 114 (2.48%). This study showed 60% increase in the rate of abnormal cervical smears in the UAE over the last 10 years. In this study the highest incidence of high grade abnormalities were seen in women above the age of 61 years (1.73%), this might be due to the fact that this group of women missed the chance of screening of cervical cancer earlier in their lives or could be explained by the well-known second peak of HPV infection seen in many prevalence studies. CONCLUSIONS: We conclude that the rate of abnormal cervical smear in the screened Abu Dhabi women is not different from the rate in developed countries. A notable increase in both low and high grade abnormalities has occurred within the last decade. PMID- 26434846 TI - Whole Liver Palliative Radiotherapy for Patients with Massive Liver Metastases. AB - BACKGROUND: The purpose of this retrospectively study was to examine the effectiveness and tolerability of a radiotherapy technique for the palliation of symptomatic liver metastases. MATERIALS AND METHODS: Twenty-seven patients with liver metastases were enrolled and received targeted whole liver irradiation consisting of mean 1, 8 Gy in five to twelve fractions to a total mean dose 17 Gy. Symptoms at baseline were hepatic pain (26 patients), lost of weight (6), lack of appetite (2), and night sweats (1). Seventeen patients (63%) had failed previous treatment with chemotherapy and/or high-dose steroids. RESULTS: Individual symptom response rates were 100% at 4 weeks. Partial or complete global symptomatic responses were noted in 11 patients (40%) after 2 months. After 3 months, 8 patients (28%) reported loss of pain. The treatment was well tolerated with one patient (3%) experiencing grade 3 toxicity (one vomiting and one diarrhoea). Overall the median survival time was 4.9 months (range 1-14 months). One year survival was 39%. CONCLUSIONS: This is simple and well tolerated treatment but to achieve good palliation effects we should carefully selected patients whose conventional treatment does not bring good analgesic control. PMID- 26434847 TI - Polymorphism of the DNA Repair Gene XRCC1 (Arg194Trp) and its role in Colorectal Cancer in Kashmiri Population: a Case Control Study. AB - BACKGROUND: Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity, which may be associated with risk of developing cancer. For colorectal cancer the importance of mutations in mismatch repair genes has been extensively documented. MATERIALS AND METHODS: In this study we focused on the Arg194Trp polymorphism of the DNA repair gene XRCC1, involved in base excision repair (BER) and its role in colorectal cancer in Kashmiri population. A case-control study was conducted including 100 cases of colorectal cancer, and 100 hospital-based age- and sex-matched healthy controls to examine the role of XRCC1 genetic polymorphisms in the context of colorectal cancer risk for the Kashmiri population. RESULTS: Genotype analysis of XRCC1 Arg194Trp was conducted with a restriction fragment length polymorphism (RFLP) method. The overall association between the XRCC1 polymorphism and the CRC cases was found to be significant (p<0.05) with both the heterozygous genotype (Arg/Trp) as well as homozygous variant genotype (Trp/Trp) being moderately associated with the elevated risk for CRC [OR=2.01 (95% CI=1.03-3.94) and OR=5.2(95% CI=1.42-19.5)] respectively. CONCLUSIONS: Our results suggest an increased risk for CRC in individuals with XRCC1 Arg194Trp polymorphism suggesting BER repair pathway modulates the risk of developing colorectal cancer in the Kashmiri population. PMID- 26434848 TI - Cervical Cancer Mortality Trends in China, 1991-2013, and Predictions for the Future. AB - BACKGROUND: To analyze cervical cancer mortality trends in China from 1991-2013 and forecast the mortality distribution in future five years (2014-2018), and provide clues for prevention and treatment. MATERIALS AND METHODS: Mortality data for cervical cancer in China from 1991 to 2013 were used to describe the epidemiological characteristics and distribution, including the trend of the standardized mortality rate, urban-rural differences, and age variation. Trend surface analysis was used to analyze the geographical distribution of mortality. Curve estimation, time series, gray modeling, and joinpoint regression were performed to predict and forecast mortality trends. RESULTS: In recent years, the mortality rate of cervical cancer has increased, and there is also a steady increase in the incidence from 2003 to 2013 in China. Mortality rates in rural areas are higher than in urban areas. The mortality dramatically increases in the 40+ yr age group, reaching a peak in the >85 yr age group. In addition, geographical analysis showed that the cervical cancer mortality increased from the southwest to west-central and from the southeast to northeast of the country. CONCLUSIONS: The incidence rate and the mortality rate are increasing from 1991 to 2013, and the predictions show this will continue in the future. Thus, implementation of prevention and management programs for cervical cancer are necessary in China, especially for rural areas, young women in urban areas, and high risk regions (the west-central). PMID- 26434849 TI - Arsenic Exposure and Haematological Derangement in Cervical Cancer Cases in India. AB - Cervical cancer is the second most common gynecological malignancy worldwide. According to HPV Information Centre, Spain (Aug'2014), in India approximately 1,22,844 women are diagnosed with the disease every year and of them 67,477 die due to the disease. CaCx is said to be mediated by HPV but recent data published reveal the role of Oxidative Stress in different Cancers. Arsenic is also one of the agents for causing Oxidative Stress. Arsenic has been linked with different types of cancer. Arsenic is considered responsible for generation of free radicals and eventually for apoptosis. Early diagnosis of CaCx is presently a matter of concern and clinical presentation in advanced stages become difficult for complete clinical response. For determination of oxidative stress, Malondialdehyde (MDA) was taken as an identifier and arsenic estimation was performed with the help of Atomic Absorption Spectrometer (AAS). RBC count and Haemoglobin levels were performed according to standard protocol. MDA was in direct proportion with arsenic concentration and inversely proportional to RBC and Haemoglobin in CaCx patients. Arsenic is one of the major causative agents for oxidative stress and hence may be a risk factor leading to cancer including CaCx. PMID- 26434850 TI - Diagnostic Performance of Diffusion-Weighted Imaging for Multiple Hilar and Mediastinal Lymph Nodes with FDG Accumulation. AB - BACKGROUND: It is sometimes difficult to assess patients who have multiple hilar and mediastinal lymph nodes (MHMLN) with FDG accumulation in PET-CT. Since it is uncertain whether diffusion-weighted magnetic resonance imaging (DWI) is useful in the assessment of such patients, its diagnostic performance was assessed. MATERIALS AND METHODS: Twenty-three patients who had three or more stations of hilar and mediastinal lymph nodes with SUVmax of 3 or more in PET-CT were included in this study. RESULTS: For diagnosis of disease, there were 20 malignancies (lung cancers 17, malignant lymphomas 2 and metastatic lung tumor 1), and 3 benign cases (sarcoidosis 2 and benign disease 1). For diagnosis of lymph nodes, there were 7 malignancies (metastasis of lung cancer 7 and malignant lymphoma 1) and 16 benign lymphadenopathies (pneumoconiosis/silicosis 7, sarcoidosis 4, benign disease 4, and atypical lymphocyte infiltration 1). The ADC value (1.57+/-0.29x10(-3) mm2/sec) of malignant MHMLN was significantly lower than that (1.99+/-0.24x10(-3) mm2/sec) of benign MHMLN (P=0.0437). However, the SUVmax was not significantly higher (10.0+/-7.34 as compared to 6.38+/-4.31) (P=0.15). The sensitivity (86%) by PET-CT was not significantly higher than that (71%) by DWI for malignant MHMLN (P=1.0). The specificity (100%) by DWI was significantly higher than that (31%) for benign MHMLN (P=0.0098). Furthermore, the accuracy (91%) with DWI was significantly higher than that (48%) with PET-CT for MHMLN (P=0.0129). CONCLUSIONS: Evaluation by DWI for patients with MHMLN with FDG accumulation is useful for distinguishing benign from malignant conditions. PMID- 26434851 TI - Predictive Value of the Platelet-To-Lymphocyte Ratio in Diagnosis of Prostate Cancer. AB - PURPOSE: To predict prostatic carcinoma using a logistic regression model on prebiopsy peripheral blood samples. MATERIALS AND METHODS: Data of a total of 873 patients who consulted Urology Outpatient Clinics of Fatih Sultan Mehmet Training and Research Hospital between February 2008 and April 2014 scheduled for prostate biopsy were screened retrospectively. PSA levels, prostate volumes, prebiopsy whole blood cell counts, neutrophil and platelet counts, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), biopsy results and Gleason scores in patients who had established diagnosis of prostate cancer (PCa) were evaluated. RESULTS: This study was performed on a total of 873 cases, with an age range 48-76 years, divided into three groups as for biopsy results. with diagnoses of benign prostatic hyperplasia (BPH) (n=304, 34.8 %), PCa (n=265, 30.4%) and histological prostatitis (n=304; 34.8%). Intra- and intergroup comparative evaluations were performed. White blood cell and neutrophil counts in the histological prostatitis group were significantly higher than those of the BPH and PCa groups (p=0.001; p=0.004; p<0.01). A statistically significant intergroup difference was found for PLR (p=0.041; p<0.05) but not lymphocyte count (p>0.05). According to pairwise comparisons, PLR were significantly higher in the PCa group relative to BPH group (p=0.018, p<0.05, respectively). Though not statistically significant, higher PLR in cases with PCa in comparison with the prostatitis group was remarkable (p=0.067, and p>0.05, respectively). CONCLUSIONS: Meta-analyses showed that in patients with PSA levels over 4 ng/ml, positive predictive value of PSA is only 25 percent. Therefore, novel markers which can both detect clinically significant prostate cancer, and also prevent unnecessary biopsies are needed. Relevant to this issue in addition to PSA density, velocity, and PCA3, various markers have been analyzed. In the present study, PLR were found to be the additional predictor of prostatic carcinoma. PMID- 26434852 TI - Temporal Epidemiological Assessment of Colorectal Cancer Incidence and Mortality in East Kazakhstan, 2004-2013. AB - Colorectal cancer incidence and mortality in Kazakhstan are relatively high but exact statistics have hitherto been lacking and trends over time are unclear. The present study was therefore undertaken to retrospectively assess data for East Kazakhstan, accessed from the central registration office, for the period 2004 2013. Approximate age standardized data for incidence and mortality were generated and compared across age groups, gender and year. It was determined that during the studied period 3,417 new cases of colorectal cancer were registered and 2,259 died of this pathology. Average cancer cancer incidence and mortality over the ten years were 24.1/105 and 15.9/105 respectively, and the overall ratio of mortality/incidence (M/I) was 0.69:1 (range 0.58-0.73). Both incidence and mortality tended to remain constant in both males and females. The male to female ratios also did not significantly vary over time but a trend for improvement of the mortality to incidence ratio was observed, especially for rectum. Whether this might be related to screening remains unclear. These preliminary data indicate that whereas colorectal cancer continues to be important, change in environmental factors are not having a great impact on incidence in East Kazakhstan. PMID- 26434853 TI - Viscum Album Var Hot Water Extract Mediates Anti-cancer Effects through G1 Phase Cell Cycle Arrest in SK-Hep1 Human Hepatocarcinoma cells. AB - Viscum album var (VAV) also known as mistletoe, has long been categorized as a traditional herbal medicine in Asia. In addition to its immunomodulating activities, mistletoe has also been used in the treatment of chronic hepatic disorders in China and Korea. There are numerous reports showing that VAV possesses anti-cancer effects, however influence on human hepatocarcinoma has never been elucidated. In the present study, hot water extracts of VAV was evaluated for its potential anti-cancer effect in vitro. SK-Hep1 cells were treated with VAV (50-400 ug/ml) for both 24 and 48 hours then cell viability was measured by cell counting kit-8 (CCK-8). Flow cytometry analysis was used to measure the proportion of SK-Hep1 in the different stages of cell cycle. RT-PCR and Western blot analysis were conducted to measure expression of cell cycle arrest related genes and proteins respectively. VAV dose dependently inhibited the proliferation of SK-Hep1 cells without any cytotoxicity with normal Chang liver cell (CCL-13). Flow cytometry analysis showed that VAV extract inhibited the cell cycle of SK-Hep1 cells via G1 phase arrest. RT-PCR and Western blot analysis both revealed that cyclin dependent kinase 2 (Cdk2) and cyclin D1 gene expression were significantly down regulated while p21 was upregulated dose dependently by VAV treatment. Combined down regulation of Cdk2, Cyclin D1 and up regulation of p21 can result in cell death. These results indicate that VAV showed evidence of anti-cancer activity through G1 phase cell cycle arrest in SK Hep1 cells. PMID- 26434854 TI - In Vitro Anticancer Activities of Anogeissus latifolia, Terminalia bellerica, Acacia catechu and Moringa oleiferna Indian Plants. AB - The present study was designed to evaluate in vitro anti-proliferative potential of extracts from four Indian medicinal plants, namely Anogeissus latifolia, Terminalia bellerica, Acacia catechu and Moringa oleiferna. Their cytotoxicity was tested in nine human cancer cell lines, including cancers of lung (A549), prostate (PC-3), breast (T47D and MCF-7), colon (HCT-16 and Colo-205) and leukemia (THP-1, HL-60 and K562) by using SRB and MTT assays. The findings showed that the selected plant extracts inhibited the cell proliferation of nine human cancer cell lines in a concentration dependent manner. The extracts inhibited cell viability of leukemia HL-60 and K562 cells by blocking G0/G1 phase of the cell cycle. Interestingly, A. catechu extract at 100 MUg/mL induced G2/M arrest in K562 cells. DNA fragmentation analysis displayed the appearance of a smear pattern of cell necrosis upon agarose gel electrophoresis after incubation of HL 60 cells with these extracts for 24 h. PMID- 26434855 TI - Glutathione S-transferase M1 and T1 Polymorphisms, Cigarette Smoking and HPV Infection in Precancerous and Cancerous Lesions of the Uterine Cervix. AB - Glutathione S-transferases (GSTs) play an important role in detoxification of carcinogenic electrophiles. The null genotypes in GSTM1 and GSTT1 have been implicated in carcinogenesis. Present study was planned to evaluate the influence of genetic polymorphisms of GSTM1 and GSTT1 gene loci in cervical carcinogenesis. The study was conducted in Lok Nayak hospital, New Delhi. DNA from clinical scrapes of 482 women with minor gynaecologic complaints attending Gynaecology OPD and tumor biopsies of 135 cervical cancer cases attending the cancer clinic was extracted. HPV DNA was detected by standard polymerase chain reaction (PCR) using L1 consensus primer pair. Polymorphisms of GSTM1 and GSTT1 were analysed by multiplex PCR procedures. Differences in proportions were tested using Pearson's Chi-square test with Odds ratio (OR) and 95% confidence interval (CI). The risk of cervical cancer was almost three times in women with GSTM1 homozygous null genotype (OR-2.62, 95%CI, 1.77-3.88; p<0.0001). No association of GSTM1 or GSTT1 homozygous null genotypes was observed in women with normal, precancerous and cervical cancerous lesions among <=35 or >35 years of age groups. Smokers with null GSTT1 genotype had a higher risk of cervical cancer as compared to non smokers (OR-3.01, 95% CI, 1.10-8.23; p=0.03). The results further showed that a significant increased risk of cervical cancer was observed in HPV positive smoker women with GSTT1 (OR-4.36, 95% CI, 1.27-15.03; p=0.02) and GSTM1T1 (OR-3.87, 95% CI, 1.05-14.23; p=0.04) homozygous null genotypes as compared to HPV positive non smokers. The results demonstrate that the GST null genotypes were alone not associated with the development of cervical cancer, but interacted with smoking and HPV to exert effects in our Delhi population. PMID- 26434856 TI - Exploratory Study to Evaluate Changes in Serum Lipid Levels as Early Diagnostic and/or Prognostic Indicators for Oral Submucous Fibrosis and Cancer among Gutkha Consumers in India. AB - BACKGROUND: In India smokeless tobacco users account for 25.9% of total tobacco use, Gutkha being the most common form. This study evaluated the association between serum lipid profile and Gutkha use as an early diagnostic and/or prognostic indicator for oral submucous fibrosis (OSMF) and oral cancer (Oral Ca) in non-smokers and non-alcohol consumers. MATERIALS AND METHODS: A total of 163 participants were recruited from two sites in India. Participants were divided into four groups: individuals without any Gutkha chewing habit and without any oral lesions (control group), individuals with Gutkha chewing habit but without any oral lesions (GWL), patients with a confirmed clinical diagnosis of OSMF, and patients with a confirmed diagnosis of Oral Ca. Mixed linear modelling (MLM) was conducted to detect the change in mean serum lipid levels among four groups. RESULTS: The sample consisted of 69% males and 31% females. Results of MLM show an inverse relationship between serum lipid levels in OSMF, and Oral Ca groups when compared to the control group. CONCLUSIONS: The results of our study demonstrated that GWL, OSMF and Oral Ca patients had lower serum lipid levels. Low serum lipid levels could be an indicator of initial neoplastic changes in oral cancer. PMID- 26434857 TI - Cell Free EGFR mRNA Expression and Implications for Survival and Metastasis in Non-Small Cell Lung Cancer Cases. AB - BACKGROUND: NSCLC is a disease involving uncontrolled cell growth, which could result in metastases into nearby tissues beyond the lungs. MATERIALS AND METHODS: The aim of the present study was to analyze the influence of epidermal growth factor receptor (EGFR) gene expression on metastasis and survival in NSCLC patients. The present case-control study included 100 cases of NSCLC patients and 100 age and sex matched controls. EGFR gene expression was analyzed by quantitative real time PCR using serum RNA. Association with NSCLC patient survival was analyzed by the Kaplan-Meier method. RESULTS: We analyzed EGFR gene expression and observed mean increased gene expression of 13.5 fold in NSCLC patients. Values reflected overall survival of patients with a median of 15.8 months in the cases of <13 fold increased gene expression vs 6.7 months with >13 fold increased EGFR gene expression (p=0.005). Distant metastatic patients with <13 fold increased EGFR gene expression had 7.9 months of median survival time while>13 fold increased EGFR gene expression had only 5 months of median survival time (p=0.03). Non metastatic patients with <13 fold increased EGFR gene expression had 18 months of median survival time as compared to only 7.1 months with >13 fold increased expression. CONCLUSIONS: Higher cell free EGFR mRNA expression may play an important role in causing distant metastases and reducing overall survival of NSCLC patients in the Indian population. PMID- 26434858 TI - Epidemiological Aspects of Osteosarcoma, Giant Cell Tumor and Chondrosarcoma Musculoskeletal Tumors--Experience of the National Rehabilitation Institute, Mexico City. AB - BACKGROUND: Primary bone neoplasms are rare, contributing only 0.2% of the global burden of all human malignancies. Osteosarcoma (OS) and chondrosarcoma (CS) are the most common malignancies of bone. The giant cell tumor of bone (GCTb) is a benign tumor with behavior characterized by osteolytic bone destruction. The OS, CS and GCTb affect both sexes, all races and generally have incidence peaks regarding the age of the patient which vary according to the tumor type. We analyzed the incidences of OS, CS and GCTb and their relations with gender and age in patients treated in the National Rehabilitation Institute (INR, for its acronym in Spanish) over a period of nine years. MATERIALS AND METHODS: In the study period, clinic pathological data for 384 patients were obtained with clinical, radiological and histopathological diagnosis for OS, GCTb and CS. Data analysis was performed using the chi-square and Fisher's exact tests. RESULTS: From 2006 to 2014 were recorded 384 cases of bone malignancies in the database of INR. The GCTb had the highest incidence (53.1%), followed by OS (31.3%) and finally the CS (15.6%). The overall average age was 33.6+/-15.8 years and the overall frequency of gender had a ratio of 1/1.03 male/female. The states with the highest incidence were Distrito Federal and Estado de Mexico with 29.2% and 25.3% respectively. Malignant neoplasms of bone assessed in the course of nine years show three significant increases in 2008, 2011 and 2014 (p=0.14). We found association between sex and tumor type (p=0.03), GCTb and CS predominated in females (54.9% and 56.6% respectively), while for the OS males were most affected (59.1%). Age was different in relation with tumor type (p=0.0001), average age was 24.3+/-11.2 years for OS, 34.5+/-13 years for GCTb and 49.2+/-18.5 years for CS. Furthermore, associations of tumor type with topographic location of the primary tumor (P=0.0001) were found. CONCLUSIONS: In this study we can see that incidence of musculoskeletal tumor in our population is continuously increasing and in nine years an approximately 200% increase of musculoskeletal tumor cases was observed. PMID- 26434859 TI - Single Nucleotide Polymorphisms in miR-149 (rs2292832) and miR-101-1 (rs7536540) Are Not Associated with Hepatocellular Carcinoma in Thai Patients with Hepatitis B Virus Infection. AB - MicroRNAs directly and indirectly influence many biological processes such as apoptosis, cell maintenance, and immune responses, impacting on tumor genesis and metastasis. They modulate gene expression at the post- transcriptional level and are associated with progression of liver disease. Hepatocellular carcinoma (HCC) is a cancer which mostly occurs in males. There are many factors affect HCC development, for example, hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV), co-infection, environmental factors including alcohol, aflatoxin consumption and host-related factors such as age, gender immune response, microRNA and single nucleotide polymorphisms (SNPs). Chronic infection with the hepatitis B virus is the major factor leading to HCC progression since it causes the liver injury. At present, there are many reports regarding the association of SNPs on miRNAs and the HCC progression. In this research, we investigated the role of miR- 149 (rs2292832) and miR-101-1 (rs7536540) with HCC progression in Thai population. The study included 289 Thai subjects including 104 HCC patients, 90 patients with chronic hepatitis B virus infection (CHB) and 95 healthy control subjects. The allele and genotype of rs2292832 and rs7536540 polymorphisms were determined by TaqMan real-time PCR assay. Our results revealed no significant association between miR-149 (rs2292832) and miR-101-1 (rs7536540) and the risk of HCC in our Thai population. However, this research is the first study of miR-149 (rs2292832) and miR-101-1 (rs7536540) in HCC in Thai populations and the results need to be confirmed with a larger population. PMID- 26434860 TI - Time--and Concentration--Dependent Effects of Resveratrol on miR 15a and miR16-1 Expression and Apoptosis in the CCRF-CEM Acute Lymphoblastic Leukemia Cell Line. AB - BACKGROUND: Chemotherapy is one of the common approaches in treatment of cancers, especially leukemia. However, drug resistance phenomena reduce the likelihood of treatment success. Resveratrol is a herbal compound which through complicated processes makes some selected cells sensitive to treatment and induction of apoptosis. In the present study, the effects of resveratrol on the expression of miR 15a and miR16-1 and apoptosis in the CCRF-CEM cell line were investigated. MATERIALS AND METHODS: The CCRF-CEM cell line was cultured under standard conditions and changes in miR 15a and miR 16-1 expression were analyzed by real time-PCR technique, with attention to reveratrol dose and time dependence. Also, apoptosis is evaluated by flow cytometry using annexin V and PI. RESULTS: CCRF CEM cells underwent dose-dependent apoptotic cell death in response to resveratrol. MiR 15a and miR 16-1 expression was up-regulated after 24 and 48 hours resveratrol treatment (p<0.05). CONCLUSIONS: The results of our study indicate that resveratrol induces apoptosis in a time and dose- dependent manner in CCRF-CEM cells. Also, increased expression level of miR 16-1 and miR 15a by means of resveratrol in CCRF-CEM cells might have a role in apoptosis induction and predisposition. According to our results resveratrol can be regarded as a dietary supplement to improve efficacy of anti-leukemia therapies. PMID- 26434861 TI - Diffusion Weighted Imaging Can Distinguish Benign from Malignant Mediastinal Tumors and Mass Lesions: Comparison with Positron Emission Tomography. AB - BACKGROUND: Diffusion-weighted magnetic resonance imaging (DWI) makes it possible to detect malignant tumors based on the diffusion of water molecules. It is uncertain whether DWI is more useful than positron emission tomography-computed tomography (PET-CT) for distinguishing benign from malignant mediastinal tumors and mass lesions. MATERIALS AND METHODS: Sixteen malignant mediastinal tumors (thymomas 7, thymic cancers 3, malignant lymphomas 3, malignant germ cell tumors 2, and thymic carcinoid 1) and 12 benign mediastinal tumors or mass lesions were assessed in this study. DWI and PET-CT were performed before biopsy or surgery. RESULTS: The apparent diffusion coefficient (ADC) value (1.51+/-0.46x10(-3) mm2/sec) of malignant mediastinal tumors was significantly lower than that (2.96+/-0.86x10(-3) mm2/sec) of benign mediastinal tumors and mass lesions (P<0.0001). Maximum standardized uptake value (SUVmax) (11.30+/-11.22) of malignant mediastinal tumors was significantly higher than that (2.53+/-3.92) of benign mediastinal tumors and mass lesions (P=0.0159). Using the optimal cutoff value (OCV) 2.21x10(-3) mm2/sec for ADC and 2.93 for SUVmax, the sensitivity (100%) by DWI was not significantly higher than that (93.8%) by PET-CT for malignant mediastinal tumors. The specificity (83.3%) by DWI was not significantly higher than that (66.7%) for benign mediastinal tumors and mass lesions. The accuracy (92.9%) by DWI was not significantly higher than that (82.1%) by PET-CT for mediastinal tumors and mass lesions. CONCLUSIONS: There was no significant difference between diagnostic capability of DWI and that of PET-CT for distinguishing mediastinal tumors and mass lesions. DWI is useful in distinguishing benign from malignant mediastinal tumors and mass lesions. PMID- 26434862 TI - Predictors of Sun-Protective Practices among Iranian Female College Students: Application of Protection Motivation Theory. AB - PURPOSE: Given the importance of sun protection in the prevention of skin cancer, this study was designed to determine predictors of sun-protective practices among a sample of Iranian female college students based on protection motivation theory (PMT) variables. MATERIALS AND METHODS: In this cross-sectional study, a total of 201 female college students in Iran University of Medical Sciences were selected. Demographic and PMT variables were assessed with a 67-item questionnaire. Multiple linear regression was used to identify demographic and PMT variables that were associated with sun-protective practices and intention. RESULTS: one percent of participants always wore a hat with a brim, 3.5% gloves and 15.9% sunglasses while outdoors. Only 10.9% regularly had their skin checked by a doctor. Perceived rewards, response efficacy, fear, self-efficacy and marital status were the five variables which could predict 39% variance of participants intention to perform sun-protective practices. Also, intention and response cost explained 31% of the variance of sun-protective practices. CONCLUSIONS: These predictive variables may be used to develop theory-based education interventions interventions to prevent skin cancer among college students. PMID- 26434863 TI - Patterns of Esophageal Cancer in the National Cancer Institute at the University of Gezira, in Gezira State, Sudan, in 1999-2012. AB - BACKGROUND: Esophageal cancer (EC) is among the most common malignancies in Eastern Africa, but the occurrence of EC in Sudan has rarely been described in the scientific literature. This paper reports the results of a consecutive case series of all EC patients who visited one of the two public cancer treatment centers in the country in 1999-2012, providing a first description of this disease in a treatment center located in central Sudan. MATERIALS AND METHODS: Clinical and demographic data for all EC patients who visited the Department of Oncology of the National Cancer Institute at the University of Gezira (NCI-UG) from 1999 to the end of 2012 were abstracted and tabulated by sex, tumor type and other characteristics. RESULTS: A total of 448 EC patients visited NCI-UG in 1999 2012, and the annual number of EC cases increased steadily from 1999. Squamous cell carcinoma (SCC) was the predominant EC tumor type (90%), and adenocarcinoma (ADC) was reported in 9.4% of the EC cases. The overall male-to-female ratio for EC was 1:1.8, but the ratio was tumor type-dependent, being 1:2 for SCC and 2:1 for ADC. Only 20% of EC patients reported having ever used tobacco and/or alcohol, and the vast majority of these patients were male. At the time of EC diagnosis, 47.3% of the patients resided in Gezira State. Some EC patients from Gezira State seek out-of-state treatment in the national capital of Khartoum instead of visiting NCI-UG. CONCLUSIONS: The annual number of EC patients visiting NCI-UG has increased in recent years, approximately half of these patients being from Gezira State. Although this consecutive series of EC patients who visited NCI-UG was complete, it did not capture all EC patients from the state. A population- based cancer registry would provide more complete data required to better understand EC patterns and risk factors. PMID- 26434864 TI - Chemopreventive Actions of Blond and Red-Fleshed Sweet Orange Juice on the Loucy Leukemia Cell Line. AB - BACKGROUND: Red-fleshed sweet orange juice (ROJ) comes from a new variety of citrus cultivated in Brazil that contains high levels of beta-carotene and lycopene, and similar amounts of hesperidin (HSP) and nutrients, equivalently to blond orange juice (BOJ). Such bioactive compounds are associated with chemopreventive actions in several cancer cell lines. The purpose of this study was to examine the cytotoxicity, cell cycle, apoptosis, and cytokine secretion after BOJ, ROJ, and HSP treatment of a novel T acute lymphoblastic leukemia cell line, Loucy. MATERIALS AND METHODS: Loucy cells were incubated for 24-h with BOJ, ROJ, and HSP, and the viability was measured using trypan blue. Cell cycling and apoptosis were assessed by propidium iodide (PI) and annexin V-FITC/PI flow cytometry, respectively. Secretion of cytokines IL-1alpha, IL1-beta, IL-2, IL-4, IL-6, IL-10, IL-17A, IFNgamma, TNFalpha, TGFbeta, MIPalpha, and MIPbeta was determined by ELISA array. RESULTS: BOJ and ROJ treatments promoted Loucy cell cytotoxicity. Additionally, BOJ induced cell cycle arrest in the G0/G1 phase, and decreased the cell accumulation in the G2/M. ROJ decreased only the G0/G1 fraction, while HSP did not change the cell cycle. BOJ led to apoptosis in a different fashion of ROJ, while the first treatment induced apoptosis by increase of late apoptosis and primary necrotic fractions, the second increased early and late apoptosis, and primary necrotic fraction compared to positive controls. HSP had no effect on apoptosis. IL-6 and IL-10 were abrogated by all treatments. CONCLUSIONS: Taking together, these results suggest potential chemopreventive effects of BOJ and ROJ on Loucy cells. PMID- 26434865 TI - Bevacizumab Regulates Cancer Cell Migration by Activation of STAT3. AB - There are numerous clinical cases indicating that long-term use of bevacizumab may increase the invasiveness of tumors. However, to date, little is known about underlying molecular mechanisms. Therefore, the purpose of our study was to investigate effects of bevacizumab in four cancer cells lines (WSU-HN6, CAL27, Tca83, and HeLa). It was found to promote migration and invasion in the WSU-HN6 and Tca83 cases, while exerting inhibitory effects in CAL27 and HeLa cells. The signal transducer and activator of transcription (STAT) 3 inhibitors niclosamide and S3I-201 inhibited the STAT3 signal pathway, which is activated by bevacizumab. These inhibitors also substantially blocked bevacizumab-induced migration of WSU-HN6 and Tca83 cells. Bevacizumab upregulated interleukin (IL)-6 and phosphorylated (p)-STAT3 expression time-dependently. Therefore, we propose that bevacizumab has differential effects on the migration of different cancer cell lines and promotes migration via the IL-6/STAT3 signaling pathway. PMID- 26434866 TI - Medullary Thyroid Carcinoma--Circulating Status of Vaspin and Retinol Binding Protein-4 in Iranian Patients. AB - BACKGROUND: Vaspin and Retinol binding protein-4 (RBP4) are new adipokines mainly produced by adipose tissue. Considering that medullary thyroid carcinoma (MTC) is a malignant neuroendocrine tumor, and to date the relationship between serum levels of vaspin and RBP4 with MTC has not been studied, in this matched case control study we evaluated their possible significance to this tumor type. MATERIALS AND METHODS: A total of 45 patients with MTC (21 males and 24 females) and 45 healthy persons as a control group (24 males and 21 females) were selected. The two groups were matched for age, sex and body mass index. Serum Vaspin and RBP4 levels were measured by enzyme-linked immunosorbent assay (ELISA) methods in both groups. Also, weight and height were measured and body mass index was calculated too. RESULTS: In total, patients with MTC had significantly higher serum vaspin levels compared to the controls (0.52 ng/ml vs. 0.45 ng/ml, P=0.0241). However, no significant difference was found in serum RBP4 concentrations between the patients with MTC and the controls (15.2+/-2.55 MUg/ml versus 15.1+/-3.34 MUg/ml, p>0.05). CONCLUSIONS: The results of this study demonstrated that serum RBP4 levels in MTC patients are not significantly different from those found in healthy individuals and did not correlate with MTC. On the other hand, higher levels of serum vaspin are associated with an increased risk of MTC. Thus Vaspin may be a novel and promising biomarker for diagnosis or confirmation of MTC in conjunction other specific tumor markers. PMID- 26434867 TI - Anticancer Effects of Curcuma C20-Dialdehyde against Colon and Cervical Cancer Cell Lines. AB - BACKGROUND: Recent attention on chemotherapeutic intervention against cancer has been focused on discovering and developing phytochemicals as anticancer agents with improved efficacy, low drug resistance and toxicity, low cost and limited adverse side effects. In this study, we investigated the effects of Curcuma C20 dialdehyde on growth, apoptosis and cell cycle arrest in colon and cervical cancer cell lines. MATERIALS AND METHODS: Antiproliferative, apoptosis induction, and cell cycle arrest activities of Curcuma C20-dialdehyde were determined by WST cell proliferation assay, flow cytometric Alexa fluor 488-annexin V/propidium iodide (PI) staining and PI staining, respectively. RESULTS: Curcuma C20 dialdehyde suppressed the proliferation of HCT116, HT29 and HeLa cells, with IC50 values of 65.4+/-1.74 MUg/ml, 58.4+/-5.20 MUg/ml and 72.0+/-0.03 MUg/ml, respectively, with 72 h exposure. Flow cytometric analysis revealed that percentages of early apoptotic cells increased in a dose-dependent manner upon exposure to Curcuma C20-dialdehyde. Furthermore, exposure to lower concentrations of this compound significantly induced cell cycle arrest at G1 phase for both HCT116 and HT29 cells, while higher concentrations increased sub-G1 populations. However, the concentrations used in this study could not induce cell cycle arrest but rather induced apoptotic cell death in HeLa cells. CONCLUSIONS: Our findings suggest that the phytochemical Curcuma C20-dialdehyde may be a potential antineoplastic agent for colon and cervical cancer chemotherapy and/or chemoprevention. Further studies are needed to characterize the drug target or mode of action of the Curcuma C20-dialdehyde as an anticancer agent. PMID- 26434868 TI - Treatment and Follow-up of Human Papillomavirus Infected Women in a Municipality in Southern Brazil. AB - BACKGROUND: This study aimed toanalyze the risk behavior for cervical cancer (CC) and the human papillomavirus (HPV) prevalence and resolution among women who received care through the private healthcare network of a municipality in southern Brazil. MATERIALS AND METHODS: This descriptive and retrospective study was conducted with 25 women aged 20 to 59 years who received care through the private healthcare network and were treated at a specialty clinic in the period from January to December 2012 in a municipality in Northwest Parana, Southern Brazil. Data from medical records with cytological and HPV results were used. Following treatment, these women were followed-up and reassessed after 6 months. Data were statistically analyzed using the t-test and chi-squared test at a 5% significance level. RESULTS: The mean age of the studied women was 27.8+/-7.75 years old, and the majority were married, with paid employment and were non smokers. The mean age at menarche was 13.0+/-0.50 years old, and the mean age at first intercourse was 17.5+/-1.78 years, with only 8.0% (2) initiating sexual activity at an age <=15 years old. The majority had 1 to 2 children (60.0%), while 88.0% reported having had one sexual partner in their lifetime, and all the women were sexually active. A total of 68.0% used a hormonal contraceptive method. All the women had leukorrhea and pain and were infected by a single HPV type. Regarding the lesion grade, 80.0% showed high risk and 20.0% low risk. The most prevalent high-risk HPV strain was 16. CONCLUSIONS: These findings provide relevant information on HPV risk factors and infection, as well as the treatment and 6-month follow-up results, in economically and socially advantaged women with no traditional risk factors, corroborating previous reports that different risk factors may be described in different populations. Thus, this study reinforces the fact that even women without the traditional risk factors should undergo HPVmonitoring and assessment to determine the persistence of infection, promoting early diagnosis of the lesions presented and appropriate treatment to thus prevent the occurrence of CC. PMID- 26434869 TI - Association between Smoking Status and Food and Nutrient Consumption in Japanese: a Large-Scale Cross-Sectional Study. AB - BACKGROUND: In Japan, in comparison with the rest of the world the death rate of lung cancer is low although the smoking rate is relatively high. This is the so called "Japanese smoking paradox". A healthy diet is proposed to attenuate the risk without quitting smoking. We here examined the relationships between smoking status (SS) and the consumption of food and nutrient in Japan. MATERIALS AND METHODS: Totals of 5,587 men and 2,718 women were divided into three (non smokers, smokers and heavy smokers) and two (non-smokers and smokers) groups, respectively, according to pack-year, which represents the amount of smoking over a long period. Food and nutrient consumption was estimated with a validated food frequency questionnaire. Using general linear models, food and nutrient consumption was estimated for each group in men and women, separately. RESULTS: In men, SS was positively related to consumption of rice, 3 alcoholic beverages, carbohydrate, alcohol and other 8 foods/nutrients (p<0.05 for all) and negatively to those of protein animal, fat, fatty acids, dietary fiber, isoflavones and 36 other foods/nutrients (p<0.05 for all). In women, SS was positively associated with intake of 13 foods/nutrients, while being negatively associated with those of rice, energy, dietary fiber, and 14 other foods/nutrients (p<0.05 for all). CONCLUSIONS: Our results support lower intake of vegetables and fruits rich in antioxidants, which are thought as preventive factors for many diseases, in smokers. PMID- 26434870 TI - Nuclear DNA Damage and Repair in Normal Ovarian Cells Caused by Epothilone B. AB - This study was designed to assess, whether a new chemotherapeutic microtubule inhibitor, Epothilone B (EpoB, Patupilone), can induce DNA damage in normal ovarian cells (MM14.Ov), and to evaluate if such damage could be repaired. The changes were compared with the effect of paclitaxel (PTX) commonly employed in the clinic. The alkaline comet assay technique and TUNEL assay were used. The kinetics of DNA damage formation and the level of apoptotic cells were determined after treatment with IC50 concentrations of EpoB and PTX. It was observed that PTX generated significantly higher apoptotic and genotoxic changes than EpoB. The peak was observed after 48 h of treatment when the DNA damage had a maximal level. The DNA damage induced by both tested drugs was almost completely repaired. As EpoB in normal cells causes less damage to DNA it might be a promising anticancer drug with potential for the treatment of ovarian tumors. PMID- 26434871 TI - Epidemiological Study of Laryngeal Carcinoma in Western Nepal. AB - BACKGROUND: Laryngeal malignancy is a common malignancy of the head and neck region. Affected patients usually present with features that are characteristic of certain subsites. The larynx is oncologically divided into three: supraglottis, glottis and subglottis. Studies from Western countries have shown that the glottis is the commonest subsite to harbour laryngeal malignancy. However, the supraglottis has been reported to be the commonest subsite in developing countries, including examples in the Indian subcontinent. To our knowledge, no study has been carried out in western Nepal about the epidemiology of laryngeal cancer to date. The purpose of this study was to analyse the epidemiology of laryngeal cancer in relation to its risk factors, age distribution,and preferred subsites and to see if there is any recent change in the subsite wise distribution of laryngeal malignancy in western Nepal. MATERIALS AND METHODS: Patients of all ages and both sexes with suspected laryngeal malignancy were enrolled in the initial study. Detailed history taking and clinical examination was performed to find out the involved subsite in relation to the clinical features. Direct laryngoscopy was performed to further confirm the subsite and to take biopsy from the growth under general anesthesia. After confirmation of malignancy from the biopsy report, patients were finally included in the study. Data were analysed and observations were made to find out the distribution of laryngeal malignancy in different subsites. RESULTS: The supraglottic larynx was the commonest subsite to harbor laryngeal malignancy. Smoking and alcohol were found to be the common risk factors. The mean age of the patients was in their sixties. CONCLUSIONS: Laryngeal malignancy is common in elderly individuals. Supraglottic laryngeal malignancy is the commonest laryngeal malignancy in people who smoke and drink alcohol in Nepal. Avoidance of alcohol use and smoking will be a milestone to reduce the incidence of laryngeal cancers and associated mortality. PMID- 26434872 TI - Transducer-like Enhancer of Split 1 as a Novel Immuno- histochemical Marker for Diagnosis of Synovial Sarcoma. AB - BACKGROUND: Synovial sarcoma is a mesenchymal neoplasm that accounts for around 10% of all soft tissue sarcomas. The diagnosis of synovial sarcoma can be a challenging task, particularly with small biopsy specimens. AIM: We investigated transducer-like enhancer of split 1 (TLE1), monoclonal antibody, expression by immunohistochemical analysis in a group of 74 synovial sarcoma cases, 20 cases of MPNST, 12 cases of neurofibroma, 15 cases of schwannoma, 5 cases of MFH, 10 cases of lieomyosarcoma and 10 cases of solitary fibrous tumor. MATERIALS AND METHODS: Whole tissue sections were examined: (39 biphasic and 35 monophasic). Nuclear immunoreactivity was scored as negative (<5% of cells positive), 1+(mild /5-25%), 2+ (moderate/25-50%), and 3+ (strong >50%). RESULTS: Overall, 71 (96%) of 74 synovial sarcomas were positive for TLE1, including 37 biphasic (95%) and 34 monophasic (97%) tumors. Other spindle cell tumors showed very low or absent staining of TLE1. CONCLUSIONS: We conclude that TLE1 is a sensitive marker and can be a useful diagnostic marker for synovial sarcoma, particularly the monophasic forms. PMID- 26434873 TI - Mechanism of Chemoprevention against Colon Cancer Cells Using Combined Gelam Honey and Ginger Extract via mTOR and Wnt/beta-catenin Pathways. AB - The PI3K-Akt-mTOR, Wnt/beta-catenin and apoptosis signaling pathways have been shown to be involved in genesis of colorectal cancer (CRC). The aim of this study was to elucidate whether combination of Gelam honey and ginger might have chemopreventive properties in HT29 colon cancer cells by modulating the mTOR, Wnt/beta-catenin and apoptosis signaling pathways. Treatment with Gelam honey and ginger reduced the viability of the HT29 cells dose dependently with IC50 values of 88 mg/ml and 2.15 mg/ml respectively, their while the combined treatment of 2 mg/ml of ginger with 31 mg/ml of Gelam honey inhibited growth of most HT29 cells. Gelam honey, ginger and combination induced apoptosis in a dose dependent manner with the combined treatment exhibiting the highest apoptosis rate. The combined treatment downregulated the gene expressions of Akt, mTOR, Raptor, Rictor, beta catenin, Gsk3beta, Tcf4 and cyclin D1 while cytochrome C and caspase 3 genes were shown to be upregulated. In conclusion, the combination of Gelam honey and ginger may serve as a potential therapy in the treatment of colorectal cancer through inhibiton of mTOR, Wnt/beta catenin signaling pathways and induction of apoptosis pathway. PMID- 26434874 TI - Does Cervical Screening in Young Women Aged 20-25 Years Lead to Unnecessary and Harmful Interventions? AB - BACKGROUND: Cervical human papillomavirus (HPV) infection among young women (20 25 years of age) is common and normally transient. There are growing concerns that referral to a colposcopy clinic may lead to unnecessary treatment with an increased risk of obstetric complications. Therefore, the purpose of this study was to determine the level of intervention for cervical abnormalities in this age group of the Northern Ireland population. MATERIALS AND METHODS: A review of all serial new patients under 25 years of age, who were referred to colposcopy clinics in Northern Ireland between January 1, 2009 to June 30, 2009 formed the basis of this study. RESULTS: During the study period, a total of 4,767 women under 25 years of age were screened. Two-hundred-and- thirty-four (4.9%) cases were referred to the colposcopy clinics. The cervical cytology results were: high grade abnormality in 35%, and low-grade abnormality in 31% of these cases. One hundred-and-seventy-eight (76%) of the referred women received at least one treatment. One-hundred-and-twenty-one of 234 (51.5%) women underwent an excisional treatment with histology showing the presence of high-grade abnormalities (CIN2-3) in 52%, CIN1 in 28%, and Koilocytosis or normal tissue in 20% of this sub-group of cases. CONCLUSIONS: Screening women under the age of 25 years cause unnecessary referral for colposcopy. This may also result in considerable anxiety and psychosexual morbidity. It leads to an over-treatment with a potential of negative impact on the future pregnancy outcomes (including pre-term delivery, low birth weight, and pre-term premature rupture of membranes). PMID- 26434875 TI - Trends of Smokeless Tobacco use among Adults (Aged 15-49 Years) in Bangladesh, India and Nepal. AB - BACKGROUND: Smokeless tobacco (SLT) has long been realized as an important component of the fight for global tobacco control. It still remains a major problem in countries like India, Bangladesh and Nepal. The objective of this study was to estimate the trends of SLT use in three countries of the SEARO WHO office. MATERIALS AND METHODS: We used data from national surveys in three countries (Bangladesh, India and Nepal) to estimate trends in prevalence of current SLT use. All available nationally representative data sources were used. Estimates were weighted, age standardized and given along with 95% confidence intervals. Significance of linear trend in prevalence over time was tested using the Cochrane-Armitage test for trend. A p value of less than 0.05 was considered statistically significant. RESULTS: We identified three surveys for Bangladesh, three for India and four for Nepal that met the selection criteria (such as Demographic and Health Surveys, WHO-STEPwise approach to Surveillance and Global Adult Tobacco Surveys). A significantly increasing trend was noticed in the prevalence of current SLT use among Bangladeshi men (20.2% to 23%, p=0.03). In India, a similar significantly increasing trend was seen among men (27.1% to 33.4%, p<0.001) and women (10.1% to 15.7%, p<0.001). In Nepal, there was a no significant trend among both men (39.1% to 31.6%, p=0.11) and women (5.6% to 4.7%, p=0.49). CONCLUSIONS: In the study countries SLT use has remained at alarmingly high levels. Usage trends do not show any signs of decline in spite of control efforts. Tobacco control measures should focus more on controlling SLT use. PMID- 26434876 TI - Applicative Value of Serum CA19-9, CEA, CA125 and CA242 in Diagnosis and Prognosis for Patients with Pancreatic Cancer Treated by Concurrent Chemoradiotherapy. AB - OBJECTIVE: To evaluate the application value of serum CA19-9, CEA, CA125 and CA242 in diagnosis and prognosis of pancreatic cancer cases treated with concurrent chemotherapy. MATERIALS AND METHODS: 52 patients with pancreatic cancer, 40 with benign pancreatic diseases and 40 healthy people were selected. The electrochemiluminescence immunoassay method was used for detecting levels of CA19-9, CEA and CA125, and a CanAg CA242 enzyme linked immunoassay kit for assessing the level of CA242. The Kaplan-Meier method was used for analyzing the prognostic factors of patients with pancreatic cancer. The Cox proportional hazard model was applied for analyzing the hazard ratio (HR) and 95% confidential interval (CI) for survival time of patients with pancreatic cancer. RESULTS: The levels of serum CA19-9, CEA, CA125 and CA242 in patients with pancreatic cancer were significantly higher than those in patients with benign pancreatic diseases and healthy people (P<0.001). The sensitivity of CA19-9 was the highest among these, followed by CA242, CA125 and CEA. The specificity of CA242 is the highest, followed by CA125, CEA and CA19-9. The sensitivity and specificity of joint detection of serum CA19-9, CEA, CA125and CA242 were 90.4% and 93.8%, obviously higher than single detection of those markers in diagnosis of pancreatic cancer. The median survival time of 52 patients with pancreatic cancer was 10 months (95% CI7.389~12.611).. Patients with the increasing level of serum CA19-9, CEA, CA125, CA242 had shorter survival times (P=0.047. 0.043, 0.0041, 0.029). COX regression analysis showed that CA19-9 was an independent prognostic factor for patients with pancreatic cancer (P=0.001, 95%CI 2.591~38.243). CONCLUSIONS: The detection of serum tumor markers (CA19.9, CEA, CA125 and CA242) is conducive to the early diagnosis of pancreatic cancer and joint detection of tumor markers helps improve the diagnostic efficiency. Moreover, CA19-9 is an independent prognostic factor for patients with pancreatic cancer. PMID- 26434877 TI - Differences in Prognostic Factors between Early and Late Recurrence Breast Cancers. AB - BACKGROUND: Breast cancer (BC) is the most frequent malignancy among females and is a leading cause of death of middle-aged women. Herein, we evaluated baseline characteristics for BC patients and also compared these variables across ealry and late recurrence groups. MATERIALS AND METHODS: Between 1995 to 2014, among female breast cancer patients referred to our oncology clinic, eighty-six were entered into our study. All had distant metastasis. Early recurrence was defined as initial recurrence within 5 years following curative surgery irrespective of site. Likewise, late recurrence was defined as initial recurrence after 5 years. No recurrence was defined for survivors to a complete minimum of 10 years follow up. Significant prognostic factors associated with early or late recurrence were selected according to the Akaike Information Criterion. RESULTS: The median follow-up was 9 years (range, 1-18 years). During follow-up period, 51 recurrences occurred (distant metastasis), 31 early and 20 late. According to the site of recurrence, there were 51 distant. In this follow-up period, 19 patients died. Compared with the early recurrence group, the no recurrence group had lower lymph node involvement and more p53 positive lesions but the late recurrence group had lower tumor size. In comparison to no recurrence, p53 (odds ratio [OR] 6.94, 95% CI 1.49-32.16) was a significant prognostic factor for early recurrence within 5 years. CONCLUSIONS: Tumor size, p53 and LN metastasis are the most important risk factors for distance recurrence especially in early recurrence and also between of them, p53 is significant prognostic factor for early recurrence. PMID- 26434878 TI - Propolis from the Stingless Bee Trigona incisa from East Kalimantan, Indonesia, Induces In Vitro Cytotoxicity and Apoptosis in Cancer Cell lines. AB - BACKGROUND: Previously, stingless bee (Trigona spp.) products from East Kalimantan, Indonesia, were successfully screened for in vitro antiproliferative activity against human cancer derived cell lines. It was established that propolis from T. incisa presented the highest in vitro cytotoxicity against the SW620 colon cancer cell line (6% cell survival in 20 MUg/mL). MATERIALS AND METHODS: Propolis from T. incisa was extracted with methanol and further partitioned with n-hexane, ethyl acetate and methanol. The in vitro cytotoxicity of the extracts was assessed by the MTT assay against human colon (SW620), liver (Hep-G2), gastric (KATO-III), lung (Chago) and breast (BT474) cancer derived cell lines. The active fractions were further enriched by silica gel quick column, absorption and size exclusion chromatography. The purity of each fraction was checked by thin layer chromatography. Cytotoxicity in BT-474 cells induced by cardanol compared to doxorubicin were evaluated by MTT assay, induction of cell cycle arrest and cell death by flow cytometric analysis of propidium iodide and annexin-V stained cells. RESULTS: A cardol isomer was found to be the major compound in one active fraction (F45) of T. incisa propolis, with a cytotoxicity against the SW620 (IC50 of 4.51+/-0.76 MUg/mL), KATO-III (IC50 of 6.06+/-0.39 MUg/mL), Hep-G2 (IC50 of 0.71+/-0.22 MUg/mL), Chago I (IC50 of 0.81+/-0.18 MUg/mL) and BT474 (IC50 of 4.28+/-0.14 MUg/mL) cell lines. Early apoptosis (programmed cell death) of SW620 cells was induced by the cardol containing F45 fraction at the IC50 and IC80 concentrations, respectively, within 2-6 h of incubation. In addition, the F45 fraction induced cell cycle arrest at the G1 subphase. CONCLUSIONS: Indonesian stingless bee (T. incisa) propolis had moderately potent in vitro anticancer activity on human cancer derived cell lines. Cardol or 5-pentadecyl resorcinol was identified as a major active compound and induced apoptosis in SW620 cells in an early period (<=6 h) and cell cycle arrest at the G1 subphase. Thus, cardol is a potential candidate for cancer chemotherapy. PMID- 26434879 TI - Ki-67 Labeling Indices in 'Classic' versus 'Blastoid' Mantle Cell Lymphomas- Proposed Cutoff Values for Routine Diagnostic Workup. AB - BACKGROUND: Mantle-cell lymphoma (MCL) is a unique entity of peripheral B-cell lymphoma that has a discrete morphologic, immunologic, and genetic phenotype, with more common 'classic' and less frequent 'blastoid' and 'pleomorphic' variants, associated with an aggressive clinical course. The aim of this study was to analyze proliferation (Ki-67) indices of 'classic' (c-MCL) and 'blastoid' (b-MCL) variants of a cohort of MCL and to suggest cut off values for the Ki-67 proliferation index in these two subsets. MATERIALS AND METHODS: MCL cases diagnosed over 4 1/2 years at Section of Histopathology, Department of Pathology and Laboratory Medicine, Aga Khan University Hospital, Karachi were retrieved and reviewed. Ki-67 labelling was scored and analysed. RESULTS: A total of 90 of cases of MCL were scrutinized. Mean age+/-SD was 60.2+/-12.5 years and the male to female ratio was 4:1, with 67 (75%) cases of c-MCL and 23 (25%) cases of b MCL. Most samples were lymph node biopsies (n=68), whereas the remainder were from various extranodal sites The mean Ki-67 proliferation index was 29.5%+/ 14.4% in classic variants and 64.4+/-15.2% for the blastoid variant, the difference being statistically significant (p=0.029). CONCLUSIONS: It was concluded that differential cut-off values of Ki-67 labeling may be used in more objective way to reliably classify MCL into classic or blastoid variants by diagnostic pathologists. We propose a <40 proliferative index to be suggestive of c-MCL and one of >50 for the blastoid variant. PMID- 26434880 TI - Clinical Study on Lobaplatin Combined with 5-Fu and Concurrent Radiotherapy in Treating Patients with Inoperable Esophageal Cancer. AB - OBJECTIVE: To investigate short- and long-term treatment effects and side reactions of lobaplatin plus 5-Fu combined and concurrent radiotherapy in treating patients with inoperable middle-advanced stage esophageal cancer. METHODS: Sixty patients with middle-advanced stage esophageal squamous cell cancer were retrospectively analyzed. All patients were administered lobaplatin (50 mg intravenously) for 2 h on day 1, and 5-Fu (500 mg/m2) injected intravenously from day 1 to 5 for 1 cycle, in an interval of 21 days for totally 4 cycles. At the same time, late-course accelerated hyperfractionated three dimensional conformal radiotherapy was performed. Patients were firstly treated with conventional fractionated irradiation (1.8 Gy/d, 5 times/week, a total of 23 treatments, and DT41.4 Gy), and then treated with accelerated hyperfractionated irradiation (1.5 Gy, 2 times/d, a total of 27 Gy in 9 days, an entire course of 6 7 weeks, and DT 68.4 Gy). RESULTS: All patients completed treatment, including 10 complete response (CR), 41 partial response (PR), 7 stable disease (SD), and 2 progressive disease (PD). The total effective rate was 85.0% (51/60). Thirty-nine patients had an increased KPS score. One-, 2-, and 3-year survival rates were 85.3%, 57.5%, and 41.7%, respectively. The median survival time was 27 months. The adverse reactions included myelosuppression, which was mainly degreeI and II. The occurrence rate of radiation esophagitis was 17.5%. No significant hepatic or renal toxicity was observed. CONCLUSION: Lobaplatin plus 5-Fu combined with concurrent radiotherapy is safe and effective in treating patients with middle advanced stage esophageal cancer. However, this result warrants further evaluation by randomized clinical studies. PMID- 26434881 TI - Creatine Kinase (CK)-MB-to-Total-CK Ratio: a Laboratory Indicator for Primary Cancer Screening. AB - BACKGROUND: For the determination of creatine kinase (CK)-MB, the immunoinhibition method is utilized most commonly. However, the estimated CK-MB activity may be influenced by the presence of CK isoenzymes in some conditions like cancer. Thus, a CK-MB-to-total-CK ratio more than 1.0 could be found in such a situation. The study aimed to explore the relationship of cancer to high CK-MB to-total-CK ratio. MATERIALS AND METHODS: From January 2011 to December 2014, laboratory data on all CK-MB and total CK test requests were extracted at Far Eastern Memorial Hospital (88,415 requests). Patients with a CK-MB-to-total-CK ratio more than 1.0 were registered in this study. Clinical data including tumor location, tumor TNM stage and metastatic status were also collected. RESULTS: A total of 846 patients were identified with a CK-MB-to-total-CK ratio more than 1.0. Of these, 339 (40.1%) were diagnosed with malignancies. The mean CK-MB-to total-CK ratio was significantly higher in malignancy than in non-malignancy (1.35+/-0.28 vs 1.25+/-0.23, p<0.001) groups. The most frequent malignancy with a CK-MB-to-total-CK ratio more than 1.0 was colorectal cancer (1.42+/-0.28, 16.5%, n=56), followed by lung cancer (1.38+/-0.24, 15.9%, n=54) and hepatocellular carcinoma (14.5%, n=49). Higher CK-MB-to-total-CK ratios in hematological malignancies (1.44+/-0.41)were also noted. Additionally, the CK-MB-to-total-CK ratio was markedly higher in advanced stage malignancy than in early stage (1.37+/-0.26 vs. 1.29+/-0.31, p=0.014) and significantly higher in liver metastasis than in non-liver metastasis (1.48+/-0.30 vs. 1.30+/-0.21, p<0.001). CONCLUSIONS: The CK-MB-to-total-CK ratio is an easily available indicator and could be clinically utilized as a primary screening tool for cancer. Higher ratio of CK-MB-to-total-CK was specifically associated with certain malignancies, like colorectal cancer, lung cancer and hepatocellular carcinoma, as well as some cancer-associated status factors such as advanced stage and liver metastasis. PMID- 26434882 TI - Information Engineering and Workflow Design in a Clinical Decision Support System for Colorectal Cancer Screening in Iran. AB - BACKGROUND: Colorectal cancer is a major cause of morbidity and mortality throughout the world. Colorectal cancer screening is an optimal way for reducing of morbidity and mortality and a clinical decision support system (CDSS) plays an important role in predicting success of screening processes. DSS is a computer based information system that improves the delivery of preventive care services. The aim of this article was to detail engineering of information requirements and work flow design of CDSS for a colorectal cancer screening program. MATERIALS AND METHODS: In the first stage a screening minimum data set was determined. Developed and developing countries were analyzed for identifying this data set. Then information deficiencies and gaps were determined by check list. The second stage was a qualitative survey with a semi-structured interview as the study tool. A total of 15 users and stakeholders' perspectives about workflow of CDSS were studied. Finally workflow of DSS of control program was designed by standard clinical practice guidelines and perspectives. RESULTS: Screening minimum data set of national colorectal cancer screening program was defined in five sections, including colonoscopy data set, surgery, pathology, genetics and pedigree data set. Deficiencies and information gaps were analyzed. Then we designed a work process standard of screening. Finally workflow of DSS and entry stage were determined. CONCLUSIONS: A CDSS facilitates complex decision making for screening and has key roles in designing optimal interactions between colonoscopy, pathology and laboratory departments. Also workflow analysis is useful to identify data reconciliation strategies to address documentation gaps. Following recommendations of CDSS should improve quality of colorectal cancer screening. PMID- 26434883 TI - Expression of Matrix Metalloproteinase-10 at Invasive Front of Squamous Cell Carcinoma and Verrucous Carcinoma in the Oral Cavity. AB - BACKGROUND: Matrix metalloproteinases (MMPs) are a family of zinc metalloproteinases capable of degrading components of connective tissues. MMP-10 is frequently expressed in human cancers. The aim of this study was to immunohistochemically evaluate its expression in oral squamous cell carcinoma (OSCC) and verrucous carcinoma (OVC). MATERIALS AND METHODS: A retrospective analysis of 73 samples (31 OSCC, 22 OVC and 20 non-neoplastic epithelium) was performed. All samples were immunohistochemically stained with monoclonal MMP-10 antibody and expression levels and staining intensity were evaluated with respect to microscopic features. Data were analyzed by SPSS (V.21), Mann-Whitney and Kruskal Wallis tests. RESULTS: MMP-10 was detected in all OSCC and OVC cases. The expression of MMP-10 in OSCC was intensive (score 3) and in OVC was low and moderate (score 1 and score 2) more frequently. Non- neoplastic epithelium did not show MMP-10 expression. Differences between groups was statistically significant (p<0.05). However, the expression of MMP- 10 was not obviously different between various grades of OSCC. CONCLUSIONS: According to our study, MMP-10 protein can be important possible factor in the transformation of normal oral epithelium to OVC and OSCC, also the level of MMP-10 expression at invasion front of the lesions can be helpful in the differentiation of OVC and OSCC. PMID- 26434884 TI - Possible Role of HER-2 in the Progression of Prostate Cancer from Primary Tumor to Androgen Independence. AB - BACKGROUND: The expression of HER-2 in prostate cancer has been linked to disease progression. We analysed the presence of HER-2 expression in primary tumors in men undergoing radical prostatectomy, its association with clinical and pathological findings, and its expression in secondary circulating prostate cells (CPCs) during follow up, as well as links with biochemical failure and the effects of androgen blockade. MATERIALS AND METHODS: Consecutive men undergoing radical prostatectomy for histologically confirmed prostate cancer were analyzed. HER-2 expression in the primary tumor was assessed using the HercepTest(r), CPCs were identified from blood samples using standard immunocytochemistry with anti PSA and positive samples with the HercepTest(r) to determine HER-2 expression. The influence of HER-2 expression on the frequency of biochemical failure and effects of androgen blockade was determined. RESULTS: 144 men with a mean age of 64.8+/-10.3 years participated, with a median follow up of 8.2 years. HER-2 was expressed in 20.8% of primary tumors; it was associated with vascular infiltration and older age, but not with other clinical pathological findings. Some 40.3% of men had secondary CPCs detected, of which 38% expressed HER-2. Men CPC (+) had a higher frequency of biochemical failure, but there was no difference in HER-2 expression of CPCs with the frequency of biochemical failure. After androgen blockade, men with HER-2 (+) positive secondary CPCs had a higher frequency of disease progression to castrate resistant disease. CONCLUSIONS: HER 2 plays a dual role in the progression of prostate cancer; firstly it may increase the potential of tumor cells to disseminate from the primary tumor via the blood by increasing vascular infiltration. In the presence of androgens, there is no survival advantage of expressing HER-2, but once biochemical failure has occurred and androgen blockade started, HER-2 positive cells are resistant to treatment, survive and grow leading to castration resistant disease. PMID- 26434885 TI - Metformin Addition to Chemotherapy in Stage IV Non-Small Cell Lung Cancer: an Open Label Randomized Controlled Study. AB - PURPOSE: To evaluate effects of metformin on clinical outcome of non-diabetic patients with stage IV NSCLC. MATERIALS AND METHODS: A prospective, randomized, open-label, controlled pilot study was conducted on patients with stage IV NSCLC with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2, excluding patients with diabetes and lactic acidosis. Thirty chemo-naive, non diabetic patients with stage IV NSCLC were enrolled. Fifteen patients received intravenous gemcitabine/cisplatin regimen alone (arm B) while fifteen patients received the same regimen plus daily oral metformin 500 mg (arm A). The effect of metformin on chemotherapy-response rates, survival, and adverse events in these patients was evaluated. RESULTS: Objective response rate (ORR) and median overall survival (OS) in arms A and B were 46.7% versus 13.3% respectively, p=0.109 and 12 months versus 6.5 months, respectively, p=0.119. Median progression free survival (PFS) in arms A and B was 5.5 months versus 5 months, p=0.062. No significant increase in toxicity was observed in arm A versus arm B. Percentage of patients who experienced nausea was significantly lower in arm A versus arm B, at 26.7% versus 66.7% respectively, p=0.028. CONCLUSIONS: Metformin administration reduced occurrence of chemotherapy induced-nausea. Non statistically significant improvements in the ORR or OS were observed. Metformin had no effect on PFS. PMID- 26434886 TI - Decitabine in the Treatment of Acute Myeloid Leukemia and Myelodysplastic Syndromes, Which Combined with Complex Karyotype Respectively. AB - BACKGROUND: We conducted a study exploring the clinical safety and efficacy of decitabine in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), combined with a complex karyotype. MATERIALS AND METHODS: From April 2009 to September 2013, a total of 35 patients with AML/MDS combined with a complex karyotype diagnosed in the First Affiliated Hospital of Soochow University were included for retrospective analysis. All patients were treated with decitabine alone (20 mg/m2 daily for 5 days) or combination AAG chemotherapy (Acla 20 mg qod*4d, Ara-C 10 mg/m2 q12h*7d, G-CSF 300 MUg qd, the dose of G-CSF adjusted to the amount in blood routinely). RESULTS: In 35 patients, 15 exhibited a complete response (CR), and 6 a partial response (PR), the overall response rate (CR+PR) being 60% (21 of 35). Median disease-free survival was 18 months and overall survival was 14 months. In the 15 MDS patients with a complex karyotype, the CR rate was 53.3% (8 of 15); in 20 AML patients with complex karyotype, the overall response rate was 65% (13 of 20). The response rate of decitabine alone (22 cases) was 56.5% (13 of 22), while in the combination chemotherapy group (13 cases), the effective rate was 61.5% (8 of 13)(P>0.05). There are 15 patients with chromosome 7 aberration, after treatment with decitabine, 7 CR, 3 PR, overall response rate was 66.7% (10 of 15). Of 18 patients with 3 to 5 kinds of chromosomal abnormalities, 66.7% demonstrated a response; of 17 with more than 5 chromosomal abnormalities, 52.9% had a response. In the total of 35 patients, with one course (23 patients) and >=two courses (12 patients), the overall response rate was 40.9% and 92.3% (P<0.05). Grade III to IV hematological toxicity was observed in 27 cases (75%). Grade III to IV infections were clinically documented in 7 (20%). Grades I to II non-hematological toxicity were infections (18 patients), haematuria (2 patients), and bleeding (3 patients). With follow-up until September 2013, 7 patients were surviving, 18 had died and 10 were lost to follow-up. In the 6 cases who underwent allogeneic hematopoietic stem cell transplantation (HSCT) all were still relapse-free survivors. CONCLUSIONS: Decitabine alone or combination with AAG can improve outcome of AML/MDS with a complex karyotype, there being no significant difference decitabine in inducing remission rates in patients with different karyotype. Increasing the number of courses can improve efficiency. This approach with fewer treatment side effects in patients with a better tolerance should be employed in order to create an improved subsequent chance for HSCT. PMID- 26434887 TI - Lived Experience among Patients Newly Diagnosed with Lung Adenocarcinoma Stage IV within One Year. AB - BACKGROUND: lung cancer (LC) is the fifth of the 10 leading causes of death in the world. LC is in first place for cancer-related mortality for both males and females in Taiwan. It is one of the most difficult cancers to treat and is often diagnosed at a late stage. Patients with stage IV are often unprepared for the diagnosis. MATERIALS AND METHODS: To explore lived experience among patients newly diagnosed with lung adenocarcinoma stage IV within one year. RESULTS: Twelve participants were recruited in this study. Content analysis of the interviews revealed four themes: (1) emotional roller coaster, (2) trying to find out causes, (3) adjusting my lifestyle, and (4) cancer fighter. CONCLUSIONS: This study provides new insight into the experiences of lung cancer patients y with newly diagnosed lung adenocarcinoma stage 4. These results will inform future supportive care service development and intervention research for patients with advanced stage cancer. PMID- 26434888 TI - Correlation between Microvascular Density and Matrix Metalloproteinase 11 Expression in Prostate Cancer Tissues: a Preliminary Study in Thailand. AB - BACKGROUND: Prostate cancer is a major concern of public health. Microvascular density (MVD) is one of the prognostic markers for various solid cancers. Matrix metalloproteinase 11 (MMP11) plays an important role in angiogenesis and changes in its expression level are known to be associated with tumor progression and clinical outcome. AIM: To investigate the relationship between MVD and MMP11 expression in prostatic adenocarcinoma tissues. MATERIALS AND METHODS: The expression levels of MMP11 and MVD were analyzed immunohistochemically for 50 specimens of prostatic adenocarcinoma. RESULTS: MMP11 was mainly expressed in stromal cells but rarely seen in epithelial cells. Mean MVD was 36/mm2, and it was correlated significantly only with bone metastases. MVD was also significantly correlated with MMP11 expression (r=0.29, p=0.044). CONCLUSIONS: MMP11 may alter the stromal microenvironment of prostate cancer to stimulate tumor angiogenesis. PMID- 26434889 TI - Helicobacter pylori cag Pathogenicity Island cagL and orf17 Genotypes Predict Risk of Peptic Ulcerations but not Gastric Cancer in Iran. AB - BACKGROUND: Gastric cancer (GC) is the third most common cancer regarding mortality in the world. The cag pathogenicity island (PAI) of Helicobacter pylori which contains genes associated with a more aggressive phenotype may involve in the pathogenesis of gastrointestinal disease. We here aimed to examine the associations of cagH, cagL, orf17, and cagG genotypes of H. pylori cag PAI with severe gastrointestinal disease. MATERIALS AND METHODS: A total of 242 H. pylori strains were genotyped. Histopathological examination and classification of subjects were performed. RESULTS: The frequencies of the cagH, cagL, cagG, and orf17 genotypes were 40/54 (74.1%), 53/54 (98.1%), 38/54 (70.4%), and 43/54 (79.6%), respectively, in patients with peptidic ulceration (PU),while in the control group, the frequencies were 87/147 (59.6%) for cagH, 121/146 (82.9%) for cagL, 109/146 (74.7%) for cagG, and 89/146 (61.0%) for orf17. The results of simple logistic regression analysis showed that the cagL and orf17 genotypes were significantly associated with an increased risk of PU not GC; the ORs (95% CI) were 10.950 (1.446-82.935), and 2.504 (1.193-5.253), respectively. No significant association was found between the cagH and cagG genotypes and the risk of both the PU and the GC in Iran (P>0.05). Finally, multiple logistic regression analysis showed that the cagL genotype was independently and significantly associated with the age- and sex-adjusted risk for PU; the OR (95% CI) was 9.557 (1.219-17.185). CONCLUSIONS: We conclude that the orf17 and especially cagL genotypes of H. pylori cag PAI could be factors for risk prediction of PU, but not GC in Iran. PMID- 26434890 TI - In Vitro Apoptosis Triggering in the BT-474 Human Breast Cancer Cell Line by Lyophilised Camel's Milk. AB - Breast cancer is a global health concern and is a major cause of death among women. In Oman, it is the most common cancer in women, with an incidence rate of 15.6 per 100,000 Omani females. Various anticancer remedies have been discovered from natural products in the past and the search is continuing for additional examples. Cytotoxic natural compounds may have a major role in cancer therapy either in potentiating the effect of chemotherapy or reducing its harmful effects. Recently, a few studies have reported advantages of using crude camel milk in treating some forms of cancer. However, no adequate data are available on the lyophilised camel's milk responsibility for triggering apoptosis and oxidative stress associated with human breast cancer. The present study aimed to address the role of the lyophilised camel's milk in inducing proliferation repression of BT-474 and HEp-2 cells compared with the non-cancer HCC1937 BL cell line. Lyophilized camel's milk fundamentally repressed BT-474 cells growth and proliferation through the initiation of either the intrinsic and extrinsic apoptotic pathways as indicated by both caspase-3 mRNA and its action level, and induction of death receptors in BT-474 but not the HEp-2 cell line. In addition, lyophilised camel's milk enhanced the expression of oxidative stress markers, heme-oxygenase-1 and reactive oxygen species production in BT-474 cells. Increase in caspase-3 mRNA levels by the lyophilised camel's milk was completely prevented by the actinomycin D, a transcriptional inhibitor. This suggests that lyophilized camel's milk increased newly synthesized RNA. Interestingly,it significantly (p<0.003) repressed the growth of HEp-2 cells and BT-474 cells after treatment for 72 hours while 24 hours treatment repressed BT-474 cells alone. This finding suggests that the lyophilised camel's milk might instigate apoptosis through initiation of an alternative apoptotic pathway. PMID- 26434891 TI - High Expression of Lung Resistance Protein mRNA at Diagnosis Predicts Poor Early Response to Induction Chemotherapy in Childhood Acute Lymphoblastic Leukemia. AB - BACKGROUND: Treatment failure in leukemia is due to either pharmacokinetic resistance or cell resistance to drugs. MATERIALS AND METHODS: Gene expression of multiple drug resistance protein (MDR-1), multidrug resistance-related protein (MRP) and low resistance protein (LRP) was assessed in 45 pediatric ALL cases and 7 healthy controls by real time PCR. The expression was scored as negative, weak, moderate and strong. RESULTS: The male female ratio of cases was 2.75:1 and the mean age was 5.2 years. Some 26/45 (58%) were in standard risk, 17/45(38%) intermediate and 2/45 (4%) in high risk categorie, 42/45 (93%) being B-ALL and recurrent translocations being noted in 5/45 (11.0%). Rapid early response (RER) at day 14 was seen in 37/45 (82.3%) and slow early response (SER) in 8/45 (17.7%) cases. Positive expression of MDR-1, LRP and MRP was noted in 14/45 (31%), 15/45 (33%) and 27/45 (60%) cases and strong expression in 3/14 (21%), 11/27 (40.7%) and 8/15 (53.3%) cases respectively. Dual or more gene positivity was noted in 17/45 (38%) cases. 46.5 % (7/15) of LRP positive cases at day 14 were in RER as compared to 100% (30/30) of LRP negative cases (p<0.05). All 8 (100%) LRP positive cases in SER had strong LRP expression (p=<0.05). Moreover, only 53.3% of LRP positive cases were in haematological remission at day 30 as compared to 100% of LRP negative cases (p=<0.05). CONCLUSIONS: Our study indicated that increased LRP expression at diagnosis in pediatric ALL predicts poor response to early treatment and hence can be used as a prognostic marker. However, larger prospective studies with longer follow up are needed, to understand the clinical relevance of drug resistance proteins. PMID- 26434892 TI - Poor Knowledge and Practice Towards Breast Cancer among Women in Baghdad City, Iraq. AB - BACKGROUND: Breast cancer is one of the most common cancers among females worldwide. The aim of this study was to assess the knowledge and practice about breast cancer and its related factors among women in Baghdad city, Iraq. MATERIALS AND METHODS: A cross-sectional study was conducted among 508 women aged 18 to 55 years from four non-governmental organizations (NGO) in Baghdad city, Iraq. A self-administered questionnaire on breast cancer knowledge and practice was distributed to participants during weekly activity of the NGO. RESULTS: A total of 61.2% of the respondents had poor knowledge, only 30.3% performed breast self-examination (BSE) and 41.8% said that they did not know the technique to perform BSE. Associations between knowledge and marital status and age were significant. For practice, working status, education, age and family income were significant. After controlling for cofounders, the most important contributing factors for poor knowledge among respondents were marital status and not performing BSE, with adjusted odds ratio of 1.6 and 1.8 respectively. CONCLUSIONS: Breast cancer knowledge and practice of BSE are poor among women in Baghdad city, Iraq. More promotion regarding breast cancer signs and symptoms and also how to perform BSE should be conducted using media such as television and internet as these constituted the main sources of information for most women in our study. PMID- 26434893 TI - Male Breast Cancer: 20 Years Experience of a Tertiary Hospital from the Middle Black Sea Region of Turkey. AB - BACKGROUND: Male breast cancer is a rare neoplasm, and its treatments are based on those of female breast cancer. This study aimed to analyze 20 years of male breast cancer clinical characteristics and treatment results from the Middle Black Sea Region of Turkey. MATERIALS AND METHODS: A retrospective analysis of 16 male breast cancer patients treated in our tertiary hospital between 1994 and 2014 was performed. Epidemiologic data, tumor characteristics, and treatments were recorded and compared with 466 female breast cancer ((premenopausal; n=230)+(postmenopausal n=236)) patients. The 5-year disease-free and overall survival rates were calculated. RESULTS: Male breast cancer constituted 0.1% of all malignant neoplasms in both sexes, 0.2% of all malignant neoplasms in males, and 0.7% of all breast cancers. The mean patient age in this study was 59.8+/-9.5 (39-74) years. The mean time between first symptom and diagnosis was 32.4+/-5.3 (3-60) months. Histology revealed infiltrative ductal carcinoma in 81.3% of patients. The most common detected molecular subtype was luminal A, in 12 (75%) patients. Estrogen receptor rate (93.8%) in male breast cancer patients was significantly higher than that in female breast cancer (70.8% in all females, p=0.003; 68.2% in postmenopausal females, p=0.002) patients. Most of the tumors (56.3%) were grade 2. Tumor stage was T4 in 50% of males. The majority (56.3%) of the patients were stage III at diagnosis. Surgery, chemotherapy, radiotherapy and endocrine-therapy were applied to 62.5%, 62.5%, 81.2% and 73.3%, respectively. Loco-regional failure did not occur in any of the cases. All recurrences were metastastic. The 5-year disease-free and overall survival rates in male breast cancer patients were 58% and 68%, respectively. CONCLUSIONS: Tumors found in male breast cancer patients were similar in size to tumors found in females, but they advanced to T4 stage more rapidly because of the lack of breast parenchymal tissues. The rate of estrogen receptor expression tended to be higher in male breast cancer patients than in female breast cancer patients. Metastasis is the most important problem in initially non-metastatic male breast cancer patients. PMID- 26434894 TI - Tumors Involving Skin, Soft Tissue and Skeletal Muscle: Benign, Primary Malignant or Metastatic? AB - BACKGROUND: Metastatic cancer with invasion of skin, soft tissue and skeletal muscle is not common. Examples presenting as soft tissue masses could sometimes lead to misdiagnosis with delayed or inappropriate management. The purpose of current study was to investigate clinical characteristics in the involvement of metastatic cancer. MATERIALS AND METHODS: A total of 1,097 patients complaining of skin or soft tissue masses and/or lesions were retrospectively reviewed from January 2012 to June 2013. Tumors involving skin, soft tissue and skeletal muscle of head and neck, chest wall, abdominal wall, pelvic region, back, upper and lower extremities were included in the study. RESULTS: Fifty-seven (5.2%) patients were recognized as having malignancies on histopathological examination. The most common involvement of malignancy was basal cell carcinoma, followed by cutaneous squamous cell carcinoma, sarcoma and melanoma. The most common anatomical location in skin and soft tissue malignancies was head and neck (52.6% of the malignancies). Four (0.36%) of the malignant group were identified as metastatic cancer with the primary cancer source from lung, liver and tonsil and the most common site was upper extremities. One of them unexpectedly expired during the operation of metastatic tumor excision at the scalp. CONCLUSIONS: Discrimination between benign and malignant soft tissue tumors is crucial. Performance of imaging study could assist in the differential diagnosis and the pre-operative risk evaluation of metastatic tumors involving skin, soft tissue and skeletal muscle. PMID- 26434895 TI - CHRNA5 rs16969968 Polymorphism Association with Risk of Lung Cancer--Evidence from 17,962 Lung Cancer Cases and 77,216 Control Subjects. AB - BACKGROUND: Genetic studies have shown a possible relationship between the rs16969968 polymorphism in CHRNA5 and the risk of lung cancer. However, the results have been conflicting. Thus we rigorously conducted a meta-analysis to clarify any association. MATERIALS AND METHODS: A total of 10 case-control studies involving 17,962 lung cancer cases and 77,216 control subjects were analysed. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to measure the strength of the association. RESULTS: We found the CHRNA5 rs16969968 polymorphism to be associated with the risk of lung cancer (AA vs GG: OR=1.60, 95%CI=1.51-1.71). On stratified analysis by smoking status, a statistically significant increased risk was observed in the smoking group (AA vs GG: OR=1.80, 95%CI=1.61-2.01). However, this polymorphism was not associated with lung cancer risk in Asians (AA vs GG: OR=0.95, 95%CI=0.35-2.59), whereas it was linked to increased risk of lung cancer among Caucasians (AA vs GG: OR=1.65, 95%CI=1.55 1.76). CONCLUSIONS: Our meta-analysis provided statistical evidence for a strong association between rs16969968 polymorphism and the risk of lung cancer, especially in smokers and Caucasians. Application of this relationship may contribute to identification of individuals at high risk of lung cancer and indicate a chemoprevention target. PMID- 26434896 TI - Accuracy of Sentinel Node in Detecting Lymph Node Metastasis in Primary Endometrial Carcinoma. AB - BACKGROUND: Endometrial carcinoma is the most common gynecological cancer and its treatment is still controversial, especially in its early stages. There are conflicting data about the efficacy of retroperitoneal lymphadenectomy during abdominal hysterectomy and bilateral salpingoophrectomy treatment. Lymphadenectomy carries a risk of severe complications, especially in women with co-morbidities. Selective lymphadenectomy has been widely employed for staging evaluation of endometrial carcinoma because it is simple and seems to provide reliable data regarding nodal metastasis. This study was designed to evaluate accuracy of sentinel node sampling in detecting lymph node metastasis in primary endometrial carcinoma during staging laparotomy. MATERIALS AND METHODS: Ninety three women with endometrial carcinoma at high-risk for nodal metastasis were studied. During laparotomy, methylene blue dye was injected into sub-serosal myometrium, then retroperitoneal spaces were opened and blue lymph nodes within pelvic and para-aortic regions were removed as separate specimens for histopathological examination (sentinel lymph nodes=SLNs). Hysterectomy and selective lymphadenectomy then performed for all women included in this study. RESULTS: Deposition of methylene dye into at least one lymph node was observed in 73.1% (68/93) of studied cases. 18.3% (17/93) of studied women had positive lymph node metastasis and 94.1% (16/17) of them had positive metastasis in SLNs. In this study, SNLs had 94.4% sensitivity and 100% specificity in prediction of lymph node metastasis. Mean number of lymph nodes removed from each case decreased when SLNs biopsy were taken. CONCLUSIONS: SLNs are the key lymph nodes in endometrial tumor metastasis and their involvement could be an indicator for whether or not complete systematic lymphadenectomy is needed during staging laparotomy. PMID- 26434897 TI - Differences in Breast and Cervical Cancer Screening Rates in Jordan among Women from Different Socioeconomic Strata: Analysis of the 2012 Population-Based Household Survey. AB - BACKGROUND: The burden of breast and cervical cancer is changing over time in developing countries. Regular screening is very important for early detection and treatment. In this study, we assessed inequalities in breast and cervical cancer screening rates in women according to household wealth status, and analyzed the potential predictors associated with a low cancer screening rate in Jordan. MATERIALS AND METHODS: A nationwide population- based cross-sectional survey collected information on different variables at the national level. All ever married women (the phrase is used throughout the text to refer to women who had ever married) aged 15-49 years were included in the survey. Analysis of breast self-examination (BSE) and clinical breast examination (CBE) at least once in the previous year was carried out in 11,068 women, while lifetime Pap-smear testing was carried out in 8,333 women, aged 20-49 years. RESULTS: Over 39% and 19% of ever-married Jordanian women reported having undergone a breast examination during the previous year and Pap smear examination at least once in their lifetime, respectively. The rate of BSE in the previous year was 31.5%, that of CBE in the previous year was 19.3%, and that of Pap smear examination at least once in life was 25.5%. The adjusted OR was higher for performing BSE (aOR 1.22, 95% CI 1.04-1.43), undergoing CBE (aOR 1.31, 95% CI 1.08-1.60) and undergoing Pap smear examination (aOR 2.38, 95% CI 1.92-2.93) among women in the highest wealth index quintile as compared to those in the lowest quintile. The concentration index was 0.11 for BSE, 0.01 for CBE, and 0.27 for Pap smear examination. Women in their twenties, living in rural or the southern region of Jordan, with an elementary school education or less, who listened to the radio or read the newspaper not more than a few times a year, and nulliparous women were less likely to undergo breast and cervical cancer screening. CONCLUSIONS: The rates of breast and cervical cancer screening are low in Jordan. Reducing the sociodemographic and economic inequalities in breast and cervical cancer screenings requires concerted outreach activities for women living under socially deprived conditions. PMID- 26434898 TI - Incidence and Clinical Characteristic of Venous Thromboembolism in Gynecologic Oncology Patients attending King Chulalongkorn Memorial Hospital over a 10 Year Period. AB - BACKGROUND: Venous thromboembolisms (VTEs) constitute a group of diseases including deep vein thrombosis (DVT) and pulmonary embolism (PE). They regarded as the second leading cause of death in cancer patients and several studies have confirmed that VTEs have a negative impact on survival and recurrent rate in both ovarian and endometrial cancer cases. The incidence of VTEs differs worldwide and depends on several risk factors including race, underlying disease, lifestyle, body weight, BMI and genetic risk factors. There is heterogeneity of DVT rates between Asian and Western countries. This study was conducted in order to evaluate the character and incidence of VTEs in gynecologic oncology patients in King Chulalongkorn Memorial Hospital over a 10 year period. MATERIALS AND METHODS: A retrospective chart review was performed with VTEs defined as objective diagnosis of acute DVT or PE with typical symptoms and signs. Diagnoses were approved byan internist and/ or confirmed with imaging studies. Data from both outpatient and inpatient sessions of the affected cases from January 2004 to December 2013 were extracted. General characteristics of the patients were collected with details of the diseases, types of cancer, stage, date of diagnosis of cancer, operative data, treatment outcome, progression free survival and overall survival. RESULTS: Thirty cases of VTEs were identified in a total 2,316 gynecologic oncology cases. The incidence of symptomatic VTEs in total gynecologic oncology patients in our institution is 1.295%. The incidence of VTEs in ovarian cancer patients in our institution was 5.9%. Duration for VTE detection ranged from 13 months before diagnosis of cancer to 33 months after diagnosis of cancer. Most of the VTE cases were detected in ovarian cancer patients (60%). The most common cell type was adenocarcinoma (moderately to poorly differentiated) which accounted for 26.7% of the cases. The second most common cell type was clear cell carcinoma with 23.3% of the cases. Thirty percent of VTE cases developed before cancer was diagnosed, 20% were diagnosed at the same time as cancer detection and fifty percent developed after cancer was diagnosed. Median disease free survival of the gynecologic oncology patients with VTE was 7.5 months. Median overall survival (OS) was 12 months. Median progession free survivals of DVT and PE groups were 11.5 and 5.5 months, respectively. OS of DVT and PE was 12.0 and 11.5 months respectively. CONCLUSIONS: The incidence of VTE in Asian countries is believed to be lower than in European or Western countries. From our retrospective review, the incidence of VTEs in all types of gynecologic oncology was 1.295%, much lower than reported in the West. The reason for the lower incidence may genetic differences. Another factor is that VTE in this review was symptomatic, which is less than asymptomatic VTE. More than half of VTEs in this study developed in ovarian cancer patients. The results are compatible with earlier reports that among gynecologic malignancies, the incidence of VTE is highest in ovarian cancer. PMID- 26434899 TI - Insomnia in Cancer--Associations and Implications. AB - BACKGROUND: Insomnia is a common condition in cancer patients. In spite of the high prevalence its associations have not been well studied. Existing data suggests that insomnia is related to depression and pain. However, the impact of ongoing chemotherapy on sleep is not investigated. AIM: To study the relationship between insomnia and chemotherapy after analysing confounding variables. MATERIALS AND METHODS: Consecutive patients who visited New England Oncology Clinic in Tamworth were recruited. Insomnia was assessed with the Bergen insomnia scale. The Montgomery Asberg Depression rating scale was used to measure depression. Pain was assessed with the Brief Pain inventory. Chronic medical conditions, type of cancer, side effects to chemotherapy, role of steroids and other drugs were studied as confounders. RESULTS: A total of 56 patients participated in the study. Age ranged from 33 to 83 years (mean: 63.6, SD=10.97). There were 29 men and 27 women. 42 patients received at least one form of chemotherapy and 15 were receiving radiotherapy at the time of assessment. Mean insomnia score was significantly higher in those receiving chemotherapy than in those without chemotherapy (8.92 vs 17.2, two tailed p=0.005, 95% CI=2.63-13.71). There was no significant variation in insomnia scores in terms of chronic medical condition, type of cancer, psychiatric history, use of steroids or adverse effects of chemotherapy. However, total insomnia score was correlated with depression rating score (Pearson correlation, r=0.39, p=0.003) and magnitude of pain (r=0.37, p=0.006). On regression analysis only pain was found to be predictive of insomnia. CONCLUSIONS: Insomnia in patients with cancer is found to be associated with concurrent chemotherapy and correlated with degree of depression and pain. Identifying factors related to insomnia in cancer population has implications in its management and patient education. PMID- 26434900 TI - Descriptive Epidemiology of Thyroid Cancers in Togo. AB - BACKGROUND: The purpose of this study was to provide epidemiological and histological data of thyroid cancers in Togo. MATERIALS AND METHODS: This was a retrospective cross-sectional study of cases of thyroid cancers diagnosed from 2000 to 2014 (15 years) at the pathology laboratory of the Sylvanus Olympio Teaching Hospital of Lome. All cases of review of a thyroid sample (biopsies, surgical specimens) were collected from the data records of that laboratory. RESULTS: Thyroid cancers represented 1.1% (7930 cases) of all cancers registered during the study period. Mean age was 45.4+/-0.3 years and the proportion of females was 78.3%. We identified 92.4% carcinomas and 7.6% lymphomas. Carcinomas were well differentiated in 80 cases and were dominated by the papillary type (47 cases). Metastasis was observed in 13% of patients. The pTNM classification evaluated in 18 cases showed a predominance of grade I (13 cases). Lymphomas were dominated by lymphoma diffuse large B-cell (5 cases). CONCLUSIONS: This study is the first global standard for thyroid cancer pathology in Togo. The high frequency of follicular form suggests an unrecognized iodine deficiency. The improvement of the technical platform of the LAP (immunohistochemistry) will increase the diagnosis of rare forms of thyroid cancer. PMID- 26434901 TI - Readability, Suitability and Health Content Assessment of Cancer Screening Announcements in Municipal Newspapers in Japan. AB - BACKGROUND: The objective of this study was to assess the readability, suitability, and health content of cancer screening information in municipal newspapers in Japan. MATERIALS AND METHODS: Suitability Assessment of Materials (SAM) and the framework of Health Belief Model (HBM) were used for assessment of municipal newspapers that were published in central Tokyo (23 wards) from January to December 2013. RESULTS: The mean domain SAM scores of content, literacy demand, and layout/typography were considered superior. The SAM scores of interaction with readers, an indication of the models of desirable actions, and elaboration to enhance readers' self-efficacy were low. According to the HBM coding, messages of medical/clinical severity, of social severity, of social benefits, and of barriers of fear were scarce. CONCLUSIONS: The articles were generally well written and suitable. However, learning stimulation/motivation was scarce and the HBM constructs were not fully addressed. PRACTICE IMPLICATIONS: Articles can be improved to motivate readers to obtain cancer screening by increasing interaction with readers, introducing models of desirable actions and devices to raise readers' self-efficacy, and providing statements of perceived barriers of fear for pain and time constraints, perceived severity, and social benefits and losses. PMID- 26434902 TI - Mortality Characteristic and Prediction of Nasopharyngeal Carcinoma in China from 1991 to 2013. AB - BACKGROUND: To analyze the mortality distribution of nasopharyngeal carcinoma in China from 1991 to 2013, to predict the mortality in the ensuing five years, and to provide evidence for prevention and treatment of nasopharyngeal carcinoma. MATERIALS AND METHODS: Mortality data for Nasopharyngeal Carcinoma in China from 1991 to 2013 were used to describe its epidemiological characteristics, such as the change of the standardized mortality rate, sex and age differences, urban rural differences. Trend-surface analysis was used to study the geographical distribution of the mortality. Curve estimation, time series, gray modeling, and joinpoint regression were used to predict the mortality for the ensuing five years in the future. RESULTS: In China, the standardized mortality rate of Nasopharyngeal Carcinoma increased with time from 1996, reaching the peak values of 1.45 /105 at the year of 2002, and decreased gradually afterwards. With males being 1.51 times higher than females, and the city had a higher rate than the rural during the past two decades. The mortality rate increased from age 40. Geographical analysis showed the mortality rate increased from middle to southern China. CONCLUSIONS: The standardized mortality rate of Nasopharyngeal Carcinoma is falling. The regional disease control for Nasopharyngeal Carcinoma should be focused on Guangdong province of China, and the key targets for prevention and treatment are rural men, especially after the age of 40. The mortality of Nasopharyngeal Carcinoma will decrease in the next five years. PMID- 26434903 TI - Breast Cancer in Surat Thani, a Province in Southern Thailand: Analysis of 2004 2012 Incidence and Future Trends. AB - BACKGROUND: With the recent epidemiologic transition in Thailand, featuring decreasing incidences of infectious diseases along with increasing rates of chronic conditions, cancer is becoming a serious problem for the country. Breast cancer has the highest incidence rates among females, not only in the southern regions, but throughout Thailand. Surat Thani is a province in the upper part of Southern Thailand. A study was needed to identify the current burden, and the future trends of breast cancer. MATERIALS AND METHODS: Here we used cancer incidence data from the Surat Thani Cancer Registry to characterize the incidences of breast cancer. Joinpoint analysis was used to investigate the incidences in the province from 2004 to 2012 and to project future trends from 2013 to 2030. RESULTS: Age-standardized incidence rates (world) of breast cancer in the upper parts of Southern Thailand increased from 35.1 to 59.2 cases per 100,000 female population, which is equivalent to an annual percentage change of 4.5-4.8%. Linear drift effects played a role in shaping the increase of incidence. Joinpoint projection suggested that incidence rates would continue to increase in the future with incidence for women aged 50 and above, at a higher rate than for women below the age of 50. CONCLUSIONS: The current early detection measures increase detection rates of early disease. Preparation of a budget for treatment facilities and human resources, both in surgical and medical oncology, is essential. PMID- 26434904 TI - Intention to Quit Smoking among Intermediate and Secondary School Students in Saudi Arabia. AB - BACKGROUND: Smoking is one of the most preventable causes of disease and death, including cancer, and quitting at an early age can reduce smoking-related morbidity and mortality. This study aimed to estimate the prevalence and to identify factors affecting the "intention to quit" among intermediate and secondary school current cigarette smoker students in Al Madinah city, Saudi Arabia. MATERIALS AND METHODS: This study cohort included 307 current smoker students in a school-based survey. The intention to quit and its related determinants were assessed using a self-administered questionnaire. RESULTS: More than half of the participants were >=17 years, and of male gender (54.7%, 77.9% respectively). An intention to quit smoking was reported in 71.7% of participants, and was been significantly associated with: male gender (OR=3.25, 95% CI=1.65-6.41): age at 1st trial of smoking. 10-15 years (OR=2.11, 95% CI=1.03 4.32) along with age of >=15 years (OR=3.10, 95% CI=1.20-7.88); days of smoking in the past 30 days (days<10 (OR=2.31, 95% CI=1.23-4.35) along with days ranging from 10-19 days (OR= 3.42, 95% CI=1.18-9.91); knowing that smoking is hazardous to health (OR=3.04, 95% CI=1.42-6.47); and finally, supporting smoking bans in public places (OR=1.89, 95% CI=1.11-3.25). CONCLUSIONS: A substantial number of participants were willing to quit smoking. Effective interventions focusing on providing information about the hazards of smoking and prohibiting smoking in public places could help initiate the intention to quit among youth smokers. PMID- 26434905 TI - Serum Level of Matrix Metalloproteinase-2 and -9 in Patients with Laryngeal Squamous Cell Carcinoma and Clinical Significance. AB - BACKGROUND: Laryngeal cancer is an important malignancy in head and neck area and squamous cell carcinoma (SCC) is the most common type accounting for 95% of cases. Increase in matrix metalloproteinases (MMPs) in different tumors and their correlation with tumor invasiveness has been documented. However, most studies have evaluated MMP-2 and MMP-9 expression and few have evaluated serum levels. The aim of current study was to evaluate serum levels in patients with laryngeal SCC compared to normal subjects and assess any relation with tumor clinicopathological findings. MATERIALS AND METHODS: In this case control study, 20 patients with oral SCC and 20 healthy subjects were included. Serum levels of MMP-2 and MMP-9 were compared between groups and correlations with findings including grade (T) and node involvement (N) were evaluated. RESULTS: Patients with laryngeal SCC had significantly higher serum levels of MMP-2 (p=0.01) and MMP-9 (p=0.03) compared to healthy subjects. Patients with higher T stage (T3,4) had significantly higher MMP-2 (p=0.04) and MMP-9 (p=0.01). There was significant positive correlation between serum levels of MMP-2 with T stage (r=0.45, p=0.04) and lymph node involvement (r=0.563, p=0.01) and between levels of MMP-9 with T stage (r=0.527, p=0.01). CONCLUSIONS: Our results showed that compared to healthy subjects, both MMP-2 and MMP-9 are significantly increased in serum of laryngeal SCC cases. MMP-2 was correlated with lymph node involvement while MMP-9 has stronger correlation with T stage compared to MMP-2. PMID- 26434906 TI - Induction of Apoptosis by Eugenol and Capsaicin in Human Gastric Cancer AGS Cells -Elucidating the Role of p53. AB - BACKGROUND: Loss of function of the p53 gene is implicated in defective apoptotic responses of tumors to chemotherapy. Although the pro-apoptotic roles of eugenol and capsaicin have been amply reported, their dependence on p53 for apoptosis induction in gastric cancer cells is not well elucidated. The aim of the study was to elucidate the role of p53 in the induction of apoptosis by eugenol and capsaicin in a human gastric cancer cell line, AGS. MATERIALS AND METHODS: AGS cells were incubated with or without various concentrations of capsaicin and eugenol for 12 hrs, in the presence and absence of p53 siRNA. Cell cycling, annexin V and expression of apoptosis related proteins Bax, Bcl-2 ratio, p21, cyt c-caspase-9 association, caspase-3 and caspase-8 were studied. RESULTS: In the presence of p53, capsaicin was a more potent pro-apoptotic agent than eugenol. However, silencing of p53 significantly abrogated apoptosis induced by capsaicin but not that by eugenol. Western blot analysis of pro-apoptotic markers revealed that as opposed to capsaicin, eugenol could induce caspase-8 and caspase-3 even in the absence of p53. CONCLUSIONS: Unlike capsaicin, eugenol could induce apoptosis both in presence and absence of functional p53. Agents which can induce apoptosis irrespective of the cellular p53 status have immense scope for development as potential anticancer agents. PMID- 26434907 TI - Repairing Facial Soft Tissue Defects by Swelling Anesthesia after Tumor Resection with Narrow Pedicle Flaps. AB - AIMS: To investigate the role of swelling anesthesia in repairing facial soft tissue defects after tumor resection and temporal superficial artery frontal branch of narrow pedicle flap. MATERIALS AND METHODS: From January 2008 to June 2008, 16 patients from Department of Ophthalmology with eye or eyelid tumors after eyeball removal of eye and part resection of surrounding soft tissue, undergoing postoperative swelling anesthesia with superficial temporal artery flap repair to prevent facial soft tissue defect formation and bone exposure, were recruited. RESULTS: In all 16 patients facial soft tissue defect repair had good effects, with limited bleeding, and short operation times. Seven days after surgery, all flaps were in good repair. On postoperative follow-up after 3 months, flaps showed a similar appearance as with facial tissue. CONCLUSIONS: Swelling anesthesia for superficial temporoparietal artery frontal branch of narrow pedicle flap to repair soft tissue defect after facial tumor resection is feasible, and is linked with good analgesic effects, high postoperative survival of skin flaps, and good cosmetic effects. PMID- 26434908 TI - Human Recombinant Endostatin Combined with Cisplatin Based Doublets in Treating Patients with Advanced NSCLC and Evaluation by CT Perfusion Imaging. AB - AIMS: To study the effectiveness of human recombinant endostatin injection (Endostar(r)) combined with cisplatin doublets in treating advanced non-small cell lung cancer (NSCLC), and to evaluate outcome by CT perfusion imaging. METHODS: From April 2011 to September 2014, 76 patients with advanced NSCLC who were treated with platinum-based doublets were divided into group A (36 patients) and group B (40 patients). Endostar(r) 15 mg/day was administered 4 days before chemotherapy and combined with chemotherapy from day 5 in group A, and combined with chemotherapy from the first day in Group B. Endostar(r) in the two groups was injected intravenously for 14 days. RESULTS: Treatment effectiveness in the two groups differed with statistical significance (p<0.05). Effectiveness evaluated by CT perfusion imaging, BF, BV, MTT and PS also demonstrated significant differences (all p<0.05). Adverse reactions in the two groups did not significantly vary (p>0.05). CONCLUSIONS: The response rate with Endostar(r) administered 4 days before chemotherapy and combined with chemotherapy from day 5 in group A was better than Endostar(r) combined with chemotherapy from the first day, and CT perfusion imaging could be a reasonable method for evaluation of patient outcomes. PMID- 26434909 TI - Type-Specific Human Papillomavirus Distribution in Invasive Squamous Cervical Carcinomas in Tunisia and Vaccine Impact. AB - BACKGROUND: High risk human papillomaviruses (HPVs) are the leading cause of cervical cancer (CC) and Pap smear screening has not been successful in preventing CC in Tunisia. HPV vaccination that targets HPV16 and 18 offers a new efficient prevention tool. Identification of HPV types in CC is thus essential to determine the impact of HPV vaccine implementation. The aim of this study is to provide specific data from Tunisia. MATERIALS AND METHODS: A total of 89 histological confirmed paraffin embedded samples isolated from patients with CC diagnosed between 2001 and 2011 were collected from five medical centres from Northern and Southern Tunisia. HPV DNA was detected using a nested PCR (MY09/MY11 GP5+/GP6+) and genotyping was assessed using a reverse blot line hybridisation assay that enables the detection of 32 HPV types. RESULTS: HPV DNA was detected in all samples. Twelve high risk types were detected; HPV16 and/or 18 were predominant, accounting together for 92.1% of all the CC cases (HPV16: 83.1%). Single infections accounted for 48.8% of the cases and were mostly linked to HPV 16 (32.6%) and less frequently to HPV 18 (2.4%). The other high risk HPV single infections were linked to HPV 35 (4.6%), 45 (4.6%), 58 (2.3%) and 59 (2.3%). Multiple infections with mixing of 2 to 4 genotypes predominately featrued HPV16 and/or 18 with HPV 35 and 45 (96.6 %) and less frequently with HPV 59, 40, 66, 73 and 58. There was no statistically significant variation in the relative distribution of HPV types with age. CONCLUSIONS: These results strongly indicate that prophylactic HPV vaccines can have a major impact in preventing CC in Tunisia. PMID- 26434910 TI - Survival Prognostic Factors of Male Breast Cancer in Southern Iran: a LASSO-Cox Regression Approach. AB - We used to LASSO-Cox method for determining prognostic factors of male breast cancer survival and showed the superiority of this method compared to Cox proportional hazard model in low sample size setting. In order to identify and estimate exactly the relative hazard of the most important factors effective for the survival duration of male breast cancer, the LASSO-Cox method has been used. Our data includes the information of male breast cancer patients in Fars province, south of Iran, from 1989 to 2008. Cox proportional hazard and LASSO-Cox models were fitted for 20 classified variables. To reduce the impact of missing data, the multiple imputation method was used 20 times through the Markov chain Mont Carlo method and the results were combined with Rubin's rules. In 50 patients, the age at diagnosis was 59.6 (SD=12.8) years with a minimum of 34 and maximum of 84 years and the mean of survival time was 62 months. Three, 5 and 10 year survival were 92%, 77% and 26%, respectively. Using the LASSO-Cox method led to eliminating 8 low effect variables and also decreased the standard error by 2.5 to 7 times. The relative efficiency of LASSO-Cox method compared with the Cox proportional hazard method was calculated as 22.39. The19 years follow of male breast cancer patients show that the age, having a history of alcohol use, nipple discharge, laterality, histological grade and duration of symptoms were the most important variables that have played an effective role in the patient's survival. In such situations, estimating the coefficients by LASSO-Cox method will be more efficient than the Cox's proportional hazard method. PMID- 26434911 TI - Effects of Definitive Chemoradiotherapy on Respiratory Function Tests and Quality of Life Scores During Treatment of Lung Cancer. AB - BACKGROUND: Chemoradiotherapy is an important treatment modality for lung cancers. The aim of this study was to investigate alterations in, as well as the interrelationship between, lung function and quality of life of patients receiving chemoradiotherapy due to locally advanced non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) limited to the thorax. MATERIALS AND METHODS: The study included patients receiving definitive chemoradiotherapy for lung carcinoma. The respiratory function of the patients was assessed by measuring forced expiratory volume in 1 s per unit (FEV1) and forced expiratory volume in 1s per unit of vital capacity (FEV1/VC) before, in the middle of and after treatment. During the study, EORTC QLQ C30 and LC13 questionnaires developed by the Committee of the European Organization for Research and Treatment of Cancer (EORTC) were employed to evaluate the quality of life on the same day as respiratory function tests (RFT). FINDINGS: The study included 23 patients in total: 19 (82.6%) diagnosed with NSCLC and 4 (17.4%) with SCLC. The average percentage FEV1 was 55.6+/-21.8% in the pre-treatment period, 56.2+/ 19.2% in the middle of treatment and 60.4+/-22% at the end of treatment. The improvement in functional scores, symptom scores and general health scores during treatment was not statistically significant (P=0.568, P=0.734, P=0.680, P=0.757 respectively). CONCLUSIONS: Although this study showed an improvement in respiratory function and quality of life of patients during treatment with thoracic chemoradiotherapy, no statistically significant results were obtained. While evaluating the effectiveness of treatments for lung carcinoma, the effects of treatment on respiratory function and quality of life should be considered. PMID- 26434912 TI - CYP2D6 Genotype and Risk of Recurrence in Tamoxifen Treated Breast Cancer Patients. AB - BACKGROUND: Despite consistent pharmacogenetic effects of CYP2D6 on tamoxifen exposure, there is considerable controversy regarding the validity of CYP2D6 as a predictor of tamoxifen outcome. Understanding the current state of evidence in this area and its limitations is important for the care of patients who require endocrine therapy for breast cancer. MATERIALS AND METHODS: A total of 101 patients with breast cancer who received tamoxifen therapy for at least 3 years, were genotyped for common alleles of the CYP2D6 gene by nested-PCR and restriction fragment length polymorphism PCR. Patients were classified as extensive or poor metabolizers (PM) based on CYP2D6*4 alleles in 3 different groups according to the menopause, Her2-neu status, and stage 3. RESULTS: The mean age of the patients with the disease recurrence was 50.8+/-6.4 and in non recurrent patients was 48.2+/-6.8. In this study 63.3% (n=64) patients were extensive metabolizers and 36.6% (n=37) were poor metabolizers. Sixty four of the 101 patients (63.3%) were Her2-neu positive. For tamoxifen- treated patients, no statistically significant difference in rate of recurrence observed between CYP2D6 metabolic variants in stage 3 and post-menopausal patients. However, there was a significant association between CYP2D6 genotype and recurrence in tamoxifen treated Her2-neu positive patients. Compared with other women with breast cancer, those with Her2-neu positive breast cancer and extensive metabolizer alleles had a decreased likelihood of recurrence. CONCLUSIONS: This study for the first time demonstrated significant effects of CYP2D6 extensive metabolizer alleles on risk of recurrence in Her2-neu positive breast cancer patients receiving adjuvant tamoxifen therapy. Therefore, CYP2D6 metabolism, as measured by genetic variation, can be a predictor of breast cancer outcome in Her2-neu positive women receiving tamoxifen. PMID- 26434913 TI - Expression of ER, PR, C-erbB-2 and Ki-67 in Endometrial Carcinoma and their Relationships with the Clinicopathological Features. AB - BACKGROUND: To analyze the expression of estrogen receptors (ER), progesterone receptors (PR), C-erbB-2 and Ki-67 in endometrial carcinoma (EC) and their relationships with the clinicopathological features. MATERIALS AND METHODS: Sixty seven EC samples, 53 normal endometrial samples and 53 atypical hyperplasia endometrial samples were all selected in Shaanxi Provincial People's Hospital from Jun., 2012 to Jun., 2014. The expression of ER, PR, C-erbB-2 and Ki-67 in EC tissue, normal endometrial tissue and atypical hyperplasia endometrial tissue was respectively detected using immunohistochemical SP method. The relationships between the expression of ER, PR, C-erbB-2 and Ki-67 and the patients' clinicopathological features as well as their correlations in EC tissue were also analyzed. RESULTS: The positive expression rates of ER and PR in EC tissue were 44.8% and 41.8%, respectively, dramatically lower than in atypical hyperplasia endometrial tissue and normal endometrial tissue (P<0.01). The positive expression rates of C-erbB-2 and Ki-67 in EC tissue were 80.6% and 64.2%, respectively, significantly higher than in atypical hyperplasia endometrial tissue and normal endometrial tissue (P<0.01). In EC tissue, the expression of ER and PR was closely associated with the differentiated degrees and depth of myometrial invasion (P<0.05), while that of C-erbB-2 and Ki-67 with the clinical staging, differentiated degrees, depth of myometrial invasion and presence or absence of lymph node metastasis (P<0.05). Spearman correlation analysis further displayed that the expression of ER was positively correlated with PR (r=0.393, P=0.001), but negatively with C-erbB-2 and Ki-67 (r=-0.469, P=0.000; r=-0.329, P=0.007); The expression of PR was negatively correlated with C-erbB-2 and Ki-67 (r=-0.273, P=0.025; r=-0.251, P=0.041), but that of C-erbB-2 positively with Ki 67 (r=0.342, P=0.005). CONCLUSIONS: Abnormal expression of ER, PR, C-erbB2 and Ki 67 might play an important role in endometrial malignant transformation and cell differentiation, so their joint detection is likely to be a comprehensive combination of immune factors, which is of great importance for EC prognosis. PMID- 26434914 TI - Spatial and Temporal Epidemiological Assessment of Breast Cancer Incidence and Mortality in Kazakhstan, 1999-2013. AB - Breast cancer incidence and mortality in Kazakhstan are considered to be increasing but exact statistics have hitherto been lacking. The present study was therefore undertaken to retrospectively assess data for the whole country, accessed from the central registration office, for the period 1999-2013. Age standardized data for incidence and mortality were generated and compared across age groups. It was determined that during the studied period 45,891 new cases of breast cancer were registered and 20,122 women died of this pathology. Average breast cancer incidence and mortality were 37.9+/-1.10/105 and 16.7+/-0.20/105 respectively, and the overall ratio of mortality/incidence (M/I) was 0.44. Incidence tended to increase (T=+2.3%), and mortality to decrease (T of =-0.3%). Peaks of incidence and mortality were noted in those aged 60-74 years and 75-84, respectively. Particularly high incidences were established in large cities of Kazakhstan, Astana (46.8+/-1.80/105) and Almaty (49.7+/-1.30/105), and high mortality was observed in the Pavlodar region (17.9+/-0.60/105) and Almaty city (20.1+/-0.40/105). Considerable variation in the mortality/incidence ratio was noted, suggesting the need for more stress on access to screening and clinical care in some regions of the country. PMID- 26434915 TI - Cancer Patients, Complementary Medicine and Unmet Needs in Saudi Arabia. PMID- 26434916 TI - A luminescent dye@MOF as a dual-emitting platform for sensing explosives. AB - An anionic metal-organic framework (MOF) with 1D nanotube channels has been constructed. The charge and size dependent ion-exchange of cationic dyes was investigated. Rho@1 could be used as a dual-emitting fluorescent sensor for sensing explosives by self-referencing energy transfer behaviors. PMID- 26434917 TI - The IMD innate immunity pathway of Drosophila influences somatic sex determination via regulation of the Doa locus. AB - The IMD pathway induces the innate immune response to infection by gram-negative bacteria. We demonstrate strong female-to-male sex transformations in double mutants of the IMD pathway in combination with Doa alleles. Doa encodes a protein kinase playing a central role in somatic sex determination through its regulation of alternative splicing of dsx transcripts. Transcripts encoding two specific Doa isoforms are reduced in Rel null mutant females, supporting our genetic observations. A role for the IMD pathway in somatic sex determination is further supported by the induction of female-to-male sex transformations by Dredd mutations in sensitized genetic backgrounds. In contrast, mutations in either dorsal or Dif, the two other NF-kappaB paralogues of Drosophila, display no effects on sex determination, demonstrating the specificity of IMD signaling. Our results reveal a novel role for the innate immune IMD signaling pathway in the regulation of somatic sex determination in addition to its role in response to microbial infection, demonstrating its effects on alternative splicing through induction of a crucial protein kinase. PMID- 26434919 TI - Single-molecule interfacial electron transfer dynamics of porphyrin on TiO2 nanoparticles: dissecting the interfacial electric field and electron accepting state density dependent dynamics. AB - Single-molecule photon-stamping spectroscopy correlated with electrochemical techniques was used to dissect complex interfacial electron transfer (ET) dynamics by probing an m-ZnTCPP molecule anchored to a TiO2 NP surface while electrochemically controlling the energetically-accessible surface states of TiO2 NPs. Application of negative potential increases the electron density in TiO2 NPs, resulting in hindered forward ET and enhanced backward ET due to the changes in the interfacial electric field and the occupancy of acceptor states. PMID- 26434918 TI - Fibronectin signals through integrin alpha5beta1 to regulate cardiovascular development in a cell type-specific manner. AB - Fibronectin (Fn1) is an evolutionarily conserved extracellular matrix glycoprotein essential for embryonic development. Global deletion of Fn1 leads to mid-gestation lethality from cardiovascular defects. However, severe morphogenetic defects that occur early in embryogenesis in these embryos precluded assigning a direct role for Fn1 in cardiovascular development. We noticed that Fn1 is expressed in strikingly non-uniform patterns during mouse embryogenesis, and that its expression is particularly enriched in the pharyngeal region corresponding with the pharyngeal arches 3, 4, and 6. This region bears a special importance for the developing cardiovascular system, and we hypothesized that the localized enrichment of Fn1 in the pharyngeal region may be essential for cardiovascular morphogenesis. To test this hypothesis, we ablated Fn1 using the Isl1(Cre) knock-in strain of mice. Deletion of Fn1 using the Isl1(Cre) strain resulted in defective formation of the 4th pharyngeal arch arteries (PAAs), aberrant development of the cardiac outflow tract (OFT), and ventricular septum defects. To determine the cell types responding to Fn1 signaling during cardiovascular development, we deleted a major Fn1 receptor, integrin alpha5 using the Isl1(Cre) strain, and observed the same spectrum of abnormalities seen in the Fn1 conditional mutants. Additional conditional mutagenesis studies designed to ablate integrin alpha5 in distinct cell types within the Isl1(+) tissues and their derivatives, suggested that the expression of integrin alpha5 in the pharyngeal arch mesoderm, endothelium, surface ectoderm and the neural crest were not required for PAA formation. Our studies suggest that an (as yet unknown) integrin alpha5-dependent signal extrinsic to the pharyngeal endothelium mediates the formation of the 4th PAAs. PMID- 26434920 TI - Effect of two different healing times on the mineralization of newly formed bone using a bovine bone substitute in sinus floor augmentation: a randomized, controlled, clinical and histological investigation. AB - PURPOSE: To investigate the amount of the mineralization of a bovine bone substitute material in sinus floor augmentation after healing times of 3 and 6 months. MATERIALS AND METHODS: Fifty-one patients were randomized into two healing time groups and received sinus floor augmentations with a bovine bone material. After 3 or 6 months of healing, trephine bone biopsies were retrieved. The biopsies were processed for histological and histomorphometric evaluations to primarily investigate the amount of mineralized bone in the augmented area and secondarily compare the amount of mineralized bone in the augmented area and in the pristine bone. Statistical tests were performed to analyse the fraction of the mineralized bone (p < 0.05). RESULTS: The biopsies of both groups showed remnants of the well-integrated bone substitute material. The histology revealed osteoblasts, osteocytes with osteoid, and osteoclasts. The mean percentage of mineralized bone in the augmented area was 23.8% (3 months group) and 23.6% (6 months group; p = 0.9246); the amount of remaining bone substitute material was 35% (3 months group) and 33.9% (6 months group; p = 0.6325). CONCLUSION: It can be concluded that the bone maturation in the augmented sinus using the bovine bone material is similar after 3 and 6 months. Thus, implant installation after 3 months following a lateral window sinus floor augmentation approach using a bovine bone material seems to be clinically acceptable. PMID- 26434921 TI - Impact of case-relevant and case-irrelevant communication within the surgical team on surgical-site infection. AB - BACKGROUND: Surgical-site infections (SSIs) are the most common complications after surgery. An influence from talking and distractions during surgery on patient outcomes has been suggested, but there is limited evidence. The aim of this prospective observational study was to assess the relationship between intraoperative communication within the surgical team and SSI, and between intraoperative distractions and SSI. METHODS: This prospective observational study included patients undergoing elective, open abdominal procedures. For each procedure, intraoperative case-relevant and case-irrelevant communication, and intraoperative distractions were observed continuously on site. The influence of communication and distractions on SSI after surgery was assessed using logistic regressions, adjusting for risk factors. RESULTS: A total of 167 observed procedures were analysed; their mean(s.d.) duration was 4.6(2.1) h. A total of 24 SSIs (14.4 per cent) were diagnosed. Case-relevant communication during the procedure was independently associated with a reduced incidence of organ/space SSI (propensity score-adjusted odds ratio 0.86, 95 per cent c.i. 0.77 to 0.97; P = 0.014). Case-irrelevant communication during the closing phase of the procedure was independently associated with increased incidence of incisional SSI (propensity score-adjusted odds ratio 1.29, 1.08 to 1.55; P = 0.006). Distractions had no association with SSI. CONCLUSION: More case-relevant communication was associated with fewer organ/space SSIs, and more case irrelevant communication during wound closure was associated with incisional SSI. PMID- 26434922 TI - Pregnancy Outcomes in Women With Rare Autoimmune Diseases. AB - OBJECTIVE: To examine pregnancy outcomes and pregnancy-related health service utilization among women with rare autoimmune diseases. METHODS: This population based cohort study of an Australian obstetric population (2001-2011) used birth records linked to hospital records for identification of rare autoimmune diseases including systemic vasculitis, vasculitis limited to the skin, Sjogren's syndrome, systemic sclerosis, Behcet's disease, polymyositis/dermatomyositis, and other systemic involvement of connective tissue. We excluded births in women with systemic lupus erythematosus or rheumatoid arthritis as well as births occurring >=6 months before the diagnosis of the rare autoimmune disease. Modified Poisson regression was used to compare study outcomes between women with autoimmune diseases and the general obstetric population. RESULTS: There were 991,701 births, including 409 births (0.04%) in 293 women with rare autoimmune diseases. Of the 409 births, 202 (49%) were delivered by cesarean section and 72 (18%) were preterm; these rates were significantly higher than those in the general obstetric population (28% and 7%, respectively). Compared to the general population, women with autoimmune diseases had higher rates of hypertensive disorders, antepartum hemorrhage, and severe maternal morbidity and required longer hospitalization at delivery, more hospital admissions, and tertiary obstetric care. Compared to other infants, those whose mothers had a rare autoimmune disease were at increased risk of admission to a neonatal intensive care unit, severe neonatal morbidity, and perinatal death. CONCLUSION: While the majority of women with rare autoimmune diseases delivered healthy infants, they were at increased risk of having both maternal complications and adverse neonatal outcomes, suggesting that their pregnancies should be closely monitored. PMID- 26434923 TI - Non-target effects of commonly used plant protection products in roses on the predatory mite Euseius gallicus Kreiter & Tixier (Acari: Phytoseidae). AB - BACKGROUND: Euseius gallicus Kreiter & Tixier (Acari: Phytoseidae) is a predatory mite recently available for use against various pests in roses. We tested in greenhouse trials the impact on the numbers of eggs and motiles of E. gallicus of the most commonly used plant protection products in roses in northern Europe: the acaricides acequinocyl and etoxazole, the insecticides azadirachtin-A, acetamiprid, flonicamid, imidacloprid, indoxacarb, thiacloprid and thiamethoxam and the fungicides boscalid and kresoxim-methyl, cyprodinil + fludioxonil, dodemorph and fluopyram + tebuconazole. RESULTS: The neonicotinoids thiacloprid, thiamethoxam, acetamiprid and imidacloprid had a negative impact on the number of eggs (47, 62, 81 and 76% reduction, respectively, compared with a water treatment) and number of motiles of E. gallicus (42.2, 42.9, 59.9 and 60.6% reduction) and were classified as slightly to moderately toxic. Also, the number of motiles was reduced after treatment with acequinocyl (47%) and etoxazole (43.9%) and after two treatments with flonicamid (41%) with a 1 week interval between treatments. CONCLUSION: Azadirachtin-A, acetamiprid, flonicamid, boscalid and kresoxim-methyl, cyprodinil + fludioxonil, dodemorph and fluopyram + tebuconazole were harmless for E. gallicus. Special attention should be paid to the impact of neonicotinoids and of acequinocyl and etoxazole, and to the application frequency with flonicamid on E. gallicus. (c) 2015 Society of Chemical Industry. PMID- 26434924 TI - Changes in actin and tubulin expression in osteogenic cells cultured on bioactive glass-based surfaces. AB - The present study evaluated whether the changes in the labeling pattern of cytoskeletal proteins in osteogenic cells cultured on bioactive glass-based materials are due to altered mRNA and protein levels. Primary rat-derived osteogenic cells were plated on Bioglass(r) 45S5, Biosilicate(r), and borosilicate (bioinert control). The following parameters were assayed: (i) qualitative epifluorescence analysis of actin and tubulin; (ii) quantitative mRNA and protein expression for actin and tubulin by real-time PCR and ELISA, respectively, and (iii) qualitative analysis of cell morphology by scanning electron microscopy (SEM). At days 3 and 7, the cells grown on borosilicate showed typical actin and tubulin labeling patterns, whereas those on the bioactive materials showed roundish areas devoid of fluorescence signals. The cultures grown on bioactive materials showed significant changes in actin and tubulin mRNA expression that were not reflected in the corresponding protein levels. A positive correlation between the mRNA and protein as well as an association between epifluorescence imaging and quantitative data were only detected for the borosilicate. SEM imaging of the cultures on the bioactive surfaces revealed cells partly or totally coated with material aggregates, whose characteristics resembled the substrate topography. The culturing of osteogenic cells on Bioglass(r) 45S5 and Biosilicate(r) affect actin and tubulin mRNA expression but not the corresponding protein levels. Changes in the labeling pattern of these proteins should then be attributed, at least in part, to the presence of a physical barrier on the cell surface as a result of the material surface reactions, thus limiting fluorescence signals. PMID- 26434925 TI - Theory of Mind in aging: Comparing cognitive and affective components in the faux pas test. AB - OBJECTIVES: Theory of Mind (ToM) is a complex human ability that allows people to make inferences on others' mental states such as beliefs, emotions and desires. Previous studies on ToM in normal aging have provided heterogeneous findings. In the present study we examined whether a mixed calculation of different aspects of ToM may have contributed to these conflicting results. We had two aims. First, we explored the age-related changes in the performance of cognitive vs. affective ToM. Second, we investigated the extent to which the effect of aging on cognitive vs. affective ToM is mediated by age-related differences in executive functions. METHOD: To address these issues three age groups (young, young-old, and old-old adults) were compared on cognitive and affective ToM using the faux pas test. In addition, participants were tested using a battery of executive function tasks tapping on inhibition, working memory updating, and word fluency. RESULTS: The analyses indicated that young adults outperform both young-old and old-old adults on cognitive ToM but not on affective ToM. Correlations showed that, whereas cognitive ToM was significantly associated with age, working memory updating, and inhibition, affective ToM was not. Finally, analyses revealed that individual differences in working memory updating (but not inhibition) mediated the effect of age on cognitive ToM. CONCLUSION: Our findings support the view of selective age-related differences on cognitive, but not affective, ToM in normal aging. The distinction between the two ToM components is further supported by a dissociable pattern of correlations with executive functions. PMID- 26434926 TI - Non-specificity of ethylene inhibitors: 'double-edged' tools to find out new targets involved in the root morphogenetic programme. AB - In the last decade, genetic and pharmacological approaches have been used to explore ethylene biosynthesis and perception in order to study the role of ethylene and ethylene/auxin interaction in root architecture development. However, recent findings with pharmacological approaches highlight the non specificity of commonly used inhibitors. This suggests that caution is required for interpreting these studies and that the use of pharmacological agents is a 'double-edged' tool. On one hand, non-specific effects make interpretation difficult unless other experiments, such as with different mutants or with multiple diversely acting chemicals, are conducted. On the other hand, the non specificity of inhibitors opens up the possibility of uncovering some ligands or modulators of new receptors such as plant glutamate-like receptors and importance of some metabolic hubs in carbon and nitrogen metabolism such as the pyridoxal phosphate biosynthesis involved in the regulation of the root morphogenetic programme. Identification of such targets is a critical issue to improve the efficiency of absorption of macronutrients in relation to root the morphogenetic programme. PMID- 26434927 TI - Bacillus subtilis vegetative isolate surviving chlorine dioxide exposure: an elusive mechanism of resistance. AB - AIMS: Oxidizing agents such as chlorine dioxide are widely used microbicides, including for disinfection of medical equipment. We isolated a Bacillus subtilis isolate from a washer-disinfector whose vegetative form demonstrated unique resistance to chlorine dioxide (0.03%) and hydrogen peroxide (7.5%). The aim of this study was to understand the mechanisms of resistance expressed by this isolate. METHODS AND RESULTS: A range of resistance mechanisms were investigated in the B. subtilis isolate and a reference B. subtilis strain (ATCC 6051) to include bacterial cell aggregation, the presence of profuse exopolysaccharide (EPS), and the expression of detoxification enzymes. The basis of resistance of the isolate to high concentrations of oxidizing agents was not linked to the presence of endospores. Although, the presence of EPS, aggregation and expression of detoxification enzymes may play a role in bacterial survival to low concentrations of chlorine dioxide, it is unlikely that the mechanisms helped tested to survive the bactericidal effect of higher oxidizer concentrations. CONCLUSIONS: Overall, the mechanisms conferring resistance to chlorine dioxide and hydrogen peroxide remains elusive. Based on recent advances in the mode of action of oxidizing agents and notably hydrogen peroxide, we postulate that additional efficient intracellular mechanisms may be involved to explain significant resistance to in-use concentrations of commonly used high-level disinfectants. SIGNIFICANCE AND IMPACT OF STUDY: The isolation of a highly resistant vegetative Gram-positive bacterium to a highly reactive oxidizing agent is worrying. Understanding the mechanisms conferring such resistance is essential to effectively control such bacterial isolates. Here, we postulate that there are still mechanisms of bacterial resistance that have not been fully characterized. PMID- 26434928 TI - Structure of the N-terminal domain of the metalloprotease PrtV from Vibrio cholerae. AB - The metalloprotease PrtV from Vibrio cholerae serves an important function for the ability of bacteria to invade the mammalian host cell. The protein belongs to the family of M6 proteases, with a characteristic zinc ion in the catalytic active site. PrtV constitutes a 918 amino acids (102 kDa) multidomain pre-pro protein that undergoes several N- and C-terminal modifications to form a catalytically active protease. We report here the NMR structure of the PrtV N terminal domain (residues 23-103) that contains two short alpha-helices in a coiled coil motif. The helices are held together by a cluster of hydrophobic residues. Approximately 30 residues at the C-terminal end, which were predicted to form a third helical structure, are disordered. These residues are highly conserved within the genus Vibrio, which suggests that they might be functionally important. PMID- 26434929 TI - Soft and Hard Tissue Changes around Tissue-Oriented Tulip-Design Implant Abutments: A 1-Year Randomized Prospective Clinical Trial. AB - BACKGROUND: The advantages of platform switching using narrower abutments remain controversial. Many researchers suggest that platform switching can yield enhanced clinical results, while others remain skeptical. We hypothesize that the effectiveness of platform switching might be associated with the degree of reduction in size of the abutment. PURPOSE: To radiographically and clinically examine a new abutment design created to move the implant-abutment interface farther medially. MATERIALS AND METHODS: This was a prospective, randomized controlled clinical trial that included 27 patients (41 MIS Lance Plus(r) implants; MIS Implant Technologies, Karmiel, Israel). The patients' age ranged from 39 to 75 years. At the second stage of the surgery, the implants were randomly assigned to either the new platform switch Tulip abutment (TA) design or to the standard platform abutment (SA). Implant probing depth (IPD) and bleeding on probing (BOP) were recorded at baseline and after 12 months. Standardized periapical radiographs were taken (at baseline and at 12 months) and the marginal bone height measured. RESULTS: All implants were successfully integrated. The mean IPD at 1 year post-op was 2.91 mm for the SA group and 2.69 mm for the TA group (p > .05). Similarly, the BOP at 1 year was almost identical in both groups. The mean values of bone resorption at baseline were 0.98 +/- 0.37 mm and 0.69 +/- 0.20 for the TA and SA groups, respectively (p > .05). Bone loss (baseline to 12 months) was significantly greater in the SA group compared with the TA group. CONCLUSIONS: Use of the new TA, with its significantly downsized diameter, resulted in reduced bone loss at 1 year. Further research will be required to assess the long-term effect of this abutment on peri-implant health. PMID- 26434930 TI - Colectomy with Permanent End Ileostomy Is More Cost-Effective than Ileal Pouch Anal Anastomosis for Crohn's Colitis. AB - BACKGROUND: Much of the economic burden of Crohn's disease (CD) is related to surgery. Twenty percent of patients with CD have isolated colonic disease. While permanent end ileostomy (EI) is generally the procedure of choice for patients with refractory CD colitis, single-center experiences suggest that restorative proctocolectomy (IPAA) is durable in select patients. AIMS: We assessed the cost effectiveness of total colectomy with permanent EI versus IPAA in medically refractory colonic CD. METHODS: We used a lifetime Markov model with 6-month cycles to simulate quality-adjusted life years (QALYs) and cost. In each of the EI and IPAA strategies, patients could transition between multiple health states. One-way and multivariable sensitivity analysis and tornado analysis were performed to identify thresholds for factors influencing cost-effectiveness. RESULTS: IPAA was more effective than EI surgery with an incremental cost effectiveness ratio of $70,715 per QALY gained. We identified the following variables of importance in our model: (1) the cost of the EI surgery, (2) the cost of infliximab, and (3) the cost of gastroenterology ambulatory visit and labs. Threshold analysis revealed that if the costs associated with EI surgery exceeded $20,167 or if the utility of IPAA with CD remission without medical therapy exceeded 0.37, IPAA became the more cost-effective strategy. CONCLUSIONS: In patients with medically refractory CD isolated to the colon, colectomy with permanent EI is more cost-effective than IPAA unless the costs associated with the EI surgery exceed $20,167 or if the utility associated with IPAA and CD remission exceeds 0.37. PMID- 26434931 TI - Significance of Endoscopic Sphincterotomy Preceding Endoscopic Papillary Large Balloon Dilation in the Management of Bile Duct Stones. AB - BACKGROUND: Endoscopic papillary large balloon dilation (EPLBD) is safe and effective in management of common bile duct stones (CBDS). Endoscopic sphincterotomy (EST) prior to EPLBD has been performed as a standard procedure. However, the significance of EST prior to EPLBD has not been well studied yet. AIMS: To compare the clinical outcomes of EPLBD with and without EST to evaluate the significance of EST. METHODS: Between April 2010 and March 2015, a total of 82 patients with naive papillae underwent EPLBD with or without EST for the management of CBDS. A retrospective analysis compared the efficacy and safety of EPLBD with and without EST. RESULTS: Basic patient characteristics were not significantly different between the groups that underwent EPLBD with EST (n = 27) and without EST (n = 55). Complete stone removal rates were similar between the groups (100 % in the EST group and 98 % in the non-EST group, p = 1.00). There was no significant difference in the median balloon size (13 mm in both groups, p = 0.445), rate of application of mechanical lithotripsy (26 vs. 35 % in the EST and non-EST groups, respectively, p = 0.463), or the median procedure time (38 vs. 34 min in the EST and non-EST groups, respectively, p = 0.682). The overall adverse event rates were not statistically different (4 vs. 7 % in the EST and non-EST groups, respectively, p = 1.00). Pancreatitis, cholangitis, and hemorrhage rates were also similar in both groups. CONCLUSIONS: EST prior to EPLBD may be unnecessary since this study did not demonstrate its benefits. PMID- 26434932 TI - GGPPS-mediated Rab27A geranylgeranylation regulates beta cell dysfunction during type 2 diabetes development by affecting insulin granule docked pool formation. AB - Loss of first-phase insulin secretion associated with beta cell dysfunction is an independent predictor of type 2 diabetes mellitus (T2DM) onset. Here we found that a critical enzyme involved in protein prenylation, geranylgeranyl pyrophosphate synthase (GGPPS), is required to maintain first-phase insulin secretion. GGPPS shows a biphasic expression pattern in islets of db/db mice during the progression of T2DM: GGPPS is increased during the insulin compensatory period, followed by a decrease during beta cell dysfunction. Ggpps deletion in beta cells results in typical T2DM beta cell dysfunction, with blunted glucose-stimulated insulin secretion and consequent insulin secretion insufficiency. However, the number and size of islets and insulin biosynthesis are unaltered. Transmission electron microscopy shows a reduced number of insulin granules adjacent to the cellular membrane, suggesting a defect in docked granule pool formation, while the reserve pool is unaffected. Ggpps ablation depletes GGPP and impairs Rab27A geranylgeranylation, which is responsible for the docked pool deficiency in Ggpps-null mice. Moreover, GGPPS re-expression or GGPP administration restore glucose-stimulated insulin secretion in Ggpps-null islets. These results suggest that GGPPS-controlled protein geranylgeranylation, which regulates formation of the insulin granule docked pool, is critical for beta cell function and insulin release during the development of T2DM. PMID- 26434933 TI - Subtotal spleen necrosis. PMID- 26434934 TI - AMG 151 (ARRY-403), a novel glucokinase activator, decreases fasting and postprandial glycaemia in patients with type 2 diabetes. AB - Phase I studies have shown that AMG 151 activates glucokinase, a key enzyme in glucose homeostasis. The present randomized, placebo-controlled phase IIa study evaluated the dose-effect relationship of the glucokinase activator AMG 151 relative to placebo on fasting plasma glucose (FPG) in 236 patients (33-35 patients per arm) with type 2 diabetes treated with metformin. Patients received oral AMG 151 at 50, 100 or 200 mg twice daily, AMG 151 at 100, 200 or 400 mg once daily or matching placebo for 28 days. A significant linear dose-effect trend was observed with the twice-daily regimen (p = 0.004) for change in FPG to day 28. No trend was observed with the once-daily regimen. A higher incidence of hypoglycaemia and hypertriglyceridaemia was observed with AMG 151 administration. AMG 151 significantly reduced FPG when administered twice daily but not when administered once daily in patients with type 2 diabetes treated with metformin. PMID- 26434935 TI - Systematic review with meta-analysis: the risk of major gastrointestinal bleeding with non-vitamin K antagonist oral anticoagulants. AB - BACKGROUND: Gastrointestinal (GI) bleeding is a common complication among anticoagulated patients. Non-vitamin K antagonist oral anticoagulants (NOACs) are associated with increased risk of GI (major and clinically relevant non-major) bleeding. However, more information is needed regarding severe events. AIM: To evaluate the risk of NOACs major GI bleeding. METHODS: We searched for phase III randomised clinical trials (RCT) evaluating NOACs (apixaban, dabigatran, edoxaban and rivaroxaban) and reporting major GI bleeding events, in MEDLINE, Cochrane Library, SciELO collection and Web of Science databases (July 2015). Meta analysis was performed to estimate risk ratio (RR) and 95% confidence intervals (95% CIs). Heterogeneity was assessed with the I(2) test. RESULTS: A total of 23 studies were included. Among patients with atrial fibrillation, the risk of major GI bleeding was not different between NOACs and vitamin K antagonists (VKA) (RR 1.08, 95% CI 0.85-1.36, I(2) = 78%; 5 RCTs) or acetylsalicylic acid (RR 0.78, 95% CI 0.36-1.72; 1 RCT). Similar results were found for patients undergoing orthopaedic surgery and those with venous thromboembolism. NOACs were not found to increase the risk compared to low-molecular-weight heparin (LWMH) alone (RR 1.42, 95% CI 0.55-3.71, I(2) = 7%; 8 RCTs), the sequential treatment with LMWH VKA (RR 0.77, 95% CI 0.49-1.21, I(2) = 43%; 7 RCTs) or placebo (RR 1.48, 95% CI 0.15-14.84, I(2) = 21%; 2 RCTs). CONCLUSION: Despite previous evidence supporting the association of non-vitamin K antagonist oral anticoagulants and overall GI bleeding, non-vitamin K antagonist oral anticoagulants are not associated with increased risk of major GI bleeding compared to other anticoagulant drugs (with known increased risk of these events). PMID- 26434936 TI - Conception rates in farm mink (Neovison vison) in relation to first mating date, age and color variety. AB - The aim of the study was to analyze the effects of the first mating date, age and color variety on the conception rates in farm mink. We analyzed female mink reproductive performance in 492 Sapphire and 463 Standard Black females over 3 or 4 years. The analysis included the number of inefficient matings, the interval between the first inefficient mating and the efficient mating (copulation) and the conception rates. The results show a significant effect of female's age and color variety on the conception rates. The youngest, yearling females of either color needed a higher number of matings per conception, as compared to older, 2- and 3-year-old females. Black females demonstrated a higher number of inefficient matings (1.066), as compared with Sapphires (0.730). Yearling females were most often mated from 1 to 10 March, and older females from 11 to 20 March. Older females achieved better conception rates than the yearlings. Dates between 11 and 25 March proved to be the optimum for the first mating, since the highest conception rates were observed if the females had mated during this period. PMID- 26434938 TI - Use of hormonal contraception after hydatidiform mole. PMID- 26434937 TI - Ultrastructural changes of mitochondria in human retinoblastoma: correlation with tumor differentiation and invasiveness. AB - Retinoblastoma still represents a challenge for pediatric tumors. Mitochondria have been implicated in tumor progression, cell differentiation, and apoptotic pathways. Electron microscopy allows the study of mitochondrial morphology and it is still debated in human retinoblastoma. Demographic, clinical, and histopathological parameters were recorded in 17 enucleated retinoblastoma specimens. Hematoxylin and eosin staining was performed to study tumor characteristics and the extent of invasion in ocular structures. The aim of this study was to describe and analyze the mitochondrial morphology in human retinoblastoma by transmission electron microscopy (TEM). There was a male preponderance in our study. Ages ranged from 2 to 78 months. Histopathological analysis revealed that 15 (88.2 %) tumors were poorly differentiated retinoblastomas. Massive choroidal invasion was the most frequent histopathological high-risk factor among the others. Histopathological high-risk factors were found in 7/17 (41.1 %) cases. Tumor samples of all patients were examined by means of TEM. All cases showed tumor cells with high nucleocytoplasmic ratio. Poorly differentiated retinoblastoma cases showed fewer mitochondria, scant cytoplasm, disorganized organelles (mitochondria), and necrosis, whereas well-differentiated retinoblastomas had larger number of mitochondria and more organized organelles. However, there was no significant difference in mitochondrial changes between invasive and noninvasive tumors. Our study observed that cristolysis and swollen mitochondria were more frequent in retinoblastoma tumors. Understanding the structural and functional characteristics of mitochondria in retinoblastoma might be essential for the design of future therapeutic strategies. The authors have no proprietary or commercial interest in any materials discussed in this article. PMID- 26434939 TI - Simultaneous determination of aminopyrine and antipyrine in porcine muscle, milk, and eggs using liquid chromatography with tandem mass spectrometry. AB - The concentrations of residual aminopyrine and antipyrine in porcine muscle, milk, and egg samples were analyzed using liquid chromatography with tandem mass spectrometry after undergoing a series of sample pretreatment steps. Owing to an ion suppression effect, matrix-matched calibrations were used for analyte quantitation with determination coefficients (R(2) ) >= 0.9931. The recovery rates for aminopyrine and antipyrine in various matrices at two spiking levels (5 and 10 ng/g) fell in the range of 60.96-68.87 and 61.87-66.99%, respectively. Meanwhile, the intra- and inter-day precisions (expressed as relative standard deviation) were 1.02-12.95 and 1.71-5.50%, respectively. The method's detection limit (1 ng/g) was very low, thus enabling the detection of low residue levels. The applicability of the developed method was demonstrated with actual market samples and none of the tested analytes was detected in any of the samples. PMID- 26434940 TI - Spatio-temporal dynamics of mosquitoes in stream pools of a biosphere reserve of Southern Western Ghats, India. AB - The spatial and temporal dynamics of mosquitoes in stream pools were examined in a biosphere reserve of the Southern Western Ghats, India. The immature mosquitoes in stream pools were collected from stream substrates of bedrock pool, boulder cavity and sand puddle. The collected larvae and pupae were reared and identified. In total, 16 species from four genera of mosquitoes were collected. The mosquito species from Culex and Anopheles were predominantly occurred. The bedrock pool had the highest diversity and abundance of mosquitoes. The statistical analyses showed that the substrate specificity and the seasons were positively related to the distribution of mosquitoes rather than spatial pattern. This study described the spatial and temporal pattern of mosquitoes in stream pools of the Southern Western Ghats. This information would be helpful to National Vector borne disease control program for surveillance and control. PMID- 26434941 TI - Combinatorial therapy for triple negative breast cancer using hyperstar polymer based nanoparticles. AB - We report the ability of a novel combinatorial therapy obtained from nanoparticles of hyperstar polymers encompassing drugs to selectively target triple negative breast cancer (TNBC) cell proliferation through STAT3 and topoisomerase-II pathways. This nano-cocktail was at least two to four fold better than the individual drugs and 6-20 times more selective than the parent drugs. PMID- 26434942 TI - Selective functionalization of mesoporous silica nanoparticles with ibuprofen and Gd(III) chelates: a new probe for potential theranostic applications. AB - Organo-modified mesoporous silica nanoparticles, loaded with ibuprofen into the pores and functionalized on the external surface with a stable Gd(iii)-DOTA monoamide chelate, were prepared and explored as potential theranostic probes. PMID- 26434943 TI - From Dibismuthenes to Three- and Two-Coordinated Bismuthinidenes by Fine Ligand Tuning: Evidence for Aromatic BiC3N Rings through a Combined Experimental and Theoretical Study. AB - The reduction of N,C,N-chelated bismuth chlorides [C6H3-2,6-(CH=NR)2]BiCl2 [where R = tBu (1), 2',6'-Me2C6H3 (2), or 4'-Me2NC6H4 (3)] or N,C-chelated analogues [C6H2-2-(CH=N-2',6'-iPr2C6H3)-4,6-(tBu)2]BiCl2 (4) and [C6H2-2-(CH2NEt2)-4,6 (tBu)2]BiCl2 (5) is reported. Reduction of compounds 1-3 gave monomeric N,C,N chelated bismuthinidenes [C6H3-2,6-(CH=NR)2]Bi [where R = tBu (6), 2',6'-Me2C6H3 (7) or 4'-Me2NC6H4 (8)]. Similarly, the reduction of 4 led to the isolation of the compound [C6H2-2-(CH=N-2',6'-iPr2C6H3)-4,6-(tBu)2]Bi (9) as an unprecedented two-coordinated bismuthinidene that has been structurally characterized. In contrast, the dibismuthene {[C6H2-2-(CH2NEt2)-4,6-(tBu)2]Bi}2 (10) was obtained by the reduction of 5. Compounds 6-10 were characterized by using (1)H and (13)C NMR spectroscopy and their structures, except for 7, were determined with the help of single-crystal X-ray diffraction analysis. It is clear that the structure of the reduced products (bismuthinidene versus dibismuthene) is ligand-dependent and particularly influenced by the strength of the N->Bi intramolecular interaction(s). Therefore, a theoretical survey describing the bonding situation in the studied compounds and related bismuth(I) systems is included. Importantly, we found that the C3NBi chelating ring in the two-coordinated bismuthinidene 9 exhibits significant aromatic character by delocalization of the bismuth lone pair. PMID- 26434948 TI - CRISPR/Cas9 system as an innovative genetic engineering tool: Enhancements in sequence specificity and delivery methods. AB - While human gene therapy has gained significant attention for its therapeutic promise, CRISPR/Cas9 technology has made a breakthrough as an efficient genome editing tool by emulating prokaryotic immune defense mechanisms. Although many studies have found that CRISPR/Cas9 technology is more efficient, specific and manipulable than previous generations of gene editing tools, it can be further improved by elevating its overall efficiency in a higher frequency of genome modifications and reducing its off-target effects. Here, we review the development of CRISPR/Cas9 technology, focusing on enhancement of its sequence specificity, reduction of off-target effects and delivery systems. Moreover, we describe recent successful applications of CRISPR/Cas9 technology in laboratory and clinical studies. PMID- 26434949 TI - Multisource Synergistic Electrocatalytic Oxidation Effect of Strongly Coupled PdM (M = Sn, Pb)/N-doped Graphene Nanocomposite on Small Organic Molecules. AB - A series of palladium-based catalysts of metal alloying (Sn, Pb) and/or (N-doped) graphene support with regular enhanced electrocatalytic activity were investigated. The peak current density (118.05 mA cm(-2)) of PdSn/NG is higher than the sum current density (45.63 + 47.59 mA cm(-2)) of Pd/NG and PdSn/G. It reveals a synergistic electrocatalytic oxidation effect in PdSn/N-doped graphene Nanocomposite. Extend experiments show this multisource synergetic catalytic effect of metal alloying and N-doped graphene support in one catalyst on small organic molecule (methanol, ethanol and Ethylene glycol) oxidation is universal in PdM(M = Sn, Pb)/NG catalysts. Further, The high dispersion of small nanoparticles, the altered electron structure and Pd(0)/Pd(II) ratio of Pd in catalysts induced by strong coupled the metal alloying and N-doped graphene are responsible for the multisource synergistic catalytic effect in PdM(M = Sn, Pb) /NG catalysts. Finally, the catalytic durability and stability are also greatly improved. PMID- 26434947 TI - Development of next-generation respiratory virus vaccines through targeted modifications to viral immunomodulatory genes. AB - Vaccines represent one of the greatest contributions of the scientific community to global health. Yet, many pathogens remain either unchallenged or inadequately hindered by commercially available vaccines. Respiratory viruses pose distinct and difficult challenges due to their ability to rapidly spread, adapt, and modify the host immune response. Considerable research has been directed to understand the role of respiratory virus immunomodulatory proteins and how they influence the host immune response. We review here efforts to develop next generation vaccines through targeting these key immunomodulatory genes in influenza virus, coronaviruses, respiratory syncytial virus, measles virus, and mumps virus. PMID- 26434950 TI - Anthropogenic effects on a tropical forest according to the distance from human settlements. AB - The protection of tropical forests is one of the most urgent issues in conservation biology because of the rapid deforestation that has occurred over the last 50 years. Even in protected forests, the anthropogenic effects from newly expanding villages such as harvesting of medicinal plants, pasturing cattle and forest fires can induce environmental modifications, especially on the forest floor. We evaluated the anthropogenic effects of the daily activities of neighboring residents on natural forests in 12 plots extending from the village boundary into a natural forest in Thailand. The basal area per unit land area did not present a significant trend; however, the species diversity of woody plants decreased linearly towards the village boundary, which caused a loss of individual density because of severe declines in small saplings compared with adult trees and large saplings in proximity to the village. An analysis of tree size categories indicates a lack of small samplings near the village boundary. The current forest appears to be well protected based on the adult tree canopy, but regeneration of the present-day forests is unlikely because of the loss of seedlings. PMID- 26434952 TI - Hepatitis E virus: seroprevalence and frequency of viral RNA detection among US blood donors. AB - BACKGROUND: Hepatitis E virus (HEV) is a nonenveloped emerging virus of increasing worldwide interest. Antibody prevalence, RNA frequencies, and transfusion transmissions have been reported. We investigated the HEV RNA and antibody frequencies in US blood donors. STUDY DESIGN AND METHODS: Individual donation HEV RNA testing was performed on 18,829 donations from six US geographic regions using a CE-marked nucleic acid test (95% limit of detection, 7.9 IU/mL). Repeat-reactive donations were confirmed by in-house, real-time polymerase chain reaction (PCR; 10.3 IU/mL). Total HEV seroprevalence in a randomly selected subset of donations (n = 4499) was assessed by a direct, double-antigen sandwich assay; reactives were further tested for immunoglobulin (Ig)G and IgM. As part of the total antibody confirmatory algorithm, the cutoff was adjusted. RESULTS: Two donations tested confirmed-positive for RNA (PCR not quantifiable, IgM/IgG positive; and 14 IU/mL, antibody negative) for a frequency of 1 in 9500 (95% confidence interval [CI], 1:2850-1:56,180) and 99.96% specificity (95% CI, 99.92% 99.98%); both donors were from the Midwest United States. Antibody prevalence was 9.5% (95% CI, 8.7-10.5) before the cutoff adjustment and 7.7% (95% CI, 7.0%-8.5%) after adjustment; 0.58% (95% CI, 0.39%-0.85%) were IgM positive. CONCLUSIONS: We confirmed comparatively low rates and low viral loads of HEV RNA in US blood donors indicating the need for individual-donation testing if screening is implemented. Antibody prevalence rates were comparable to those reported by one US study using a different assay, but lower than those reported in another study using yet a third assay. We did not answer the question of whether US blood donation screening is warranted. Selective strategies involving providing HEV negative blood to severely immunosuppressed patients at risk of developing hepatitis may be considered. PMID- 26434951 TI - An ace-1 gene duplication resorbs the fitness cost associated with resistance in Anopheles gambiae, the main malaria mosquito. AB - Widespread resistance to pyrethroids threatens malaria control in Africa. Consequently, several countries switched to carbamates and organophophates insecticides for indoor residual spraying. However, a mutation in the ace-1 gene conferring resistance to these compounds (ace-1(R) allele), is already present. Furthermore, a duplicated allele (ace-1(D)) recently appeared; characterizing its selective advantage is mandatory to evaluate the threat. Our data revealed that a unique duplication event, pairing a susceptible and a resistant copy of the ace-1 gene spread through West Africa. Further investigations revealed that, while ace 1(D) confers less resistance than ace-1(R), the high fitness cost associated with ace-1(R) is almost completely suppressed by the duplication for all traits studied. ace-1 duplication thus represents a permanent heterozygote phenotype, selected, and thus spreading, due to the mosaic nature of mosquito control. It provides malaria mosquito with a new evolutionary path that could hamper resistance management. PMID- 26434954 TI - Strong magnetic frustration and anti-site disorder causing spin-glass behavior in honeycomb Li2RhO3. AB - With large spin-orbit coupling, the electron configuration in d-metal oxides is prone to highly anisotropic exchange interactions and exotic magnetic properties. In 5d(5) iridates, given the existing variety of crystal structures, the magnetic anisotropy can be tuned from antisymmetric to symmetric Kitaev-type, with interaction strengths that outsize the isotropic terms. By many-body electronic structure calculations we here address the nature of the magnetic exchange and the intriguing spin-glass behavior of Li2RhO3, a 4d(5) honeycomb oxide. For pristine crystals without Rh-Li site inversion, we predict a dimerized ground state as in the isostructural 5d(5) iridate Li2IrO3, with triplet spin dimers effectively placed on a frustrated triangular lattice. With Rh-Li anti-site disorder, we explain the observed spin-glass phase as a superposition of different, nearly degenerate symmetry-broken configurations. PMID- 26434953 TI - p38 MAPK regulates PKAalpha and CUB-serine protease in Amphibalanus amphitrite cyprids. AB - The MKK3-p38 MAPK pathway has been reported to mediate larval settlement in Amphibalanus (=Balanus) amphitrite. To clarify the underlying molecular mechanism, we applied label-free proteomics to analyze changes in the proteome of cyprids treated with a p38 MAPK inhibitor. The results showed that the expression levels of 80 proteins were significantly modified (p < 0.05). These differentially expressed proteins were assigned to 15 functional groups according to the KOG database and 9 pathways were significantly enriched. Further analysis revealed that p38 MAPK might regulate the energy supply and metamorphosis. Two potential regulatory proteins, CUB-serine protease and PKAalpha, were both down regulated in expression. CUB-serine protease localized to postaxial seta 2 and 3, as well as the 4 subterminal sensilla in the antennule. Importantly, it was co localized with the neuron transmitter serotonin in the sections, suggesting that the CUB-serine protease was present in the neural system. PKAalpha was highly expressed during the cyprid and juvenile stages, and it was co-localized with phospho-p38 MAPK (pp38 MAPK) to the cement gland, suggesting that PKAalpha might have some functions in cement glands. Overall, p38 MAPK might regulate multiple functions in A. amphitrite cyprids, including the energy supply, metamorphosis, neural system and cement glands. PMID- 26434955 TI - Theoretical Elucidation of Glucose Dehydration to 5-Hydroxymethylfurfural Catalyzed by a SO3H-Functionalized Ionic Liquid. AB - While the catalytic conversion of glucose to 5-hydroxymethyl furfural (HMF) catalyzed by SO3H-functioned ionic liquids (ILs) has been achieved successfully, the relevant molecular mechanism is still not understood well. Choosing 1-butyl-3 methylimidazolium chloride [C4SO3HmimCl] as a representative of SO3H-functioned IL, this work presents a density functional theory (DFT) study on the catalytic mechanism for conversion of glucose into HMF. It is found that the conversion may proceed via two potential pathways and that throughout most of elementary steps, the cation of the IL plays a substantial role, functioning as a proton shuttle to promote the reaction. The chloride anion interacts with the substrate and the acidic proton in the imidazolium ring via H-bonding, as well as provides a polar environment together with the imidazolium cation to stabilize intermediates and transition states. The calculated overall barriers of the catalytic conversion along two potential pathways are 32.9 and 31.0 kcal/mol, respectively, which are compatible with the observed catalytic performance of the IL under mild conditions (100 degrees C). The present results provide help for rationalizing the effective conversion of glucose to HMF catalyzed by SO3H-functionalized ILs and for designing IL catalysts used in biomass conversion chemistry. PMID- 26434956 TI - Opportunities, Risks, and Limitations of Genetic Testing: Looking to the Future From Patients' Point of View. PMID- 26434957 TI - Impact of Statins on Physical Activity and Fitness: Ally or Adversary? PMID- 26434958 TI - Hyponatremia Management: Walking the Tightrope Without a Net. PMID- 26434959 TI - Living at Risk: Factors That Affect the Experience of Direct-to-Consumer Genetic Testing. PMID- 26434960 TI - Whole-Exome Sequencing of 10 Scientists: Evaluation of the Process and Outcomes. AB - OBJECTIVE: To understand motivations, educational needs, and concerns of individuals contemplating whole-exome sequencing (WES) and determine what amount of genetic information might be obtained by sequencing a generally healthy cohort so as to more effectively counsel future patients. PATIENTS AND METHODS: From 2012 to 2014, 40 medically educated, generally healthy scientists at Mayo Clinic were invited to have WES conducted on a research basis; 26 agreed to be in a drawing from which 10 participants were selected. The study involved pre- and posttest genetic counseling and completion of 4 surveys related to the experience and outcomes. Whole-exome sequencing was conducted on DNA from blood from each person. RESULTS: Most variants (76,305 per person; range, 74,505-77,387) were known benign allelic variants, variants in genes of unknown function, or variants of uncertain significance in genes of known function. The results of suspected pathogenic/pathogenic variants in Mendelian disorders and pharmacogenomic variants were disclosed. The mean number of suspected pathogenic/pathogenic variants was 2.2 per person (range, 1-4). Four pharmacogenomic genes were included for reporting; variants were found in 9 of 10 participants. CONCLUSION: This study provides data that may be useful in establishing reality-based patient expectations, outlines specific points to cover during counseling, and increases confidence in the feasibility of providing adequate preparation and counseling for WES in generally healthy individuals. PMID- 26434961 TI - Effects of Statin Therapy on Exercise Levels in Participants in the National Runners' and Walkers' Health Study. AB - OBJECTIVES: To determine whether decreases in exercise 1) were greater in individuals who were diagnosed as having hypercholesterolemia than in those without the diagnosis during follow-up and 2) were greater in incident hypercholesterolemic participants starting statins than in those not treated with cholesterol-lowering medications. PARTICIPANTS AND METHODS: Regression analyses of changes since baseline (Delta) in exercise vs diagnosis of hypercholesterolemia and its treatment in 66,377 runners and 12,031 walkers not using cholesterol medications at baseline who were resurveyed during the National Runners' and Walkers' Health Study follow-up (January 1, 1991, through December 31, 2006). RESULTS: A total of 3510 runners began statin treatment, 1779 began other or unspecified cholesterol-lowering drug treatment, and 2583 had untreated hypercholesterolemia; 58,505 runners remained nonhypercholesterolemic controls during the mean 7.2-year follow-up. Usual distance run decreased significantly more in hypercholesterolemic runners who began taking statins (mean +/- SE: 0.47+/-0.06 km/d) than in runners who remained nonhypercholesterolemic during follow-up (-0.08+/-0.02 km/d) (P<.001). However, running distance also decreased significantly more in hypercholesterolemic runners who began unspecified/other ( 0.52+/-0.08 km/d) or no (-0.47+/-0.07 km/d) cholesterol drugs than in nonhypercholesterolemic runners during follow-up. Moreover, Deltarunning distance did not differ significantly between hypercholesterolemic runners who were statin treated vs those treated with other/unspecified (P=.64) or no (P=.94) cholesterol drugs. Initiating statin therapy was not associated with Deltarunning pace in hypercholesterolemic runners or Deltawalking distances in hypercholesterolemic walkers. CONCLUSION: These results are consistent with the premise that a decrease in running distance is associated with hypercholesterolemia and do not suggest that statins reduce exercise level or intensity. PMID- 26434962 TI - Sodium Correction Practice and Clinical Outcomes in Profound Hyponatremia. AB - OBJECTIVES: To assess the epidemiology of nonoptimal hyponatremia correction and to identify associated morbidity and in-hospital mortality. PATIENTS AND METHODS: An electronic medical record search identified all patients admitted with profound hyponatremia (sodium <120 mmol/L) from January 1, 2008, through December 31, 2012. Patients were classified as having optimally or nonoptimally corrected hyponatremia at 24 hours after admission. Optimal correction was defined as sodium correction in 24 hours of 6 through 10 mmol/L. We investigated the association between sodium correction and demographic and outcome variables, including occurrence of osmotic demyelination syndrome (ODS). Baseline characteristics by correction outcome categories were compared using the Kruskal Wallis test for continuous variables and the chi(2) test for categorical variables. Odds ratios for in-hospital mortality between groups were assessed using logistic regression. Adjusted differences in hospital length of stay (LOS) and intensive care unit (ICU) LOS were assessed using the Dunnett 2-tailed t test. RESULTS: A total of 412 patients satisfied inclusion criteria of whom 174 (42.2%) were admitted to the ICU. A total of 211 (51.2%) had optimal correction of their hyponatremia at 24 hours, 87 (21.1%) had undercorrected hyponatremia, and 114 (27.9%) had overcorrected hyponatremia. Both patient factors and treatment factors were associated with nonoptimal correction. There was a single case of ODS. Overcorrection was not associated with in-hospital mortality or ICU LOS. When adjusted for patient factors, undercorrection of profound hyponatremia was associated with an increase in hospital LOS (9.3 days; 95% CI, 1.9-16.7 days). CONCLUSION: Nonoptimal correction of profound hyponatremia is common. Fortunately, nonoptimal correction is associated with serious morbidity only infrequently. PMID- 26434964 TI - Answers to Common Questions About the Use and Safety of CT Scans. AB - Articles in the scientific literature and lay press over the past several years have implied that computed tomography (CT) may cause cancer and that physicians and patients must exercise caution in its use. Although there is broad agreement on the latter point--unnecessary medical tests of any type should always be avoided--there is considerable controversy surrounding the question of whether, or to what extent, CT scans can lead to future cancers. Although the doses used in CT are higher than those used in conventional radiographic examinations, they are still 10 to 100 times lower than the dose levels that have been reported to increase the risk of cancer. Despite the fact that at the low doses associated with a CT scan the risk either is too low to be convincingly demonstrated or does not exist, the magnitude of the concern among patients and some medical professionals that CT scans increase cancer risk remains unreasonably high. In this article, common questions about CT scanning and radiation are answered to provide physicians with accurate information on which to base their medical decisions and respond to patient questions. PMID- 26434963 TI - Association of Cardiorespiratory Fitness With Coronary Heart Disease in Asymptomatic Men. AB - OBJECTIVE: To examine the association of cardiorespiratory fitness (CRF) with risk of coronary heart disease (CHD) while controlling for an individual's Framingham Risk Score (FRS)-predicted CHD risk. PATIENTS AND METHODS: The study included 29,854 men from the Aerobics Center Longitudinal Study, who received a baseline examination from January 1, 1979, to December 31, 2002. Coronary heart disease events included self-reported myocardial infarction or revascularization or CHD death. Multivariable survival analysis investigated the association between CRF, FRS, and CHD. Cardiorespiratory fitness was analyzed as both a continuous and a categorical variable. The population was stratified by "low" and "moderate or high" risk of CHD to test for differences in the FRS stratified by CRF. RESULTS: Compared with men without incident CHD, men with incident CHD were older (mean age, 51.6 years vs 44.6 years), had lower average maximally achieved fitness (10.9 metabolic equivalent of tasks vs 12.0 metabolic equivalent of tasks [METs]), and were more likely to have moderate or high 10-year CHD risk (P<.001). Cardiorespiratory fitness, defined as maximal METs, exhibited a 20% lower risk of CHD (hazard ratio, 0.80; 95% CI, 0.77-0.83) for each 1-unit MET increase. Among men in the low CRF strata, individuals with moderate or high 10-year CHD risk, according to the FRS, had a higher CHD risk (hazard ratio, 6.55; 95% CI, 3.64 11.82) than men with low CHD risk according to the FRS. CONCLUSION: Clinicians should promote physical activity to improve CRF so as to reduce CHD risk, even to patients with otherwise low CHD risk. PMID- 26434965 TI - The Role of Environmental Exposures in the Etiology of Eosinophilic Esophagitis: A Systematic Review. AB - Eosinophilic esophagitis (EoE) is an emerging clinicopathologic entity defined by abnormal esophageal eosinophilic infiltration. Management of this disease is hampered by limited understanding of etiologic and controllable risk factors. The aim of this systematic review was to determine the environmental risk factors for EoE. We searched the PubMed, Web of Science, and EMBASE databases from January 1, 1950, through June 30, 2015. To identify additional relevant studies, we hand searched bibliographies of included articles. We limited the review to articles using human subjects and consisting of case reports, case series, cross-sectional and cohort studies, and clinical trials. Nineteen articles discuss the risk of environmental exposures on EoE and indicate that environment plays a large role in the etiology of EoE. Seasonal, geographic, and climate-based differences in disease prevalence have been reported, but the exact mediators of this process, possibly aeroallergens that vary over time and from place to place, remain elusive. PMID- 26434966 TI - Food Allergy: Common Causes, Diagnosis, and Treatment. AB - Food allergy is a growing concern, and recognition of symptoms, knowledge of common food allergens, and management of reactions are important for patients and practitioners. Symptoms of a classic IgE-mediated food allergy vary in severity and can include any combination of laryngeal edema, wheezing, nausea, vomiting, diarrhea, urticaria, angioedema, and hypotension. Many foods can induce an allergic reaction, but the most commonly implicated foods include cow's milk, egg, peanut, tree nut, soy, wheat, fish, and shellfish. Milk and egg allergy generally develop and are outgrown in childhood. Peanut and tree nut allergy can occur during childhood or adulthood, are less likely to be outgrown, and tend to cause more fatal reactions. Given the possibility of life-threatening reactions, it is important to recognize the potential for cross-reactivity among food groups. Diagnosis of food allergy includes skin prick testing, specific serum IgE testing, and oral food challenges. Management is centered on avoidance of allergenic and cross-reacting foods and early recognition and immediate treatment of reactions. Treatment protocols to desensitize patients to food are currently under investigation. PMID- 26434967 TI - 50-Year-Old Man With New-Onset Acute Kidney Injury. PMID- 26434968 TI - Cancer Pain Management. AB - Safe, effective, and evidence-based management of cancer-related pain is a cornerstone of comprehensive cancer care. Despite increasing interest in and efforts to improve its management, pain remains poorly controlled in nearly half of all patients with cancer, with little change in the past 20 years. Limited training in pain assessment and management, overestimation of providers' own skills to treat pain, and failure to refer patients to pain specialists can result in suboptimal pain management with devastating effects on quality of life, physical functioning, and increased psychological distress. From a thorough assessment of cancer-related pain to appropriate treatments that may include opiates, adjuvant medications, nerve blocks, and nondrug interventions, this article is intended as a brief overview of the mechanisms and types of pain as well as a review of current, new, and promising approaches to its management. PMID- 26434970 TI - Teachable Action for Leaders Committed to Improving Physician Work Life: Continuing Education. PMID- 26434971 TI - Vinpocetine: An Unapproved Drug Sold as a Dietary Supplement. PMID- 26434969 TI - Diagnosis and Treatment of Chronic Myeloid Leukemia in 2015. AB - Few neoplastic diseases have undergone a transformation in a relatively short period like chronic myeloid leukemia (CML) has in the last few years. In 1960, CML was the first cancer in which a unique chromosomal abnormality was identified and a pathophysiologic correlation suggested. Landmark work followed, recognizing the underlying translocation between chromosomes 9 and 22 that gave rise to this abnormality and, shortly afterward, the specific genes involved and the pathophysiologic implications of this novel rearrangement. Fast forward a few years and this knowledge has given us the most remarkable example of a specific therapy that targets the dysregulated kinase activity represented by this molecular change. The broad use of tyrosine kinase inhibitors has resulted in an improvement in the overall survival to the point where the life expectancy of patients today is nearly equal to that of the general population. Still, there are challenges and unanswered questions that define the reasons why the progress still escapes many patients, and the details that separate patients from ultimate cure. In this article, we review our current understanding of CML in 2015, present recommendations for optimal management, and discuss the unanswered questions and what could be done to answer them in the near future. PMID- 26434972 TI - Nonictal Near Sudden Unexpected Death in Epilepsy. PMID- 26434973 TI - Iron-Deficiency Anemia With an Itch. PMID- 26434974 TI - 63-Year-Old Woman With Generalized Fatigue and Left Flank Pain. PMID- 26434975 TI - Ernesto "Che" Guevara de la Serna: Argentinian Marxist Revolutionary. PMID- 26434978 TI - Porphyrin Metalation at the MgO Nanocube/Toluene Interface. AB - Molecular insights into porphyrin adsorption on nanostructured metal oxide surfaces and associated ion exchange reactions are key to the development of functional hybrids for energy conversion, sensing, and light emission devices. Here we investigated the adsorption of tetraphenyl-porphyrin (2HTPP) from toluene solution on two types of MgO powder. We compare MgO nanocubes with an average size d < 10 nm and MgO cubes with 10 nm <= d <= 1000 nm. Using molecular spectroscopy techniques such as UV/vis transmission and diffuse reflectance (DR), photoluminescence (PL), and diffuse reflectance infrared Fourier-transform (DRIFT) spectroscopy in combination with structural characterization techniques (powder X-ray diffraction and transmission electron microscopy, TEM), we identified a new room temperature metalation reaction that converts 2HTPP into magnesium tetraphenyl-porphyrin (MgTPP). Mg(2+) uptake from the MgO nanocube surfaces and the concomitant protonation of the oxide surface level off at a concentration that corresponds to roughly one monolayer equivalent adsorbed on the MgO nanocubes. Larger MgO cubes, in contrast, show suppressed exchange, and only traces of MgTPP can be detected by photoluminescence. PMID- 26434979 TI - Investigation and Sensory Characterization of 1,4-Cineole: A Potential Aromatic Marker of Australian Cabernet Sauvignon Wine. AB - This work reports the quantitation and sensory characterization of 1,4-cineole in red wine for the first time. A headspace-solid-phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) method was developed to quantitate 1,4-cineole and 1,8-cineole in 104 commercial Australian red wines. 1,4-Cineole was detected in all of the wines analyzed, with concentrations ranging from 0.023 to 1.6 MUg/L. An important varietal effect was observed, with concentrations of 1,4-cineole in Cabernet Sauvignon wines (mean of 0.6 +/- 0.3 MUg/L) significantly higher than in Shiraz (0.07 +/- 0.04 MUg/L) and Pinot Noir (0.2 +/- 0.2 MUg/L) wines. Regional variations of both cineole isomer concentrations have been measured between wines originating from different Australian regions. Sensory studies demonstrated that the addition of 0.54 MUg/L 1,4-cineole in a Cabernet Sauvignon wine, to produce a final concentration of 0.63 MUg/L, was perceived significantly by a sensory panel (p < 0.05). Descriptive analyses revealed that 1,4-cineole and 1,8-cineole may contribute to the hay, dried herbs, and blackcurrant aromas reported in Australian Cabernet Sauvignon wines and may be potential markers of regional typicality of these wines. PMID- 26434980 TI - Colorimetric Signal Amplification Assay for Mercury Ions Based on the Catalysis of Gold Amalgam. AB - Mercury is a major threat to the environment and to human health. It is highly desirable to develop a user-friendly kit for on-site mercury detection. Such a method must be able to detect mercury below the threshold levels (10 nM) for drinking water defined by the U.S. Environmental Protection Agency. Herein, we for the first time reported catalytically active gold amalgam-based reaction between 4-nitrophenol and NaBH4 with colorimetric sensing function. We take advantage of the correlation between the catalytic properties and the surface area of gold amalgam, which is proportional to the amount of the gold nanoparticle (AuNP)-bound Hg(2+). As the concentration of Hg(2+) increases until the saturation of Hg onto the AuNPs, the catalytic performance of the gold amalgam is much stronger due to the formation of gold amalgam and the increase of the nanoparticle surface area, leading to the decrease of the reduction time of 4 nitrophenol for the color change. This sensing system exhibits excellent selectivity and ultrahigh sensitivity up to the 1.45 nM detection limit. The practical use of this system for Hg(2+) determination in tap water samples is also demonstrated successfully. PMID- 26434977 TI - Synthetic and Biological Studies of Sesquiterpene Polygodial: Activity of 9 Epipolygodial against Drug-Resistant Cancer Cells. AB - Polygodial, a terpenoid dialdehyde isolated from Polygonum hydropiper L., is a known agonist of the transient receptor potential vanilloid 1 (TRPV1). In this investigation a series of polygodial analogues were prepared and investigated for TRPV1-agonist and anticancer activities. These experiments led to the identification of 9-epipolygodial, which has antiproliferative potency significantly exceeding that of polygodial. 9-Epipolygodial was found to maintain potency against apoptosis-resistant cancer cells as well as those displaying the multidrug-resistant (MDR) phenotype. In addition, the chemical feasibility for the previously proposed mechanism of action of polygodial, involving the formation of a Paal-Knorr pyrrole with a lysine residue on the target protein, was demonstrated by the synthesis of a stable polygodial pyrrole derivative. These studies reveal rich chemical and biological properties associated with polygodial and its direct derivatives. These compounds should inspire further work in this area aimed at the development of new pharmacological agents, or the exploration of novel mechanisms of covalent modification of biological molecules with natural products. PMID- 26434981 TI - Peptide-Conjugated Gold Nanoprobe: Intrinsic Nanozyme-Linked Immunsorbant Assay of Integrin Expression Level on Cell Membrane. AB - Precisely quantifying the membrane protein expression level on cell surfaces is of vital importance for early cancer diagnosis and efficient treatment. We demonstrate that gold nanoparticle bioconjugated by a rationally designed peptide as nanoprobe possesses selective labeling and accurate quantification capacity of integrin GPIIb/IIIa on the human erythroleukemia cell line. Through selective recognition and marking of integrin, two-photon photoluminescence of the nanoprobe is exploited for direct observation of protein spatial distribution on cell membrane. More importantly, utilizing intrinsic enzyme-like catalysis property of the nanoprobe, the expression level of integrin on human erythroleukemia cells can be quantitatively counted in an amplified and reliable colorimetric assay without cell lysis and protein extraction process. In addition, the analysis of the correlation between the gold nanoparticle and the membrane protein via relevant inductively coupled plasma mass spectrometry measurement verifies the reliability of the new analytical method. It is anticipated that this facile and efficient strategy holds a great promise for a rapid, precise, and reliable quantification of interested functional membrane proteins on the cell surface. PMID- 26434983 TI - The SR/ER-mitochondria calcium crosstalk is regulated by GSK3beta during reperfusion injury. PMID- 26434984 TI - Semiconductor-Insulator-Semiconductor Diode Consisting of Monolayer MoS2, h-BN, and GaN Heterostructure. AB - We propose a semiconductor-insulator-semiconductor (SIS) heterojunction diode consisting of monolayer (1-L) MoS2, hexagonal boron nitride (h-BN), and epitaxial p-GaN that can be applied to high-performance nanoscale optoelectronics. The layered materials of 1-L MoS2 and h-BN, grown by chemical vapor deposition, were vertically stacked by a wet-transfer method on a p-GaN layer. The final structure was verified by confocal photoluminescence and Raman spectroscopy. Current voltage (I-V) measurements were conducted to compare the device performance with that of a more classical p-n structure. In both structures (the p-n and SIS heterojunction diode), clear current-rectifying characteristics were observed. In particular, a current and threshold voltage were obtained for the SIS structure that was higher compared to that of the p-n structure. This indicated that tunneling is the predominant carrier transport mechanism. In addition, the photoresponse of the SIS structure induced by the illumination of visible light was observed by photocurrent measurements. PMID- 26434982 TI - Age-associated inflammation connects RAS-induced senescence to stem cell dysfunction and epidermal malignancy. AB - Aging is the single biggest risk factor for malignant transformation. Among the most common age-associated malignancies are non-melanoma skin cancers, comprising the most common types of human cancer. Here we show that mutant H-Ras activation in mouse epidermis, a frequent event in cutaneous squamous cell carcinoma (SCC), elicits a differential outcome in aged versus young mice. Whereas H-Ras activation in the young skin results in hyperplasia that is mainly accompanied by rapid hair growth, H-Ras activation in the aged skin results in more dysplasia and gradual progression to in situ SCC. Progression is associated with increased inflammation, pronounced accumulation of immune cells including T cells, macrophages and mast cells as well as excessive cell senescence. We found not only an age-dependent increase in expression of several pro-inflammatory mediators, but also activation of a strong anti-inflammatory response involving enhanced IL4/IL10 expression and immune skewing toward a Th2 response. In addition, we observed an age-dependent increase in the expression of Pdl1, encoding an immune suppressive ligand that promotes cancer immune evasion. Moreover, upon switching off oncogenic H-Ras activity, young but not aged skin regenerates successfully, suggesting a failure of the aged epidermal stem cells to repair damaged tissue. Our findings support an age-dependent link between accumulation of senescent cells, immune infiltration and cancer progression, which may contribute to the increased cancer risk associated with old age. PMID- 26434985 TI - The relationship between specific cognitive defects and burden of care in Parkinson's disease. AB - BACKGROUND: In spite of the recognized physical and psychosocial effects of caring for patients with Parkinson's disease (PD), caregiver burden (CB) in this setting is poorly understood. The objective of this research was to identify factors that were associated with CB in an Australian population of PD caregivers using a novel instrument - the Parkinson's Disease Caregiver Burden (PDCB) questionnaire. METHODS: Fifty patient-caregiver couples were recruited from three movement disorders clinics in Melbourne, Australia. Burden on caregivers was rated using the PDCB questionnaire. Burden scores were correlated with patient factors, including motor symptom severity (Unified Parkinson's Disease Ratings Scale and Hoehn & Yahr (H&Y) scale), patient cognition (Neuropsychiatry Unit Cognitive Assessment Tool; NUCOG), presence of impulsive and compulsive behaviors (Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease), and patient olfaction. Caregiver and patient demographics, as well as results for depression and anxiety (Hospital Anxiety and Depression Scale; HADS), were also examined for their relationship with CB. RESULTS: H&Y stage, depression or anxiety in either caregiver or patient, and decreased patient NUCOG score were significantly associated with higher PDCB score. Multiple linear regression analysis identified caregiver and patient depression score and patient score for the visuoconstructional subscale of NUCOG to predict burden score. In addition, disease duration, duration of caregiving, and increased hours per day spent in giving care were significantly associated with increased burden. CONCLUSIONS: We found psychiatric and cognitive factors to be the most relevant factors in the perception of burden in PD caregivers. On top of this, we found deficits in the domain of visuoconstruction predicted burden - a relationship not yet described in literature. Targeting depression and anxiety in this setting as well as identifying caregivers at high risk of burden may give clinicians the chance to optimize care of patients with PD through the caregiver. PMID- 26434986 TI - Should an intercalated degree be compulsory for undergraduate medical students? AB - Undertaking an intercalated year whilst at medical school involves taking time out of the medicine undergraduate programme in order to pursue a separate but related degree. It is widely seen as a challenging but rewarding experience, with much to be gained from the independent project or research component of most additional degrees. However, whilst intercalating is encouraged at many universities and is incorporated into some undergraduate curricula, it is by no means compulsory for all students. The literature would suggest that those who have intercalated tend to do better academically, both for the remainder of medical school and after graduating. Despite this, the issue of making intercalation mandatory is one of considerable debate, with counter-arguments ranging from the detrimental effect time taken out of the course can have to the lack of options available to cater for all students. Nonetheless, the research skills developed during an intercalated year are invaluable and help students prepare for taking a critical evidence-based approach to medicine. If intercalated degrees were made compulsory for undergraduates, it would be a step in the right direction. It would mean the doctors of tomorrow would be better equipped to practise medicine in disciplines that are constantly evolving. PMID- 26434987 TI - Prediction of drug's Anatomical Therapeutic Chemical (ATC) code by integrating drug-domain network. AB - Predicting Anatomical Therapeutic Chemical (ATC) code of drugs is of vital importance for drug classification and repositioning. Discovering new association information related to drugs and ATC codes is still difficult for this topic. We propose a novel method named drug-domain hybrid (dD-Hybrid) incorporating drug domain interaction network information into prediction models to predict drug's ATC codes. It is based on the assumption that drugs interacting with the same domain tend to share therapeutic effects. The results demonstrated dD-Hybrid has comparable performance to other methods on the gold standard dataset. Further, several new predicted drug-ATC pairs have been verified by experiments, which offer a novel way to utilize drugs for new purposes effectively. PMID- 26434989 TI - [Migraine]. PMID- 26434988 TI - Role of Vasodilator Testing in Pulmonary Hypertension. AB - Pulmonary hypertension is clinically defined by a mean pulmonary artery (PA) pressure of 25mm Hg or more at rest, as measured by right heart catheterization. To identify patients who are likely to have a beneficial response to calcium channel blockers (CCBs) and therefore a better prognosis, acute vasodilator testing should be performed in patients in certain subsets of pulmonary arterial hypertension (PAH). A near normalization of pulmonary hemodynamics is needed before patients can be considered for therapy with CCBs. Intravenous adenosine, intravenous epoprostenol, inhaled nitric oxide, or inhaled iloprost are the standard agents used for vasoreactivity testing in patients with idiopathic PAH. In this review we describe the various aspects of vasodilator testing including the rationale, pathophysiology and agents used in the procedure. PMID- 26434990 TI - [Acute kidney injury in paracetamol poisoning]. PMID- 26434991 TI - [Diagnosis of nodular thyroid disease: An update]. PMID- 26434992 TI - [Systemic lupus erythematosus today]. PMID- 26434993 TI - Association of early and late maternal smoking during pregnancy with offspring body mass index at 4 to 5 years of age. AB - The objective was to investigate the association between early and late maternal smoking during pregnancy on offspring body mass index (BMI). We undertook a retrospective cohort study using linked records from the Women's and Children's Health Network in South Australia. Among a cohort of women delivering a singleton, live-born infants between January 2000 and December 2005 (n=7658), 5961 reported not smoking during pregnancy, 297 reported quitting smoking during the first trimester of pregnancy, and 1400 reported continued smoking throughout pregnancy. Trained nurses measured the height and weight of the children at preschool visits in a state-wide surveillance programme. The main outcome measure was age- and sex-specific BMI z-score. At 4 to 5 years, mean (s.d.) BMI z-score was 0.40 (1.05), 0.60 (1.07) and 0.65 (1.18) in children of mothers who reported never smoking, quitting smoking and continued smoking during pregnancy, respectively. Compared with the group of non-smokers, both quitting smoking and continued smoking were associated with an increase in child BMI z-score of 0.15 (95% confidence interval: 0.01-0.29) and 0.21 (0.13-0.29), respectively. A significant dose-response relationship was also observed between the number of cigarettes smoked per day on average during the second half of pregnancy and the increase in offspring BMI z-score (P<0.001). In conclusion, any maternal smoking in pregnancy, even if mothers quit, is associated with an increase in offspring BMI at 4 to 5 years of age. PMID- 26434994 TI - Nck1 deficiency improves pancreatic beta cell survival to diabetes-relevant stresses by modulating PERK activation and signaling. AB - Increasing evidence strongly supports a critical role for PERK in regulating pancreatic beta cell function. In agreement, we previously reported that enhancing PERK basal activity, by silencing the SH domain-containing adaptor protein Nck1 in pancreatic beta cells, increased insulin content in a PERK dependent manner. Here we report that Nck1-deficient MIN6 cells display normal overall morphology while as expected increased number of secretory granules. Furthermore, we demonstrate that cell survival to diabetes-relevant stresses is increased, while cell viability in response to chemical endoplasmic reticulum (ER) stress inducers is not changed. In agreement, PERK activation in Nck1 depleted MIN6 cells exposed to palmitate was significantly reduced while it remained strongly induced by the ER stress inducer thapsigargin. Interestingly, silencing Nck1 in MIN6 cells results in increased PERK basal activity and expression of the PERK downstream target sestrin2, which promotes autophagy by attenuating mTORC1 activation through AMPK-dependent and -independent mechanisms. Accordingly, activated AMPK was increased, mTORC1 signaling decreased, and autophagy markers increased in Nck1-silenced MIN6 cells. Increased autophagy was recapitulated in Nck1(-/-) mice pancreatic beta cells. In addition, basal levels of the PERK substrate Nrf2 and its antioxidant gene targets (HO-1 and Nqo1) were upregulated in Nck1-silenced MIN6 cells, revealing an active PERK-Nrf2 signaling in these cells. Finally, Akt activation was increased in Nck1-silenced MIN6 cells. Altogether, this study demonstrates that Nck1 silencing in pancreatic beta cells promotes PERK activation and signaling to protect beta cells against pathological stresses. These findings further provide new perspectives to advance our understanding of molecular mechanisms and signaling systems regulating pancreatic beta cell fates. PMID- 26434996 TI - Dual regulation of energy metabolism by p53 in human cervix and breast cancer cells. AB - The role of p53 as modulator of OxPhos and glycolysis was analyzed in HeLa-L (cells containing negligible p53 protein levels) and HeLa-H (p53-overexpressing) human cervix cancer cells under normoxia and hypoxia. In normoxia, functional p53, mitochondrial enzyme contents, mitochondrial electrical potential (DeltaPsim) and OxPhos flux increased in HeLa-H vs. HeLa-L cells; whereas their glycolytic enzyme contents and glycolysis flux were unchanged. OxPhos provided more than 70% of the cellular ATP and proliferation was abolished by anti mitochondrial drugs in HeLa-H cells. In hypoxia, both cell proliferations were suppressed, but HeLa-H cells exhibited a significant decrease in OxPhos protein contents, DeltaPsim and OxPhos flux. Although glycolytic function was also diminished vs. HeLa-L cells in hypoxia, glycolysis provided more than 60% of cellular ATP in HeLa-H cells. The energy metabolism phenotype of HeLa-H cells was reverted to that of HeLa-L cells by incubating with pifithrin-alpha, a p53 inhibitor. In normoxia, the energy metabolism phenotype of breast cancer MCF-7 cells was similar to that of HeLa-H cells, whereas p53shRNAMCF-7 cells resembled the HeLa-L cell phenotype. In hypoxia, autophagy proteins and lysosomes contents increased 2-5 times in HeLa-H cells suggesting mitophagy activation. These results indicated that under normoxia p53 up-regulated OxPhos without affecting glycolysis, whereas under hypoxia, p53 down-regulated both OxPhos (severely) and glycolysis (weakly). These p53 effects appeared mediated by the formation of p53 HIF-1alpha complexes. Therefore, p53 exerts a dual and contrasting regulatory role on cancer energy metabolism, depending on the O2level. PMID- 26434995 TI - Towards the molecular mechanism of the integration of peroxisomal membrane proteins. AB - The correct topogenesis of peroxisomal membrane proteins is a crucial step for the formation of functioning peroxisomes. Although this process has been widely studied, the exact mechanism with which it occurs has not yet been fully characterized. Nevertheless, it is generally accepted that peroxisomes employ three proteins - Pex3, Pex19 and Pex16 in mammals - for the insertion of peroxisomal membrane proteins into the peroxisomal membrane. Structural biology approaches have been utilized for the elucidation of the mechanistic questions of peroxisome biogenesis, mainly by providing information on the architecture of the proteins significant for this process. This review aims to summarize, compare and put into perspective the structural knowledge that has been generated mainly for Pex3 and Pex19 and their interaction partners in recent years. PMID- 26434997 TI - Peroxisome homeostasis: Mechanisms of division and selective degradation of peroxisomes in mammals. AB - Peroxisome number and quality are maintained by its biogenesis and turnover and are important for the homeostasis of peroxisomes. Peroxisomes are increased in number by division with dynamic morphological changes including elongation, constriction, and fission. In the course of peroxisomal division, peroxisomal morphogenesis is orchestrated by Pex11beta, dynamin-like protein 1 (DLP1), and mitochondrial fission factor (Mff). Conversely, peroxisome number is reduced by its degradation. Peroxisomes are mainly degraded by pexophagy, a type of autophagy specific for peroxisomes. Upon pexophagy, an adaptor protein translocates on peroxisomal membrane and connects peroxisomes to autophagic machineries. Molecular mechanisms of pexophagy are well studied in yeast systems where several specific adaptor proteins are identified. Pexophagy in mammals also proceeds in a manner dependent on adaptor proteins. In this review, we address the recent progress in studies on peroxisome morphogenesis and pexophagy. PMID- 26434998 TI - The risks and benefits of disclosing psychotherapy records to the legal system: What psychologists and patients need to know for informed consent. AB - When psychologists release patient records to the legal system, the typical practice is to obtain the patient's signature on a consent form, but rarely is a formal informed-consent obtained from the patient. Although psychologists are legally and ethically required to obtain informed consent for all services (including disclosure of records), there are a number of barriers to obtaining truly informed consent. Furthermore, compared to disclosures to nonlegal third parties, there are significantly greater risks when records are disclosed to the legal system. For these reasons, true informed consent should be obtained from the patient when records are disclosed to the legal system. A model for informed consent is proposed. This procedure should include a description of risks and benefits of disclosing or refusing to disclose by the psychotherapist, an opportunity to ask questions, and indication by the patient of a freely made choice. Both psychotherapist and patient share decision making responsibilities in our suggested model. The patient should be informed about potential harm to the therapeutic relationship, if applicable. Several recommendations for practice are described, including appropriate communications with attorneys and the legal system. A sample form, for use by psychotherapists, is included. PMID- 26434999 TI - Development and in vitro assessment of alginate bilayer films containing the olive compound hydroxytyrosol as an alternative for topical chemotherapy. AB - Topical chemotherapy is the application of cancer drugs directly onto the skin, which has become a standard treatment for basal cell carcinoma. Due to the promising results in the treatment of skin cancer, topical chemotherapy has recently been applied to breast cancer patients because some breast cancer tissues are only superficial. Hydroxytyrosol, a phenolic compound from olives that is present in high amounts in Hidrox((r)) olive extract, has been shown to have a protective effect on normal cells and selective antitumor activities on cancerous cells. The aims of the present study were to develop an alginate bilayer film containing Hidrox((r)) and to investigate its potential use as a topical chemotherapeutic agent. Alginate films were characterized for swelling and for physical, thermal, rheological, and mechanical properties. Drug content uniformity and in vitro drug release tests were also investigated. The alginate bilayer films containing Hidrox((r)), HB2, showed controlled release of hydroxytyrosol at a flux of 0.094+/-0.009 mg/cm(2)/h. The results of the cytotoxic assay showed that the HB2 films were dose-dependent and could significantly reduce the growth of breast cancer cells (MCF-7) at 150 MUg/mL for a cell viability of 29.34+/-4.64%. In conclusion, an alginate bilayer film containing Hidrox((r)) can be a potential alternative for topical chemotherapeutic agent for skin and breast cancer treatment. PMID- 26435000 TI - Chlorpyrifos induces NLRP3 inflammasome and pyroptosis/apoptosis via mitochondrial oxidative stress in human keratinocyte HaCaT cells. AB - Chlorpyrifos (CPF) has been widely used around the world as a pesticide for both agricultural and residential application. Although various studies have reported toxicity and health-related effects from CPF exposure, the molecular mechanism of CPF toxicity to skin has not been well-characterized. The present study determined the potential mechanism involved in skin toxicity of CPF using the HaCaT human skin keratinocyte cell line. After treating to HaCaT cells, CPF triggered reactive oxygen species (ROS) generation and mitochondrial oxidative stress. We focused on NLRP3 inflammasome, known to induce innate immune response. We used mitochondrial ROS (mROS) scavenger mitoTEMPO to demonstrate a role for mROS in NLRP3 inflammasome and programmed cell death induced by CPF. Our results showed that CPF provoked NLRP3 inflammasome and pyroptosis/apoptosis via an increase of mROS in HaCaT cells. This study proposes that CPF induces innate immune response and skin inflammation through activating the NLRP3 inflammasome in skin epithelial cells. CPF may lead to cutaneous disease conditions and antioxidants could be proposed for therapy against skin exposure to CPF. PMID- 26435001 TI - Bisphenol AF stimulates transcription and secretion of C-X-C chemokine ligand 12 to promote proliferation of cultured T47D breast cancer cells. AB - Bisphenol AF (4,4'-hexafluoroisopropylidene-2-diphenol, BPAF), an endocrine disruptor, has been shown to stimulate the proliferation of human breast cancer cells. However, the underlying mechanism has not been fully elucidated. We found that BPAF promoted the in vitro proliferation of estrogen receptor alpha (ERalpha)-positive breast cancer cells (T47D and MCF7), but not ERalpha-negative cells (MDA-MB-231 and MDA-MB-435s). BPAF significantly stimulated the proliferation of cultured T47D cell in a dose-dependent manner, and the half maximal effective concentration (EC50) was approximately 123 nM. We employed lentivirus-mediated short hairpin RNA (shRNA) to knockdown ERalpha and ER antagonist ICI 182780 to inhibit ER activation, which resulted in the repression of BPAF-induced proliferation of T47D and MCF7 cells. We observed that C-X-C chemokine ligand 12 (CXCL12) was up-regulated in T47D cells under treatment with BPAF. Quantitative real-time PCR results showed that BPAF caused a time and dose dependent increase in mRNA level of CXCL12. Furthermore, treatment of T47D cells with BPAF increased CXCL12 secretion according to ELISA assay. BPAF-induced CXCL12 transcription and secretion was significantly attenuated by small interfering RNA (siRNA) targeting ERalpha and ICI 182780, indicating BPAF-induced CXCL12 expression is mediated through ERalpha. Notably, knockdown CXCL12 in T47D cells significantly attenuated BPAF-induced cell proliferation. We also observed that inhibition of CXCL12 binding to its receptors CXCR4 and CXCR7 by chalcone 4 blocked BPAF-induced cell growth. Our results indicated that CXCL12 facilitated BPAF-induced proliferation of T47D cells. Taken together, our data provided support that BPAF stimulated transcription and secretion of CXCL12 depending on ERalpha, and ERalpha/CXCL12 signaling positively regulated BPAF-induced proliferation of cultured T47D breast cancer cells. PMID- 26435002 TI - Horizontal gene transfer of a Chlamydial tRNA-guanine transglycosylase gene to eukaryotic microbes. AB - tRNA-guanine transglycosylases are found in all domains of life and mediate the base exchange of guanine with queuine in the anticodon loop of tRNAs. They can also regulate virulence in bacteria such as Shigella flexneri, which has prompted the development of drugs that inhibit the function of these enzymes. Here we report a group of tRNA-guanine transglycosylases in eukaryotic microbes (algae and protozoa) which are more similar to their bacterial counterparts than previously characterized eukaryotic tRNA-guanine transglycosylases. We provide evidence demonstrating that the genes encoding these enzymes were acquired by these eukaryotic lineages via horizontal gene transfer from the Chlamydiae group of bacteria. Given that the S. flexneri tRNA-guanine transglycosylase can be targeted by drugs, we propose that the bacterial-like tRNA-guanine transglycosylases could potentially be targeted in a similar fashion in pathogenic amoebae that possess these enzymes such as Acanthamoeba castellanii. This work also presents ancient prokaryote-to-eukaryote horizontal gene transfer events as an untapped resource of potential drug target identification in pathogenic eukaryotes. PMID- 26435003 TI - Molecular phylogeny reveals genital convergences and reversals in the barklouse genus Trichadenotecnum (Insecta: Psocodea: 'Psocoptera': Psocidae). AB - Trichadenotecnum is one of the most diverse genera among the non-parasitic members of Psocodea (Insecta: "Psocoptera"). The genus shows a world-wide distribution (excluding the Australian Region, where only one introduced species is known) with its center of diversity in southern to eastern Asia. Several species groups had been proposed for this large genus based on morphology, but their validity and phylogenetic relationships are still unclear because of great morphological diversity in the genitalia, systematically the most relevant character. In this study, we estimated the molecular phylogeny of the Old World species of Trichadenotecnum based on extensive taxon sampling. As a result, the monophyly of morphology-based species groups was very strongly supported in most cases. However, two groups were recovered as non-monophyletic, which had been inadequately defined on the basis of plesiomorphies or convergences of genital characters. First, the monophyly of the sexpunctatum group was not supported because the medium group was found to be embedded within this group. The simpler genitalia observed in the medium group were considered to be derived from the more complicated genitalia present in the sexpunctatum group. Second, the monophyly of the majus group was not supported for two reasons: (1) It was divided into two distant clades which initially had been united on the basis of convergent similarities of the male genitalia. (2) Two species groups were revealed to be embedded within the main clade of the majus group; the initial separation of these groups had been based on reversals to the ancestral genital condition. PMID- 26435005 TI - Clinical characteristics and genotype-phenotype correlations in C3 deficiency. PMID- 26435006 TI - Menopause as a predictor of new-onset asthma: A longitudinal Northern European population study. AB - BACKGROUND: There is limited and conflicting evidence on the effect of menopause on asthma. OBJECTIVES: We sought to study whether the incidence of asthma and respiratory symptoms differ by menopausal status in a longitudinal population based study with an average follow-up of 12 years. METHODS: The Respiratory Health in Northern Europe study provided questionnaire data pertaining to respiratory and reproductive health at baseline (1999-2001) and follow-up (2010 2012). The study cohort included women aged 45 to 65 years at follow-up, without asthma at baseline, and not using exogenous hormones (n = 2322). Menopausal status was defined as nonmenopausal, transitional, early postmenopausal, and late postmenopausal. Associations with asthma (defined by the use of asthma medication, having asthma attacks, or both) and respiratory symptoms scores were analyzed by using logistic (asthma) and negative binomial (respiratory symptoms) regressions, adjusting for age, body mass index, physical activity, smoking, education, and study center. RESULTS: The odds of new-onset asthma were increased in women who were transitional (odds ratio, 2.40; 95% CI, 1.09-5.30), early postmenopausal (odds ratio, 2.11; 95% CI, 1.06-4.20), and late postmenopausal (odds ratio, 3.44; 95% CI, 1.31-9.05) at follow-up compared with nonmenopausal women. The risk of respiratory symptoms increased in early postmenopausal (coefficient, 0.40; 95% CI, 0.06-0.75) and late postmenopausal (coefficient, 0.69; 95% CI, 0.15-1.23) women. These findings were consistent irrespective of smoking status and across study centers. CONCLUSIONS: New-onset asthma and respiratory symptoms increased in women becoming postmenopausal in a longitudinal population-based study. Clinicians should be aware that respiratory health might deteriorate in women during reproductive aging. PMID- 26435004 TI - Protein disulfide isomerase-endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness. AB - BACKGROUND: Evidence for association between asthma and the unfolded protein response is emerging. Endoplasmic reticulum resident protein 57 (ERp57) is an endoplasmic reticulum-localized redox chaperone involved in folding and secretion of glycoproteins. We have previously demonstrated that ERp57 is upregulated in allergen-challenged human and murine lung epithelial cells. However, the role of ERp57 in asthma pathophysiology is unknown. OBJECTIVES: Here we sought to examine the contribution of airway epithelium-specific ERp57 in the pathogenesis of allergic asthma. METHODS: We examined the expression of ERp57 in human asthmatic airway epithelium and used murine models of allergic asthma to evaluate the relevance of epithelium-specific ERp57. RESULTS: Lung biopsy specimens from asthmatic and nonasthmatic patients revealed a predominant increase in ERp57 levels in epithelium of asthmatic patients. Deletion of ERp57 resulted in a significant decrease in inflammatory cell counts and airways resistance in a murine model of allergic asthma. Furthermore, we observed that disulfide bridges in eotaxin, epidermal growth factor, and periostin were also decreased in the lungs of house dust mite-challenged ERp57-deleted mice. Fibrotic markers, such as collagen and alpha smooth muscle actin, were also significantly decreased in the lungs of ERp57-deleted mice. Furthermore, adaptive immune responses were dispensable for house dust mite-induced endoplasmic reticulum stress and airways fibrosis. CONCLUSIONS: Here we show that ERp57 levels are increased in the airway epithelium of asthmatic patients and in mice with allergic airways disease. The ERp57 level increase is associated with redox modification of proinflammatory, apoptotic, and fibrotic mediators and contributes to airways hyperresponsiveness. The strategies to inhibit ERp57 specifically within the airways epithelium might provide an opportunity to alleviate the allergic asthma phenotype. PMID- 26435008 TI - Recent advances in clay mineral-containing nanocomposite hydrogels. AB - Clay mineral-containing nanocomposite hydrogels have been proven to have exceptional composition, properties, and applications, and consequently have attracted a significant amount of research effort over the past few years. The objective of this paper is to summarize and evaluate scientific advances in clay mineral-containing nanocomposite hydrogels in terms of their specific preparation, formation mechanisms, properties, and applications, and to identify the prevailing challenges and future directions in the field. The state-of-the art of existing technologies and insights into the exfoliation of layered clay minerals, in particular montmorillonite and LAPONITE(r), are discussed first. The formation and structural characteristics of polymer/clay nanocomposite hydrogels made from in situ free radical polymerization, supramolecular assembly, and freezing-thawing cycles are then examined. Studies indicate that additional hydrogen bonding, electrostatic interactions, coordination bonds, hydrophobic interaction, and even covalent bonds could occur between the clay mineral nanoplatelets and polymer chains, thereby leading to the formation of unique three-dimensional networks. Accordingly, the hydrogels exhibit exceptional optical and mechanical properties, swelling-deswelling behavior, and stimuli responsiveness, reflecting the remarkable effects of clay minerals. With the pivotal roles of clay minerals in clay mineral-containing nanocomposite hydrogels, the nanocomposite hydrogels possess great potential as superabsorbents, drug vehicles, tissue scaffolds, wound dressing, and biosensors. Future studies should lay emphasis on the formation mechanisms with in-depth insights into interfacial interactions, the tactical functionalization of clay minerals and polymers for desired properties, and expanding of their applications. PMID- 26435007 TI - Women's work in farming, child feeding practices and nutritional status among under-five children in rural Rukwa, Tanzania. AB - Some progress has been achieved in reducing the prevalence of undernutrition among children under 5 years of age in Tanzania. In the Rukwa region (2010), the level of stunted and underweight children was 50.4 and 13.5 %, respectively. The aim of this study was to assess the nutritional status of children under 5 years of age, feeding practices and risk factors of undernutrition in a rural village in the Rukwa region, as well as to discuss the results in light of a similar study conducted in 1987/1988. This cross-sectional study was conducted in 152 households with children under 5 years of age. Data were obtained from the child's main caretaker and the household head, using a structured questionnaire and a 24 h dietary recall. Children's length/height and weight were measured. The prevalence of stunting and underweight was found to be 63.8 and 33.6 % (Z-score< 2 of WHO 2006 CGS), respectively. Sugar-water was given to 72.3 % of the children on the first day after birth. A thin gruel was introduced after a median of 2 months (25th-75th percentiles; 1-3). The time mothers spent farming was a significant risk factor for stunting (P=0.04). Illness, food shortage and dry season cultivation were significant risk factors for underweight (P<0.01). Using the NCHS/WHO 1983 growth reference (<75 % of the median), the prevalence of underweight was 25.0 %, similar to that reported in 1987/1988 (26.4 %). In conclusion, the underweight prevalence was found to be at the same level in 2010 as was recorded in 1987/1988. Current child-feeding practices were not in line with WHO recommendations. Women working in farms, food shortage, dry-season cultivation and diseases partly explain the children's poor nutritional status. PMID- 26435009 TI - Persistent alterations in active and passive electrical membrane properties of regenerated nerve fibers of man and mice. AB - Excitability of regenerated fibers remains impaired due to changes in both passive cable properties and alterations in the voltage-dependent membrane function. These abnormalities were studied by mathematical modeling in human regenerated nerves and experimental studies in mice. In three adult male patients with surgically repaired complete injuries of peripheral nerves of the arm 22 months-26 years prior to investigation, deviation of excitability measures was explained by a hyperpolarizing shift in the resting membrane potential and an increase in the passive 'Barrett and Barrett' conductance (GBB) bridging the nodal and internodal compartments. These changes were associated with an increase in the 'fast' K(+) conductance and the inward rectifier conductance (GH). Similar changes were found in regenerated mouse tibial motor axons at 1 month after a sciatic crush lesion. During the first 5 months of regeneration, GH showed partial recovery, which paralleled that in GBB. The internodal length remained one-third of normal. Excitability abnormalities could be reversed by the energy dependent Na(+)/K(+) pump blocker ouabain resulting in membrane depolarization. Stressing the Na(+) pumping system during a strenuous activity protocol triggered partial Wallerian degeneration in regenerated nerves but not in control nerves from age-matched mice. The current data suggest that the nodal voltage-gated ion channel machinery is restored in regenerated axons, although the electrical separation from the internodal compartment remains compromised. Due to the persistent increase in number of nodes, the increased activity-dependent Na(+) influx could lead to hyperactivity of the Na(+)/K(+) pump resulting in membrane hyperpolarization and neurotoxic energy insufficiency during strenuous activity. PMID- 26435010 TI - The electronic structures of group-V-group-IV hetero-bilayer structures: a first principles study. AB - Recent findings of group-V nanosheets provide new building units for van der Waals hetero-nanostructures. Based on first-principles calculation, we investigate the structural and electronic properties of bilayer hetero-sheets composed of group-V (arsenene/antimonene) and group-IV (graphene/silicene) layers. These hetero-sheets exhibit typical van der Waals features with small binding energies and soft interlayer elastic constants. In the hetero-sheets, the Dirac characteristics of the group-IV layer and the semiconducting feature of the group-V one are well preserved, which causes a Schottky contact at the metal semiconductor interface. The Schottky barriers are always p-type in the Si-based hetero-sheets, whereas in the C-based ones, the interfacial feature is sensitive to the interlayer distance. A tensile strain would induce a p-type-to-n-type Schottky barrier transition for the As-C hetero-sheet, while a compressive strain can cause a Schottky-to-ohmic contact transition in the Sb-C one. Moreover, due to the inhomogeneous charge redistribution, a sizeable band gap is opened at the Dirac point of the Sb-Si hetero-sheet, which could be linearly modulated by perpendicular strains around the equilibrium site. The versatile electronic structures and tunable interfacial properties enable the group-V-group-IV hetero bilayer structures to have many potential applications in nano-devices and nano electronics. PMID- 26435011 TI - Highly active self-immobilized FI-Zr catalysts in a PCP framework for ethylene polymerization. AB - A series of zirconium-based porous coordination polymers (PCPs) containing FI catalysts in the frameworks have been developed and studied as catalysts for ethylene polymerization. These PCPs exhibit good catalytic activities and long life times, producing polyethylenes with high molecular weights and bimodal molecular weight distribution in the form of particles. PMID- 26435014 TI - The perspective of caffeine and caffeine derived compounds in therapy. AB - Caffeine (1,3,7-trimethylxanthine) is a plant secondary metabolite with a significant impact on multiple processes and regulatory pathways in the body. Though major part of the population meets caffeine via coffee, tea or chocolate, it has also an important role in pharmacology and it is used as a supplementary substance in medicaments. Currently, the ability of caffeine to ameliorate some neurodegenerative disorders is proved in some studies. This review describes basic data about caffeine including toxicity, pharmacokinetics, biological mechanism of the action, and metabolism. Beside this, promising applications of caffeine, new medicaments and derivatives are discussed. Relevant papers and inventions are depicted in the manuscript. Caffeine is a pharmacologically promising substance that deserves big consideration in the current research and development. The compound has several reasons to be an object of scientific interest and to be used for pharmacology purposes. Despite an extensive research for a long time, no significantly negative effects on human health were proved hence caffeine can be considered as a completely safe compound. The recent data about amelioration of neurodegenerative and other disorders are promising and deserving more work on the issue. ARTICLE HIGHLIGHTS: Caffeine is a purine alkaloid from plants and it has a broad use in current pharmacology. Caffeine is a competitive antagonist of neurotransmitter adenosine on adenosine receptors. The substance is added as a supplementary to drugs and food.Besides interfering on adenosine receptors, caffeine interacts with acetylcholinesterase, monoamine oxidase, phosphodiesterase, ryanodine receptors and others.Current research is devoted to the role of caffeine in neurodegenerative diseases and immunity alteration. New chemical compounds based on caffeine moiety are prepared (Tab. 4, Fig. 6, Ref. 149). PMID- 26435015 TI - Physician-Pharmacist collaboration in a pay for performance healthcare environment. AB - Healthcare is becoming more complex and costly in both European (Slovak) and American models. Healthcare in the United States (U.S.) is undergoing a particularly dramatic change. Physician and hospital reimbursement are becoming less procedure focused and increasingly outcome focused. Efforts at Mercy Hospital have shown promise in terms of collaborative team based care improving performance on glucose control outcome metrics, linked to reimbursement. Our performance on the Centers for Medicare and Medicaid Services (CMS) post operative glucose control metric for cardiac surgery patients increased from a 63.6% pass rate to a 95.1% pass rate after implementing interventions involving physician-pharmacist team based care.Having a multidisciplinary team that is able to adapt quickly to changing expectations in the healthcare environment has aided our institution. As healthcare becomes increasingly saturated with technology, data and quality metrics, collaborative efforts resulting in increased quality and physician efficiency are desirable. CONCLUSION: Multidisciplinary collaboration (including physician-pharmacist collaboration) appears to be a viable route to improved performance in an outcome based healthcare system (Fig. 2, Ref. 12). PMID- 26435012 TI - EPA, not DHA, prevents fibrosis in pressure overload-induced heart failure: potential role of free fatty acid receptor 4. AB - Heart failure with preserved ejection fraction (HFpEF) is half of all HF, but standard HF therapies are ineffective. Diastolic dysfunction, often secondary to interstitial fibrosis, is common in HFpEF. Previously, we found that supra physiologic levels of omega3-PUFAs produced by 12 weeks of omega3-dietary supplementation prevented fibrosis and contractile dysfunction following pressure overload [transverse aortic constriction (TAC)], a model that resembles aspects of remodeling in HFpEF. This raised several questions regarding omega3 concentration-dependent cardioprotection, the specific role of EPA and DHA, and the relationship between prevention of fibrosis and contractile dysfunction. To achieve more clinically relevant omega3-levels and test individual omega3-PUFAs, we shortened the omega3-diet regimen and used EPA- and DHA-specific diets to examine remodeling following TAC. The shorter diet regimen produced omega3-PUFA levels closer to Western clinics. Further, EPA, but not DHA, prevented fibrosis following TAC. However, neither omega3-PUFA prevented contractile dysfunction, perhaps due to reduced uptake of omega3-PUFA. Interestingly, EPA did not accumulate in cardiac fibroblasts. However, FFA receptor 4, a G protein-coupled receptor for omega3-PUFAs, was sufficient and required to block transforming growth factor beta1-fibrotic signaling in cultured cardiac fibroblasts, suggesting a novel mechanism for EPA. In summary, EPA-mediated prevention of fibrosis could represent a novel therapy for HFpEF. PMID- 26435013 TI - Orienting Toward Face-Like Stimuli in Early Childhood. AB - Newborn infants orient preferentially toward face-like or "protoface" stimuli and recent studies suggest similar reflexive orienting responses in adults. Little is known, however, about the operation of this mechanism in childhood. An attentional-cueing procedure was therefore developed to investigate protoface orienting in early childhood. Consistent with the extant literature, 5- to 6-year old children (n = 25) exhibited orienting toward face-like stimuli; they responded faster when target location was cued by the appearance of a protoface stimulus than when location was cued by matched control patterns. The potential of this procedure to investigate the development of typical and atypical social perception is discussed. PMID- 26435016 TI - More risk factors generate lower mortality--a useful advice for improved health in the world. PMID- 26435017 TI - The use of antiplatelet medication in hospitalised elderly patients. AB - BACKGROUND: The use of antiplatelet agents is strongly recommended for the secondary prevention of ischemic events such as myocardial infarction, stroke/transient ischemic attack (TIA). OBJECTIVES: The aim of our study was to analyse the use of antiplatelet medication in patients after myocardial infarction, stroke/TIA, and patients with both conditions and to identify patient related characteristics, which determine the use of such drugs in elderly patients. METHODS: Study sample (n=372) was derived from 2,157 patients admitted to long-term care departments of three municipal hospitals. The study included patients aged >=65 years after myocardial infarction, stroke/TIA or both. RESULTS: Antiplatelet medications were prescribed in 54.8 % and 68.5 % of patients at hospital admission and discharge, respectively. Hospitalisation led to a significant increase in the use of antiplatelet medication in patients after myocardial infarction and in those with the combination of both events. However, in patients after only stroke/TIA, we did not find any significant difference comparing the use of antiplatelet medication at the time of hospital admission and discharge, respectively. CONCLUSION: Our study revealed that physicians are more aware of the benefits of antiplatelet medication in elderly patients after myocardial infarction or those after both myocardial infarction and stroke/TIA in comparison with patients after only stroke/TIA (Tab. 3, Ref. 32). PMID- 26435018 TI - Surgical treatment of hepatocellular carcinoma. AB - The incidence of hepatocellular carcinoma (HCC) in Europe and throughout the world is currently increasing. This is caused by an increase in the number of patients with alcoholic liver damage, metabolic syndrome, and by increasing incidence of hepatitis B and C.From January 1, 2004 to December 31, 2013, resection or radiofrequency ablation of the liver was done in 360 patients with benign lesions or malignant tumors of the liver. In 28 patients HCC was diagnosed and histologically confirmed (7.8 %). Seven patients had HCC associated with liver cirrhosis (25 %), and 21 patients were without histologically confirmed cirrhosis (75 %). R0 resection was done in 18 (64 %) patients.Surgical complications occurred in 6 (21 %) patients and reoperation due to tumor relapse or progression was done eight times in 6 (21 %) patients. One-year and five-year patients' survivals were 64 % and 10 %, repectively, and did not statistically differ from the survival of the whole set of patients with tumor diseases in the given time period. In the future it will be possible to improve the long-term survival of patients with HCC by using screening methods for presymptomatic diagnosis of HCC, precise preoperative diagnosis and efforts for R0 resection (Tab. 1, Fig. 4, Ref. 11). PMID- 26435019 TI - Preimplantation genetic diagnosis of X-linked diseases examined by indirect linkage analysis. AB - BACKGROUND: Many centers of assisted reproduction in the Czech Republic offer preimplantation genetic diagnosis with fluorescent in situ hybridization (FISH) to couples requiring preimplantation genetic diagnosis (PGD) of X-linked diseases. However, this process results in discarding all male embryos and is not able to distinguish a carrier or healthy female embryo in X-linked recessive disorders. OBJECTIVES: The main aim of this study was to summarize a six-year period of PGD of X-linked monogenic diseases using indirect linkage analysis. METHODS AND RESULTS: We wanted to accentuate the advantage indirect analysis of PGD using multiple displacement amplification (MDA) followed by short tandem repeat (STR) analysis. We present forty-six PGD cycles, including pre-case haplotyping (PGH) panel, for fifteen X-linked diseases. Embryo transfer was made thirty-eight times and gravidity was confirmed in thirteen female probands with a success rate of pregnancy calculated at 42 %. CONCLUSIONS: PGD procedure using MDA amplification followed by STR analysis provides help in identifying genetic defects within embryos prior to implantation. The reliability of the method was also supported by high pregnancy rate compared to other publications, which commonly achieved a 30-35 % success rate (Tab. 2, Fig. 1, Ref. 33). PMID- 26435020 TI - Petroselinum crispum extract attenuates hepatic steatosis in rats fed with fructose enriched diet. AB - Non alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and ongoing research efforts are focused on understanding the underlying pathophysiology of hepatic steatosis with the anticipation that these efforts will identify novel therapeutic targets. This study investigated the Petroselinum crispum extract in hepatic steatosis in rats fed with fructose enriched diet. Rats were divided into the 4 groups: Group 1 rats received standard pellet diet with corn starch for the entire experimental period of 8 weeks. Group 2 rats received standard pellet diet and 2 gm/kg body weight crude Parsley leaf ethanol extract for the entire experimental period of 8 weeks. Group 3 rats received modified fructose diet. Group 4 rats received modified fructose diet and 2gm/kg crude Parsley leaf ethanol extract. Hepatic function and structure was evaluated in these rats. Modified fructose diet produced dyslipidemia, hepatic steatosis and infiltration of inflammatory cells in the liver and higher plasma hepatic markers. Petroselinum crispum extract reversed metabolic changes such as abnormal crispum extract attenuated chronic changes in modified fructose diet induced NAFLD (Tab. 2, Fig. 3, Ref. 43). PMID- 26435021 TI - Effect of sinapic acid on 1,2 dimethylhydrazine induced aberrant crypt foci, biotransforming bacterial enzymes and circulatory oxidative stress status in experimental rat colon carcinogenesis. AB - AIM: This study was aimed to investigate the effect of sinapic acid (SA) on 1,2 dimethylhydrazine (DMH) induced experimental rat colon carcinogenesis. MATERIALS AND METHODS: Rats were assorted into six groups, group 1 served as control, group 2 received SA (80 mg/kg b.w.) post orally every day until the end of the experimental period of 16 weeks, groups 3-6 rats were injected DMH (20 mg/kg b.w.) subcutaneously once a week for first four weeks. In addition, groups 4-6 rats received different doses of SA (20, 40 and 80 mg/kg b.w.). RESULTS: Our results showed that DMH induced rats revealed significantly increased ACF development and multiplicity, which were significantly inhibited on supplementation with SA. Moreover, elevated levels/activities of circulatory oxidative stress markers, faecal and colonic mucosal bacterial enzymes were observed in DMH exposed rats, which were diminished on supplementation with SA. CONCLUSION: Overall, our findings revealed that supplementation with SA offers significant protection against DMH induced rat colon carcinogenesis and the effect of SA at the dose of 40 mg/kg b.w. was more pronounced as compared to the other two doses. (Tab.5, Fig. 3, Ref. 46) PMID- 26435022 TI - The role of mitochondrial ATP-sensitive potassium channels on cardiovascular effects of thiopental and ketamine in rats. AB - OBJECTIVE: We aimed to investigate whether mitochondrial ATP-sensitive potassium (mitoKATP) channels play any role on cardiovascular effects of thiopental (TP) or ketamine (K) anesthesia in rats. BACKGROUND: mitoKATP channels are the end effectors of cardioprotection induced by some anesthetics. TP and K are the most frequently used anesthetics with their own cardiovascular effects in experimental studies. To the best of our knowledge, there is no study investigating the cardiovascular effects of TP and K associated with mitoKATP channels. MATERIALS AND METHODS: The experimental groups: TP control, K/Xylazine (X) control, TP+5 hydroxydecanoate (5-HD; mitoKATP channel blocker) and K/X+5-HD. Mean arterial blood pressure (MABP), heart rate (HR) and standard limb lead II ECG were recorded and arrhythmia parameters were evaluated. RESULTS: Blockage of mitoKATP channels by 5-HD increased MABP and decreased HR in the TP+5-HD and K/X+5-HD groups, respectively. 5-HD caused an increase in ventricular ectopic beat (VEB) incidence. Moreover, VEB incidence was significantly different in TP+5-HD (100%) than K/X+5-HDgroup (66.6%) and ventricular tachycardia was only seen in TP+5-HD (incidence was 88.3%). CONCLUSION: mitoKATP channels play different roles in influencing cardiovascular effects of K/X and TP anesthesia in rats. The differences in hemodynamic parameters and arrhythmia scores of these anesthetics should be considered when they are used in an experimental study associated with mitoKATP channels (Fig. 3, Ref. 35). PMID- 26435023 TI - Continuous epidural analgesia, a new prospect in analgesia of newborns. AB - The popularity of continuous caudal epidural block in post-operative analgesia in very young children has been growing. This method of analgesia is used in major abdominal and urological surgeries. A local anaesthetic, usually levobupivacaine, is administered through an epidural catheter introduced via hiatus canalis sacralis. The usual type of the catheter is Arrow G20 armed with a metal spiral, which can be used for children of up to approximately 2000 g of body weight. We want to introduce a modification of the method which uses the thin silicone catheter Premicath G28. This catheter allows for the administration of caudal epidural analgesia even in premature children of approximately 500 g of body weight. This solution eliminates adverse effects of systemic opioid analgesia, accelerates surgical wound healing and disconnection from ventilation system, and improves the potential of enteral nutrition. Depth and quality of analgesia in very young children are monitored using a complex scheme called Comfort Neo Scale (Tab. 1, Fig. 2, Ref. 7). PMID- 26435024 TI - Extremely rare tumour--malignant mesothelioma of tunica vaginalis testis. AB - INTRODUCTION: Malignant mesothelioma of tunica vaginalis testis is an extremely rare tumour. It is often caused by exposition to asbestos, however, more often its occurrence is sporadic. The diagnosis is usually set secondarily during hydrocele surgery. This type of tumour should be considered in cases with with atypical hydrocele, especially haematocele or atypical shape of seminal covering. RESULTS: A case of an asbestos-exposed patient with described disease and long term hydrocele is presented. The number of patients is so small that the guidelines are limited due to low statistical power (Fig. 2, Ref. 14). PMID- 26435025 TI - Prokineticin 2 facilitates mechanical allodynia induced by alpha,beta-methylene ATP in rats. AB - Prokineticin 2 (PK2), a new chemokine, causes mechanical hypersensitivity in the rat hind paw, but little is known about the molecular mechanism. Here, we have found that ionotropic P2X receptor is essential to mechanical allodynia induced by PK2. First, intraplantar injection of high dose (3 or 10 pmol) of PK2 significantly increased paw withdrawal response frequency (%) to innocuous mechanical stimuli (mechanical allodynia). And the mechanical allodynia induced by PK2 was prevented by co-administration of TNP-ATP, a selective P2X receptor antagonist. Second, although low dose (0.3 or 1 pmol) of PK2 itself did not produce an allodynic response, it significantly facilitated the mechanical allodynia evoked by intraplantar injection of alpha,beta-methylene ATP (alpha,beta-meATP). Third, PK2 concentration-dependently potentiated alpha,beta meATP-activated currents in rat dorsal root ganglion (DRG) neurons. Finally, PK2 receptors and intracellular signal transduction were involved in PK2 potentiation of alpha,beta-meATP-induced mechanical allodynia and alpha,beta-meATP-activated currents, since the potentiation were blocked by PK2 receptor antagonist PKRA and selective PKC inhibitor GF 109203X. These results suggested that PK2 facilitated mechanical allodynia induced by alpha,beta-meATP through a mechanism involved in sensitization of cutaneous P2X receptors expressed by nociceptive nerve endings. PMID- 26435026 TI - Inhibition of development of experimental abdominal aortic aneurysm by c-jun N terminal protein kinase inhibitor combined with lysyl oxidase gene modified smooth muscle progenitor cells. AB - Chronic inflammation, imbalance between the extracellular matrix synthesis and degradation, and loss of vascular smooth muscle cells (SMCs) contribute to the development of abdominal aortic aneurysm (AAA). The purpose of this study was to investigate the effect of the therapy with periaortic incubation of c-Jun N terminal protein kinase inhibitor SP600125 infused from an osmotic pump and subadventitial injection of lysyl oxidase (LOX) gene modified autologous smooth muscle progenitor cells (SPCs) on treatment of AAA in a rabbit model. Obvious dilation of the abdominal aorta in the control group was caused by periaortic incubation of calcium chloride and elastase. But the progression of aortic dilation was significantly decreased after the treatment with SP600125 and LOX gene modified SPCs compared to the treatment with phosphate-buffered saline. This therapy could inhibit matrix metalloproteinases expression, enhance elastin synthesis, improve preservation of elastic laminar integrity, benefit SPCs survival and restore SMCs population. It seemed that this method might provide a novel therapeutic strategy to treat AAA. PMID- 26435027 TI - The role of nitric oxide donors in schizophrenia: Basic studies and clinical applications. AB - Schizophrenia is a complex and chronic mental health disease that affects nearly 1% of the population worldwide. While the current antipsychotic medications have profoundly impacted the treatment of schizophrenia over the past 50 years, the newer atypical antipsychotics have not fulfilled initial expectations, and enormous challenges remain in long-term treatment of this debilitating disease. In particular, improved treatment of the negative symptoms and cognitive dysfunction in schizophrenia which greatly impact overall morbidity is required. Nitric oxide (NO) is considered as an intra- and inter-cellular messenger in the brain. The implication of NO in the pathogenesis of schizophrenia is documented. Specifically, underproduction of NO is linked to this pathology. This, in turn, indicates that enhancement of nitrergic activity might be beneficial in this disease. Therefore, novel molecules aiming to increase NO production such as NO donors might constitute potential candidates for the treatment of schizophrenia. Here I intended to critically review advances in research of these emerging molecules for the treatment of this psychiatric disorder. Present analysis suggests that NO donors might be a promising class of compounds for the treatment of schizophrenia. However, the potential neurotoxicity and the narrow therapeutic window of NO donors would add a note of caution in this context. PMID- 26435028 TI - Bidirectional effects of dexmedetomidine on human platelet functions in vitro. AB - Platelets express the imidazoline (I)-receptor, I1 and I2, as well as the alpha2 adrenoceptor. Although dexmedetomidine, a selective alpha2-adrenoceptor agonist with some affinity for the I-receptor is expected to affect platelet function, the effects of dexmedetomidine on platelet functions remain unclear. In the present study, we investigated the effects of dexmedetomidine on human platelet functions in vitro. The effects of dexmedetomidine on platelet aggregation were examined using aggregometers. The formation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in platelets was measured by an enzyme immunoassay. In addition, P-selectin expression in platelets was estimated by flow cytometry. We showed that dexmedetomidine enhances platelet aggregation. But in the presence of yohimbine, an alpha2-antagonist, dexmedetomidine suppressed platelet aggregation. Efaroxan, an I1-antagonist, and methylene blue, a soluble guanylate cyclase inhibitor, abolished the suppressive effect of dexmedetomidine, whereas idazoxan, an I2-antagonist, showed no effect. Dexmedetomidine suppressed cAMP formation and enhanced P-selectin expression in platelets, and these effects were inhibited by yohimbine. Dexmedetomidine increased cGMP formation in platelets in the presence of yohimbine, and this increase was suppressed by efaroxan. These results demonstrated that dexmedetomidine has both enhancing and suppressive effects on human platelet functions through its action on the alpha2-adrenoceptor and on the I1-imidazoline receptor, respectively. PMID- 26435029 TI - Dinuclear planar chiral ferrocenyl gold(I) & gold(II) complexes. AB - Oxidation of Au(I) in the presence of Fe(II) allowed for the synthesis of unique dinuclear ferrocenyl Au(II) complexes via the first reported enantiopure planar chiral ferrocenyl Au(I) complex. (Spectro)electrochemical studies show that oxidation at Fe(II) is favoured, but DFT studies suggest that the energy differences for oxidation of one or the other metal should be quite small. PMID- 26435030 TI - Diffuse cutaneous bullous mastocytosis with IgM deposits at dermo-epidermal junction. AB - Cutaneous mastocytosis is a disease characterized by the infiltration and proliferation of mast cells in the skin. In children, the most common form of presentation is urticaria pigmentosa, while the diffuse cutaneous bullous mastocytosis is one of the rarest subtypes seen. The aim of this paper is to present a case of diffuse bullous mastocytosis with detection of IgM deposits at dermo-epidermal junction using direct immunofluorescence (DIF) microscopy. The diagnosis of diffuse bullous mastocytosis is a challenge, and DIF microscopy is necessary in order to exclude an autoimmune bullous disorder. However, IgM deposits at dermo-epidermal junction can be nonspecific, being found in a variety of skin disorders. A 6-month-old girl presented with bullous lesions and erosions on the scalp and the trunk. During hospitalization, further bullous lesions appeared, along with generalized erythrodermia. Skin biopsy revealed aspects of urticaria pigmentosa. Taking into account the clinical findings, the case was enclosed as bullous mastocytosis. Treatment included the avoidance of trigger factors, and administration of antihistamines along with a short-term course of systemic steroids. The evolution was favorable, with remission of the existing lesions and without occurrence of new ones. PMID- 26435031 TI - Intraguild predation of Geocoris punctipes on Eretmocerus eremicus and its influence on the control of the whitefly Trialeurodes vaporariorum. AB - BACKGROUND: Geocoris punctipes (Hemiptera: Lygaeidae) and Eretmocerus eremicus (Hymenoptera: Aphelinidae) are whitefly natural enemies. Previously, under laboratory conditions, we showed that G. punctipes engages in intraguild predation (IGP), the attack of one natural enemy by another, on E. eremicus. However, it is unknown whether this IGP interaction takes place under more complex scenarios, such as semi-field conditions. Even more importantly, the effect of this interaction on the density of the prey population requires investigation. Therefore, the present study aimed to establish whether this IGP takes place under semi-field conditions and to determine whether the predation rate of G. punctipes on the whitefly decreases when IGP takes place. RESULTS: Molecular analysis showed that, under semi-field conditions, G. punctipes performed IGP on E. eremicus. However, although IGP did take place, the predation rate by G. punctipes on the whitefly was nevertheless higher when both natural enemies were present together than when the predator was present alone. CONCLUSION: While IGP of G. punctipes on E. eremicus does occur under semi-field conditions, it does not adversely affect whitefly control. The concomitant use of these two natural enemies seems a valid option for inundative biological control programmes of T. vaporariorum in tomato. (c) 2015 Society of Chemical Industry. PMID- 26435032 TI - Analysis-preserving video microscopy compression via correlation and mathematical morphology. AB - The large amount video data produced by multi-channel, high-resolution microscopy system drives the need for a new high-performance domain-specific video compression technique. We describe a novel compression method for video microscopy data. The method is based on Pearson's correlation and mathematical morphology. The method makes use of the point-spread function (PSF) in the microscopy video acquisition phase. We compare our method to other lossless compression methods and to lossy JPEG, JPEG2000, and H.264 compression for various kinds of video microscopy data including fluorescence video and brightfield video. We find that for certain data sets, the new method compresses much better than lossless compression with no impact on analysis results. It achieved a best compressed size of 0.77% of the original size, 25* smaller than the best lossless technique (which yields 20% for the same video). The compressed size scales with the video's scientific data content. Further testing showed that existing lossy algorithms greatly impacted data analysis at similar compression sizes. PMID- 26435033 TI - Impact of insulin initiation on glycaemic variability and glucose profiles in a primary healthcare Type 2 diabetes cohort: analysis of continuous glucose monitoring data from the INITIATION study. AB - AIM: To use continuous glucose monitoring to examine the effects of insulin initiation with glargine, with or without glulisine, on glycaemic variability and glycaemia in a cohort of people with Type 2 diabetes receiving maximum oral hypoglycaemic agents in primary healthcare. METHODS: We conducted a post hoc analysis of continuous glucose monitoring data from 89 participants at baseline and at 24 weeks after insulin commencement. Indicators of glycaemic variability (standard deviation, J-index and mean amplitude of glycaemic excursion) and glycaemia (HbA1c , mean glucose, area under the glucose-time curve) were assessed. Multi-level regression analysis was used to identify the predictors of change. RESULTS: Complete glycaemic variability data were available for 78 participants. Of these participants, 41% were women, their mean (sd) age was 59.2 (10.4) years, the median (interquartile range) diabetes duration was 10.4 (6.5, 13.3) years and the median (interquartile range) baseline HbA1c was 82.5 (71.6, 96.7) mmol/mol [9.7 (8.7, 11.0)%]. At baseline, BMI correlated negatively with standard deviation (r = -0.30) and mean amplitude of glycaemic excursion (r = 0.26), but not with J-index; HbA1c correlated with J-index (r = 0.61) but not with mean amplitude of glycaemic excursion and standard deviation. After insulin initiation the mean (sd) glucose level decreased [from 12.0 (3.0) to 8.5 (1.6) mmol/l; P < 0.001], as did the median (interquartile range) J-index [from 66.9 (47.7, 95.1) to 36.9 (27.6, 49.8) mmol/l; P < 0.001]. Baseline HbA1c correlated with a greater J-index reduction (r = -0.45; P < 0.001). The mean amplitude of glycaemic excursion and standard deviation values were unchanged. The baseline temporal profile, showing elevated postprandial morning glucose levels, was unchanged after insulin initiation, despite an overall reduction in glycaemia. CONCLUSION: Insulin initiation reduced hyperglycaemia but did not alter glycaemic variability in adults with Type 2 diabetes receiving maximum oral hypoglycaemic agents. The most significant postprandial excursions were seen in the morning, which identifies prebreakfast as the most effective target for short-acting insulin therapy. PMID- 26435034 TI - Changes in prevalence of, and risk factors for, lameness in random samples of English sheep flocks: 2004-2013. AB - The aims of this study were to update the prevalence of lameness in sheep in England and identify novel risk factors. A total of 1260 sheep farmers responded to a postal survey. The survey captured detailed information on the period prevalence of lameness from May 2012-April 2013 and the prevalence and farmer naming of lesions attributable to interdigital dermatitis (ID), severe footrot (SFR), contagious ovine digital dermatitis (CODD) and shelly hoof (SH), management and treatment of lameness, and farm and flock details. The global mean period prevalence of lameness fell between 2004 and 2013 from 10.6% to 4.9% and the geometric mean period prevalence of lameness fell from 5.4% (95% CL: 4.7% 6.0%) to 3.5% (95% CI: 3.3%-3.7%). In 2013, more farmers were using vaccination and antibiotic treatment for ID and SFR and fewer farmers were using foot trimming as a routine or therapeutic treatment than in 2004. Two over-dispersed Poisson regression models were developed with the outcome the period prevalence of lameness, one investigated associations with farmer estimates of prevalence of the four foot lesions and one investigated associations with management practices to control and treat lameness and footrot. A prevalence of ID>10%, SFR>2.5% and CODD>2.5% were associated with a higher prevalence of lameness compared with those lesions being absent, however, the prevalence of SH was not associated with a change in risk of lameness. A key novel management risk associated with higher prevalence of lameness was the rate of feet bleeding/100 ewes trimmed/year. In addition, vaccination of ewes once per year and selecting breeding replacements from never-lame ewes were associated with a decreased risk of lameness. Other factors associated with a lower risk of lameness for the first time in a random sample of farmers and a full risk model were: recognising lameness in sheep at locomotion score 1 compared with higher scores, treatment of the first lame sheep in a group compared with waiting until >5 were lame, treatment of lame sheep within 3 days, ease of catching lame sheep and quarantine for >21 days. A previously known factor associated with a lower risk of lameness was footbathing to prevent ID. We conclude that the prevalence of lameness in sheep in England has fallen and that this might be in part because of increased uptake of managements recently reported as beneficial to control lameness. Routine foot trimming should be avoided. PMID- 26435035 TI - Should we monitor mycophenolic acid plasma levels in pediatric renal transplantation? PMID- 26435037 TI - Resistant Hypertension and Susceptible Outcomes: Exploring the Benefits of Aggressive Blood Pressure Control. PMID- 26435036 TI - Caenorhabditis elegans NONO-1: Insights into DBHS protein structure, architecture, and function. AB - Members of the Drosophila behavior/human splicing (DBHS) protein family have been characterized in the vertebrates Homo sapiens and Mus musculus, and the invertebrates Drosophila melanogaster and Chironomus tentans. Collectively, both vertebrate and invertebrate DBHS proteins function throughout gene regulation, largely but not always, within the nucleus. In this study, we report a structural and bioinformatic analysis of the DBHS protein family to guide future studies into DBHS protein function. To explore the structural plasticity of the family, we describe the 2.4 A crystal structure of Caenorhabditis elegans non-POU domain containing octamer-binding protein 1 (NONO-1). The structure is dimeric, with a domain arrangement consistent with mammalian DBHS proteins. Comparison with the DBHS structures available from H. sapiens reveals that there is inherent domain flexibility within the homologous DBHS region. Mapping amino acid similarity within the family to the NONO-1 dimer highlights the dimer interface, coiled-coil oligomerization motif, and putative RNA binding surfaces. Surprisingly, the interior surface of RNA recognition motif 2 (RRM2) that faces a large internal void is highly variable, but the external beta2-beta3 loops of RRM2 show remarkable preservation. Overall, the DBHS region is under strong purifying selection, whereas the sequences N- and C-terminal to the DBHS region are less constrained. The findings described in this study provide a molecular basis for further investigation into the mechanistic function of the DBHS protein family in biology. PMID- 26435038 TI - Prospective comparison of early bone marrow evaluation on day 5 versus day 14 of the "3 + 7" induction regimen for acute myeloid leukemia. AB - Evaluation of early response during induction therapy for acute myeloid leukemia (AML) is used for prognostication and re-induction strategy, yet the optimal evaluation time point is unknown. Clearance of bone marrow (BM) blasts by day 14 of therapy does not ensure remission; thus, some patients requiring re-induction are neglected. This study aimed to examine the role of earlier BM evaluation during induction for predicting remission and overall survival. Results of BM testing on the 5th and 14th day of intensive induction were prospectively compared in 127 adult patients with AML. Re-induction was given, based on Day 14 results, to 25 patients. Reduction of the BM blast count to <5% as early as by the fifth day of induction was more specifically associated with the achievement of remission compared to Day 14 (88.2% vs. 60%, respectively). Rapid responders have a better 3-year overall survival (OS). Day 5 results are a stronger predictor of OS by multivariate analysis and better segregate long-term survivors than the Day 14th BM count (66% vs. 30%, P = 0.0001 and 48% vs. 37%, respectively, P = 0.04). The Day 5 evaluation of BM carries significant clinical information. The benefit of prescribing re-induction based on such early evaluation should be prospectively studied. PMID- 26435040 TI - Smoking behaviour and knowledge of the health effects of smoking in patients with inflammatory bowel disease. AB - BACKGROUND: The detrimental effect of smoking on development and progression of Crohn's disease (CD) is generally accepted. AIM: To evaluate the awareness of smoking risks in a Belgian inflammatory bowel disease (IBD) population. METHODS: In the out-patient clinic of a tertiary referral centre, 625 consecutive patients with CD, 238 patients with ulcerative colitis (UC) and 289 non-IBD controls, filled out a simple questionnaire. This questionnaire included data on smoking behaviour and awareness of smoking-related health effects, including effects on IBD. RESULTS: At diagnosis, more CD patients were active smokers compared to UC (40% vs. 17%, P < 0.001). Remarkably, smoking cessation rates after diagnosis were similar for CD and UC (both 56%, P = 0.997). The great majority recognised a detrimental influence of smoking on general health (98-99%), lung cancer (95 97%), myocardial infarction (89-92%) and stroke (78-87%). Although CD patients more frequently acknowledged risks of smoking on their disease, only 37% were aware of a link with CD development, 30% of increased surgical rates and 27% of increased post-operative CD recurrence. Active smokers more frequently denied an increased risk of surgery and higher post-operative CD recurrence. Intriguingly, within the active smokers with CD, those not willing to quit smoking most often denied a potential bad influence of smoking. Taking into account disease duration, previous surgery, education level, working status and nicotine dependence, we were unable to define specific subgroups of patients requiring extra education. CONCLUSION: Although patients with Crohn's disease were better informed on the detrimental effects of smoking, the awareness rate was still low. PMID- 26435041 TI - Polysaccharides from Acanthopanax senticosus enhances intestinal integrity through inhibiting TLR4/NF-kappaB signaling pathways in lipopolysaccharide challenged mice. AB - To investigate the role of polysaccharide from Acanthopanax senticosus (ASPS) on lipopolysaccharide (LPS)-induced intestinal injury, mice in three treatments were administrated orally with or without ASPS (300 mg/kg body weight) for 14 days, followed by challenge with LPS or saline. At 4 h post-injection, blood and intestinal samples of six mice / treatment were collected. The results showed ASPS ameliorated LPS-induced intestinal morphological deterioration, proven by improved villus height (P < 0.05) and villus height : crypt depth ratio (P < 0.05). ASPS also elevated the mucosal barrier of LPS-challenged mice, supported by reduced plasma diamine oxidase (DAO) activity (P < 0.05) and L-lactate (P < 0.05), increased mucosal DAO activity (P < 0.05) as well as enhanced intestinal tight junction proteins expression involving occludin-1 (P < 0.05) and zonula occludens-1 (P < 0.05). In addition, ASPS decreased LPS-induced secretion of inflammatory mediators, including tumor necrosis factor (TNF)-alpha (P < 0.05) and prostaglandin E2 (P < 0.05). Also, ASPS down-regulated messenger RNA expression of toll-like receptor 4 (TLR4) and its downstream signals, including myeloid differentiation factor 88 (P < 0.05), TNF-alpha receptor-associated factor 6 (P < 0.05), as well as nuclear factor (NF)-kappaB p65 (P < 0.05) and its protein expression. These findings suggest that ASPS improves intestinal integrity under inflammation conditions connected with inhibiting TLR4/NF-kappaB signaling pathways. PMID- 26435039 TI - Retinal vascular imaging in early life: insights into processes and risk of cardiovascular disease. AB - Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. In recent years, studies have shown that the origins of CVD may be traced to vascular and metabolic processes in early life. Retinal vascular imaging is a new technology that allows detailed non-invasive in vivo assessment and monitoring of the microvasculature. In this systematic review, we described the application of retinal vascular imaging in children and adolescents, and we examined the use of retinal vascular imaging in understanding CVD risk in early life. We reviewed all publications with quantitative retinal vascular assessment in two databases: PubMed and Scopus. Early life CVD risk factors were classified into four groups: birth risk factors, environmental risk factors, systemic risk factors and conditions linked to future CVD development. Retinal vascular changes were associated with lower birth weight, shorter gestational age, low-fibre and high-sugar diet, lesser physical activity, parental hypertension history, childhood hypertension, childhood overweight/obesity, childhood depression/anxiety and childhood type 1 diabetes mellitus. In summary, there is increasing evidence supporting the view that structural changes in the retinal microvasculature are associated with CVD risk factors in early life. Thus, the retina is a useful site for pre-clinical assessment of microvascular processes that may underlie the future development of CVD in adulthood. PMID- 26435043 TI - Hydrocarbon Release During Fuel Storage and Transfer at Gas Stations: Environmental and Health Effects. AB - At gas stations, fuel is stored and transferred between tanker trucks, storage tanks, and vehicle tanks. During both storage and transfer, a small fraction of unburned fuel is typically released to the environment unless pollution prevention technology is used. While the fraction may be small, the cumulative release can be substantial because of the large quantities of fuel sold. The cumulative release of unburned fuel is a public health concern because gas stations are widely distributed in residential areas and because fuel contains toxic and carcinogenic chemicals. We review the pathways through which gasoline is chronically released to atmospheric, aqueous, and subsurface environments, and how these releases may adversely affect human health. Adoption of suitable pollution prevention technology should not only be based on equipment and maintenance cost but also on energy- and health care-saving benefits. PMID- 26435042 TI - The gap between policy and practice: a systematic review of patient-centred care interventions in chronic heart failure. AB - Patient-centred care (PCC) is recommended in policy documents for chronic heart failure (CHF) service provision, yet it lacks an agreed definition. A systematic review was conducted to identify PCC interventions in CHF and to describe the PCC domains and outcomes. Medline, Embase, CINAHL, PsycINFO, ASSIA, the Cochrane database, clinicaltrials.gov, key journals and citations were searched for original studies on patients with CHF staged II-IV using the New York Heart Association (NYHA) classification. Included interventions actively supported patients to play informed, active roles in decision-making about their goals of care. Search terms included 'patient-centred care', 'quality of life' and 'shared decision making'. Of 13,944 screened citations, 15 articles regarding 10 studies were included involving 2540 CHF patients. Three studies were randomised controlled trials, and seven were non-randomised studies. PCC interventions focused on collaborative goal setting between patients and healthcare professionals regarding immediate clinical choices and future care. Core domains included healthcare professional-patient collaboration, identification of patient preferences, patient-identified goals and patient motivation. While the strength of evidence is poor, PCC has been shown to reduce symptom burden, improve health related quality of life, reduce readmission rates and enhance patient engagement for patients with CHF. There is a small but growing body of evidence, which demonstrates the benefits of a PCC approach to care for CHF patients. Research is needed to identify the key components of effective PCC interventions before being able to deliver on policy recommendations. PMID- 26435044 TI - Comprehensive proteomic analysis of the wheat pathogenic fungus Zymoseptoria tritici. AB - Zymoseptoria tritici causes Septoria tritici blotch disease of wheat. To obtain a comprehensive protein dataset of this fungal pathogen, proteomes of Z. tritici growing in nutrient-limiting and rich media and in vivo at a late stage of wheat infection were fractionated by 1D gel or strong cation exchange (SCX) chromatography and analyzed by LC-MS/MS. A total of 5731, 5376 and 3168 Z. tritici proteins were confidently identified from these conditions, respectively. Of these in vitro and in planta proteins, 9 and 11% were predicted to contain signal peptides, respectively. Functional classification analysis revealed the proteins were involved in the various cellular activities. Comparison of three distinct protein expression profiles demonstrates the elevated carbohydrate, lipid and secondary metabolisms, transport, protein processing and energy production specifically in the host environment, in contrast to the enhancement of signaling, defense, replication, transcription and cell division in vitro. The data provide useful targets towards a better understanding of the molecular basis of Z. tritici growth, development, stress response and pathogenicity. PMID- 26435045 TI - Delivery mode and pelvic organ prolapse: a retrospective observational study. AB - OBJECTIVE: To analyse the associations between delivery mode and symptoms and signs of pelvic organ prolapse (POP) in a cohort of symptomatic women. DESIGN: Retrospective observational study. POPULATION: A total of 1258 consecutive women attending a tertiary urogynaecological unit for the investigation of lower urinary tract or pelvic floor disorders between January 2012 and December 2014. METHODS: Obstetric history and clinical examination data were obtained from the unit database. Prolapse quantification on imaging was performed using stored four dimensional translabial ultrasound volume data sets. Women were grouped into four groups according to the most traumatic delivery reported. The presence of symptoms and signs of POP were compared between delivery groups while controlling for potential confounders. MAIN OUTCOME MEASURES: Prolapse symptoms, visual analogue score for prolapse bother, International Continence Society Prolapse Quantification System findings and ultrasound findings of anterior, central and posterior compartment descent. RESULTS: Nulliparae showed the lowest prevalence of most measures of POP, followed by women exclusively delivered by caesarean section. Highest prevalences were consistently found in women delivered at least once by forceps, although the differences between this group and women delivered by normal vaginal delivery and/or vacuum extraction were significant in three out of eight measures only. Compared with women in the caesarean section group, the adjusted odds ratios for reporting symptoms of prolapse were 2.4 (95% CI 1.30 4.59) and 3.2 (95% CI 1.65-6.12) in the normal vaginal delivery/vacuum extraction group and forceps group, respectively. CONCLUSIONS: There is a clear link between vaginal delivery and symptoms and signs of pelvic organ prolapse in urogynaecological patients. TWEETABLE ABSTRACT: Compared with caesarean section a history of vaginal delivery more than doubles the risk for POP. PMID- 26435046 TI - Clinical outcomes with transoral robotic surgery for supraglottic squamous cell carcinoma: Experience of a French evaluation cooperative subgroup of GETTEC. AB - BACKGROUND: Transoral, minimally invasive, organ preservation surgeries are increasingly used to treat laryngopharyngeal carcinomas to avoid the toxicity associated with combined chemoradiotherapy (CRT) regimens. This study investigated the efficiency, safety, and functional outcomes of using transoral robotic surgery (TORS) to perform supraglottic laryngectomy (SGL). METHODS: This was a multicenter study using a case series with planned data collection from 2009 to 2012 for patients with supraglottic squamous cell carcinomas (SCCs) who underwent an SGL using TORS. RESULTS: Eighty-four of the 262 patients underwent TORS for a supraglottic SCC. Within 24 hours of surgery, 24% of the patients began an oral diet. The median use of a feeding tube was 8 days for 76% of other patients. Definitive percutaneous gastrostomy feeding was necessary for 9.5% of the patients. Twenty-four percent of the patients did require a tracheostomy, and the median use was 8 days. One percent of the patients had a definitive tracheostomy. Aspiration pneumonia was observed in 23% of the patients during the postoperative course, and was responsible for the death of 1 patient. Postoperative bleeding occurred in 18% of the patients. Based on the pathology results, 51% of the patients received adjuvant radiation therapy. CONCLUSION: TORS for SGL, in the intermediate stage of SCC, provides a safe procedure with good functional outcomes and fast recovery times; however, adverse events are possible. Consequently, this technique requires good selection criteria for the patients to reduce the risk of postoperative complications. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1097-E1101, 2016. PMID- 26435047 TI - Effect of obesity on neonatal outcomes in pregnancies with preterm premature rupture of membranes. AB - BACKGROUND: Maternal obesity is associated with increased systemic inflammation and an increased risk of preterm premature rupture of membranes. There is an established association between an inflammatory intrauterine environment and adverse neonatal outcomes that is independent of gestational age and mediated by the fetal inflammatory response. It is unknown whether the maternal systemic inflammation that is present in obese women influences the intrauterine environment and predisposes the fetus to adverse neonatal outcomes after preterm premature rupture of membranes. OBJECTIVE: The purpose of this study was to determine whether maternal obesity is associated with adverse neonatal outcomes in pregnancies that are complicated by preterm premature rupture of membranes. STUDY DESIGN: This was a secondary analysis of the Maternal-Fetal Medicine Units Network Randomized Clinical Trial on the Beneficial Effects of Antenatal Magnesium Sulfate. Women with singleton pregnancies that were affected by preterm premature rupture of membranes who delivered live-born infants between 24 + 0 and 33 + 6 weeks of gestation were included. An adverse neonatal outcome was defined as a composite outcome of neonatal death, severe necrotizing enterocolitis, respiratory distress syndrome, sepsis, or severe intraventricular hemorrhage. The rates of the composite outcome were compared between obese (body mass index, >=30 kg/m(2)) and nonobese women. Multivariable logistic regression was used to evaluate the independent effect of obesity on neonatal outcomes. Magnesium sulfate administration, steroid administration, maternal diabetes mellitus, gestational age at delivery, indomethacin exposure, birthweight, and chorioamnionitis were all considered as possible covariates in the multivariable regression models. RESULTS: Three hundred twenty-five of the 1288 women (25.2%) who were included were obese, and 202 of these women (62.2%) had neonates with adverse outcomes. In univariable analysis, maternal prepregnancy obesity was associated with increased odds of an adverse neonatal outcome (odds ratio, 0.30, 95% confidence interval, 1.00-1.68). However, in our multivariable logistic regression model, gestational age at delivery (odds ratio, 0.93, 95% confidence interval, 0.92-0.94 per day), but not maternal obesity (odds ratio, 1.02, 95% confidence interval, 0.75-1.38), was associated with adverse neonatal outcomes. Obese African American women experienced preterm premature rupture of membranes (189 vs 196 days; p < .001) and delivery (199 vs 205 days; p < .001) earlier than nonobese African American women. This difference was not seen in non-African American women. CONCLUSIONS: Maternal obesity was not associated independently with adverse neonatal outcomes in pregnancies that were affected by preterm premature rupture of membranes after adjustment for gestational age at birth. However, obese African American women rupture and deliver earlier than other women, which causes increased neonatal morbidity. PMID- 26435048 TI - Electronic storage capacity of ceria: role of peroxide in Aux supported on CeO2(111) facet and CO adsorption. AB - Density functional theory (DFT+U) was used to study the adsorption of Aux (x = 1 4) clusters on the defective CeO2(111) facet and CO adsorption on the corresponding Aux/CeO2-x catalyst, in this work Aux clusters are adsorbed onto the CeO2-x + superoxide/peroxide surface. When Au1 is supported on the CeO2(111) facet with an O vacancy, the strong electronegative Au(delta-) formed is not favorable for CO adsorption. When peroxide is adsorbed on the CeO2(111) facet with the O vacancy, Aux was oxidized, resulting in stable Aux adsorption on the defective ceria surface with peroxide, which promotes CO adsorption on the Aux/CeO2-x catalyst. With more Au atoms in supported Aux clusters, CO adsorption on this surface becomes stronger. During both the Au being supported on CeO2-x and CO being adsorbed on Aux/CeO2-x, CeO2 acts as an electron buffer that can store/release the electrons. These results provide a scientific understanding for the development of high-performance rare earth catalytic materials. PMID- 26435049 TI - Reducing consistency in human realism increases the uncanny valley effect; increasing category uncertainty does not. AB - Human replicas may elicit unintended cold, eerie feelings in viewers, an effect known as the uncanny valley. Masahiro Mori, who proposed the effect in 1970, attributed it to inconsistencies in the replica's realism with some of its features perceived as human and others as nonhuman. This study aims to determine whether reducing realism consistency in visual features increases the uncanny valley effect. In three rounds of experiments, 548 participants categorized and rated humans, animals, and objects that varied from computer animated to real. Two sets of features were manipulated to reduce realism consistency. (For humans, the sets were eyes-eyelashes-mouth and skin-nose-eyebrows.) Reducing realism consistency caused humans and animals, but not objects, to appear eerier and colder. However, the predictions of a competing theory, proposed by Ernst Jentsch in 1906, were not supported: The most ambiguous representations-those eliciting the greatest category uncertainty-were neither the eeriest nor the coldest. PMID- 26435051 TI - Enhancement of Solar Fuel Production Schemes by Using a Ru,Rh,Ru Supramolecular Photocatalyst Containing Hydroxide Labile Ligands. AB - Polyazine-bridged Ru(II)Rh(III)Ru(II) complexes with two halide ligands, Cl(-) or Br(-), bound to the catalytically active Rh center are efficient single-component photocatalysts for H2O reduction to H2 fuel, with the coordination environment on Rh impacting photocatalysis. Herein reported is a new, halide-free Ru(II)Rh(III)Ru(II) photocatalyst with OH(-) ligands bound to Rh, further enhancing the photocatalytic reactivity of the structural motif. H2 production experiments using the photocatalyst bearing OH(-) ligands at Rh relative to the analogues bearing halides at Rh in solvents of varying polarity (DMF, CH3CN, and H2O) suggest that ion pairing with halides deactivates photocatalyst function, representing an exciting phenomenon to exploit in the development of catalysts for solar H2 production schemes. PMID- 26435050 TI - The effect of auditory verbal imagery on signal detection in hallucination-prone individuals. AB - Cognitive models have suggested that auditory hallucinations occur when internal mental events, such as inner speech or auditory verbal imagery (AVI), are misattributed to an external source. This has been supported by numerous studies indicating that individuals who experience hallucinations tend to perform in a biased manner on tasks that require them to distinguish self-generated from non self-generated perceptions. However, these tasks have typically been of limited relevance to inner speech models of hallucinations, because they have not manipulated the AVI that participants used during the task. Here, a new paradigm was employed to investigate the interaction between imagery and perception, in which a healthy, non-clinical sample of participants were instructed to use AVI whilst completing an auditory signal detection task. It was hypothesized that AVI usage would cause participants to perform in a biased manner, therefore falsely detecting more voices in bursts of noise. In Experiment 1, when cued to generate AVI, highly hallucination-prone participants showed a lower response bias than when performing a standard signal detection task, being more willing to report the presence of a voice in the noise. Participants not prone to hallucinations performed no differently between the two conditions. In Experiment 2, participants were not specifically instructed to use AVI, but retrospectively reported how often they engaged in AVI during the task. Highly hallucination prone participants who retrospectively reported using imagery showed a lower response bias than did participants with lower proneness who also reported using AVI. Results are discussed in relation to prominent inner speech models of hallucinations. PMID- 26435052 TI - Influence of Y(3+), Gd(3+), and Lu(3+) co-doping on the phase and luminescence properties of monoclinic Eu:LaVO4 particles. AB - Nano-sized particles of monoclinic-LaVO4 were prepared in a short reaction time of 30 minutes by employing a microwave assisted hydrothermal synthesis in the presence of glycerol, which was used both as a solvent and structure-directing agent. The tetragonal-LaVO4 is known to show strong luminescence properties when doped with Ln(3+), whereas the monoclinic-LaVO4 is usually considered not suitable for luminescence and therefore luminescence properties of monoclinic LaVO4 doped with Ln(3+) ions are seldom investigated. Due to the scarce amount of research on the topic of luminescence of Ln(3+) doped monoclinic-LaVO4 in this paper a detailed study of solid state luminescence properties, including quantum yields, of nano-sized monoclinic-LaVO4 doped with different molar percentages of Eu(3+) is presented. It was observed that the 12.5%Eu(3+) doped sample showed the strongest luminescence properties. Additionally a study of the influence of different rare-earth ions (Y(3+), Gd(3+), Lu(3+)) co-doped into the particles was performed in order to explore the potential of increasing the luminescence of these materials. Furthermore stable colloidal suspensions of the Eu(3+) doped monoclinic-LaVO4 nanoparticles showing strong red emission could be obtained. PMID- 26435053 TI - Role of RNA Branchedness in the Competition for Viral Capsid Proteins. AB - To optimize binding-and packaging-by their capsid proteins (CP), single-stranded (ss) RNA viral genomes often have local secondary/tertiary structures with high CP affinity, with these "packaging signals" serving as heterogeneous nucleation sites for the formation of capsids. Under typical in vitro self-assembly conditions, however, and in particular for the case of many ssRNA viruses whose CP have cationic N-termini, the adsorption of CP by RNA is nonspecific because the CP concentration exceeds the largest dissociation constant for CP-RNA binding. Consequently, the RNA is saturated by bound protein before lateral interactions between CP drive the homogeneous nucleation of capsids. But, before capsids are formed, the binding of protein remains reversible and introduction of another RNA species-with a different length and/or sequence-is found experimentally to result in significant redistribution of protein. Here we argue that, for a given RNA mass, the sequence with the highest affinity for protein is the one with the most compact secondary structure arising from self complementarity; similarly, a long RNA steals protein from an equal mass of shorter ones. In both cases, it is the lateral attractions between bound proteins that determines the relative CP affinities of the RNA templates, even though the individual binding sites are identical. We demonstrate this with Monte Carlo simulations, generalizing the Rosenbluth method for excluded-volume polymers to include branching of the polymers and their reversible binding by protein. PMID- 26435054 TI - Impairment of the non-homologous end joining and homologous recombination pathways of DNA double strand break repair: Impact on spontaneous and radiation induced mammary and intestinal tumour risk in Apc min/+ mice. AB - Female Apc(min/+) mice carrying the BALB/c variant of Prkdc or heterozygous knockout for Xrcc2, were sham- or 2 Gy X-irradiated as adults to compare the effect of mild impairments of double-strand break (DSB) repair pathways, non homologous end joining (NHEJ) and homologous recombination (HR) respectively on spontaneous and radiation-induced mammary and intestinal tumorigenesis. Mice with impaired NHEJ showed no difference in incidence of spontaneous mammary tumours, compared with matched controls, (2.46 fold, P=0.121) and significantly less following irradiation (radiation-induced excess; 0.35 fold, P=0.008). In contrast mice with impaired HR presented with significantly less spontaneous mammary tumours than matched controls (0.33 fold, P=0.027) and significantly more following irradiation (radiation-induced excess; 3.3 fold, P=0.016). Spontaneous and radiation-induced intestinal adenoma multiplicity in the same groups were significantly greater than matched controls for mice with impaired NHEJ (sham; 1.29 fold, P<0.001, radiation-induced excess; 2.55 fold, P<0.001) and mice with impaired HR showed no significant differences (sham; 0.92 fold, P=0.166, radiation-induced excess; 1.16, P=0.274). Genetic insertion events were common in spontaneous tumours from NHEJ impaired mice compared with matched controls. gammaH2AX foci analysis suggests a significantly faster rate of DSB repair (MANOVA P<0.001) in intestinal than mammary tissue; apoptosis was also higher in irradiated intestine. To conclude, results suggest that pathway of choice for repair of spontaneous and radiation-induced DSBs is influenced by tissue type. NHEJ appears to play a greater role in DSB repair in intestinal tissue since impairment by functional change of Prkdc significantly increases the rate of mis repair in intestinal but not mammary tissue. HR appears to play a greater role in DSB repair in adult mammary tissue since impaired HR results in significant changes in mammary but not in the intestinal tumorigenesis. This indicates that early DNA damage response and repair is important for cancer susceptibility and plays a role in determining tissue specificity of cancer risk. PMID- 26435055 TI - Concomitant versus sequential therapy for the treatment of Helicobacter pylori infection: a Greek randomized prospective study. AB - OBJECTIVE: The objective of this study is to compare, in Greece, a region with >20% local resistance to clarithromycin, the efficacy rates of the concomitant versus the sequential H. pylori eradication therapy. MATERIALS AND METHODS: Our prospective randomized study included 364 patients with newly diagnosed H. pylori infection, randomized to receive a 10-day concomitant or 10-day sequential therapy. Treatment outcome was assessed by C(13)-urea breath test at least 4 weeks after therapy. Intention to treat (ITT) and per protocol (PP) analysis of the eradication rates were performed. Secondary end points included patient compliance and safety. RESULTS: The concomitant therapy group achieved statistically significant higher eradication rates when compared with the sequential treatment group, both in the ITT and in the PP analysis (84.6% versus 70.9%, p = 0.002, and 90.6% versus 78.1%, p = 0.001, respectively), after adjusting for age, gender, smoking status, and the presence or not of ulcer and/or non-ulcer dyspepsia. Both groups displayed excellent compliance rates (99.5% for the concomitant therapy group and 96.2% for the sequential therapy group, p = 0.067). Regarding treatment safety, major adverse events that led to the discontinuation of both regimens were few, with no statistical difference between the two groups (7.0% for the concomitant therapy group and 2.9% for the sequential therapy group). CONCLUSIONS: Concomitant therapy led to statistically significant higher eradication rates over sequential therapy. Both therapies showed excellent compliance and an acceptable safety profile. The 10-day quadruple concomitant scheme should be the adopted for first-line H. pylori eradication in Greece. PMID- 26435057 TI - Surgical management of abnormally invasive placenta: is decreased blood loss due to participation of gynecologic oncologists? PMID- 26435056 TI - Analysis of a transgenic Oct4 enhancer reveals high fidelity long-range chromosomal interactions. AB - Genome structure or nuclear organization has fascinated researchers investigating genome function. Recently, much effort has gone into defining relationships between specific genome structures and gene expression in pluripotent cells. We previously analyzed chromosomal interactions of the endogenous Oct4 distal enhancer in pluripotent cells. Here, we derive ES and iPS cells from a transgenic Oct4 distal enhancer reporter mouse. Using sonication-based Circularized Chromosome Conformation Capture (4C) coupled with next generation sequencing, we determined and compared the genome-wide interactome of the endogenous and transgenic Oct4 distal enhancers. Integrative genomic analysis indicated that the transgenic enhancer binds to a similar set of loci and shares similar key enrichment profiles with its endogenous counterpart. Both the endogenous and transgenic Oct4 enhancer interacting loci were enriched in the open nucleus compartment, which is associated with active histone marks (H3K4me1, H3K27ac, H3K4me3 and H3K9ac), active cis-regulatory sequences (DNA hypersensitivity sites (DHS)), 5-hydroxymethylcytosine (5-hmc), and early DNA replication domains. In addition, binding of some pluripotency-related transcription factors was consistently enriched in our 4C sites, and genes in those sites were generally more highly expressed. Overall, our work reveals critical features that may function in gene expression regulation in mouse pluripotent cells. PMID- 26435058 TI - Coexistence of glutamatergic spine synapses and shaft synapses in substantia nigra dopamine neurons. AB - Dopamine neurons of the substantia nigra have long been believed to have multiple aspiny dendrites which receive many glutamatergic synaptic inputs from several regions of the brain. But, here, using high-resolution two-photon confocal microscopy in the mouse brain slices, we found a substantial number of common dendritic spines in the nigral dopamine neurons including thin, mushroom, and stubby types of spines. However, the number of dendritic spines of the dopamine neurons was approximately five times lower than that of CA1 pyramidal neurons. Immunostaining and morphological analysis revealed that glutamatergic shaft synapses were present two times more than spine synapses. Using local two-photon glutamate uncaging techniques, we confirmed that shaft synapses and spine synapses had both AMPA and NMDA receptors, but the AMPA/NMDA current ratios differed. The evoked postsynaptic potentials of spine synapses showed lower amplitudes but longer half-widths than those of shaft synapses. Therefore, we provide the first evidence that the midbrain dopamine neurons have two morphologically and functionally distinct types of glutamatergic synapses, spine synapses and shaft synapses, on the same dendrite. This peculiar organization could be a new basis for unraveling many physiological and pathological functions of the midbrain dopamine neurons. PMID- 26435059 TI - Phenotype Prediction of Pathogenic Nonsynonymous Single Nucleotide Polymorphisms in WFS1. AB - Wolfram syndrome (WS) is a rare, progressive, neurodegenerative disorder that has an autosomal recessive pattern of inheritance. The gene for WS, wolfram syndrome 1 gene (WFS1), is located on human chromosome 4p16.1 and encodes a transmembrane protein. To date, approximately 230 mutations in WFS1 have been confirmed, in which nonsynonymous single nucleotide polymorphisms (nsSNPs) are the most common forms of genetic variation. Nonetheless, there is poor knowledge on the relationship between SNP genotype and phenotype in other nsSNPs of the WFS1 gene. Here, we analysed 395 nsSNPs associated with the WFS1 gene using different computational methods and identified 20 nsSNPs to be potentially pathogenic. Furthermore, to identify the amino acid distributions and significances of pathogenic nsSNPs in the protein of WFS1, its transmembrane domain was constructed by the TMHMM server, which suggested that mutations outside of the TMhelix could have more effects on protein function. The predicted pathogenic mutations for the nsSNPs of the WFS1 gene provide an excellent guide for screening pathogenic mutations. PMID- 26435061 TI - Synthesis of Lipophilic Antioxidants by a Lipase-B-Catalyzed Addition of Peracids to the Double Bond of 4-Vinyl-2-methoxyphenol. AB - 4-Vinyl guaiacol (2) was lipophilized through the electrophilic addition of peracids to its vinylic double bond. Those peracids were formed in situ, by the Candida antarctica lipase-B-assisted perhydrolysis of carboxylic acids ranging from C2 to C18, in hydrogen peroxide solution. The addition of peracids with 4-8 carbons in their alkyl chains led to the formation of two regioisomers, with the prevalence of hydroxyesters bearing a primary free hydroxyl (4c-4e). This prevalence became more pronounced when peracids with longer alkyl chains (C10 C18) were used. In this case, only isomers 4f-4h were formed. The antioxidant activity of the resulting hydroxyesters was assessed by means of the conjugated autoxidizable triene (CAT) assay, and it was found out that the 4-vinyl guaiacol antioxidant activity was significantly increased by grafting alkyl chains with 2 8 carbons. PMID- 26435060 TI - Differential Responses of Plasma Adropin Concentrations To Dietary Glucose or Fructose Consumption In Humans. AB - Adropin is a peptide hormone encoded by the Energy Homeostasis Associated (ENHO) gene whose physiological role in humans remains incompletely defined. Here we investigated the impact of dietary interventions that affect systemic glucose and lipid metabolism on plasma adropin concentrations in humans. Consumption of glucose or fructose as 25% of daily energy requirements (E) differentially affected plasma adropin concentrations (P < 0.005) irrespective of duration, sex or age. Glucose consumption reduced plasma adropin from 3.55 +/- 0.26 to 3.28 +/- 0.23 ng/ml (N = 42). Fructose consumption increased plasma adropin from 3.63 +/- 0.29 to 3.93 +/- 0.34 ng/ml (N = 45). Consumption of high fructose corn syrup (HFCS) as 25% E had no effect (3.43 +/- 0.32 versus 3.39 +/- 0.24 ng/ml, N = 26). Overall, the effect of glucose, HFCS and fructose on circulating adropin concentrations were similar to those observed on postprandial plasma triglyceride concentrations. Furthermore, increases in plasma adropin levels with fructose intake were most robust in individuals exhibiting hypertriglyceridemia. Individuals with low plasma adropin concentrations also exhibited rapid increases in plasma levels following consumption of breakfasts supplemented with lipids. These are the first results linking plasma adropin levels with dietary sugar intake in humans, with the impact of fructose consumption linked to systemic triglyceride metabolism. In addition, dietary fat intake may also increase circulating adropin concentrations. PMID- 26435062 TI - Caregiver burden in atypical dementias: comparing frontotemporal dementia, Creutzfeldt-Jakob disease, and Alzheimer's disease. AB - BACKGROUND: Caregiver burden is a significant issue in the treatment of dementia and a known contributor to institutionalization of patients with dementia. Published data have documented increased caregiver burden in behavioral variant frontotemporal dementia (bvFTD) compared to Alzheimer's disease (AD). Another atypical dementia with high-perceived caregiver burden is sporadic Creutzfeldt Jakob disease (sCJD), but no formal studies have assessed this perception. The aim of this study was to compare caregiver burden across atypical dementia etiologies. METHODS: 76 adults with atypical dementia (young-onset AD [YOAD], bvFTD, language variant FTD [lvFTD], and sCJD) were administered an abbreviated version of the Zarit Burden Interview (ZBI), Neuropsychiatric Inventory (NPI-Q), and other assessment instruments during a five-year time period at Johns Hopkins Hospital (JHH). A Cox regression model examined differences between disease categories that impact mean ZBI scores. RESULTS: Mean ZBI scores were significantly different between dementia etiologies, with bvFTD and sCJD having the highest caregiver burden (p = 0.026). Mean NPI-Q caregiver distress scores were highest in bvFTD and sCJD (p = 0.002), with sCJD and bvFTD also having the highest number of endorsed symptom domains (p = 0.012). On regression analyses, an interactive variable combining final diagnosis category and NPI-Q total severity score demonstrated statistically significant differences in mean ZBI scores for sCJD and bvFTD. CONCLUSIONS: This study demonstrates that bvFTD and sCJD have increased levels of caregiver burden, NPI-Q caregiver distress, total severity scores, and number of endorsed symptom domains. These results suggest that higher caregiver burden in bvFTD and sCJD are disease specific and possibly related to neuropsychiatric symptoms. PMID- 26435063 TI - Hypoionic shock treatment enables aminoglycosides antibiotics to eradicate bacterial persisters. AB - Bacterial persisters, usually being considered as dormant cells that are tolerant to antibiotics, are an important source for recurrent infection and emergence of antibiotic resistant pathogens. Clinical eradication of pathogenic persisters is highly desired but greatly difficult mainly due to the substantial reduction in antibiotics uptake as well as the non-active state of the drug targets. Here we report that bacterial persisters (normal growing cells as well) can be effectively eradicated by aminoglycoside antibiotics upon hypoionic shock (e.g. pure water treatment) even for less than one minute. Such hypoionic shock potentiation effect on aminoglycosides is proton motive force-independent, and is apparently achieved by promoting the entrance of aminoglycosides, speculatively through the mechanosensitive ion channels. Our revelations may provide a simple and powerful strategy to eradicate pathogen persisters. PMID- 26435064 TI - Alternating Voltage Introduced NiCo Double Hydroxide Layered Nanoflakes for an Asymmetric Supercapacitor. AB - An electrochemical alternating voltage approach of producing NiCo double hydroxide (NiCoDH) layered ultrathin nanoflakes with large specific surface area (355.8 m(2) g(-1)), remarkable specific capacitance and rate capability is presented. The obtained NiCoDH as anode for asymmetric supercapacitors shows excellent energy density of 17.5 Wh kg(-1) at high power density of 10.5 kW kg( 1) and cycling stability (91.2% after 10,000 cycles). PMID- 26435065 TI - Self-Assembled Pico-Liter Droplet Microarray for Ultrasensitive Nucleic Acid Quantification. AB - Nucleic acid detection and quantification technologies have made remarkable progress in recent years. Among existing platforms, hybridization-based assays have the advantages of being amplification free, low instrument cost, and high throughput, but are generally less sensitive compared to sequencing and PCR assays. To bridge this performance gap, we developed a quantitative physical model for the hybridization-based assay to guide the experimental design, which leads to a pico-liter droplet environment with drastically enhanced performance and detection limit several order above any current microarray platform. The pico liter droplet hybridization platform is further coupled with the on-chip enrichment technique to yield ultrahigh sensitivity both in terms of target concentration and copy number. Our physical model, taking into account of molecular transport, electrostatic intermolecular interactions, reaction kinetics, suggests that reducing liquid height and optimizing target concentration will maximize the hybridization efficiency, and both conditions can be satisfied in a highly parallel, self-assembled pico-liter droplet microarray that produces a detection limit as low as 570 copies and 50 aM. The pico-liter droplet array device is realized with a micropatterned superhydrophobic black silicon surface that allows enrichment of nucleic acid samples by position defined evaporation. With on-chip enrichment and oil encapsulated pico-liter droplet arrays, we have demonstrated a record high sensitivity, wide dynamic range (6 orders of magnitude), and marked reduction of hybridization time from >10 h to <5 min in a highly repeatable fashion, benefiting from the physics driven design and nanofeatures of the device. The design principle and technology can contribute to biomedical sensing and point-of-care clinical applications such as pathogen detection and cancer diagnosis and prognosis. PMID- 26435067 TI - The regulation of the Treg/Th17 balance by mesenchymal stem cells in human systemic lupus erythematosus. AB - BACKGROUND AND OBJECTIVE: Umbilical cord (UC)-derived mesenchymal stem cells (MSCs) have shown immunoregulation of various immune cells. The aim of this study was to investigate the mechanism of UC MSCs in the regulation of peripheral regulatory T cells (Treg) and T helper 17 (Th17) cells in patients with systemic lupus erythematosus (SLE). METHODS: Thirty patients with active SLE, refractory to conventional therapies, were given UC MSCs infusions. The percentages of peripheral blood CD4+CD25+Foxp3+ regulatory T cells (Treg) and CD3+CD8-IL17A+ Th17 cells and the mean fluorescence intensities (MFI) of Foxp3 and IL-17 were measured at 1 week, 1 month, 3 months, 6 months, and 12 months after MSCs transplantation (MSCT). Serum cytokines, including transforming growth factor beta (TGF-beta), tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and IL-17A were detected using ELISA. Peripheral blood mononuclear cells from patients were collected and co-cultured with UC MSCs at ratios of 1:1, 10:1, and 50:1, respectively, for 72 h to detect the proportions of Treg and Th17 cells and the MFIs of Foxp3 and IL-17 were determined by flow cytometry. The cytokines in the supernatant solution were detected using ELISA. Inhibitors targeting TGF beta, IL-6, indoleamine 2,3-dioxygenase (IDO), and prostaglandin E2 were added to the co-culture system, and the percentages of Treg and Th17 cells were observed. RESULTS: The percentage of peripheral Treg and Foxp3 MFI increased 1 week, 1 month, and 3 months after UC MSCs transplantation, while the Th17 proportion and MFI of IL-17 decreased 3 months, 6 months, and 12 months after the treatment, along with an increase in serum TGF-beta at 1 week, 3 months, and 12 months and a decrease in serum TNF-alpha beginning at 1 week. There were no alterations in serums IL-6 and IL-17A before or after MSCT. In vitro studies showed that the UC MSCs dose-dependently up-regulated peripheral Treg proportion in SLE patients, which was not depended on cell-cell contact. However, the down-regulation of Th17 cells was not dose-dependently and also not depended on cell-cell contact. Supernatant TGF-beta and IL-6 levels significantly increased, TNF-alpha significantly decreased, but IL-17A had no change after the co-culture. The addition of anti-TGF-beta antibody significantly abrogated the up-regulation of Treg, and the addition of PGE2 inhibitor significantly abrogated the down regulation of Th17 cells. Both anti-IL-6 antibody and IDO inhibitor had no effects on Treg and Th17 cells. CONCLUSIONS: UC MSCs up-regulate Treg and down regulate Th17 cells through the regulation of TGF-beta and PGE2 in lupus patients. PMID- 26435066 TI - Guiding dengue vaccine development using knowledge gained from the success of the yellow fever vaccine. AB - Flaviviruses comprise approximately 70 closely related RNA viruses. These include several mosquito-borne pathogens, such as yellow fever virus (YFV), dengue virus (DENV), and Japanese encephalitis virus (JEV), which can cause significant human diseases and thus are of great medical importance. Vaccines against both YFV and JEV have been used successfully in humans for decades; however, the development of a DENV vaccine has encountered considerable obstacles. Here, we review the protective immune responses elicited by the vaccine against YFV to provide some insights into the development of a protective DENV vaccine. PMID- 26435069 TI - A Rare Cause of Dysphagia: Squamous Papillomatosis of the Esophagus. PMID- 26435068 TI - Carbon monoxide decreases interleukin-1beta levels in the lung through the induction of pyrin. AB - Carbon monoxide (CO) can act as an anti-inflammatory effector in mouse models of lung injury and disease, through the downregulation of pro-inflammatory cytokines production, though the underlying mechanisms remain unclear. The nucleotide binding oligomerization domain-, leucine-rich region-, and pyrin domain containing-3 (NLRP3) inflammasome is a protein complex that regulates the maturation and secretion of pro-inflammatory cytokines, including interleukin 1beta (IL-1beta). In this report, we show that the CO-releasing molecule (CORM-2) can stimulate the expression of pyrin, a negative regulator of the NLRP3 inflammasome. CORM-2 increased the transcription of pyrin in the human leukemic cell line (THP-1) in the absence and presence of lipopolysaccharide (LPS). In THP 1 cells, CORM-2 treatment dose-dependently reduced the activation of caspase-1 and the secretion of IL-1beta, and increased the levels of IL-10, in response to LPS and adenosine 5'-triphosphate (ATP), an NLRP3 inflammasome activation model. Genetic interference of IL-10 by small interfering RNA (siRNA) reduced the effectiveness of CORM-2 in inhibiting IL-1beta production and in inducing pyrin expression. Genetic interference of pyrin by siRNA increased IL-1beta production in response to LPS and ATP, and reversed CORM-2-dependent inhibition of caspase-1 activation. CO inhalation (250 ppm) in vivo increased the expression of pyrin and IL-10 in lung and spleen, and decreased the levels of IL-1beta induced by LPS. Consistent with the induction of pyrin and IL-10, and the downregulation of lung IL-1beta production, CO provided protection in a model of acute lung injury induced by intranasal LPS administration. These results provide a novel mechanism underlying the anti-inflammatory effects of CO, involving the IL-10-dependent upregulation of pyrin expression. PMID- 26435070 TI - Cancelled and Missed Colonoscopy Appointments Not Easy to Measure. PMID- 26435071 TI - Reply. PMID- 26435073 TI - Determination of Hg, Fe, Ni, and Co by Miniaturized Optical Emission Spectrometry Integrated with Flow Injection Photochemical Vapor Generation and Point Discharge. AB - A compact and robust OES technique was developed for the sensitive determination of Hg, Fe, Ni, and Co by utilizing photochemical vapor generation and point discharge as the sampling technique and the excitation source, respectively. Mercury cold vapor and the volatile species of Fe, Ni, and Co were generated when standard or sample solutions containing formic acid were exposed to a UV photochemical reactor and subsequently separated from the liquid phase for transport to the microplasma and detection of their atomic emission. Limits of detection (LODs) of 0.10, 10, 0.20, and 4.5 MUg L(-1) were obtained for Hg, Fe, Ni and Co, respectively. Compared to conventional microplasma OES, this method not only broadens the scope of elements amenable to determination, but also provides 2- and 7-fold improvement in the LODs for Hg and Ni, respectively. Method validation was demonstrated by analysis of three Certified Reference Materials (GBW08607, DORM-3, and DORM-4) with satisfactory results, and by good spike recoveries (93-111%) from three real water samples. PMID- 26435072 TI - Aryl Bis-Sulfonamide Inhibitors of IspF from Arabidopsis thaliana and Plasmodium falciparum. AB - 2-Methylerythritol 2,4-cyclodiphosphate synthase (IspF) is an essential enzyme for the biosynthesis of isoprenoid precursors in plants and many human pathogens. The protein is an attractive target for the development of anti-infectives and herbicides. Using a photometric assay, a screen of 40 000 compounds on IspF from Arabidopsis thaliana afforded symmetrical aryl bis-sulfonamides that inhibit IspF from A. thaliana (AtIspF) and Plasmodium falciparum (PfIspF) with IC50 values in the micromolar range. The ortho-bis-sulfonamide structural motif is essential for inhibitory activity. The best derivatives obtained by parallel synthesis showed IC50 values of 1.4 MUm against PfIspF and 240 nm against AtIspF. Substantial herbicidal activity was observed at a dose of 2 kg ha(-1) . Molecular modeling studies served as the basis for an in silico search targeted at the discovery of novel, non-symmetrical sulfonamide IspF inhibitors. The designed compounds were found to exhibit inhibitory activities in the double-digit micromolar IC50 range. PMID- 26435074 TI - Electron tomography image reconstruction using data-driven adaptive compressed sensing. AB - Electron tomography (ET) is an increasingly important technique for the study of the three-dimensional morphologies of nanostructures. ET involves the acquisition of a set of two-dimensional projection images, followed by the reconstruction into a volumetric image by solving an inverse problem. However, due to limitations in the acquisition process, this inverse problem is ill-posed (i.e., a unique solution may not exist). Furthermore, reconstruction usually suffers from missing wedge artifacts (e.g., star, fan, blurring, and elongation artifacts). Recently, compressed sensing (CS) has been applied to ET and showed promising results for reducing missing wedge artifacts. This uses image sparsity as a priori knowledge to improve the accuracy of reconstruction, and can require fewer projections than other reconstruction techniques. The performance of CS relies heavily on the degree of sparsity in the selected transform domain and this depends essentially on the choice of sparsifying transform. We propose a new image reconstruction algorithm for ET that learns the sparsifying transform adaptively using a dictionary-based approach. We demonstrate quantitatively using simulations from complex phantoms that this new approach reconstructs the morphology with higher fidelity than either analytically based CS reconstruction algorithms or traditional weighted back projection from the same dataset. SCANNING 38:251-276, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26435075 TI - The Interplay of Size and Surface Functionality on the Cellular Uptake of Sub-10 nm Gold Nanoparticles. AB - Correlation of the surface physicochemical properties of nanoparticles with their interactions with biosystems provides key foundational data for nanomedicine. We report here the systematic synthesis of 2, 4, and 6 nm core gold nanoparticles (AuNP) featuring neutral (zwitterionic), anionic, and cationic headgroups. The cellular internalization of these AuNPs was quantified, providing a parametric evaluation of charge and size effects. Contrasting behavior was observed with these systems: with zwitterionic and anionic particles, uptake decreased with increasing AuNP size, whereas with cationic particles, uptake increased with increasing particle size. Through mechanistic studies of the uptake process, we can attribute these opposing trends to a surface-dictated shift in uptake pathways. Zwitterionic NPs are primarily internalized through passive diffusion, while the internalization of cationic and anionic NPs is dominated by multiple endocytic pathways. Our study demonstrates that size and surface charge interact in an interrelated fashion to modulate nanoparticle uptake into cells, providing an engineering tool for designing nanomaterials for specific biological applications. PMID- 26435076 TI - Identification of six new RHCE variant alleles in individuals of diverse racial origin. AB - BACKGROUND: The introduction of molecular methods into routine blood typing is prompting the identification of new blood group alleles. Discrepancies between the results of genotyping and serology or chance events uncovered during genotyping prompted additional investigations, which revealed six new RHCE variant alleles. STUDY DESIGN AND METHODS: Samples from eight blood donors, two patients (one prenatal), and a patient's relative, all of diverse racial origin, were analyzed by standard serology methods, targeted genotyping arrays, DNA sequencing, and allele-specific polymerase chain reaction. RESULTS: Six new RHCE alleles were identified, namely, RHCE*cE84A, RHCE*ce202G, RHCE*ce307T, RHCE*Ce377G, RHCE*ce697G,712G,733G,744C, and RHCE*Ce733G. CONCLUSION: While implementation of new assays in commercial genotyping platforms to detect the polymorphisms reported here may not be justified given their apparent rarity, software interpretative algorithms may benefit from the identification of new alleles for a more accurate determination of genotypes and prediction of phenotypes. PMID- 26435077 TI - Multiple functions of syncytiotrophoblast mitochondria. AB - The human placenta plays a central role in pregnancy, and the syncytiotrophoblast cells are the main components of the placenta that support the relationship between the mother and fetus, in apart through the production of progesterone. In this review, the metabolic processes performed by syncytiotrophoblast mitochondria associated with placental steroidogenesis are described. The metabolism of cholesterol, specifically how this steroid hormone precursor reaches the mitochondria, and its transformation into progesterone are reviewed. The role of nucleotides in steroidogenesis, as well as the mechanisms associated with signal transduction through protein phosphorylation and dephosphorylation of proteins is discussed. Finally, topics that require further research are identified, including the need for new techniques to study the syncytiotrophoblast in situ using non-invasive methods. PMID- 26435078 TI - The role of bariatric surgery in the management of nonalcoholic fatty liver disease and metabolic syndrome. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD is strongly associated with obesity and metabolic syndrome (MetS). Current treatment of NAFLD is based on weight reduction. Bariatric surgery is the most effective treatment for morbid obesity and its associated metabolic comorbidities. There is evidence indicating that bariatric surgery improves histological and biochemical parameters of NAFLD, but currently is not considered a treatment option for NAFLD. The aim of this work is to review the evidence for the effects of bariatric surgery on NAFLD and the MetS. We found that insulin resistance, alterations in glucose metabolism, hypertension, plasma lipids, transaminases, liver steatosis, steatohepatitis and fibrosis improve after bariatric surgery. Weight loss and improvement of NAFLD are greater after RYGB than after other interventions. These findings were obtained from retrospective or cohort studies. There are no studies designed to evaluate liver specific mortality, liver transplantation, or quality of life. Patients with indications for bariatric surgery will benefit from the improvements in the MetS and NAFLD. PMID- 26435079 TI - Gesture and speech during shared book reading with preschoolers with specific language impairment. AB - This study examined (a) the relationship between gesture and speech produced by children with specific language impairment (SLI) and typically developing (TD) children, and their mothers, during shared book-reading, and (b) the potential effectiveness of gestures accompanying maternal speech on the conversational responsiveness of children. Fifteen preschoolers with expressive SLI were compared with fifteen age-matched and fifteen language-matched TD children. Child and maternal utterances were coded for modality, gesture type, gesture-speech informational relationship, and communicative function. Relative to TD peers, children with SLI used more bimodal utterances and gestures adding unique information to co-occurring speech. Some differences were mirrored in maternal communication. Sequential analysis revealed that only in the SLI group maternal reading accompanied by gestures was significantly followed by child's initiatives, and when maternal non-informative repairs were accompanied by gestures, they were more likely to elicit adequate answers from children. These findings support the 'gesture advantage' hypothesis in children with SLI, and have implications for educational and clinical practice. PMID- 26435080 TI - Cue conflicts in context: interplay between morphosyntax and discourse context in Danish preschoolers' semantic role assignment. AB - When learning their first language, children develop strategies for assigning semantic roles to sentence structures, depending on morphosyntactic cues such as case and word order. Traditionally, comprehension experiments have presented transitive clauses in isolation, and cross-linguistically children have been found to misinterpret object-first constructions by following a word-order strategy (Chan, Lieven & Tomasello, 2009; Dittmar, Abbot-Smith, Lieven & Tomasello, 2008; Hakuta, 1982; McDonald, 1989; Slobin & Bever, 1982). In an act out study, we replicated this finding with Danish preschoolers. However, object first clauses may be context-sensitive structures, which are infelicitous in isolation. In a second act-out study we presented OVS clauses in supportive and unsupportive discourse contexts and in isolation and found that five- to six-year olds' OVS comprehension was enhanced in discourse-pragmatically felicitous contexts. Our results extend previous findings of preschoolers' sensitivity to discourse-contextual cues in sentence comprehension (Hurewitz, 2001; Song & Fisher, 2005) to the basic task of assigning agent and patient roles. PMID- 26435081 TI - Prelinguistic vocalizations distinguish pointing acts. AB - The current study investigated whether point-accompanying characteristics, like vocalizations and hand shape, differentiate infants' underlying motives of prelinguistic pointing. We elicited imperative (requestive) and declarative (expressive and informative) pointing acts in experimentally controlled situations, and analyzed accompanying characteristics. Experiment 1 revealed that prosodic characteristics of point-accompanying vocalizations distinguished requestive from both expressive and informative pointing acts, with little differences between the latter two. In addition, requestive points were more often realized with the whole hand than the index finger, while this was the opposite for expressive and informative acts. Experiment 2 replicated Experiment 1, revealing distinct prosodic characteristics for requestive pointing also when the referent was distal and when it had an index-finger shape. Findings reveal that beyond the social context, point-accompanying vocalizations give clues to infants' underlying intentions when pointing. PMID- 26435082 TI - Attention to the mouth and gaze following in infancy predict language development - CORRIGENDUM. PMID- 26435083 TI - The role of S100 proteins and their receptor RAGE in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with low survival rates. Current therapeutic treatments have very poor response rates due to the high inherent chemoresistance of the pancreatic-cancer cells. Recent studies have suggested that the receptor for advanced glycation end products (RAGE) and its S100 protein ligands play important roles in the progression of PDAC. We will discuss the potential role of S100 proteins and their receptor, RAGE, in the development and progression of pancreatic cancer. PMID- 26435084 TI - Bcl-xL-mediated antioxidant function abrogates the disruption of mitochondrial dynamics induced by LRRK2 inhibition. AB - We have used the human neuroblastoma cell line SH-SY5Y overexpressing Bcl-xL (SH SY5Y/Bcl-xL) to clarify the effects of this mitochondrial protein on the control of mitochondrial dynamics and the autophagic processes which occur after the inhibition of leucine-rich repeat kinase 2 (LRRK2) with GSK2578215A. In wild type (SH-SY5Y/Neo) cells, GSK2578215A (1nM) caused a disruption of mitochondrial morphology and an imbalance in intracellular reactive oxygen species (ROS) as indicated by an increase in dichlorofluorescein fluorescence and 4 hydroxynonenal. However, SH-SY5Y/Bcl-xL cells under GSK2578215A treatment, unlike the wild type, preserved a high mitochondrial membrane potential and did not exhibit apoptotical chromatins. In contrast to wild type cells, in SH-SY5Y/Bcl-xL cells, GSK2578215A did not induce mitochondrial translocation of neither dynamin related protein-1 nor the proapoptotic protein, Bax. In SH-SY5Y/Neo, but not SH SY5Y/Bcl-xL cells, mitochondrial fragmentation elicited by GSK2578215A precedes an autophagic response. Furthermore, the overexpression of Bcl-xL protein restores the autophagic flux pathway disrupted by this inhibitor. SH-SY5Y/Neo, but not SH-SY5Y/Bcl-xL cells, responded to LRRK2 inhibition by an increase in the levels of acetylated tubulin, indicating that this was abrogated by Bcl-xL overexpression. This hyperacetylation of tubulin took place earlier than any of the above-mentioned events suggesting that it is involved in the autophagic flux interruption. Pre-treatment with tempol prevented the GSK2578215A-induced mitochondrial fragmentation, autophagy and the rise in acetylated tubulin in SH SY5Y/Neo cells. Thus, these data support the notion that ROS act as a second messenger connexion between LRRK2 inhibition and these deleterious responses, which are markedly alleviated by the Bcl-xL-mediated ROS generation blockade. PMID- 26435085 TI - An efficient and reproducible method for improving growth of a soil alga (Chlorococcum infusionum) for toxicity assays. AB - This study evaluated five methods of soil inoculation using the soil alga Chlorococcum infusionum to determine the most efficient and reproducible method for promoting the growth of soil algae for toxicity testing. The five techniques included application of C. infusionum in a circle on top of the soil, to a central spot on top of the soil, to a central spot in the subsoil, to one side on top of the soil, and application divided between a circle and a central spot on top of the soil. Of these, the first method generated the greatest amount of chlorophyll fluorescence and was the method with the best reproducibility. We evaluated the applicability of this method in an assessment of the toxicity of copper and nickel to C. infusionum in two representative standard soils. Copper (20-75 mg/kg for OECD soil and 20-60 mg/kg Lufa 2.2 soil) and nickel (400-500 mg/kg for OECD soil and 60-100 mg/kg Lufa 2.2 soil) reduced the chlorophyll fluorescence of C. infusionum when the inoculation was delivered in a circle on top of both soil types. To our knowledge, this is the first study to assess the suitability of different soil algal inoculation methods for terrestrial toxicity testing. PMID- 26435086 TI - Short-Term Effects of Kinesiotaping on Pain and Joint Alignment in Conservative Treatment of Hallux Valgus. AB - OBJECTIVE: The main aim of this study was to measure short-term effects of kinesiotaping on pain and joint alignment in the conservative treatment of hallux valgus. METHOD: Twenty-one female patients diagnosed with a total of 34 feet with hallux valgus (13 bilateral, 6 right, and 2 left) participated in this study. Kinesiotaping was implemented after the first assessment and renewed in days 3, 7, and 10. The main outcome measures were pain, as assessed using visual analog scale, and hallux adduction angle, as measured by goniometry. Secondary outcome measure was patients' functional status, as measured by Foot Function Index and the hallux valgus scale of the American Orthopaedic Foot and Ankle Society (AOFAS). The radiographic results were also measured before and after 1 month of treatment. The Wilcoxon test was used to compare the differences between initial and final scores of AOFAS, as well as FFI scales and hallux valgus angle assessment scores. RESULTS: There was a significant reduction in goniometric measurement of hallux valgus angle (P = .001). There was a significant reduction in pain intensity (P = .001) and AOFAS and Foot Function Index scores at the end of the treatment (P = .001 and P = .001, respectively). There was a significant difference between radiographic results in 1-month control (P = .009). CONCLUSIONS: For this group of female patients, pain and joint alignment were improved after a 10-day kinesiotape implementation in patients with hallux valgus. The findings showed short-term decreased pain and disability in hallux valgus deformity. PMID- 26435087 TI - Effect of Interactive Neurostimulation Therapy on Inflammatory Response in Patients With Chronic and Recurrent Mechanical Neck Pain. AB - OBJECTIVE: The purpose of this study is to evaluate the effect of treatment with a novel noninvasive interactive neurostimulation device (InterX5000) on the production of inflammatory biomarkers in chronic and recurrent mechanical neck pain (NP) syndrome. METHODS: This study represents pilot biological data from a randomized controlled clinical trial. Twenty-five NP patients and 14 asymptomatic subjects included for baseline comparison only completed the study. The patients received 6 InterX5000 or placebo treatments within 2 weeks, and pretreatment and post-treatment blood samples were collected for in vitro determination of biomarker production. Whole blood cell cultures were activated by lipopolysaccharide or by the combination of lipopolysaccharide and phytohemagglutinin for 24 to 48 hours. The levels of tumor necrosis factor alpha (TNFalpha) and its soluble type II receptor (sTNFR II), interleukin (IL) 1, IL-1 receptor antagonist (IL-1RA), IL-6, IL-10, and monocyte chemotactic protein (CCL2/MCP-1) were determined by specific immunoassays. RESULTS: Compared with asymptomatic subjects, baseline production levels of all proinflammatory mediators (TNFalpha, IL-1beta, IL-6, and CCL2/MCP-1) were significantly augmented or trended higher (P = .000-.008) in patients with NP. Of the anti-inflammatory markers, only IL-1RA was significantly elevated (P = .004). The increase in IL-10 and tumor necrosis factor receptor II levels did not reach statistical significance. Neither InterX5000 nor placebo therapy had any significant effect on the production of the inflammatory mediators over the study period. CONCLUSION: This investigation determined that inflammatory cytokine pathways are activated in NP patients but found no evidence that a short course of InterX5000 treatment normalized the production of inflammatory biomarkers. PMID- 26435095 TI - Limitations of care and do not resuscitate orders: A patient's/relative's perspective. PMID- 26435094 TI - Novel in vivo imaging analysis of an inner ear drug delivery system: Drug availability in inner ear following different dose of systemic drug injections. AB - Systemic application of drugs is commonly used in clinical situations. Some of these drugs are ototoxic. Since there are few studies on in vivo monitoring of drug delivery dynamics, the time course or bioavailability of drugs in the inner ear of live animals following systemic drug application remains unknown. For instance, it is unknown whether the volume of a drug delivered systemically correlates with its inner ear pharmacokinetics. We previously established a new in vivo imaging system to monitor drug delivery in live mice. In the present study, we used this system to compare drug concentration in the inner ear over time after systemic drug injections. We used transgenic GFAP-Luc mice that harbor a firefly luciferase gene expression cassette regulated by 12 kb of murine GFAP promoter and human beta-globin intron 2. Luciferin delivered into the inner ear of these mice reacts with luciferase, and the resulting signals are detected in GFAP-expressing cells in the cochlear nerve. Thus, we assessed in the inner ear the intensity and duration of luciferin/luciferase signals after systemic injections of different volumes of luciferin. An IVIS((r)) imaging system was used to observe signals, and these signals were compared to the drug dynamics of luciferin delivered through subcutaneous (sc) injections. The volume of sc injected drug correlated significantly with photon counts measured in the inner ear. Photons were detected almost immediately after injection, peaking 20 min after injection. Drug concentration did not affect inner ear signals. Luciferin injected systemically appeared in the inner ear between highest and lowest concentration. Drug volume is an important parameter to know if the inner ear requires a higher level of the drug. We observed that it is the volume of a drug not its concentration-that is the important factor. Indeed, the more volume of a drug injected systemically increased the concentration of that drug in the inner ear. This study provides a better understanding of in vivo drug delivery dynamics measured in the inner ear. Further studies will show whether a high dosage of drug is effective or not. PMID- 26435096 TI - Determinants of Dyspnea in Chronic Heart Failure. AB - BACKGROUND: Dyspnea is a hallmark symptom of heart failure (HF), associated with impaired functional capacity and quality of life. The experience of dyspnea is multifactorial and may originate from different sources. This study set out to examine the relative importance of potential contributors to dyspnea, ie, disease severity, inflammation and psychologic distress in a large prospective cohort of chronic HF patients. This study further aimed to examine the differential influence of cognitive and somatic symptoms of psychologic distress. METHODS AND RESULTS: Dyspnea complaints (Health Complaints Scale), demographic and clinical variables, and psychologic factors (ie, depression, anxiety, and Type D personality) were assessed in 464 HF patients (mean age 66.0 y, 70% men) at baseline and 1-year follow-up. Inflammatory markers (ie, tumor necrosis factor [TNF] alpha, interleukin [IL] 6, IL-10, soluble TNF receptors 1 and 2) were also assessed at both time points in a subsample (n = 247). Linear mixed modeling analysis with maximum likelihood estimation showed that when determinant clusters were entered separately, comorbid chronic obstructive pulmonary disease (COPD) was significantly associated with dyspnea complaints (P = .039), as were depression (P < .001) and anxiety (P < .001), whereas inflammation did not significantly affect dyspnea complaints. When all determinant clusters and covariates were entered together, results showed that body mass index (P = .013), COPD (P = .034), age (P = .005), depression (P < .001), and anxiety (P < .001) were significant independent associates of dyspnea complaints. Somatic depressive and somatic anxiety symptoms were responsible for these latter associations. CONCLUSIONS: The experience and report of dyspnea in HF is determined foremost by somatic symptoms of psychologic distress, being of older age, being overweight, and having comorbid COPD, with disease severity and systemic inflammation levels playing an ancillary role. These findings suggest that psychologic distress should be considered when treating dyspnea complaints in patients with HF. PMID- 26435098 TI - Home-based supervised exercise versus hospital-based supervised exercise or unsupervised walk advice as treatment for intermittent claudication: a systematic review. AB - OBJECTIVE: To evaluate the effects of home-based supervised exercise vs hospital based supervised exercise, and the effects of home-based supervised exercise vs unsupervised "go home and walk advice" on daily life and corridor-walking capacity, health-related quality of life and patient-reported functional walking capacity in patients with intermittent claudication. DATA SOURCES: Systematic literature searches were conducted in PubMed, EMBASE, ProQuest, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED), the Cochrane Library, and a number of Health Technology Assessment (HTA)-databases in October 2014. STUDY SELECTION: Randomized controlled trials and non-randomized controlled trials (> 100 patients) were considered for inclusion. DATA EXTRACTION: Data extraction and risk of bias assessment was performed independently and discussed in meetings. DATA SYNTHESIS: Seven randomized controlled trials and 2 non-randomized controlled studies fulfilled the inclusion criteria. The included studies had some, or major, limitations. CONCLUSION: Based on a low quality of evidence, home based supervised exercise may lead to less improvement in maximum and pain-free walking distance, and in more improvement in daily life walking capacity, compared with hospital-based supervised exercise. Home-based supervised exercise may improve maximum and pain-free walking distance compared with "go home and walk advice" and result in little or no difference in health-related quality of life and functional walking capacity compared with hospital-based supervised exercise or "go home and walk advice". Further research is needed to establish the optimal exercise modality for these patients. PMID- 26435097 TI - Intersections Between Microbiome and Heart Failure: Revisiting the Gut Hypothesis. AB - Microbes play an important role in human health and disease. In the setting of heart failure (HF), substantial hemodynamic changes, such as hypoperfusion and congestion in the intestines, can alter gut morphology, permeability, function, and possibly the growth and composition of gut microbiota. These changes can disrupt the barrier function of the intestines and exacerbate systemic inflammation via microbial or endotoxin translocation into systemic circulation. Furthermore, cardiorenal alterations via metabolites derived from gut microbiota can potentially mediate or modulate HF pathophysiology. Recently, trimethylamine N-oxide (TMAO) has emerged as a key mediator that provides a mechanistic link between gut microbiota and multiple cardiovascular diseases, including HF. Potential intervention strategies which may target this microbiota-driven pathology include dietary modification, prebiotics/probiotics, and selective binders of microbial enzymes or molecules, but further investigations into their safety and efficacy are warranted. PMID- 26435099 TI - Development of a patient-reported outcome: the Neck OutcOme Score (NOOS)--Content and construct validity. AB - OBJECTIVE: To develop a patient-reported outcome evaluating the impact of neck pain. The results of item generation and reduction and subscale structure in support of the content and construct validity of the measure are reported. METHODS: Items were generated from the literature and through focus groups including patients with neck pain and healthcare professionals, respectively. Item reduction was based on focus groups and field-tested questionnaire data. Construct validity was assessed using exploratory factor analysis. RESULTS: Focus groups containing 24 patients (mean age 57.2 (standard deviation (SD) 15.9) years, range 24-85 years); 19 women) and 12 healthcare professionals were conducted before data saturation was achieved. A total of 196 patients with neck pain (mean age 47.8 (SD 13.7) years), range 18-89 years; 146 women) completed the preliminary questionnaire. Overall 35 items were removed from the original 69. A multidimensional questionnaire, divided into five subscales, was developed from the remaining 34 items: mobility; symptoms; sleep disturbance; everyday activity and pain; and participation in everyday life. Exploratory factor analysis supported a 5-subscale structure. CONCLUSION: The Neck OutcOme Score has excellent content validity and preliminary results support a 5-subscale structure. Additional work is needed to assess the reliability, further construct validity and responsiveness. PMID- 26435100 TI - Reply by Hueber et al. PMID- 26435102 TI - Reply by Elshal et al. PMID- 26435101 TI - Re: Photoselective Vaporization of the Prostate for Benign Prostatic Hyperplasia Using the 180 Watt System: Multicenter Study of the Impact of Prostate Size on Safety and Outcomes and Re: GreenLightTM Laser (XPS) Photoselective Vapo Enucleation versus Holmium Laser Enucleation of the Prostate for the Treatment of Symptomatic Benign Prostatic Hyperplasia: A Randomized Controlled Study: P. A. Hueber, M. N. Bienz, R. Valdivieso, H. Lavigueur-Blouin, V. Misrai, M. Rutman, A. E. Te, B. Chughtai, N. J. Barber, A. M. Emara, R. Munver, Q. D. Trinh and K. C. Zorn J Urol 2015; 194: 462-469. and A. M. Elshal, M. A. Elkoushy, A. R. El-Nahas, A. M. Shoma, A. Nabeeh, S. Carrier and M. M. Elhilali J Urol 2015; 193: 927-934. PMID- 26435103 TI - Derivation and validation of simple anthropometric equations to predict adipose tissue mass and total fat mass with MRI as the reference method. AB - The reference organ-level body composition measurement method is MRI. Practical estimations of total adipose tissue mass (TATM), total adipose tissue fat mass (TATFM) and total body fat are valuable for epidemiology, but validated prediction equations based on MRI are not currently available. We aimed to derive and validate new anthropometric equations to estimate MRI-measured TATM/TATFM/total body fat and compare them with existing prediction equations using older methods. The derivation sample included 416 participants (222 women), aged between 18 and 88 years with BMI between 15.9 and 40.8 (kg/m2). The validation sample included 204 participants (110 women), aged between 18 and 86 years with BMI between 15.7 and 36.4 (kg/m2). Both samples included mixed ethnic/racial groups. All the participants underwent whole-body MRI to quantify TATM (dependent variable) and anthropometry (independent variables). Prediction equations developed using stepwise multiple regression were further investigated for agreement and bias before validation in separate data sets. Simplest equations with optimal R (2) and Bland-Altman plots demonstrated good agreement without bias in the validation analyses: men: TATM (kg)=0.198 weight (kg)+0.478 waist (cm)-0.147 height (cm)-12.8 (validation: R 2 0.79, CV=20 %, standard error of the estimate (SEE)=3.8 kg) and women: TATM (kg)=0.789 weight (kg)+0.0786 age (years)-0.342 height (cm)+24.5 (validation: R (2) 0.84, CV=13 %, SEE=3.0 kg). Published anthropometric prediction equations, based on MRI and computed tomographic scans, correlated strongly with MRI-measured TATM: (R (2) 0.70-0.82). Estimated TATFM correlated well with published prediction equations for total body fat based on underwater weighing (R (2) 0.70-0.80), with mean bias of 2.5 4.9 kg, correctable with log-transformation in most equations. In conclusion, new equations, using simple anthropometric measurements, estimated MRI-measured TATM with correlations and agreements suitable for use in groups and populations across a wide range of fatness. PMID- 26435104 TI - Formation of a Neurosensory Organ by Epithelial Cell Slithering. AB - Epithelial cells are normally stably anchored, maintaining their relative positions and association with the basement membrane. Developmental rearrangements occur through cell intercalation, and cells can delaminate during epithelial-mesenchymal transitions and metastasis. We mapped the formation of lung neuroepithelial bodies (NEBs), innervated clusters of neuroendocrine/neurosensory cells within the bronchial epithelium, revealing a targeted mode of cell migration that we named "slithering," in which cells transiently lose epithelial character but remain associated with the membrane while traversing neighboring epithelial cells to reach cluster sites. Immunostaining, lineage tracing, clonal analysis, and live imaging showed that NEB progenitors, initially distributed randomly, downregulate adhesion and polarity proteins, crawling over and between neighboring cells to converge at diametrically opposed positions at bronchial branchpoints, where they reestablish epithelial structure and express neuroendocrine genes. There is little accompanying progenitor proliferation or apoptosis. Activation of the slithering program may explain why lung cancers arising from neuroendocrine cells are highly metastatic. PMID- 26435105 TI - A Molecular Code for Identity in the Vomeronasal System. AB - In social interactions among mammals, individuals are recognized by olfactory cues, but identifying the key signals among thousands of compounds remains a major challenge. To address this need, we developed a new technique, component activity matching (CAM), to select candidate ligands that "explain" patterns of bioactivity across diverse complex mixtures. Using mouse urine from eight different sexes and strains, we identified 23 components to explain firing rates in seven of eight functional classes of vomeronasal sensory neurons. Focusing on a class of neurons selective for females, we identified a novel family of vomeronasal ligands, steroid carboxylic acids. These ligands accounted for much of the neuronal activity of urine from some female strains, were necessary for normal levels of male investigatory behavior of female scents, and were sufficient to trigger mounting behavior. CAM represents the first step toward an exhaustive characterization of the molecular cues for natural behavior in a mammalian olfactory system. PMID- 26435107 TI - Molecular structure of self-healing polyampholyte hydrogels analyzed from tensile behaviors. AB - Recently, charge balanced polyampholytes (PA) have been found to form tough and self-healing hydrogels. This class of physical hydrogels have a very high equilibrated polymer concentration in water (ca. 40-50 wt%), and are strongly viscoelastic. They are synthesized by random copolymerization of equal amounts of oppositely charged monomers at a high concentration, followed by a dialysis process of the small counter-ions and co-ions in water. The randomly distributed, opposite charges of the polymer form multiple ionic bonds of intra- and inter chains with strength distribution. The strong inter-chain bonds, stabilized by topological entanglement, serve as quasi-permanent crosslinks, imparting the elasticity, while the weak bonds, both inter- and intra-chains, reversibly break and re-form to dissipate energy to toughen the materials. In this work, we intend to clarify the structure of the physical PA hydrogels from the tensile behaviors of the PA hydrogels. To clarify the structure and its formation mechanism, we analysed the tensile behaviors of the samples before and after the dialysis. We separated the quasi-permanent crosslinking of strong inter-chain bonds and the dynamic crosslinking of weak inter-chain bonds by using a combined model that consists of the Upper Convected Maxwell model and the Gent strain hardening model. The model fitting of the tensile behaviors extracts quantitative structural parameters, including the densities of weak and strong inter-chain bonds and the theoretical finite extensibility of polymer chains. Based on the fitting results of the combined model, the structural parameters of partial chains at a fixed observation time, including the Kuhn number, Kuhn length, and chain conformation, are determined using the scaling theory. The effects of monomer concentration at preparation, the effect of dialysis and the initial strain rate on the dynamic structure of PA gels, are discussed based on these analyses. PMID- 26435108 TI - Fighting Breast Cancer: Better Detection and Better Therapy Make for a Strong One Two Punch in the Fight Against Breast Cancer. PMID- 26435109 TI - The Surpassing Joys of Leadership. PMID- 26435106 TI - Mapping Synaptic Input Fields of Neurons with Super-Resolution Imaging. AB - As a basic functional unit in neural circuits, each neuron integrates input signals from hundreds to thousands of synapses. Knowledge of the synaptic input fields of individual neurons, including the identity, strength, and location of each synapse, is essential for understanding how neurons compute. Here, we developed a volumetric super-resolution reconstruction platform for large-volume imaging and automated segmentation of neurons and synapses with molecular identity information. We used this platform to map inhibitory synaptic input fields of On-Off direction-selective ganglion cells (On-Off DSGCs), which are important for computing visual motion direction in the mouse retina. The reconstructions of On-Off DSGCs showed a GABAergic, receptor subtype-specific input field for generating direction selective responses without significant glycinergic inputs for mediating monosynaptic crossover inhibition. These results demonstrate unique capabilities of this super-resolution platform for interrogating neural circuitry. PMID- 26435110 TI - Authors' Reply. PMID- 26435111 TI - Referring Providers' Knowledge About Studies Ordered for Their Patients. PMID- 26435112 TI - Re: "Patients Prefer Results From the Ordering Provider and Access to Their Radiology Reports". PMID- 26435113 TI - Communication of Radiology Reports to Patients: Does One Size Fit All? PMID- 26435114 TI - Diagnostic Reference Levels as They Are or as They Should Be: A Reply to Miller, Vano, and Rehani. PMID- 26435115 TI - Complexity and the Impact of Chronic Diseases. PMID- 26435116 TI - CT Pulmonary Angiography: Using Decision Rules in the Emergency Department. AB - PURPOSE: The aim of this study was to assess the appropriateness of utilization and diagnostic yields of CT pulmonary angiography (CTPA), comparing two commonly applied decision rules, the pulmonary embolism (PE) rule-out criteria (PERC) and the modified Wells criteria (mWells), in the emergency department (ED) setting. METHODS: Institutional review board approval was obtained for this HIPAA compliant, prospective-cohort, academic single-center study. Six hundred two consecutive adult ED patients undergoing CTPA for suspected PE formed the study population. The outcome was positive or negative for PE by CTPA and at 6-month follow-up. PERC and mWells scores were calculated. A positive PERC score was defined as meeting one or more criteria and a positive mWells score as >4. The percentage of CT pulmonary angiographic examinations that could have been avoided and the diagnostic yield of CTPA using PERC, mWells, and PERC applied to a negative mWells score were calculated. RESULTS: The diagnostic yield of CTPA was 10% (61 of 602). By applying PERC, mWells, and PERC to negative mWells score, 17.6% (106 of 602), 45% (273 of 602), and 17.1% (103 of 602) of CT pulmonary angiographic examinations, respectively, could have been avoided. The diagnostic yield in PERC-positive patients was higher than in mWells-positive patients (10% [59 of 602] vs 8% [49 of 602], P < .0001). Among PERC-negative and mWells negative patients, the diagnostic yields for PE were 1.9% (2 of 106) and 4% (12 of 273), respectively (P = .004). The diagnostic yield of a negative PERC score applied to a negative mWells score was 1.9% (2 of 103). CONCLUSIONS: The use of PERC in the ED has the potential to significantly reduce the utilization of CTPA and misses fewer cases of PE compared with mWells, and it is therefore a more efficient decision tool. PMID- 26435117 TI - Opportunistic Osteoporosis Screening: Addition of Quantitative CT Bone Mineral Density Evaluation to CT Colonography. AB - PURPOSE: For patients undergoing CT colonography (CTC), the screening presents an opportunity for concurrent osteoporosis screening, without increasing radiation exposure or the time involved for the patient, using proximal femur quantitative CT-CT x-ray absorptiometry (QCT-CTXA). METHODS: This cohort included 129 women and 112 men (mean age: 60.1 +/- 8.2 years; range: 50-95 years) who underwent CTC between March 2013 and September 2014. Areal bone mineral density (BMD; g/cm(2)), and resultant left femoral neck T-score, was prospectively measured on the supine CT series. QCT results were reported with the CTC. Chart review evaluated whether the patients were eligible for BMD screening according to guidelines from the US Preventive Services Task Force and the National Osteoporosis Foundation guidelines; whether they had undergone prior BMD testing; and whether QCT results changed patient management. RESULTS: Overall, 68.0% (164 of 241) of patients from this cohort had not previously undergone BMD screening. According to the National Osteoporosis Foundation guidelines, 44.0% (106 of 241) of patients were eligible for screening. T-scores within the osteopenic and osteoporotic range were detected in 32.3% (78 of 241) and 5.0% (12 of 241) of patients, respectively. Of these patients with low BMD, 66.7% (60 of 90) either had not previously undergone screening or were eligible for BMD testing. Reporting of QCT-CTXA T-scores altered management in 9 patients (3.7%) who had low BMD. CONCLUSIONS: Maximizing the pre-existing value from imaging studies is crucial in the current era of health care reform. We demonstrate that colorectal and osteoporosis screening can be combined at CT examination, adding clinical and likely economic value. PMID- 26435118 TI - ACR Appropriateness Criteria Crohn Disease. AB - Crohn disease is a chronic inflammatory disorder involving the gastrointestinal tract, characterized by episodic flares and times of remission. Underlying structural damage occurs progressively, with recurrent bouts of inflammation. The diagnosis and management of this disease process is dependent on several clinical, laboratory, imaging, endoscopic, and histologic factors. In recent years, with the maturation of CT enterography, and MR enterography, imaging has played an increasingly important role in relation to Crohn Disease. In addition to these specialized examination modalities, ultrasound and routine CT have potential uses. Fluoroscopy, radiography, and nuclear medicine may be less beneficial depending on the clinical scenario. The imaging modality best suited to evaluating this disease may change, depending on the target population, severity of presentation, and specific clinical situation. This document presents seven clinical scenarios (variants) in both the adult and pediatric populations and rates the appropriateness of the available imaging options. They are summarized in a consolidated table, and the underlying rationale and supporting literature are presented in the accompanying narrative. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 26435119 TI - Can We Predict Patient Wait Time? AB - PURPOSE: The importance of patient wait-time management and predictability can hardly be overestimated: For most hospitals, it is the patient queues that drive and define every bit of clinical workflow. The objective of this work was to study the predictability of patient wait time and identify its most influential predictors. METHODS: To solve this problem, we developed a comprehensive list of 25 wait-related parameters, suggested in earlier work and observed in our own experiments. All parameters were chosen as derivable from a typical Hospital Information System dataset. The parameters were fed into several time-predicting models, and the best parameter subsets, discovered through exhaustive model search, were applied to a large sample of actual patient wait data. RESULTS: We were able to discover the most efficient wait-time prediction factors and models, such as the line-size models introduced in this work. Moreover, these models proved to be equally accurate and computationally efficient. Finally, the selected models were implemented in our patient waiting areas, displaying predicted wait times on the monitors located at the front desks. The limitations of these models are also discussed. CONCLUSIONS: Optimal regression models based on wait-line sizes can provide accurate and efficient predictions for patient wait time. PMID- 26435120 TI - Modality Access: Strategies for Optimizing Throughput. PMID- 26435121 TI - Unnecessary Repeat Radiologic Examinations in the Emergency Department After Interfacility Transfer. PMID- 26435122 TI - The Radiology Communication Quiz: Are You an Effective Communicator? PMID- 26435123 TI - Radiology Resident Education in France from Medical School Through Board Certification. PMID- 26435124 TI - Curies, and Grays, and Sieverts, Oh My: A Guide for Discussing Radiation Dose and Risk of Molecular Breast Imaging. PMID- 26435125 TI - Radiology and Radiation Oncology Practices Should Provide Lactation Facilities for All Eligible Employees. PMID- 26435126 TI - Functionalized ZnO/ZnO2 n-N straddling heterostructure achieved by oxygen plasma bombardment for highly selective methane sensing. AB - Metal oxide semiconductors have been extensively used as reducing gas sensors with major limitations regarding selectivity and operating temperature which is relatively high for most of the cases making the device unusable in some critical situations. Higher operating temperature is also associated with the higher power consumption, which goes against the miniaturization of the device. In order to resolve these problems, here we introduced a ZnO/ZnO2 straddling 'n-N' isotype heterostructure as a highly selective and sensitive methane sensor at moderately low operating temperature. ZnO-Zn(OH)2 precursor films were treated in oxygen plasma in a pulsed DC magnetron sputtering system. Morphological analyses by field emission scanning electron microscopy showed flake like growth of the grains with high surface roughness, whereas X-ray diffraction (XRD) showed polycrystalline nature of the films. Polycrystalline ZnO2 peaks were observed in the XRD pattern in addition to the existing ZnO, which indicates modification of the precursor to oxygen rich heterostructure of ZnO/ZnO2. This was further supported by the shifting of the O1s peak in the X-ray photoelectron spectroscopic analysis. Plasma treated ZnO/ZnO2 heterostructured films were found to show high selectivity towards methane (with respect to H2S and CO) and sensitivity (~96%) at a comparatively low operating temperature. PMID- 26435127 TI - A novel AgNP/DNA/TPdye conjugate-based two-photon nanoprobe for GSH imaging in cell apoptosis of cancer tissue. AB - In the present study, a novel two-photon nanoprobe has been developed and successfully applied in glutathione (GSH) imaging in cell apoptosis of cancer tissue. PMID- 26435128 TI - Implicit Racial Biases in Preschool Children and Adults From Asia and Africa. AB - This research used an Implicit Racial Bias Test to investigate implicit racial biases among 3- to 5-year-olds and adult participants in China (N = 213) and Cameroon (N = 257). In both cultures, participants displayed high levels of racial biases that remained stable between 3 and 5 years of age. Unlike adults, young children's implicit racial biases were unaffected by the social status of the other-race groups. Also, unlike adults, young children displayed overt explicit racial biases, and these biases were dissociated from their implicit biases. The results provide strong evidence for the early emergence of implicit racial biases and point to the need to reduce them in early childhood. PMID- 26435129 TI - The 2012/2013 ABRF Proteomic Research Group Study: Assessing Longitudinal Intralaboratory Variability in Routine Peptide Liquid Chromatography Tandem Mass Spectrometry Analyses. AB - Questions concerning longitudinal data quality and reproducibility of proteomic laboratories spurred the Protein Research Group of the Association of Biomolecular Resource Facilities (ABRF-PRG) to design a study to systematically assess the reproducibility of proteomic laboratories over an extended period of time. Developed as an open study, initially 64 participants were recruited from the broader mass spectrometry community to analyze provided aliquots of a six bovine protein tryptic digest mixture every month for a period of nine months. Data were uploaded to a central repository, and the operators answered an accompanying survey. Ultimately, 45 laboratories submitted a minimum of eight LC MSMS raw data files collected in data-dependent acquisition (DDA) mode. No standard operating procedures were enforced; rather the participants were encouraged to analyze the samples according to usual practices in the laboratory. Unlike previous studies, this investigation was not designed to compare laboratories or instrument configuration, but rather to assess the temporal intralaboratory reproducibility. The outcome of the study was reassuring with 80% of the participating laboratories performing analyses at a medium to high level of reproducibility and quality over the 9-month period. For the groups that had one or more outlying experiments, the major contributing factor that correlated to the survey data was the performance of preventative maintenance prior to the LC-MSMS analyses. Thus, the Protein Research Group of the Association of Biomolecular Resource Facilities recommends that laboratories closely scrutinize the quality control data following such events. Additionally, improved quality control recording is imperative. This longitudinal study provides evidence that mass spectrometry-based proteomics is reproducible. When quality control measures are strictly adhered to, such reproducibility is comparable among many disparate groups. Data from the study are available via ProteomeXchange under the accession code PXD002114. PMID- 26435131 TI - Diabetes in Asians. AB - The prevalence of diabetes is increasing globally, particularly in Asia. According to the 2013 Diabetes Atlas, an estimated 366 million people are affected by diabetes worldwide; 36% of those affected live in the Western Pacific region, with a significant proportion in East Asia. The reasons for this marked increase in the prevalence of diabetes can be extrapolated from several distinct features of the Asian region. First, the two most populated countries, China and India, are located in Asia. Second, Asians have experienced extremely rapid economic growth, including rapid changes in dietary patterns, during the past decades. As a result, Asians tend to have more visceral fat within the same body mass index range compared with Westerners. In addition, increased insulin resistance relative to reduced insulin secretory function is another important feature of Asian individuals with diabetes. Young age of disease onset is also a distinctive characteristic of these patients. Moreover, changing dietary patterns, such as increased consumption of white rice and processed red meat, contributes to the deteriorated lifestyle of this region. Recent studies suggest a distinctive responsiveness to novel anti-diabetic agents in Asia; however, further research and efforts to reverse the increasing prevalence of diabetes are needed worldwide. PMID- 26435132 TI - Exercise and Depression. PMID- 26435130 TI - Mutation Profile of Well-Differentiated Thyroid Cancer in Asians. AB - Recent advances in molecular diagnostics have led to significant insights into the genetic basis of thyroid tumorigenesis. Among the mutations commonly seen in thyroid cancers, the vast majority are associated with the mitogen-activated protein kinase pathway. B-Raf proto-oncogene (BRAF) mutations are the most common mutations observed in papillary thyroid cancers (PTCs), followed by RET/PTC rearrangements and RAS mutations, while follicular thyroid cancers are more likely to harbor RAS mutations or PAX8/peroxisome proliferator-activated receptor gamma (PPARgamma) rearrangements. Beyond these more common mutations, alterations in the telomerase reverse transcriptase (TERT) promoter have recently been associated with clinicopathologic features, disease prognosis, and tumorigenesis in thyroid cancer. While the mutations underlying thyroid tumorigenesis are well known, the frequency of these mutations is strongly associated with geography, with clear differences reported between Asian and Western countries. Of particular interest is the prevalence of BRAF mutations, with Korean patients exhibiting the highest rate of BRAF-associated thyroid cancers in the world. Here, we review the prevalence of each of the most common mutations in Asian and Western countries, and identify the characteristics of well-differentiated thyroid cancer in Asians. PMID- 26435133 TI - Helicobacter pylori Stool Antigen Levels and Serological Biomarkers of Gastric Inflammation are Associated with Cardio-Metabolic Risk Factors in Type 2 Diabetic Patients. AB - BACKGROUND: Helicobacter pylori infection and subsequent gastric inflammation have been proposed as risk factors for the development of insulin resistance and cardiovascular disease. In this study we assessed the possible association of H. pylori bacterial load, and serum biomarker of gastric inflammation with cardiometabolic risk factors in diabetic patients. METHODS: In this cross sectional study, 84 H. pylori-infected type 2 diabetic patients were assessed for anthropometrics, biochemical and clinical measurements. Pearson correlation test, linear, and logarithmic regression curve estimation models were used to assess the association of H. pylori stool antigen (HpSAg) levels, and pepsinogen I (PGI) to pepsinogen II (PGII) ratio with fasting serum glucose, insulin, serum lipid and lipoprotein parameters, malondialdehyde, high-sensitive C-reactive protein (hs-CRP), systolic and diastolic blood pressure, body weight, waist circumference and lipid accumulation product (LAP) index. RESULTS: The mean age of participants was 54+/-10 years, and 44% were men. Mean HpSAg levels and PGI/PGII ratio were 0.24+/-0.23 MUg/mL and 9.9+/-9.0, respectively. Higher HpSAg as well as lower PGI/PGII was correlated with higher anthropometric measures and LAP. A significant negative correlation between PGI/PGII ratio and blood pressure (r= 0.21 and r=-0.22, systolic and diastolic, respectively, P<0.05), serum insulin (r=-0.17, P=0.05), and hs-CRP (r=-0.17, P=0.05) was observed. A significant linear association between PGI/PGII ratio with serum triglycerides (gamma=-0.24, P<0.05), serum high density lipoprotein cholesterol (HDL-C; gamma=0.43, P<0.01), and triglycerides/HDL-C ratio (gamma=-0.28, P<0.05) were observed. CONCLUSION: Higher H. pylori bacterial load and lower PGI/PGII ratio was associated with higher levels of cardiometabolic risk factors in H. pylori infected type 2 diabetic patients. PMID- 26435134 TI - Serum Concentrations of Ghrelin and Leptin according to Thyroid Hormone Condition, and Their Correlations with Insulin Resistance. AB - BACKGROUND: Thyroid hormones can influence energy metabolism and insulin sensitivity via their interaction with adipocytokines and gut hormones. The aims of this study were to evaluate differences in serum ghrelin and leptin concentrations according to thyroid hormone levels, and to investigate the correlation of insulin resistance. METHODS: A total of 154 patients (57 hyperthyroid patients, 61 euthyroid patients, and 36 hypothyroid patients; mean age, 47.9 years) were enrolled. Serum leptin, ghrelin, and insulin levels were measured and insulin resistance was calculated using the formula of the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: There were no differences in mean concentrations of ghrelin or leptin among the three groups. There were no significant differences in insulin levels between the groups (P=0.06), although hyperthyroid patients had borderline statistically significantly higher levels of insulin than did euthyroid subjects by post hoc test (26.4 MUIU/mL vs. 16.1 MUIU/mL, P=0.057). Regarding HOMA-IR index, the mean levels were highest in the hyperthyroid group among those of the three groups (hyperthyroid vs. euthyroid vs. hypothyroid, 6.7 vs. 3.8 vs. 4.4, P=0.068). Plasma levels of ghrelin were significantly negatively correlated with age, insulin, glucose, body mass index (BMI), and HOMA-IR. Plasma levels of leptin showed significant positive correlation with BMI and triglyceride. There were no significant correlations among thyroid hormone, thyrotropin, ghrelin, leptin, or insulin. CONCLUSION: The present study found that serum ghrelin, leptin, and insulin levels didn't differ according to thyroid function conditions. Further studies with larger numbers of patients are required to establish a direct relationship between plasma ghrelin, leptin, and thyroid hormone. PMID- 26435135 TI - Sugar-Sweetened Beverage Consumption Is Associated with Metabolic Syndrome in Iranian Adults: Tehran Lipid and Glucose Study. AB - BACKGROUND: Metabolic syndrome (MetS), a cluster of multiple metabolic abnormalities, is one of the major public health challenges worldwide. The current study was conducted to evaluate the association between sugar-sweetened beverage (SSB) consumption and MetS and its components in Iranian adults. METHODS: This cross-sectional study was conducted among 5,852 men and women, aged 19 to 70 years, who participated in the fourth phase (2009 to 2011) of the Tehran Lipid and Glucose Study. Demographics, anthropometrics, biochemical measurements, and blood pressure (BP) were assessed and MetS was defined by National Cholesterol Education Program Adult Treatment Panel III definition. Frequency and quantity of SSB intakes including carbonated drinks and synthetic fruit juices were collected using a validated semiquantitative food frequency questionnaire. RESULTS: Mean age of participants (43%, men) was 40.6+/-12.9 years. Significant positive associations between SSBs and waist circumference, triglyceride level, systolic and diastolic BP in the third and fourth quartile of SSBs were observed, after adjustment for all potential confounding variables. The odds of MetS in the third and fourth quartiles compared to the first quartile category of SSBs was 1.21 (95% confidence interval [CI], 1.01 to 1.45) and 1.30 (95% CI, 1.06 to 1.58), respectively (P for trend=0.03). The odds of MetS, abdominal obesity, low high density lipoprotein cholesterol and elevated BP had increasing trends across increasing of SSB consumption (P for trend <0.05). CONCLUSION: Higher intake of SSBs was associated with the higher odds of MetS in adults. It is suggested that reducing consumption of SSBs could be a practical approach to prevent metabolic abnormalities. PMID- 26435136 TI - Sumoylation of Hes6 Regulates Protein Degradation and Hes1-Mediated Transcription. AB - BACKGROUND: Hes6 is a transcriptional regulator that induces transcriptional activation by binding to transcription repressor Hes1 and suppressing its activity. Hes6 is controlled by the ubiquitin-proteosome-mediated degradation system. Here we investigated the sumoylation of Hes6 and its functional role in its rhythmic expression. METHODS: Hes6, SUMO, and ubiquitin were transfected into HeLa cells and the expression pattern was observed by Western blot and immunoprecipitation. To confirm the effect of sumoylation on the rhythmic expression of Hes6, we generated mouse Hes6 promoter-driven GFP-Hes6 fusion constructs and expressed these constructs in NIH 3T3 cells. RESULTS: Overexpression of SUMO led to sumoylation of Hes6 at both lysine 27 and 30. Protein stability of Hes6 was decreased by sumoylation. Moreover, expression of a Hes6 sumoylation-defective mutant, the 2KR (K27/30R) mutant, or co-expression of SUMO protease SUSP1 with native Hes6, strongly reduced ubiquitination. In addition, sumoylation was associated with both the rhythmic expression and transcriptional regulation of Hes6. Wild type Hes6 showed oscillatory expression with about 2-hour periodicity, whereas the 2KR mutant displayed a longer period. Furthermore, sumoylation of Hes6 derepressed Hes1-induced transcriptional repression. CONCLUSION: Hes6 sumoylation plays an important role in the regulation of its stability and Hes1-mediated transcription. These results suggest that sumoylation may be crucial for rhythmic expression of Hes6 and downstream target genes. PMID- 26435137 TI - Two Cases of Allergy to Insulin in Gestational Diabetes. AB - Allergic reaction to insulin is uncommon since the introduction of human recombinant insulin preparations and is more rare in pregnant than non-pregnant females due to altered immune reaction during pregnancy. Herein, we report two cases of allergic reaction to insulin in gestational diabetes that were successfully managed. One case was a 33-year-old female using isophane-neutral protamine Hagedorn human insulin and insulin lispro. She experienced dyspnea, cough, urticaria and itching sensation at the sites of insulin injection immediately after insulin administration. We discontinued insulin therapy and started oral hypoglycemic agents with metformin and glibenclamide. The other case was a 32-year-old female using insulin lispro and insulin detemer. She experienced pruritus and burning sensation and multiple nodules at the sites of insulin injection. We changed the insulin from insulin lispro to insulin aspart. Assessments including immunoglobulin E (IgE), IgG, eosinophil, insulin antibody level and skin biopsy were performed. In the two cases, the symptoms were resolved after changing the insulin to oral agents or other insulin preparations. We report two cases of allergic reaction to human insulin in gestational diabetes due to its rarity. PMID- 26435138 TI - Letter: Comparison of Serum Adipocytokine Levels according to Metabolic Health and Obesity Status (Endocrinol Metab 2015;30:185-94, Tae Hoon Lee et al.). PMID- 26435139 TI - Response: Comparison of Serum Adipocytokine Levels according to Metabolic Health and Obesity Status (Endocrinol Metab 2015;30:185-94, Tae Hoon Lee et al.). PMID- 26435140 TI - Potential Risks and Mitigation Strategies Before the Conduct of a Clinical Trial: An Industry Perspective. AB - Conduct of clinical trials has undergone substantial changes over the last two decades. Newer markets, evolving guidelines and documentation and high cost involved in conducting the trials have led pharmaceutical companies to prepare a risk mitigation plan. Extensive monitoring of potential risks is an essential element of clinical trials which helps to ensure quality and integrity of a clinical investigation. Every clinical trial has pre (before the trial), conduct and post phase. This article which has been developed as a result of extensive research at ground level by a reputed pharmaceutical company to identify the potential stages of risks that could affect the overall quality and safety of a trial and its outcome during the pre-phase of trial (the stage of the trial where the study design is being planned before initiation of the clinical trial). It includes risks associated with basic study concept, protocol design, Confidential Disclosure Agreement (CDA) and Clinical Trial Authorization (CTA) application signing, vendors of central drug laboratory, site and investigator selection, Clinical Research Coordinator (CRC) meet, Informed Consent Form (ICF), Case Report Form (CRF)/ Status Report Form (SRF) preparation, Ethics Committee (EC) submission, etc. have been highlighted. The risk based mitigation strategy (to develop an effective risk monitoring plan before staring a clinical trial) has also been suggested by authors. A well-tailored and integrated plan, recognition of potential risks and their mitigation strategy can result in the pre exclusion or end to end solution of all the risks associated with pre- phase of clinical trials. PMID- 26435142 TI - Modulation of ROS production in photodynamic therapy using a pH controlled photoinduced electron transfer (PET) based sensitiser. AB - A new sensitiser (4) for use in photodynamic therapy (PDT) has been developed to enable control of ROS production as a function of pH. This pH dependent PDT behaviour was tested in HeLa cells and in SCID mice bearing human xenograft pancreatic cancer (BxPC-3) tumours. PMID- 26435143 TI - An amphipathic sequence in the cytoplasmic tail of HIV-1 Env alters cell tropism and modulates viral receptor specificity. AB - The human immunodeficiency virus type 1 (HIV-1) 92UG046 Env protein, obtained from a CD4-independent HIV-1 primary isolate (Zerhouni et al., 2004), has the ability to initiate an infection in HeLa cells expressing CD4 when carrying the full-length (FL) Env, but uses CD8 molecules for receptor-mediated entry when carrying a truncated Env (CT84). To determine whether a specific length or structure in the cytoplasmic tail (CT) is responsible for this alteration of tropism, we compared a series of Env constructs with different CT truncations and the presence or absence of an amphipathic alpha- helical sequence. We found that truncated constructs containing the alpha-helical LLP-2 structure in their CT domains conferred a switch from CD4 to CD8 tropism. The results support the conclusion that the structure of the CT domain can play an important role in determining receptor specificity. PMID- 26435144 TI - Curcumin inhibits bovine herpesvirus type 1 entry into MDBK cells. AB - The generation of antiviral drugs from herbs and other natural resources with traditionally long-confirmed effects is an efficient approach. So far, no herb or components from herbs that could inhibit bovine herpesvirus type 1 (BoHV-1) replication have been described. In this study, the antiviral effect of curcumin, a natural phenolic constituent of the spice turmeric, on BoHV-1 replication was evaluated in cell culture. We demonstrated that curcumin impairs BoHV-1 viral particles and affects the virus post-binding entry process. Furthermore, curcumin upregulated the proportion of the plasma membrane adopting a lipid raft conformation in MDBK cells, which supported the previous reports that curcumin can modulate the lipid bilayer. Though the antiviral mechanism of curcumin on BoHV-1 needs further study, we identified for the first time a component from herb that could inhibit BoHV-1 replication, in vitro. PMID- 26435141 TI - Asparagine deamidation reduces DNA-binding affinity of the Drosophila melanogaster Scr homeodomain. AB - Spontaneous deamidation of asparagine is a non-enzymatic post-translational modification of proteins. Residue Asn 321 is the main site of deamidation of the Drosophila melanogaster Hox transcription factor Sex Combs Reduced (Scr). Formation of iso-aspartate, the major deamidation product, is detected by HNCACB triple-resonance NMR spectroscopy. The rate of deamidation is quantified by fitting the decay of Asn NH2 side-chain signals in a time-series of (15)N-(1)H HSQC NMR spectra. The deamidated form of Scr binds to specific DNA target sequences with reduced affinity as determined by an electrophoretic mobility shift assay. PMID- 26435145 TI - Structural features of the O-antigen of Rickettsia typhi, the etiological agent of endemic typhus. AB - Elucidation of the O-specific polysaccharide chain of lipopolysaccharide (LPS) from Rickettsia typhi, the etiological agent of endemic typhus, is described. Structural information was established by a combination of monosaccharide and methylation analyses of the O-chain, and by mass (MS) and nuclear magnetic resonance (NMR) spectrometries of oligosaccharides arised through its hydrofluoric (HF) acid degradation. Based on the combined data from these experiments, two major polymer populations of the O-specific chain have been determined with the following structural features: alpha-L-QuiNAc-(1->4)-[alpha-D Glc-(1->3)-alpha-L-QuiNAc-(1->4)]n-alpha-D-Glc-(1->4)-alpha-D-Glc->, alpha-D-Glc (1->3)-alpha-L-QuiNAc-(1->4)-[alpha-D-Glc-(1->3)-alpha-L-QuiNAc-(1->4)]n-alpha-D Glc->. The linear backbone is most probably flanked with short side chains of D GlcNAc-(1->3)-alpha-L-QuiNAc-(1->3)-D-GlcNAc-> that are attached to it via L QuiNAc as a branching point. It is suggested that a dimer alpha-L-QuiNAc-(1->3) alpha-D-GlcNAc may represent a common epitope in the O-antigens of Proteus vulgaris OX19 and R. typhi responsible for the observed serological cross reactivity. PMID- 26435146 TI - Standardization of serum neutralization assay of Japanese encephalitis virus (Nakayama NIH strain) on BHK-21 (Cl-13) cell line. AB - Potency testing of Japanese encephalitis (JE) vaccine has been a complex process since its inception. To overcome difficulties encountered therein, an alternative assay, serum neutralization test (SNT), using Baby Hamster Kidney 21 cell line, has been standardized. The antibody response generated against JE vaccine was quantified and the assay was found to be sensitive and specific enough with significant accuracy and precision. On analysis of cell count, a cell concentration of 1.5 x 104 was selected as the optimum, since concentrations above and below this resulted in problems of confluent monolayer formation and incomplete monolayer formation. Incubation time has also been standardized for measuring cytopathic effect (CPE). Out of the four different time points selected, 90 min was found to be adequate for 50% reduction in the amount of CPE. The accuracy of SNT assay is explained in terms of fiducial limits at 95% level. Inter- and intra-assay reproducibility testing was also performed. A comparison of potency of JE vaccine by plaque reduction neutralization test (PRNT) and SNT method was conducted and it was found that SNT can be a reliable approach for estimating the potency of JE vaccine. The results of this study throw a light on the utility of SNT assay for the potency estimation of JE vaccine in routine practice. PMID- 26435147 TI - Antigenic validation of recombinant hemagglutinin-neuraminidase protein of Newcastle disease virus expressed in Saccharomyces cerevisiae. AB - The outer membrane glycoprotein, hemagglutinin-neuraminidase (HN) of Newcastle disease virus (NDV) is important for virus infection and subsequent immune response by host, and offers target for development of recombinant antigen-based immunoassays and subunit vaccines. In this study, the expression of HN protein of NDV is attempted in yeast expression system. Yeast offers eukaryotic environment for protein processing and posttranslational modifications like glycosylation, in addition to higher growth rate and easy genetic manipulation. Saccharomyces cerevisiae was found to be better expression system for HN protein than Pichia pastoris as determined by codon usage analysis. The complete coding sequence of HN gene was amplified with the histidine tag, cloned in pESC-URA under GAL10 promotor and transformed in Saccharomyces cerevisiae. The recombinant HN (rHN) protein was characterized by western blot, showing glycosylation heterogeneity as observed with other eukaryotic expression systems. The recombinant protein was purified by affinity column purification. The protein could be further used as subunit vaccine. PMID- 26435148 TI - Monoclonal antibody profiling of cell surface proteins associated with the viral biofilms on HTLV-1 transformed cells. AB - Human T lymphotropic virus 1 (HTLV-1) is a pathogenic retrovirus that spreads predominantly via cell-to-cell contact. Two models of cell-to-cell virus transmission are proposed: virological synapse (VS) and viral biofilms (VB). Both infectious structures can be involved in transmission and synergistically enhance HTLV-1 spread between cells. Although transmission of virus via VB has been reported, the molecular composition of VB remains poorly understood. In this study we generated new anti-VB monoclonal antibodies (MAbs) and screenedthem along with a panel of anti-human cluster of differentiation (CD) MAbs to select antigens associated with VB. Among four MAbs generated against VB, two MAbs were identified as anti-CD25 (IL-2RA). We found that antigens CD4, CD150, CD25, CD70, and CD80 were enriched in VB. We also determined that expression of viral protein Tax, a central molecule in HTLV-1 transmission, upregulates intercellular adhesion molecule 1 (ICAM-1), CD95, CD25, CD70, and CD80. Whether these antigens are essential for VB formation and HTLV-1 infection remains unknown and will be determined in further experiments. PMID- 26435149 TI - Effect of ORF119 gene deletion on the replication and virulence of orf virus. AB - Orf is a severe infectious disease of sheep and goats caused by orf virus (ORFV). To investigate the role of ORF119 gene of ORFV, we constructed ORFV with deleted ORF119 gene and LacZ as reporter gene (ORFV-Delta119-LacZ) via homologous recombination. The results showed that wild-type ORF-SHZ1 and ORFV-Delta119-LacZ deletion viruses replicated in Vero cells to similar titers. Relative transcriptional levels of virulence genes OVIFNR, GIF, VEGF and VIL-10 of ORFV Delta119-LacZ deletion virus were slightly but not significantly lower after 24 hr compared with the wtORF-SHZ1 virus. In vivo experiments showed that 2-month old lambs inoculated with ORFV-Delta119-LacZ deletion virus exhibited a similar total clinical score compared with those inoculated with wtORF-SHZ1 virus. Based on these results, we conclude that deletion of the ORF119 gene has no significant effect on ORFV replication and virulence. PMID- 26435150 TI - Porcine epidemic diarrhea virus M protein blocks cell cycle progression at S phase and its subcellular localization in the porcine intestinal epithelial cells. AB - Porcine epidemic diarrhea (PED) caused by virulent strains of porcine epidemic diarrhea virus (PEDV) is a highly contagious enteric disease of swine characterized by severe enteritis, vomiting, and watery diarrhea. This study investigates the subcellular localization and function of PEDV M protein through examination of its effects on cell growth, cell cycle progression, and interleukin 8 (IL-8) expression. Our results revealed that the PEDV M protein is localized throughout the cytoplasm. The M protein altered swine intestinal epithelial cell line (IEC) growth and induced cell cycle arrest at the S-phase via the cyclin A pathway. The S-phase arrest is associated with a decrease in level of cyclin A. Furthermore, our results revealed that the M protein of PEDV does not induce endoplasmic reticulum (ER) stress and does not activate NF-kappaB which is responsible for IL-8 and Bcl-2 expression. This is the first report to demonstrate that the PEDV M protein is localized in the whole cell and induces cell cycle arrest at the S-phase. This study provides novel findings in the function of M proteins of PEDV. PMID- 26435151 TI - Analysis of different HCV NS4B domains for the development of global consensus sequence. AB - The non-structural 4B (NS4B) protein of hepatitis C virus (HCV) is a hydrophobic protein implicated recently in the formation of membranous web, a platform for the formation of replication complex and thus is potential target for antivirals. The CLC main workbench was used to generate genotype-specific consensus sequence, global consensus sequence and a representative phylogenetic tree from non structural 4 B (NS4B) protein sequences of seven different HCV genotypes reported from all over the world. The C-terminal domain (CTD) of NS4B protein especially the residues involved in interaction with ER membrane were found to be highly conserved. Other residues found to be highly conserved across all HCV genotypes included; 5 aromatic residues of N-terminal domain (NTD) (F49, W50, W55, F57, and Y63), 3 hydrophobic leucine residues (L237, L240, L245), and 2 positively charged residues of CTD (R248 and H250), dimerization motif of transmembrane domain 3 (TMD3) (G143YGAG147) and its surrounding residues (F118 and F155) and TMD1 Ser/Thr cluster residues (T87, S88 and T95) involved in the hydrogen (H) bond interactions. In short, amino acids of NTD, TMD and CTD domains involved in the membrane association/anchoring of NS4B and formation of membranous web are highly conserved and can serve as potential targets for antivirals and peptide vaccines. These conserved residues formed the basis for the development of five short peptides proposed to serve as potential therapeutic target. The phylogenetic analysis was particularly interesting for NS4B sequences of 3a Pakistani isolates. The high degree of variability prevented the clustering of Pakistani isolates with other sequences in phylogenetic tree, revealing geographical disparity. PMID- 26435152 TI - Molecular characterization and fluorescence analysis of HCV non-structural proteins NS3, NS3-4A and NS4A of genotype 3a. AB - Hepatitis C virus (HCV) chronically infects almost 2% of world's population. Chronic infection can lead to liver failure and hepatocellular carcinoma (HCC). Approximately 10% of the Pakistani population is infected with HCV and type 3 is the most prevalent genotype with 75-90% prevalence. In this study we have developed transiently expressing cell culture based system for the expression of HCV non-structural NS3, NS3-4A and NS4A proteins of genotype 3a. HCV non structural genes NS3, NS3-4A and NS4A were cloned in to pFLAG-CMV2 and pEGFP C1vectors. All vectors were transfected separately to Huh-7 cells and their protein expression was analyzed by Western blot and immunofluorescence. All proteins were expressed correctly and in the transfection we have obtained 42-70% efficiency for all clones. This system can be used for the development of novel antiviral strategies to inhibit the viral replication, to study apoptosis pathways induced by HCV, for the evaluation of vaccine candidates and also to study the role of HCV different signaling pathways. PMID- 26435153 TI - Preparation and identification of an antiserum against recombinant UL31 protein of pseudorabies virus. AB - Pseudorabies virus (PRV) early protein UL31 is a homologue of herpes simplex virus 1 (HSV-1) UL31, which is a multifunctional protein important for HSV-1 infection. However, the precise roles of PRV UL31 in virus life cycle are still poorly understood. A relatively crucial tool for uncovering the function of UL31 is an antiserum that specifically detects UL31 in the PRV-infected cells. For this purpose, a recombinant UL31 protein consisting of N-terminal 27 aa of UL31 fused to EYFP and His-tag was expressed, purified and used for the preparation of antiserum in BALB/c mice. Our results show that Western blot analysis and immunofluorescence assay showed that this antiserum could specifically detect the purified recombinant UL31 as well as full-length UL31 in the PRV infected cells. These results demonstrate that the prepared antiserum could serve as a valuable tool for further studies of UL31 functions in PRV infection. PMID- 26435154 TI - Porcine encephalomyocarditis virus strain BD2 isolated from northern China is highly virulent for BALB/c mice. AB - Encephalomyocarditis virus (EMCV) can cause acute myocarditis in young pigs or reproductive failure in sows. The BD2 strain was isolated from the suspected piglets with EMCV in China. In order to establish an experimental animal model of EMCV, eight-weeks-old male BALB/c mice were intraperitonealy inoculated with 0.1 ml of 4*10(5) TCID50 suspension of the EMCV. Infected mice demonstrated hind limb paralysis, and movement disorder. The mortality rate of the infected group was 100% during the one-week observation period. The viral load in the brain of challenged mice gradually increased, with a peak level being 6.53 log CCID50/0.1 ml 5 days post infection. The pathological injury in infected mice was presented as neuronal necrosis. Brown positive staining could be detected in the cytoplasm of cerebral neurons. These results indicate that the porcine EMCV isolated from China could replicate in brain tissues and induce acute encephalitis in BALB/c mice. PMID- 26435155 TI - Spectrum of VP1 region genetic variants in the foot-and-mouth disease virus serotype O populations derived from infected cattle tongue epithelium. AB - RNA virus population exists as a complex distribution of non-identical but closely related sequences known as viral quasispecies. Variant strains are selected from this quasispecies population in response to changing environment. The quasispecies dynamics of a virus existing within an infected host differs from that in a cell culture-adapted population. This study was carried out to explore the genetic variations present in the VP1 coding region of the foot-and mouth disease (FMD) virus serotype O derived directly from infected cattle tongue epithelium. Molecular clonal populations of two serotype O strains belonging to lineages Ind2001 (IND 30/2011) and PanAsia2 (IND 5/2011) were sequenced at VP1 coding region. For IND 30/2011, 19 clones were sequenced and analysis showed variations at 12 nucleotide positions (nt) resulting in 8 amino acid (aa) replacements. Similarly, for IND 5/2011 virus, 18 clones were sequenced, of which six showed nt variations leading to 3 aa replacements. Most of the variable positions mapped to the surface-exposed loops and some of them were found in the neutralizing antigenic sites (position 81, 149, 169, 186 and 202 of IND 30/2011 and 141 of IND 5/2011), which potentially could be beneficial in rapid adaptive evolution of the virus by giving rise to antigenic variants to overcome neutralizing antibodies. These findings encourage further research into the landscape of the viral quasispecies population in vivo and its implication for viral ecology. PMID- 26435156 TI - The association of HBV infection with DNA methyltransferases expression in hepatocellular carcinoma. PMID- 26435157 TI - Pyoderma gangrenosum along superficial vein thrombosis during pregnancy. PMID- 26435158 TI - The controversial existence of the human superior fronto-occipital fasciculus: Connectome-based tractographic study with microdissection validation. AB - The superior fronto-occipital fasciculus (SFOF), a long association bundle that connects frontal and occipital lobes, is well-documented in monkeys but is controversial in human brain. Its assumed role is in visual processing and spatial awareness. To date, anatomical and neuroimaging studies on human and animal brains are not in agreement about the existence, course, and terminations of SFOF. To clarify the existence of the SFOF in human brains, we applied deterministic fiber tractography to a template of 488 healthy subjects and to 80 individual subjects from the Human Connectome Project (HCP) and validated the results with white matter microdissection of post-mortem human brains. The imaging results showed that previous reconstructions of the SFOF were generated by two false continuations, namely between superior thalamic peduncle (STP) and stria terminalis (ST), and ST and posterior thalamic peduncle. The anatomical microdissection confirmed this finding. No other fiber tracts in the previously described location of the SFOF were identified. Hence, our data suggest that the SFOF does not exist in the human brain. PMID- 26435159 TI - Adrenal cavernous hemangioma associated with myelolipomatous metaplasia. PMID- 26435160 TI - Response to Donovan et al. Does exposure to hyperglycaemia in utero increase the risk of obesity and diabetes in the offspring? A critical reappraisal. PMID- 26435161 TI - Unleashing Optics and Optoacoustics for Developmental Biology. AB - The past decade marked an optical revolution in biology: an unprecedented number of optical techniques were developed and adopted for biological exploration, demonstrating increasing interest in optical imaging and in vivo interrogations. Optical methods have become faster and have reached nanoscale resolution, and are now complemented by optoacoustic (photoacoustic) methods capable of imaging whole specimens in vivo. Never before were so many optical imaging barriers broken in such a short time-frame: with new approaches to optical microscopy and mesoscopy came an increased ability to image biology at unprecedented speed, resolution, and depth. This review covers the most relevant techniques for imaging in developmental biology, and offers an outlook on the next steps for these technologies and their applications. PMID- 26435162 TI - Porous Molybdenum-Based Hybrid Catalysts for Highly Efficient Hydrogen Evolution. AB - We have synthesized a porous Mo-based composite obtained from a polyoxometalate based metal-organic framework and graphene oxide (POMOFs/GO) using a simple one pot method. The MoO2 @PC-RGO hybrid material derived from the POMOFs/GO composite is prepared at a relatively low carbonization temperature, which presents a superior activity for the hydrogen-evolution reaction (HER) in acidic media owing to the synergistic effects among highly dispersive MoO2 particles, phosphorus doped porous carbon, and RGO substrates. MoO2 @PC-RGO exhibits a very positive onset potential close to that of 20 % Pt/C, low Tafel slope of 41 mV dec(-1) , high exchange current density of 4.8*10(-4) A cm(-2) , and remarkable long-term cycle stability. It is one of the best high-performance catalysts among the reported nonprecious metal catalysts for HER to date. PMID- 26435163 TI - Use of carbonate extraction in analyzing moderately hydrophobic transmembrane proteins in the mitochondrial inner membrane. AB - Resistance to sodium carbonate extraction is regarded as a canonical way to distinguish integral membrane proteins (MPs) from other membrane-associated proteins. However, it has been observed that carbonate extraction releases some mitochondrial integral MPs. Here, by analyzing both artificially designed and native mitochondrial inner MPs containing transmembrane domains (TMDs) of different hydrophobicities, we show that carbonate treatment can release moderately hydrophobic TMDs from the mitochondrial inner membrane. These results suggest that resistance and sensitivity to carbonate extraction may be interpreted with caution when analyzing the nature of mitochondrial inner MPs. PMID- 26435164 TI - Gap junction coupling confers isopotentiality on astrocyte syncytium. AB - Astrocytes are extensively coupled through gap junctions into a syncytium. However, the basic role of this major brain network remains largely unknown. Using electrophysiological and computational modeling methods, we demonstrate that the membrane potential (VM) of an individual astrocyte in a hippocampal syncytium, but not in a single, freshly isolated cell preparation, can be well maintained at quasi-physiological levels when recorded with reduced or K(+) free pipette solutions that alter the K(+) equilibrium potential to non-physiological voltages. We show that an astrocyte's associated syncytium provides powerful electrical coupling, together with ionic coupling at a lesser extent, that equalizes the astrocyte's VM to levels comparable to its neighbors. Functionally, this minimizes VM depolarization attributable to elevated levels of local extracellular K(+) and thereby maintains a sustained driving force for highly efficient K(+) uptake. Thus, gap junction coupling functions to achieve isopotentiality in astrocytic networks, whereby a constant extracellular environment can be powerfully maintained for crucial functions of neural circuits. PMID- 26435165 TI - Prognostic Value of Ambulatory Blood Pressure in the Obese: The Ambulatory Blood Pressure-International Study. AB - The purpose of this study was to compare the predictive value of ambulatory blood pressure (BP) vs office BP for cardiovascular events during a 5.8-year follow-up period in the obese and nonobese participants of the Ambulatory Blood Pressure International Study (n=10,817). Both ambulatory BP and office BP considered separately were predictive of cardiovascular events. However, in Cox models including both pressures, only ambulatory BP was associated with outcome. Among obese patients, the hazard ratios for a 10-mm Hg increase in 24-hour and office systolic BPs were 1.37 (95% confidence interval, 1.20-1.53) and 0.91 (95% confidence interval, 0.76-1.07), respectively. Among nonobese patients, the corresponding hazard ratios were 1.39 (95% confidence interval, 1.31-1.47) and 0.94 (95% confidence interval, 0.88-1.00) (P=not significant vs obese). Similar results were obtained for diastolic BP and for daytime and nighttime BPs. Ambulatory BP has similar predictive capacity in obese and nonobese patients, suggesting that ambulatory BP monitoring is a useful diagnostic tool for the assessment of obese individuals. PMID- 26435166 TI - The proportional recovery rule for stroke revisited. PMID- 26435168 TI - Prevalence of migraine in persons with the 3243A>G mutation in mitochondrial DNA. AB - BACKGROUND AND PURPOSE: Over the last three decades mitochondrial dysfunction has been postulated to be a potential mechanism in migraine pathogenesis. The lifetime prevalence of migraine in persons carrying the 3243A>G mutation in mitochondrial DNA was investigated. METHODS: In this cross-sectional study, 57 mDNA 3243A>G mutation carriers between May 2012 and October 2014 were included. As a control group, a population-based cohort from our epidemiological studies on migraine in Danes was used. History of headache and migraine was obtained by telephone interview, based on a validated semi-structured questionnaire, performed by trained physicians. RESULTS: The prevalence of migraine is significantly higher in persons carrying the 3243A>G mutation than in controls (58% vs. 18%; P < 0.001). This applies for both subforms of migraine, migraine without aura (47% vs. 12%; P < 0.001) and migraine with aura (18% vs. 6%; P < 0.001), and in females (58% vs. 24%; P < 0.001) and males (58% vs. 12%; P < 0.001) for any migraine. CONCLUSIONS: A high prevalence of migraine in persons with the mDNA 3243A>G mutation was found. This finding suggests a clinical association between a monogenetically inherited disorder of mitochondrial dysfunction and susceptibility to migraine. Mitochondrial DNA aberrations may contribute to the pathogenesis of migraine. PMID- 26435169 TI - Network-based proteomic analysis for postmenopausal osteoporosis in Caucasian females. AB - Menopause is one of the crucial physiological events during the life of a woman. Transition of menopause status is accompanied by increased risks of various health problems such as osteoporosis. Peripheral blood monocytes can differentiate into osteoclasts and produce cytokines important for osteoclast activity. With quantitative proteomics LC-nano-ESI-MS(E) (where MS(E) is elevated energy MS), we performed protein expression profiling of peripheral blood monocytes in 42 postmenopausal women with discordant bone mineral density (BMD) levels. Traditional comparative analysis showed proteins encoded by four genes (LOC654188, PPIA, TAGLN2, YWHAB) and three genes (LMNB1, ANXA2P2, ANXA2) were significantly down- and upregulated, respectively, in extremely low- versus high BMD subjects. To study functionally orchestrating groups of detected proteins in the form of networks, we performed weighted gene coexpression network analysis and gene set enrichment analysis. Weighted gene coexpression network analysis showed that the module including the annexin gene family was most significantly correlated with low BMD, and the lipid-binding related GO terms were enriched in this identified module. Gene set enrichment analysis revealed that two significantly enriched gene sets may be involved in postmenopausal BMD variation by regulating pro-inflammatory cytokines activities. To gain more insights into the proteomics data generated, we performed integrative analyses of the datasets available to us at the genome (DNA level), transcriptome (RNA level), and proteome levels jointly. PMID- 26435170 TI - Platelet Adhesion and Thrombus Formation in Whole Blood at Arterial Shear Rate at the End of Pregnancy. AB - PROBLEM: Platelet reactivity has not been evaluated in integrated functional testing during normal pregnancy. Here, we analysed platelet functions under arterial shear rate in comparison with static conditions. METHOD OF STUDY: Thirty pregnant women with uncomplicated pregnancies and 30 healthy non-pregnant women were enrolled in this study. Platelet adhesion to collagen and fibrinogen and subsequent thrombus formation were measured at arterial shear rate in whole blood using a microfluidic and imaging system. Standard light transmission aggregometry, flow cytometry of activation markers in washed platelets and impedance aggregometry in whole blood were also used to assess platelet responsiveness in static conditions. RESULTS: Compared to non-pregnant controls, thrombus formation on collagen fibres and firm platelet adhesion on fibrinogen under arterial shear rate were significantly reduced in pregnant women. Platelet aggregometry assays in suspension showed a slight increase in platelet reactivity in pregnant women. CONCLUSION: While platelet aggregometry and platelet activation markers in static conditions show little changes in platelet reactivity, monitoring of platelet adhesion and thrombus growth on collagen or fibrinogen under flow condition in whole blood indicates a significant decrease in pregnant women compared to controls. This decrease might contribute to counteract a hypercoagulable state and to reduce the risk of arterial thrombosis. PMID- 26435171 TI - Antibiotic prophylaxis for women undergoing caesarean section and infant health. PMID- 26435167 TI - Diabetes and ageing-induced vascular inflammation. AB - Diabetes and the ageing process independently increase the risk for cardiovascular disease (CVD). Since incidence of diabetes increases as people get older, the diabetic older adults represent the largest population of diabetic subjects. This group of patients would potentially be threatened by the development of CVD related to both ageing and diabetes. The relationship between CVD, ageing and diabetes is explained by the negative impact of these conditions on vascular function. Functional and clinical evidence supports the role of vascular inflammation induced by the ageing process and by diabetes in vascular impairment and CVD. Inflammatory mechanisms in both aged and diabetic vasculature include pro-inflammatory cytokines, vascular hyperactivation of nuclear factor kB, increased expression of cyclooxygenase and inducible nitric oxide synthase, imbalanced expression of pro/anti-inflammatory microRNAs, and dysfunctional stress-response systems (sirtuins, Nrf2). In contrast, there are scarce data regarding the interaction of these mechanisms when ageing and diabetes co-exist and its impact on vascular function. Older diabetic animals and humans display higher vascular impairment and CVD risk than those either aged or diabetic, suggesting that chronic low-grade inflammation in ageing creates a vascular environment favouring the mechanisms of vascular damage driven by diabetes. Further research is needed to determine the specific inflammatory mechanisms responsible for exacerbated vascular impairment in older diabetic subjects in order to design effective therapeutic interventions to minimize the impact of vascular inflammation. This would help to prevent or delay CVD and the specific clinical manifestations (cognitive decline, frailty and disability) promoted by diabetes-induced vascular impairment in the elderly. PMID- 26435172 TI - Characterizing nerve growth factor-p75(NTR) interactions and small molecule inhibition using surface plasmon resonance spectroscopy. AB - Nerve growth factor (NGF) is critical for the proliferation, differentiation, and survival of neurons through its binding to the p75(NTR) and TrkA receptors. Dysregulation of NGF has been implicated in several pathologies, including neurodegeneration (i.e., Parkinson's and Alzheimer's diseases) and both inflammatory and neuropathic pain states. Therefore, small molecule inhibitors that block NGF-receptor interactions have significant therapeutic potential. Small molecule antagonists ALE-0540, PD90780, Ro 08-2750, and PQC 083 have all been reported to inhibit NGF from binding the TrkA receptor. Interestingly, the characterization of the ability of these molecules to block NGF-p75(NTR) interactions has not been performed. In addition, the inhibitory action of these molecules has never been evaluated using surface plasmon resonance (SPR) spectroscopy, which has been proven to be highly useful in drug discovery applications. In the current study, we used SPR biosensors to characterize the binding of NGF to the p75(NTR) receptor in addition to characterizing the inhibitory potential of the known NGF antagonists. The results of this study provide the first evaluation of the ability of these compounds to block NGF binding to p75(NTR) receptor. In addition, only PD90780 was effective at inhibiting the interaction of NGF with p75(NTR), suggesting receptor selectivity between known NGF inhibitors. PMID- 26435173 TI - Si78 double cage structure and special optical properties. AB - We performed first-principles calculations to study the structural stability of Si78 clusters with or without hydrogen passivation. The calculations reveal that an endohedral double cage isomer is more stable than the diamond-like structure, whereas the opposite is found for the hydrogen passivated isomers. In particular, the hydrogenated double cage and diamond-like structure may display blue shifts to the visible and UV regions, respectively. The IR vibration spectra, ionization potential (IP) and electronic density-of-states of the clusters were calculated and discussed. PMID- 26435174 TI - Influence of BMP-2 on early follicular development and mRNA expression of oocyte specific genes in bovine preantral follicles cultured in vitro. AB - This study evaluates the effect of different concentrations (0, 10, 50 and 100ng/mL) of bone morphogenetic protein-2 (BMP-2) on primordial and secondary follicle development. It also investigates the effects of FSH and BMP-2 on the growth, morphology, ultrastructure and expression of mRNA for GDF9, NLRP5 and NPM2 genes in secondary follicles cultured for 18 days. The presence of BMP-2 at all tested concentrations increased the development of primordial follicles in vitro, but the highest concentration of BMP-2 (100 ng/mL) reduced the percentage of normal follicles when compared with tissues cultured with 10 ng/mL BMP-2. During culture of secondary follicles, in contrast to higher concentrations (50 or 100 ng/mL), 10 ng/mL BMP-2 kept the morphology of follicles during initial stages of in vitro culture. This concentration of BMP-2 also benefits maintenance of the ultrastructure of 18-day cultured follicles. The presence of both BMP-2 and FSH in culture medium resulted in a significant (P<0.05) increase in follicular diameter after 18 days of culture. However, both FSH and BMP-2 reduced follicular mRNA expression of GDF9 and NLRP5 when compared to follicles cultured in media containing only FSH. In combination with FSH, BMP-2 reduced the mRNA levels of NPM2, when compared to follicles cultured in control medium. It is concluded from these data that 10 ng/mL BMP-2 promotes the growth of primordial in vitro and it helps to maintain the ultrastructure of secondary follicles, while FSH is more important for better expression of follicular markers like GDF9 and NLRP5. PMID- 26435175 TI - Graphic Somatography: Life Writing, Comics, and the Ethics of Care. AB - This essay considers the ways in which graphic caregiving memoirs complicate the idealizing tendencies of ethics of care philosophy. The medium's "capacious" layering of words, images, temporalities, and perspectives produces "productive tensions. . . The words and images entwine, but never synthesize" (Chute 2010, 5). In graphic memoirs about care, this "capaciousness" allows for quick oscillation between the rewards and struggles of care work, representing ambiguous, even ambivalent attitudes toward care. Graphic memoirs effectively represent multiple perspectives without synthesis, part of a structural and thematic ambivalence that provides a provocative counterpart to the abstract idealism of ethics of care philosophy. PMID- 26435180 TI - Transition-Metal-Free N-Arylation of Pyrazoles with Diaryliodonium Salts. AB - A new synthetic method was developed for the N-arylation of pyrazoles using diaryliodonium salts. The transformation does not require any transition-metal catalyst and provides the desired N-arylpyrazoles rapidly under mild reaction condition in the presence of aqueous ammonia solution as a mild base without the use of inert atmosphere. The chemoselectivity of unsymmetric diaryliodonium salts was also explored with large number of examples. PMID- 26435179 TI - Children with Autism Spectrum Disorder scan own-race faces differently from other race faces. AB - It has been well documented that people recognize and scan other-race faces differently from faces of their own race. The current study examined whether this cross-racial difference in face processing found in the typical population also exists in individuals with Autism Spectrum Disorder (ASD). Participants included 5- to 10-year-old children with ASD (n=29), typically developing (TD) children matched on chronological age (n=29), and TD children matched on nonverbal IQ (n=29). Children completed a face recognition task in which they were asked to memorize and recognize both own- and other-race faces while their eye movements were tracked. We found no recognition advantage for own-race faces relative to other-race faces in any of the three groups. However, eye-tracking results indicated that, similar to TD children, children with ASD exhibited a cross racial face-scanning pattern: they looked at the eyes of other-race faces longer than at those of own-race faces, whereas they looked at the mouth of own-race faces longer than at that of other-race faces. The findings suggest that although children with ASD have difficulty with processing some aspects of faces, their ability to process face race information is relatively spared. PMID- 26435181 TI - Slow magnetic relaxation of light lanthanide-based linear LnZn2 trinuclear complexes. AB - Four isostructural LnZn2 trinuclear complexes, [Ln(NO3){Zn(L)(SCN)}2] (H2L is a Schiff base ligand derived from o-vanillin and ethylenediamine), were synthesized, which include light lanthanide ions as spin carriers (Ln = Ce 1, Pr 2, Nd 3, and Sm 4). These complexes involve a linear Zn(ii)-Ln(iii)-Zn(ii) array, which leads to an axially stressed ligand field and can also cause single moleluce magnet (SMM) behavior in oblate-type electronic distributions of ground sublevels found in Ce(iii), Pr(iii), and Nd(iii). Slow magnetic relaxation behavior was observed in 1 and 3 under an applied bias dc field of 1000 Oe, whereas such a slow relaxation was not observed in 2 and 4. The appearance of field-induced SMM behavior in 1 and 3 was correlated with the even-numbered Jz sublevels of Ce(iii) and Nd(iii) ions known as the Kramers system. PMID- 26435182 TI - Generic finite element models of orthodontic mini-implants: Are they reliable? AB - Many finite element (FE) studies used different settings for modeling orthodontic mini-implants (OMIs). This study aims to compare different approaches for modeling OMI with FE method, to exhibit the role of key factors in modeling process. A computerized tomography (CT) dataset of a living human is used to develop subject-specific FE model of bone specimen, and a microCT was used to generate the geometry of OMI. Another five models were developed to assess the effect of changing different settings of FE modeling process. These five models differed from the subject-specific model in either: (i) bone properties' assignment method, (ii) geometries and constrains' conditions, or (iii) simulation method of bone-implant contact (BIC). The models presented significant differences in maximum principal strain distribution. These differences were most apparent when the models differed either in the nature of BIC or the method of assigning bone properties. The models different only in bone geometries showed differences in the intensity of strain rather than its distribution pattern. There is a need for assessment and validation of all FE modeling approaches currently used for simulation of mechanical environment in the bone surrounding OMIs. PMID- 26435183 TI - Performance of local optimization in single-plane fluoroscopic analysis for total knee arthroplasty. AB - Fluoroscopy-derived joint kinematics plays an important role in the evaluation of knee prostheses. Fluoroscopic analysis requires estimation of the 3D prosthesis pose from its 2D silhouette in the fluoroscopic image, by optimizing a dissimilarity measure. Currently, extensive user-interaction is needed, which makes analysis labor-intensive and operator-dependent. The aim of this study was to review five optimization methods for 3D pose estimation and to assess their performance in finding the correct solution. Two derivative-free optimizers (DHSAnn and IIPM) and three gradient-based optimizers (LevMar, DoNLP2 and IpOpt) were evaluated. For the latter three optimizers two different implementations were evaluated: one with a numerically approximated gradient and one with an analytically derived gradient for computational efficiency. On phantom data, all methods were able to find the 3D pose within 1mm and 1 degrees in more than 85% of cases. IpOpt had the highest success-rate: 97%. On clinical data, the success rates were higher than 85% for the in-plane positions, but not for the rotations. IpOpt was the most expensive method and the application of an analytically derived gradients accelerated the gradient-based methods by a factor 3-4 without any differences in success rate. In conclusion, 85% of the frames can be analyzed automatically in clinical data and only 15% of the frames require manual supervision. The optimal success-rate on phantom data (97% with IpOpt) on phantom data indicates that even less supervision may become feasible. PMID- 26435184 TI - Patterning Poly(dimethylsiloxane) Microspheres via Combination of Oxygen Plasma Exposure and Solvent Treatment. AB - Here a simple low-cost yet robust route has been developed to prepare poly(dimethylsiloxane) (PDMS) microspheres with various surface wrinkle patterns. First, the aqueous-phase-synthesized PDMS microspheres are exposed to oxygen plasma (OP), yielding the oxidized SiOx layer and the corresponding stiff shell/compliant core system. The subsequent solvent swelling and solvent evaporation induce the spontaneous formation of a series of curvature and overstress-sensitive spherical wrinkles such as dimples, short rodlike depressions, and herringbone and labyrinth patterns. The effects of the experimental parameters, including the radius and Young's modulus of the microspheres, the OP exposure duration, and the nature of the solvents, on these tunable spherical wrinkles have been systematically studied. The experimental results reveal that a power-law dependence of the wrinkling wavelength on the microsphere radius exists. Furthermore, the induced wrinkling patterns are inherently characteristic of a memory effect and good reversibility. Meanwhile, the corresponding phase diagram of the wrinkle morphologies on the spherical surfaces vs the normalized radius of curvature and the excess swelling degree has been demonstrated. It is envisioned that the introduced strategy in principle could be applied to other curved surfaces for expeditious generation of well defined wrinkle morphologies, which not only enables the fabrication of solids with multifunctional surface properties, but also provides important implications for the morphogenesis in soft materials and tissues. PMID- 26435185 TI - One-step separation of nine structural analogues from Poria cocos (Schw.) Wolf. via tandem high-speed counter-current chromatography. AB - A novel one-step separation strategy-tandem high-speed counter-current chromatography (HSCCC) was developed with a six-port valve serving as the switch interface. Nine structural analogues including three isomers were successfully isolated from Poria cocos (Schw.) Wolf. by one step. Compared with conventional HSCCC, peak resolution of target compounds was effectively improved in tandem one. Purities of isolated compounds were all over 90% as determined by HPLC. Their structures were then identified via UV, MS and (1)H NMR, and eventually assigned as poricoic acid B (1), poricoic acid A (2), 3beta,16alpha dihydroxylanosta-7, 9(11), 24-trien-21-oic acid (3), dehydrotumulosic acid (4), polyporenic acid C (5), 3-epi-dehydrotumulosic acid (6), 3-o-acetyl-16alpha hydroxydehydrotrametenolic acid (7), dehydropachymic acid (8) and dehydrotrametenolic acid (9) respectively. The results indicated that tandem HSCCC can effectively improve peak resolution of target compounds, and can be a good candidate for HSCCC separation of structural analogues. PMID- 26435186 TI - Simultaneous qualitation and quantitation of natural trans-1,4-polyisoprene from Eucommia ulmoides Oliver by gel permeation chromatography (GPC). AB - Natural trans-1,4-polyisoprene (TPI) as a functional biomaterial has aroused great interest for rubber industrial product use. Here, we proposed a method that enables simultaneous analysis of the content and molecular-weight distribution (MWD) of natural TPI by gel permeation chromatography (GPC). The natural TPIs were collected from leaves, fruit coatings and bark of Eucommia ulmoides Oliver (E. ulmoides) through toluene extraction followed by ethanol purification. The results of TPI contents from leaves and fruit coatings were shown ca. 3.5% and 13.8%, respectively. Accordingly, limits of detection (LODs) of TPI were 0.58mg/mL from leaves and 0.47mg/mL from fruit coatings. The MWDs of TPI demonstrated a bimodal distribution from leaves, a unimodal distribution from bark, and a unimodal distribution with a tiny peak shoulder from fruit coatings. In real-life E. ulmoides analysis, the results from three independent methods (GPC, gravimetric method, and infrared spectroscopy) were obtained with good consistency. PMID- 26435187 TI - Corrigendum: A Novel Role of Numb as A Regulator of Pro-inflammatory Cytokine Production in Macrophages in Response to Toll-like Receptor 4. PMID- 26435188 TI - Understanding Cooperative Behavior Based on the Coevolution of Game Strategy and Link Weight. AB - In reality, the dependency relationship among individuals is heterogeneous and time-varying. Based on this fact, we present a new mechanism of coevolution of game strategy and link weight when analyzing the evolution of cooperation. In detail, we model the population on a regular network, on which the relationship between players is depicted by a weighted link, and prisoner's dilemma has been applied to describe the interaction of players. Further, the impact of this mechanism on the cooperative behavior has been outlined. By conducting large scale Monte Carlo simulations, we can easily draw a conclusion that this mechanism can promote cooperation efficiently. Compared with the traditional case, when the temptation of defection b is large, the fraction of cooperation is still able to keep in a high level. With a comprehensive examination of the distribution of stable link weight, it is evident that the coevolution mechanism would deviate the initial distribution. This mechanism induces the heterogeneity of players, which enhances the fraction of cooperation. Numerical simulations also indicate that an intermediate value of Delta/delta warrants an optimal resolution of prisoner's dilemma. The mechanism of coevolution of game strategy and link weight has a practical significance and will provide new insight for the further research. PMID- 26435189 TI - Systematic review of economic evaluations of vaccination programs in mainland China: Are they sufficient to inform decision making? AB - The purpose of the study was to systematically review economic evaluations of vaccine programs conducted in mainland China. We searched for economic evaluations of vaccination in China published prior to August 3, 2015 in eight English-language and three Chinese-language databases. Each article was appraised against the 19-item Consensus on Health Economic Criteria list (CHEC-list). We found 23 papers evaluating vaccines against hepatitis B (8 articles), Streptococcus pneumoniae (5 articles), human papillomavirus (3 articles), Japanese encephalitis (2 articles), rotavirus (2 articles), hepatitis A (1 article), Enterovirus 71 (1 article) and influenza (1 article). Studies conformed to a mean of 12 (range: 6-18) items in the CHEC-list criteria. Five of six Chinese-language articles conformed to fewer than half of the 19 criteria items. The main criteria that studies failed to conform to included: inappropriate measurement (20 articles) and valuation (18 articles) of treatment and/or vaccination costs, no discussion about distributional implications (18 articles), missing major health outcomes (14 articles), no discussion about generalizability to other contexts (14 articles), and inadequate sensitivity analysis (13 articles). In addition, ten studies did not include major cost components of vaccination programs, and nine did not report outcomes in terms of life years even in cases where QALYs or DALYs were calculated. Only 13 studies adopted a societal perspective for analysis. All studies concluded that the appraised vaccination programs were cost-effective except for one evaluation of universal 7 valent pneumococcal conjugate vaccine (PCV-7) in children. However, three of the five studies on PCV-7 showed poor overall quality, and the number of studies on vaccines other than hepatitis B vaccine and PCV-7 was limited. In conclusion, major methodological flaws and reporting problems exist in current economic evaluations of vaccination programs in China. Local guidelines for good practice and reporting, institutional mechanisms and education may help to improve the overall quality of these evaluations. PMID- 26435190 TI - An enriched medical home intervention using community health workers improves adherence to immunization schedules. AB - IMPORTANCE: Disparities in childhood vaccination rates persist. OBJECTIVE: To evaluate the impact of an enriched medical home intervention using community health workers on improving immunization adherence among young children. DESIGN: The intervention group received home visits from trained community health workers to support families in adhering to recommended care while the comparison group received usual care (i.e. no home visits/reminders). Immunization history and socio-demographic data were collected using medical records and a validated questionnaire. The doubly robust estimation of risk difference, which combines weighting via propensity score and outcome regression model, was used to compare immunization adherence rates between two groups. SETTING: Primary care practices affiliated with a suburban tertiary care academic medical center serving a socioeconomically diverse population. PARTICIPANTS: The study sample included children <= 2 years of age at enrollment who crossed at least one age time point of 3, 7, 15, or 24 months during their 6 months post-enrollment period. MAIN OUTCOMES AND MEASURES: The primary outcome was age-specific immunization up-to date status defined by CDC guidelines. The primary predictor was participation in the intervention. RESULTS: The analysis included 201 children in the usual care group and 110 children in the intervention group. The usual care and intervention groups were divided into subgroups of newborn and infant/toddler to account for prior immunization history. After adjusting for differences in group characteristics, we found a significant absolute increase in the up-to-date immunization likelihood for both newborns (20.9%, p=0.01) and infants/toddlers (16.8%, p=0.01) receiving the intervention when compared to their peers receiving usual clinical care. CONCLUSIONS AND RELEVANCE: Our findings demonstrate the positive impact of an enriched medical home intervention using community health worker home visitation on early childhood immunization up-to-date status. With further study, this model may provide a cost-effective approach to improving childhood vaccination rates, especially for vulnerable groups. PMID- 26435191 TI - Functional roles of enhancer of zeste homolog 2 in gliomas. AB - Gliomas are the most common and lethal type of primary malignant brain tumor. Due to the infiltrative nature and high resistance to standard first line treatment with combinations of radiation and chemotherapy, the prognosis of patient is very poor. Recently, accumulated evidence suggests that enhancer of zeste homolog 2 (EZH2) serves as an oncogene and is involved in multiple glioma cell processes, including cell cycle, invasion, glioma stem cell maintenance, drug and radiotherapy resistance and so on. In this review, we will focus on updating current knowledge of EZH2 in gliomas. Moreover, the regulation of EZH2 by microRNAs and long non-coding RNAs and the therapeutic strategies targeting EZH2 for gliomas will also be discussed. PMID- 26435192 TI - De novo transcriptome sequencing and discovery of genes related to copper tolerance in Paeonia ostii. AB - Paeonia ostii, an important ornamental and medicinal plant, grows normally on copper (Cu) mines with widespread Cu contamination of soils, and it has the ability to lower Cu contents in the Cu-contaminated soils. However, very little molecular information concerned with Cu resistance of P. ostii is available. In this study, high-throughput de novo transcriptome sequencing was carried out for P. ostii with and without Cu treatment using Illumina HiSeq 2000 platform. A total of 77,704 All-unigenes were obtained with a mean length of 710 bp. Of these unigenes, 47,461 were annotated with public databases based on sequence similarities. Comparative transcript profiling allowed the discovery of 4324 differentially expressed genes (DEGs), with 2207 up-regulated and 2117 down regulated unigenes in Cu-treated library as compared to the control counterpart. Based on these DEGs, Gene Ontology (GO) enrichment analysis indicated Cu stress relevant terms, such as 'membrane' and 'antioxidant activity'. Meanwhile, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis uncovered some important pathways, including 'biosynthesis of secondary metabolites' and 'metabolic pathways'. In addition, expression patterns of 12 selected DEGs derived from quantitative real-time polymerase chain reaction (qRT-PCR) were consistent with their transcript abundance changes obtained by transcriptomic analyses, suggesting that all the 12 genes were authentically involved in Cu tolerance in P. ostii. This is the first report to identify genes related to Cu stress responses in P. ostii, which could offer valuable information on the molecular mechanisms of Cu resistance, and provide a basis for further genomics research on this and related ornamental species for phytoremediation. PMID- 26435193 TI - USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination. AB - Ubiquitin modification of the TGF-beta pathway components is emerging as a key mechanism of TGF-beta pathway regulation. To limit TGF-beta responses, TGF-beta signaling is regulated through a negative feedback loop whereby the E3 ligase SMURF2 targets the TGF-beta receptor (TbetaR) complex for ubiquitin-mediated degradation. Counteracting this process, a number of deubiquitinating (DUBs) enzymes have recently been identified that deubiquitinate and stabilize the TbetaR. However the precise mechanism by which these DUBs act on TbetaR function remains poorly defined. Here, we demonstrate that apart from targeting the TbetaR complex directly, USP15 also deubiquitinates SMURF2 resulting in enhanced TbetaR stability and downstream pathway activation. Through proteomic analysis, we show that USP15 modulates the ubiquitination of Lys734, a residue required for SMURF2 catalytic activity. Our results show that SMURF2 is a critical target of USP15 in the TGF-beta pathway and may also explain how USP15 and SMURF2 target multiple complementary protein complexes in other pathways. PMID- 26435195 TI - Noise in Graphene Superlattices Grown on Hexagonal Boron Nitride. AB - Existing in almost all electronic systems, the current noise spectral density, originated from the fluctuation of current, is by nature far more sensitive than the mean value of current, the most common characteristic parameter in electronic devices. Existing models on its origin of either carrier number or mobility are adopted in practically all electronic devices. For the past few decades, there has been no experimental evidence for direct association between 1/f noise and any other kinetic phenomena in solid state devices. Here, in the study of a van der Waals heterostructure of graphene on hexagonal BN superlattice, satellite Dirac points have been characterized through 1/f noise spectral density with pronounced local minima and asymmetric magnitude associated with its unique energy dispersion spectrum, which can only be revealed by scanning tunneling microscopy and low temperature magneto-transport measurement. More importantly, these features even emerge in the noise spectra of devices showing no minima in electric current, and are robust at all temperatures down to 4.3 K. In addition, graphene on h-BN exhibits a record low noise level of 1.6 * 10(-9) MUm(2) Hz(-1) at 10 Hz, more than 1 order of magnitude lower than previous results for graphene on SiO2. Such an epitaxial van der Waals material system not only enables an unprecedented characterization of fundamentals in solids by 1/f noise, but its superior interface also provides a key and feasible solution for further improvement of the noise level for graphene devices. PMID- 26435194 TI - Plasma membrane restricted RhoGEF activity is sufficient for RhoA-mediated actin polymerization. AB - The small GTPase RhoA is involved in cell morphology and migration. RhoA activity is tightly regulated in time and space and depends on guanine exchange factors (GEFs). However, the kinetics and subcellular localization of GEF activity towards RhoA are poorly defined. To study the mechanism underlying the spatiotemporal control of RhoA activity by GEFs, we performed single cell imaging with an improved FRET sensor reporting on the nucleotide loading state of RhoA. By employing the FRET sensor we show that a plasma membrane located RhoGEF, p63RhoGEF, can rapidly activate RhoA through endogenous GPCRs and that localized RhoA activity at the cell periphery correlates with actin polymerization. Moreover, synthetic recruitment of the catalytic domain derived from p63RhoGEF to the plasma membrane, but not to the Golgi apparatus, is sufficient to activate RhoA. The synthetic system enables local activation of endogenous RhoA and effectively induces actin polymerization and changes in cellular morphology. Together, our data demonstrate that GEF activity at the plasma membrane is sufficient for actin polymerization via local RhoA signaling. PMID- 26435196 TI - Effects of Agar Gel Strength and Fat on Oral Breakdown, Volatile Release, and Sensory Perception Using in Vivo and in Vitro Systems. AB - The density and composition of a food matrix affect the rates of oral breakdown and in-mouth flavor release as well as the overall sensory experience. Agar gels of increasing concentration (1.0, 1.7, 2.9, and 5% agarose) with and without added fat (0, 2, 5, and 10%) were spiked with seven aroma volatiles. Differences in oral processing and sensory perception were systematically measured by a trained panel using a discrete interval time intensity method. Volatile release was measured in vivo and in vitro by proton transfer reaction mass spectrometry. Greater oral processing was required as agar gel strength increased, and the intensity of flavor-related sensory attributes decreased. Volatile release was inversely related to gel strength, showing that physicochemical phenomena were the main mechanisms underlying the perceived sensory changes. Fat addition reduced the amount of oral processing and had differential effects on release, depending on the fat solubility or lipophilicity of the volatiles. PMID- 26435197 TI - Hofmeister effect of anions on calcium translocation by sarcoplasmic reticulum Ca(2+)-ATPase. AB - The occurrence of Hofmeister (specific ion) effects in various membrane-related physiological processes is well documented. For example the effect of anions on the transport activity of the ion pump Na(+), K(+)-ATPase has been investigated. Here we report on specific anion effects on the ATP-dependent Ca(2+) translocation by the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA). Current measurements following ATP concentration jumps on SERCA-containing vesicles adsorbed on solid supported membranes were carried out in the presence of different potassium salts. We found that monovalent anions strongly interfere with ATP-induced Ca(2+) translocation by SERCA, according to their increasing chaotropicity in the Hofmeister series. On the contrary, a significant increase in Ca(2+) translocation was observed in the presence of sulphate. We suggest that the anions can affect the conformational transition between the phosphorylated intermediates E1P and E2P of the SERCA cycle. In particular, the stabilization of the E1P conformation by chaotropic anions seems to be related to their adsorption at the enzyme/water and/or at the membrane/water interface, while the more kosmotropic species affect SERCA conformation and functionality by modifying the hydration layers of the enzyme. PMID- 26435198 TI - Upregulation of 14-3-3 eta in chronic liver fluke infection is a potential diagnostic marker of cholangiocarcinoma. AB - PURPOSE: To discover protein markers in chronic/advanced opisthorchiasis for the early detection of Opisthorchis viverrini (OV)-associated cholangiocarcinoma (CCA). EXPERIMENTAL DESIGN: Liver tissues derived from normal hamsters and those with chronic/advanced opisthorchiasis (n = 5 per group) were subjected to 2DE and LC-MS/MS. Candidate protein expression was confirmed in hamster models and human CCA tissue microarray (TMA) using immunohistochemistry and Western blot. RESULT: Proteomics analysis detected 14-3-3 eta only in infected hamsters, not in uninfected controls. Immunohistochemistry and Western blot analysis confirmed low expression of 14-3-3 eta in normal hamster livers and demonstrated increased expression through time in infected livers. This protein was also observed in parasite organs, especially during the chronic phase of opisthorchiasis. Moreover, increased expression of 14-3-3 eta, relative to normal hamster livers, was observed during the early stage of CCA induced by OV infection and administration of N-nitrosodimethylamine. Immunohistochemical analysis of human TMA revealed that 14-3-3 eta was highly expressed in CCA (84.23%, 187/222 cases) but was not found in hepatocellular carcinoma or healthy liver tissues. CONCLUSIONS AND CLINICAL RELEVANCE: 14-3-3 eta protein has potential as a screening and early diagnostic marker for CCA. PMID- 26435199 TI - Knowledge and attitudes regarding clinical trials and willingness to participate among prostate cancer patients. AB - BACKGROUND: Enrollment of minorities in clinical trials remains low. Through a California population-based study of men with early stage prostate cancer, we examined the relationships between race/ethnicity and 1) attitudes, 2) knowledge and 3) willingness to participate in clinical trials. METHODS: From November 2011 November 2012, we identified all incident cases of prostate cancer in African American, Latino, and Asian American men ages 18-75 years, and a random sample of white men diagnosed in 2008, through the California Cancer Registry, living within 60 miles of a site offering >= 1 clinical trial. Participants completed a 30-min telephone interview in English, Spanish, or Chinese. In this cross sectional population-based study, multivariable logistic regression was used to estimate associations between race/ethnicity and 1) attitudes, 2) knowledge and 3) willingness to participate. RESULTS: Of 855 participants, 52% were >= 65 years, 42% were white, 24% Latino, 19% African American and 15% Asian American. The majority (81%) had medium-to-high health literacy. Compared to non-Latino white men, African American men were less likely to have above average knowledge of clinical trials (OR=0.55; CI=0.35-0.86), as were Asian American (OR=0.55; CI=0.33-0.93) and Latino men (OR=0.30; CI=0.18-0.48). There were no racial/ethnic differences in willingness to participate. The attitude that "researchers are the main beneficiaries" was negatively associated with willingness (OR=0.63; CI=0.43 0.93); the attitude that "patients are the main beneficiaries" was positively associated with willingness to participate (OR=1.57; CI=1.07-2.29). CONCLUSIONS: Men with early stage prostate cancer are willing to take part in clinical trials and this willingness does not vary by race/ethnicity. PMID- 26435200 TI - Treatment preference and patient centered prostate cancer care: Design and rationale. AB - Prostate cancer is a slow progressing cancer that affects millions of men in the US. Due to uncertainties in outcomes and treatment complications, it is important that patients engage in informed decision making to choose the "optimal treatment". Patient centered care that encompasses informed decision-making can improve treatment choice and quality of care. Thus, assessing patient treatment preferences is critical for developing an effective decision support system. The objective of this patient-centered randomized clinical trial was to study the comparative effectiveness of a conjoint analysis intervention compared to usual care in improving subjective and objective outcomes in prostate cancer patients. We identified preferred attributes of alternative prostate cancer treatments that will aid in evaluating attributes of treatment options. In this two-phase study, in Phase 1 we used mixed methods to develop an adaptive conjoint task instrument. The conjoint task required the patients to trade-off attributes associated with treatments by assessing their relative importance. Phase 2 consisted of a randomized controlled trial of men with localized prostate cancer. We analyzed the effect of conjoint task intervention on the association between preferences, treatment and objective and subjective outcomes. Our conjoint task instrument can lead to a values-based patient-centered decision aid tool and help tailor treatment decision making to the values of prostate cancer patients. This will ultimately improve clinical decision making, clinical policy process, enhance patient centered care and improve prostate cancer outcomes. PMID- 26435201 TI - Highly Dispersed Ultrafine Pt Nanoparticles on Reduced Graphene Oxide Nanosheets: In Situ Sacrificial Template Synthesis and Superior Electrocatalytic Performance for Methanol Oxidation. AB - We report a simple and environmentally friendly route to prepare platinum/reduced graphene oxide (Pt/rGO) nanocomposites (NCs) with highly reactive MnOx colloids as reducing agents and sacrificial templates. The colloids are obtained by laser ablation of a metallic Mn target in graphene oxide (GO)-containing solution. Structural and morphological investigations of the as-prepared NCs revealed that ultrafine Pt nanoparticles (NPs) with an average size of 1.8 (+/-0.6) nm are uniformly dispersed on the surfaces of rGO nanosheets. Compared with commercial Pt/C catalysts, Pt/rGO NCs with highly electrochemically active surface areas show remarkably improved catalytic activity and durability toward methanol oxidation. All of these superior characteristics can be attributed to the small particle size and uniform distribution of the Pt NPs, as well as the excellent electrical conductivity and stability of the rGO catalyst support. These findings suggest that Pt/rGO electrocatalysts are promising candidate materials for practical use in fuel cells. PMID- 26435202 TI - Predictive value of red blood cell distribution width for coronary artery lesions in patients with Kawasaki disease. AB - Recent studies have shown that elevated red blood cell distribution width is associated with poor outcome in cardiovascular diseases. In order to assess the predictive value of red blood cell distribution width, before treatment with intravenous immunoglobulins, for coronary artery lesions in patient with Kawasaki disease, we compared 83 patients with coronary artery lesions and 339 patients without coronary artery lesions before treatment with intravenous immunoglobulin. Clinical, echocardiographic, and biochemical values were evaluated along with red blood cell distribution width. A total of 422 consecutive patients with Kawasaki disease were enrolled into our study. According to receiver operating characteristic curve analysis, the optimal red blood cell distribution width cut off value for predicting coronary artery lesions was 14.55% (area under the curve was 0.721; p=0.000); eighty-three patients (19.7%) had coronary artery lesions, and 70% of the patients with coronary artery lesions had red blood cell distribution width level >14.55%. Logistic regression analysis revealed that fever duration >14 days (odds ratio was 3.42, 95% confidence interval was 1.27 9.22; p=0.015), intravenous immunoglobulin resistance (odds ratio was 2.33, 95% confidence interval was 1.02-5.29; p=0.04), and red blood cell distribution width >14.55% (odds ratio was 3.49, 95% confidence interval was 2.01-6.05; p=0.000) were independent predictors of coronary artery lesions in patients with Kawasaki disease. In Conclusion, red blood cell distribution width may be helpful for predicting coronary artery lesions in patients with Kawasaki disease. PMID- 26435203 TI - Optical and surface properties of optically transparent Li3 PO4 solid electrolyte layer for transparent solid batteries. AB - In this study, optical and surface properties of the optically transparent Li3 PO4 solid electrolyte layer for transparent solid battery have been investigated for the first time. To determine the optical properties, transmittance, absorbance, reflection, refractive index spectra, and optical band gap were determined by UV-Vis spectrophotometer and optical interferometer. The surface property of the transparent Li3 PO4 solid electrolyte was analyzed using atomic force microscopy. One another important parameter is contact angle (CA) surface free energy (SFE). CA and SFE were determined by optical tensiometer. These values probably are a most important parameter for polymer and hybrid battery performance. For the best performance, value of CA should be low. As a result, solid electrolyte layer is a highly transparent and it has a high wettability. SCANNING 38:317-321, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26435204 TI - Mesoporous Silica Nanoparticles with pH-Sensitive Nanovalves for Delivery of Moxifloxacin Provide Improved Treatment of Lethal Pneumonic Tularemia. AB - We have optimized mesoporous silica nanoparticles (MSNs) functionalized with pH sensitive nanovalves for the delivery of the broad spectrum fluoroquinolone moxifloxacin (MXF) and demonstrated its efficacy in treating Francisella tularensis infections both in vitro and in vivo. We compared two different nanovalve systems, positive and negative charge modifications of the mesopores, and different loading conditions-varying pH, cargo concentration, and duration of loading-and identified conditions that maximize both the uptake and release capacity of MXF by MSNs. We have demonstrated in macrophage cell culture that the MSN-MXF delivery platform is highly effective in killing F. tularensis in infected macrophages, and in a mouse model of lethal pneumonic tularemia, we have shown that the drug-loaded MSNs are much more effective in killing F. tularensis than an equivalent amount of free MXF. PMID- 26435205 TI - The association between platelet transfusion and idiopathic pneumonia syndrome is unaffected by platelet product type. AB - BACKGROUND: Methods used to produce platelet (PLT) components, pooling of PLT rich plasma (PRP-PLT) and apheresis (AP-PLT), may variably contribute to the pathogenesis and severity of idiopathic pneumonia syndrome (IPS). STUDY DESIGN AND METHODS: We performed a retrospective cohort study of 906 allogeneic hematopoietic cell transplant recipients to examine associations between PLT product type and risks of developing IPS and dying after IPS onset. Proportional hazards models included separate terms for the sum of all PLT transfusions and the sum of PRP-PLT units received in the 3 or 7 days before IPS onset. Similarly constructed models analyzed the outcome of time to death after IPS onset. All analyses were adjusted for known IPS risk factors. RESULTS: Patients received a median of three PRP-PLT transfusions (interquartile range [IQR], 0-6) and five AP PLT transfusions (IQR, 1-13) while at risk for IPS. Seventy-five patients (8%) developed IPS by Posttransplant Day 120. The proportion of PRP-PLT transfusions was not associated with risk of developing IPS (3-day hazard ratio [HR] 0.98, 95% CI 0.74-1.29, p = 0.86; 7-day HR 1.00, 95% CI 0.86-1.15, p = 0.95) or dying after IPS onset (3-day HR 0.99, 95% CI 0.75-1.31, p = 0.97; 7-day HR 0.98, 95% CI 0.78 1.12, p = 0.47). CONCLUSION: The association between PLT transfusions and risk of developing IPS or dying after IPS onset does not differ according to PLT product type. Further research is required to identify potentially modifiable steps in PLT component production that contribute to IPS. PMID- 26435206 TI - Trends Form Follows Function: New Ways to Inform and Inspire. PMID- 26435207 TI - Trying to Drink from a Fire Hose: Too Much of the Wrong Kind of Health Care News. PMID- 26435208 TI - Biologic Approaches to Treat Substance-Use Disorders. AB - In contrast to traditional pharmacodynamic approaches to treat substance-use disorders (SUDs), the use of biologics (vaccines, monoclonal antibodies, and genetically modified enzymes) is based on a pharmacokinetic principle: reduce the amount of (and, ideally, eliminate) abused drug entering the central nervous system (CNS). Preclinical studies indicate that biologics are effective in both facilitating abstinence and preventing relapse to abused substances ranging from nicotine to heroin. While data are still emerging, the results from multiple clinical trials can best be described as mixed. Nonetheless, these clinical studies have already provided important insights using 'first-generation' tools that may inform the development of effective and commercially viable biologics to treat tobacco-, cocaine-, and methamphetamine-use disorders. PMID- 26435209 TI - Gatekeepers Controlling GPCR Export and Function. AB - Regulated export of G protein-coupled receptors (GPCRs) from intracellular stores involves chaperones and escort proteins, which promote their progression to the cell surface, and gatekeepers, which retain them in intracellular compartments. Functional gamma-aminobutyric acid (GABA)B receptors, the paradigm of this phenomenon, comprise GB1 and GB2 subunits forming a heterodimer. GB1 is retained in the endoplasmic reticulum (ER) in the absence of GB2. A specific ER-resident gatekeeper, prenylated Rab acceptor family 2 (PRAF2), is involved in GB1 retention and prevents its progression into the biosynthetic pathway. GB1 can be released from PRAF2 only on competitive interaction with GB2. PRAF2 is ubiquitous and belongs to a subgroup of the mammalian Ypt-interacting protein (Yip) family. Several other GPCRs are likely to be regulated by Yip proteins, which might be involved in the pathophysiology of human diseases that are associated with impaired receptor targeting to the cell surface. PMID- 26435211 TI - Protein Tyrosine Phosphatases in Hypothalamic Insulin and Leptin Signaling. AB - The hypothalamus is critical to the coordination of energy balance and glucose homeostasis. It responds to peripheral factors, such as insulin and leptin, that convey to the brain the degree of adiposity and the metabolic status of the organism. The development of leptin and insulin resistance in hypothalamic neurons appears to have a key role in the exacerbation of diet-induced obesity. In rodents, this has been attributed partly to the increased expression of the tyrosine phosphatases Protein Tyrosine Phosphatase 1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP), which attenuate leptin and insulin signaling. Deficiencies in PTP1B and TCPTP in the brain, or specific neurons, promote insulin and leptin signaling and prevent diet-induced obesity, type 2 diabetes mellitus (T2DM), and fatty liver disease. Although targeting phosphatases and hypothalamic circuits remains challenging, recent advances indicate that such hurdles might be overcome. Here, we focus on the roles of PTP1B and TCPTP in insulin and leptin signaling and explore their potential as therapeutic targets. PMID- 26435210 TI - Therapeutic Targeting of Siglecs using Antibody- and Glycan-Based Approaches. AB - The sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of immunomodulatory receptors whose functions are regulated by their glycan ligands. Siglecs are attractive therapeutic targets because of their cell type-specific expression pattern, endocytic properties, high expression on certain lymphomas/leukemias, and ability to modulate receptor signaling. Siglec-targeting approaches with therapeutic potential encompass antibody- and glycan-based strategies. Several antibody-based therapies are in clinical trials and continue to be developed for the treatment of lymphoma/leukemia and autoimmune disease, while the therapeutic potential of glycan-based strategies for cargo delivery and immunomodulation is a promising new approach. Here we review these strategies with special emphasis on emerging approaches and disease areas that may benefit from targeting the Siglec family. PMID- 26435212 TI - Apolipoprotein C-III: From Pathophysiology to Pharmacology. AB - Apolipoprotein C-III (apoC-III) has a critical role in the metabolism of triglyceride (TG)-rich lipoproteins (TRLs). Animal models lacking the APOC3 gene exhibit reduced plasma TG levels, whereas the overexpression of APOC3 leads to increased TG levels. In humans, loss-of-function mutations in APOC3 are associated with reduced plasma TG levels and reduced risk for ischemic vascular disease and coronary heart disease. Several hypolipidemic agents have been shown to reduce apoC-III, including fibrates and statins, and antisense technology aimed at inhibiting APOC3 mRNA to decrease the production of apoC-III is currently in Phase III of clinical development. Here, we review the pathophysiological role of apoC-III in TG metabolism and the evidence supporting this apolipoprotein as an emerging target for hypertriglyceridemia (HTG) and associated cardiovascular disorders. PMID- 26435213 TI - Ligands for the Nuclear Peroxisome Proliferator-Activated Receptor Gamma. AB - Nuclear receptors are ligand-activated transcription factors, which represent a primary class of drug targets. The nuclear receptor peroxisome proliferator activated receptor gamma (PPARgamma) is a key player in various biological processes. PPARgamma is widely known as the target protein of the thiazolidinediones for treating type 2 diabetes. Moreover, PPARgamma ligands can induce anti-inflammatory and potentially additional beneficial effects. Recent mechanistic insights of PPARgamma modulation give hope the next generation of efficient PPARgamma-based drugs with fewer side effects can be developed. Furthermore, chemical approaches that make use of synergistic action of combinatorial ligands are promising alternatives for providing tailored medicine. Lessons learned from fine-tuning the action of PPARgamma can provide avenues for efficient molecular intervention via many other nuclear receptors to combat common diseases. PMID- 26435214 TI - Silent information regulator 1 (SIRT1) ameliorates liver fibrosis via promoting activated stellate cell apoptosis and reversion. AB - SIRT1 (silent information regulator 1), a conserved NAD+-dependent histone deacetylase, is closely related with various biological processes. Moreover, the important role of SIRT1 in alcoholic liver disease, nonalcoholic fatty liver and HCC had been widely reported. Recently, a novel role of SIRT1 was uncovered in organ fibrosis diseases. Here, we investigated the inhibitory effect of SIRT1 in liver fibrogenesis. SIRT1 protein was dramatically decreased in CCl4-treated mice livers. Stimulation of LX-2 cells with TGF-beta1 also resulted in a significant suppression of SIRT1 protein. Nevertheless, TGF-beta1-induced LX-2 cell activation was inhibited by SIRT1 plasmid, and this was accompanied by up regulation of cell apoptosis-related proteins. Overexpression of SIRT1 also attenuated TGF-beta1-induced expression of myofibroblast markers alpha-SMA and COL1a. However, the important characteristic of the recovery of liver fibrosis is not only the apoptosis of activated stellate cells but also the reversal of the myofibroblast-like phenotype to a quiescent-like phenotype. Restoration of SIRT1 protein was observed in the in vivo spontaneously liver fibrosis reversion model and in vitro MDI (isobutylmethylxanthine, dexamethasone, and insulin)-induced reversed stellate cells, and forced expression of SIRT1 also promoted the reversal of activated stellate cells. Furthermore, lncRNA MALAT1 (metastasis associated lung adenocarcinoma transcript 1) was increased in liver fibrosis. RNAi-mediated suppression of MALAT1 resulted in a decrease of myofibroblast markers and restoration of SIRT1 protein. These observations suggested that SIRT1 contributed to apoptosis and reversion of activated LX-2 cells and SIRT1 might be regulated by MALAT1 in liver fibrosis. Therefore, SIRT1 could be considered as a valuable therapeutic target for translational studies of liver fibrosis. PMID- 26435216 TI - Evaluation of different pig oral mucosa sites as permeability barrier models for drug permeation studies. AB - The objective of the present study was to investigate the influence of preparation and storage conditions on the histology and permeability of different parts of porcine oral mucosa used for in vitro studies of transbuccal formulations. Fresh and frozen (-20 degrees C and -80 degrees C, with or without cryoprotectant) epithelia of porcine palatal, gingival, dorsum of the tongue, and buccal mucosa were submitted for histological analyses to determine the effects of storage conditions on barrier integrity. Permeation of lidocaine hydrochloride (used as a hydrophilic model drug) across fresh and previously frozen oral epithelium was measured in order to evaluate the barrier function. Histological evaluation demonstrated that the oral epithelium was successfully separated from the connective tissue, except for gingival mucosa. After storage under different conditions, all tissues presented desquamation of superficial layers and spherical spaces induced by the freezing process. The permeability of lidocaine hydrochloride varied among the fresh oral mucosa and generally increased after freezing. In conclusion, fresh epithelium from the buccal and dorsum of the tongue mucosa should be used for in vitro studies investigating hydrophilic drug transport when these are the desired clinical application sites. However, when the palate is the target site, both fresh and frozen (for up to 4weeks, without addition of cryoprotectant) samples could be used. The addition of glycerol as a cryoprotectant should be avoided due to increased lidocaine hydrochloride permeability. PMID- 26435215 TI - Site specific modification of the human plasma proteome by methylglyoxal. AB - Increasing evidence identifies dicarbonyl stress from reactive glucose metabolites, such as methylglyoxal (MG), as a major pathogenic link between hyperglycemia and complications of diabetes. MG covalently modifies arginine residues, yet the site specificity of this modification has not been thoroughly investigated. Sites of MG adduction in the plasma proteome were identified using LC-MS/MS analysis in vitro following incubation of plasma proteins with MG. Treatment of plasma proteins with MG yielded 14 putative MG hotspots from five plasma proteins (albumin [nine hotspots], serotransferrin, haptoglobin [2 hotspots], hemopexin, and Ig lambda-2 chain C regions). The search results revealed two versions of MG-arginine modification, dihydroxyimidazolidine (R+72) and hydroimidazolone (R+54) adducts. One of the sites identified was R257 in human serum albumin, which is a critical residue located in drug binding site I. This site was validated as a target for MG modification by a fluorescent probe displacement assay, which revealed significant drug dissociation at 300 MUM MG from a prodan-HSA complex (75 MUM). Moreover, twelve human plasma samples (six male, six female, with two type 2 diabetic subjects from both genders) were analyzed using multiple reaction monitoring (MRM) tandem mass spectrometry and revealed the presence of the MG-modified albumin R257 peptide. These data provide insights into the nature of the site-specificity of MG modification of arginine, which may be useful for therapeutic treatments that aim to prevent MG-mediated adverse responses in patients. PMID- 26435217 TI - Towards a test to predict 5-fluorouracil toxicity: Pharmacokinetic data for thymine and two sequential metabolites following oral thymine administration to healthy adult males. AB - The fluoropyrimidine drugs 5-fluorouracil and its oral prodrug capecitabine remain first line therapy for solid tumours of the neck, breast and colon. However, significant and unpredictable toxicity affects about 10-25% of patients depending upon the mode of 5-fluorouracil delivery. The pharmacokinetics of thymine (5-methyluracil) may provide an approach for screening for 5-fluorouracil toxicity, based on the rationale that thymine is a close structural analogue of 5 fluorouracil and is catabolized by the same enzymatic pathway. Oral thymine loading tests were performed on 12 healthy volunteers. Each subject was given a single oral dose of 250mg thymine in capsule form. Blood, urine and saliva samples were collected pre-dose and up to 5h post-dose. Concentrations of thymine, and its catabolites dihydrothymine and beta-ureidoisobutyrate were analysed by HPLC-tandem mass spectrometry in plasma, urine and saliva. The pharmacokinetic data of healthy volunteers were analysed assuming a non compartmental model. Thymine peaked quickly (30-45min) in plasma to a maximum concentration of 170+/-185MUg/L (mean+/-SD). Clearance was high (mean 57.9L/h/kg) exceeding normal human liver blood flow, suggesting low systemic bioavailability; urinary recovery of the thymine dose was low (<1%). Apparent formation rate limited kinetics were observed for dihydrothymine, and the plasma concentration of dihydrothymine was consistently 10-fold higher than that of thymine. Plasma beta-ureidoisobutyrate concentrations, on the other hand, were similar to that of thymine. Genotyping confirmed that pathological mutations of the DPYD gene were absent. The urinary excretion ratio of thymine/dihydrothymine was informative of the maximum concentration. Saliva thymine was highly variable. These data are potentially useful as a basis for developing of a screening procedure to prospectively identify patients who are at risk of toxicity from fluoropyrimidine drugs. PMID- 26435218 TI - Isolation and characterization of three cadmium-inducible promoters from Oryza sativa. AB - Cadmium (Cd) is an important soil pollutant. Developing genetically engineered crops might be a feasible strategy for Cd decontamination and damage prevention. Both genes and promoters are critical for the effective construction of genetically modified plants. Although many functional genes for Cd tolerance and accumulation have been identified, few reports have focused on plant Cd-inducible promoters. Here, we identified three Cd-inducible genes in the rice genome: two tau class glutathione S-transferase (GSTU) genes, OsGSTU5 and OsGSTU37, and an HSP20/alpha crystallin family protein gene, OsHSP18.6. The promoter sequences were isolated and tested in transgenic rice lines using a GUSplus reporter gene. All of the promoters exhibited low background expression under normal conditions and could be strongly induced by Cd stress. Although their strength was comparable to that of the constitutive OsACTIN promoter under Cd stress, their time-dependent expression patterns under both short- and long-term Cd exposure were markedly different. The responses of the three promoters to other heavy metals were also examined. Furthermore, heavy metal-responsive cis elements in the promoters were computationally analyzed, and regions determining the Cd stress response were analyzed using a series of truncations. Our results indicate that the three Cd-inducible rice promoters described herein could potentially be used in applications aimed at improving heavy metal tolerance in crops or for the bio-monitoring of environmental contamination. PMID- 26435219 TI - Emulating human microcapillaries in a multi-organ-chip platform. AB - Current microfluidic chip-based tissue culture systems lack a capillary endothelial vessel system, which would enable perfusion with blood. We utilise spatial cell cultures to populate a perfused multi-organ-chip platform-a microfluidic device recently introduced for substance testing. Complete biological vascularization of such culture systems is vital to properly emulate physiological tissue behaviour. In this study, we incorporated a fibrin scaffold into the two-organ-chip design. Herein, adipose-derived stromal cells (ASCs) directed human umbilical vein endothelial cells (HUVECs) to organise into tube like structures. The ASCs induced tube formation of HUVECs in static and dynamic conditions. The replacement of full medium enriched with growth factors and foetal calf serum with basal medium resulted in viable cells with similar gene expression profiles. We regard this as a prerequisite for studies with organ constructs that have a need for a different medium formulation. Furthermore, we here address stability issues of the fibrin gel and fibrin composition for optimal microvessel formation. PMID- 26435221 TI - Reply to: Improving Research Standards to Restore Trust in Intranasal Oxytocin. PMID- 26435220 TI - Homology analysis and cross-immunogenicity of OmpA from pathogenic Yersinia enterocolitica, Yersinia pseudotuberculosis and Yersinia pestis. AB - The outer membrane protein A (OmpA) is one of the intra-species conserved proteins with immunogenicity widely found in the family of Enterobacteriaceae. Here we first confirmed OmpA is conserved in the three pathogenic Yersinia: Yersinia pestis, Yersinia pseudotuberculosis and pathogenic Yersinia enterocolitica, with high homology at the nucleotide level and at the amino acid sequence level. The identity of ompA sequences for 262 Y. pestis strains, 134 Y. pseudotuberculosis strains and 219 pathogenic Y. enterocolitica strains are 100%, 98.8% and 97.7% similar. The main pattern of OmpA of pathogenic Yersinia are 86.2% and 88.8% identical at the nucleotide and amino acid sequence levels, respectively. Immunological analysis showed the immunogenicity of each OmpA and cross-immunogenicity of OmpA for pathogenic Yersinia where OmpA may be a vaccine candidate for Y. pestis and other pathogenic Yersinia. PMID- 26435222 TI - Psychiatrists' Attitudes Toward Transcranial Magnetic Stimulation. PMID- 26435223 TI - Improving Research Standards to Restore Trust in Intranasal Oxytocin. PMID- 26435224 TI - The local knowledge of medicinal plants trader and diversity of medicinal plants in the Kabanjahe traditional market, North Sumatra, Indonesia. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Market is the main place for transactions of medicinal plants and traditional ingredients by local community in the Karo regency, North Sumatra, Indonesia. This is the first study to document the local knowledge of traders on and the diversity of the medicinal plants. The investigation was carried out in the Kabanjahe traditional market, in the Karo regency. The research goal was to reveal the local knowledge, diversity and utilization of medicinal plants, which have been traded in the Kabanjahe traditional market, as a basis for conservation efforts. MATERIALS AND METHODS: The study was conducted through ethnobotanical approach using market surveys. All traders of medicinal plants were surveyed applying in-depth interviews and participative observations. Data were analyzed qualitatively using descriptive statistics. The diversity of medicinal plants was expressed in term of the Shannon-Wiener diversity index (H'), whereas the similarity among traders was indicated by Jaccard index (Ji). RESULTS: Traders of medicinal plants stored the simplicia of medicinal plants in chest of drawers, plastic baskets, plastic bags, and in the air by suspending them from the the stall ceilings. We recorded 344 species, 217 genera and 90 families of medicinal plants. Those that were sold mostly belong to Zingeberaceae (20 species), Poaceae (19 species), and Asclepiadaceae (17 species), and the species received high consumers demand, mostly belong to Zingiberaceae, Rutaceae, and Asclepidiaceae. Asclepidiaceae was used to treat diseases like cancer and heart problems. The Shannon-Wiener diversity index of medicinal plants at the Kabanjahe traditional market was high (H'= 5.637). The high Jaccard similarity index (Ji>0.56) suggested that the traders were trading similar species of medicinal plants. CONCLUSION: Kabanjahe traditional market is the center for the sale of of medicinal plants as traditional ingredients. Several species are well known for their pharmacological properties but others, [such as: Dischidia imbricata (Blume) Steud., Dischidia nummularia R.Br., Hoya macrophylla Blume, and Hoya coriacea Blume] have been used for cancer treatment by local communities, but pharmacologically unknown, hence they are promising candidates for further investigation. PMID- 26435226 TI - Tension band plating in growth modulation : A review of current evidences. AB - Tension band plating (TBF) has been pitted as the best method for correcting the angular deformities and limb length discrepancies (LLD) in growing children. In this review we examined the superiority of the tension band plating over other methods of growth modulation, in terms of safety and efficacy. As per the current literature, in angular deformities TBP has similar correction rates with lesser complications. However in LLD the results are less promising. PMID- 26435225 TI - Tetramethylpyrazine identified by a network pharmacology approach ameliorates methotrexate-induced oxidative organ injury. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Tetramethylpyrazine (TMP) is one of the active constituents extracted from a frequently used herb, Ligusticum wallichii Franchat (Chuan-Xiong in Chinese), in traditional Chinese medicine. TMP can exert multiple pharmacological actions such as anti-inflammatory, anti-oxidative damage, anti platelet and neuroprotective effects, and its applications deserve further explored. AIM OF THE STUDY: This study aimed to determine the new role of TMP identified by a network pharmacology approach to alleviate the methotrexate (MTX) induced oxidative injury and characterize their mechanism of combinational actions. MATERIALS AND METHODS: A network pharmacology-based screening strategy is applied for target profile prediction and pharmacological characterization of herbal compounds, which is used to guide the following in vitro and in vivo experiments. The effect of herbal compounds identified by network pharmacology approaches to reduce the toxicity of MTX was assessed by MTX-induced rat toxicity model. The potential targets of TMP in this study were evaluated using standard protocols provided by Cerep, Inc. RESULTS: This strategy identified TMP from Ligusticum wallichii Franchat as a potent compound for ameliorating the oxidative organ injury of MTX. According to the predicted target profiles of TMP, a possible mechanism of the abrogation of MTX-induced toxicity is that TMP could upregulate cAMP by inhibiting phosphodiesterase (PDE) 10A2 activity. Another novel finding is that the competitive binding and antagonistic effects of TMP on adenosine receptor 2A and 2B appear to play important roles in the TMP-mediated reversal of MTX-induced hepatic injury. CONCLUSION: TMP identified by a network pharmacology approach could ameliorate MTX-induced oxidative organ injury. This study provides important evidence for the preclinical evaluation of TMP and MTX as a novel combinatorial remedy. PMID- 26435227 TI - Internal fixation of femoral neck stress fractures in young female athletes with a dynamic locking plate. AB - PURPOSE: Displaced stress fractures of the femoral neck in young female athletes are a rare but a difficult injury to treat with a favourable outcome, as there is a reported high incidence of avascular necrosis. Traditionally they are internally fixed with either cannulated screws or a sliding hip screw. Our study aims to highlight the Targon Femoral Neck (FN, B-Braun, Aesculap Inc, Germany) implant as a safe alternative for fixation of these injuries. METHODS: Three consecutive young female recreational athletes were reviewed from our institution with a displaced stress fracture of the femoral neck treated with the dynamic locking plate. RESULTS: Two patients achieved good results with full union and no complications. One patient had a poor result as she developed avascular necrosis 5 months post-operatively requiring revision to a total hip arthroplasty. CONCLUSION: Our study highlights the Targon FN implant is a safe alternative for internal fixation of displaced stress fractures of the femoral neck in young female recreational athletes. PMID- 26435228 TI - The role of external fixators in paediatric trauma. AB - We report a retrospective review of all paediatric trauma patients managed with an external fixator admitted to our institution over a 7-year period. We identified 30 fractures in 28 children. The fractures included 20 tibiae, 5 femurs, 2 humerii, 2 radii and 1 phalanx. The indications were 23 open fractures, 4 comminuted fractures and 3 closed fractures in poly-traumatised patients. It was the definitive treatment in 13 fractures. The mean length of total time with an external fixator was 9.6 weeks (range 1-38 weeks.) Difficulties encountered were eight problems, one obstacle and two true complications. There were no cases of re-fracture following removal of the external fixator. This review confirms that there is a role for the use of external fixation in selected paediatric fractures with a low complication rate. PMID- 26435229 TI - (Un)importance of physical therapy in treatment of displaced supracondylar humerus fractures in children. AB - Elbow joint stiffness is a common complication following supracondylar humerus fractures. In prospective study, dynamics of establishing a full range of motion in the elbow joint following the treatment of supracondylar humerus fractures were assessed, together with the effects of physical therapy on improvement in the range of motion. Two groups of patients were observed. Physical therapy was administered to the first group, comprised of 25 patients. The second group, comprised of 28 patients, underwent no physical therapy. In the first few months following treatment, the range of motion was significantly greater in the patients who had undergone physical therapy, but after 12 months, the range of motion was almost equal in the two groups. This study has shown that it takes about 12 months to establish a full range of motion after the injury, and that it is not necessary to apply physical therapy in patients with elbow fractures. PMID- 26435230 TI - Outcome of one-stage surgical treatment of developmental dysplasia of the hip in children from 1.5 to 6 years old. A retrospective study. AB - This study aimed to evaluate the outcome of one-stage treatment for developmental dysplasia of the hip (DDH) in patients after walking age. A Total of 58 children (67 hips) were retrospectively investigated to assess the efficacy and safety of one-stage treatment of developmental dysplasia of the hip (DDH) in children from 1.5 to 6 years of age with a mean follow-up of 4.00+/-0.43 (range 3-6.8) years. Eleven (19%) were male, forty-seven (81%) were female. Our method consisted of open reduction, Salter innominate osteotomy, femoral shortening and derotation. The patients were distributed into three groups according to the age at which they were operated: 12 (20.7%) patients with 12 hips (17.9%) were operated between 1.5 and 2 years of age (Group I), 35 (60.3%) patients with 44 hips (65.7%) were operated between 2 and 4 years (Group II), 11 (19%) patients with 11 hips (16.4%) were operated between 4 and 6 years (Group III). Clinical and radiological assessment at final follow-up showed that the outcome was not significantly different between group I and group II. But clinically, there was significant difference between group I and group III, and also between group II and group III. Although in the outcome of radiological assessment there was no significant difference between group I and group II compared with group III. The rate of avascular nerosis in group I was lower than in group II or in group III. Children with DDH between 1.5 and 6 years of age were treated successfully with one-stage treatment, but in our hands the best age at surgery is before 4 years of age. PMID- 26435231 TI - Shaft-Condylar Angle for surgical correction in neglected and displaced lateral humeral condyle fracture in children. AB - PURPOSE: To assess the outcome after using the Shaft-Condylar angle (SCA) as intraoperative reference for sagittal plane correction in displaced lateral humeral condyle fractures in children presented 3-weeks after injury. METHODS: Ten children, with delayed presentation of a displaced lateral humeral condyle fracture and undergoing surgery during 1999-2011, were reviewed. The goal was to obtain a smooth articular surface with an intraoperative SCA of nearly 40 degrees and nearest-anatomical carrying angle. They were allocated into two groups according to the postoperative SCA [Good-reduction group (SCA=30-50 degrees ), and Bad-reduction group (SCA<30 degrees , >50 degrees )] and the final outcomes were then compared. RESULTS: All fractures united without avascular necrosis. The Good-reduction group (n=7) showed a significant improvement in final range of motion and functional outcome compared to the Bad-reduction group (n=3) (p=0.02). However, there was no significant difference in pain, carrying angle and overall outcome between both groups. CONCLUSION: SCA is a possible intraoperative reference for sagittal alignment correction in late presented displaced lateral humeral condyle fractures. PMID- 26435232 TI - Distal Femoral Cortical Irregularity in children. AB - Cortical abnormalities at the distal postero-medial femoral metaphysis may be relatively common. We reviewed the plain radiographs of 197 knees in 130 children aged between 5 and 12 years to investigate the incidence of distal femoral cortical irregularities (DFCI) and their association with symptoms. An adductor magnus lesion was found in 15% of cases, with an even number of irregular and cystic lesions. A medial gastrocnemius lesion was found in 5% of cases, but no association was found between symptoms and the lesion. Overall, lesions were found in 25% of cases aged 5 to 9 years, but in only 13% of cases aged 12 and 13 years. Boys showed a higher incidence of both adductor magnus and medial gastrocnemius lesions. DFCI is a benign, self-limited entity and a relatively common radiologic finding. Regardless of whether or not symptoms are present, imaging findings should be carefully interpreted to avoid unnecessary diagnostic and invasive therapeutic procedures. PMID- 26435233 TI - Isokinetic performance of hip muscles after revision total hip arthroplasty via previous anterolateral approach. AB - We investigated the isokinetic performance of hip muscles and clinical outcomes after revision total hip arthroplasty (THA) via same anterolateral approach used in primary surgery. Thirty patients who had undergone previous THA via an anterolateral approach underwent both acetabular and femoral component revision after aseptic loosening. The Harris Hip Score (HHS) was evaluated during a minimum 2-year follow-up. The isokinetic muscle strength of the operated and nonoperated hips was assessed 1 year after surgery. The HHS improved from 49.0 to 77.4. Operated and nonoperated hips exhibited similar isokinetic performance during all measurements (flexion, extension, and abduction) (p>0.05). This prospective study showed that the anterolateral approach preserves abductor strength after revision THA in aseptic cases with acceptable functional and clinical results. The main clinical relevance of this study is that the same anterolateral approach used in previous primary THA is also safe and viable for revision THA. PMID- 26435234 TI - Stage-related results in treatment of hip osteonecrosis with core-decompression and autologous mesenchymal stem cells. AB - Our aim is to analyse the clinical outcome of a series of patients affected by avascular necrosis of the femoral head and treated with core-decompression technique and autologous stromal cells of the bone marrow.We enrolled in our study 29 patients with 31 hips in total affected by avascular necrosis of the femoral head. The clinical and radiological outcome has been assessed through self-administered questionnaires (HHS, VAS and SF12) X-ray and Magnetic Resonance.Of all the examined hips, 25 showed a relief of the symptoms and a resolution of the osteonecrosis, 11 of these were at Stage I and 14 at Stage II. The progression of the disease occurred in 6 hips (2 Stage II, 2 Stage III and 2 Stage IV). Our results show a significant decrease in joint pain level and a success in avoiding or delaying the need of hip replacement in early stages of osteonecrosis. PMID- 26435235 TI - Results of Conserve Plus Hip Resurfacing: prospective clinical, radiographic and ion study. AB - We report the 3- to 5-year clinical, radiographic and serum ion level results of a prospective consecutive cohort of 42 hip resurfacing arthroplasties using the Conserve Plus implant in 39 male patients that were operated on by a single surgeon in a community hospital. Average age was 53 years (range 34-67) at surgery. There was one revision for a subcapital neck fracture. There were no surgery related complications. The survival of the implant was 95%. Clinical evaluation showed excellent results with a modified Charnley score of 17.6/18, Harris Hip Score of 96.2/100, WOMAC of 95.1/100, Oxford Score 15.3, and UCLA Activity Score of 8/10. Radiographic analysis showed no implant at risk, no migration or signs of loosening, no neck narrowing and no osteolysis at final follow-up. Average cup inclination angle was 43.5 degrees with 2 outliers (34 degrees and 57 degrees ). Ion level study showed average cobalt in serum 1.04 ug/l (range 0-4) for the whole group, 0.7 ug/l (range 0-3) in patients with unilateral resurfacing and 2.0 ug/l (range 0-4) in patients with bilateral resurfacing. All patients had ion levels within the safe zone. This independent series of Conserve Plus HRA confirms good results at short- to mid-term with excellent wear characteristics. Results for avascular necrosis were equal to those for osteoarthritis. PMID- 26435236 TI - Evaluation of results of conservative therapy in patients with transient osteoporosis of hip. AB - The present study aimed to review the general characteristics of 18 cases diagnosed with transient osteoporosis of the hip (TOH) in our hospital within a 3 year period and to present their follow-up results after conservative treatment. A retrospective evaluation was made of the treatment and results of follow-up of TOH cases using physical examination and laboratory findings, hip radiographs and magnetic resonance imaging (MRI) and Harris Hip Scores (HHS). The mean duration of complaints of 6 females (mean age, 34.3+/-4.3 years) and 12 males (mean age, 40.7+/-10.5 years) was 6.1+/-2.7 weeks before the treatment. Three female patients had a history of giving birth by cesarean delivery. None of the patients had any history of trauma. MRI revealed increased intensity in T2 sequences and decreased intensity in T1 sequences in the proximal aspect of the femur. None of the patients had subchondral collapse or intra-articular effusion. For 3 female patients who were breastfeeding, no medical therapy was given, but only hyperbaric oxygen (HBO) therapy and forearm crutches. As standard management, the other patients were prevented from weight-bearing with the use of forearm crutches and medical therapy of diclofenac sodium, acetylsalicylic acid, and risedronate sodium was administered and additional HBO therapy. Clinical and radiological improvements were observed in all patients. None of the patients had avascular necrosis (AVN) of the femoral head. There was no record of therapy related complications. While HHS was 55.6+/-7.8 before the treatment, it increased to 88.8+/-5.8 in the 3rd month and to 96.0+/-1.8 in the 6th month after the treatment. This change in score over time was found to be significant. PMID- 26435237 TI - Short-term results of surgical treatment with cephalomedullary nails for basicervical proximal femoral fractures. AB - The treatment of basicervical femoral fractures remains controversial. The aim of this study was to examine the efficacy of intramedullary nail use in the surgical treatment of basicervical fractures. In total, 28 patients with basicervical fractures treated with proximal femoral nails were examined retrospectively. Fracture healing was observed in all patients, who were followed at least for 6 months. While the average radiological fracture healing timing was ~10.5 (8-14) weeks, clinical fracture healing occurred in 6 (5-9) weeks on average. Screw cut out, avascular necrosis, femur fracture, and surgical wound infections did not occur in any patient. Severe collapse (>10%) was not noted in any patient. The postoperative mean Harris hip score was 81.2+/-21.3. Osteosynthesis application with a proximal femoral nail in basicervical proximal femur fractures is a surgical treatment that can be performed with minimally invasive techniques without open surgery. This is a rapid, sound, and simple treatment method with low morbidity. PMID- 26435238 TI - Test-retest reliability of the 50-foot timed walk and 30-second chair stand test in patients with total hip arthroplasty. AB - The purpose was to investigate the test-retest reliability of the 50-Foot Timed Walk (50FWT), and 30-Second Chair Stand Test (30CST) in the patients with total hip arthroplasty (THA). The study was a test-retest study. Thirty-seven patients with THA performed two trials for both the 30CTS and 50FWT on the same day with one hour interval. To assess reliability, the intra-class correlation coefficient [ICC(2,1)], standard error of measurement (SEM), the smallest real difference at the 95% confidence level (SRD95) were calculated. The ICCs for the 50FWT and 30CTS were 0.98 and 0.94, respectively. The SEM and SRD95 for the 50FWT and 30CTS were 0.3 and 0.8 seconds and 0.4 and 1.2 repeats, respectively. The test-retest reliability of the tests was very high. The 50FWT and 30CST are very reliable to measure the functional performance in patients with THA in the clinical settings. PMID- 26435239 TI - Surgical technique for treatment of concomitant grade II MCL lesion in patients with ACL rupture. AB - Combined lesions of anterior cruciate ligament (ACL) and medial collateral ligament (MCL) are frequent in athletes. While surgical treatment of ACL injury is mandatory treatment regime of concomitant grade II MCL lesions remains unclear with tendency to surgical intervention. Standardized surgical technique is lacking. Present study wants to introduce surgical technique for treatment of concomitant grade II MCL lesion and report short term outcome results. 5 Patients with acute ACL rupture and grade II MCL-lesion were included. All patients received surgical treatment of concomitant MCL lesion by distinct surgical technique and ACL reconstruction. We evaluated valgus instability, anterior instability and range of motion (ROM) according to international knee documentation commitee (IKDC) and Lysholm-Score both preoperative and after 6, 16 weeks and 9 months postoperative. All Patients showed excellent clinical results at final follow-up. Valgus and anterior stability could be restored in all patients. 1 patient (20%) lost 15 degrees in flexion of ROM at final follow up. However in all 5 patients (100%) the findings were graded as normal or nearly nor mal according to IKDC knee examination form. Lysholm-Score averaged 94,6. Therefore presented surgical technique improved both, valgus and anterior stability, and led to excellent short term results at final follow up. PMID- 26435240 TI - Early follow-up after primary total knee and total hip arthroplasty with rapid recovery : Focus groups. AB - Rapid recovery protocols reduce the length of hospital stay after Total Knee Arthroplasty (TKA) and Total Hip Arthroplasty (THA). However, little is known about the early postoperative phase. The purpose of this study was to examine which problems patients encountered during the first six weeks after primary TKA or THA surgery with rapid recovery. We invited twenty patients for a focus group meeting which discussed various subjects regarding the first six weeks after hospital discharge. The focus group meetings were analysed qualitatively. Patients were mostly satisfied by the short length of hospital stay. Patients who lived alone needs more care and would like to stay longer in the hospital. After THA surgery all patients complained of inability to sleep. More patients experienced pain after TKA surgery compared to THA surgery. All patients had various experiences regarding physical therapy therefore an evidence based rehabilitation protocol might be needed. PMID- 26435241 TI - Comparative study of innovative postoperative wound dressings after total knee arthroplasty. AB - PURPOSE: Postoperative wound complications, especially surgical site infections, influence the outcome after total knee arthroplasty. The purpose of our study was to compare four different wound dressings. Following research questions were asked : (1) Which dressing is associated with least wound complications? (2) Which dressing application is the cheapest? (3) Which dressing is most comfortable for the patient? METHODS: 111 patients undergoing a total knee arthroplasty were randomized in 4 groups. Each group received a different dressing with its specific wound management protocol : (1) Zetuvit(r) with Cosmopor E(r), (2) Zetuvit(r) with Opsite Post-Op Visible(r), (3) Aquacel Surgical(r) and (4) Mepilex Border(r). Follow-up evaluations were performed on the fifth postoperative day and included assessment of the wound, status of the wound dressing and the patient's own judgment. Cumulative costs were calculated. RESULTS: Clinically Mepilex Border(r), a silicone dressing, scored the best. No wound complications were seen in this group. The mean number of dressing renewals was 1.9 for the standard dressing which was significantly higher (p<.0001) compared to the other dressings. Opsite Post-op Visible(r) was the cheapest dressing. Mepilex Border(r) had the best scores for pain, freedom of movement and general comfort. CONCLUSIONS: Mepilex Border(r) is the most skin-friendly dressing. The number of dressing renewals is a defining factor to calculate the costs. Mepilex Border(r) appeared to be the best dressing to use after a total knee arthroplasty. PMID- 26435242 TI - The indirect cost of Patient-Specific Instruments. AB - PURPOSE: To calculate the indirect costs of Patient Specific Instruments (PSI) based on an opportunity cost, cost of efforts and a supply chain cost model to compare PSI for value with conventional total knee arthroplasty (TKA). METHODS: In 81 patients the total (direct+indirect) cost of PSI-assisted TKA was compared with conventional TKA. Surgical times and coronal mechanical alignment were measured to evaluate the effectiveness of the PSI system. RESULTS: Indirect costs (459 euro) make up 40% of the total cost that can run up to 1142 euro for a patient operated with PSI guides. No difference in surgical times or coronal alignment was observed in between both groups. CONCLUSION: Considering the total cost of PSI no value was found for the use of PSI in primary TKA as measured by surgical times or for obtaining a neutral mechanical axis in the coronal plane. PMID- 26435243 TI - Current opinions about coronal plane alignment in total knee arthroplasty: A survey article. AB - PURPOSE: To survey an audience of international knee surgeons about their current opinions on the analysis of coronal knee alignment and their objectives for postoperative alignment in total knee arthroplasty. METHODS: Survey of 300 surgeons from 32 different countries with an audience response system allowing three possible answers being either a positive or negative answer or an abstention. RESULTS: Surveyed surgeons perform rarely preoperative and postoperative full leg radiographs and evaluate radiological outcomes more with short films. The main trend in this survey was towards neutral mechanical alignment, however varus alignment is acceptable in constitutional varus patients. This residual varus should be obtained through a femoral varus cut rather than a tibial varus cut. The valgus knee can remain in slight valgus but most of the correction will be performed at the femoral level. The main objective of postoperative alignment in TKA is a joint line parallel to the floor and a central load-bearing axis through the middle of the arthroplasty. Surgeons prefer unicompartmental arthroplasty more for themselves than for their patients in case of medial bone on bone arthritis. CONCLUSIONS: Neutral mechanical axis with a joint line parallel to the floor and a centrally running load bearing axis remains the central scope of the surveyed surgeons. Because of the literature on residual varus it becomes more acceptable for the orthopaedic community to accept this type of outlier before aiming at a surgical correction. PMID- 26435244 TI - Is systematic long-term sonographic follow-up after arthroscopic rotator cuff repair useful in asymptomatic patients? AB - OBJECTIVE: To establish whether ultrasonographic (US) appearance is correlated to functional outcome in asymptomatic patients 12 months after rotator cuff repair. MATERIAL AND METHODS: 26 asymptomatic patients at twelve months after arthroscopic cuff repair and 26 controls were retrospectively included. A clinical score (Constant's Shoulder Score, CSS) was compared with a US score (the modified Sugaya Score, mSS). The minimal thickness of the anterior and posterior parts of the cuff was also measured. RESULTS: CSS improved significantly from preoperatively to postoperatively (mean increased from 41 to 82.6, p<.001). Correlation between the postoperative CSS and the minimal thickness of the cuff at its anterior and posterior part (p=0.55 and p=0.13) was not significant. There was also no significant correlation between the postoperative CSS and mSS (p=0.34). CONCLUSION: The sonographic appearance of the cuff repair is not correlated to the functional outcome at 12 months after arthroscopic surgery in asymptomatic patients. PMID- 26435245 TI - Passive mobilization after arthroscopic rotator cuff repair is not detrimental in the early postoperative period. AB - This prospective randomized study compares the clinical results of immediate passive mobilization versus delayed mobilization in the rehabilitation of rotator cuff repair during the early postoperative period. The mobilization group (79 patients) received immediate daily passive mobilization. The immobilization group (51 patients) was immobilized for 4 weeks until physiotherapy was started. Passive range of motion was noted preoperatively, at 6 weeks and 4 months. Strength was measured preoperatively and at 4 months. Constant-Murley, Simple Shoulder Test, SPADI and UCLA scores were noted at baseline and at 4 months. Ultrasonography was performed at 6 weeks to exclude early failures of repair. We noted no significant difference between the two groups regarding range of motion at 6 weeks and range of motion, strength and functional outcome scores at 4 months. Ultrasound didn't show a difference in healing at 6 w in either of both groups. Both rehabilitation protocols seem applicable as well as safe in the early post-operative phase. PMID- 26435246 TI - Fracture-dislocation of the humeral condyles in adults: results of surgical treatment. AB - Fracture-dislocation of the humeral condyle is exceptional in adults. The purpose was to analyze the results of surgical treatment by open reduction and internal fixation without ligamentous repair. There were six men with an average age of 31 years. According to the AO classification, five fractures were classified as AO type B1 and one as B2. Dislocation was reduced in emergency before osteosynthesis. Postoperatively, the joint was held immobile with a brace for 25.40 days. Five patients were reviewed after a mean follow-up of 52.96 months. The median arc of flexion/extension was 104.80 degrees and 157.8 degrees for pronation-supination. All elbows were stable and all fractures were consolidated. Two elbows were painful. The results were satisfactory in five patients. The elbow stability can be ensured only by the synthesis of bone structures. Surgical treatment should restore exact anatomy between the condyle and trochlea. This protocol may provide a joint stability and satisfactory results. PMID- 26435247 TI - Operative management of humeral nonunions. Factors that influence the outcome. AB - The purpose of this study is to present the outcome of surgically treated humeral nonunions and find factors that affect the outcome. Forty-two patients with humeral nonunions (30 shaft, 7 proximal and 5 distal) were reviewed in a prospective manner. Treatment was based on a specific algorithm. Demographics, time to union, range of motion, functional outcome and complications were recorded and analysed. RESULTS: Mean follow-up was 78 months and mean time to union was 4.3 months. Infection was associated with delayed union of the pseudarthrosis, while range of motion was negatively affected by the location (proximal) and the AO type of the initial fracture. Complication rate was 17%. CONCLUSION: The surgical management of humeral nonunions yields a favourable outcome with reduced rate of complications. Infection prolonged healing time, while proximal location of the nonunion and the type B or C fracture according to AO/OTA classification adversely affected range of motion. PMID- 26435248 TI - Correlation between dorsovolar translation and rotation of the radius on the distal radioulnar joint during supination and pronation of forearm. AB - This study aimed to describe the patterns of movements about radius and ulna in individual degrees of forearm rotation. And, we also determined the effect of forearm rotation on translation and rotation of the radius with reference to the ulna, and to measure the relationship between forearm rotation, translation and rotation of the radius. Computed tomography of multiple, individual forearm positions, from 90 degrees pronation to 90 degrees supination, was conducted in 26 healthy volunteers (mean age, 43.9 years) to measure dorsovolar translation and rotation of the radius in the DRUJ in each forearm position. The mean dorsovolar translations were within 1.99 mm at 90 degrees pronation to -2.03 mm at 90 degrees supination. The rotations of the radius were 71.20 degrees at 90 degrees pronation and -46.63 degrees at 90 degrees supination. There were strong correlations between degrees of forearm rotation and dorsovolar translation (r=0.861, p<0.001) and rotation of the radius (r=0.960, p<0.001), suggesting that the DRUJ, carpal joints, and rotatory laxity of the carpal ligament, especially in supination, contribute to forearm supination and pronation. These findings provide an understanding of wrist kinematics, are may be useful in reconstructive wrist surgery to achieve normal range of motion, and are may be helpful for the design of DRUJ reconstruction using prostheses. PMID- 26435249 TI - Management of infectious fractures with "Non-Contact Plate" (NCP) method. AB - The aim of this study was to evaluate the outcomes of internal fixation with Non Contact Plating (NCP) after deep infection caused by previous surgeries of the tibia or femur fractures. The study included 15 patients (4 female and 11 male). The mean age patients was 36.6 years (range, 21-64 years). There were 6 femur and 9 tibia fractures. The mean follow-up period was 25.7 months (range, 15-45 months). The study comprised 11 open and 4 closed fractures. External fixator was used in 3, plate in 4, and intramedullary nail in 8 patients for index surgery. Deep infection was diagnosed via clinical findings, laboratory parameters, and microbiological evaulation. Deep infection was diagnosed within a mean period of 5.5 weeks (range, 2-10 weeks). The infecting organism was methicillin-resistant staphylococcus aureus (MRSA) in 5, methicillin-sensitive staphylococcus aureus (MSSA) in 6, pseudomonas auroginosa in 2, and enterobacteriacea in 2 patients. Union achieved in all patients. Mean time to union was 17 (range, 11-38) weeks. Delayed union was observed in 3 patients who required additional surgeries. Of these one patient developed osteomyelitis. The NCP is an effective alternative method in the treatment of deep infection encountered after internal or external fixation for the tibia, or femur fractures. PMID- 26435250 TI - Oncological approach with antihelminthic chemotherapy and wide resection in the treatment of musculoskeletal hydatidosis. A review of 10 cases with mean follow up of 64 months. AB - The objective of this retrospective study was to evaluate clinical outcomes, local recurrence and complication rates of antihelminthic chemotherapy and wide resection in patients with muscle or bone hydatidosis. The authors treated 10 patients (6 females, 4 males) between 2004 and 2012: 8 with muscle and 2 with bone hydatidosis. The mean age at surgery was 42.5 years (range, 11-66 years). All patients were treated with wide resection and pre- and postoperative chemotherapy with albendazole. The mean follow-up was 64 months (range, 28-120 months). All patients achieved satisfactory clinical outcomes. There were no local recurrences. Surgical complications were seen in 3 patients (30%) : one superficial infection, one deep infection, and one hematoma. Two (20%) required additional surgery. An aggressive oncological approach, consisting of antihelminthic chemotherapy and wide resection, can provide favorable clinical outcomes and prevent local recurrence in patients with musculoskeletal hydatidosis. Potential complications of aggressive surgery should be preferred to potential morbidity of local and systemic dissemination. PMID- 26435251 TI - Analysis of sagittal balance using spinopelvic parameters in ankylosing spondylitis patients treated with vertebral column decancellation surgery. AB - This study was designed to explore the change of spinopelvic parameters after vertebral column decancellation (VCD) for the management of thoracolumbar kyphosis secondary to ankylosing spondylitis (AS). Forty-two AS patients including thirty-six males and six females with thoracolumbar kyphosis, who underwent VCD from April 2005 to June 2012 in our hospital, were retrospectively reviewed. A series of spinopelvic parameters including thoracic kyphosis (TK), lumbar lordosis (LL), sacral slope (SS), pelvic incidence (PI), pelvic tilt (PT) and sagittal vertical axis (SVA) measured on preoperative and postoperative free standing radiographs were obtained and analyzed. Also clinical assessments were performed with the Oswestry disability index (ODI) and the Bath Ankylosing Spondylitis Activity and Function Index (BASDAI and BASFI) so as to seek correlations between radiological parameters and symptoms. Except for pelvic incidence (PI), significant difference was found in all radiological spinopelvic parameters between the preoperative and follow-up values. Furthermore, there was significant improvement in the clinical assessment parameters ODI, BASDAI and BASFI, which all correlated significantly with the postoperative pelvic tilt (PT). The results of this study show that posterior VCD is an effective option to manage sagittal imbalance in AS. In the current series, patients improving LL and PT were found to achieve good clinical outcomes. Overall, our findings show that it is important to quantify sagittal spinopelvic parameters and promote sagittal balance in the surgery for AS. PMID- 26435252 TI - Long-term follow-up of the anterior lumbar interbody fusion procedure. AB - PURPOSE: To evaluate the long-term clinical results and the effectiveness of the anterior lumbar interbody fusion procedure. METHODS: Between 1999 and 2005, 60 ALIFs were performed in 59 patients. Mean age was 41.1 years. Clinically, patients were evaluated at a mean follow-up of 9.5 years using the Visual Analogue Scale grading scale, the Oswestry Disability score and the SF-36 questionnaire. RESULTS: Preoperative and postoperative clinical evaluation scores of 38 patients were available. Nineteen patients were lost to follow-up, and 2 patients died during the follow-up. The fusion rate was 84%. Mean preoperative VAS-score for back pain was 6.69 (+/-2.15) ; in the long term, the mean VAS-score was 4.95 (+/-2.95), which was a significant improvement. (p<0.01). The postoperative ODI-score was 36.11 (+/-22.32), while the preoperative ODI-score was 59.31 (+/-17.16), which demonstrates a significant improvement. According to the SF-36, mild to good results were observed. CONCLUSIONS: The ALIF procedure can offer significant pain relief and improved function if a strict indication policy is followed. PMID- 26435253 TI - Neglected Achilles Tendon Rupture Treated with Flexor Hallucis Longus transfer with two turndown gastrocnemius fascia flap and reinforced with plantaris tendon. AB - Neglected Achilles Tendon Ruptures are commonly seen by orthopaedic surgeons. In cases resistant to conservative treatment, a variety of surgical procedures have been utilized in the past. The senior -surgeon at our institution has utilized a technique -employing two turndown fascia flaps fashioned from the proximal Achilles tendon augmented by a tenomyodesis of the flexor hallucis longus and plantaris tendon. The purpose of this study was to assess the clinical outcome of all patients who underwent this procedure. The medical records of 10 cases that underwent this procedure were retrospectively reviewed. We completed data collection sets using the American Orthopaedic Foot and Ankle Society ankle-hind foot scores, isokinetic evaluation, and postoperative magnetic resonance imaging (MRI) at 1 year of follow-up. The mean American Orthopaedic Foot and Ankle Society ankle-hind foot scores improved from 64.4+/-3.54. Isokinetic testing at 30o/sec and 120o/sec revealed an mean deficits of 24.5%, respectively, in the plantar flexion peak torque of the involved ankle than non-involved ankle. The flexor hallucis longus tendon, gastrocnemius fascia flap and plantaris were well integrated into the Achilles tendon forming a homogenous tendon, which was confirmed in MRI. Our subjective and objective data indicate that the reconstructive technique using flexor hallucis longus transfer with two turndown gastrocnemius fascia flaps and plantaris tendon is a good option for repairing large gap defect of Achilles tendon. PMID- 26435254 TI - Habitual suppression relates to difficulty in regulating emotion with cognitive reappraisal. AB - One common strategy to cope with the difficulties of daily life is suppression. Habitual users of suppression tend to suppress their feelings rather than expressing them. Although this strategy may reduce outward response to emotion, it is not thought to lessen induced negative affect. Moreover, it remains unclear whether people with high suppression scores can reduce negative affect through cognitive reappraisal. In the present study, twenty-nine healthy participants differing in suppression scores were directed to reappraise aversive stimuli during functional magnetic resonance imaging (fMRI). Results showed that higher suppression scores correlated with decreased response of dorsomedial prefrontal cortex (dmPFC) during cognitive reappraisal. Further, high suppression scores related to enhanced negative affect to stimuli with greater negative affect correlating with decreased dmPFC response during cognitive reappraisal. This study suggests that people with high suppression scores experience difficulty in reducing negative affect through cognitive reappraisal and implicates neurobiological processes that may underlie this difficulty. PMID- 26435255 TI - The "Cryptic" Escherichia. AB - In 2009, five monophyletic Escherichia clades were described and referred to as "cryptic" based on the inability to distinguish them from representative E. coli isolates using diagnostic biochemical reactions. Since this original publication, a number of studies have explored the genomic, transcriptomic, and phenotypic diversity of cryptic clade isolates to better understand their phylogenetic, physiological, and ecological distinctiveness with respect to previously named Escherichia species. This chapter reviews the original discovery of the cryptic clades, discusses available evidence that some are environmentally adapted, and evaluates current support for taxonomic designations of these microorganisms. The importance of these clades to clinical research, epidemiology, population genetics, and microbial speciation is also discussed. PMID- 26435256 TI - DNA Topoisomerases. AB - DNA topoisomerases are enzymes that control the topology of DNA in all cells. There are two types, I and II, classified according to whether they make transient single- or double-stranded breaks in DNA. Their reactions generally involve the passage of a single- or double-strand segment of DNA through this transient break, stabilized by DNA-protein covalent bonds. All topoisomerases can relax DNA, but DNA gyrase, present in all bacteria, can also introduce supercoils into DNA. Because of their essentiality in all cells and the fact that their reactions proceed via DNA breaks, topoisomerases have become important drug targets; the bacterial enzymes are key targets for antibacterial agents. This article discusses the structure and mechanism of topoisomerases and their roles in the bacterial cell. Targeting of the bacterial topoisomerases by inhibitors, including antibiotics in clinical use, is also discussed. PMID- 26435257 TI - Biosynthesis and Insertion of the Molybdenum Cofactor. AB - The transition element molybdenum (Mo) is of primordial importance for biological systems, because it is required by enzymes catalyzing key reactions in the global carbon, sulfur, and nitrogen metabolism. To gain biological activity, Mo has to be complexed by a special cofactor. With the exception of bacterial nitrogenase, all Mo-dependent enzymes contain a unique pyranopterin-based cofactor coordinating a Mo atom at their catalytic site. Various types of reactions are catalyzed by Mo-enzymes in prokaryotes including oxygen atom transfer, sulfur or proton transfer, hydroxylation, or even nonredox reactions. Mo-enzymes are widespread in prokaryotes and many of them were likely present in the Last Universal Common Ancestor. To date, more than 50--mostly bacterial--Mo-enzymes are described in nature. In a few eubacteria and in many archaea, Mo is replaced by tungsten bound to the same unique pyranopterin. How Mo-cofactor is synthesized in bacteria is reviewed as well as the way until its insertion into apo-Mo enzymes. PMID- 26435259 TI - Acute effects of active gaming on ad libitum energy intake and appetite sensations of 8-11-year-old boys. AB - The present study examined the acute effects of active gaming on energy intake (EI) and appetite responses in 8-11-year-old boys in a school-based setting. Using a randomised cross-over design, twenty-one boys completed four individual 90-min gaming bouts, each separated by 1 week. The gaming bouts were (1) seated gaming, no food or drink; (2) active gaming, no food or drink; (3) seated gaming with food and drink offered ad libitum; and (4) active gaming with food and drink offered ad libitum. In the two gaming bouts during which foods and drinks were offered, EI was measured. Appetite sensations - hunger, prospective food consumption and fullness - were recorded using visual analogue scales during all gaming bouts at 30-min intervals and at two 15-min intervals post gaming. In the two bouts with food and drink, no significant differences were found in acute EI (MJ) (P=0.238). Significant differences were detected in appetite sensations for hunger, prospective food consumption and fullness between the four gaming bouts at various time points. The relative EI calculated for the two gaming bouts with food and drink (active gaming 1.42 (sem 0.28) MJ; seated gaming 2.12 (sem 0.25) MJ) was not statistically different. Acute EI in response to active gaming was no different from seated gaming, and appetite sensations were influenced by whether food was made available during the 90-min gaming bouts. PMID- 26435258 TI - Correlation of plasma nitrite/nitrate levels and inducible nitric oxide gene expression among women with cervical abnormalities and cancer. AB - Cervical cancer is caused by infection with high risk human papillomavirus (HR HPV). Inducible nitric oxide synthase (iNOS), a soluble factor involved in chronic inflammation, may modulate cervical cancer risk among HPV infected women. The aim of the study was to measure and correlate plasma nitrite/nitrate levels with tissue specific expression of iNOS mRNA among women with different grades of cervical lesions and cervical cancer. Tissue biopsy and plasma specimens were collected from 120 women with cervical neoplasia or cancer (ASCUS, LSIL, HSIL and invasive cancer) and 35 women without cervical abnormalities. Inducible nitric oxide synthase (iNOS) mRNA from biopsy and plasma nitrite/nitrate levels of the same study subjects were measured. Single nucleotide polymorphism (SNP) analysis was performed on the promoter region and Ser608Leu (rs2297518) in exon 16 of the iNOS gene. Differences in iNOS gene expression and plasma nitrite/nitrate levels were compared across disease stage using linear and logistic regression analysis. Compared to normal controls, women diagnosed with HSIL or invasive cancer had a significantly higher concentration of plasma nitrite/nitrate and a higher median fold-change in iNOS mRNA gene expression. Genotyping of the promoter region showed three different variations: A pentanucleotide repeat (CCTTT) n, -1026T > G (rs2779249) and a novel variant -1153T > A. These variants were associated with increased levels of plasma nitrite/nitrate across all disease stages. The higher expression of iNOS mRNA and plasma nitrite/nitrate among women with pre-cancerous lesions suggests a role for nitric oxide in the natural history of cervical cancer. PMID- 26435260 TI - Expression and regulation of tissue inhibitors of metalloproteinases (TIMP1 and TIMP3) in goat oviduct. AB - Tissue inhibitors of metalloproteinases (TIMPs) are associated with several reproductive processes, such as mammalian follicular growth, ovulation, CL formation, and embryonic development. However, the expression and function of TIMPs in goat oviducts remain unclear. This work aimed to identify TIMP1 and TIMP3 expression in the goat oviduct during the estrous cycle via immunohistochemistry, real-time polymerase chain reaction (PCR), and functional studies in cultured goat oviductal epithelial cells. Real-time PCR results demonstrated that TIMP1 and TIMP3 messenger RNAs were expressed in all goat oviductal regions at all stages of the estrous cycle. TIMP1 and TIMP3 proteins were also highly expressed in oviductal epithelial cells with very limited expression in other cell types. Oviductal epithelial cells were treated in vitro with various estradiol concentrations (1-100 nM) for 24 hours. The findings showed that TIMP1 expression increased up to 20 nM but then gradually decreased, whereas no significant effects existed among TIMP3 messenger RNA levels. Time course studies indicated that estradiol significantly increased TIMP1 expression in a time-dependent manner from 8 hours to 24 hours. By contrast, TIMP3 expression was transiently induced in oviductal epithelial cells at 2 and 4 hours after estradiol treatment. Furthermore, treatment with TIMP1 functionally increased the viability of cultured oviductal epithelial cells. Overall, the results suggested that the differential regulation and function between TIMP1 and TIMP3 might be associated with their unique roles in fertilization and early embryonic development. PMID- 26435261 TI - Mechanism for greater frequency of contralateral than ipsilateral relationships between corpus luteum and ovulatory follicle for wave 3 in heifers. AB - During the last wave of the interovulatory interval (IOI), the permutations of the relationship between the ovulatory follicle and the CL (ipsilateral vs. contralateral) and the number of follicular waves (two vs. three) per IOI differ in frequency of occurrence as follows: ipsilateral relationship and two waves (34%), contralateral relationship and two waves (34%), ipsilateral relationship and three waves (8%), and contralateral relationship and three waves (24%). Deviation or the continuation in growth rate of the future ovulatory follicle and a decrease in growth rate of the future subordinate follicles begin well before luteolysis in two-wave IOIs and during luteolysis in three-wave IOIs. The largest follicle decreases in diameter and loses its dominant status before completion of deviation when it is ipsilateral and adjacent to the regressing CL during wave 3. Dominant status switches from the largest follicle in the ipsilateral ovary to the next-largest follicle which may be in either ovary. Switching accounts for the greater frequency of a contralateral follicle-CL relationship than for ipsilateral follicle-CL relationship during the ovulatory wave in three-wave IOIs. It is proposed that the phenomenon results from commonality in angioarchitecture so that the decrease in blood flow to the regressing CL is associated with a decrease in blood flow to adjacent follicles. PMID- 26435262 TI - Contribution of semen trait selection, artificial insemination technique, and semen dose to the profitability of pig production systems: A simulation study. AB - The economic impact of selection for semen traits on pig production systems and potential interaction with artificial insemination (AI) technique and semen dose remains partially understood. The objectives of this study were to compare the financial indicators (gross return, net profit, cost) in a three-tier pig production system under one of two selection strategies: a traditional strategy including nine paternal and maternal traits (S9) and an advanced strategy that adds four semen traits (S13). Maternal traits included the number of pigs born alive, litter birth weight, adjusted 21-day litter weight, and the number of pigs at 21 days, and paternal traits included days to 113.5 kg, back fat, average daily gain, feed efficiency, and carcass lean percentage. The four semen traits included volume, concentration, progressive motility of spermatozoa, and abnormal spermatozoa. Simultaneously, the impact of two AI techniques and a range of fresh refrigerated semen doses including cervical AI with 3 * 10(9) (CAI3) and 2 * 10(9) (CAI2) sperm cells/dose, and intrauterine AI with 1.5 * 10(9) (IUI1.5), 0.75 * 10(9) (IUI0.75), and 0.5 * 10(9) (IUI0.5) sperm cells/dose were evaluated. These factors were also evaluated using a range of farrowing rates (60%-90%), litter sizes (8-14 live-born pigs), and a selected semen collection frequency. The financial impact of the factors was assessed through simulation of a three way crossbreeding system (maternal nucleus lines A and B and paternal nucleus line C) using ZPLAN. The highest return on investment (profit/cost) of boars was observed at 2.33 collections/wk (three periods of 24 hours between collections). Under this schedule, a significant (P < 0.0001) interaction between the selection strategy and the AI technique-dose combination was identified for the gross return; meanwhile, significant (P < 0.0001) additive effects of the selection strategy and AI technique-dose combination were observed for the net profit. The highest gross return was obtained under S13 with IUI0.75 and IUI0.5. The net profit of S13 was 34.37% higher than the traditional S9 (P < 0.0001). The net profit favored IUI0.5 with relative differences of 4.13%, 2.41%, 1.72%, and 0.43% compared to CAI3, CAI2, IUI1.5, and IUI0.75, respectively. The advanced selection strategy proposed including four semen traits is recommended on the basis of the higher profitability relative to the traditional strategy. PMID- 26435263 TI - Analysis of sacro-iliac joint screw fixation: does quality of reduction and screw orientation influence joint stability? A biomechanical study. AB - INTRODUCTION: Treatment of posterior pelvic ring injuries is frequently associated with pain or/and high mortality rates. Percutaneous sacro-iliac (SI) screw fixation has proved to be one of the methods of choice, providing minimal operative time, blood loss and wound-related morbidity. However, fixation failures due to secondary fracture dislocation or screw backing out have been reported. There is a little knowledge regarding the impact of varying screw orientation and quality of reduction on the fixation strength. PURPOSE: The purpose of the present study was biomechanical investigation of joint stability after SI screw fixation and its dependence on quality of reduction and screw orientation. METHODS: Thirty-two artificial hemi-pelvices were assigned to four study groups and simulated SI dislocations were fixed with two SI screws in oblique or transverse screw orientation and anatomical or non-anatomical reduction in group A (oblique/anatomical), B (transverse/anatomical), C (oblique/non-anatomical) and D (transverse/non-anatomical). Mechanical testing was performed under progressively increasing cyclic axial loading until fixation failure. SI joint movements were captured via optical motion tracking. Fixation performance was statistically evaluated at a level of significance p = 0.05. RESULTS: The highest cycles to failure were observed in group A (14038 +/- 1057), followed by B (13909 +/- 1217), D (6936 +/- 1654) and C (6706 +/- 1295). Groups A and B revealed significantly longer endurance than C and D (p <= 0.01). CONCLUSIONS: Different screw orientations in the presented model do not influence substantially SI joint stability. However, anatomical reduction is not only mandatory to restore a malalignment, but also to increase the SI screw fixation strength and prevent fixation failures. PMID- 26435265 TI - Dynamical heterogeneities and defects in two-dimensional soft colloidal crystals. AB - In this paper we study a two-dimensional system of charged colloidal particles using Brownian dynamics simulations. We determine the phase diagram and investigate the dynamics of this system in the density regime where hexatic and solid phases are stable. We find that the dynamics in these phases is heterogeneous by means of the spontaneous formation and diffusion of highly mobile defects. We identify two key mechanisms associated with the areas of high mobility. The first mechanism involves the highly cooperative motion of a closed loop of particles which shift coherently along the loop until each particle has replaced the position of its predecessor in the chain. The second mechanism involves the spontaneous creation of vacancy-interstitial pairs which diffuse within the hexatic and solid phases. We further explore quantitatively the properties of the open-ended and closed rearrangement strings and find that in the crystal phase the string-size distribution can be approximately matched with a simple, random walk description of vacancies and interstitials on a lattice. PMID- 26435264 TI - Complications and revisions after semi-constrained total elbow arthroplasty: a mono-centre analysis of one hundred cases. AB - BACKGROUND: The complication rate after total elbow arthroplasties is higher than for other arthroplasties. PURPOSE: The purpose of this study was to evaluate the complications and revision rate after 100 semi-constrained total elbow arthroplasties from various types of aetiologies performed in our university hospital. METHODS: One hundred linked semiconstrained total elbow arthroplasties were performed and were reviewed with 24-months minimum follow-up. Indications were rheumatoid arthritis (45), trauma (33), revisions (16) and others (6). RESULTS: At five years average follow-up (range, 2-11), the complication rate was 37 %. Most frequent complications were ulnar nerve involvement (9 %) and triceps insufficiency (7 %). Five implants were aseptically loosed. The infection rate was 4 % with loosening of the implant in two. Four fractures were observed, including three at the ulna and one at the humerus proximal or distal to the stem. The radial nerve was injured in two cases. Failure of the locking system of the prosthesis was noted in one case and a fracture of the ulnar component was found in another patient. A revision surgery was performed in 13 cases (13 %). At follow-up 94 prostheses were still in place and the survival rate was 98 % at five years and 86 % at ten years. CONCLUSION: Total elbow arthroplasty remains a difficult procedure with sometimes a high rate of complications necessitating revision procedures. Selection of the patients, a rigorous surgical technique, and a systematic follow-up are prerequisite to limit this incidence. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 26435266 TI - Excellent optical and interfacial performance of a PEDOT-b-PEG block copolymer counter electrode for polymer electrolyte-based solid-state dye-sensitized solar cells. AB - A poly(3,4-ethylenedioxythiophene)-b-poly(ethylene glycol) (PEDOT-b-PEG) block copolymer doped with perchlorate on FTO shows excellent optical and interfacial performance as a counter electrode (CE), such as low charge transfer resistance and low reflectivity for polymer electrolyte-based solid-state dye-sensitized solar cells (DSCs), resulting in 8.45% energy conversion efficiency, greater than the common Pt CE, via a facile room-temperature process. PMID- 26435267 TI - Ultrasonically treated liquid interfaces for progress in cleaning and separation processes. AB - Ultrasound and acoustic cavitation enable ergonomic and eco-friendly treatment of complex liquids with outstanding performance in cleaning, separation and recycling of resources. A key element of ultrasonic-based technology is the high speed of mixing by streams, flows and jets (or shock waves), which is accompanied by sonochemical reactions. Mass transfer across the phase boundary with a great variety of catalytic processes is substantially enhanced through acoustic emulsification. Encapsulation, separation and recovery of liquids are fast with high production yield if applied by ultrasound. Here we discuss the state of knowledge of these processes by ultrasound and acoustic cavitation from a perspective of a physico-chemical model in order to predict and control the outcome. We focus on the physical interpretation and quantification of ultrasonic parameters and properties of liquids to understand the chemistry of liquid/liquid interfaces in acoustic fields. The roles of thermodynamic enthalpy and entropy (incl. Laplace and osmotic pressure) in the context of sonochemical reactions (separation, catalysis, degradation, cross-linking, ion exchange and phase transfer) are outlined. The synergy of ultrasound and electric fields or continuous flow chemistry for cleaning and separation via emulsification is highlighted by specific strategies involving polymers and ultrasonic membranes. PMID- 26435269 TI - Model free audit methodology for bias evaluation of tumour progression in oncology. AB - Many oncology studies incorporate a blinded independent central review (BICR) to make an assessment of the integrity of the primary endpoint, progression free survival. Recently, it has been suggested that, in order to assess the potential for bias amongst investigators, a BICR amongst only a sample of patients could be performed; if evidence of bias is detected, according to a predefined threshold, the BICR is then assessed in all patients, otherwise, it is concluded that the sample was sufficient to rule out meaningful levels of bias. In this paper, we present an approach that adapts a method originally created for defining futility bounds in group sequential designs. The hazard ratio ratio, the ratio of the hazard ratio (HR) for the treatment effect estimated from the BICR to the corresponding HR for the investigator assessments, is used as the metric to define bias. The approach is simple to implement and ensures a high probability that a substantial true bias will be detected. In the absence of bias, there is a high probability of accepting the accuracy of local evaluations based on the sample, in which case an expensive BICR of all patients is avoided. The properties of the approach are demonstrated by retrospective application to a completed Phase III trial in colorectal cancer. The same approach could easily be adapted for other disease settings, and for test statistics other than the hazard ratio. PMID- 26435268 TI - Sleep Disturbance and Expressive Language Development in Preschool-Age Children With Down Syndrome. AB - Recent evidence has suggested that sleep may facilitate language learning. This study examined variation in language ability in 29 toddlers with Down syndrome (DS) in relation to levels of sleep disruption. Toddlers with DS and poor sleep (66%, n = 19) showed greater deficits on parent-reported and objective measures of language, including vocabulary and syntax. Correlations between sleep and language were found in groups with equivalent medical and social backgrounds and after control for relevant behavioral comorbidities, including autism symptoms. These results emphasize the important role of quality sleep in all children's expressive language development, and may help increase our understanding of the etiology of language deficits in developmental disorders, potentially leading to new treatment approaches. PMID- 26435270 TI - Transient and 2-Dimensional Shear-Wave Elastography Provide Comparable Assessment of Alcoholic Liver Fibrosis and Cirrhosis. AB - BACKGROUND & AIMS: Alcohol abuse causes half of all deaths from cirrhosis in the West, but few tools are available for noninvasive diagnosis of alcoholic liver disease. We evaluated 2 elastography techniques for diagnosis of alcoholic fibrosis and cirrhosis; liver biopsy with Ishak score and collagen-proportionate area were used as reference. METHODS: We performed a prospective study of 199 consecutive patients with ongoing or prior alcohol abuse, but without known liver disease. One group of patients had a high pretest probability of cirrhosis because they were identified at hospital liver clinics (in Southern Denmark). The second, lower-risk group, was recruited from municipal alcohol rehabilitation centers and the Danish national public health portal. All subjects underwent same day transient elastography (FibroScan), 2-dimensional shear wave elastography (Supersonic Aixplorer), and liver biopsy after an overnight fast. RESULTS: Transient elastography and 2-dimensional shear wave elastography identified subjects in each group with significant fibrosis (Ishak score >=3) and cirrhosis (Ishak score >=5) with high accuracy (area under the curve >=0.92). There was no difference in diagnostic accuracy between techniques. The cutoff values for optimal identification of significant fibrosis by transient elastography and 2 dimensional shear wave elastography were 9.6 kPa and 10.2 kPa, and for cirrhosis 19.7 kPa and 16.4 kPa. Negative predictive values were high for both groups, but the positive predictive value for cirrhosis was >66% in the high-risk group vs approximately 50% in the low-risk group. Evidence of alcohol-induced damage to cholangiocytes, but not ongoing alcohol abuse, affected liver stiffness. The collagen-proportionate area correlated with Ishak grades and accurately identified individuals with significant fibrosis and cirrhosis. CONCLUSIONS: In a prospective study of individuals at risk for liver fibrosis due to alcohol consumption, we found elastography to be an excellent tool for diagnosing liver fibrosis and for excluding (ruling out rather than ruling in) cirrhosis. PMID- 26435271 TI - Endoplasmic Reticulum Stress in Hepatic Stellate Cells Promotes Liver Fibrosis via PERK-Mediated Degradation of HNRNPA1 and Up-regulation of SMAD2. AB - BACKGROUND & AIMS: Endoplasmic reticulum (ER) stress has been implicated in a variety of diseases. Hepatic stellate cells (HSCs) contribute to the development of liver fibrosis. Information on the link between ER stress and HSC activation is scarce. We investigated the effects of ER stress in HSCs on the progression of liver fibrosis and the regulation of this process in cells and mice. METHODS: Proteins and messenger RNAs were measured in 2 sets of liver samples (n = 25 and n = 44) collected from patients with chronic hepatitis C virus infection and/or fibrosis. ER stress was induced in cells and mice using chemical agents. Lentiviral vectors were constructed to express glucose-regulated protein 78 (GRP78; also known as HSPA5) or heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) from the alpha-smooth muscle actin promoter and injected into C57BL/6 mice for HSC-specific gene expression. Liver tissues and HSCs were collected from mice or rats and analyzed using immunoblottings and quantitative reverse transcription polymerase chain reaction. LX-2 cells were transfected with small interfering RNAs, microRNA mimics, or overexpression vectors. RESULTS: Hepatic ER stress was much higher in liver tissues from patients with severe vs mild fibrosis. ER stress induced fibrogenic genes in HSCs. Targeted lentiviral delivery of glucose-regulated protein 78 to HSCs in mice reduced fiber accumulation in liver. Levels of SMAD2, but not SMAD3, were increased in fibrotic liver tissues from patients or mice exposed to ER stress; small interfering RNA mediated knockdown of SMAD2 reduced ER stress-mediated activation of HSCs. In rat HSCs, ER stress increased levels of SMAD2 messenger RNA by decreasing levels of microRNA 18a (MIR18A), an inhibitor of SMAD2 expression, rather than transactivating the SMAD2 gene. ER stress-activated PKR-like endoplasmic reticulum kinase, also known as EIF2AK3 (PERK) phosphorylated HNRNPA1, a protein required for the maturational processing of primary MIR18A, at Thr51, accelerating its degradation. Overexpression of HNRNPA1 (or its T51A mutant) in HSCs of mice inhibited liver fibrosis. Severe fibrotic liver tissues from patients had increased levels of phosphorylated PERK and reduced levels of HNRNPA1 in HSCs, compared with mild fibrotic liver tissues. CONCLUSIONS: ER stress in HSCs promotes liver fibrosis by inducing overexpression of SMAD2, via dysregulation of MIR18A; this dysregulation is mediated by PERK phosphorylation and destabilization of HNRNPA1. PMID- 26435272 TI - Continuous chemical operations and modifications on magnetic gamma-Fe2O3 nanoparticles confined in nanoliter droplets for the assembly of fluorescent and magnetic SiO2@gamma-Fe2O3. AB - We present a microfluidic platform that allows undergoing different chemical operations in a nanoliter droplet starting from the colloidal suspension of magnetic iron oxide (gamma-Fe2O3) nanoparticles "NPs" (ferrofluid). These operations include: mixing, flocculation, magnetic decantation, colloidal redispersion, washing, surface functionalization, heating and colloidal assembly. To prove the platform capabilities, we produced fluorescent and magnetic nanoassemblies composed of fluorescent silica and magnetic NPs. PMID- 26435273 TI - PDGFR-beta Plays a Key Role in the Ectopic Migration of Neuroblasts in Cerebral Stroke. AB - The neuroprotective agents and induction of endogenous neurogenesis remain to be the urgent issues to be established for the care of cerebral stroke. Platelet derived growth factor receptor beta (PDGFR-beta) is mainly expressed in neural stem/progenitor cells (NSPCs), neurons and vascular pericytes of the brain; however, the role in pathological neurogenesis remains elusive. To this end, we examined the role of PDGFR-beta in the migration and proliferation of NSPCs after stroke. A transient middle cerebral-arterial occlusion (MCAO) was introduced into the mice with conditional Pdgfrb-gene inactivation, including N-PRbeta-KO mice where the Pdgfrb-gene was mostly inactivated in the brain except that in vascular pericytes, and E-PRbeta-KO mice with tamoxifen-induced systemic Pdgfrb-gene inactivation. The migration of the DCX(+) neuroblasts from the subventricular zone toward the ischemic core was highly increased in N-PRbeta-KO, but not in E PRbeta-KO as compared to Pdgfrb-gene preserving control mice. We showed that CXCL12, a potent chemoattractant for CXCR4-expressing NSPCs, was upregulated in the ischemic lesion of N-PRbeta-KO mice. Furthermore, integrin alpha3 intrinsically expressed in NSPCs that critically mediates extracellular matrix dependent migration, was upregulated in N-PRbeta-KO after MCAO. NSPCs isolated from N-PRbeta-KO rapidly migrated on the surface coated with collagen type IV or fibronectin that are abundant in vascular niche and ischemic core. PDGFR-beta was suggested to be critically involved in pathological neurogenesis through the regulation of lesion-derived chemoattractant as well as intrinsic signal of NSPCs, and we believe that a coordinated regulation of these molecular events may be able to improve neurogenesis in injured brain for further functional recovery. PMID- 26435274 TI - Editorial Comment from Dr. Keoghane to Application of nephrostomy tubes with balloon after percutaneous nephrolithotomy: A randomized controlled clinical trial. PMID- 26435275 TI - Retracted: Impact of Type 2 diabetes prevention programmes based on risk identification and lifestyle intervention intensity strategies: a cost effectiveness analysis. AB - The following article, published online on 17 November 2015 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor in Chief, Richard Holt and John Wiley & Sons Ltd. The retraction has been agreed due the fact the authors have made Wiley aware that there was an error in the way the diabetes prevention intervention effect was implemented in this version of the model. The underlying model is not affected by this error. However, the magnitude of the cost savings and health benefits are substantially lower than stated. Reference 1 Breeze R, Thomas C, Squires H, Brennan A, Greaves C, Diggle PJ, Brunner E, Tabak A, Preston L, Chilcott J. Impact of Type 2 diabetes prevention programmes based on risk identification and lifestyle intervention intensity strategies: a cost-effectiveness analysis. Diabet Med 2015; doi: 10.1111/dme.12981. PMID- 26435276 TI - In vitro anti-foot-and-mouth disease virus activity of magnesium oxide nanoparticles. AB - Foot-and-mouth disease (FMD) is an extremely contagious viral disease of cloven hoofed animals that can lead to huge economic losses in the livestock production. No antiviral therapies are available for treating FMD virus (FMDV) infections in animals. The antiviral effects of magnesium oxide nanoparticles (MgO NPs) on the FMDV were investigated in cell culture. The viability of the cells after MgO NP treatment was determined using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide] assay. The direct effects of MgO NPs on the FMDV in extracellular (virucidal assay) and also different stages of virus replication (antiviral assay) were evaluated by plaque reduction assay. The results showed that MgO NPs were safe at concentrations up to 250 ug/ml in the Razi Bovine kidney cell line. The treatments with NPs indicated that the MgO NPs exerted in vitro virucidal and antiviral activities. Plaque reduction assay revealed that MgO NPs can inhibit FMDV by more than 90% at the early stages of infection such as attachment and penetration but not after penetration. The results of this study suggested that NPs might be applied locally as an antiviral agent in early stages of infection in susceptible animals. PMID- 26435277 TI - Biosynthesis of silver and platinum nanoparticles using orange peel extract: characterisation and applications. AB - This study focuses on the green synthesis of noble metal nanoparticles (silver (Ag) and platinum (Pt)) and how the size and shape of the nanoparticles produced can be controlled through changes in the initial pH value of the precursor solution. The nanoparticles were characterised by ultra-violet-visible spectroscopy, transmission electron microscopy and X-ray diffraction. This simple and environmentally friendly method allows the synthesis of diverse nanostructures in the absence of a surfactant or polymer to direct nanoparticle growth, and without externally adding seed crystallites. The antibacterial effects of Ag nanoparticles and catalytic properties of Pt nanoparticles were explored for future promising biotechnological approaches in different fields. PMID- 26435278 TI - Biosensing application of multiwall boron nitride nanotube-based nanoresonator for detecting various viruses. AB - This study explores the suitability of biosensors using multi-walled boron nitride nanotubes (MW-BNNTs) with virus/bacterium attached at the free end of cantilever through vibration analysis. Various viruses/bacteria having mass of the order of zeptogram level are considered for obtaining resonance frequencies of cantilevered triple-walled boron nitride nanotube (TW-BNNT) by means of a continuum mechanics-based analytical approach. The simulation with various viruses/bacteria attached at the tip of cantilevered TW-BNNT is carried out for different lengths. The finite element method simulated resonance frequency values are compared with results obtained from the analytical method by taking into account the effective wall thickness of tubes and van der Waals interaction between various BNNTs. A close proximity is observed between results obtained from the two approaches, which further confirms the validity of the proposed model. The obtained results suggest that shorter length TW-BNNT is more sensitive for detecting viruses/bacteria having mass of zeptogram order. PMID- 26435279 TI - Plumbagin-silver nanoparticle formulations enhance the cellular uptake of plumbagin and its antiproliferative activities. AB - Colloidal silver nanoparticles (AgNPs) have attracted much attention in recent years as diagnostics and new drug delivery system in cancer medicine. To study the effects of plumbagin (PLB), a relatively non-toxic napthaquinone isolated from the roots of Plumbago indica in human cervical cancer cell line and developed a formulation to enhance its cytotoxic activities. Silver nanoparticles were synthesised by chemical reduction method and complexed with PLB. Both the AgNPs and the complex PLB-AgNPs were characterised by dynamic light scattering, high-resolution scanning electron microscopy and transmission electron microscopy. The amount of PLB and PLB-AgNPs internalised was determined by ultra violet-visible spectrophotometer. Cell inhibition was determined by sulphorhodamine B assay. Mitotic index was determined by Wright-Giemsa staining. Apoptosis induction was assessed by western blot using cleaved poly adenosine diphosphate-ribose polymerase antibody. The scanning electron microscope analysis indicated an average particle size of 32+/-8 nm in diameter. Enhanced internalisation of PLB into the HeLa cells was observed in PLB-AgNPs. PLB inhibited proliferation of cells with IC50 value of about 18+/-0.6 uM and blocked the cells at mitosis in a concentration-dependent manner. PLB also inhibited the post-drug exposure clonogenic survival of cells and induced apoptosis. The antiproliferative, antimitotic and apoptotic activities were also found to be increased when cells were treated with PLB-AgNPs. The authors results support the idea that AgNP could be a promising and effective drug delivery system for enhanced activity of PLB in cancer treatment. PMID- 26435280 TI - Escherichia coli bacteria detection by using graphene-based biosensor. AB - Graphene is an allotrope of carbon with two-dimensional (2D) monolayer honeycombs. A larger detection area and higher sensitivity can be provided by graphene-based nanosenor because of its 2D structure. In addition, owing to its special characteristics, including electrical, optical and physical properties, graphene is known as a more suitable candidate compared to other materials used in the sensor application. A novel model employing a field-effect transistor structure using graphene is proposed and the current-voltage (I-V) characteristics of graphene are employed to model the sensing mechanism. This biosensor can detect Escherichia coli (E. coli) bacteria, providing high levels of sensitivity. It is observed that the graphene device experiences a drastic increase in conductance when exposed to E. coli bacteria at 0-10(5) cfu/ml concentration. The simple, fast response and high sensitivity of this nanoelectronic biosensor make it a suitable device in screening and functional studies of antibacterial drugs and an ideal high-throughput platform which can detect any pathogenic bacteria. Artificial neural network and support vector regression algorithms have also been used to provide other models for the I-V characteristic. A satisfactory agreement has been presented by comparison between the proposed models with the experimental data. PMID- 26435281 TI - Three Phoma spp. synthesised novel silver nanoparticles that possess excellent antimicrobial efficacy. AB - The authors report extracellular mycosynthesis of silver nanoparticles (AgNPs) by Phoma capsulatum, Phoma putaminum and Phoma citri. The AgNPs thus synthesised were characterised by UV-visible spectrophotometer, Fourier transform infrared spectroscopy, Nanosight LM20 and transmission electron microscopy, which confirmed the synthesis of mostly spherical and polydisperse nanoparticles capped with proteins. The size of AgNPs was found in the range of 10-80 , 5-80 and 5-90 nm with an average size of 31.85, 25.43 and 23.29 nm by P. capsulatum, P. putaminum and P. citri, respectively. Further, potential antimicrobial activity was reported against Aspergillus niger, Candida albicans, Salmonella choleraesuis, Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli. The lowest minimal inhibitory concentration (MIC) (0.85 ug/ml) was reported for AgNPs synthesised from P. citri against S. choleraesuis. However, AgNPs synthesised from P. capsulatum showed the highest MIC (10.62 ug/ml) against S. choleraesuis, P. aeruginosa and E. coli (clinical isolate). The same MIC values (10.62 ug/ml) were also reported against P. aeruginosa and both clinical and standard isolates of E. coli for AgNPs synthesised from P. citri. It was also observed that all the silver nanoparticles showed remarkable antifungal and antibacterial activity against these tested pathogens as compared with the commercially available antifungal and antibacterial agents. PMID- 26435282 TI - Biosynthesis, characterisation and antimicrobial activity of silver nanoparticles using Hibiscus rosa-sinensis petals extracts. AB - Green synthesis of metallic nanoparticles has lured the world from the chemical and physical approaches owing to its rapid, non-hazardous and economic aspect of production mechanism. In this study, silver nanoparticles (AgNPs) were synthesised using petal extracts of Hibiscus rosa-sinensis. The AgNPs displayed characteristic surface plasmon resonance peak at around 421 nm having a mean particle size of 76.25+/-0.17 nm and carried a charge of -41+/-0.2 mV. The X-ray diffraction patterns displayed typical peaks of face centred cubic crystalline silver. The surface morphology was characterised by scanning electron microscopy and atomic force microscopy. Fourier transform infrared spectroscopy studies confirmed the surface modifications of the functional groups for the synthesis of AgNPs. Furthermore, the synthesised AgNPs displayed proficient antimicrobial activity against pathogenic strains of Vibrio cholerae, Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus. PMID- 26435283 TI - Preparation and in vitro investigation of antigastric cancer activities of carvacrol-loaded human serum albumin nanoparticles. AB - In this study, carvacrol-loaded human serum albumin (HSA) nanoparticles were developed and characterised. Nanoparticles were prepared by desolvation and emulsion/desolvation methods. Encapsulation efficiency (EE%) and loading capacity (LC%) of nanoparticles prepared by desolvation method were 48.4 and 45.1%, respectively. Carvacrol-loaded nanoparticles had 132+/-42 nm in diameter with monomodal distribution. Carvacrol-loaded nanoparticles which is prepared by emulsion/desolvation method had EE% and LC% of 32 and 32.3%, respectively, and 230+/-38 nm in size. The release of carvacrol from nanoparticles was monitored in phosphate-buffered saline (pH=7.4), 100 rpm at 37 degrees C for 10 days. About 21.4% of carvacrol was released after 3 h from nanoparticles that were prepared by desolvation method. In emulsion/desolvation method, 26.8% of total carvacrol was released during 3 h of incubation. Cytotoxicity effect of loaded carvacrol was assessed by 3-[4, 5 dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) test on gastric cancer cells line (AGS). Cell line was exposed to the free carvacrol, unloaded and carvacrol-loaded nanoparticles for 48 h. The half maximal inhibitory concentration (IC50) for free carvacrol, unloaded and carvacrol-loaded HSA nanoparticles were 30, 1070 and 120 ug/ml, respectively. In conclusion, the results of this study showed applications of HSA nanoparticles for entrapment of carvacrol and antigastric cancer activity. Moreover, loading of carvacrol in combination with chemotherapy agents into the HSA nanoparticles may treat cancer cells better than single drug loaded nanoparticles. PMID- 26435284 TI - Biosynthesis of tellurium nanoparticles by Lactobacillus plantarum and the effect of nanoparticle-enriched probiotics on the lipid profiles of mice. AB - Hypercholesterolemia is an important risk factor contributing to atherosclerosis and coronary heart disease. Lactic acid bacteria have attracted much attention regarding their promising effect on serum cholesterol levels. Tellurium (Te) is a rare element that has also gained considerable interest for its biological effects. There have been some recent in vivo reports on the reduction effect of Te on cholesterol content. In this study, Lactobacillus plantarum PTCC 1058 was employed for the intracellular biosynthesis of Te NPs. The UV-visible spectrum of purified NPs showed a peak at 214 nm related to the surface plasmon resonance of the Te NPs. Transmission electron microscopy showed that spherical nanoparticles without aggregation had the average size of 45.7 nm as determined by the laser scattering method. The energy dispersive X-ray pattern confirmed the presence of Te atoms without any impurities. A significant reduction was observed in group which received L. plantarum with or without Te NPs during propylthiouracil and cholesterol diet in compare with the control group which received just propylthiouracil and cholesterol. The levels of triglycerides also remarkably decrease (p<0.05) in mice given L. plantarum with intracellular Te NPs. PMID- 26435285 TI - Optimisation of processing variables effective on self-assembly of folate targeted Synpronic-based micelles for docetaxel delivery in melanoma cells. AB - Polymeric micelles (PMs) were formulated as nano carriers for docetaxel intended for both intravenous administration and improve therapeutic efficacy of the drug. The PMs were formulated using folic acid conjugated Synpronic F127-cholesterol copolymer and were optimised using a 2(3) full factorial design. The effects of different formulation variables were evaluated on the particle size, entrapment efficiency (EE), zeta potential and release efficiency of the micelles. The in vitro cytotoxicity of DTX-loaded FA targeted micelles was studied on B16F10 melanoma cells which over expressed FA receptor. Among the studied single factors, solvent type was the most effective parameter on the EE and release efficiency. Polymer/drug ratio had the most considerable effect on the particle size while, zeta potential was more affected by temperature. Finally, the PMs with polymer/drug ratio of 12 prepared at 25 degrees C by dimethyl sulfoxide as the dialyzing solvent was shown to be the optimum formulation with desirability factor of 84.9%. The optimised formulation exhibited a particle size of 171.3 nm, 99.59% drug EE, zeta potential of -7.80 mV, drug release efficiency of about 70% at 144 h and polydispersity index of 0.32. The MTT assay indicated DTX-loaded FA targeted micelles were significantly more cytotoxic than non-targeted micelles and free drug. PMID- 26435286 TI - Catalytic role of traditional enzymes for biosynthesis of biogenic metallic nanoparticles: a mini-review. AB - Although the formation mechanism of biogenically metallic nanoparticles is broadly associated to enzyme mediation, major attention has been given to the role of proteins and peptides in oxido-reduction of metallic ions leading to these nanostructures. Among the wide range of biomolecules that can act not only as capping agents but also as non-enzymatic agents to form nanoparticles, disulphide bridge-containing peptides and amino acids particularly stand out. The literature proposes that they actively participate in the process of nanoparticles' synthesis, with thiols groups and disulphide bridge moieties as the reaction catalytic sites. Similarly, denaturated enzymes containing exposed S S or S-H moieties are also able to reduce metallic ions to form nanoparticles. This mini-review is focused on the biogenic synthesis of metallic nanoparticles such as gold, silver, copper, platinum, palladium, lead and selenium, in which proteins, peptides, reductases and even oxido-reductases act as non-enzymatic catalysts of the reduction reaction, opening economically and ecologically favourable perspectives in the nanoparticles synthesis field. PMID- 26435287 TI - Editorial: The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial: The Operations Behind a Herculean Task. PMID- 26435288 TI - Managing Multi-Center Recruitment in the PLCO Cancer Screening Trial. AB - There were significant recruitment challenges specific to the PLCO Cancer Screening Trial. Large numbers of participants were to be randomized from ten catchment areas nationwide within time and budgetary constraints. The eligible population was elderly and had to meet health and behavioral thresholds. Informed consent was required to participate and be randomized to screening for three cancers at periodic clinic visits or to a usual care arm that included no clinical visits. Consenting required special efforts to fully explain the trial and its potential scientific benefit to future patients with potentially no benefits but possible harms to PLCO participants. Participation would include continued follow-up for at least 13 years after randomization. Strong collaborative investments were required by the NCI and screening centers (SCs) to assure timely recruitment and appropriate racial participation. A trial-wide pilot phase tested recruitment and protocol follow through at SCs and produced a vanguard population of 11,406 participants. NCI announced the trial nationally in advance of the pilot and followed with an even more intense collaborative role with SCs for the main phase to facilitate trial-wide efficient and timely recruitment. Special efforts to enhance recruitment in the main phase included centralized and local monitoring of progress, cross-linking SCs to share experiences in problem solving, centralized training, substantial additional funding dedicated to recruitment and retention, including specialized programs for minority recruitment, obtaining national endorsement by the American Cancer Society, launching satellite recruitment and screening centers, including minority focused satellites, and adding a new SC dedicated to minority recruitment. PMID- 26435290 TI - Cancer Cachexia: One Step Ahead. AB - Cachexia is one of the most common manifestations in advanced cancer patients, but too often it remains under- recognized and under-treated. Starvation is not the same of cachexia. Cachexia is defined by "weight loss >5% over past 6 months in absence of simple starvation or the combination of ongoing weight loss>2% with BMI <20 or sarcopenia". The pathogenesis of cancer cachexia is not fully understood, but inflammation and an increased catabolic response to a number of cancer-related factors seem to represent the basis of any assumption. Early diagnosis of a pre-cachectic or cachectic state is a key moment for the treatment of this complex syndrome, in order to guarantee an adequate food intake and suitable exercise and to interfere with the inflammatory processes that are typical of cachexia. Therefore, one of the main aims is to identify those patients most likely to develop the syndrome early. A multimodality baseline approach to cancer cachexia addresses reversible clinical contributory factors. There are currently no medicinal products that have a proven efficacy in the medical approach to cancer cachexia. Recently, anamorelin, a synthetic orally active ghrelin receptor agonist, showed promising results, but the best approach to cancer cachexia probably remains an early multimodal interventions consisting in nutritional intervention, exercise and rehabilitation program, and multi target drug therapies. This review summarizes what we know and what still need to know about cancer cachexia syndrome. PMID- 26435289 TI - PLCO: Evolution of an Epidemiologic Resource and Opportunities for Future Studies. AB - The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), a large-scale, multi-institutional, randomized controlled trial, was launched in 1992 to evaluate the effectiveness of screening modalities for prostate, lung, colorectal, and ovarian cancer. However, PLCO was additionally designed to serve as an epidemiologic resource and the National Cancer Institute has invested substantial resources over the years to accomplish this goal. In this report, we provide a summary of changes to PLCO's follow-up after conclusion of the screening phase of the trial and highlight recent data and biospecimen collections, including ancillary studies, geocoding, administration of a new medication use questionnaire, consent for linkage to Medicare, and additional tissue collection that enhance the richness of the PLCO resource and provide further opportunities for scientific investigation into the prevention, early detection, etiology and treatment of cancer. PMID- 26435291 TI - Copying of RNA Sequences without Pre-Activation. AB - Template-directed incorporation of nucleotides at the terminus of a growing complementary strand is the basis of replication. For RNA, this process can occur in the absence of enzymes, if the ribonucleotides are first converted to an active species with a leaving group. Thus far, the activation required a separate chemical step, complicating prebiotically plausible scenarios. Here we show that a combination of a carbodiimide and an organocatalyst induces near-quantitative incorporation of any of the four ribonucleotides. Upon in situ activation, adenosine monophosphate was found to also form oligomers in aqueous solution. So, both de novo strand formation and sequence-specific copying can occur without an artificial synthetic step. PMID- 26435292 TI - Being in a critical illness-recovery process: a phenomenological hermeneutical study. AB - AIMS AND OBJECTIVE: The aim of this study was to describe and interpret the essential meaning of the lived experiences of being in a critical illness recovery process after a life-threatening condition. BACKGROUND: The critical illness-recovery process after a life-threatening condition takes several years and does not only include patients' experiences during intensive care. Previous research has mainly focused on what critically ill patients recall. However, from a phenomenological point of view, experiences are more than memories alone. To plan and perform relevant health care and social support for patients who have survived a life-threatening condition, a more profound understanding about their lived experiences is needed. DESIGN AND METHOD: In this qualitative study, a phenomenological hermeneutical approach was used. Interviews were conducted with seven patients, two to four years after they had received care in an intensive care unit in Sweden. RESULTS: The comprehensive understanding of the results shows that the critical illness-recovery process after a life-threatening condition means an existential struggle to reconcile with an unfamiliar body and with ordinary life. This can be understood as an 'unhomelikeness' implying a struggle to create meaning and coherence from scary and fragmented memories. The previous life projects, such as work and social life become unfamiliar when the patient's fragile and weak body is disobedient and brings on altered sensations. CONCLUSIONS: Patients who survive a life-threatening condition have an immense need for care and support during the entire critical illness-recovery process, and also after the initial acute phase. They need a coherent understanding of what happened, and support to be able to perform their changed life projects. RELEVANCE TO CLINICAL PRACTICE: Supporting and caring for patients' recovery from a life- threatening condition involves recognising the patients' struggle and responding to their existential concerns. PMID- 26435293 TI - Childhood-Onset Essential Hypertension and the Family Structure. AB - The prevalence and effect of single-parent families in childhood-onset essential hypertension (EH) is unknown. Children with EH and age-, sex-, and ethnicity matched controls were enrolled. Family structure data were obtained by in-person interview. A total of 148 families (76 hypertension probands, 72 control probands; median 14 years) were prospective-ly enrolled in the study. Single parent status was seen in 42% of the families--with and without EH (38% vs 46%, P=.41; odds ratio, 0.7; 95% confidence interval, 0.4-1.4). After multivariable analysis, a statistically significant sociofamilial contributor to the development of childhood-onset EH was not identified. A significant number of single-parent families (42%), the majority with single mothers, were found in our pedigree study. Sociofamilial factors are known to contribute to the expression of adult-onset EH, but findings in our study suggest that they appear to contribute less in the expression of childhood-onset EH. PMID- 26435294 TI - Synthesis and Anti-Hepatitis B Virus Evaluation of 7-Methoxy-3-heterocyclic quinolin-6-ols. AB - A series of novel 7-methoxy-3-heterocyclic quinolin-6-ol derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities and cytotoxicities in the HepG2.2.15 cell line. Five compounds, 14a, 15c, 15e, 16b, and 16f, displayed excellent potency and selectivity toward the HBV, with IC50 values of less than 5.0 uM and selectivity index values of 11.0-71.5. Structure activity relationship studies indicated that the 1,3,4-thiadiazole and sulfinylmethyl derivatives showed the most potent activities against the HBV. PMID- 26435295 TI - The impact of age on cerebral perfusion, oxygenation and metabolism during exercise in humans. AB - Age is one of the most important risk factors for dementia and stroke. Examination of the cerebral circulatory responses to acute exercise in the elderly may help to pinpoint the mechanisms by which exercise training can reduce the risk of brain diseases, inform the optimization of exercise training programmes and assist with the identification of age-related alterations in cerebral vascular function. During low-to-moderate intensity dynamic exercise, enhanced neuronal activity is accompanied by cerebral perfusion increases of ~10 30%. Beyond ~60-70% maximal oxygen uptake, cerebral metabolism remains elevated but perfusion in the anterior portion of the circulation returns towards baseline, substantively because of a hyperventilation-mediated reduction in the partial pressure of arterial carbon dioxide (P aC O2) and cerebral vasoconstriction. Cerebral perfusion is lower in older individuals, both at rest and during incremental dynamic exercise. Nevertheless, the increase in the estimated cerebral metabolic rate for oxygen and the arterial-internal jugular venous differences for glucose and lactate are similar in young and older individuals exercising at the same relative exercise intensities. Correction for the age-related reduction in P aC O2 during exercise by the provision of supplementary CO2 is suggested to remove ~50% of the difference in cerebral perfusion between young and older individuals. A multitude of candidates could account for the remaining difference, including cerebral atrophy, and enhanced vasoconstrictor and blunted vasodilatory pathways. In summary, age-related reductions in cerebral perfusion during exercise are partly associated with a lower P aC O2 in exercising older individuals; nevertheless the cerebral extraction of glucose, lactate and oxygen appear to be preserved. PMID- 26435296 TI - Open-label study evaluating outpatient urethral sphincter injections of onabotulinumtoxinA to treat women with urinary retention due to a primary disorder of sphincter relaxation (Fowler's syndrome). AB - OBJECTIVES: To assess the efficacy (defined as improvements in maximum urinary flow rate [Qmax ] of >=50%, post-void residual urine volume [PVR] and scores on the International Prostate Symptom Score [IPSS] questionnaire) and safety of urethral sphincter injections of onabotulinumtoxinA in women with a primary disorder of urethral sphincter relaxation, characterised by an elevated urethral pressure profile (UPP) and specific findings at urethral sphincter electromyography (EMG), i.e. Fowler's syndrome. PATIENTS AND METHODS: In this open-label pilot Institutional Review Board-approved study, 10 women with a primary disorder of urethral sphincter relaxation (elevated UPP, sphincter volume, and abnormal EMG) presenting with obstructed voiding (five) or in complete urinary retention (five) were recruited from a single tertiary referral centre. Baseline symptoms were assessed using the IPSS, and Qmax and PVR were measured. After 2% lidocaine injection, 100 U of onabotulinumtoxinA was injected into the striated urethral sphincter, divided on either side, under EMG guidance. Patients were reviewed at 1, 4 and 10 weeks after injection, and assessed using the IPSS, Qmax and PVR measurements. The UPP was repeated at week 4. RESULTS: The mean (range) patient age was 40 (25-65) years, and the mean symptom scores on the IPSS improved from 25.6 to 14.1, and the mean 'bother' score reduced from 6.1 to 3.5 at week 10. As compared with a baseline mean Qmax of 8.12 mL/s in the women who could void, the Qmax improved to 15.8 mL/s at week 10. Four of the five women in complete retention could void spontaneously, with a mean Qmax of 14.3 mL/s at week 10. The mean PVR decreased from 260 to 89 mL and the mean static UPP improved from 113 cmH2 O at baseline to 90 cmH2 O. No serious side-effects were reported. Three women with a history of recurrent urinary tract infections developed a urinary tract infection. There were no reports of stress urinary incontinence. Seven of the 10 women opted to return for repeat injections. CONCLUSIONS: This pilot study shows an improvement in patient-reported lower urinary tract symptoms, and the objective parameters of Qmax , PVR and UPP, at 10 weeks after urethral sphincter injections of onabotulinumtoxinA. No serious side effects were reported. This treatment could represent a safe outpatient treatment for young women in retention due to a primary disorder of urethral sphincter relaxation. However, a larger study is required to confirm the findings of this pilot study. PMID- 26435297 TI - Novel population-based study finding higher than reported hepatocellular carcinoma incidence suggests an updated approach is needed. AB - Hepatocellular carcinoma (HCC) incidence is rising rapidly in many developed countries. Primary epidemiological data have invariably been derived from cancer registries that are heterogeneous in data quality and registration methodology; many registries have not adopted current clinical diagnostic criteria for HCC and still rely on histology for classification. We performed the first population based study in Australia using current diagnostic criteria, hypothesizing that HCC incidence may be higher than reported. Incident cases of HCC (defined by American Association for the Study of Liver Diseases diagnostic criteria or histology) were prospectively identified over a 12-month period (2012-2013) from the population of Melbourne, Australia. Cases were captured from multiple sources: admissions to any of Melbourne's seven tertiary hospitals; attendances at outpatients; and radiology, pathology, and pharmacy services. Our cohort was compared to the Victorian Cancer Registry (VCR) cohort (mandatory notified cases) for the same population and period, and incidence rates were compared for both cohorts. There were 272 incident cases (79% male; median age: 65 years) identified. Cirrhosis was present in 83% of patients, with hepatitis C virus infection (41%), alcohol (39%), and hepatitis B virus infection (22%) the commonest etiologies present. Age-standardized HCC incidence (per 100,000, Australian Standard Population) was 10.3 (95% confidence interval [CI]: 9.0-11.7) for males and 2.3 (95% CI: 1.8 to 3.0) for females. The VCR reported significantly lower rates of HCC: 5.3 (95% CI: 4.4 to 6.4) and 1.0 (95% CI: 0.7 to 1.5) per 100,000 males and females respectively (P < 0.0001). CONCLUSIONS: HCC incidence in Melbourne is 2-fold higher than reported by cancer registry data owing to under-reporting of clinical diagnoses. Adoption of current diagnostic criteria and additional capture sources will improve registry completeness. Chronic viral hepatitis and alcohol remain leading causes of cirrhosis and HCC. PMID- 26435298 TI - Traumatic brain injury in Africa in 2050: a modeling study. AB - BACKGROUND AND PURPOSE: Our aim was to provide estimates of traumatic brain injury (TBI) in 2050 for the African population by region, sex and age strata. METHODS: A literature search was performed in October 2014 in PubMed for population-based studies of TBI in different geographical locations. Articles were selected from Kenya (model 1), New Zealand (model 2) and the USA (model 3). In model 1, rates of road traffic injury in Kenya were used to estimate TBI rates in the African continent. Models 2 and 3 used existing TBI incidence estimates from other locations to estimate the burden of TBI for Africa in 2050. The 2050 African population, as projected by the United Nations, was used as a base population. RESULTS: Based on rates from model 1, the estimated total TBI count in Africa in 2050 is 5.98 +/- 0.03 million, with the highest count in eastern (2.04 +/- 0.01 million) and lowest count in southern (0.15 +/- 0.00 million) Africa. A higher TBI count is predicted by models 2 (14.25 +/- 0.75 million) and 3 (10.40 +/- 0.02 million). Estimated TBI count is highest for males aged 15-34 (5.47 +/- 0.55 million in model 2 and 3.21 +/- 0.13 million in model 3). CONCLUSIONS: Projected estimates of TBI in Africa are high, with a burden of anywhere between approximately 6 and 14 million new cases in 2050. This emphasizes the importance of developing accurate surveillance systems of TBI at a population level and public health measures to mitigate the risk and burden of TBI. PMID- 26435300 TI - A comparison of recommendations for pharmacologic thromboembolism prophylaxis after caesarean delivery from three major guidelines. AB - OBJECTIVE: Guidelines for pharmacologic obstetric venous thromboembolism (VTE) prophylaxis from the American Congress of Obstetricians (ACOG), the Royal College of Obstetricians and Gynaecologists (RCOG), and the American College of Chest Physicians (Chest) vary significantly. The objective of this study was to determine the practical implications of these recommendations in terms of prophylaxis rates for a tertiary obstetric population. STUDY DESIGN: Cross sectional. SETTING: Tertiary referral hospital. POPULATION: Patients post operative day 1 after caesarean delivery. METHODS: This cross-sectional study evaluated rates of pharmacologic prophylaxis for women based on RCOG, ACOG, and Chest recommendations. Medical, obstetric, and demographic risk factors for thromboembolism were reviewed for individual patients. Rates of prophylaxis based on each of the guidelines with 95% confidence intervals were calculated. OUTCOME MEASURE: Recommended pharmacologic prophylaxis. RESULTS: About 293 patients were included in the analysis. Under RCOG guidelines, 85.0% of patients would receive post-caesarean pharmacologic prophylaxis [95% confidence interval (CI) 80.5 88.6%] compared with 1.0% of patients under ACOG guidelines (95% CI 0.3-3.0%) and 34.8% of patients under Chest guidelines (95% CI 29.6-40.4%). Caesarean during labour, obesity, advanced maternal age, pre-eclampsia, and multiple gestation were among the most commonrisk factors. CONCLUSION: Recommended prophylaxis differed significantly. Under ACOG recommendations a small minority of patients would receive prophylaxis, whereas under RCOG recommendations a large majority of patients would receive low-molecular-weight heparin. Given the large differences in prophylaxis rates for post-caesarean thromboprophylaxis based on different guidelines, further research is urgently needed to compare the risks and benefits of recommendations. TWEETABLE ABSTRACT: Recommendations from major society guidelines for post-caesarean thromboprophylaxis differ greatly. PMID- 26435299 TI - Thiol-ene Photocrosslinking of Cytocompatible Resilin-Like Polypeptide-PEG Hydrogels. AB - A range of chemical strategies have been used for crosslinking recombinant polypeptide hydrogels, although only a few have employed photocrosslinking approaches. Here, we capitalize on the novel insect protein, resilin, and the versatility of click reactions to introduce a resilin-like polypeptide (RLP) that is capable of photoinitiated thiol-ene crosslinking. Lysine residues of the RLP were functionalized with norbornene acid as confirmed via 1H-NMR spectroscopy. The RLPNs were subsequently photocrosslinked with multi-arm PEG thiols in the presence of a photoinitiator to form elastic hybrid hydrogels. The crosslinking reaction and resulting RLP-PEG networks demonstrated cytocompatibility with human mesenchymal stem cells in both 2D cell-adhesion and 3D photoencapsulation studies. PMID- 26435301 TI - Imaging and Clinical Characteristics Predict Near-Term Disablement From Bone Metastases: Implications for Rehabilitation. AB - OBJECTIVE: To distinguish which patients with bone metastases are at risk for near-term disablement in order to assist clinicians in assessing the appropriateness of referrals for rehabilitation services. DESIGN: Prospective cohort study. SETTING: National Cancer Institute-designated comprehensive cancer center imbedded in a tertiary medical center. PARTICIPANTS: Data were collected from members (n=78) of a patient cohort (N=311) with stage IIIB or IV non-small cell lung cancer or extensive-stage small-cell lung cancer who developed new or progressive imaging-confirmed bone metastases during the 2-year course of the study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Functional capabilities were assessed at 3- to 4-week intervals over the study's 2-year duration with the Activity Measure for Post-Acute Care Computer Adaptive Testing. RESULTS: Seventy-eight participants developed new or progressive bone metastases during the study. Most were men, and 83% had non-small-cell lung cancer. Metastases were most frequently located in the ribs (n=62), pelvis (n=49), or the thoracic (n=60) and lumbar spine (n=44). While neither the number of bone metastases nor their specific location was associated with near-term changes in patient mobility, their association with pain or a focal neurologic deficit was strongly associated with large declines in mobility. Similarly, patients whose imaging studies revealed new metastases and the expansion of established metastases were more likely to lose mobility. CONCLUSIONS: The total burden, specific locations, and overall distribution of bone metastases did not predict disablement. Patients with lung cancer-associated bone metastases are at markedly increased risk for declining mobility when their metastases are expanding in size and increasing in number, or are associated with pain or with new neurologic deficits. PMID- 26435302 TI - Using Wearable Sensors and Machine Learning Models to Separate Functional Upper Extremity Use From Walking-Associated Arm Movements. AB - OBJECTIVE: To improve measurement of upper extremity (UE) use in the community by evaluating the feasibility of using body-worn sensor data and machine learning models to distinguish productive prehensile and bimanual UE activity use from extraneous movements associated with walking. DESIGN: Comparison of machine learning classification models with criterion standard of manually scored videos of performance in UE prosthesis users. SETTING: Rehabilitation hospital training apartment. PARTICIPANTS: Convenience sample of UE prosthesis users (n=5) and controls (n=13) similar in age and hand dominance (N=18). INTERVENTIONS: Participants were filmed executing a series of functional activities; a trained observer annotated each frame to indicate either UE movement directed at functional activity or walking. Synchronized data from an inertial sensor attached to the dominant wrist were similarly classified as indicating either a functional use or walking. These data were used to train 3 classification models to predict the functional versus walking state given the associated sensor information. Models were trained over 4 trials: on UE amputees and controls and both within subject and across subject. Model performance was also examined with and without preprocessing (centering) in the across-subject trials. MAIN OUTCOME MEASURE: Percent correct classification. RESULTS: With the exception of the amputee/across-subject trial, at least 1 model classified >95% of test data correctly for all trial types. The top performer in the amputee/across-subject trial classified 85% of test examples correctly. CONCLUSIONS: We have demonstrated that computationally lightweight classification models can use inertial data collected from wrist-worn sensors to reliably distinguish prosthetic UE movements during functional use from walking-associated movement. This approach has promise in objectively measuring real-world UE use of prosthetic limbs and may be helpful in clinical trials and in measuring response to treatment of other UE pathologies. PMID- 26435303 TI - Combined theoretical and time-resolved photoluminescence investigations of [Mo6Bri8Br(a)6]2- metal cluster units: evidence of dual emission. AB - The combined time-resolved photoluminescence (PL) and theoretical study performed on luminescent [Mo6Br(i)8Br(a)6](2-)-based systems unambiguously shows that their NIR-luminescence is due to at least two emissive states. By quantum chemical studies, we show for the first time that important geometrical relaxations occur at the triplet states either by the outstretching of an apex away from the square plane of the Mo6 octahedron or by the elongation of one Mo-Mo bond. Experimental PL measurements demonstrate that the external environment (counter-ions, crystal packing) of the cluster has a noticeable impact on its relaxation processes. Temperature and excitation wavelength dependence of the two components of the luminescence spectra is representative of multiple competitive de-excitation processes in contradiction with Kasha's rule. Our results also demonstrate that the relaxation processes before and after emission can be tracked via fast time resolved spectroscopy. They also show that the surroundings of the luminescent cluster unit and the excitation wavelength could be modulated for target applications. PMID- 26435307 TI - Making Dimethylamino a Transformable Directing Group by Nickel-Catalyzed C-N Borylation. AB - The dimethylamino (Me2N) group is arguably the most versatile functional group capable of highly efficient and site-selective directed aromatic functionalizations at the ortho-, meta-, and para-positions depending on reaction conditions. While the repertoire of Me2N-directed reactions is growing at a rapid pace, the lack of a general method to transform this group to other functionalities hampers its wider application in organic synthesis. Here we report nickel-catalyzed C-N borylations of aryl- and benzyl-dimethylamines that permit the conversion of a huge library of largely underutilized Me2N-containing organic molecules into various functional molecules by taking advantage of the wealth of existing C-B functionalization methods. PMID- 26435308 TI - Sample extraction techniques for biological samples: recent advances and novel applications. PMID- 26435309 TI - Modification of a commercial gas chromatography isotope ratio mass spectrometer for on-line carbon isotope dilution: Evaluation of its analytical characteristics for the quantification of organic compounds. AB - We describe the instrumental modification of a commercial gas chromatography isotope ratio mass spectrometer (GC-IRMS) and its application for on-line carbon isotope dilution. The main modification consisted in the addition of a constant flow of enriched (13)CO2 diluted in helium after the chromatographic column through the splitter holder located inside the chromatographic oven of the instrument. In addition, and in contrast to the conventional mode of operation of GC-IRMS instruments where the signal at m/z 45 is amplified 100-fold with respect to the signal at m/z 44, the same signal amplification was used in both Faraday cups at m/z 44 and 45. Under these conditions isotope ratio precision for the ratio 44/45 was around 0.05% RSD (n=50). The evaluation of the instrument was performed with mixtures of organic compounds including 11 n-alkanes, 16 PAHs, 12 PCBs and 3 benzothiophenes. It was observed that compounds of very different boiling points could be analysed without discrimination in the injector when a Programmable Temperature Vaporizer (PTV) injector was employed. Moreover, the presence of heteroatoms (Cl or S) in the structure of the organic compounds did not affect their combustion efficiency and therefore the trueness of the results. Quantitative results obtained for all the analytes assayed were excellent in terms of precision (<3% RSD) and accuracy (average relative error<=4%) and what is more important using a single and simple generic internal standard for quantification. PMID- 26435310 TI - Introduction to "Comparison between the efficiencies of columns packed with fully and partially porous C18-bonded silica materials" by F. Gritti, A. Cavazzini, N. Marchetti, G. Guiochon [J. Chromatogr. A 1157 (2007) 289-303]. PMID- 26435311 TI - Development and validation of methodologies for the quantification of phytosterols and phytosterol oxidation products in cooked and baked food products. AB - Chromatography-mass spectrometry (GC-MS) methodologies for the analysis of the main phytosterols (PS) and phytosterol oxidation products (POPs) present in 19 different foodstuffs cooked or baked using margarines with or without added plant sterols are presented. Various methods for fat extraction were evaluated to allow the GC-MS analysis of large numbers of prepared vegetable, fish and meat products, egg and bakery items in a practically feasible manner. The optimized methods resulted in a good sensitivity and allowed the analysis of both PS and POPs in the broad selection of foods at a wide range of concentrations. Calibration curves for both PS and POPs showed correlation coefficients (R(2)) better than 0.99. Detection limits were below 0.24mgkg(-1) for PS and 0.02mgkg( 1) for POPs, respectively. Average recovery data were between 81% and 105.1% for PS and between 65.5 and 121.8% for POPs. Good results were obtained for within- and between-day repeatability, with most values being below 10%. Entire sample servings were analyzed, avoiding problems with inhomogeneity and making the method an exact representation of the typical use of the food by the consumer. PMID- 26435312 TI - Separation of bimodal high density polyethylene using multidimensional high temperature liquid chromatography. AB - High-temperature two-dimensional liquid chromatography (HT 2D-LC) using HT-HPLC as first dimension and HT-SEC as second dimension holds enormous potential to investigate the distribution according to molar mass and chemical composition of bimodal high density polyethylene (BiHDPE), as it avoids drawbacks of crystallization-based techniques. In this study, we have stepwise optimized the chromatographic parameters of 1D, comprising gradient slope and temperature, using model homo- and copolymers of ethylene with the aim to minimize the impact of molar mass on the compositional separation. Then the HT-HPLC was hyphenated to HT-SEC and optimum conditions for the volume of the sample transfer loop were probed with regard to the resolution of BiHDPE into the individual constituents HDPE and LLDPE. A particular important aspect was the use of infrared (IR) detection, and the demands it puts on the chromatographic aspects: We have shown that IR detection can be successfully applied in HT 2D-LC of BiHDPE, which is broadly distributed with regard to short chain branching and molar mass, only when the separation in 2D is optimized with regard to chromatographic resolution. As final result a bimodality is evident in the contour and the 3D surface plots as well as in both HPLC and SEC projections generated from HT 2D-LC. PMID- 26435313 TI - Effervescence and graphitized multi-walled carbon nanotubes assisted microextraction for natural antioxidants by ultra high performance liquid chromatography with electrochemical detection and quadrupole time-of-flight tandem mass spectrometry. AB - In this article, effervescence and graphitized multi-walled carbon nanotubes assisted microextraction was first developed for the extraction of antioxidants in hawthorn samples. The use of an effervescent tablet composed of sodium dihydrogen phosphate, sodium carbonate and micro-scale carboxyl graphitized multi walled carbon nanotubes (extraction sorbent) was the core of the method. In this study, ultra high performance liquid chromatography coupled with electrochemical detection and quadrupole time-of-flight tandem mass spectrometry was performed for qualitative and quantitative analyses of target analytes in hawthorn foodstuffs. Several experimental factors, such as amount of effervescent salts, the sorbent, elution time and elution solvent, were systematically assessed. Under the optimized conditions, a good linearity with R values better than 0.9980 was obtained. The detection limits estimated at a signal-to-noise ratio of 3:1 were ranging from 0.01 to 0.18ng/mL. These results suggested that the proposed method could be an alternative and promising sample preparation tool in future food analysis. PMID- 26435314 TI - Gel-assisted crystallization of [Ir4(IMe)7(CO)H10](2+) and [Ir4(IMe)8H9](3+) clusters derived from catalytic glycerol dehydrogenation. AB - The two title clusters were formed during iridium-catalyzed glycerol dehydrogenation and display a remarkably high NHC content. They were crystallized in either agarose or polyethylene oxide gel matrices, while more conventional crystallization techniques proved unsuccessful. Cluster [Ir4(IMe)8H9](3+), with a net charge of +3, was only crystallizable with a polyoxometalate Keggin trianion. The crystal packing of this intercluster compound is discussed. Computational studies position the iridium hydrides and provide insights into the bonding. PMID- 26435315 TI - Sterilization Resistance of Bacterial Spores Explained with Water Chemistry. AB - Bacterial spores can survive for long periods without nutrients and in harsh environmental conditions. This survival is influenced by the structure of the spore, the presence of protective compounds, and water retention. These compounds, and the physical state of water in particular, allow some species of bacterial spores to survive sterilization schemes with hydrogen peroxide and UV light. The chemical nature of the spore core and its water has been a subject of some contention and the chemical environment of the water impacts resistance paradigms. Either the spore has a glassy core, where water is immobilized along with other core components, or the core is gel-like with mobile water diffusion. These properties affect the movement of peroxide and radical species, and hence resistance. Deuterium solid-state NMR experiments are useful for examining the nature of the water inside the spore. Previous work in our lab with spores of Bacillus subtilis indicate that, for spores, the core water is in a more immobilized state than expected for the gel-like core theory, suggesting a glassy core environment. Here, we report deuterium solid-state NMR observations of the water within UV- and peroxide-resistant spores from Bacillus pumilus SAFR-032. Variable-temperature NMR experiments indicate no change in the line shape after heating to 50 degrees C, but an overall decrease in signal after heating to 100 degrees C. These results show glass-like core dynamics within B. pumilus SAFR-032 that may be the potential source of its known UV-resistance properties. The observed NMR traits can be attributed to the presence of an exosporium containing additional labile deuterons that can aid in the deactivation of sterilizing agents. PMID- 26435316 TI - Novel Symbol Learning-Induced Stroop Effect: Evidence for a Strategy-Based, Utility Learning Model. AB - The automaticity level and attention priority/strategy are two major theories that have attempted to explain the mechanism underlying the Stroop effect. Training is an effective way to manipulate the experience with the two dimensions (ink color and color word) in the Stroop task. In order to distinguish the above two factors (the automaticity or attention/strategy), we revised the training paradigm of MacLeod's study (J Exp Psychol Learn Mem Cogn 14(1):126-135, 1988) by adding a control condition for the Stroop task on Chinese. We found that with training, the changing pattern for the Stroop effect was similar in Stroop tasks in novel symbols and in Chinese, showing markedly increasing interference and marginally decreasing facilitation. The current findings support the strategy based learning account at early stages of novel learning of written symbols. PMID- 26435317 TI - Corrigendum: Sound Packing DNA: packing open circular DNA with low-intensity ultrasound. PMID- 26435318 TI - On the correlation between microscopic structural heterogeneity and embrittlement behavior in metallic glasses. AB - In order to establish a relationship between microstructure and mechanical properties, we systematically annealed a Zr-based bulk metallic glass (BMG) at 100 ~ 300 degrees C and measured their mechanical and thermal properties. The as cast BMG exhibits some ductility, while the increase of annealing temperature and time leads to the transition to a brittle behavior that can reach nearly-zero fracture energy. The differential scanning calorimetry did not find any significant changes in crystallization temperature and enthalpy, indicating that the materials still remained fully amorphous. Elastic constants measured by ultrasonic technique vary only slightly with respect to annealing temperature and time, which does obey the empirical relationship between Poisson's ratio and fracture behavior. Nanoindentation pop-in tests were conducted, from which the pop-in strength mapping provides a "mechanical probe" of the microscopic structural heterogeneities in these metallic glasses. Based on stochastically statistic defect model, we found that the defect density decreases with increasing annealing temperature and annealing time and is exponentially related to the fracture energy. A ductile-versus-brittle behavior (DBB) model based on the structural heterogeneity is developed to identify the physical origins of the embrittlement behavior through the interactions between these defects and crack tip. PMID- 26435319 TI - Expansion dynamics in a one-dimensional hard-core boson model with three-body interactions. AB - Using the adaptive time-dependent density matrix renormalization group method, we numerically investigate the expansion dynamics of bosons in a one-dimensional hard-core boson model with three-body interactions. It is found that the bosons expand ballistically with weak interaction, which are obtained by local density and the radius Rn. It is shown that the expansion velocity V, obtained from Rn = Vt, is dependent on the number of bosons. As a prominent result, the expansion velocity decreases with the enhancement of three-body interaction. We further study the dynamics of the system, which quenches from the ground state with two thirds filling, the results indicate the expansion is also ballistic in the gapless phase regime. It could help us detect the phase transition in the system. PMID- 26435320 TI - Imaging Local Heating and Thermal Diffusion of Nanomaterials with Plasmonic Thermal Microscopy. AB - Measuring local heat generation and dissipation in nanomaterials is critical for understanding the basic properties and developing applications of nanomaterials, including photothermal therapy and joule heating of nanoelectronics. Several technologies have been developed to probe local temperature distributions in nanomaterials, but a sensitive thermal imaging technology with high temporal and spatial resolution is still lacking. Here, we describe plasmonic thermal microscopy (PTM) to image local heat generation and diffusion from nanostructures in biologically relevant aqueous solutions. We demonstrate that PTM can detect local temperature change as small as 6 mK with temporal resolution of 10 MUs and spatial resolution of submicrons (diffraction limit). With PTM, we have successfully imaged photothermal generation from single nanoparticles and graphene pieces, studied spatiotemporal distribution of temperature surrounding a heated nanoparticle, and observed heating at defect sites in graphene. We further show that the PTM images are in quantitative agreement with theoretical simulations based on heat transport theories. PMID- 26435321 TI - Lysine Methyltransferase SETD7 (SET7/9) Regulates ROS Signaling through mitochondria and NFE2L2/ARE pathway. AB - Reactive oxygen species (ROS) homeostasis requires stringent regulation. ROS imbalance, especially ROS accumulation, has profound implications in various disease pathogenesis. Lysine methylation of histone and non-histone proteins has been implicated in various cellular responses. The main objective of this study is to investigate the role of SET domain containing lysine methyltransferase SETD7 (SET7/9) in the regulation of ROS-mediated signaling. Here we report that inhibition of SETD7 with siRNA or a SETD7 small molecule inhibitor in both macrophages and a human bronchial epithelial cell line (Beas-2B) were able to counter NF-KB-induced oxidative stress and pro-inflammatory cytokine production. Meanwhile, inhibition of SETD7 elevates mitochondria antioxidant functions via negative regulation of PPARGC1A and NFE2L2. Using a co-expression system and purified proteins, we detected direct interaction between SETD7 and NFE2L2. These results indicate that lysine methylation by SETD7 is important for the fine tuning of ROS signaling through its regulation on pro-inflammatory responses, mitochondrial function and the NFE2L2/ARE pathway. Up-regulation of multiple antioxidant genes and improved ROS clearance by inhibition of SETD7 suggests the potential benefit of targeting SETD7 in treating ROS-associated diseases. PMID- 26435322 TI - Ezrin is a Major Regulator of Membrane Tension in Epithelial Cells. AB - Plasma membrane tension is responsible for a variety of cellular functions such as motility, cell division, and endocytosis. Since membrane tension is dominated by the attachment of the actin cortex to the inner leaflet of the plasma membrane, we investigated the importance of ezrin, a major cross-linker of the membrane-cytoskeleton interface, for cellular mechanics of confluent MDCK II cells. For this purpose, we carried out ezrin depletion experiments and also enhanced the number of active ezrin molecules at the interface. Mechanical properties were assessed by force indentation experiments followed by membrane tether extraction. PIP2 micelles were injected into individual living cells to reinforce the linkage between plasma membrane and actin-cortex, while weakening of this connection was reached by ezrin siRNA and administration of the inhibitors neomycin and NSC 668394, respectively. We observed substantial stiffening of cells and an increase in membrane tension after addition of PIP2 micelles. In contrast, reduction of active ezrin led to a decrease of membrane tension accompanied by loss of excess surface area, increase in cortical tension, remodelling of actin cytoskeleton, and reduction of cell height. The data confirm the importance of the ezrin-mediated connection between plasma membrane and cortex for cellular mechanics and cell morphology. PMID- 26435323 TI - Inhibition of myostatin in mice improves insulin sensitivity via irisin-mediated cross talk between muscle and adipose tissues. AB - BACKGROUND/OBJECTIVE: In mice, a high-fat diet (HFD) induces obesity, insulin resistance and myostatin production. We tested whether inhibition of myostatin in mice can reverse these HFD-induced abnormalities. SUBJECTS/METHODS: C57BL/6 mice were fed a HFD for 16 weeks including the final 4 weeks some mice were treated with an anti-myostatin peptibody. Body composition, the respiratory exchange ratio plus glucose and insulin tolerance tests were examined. Myostatin knock down in C2C12 cells was performed using small hairpin RNA lentivirus. Adipose tissue-derived stem cells were cultured to measure their responses to conditioned media from C2C12 cells lacking myostatin, or to recombinant myostatin or irisin. Isolated peritoneal macrophages were treated with myostatin or irisin to determine whether myostatin or irisin induce inflammatory mechanisms. RESULTS: In HFD-fed mice, peptibody treatment stimulated muscle growth and improved insulin resistance. The improved glucose and insulin tolerances were confirmed when we found increased muscle expression of p-Akt and the glucose transporter, Glut4. In HFD-fed mice, the peptibody suppressed macrophage infiltration and the expression of proinflammatory cytokines in both the muscle and adipocytes. Inhibition of myostatin caused the conversion of white (WAT) to brown adipose tissue, whereas stimulating fatty acid oxidation and increasing energy expenditure. The related mechanism is a muscle-to-fat cross talk mediated by irisin. Myostatin inhibition increased peroxisome proliferator-activated receptor gamma, coactivator 1alpha expression and irisin production in the muscle. Irisin then stimulated WAT browning. Irisin also suppresses inflammation and stimulates macrophage polarization from M1 to M2 types. CONCLUSIONS: These results uncover a metabolic pathway from an increase in myostatin that suppresses irisin leading to the activation of inflammatory cytokines and insulin resistance. Thus, myostatin is a potential therapeutic target to treat insulin resistance of type II diabetes as well as the shortage of brown/beige fat in obesity. PMID- 26435324 TI - IL-10 gene transfer upregulates arcuate POMC and ameliorates hyperphagia, obesity and diabetes by substituting for leptin. AB - BACKGROUND: Obesity and metabolic syndrome are the major risk factors for cardiovascular disease. Obesity is caused by increased food intake and/or decreased energy expenditure. Leptin potently inhibits food intake and promotes energy expenditure. These effects of leptin involve the activation of proopiomelanocortin (POMC) neurons in the hypothalamus arcuate nucleus (ARC). Disruption of leptin signaling in POMC neuron is considered one of the major causes for obesity. AIMS: The present study aimed to examine whether overexpression of interleukin-10 (IL-10) could substitute for the leptin action and ameliorate obesity in leptin-deficient Lep(ob/ob) mice. DESIGN: Adeno associated virus (AAV) expressing murine IL-10 (AAV-mIL-10) was injected into the skeletal muscle to overexpress IL-10 in mice. These mice were subsequently subjected to analysis of body weight, food intake, glucose metabolism and underlying mechanisms. RESULTS: In Lep(ob/ob) mice, AAV-IL-10 ameliorated hyperphagia, obesity, glucose intolerance and insulin resistance, as well as attenuated tumor necrosis factor-alpha expression. The IL-10 treatment also improved glucose-induced insulin release. Furthermore, IL-10 treatment increased POMC mRNA expression in ARC and phosphorylation of signal transducer and activator of transcription-3 (STAT3) in ARC and white adipose tissue (WAT). In neuron-specific STAT3-null mice that exhibited obesity and hyperphagia, AAV-mIL 10 administration failed to affect food intake, body weight and phosphorylation of STAT3 in WAT. CONCLUSIONS: These results demonstrate that peripheral overexpression of IL-10 induces STAT3 phosphorylation in ARC POMC neurons, and thereby ameliorates hyperphagia and obesity caused by leptin deficiency. IL-10 gene transfer may provide an effective approach for preventing progression of metabolic syndrome due to leptin resistance. PMID- 26435325 TI - Apigenin induced apoptosis in esophageal carcinoma cells by destruction membrane structures. AB - Apigenin has shown to have killing effects on some kinds of solid tumor cells. However, the changes in cell membrane induced by apigenin on subcellular- or nanometer-level were still unclear. In this work, human esophageal cancer cells (EC9706 and KYSE150 cells) were employed as cell model to detect the cytotoxicity of apigenin, including cell growth inhibition, apoptosis induction, membrane toxicity, etc. MTT assay showed that apigenin could remarkably inhibit the growth and proliferation in both types of cells. Annexin V/PI-based flow cytometry analysis showed that the cytotoxic effects of apigenin in KYSE150 cells were mainly through early apoptosis induction, while in EC9706 cells, necrosis, and apoptosis were both involved in cell death. The morphological and ultrastructural properties induced by apigenin were investigated at single cellular- or nanometer level using atomic force microscopy (AFM). Additionally, lactate dehydrogenase (LDH) leakage was measured to assess the changes in membrane permeability. The results indicated that apigenin increased the membrane permeability and caused leakage of LDH, which was consistent with damages on membrane ultrastructure detected by AFM. Therefore, membrane toxicity, including membrane ultrastructure damages and enhanced membrane permeability, played vital roles in apigenin induced human esophageal cancer cell apoptosis. SCANNING 38:322-328, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26435326 TI - Iron-Binding Capacity of Defatted Rice Bran Hydrolysate and Bioavailability of Iron in Caco-2 Cells. AB - The present study was aimed at utilizing defatted rice bran (DRB) protein as an iron-binding peptide to enhance iron uptake in humans. DRB samples were treated with Alcalase and Flavourzyme, and the total extractable peptides were determined. Furthermore, the iron-binding capacities of the DRB protein hydrolysates were determined, whereas iron bioavailability studies were conducted using an in vitro digestion and absorption model (Caco-2 cells). The results showed that the DRB protein hydrolysates produced by combined Alcalase and Flavourzyme hydrolysis had the best iron-binding capacity (83%) after 90 min of hydrolysis. The optimal hydrolysis time to produce the best iron-uptake in Caco-2 cells was found to be 180 min. The results suggested that DRB protein hydrolysates have potent iron-binding capacities and may enhance the bioavailability of iron, hence their suitability for use as iron-fortified supplements. PMID- 26435327 TI - Ultrafine FePd Nanoalloys Decorated Multiwalled Cabon Nanotubes toward Enhanced Ethanol Oxidation Reaction. AB - Ultrafine iron-palladium (FePd) nanoalloys deposited on gamma-Fe2O3, FePd-Fe2O3, further anchored on carboxyl multiwalled carbon nanotubes (MWNTs-COOH), FePd Fe2O3/MWNTs, were successfully synthesized by a facile one-pot solution based method as thermally decomposing palladium acetylacetonate (Pd(acac)2) and iron pentacarbonyl (Fe(CO)5) in a refluxing dimethylformamide solution in the presence of MWNTs-COOH. A 3.65 fold increase of peak current density was observed in cyclic voltammetry (CV) for ethanol oxidation reaction (EOR) compared with that of Pd/MWNTs after normalizing to Pd mass. The greatly enhanced tolerance stability toward poisoning species and largely reduced charge transfer resistance were also obtained in chronoamperometry and electrochemical impedance spectroscopy due to the downward shifted d-band center of FePd alloy, easily formed oxygen containing species on Fe2O3, and the stabilizing role of the MWNTs. PMID- 26435328 TI - Pathogenesis of solitary right aortic arch: a mass effect hypothesis based on observations of serial human embryonic sections. AB - In general, solitary right aortic arch carries the left-sided ductus arteriosus communicating between the left subclavian and pulmonary arteries or the right sided ductus connecting the descending aorta to the left pulmonary artery. Serial sections of fifteen 5- to 6-week-old embryos and ten 8- to 9-week-old fetuses suggested that the pathogenesis was unrelated to inversion due to dysfunction in gene cascades that control the systemic left/right axis. With inversion, conversely, the ductus or the sixth pharyngeal arch artery should connect to the right pulmonary artery. The disappearance of the right aortic arch started before the caudal migration of the aortic attachment of the ductus. Sympathetic nerve ganglia developed immediately posterior to both aortae, with a single embryonic specimen showing a large ganglion at the midline close to the union of the aortic arches. These ganglia may interfere with blood flow through the distal left arch, resulting in the ductus ending at the descending aorta behind the oesophagus. In another fetus examined, a midline shift of the ductus course resulted in the trachea curving posteriorly. Therefore, solitary right arch is likely to accompany abnormalities of the surrounding structures. The timing and site of the obstruction should be different between types: an almost midline obstruction near the aortic union needed for the development of the left-sided ductus and a distal obstruction near the left subclavian arterial origin needed for the development of the right-sided ductus. A mass effect of the sympathetic ganglia may explain the pathogenesis of any type of anomalous ductus arteriosus shown in previous reports of the solitary right arch. PMID- 26435329 TI - Morphology of the greater palatine grooves of the hard palate: a cone beam computed tomography study. AB - BACKGROUND: There is increasing frequency of dentoalveolar and palatal implants placed in the posterior maxilla for prosthodontic and orthodontic purposes. The purpose of this study is to provide information on the location and morphology of the greater palatine grooves (GPG) in the hard palate and to promote awareness of this structure. METHODS: Eighty-nine cone beam computed tomography (CBCT) scans were analysed for the presence of a groove, crest or bridging. RESULTS: This study on the morphology of the GPG in the maxillary first and second molar regions showed three distinct appearances: (1) no palatal groove; (2) one palatal groove; (3) two palatal grooves. The detection frequency of no palatal groove in the first molar region was 60%, 34% had one groove and 6% having two grooves. The detection frequency of no palatal groove in the second molar region was 72%, 26% had one groove and 2% had two grooves. The number of crests in the first and second molar regions ranged from 0 to 3. CONCLUSIONS: The present study demonstrates a great variation in morphology of the GPG of the hard palate. Knowledge of the GPG will decrease possible complications of implant surgery, particularly palatal implant surgery and to not confuse the GPG with pathology. PMID- 26435330 TI - Genetic diversity of clinical Mycobacterium avium subsp. hominissuis and Mycobacterium intracellulare isolates causing pulmonary diseases recovered from different geographical regions. AB - Mycobacterium avium complex (MAC) infections are increasing annually in many countries. MAC strains are the most common nontuberculous mycobacterial pathogens isolated from respiratory samples and predominantly consist of two species, Mycobacterium avium and Mycobacterium intracellulare. The aim of this study was to analyze the molecular epidemiology and genetic backgrounds of clinical MAC isolates collected from The Netherlands, Germany, United States, Korea and Japan. Variable numbers of tandem repeats (VNTR) analysis was used to examine the genetic relatedness of clinical isolates of M. avium subsp. hominissuis (n=261) and M. intracellulare (n=116). Minimum spanning tree and unweighted pair group method using arithmetic averages analyses based on the VNTR data indicated that M. avium subsp. hominissuis isolates from Japan shared a high degree of genetic relatedness with Korean isolates, but not with isolates from Europe or the United States, whereas M. intracellulare isolates did not show any specific clustering by geographic origin. The findings from the present study indicate that strains of M. avium subsp. hominissuis, but not M. intracellulare, exhibit geographical differences in genetic diversity and imply that MAC strains may have different sources, routes of transmission and perhaps clinical manifestations. PMID- 26435331 TI - Effects of eribulin on microtubule binding and dynamic instability are strengthened in the absence of the betaIII tubulin isotype. AB - Eribulin mesylate (Halaven) is a microtubule-targeted anticancer drug used to treat patients with metastatic breast cancer who have previously received a taxane and an anthracycline. It binds at the plus ends of microtubules and has been shown to suppress plus end growth selectively. Because the class III beta tubulin isotype is associated with resistance to microtubule targeting drugs, we sought to determine how betaIII tubulin might mechanistically influence the effects of eribulin on microtubules. We found that while [(3)H]eribulin bound to bovine brain soluble tubulin depleted of betaIII tubulin in a manner similar to that of unfractionated tubulin, it bound to plus ends of microtubules that were depleted of betaIII-depleted tubulin with a maximal stoichiometry (20 +/- 3 molecules per microtubule) higher than that of unfractionated microtubules (9 +/- 2 molecules per microtubule). In addition, eribulin suppressed the dynamic instability behavior of betaIII-depleted microtubules more strongly than and in a manner different from that of microtubules containing betaIII tubulin. Specifically, with betaIII tubulin present in the microtubules, 100 nM eribulin suppressed the growth rate by 32% and marginally reduced the catastrophe frequency (by 17%) but did not modulate the rescue frequency. However, in the absence of betaIII tubulin, eribulin not only reduced the growth rate but also strongly reduced the shortening rate (by 43%) and the catastrophe and the rescue frequencies (by 49 and 32%, respectively). Thus, when present in microtubules, betaIII tubulin substantially weakens the effects of eribulin. PMID- 26435332 TI - Solar Thermochemical Energy Storage Through Carbonation Cycles of SrCO3/SrO Supported on SrZrO3. AB - Solar thermochemical energy storage has enormous potential for enabling cost effective concentrated solar power (CSP). A thermochemical storage system based on a SrO/SrCO3 carbonation cycle offers the ability to store and release high temperature (~1200 degrees C) heat. The energy density of SrCO3/SrO systems supported by zirconia-based sintering inhibitors was investigated for 15 cycles of exothermic carbonation at 1150 degrees C followed by decomposition at 1235 degrees C. A sample with 40 wt % of SrO supported by yttria-stabilized zirconia (YSZ) shows good energy storage stability at 1450 MJ m(-3) over fifteen cycles at the same cycling temperatures. After further testing over 45 cycles, a decrease in energy storage capacity to 1260 MJ m(-3) is observed during the final cycle. The decrease is due to slowing carbonation kinetics, and the original value of energy density may be obtained by lengthening the carbonation steps. PMID- 26435334 TI - Comparative effectiveness of Pilates and yoga group exercise interventions for chronic mechanical neck pain: quasi-randomised parallel controlled study. AB - OBJECTIVES: To determine the effectiveness of Pilates and yoga group exercise interventions for individuals with chronic neck pain (CNP). DESIGN: Quasi randomised parallel controlled study. SETTING: Community, university and private practice settings in four locations. PARTICIPANTS: Fifty-six individuals with CNP scoring >=3/10 on the numeric pain rating scale for >3 months (controls n=17, Pilates n=20, yoga n=19). INTERVENTIONS: Exercise participants completed 12 small group sessions with modifications and progressions supervised by a physiotherapist. MAIN OUTCOME MEASURES: The primary outcome measure was the Neck Disability Index (NDI). Secondary outcomes were pain ratings, range of movement and postural measurements collected at baseline, 6 weeks and 12 weeks. Follow-up was performed 6 weeks after completion of the exercise classes (Week 18). RESULTS: NDI decreased significantly in the Pilates {baseline: 11.1 [standard deviation (SD) 4.3] vs Week 12: 6.8 (SD 4.3); mean difference -4.3 (95% confidence interval -1.64 to -6.7); P<0.001} and yoga groups [baseline: 12.8 (SD 7.4) vs Week 12: 8.1 (SD 5.6); mean difference -4.7 (95% confidence interval -2.1 to -7.4); P<0.00], with no change in the control group. Pain ratings also improved significantly. Moderate-to-large effect sizes (0.7 to 1.8) and low numbers needed to treat were found. There were no differences in outcomes between the exercise groups or associated adverse effects. No improvements in range of movement or posture were found. CONCLUSIONS: Pilates and yoga group exercise interventions with appropriate modifications and supervision were safe and equally effective for decreasing disability and pain compared with the control group for individuals with mild-to-moderate CNP. Physiotherapists may consider including these approaches in a plan of care. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01999283. PMID- 26435333 TI - Trimodal Therapy: Combining Hyperthermia with Repurposed Bexarotene and Ultrasound for Treating Liver Cancer. AB - Repurposing of existing cancer drugs to overcome their physical limitations, such as insolubility, represents an attractive strategy to achieve enhanced therapeutic efficacy and broaden the range of clinical applications. Such an approach also promises to offer substantial cost savings in drug development efforts. Here we repurposed FDA-approved topical agent bexarotene (Targretin), currently in limited use for cutaneous manifestations of T-cell lymphomas, and re engineer it for use in solid tumor applications by forming self-assembling nanobubbles. Physico-chemical characterization studies of the novel prodrug nanobubbles demonstrated their stability, enhanced target cell internalization capability, and highly controlled release profile in response to application of focused ultrasound energy. Using an in vitro model of hepatocellular carcinoma and an in vivo large animal model of liver ablation, we demonstrate the effectiveness of bexarotene prodrug nanobubbles when used in conjunction with catheter-based ultrasound, thereby highlighting the therapeutic promise of this trimodal approach. PMID- 26435336 TI - Key interactions of surfactants in therapeutic protein formulations: A review. AB - Proteins as amphiphilic, surface-active macromolecules, demonstrate substantial interfacial activity, which causes considerable impact on their multifarious applications. A commonly adapted measure to prevent interfacial damage to proteins is the use of nonionic surfactants. Particularly in biotherapeutic formulations, the use of nonionic surfactants is ubiquitous in order to prevent the impact of interfacial stress on drug product stability. The scope of this review is to convey the current understanding of interactions of nonionic surfactants with proteins both at the interface and in solution, with specific focus to their effects on biotherapeutic formulations. PMID- 26435335 TI - The Association of Statin Use with Age-Related Macular Degeneration Progression: The Age-Related Eye Disease Study 2 Report Number 9. AB - PURPOSE: To evaluate the association of statin use with progression of age related macular degeneration (AMD). DESIGN: Preplanned, prospective cohort study within a controlled clinical trial of oral supplementation for age-related eye diseases. PARTICIPANTS: Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50 to 85 years. METHODS: Factors, including age, gender, smoking status, aspirin use, and history of diabetes, hypertension, heart disease, angina, and stroke-all known to be associated with statin use-were included in a logistic regression model to estimate propensity scores for each participant. Age-adjusted proportional hazards regression models, with and without propensity score matching, were performed to evaluate the association of statin use with progression to late AMD. Analyses adjusting for the competing risk of death were also performed. MAIN OUTCOME MEASURES: Baseline and annual stereoscopic fundus photographs were assessed centrally by masked graders for the development of late AMD, either neovascular AMD or geographic atrophy (GA). RESULTS: Of the 3791 participants (2462 with bilateral large drusen and 1329 with unilateral late AMD at baseline), 1659 (43.8%) were statin users. The overall analysis, with no matching of propensity scores and no adjustment for death as a competing risk, showed that statin use was not associated with progression to late AMD (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.83-1.41; P = 0.56). When matched for propensity scores and adjusted for death as a competing risk, the result was not statistically significant (HR, 0.81; 95% CI, 0.55-1.20; P = 0.29). Furthermore, subgroup analyses of persons with or without late AMD at baseline and the various components of late AMD (neovascular AMD, central GA, or any GA) also showed no statistically significant association of statin use with progression to AMD. CONCLUSIONS: Statin use was not statistically significantly associated with progression to late AMD in the AREDS2 participants, and these findings are consistent with findings in the majority of previous studies. Statins have been demonstrated to reduce the risk of cardiovascular disease, but our data do not provide evidence of a beneficial effect on slowing AMD progression. PMID- 26435337 TI - Electrophoretic RNA genomic profiles of Brazilian Picobirnavirus (PBV) strains and molecular characterization of a PBV isolated from diarrheic calf. AB - Picobirnavirus (PBV) belongs to the family Picobirnaviridae. PBV are a group of emerging non-enveloped viruses, with a bisegmented double-stranded RNA genome that can infect a wide range of hosts. This study reports the occurrence of PBV in fecal samples from five Brazilian dairy cattle herds. From the 289 stool samples of individual calves analyzed by silver-stained polyacrylamide gel electrophoresis (ss-PAGE) the PBV was detected in 8.3 % (24/289), of which 10.2% (18/176) had diarrheic consistency. Of the 24 positive samples in ss-PAGE, 5 (20.8%) of them showed a small electrophoretic profile and 19 (79.2%) samples had large profile. From the 24 positives samples by ss-PAGE, 15 (62.5%) were successfully amplified (201 bp) using GI specific primers targeting the RdRp gene of PBV. The analysis of nucleotide identity matrix revealed that the bovine PBV strain identified in this study, showed the highest nucleotide identity (81%) with PBV strain detected in turkey (MD-2010/HM803965). This is the first nucleotide sequence of a bovine PBV strain in the American continent and the first detection of small genome profile of PBV-like strains in bovine hosts. PMID- 26435338 TI - Purification and characterization of saxitoxin from Mytilus chilensis of southern Chile. AB - In the current communication we describe an innovative method to purify saxitoxin (STX), a toxin presents in contaminated muscle of Mylitus chilensis extracted in the southern part of Chile, using a liquid chromatographic methodology based on ionic pairs. The STX was extracted using HCl and treated with ammonium sulfate following a treatment with trichloroacetic acid and hexane/diethyl ether (97/3). The samples were analyzed by a semi-preparative HPLC in order to collect pure fractions of STX and these fractions were eluted in solid-phase cationic interchange SCX extraction columns. The purified STX was stable and homogeneous and its identity was confirmed by LC-MS-MS, which demonstrated a high quality purification of STX, without presence of analogs such as neosaxitoxin (Neo) and decarbamoyl saxitoxin (dcSTX). The STX biological activity was analyzed in a bioassay in mice model and compared to the standard STX produced by the FDA and no significant differences were observed. PMID- 26435339 TI - Effects of long-term administration of Senna occidentalis seeds on the hematopoietic tissue of rats. AB - Senna occidentalis (S. occidentalis) is a toxic leguminous plant that contaminates crops and has been shown to be toxic to several animal species. All parts of the plant are toxic, but most of the plant's toxicity is due to its seeds. Despite its toxicity, S. occidentalis is widely used for therapeutic purposes in humans. The aim of the present work was to investigate, for the first time, the effects of the chronic administration of S. occidentalis seeds on hematopoietic organs, including the bone marrow and spleen. Fifty male Wistar rats were divided into five groups of 10 animals. Rats were treated with diets containing 0% (control), 0.5% (So0.5), 1% (So1), or 2% (So2) S. occidentalis seeds for a period of 90 days. Food and water were provided ad libitum, except to pair-fed (PF) group which received the same amount of ration to those of So2 group, however free of S. occidentalis seeds. It was verified that rats treated with 2% S. occidentalis seeds presented changes in hematological parameters. The blood evaluation also showed a significant decrease of the Myeloid/Erythroid (M/E) ratio. Chronic treatment with S. occidentalis promoted a reduction in the cellularity of both the bone marrow and spleen. Additionally, we observed changes in bone marrow smears, iron stores and spleen hemosiderin accumulation. Histological analyses of bone marrow revealed erythroid hyperplasia which was consistent with the increased reticulocyte count. These findings suggest that the long-term administration of S. occidentalis seeds can promote blood toxicity. PMID- 26435340 TI - Characterization of the antinociceptive effect of PhTx3-4, a toxin from Phoneutria nigriventer, in models of thermal, chemical and incisional pain in mice. AB - Venom-derived peptides constitute a unique source of drug prototypes for the pain management. Many of them can modulate voltage-gated calcium channels that are central in the processing of pain sensation. PhTx3-4 is a peptide isolated from Phoneutria nigriventer venom, which blocks high voltage-activated calcium channels with low specificity, thereby leading to neuroprotection in models of ischemia in vitro. The aim of the present work was evaluating the potential of intrathecal PhTx3-4 in the reversal of different nociceptive states in mice, furthermore assessing the potential of PhTx3-4 in triggering motor side effects. We found that bellow 100 pmol/site, PhTx3-4 did not cause major motor side effects. By comparison, omega-conotoxin MVIIA and omega-conotoxin MVIIC triggered motor side effects at the doses of 10 and 100 pmol/site, respectively. Also, PhTx3-4 (30 pmol/site) caused no significant alterations in the forced locomotor activity test (rotarod) and in the exploratory activity test (versamax). In a model of inflammatory persistent pain (formalin test), PhTx3-4 reversed nociceptive behavior both pre or post-administered, although this effect was observed only at the inflammatory phase of the test and not at the neurogenic phase. Comparatively, omega-conotoxin MVIIC was effective only when post administered in the formalin test. Nonetheless, PhTx3-4 treatment was devoid of action in acute nociceptive thermal model (hotplate test), whereas morphine showed efficacy in this test. Efficacy of PhTx3-4 in the formalin test was associated with inhibition of formalin-induced glutamate release in the cerebrospinal fluid. PhTx3-4, but not omega-conotoxin MVIIC, reversed NMDA induced nociceptive behavior indicating a putative role of PhTx3-4 at ionotropic glutamate receptors. Finally, we observed efficacy of PhTx3-4 in ameliorating mechanical hypersensitivity induced by paw incision, a post-operative and more clinically relevant pain model. Taken together, our data show that PhTx3-4 possesses antinociceptive effect in different models of pain in mice, suggesting that this toxin may serve as drug prototype for pain control. PMID- 26435341 TI - Recombinant expression and predicted structure of parborlysin, a cytolytic protein from the Antarctic heteronemertine Parborlasia corrugatus. AB - The heteronemertine Parborlasia corrugatus contains a cytolytic protein, parborlysin, which after extensive purification was found by Edman sequencing to be a mixture of several homologues. To investigate this microheterogeneity and enable the analysis of single toxins, we have obtained seven parborlysin isoform genes from P. corrugatus collected in Antarctica. Total RNA was isolated from the homogenized head region and parborlysin genes were identified from a cDNA library using degenerate primers. The translated sequences reveal that the isoforms are ~ 10 kDa basic (pI ~ 10) proteins of which all but one harbour six cysteine residues. We generated a model of the three dimensional structure of parborlysins, which suggests that they are composed of five alpha-helical segments that include large, exposed hydrophobic surfaces. Finally, we constructed plasmids and inserted them into Escherichia coli to obtain overexpressed amino- or carboxy-terminal polyhistidine-tagged parborlysin isoforms fused to the third domain of the E. coli periplasmic-protein TolA to facilitate toxin isolation. One of the isoforms adversely affected growth in the E. coli expressing it. Although we succeeded in isolating one of the recombinant parborlysin constructs, it lacked haemolytic activity. PMID- 26435342 TI - cDNA cloning and expression of Contractin A, a phospholipase A2-like protein from the globiferous pedicellariae of the venomous sea urchin Toxopneustes pileolus. AB - Venomous sea urchins contain various biologically active proteins that are toxic to predators. Contractin A is one such protein contained within the globiferous pedicellariae of the venomous sea urchin Toxopneustes pileolus. This protein exhibits several biological activities, such as smooth muscle contraction and mitogenic activity. N-terminal amino acid residues of Contractin A have been determined up to 37 residues from the purified protein. In this study, we cloned cDNA for Contractin A by reverse transcription-PCR using degenerate primers designed on the basis of its N-terminal amino acid sequence. Analysis of the cDNA sequence indicated that Contractin A is composed of 166 amino acid residues including 31 residues of a putative signal sequence, and has homology to the sequence of phospholipase A2 from various organisms. In this study, recombinant Contractin A was expressed in Escherichia coli cells, and the protein was subjected to an assay to determine lipid-degrading activity using carboxyfluorescein-containing liposomes. As a result, Contractin A was found to exhibit Ca(2+)-dependent release of carboxyfluorescein from the liposomes, suggesting that Contractin A has phospholipase A2 activity, which may be closely associated with its biological activities. PMID- 26435344 TI - A Cell ELISA for the quantification of MUC1 mucin (CD227) expressed by cancer cells of epithelial and neuroectodermal origin. AB - Quantitative analysis of MUC1, a cell membrane associated mucin, expressed by intact cells of epithelial origin previously has been limited to flow cytometry, which requires using large quantities of cells and antibodies. Here, for the first time, we report the development of a novel Cellular-based Enzyme Linked Immunosorbent Assay (Cell ELISA) to quantify the expression of MUC1 by cell lines of epithelial and neuroectodermal origin using an antibody recognizing a specific tandem repeat found in the extracellular domain of MUC1. In contrast to flow cytometry, this method requires a much lower number of cells. We report here the results obtained from two variants of this Cell ELISA in live and fixed cells. We found that the Cell ELISA in live cells was not sensitive enough to detect a difference in MUC1 levels between the normal cells and tumor cells. However, we found that Cell ELISA in fixed cells followed by whole cell staining was a dependable method of MUC1 level detection in the normal and tumor cells showing significantly higher levels of MUC1 receptor in the tumor cells when compared to the normal controls. Therefore, we conclude that the Cell ELISA in fixed cells is an efficient method for quantifying the expression of MUC1 by epithelial and neuroectodermal cancer cell lines. PMID- 26435345 TI - T cell response to FVIII. AB - Several lines of evidence indicate that the immune response to Factor VIII (FVIII) in patients with hemophilia A is T cell-dependent. This review highlights the link between the epitope specificity of FVIII-specific T cells and their potential roles in different categories of patients. FVIII-specific T cells able to recognize wild-type (i.e. therapeutic) FVIII but not the mutated self FVIII of hemophilia patients have been identified in patients with mild/moderate hemophilia carrying some point mutations. Such T cells likely contribute to the higher frequency of neutralizing anti-FVIII antibodies (inhibitors) development in these patients. In contrast, as yet no T cells have been identified that can differentiate between FVIII molecules with non-hemophilia-causing single amino acid variants encoded by non-synonymous single-nucleotide polymorphisms in the F8 gene. Other mechanisms are therefore still to be identified that will explain the clinically noted differences in the incidence of inhibitor development between patients of different races who are known to have differences at these sites. Beside information about the mechanism of inhibitor development, the analysis of FVIII-specific T cells has provided tools to develop novel diagnostic and therapeutic approaches, such as the generation of FVIII-specific regulatory T cells that may be useful in preventing or suppressing the immune response to FVIII. PMID- 26435343 TI - Tolerance and immune suppression in the tumor microenvironment. AB - The concept of immunological tolerance has guided and permeated much of modern immunology. Ray Owen's ground-breaking observations in twin cattle provided the first mechanistic explanation for tolerance to self-molecules and established tolerance as a beneficial process that protects the host against autoreactivity. However, his studies also opened the door to understanding that tolerance may be detrimental, such as occurs when cancer cells induce tolerance/immune suppression resulting in inhibition of anti-tumor immunity. This article briefly traces the early history of the field of tumor immunology with respect to tolerance, and then focuses on a relatively recently identified population of cells called myeloid-derived suppressor cells (MDSCs). MDSC are instrumental in causing tolerance/immune suppression in individuals with cancer. They are present in most individuals with cancer and because of their potent immune suppressive activity are a major deterrent to natural anti-tumor immunity and a significant obstacle to immunotherapy. PMID- 26435346 TI - Senescence as a general cellular response to stress: A mini-review. AB - Cellular senescence was initially described as the phenomenon of limited cell divisions that normal cells in culture can undergo during long-term-cultivation. Later it was found that senescence may be induced by various stress factors. The intriguing resemblance between stress-induced and replicative senescence makes questionable the distinction between both types and suggests that the cellular senescence is a common outcome of stress response. Growing evidences support the idea that stress-induced senescence is the cell-type specific. PMID- 26435347 TI - Absence of caveolin-1 leads to delayed development of chronic lymphocytic leukemia in EMU-TCL1 mouse model. AB - Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States. The tissue microenvironment, specifically the lymph nodes, influences the biological and clinical behavior of CLL cells. Gene expression profiling of CLL cells from peripheral blood, bone marrow, and lymph nodes revealed Cav-1 as one of the genes that might be involved in the pathogenesis of CLL. We have previously reported that the knockdown of Cav-1 in primary CLL cells exhibits a significant decrease in cell migration and immune synapse formation. However, the precise role of Cav-1 in CLL initiation and progression in vivo is not known. Therefore, we decreased the expression of Cav-1 in vivo by breeding EMU-TCL1 with cav-1 knockout mice. We observed a significant decrease in the number of CLL cells and rate of proliferation of CLL cells in spleen, liver, and bone marrow from EMU-TCL1-Cav1(-/+) and EMU-TCL1-Cav1(-/-) mice as compared with EMU-TCL1 mice. In addition, there was a significant increase in survival of EMU TCL1-Cav1(-/+) and EMU-TCL1-Cav1(-/-) compared with EMU-TCL1 mice. Mechanistically, we observed a decrease in MAPK-Erk signaling measured by p-Erk levels in EMU-TCL1-Cav1(-/+) mice when compared with EMU-TCL1-Cav(wt/wt). Together these results indicate that decreased Cav-1 in EMU-TCL1 mice significantly delays the onset of CLL and decreases leukemic progression by inhibiting MAPK-Erk signaling, suggesting a role for Cav-1 in the proliferation and progression of CLL. PMID- 26435348 TI - Pac-Man for biotechnology: co-opting degrons for targeted protein degradation to control and alter cell function. AB - Protein degradation in normal living cells is precisely regulated to match the cells' physiological requirements. The selectivity of protein degradation is determined by an elaborate degron-tagging system. Degron refers to an amino acid sequence that encodes a protein degradation signal, which is oftentimes a poly ubiquitin chain that can be transferred to other proteins. Current understanding of ubiquitination dependent and independent protein degradation processes has expanded the application of degrons for targeted protein degradation and novel cell engineering strategies. Recent findings suggest that small molecules inducing protein association can be exploited to create degrons that target proteins for degradation. Here, recent applications of degron-based targeted protein degradation in eukaryotic organisms are reviewed. The degron mediated protein degradation represents a rapidly tunable methodology to control protein abundance, which has broad application in therapeutics and cellular function control and monitoring. PMID- 26435349 TI - Brain size and thermoregulation during the evolution of the genus Homo. AB - Several hypotheses have been proposed to explain the evolution of an energetically costly brain in the genus Homo. Some of these hypotheses are based on the correlation between climatic factors and brain size recorded for this genus during the last millions of years. In this study, we propose a complementary climatic hypothesis that is based on the mechanistic connection between temperature, thermoregulation, and size of internal organs in endothermic species. We hypothesized that global cooling during the last 3.2 my may have imposed an increased energy expenditure for thermoregulation, which in the case of hominids could represent a driver for the evolution of an expanded brain, or at least, it could imply the relaxation of a negative selection pressure acting upon this costly organ. To test this idea, here we (1) assess variation in the energetic costs of thermoregulation and brain maintenance for the last 3.2 my, and (2) evaluate the relationship between Earth temperature and brain maintenance cost for the same period, taking into account the effects of body mass and fossil age. We found that: (1) the energetic cost associated with brain enlargement represents an important fraction (between 47.5% and 82.5%) of the increase in energy needed for thermoregulation; (2) fossil age is a better predictor of brain maintenance cost than Earth temperature, suggesting that (at least) another factor correlated with time was more relevant than ambient temperature in brain size evolution; and (3) there is a significant negative correlation between the energetic cost of brain and Earth temperature, even after accounting for the effect of body mass and fossil age. Thus, our results expand the current energetic framework for the study of brain size evolution in our lineage by suggesting that a fall in Earth temperature during the last millions of years may have facilitated brain enlargement. PMID- 26435350 TI - Gut morphology and hepatic oxidative status of European sea bass (Dicentrarchus labrax) juveniles fed plant feedstuffs or fishmeal-based diets supplemented with short-chain fructo-oligosaccharides and xylo-oligosaccharides. AB - The effects of short-chain fructo-oligosaccharides (scFOS) and xylo oligosaccharides (XOS) on gut morphology and hepatic oxidative status were studied in European sea bass juveniles weighing 60 g. Fish were fed diets including fishmeal (FM diets) or plant feedstuffs (PF diets; 30 FM:70 PF) as main protein sources (control diets). Four other diets were formulated similar to the control diets but including 1 % scFOS or 1 % XOS. At the end of the trial, fish fed PF-based diets presented histomorphological alterations in the distal intestine, whereas only transient alterations were observed in the pyloric caeca. Comparatively to fish fed FM-based diets, fish fed PF diets had higher liver lipid peroxidation (LPO), superoxide dismutase (SOD) and catalase (CAT) activities, and lower glutathione peroxidase, glutathione reductase and glucose 6 phosphate dehydrogenase activities. In fish fed the PF diets, prebiotic supplementation decreased SOD activity and XOS supplementation further decreased CAT activity. In fish fed the FM diets, XOS supplementation promoted a reduction of all antioxidant enzyme activities. Overall, dietary XOS and scFOS supplementation had only minor effects on gut morphology or LPO levels. However, dietary XOS reduced antioxidant enzymatic activity in both PF and FM diets, which indicate a positive effect on reduction of hepatic reactive oxygen species production. PMID- 26435351 TI - Implementing the Incident Command System into a Community Health System. PMID- 26435352 TI - When Someone Dies in the Emergency Department: Perspectives of Emergency Nurses. AB - Emergency nurses work in a clinical area where treatment measures usually are provided quickly, and they have little time to establish relationships. In addition to performing life-saving interventions, emergency nurses provide care for patients who are dying. Little is known about the experiences of emergency nurses who care for patients who die in the emergency department in the Canadian context. METHODS: This study used a qualitative design with an interpretive descriptive approach. Semistructured interviews were conducted with 11 ED nurses from a large Canadian academic health sciences system. RESULTS: In-depth analysis of the data resulted in 3 major themes: "It's not a nice place to die," "I see the grief," and "Needing to know you've done your best." Findings revealed that emergency nurses believed the environment made it difficult to care for dying patients and their families because of unpredictability, busyness, noise, lack of privacy, and the need to manage many patients simultaneously. These nurses were also put in the position of caring for the suddenly bereaved family members, which was viewed as an especially challenging aspect of their role. DISCUSSION: Caring for adults who die in the emergency department is a difficult and challenging aspect of the emergency nursing role. Emergency nurses believed they did their best to provide end-of-life care interventions, which brought a sense of professional satisfaction. Recommended future interventions include advocating for ED design and physical layout to support compassionate end-of-life care, provision of policies and training to support families and family presence, and support of nursing staff. PMID- 26435353 TI - Mental Status Changes--A Red Flag. PMID- 26435354 TI - A Systematic Review of Evidence on the Use of Very Low Calorie Diets in People with Diabetes. AB - BACKGROUND: Recent interest has emerged regarding the effects of Very Low Calorie Diet (VLCD) in people with type 2 diabetes (T2D). We therefore performed a systematic review to investigate the effects of VLCD on HbA1c, weight and cardiovascular risk profile outcomes as well as its safety and tolerability among people with T2D. METHODS: We conducted searches of Cochrane Database of Systematic Reviews, Centre for reviews and Dissemination databases, Medline, Embase, Pubmed, Web of Science, Web of Knowledge and Turning Research into Practice (TRIP) as well as ongoing trial resources. We included all studies involving VLCD and diabetes published until December 2013. Outcome measures include weight, HbA1c, fasting glucose, fasting insulin, lipid profile, blood pressure, safety and drop out rates. RESULTS: 17 studies were included in the systematic review. Duration of VLCD duration ranged from 5 days to 6 months and duration of follow up ranged from 8 days to 5 years. The age range was 14 years to 59 years of age. Mean weight loss was 13.2kg, ranging from 4.1 to 24kg. Mean Hba1c reduction was 1.4% (ranging between 0.1 to 3.1% reduction across different studies). Three studies reported a significant reduction in the daily doses of insulin. All studies which reported cardiovascular risk profile showed a significant decrease in total cholesterol, systolic and diastolic blood pressure post VLCD. Apart from two studies, all of the other studies showed that the decrease in blood pressure and total cholesterol was not only present immediately post VLCD, but it was also maintained at follow up. However it is important to note that the follow up periods did differ between studies. Overall, drop out rates ranged from 4.7% to 33% and appeared to be lower during the active intervention phase compared with during the follow-up period. No major adverse event was reported apart from one study which recorded a non-fatal myocardial infarction. CONCLUSION: This review demonstrated that VLCD in people with T2D was associated with significant weight loss, reduction in blood glucose profile and improvement in cardiovascular risk profile, high tolerability and good safety outcomes. Studies were heterogeneous and longer term outcomes data post VLCD is still required. PMID- 26435355 TI - Persistence length of dendronized polymers: the self-consistent field theory. AB - We present numerical results for the thermodynamic rigidity and induced persistence length of dendronized polymers with systematically varied topology of their grafts obtained by the Scheutjens-Fleer self-consistent field method. The results were compared to predictions of an analytical mean-field theory. The two approaches have marked different predictions. In particular, the analytical theory predicts that the induced persistence length and the effective segment aspect ratio of dendronized polymers are increasing functions of the degree of branching of their side chains, whereas numerical calculations provide evidence of the opposite dependences. This discrepancy is argued to be due to the ability of side chains to repartition from the compressed to the dilated regions of a curved bottle brush, which is accounted for by the numerical, but not by the analytical method. The difference is most crucial in the light of the expected ability of dendronized polymers to have a liquid crystalline ordering in semi dilute solutions. PMID- 26435356 TI - Policies to foster quality improvement registries: lessons from the Swedish case. AB - BACKGROUND AND OBJECTIVES: Multi-institutional quality improvement registries (QI registries) are a promising approach to quality improvement. They are also used for clinical research, public quality reporting and other valuable purposes. The aim of this study was to identify elements and outcomes of national policies to promote registries in Sweden and to compare them with recent policies in the USA. METHODS: This case study draws on previous studies of Swedish registries and on interviews, observations and document studies conducted in Sweden and the USA. RESULTS: In Sweden, registries are fostered by favourable patient data regulation and an indirect control approach combining government funding with soft regulation and professional self-governance. This enables the development of high quality QI registries which are used for improvements by engaged clinicians, for clinical research and for decision support for practitioners and stakeholders. For example, Riks-HIA/Swedeheart achieved improved outcomes in cardiac intensive care, SCAAR/Swedeheart was used in a unique registry-based randomized trial, and the Swedish Rheumatology Quality Register provides a Web interface for patient encounters and clarifies adverse effects of biologic drugs. Still, the system has persistent limitations, especially the administrative burden on participants. In the USA, Medicare's programme for qualified clinical data registries and other recent changes mirror Swedish policies. Automated data capture is a US advantage, but uncertain funding and complex data regulations stall registry development in the USA. CONCLUSION: The findings of this study indicate that tailor-made data regulation and a soft regulatory policy approach foster high-quality QI registries with multiple meaningful uses. These findings offer a framework for further cross-country comparative study to evaluate registry policies. PMID- 26435357 TI - Complete hydrogen release from aqueous ammonia-borane over a platinum-loaded titanium dioxide photocatalyst. AB - Complete H2 release from ammonia-borane (NH3BH3, AB) in water was achieved by using platinum-loaded TiO2 (Pt/TiO2) via two consecutive reaction steps, i.e., hydrolysis of AB and photocatalytic decomposition of thus formed NH3 in water, under inert conditions at 298 K. PMID- 26435358 TI - Natural inorganic nanoparticles--formation, fate, and toxicity in the environment. AB - The synthesis, stability, and toxicity of engineered metal nanoparticles (ENPs) have been extensively studied during the past two decades. In contrast, research on the formation, fate, and ecological effects of naturally-occurring nanoparticles (NNPs) has become a focus of attention only recently. The natural existence of metal nanoparticles and their oxides/sulfides in waters, wastewaters, ore deposits, mining regions, and hydrothermal vents, as exemplified by the formation of nanoparticles containing silver and gold (AgNPs and AuNPs), Fe, Mn, pyrite (FeS2), Ag2S, CuS, CdS, and ZnS, is dictated largely by environmental conditions (temperature, pH, oxic/anoxic, light, and concentration and characteristics of natural organic matter (NOM)). Examples include the formation of nanoparticles containing pyrite, Cu and Zn-containing pyrite, and iron in hydrothermal vent black smoker emissions. Metal sulfide nanoparticles can be formed directly from their precursor ions or indirectly by sulfide ion assisted transformation of the corresponding metal oxides under anaerobic conditions. This tutorial focuses on the formation mechanisms, fate, and toxicity of natural metal nanoparticles. Natural waters containing Ag(I) and Au(III) ions in the presence of NOM generate AgNPs and AuNPs under thermal, non-thermal, and photochemical conditions. These processes are significantly accelerated by existing redox species of iron (Fe(II)/Fe(III)). NOM, metal-NOM complexes, and reactive oxygen species (ROS) such as O2(-), OH, and H2O2 are largely responsible for the natural occurrence of nanoparticles. AgNPs and AuNPs emanating from Ag(I)/Au(III)-NOM reactions are stable for several months, thus indicating their potential to be transported over long distances from their point of origin. However, endogenous cations present in natural waters can destabilize the nanoparticles, with divalent cations (e.g., Ca(2+), Mg(2+)) being more influential than their monovalent equivalents (e.g., Na(+), K(+)). The toxicity of NNPs may differ from that of ENPs because of differences in the coatings on the nanoparticle surfaces. An example of this phenomenon is presented and is briefly discussed. PMID- 26435359 TI - Development of the pancreas in medaka, Oryzias latipes, from embryo to adult. AB - To address conserved and unique features of fish pancreas development, we performed extensive analyses of pancreatic development in medaka embryos and adults using pdx1- and ptf1a-transgenic medaka, in situ hybridization and immunohistochemistry. The markers used in these analyses included pdx1, nkx6.1, nkx6.2, nkx2.2, Islet1, insulin, Somatostatin, glucagon, ptf1a, ela3l, trypsin, and amylase. The double transgenic (Tg) fish produced in the present study visualizes the development of endocrine (pdx1+) and exocrine (ptf1a+) parts simultaneously in living fishes. Like other vertebrates, the medaka pancreas develops as two (dorsal and ventral) buds in the anterior gut tube, which soon fuse into a single anlagen. The double Tg fish demonstrates that the differential property between the two buds is already established at the initial phase of bud development as indicated by strong pdx1 expression in the dorsal one. This Tg fish also allowed us to examine the gross morphology and the structure of adult pancreas and revealed unique characters of medaka pancreas such as broad and multiple connections with the gut tube along the anterior-posterior axis. PMID- 26435360 TI - Local co-delivery of rhBMP-2 and cathepsin K inhibitor L006235 in poly(d,l lactide-co-glycolide) nanospheres. AB - Cathepsin K inhibitors (CKIs) are an emerging class of drugs that are potent antagonists of osteoclastic activity. We speculated that they may be beneficial in bone tissue engineering, where a stress shielded environment can lead to rapid resorption of new bone. Most CKIs require frequent dosing, so to achieve a sustained release we manufactured polymer nanoparticles encapsulating the CKI L006235 (CKI/nP). CKI/nP and the collagen matrices that were used to deliver them were characterized by electron microscopy and fluorescent confocal microscopy, and data indicated that the particles were evenly distributed throughout the collagen. Elution studies indicated a linear release of the inhibitor from the CKI/nP, with approximately 2% of the drug being released per day. In an in vivo study, mice were implanted with collagen scaffolds containing rhBMP-2 that were loaded with the CKI/nP. Measurement of bone volume (BV) by microCT showed no significant increase with CKI/nP incorporation, and other parameters similarly showed no statistical differences. Cell culture studies confirmed the activity of the drug, even at low concentrations. These data indicate that polymer nanoparticles are an effective method for sustained drug delivery of a CKI, however, this may not be readily translatable to substantively improved bone tissue engineering outcomes. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 136-144, 2017. PMID- 26435361 TI - Steroidogenesis by testis and accessory glands of the Lusitanian toadfish, Halobatrachus didactylus, during reproductive season. AB - In teleost fish sex steroids are essential for gonadal function and have marked effects in reproductive and agonistic behavior and in the expression of secondary sexual characteristics. The Lusitanian toadfish, Halobatrachus didactylus, has two male morphotypes: type I males are territorial nest-holders and have large accessory glands while type II males are smaller, have a relatively large testis and small accessory glands. In the present study, the steroidogenic activity of the testis and accessory testicular glands of the Lusitanian toadfish were examined in vitro as well as their presence in urine. The testis of type I males produced 11-ketotestosterone (11KT) and 11beta-hydroxy-4-androstene-3,17-dione (11betaA) from tritiated 17-hydroxyprogesterone, while those of type II males produced testosterone (T) and 11beta,17beta-dihydroxy-4-andosten-3-one (11betaT), but not 11KT. Additionally, the testis and accessory glands of both morphs produced mostly 5beta,3alpha-reduced and 17,20alpha-hydroxylated metabolites. Type I, but not of type II, males synthesised 5beta-reduced androgens in their accessory glands. The presence of 11betaA exclusively in the urine of type I males during reproductive season suggests an association with maintenance of secondary sexual characteristics and behavior in this morph. The urine of both types of males contained two 5alpha-androstane and 5beta-pregnane glucuronides. Among the latter steroids, those that are 17,21-dihydroxylated are potentially metabolites from cortisol and were found only in type I males during the spawning season. The diversity of metabolites produced by the testis and accessory glands and the presence of some in urine is suggestive of a potential role in chemical communication and reproductive behavior. PMID- 26435362 TI - Controlled generation of highly saddled (porphyrinato)iron(III) iodide, tri iodide and one-electron oxidized complexes. AB - For the first time, three iron(III) porphyrinato complexes have been synthesized selectively by varying the iodine concentration in the reaction mixture which eventually forms both five and six coordinate complexes with iodide and/or tri iodide as axial ligands. Combined analysis using single crystal X-ray structure determination, and Mossbauer, (1)H NMR and EPR studies as well as VT magnetic studies has revealed the admixed-intermediate (iodo complex), pure intermediate (tri-iodide complex) and high-spin (1e-oxidized complex) states of iron. PMID- 26435364 TI - Influence of dose reduction of vincristine in R-CHOP on outcomes of diffuse large B cell lymphoma. AB - Dose intensity (DI) of chemotherapy affects prognosis of diffuse large B cell lymphoma (DLBCL). Myelotoxicity is the major dose-limiting toxicity (DLT) of most cytotoxic agents for hematological malignancies, whereas DLT of vincristine (VCR) is mainly neurological toxicity. Although VCR is a key drug and its combination with other cytotoxic agents needs consideration, studies focused on relative DI (RDI) of VCR have not been done before. We retrospectively analyzed 86 cases of DLBCL that received six or more cycles of cyclophosphamide (CPM), doxorubicin (DXR), VCR, prednisolone, and rituximab [R-CHOP] and calculated RDI of each cytotoxic agent to analyze its influence on treatment outcome. The median RDI of CPM, doxorubicin, and VCR was 80.0, 81.7, and 78.4 %, respectively (p = 0.002). The average RDI (ARDI) of these three agents was 80.0 %. The overall survival was significantly worse in the low ARDI (<85 %) than in the high ARDI (>85 %) group (2-year survival rate 67.2 vs 93.4 %, p = 0.011). The survival rate with low RDI VCR (<85 %) was lower than that with high RDI VCR (>85 %), even when the remaining two agents had high ARDI (2-year survival rate 74.3 vs 95.8 %, p = 0.047). In conclusion, VCR dose tended to be reduced compared with CPM and DXR in R-CHOP. Lower ARDI of cytotoxic agents and lower RDI of VCR could lead to poor prognosis in the treatment of DLBCL with R-CHOP. We thought these observations should be confirmed in a prospective study. PMID- 26435363 TI - Daylight photodynamic therapy with methyl aminolevulinate cream is effective and nearly painless in treating actinic keratoses: a randomised, investigator blinded, controlled, phase III study throughout Europe. AB - BACKGROUND: Unmet needs exist in actinic keratosis (AK) treatment. Daylight photodynamic therapy (DL-PDT) has shown good efficacy and safety results compared to conventional PDT (c-PDT) in a recent Phase III multi-centre randomised controlled trial in Australia among 100 subjects with AKs. OBJECTIVES: Demonstrate non-inferior efficacy and superior safety of DL-PDT compared to c-PDT in treating multiple mild and/or moderate facial/scalp AKs. METHODS: Phase III, 12 week, multi-centre, randomised, investigator-blinded, controlled, intra individual study conducted at different latitudes in Europe. AKs of adult subjects were treated once with methyl aminolevulinate (MAL) DL-PDT on one side of the face and MAL c-PDT contralaterally. Endpoints for DL-PDT concerned efficacy (non-inferiority regarding complete lesion response at week 12) and safety (superiority regarding subject's assessment of pain after treatment, on an 11-point numeric rating scale). Safety evaluation also included incidence of adverse events. Subject satisfaction was described using a questionnaire at baseline and last visit. RESULTS: At week 12, the total lesion complete response rate with DL-PDT was similar (non-inferior) to c-PDT (70% vs. 74%, respectively; 95% CI [-9.5; 2.4] in PP analysis, confirmed in ITT analysis). In addition, efficacy of DL-PDT was demonstrated regardless of weather conditions (sunny or cloudy). DL-PDT was nearly painless compared to c-PDT (0.7 vs. 4.4, respectively; P < 0.001), better tolerated and resulted in higher subject satisfaction. CONCLUSION: DL-PDT in comparison with c-PDT was as effective, better tolerated and nearly painless with high patient satisfaction, and may be considered a treatment of choice to meet needs of patients with mild or moderate facial/scalp AKs. PMID- 26435366 TI - [Delayed Brain Injury after Aneurysmal Subarachnoid Hemorrhage:Update and Perspective]. PMID- 26435365 TI - Twice-daily insulin degludec/insulin aspart provides superior fasting plasma glucose control and a reduced rate of hypoglycaemia compared with biphasic insulin aspart 30 in insulin-naive adults with Type 2 diabetes. AB - AIM: To evaluate the efficacy and safety of twice-daily insulin degludec/insulin aspart vs. twice-daily biphasic insulin aspart 30 in people with Type 2 diabetes mellitus who were naive to insulin. METHODS: In this 26-week, multinational, open label, controlled, two-arm, parallel-group, treat-to-target trial, participants [mean (+/- sd) age 58.9 (+/-8.9) years, duration of diabetes 9.5 (+/-5.9) years, HbA1c 68 (+/-8.7) mmol/mol or 8.4 (+/-0.8)% and BMI 31.2 (+/-4.2) kg/m(2) ) were randomized (1:1) to insulin degludec/insulin aspart (n = 197) or biphasic insulin aspart 30 (n = 197), administered with breakfast and the main evening meal, titrated to a self-monitored plasma glucose target > 3.9 and <= 5.0 mmol/l. RESULTS: The mean HbA1c was reduced to 49 mmol/mol (6.6%) with insulin degludec/insulin aspart and 48 mmol/mol (6.5%) with biphasic insulin aspart 30. Insulin degludec/insulin aspart achieved the prespecified non-inferiority margin (estimated treatment difference 0.02%; 95% CI -0.12, 0.17). Insulin degludec/insulin aspart was superior in lowering fasting plasma glucose (estimated treatment difference -1.00 mmol/l; 95% CI -1.4, -0.6; P < 0.001) and reducing overall and nocturnal confirmed hypoglycaemia at a similar overall insulin dose compared with biphasic insulin aspart 30. Similar proportions of participants in each arm experienced severe hypoglycaemia. Adverse events were equally distributed. CONCLUSIONS: Consistent with previous findings, insulin degludec/insulin aspart twice daily effectively improved long-term glycaemic control, with superior reductions in FPG, and significantly less overall and nocturnal confirmed hypoglycaemia compared with biphasic insulin aspart 30 in people with Type 2 diabetes who were insulin-naive. PMID- 26435367 TI - [Traumatic Brain Injury Data Bank]. PMID- 26435368 TI - [Effects of Endovascular Treatment on Cranial Nerve Palsy due to Unruptured Intracranial Aneurysms]. AB - This study aimed to assess the effects of endovascular treatment on cranial nerve palsy due to unruptured intracranial aneurysms. Endovascular coiling was performed in 203 patients with intracranial aneurysms between April 2002 and March 2012 in our hospital. Of these patients, 8(3.9%)presented with cranial nerve palsy due to unruptured intracranial aneurysms. Cranial nerve palsy involved the oculomotor nerve in 8 patients and the optic nerve in 2 patients. Two patients had both optic nerve and oculomotor nerve dysfunction. Patients with incomplete oculomotor nerve palsy at admission were more likely to have full recovery after coiling. Optic nerve dysfunction did not improve after coiling. Incomplete oculomotor nerve palsy, early treatment(<=15 days), and small aneurysms(<=10 mm)were likely to be associated with complete recovery after coiling. This study indicates that endovascular coiling may resolve cranial nerve palsy due to unruptured intracranial aneurysms in patients who have incomplete oculomotor nerve palsy due to small aneurysms and are treated as early as possible after symptom onset. PMID- 26435369 TI - [Clinical Study on Cerebellar Contusion:A Report on 9 Cases and Literature Review]. AB - We report 9 cases of cerebellar contusion from April 2011 to September 2014 at our department. Frequency, clinicoradiological findings, mechanism of injury, treatments, and outcomes were retrospectively analyzed. Of 239 head injury cases admitted to our department during the same period, 9(3.8%)were diagnosed as cerebellar contusion. Among these 9 cases, 7 were men, and 2 were women. The patient age ranged from 12 to 83 years with a mean age of 64.7 years. The mechanism of injury was traffic accident in one patient, and fall in 8. All cases were associated with direct head trauma to the occiput, and radiographic studies showed occipital bone fracture in 8 cases. Six cases were managed conservatively. Three cases underwent suboccipital craniectomies and clot evacuations. Glasgow Outcome Scale(GOS)score at discharge were Good Recovery(GR)in 2, Moderate Disability(MD)in 2, Severe Disability(SD)in 3, Vegetative State(VS)in 1, and Dead(D)in 1. GOS scores in surgically treated cases were GR in 1, SD in 1, and VS in 1. Supratentorial severe traumatic lesions were concomitant with poor prognosis. Coup injury was a significant cause of cerebellar contusion. External decompression and clot evacuation were useful in patients who suffered severe cerebellar contusion;however, concomitant supratentorial lesions influenced the prognosis. PMID- 26435370 TI - [Application of Silicone Rubber Stents in Intracranial Arterial Microanastomosis for Vessels with Intimal Dissection:A Technical Note]. AB - Intracranial arterial microanastomosis remains an important neurosurgical technique. Intimal dissection of donor or recipient arteries can cause bypass failure. We used a silicone rubber stent while performing arterial microanastomoses, and achieved an excellent postoperative patency rate. In this study, we evaluated the efficacy of the stent in cases of extensive intimal dissection. In 5 cases involving extensive intimal dissection of vessels out of a total of 856 microanastomoses that were performed between November 2000 and August 2014, we placed a silicone rubber stent in the lumen of the recipient artery for donor to recipient suturing. Surgery was performed in 3 cases of cerebrovascular atherosclerotic disease and in 2 cases requiring cerebral revascularization for the treatment of aneurysm recurrence. In one of the 5 cases in which arterial microanastomosis was performed in the spasm period after subarachnoid hemorrhage, a patent anastomosis could not be confirmed. We observed the following advantages of silicone stent use: clear visualization of the orifice created in the vessel, avoidance of suturing or damaging the contralateral side vessel edges, and maintenance of the shape of the anastomosed vessel segment. These advantages made it easier to visualize the intima and to achieve fixation by using tacking sutures. PMID- 26435371 TI - [Usefulness of a Transbrachial Guide Sheath Specifically Designed for Direct Common Carotid Artery Cannulation in Common Carotid Artery Stenting]. AB - The transfemoral approach is a common technique for carotid artery stenting(CAS)and involves the risk of distal embolism when a high-grade stenosis occurs at the common carotid artery(CCA). In this study, to minimize the risk of thromboembolic complications, we used a guide sheath that was specifically designed for direct cannulation to the CCA without the use of a guidewire or coaxial catheter. This study included 5 patients who underwent CAS of the CCA by using a guide sheath. Of these patients, 2 had right CCA stenosis and the other 3 had left CCA lesions. In all cases, direct cannulation to the target CCA by using the guide sheath was achieved, and CAS was performed safely. The median time from puncture to the end of the procedure was 61 min(interquartile range: 53-63). No periprocedural complications or cardiovascular events occurred within 30 days after CAS. CAS was safely and successfully performed for CCA stenosis by using the transbrachial guide sheath that was specifically designed for direct cannulation to the CCA. PMID- 26435372 TI - [A Case of Transorbital Penetrating Brain Injury Caused by a Steel Wire Entirely Embedded in the Brain Parenchyma]. AB - Penetrating brain injury(PBI)is very rare in Japan. Because there is a very wide variety of pathological condition of PBI, the guideline for the treatment of PBI has not been established yet. We report the unique case of PBI caused by a steel wire piece completely embedded in the brain parenchyma. A 75-year-old man was brought to the emergency department due to ocular injury caused by a steel wire piece. Neurological examination revealed only left visual disturbance. CT scan revealed a steel wire piece located intraparenchymally between the left frontal lobe and the ventricles, but digital subtraction angiography showed no significant vascular injury in the surrounding structures. We performed an open surgery and removed the steel wire piece. Because the steel wire piece was completely embedded in the brain, we used intraoperative X-ray fluoroscopy to choose a less invasive approach for the brain. The patient suffered no additional neurological deficit and no sign of cerebral infection or seizure after surgery. He was discharged after a 4-week administration of antibiotics. In most cases of PBI caused by low velocity injury, foreign bodies are not completely embedded in the brain except for remnants after surgical removal. This is the first report of low velocity PBI caused by a foreign body completely embedded in the brain. PMID- 26435373 TI - [Metronidazole-Induced Encephalopathy during Brain Abscess Treatment:Two Case Reports]. AB - Metronidazole is a widely used antibiotic against anaerobic bacteria and protozoa. We report two cases of metronidazole-induced encephalopathy(MIE)during treatment of a brain abscess with metronidazole. The patients developed mental disturbance, and brain MRI showed reversible signals on DWI, FLAIR, and T2. Case 1: A 48-year-old woman was admitted to our hospital with a cerebellar abscess. We initiated treatment with oral metronidazole. After taking the medication, she developed mental disturbance, and her brain MRI showed a hyperintensity within the corpus callosum. We suspected metronidazole toxicity and discontinued metronidazole treatment. The symptoms resolved rapidly within a week, and the hyperintensity on the MRI disappeared. Case 2: A 22-year-old man was admitted to our hospital with a brain abscess. We initiated treatment with oral metronidazole. On day 38, he developed mental disturbance, and his MRI showed hyperintensities within the bilateral dentate nuclei and corpus callosum. These symptoms were consistent with MIE. After cessation of metronidazole, his symptoms and abnormal MRI signals completely disappeared. PMID- 26435374 TI - [A Single-Stage Combined Supra- and Infra-Sellar Approach for Recurrent Large Pituitary Adenomas:Report of Two Cases]. AB - Despite the recent technological advances in operative instruments and development of novel techniques for endoscopic skull-base surgeries, surgical treatment of primary or recurrent large/giant pituitary adenomas remains a challenge. Postoperative hemorrhage from the residual tumor and the associated impairment of the adjacent cranial nerve functions can cause severe morbidity. To manage such operative risks, a combined supra- and infra-sellar approach(CSISA)can be used as a surgical option for difficult-to-resect large/giant pituitary adenomas. We successfully performed a single-stage CSISA in two patients with large recurrent pituitary adenomas with favorable outcomes. Both patients had recurrent adenomas after multiple trans-sphenoidal surgeries and presented with visual impairment due to tumor regrowth. Each tumor had a maximum diameter of more than 4 cm. One tumor extended into the anterior skull base, while the other extended into the supra-sellar region with extremely lateral invasion. The CSISA helped surgeons visualize the tumors and the surrounding structures through a combination of different operative views. Subtotal resection was safely achieved in both cases, with no postoperative hemorrhage and deterioration of visual and pituitary function. The CSISA is useful not only for pituitary adenomas with anterior or lateral extension and multi-lobular growth, but also for certain cases with recurrent large/giant pituitary adenomas. PMID- 26435375 TI - Factors associated with failure to achieve a glycated haemoglobin target of <8.0% in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. AB - The aim of this study was to identify the clinical features of participants in the standard therapy arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) glycaemia trial who failed to reach the glycated haemoglobin (HbA1c) target. We analysed 4685 participants in the standard therapy arm, comparing participants who reached the HbA1c target of <8.0% with those whose HbA1c level was >=8.0% 12 months after randomization. Baseline and 12-month clinical characteristics were compared. At 12 months after randomization, 3194 participants had HbA1c <8.0% and 1491 had HbA1c >=8.0%. Black race [odds ratio (OR) 0.74, 95% confidence interval (CI) 0.61-0.89; p = 0.002], severe hypoglycaemia (OR 0.57, CI 0.37-0.89; p = 0.014) and insulin use (OR 0.51, CI 0.40-0.65; p < 0.001) were associated with failure to reach HbA1c goal at 12 months in the adjusted model. Even with free medications, free visits with clinicians and aggressive titration of medications, >30% of participants in the standard arm of the ACCORD trial had an HbA1c >=8.0% at 1 year. Participants who were black, had severe hypoglycaemia and were on insulin were more likely to have an above-target HbA1c concentration after 12 months on the standard protocol. PMID- 26435376 TI - Spontaneous Formation of RNA Strands, Peptidyl RNA, and Cofactors. AB - How the biochemical machinery evolved from simple precursors is an open question. Here we show that ribonucleotides and amino acids condense to peptidyl RNAs in the absence of enzymes under conditions established for genetic copying. Untemplated formation of RNA strands that can encode genetic information, formation of peptidyl chains linked to RNA, and formation of the cofactors NAD(+), FAD, and ATP all occur under the same conditions. In the peptidyl RNAs, the peptide chains are phosphoramidate-linked to a ribonucleotide. Peptidyl RNAs with long peptide chains were selected from an initial pool when a lipophilic phase simulating the interior of membranes was offered, and free peptides were released upon acidification. Our results show that key molecules of genetics, catalysis, and metabolism can emerge under the same conditions, without a mineral surface, without an enzyme, and without the need for chemical pre-activation. PMID- 26435377 TI - Transannular [6 + 4] and Ambimodal Cycloaddition in the Biosynthesis of Heronamide A. AB - The transannular [6 + 4] cycloaddition proposed as a step in the biosynthesis of heronamide A has been modeled using density functional theory. The proposed cycloaddition is highly stereoselective, affording a single product. The reaction proceeds through an ambimodal transition state that directly leads to a [4 + 2] adduct in addition to the observed [6 + 4] adduct. Interconversion of these adducts is possible via a facile Cope rearrangement. The [6 + 4] adduct is thermodynamically more stable than the [4 + 2] adduct by 5.2 kcal mol(-1) due to a combination of the ring and steric strain in the [4 + 2] product. The results strongly support the plausibility of the proposed transannular [6 + 4] cycloaddition in the biogenesis of heronamide A and may provide insights to designing substrates that selectively undergo [6 + 4] cycloaddition to form unbridged 10-membered rings. PMID- 26435378 TI - Microscopic haematuria at time of diagnosis is associated with lower disease stage in patients with newly diagnosed bladder cancer. AB - OBJECTIVES: To determine whether the severity of haematuria (microscopic or gross) at diagnosis influences the disease stage at presentation in patients diagnosed with bladder cancer. PATIENTS AND METHODS: We conducted a multi institutional observational cohort study of patients who were newly diagnosed with bladder cancer between August 1999 and May 2012. We reviewed the degree of haematuria, demographic information, clinical and social history, imaging, and pathology. The association of haematuria severity with incident tumour stage and grade was evaluated using logistic regression. RESULTS: Patients diagnosed with bladder cancer presented with gross haematuria (GH; 1 083, 78.3%), microscopic haematuria (MH; 189, 13.7%) or without haematuria (112, 8.1%). High-grade disease was found in 64% and 57.1% of patients presenting with GH and MH, respectively, and severity of haematuria was not associated with higher grade disease. Stage of disease at diagnosis for patients presenting with MH was Ta/carcinoma in situ (CIS) in 68.8%, T1 in 19.6%, and >=T2 in 11.6%. Stage of disease at diagnosis for patients presenting with GH was Ta/CIS in 55.9%, T1 in 19.6%, and >=T2 in 17.9%. On multivariate analyses, GH was independently associated with >=T2 disease at diagnosis (odds ratio 1.69, 95% confidence interval 1.05-2.71, P = 0.03). CONCLUSIONS: Among patients with newly diagnosed bladder cancer, presentation with GH is associated with a more advanced pathological stage. Earlier detection of disease, before development of GH, could influence survival in patients with bladder cancer. Type of haematuria at presentation does not impact grade of disease. PMID- 26435379 TI - Prediction of Blood Pressure and Blood Pressure Change With a Genetic Risk Score. AB - The authors investigated whether a genetic risk score (GRS) constructed of 32 single nucleotide polymorphisms would predict incident hypertension and blood pressure (BP) change over time in a population cohort during an 11-year follow-up (n=5402 at baseline, 3266 at follow-up). In multivariable models, GRS was associated with higher systolic/diastolic BP values at baseline (beta+/-standard error [SE], 1.04+/-0.14/1.11+/-0.13 mm Hg; P<.0001 for both) and at reinvestigation (beta+/-SE, 0.84+/-0.18/0.79+/-0.16 mm Hg; P<.0001 for both). Among participants who were normotensive at baseline (n=2045), GRS was not independently associated with systolic/diastolic BP change over time (beta+/-SE, 0.16+/-0.18/0.20+/-0.18 mm Hg; P>=.28 for both). In participants in the top tertile of the GRS, as compared with the bottom tertile, the predicted increase in systolic/diastolic BP was 1.18+/-0.78/0.70+/-0.49 mm Hg (P=.046/.15) greater and the odds ratio for incident hypertension was 33% higher (P=.03). These data show that GRS is strongly associated with BP but weakly associated with BP increase and incident hypertension in a late middle-aged population. PMID- 26435380 TI - Clearance from the mouse brain by convection of interstitial fluid towards the ventricular system. AB - BACKGROUND: In the absence of a true lymphatic system in the brain parenchyma, alternative clearance pathways for excess fluid and waste products have been proposed. Suggested mechanisms for clearance implicate a role for brain interstitial and cerebrospinal fluids. However, the proposed direction of flow, the anatomical structures involved, and the driving forces are controversial. METHODS: To trace the distribution of interstitial and cerebrospinal fluid in the brain, and to identify the anatomical structures involved, we infused a mix of fluorescent tracers with different sizes into the cisterna magna or striatum of mouse brains. We subsequently performed confocal fluorescence imaging of horizontal brain sections and made 3D reconstructions of the mouse brain and vasculature. RESULTS: We observed a distribution pattern of tracers from the parenchyma to the ventricular system, from where tracers mixed with the cerebrospinal fluid, reached the subarachnoid space, and left the brain via the cribriform plate and the nose. Tracers also entered paravascular spaces around arteries both after injection in the cisterna magna and striatum, but this appeared to be of minor importance. CONCLUSION: These data suggest a bulk flow of interstitial fluid from the striatum towards the adjacent lateral ventricle. Tracers may enter arterial paravascular spaces from two sides, both through bulk flow from the parenchyma and through mixing of CSF in the subarachnoid space. Disturbances in this transport pathway could influence the drainage of amyloid beta and other waste products, which may be relevant for the pathophysiology of Alzheimer's disease. PMID- 26435381 TI - Malignancies in bullous pemphigoid: A controversial association. AB - Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disorder that has been reported to be associated with malignancies. Some authors described several cases of pemphigoid associated with malignancies (PAM); however, the evidence of this correlation still remains controversial. Several theories have been postulated to explain the relationship between malignant neoplasms and BP; the main theory suggests that antibodies directed against tumor-specific antigens of malignant cells may cross-react with antigens (like BP antigens) in the basement membrane zone leading to the formation of blisters. We performed an extensive review of the English published work focusing on the epidemiology, the pathogenetic theories and the clinical and histological aspects of the disease. We identified 40 cases of PAM: of these, seven cases were associated with hematological malignancies and 33 with solid tumors. Physicians should be aware of the existence of PAM and we suggest an oncological screening in early-onset pemphigoid, in patients with a former oncological history, in those with signs and symptoms that could be related to a neoplasm and in BP refractory to common immunosuppressive therapy. PMID- 26435382 TI - Therapeutic Targeting of microRNAs in Cancer: Future Perspectives. AB - Preclinical Research The discovery of microRNAs (miRNAs) and their link with cancer has opened a new era in cancer therapeutics. Approximately, 18 - 24 nucleotides long, miRNAs can up-regulate or down-regulate gene expression in many cancer types and are respectively categorized as oncogenes (oncomirs) or tumor suppressors. Expression profiles of miRNAs with biomarker potential can be used for the classification, diagnosis, therapeutic treatment, and prognosis of different cancer types. miRNA mimics and miRNA antagonists are the two main approaches to miRNA-based cancer therapies that respectively inhibit oncomirs or restore the expression of tumor suppressive miRNAs. This review serves to provide some general insight into miRNA biogenesis, cancer related miRNAs, and miRNA therapeutics. PMID- 26435383 TI - Predicting the future relapse of alcohol-dependent patients from structural and functional brain images. AB - In alcohol dependence, individual prediction of treatment outcome based on neuroimaging endophenotypes can help to tailor individual therapeutic offers to patients depending on their relapse risk. We built a prediction model for prospective relapse of alcohol-dependent patients that combines structural and functional brain images derived from an experiment in which 46 subjects were exposed to alcohol-related cues. The patient group had been subdivided post hoc regarding relapse behavior defined as a consumption of more than 60 g alcohol for male or more than 40 g alcohol for female patients on one occasion during the 3 month assessment period (16 abstainers and 30 relapsers). Naive Bayes, support vector machines and learning vector quantization were used to infer prediction models for relapse based on the mean and maximum values of gray matter volume and brain responses on alcohol-related cues within a priori defined regions of interest. Model performance was estimated by leave-one-out cross-validation. Learning vector quantization yielded the model with the highest balanced accuracy (79.4 percent, p < 0.0001; 90 percent sensitivity, 68.8 percent specificity). The most informative individual predictors were functional brain activation features in the right and left ventral tegmental areas and the right ventral striatum, as well as gray matter volume features in left orbitofrontal cortex and right medial prefrontal cortex. In contrast, the best pure clinical model reached only chance level accuracy (61.3 percent). Our results indicate that an individual prediction of future relapse from imaging measurement outperforms prediction from clinical measurements. The approach may help to target specific interventions at different risk groups. PMID- 26435384 TI - Imidazole tailored deep eutectic solvents for CO2 capture enhanced by hydrogen bonds. AB - Deep eutectic solvents (DESs) have emerged as promising alternative candidates for CO2 capture in recent years. In this work, several novel DESs were firstly prepared to enhance CO2 absorption. Structural and physical properties of DESs were investigated, as well as their absorption performance of CO2. A distinct depression in the melting point up to 80 K of DESs was observed compared with that of BMIMCl. The observed red shifts of the C2H group in an imidazolium ring and its chemical shifts downfield in NMR spectra are indicative of a hydrogen bond interaction between BMIMCl and MEA. In particular, CO2 uptake in MEA : ILs (4 : 1) at room temperature and atmospheric pressure is up to 21.4 wt%, which is higher than that of 30 wt% MEA (13%). A hydrogen bond related mechanism was proposed in which ILs act as a medium to improve CO2 uptake through hydrogen bonds. Finally, the firstly reported overall heat of CO2 absorption is slightly higher than that of 30 wt% MEA, implying that the hydrogen bonds of DESs contribute to the overall heat of CO2 absorption. This study reveals that the heat of CO2 absorption can be tailored by the proper molar ratio of MEA and ILs. PMID- 26435385 TI - Multicomponent T2 analysis of articular cartilage with synovial fluid partial volume correction. AB - PURPOSE: To investigate the use of a three-pool model to account for the confounding effects of synovial fluid on multicomponent T2 analysis of articular cartilage using Multicomponent Driven Equilibrium Single Shot Observation of T1 and T2 (mcDESPOT). MATERIALS AND METHODS: mcDESPOT was performed on the knee of eight asymptomatic volunteers and eight patients with osteoarthritis at 3.0T with multicomponent T2 maps created using the two-pool model and a three-pool model containing a nonexchanging synovial fluid water pool. The fraction of the fast relaxing water component (FF ) and the T2 relaxation times for the fast-relaxing (T2F ) and slow-relaxing (T2S ) water components were measured in the superficial and deep layers of patellar cartilage using the two-pool and three-pool models in asymptomatic volunteers and patients with osteoarthritis and were compared using Wilcoxon signed rank tests. RESULTS: Within the superficial layer of patellar cartilage, FF was 22.5% and 25.6% for asymptomatic volunteers and 21.3% and 22.8% for patients with osteoarthritis when using the two-pool and three-pool models, respectively, while T2S was 73.9 msec and 62.0 msec for asymptomatic volunteers and 72.0 msec and 63.1 msec for patients with osteoarthritis when using the two pool and three-pool models, respectively. For both asymptomatic volunteers and patients with osteoarthritis, the two-pool model provided significantly (P < 0.05) lower FF and higher T2S than the three-pool model, likely due to the effects of synovial fluid partial volume averaging. CONCLUSION: The effects of partial volume averaging between superficial cartilage and synovial fluid may result in biased multicomponent T2 measurements that can be corrected using an mcDESPOT three-pool model containing a nonexchanging synovial fluid water pool. PMID- 26435387 TI - Response of authors to Ganju and Dias' comments on 'Inclusion of Placebos and Blinding for Ascending Dose First-in-Human Studies and Other Underpowered Phase 1 Studies Has Not Been Justified and on Balance is Not Useful' by D. A. Parasrampuria and L. Z. Benet. PMID- 26435386 TI - Endometriosis diagnosis and staging by operating surgeon and expert review using multiple diagnostic tools: an inter-rater agreement study. AB - OBJECTIVE: To determine agreement on endometriosis diagnosis between real-time laparoscopy and subsequent expert review of digital images, operative reports, magnetic resonance imaging (MRI), and histopathology, viewed sequentially. DESIGN: Inter-rater agreement study. SETTING: Five urban surgical centres. POPULATION: Women, aged 18-44 years, who underwent a laparoscopy regardless of clinical indication. A random sample of 105 women with and 43 women without a postoperative endometriosis diagnosis was obtained from the ENDO study. METHODS: Laparoscopies were diagnosed, digitally recorded, and reassessed. MAIN OUTCOME MEASURES: Inter-observer agreement of endometriosis diagnosis and staging according to the revised American Society for Reproductive Medicine criteria. Prevalence and bias-adjusted kappa values (kappa) were calculated for diagnosis, and weighted kappa values were calculated for staging. RESULTS: Surgeons and expert reviewers had substantial agreement on diagnosis and staging after viewing digital images (n = 148; mean kappa = 0.67, range 0.61-0.69; mean kappa = 0.64, range 0.53-0.78, respectively) and after additionally viewing operative reports (n = 148; mean kappa = 0.88, range 0.85-0.89; mean kappa = 0.85, range 0.84-0.86, respectively). Although additionally viewing MRI findings (n = 36) did not greatly impact agreement, agreement substantially decreased after viewing histological findings (n = 67), with expert reviewers changing their assessment from a positive to a negative diagnosis in up to 20% of cases. CONCLUSION: Although these findings suggest that misclassification bias in the diagnosis or staging of endometriosis via visualised disease is minimal, they should alert gynaecologists who review operative images in order to make decisions on endometriosis treatment that operative reports/drawings and histopathology, but not necessarily MRI, will improve their ability to make sound judgments. TWEETABLE ABSTRACT: Endometriosis diagnosis and staging agreement between expert reviewers and operating surgeons was substantial. PMID- 26435388 TI - Utility of heme analogues to intentionally modify heme-globin interactions in myoglobin. AB - Myoglobin reconstitution with various synthetic heme analogues was reviewed to follow the consequences of modified heme-globin interactions. Utility of dimethyl sulfoxide as the solvent for water-insoluble hemes was emphasized. Proton NMR spectroscopy revealed that loose heme-globin contacts in the heme pocket eventually caused the dynamic heme rotation around the iron-histidine bond. The full rotational rate was estimated to be about 1400 s(-1) at room temperature for 1,4,5,8-tetramethylhemin. The X-ray analysis of the myoglobin containing iron porphine, the smallest heme without any side chains, showed that the original globin fold was well conserved despite the serious disruption of native heme globin contacts. Comparison between the two myoglobins with static and rotatory prosthetic groups indicated that the oxygen and carbon monoxide binding profiles were almost unaffected by the heme motion. On the other hand, altered tetrapyrrole array of porphyrin dramatically changed the dissociation constant of oxygen from 0.0005 mm Hg of porphycene-myoglobin to infinity in oxypyriporphyrin myoglobin. Heme-globin interactions in myoglobin were also monitored with circular dichroism spectroscopy. The observation on several reconstituted protein revealed an unrecognized role of the propionate groups in protoheme. Shortening of heme 6,7-propionates to carboxylates resulted in almost complete disappearance of the positive circular dichroism band in the Soret region. The theoretical analysis suggested that the disappeared circular dichroism band reflected the cancellation effects between different conformers of the carboxyl groups directly attached to heme periphery. The above techniques were proposed to be applicable to other hemoproteins to create new biocatalysts. This article is part of a Special Issue entitled Biodesign for Bioenergetics--the design and engineering of electronic transfer cofactors, proteins and protein networks, edited by Ronald L. Koder and J.L. Ross Anderson. PMID- 26435389 TI - Unraveling the electron transfer processes of a nanowire protein from Geobacter sulfurreducens. AB - The extracellular electron transfer metabolism of Geobacter sulfurreducens is sustained by several multiheme c-type cytochromes. One of these is the dodecaheme cytochrome GSU1996 that belongs to a new sub-class of c-type cytochromes. GSU1996 is composed by four similar triheme domains (A-D). The C-terminal half of the molecule encompasses the domains C and D, which are connected by a small linker and the N-terminal half of the protein contains two domains (A and B) that form one structural unit. It was proposed that this protein works as an electrically conductive device in G. sulfurreducens, transferring electrons within the periplasm or to outer-membrane cytochromes. In this work, a novel strategy was applied to characterize in detail the thermodynamic and kinetic properties of the hexaheme fragment CD of GSU1996. This characterization revealed the electron transfer process of GSU1996 for the first time, showing that a heme at the edge of the C-terminal of the protein is thermodynamic and kinetically competent to receive electrons from physiological redox partners. This information contributes towards understanding how this new sub-class of cytochromes functions as nanowires, and also increases the current knowledge of the extracellular electron transfer mechanisms in G. sulfurreducens. PMID- 26435390 TI - Estimation of the driving force for dioxygen formation in photosynthesis. AB - Photosynthetic water oxidation to molecular oxygen is carried out by photosystem II (PSII) over a reaction cycle involving four photochemical steps that drive the oxygen-evolving complex through five redox states Si (i = 0,..., 4). For understanding the catalytic strategy of biological water oxidation it is important to elucidate the energetic landscape of PSII and in particular that of the final S4 -> S0 transition. In this short-lived chemical step the four oxidizing equivalents accumulated in the preceding photochemical events are used up to form molecular oxygen, two protons are released and at least one substrate water molecule binds to the Mn4CaO5 cluster. In this study we probed the probability to form S4 from S0 and O2 by incubating YD-less PSII in the S0 state for 2-3 days in the presence of (18)O2 and H2(16)O. The absence of any measurable (16,18)O2 formation by water-exchange in the S4 state suggests that the S4 state is hardly ever populated. On the basis of a detailed analysis we determined that the equilibrium constant K of the S4 -> S0 transition is larger than 1.0 * 10(7) so that this step is highly exergonic. We argue that this finding is consistent with current knowledge of the energetics of the S0 to S4 reactions, and that the high exergonicity is required for the kinetic efficiency of PSII. PMID- 26435391 TI - Arsenic accumulation in Brassicaceae seedlings and its effects on growth and plant anatomy. AB - We wished to evaluate the effects of arsenic on the morphology and anatomy of Brassica oleracea, Raphanus sativus, Brassica juncea, Brassica oleracea var. capitata and Brassica oleracea var. italica. Seeds were subjected to concentrations 0uM, 250uM, 350uM and 450uM arsenic in the form of sodium arsenate (Na2HAsO4.7H2O) during 12 days. All species accumulated more arsenic in the roots than in the shoots, except for B. oleracea var. capitata. There was no difference of translocation factor between species and treatments. Growth decrease was observed in roots of B. oleracea and R. sativus, and in shoots of R. sativus and B. oleracea var. italica. All species presented anatomical alterations in the roots, such as: cell hypertrophy, protoplast retraction, cellular plasmolysis, and necrotic regions. B. juncea presented collapse and hypertrophy of cells from the leaf blade tissues. Quantitative anatomical analyses performed on the root and leaves of B. oleracea and B. juncea revealed that arsenic interfered on the root vascular cylinder diameter and on height of epidermal cells of the adaxial leaf surface of both species. We concluded that arsenic was absorbed from the culture medium and induced alterations both on root and shoot growth of the seedlings. Retention of arsenic within the root was responsible for major damage in this organ. PMID- 26435392 TI - Integrated Proteomic and Genomic Analysis of Gastric Cancer Patient Tissues. AB - V-erb-b2 erythroblastic leukemia viral oncogene homologue 2, known as ERBB2, is an important oncogene in the development of certain cancers. It can form a heterodimer with other epidermal growth factor receptor family members and activate kinase-mediated downstream signaling pathways. ERBB2 gene is located on chromosome 17 and is amplified in a subset of cancers, such as breast, gastric, and colon cancer. Of particular interest to the Chromosome-Centric Human Proteome Project (C-HPP) initiative is the amplification mechanism that typically results in overexpression of a set of genes adjacent to ERBB2, which provides evidence of a linkage between gene location and expression. In this report we studied patient samples from ERBB2-positive together with adjacent control nontumor tissues. In addition, non-ERBB2-expressing patient samples were selected as comparison to study the effect of expression of this oncogene. We detected 196 proteins in ERBB2-positive patient tumor samples that had minimal overlap (29 proteins) with the non-ERBB2 tumor samples. Interaction and pathway analysis identified extracellular signal regulated kinase (ERK) cascade and actin polymerization and actinmyosin assembly contraction as pathways of importance in ERBB2+ and ERBB2- gastric cancer samples, respectively. The raw data files are deposited at ProteomeXchange (identifier: PXD002674) as well as GPMDB. PMID- 26435393 TI - Comparative study of CT appearances in mucinous tubular and spindle cell carcinoma and collecting duct carcinoma of the kidney. AB - OBJECTIVE: To characterize the multidetector CT (MDCT) imaging characteristics of mucinous tubular and spindle cell carcinoma (MTSCC) and collecting duct carcinoma (CDC) of the kidney. METHODS: 21 patients with MTSCC and 18 patients with CDC were studied retrospectively. MDCT was undertaken to investigate differences in tumour characteristics. RESULTS: Five patients with MTSCC had calcifications as did nine patients with CDC (p = 0.108). In three patients with MTSCC and four patients with CDC, the tumours had a clear boundary (p = 0.682). No patient with MTSCC had retroperitoneal lymph node metastasis as did five patients with CDC (p = 0.015). 16 patients with MTSCC showed homogeneous enhancement, whereas 11 patients with CDC showed heterogeneous enhancement (p = 0.025). The attenuation value of CDC tumours was greater than that of MTSCC and normal renal parenchyma on an unenhanced CT (p = 0.027). MTSCC and CDC tumour enhancement was less than the normal renal cortex and medulla in all phases (p < 0.001). Tumour enhancement was greater for CDC than that for MTSCC in all phases (p = 0.011, p = 0.006 and p = 0.052). CONCLUSION: Unenhanced and dynamic MDCT may aid in diagnosis and differentiation of MTSCC and CDC of the kidney. ADVANCES IN KNOWLEDGE: This is the first series evaluating the imaging findings of MTSCC and CDC of which we are aware, and identification of such findings may improve diagnosis of these two rare tumours. PMID- 26435394 TI - Lewis acid-base 1,2-addition reactions: synthesis of pyrylium borates from en ynoate precursors. AB - Treatment of methyl (Z)-2-alken-4-ynoates with the strong Lewis acid tris(pentafluorophenyl) borane, B(C6F5)3, yield substituted zwitterionic pyrylium borate species via an intramolecular 6-endo-dig cyclisation reaction. PMID- 26435398 TI - Functional analysis of an unusual type IV pilus in the Gram-positive Streptococcus sanguinis. AB - Type IV pili (Tfp), which have been studied extensively in a few Gram-negative species, are the paradigm of a group of widespread and functionally versatile nano-machines. Here, we performed the most detailed molecular characterisation of Tfp in a Gram-positive bacterium. We demonstrate that the naturally competent Streptococcus sanguinis produces retractable Tfp, which like their Gram-negative counterparts can generate hundreds of piconewton of tensile force and promote intense surface-associated motility. Tfp power 'train-like' directional motion parallel to the long axis of chains of cells, leading to spreading zones around bacteria grown on plates. However, S. sanguinis Tfp are not involved in DNA uptake, which is mediated by a related but distinct nano-machine, and are unusual because they are composed of two pilins in comparable amounts, rather than one as normally seen. Whole genome sequencing identified a locus encoding all the genes involved in Tfp biology in S. sanguinis. A systematic mutational analysis revealed that Tfp biogenesis in S. sanguinis relies on a more basic machinery (only 10 components) than in Gram-negative species and that a small subset of four proteins dispensable for pilus biogenesis are essential for motility. Intriguingly, one of the piliated mutants that does not exhibit spreading retains microscopic motility but moves sideways, which suggests that the corresponding protein controls motion directionality. Besides establishing S. sanguinis as a useful new model for studying Tfp biology, these findings have important implications for our understanding of these widespread filamentous nano-machines. PMID- 26435399 TI - Corrigendum: Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects. PMID- 26435400 TI - Germanium: a new catalyst for diamond synthesis and a new optically active impurity in diamond. AB - Diamond attracts considerable attention as a versatile and technologically useful material. For many demanding applications, such as recently emerged quantum optics and sensing, it is important to develop new routes for fabrication of diamond containing defects with specific optical, electronic and magnetic properties. Here we report on successful synthesis of diamond from a germanium carbon system at conditions of 7 GPa and 1,500-1,800 degrees C. Both spontaneously nucleated diamond crystals and diamond growth layers on seeds were produced in experiments with reaction time up to 60 h. We found that diamonds synthesized in the Ge-C system contain a new optical centre with a ZPL system at 2.059 eV, which is assigned to germanium impurities. Photoluminescence from this centre is dominated by zero-phonon optical transitions even at room temperature. Our results have widened the family of non-metallic elemental catalysts for diamond synthesis and demonstrated the creation of germanium-related optical centres in diamond. PMID- 26435401 TI - Delayed Carotid Dissection Following Lower Lip Revascularization in the Setting of Hyoid Fracture--A Case Report and Review of the Literature. AB - Traumatic injuries to the lip are common, but injuries that require revascularization of the lower lip are infrequent and pose a major challenge to the reconstructive surgeon. This report describes the case of a 53-year-old woman who sustained a lower lip avulsion injury, a comminuted mandibular parasymphyseal fracture, and a hyoid bone fracture secondary to a bicycle accident. Trauma workup included computed tomographic angiography of the head and neck, which did not show vascular injury. Despite successful revascularization of the lower lip, on postoperative day 11 the patient developed a large internal carotid artery dissection and middle cerebral artery stroke. This case highlights the importance of careful postoperative monitoring after high-energy facial trauma, particularly in the setting of vascular and bony injuries. PMID- 26435402 TI - Distinguishing time-delayed causal interactions using convergent cross mapping. AB - An important problem across many scientific fields is the identification of causal effects from observational data alone. Recent methods (convergent cross mapping, CCM) have made substantial progress on this problem by applying the idea of nonlinear attractor reconstruction to time series data. Here, we expand upon the technique of CCM by explicitly considering time lags. Applying this extended method to representative examples (model simulations, a laboratory predator-prey experiment, temperature and greenhouse gas reconstructions from the Vostok ice core, and long-term ecological time series collected in the Southern California Bight), we demonstrate the ability to identify different time-delayed interactions, distinguish between synchrony induced by strong unidirectional forcing and true bidirectional causality, and resolve transitive causal chains. PMID- 26435403 TI - Highly Efficient, Color-Reproducible Full-Color Electroluminescent Devices Based on Red/Green/Blue Quantum Dot-Mixed Multilayer. AB - Over the past few years the performance of colloidal quantum dot-light-emitting diode (QLED) has been progressively improved. However, most of QLED work has been fulfilled in the form of monochromatic device, while full-color-enabling white QLED still remains nearly unexplored. Using red, green, and blue quantum dots (QDs), herein, we fabricate bichromatic and trichromatic QLEDs through sequential solution-processed deposition of poly(9-vinlycarbazole) (PVK) hole transport layer, two or three types of QDs-mixed multilayer, and ZnO nanoparticle electron transport layer. The relative electroluminescent (EL) spectral ratios of constituent QDs in the above multicolored devices are found to inevitably vary with applied bias, leading to the common observation of an increasing contribution of a higher-band gap QD EL over low-band gap one at a higher voltage. The white EL from a trichromatic device is resolved into its primary colors through combining with color filters, producing an exceptional color gamut of 126% relative to National Television Systems Committee (NTSC) color space that a state-of-the-art full-color organic LED counterpart cannot attain. Our trichromatic white QLED also displays the record-high EL performance such as the peak values of 23,352 cd/m(2) in luminance, 21.8 cd/A in current efficiency, and 10.9% in external quantum efficiency. PMID- 26435404 TI - The role of putrescine in the regulation of proteins and fatty acids of thylakoid membranes under salt stress. AB - Polyamines can alleviate the inhibitory effects of salinity on plant growth by regulating photosynthetic efficiency. However, little information is available to explain the specific mechanisms underlying the contribution of polyamines to salt tolerance of the photosynthetic apparatus. Here, we investigated the role of putrescine (Put) on the photosynthetic apparatus of cucumber seedlings under salt stress. We found that NaCl stress resulted in severe ion toxicity and oxidative stress in cucumber chloroplasts. In addition, salinity caused a significant increase in the saturated fatty acid contents of thylakoid membranes. Put altered unsaturated fatty acid content, thereby alleviating the disintegration of thylakoid grana lamellae and reducing the number of plastoglobuli in thylakoid membranes. BN-PAGE revealed Put up-regulated the expression of ATP synthase, CP47, D1, Qb, and psbA proteins and down-regulated CP24, D2, and LHCII type III in NaCl-stressed thylakoid membranes. qRT-PCR analysis of gene expression was used to compare transcript and protein accumulation among 10 candidate proteins. For five of these proteins, induced transcript accumulation was consistent with the pattern of induced protein accumulation. Our results suggest that Put regulates protein expression at transcriptional and translational levels by increasing endogenous polyamines levels in thylakoid membranes, which may stabilise photosynthetic apparatus under salt stress. PMID- 26435405 TI - Parturition failure in mice lacking Mamld1. AB - In mice, the onset of parturition is triggered by a rapid decline in circulating progesterone. Progesterone withdrawal occurs as a result of functional luteolysis, which is characterized by an increase in the enzymatic activity of 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) in the corpus luteum and is mediated by the prostaglandin F2alpha (PGF2alpha) signaling. Here, we report that the genetic knockout (KO) of Mamld1, which encodes a putative non-DNA-binding regulator of testicular steroidogenesis, caused defective functional luteolysis and subsequent parturition failure and neonatal deaths. Progesterone receptor inhibition induced the onset of parturition in pregnant KO mice, and MAMLD1 regulated the expression of Akr1c18, the gene encoding 20alpha-HSD, in cultured cells. Ovaries of KO mice at late gestation were morphologically unremarkable; however, Akr1c18 expression was reduced and expression of its suppressor Stat5b was markedly increased. Several other genes including Prlr, Cyp19a1, Oxtr, and Lgals3 were also dysregulated in the KO ovaries, whereas PGF2alpha signaling genes remained unaffected. These results highlight the role of MAMLD1 in labour initiation. MAMLD1 likely participates in functional luteolysis by regulating Stat5b and other genes, independent of the PGF2alpha signaling pathway. PMID- 26435406 TI - Honey prevents neurobehavioural deficit and oxidative stress induced by lead acetate exposure in male Wistar rats- a preliminary study. AB - This research sought to investigate the possible neuroprotective effects of honey against lead (Pb)-induced neurotoxicity. Twenty four male Wistar rats were divided into four groups: Control group that received 1 ml/kg distilled orally for 28 days; while groups II-IV received 0.2% lead in drinking water and 1 ml/kg of distilled water, 1 ml/kg of honey, 1.5 ml/kg of honey respectively for 28 days. Anxiety and exploratory activities were determined in the open field test. Memory function was determined using Morris water maze after which the animals were sacrificed. The brains were then excised, homogenized and Lipid peroxidation (MDA), Superoxide dismutase (SOD), Catalase, Glutathione (GSH) and Glutathione -S Transferase (GST) activities were determined in the brains. Results showed that lead exposure causes decrease in locomotor and exploratory activities; increase anxiety, memory impairment, lipid peroxidation and decrease antioxidant activities. However, co-administration of honey with lead inhibited neurotoxicity as indicated by the improvement in memory function as evidenced by decreased latency period and increased in time spent in target quadrant in honey-fed rats compared to the lead-exposed animals. Furthermore, honey increased locomotion, exploration and decreased anxiety in lead-exposed rats as indicated by the frequency of rearing, freezing duration and the number of line crossed by animals. Also administration of honey improves antioxidant activities as shown by increased brain SOD, GST and GSH activities compared to the lead-treated groups but no significant effect on MDA level. It can be concluded that honey has neuroprotective effects against lead-induced cognitive deficit probably by enhancing antioxidant activities. PMID- 26435407 TI - Effects of common chronic medical conditions on psychometric tests used to diagnose minimal hepatic encephalopathy. AB - Many chronic medical conditions are accompanied by cognitive disturbances but these have only to a very limited extent been psychometrically quantified. An exception is liver cirrhosis where hepatic encephalopathy is an inherent risk and mild forms are diagnosed by psychometric tests. The preferred diagnostic test battery in cirrhosis is often the Continuous Reaction Time (CRT) and the Portosystemic Encephalopathy (PSE) tests but the effect on these of other medical conditions is not known. We aimed to examine the effects of common chronic (non cirrhosis) medical conditions on the CRT and PSE tests. We studied 15 patients with heart failure (HF), 15 with end stage renal failure (ESRF), 15 with dysregulated type II diabetes (DMII), 15 with chronic obstructive pulmonary disease (COPD), and 15 healthy persons. We applied the CRT test, which is a 10 min computerized test measuring sustained attention and reaction time stability and the PSE test, which is a paper-pencil test battery consisting of 5 subtests. We found that a high fraction of the patients with HF (8/15, 0.002) or COPD (7/15, p = 0.006) had pathological CRT test results; and COPD patients also frequently had an abnormal PSE test result (6/15, p < 0.0001). Both tests were unaffected by ESRF and DMII. Half of the patients with HF or COPD had psychometrically measurable cognitive deficits, whereas those with ESRF or DMII had not. This adds to the understanding of the clinical consequences of chronic heart- and lung disease, and implies that the psychometric tests should be interpreted with great caution in cirrhosis patients with heart- or lung comorbidity. PMID- 26435408 TI - PAX4 Gene Transfer Induces alpha-to-beta Cell Phenotypic Conversion and Confers Therapeutic Benefits for Diabetes Treatment. AB - The transcription factor Pax4 plays a critical role in the determination of alpha versus beta-cell lineage during endocrine pancreas development. In this study, we explored whether Pax4 gene transfer into alpha-cells could convert them into functional beta-cells and thus provide therapeutic benefits for insulin-deficient diabetes. We found that Pax4 delivered by adenoviral vector, Ad5.Pax4, induced insulin expression and reduced glucagon expression in alphaTC1.9 cells. More importantly, these cells exhibited glucose-stimulated insulin secretion, a key feature of functional beta-cells. When injected into streptozotocin-induced diabetic mice, Pax4-treated alphaTC1.9 cells significantly reduced blood glucose, and the mice showed better glucose tolerance, supporting that Pax4 gene transfer into alphaTC1.9 cells resulted in the formation of functional beta-cells. Furthermore, treatment of primary human islets with Ad5.Pax4 resulted in significantly improved beta-cell function. Detection of glucagon(+)/Pax4(+)/Insulin(+) cells argued for Pax4-induced alpha-to-beta cell transitioning. This was further supported by quantification of glucagon and insulin bi-hormonal cells, which was significantly higher in Pax4-treated islets than in controls. Finally, direct administration of Ad5.Pax4 into the pancreas of insulin-deficient mice ameliorated hyperglycemia. Taken together, our data demonstrate that manipulating Pax4 gene expression represents a viable therapeutic strategy for the treatment of insulin deficient diabetes. PMID- 26435410 TI - Effect of self-assembling peptide P11 -4 on enamel erosion: AFM and SEM studies. AB - The aim of the present in vitro study was to evaluate the protective effect of self-assembling peptide P11 -4 (CurodontTM Protect/Credentis) on enamel erosion produced by a soft-drink, by using Atomic Force Microscopy (AFM) and Scanning Electron Microscopy (SEM). Thirty human incisors were equally and randomly assigned to 6 groups. Group 1: intact enamel, group 2: soft drink, group 3: Curodont(TM) Protect applied, group 4: Curodont(TM) Protect applied + soft drink, group 5: soft drink + Curodont(TM) Protect applied, group 6: soft drink + Curodont(TM) Protect applied + soft drink. Specimens were observed through atomic force microscopy (AFM). The root mean-square roughness (Rrms) was obtained from the AFM images and the differences in the averaged values among the groups were analyzed by Shapiro-Wilk test in order to assess the normality of the distribution. Parametric ANOVA and post hoc Tuckey test were performed to assess the differences between the different groups. After demineralization process, enamel demonstrated a high degree of surface porosity. This morphological aspect was reflected in the increase of Rrms values. No significant differences (p > 0.05) were reported between intact enamel and enamel only treated with P11 -4 and between eroded enamel and enamel treated with P11 -4 and then demineralized. However significant differences (p < 0.05) were recorded when comparing softened enamel with softened enamel further remineralized with biomimetic self-assembling peptides and enamel treated with the protective paste between two acid attacks. The use of P11 -4 remineralizing may offer a degree of protection from enamel erosion. SCANNING 38:344-351, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26435409 TI - Modeling Human Bone Marrow Failure Syndromes Using Pluripotent Stem Cells and Genome Engineering. AB - The combination of epigenetic reprogramming with advanced genome editing technologies opened a new avenue to study disease mechanisms, particularly of disorders with depleted target tissue. Bone marrow failure syndromes (BMFS) typically present with a marked reduction of peripheral blood cells due to a destroyed or dysfunctional bone marrow compartment. Somatic and germline mutations have been etiologically linked to many cases of BMFS. However, without the ability to study primary patient material, the exact pathogenesis for many entities remained fragmentary. Capturing the pathological genotype in induced pluripotent stem cells (iPSCs) allows studying potential developmental defects leading to a particular phenotype. The lack of hematopoietic stem and progenitor cells in these patients can also be overcome by differentiating patient-derived iPSCs into hematopoietic lineages. With fast growing genome editing techniques, such as CRISPR/Cas9, correction of disease-causing mutations in iPSCs or introduction of mutations in cells from healthy individuals enable comparative studies that may identify other genetic or epigenetic events contributing to a specific disease phenotype. In this review, we present recent progresses in disease modeling of inherited and acquired BMFS using reprogramming and genome editing techniques. We also discuss the challenges and potential shortcomings of iPSC-based models for hematological diseases. PMID- 26435411 TI - Expanding horizons of cellular plasticity in regenerative medicine. AB - This Guest Editorial introduces the Regenerative Medicine Theme Issue, which provides critical insight into the unfolding frontier of regenerative medicine. PMID- 26435412 TI - Hepatic expression of serum amyloid A1 is induced by traumatic brain injury and modulated by telmisartan. AB - Traumatic brain injury affects the whole body in addition to the direct impact on the brain. The systemic response to trauma is associated with the hepatic acute phase response. To further characterize this response, we performed controlled cortical impact injury on male mice and determined the expression of serum amyloid A1 (SAA1), an apolipoprotein, induced at the early stages of the acute phase response in liver and plasma. After cortical impact injury, induction of SAA1 was detectable in plasma at 6 hours post-injury and in liver at 1 day post injury, followed by gradual diminution over time. In the liver, cortical impact injury increased neutrophil and macrophage infiltration, apoptosis, and expression of mRNA encoding the chemokines CXCL1 and CXCL10. An increase in angiotensin II AT1 receptor mRNA at 3 days post-injury was also observed. Administration of the AT1 receptor antagonist telmisartan 1 hour post-injury significantly decreased liver SAA1 levels and CXCL10 mRNA expression, but did not affect CXCL1 expression or the number of apoptotic cells or infiltrating leukocytes. To our knowledge, this is the first study to demonstrate that SAA1 is induced in the liver after traumatic brain injury and that telmisartan prevents this response. Elucidating the molecular pathogenesis of the liver after brain injury will assist in understanding the efficacy of therapeutic approaches to brain injury. PMID- 26435414 TI - Sphingosine-1-phosphate receptor antagonism enhances proliferation and migration of engrafted neural progenitor cells in a model of viral-induced demyelination. AB - The oral drug FTY720 affects sphingosine-1-phosphate (S1P) signaling on targeted cells that bear the S1P receptors S1P1, S1P3, S1P4, and S1P5. We examined the effect of FTY720 treatment on the biology of mouse neural progenitor cells (NPCs) after transplantation in a viral model of demyelination. Intracerebral infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV) resulted in an acute encephalomyelitis, followed by demyelination similar in pathology to the human demyelinating disease, multiple sclerosis. We have previously reported that intraspinal transplantation of mouse NPCs into JHMV-infected animals resulted in selective colonization of demyelinated lesions, preferential differentiation into oligodendroglia accompanied by axonal preservation, and increased remyelination. Cultured NPCs expressed transcripts for S1P receptors S1P1, S1P2, S1P3, S1P4, and S1P5. FTY720 treatment of cultured NPCs resulted in increased mitogen-activated protein kinase phosphorylation and migration after exposure to the chemokine CXCL12. Administration of FTY720 to JHMV-infected mice resulted in enhanced migration and increased proliferation of transplanted NPCs after spinal cord engraftment. FTY720 treatment did not improve clinical disease, diminish neuroinflammation or the severity of demyelination, nor increase remyelination. These findings argue that FTY720 treatment selectively increases NPC proliferation and migration but does not either improve clinical outcome or enhance remyelination after transplantation into animals in which immune-mediated demyelination is initiated by the viral infection of the central nervous system. PMID- 26435413 TI - Deletion of Galgt2 (B4Galnt2) reduces muscle growth in response to acute injury and increases muscle inflammation and pathology in dystrophin-deficient mice. AB - Transgenic overexpression of Galgt2 (official name B4Galnt2) in skeletal muscle stimulates the glycosylation of alpha dystroglycan (alphaDG) and the up regulation of laminin alpha2 and dystrophin surrogates known to inhibit muscle pathology in mouse models of congenital muscular dystrophy 1A and Duchenne muscular dystrophy. Skeletal muscle Galgt2 gene expression is also normally increased in the mdx mouse model of Duchenne muscular dystrophy compared with the wild-type mice. To assess whether this increased endogenous Galgt2 expression could affect disease, we quantified muscular dystrophy measures in mdx mice deleted for Galgt2 (Galgt2(-/-)mdx). Galgt2(-/-) mdx mice had increased heart and skeletal muscle pathology and inflammation, and also worsened cardiac function, relative to age-matched mdx mice. Deletion of Galgt2 in wild-type mice also slowed skeletal muscle growth in response to acute muscle injury. In each instance where Galgt2 expression was elevated (developing muscle, regenerating muscle, and dystrophic muscle), Galgt2-dependent glycosylation of alphaDG was also increased. Overexpression of Galgt2 failed to inhibit skeletal muscle pathology in dystroglycan-deficient muscles, in contrast to previous studies in dystrophin-deficient mdx muscles. This study demonstrates that Galgt2 gene expression and glycosylation of alphaDG are dynamically regulated in muscle and that endogenous Galgt2 gene expression can ameliorate the extent of muscle pathology, inflammation, and dysfunction in mdx mice. PMID- 26435416 TI - In Vitro Bioaccessibility and Bioavailability of Iron from Potatoes with Varying Vitamin C, Carotenoid, and Phenolic Concentrations. AB - The bioaccessibility and bioavailability of iron from 12 Andean potato clones were estimated using an in vitro gastrointestinal digestion procedure and the Caco-2 cell line as a model of human intestine, with ferritin formation as a marker of iron absorption. We first showed that 63.7% (for the genotype CIP_311422.016) to 79.0% (for the genotype CIP_311575.003) of the iron is released from the potato tuber matrix during in vitro gastrointestinal digestion and is therefore available at the intestinal level. On average, 32 and 24.5% of the hydrophilic bioactive components, vitamin C and chlorogenic acid, respectively, were also bioaccessible from boiled tubers. Intestinal absorption of intrinsic iron from potato tubers could not be detected using our in vitro Caco-2 cell model. When an extrinsic source of iron (20 MUM FeCl3 and 1 mM ascorbic acid) was added to the digestion mixture, iron absorption varied from 1.8 to 8% for the genotypes CIP_311422.016 and CIP_311624.021, respectively, as compared to the reference control. Principal component analysis revealed negative relationships between bioavailable iron values and phenolic concentrations, whereas vitamin C concentrations were positively associated with the ferritin values. Further controlled intervention trials would be needed to conclusively assess the bioavailability of intrinsic iron from potato tubers. PMID- 26435415 TI - Human polycystin-2 transgene dose-dependently rescues ADPKD phenotypes in Pkd2 mutant mice. AB - Although much is known about the molecular genetic mechanisms of autosomal dominant polycystic kidney disease (ADPKD), few effective treatment is currently available. Here, we explore the in vivo effects of causal gene replacement in orthologous gene models of ADPKD in mice. Wild-type mice with human PKD2 transgene (PKD2(tg)) overexpressed polycystin (PC)-2 in several tissues, including the kidney and liver, and showed no significant cyst formation in either organ. We cross-mated PKD2(tg) with a Pkd2-null mouse model, which is embryonically lethal and forms renal and pancreatic cysts. Pkd2(-/-) mice with human PKD2 transgene (Pkd2(-/-);PKD2(tg)) were born in expected Mendelian ratios, indicating that the embryonic lethality of the Pkd2(-/-) mice was rescued. Pkd2( /-);PKD2(tg) mice survived up to 12 months and exhibited moderate to severe cystic phenotypes of the kidney, liver, and pancreas. Moreover, Pkd2(-/-) mice with homozygous PKD2(tg)-transgene alleles (Pkd2(-/-);PKD2(tg/tg)) showed significant further amelioration of the cystic severity compared to that in Pkd2( /-) mice with a hemizygous PKD2(tg) allele (Pkd2(-/-);PKD2(tg)), suggesting that the ADPKD phenotype was improved by increased transgene dosage. On further analysis, cystic improvement mainly resulted from reduced proliferation, rather apoptosis, of cyst-prone epithelial cells in the mouse model. The finding that the functional restoration of human PC2 significantly rescued ADPKD phenotypes in a dose-dependent manner suggests that increasing PC2 activity may be beneficial in some forms of ADPKD. PMID- 26435417 TI - HIV Infection Is Associated with Impaired Striatal Function during Inhibition with Normal Cortical Functioning on Functional MRI. AB - The aim of the present study was to investigate the effect of HIV infection on cortical and subcortical regions of the frontal-striatal system involved in the inhibition of voluntary movement. Functional MRI (fMRI) studies suggest that human immunodeficiency virus (HIV) infection is associated with frontostriatal dysfunction. While frontostriatal systems play a key role in behavioral inhibition, there are to our knowledge no fMRI studies investigating the potential impact of HIV on systems involved during the inhibition of voluntary movement. A total of 17 combined antiretroviral therapy (cART) naive HIV+ participants as well as 18 age, gender, ethnic, education matched healthy controls performed a modified version of the stop-signal paradigm. This paradigm assessed behavior as well as functional brain activity associated with motor execution, reactive inhibition (outright stopping) and proactive inhibition (anticipatory response slowing before stopping). HIV+ participants showed significantly slower responses during motor execution compared to healthy controls, whereas they had normal proactive response slowing. Putamen hypoactivation was evident in the HIV+ participants based on successful stopping, indicating subcortical dysfunction during reactive inhibition. HIV+ participants showed normal cortical functioning during proactive inhibition. Our data provide evidence that HIV infection is associated with subcortical dysfunction during reactive inhibition, accompanied by relatively normal higher cortical functioning during proactive inhibition. This suggests that HIV infection may primarily involve basic striatal-mediated control processes in cART naive participants. PMID- 26435419 TI - Quantitative proteomic analysis of Araucaria angustifolia (Bertol.) Kuntze cell lines with contrasting embryogenic potential. AB - GeLC-MS/MS based label free proteomic profiling was used in the large scale identification and quantification of proteins from Brazilian pine (Araucaria angustifolia) embryogenic cell (EC) lines that showed different propensities to form somatic embryos. Using a predicted protein sequence database that was derived from A. angustifolia RNA-Seq data, 2398 non-redundant proteins were identified. The log2 of the spectral count values of 858 proteins of these proteins showed a normal distribution, and were used for statistical analysis. Statistical tests indicated that 106 proteins were significantly differentially abundant between the two EC lines, and that 35 were more abundant in the responsive genotype (EC line SE1) and 71 were more abundant in the blocked genotype (EC line SE6). An increase in the abundance of proteins related to cell defense, anti-oxidative stress responses, and storage reserve deposition was observed in SE1. Moreover, in SE6 we observed an increased abundance of two proteins associated with seed development during the embryogenic cell proliferation stage, which we suggest is associated with genotypes showing a low responsiveness to embryo formation. Differences in protein abundance between the EC lines are discussed in terms of carbohydrate metabolism, cell division, defense response, gene expression, and response to reactive oxygen species. PMID- 26435418 TI - SILAC-based proteomic analysis reveals that salidroside antagonizes cobalt chloride-induced hypoxic effects by restoring the tricarboxylic acid cycle in cardiomyocytes. AB - Hypoxic status alters the energy metabolism and induces cell injury in cardiomyocytes, and it further triggers the occurrence and development of cardiovascular diseases. Our previous studies have shown that salidroside (SAL) exhibits anti-hypoxic activity. However, the mechanisms remain obscure. In the present study, we successfully screened 92 different expression proteins in CoCl2 induced hypoxic conditions, 106 different expression proteins in the SAL-mediated anti-hypoxic group were compared with the hypoxic group using quantitative proteomics strategy, respectively. We confirmed that SAL showed a positive protective function involving the acetyl-CoA metabolic, tricarboxylic acid (TCA) cycle using bioinformatics analysis. We also demonstrated that SAL plays a critical role in restoring the TCA cycle and in protecting cardiomyocytes from oxidative injury via up-regulation expressions of PDHE1-B, ACO2, SUCLG1, SUCLG2 and down-regulation of MDH2. SAL also inhibited H9c2 cell apoptosis by inhibiting the activation of pro-apoptotic molecules caspase 3 and caspase 9 as well as activation of the anti-apoptotic molecular Bcl-2. Additionally, SAL also improved mitochondrial membrane potential (DeltaPsim), reduced reactive oxygen species (ROS) and intercellular Ca(2+) concentration ([Ca(2+)]i) accumulation and inhibited the excessive consumption of ATP in H9c2 cells. PMID- 26435420 TI - Putrescine induces somatic embryo development and proteomic changes in embryogenic callus of sugarcane. AB - Somatic embryogenesis, an important biotechnological technique, has great potential for application in sugarcane breeding and micropropagation. Polyamines have been associated with the regulation of several physiological processes, including the acquisition of embryogenic competence and somatic embryogenesis. In this study, we used a proteomic approach to evaluate the effects of exogenous polyamine on sugarcane somatic embryo development to better understand this process. Embryogenic cultures were treated with different concentrations of putrescine, spermidine, and spermine. Proteomic analyses combined the shotgun method and the nanoESI-HDMS(E) technology. Among polyamines, 500 MUM putrescine gave rise to the highest number of somatic embryos; however, no differences in the amount of fresh matter were observed between polyamines and control. Differences in protein abundance profiles resulting from the effect of 500 MUM putrescine on sugarcane somatic embryo maturation were observed. Proteomic analyses of putrescine and control treatment showed differences in the abundances of proteins related to somatic embryogenesis, such as arabinogalactan proteins, peroxidases, heat shock proteins, glutathione s-transferases, late embryogenesis abundant proteins, and 14-3-3 proteins. These results show that putrescine and the identified proteins play important roles in protecting the cells against an in vitro stress environment, contributing to the formation of somatic embryos during the maturation treatment. BIOLOGICAL SIGNIFICANCE: Despite all studies with somatic embryogenesis, the molecular mechanisms controlling the process have not been completely understood. In this study, we highlighted the effects of the polyamine putrescine on somatic embryogenesis of sugarcane and the differentially abundant proteins related to somatic embryo development. We identified six groups of important stress related proteins that are involved in the adaptation of cells to the stress environment of in vitro culture and may also be part of the mechanisms associated to the somatic embryogenesis process. Therefore, our research is trying to understand the complexity of how one single somatic cell becomes a whole plant. PMID- 26435421 TI - Membrane composition influences the activity of in vitro refolded human vitamin K epoxide reductase. AB - Human vitamin K epoxide reductase (hVKOR) is an integral membrane protein responsible for the maintenance of reduced vitamin K pools, a prerequisite for the action of gamma-glutamyl carboxylase and hence for hemostasis. Here we describe the recombinant expression of hVKOR as an insoluble fusion protein in Escherichia coli, followed by purification and chemical cleavage under denaturing conditions. In vitro renaturation and reconstitution of purified solubilized hVKOR in phospholipids could be established to yield active protein. Crucially, the renatured enzyme is inhibited by the powerful coumarin anticoagulant warfarin, and we demonstrate that enzyme activity depends on lipid composition. The completely synthetic system for protein production allows a rational investigation of the multiple variables in membrane protein folding and paves the way for the provision of pure, active membrane protein for structural studies. PMID- 26435422 TI - Immunolocalization and distribution of proteoglycans in carious dentine. AB - BACKGROUND: Collagen type I, proteoglycans (PG) and non-collagenous proteins represent important building blocks of the dentine matrix. While different PGs have been identified in dentine, changes in the distribution of these macromolecules with the progression of caries have been poorly characterized. The aim of this study was to compare the immunolocalization of three small collagen binding PGs (biglycan, fibromodulin and lumican) as well as collagen (types I and VI) in healthy versus carious dentine. METHODS: Longitudinal demineralized sections of extracted teeth were stained with antibodies recognizing specific PG core proteins and collagens, as well as glycosaminoglycans (GAGs) with toluidine blue. RESULTS: In healthy dentine, PGs appeared to be more abundant near the tubule walls and directly under the cusps. Conversely, in carious dentine, specific locations appeared to be more prone to PG degradation than others. These degradation patterns were well correlated with the progression of caries into the tissue, and also appeared to trigger interesting morphological changes in the tissue structure, such as the deformation of dentine tubules near highly infected areas and the lower concentration of PG in tertiary dentine. CONCLUSIONS: This study presents new insights into the involvement of PGs in the progression of caries. PMID- 26435423 TI - Pt/Fe3O4 Core/Shell Triangular Nanoprisms by Heteroepitaxy: Facet Selectivity at the Pt-Fe3O4 Interface and the Fe3O4 Outer Surface. AB - Pt/Fe3O4 core/shell triangular nanoprisms were synthesized using seed-mediated heteroepitaxy. Their well-defined shape, facets, and ordered-assembly allowed detailed analysis of mechanism of the heteroepitaxy. At the Pt-Fe3O4 interface, existence of both lattice and chemical mismatch resulted in facet-selective epitaxy along ?111? directions of two lattices. X-ray absorption fine structure measurements demonstrated that the Pt seed nanocrystals were composed of an iron rich Pt-Fe metallic thin layer sandwiched between the Pt core and a Fe-O outer surface. The Fe-O outer-surface of the seed nanocrystals presumably offered epitaxial sites for the following deposition of the Fe3O4 shell. Each tip and side of a triangular nanoprism respectively possessed a groove and a ridge, and a (111) plane parallel to the basal planes linked all grooves and ridges. This interesting (111) plane approximately bisected the triangle nanoprisms and located near the Pt-seed. The outer surface of the hybrid nanocrystals was also found to be facet-selective, that is, solely {111} facets of Fe3O4 lattice. These polar {111} facets allowed the surface to be only occupied with high-density iron ions, and thus offered best surface coordination for the electron donating ligands in the solution. PMID- 26435424 TI - Discussion. PMID- 26435425 TI - FGF23, metabolic risk factors, and blood pressure in patients with primary hyperparathyroidism undergoing parathyroid adenomectomy. AB - BACKGROUND: Fibroblast growth factor-23 (FGF23), a regulator of secretion of parathyroid hormone (PTH), is implicated in the development of cardiovascular disease. The role of FGF23 in primary hyperparathyroidism (pHPT) is unclear. METHODS: A total of 150 consecutive patients with pHPT were examined with ambulatory blood pressure monitoring ((24h)ABP) before parathyroid adenomectomy (PTX). Blood samples were collected 6 +/- 2 weeks before and 6 +/- 2 weeks after PTX. RESULTS: Plasma FGF23 levels decreased after PTX from a median of 45.2 pg/mL (interquartile range 37.6-54.8) to 36.8 pg/mL (26.7-48.7); P < .001. This postoperative decrease correlated with the decrease in ionized calcium (r = 0.24; P < .01). Greater FGF23 concentrations at baseline were associated with a greater weight of the adenoma and PTH levels, as well as with body mass index, triglycerides, and insulin levels and greater postoperative decreases in FGF23, ionized calcium, insulin growth-like factor 1, and insulin. FGF23 and PTH both correlated with greater blood pressures on (24h)ABP, especially at nighttime (r = 0.31 and r = 0.28; P <= .01), whereas after multivariate adjustment, only PTH remained independently associated with (24)ABP. CONCLUSION: Circulating FGF23 is increased in pHPT and is associated independently with the metabolic risk profile. The long-term benefit of decreasing FGF23 in pHPT after PTX remains to be established. PMID- 26435426 TI - Same thyroid cancer, different national practice guidelines: When discordant American Thyroid Association and National Comprehensive Cancer Network surgery recommendations are associated with compromised patient outcome. AB - BACKGROUND: The American Thyroid Association (ATA) and National Comprehensive Cancer Network (NCCN) guidelines have discordant recommendations for managing patients with differentiated thyroid cancer (DTC). We hypothesized that physician adherence to either of the 2009 extent of surgery guidelines of the ATA or NCCN was associated with improved survival, and that practice is most standardized nationally when guidelines are concordant. METHODS: Adult patients undergoing surgery for DTC were included from the National Cancer Database. Multivariable modeling was used to identify factors associated with nonadherence to the 2009 ATA or NCCN guidelines (2010-2011) and hypothetically examine the association of retrospective adherence to guidelines with survival (1998-2006). RESULTS: A total of 39,687 patients with DTC were included; 2,249 were not treated in accordance with ATA or NCCN guidelines. Factors independently associated with nonadherence were discordance between ATA and NCCN recommendations, black race, and treatment at nonacademic centers (P < .01). After adjustment, care not in accordance with either set of guidelines was associated with compromised survival (hazard ratio 1.16, P = .02). CONCLUSION: A minority of patients received surgery for DTC not aligned with guidelines; nonadherent care was associated with compromised survival. Discordance in recommendations between guidelines is associated with reduction in adherent care, suggesting that standardizing guidelines could decrease confusion, increase adherence, and thereby may improve outcomes. PMID- 26435427 TI - Cost disparity between health care systems--it's not the surgeons: A cost analysis of thyroid cancer care between the United States and France. AB - BACKGROUND: The cost disparity between the United States and other advanced health care systems, including France, is expanding. In this report we identified the management of papillary thyroid cancer (PTC) that contribute to reimbursement disparity. METHODS: A tri-institutional, retrospective review included 200 patients with PTC (100 from the United States, 100 from France) treated by total thyroidectomy with/without central neck dissection. A cost model was generated incorporating perioperative management variables (within 1 year) and their reimbursement rates according to the 2014 US Medicare and French government fee schedules. RESULTS: In the United States, total thyroidectomy with central neck dissection was more frequent (92% vs 35%, P < .001), median duration of stay was less (1 vs 3 days, P < .001), and use of radioactive iodine was less (66% vs 93%, P < .001), although Thyrogen stimulation was more prevalent (100% vs 43%, P < .001). Overall, the median cost per patient was greater in the United States ($14,069 vs $4,590, P < .001). Reimbursements to the hospital facility accounted for 70% of the disparity, despite lesser durations of stay. Nuclear medicine accounted for 19%, mostly from Thyrogen reimbursement despite less use of radioactive iodine. Surgeon fees accounted for 6%, followed by office visits, laboratory/imaging, anesthesia/pathology fees, and medications. CONCLUSION: The costs of management of PTC are substantially greater in the US compared with France. Efforts to decrease this disparity should focus on reimbursements for hospital facility and use of nuclear medicine imaging. PMID- 26435428 TI - Effect of malignancy rates on cost-effectiveness of routine gene expression classifier testing for indeterminate thyroid nodules. AB - BACKGROUND: The value of gene expression classifier (GEC) testing for cytologically indeterminate thyroid nodules lies in its negative predictive value, which is influenced by the prevalence of malignancy. We incorporated actual GEC test performance data from a tertiary referral center into a cost effectiveness analysis of GEC testing. METHODS: We evaluated consecutive patients who underwent GEC testing for Bethesda category III and IV nodules from 2012 to 2014. Routine GEC testing was compared with conventional management by the use of a decision tree model. Additional model variables were determined via literature review. A cost-effectiveness threshold of $100,000 per quality-adjusted life-year (QALY) was used. RESULTS: The prevalence of malignancy was 24.3% (52/214). Sensitivity and specificity of GEC testing were 96% and 60%. Conventional management cost $11,119 and yielded 22.15 QALYs. Routine GEC testing was more effective and more costly, with an incremental cost-effectiveness ratio of $119,700/QALY, making it not cost-effective. At malignancy rates of 15, 25, or 35%, routine GEC testing became cost-effective when the cost of GEC testing fell below $3,167, $2,595, or $2,023. CONCLUSION: The cost-effectiveness of routine GEC testing varies inversely with the underlying prevalence of malignancy in the tested population. The value of routine GEC testing should be assessed within the context of institution-specific malignancy rates. PMID- 26435429 TI - Acute deterioration after emergency paraesophageal hernia repair. PMID- 26435430 TI - Discussion. PMID- 26435431 TI - Diagnostic utility of data from adrenal venous sampling for primary aldosteronism despite failed cannulation of the right adrenal vein. AB - BACKGROUND: Adrenal venous sampling is an important lateralization study for primary aldosteronism, but inability to cannulate the right adrenal vein is not uncommon and interpreted as a failed study. We challenged this notion by examining whether data from incomplete left-sided adrenal venous sampling could accurately predict lateralization. METHODS: Sixty-two adrenal venous sampling studies from 2007 to 2014 at 2 tertiary-care institutions were reviewed. For this analysis, data from the right adrenal vein were excluded. The study variable was the aldosterone:cortisol ratio of the left adrenal vein compared with the inferior vena cava (LAV/IVC). Scatterplot analysis identified high and low LAV/IVC cutoffs that predicted accurately unilateral disease in 1 institutional cohort and validated in the second cohort. RESULTS: Thirty-six studies of adrenal venous sampling were evaluated at the first institution and divided into 3 diagnostic categories: unilateral-left (n = 14), unilateral-right (n = 12), and bilateral (n = 10). Cutoff values of the ratios of LAV/IVC of >= 5.5 and <= 0.5 accurately predicted left- and right-sided disease, respectively, and were validated in 26 studies from the second institution (100% PPV). The "5.5-0.5 criteria" salvaged accuracy for predicting lateralization in 50% of cases. CONCLUSION: Even in the setting of failed cannulation of the right adrenal vein, the actual data from the remaining adrenal venous sampling can predict lateralization accurately in many patients. A "failed" adrenal venous sampling study may be of greater predictive utility than believed traditionally. PMID- 26435432 TI - Discussion. PMID- 26435433 TI - Selective strategy for intensive monitoring after pheochromocytoma resection. AB - BACKGROUND: Guidelines recommend 24-48 hours of intensive monitoring after resection of pheochromocytoma. However, many patients do not require it. The objective of this study is to identify preoperative risk factors associated with postoperative hemodynamic instability (HDI) so as to select patients who may not require intensive postoperative monitoring. METHODS: Medical records of patients undergoing pheochromocytoma resection over a 12-year period were reviewed. Postoperative HDI was defined as systolic blood pressure of >200 or <90, heart rate >110 or <50 or needing active resuscitation. RESULTS: We included 41 patients; 49% had postoperative HDI but only 34% had HDI > 6 hours. Risk factors for HDI were preoperative mean arterial pressure (MAP) > 100 mm Hg (14% vs 45%), norepinephrine/normetanephrine levels >3x normal (44 vs 82%), and resection of another solid organ (0 vs 20%). Avoidance of planned postoperative monitoring for low-risk patients would have reduced estimated costs by 34%. CONCLUSION: Fewer than one-half of patients undergoing resection for pheochromocytoma benefit from intensive monitoring. High preoperative MAP, high norepinephrine/normetanephrine levels, and concomitant resection of another organ are risk factors for postoperative HDI. After a 6-hour interval of postoperative stability, selective rather than routine use of intensive monitoring may be an efficient strategy for monitoring lower risk patients. PMID- 26435434 TI - A pilot study investigating the effect of parathyroidectomy on arterial stiffness and coronary artery calcification in patients with primary hyperparathyroidism. AB - BACKGROUND: Arterial stiffness (AS) and coronary artery calcification (CAC) are predictors of cardiovascular risk and can be measured noninvasively. The aim of this study was to analyze the effects of parathyroidectomy on AS and CAC in patients with primary hyperparathyroidism (PHP). METHODS: This prospective, institutional review board-approved study included 21 patients with PHP, who underwent parathyroidectomy. Before and 6 months after parathyroidectomy, AS was assessed by measuring central systolic pressure (CSP), central pulse pressure, augmentation pressure (AP), and augmentation index (AIx); the CAC score (Agatston) was calculated on noncontrast computed tomography. AS parameters were compared with unaffected controls from donor nephrectomy database. RESULTS: Preoperative CSP and AIx parameters in PHP patients were higher than those in donor nephrectomy patients (P = .004 and P = .039, respectively). Preoperative total CAC score was zero in 15 patients (65%) and ranged from the 72nd to the 99th percentile in 6 patients (26%). Although there were no changes in CAC or AS after parathyroidectomy on average, there was variability in individual patient responses on AS. CONCLUSION: This pilot study demonstrates that CAC is not altered in PHP patients at short-term follow-up after parathyroidectomy. The heterogeneous changes in AS after parathyroidectomy warrant further investigation in a larger study with longer follow-up. PMID- 26435435 TI - Discussion. PMID- 26435436 TI - Risk factors for central lymph node metastasis in papillary thyroid carcinoma: A National Cancer Data Base (NCDB) study. AB - BACKGROUND: There is no consensus regarding prophylactic central lymph node dissection (pCLND) in patients with papillary thyroid carcinoma (PTC). Identification of risk factors for central lymph node metastasis (CLNM) in patients with PTC could assist surgeons in determining whether to perform selective pCLND. METHODS: The National Cancer database was queried from 1998 to 2011 for patients with clinical staging T1-4cN0M0 PTC. All patients underwent near, sub-, or total thyroidectomy with or without pCLND. Univariate and multivariable logistic regressions were performed on the following clinical variables: age, sex, race and tumor size as risk factors for pathologic CLNM (pN1a). RESULTS: In 39,562 patients with T1-4cN0M0 PTC, 61% underwent pCLND. Patients with age >45 years, African American race, tumor size <= 1 cm, unifocal tumors, follicular variant PTC, no insurance, and treatment at community cancer facilities were less likely to have pCLND (P < .001). In the pCLND group, 15.6% of patients had CLNM. On adjusted multivariable logistic regression, age <= 45 years, Asian race, male sex, and larger tumors were statistically significantly associated with CLNM. CONCLUSION: Age <= 45 years, Asian race, male sex, and larger tumors are associated with the presence of CLNM, which allows for selective pCLND in PTC. PMID- 26435437 TI - Discussion. PMID- 26435438 TI - Outcome of inferior vena cava and noncaval venous leiomyosarcomas. AB - BACKGROUND: Leiomyosarcoma (LMS) is a rare tumor arising from the smooth muscle cells of arteries and veins. LMS may affect both the inferior vena cava (IVC) and non-IVC veins. Because of its rarity, the experience with the outcome of the disease originating from the IVC compared with that with non-IVC offspring is overall limited. In this study, we compared the clinical features and outcomes after operative resection of IVC and non-IVC LMS to detect possible significant differences that could affect treatment and prognosis. METHODS: Twenty-seven patients undergoing operative resection of a venous LMS at a single tertiary care center and one secondary care hospital were reviewed retrospectively and divided into 2 groups: IVC-LMS (Group A, n = 18) and non-IVC LMS (Group B, n = 9). As primary end points, postoperative mortality and morbidity, disease-specific survival and, if applicable, patency of venous reconstruction were considered. Bivariate differences were compared with the chi(2) test. Disease-specific survival was expressed by a life-table analysis and compared using the log-rank test. RESULTS: No postoperative mortality was observed in either group. Postoperative morbidity was 28% in group A and 11% in group B (P = .33). The mean duration of follow-up was 60 months (range, 13-140). Disease-specific survival was 60% in group A and 75% in group B at 3 years (P = .48), and it was 54% in group A and 62% in group B at 5 years (P = .63). Seven grafts were occluded in group A (39%) and 1of 3 were occluded in group B (33%) (P = .85). CONCLUSION: IVC and non-IVC LMS exhibit similar outcomes in terms of postoperative course and survival. Operative resection associated with vascular reconstruction, if applicable, eventually followed by radiation and chemotherapy may be curative and is associated with good functional results. PMID- 26435439 TI - Discussion. PMID- 26435441 TI - Discussion. PMID- 26435440 TI - Recurrence of papillary thyroid carcinoma with lateral cervical node metastases: Predictive factors and operative management. AB - BACKGROUND: Lateral neck lymph node (LN) metastases (N1b) have been identified as independent risk factors of recurrence in patients with papillary thyroid carcinoma (PTC). OBJECTIVE: This study aimed to determine the predictive factors of recurrence in N1b PTC patients and to clarify the postoperative event patterns. METHODS: All patients who underwent operation for N1b PTC between 1978 and 2012 were reviewed. The median follow-up period was 6.5 years. RESULTS: In total, 344 N1b patients were included. Twenty-four patients (7%) were lost to long-term follow-up. Among the remaining 320 patients, the mean (+/- SD) follow up time was 8.9 +/- 8.8 years (median, 6.5; range, 2-36.4). Eighty-two patients (26%) presented with lymph node recurrence (LR). Multivariate analyses showed that LN metastases with extracapsular extension and the LN ratio (ratio between the number of N1 and number of resected LN) in the lateral compartment were independent predictors of recurrent disease. The median time to reoperation was 19 months (range, 3-173), with 79% of reoperations occurring within 2 years after the initial thyroidectomy. Reoperations for LR (75 patients) were performed in 76% of the patients with a focused minimal access approach or selective LN dissection. After curative reoperative surgery for recurrence, complications occurred in 6 patients (8%), including a 1% permanent complication rate. CONCLUSION: Extranodal extension of LN metastases and the LN ratio in the lateral compartment are prognostic factors for recurrence. In most cases, reoperation for LR can be performed with a focused minimal access approach, with a low morbidity rate. PMID- 26435442 TI - Discussion. PMID- 26435443 TI - Discussion. PMID- 26435444 TI - Facilitators and barriers of implementing enhanced recovery in colorectal surgery at a safety net hospital: A provider and patient perspective. AB - BACKGROUND: Enhanced Recovery After Surgery (ERAS) pathways are known to decrease complications and duration of stay in colorectal surgery patients. However, it is unclear whether an ERAS pathway would be feasible and effective at a safety-net hospital. The aim of this study was to identify local barriers and facilitators before the adoption of an ERAS pathway for patients undergoing colorectal operations at a safety-net hospital. METHODS: Semistructured interviews were conducted to assess the perceived barriers and facilitators before ERAS adoption. Stratified purposive sampling was used. Interviews were audiotaped, transcribed verbatim, and analyzed using content analysis. Analytic and investigator triangulation were used to establish credibility. RESULTS: Interviewees included 8 anesthesiologists, 5 surgeons, 6 nurses, and 18 patients. Facilitators identified across the different medical professions were (1) feasibility and alignment with current practice, (2) standardization of care, (3) smallness of community, (4) good teamwork and communication, and (5) caring for patients. The barriers were (1) difficulty in adapting to change, (2) lack of coordination between different departments, (3) special needs of a highly comorbid and socioeconomically disadvantaged patient population, (4) limited resources, and (5) rotating residents. Facilitators identified by the patients were (1) welcoming a speedy recovery, (2) being well-cared for and satisfied with treatment, (3) adequate social support, (4) welcoming early mobilization, and (5) effective pain management. The barriers were (1) lack of quiet and private space, (2) need for more patient education and counseling, and (3) unforeseen complications. CONCLUSION: Although limited hospital resources are perceived as a barrier to ERAS implementation at a safety-net hospital, there is strong support for such pathways and multiple factors were identified that may facilitate change. Inclusion of patient perspectives is critical to identifying challenges and facilitators to implementing ERAS changes focused on optimizing patient perioperative health and outcomes. PMID- 26435445 TI - Defining competencies for safe thyroidectomy: An international Delphi consensus. AB - BACKGROUND: Current methods for teaching and assessing competencies that characterize expert intraoperative performance are inconsistent, subjective, and lack standardization. This mixed-methods study was designed to define and establish expert consensus on the most important competencies required to perform a thyroidectomy safely. METHODS: Cognitive task analyses for thyroidectomy were performed with semistructured interviews of experts in thyroid surgery. Verbal data were transcribed verbatim, coded, and categorized according to themes that were synthesized into a list of items. Once qualitative data reached saturation, 26 experts were invited to complete 2-round online Delphi surveys to rank each item on a Likert scale of importance (1-7). Consensus was predefined as a Cronbach's alpha >= 0.80. RESULTS: Sixty items were synthesized from 5 interviews and categorized into 8 sections: preparation (n = 8), incision/exposure (n = 11), general considerations (n = 4), middle thyroid vein (n = 1), superior pole (n = 5), inferior pole (n = 5), posterolateral dissection (n = 19), and closure (n = 7). Eighteen (69%) experts from 3 countries participated in the Delphi survey. Consensus was achieved after 2 voting rounds (Cronbach's alpha = 0.95). Greatest weighted sections included "Superior Pole Dissection" and "Posterolateral Dissection." CONCLUSION: Consensus was achieved on defining the most important competencies for safe thyroidectomy. This blueprint serves as the basis for instructional design and objective assessment tools to evaluate performance. PMID- 26435446 TI - Transition State Gauche Effects Control the Torquoselectivities of the Electrocyclizations of Chiral 1-Azatrienes. AB - Hsung et al. have reported a series of torquoselective electrocyclizations of chiral 1-azahexa-1E,3Z,5E-trienes that yield functionalized dihydropyridines. To understand the origins of the torquoselectivities of these azaelectrocyclizations, we modeled these electrocyclic ring closures using the M06-2X density functional. A new stereochemical model that rationalizes the observed 1,2 stereoinduction emerges from these computations. This model is an improvement and generalization of the "inside-alkoxy" model used to rationalize stereoselectivities of the 1,3-dipolar cycloaddition of chiral allyl ethers and emphasizes a stabilizing hyperconjugative effect, which we have termed a transition state gauche effect. This stereoelectronic effect controls the conformational preferences at the electrocyclization transition states, and only in one of the allowed disrotatory electrocyclization transition states is the ideal stereoelectronic arrangement achieved without the introduction of a steric clash. Computational experiments confirm the role of this effect as a stereodeterminant since substrates with electropositive groups and electronegative groups have different conformational preferences at the transition state and undergo ring closure with divergent stereochemical outcomes. This predicted reversal of stereoselectivity for the ring closures of several silyl substituted azatrienes have been demonstrated experimentally. PMID- 26435447 TI - Does Medial Meniscal Allograft Transplantation With the Bone-Plug Technique Restore the Anatomic Location of the Native Medial Meniscus? AB - BACKGROUND: Previous work has shown the importance of restoring the normal structure of the native meniscus with meniscal allograft transplantation. PURPOSE/HYPOTHESIS: The purpose of this study was to compare the anatomic positions of the anterior horn and posterior horn between the preoperative medial meniscus and the postoperative meniscal allograft after medial meniscal allograft transplantation with the bone-plug technique. The hypothesis was that the bone plug technique could restore the preoperative structure of the native medial meniscus. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between December 1999 and December 2013, a total of 59 patients (49 male, 10 female) underwent medial meniscal allograft transplantation by use of the bone-plug technique. The anatomic positions of both horns in the native medial meniscus and in the meniscal allograft were measured via MRI. The percentage reference method was used to measure the locations of both horns. RESULTS: On coronal MRI, the mean absolute distance of the posterior horn from the lateral border of the tibial plateau changed from 45.2 +/- 3.3 to 48.1 +/- 4.2 mm (P < .05), and the percentage distance of the posterior horn changed from 59.6% to 63.0% (P < .05). On sagittal MRI, the mean absolute distance of the posterior horn from the anterior reference point changed from 40.3 +/- 3.0 to 42.0 +/- 3.5 mm (P < .05), and the mean percentage distance of the posterior horn changed from 76.5% to 79.4% (P <.05). On coronal MRI, the mean absolute distance of the anterior horn from the lateral border of the tibial plateau changed from 41.3 +/- 4.2 to 48.5 +/- 5.6 mm (P < .05), and the mean percentage distance of the anterior horn changed from 54.5% to 63.8% (P < .05). On sagittal MRI, the mean absolute distance of the anterior horn from the anterior reference point changed from 5.5 +/- 1.0 to 9.9 +/- 2.9 mm (P < .05), and the mean percentage distance of the anterior horn changed from 10.6% to 19.0% (P < .05). CONCLUSION: Despite attempts to place the meniscal allograft in the same position as the native meniscus, the anatomic locations of both horns were shifted posteromedially compared with those of the native medial meniscus. There were significant differences, attributed to several limitations in the bone-plug technique, between the preoperative and postoperative values of both horns. However, the posterior horn showed a location change of <5 mm, on average, in both the coronal and sagittal planes, whereas the anterior horn showed a location change of >= 5 mm in the coronal plane but <5 mm in the sagittal plane. PMID- 26435448 TI - Factors Affecting the Outcomes of Double-Bundle Medial Patellofemoral Ligament Reconstruction for Recurrent Patellar Dislocations Evaluated by Multivariate Analysis. AB - BACKGROUND: Many factors are involved in causing patellar instability or recurrent patellar dislocations. However, factors affecting the outcomes of anatomic medial patellofemoral ligament (MPFL) reconstruction have not been fully documented. PURPOSE: To evaluate the rate of recurrent patellar instability after isolated MPFL reconstruction and to elucidate factors affecting the outcomes of isolated MPFL reconstruction using multivariable statistics. STUDY DESIGN: Case control study; Level of evidence, 3. METHODS: A total of 42 patients (44 knees) who underwent isolated, anatomic MPFL reconstruction using a semitendinosus autograft without any additional patellar stabilization procedures for treating recurrent patellar dislocations were included in this study. All patients were followed for more than 2 years; the mean follow-up period was 3.2 years (range, 2 9 years). Postoperative patellofemoral instability was diagnosed when the patient complained of recurrent patellar subluxations or dislocations or had a positive apprehension sign during follow-up. Preoperative radiographic findings were obtained using plain radiography and computed tomography. Femoral tunnel positions were assessed on postoperative radiographs. The strength of the relationship between postoperative patellofemoral instability and potential risk factors such as preoperative age, sex, body mass index, patellar type, sulcus angle, congruence angle, lateral tilt angle, patellar height, tibial tubercle trochlear groove (TT-TG) distance, degree of trochlear dysplasia, and femoral bone tunnel position were evaluated by univariate and multivariate logistic regression analyses. RESULTS: At follow-up, 2 knees had experienced a redislocation (4.5%). A positive apprehension sign was still evident in 8 knees (18.2%). Three factors, including the sulcus angle, the congruence angle, and trochlear dysplasia, were extracted by single linear regression analysis. Univariate logistic regression analysis showed that the sulcus angle (odds ratio [OR], 1.11; 95% CI, 1.01-1.22; P = .04) and trochlear dysplasia (OR, 3.04; 95% CI, 1.39-6.63; P = .01) were associated with postoperative patellofemoral instability. Trochlear dysplasia was independently associated with postoperative patellofemoral instability by multivariable logistic regression analysis (P < .05). An increased TT-TG distance exerted a significant effect on the outcomes of MPFL reconstruction, particularly in patients with type D trochlea. CONCLUSION: Severe trochlear dysplasia is the most important predictor of residual patellofemoral instability after isolated MPFL reconstruction. In addition, an increased TT-TG distance affected the outcomes in patients with type D trochlea. Additional patellar stabilization procedures should be considered for patients with severe trochlear dysplasia and an increased TT-TG distance. PMID- 26435449 TI - The role of vitamin A and retinoic acid receptor signaling in post-natal maintenance of bone. AB - Vitamin A and retinoid derivatives are recognized as morphogens that govern body patterning and skeletogenesis, producing profound defects when in excess. In post natal bone, both high and low levels of vitamin A are associated with poor bone heath and elevated risk of fractures. Despite this, the precise mechanism of how retinoids induce post-natal bone changes remains elusive. Numerous studies have been performed to discover how retinoids induce these changes, revealing a complex morphogenic regulation of bone through interplay of different cell types. This review will discuss the direct and indirect effects of retinoids on mediators of bone turnover focusing on differentiation and activity of osteoblasts and osteoclasts and explains why some discrepancies in this field have arisen. Importantly, the overall effect of retinoids on the skeleton is highly site-specific, likely due to differential regulation of osteoblasts and osteoclasts at trabecular vs. cortical periosteal and endosteal bone surfaces. Further investigation is required to discover the direct gene targets of retinoic acid receptors (RARs) and molecular mechanisms through which these changes occur. A clear role for RARs in regulating bone is now accepted and the therapeutic potential of retinoids in treating bone diseases has been established. PMID- 26435450 TI - Complete androgen insensitivity syndrome caused by a novel splice donor site mutation and activation of a cryptic splice donor site in the androgen receptor gene. AB - The androgen insensitivity syndrome is an X-linked recessive genetic disorder characterized by resistance to the actions of androgens in an individual with a male karyotype. We evaluated a 34-year-old female with primary amenorrhea and a 46,XY karyotype, with normal secondary sex characteristics, absence of uterus and ovaries, intra-abdominal testis, and elevated testosterone levels. Sequence analysis of the androgen receptor (AR) gene revealed a novel splice donor site mutation in intron 4 (c.2173+2T>C). RT-PCR analysis showed that this mutation resulted in the activation of a cryptic splice donor site located in the second half of exon 4 and in the synthesis of a shorter mRNA transcript and an in-frame deletion of 41 amino acids. This novel mutation associated with a rare mechanism of abnormal splicing further expands the spectrum of mutations associated with the androgen insensitivity syndrome and may contribute to the understanding of the molecular mechanisms involved in splicing defects. PMID- 26435452 TI - Computational analysis of liquid chromatography-tandem mass spectrometric steroid profiling in NCI H295R cells following angiotensin II, forskolin and abiraterone treatment. AB - Adrenal steroid hormones, which regulate a plethora of physiological functions, are produced via tightly controlled pathways. Investigations of these pathways, based on experimental data, can be facilitated by computational modeling for calculations of metabolic rate alterations. We therefore used a model system, based on mass balance and mass reaction equations, to kinetically evaluate adrenal steroidogenesis in human adrenal cortex-derived NCI H295R cells. For this purpose a panel of 10 steroids was measured by liquid chromatographic-tandem mass spectrometry. Time-dependent changes in cell incubate concentrations of steroids including cortisol, aldosterone, dehydroepiandrosterone and their precursors - were measured after incubation with angiotensin II, forskolin and abiraterone. Model parameters were estimated based on experimental data using weighted least square fitting. Time-dependent angiotensin II- and forskolin-induced changes were observed for incubate concentrations of precursor steroids with peaks that preceded maximal increases in aldosterone and cortisol. Inhibition of 17-alpha hydroxylase/17,20-lyase with abiraterone resulted in increases in upstream precursor steroids and decreases in downstream products. Derived model parameters, including rate constants of enzymatic processes, appropriately quantified observed and expected changes in metabolic pathways at multiple conversion steps. Our data demonstrate limitations of single time point measurements and the importance of assessing pathway dynamics in studies of adrenal cortical cell line steroidogenesis. Our analysis provides a framework for evaluation of steroidogenesis in adrenal cortical cell culture systems and demonstrates that computational modeling-derived estimates of kinetic parameters are an effective tool for describing perturbations in associated metabolic pathways. PMID- 26435451 TI - Sex differences in neurodevelopmental and neurodegenerative disorders: Focus on microglial function and neuroinflammation during development. AB - Several neurological conditions are associated with sex differences in prevalence or outcome. For example, autism predominantly affects boys, depression is more common in women, Parkinson's disease more common in men, and multiple sclerosis in women. In the case of stroke, women have a less favorable outcome and suffer from a more precipitous drop in health status compared to men. As a result, treatment of such diseases is difficult and yields variable results. Despite this, sex is rarely considered when making treatment decisions. The mechanisms underlying sex differences in disease progression are not well understood, however a strong link exists between different inflammation states of men and women and their propensity to develop certain diseases. As neuroinflammation is an important component of pathophysiology in many neurological conditions, it can be speculated that any changes in the state of inflammation in the brain during normal development can potentially lead to an increase in susceptibility to neurological and neurodegenerative diseases. Microglia play a crucial role in onset and modulation of inflammation and thus sex differences in microglial function could explain, at least in part, differences observed in susceptibilities and outcomes of neurological disorders in men and women. Understanding the mechanisms behind sex differences could help develop more targeted therapy with higher success rate, especially in diseases where sex differences are most prominent. PMID- 26435453 TI - Intracellular localization and dynamics of Hypericin loaded PLLA nanocarriers by image correlation spectroscopy. AB - The study of cell-nanoparticle interactions is an important aspect for understanding drug delivery using nanocarriers. In this regard, advances in fluorescence based microscopy are useful for the investigation of temporal and spatial behavior of nanoparticles (NPs) within the intracellular environment. In this work, we focus on the delivery of the naturally-occurring hydrophobic photosensitizer Hypericin in human lung carcinoma A549 cells by using biodegradable poly L-lactic acid NPs. For the first time, Hypericin containing NPs are prepared by combining the miniemulsion technique with the solvent evaporation method. This approach yields an efficient loading of the NPs with Hypericin and allows for additional cargo molecules. To monitor the release of Hypercin from the NPs, an additional fluorescent lipophilic dye Coumarin-6 is incorporated in the NPs. Temporal and spatiotemporal image correlation spectroscopy is used to determine the fate of the NPs carrying the potential cargo. Both directed and non-directed motions are detected. By using image cross correlation spectroscopy and specific fluorescent labeling of endosomes, lysosomes and mitochondria, the dynamics of the cargo loaded NPs in association with the organelles is studied. PMID- 26435454 TI - Delivery strategies for treatment of age-related ocular diseases: From a biological understanding to biomaterial solutions. AB - Age-related ocular diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and glaucoma, result in life-long functional deficits and enormous global health care costs. As the worldwide population ages, vision loss has become a major concern for both economic and human health reasons. Due to recent research into biomaterials and nanotechnology major advances have been gained in the field of ocular delivery. This review provides a summary and discussion of the most recent strategies employed for the delivery of both drugs and cells to the eye to treat a variety of age-related diseases. It emphasizes the current challenges and limitations to ocular delivery and how the use of innovative materials can overcome these issues and ultimately provide treatment for age-related degeneration and regeneration of lost tissues. This review also provides critical considerations and an outlook for future studies in the field of ophthalmic delivery. PMID- 26435457 TI - Paratesticular Rhabdomyosarcoma Presenting With a Giant Abdominoscrotal Hydrocele in a Toddler. AB - Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in infants and children. Paratesticular RMS accounts for approximately 7% of all RMSs. It commonly presents as a painless scrotal mass, which is usually distinct from the testis. We report an unusual case of paratesticular RMS presenting with a giant abdominoscrotal hydrocele in a toddler. To the best of our knowledge, this is the first case of paratesticular RMS presenting with an abdominoscrotal hydrocele. PMID- 26435456 TI - Inter-polyelectrolyte nano-assembly induces folding and activation of functional peptides. AB - Insufficient solubility, fragile folding structure and short half-life frequently hamper use of peptides as biological reagents or therapies. To enhance the peptide function, the effect of complexation of the peptides with ionic graft copolymers with water-soluble graft chains was tested in this study. Amphiphilic anionic peptide E5 acquires membrane disrupting activity at acidic pH due to folding from the random coil state to an ordered alpha-helical structure. Aggregation and imprecise folding of the peptide limited membrane disrupting activity of the peptide. In the presence of a cationic graft copolymer, E5 and its analogs adopted an ordered conformation without aggregation. The mixture of the peptides and the copolymer functioned more efficiently than peptide alone at not only acidic pH but also neutral pH at which the peptide alone had no activity. Similarly, a cationic peptide was successfully folded and activated by an anionic graft copolymer. Thus, our analysis indicated that spontaneous nano assembly of ionic peptides with graft copolymers having opposite ionic charges triggers the folding of peptides without loss of solubility, leading to enhanced bioactivity. PMID- 26435458 TI - Adult Pleomorphic Juxtaglomerular Cell Tumor. AB - A 40-year-old male with chronic hypertension since his teens presented to the emergency department following a motor vehicle collision. Computed tomography scan demonstrated an incidental 1.8-cm renal mass. Partial nephrectomy revealed a vascular tumor with predominantly monomorphic epithelioid cells arranged in sheets and trabeculae with foci of nuclear pleomorphism. Tumor cells were positive for vimentin, CD34, and c-KIT. Juxtaglomerular cell tumor is a rare, benign neoplasm typically found in young adults. Pleomorphism is uncommon and, in combination with older age at diagnosis, can lead to an inaccurate malignant diagnosis. Immunohistochemistry and clinical history helps in correctly diagnosing this benign entity. PMID- 26435459 TI - Value of transverse relaxometry difference methods for iron in human brain. AB - PURPOSE: To investigate the brain iron dependence of transverse relaxation rate difference methods derived from spin echo and gradient echo measurements from two field strengths. METHODS: Transverse relaxation rates R2 and R2(*) were measured in human brain in 17 healthy subjects at 1.5T and 4.7T using multi-slice, multiecho spin echo and gradient echo sequences. R2 quantification used stimulated echo compensation and R2(*) quantification used linear background gradient correction at 4.7T only. Subtraction of R2 from R2(*) within each field strength yielded R2('), and R2 subtraction across fields yielded Field Dependent R2 Increase (FDRI). All transverse relaxation measures were then correlated with published post-mortem iron concentrations using linear regression analysis. Regional differences were tested using paired t-tests. Phantom measurements of FDRI were also performed. RESULTS: In deep grey matter, all transverse relaxation rates (R2, R2(*), R2(')) at both 1.5T and 4.7T, and FDRI had moderate to strong correlations (r>0.71, p<0.0001) with estimated non-heme iron. The 4.7T methods and FDRI had higher correlations (r>0.9) than 1.5T measures. R2, R2(*), R2' at 4.7T and FDRI had slopes 0.49, 1.96, 1.48 and 0.33 [s(-1)/mg Fe/100g wt. tissue] and intercepts 14.40, 16.87, 2.47 and 3.21 [s(-1)] respectively. Even though FDRI yielded a zero intercept in phantom, in vivo FDRI was found to be ineffective at fully removing non-iron contributions and yielded a large intercept. The slope for R2(') was 3.4 times greater at 4.7T than 1.5T. For white matter fiber tracts oriented predominantly perpendicular versus parallel to B0, R2(') increased by ~50% at 4.7T and ~30% at 1.5T, while R2 and FDRI in white matter was insensitive to its orientation with respect to B0. CONCLUSION: The transverse relaxation difference methods FDRI and R2(') at 4.7T had high correlations to predicted iron content similar to R2 and R2(*) at 4.7T. Although R2(') had smaller y-intercept with estimated iron concentration than FDRI, in white matter R2(') demonstrated strongest dependence on fiber orientation with respect to B0. These results suggest that for brain iron correlation, there is minimal value of transverse difference methods over a single R2(*) measurement at highest available field, which was 4.7T. PMID- 26435460 TI - Ultrashort echo (UTE) versus pointwise encoding time reduction with radial acquisition (PETRA) sequences at 3 Tesla for knee meniscus: A comparative study. AB - PURPOSE: The purposes of this study were to (1) correlate the ultrashort echo time (TE) signal intensity of the pointwise encoding time reduction with radial acquisition (PETRA) sequence with that of the ultrashort echo (UTE) sequence using in vivo meniscal ultrashort TE imaging of the knee with a 3-Tesla (3T) clinical magnetic resonance imaging (MRI) scanner and (2) compare the two ultrashort TE sequences in three groups of patients with normal, degenerated, and torn knee menisci. MATERIALS AND METHODS: Following institutional review board approval, we analyzed 47 knee MRIs of 46 patients who presented with knee pain and underwent knee MRIs, including both the prototype 3D PETRA sequence knee MRI (TE: 70MUs) and the prototype 3D UTE sequence (TE: 70 MUs) using a 3T MRI scanner (MAGNETOM Trio, Siemens, Erlangen, Germany). The study group was classified into three subgroups: (1) normal meniscus on conventional MRI, with no positive meniscus-related physical examination on medical records; (2) meniscal degeneration; and (3) meniscal tear. For quantitative assessment, the mean signal intensities inside user-drawn regions of interest (ROIs) for each image set were drawn on the medical menisci as well as on the bone marrow of medical femoral condyle. For statistical analyses, the Pearson correlation test was used for correlation of the ultrashort TE signal intensity on the UTE and the PETRA sequences, and one-way ANOVA with post-hoc analysis using the Scheffe test was conducted to compare groups. RESULTS: The correlation test showed moderate correlation between the mean signal intensity values of the two ultrashort TE sequences (Pearson's coefficient: 0.4817; P<0.05; 95% CI: 0.3113-0.6221). The normalized mean signal intensity values were lower for patients with meniscal degeneration and tear on both the PETRA and the UTE images. The PETRA images showed the significantly difference between normal and tear groups and between degeneration and normal groups (P<0.05) whereas the UTE images showed significantly difference between normal and tear groups (P<0.05). CONCLUSION: Both the PETRA sequence and the UTE sequence can visualize the short T2 tissue. We demonstrated that there was significantly lower signal intensity on the ultrashort TE UTE and the PETRA images of patients with meniscal tear. PMID- 26435455 TI - Targeted endothelial nanomedicine for common acute pathological conditions. AB - Endothelium, a thin monolayer of specialized cells lining the lumen of blood vessels is the key regulatory interface between blood and tissues. Endothelial abnormalities are implicated in many diseases, including common acute conditions with high morbidity and mortality lacking therapy, in part because drugs and drug carriers have no natural endothelial affinity. Precise endothelial drug delivery may improve management of these conditions. Using ligands of molecules exposed to the bloodstream on the endothelial surface enables design of diverse targeted endothelial nanomedicine agents. Target molecules and binding epitopes must be accessible to drug carriers, carriers must be free of harmful effects, and targeting should provide desirable sub-cellular addressing of the drug cargo. The roster of current candidate target molecules for endothelial nanomedicine includes peptidases and other enzymes, cell adhesion molecules and integrins, localized in different domains of the endothelial plasmalemma and differentially distributed throughout the vasculature. Endowing carriers with an affinity to specific endothelial epitopes enables an unprecedented level of precision of control of drug delivery: binding to selected endothelial cell phenotypes, cellular addressing and duration of therapeutic effects. Features of nanocarrier design such as choice of epitope and ligand control delivery and effect of targeted endothelial nanomedicine agents. Pathological factors modulate endothelial targeting and uptake of nanocarriers. Selection of optimal binding sites and design features of nanocarriers are key controllable factors that can be iteratively engineered based on their performance from in vitro to pre clinical in vivo experimental models. Targeted endothelial nanomedicine agents provide antioxidant, anti-inflammatory and other therapeutic effects unattainable by non-targeted counterparts in animal models of common acute severe human disease conditions. The results of animal studies provide the basis for the challenging translation endothelial nanomedicine into the clinical domain. PMID- 26435461 TI - Ca2+ influx through L-type Ca2+ channels and Ca2+-induced Ca2+ release regulate cAMP accumulation and Epac1-dependent ERK 1/2 activation in INS-1 cells. AB - We previously reported that INS-1 cells expressing the intracellular II-III loop of the L-type Ca(2+) channel Cav1.2 (Cav1.2/II-III cells) are deficient in Ca(2+) induced Ca(2+) release (CICR). Here we show that glucose-stimulated ERK 1/2 phosphorylation (GSEP) is slowed and reduced in Cav1.2/II-III cells compared to INS-1 cells. This parallels a decrease in glucose-stimulated cAMP accumulation (GS-cAMP) in Cav1.2/II-III cells. Influx of Ca(2+) via L-type Ca(2+) channels and CICR play roles in both GSEP and GS-cAMP in INS-1 cells since both are inhibited by nicardipine or ryanodine. Further, the Epac1-selective inhibitor CE3F4 abolishes glucose-stimulated ERK activation in INS-1 cells, as measured using the FRET-based sensor EKAR. The non-selective Epac antagonist ESI-09 but not the Epac2-selective antagonist ESI-05 nor the PKA antagonist Rp-cAMPs inhibits GSEP in both INS-1 and Cav1.2/II-III cells. We conclude that L-type Ca(2+) channel dependent cAMP accumulation, that's amplified by CICR, activates Epac1 and drives GSEP in INS-1 cells. PMID- 26435462 TI - Controversies in guidelines for the control of multidrug-resistant Gram-negative bacteria in EU countries. AB - The various guidelines that are available for multidrug-resistant Gram-negative bacteria are useful, and contain broad areas of agreement. However, there are also important areas of controversy between the guidelines in terms of the details of applying contact precautions, single-room isolation and active surveillance cultures, differences in the approach to environmental cleaning and disinfection, and whether or not to perform staff and patient cohorting, healthcare worker screening or patient decolonization. The evidence-base is extremely limited and further research is urgently required to inform an evidence based approach to multidrug-resistant Gram-negative bacteria prevention and control. PMID- 26435463 TI - Membrane protein structures without crystals, by single particle electron cryomicroscopy. AB - It is an exciting period in membrane protein structural biology with a number of medically important protein structures determined at a rapid pace. However, two major hurdles still remain in the structural biology of membrane proteins. One is the inability to obtain large amounts of protein for crystallization and the other is the failure to get well-diffracting crystals. With single particle electron cryomicroscopy, both these problems can be overcome and high-resolution structures of membrane proteins and other labile protein complexes can be obtained with very little protein and without the need for crystals. In this review, I highlight recent advances in electron microscopy, detectors and software, which have allowed determination of medium to high-resolution structures of membrane proteins and complexes that have been difficult to study by other structural biological techniques. PMID- 26435464 TI - Effect of dietary manganese on antioxidant status and expression levels of heat shock proteins and factors in tissues of laying broiler breeders under normal and high environmental temperatures. AB - To investigate the effect of Mn on antioxidant status and expression levels of heat-shock proteins/factors in tissues of laying broiler breeders subjected to heat challenge, we used a completely randomised design (n 6) with a factorial arrangement of 2 environmental temperatures (normal, 21 (sem 1) degrees C and high, 32 (sem 1) degrees C)*3 dietary Mn treatments (an Mn-unsupplemented basal diet (CON), or a basal diet supplemented with 120 mg Mn/kg diet as inorganic Mn sulphate (iMn) or organic Mn proteinate (oMn)). There were no interactions (P>0.10) between environmental temperature and dietary Mn in all of the measured indices. High temperature decreased (P<0.003) Mn content, and also tended (P=0.07) to decrease copper zinc superoxide dismutase (CuZnSOD) activity in the liver and heart. However, an increased manganese superoxide dismutase (MnSOD) activity (P<0.05) and a slight increase of malondialdehyde level (P=0.06) were detected in breast muscle. Up-regulated (P<0.05) expression levels of heat-shock factor 1 (HSF1) and HSF3 mRNA and heat-shock protein 70 (HSP70) mRNA and protein were found in all three tissues. Broiler breeders fed either iMn or oMn had higher tissue Mn content (P<0.0001), heart MnSOD and CuZnSOD activities (P<0.01) and breast muscle MnSOD protein levels (P<0.05), and lower (P<0.05) breast muscle HSP70 mRNA and protein levels than those fed CON. Broiler breeders fed oMn had higher (P<0.03) bone Mn content than those fed iMn. These results indicate that high temperature decreases Mn retention and increases HSP70 and HSF1, HSF3 expression levels in tissues of laying broiler breeders. Furthermore, dietary supplementation with Mn in either source may enhance heart antioxidant ability and inhibit the expression of HSP70 in breast muscle. Finally, the organic Mn appears to be more available than inorganic Mn for bone in laying broiler breeders regardless of environmental temperatures. PMID- 26435465 TI - A naphthalimide-based [12]aneN3 compound as an effective and real-time fluorescence tracking non-viral gene vector. AB - A novel bifunctional naphthalimide-based [12]aneN3 compound 1 was successfully applied as an effective non-viral gene vector in cancer cells, the fluorescence properties of 1 clearly demonstrated the process of cellular uptake, DNA translocation and release based on real-time fluorescence tracking. PMID- 26435466 TI - Structure and rheology of star polymers in confined geometries: a mesoscopic simulation study. AB - Mesoscopic simulations of star polymer melts adsorbed onto solid surfaces are performed using the dissipative particle dynamics (DPD) method. A set of parameters is developed to study the low functionality star polymers under shear. The use of a new bond-angle potential between the arms of the star creates more rigid chains and discriminates between different functionalities at equilibrium, but still allows the polymers to deform appropriately under shear. The rheology of the polymer melts is studied by calculating the kinetic friction and viscosity and there is good agreement with experimental properties of these systems. The study is completed with predictive simulations of star polymer solutions in an athermal solvent. PMID- 26435467 TI - Probing zeolites by vibrational spectroscopies. AB - This review addresses the most relevant aspects of vibrational spectroscopies (IR, Raman and INS) applied to zeolites and zeotype materials. Surface Bronsted and Lewis acidity and surface basicity are treated in detail. The role of probe molecules and the relevance of tuning both the proton affinity and the steric hindrance of the probe to fully understand and map the complex site population present inside microporous materials are critically discussed. A detailed description of the methods needed to precisely determine the IR absorption coefficients is given, making IR a quantitative technique. The thermodynamic parameters of the adsorption process that can be extracted from a variable temperature IR study are described. Finally, cutting-edge space- and time resolved experiments are reviewed. All aspects are discussed by reporting relevant examples. When available, the theoretical literature related to the reviewed experimental results is reported to support the interpretation of the vibrational spectra on an atomic level. PMID- 26435468 TI - Human Cytomegalovirus and Epstein-Barr Virus Genotypes in Apical Periodontitis Lesions. AB - INTRODUCTION: Different genotypes of human cytomegalovirus (HCMV) and Epstein Barr virus (EBV) possess specific pathogenic abilities because of various interactions with the host's immune system and differences in cell tropism. The aim of this study was to determine the distribution of HCMV and EBV genotypes in apical periodontitis lesions in relation to their clinical and histopathologic features. METHODS: One hundred samples of apical periodontitis lesions and 25 control samples (healthy pulp tissue) were collected. The presence of HCMV glycoprotein B (gB) and EBV nuclear antigen-2 genotypes was analyzed by nested polymerase chain reaction and restriction fragment length polymorphisms analysis. RESULTS: EBV and HCMV were detected in apical periodontitis lesions at significantly higher frequencies than in healthy pulp controls (P = .020 and P = .020, respectively). HCMV gB type II was significantly more frequent compared with gB type I in the examined groups (P = .036). No HCMV gB type III or IV products were found. In both periapical lesions and controls, EBV-1 occurred more often compared with EBV-2 (P = .001). Dual EBV and HCMV coinfection was more frequently detected in large-size periapical lesions (P = .038). CONCLUSIONS: Both HCMV and EBV are associated with inflammatory processes of periapical bone destruction. HCMV gB type II and EBV-1 are the most prevalent genotypes in apical periodontitis lesions. PMID- 26435469 TI - Combined Effects of Growth Hormone and Mineral Trioxide Aggregate on Growth, Differentiation, and Angiogenesis in Human Dental Pulp Cells. AB - INTRODUCTION: The aim of this study was to evaluate the effects of growth hormone (GH) on mineral trioxide aggregate (MTA) with regard to cell adhesion, growth, odontoblastic differentiation, and angiogenesis in human dental pulp cells and the underlying signal pathway mechanisms. METHODS: Cell adhesion and proliferation were assessed by adhesion analysis and cell counting. Differentiation was examined by alkaline phosphatase activity, alizarin red staining, and reverse transcriptase polymerase chain reaction for marker genes. Angiogenesis was evaluated by human umbilical vein endothelial cell migration and capillary tube formation assays. Signaling pathways were analyzed by Western blotting and confocal microscopy. RESULTS: Combined treatment with GH and MTA enhanced cell adhesion, growth, alkaline phosphatase activity, calcified nodules, expression of marker mRNAs, migration, and capillary tube formation, compared with treatment with MTA or GH alone. In addition, GH plus MTA increased expression of bone morphogenetic protein-2 mRNA, phosphorylation of Smad 1/5/8, extracellular signal-regulated kinase, JNK, and p38 MAPK, and increased the levels of the transcription factors Runx2 and Osterix, compared with MTA alone. CONCLUSIONS: Collectively, our results demonstrate that a combination of MTA and GH promotes cell adhesion, growth, differentiation, and angiogenesis of MTA in human dental pulp cells via the activation of bone morphogenetic protein and MAPK pathway. PMID- 26435470 TI - Calcium Hydroxide versus Mineral Trioxide Aggregate for Direct Pulp Capping: A Cost-effectiveness Analysis. AB - INTRODUCTION: Recent evidence finds mineral trioxide aggregate (MTA) more effective than calcium hydroxide (CH) for direct pulp capping (DPC). The present study assessed the cost-effectiveness of MTA versus CH for DPC using a model based simulation approach. METHODS: A mixed public/private payer perspective in the context of German health care was adopted. We modeled a permanent molar with a vital asymptomatic, exposed pulp treated via DPC with either MTA or CH. The tooth was followed over the lifetime of a 20-year-old patient using Markov models. Transition probabilities were obtained from systematically and nonsystematically collected data. The primary health outcome was tooth retention time. Costs for DPC were estimated via microcosting. Required personnel time for application was estimated using a survey among German specialized and general dentists. Material expenses were calculated based on market prices in 2015. All other costs were derived from public and private item fee catalogues. Uncertainty was introduced via probabilistic and univariate sensitivity analyses. RESULTS: DPC using MTA was both more effective and less costly (52 years retention, lifetime costs = 1368 Euro) than CH (49 years, 1527 Euro). Regardless of a payer's willingness to pay, DPC with MTA had the higher probability of being cost effective. The identified ranking was not affected by parameter or structural uncertainty or heterogeneity. CONCLUSIONS: MTA was more cost-effective than CH for DPC despite higher initial treatment costs because expensive retreatments were avoided. Our estimates apply only on the basis of current evidence and within the chosen health care setting. From a payer's perspective, MTA should be used for DPC. PMID- 26435471 TI - Editorial: Small Molecules and Peptides Targeting the Eph-Ephrin System. PMID- 26435472 TI - Comparison of insulin degludec with insulin detemir in type 1 diabetes: a 1-year treat-to-target trial. AB - The long-term safety and tolerability of insulin degludec (IDeg) was compared with that of insulin detemir (IDet), as basal treatment in participants with type 1 diabetes mellitus (T1DM). In the present multinational, 26-week core + 26-week extension, controlled, open-label, parallel-group trial, adults with T1DM were randomized to IDeg or IDet as basal insulin treatment combined with meal-time bolus insulin aspart. IDeg was administered once daily, whilst IDet was administered once or twice daily depending on patients' glycaemic control. After 1 year, IDeg provided a 33% lower rate of nocturnal hypoglycaemia compared with IDet: estimated rate ratio (IDeg : IDet) 0.67 [95% confidence interval (CI) 0.51; 0.88]; p < 0.05. IDeg improved glycated haemoglobin after 1 year of treatment, similarly to IDet, but IDeg also provided a significantly greater reduction in fasting plasma glucose compared with IDet: estimated difference (IDeg - IDet) 1.11 (95% CI -1.83; -0.40) mmol/l; p < 0.05. The present study confirmed the long term safety and tolerability profile of IDeg in patients with T1DM. IDeg provided a lower risk of nocturnal confirmed hypoglycaemia than IDet. PMID- 26435473 TI - Chewing-induced hypertension in afferent baroreflex failure: a sympathetic response? AB - NEW FINDINGS: What is the central question of this study? Our goal was to understand the autonomic responses to eating in patients with congenital afferent baroreflex failure, by documenting changes in blood pressure and heart rate with chewing, swallowing and stomach distension. What is the main finding and its importance? Patients born with lesions in the afferent baroreceptor pathways have an exaggerated pressor response to food intake. This appears to be a sympathetically mediated response, triggered by chewing, that occurs independently of swallowing or distension of the stomach. The chewing-induced pressor response may be useful as a counter-manoeuvre to prevent orthostatic hypotension in these patients. Familial dysautonomia (FD) is a rare genetic disease with extremely labile blood pressure resulting from baroreflex deafferentation. Patients have marked surges in sympathetic activity, frequently surrounding meals. We conducted an observational study to document the autonomic responses to eating in patients with FD and to determine whether sympathetic activation was caused by chewing, swallowing or stomach distension. Blood pressure and R-R intervals were measured continuously while chewing gum (n = 15), eating (n = 20) and distending the stomach by percutaneous endoscopic gastrostomy tube feeding (n = 9). Responses were compared with those of normal control subjects (n = 10) and of patients with efferent autonomic failure (n = 10) who have chronically impaired sympathetic outflow. In patients with FD, eating was associated with a marked but transient pressor response (P < 0.0001) and additional signs of sympathetic activation, including tachycardia, diaphoresis and flushing of the skin. Chewing gum evoked a similar increase in blood pressure that was higher in patients with FD than in control subjects (P = 0.0001), but was absent in patients with autonomic failure. In patients with FD, distending the stomach by percutaneous endoscopic gastrostomy tube feeding failed to elicit a pressor response. The results provide indirect evidence that chewing triggers sympathetic activation. The increase in blood pressure is exaggerated in patients with FD as a result of blunted afferent baroreceptor signalling. The chewing pressor response may be useful as a counter-manoeuvre to raise blood pressure and prevent symptomatic orthostatic hypotension in patients with FD. PMID- 26435474 TI - Memory enhancement by Tamoxifen on amyloidosis mouse model. AB - Tamoxifen (TMX) is a selective estrogen receptor modulator (SERM) used in the treatment of breast cancer. Earlier studies show its neuroprotection via regulating apoptosis, microglial functions, and synaptic plasticity. TMX also showed memory enhancement in ovariectomized mice, and protection from amyloid induced damage in hippocampal cell line. These reports encouraged us to explore the role of TMX in relevance to Alzheimer's disease (AD). We report here, the effect of TMX treatment a) on memory, and b) levels of neurotransmitters (acetylcholine (ACh) and dopamine (DA)) in breeding-retired-female mice injected with beta amyloid1-42 (Abeta1-42). Mice were treated with TMX (10mg/kg, i.p.) for 15 days. In Morris water maze test, the TMX treated mice escape latency decreased during training trials. They also spent longer time in the platform quadrant on probe trial, compared to controls. In Passive avoidance test, TMX treated mice avoided stepping on the shock chamber. This suggests that TMX protects memory from Abeta induced toxicity. In frontal cortex, ACh was moderately increased, with TMX treatment. In striatum, dopamine was significantly increased, 3,4 dihydroxyphenylacetic acid (DOPAC) level and DOPAC/DA ratio was decreased post TMX treatment. Therefore, TMX enhances spatial and contextual memory by reducing dopamine metabolism and increasing ACh level in Abeta1-42 injected-breeding retired-female mice. PMID- 26435475 TI - Thyroid hormone status affects expression of daily torpor and gene transcription in Djungarian hamsters (Phodopus sungorus). AB - Thyroid hormones (TH) play a key role in regulation of seasonal as well as acute changes in metabolism. Djungarian hamsters (Phodopus sungorus) adapt to winter by multiple changes in behaviour and physiology including spontaneous daily torpor, a state of hypometabolism and hypothermia. We investigated effects of systemic TH administration and ablation on the torpor behaviour in Djungarian hamsters adapted to short photoperiod. Hyperthyroidism was induced by giving T4 or T3 and hypothyroidism by giving methimazole (MMI) and sodium perchlorate via drinking water. T3 treatment increased water, food intake and body mass, whereas MMI had the opposite effect. Continuous recording of body temperature revealed that low T3 serum concentrations increased torpor incidence, lowered Tb and duration, whereas high T3 serum concentrations inhibited torpor expression. Gene expression of deiodinases (dio) and uncoupling proteins (ucp) were analysed by qPCR in hypothalamus, brown adipose tissue (BAT) and skeletal muscle. Expression of dio2, the enzyme generating T3 by deiodination of T4, and ucps, involved in thermoregulation, indicated a tissue specific response to treatment. Torpor per se decreased dio2 expression irrespective of treatment or tissue, suggesting low intracellular T3 concentrations during torpor. Down regulation of ucp1 and ucp3 during torpor might be a factor for the inhibition of BAT thermogenesis. Hypothalamic gene expression of neuropeptide Y, propopiomelanocortin and somatostatin, involved in feeding behaviour and energy balance, were not affected by treatment. Taken together our data indicate a strong effect of thyroid hormones on torpor, suggesting that lowered intracellular T3 concentrations in peripheral tissues promote torpor. PMID- 26435476 TI - "Retronychia--clinical and pathophysiological aspects". AB - Retronychia represents proximal ingrowth of the nail that occurs when the nail embeds backwards into the proximal nail fold. It is suspected when there is a persistent paronychia, particularly in the setting of trauma. Important clinical criteria for diagnosis are inflammation of the proximal nail fold, granulation tissue emerging from under the nail fold, thickening of the proximal portion of the nail plate and interruption of nail growth. The condition is rarely diagnosed and often misinterpreted, and is therefore unnecessarily treated with systemic antibiotics and antifungals. Avulsion of the nail confirms the diagnosis and it is the curative treatment. Conservative treatment with an adhesive technique is a valid option in early cases. We report 20 cases of retronychia diagnosed in our department between 2010 and 2013. PMID- 26435477 TI - Suppression of CD300A inhibits the growth of diffuse large B-cell lymphoma. AB - CD300A is a type I transmembrane receptor protein which has shown inhibitory effects on B-cell receptor-mediated signals. In an analysis of public dataset, we found that CD300A mRNA levels were inversely correlated with the overall survival time of patients with diffuse large B-cell lymphoma (DLBCL). To decipher the role of CD300A in DLBCL, we knocked down the expression levels of CD300A in DLBCL cells and found that decreasing levels of CD300A significantly inhibited cell proliferation of OCI-Ly01, Farage, and SUDHL-4 cells, but not of VAL, OCI-Ly10, or SUDHL-8 cells. Mechanistically, reduced expression of CD300A resulted in a marked attenuation of AKT phosphorylation, a key molecular event in tumorigenesis, in OCI-Ly01, Farage, and SUDHL-4 cells. Pharmacologic inhibition of PI3K displayed a similar inhibitory effect on cell proliferation. Furthermore, using a xenograft animal model, we found that decreasing levels of CD300A in OCI Ly01 and Farage cells significantly inhibited tumor formation in vivo. Collectively, our results suggested an oncogenic role of CD300A in DLBCL which could serve as a potential biomarker and therapeutic target for this malignant disease. PMID- 26435479 TI - Rapid targeted somatic mutation analysis of solid tumors in routine clinical diagnostics. AB - Tumor genotyping is an essential step in routine clinical practice and pathology laboratories face a major challenge in being able to provide rapid, sensitive and updated molecular tests. We developed a novel mass spectrometry multiplexed genotyping platform named PentaPanel to concurrently assess single nucleotide polymorphisms in 56 hotspots of the 5 most clinically relevant cancer genes, KRAS, NRAS, BRAF, EGFR and PIK3CA for a total of 221 detectable mutations. To both evaluate and validate the PentaPanel performance, we investigated 1025 tumor specimens of 6 different cancer types (carcinomas of colon, lung, breast, pancreas, and biliary tract, and melanomas), systematically addressing sensitivity, specificity, and reproducibility of our platform. Sanger sequencing was also performed for all the study samples. Our data showed that PentaPanel is a high throughput and robust tool, allowing genotyping for targeted therapy selection of 10 patients in the same run, with a practical turnaround time of 2 working days. Importantly, it was successfully used to interrogate different DNAs isolated from routinely processed specimens (formalin-fixed paraffin embedded, frozen, and cytological samples), covering all the requirements of clinical tests. In conclusion, the PentaPanel platform can provide an immediate, accurate and cost effective multiplex approach for clinically relevant gene mutation analysis in many solid tumors and its utility across many diseases can be particularly relevant in multiple clinical trials, including the new basket trial approach, aiming to identify appropriate targeted drug combination strategies. PMID- 26435478 TI - Apigenin blocks IKKalpha activation and suppresses prostate cancer progression. AB - IKKalpha has been implicated as a key regulator of oncogenesis and driver of the metastatic process; therefore is regarded as a promising therapeutic target in anticancer drug development. In spite of the progress made in the development of IKK inhibitors, no potent IKKalpha inhibitor(s) have been identified. Our multistep approach of molecular modeling and direct binding has led to the identification of plant flavone apigenin as a specific IKKalpha inhibitor. Here we report apigenin, in micro molar range, inhibits IKKalpha kinase activity, demonstrates anti-proliferative and anti-invasive activities in functional cell based assays and exhibits anticancer efficacy in experimental tumor model. We found that apigenin directly binds with IKKalpha, attenuates IKKalpha kinase activity and suppresses NF-KB/p65 activation in human prostate cancer PC-3 and 22Rv1 cells much more effectively than IKK inhibitor, PS1145. We also showed that apigenin caused cell cycle arrest similar to knockdown of IKKalpha in prostate cancer cells. Studies in xenograft mouse model indicate that apigenin feeding suppresses tumor growth, lowers proliferation and enhances apoptosis. These effects correlated with inhibition of p-IKKalpha, NF-KB/p65, proliferating cell nuclear antigen and increase in cleaved caspase 3 expression in a dose-dependent manner. Overall, our results suggest that inhibition of cell proliferation, invasiveness and decrease in tumor growth by apigenin are mediated by its ability to suppress IKKalpha and downstream targets affecting NF-KB signaling pathways. PMID- 26435480 TI - Development and validation of a pretreatment prognostic index to predict death and lung metastases in extremity osteosarcoma. AB - BACKGROUND: To develop a prognostic index to predict the 5-year overall survival (OS) and 5-year lung metastasis-free survival (LMFS) of patients with extremity osteosarcoma at the time of diagnosis. METHODS: We retrospectively evaluated 454 patients with extremity osteosarcoma at our center from 2005 to 2013. The cohort was randomly divided into training and validation sets. The association of potential risk factors with OS and LMFS was assessed by Cox proportional hazards analysis in the training set, and a prognostic index was created according to scores that were proportional to a regression coefficient for each factor. This prognostic index was assessed in the validation set. RESULTS: For the 5-year OS, 5 independent prognostic factors were identified: tumor size, Enneking stage, pretreatment platelet, alkaline phosphatase(ALP), and neutrophils. The multivariate Cox model identified tumor size, pretreatment platelets, ALP, and neutrophils as associated with the 5-year LMFS. A prognostic index for death and lung metastases was calculated. Three risk groups were defined for each survival point: low, intermediate, and high risk for the 5-year OS; low, intermediate, and high risk for the 5-year LMFS. The C statistic for the 5-year OS was 0.723 in the training set and 0.710 in the validation set. The C statistic for the 5-year LMFS was 0.661 and 0.693 respectively. CONCLUSIONS: This prognostic index is based on routine tests and characteristics of extremity osteosarcoma patients and is a useful predictor of OS and lung metastases. This index could be applied to clinical practice and trials for individualized risk-adapted therapies. PMID- 26435482 TI - Human Rights, Humanitarianism, and State Violence: Medical Documentation of Torture in Turkey. AB - State authorities invested in developing official expert discourses and practices to deny torture in post-1980 coup d'etat Turkey. Documentation of torture was therefore crucial for the incipient human rights movement there in the 1980s. Human rights physicians used their expertise not only to treat torture victims but also to document torture and eventually found the Human Rights Foundation of Turkey (HRFT) in 1990. Drawing on an ethnographic and archival research at the HRFT, this article examines the genealogy of anti-torture struggles in Turkey and argues that locally mediated intimacies and/or hostilities between victims of state violence, human rights physicians, and official forensics reveal the limitations of certain universal humanitarian and human rights principles. It also shows that locally mediated long-term humanitarian encounters around the question of political violence challenge forensic denial of violence and remake the legitimate levels of state violence. PMID- 26435481 TI - HER2 as a novel therapeutic target for cervical cancer. AB - Surgery and radiation are the current standard treatments for cervical cancer. However, there is no effective therapy for metastatic or recurrent cases, necessitating the identification of therapeutic targets. In order to create preclinical models for screening potential therapeutic targets, we established 14 patient-derived xenograft (PDX) models of cervical cancers using subrenal implantation methods. Serially passaged PDX tumors retained the histopathologic and genomic features of the original tumors. Among the 9 molecularly profiled cervical cancer patient samples, a HER2-amplified tumor was detected by array comparative genomic hybridization and targeted next-generation sequencing. We confirmed HER2 overexpression in the tumor and serially passaged PDX. Co administration of trastuzumab and lapatinib in the HER2-overexpressed PDX significantly inhibited tumor growth compared to the control. Thus, we established histopathologically and genomically homologous PDX models of cervical cancer using subrenal implantation. Furthermore, we propose HER2 inhibitor-based therapy for HER2-amplified cervical cancer refractory to conventional therapy. PMID- 26435483 TI - Dual fluorescent deoxyguanosine mimics for FRET detection of G-quadruplex folding. AB - Replacement of deoxyguanosine (dG) nucleobases within G-tetrads of G-quadruplex folding oligonucleotides with donor (D)/acceptor (A) fluorescent 8aryldG residues provides diagnostic FRET signalling for G-quadruplex detection. PMID- 26435484 TI - New High- and Low-Temperature Phase Changes of ZIF-7: Elucidation and Prediction of the Thermodynamics of Transitions. AB - We have found that the 3D zeolitic imidazolate framework ZIF-7 exhibits far more complex behavior in response to the adsorption of guest molecules and changes in temperature than previously thought. We believe that this arises from the existence of different polymorphs and different types of adsorption sites. We report that ZIF-7 undergoes a displacive, nondestructive phase change upon heating to above ~700 degrees C in vacuum, or to ~500 degrees C in CO2 or N2. This is the first example of a temperature-driven phase change in 3D ZIF frameworks. We predicted the occurrence of the high-temperature transition on the basis of thermodynamic arguments and analyses of the solid free-energy differences obtained from CO2 and n-butane adsorption isotherms. In addition, we found that ZIF-7 exhibits complex behavior in response to the adsorption of CO2 manifesting in double transitions on adsorption isotherms and a doubling of the adsorption capacity. We report adsorption microcalorimetry, molecular simulations, and detailed XRD investigations of the changes in the crystal structure of ZIF-7. Our results highlight mechanistic details of the phase transitions in ZIF-7 that are driven by adsorption of guest molecules at low temperature and by entropic effects at high temperature. We derived a phase diagram of CO2 in ZIF-7, which exhibits surprisingly complex re-entrant behavior and agrees with our CO2 adsorption measurements over a wide range of temperatures and pressures. We predicted phase diagrams of CH4, C3H6, and C4H10. Finally, we modeled the temperature-induced transition in ZIF-7 using molecular dynamics simulations in the isobaric-isothermal ensemble, confirming our thermodynamic arguments. PMID- 26435485 TI - Quantitative analysis of Cryptosporidium growth in in vitro culture--the impact of parasite density on the success of infection. AB - Cryptosporidium is an important waterborne pathogen for which no treatment or vaccination is available. This study set out to quantify DNA replication of Cryptosporidium parvum in vitro. Cryptosporidium DNA could be detected at up to 60 % of input level in both host-cell-free and host cell containing cultures 6 days after infection with living sporozoites, but was lost within 2 days in cultures inoculated with UV-inactivated sporozoites. Total DNA increased between days 2 and 6, evidence of successful DNA replication in both cell-free and host cell-containing cultures. Overall however, only a small fraction (up to 5 %) of parasite DNA could be found associated with host cells or bound to plastic of the cell-free cultures, and the majority of parasite DNA was present in the cell culture medium, separable by simple decantation. After 2 days, in host-cell containing cultures, the parasite DNA could be concentrated by slow centrifugation, suggesting that it was associated with intact parasite cells, but at 6 days, the majority could not be centrifuged and is therefore thought to have represented copies associated with dead and degraded parasites. In cell-free cultures and in larger plates, the majority of DNA was in this form. Performance of the parasite was best in small culture plates, and least in the largest plate sizes. We interpret these results as suggesting that Cryptosporidium sporozoites first bind to the host cell monolayer or to the plasticware, but then by 2 days, there has been a substantial release of parasites back into the medium. Host-cell free cultures also supported modest replication and may have represented DNA synthesis in cells beginning merogony. The role of the host cells is unclear, as so much of the parasite DNA is released into the medium. Host cells may provide a feeder role, conditioning the medium for Cryptosporidium development. PMID- 26435486 TI - Robot-assisted partial nephrectomy with intracorporeal renal hypothermia using ice slush: step-by-step technique and matched comparison with warm ischaemia. AB - OBJECTIVES: To outline our step-by-step technique for intracorporeal renal cooling during robot-assisted partial nephrectomy (RAPN). PATIENTS AND METHODS: Patient selection was performed during a preoperative clinic visit. Cases where we estimated during preoperative assessment that warm ischaemia time would be >30 min, as determined by whether the patient had a complex renal mass, were selected. The special equipment required for this procedure includes an Ecolab Hush Slush machine (Microtek Medical Inc., Columbus, MS, USA) a Mon-a-therm needle thermocouple device (Covidien, Mansfield, MA, USA) and six modified 20-mL syringes. Patients are arranged in a 60 degrees modified flank position with the operating table flexed slightly at the level of the anterior superior iliac spine. For the introduction of a temperature probe and ice slush, an additional 12-mm trocar is placed along the mid-axillary line beneath the costal margin. Modified 10/20 mL syringes are prefilled with ice slush for instillation via an accessory trocar. Peri-operative and 6-month functional outcomes in the cold ischaemia group were compared with those of a cohort of patients who underwent RAPN with warm ischaemia in a 2:1 matched fashion. Matching was performed based on preoperative estimated glomerular filtration rate (GFR), ischaemia time and RENAL nephrometry score. RESULTS: Strategies for successful intracorporeal renal cooling include: (i) placement of accessory port directly over the kidney; (ii) uniform ice consistency and modified syringes; (iii) sequential clamping of renal artery and vein; (iv) protection of the neighbouring intestine with a laparoscopic sponge; and (v) complete mobilization of the kidney. Kidney temperature is monitored via a needle thermocoupler device, while core body temperature is concurrently monitored via an oesophageal probe in real time. Renal function was assessed by serum creatinine level, estimated GFR (eGFR) and mercaptoacetyltriglycine (MAG-3) renal scan, peri-operatively and at 6-month follow-up. In the separate matched analysis, cold ischaemia during RAPN was found to be associated with a 12.9% improvement in preservation of postoperative eGFR. No difference was seen in either group at 6-month follow-up. CONCLUSIONS: We conclude that RAPN with intracorporeal renal hypothermia using ice slush is technically feasible and may improve postoperative renal function in the short term. Our technique for intracorporeal hypotheramia is cost-effective, simple and highly reproducible. PMID- 26435487 TI - Elevated Serum Beta-Trace Protein Levels are Associated With the Presence of Atrial Fibrillation in Hypertension Patients. AB - Beta-trace protein (BTP) has emerged as a novel biomarker of cardiovascular risk. In this study, the authors aimed to assess the relationship between BTP levels and presence of atrial fibrillation in patients who had controlled hypertension (HTN) and normal renal function. A total of 80 controlled HTN patients with paroxysmal atrial fibrillation (PAF) and 80 age- and sex-matched controls with controlled HTN were enrolled. Serum BTP levels were measured by enzyme-linked immunosorbent assay. BTP levels were found to be significantly higher in patients with PAF (P<.001). Other parameters including mean systolic and diastolic blood pressure values, serum creatinine levels, and glomerular filtration rate were similar between the two groups. Along with left atrial diameter (odds ratio, 1.504; P<.001), BTP levels (odds ratio, 1.015; P<.001) were independently associated with the presence of PAF. BTP levels were increased in controlled HTN patients with PAF compared with controls, and this association was observed within normal renal functions as reflected by normal glomerular filtration rate. PMID- 26435488 TI - Dermoscopy as a diagnostic aid in a case of systemic amyloidosis with initial presentation in skin. PMID- 26435489 TI - Differential impact of upward and downward comparisons on diverse women's disordered eating behaviors and body image. AB - OBJECTIVE: Etiological models of disordered eating are limited in their consideration of racial/ethnic differences in risk factors. Appearance comparisons are consistent predictors of disordered eating outcomes, but research predominantly examines these associations among White women and overlooks the potential differential impact of upward (comparing to someone perceived as better off) versus downward comparisons (comparing to someone perceived as worse off). This study investigated race/ethnicity as a moderator of the associations between upward and downward appearance comparisons and disordered eating outcomes and body satisfaction of young adult women. METHOD: Measures of upward and downward appearance comparisons, body satisfaction, and disordered eating were administered to 1,014 young adult women. A multiple group (by race/ethnicity) path analysis was estimated using maximum likelihood estimation for each disordered eating and body satisfaction outcome, controlling for age and BMI. RESULTS: Upward comparisons were associated with higher levels of disordered eating behaviors and lower body satisfaction for women of all racial/ethnic groups. Downward appearance comparisons emerged as detrimental for Hispanic/Latina women, but were protective for Asian and White women. DISCUSSION: Findings challenge the belief that appearance comparisons impact all women similarly and that downward comparisons are universally protective, a position often promulgated by clinical treatment approaches. (c) 2015 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:519-523). PMID- 26435490 TI - On the effect of sodium salts on the coil-to-globule transition of poly(N isopropylacrylamide). AB - It has been shown that sodium salts significantly affect the temperature of the coil-to-globule collapse transition of poly(N-isopropylacrylamide) [J. Am. Chem. Soc., 2005, 127, 14505]. Since this phenomenon resembles the cold renaturation of globular proteins, it can be studied by means of the theoretical approach devised to rationalise the occurrence and the mechanism of cold denaturation [G. Graziano, Phys. Chem. Chem. Phys., 2010, 12, 14245; Phys. Chem. Chem. Phys., 2014, 16, 21755]. It emerges that the collapse transition is driven by the decrease in the solvent-excluded volume in order to maximise the translational entropy of water molecules and ions. At a given temperature, the aqueous solutions of sodium salts have densities higher than that of water. For this reason, the magnitude of the solvent-excluded volume effect proves to be larger, stabilizing the globular conformations of poly(N-isopropylacrylamide). On the other hand, two large ions, iodide and thiocyanate, are poorly hydrated and stabilise the coil conformations of the polymer by a preferential binding mechanism. PMID- 26435491 TI - The role of family carers in the use of personal budgets by people with mental health problems. AB - Personal budgets aim to increase choice and independence for people with social care needs but they remain underused by people with mental health problems compared to other disability groups. The use of personal budgets may impact on families in a variety of ways, both positive and negative. This paper draws on interviews, undertaken in 2012-2013 with 18 family carers and 12 mental health service users, that explored experiences of family involvement in accessing and managing personal budgets for a person with mental health-related social care needs. The sample was drawn from three sites across England, with additional carers being recruited via voluntary sector networks. Our findings show that for many people with severe mental health needs who lack motivation and confidence to negotiate access to personal budgets, carers may provide the necessary support to enable them to benefit from this form of social care support. We illustrate the role carers may play in initiating, pursuing and maximising the level of support available through personal budgets. However, some carers interviewed considered that personal budget funding was reduced because of practitioners' assumptions about carers' willingness and ability to provide support. We also report perceived tensions between family carers and practitioners around appropriate involvement in decision-making. The study findings have implications for local authorities, practitioners and family carers in supporting the involvement of family carers in support for people with severe mental health problems. PMID- 26435492 TI - Endoscopic endonasal greater palatine artery cauterization at the incisive foramen for control of anterior epistaxis. AB - OBJECTIVES/HYPOTHESIS: To describe the anatomy of the incisive foramen and the transnasal endoscopic approach to the greater palatine artery at this foramen, and to evaluate the importance of the greater palatine artery as a cause of recurrent anterior epistaxis. STUDY DESIGN: Anatomical dissection, radiographic study, and prospective case series. SETTING: Academic Medical Center. METHODS: Sixty-nine computed tomography scans were reviewed, and measurements were made of the incisive foramina's distance to the anterior nasal spine and subnasale. Twenty-two cadavers had sagittal split craniotomies performed prior to the measurements. The distance from the anterior nasal spine to the incisive foramen was documented. We also present an illustrative case series of patients who underwent endoscopic cautery of the greater palatine artery at the incisive foramen. RESULTS: Radiographic review of the incisive foramen revealed a mean anterior nasal spine to incisive foramen distance on the right and left of 7.9 and 8.1 mm, respectively. The mean distance from the subnasale to incisive foramen on the right and left were 24.7 and 24.9 mm, respectively. CONCLUSIONS: Endoscopic cauterization of the greater palatine artery at the incisive foramen is a safe and effective method to control recurrent anterior epistaxis. The incisive foramen can be predictively found within 1 cm of the anterior nasal spine. Our case series corroborates the above. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1033-1038, 2016. PMID- 26435493 TI - Reproducibility of cerebrovascular reactivity measures in children using BOLD MRI. AB - PURPOSE: To evaluate the reproducibility of cerebrovascular reactivity (CVR) measurements acquired in children using magnetic resonance imaging (MRI) in combination with a computer-controlled carbon dioxide (CO2 ) stimulus. MATERIALS AND METHODS: Ten healthy children (age 16.1 +/- 1.6 years) underwent CVR imaging on a 3T scanner using a blood-oxygen level-dependent (BOLD) MRI sequence. Targeted hypercapnia was induced during imaging with a CO2 gas challenge delivered using a specialized gas sequencer (RespirAct). A total of four BOLD scans were performed over 2 separate days to test within-day and between-day consistency of the data. CVR values were computed by correlating the relative change in BOLD signal in response to the CO2 stimulus delivered to the each subject. RESULTS: Intraclass correlation coefficients (ICCs) of within-day values show highly reproducible measures in both the gray matter (ICC = 0.857, P < 0.001) and white matter (ICC = 0.895, P < 0.001). Relatively lower between-day reproducibility was observed in both the gray matter (ICC = 0.776, P = 0.001) and white matter (ICC = 0.719, P = 0.004). CONCLUSION: Using a computer-controlled CO2 stimulus, we have demonstrated the reliability of BOLD-CVR measurements in pediatric subjects. Within-day and between-day metrics of reproducibility were comparable to adult data. PMID- 26435494 TI - Uterine balloon tamponade: the case against technology. PMID- 26435496 TI - First-Trimester Pregnancy Exposure to Venlafaxine or Duloxetine and Risk of Major Congenital Malformations: A Systematic Review. AB - Major depressive disorder is common among women in child-bearing age, and medical treatment is subject to substantial discussions and controversies. For Selective Serotonin reuptake inhibitors, SSRIs, a vast amount of data are available. For the newer antidepressant group of serotonin and noradrenaline reuptake inhibitors, SNRIs, significantly less data are available. Following the PRISMA guideline for systematic reviews, we performed a systematic search on the risk of major congenital malformations after first trimester in utero exposure to venlafaxine or duloxetine. We identified eight cohort studies reporting on the outcome upon in utero exposure to venlafaxine or duloxetine during the first trimester. The cumulated data for venlafaxine were 3186 exposed infants and 107 major malformations, resulting in a relative risk estimate and 95% confidence interval of 1.12 (0.92-1.35). The corresponding data for duloxetine were 668 infants and 16 major malformations, resulting in a relative risk estimate and 95% confidence interval of 0.80 (0.46-1.29). First-trimester in utero exposure to venlafaxine is not associated with an increased risk of major congenital malformations. The amount of data for duloxetine are significantly smaller but does not suggest a clinically important increased risk. PMID- 26435495 TI - Fatigue in chronic inflammation - a link to pain pathways. AB - Fatigue is a frequent symptom in several inflammatory diseases, particularly in rheumatic diseases. Elements of disease activity and cognitive and behavior aspects have been reported as causes of fatigue in patients with rheumatoid arthritis. Fatigue could be associated with activity of inflammatory rheumatism. Indeed, biologic agents targeting inflammatory cytokines are effective in fatigue. Fatigue is also associated with pain and depressive symptoms. Different pathways could be involved in fatigue and interact: the immune system with increased levels of pro-inflammatory cytokines (interleukin-1 and -6 and tumor necrosis factor alpha), dysregulation of the hypothalamic-pituitary-adrenal axis and neurological phenomena involving the central and autonomic nervous systems. A pro-inflammatory process could be involved in pain and behavioral symptoms. Inflammation could be a common link between fatigue, pain, and depression. PMID- 26435497 TI - Differential expression profiles and roles of inducible DUSPs and ERK1/2-specific constitutive DUSP6 and DUSP7 in microglia. AB - Dual-specificity phosphatases (DUSPs) show distinct substrate preferences for specific MAPKs. DUSPs sharing a substrate preference for ERK1/2 may be classified as inducible or constitutive. In contrast to the inducible DUSPs which also dephosphorylate p38 MAPK and JNK in the major inflammatory pathways, constitutive DUSP6 and DUSP7 are specific to ERK1/2 and have not been studied in microglia and other immune cells to date. In the present study, we differentiated mRNA expression profiles of inducible and constitutive DUSPs that dephosphorylate ERK1/2 in microglia. Lipopolysaccharide (LPS) at 1 ng/ml induced prompt phosphorylation of ERK1/2 with peak induction at 30 min. LPS induced expression of DUSP1, DUSP2, and DUSP5 within 60 min, whereas DUSP4 expression was induced more slowly. DUSP6 and DUSP7 exhibited constitutive basal expression, which decreased immediately after LPS stimulation but subsequently returned to basal levels. The expression of DUSP6 and DUSP7 was regulated inverse to the phosphorylation of ERK1/2 in LPS-stimulated microglia. Therefore, we next investigated the correlation between DUSP6 and DUSP7 expression and ERK1/2 phosphorylation in resting and LPS-stimulated microglia. Inhibition of the ERK1/2 pathway by PD98059 and FR180204 resulted in a decrease in DUSP6 and DUSP7 expression, both in resting and LPS-stimulated microglia. These inhibitors partially blocked the LPS-induced expression of DUSP1, DUSP2, and DUSP4, but had no effect on DUSP5. Finally, we examined the role of DUSP6 activity in the downregulation of ERK1/2 phosphorylation. BCI, an inhibitor of DUSP6, increased the phosphorylation of ERK1/2. However, pretreatment with BCI inhibited the LPS induced phosphorylation of ERK1/2. These results demonstrate that constitutive DUPS6 and DUSP7 expression was downregulated inverse to the expression of inducible DUSPs and the phosphorylation of ERK1/2 in LPS-stimulated microglia. The expression of DUPS6 and DUSP7 was mediated by ERK1/2 activity both in resting and LPS-stimulated microglia. In turn, DUSP6 suppressed the basal phosphorylation of ERK1/2, but exerted no suppressive effect on LPS-induced phosphorylation. Although DUSP6 is acknowledged as a negative regulator of the ERK1/2 pathway, such roles of DUSP6 need to be examined further in activated microglia. PMID- 26435498 TI - Impaired degradation of WNK by Akt and PKA phosphorylation of KLHL3. AB - Mutations in with-no-lysine kinase (WNK) 1, WNK4, Kelch-like 3 (KLHL3), and Cullin3 result in an inherited hypertensive disease, pseudohypoaldosteronism type II. WNK activates the Na-Cl cotransporter (NCC), increasing sodium reabsorption in the kidney. Further, KLHL3, an adapter protein of Cullin3-based E3 ubiquitin ligase, has been recently found to bind to WNK, thereby degrading them. Insulin and vasopressin have been identified as powerful activators of WNK signaling. In this study, we investigated effects of Akt and PKA, key downstream substrates of insulin and vasopressin signaling, respectively, on KLHL3. Mass spectrometry analysis revealed that KLHL3 phosphorylation at S433. Phospho-specific antibody demonstrated defective binding between phosphorylated KLHL3 and WNK4. Consistent with the fact that S433 is a component of Akt and PKA phosphorylation motifs, in vitro kinase assay demonstrated that Akt and PKA can phosphorylate KLHL3 at S433, that was previously reported to be phosphorylated by PKC. Further, forskolin, a representative PKA stimulator, increased phosphorylation of KLHL3 at S433 and WNK4 protein expression in HEK293 cells by inhibiting the KLHL3 effect that leads to WNK4 degradation. Insulin also increased phosphorylation of KLHL3 at S433 in cultured cells. In conclusion, we found that Akt and PKA phosphorylated KLHL3 at S433, and phosphorylation of KLHL3 by PKA inhibited WNK4 degradation. This could be a novel mechanism on how insulin and vasopressin physiologically activate the WNK signal. PMID- 26435499 TI - Down-regulation of TCF21 by hypermethylation induces cell proliferation, migration and invasion in colorectal cancer. AB - Epigenetic alteration induced loss function of the transcription factor 21 (TCF21) has been associated with different types of human cancers. However, the epigenetic regulation and molecular functions of TCF21 in colorectal cancer (CRC) remain unknown. In this study, TCF21 expression levels and methylation status of its promoter region in CRC cell lines (n = 5) and CRC tissues (n = 151) as well as normal colorectal mucosa (n = 30) were assessed by RTq-PCR and methylation analysis (methylation specific PCR, MSP and bisulfite sequencing PCR, BSP), respectively. The cellular functions of TCF21 on CRC cell proliferation, apoptosis, invasion and migration were investigated in vitro. Our data revealed that TCF21 was frequently silenced by promoter hypermethylation in both tested CRC cell lines and primary CRC, and correlation analysis between methylation status and clinicopathologic parameters found that TCF21 methylation was significantly correlated with lymph node invasion (P = 0.013), while no significant correlation was found in other parameters. In addition, demethylation treatment resulted in re-expression of TCF21 in CRC cell lines, and cellular function experiments revealed that restoration of TCF21 inhibited CRC cell proliferation, promoted apoptosis and suppressed cell invasion and migration, suggesting that TCF21 may function as a tumor suppressor gene, which is downregulated through promoter hypermethylation in CRC development. PMID- 26435500 TI - Ubiquitination-dependent degradation of p73 by the mitochondrial E3 ubiquitin ligase Hades. AB - p73 is a member of the p53 family of transcription factors which plays an essential role in tumor suppression. p73 is associated with the sensitivity of cancer cells to chemotherapy and the prognosis of many cancers. In this study, we showed the ubiquitination-dependent degradation of p73 by the mitochondrial E3 ubiquitin ligase Hades. First, the binding between p73 and Hades was identified by co-immunoprecipitation experiments, and it was found that the Hades RING finger domain mediates the interaction with p73. Immunofluorescence analysis showed that p73 moves to the mitochondria and colocalizes with Hades during etoposide-induced apoptosis. By performing in vivo and in vitro ubiquitination assays, we observed that the Hades RING-finger domain promotes ubiquitination of p73. Finally, it was shown that SiRNA-mediated depletion of Hades stabilizes p73. Taken together, our results showed that Hades mediates the ubiquitination dependent degradation of mitochondrial p73 under apoptotic conditions. These findings suggest that Hades-mediated p73 ubiquitination is a novel regulatory mechanism for the exonuclear function of p73. PMID- 26435501 TI - Angiopoietin-like protein 2 induces proinflammatory responses in peritoneal cells. AB - Monocytes and macrophages are important effectors and regulators of inflammation, and both their differentiation and activation are regulated strictly in response to environmental cues. Angiopoietin-like protein 2 (Angptl2) is a multifaceted protein, displaying many physiological and pathological functions in inflammation, angiogenesis, hematopoiesis, and tumor development. Although recent studies implicate Angptl2 in chronic inflammation, the mechanisms of inflammation caused by Angptl2 remain unclear. The purpose of the present study was to elucidate the role of Angptl2 in inflammation by understanding the effects of Angptl2 on monocytes/macrophages. We showed that Angptl2 directly activates resident murine peritoneal monocytes and macrophages and induces a drastic upregulation of the transcription of several inflammatory genes including nitric oxide synthase 2 and prostaglandin-endoperoxide synthase 2, and several proinflammatory cytokine genes such as interleukin (IL)-1beta, IL-6, TNFalpha, and CSF2, along with activation of ERK, JNK, p38, and nuclear factor kappa B signaling pathways. Concordantly, proinflammatory cytokines IL-1beta, IL-6, TNFalpha, and GM-CSF, were rapidly elevated from murine peritoneal monocytes and macrophages. These results demonstrate a novel role for Angptl2 in inflammation via the direct activation of peritoneal monocytes and macrophages. PMID- 26435502 TI - Podocyte-specific deletion of Rac1 leads to aggravation of renal injury in STZ induced diabetic mice. AB - Rac1, a GTPase of the Rho subfamily, has a crucial role in cytoskeletal architecture, as well as the regulation of cell migration and growth. However, renal injury in mice with podocyte-specific deletion of Rac1 has yet to be elucidated fully due to conflicting findings. Herein, we identified a possible role for Rac1 in podocytes of streptozotocin- (STZ) induced diabetic mice. The urinary albumin/creatinine ratio (ACR) in the knockout (KO) group was significantly higher than that in the wild type (WT) group at any week of age. A more marked ACR increase was observed in STZ/KO group than STZ/WT group, although ACR did increase with weeks of age in both diabetic groups. The kidney sections from diabetic mice revealed a glomerular hypertrophy with mesangial expansion, but there was no appreciable difference in glomerular findings under a light microscope between STZ/WT and STZ/KO mice. However, an electron microscopy analysis revealed that regardless of the presence or absence of diabetes, both KO (KO and STZ/KO) groups had a higher rate of foot process effacement compared with both WT (WT and STZ/WT) groups. The expression levels of the slit diaphragm protein, podocin, was reduced with the induction of diabetes, and the levels in the STZ/KO group experienced a further reduction compared with the STZ/WT group. The number of WT1-positive cells in the STZ/KO group was more significantly decreased than that in the other three groups. In contrast, the numbers of cleaved caspase 3- and TUNEL-positive cells in the glomeruli of the STZ/KO group were more increased than those in the STZ/WT group. Thus, this study provides evidence that podocyte-specific deletion of Rac1 results in morphological alteration in podocytes, and that the induction of apoptosis or decreased expression of the slit diaphragm proteins by hyperglycemic stimuli are associated with the progression of diabetic nephropathy. PMID- 26435503 TI - NFkappaB-p50 as a blood based protein marker for early diagnosis and prognosis of head and neck squamous cell carcinoma. AB - Head and neck squamous cell carcinoma (HNSCC) is the major health concern in Indian population. Despite of advanced treatment the mortality rate for this disease has not been improved very much. Current research focused on development of protein marker for the diagnosis and prognosis of HNSCC. The case control study was performed with 125 HNSCC patients and 104 control cases. The level of p50 and IkappaBalpha proteins in serum were evaluated at pre and post therapy by label free real time surface plasmon resonance (SPR) and western blot analysis. The serum p50 concentration were significantly (P < 0.0001) higher at the time of diagnosis i.e. pre therapy (Mean +/- SD = 27.06 +/- 4.88 ng/MUl) as compared to controls (Mean +/- SD = 16.96 +/- 4.04 ng/MUl) while it decline at post therapy (Mean +/- SD = 21.01 +/- 4.98 ng/MUl). Similarly, the concentration of IkappaBalpha protein in serum were slightly higher at pre therapy (Mean +/- SD = 8.33 +/- 1.85 ng/MUl) as compared to controls (Mean +/- SD = 7.27 +/- 1.84 ng/MUl) and declined at post therapy (Mean +/- SD = 7.09 +/- 1.24 ng/MUl). The level of p50 was also high at the early stage of the disease. The specificity and sensitivity of p50 proteins obtained from ROC analysis revealed the potentiality to be diagnostic protein marker for HNSCC for its accuracy in the study cohort. PMID- 26435504 TI - T gene isoform expression pattern is significantly different between chordomas and notochords. AB - The T gene plays a key role in chordoma pathology. To investigate the role of T gene isoforms in chordoma, 22 skull base chordomas, three chordoma cell lines and 9 infant notochords, which were used as normal controls, were collected. We first conducted droplet digital PCR to quantify the absolute expression levels of the long and short isoforms of the T gene (T-long and T-short, respectively) and revealed that T-long was dominantly expressed in all chordomas and chordoma cell lines, but not in the notochords. The T-long/T-short ratio was significantly different between the chordomas and the notochords. Next, we validated the isoform expression pattern at protein expression level using Western blot in 9 chordomas. Furthermore, the T gene single nucleotide polymorphism site rs2305089, which is the only marker reported to be associated with chordomas, was sequenced in all of the chordoma samples. Association between rs2305089 and T-long/T-short ratio was not significant, indicating it was not involved in T gene alternative splicing. In conclusion, two T gene isoforms were investigated in skull base chordomas and chordoma cell lines, and the longer isoform was dominantly expressed. The distinct expression patterns of these T gene isoforms may contribute to the pathogenesis of skull base chordomas. However, further studies on the function of these isoforms are needed. PMID- 26435506 TI - Analysis of the electrostatics in Dy(III) single-molecule magnets: the case study of Dy(Murex)3. AB - A Dy(III)-based single-molecule magnet is reported. Ab initio calculations highlight that molecular symmetry plays a predominant role over site symmetry in determining the shape and orientation of Dy(III) magnetic anisotropy. Moreover the dipolar component of the electrostatic potential created by the surrounding ligands is shown to be the driving force of its magnetic behaviour. PMID- 26435505 TI - Inhibition of LSD1 by Pargyline inhibited process of EMT and delayed progression of prostate cancer in vivo. AB - Recently, lysine-specific demethylase 1 (LSD1) was identified as the first histone demethylase. LSD1 interacted with androgen receptor (AR) and promoted androgen-dependent transcription of target genes, such as PSA, by ligand-induced demethylation of mono- and dimethylated histone H3 at Lys 9 (H3K9). Meanwhile, the phenomenon of epithelial-mesenchymal transition (EMT) had received considerable attention in tumor recurrence and metastasis. This study examined the effect of Pargyline (an inhibitor of LSD1) on the process of EMT in vitro and in vivo. SCID mice were injected subcutaneously with LNCap cells. Pargyline was given intraperitoneally or not after castration (implemented with Bilateral orchidectomy), then PSA levels in serum and tumor were determined to assess time to androgen-independent progression. The results showed that LSD1 expression was up-regulated when PCa progressed to Castration Resistant Prostate Cancer (CRPC). Pargyline reduced LNCap cells migration and invasion ability, and inhibited the process of EMT by up-regulating expression of E-cadherin, and down-regulating expressions of N-cadherin and Vimentin in vitro and in vivo. Although, Pargyline did not change the level of AR, it reduced PSA expression both in vitro and in vivo. Furthermore, Pargyline delayed prostate cancer transition from androgen dependent to androgen-independent state (CRPC). These findings indicated that inhibition of LSD1 might be a promise adjunctive therapy with androgen deprivation therapy (ADT) for locally advanced or metastatic prostate cancer. PMID- 26435507 TI - Characterizing Cardiac Molecular Mechanisms of Mammalian Hibernation via Quantitative Proteogenomics. AB - This study uses advanced proteogenomic approaches in a nonmodel organism to elucidate cardioprotective mechanisms used during mammalian hibernation. Mammalian hibernation is characterized by drastic reductions in body temperature, heart rate, metabolism, and oxygen consumption. These changes pose significant challenges to the physiology of hibernators, especially for the heart, which maintains function throughout the extreme conditions, resembling ischemia and reperfusion. To identify novel cardioadaptive strategies, we merged large-scale RNA-seq data with large-scale iTRAQ-based proteomic data in heart tissue from 13 lined ground squirrels (Ictidomys tridecemlineatus) throughout the circannual cycle. Protein identification and data analysis were run through Galaxy-P, a new multiomic data analysis platform enabling effective integration of RNA-seq and MS/MS proteomic data. Galaxy-P uses flexible, modular workflows that combine customized sequence database searching and iTRAQ quantification to identify novel ground squirrel-specific protein sequences and provide insight into molecular mechanisms of hibernation. This study allowed for the quantification of 2007 identified cardiac proteins, including over 350 peptide sequences derived from previously uncharacterized protein products. Identification of these peptides allows for improved genomic annotation of this nonmodel organism, as well as identification of potential splice variants, mutations, and genome reorganizations that provides insights into novel cardioprotective mechanisms used during hibernation. PMID- 26435508 TI - The role of gluconate production by Pseudomonas spp. in the mineralization and bioavailability of calcium-phytate to Nicotiana tabacum. AB - Organic phosphorus (P) is abundant in most soils but is largely unavailable to plants. Pseudomonas spp. can improve the availability of P to plants through the production of phytases and organic anions. Gluconate is a major component of Pseudomonas organic anion production and may therefore play an important role in the mineralization of insoluble organic P forms such as calcium-phytate (CaIHP). Organic anion and phytase production was characterized in 2 Pseudomonas spp. soil isolates (CCAR59, Ha200) and an isogenic mutant of strain Ha200, which lacked a functional glucose dehydrogenase (Gcd) gene (strain Ha200 gcd::Tn5B8). Wild-type and mutant strains of Pseudomonas spp. were evaluated for their ability to solubilize and hydrolyze CaIHP and to promote the growth and assimilation of P by tobacco plants. Gluconate, 2-keto-gluconate, pyruvate, ascorbate, acetate, and formate were detected in Pseudomonas spp. supernatants. Wild-type pseudomonads containing a functional gcd could produce gluconate and mineralize CaIHP, whereas the isogenic mutant could not. Inoculation with Pseudomonas improved the bioavailability of CaIHP to tobacco plants, but there was no difference in plant growth response due to Gcd function. Gcd function is required for the mineralization of CaIHP in vitro; however, further studies will be needed to quantify the relative contribution of specific organic anions such as gluconate to plant growth promotion by soil pseudomonads. PMID- 26435512 TI - Mutational mapping of the transmembrane binding site of the G-protein coupled receptor TGR5 and binding mode prediction of TGR5 agonists. AB - TGR5 (Gpbar-1, M-Bar) is a class A G-protein coupled bile acid-sensing receptor predominately expressed in brain, liver and gastrointestinal tract, and a promising drug target for the treatment of metabolic disorders. Due to the lack of a crystal structure of TGR5, the development of TGR5 agonists has been guided by ligand-based approaches so far. Three binding mode models of bile acid derivatives have been presented recently. However, they differ from one another in terms of overall orientation or with respect to the location and interactions of the cholane scaffold, or cannot explain all results from mutagenesis experiments. Here, we present an extended binding mode model based on an iterative and integrated computational and biological approach. An alignment of 68 TGR5 agonists based on this binding mode leads to a significant and good structure-based 3D QSAR model, which constitutes the most comprehensive structure based 3D-QSAR study of TGR5 agonists undertaken so far and suggests that the binding mode model is a close representation of the "true" binding mode. The binding mode model is further substantiated in that effects predicted for eight mutations in the binding site agree with experimental analyses on the impact of these TGR5 variants on receptor activity. In the binding mode, the hydrophobic cholane scaffold of taurolithocholate orients towards the interior of the orthosteric binding site such that rings A and B are in contact with TM5 and TM6, the taurine side chain orients towards the extracellular opening of the binding site and forms a salt bridge with R79(EL1), and the 3-hydroxyl group forms hydrogen bonds with E169(5.44) and Y240(6.51). The binding mode thus differs in important aspects from the ones recently presented. These results are highly relevant for the development of novel, more potent agonists of TGR5 and should be a valuable starting point for the development of TGR5 antagonists, which could show antiproliferative effects in tumor cells. PMID- 26435513 TI - Synthesis, antimycobacterial and antibacterial activity of fluoroquinolone derivatives containing an 3-alkoxyimino-4-(cyclopropylanimo)methylpyrrolidine moiety. AB - A series of novel fluoroquinolone derivatives containing an 3-alkoxyimino-4 (cyclopropylanimo)methylpyrrolidine moiety were designed, synthesized and evaluated for their biological activity. Our results revealed that 19b2 shows good activity against MTB H37Rv ATCC 27294 (MIC: <0.25 MUg/mL) and MDR-MTB 6133 clinical isolate (MIC: 0.11 MUg/mL). Most of them have potent potency against Gram-positive strains, although they are generally poor active against Gram negative strains. Especially, compounds 22b1 and 23a3 (MICs: <0.008-8 MUg/mL) were found to 2-128 times more potent than ciprofloxacin and levofloxacin against all of the tested Gram-positive strains including quinolone-resistant MRSA, MRSE, Enterococcus faecium and Enterococcus faecalis. PMID- 26435515 TI - Rational design of YAP WW1 domain-binding peptides to target TGFbeta/BMP/Smad-YAP interaction in heterotopic ossification. AB - The transforming growth factor-beta/bone morphogenic protein/Smad signaling pathway has been raised as a new and promising therapeutic target of heterotopic ossification, which is mediated by recruitment of transcription coactivator Yes associated protein (YAP) to Smad. Here, we described a successful integration of computational modeling and experimental assay to rationally design novel peptide aptamers to disrupt YAP-Smad interaction by targeting YAP WW1 domain. In the protocol, a computational genetic evolution strategy was used to improve a population of potential YAP WW1-binding peptides generated from the YAP recognition site in Smad protein, from which several promising peptides were selected and their affinities toward YAP WW1 domain were determined using binding assay. In addition, a high-activity peptide was further optimized based on its complex structure with YAP WW1 domain to derive a number of derivative peptides with higher binding potency to the domain. We also found that a strong YAP WW1 binder should have a negatively charged N-terminus, a positively charged C terminus and a nonpolar core to match the electrostatic distribution pattern in peptide-binding pocket of YAP WW1 domain, which may also form additional nonbonded interactions such as hydrogen bond, salt bridge and pi-pi stacking to confer stability and specificity for the domain-peptide recognition. PMID- 26435514 TI - Preliminary evaluation of fluoro-pegylated benzyloxybenzenes for quantification of beta-amyloid plaques by positron emission tomography. AB - A new series of fluoro-pegylated benzyloxybenzenes were designed, synthesized and evaluated as PET probes for early detection of Abeta plaques. Molecular docking revealed that all of the flexible benzyloxybenzenes inserted themselves into the hydrophobic Val18_Phe20 cleft on the flat spine of the Abeta fiber, in a manner similar to that of IMPY molecule. The most potent probe, [(18)F]9a, exhibited a combination of high binding affinity to Abeta aggregates (Ki = 21.0 +/- 4.9 nM), high initial brain uptake (9.14% ID/g at 2 min), fast clearance from normal brain tissue (1.79% ID/g at 60 min), and satisfactory in vivo biostability in the brain (95% of intact form at 2 min). [(18)F]9a clearly labeled Abeta plaques in in vitro autoradiography of postmortem AD patients and Tg mice brain sections. Ex vivo autoradiography further demonstrated that [(18)F]9a did penetrate the intact BBB and specifically bind to Abeta plaques in vivo. Overall, [(18)F]9a may be a potential PET probe for imaging Abeta plaques in AD brains. PMID- 26435516 TI - A new potential energy surface for the H2S system and dynamics study on the S((1)D) + H2(X(1)Sigmag(+)) reaction. AB - We constructed a new global potential energy surface (PES) for the electronic ground state ((1)A') of H2S based on 21,300 accurate ab initio energy points over a large configuration space. The ab initio energies are obtained from multireference configuration interaction calculations with a Davidson correction using basis sets of quadruple zeta quality. The neural network method is applied to fit the PES, and the root mean square error of fitting is small (1.68 meV). Time-dependent wave packet studies for the S((1)D) + H2(X(1)Sigmag(+)) -> H((2)S) + SH(X(2)Pi) reaction on the new PES are conducted to study the reaction dynamics. The calculated integral cross sections decrease with increasing collision energy and remain fairly constant within the high collision energy range. Both forward and backward scatterings can be observed as expected for a barrierless reaction with a deep well on the PES. The calculated integral cross sections and differential cross sections are in good agreement with the experimental results. PMID- 26435517 TI - Translocation from nuclei to cytoplasm is necessary for anti A-PCD activity and turnover of the Type II IAP BcBir1. AB - Type II inhibitors of apoptosis (IAPs) belong to a subgroup of IAP-related proteins. While IAPs are restricted to animals, Type II IAPs are found in other phyla, including fungi. BcBir1, a Type II IAP from Botrytis cinerea has anti apoptotic-like programmed cell death (A-PCD) activity, which is important for pathogenicity of this fungus. Here we report on the role of sub-cellular localization of BcBir1 in protein turnover and anti A-PCD activity. Expression of BcBir1 in Saccharomyces cerevisiae had no effect on sensitivity of the yeast cells to A-PCD-inducing conditions, whereas expression of a truncated N' part reduced sensitivity of the cells to these conditions. The full-length BcBir1 protein was detected only in the yeast nucleus, whereas the N' part was observed both in the nucleus and cytoplasm. In B. cinerea, BcBir1 was mainly nuclear under optimal conditions, whereas under A-PCD-inducing conditions it shuttled to the cytoplasm and then it was completely degraded. Collectively, our results show that anti A-PCD activity of BcBir1 occurs in the cytoplasm, the C' end mediates regulation of steady state level of BcBir1 in the nucleus, and the N' end mediates anti A-PCD activity as well as fast degradation of BcBir1 in the cytoplasm. PMID- 26435518 TI - Multilayer hexagonal silicon forming in slit nanopore. AB - The solidification of two-dimensional liquid silicon confined to a slit nanopore has been studied using molecular dynamics simulations. The results clearly show that the system undergoes an obvious transition from liquid to multilayer hexagonal film with the decrease of temperature, accompanied by dramatic change in potential energy, atomic volume, coordination number and lateral radial distribution function. During the cooling process, some hexagonal islands randomly appear in the liquid first, then grow up to grain nuclei, and finally connect together to form a complete polycrystalline film. Moreover, it is found that the quenching rate and slit size are of vital importance to the freezing structure of silicon film. The results also indicate that the slit nanopore induces the layering of liquid silicon, which further induces the slit size dependent solidification behavior of silicon film with different electrical properties. PMID- 26435519 TI - Increasing prevalence of ciprofloxacin-resistant food-borne Salmonella strains harboring multiple PMQR elements but not target gene mutations. AB - Fluoroquinolone resistance in Salmonella has become increasingly prevalent in recent years. To probe the molecular basis of this phenomenon, the genetic and phenotypic features of fluoroquinolone resistant Salmonella strains isolated from food samples were characterized. Among the 82 Salmonella strains tested, resistance rate of the three front line antibiotics of ceftriaxone, ciprofloxacin and azithromycin was 10%, 39% and 25% respectively, which is significantly higher than that reported in other countries. Ciprofloxacin resistant strains typically exhibited cross-resistance to multiple antibiotics including ceftriaxone, primarily due to the presence of multiple PMQR genes and the blaCTX-M-65, blaCTX M-55 blaCMY-2 and blaCMY-72 elements. The prevalence rate of the oqxAB and aac(6')-Ib-cr genes were 91% and 75% respectively, followed by qnrS (66%), qnrB (16%) and qnrD (3%). The most common PMQR combination observable was aac(6')-Ib cr-oqxAB-qnrS2, which accounted for 50% of the ciprofloxacin resistant strains. Interestingly, such isolates contained either no target mutations or only a single gyrA mutation. Conjugation and hybridization experiments suggested that most PMQR genes were located either in the chromosome or a non-transferrable plasmid. To summarize, findings in this work suggested that PMQRs greatly facilitate development of fluoroquinolone resistance in Salmonella by abolishing the requirement of target gene mutations. PMID- 26435520 TI - Meckel diverticulum in children: Evaluation of macroscopic appearance for guidance in subsequent surgery. AB - BACKGROUND: The treatment of incidentally encountered asymptomatic Meckel diverticulum (MD) is controversial. We evaluated whether the macroscopic appearance correlates with clinical features, histopathological findings, future complications, and management decisions. METHODS: Patients who underwent MD resection at a single institution from 2000 to 2012 were retrospectively analyzed in terms of age, sex, clinical features, laboratory data, perioperative findings (diverticulum length, diameter, depth, thickening, and height-to diameter ratio [HDR]), pathology, and postoperative follow-up. RESULTS: Fifty children were enrolled. Sixteen percent of the resected MDs were found incidentally. Of 42 complicated MDs, 17 (40%) were long (HDR >=2), 14 (33%) were thickened, and 29 (70%) exhibited base widening. Histopathologically, ectopic mucosa was found in 32 (64%) of all MDs and in 5 (62%) of incidentally removed MDs. There was no statistical difference between the macroscopic appearance and clinical signs, sex, or presence of ectopic tissue based on palpation. CONCLUSION: The macroscopic appearance of MD does not indicate the presence or absence of HGM and cannot be used to guide subsequent surgery. Additionally, 40% of symptomatic patients in our study had life-threatening complications requiring prompt fluid resuscitation. We consider that incidentally detected MD should be removed regardless of its macroscopic appearance. PMID- 26435521 TI - Enteral refeeding is useful for promoting growth in neonates with enterostomy before stoma closure. AB - BACKGROUND: Enterostomy may lead to fluid and electrolyte imbalance, or impaired absorption of nutrition followed by impairment of growth. This study aimed to clarify the effectiveness of enteral refeeding (ER) in premature and full-term neonates. METHODS: A retrospective database of all consecutive neonates who had enterostomy during 2000-2014 in a regional center was analyzed. Thirteen patients with ER (ER group) and 14 patients without ER (control group) were included. Detailed clinical data were evaluated with reference to the increment in body weight during ER. RESULTS: The ER group had a significantly higher rate in weight gain compared with the control group (P=0.0012), despite the gestational age (<37weeks: P=0.0012, >=37weeks: P=0.029). ER starting at a lower body weight was also associated with a higher weight gain (P=0.0002). Moreover, univariate and multivariate analyses showed that only the ER procedure (P<0.0001) and birth weight (P=0.049) were significantly independent predictors of good weight gain. CONCLUSIONS: Using ER, low-birth-weight infants may have benefits, such as better acceleration of growth, than normal-birth-weight infants. We do not hesitate to perform ER, even in low-birth-weight neonates or those with low body weight, when starting ER. PMID- 26435522 TI - Back to the future: Does in-hospital delay to appendectomy for pediatric uncomplicated appendicitis increase risk for perforation? PMID- 26435525 TI - A new tool for long-term studies of POM-bacteria interactions: overcoming the century-old Bottle Effect. AB - Downward fluxes of particulate organic matter (POM) are the major process for sequestering atmospheric CO2 into aquatic sediments for thousands of years. Budget calculations of the biological carbon pump are heavily based on the ratio between carbon export (sedimentation) and remineralization (release to the atmosphere). Current methodologies determine microbial dynamics on POM using closed vessels, which are strongly biased towards heterotrophy due to rapidly changing water chemistry (Bottle Effect). We developed a flow-through rolling tank for long term studies that continuously maintains POM at near in-situ conditions. There, bacterial communities resembled in-situ communities and greatly differed from those in the closed systems. The active particle-associated community in the flow-through system was stable for days, contrary to hours previously reported for closed incubations. In contrast to enhanced respiration rates, the decrease in photosynthetic rates on particles throughout the incubation was much slower in our system than in traditional ones. These results call for reevaluating experimentally-derived carbon fluxes estimated using traditional methods. PMID- 26435523 TI - Endometrial gene expression profile of pregnant sows with extreme phenotypes for reproductive efficiency. AB - Prolificacy can directly impact porcine profitability, but large genetic variation and low heritability have been found regarding litter size among porcine breeds. To identify key differences in gene expression associated to swine reproductive efficiency, we performed a transcriptome analysis of sows' endometrium from an Iberian x Meishan F2 population at day 30-32 of gestation, classified according to their estimated breeding value (EBV) as high (H, EBV > 0) and low (L, EBV < 0) prolificacy phenotypes. For each sample, mRNA and small RNA libraries were RNA-sequenced, identifying 141 genes and 10 miRNAs differentially expressed between H and L groups. We selected four miRNAs based on their role in reproduction, and five genes displaying the highest differences and a positive mapping into known reproductive QTLs for RT-qPCR validation on the whole extreme population. Significant differences were validated for genes: PTGS2 (p = 0.03; H/L ratio = 3.50), PTHLH (p = 0.03; H/L ratio = 3.69), MMP8 (p = 0.01; H/L ratio =4.41) and SCNN1G (p = 0.04; H/L ratio = 3.42). Although selected miRNAs showed similar expression levels between H and L groups, significant correlation was found between the expression level of ssc-miR-133a (p < 0.01) and ssc-miR-92a (p < 0.01) and validated genes. These results provide a better understanding of the genetic architecture of prolificacy-related traits and embryo implantation failure in pigs. PMID- 26435527 TI - Hit and lead criteria in drug discovery for infectious diseases of the developing world. AB - Reducing the burden of infectious diseases that affect people in the developing world requires sustained collaborative drug discovery efforts. The quality of the chemical starting points for such projects is a key factor in improving the likelihood of clinical success, and so it is important to set clear go/no-go criteria for the progression of hit and lead compounds. With this in mind, the Japanese Global Health Innovative Technology (GHIT) Fund convened with experts from the Medicines for Malaria Venture, the Drugs for Neglected Diseases initiative and the TB Alliance, together with representatives from the Bill &Melinda Gates Foundation, to set disease-specific criteria for hits and leads for malaria, tuberculosis, visceral leishmaniasis and Chagas disease. Here, we present the agreed criteria and discuss the underlying rationale. PMID- 26435524 TI - Neural substrates of cue reactivity: association with treatment outcomes and relapse. AB - Given the strong evidence for neurological alterations at the basis of drug dependence, functional magnetic resonance imaging (fMRI) represents an important tool in the clinical neuroscience of addiction. fMRI cue-reactivity paradigms represent an ideal platform to probe the involvement of neurobiological pathways subserving the reward/motivation system in addiction and potentially offer a translational mechanism by which interventions and behavioral predictions can be tested. Thus, this review summarizes the research that has applied fMRI cue reactivity paradigms to the study of adult substance use disorder treatment responses. Studies utilizing fMRI cue-reactivity paradigms for the prediction of relapse and as a means to investigate psychosocial and pharmacological treatment effects on cue-elicited brain activation are presented within four primary categories of substances: alcohol, nicotine, cocaine and opioids. Lastly, suggestions for how to leverage fMRI technology to advance addiction science and treatment development are provided. PMID- 26435528 TI - Regulatory watch: Characterizing the US FDA's approach to promoting transformative innovation. PMID- 26435529 TI - Imaging normal and cancerous human gastric muscular layer in transverse and longitudinal sections by multiphoton microscopy. AB - Multiphoton microscopy (MPM) based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) has been widely used for imaging microstructure of biological tissues. In this article, we used MPM to investigate the microstructure changes of normal and cancerous human gastric muscular layer in transverse and longitudinal sections. The results displayed different patterns of microstructure changes of smooth muscular tissue, cell morphology and interstitial fibers in transverse and longitudinal sections, being similar to standard histopathological images but without the need for tissue processing. Our study demonstrated that MPM can bring more detailed complementary information on tissue architecture through observing transverse and longitudinal sections of tissues, which are the important pathological information when the pathologists diagnose the gastrointestinal lesions. These observations indicate that MPM could be an important potential tool to provide real-time pathological diagnosis for gastric cancer in the future. SCANNING 38:357-364, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26435531 TI - Cathinones: Isotopic profiling as an aid to linking seizures. AB - The number of cathinone derivatives available to the street market has increased steadily since 2008. Many of these compounds have proven to be potent psychostimulants and fatalities have occurred through their recreational use. The method of manufacture is essentially the same for each cathinone, i.e., (i) selection of the appropriate beta-ketoarylalkane, (ii) bromination alpha to the keto group, followed by (iii) amination using the desired amine. The cathinone derivatives are usually prepared at a very high purity and little information is available from an organic manufacturing by-products profile because the product is so pure. To provide law enforcement agencies with a tool that would enable links to be identified between samples from the same production batch, the carbon, hydrogen, and nitrogen stable isotope ratios in a number of cathinones were investigated. The aim was to determine if sufficient diversity existed in the light element stable isotope ratios of cathinones to allow the isotopic ratios to be used to discriminate between different seizures and to assist in linking samples from the same seizure. Careful measurement of the delta(13) C, delta(15) N, and delta(2) H values in each sample revealed that the stable isotope ratios for a particular cathinone analogue vary from one seizure to another. In the seizures studied, carbon, hydrogen, and nitrogen stable isotope ratios were found to vary from -32.80/00 to -26.10/00, -1520/00 to +720/00, and 16.60/00 to -2.70/00, respectively. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26435532 TI - Temperature effects on polygraph detection of concealed information. AB - Thermoregulatory influences on electrodermal and cardiovascular activity may interfere with the detection of concealed information using a polygraph. This possibility was assessed by means of a mock terrorism scenario. Seventy-two participants were assigned to either a guilty or an innocent role. They were given a polygraph test at one of three ambient temperatures: 10 degrees C, 22 degrees C, or 34 degrees C. Among guilty participants, electrodermal and cardiovascular measures were least effective at 10 degrees C. Electrodermal results were optimal at 22 degrees C, whereas cardiovascular results were optimal at 34 degrees C. Among innocent participants, the effectiveness of these same measures was not affected by ambient temperature. Temperature had no significant impact on respiration results within the guilty or the innocent groups. Taken together, these findings have implications for those who use polygraphs in uncontrolled testing environments. PMID- 26435530 TI - Mutations in circularly permuted GTPase family genes AtNOA1/RIF1/SVR10 and BPG2 suppress var2-mediated leaf variegation in Arabidopsis thaliana. AB - Leaf variegation mutants constitute a unique group of chloroplast development mutants and are ideal genetic materials to dissect the regulation of chloroplast development. We have utilized the Arabidopsis yellow variegated (var2) mutant and genetic suppressor analysis to probe the mechanisms of chloroplast development. Here we report the isolation of a new var2 suppressor locus SUPPRESSOR OF VARIEGATION (SVR10). Genetic mapping and molecular complementation indicated that SVR10 encodes a circularly permuted GTPase that has been reported as Arabidopsis thaliana NITRIC OXIDE ASSOCIATED 1 (AtNOA1) and RESISTANT TO INHIBITION BY FOSMIDOMYCIN 1 (RIF1). Biochemical evidence showed that SVR10/AtNOA1/RIF1 likely localizes to the chloroplast stroma. We further demonstrate that the mutant of a close homologue of SVR10/AtNOA1/RIF1, BRASSINAZOLE INSENSITIVE PALE GREEN 2 (BPG2), can also suppress var2 leaf variegation. Mutants of SVR10 and BPG2 are impaired in photosynthesis and the accumulation of chloroplast proteins. Interestingly, two-dimensional blue native gel analysis showed that mutants of SVR10 and BPG2 display defects in the assembly of thylakoid membrane complexes including reduced levels of major photosynthetic complexes and the abnormal accumulation of a chlorophyll-protein supercomplex containing photosystem I. Taken together, our findings suggest that SVR10 and BPG2 are functionally related with VAR2, likely through their potential roles in regulating chloroplast protein homeostasis, and both SVR10 and BPG2 are required for efficient thylakoid protein complex assembly and photosynthesis. PMID- 26435533 TI - Exercise level before pregnancy and engaging in high-impact sports reduce the risk of pelvic girdle pain: a population-based cohort study of 39 184 women. AB - OBJECTIVE: To examine whether an association exists between exercise levels pre pregnancy and pelvic girdle pain in pregnancy. Pelvic girdle pain in pregnancy has been associated with physical inactivity, a risk factor for adverse pregnancy outcomes. METHODS: We used data from a population-based cohort study including 39 184 nulliparous women with a singleton pregnancy enrolled in the Norwegian Mother and Child Cohort study. Pre-pregnancy exercise frequency and types were assessed by questionnaire in pregnancy week 17. Pelvic girdle pain, defined as combined pain in the anterior pelvis and in the posterior pelvis bilaterally, was self reported in pregnancy week 30. Multivariable Poisson regression estimated risks of pelvic girdle pain associated with pre-pregnancy exercise. We examined a dose response association of prepregnancy exercise frequency using restricted cubic splines. A test for non-linearity was also conducted. Final models were adjusted for pre-pregnancy BMI, age, education, history of low back pain and history of depression. RESULTS: 4069 women (10.4%) reported pelvic girdle pain in pregnancy and the prevalence among women who were non-exercisers prepregnancy was 12.5%. There was a non-linear association for pre-pregnancy exercise and risk of pelvic girdle pain (test for non-linearity, p=0.003). Compared to non-exercisers, women exercising 3-5 times weekly pre-pregnancy had a 14% lower risk of developing pelvic girdle pain in pregnancy (aRR 0.86, 95% CI 0.77 to 0.96). Taking part in high-impact exercises such as running, jogging, orienteering, ballgames, netball games and high-impact aerobics were associated with less risk of pelvic girdle pain. SUMMARY: Women who exercise regularly and engage in high-impact exercises before the first pregnancy may have a reduced risk of pelvic girdle pain in pregnancy. PMID- 26435534 TI - Validation of web-based, multiple 24-h recalls combined with nutritional supplement intake questionnaires against nitrogen excretions to determine protein intake in Dutch elite athletes. AB - Information on dietary composition is vitally important for elite athletes to optimise their performance and recovery, which requires valid tools. The aim of the present study was to investigate the validity of assessing protein intake using three web-based 24-h recalls and questionnaires, by comparing these with three urinary N excretions on the same day. A total of forty-seven Dutch elite top athletes, both disabled and non-disabled, aged between 18 and 35 years, with a BMI of 17.5-31 kg/m2, exercising >12 h/week were recruited. Estimated mean dietary protein intake was 109.6 (sd 33.0) g/d by recalls and questionnaires v. 141.3 (sd 38.2) g/d based on N excretions in urine; the difference was 25.5 (sd 21.3) % between the methods (P<0.05). We found a reasonably good association between methods for protein intake of 0.65 (95 % CI 0.45, 0.79). On an individual level, under-reporting was larger with higher protein intakes than with lower intakes. No significant differences were found in reporting absolute differences between subcategories (sex, under-reporting, BMI, collection of recalls within a certain amount of time and using protein supplements or not). In conclusion, combined, multiple, 24-h recalls and questionnaires underestimated protein intake in these young elite athletes more than that reported for non-athlete populations. The method proved to be suitable for ranking athletes according to their protein intake as needed in epidemiological studies. On an individual level, the magnitude of underestimation was about equal for all athletes except for those with very high protein intakes. PMID- 26435535 TI - Tuning B cell responsiveness by antigen receptor isotype. PMID- 26435536 TI - Screening for peripheral neuropathy and peripheral arterial disease in persons with diabetes mellitus in a Nigerian University Teaching Hospital. AB - BACKGROUND: Identifying the risk factors for diabetes mellitus related foot ulceration would save more limbs from amputation. This report focuses on the determining the burden of peripheral arterial disease and neuropathy in persons with diabetes mellitus (DM). METHODS: This is a descriptive study carried out in the Diabetic Clinic of the Lagos State University Teaching Hospital in patients with DM who had no past/present history of foot ulceration. Biothesiometry was employed and ankle brachial pressure indices were measured to evaluate for neuropathy and peripheral arterial disease (PAD) respectively. RESULTS: A total of 225 persons living with DM who met inclusion criteria were recruited consecutively over a 3 months period. Age range was 28-87 years with the mean [61.4 (10.8)] and median (63) years respectively. Patients symptomatic for neuropathy and PAD were 37 and 40 % respectively of the study population. An older age of >60 years and poor glycaemic control were potential predictors of neuropathy. Neuropathy and PAD occurred commonly in the seventh decade of life. CONCLUSION: Given the fairly high proportions of neuropathy and PAD in our patients with DM, we recommend that they be routinely examined in persons with DM. PMID- 26435537 TI - Effects of Sleeve Gastrectomy and Gastric Bypass on Postprandial Lipid Profile in Obese Type 2 Diabetic Patients: a 2-Year Follow-up. AB - BACKGROUND: Bariatric surgery (BS) is known to favorably impact fasting lipid profile. Fasting and postprandial lipids were evaluated before and 2 years after BS in obese type 2 diabetic (T2DM) patients. METHODS: A prospective study was conducted in 19 obese T2DM patients: ten undergoing sleeve gastrectomy (SG) and nine undergoing Roux-en-Y gastric bypass (RYGB). Before and 2 years after BS, clinical parameters and the response of lipid and incretin hormones to a mixed meal (MM) were assessed. RESULTS: The two groups had similar characteristics at baseline. After BS, weight loss was similar in the two groups (p <= 0.01). Fasting glucose, insulin, and triglycerides decreased while HDL cholesterol increased in a similar way (p < 0.05); in contrast, fasting LDL cholesterol decreased only after RYGB (p < 0.05). Post-meal glucose concentrations decreased while early insulin response significantly improved after both procedures (p < 0.001 for both). Postprandial triglycerides decreased after both procedures (p < 0.05) while postprandial LDL cholesterol decreased only after RYGB (p < 0.05). Meal-GLP-1 increased postoperatively in both groups although to a greater extent after RYGB (p < 0.001 vs. SG). GIP decreased after both procedures, especially after RYGB (p = 0.003). At multivariate analysis, GLP-1 peak was the best predictor of LDL reduction (beta = -0.552, p = 0.039) while the improvement of HOMA-IR (beta = 0.574, p = 0.014) and weight loss (beta = 0.418, p = 0.036) predicted triglycerides reduction. CONCLUSIONS: Both surgical procedures markedly reduce fasting and postprandial triglycerides and increase HDL cholesterol levels. LDL cholesterol decreases only after RYGB through a mechanism likely mediated by the restoration of GLP-1. PMID- 26435541 TI - Reproductive ability of a cloned male detector dog and behavioral traits of its offspring. AB - In 2007, seven detector dogs were produced by somatic cell nuclear transfer using one nuclear donor dog, then trained and certified as excellent detector dogs, similar to their donor. In 2011, we crossed a cloned male and normal female by natural breeding and produced ten offspring. In this study, we investigated the puppies' temperaments, which we later compared with those of the cloned parent male. The results show that the cloned male had normal reproductive abilities and produced healthy offspring. All puppies completed narcotic detector dog training with a success rate for selection of 60%. Although the litter of cloned males was small in this study, a cloned male dog bred by natural mating produced puppies that later successfully completed the training course for drug detection. In conclusion, cloning an elite dog with superior genetic factors and breeding of the cloned dog was found to be a useful method to efficiently procure detector dogs. PMID- 26435543 TI - Development and evaluation of a competitive enzyme-linked immunosorbent assay using a monoclonal antibody for diagnosis of severe fever with thrombocytopenia syndrome virus in bovine sera. AB - Severe fever with thrombocytopenia syndrome (SFTS) caused by the SFTS virus (SFTSV), a phlebovirus in the family Bunyaviridae, is an emerging tick-borne infectious disease that impacts humans. This disease manifests as a decreased blood cell count and multi-organ failure, with a case-fatality rate of more than 12% in China. Because vaccines or antiviral drugs for the treatment of this disease are not available, monitoring the SFTS circulation in animals and controlling the tick-mammal cycle are important for preventing SFTS. Monoclonal antibodies against the recombinant nucleoprotein of SFTSV were generated to develop a competitive enzyme-linked immunosorbent assay (cELISA) for the detection of antibodies against SFTSV infection in cattle. The specificity and sensitivity of cELISA was assessed by comparing the results of this assay to those of an immunofluorescence assay (IFA). The results of the cELISA using 416 field bovine serum samples and laboratory-immunized positive sera showed 98.1% consistency with those of the IFA. The cELISA used in this study did not show cross-reactivity with antisera against other viral cattle diseases. The cELISA presented in this study can be applied to detect antibodies against SFTSV in cattle. PMID- 26435544 TI - Time-course changes of hippocalcin expression in the mouse hippocampus following pilocarpine-induced status epilepticus. AB - Hippocalcin participates in the maintenance of neuronal calcium homeostasis. In the present study, we examined the time-course changes of neuronal degeneration and hippocalcin protein level in the mouse hippocampus following pilocarpine induced status epilepticus (SE). Marked neuronal degeneration was observed in the hippocampus after SE in a time-dependent manner, although neuronal degeneration differed according to the hippocampal subregions. Almost no hippocalcin immunoreactivity was detected in the pyramidal neurons of the cornu ammonis 1 (CA1) region from 6 h after SE. However, many pyramidal neurons in the CA2 region showed hippocalcin immunoreactivity until 24 h after SE. In the CA3 region, only a few hippocalcin immunoreactive cells were observed at 12 h after SE, and almost no hippocalcin immunoreactivity was observed in the pyramidal neurons from 24 h after SE. Hippocalcin immunoreactivity in the polymorphic cells of the dentate gyrus was markedly decreased from 6 h after SE. In addition, hippocalcin protein level in the hippocampus began to decrease from 6 h after SE, and was significantly decreased at 24 h and 48 h after pilocarpine-induced SE. These results indicate that marked reduction of hippocalcin level may be closely related to neuronal degeneration in the hippocampus following pilocarpine-induced SE. PMID- 26435545 TI - Choice of Model for Estimation of Adsorption Isotherm Parameters in Gradient Elution Preparative Liquid Chromatography. AB - The inverse method is a numerical method for fast estimation of adsorption isotherm parameters directly from a few overloaded elution profiles and it was recently extended to adsorption isotherm acquisition in gradient elution conditions. However, the inverse method in gradient elution is cumbersome due to the complex adsorption isotherm models found in gradient elution. In this case, physicochemically correct adsorption models have very long calculation times. The aim of this study is to investigate the possibility of using a less complex adsorption isotherm model, with fewer adjustable parameters, but with preserved/acceptable predictive abilities. We found that equal or better agreement between experimental and predicted elution profiles could be achieved with less complex models. By being able to select a model with fewer adjustable parameters, the calculation times can be reduced by at least a factor of 10. PMID- 26435546 TI - Computational modeling and simulation of spall fracture in polycrystalline solids by an atomistic-based interfacial zone model. AB - The focus of this work is to investigate spall fracture in polycrystalline materials under high-speed impact loading by using an atomistic-based interfacial zone model. We illustrate that for polycrystalline materials, increases in the potential energy ratio between grain boundaries and grains could cause a fracture transition from intergranular to transgranular mode. We also found out that the spall strength increases when there is a fracture transition from intergranular to transgranular. In addition, analysis of grain size, crystal lattice orientation and impact speed reveals that the spall strength increases as grain size or impact speed increases. PMID- 26435547 TI - Wives' and Husbands' Nonfamily Experiences and First-Birth Timing. PMID- 26435548 TI - Institutionalization of Migration Policy Frameworks in Armenia, Azerbaijan and Georgia. AB - This article is a comparative study of the institutionalization of the migration policy frameworks of post-Soviet states Armenia, Azerbaijan and Georgia since the collapse of the Soviet Union in 1991. All three countries share common historical legacies: a Soviet past, wars and conflicts, unemployment, high emigration, and commitment to integration into European bodies. To what extent do the migration policies of these three countries (driven by contextual forces, i.e. domestic challenges) address country-specific migration dynamics? Or are they imposed by the European Union? In which dimensions have the national policies on migration of Armenia, Azerbaijan and Georgia evolved, and around which issues have they converged or diverged? Have these trends led to an integration of migration policymaking at the regional level in the South Caucasus? PMID- 26435549 TI - The solubility and site preference of Fe3+ in Li7-3x Fe x La3Zr2O12 garnets. AB - A series of Fe3+-bearing Li7La3Zr2O12 (LLZO) garnets was synthesized using solid state synthesis methods. The synthetic products were characterized compositionally using electron microprobe analysis and inductively coupled plasma optical emission spectroscopy (ICP-OES) and structurally using X-ray powder diffraction and 57Fe Mossbauer spectroscopy. A maximum of about 0.25 Fe3+ pfu could be incorporated in Li7-3x Fe x La3Zr2O12 garnet solid solutions. At Fe3+ concentrations lower than about 0.16 pfu, both tetragonal and cubic garnets were obtained in the synthesis experiments. X-ray powder diffraction analysis showed only a garnet phase for syntheses with starting materials having intended Fe3+ contents lower than 0.52 Fe3+ pfu. Back-scattered electron images made with an electron microprobe also showed no phase other than garnet for these compositions. The lattice parameter, a0, for all solid-solution garnets is similar with a value of a0~12.98 A regardless of the amount of Fe3+. 57Fe Mossbauer spectroscopic measurements indicate the presence of poorly- or nano crystalline FeLaO3 in syntheses with Fe3+ contents greater than 0.16 Fe3+ pfu. The composition of different phase pure Li7-3x Fe x La3Zr2O12 garnets, as determined by electron microprobe (Fe, La, Zr) and ICP-OES (Li) measurements, give Li6.89Fe0.03La3.05Zr2.01O12, Li6.66Fe0.06La3.06Zr2.01O12, Li6.54Fe0.12La3.01Zr1.98O12, and Li6.19Fe0.19La3.02Zr2.04O12. The 57Fe Mossbauer spectrum of cubic Li6.54Fe0.12La3.01Zr1.98O12 garnet indicates that most Fe3+ occurs at the special crystallographic 24d position, which is the standard tetrahedrally coordinated site in garnet. Fe3+ in smaller amounts occurs at a general 96h site, which is only present for certain Li-oxide garnets, and in Li6.54Fe0.12La3.01Zr1.98O12 this Fe3+ has a distorted 4-fold coordination. PMID- 26435550 TI - Developmental, Component-Based Model of Reading Fluency: An Investigation of Predictors of Word-Reading Fluency, Text-Reading Fluency, and Reading Comprehension. AB - The primary goal was to expand our understanding of text reading fluency (efficiency or automaticity)-how its relation to other constructs (e.g., word reading fluency and reading comprehension) changes over time and how it is different from word reading fluency and reading comprehension. We examined (1) developmentally changing relations among word reading fluency, listening comprehension, text reading fluency, and reading comprehension; (2) the relation of reading comprehension to text reading fluency; (3) unique emergent literacy predictors (i.e., phonological awareness, orthographic awareness, morphological awareness, letter name knowledge, vocabulary) of text reading fluency vs. word reading fluency; and (4) unique language and cognitive predictors (e.g., vocabulary, grammatical knowledge, theory of mind) of text reading fluency vs. reading comprehension. These questions were addressed using longitudinal data (two timepoints; Mean age = 5;24 & 6;08) from Korean-speaking children (N = 143). Results showed that listening comprehension was related to text reading fluency at time 2, but not at time 1. At both times text reading fluency was related to reading comprehension, and reading comprehension was related to text reading fluency over and above word reading fluency and listening comprehension. Orthographic awareness was related to text reading fluency over and above other emergent literacy skills and word reading fluency. Vocabulary and grammatical knowledge were independently related to text reading fluency and reading comprehension whereas theory of mind was related to reading comprehension, but not text reading fluency. These results reveal developmental nature of relations and mechanism of text reading fluency in reading development. PMID- 26435551 TI - Click chemistry oligomerisation of azido-alkyne-functionalised galactose accesses triazole-linked linear oligomers and macrocycles that inhibit Trypanosoma cruzi macrophage invasion. AB - Reaction of 2-(2-(2-azidoethoxy)ethoxy)ethyl 6-O-(prop-2-ynyl)-beta-d galactopyranoside (7) under CuAAC conditions gives rise to mixed cyclic and linear triazole-linked oligomers, with individual compounds up to d.p. 5 isolable, along with mixed larger oligomers. The linear compounds resolve en bloc from the cyclic materials by RP HPLC, but are separable by gel permeation chromatography. The triazole-linked oligomers-pseudo-galactooligomers-were demonstrated to be acceptor substrates for the multi-copy cell surface trans sialidase of the human parasite Trypanosoma cruzi. In addition, these multivalent TcTS ligands were able to block macrophage invasion by T. cruzi. PMID- 26435552 TI - Predicting the evolution of social networks with life cycle events. AB - This paper presents a model of social network evolution, to predict and simulate changes in social networks induced by lifecycle events. We argue that social networks change with lifecycle events, and we extend a model of friendship selection to incorporate these dynamics of personal social networks. The model uses theories of homophily and reciprocity and is formulated in a random utility maximization framework to predict the formation of social ties between individuals in the population. It is then extended to predict the evolution of social networks in response to life cycle events. The model is estimated using attribute data of a national sample and an event-based retrospective dataset collected in 2009 and 2011 respectively. Findings suggest that homophily has a strong effect on the formation of new ties. However, heterophily also plays a role in maintaining existing ties. Although the motivation of this research stems from incorporating social network dynamics in large-scale travel behaviour micro simulation models, the research can be used in a variety of fields for similar purposes. PMID- 26435553 TI - The Infrared Spectra of Polycyclic Aromatic Hydrocarbons with Excess Peripheral H Atoms (Hn-PAHs) and their Relation to the 3.4 and 6.9 um PAH Emission Features. AB - Polycyclic aromatic hydrocarbons (PAHs) are likely responsible for the family of infrared emission features seen in a wide variety of astrophysical environments. A potentially important subclass of these materials are PAHs whose edges contain excess H atoms (Hn-PAHs). This type of compound may be present in space, but it has been difficult to assess this possibility because of a lack of suitable laboratory spectra to assist with analysis of astronomical data. We present 4000 500 cm-1 (2.5-20 um) infrared spectra of 23 Hn-PAHs and related molecules isolated in argon matrices under conditions suitable for interpretation of astronomical data. Spectra of molecules with mixed aromatic and aliphatic domains show characteristics that distinguish them from fully aromatic PAH equivalents. Two major changes occur as PAHs become more hydrogenated: (1) aromatic C-H stretching bands near 3.3 um weaken and are replaced with stronger aliphatic bands near 3.4 um, and (2) aromatic C-H out-of-plane bending mode bands in the 11 15 um region shift and weaken concurrent with growth of a strong aliphatic -CH2 deformation mode near 6.9 um. Implications for interpreting astronomical spectra are discussed with emphasis on the 3.4 and 6.9 um features. Laboratory data is compared with emission spectra from IRAS 21282+5050, an object with normal PAH emission features, and IRAS 22272+5435 and IRAS 0496+3429, two protoplanetary nebulae with abnormally large 3.4 um features. We show that 'normal' PAH emission objects contain relatively few Hn-PAHs in their emitter populations, but less evolved protoplanetary nebulae may contain significant abundances of these molecules. PMID- 26435554 TI - Thermophysical properties of two ammonium-based protic ionic liquids. AB - Experimental data for density, viscosity, refractive index and surface tension are reported, for the first time, in the temperature range between 288.15 K and 353.15 K and at atmospheric pressure for two protic ionic liquids, namely 2 (dimethylamino)-N,N-dimethylethan-1-ammonium acetate, [N11{2(N11)}H][CH3CO2], and N-ethyl-N,N-dimethylammonium phenylacetate, [N112H][C7H7CO2]. The effect of the anion aromaticity and the cation's aliphatic tails on the studied properties is discussed. From the measured properties temperature dependency the derived properties, such as the isobaric thermal expansion coefficient, the surface entropy and enthalpy, and the critical temperature, were estimated. PMID- 26435556 TI - Roof Instability: What Reportable Noninjury Roof Falls in Underground Coal Mines Can Tell Us. PMID- 26435555 TI - Cross-Sectional Predictors of Sexual Assault Perpetration in a Community Sample of Single African American and Caucasian Men. AB - Computer-assisted self-interviews were completed with a random sample of 163 unmarried Caucasian and African American men in a large metropolitan area. Almost a quarter (24.5%) of these men acknowledged committing an act since the age of 14 that met standard legal definitions of attempted or completed rape; an additional 39% had committed another type of sexual assault involving forced sexual contact or verbal coercion. An expanded version of the Malamuth et al. [1991] confluence model was examined using path analysis. The number of sexual assaults perpetrated by participants was associated with the direct or indirect effects of childhood sexual abuse, adolescent delinquency, alcohol problems, sexual dominance, positive attitudes about casual sexual relationships, and pressure from peers to engage in sexual relationships. Additionally, empathy buffered the relationship between sexual dominance and perpetration. The pattern of results was highly similar for African American and Caucasian men. The implications of these findings for sexual assault measurement are discussed and suggestions are made for alternative treatment programs. PMID- 26435557 TI - Integration of vertical and in-seam horizontal well production analyses with stochastic geostatistical algorithms to estimate pre-mining methane drainage efficiency from coal seams: Blue Creek seam, Alabama. AB - Coal seam degasification and its efficiency are directly related to the safety of coal mining. Degasification activities in the Black Warrior basin started in the early 1980s by using vertical boreholes. Although the Blue Creek seam, which is part of the Mary Lee coal group, has been the main seam of interest for coal mining, vertical wellbores have also been completed in the Pratt, Mary Lee, and Black Creek coal groups of the Upper Pottsville formation to degasify multiple seams. Currently, the Blue Creek seam is further degasified 2-3 years in advance of mining using in-seam horizontal boreholes to ensure safe mining. The studied location in this work is located between Tuscaloosa and Jefferson counties in Alabama and was degasified using 81 vertical boreholes, some of which are still active. When the current long mine expanded its operation into this area in 2009, horizontal boreholes were also drilled in advance of mining for further degasification of only the Blue Creek seam to ensure a safe and a productive operation. This paper presents an integrated study and a methodology to combine history matching results from vertical boreholes with production modeling of horizontal boreholes using geostatistical simulation to evaluate spatial effectiveness of in-seam boreholes in reducing gas-in-place (GIP). Results in this study showed that in-seam wells' boreholes had an estimated effective drainage area of 2050 acres with cumulative production of 604 MMscf methane during ~2 years of operation. With horizontal borehole production, GIP in the Blue Creek seam decreased from an average of 1.52 MMscf to 1.23 MMscf per acre. It was also shown that effective gas flow capacity, which was independently modeled using vertical borehole data, affected horizontal borehole production. GIP and effective gas flow capacity of coal seam gas were also used to predict remaining gas potential for the Blue Creek seam. PMID- 26435558 TI - Geostatistical modeling of the gas emission zone and its in-place gas content for Pittsburgh-seam mines using sequential Gaussian simulation. AB - Determination of the size of the gas emission zone, the locations of gas sources within, and especially the amount of gas retained in those zones is one of the most important steps for designing a successful methane control strategy and an efficient ventilation system in longwall coal mining. The formation of the gas emission zone and the potential amount of gas-in-place (GIP) that might be available for migration into a mine are factors of local geology and rock properties that usually show spatial variability in continuity and may also show geometric anisotropy. Geostatistical methods are used here for modeling and prediction of gas amounts and for assessing their associated uncertainty in gas emission zones of longwall mines for methane control. This study used core data obtained from 276 vertical exploration boreholes drilled from the surface to the bottom of the Pittsburgh coal seam in a mining district in the Northern Appalachian basin. After identifying important coal and non-coal layers for the gas emission zone, univariate statistical and semivariogram analyses were conducted for data from different formations to define the distribution and continuity of various attributes. Sequential simulations performed stochastic assessment of these attributes, such as gas content, strata thickness, and strata displacement. These analyses were followed by calculations of gas-in-place and their uncertainties in the Pittsburgh seam caved zone and fractured zone of longwall mines in this mining district. Grid blanking was used to isolate the volume over the actual panels from the entire modeled district and to calculate gas amounts that were directly related to the emissions in longwall mines. Results indicated that gas-in-place in the Pittsburgh seam, in the caved zone and in the fractured zone, as well as displacements in major rock units, showed spatial correlations that could be modeled and estimated using geostatistical methods. This study showed that GIP volumes may change up to 3 MMscf per acre and, in a multi-panel district, may total 9 Bcf of methane within the gas emission zone. Therefore, ventilation and gas capture systems should be designed accordingly. In addition, rock displacements within the gas emission zone are spatially distributed. From an engineering and practical point of view, spatial distributions of GIP and distributions of rock displacements should be correlated with in-mine emissions and gob gas venthole productions. PMID- 26435559 TI - Comprehensive Study on the Impact of the Cation Alkyl Side Chain Length on the Solubility of Water in Ionic Liquids. AB - A comprehensive study on the phase behaviour of two sets of ionic liquids (ILs) and their interactions with water is here presented through combining experimental and theoretical approaches. The impact of the alkyl side chain length and the cation symmetry on the water solubility in the asymmetric [C N 1C1im][NTf2] and symmetric [C N-1C N-1im][NTf2] series of ILs (N up to 22), from 288.15 K to 318.15 K and at atmospheric pressure, was studied. The experimental data reveal that the solubility of water in ILs with an asymmetric cation is higher than in those with the symmetric isomer. Several trend shifts on the water solubility as a function of the alkyl side chain length were identified, namely at [C6C1im][NTf2] for asymmetric ILs and at [C4C4im][NTf2] and [C7C7im][NTf2] for the symmetric ILs. To complement the experimental data and to further investigate the molecular-level mechanisms behind the dissolution process, Density Functional Theory calculations, using the Conductor-like Screening Model for Real Solvents (COSMO-RS) and the Electrostatic potential-derived CHelpG, were performed. The COSMO-RS model is able to qualitatively predict water solubility as function of temperature and alkyl chain lengths of both symmetric and asymmetric cations. Furthermore, the model is also capable to predict the somewhat higher water solubility in the asymmetric cation, as well as the trend shift as function of alkyl chain lengths experimentally observed. Both COSMO-RS and the electrostatic potential-derived CHelpG show that the interactions of water and the IL cation take place on the IL polar region, namely on the aromatic head and adjacent methylene groups what explains the differences in water solubility observed for cations with different chain lengths. Furthermore, the CHelpG calculations for the isolated cations in the gas phase indicates that the trend shift of water solubility as function of alkyl chain lengths and the difference of water solubility in symmetric may also result from the partial positive charge distribution/contribution of the cation. PMID- 26435560 TI - The Parzen Window method: In terms of two vectors and one matrix. AB - Pattern classification methods assign an object to one of several predefined classes/categories based on features extracted from observed attributes of the object (pattern). When L discriminatory features for the pattern can be accurately determined, the pattern classification problem presents no difficulty. However, precise identification of the relevant features for a classification algorithm (classifier) to be able to categorize real world patterns without errors is generally infeasible. In this case, the pattern classification problem is often cast as devising a classifier that minimizes the misclassification rate. One way of doing this is to consider both the pattern attributes and its class label as random variables, estimate the posterior class probabilities for a given pattern and then assign the pattern to the class/category for which the posterior class probability value estimated is maximum. More often than not, the form of the posterior class probabilities is unknown. The so-called Parzen Window approach is widely employed to estimate class-conditional probability (class specific probability) densities for a given pattern. These probability densities can then be utilized to estimate the appropriate posterior class probabilities for that pattern. However, the Parzen Window scheme can become computationally impractical when the size of the training dataset is in the tens of thousands and L is also large (a few hundred or more). Over the years, various schemes have been suggested to ameliorate the computational drawback of the Parzen Window approach, but the problem still remains outstanding and unresolved. In this paper, we revisit the Parzen Window technique and introduce a novel approach that may circumvent the aforementioned computational bottleneck. The current paper presents the mathematical aspect of our idea. Practical realizations of the proposed scheme will be given elsewhere. PMID- 26435561 TI - Simultaneous optical flow and source estimation: Space-time discretization and preconditioning. AB - We consider the simultaneous estimation of an optical flow field and an illumination source term in a movie sequence. The particular optical flow equation is obtained by assuming that the image intensity is a conserved quantity up to possible sources and sinks which represent varying illumination. We formulate this problem as an energy minimization problem and propose a space-time simultaneous discretization for the optimality system in saddle-point form. We investigate a preconditioning strategy that renders the discrete system well conditioned uniformly in the discretization resolution. Numerical experiments complement the theory. PMID- 26435562 TI - IMMIGRATION ENFORCEMENT AND MIXED-STATUS FAMILIES: THE EFFECTS OF RISK OF DEPORTATION ON MEDICAID USE. AB - As Congress priorities the immigration debate on increased border security, the fate of an estimated 11 million undocumented citizens remains uncertain. Stuck in between partisan politics and practical solutions are mixed-status families in which some members of the family are U.S. citizens while other members are in the country without proper authorization. This paper, examines the relationship between risk of deportation and Medicaid use drawing from a nationally sample of mothers from the Fragile Families and Child Wellbeing Survey. These data are then merged with data from the U.S. Citizenship and Immigration Services to create a contextual risk of deportation measure. Findings suggest that an increase in risk of deportation is associated with a decrease in Medicaid use. The implications of this work have tremendous impacts for health service providers and policy makers interested in preventing and reducing health disparities in complex family structures. PMID- 26435563 TI - Distribution-free Inference of Zero-inated Binomial Data for Longitudinal Studies. AB - Count reponses with structural zeros are very common in medical and psychosocial research, especially in alcohol and HIV research, and the zero-inflated poisson (ZIP) and zero-inflated negative binomial (ZINB) models are widely used for modeling such outcomes. However, as alcohol drinking outcomes such as days of drinkings are counts within a given period, their distributions are bounded above by an upper limit (total days in the period) and thus inherently follow a binomial or zero-inflated binomial (ZIB) distribution, rather than a Poisson or zero-inflated Poisson (ZIP) distribution, in the presence of structural zeros. In this paper, we develop a new semiparametric approach for modeling zero-inflated binomial (ZIB)-like count responses for cross-sectional as well as longitudinal data. We illustrate this approach with both simulated and real study data. PMID- 26435564 TI - Examining the complexity and variation of health care system distrust across neighborhoods: Implications for preventive health care. AB - PURPOSE: Recently, the institutional performance model has been used to explain the increased distrust of health care system by arguing that distrust is a function of individuals' perceptions on the quality of life in neighborhood and social institutions. We examined (1) whether individuals assess two dimensions of distrust consistently, (2) if the multilevel institutional performance model explains the variation of distrust, and (3) how distrust patterns affect preventive health care behaviors. METHODOLOGY: Using data from 9,497 respondents in 914 census tracts (neighborhoods) in Philadelphia, we examined the patterns of how individuals evaluate the competence and values distrust using the Multilevel Latent Class Analysis (MLCA), and then investigated how neighborhood environment factors are associated with distrust patterns. Finally, we used regression to examine the relationships between distrust patterns and preventive health care. FINDINGS: The MLCA identified four distrust patterns: Believers, Doubters, Competence Skeptics, and Values Skeptics. We found that 55 % of the individuals evaluated competence and values distrust coherently, with Believers reporting low levels and Doubters having high levels of distrust. Competence and Values Skeptics assessed distrust inconsistently. Believers were the least likely to reside in socioeconomically disadvantaged and racially segregated neighborhoods than other patterns. In contrast to Doubters, Believers were more likely to use preventive health care, even after controlling for other socioeconomic factors including insurance coverage. PRACTICAL IMPLICATIONS: Our findings suggest that distrust patterns are function of neighborhood conditions and distrust patterns are associated with preventive health care. This study provides important policy implications for health care and future interventions. PMID- 26435565 TI - Extracellular Vesicles as Biomarkers of Systemic Lupus Erythematosus. AB - Systemic lupus erythematosus is an autoimmune disease that predominantly affects women and typically manifests in multiple organs. The damage caused by this disorder is characterized by a chronic inflammatory state. Extracellular vesicles (EVs), including microvesicles (also known as microparticles), apoptotic bodies, and exosomes, are recognized vehicles of intercellular communication, carrying autoantigens, cytokines, and surface receptors. Therefore, the evidence of EVs and their cargo as biomarkers of autoimmune disease is rapidly expanding. This review will focus on biogenesis of extracellular vesicles, their pathophysiological roles, and their potential as biomarkers and therapeutics in inflammatory disease, especially in systemic lupus erythematosus. PMID- 26435566 TI - Influence of GSTM1, GSTT1, and GSTP1 Polymorphisms on Type 2 Diabetes Mellitus and Diabetic Sensorimotor Peripheral Neuropathy Risk. AB - BACKGROUND AND AIMS: Diabetic neuropathy is a frequent complication of type 2 diabetes mellitus (T2DM). Genetic susceptibility and oxidative stress may play a role in the appearance of T2DM and diabetic neuropathy. We investigated the relation between polymorphism in genes related to oxidative stress such as GSTM1, GSTT1, and GSTP1 and the presence of T2DM and diabetic neuropathy (DN). METHODS: Samples were collected from 84 patients with T2DM (42 patients with DN and 42 patients without DN) and 98 healthy controls and genotyped by using polymerase chain reaction and restriction fragment length polymorphism method. RESULTS: GSTP1 Ile105Val polymorphism was associated with the risk of developing T2DM (p = 0.05) but not with the risk of developing DN in diabetic cases. GSTM1 and GSTT1 gene polymorphisms were associated with neither the risk of developing T2DM nor the risk of DN occurrence in diabetic patients. No association was observed between the patients with T2DM and DSPN (diabetic sensorimotor peripheral neuropathy) and T2DM without DSPN regarding investigated polymorphism. CONCLUSION: Our data suggest that GSTP1 gene polymorphisms may contribute to the development of T2DM in Romanian population. GSTM1, GSTT1, and GSTP1 gene polymorphisms are not associated with susceptibility of developing diabetic neuropathy in T2DM patients. PMID- 26435567 TI - Plasma Interleukin-37 Is Elevated in Patients with Rheumatoid Arthritis: Its Correlation with Disease Activity and Th1/Th2/Th17-Related Cytokines. AB - Interleukin- (IL-) 37 is a novel anti-inflammatory cytokine that suppresses immune response and inflammation. This study was performed to determine whether IL-37 was elevated in patients with rheumatoid arthritis (RA) and investigate the correlation between IL-37 level and disease activity and the concentration of Th1/Th2/Th17-related cytokines. Clinical parameters of disease activity, including the 28-joint disease activity score (DAS28) and C-reactive protein (CRP), were collected in 34 RA patients and 34 age- and sex-matched healthy controls. Plasma IL-37 was measured by ELISA. Plasma levels of TNF-alpha, IL 1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, G-CSF, GM CSF, IFN-gamma, MCP-1, and MIP-1beta were analyzed using the Bio-Plex suspension array system. It was found that IL-37 levels were elevated markedly in RA patients and almost undetectable in healthy controls. In addition, IL-37 levels in patients with active RA were significantly enhanced as compared with those in patients of remission. More importantly, IL-37 showed a significant correlation with disease activity (DAS28) and IL-4, IL-7, IL-10, IL-12, and IL-13 concentrations in RA patients. These findings suggest that IL-37 plays an important role in the pathogenesis of RA and may prove to be a potential biomarker of active RA. PMID- 26435568 TI - Identification of Circulating miRNAs in a Mouse Model of Nerve Allograft Transplantation under FK506 Immunosuppression by Illumina Small RNA Deep Sequencing. AB - BACKGROUND: This study aimed to establish the expression profile of circulating microRNAs (miRNAs) during nerve allotransplantation in the presence and absence of FK506 immunosuppression. METHODS: A 1 cm BALB/c donor sciatic nerve graft was transplanted into the sciatic nerve gaps created in recipient C57BL/6 mice with or without daily FK506 immunosuppression [1 mg/(kg.d)]. At 3, 7, and 14 d after nerve allotransplantation, serum samples were collected for miRNA expression analysis by Illumina small RNA deep sequencing. RESULTS: Sequence analysis showed that the dominant size of circulating small RNAs after nerve allotransplantation was 22 nucleotides, followed by 23-nucleotide sequences. Nine upregulated circulating miRNAs (let-7e-5p, miR-101a-3p, miR-151-5p, miR-181a-5p, miR-204-5p, miR-340-5p, miR-381-3p, miR-411-5p, miR-9-5p, and miR-219-2-3p) were identified at 3 d, but none was identified at 7 or 14 d. Among them, miR-9-5p had the highest fold-change of >50-fold, followed by miR-340-5p with 38.8-fold. The presence of these nine miRNAs was not significant at 7 and 14 d after nerve allotransplantation with or without immunosuppression, showing that these miRNAs are not ideal biomarkers for monitoring rejection of deep-buried nerve allografts, a response usually observed later. CONCLUSIONS: We identified nine upregulated circulating miRNAs, which may have a biological function, particularly during the early stages after nerve allotransplantation under FK506 immunosuppression. PMID- 26435570 TI - Evaluating the impacts of new walking and cycling infrastructure on carbon dioxide emissions from motorized travel: a controlled longitudinal study. AB - Walking and cycling is widely assumed to substitute for at least some motorized travel and thereby reduce energy use and carbon dioxide (CO2) emissions. While the evidence suggests that a supportive built environment may be needed to promote walking and cycling, it is unclear whether and how interventions in the built environment that attract walkers and cyclists may reduce transport CO2 emissions. Our aim was therefore to evaluate the effects of providing new infrastructure for walking and cycling on CO2 emissions from motorised travel. A cohort of 1849 adults completed questionnaires at baseline (2010) and one-year follow-up (2011), before and after the construction of new high-quality routes provided as part of the Sustrans Connect2 programme in three UK municipalities. A second cohort of 1510 adults completed questionnaires at baseline and two-year follow-up (2012). The participants reported their past-week travel behaviour and car characteristics from which CO2 emissions by mode and purpose were derived using methods described previously. A set of exposure measures of proximity to and use of the new routes were derived. Overall transport CO2 emissions decreased slightly over the study period, consistent with a secular trend in the case study regions. As found previously the new infrastructure was well used at one- and two year follow-up, and was associated with population-level increases in walking, cycling and physical activity at two-year follow-up. However, these effects did not translate into sizeable CO2 effects as neither living near the infrastructure nor using it predicted changes in CO2 emissions from motorised travel, either overall or disaggregated by journey purpose. This lack of a discernible effect on travel CO2 emissions are consistent with an interpretation that some of those living nearer the infrastructure may simply have changed where they walked or cycled, while others may have walked or cycled more but few, if any, may have substituted active for motorised modes of travel as a result of the interventions. While the findings to date cannot exclude the possibility of small effects of the new routes on CO2 emissions, a more comprehensive approach of a higher 'dosage' of active travel promotion linked with policies targeted at mode shift away from private motorized transport (such as urban car restraint and parking pricing, car sharing/pooling for travel to work, integrating bike sharing into public transport system) may be needed to achieve the substantial CO2 savings needed to meet climate change mitigation and energy security goals. PMID- 26435569 TI - Optimal Vitamin D Supplementation Levels for Cardiovascular Disease Protection. AB - First described in relation to musculoskeletal disease, there is accumulating data to suggest that vitamin D may play an important role in cardiovascular disease (CVD). In this review we aim to provide an overview of the role of vitamin D status as both a marker of and potentially causative agent of hypertension, coronary artery disease, heart failure, atrial fibrillation, stroke, and peripheral vascular disease. The role of vitamin D levels as a disease marker for all-cause mortality is also discussed. We review the current knowledge gathered from experimental studies, observational studies, randomised controlled trials, and subsequent systematic reviews in order to suggest the optimal vitamin D level for CVD protection. PMID- 26435571 TI - Ten years of invasion: Harmonia axyridis (Pallas) (Coleoptera: Coccinellidae) in Britain. AB - 1. Harmonia axyridis was first recorded in Britain in 2004. Two subsequent earlier records were received from 2003. 2. The UK Ladybird Survey, a citizen science initiative involving online recording, was launched in 2005 to encourage people across Britain to track the spread of H. axyridis. Tens of thousands of people have provided records of H. axyridis and other species of ladybirds, creating an invaluable dataset for large-scale and long-term research. Declines in the distribution of seven (of eight assessed) native species of ladybird have been demonstrated, and correlated with the arrival of H. axyridis, using the records collated through the UK Ladybird Survey. 3. Experimental research and field surveys have also contributed to our understanding of the ecology of H. axyridis and particularly the process of invasion. Harmonia axyridis arrived in Britain through dispersal and introduction events from regions in which it was deliberately released as a biological control agent. The rapid spread of this species has been attributed to its high natural dispersal capability by means of both flight and anthropogenic transport. A number of factors have contributed to the successful establishment and indeed dominance of this polymorphic species within aphidophagous guilds, including high reproductive capacity, intra-guild predation, eurytopic nature, high resistance to natural enemies within the invaded range, and potentially phenotypic plasticity. 4. The global invasion by H. axyridis and subsequent research on this species has contributed to the general understanding of biological invasions. PMID- 26435572 TI - Using Social Judgment Theory method to examine how experienced occupational therapy driver assessors use information to make fitness-to-drive recommendations. AB - INTRODUCTION: As people with a range of disabilities strive to increase their community mobility, occupational therapy driver assessors are increasingly required to make complex recommendations regarding fitness-to-drive. However, very little is known about how therapists use information to make decisions. The aim of this study was to model how experienced occupational therapy driver assessors weight and combine information when making fitness-to-drive recommendations and establish their level of decision agreement. METHOD: Using Social Judgment Theory method, this study examined how 45 experienced occupational therapy driver assessors from the UK, Australia and New Zealand made fitness-to-drive recommendations for a series of 64 case scenarios. Participants completed the task on a dedicated website, and data were analysed using discriminant function analysis and an intraclass correlation coefficient. RESULTS: Accounting for 87% of the variance, the cues central to the fitness-to drive recommendations made by assessors are the client's physical skills, cognitive and perceptual skills, road law craft skills, vehicle handling skills and the number of driving instructor interventions. Agreement (consensus) between fitness-to-drive recommendations was very high: intraclass correlation coefficient = .97, 95% confidence interval .96-.98). CONCLUSION: Findings can be used by both experienced and novice driver assessors to reflect on and strengthen the fitness-to-drive recommendations made to clients. PMID- 26435573 TI - Optimal firm growth under the threat of entry. AB - The paper studies the incumbent-entrant problem in a fully dynamic setting. We find that under an open-loop information structure the incumbent anticipates entry by overinvesting, whereas in the Markov perfect equilibrium the incumbent slightly underinvests in the period before the entry. The entry cost level where entry accommodation passes into entry deterrence is lower in the Markov perfect equilibrium. Further we find that the incumbent's capital stock level needed to deter entry is hump shaped as a function of the entry time, whereas the corresponding entry cost, where the entrant is indifferent between entry and non entry, is U-shaped. PMID- 26435574 TI - Thermophysical properties of phosphonium-based ionic liquids. AB - Experimental data for density, viscosity, refractive index and surface tension of four phosphonium-based ionic liquids were measured in the temperature range between (288.15 and 353.15) K and at atmospheric pressure. The ionic liquids considered include tri(isobutyl) methylphosphonium tosylate, [P i(444)1][Tos], tri(butyl)methylphosphonium methylsulfate, [P4441][CH3SO4], tri(butyl)ethylphosphonium diethylphosphate, [P4442][(C2H5O)2PO2], and tetraoctylphosphonium bromide, [P8888][Br]. Additionally, derivative properties, such as the isobaric thermal expansion coefficient, the surface thermodynamic properties and the critical temperatures for the investigated ionic liquids were also estimated and are presented and discussed. Group contribution methods were evaluated and fitted to the density, viscosity and refractive index experimental data. PMID- 26435575 TI - Attitudinal, Experiential, and Situational Predictors of Sexual Assault Perpetration. AB - Past research demonstrates that sexual assault perpetration is caused by multiple factors including attitudes, early experiences, and situational factors. In this study, 343 college men described either a sexual assault they had committed or their worst date. Discriminant function analysis indicated that attitudes about gender roles and alcohol, number of consensual sex partners, how well the man knew the woman, how isolated the setting was, alcohol consumption during the event, the man's misperception of the woman's cues during the event, and prior consensual sexual activity between the man and the woman discriminated between sexual assaults and worst dates. Additionally, tactics used to obtain sex, self attributions, the perceived seriousness of the assault, and the extent to which it disrupted relationships with others significantly discriminated between men who committed forced sexual contact, sexual coercion, and rape. These results demonstrate the importance of considering both individual characteristics and situational factors in theories and prevention activities. PMID- 26435576 TI - Solution-Crystallization and Related Phenomena in 9,9-Dialkyl-Fluorene Polymers. I. Crystalline Polymer-Solvent Compound Formation for Poly(9,9-dioctylfluorene). AB - Polymer-solvent compound formation, occurring via co-crystallization of polymer chains and selected small-molecular species, is demonstrated for the conjugated polymer poly(9,9-dioctylfluorene) (PFO) and a range of organic solvents. The resulting crystallization and gelation processes in PFO solutions are studied by differential scanning calorimetry, with X-ray diffraction providing additional information on the resulting microstructure. It is shown that PFO-solvent compounds comprise an ultra-regular molecular-level arrangement of the semiconducting polymer host and small-molecular solvent guest. Crystals form following adoption of the planar-zigzag beta-phase chain conformation, which, due to its geometry, creates periodic cavities that accommodate the ordered inclusion of solvent molecules of matching volume. The findings are formalized in terms of nonequilibrium temperature-composition phase diagrams. The potential applications of these compounds and the new functionalities that they might enable are also discussed. (c) 2015 The Authors. Journal of Polymer Science Part B: Polymer Physics published by Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015, 53, 1481-1491. PMID- 26435577 TI - Re-visioning Ultrasound through Women's Accounts of Pre-abortion Care in England. AB - Feminist scholarship has demonstrated the importance of sustained critical engagement with ultrasound visualizations of pregnant women's bodies. In response to portrayals of these images as "objective" forms of knowledge about the fetus, it has drawn attention to the social practices through which the meanings of ultrasound are produced. This article makes a novel contribution to this project by addressing an empirical context that has been neglected in the existing feminist literature concerning ultrasound, namely, its use during pregnancies that women decide to terminate. Drawing on semi-structured interviews with women concerning their experiences of abortion in England, I explore how the meanings of having an ultrasound prior to terminating a pregnancy are discursively constructed. I argue that women's accounts complicate dominant representations of ultrasound and that in so doing, they multiply the subject positions available to pregnant women. PMID- 26435578 TI - Applications of seaweed extracts in Australian agriculture: past, present and future. AB - A rapidly growing world population has highlighted the need to significantly increase food production in the context of a world with accelerating soil and water shortages as well as climatic stressors. This situation has generated new interest in the application of liquid seaweed extracts because of their potent plant growth-enhancing properties through metabolic benefits, triggering disease response pathways and increasing stress tolerance. The basis for these benefits is complex and poorly understood. Liquid seaweed extracts are complex and have been demonstrated to possess novel mechanisms for increasing crop productivity. The benefits of seaweed extracts to crops have previously been reviewed in the context of the northern hemisphere, but not in the context of Australia, its crops and unique stressors. This review considers the application of seaweed extracts in Australian agriculture by (i) introducing the history of the Australian liquid seaweed extract industry and (ii) focusing on evidence of Australian research related to seaweed extract composition, plant growth properties during plant establishment, pathogenic disease and new approaches to phenotyping the biological efficacy of seaweed extracts. This type of research is essential for future Australian agriculture to develop effective strategies for the use of liquid seaweed extracts. PMID- 26435579 TI - The suppressive effect of a commercial extract from Durvillaea potatorum and Ascophyllum nodosum on infection of broccoli by Plasmodiophora brassicae. AB - A sand solution technique demonstrated the capacity for a commercial seaweed extract from Durvillaea potatorum and Ascophyllum nodosum (Seasol Commercial(r)) to significantly suppress infection of broccoli by Plasmodiophora brassicae. In the primary stages of infection, the extract reduced the number of plasmodia formed in the root hairs by 55 %. Later, in the secondary stages of infection, the extract reduced plasmodia in the root cortical cells by up to 84 %. The suppression of infection was found to be independent of the dilution of the extract applied (1:25 and 1:500). The basis for these results is unlikely to be a nutrient or pH effect since the extract had little impact on these parameters, particularly at the lower dilution (1:200). Rather, we hypothesise that the suppression of infection by the seaweed extract was due to its stimulation of resistance mechanisms in the host, which is possibly related to laminarins in the extract and/or the effect of exogenous growth regulators or undiscovered molecules in the extract disrupting the infection process. PMID- 26435580 TI - A Double Team Semantics for Generalized Quantifiers. AB - We investigate extensions of dependence logic with generalized quantifiers. We also introduce and investigate the notion of a generalized atom. We define a system of semantics that can accommodate variants of dependence logic, possibly extended with generalized quantifiers and generalized atoms, under the same umbrella framework. The semantics is based on pairs of teams, or double teams. We also devise a game-theoretic semantics equivalent to the double team semantics. We make use of the double team semantics by defining a logic [Formula: see text] which canonically fuses together two-variable dependence logic[Formula: see text] and two-variable logic with counting quantifiers[Formula: see text]. We establish that the satisfiability and finite satisfiability problems of [Formula: see text] are complete for [Formula: see text]. PMID- 26435581 TI - Gravimetric Analysis of Particulate Matter using Air Samplers Housing Internal Filtration Capsules. AB - An evaluation was carried out to investigate the suitability of polyvinyl chloride (PVC) internal capsules, housed within air sampling devices, for gravimetric analysis of airborne particles collected in workplaces. Experiments were carried out using blank PVC capsules and PVC capsules spiked with 0,1 - 4 mg of National Institute of Standards and Technology Standard Reference Material(r) (NIST SRM) 1648 (Urban Particulate Matter) and Arizona Road Dust (Air Cleaner Test Dust). The capsules were housed within plastic closed-face cassette samplers (CFCs). A method detection limit (MDL) of 0,075 mg per sample was estimated. Precision Sr at 0,5 - 4 mg per sample was 0,031 and the estimated bias was 0,058. Weight stability over 28 days was verified for both blanks and spiked capsules. Independent laboratory testing on blanks and field samples verified long-term weight stability as well as sampling and analysis precision and bias estimates. An overall precision estimate Srt of 0,059 was obtained. An accuracy measure of +/-15,5% was found for the gravimetric method using PVC internal capsules. PMID- 26435582 TI - Microbial keratitis: a community eye health approach. PMID- 26435583 TI - Diagnosing and managing microbial keratitis. PMID- 26435584 TI - Distinguishing fungal and bacterial keratitis on clinical signs. PMID- 26435585 TI - Taking a corneal scrape and making a diagnosis. PMID- 26435586 TI - Performing a tarsorrhaphy. PMID- 26435587 TI - Measuring the outcome of cataract surgery: the importance of the patient perspective. PMID- 26435589 TI - Electrosurgical units - how they work and how to use them safely. PMID- 26435588 TI - School eye health - going beyond refractive errors. PMID- 26435590 TI - Techniques for aseptic dressing and procedures. PMID- 26435591 TI - Treatment coverage surveys as part of a trachoma control programme. PMID- 26435592 TI - Vitamin D Deficiency: Is The Pandemic for Real? PMID- 26435593 TI - Right to health: Challenges and Opportunities. PMID- 26435594 TI - Essential Medicines: An Indian Perspective. AB - The concept of defining essential medicines and establishing a list of them was aimed to improve the availability of affordable medicines for the world's poor. Access to essential medicines is a major determinant of health outcomes. Several countries have made substantial progress towards increasing access to essential medicines, but access to essential medicines in developing countries like India is not adequate. In this review we have tried to present the Indian scenario in respect to availability and accessibility of essential medicines over last one decade. To enhance the credibility of Indian healthcare system, procurement and delivery systems of essential medicines have to be strengthened through government commitment, careful selection, adequate public sector financing, efficient distribution systems, control on taxes and duties, and inculcating a culture of rational use of medicines in current and future prescribers. PMID- 26435595 TI - Three Sides of a Coin in the Life of People Living with HIV (PLWH). AB - BACKGROUND: Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS) is a global epidemic, a major challenge as a health care problem of modern times. As the survival of life increases from the time of an HIV positive diagnosis, growing concern for the quality of the life has been extended. OBJECTIVES: To assess and correlate the coping, social support and quality of life. MATERIALS AND METHODS: A descriptive cross-sectional study was conducted at antiretroviral therapy (ART) clinic of AIIMS, New Delhi. The sample comprised people living with HIV/AIDS (PLWHA) who were seropositive for last six months. The tools used to assess the coping, social support and quality of life were BREF COPE, MOS social support survey and WHO QOL-HIV BREF, respectively. Permission was taken from the authors of the tools. The ethical permission was taken from the center. The coping, social support and quality of life were assessed and their association was observed. Data were analyzed using SPSS 17. RESULTS: The most commonly used coping styles were acceptance and religion. The social support used by most of PLWHA was tangible support and affectionate support, while the least used support was positive social interaction. The lowest quality of life is seen in social relations, followed by physical quality of life. There was positive association seen between coping and quality of life as well as social support and quality of life. CONCLUSION: There was positive association between coping, social support and quality of life. PMID- 26435596 TI - Evaluation of the Universal Immunization Program and Challenges in Coverage of Migrant Children in Haridwar, Uttarakhand, India. AB - BACKGROUND: Studies show that immunization among migrant children is poor. India has a dropout rate of 17.7% between Bacillus Calmette-Guiotarin (BCG) and measles (District Level Household Survey (DLHS)-3). Haridwar district had the highest dropout rate of 27.4% from BCG to diphtheria, pertussis, and tetanus (DPT) 3 (DLHS-3) in Uttarakhand. We evaluated the Universal Immunization Programme (UIP) among migrants in Haridwar in two blocks. MATERIALS AND METHODS: We developed input, process, and output indicators on infrastructure, human resources, and service delivery. A facility, session site and cross-sectional survey of 180 children were done and proportions for various indicators were estimated. We determined factors associated with not taking vaccination using multivariate analysis. RESULTS: We surveyed 11 cold chain centers, 25 subcenters, 14 sessions, and interviewed 180 mothers. Dropouts were supposed to be tracked using vaccination card counterfoils and tracking registers. The dropout rate from BCG to DPT3 was 30%. Lack of knowledge (adjusted odds ratio (AOR) 6.6,95% confidence interval (CI) 2.6-16.7), mother not being decision maker (AOR 4.0,95%CI 1.7-9.2), lack of contact by Accredited Social Health Activist (ASHA; AOR 3.0,95%CI 1.1 7.7), not being given four post-vaccination messages (AOR 7.7, 95% CI 2.9-20.2), and longer duration of stay in Haridwar (AOR 3.0 95% 1.9-7.6) were risk factors for nonimmunization. The reasons stated by mothers included lack of awareness of session site location (67%) and belief that child should only be vaccinated in their resident district (43%). CONCLUSIONS: There was low immunization coverage among migrants within adequate supervision, poor cold chain maintenance, and improper tracking of dropouts. Mobile immunization teams, prelisting of migrant children, and change in incentives of ASHAs for child tracking were needed. A monitoring plan for sessions and cold chain needed enforcement. PMID- 26435597 TI - An Epidemiological Study of Child Marriages in a Rural Community of Gujarat. AB - CONTEXT: India has the maximum number of child marriages (CMs; < 18 years) because of the size of its population, and in 47% of all marriages the bride is a child. Children who are married at young age are exposed to multiple risks pertaining to their physical, mental, and social health. AIMS: (i) To estimate the prevalence of CM in rural population. (ii) To study the determinants and health effects of CM. (iii) To assess the awareness among the married women regarding the health implications of CM. SETTINGS AND DESIGN: Community-based cross-sectional study conducted in Ardi village of Anand district. MATERIALS AND METHODS: All the married women of the village were surveyed to find out the prevalence of CM. For collection of other relevant information, only those women having a married life of less than 10years were interviewed using semicoded and pretested questionnaire. Data collected were analyzed using Statistical Package for Social Sciences (SPSS) 17.0 software. STATISTICAL ANALYSIS USED: Proportions, ratios, chi(2) test, and Fisher's exact test. RESULTS: The prevalence of CM was found to be 71.5%. Caste and spouse's education were revealed as important determinants for CM. CM was found to be significantly associated with mother's age at birth of first child, delayed antenatal care (ANC), spontaneous abortion, preterm delivery, low birth weight (LBW), health problems in new born baby, faulty feeding practices, lack of knowledge regarding family welfare methods, and health implications of CM. CONCLUSION: Exceptionally high prevalence of CM in rural community and its serious health consequences warrant stricter enforcement of legislation, better educational opportunities for girls, and easy access to quality health services. PMID- 26435598 TI - A Comparative Evaluation of Public Health Centers with Private Health Training Centers on Primary Healthcare Parameters in India: a Study by Data Envelopment Analysis Technique. AB - BACKGROUND: The evaluation of primary healthcare services provided by health training centers of a private medical college has not been studied in comparison with government health facilities in Indian context. Data envelopment analysis (DEA) is one such technique of operations research, which can be used on health facilities for identifying efficient operating practices and strategies for relatively efficient or inefficient health centers by calculating their efficiency scores. MATERIALS AND METHODS: This study was carried out by DEA technique by using basic radial models (constant ratio to scale (CRS)) in linear programming via DEAOS free online Software among four decision making units (DMUs; by comparing efficiency of two private health centers of a private medical college of India with two public health centers) in district Muzaffarnagar of state Uttar Pradesh. The input and output records of all these health facilities (two from private and two from Government); for 6 months duration from 1(st) Jan 2014 to 1(st) July 2014 was taken for deciding their efficiency scores. RESULTS: The efficiency scores of primary healthcare services in presence of doctors (100 vs 30%) and presence of health staff (100 vs 92%) were significantly better from government health facilities as compared to private health facilities (P < 0.0001). CONCLUSIONS: The evaluation of primary healthcare services delivery by DEA technique reveals that the government health facilities group were more efficient in delivery of primary healthcare services as compared to private training health facilities group, which can be further clarified in by more in depth studies in future. PMID- 26435599 TI - Risk Factors and Hospitalization Costs of Dementia Patients: Examining Race and Gender Variations. AB - AIMS: To examine the variation in risk factors and hospitalization costs among four elderly dementia cohorts by race and gender. MATERIALS AND METHODS: The 2008 Tennessee Hospital Discharged database was examined. The prevalence, risk factors and cost of inpatient care of dementia were examined for individuals aged 65 years and above, across the four race gender cohorts - white males (WM), black males (BM), white females (WF), and black females (BF). RESULTS: 3.6% of patients hospitalized in 2008 had dementia. Dementia was higher among females than males, and higher among blacks than whites. Further, BF had higher prevalence of dementia than WF; similarly, BM had a higher prevalence of dementia than WM. Overall, six risk factors were associated with dementia for the entire sample including HTN, DM, CKD, CHF, COPD, and stroke. These risk factors varied slightly in predicting dementia by race and gender. Hospital costs were 14% higher among dementia patients compared to non-dementia patients. CONCLUSIONS: There exist significant race and gender disparities in prevalence of dementia. A greater degree of co-morbidity, increased duration of hospital stay, and more frequent hospitalizations, may result in a higher cost of inpatient dementia care. Aggressive management of risk factors may subsequently reduce stroke and cost of dementia care, especially in the black population. Race and gender dependent milestones for management of these risk factors should be considered. PMID- 26435600 TI - Sociodemographic Parameters of Esophageal Cancer in Northwest India: A Regional Cancer Center Experience of 10 Years. AB - BACKGROUND: Despite various advances in the treatment of Esophageal Cancer (EC), being one of the least responsive tumors to cancer therapy, the overall prognosis remains poor. Therefore, it is significant to understand various sociodemographic factors associated with EC to find out various schemes for primary prevention of the disease. MATERIALS AND METHODS: This is a retrospective analysis of medical records of the EC patients registered in the regional cancer center of northwest India from January 2003 to December 2012. The site of the disease and the histology were also recorded in addition to the various sociodemographic parameters. RESULTS: Out of 55,742 patients registered in our hospital; 3,667 were diagnosed to have EC. Male:female ratio was 1.15:1. The mean age was 54.6 +/ 11.74 years; 66.15% of the patients were illiterate and 48.6% belonged to the low socioeconomic status. Smoking and alcohol consumption were identified as risk factors in 48 and 25.6% of the patients, respectively. CONCLUSIONS: The etiology in majority of the patients is linked to tobacco and alcohol, thus, modification of life style with limiting the use of addictions may be an effective strategy in the prevention of this dreaded and mostly incurable disease. PMID- 26435601 TI - Are we Underestimating the Real Burden of Malnutrition? An Experience From Community-Based Study. AB - BACKGROUND: Since the inception of childhood nutritional programs in India, underweight has been taken to judge the nutritional status of children; but is it a true indicator of overall prevalence of malnutrition in a community? OBJECTIVE: To estimate the overall prevalence of malnutrition by using Composite Index of Anthropometric Failure (CIAF) and to assess its usefulness over various conventional anthropometric indicators among under 5 children residing in Agra city. MATERIALS AND METHODS: A cross-sectional, community-based study was conducted among under 5 years age children, from June 2012 to July 2013 in an urban slum of Agra. Nutritional status was assessed using anthropometry and clinical examination, and classified as per World Health Organization (WHO) 2006 Growth Standards and CIAF. RESULTS: Of the 458 children studied, 42.8% were underweight, 41.9% had stunting, while 22.7% had wasting. However, 60.04% of children were found to be malnourished as per the CIAF. Unlike three conventional anthropometric indicators of malnutrition, CIAF was observed to have a much consistent association with morbidity like diarrhea episodes in past 3 months (odds ratio (OR) = 2.09), acute respiratory tract infection (ARI) episode in past 3 months (OR = 1.58), and any illness requiring hospitalization (OR = 1.29). CONCLUSION: The CIAF should supplement the conventional indices of malnourishment, to provide a single, aggregated figure of actual number of undernourished children in a given population. PMID- 26435602 TI - Hypertension in Pregnancy: A Community-Based Study. AB - BACKGROUND: Hypertensive disorders during pregnancy occur in women with preexisting primary or secondary chronic hypertension, and in women who develop new-onset hypertension in the second half of pregnancy. The present study was undertaken to study the prevalence and correlates of hypertension in pregnancy in a rural block of Haryana. MATERIALS AND METHODS: This cross-sectional study was carried out in the all 20 subcenters under Community Health Center (CHC) Chiri, Block Lakhanmajra. All the pregnant women registered at the particular subcenter at a point of time of visit were included in the study. Appropriate statistical tests were used for analysis. RESULTS: A total of 931 pregnant women were included in the present study. Prevalence of hypertension in pregnancy was found to be 6.9%. Maternal age >=25 years, gestational period <=20 weeks, history of cesarean section, history of preterm delivery, and history of hypertension in previous pregnancy were found to be significantly associated with prevalence of hypertension in pregnancy. CONCLUSION: Nearly one in 14 pregnant women in rural areas of Haryana suffers from a hypertensive disorder of pregnancy. Early diagnosis and treatment through regular antenatal checkup is a key factor to prevent hypertensive disorders of pregnancy and its complications. PMID- 26435603 TI - Prevalence and Risk Factors of Abuse among Community Dwelling Elderly of Guwahati City, Assam. AB - BACKGROUND: In spite of tremendous impact on health, elder abuse is still an underreported and unrecognized issue. OBJECTIVES: To assess the prevalence of abuse among community dwelling elderly and to identify the various risk factors. MATERIALS AND METHODS: This community-based cross-sectional study was conducted in 10 randomly selected wards of Guwahati city. A total of 331 elderly (60 years and above) were interviewed. Abuse was screened by Hwalek-Sengstock Elder Abuse Screening Test (H-S EAST). RESULTS: The study revealed 9.31% prevalence. Neglect was the most common type of abuse reported. Age, sex, socioeconomic status, living status, and functional status were found to be significantly associated with abuse. CONCLUSION: Abuse is prevalent among elderly population. PMID- 26435604 TI - Health Issues among Call Center Employees. PMID- 26435605 TI - An Outbreak of Cholera due to Contaminated Water, Medak District, Andhra Pradesh, India, 2013. PMID- 26435606 TI - Guest Editorial. PMID- 26435607 TI - Comparative Study of the Effect of Acid Etching on Enamel Surface Roughness between Pumiced and Non-pumiced Teeth. AB - BACKGROUND: The objective was to perform a comparative analysis of the effect of acid etching on enamel roughness between pumiced and non-pumiced teeth. MATERIALS AND METHODS: The sample was composed of 32 dental surfaces divided into two groups: Group 1-16 surfaces having received pumice prophylaxis; and Group 2-16 surfaces not having received pumice prophylaxis. The teeth were kept in saline until the first record of surface roughness prior to etching. For each surface, a roughness graph was obtained through trials using a surface roughness tester. This procedure was repeated two more times at different locations for a total of three readings which, later, were converted in a mean value. The teeth were then acid etched with a 37% phosphoric acid for 60 s, rinsed with water, air dried, and tested with the roughness tester again using the same protocol described for baseline. The Quantikov image analysis program was used to measure the length of the graphs. The average value of the lengths was recorded for each surface before and after etching. The increase in roughness caused by acid etching was calculated and compared between groups. RESULTS: The mean increase in roughness caused by the etching was 301 um (11.37%) in Group 1 and 214 um (8.33%) in Group 2. No statistically significant difference was found between samples with and without pumice prophylaxis (P = 0.283). CONCLUSION: The present study showed that the effect of acid etching on enamel roughness was not significantly affected by prior pumice prophylaxis. PMID- 26435608 TI - Comparing the Marginal Adaptation of Cold Ceramic and Mineral Trioxide Aggregate by Means of Scanning Electron Microscope: An In vitro Study. AB - BACKGROUND: Long-term success of endodontic surgeries is often influenced by the type of root-end filling material (RFM). The aim of present study was to compare the marginal adaptation of two different RFM, cold ceramic (CC) and mineral trioxide aggregate (MTA), using scanning electron microscope (SEM). MATERIALS AND METHODS: About 20 extracted human single-rooted teeth were collected and stored into sodium hypochlorite 5.25%. The teeth were decronated from the cemento-enamel junction to prepare 16 mm roots. The working length was measured, and 1/3 coronal of the canal was prepared by Gates-Glidden drills. Apical flaring was followed by K file size # 40-70 based on step back technique. After filling of the canals, 3 mm above the apex was cut at 90 degrees to the long axis. Furthermore, 3 mm of the filling was removed from the apical part using the ultrasonic device. All of the prepared specimens were divided into two groups and were retro filled by MTA and CC. The roots were cut horizontally from 1 mm above the apical part, and dentin-filling material interface was observed by SEM. Finally, the collected data were analyzed by Mann-Whitney test and using SPSS software version 18 at a significant level of 0.05. RESULTS: The mean interfacial adaptation was higher in CC group. However, no significant differences were observed by statistical test (P = 0.35). CONCLUSION: Both CC and MTA had similar marginal adaptation as RFM however in vivo studies are recommended for better determination. PMID- 26435609 TI - Meta-analysis of Failure and Survival Rate of Implant-supported Single Crowns, Fixed Partial Denture, and Implant Tooth-supported Prostheses. AB - BACKGROUND: Dental implants have become the most viable option for rehabilitation. Although, many studies report the success of these reconstructions using implants, a cumulative data about the various studies and the failure rate still remain unaddressed. Therefore, the purpose of this systematic review was to analyze these data and to derive the cumulative survival rate of different implant-supported prosthesis. MATERIALS AND METHODS: Manual searches followed by a MEDLINE search were conducted to select prospective and retrospective cohort studies on single crowns (SCs), fixed partial denture (FPD), and tooth implant connected prostheses with a mean follow-up time of minimum of 5 years. Random-effects Poisson's regression models have been used to obtain summary estimates for implant failure and survival rates. RESULTS: Data were extracted from the final selected 63 studies. In a meta-analysis of these studies, the survival rate of SCs supported by implants (95% CI) was 96.363%, for FPDs was 94.525% and implant tooth-supported prostheses was 91.27% after 5 years of function. The cumulative failure rate per 100 FPD years of the SCs, FPDs, and implant tooth-supported prostheses were 0.684, 0.881, and 1.514, respectively. CONCLUSION: The study concludes high survival rates for implant-supported SCs followed by implant-supported FPDs can be expected over an observation period of 5 years. However, tooth implant-supported prostheses can be provided if there are certain limitations prohibiting the completely implant-supported prostheses. PMID- 26435610 TI - An Analysis of Maxillary Anterior Teeth Dimensions for the Existence of Golden Proportion: Clinical Study. AB - BACKGROUND: Appearance of the face is a great concern to everyone, as it is a significant part of self-image. The study analyzed the clinical crown dimensions of the maxillary anterior teeth with respect to their apparent mesiodistal widths, width-to-height ratio to determine whether golden proportion existed among the South Indian population. MATERIALS AND METHODS: A total of 240 dentulous subjects were chosen for the study (120 males and 120 females) age ranging between 18 and 28 years. Full face and anterior teeth images of the subjects were made on specially designed device resembling a face-bow, mounted onto the wall under a standard light source. The width and height of the maxillary central incisors were measured on the stone casts using a digital caliper. RESULTS: The mean perceived maxillary lateral incisor to central incisor width ratio was 0.67 in males and 0.703 in females. The mean perceived maxillary canine to lateral incisor width ratio was 0.744 in males and 0.714 in females. The mean width-to-height ratio of the maxillary central incisor was 79.49% in males and 79.197% in females. CONCLUSION: The golden proportion was not found between perceived mesiodistal widths of maxillary central and lateral incisors and nor between perceived mesiodistal widths of maxillary lateral incisors and canines. In the majority of subjects, the width-to-height ratio of maxillary central incisor was within 75-80%. There are no statistically significant differences in maxillary anterior teeth proportions between males and females. The results may serve as guidelines for treatment planning in restorative dentistry and periodontal surgery. PMID- 26435611 TI - Comparative Evaluation of Dimensional Accuracy of Elastomeric Impression Materials when Treated with Autoclave, Microwave, and Chemical Disinfection. AB - BACKGROUND: Impression materials during impression procedure often get infected with various infectious diseases. Hence, disinfection of impression materials with various disinfectants is advised to protect the dental team. Disinfection can alter the dimensional accuracy of impression materials. The present study was aimed to evaluate the dimensional accuracy of elastomeric impression materials when treated with different disinfectants; autoclave, chemical, and microwave method. MATERIALS AND METHODS: The impression materials used for the study were, dentsply aquasil (addition silicone polyvinylsiloxane syringe and putty), zetaplus (condensation silicone putty and light body), and impregum penta soft (polyether). All impressions were made according to manufacturer's instructions. Dimensional changes were measured before and after different disinfection procedures. RESULT: Dentsply aquasil showed smallest dimensional change ( 0.0046%) and impregum penta soft highest linear dimensional changes (-0.026%). All the tested elastomeric impression materials showed some degree of dimensional changes. CONCLUSION: The present study showed that all the disinfection procedures produce minor dimensional changes of impression material. However, it was within American Dental Association specification. Hence, steam autoclaving and microwave method can be used as an alternative method to chemical sterilization as an effective method. PMID- 26435612 TI - A Comparative Evaluation of Adherence of Microorganism to Different Types of Brackets: A Scanning Electron Microscopic Study. AB - BACKGROUND: The purpose of this study was to evaluate and compare the adherence of microorganism to different types of brackets using the scanning electron microscope (SEM). A double-blinded study was undertaken to evaluate and adherence of microorganisms to different types of brackets using SEM. MATERIALS AND METHODS: At random, 12 patients reporting for treatment to the department of Orthodontics VS Dental College and Hospital were selected. Four types of brackets were included in the present study stainless steel, titanium, composite, and ceramic. Brackets were bonded to teeth of the patient on all the four quadrants. The teeth included for bonding were lateral incisor, canine, first premolar, and second premolar. The brackets were left for 72 h. After 72 h brackets were debonded, and they were evaluated by SEM for adherence of microorganism in the slot and tie wings surface. The SEM images were graded, and the adherence of microorganism to the brackets in the surfaces and the four different quadrants were recorded. RESULTS: There is a significant difference in adherence of microorganisms to the various types of brackets (P < 0.001) and the surfaces (P < 0.05) included in the study. However, there is no significance in the mean adherence of microorganisms in the different quadrants (P > 0.05) included in the study. The interaction of bracket/surface, bracket/quadrant, surface/quadrants was analyzed, there was no significance of comparison of bracket/surfaces/quadrant but the interaction of bracket/quadrant was found to be significant (<0.011). The interaction of bracket/surfaces/quadrant was also found to be significant (<0.003). CONCLUSION: The maximum adherence of microorganisms was observed with the composite bracket material and the least adherence of microorganisms was observed with the titanium bracket material. The adherence of microorganisms is relatively more in the slot area, when compare to the tie wings surface maximum adherence of microorganism is observed in the upper left quadrant and least adherence of microorganism is observed in the lower right quadrant. There is a significant difference in adherence of microorganisms to various types of brackets and the surfaces included in the study. There is no significant difference in the adherence of microorganism to the bracket surfaces in the four quadrants included in the study. PMID- 26435613 TI - Evaluation of Shear Bond Strength of Newer Bonding Systems on Superficial and Deep Dentin. AB - BACKGROUND: The purpose of this study was to compare the shear bond strength of nanocomposite resin to superficial dentin and deep dentin using two different dentin bonding systems. MATERIALS AND METHODS: All teeth were sectioned at various levels (superficial dentin: Dentin within 0.5-1 mm of dentinoenamel junction; deep dentin: Dentin within 0.5 mm of the highest pulp horn) using a Carborundum Disc and embedded in acrylic block of specific size. Selected specimens (60 premolar teeth) were grouped randomly into three groups, the groups were differentiated into superficial dentin, deep dentin, and control group which were further divided into sub Group A and Subgroup B containing 10 teeth each, depending on the bonding agents used. In Subgroup A, Tetric N Bond, and in Subgroup B Single Bond Universal were used. In the control group no bonding agent was used. The specimens were thermocycled for 500 cycles between 5 degrees C and 55 degrees C water bath for 40 s. Finally, the specimens were subjected to shear bond strength study under INSTRON machine (Universal Testing Machine). The maximum shear bond strengths were noted at the time of fracture (de-bonding) of the restorative material. Results were analyzed using ANOVA test, Bonferroni test, and paired t-test. RESULTS: Bond strength values of fifth generation bonding system (Tetric N Bond) showed higher mean shear bond strength compared to seventh generation bonding system (Single Bond Universal). There was a significant fall in bond strength values as one reaches deeper levels of dentin from superficial to deep dentin. CONCLUSION: There was a significant difference between the bond strength of fifth generation bonding system (Tetric N Bond) and seventh generation bonding system (Single Bond Universal). Decrease in the bond strength values is seen for the deeper level of dentin as compared to superficial dentin. PMID- 26435614 TI - Microhardness Properties of Mineral Trioxide Aggregate and Calcium-enriched Mixture Cement Plugs at Different Setting Conditions. AB - BACKGROUND: Providing an apical stop in open apex roots is one of the endodontic challenges. The aim of present study was to compare the surface hardness of both mineral trioxide aggregate (MTA) and calcium-enriched mixture (CEM) cement at different setting situations. MATERIALS AND METHODS: A total of 40 freshly extracted human teeth with a single root and normal apex and no obvious caries or curvatures were selected. The teeth were sectioned horizontally from the cement enamel junction and 2 mm above the apex. Standard technique was administered for cleaning and shaping of the canals. Open apex root canal was prepared by using Peso reamer. The prepared teeth were randomly divided into four groups in which two groups were filled by MTA and the other groups were filled by CEM. White MTA and CEM cement plugs were prepared and condensed up to the apical end. In two groups, moistened paper point was placed in the canals and in the other group dried paper points was used. Vickers test was done to evaluate the microhardness and the collected data were analyzed by Kruskal-Wallis and three-way ANOVA tests using SPSS software version 18 at a significant level of 0.05. RESULTS: The highest and lowest surface hardness was observed in CEM group at dried condition with 4 mm thickness indentation (145.10 +/- 7.60 kg/mm(2)) and moist MTA group indented at 8 mm thickness (111.25 +/- 5.37 kg/mm(2)). However, no significant difference was noticed (P > 0.05). CONCLUSION: Humidity condition might not influence the microhardness properties of both MTA and CEM cement apical plugs at different tested indentation thickness. PMID- 26435615 TI - A Comparative Study of Three Types of Rapid Maxillary Expansion Devices in Surgically Assisted Maxillary Expansion: A Finite Element Study. AB - OBJECTIVES: The aim of this study was to analyze the displacement pattern and stress distribution during surgically assisted rapid maxillary expansion (RME) with three different types of RME devices by constructing a finite element model. MATERIALS AND METHODS: A finite element model is constructed from the computerized tomography scans. According to the type of RME device, 3 groups were simulated on this mesh model. The experimental groups were as follows; Group I (tooth borne appliance), Group II (bone borne appliance), and Group III (hybrid appliance). A Le fort I osteotomy with bilateral pterygomaxillary disjunction and midpalatal split osteotomy cuts were incorporated in all the groups. The displacement pattern and stress distribution for each 1 mm of activation of appliance up to 10 mm is noted and analyzed. The data were analyzed using Student's t-test, Analysis of Variance and Duncan new multiple range test. RESULTS: Tooth borne appliance has more rotational tendencies. The bone borne and the hybrid appliance exhibited similar stress patterns for the dissipation of the forces produced by RME appliances. The pivoting effect decreased with the hybrid and the bone borne appliance and can be utilized in patient with hyper divergent growth. CONCLUSION: The pivoting effect is least with the hybrid appliances. PMID- 26435616 TI - Comparative Study of Probiotic Ice Cream and Probiotic Drink on Salivary Streptococcus mutans Levels in 6-12 Years Age Group Children. AB - BACKGROUND: Dental caries is one of the most common health problems in the world. Probiotics are one the various preventive methods to reduce dental caries. The aim of this study is to compare the effectiveness of probiotic ice cream and drink on salivary Streptococcus mutans levels in children of 6-12 years age group. MATERIALS AND METHODS: A three phase study was carried out in children (n = 50) of 6-12 years age with zero decayed missing filled teeth (dmft)/DMFT. They were randomly divided into two equal groups. Saliva samples were collected before the consumptions of probiotic ice cream and probiotic drink. Colony count obtained was recorded as baseline data. For both groups probiotic ice cream and drink was given randomly for 7 days and a washout period of 90 days were given and then the saliva samples were collected and colony counting was done. RESULTS: Statistical analysis was performed using Student's paired t-test and multiple comparisons by Tukey's honest significant difference test which showed, there is a significant reduction in salivary S. mutans level in both groups after 7 days period. However, after washout period only probiotic ice cream showed reduction whereas drink did not. Also, there was no significant difference between probiotic ice cream and drink. CONCLUSION: Probiotic organisms definitely have a role in reducing the salivary S. mutans level and ice cream would be a better choice than drink. However, the prolonged use of the agents and their effects on caries is still to be determined. PMID- 26435617 TI - Oral Health Status and Treatment Needs of Police Personnel in Mathura City. AB - BACKGROUND: All men are born equal and are endowed by their creator with some basic rights. As the military is to defend the country from external threats, so is the police for maintenance of the internal peace of the community. The irregular shifts in their work schedule lead to neglecting or skipping of their regular diet and indulging into adverse habits. It is the responsibility of the society to safeguard the health of their defenders. MATERIALS AND METHODS: A cross-sectional study was carried out on 475 central reserve police personnels in Mathura city. Consent was obtained from the concerned authorities and the subjects were clinically examined using WHO 2013 "Oral Health Assessment Form." RESULTS: This study revealed that 99.6% subjects were males, 62% subjects were of 21-35 years age group, mean dentition status was found to be 0.66 +/- 2.08 and, most of the subjects needed prompt treatment including scaling. CONCLUSION: Police personnels provide a unique opportunity to study a large population from diverse geographic backgrounds. Prevention oriented health education lectures should be delivered and possibly, should also form part of their training curriculum. PMID- 26435618 TI - Estimation of Specific Salivary Enzymatic Biomarkers in Individuals with Gingivitis and Chronic Periodontitis: A Clinical and Biochemical Study. AB - BACKGROUND: Host response to periodontal disease includes the release of different enzymes from stromal, epithelial or inflammatory cells. The enzymes which are produced from these cells are associated with cell injury and cell death like: Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase (ALP) and Blood urea nitrogen (BUN). Normal enzymatic activity of these enzymes is necessary for healthy functioning of gingiva and periodontium. The aim of the study is to estimate the levels of enzymes AST, ALT, ALP and BUN and to correlate the level of estimated enzymes with that of clinical parameters in the saliva of Healthy subjects, Gingivitis patients and patients with chronic periodontitis. METHODS: The study included a total of 40 male subjects within the age group of 21 to 50 years, and examined the activity of enzymes AST, ALT, ALP and BUN in saliva spectrophotometrically and compared their values between healthy subjects, gingivitis and chronic periodontitis patients. Clinical parameters like OHI - S (Oral hygiene index - Simplified, SBI (Sulcus Bleeding Index), PPD (Probing Pocket Depth), CAL (Clinical Attachment Level), and PI (Periodontal Index) were recorded. RESULTS: Obtained results showed statistically significant increases of activity of AST, ALT, ALP, and BUN in saliva from patients with periodontal disease (p<0.001) in relation to gingivitis and control groups. There was also an increase in periodontal parameters with an increase in salivary enzymes. CONCLUSION: The present study shows that the salivary enzyme activity can be used as biomarkers to determine periodontal tissue damage, which may be useful in diagnosis, prognosis and evaluation of post therapy effects in periodontal disease. PMID- 26435619 TI - Evaluation and Comparison of Intermaxillary Tooth Size Discrepancy among Class I, Class II Division 1, and Class III Subjects Using Bolton's Analysis: An in vitro Study. AB - AIM: The aim of the present study was to evaluation and comparison of intermaxillary tooth size discrepancy among Class I, Class II division 1, and Class III subjects using Bolton's analysis. MATERIALS AND METHODS: The pre treatment casts were selected from the records of patients attending the Department of Orthodontics of Meenakshi Ammal Dental College, Chennai. The sample consists of 180 pre-treatment casts with both sexes evenly distributed with 60 casts in each type of malocclusion, i.e., Class I, Class II div 1, and Class III malocclusion. The sample was selected according to angles classification. All patients were Indian nationals, between the age group of 12 to 20 years and Bolton's analysis done on all the casts. RESULTS: Statistically no significant difference in all types of malocclusion except anterior Bolton's discrepancy in Class III. CONCLUSION: Mean Bolton's anterior ratio for angles Class III subjects was significantly greater than for Class I and Class II subjects. When Bolton's overall ratio was compared there was no statistically significant difference among Class I, Class II div 1, and Class III malocclusions. PMID- 26435620 TI - Occupational Stress, Salivary Cortisol, and Periodontal Disease: A Clinical and Laboratory Study. AB - BACKGROUND: Periodontitis is a multifactorial disease, commonly associated with most of the lifestyle diseases. In the recent years, the association between periodontitis with occupational stress has evolved in various studies in many developed settings. This study aims at studying the prevalence of periodontal disease and its relationship with job stress among industrial labor workers covered under Employee's State Insurance Corporation Scheme. MATERIALS AND METHODS: The study included 180 subjects who were informed about the research goals, and also requested to sign consents. The questionnaire included parts from the generic job stress questionnaire from the National Institute of Job Stress and Health. Dental examinations based on community periodontal index protocol were done using WHO probe. Participants with moderate to severe periodontitis (score 3, 4) were informed about the salivary cortisol test. The saliva samples were collected and transported to the lab. Data were entered in EPI info 3.1.1 and analyzed in SPSS 14. The Chi-square analysis was done to measure association, and logistic regression analysis was done to identify the independent association of job stress to periodontitis. RESULTS: The study shows that 48% of the participants reported to have job stress, and 55% had periodontitis. The mean salivary cortisol level was 3.42 ng/dl. The results also indicated a higher odds of having low levels of salivary cortisol among those who reported job stress. Bi variant regression analyses show the relationship of periodontitis with job stress to be much higher on controlling for other risk factors. The odds of having periodontitis in relation to positive job stress were 6 times higher than those who did not have positive job stress. CONCLUSIONS: This study shows a high prevalence of job stress related periodontitis among industrial workers in India. This research recommends the health and labor ministry to improve access to dental care especially in rural areas and include psychiatric units and oral health care as a part of primary health care. The factories administration should encourage recreation and retreat of the workers so as to reduce the level of stress at work. The factory administrations were recommended to have counselors to help their employees. PMID- 26435621 TI - Management of Biomedical Waste: An Exploratory Study. AB - BACKGROUND: Dental operatories pose a threat due to the high chances of infection transmission both to the clinician and the patients. Hence, management of dental waste becomes utmost importance not only for the health benefit of the dentist himself, but also people who can come into contact with these wastes directly or indirectly. The present study was conducted to find out the management of biomedical waste in private dental practice among 3 districts of Karnataka. MATERIALS AND METHODS: The study population included 186 private practitioners in 3 districts of Karnataka (Coorg, Mysore, Hassan), South India. A pre-tested self administered questionnaire was distributed to assess the knowledge and practices regarding dental waste management. Descriptive statistics was used to summarize the results. RESULTS: Out of 186 study subjects, 71 (38%) were females and 115 (62%) were males. The maximum number of participants belonged to the age group of 28-33 years (29%). Undergraduate qualification was more (70%). 90 (48%) participants had an experience of 0-5 years. Chi-square analysis showed a highly significant association between participant who attended continuing dental education (CDE) program and their practice of dental waste management. CONCLUSION: Education with regards to waste management will help in enhancing practices regarding the same. In order to fill this vacuum CDE programs have to be conducted in pursuance to maintain health of the community. PMID- 26435622 TI - Prevalence of Spaced and Non-Spaced Dentition and Occlusal Relationship of Primary Dentition and its Relation to Malocclusion in School Children of Davangere. AB - BACKGROUND: The aim of the current study was carried to determine the relation of spacing, closed dentition, and occlusal relation with malocclusion in the primary dentition in children during deciduous dentition period among school children of Davangere. MATERIALS AND METHODS: A total of 945 school children all having deciduous teeth were included in the study. Informed consent for the child's participation is taken from the school principal. The dentition was examined under natural daylight, and the data was recorded. All the school children were screened for spaced and non-spaced dentition, molar and canine relationship. RESULTS: The results concluded that most of the children showed spaced dentition (82.1%) when compared to non-spaced dentition (17.9%) with males shown more spaced dentition than compared to females. Among all children examined for molar and canine relation, flush terminal molar relation (65%) showed highest among all molar relation followed by mesial step (31%) and distal step (4%), and Class I canine relation (90%) was significant followed by Class II (6%) and Class III canine relation (4%). No significant difference was seen between right and left side. CONCLUSION: The study concludes that determining the malocclusion and its correction at an early age helps in preventing a future complication in permanent dentition since stable primary occlusion leads to ideal occlusion in permanent dentition. Spacing, i.e., primate and physiologic space with the terminal molar relation in primary dentition indicates proper alignment of the permanent dentition. PMID- 26435623 TI - Patient's Perceptions Regarding Orthodontic Needs and Satisfactory Level with the Procedure. AB - BACKGROUND: In order to keep the patients satisfied with Orthodontic treatment and to address the growing concern among new orthodontic patients, this study was undertaken to evaluate patient's perceptions of their orthodontic treatment needs and the satisfactory level with the procedure. METHODOLOGY: This cross-sectional study was conducted among a sample of 362 patients who had received orthodontic treatment. Questionnaires included information factors that encouraged them to take orthodontic treatment, painful experience of orthodontic therapy, and also to know the effectiveness of the treatment. Student's t-test and ANOVA test were used to analyze results at P = 0.05. RESULTS: Most of the participants faced problems due to their dentition (60.2%), followed by mastication 23.6%. It was found that most of the study subjects were motivated by orthodontist to receive the treatment (29.7%). When the participants were asked about the complications faced by them during the procedure and the most common answer was a longer duration of the treatment (23.3%). Pain was also a common factor faced by the participants (15.9%). Significant results were seen according to gender and age. CONCLUSION: The study concluded that problems in the dentition were the main factor to seek orthodontic treatment and most of the subjects were convinced by the specialist to undergo orthodontic therapy. Many problems faced during the treatment, but still majority gave a positive response to the treatment. PMID- 26435624 TI - Assessment of Ethnicity in Indian Population using Tooth Crown Metric Dental Traits. AB - BACKGROUND: Tooth crown dimensions vary between different ethnic groups, providing insights into the factors controlling human dental development. This present study compares permanent mesiodistal (MD) and buccolingual crown dimensions between four ethnic groups, highlighting patterns of tooth size between these groups and considers the findings in relation to genetic and environmental influences. MATERIALS AND METHODS: MD and buccolingual tooth crown dimensions were recorded using digital vernier calipers on dental casts derived from four different human population: Iranians, Hindus, Muslims, and Christians. RESULTS: Obtained measurements were subjected to statistical analysis. The Christian sample was found to have the largest teeth overall, whereas the Iranian sample generally displayed the smallest MD and buccolingual crown dimensions (P < 0.001). Comparisons of coefficients of variation for teeth within each class showed that the later-forming teeth displayed greater variation in MD size than the earlier-forming teeth. CONCLUSION: The different patterns of tooth size observed between the study samples are thought to reflect differences in the relative contributions of genetic and environmental influences to dental development between the four population. Using a standardized methodology, significant differences in MD and buccolingual crown dimensions have been demonstrated between four human ethnic groups. There were also distinct differences in the patterns of crown size between the groups, with the later forming teeth in each type generally showing greater size variation. PMID- 26435625 TI - The Effect of Four Commonly used Root Canal Irrigants on the Removal of Smear Layer: An In-vitro Scanning Electron Microscope Study. AB - BACKGROUND: The objective of this study was to compare the efficiency of four commonly used chemicals in their ability to remove smear layer after instrumentation using scanning electron microscope (SEM). MATERIALS AND METHODS: Seventy-five extracted single canaled teeth of roots ranging 10-12 mm in length were used for the study. Teeth were divided into 4 study groups and 1 control group of 15 teeth each. Standard access to the pulp chambers were performed with diamond burs. The lengths of the teeth were determined by the introduction of a size 15 K-file into the root canal until the tip reached the apical foramen. The working length for preparation of the canal is set 0.5 mm shorter than the measurement. Irrigation was performed using 2 ml of irrigant for every instrument change and finally rinsed using 5 ml of the respective solutions. The roots were then split with a chisel and hammer. One-half of each tooth was selected and prepared for SEM examination. After assembly on coded stubs, the specimens were placed in a vacuum chamber and sputter-coated with a 300 A gold layer. The specimens were then analyzed using a Philips SEM XL 30. The dentinal wall of the cervical, middle and apical thirds was observed at magnifications of up to *1000 for the presence/absence of smear layer and visualization of the entrance to dentinal tubules. Photomicrographs (*1000) of these areas on each of the coronal, middle and apical thirds were made Data were analyzed using Kruskal-Wallis test and Mann-Whitney U test. RESULTS: SEM study done on these prepared teeth with the popularly used four chemicals, namely, 3% NaOCl (Group A), 3% NaOCl followed by 17% ethylene diamine-tetra-acetic acid (Group B), 0.2% chlorhexidine (Group C) and 3% NaOCl followed by MTAD (Group D), with distilled water (Group E) which is used as control, revealed that NaOCl showed statistically significant, better cleansing effect than distilled water. Chlorhexidine and NaOCl showed equal kind of efficacy but were statistically significant, with lower efficacy than MTAD. It may be concluded that MTAD appears to be the most effective solution compared to the rest. CONCLUSION: The study demonstrated that MTAD as a final rinse after the entire instrumentation with 3% NaOCl as irrigant provided the best cleansing in all parts of the root canal system. The smear layer has been shown to hinder the penetration of intracanal disinfectants and sealers into dentinal tubules and has the potential of compromising the seal of the root filling. Degradation of the smear layer after treatment may contribute to leakage and reinfection of the root canal space. Removal of the smear layer reduced the penetration of bacteria through the root canal system after root filling. PMID- 26435626 TI - Anxiety and Depression in Facial Injuries: A Comparative Study. AB - BACKGROUND: This study was performed to identify the presence of anxiety and depression in patients who had sustained facial injuries; additionally we aimed to identify other variables that may modify the psychological response to trauma that include gender and age. MATERIALS AND METHODS: The participants were 153 patients from multimodal trauma centers in Bangalore city who sustained disfiguring facial injuries were taken up. Of the 153 patients, 81 patients were male (51 less than 50 years of age and 30 more than 50 years of age) and 72 patients were female (40 less than 50 years of age and 32 more than 50 years of age) and 111 patients with non-disfiguring facial injuries out of which 54 were male patients and 57 were female patients. The assessments were carried out at 3 time intervals (the date of discharge [DOD], 1-month post-operatively and 6 months post-operatively) of the follow-up. The hospital anxiety and depression scale (HADS) was used to assess the anxiety and depression of the facial trauma patients. RESULTS: Statistically significant higher means of HADS both for anxiety and depression were present in patients with disfiguring facial injuries compared to non-disfiguring facial injuries, female patients compared to male patients after the 1-month and 6 months post-operatively, the mean anxiety and depression scores of males and female patients were significantly higher for those who aged less than 50 years compared to those who aged more than 50 years. CONCLUSION: The results of this study led to the conclusion that in comparison with patients who had facial disfiguring injuries and non-disfiguring facial injuries, the mean HADS scores were significantly higher in the disfiguring facial injury patient. This indicates increased Anxiety and Depression levels and this was observed at all three study intervals (DOD, 1-month and 6 months post operatively). The HADS was higher in female patients who were lesser than 50 years age compared to male patients of the same age group, which implies higher anxiety and depression levels. PMID- 26435627 TI - Revelation of Viral - Bacterial Interrelationship in Aggressive Periodontitis via Polymerase Chain Reaction: A Microbiological Study. AB - BACKGROUND: Periodontal disease is one of the most common and complex disease affecting mankind. Being multifactorial in etiology it encompasses a variety of infectious entities with various unique microbial constellations and immune responses. A bacteriologic cause alone seems insufficient in explaining several clinical features of the periodontal disease. Recent studies suggest that periodontal herpes viruses comprise an important source of triggering periodontal tissue destruction. The following study aims to assess human cytomegalovirus (HCMV), Epstein-Barr virus (EBV-I) interaction with the established periodontopathic bacteriae, Porphyromonas gingivalis (Pg) and Aggregatibacter actinomycetemcomitans (Aa) in pathogenesis of aggressive periodontitis (AgP) using Hotstart polymerase chain reaction (PCR). MATERIALS AND METHODS: A total of 30 subjects, 15 with AgP and 15 healthy controls contributed random subgingival plaque samples. PCR methodology was used to identify the subgingival herpesviruses, Pg, and Aa. Yates corrected Chi-square test was employed to identify a statistical association between herpesviruses and periodontopathic bacteriae. RESULTS: Findings suggested that viruses may be pertinent to disease progression. The prevalence of the periodontopathic bacteria Aa was found in 53.33% (P = 0.0168, S) and Pg in 40% (P = 0.2155, NS) of the AgP patients. Herpesviruses, HCMV and EBV-I were found to have a prevalence of 46.67% (P = 0.039, S) and 40% (P = 0.084, NS). The viral and bacterial co-infection was found to be 77.78% (P = 0.0002, S) with Aa and HCMV. CONCLUSION: The present data reveals, viruses may exert periodontopathic effect by causing local immunosupression which may set a stage for the subgingival colonization and multiplication of periodontal bacteriae. Further studies are needed to develop an understanding into the significance of herpesviruses in human periodontitis which, may allow for improved diagnosis, more specific therapy and ultimately disease prevention. PMID- 26435628 TI - Comparison of Frictional Forces Generated by a New Ceramic Bracket with the Conventional Brackets using Unconventional and Conventional Ligation System and the Self-ligating Brackets: An In Vitro Study. AB - BACKGROUND: Fixed orthodontic mechanotherapy is associated with friction between the bracket - wire - ligature interfaces during the sliding mechanics. A sound knowledge of the various factors affecting the magnitude of friction is of paramount importance. The present study was done to analyze and compare the frictional forces generated by a new ceramic (Clarity Advanced) bracket with the conventional, (metal and ceramic) brackets using unconventional and conventional ligation system, and the self-ligating (metal and ceramic) brackets in the dry condition. MATERIALS AND METHODS: The various bracket wire ligation combinations were tested in dry condition. The brackets used were of 0.022" * 0.028" nominal slot dimension of MBT prescription: Stainless steel (SS) self-ligating bracket (SLB) of (SmartClip), SS Conventional bracket (CB) (Victory series), Ceramic SLB (Clarity SL), Conventional Ceramic bracket with metal slot (Clarity Bracket), Clarity Advanced Ceramic Brackets (Clarity(TM) ADVANCED, 3M Unitek). These brackets were used with two types of elastomeric ligatures: Conventional Elastomeric Ligatures (CEL) (Clear medium mini modules) and Unconventional Elastomeric Ligatures (UEL) (Clear medium slide ligatures, Leone orthodontic products). The aligning and the retraction wires were used, i.e., 0.014" nickel titanium (NiTi) wires and 0.019" * 0.025" SS wires, respectively. A universal strength testing machine was used to measure the friction produced between the different bracket, archwires, and ligation combination. This was done with the use of a custom-made jig being in position. RESULTS: Mean, standard deviation, and range were computed for the frictional values obtained. Results were subjected to statistical analysis through ANOVA. The frictional resistance observed in the new Clarity Advanced bracket with a conventional elastomeric ligature was almost similar with the Clarity metal slot bracket with a conventional elastomeric ligature. When using the UEL, the Clarity Advanced bracket produced lesser friction than the conventional metal bracket; but not less than the ceramic metal slot bracket. Ceramic SLB produced lesser friction when compared with the Clarity Advanced bracket with UEL, but the metal SLB produced the least friction among all the groups and subgroups. CONCLUSION: The present study concluded that the SS SLB produced least friction among all groups. Using the archwire and ligation method, frictional forces observed in the Clarity Advanced bracket and the conventional ceramic with metal slot bracket were almost similar; but the least resistance was determined in SS CB using both the ligation (CEL and UEL) system. PMID- 26435629 TI - Stress Induced in Periodontal Ligament under Orthodontic Loading (Part II): A Comparison of Linear Versus Non-Linear Fem Study. AB - BACKGROUND: Simulation of periodontal ligament (PDL) using non-linear finite element method (FEM) analysis gives better insight into understanding of the biology of tooth movement. The stresses in the PDL were evaluated for intrusion and lingual root torque using non-linear properties. MATERIALS AND METHODS: A three-dimensional (3D) FEM model of the maxillary incisors was generated using Solidworks modeling software. Stresses in the PDL were evaluated for intrusive and lingual root torque movements by 3D FEM using ANSYS software. These stresses were compared with linear and non-linear analyses. RESULTS: For intrusive and lingual root torque movements, distribution of stress over the PDL was within the range of optimal stress value as proposed by Lee, but was exceeding the force system given by Proffit as optimum forces for orthodontic tooth movement with linear properties. When same force load was applied in non-linear analysis, stresses were more compared to linear analysis and were beyond the optimal stress range as proposed by Lee for both intrusive and lingual root torque. To get the same stress as linear analysis, iterations were done using non-linear properties and the force level was reduced. CONCLUSION: This shows that the force level required for non-linear analysis is lesser than that of linear analysis. PMID- 26435630 TI - Association of Postmenopausal Osteoporosis and Periodontal Disease: A Double Blind Case-Control Study. AB - BACKGROUND: Both osteoporosis (OP) and periodontitis are chronic inflammatory diseases associated with bone loss mediated by local and systemic factors. The two diseases share common risk factors. Previous studies have suggested that OP in itself is a predisposing factor for periodontal tissue destruction in postmenopausal women. However, only a moderate correlation has been shown between the two conditions. In this study, we compared the severity of periodontal disease in postmenopausal osteoporotic women and postmenopausal women without OP. MATERIALS AND METHODS: The study group consisted of 100 postmenopausal women in the age group of 50-65 years: Group 1 (50 osteoporotic) and Group 2 (50 non osteoporotic women). Periodontal parameters included sulcus bleeding index, oral hygiene index simplified, probing pocket depth (PPD), and clinical attachment loss (CAL), interproximal alveolar bone loss (ABL), and number of missing teeth. The correlation of periodontal disease status with systemic bone mineral density (BMD) was evaluated by dual-energy X-ray absorptiometry. RESULTS: The results indicated that osteoporotic (Group 1) women had a significantly greater PPD, CAL, and ABL when compared with the non-osteoporotic Group 2 (P < 0.0001). There was no significant correlation between BMD and various parameters between the groups. CONCLUSIONS: Within the limitations of the present study it was noted that postmenopausal OP is associated with an increased incidence and severity of periodontal disease. Educating postmenopausal osteoporotic women regarding the importance of good oral care should be part of their management regime. Hence, it could be inferred a possibility of a probable relationship between OP and periodontal disease, but long-term prospective studies are warranted in the future in order to provide definitive evidence. PMID- 26435631 TI - Modified Esthetic Splint Design for Management of Multiple Traumatic Injuries in Children: A Case Report. AB - Traumatic injuries to the dento-alveolar structures are emergencies that compromise the quality of life of the patients. In addition to symptomatic management, definitive functional restoration and suitable rehabilitation becomes a major treatment objective in such cases. The dynamics of the traumatic forces may cause multiple injuries of different grades to the oral and para-oral structures, which makes comprehensive management a greater challenge to the dentist. The present case report elaborates a modified esthetic splint designed to treat multiple dental injuries in children, which can promote healing, restore optimal functionality along with esthetic rehabilitation to psychologically benefit the child during the time of recovery. PMID- 26435632 TI - Open Sinus Lift Surgery and the Importance of Preoperative Cone-Beam Computed Tomography Scan: A Review. AB - Open sinus lift surgery is a form of pre-prosthetic surgery for increasing the quality and quantity of bone in the posterior region of the maxilla. Pre operative assessment of the maxillary sinus is essential for the success of this surgery. PubMed search was carried out in English language literature for open sinus lift surgery and cone-beam computed tomography (CBCT). The results focused on anatomic variants, vascular anatomy, complications, osteotomy/ostectomy window dimensions and thickness of the Schneiderian Membrane. 59 articles were included in this review. Features other than the height and the width of the residual alveolar ridge that should be evaluated in preoperative CBCT scan include the thickness of the lateral maxillary sinus wall, the presence of the alveolar antral artery and its diameter, the maxillary sinus floor width and angulation, irregularity of sinus floor, intimate relation of Schneiderian membrane with the roots of the adjacent teeth, sinus septum, and the quality of subantral bone. Other conditions that occasionally may be observed in special situations are also explained. More than ten parameters should be checked in evaluating CBCT images of paranasal sinuses other than the width and the length of the residual ridge in the posterior region of the maxilla. Each of them may have a significant impact on the results of the open sinus lift surgery. PMID- 26435633 TI - Microdentistry with Lasers. AB - Treating infants and young children is a rewarding experience, especially when we guide parents and children down the path of prevention and interception of oral disease. The pediatric dentist has to be updated about the new technologies to treating patients along with basic principles. This article gives a brief discussion on the types, applications, advantages, and limitations of the use of lasers in pediatric dentistry. PMID- 26435634 TI - Tissue Engineering: Step Ahead in Maxillofacial Reconstruction. AB - Within the precedent decade, a new field of "tissue engineering" or "tissue regeneration" emerge that offers an innovative and exhilarating substitute for maxillofacial reconstruction. It offers a new option to supplement existing treatment regimens for reconstruction/regeneration of the oral and craniofacial complex, which includes the teeth, periodontium, bones, soft tissues (oral mucosa, conjunctiva, skin), salivary glands, and the temporomandibular joint (bone and cartilage), as well as blood vessels, muscles, tendons, and nerves. Tissue engineering is based on harvesting the stem cells which are having potential to form an organ. Harvested cells are then transferred into scaffolds that are manufactured in a laboratory to resemble the structure of the desired tissue to be replaced. This article reviews the principles of tissue engineering and its various applications in oral and maxillofacial surgery. PMID- 26435635 TI - Telescopic Partial Dentures-Concealed Technology. AB - The ideal goal of good dentist is to restore the missing part of oral structure, phonetics, his look and the most important is restored the normal health of the patient, which is hampered due to less or insufficient intake of food. Removable partial denture (RPD) treatment option is considered as a notion, which precludes the inevitability of "floating plastic" in edentulous mouth, that many times fail to fulfill the above essential of the patients. In modern dentistry, though the dental implants or fixed partial denture is the better options, but they have certain limitations. However, overdentures and particularly telescopic denture is the overlooked technology in dentistry that would be a boon for such needy patients. Telescopic denture is especially indicated in the distal edentulous area with minimum two teeth bilaterally present with a good amount of periodontal support. This treatment modality is sort of preventive prosthodontics remedy, which in a conservative manner preserve the remaining teeth and helps in conservation of alveolar bone ultimately. There are two tenets related to this option, one is constant conservation edentulous ridge around the retained tooth and the most important is the endless existence of periodontal sensory action that directs and monitor gnathodynamic task. In this option the primary coping or inner coping are cemented on the prepared tooth, and a similar removable outer or inner telescopic crown placed tightly by using a mechanism of tenso-friction, this is firmly attached to a removable RPD in place without moving or rocking of the prosthesis, which is the common compliant of almost all patients of RPD. Copings are also protecting the abutment from tooth decay and also offers stabilization and maintaining of the outer crown. The outer crown engages the inner coping and gives as an anchor for the remainder of the dentition. This work is the review of telescopic prosthesis which is well supported by the case discussion, and designates the utilization of favorable retained tooth/teeth as abutment that drastically minimized alveolar bone resorption beneath the prosthesis and give the maximum tactile sensation of natural teeth to the patient, which is not possible with other type of RPD. PMID- 26435636 TI - Pseudoepitheliomatous Hyperplasia in Oral Lesions: A Review. AB - Pseudoepitheliomatous hyperplasia (PEH) is a histopathological reaction pattern to various stimuli, which includes trauma, infection, inflammation, neoplasia. It is seen as tongue like epithelial proliferation invading the connective tissue and should not be mistaken for squamous cell carcinoma (SCC). This review enlists oral lesions which exhibit PEH with a note on how to differentiate SCC from PEH. PMID- 26435637 TI - Mesenchymal-Epithelial Transition in Oral Cancer. PMID- 26435638 TI - Closed-Loop Multitarget Optimization for Discovery of New Emulsion Polymerization Recipes. AB - Self-optimization of chemical reactions enables faster optimization of reaction conditions or discovery of molecules with required target properties. The technology of self-optimization has been expanded to discovery of new process recipes for manufacture of complex functional products. A new machine-learning algorithm, specifically designed for multiobjective target optimization with an explicit aim to minimize the number of "expensive" experiments, guides the discovery process. This "black-box" approach assumes no a priori knowledge of chemical system and hence particularly suited to rapid development of processes to manufacture specialist low-volume, high-value products. The approach was demonstrated in discovery of process recipes for a semibatch emulsion copolymerization, targeting a specific particle size and full conversion. PMID- 26435639 TI - Nesfatin-1 and its effects on different systems. AB - Nesfatin-1 is a peptide secreted by peripheral tissues, central and peripheral nervous system. It is involved in the regulation of energy homeostasis related with food regulation and water intake. Nesfatin-1 can pass through the blood brain barrier in both directions. It suppresses feeding independently from the leptin pathway and increases insulin secretion from pancreatic beta islet cells. That is why nesfatin-1 has drawn attention as a new therapeutic agent, especially for the treatment of obesity and diabetes mellitus. Its effects on nutrition have been studied in more detail in literature. On the other hand, its effects on other physiological parameters and mechanisms of action still need to be clarified. Synthesizing the research on nesfatin-1 can help us better understand this field. Hippokratia 2015, 19 (1): 4-10. PMID- 26435640 TI - Constipation in Childhood. An update on evaluation and management. AB - OBJECTIVE: Constipation is a frequent problitalic in childhood and may be defined as delay or difficulty in defecation that persists for longer than two weeks. It is one of the ten most frequent pathological conditions that a general paediatrician deals with. The aim of this review is to provide the general paediatrician an overview of constipation in children discussing the etiology, differential diagnosis, signs and symptoms and patient evaluation. METHODS: We provide an overview on the pathogenesis, the diagnostic approach and the managitalicent of constipation based on electronic literature searches using the best available evidence from PubMed, Medline, Google Scholar, the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). RESULTS: The most common type of constipation is functional accounting for 90-95% of all cases. In a small percentage of children, who may have an organic cause of constipation, an appropriate laboratory investigation and imagine studying is warranted. CONCLUSIONS: Functional constipation ritalicains a frequent problitalic in childhood. Treatment options differ between infants and children. italicphasis on recommended regimens for maintenance and how to reduce medication will help to improve the long-term outcome. Moreover, it is of great importance to follow constipated children closely and restart medication promptly. On treatment failure or on suspicion of organic disease the patient should be referred for further evaluation. Hippokratia 2015, 19 (1): 11 19. PMID- 26435641 TI - Research on intraoperative iris behavior in rabbits treated with tamsulosin and finasteride. AB - AIM: The purpose of this study was to investigate intraoperative iris behavior during some phacoemulsification maneuvers in rabbits treated with tamsulosin or finasteride. MATERIAL AND METHOD: An experimental study was conducted on 26 Metis male rabbits aged 1.5 - 2 years, body weight between 3.4 and 5.6 kg, divided into three groups: Group 1 - Control, 6 rabbits; Group 2 - tamsulosin, 10 rabbits; Group 3 - finasteride, 10 rabbits. Dose calculation was performed according to body surface area ratio man/rabbit, taking into account the median lethal dose LD50. Surgery study in rabbits was done over two days by the same specialist using an adapted protocol. He was not informed before or during surgeries which group the animal belonged to, the order being random with a quasi-uniform distribution. Valid results for a modified iris behavior were obtained from two steps of the procedure (cannula irrigation maneuver and irrigation-aspiration). The iris billowing was graded from 0 to 3, according to severity. RESULTS: The risk of intraoperative iris billowing was higher in rabbits included in tamsulosin group [OR=8.33 (CI 95% 0.63-110.09)], but insignificant statistically compare with control group (p= 0.13). In rabbits treated with finasteride the risk of intraoperative iris billowing is increased compared with those without treatment [OR=11.6 (CI 95% 0.92-147.6)], but insignificant statistically (p= 0.11). CONCLUSION: In our research, we showed an increased risk of intraoperative iris billowing in rabbits treated with finasteride, almost similar with those obtained in rabbits treated with tamsulosin. Further experimental or clinical studies to confirm the role of finasteride in the etiology of intraoperative floppy iris syndrome in humans are needed. Hippokratia 2015, 19 (1): 20-24. PMID- 26435642 TI - Common VDR polymorphisms and idiopathic short stature in children from northern Greece. AB - BACKGROUND: A Vitamin D Receptor gene (VDR) polymorphism, rs10735810 (Fok1), has been associated in the past with idiopathic short stature (ISS) in a linkage study. We have investigated the association of the same, as well as a different polymorphism in the same gene [rs731236 (Taq1)] with ISS, in an independent study in Greek children. METHODS: The VDR rs10735810 (Fok1) and rs731236 (Taq1) polymorphisms were genotyped in a group of ISS children (n= 47) and an age and sex-matched group of normal height children (n= 60) from northern Greece. Genotyping was accomplished through established PCR-RFLP methods. RESULTS: An association trend of rs10735810 with ISS was observed, with the TT (ff) genotype being apparently underrepresented among ISS children compared to controls (p= 0.076; OR= 0.165, 95% CI= 0.025-1.094). CONCLUSIONS: The above results, together with recent evidence related to the functionality of the rs10735810 polymorphism, cannot exclude an involvement of VDR in the pathogenesis of ISS. Hippokratia 2015, 19 (1): 25-29. PMID- 26435643 TI - Validation of revised Epstein's criteria for insignificant prostate cancer prediction in a Greek subpopulation. AB - BACKGROUND: Different treatment options for patients with prostate cancer (PCa) are applicable after stratifying patients according to various classification criteria. The purpose of our study is to evaluate the revised Epstein's criteria for insignificant PCa prediction in a Greek subpopulation. METHODS: During a 4 year-period, 172 Cretan patients were submitted to radical retropubic prostatectomy in our institution. 23 out of them met the revised Epstein's criteria for the presence of clinically insignificant PCa (clinical stage T1c, prostate specific antigen density < 0.15 ng/ml/g, absence of Gleason pattern 4-5, <3 positive biopsy cores, presence of <50% tumor per core) during pre-treatment evaluation and were retrospectively included in the study. Post-surgery outcomes were evaluated including pathological stage, surgical margins and Gleason score upgrade. RESULTS: Organ confined disease and insignificant PCa were predicted with a 74% and 31% accuracy, respectively. These figures are remarkably lower than those derived from similar studies worldwide. CONCLUSIONS: Due to the high variation in the revised Epstein's criteria prediction accuracy observed worldwide, the development and implementation of novel tools/nomograms with a greater predictive accuracy is still warranted. Hippokratia 2015, 19 (1): 30-33. PMID- 26435644 TI - West Nile virus IgM and IgG antibodies three years post- infection. AB - BACKGROUND: West Nile virus (WNV) causes to humans a variety of symptoms, from asymptomatic infection to severe neuroinvasive disease. In a previous study, it was shown that WNV IgM antibodies persisted in three of 26 (12%) patients, nine months after onset of the symptoms. The aim of the present study was to test 10 of these patients, three years post-infection for probable persistence of IgM antibodies and to investigate their IgG antibody patterns. MATERIAL AND METHODS: In summer 2013 serum samples were collected from 10 persons who were infected with WNV in 2010; 6 of them had a neuroinvasive disease. The three persons with detectable WNV IgM antibodies, nine months after onset of the symptoms, were included in the study. All samples were tested by ELISA in parallel with their stored paired samples taken in 2011. The positive results were confirmed by neutralization test. RESULTS: WNV IgM antibodies were still detectable in the three persons, while high levels of WNV IgG and neutralizing antibodies were present in nine of the 10 persons, regardless the involvement of the nervous system. CONCLUSIONS: WNV IgM antibodies persist for more than three years in 12% of patients with WNV infection, while WNV IgG antibodies persist and even increase their levels, regardless the involvement of the nervous system, suggesting that the immune response in the symptomatic WNV infections is strong and long-lasting. Hippokratia 2015, 19 (1): 34-36. PMID- 26435645 TI - Characteristics and outcome of patients with difficult weaning from mechanical ventilation: an 18 years' experience of a respiratory intermediate unit attached to a pulmonary department. AB - BACKGROUND: Respiratory dysfunction often persists in post intensive care unit (ICU) patients and intermediate care facilities have been established to ensure the continuous of appropriate care. METHODS: The data of patients with difficult weaning from mechanical ventilation admitted to a respiratory intermediate unit (RIU) attached to a pulmonary department of a General Hospital, were retrospectively analyzed. Clinical characteristics, weaning from mechanical ventilation and tracheostomy, ICU readmission and RIU mortality were examined over a period of 18 years (1993- 2010) that was randomly divided into three six year-periods. RESULTS: A total of 548 patients (age 56.7+/-17.9 years) [mean +/- standard deviation (SD)], of whom 80% with tracheostomy in place and 37.6% with pressure ulcers, were examined. The ICU stay was 30.1+/-24.7 days (mean +/- SD) and increased over time (p<0.05). Patients' baseline disorders were: chronic respiratory disease (41.3%), chronic cardiovascular diseases (10.6%), neuromuscular disease (22.8%) and miscellaneous (25.3%). The length of RIU stay (22.8+/-19.5 days) was constant over the examined periods but an increase in age and maintenance of tracheostomy were observed; 80% of patients were liberated from mechanical ventilation and 58.5% from tracheostomy, whereas the RIU mortality was 15%. CONCLUSION: In their vast majority patients with chronic respiratory failure, who were admitted to RIU,were weaned from mechanical ventilation, although in a substantial percentage the maintenance of tracheostomy was mandatory after discharge. Hippokratia 2015, 19 (1): 37-40. PMID- 26435646 TI - Urate crystals induce NLRP3 inflammasome-dependent IL-1beta secretion and proliferation in isolated primary human T-cells. AB - BACKGROUND: Urate through NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-dependent caspase-1 activation stimulates macrophages to secrete inteleukin-1beta (IL-1beta). Urate also enhances adaptive immunity indirectly through its effect on antigen presenting cells. In this study, the direct effect of urate on isolated primary human T-cells was evaluated. METHODS: Isolated T-cells were cultured with or without monosodium urate crystals in the presence or not of the NLRP3 inflammasome inhibitor glyburide. Activated cleaved caspase-1 was assessed by means of western blotting, whereas caspase-1 activity was measured colorimetrically in the cell lysates. IL-1beta was measured in the supernatants by means of enzyme-linked immunosorbent assay. T-cell proliferation was assessed by means of bromodeoxyuridine labelling and immunoenzymatic detection. RESULTS: Urate induced caspase-1 activation and IL-1beta release by T cells. It also induced proliferation of T-cells. Glyburide inhibited urate induced caspase-1 activation, IL-1beta secretion and proliferation. CONCLUSIONS: Urate, a well defined danger signal, stimulates directly human T-cells in a NLRP3 infmmasomela-dependent way. The subsequent IL-1beta secretion could enhance inflammation, whereas expansion of T-cell clones could facilitate a subsequent adaptive immune response. Hippokratia 2015, 19 (1): 41-46. PMID- 26435647 TI - Use of lung clearance index to assess the response to intravenous treatment in cystic fibrosis. AB - BACKGROUND: Progressive lung disease is the main cause of clinical deterioration and mortality in cystic fibrosis (CF) patients. Being able to assess the effectiveness of interventions is very significant. OBJECTIVES: To assess the response to intravenous (IV) treatment among CF patients, using forced expired volume in 1(st) second (FEV1) and Lung Clearance Index (LCI) as outcome measures and to compare the effect of IV treatment on lung function and LCI between CF children being treated on a regular basis, or in case of a pulmonary exacerbation. SUBJECTS AND METHODS: Thirty-two CF patients (15 males) with mean age 9.90 (range: 2-23) years, performed spirometry and multiple breath washout (MBW) before and one month after IV antibiotic treatment. Nineteen patients received a course of elective treatment (group A) and 13 received IV antibiotic regimens for an acute exacerbation (group B). RESULTS: Statistically significant differences after treatment were seen in LCI (p<=0.001), and Forced Expiratory Flow (FEF) z-scores (p<0.05). FEV1 did not change significantly after drug intervention. Dividing patients into two groups, only LCI showed significant change (p<0.05), when treatment was administered on a regular basis. Patients being treated for an acute pulmonary exacerbation showed significant improvement in most of the lung function parameters: LCI (p=0.0001), FEV1% (p=0.05), FEV1 z score (p=0.033) and FEF25-75 (p=0.046). The mean LCI difference was significantly greater in group B compared to group A (p=0.001). CONCLUSION: LCI is more sensitive marker than FEV1 to assess the effect of IV antibiotic treatment among CF children. IV antibiotics are more effective on lung function parameters, when they are administered for an acute exacerbation, than when they are given on a regular basis. Hippokratia 2015, 19 (1): 47-52. PMID- 26435648 TI - Difference in efficacy of proton pump inhibitor between new-onset and recurrent gastroesophageal reflux disease: Result from a study of on-demand versus continuous maintenance therapy in Japan. AB - BACKGROUND-OBJECTIVE: No study has focused on the difference in efficacy of maintenance therapy between patients with new-onset and recurrent gastroesophageal reflux disease (GERD). The aim of this study is to reveal this point. METHODS: Endoscopically proven GERD patients who had completed 8-week initial therapy were sequentially randomized to continuous arm (Omeprazole 20mg od) or on-demand arm (Omeprazole 20mg on-demand). Patients filled in daily symptoms and tablet usages for 24 weeks. Patients underwent upper GI endoscopy at 24 weeks. Symptom relief was defined as no symptoms for>6 days during a week. The numbers of patients who achieved symptom relief and mucosal healing were compared between the new-onset and recurrent groups in the continuous arm and in the on demand arm, respectively. RESULTS: Among new-onset GERD [n=82 (continuous: 42 patients, on-demand: 40)], continuous arm achieved significant symptom-relief than in on-demand arm at 4*,5*,6** and 17*week. Among recurrent GERD [n=36(continuous: 17 patients, on-demand: 19)], continuous arm achieved significant symptom-relief at 1**,2*,3*,4*,5**,7**,8**,17* and 18* week, respectively (*<0.05,**<0.01). The number of healed patients was significantly higher in new-onset group (60/68, 88.2%) than in recurrent group (17/30, 56.7%) (<0.01). CONCLUSION: Since therapeutic response during maintenance therapy was poor in recurrent GERD, continuous therapy is recommended in order to maintain symptom-relief and mucosal healing. Hippokratia 2015, 19 (1): 53-56. PMID- 26435649 TI - In vitro subminimum inhibitory concentrations of macrolide antibiotics induce macrolide resistance in Mycoplasma pneumoniae. AB - AIM: This study aims to investigate the inducing effect of subminimum inhibitory concentrations of macrolide antibiotics on Mycoplasma pneumoniae (M. pneumoniae) resistance to drugs. MATERIALS AND METHODS: One M. pneumoniae reference strain M129 (ATCC 29342) and 104 clinical isolates were incubated at 37C for 6-8 days. Genomic DNA of M. pneumoniae was extracted using TIANamp Bacteria DNA kit and amplified by polymerase chain reaction (PCR). RESULTS: Ten sensitive isolates obtained from 104 M. pneumoniae clinical isolates were induced by subminimum inhibitory concentrations of macrolide antibiotics. Among them, three were found to possess mutations in L4 and L22 ribosomal proteins. Two cases carried simultaneously the C162A and A430G mutations of L4 and the T279C mutation of L22. In addition, one case had only the A209T mutation of L4. CONCLUSIONS: Repeated in vitro exposure to subminimum inhibitory concentrations of macrolide antibiotics could induce selective mutations in ribosomal genes of M. pneumoniae clinical isolates that cause resistance to macrolide antibiotics. Hippokratia 2015, 19 (1): 57-62. PMID- 26435650 TI - Evaluation of children with juvenile idiopathic arthritis in southeastern Turkey: a single center experience. AB - BACKGROUND: The aim of this study was to investigate the disease characteristics of children with juvenile idiopathic arthritis (JIA) in southeast Turkey. METHODS: The International League of Associations for Rheumatology (ILAR) criteria were used to diagnose JIA. Hospital records of the Pediatric Rheumatology Unit, of the Dicle University Hospital, were reviewed retrospectively and demographic, clinical and laboratory data were recorded. RESULTS: Totally 213 children (103 boys, 110 girls), with an age range of 1.6-18 years were enrolled. The mean age of the disease onset was 8.1 years. Polyarticular type was the most common (42.3%) presentation. The frequencies of other JIA subtypes were as follows: oligoarticular 37.1%, systemic 8.9%, enthesitis-related arthritis (ERA) 10.8% and psoriatic arthritis 0.9%. The knees (74.2%) and ankles (54.0%) were the most commonly affected joints. Uveitis was found in 4.2% of patients. Anti-nuclear antibodies were positive in 11.7% and HLA B27 in 2.8% of patients. Active disease was seen in 57 (26.7%) patients at the last visit. CONCLUSION: In the present study, polyarticular JIA was the predominant subtype and there were fewer patients with positive ANA or uveitis compared to previous studies. Hippokratia 2015, 19 (1): 63-68. PMID- 26435651 TI - The role of gasless laparoscopy in differential diagnosis of acute abdomen. AB - BACKGROUND: The diagnosis of acute abdomen in the emergency setting, still remains a challenging problem. In these cases timely diagnosis and management is of great importance, while the anesthetic risk is high. The combination of the risk of an open laparotomy and the relative high likelihood of negative findings when performed, creates the need for a better approach. The alternative actually exists since 1911 when Eruheim made the first gasless laparoscopy. The aim of this study is to put back into the spotlight, gasless laparoscopy in the differential diagnosis of acute abdomen and to underline the advantages of this simple, cheap and very useful technique, especially in patients that require prompt diagnosis and have relative or absolute contraindications to general anesthesia or pneumoperitoneum. METHODS: This study included 49 patients that were managed with gasless laparoscopy for the diagnosis of acute abdomen, from 2011 to 2013. Two techniques were used: the mechanical lift of the anterior abdominal wall and the LapVision device. RESULTS: From the 49 patients included in the study, 41 were diagnosed with gasless laparoscopy while in eight the results were uncertain or there wasn't any pathology involved. With both techniques used, sample of the intraperitoneal fluid or biopsy could be obtained. CONCLUSION: The gasless technique for laparoscopy is an extremely useful mean of diagnosis in emergency conditions, or for patients with contraindications to undergo laparoscopy by pneumoperitoneum. Requiring only local or regional anesthesia, this technique could easily find application in diagnosis and treatment, while avoiding unnecessary laparotomies. Hippokratia 2015, 19 (1): 69 72. PMID- 26435652 TI - Surgical management of gastrointestinal stromal tumors: a single centre's experience. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) represent 85% of all mesenchymal neoplasms that affect the gastrointestinal track. Aim of this study is to report a case series of 18 GISTs treated surgically in a single centre and to discuss the diagnostic and therapeutic issues regarding these tumors. CASE SERIES: A retrospective search of the unit's medical records from 2002 to 2014 was carried out, to collect all cases diagnosed and treated for GISTs. Demographics and clinical features was obtained for all relevant cases. RESULTS: Eighteen cases (18) of GIST were identified. Eleven tumors were located in the stomach, 3 tumors in the duodenum and 4 tumors in the jejunum. The mean age at diagnosis was 62.5 (range 42-81) years, while the male to female ratio was 1.57/1 (11 males/7 females). Patients presented with a variety of symptoms and all underwent surgery. The 5-year-survival rate of these patients was 50%. CONCLUSION: Due to non-specific presentation of GISTs, initial diagnosis of these tumors may be delayed. High clinical suspicion and knowledge of their characteristics are essentials in order to achieve an early diagnosis and lead patients to surgery as soon as possible. Hippokratia 2015, 19 (1): 73-75. PMID- 26435653 TI - Symptomatic cervical perineural (Tarlov) cyst: a case report. AB - BACKGROUND: Perineural (Tarlov) cysts are benign, usually asymptomatic, cerebrospinal fluid filled cysts of the spine, most often found in the sacral region. DESCRIPTION OF CASE: We report a Tarlov cyst, located in the cervical spine, in a 44-year-old woman who presented with a 3-week history of radicular symptoms of the right C6 root. The perineural cyst was identified at the C5-C6 level following magnetic resonance imaging of the cervical spine. A conservative approach was chosen, with the use of a soft cervical collar for two weeks, a 15 day-course of oral non-steroidal anti-inflammatory medication and instructions concerning limitation of her activities. The outcome of this approach was 90% improvement of her symptoms 24 months after her diagnosis. CONCLUSION: This is the first report of a cervical Tarlov cyst treated conservatively without the use of oral or injected steroids. The perineural cyst should be included in the differential diagnosis of patients presenting with radicular symptoms. Hippokratia 2015, 19 (1): 76-77. PMID- 26435654 TI - Hypercalcemia and multiple osteolytic lesions in an adult patient with relapsed pre-B acute lymphoblastic leukemia: a case report. AB - BACKGROUND: Hypercalcemia and severe osteolytic lesions are rare complications of acute lymphoblastic leukemia (ALL) in childhood, and those cases share similar clinical features. Similarly, hypercalcemia is a rare feature in adult ALL. Here, we report an uncommon case of an adult patient with relapsed precursor B ALL (pre B ALL) who developed multiple osteolytic lesions and hypercalcemia. CASE DESCRIPTION: A 24-year-old male patient, diagnosed with pre-B ALL, was admitted in our hospital due to severe lumbar pain. After reviewing laboratory, radiological and clinical findings, the patient was diagnosed as having relapse of a mixed phenotype acute leukemia, according to bone marrow aspiration (9% blasts) and cytogenetic analysis, with multiple osteolytic lesions in all lumbar vertebrae, sacrum and ilium and severe hypercalcemia (13.3 mg/dL). Thus, FLAG-IDA rescue therapy and hydration plus furosemide, corticoids and bisphosphonates were administered. Despite initial amelioration, his hematological condition deteriorated and he died due to severe sepsis as a result of severe immunosuppression. CONCLUSION: Two possible mechanisms have been suggested for hypercalcemia in hematological malignancy, either the leukemic infiltration or the paraneoplastic production of a variety of humoral factors and proinflammatory cytokines. However, hypercalcemia and severe osteolytic lesions are rare features in ALL adult patients and their combination may be indicator of poor prognosis. Hippokratia 2015, 19 (1): 78-81. PMID- 26435655 TI - Ewing's sarcoma of the proximal phalanx of the foot: A rare case report. AB - BACKGROUND: Ewing's sarcoma localized to foot is extremely rare. Local control is mandatory because of the aggressive nature of the tumor. Therapeutic options for these local tumors include neoadjuvant chemotherapy followed by surgery. DESCRIPTION OF THE CASE: A 17-year-old female patient presented with a 6-month history of progressive swelling and intermittent pain of the left great toe. Plain radiography and magnetic resonance imaging revealed an expansile mass that had originated from the proximal phalanx of the great toe and was destructing and surrounding the distal phalanx. Her erythrocyte sedimentation rate and serum lactate dehydrogenase levels were slightly elevated. Distant metastasis was not detected. The patient underwent an open biopsy, which confirmed the diagnosis of Ewing's sarcoma. She was treated with neoadjuvant chemotherapy and disarticulation above the metatarsophalangeal joint. She received adjuvant chemotherapy following the operation. The patient died 50 months after the operation as a result of disseminated disease. CONCLUSION: The distal phalanx of the foot is an extremely rare site for the development of Ewing's sarcoma. As local control is important to avoid dissemination of the disease, neoadjuvant chemotherapy followed by amputation or disarticulation of the affected digit and subsequently adjuvant chemotherapy may be favorable modality for increasing the patient's duration of survival. Hippokratia 2015, 19 (1): 82-84. PMID- 26435656 TI - Anaplastic thyroid carcinoma presenting with gastric metastasis: a case report. AB - INTRODUCTION: Anaplastic thyroid carcinoma (ATC) has the most aggressive progression among thyroid malignancies. Most of the patients have metastasis, especially to the lungs, liver and regional lymph nodes, at the time of diagnosis. Gastrointestinal tract metastasis of ATC has been rarely reported. We report a case who presented with gastrointestinal bleeding and was diagnosed with ATC accompanied with gastric, skin, lung and adrenal gland metastases. CASE REPORT: A 72-year-old male patient presented with one month history of neck mass, weight loss and weakness and three-day-history of melena. On examination his thyroid gland was tender on palpation and hyperplasic, multiple, painful, solid, and fixed nodules were palpated.Ultrasonographic neck examination demonstrated an enlarged thyroid gland and multiple hypoechoic nodules including cystic degenerative areas; the largest 28 x 23 mm in size. Thyroid fine needle aspiration biopsy was performed and biopsy results indicated ATC. Gastroscopy, performed due to the gastrointestinal bleeding, detected a 4 x 6 mm polypoid lesion on sternal pili of the gastric cardia and histopathological examination of its biopsy demonstrated metastasis of ATC. CONCLUSION: We reported a case of ATC with gastric, skin, lung and adrenal gland metastases, initially presenting with gastrointestinal bleeding due to the gastric metastasis. Hippokratia 2015, 19 (1): 85-87. PMID- 26435657 TI - Synchronous adenocarcinoma and echinococcosis in the same ovary: a rare clinical entity. AB - BACKGROUND: Serous adenocarcinoma is the most common subtype of ovarian carcinoma, while ovarian echinococcosis is a rare disease of the female genital system. The simultaneous presence of adenocarcinoma and echinococcosis in the same ovary is extremely rare and little data exist regarding diagnosis and treatment approach. MATERIALS AND METHODS: In the present paper, we report a rare case of a 66-year-old Greek Caucasian woman of rural origin, with an adnexal mass, ascitic and pleural fluid. The patient underwent exploratory laparotomy following neoadjuvant chemotherapy, based on positive for malignancy pleural and ascitic fluid cytology results. RESULTS: Histological examination of the surgical specimen indicated the synchronous presence of echinococcosis and adenocarcinoma in the same ovary. CONCLUSIONS: Ovarian hydatid cyst is extremely rare, but should be suspected in patients with echinococcosis in other organs and those coming from endemic areas. Moreover, the disease could mimic ovarian cancer, as there are no specific symptoms and clinical signs. The coexistence of these two diseases in the same ovary, although rare, is possible. It seems that the presence of the hydatid cyst does not change the treatment approach of the malignancy so that surgery with neoadjuvant or adjuvant chemotherapy, according to the present guidelines, should be administered. Hippokratia 2015, 19 (1): 89 91. PMID- 26435658 TI - Paraproteinemia and central retinal vein occlusion. PMID- 26435659 TI - Post Kala Azar dermal leishmaniasis in a 15-month-old Greek boy. PMID- 26435660 TI - Sevoflurane induction of anesthesia for a large epiglottic cyst removal when awake intubation is not an option. PMID- 26435661 TI - A rare case of left inferior vena cava with azygous continuation and presence of the suprarenal segment of a right inferior vena cava. PMID- 26435662 TI - Urgent bedside appendectomy for drain site evisceration. PMID- 26435663 TI - Stickhandling my way to an unexpected career in academic paediatrics and research. PMID- 26435664 TI - Case 1: Cholestatic jaundice in an infant with Down syndrome. PMID- 26435665 TI - Case 2: Acute paralysis in a 10-year-old girl. PMID- 26435666 TI - Caring for children, focusing on children. AB - Two First Nations girls with leukemia received a significant amount of media attention in 2014 and 2015. In both cases, the parents refused to continue chemotherapy, the only proven effective treatment; they opted instead for a combination of traditional Aboriginal healing approaches and alternative therapies offered in a facility outside of the country. One child has died; the other relapsed and required chemotherapy to avoid death. Media reports were polarized, focusing either on the historical legacy of distrust felt by First Nations people when accessing health care, or the need for child protection services to intervene. One article in the Canadian Medical Association Journal focused on the legacy of mistrust and methods of countering it, but did not address the legal and ethical duties of physicians in such situations. The present commentary describes the events, responsibilities of professionals involved and a course of action for physicians when faced with similar circumstances. PMID- 26435667 TI - Administration of inhaled gases at a temperature of 33.5 degrees C versus 37 degrees C for ventilated asphyxiated newborns undergoing therapeutic hypothermia. PMID- 26435668 TI - Using simplified blood pressure tables to avoid underdiagnosing childhood hypertension. AB - BACKGROUND: Recent studies have revealed that hypertension remains underdiagnosed in a significant number of children despite their recorded office blood pressure (OBP) exceeding the recommended fourth report OBP thresholds. Simplified OBP thresholds have been proposed to reduce this underdiagnosis of hypertension in children. In clinical practice, OBP screened as elevated according to the fourth report OBP thresholds are referred for ambulatory blood pressure (ABP) monitoring to rule out 'white coat' hypertension. OBJECTIVES: The present study tested the usefulness of simplified OBP thresholds to screen abnormal OBP for ABP monitoring referral. METHODS: A total of 155 subjects were retrospectively analyzed with paired OBP and ABP recordings obtained from an outpatient referral clinic. OBP recordings were classified as abnormal according to the simplified and fourth report OBP thresholds. ABP measurements were classified as abnormal according to the ABP reference tables. RESULTS: Simplified blood pressure (BP) tables correctly identified all OBP classified as abnormal according to fourth report BP thresholds (kappa [kappa] 0.72 [95% CI 0.61 to 0.83]) for systolic OBP; kappa 0.92 [95% CI 0.86 to 0.99] for diastolic OBP). OBP classified as abnormal by the simplified BP thresholds and by the fourth report BP thresholds performed similarly for correctly identifying abnormal ABP measurements as per ABP references (overlapping 95% CIs of the sensitivity, specificity and predictive values and likelihood ratios). CONCLUSIONS: Simplified BP tables, proposed to reduce the underdiagnosis of hypertension in children, can serve as a useful screening tool to decide a referral for ABP monitoring. Future prospective studies are needed to establish these findings. PMID- 26435670 TI - Interventions for congenital talipes equinovarus (clubfoot). PMID- 26435669 TI - Risk factors, practice variation and hematological outcomes of children identified with non-anemic iron deficiency following screening in primary care setting. AB - OBJECTIVES: To determine the prevalence, risk factors, physician practice patterns and longitudinal hematological outcome of children following screening for non-anemic iron deficiency (NAID). METHODS: The present analysis was a longitudinal cohort study invovling healthy children one to five years of age. Descriptive statistics were used to describe the prevalence, risk factors, practice patterns and hematological outcome of children identified with NAID. The association between NAID and potential risk factors were examined using multivariate logistic regression analysis. RESULTS: Of 2276 children undergoing screening, 155 had NAID, corresponding to a prevalence of 7% (95% CI 5.95% to 8.05%). Risk factors significantly associated with NAID included: younger age (OR 1.08 [95% CI 1.06 to 1.11]), higher body mass index z-score (OR 1.22 [95% CI 1.01 to 1.48]), longer duration of breastfeeding (OR 1.05 [95% CI 1.01 to 1.08]) and increased volume of cow's milk intake (OR 1.13 [95% CI 1.01 to 1.26]). An assessment of practice patterns revealed that for 37% of children, an intervention for NAID was documented; and for 8.4% a physician-ordered follow-up laboratory test was completed to re-evaluate iron status. A total of 58 (37%) children underwent a follow-up laboratory test, of whom 38 (65.5%) had resolution of NAID, 15 (25.9%) had persistence of NAID and two (3.4%) had progression of NAID to anemia. CONCLUSION: NAID is common in early childhood and is associated with modifiable risk factors. Substantial practice variation exists in the management of NAID. Further research is necessary to understand the benefits of screening for NAID and evidence-informed practice guidelines may reduce practice variation in the management of NAID in early childhood. PMID- 26435671 TI - Acute flaccid paralysis surveillance: The need for ruling out polio infection. PMID- 26435672 TI - Newborn male circumcision. AB - The circumcision of newborn males in Canada has become a less frequent practice over the past few decades. This change has been significantly influenced by past recommendations from the Canadian Paediatric Society and the American Academy of Pediatrics, who both affirmed that the procedure was not medically indicated. Recent evidence suggesting the potential benefit of circumcision in preventing urinary tract infection and some sexually transmitted infections, including HIV, has prompted the Canadian Paediatric Society to review the current medical literature in this regard. While there may be a benefit for some boys in high risk populations and circumstances where the procedure could be considered for disease reduction or treatment, the Canadian Paediatric Society does not recommend the routine circumcision of every newborn male. PMID- 26435674 TI - Corrigendum. AB - [This corrects the article on p. 237 in vol. 20, PMID: 26175558.]. PMID- 26435673 TI - Preventing hospitalizations for respiratory syncytial virus infection. AB - Respiratory syncytial virus infection is the leading cause of lower respiratory tract infections in young children. Palivizumab has minimal impact on RSV hospitilization rates as it is only practical to offer it to the highest risk groups. The present statement reviews the published literature and provides updated recommendations regarding palivizumab use in children in Canada. PMID- 26435675 TI - Accuracy of a new clean-catch technique for diagnosis of urinary tract infection in infants younger than 90 days of age. AB - OBJECTIVE: To evaluate the accuracy of diagnosing urinary tract infections using a new, recently described, standardized clean-catch collection technique. METHODS: Cross-sectional study of infants <90 days old admitted due to fever without a source, with two matched samples of urine obtained using two different methods: clean-catch standardized stimulation technique and bladder catheterization. RESULTS: Sixty paired urine cultures were obtained. The median age was 44-days-old. Seventeen percent were male infants. Clean-catch technique sensitivity was 97% (95% CI 82% to 100%) and specificity was 89% (95% CI 65% to 98%). The contamination rate of clean-catch samples was lower (5%) than the contamination rate of catheter specimens (8%). CONCLUSIONS: The sensitivity and specificity of urine cultures obtained using the clean-catch method through the new technique were accurate and the contamination rate was low. These results suggest that this technique is a valuable, alternative method for urinary tract infection diagnosis. PMID- 26435676 TI - Cognitive and motor function of neurologically impaired extremely low birth weight children. AB - BACKGROUND: Rates of neurological impairment among extremely low birth weight children (ELBW [<1 kg]) have decreased since 2000; however, their functioning is unexamined. OBJECTIVE: To compare motor and cognitive functioning of ELBW children with neurological impairment, including cerebral palsy and severe hypotonia/hypertonia, between two periods: 1990 to 1999 (n=83) and 2000 to 2005 (n=34). METHODS: Measures of function at 20 months corrected age included the Mental and Psychomotor Developmental Indexes of the Bayley Scales of Infant Development and the Gross Motor Functional Classification System as primary outcomes and individual motor function items as secondary outcomes. RESULTS: Analysis failed to reveal significant differences for the primary outcomes, although during 2000 to 2005, sitting significantly improved in children with neurological impairment (P=0.003). CONCLUSION: Decreases in rates of neurological impairment among ELBW children have been accompanied by a suggestion of improved motor function, although cognitive function has not changed. PMID- 26435679 TI - OXIDATIVE STRESS IN HUMAN LEUKEMIA (HL-60), HUMAN LIVER CARCINOMA (HepG2), AND HUMAN (JURKAT-T) CELLS EXPOSED TO ARSENIC TRIOXIDE. AB - Recent studies have shown that arsenic trioxide can induce a clinical remission in patients with acute promyelocytic leukemia. However, the molecular mechanisms of action remain to be elucidated. In this research, we performed the MTT assay to evaluate the cytotoxic effects of arsenic trioxide (ATO) to HL-60 cells and to compare their relative sensitivity to that of HepG2, and Jurkat T cells. We also performed the thiobarbituric acid test to determine the levels of malondialdehyde (MDA) plus 4-hydroxy-2 (E)-nonenal (4-HAE) production in these three cell lines following exposure to arsenic trioxide. The result of MTT assay clearly demonstrated that ATO has a significant cytotoxic effect on HL-60, Jurkat, and HepG2 cells; showing 24 hrs LD50 values of 6.4 +/- 0.6 MUg/mL, 15 +/- 3.84 MUg/mL, and 23.2 +/- 6.03 MUg/mL, respectively. These data indicated that HL-60 cells are about twice as sensitive to arsenic toxicity compared to Jurkat T cells and about 3 times more sensitive to arsenic trioxide compared to HepG2 cells. The result of the thiobarbituric acid test demonstrated that arsenic trioxide treatment resulted in a significant increase (p <0.05) of MDA and HAE production, indicating that oxidative stress plays a key role in arsenic induced toxicity and cell injury. MDA and HAE levels were significantly higher in arsenic trioxide treated HL-60 cells, indicating that these cells appear to be more sensitive to oxidative stress than HepG2 and Jurkat T- cells. In summary, these results indicate that the pharmacology of ATO as an effective anti-cancer drug is associated with its cytotoxic effects in human promyelocytic leukemic cells. This cytotoxicity is found to be mediated by oxidative stress, a biomarker of cellular injury. PMID- 26435680 TI - Population doubling level-dependent change of secreted glycosaminoglycan in equine bone marrow-derived mesenchymal stem cells. AB - In regenerative medicine using transplantation of mesenchymal stem cells (MSCs), the importance of regulating the quality of MSCs has been well recognized; however, there is little information concerning the relationship between the population doubling level (PDL) and the stemness of MSCs in equine medicine. In this study, we showed that the amount of glycosaminoglycan (GAG) secreted by bone marrow-derived MSCs (BMSCs) decreases with increase of PDL. Enzymatic digestion and two-dimensional electrophoresis revealed that a main component of GAG produced by BMSCs was hyaluronan with a small amount of chondroitin sulfate. Increase of PDL downregulated the expression of MSC CD markers, including CD44, CD73, CD90, CD105, and CD146, along with loss of differentiation capacity. Thus, the effect of hyaluronan supplement to the growth medium on both expression of CD markers and the tri-lineage potential of BMSCs was evaluated. Expression of CD73 and CD90 was preserved by continuous addition of hyaluronan to the growth medium, whereas mRNA levels corresponding to CD44, CD105 and CD146 were not preserved by supplementation of hyaluronan. BMSCs subcultured with hyaluronan-supplemented growth medium to PDL-12 showed osteogenic capacity, however adipogenic and chondrogenic activities at PDL-12 were not preserved by exogenous hyaluronan. These results suggest that downregulation of CD44, CD105 and CD146 might not affect the osteogenic capacity. Taken together, the results suggested that supplementation of hyaluronan to the growth medium might be effective at maintaining the osteogenic capacity of equine BMSCs. PMID- 26435681 TI - Experimental investigation of bone mineral density in Thoroughbreds using quantitative computed tomography. AB - Bone mineral density (BMD) is one of the indications of the strength and health. BMD measured by quantitative computed tomography (QCT) was compared with that measured by dual energy X-ray absorptiometry (DXA) and radiographic bone aluminum equivalence (RBAE). Limbs were removed from horses that had been euthanized for reasons not associated with this study. Sixteen limbs (left and right metacarpals and metatarsals) from 4 horses were used to compare BMD as measured by QCT with those measured by DXA and RBAE. There was a strong correlation between BMD values measured by QCT and those measured by DXA (R(2)=0.85); correlation was also observed between values obtained by QCT and those obtained by RBAE (R(2)=0.61). To investigate changes in BMD with age, 37 right metacarpal bones, including 7 from horses euthanized because of fracture were examined by QCT. The BMD value of samples from horses dramatically increased until 2 years of age and then plateaued, a pattern similar to the growth curve. The BMD values of bone samples from horses euthanized because of fracture were within the population range, and samples of morbid fracture were not included. The relationship between BMD and age provides a reference for further quantitative studies of bone development and remodeling. Quantitative measurement of BMD using QCT may have great potential for the evaluation of bone biology for breeding and rearing management. PMID- 26435682 TI - Presumed monozygotic twins develop following transfer of an in vitro-produced equine embryo. AB - An equine embryo produced by intracytoplasmic sperm injection (ICSI) was trans cervically transferred to a recipient mare and pregnancy was confirmed via ultrasound examination on days 11, 12 and 15. On days 20 and 22, a single embryonic proper with a heartbeat was observed. On day 29, two embryos proper appeared during ultrasound examination, each possessing a heartbeat. Subsequent examinations on days 35 and 39 revealed continued viability and development of both embryos proper. On day 49, demise of both fetuses was present. Although no DNA analysis or post-partum examinations were performed, it is presumed that the fetuses were monozygotic twins based on membrane classification by ultrasound imaging as well as development occurring after the transfer of a single in vitro produced embryo. PMID- 26435683 TI - Methicillin-resistant Staphylococcus aureus ulcerative keratitis in a Thoroughbred racehorse. AB - We report the first case of methicillin-resistant Staphylococcus aureus (MRSA) keratitis in a racehorse. A 5-year-old mare developed punctate keratitis after racing. The corneal ulcer continued to expand despite ophthalmic antimicrobial therapy. On day 6, a conjunctival graft surgery was performed. The mare was euthanized, following colitis and laminitis development on day 10. MRSA was isolated from the corneal swab taken at the time of euthanasia. Immunohistochemical analysis demonstrated gram-positive and anti-S. aureus monoclonal antibody-positive cocci infiltration of the corneal stroma; and a diagnosis of MRSA ulcerative keratitis was made. An ophthalmic antimicrobial against the isolated MRSA did not improve the ocular lesion. The MRSA strain was found to be staphylococcal cassette chromosome mec type II, a strain frequently isolated from humans in Japan. PMID- 26435684 TI - Improving spatial nitrogen dioxide prediction using diffusion tubes: A case study in West Central Scotland. AB - It has been well documented that air pollution adversely affects health, and epidemiological pollution-health studies utilise pollution data from automatic monitors. However, these automatic monitors are small in number and hence spatially sparse, which does not allow an accurate representation of the spatial variation in pollution concentrations required for these epidemiological health studies. Nitrogen dioxide (NO2) diffusion tubes are also used to measure concentrations, and due to their lower cost compared to automatic monitors are much more prevalent. However, even combining both data sets still does not provide sufficient spatial coverage of NO2 for epidemiological studies, and modelled concentrations on a regular grid from atmospheric dispersion models are also available. This paper proposes the first modelling approach to using all three sources of NO2 data to make fine scale spatial predictions for use in epidemiological health studies. We propose a geostatistical fusion model that regresses combined NO2 concentrations from both automatic monitors and diffusion tubes against modelled NO2 concentrations from an atmospheric dispersion model in order to predict fine scale NO2 concentrations across our West Central Scotland study region. Our model exhibits a 47% improvement in fine scale spatial prediction of NO2 compared to using the automatic monitors alone, and we use it to predict NO2 concentrations across West Central Scotland in 2006. PMID- 26435685 TI - Substrate Topography Guides Pore Morphology Evolution in Nanoporous Gold Thin Films. AB - This paper illustrates the effect of substrate topography on morphology evolution in nanoporous gold (np-Au) thin films. One micron-high silicon ridges with widths varying between 150 nm to 50 um were fabricated and coated with 500 nm-thick np Au films obtained by dealloying sputtered gold-silver alloy films. Analysis of scanning electron micrographs of the np-Au films following dealloying and thermal annealing revealed two distinct regimes where the ratio of film thickness to ridge width determines the morphological evolution of np-Au films. PMID- 26435686 TI - Enhancing imagined contact to reduce prejudice against people with schizophrenia. AB - Four studies investigated the effect of imagining intergroup contact on prejudice against people with schizophrenia. Experiments 1 and 2 demonstrated that a neutral imagined contact task can have negative effects, compared to a control condition, even when paired with incidental positive information (Experiment 2). Experiments 3 and 4 demonstrated, however, that an integrated positive imagined contact scenario does result in less intergroup anxiety and more positive attitudes, even toward this challenging group. Analyses of participants' descriptions of the imagined interactions in and across the first three studies confirm that positive and high quality imagined contact is important for reducing prejudice, but failing to ensure that imagined contact is positive may have deleterious consequences. We emphasize the importance of investigating the quality of the imagined contact experience, and discuss the implications for using imagined contact as a prejudice-reducing intervention. PMID- 26435687 TI - Good's buffers as novel phase-forming components of ionic-liquid-based aqueous biphasic systems. AB - Aiming at the development of self-buffering and benign extraction/separation processes, this work reports a novel class of aqueous biphasic systems (ABS) composed of ionic liquids (ILs) and organic biological buffers (Good's buffers, GBs). A large array of ILs and GBs was investigated, revealing than only the more hydrophobic and fluorinated ILs are able to form ABS. For these systems, the phase diagrams, tie-lines, tie-line lengths, and critical points were determined at 25 degrees C. The ABS were then evaluated as alternative liquid-liquid extraction strategies for two amino acids (L-phenylalanine and L-tryptophan). The single-step extraction efficiencies for the GB-rich phase range between 22.4 and 100.0 % (complete extraction). Contrarily to the most conventional IL-salt ABS, in most of the systems investigated, the amino acids preferentially migrate for the most biocompatible and hydrophilic GB-rich phase. Remarkably, in two of the studied ABS, L-phenylalanine completely partitions to the GB-rich phase while L tryptophan shows a preferential affinity for the opposite phase. These results show that the extraction efficiencies of similar amino acids can be tailored by the design of the chemical structures of the phase-forming components, creating thus new possibilities for the use of IL-based ABS in biotechnological separations. PMID- 26435688 TI - Perspectives on the design of safer nanomaterials and manufacturing processes. AB - A concerted effort is being made to insert Prevention through Design principles into discussions of sustainability, occupational safety and health, and green chemistry related to nanotechnology. Prevention through Design is a set of principles that includes solutions to design out potential hazards in nanomanufacturing including the design of nanomaterials, and strategies to eliminate exposures and minimize risks that may be related to the manufacturing processes and equipment at various stages of the lifecycle of an engineered nanomaterial. PMID- 26435689 TI - Constraints on tensor and scalar couplings from [Formula: see text] and [Formula: see text]. AB - The angular distribution of [Formula: see text] ([Formula: see text]) depends on two parameters, the lepton forward-backward asymmetry, [Formula: see text], and the flat term, [Formula: see text]. Both are strongly suppressed in the standard model and constitute sensitive probes of tensor and scalar contributions. We use the latest experimental results for [Formula: see text] in combination with the branching ratio of [Formula: see text] to derive the strongest model-independent bounds on tensor and scalar effective couplings to date. The measurement of [Formula: see text] provides a complementary constraint to that of the branching ratio of [Formula: see text] and allows us - for the first time - to constrain all complex-valued (pseudo-)scalar couplings and their chirality-flipped counterparts in one fit. Based on Bayesian fits of various scenarios, we find that our bounds even become tighter when vector couplings are allowed to deviate from the standard model and that specific combinations of angular observables in [Formula: see text] are still allowed to be up to two orders of magnitude larger than in the standard model, which would place them in the region of LHCb's sensitivity. PMID- 26435690 TI - Adapted Resistance to the Knockdown Effect of shRNA-Derived Srsf3 siRNAs in Mouse Littermates. AB - Gene silencing techniques are widely used to control gene expression and have potential for RNAi-based therapeutics. In this report, transgenic mouse lines were created for conditional knockdown of Srsf3 (SRp20) expression in liver and mammary gland tissues by expressing Srsf3-specific shRNAs driven by a U6 promoter. Although a small portion of the transgenic mouse littermates were found to produce siRNAs in the targeted tissues, most of the transgenic littermates at two months of age failed to display a knockdown phenotype of Srsf3 expression in their liver and mammary gland tissues where an abundant level of Srsf3 siRNAs remained. We saw only one of four mice with liver/mammary gland expressing Srsf3 siRNA displayed a suppressed level of Srsf3 protein, but not the mRNA. Data indicate that the host resistance to a gene-specific siRNA targeting an essential gene transcript can be developed in animals, presumably as a physiological necessity to cope with the hostile perturbation. PMID- 26435692 TI - Serum C3 Enhances Complement Receptor 3-Mediated Phagocytosis of Borrelia burgdorferi. PMID- 26435691 TI - NF-kappaB-DICER-miRs Axis Regulates TNF-alpha Expression in Responses to Endotoxin Stress. AB - Unbalanced tumor necrosis factor (TNF)-alpha production is associated with pathogenesis of a variety of human diseases. However, the molecular pathways maintaining TNF-alpha homeostasis remain elusive. Here, we report that NF kappaB/p65-DICER-miRs axis negatively regulates TNF-alpha production. We demonstrated that NF-kappaB bound to DICER promoter and transcriptionally regulated DICER expression. In addition, the NF-kappaB/DICER signaling suppresses TNF-alpha expression by generating mature forms of miR-125b and miR-130a which negatively regulate TNF-alpha mRNA. Furthermore, we showed that the hepatocyte specific depletion of Dicer in mice resulted in TNF-alpha overproduction and sensitized the mice to endotoxin, which could be corrected by administration of miR-125b mimics. These data suggest that NF-kappaB/p65-DICER-miRs axis involved in maintaining of TNF-alpha homeostasis, and injection of miR-125b as a potential therapeutic method for septic shock. PMID- 26435693 TI - AICAR and Metformin Exert AMPK-dependent Effects on INS-1E Pancreatic beta-cell Apoptosis via Differential Downstream Mechanisms. AB - The role of AMP-activated protein kinase (AMPK) in pancreatic beta-cell apoptosis is still controversial, and the reasons for the discrepancies have not been clarified. In the current study, we observed the effects of two well-known AMPK activators 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and metformin, on apoptosis in rat insulinoma INS-1E cells, and further explored their possible mechanisms. Both AICAR and metformin protected INS-1E cells from palmitate induced apoptosis, as reflected by decreases in both cleaved caspase 3 protein expression and caspase 3/7 activity, and these protective effects were abrogated by AMPK inhibitor compound C. The protective action of AICAR was probably mediated by the suppression of triacylglycerol accumulation, increase in Akt phosphorylation and decrease in p38 MAPK phosphorylation, while metformin might exert its protective effect on INS-1E cells by decreases in both JNK and p38 MAPK phosphorylation. All these regulations were dependent on AMPK activation. However, under standard culture condition, AICAR increased JNK phosphorylation and promoted INS-1E cell apoptosis in an AMPK-dependent manner, whereas metformin showed no effect on apoptosis. Our study revealed that AMPK activators AICAR and metformin exhibited different effects on INS-1E cell apoptosis under different culture conditions, which might be largely attributed to different downstream mediators. Our results provided new and informative clues for better understanding of the role of AMPK in beta-cell apoptosis. PMID- 26435694 TI - Structure-Based Analysis of the Ligand-Binding Mechanism for DhelOBP21, a C-minus Odorant Binding Protein, from Dastarcus helophoroides (Fairmaire; Coleoptera: Bothrideridae). AB - Odorant binding proteins (OBPs) transport hydrophobic odor molecules across the sensillar lymph to trigger a neuronal response. Herein, the Minus-C OBP (DhelOBP21) was characterized from Dastarcus helophoroides, the most important natural parasitic enemy insect that targets Monochamus alternatus. Homology modeling and molecular docking were conducted on the interaction between DhelOBP21 and 17 volatile molecules (including volatiles from pine bark, the larva of M. alternatus, and the faeces of the larva). The predicted three dimensional structure showed only two disulfide bridges and a hydrophobic binding cavity with a short C-terminus. Ligand-binding experiments using N phenylnaphthylamine (1-NPN) as a fluorescent probe showed that DhelOBP21 exhibited better binding affinities against those ligands with a molecular volume between 100 and 125 A(3) compared with ligands with a molecular volume between 160 and 185 A(3). Molecules that are too big or too small are not conducive for binding. We mutated the amino acid residues of the binding cavity to increase either hydrophobicity or hydrophilia. Ligand-binding experiments and cyber molecular docking assays indicated that hydrophobic interactions are more significant than hydrogen-bonding interactions. Although hydrogen-bond interactions could be predicted for some binding complexes, the hydrophobic interactions had more influence on binding following hydrophobic changes that affected the cavity. The orientation of ligands affects binding by influencing hydrophobic interactions. The binding process is controlled by multiple factors. This study provides a basis to explore the ligand-binding mechanisms of Minus-C OBP. PMID- 26435695 TI - Transgenic Cotton Plants Expressing Double-stranded RNAs Target HMG-CoA Reductase (HMGR) Gene Inhibits the Growth, Development and Survival of Cotton Bollworms. AB - RNA interference (RNAi) has been developed as a powerful technique in the research of functional genomics as well as plant pest control. In this report, double-stranded RNAs (dsRNA) targeting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) gene, which catalyze a rate-limiting enzymatic reaction in the mevalonate pathway of juvenile hormone (JH) synthesis in cotton bollworm, was expressed in cotton plants via Agrobacterium tumefaciens-mediated transformation. PCR and Sothern analysis revealed the integration of HMGR gene into cotton genome. RT-PCR and qRT-PCR confirmed the high transcription level of dsHMGR in transgenic cotton lines. The HMGR expression both in transcription and translation level was significantly downregulated in cotton bollworms (helicoverpa armigera) larvae after feeding on the leaves of HMGR transgenic plants. The transcription level of HMGR gene in larvae reared on transgenic cotton leaves was as much as 80.68% lower than that of wild type. In addition, the relative expression level of vitellogenin (Vg, crucial source of nourishment for offspring embryo development) gene was also reduced by 76.86% when the insect larvae were fed with transgenic leaves. The result of insect bioassays showed that the transgenic plant harboring dsHMGR not only inhibited net weight gain but also delayed the growth of cotton bollworm larvae. Taken together, transgenic cotton plant expressing dsRNAs successfully downregulated HMGR gene and impaired the development and survival of target insect, which provided more option for plant pest control. PMID- 26435696 TI - Temporal Gene Expression Profiles of Pre Blood-Fed Adult Females Immediately Following Eclosion in the Southern House Mosquito Culex Quinquefasciatus. AB - Prior to acquisition of the first host blood meal, the anautogenous mosquito Culex quinquefasciatus requires a period of time in order to prepare for the blood feeding and, later, vitellogenesis. In the current study, we conducted whole transcriptome analyses of adult female Culex mosquitoes to identify genes that may be necessary for both taking of the blood meal, and processing of the blood meal in adult female mosquitoes Cx. quinquefasciatus. We examined temporal expression of genes for the periods of post eclosion and prior to the female freely taking a blood meal. We further evaluated the temporal expression of certain genes for the periods after the taking of a blood meal to identify genes that may be necessary for both the taking of the blood meal, and the processing of the blood meal. We found that adult females required a minimum of 48 h post eclosion before they freely took their first blood meal. We hypothesized that gene expression signatures were altered in the mosquitoes before blood feeding in preparation for the acquisition of the blood meal through changes in multiple gene expression. To identify the genes involved in the acquisition of blood feeding, we quantified the gene expression levels of adult female Cx. quinquefasciatus using RNA Seq throughout a pre-blooding period from 2 to 72 h post eclosion at 12 h intervals. A total of 325 genes were determined to be differentially-expressed throughout the pre-blooding period, with the majority of differentially-expressed genes occurring between the 2 h and 12 h post-eclosion time points. Among the up-regulated genes were salivary proteins, cytochrome P450s, odorant-binding proteins, and proteases, while the majority of the down regulated genes were hypothetical or cuticular genes. In addition, Trypsin was found to be up-regulated immediately following blood feeding, while trypsin and chymotrypsin were up-regulated at 48 h and 60 h post blood-feeding, respectively, suggesting that these proteases are likely involved in the digestion of the blood meal. Overall, this study reviewed multiple genes that might be involved in the adult female competency for blood meal acquisition in mosquitoes. PMID- 26435697 TI - Interaction mechanisms and kinetics of ferrous ion and hexagonal birnessite in aqueous systems. AB - BACKGROUND: In soils and sediments, manganese oxides and oxygen usually participate in the oxidation of ferrous ions. There is limited information concerning the interaction process and mechanisms of ferrous ions and manganese oxides. The influence of air (oxygen) on reaction process and kinetics has been seldom studied. Because redox reactions usually occur in open systems, the participation of air needs to be further investigated. RESULTS: To simulate this process, hexagonal birnessite was prepared and used to oxidize ferrous ions in anoxic and aerobic aqueous systems. The influence of pH, concentration, temperature, and presence of air (oxygen) on the redox rate was studied. The redox reaction of birnessite and ferrous ions was accompanied by the release of Mn2+ and K+ ions, a significant decrease in Fe2+ concentration, and the formation of mixed lepidocrocite and goethite during the initial stage. Lepidocrocite did not completely transform into goethite under anoxic condition with pH about 5.5 within 30 days. Fe2+ exhibited much higher catalytic activity than Mn2+ during the transformation from amorphous Fe(III)-hydroxide to lepidocrocite and goethite under anoxic conditions. The release rates of Mn2+ were compared to estimate the redox rates of birnessite and Fe2+ under different conditions. CONCLUSIONS: Redox rate was found to be controlled by chemical reaction, and increased with increasing Fe2+ concentration, pH, and temperature. The formation of ferric (hydr)oxides precipitate inhibited the further reduction of birnessite. The presence of air accelerated the oxidation of Fe2+ to ferric oxides and facilitated the chemical stability of birnessite, which was not completely reduced and dissolved after 18 days. As for the oxidation of aqueous ferrous ions by oxygen in air, low and high pHs facilitated the formation of goethite and lepidocrocite, respectively. The experimental results illustrated the single and combined effects of manganese oxide and air on the transformation of Fe2+ to ferric oxides. Graphical abstract:Lepidocrocite and goethite were formed during the interaction of ferrous ion and birnessite at pH 4-7. Redox rate was controlled by the adsorption of Fe2+ on the surface of birnessite. The presence of air (oxygen) accelerated the oxidation of Fe2+ to ferric oxides and facilitated the chemical stability of birnessite. PMID- 26435698 TI - Swedish student nurses' perception of peer learning as an educational model during clinical practice in a hospital setting-an evaluation study. AB - BACKGROUND: Peer learning, a collaborative learning model has no tradition in clinical education for undergraduate student nurses in Sweden, and little is reported of the student experience. An increasing number of students have led to a pressing need for preceptors and clinical placements thus, highlighting the need for a supportive educational model. The objectives for the current study were to explore how student nurses' evaluated peer learning as an educational model during clinical practice in a hospital setting, and to compare perceptions among student nurses from year one and three. METHODS: A questionnaire developed for the purpose of this study was developed and responded to by 62 (year one) and 73 (year three) student nurses. Data were collected between 2011 and 2013. The questionnaire contained six open- ended and eight closed questions on a four point Likert-scale. Written responses were analysed by content analysis and the closed questions by using descriptive statistics. Mann-Whitney U-test was used to examine differences in relation to students from year one and three. RESULTS: The peer learning experience was evaluated in a positive way. Statistical significance differences were shown for two out of eight closed questions. The peer learning activities were evaluated as supportive and relevant for learning. Three categories emerged from the content analysis: "a feeling of safety", "a sense of competition" and "the learning experience". CONCLUSION: A feeling of safety seems to be connected to students' perception of increased learning and independence. However, the sense of negative competition needs to be addressed when students are prepared for the teaching and learning activities in the peer learning model. Finally, what needs to be further investigated is what challenges and opportunities the peer learning model presents to preceptors. PMID- 26435699 TI - School holidays: examining childhood, gender norms, and kinship in children's shorter-term residential mobility in urban Zambia. AB - This article discusses a practice of child residential mobility in Zambia that is frequently overlooked in migration studies and difficult to capture through standard survey methods: the practice of 'going on holiday' to the homes of relatives during breaks in the school term. Drawing on child-centered and quantitative research, this article examines the multiple dimensions of 'going on holiday' for children living in a low-income urban settlement in Lusaka. Findings suggest that the practice was gendered and may map onto changing norms in schooling in Zambia. Within a context where resources are severely constrained, going on holiday may serve as one means for cultivating reciprocity, sharing the burden of care and household labor, and strengthening kin ties. This work further demonstrates the importance of using locally meaningful terms and practices in survey research where general questions about children's mobility may fail to capture the nature and extent of children's movements. PMID- 26435700 TI - Obesity-associated hypertension is ameliorated in patients with TLR4 single nucleotide polymorphism (SNP) rs4986790. AB - BACKGROUND: Obesity is strongly associated with hypertension. Despite numerous mechanistic links the association is not fully understood. Western diet increases uptake of Toll-Like receptor 4 (TLR4) ligands such as free fatty acids or endotoxin. We recently demonstrated that TLR4 ligands are involved in the development of hypertension. We hypothesized that TLR4 ligands are involved in obesity-associated hypertension and investigated the TLR4 single nucleotide polymorphism (SNP rs 498790). This SNP is frequent, associated with cardiovascular disease and characterized by blunted response upon exposure to TLR4 ligands. METHODS: We investigated 3657 patients undergoing coronary angiography. Blood pressure was determined in standardized manner prior angiography. The diagnosis of hypertension was based on record data. Patients were characterized for TLR4 single nucleotide polymorphism (SNP) rs4986790. Patients were stratified according to quartiles of Body mass index (BMI) and according to the polymorphism. The association between the TLR4 polymorphism and blood pressure in obese patients (BMI > 30 kg/m(2)) was investigated by multivariate regression analysis. RESULTS: Out of 3657 patients 3017 patients fulfilled inclusion criteria. In the whole cohort a significant increase of SBP, pulse pressure and diagnosis of hypertension was observed across BMI quartiles. By contrast, no significant increase of SBP, pulse pressure or diagnosis of hypertension was observed in the 319 cases with TLR4 SNP rs4986790 across BMI quartiles. These obese cases had significantly lower SBP, lower pulse pressure (7.0 and 7.6 mmHg) and less diagnosis of hypertension as controls. In obesity the TLR4 SNP rs4986790 was an independent predictor of SBP. CONCLUSION: Systolic blood pressure increase with obesity was blunted in cases with TLR4 SNP rs4986790. PMID- 26435701 TI - Role of genomics in eliminating health disparities. AB - The Texas Center for Health Disparities, a National Institute on Minority Health and Health Disparities Center of Excellence, presents an annual conference to discuss prevention, awareness education, and ongoing research about health disparities both in Texas and among the national population. The 2014 Annual Texas Conference on Health Disparities brought together experts in research, patient care, and community outreach on the "Role of Genomics in Eliminating Health Disparities." Rapid advances in genomics and pharmacogenomics are leading the field of medicine to use genetics and genetic risk to build personalized or individualized medicine strategies. We are at a critical juncture of ensuring such rapid advances benefit diverse populations. Relatively few forums have been organized around the theme of the role of genomics in eliminating health disparities. The conference consisted of three sessions addressing "Gene Environment Interactions and Health Disparities," "Personalized Medicine and Elimination of Health Disparities," and "Ethics and Public Policy in the Genomic Era." This article summarizes the basic science, clinical correlates, and public health data presented by the speakers. PMID- 26435702 TI - Validation of a new predictive risk model: measuring the impact of the major modifiable risks of death for patients and populations. AB - BACKGROUND: Modifiable risks account for a large fraction of disease and death, but clinicians and patients lack tools to identify high risk populations or compare the possible benefit of different interventions. METHODS: We used data on the distribution of exposure to 12 major behavioral and biometric risk factors inthe US population, mortality rates by cause, and estimates of the proportional hazards of risk factor exposure from published systematic reviews to develop a risk prediction model that estimates an adult's 10 year mortality risk compared to a population with optimum risk factors. We compared predicted risk to observed mortality in 8,241 respondents in NHANES 1988-1994 and NHANES 1999-2004 with linked mortality data up to the end of 2006. RESULTS: Predicted risk showed good discrimination with an area under the receiver operating characteristic (ROC) curve of 0.84 (standard error 0.01) for women and 0.84 (SE 0.01) for men. Across deciles of predicted risk, mortality was accurately predicted in men ((Chi (2) statistic = 12.3 for men, p=0.196) but slightly overpredicted in the highest decile among women (Chi (2) statistic = 22.8, p=0.002). Mortality risk was highly concentrated; for example, among those age 30-44 years, 5.1 % (95 % CI 4.1 % - 6.0 %) of the male and 5.9 % (95 % CI 4.8 % - 6.9 %) of the female population accounted for 25 % of the risk of death. CONCLUSION: The risk model accurately predicted mortality in a representative sample of the US population and could be used to help inform patient and provider decision-making, identify high risk groups, and monitor the impact of efforts to improve population health. PMID- 26435703 TI - Control of Assembly of Dihydropyridyl and Pyridyl Molecules via Directed Hydrogen Bonding. AB - The crystallization of two dihydropyridyl molecules, 1,4-bis(4-(3,5-dicyano-2,6 dipyridyl)dihydropyridyl)benzene ([C40H24N10].2DMF, 1.2DMF; DMF = dimethylformamide) and 1,4-bis(4-(3,5-dicyano-2,6 dipyridyl)dihydropyridyl)phenylbenzene ([C46H28N10].2DMF, 3.2DMF), and their respective oxidized pyridyl analogues, 1,4-bis(4-(3,5-dicyano-2,6 dipyridyl)pyridyl)benzene ([C40H20N10], 2) and 1,4-bis(4-(3,5-dicyano-2,6 dipyridyl)pyridyl)phenylbenzene ([C46H24N10].DMF, 4.DMF), has been achieved under solvothermal conditions. The dihydropyridyl molecules are converted to their pyridyl products via in situ oxidative dehydrogenation in solution. The structures of the four molecules have been fully characterized by single crystal and powder X-ray diffraction. The oxidized pyridyl products, 2 and 4, are more elongated due to aromatization of the dihydropyridyl rings at each end of their parent molecules 1 and 3, respectively. The solid-state supramolecular structures of the pyridyl molecules are distinct from the dihydropyridyl molecules in terms of their hierarchical assembly via hydrogen bonding due to the loss of primary N H hydrogen bond donors in the two electron oxidized tectons. Overall, the geometrically shorter molecules 1 and 3 display close-packed structures, whereas the more extended 2 and 4 assemble into more open supramolecular systems. PMID- 26435704 TI - Nontyphoidal Salmonella: An Occupational Hazard for Clinical Laboratory Workers. AB - Laboratory-acquired infections due to nontyphoidal Salmonella are rare. Yet, recent outbreaks in microbiology teaching laboratories show that these species are still an appreciable occupational hazard for laboratory employees. This article presents two cases of nontyphoidal Salmonella that occurred at the authors' institution-an infected patient and a clinical laboratory worker who acquired the infection by handling this patient's specimens. PMID- 26435705 TI - Histone post-translational modifications in frontal cortex from human donors with Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) is the sixth leading cause of death and the most costly disease in the US. Despite the enormous impact of AD, there are no treatments that delay onset or stop disease progression currently on the market. This is partly due to the complexity of the disease and the largely unknown pathogenesis of sporadic AD, which accounts for the vast majority of cases. Epigenetics has been implicated as a critical component to AD pathology and a potential "hot spot" for treatments. Histone post-translational modifications (PTMs) are a key element in epigenetic regulation of gene expression and are known to be associated with the pathology of numerous diseases. Investigation of histone PTMs can help elucidate AD pathology and identify targets for therapies. RESULTS: A multiple reaction monitoring mass spectrometry assay was used to measure changes in abundance of several histone PTMs in frontal cortex from human donors affected with AD (n = 6) and age-matched, normal donors (n = 6). Of the changes observed, notable decreases in methylation of H2B residue K108 by 25 % and H4 residue R55 by 35 % were measured and are likely associated with hydrogen bonding networks important for nucleosome stability. Additionally, a 91 % increase in ubiquitination of K120 on H2B was measured as well as an apparent loss in acetylation of the region near the N-terminus of H4. Our method of quantification was also determined to be precise and robust, signifying measured changes were representative of true biological differences between donors and sample groups. CONCLUSION: We are the first to report changes in methylation of H2B K108, methylation of H4 R55, and ubiquitination of H2B K120 in frontal cortex from human donors with AD. These notable PTM changes may be of great importance in elucidating the epigenetic mechanism of AD as it relates to disease pathology. Beyond the structural and functional impacts of the changes we have measured, the sites of altered PTMs may be used to identify enzymes responsible for their modulation, which could be used as prospective drug targets for highly specific AD therapies. PMID- 26435706 TI - Current approaches to cyanotoxin risk assessment and risk management around the globe. AB - Toxic cyanobacteria became more widely recognized as a potential health hazard in the 1990s, and in 1998 the World Health Organization (WHO) first published a provisional Guideline Value of 1 MUg L-1 for microcystin-LR in drinking-water. In this publication we compare risk assessment and risk management of toxic cyanobacteria in 17 countries across all five continents. We focus on the three main (oral) exposure vehicles to cyanotoxins: drinking-water, water related recreational and freshwater seafood. Most countries have implemented the provisional WHO Guideline Value, some as legally binding standard, to ensure the distribution of safe drinking-water with respect to microcystins. Regulation, however, also needs to address the possible presence of a wide range of other cyanotoxins and bioactive compounds, for which no guideline values can be derived due to insufficient toxicological data. The presence of microcystins (commonly expressed as microcystin-LR equivalents) may be used as proxy for overall guidance on risk management, but this simplification may miss certain risks, for instance from dissolved fractions of cylindrospermopsin and cyanobacterial neurotoxins. An alternative approach, often taken for risk assessment and management in recreational waters, is to regulate cyanobacterial presence - as cell numbers or biomass - rather than individual toxins. Here, many countries have implemented a two or three tier alert level system with incremental severity. These systems define the levels where responses are switched from Surveillance to Alert and finally to Action Mode and they specify the short-term actions that follow. Surface bloom formation is commonly judged to be a significant risk because of the elevated concentration of microcystins in a scum. Countries have based their derivations of legally binding standards, guideline values, maximally allowed concentrations (or limits named otherwise) on very similar scientific methodology, but underlying assumptions such as bloom duration, average body size and the amount of water consumed while swimming vary according to local circumstances. Furthermore, for toxins with incomplete toxicological data elements of expert judgment become more relevant and this also leads to a larger degree of variation between countries' thresholds triggering certain actions. Cyanobacterial blooms and their cyanotoxin content are a highly variable phenomenon, largely depending on local conditions, and likely concentrations can be assessed and managed best if the specific conditions of the locality are known and their impact on bloom occurrence are understood. Risk Management Frameworks, such as for example the Water Safety Plan concept of the WHO and the 'bathing water profile' of the European Union are suggested to be effective approaches for preventing human exposure by managing toxic cyanobacteria from catchment to consumer for drinking water and at recreational sites. PMID- 26435707 TI - Model of Polarization Selectivity of the Intermediate Filament Optical Channels. AB - Recently we have analyzed light transmission and spectral selectivity by optical channels in Muller cells and other transparent cells, proposing a model of their structure, formed by specialized intermediate filaments [1,2]. Our model represents each optical channel by an axially symmetric tube with conductive walls. Presently, we analyze the planar polarization selectivity in long nanostructures, using the previously developed approach extended to structures of the elliptic cross-section. We find that the output light polarization angle depends on the a/b ratio, with a and b the semiaxes of the ellipse. Experimental tests used a Cr nano-strip device to evaluate the transmitted light polarization. The model adapted to the experimental geometry provided an accurate fit of the experimental results. PMID- 26435708 TI - Natural infection of phlebotomines (Diptera: Psychodidae) by Leishmania (Leishmania) amazonensis in an area of ecotourism in Central-Western Brazil. AB - BACKGROUND: Bonito municipality, known as an area of ecoturism, in Mato Grosso do Sul state, Brazil, is also a focus of visceral and cutaneous leishmaniases, with cases registered in both human and canine populations. This study sought to investigate natural infection by flagellate forms of Leishmania in phlebotomines of the urban area of Bonito. FINDINGS: Sand flies were collected fortnightly from October 2005 to July 2006 with modified automatic light traps installed in peridomiciles and animal shelters in the center and on the outskirts of the city. The females were dissected and their guts observed under an optical microscope. A total of 1977 specimens were captured, Lutzomyia longipalpis (88.4 %) and Bichromomyia flaviscutelata (3.0 %) being the most frequent species. Bi. flaviscutellata was found infected by flagellates that were identified as Leishmania (Leishmania) amazonensis by indirect immunofluorescence reaction, employing monoclonal antibodies and the biotin-avidin system. This is the first report of natural infection by L. amazonensis in Bi. flaviscutellata in a Brazilian urban area. CONCLUSIONS: As Bi. flaviscutellata is only slightly attracted by humans, the transmission of L. amazonensis in the study area may have a zoonotic character; however, the sympatric occurrence of this parasite and Lu. longipalpis should be taken into consideration by the local health authorities since this sand fly has already been found with L. amazonensis DNA in a focus of canine visceral leishmaniasis in Bonito municipality. PMID- 26435709 TI - Review of the Structural and Dynamic Mechanisms of PPARgamma Partial Agonism. AB - PPARgamma (peroxisome proliferator activated receptor gamma) is a ligand activated transcription factor of the nuclear receptor superfamily that controls the expression of a variety of genes involved in fatty acid metabolism, adipogenesis, and insulin sensitivity. While endogenous ligands of PPARgamma include fatty acids and eicosanoids, synthetic full agonists of the receptor, including members of the thiazolidinedione (TZD) class, have been widely prescribed for the treatment of type II diabetes mellitus (T2DM). Unfortunately, the use of full agonists has been hampered by harsh side effects with some removed from the market in many countries. In contrast, partial agonists of PPARgamma have been shown to retain favourable insulin sensitizing effects while exhibiting little to no side effects and thus represent a new potential class of therapeutics for the treatment of T2DM. Partial agonists have been found to not only display differences in transcriptional and cellular outcomes, but also act through distinct structural and dynamic mechanisms within the ligand binding cavity compared to full agonists. PMID- 26435710 TI - Genome-Wide Comparative Analysis of Flowering-Related Genes in Arabidopsis, Wheat, and Barley. AB - Early flowering is an important trait influencing grain yield and quality in wheat (Triticum aestivum L.) and barley (Hordeum vulgare L.) in short-season cropping regions. However, due to large and complex genomes of these species, direct identification of flowering genes and their molecular characterization remain challenging. Here, we used a bioinformatic approach to predict flowering related genes in wheat and barley from 190 known Arabidopsis (Arabidopsis thaliana (L.) Heynh.) flowering genes. We identified 900 and 275 putative orthologs in wheat and barley, respectively. The annotated flowering-related genes were clustered into 144 orthologous groups with one-to-one, one-to-many, many-to-one, and many-to-many orthology relationships. Our approach was further validated by domain and phylogenetic analyses of flowering-related proteins and comparative analysis of publicly available microarray data sets for in silico expression profiling of flowering-related genes in 13 different developmental stages of wheat and barley. These further analyses showed that orthologous gene pairs in three critical flowering gene families (PEBP, MADS, and BBX) exhibited similar expression patterns among 13 developmental stages in wheat and barley, suggesting similar functions among the orthologous genes with sequence and expression similarities. The predicted candidate flowering genes can be confirmed and incorporated into molecular breeding for early flowering wheat and barley in short-season cropping regions. PMID- 26435712 TI - Breeding Sites of Aedes aegypti: Potential Dengue Vectors in Dire Dawa, East Ethiopia. AB - Background and Objectives. Entomological survey was carried out from May-June to September-October 2014 to investigate the presence of dengue vectors in discarded tires and artificial water containers in houses and peridomestic areas. Methods. A cross-sectional immature stage survey was done indoors and outdoors in 301 houses. Mosquito larval sampling was conducted using pipette or dipper depending on container types. Larvae were identified morphologically and larval indices were also calculated. Results. A total of 750 containers were inspected, and of these 405 were positive for mosquito larvae. A total of 1,873 larvae were collected and morphologically identified as Aedes aegypti (n = 1580: 84.4%) and Culex (n = 293: 15.6%). The larval indices, house index, container index, and breteau index, varied from 33.3 to 86.2, from 23.2 to 73.9, and from 56.5 to 188.9, respectively. Conclusion. Aedes aegypti is breeding in a wide range of artificial containers. To control these mosquitoes, the integration of different methods should be taken into consideration. PMID- 26435711 TI - Melatonin and Ischemic Stroke: Mechanistic Roles and Action. AB - Stroke is one of the most devastating neurological disabilities and brain's vulnerability towards it proves to be fatal and socio-economic loss of millions of people worldwide. Ischemic stroke remains at the center stage of it, because of its prevalence amongst the several other types attacking the brain. The various cascades of events that have been associated with stroke involve oxidative stress, excitotoxicity, mitochondrial dysfunction, upregulation of Ca(2+) level, and so forth. Melatonin is a neurohormone secreted by pineal and extra pineal tissues responsible for various physiological processes like sleep and mood behaviour. Melatonin has been implicated in various neurological diseases because of its antioxidative, antiapoptotic, and anti-inflammatory properties. We have previously reviewed the neuroprotective effect of melatonin in various models of brain injury like traumatic brain injury and spinal cord injury. In this review, we have put together the various causes and consequence of stroke and protective role of melatonin in ischemic stroke. PMID- 26435713 TI - Switching from Twice-Daily Basal Insulin Injections to Once-Daily Insulin Degludec Injection for Basal-Bolus Insulin Regimen in Japanese Patients with Type 1 Diabetes: A Pilot Study. AB - The aim of this study was to investigate the efficacy of insulin degludec used for basal-bolus insulin regimen after switching from twice-daily basal insulin in Japanese patients with type 1 diabetes mellitus. The subjects were 22 type 1 diabetes patients treated with basal-bolus insulin regimen with twice-daily basal insulin. Basal insulin was switched to once-daily injection of insulin degludec with 10% dose reduction. HbA1c and fasting plasma glucose (FPG) were measured before and 12 weeks after switching. The frequency of hypoglycemic episodes, standard deviation (SD) of blood glucose, and mean of daily difference (MODD) were evaluated by continuous glucose monitoring (CGM) before and 4 weeks after switching. HbA1c and FPG before and 12 weeks after switching were comparable (HbA1c 8.5 +/- 1.4 versus 8.7 +/- 1.6%, P = 0.28; FPG 203.2 +/- 81.2 versus 206.5 +/- 122.4 mg/dL, P = 0.91). The frequency of hypoglycemia during nighttime was not significantly different at 4 weeks after switching (14.4 +/- 17.0 versus 11.1 +/- 15.0%, P = 0.45). In addition, SD and MODD before and 4 weeks after switching were also comparable. In conclusion, glycemic control under once-daily insulin degludec injection was almost comparable to that under twice-daily basal insulin injections in Japanese type 1 diabetes patients. This study was registered with ID: UMIN000010474. PMID- 26435714 TI - Thyroid Dysfunction and Associated Risk Factors among Nepalese Diabetes Mellitus Patients. AB - Objectives. To assess thyroid function and associated risk factors in Nepalese diabetes mellitus patients. Methods. A cross-sectional study was carried out among 419 diabetes mellitus patients at B. P. Koirala Institute of Health Sciences, Dharan, Nepal. Information on demographic and anthropometric variables and risk factors for thyroid dysfunction was collected. Blood samples were analysed to measure thyroid hormones, blood sugar, and lipid profile. Results. Prevalence rate of thyroid dysfunction was 36.03%, with subclinical hypothyroidism (26.5%) as the most common thyroid dysfunction. Thyroid dysfunction was much common in females (42.85%) compared to males (30.04%) (p = 0.008) and in type 1 diabetes (50%) compared to type 2 diabetes mellitus (35.41%) (p = 0.218). Diabetic patients with thyroid dysfunction had higher total cholesterol, HDL cholesterol, and LDL cholesterol in comparison to patients without thyroid dysfunction. Significant risk factors for thyroid dysfunction, specifically hypothyroidism (overt and subclinical), were smoking (relative risk of 2.56 with 95% CI (1.99-3.29, p < 0.001)), family history of thyroid disease (relative risk of 2.57 with 95% CI (2.0-3.31, p < 0.001)), and female gender (relative risk of 1.44 with 95% CI (1.09-1.91, p = 0.01)). Conclusions. Thyroid dysfunction is common among Nepalese diabetic patients. Smoking, family history of thyroid disease, and female gender are significantly associated with thyroid dysfunction. PMID- 26435715 TI - Determinants of Overall and Progression-Free Survival of Nigerian Patients with Philadelphia-Positive Chronic Myeloid Leukemia. AB - Objective. The tyrosine kinase inhibitors have markedly changed the disease course for patients with Ph(+) and/or BCR-ABL1 (+) chronic myeloid leukemia (CML). This study was embarked upon to assess the long-term effects of imatinib therapy on survival in adult Nigerian patients with CML. Methods. All adult patients on imatinib (400-600 mg) seen from July 2003 to December 2010 were assessed. Male/female distribution was 171/101, with a median age of 38 (range, 20-75) years. Overall survival (OS) and progression-free survival (PFS) were determined using the Kaplan-Meier techniques. Results. Of all the 272 patients, 205 were in chronic phase, 54 in accelerated phase, and five in blastic phase, at commencement of imatinib. As at December 2010, 222 were alive. OS at 1 and 5 years was 94% and 63%, while PFS was 89% and 54%, respectively. Similarly, amongst the 205 patients in chronic phase, OS at 1 and 5 years was 97% and 68%, while PFS was 92% and 57%. Conclusion. Imatinib's place as first-line therapy in the treatment of CML has further been reinforced in our patients, with improved survival and reduced morbidity, comparable with outcomes in other populations. PMID- 26435716 TI - Pulmonary Silicosis Presents with Pleural Effusion. AB - Silica and silicate mineral dust inhalation can cause a variety of histopathological changes in the lungs and pleura. These include pulmonary silicotic nodules, interstitial infiltrate, fibrosis, and pleural thickening. Pleural effusion is an extremely rare presentation of silicosis. To our best knowledge, there have been only 2 cases of silicosis with pleural effusion reported in medical literature. Herein, we describe a case of a 77-year-old male with almost 50 years' history of occupational silica exposure. He presented with a 4-week history of exertional shortness of breath. He is a lifetime nonsmoker, with no known other significant pulmonary disease. He had chest X-ray which showed a right lung infiltrate and bilateral pleural thickening and effusion. Chest CT showed moderate-sized bilateral pleural effusion and thickening with multiple bilateral intrapulmonary nodules seen. He had undergone extensive workup and was diagnosed with silicosis. PMID- 26435717 TI - Prevalence and Pattern of Soil-Transmitted Helminthic Infection among Primary School Children in a Rural Community in Imo State, Nigeria. AB - Background. Soil-transmitted helminthic infection is a common public health challenge of primary school children in resource challenged and developing countries. Our aim was to determine the prevalence and pattern of soil transmitted helminthic infection among primary school children in a rural community in Imo State, Nigeria. Method. The study involved a cross-sectional survey of 284 primary school children in a rural community. Results. The overall prevalence of soil-transmitted helminthic infection (STHI) was 30.3%. Of all STHIs, hookworm was the commonest geohelminth observed, 81 (94.2%). The prevalence of soil-transmitted helminthic infection was more in males, 58 (38.4%), than in females, 28 (21.1%). This difference was statistically significant (P = 0.001). Conclusion. The high prevalence rate of soil-transmitted helminthic infection amongst the study population is worrisome. There is need for organized and routine deworming among school children in the community. PMID- 26435718 TI - Safety of a Bioactive Polyphenol Dietary Supplement in Pediatric Subjects with Acute Diarrhoea. AB - The hematological and clinical chemistry profile for children aged 6 months to 5 years with acute diarrhoea was measured in a double blind clinical trial. Subjects were randomized to the study group (N = 44) given a bioactive polyphenol dietary supplement in oral rehydration solution (ORS) or to the control group (N = 41) given distilled water as a placebo in ORS twice daily for up to 4 days. All subjects received 10 mg zinc daily for the 4 days in the study. Venous blood was collected for complete blood count, electrolytes, liver function, and creatinine upon enrollment (baseline) and at the end of 4 days (end of study); mean values were compared by 95% confidence intervals. Overall, blood factors measured either remained the same over the 4 days or increased or decreased at the same levels between the two groups during the study period. All values were within accepted ranges for paediatric subjects except serum AST (SGOT), where the mean value of the study group approached the upper bound of the range on day 4 but was comparable to the value of the control group. Consumption of this supplement twice daily for 4 days is safe for children and infants. PMID- 26435719 TI - Peptide-Induced Amyloid-Like Conformational Transitions in Proteins. AB - Changes in protein conformation can occur both as part of normal protein functioning and during disease pathogenesis. The most common conformational diseases are amyloidoses. Sometimes the development of a number of diseases which are not traditionally related to amyloidoses is associated with amyloid-like conformational transitions of proteins. Also, amyloid-like aggregates take part in normal physiological processes such as memorization and cell signaling. Several primary structural features of a protein are involved in conformational transitions. Also the protein proteolytic fragments can cause the conformational transitions in the protein. Short peptides which could be produced during the protein life cycle or which are encoded by short open reading frames can affect the protein conformation and function. PMID- 26435720 TI - Retracted: Immunopathology and Immunogenetics of Allergic Bronchopulmonary Aspergillosis. AB - [This retracts the article DOI: 10.1155/2011/785983.]. PMID- 26435721 TI - The Falsified Medicines Directive: How to secure your supply chain. PMID- 26435722 TI - Neuroprotective Effects of Cistanches Herba Therapy on Patients with Moderate Alzheimer's Disease. AB - Cistanches Herba (CH) is thought to be a "Yang-invigorating" material in traditional Chinese medicine. We evaluated neuroprotective effects of Cistanches Herba on Alzheimer's disease (AD) patients. Moderate AD participants were divided into 3 groups: Cistanches Herba capsule (CH, n = 10), Donepezil tablet (DON, n = 8), and control group without treatment (n = 6). We assessed efficacy by MMSE and ADAS-cog, and investigated the volume changes of hippocampus by 1.5 T MRI scans. Protein, mRNA levels, and secretions of total-tau (T-tau), tumor necrosis factor alpha (TNF-alpha), and interleukin- (IL) 1beta (IL-1beta) in cerebrospinal fluid (CSF) were detected by Western blot, RT-PCR, and ELISA. The scores showed statistical difference after 48 weeks of treatment compared to control group. Meanwhile, volume changes of hippocampus were slight in drug treatment groups but distinct in control group; the levels of T-tau, TNF-alpha, and IL-1beta were decreased compared to those in control group. Cistanches Herba could improve cognitive and independent living ability of moderate AD patients, slow down volume changes of hippocampus, and reduce the levels of T-tau, TNF-alpha, and IL 1beta. It suggested that Cistanches Herba had potential neuroprotective effects for moderate AD. PMID- 26435723 TI - The Chondroprotective Role of TMF in PGE2-Induced Apoptosis Associating with Endoplasmic Reticulum Stress. AB - Endoplasmic reticulum stress (ERS) has been demonstrated to exhibit a critical role in osteoarthritic chondrocytes. Whether 5,7,3',4'-tetramethoxyflavone (TMF) plays the chondroprotective role in inhibition of PGE2-induced chondrocytes apoptosis associating with ERS has not been reported. To investigate this, the activation of PERK, ATF6, and IRE1 signaling pathways in ERS in chondrocytes pretreated with PGE2 was studied. By treatment with PGE2, the chondrocytes apoptosis was significantly increased, the proapoptotic CHOP and JNK were upregulated, the prosurvival GRP78 and XBP1 were downregulated, and GSK-3beta was also upregulated. However, TMF exhibited the effectively protective functions via counteracting these detrimental effects of PGE2. Finally, the inflammatory cytokine PGE2 can activate ERS signaling and promote chondrocytes apoptosis, which might be associated with upregulation of GSK-3beta. TMF exhibits a chondroprotective role in inhibiting PGE2-induced ERS and GSK-3beta. PMID- 26435724 TI - Effect of Aqueous Extract from Morinda officinalis F. C. How on Microwave-Induced Hypothalamic-Pituitary-Testis Axis Impairment in Male Sprague-Dawley Rats. AB - The present study aimed to assess the protective effects of aqueous extract from Morinda officinalis F. C. How on microwave-induced reproductive impairment in male rats. Microwave exposure injury was induced by exposure of 900 MHz microwaves at 218 MUm/cm(2)radiation densities, 24 hours/day for 10 days. Male Sprague-Dawley rats were randomized to: normal control, microwave exposure model, or water layer or ethyl acetate layer of aqueous extract 40 g/kg treatment groups. After 2 weeks of treatment, sexual performance, serum levels of gonadotrophin-releasing hormone (GnRH), luteinizing hormone (LH), follicle stimulating hormone (FSH) or testosterone, morphological analysis of testis and epididymis, and GnRH protein expression in the hypothalamus were measured. Pretreatment with water layer of aqueous extract 40 g/kg significantly improved sexual performance, increased serum testosterone level, and decreased LH and GnRH level compared with microwave exposed model rats (all P < 0.05). Water layer of aqueous extract treatment significantly increased seminiferous cell or sperm number in testis and epididymis. Protein expression of GnRH in the hypothalamus significantly decreased in the water layer of aqueous extract treated group (P < 0.05). Ethyl acetate layer of aqueous extract did not show obvious effects on the measured parameters. These findings suggest that water layer of aqueous extract 40 g/kg ameliorates microwave-reduced reproductive impairment. PMID- 26435725 TI - External Application of Traditional Chinese Medicine for Venous Ulcers: A Systematic Review and Meta-Analysis. AB - Objective. To evaluate the effectiveness of external application of traditional Chinese medicine (EA-TCM) on venous ulcers. Methods. Seven databases were searched until April 2015 for randomized controlled trials (RCTs) of EA-TCM for venous ulcers. Risk of bias was assessed using Cochrane Handbook guidelines. Study outcomes were presented as risk ratios (RRs) for dichotomous data or mean differences (MDs) for continuous data. Results. Sixteen of 193 potentially relevant trials met the inclusion criteria; however, their methodological qualities were low. Comparison of the same intervention strategies revealed significant differences in total effectiveness rates between EA-TCM and conventional therapy groups (RR = 1.22, 95% confidence interval [CI] = 1.16-1.29, and P < 0.00001). Compared to conventional therapy, EA-TCM combined with conventional therapy had a superior total effectiveness rate (RR = 1.11, 95% CI = 1.04-1.19, and P = 0.003). There were no significant differences in recurrence rates during followup and final pain measurements between the experimental and those in the control groups (RR = 0.86, 95% CI = 0.31-2.39, and P = 0.85; MD 0.75, 95% CI = -2.15-0.65, and P = 0.29). Conclusion. The evidence that EA-TCM is an effective treatment for venous ulcers is encouraging, but not conclusive due to the low methodological quality of the RCTs. Therefore, more high-quality RCTs with larger sample sizes are required. PMID- 26435726 TI - The immunological footprint of CMV in HIV-1 patients stable on long-term ART. AB - BACKGROUND: Most HIV-infected persons are cytomegalovirus (CMV) seropositive and retain latent virus that can be reactivated by immune activation. Their T cell populations express markers reflecting a late stage of differentiation, but the contributions of HIV and CMV to this profile are unclear. We investigated the immunological "footprint" of CMV in HIV patients who had a history of extreme immunodeficiency but were now stable on antiretroviral therapy (ART). RESULTS: Twenty CMV seropositive HIV patients >50 years old with nadir CD4 T-cell counts <200 cells/MUl were studied after >12 years on ART. 16 CMV seropositive and 9 CMV seronegative healthy controls were included. CMV antibody titres were higher in HIV patients than controls (P < 0.001-0.003). Levels of soluble B-cell activating factor (sBAFF) were elevated in patients (P = 0.002) and correlated with levels of CMV antibodies (P = 0.03-0.002), with no clear relationship in controls. CD8 T cell IFNgamma responses to the IE1 peptide (VLE) remained elevated in HIV patients (P = 0.005). The CD57(+)CD45RA(+)CD27(-) phenotype of CD8 T-cells correlated with age (r = 0.60, P = 0.006), antibodies against CMV IE1 protein (r = 0.44, P = 0.06) and CD4 T-cell IFNgamma response to CMV lysate (r = 0.45, P = 0.05). CONCLUSIONS: Humoral and T-cell responses to CMV remained elevated in HIV patients after >12 years on ART. Age and presence of CMV disease influenced CD8 T cell phenotypes. Elevated levels of sBAFF may be a consequence of HIV disease and contribute to high titres of CMV antibody. PMID- 26435727 TI - Defining the fitness of HIV-1 isolates with dual/mixed co-receptor usage. AB - BACKGROUND: CCR5-using (r5) HIV-1 predominates during asymptomatic disease followed by occasional emergence of CXCR4-using (x4) or dual tropic (r5x4) virus. We examined the contribution of the x4 and r5 components to replicative fitness of HIV-1 isolates. METHODS: Dual tropic r5x4 viruses were predicted from average HIV-1 env sequences of two primary subtype C HIV-1 isolates (C19 and C27) and from two patient plasma samples (B12 and B19). Chimeric Env viruses with an NL4-3 backbone were constructed from the B12 and B19 env sequences. To determine replicative fitness, these primary and chimeric dual tropic HIV-1 were then competed against HIV-1 reference isolates in U87.CD4 cells expressing CXCR4 or CCR5 or in PBMCs +/- entry inhibitors. Contribution of the x4 and r5 clones within the quasispecies of these chimeric or primary HIV-1 isolates were then compared to the frequency of x4, r5, and dual tropic clones within the quasispecies as predicted by phenotypic assays, clonal sequencing, and 454 deep sequencing. RESULTS: In the primary HIV-1 isolates (C19 and C27), subtype C dual tropic clones dominated over x4 clones while pure r5 clones were absent. In two subtype B chimeric viruses (B12 and B19), r5 clones were >100-fold more abundant than x4 or r5/x4 clones. The dual tropic C19 and C27 HIV-1 isolates outcompeted r5 primary HIV-1 isolates, B2 and C3 in PBMCs. When AMD3100 was added or when only U87.CD4.CCR5 cells were used, the B2 and C3 reference viruses now out competed the r5 component of the dual tropic C19 and C27. In contrast, the same replicative fitness was observed with dualtropic B12 and B19 HIV-1 isolates relative to x4 HIV-1 A8 and E6 or the r5 B2 and C3 viruses, even when the r5 or x4 component was inhibited by maraviroc (or AMD3100) or in U87.CD4.CXCR4 (or CCR5) cells. CONCLUSIONS: In the dual tropic HIV-1 isolates, the x4 replicative fitness is higher than r5 clones but the x4 or x4/r5 clones are typically at low frequency in the intrapatient virus population. Ex vivo HIV propagation promotes outgrowth of the x4 clones and provides an over-estimate of x4 dominance in replicative fitness within dual tropic viruses. PMID- 26435729 TI - Quality of public information matters in mate-choice copying in female zebra finches. AB - BACKGROUND: Mate-choice copying is a form of social learning in which an individual gains information about potential mates by observing conspecifics. However, it is still unknown what kind of information drives the decision of an individual to copy the mate choice of others. Among zebra finches (Taeniopygia guttata castanotis), only females (not males) copy the mate choice of others. We tested female zebra finches in a binary choice test where they, first, could choose between two males of different phenotypes: one unadorned male and one male artificially adorned with a red feather on the forehead. After this mate-choice test, females could observe a single unadorned male and a pair of zebra finches, i.e. a wild-type female and her adorned mate. Pair interactions were either restricted to acoustic and visual communication (clear glass screen between pair mates) or acoustic communication alone (opaque screen between pair mates). After the observation period, females could again choose between new males of the two phenotypes in a second mate-choice test. RESULTS: In experiments with a clear glass screen, time spent with the respective males changed between the two mate choice tests, and females preferred adorned over unadorned males during the second mate-choice test. In experiments with an opaque screen, time spent with the respective males did not change between the two mate-choice tests, although females lost an initial preference for unadorned males. CONCLUSIONS: Our results demonstrate that the quality of the received public information (visual and acoustic interaction of the observed pair) influences mate-choice copying in female zebra finches. PMID- 26435728 TI - Host sex and age influence endoparasite burdens in the gray mouse lemur. AB - INTRODUCTION: Immunosenescence (deteriorating immune function at old age) affects humans and laboratory animals, but little is known about immunosenescence in natural populations despite its potential importance for population and disease dynamics and individual fitness. Although life histories and immune system profiles often differ between the sexes, sex-specific effects of aging on health are rarely studied in the wild. Life history theory predicts that due to their shorter lifespan and higher investment into reproduction at the expense of immune defences, males might experience accelerated immunosenescence. We tested this hypothesis by examining sex-specific age trajectories of endoparasite burden (helminth prevalence and morphotype richness measured via fecal egg counts), an indicator of overall health, in wild gray mouse lemurs (Microcebus murinus). To account for potential interactions between seasonality and host sex or age we examined the predictors of parasite burdens separately for the dry and rainy season. RESULTS: Contrary to the prediction of immunosenescence, parasite prevalence and morphotype richness decreased at old age in the dry season, indicating acquired immunity by older animals. This pattern was primarily caused by within-individual decline in parasite loads rather than the earlier mortality of highly parasitized individuals. With the exception of an increasing cestode prevalence in males from yearlings to prime age in the rainy season, no evidence was found of male-biased ageing in parasite resistance. Besides this sex*age interaction, host age was uncorrelated with rainy season parasite loads. Seasonality did not affect the overall parasite loads but seasonal patterns were found in the predictors of parasite prevalence and morphotype richness. CONCLUSIONS: These results provide rare information about the age-related patterns of health in a wild vertebrate population and suggest improvement rather than senescence in the ability to resist helminth infections at old age. Overall, males appear not to suffer from earlier immunosenescence relative to females. This may partially reflect the earlier mortality of males, which can render senescence difficult to detect. While helminth infections are not strongly associated with survival in wild gray mouse lemurs, parasite load may, however, reflect overall good phenotypic quality of long-lived individuals, and is a potential correlate of fitness. PMID- 26435730 TI - The relationship between poison frog chemical defenses and age, body size, and sex. AB - INTRODUCTION: Amphibians secrete a wide diversity of chemicals from skin glands as defense against predators, parasites, and pathogens. Most defensive chemicals are produced endogenously through biosynthesis, but poison frogs sequester lipophilic alkaloids from dietary arthropods. Alkaloid composition varies greatly, even among conspecific individuals collected at the same time and place, with some individuals having only a few micrograms of one or a few alkaloids and others possessing >1 mg of >30 alkaloids. The paucity of alkaloids in juveniles and their abundance in adults suggests that alkaloids accumulate over time; however, alkaloid diversity is highly variable among adult poison frogs and has never been studied in relation to individual age. Using skeletochronology to infer individual ages and gas chromatography-mass spectrometry and vapor phase Fourier-transform infrared spectral analysis to identify the defensive chemicals of 63 individuals, we tested the relationship between defensive chemicals and age, size, and sex in the Brazilian red-belly toad, Melanophryniscus moreirae, a poison frog that possesses both sequestered alkaloids and the biosynthesized indolealkylamine bufotenine. RESULTS: Adult females were, on average, older and larger than adult males. Juveniles were smaller but not necessarily younger than adults and possessed bufotenine and 18 of the 37 alkaloids found in adults. Alkaloid richness was positively related to age, but not size, whereas the quantities of sequestered alkaloids and bufotenine were positively related to size, but not age. Defensive chemicals were unrelated to sex, independent of size. CONCLUSIONS: The relationship between alkaloid richness and age appears to result from the gradual accumulation of alkaloids over a frog's lifetime, whereas the relationship between the quantity of defensive chemicals and size appears to be due to the greater storage capacity of larger individuals. The decoupling of age and size effects increases the amount of individual variation that can occur within a population, thereby possibly enhancing anti-predator efficacy. Further, given that both richness and quantity contribute to the overall chemical defense of individual frogs, our results suggest that older, larger individuals are better defended than younger, smaller ones. These considerations underscore the importance of including age in studies of the causes and consequences of variation in poison frog chemical defenses. PMID- 26435731 TI - Lung function and fractional exhaled nitric oxide among petroleum refinery workers. AB - BACKGROUND: Occupational and environmental exposure to petroleum refinery products poses a great threat to human health. This study aimed to assess the lung function and Fractional Exhaled Nitric Oxide (FeNO) among petroleum refinery workers. METHODS: In this cross-sectional study, 112 participants (56 petroleum refinery workers with mean age 35.20 +/- 1.62 years, and 56 age, weight, height, ethnicity and socioeconomically matched control subjects with mean age 30.02 +/- 1.76 years) were recruited. A comprehensive clinical history and examination was conducted to decide whether to include in the study or not. Ventilatory lung function test parameters were recorded by using a Spirometer and Fractional Exhaled Nitric Oxide (FeNO) was measured by Niox Mino. RESULTS: A significant decline in lung function parameters FEV1 (p = 0.0001), FEV1/FVC Ratio (p = 0.01), PEF (p = 0.0001), FEF 25 % (p = 0.0001), FEF-50 % (p = 0.012) was observed among oil refinery workers compared to their matched controls. However, there was no difference in the mean values of FeNO between the groups. CONCLUSION: Subjects working in the petroleum refinery have significantly impaired lung functions. However, there was no change in the values of FENO between the groups. The lung function impairment pattern provide evidence in the favor of an obstructive lung disease. PMID- 26435732 TI - Biomarkers of primary open-angle glaucoma. AB - Primary open-angle glaucoma (POAG) is a primary neuronal disease of the optic nerve without a definable cause, and is often associated with increased intraocular pressure. Worldwide, POAG is the second leading cause of blindness; there are 45 million people today with POAG and bilateral blindness is present in 4.5 million of these. In order to elucidate the possible etiologic factors in POAG, we have cataloged all known biomarkers in the aqueous humor, trabecular meshwork, optic nerve and blood into four categories, namely extracellular matrix (ECM), cell signaling molecules, aging/stress and immunity-related changes. We present a theoretical model to show possible signaling pathways of the ECM, cell signaling and innate immune response through activation of Toll-like receptor 4. Our article suggests that ECM and innate immune biomarkers are the lead candidates for developing the 'POAG biomarker signature'. We suggest that current research is critical to pinpoint the causes of the disease so that new treatment modalities can become available for better regulation of the intraocular pressure and neuroprotection of the optic nerve. PMID- 26435734 TI - Prediction of 1-octanol solubilities using data from the Open Notebook Science Challenge. AB - BACKGROUND: 1-Octanol solubility is important in a variety of applications involving pharmacology and environmental chemistry. Current models are linear in nature and often require foreknowledge of either melting point or aqueous solubility. Here we extend the range of applicability of 1-octanol solubility models by creating a random forest model that can predict 1-octanol solubilities directly from structure. RESULTS: We created a random forest model using CDK descriptors that has an out-of-bag (OOB) R2 value of 0.66 and an OOB mean squared error of 0.34. The model has been deployed for general use as a Shiny application. CONCLUSION: The 1-octanol solubility model provides reasonably accurate predictions of the 1-octanol solubility of organic solutes directly from structure. The model was developed under Open Notebook Science conditions which makes it open, reproducible, and as useful as possible.Graphical abstract. PMID- 26435733 TI - Epidemiological patterns of cervical human papillomavirus infection among women presenting for cervical cancer screening in North-Eastern Nigeria. AB - BACKGROUND: Sub-Saharan countries including Nigeria have the highest burden of Human Papillomavirus (HPV) infection in the world. Most studies on HPV surveillance in Nigeria were done in the southern part of the country. Geographical and socio-cultural diversity of Nigeria makes these data unlikely to be universally representative for the entire country. Northern Nigeria especially the North-East carries a higher prevalence of cervical cancer and many of its risk factors. The region may be harbouring a higher prevalence of HPV infection with a possibility of different genotypic distribution. This study was carried out to determine the burden and confirm the predominant HPV genotypes among women presenting for cervical cancer screening at the Federal Teaching Hospital Gombe (FTHG), North-eastern, Nigeria. METHODS: The study was an observational hospital based cross sectional study among women who presented for cervical cancer screening in FTHG. A total of 209 consenting women were tested for cervical HPV infection using PCR. DNA sequencing was carried out on positive samples to determine the prevalent HPV genotypes. RESULTS: The prevalence of cervical HPV infection among the participants with mean age of 39.6 +/- 10.4 years was 48.1 %. The five most predominant genotypes were 18, 16, 33, 31 and 35, with prevalence of 44.7 %, 13.2 %, 7.9 %, 5.3 % and 5.3 % respectively. Other genotypes observed were 38, 45, 56, 58, 82 and KC5. Multiple HPV infections were detected among 7.9 % of participants. Risk factors such as level of education (X (2) = 15.897; p = 0.007), age at sexual debut (X (2) = 6.916; p = 0.009), parity (X (2) = 23.767; p = 0.000), number of life time sexual partners (X (2) = 7.805; p = 0.005), age at first pregnancy (X (2) = 10.554; p = 0.005) and history of other malignancies (X (2) = 7.325; p = 0.007) were found to have a statistically significant association with HPV infection. CONCLUSION: This study identified a high burden of HPV infection in Northern Nigeria while also confirming HPV 18 and 16 as the most predominant genotypes. It further justifies the potential benefit of the currently available HPV vaccines in the area. A larger and community based study is however recommended for better representation of the area. PMID- 26435735 TI - Synthesis and antibacterial activity of novel 5,6,7,8-tetrahydroimidazo[1,2 a]pyrimidine-2-carbohydrazide derivatives. AB - BACKGROUND: The intensely increasing multi-drug resistant microbial infections have encouraged the search for new antimicrobial agents. Hydrazone derivatives are known to exhibit a wide variety of biological activities including anti microbial. In heterocyclic moiety, imidazo[1,2-a]pyrimidines are the subject of immense interest for their antimicrobial activity and also for their analgesic, antipyretic and anti-inflammatory properties. RESULTS: Condensation of 5,6,7,8 tetrahydroimidazo[1,2-a]pyrimidine-2-carbohydrazide 7 with aromatic aldehydes a-k in ethanol at reflux led to the generation of hydrazone derivatives 8a-k in 80 92% yield. The synthesis of carbohydrazide 7 was accomplished in six steps from commercially available 2-amino pyrimidine. The structures of the synthesized compounds were confirmed by 1H, 13C NMR, Mass and IR spectral data. All the synthesized hydrazone derivatives 8a-k were tested in vitro for their antibacterial activity. Compounds 8d, 8e and 8f exhibited excellent antibacterial activity with zone of inhibition 30-33 mm against E. coli (Gram negative bacteria) and S. aureus (Gram positive bacteria). These compounds also exhibited excellent antibacterial activity with zone of inhibition 22-25 mm against P. aeruginosa (Gram negative bacteria) and S. pyogenes (Gram positive bacteria). CONCLUSION: Synthesized and recorded antibacterial activity of some new 5,6,7,8 tetrahydro-imidazo[1,2-a]pyrimidine-hydrazone derivatives.Graphical abstract:Synthesis of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-2-carbohydrazide derivatives. PMID- 26435736 TI - Diagnostic techniques in deflagration and detonation studies. AB - Advances in experimental, high-speed techniques can be used to explore the processes occurring within energetic materials. This review describes techniques used to study a wide range of processes: hot-spot formation, ignition thresholds, deflagration, sensitivity and finally the detonation process. As this is a wide field the focus will be on small-scale experiments and quantitative studies. It is important that such studies are linked to predictive models, which inform the experimental design process. The stimuli range includes, thermal ignition, drop weight, Hopkinson Bar and Plate Impact studies. Studies made with inert simulants are also included as these are important in differentiating between reactive response and purely mechanical behaviour. PMID- 26435737 TI - Phytochemical composition, antiparasitic and alpha-glucosidase inhibition activities from Pelliciera rhizophorae. AB - BACKGROUND: Panama has an extensive mangrove area and it is one of the countries with the highest biodiversity in America. Mangroves are widely used in traditional medicine, nevertheless, there are very few studies that validates their medicinal properties in America. Given the urgent need for therapeutic options to treat several diseases of public health importance, mangrove ecosystem could be an interesting source of new bioactive molecules. This study was designed to evaluate the potential of Pelliciera rhizophorae as a source of bioactive compounds. RESULTS: The present investigation was undertaken to explore the possible antiparasitic potential and alpha-glucosidase inhibition by compounds derived from the Panamanian mangrove Pelliciera rhizophorae. Bioassay guided fractionation of the crude extract led to the isolation of ten chemical compounds: alpha-amyrine (1), beta-amyrine (2), ursolic acid (3), oleanolic acid (4), betulinic acid (5), brugierol (6) iso-brugierol (7), kaempferol (8), quercetin (9), and quercetrin (10). The structures of these compounds were established by spectroscopic analyses including APCI-HR-MS and NMR. Compounds 4 (IC50 = 5.3 uM), 8 (IC50 = 22.9 uM) and 10 (IC50 = 3.4 uM) showed selective antiparasitic activity against Leishmania donovani, while compounds 1 (IC50 = 19.0 uM) and 5 (IC50 = 18.0 uM) exhibited selectivity against Tripanosoma cruzi and Plasmodium falciparum, respectively. Moreover, compounds 1-5 inhibited alpha glucosidase enzyme in a concentration-dependent manner with IC50 values of 1.45, 0.02, 1.08, 0.98 and 2.37 uM, respectively. Their inhibitory activity was higher than that of antidiabetic drug acarbose (IC50 217.7 uM), used as a positive control. Kinetic analysis established that the five compounds acted as competitive inhibitors. Docking analysis predicted that all triterpenes bind at the same site that acarbose in the human intestinal alpha-glucosidase (PDB: 3TOP). CONCLUSIONS: Three groups of compounds were isolated in this study (triterpenes, flavonols and dithiolanes). Triterpenes and flavones showed activity in at least one bioassay (antiparasitic or alpha-glucosidase). In addition, only the pentacyclic triterpenes exhibited a competitive type of inhibition against alpha-glucosidase. PMID- 26435738 TI - Gold nanoparticle-labeled biosensor for rapid and sensitive detection of bacterial pathogens. AB - BACKGROUND: Escherichia coli O157:H7 is one of the major foodborne bacterial pathogens and also a biodefense agent. To ensure food safety and public health, it is very important to develop rapid methods for E. coli O157:H7 detection. In this study, we designed a nanoparticle-labeled biosensor for the rapid detection of E. coli O157:H7 in broth. RESULTS: Magnetic nanoparticles (MNPs) were conjugated with monoclonal antibodies (Abs) to separate target E. coli O157:H7 cells from broth samples. Gold nanoparticles (AuNPs) were conjugated with polyclonal Abs, and were then introduced to the MNP-target complex to form a sandwich MNP-target-AuNP. By measuring the amount of AuNPs through an electrochemical method, the presence and the amount of the target bacteria were determined. Results showed a sensitivity of 10(1) colony forming units per milliliter (cfu/ml) with a linear range of 10(1)-10(6) cfu/ml. CONCLUSIONS: Compared to conventional culture plating methods, the biosensor reduced the detection time from 2 to 4 days to less than 1 hour with a simple target extraction method. The AuNP-labeled biosensor has potential applications in the rapid detection of infectious agents for public health, biodefense, and food/water safety. PMID- 26435739 TI - Standards not that standard. AB - There is a general assent on the key role of standards in Synthetic Biology. In two consecutive letters to this journal, suggestions on the assembly methods for the Registry of standard biological parts have been described. We fully agree with those authors on the need of a more flexible building strategy and we highlight in the present work two major functional challenges standardization efforts have to deal with: the need of both universal and orthogonal behaviors. We provide experimental data that clearly indicate that such engineering requirements should not be taken for granted in Synthetic Biology. PMID- 26435740 TI - Comparative evaluation of triplet antiemetic schedule versus doublet antiemetic schedule in chemotherapy-induced emesis in head and neck cancer patients. AB - PURPOSE: To compare the antiemetic combination of palonosetron, dexamethasone, and aprepitant (PDA) with antiemetic combination of ondansetron and dexamethasone (OD) in head and neck cancer patients receiving docetaxel, carboplatin, and 5-FU based chemotherapy. METHODS: Sixty previously untreated patients were randomly divided into two groups of thirty patients each. The PDA group received a combination of palonosetron 0.25 mg intravenously (IV), dexamethasone 12 mg IV, and capsule aprepitant per oral. OD group received ondansetron 16 mg IV, and dexamethasone 12 mg IV for emesis control. The primary objective was to compare the efficacy of two antiemetic schedules for preventing acute and delayed CINV (chemotherapy-induced nausea and vomiting). The primary efficacy end point was complete response (CR). RESULTS: All the patients tolerated both schedules well. The antiemetic response for acute emesis (first 24 hours) in PDA versus OD group was: CR was 86.7 versus 60%. For delayed emesis (from day 2-5) in PDA versus OD group CR was 83.3 versus 53.3%. The intensity of acute nausea (first 24 hours) in PDA versus OD group was: no nausea-70 versus 46.6%. The intensity of delayed nausea (from day 2-5) in PDA versus OD was: no nausea-76.6 versus 43.3%. The CR to both acute and delayed emesis (no vomiting from day 1-5) in PDA versus OD group was 83.3 versus 53.3% (p < 0.05, significant). The CR to nausea (no nausea from day 1-5) in PDA versus OD group was 70 versus 43.3% (p < 0.05, significant). CONCLUSION: Although both the schedules were tolerated well, the PDA schedule (palonosetron, aprepitant, and dexamethasone) was significantly better than the OD schedule (ondansetron and dexamethasone) in controlling cancer CINV in the acute as well as delayed phases. PMID- 26435741 TI - Repurposing Drugs in Oncology (ReDO)-nitroglycerin as an anti-cancer agent. AB - Nitroglycerin (NTG), a drug that has been in clinical use for more than a century, has a range of actions which make it of particular interest in an oncological setting. It is generally accepted that the main mechanism of action of NTG is via the production of nitric oxide (NO), which improves cardiac oxygenation via multiple mechanisms including improved blood flow (vasodilation), decreased platelet aggregation, increased erythrocyte O2 release and decreased mitochondrial utilization of oxygen. Its vasoactive properties mean that it has the potential to exploit more fully the enhanced permeability and retention effect in delivering anti-cancer drugs to tumour tissues. Moreover NTG can reduce HIF-1alpha levels in hypoxic tumour tissues and this may have anti-angiogenic, pro-apoptotic and anti-efflux effects. Additionally NTG may enhance anti-tumour immunity. Pre-clinical and clinical data on these anti-cancer properties of NTG are summarised and discussed. While there is evidence of a positive action as a monotherapy in prostate cancer, there are mixed results in NSCLC where initially positive results have yet to be fully replicated. Based on the evidence presented, a case is made that further exploration of the clinical benefits that may accrue to cancer patients is warranted. Additionally, it is proposed that NTG may synergise with a number of other drugs, including other repurposed drugs, and these are discussed in the supplementary material appended to this paper. PMID- 26435744 TI - Metastatic lobular carcinoma of breast mimics primary cervix carcinoma: two case reports and a review of the literature. AB - Invasive lobular carcinoma (ILC) of the breast exhibits unusual clinicopathological, radiological, histological, and metastatic patterns. We present here two cases of ILC of the breast that presented with an unusual pattern of metastasis involving the uterus. Our first patient presented to her primary gynaecologist with profuse vaginal bleeding and underwent total abdominal hysterectomy and bilateral salpingo-oophrectomy. She had fibroadenoma excised from her left breast four years previously. Histopathology revealed lobular carcinoma diffusely infiltrating uterus, cervix, and bilateral ovaries. Retrospective examination of the left breast showed induration along the previous fibroadenoma excision scar. A biopsy from the scar suggested lobular carcinoma. Our second patient presented with a hard indurated cervix mass that mimicked primary cervix carcinoma. She had ILC of the right breast four years previously for which she underwent mastectomy followed by adjuvant chemotherapy and radiotherapy. She was on tamoxifen. Further evaluation at presentation with imaging showed extensive intra-abdominal disease involving peritoneum with moderate ascites, adnexal masses, and confluent para-aortic nodal mass. A cervix biopsy confirmed metastasis from lobular carcinoma. Metastatic involvement of the genital tract should be considered in women with a history of breast cancer who present with abnormal vaginal bleeding, suspicious pelvic examination, or radiological findings. We suggest such patient be vigorously screened with biopsy even if the patient is disease-free for several years. It is crucial to differentiate the metastasis from primary carcinoma of the genital tract as there are vast differences in the management of each. PMID- 26435742 TI - miRNAs and resistance to EGFR-TKIs in EGFR-mutant non-small cell lung cancer: beyond 'traditional mechanisms' of resistance. AB - Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have dramatically changed the prognosis of advanced non-small cell lung cancers (NSCLCs) that harbour specific EGFR activating mutations. However, the efficacy of an EGFR-TKI is limited by the onset of acquired resistance, usually within one year, in virtually all treated patients. Moreover, a small percentage of EGFR mutant NSCLCs do not respond to an EGFR-TKI, thus displaying primary resistance. At the present time, several mechanisms of either primary and acquired resistance have been elucidated, and new drugs are currently under preclinical and clinical development in order to overcome resistance to treatment. Nevertheless, there still remains much to be thoroughly investigated, as so far research has mainly focused on the role of proteincoding genes involved in resistance to EGFR-TKIs. On the other hand, in line with the data underscoring the relevance of non-coding RNAs in the pathogenesis of lung cancer and modulation of response to systemic therapies, microRNAs (miRNAs) have been supposed to play an important role in resistance to EGFR-TKIs. The aim of this review is to briefly summarise the existing relationship between miRNAs and resistance to EGFR-TKIs, and also focusing on the possible clinical applications of miRNAs in reverting and overcoming such resistance. PMID- 26435743 TI - The clinical role of multimodality imaging in the detection of prostate cancer recurrence after radical prostatectomy and radiation therapy: past, present, and future. AB - Detection of the recurrence sites in prostate cancer (PCa) patients affected by biochemical recurrence after radical prostatectomy (RP) and radiation therapy (RT) is still a challenge for clinicians, nuclear medicine physicians, and radiologists. In the era of personalised and precision care, this task requires the integration, amalgamation, and combined analysis of clinical and imaging data from multiple sources. At present, multiparametric Magnetic Resonance Imaging (mpMRI) and choline-positron emission tomography (PET) are giving encouraging results; their combination allows the effective detection of local, lymph nodal, and skeletal recurrences at low PSA levels. Future diagnostic perspectives include the clinical implementation of PET/MRI scanners, multimodal fusion imaging platforms for retrospective co-registration of PET and MR images, real time transrectal ultrasound/mpMRI fusion imaging, and novel organ-specific PET radiotracers. PMID- 26435745 TI - The role of the implementation of policies for the prevention of exposure to Radon in Brazil-a strategy for controlling the risk of developing lung cancer. AB - Lung cancer is the leading cause of cancer death in the United States and other industrialised countries. The most important risk factor is active smoking. However, given the increased incidence of lung cancer in non-smokers, it is necessary to improve knowledge regarding other risk factors. Radon (Rn) is a noble gas and is the most important natural source of human exposure to ionizing radiation. Exposure to high levels of this radioactive gas is related to an increased risk of developing lung cancer. The objective of this work is to highlight the importance of measuring indoor concentration of this gas and identify which steps should be taken for achieving radiological protection. A survey was conducted on the websites of the National Health Surveillance Agency (ANVISA), LAMIN (Mineral Analysis Laboratory), CPRM (Geological Survey of Brazil), Ministry of Health and PubMed. Using the words 'radon', 'lung', 'cancer', and PubMed(r), 1,371 results were obtained; when using the words 'radon', 'lung', 'cancer', and with 'Brazil' or 'Brazilians', only six results were obtained. We emphasise that lung cancer is a major public health problem and the exposure to Rn indoors should be considered as a risk factor for lung cancer in non-smokers. Buildings or houses with high concentrations of Rn should be identified. However, currently in Brazil-a country with great potential for mineral extraction-there are no specific regulated recommendations to control indoor exposure to Rn. PMID- 26435746 TI - Laparoscopic extraperitoneal para-aortic lymphadenectomy. AB - Lymph nodes are the main pathway in the spread of gynaecological malignancies, being a well-known prognostic factor. Lymph node dissection is a complex surgical procedure and requires surgical expertise to perform the procedure, thereby minimising complications. In addition, lymphadenectomy has value in the diagnosis, prognosis, and treatment of patients with gynaecologic cancer. Therefore, a video focused on the para-aortic retroperitoneal anatomy and the surgical technique of the extraperitoneal para-aortic lymphadenectomy is presented. PMID- 26435747 TI - Living better or living longer? Perceptions of patients and health care professionals in oncology. AB - BACKGROUND: Cancer can influence the views of patients on treatment goals and make them different from those of health care professionals (HCPs). It is crucial to understand patient expectations regarding cancer treatment. METHODS: We performed a cross-sectional survey of patients with cancer and HCPs to evaluate their perceptions about treatment priorities and to analyse variables that might influence their opinions. To identify treatment choices, we interviewed all participants using a structured questionnaire with fictitious case vignettes. RESULTS: We enrolled a total of 230 participants, including 144 patients and 86 HCPs (35 nurses, 21 physicians, 30 others). Treatment priority between survival time (28.5% for patients vs. 8.1% for HCP) and quality of life (45.8% vs. 87.2%) differed significantly, with the remaining participants stating they were uncertain or unwilling to respond, or providing invalid responses (P < 0.01). In logistic regression, prioritising survival time was more frequent in patients, adjusting for age and gender (odds ratio (OR) = 3.95; P < 0.01). The view that the physician alone should be responsible for treatment choices was more frequent among patients than HCPs (18.8 vs. 5.8%; P = 0.01). CONCLUSIONS: In Brazil, our results suggest that survival time is more important for patients with cancer than for HCPs, whereas quality of life is more important for HCPs than for patients with cancer, who place great emphasis on physicians as decision-makers. Given that Brazilian patients often rely on physicians for decisions, the potential impact of different priorities between survival time and quality of life when patients and HCPs are compared is unknown. PMID- 26435748 TI - The Role of Molecular Imaging in Drug Delivery. AB - The parallel development of molecular imaging and drug delivery allows the combination of therapeutic agents with imaging moieties, which facilitates visualisation of the drug delivery process and provides a realtime readout on the in vivo efficacy of a therapeutic agent. Although challenging, it is feasible to construct a highly versatile, multifunctional single 'theranostic' probe for quantitative molecular imaging, targeted drug delivery and controlled drug release to obtain an effective therapeutic response. Compared with conventional methods for the evaluation of pharmacokinetics/pharmacodynamics, molecular imaging has advantages such as substantially decreasing the workload and increasing the volume of more precise data with statistical relevance. More importantly, molecular imaging techniques bridge the gap between pre-clinical and clinical research to develop candidate drugs that have the optimal target specificity, pharmacodynamics and efficacy. With the advancement and integration of technology in various fields, diverse types of targeted imaging probe coupled with drug delivery potential have been developed. Preliminary data have demonstrated that it is feasible and promising to use these targeted carriers for simultaneous target imaging and drug delivery. PMID- 26435749 TI - Epigenetics and the overhealing wound: the role of DNA methylation in fibrosis. AB - Fibrosis is a progressive and potentially fatal process that can occur in numerous organ systems. Characterised by the excessive deposition of extracellular matrix proteins such as collagens and fibronectin, fibrosis affects normal tissue architecture and impedes organ function. Although a considerable amount of research has focused on the mechanisms underlying disease pathogenesis, current therapeutic options do not directly target the pro-fibrotic process. As a result, there is a clear unmet clinical need to develop new agents. Novel findings implicate a role for epigenetic modifications contributing to the progression of fibrosis by alteration of gene expression profiles. This review will focus on DNA methylation; its association with fibroblast differentiation and activation and the consequent buildup of fibrotic scar tissue. The potential use of therapies that modulate this epigenetic pathway for the treatment of fibrosis in several organ systems is also discussed. PMID- 26435750 TI - Global DNA Methylation patterns on marsupial and devil facial tumour chromosomes. AB - BACKGROUND: Despite DNA methylation being one of the most widely studied epigenetic modifications in eukaryotes, only a few studies have examined the global methylation status of marsupial chromosomes. The emergence of devil facial tumour disease (DFTD), a clonally transmissible cancer spreading through the Tasmanian devil population, makes it a particularly pertinent time to determine the methylation status of marsupial and devil facial tumour chromosomes. DNA methylation perturbations are known to play a role in genome instability in human tumours. One of the interesting features of the devil facial tumour is its remarkable karyotypic stability over time as only four strains with minor karyotypic differences having been reported. The cytogenetic monitoring of devil facial tumour (DFT) samples collected over an eight year period and detailed molecular cytogenetic analysis performed on the different DFT strains enables chromosome rearrangements to be correlated with methylation status as the tumour evolves. RESULTS: We used immunofluorescent staining with an antibody to 5 methylcytosine on metaphase chromosomes prepared from fibroblast cells of three distantly related marsupials, including the Tasmanian devil, as well as DFTD chromosomes prepared from samples collected from different years and representing different karyotypic strains. Staining of chromosomes from male and female marsupial cell lines indicate species-specific differences in global methylation patterns but with the most intense staining regions corresponding to telomeric and/or centromeric regions of autosomes. In males, the X chromosome was hypermethylated as was one X in females. Similarly, telomeric regions on DFTD chromosomes and regions corresponding to material from one of the two X chromosomes were hypermethylated. No difference in global methylation in samples of the same strain taken in different years was observed. CONCLUSIONS: The methylation patterns on DFTD chromosomes suggests that the hypermethylated active X was shattered in the formation of the tumour chromosomes, with atypical areas of methylation on DFTD chromosomes corresponding to locations of X chromosome material from the shattered X. The incredibly stable broad methylation patterns observed between strains and over time may reflect the overall genomic stability of the devil facial tumour. PMID- 26435751 TI - Neurologic injuries after primary total ankle arthroplasty: prevalence and effect on outcomes. AB - BACKGROUND: Neurologic injuries are complications that can arise after total joint arthroplasty. However, no comprehensive study has been conducted on peripheral nerve injuries after total ankle arthroplasty. The purpose of the present study was to identify the prevalence of neurologic injury following primary total ankle arthroplasty, the predisposing factors, and evaluate the effect on clinical outcomes. METHODS: We retrospectively analyzed 150 consecutive primary total ankle arthroplasty using the mobile-bearing prosthesis between January 2005 and December 2011, in 150 patients with symptomatic ankle end-stage arthritis. All the patients were divided into groups according to whether they had postoperative peripheral neuropathy (23 patients) or not (127 patients). We investigated the prevalence, predisposing factors, and effect on clinical outcomes of neurologic injuries. The mean age was 61.3 years, and the mean follow up period was 41.8 months. RESULTS: There were 23 nerve injuries (15.3 %), including nine in posterior tibial nerves, six superficial peroneal nerves, six deep peroneal nerves, one saphenous nerve, and one sural nerve. Neurologic injury was significantly associated with the development of posttraumatic osteoarthritis, but it was not significantly associated with other predisposing factors, such as age, gender, body mass index, and symptom duration. Of the 23 nerve injuries, 13 (56.5 %) presented a complete, spontaneous recovery, 9 (39.1 %) presented an incomplete recovery, and 1 (4.3 %) presented no recovery. The patients with neurologic injury had significantly lower American Orthopaedic Foot and Ankle Society scores and lower levels of patient satisfaction. CONCLUSIONS: The results of this study suggest that the prevalence of neurologic injury after total ankle arthroplasty is considerable, and that neurologic injury is associated with low levels of patient satisfaction and poor clinical outcomes at mean of 3 years, postoperatively. Care is needed to reduce the occurrence of neurologic injuries. PMID- 26435752 TI - Specific detection of OCT4 isoforms in inflammatory bowel disease. AB - BACKGROUND: Developmentally early cells are mobilized into peripheral blood in Crohn's disease (CD) patients. OCT4, is considered to be important in sustaining the pluripotency of stem cells. OCT4 splicing variants are differentially expressed in pluripotent and non-pluripotent cells. Our study aims to investigate the expression pattern of OCT4 variants and SOX-2, an essential factor implicated in self-renewal and pluripotency, in tissue and blood samples from patients with IBD. METHODS: Peripheral blood and tissue samples were collected from patients with active CD and ulcerative colitis (UC), and from healthy individuals. OCT4 expression was documented by Western blot, immunohistochemistry and by reverse transcription-real-time PCR. OCT4 isoform determination was documented using specific primers. SOX-2 expression levels were also evaluated. RESULTS: OCT4 protein levels were significantly higher in CD tissue samples than in CD blood samples, and in UC tissue samples. OCT4 protein was localized mainly in the cytosol. In all samples, only the OCT4 pseudogenes and the OCT4B1 variant were detected. OCT4B1 expression levels were elevated in both tissue and blood samples from CD and UC cases compared to healthy controls. In CD patients only SOX-2 mRNA levels were found slightly increased compared to healthy controls. CONCLUSION: Our results suggest that OCT4 is expressed in patients with IBD. Furthermore, we found the presence of the OCT4B1 isoform in IBD in both tissue and blood samples. Our results have shown, that developmentally early cells might be mobilized into peripheral blood as result of tissue damage, indicating a possible role of these cells in repair of injured intestinal tract. PMID- 26435753 TI - Differential expression of genes encoding proteins of the HGF/MET system in insulinomas. AB - BACKGROUND: Insulinomas are the most common functional pancreatic neuroendocrine tumors, whereas histopathological features do not predict their biological behaviour. In an attempt to better understand the molecular processes involved in the tumorigenesis of islet beta cells, the present study evaluated the expression of genes belonging to the hepatocyte growth factor and its receptor (HGF/MET) system, namely, MET, HGF; HGFAC and ST14 (encode HGF activator and matriptase, respectively, two serine proteases that catalyze conversion of pro-HGF to active HGF); and SPINT1 and SPINT2 (encode serine peptidase inhibitors Kunitz type 1 and type 2, respectively, two inhibitors of HGF activator and of matriptase). METHODS: Quantitative real-time reverse transcriptase polymerase chain reaction was employed to assess RNA expression of the target genes in 24 sporadic insulinomas: 15 grade 1 (G1), six grade 2 (G2) and three hepatic metastases. Somatic mutations of MET gene were searched by direct sequencing of exons 2, 10, 14, 16, 17 and 19. RESULTS: Overexpression of MET was observed in the three hepatic metastases concomitantly with upregulation of the genes encoding HGF and matriptase and downregulation of SPINT1. A positive correlation was observed between MET RNA expression and Ki-67 proliferation index while a negative correlation was detected between SPINT1 expression and the mitotic index. No somatic mutations were found in MET gene. CONCLUSION: The final effect of the increased expression of HGF, its activator (matriptase) and its specific receptor (MET) together with a decreased expression of one potent inhibitor of matriptase (SPINT1) is probably a contribution to tumoral progression and metastatization in insulinomas. PMID- 26435755 TI - Rapid morphological characterization of isolated mitochondria using Brownian motion. AB - Mitochondrial morphology has been associated with numerous pathologies including cancer, diabetes, obesity and heart disease. However, the connection is poorly understood-in part due to the difficulty of characterizing the morphology. This impedes the use of morphology as a tool for disease detection/monitoring. Here, we use the Brownian motion of isolated mitochondria to characterize their size and shape in a high throughput fashion. By using treadmill exercise training, mitochondria from heart and gastrocnemius of Balb/c mice were modulated in size and used to investigate the protocol. Consistent with previous reports, the heart mitochondria of untrained mice increased 5% in diameter immediately after a single bout of moderate exercise (1.091 +/- 0.004 MUm) as compared to completely sedentary controls (1.040 +/- 0.022 MUm). In addition, no change was observed in the size of gastrocnemius mitochondria (1.025 +/- 0.018 MUm), which was also in agreement with previous studies. The method was also successfully applied to smaller Saccharomyces cerevisiae mitochondria. PMID- 26435756 TI - Rapid vs. delayed infrared responses after ischemia reveal recruitment of different vascular beds. AB - Continuous infrared imaging revealed transient changes in forearm temperature during arterial occlusion, reperfusion, and recovery in a healthy subject group. Processing the imaging data with the k-means algorithm further revealed reactive vascular sites in the skin with rapid or delayed temperature amplification. The observed temporal and spatial diversity of blood-flow-derived forearm temperature allow consideration of thermal-imaging guided placement of skin sensors to achieve enhanced sensitivity in monitoring of skin hemodynamics. PMID- 26435754 TI - Spotting the enemy within: Targeted silencing of foreign DNA in mammalian genomes by the Kruppel-associated box zinc finger protein family. AB - Tandem C2H2-type zinc finger proteins (ZFPs) constitute the largest transcription factor family in animals. Tandem-ZFPs bind DNA in a sequence-specific manner through arrays of multiple zinc finger domains that allow high flexibility and specificity in target recognition. In tetrapods, a large proportion of tandem ZFPs contain Kruppel-associated-box (KRAB) repression domains, which are able to induce epigenetic silencing through the KAP1 corepressor. The KRAB-ZFP family continuously amplified in tetrapods through segmental gene duplications, often accompanied by deletions, duplications, and mutations of the zinc finger domains. As a result, tetrapod genomes contain unique sets of KRAB-ZFP genes, consisting of ancient and recently evolved family members. Although several hundred human and mouse KRAB-ZFPs have been identified or predicted, the biological functions of most KRAB-ZFP family members have gone unexplored. Furthermore, the evolutionary forces driving the extraordinary KRAB-ZFP expansion and diversification have remained mysterious for decades. In this review, we highlight recent studies that associate KRAB-ZFPs with the repression of parasitic DNA elements in the mammalian germ line and discuss the hypothesis that the KRAB-ZFP family primarily evolved as an adaptive genomic surveillance system against foreign DNA. Finally, we comment on the computational, genetic, and biochemical challenges of studying KRAB-ZFPs and attempt to predict how these challenges may be soon overcome. PMID- 26435757 TI - Influence of restoration adjustments on prefrontal blood flow: A simplified NIRS preliminary study. AB - OBJECTIVE: The aim of this study was to examine, after setting several restorations, the influence of adjusted occlusal interference during gum chewing on blood flow in the prefrontal area as determined using near-infrared spectroscopy. MATERIAL AND METHODS: The physiological rate was assessed using a visual analog scale (VAS) questionnaire. We selected 16 patients who desired prosthetic restorative treatment on the lateral dentition, and eight healthy volunteers. Subjects were divided into three eight-person groups. One group received restorations on the premolar area (PA), another group received restorations on the molar area (MA), and the control group (CT) received no prosthetic restorations. The spectroscope was fastened to the frontal region of the head after placement of the final restoration, but before adjustment. RESULTS: Pre-adjustment (first gum chewing for CT) blood flow in the prefrontal cortex was measured during gum chewing. Blood flow was again measured during gum chewing after the restoration (second gum chewing for CT) had been adjusted in accordance with the subjective assessment of the patient while wearing the device. The VAS provided quantification of comfort during gum chewing before and after restoration adjustment. For the PA and MA groups, adjusting restorations decreased discomfort significantly during gum chewing. Moreover, in the MA group, prefrontal blood flow was significantly reduced, and blood flow correlated with discomfort. CONCLUSIONS: Activation of the prefrontal area may provide an objective criterion for judging the functionality of occlusion after prosthetic occlusal reconstruction and/or orthodontics. PMID- 26435759 TI - Man, You Might Look Like a Woman-If a Child Is Next to You. AB - Gender categorization seems prone to a pervasive bias: Persons about whom null or ambiguous gender information is available are more often considered male than female. Our study assessed whether such a male-bias is present in non-binary choice tasks and whether it can be altered by social contextual information. Participants were asked to report their perception of an adult figure's gender in three context conditions: (1) alone, (2) passively besides a child, or (3) actively helping a child (n = 10 pictures each). The response options male, female and I don't know were provided. As a result, participants attributed male gender to most figures and rarely used the I don't know option in all conditions, but were more likely to attribute female gender to the same adult figure if it was shown with a child. If such social contextual information was provided in the first rather than the second block of the experiment, subsequent female gender attributions increased for adult figures shown alone. Additionally, female gender attributions for actively helping relative to passive adults were made more often. Thus, we provide strong evidence that gender categorization can be altered by social context even if the subject of gender categorization remains identical. PMID- 26435758 TI - Cheminformatics Research at the Unilever Centre for Molecular Science Informatics Cambridge. AB - The Centre for Molecular Informatics, formerly Unilever Centre for Molecular Science Informatics (UCMSI), at the University of Cambridge is a world-leading driving force in the field of cheminformatics. Since its opening in 2000 more than 300 scientific articles have fundamentally changed the field of molecular informatics. The Centre has been a key player in promoting open chemical data and semantic access. Though mainly focussing on basic research, close collaborations with industrial partners ensured real world feedback and access to high quality molecular data. A variety of tools and standard protocols have been developed and are ubiquitous in the daily practice of cheminformatics. Here, we present a retrospective of cheminformatics research performed at the UCMSI, thereby highlighting historical and recent trends in the field as well as indicating future directions. PMID- 26435760 TI - The Prediction of Students' Academic Performance With Fluid Intelligence in Giving Special Consideration to the Contribution of Learning. AB - The present study provides a new account of how fluid intelligence influences academic performance. In this account a complex learning component of fluid intelligence tests is proposed to play a major role in predicting academic performance. A sample of 2, 277 secondary school students completed two reasoning tests that were assumed to represent fluid intelligence and standardized math and verbal tests assessing academic performance. The fluid intelligence data were decomposed into a learning component that was associated with the position effect of intelligence items and a constant component that was independent of the position effect. Results showed that the learning component contributed significantly more to the prediction of math and verbal performance than the constant component. The link from the learning component to math performance was especially strong. These results indicated that fluid intelligence, which has so far been considered as homogeneous, could be decomposed in such a way that the resulting components showed different properties and contributed differently to the prediction of academic performance. Furthermore, the results were in line with the expectation that learning was a predictor of performance in school. PMID- 26435761 TI - Executive Resources and Item-Context Binding: Exploring the Influence of Concurrent Inhibition, Updating, and Shifting Tasks on Context Memory. AB - Previous research has demonstrated that context memory performance decreases as a result of cognitive load. However, the role of specific executive resources availability has not been specified yet. In a dual-task experiment, participants performed three kinds of concurrent task engaging: inhibition, updating, or shifting operations. In comparison with a no-load single-task condition, a significant decrease in item and context memory was observed, regardless of the kind of executive task. When executive load conditions were compared with non specific cognitive load conditions, a significant interference effect was observed in the case of the inhibition task. The inhibition process appears to be an aspect of executive control, which relies on the same resource as item-context binding does, especially when binding refers to associations retrieved from long term memory. PMID- 26435762 TI - Effects of Neighborhood Density on Adult Word Repetition. AB - Presumable lexical competition has been found to result in higher perceptual accuracy for words with few versus many neighbors. Previous studies have typically only analyzed the lexical-semantic level, however. In order to also explore the possibility of phonological effects, a word repetition task was administered to 46 typical adults in which 80 stimuli differed only in neighborhood density. In contrast to previous studies, verbal responses were elicited in order to analyze productions holistically and segmentally at the phonological level. An additional error analysis examined differences in neighborhood density between target words and substitutions. Findings revealed that words with more neighbors facilitated recognition, and were more accurately repeated than those with fewer neighbors. When a target word was misperceived, its substitution tended to be higher in neighborhood density, unrelated to word frequency. In order to interpret these results, an account of lexical competition is re-visited with consideration of characteristics of the lexicon discovered using graph theory (Vitevitch, 2008). PMID- 26435763 TI - Vaginal and Oral Sex Initiation Timing: A Focus on Gender and Race/Ethnicity. AB - OBJECTIVES: Most previous studies on sexual initiation timing have examined its effects on a variety of subsequent outcomes without first examining the correlates and predictors of these timing categories. Studies that do exist often do not utilize samples through young adulthood, leading to a misclassified set of sexual timing categories. In addition, the literature does not adequately address the issues of oral sex timing. Therefore, the objectives of this study were 1) to explore age-cutoffs that mark the "normative" and "non-normative" entry into vaginal and oral sex among young women and men in the U.S., creating sexual four sexual initiation timing categories - "early," "normative," "late," and "inexperienced," and; 2) to examine the association between race/ethnicity and sexual initiation timing by gender. METHODS: The National Longitudinal Study of Adolescent to Adult Health (Add Health) was used in both descriptive and multivariate contexts to determine the net association of gender and race/ethnicity with vaginal and oral sex initiation timing. RESULTS: Age-cutoffs for vaginal sex timing were similar for women and men, yet differed by gender for oral sex timing. Women were more likely than men to initiate vaginal sex (20% vs. 18%) and oral sex (19% vs. 16%) at an early age and less likely than men to initiate these behaviors at a late age (18% vs. 19% for vaginal sex, and 15% vs. 16% for oral sex). Although most respondents initiated these two behaviors by young adulthood, a considerable proportion remained inexperienced, with men more likely than women to report inexperience with vaginal sex (7% vs. 5%), and women more likely than men to report abstaining from oral sex (8% vs. 6%). Race/ethnic differences in sexual initiation timing remained robust in the face of controls for both women and men. CONCLUSIONS: Understanding the timing at which adolescents and young adults transition to first vaginal and first oral sex is critical for sex education curriculum and policy makers. PMID- 26435764 TI - Exsolution of Fe and SrO Nanorods and Nanoparticles from Lanthanum Strontium Ferrite La0.6Sr0.4FeO3-delta Materials by Hydrogen Reduction. AB - Formation of uniform Fe and SrO rods as well as nanoparticles following controlled reduction of La0.6Sr0.4FeO3-delta (LSF) and Ni-LSF samples in dry and moist hydrogen is studied by aberration-corrected electron microscopy. Metallic Fe and SrO precipitate from the perovskite lattice as rods of several tenths of nm and thicknesses up to 20 nm. Based on a model of Fe whisker growth following reduction of pure iron oxides, Fe rod exsolution from LSF proceeds via rate limiting lattice oxygen removal. This favors the formation of single iron metal nuclei at the perovskite surface, subsequently growing as isolated rods. The latter is only possible upon efficient removal of reduction-induced water and, subsequently, reduction of Fe +III/+IV to Fe(0). If water remains in the system, no reduction or rod formation occurs. In contrast, formation of SrO rods following reduction in dry hydrogen is a catalytic process aided by Ni particles. It bears significant resemblance to surface diffusion-controlled carbon whisker growth on Ni, leading to similar extrusion rods and filaments. In addition to SrO rod growth, the exsolution of Fe nanoparticles and, subsequently, Ni-Fe alloy particles is observed. The latter have also been observed under static hydrogen reduction. Under strict control of the experimental parameters, the presented data therefore open an attractive chemically driven pathway to metal nanoarchitectures beyond the formation of "simple" nanoparticles. PMID- 26435765 TI - A Synthetic Butenolide Diterpene is now a Natural Product Isolated from Metaporana sericosepala, a Plant from the Madagascar Dry Forest. AB - Antiproliferative bioassay-guided fractionation of the ethanolic extract of the endemic Madagascan plant Metaporana sericosepala led to the first natural product isolation of a butenolide diterpene, which was synthesized during an anti inflammatory study in 1988. The structure of the compound was elucidated as 3 homofarnesyl-4-hydroxybutenolide (1) by analysis of its spectroscopic data, including 1D- and 2D-NMR data and chemical evidence. The once synthetic compound can now also be considered as a natural product. Compound 1 had modest antiproliferative activity towards the A2780 ovarian cancer cell line,with an IC50 value of 8 uM. PMID- 26435766 TI - Reduction Mammoplasty: A Comparison Between Operations Performed by Plastic Surgery and General Surgery. AB - BACKGROUND: Reduction mammoplasty is an often-performed procedure by plastic surgeons and increasingly by general surgeons. The question has been posed in both general surgical literature and plastic surgical literature as to whether this procedure should remain the domain of surgical specialists. Some general surgeons are trained in breast reductions, whereas all plastic surgeons receive training in this procedure. The National Surgical Quality Improvement Project provides a unique opportunity to compare the 2 surgical specialties in an unbiased manner in terms of preoperative comorbidities and 30-day postoperative complications. METHODS: The National Surgical Quality Improvement Project database was queried for the years 2005-2012. Patients were identified as having undergone a reduction mammoplasty by Current Procedural Terminology codes. RESULTS were refined to include only females with an International Classification of Diseases, Ninth Revision, code of 611.1 (hypertrophy of breasts). Information was collected regarding age, surgical specialty performing procedure, body mass index, and other preoperative variables. The outcomes utilized were presence of superficial surgical site infection, presence of deep surgical site infection, presence of wound dehiscence, postoperative respiratory compromise, pulmonary embolism, deep vein thrombosis, perioperative transfusion, operative time, reintubation, reoperation, and length of hospital stay. RESULTS: During this time period, there were 6239 reduction mammaplasties performed within the National Surgical Quality Improvement Project database: 339 by general surgery and 5900 by plastic surgery. No statistical differences were detected between the 2 groups with regard to superficial wound infections, deep wound infections, organ space infections, or wound dehiscence. There were no significant differences noted between within groups with regard to systemic postoperative complications. Patients undergoing a procedure by general surgery were more likely to experience a failure of skin flaps, necessitating a return to the operative room (P < .05). Operative time was longer in procedures performed by general surgery (P < .05). CONCLUSION: Several important differences appear to exist between reduction mammaplasties performed by general surgery and plastic surgery. A focused training in reduction mammoplasty appears to be beneficial to the patient. The limitations of this study include a lack of long-term follow-up with regard to aesthetic outcome, nipple malposition, nipple sensation, and late wound sequelae. PMID- 26435767 TI - Continuous Re-Exposure to Environmental Sound Cues During Sleep Does Not Improve Memory for Semantically Unrelated Word Pairs. AB - Two recent studies illustrated that cues present during encoding can enhance recall if re-presented during sleep. This suggests an academic strategy. Such effects have only been demonstrated with spatial learning and cue presentation was isolated to slow wave sleep (SWS). The goal of this study was to examine whether sounds enhance sleep-dependent consolidation of a semantic task if the sounds are re-presented continuously during sleep. Participants encoded a list of word pairs in the evening and recall was probed following an interval with overnight sleep. Participants encoded the pairs with the sound of "the ocean" from a sound machine. The first group slept with this sound; the second group slept with a different sound ("rain"); and the third group slept with no sound. Sleeping with sound had no impact on subsequent recall. Although a null result, this work provides an important test of the implications of context effects on sleep-dependent memory consolidation. PMID- 26435768 TI - Emerging role of microRNAs in cancer stem cells: Implications in cancer therapy. AB - A small subset of cancer cells that act as tumor initiating cells or cancer stem cells (CSCs) maintain self-renewal and growth promoting capabilities of cancer and are responsible for drug/treatment resistance, tumor recurrence and metastasis. Due to their potential clinical importance, many researchers have put their efforts over decades to unravel the molecular mechanisms that regulate CSCs functions. MicroRNAs (miRNAs) which are 21-23 nucleotide long, endogenous non coding RNAs, regulate gene expression through gene silencing at post transcriptional level by binding to the 3'-untranslated regions or the open reading frames of target genes, thereby result in target mRNA degradation or its translational repression and serve important role in several cellular, physiological and developmental processes. Aberrant miRNAs expression and their implication in CSCs regulation by controlling asymmetric cell division, drug/treatment resistance and metastasis make miRNAs a tool of great therapeutic potential against cancer. Recent advancements on the biological complexities of CSCs, modulation in CSCs properties by miRNA network and development of miRNA based treatment strategies specifically targeting the CSCs as an attractive therapeutic targets for clinical application are being critically analysed. PMID- 26435770 TI - From cellular to chemical approach for acute neural and alternative options for age-induced functional diseases. AB - Endogenous "stem cell niche" (SCN) accompanying vessels contains immune system components which in vivo determine differentiation of multi potent stem cells toward proper cell types in given tissue. Combinations of sex steroids may represent novel chemical approach for neuronal areas of regenerative medicine, since they cause transformation of vascular smooth muscle stem cells into differentiating neuronal cells. Circulating sex steroids are present during pregnancy and can be utilized where needed, when various embryonic/fetal tissues develop from their stem cells. Utilization of induced regeneration of tissues (regenerative medicine) is expected being more effective in sudden failures of younger individuals carrying intact SCN, as compared to established chronic disorders caused by SCN alteration. An essential component of SCN are monocyte derived cells exhibiting tissue-specific "stop effect" (SE) preventing, for instance, an aging of neuronal cells. Its alteration causes that implantation of neuronal stem cells will also result in their differentiation toward aging cells. When we repair the SE by supply of circulating mononuclear cells from young healthy individuals, we may be able to provide novel regenerative treatments of age-induced neural diseases by sex steroid combinations. Questions regarding some age-induced body alterations are also addressed. PMID- 26435772 TI - Autologous tissue patch rich in stem cells created in the subcutaneous tissue. AB - AIM: To investigate whether we could create natural autologous tissue patches in the subcutaneous space for organ repair. METHODS: We implanted the following three types of inert foreign bodies in the subcutaneous tissue of rats to produce autologous tissue patches of different geometries: (1) a large-sized polyvinyl tube (L = 25 mm, internal diameter = 7 mm) sealed at both ends by heat application for obtaining a large flat piece of tissue patch for organ repair; (2) a fine polyvinyl tubing (L = 25 mm, internal diameter = 3 mm) for creating cylindrically shaped grafts for vascular or nerve repair; and (3) a slurry of polydextran particle gel for inducing a bladder-like tissue. Implantation of inert materials was carried out by making a small incision on one or either side of the thoracic-lumbar region of rats. Subcutaneous pockets were created by blunt dissection around the incision into which the inert bodies were inserted (1 or 2 per rat). The incisions were closed with silk sutures, and the animals were allowed to recover. In case of the polydextran gel slurry 5 mL of the slurry was injected in the subcutaneous space using an 18 gauge needle. After implanting the foreign bodies a newly regenerated encapsulating tissue developed around the foreign bodies. The tissues were harvested after 4-42 d of implantation and studied by gross examination, histology, and histochemistry for organization, vascularity, and presence of mesenchymal stem cells (MSCs) (CD271+CD34+ cells). RESULTS: Implanting a large cylindrically shaped polyvinyl tube resulted in a large flat sheet of tissue that could be tailored to a specific size and shape for use as a tissue patch for repairing large organs. Implanting a smaller sized polyvinyl tube yielded a cylindrical tissue that could be useful for repairing nerves and blood vessels. This type of patch could be obtained in different lengths by varying the length of the implanted tube. Implanting a suspension of inert polydextran suspension gave rise to a bladder-like tissue that could be potentially used for repairing heart valves. Histologically, the three different types of tissue patches generated were organized similarly, consisting of three layers, increasing in thickness until day 14. The inner layer in contact with the inert material was avascular; a middle layer that was highly vascular and filled with matrix, and an outer layer consisting of loose connective tissue. MSCs identified as CD271+CD34+ cells were present in the medial layer and around major blood vessels at day 4 but absent at later time points. The early-harvested tissues, endowed with MSCs, could be used for tissue repair, while the later harvested tissues, being less vascular but thicker and tougher, could be used as filler tissue for cosmetic purposes. CONCLUSION: An autologous, vascularized tissue patch of desired shape and size can be created in the subcutaneous space by implanting different types of inert bodies. PMID- 26435771 TI - Stem cells: An eventual treatment option for heart diseases. AB - Stem cells are of global excitement for various diseases including heart diseases. It is worth to understand the mechanism or role of stem cells in the treatment of heart failure. Bone marrow derived stem cells are commonly practiced with an aim to improve the function of the heart. The majority of studies have been conducted with acute myocardial infarction and a few has been investigated with the use of stem cells for treating chronic or dilated cardiomyopathy. Heterogeneity in the treated group using stem cells has greatly emerged. Ever increasing demand for any alternative made is of at most priority for cardiomyopathy. Stem cells are of top priority with the current impact that has generated among physicians. However, meticulous selection of proper source is required since redundancy is clearly evident with the present survey. This review focuses on the methods adopted using stem cells for heart diseases and outcomes that are generated so far with an idea to determine the best therapeutic possibility in order to fulfill the present demand. PMID- 26435769 TI - Complement activation in the context of stem cells and tissue repair. AB - The complement pathway is best known for its role in immune surveillance and inflammation. However, its ability of opsonizing and removing not only pathogens, but also necrotic and apoptotic cells, is a phylogenetically ancient means of initiating tissue repair. The means and mechanisms of complement-mediated tissue repair are discussed in this review. There is increasing evidence that complement activation contributes to tissue repair at several levels. These range from the chemo-attraction of stem and progenitor cells to areas of complement activation, to increased survival of various cell types in the presence of split products of complement, and to the production of trophic factors by cells activated by the anaphylatoxins C3a and C5a. This repair aspect of complement biology has not found sufficient appreciation until recently. The following will examine this aspect of complement biology with an emphasis on the anaphylatoxins C3a and C5a. PMID- 26435773 TI - Easily-handled method to isolate mesenchymal stem cells from coagulated human bone marrow samples. AB - AIM: To establish an easily-handled method to isolate mesenchymal stem cells (MSCs) from coagulated human bone marrow samples. METHODS: Thrombin was added to aliquots of seven heparinized human bone marrow samples to mimic marrow coagulation. The clots were untreated, treated with urokinase or mechanically cut into pieces before culture for MSCs. The un-coagulated samples and the clots were also stored at 4 degrees C for 8 or 16 h before the treatment. The numbers of colony-forming unit-fibroblast (CFU-F) in the different samples were determined. The adherent cells from different groups were passaged and their surface profile was analyzed with flow cytometry. Their capacities of in vitro osteogenesis and adipogenesis were observed after the cells were exposed to specific inductive agents. RESULTS: The average CFU-F number of urokinase-treated samples (16.85 +/- 11.77/10(6)) was comparable to that of un-coagulated control samples (20.22 +/- 10.65/10(6), P = 0.293), which was significantly higher than those of mechanically-cut clots (6.5 +/- 5.32/10(6), P < 0.01) and untreated clots (1.95 +/- 1.86/10(6), P < 0.01). The CFU-F numbers decreased after samples were stored, but those of control and urokinase-treated clots remained higher than the other two groups. Consistently, the numbers of the attached cells at passage 0 were higher in control and urokinase-treated clots than those of mechanically-cut clots and untreated clots. The attached cells were fibroblast-like in morphology and homogenously positive for CD44, CD73 and CD90, and negative for CD31 and CD45. Also, they could be induced to differentiate into osteoblasts and adipocytes in vitro. CONCLUSION: Urokinase pretreatment is an optimal strategy to isolate MSCs from human bone marrow samples that are poorly aspirated and clotted. PMID- 26435774 TI - Role of computed tomography angiography in detection and staging of small bowel carcinoid tumors. AB - Small-bowel carcinoid tumors are the most common form (42%) of gastrointestinal carcinoids, which by themselves comprise 70% of neuroendocrine tumors. Although primary small bowel neoplasms are overall rare (3%-6% of all gastrointestinal neoplasms), carcinoids still represent the second most common (20%-30%) primary small-bowel malignancy after small bowel adenocarcinoma. Their imaging evaluation is often challenging. State-of-the-art high-resolution multiphasic computed tomography together with advanced postprocessing methods provides an excellent tool for their depiction. The manifold interactive parameter choices however require knowledge of when to use which technique. Here, we discuss the imaging appearance and evaluation of duodenal, jejunal and ileal carcinoid tumors, including the imaging features of the primary tumor, locoregional mesenteric nodal metastases, and distant metastatic disease. A protocol for optimal lesion detection is presented, including the use of computed tomography enterography, volume acquisition, computed tomography angiography and three-dimensional mapping. Imaging findings are illustrated with a series of challenging cases which illustrate the spectrum of possible disease in the small bowel and mesentery, the range of possible appearances in the bowel itself on multiphase data and extraluminal findings such as the desmoplastic reaction in mesentery and hypervascular liver metastases. Typical imaging pitfalls and pearls are illustrated. PMID- 26435776 TI - Imaging evaluation of traumatic thoracolumbar spine injuries: Radiological review. AB - Spine fractures account for a large portion of musculoskeletal injuries worldwide. A classification of spine fractures is necessary in order to develop a common language for treatment indications and outcomes. Several classification systems have been developed based on injury anatomy or mechanisms of action, but they have demonstrated poor reliability, have yielded little prognostic information, and have not been widely used. For this reason, the Arbeitsgemeinschaftfur Osteosynthesefragen (AO) committee has classified thorocolumbar spine injuries based on the pathomorphological criteria into3 types (A: Compression; B: Distraction; C: Axial torque and rotational deformity). Each of these types is further divided into 3 groups and 3 subgroups reflecting progressive scale of morphological damage and the degree of instability. Because of its highly detailed sub classifications, the AO system has shown limited interobserver variability. It is similar to its predecessors in that it does not incorporate the patient's neurologic status.The need for a reliable, reproducible, clinically relevant, prognostic classification system with an optimal balance of ease of use and detail of injury description contributed to the development of a new classification system, the thoracolumbar injury classification and severity score (TLICS). The TLICS defines injury based on three clinical characteristics: injury morphology, integrity of the posterior ligamentous complex, and neurologic status of the patient. The severity score offers prognostic information and is helpful in decision making about surgical vs nonsurgical management. PMID- 26435775 TI - Ankylosing spondylitis: A state of the art factual backbone. AB - Ankylosing spondylitis (AS) is a chronic inflammatory disease that affects 1% of the general population. As one of the most severe types of spondyloarthropathy, AS affects the spinal vertebrae and sacroiliac joints, causing debilitating pain and loss of mobility. The goal of this review is to provide an overview of AS, from the pathophysiological changes that occur as the disease progresses, to genetic factors that are involved with its onset. Considering the high prevalence in the population, and the debilitating life changes that occur as a result of the disease, a strong emphasis is placed on the diagnostic imaging methods that are used to detect this condition, as well as several treatment methods that could improve the health of individuals diagnosed with AS. PMID- 26435778 TI - Inter- and intra-rater reliability of diffusion tensor imaging parameters in the normal pediatric spinal cord. AB - AIM: To assess inter- and intra-rater reliability (agreement) between two region of interest (ROI) methods in pediatric spinal cord diffusion tensor imaging (DTI). METHODS: Inner-Field-of-View DTI data previously acquired from ten pediatric healthy subjects (mean age = 12.10 years) was used to assess for reliability. ROIs were drawn by two neuroradiologists on each subject data twice within a 3-mo interval. ROIs were placed on axial B0 maps along the cervical spine using free-hand and fixed-size ROIs. Agreement analyses for fractional anisotropy (FA), axial diffusivity, radial diffusivity and mean diffusivity were performed using intra-class-correlation (ICC) and Cronbach's alpha statistical methods. RESULTS: Inter- and intra-rater agreement between the two ROI methods showed moderate (ICC = 0.5) to strong (ICC = 0.84). There were significant differences between raters in the number of pixels selected using free-hand ROIs (P < 0.05). However, no significant differences were observed in DTI parameter values. FA showed highest variability in ICC values (0.10-0.87). Cronbach's alpha showed moderate-high values for raters and ROI methods. CONCLUSION: The study showed that high reproducibility in spinal cord DTI can be achieved, and demonstrated the importance of setting detailed methodology for post-processing DTI data, specifically the placement of ROIs. PMID- 26435777 TI - Radiation signature on exposed cells: Relevance in dose estimation. AB - The radiation is considered as a double edged sword, as its beneficial and detrimental effects have been demonstrated. The potential benefits are being exploited to its maximum by adopting safe handling of radionuclide stipulated by the regulatory agencies. While the occupational workers are monitored by personnel monitoring devices, for general publics, it is not a regular practice. However, it can be achieved by using biomarkers with a potential for the radiation triage and medical management. An ideal biomarker to adopt in those situations should be rapid, specific, sensitive, reproducible, and able to categorize the nature of exposure and could provide a reliable dose estimation irrespective of the time of the exposures. Since cytogenetic markers shown to have many advantages relatively than other markers, the origins of various chromosomal abnormalities induced by ionizing radiations along with dose-response curves generated in the laboratory are presented. Current status of the gold standard dicentric chromosome assay, micronucleus assay, translocation measurement by fluorescence in-situ hybridization and an emerging protein marker the gamma-H2AX assay are discussed with our laboratory data. With the wide choice of methods, an appropriate assay can be employed based on the net. PMID- 26435779 TI - Intraperitoneal tuberculous abscess: Computed tomography features. AB - AIM: To evaluate the computed tomography (CT) features of intraperitoneal tuberculous abscess (IPTA). METHODS: Eight patients with IPTA confirmed by pathology were analyzed retrospectively. The clinical symptoms, medical images, and surgical findings were evaluated. Involvement of the intestine, peritoneum, viscera, and lymph nodes was also assessed. RESULTS: All 8 patients had a history of abdominal discomfort for 1 to 6 mo. Physical examination revealed a palpable abdominal mass in 6 patients. Three patients had no evidence of pulmonary tuberculosis (TB). All IPTAs (11 abscesses) were seen as a multiseptated, peripherally enhanced, hypodense mass with enlarged, rim-enhanced lymph nodes. The largest abscess diameter ranged from 4.5 cm to 12.2 cm. CT showed 2 types of IPTA: Lymph node fusion and encapsulation. Of the 8 patients, one had liver tuberculosis and one had splenic and ovarian tuberculosis. Two cases showed involvement of the terminal ileum and ileocecal junction. Ascites were found in 4 cases. Three patients had peritonitis and mesenteritis. Three patients showed involvement of the omentum. Three patients had histological evidence of caseating granuloma, and 5 had histological evidence of acid-fast bacilli. CONCLUSION: CT is crucial in the detection and characterization of IPTA. Certain CT findings are necessary for correct diagnosis. PMID- 26435780 TI - Pulmonary fibrosis and emphysema: Is the emphysema type associated with the pattern of fibrosis? AB - AIM: To investigate whether the predominant emphysema type is associated with the high resolution computed tomography (HRCT) pattern of fibrosis in combined pulmonary fibrosis and emphysema (CPFE). METHODS: Fifty-three smokers with upper lobe emphysema and lower lobe pulmonary fibrosis on - HRCT - were retrospectively evaluated. Patients were stratified into 3 groups according to the predominant type of emphysema: Centrilobular (CLE), paraseptal (PSE), CLE = PSE. Patients were also stratified into 3 other groups according to the predominant type of fibrosis on HRCT: Typical usual interstitial pneumonia (UIP), probable UIP and nonspecific interstitial pneumonia (NSIP). HRCTs were scored at 5 predetermined levels for the coarseness of fibrosis (Coarseness), extent of emphysema (emphysema), extent of interstitial lung disease (TotExtILD), extent of reticular pattern not otherwise specified (RetNOS), extent of ground glass opacity with traction bronchiectasis (extGGOBx), extent of pure ground glass opacity and extent of honeycombing. HRCT mean scores, pulmonary function tests, diffusion capacity (DLCO) and systolic pulmonary arterial pressure were compared among the groups. RESULTS: The predominant type of emphysema was strongly correlated with the predominant type of fibrosis. The centrilobular emphysema group exhibited a significantly higher extent of emphysema (P < 0.001) and a lower extent of interstitial lung disease (P < 0.002), reticular pattern not otherwise specified (P < 0.023), extent of ground glass opacity with traction bronchiectasis (P < 0.002), extent of honeycombing (P < 0.001) and coarseness of fibrosis (P < 0.001) than the paraseptal group. The NSIP group exhibited a significantly higher extent of emphysema (P < 0.05), total lung capacity (P < 0.01) and diffusion capacity (DLCO) (P < 0.05) than the typical UIP group. The typical UIP group exhibited a significantly higher extent of interstitial lung disease, extent of reticular pattern not otherwise specified, extent of ground glass opacity with traction bronchiectasis, extent of honeycombing and coarseness of fibrosis (0.039 > P > 0.000). Although the pulmonary arterial pressure was higher in typical UIP group relative to the NSIP group, the difference was not statistically significant. CONCLUSION: In CPFE patients, paraseptal emphysema is associated more with UIP HRCT pattern and higher extent of fibrosis than centrilobular emphysema. PMID- 26435781 TI - Development of CAD/CAM Based Brace Models for the Treatment of Patients with Scoliosis-Classification Based Approach versus Finite Element Modelling. AB - STUDY DESIGN: Retrospective controlled cohort study comparing the in-brace correction of two samples of scoliosis patients with braces of different computer aided design (CAD). PURPOSE: In-brace correction and compliance correlate with outcome. The more standardized CAD braces that are available should enable improved in-brace correction and outcome. This study compared recent CAD brace developments with respect to in-brace corrections. OVERVIEW OF LITERATURE: A 2013 randomized controlled trial demonstrated that 72% of a population complying to Scoliosis Research Society inclusion criteria on bracing did not progress using braces (mainly Boston braces) used in the United States and Canada with moderate corrective effect. METHODS: In-brace corrections achieved in a sample of patients fulfilling the inclusion criteria for studies on bracing using the classification based approach (CBA) were compared to the recent individual CAD/computer aided manufacturing bracing based on finite element modelling approach (FEMA). RESULTS: In-brace corrections using the different approaches differed widely. CBA in-brace corrections were 66% of the initial value. FEMA in-brace correction was 42% of the initial value. CONCLUSIONS: Considering the fact that in-brace correction (and compliance) determines the end result of bracing in the treatment of scoliosis, scoliosis braces based on CBA are superior to the FEMA and the standard plaster based brace applications. PMID- 26435782 TI - A Comparative Study of Lateral Lumbar Interbody Fusion and Posterior Lumbar Interbody Fusion in Degenerative Lumbar Spondylolisthesis. AB - STUDY DESIGN: Level 4 retrospective review. PURPOSE: To compare the radiographic and clinical outcomes between posterior lumbar interbody fusion (PLIF) and lateral lumbar interbody fusion (LLIF) with posterior segmental spinal instrumentation (SSI) for degenerative lumbar spondylolisthesis. OVERVIEW OF LITERATURE: Both PLIF and LLIF have been performed for degenerative spondylolisthesis with good results, but no study has directly compared these two techniques so far. METHODS: The electronic medical and radiographic records of 78 matched patients were analyzed. In one group, 39 patients underwent PLIF with SSI at 41 levels (L3-4/L4-5), while in the other group, 39 patients underwent the LLIF procedure at 48 levels (L3-4/L4-5). Radiological outcomes such as restoration of disc height and neuroforaminal height, segmental lumbar lordosis, total lumbar lordosis, incidence of endplate fracture, and subsidence were measured. Perioperative parameters were also recorded in each group. Clinical outcome in both groups was assessed by the short form-12, Oswestry disability index and visual analogue scale scores. The average follow-up period was 16.1 months in the LLIF group and 21 months in the PLIF group. RESULTS: The restoration of disc height, foraminal height, and segmental lumbar lordosis was significantly better in the LLIF group (p<0.001). The duration of the operation was similar in both groups, but the average blood loss was significantly lower in the LLIF group (p<0.001). However, clinical outcome scores were similar in both groups. CONCLUSIONS: Safe, effective interbody fusion can be achieved at multiple levels with neuromonitoring by the lateral approach. LLIF is a viable treatment option in patients with new onset symptoms due to degenerative spondylolisthesis who have had previous lumbar spine surgery, and it results in improved sagittal alignment and indirect foraminal decompression. PMID- 26435783 TI - Prognostic Value of Preoperative Coping Strategies for Pain in Patients with Residual Neuropathic Pain after Laminoplasty for Compressive Cervical Myelopathy. AB - STUDY DESIGN: Single-center retrospective cohort study. PURPOSE: To clarify the prognostic value of preoperative coping strategies for pain due to compressive cervical myelopathy. OVERVIEW OF LITERATURE: Preoperative physical function, imaging and electrophysiological findings are known predictors of surgical outcomes. However, coping strategies for pain have not been considered. METHODS: Postoperative questionnaires, concerning health-related quality of life (HRQOL) and daily living activities, were sent to 78 patients with compressive cervical myelopathy who had suffered from neuropathic pain before laminoplasty, and been preoperatively assessed with respect to their physical and mental status and coping strategies for pain. Hierarchical multiple regression analysis was performed to clarify the extent to which the patient's preoperative coping strategies could explain the variance in postoperative HRQOL and activity levels. RESULTS: Forty-two patients with residual neuropathic pain after laminoplasty were analyzed by questionnaires (28 men, 14 women; mean age, 62.7+/-10.2 years; symptom duration, 48.0+/-66.0 months). The valid response rate was 53.8%. Hierarchical multiple regression analysis showed that preoperative coping strategies, which involved coping self-statements, diverting attention, and catastrophizing, were independently associated with postoperative HRQOL and activity level, and could explain 7% to 11% of their variance. Combinations of the coping strategies for pain and upper/lower motor functions could explain 26% to 36% of the variance in postoperative HRQOL and activity level. CONCLUSIONS: Preoperative coping strategies for pain are good predictors of postoperative HRQOL and activities of daily living in patients with postoperative residual neuropathic pain due to compressive cervical myelopathy. PMID- 26435784 TI - Effectiveness of Doppler Image of the Vertebral Artery as an Anatomical Landmark for Identification of Ultrasound-Guided Target Level in Cervical Spine. AB - STUDY DESIGN: A prospective sonographic study. PURPOSE: To verify the effectiveness of simultaneous application of two landmarks, Doppler image of the vertebral artery and shape of the transverse tubercle of the seventh cervical (C7) vertebra. OVERVIEW OF LITERATURE: Counting upwards from the C7 vertebra which only has a posterior tubercle of the transverse process is a commonly used method for ultrasound-guided cervical nerve root block. However, each transverse process has a different shape. METHODS: Sonograms of 20 volunteers were examined. At first, we identified the C7 transverse process based on the presence of the vertebral artery without the anterior tubercle. The C5 and C6 transverse processes were identified based on the presence of anterior tubercle without the vertebral artery. Subsequently, we placed needles on the C5, C6, and C7 transverse processes and the location and direction of needles were confirmed by fluoroscopy. RESULTS: In the 120 segments, 93.3% of needles were placed correctly as desired; 97.5% of needles were placed on the 5C transverse process; 97.5% of needles were placed on the C6 transverse process; and 85.0% of needles were placed on the C7 transverse process, respectively. Both sides showed the same accuracy of 93.3%. CONCLUSIONS: Simultaneous application of Doppler image of the vertebral artery and shape of the C7 transverse tubercle showed 93.3% accuracy in identifying the target cervical level. Therefore, Doppler image of the vertebral artery can be considered to be a useful landmark for ultrasound-guided cervical nerve root block. PMID- 26435785 TI - Role of the Self-Administered, Self-Reported History Questionnaire to Identify Types of Lumbar Spinal Stenosis: A Sensitivity Analysis. AB - STUDY DESIGN: Case-control design. PURPOSE: To evaluate the role of the self administered, self-reported history questionnaire (SSHQ) in identifying types of lumbar spinal stenosis (LSS). OVERVIEW OF LITERATURE: Diagnosis of types of LSS is controversial. METHODS: A total of 235 patients with LSS were asked to respond to the SSHQ. All of these patients recovered following surgical treatment. The classification of LSS patients was based on history, physical examinations, and imaging studies. It is considered to be the gold standard. Radicular and neurogenic claudication types of LSS were based on the SSHQ developed by Konno et al. Two categories of LSS were determined based on the SSHQ tool and gold standard. Finally, a sensitivity analysis was carried out to evaluate the diagnostic value of the SSHQ. RESULTS: The mean age of patients was 59.4 years. According to the criteria for gold standard, patients were diagnosed with the radicular type (n=103), and neurogenic claudication type (n=132). The questionnaire had desirable sensitivity, specificity, and accuracy in categorizing the two types of LSS: 97.8%, 66.6%, and 96.8% for the radicular type, and 97.0%, 80.0%, and 95.7% for the neurogenic claudication type. CONCLUSIONS: Our findings indicate that the SSHQ is a reliable and a valid measure and it may be a clinical diagnosis support tool for identifying patients with two types of LSS. PMID- 26435786 TI - Prognostic Factors for Postsurgical Recovery of Deltoid Palsy due to Cervical Disc Herniations. AB - STUDY DESIGN: Retrospective multicenter study. PURPOSE: We aimed to investigate prognostic factors affecting postsurgical recovery of deltoid palsy due to cervical disc herniation (CDH). OVERVIEW OF LITERATURE: Little information is available about prognostic factors affecting postsurgical recovery of deltoid palsy due to CDH. METHODS: Sixty-one patients with CDH causing deltoid palsy (less than grade 3) were included in this study: 35 soft discs and 26 hard discs. Average duration of preoperative deltoid palsy was 11.9 weeks. Thirty-two patients underwent single-level surgery, 22 two-level, four three-level, and three four-level. Patients with accompanying myelopathy, shoulder diseases, or peripheral neuropathy were excluded from the study. RESULTS: Deltoid palsy (2.4 grades vs. 4.5 grades, p<0.001) and radiculopathy (6.4 points vs. 2.1 points, p<0.001) significantly improved after surgery. Thirty-six of 61 patients (59%) achieved full recovery (grade 5) of deltoid palsy, with an average time of 8.4 weeks. Longer duration of preoperative deltoid palsy and more severe radiculopathy negatively affected the degree of improvement in deltoid palsy. Age, gender, number of surgery level, and disc type did not affect the degree of improvement of deltoid palsy. Contrary to our expectations, severity of preoperative deltoid palsy did not affect the degree of improvement. Due to the shorter duration of preoperative deltoid palsy, in the context of rapid referral, early surgical decompression resulted in significant recovery of more severe grades (grade 0 or 1) of deltoid palsy compared to grade 2 or 3 deltoid palsy. CONCLUSIONS: Early surgical decompression significantly improved deltoid palsy caused by CDH, irrespective of age, gender, number of surgery level, and disc type. However, longer duration of deltoid palsy and more severe intensity of preoperative radiating pain were associated with less improvement of deltoid palsy postoperatively. PMID- 26435787 TI - Surgical Outcome for Hemodialysis-Related Upper Cervical Lesions. AB - STUDY DESIGN: A retrospective study. PURPOSE: To investigate the surgical outcome for hemodialysis-related upper cervical lesions. OVERVIEW OF LITERATURE: Surgical outcome of lower cervical lesions in patients undergoing hemodialysis has been reported. However, surgical outcome for upper cervical lesions in hemodialysis patients is unclear. METHODS: Upper cervical lesions in nine patients undergoing hemodialysis were surgically treated. Mean age at surgery was 61.6 years (range, 52-68 years), and the mean follow-up period was 45.4 months (range, 2-98 months). Patients had undergone hemodialysis for an average of 25.3 years (range, 16-40 years) at surgery. Seven patients with destructive spondyloarthropathy (DSA) of the upper cervical spine were treated with atlantoaxial or occipitocervical fixation. Two patients with retro-odontoid pseudotumors were treated with C1 posterior arch resection alone. Japanese Orthopedic Association (JOA) scores for cervical myelopathy, postoperative complications, postoperative radiography, and preoperative and postoperative occipital pain were evaluated. RESULTS: Mean preoperative and postoperative JOA score was 3.7 and 8.1, respectively. The seven patients with DSA had severe preoperative occipital pain that disappeared postoperatively. Postoperative radiography showed solid bone union in DSA cases and no instability in pseudotumor cases. CONCLUSIONS: Satisfactory surgical outcome was observed for hemodialysis-related upper cervical lesions. PMID- 26435788 TI - Prognostic Factors of Surgical Outcome after Spinous Process-Splitting Laminectomy for Lumbar Spinal Stenosis. AB - STUDY DESIGN: A retrospective case review. PURPOSE: To assess the clinical and radiographic outcomes and identify the predictive factors associated with poor clinical outcomes after lumbar spinous process-splitting laminectomy (LSPSL) for lumbar spinal stenosis (LSS). OVERVIEW OF LITERATURE: LSPSL is an effective surgical treatment for LSS. Special care should be taken in patients with degenerative lumbar scoliosis (DLS). METHODS: A consecutive retrospective case review of patients undergoing LSPSL for LSS with a minimum 2-year follow-up was performed. Mild DLS and mild degenerative spondylolisthesis (DS) were included in the study. The Japanese Orthopedic Association (JOA) score and recovery rate were reviewed. Poor clinical outcome was defined as a recovery rate <50% using Hirabayashi's method. RESULTS: A total of 52 patients (mean age, 72 years) met the inclusion criteria and had a mean follow-up of 2.6 years (range, 2-4.5 years). The preoperative diagnosis was LSS in 19, DS in 19, and DLS in 14 cases. The mean JOA score significantly increased from 14.6 to 23.2 at the final follow up. The overall mean recovery rate was 60.1%. Thirteen patients (25%) were assigned to the poor outcome group. A higher rate of pre-existing DLS was observed in the poor outcome (poor) group (good, 15%; poor, 62%; p=0.003) than in the good outcome (good) group. None of the patient factors examined were associated with a poor outcome. A progression of slippage >=5 mm was found in 8 of 24 patients (33%) in the DS group. A progression of curvature >=5 degrees was found in 5 of 14 patients (36%) in the DLS group. The progression of scoliosis and slippage did not influence the clinical outcome. CONCLUSIONS: The clinical and radiographic outcomes of LSPSL for LSS were favorable. Pre-existing DLS was significantly associated with poor clinical outcome. PMID- 26435789 TI - Clinical and Radiological Results of Microsurgical Posterior Lumbar Interbody Fusion and Decompression without Posterior Instrumentation for Lateral Recess Stenosis. AB - STUDY DESIGN: A single-center, retrospective patient review of clinical and radiological outcomes of microsurgical posterior lumbar interbody fusion and decompression, without posterior instrumentation, for the treatment of lateral recess stenosis. PURPOSE: This study documented the clinical and radiological results of microsurgical posterior lumbar interbody fusion and decompression of the lateral recess using interbody cages without posterior instrumentation for the treatment of lateral recess stenosis. OVERVIEW OF LITERATURE: Although microsurgery has some advantages, various complications have been reported following microsurgical decompression, including cage migration, pseudoarthrosis, neurologic deficits, and persistent pain. METHODS: A total of 34 patients (13 men, 21 women), with a mean age of 56.65+/-9.1 years (range, 40-77 years) confirmed spinal stability, and preoperative radiological findings of lateral recess stenosis, were included in the study. Interbody polyetheretherketone cages and auto grafts were used in all patients. Posterior instrumentation was not used because of limited resection of the posterior lumbar structures. Preoperative and postoperative radiographs, computed tomography scans, and magnetic resonance imaging were assessed and compared to images taken at the final follow-up. Functional recovery was also evaluated according to the Macnab criteria at the final follow-up. RESULTS: The average follow-up time was 35.05+/-8.65 months (range, 24-46 months). The clinical results, operative time, intraoperative blood loss, and duration of hospital stay were similar to previously published results; the fusion rate (85.2%) was decreased and the migration rate (5.8%) was increased, compared with prior reports. CONCLUSIONS: Although microsurgery has some advantages, migration and pseudoarthrosis remain challenges to achieving adequate lumbar interbody fusion. PMID- 26435790 TI - Foramen Magnum Decompression and Duraplasty is Superior to Only Foramen Magnum Decompression in Chiari Malformation Type 1 Associated with Syringomyelia in Adults. AB - STUDY DESIGN: Retrospective cohort study. PURPOSE: To compare surgical results of foramen magnum decompression with and without duraplasty in Chiari malformation type 1 (CM-1) associated syringomyelia (SM). OVERVIEW OF LITERATURE: The optimal surgical treatment of CM-1 associated with SM is unclear. METHODS: Twenty-five cases of CM-1 with SM were included. There were 12 patients (48%) in the non duraplasty group and 13 patients (52%) in the duraplasty group. The rate of improvement, state of postoperative SM size, amount of tonsillar herniation, preoperative symptom duration, complications and reoperation rates were analysed. RESULTS: The rate of clinical improvement was significantly higher with duraplasty (84.6%) than without (33.3%, p <0.05). The rate of postoperative syrinx regression was significantly higher in the duraplasty group (84.6%) than in the non-duraplasty group (33.3%, p <0.05). One case in the duraplasty group needed a reoperation compared with five cases in the non-duraplasty group (p =0.059). CONCLUSIONS: Duraplasty is superior to non-duraplasty in CM-1 associated with SM despite a slightly higher complication rate. PMID- 26435791 TI - Recurrent Lumbar Disc Herniation: Results of Revision Surgery and Assessment of Factors that May Affect the Outcome. A Non-Concurrent Prospective Study. AB - STUDY DESIGN: Non-concurrent prospective study. PURPOSE: To determine the functional outcome after open 'fragment' discectomy for recurrent lumbar disc herniation, and to analyze the factors that may affect the outcome. OVERVIEW OF LITERATURE: Literature search revealed only four studies where the factors affecting the outcome of a revision surgery for recurrent disc herniation have been evaluated. None of these studies analyzed for diabetes, disc degeneration and facet arthropathy. We have analyzed these features, in addition to the demographic and clinical factors. METHODS: Thirty-four patients who underwent the procedure were followed up for an average period of 27.1 months. The Japanese Orthopaedic Association (JOA) score and Oswestry disability index (ODI) were used to assess the functional outcome. Age, gender, smoking, diabetic status, duration of recurrent symptoms, the side of leg pain, level and type of disc herniation, degree of disc degeneration on magnetic resonance imaging, and facet joint arthritis before first and second surgeries, were analyzed as factors affecting the outcome. RESULTS: The average Hirabayashi improvement in JOA was 56.4%. The mean preoperative ODI was 74.5% and the mean ODI at final follow-up was 32.2%, the difference being statistically significant (p<0.01). Patients with diabetes, all of whom had poor long term glycemic control, were found to have a poor outcome in terms of ODI improvement (p=0.03). CONCLUSIONS: Open fragment discectomy is a safe and effective surgical technique for the treatment of recurrent disc herniation. However, patients with uncontrolled diabetes may have a less favorable outcome. PMID- 26435792 TI - Frequency of Vertebral Endplate Modic Changes in Patients with Unstable Lumbar Spine and Its Effect on Surgical Outcome. AB - STUDY DESIGN: Prospective cohort study. PURPOSE: In this study, we investigated the frequency of vertebral endplate Modic changes (MCs) and their effects on surgical outcomes in patients with unstable lumbar spines. OVERVIEW OF LITERATURE: Signal changes in endplates have been classified into three types by Modic. The prognostic role of MCs has been investigated in various spinal disorders. METHODS: A series of 70 patients with clinical and radiographic unstable lumbar spine were included in the study. Endplate signal intensity was determined according to Modic classification. All patients underwent instrumented posterolateral fusion. Functional evaluation was made using the visual analog scale (VAS) and Oswestry disability index (ODI). RESULTS: Eighteen patients (26%) had normal endplate intensity, 31 patients (44%) had MC type I, 20 patients (28%) had MC type II, and one patient (1.4%) had MC type III. Pain level VAS and ODI decreased significantly from the preoperative evaluation to the six-month and one year postoperative evaluations. The surgical outcome (VAS and ODI) was not significantly different between the various types of MC. CONCLUSIONS: Posterolateral fusion is an effective treatment in patients with unstable lumbar spines. MC do not have a significant effect on the surgical outcome of these patients. PMID- 26435793 TI - Evaluation of the Behavior of Spinal Deformities in Tuberculosis of the Spine in Adults. AB - STUDY DESIGN: A prospective clinical study. PURPOSE: The objective of the present study was to evaluate the behavior of spinal deformities in tuberculosis (TB) of the spine during the initial 2 years and to suggest remedial measures. OVERVIEW OF LITERATURE: Spinal TB is the most common cause of a kyphotic deformity in many parts of the world. Treatment of the established deformity is difficult, hazardous and has a high complication rate. METHODS: We followed 50 adult patients treated for spinal TB for a minimum of 2 years. Average values of vertebral body height loss (VBL), deformity angle, kyphosis angle, and lumbosacral joint angle at the final follow-up were compared with the values at initial presentation. The relationship between the amount of initial VBL and final kyphotic angle was analyzed. RESULTS: Average values of VBL, deformity angle, kyphosis angle, and lumbosacral joint angle at initial presentation were 0.26, 12.51 degrees , 2.26 degrees , and 12.3 degrees , respectively; and the corresponding values at the final follow-up were 0.7, 17.8 degrees , 5.64 degrees , and 10.8 degrees , respectively. The increase was extremely significant for the deformity angle (initial vs. 6th month, p=0.000; 6th month vs. 24th month, p=0.000) and kyphotic angle (initial vs. 6th month, p=0.003; 6th month vs. 24th month, p=0.000) in the thoracic and thoracolumbar regions during the first 2 years of the disease process. The increase in the deformity angle in the lumbar region was significant only in the initial 6 months (p=0.01). We could not find any correlation between the initial VBL and the final kyphotic angle (r=0.302, p>0.05). CONCLUSIONS: Different regions of the vertebral column respond differently to bony destruction caused by spinal TB. Deformity progression is more significant during the initial 6 months of the disease process, and this may be the best time to take remedial measures to prevent development/progression of the deformity. Kyphotic deformity keeps increasing even after 6 months of antituberculous treatment, and it does not correlate with the initial VBL in adults. PMID- 26435794 TI - Evaluation of Traumatic Spine by Magnetic Resonance Imaging and Correlation with Neurological Recovery. AB - STUDY DESIGN: Prospective study. PURPOSE: To compare magnetic resonance imaging (MRI) findings with clinical profile and neurological status of the patient and to correlate the MRI findings with neurological recovery of the patients and predict the outcome. OVERVIEW OF LITERATURE: Previous studies have reported poor neurological recovery in patients with cord hemorrhage, as compared to cord edema in spine injury patients. High canal compromise, cord compression along with higher extent of cord injury also carries poor prognostic value. METHODS: Neurological status of patients was assessed at the time of admission and discharge in as accordance with the American Spine Injury Association (ASIA) impairment scale. Mean stay in hospital was 14.11+/-5.74 days. Neurological status at admission and neurological recovery at discharge was compared with various qualitative cord findings and quantitative parameters on MRI. In 27 patients, long-term follow-up was done at mean time of 285.9+/-43.94 days comparing same parameters. RESULTS: Cord edema and normal cord was associated with favorable neurological outcome. Cord contusion showed lesser neurological recovery, as compared to cord edema. Cord hemorrhage was associated with worst neurological status at admission and poor neurological recovery. Mean canal compromise (MCC), mean spinal cord compression (MSCC) and lesion length values were higher in patients presenting with ASIA A impairment scale injury and showed decreasing trends towards ASIA E impairment scale injury. Patients showing neurological recovery had lower mean MCC, MSCC, and lesion length, as compared to patients showing no neurological recovery (p<0.05). CONCLUSIONS: Cord hemorrhage, higher MCC, MSCC, and lesion length values have poor prognostic value in spine injury patients. PMID- 26435795 TI - The Use of T1 Sagittal Angle in Predicting Cervical Disc Degeneration. AB - STUDY DESIGN: Retrospective evaluation. PURPOSE: To analyze the effect of T1 slope on degree of degeneration in patients with cervical disc degeneration. OVERVIEW OF LITERATURE: The T1 slope is well known parameter that may be very useful in evaluating sagittal balance. There are no reports on the analysis of the relationship between T1 slope and cervical disc degeneration. We hypothesized that T1 slope has an effect on the degree of cervical degeneration. METHODS: Sixty patients who had cervical spine magnetic resonance imaging (MRI) in our orthopedic clinic were enrolled. Patients were divided into two groups according to T1 slope. Radiologic parameters obtained from radiography and cervical spine MRI were compared between low T1 slope group (<=25) and high T1 slope group (>25). RESULTS: Among low T1 slope group, average degeneration grade of each cervical segment was 2.65 in C2-3, 2.50 in C3-4, 2.62 in C4-5, 3.23 in C5-6, and 2.81 in C6-7. And that of high T1 group was 2.35 in C2-3, 2.32 in C3-4, 2.59 in C4-5, 2.79 in C5-6, and 2.32 in C6-7. Grade of degeneration of low T1 group was significantly higher, as compared with high T1 group in C5-6 (p=0.028) and C6-7 (p=0.009). Percentage of high grade degeneration of more than grand III was 65.4% in low T1 group and 32.4% in high T1 group (p=0.018). Risk of high grade degeneration of C6-7 was significantly higher in low T1 group (odds ratio, 5.63; 95% confidence interval, 1.665-19.057; p=0.005). CONCLUSIONS: Patients with low T1 slope had higher grade of degeneration regardless of age and gender. Low T1 slope is a potential risk factor of cervical spondylosis especially in the C6-7 cervical segment. PMID- 26435796 TI - The Effect of Standing and Different Sitting Positions on Lumbar Lordosis: Radiographic Study of 30 Healthy Volunteers. AB - STUDY DESIGN: Radiographic review of healthy volunteers. PURPOSE: To determine the ideal sitting positions by measuring changes in lumbar lordosis (LL) and pelvic parameters (PPs) in various positions. OVERVIEW OF LITERATURE: Prolonged sitting is generally accepted as an important risk factor for low back pain (LBP). It is now recognized that spinopelvic alignment is important for maintaining an energy-efficient posture. METHODS: Lateral spine radiographs of thrirty healthy volunteers (male participants) were taken in standing and five sitting positions. Radiographic measurement of LL and PPs was performed in each position. Statistical analysis was performed to identify a correlation between changes in the LL and PPs in each positions. RESULTS: LL in standing was 48.5 degrees +/-8.7 degrees . Sitting significantly decreased LL and segmental angle when compared with standing (p<0.05). The lower lumbar segmental angles (L4-5 and L5-S1) significantly decreased in all sitting positions (p<0.05), but the decrease was relatively less on the chair with lumbar support and in the 90 degrees -angled chair. The sacral slope (SS) decreased and the pelvic tilt increased with decreasing LL in the sitting positions. CONCLUSIONS: Sitting causes a reduction in LL and SS when compared with standing. It might cause a spinopelvic imbalance and result in chronic LBP. Our study showed that sitting on a chair with back support induced minimal changes to LL. Consequently, it is proposed that sitting on a chair with back support would be a much more ideal position than sitting on other types of chairs. PMID- 26435797 TI - Relative Contribution of Upper and Lower Lumbar Spinal Segments to Flexion/Extension: Comparison between Normal Spines and Spines with Disc Disease in Asian Patients. AB - STUDY DESIGN: Prospective cohort study. PURPOSE: To evaluate the contribution of upper and lower lumbar segments to flexion and extension of the lumbar spine in normal and diseased spines. OVERVIEW OF LITERATURE: The specific contributions of upper and lower lumbar segments during flexion/extension have rarely been reported. Furthermore, no comparisons between the flexion/extension behaviors of normal and diseased spines have been reported until now. METHODS: Flexion and extension lateral radiographs of 52 adult, asymptomatic volunteers, and 67 adult patients with lumbar spine disc disease were measured using software for total lumbar lordosis, upper lumbar lordosis and lower lumbar lordosis and the intervertebral angles of all segments. RESULTS: In asymptomatic volunteers, the range of movement between flexion and extension was a mean of only 4.2 degrees in the lower lumbar spine and a mean of 19.4 degrees in the upper lumbar spine. In patients with disc degeneration, the range of movement between flexion and extension was an average 6.5 degrees for lower lumbar spine and 15.6 degrees for the upper lumbar spine. CONCLUSIONS: The results showed that upper lumbar spine contributes more to the range of motion in flexion and extension than the lower lumbar spine in asymptomatic individuals without lumbar disc disease, as well as in patients with disc degeneration. PMID- 26435798 TI - Role of Magnetic Resonance Imaging in Differentiating Spondylitis from Vertebral Metastasis. AB - STUDY DESIGN: Observational analytic design with a cross-sectional approach. PURPOSE: To analyze the suitability of magnetic resonance imaging (MRI) in distinguishing radiology images with a corresponding delineation of spondylitis and vertebral metastasis confirmed by histology results. OVERVIEW OF LITERATURE: MRI is an accurate modality for assessing vertebrae and their disorders. Infections and metastasis are most commonly found in the vertebrae. It is difficult to differentiate between these two disorders both clinically and radiographically, particularly in atypical cases. METHODS: McNemar statistical test was used to analyze the data. Samples were chosen using the consecutive method. There were 35 samples (14 males and 21 females), consisting of 22 samples of spondylitis and 13 samples of metastasis confirmed on histology examination. RESULTS: Nineteen (86%) out of the 22 samples of histological spondylitis were diagnosed as having spondylitis on MRI, whereas all 13 samples of metastasis were 100% accurately diagnosed on MRI. CONCLUSIONS: There was no statistically significant difference between diagnostic radiology using MRI and histological diagnosis with a p=0.250 (p>0.05). In this respect, MRI was more precise in diagnosing metastasis. Typical MRI description of spondylitis was the involvement of anterior vertebrae and components of intervertebral discs, stiffening of discs, paravertebral abscess, and involvement of the vertebral segment sequence. Typical MRI delineation of metastasis was involvement of the anterior posterior vertebral component, paravertebral mass, and skip lesions. PMID- 26435799 TI - Bilateral Pedicle and Crossed Translaminar Screws in C2. AB - Multiple techniques exist for the fixation of C2, including axial pedicle screws and bilateral translaminar screws. We describe a novel method of incorporating both the translaminar and pedicle screws within C2 to improve fixation to the subaxial spine in patients requiring posterior cervical instrumentation for deformity correction or instability. We report three cases of patients with cervical spinal instability, who underwent cervical spine instrumentation for stabilization and/or deformity correction. Bilateral C2 pedicle screws were inserted, followed by bilateral crossed laminar screws. The instrumentation method successfully achieved fixation in all three patients. There were no immediate postoperative complications, and hardware positioning was satisfactory. Instrumenting C2 with translaminar and pedicle screws is technically feasible, and it may improve fixation to the subaxial spine in patients with poor bone quality or severe subaxial deformity, which require a stronger instrumentation construct. PMID- 26435800 TI - Simultaneous Use of Both Bilateral Intralaminar and Pedicle Screws for C2 Stabilization. AB - Four patients underwent stabilization surgery using both bilateral C2 pedicle screw (PS) and intralaminar screw (LS). Neural and vascular injury resulting from incorrect screw placement was assessed using computed tomography (CT). The evaluation of bone union was assessed by lateral flexion-extension X-ray films and CT. The symptoms were improved in all patients. There were no intraoperative complications. Furthermore, there were no cases of neurological worsening or vascular injury from incorrect screw placement. Failure of instrumentation or screw loosening during the follow-up period did not occur in any of the patients. All cases had accomplished bone union at the final follow-up. Theoretically, the stabilization technique using both bilateral C2 PS and LS at the same time can provide more stability than any other single technique. Simultaneous use of both bilateral C2 PS and LS is potentially a good choice for surgical repair. PMID- 26435801 TI - Severe Spinal Injury in Hirayama Disease. AB - Hirayama disease is a rare neurological disorder characterized by an insidious progressive subacute unilateral or bilateral weakness of the hands and forearm muscles leading to a painless amyotrophy. The disease primarily affects young men in the second to third decades of life. It has always been described as a second motor neuron disease, thus sparing the pyramidal and sensitive pathways. It usually has a slow progression course of 3 to 5 years followed by stabilization. Since its initial description by Keyzo Hirayama in 1959, most cases have been reported in Asia, particularly Japan and India, although the disease reportedly has worldwide distribution. PMID- 26435802 TI - Lumbar Cryptococcal Osteomyelitis Mimicking Metastatic Tumor. AB - Cryptococcus is an encapsulated, yeast-like fungus that rarely causes infection in immunocompetent patients. We present the case report of a 66-year-old female patient with a history of rectal cancer with an isolated lumbar vertebral cryptococcosis proven by biopsy performed during operation. The patient was not an immunocompromised host and did not have any other risk factors except the history of cured rectal cancer. The presumptive diagnosis based on imaging studies was metastatic spine cancer, so operation was performed. However, cryptococcal osteomyelitis was diagnosed in the pathologic examination. This case report emphasizes that we should be aware that lumbar cryptococcosis can be a rare cause of mimicking lesions with metastatic cancer. PMID- 26435803 TI - Iatrogenic Lumbar Vertebral Fracture during Osteosynthesis for a Trochanteric Fracture of the Femur in Diffuse Idiopathic Skeletal Hyperostosis. AB - Vertebral fractures occur with only slight trauma in patients with diffuse idiopathic skeletal hyperostosis (DISH). However, a lumbar vertebra fracture, due to an intraoperative body position has not been previously reported. An 87-year old woman with kyphosis sustained a left trochanteric fracture of her femur. The patient was placed in a supine position during the operation. Postoperatively, the patient experienced severe right thigh pain. Magnetic resonance imaging revealed an L4 vertebral fracture. Computed tomography revealed ankylosis from the upper thoracic spine to the sacrum. While in a supine position under general anesthesia, the contact of the patient's lower back with operating table likely created a fulcrum at her lumbosacral spine acting as a long lever arm, bearing the mass of her upper body. We performed L1-S2 posterior stabilization. DISH patients with kyphosis placed in a supine position have an increased risk for lumbar vertebral fracture. PMID- 26435804 TI - Adjacent Segment Pathology after Lumbar Spinal Fusion. AB - One of the major clinical issues encountered after lumbar spinal fusion is the development of adjacent segment pathology (ASP) caused by increased mechanical stress at adjacent segments, and resulting in various radiographic changes and clinical symptoms. This condition may require surgical intervention. The incidence of ASP varies with both the definition and methodology adopted in individual studies; various risk factors for this condition have been identified, although a significant controversy still exists regarding their significance. Motion-preserving devices have been developed, and some studies have shown their efficacy of preventing ASP. Surgeons should be aware of the risk factors of ASP when planning a surgery, and accordingly counsel their patients preoperatively. PMID- 26435806 TI - Erector Spinae Tubercular Abscess. PMID- 26435805 TI - Lumbar Stenosis: A Recent Update by Review of Literature. AB - Degeneration of the intervertebral disc results in initial relative instability, hypermobility, and hypertrophy of the facet joints, particularly at the superior articular process. This finally leads to a reduction of the spinal canal dimensions and compression of the neural elements, which can result in neurogenic intermittent claudication caused by venous congestion and arterial hypertension around nerve roots. Most patients with symptomatic lumbar stenosis had neurogenic intermittent claudication with the risk of a fall. However, although the physical findings and clinical symptoms in lumbar stenosis are not acute, the radiographic findings are comparatively severe. Magnetic resonance imaging is a noninvasive and good method for evaluation of lumbar stenosis. Though there are very few studies pertaining to the natural progression of lumbar spinal stenosis, symptoms of spinal stenosis usually respond favorably to non-operative management. In patients who fail to respond to non-operative management, surgical treatments such as decompression or decompression with spinal fusion are required. Restoration of a normal pelvic tilt after lumbar fusion correlates to a good clinical outcome. PMID- 26435807 TI - Author Response: Isolated Spontaneous Primary Tubercular Erector Spinae Abscess: A Case Report and Review of Literature. PMID- 26435809 TI - Barrier Factors to the Completion of Diabetes Education in Korean Diabetic Adult Patients: Korea National Health and Nutrition Examination Surveys 2007-2012. AB - BACKGROUND: Diabetes is a disease with high social burdens and is expected to increase gradually. A long-term management is essential for the treatment of diabetes, requiring patient self-cares. Diabetes education is important for such self-cares, but it does not sufficiently take place. In addition, little studies have been conducted on the barriers to the completion of diabetes education. This study, thus, aimed to analyze the factors related to the completion of diabetes education and investigate its barriers. METHODS: Of 50,405 respondents to the fourth and fifth Korea National Health and Nutrition Examination Survey, a total of 3,820 were selected for the analysis, excluding those aged 29 or younger and those with missing values. The completion of diabetes education was set as a dependent variable and an analysis was made on the factors that affect the dependent variable. A multivariable logistic regression was employed for the analysis. RESULTS: Lower educational level was associated with less diabetes education, and the degree of diabetes education was lower in the group with male, the group that didn't have a family history or was not aware of a family history, the group that was not currently aware of diabetes and the group without a spouse. There was no difference in the completion of diabetes education by underlying diseases, family income level, age, residing area, economic activity status, insurance coverage, smoking, and drinking. CONCLUSION: Diabetes education is of importance for the treatment and management of diabetes. Currently, however, diabetes education is not sufficiently carried out in Korea. The completion rate of diabetes education was low in male, patients without or not knowing a family history, patients who were not currently aware of their diabetes, patients without a spouse, and patients with low educational level. Therefore, encouraging these patients to take the education will be a more effective approach to increase the completion rate of diabetes education. PMID- 26435808 TI - An Overview and Update of Chronic Myeloid Leukemia for Primary Care Physicians. AB - Chronic myeloid leukemia (CML) accounts for approximately 15% of adult leukemias. Forty percent of patients with CML are asymptomatic, in whom the disease is detected solely based on laboratory abnormalities. Since the introduction of tyrosine kinase inhibitor therapy in 2001, CML has become a chronic disease for the majority of patients. Primary care physicians may be the first to recognize a new diagnosis of CML. In patients with known CML, the primary care physician may be the first to detect disease progression or adverse effects to therapy. This article provides an overview of the clinical presentation, diagnostic approach, and treatment considerations of CML. PMID- 26435810 TI - Perceived Stress, Alexithymia, and Psychological Health as Predictors of Sedative Abuse. AB - BACKGROUND: The harmful effects of sedative medications and substances in conjunction with limited research regarding predictive psychological constructs of drug abuse necessitate further investigation of associated factors. Therefore, the present study aimed to elucidate the roles of perceived stress, alexithymia, and psychological health as predictors of sedative abuse in medical students. METHODS: In this cross-sectional study, 548 students at Kermanshah University of Medical Sciences, Iran, were selected using stratified random sampling. The data were obtained using the Perceived Stress Scale, an alexithymia scale (Farsi version of the Toronto Alexithymia Scale-20), and a General Health Questionnaire to assess psychological health. Data were analyzed using discriminant analyses. RESULTS: The results demonstrated that the user and non-user of sedative substances groups had significantly different predictive variables (except for social function disorder) (P>0.05). Physical complaints, alexithymia, and perceived stress, which had standard coefficients of 0.80, 0.60, and -0.27, respectively, predicted sedative drug use. CONCLUSION: The results of the present study indicate that perceived stress, alexithymia, physical complaints, anxiety, and depression are associated with sedative drug abuse. PMID- 26435811 TI - Breast Feeding Is Associated with Postmenopausal Bone Loss: Findings from the Korea National Health and Nutrition Examination Survey. AB - BACKGROUND: Postmenopausal osteoporosis is a common disease which can cause various morbidity and economic burden. Lactation is known to cause a decline in bone mineral density (BMD), but there are controversies on whether decreased BMD is fully recovered after lactation and whether lactation duration has an influence on postmenopausal BMD. This study was conducted to see whether breastfeeding is associated with postmenopausal bone loss using a highly representative sample of Korean population. METHODS: Retrospective cross sectional study was done using data collected from Korea National Health and Nutrition Examination Survey V. The study outcome was BMD measured with dual energy X-ray absorptiometry and divided into 2 groups: normal or low BMD (T score<-1), and breastfeeding duration was categorized into 4 groups (never, 1st, 2nd, and 3rd tertile). Logistic regression analysis was done to examine the association between lactation duration and BMD. RESULTS: Among 1,694 postmenopausal women (mean age, 63.5+/-9.1), 85.71% were in low BMD group. Compared to never breastfeeding group, postmenopausal women with longer than 79 months of breastfeeding duration are more likely to have low BMD (adjusted risk ratio [ARR]=1.24; 95% confidence interval, 1.17 to 1.32). As the duration of breastfeeding increases, ARR and risk difference for low BMD also increases (P for trend=0.008). CONCLUSION: The study results showed that total breastfeeding duration was associated with postmenopausal low BMD. All women planning on breastfeeding should be aware of its risks and should take adequate dietary calcium and vitamin D before, during, and after breastfeeding. PMID- 26435812 TI - Time to First Cigarette and Hypertension in Korean Male Smokers. AB - BACKGROUND: Morning blood pressure surge affects to cardiovascular disease risk. Short time to first cigarette (TTFC) after waking can enhance morning blood pressure surge, and accelerate atherosclerosis. METHODS: We investigated that the relationship between TTFC and blood pressure. The study subjects included male current smokers (n=211) who had health check-up in Hallym University Sacred Heart Hospital from July to September, 2014. We categorized the subjects into 2 groups according to TTFC; early TTFC (TTFC <30 minutes) and late TTFC (TTFC >=30 minutes), and the subjects who were taking antihypertensive medications or had a high blood pressure (>140 mm Hg or 90 mm Hg) were defined as hypertensive group. Multivariate logistic regression was performed to estimate the odds ratio and 95% confidence interval to investigate the association between TTFC and hypertensive group. RESULTS: Compared with late TTFC, early TTFC had higher odds (odds ratio [OR], 3.87; 95% confidence interval [CI], 1.89-7.94) for hypertensive group. After adjusting confounding factors, early TTFC was significantly associated with an increased risk of hypertension (OR, 4.43; 95% CI, 1.84-10.70). CONCLUSION: early TTFC after waking is associated with hypertension. It suggests delaying TTFC might help to control of blood pressure among the current smokers who are not ready to immediately quit smoking. PMID- 26435813 TI - Association between Helicobacter pylori Infection and Cerebral Small Vessel Disease. AB - BACKGROUND: Small vessel disease is an important cause of cerebrovascular diseases and cognitive impairment in the elderly. There have been conflicting results regarding the relationship between Helicobacter pylori infection and ischemic stroke. This study aimed to examine the association between H. pylori infection and cerebral small vessel disease. METHODS: The study included 1,117 patients who underwent brain magnetic resonance imaging and H. pylori identification between 2005 and 2013 at Health Promotion Center, Seoul National University Hospital. Multivariable logistic regression analysis was used to assess the association between H. pylori infection and small vessel disease with adjustment for age, sex, hypertension, diabetes mellitus, dyslipidemia, body mass index, smoking status, problem drinking, and antiplatelet use. RESULTS: The adjusted odds ratios (aORs) for the association between H. pylori infection and silent brain infarction and cerebral microbleeds were 1.03 (95% confidence interval [CI], 0.66-1.61) and 0.70 (95% CI, 0.38-1.28), respectively. The aORs for silent brain infarction and cerebral microbleeds were 0.81 (95% CI, 0.44 1.44) and 0.59 (95% CI, 0.30-1.18) in patients aged <65 years and 1.59 (95% CI, 0.78-3.22) and 1.89 (95% CI, 0.38-9.33) in those aged >65 years, respectively. Moreover, the aORs for silent brain infarction and cerebral microbleeds were 0.96 (95% CI, 0.54-1.71) and 0.74 (95% CI, 0.33-1.69) in H. pylori-infected patients without atrophic gastritis and 0.89 (95% CI, 0.48-1.62) and 0.99 (95% CI, 0.43 2.27) in those with atrophic gastritis, respectively. CONCLUSION: No association between H. pylori infection and small vessel disease was observed. H. pylori induced inflammation may not be a risk factor for microcirculatory damage in the brain. PMID- 26435814 TI - Clinical Characteristics and Metabolic Health Status of Obese Korean Children and Adolescents. AB - BACKGROUND: This study aimed to determine the prevalence of metabolically healthy and unhealthy obesity (MHO and MUO, respectively) and examine the demographic, anthropometric, and lifestyle predictors of metabolic health status in Korean children and adolescents. METHODS: This study was based on data collected from the Korean Children-Adolescent Study in 2010. A total of 1,700 children (846 boys and 854 girls) were included in the primary cohort and classified into metabolically healthy and unhealthy groups according to factors related to the metabolic syndrome. Demographic and biochemical features were evaluated in study participants. Logistic regression estimated the odds ratios of having more fat mass among MUO compared with MHO children after adjusting for confounding factors. RESULTS: Mean body mass index was higher in the MUO group than in the MHO group (24.83 vs. 23.02 kg/m(2), respectively). The proportion of obese participants was also higher in the MUO group (59.4%) than in the MHO group (20.7%). MHO children were more likely to have parents with better socioeconomic status and a higher fruit and vegetable intake compared with MUO children. Higher fat mass and percent fat was associated with MUO according to multiple logistic regression analysis. CONCLUSION: Fat mass and percent fat are associated with metabolically healthy phenotypes of obesity among children and adolescents. PMID- 26435815 TI - Helicobacter pylori: A Possible Risk Factor for Bone Health. AB - BACKGROUND: Helicobacter pylori (H. pylori) infection may cause systemic inflammation and increase the production of tumor necrosis factor-alpha, interleukin-1, and interleukin-6. Unfortunately, bone mineral density also may be affected by these cytokines. This study aimed to evaluate the association between bone mineral density and H. pylori infection. METHODS: A cross-sectional study evaluated 1,126 men undergoing a comprehensive health screening in a private Korean screening center. Subjects' sera were tested for H. pylori antibodies (immunoglobulin G) using an enzyme-linked immunosorbent assay, and bone mineral densities (g/cm(2)) of the lumbar spine, femoral neck, and total femur were obtained using dual-energy X-ray absorptiometry. To evaluate the difference in bone mineral density according to H. pylori infection status, the adjusted mean bone mineral densities at each site were compared after adjusting for potential confounders, including age, sex, body mass index, smoking, alcohol consumption, and exercise. RESULTS: H. pylori infection was associated with a significant decrease in mean lumbar bone mineral density (H. pylori-positive, 1.190 g/cm(2); H. pylori-negative, 1.219 g/cm(2); P=0.006), which was greatest among men who were >=50 years old (H. pylori-positive, 1.193 g/cm(2); H. pylori-negative, 1.233 g/cm(2); P=0.006). However, no significant association was observed in the bone mineral densities of the total femur and femoral neck. CONCLUSION: In men, H. pylori infection was negatively associated with lumbar bone mineral density. This association may be useful in the early detection, prevention, and management of male osteoporosis. PMID- 26435817 TI - Incidence of Type 2 Diabetes Mellitus among Emirati Residents in Ajman, United Arab Emirates. AB - BACKGROUND: Diabetes mellitus (DM), particularly type-2 is a major public health concern worldwide. Not much information is available with regard to the incidence of DM in United Arab Emirates (UAE). This study aimed at determining the incidence rate of diabetes mellitus among Emirati population in Ajman, UAE. This is a retrospective cohort study. METHODS: This study was conducted in all primary health care centers and Shaikh Khalifa and GMC Hospitals, Ajman, UAE where the Emirati population primarily go for diagnosis and treatment. The incident cases of diabetes mellitus were collected during the period 2010 January to December. RESULTS: A total of 158 cases newly detected in 2010, 54 were among non-Emiratis and one was type-1 diabetes. Eliminating these, the remaining 101 were included in the analysis. The age of the patients ranged from 23 years to 78 years; 35 (34.7%) males and 66 (65.3%) were females. The overall incidence observed was 4.8/1,000 person-years (PY) with a female predominance of 6.3/1,000 PY against incidence among males of 3.3/1,000 PY. With regard to age specific incidence rate among males, it increases with age till 60 years and then showed a decreasing trend. Among females also the same trend was observed but not as similar to males. CONCLUSION: The highest incidence rate was observed in the 55-59 age group among males, 23.4/1,000 PY and females, 32.4/1,000 PY. Among males the incidence rate was much less compared to females in-the age groups older than 59 years. PMID- 26435818 TI - Comments on Statistical Issues in September 2015. PMID- 26435816 TI - Dietary Fat Intake and the Risk of Metabolic Syndrome in Korean Adults. AB - BACKGROUND: The effect of dietary fat intake on the risk of cardiovascular disease remains unclear. We investigated the association between dietary fat and specific types of fat intake and the risk of metabolic syndrome. METHODS: The study population included 1,662 healthy adults who were 50.2 years of age and had no known hypertension, diabetes, hyperlipidemia, or metabolic syndrome at the initial visit. Dietary intake was obtained from a 1-day food record. During 20.7 months of follow-up, we documented 147 cases of metabolic syndrome confirmed by self-report, anthropometric data, and blood test results. The intakes of total fat, vegetable fat, animal fat, saturated fatty acid (SFA), polyunsaturated fatty acid (PUFA), monounsaturated fatty acid (MUFA), and cholesterol level divided by quintile. Multivariate analyses included age, sex, body mass index, smoking status, alcohol intake, physical activity, total calorie, and protein intake. RESULTS: Vegetable fat intake was inversely associated with metabolic syndrome risk (odds ratio for the highest vs. the lowest quintile, 0.33; 95% confidence interval, 0.14 to 0.76). Total fat, animal fat, SFA, PUFA, MUFA, and cholesterol intakes showed no association with metabolic syndrome. Vegetable fat intake was inversely associated with the risk of hypertriglyceridemia among the components of metabolic syndrome. CONCLUSION: These data support an inverse association between vegetable fat and the risk of metabolic syndrome. PMID- 26435819 TI - Tuberculosis in Chronic Obstructive Pulmonary Disease. PMID- 26435820 TI - Preventive effect of Malva on urinary toxicity after radiation therapy in prostate cancer patients: A multi-centric, double-blind, randomized clinical trial. AB - BACKGROUND: For patients receiving external beam radiation therapy (EBRT) after radical prostatectomy as adjuvant treatment or patients receiving EBRT as definitive treatment, partial irradiation of the urinary bladder is common. Many of such patients experience some degree of radiation-induced cystitis during or after EBRT. There is currently no efficient treatment for preventing radiation cystitis. OBJECTIVE: The aim of this study was to evaluate the effectiveness of one of the safe mucilaginous herbs (Malva) in preventing radiation-induced dysuria in patients who are undergoing EBRT for prostate cancer. METHODS: From April 2013 to August 2014, 68 patients were randomized into two groups using four block randomization, 34 to the drug (Malva) group and 34 to the placebo group. Of the 68 patients who began the study, 60 completed it. They were instructed to use the medication, i.e., Malva or the placebo, three times a day for six weeks. They were followed by a physician every two weeks for eight weeks, and urinary function was assessed in each visit by asking questions based on the Visual Prostate Symptom Score (VPSS) and a dysuria severity score. The changes in the VPSS and dysuria severity score between baseline and each follow-up visit were compared between the two groups in the study using repeated measures analysis of variance (ANOVA) and t-tests. RESULTS: The median age of the 68 patients was 66. Twenty-one of 27 patients in the control group (77.7%) suffered from dysuria, while dysuria was detected in 23 of 33 patients (69.6%) who received Malva (odds ratio=2.70 for dysuria). After two weeks, four weeks, and six weeks of treatment with Malva, dysuria due to EBRT was milder in the treatment group than in the control group, and the differences were statistically significant (p = 0.005, p = 0.004, p = 0.001, respectively). CONCLUSION: To the best of our knowledge, our study is the first study to assess the protective effect of a mucilaginous herb (Malva) against urinary toxicity induced by EBRT. The positive results of this study warrant further studies in this field. PMID- 26435821 TI - Detection of Rotavirus in children with acute gastroenteritis in Zagazig University Hospitals in Egypt. AB - INTRODUCTION: Rotavirus is the major cause of acute gastroenteritis (AGE) in infants and young children all over the world. The objective of the study was to compare different methods for detecting rotavirus and to assess the burden of rotavirus as a causative agent for AGE in children younger than five. METHODS: This case control study included 65 children with AGE and 35 healthy control children. They were chosen from the Pediatric Department of Zagazig University Hospitals from October 2014 to March 2015. Stool samples were obtained and assayed for rotavirus by the immunochromatography test (ICT), enzyme linked immunosorbent assay (ELISA) and quantitative real time RT-PCR (qr RT-PCR). RESULTS: Fifty out of the 65 patients (76.9%) were positive for qr RT-PCR. Forty five (69.2%) and 44 (67.7%) were positive for ICT and ELISA, respectively. There was a significant association between the severity of the disease as determined by the Vesikari score and rotavirus infection. CONCLUSION: This study demonstrated that ICT is a useful method for the rapid screening of group A rotavirus in fecal specimens, because it is rapid, inexpensive, easy to perform, and requires very little equipment. In addition, this study highlights the substantial health burden of rotavirus AGE among children less than five. PMID- 26435822 TI - First report of death due to Hemiscorpius acanthocercus envenomation in Iran: Case report. AB - Scorpion stings are significant causes of death in the western and southern regions of Iran. To date, reports have indicated that the H. lepturus species is the main cause of mortality due to scorpion stings. One of the species that belongs to this genus is Hemiscorpius acanthocercus (H. acanthocercus). This scorpion's venom is cytotoxic, and it causes pathological changes in the blood and can cause severe damage to the kidneys. The pain of Hemiscorpius' sting is mild and asymptomatic in the early hours. Delays in the treatment of these victims can cause hemolysis, hematuria, kidney failure, and even death. In this paper, we report the first known death due to an H. acanthocercus' sting in Iran. PMID- 26435823 TI - Post-traumatic growth: a qualitative analysis of experiences regarding positive psychological changes among Iranian women with breast cancer. AB - INTRODUCTION: Cancer diagnosis is an extremely stressful experience that has a profound impact on a patient's life. Cancer related perceived stress and complications may lead to the experience of positive psychological changes and post-traumatic growth (PTG). Since there is lack of qualitative research assessing the experience of PTG in Iranian women with breast cancer, this study aims to investigate experiences relating to PTG of Iranian women. METHODS: A qualitative phenomenological approach was selected to explore the experiences of Iranian women with PTG. Data were gathered using semi-structured, in-depth interviews with 18 eligible patients, which were then transcribed and analyzed using Van Manen's thematic analysis approach. Data gathering and analyses were conducted simultaneously. In addition, MAXQDA software was used for data management. RESULTS: In this study, the participants were 18 Iranian women between the ages of 31 and 65 years. Four prominent themes were extracted from the participant's statements that demonstrated the Iranian women's experiences with breast cancer-induced psychological growth and maturity: 1) appreciate of life, 2) stability, 3) spiritual prosperity, and 4) effective interaction. CONCLUSION: Health care professionals are strongly recommended to design robust and timely intervention programs to improving PTG among breast cancer survivors and reduce their perceived distress resulting from cancer diagnosis. PMID- 26435824 TI - Prediction of trauma-specific death rates of pedestrians of Fars Province, Iran. AB - INTRODUCTION: Pedestrians are the most vulnerable group to accidents among road users. Due to the well-known concerns and complications of accidents involving pedestrians, the aim of this study was to identify the rate of such accidents for five-year period. METHODS: We analyzed all fatalities among pedestrians caused by traffic accidents during years of 2009-2013 in Fars Province in Iran. The study was a cross-sectional study in which logistic regression analysis was used to predict the death rate among pedestrians. Sensitivity analysis using the Monte Carlo method was used to increase the accuracy of the results. Then, we predicted the death rates for the years 2014-2018 predicted and compared the results with the actual data from the previous five-year period (2009-2013). RESULTS: During 2009-2013, 1723 out of 8689 (20.3%) of the people killed in traffic accidents were pedestrians. The death rate for male pedestrians in 2011 was estimated to be 10.86 per 100,000 (with an uncertainty interval of 95% giving a range of 9.85 12.05 per 100,000). Compared to the data for 2006, this represented a decrease of 20% (with a mean decrease of 4% per year). Based on these data, the death date in 2018n was projected to be 8.08 per 100,000 (with an uncertainty interval of 95% giving a range of 7.26-8.87). Similar data and analysis for women indicated that the reduction in the rate of fatalities has been smaller than that for men in recent years, i.e., 2.2% versus 4%. CONCLUSION: Although great progress has been made in reducing traffic accidents, to date, the death rate is still high among pedestrians. It is essential to continue to find ways to reduce traffic accidents and the pedestrians' deaths associated with them, especially among the elderly, who make up a disproportionate fraction of the deaths. PMID- 26435825 TI - Probiotic for irritable bowel syndrome in pediatric patients: a randomized controlled clinical trial. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder in children. Recently, probiotics have been suggested as a treatment option for gastrointestinal disorders. The most effective species and the most appropriate doses are still unknown. OBJECTIVE: The aim of this study was to assess the effects of Lactobacillus GG (LGG) for treating IBS in pediatric patients. METHODS: In a controlled, double blind, randomized trial, patients with IBS diagnosed by Rome III criteria from August 2012 to September 2012 at Dr. Sheikh Hospital, Mashhad University of Medical Sciences, Iran, were assigned to one of two groups, i.e., intervention and control groups. For four weeks, the intervention group received a probiotic in capsule form that contained LGG at a concentration of 1*10(10) cfu/ml bacteria. For the same period, the control group received a placebo capsule that had the same shape and color but only contained inulin, which also was present in the LGG capsules. The primary outcome was any change in the severity of the patients' pain, and we used a five-point Likert scale to evaluate the severity of their pain. Secondary outcomes were ghanges of the functional scale, stool patterns, and associated problems. RESULTS: Fifty-two patients participated in the study, and 26 patients were assigned randomly to each of the two groups. The severity of the patients' pain decreased significantly in the intervention group after one, two, three, and four weeks of treatment, as indicated by P-values of 0.01, 0.00, 0.00, and 0.00, respectively. Also, there was significant improvement in the functional scale after two weeks of treatment (P-value <= 0.00). CONCLUSION: Lactobacillus GG at a concentration of 1*10(10) cfu/ml for a period of four weeks can lessen the severity of the patients' pain and improve the functional scale in patients with irritable bowel syndrome. Probiotics can have therapeutic effects for IBS patients. PMID- 26435826 TI - The Effect of Educational Intervention on Nurses' Attitudes Toward the Importance of Family-Centered Care in Pediatric Wards in Iran. AB - INTRODUCTION: Family-centered care sustains the unity of the child's and the family's health. The aim of this study was to determine nurses' attitudes toward parents' participation in the care of their hospitalized children in Iran in 2015. METHODS: In this experimental study, 200 pediatric nurses from hospitals affiliated with the Shaheed Beheshti University of Medical Sciences in Tehran were selected using the multi-stage, random-sampling method. Data were gathered using a questionnaire that covered demographic information and nurses' attitudes. The questionnaire consisted of 31 items and was completed by the nurses in three stages: 1) before intervention (pre-test), 2) immediately after intervention (post-test), and 3) three months after intervention (follow-up). The data were analyzed via SPSS software and using descriptive and analytical methods. Descriptive statistics, the Spearman Correlation Coefficient, and Repeated Measure Analysis (the Bonferroni method) were used to assess the data. RESULTS: The results indicated that there was a significant increase in the mean score of attitude after intervention [M (pre) = 3.35%, M (post) = 3.97%, p < 0.001)]. Most of subjects had neutral attitudes toward family participation in their children's care. There were no significant relationship between the nurses' socio demographic characteristics and their attitudes. CONCLUSION: The nurses' attitudes toward the family's participation in the care of their hospitalized children were moderate. The nurses' attitudes should be improved by taking part in continuous training programs. PMID- 26435827 TI - The Role of Hemostatic Factors in Atherosclerosis in Patients with Chronic Renal Disease. AB - INTRODUCTION: Atherosclerotic cardiovascular disease remains the leading cause of increased morbidity and mortality observed in chronic kidney disease (CKD) patients. Endothelial dysfunction (ED) is thought to be a key initial event in the development of atherosclerosis. The aim of this study was to evaluate the potential role of hemostatic factors in atherosclerosis, thrombosis and cardiovascular complications in patients suffering from chronic renal disease. METHODS: The study was conducted on 50 renal patients divided into two groups of equal size. Group 1 consisted of 25 patients with end-stage renal disease (ESRD) on regular hemodialysis. Group 2 consisted of 25 chronic renal disease patients on conservative treatment. Twenty age- and sex-matched healthy subjects were included in the study to serve as a control group. Thrombomodulin (TM), von Willebrand factor (vWF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1) and hsCRP were assessed. High-resolution B-mode ultrasonography of both the common and internal carotid arteries to measure carotid intima media thickness (CIMT) was performed on all subjects. RESULTS: There were highly significant increases in hsCRP, TM, vWF, tPA and PAI-1 in both patient groups compared to the control group (P<0.01 for all except for TM between group 2 and 3 P<0.05) with significant increase in group 1 compared to group 2 (P<0.01). In addition, there was a highly significant increase in CIMT in both patient groups compared to the control group (P<0.01) with a significant increase in group 1 compared to group 2 (P<0.05). The study revealed significant positive correlation of hemostatic factors (TM, vWf, PAI-1 & t-PA) with creatinine, urea, hsCRP & CIMT. CONCLUSION: CKD patients have increased risk of atherosclerosis as measured by CIMT, which is used as a surrogate marker of early atherosclerosis and has been shown to be a strong predictor of future myocardial infarction and stroke. They have high levels of TM, vWF, tPA, PAI-1 that correlate with kidney function, hsCRP and CIMT. Therefore, these abnormalities in hemostasis may account for the increased risk of atherothrombosis in these patients. The elevated hsCRP levels and their correlation to hemostatic factors and CIMT might provide an important clue to link a systemic marker of inflammation to atherosclerosis. Further research is required to better understand the procoagulant state in patients with CKD. PMID- 26435828 TI - Iontophoresis Versus Cyriax-Type exercises in Chronic Tennis Elbow among industrial workers. AB - INTRODUCTION: Tennis elbow (TE) is one of the most commonly encountered upper limb conditions. It mainly affects people who use the hand grip against resistance frequently, resulting in microtrauma to the wrist extensors tendon, causing pain. This study was conducted to compare the application of iontophoresis of 0.4% dexamethasone and Cyriax-type exercises in the treatment of chronic tennis elbow (CTE). METHODS: Twenty-two industrial worker diagnosed as having CTE participated in this study, and their ages ranged from 25 to 52. They were assigned randomly to two groups, i.e., "group A" in which the workers were treated by iontophoresis of 0.4% Dexamethasone and "group B" in which the workers were treated by conducting Cyriax-type exercises on the affected tendon. Both groups received stretching exercises for the common extensors tendon for 10 minutes in addition to five minutes of pulsed US 1.1 W/cm2 six times over two weeks. The outcome of the treatment was assessed one week after the last session by the visual analog scale (VAS) to assess pain, by the Oxford elbow score (OES) to measure the patient's satisfaction, and by a handgrip dynamometer to measure the strength of the handgrip. RESULTS: The application of 0.4% dexamethasone iontophoresis and the use of Cyriax-type exercises both provided significant improvement in the pain, patient's satisfaction, and the power of the handgrip, and there were no significant difference (p > 0.001) in any of the three measures after the first week's treatment. CONCLUSIONS: Both iontophoresis of 0.4% dexamethasone and Cyriax-type exercises were successful as treatment modalities for patients with CTE, and there were no significant differences between both of them in the treatment of those cases. PMID- 26435829 TI - Study of the self-confidence of midwifery graduates from Mashhad College of nursing and midwifery in fulfilling clinical skills. AB - INTRODUCTION: Self-confidence is one of the main components of clinical competence, and it is considered to be an important indicator of ability and competence. The aim of this study was to determine the confidence of midwifery graduates from Mashhad College of nursing and midwifery in fulfilling the required clinical skills. METHODS: The study was in the form of a cross-sectional study, and it was performed in 2011 on 50 midwifery graduates who had been working in health centers in Mashhad for six months to three years providing midwifery services, as well as on their supervisors having a minimum of 6 months experiences of responsibility in these centers. The research tools included self assessment tools of self-confidence in midwives and assessment tools of self confidence in midwifery graduates in fulfilling clinical skills performed by the supervisors. The validity of the tools was confirmed by face validity and content validity, and the reliability of the test was confirmed by test-retest (r = 0.82). After the data were extracted and encoded, they were analyzed using SPSS software version 11.5, descriptive statistics, the t-test, and Pearson's test. RESULTS: Among the midwifery graduates, 84.57% of them had confidence in the area of management of low-risk situations, and 55.51% had confidence in their ability to manage high-risk situations. The self-confidence levels of graduates in fulfilling clinical skills in the management of low-risk and high-risk situations were significantly different (P < 0.05). Clinical skills had a positive correlation with self-confidence (P < 0.05, r = 0.85). CONCLUSION: Improvements were needed in the self-confidence of graduates in fulfilling clinical skills in the management of high-risk situations. In order to achieve such improvement, it is necessary to identify and use methods of increasing graduates' self-confidence in the learning environment by developing an enhanced midwifery curriculum and improved teaching methods. PMID- 26435830 TI - Diacerein: A potential therapeutic drug for the management of experimental periodontitis in rats. AB - INTRODUCTION: Knowledge about the pathogenic process in the progression of periodontal disease indicates that the central cause of periodontal disease is the loss of a healthy balance between microbial virulence factors and the host's inflammatory response. The aim of this study was to evaluate the potential effectiveness of diacerein as an anti-inflammatory drug in the management of experimental periodontitis in rats. METHODS: The study included 60 albino rats that were divided into two groups. Periodontitis was induced in both groups. The drug group received systemic administration of diacerein, and the control group received a placebo. IL-1beta was measured two weeks after the induction of periodontitis and before the administration of the drug (baseline measurement), and it was measured again at the end of two and end of four weeks after scaling and root planning and diacerein administration. RESULTS: The results indicated that there was a significant decrease in IL-1beta level in both groups. For the control group, there were significant decreases of the IL-1beta values from the baseline to two weeks and also from the baseline to four weeks, with p-values of 0.0001 for both comparisons. The same results were obtained for the drug group. CONCLUSION: It was concluded that it is likely that diacerein may play a therapeutic role as a potent anti-inflammatory drug in the management of periodontitis. PMID- 26435831 TI - Evaluation of the orientation of the steepest meridian of regular astigmatism among highly myopic Egyptian patients seeking non-ablative surgical correction of the refractive error. AB - INTRODUCTION: LASIK surgery is currently the preferred procedure to correct low to moderate myopia. The aim of this study was to determine the orientation of the steepest meridian of regular astigmatism in order to determine the relative incidence of vertical, horizontal, and oblique regular astigmatism among highly myopic Egyptian patients seeking non-ablative surgical correction of the refractive error. METHODS: One hundred and one eyes of 68 highly myopic patients who were seeking refractive surgery were included in this consecutive case series study. The refractive errors were measured using an autorefractometer and confirmed by trial. We measured the uncorrected and best corrected visual acuity in Snellen lines. Keratometry, central corneal thickness, and anterior chamber depth also were measured. The cylinder power in diopters and the axis in degrees were reported. Astigmatism was graded as with the rule (i.e., vertical meridian steeper), against the rule (i.e., horizontal meridian steeper), and oblique astigmatism. The number and the percentage of eyes with the rule, against the rule, and oblique astigmatism were calculated, and the chi-squared test was performed to analyze the data. RESULTS: The spherical refractive error ranged from -6.5 to -24.5 diopters (-13.45 +/- 4.60). The cylinder power (Cyl) ranged from -0.25 to -7.5 diopters (-2.23 +/- 1.28). The uncorrected visual acuity (UCVA) in Snellen lines ranged from 0.01 - 0.1 (0.03 +/- 0.02). The mean for best corrected visual acuity (BCVA) in Snellen lines was 0.40 (+/- 0.23). The steepest meridian was vertical (i.e., with-the-rule astigmatism) in 44 eyes (43.56%), horizontal (i.e., against-the-rule astigmatism) in 27 eyes (26.73%), and oblique (i.e., oblique astigmatism) in 30 eyes (29.70%). CONCLUSIONS: The incidence of with-the-rule astigmatism in patients with high myopia was found to be much lower than in previous studies for non-myopic patients, with a higher incidence for against-the-rule astigmatism and oblique astigmatism. PMID- 26435832 TI - Insistence on sameness relates to increased covariance of gray matter structure in autism spectrum disorder. AB - BACKGROUND: Autism spectrum disorder (ASD) is characterized by atypical development of cortical and subcortical gray matter volume. Subcortical structural changes have been associated with restricted and repetitive behavior (RRB), a core component of ASD. Behavioral studies have identified insistence on sameness (IS) as a separable RRB dimension prominent in high-functioning ASD, though no simple brain-behavior relationship has emerged. Structural covariance, a measure of morphological coupling among brain regions using magnetic resonance imaging (MRI), has proven an informative measure of anatomical relationships in typical development and neurodevelopmental disorders. In this study, we use this measure to characterize the relationship between brain structure and IS. METHODS: We quantified the structural covariance of cortical and subcortical gray matter volume in 55 individuals with high-functioning ASD using 3T MRI. We then related these structural metrics to individual IS scores, as assessed by the Repetitive Behavior Scale-Revised (RBS-R). RESULTS: We found that increased coupling among subcortical regions and between subcortical and cortical regions related to greater IS symptom severity. Most pronounced, the striatum and amygdala participated in a plurality of identified relationships, indicating a central role for these structures in IS symptomatology. These structural associations were specific to IS and did not relate to any of the other RRB subcomponents measured by the RBS-R. CONCLUSIONS: This study indicates that behavioral dimensions in ASD can relate to the coordination of development across multiple brain regions, which might be otherwise obscured using typical brain-behavior correlations. It also expands the structures traditionally related to RRB in ASD and provides neuroanatomical evidence supportive of IS as a separate RRB dimension. TRIAL REGISTRATION: ClinicalTrials.gov NCT01031407. PMID- 26435834 TI - Stem cell aging in adult progeria. AB - Aging is considered an irreversible biological process and also a major risk factor for a spectrum of geriatric diseases. Advanced age-related decline in physiological functions, such as neurodegeneration, development of cardiovascular disease, endocrine and metabolic dysfunction, and neoplastic transformation, has become the focus in aging research. Natural aging is not regarded as a programmed process. However, accelerated aging due to inherited genetic defects in patients of progeria is programmed and resembles many aspects of natural aging. Among several premature aging syndromes, Werner syndrome (WS) and Hutchinson-Gilford progeria syndrome (HGPS) are two broadly investigated diseases. In this review, we discuss how stem cell aging in WS helps us understand the biology of aging. We also discuss briefly how the altered epigenetic landscape in aged cells can be reversed to a "juvenile" state. Lastly, we explore the potential application of the latest genomic editing technique for stem cell-based therapy and regenerative medicine in the context of aging. PMID- 26435836 TI - Are personality disturbances in anorexia nervosa related to emotion processing or eating disorder symptomatology? AB - BACKGROUND: Anorexia Nervosa (AN) is a psychiatric illness associated with a number of personality disturbances. However, whether these personality characteristics are related to eating disorder symptomatology or emotion regulation is unclear. The aim of this study was to investigate these relationships. RESULTS: Twenty-four individuals with AN and 25 age- and premorbid intelligence-matched controls completed the Personality Diagnostic Questionnaire, and scores were correlated with measures of emotionality and negative mood states, and eating disorder symptomatology. AN was associated with increased scores on schizoid, borderline, avoidant, dependent, obsessive compulsive, negativistic and depressive personality dimensions, relative to controls. In AN, eating disorder symptomatology did not significantly correlate with scores on any personality dimension. However, a number of personality characteristics were found to correlate with negative mood states. CONCLUSIONS: The findings suggest that personality disturbances in AN are not related to disorder-specific symptoms, but are related to negative mood states. PMID- 26435837 TI - The effect of indoor office environment on the work performance, health and well being of office workers. AB - BACKGROUND: The effect of indoor environment may have an influence on the performance, productivity health and well-being of office workers. METHODS: Environmental factors such as indoor temperature and illumination have been investigated at three levels. A neurobehavioral test (NBT) has been proposed for the evaluation of office workersc performance. A field lab to emulate an office has been created. In controlled condition of environmental factors, the neurobehavioral test was conducted. The response time and the number of errors in each test have been recorded. A randomized block factorial design was used to analyze the responses of office worker's performance. RESULTS: The results revealed that the independent and interaction effect of temperature and illumination have significant effect on the office workers' performance. The effect of indoor room temperature has more influences than the effect of illumination. The effect of indoor temperature has 38.56% of contribution on the performance. The optimum levels of indoor temperature at 21 degrees C and illumination at 1000 lux have improved the work performance and health of office workers. CONCLUSION: The indoor room temperature and illumination are more influence on the performance of the office workers. It may be concluded that the impact of indoor room temperature (38.56%) is more on the office worker's performance than the effect of illumination (19.91%). Further, it may be concluded that the optimum level of indoor room temperature (21 degrees C) and illumination (1000lux) have improved the work performance, health and productivity of office workers. PMID- 26435835 TI - Enzymatic and non-enzymatic isolation systems for adipose tissue-derived cells: current state of the art. AB - In the past decade, adipose tissue became a highly interesting source of adult stem cells for plastic surgery and regenerative medicine. The isolated stromal vascular fraction (SVF) is a heterogeneous cell population including the adipose derived stromal/stem cells (ASC), which showed regenerative potential in several clinical studies and trials. SVF should be provided in a safe and reproducible manner in accordance with current good manufacturing practices (cGMP). To ensure highest possible safety for patients, a precisely defined procedure with a high quality control is required. Hence, an increasing number of adipose tissue derived cell isolation systems have been developed. These systems aim for a closed, sterile, and safe isolation process limiting donor variations, risk for contaminations, and unpredictability of the cell material. To isolate SVF from adipose tissue, enzymes such as collagenase are used. Alternatively, in order to avoid enzymes, isolation systems using physical forces are available. Here, we provide an overview of known existing enzymatic and non-enzymatic adipose tissue derived cell isolation systems, which are patented, published, or already on the market. PMID- 26435838 TI - Improving preparedness of medical students and junior doctors to manage patients with diabetes. AB - OBJECTIVE: New medical graduates are the front-line staff in many hospital settings and manage patients with diabetes frequently. Prescribing is an area of concern for junior doctors, however, with insulin prescribing reported as a particular weakness. This study aimed to produce an educational intervention which aimed to improve preparedness to manage patients with diabetes and evaluate it using a mixed methods approach. RESEARCH DESIGN AND METHODS: An e-resource (http://www.diabetesscenariosforjuniordoctors.co.uk) was created to contain commonplace and authentic diabetes decision-making scenarios. -32 junior doctors (n=20) and year 5 students (n=12) in South West England worked through the scenarios while 'thinking aloud' and then undertook a semistructured interview. Qualitative data were transcribed verbatim and analyzed thematically. Participant confidence to manage patients with diabetes before, immediately after, and 6 weeks after the educational intervention was also measured using a self-rating scale. RESULTS: Participants reported that patients with diabetes were daunting to manage because of the wide array of insulin products, their lack of confidence with chronic disease management and the difficulty of applying theory to practice. The e-resource was described as authentic, practical, and appropriate for the target audience. Junior doctors' self-rated confidence to manage patients with diabetes increased from 4.7 (of 10) before using the e-resource, to 6.4 immediately afterwards, and 6.8 6 weeks later. Medical students' confidence increased from 5.1 before, to 6.4 immediately afterwards, and 6.4 6 weeks later. CONCLUSIONS: Providing opportunities to work with authentic scenarios in a safe environment can help to ameliorate junior doctors' lack of confidence to manage patients with diabetes. PMID- 26435839 TI - Lipid-lowering treatment patterns among patients with type 2 diabetes mellitus with high cardiovascular disease risk. AB - OBJECTIVE: To examine real-world treatment patterns of lipid-lowering treatment and their possible associated intolerance and/or ineffectiveness among patients with type 2 diabetes mellitus initiating statins and/or ezetimibe. RESEARCH DESIGN AND METHODS: Adult (aged >=18 years) patients diagnosed with type 2 diabetes who initiated statins and/or ezetimibe from January 1, 2007 to June 30, 2011 were retrospectively identified from the IMS LifeLink Pharmetrics Plus commercial claims database. Patients were further classified into 3 high-risk cohorts: (1) history of cardiovascular event (CVE); (2) two risk factors (age and hypertension); (3) aged >=40 years. Patients had continuous health plan enrolment >=1 year preindex and postindex date (statin and/or ezetimibe initiation date). Primary outcomes were index statin intensity, treatment modification(s), possible associated statin/non-statin intolerance and/or ineffectiveness issues (based on treatment modification type), and time-to-treatment modification(s). Analyses for each cohort were stratified by age groups (<65 and >=65 years). RESULTS: A total of 9823 (history of CVE), 62 049 (2 risk factors), and 128 691 (aged >=40 years) patients were included. Among patients aged <65 years, 81.4% and 51.8% of those with history of CVE, 75.6% and 44.4% of those with 2 risk factors, and 77.9% and 47.1% of those aged >=40 years had >=1 and 2 treatment modification(s), respectively. Among all patients, 23.2-28.4% had possible statin intolerance and/or ineffectiveness issues after accounting for second treatment modification (if any). CONCLUSIONS: Among patients with type 2 diabetes with high cardiovascular disease risk, index statin treatment modifications that potentially imply possible statin intolerance and/or ineffectiveness were frequent. PMID- 26435840 TI - The talent study: a multicentre randomized controlled trial assessing the impact of a 'tailored lifestyle self-management intervention' (talent) on weight reduction. AB - BACKGROUND: Overweight is considered an important risk factor for diseases in the context of metabolic syndrome. Lifestyle modifications are the means of choice to reduce weight in persons with a Body Mass Index of 28 to 35. The study examines whether there are any differences between two intervention strategies regarding weight reduction in overweight persons. METHODS/DESIGN: The study is a multicentre randomized controlled trial with observation duration of 12 months. Eight study centres are involved to include a minimal sample size of 150 participants. Randomization ratio is 2:1. Feasible persons are checked according to inclusion and exclusion criteria and after given informed consent are assigned randomly to one of two intervention programs: A) intervention group: comprehensive lifestyle modification program (Individual Health Management IHM) with 3 months reduction phase plus 9 months maintaining phase, B) control group: written information with advice for healthy food habits (Usual care UC). Participants of the IHM group have access to a web-based health portal and join 3 full-day and 10 two-hour training sessions during the first 3 months. During the remaining 9 months four refresh trainings will be performed. There are 3 different diet strategies (fasting, two-day diet, meal replacement) for free choice. Participants of the control group are provided with acknowledged rules for healthy food according to the German Nutrition Society (DGE). Examinations are conducted at baseline, after 3, 6, 9 and 12 months. They include body weight, waist circumference, blood pressure, laboratory findings and a bio-impedance analysis to measure body composition. Statistical analysis of the primary outcome 'change of body weight after 12 months' is based on ITT population including analysis of variance of the weight differences between month 0 and 12 with the factors 'group', 'baseline value' and 'study centre'. Secondary outcomes will be analyzed exploratively. DISCUSSION: The monitoring of the study will implement different measures to enhance compliance, avoid attrition and ensure data quality. Based on a blended learning concept and using web-based e-health tools the program promises to achieve sustainable effects in weight reduction. TRIAL REGISTRATION: German Clinical Trials Register Freiburg (DRKS): DRKS00006736 (date registered 20/09/2014). PMID- 26435841 TI - Coronary artery disease is associated with persistent lower quality of life in women. PMID- 26435842 TI - Sticks AND Carrots: Encouraging Open Science at its source. AB - The Open Science (OS) movement has been seen as an important facilitator for public participation in science. This has been underpinned by the assumption that widespread and free access to research outputs leads to (i) better and more efficient science, (ii) economic growth, in particular for small and medium-sized enterprises wishing to capitalise on research findings and (iii) increased transparency of knowledge production and its outcomes. The latter in particular could function as a catalyst for public participation and engagement. Whether OS is likely to help realise these benefits, however, will depend on the emergence of systemic incentives for scientists to utilise OS in a meaningful manner. While some areas, the environmental sciences have a long tradition of open ethos, citizen inclusion and global collaborations, such activities need to be more systematically supported and promoted by funders and learned societies in order to improve scientific research and public participation. PMID- 26435844 TI - Performance and carcass characteristics of Australian purebred and crossbred lambs supplemented with Rice Bran. AB - BACKGROUND: This study examined the effects of dietary supplementation with rice bran, sire breed and gender on live animal performance and carcass characteristics in Australian crossbred and purebred Merino lambs. METHODS: Forty eight lambs balanced by sire breed (Dorset, White Suffolk, Merino) and gender (ewe, wether) were randomly allocated into three dietary supplementation groups (Control- 24 lambs fed wheat/barley-based pellets, Low- 12 animals fed a 50/50 ratio of wheat-based/rice bran pellets, and High- 12 lambs fed rice bran pellets). The Rice bran pellets replaced 19 % of the barley component of the feed. Animals were group-fed at the rate of 1000 g of the supplement per head per day with ad libitum access to lucerne hay as the basal diet and water. The duration of the feeding trial was 49 days with an initial 21-day adjustment period. RESULTS: Sire breed differences were evident for initial (p < 0.0002) and final (p < 0.0016) liveweights, hot carcass (p < 0.0030) and cold carcass (p < 0.0031) weights, as well as dressing percentage (p < 0.0078), fat thickness (p < 0.0467), yield grade (p < 0.0470) and rib eye area (p < 0.0022) with purebred Merino under-performing compared to the crossbreds. Concentrate feed conversion efficiency, costs per unit of liveweight gain and over the hooks income were comparable between treatments regardless of the observed trend where the high supplementation group tended to show lower feed intake (745.8 g/day) compared to both the control (939.9 g/day) and low supplementation groups (909.6 g/day). No significant differences (p > 0.05) were observed between treatments for live animal performance, carcass characteristics, gender and their second-order interactions. CONCLUSIONS: Results indicate that Rice bran can be utilised as a cost-effective supplementary feed source in genetically divergent sheep over a 49 day feeding period without detrimental effects on overall live animal performance or carcass characteristics. PMID- 26435843 TI - Improving mental health among people living with HIV: a review of intervention trials in low- and middle-income countries. AB - People living with HIV (PLWH) experience greater psychological distress than the general population. Evidence from high-incomes countries suggests that psychological interventions for PLWH can improve mental health symptoms, quality of life, and HIV care engagement. However, little is known about the effectiveness of mental health interventions for PLWH in low and middle-income countries (LMICs), where the large majority of PLWH reside. This systematized review aims to synthesize findings from mental health intervention trials with PLWH in LMICs to inform the delivery of mental health services in these settings. A systematic search strategy was undertaken to identify peer-reviewed published papers of intervention trials addressing negative psychological states or disorders (e.g., depression, anxiety) among PLWH in LMIC settings. Search results were assessed against pre-established inclusion and exclusion criteria. Data from papers meeting criteria were extracted for synthesis. Twenty-six papers, published between 2000 and 2014, describing 22 unique interventions were identified. Trials were implemented in sub-Saharan Africa (n=13), Asia (n=7), and the Middle East (n=2), and addressed mental health using a variety of approaches, including cognitive-behavioral (n=18), family-level (n=2), and pharmacological (n=2) treatments. Four randomized controlled trials reported significant intervention effects in mental health outcomes, and eleven preliminary studies demonstrated promising findings. Among the limited mental health intervention trials with PLWH in LMICs, few demonstrated efficacy. Mental health interventions for PLWH in LMICs must be further developed and adapted for resource-limited settings to improve effectiveness. PMID- 26435845 TI - Unpacking externalising problems: negative parenting associations for conduct problems and irritability. AB - BACKGROUND: Reciprocal associations between negative parenting and child externalising problems are well documented, but measures commonly include child irritability, masking potential distinct associations for irritability and conduct problems. AIMS: To illuminate links between negative parenting, child conduct problems and irritability over time. METHOD: A cross-lagged monozygotic (MZ) twin differences design was used in a UK sample (3154 twin pairs) at 4, 7 and 9 years. RESULTS: Within-pair MZ differences in negative parenting were found to relate longitudinally to differences in conduct problems and irritability. Of note, negative parenting at age 7 was found to relate particularly to increased irritability at 9 years. CONCLUSIONS: Once genetics are taken into account, irritability in middle childhood may be particularly vulnerable to negative parenting, suggesting support for its malleability to parent-based intervention. PMID- 26435847 TI - Molecular Imaging of Tumors Using a Quantitative T 1 Mapping Technique via Magnetic Resonance Imaging. AB - Magnetic resonance imaging (MRI) of glioblastoma multiforme (GBM) with molecular imaging agents would allow for the specific localization of brain tumors. Prior studies using T 1-weighted MR imaging demonstrated that the SBK2-Tris-(Gd-DOTA)3 molecular imaging agent labeled heterotopic xenograft models of brain tumors more intensely than non-specific contrast agents using conventional T 1-weighted imaging techniques. In this study, we used a dynamic quantitative T 1 mapping strategy to more objectively compare intra-tumoral retention of the SBK2-Tris-(Gd DOTA)3 agent over time in comparison to non-targeted control agents. Our results demonstrate that the targeted SBK2-Tris-(Gd-DOTA)3 agent, a scrambled-Tris-(Gd DOTA)3 control agent, and the non-specific clinical contrast agent Optimark(TM) all enhanced flank tumors of human glioma cells with similar maximal changes on T 1 mapping. However, the retention of the agents differs. The non-specific agents show significant recovery within 20 min by an increase in T 1 while the specific agent SBK2-Tris-(Gd-DOTA)3 is retained in the tumors and shows little recovery over 60 min. The retention effect is demonstrated by percent change in T 1 values and slope calculations as well as by calculations of gadolinium concentration in tumor compared to muscle. Quantitative T 1 mapping demonstrates the superior binding and retention in tumors of the SBK2-Tris-(Gd-DOTA)3 agent over time compared to the non-specific contrast agent currently in clinical use. PMID- 26435846 TI - Potential Risks in the Paradigm of Basic to Translational Research: A Critical Evaluation of qPCR Telomere Size Techniques. AB - Real time qPCR has become the method of choice for rapid large-scale telomere length measurements. Large samples sizes are critical for clinical trials, and epidemiological studies. QPCR has become such routine procedure that it is often used with little critical analysis. With proper controls, the mean telomere size can be derived from the data and even the size can be estimated. But there is a need for more consistent and reliable controls that will provide closer to the actual mean size can be obtained with uniform consensus controls. Although originating at the level of basic telomere research, many researchers less familiar with telomeres often misunderstand the source and significance of the qPCR metric. These include researchers and clinicians who are interested in having a rapid tool to produce exciting results in disease prognostics and diagnostics than in the multiple characteristics of telomeres that form the basis of the measurement. But other characteristics of the non-bimodal and heterogeneous telomeres as well as the complexities of telomere dynamics are not easily related to qPCR mean telomere values. The qPCR metric does not reveal the heterogeneity and dynamics of telomeres. This is a critical issue since mutations in multiple genes including telomerase can cause telomere dysfunction and a loss of repeats. The smallest cellular telomere has been shown to arrest growth of the cell carrying the dysfunction telomere. A goal for the future is a simple method that takes into account the heterogeneity by measuring the highest and lowest values as part of the scheme to compare. In the absence of this technique, Southern blots need to be performed in a subset of qPCR samples for both mean telomere size and the upper and lower extremes of the distribution. Most importantly, there is a need for greater transparency in discussing the limitations of the qPCR data. Given the potentially exciting qPCR telomere size results emerging from clinical studies that relate qPCR mean telomere size estimates to disease states, the current ambiguities have become urgent issues to validate the findings and to set the right course for future clinical investigations. PMID- 26435848 TI - Screening of Small Molecule Microarrays for Ligands Targeted to the Extracellular Epitopes of Living Cells. AB - The screening of living cells using high-throughput microarrays is technically challenging. Great care must be taken in the chemical presentation of potential ligands and the number of collisions that cells make with them. To overcome these issues, we have developed a glass slide-based microarray system to discover small molecule ligands that preferentially bind to one cell type over another, including when the cells differ by only a single receptor. Chemical spots of 300 +/- 10 MUm in diameter are conjugated covalently to glass slides using an arraying robot, and novel near-infrared fluorophores with peak emission at 700 nm and 800 nm are used to label two different cell types. By carefully optimizing incubation conditions, including cell density, motion, kinetics, detection, etc. we demonstrate that cell-ligand binding occurs, and that the number of cells bound per chemical spot correlates with ligand affinity and specificity. This screening system lays the foundation for high-throughput discovery of novel ligands to the cell surface. PMID- 26435849 TI - Weight Maintenance with Litramine (IQP-G-002AS): A 24-Week Double-Blind, Randomized, Placebo-Controlled Study. AB - BACKGROUND: Litramine (IQP-G-002AS) was shown to be effective and safe for weight loss in overweight and obese subjects. However, long-term effectiveness on maintenance of body weight loss has yet to be ascertained. OBJECTIVE: To assess effect of Litramine on maintenance of body weight loss. METHODS: A double-blind, randomised, placebo-controlled trial on overweight and obese patients was conducted over two sites in Germany for 24 weeks. Subjects with documented previous weight loss of 3% over the last 3-6 months were randomised to groups given either Litramine (3 g/day) or a matching placebo. Primary endpoints were difference of mean body weight (kg) between baseline and end of study and maintenance of initially lost body weight in verum group, where maintenance is defined as <=1% weight gain. RESULTS: Subjects who were taking Litramine lost significantly more body weight compared to the subjects taking placebo who gained weight instead (-0.62 +/- 1.55 kg versus 1.62 +/- 1.48 kg, p < 0.001). More importantly, 92% of subjects in Litramine group were able to maintain their body weight after initial weight loss, versus 25% in placebo group. No serious adverse events were reported throughout. CONCLUSION: Litramine is effective and safe for long-term body weight maintenance. Trial Registration. This trial is registered with Clinicaltrials.gov identifier: NCT01505387. PMID- 26435850 TI - Visual Interhemispheric and Striate-Extrastriate Cortical Connections in the Rabbit: A Multiple Tracer Study. AB - Previous studies in rabbits identified an array of extrastriate cortical areas anatomically connected with V1 but did not describe their internal topography. To address this issue, we injected multiple anatomical tracers into different regions in V1 of the same animal and analyzed the topography of resulting extrastriate labeled fields with reference to the patterns of callosal connections and myeloarchitecture revealed in tangential sections of the flattened cortex. Our results extend previous studies and provide further evidence that rabbit extrastriate areas resemble the visual areas in rats and mice not only in their general location with respect to V1 but also in their internal topography. Moreover, extrastriate areas in the rabbit maintain a constant relationship with myeloarchitectonic borders and features of the callosal pattern. These findings highlight the rabbit as an alternative model to rats and mice for advancing our understanding of cortical visual processing in mammals, especially for projects benefiting from a larger brain. PMID- 26435851 TI - Novel Longitudinal and Propensity Score Matched Analysis of Hands-On Cooking and Nutrition Education versus Traditional Clinical Education among 627 Medical Students. AB - Background. Physicians are inadequately equipped to respond to the global obesity and nutrition-associated chronic disease epidemics. We investigated superiority of simulation-based medical education with deliberate practice (SBME-DP) hands-on cooking and nutrition elective in a medical school-based teaching kitchen versus traditional clinical education for medical students. Materials and Methods. A 59 question panel survey was distributed to an entire medical school twice annually from September 2012 to May 2014. Student diet and attitudes and competencies (DACs) counseling patients on nutrition were compared using conditional multivariate logistic regression, propensity score-weighted, and longitudinal panel analyses. Inverse-variance weighted meta-analysis (IVWM) was used for planned subgroup analysis by year and treatment estimates across the three methods. Results. Of the available 954 students, 65.72% (n = 627) unique students were followed to produce 963 responses. 11.32% (n = 109) of responses were from 84 subjects who participated in the elective. SBME-DP versus traditional education significantly improved fruit and vegetable diet (OR = 1.38, 95% CI: 1.07-1.79, p = 0.013) and attitudes (OR = 1.81, 95% CI: 1.40-2.35, p < 0.001) and competencies (OR = 1.72, 95% CI: 1.54-1.92, p < 0.001). Conclusions. This study reports for the first time superiority longitudinally for SBME-DP style nutrition education for medical students which has since expanded to 13 schools. PMID- 26435852 TI - A Report of Accelerated Coronary Artery Disease Associated with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common heritable form of vascular dementia and it is caused by mutations in the NOTCH3 gene. The neurologic manifestations of CADASIL syndrome have been well characterized; however, here we report one of the first de novo cases of CADASIL-associated coronary artery disease. A 45-year-old woman with a history of CADASIL and remote tobacco use presented with unstable angina. She was found to have diffuse and irregular narrowing of the left anterior descending artery and a drug eluting stent was deployed. Months later, she developed two subsequent episodes of unstable angina, requiring stent placement in the distal left anterior descending artery and the right coronary artery. Though the neurologic manifestations of CADASIL have been well described, these patients may also be predisposed to developing premature coronary artery disease. Patients with CADASIL and their physicians should be aware of this possible association because these patients may not be identified as high risk by traditional cardiovascular risk estimators. These patients may benefit from more aggressive interventions to reduce cardiac risk. PMID- 26435853 TI - Culture Negative Stent Infection in an Infant with Hypoplastic Left Heart and Persistent Fever. AB - We present an infant with hypoplastic left heart with persistent fever despite two courses of antibiotics and repeatedly negative blood cultures. He eventually underwent surgical extraction of two stents. The stent cultures became positive; he was treated with 4 weeks of antibiotics and the fever resolved. PMID- 26435854 TI - A Rare Case of Aortic Valve Thrombosis in Patient with Idiopathic Hypereosinophilic Syndrome. AB - Idiopathic hypereosinophilic syndrome (HES) is characterized by persistent eosinophilia and eosinophil-mediated organ-system damage. Cardiac thrombosis and thromboembolic complications represent common causes of morbidity and mortality and usually involve cardiac ventricles or mitral and prosthetic valves, while the involvement of the aortic valve is extremely rare in HES. Here we report peculiar multimodality images of an atypical case of extended thrombosis of the aortic valve, complicated by myocardial ischemia and asymptomatic cerebral ischemia, likely due to thrombus embolization, occurring in a 48-year-old man with HES. Prompt anticoagulant and steroid therapy lead to rapid and complete resolution of the thrombotic lesions, allowing preserving the native valve and preventing further embolic events. PMID- 26435855 TI - Mediastinal Packing for Intractable Coagulopathy in Acute Aortic Dissection (Types 1 and 2 DeBakey): A Life-Saving Technique-Report of Experiences. AB - Nonsurgical bleeding after complex thoracic aortic procedures (such as aortic dissection and aortic aneurysm) is a great challenge for cardiac surgeons because of severe coagulopathy, exsanguinous bleeding, and inevitable death. Temporary mediastinal packing (with sponge) in such cases is the only life-saving technique with good result in most cases. Herein, we presented three cases with acute aortic dissection with intractable bleeding that was successfully managed with mediastinal packing. PMID- 26435857 TI - Dental Considerations in Children with Glucose-6-phosphate Dehydrogenase Deficiency (Favism): A Review of the Literature and Case Report. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an uncommon inherited enzyme deficiency characterized by hemolytic anemia, caused by the inability of erythrocytes to detoxify oxidizing agents such as drugs, infectious diseases, or fava bean ingestion. In this later case, the disorder is known as favism. The aim of the present report was to present a review of the literature in this disease, to describe a case report concerning an affected 9-year-old male, and to review the main implications and precautions in pediatric dental management. PMID- 26435856 TI - Primary Chronic Osteomyelitis of the Jaws in Children: An Update on Pathophysiology, Radiological Findings, Treatment Strategies, and Prospective Analysis of Two Cases. AB - Objective. Primary chronic osteomyelitis (PCO) of the jaws in children is associated with pain, trismus, and swelling. In children, temporomandibular joint involvement is rare and few studies have been published due to the relatively low incidence. This paper presents two cases of mandibular PCO in children with the involvement of the collum mandibulae. In addition, a review of the literature regarding demographic data, histological, radiological, and laboratory findings, and treatment strategies of PCO was also performed. Material and Methods. Prospective analyses of two PCO cases. A PubMed search was used and the articles were sorted according to their corresponding key area of focus. Results. Review of the literature revealed twenty-four cases of PCO with two cases of mandibular condyle involvement. The mean age was 18 years; the male to female ratio was 1 : 3. Most of the patients were treated with anti-inflammatory drugs in combination with decortication. Clinical recurrence was seen in 7 cases. Conclusion. A combination of anti-inflammatory drugs and surgical intervention appears to be the first choice of treatment. However, surgical removal of necrotic tissue adjacent to collum mandibulae has its limitations in children. Further investigations are of utmost importance in order to increase our knowledge and understanding of this disease. PMID- 26435858 TI - Omalizumab for Urticarial Vasculitis: Case Report and Review of the Literature. AB - Urticarial vasculitis is characterised by inflamed itching or burning red patches or wheals that resemble urticaria but persist for greater than 24 hours. It is often idiopathic but is sometimes associated with collagen-vascular disease, particularly systemic lupus erythematosus. Treatment options include oral antihistamines, oral corticosteroids, dapsone, colchicine or hydroxychloroquine. We describe a male patient with urticarial vasculitis who was treated with omalizumab (anti-IgE) with convincing results and provide a review of previous reports of patients with urticarial vasculitis treated with omalizumab. PMID- 26435859 TI - A Missed Case of Occult Bilateral Temporomandibular Dislocation Mistaken for Dystonia. AB - A 24-year-old male with a history of psychiatric disorder and no prior significant temporomandibular joint (TMJ) pathology presented to the emergency department for "lockjaw." Plain film X-rays of the mandible were read as unremarkable by an attending radiologist, leading to the initial diagnosis of medication-induced dystonic reaction. Following unsuccessful medical treatment a maxillofacial computed tomography (CT) was ordered. CT confirmed bilateral dislocation, illustrating the importance of clinical judgment, and limitations of certain radiographic images. The authors believe this case to be the first reported case in the medical literature of bilateral anterior TMJ dislocation with a false negative X-ray. PMID- 26435861 TI - Comment on "A Case of Healthcare Associated Pneumonia Caused by Chryseobacterium indologenes in an Immunocompetent Patient". PMID- 26435860 TI - Third Case of Streptococcus suis Infection in Greece. AB - Streptococcus suis is a facultative anaerobic, Gram-positive coccus that can cause severe disease to both pigs and humans. Its zoonotic potential was first recognized in 1968 when the first human case of meningitis was reported in Denmark. Since then, over 1600 human cases have been reported worldwide, the vast majority of which originated in Southeast Asia, and, thus, S. suis has been fairly characterized as an emerging pathogen. Infection in humans presents most commonly as bacteremia and/or meningitis while less common clinical manifestations such as endocarditis and septic arthritis can occur. S. suis infection is extremely uncommon in Greece and this is the third human case to be reported. Correct identification is of importance for optimization of antimicrobial treatment and epidemiological monitoring. PMID- 26435862 TI - Miliary Tuberculosis Induced Acute Liver Failure. AB - Hepatobiliary tuberculosis is uncommon even in endemic countries. It is associated with a high mortality and is even diagnosed early in the disease course. Acute liver failure (ALF) caused by tuberculosis bacilli has been reported in only a few reports. All previous cases have been diagnosed by postmortem examination. Time to antituberculosis treatment is very critical. In case of suggestive findings on clinical and radiologic examination, antituberculosis treatment should be initiated immediately. Drug use can be a challenge in patients with ALF. However, as long as the other possible causes of ALF can be excluded and hepatotoxic drugs were avoided during the early course of treatment, such a highly fatal presentation of tuberculosis can be treated safely. Here, we report a case of acute liver failure as a presentation of miliary tuberculosis. He was treated successfully with antituberculosis treatment. PMID- 26435863 TI - A Rare Case of Diffuse Alveolar Hemorrhage Secondary to Acute Pulmonary Histoplasmosis. AB - Diffuse alveolar hemorrhage (DAH) is a rare presentation of acute pulmonary histoplasmosis. While histoplasmosis has been reported to cause hemoptysis and alveolar hemorrhage in children, the English language literature lacks any adult case reports documenting this association. We report a case of pulmonary histoplasmosis where the initial presentation was pneumonia with a subsequent diagnosis of DAH. PMID- 26435864 TI - A Case of Subacute Combined Degeneration of the Spinal Cord with Infective Endocarditis. AB - Background. Subacute combined degeneration (SCD) is a rare cause of demyelination of the dorsal and lateral columns of spinal cord and is a neurogenic complication due to cobalamin deficiency. Anemia of chronic disease (ACD) occurs in patients with acute or chronic immune activation, including infective endocarditis. It remains to be elucidated whether ACD patients are more sensitive to suffer from SCD. Little cases about SCD patients accompanied with ACD have been reported till now. Here we reported a 36-year-old man with SCD with a medical history of mitral inadequacy over 20 years, who was admitted and transported from another hospital to our hospital due to an 8-month history of gait disturbance, lower limb weakness and paresthesia, and loss of proprioception. Significant laboratory results and echocardiography suggest iron deficiency anemia and infective endocarditis (IE). The SCD diagnosis was confirmed by MRI, which showed selective demyelination in the dorsal and lateral columns of spinal cord. In conclusion, the ACD patients may suffer from SCD, which can be diagnosed by 3 Tesla magnetic resonance imaging. PMID- 26435865 TI - Didelphys Uterus: A Case Report and Review of the Literature. AB - Background. Mullerian duct anomalies (MDAs) are congenital defects of the female genital system that arise from abnormal embryological development of the Mullerian ducts. A didelphys uterus, also known as a "double uterus," is one of the least common amongst MDAs. This report discusses a case of didelphys uterus that successfully conceived, carried her pregnancy to term, and delivered vaginally without any significant complications. Case. Patient is a 29-year-old G2P0010 from Bangladesh, initially came a year prior in her first pregnancy, with spontaneous abortion (SAB). Pelvic Sonogram at that time showed a diagnosis of bicornuate versus didelphys uterus. There were no renal anomalies on subsequent abdominal CT scan. Patient presented with the second pregnancy and had uncomplicated prenatal care and did not have signs of preterm labor; fetus showed appropriate growth and the pregnancy was carried in the left uterus. Patient presented at 38 4/7 wks with Premature Rupture of Membrane and underwent induction of labor with Cytotec. Antibiotics were started for chorioamnionitis. Patient had a vaginal delivery with left mediolateral episiotomy and complete tear of vaginal septum. Third stage of labor was complicated with retained placenta, which was removed manually in the operating room with total EBL of 600 cc. PMID- 26435866 TI - Persistent Notochord in a Fetus with COL2A1 Mutation. AB - Multiple anomalies including micromelia, poor mineralization of the vertebrae, and a persistent notochord were identified on second trimester ultrasound in a fetus with a COL2A1 mutation. To our knowledge, this represents the first case of a persistent notochord associated with a COL2A1 mutation in humans. In this case report, we describe ultrasound and postmortem findings and review the pathogenesis associated with a persistent notochord. PMID- 26435867 TI - Traumatic Death due to Simultaneous Double Spine Fractures in Patient with Ankylosing Spondylitis. AB - The aim of this study is to report the rare occurrence of simultaneous double spine fractures in a patient with progressive ankylosing spondylitis (AS). An 82 year-old male with established AS had low-energy falls. He had sustained simultaneous double spine fractures and died. Plain radiographs of the cervical spine were unremarkable in detecting a cervical spine fracture in a patient with AS and a spinal cord injury following a fall. CT scan showed a displaced fracture at the C6/C7 with American Spinal Injury Association-A spinal cord injury and displaced fracture at L1. The cause of death was determined to be upper spinal cord injury caused by cervical spinal fracture and dislocation that were facilitated by spinal rigidity from AS. This case report illustrates the importance of obtaining a detailed medical history and thorough imaging study when investigating deaths, including nonfatal conditions, such as AS. Furthermore, it shows the value of entire spine CT scan in the evaluation of the mechanism, further spine fractures, and manner of death. Despite the occurrence of spine fracture in AS patients, simultaneous double or multiple spine fractures are extremely rare and can be missed. Care should be taken for the further spine fracture in the entire spine in patient with AS. PMID- 26435868 TI - Pediatric Ramsay Hunt Syndrome: Analysis of Three Cases. AB - Ramsay Hunt syndrome (RHS) is a disorder characterized by herpetic eruptions on the auricle, facial paralysis, and vestibulocochlear dysfunction and is attributed to varicella zoster virus (VZV) infection in the geniculate ganglion. Although it is a common cause of acute peripheral facial paralysis, children are not usually affected. The diagnosis is based on history and physical findings. Treatment of RHS uses a combination of high-dose corticosteroids and acyclovir. This paper presents three cases diagnosed as RHS in the pediatric age group in association with the literature review. The aim of this paper is to emphasize the importance of careful examination and early initiation of therapy in suspected cases of RHS. PMID- 26435869 TI - Cardiac Tamponade Associated with the Presentation of Anaplastic Large Cell Lymphoma in a 2-Year-Old Child. AB - The anaplastic large cell lymphoma is a rare entity in pediatric patients. We present an unusual case of pericardial involvement, quite uncommon as extranodal presentation of this type of disorder, that provoked a life-risk situation requiring an urgent pericardiocentesis. To our knowledge, this is the first report on a child with pericardial involvement without an associated cardiac mass secondary to anaplastic large cell lymphoma in pediatric age. We report the case of a 21-month-old Caucasian male infant with cardiac tamponade associated with the presentation of anaplastic large cell lymphoma. Initially, the child presented with 24-day prolonged fever syndrome, cutaneous lesions associated with hepatomegaly, inguinal adenopathies, and pneumonia. After a 21-day asymptomatic period, polypnea and tachycardia were detected in a clinical check-up. Chest X ray revealed a remarkable increase of the cardiothoracic index. The anaplastic large cell lymphoma has a high incidence of extranodal involvement but myocardial or pericardial involvements are rare. For this reason, we recommend a close monitoring of patients with a differential diagnosis of anaplastic large cell lymphoma. PMID- 26435870 TI - Paravertebral and Retroperitoneal Vascular Tumour Presenting with Kasabach Merritt Phenomenon in Childhood, Diagnosed with Magnetic Resonance Imaging. AB - Kasabach-Merritt phenomenon (KMP) is characterized by vascular tumour and consumptive coagulopathy with life-threatening thrombocytopenia, prolonged prothrombin time and partial thromboplastin time, hypofibrinogenemia, and the presence of high fibrin split products. We report a case of 3-year-old boy with local aggressive vascular lesions associated with KMP. Magnetic resonance imaging revealed an extensive lesion at paravertebral and retroperitoneal regions that was infiltrating vertebrae. Although we did not get any response to steroid or propranolol treatment, partial response was observed radiologically with interferon-alpha treatment. Unfortunately, the patient died because of the uncontrolled consumptive coagulopathy that led to intracranial hemorrhage which was caused by huge knee hematoma after minor trauma. PMID- 26435871 TI - Severe Pulmonary Arterial Hypertension: Comprehensive Evaluation by Magnetic Resonance Imaging. AB - Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary artery (PA) pressure, which negatively affects the right ventricular (RV) function. This report shows a patient with severe PAH, on whom a comprehensive MRI exam was performed to evaluate both PA and RV. New imaging sequences were implemented for obtaining additional parameters about the patient's condition. The results show the capabilities of the developed exam of providing complete picture of the cardiovascular system in PAH, which helps the physician optimize treatment. PMID- 26435872 TI - Anastomosing Haemangioma of the Kidney Involving a Segmental Branch of the Renal Vein. AB - Anastomosing variant of capillary haemangioma is a rare and recently described vascular tumour with a proclivity for the genitourinary tract. Here we present the case of a 64-year-old man with incidental finding of 3.4 cm renal mass on CT who had laparoscopic nephrectomy with a good postoperative recovery. Histopathological diagnosis of anastomosing haemangioma of the kidney was made and the patient was followed up for 10 months without evidence of tumour recurrence. PMID- 26435873 TI - Xanthogranulomatous Pyelonephritis of a Lower Pole Moiety in a Duplicated Collecting System Kidney. AB - Xanthogranulomatous pyelonephritis (XGP) is a destructive inflammatory process which is frequently caused by recurrent urinary tract infections or chronic obstruction by kidney stones. We present a 56-year-old female with an extensive retroperitoneal urinoma and xanthogranulomatous pyelonephritis of the lower pole moiety in a kidney with a duplicated collecting system due to obstructive nephrolithiasis. After drainage of the urinoma, the patient underwent a definitive lower pole heminephrectomy with preservation of the functional upper pole. We review important clinical features of xanthogranulomatous pyelonephritis and considerations for surgery on a duplicated kidney. PMID- 26435874 TI - Palpable Penile Metastases: A Bizarre Presentation of Rectal Adenocarcinoma. AB - Metastasis to the penis is an uncommon occurrence, with only about 370 cases reported in the literature to date. The majority of the primary tumors are genitourinary in origin. We report on a patient with undiagnosed disseminated rectal adenocarcinoma, who first presented with lesions of the corporal bodies. A review of the literature indicates that corporeal metastasis as an initial presentation of malignancy is an extremely rare occurrence and carries a very poor prognosis. PMID- 26435875 TI - Calcification Characteristics of Low-Flow Low-Gradient Severe Aortic Stenosis in Patients Undergoing Transcatheter Aortic Valve Replacement. AB - Low-flow low-gradient severe aortic stenosis (LFLGAS) is associated with worse outcomes. Aortic valve calcification patterns of LFLGAS as compared to non-LFLGAS have not yet been thoroughly assessed. 137 patients undergoing transcatheter aortic valve replacement (TAVR) with preprocedural multidetector computed tomography (MDCT) and postprocedural transthoracic echocardiography were enrolled. Calcification characteristics were assessed by MDCT both for the total aortic valve and separately for each leaflet. 34 patients had LFLGAS and 103 non LFLGAS. Total aortic valve calcification volume (p < 0.001), mass (p < 0.001), and density (p = 0.004) were lower in LFLGAS as compared to non-LFLGAS patients. At 30-day follow-up, mean transaortic pressure gradients and more than mild paravalvular regurgitation did not differ between groups. In conclusion, LFLGAS and non-LFLGAS express different calcification patterns which, however, did not impact on device success after TAVR. PMID- 26435876 TI - Single Center Retrospective Analysis of Conventional and Radial TIG Catheters for Transradial Diagnostic Coronary Angiography. AB - Current guidelines favor the radial approach for coronary angiography. Therefore, specialty radial diagnostic catheters were designed to engage both coronary arteries with a single device. However, it is unclear if single catheters are superior to conventional catheters. A retrospective analysis was performed of consecutive right radial coronary angiographies to determine catheter use, fluoroscopy time, radiation dosage, and consumption of contrast. Procedures were performed with a single TIG catheter or conventional catheters (CONV). Procedures with coronary artery bypass grafts or ventricular angiographies were excluded. 273 transradial procedures were performed successfully. 95 procedures were performed with CONV and 178 procedures with a TIG. Crossover to additional catheters was higher in TIG (15.2%) compared to CONV (5.3%, p = 0.02). Fluoroscopy time was comparable between CONV and TIG, without crossover (2.2 +/- 1.2 min versus 2.3 +/- 1.2 min; n.s.), however, greater in the case of crossover for CONV (5.8 +/- 0.7) and TIG (7.6 +/- 3.0; p = 0.0001). Radiation dosage was similar in CONV and the TIG, without crossover (1419 +/- 1075, cGy*cm(2) versus 1690 +/- 1138; n.s.), however, greater for CONV (2374 +/- 620) and TIG (3733 +/- 2281, p = 0.05) with crossover. Overall, the amount of contrast was greater in TIG (56 +/- 13 mL) versus CONV (48 +/- 3 mL; p = 0.0003). CONV femoral catheters may be the primary choice for radial approach. PMID- 26435877 TI - Tuberculosis of the Penis: A Review of the Literature. AB - Background. Tuberculosis of the penis (TBP) is rare. Aim. To review the literature. Method. Various internet data bases were searched. Literature Review. TBP could be primary or secondary, may develop following circumcision performed by a person who had pulmonary Tb, and may be transmitted to the penis from ejaculation, contamination from clothing, or from contact with endometrial secretions, following an earlier pulmonary Tb or Tb elsewhere. TBP presents with a painless/painful small nodule, ulcer, mass on penis which gradually enlarges, and induration/swelling of penis, with or without erectile dysfunction. Inguinal lymph nodes may or may not be palpable. The patient's voiding is normal. There may or may not be history of circumcision, pulmonary Tb, and BCG immunization. TBP mimics penile carcinoma, granulomatous syphilis penile ulcer, genital herpes simplex, granuloma inguinale, and HIV infection. Diagnosis is established by microscopic examination finding of granulomas +/-AFB in penile discharge or biopsy of lesion or culture of Tb organism from discharge or biopsy specimens or positive Elisa serology/PCR for Tb. PTBs respond to first- or 2nd-line anti-Tb 6 month treatment. Close contacts should be screened. Extrapulmonary Tb should be excluded. Conclusions. Clinicians should consider possibility of PTB in cases of penile lesions and erectile failure. PMID- 26435878 TI - SPECTROSCOPY/MICROSCOPY: Nonlinear Raman microscopy eyes clinical application. AB - Nonlinear Raman microscopy is an emerging technique in biomedical imaging. An inexpensive prototype system, based on coherent anti-Stokes Raman scattering (CARS), demonstrates value for real-time, minimally invasive chemical analysis of cells and tissues. It overcomes drawbacks of both Raman and CARS, and in doing so demonstrates potential for clinical application-including blood analysis and breast cancer detection. PMID- 26435879 TI - The Process of Adapting the Evidence-Based Treatment for Tobacco Dependence for Smokers of Lower Socioeconomic Status. AB - INTRODUCTION: Tobacco use is the leading cause of preventable death and disease and contributes significantly to socioeconomic health disparities. The prevalence of smoking among individuals of lower socioeconomic status (SES) in the US, many of whom are African American (AA), is three to four times greater than the prevalence of smoking among individuals of higher SES. The disparity in tobacco dependence treatment outcomes between lower and higher SES smokers contributes to tobacco-related health disparities and calls for adapting evidence-based treatment to more fully meet the needs of lower SES smokers. AIMS: We sought to adapt the evidence-based treatment for tobacco dependence using recommended frameworks for adapting evidence-based treatments. METHODS: We systematically applied the recommended steps for adapting evidence-based treatments described by Barrera and Castro and Lau. The steps included information gathering, preliminary adaptation design, preliminary adaptation tests, and adaptation refinement. We also applied the PEN-3 Model for incorporating AA values and experiences into treatment approaches and a community-engaged approach. RESULTS/FINDINGS: Findings from each step in the process contributed to the results. The final results were incorporated into a revised treatment called the RITCh Study Tobacco Dependence Treatment Manual and Toolkit. CONCLUSIONS: To our knowledge, this is the first adaptation of evidence-based treatment for tobacco dependence that has systematically applied these recommended frameworks. The efficacy of the treatment to reduce treatment outcome disparities is now being examined in a randomized controlled trial in which the revised treatment is being compared with a standard, individualized cognitive-behavioral approach. PMID- 26435880 TI - Cystathionine Levels in Patients With Huntington Disease. AB - BACKGROUND: Recently a profound depletion of cystathionine gamma-lyase (CSE), the principal enzyme involved in the generation of cysteine from cystathionine, was shown in Huntington disease (HD) patients and several transgenic HD mouse models. We therefore hypothesized that blood and urine cystathionine levels may be increased in HD patients and that this increase might correlate with disease progression. METHODS: We measured concentrations of cystathionine as well as 22 other amino acids in fasting plasma and 24-h urine samples of nine early-stage HD patients and nine age, sex, and body mass index matched controls. RESULTS: There were no significant differences in the plasma or urine concentrations of cystathionine or any other amino acid between HD patients and controls. CONCLUSION: We found no evidence for changes in plasma or urine concentrations of cystathionine in early-stage HD patients. Therefore, cystathionine levels are unlikely to be useful as a state biomarker in HD. PMID- 26435881 TI - Mobile genetic elements are involved in bacterial sociality. AB - Mobile genetic elements in bacteria are enriched in genes participating in social behaviors, suggesting an evolutionary link between gene mobility and social evolution. Cooperative behaviors, like the production of secreted public good molecules, are susceptible to the invasion of non-cooperative individuals, and their evolutionary maintenance requires mechanisms ensuring that benefits are directed preferentially to cooperators. In order to investigate the reasons for the mobility of public good genes, we designed a synthetic bacterial system where we control and quantify the transfer of public good production genes. In our recent study, we have experimentally shown that horizontal transfer helps maintain public good production in the face of both non-producer organisms and non-producer plasmids. Transfer spreads genes to neighboring cells, thus increasing relatedness and directing a higher proportion of public good benefits to producers. The effect is the strongest when public good genes undergo epidemics dynamics, making horizontal transfer especially relevant for pathogenic bacteria that repeatedly infect new hosts and base their virulence on costly public goods. The promotion of cooperation may be a general consequence of horizontal gene transfer in prokaryotes. Our work has an intriguing parallel, cultural transmission, where horizontal transfer, such as teaching, may preferentially promote cooperative behaviors. PMID- 26435882 TI - Household Wealth in China. AB - With new nationwide longitudinal survey data now available from the China Family Panel Studies (CFPS), we study the level, distribution, and composition of household wealth in contemporary China. We find that the wealth Gini coefficient of China was 0.73 in 2012. The richest 1 percent owned more than one-third of the total national household wealth, while the poorest 25 percent owned less than 2 percent. Housing assets, which accounted for over 70 percent, were the largest component of household wealth. Finally, the urban-rural divide and regional disparities played important roles in household wealth distribution, and institutional factors significantly affected household wealth holdings, wealth growth rate, and wealth mobility. PMID- 26435883 TI - Period homolog LIN-42 regulates miRNA transcription to impact developmental timing. AB - Two recent studies by Van Wynsberghe et al. and Perales et al. in the nematode C. elegans have demonstrated a new function of the Period protein homolog LIN-42 in negatively regulating microRNA (miRNA) biogenesis at the transcriptional level. LIN-42 is a complex gene with 4 isoforms and multiple functions including the regulation of molting, developmental timing and entry into dauer. These recent studies uncover an additional function of LIN-42 as a negative regulator of miRNA transcription. Approximately 95% of miRNAs present in eggs and 33% of miRNAs present in L4 stage worms were upregulated in lin-42 mutant worms relative to wild type (WT) worms, suggesting that LIN-42 globally regulates miRNA biogenesis. Expression from both a let-7 miRNA and a lin-4 miRNA transcriptional reporter were enhanced in the absence of lin-42. Additionally, chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq) of late larval stage worms showed that LIN-42 bound the let-7 promoter, suggesting that LIN-42 affects mature miRNA levels by inhibiting their transcription. In addition to miRNAs, LIN-42 also predominantly bound to the promoters of many diverse protein-coding genes. These findings support the action of LIN-42 at multiple points within the heterochronic and other regulatory pathways to impact a multitude of functions including developmental timing. PMID- 26435884 TI - Robust tracking and quantification of C. elegans body shape and locomotion through coiling, entanglement, and omega bends. AB - The behavior of the well-characterized nematode, Caenorhabditis elegans (C. elegans), is often used to study the neurologic control of sensory and motor systems in models of health and neurodegenerative disease. To advance the quantification of behaviors to match the progress made in the breakthroughs of genetics, RNA, proteins, and neuronal circuitry, analysis must be able to extract subtle changes in worm locomotion across a population. The analysis of worm crawling motion is complex due to self-overlap, coiling, and entanglement. Using current techniques, the scope of the analysis is typically restricted to worms to their non-occluded, uncoiled state which is incomplete and fundamentally biased. Using a model describing the worm shape and crawling motion, we designed a deformable shape estimation algorithm that is robust to coiling and entanglement. This model-based shape estimation algorithm has been incorporated into a framework where multiple worms can be automatically detected and tracked simultaneously throughout the entire video sequence, thereby increasing throughput as well as data validity. The newly developed algorithms were validated against 10 manually labeled datasets obtained from video sequences comprised of various image resolutions and video frame rates. The data presented demonstrate that tracking methods incorporated in WormLab enable stable and accurate detection of these worms through coiling and entanglement. Such challenging tracking scenarios are common occurrences during normal worm locomotion. The ability for the described approach to provide stable and accurate detection of C. elegans is critical to achieve unbiased locomotory analysis of worm motion. PMID- 26435885 TI - Proteomic identification of germline proteins in Caenorhabditis elegans. AB - Sexual reproduction involves fusion of 2 haploid gametes to form diploid offspring with genetic contributions from both parents. Gamete formation represents a unique developmental program involving the action of numerous germline-specific proteins. In an attempt to identify novel proteins involved in reproduction and embryonic development, we have carried out a proteomic characterization of the process in Caenorhabditis elegans. To identify candidate proteins, we used 2D gel electrophoresis (2DGE) to compare protein abundance in nucleus-enriched extracts from wild-type C. elegans, and in extracts from mutant worms with greatly reduced gonads (glp-4(bn2) worms reared at 25 degrees C); 84 proteins whose abundance correlated with germline presence were identified. To validate candidates, we used feeding RNAi to deplete candidate proteins, and looked for reduction in fertility and/or germline cytological defects. Of 20 candidates so screened for involvement in fertility, depletion of 13 (65%) caused a significant reduction in fertility, and 6 (30%) resulted in sterility (<5 % of wild-type fertility). Five of the 13 proteins with demonstrated roles in fertility have not previously been implicated in germline function. The high frequency of defects observed after RNAi depletion of candidate proteins suggests that this approach is effective at identifying germline proteins, thus contributing to our understanding of this complex organ. PMID- 26435886 TI - The C. elegans UNC-23 protein, a member of the BCL-2-associated athanogene (BAG) family of chaperone regulators, interacts with HSP-1 to regulate cell attachment and maintain hypodermal integrity. AB - Mutations in the unc-23 gene in the free-living nematode, Caenorhabditis elegans result in detachment and dystrophy of the anterior body wall musculature and a bent-head phenotype when grown on solid substrate. We have determined that the unc-23 gene product is the nematode ortholog of the human BAG-2 protein, a member of the Bcl-2 associated athanogene (BAG) family of molecular chaperone regulators. We show that a functional GFP-tagged UNC-23 protein is expressed throughout development in several tissues of the animal, including body wall muscle and hypodermis, and associates with adhesion complexes and attachment structures within these 2 tissues. In humans, the BAG protein family consists of 6 members that all contain a conserved 45 amino acid BAG domain near their C termini. These proteins bind to and modulate the activity of the ATPase domain of the heat shock cognate protein 70, Hsc70. We have isolated missense mutations in the ATPase domain of the C. elegans heat shock 70 protein, HSP-1 that suppress the phenotype exhibited by unc-23(e25) mutant hermaphrodites and we show that UNC 23 and HSP-1 interact in a yeast-2-hybrid system. The interaction of UNC-23 with HSP-1 defines a role for HSP-1 function in the maintenance of muscle attachment during development. PMID- 26435887 TI - New links between protein N-terminal acetylation, dauer diapause, and the insulin/IGF-1 signaling pathway in Caenorhabditis elegans. AB - Protein N-terminal acetylation is a widespread posttranslational modification in eukaryotes that is catalyzed by N-terminal acetyltransferases (NATs). The biochemical activity of NATs has been characterized extensively, whereas the biological function of NATs is only beginning to be defined. Here we comment on recent progress in understanding the function of NAT activity in C. elegans based on the characterization of natc-1 by Warnhoff et al. (2014) and daf-31 by Chen et al. (2014).(1,2) natc-1 encodes an auxiliary subunit of the NatC complex and modulates stress tolerance, dauer entry, and adult lifespan. daf-31 encodes the catalytic subunit of the NatA complex and affects dauer entry, dauer formation, and adult lifespan. The analysis of these genes and genetic studies of NATs in other organisms suggests protein N-terminal acetylation plays an evolutionarily conserved role in promoting growth and development and inhibiting stress resistance. Furthermore, we propose that NATs may regulate growth and development in response to external cues such as nutrient deprivation and other physiologic stresses. PMID- 26435888 TI - Factors Associated with Colorectal Cancer Screening among Younger African American Men: A Systematic Review. AB - Of cancers affecting both men and women, colorectal cancer (CRC) is the second leading cancer killer among African Americans in the U.S. Compared to White men, African American men have incidence and mortality rates 25% and 50% higher from CRC. Despite the benefits of early detection and the availability of effective screening, most adults over age 50 have not undergone testing, and disparities in colorectal cancer screening (CRCS) persist. Owing to CRC's high incidence and younger age at presentation among African American men, CRCS is warranted at age 45 rather than 50. However, the factors influencing young adult (i.e., age < 50) African American men's intention to screen and/or their CRCS behaviors has not been systematically assessed. To assess whether the factors influencing young adult African American men's screening intentions and behaviors are changeable through structured health education interventions, we conducted a systematic review, with the two-fold purpose of: (1) synthesizing studies examining African American men's knowledge, beliefs, and behaviors regarding CRCS; and (2) assessing these studies' methodological quality. Utilizing Garrard's Matrix Method, a total of 28 manuscripts met our inclusion/exclusion criteria: 20 studies followed a non-experimental research design, 4 comprised a quasi experimental design, and 4, an experimental design. Studies were published between 2002 and 2012; the majority, between 2007 and 2011. The factors most frequently assessed were behaviors (79%), beliefs (68%), and knowledge (61%) of CRC and CRCS. Six factors associated with CRC and CRCS emerged: previous CRCS, CRC test preference, perceived benefits, perceived barriers, CRC/CRCS knowledge, and physician support/recommendation. Studies were assigned a methodological quality score (MQS - ranging from 0 to 21). The mean MQS of 10.9 indicated these studies were, overall, of medium quality and suffered from specific flaws. Alongside a call for more rigorous research, this review provides important suggestions for practice and culturally relevant interventions. PMID- 26435889 TI - Randomized sham controlled trial of cranial microcurrent stimulation for symptoms of depression, anxiety, pain, fatigue and sleep disturbances in women receiving chemotherapy for early-stage breast cancer. AB - PURPOSE: Women with breast cancer may experience symptoms of depression, anxiety, pain, fatigue and sleep disturbances during chemotherapy. However, there are few modalities that address multiple, commonly occurring symptoms that may occur in individuals receiving cancer treatment. Cranial electrical stimulation (CES) is a treatment that is FDA cleared for depression, anxiety and insomnia. CES is applied via electrodes placed on the ear that deliver pulsed, low amplitude electrical current to the head. METHODS: This phase III randomized, sham controlled study aimed to examine the effects of cranial microcurrent stimulation on symptoms of depression, anxiety, pain, fatigue, and sleep disturbances in women receiving chemotherapy for early-stage breast cancer. Patients were randomly assigned to either an actual or sham device and used the device daily for 1 h. The study was registered at clinicaltrials.gov, NCT00902330. RESULTS: The sample included N = 167 women with early-stage breast cancer. Symptom severity of depression, anxiety, and fatigue and sleep disturbances were generally mild to moderate. Levels of pain were low. Anxiety was highest prior to the initial chemotherapy and decreased over time. The primary outcome assessment (symptoms of depression, anxiety, fatigue, pain, sleep disturbances) revealed no statistically significant differences between the two groups, actual CES vs. sham. CONCLUSION: In this study, women receiving chemotherapy for breast cancer experienced multiple symptoms in the mild to moderate range. Although there is no evidence for the routine use of CES during the chemotherapy period for symptom management in women with breast cancer, further symptom management modalities should be evaluated to mitigate symptoms of depression, anxiety, fatigue, pain and sleep disturbances over the course of chemotherapy. PMID- 26435890 TI - A Markov chain Monte Carlo (MCMC) methodology with bootstrap percentile estimates for predicting presidential election results in Ghana. AB - Although, there exists numerous literature on the procedure for forecasting or predicting election results, in Ghana only opinion poll strategies have been used. To fill this gap, the paper develops Markov chain models for forecasting the 2016 presidential election results at the Regional, Zonal (i.e. Savannah, Coastal and Forest) and the National levels using past presidential election results of Ghana. The methodology develops a model for prediction of the 2016 presidential election results in Ghana using the Markov chains Monte Carlo (MCMC) methodology with bootstrap estimates. The results were that the ruling NDC may marginally win the 2016 Presidential Elections but would not obtain the more than 50 % votes to be declared an outright winner. This means that there is going to be a run-off election between the two giant political parties: the ruling NDC and the major opposition party, NPP. The prediction for the 2016 Presidential run-off election between the NDC and the NPP was rather in favour of the major opposition party, the NPP with a little over the 50 % votes obtained. PMID- 26435891 TI - Occurrence and prevalence of Cronobacter spp. in plant and animal derived food sources: a systematic review and meta-analysis. AB - Cronobacter species are motile, non-spore forming, Gram negative emerging opportunistic pathogens mostly associated with bacteremia, meningitis, septicemia, brain abscesses and necrotizing enterocolitis in infected neonates, infants and immunocompromised adults. Members of the genus Cronobacter are previously associated with powdered infant formula although the main reservoir and routes of contamination are yet to be ascertained. This study therefore aim to summarize occurrence and prevalence of Cronobacter spp. from different food related sources. A retrospective systematic review and meta-analysis of peer reviewed primary studies reported between 2008 and 2014 for the occurrence and prevalence of Cronobacter spp. in animal and plant related sources was conducted using "Cronobacter isolation", "Cronobacter detection" and "Cronobacter enumeration" as search terms in the following databases: Web of Science (Science Direct) and ProQuest. Data extracted from the primary studies were then analyzed with meta-analysis techniques for effect rate and fixed effects was used to explore heterogeneity between the sources. Publication bias was evaluated using funnel plot. A total of 916 articles were retrieved from the data bases of which 28 articles met inclusion criteria. Cronobacter spp. could only be isolated from 103 (5.7 %) samples of animal related food while 123 (19 %) samples of plant related food samples harbors the bacteria. The result of this study shows that occurrence of Cronobacter was more prevalent in plant related sources with overall prevalence rate of 20.1 % (95 % CI 0.168-0.238) than animal originated sources with overall prevalence rate of 8 % (95 % CI 0.066-0.096). High heterogeneity (I (2) = 84) was observed mostly in plant related sources such as herbs, spices and vegetables compared to animal related sources (I (2) = 82). It could be observed from this study that plant related sources serve as reservoir and contamination routes of Cronobacter spp. PMID- 26435892 TI - Amino acids in sandal (Santalum album L) with special reference to cis-4-hydroxy l-proline and sym. homospermidine. AB - Sandal (Santalum album L) contains several interesting amino acids and amines which are not seen in other plants. This includes cis-4-hydroxy-l-proline in free form in leaves, flowers and seeds while trans-4-hydroxy-l-proline in bound form. Traces of 3, 4 dehydroproline is also detected in sandal leaves. Biosynthesis of cis-4-hydroxy proline indicates that hydroxylation taken place at proline present in peptidyl form especially bound to glutamic acid and aspartic acid. Pyrrolizidine-2-carboxylic acid an interesting isatin positive heterocyclic compound is also present in sandal leaves. Sandal also contains sym. homospermidine which is not present in any other plants till today. Biosynthesis of sym. homospermidine goes by a unique pathway of putrescine oxidation, Schiff base formation, condensation and reduction. Moreover sandal leaves contain gamma glutamyl derivative of the lachrymatory precursor of onion, gamma-glutamyl-S propenyl cysteine superoxide. This review summarizes the studies on the amino acids in sandal. PMID- 26435893 TI - IgA nephropathy in Brazil: apropos of 600 cases. AB - IgA nephropathy (IgAN) is th e commonest primary glomerular disease worldwide. Studies on its prevalence in Brazil are however scarce. Databases and clinical records from 10 reference centres were retrospectively reviewed. Clinical and laboratory features at the moment of the biopsy were retrieved (age, gender, presence of hematuria, serum creatinine [mg/dL], proteinuria [g/24 h]). Renal biopsy findings were classified according to Haas single grade classification scheme and the Oxford Classification of IgAN. 600 cases of IgAN were identified, of which 568 (94.7 %) were on native kidneys. Male to female ratio was 1.24:1. Patients averaged 32.76 +/- 15.12 years old (range 4-89, median 32). Proteinuria and hematuria were observed, respectively in 56.63 and 72.29 % of patients. The association of both these findings occurred in 37.95 % of the cases. Serum creatinine averaged 1.65 +/- 0.67 mg/dL (median 1.5 mg/dL) at diagnosis. Segmental sclerosis and mesangial hypercellularity were the main glomerular findings (47.6 and 46.2 %) The commonest combination by Oxford Classification of IgAN, was M0 E0 S0 T0 (22.4 %). Chronic tubulo-interstitial lesions with an extension wider than 25 % of the renal cortex could be identified in 32.2 % of the cases. Tubular atrophy and interstitial fibrosis were more strongly associated with higher 24-h proteinuria and serum creatinine levels. Segmental sclerosis (S1) showed a stronger tendency of association with the presence of tubulo-interstitial lesions (T1 and T2) than other glomerular variables. To the best of our knowledge this is the largest series of IgAN in Brazil. It depicts the main biopsy findings and their possible clinical correlates. Our set of data is comparable to previous reports. PMID- 26435894 TI - Binding interaction of a novel fluorophore with serum albumins: steady state fluorescence perturbation and molecular modeling analysis. AB - Fluorescence emission and anisotropy are widely used to measure the binding parameters and kinetic behavior of reactions that cause a change in the rotational time of a fluorescent molecule. We report here fluorescence emission and anisotropy behavior of a newly synthesized novel naphthalene base fluorophore (methyl 3-[(6-{[2-(tert-butoxy)-2-oxoethyl] (4-methoxyphenyl)amino}naphthalen-2 yl)formamido]propanoate) in several solution conditions including its binding to human and bovine serum albumin proteins both in their native and denatured states. The fluorescence yield of the compound substantially increased inside hydrophobic protein surface and ~30 nm decrease in Stokes' shift, compared to aqueous solution, was observed. Shift in fluorescence excitation peak position from the absorption peak of the molecule was ~8 nm in protein solution. This indicated possible alteration of excited state geometry of the compound by the globular fold of albumins. In addition, we measured the steady state fluorescence anisotropy of the molecule to evaluate several thermodynamic parameters and the results suggested the binding was energetically favorable. The measured DeltaG degrees was ~-30 kJ mol(-1) and the derived dissociation constant was ~10(-6) M. The molecular docking analysis further highlighted the nonspecific association of the compound with the proteins and hydrophobic forces may have a significant role in the binding processes. Under the denatured condition of the protein, the compound lost its binding efficacy and reduction in fluorescence intensity was observed. Thus, the molecule appears as a new fluorescence probe to report the nature of its binding site in terms of increased fluorescence quantum yield and decreased Stokes' shift. It can also report the changes in the binding site due to global change in protein structure such as unfolding/misfolding often linked to several human disorder. Further it could be useful to detect and study the drug binding site of specific protein of interest. PMID- 26435895 TI - Secure land tenure as prerequisite towards sustainable living: a case study of native communities in Mantob village, Sabah, Malaysia. AB - Sustainable livelihoods, once enjoyed by native communities, are often threatened and in danger of extinction when new regulations and other forms of restrictions are introduced. These restrictions are often promoted with intended purposes, such as protecting the environment or securing resources from encroachment. However, these acts are slowly replacing the traditional adat (customs and traditions), which are used to define the rights attached to the use of communal and ancestral land. This is especially true when comes to access to forest products and land, in which native communities have used for generations. What the natives see as legitimate and traditional use, the state sees as an encroachment of property; and it has now become illegal to utilise these resources. This paper presents how native communities have adapted to such restrictions and continued to live in a sustainable manner through an adaptive strategy that is in line with state policy changes. A combination of quantitative and qualitative method is used to understand the dynamics of the strategy used by the native communities to adapt to these policy changes. The findings reveal how the natives have employed an adaptive strategy in response to state policy changes. The lessons learned from this study can provide useful pointers as to how state policies, in relation to highland settlements in the state of Sabah, Malaysia, can be improved. PMID- 26435896 TI - Secondary headache due to aspergillus sellar abscess simulating a pituitary neoplasm: case report and review of literature. AB - Fungal sellar abscess is rare. A 42-year-old man was admitted with 2-month headache characterized by right peri-orbital pain. An intrasellar mass was found to be simulated a pituitary neoplasm after magnetic resonance imaging examination, and operated on via an endoscopic trans-sphenoidal approach. Milk like pus and a mass of ash black mixed and necrotic material were found and removed. Histopathology revealed numerous aspergillus hyphae. Itraconazole was given on a dosage of 200 mg twice a day orally for 6 weeks. No recurrence was observed during follow-up. Complete surgical resection through endoscopic trans sphenoidal approach combined with systemic anti-fungal therapy, should be considered as the optimal treatment. PMID- 26435897 TI - An improved fault detection classification and location scheme based on wavelet transform and artificial neural network for six phase transmission line using single end data only. AB - Restrictions on right of way and increasing power demand has boosted development of six phase transmission. It offers a viable alternative for transmitting more power, without major modification in existing structure of three phase double circuit transmission system. Inspite of the advantages, low acceptance of six phase system is attributed to the unavailability of a proper protection scheme. The complexity arising from large number of possible faults in six phase lines makes the protection quite challenging. The proposed work presents a hybrid wavelet transform and modular artificial neural network based fault detector, classifier and locator for six phase lines using single end data only. The standard deviation of the approximate coefficients of voltage and current signals obtained using discrete wavelet transform are applied as input to the modular artificial neural network for fault classification and location. The proposed scheme has been tested for all 120 types of shunt faults with variation in location, fault resistance, fault inception angles. The variation in power system parameters viz. short circuit capacity of the source and its X/R ratio, voltage, frequency and CT saturation has also been investigated. The result confirms the effectiveness and reliability of the proposed protection scheme which makes it ideal for real time implementation. PMID- 26435898 TI - Performance of technical trading rules: evidence from Southeast Asian stock markets. AB - This paper examines the profitability of technical trading rules in the five Southeast Asian stock markets. The data cover a period of 14 years from January 2000 to December 2013. The instruments investigated are five Southeast Asian stock market indices: SET index (Thailand), FTSE Bursa Malaysia KLC index (Malaysia), FTSE Straits Times index (Singapore), JSX Composite index (Indonesia), and PSE composite index (the Philippines). Trading strategies investigated include Relative Strength Index, Stochastic oscillator, Moving Average Convergence-Divergence, Directional Movement Indicator and On Balance Volume. Performances are compared to a simple Buy-and-Hold. Statistical tests are also performed. Our empirical results show a strong performance of technical trading rules in an emerging stock market of Thailand but not in a more mature stock market of Singapore. The technical trading rules also generate statistical significant returns in the Malaysian, Indonesian and the Philippine markets. However, after taking transaction costs into account, most technical trading rules do not generate net returns. This fact suggests different levels of market efficiency among Southeast Asian stock markets. This paper finds three new insights. Firstly, technical indicators does not help much in terms of market timing. Basically, traders cannot expect to buy at a relative low price and sell at a relative high price by just using technical trading rules. Secondly, technical trading rules can be beneficial to individual investors as they help them to counter the behavioral bias called disposition effects which is the tendency to sell winning stocks too soon and holding on to losing stocks too long. Thirdly, even profitable strategies could not reliably predict subsequent market directions. They make money from having a higher average profit from profitable trades than an average loss from unprofitable ones. PMID- 26435899 TI - A practical route to beta(2,3)-amino acids with alkyl side chains. AB - Enantiopure N(Boc)-beta(3)-amino nitriles, valuable synthetic intermediates in the multistep homologation of alpha-amino acids, were alkylated using n-BuLi as base. Alkylations afforded easily separable, almost equimolecular mixtures of diastereomeric N(Boc)-protected syn and anti beta(2,3)-amino nitriles. Suitable manipulations of both cyano and amino groups eventually led to enantiopure N- and/or C-protected beta(2,3)-amino acids. For example, methanolysis using conc. HCl gas in MeOH, provides C-protected beta(2,3) amino acids in excellent yields. This methodology is applied to the synthesis of a series N(Boc)-beta(2,3)-dialkyl amino nitriles derived from l-phenylalanine, d-phenylalanine, l-valine and one C protected beta(2,3) amino acid. We demonstrate an efficient procedure for the preparation of anti and syn beta(2,3)-amino acids with alkyl side chains, from alpha-amino acids in reasonable yields. PMID- 26435900 TI - Power transformation for enhancing responsiveness of quality of life questionnaire. AB - We investigate the effect of power transformation of raw scores on the responsiveness of quality of life survey. The procedure maximizes the paired t test value on the power transformed data to obtain an optimal power range. The parallel between the Box-Cox transformation is also investigated for the quality of life data. PMID- 26435901 TI - Four weeks of regular static stretching reduces arterial stiffness in middle-aged men. AB - Trunk flexibility may be associated with arterial stiffness in young, middle aged, and older healthy men after adjusting for blood pressure. This study assessed the effects of 4 weeks of regular static stretching on arterial stiffness in middle-aged men. Sixteen healthy men (43 +/- 3 years) were assigned to control or intervention groups (n = 8 each). The control group did not alter their physical activity levels throughout the study period. The intervention group participated in five supervised stretching sessions per week for 4 weeks. Each session comprised 30 min of mild stretching that moved the major muscle groups through the full range of motion and stretches were held three times for 20 s at the end range. Flexibility was assessed by sit-and-reach test. Arterial stiffness was assessed by brachial-ankle pulse wave velocity (baPWV) and cardio ankle vascular index (CAVI). Four weeks of stretching increased sit-and-reach (Control, Pre: 31.4 +/- 2.1, Post: 30.8 +/- 2.7 vs. Intervention, Pre: 30.6 +/- 5.3, Post: 43.9 +/- 4.3 cm), and reduced baPWV (Control, Pre: 1204 +/- 25, Post: 1205 +/- 38 vs. Intervention, Pre: 1207 +/- 28, Post: 1145 +/- 19 cm/s) and CAVI (Control, Pre: 7.6 +/- 0.3, Post: 7.5 +/- 0.3 vs. Intervention, Pre: 7.7 +/- 0.2, Post: 7.2 +/- 0.2 units) in the intervention group. However, the change in sit and-reach did not significantly correlate with the changes in arterial stiffness. These findings suggest that short-term regular stretching induces a significant reduction in arterial stiffness in middle-aged men. PMID- 26435902 TI - Inspiratory muscle warm-up has no impact on performance or locomotor muscle oxygenation during high-intensity intermittent sprint cycling exercise. AB - The purpose of this study was to investigate the effect of inspiratory muscle (IM) warm-up on performance and locomotor muscle oxygenation during high intensity intermittent sprint cycling exercise. Ten subjects performed identical exercise tests (10 * 5 s with 25-s recovery on a cycle ergometer) after performing one of two different IM warm-up protocols. The IM warm-up consisted of two sets of 30 inspiratory efforts against a pressure-threshold load equivalent to 15 % (PLA) or 40 % (IMW) of maximal inspiratory pressure (MIP). MIP was measured with a portable autospirometer. Peak power and percent decrease in power were determined. Oxyhemoglobin (O2Hb) was measured using near-infrared spectroscopy. The MIP increased relative to baseline after IMW (115 +/- 21 vs. 123 +/- 17 cmH2O, P = 0.012, ES = 0.42), but not after PLA (115 +/- 20 vs. 116 +/ 17 cmH2O). Peak power (PLA: 10.0 +/- 0.6 vs. IMW: 10.2 +/- 0.5 W kg(-1)), percent decrease in power (PLA: 13.4 +/- 5.6 vs. IMW: 13.2 +/- 5.5 %), and changes in O2Hb levels (PLA: -10.8 +/- 4.8 vs. -10.7 +/- 4.1 MUM) did not differ between the trials. IM function was improved by IMW. However, this did not enhance performance or locomotor muscle oxygenation during high-intensity intermittent sprint cycling exercise in untrained healthy males. PMID- 26435903 TI - Relationships between physical activity and muscular strength among healthy adults across the lifespan. AB - The purpose of this study was to examine relationships between objective and self report measures of physical activity and muscle strength among healthy adults ranging in age from 20 to 91 years. Participants (n = 412) were mostly Caucasian men (48 %) and women (52 %) 43.9 +/- 16.1 year of age with a body mass index (BMI) of 26.4 +/- 4.8 kg/m(2). Physical activity was measured objectively with an accelerometer and by self-report with the Paffenbarger Physical Activity Questionnaire. Upper and lower body muscle strength were measured with an isokinetic dynamometer and handgrip strength with a static dynamometer. Multivariate regression assessed relationships between physical activity and muscle strength. The strongest correlates of upper body strength including handgrip strength were gender (r = -0.861 to -0.716), age (r = -0.445 to -0.241), BMI (r = 0.134-0.397), and physical activity (r = 0.093-0.186). The strongest correlates of lower body strength were gender (r = -0.772 to -0.634), age (r = 0.663 to -0.445), BMI (r = 0.160-0.266), and physical activity (r = -0.139 to 0.151). The strongest correlates of muscle strength were gender (explaining 40-74 % of the variance), age (6-44 %), and BMI (2-16 %), while physical activity correlations were weaker (1-3 %). Conflict surrounding the influence of a physically active lifestyle on muscle strength with age may be due to the stronger influences of other factors that supersede those of physical activity whether measured objectively or by self-report methods. PMID- 26435904 TI - Embryonic and mature astrocytes exert different effects on neuronal growth in rat ventral mesencephalic slice cultures. AB - One obstacle with grafting of dopamine neurons in Parkinson's disease is the insufficient ability of the transplant to reinnervate the host striatum. Another issue is the prospective interaction between the donor fetal tissue and the adult astrocytes of the host. To study nerve fiber growth and its interaction with immature/mature astrocytes, ventral mesencephalic (VM) organotypic rat tissue cultures from embryonic days (E) 12, E14, and E18 were studied up to 35 days in vitro (DIV), and co-cultures of E14 VM tissue and mature green fluorescent protein (GFP)-positive astrocytes were performed. Generally, nerve fibers grew from the tissue slice either in association with a monolayer of migrated astroglia surrounding the tissue (glial-associated), or distal to the astroglia as non-glial-associated outgrowth. The tyrosine hydroxylase (TH)-positive glial associated nerve fiber outgrowth reached a plateau at 21 DIV in E12 and E14 cultures. In E18 cultures, TH-positive neurons displayed short processes and migrated onto the astrocytes. While the non-glial-associated nerve fiber outgrowth dominated the E14 cultures, it was found absent in E18 cultures. The GFP-positive cells in the VM and GFP-positive astrocyte co-cultures were generally located distal to the monolayer of migrated fetal astrocytes, a few GFP positive cells were however observed within the astrocytic monolayer. In those cases TH-positive neurons migrated towards the GFP-positive cells. Both the non glial- and glial-associated nerve fibers grew onto the GFP-positive cells. Taken together, the glial-associated growth has limited outgrowth compared to the non glial-associated nerve fibers, while none of the outgrowth types were hampered by the mature astrocytes. PMID- 26435905 TI - Activation of oxidative carbon metabolism by nutritional enrichment by photosynthesis and exogenous organic compounds in the red alga Cyanidioschyzon merolae: evidence for heterotrophic growth. AB - Respiration is an important process in photosynthetic organisms, as it is in other organisms, for the supply of ATP and metabolites required for biosynthesis. Furthermore, individual enzymatic activity is subject to regulation by metabolic intermediates in glycolysis and the citric acid cycle. However, little is known about how glycolysis or catabolism are related to photosynthetic activity or accumulation of photosynthetic products. We previously developed a flat-plate culture apparatus assembled from materials commonly used for gel electrophoresis, which enables high-density culture of the unicellular red alga Cyanidioschyzon merolae. In this study, a stationary dense culture of C. merolae, when re activated in this culture apparatus, exhibited an accumulation of photosynthetically produced starch. We demonstrated that respiratory activity increased during the culture period, while photosynthetic activity remained constant. Gene expression analysis revealed that the genes involved in cytosolic glycolysis and the citric acid cycle were selectively activated, compared to the genes for the oxidative pentose phosphate pathway and the Calvin-Benson cycle. Measurements of the respiratory rate after addition of various organic substances showed that C. merolae can utilize almost any exogenous organic compound as a respiratory substrate, although the effectiveness of each compound was dependent on the culture time in the flat-plate culture, suggesting that glycolysis was rate-limiting to respiration, and its activity depended on the level of photosynthetic products within the cells. We also demonstrated that organic substances increased the rate of cell growth under dim light and, interestingly, C. merolae could grow heterotrophically in the presence of glycerol. Obligate photoautotrophy should be considered an ecological, rather than physiological, characteristic of C. merolae. PMID- 26435906 TI - Subjective socioeconomic status and cigarette smoking interact to delay discounting. AB - People generally discount future outcomes, and accordingly accept immediate but smaller gain. This research examined whether this tendency (i.e., delay discounting) is associated with socioeconomic status (SES) and smoking status, and hypothesized that the influence of SES on delay discounting would be moderated by smoking status. Using an Internet survey, 206 participants made choices between receiving hypothetical monetary rewards immediately or with a delay of 1 year. As predicted, the rates of delay discounting were higher as subjective socioeconomic status indicating one's relative position and standing in a society was lower. Moreover, the tendency was clearer in smokers than in non smokers, suggesting that cigarette smoking has a moderating effect. In contrast, there was no effect of objective socioeconomic status representing how individuals are able to access valued goods and services. PMID- 26435907 TI - Primary hepatic mucosa-associated lymphoid tissue lymphoma: a case report and literature review. AB - Primary hepatic mucosa-associated lymphoid tissue (MALT) lymphoma is an extremely rare disease. We herein describe the findings in a 74-year-old man with elevated liver enzyme levels. Dynamic computed tomography showed focal biliary dilation and atrophy in the posterior segment, while dynamic magnetic resonance images revealed a small, highly enhanced small mass located at the root of posterior branch of the biliary ducts. As the mass was not detected on abdominal ultrasonography, a biopsy could not be performed. Cholangiocellular carcinoma was suspected, and surgery was performed. However, the surgically resected hepatic tumor was a nodule of aggregated lymphocytes that formed a lymphoepithelial lesion. Immunohistochemical analysis revealed that the lymphoma cells were positive for CD20 and CD79a, but negative for CD3. No other lymphoid lesions were found during additional postoperative examinations. Therefore, the patient was diagnosed with primary hepatic MALT lymphoma. He was also diagnosed with Helicobacter pylori infection, and thus, pylorus eradication was performed. At the time of this report, the patient was free of disease for 2 years without any additional treatment. The present case contributed to the diagnosis and management of this rare disease, as previously published case reports described varying imaging features; it also suggested that preoperative diagnosis was often difficult without biopsy. PMID- 26435908 TI - A case of advanced rectal cancer with rectovesical and ileal fistulae that developed hyperammonemic encephalopathy. AB - Hyperammonemic encephalopathy is rarely caused by a urinary diversion. We herein experienced a case of rectal carcinoma with rectovesical and ileal fistulae that developed hyperammonemic encephalopathy. A 72-year-old man suffered from a fever, diarrhea, pneumaturia, and fecaluria beginning in April 2013 and was referred to our hospital in May 2013. He developed a loss of consciousness and whole body cramping on the first hospital day. The laboratory data indicated an inflammatory reaction and hyperammonemia with a highly elevated serum ammonia (NH3) level of 703 MUg/dl. The patient was diagnosed to have rectal carcinoma with rectovesical and ileal fistulae according to computed tomography (CT) and a water-soluble contrast enema. We administered a solution of branched chain amino acids (BCAA) and antibiotics. Furthermore, we repeatedly irrigated bladder through the urethral catheter. The patient's symptoms recovered, and the serum ammonia levels on the second and third hospital day were decreased to 210 and 135 MUg/dl, respectively. However, the symptoms of infection and confusion were suspected to repeat; we elected to perform surgical treatment. An ileal disconnection with ileocecal bypass and sigmoidostomy were effective for preventing hyperammonemic encephalopathy. PMID- 26435909 TI - Accessory right hepatic artery branched from gastroduodenal artery. AB - The right hepatic artery usually branches from the common hepatic artery, however, there are cases showing anatomic variations. We present 41-year-old female patient with gallbladder cancer. In this case, the accessory right hepatic artery branched from the gastroduodenal artery, passed in front of the common bile duct and fed into the anterior segment of the liver. Cholecystectomy and resection of the extrahepatic bile duct with hepaticoenterostomy were performed successfully, preserving the accessory right hepatic artery. There are few reports presenting such an extremely rare anomaly of hepatic arteries in the English literature. Additionally, we herein present a review of the English literature regarding anatomic variations of right hepatic artery. PMID- 26435911 TI - Social media in clinical radiology: have you updated your status? PMID- 26435912 TI - Why China is currently underperforming in medical innovation and what China can do about it?-Part III: social psychology and evolutionary psychology perspectives. PMID- 26435910 TI - Obesity-Related Oxidative Stress: the Impact of Physical Activity and Diet Manipulation. AB - Obesity-related oxidative stress, the imbalance between pro-oxidants and antioxidants (e.g., nitric oxide), has been linked to metabolic and cardiovascular disease, including endothelial dysfunction and atherosclerosis. Reactive oxygen species (ROS) are essential for physiological functions including gene expression, cellular growth, infection defense, and modulating endothelial function. However, elevated ROS and/or diminished antioxidant capacity leading to oxidative stress can lead to dysfunction. Physical activity also results in an acute state of oxidative stress. However, it is likely that chronic physical activity provides a stimulus for favorable oxidative adaptations and enhanced physiological performance and physical health, although distinct responses between aerobic and anaerobic activities warrant further investigation. Studies support the benefits of dietary modification as well as exercise interventions in alleviating oxidative stress susceptibility. Since obese individuals tend to demonstrate elevated markers of oxidative stress, the implications for this population are significant. Therefore, in this review our aim is to discuss (i) the role of oxidative stress and inflammation as associated with obesity-related diseases, (ii) the potential concerns and benefits of exercise-mediated oxidative stress, and (iii) the advantageous role of dietary modification, including acute or chronic caloric restriction and vitamin D supplementation. PMID- 26435913 TI - The effect of changes to MOLLI scheme on T1 mapping and extra cellular volume calculation in healthy volunteers with 3 tesla cardiovascular magnetic resonance imaging. AB - BACKGROUND: Diffuse myocardial fibrosis may be quantified with magnetic resonance (MR) by calculating extracellular volume (ECV) fraction from native and post contrast T1 values. The ideal modified look-locker inversion recovery (MOLLI) sequence for deriving T1 values has not been determined. This study aims to establish if systematic differences exist between suggested MOLLI schemes. METHODS: Twelve phantom gels were studied with inversion recovery spin echo MR at 3.0 tesla to determine reference T1. Gels were then scanned with six MOLLI sequences (3s)3b(3s)5b; 4b(3s)3b(3s)2b; 5b(3s)3b with flip angles of both 35 degrees and 50 degrees at a range of heart rates (HRs). In 10 healthy volunteers MOLLI studies were performed on two separate occasions. Mid ventricular native and post contrast T1 was measured and ECV (%) calculated. RESULTS: In phantoms, the co-efficient of variability at simulated HR [40-100] with a flip angle of 35 degrees ranged from 6.77 to 9.55, and at 50 degrees from 7.71 to 11.10. T1 was under-estimated by all MOLLI acquisitions. Error was greatest with longer T1, and increased as HR increased. The 10 volunteers had normal MR studies. Native T1 time was similar for all acquisitions but highest with the 5b(3s)3b 35 degrees scheme (1,189.1+/-33.46 ms). Interstudy reproducibility was similar for all MOLLIs. CONCLUSIONS: The 5b(3s)3b MOLLI scheme agreed best with reference T1, without statistical difference between the six schemes. The shorter breath-hold time of 5b(3s)3b scheme may be preferable in clinical studies and warrants further investigation. PMID- 26435914 TI - Prenatal and early postnatal lead exposure in mice: neuroimaging findings. AB - BACKGROUND: Childhood lead exposure has been linked to adult gray matter loss accompanied by changes in myelination and neurochemistry noninvasively revealed by magnetic resonance imaging (MRI) methods. However, the extent, duration and timing of lead exposure required to produce such imaging changes in humans are difficult to ascertain. METHODS: To determine if such changes are related to early exposure to low levels of lead, we treated mouse dams with 0, 3, or 30 ppm of lead acetate in drinking water for 2 months prior to mating through gestation until weaning of the offspring at post-natal day 21. Two male and two female pups from each litter were imaged at post-natal day 60. Volumetric, diffusion tensor imaging and magnetic resonance spectroscopy (MRS) measurements were obtained using a seven Tesla Bruker animal MRI scanner. RESULTS: Postnatal blood lead levels were identical between groups at the time of imaging. No effects of lead exposure were detected in the volumetric or MRS data. Mean diffusivity in the hippocampus showed significant effects of lead exposure and gender. CONCLUSIONS: These data suggest that low-level, gestational lead exposure in a mouse model produces minimal changes observed by MRI. PMID- 26435915 TI - Application of modified reverse panoramic radiograph on lambdoid suture for age estimation. AB - BACKGROUND: Cranial suture closure has long been recognized as a character of human development related to aging. For this reason, it has been utilized for various forensic and archaeological studies to determine the age of an unidentified/or skeletonized individuals. Various cadaveric studies have established the role of lambdoid suture in age estimation, but not routinely practiced. The objective is to establish if any correlation exists between individual's age and lambdoid sutures closure status (ectocranially) in mortals through modified reverse panoramic radiograph (RPRg). METHODS: Total number of 85 subjects, 25 years and beyond were included in the study, and divided into four groups with an age interval of 10 years. Assessment of lambdoid suture closure was done according to Frederic Rating Scale on modified RPRg. Data obtained was subjected to statistical analysis using Spearman's correlation test. RESULTS: A significant difference was observed between the age group and suture closure. Correlation coefficient of 0.570 was obtained, and was interpreted as a good correlation between the age and suture closure status with a P value of <0.001. CONCLUSIONS: Lambdoid suture can be very effective and practical tool for age assessment in mortals through modified RPRg (ectocranially). PMID- 26435916 TI - Use of 100 kV versus 120 kV in computed tomography pulmonary angiography in the detection of pulmonary embolism: effect on radiation dose and image quality. AB - OBJECTIVE: To determine the effective radiation dose and image quality resulting from 100 versus 120 kilovoltage (kV) protocols among patients referred for computed tomography pulmonary angiography (CTPA). METHODS: Sixty-six patients with clinical suspicion of pulmonary embolism (PE) were prospectively enrolled. Two CTPA protocols (group A: n=33, 100 kV/115 mAs; group B: n=33, 120 kV/90 mAs) were compared. Two experienced radiologists assessed image quality in terms of diagnostic performance and effect of artefacts. Image quality parameters [CT attenuation, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR)] and effective radiation dose between the two protocols were compared. RESULTS: The contrast enhancement in central and peripheral pulmonary arteries was significantly higher in group A than in group B (P<0.001) with the identical SNR (P=0.26), whereas the CNR was significantly higher in group A than in group B (P<0.001). The effective radiation dose for the 100 and 120 kV scans was 3.2 and 6.8 mSv, respectively. CONCLUSIONS: Reducing the tube voltage from 120 to 100 kV in CTPA allows a significant reduction of radiation dose without significant loss of diagnostic image quality. PMID- 26435917 TI - Total gadolinium tissue deposition and skin structural findings following the administration of structurally different gadolinium chelates in healthy and ovariectomized female rats. AB - OBJECTIVE: To assess the retention of gadolinium (Gd) in skin, liver, and bone following gadodiamide or gadoteric acid administration. METHODS: Gd was measured in skin, liver and femur bone in female rats 10 weeks after administration of 17.5 mmol Gd/kg over 5 days of Gd agents. Rat skin microscopy, energy filtering transmission electron microscopy and elemental analysis were performed, and repeated after receiving the same dosage of gadodiamide in rats with osteoporosis induced with bilateral ovariectomy (OVX). The OVX was performed 60 days after the last injection of gadodiamide and animals sacrificed 3 weeks later. RESULTS: Gd concentration was 180-fold higher in the skin, 25-fold higher in the femur, and 30-fold higher in the liver in rats received gadodiamide than rats received gadoteric acid. The retention of Gd in the skin with gadodiamide was associated with an increase in dermal cellularity, and Gd encrustation of collagen fibers and deposition inside the fibroblasts and other cells. No differences in Gd concentration in liver, skin, and femur were observed between rats receiving gadodiamide with or without OVX. CONCLUSIONS: Gd tissue retention with gadodiamide was higher than gadoteric acid. Tissues Gd deposition did not alter following gadodiamide administration to ovariectomized rats. PMID- 26435918 TI - Decoupling and matching network for monopole antenna arrays in ultrahigh field MRI. AB - BACKGROUND: Radiative coil arrays, e.g., dipole or monopole arrays, are increasingly used in MR signal excitation and reception for ultrahigh field MRI. Technically, it is challenging to suppress the electromagnetic (EM) coupling of radiative array elements due to their unique structures. METHODS: In this study, we proposed a combined decoupling and matching network (DMN) for monopole arrays for MRI applications. Compared with separate decoupling network and matching network, the combined network proposed here needs less components and rather suitable for decoupling radiative arrays in MRI. RESULTS: Our study shows that the transmission coefficient between two coupled monopoles can be reduced from -5 dB to -24.8 dB by using the combined DMN. It is also clearly demonstrated in this study that this decoupling method is a port decoupling method rather than an element decoupling method. CONCLUSIONS: With the proposed DMN, the monopole coil provides locally strong and spatially diverse B1 fields, which is essential to the improvement of MR sensitivity and parallel imaging performance. PMID- 26435919 TI - Automatic multi-parametric quantification of the proximal femur with quantitative computed tomography. AB - BACKGROUND: Quantitative computed tomography (QCT) imaging is the basis for multiple assessments of bone quality in the proximal femur, including volumetric bone mineral density (vBMD), tissue volume, estimation of bone strength using finite element modeling (FEM), cortical bone thickness, and computational-anatomy based morphometry assessments. METHODS: Here, we present an automatic framework to perform a multi-parametric QCT quantification of the proximal femur. In this framework, the proximal femur is cropped from the bilateral hip scans, segmented using a multi-atlas based segmentation approach, and then assigned volumes of interest through the registration of a proximal femoral template. The proximal femur is then subjected to compartmental vBMD, compartmental tissue volume, FEM bone strength, compartmental surface-based cortical bone thickness, compartmental surface-based vBMD, local surface-based cortical bone thickness, and local surface-based cortical vBMD computations. Consequently, the template registrations together with vBMD and surface-based cortical bone parametric maps enable computational anatomy studies. The accuracy of the segmentation was validated against manual segmentations of 80 scans from two clinical facilities, while the multi-parametric reproducibility was evaluated using repeat scans with repositioning from 22 subjects obtained on CT imaging systems from two manufacturers. RESULTS: Accuracy results yielded a mean dice similarity coefficient of 0.976+/-0.006, and a modified Haussdorf distance of 0.219+/-0.071 mm. Reproducibility of QCT-derived parameters yielded root mean square coefficients of variation (CVRMS) between 0.89-1.66% for compartmental vBMD; 0.20 1.82% for compartmental tissue volume; 3.51-3.59% for FEM bone strength; 1.89 2.69% for compartmental surface-based cortical bone thickness; and 1.08-2.19% for compartmental surface-based cortical vBMD. For local surface-based assessments, mean CVRMS were between 3.45-3.91% and 2.74-3.15% for cortical bone thickness and vBMD, respectively. CONCLUSIONS: The automatic framework presented here enables accurate and reproducible QCT multi-parametric analyses of the proximal femur. Our subjects were elderly, with scans obtained across multiple clinical sites and manufacturers, thus documenting its value for clinical trials and other multi site studies. PMID- 26435920 TI - Correlation of normal thyroid ultrasonography with thyroid tests. AB - BACKGROUND: Thyroid disorders are frequently seen in the community. Thyroid ultrasonography (US) is commonly used in the diagnosis of thyroid diseases. The relationship between heterogeneous echogenicity of thyroid gland and thyroid tests are well known. METHODS: The aim of this study is to evaluate the correlation of normal US with the thyroid tests. A total of 681 individuals were enrolled in the study. Individuals were separated into two groups as normal (group 1) and hypoechoic (group 2) according to the echogenicity in US. Subjects with nodular thyroid lesions were excluded from the study. Thyroid stimulating hormone (TSH), free T4 (fT4), thyroid peroxidase antibody (TPOAb) and anti thyroglobulin antibody (TgAb) values were recorded in both groups and thyroid stimulating hormone receptor antibody (TRAb) was recorded in individuals with low TSH. RESULTS: 86.1% of individuals in group 1 had normal TSH, 93.7% had normal thyroid antibodies and in 77.6% of individuals, all thyroid tests performed were normal. In the 6.9% of the group 2, all reviewed thyroid tests were normal (P<0.001). CONCLUSIONS: Our study shows that US is correlated with normal thyroid function tests and is a valuable tool in the prediction of normal thyroid function. PMID- 26435921 TI - Analyzing bone remodeling patterns after total hip arthroplasty using quantitative computed tomography and patient-specific 3D computational models. AB - BACKGROUND: Computational models in the form of finite element analysis technique that incorporates bone remodeling theories along with DEXA scans has been extensively used in predicting bone remodeling patterns around the implant. However, majority of such studies used generic models. Therefore, the aim of this study is to develop patient-specific finite element models of total hip replacement patients using their quantitative computed tomography (QCT) scans and accurately analyse bone remodelling patterns after total hip arthroplasty (THA). METHODS: Patient-specific finite element models have been generated using the patients' QCT scans from a previous clinical follow-up study. The femur was divided into five regions in proximal-distal direction and then further divided into four quadrants for detailed analysis of bone remodeling patterns. Two types of analysis were performed-inter-patient and intra patient to compare them and then the resulting bone remodeling patterns were quantitatively analyzed. RESULTS: Our results show that cortical bone density decrease is higher in diaphyseal region over time and the cancellous bone density decreases significantly in metaphyseal region over time. In metaphyseal region, posterior medial (P-M) quadrant showed high bone loss while diaphyseal regions show high bone loss in anterior-lateral (A-L) quadrant. CONCLUSIONS: Our study demonstrated that combining QCT with 3D patient-specific models has the ability of monitoring bone density change patterns after THA in much finer details. Future studies include using these findings for the development of a bone remodelling algorithm capable of predicting surgical outcomes for THA patients. PMID- 26435922 TI - Errors in quantitative T1rho imaging and the correction methods. AB - The spin-lattice relaxation time constant in rotating frame (T1rho) is useful for assessment of the properties of macromolecular environment inside tissue. Quantification of T1rho is found promising in various clinical applications. However, T1rho imaging is prone to image artifacts and quantification errors, which remains one of the greatest challenges to adopt this technique in routine clinical practice. The conventional continuous wave spin-lock is susceptible to B1 radiofrequency (RF) and B0 field inhomogeneity, which appears as banding artifacts in acquired images. A number of methods have been reported to modify T1rho prep RF pulse cluster to mitigate this effect. Adiabatic RF pulse can also be used for spin-lock with insensitivity to both B1 RF and B0 field inhomogeneity. Another source of quantification error in T1rho imaging is signal evolution during imaging data acquisition. Care is needed to affirm such error does not take place when specific pulse sequence is used for imaging data acquisition. Another source of T1rho quantification error is insufficient signal to-noise ratio (SNR), which is common among various quantitative imaging approaches. Measurement of T1rho within an ROI can mitigate this issue, but at the cost of reduced resolution. Noise-corrected methods are reported to address this issue in pixel-wise quantification. For certain tissue type, T1rho quantification can be confounded by magic angle effect and the presence of multiple tissue components. Review of these confounding factors from inherent tissue properties is not included in this article. PMID- 26435923 TI - Identifying osteoporotic vertebral fracture. AB - Osteoporosis per se is not a harmful disease. It is the sequela of osteoporosis and most particularly the occurrence of osteoporotic fracture that makes osteoporosis a serious medical condition. All of the preventative measures, investigations, treatment and research into osteoporosis have one primary goal and that is to prevent the occurrence of osteoporotic fracture. Vertebral fracture is by far and away the most prevalent osteoporotic fracture. The significance and diagnosis of vertebral fracture are discussed in this article. PMID- 26435924 TI - State-of-the-art in retinal optical coherence tomography image analysis. AB - Optical coherence tomography (OCT) is an emerging imaging modality that has been widely used in the field of biomedical imaging. In the recent past, it has found uses as a diagnostic tool in dermatology, cardiology, and ophthalmology. In this paper we focus on its applications in the field of ophthalmology and retinal imaging. OCT is able to non-invasively produce cross-sectional volumetric images of the tissues which can be used for analysis of tissue structure and properties. Due to the underlying physics, OCT images suffer from a granular pattern, called speckle noise, which restricts the process of interpretation. This requires specialized noise reduction techniques to eliminate the noise while preserving image details. Another major step in OCT image analysis involves the use of segmentation techniques for distinguishing between different structures, especially in retinal OCT volumes. The outcome of this step is usually thickness maps of different retinal layers which are very useful in study of normal/diseased subjects. Lastly, movements of the tissue under imaging as well as the progression of disease in the tissue affect the quality and the proper interpretation of the acquired images which require the use of different image registration techniques. This paper reviews various techniques that are currently used to process raw image data into a form that can be clearly interpreted by clinicians. PMID- 26435925 TI - Bedside ultrasonography for diagnosis of pneumothorax. AB - Ultrasonography (US) has found its way into the critical care and emergency settings for the evaluation of acute respiratory failure conditions in recent years. It is useful for the diagnosis of varieties of abnormalities involving pleura and lung such as pleural effusion, alveolar interstitial syndrome, and pneumothorax (PTX). In addition to its reproducibility and timeliness, US has high sensitivity and specificity for the diagnosis of these conditions. The most widely used method for bedside evaluation of PTX is chest X-ray (CXR). However, the diagnostic sensitivity of CXR in detecting PTX is limited especially in occult PTX and when the patient is assumed supine position. Computed tomography (CT) is the gold standard in the evaluation of PTX, but is limited by its high radiation exposure and safety concerns in transporting critically ill patients. In this paper we review current advances in PTX diagnosis using US. PMID- 26435926 TI - Tracheal septum: real or virtual? AB - Tracheal septum has never been reported in human beings, though it's a common occurrence in few lower vertebrates. We are presenting a case of thick tracheal secretion that appeared as a midline tracheal septum and prompted the clinician to go for bronchoscopy. PMID- 26435927 TI - Changes in the skeletal system and extramedullary hematopoiesis in a patient with thalassemia. PMID- 26435928 TI - Fahr disease: use of susceptibility-weighted imaging for diagnostic dilemma with magnetic resonance imaging. AB - Fahr disease (FD) is a well-defined rare neurodegenerative disease that is characterized by idiopathic bilateral symmetric extensive striopallidodentate calcifications. The patients may present with diverse manifestations, most commonly movement disorder, cognitive impairment, and ataxia. Computed tomography (CT) is considered to be critical for accurate diagnosis because it is difficult to reliably identify calcifications by routine magnetic resonance imaging (MRI). Susceptibility-weighted imaging (SWI) is a relatively new 3D gradient-echo (GE) MR sequence with special phase and magnitude processing. SWI phase images can recognize calcifications definitively with higher sensitivity compared to other MRI sequences. In this article, we present two cases of FD with different manifestations and neuroimaging in different age groups and genders, which were diagnosed by SWI and confirmed with CT, and we discuss the contribution of SWI in the diagnosis of FD. In conclusion, we suggest integrating SWI with MRI protocol to identify calcifications in suspicion of neurodegenerative disorders. PMID- 26435929 TI - Flow void artifact mimicking aneurysm in the anterior communicating artery region on T1- and T2-weighted images. PMID- 26435930 TI - Four dimensional magnetic resonance velocimetry for complex flow in the jugular vein. PMID- 26435931 TI - Three-dimensional speckle-tracking echocardiography for spatial evaluation of pulmonary vein (from the MAGYAR-Path Study). PMID- 26435932 TI - Anatomical Variations of Upper Segmental Renal Artery and Clinical Significance. AB - INTRODUCTION: Classically each kidney is supplied by a single renal artery. In its course renal artery divides into anterior and posterior division, both of these division further divide into segmental arteries that are apical, upper, middle, lower and posterior. Segmental arteries are representing an end artery and they form independent renal segments. In their course they are closely related with collecting system. So, a thorough in depth knowledge of the variations in segmental arteries is a basic requirement for surgeons. AIM: To observe and investigate the anatomical variations in arterial pattern of upper segmental renal artery and its relations with collecting system of ducts in human kidneys. MATERIALS AND METHODS: Fifty human kidneys of both sexes were observed and studied by corrosion cast method. Different colour coded cast material (butyl butyrate) like red for artery and black for collecting ducts were used. 20% solution of butyl butyrate in acetone was injected into renal artery and ureter of the kidneys. After polymerization (24 hours) these kidneys were kept immersed in a bath of concentrated KOH solution at 50(0)C for 24-48 hours for corrosion to obtain the endocasts. These endocasts were cleaned and washed under running tap water and photographed. RESULTS: In present study upper segmental artery was found in 49 (98%) kidneys. It was absent in 1 (2%) kidney. We observed four types of variations in arterial pattern of upper segmental artery namely Upper Segmental Artery Type-1 (USAT1), Upper Segmental Artery Type-2 (USAT2), Upper Segmental Artery Type-3 (USAT3), Upper Segmental Artery Type-4 (USAT4) and they were found in 20 (40%), 14 (28%), 10 (20%), 5 (10%) kidneys respectively. We also observed two different variations in the anatomical relations between upper segmental artery and collecting system namely Upper Segmental Artery Group -1 (USAG1) and Upper Segmental Artery Group-2 (USAG2). USAG1 was found in 40 (80%) kidneys and USAG2 in 9 (18%) kidneys respectively. CONCLUSION: Anatomical knowledge of these variations is very important and useful for the uro-surgeons for best outcome and minimal complications in and during nephrectomies, removal of calculi, surgery of renal tumors or other various intrarenal surgeries. PMID- 26435933 TI - Morphology of Sigmoid Colon in South Indian Population: A Cadaveric Study. AB - INTRODUCTION: Sigmoid volvulus is a common etiological factor in acute large bowel obstruction. The increased length of sigmoid colon is attributed as one of the causes of sigmoid volvulus. AIM: The aim of this study was to find the morphology of sigmoid colon in South Indian population using cadavers. MATERIALS AND METHODS: The present study was performed with 31 cadavers used for teaching purpose. The sigmoid colon was classified into classical, long-narrow and long- broad types by their disposition in the abdominal cavity. The sigmoid loop's relation to pelvic brim was also observed and grouped as pelvic and suprapelvic in position. The length of sigmoid colon along the mesenteric and antimesenteric border, height and width of sigmoid mesocolon in relation to the pelvic brim and the root of mesentery were measured in the study. RESULTS: The study showed that the majority of the sigmoid colons fell into the classical type (47.6%). The sigmoid colon in pelvic position was significantly more prevalent. The mean length of sigmoid colon was 15.2 +/- 4.4cm and 19.2 +/- 6cm considering the pelvic brim and root of mesentery as reference points of measurement respectively. The mean length along antimesenteric border was 22.3 +/- 7.9cm and 25 +/- 8.7cm along the same reference points. The mean length of mesocolon height was 6.5 +/- 3cm with reference to pelvic brim and 7.3 +/- 3cm with reference to root of Sigmoid mesocolon respectively. The mean width of mesocolon was 7.4 +/- 3cm (pelvic brim) and 8 +/- 2cm (root of Sigmoid mesocolon) There was a positive correlation of sigmoid colon length with the height of the mesocolon. The gender analysis showed that males had statistically significant longer sigmoid colon and mesocolon. CONCLUSION: This study documents that the South Indian population has a more classical type of sigmoid colon and that the anatomical dimensions of sigmoid colon and its mesocolon is significantly longer in males. PMID- 26435934 TI - A Morphometric Study of the Patterns and Variations of the Acromion and Glenoid Cavity of the Scapulae in Egyptian Population. AB - BACKGROUND: Owing to its many variations, scapula became one of the most interesting bones of the human skeleton. AIM: To measure acromial and glenoid morphology in to describe their anatomical patterns and variations in Egyptians to establish possible morphofunctional correlations related to race, geographic region and literature data. MATERIALS AND METHODS: One hundred and sixty scapulae of unknown age and sex were studied. Morphological shapes of the tip of the acromion; types of acromion; and morphological shapes of the glenoid were evaluated. Length and width of the scapulae, length, breadth and thickness of the acromion process and distances of the acromio-coracoid and acromio-glenoid in addition to glenoid diameters were measured. STATISTICAL ANALYSIS: The morphometric values of the two sides were analysed using an unpaired t-test. Statistical significance was set p<= 0.05. RESULTS: The intermediate shape of the acromion presented with the highest incidence, while the cobra shaped presented with the lowest distribution in both sides. The oval shaped glenoid cavity presented with the highest incidence while the inverted coma shaped showed the lowest incidence. These results are in match with other population. However, the morphometric values of the scapula, acromion process and glenoid cavity were higher than reported in Turkish and Indians. CONCLUSION: Our data are important to compare Egyptian scapulae to those from various other races that could contribute to demographic studies of shoulder disease probability and management in Egyptian population. PMID- 26435935 TI - A Study of Variations in the Origin of Obturator Artery and its Clinical Significance. AB - INTRODUCTION: The large number of organs and anatomical structures within the cramped pelvic cavity makes the study of vascular pattern and their variations of much importance in this particular anatomical region. Clear awareness of the vascular anatomy of pelvis is critical in surgeries performed here, which require ligation of the arteries concerned and also because such anomalous origins may cause profuse bleeding during surgical procedures. This is particularly true with regard to the variations in the origin of the obturator artery, while performing pelvic and groin surgeries. AIM: The aim of the present study was to find out the prevalence of normal and aberrant origins of obturator artery and to describe its surgical implications. MATERIALS AND METHODS: The study was carried out on fifty hemipelvises of embalmed cadavers and the origin and course of the arteries were traced and noted. RESULTS: Of the 50 pelvic halves, in 27 specimens, the obturator took origin from the anterior division of internal iliac artery. Remaining 23 specimens showed variations. The origin of the obturator artery was from the inferior epigastric artery in 11 cases, from the common stem of the internal iliac artery and the external iliac artery in 2 cases each, from the posterior trunk of the internal iliac artery in 5 and one each from superior gluteal, inferior gluteal, and internal pudendal artery. CONCLUSION: The present study indicates that the origin of the obturator artery is highly variable. It can take origin from the stem of the internal iliac artery or from its anterior or posterior division, or from one of the branches of the divisions. It can also take origin from external iliac artery or its inferior epigastric branch. Advancements in diagnostic and surgical techniques in obstetric procedures and urogenital interventions make it essential to have a clear-cut understanding of the vasculature in the abdomen and pelvis. PMID- 26435936 TI - Anatomical Description and Clinical Relevance of a Rare Variation in the Mesenteric Arterial Arcade Pattern. AB - Solitary vascular variations of the mesenteric arteries are extremely rare and have been seldom reported in the past. The aim of this study is to emphasize the anatomical and clinical relevance of one such rare variation of inferior mesenteric artery (IMA). The current case anomaly was incidentally observed while guiding the undergraduate medical students in the dissection of the mesenteric region of the abdomen in an Indian cadaver. An Accessory left colic artery was seen to be branching off from the Inferior Mesenteric artery and further dividing into two transverse branches which took part in the formation of arterial arc for the perfusion of the transverse and the descending colon. Awareness of such aberrant branches of Inferior Mesenteric artery helps in optimal selection of the mode of treatment or operative planning. Additionally, this knowledge minimizes possible iatrogenic injuries resulting from surgeries. Moreover, surgical anatomy of anomalous branches of Inferior Mesenteric artery is extremely essential for planning and successfully executing reconstructive procedures using these branches as pedicles for the transposed part of the colon. PMID- 26435937 TI - Congenital Fusion of C6 and C7 Vertebra-A Case Report. PMID- 26435938 TI - Comparative Analysis of Urinary Total Proteins by Bicinchoninic Acid and Pyrogallol Red Molybdate Methods. AB - BACKGROUND: The concentration of total proteins in urine is a good index of renal function, but its determination is found to be unreliable. The pyrogallol red molybdate (PRM) method for urine total proteins is being widely used in most of the hospitals because of its high sensitivity, better precision and its practicability. Bicinchoninic acid method (BCA) is also used for protein estimation and there have been no studies comparing this method with the PRM method in human urine samples. BCA method overestimates the urinary protein concentration in the presence of interfering substances. After removing the interfering substances present in the human urine samples the results of BCA method were compared with the PRM method. AIM: The purpose of the study is to identify whether the results of urine total proteins by BCA method are comparable to PRM method and can be used as an alternative to the PRM method. SETTING AND DESIGN: This is a cross-sectional study done on fresh urine specimens from the hospital laboratory, covering a wide range of protein concentrations. MATERIAL AND METHODS: Fresh urine specimens covering a wide range of protein concentrations (urine dipstick: nil, trace, 1+, 2+ and >= 3+) of 36 patients were analysed by both the methods. STATISTICAL ANALYSIS: Imprecision was determined by repeated analysis study and Inaccuracy was assessed by comparing the results of the patient's urine samples by both the methods using correlation plots, Bland and Altman, and Passing and Bablok regression analyses. RESULTS: The coefficient of variation and mean (SD) for the BCA method were 4.6% and 799.1 (882.5) mg/L and for the PRM method were 5.1% and 802.1 (911.9) mg/L. The Pearson correlation coefficient, r was 0.93 (p < 0.0001). Method agreement studies showed no significant constant and proportional bias between both the methods. CONCLUSION: In urine which is subjected to removal of interfering substances, the BCA results are comparable to PRM method. PMID- 26435939 TI - Comparing Utility of Anthropometric Indices Based on Gender Differences in Predicting Dyslipidaemia in Healthy Adults. AB - INTRODUCTION: Anthropometry is a simple reliable method for quantifying body proportions by measuring body length, weight and circumferences. AIM: Our intention in this study was to compare sensitivities and positive predictive values of waist circumference (WC), waist-hip ratio (WHR), waist-height ratio (WHtR) and body mass index (BMI) in identifying healthy subjects, males and females separately for identifying obesity associated dyslipidemia. MATERIALS AND METHODS: We analysed randomly selected 100 healthy subjects (males:58%, females:42%) between 25 and 60 years of age attending tertiary health care center in South India, after obtaining informed consent and Institutional Ethical Clearance. WC, WHR, WHtR and BMI of all the enrolled subjects were measured and estimated. Their fasting serum lipid profile was assessed. Subjects were divided based on their gender and each group was then categorized as obese and non-obese using anthropometric parameters and their individual serum lipid profile values depending on the cut off standards as per WHO and ATP III guidelines and compared. Data obtained was statistically analysed. RESULTS: Mean values of WC, WHR, WHtR and BMI were highly significant (p<0.000) in obese in both males (97.43 +/- 6.21cm, 0.96 +/- 0.04, 0.61 +/- 0.05, 27.72 +/- 2.45kg/m(2)) and females (91.82 +/- 5.18cm, 0.92 +/- 0.06, 0.60 +/- 0.04, 27.70 +/- 3.44kg/m(2)) when considered separately compared to non-obese males (82.27 +/- 5.33cm, 0.83 +/- 0.033, 0.51 +/- 0.03, 22.80 +/- 2.11kg/m(2)) and females (71.68 +/- 7.33cm, 0.78 +/- 0.03, 0.48 +/- 0.03, 21.82 +/- 1.98kg/m(2) respectively). WC was more sensitive for predicting the altered lipid profile (85%) in females and WHR (65%) in males. WHR showed higher ability to correctly predict the occurrence of dyslipidemia in the obese males (90% positive predictive value) and WHtR in females (92%). CONCLUSION: The present study inferred that WC, WHR are more sensitive while WHR and WHtR have a higher positive predictive value than BMI in identifying dyslipidemia in healthy males and females. PMID- 26435940 TI - Analysis of Antibiotic Resistance Genes and its Associated SCCmec Types among Nasal Carriage of Methicillin Resistant Coagulase Negative Staphylococci from Community Settings, Chennai, Southern India. AB - OBJECTIVE: The study was designed to find the distribution of SCCmec types and the various antibiotic resistance genes amongst MR-CoNS isolates from asymptomatic individuals. MATERIALS AND METHODS: A total of 145 nasal swabs were collected from asymptomatic healthy individuals from community settings. Identification and speciation of CoNS were done by standard biochemical methods. Screening of methicillin resistance (mecA gene) and detection of various antibiotic resistant genes were done using multiplex PCR method. SCCmec types (I V) were determined using multiplex PCR. RESULTS: 50 (44.6%) isolates were found to be methicillin resistant both by cefoxitin method and multiplex PCR. S. epidermidis (40%) was the predominant species followed by S. haemolyticus (28%), S. hominis (20%) and S. warneri (12%). Highest resistance was shown for cotrimoxazole (26%), followed by ciprofloxacin (24%), tetracycline (20%), erythromycin (18%), fusidic acid (10%) and mupirocin (6%). Among SCCmec types, 44 isolates showed single type, including type I (30%), type IV (24%), type II (18%), type V (14%) and type III (2%). 6 isolates showed two types, III+IV (n= 2), II+V (n=2), IV+V (n=1) and type I+V (n=1). CONCLUSION: In conclusion, to the best of our knowledge, this is the first study in India to study the distribution of antibiotic resistant genes and SCCmec types among MR-CoNS from community settings. This study highlights high prevalence of MR-CoNS in community and its role in harbouring genetically diverse SCCmec elements as antibiotic resistance determinant. PMID- 26435941 TI - Evaluation of LAMP Assay Using Phenotypic Tests and Conventional PCR for Detection of nuc and mecA genes Among Clinical Isolates of Staphylococcus spp. AB - INTRODUCTION: The purpose of this study is to develop a nuc and mecA gene specific Loop-mediated isothermal Amplification (LAMP) assay for rapid identification and detection of methicillin resistant Staphylococcus aureus among clinical isolates. MATERIALS AND METHODS: A total of 100 (70 from pus and 30 from blood), clinical isolates of Staphylococcus spp were screened for the nuc gene to differentiate between S.aureus and Coagulase negative Staphylococci (CONS) by a nuc gene specific LAMP assay. The isolates were also screened for the presence of the mec Agene by the mecA specific LAMP assay. The results were compared with the phenotypic identification and methicillin resistance by Vitek-2 system (bioMerieux, Marcy l'Etoile, France) and conventional PCR. RESULTS: Among 100 Staphylococcus isolates, there were 82 (82%) Staphylococcus aureus isolates and 18 (18%) coagulase negative Staphylococcus as detected by the Vitek 2, conventional PCR and the LAMP assay using the nuc gene. The mecA gene was detected by the LAMP assay in 56(56%) isolates (44 Methicillin resistant Staphylococcus aureus (MRSA) and 12 Methicillin resistant coagulase negative Staphylococcus (MRCONS), which were also identified by the Vitek 2 and conventional PCR as methicillin resistant. The results of the LAMP assay were available within 90min as compared to the Vitek 2 results (18- 24hours) and conventional PCR (3-4 hours). CONCLUSION: The present study proved that LAMP assay can be used for the simultaneous differentiation of Staphylococcal spp and detection of methicillin resistance. PMID- 26435942 TI - Aerobic Bacteriological Study of Acute Exacerbations of Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: The natural history of chronic obstructive pulmonary disease is characterized by frequent exacerbations. Majority of exacerbations are infectious and bacteria responsible for 30-50% of these cases. The purpose of this study was to determine the bacteriology of acute exacerbations of chronic obstructive pulmonary disease in hospitalized patients in our institution and their antibiotic susceptibility pattern to formulate cost effective antibiotic strategy and reducing the emergence of drug resistance. MATERIALS AND METHODS: One hundred and seven clinically diagnosed cases of acute exacerbations of chronic obstructive pulmonary disease admitted in medicine, tuberculosis and chest wards were selected for the study. Direct gram stain was done for all sputum samples. The suitable sputum samples were cultured. Identification of organism and antimicrobial susceptibility testing was done by standard microbiological techniques. RESULTS: Our study showed growth of pathogenic organisms in 41.12% cases. Males (67.29%) are more affected than females (32.71%). Gram negative bacilli were more isolated than gram positive cocci. The commonest isolate was Klebsiella pneumoniae 15 (38.46%), followed by Staphylococcus aureus 9 (23.08%), Streptococcus species 6 (15.39%), Pseudomonas aeruginosa 4 (10.26%), E.coli 2 (5.13%), Acinetobacter species 2 (5.13%) and Enterobacter species 1(2.56%). The antibiotic susceptibility reveals that vancomycin, linezolid, azithromycin and clarithromycin were most effective drugs for gram positive cocci, meropenem & piperacillin-tazobactam for gram negative bacilli and amikacin & levofloxacin for both gram positive cocci & gram negative bacilli. CONCLUSION: In developing country like India acute exacerbations of chronic obstructive pulmonary disease is common in adults more than 50 years of age due to smoking habits and high indoor pollution. This leads to a major impact on the quality of life of patients with the condition. They are a major cause of hospital admission and health care utilization. PMID- 26435943 TI - Invitro Antibacterial Activity of the Prosopis Juliflora Seed Pods on Some Common Pathogens. AB - INTRODUCTION: Prosopis juliflora is probably the most widespread species of genus Prosopis and it is a good source of compounds that have been shown to be pharmacologically active. This plant has been used as a traditional treatment for several diseases. AIM: To investigate the in-vitro antibacterial activity of the P. juliflora seed pods from Bushehr, South West of Iran. MATERIALS AND METHODS: In the present study, the antibacterial activity of P. juliflora seed pods extract was tested against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and Pseudomonas aeruginosa. The minimum inhibitory concentration (MIC) of the extract was determined for each test microorganism. RESULTS: P. juliflora seed pods extract exhibited antibacterial activity against all four test organisms. The MIC of the extract was 0.312 mg/ml and 0.078 mg/ml for S. aureus and S. epidermidis, respectively and 1.25 mg/ml for both E.coli and P.aeruginosa. CONCLUSION: P. juliflora seed pods from Bushehr, South West of Iran could be an appropriate source of antibacterial compounds that makes it a promising candidate for further studies. PMID- 26435944 TI - Evaluation of Ica Gene in Comparison with Phenotypic Methods for Detection of Biofilm Production by Coagulase Negative Staphylococci in a Tertiary Care Hospital. AB - BACKGROUND: Biofilm producing bacteria are responsible for several chronic infections and are difficult to treat as they show much greater resistance to antibiotics. The major virulence factor determining the pathogenicity of CoNS has now well defined and found to be biofilm production. OBJECTIVE: The study was conducted to isolate and characterize Coagulase Negative Staphylococci (CoNS) and their ability to form biofilms was evaluated by phenotypic and genotypic methods. MATERIALS AND METHODS: A total of 96 clinical isolates of CoNS were characterized and subjected to biofilm detection by tissue culture plate method (TCP), tube method (TM), congo red agar method (CRA) and PCR. RESULTS: Staphylococcus epidermidis was the most commonly isolated species 76(79.17%). The ica gene was present in 35 (36.45%) of CoNS isolates which were detected as biofilm producers by TCP. Biofilm producing isolates showed higher antibiotic resistance(72.1%). Majority of biofilm producers had strong association with medical device related infections. CONCLUSION: To compare PCR based dectection method for presence of ica genes with TCP, the test share the specific identification rates. The sensitivity and specificity of TCP method in detection of biofilm was high in comparison with TM and CRA. TCP can be recommended as a general screening test for biofilm detection. PMID- 26435945 TI - Inducible Clindamycin Resistance among Clinical Isolates of Staphylococcus aureus from Sub Himalayan Region of India. AB - INTRODUCTION: Clindamycin is an alternative antibiotic in the treatment of Staphylococcus aureus (S.aureus) infections, both in infections by methicillin susceptible and resistant (MSSA and MRSA) strains. The major problem of use of clindamycin for staphylococcal infections is the presence of inducible clindamycin resistance that can lead to treatment failure in such infections. AIM: To determine inducible and constitutive clindamycin resistance among clinical isolates of S. aureus in a tertiary care centre of sub Himalayan region of India. MATERIALS AND METHODS: A total of 350 isolates of S. aureus from various clinical samples were subjected to routine antibiotic sensitivity testing by Kirby Bauer disc diffusion method. Methicillin resistance was detected by cefoxitin (30MUg) disc. All isolates were subjected to inducible clindamycin resistance was by Clinical Laboratory Standards Institute (CLSI) recommended D test. RESULTS: Among 350 S.aureus isolates, 82 (23.42%) were MRSA and 268 (76.57%) were MSSA. Erythromycin resistance was detected in 137 (39.14%) isolates. Erythromycin resistance in MRSA and MSSA was 71.6% and 29.36% respectively. Overall clindamycin resistance was seen in 108 (30.85%) isolates. Constitutive MSLB phenotype predominated (29.62% MRSA; 13.38% MSSA) followed by iMLSB (28.39% MRSA; 9.29% MSSA) and MS phenotypes (13.58% MRSA; 6.69%MSSA). Both inducible and constitutive clindamycin resistance was significantly higher (p=0.00001, 0.0008 respectively) in methicillin resistant strains than in methicillin susceptible strains. CONCLUSION: The present study gives a magnitude of clindamycin resistance among clinical isolates of S. aureus from this region of the country. Our study recommends routine testing of inducible clindamycin resistance at individual settings to guide optimum therapy and to avoid treatment failure. PMID- 26435946 TI - Optical Whole-Genome Restriction Mapping as a Tool for Rapidly Distinguishing and Identifying Bacterial Contaminants in Clinical Samples. AB - INTRODUCTION: Optical restriction genome mapping is a technology in which a genome is linearized on a surface and digested with specific restriction enzymes, giving an arrangement of the genome with gaps whose order and size are unique for a given organism. Current applications of this technology include assisting with the correct scaffolding and ordering of genomes in conjunction with whole-genome sequencing, observation of genetic drift and evolution using comparative genomics and epidemiological monitoring of the spread of infections. Here, we investigated the suitability of genome mapping for use in clinical labs as a potential diagnostic tool. MATERIALS AND METHODS: Using whole genome mapping, we investigated the basic performance of the technology for identifying two bacteria of interest for food-safety (Lactobacilli spp. and Enterohemorrhagic Escherichia coli). We further evaluated the performance for identifying multiple organisms from both simple and complex mixtures. RESULTS: We were able to successfully generate optical restriction maps of four Lactobacillus species as well as a strain of Enterohemorrhagic Escherichia coli from within a mixed solution, each distinguished using a common compatible restriction enzyme. Finally, we demonstrated that optical restriction maps were successfully obtained and the correct organism identified within a clinical matrix. CONCLUSION: With additional development, whole genome mapping may be a useful clinical tool for rapid invitro diagnostics. PMID- 26435947 TI - Amphotericin B Resistant Apophysomyces elegans Causing Rhino-oculo-Cerebral Mucormycosis in an Immunocompetent Host. AB - Mucormycosis, an angioinvasive infection is caused by the ubiquitous filamentous fungi of the order Mucorales and class Mucormycetes. Reports of this disease are on the rise over the past few decades. Rhino-oculo-Cerebral presentation associated with uncontrolled diabetes is the predominant characteristic of this entity. We report here a case of rhinooculocerebral mucormycosis (ROCM) due to Apophysomyces elegans (A. elegans) in a 45-year-old diabetic lady with background illness of hypothyroidism and polyradiculoneuropathy. Though this condition is usually managed with surgical debridement of the affected tissue and medical therapy with Amphotericin B, the isolate recovered in our case was found to be resistant to Amphotericin B. PMID- 26435948 TI - A Case of Lower Respiratory Tract Infection with Canine-associated Pasteurella canis in a Patient with Chronic Obstructive Pulmonary Disease. AB - This is the report of lower respiratory tract infection with Pasteurella canis in a chronic obstructive pulmonary disease (COPD) patient with history of casual exposure to cats. Pasteurella species are part of the oral and gastrointestinal flora in the canine animals. These organisms are usually implicated in wound infection following animal bites, but can also be associated with a variety of infections including respiratory tract infections. PMID- 26435949 TI - Clinico-Microbiological Investigation of Catheter Associated Urinary Tract Infection by Enterococcus faecalis: vanA Genotype. AB - Prolonged hospitalization and exposure to third generation cephalosporins are reported to facilitate the acquisition and colonization of Vancomycin Resistant Enterococci (VRE). Though VRE is not uncommon in India, urinary tract infection with a vanA genotype is a cause of serious concern as VRE co-exhibit resistance to aminoglycosides. In India, majority of the VRE isolates recovered from hospitalized patients include Enterococcus faecium. We report a case of catheter associated urinary tract infection by an endogenous, multidrug resistant E. faecalis of vanA genotype following prolonged hospitalization, ICU stay, catheterisation and exposure to 3G cephalosporin and metronidazole. The patient responded to linezolid therapy. PMID- 26435950 TI - A Comparative Study of Histopathology of Astrocytomas with Intraoperative Cytology with Special Reference to MIB-1 Labelling Index. AB - BACKGROUND: Although radiological imaging and surgical techniques have substantially improved, assessment of prognosis by grading astrocytoma has been challenging task for pathologists. We have tried to assess these tumours intraoperatively for rapid diagnosis. Also MIB-1Labelling index (MIB-1 LI) was done to study their proliferative activity. AIMS: To compare and grade squash smear technique with histopathology to study its utility in diagnosis of astrocytomas. Further, to study correlation of various grades with their MIB-1 labelling index. SETTING AND DESIGNS: This study was carried out in the Department of Pathology, SMS Medical College, Jaipur over a period of one year. MATERIALS AND METHODS: Forty five cases of radiologically suspected astrocytomas were submitted for intraoperative cytology and later for histopathology. Two techniques were compared for ability to diagnose as well as grade the tumour. Also, MIB-1 LI were performed in biopsy tissue. Histopathological and immunological grades were compared. RESULTS: Out of 45 cases 44(97.7%) correctly diagnosed by squash smear technique. Further significant differences seen in values of MIB-1 LI of high-grade and low-grade astrocytomas. A progressive increase in the MIB-1 LI was observed with increasing grades. In grade I astrocytoma MIB-1 LI was <0.05%. In grade II astrocytoma it varied from 0.8-2.6% except in one case where it was 3.2% who presented with a recurrent mass. In grade III, MIB-1 LI was 3.5% to 7.5%. In grade IV was 10-20%. CONCLUSION: Intraoperative cytology is fairly accurate and useful in intraoperative consultation. Also, MIB-1 LI can be a useful adjunct for grading particularly in small biopsies. PMID- 26435951 TI - Analysis of Human Papilloma Virus 16/18 DNA and its Correlation with p16 Expression in Oral Cavity Squamous Cell Carcinoma in North-Eastern India: A Chromogenic in-situ Hybridization Based Study. AB - BACKGROUND: The incidence of head and neck squamous cell carcinoma (HNSCC) is quite high in North Eastern India. Apart from the traditional risk factors like tobacco and alcohol consumption, human papilloma virus (HPV) is now considered an established causative agent. These HPV related tumour have a clinico-pathological profile that is quite divergent from conventional non-HPV related tumours. Association of HPV in oral cancers has not been explored in north-east India. MATERIALS AND METHODS: Thirty-one patients with oral cavity squamous cell carcinoma (OSCC) on treatment from October 2010 to January 2013 were included in the study. Patients who received neo-adjuvant chemotherapy were excluded. HPV 16/18 DNA was evaluated using Chromogenic in-situ Hybridization (CISH). Presence of nuclear signals was taken as positive HPV expression. p16 was evaluated using immunohistochemistry and was considered positive if >= 80% of the tumour cells showed strong and diffuse nuclear/cytoplasmic immunostaining. The results were analysed using Fisher exact test and confidence interval was calculated where required. RESULTS: The study group age ranged from 30 to 80 years (median age- 54.2 years). The most common site was gum, with well differentiated squamous cell carcinoma being the most common histology. HPV 16/18 DNA was positive in 29% (95% CI: 13.03% - 44.97%) cases and had a clear tendency towards statistical significance with non-smoker cases (p=0.05), lymph node metastasis (p=0.05) and a significant correlation with p16 overexpression (p=0.04). There was no significant correlation with other clinico-pathological parameters. CONCLUSION: HPV 16/18 is associated with OSCC, commonly seen among non-smokers and may be related to nodal metastasis. So, HPV may be used as a prognostic factor in OSCC and p16 may be considered as a surrogate marker for HPV. PMID- 26435952 TI - Enteric Duplication Cysts in Children: A Clinicopathological Dilemma. AB - AIM: Enteric duplication cysts are rare and uncommon congenital malformations formed during the embryonic period of the development of human digestive system and are mainly encountered during infancy or early childhood, but seldom in adults. The clinical presentation is extremely variable depending upon its size, location and type. We present six cases of enteric duplication cysts with diverse clinico-pathological features. MATERIALS AND METHODS: This study was carried out in the Department of Pathology and Department of Paediatric Surgery, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India for a period of 2 years (January 2013 - December 2014). We retrospectively analyzed six patients of enteric duplication cysts based on data obtained, which consisted of patient's age, sex, clinical presentation, radiological features, operative findings and histopathology report. The data collected was analyzed by descriptive statistics. RESULTS: Six children between age range of 3 days to 10 years had enteric duplication cysts. Two had ileal and one each were of pyloroduodenal, colonic and rectal duplication cyst. In one patient a presumptive diagnosis of enteric duplication cyst was made. Radiology played an important contributory role in diagnosis of these cysts in all the patients but histopathology proved to be gold standard for its confirmation. All these patients were managed by surgical excision. The postoperative and follow up period in all the cases was uneventful. CONCLUSION: It is important to be aware and make a definitive diagnosis of this rare congenital anomaly as they can present in various clinical forms and can cause significant morbidity and even mortality if left untreated by causing life threatening complications. PMID- 26435953 TI - Bilateral Multifocal Renal Angiomyolipoma Associated with Wunderlich's Syndrome in A Tuberous Sclerosis Patient. AB - Renal Angiomyolipoma (renal AML) is a benign clonal neoplasm with a incidence of 0.3-3%, occurring as isolated sporadic entity or in association with Tuberous sclerosis (TS) in 80% cases. Multiple, bilateral renal AML are considered diagnostic of Tuberous sclerosis. Wunderlich's syndrome, a urological emergency is a spontaneous nontraumatic bleeding into subcapsular and or peri-renal space and is a life threatening complication of renal AML occurring in 10% cases which has to be timely diagnosed and treated. Here, we present an unusual case of TS with bilateral, multifocal renal AML in a 25-year-old female who presented with Wunderlich's syndrome, which is a rare but life threatening complication that has to be suspected, timely diagnosed and treated. We have discussed the importance of early diagnosis, timely treatment, follow up and education of patient and relatives of the possible complications associated. PMID- 26435954 TI - Intracystic Papillary Carcinoma in Male Breast with High Nuclear Grade: A Case Report. AB - Intracystic papillary carcinoma (IPC) in men is an extremely rare disease that accounts for less than 1% of all malignancies with only a few case presentations published so far. This report presents a case of 53-year-old male, who presented a painless swelling of his left breast. The left breast mass was 6 cm maximally and was found to be non-invasive IPC. The tumour is consistently positive for GCDFP-15, ER or PR and negative for HER-2. It consists of predominantly fibrovascular stromal lined by monotonous epithelial cells retaining intermediate to high histological grade with a high nuclear cytoplasmic ratio. In addition, increased numbers of mitotic figures were also seen. Chest X-ray, liver ultrasound and bone centigram showed no evidence of distant metastases. In short, this is the first case report from Saudi Arabia of a male having IPC, with increased number of mitotic figures and high nuclear grades. PMID- 26435955 TI - Hepatoid Adenocarcinoma of the Gall Bladder-A Rare Variant. AB - Hepatoid adenocarcinoma is a rare variant of extra hepatic adenocarcinoma, consisting of foci of both adenomatous and hepatocellular differentiation with morphological and functional resemblance to hepatocellular carcinoma and hence correct diagnosis is a challenge. The most frequent site is stomach. We present this case of hepatoid carcinoma of the gallbladder for its rarity and difficulty in diagnosis which on histology showed papillae, sheets and trabaculae of polygonal cells with eosinophilic cytoplasm and vesicular nuclei with prominent nucleoli with adjacent foci showing high grade dysplasia. PMID- 26435956 TI - Metaplastic Carcinoma of Breast with Extensive Chondroid Differentiation: A Case Report with Review of Literature. AB - Metaplastic carcinoma of breast (MBC) is a rare and aggressive type of invasive breast cancer. As it encompasses a variety of distinct histopathologic designations, diagnostic challenges abound. We present a case report of metaplastic carcinoma with extensive chondroid differentiation. This case merits presentation because of its rarity and difficulty to diagnose, especially if the tumour is composed mainly of sarcomatous elements. Standard chemotherapy regimes are ineffective against MBC. The prognosis of MBC is poor in comparison to classical invasive breast cancer. Data focusing on MBC is limited due to its rare incidence. PMID- 26435957 TI - Concurrent Lactating Adenoma and Infiltrating Ductal Carcinoma: A Case Report. AB - A lactating adenoma is a benign tumour which usually occurs in younger women who are either pregnant or breast feeding. In some instances these lactating adenomas can occur simultaneously with breast carcinoma, so they have to be carefully evaluated. We report an unusual case of simultaneous occurrence of a lactating adenoma and infiltrating ductal carcinoma occurring in a 25-year-old lactating mother. PMID- 26435958 TI - Intra-Arterial Angiolymphoid Hyperplasia with Eosinophilia: A Rare Case Report of Peripheral Medium Sized Muscular Artery Involvement. AB - Angiolymphoid hyperplasia with eosinophilia (ALHE) is an uncommon benign vasoproliferative disease with distinct clinical and histopathological features. The most common clinical presentation is dermal and subcutaneous painless nodules in the head and neck region. The involvement of medium sized peripheral muscular artery is uncommon. It predominantly affects Caucasian adults during the third and fourth decades, but is also known to occur in Asians and it very rarely occurs in children. We here by present a case of intravascular ALHE in a 46-year old female presenting with subcutaneous forearm nodule clinically diagnosed as ulnar artery thrombosis. PMID- 26435959 TI - Bilateral Cystic Lymphangioma of Ovary Associated with Chylous Ascites. AB - Intraabdominal cystic lymphangiomas are rare and are located in retroperitoneum, mesentery, omentum and other visceral organs. Lymphangiomas of the ovary are rare and are usually unilateral. Cases with bilateral cystic lymphangiomas of the ovary are reported very rarely in literature. We report a rare case of bilateral cystic lymphangioma of ovary associated with chylous ascites in a 35-year-old lady who presented with complaints of severe dysmenorrhoea and oligomenorrhoea since 6 months with history of chyluria for the past 3 years. PMID- 26435960 TI - Clear Cell Hidradenoma of the Ear Lobule: An Unusual Site of Presentation. AB - The origin of hidradenoma was from the eccrine sweat glands, generally found in the head, face, and upper extremity regions. This lesion has not been reported to be large enough to present in the ear lobule. Hence, its description in the otolaryngology literature is extremely rare. The rarity of this neoplasm and failure to identify its morphologic features may lead to misdiagnosis. We present a benign clear cell hidradenoma of the right ear lobule in a 45-year adult male. We encountered a tumour measuring 4 cm in diameter. Mass shows ulcerated surface, bleeds on touch and remained a diagnostic dilemma till an excision biopsy was carried out and a histopathological report confirmed that it was a hidradenoma of clear cell variant. The aim of presenting this case report was interesting in the fact that it has added clear cell hidradenoma in the final diagnosis, in an uncommon site of presentation. PMID- 26435961 TI - Adult Multicystic Nephroma: Case Report and Review of the Literature. AB - Multicystic nephroma (MCN) is relatively a rare, nongenetic and benign lesion of the kidney which has a bimodal distribution. The congenital form is commonly seen under the age of 2. Adult-onset MCN is more often seen in women, especially in post menopausal females. The aetiopathogenesis of MCN is still unknown. Ovarian like stroma of the tumour indicates the tumour originates from the mullerian tissue of the kidney. Hormonal theory is suggestive as the stroma of the tumour is positive for estrogen and progesteron. Preoperative diagnosis of MCN is difficult. Surgical approach is recommended both for the histological diagnosis and the treatment of the disease. We here present a 53-year-old female patient with MCN admitted to the urology clinic with left flank pain treated successfully with partial nephrectomy. No recurrence was noted after six months of clinical and radiological follow-up. PMID- 26435962 TI - A Survivor of Neonatal Intestinal Mucormycosis. AB - Gastrointestinal mucormycosis (GIM) is a rare opportunistic fungal infection. One third of all patients are children and of these, 50% are infants. The most common clinical mimic is necrotizing enterocolitis (NEC). It has to be differentiated from this entity as the treatment is entirely different. High index of suspicion by the clinicians and the pathologists aids in early diagnosis and immediate treatment. If untreated, it has a frequent fatal outcome. Very few survivors of GIM are found in literature. We report a rare case of a surviving neonate of GIM. PMID- 26435963 TI - Prediabetes Awareness and Practice Among Indian Doctors- A Cross-sectional Study. AB - INTRODUCTION: Prediabetes is an intermediate state between diabetes and normoglycaemia, where the glucose levels are higher than normal but not significant to be diagnosed as diabetes mellitus. Guidelines from various associations suggest different types of management in this situation. OBJECTIVE: To assess knowledge and attitude of the doctors regarding prediabetes using questionnaire. MATERIALS AND METHODS: A cross-sectional questionnaire based study was conducted to assess the knowledge, attitude and practice among doctors regarding prediabetes treatment. One hundred twenty two (of 150) filled questionnaires were received from general practitioners, post graduates (PGs), physicians and super specialists in and around Kolar and Bangalore. Data was analysed using descriptive statistics and expressed as percentage. RESULTS: A total of 81.3% responded to the questionnaire, of which 14 were general practitioners (MBBS), 48 PGs in General Medicine, 46 physicians (MD General Medicine), and 14 super specialists (DM). Knowledge response was 85.7% (definition - 100%, prevalence - 50.8%, approved drug- 45.2%, progression- 86.2%). Screening for prediabetes was done by 71% of the general practitioners and physicians, but specialists would screen all. 100% general practitioners, 97.9% post graduates, 91.3% of physicians and 64.2 % specialist preferred diet and exercise and rest of them opted for oral antidiabetic drug (OAD) along with diet and exercise, but none of the doctors considered OAD alone for prediabetes. Among OADs metformin (77.45%) was the most preferred followed by voglibose (20.6%) and sitagliptin (1.9%). CONCLUSION: All doctors had awareness of prediabetes and most of them would regularly screen and treat prediabetes. Majority considered diet and exercise as first modality of treatment. The OAD opted commonly was metformin. PMID- 26435964 TI - An Experimental Study to Evaluate the Effect of Memantine in Animal Models of Anxiety in Swiss Albino Mice. AB - BACKGROUND: Due to the adverse effects produced by the present conventional medicines for anxiety disorders, research for newer drugs is still desirable. From the literature it is evident that NMDA receptors play a key role in animal models of anxiety. AIM: The present study is done to evaluate the antianxiety effect of memantine in swiss albino mice. MATERIALS AND METHODS: The experimental study was conducted from November 2014 to January 2015. Animals were divided into four groups. Twelve mice were randomly allotted in each group. Animals in the first group received normal saline as a control 10ml/kg, lorazepam 0.5mg/kg was administered to second group, memantine 3mg/kg as a test drug was given to the third group and memantine 3mg/kg + lorazepam 0.5mg/kg was administered to the fourth group. All the drugs were given for 7 consecutive days by intraperitoneal route. RESULTS: Results were analyzed by one-way ANOVA followed by Post-hoc Tukey's test. On the 1(st) day, memantine treated group did not show statistical significant anxiolytic effect in both the behavioural paradigms when compared to control group. On the 8(th) day, the animals showed significant decrease p<0.001 in step down latency period in shock free zone (185.4+/-3.87 Vs 278.3+/-5.49), significant increase p<0.001 in step down errors (6.8+/-0.78 Vs 1.4+/-0.19) and significant increase p<0.001 in total time spent in shock zone (32.1+/-2.22 Vs 5.6+/-0.6). In open field test, on 8(th) day the animals treated with memantine when compared to control group, showed significant increase p<0.001 in number of squares crossed (112.7+/- 2.69 Vs 83.2+/-2.96), time spent in central square (11.5+/-1.26 Vs 3.4+/-0.65), no. of rearings (32.4+/-2.61 Vs 17+/-1.81) and significant decrease p<0.001 in freezing time (15.2+/-1.12 Vs 20.2+/-2.29). Memantine showed synergistic antianxiety effect when combined with lorazepam. CONCLUSION: Memantine showed significant anxiolytic effect in open field and passive avoidance response tests which are commonly used experimental models to assess anxiety states in animals. PMID- 26435965 TI - Intrauterine Fetal Death in Gunshot Injury to the Gravid Uterus: Forensic Perspective. AB - Assault on pregnant women is not a rare event; however forensic analysis of gunshot injuries among the same group requires a greater deliberation. This is the report of a 38-week-old fetus which succumbed following gunshot injuries to the mother while the latter survived. The uniqueness of fetal injuries in the form of avulsed wound with complete detachment of anus is of great forensic interest. Such unusual wound pattern could have been the result of a blast wave effect created due to the high velocity projectile affecting the fluid filled uterine cavity. PMID- 26435966 TI - An Audit of VDRL Testing from an STI Clinic in India: Analysing the Present Scenario with Focus on Estimating and Optimizing the Turnaround Time. AB - BACKGROUND: Timeliness of reporting is of utmost importance to limit the spread of syphilis. The present analysis was undertaken to evaluate the turnaround time of syphilis testing (mainly Venereal disease research laboratory /VDRL test) in a sexually transmitted infections (STI) clinic in India; to find out the possible reasons for delay; to describe the trends of clinical indications for syphilis testing from an STI clinic; to assess the frequency of a positive syphilis serology among STI clinic attendees; and to analyse the follow-up rates of VDRL report collection. MATERIALS AND METHODS: Two hundred consecutive VDRL requests received at the serology laboratory of a tertiary care health facility from the STI clinic of the linked hospital were prospectively analysed to evaluate the above parameters. RESULTS: For the 200 requests audited, the mean absolute turnaround time of VDRL test was 7.46+/-2.81 days. The mean duration of the pre laboratory, laboratory and post laboratory phases was 0, 4.69+/-2.13 and 2.77+/ 2.51 days respectively. The interval from specimen receipt to performance of tests (mean duration=4.25+/-1.96 days) was the major reason for long VDRL turnaround time. The common indications for syphilis testing in STI clinic attendees were lower abdominal pain (33%), vaginal discharge (26.5%) and genital ulcer disease (9%); and the follow-up rate for report collection was 71%. CONCLUSION: Our study highlights the strong need to shift to alternative testing methods, mainly rapid point of care procedures for serodiagnosis of syphilis in order to circumvent the problems of long turnaround time and low patient follow up rates. PMID- 26435967 TI - Assessment of Critical Care Provider's Application of Preventive Measures for Ventilator-Associated Pneumonia in Intensive Care Units. AB - BACKGROUND: The implementation of guidelines for the prevention of Ventilator associated pneumonia has been shown to have a significant effect in reducing the incidence of VAP. OBJECTIVE: The aim of the present study was to evaluate the implementation of the preventive strategies for VAP in ICUs of university hospitals of Sari, Iran. MATERIALS AND METHODS: This cross-sectional study was carried out in 600 beds/day in the ICUs of university hospitals of Sari from April to June 2012. Sampling was done by availability technique in patients receiving mechanical ventilation in the ICU. The implementation of the preventive measures was assessed by a standard checklist with previously approved validity and reliability. RESULTS: The percentage of implementing each of the measures was as follows: sterile suction, 88.44%; semi-recumbent position, 76.8%; oral hygiene, 58.45%; using heat and moisture exchanges (HMEs), 58%; controlling cuff pressure, 46.8%; hand hygiene, 32.8%; using anti-coagulants, 26.8% and physiotherapy, 25.5%. Closed suction system, continuous drainage of subglottic secretions and kinetic beds were not used at all. CONCLUSION: The overall mean percentage of implementing preventive measures was low and required designing integrated guidelines by considering the conditions of the ICUs in each country, as well as educating and encouraging the staffs to use the recommended guidelines. PMID- 26435968 TI - Dr. A.P.J Abdul Kalam-"A Man Beyond Science". PMID- 26435969 TI - Peer Teaching to Foster Learning in Physiology. AB - INTRODUCTION: Peer teaching is an effective tool to promote learning and retention of knowledge. By preparing to teach, students are encouraged to construct their own learning program, so that they can explain effectively to fellow learners. Peer teaching is introduced in present study to foster learning and pedagogical skills amongst first year medical under-graduates in physiology with a Hypothesis that teaching is linked to learning on part of the teacher. MATERIALS AND METHODS: Non-randomized, Interventional study, with mixed methods design. Cases experienced peer teaching whereas controls underwent tutorials for four consecutive classes. Quantitative Evaluation was done through pre/post test score analysis for Class average normalized gain and tests of significance, difference in average score in surprise class test after one month and percentage of responses in closed ended items of feedback questionnaire. Qualitative Evaluation was done through categorization of open ended items and coding of reflective statements. RESULTS: The average pre and post test score was statistically significant within cases (p = 0.01) and controls (p = 0.023). The average post test scores was more for cases though not statistically significant. The class average normalized gain (g) for Tutorials was 49% and for peer teaching 53%. Surprise test had average scoring of 36 marks (out of 50) for controls and 41 marks for cases. Analysed section wise, the average score was better for Long answer question (LAQ) in cases. Section wise analysis suggested that through peer teaching, retention was better for descriptive answers as LAQ has better average score in cases. Feedback responses were predominantly positive for efficacy of peer teaching as a learning method. The reflective statements were sorted into reflection in action, reflection on action, claiming evidence, describing experience, and recognizing discrepancies. CONCLUSION: Teaching can stimulate further learning as it involves interplay of three processes: metacognitive awareness; deliberate practice, and self-explanation. Coupled with immediate feedback and reflective exercises, learning can be measurably enhanced along with improved teaching skills. PMID- 26435970 TI - The Use of Ice Pack for Pain Associated with Arterial Punctures. AB - BACKGROUND: Arterial punctures for monitoring respiratory problems are one of the most painful procedures in hospitalized patients. The knowledge regarding non pharmacologic methods of pain management, including cold application is limited. OBJECTIVE: This aim of this study was to determine if the application of ice pack before the procedure would decrease the pain perception of patients during the arterial puncture. MATERIALS AND METHODS: This experimental study was undertaken among patients admitted to emergency ward in a public educational center affiliated to Ilam University of Medical Sciences, Ilam/Iran. Sixty-one eligible subjects were randomly assigned to two groups. The treatment group (n=31) received ice pack before arterial puncture, whereas the control group (n=30) received no intervention for pain management. Pain immediately and 5 minute after the arterial puncture were scored on a visual analog scale (VAS) from 0 to 10. RESULTS: The mean of pain score immediately after the arterial puncture were 3.12 (1.68) and 4.6 (1.56) for treatment and control group, respectively (p<0. 001). The mean pain score 5 minute after the punctures were 1.9 (1.51) for treatment group and 2.53 (1.85) for control group. This difference was not statistically significant. The mean of heart rate during the procedure were 75.45 (9.76) beats/min for the treatment subjects and 75.46 (9.36) beats/min for the control group (p>0.05). Patients with previous arterial puncture reported higher pain intensity. CONCLUSION: Cold pack is a simple, non-invasive and inexpensive technique for pain management before the arterial puncture. However, there is a need for further research regarding this topic. PMID- 26435971 TI - Ophthalmology Teaching-Learning in Undergraduate Classes: Roadblocks and The Remedies. AB - The curriculum needs to run apace with the changing morbidity pattern and social needs. Teaching methodology requires constant evolution. With a static curriculum and teaching methods undergraduate ophthalmology proves difficult for many students. This article briefly analyses the ophthalmology curriculum, highlights the problems of teaching and offers some solutions. PMID- 26435972 TI - Evaluation of Dietary Choices, Preferences, Knowledge and Related Practices Among Pregnant Women Living in An Indian Setting. AB - INTRODUCTION: Healthy and nutritious diet is very essential component of Antenatal care along with clinical advice. The objective of this study was to understand the dietary choices, preferences, knowledge and related practices among pregnant women living in an Indian setting. MATERIALS AND METHODS: Hundred pregnant women were enrolled in this cross-sectional study. Information about Socio-demographic profile, food item price and approach during inflation, nutrition related knowledge, attitude and practices and 24 hour dietary recall was acquired. RESULTS: Majority of the participants (87%) reported regular antenatal care visits and intake of iron and folic acid tablets. Eighty two percent of the participants were acquainted with standardized marks on food items and 64% of them reported checking of these marks before purchasing. Thirty two percent of the participants did not know about balanced diet. Fifty eight percent of the participants felled in fair category of dietary recall final scores. CONCLUSION: There is still vast room for improvement of the nutritional status of pregnant women as none of the participants were able to achieve excellent status on 24 hour food record scoring sheet. PMID- 26435973 TI - Pubertal Timing and Demographic Predictors of Adolescents in Southwest Nigeria. AB - BACKGROUND: Changes in the timing of puberty have been an area of research interest in developed countries because of its associated health and psychosocial problems. Adolescents in Africa are no exception as they are reaching adulthood today much earlier than before. This changing trend may have a major influence on adolescents' sexual behaviour. AIM: This study determined the timing of puberty and demographic predictors among the adolescents in southwest Nigeria. MATERIALS AND METHODS: The study was a cross-sectional study. Using Modified Sexual Maturity Scale (MSMS) of pubertal assessment, data were collected from 1000 respondents from rural and urban areas of Osun state, Nigeria. Data were collected using pre-tested Assisted Self Completion Questionnaires (ASCQ). The rate of pubertal development was based on age group and current pubertal stage. Data were analysed using SPSS version 16. Chi-square and logistic regression analyses were done to identify significant demographic predictors. Statistical significance was at 5% level. RESULTS: The overall mean age of the respondents was 14.22+/-2.47 years. The mean age for males was 14.19+/-2.38 years and 14.25+/ 2.57 years for females. A total of 52.9% of the respondents were males and 47.1% were females. Higher proportions of the females, 41.6% were already in late puberty stages compared to their male counterparts where 21.9% were at this stage. With regards to this rate of pubertal development, more males, 14.2% significantly had late rate of pubertal development than the females 5.1%. The significant demographic predictors was socio-economic class in females only. CONCLUSION: From this study, the timing of puberty was early for females and socio-economic class is an important demographic predictor for pubertal development. This study was however limited because intrinsic factors such as genetic makeup and nutritional status which could affect the finding were not be excluded. PMID- 26435974 TI - Ganglioneuroblastoma of Skull Base. AB - Neuroblastic tumours are common in childhood and adrenal glands are the most common site. Head and neck ganglioneuroblastomas are extremely rare and nose is a very uncommon site for a ganglioneuroblastoma. The management of this primitive sympathogonic tumour may vary depending on the age of the patient and stage of the tumour. We present a middle-aged man with a ganglioneuroblastoma of skull base, management of this tumour and a review of literature. PMID- 26435975 TI - Is There a Critical Period for Amblyopia Therapy? Results of a Study on Older Anisometropic Amblyopes. AB - PURPOSE: Amblyopia, a common cause of low vision, is rarely treated in adults. Improvement in vision has been seen beyond the critical period at times. Hence, this study was taken up to study the effect of minimal occlusion therapy (2-4 hours/day) in anisometropic amblyopic patients in the age group of 12-30 years. MATERIALS AND METHODS: The study is a prospective, randomized case series of anisometropic amblyopia patients aged 12-30 years who reported in the outpatient department of Hakeem Abdul Hameed Centenary Hospital, New Delhi, from December 2011 to November 2013. Thorough ocular examination and cycloplegic refraction was done to rule out other ocular disease. Anisometropic Amblyopia was diagnosed only after four weeks of spectacle wear. The selected patients were then advised occlusion therapy of 2-4 hours per day of better eye with stress on near visual task. Videogames, computers, mobile phone gaming and colouring in especially designed patterns were used as vision training aids. The outcome measure selected was best corrected visual acuity (BCVA) achieved that remained stable for three consecutive months of occlusion. RESULTS: Sixty one patients of anisometropic amblyopia were included in the study (32 males and 29 females) aged 12-30 years (mean age 17 years). Mean BCVA at the start of treatment was 20/125 (0.8 log MAR units) and 20/32 (0.2 log MAR units) at the end of the treatment. Thirty three patients (54%) out of 61 had BCVA of 20/20, while 58 patients (95%) had >= 20/40 BCVA, 01(1.6%) had 20/50 and 02 (3.27%) had 20/80 BCVA at the end of therapy. The results were statistically significant (p- value <0.0001) with a 95% confidence interval. CONCLUSION: This study clearly proves that there is no critical period for the treatment in older (12-30 years) anisometropic amblyope. Even 2-4 hours per day of occlusion of better eye with vision training thorough near visual task of amblyopic eye is effective. However, counseling and patient compliance is important for successful outcome of therapy. PMID- 26435976 TI - Potential for Hospital Based Corneal Retreival in Hassan District Hospital. AB - CONTEXT: In developing countries, corneal diseases are the second leading cause of blindness. This corneal blindness can be treated through corneal transplantation. Though the present infrastructure is strong enough to increase keratoplasty numbers at a required rate, India has largest corneal blind population in the world. So a constant supply of high quality donor corneal tissue is the key factor for reduction of prevalence of corneal blindness. Considering the magnitude of corneal blindness and shortage of donor cornea, there is a huge gap in the demand and supply. AIM: To study the potential for hospital based retrieval of donor corneal tissue in Hassan district hospital after analysing the indicated and contraindicated causes of deaths, so that hospital corneal retrieval program in Hassan district hospital can be planned. MATERIALS AND METHODS: The cross-sectional, retrospective and record-based study included all hospital deaths with age group more than two years occurred during one year period (January 2014 to December 2014). Data regarding demographic profile, cause of death, treatment given and presence of any systemic diseases were collected. The causes of deaths which are contraindicated for the retrieval of corneas were analysed and noted. The contraindications were based on the NPCB guidelines for standard of eye banking in India 2009. RESULTS: Out of 855 deaths, number of deaths in males (565) was greater than females (290). Numbers of deaths were highest between 41-60 years age group (343). Deaths due to HIV, septicaemia, meningitis, encephalitis, disseminated malignancies were contraindicated for corneal retrieval. Corneas could be retrieved from 736 deaths out of 855. Potential for corneal retrieval in a period of one year in Hassan District hospital was 86%. CONCLUSION: Hospital corneal retrieval program has got a great potential to bridge the gap between the need for the cornea and actually collected corneas which will contribute enormously in eliminating corneal blindness. In present study there was 86% potential for corneal retrieval among the hospital deaths. PMID- 26435978 TI - Tubercular Nodular Episcleritis: A Case Report. AB - Tuberculosis (TB) is an infectious disease caused by the acid-fast bacillus Mycobacterium tuberculosis and is an important cause of death worldwide. Tuberculosis most commonly affects the lungs, but has many extrapulmonary manifestations as well, including intraocular involvement. Tubercular nodular episcleritis is a very rare presentation and no such case in an adult male has been reported in the literature. Herein, we present the very first case of tubercular nodular episcleritis in a 30-year-old Indian male. PMID- 26435977 TI - Evaluation of Choroidal Thickness and Volume during the Third Trimester of Pregnancy using Enhanced Depth Imaging Optical Coherence Tomography: A Pilot Study. AB - BACKGROUND: During pregnancy the maternal choroid is exposed to the multiple haemodynamic and hormonal alterations inherent to this physiological condition. These changes may influence choroidal anatomy. In this study a quantitative assessment of overall choroidal structure is performed, by constructing a 3 dimensional topographic map of this vascular bed. PURPOSE: To compare the thickness and volume of the maternal choroidal in the third trimester of pregnancy with that of an age-matched control group of women. MATERIALS AND METHODS: Twenty-four eyes of 12 pregnant women in the last trimester and 12 age matched healthy controls (24 eyes) were included. Optical coherence tomography in enhanced depth imaging mode was used to construct maps of the choroid of the macular area. Choroidal thickness and volume were automatically calculated for the 9 subfields defined by the Early Treatment Diabetic Retinopathy Study (ETDRS). A comparative analysis between the two groups was performed using the two-way ANOVA test. RESULTS: The average thickness of the choroid for the entire ETDRS area of the pregnant group was 295.15 +/-42.40MUm and 271.56 +/-37.65MUm in the control group (p=0.051). The average choroidal volume was 8.05 +/-1.12mm(3) and 7.46 +/-1.03mm(3), respectively (p=0.067). Although the choroid of the pregnant group had larger thickness and volume in all subfields compared to the control group, this difference was statistically significant only in three regions - the central subfield, minimum foveal thickness and inferior inner macula (p<0.05). CONCLUSION: Our study suggests that in the third trimester of pregnancy the choroid may be subjected to physiological changes in structure. Whether these changes are a result of hormonal and/or haemodynamic adaptations of pregnancy remains to be studied. PMID- 26435979 TI - Unexplained Anterior Uveitis: Viral Causes. PMID- 26435980 TI - Correlation between Six Minute Walk Test and Spirometry in Chronic Pulmonary Disease. AB - INTRODUCTION: Six minute walk test (6MWT), is an exercise test, used as a clinical indicator of the functional capacity, in patients with cardiopulmonary diseases. The present study assessed the correlation of six minute walk test with pulmonary function variables, in patients with chronic pulmonary diseases, in local population. AIMS & OBJECTIVES: The objectives were to study correlation of different spirometry variables with variables of six minute walk test like percent predicted 6 minute walk distance (% Predicted 6MWD) as per Enright et al., formula and Indian reference equation, pre and post exercise pO2 and pCO2 and exercise desaturation. MATERIALS AND METHODS: All consecutive patients with confirmed diagnosis of chronic pulmonary diseases were included from January 2013 to June 2014 in tertiary care institute. 6MWT was performed as per the ATS guidelines. Among 130 patients 108 were also subjected to arterial blood gases pre and post test. Spirometry was performed as per ATS guidelines. Percent (%) predicted 6MWD was calculated. Correlation between spirometry and 6MWT was assessed. RESULTS: One hundred and thirty patients with chronic pulmonary disease were taken. Out of them there was 102 patients with obstructive airway disease and 58 patients with interstitial lung disease. FEV1 significantly correlated with %predicted 6MWD &; with basal pO2 and pCO2 and with post exercise pCO2 and pO2. FVC also correlated with %predicted 6MWD, with basal pO2 and pCO2 and post exercise pO2. FEV1/FVC correlated only with post exercise pCO2 while MVV correlated with %predicted 6MWD and only basal pCO2. Exercise desaturation correlated only with FVC. Percent predicted 6MWD also correlated with basal pO2 & post exercise pO2. CONCLUSION: Thus significant correlation found between 6MWT & spirometry variables (FEV1, FVC, MVV & FEV1/FVC). PMID- 26435981 TI - Pattern of Use of Antibiotics Following Snake Bite in a Tertiary Care Hospital. AB - INTRODUCTION: There are several conflicting recommendations on the use of antibiotics in snakebite victims. This study aimed to identify the pattern of antibiotics used following snake envenomation in a tertiary care hospital of Kerala. MATERIALS AND METHODS: Retrospective review of case records from January to August 2011 was done and all the cases filed as snakebite were reviewed and details entered in a structured performa. Data was analysed using SPSS 16 and results were expressed mainly using descriptive statistics. RESULTS: Three hundred and thirteen cases were evaluated with mean age 37.58+/- 14.54 year and 51.1% were males. Out of total, 94.6% received antibiotics of which 88.85% were oral, 8.1% parenteral and 3.04% both. There were total 454 prescriptions of antibiotics. In all seven different types of antibiotics were prescribed alone or in combination of which Ampicillin (205) was the commonest followed by Cloxacillin (194). The mean antibiotic usage was 1.46+/-0.716 per patient and the mean duration of antibiotic use was 3.16+/-1.446 days. In patients with no envenomation the mainly prescribed antibiotic was Cloxacillin (126). Intravenous antibiotics like Piperacillin plus Tazobactam were given only in patients with either local or systemic envenomation. CONCLUSION: The main pattern of use of antibiotics following snakebite envenomation is Ampicillin alone or in combination empirically, Cloxacillin prophylatically and Piperacillin with Tazobactam for severe established infections. The choice of antibiotics is based on the clinician's discretion. Since the study setting is in a developing country the prophylactic use of antibiotics may be justified weighing the concerns of secondary infections. PMID- 26435982 TI - Short Term Safety and Tolerability of a Fixed Dose Combination of Olmesartan, Amlodipine and Hydrochlorothiazide. AB - OBJECTIVE: To assess the short term safety and tolerability of a fixed dose combination (FDC) of olmesartan, amlodipine and hydrochlorothiazide (OAH) in real world clinical setting in India. MATERIALS AND METHODS: Physicians were requested to provide eight weeks observational clinical event data of the patients prescribed with FDC of Olmesartan (20/40mg), Amlodipine (5mg) and hydrochlorothiazide (12.5mg) in the prescription event monitoring (PEM) forms. Data on patients' demographics, indication for FDC, concomitant medication and other relevant history was also collected and was analysed with descriptive statistics. RESULTS: Two hundred thirty eight physicians provided data of 4763 patients. Mean age of the population was 55+/-7 years and males were 59.3%. The commonest indication for the FDC was uncontrolled hypertension (60.7%). Diabetes and dyslipidemia were present in 37.9% and 35.1% respectively. Concomitant medications included statins (42.3%), oral anti-diabetic (33.7%) and antiplatelet agents (24.7%). Pedal oedema (0.29%) was the most common adverse event (AE) reported followed by headache (0.16%), giddiness (0.15%), light headedness (0.15) and stroke (0.15%). Other less common (0.04%) reported AEs were tiredness, dizziness, gastritis, hypersomnia, hypoglycaemia, lower respiratory tract infection (LRTI), weakness, diarrhea, labyrinthitis, urinary tract infection, hyponatremia and hypotension. Occurrence of AEs was more common in patients with uncontrolled hypertension (60.74%). CONCLUSION: The FDC of olmesartan, amlodipine and hydrochlorothiazide prescribed most frequently for patients with uncontrolled hypertension and co-morbidities was found to be safe and well tolerated over a short period of observation. PMID- 26435983 TI - HIV Status Disclosure Among People Living with HIV in the Era of Combination Antiretroviral Therapy (cART). AB - INTRODUCTION: As patients with HIV live longer due to Combination Anti-Retroviral Therapy (cART) serostatus disclosure becomes an important issue. Disclosure can have both positive and negative outcomes. Disclosure of HIV status has been associated with better adherence to medication and reduction in levels of psychological distress. Stigma and disruption of family relationships are barriers for disclosure. Most studies regarding disclosure status have been conducted in West. There are many cultural differences in Indian society when compared to west. There is a dearth of research in the field of disclosure of HIV infection in India. AIM: To determine the prevalence of HIV status disclosure among people living with HIV (PLHIV) in South India. MATERIALS AND METHODS: This descriptive cross-sectional study was done in the hospital attached to Kasturba Medical College (KMC), Mangalore, India from May-June 2013. PLHIV of age more than 18 years were included. During the study period 111 consecutive patients who consented for the study were enrolled. STATISTICAL ANALYSIS: Data was collected using a pre-tested interviewer administered semi structured questionnaire. Data collected was analysed using SPSS Version 11.5 statistical software. Descriptive statistics were done and the results are presented as proportions and mean. RESULTS: The mean age of the study population was 44.86 +/- 10.8 years. Majority of the study subjects were men 76 (68.4%). Out of 111 study subjects, 102 (91.9%) had disclosed their HIV status to at least one person while 9 (8.1%) had not disclosed their HIV status to anyone. Disclosure on doctor's advice was the main reason for 56 (54.9%) participants to disclose their HIV status. The main reason for non-disclosure was fear of shame in family. CONCLUSION: Disclosure rate was high in our study in the era of cART. Society must stop discriminating against PLHIV so that they can disclose their serostatus and gain access to care and treatment services without any fear of stigma. In our study the main reason for disclosure was doctor's advice which clearly states the importance of the commitment of doctors in creating awareness among PLHIV about the need for voluntary disclosure. PMID- 26435984 TI - Risk Factors Affecting the Prognosis in Patients with Pulmonary Contusion Following Chest Trauma. AB - INTRODUCTION: Thoracic injury and its complications are responsible for as much as 25% for blunt trauma mortality. Pulmonary contusion occurs in 30%-75% of these cases. Despite advances in pulmonary care and intensive care management pulmonary contusion still contributes to higher mortality and morbidity for patients with severe injuries. AIM: To assess the outcome of pulmonary contusions in patients with chest trauma and various factors determining mortality in these patients. MATERIALS AND METHODS: A retrospective case study, over a period of one year, of all chest trauma cases with pulmonary contusions confirmed by X-rays or CT scan of thorax, were included in the study. All the cases were assessed for age, associated injuries, APACHE II score, SAPS II score, SOFA score, paO2/Fio2 ratio, fracture of ribs, presence of haemothorax or pneumothorax, ventilator and ICU days and finally hospital outcome. RESULTS: A total of 16 cases of pulmonary contusions were included in the study. Five patients died during the ICU stay and 11 survived. All patients had associated injuries. There was significant difference seen in APACHE II score (p<0.001), SAPS II score (p<0.001), SOFA score (p<0.001), paO2/Fio2 ratio (p<0.022) and ventilator days (p<0.001) among the survivors and non-survivors. However, no significant difference was seen in presence of fracture of ribs and presence of either haemothorax or pneumothorax. CONCLUSION: The risk factors that were associated with higher mortality in patients with pulmonary contusions following chest trauma were APACHE II score, SAPS II score, SOFA score, paO2/Fio2 ratio and ventilator days. Close monitoring to improve the gas exchange and better fluid management will help in improving the survival in these patients. PMID- 26435985 TI - Study on Diastolic Dysfunction in Newly Diagnosed Type 2 Diabetes Mellitus and its Correlation with Glycosylated Haemoglobin (HbA1C). AB - INTRODUCTION: Left ventricular diastolic dysfunction (LVDD) represents the first stage of diabetic cardiomyopathy preceding changes in systolic function, reinforcing the importance of early examination of ventricular function in individuals with diabetes mellitus (DM). This cross-sectional study was conducted to determine the incidence of asymptomatic LVDD in newly diagnosed normotensive cases of type 2 diabetes subjects, and its relation to glycosylated haemoglobin (HbA1C), age at the time of diagnosis, body mass index (BMI) and serum total cholesterol. AIM AND OBJECTIVE: To study the incidence of left ventricular diastolic dysfunction (LVDD) and its correlation with HbA1C in normotensive, newly diagnosed type 2 diabetic patients. MATERIALS AND METHODS: This cross sectional study was done in western U.P. on 100 patients of newly diagnosed (within 1 month) type 2 DM between patients 30 and 60 years of age, visiting the Medicine and Endocrinology outpatient Department of LLRM Medical College, Meerut. Patients with established type 2 diabetes and already taking antidiabetic treatment, cardiac diseases like valvular heart disease, ischemic and hypertensive heart disease, congestive heart failure, cardiomyopathy, renal failure, chronic pulmonary disease, severe anaemia and haemoglobinopathies were excluded from the study. These patients were informed about the study and informed consent was obtained before proceeding with the investigations. Patients selected were evaluated with relevant investigations like fasting and post prandial blood sugar, HbA1C level, lipid profile and 2D echocardiography to assess LVDD. These selected patients were divided in 2 groups; one with left ventricular diastolic dysfunction (LVDD) and second group of subjects without LVDD. Various parameters like HbA1C, age, body mass index and serum cholesterol were evaluated between these 2 groups. Statistical analysis was performed using Student t-test, Chi-square and Fisher Exact-test. RESULTS: Out of 100 patients 65 were males and 35 females. Mean age of the population was 50.08 +/- 6.32 years. Overall incidence of LVDD was 41%. Grade 1 LVDD was most common. Mean HbA1C level of LVDD group was found higher as compared to those without LVDD. CONCLUSION: LVDD is very common at the time of diagnosis of type 2 DM even in normotensive patients independent of confounding effect of hypertension, ischemia and BMI. HbA1C and age, were found to be strong indicators of LVDD in newly diagnosed cases of Type 2 DM. PMID- 26435986 TI - Nine-Months Clinical Outcome of Biodegradable Polymer Coated Sirolimus-eluting Stent System: A Multi-Centre "Real-World" Experience. AB - BACKGROUND: The main culprit in first-generation drug eluting stents is 'durable' polymer, whose continuous presence may impair arterial healing and ultimately have a negative impact on late outcomes. The main enigma behind the biodegradable polymer usage is its degradation after elution of drug. This reduces adverse events in unselected patients with complex coronary artery lesions treated with biodegradable polymer coated sirolimus-eluting stents. AIM: The aim of the INDOLIMUS-G Registry was to evaluate safety and efficacy of the Indolimus (Sahajanand Medical Technologies Pvt. Ltd., Surat, India) sirolimus-eluting stents in large cohorts of unselected patients with complex coronary artery lesions. MATERIALS AND METHODS: It is a multi-centre, non-randomized retrospective registry with a clear aim of evaluating safety and efficacy of the Indolimus sirolimus-eluting stents in consecutive patients enrolled between April 2012 and May 2014. The primary end-point of the study was major adverse cardiac events (MACE), which is a composite of cardiac death, myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR) and stent thrombosis (ST) at the end of follow-up. Clinical follow-up were scheduled at the end of 30-days, 6-months, and 9-months period. RESULTS: The mean age of enrolled patients was 52.6 +/- 11.0 years. A total of 1137 lesions were intervened successfully with 1242 stents (1.09 +/- 0.30 stent per lesion). The average stent length and diameter was 27.42 +/- 9.01 mm and 3.12 +/- 0.36 mm respectively. There were 740 (73.40%) male patients, indicating their high prevalence. Diabetes, hypertension and totally occluded lesions were found in 372 (36.90%), 408 (40.47%) and 170 (16.86%) patients, respectively. This showed that study also included high risk complex lesions and not ideal recruited lesions. The incidence of MACE at 30-days, 6-months and 9-months were 3 (0.30%), 18 (1.80%) and 22 (2.20%) respectively. At 9-months, TLR was found in 6 (0.50%) patients. There were 2 (0.20%) cases of ST, 10 (1.0%) cases of MI and 4 (0.40%) cases of cardiac death at 9-month follow-up. CONCLUSION: The lower incidence of MACE, TLR and ST at 9-month follow-up clearly delineates safety and efficacy of Indolimus SES in large cohorts of unselected patients with complex coronary lesions. PMID- 26435987 TI - Purple Urine Bag Syndrome. AB - Purple urine bag syndrome (PUBS) is a rare disorder seen in elderly persons, wherein the urinary bag and the tubing turn in to purple colour. It is usually seen in patients who are on urinary catheters for a long time. Purple coloured urine occurs due to the accumulation of indigo and indirubin, which are the end products of tryptophan metabolism due to the action of sulfatases and phosphatases formed by bacteria like Providencia, Citrobacter, Enterobacter, Klebsiella etc. We present this interesting phenomenon of purple urine in a young male who was on prolonged urinary catheterization. The urine culture was positive for Providencia and constipation was an added risk factor for the purple urine. The urinary catheter and tubing was changed along with a course of antibiotics which lead to the normalization of the urine colour. PMID- 26435988 TI - Paroxysmal Nocturnal Haemoglobinuria Masquerading as Malaria: A Case Report. AB - Paroxysmal Nocturnal Haemoglobinuria (PNH) is a rare type of acquired Haemolytic anaemia that is described as a triad of acquired intravascular Haemolysis, venous thrombosis and anaemia with pancytopenia sometimes due to bone marrow failure. However the classical triad may not be observed at once and fever due to leucocytopenia may confuse the clinical picture. Since this is a rare disease, other epidemiologically common causes may be attributed to the illness. We report a case of PNH with a rare association of malaria due to Falciparum and Vivax species which was undiagnosed for 6 years in a young man. PMID- 26435989 TI - Atrial Fibrillation Due to Over The Counter Stimulant Drugs in A Young Adult. AB - The usage of over the counter stimulant drugs and energy drinks is increasing on a day to day basis for various purposes including work, sports and leisure among individuals in all age groups. Multiple formulations are available in the market including pills, liquid capsules and drinks in various flavours. Many of them contain excessively high doses of caffeine along with a variety of stimulant compounds that have multiple effects in different parts of the human body. The consumption of such high amounts of caffeine itself has shown to have caused cardiac arrhythmias in healthy individuals and when it is mixed with a number of stimulant compounds can be associated with a number of adverse effects in the human body. However, the awareness of such life threatening complications associated with these energy drinks does not exist among people who consume it on a day to day basis. We report a case of 25-year-old Caucasian male with no significant past medical history for cardiac diseases, no risk factors for atrial fibrillation, non smoker, occasional alcohol drinker who presents with new onset atrial fibrillation with rapid ventricular response due to the consumption of over the counter stimulant energy capsule which had high doses of caffeine. PMID- 26435990 TI - Ethionamide: Unusual Cause of Hypothyroidism. AB - Multidrug-Resistant tuberculosis (MDR TB) is major health hazard to the people living in developing countries. As incidence rate of MDR TB has gone up, its therapy has become crucial. MDR TB therapy is known to cause multiple adverse effects however the data related to them is minimal. Hypothyroidism is one of the important adverse effects which usually manifests with vague symptoms and is frequently missed. We present a case of 24-year-old woman who was diagnosed to have MDR TB and started on ethionamide based regimen for same. After 6 months of therapy the patient had clinical symptoms suggestive of hypothyroidism, laboratory investigations confirmed it. As ethionamide is an integral component of MDR TB therapy it was continued and thyroxine replacement therapy was given with which she improved. Hypothyroidism completely resolved after 2 months of stoppage of MDR TB therapy suggesting the reversible aetiology of ethionamide. PMID- 26435991 TI - An Unusual Presentation of Chronic Lymphocytic Leukaemia. PMID- 26435992 TI - Waist-Hip Ratio in Patients with Acute Myocardial Infarction. PMID- 26435993 TI - Coronal/Hemicoronal Approach - A Gateway to Craniomaxillofacial Region. AB - AIMS: The coronal incision with its various modifications provides the most versatile approach to various areas in the craniomaxillofacial region coupled with excellent exposure. The aesthetic advantage of a hidden scar in the hairline, accounts for its continued popularity. The aim of this study was to review the surgical anatomy, technique and problems of post-operative morbidity pertinent to coronal approach in various clinical situations such as craniofacial trauma, tumour resections and reconstructive craniofacial procedures. MATERIALS AND METHODS: In this study, ten patients who presented to Oral and maxillofacial surgery department with various craniofacial problems requiring the use of coronal and hemicoronal approach for treatment were evaluated over a period of two years. Five patients needed coronal approach and another five underwent the surgical procedures through hemicoronal approach. This was an observational study. RESULTS: It was observed that a well-planned and carefully designed coronal/hemicoronal incision with strict adherence to surgical principles posed minimal complication during surgery as well as post-operatively. None of the patients developed infection or heamatoma in the postoperative period. Sensory nerve deficits along the distribution of supraorbital nerve was observed in four patients of bicoronal approach and three patients of hemicoronal approach which completely resolved at the end of six months. Motor nerve weakness was observed in four patients in immediate postoperative period which gradually improved. But it persisted in one patient even after six months who had pathology of temporo orbital region. All the patients had transient alopecia along the line of incision which improved at the end of six months. No other significant disadvantages or complications were noted. CONCLUSION: This approach offers widest accessibility and visibility to the entire upper and middle one third of the face in less than twenty minutes as observed in our study. The postoperative complications are minimal, minor and outweigh the advantages for surgical treatment in any given clinical situation as observed in this study. This proves the brilliance of coronal approach in solving an array of surgical problems pertinent to craniomaxillofacial region with superior aesthetic outcomes. ABBREVIATIONS: ZMC-Zygomatico maxillary complex, NOE-Nasoethmoidal complex, LF Lefort, ORIF-open reduction internal fixation. PMID- 26435994 TI - Study on Surgical Management of Post Burn Hand Deformities. AB - CONTEXT: Functionality of the hands is the major determinants of the quality of life in burns survivors. If contractures or scarring affect the dominant hand, as they do on most occasions, the vocation and there by the economic status of the patient suffer. AIM: The aim of this study is to evaluate the different surgical procedures for resurfacing after release of post-burn hand contractures in terms of functional recovery and aesthetic outcome. SETTINGS AND DESIGN: It's a prospective, non-randomised study of 50 patients admitted and undergoing surgical reconstructive procedures for post burn hand contractures in our plastic surgery department. MATERIALS AND METHODS: Resurfacing procedures were done according to type of contracture with individualisation for each case. All cases were followed up with physiotherapy and splinting advices. Functional and aesthetic outcome and recurrence of contracture for each procedure was noted at 6 months. RESULTS: Forty seven percent of the cases were reconstructed with skin grafting, 30% cases with Z plasties and 23% with flap coverage. Split thickness skin grafts (STSG) and full thickness graft (FTSG) reconstructed cases had good recovery of joint mobility in 43% and 75% of cases respectively. Reconstructive procedures were aesthetically acceptable to the patients in 63%, 75% and 94% of STSG, FTSG and Z plasty cases respectively. Recurrence was seen in 17% of STSG done cases. CONCLUSION: Most of the cases can be resurfaced with skin grafting and few cases have clear indication for flap coverage which needs to be planned and executed cautiously. Z plasties with proper planning gives maximum length gain with no donor morbidity as other procedures. Postoperative physiotherapy and splinting is must for better outcome in all cases. PMID- 26435995 TI - Osteoplastic Reconstruction for Post Traumatic Thumb Amputations Around Metacarpophalangeal Joint. AB - INTRODUCTION: Loss of a thumb due to trauma warrants replantation which is the best method of reconstruction. When replantation is not possible, thumb reconstruction is the procedure of choice. The level of thumb amputation guides the type of reconstruction. There are five goals for reconstructing a thumb: restoration of (1) functional length (2) stability (3) mobility (especially opposition) (4) sensibility and (5) aesthetic appearance. AIM: This study was conducted to evaluate the functional outcome of two main techniques of osteoplastic thumb reconstruction (1) Osteocutaneous distally based radial forearm flap (2) Groin flap with iliac crest bone graft. MATERIALS AND METHODS: Total 13 patients underwent osteoplastic reconstruction in the duration from August 2012 to December 2014. Thumb reconstruction was done using distally based radial forearm osteocutaneous flap in 7 patients and two staged reconstruction by groin flap with iliac crest bone graft in 6 patients. Postoperatively results were assessed in terms of range of motion, hand grip, functional recovery, donor site morbidity and patient satisfaction. RESULTS: All reconstructive thumbs were functionally acceptable. Cosmetically, donor site morbidity was an issue for 2 patients with radial forearm flap and 1 patient with groin flap. Suture line dehiscence and plate exposure required intervention in local anaesthesia in one patient with radial forearm flap. After reconstruction absence of pain, temperature and touch sensation were observed. CONCLUSION: We suggest that osteoplastic reconstruction is a reliable procedure in terms of stability, length, strength and opposability if basal joint is intact. Most of the patients in this study were manual labourers who went back to previous occupation and were able to use their thumb for daily activities for earning livelihood. PMID- 26435996 TI - Large Cervical Paraspinal Haemangioma in Association with Intraosseous Haemangioma: A Rare Case Report. AB - Haemangiomas are most commonly found in skin and subcutaneous tissue and are very rare in intramuscular region. Paraspinal musculature has been barely reported as location of intramuscular haemangioma while we could not find any literature reporting haemangioma in cervical paraspinal previously. We report a case of middle aged woman with a large intamuscular haemangioma involving left cervical paraspinal musculature extending from suboccipital region to C5 vertebra and reaching upto left parotid gland along with C6 vertebral body haemangioma. PMID- 26435997 TI - Primary Squamous Cell Carcinoma of Submandibular Salivary Gland with Sialo Cutaneous Fistula: A Rare Case Report. AB - Malignant tumours of the submandibular salivary glands are rare entities. Most common malignant tumour of submandibular gland is mucoepidermoid carcinoma. Histological finding of squamous cell carcinoma is very rare in submandibular salivary gland. Metastasis from distant primary squamous malignancy, direct invasion from cutaneous or mucosal squamous carcinoma, squamous component of mucoepidermoid carcinoma or primary squamous cell carcinoma of salivary origin are some of the possible causes. Of these, the latter is distinctly uncommon. Primary squamous malignancy is diagnosed only after ruling out other possible explanations. A positive mucin stain in the tumour or synchronous/ metachronous squamous carcinoma elsewhere excludes the diagnosis of a primary carcinoma. Primary squamous carcinoma is seen most commonly in parotid gland and rarely in submandibular gland. We present a case of primary squamous cell carcinoma of right submandibular salivary gland in a 45-year old-man. This case is presented for the rare entity of primary squamous cell carcinoma in submandibular salivary gland. PMID- 26435998 TI - Marjolin's Ulcer in a Post Burn Scar of the Hand. AB - Marjolin's ulcer arising from a post burn scar is rare. Here, we present a case of an elderly male with a Marjolin's ulcer of the hand arising from a post burn scar sustained two decades ago. The patient was not willing for an amputation, so he was managed with a spit skin graft after explaining the possibility of recurrence. PMID- 26435999 TI - Membrane Sweeping for Vaginal Birth after Caesarean Section and its Outcome -A Comparative Study. AB - INTRODUCTION: Sweeping of membrane is a method of induction of labour. This is used to avoid prolonged labour. However, there is paucity of data about the use of this method for induction of labour and reducing prolonged labour in pregnancy with previous caesarean section. This study is an effort to find the effect of membrane sweeping in previous caesarean section. OBJECTIVE: To initiate labour in previous LSCS patients by membrane sweeping and maternal outcome. STUDY SETTING: This prospective randomised control study was conducted in Mahatma Gandhi Medical College and Research Institute, Puducherry between January 2011 to June 2012. MATERIALS AND METHODS: Seventy five women were randomly assigned to membrane sweeping and seventy five to control. In study group serial membrane sweeping was done once weekly from 39 weeks of gestation until the onset of labour up to 41weeks of gestation. In control group, no intervention up to 41 weeks of gestation. All the cases were monitored by biophysical profile. OUTCOME MEASURES: The primary outcomes measured were number of patients who had onset of labour. The secondary outcome included the successful vaginal delivery, number of membrane sweeping to initiate labour, sweeping to delivery interval and amount of oxytocin required. RESULTS: The onset of labour in study group was 61.3% similar in control group 64% with p 0.736. The mean interval from sweeping to labour onset was 50.15+/-8 hours. The rate of VBAC was 17.3% in study group in compared to 18.7% in control group and LSCS was 82.7% in study group in compared to 81.3% in control group respectively. The mean gestation age at delivery 40+/-0.56 weeks for study group compared with 39.92+/-0.55 weeks for control group. CONCLUSION: Although membrane sweeping is an easy way of inducing labour, present study failed to demonstrate its beneficial effect on obstetrical outcome. PMID- 26436000 TI - Shoulder Tip Pain After Cesarean Section. AB - AIM: The aim of this study was to investigate the frequency of postoperative shoulder tip pain (STP) after cesarean section and compare spinal and general anaesthesia with respect to STP. MATERIALS AND METHODS: Three hundred patients who underwent cesarean section were randomly assigned to either spinal anaesthesia group (Group SA, n=143) or general anaesthesia group (Group GA, n=157). Postoperative STP was assessed at 8 hours and 24 hours after operation by Visual Analogue Scale of Pain (VAS). RESULTS: There were no statistically significant difference between the groups in terms of demographic data, operative findings, and clinical outcomes. The overall incidence of STP in study population was 35.7%. The incidence of STP in group SA (26.6%) was lower than that in group GA (43.9%)(p=0.005). Moreover VAS scores for STP at 6 hours and 24 hours were significantly lower in Group SA (p=0.001 and p<0.001, respectively). CONCLUSION: Shoulder tip pain is a common complaint after cesarean section, which is more prevalent in general anaesthesia. PMID- 26436001 TI - Successful Outcome of Twin Gestation with Partial Mole and Co-Existing Live Fetus: A Case Report. AB - Sad fetus syndrome comprising of a live twin gestation with a hydatidiform mole is a rare entity. The condition is even rarer when the co-existing live fetus is associated with a partial mole than a complete mole. We report the case of a 24 year-old G2P1L1 at 28 weeks gestation who presented to our casualty in the second stage of labour. She had a previous ultrasound scan at 13 weeks which showed a live fetus with a focal area of multicystic placenta. She delivered an alive preterm male fetus weighing 1.32 kg vaginally. Following expulsion of normal placenta of the live fetus, partial mole was expelled. The fetus was admitted to neonatal ICU and discharged after two weeks. Soon after delivery, beta-hCG (human chorionic gonadotropin) was 1,21,993 mIU/ml which decreased to 30mIU/ml within two weeks. The patient was discharged with advice of regular follow up of beta hCG reports. PMID- 26436002 TI - Proboscis Lateralis : A Rare Bilateral Case in Association with Holoprosencephaly. AB - Proboscis lateralis is a very rare congenital craniofacial malformation characterized by a trunk like tubular appendage arising commonly from roof of the orbit near medial canthus. It may be seen as an isolated defect with sporadic occurrence or it may be associated with a spectrum of anomalies. It is usually unilateral and very few bilateral cases of proboscis lateralis have been reported in the literature worldwide. Alobar holoprosencephaly is commonly associated with a single central proboscis and cyclopia. Here we report an unusual case of a bilateral proboscis lateralis seen in association with holoprosencephaly. PMID- 26436003 TI - Distinguishing Myasthenia Exacerbation from Severe Preeclampsia: A Diagnostic and Therapeutic Challenge. AB - Myasthenia gravis is an acquired, autoimmune neuromuscular disorder characterized by voluntary muscle weakness. Pregnant patients may have disease exacerbation, respiratory failure, crisis, adverse drug reaction, surprisingly enough remission at any trimester or postnatal period. Concurrence of myasthenia gravis with severe preeclampsia is a dreadful condition raising diagnostic and management issues. We hereby discuss a case of myasthenic woman who developed severe preeclampsia during pregnancy and presented in last trimester with clinical features mimicking signs of impending eclampsia. Keeping in mind the history of myasthenia gravis, urgent neurology review taken and diagnosis of myasthenic exacerbation was entertained. She responded well to injection neostigmine and in this way inadvertent use of magnesium sulphate was avoided. PMID- 26436004 TI - Primary Peritoneal Hydatid Cyst Presenting as Ovarian Cyst Torsion: A Rare Case Report. AB - Hydatid cyst disease is a zoonotic disease caused by Echinococcus granulosus, E.multilocularis or E.Vogli. The most common primary site is liver (75%) followed by lungs (5-15%) and other organs constitute 10-20%. Peritoneal hydatid cysts are very rare especially primary peritoneal hydatid. Secondary peritoneal hydatid cysts are relatively common, which usually occurs due to rupture of primary hepatic hydatid cyst. We present a rare case of large primary peritoneal hydatid cyst misdiagnosed as torsion of ovarian cyst that underwent Laparotomy with cyst excision and postoperative Albendazole therapy. PMID- 26436005 TI - Catamenial Pain in Umbilical Hernia with Spontaneous Reduction: An Unusual Presentation of a Rare Entity. AB - Spontaneous umbilical endometriosis occurring in absence of any previous abdominal or uterine surgery is extremely atypical. Its association with umbilical hernia is very rare and hernia getting spontaneously resolved has not been reported in literature so far. Here we report a case of a patient with spontaneous umbilical endometriosis associated with umbilical hernia which led to spontaneous hernia reduction. This was also associated with multiple uterine fibromyoma and bilateral ovarian endometrioma which were simultaneously treated by total abdominal hysterectomy with bilateral salpingo-oopherectomy along with surgical excision of the endometriotic tissue and repair of the abdominal wall defect. To the best of our knowledge, this is the first described case of spontaneous umbilical hernia reduction due to development of endometriosis. PMID- 26436006 TI - Comment on "Is It Safe to Provide Abortion Pills Over The Counter? A Study on Outcome Following Self-Medication with Abortion Pills". PMID- 26436007 TI - High Incidence of Stress Fractures in Military Cadets During Training: A Point of Concern. AB - INTRODUCTION: Stress fractures occur due to repetitive cumulative micro trauma on the bone over a period of time. Stress fractures in military cadets is a rising cause of concern. It increases morbidity, long periods of absence from training and economic losses. AIM: The purpose of this prospective study was to determine the incidence and distribution of stress fracture (SFs) in Border Security Forces (BSF) cadets in Bangalore during their basic training tenure. MATERIALS AND METHODS: A detailed analysis of history and physical assessment was performed of those presenting with symptoms of pain, swelling or deformity. These cadets then underwent radiographic imaging for the evaluation of symptoms. All cadets with clinical and radiological diagnosis of SFs were appropriately managed and followed up every two weeks till the time of union. RESULTS: Three hundred BSF candidates had clinical and radiological signs of SF with an overall incidence rate of 15%. The average age of the patients with SFs was 23 years (range 20-26). The incidence of SFs was highest during their physical training exercises and reached maximum at 12 weeks of the training schedule. Overall, the most common sites of bone injuries were the tibia (87.66%), fibula (7.8%), and metatarsals (2%). There were 5 femur fractures including one bilateral femur(1.67%) and two neck of femur (0.67%). Three tibia, three femur shaft and two neck femur fractures were operated and rest treated conservatively. All fractures healed in an average period of seven weeks. All cadets returned to their full activity in an average period of nine weeks. CONCLUSION: The study provides evidence that SF among BSF cadets occur frequently during their training period with undoubtedly high incidence rate which is probably underrated in Indian setting. To prevent stress fractures, modifiable causes and risk factors must be identified and a proactive approach which can help the cadets withstand intense physical activity should be adopted. PMID- 26436009 TI - Role of Arthroscopy in the Treatment of Osteoarthritis of Knee. AB - BACKGROUND: A variety of procedures have been described for treatment of the osteoarthritic knee. Comprehensive Arthroscopic treatment regime has definite role in treating patients with knee Osteoarthritis. AIM: To evaluate the role of arthroscopy in functional and subjective outcomes of patient with moderate to severe osteoarthritis of knee. MATERIALS AND METHODS: Between October 2011 to September 2013, 30 patients were treated with an arthroscopic regimen. Patients with primary osteoarthritis who fulfilled clinical and radiographic classification criteria of American College of Rheumatology for osteoarthritis were included. All patients were followed for 18 months. All patients were subjected to comprehensive arthroscopic treatment. RESULTS: Overall, mean age was 59 years, with 17 females and 13 males. According to Kellgren Lawrence scale, 17 patients had grade 2 osteoarthritis, 10 had grade 3 osteoarthritis and 3 patients had grade 4. The average preoperative Lysholm score was 38.8. According to Outerbridge grading of chondral surface lesions, 14 patients were in grade-1, 5 in grade-2, 8 in grade-3 and 3 patients were in grade-4. The average 18 months postoperative Lysholm score was 83.3 (range 60- 96). 73.33% patients showed good/ excellent outcome. 80% of patients with chondral and meniscal lesions showed excellent/good outcome. CONCLUSION: This arthroscopic treatment regimen can improve function and activity levels in patients with moderate to severe osteoarthritis. Patients with meniscal and chondral pathology will be benefited more by arthroscopic treatment. PMID- 26436008 TI - Serum Osteocalcin as a Diagnostic Biomarker for Primary Osteoporosis in Women. AB - INTRODUCTION: Osteoporosis, a major health problem in elderly population, especially in post-menopausal females, is diagnosed basically on clinical suspicion and bone mineral density measurement. Dual energy x-ray absorptiometry (DEXA) scan though a gold standard of diagnosis becomes unfit for screening purpose due to its prohibitive cost, unportability and lack of availability of machine. AIM: To assess the diagnostic potential of serum osteocalcin levels in primary osteoporosis. MATERIALS AND METHODS: In a case-control study, 82 post menopausal females, between 40-70 years, were subjected to measurements of bone mineral density and serum osteocalcin levels. Based on the results of DEXA scan they were divided into two: a) Control group and B) Case group. Case group was further subdivided as Osteopenia and Osteoporosis depending on their t-scores. Correlation between different BMD grades and the levels of serum osteocalcin were analysed statistically. RESULTS: A negative correlation was found between serum osteocalcin levels and BMD grading. Significant association of age and years since menopause (YSM) was found with serum osteocalcin levels and BMD. No association of BMI and serum osteocalcin was observed with BMD. Statistically significant difference between values of serum osteocalcin in postmenopausal non osteoporotic women, post-menopausal women with low bone mass (osteopenia) and post-menopausal women with osteoporosis were seen. CONCLUSION: Serum osteocalcin level measurement can be used for screening purpose in post-menopausal patients. Subjects can be further assessed by DEXA scan to, if indicated. PMID- 26436010 TI - Clinical and Genetic Analysis of Fibrodysplasia Ossificans Progressiva: A Case Report and Literature Review. AB - Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital malformation of the great toes and disabling heterotopic ossification in specific anatomic locations with a world wide prevalence of 1 in 2 million population. Nearly 90% of patients with FOP are misdiagnosed and mismanaged. We present a case of a four-year-old boy brought by his parents with the complaints of stiffness of right shoulder, neck and multiple swellings over the upper back noted over the past 4 months. On examination bilateral symmetrical hallux valgus with microdactyly of great toes and multiple bony hard swellings on both the scapulae were noted. Skeletal survey revealed all the classical features of FOP. Mutation of the ACVR1gene on genetic analysis confirmed the diagnosis of FOP. Invasive surgical procedures including biopsy and manipulations for stiff joints were avoided as they strikingly end up in rapid progression of FOP. Congenital hallux valgus with short great toe in a child should be considered as an early diagnostic tool for FOP even before the onset of mass lesions. Genetic analysis for mutation of ACVR1gene is confirmatory. Prevention of injury, medical management of acute painful flare-ups and rehabilitation are the mainstay of treatment. PMID- 26436011 TI - Six Sesamoid Bones on Both Feet: Report of a Rare Case. AB - There is a variation of the total number of distinct bones in the human in the literature. This difference is mainly caused by the variable existence of sesamoid bones. Sesamoid bones at the first MTP are seen regularly. In contrast additional sesamoid bones at the second to fifth MTP are rare. We report a case of additional sesamoid bones at every metatarsophalangeal joint (MTP) of both feet. A 22-year-old female Caucasian presented with weight-dependent pain of the second MTP of the left foot. In the radiographs of both feet additional sesamoid bones at every MTP could be seen. This case reports a very rare variation in human anatomy. A similar case has not been displayed to the academic society and therefore should be acknowledged. PMID- 26436012 TI - The Incidence of Allergic Disorders in First Degree Relatives of Neonates with Transient Tachypnea of Neonate. AB - BACKGROUND: The role of maternal allergic disorders to increase the risk of Transient Tachypnea of Neonate (TTN) in neonates remained unclear. We determined the incidence of allergic disorders in first degree relatives of neonates suffered from TTN to clear role of these allergic disorders to predispose TTN in neonates. MATERIALS AND METHODS: In a cross-sectional study carried out at Fatemieh hospital between September 2010 and September 2011, all consecutive neonates with the diagnosis of TTN were included into the study. Those neonates were not treated after 5 days of hospitalization were excluded. Baseline information with regard to the history of allergic diseases among first degree relatives of neonates were charted from family members using a structured questionnaire at enrolment by interviewing and examination if required. RESULTS: The two groups were matched for baseline data including neonate gender, birth weight, and type of delivery. In the TTN group, one of first degree relatives (2.9%) suffered from bronchial asthma and two of them (5.7) had atopic dermatitis. In total, allergic diseases was revealed in 8.6% of first degree relatives of neonates with TTN. Besides, none of the first degree relatives of neonates in healthy neonates group experienced bronchial asthma or atopic dermatitis. Allergic rhinitis was not also found in the relatives of the two study neonates groups. Comparing incidence of allergic diseases in first degree relatives of neonates in TTN and healthy groups showed no significant difference (8.6% in TTN group versus 0.0% in healthy group, p = 0.076). CONCLUSION: Our study showed that the incidence of allergic disorders in first degree relatives of neonates suffered from TTN is higher than healthy newborns, but these differences are not statistically significant. PMID- 26436013 TI - Clinical and Laboratory Potential Predictors of Blood Culture Positivity in Under Five Children with Clinically Severe Pneumonia - Khartoum -Sudan. AB - BACKGROUND: Blood culture is necessary for appropriate management of clinically severe pneumonia in children under five years of age. However, in limited resource countries it might be unduly costly and waste of valuable time because of the high negative culture rate. OBJECTIVES: This study aims to identify clinical and laboratory parameters that potentially predict a positive blood culture in cases of severe pneumonia. MATERIALS AND METHODS: A hospital based study, enrolled 189 cases satisfying the WHO definition of severe pneumonia. Age, gender, clinical history, physical examination, temperature, complete blood count, C-reactive protein, blood culture and Chest X Ray for all the patients were recorded. RESULTS: Forty one patients had positive blood culture giving a prevalence of 21.7%. All variables were used in a dichotomous manner. White Blood Count (WBC) more than 20 000, very high C-reactive protein (C-RP >=8mg/L) and Temperature more than 40(o)C, had a positive predictive value of 46.1%, 44.3% and 40.0% respectively for a positive culture as well as a Negative Predictive Value of 91.1%, 91.6% and 91.7% respectively. The WBC more than 20 000 and temperature above 40(o)C had a significant association with a positive blood culture. Their adjusted Odds Ratios were 3.9 (95% CI: 1.4-10.90) and 3.1 (95% CI: 1.2-8.4) respectively. This was not the case for C-RP (Odds Ratio=2.2, 95% CI: 0.7-2.2) or positive Chest X Ray (Odds Ratio=1.5, 95% CI: 0.6-3.6). CONCLUSION AND RECOMMENDATION: Temperature of more than 40(o)C, Very high C-RP and WBC of more than 20 000 are good indicators of a potential positive blood culture. It is therefore recommended that further research be undertaken to refine these predictors as screening tools before resorting to blood culture. It is also recommended that antibiotic treatment may be initiated on the basis of the high temperature and WBC, while waiting for the culture results. PMID- 26436014 TI - Modified Computed Tomography Severity Index for Evaluation of Acute Pancreatitis and its Correlation with Clinical Outcome: A Tertiary Care Hospital Based Observational Study. AB - BACKGROUND: Acute Pancreatitis is a very common condition leading to the emergency visits in both developed and developing countries. Computed Tomography plays a pivotal role in the diagnosis and subsequent management of pancreatitis. The modified CT severity index includes a simplified assessment of pancreatic inflammation and necrosis as well as an assessment of extra pancreatic complications. AIM: To study role of modified computed tomography severity index in evaluation of acute pancreatitis and its correlation with clinical outcome. MATERIALS AND METHODS: This was a hospital based prospective correlative study done on patients of all age groups referred to the Department of Radio diagnosis from the various indoor and outdoor departments of the hospital, with clinical/Laboratory/ultrasonography findings suggestive of acute pancreatitis. The severity of pancreatitis was scored using Modified CT severity index & CT severity index and classified into mild, moderate and severe categories. Total of 50 patients of acute pancreatitis presenting to the emergency department of our hospital were included in the study. Clinical outcome parameters for correlation collected from respective referral departments included, the length of hospital stay (in days), need for surgical intervention, need for percutaneous intervention (aspiration and drainage), evidence of infection in any organ system (combination of a fever > 100 degrees F and elevated WBC >15,000/ mm(3)), evidence of organ failure (PaO2 < 60 mm Hg or need of ventilation, systolic BP of < 90 mm Hg, serum creatinine of >300MUmoles/L or urine output of < 500 ml / 24 h) and death. RESULTS: The age of the patients in the study group was in the range of 17 to 80 years. Maximum patients were in the age group 40-50 years (42.0%). The mean age was 42.32 years. Out of 50 cases, 33 (66%) were male and 17 (34%) were females with a male to female ratio of 2:1. Cholelithiasis was found to be most common aetiological factor for acute pancreatitis in 40% cases. Alcoholic pancreatitis was seen in 36% of cases. Together cholelithiasis and alcoholism accounted for 76% of cases. Pleural effusion was the most common extra-pancreatic complication, 28 patients (56%), followed by ascites. Majority of patients were categorized as severe pancreatitis (44%). 38% patients were grouped into moderate pancreatitis and 18% were categorized in mild pancreatitis. The outcome parameters in terms of length of hospital stay, need of intervention, development of infection, and development of organ failure were more in patients with higher modified CT severity index. CONCLUSION: In conclusion CECT was found to be an excellent imaging modality for diagnosis, establishing the extent of disease process and in grading its severity. The Modified CT Severity Index is a simpler scoring tool and more accurate than the Balthazar CT Severity Index. In this study, it had a stronger statistical correlation with the clinical outcome, be it the length of hospital stay, development of infection, occurrence of organ failure and overall mortality. It could also predict the need for interventional procedures. PMID- 26436015 TI - Primary Hydatid Cyst of the Diaphragm Mimicking Diaphragmatic Tumour: A Case Report. AB - Echinococcus commonly affects the liver and the lung, but several organs can be affected by this disease. The isolated primary diaphragmatic hydatid cyst, not associated with liver or lung, is very rare. We report a case of hydatid cyst in a 55-year-old male, located in the abdominal side of the left hemidiaphragm which mimicked a hypovascular diaphragmatic tumour and exophytic splenic cyst. In our case the diagnosis was confirmed only with histopathological examination done after surgical excision of the cyst. The aim of this work lies in the fact that knowledge of this clinical entity especially in endemic areas as in India will enable radiologists to guide the clinicians in proper diagnosis and adequate pre operative planning. PMID- 26436016 TI - H' Shaped Bilobate Placental Partition: A Rare Placenta Variation. AB - Anomalies of placental growth with respect to its shape have been associated with adverse pregnancy outcomes. A very rare form of 'H' bilobate placental partition was observed in a 31-year-old woman presenting at 24 weeks of gestation. This observation was made during a routine obstetrics scan. Sonographic features showed that it was a non-fibroid partition. The placenta featured anterior and posterior portions separated by a large middle, vertical portion. The placenta was antero-posterior semi-circumferential in shape, measuring approximately 16.70 cm in length and 12.48 cm at shorter chorionic plate (minor axis). The middle, vertical part of the placenta partitioned the uterine cavity into two, creating the impression of two separate gestational sacs. The fetus was located in one of these. The patient was eventually delivered through caesarean section at gestational age (GA) of 36 weeks 6 days. The baby had a low birth weight of 1.70 kg. The early detection of this placental anomaly underlines the importance of ultrasonography in obstetrics. PMID- 26436017 TI - Spontaneous Partial Vanishing Cytomegalovirus Pseudotumour of Colon in an Immunocompetent Patient. AB - Cytomegalovirus (CMV) pseudotumour of the gastrointestinal tract, is a rare benign entity which is treated with antiviral medications and known to resolve spontaneously in a few cases. This is a case report of a 58-year-old man who presented with right lower quadrant abdominal pain. Contrast enhanced computerized tomography of abdomen and pelvis showed apple core lesion involving proximal transverse colon, ceacum, ascending colon, ileoceacal valve and terminal ileum. Synchronous carcinoma of colon was suspected. At laparotomy, there was growth palpable only in the proximal transverse colon. Histological findings of biopsy specimen revealed CMV pseudotumour. CMV pseudo tumour should be included in the differential diagnosis of apple core lesions of the colon even in immunocompetent adults. Endoscopy and biopsy are strongly recommended before surgery in colonic mass lesions to make a definitive diagnosis and to avoid unnecessary surgery. PMID- 26436018 TI - Hirayama Disease: Escaping From the Quotidian Imaging. AB - Hirayama disease is a rare type of neurological disease commonly manifesting as brachial monomelic amyotrophy in young males of Asian origin, easily understood as juvenile non-progressive cervical amyotrophy. The first case was reported by Hirayama in 1959. The pathogenesis is attributed towards chronic compression of cervical spinal cord during flexion movements of neck in cases where there is detachment of posterior dura mater. This chronic event, invariably leads to features of cord atrophy along with other MRI features. We report a case of 21 year-old male who presented with atrophy of distal muscles of his right hand and was sent for MRI of cervical spine which revealed prominent posterior epidural venous plexus without significant cord atrophy. Clinico-radiologic profile of the patient leads toward the diagnosis of Hirayama disease which was considered as borderline because of asymmetrical cord atrophy which is a not a routine imaging feature of the entity. PMID- 26436019 TI - Osteopetrosis - Classic Imaging Findings in the Spine. PMID- 26436020 TI - Role of Advanced Diagnostic Imaging in Intracranial Tuberculoma: MR Spectroscopy. PMID- 26436021 TI - A Comparison of Efficacy of Segmental Epidural Block versus Spinal Anaesthesia for Percutaneous Nephrolithotomy. AB - INTRODUCTION: Percutaneous nephrolithotomy (PCNL) is done under general anaesthesia in most of the centres. Associated complications and cost are higher for general anaesthesia than for regional anaesthesia. Present study is designed to compare the efficacy of epidural block versus spinal anaesthesia with regards to intraoperative mean arterial pressure, heart rate, postoperative pain intensity, analgesic requirement, Postoperative complications and patient satisfaction in patients undergoing PCNL. MATERIALS AND METHODS: After taking Ethical Committee clearance, patients were randomly allocated into 2 groups using table of randomization (n= 40 each) Group E- Epidural block, Group S- Spinal block. Various parameters like intraoperative mean arterial pressure, heart rate, postoperative pain intensity, analgesic requirement, postoperative complications and patient satisfaction were studied in these groups. STATISTICAL ANALYSIS: Quantitative data was analysed using unpaired t-test and qualitative data was analysed using chi-square test. RESULTS: Twenty four times in Epidural as compared to fifteen times in spinal anaesthesia two or more attempts required. Mean time (min) required to achieve the block of anaesthesia in group E and group S was 15.45+/-2.8 and 8.52+/-2.62 min respectively. Mean arterial pressure (MAP) at 5 min, 10 min and 15 min were significantly lower in spinal group as compared to epidural group. After 30 minutes, differences were not significant but still MAP was lower in spinal group. After 30 minutes difference in heart rate between two groups was statistically significant and higher rate recorded in spinal group till the end of 3 hours. Postoperative VAS score was significantly higher in spinal group and 4 hours onwards difference was highly significant. Postoperative Nausea Vomiting (PONV) Score was significantly higher in spinal group as compared to epidural group. CONCLUSION: For PCNL, segmental epidural block is better than spinal anaesthesia in terms of haemodynamic stability, postoperative analgesia, patient satisfaction and reduced incidence of PONV. Epidural anaesthesia is difficult to execute and takes longer time to act as compared to spinal block which limits its use. PMID- 26436022 TI - A Pilot Study of Cerebral and Hemodynamic Changes During Sedation with Low Dose of Thiopental Sodium or Propofol in Patients with Acute Brain Injury. AB - BACKGROUND: One of the most important therapeutic maneuvers in head injury patients is to maintain Intracranial Pressure (ICP) and Cerebral Perfusion Pressure (CPP) within normal levels. AIMS: To compare the effects of low dose of thiopental sodium and propofol on reducing ICP and CPP in patients with head injury that scheduled for neurosurgical interventions. SETTINGS AND DESIGN: Using a randomized, crossover pilot study, we enrolled patients with head injury that scheduled for neurosurgical interventions admitted to ICU unit of a teaching hospital during 2010 to 2011. MATERIALS AND METHODS: In this pilot study, patients randomized into two equal groups. The first group received bolus injection of thiopental sodium 2 mg/kg and a maintenance dose of 2 mg/kg/h and the second group was given a bolus dose of propofol 0.5 mg/kg followed by propofol infusion 20 MUg/kg/min. All of patients were given dexamethasone 8 mg at time of catheter insertion. ICP measurement catheter was inserted for each patient and ICP, CPP, SPO2 and MAP were recorded hourly for a period of 6 hours. RESULTS: There was no significant difference in sex and age between the two study groups (p>0.05). The mean ICP, CPP, SPO2 and arterial blood pressure were found to be similar with no significant difference between both groups (p>0.05). CONCLUSION: Both propofol and thiopental sodium were equally effective in monitoring and maintaining CPP and MAP and eventually an ideal SPO2. PMID- 26436023 TI - Naphthalene Poisoning following Ingestion of Mothballs: A Case Report. AB - Naphthalene is a widely used industrial and household chemical in the form of mothballs. But it has rarely been an agent of poisoning worldwide. We describe a case of ingestional naphthalene poisoning with a good outcome after proper management. A 29-year-old girl ingested 8 mothballs, and presented two days later with haemolysis and methaemoglobinaemia. She was given intravenous methylene blue, N-acetylcysteine and ascorbic acid, besides supportive treatment. Renal replacement therapy in the form of SLED of 8 hours was done on a daily basis. She was discharged after ten days on twice a week outpatient follow-up haemodialysis. PMID- 26436024 TI - TIVA-A Promising Approach to Anaesthetic Management of Montgomery T-tube Insertion. AB - One of the treatment modalities for tracheal stenosis is tracheal dilatation and stenting using silicone Montgomery T-tube. Various techniques have been reported for this procedure. For safe anaesthetic management, anaesthesiologist must be aware of the surgical procedure, limitations of T-tube, likelihood of compromised airway besides the inherent problems of sharing the airway with surgeons. Total intravenous anaesthesia (TIVA) is a technique which has become very popular and possible now a days for various surgical procedures owing to its advantages. The anaesthetic technique should be based on the provider's experience and severity of tracheal stenosis. We present here the anaesthetic management using TIVA technique with propofol and atracurium for the insertion of Montgomery T-tube in a case of post intubation tracheal stenosis. PMID- 26436025 TI - Is 'Pure' Dhat Syndrome a Stable Diagnostic Entity? A Naturalistic Long Term Follow Up Study from a Tertiary Care Centre. AB - BACKGROUND: Very little is known about the long term diagnostic stability of Dhat (semen loss) syndrome owing to a dearth of follow up studies on this condition. AIM: The aim of the study was to assess the diagnostic stability and naturalistic long term outcomes in a group of pure Dhat syndrome cases. MATERIALS AND METHODS: The study was carried out in the outpatient psychiatry department of a tertiary care hospital in South India, using a retrospective cohort design. Forty one cases of 'pure' Dhat syndrome (with no other concurrent diagnosis) were selected by a chart review of patients attending the outpatient Psychiatry department. Out of this initial cohort, follow up interviews were held for 36 patients. Direct clinical interviews were held with all participants to assess change in diagnosis. Those who no longer qualified for Dhat syndrome were interviewed with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) to generate other diagnoses. For analysis, the patients were divided into two groups - those who positively endorsed symptoms of Dhat syndrome at follow up (DSP group) and those who no longer did (DSN group). These groups were compared using chi-square test for categorical variables and student t-test for continuous variables to look for significant differences. Frequencies and percentages were used to depict socio-demographic data and the follow up diagnoses. STATISTICAL ANALYSIS: Data was analysed using SPSS for Windows, Version 16.0 (Chicago, SPSS Inc.). RESULTS: The mean duration of follow up was 6+/-3.5 years. Nearly two thirds of the sample no longer fulfilled criteria for Dhat syndrome in follow up. The most common revisional diagnosis in these patients was somatoform disorders. Age, marital status and literacy distinguished the two groups. About a quarter of the sample (26.07%) was in complete remission. CONCLUSION: Even the purest variety of Dhat syndrome is not a stable diagnosis in the majority of patients. The condition may be better conceptualized as a subtype of somatoform disorder with culturally determined explanation for somatic symptoms. Clinicians should look at explanations of semen loss as fluid cultural idioms of distress rather than as a standalone diagnostic entity. PMID- 26436026 TI - A 16-Year-old Boy with Combined Volatile and Alcohol Dependence: A Case Report. AB - Substance abuse has been defined as the use of chemical substances for non medical purposes in order to achieve alterations in psychological functioning. The substances commonly abused in India include nicotine, alcohol, cannabis and opioids. However, the use of solvents and propellants is also on the rise as these are inexpensive, legally available household, industrial, office and automobile products; which are more commonly available to children and adolescents. We hereby describe a 16-year-old boy with combined volatile and alcohol abuse; who presented with increasing ataxia, visual and hearing disturbances. PMID- 26436027 TI - A Hospital-based Study to Determine Causes of Diffuse Hair Loss in Women. AB - BACKGROUND: Diffuse hair loss is a common complaint encountered by dermatologists in their daily clinical practice. Hair loss in women is a distressing condition. Various underlying factors individually or in combination contribute to the pathogenesis. OBJECTIVES: To determine causes of diffuse hair loss in women and to find the association between probable causes and relevant laboratory parameters, wherever applicable. MATERIALS AND METHODS: One hundred and eighty women with diffuse hair loss were included in the study. Detailed history and clinical examination including hair pull test and hair microscopy were done in all study subjects. Specific laboratory investigations for determining iron deficiency anaemia, thyroid dysfunction and parasitic infestation were done. RESULTS: Among 180 patients, 116 (64.44%) had telogen effluvium, 28 (15.55%) had CTE, 21 (11.66%) had FPHL and 1 (0.55%) had AE. Fourteen patients (7.77%) had more than one aetiological diagnosis of diffuse hair loss. TE was the commonest type of diffuse hair loss. Incidence of TE and FPHL were highest in the age group of 21-30 years, whereas CTE in 30-40 years. Psychological stress and iron deficiency anaemia were the most common underlying aetiological factors for TE, which is statistically significant (p<0.05). Out of 130 patients with TE, more than one aetiological factor was recorded in 10 cases whereas in 32 cases probable aetiological factors could not be elicited from history. Most cases of CTE were idiopathic. No significant relationship was observed between CTE, haemoglobin level and serum ferritin level. Out of 35 patients with FPHL, low haemoglobin level was observed in 6/20 (30%) and low serum ferritin level in 14/17 (82.35%). CONCLUSION: Diffuse hair loss is a multifactorial condition. A detailed history, thorough clinical examination and appropriate investigations help to identify the causative factors and treat them accordingly. PMID- 26436028 TI - Pattern of Cancers Treated with Radiotherapy in Uduth Sokoto: A New Center Experience. AB - BACKGROUND: Cancer is a leading public health problem worldwide. In many developing countries, cancer tends to present in predominantly advanced stages, to a certain extent due to lack of comprehensive screening and poor access to efficient management. This study was carried out to describe the pattern of cancers managed in the Department of Radiotherapy and Oncology in Usmanu Danfodiyo University Teaching Hospital Sokoto, North-western Nigeria. MATERIALS AND METHODS: This was a cross-sectional descriptive study involving patients with malignancies that attended the new Oncology Department of the Usman Danfodiyo University Teaching Hospital Sokoto, North-West Nigeria for the period of one year (June 2013 - May 2014). The data was analyzed using SPSS (versions 20). RESULT: A total of 210 patients with complete records met the criteria for the study. Majority 162 (77.1%) were females with a mean age of 45.68+/-12.4 years. The male patients were 48 (22.9%) with mean age 46.27+/-16.5. The spectrum of malignant lesions observed were cancer of the cervix 77 (36.67%), breast cancer 74 (35.24%), nasopharyngeal cancer 20 (9.52%), cancer of the larynx 18 (8.57%) and rectal cancer 14 (6.67%). Late presentation was most common with 6 (3%), 101 (49.8%) and 58 (28.6%) patients presenting at stage I, III and IV, respectively. CONCLUSION: The study demonstrates that Cancer of the cervix is the leading malignancy in the study population. PMID- 26436029 TI - Oral Cancer Knowledge, Attitudes and Practices: A Survey of Undergraduate Medical Students in Himachal Pradesh, India. AB - BACKGROUND: Oral cancer is the sixth most common cancer among Indian males and the third most common cancer among Indian females. Early detection of oral cancers makes them more amenable to treatment and allows the greatest chance of cure. Lack of awareness among the health care providers is the most significant factor in delaying diagnosis and treatment of oral cancer. So the aim of the study was to assess the knowledge, attitude and practices of oral cancer among undergraduate medical students in Indira Gandhi Medical College, Shimla, India. MATERIALS AND METHODS: A cross-sectional questionnaire study was conducted among 186 undergraduate medical students between the third to fifth years in Indira Gandhi Medical College, Shimla. The questionnaire consisted of 15 questions, five each on knowledge, attitudes and practices. The data were analysed by Statistical Package for the Social Sciences version 16. Test used were t-test, Chi-square and ANOVA. RESULTS: The response rate of the study was 96.5%. The mean knowledge percent of the sample was good. Mean knowledge percent was higher in females than males. Higher percentage of students in 5(th) year (internship) had excellent knowledge. The knowledge and practices about risk factors was not satisfactory. One hundred and twenty four (66.6%) of the subjects disagreed/strongly disagreed that their knowledge regarding the prevention and detection of oral cancer is current adequate. One hundred and seventy six and (94.6%) agreed/strongly agreed that there is need for additional training/information regarding oral cancer. CONCLUSION: It can be concluded that though the mean knowledge of the population was good but the knowledge and practices about risk factors had to be reinforced among these students so that they can help the patients in tobacco and alcohol cessation and contribute in prevention of oral cancers. PMID- 26436030 TI - PNET of the Abdominal Wall: A Rare Presentation. AB - Primitive neuroectodermal tumours (PNETs) are a malignant group of neoplasms and are neuroectodermal in origin. In most large series published to date, peripheral primitive neuroectodermal tumours usually present in the second decade of life, with a slight male preponderance. Those which occurs peripherally resemble soft tissue sarcomas. Peripheral PNET is rare in presentation and of which only few cases involving the soft tissues of the abdominal wall have been reported. We present a case affecting a young female who presented to us with a progressively enlarging swelling involving the anterior abdominal wall. She underwent wide excision followed by adjuvant therapy based on final histopathology report. PMID- 26436031 TI - Dermatofibrosarcoma Protuberans of Lumbar Region with Metastasis to Lung: A Rare Presentation. AB - Dermatofibrosarcoma protuberans (DFSP) is a cutaneous slow growing soft tissue sarcoma associated with a high local recurrence rate. Common site of presentation is trunk followed by proximal extremity and head and neck region. A case of recurrent DFSP of left lumbar region with metastasis in lung in a 50-year-old woman presented here. Absence of symptoms often leads to a delay in diagnosis. DFSP is often mistaken for other skin conditions, particularly in its early stages. PMID- 26436032 TI - Radiotherapy-Induced Vitiligo in a Patient with Carcinoma Buccal Mucosa: A Case Report. AB - Vitiligo significantly affects self-esteem and deteriorates the quality of life of affected persons. Radiotherapy has several early and late effects but it is not known to induce vitiligo. This is a case report of a patient suffering from carcinoma buccal mucosa that had developed vitiligo in the radiotherapy portal. To the best of my knowledge this is a one of the first case reports of its kind as this patient had no history of vitiligo but developed it soon after radiotherapy. Since radiotherapy is an essential component of cancer management, the radiation oncologist must be aware of this toxicity of radiotherapy. Choosing the high energy of photon beam may reduce the risk of such toxicities. PMID- 26436033 TI - Ectopic Male Breast Cancer: A Case Report. AB - Carcinoma of male breast constitutes 1% of total breast malignancy. Carcinoma arising from ectopic breast tissue in male is an extremely rare entity and can be misdiagnosed. Ectopic breast tissue may be supernumerary or aberrant one. Despite morphologic difference, ectopic breast tissue presents characteristics analogous to orthoptic breast in terms of functional and pathologic degeneration. Most of the ectopic breast tissue occurs in thoracic or abdominal portion of milk line. If found in a location outside the milk line, it proves a diagnostic dilemma. We are reporting a case of 60-year-old male who presented with a fixed mass of size 10cm*8cm, in right chest wall infraclavicular area of 6 months duration. Histopathology of the mass revealed invasive duct carcinoma. He had no evidence of malignant or occult primary lesion in the bilateral mammary glands. Due to the paucity of the literature, incidence of ectopic male breast cancer and its management is not well understood. There is high probability of misdiagnosis of this disease. To the best of our knowledge this is the first described case of ectopic male breast cancer in the chest wall, not along the milk line, which is being reported here for documentation. PMID- 26436034 TI - Changes in Capacity and Performance in Mobility Across Different Environmental Settings in Children with Cerebral Palsy: An Exploratory Study. AB - BACKGROUND: Children with cerebral palsy, although having similar diagnosis, varies in their abilities & level of functioning within & across different environmental context e.g. home, school or community setting. Capacity (what a child can do in standardized, controlled environment) may or may not be the same as performance (what a child actually does do in her/her daily environment). MATERIALS AND METHODS: After getting approval from Institutional Ethic's Committee (IEC), 63 children with cerebral palsy (4-16 year, mean 7.4 year with SD 0.39) of all clinical types, Gross Motor Functional Classification System (GMFCS) level I-V were examined for mobility using Gross Motor Functional Measure 88 (GMFM). Motor capacity was assessed in clinical setting by highest of 3 GMFM items attained, i.e., crawling (44), walks with support (68) & walks without support (70). Motor performance was measured by Functional Mobility Scale version 2. RESULT: On analysis of motor capacity 42.85% children were walking without support, 15.87% were able to crawl & 26.98% were able walk with support in clinical setting. Spearman's Correlation was done between GMFM item 70 with FMS 5 (home setting) to check correlation of capacity with performance & was found to be significantly correlated (r=0.586, p=0.04). All three GMFM items were correlated with FMS 5, 50, 500 & found positively correlated. For community setting (FMS 500), 52.38% children were lifted by parents & only 6.34% were using wheel chair mobility. A total of 21.87% patients were able to walk with or without support & still lifted by parents in school or community setting. CONCLUSION: Change in capacity and performance of mobility exists mainly in school and community setting in studied population. Context should be given importance to prioritize rehabilitation process. PMID- 26436035 TI - Validity of Moyers Mixed Dentition Analysis and a New Proposed Regression Equation as a Predictor of Width of Unerupted Canine and Premolars in Children. AB - INTRODUCTION: The Moyer's mixed dentition analysis forms an essential part of diagnostic procedures to determine adequacy of the space available for the erupting permanent teeth. However, its reliability among different racial groups has been questioned. OBJECTIVES: The objectives of this study were to test the reliability of Moyer's method and to produce new regression equation for Bangalore population for predicting the mesiodistal diameters of the unerupted permanent canines and premolars. MATERIALS AND METHODS: Data was collected from study models of 400 randomly selected Bangalore subjects aged 13 to 16 years with fully erupted, intact dentitions and no significant malocclusion. The mesiodistal widths of the incisors, canines and premolars of both arches were measured. This data was then utilized to predict the mesiodistal widths of canines and premolars and further compared with Moyer's table. CONCLUSION: It was found that 50% is more applicable to boys and 75% to girls. The canine premolar segment in both arches is statistically larger in men than in women (p<0.05). New regression equation was formulated, the accuracy of which needs to be evaluated further in a larger sample. PMID- 26436036 TI - Invitro Anti-mycotic Activity of Hydro Alcoholic Extracts of Some Indian Medicinal Plants against Fluconazole Resistant Candida albicans. AB - BACKGROUND: Candidiasis is one of the most common opportunistic infections caused by Candida albicans. Fluconazole is the drug of choice for prevention and management of this condition. However, the emergence of fluconazole resistant candidal strains has become a major concern. Many herbs like fenugreek, cinnamon, papaya, oregano, garlic are rich in phytochemical constituents known to express antimycotic activity. With the available information, the present research study was carried out to assess the invitro anti-mycotic activity of hydro alcoholic extracts of Trigonella foenum-graecum seeds, Cinnamomum verum bark and Carica papaya leaves and seeds against fluconazole resistant Candida albicans. MATERIALS AND METHODS: Hydro alcoholic extracts of Trigonella foenum-graecum (seeds), Cinnamomum verum (bark), Carica papaya CO.2 strain (male and female leaves) and Carica papaya CO.2 strain (seeds) were prepared by maceration. The anti-mycotic activity of the prepared extracts against Candida albicans was assessed by agar well diffusion method. Three independent experiments were performed in triplicates and the mean and standard deviation were calculated. Minimum inhibitory concentration was determined. RESULTS: The results of the present study revealed that all the extracts exhibited anti-mycotic activity in a dose dependent manner and minimum inhibitory concentration of all the extracts was found to be 15.62 MUg/ml. CONCLUSION: The results of the present study shed light on the fact that plant extracts could be used not only as an alternate drug for management of fluconazole resistant candidiasis but also explored further for oral cancer prevention as a therapeutic adjunct. PMID- 26436037 TI - A Comparative Evaluation of the Amount of Fluoride Release and Re-Release after Recharging from Aesthetic Restorative Materials: An in vitro Study. AB - AIM: To measure the amount of fluoride released and re released after recharging from various restorative materials: Conventional Glass Ionomer Cement (Fuji II), Light Cure Resin Modified GIC (Fuji II LC), Giomer (Beautifil II), Compomer (Dyract). MATERIALS AND METHODS: Fifteen cylindrical specimens were prepared from each material. The specimens were immersed in 20 ml of deionized water. The amount of released fluoride was measured during the 1(st) day, 7(th) day and on the day15 by using specific fluoride electrode and an ion-analyser. After 15 days each material was divided into three Sub Groups of five samples each. Sub Group A served as control, Sub Group B was exposed to 2% NaF solution, Sub Group C to 1000ppm F toothpaste. The amount of fluoride re-released was measured during the 1(st) day, 7(th) day and on the day15 by using specific fluoride electrode and an ion-analyser. The results were statistically analysed using analysis of variance (one-way ANOVA) and Tukey Kramer multiple comparison tests (p<=0.05). RESULTS: Independent of the observation time period of the study the Conventional GIC released the highest amount of fluoride followed by RMGIC, Giomer and Compomer. The initial burst effect was seen with GIC'S but not with Giomer and Compomer. After topical fluoride application fluoride re release was highest in Sub Group B and GIC had a greater recharging ability followed by RMGIC, Giomer and Compomer. The fluoride re release was greatest on 1(st) day followed by rapid return to near exposure levels. CONCLUSION: From the study it was concluded that, the initial Fluoride release was highest from Conventional GIC followed by Resin Modified GIC, Giomer and Compomer. The Fluoride re release was high when recharging with professional regime (2% NaF) as compared to home regime (Toothpaste). Conventional GIC had a greater recharging ability followed by Resin Modified GIC, Giomer and Compomer. PMID- 26436038 TI - Comparative Evaluation of Three Different Obturating Techniques Lateral Compaction, Thermafil and Calamus for Filling Area and Voids Using Cone Beam Computed Tomography: An Invitro study. AB - INTRODUCTION: The success of root canal treatment depends upon the proper sealing of root canal system. Improper apical seal leads to the microleakage which can be prevented by proper obturation technique. AIM: To compare the quality of three different root canal obturation techniques: lateral compaction, Thermafil and Calamus by using cone beam computed tomography. MATERIALS AND METHODS: A total of 30 central incisors were selected. Biomechanical preparation was done by Reciproc file no 25. Teeth were divided into 3 groups of 10 teeth each according to the obturation technique i.e. Calamus, Thermafil and lateral compaction. Cone beam computed tomography was used to measure filling area and voids at coronal, middle and apical third of the root canal after obturation by different techniques. Data was statistically analysed by One-Way Anova and multiple comparison of Tukey HSD tests. RESULT: The maximum amount of obturating material was observed in Calamus group followed by Thermafil and lateral compaction. Minimum voids were seen in obturation by Calamus technique. CONCLUSION: Within the limitations of this study, it can be concluded that Calamus may be a good obturation technique. PMID- 26436039 TI - The Effect of Various Finish Line Configurations on the Marginal Seal and Occlusal Discrepancy of Cast Full Crowns After Cementation - An In-vitro Study. AB - BACKGROUND: The marginal fit of crowns is of clinical importance. It is found that marginal and occlusal discrepancies are commonly increased following cementation. The resistance of cementing materials is a factor that prevents cast restorations from being correctly seated. Different finish lines behave differently in facilitating the escape of the cement. When the escape path of the cement decreases, the crown fails to seat further. MATERIALS AND METHODS: This study was planned with an aim to evaluate the effect of various finish lines on the marginal seal and occlusal seat of full crown preparations. Six stainless steel metal dies were machined to simulate molar crown preparations. The diameter was 10 mm and height was 6mm. The occlusal surface was kept flat and a small circular dimple was machined for reorientation of the wax pattern and metal copings, margins of various designs were machined accurately. The margins prepared were Group A- 90(0)C shoulder, Group B- Rounded shoulder, Group C- 45 degree sloped shoulder, Group D- Chamfer, Group E- Long chamfer, Group F- Feather edge. Full cast metal crowns of base metal alloy were fabricated over the metal dies. Zinc phosphate luting cement was used for the cementation. After twenty four hours, the cemented crown and die assembly were embedded in clear acrylic resin so as to hold the assembly together while sectioning. Twenty four hours later, all the samples were sectioned sagitally. The sectioned halves were focused under a stereomicroscope and the cement spaces were measured to the nearest micron. The cement thickness was measured at two points on the occlusal surface and one at each margin. RESULTS: Significant differences were observed in the occlusal seat and marginal seal of all the finish line configurations. The rounded shoulder had the best occlusal seat, followed by 90(0)C shoulder. The occlusal seat and marginal seal afforded by the shoulder finish lines were similar whereas there was a vast difference in the seating and sealing of long chamfer and feather edged preparations. They showed the worst occlusal seat. CONCLUSION: It was found that the finish lines like shoulder preparations which exhibit poor sealing prior to complete cementation allow good seating whereas margins which seal earlier do not allow escape of cement and hence do not seat completely. PMID- 26436040 TI - A Noble, Easy and Conceptual Radiographic Analysis to Assess the Type of Tooth Movement (Molar Distalization). AB - CONTEXT AND AIM: Bodily tooth movement is desirable in the field of Orthodontics and so is with molar distalization. Till date there is no such analysis available which could gauge and quantify the molar distalization and the type of tooth movement achieved, therefore one was required. MATERIALS AND METHODS: An OPG and Lateral cephalogram was used taking Inter orbitale plane and FH plane respectively as reference lines and the analysis was devised to measure the amount and type of tooth movement achieved in distalization of molar. CONCLUSION: This analysis is a noble, easy and conceptual analysis to assess the type of tooth movement achieved during molar distalization and other molar movements using Lateral cephalogram and orthopantomogram. PMID- 26436041 TI - Effectiveness of CoQ10 Oral Supplements as an Adjunct to Scaling and Root Planing in Improving Periodontal Health. AB - INTRODUCTION: Deficiency of CoQ 10 was found in human inflamed gingiva and has been found to be responsible for periodontal destruction. AIM: To evaluate the effectiveness of CoQ 10 supplementation as an adjunct to scaling and rootplaning in reducing gingival inflammation and periodontal pocket depth. MATERIALS AND METHODS: The study was a randomized, double-blind, controlled, parallel group design clinical trial. Thirty subjects with plaque induced gingival inflammation and having atleast three nonadjacent interproximal sites with a probing pocket depth >= 5mm were included in the study. The subjects were randomly divided into two groups. The test group (n=15) in which patients were given oral CoQ10 supplements after scaling and root planing and the control group (n=15) in which patients were given an oral placebo after scaling and rootplaning. The plaque index, gingival index and probing depth were recorded at baseline, 1 month and 3 months. Statistical analysis done by using Student's paired t-test for intragroup comparison and unpaired t-test for inter-group comparison. RESULTS: Both the groups showed marked reduction of afore mentioned periodontal parameters at one month and three months when compared to baseline. Though there was no significant difference in plaque index and probing pocket depth between the two groups at any given time period, test group showed significant difference in gingival inflammation at one month and three months when compared to control group. CONCLUSION: In the present study use of Coenzyme Q10 oral supplements as an adjunct to scaling and root planing showed significant reduction in gingival inflammation when compared to scaling and rootplaning alone. PMID- 26436042 TI - Management of Chronic Periodontitis Using Subgingival Irrigation of Ozonized Water: A Clinical and Microbiological Study. AB - INTRODUCTION: Adjunctive use of professional subgingival irrigation with scaling and root planing (SRP) has been found to be beneficial in eradicating the residual microorganisms in the pocket. OBJECTIVE: To evaluate the effect of ozonized water subgingival irrigation on microbiologic parameters and clinical parameters namely Gingival index, probing pocket depth, and clinical attachment level. MATERIALS AND METHODS: Thirty chronic periodontitis patients with probing pocket depth >=6mm on at least one tooth on contra lateral sides of opposite arches were included in the study. The test sites were subjected to ozonized water subgingival irrigation with subgingival irrigation device fitted with a modified subgingival tip. Control sites were subjected to scaling and root planing only. The following clinical parameters were recorded initially and after 4 weeks at the test sites and control sites. Plaque Index, Gingival Index, probing pocket depth, clinical attachment level. Microbiologic sampling was done for the test at the baseline, after scaling, immediately after ozonized water subgingival irrigation and after 4 weeks. In control sites microbiologic sampling was done at the baseline, after scaling and after 4 weeks. The following observations were made after 4 weeks. The results were statistically analysed using independent t-test and paired t-test. RESULT: Test sites showed a greater reduction in pocket depth and gain in clinical attachment compared to control sites. The total anaerobic counts were significantly reduced by ozonized water subgingival irrigation along with SRP compared to SRP alone. CONCLUSION: Ozonized water subgingival irrigation can improve the clinical and microbiological parameters in patients with chronic periodontitis when used as an adjunct to scaling and root planing. PMID- 26436043 TI - Direct Immunofluorescence in Oral Lichen Planus. AB - INTRODUCTION: Oral lichen planus (OLP) is a common immune-mediated oral mucosal disease. Diagnosis of OLP depends mainly on both clinical and histopathological features. Direct immunofluorescence (DIF) is a useful investigation method to distinguish between similar lesions and to confirm diagnosis in cases of uncharacterized features. AIM: The purpose of this study was to evaluate the prevalence and pattern of DIF in a group of Thai patients with OLP. MATERIALS AND METHODS: Records of clinically and histologically diagnosed OLP patients attending the Oral Medicine Clinic, Faculty of Dentistry, Mahidol University, Bangkok, Thailand were consecutively reviewed for DIF results. The DIF patterns in these patients were analysed. RESULTS: There were 82 atrophic and/or erosive OLP patients with a mean age of 51.6 years. Male to female ratio was 1:5. Of these, 82.9% showed positive DIF. Buccal mucosa was superior to the gingiva and palate in terms of sensitivity for DIF. All specimens except one (98.5%) demonstrated deposition of fibrinogen at the basement membrane zone (BMZ) in a shaggy pattern. The most common DIF pattern was shaggy fibrinogen at BMZ with IgM deposition on the colloid bodies (CB) (35.3%) followed by shaggy fibrinogen along BMZ (27.9%). CONCLUSION: The prevalence of positive DIF in Thai OLP patients was 82.9%. The most common finding was shaggy fibrinogen at BMZ. The typical pattern was shaggy fibrinogen along BMZ with or without positive IgM at CB. DIF pattern could be evaluated for the diagnosis of OLP lacking clinical and/or histopathological characteristic features. PMID- 26436044 TI - Prevalence of Osteosclerosis Among Patients Visiting Dental Institute in Rural Area of Western India. AB - BACKGROUND: Idiopathic osteosclerosis (IO) is a benign lesion of unknown aetiology and is not attributed to any dysplastic, inflammatory, neoplasia, or systemic disorder. AIMS AND OBJECTIVES: To assess the prevalence and distribution of IO according to its location and to patients' age and gender, among rural population of western India. MATERIALS AND METHODS: Seven hundred and fifty patients were examined for the presence of IO in the jaw bone. After a thorough clinical examination, radiographic examination was done using OPG. Age specified by WHO were used 5, 12, 15, 35-44 and 65-74. The data collected was than tabulated and subjected to descriptive statistics and chi square test. RESULTS: Among the total study population 89 (11.8%) were found to be suffering from IO out of which 27 (7.2%) were males and 62 (16.53%) were females. The maximum number of IO cases cases was seen among the age group of 35-44 y, 33 (22.0%) and minimum in 5 y 9 (6%). CONCLUSION: IO is higher among the females as compared to males and mostly seen among the 3(rd) and 4(th) decade individuals. PMID- 26436045 TI - Knowledge and Awareness of Teledentistry among Dental Professionals - A Cross Sectional Study. AB - BACKGROUND: The use of technology in the form of smart phones and other electronic media in day to day life has become an integral part of life today. Technology today is seeing a paradigm shift towards better inter-professional communications which can help doctors, patients and the masses as a whole. Putting these technological advancements to good use evolves as a major milestone in medicine/ dentistry in the form of telemedicine/teledentistry. AIM: The present study was aimed at knowing the knowledge and awareness of teledentistry among dental professionals of a dental college in India. SETTINGS AND DESIGN: The study was conducted in a dental college in India and was circulated among dental professionals. MATERIALS AND METHODS: A questionnaire was prepared to assess the knowledge and awareness of teledentistry and was circulated among dental professionals in a dental college. The data thus collected was statistically analysed and results obtained. STATISTICAL ANALYSIS: The data collected was statistically analysed using SPSS software. RESULTS: A total of 406 persons responded to the questionnaire. In the present study it was found that the knowledge and awareness about teledentistry was very low among post graduates (7.23%) and interns (9.38%) when compared to I & II BDS while most of them agreed that teledentistry is a practice of dentistry through various media options with limited application in dentistry without a legal issue. CONCLUSION: In the present study, it was apparent that most of the respondents were lacking adequate knowledge and awareness on teledentistry. Hence, there is an immense need to create awareness among dental professionals on teledentistry as the future lies in technological advancement. Tele dentistry can mark the beginning of a new era in dentistry. This can be achieved by conducting CDE programs and awareness campaigns/programs which helps in various levels. PMID- 26436046 TI - Association Between Harmful Oral Habits and Sign and Symptoms of Temporomandibular Joint Disorders Among Adolescents. AB - CONTEXT: Temporomandibular disorder (TDM) is defined as a heterogenous group of psychophysiological disorders commonly characterised by orofacial pain, chewing dysfunction or both. Various Epidemiological studies had shown occurrence of TMD in all age groups including children. Also research had shown that non nutritional oral habits to be associated with TMD. AIM: Present study aimed to find whether harmful oral habits are associated with sign and symptoms of TMD among adolescents in Greater Noida. SETTING AND DESIGN: Schools in Gautam Buddha district and descriptive study. MATERIALS AND METHODS: Cross sectional study was carried out among 240 adolescents (10 - 19 years) studying in schools of Greater Noida. Study population were selected by random sampling to whom screening questionnaires recommended by American Academy of Orofacial Pain (AAOP) were distributed. Patient history and clinical examination was used to determine harmful oral habits. Data analysis was done in SPSS version 21 and Chi-square test was applied. RESULTS: Sixty one participants (25.4%) displayed no sign and symptoms of TMD, 34 (14.2%) responded affirmatively to atleast one item on the questionnaire and 108(46%) gave at least three affirmative responses. Headache, Neckpain and Toothache were most frequent reported sign and symptoms of TMD (46.2%). There was statistically significant association between gender and sign and symptoms of TMD on three items of the questionnaire (p < 0.05). Nail Biting (45.8%), Biting Lips/objects (37%) were most common habits among the study group. There was statistically significant association between Nail Biting (p = 0.001), Lip Biting/ object biting (p=0.001), Grinding of teeth (p = 0.01) and sign and symptoms of TMD. CONCLUSION: A statistically significant association was found between nail biting, lip/ object biting and grinding of teeth with signs and/or symptoms of TMD. Thus there is need for preventive dental treatment and community dental education so that young adults realize importance of early diagnosis and treatment of TMJ disorders. PMID- 26436047 TI - Awareness, Attitude and Barriers Towards Evidence Based Dental Practice Amongst Practicing Dentists of Bhopal City. AB - INTRODUCTION: Evidence based dental practice is said to be the recent best approach to provide treatments or interventions, methodically proven to be safe and sound, efficient and cost effective. So, for providing quality dental care, clinical expertise, research evidence and patient's preferences all should be given equal importance. AIM: To assess the awareness, attitude & barriers of evidence-based dental practice (EBDP) amongst dentists of Bhopal city. MATERIALS AND METHODS: The target population of this cross-sectional study involves dentists of Bhopal city. Two hundred fifty private dentists of Bhopal were selected using convenience sampling technique. Data was collected using a self administered questionnaire containing 15 questions for assessing Knowledge, attitude, practice & barriers in Evidence based practice. Chi-square, t-test & one-way ANOVA were applied for data analysis and p<0.05 was considered statistically significant. RESULTS: The study revealed that dental practitioners had low knowledge about evidence based dental practices but they showed positive attitude towards adopting it in their future practice. There exist certain barriers in practice of evidence based dentistry. CONCLUSION: Including evidence based dental practice teaching in dental curriculum may prove to be a significant step in effective and efficient dental care delivery to the patients. Barriers in evidence based practice needs to be identified & eliminated. PMID- 26436048 TI - The Evaluation of Head and Craniocervical Posture among Patients with and without Temporomandibular Joint Disorders- A Comparative Study. AB - INTRODUCTION: Temporomandibular disorders (TMD) are the most common non-dental cause of orofacial pain with a multifactorial aetiology. AIM: To evaluate the head and craniocervical posture between individuals with and without TMD and its sub types by photographic and radiographic method. MATERIALS AND METHODS: Thirty four TMD patients diagnosed according to Research Diagnostic Criteria for TMD's (RDC/TMD) and were divided into 2 groups: Group I (muscle disorder), Group II (disc displacement). Control group comprised of 34 age and sex matched subjects without TMD. Lateral view photographs were taken and the head posture angle was measured. Craniocervical posture was assessed on lateral skull radiograph with two angles (Craniocervical Angle, Cervical Curvature Angle) and two distances (Suboccipital Space, Atlas-Axis Distance). To compare the results, t-test was used with significance level of 0.05. RESULTS: Head posture showed no statistical significant difference (p > 0.05) between Group I, II and control group in both photographic and radiographic methods. The cervical curvature angle showed significant difference (p = 0.045) in Group I only. Atlas-Axis Distance was statistically significant in Group II (p = 0.001). CONCLUSION: The present study confirmed that there is a negative association of head posture and TMD whereas, cervical lordosis was present in Group I only. PMID- 26436049 TI - Use of Curcumin Mouthrinse in Radio-Chemotherapy Induced Oral Mucositis Patients: A Pilot Study. AB - INTRODUCTION: Oral Mucositis is a complex and distinct pathobiologic entity resulting in injuries in mucosa that is a common complication in cancer patients undergoing chemotherapy (CT) and radiation therapy (RT). Phytochemicals, such as Curcumin, turmeric extract, has attracted great attention for its therapeutic benefits in clinical oncology due to its chemopreventive, antitumoral, chemosensibilizing and radiosensibilizing activities against various types of cancers and the complications associated with their management. AIM: To evaluate the efficacy and safety of curcumin mouthwash in the management of Oral Mucositis in cancer patients undergoing radio-chemotherapy. MATERIALS AND METHODS: The research group consisted of 20 adult cancer patients undergoing radio chemotherapy at the Regional Oncology Centre, who were evaluated for signs and symptoms of oral mucositis and then randomly divided into two groups. Standard preventive oral care i.e. chlorhexidine mouthwash 0.2% was given to one group while the other group was provided with freshly prepared curcumin mouthwash; each to be used thrice daily. Oral mucositis was assessed at days 0, 10 and 20. The World Health Organization (WHO) scale, the Oral Mucositis Assessment Scale (OMAS), and a Numerical Rating Scale (NRS; patient reporting scale of 0-10) were used. Adverse events were tracked. STATISTICAL ANALYSIS: Descriptive statistics, Independent sample t-test and repeated measure ANOVA test were performed. RESULTS: Statistically significant difference was found in the NRS (p=0.000), Erythema (p=0.050), ulceration (p=0.000) and WHO scores (p=0.003) between the two groups. CONCLUSION: Curcumin was found to be better than chlorhexidine mouth wash in terms of rapid wound healing and better patient compliance in management of radio-chemotherapy induced oral mucositis. No oral or systemic complications were reported. PMID- 26436050 TI - Assessment of Tooth Wear Among Glass Factory Workers: WHO 2013 Oral Health Survey. AB - BACKGROUND: Glass factory workers are often exposed to the hazardous environment that leads to deleterious oral health and subsequently, general health. We planned to determine the effects of the particulates present in the milieu on the tooth wear among workers. AIM: To assess tooth wear among glass factory workers in Jaipur, Rajasthan, India. SETTINGS AND DESIGN: A descriptive cross-sectional survey was conducted among 936 glass workers in Jaipur, Rajasthan, India from January-June 2014. MATERIALS AND METHODS: A survey proforma was designed for tooth wear evaluation with the help of WHO Oral Health Assessment form 2013 (for adults). Information regarding oral health practices, adverse habits and dietary habits, demographic details was gathered and clinical parameters were recorded. STATISTICAL ANALYSIS: The Chi-square test, t-test, One-way Analysis of Variance and a Stepwise multiple linear regression analysis. RESULTS: The most prevalent form of erosion was enamel erosion (589, 62.93%) with few subjects of deeper dentinal erosion and the difference was statistically significant (p=0.001). Dental erosion was found to be higher among males compared to females. Years of experience and educational status were identified as best predictors for dental erosion. CONCLUSION: It was concluded that there was considerable evidence of dental erosion found among the factory workers. Due to ignorance on social, cultural and health aspects, professional approach with regular dental care services for detection of early symptoms and planning of preventive strategies is warranted. PMID- 26436051 TI - Use of Clinical UV Chamber to Disinfect Dental Impressions: A Comparative Study. AB - INTRODUCTION: Dental impressions are potential source of infection in a prosthodontic practice. Risk of transmission of infection through saliva, blood etc is considered as hazard for both dentist as well as dental auxiliary staff. A number of methods are currently employed for disinfecting the impressions which are technique sensitive and time consuming. This study focuses on disinfecting impression using dental UV chamber which is commonly employed for storing sterilized instruments. AIM: The aim of this invitro study was to evaluate the use of clinical UV chamber to disinfect various impression materials at different time intervals and its comparison with 2% glutaraldehyde using standard immersion technique. MATERIALS AND METHODS: Total sample size of 180 specimens was taken from three different impression materials. The impressions were made from 30 dentulous subjects. A total of ten impressions were made for each impression material i.e. alginate, addition silicone and polyether impression material. Six punch samples were taken from each impression. Out of 6 punch sample, one was kept as control, second was disinfected by immersing in freshly prepared 2% glutaraldehyde solution for 10 minutes and remaining four were exposed to UV rays for 3 minutes, 6 minutes, 10 minutes and 15 minutes using dental UV chamber. Amount of disinfection achieved was evaluated by counting the colonies over the culture plates with the help of digital colony. RESULTS: The results showed that the mean CFUs for alginate were found to be i.e. 11797.40 +/- 5989.73 (mean +/- SD). The mean CFUs for addition silicone impression material was found 7095.40 with a standard deviation of 4268.83 and the mean CFUs for polyether impression material was found to be 2168.92 +/- 1676 (mean +/- SD). CONCLUSION: For alginate and addition silicone impression material, disinfection was achieved on exposure to UV rays for a period of 10 minutes. However, for polyether impression material 3 minutes of exposure to UV rays was sufficient to cause complete disinfection. PMID- 26436052 TI - Morphological Study of Soft Palate by Using Computed Tomography-A Prospective Study. AB - BACKGROUND: Soft palate is an important part of oro-naso-pharyngeal apparatus. The morphometric assessment of soft palate is well-performed on computed tomography (CT). AIM: To evaluate the morphology of soft palate in healthy individuals by using Computed tomography. MATERIALS AND METHODS: The study was conducted on 300 healthy voluntary participants who were subjected to CT scan (sagittal view) of head and neck region. The measurements of antero-posterior and supero-inferior length of soft palate were performed by using Syngo CT 2009E software. STATISTICAL ANALYSIS: The statistical analysis was performed by using SPSS software version 16 and test applied were one-way ANOVA, independent t-test, chi-square and Karl Pearson's co-relation coefficient. RESULTS: The participant's age ranged from 18-80 years with mean of 39.51+/-14.64. The study had equal number of males (n=150) and females (n=150). Out of six shapes of soft palate, Butt type (38.7%) was the commonest. The morphology of soft palate in different age groups was statistically not significant (p>0.05). The total mean of antero posterior length (30.31+/-3.39 mm) of soft palate was more than supero-inferior length (10.72+/-1.71 mm). The mean of antero-posterior length in males (30.69+/ 3.42 mm) was more than females (29.92+/-3.32 mm); which was statistically significant (p<0.05). The mean of supero-inferior length in males (10.67+/-1.78 mm) was less than females (10.78+1.64 mm), which was statistically not significant (p>0.05). CONCLUSION: CT scan is an important diagnostic aid for studying the accurate morphology of soft palate. PMID- 26436053 TI - Evaluation of Hi-Tec Implant Restoration in Mandibular First Molar Region- A Prospective Clinical Study. AB - BACKGROUND AND AIMS: Missing teeth lead to loss of structural balance, inefficient function, poor aesthetics and psychological effects on human beings, which needs restoration for normal contour, function and aesthetics. Several natural or synthetic substitutes are being used for replacement of missing tooth since centuries. Implants are the latest modality of replacement. So, the study was aimed to assess clinical success rate of Hi-Tec implant; which is economical and new in market. Results of the study will help clinician for appropriate implant selection. MATERIALS AND METHODS: The study included 10 patients from 19 to 31 years and needed restoration of missing mandibular first molar. Restoration had done using Hi Tec Single-tooth implants with metal-ceramic single crown prosthesis after three months of osseointegration. The implants were evaluated clinically (bleeding on probing, probing depth, implant mobility- periotest) and radiographically (marginal bone loss and peri-implant radiolucency) for six years. The observers were blinded for the duration of the study to prevent bias. RESULTS: All the patients had uneventful post-surgical healing. No bleeding on probing, Implant mobility, peri-implant radiolucency with minimal marginal bone loss and constant probing depths were observed well within the normal range during follow-up periods. CONCLUSION: Two stage single-tooth Hi Tec implant restoration can be used as a successful treatment modality for replacing mandibular first molar in an economic way. However, these results were obtained after 6 years of follow up with a smaller sample size, so long term multi center studies with a larger sample size is recommended for the predictability of success rate conclusively. PMID- 26436054 TI - Electromyographic Evaluation of the Effect of Lined Dentures on Masticatory Muscle Activity in Edentulous Subjects. AB - AIM: The purpose of this study was to examine changes in relative electromyographic (EMG) activities of temporal and masseter muscles after relining the dentures with silicone and acrylic-resin based denture liners. MATERIALS AND METHODS: Conventional complete dentures were fabricated for 20 edentulous patients. One month after completing adjustments of the dentures, electromyography of the masseter and temporalis muscle during maximum intercuspation was recorded. The dentures were then relined with a silicone denture liner and after an adaptation period of one month, were again subjected for electromyographic evaluation. Further, the dentures were relined with acrylic denture liner and subjected to electromyographic evaluation. Data was analysed using Statistical Package for Social Sciences (SPSS) version 15.0. Intergroup comparisons were done using ANOVA followed by post-hoc assessments using Tukey HSD test. RESULTS: Mean amplitude and duration with conventional dentures was found to be significantly lower as compared to silicone lined and acrylic lined dentures for all the comparisons. Statistically, no significant difference between silicone lined and acrylic lined dentures was observed for any of the comparisons. CONCLUSION: Within the limitations of this experimental design, it was concluded that relining significantly increases electromyographic activity of the masseter and temporalis muscles. Thus, resulting in an improved biting force, chewing efficiency and masticatory performance. There were no significant differences between silicone and acrylic based denture liners for both electromyographic variables. PMID- 26436055 TI - Comparative Evaluation of Shear Bond Strength of Luting Cements to Different Core Buildup Materials in Lactic Acid Buffer Solution. AB - AIM AND OBJECTIVES: The core buildup material is used to restore badly broken down tooth to provide better retention for fixed restorations. The shear bond strength of a luting agent to core buildup is one of the crucial factors in the success of the cast restoration. The aim of this invitro study was to evaluate and compare the shear bond strength of luting cements with different core buildup materials in lactic acid buffer solution. MATERIALS AND METHODS: Two luting cements {Traditional Glass Ionomer luting cement (GIC) and Resin Modified Glass Ionomer luting cement (RMGIC)} and five core buildup materials {Silver Amalgam, Glass ionomer (GI), Glass Ionomer Silver Reinforced (GI Silver reinforced), Composite Resin and Resin Modified Glass Ionomer(RMGIC)} were selected for this study. Total 100 specimens were prepared with 20 specimens for each core buildup material using a stainless steel split metal die. Out of these 20 specimens, 10 specimens were bonded with each luting cement. All the bonded specimens were stored at 37(0)c in a 0.01M lactic acid buffer solution at a pH of 4 for 7days. Shear bond strength was determined using a Universal Testing Machine at a cross head speed of 0.5mm/min. The peak load at fracture was recorded and shear bond strength was calculated. The data was statistically analysed using Two-way ANOVA followed by HOLM-SIDAK method for pair wise comparison at significance level of p<0.05. RESULTS: Two-Way ANOVA showed significant differences in bond strength of the luting cements (p<0.05) and core materials (p<0.05) and the interactions (p<0.05). Pairwise comparison of luting cements by HOLM-SIDAK test, showed that the RMGIC luting cement had higher shear bond strength values than Traditional GIC luting cement for all the core buildup materials. RMGIC core material showed higher bond strength values followed by Composite resin, GI silver reinforced, GI and silver amalgam core materials for both the luting agents. CONCLUSION: Shear bond strength of RMGIC luting cement was significantly higher than traditional GIC luting cement for all core buildup materials except, for silver amalgam core buildup material. RMGIC core material showed highest shear bond strength values followed by Composite resin, GI Silver Reinforced, GI and Silver Amalgam core materials irrespective of luting cements. PMID- 26436056 TI - Comparison of Effect of C-Factor on Bond Strength to Human Dentin Using Different Composite Resin Materials. AB - BACKGROUND: The study was planned to assess the use of low shrinkage composites for restoring cavities with high configuration factor (C-factor) which are subjected to high stresses. AIM: The aim of the study was to evaluate the effect of C- factor on tensile bond strength to human dentin using methacrylate based nanohybrid and low shrinkage silorane composite. MATERIALS AND METHODS: In this study 40 non carious human molar teeth were selected and assigned into two main groups - cavity (Class I cavity with high C-factor) and flat group (flat surface with low C-factor). Two different composite materials- methacrylate based and silorane low shrinkage composite were used to restore the teeth. Dentin surface was treated, adhesive application was done and composite was applied as per manufacturer's instructions. Samples were stored in distilled water then subjected to tensile bond strength measurement using universal testing machine. RESULTS: Statistical analysis was done using Independent sample t-test. The mean bond strength in methacrylate based and silorane composite was significantly higher in flat preparation (Low C-factor) than cavity preparation. The mean bond strength in both cavity (High C-factor) and flat preparation(Low C-factor) was significantly higher in silorane than in conventional methacrylate based composite. CONCLUSION: The bond strength of composites to dentin is strongly influenced by C-factor and type of composite resin material used. PMID- 26436057 TI - Angiotensin II Levels in Gingival Tissues from Healthy Individuals, Patients with Nifedipine Induced Gingival Overgrowth and Non Responders on Nifedipine. AB - CONTEXT: The Renin Angiotensin system has been implicated in the pathogenesis of Drug Induced Gingival Overgrowth (DIGO), a fibrotic condition, caused by Phenytoin, Nifedipine and Cyclosporine. AIM: This study quantified Angiotensin II levels in gingival tissue samples obtained from healthy individuals, patients on Nifedipine manifesting/not manifesting drug induced gingival overgrowth. MATERIALS AND METHODS: Gingival tissue samples were obtained from healthy individuals (n=24), patients on nifidipine manifesting gingival overgrowth (n= 18) and patients on nifidipine not manifesting gingival overgrowth (n=8). Angiotensin II levels were estimated in the samples using a commercially available ELISA kit. RESULTS: Angiotensin II levels were significantly elevated in patients on Nifedipine manifesting gingival overgrowth compared to the other 2 groups (p<0.01). CONCLUSION: The results of the study give an insight into the role played by Angiotensin II in the pathogenesis of drug induced gingival overgrowth. PMID- 26436058 TI - Anaesthetic Efficacy of Topical Benzocaine Gel Combined with Hyaluronidase for Supplemental Intrapulpal Injection in Teeth with Irreversible Pulpitis- A Double Blinded Clinical Trial. AB - OBJECTIVE: Intrapulpal injection technique is one of the most commonly employed method to achieve profound pulpal anaesthesia during an endodontic procedure. To determine if the topical application of benzocaine gel along with hyaluronidase to the pulp chamber could reduce the pain felt with the intrapulpal injection technique. MATERIALS AND METHODS: Two hundred patients with chronic irreversible pulpitis undergoing endodontic treatment for mandibular first molars in which the primary anaesthetic technique failed were selected and randomly divided into 2 groups. In the control group intrapulpal injection was administered with backpressure. In the experimental group topical application of 20% benzocaine gel mixed with hyaluronidase was done over the exposed pulp following which intrapulpal injection was administered with backpressure. Pain assessment was done on a visual analogue scale. RESULTS: There was statistically significant difference (p<0.001) between the two groups. The mean value in the control group corresponded to the pain perception "strong", whereas that of the experimental group corresponded to the pain perception "weak". CONCLUSION: Topical application of 20% benzocaine gel mixed with hyaluronidase to the exposed pulp reduces the pain encountered with the intrapulpal injection. PMID- 26436059 TI - Dimensional Changes of Alginate Dental Impression Materials-An Invitro Study. AB - BACKGROUND: Dentists are always looking ahead for more dimensionally stable material for accurate and successful fabrication of prosthesis in this competitive world. Arrival of newer materials and increased material market puts dentists in dilemma for selection of material. AIM: The study evaluated the effect of variations in time of pour and temperature on dimensional stability of three brands of commercially available alginates. MATERIALS AND METHODS: Velplast, Marieflex & Zelgan alginate impression materials were evaluated by measuring dimensional accuracy of the master cast. A die was prepared and mounted on the apparatus for the ease of impression making. The prepared casts were categorized into five groups and made up of three brands of alginate impression material with variation in time of pour viz: immediate, 20&40 minutes interval and with varying temperature of 25(0)C, 30(0)C & 40(0)C. RESULTS: Impressions showed least distortion at varying degrees of temperature for 20 minutes, but the values obtained by storing of alginate impressions for 20 minutes at 30(0)C were found to be nearly accurate than the values obtained by storing of impression at 40(0)C. However, storing showed shrinkage of impressions. CONCLUSION: Marieflex showed better accuracy in comparison with other two materials. Maintenance of temperature and humidity play key role during storage & transport to prevent distortion. But the study suggests immediate pouring which will minimize the distortion. The manipulation instructions, temperature of mixing water, environment & water powder ratio also plays key role in minimizing the distortion. PMID- 26436060 TI - Pathologic Surface Changes in the Submental Flap Used for Intraoral Reconstruction: Report of Two Cases. AB - Soft tissue reconstruction is often necessary after pathologic resection of oral squamous cell carcinoma. Although morphologic changes are common after transfer of the flaps to the oral cavity, pathologic changes within the transferred flaps, used for intraoral reconstruction, are rare events. Despite the widespread use of submental flap for oral cavity reconstruction, there are no reports in this respect. In this article, pathologic changes in the surface epithelium of transferred submental flaps are demonstrated with the report of two cases. The occurrence of lichen planus in a submental flap that had been used for reconstruction of lateral tongue border is reported in one case and in another patient, squamous cell carcinoma arising in the transferred de-epithelialized submental flap, used for maxillary and buccal reconstruction, is shown. PMID- 26436061 TI - Conservative Management of Horizontal Root Fracture - A Case Series. AB - Root fracture has been defined as a fracture involving dentin, cementum, pulp and periodontal ligament. Depending on the level of the fracture line various treatment modalities may be employed by the clinician to promote healing. The following case reports highlight how changes in technique allow for conservative management of horizontal root fractures at different levels. This approach allows the patient to retain their natural dentition at an affordable cost and provide a viable alternative to the use of more invasive and expensive alternatives. These patients presented with complaints of pain and mobility in upper front tooth region following trauma. Diagnosis was confirmed on the basis of intra-oral periapical radiographs following which non-surgical root canal treatment was performed. PMID- 26436062 TI - Restoration of Long Standing Traumatized Teeth: A Case Report. AB - Children are uniquely susceptible to craniofacial trauma. Injuries to the teeth occur often as a result of falls and sport activities. The pulp often gets infected after dental trauma resulting in to numerous complications. The authors present a case report of successful restoration of traumatized teeth with open apex which were weakened due to long standing infection and internal resorption. Initially antibiotic combination of 3- mix was used to disinfect the root canals. One tooth is treated with conventional endodontic treatment and the other tooth with open apex and perforation is managed by MTA apexification followed by canal reinforcement using glass ionomer cement and fiber reinforced composite post. Core build up is done using light cure composite resin followed by aesthetic crowns. The patient also presented with the peg shaped lateral incisors, which were built to an aesthetic appearance using light cure composite resins. PMID- 26436063 TI - Idiopathic Juvenile Osteoporosis: A Case Report. AB - Idiopathic Juvenile Osteoporosis (IJO) is a very rare disease, self restrictive and shows marked, spontaneous improvement during adolescence. The major clinical features were pain with difficulty walking, growth retardation, oral and dental abnormalities with radiographically porous bone structure. A 13-year-old male referred to paediatric dentistry clinic for toothache. The observations made with extra-intraoral clinic examination that one revealed short and skinny stature, diffuse caries in deciduous teeth, abraded lower incisor, deep bite and dysmorphic appearance in permanent incisor. This report emphasizes the recognized features of IJO as well as describes facio-dental findings that could aid in the diagnosis and management of these patients. PMID- 26436064 TI - Surgical Approaches and Management of Panfacial Trauma: A Case Report. AB - Patients with multiple fractures involving upper third of the face, the mid-face and the lower third are generally referred to as Pan-facial fractures and managing these cases is extremely complicated. Proximity of the maxillofacial region to the important features or senses such as visual function (diplopia), olfaction, respiration (airway management), chewing or mastication (occlusion), deglutition and aesthetics; makes the scenario a little more complex for the surgeon operating in this particular region than the surgeon operating any other part of the body. Inability to directly visualize and reduce all the components of a pan facial injury along with inadequate stability of the fractured bones leads to persistent deformity. It is challenging to follow an established pattern for repairing the pan facial fractures. Each case with this type of fracture is unique and requires skill and expertise of the surgeon to restore the pre traumatic anatomy and facial aesthetics. Despite all the aggressive treatment, most of the patient's with pan facial trauma may have some residual deformity which may require another correction surgery later. This article briefs about the management and simple approaches used to reduce and fix a case of pan facial trauma in a 23-year-old male. PMID- 26436065 TI - Single Rooted Permanent Premolars and Molars - A Rare Clinical Presentation Confirmed using Cone Beam Computed Tomography. AB - The morphology of the root and root canal system plays a significant role in the treatment outcome of endodontic procedures. The necessity of clear and high contrast images for tissues like bone and teeth has made the usage of newer imaging techniques inevitable. This is a rare case report wherein, the permanent posterior dentition of both arches was single rooted. While sporadic cases of single rooted teeth have been reported, it is rare for all the premolars and molars to show such variation. This rare clinical observation has been enhanced by Cone Beam Computed Tomography (CBCT), which provides a clear image with added benefits of 3D (Three Dimensional) image reconstruction, low dosage and rapid scan time. PMID- 26436067 TI - Economical, Efficient, Simple Device for Controlled Annealing NiTi Archwire. AB - In fixed orthodontic treatment, for the cinch back purpose, there is need of annealing of distal end of NiTi arch wire. During this procedure the area or length to be annealed is difficult to control. This inappropriate heating leads to deleterious effect on property of the wire. To prevent this problem a simple economical and efficient device was prepared that prevents annealing of excessive length of wire and thus prevents the deterioration of wire required for appropriate action. PMID- 26436066 TI - Hyperactive Dental Lamina in a 24-Year-old Female - A Case Report and Review of Literature. AB - An extra tooth to the normal formula of teeth sequence in any region of dental arch is regarded as Supernumerary teeth (ST). The reasons are still not clearly known, one of them being dichotomy of tooth bud, but the more accepted reason is the hyperactivity theory. Supernumerary teeth are present more in permanent dentition than in primary dentition and can present as a single entity or multiple, unilaterally or bilaterally, impacted or erupted, in either or both the dental arches. This article discusses the supernumerary teeth in detail with a case discussion of a non-syndromic 24-year-old girl, with six ST (bicuspids) present in all the four quadrants. In the mandible, ST's showed a classical clustered flower like presentation. The interesting feature in the presented case was the sequential orthopantomographs taken at various ages of the patient that showed continuous development of STs in all four quadrants, thus pointing to the theory of hyperactive dental lamina or atavism. An electronic search was conceded in PubMed, Cochrane Library and google scholar databases, and articles dated between December 1932 and December 2012 were selected to review the occurrence patterns of supernumerary teeth in non-syndromic cases. PMID- 26436068 TI - Accidental Swallowing of Mandibular Partial Denture. PMID- 26436069 TI - Role of Fenugreek in the prevention of type 2 diabetes mellitus in prediabetes. AB - BACKGROUND: It is hypothesized that dietary supplementation with Fenugreek modulates glucose homeostasis and potentially prevents diabetes mellitus in people with prediabetes. The objective of present study is to determine whether Fenugreek can prevent the outcome of T2DM in non diabetic people with prediabetes. METHODS: A 3-year randomized, controlled, parallel study for efficacy of Fenugreek (n = 66) and matched controls (n = 74) was conducted in men and women aged 30-70 years with criteria of prediabetes. Fenugreek powder, 5 g twice a day before meals, was given to study subjects and progression of type 2 diabetes mellitus (T2DM) was monitored at baseline and every 3 months for the 3 year study. RESULTS: By the end of intervention period, cumulative incidence rate of diabetes reduced significantly in Fenugreek group when compared to controls. The Fenugreek group also saw a significant reduction in fasting plasma glucose (FPG), postprandial plasma glucose (PPPG) and low density lipoprotein cholesterol (LDLc) whereas serum insulin increased significantly. It was observed that controls had 4.2 times higher chance of developing diabetes compared to subjects in the Fenugreek group. The outcome of diabetes in Fenugreek group was positively associated with serum insulin and negatively associated with insulin resistance (HOMA IR). CONCLUSIONS: Dietary supplementation of 10 g Fenugreek/day in prediabetes subjects was associated with lower conversion to diabetes with no adverse effects and beneficial possibly due to its decreased insulin resistance. PMID- 26436070 TI - Heart and Lung Metastases From Endometrial Stromal Sarcoma in a Forty-Two-Year Old Woman. AB - INTRODUCTION: Low-grade endometrial stromal sarcoma (LG-ESS) is a malignant intrauterine tumor that rarely presents with distant metastasis. Simultaneous lung and cardiac metastases from LG-ESS is also an extremely rare event. CASE PRESENTATION: A 42-year-old woman presented with dyspnea and exercise intolerance. She had a history of hysterectomy and left salpingoophorectomy. She underwent second laparotomy as well as right oophorectomy after new finding of vaginal mass with histopathologic diagnosis of LG-ESS. Cardiac imaging techniques demonstrated tumoral process in the right atrium and ventricle, coronary sinus, and pulmonary outlet tract as well as multiple metastases in the lung fields. Successful complete surgical resection of the metastatic tumor in the right side of the heart and then radiotherapy were done. After 28 months, follow-up examination revealed no abnormality. CONCLUSIONS: We describe the first documented case of isolated intracardiac and lung metastases of a LG-ESS without concurrent abdominal or caval metastasis. PMID- 26436071 TI - Lower Doses of Bosentan in Combination With Sildenafil Might be Beneficial in Pulmonary Arterial Hypertension. AB - BACKGROUND: Endothelin-receptor-antagonist, bosentan, has been found to improve the functional capacity and cardiopulmonary hemodynamics in Pulmonary Arterial Hypertension (PAH). Clinical trials have shown the preferable dosage of 125 mg, twice daily, regarding both efficacy and safety. OBJECTIVES: The purpose of this study was to investigate the effects of lower doses of bosentan (62.5 mg, twice daily) in combination with sildenafil on exercise capacity and clinical events, in 41 patients with idiopathic pulmonary hypertension or chronic thromboembolic pulmonary hypertension (CTEPH). PATIENTS AND METHODS: We assigned 41 patients with PAH (non-reactive idiopathic or non-operable chronic thromboembolic) to receive 62.5 mg of bosentan twice daily as combination therapy and evaluated the New York heart association (NYHA) functional class, 6-minutes-walk-distance (6MWD), time to clinical worsening, echocardiographic indexes and clinical events, for an average of 18.5 +/- 9.5 months. RESULTS: No adverse drug reaction was observed during the follow-up. Clinical worsening occurred in six (14%) patients, at least one year after treatment, two of the cases failed to respond to 125 mg, twice daily and died. Eight (19%) remained in FC I_II, but didn't reach the goal of 380 meters for 6MWD. All other patients reached the treatment goals according to the latest European society of cardiology (ESC) guidelines. CONCLUSIONS: We observed acceptable results regarding both efficacy and safety with 62.5 mg of bosentan, twice daily in this group of patients. Further clinical trials investigating PAH with lower dosages of bosentan may be warranted. PMID- 26436072 TI - Arrhythmogenic Risk Assessment Following Four-Week Pretreatment With Nicotine and Black Tea in Rat. AB - BACKGROUND: There is the controversy concerning the main component of tobacco, which is responsible for its arrhythmogenesis. In addition, there is the lack of adequate information about the influence of combination of black tea and nicotine on heart rhythm. OBJECTIVES: This study aimed to examine whether pretreatment with black tea and nicotine could modulate the susceptibility to lethal ventricular arrhythmias. MATERIALS AND METHODS: Animals were randomized to control, black tea, nicotine, and black tea plus nicotine groups. Test groups were treated with black tea brewed (orally) and nicotine (2 mg/kg, subcutaneous), alone and in combination for four weeks. On day 29, aconitine was infused intravenously for induction of cardiac arrhythmia. RESULTS: In comparison with the control group, each of tea and nicotine significantly decreased the duration of the ventricular tachycardia (VT) plus ventricular fibrillation (VF) and the score of arrhythmia severity (P < 0.05 and P < 0.01, respectively,). The latency for the first VT event was significantly longer in the all test groups, but VF latency was significant only in tea and nicotine groups compared with control group (P < 0.05 and P < 0.01, respectively).Threshold dose of aconitine for inducing VT and VF increased in all test groups, but only VT showed a significant difference in comparison to the control group (P < 0.001). CONCLUSIONS: The findings suggest that sub-chronic consumption of nicotine or black tea alone with appropriate doses could potentially be antiarrhythmic and its combination regimen does not increase the risk of fatal ventricular arrhythmias during four-week consumption period in rats. PMID- 26436073 TI - Anesthetic Management in a Patient With Type A Aortic Dissection and Superior Vena Cava Syndrome. AB - INTRODUCTION: Induction of general anesthesia in patients with superior vena cava (SVC) syndrome may cause airway obstruction and cardiovascular collapse. CASE PRESENTATION: Herein, we introduced a patient with the diagnosis of dissecting aneurysm of the ascending aorta who was candidate for emergency surgery. He also had symptoms of SVC syndrome. To maintain airway patency during anesthetic management, we decided to perform femoro-femoral cardiopulmonary bypass followed by general anesthesia and tracheal intubation. CONCLUSIONS: Femoro-femoral bypass prior to initiation of sternotomy is a safe and easy method in patients with aortic dissection and SVC syndrome in whom earlier endotracheal intubation may not be feasible. PMID- 26436074 TI - Avoiding Heparinization of Arterial Line and Maintaining Acceptable Arterial Waveform After Cardiac Surgery: A Randomized Clinical Trial. AB - BACKGROUND: Invasive and continuous blood pressure (BP) monitoring is crucial after cardiac surgery. Accuracy of BP measurement mostly depends on patency of arterial catheter and acceptable waveform. Heparinized saline flush usually used for this purpose may be accompanied by potential heparin adverse effects. OBJECTIVES: The aim of this study was to compare heparinized and non-heparinized saline flush to maintain acceptable arterial waveform after cardiac surgery. MATERIALS AND METHODS: In a double blind randomized trial study, 100 patients undergoing elective cardiac surgery were randomized to using heparinized (n = 50) or non-heparinized (normal) saline flush (n = 50) to maintain patency of arterial catheter after operation. Indwelling arterial catheters were checked daily for acceptable arterial waveform for three days as primary outcome measures. RESULTS: Frequency of acceptable arterial waveform ranged from 66% to 80%, in first, second and third postoperative days. There were no statistically significant differences between heparinized and non-heparinized saline groups regarding acceptable arterial waveforms in all the three postoperative days (all P values > 0.05). CONCLUSIONS: Using non-heparinized normal saline is suitable to maintain acceptable arterial waveform for short-term (three days) after adult cardiac surgery considering potential adverse effects of heparin. PMID- 26436075 TI - Inferior Vena Cava and Hemodynamic Congestion. AB - BACKGROUND: Among the indices able to replace invasive central venous pressure (CVP) measurement for patients with acute decompensated heart failure (ADHF) the diameters of the inferior vena cava (IVC) and their respiratory fluctuations, so called IVC collapsibility index (IVCCI), measured by echocardiography, have recently gained ground as a quite reliable proxy of CVP. OBJECTIVES: The aims of our study were to compare three different ways of evaluating cardiac overload by using the IVC diameters and/or respiratory fluctuations and by calculating the inter-method agreement. PATIENTS AND METHODS: Medical records of patients hospitalized for right or bi-ventricular acute decompensated heart failure from January to December 2013 were retrospectively evaluated. The predictive significance of the IVC expiratory diameter and IVC collapsibility index (IVCCI) was analyzed using three different methods, namely a) the criteria for the indirect estimate of right atrial pressure by Rudski et al. (J Am Soc Echocardiogr. 2010); b) the categorization into three IVCCI classes by Stawicki et al. (J Am Coll Surg. 2009); and c) the subdivision based on the value of the maximum IVC diameter by Pellicori et al. (JACC Cardiovasc Imaging. 2013). RESULTS: Among forty-seven enrolled patients, those classified as affected by persistent congestion were 22 (46.8%) using Rudski's criteria, or 16 (34%) using Stawicki's criteria, or 13 (27.6%) using Pellicori's criteria. The inter-rater agreement was rather poor by comparing Rudski's criteria with those of Stawicki (Cohen's kappa = 0.369; 95% CI 0.197 to 0.54), as well as by comparing Rudski's criteria with those of Pellicori (Cohen's kappa = 0.299; 95% CI 0.135 to 0.462). Further, a substantially unsatisfactory concordance was also found for Stawicki's criteria compared to those of Pellicori (Cohen's kappa= 0.468; 95% CI 0.187 to 0.75). CONCLUSIONS: The abovementioned IVC ultrasonographic criteria for hemodynamic congestion appear clearly inconsistent. Alternatively, a sequential or simultaneous combination of clinical scores of congestion, IVC ultrasonographic indices, and circulating levels of natriuretic peptides could be warranted. PMID- 26436077 TI - The Schwartz-Jampel syndrome: Case report and review of literature. AB - Schwartz-Jampel syndrome (SJS), first described in the United States in 1962, is a hereditary disorder characterized by facial dysmorphism and muscle stiffness. We describe the first case of a Persian 9-year-old boy with SJS and review the literature. The child had a short neck, blepharophimosis, flattened face, hypertrichosis of the eyelids, prominent eyebrows, high arched palate, low set ears, micrognathia, short stature, and skeletal deformities. He had proximal muscle hypertrophy, distal muscle wasting and generalized hyporeflexia. Bone X ray revealed pseudofracture of humerus. Needle electromyography revealed continuous myotonic discharges at rest with no waxing and waning in all tested muscles. Based on clinical and electrodiagnostic findings, the diagnosis of SJS type 1B was made and procainamide was started which resulted in clinical improvement. The diagnosis of SJS should be suspected when a child presents with the triad of myotonia, facial dysmorphism and skeletal deformities. PMID- 26436076 TI - Distribution of cytokine gene single nucleotide polymorphisms among a multi ethnic Iranian population. AB - BACKGROUND: Cytokine gene single nucleotide polymorphisms (SNPs) are widely used to study susceptibility to complex diseases and as a tool for anthropological studies. MATERIALS AND METHODS: To investigate cytokine SNPs in an Iranian multi ethnic population, we have investigated 10 interleukin (IL) SNPs (IL-1beta (C 511T, T-31C), IL-2 (G-384T), IL-4 (C-590T), IL-6 (G-174C), IL-8 (T-251A), IL-10 (G-1082A, C-819T, C-592A) and tumor necrosis factor-alpha (TNF-alpha) (G-308A) in 415 Iranian subjects comprising of 6 different ethnicities. Allelic and genotypic frequencies as well as Hardy-Weinberg equilibrium (HWE) were calculated by PyPop software. Population genetic indices including observed heterozygosity (Ho), expected heterozygosity (He), fixation index (FIS), the effective number of alleles (N e) and polymorphism information content (PIC) were derived using Popgene 32 software. Multidimensional scaling (MDS) was constructed using Reynold's genetic distance obtained from the frequencies of cytokine gene polymorphism. RESULTS: Genotypic distributions were consistent with the HWE assumptions, except for 3 loci (IL-4-590, IL-8-251 and IL-10-819) in Fars and 4 loci (IL-4-590, IL-6-174, IL-10-1082 and TNF-alpha-308) in Turks. Pairwise assessment of allelic frequencies, detected differences at the IL-4-590 locus in Gilakis versus Kurds (P = 0.028) and Lurs (P = 0.022). Mazanis and Gilakis displayed the highest (Ho= 0.50 +/- 0.24) and lowest (Ho= 0.34 +/- 0.16) mean observed heterozygosity, respectively. CONCLUSIONS: MDS analysis of our study population, in comparison with others, revealed that Iranian ethnicities except Kurds and Mazanis were tightly located within a single cluster with closest genetic affinity to Europeans. PMID- 26436078 TI - Comparison of emotional and non-emotional word repetitions in patients with aphasia. AB - BACKGROUND: Aphasia is a language disorder caused by left hemisphere damage. For treatment of aphasia, in some of therapeutic approaches, the right hemisphere (RH) abilities, such as, emotional perception, is used for stimulation of the language process in the left hemisphere. The aim of this study is to investigate emotional word repetition in aphasia after a stroke, in Persian language patients. MATERIALS AND METHODS: Fifteen aphasic patients (eleven male and four female) between 45 and 65 (58/4 +/- 7/8) years of age, participated in this cross sectional study. A list of 20 emotional words and a list of 20 neutral words as stimuli were prepared and the patients were asked to repeat each word after five seconds; if a patient needed to repeat a word again, it was repeated for him/her again, and the total score for each subject was calculated. The paired t-test was used to test group mean differences and the significant level was 0.05. RESULTS: The mean and standard deviation for emotional word repetitions were 6.93 +/- 1.72 and for non-emotional word repetition was 7.10 +/- 2.23, and the P value = 0.892, thus, no significant difference between emotional and non-emotional word repetitions was noticed. The mean and standard deviation for the positive emotional word repetitions were 3.53 +/- 3.29 and for negative word repetitions were 3.40 +/- 3.56, (P = 0.751), with no significant difference between positive and negative emotional word repetitions. CONCLUSION: Despite the main hypothesis that the right hemisphere is involved in the processing of emotions, it can be stated that both hemispheres are involved in the processing of emotional words, albeit in a different and probably complementary manner. PMID- 26436079 TI - Preliminary study on patients located at the Kashani/Isfahan Hospital with multiple sclerosis between the years 2011 and 2013. AB - BACKGROUND: Multiple sclerosis (MS) is a multifactorial disease that could result from demyelination of the myelin sheath. The aim of this study is to investigate the demographic features and rank the immunomodulating drugs in patients with MS. MATERIALS AND METHODS: This study was conducted in the MS clinic of the Isfahan Kashani Hospital, from 22 May, 2011 to 18 March, 2013. The data analyses (n = 1067) were divided into two periods: (1) 2011/05/22 to 2012/03/18 denoted as P1 and (2) 2012/04/02 to 2013/03/18 denoted as P2. RESULTS: Most of drugs prescribed within the population studied were: Avonex, Betaferone, and Rebif. There was an increase in the number of female (n = 811) and male subjects (n = 256). During P1/P2 there was an increase from 460 to 607 in the total number of patients, respectively. The number of patients who attended the MS clinic once was 250 (P1) versus 430 (P2), and those more than four times was 71 (P1) versus 59 (P2) correspondingly. CONCLUSION: The number of females increased from 2011 to 2013. Because of dissimilar ingredients additive of different pharmaceutical companies, it could be suggested that pharmacotherapy strategies, especially in Iranian population of MS with first-line treatment using Avonex, Betaferone and Rebif, more spotlighted on inter- and intra-individual variability based on clinical pharmacokinetics parameters. PMID- 26436080 TI - Preliminary analysis of month of birth in Iranian/Isfahan patients with multiple sclerosis. AB - BACKGROUND: Previous publications reported that an individual's month of birth (MOB) might have an important correlation to that consequent risk of multiple sclerosis (MS). AIM: The aim of this preliminary study was to investigate the distribution of different MOBs inpatients with MS in Isfahan, Iran. MATERIALS AND METHODS: This investigation was conducted to the Isfahan Neurosciences Research Centre. 1283 patients with MS were studied. Clinical data were recorded in d-Base and analyzed using SPSS (version 18) for Windows. RESULTS: Of the total population studied there were 979 females and 304 males. The mean age of all the patients was 34.6 years (range 10-87 years). Within the total population, the MOBs in the 62% of patients were in the season's spring and summer, and in 38% of patients they were in the season's autumn and winter. As the MOB might be recognized to have a bearing on an individual's risk of contracting MS, the highest and lowest correlations seem to be linked with April, September, May (?), and November (?), respectively. CONCLUSIONS: The seasonal relationship between MOBs and MS risk might be pointed toward a potential function for vitamin D throughout pregnancy or the early life of the newborn. Further studies are needed to confirm these correlations. PMID- 26436081 TI - Effect of omega-3 supplementation on inflammatory parameters in patients on chronic ambulatory peritoneal dialysis. AB - BACKGROUND: End stage renal disease (ESRD) is a state of micro inflammation that attenuates patient's life span and quality of life. Inflammatory markers like interlukin 6 (IL-6) and C- reactive protein (CRP) can predict inflammatory state in ESRD patients. Dietary limitations are risk factors for omega-3 deficiency in these patients. Omega-3 supplementation is an attractive material that proposed in inflammation modulation. The aim of this study is evaluation of effect of omega-3 supplementation on IL-6 and CRP level in chronic ambulatory peritoneal dialysis (CAPD) patients. MATERIALS AND METHODS: This randomized controlled double-blind clinical trial is performed in 40 CAPD patients in two academic hospitals in Isfahan, Iran. One group received 1000 mg omega-3 capsule (each capsule contains 180 mg Eicosapentanoic and 120 mg Dosahexanoic acid) three times a day orally for 8 weeks (n = 20) and the other matched group by placebo (n = 20). Serum level of IL-6 and quantitative CRP (Q-CRP) were measured in beginning and the end of the study. Finally all data were analyzed by SPSS version 18. RESULTS: Mean age of patients was 53 years old in omega-3 group patients and 54 years old in placebo group. There were not any differences in CRP and IL-6 level in the beginning and the end of study between two groups (P: 0.81 and 0.10 for CRP and 0.26 and 0.23 for IL-6, respectively). CONCLUSION: Omega-3 supplementation did not effect on inflammatory markers (Q-CRP and IL-6) in CAPD patients after 8 weeks. PMID- 26436082 TI - The relationship between quality of life and coping strategies in polycystic ovary syndrome patients. AB - BACKGROUND: There are many factors that affect the quality of life, for example, stress and the coping strategies. Polycystic ovary syndrome is a common hormonal disorder leading to menstrual disorders, hirsutism, acne, obesity, infertility and abortion. In such cases, the patients suffer from a variety of stresses and face problems in their coping strategies with life's problems which can affect the quality of life and cause psychological distress and low the quality of life. The quality of life is a descriptive term which points to health and emotional, social and physical promotion of individuals as well as their ability to perform daily living tasks. The purpose of this study was to investigate the relationship between quality of life and coping strategies in patients with polycystic ovary syndrome. MATERIALS AND METHODS: To perform this study, randomly 200 women who had inclusion criteria and were referred to Ali Shariati Hospital in Isfahan were selected and responded DLQI questionnaire and Carver coping strategies and form of demographic characteristics. RESULTS: The mean score of quality of life in the patients was 4.14 +/- 5.57. It was shown that acne has no effective role on quality of life and coping strategies in contrast in hirsute and non-hirsute patients; there was a significant difference in quality of life P value < 0.001). Also there is a significant relationship between the quality of life and coping strategies (problem solving, cognitive, emotional and social support) (P < 0.05) and quality of life has the highest correlation with emotional strategies (r = 0.46). CONCLUSION: According to results of this study, patients with PCOS are at risk pcychologicla disorders that may be led to decrease of quality of life. Thus this patients need to support by oppositions strategies. Also not only physical treatment but also psychological surveillance especially social support must be done for them. PMID- 26436083 TI - Two unusual sites of cystic lymphangioma in a child: A report of imaging profile with surgical and histopathologic findings. AB - Cystic lymphangioma (CL) is a benign lymphatic malformation mostly seen in the head and neck of neonates and infants. Abdominal CL is an unusual entity which may present in omentum, mesentery, abdominal wall, or solid organs. The authors present an unusual case with two separate abdominal cystic lymphangiomas. PMID- 26436084 TI - Herpes zoster segmental paresis in an immunocompromised breast cancer woman. AB - Herpes zoster is an infectious disease with neurological complications caused by reactivation of varicella zoster virus in dorsal root ganglia of spinal cord which is also known as "Shingles." Suppression of immune system is the major predisposing factor for reactivation of latent virus. Disease is mainly characterized by rash, vesicles and pain along one or more dermatomes which are innervated from one or more spinal nerve roots. Complications may be present after a while despite of patient treatment. Motor involvement is included. Some previous studies showed segmental zoster paresis as a rare complication, a few weeks after first presentation, among immunocompetent individuals. We present post herpetic motor involvement of C5 and C6 in a 59-year-old woman who underwent chemotherapy and radiotherapy due to breast cancer, manifesting left upper limb weakness and paresis, 6 months after left partial mastectomy. Segmental paresis of zoster virus should be considered as a cause of motor impairment in an immunocompromised person suffering from shingles. PMID- 26436085 TI - Targeted Therapy in Hematological Malignancies: From Basic Research to Clinical Practice. PMID- 26436086 TI - Missense Mutations in Exons 18-24 of EGFR in Hepatocellular Carcinoma Tissues. AB - Epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase receptor, plays important roles in various cancers. In nonsmall cell lung cancer (NSCLC), EGFR mutations cluster around the ATP-binding pocket (exons 18-21) and some of these mutations activate the kinase and induce an increased sensitivity to EGFR-tyrosine kinase inhibitors. Nevertheless, data of EGFR mutations in HCC are limited. In this study, we investigated EGFR expression by immunohistochemistry and EGFR mutations (exons 18-24) by PCR cloning and sequencing. EGFR overexpression in HCC and matched nontumor tissues were detected in 13/40 (32.5%) and 10/35 (28.6%), respectively. Moreover, missense and silent mutations were detected in 13/33 (39.4%) and 11/33 (33.3%) of HCC tissues, respectively. The thirteen different missense mutations were p.L730P, p.V742I, p.K757E, p.I780T, p.N808S, p.R831C, p.V851A, p.V897A, p.S912P, p.P937L, p.T940A, p.M947V, and p.M947T. We also found already known SNP, p.Q787Q (CAG>CAA), in 13/33 (39.4%) of HCC tissues. However, no significant association was detected between EGFR mutations and EGFR overexpression, tissue, age, sex, tumor size, AFP, HBsAg, TP53, and Ki-67. Further investigation is warranted to validate the frequency and activity of these missense mutations, as well as their roles in HCC tumorigenesis and in EGFR-targeted therapy. PMID- 26436087 TI - Recent Advances in Genetic Technique of Microbial Report Cells and Their Applications in Cell Arrays. AB - Microbial cell arrays have attracted consistent attention for their ability to provide unique global data on target analytes at low cost, their capacity for readily detectable and robust cell growth in diverse environments, their high degree of convenience, and their capacity for multiplexing via incorporation of molecularly tailored reporter cells. To highlight recent progress in the field of microbial cell arrays, this review discusses research on genetic engineering of reporter cells, technologies for patterning live cells on solid surfaces, cellular immobilization in different polymers, and studies on their application in environmental monitoring, disease diagnostics, and other related fields. On the basis of these results, we discuss current challenges and future prospects for novel microbial cell arrays, which show promise for use as potent tools for unraveling complex biological processes. PMID- 26436089 TI - Comment on "Nontuberculous Mycobacteria Isolation from Clinical and Environmental Samples in Iran: Twenty Years of Surveillance". PMID- 26436088 TI - MicroRNA181a Is Overexpressed in T-Cell Leukemia/Lymphoma and Related to Chemoresistance. AB - MicroRNAs (miRs) play an important role in tumorogenesis and chemoresistance in lymphoid malignancies. Comparing with reactive hyperplasia, miR181a was overexpressed in 130 patients with T-cell leukemia/lymphoma, including acute T cell lymphoblastic leukemia (n = 32), T-cell lymphoblastic lymphoma (n = 16), peripheral T-cell lymphoma, not otherwise specified (n = 45), anaplastic large cell lymphoma (n = 15), and angioimmunoblastic T-cell lymphoma (n = 22). Irrespective to histological subtypes, miR181a overexpression was associated with increased AKT phosphorylation. In vitro, ectopic expression of miR181a in HEK 293T cells significantly enhanced cell proliferation, activated AKT, and conferred cell resistance to doxorubicin. Meanwhile, miR181a expression was upregulated in Jurkat cells, along with AKT activation, during exposure to chemotherapeutic agents regularly applied to T-cell leukemia/lymphoma treatment, such as doxorubicin, cyclophosphamide, cytarabine, and cisplatin. Isogenic doxorubicin-resistant Jurkat and H9 cells were subsequently developed, which also presented with miR181a overexpression and cross-resistance to cyclophosphamide and cisplatin. Meanwhile, specific inhibition of miR181a enhanced Jurkat and H9 cell sensitivity to chemotherapeutic agents, further indicating that miR181a was involved in acquired chemoresistance. Collectively, miR181a functioned as a biomarker of T-cell leukemia/lymphoma through modulation of AKT pathway. Related to tumor cell chemoresistance, miR181a could be a potential therapeutic target in treating T-cell malignancies. PMID- 26436090 TI - Efficacy of Biodentine as an Apical Plug in Nonvital Permanent Teeth with Open Apices: An In Vitro Study. AB - The aim of this study was to evaluate the apical microleakage of Biodentine and MTA orthograde apical plugs and to compare the effect of thickness of these biomaterials on their sealing ability. A total of eighty maxillary anterior teeth were used. The apices were removed by cutting with a diamond disc (Jota, Germany) 2 mm from the apical root end in an attempt to standardize the working length of all specimens to 15 +/- 1 mm. Both materials were placed in 1-4 mm thickness as apical plugs root canal. Root canal leakage was evaluated by the fluid filtration technique. One-way ANOVA was used in order to determine normality of dispersal distribution of parameters; thereafter, results were analyzed by Kolmogorov Smirnov test. Overall, between microleakage values of MTA and Biodentine regardless of apical plug thickness, no difference was observed. In terms of plug thickness, a statistically significant difference was observed between the subgroups of MTA and Biodentine (p < 0.05). The apical sealing ability of Biodentine was comparable to MTA at any apical plug thickness. PMID- 26436091 TI - Computational and Theoretical Analysis of Human Diseases Associated with Infectious Pathogens. PMID- 26436092 TI - Changes in B-Cell Counts and Percentages during Primary HIV Infection Associated with Disease Progression in HIV-Infected Men Who Have Sex with Men: A Preliminary Study. AB - Numerous anomalies in B-cell phenotypes and functions have been described in HIV infected individuals. However, the actual relationship between B cells and disease progression remains unclear. In this study, we investigated B-cell counts/percentages during a 12-month infection period in HIV-infected individuals that eventually developed into typical progressors (TPs) or rapid progressors (RPs). We found, after 12 months of infection, the baseline B-cell counts/percentages correlated positively with CD4(+) T-cell counts (P = 0.0006 and P = 0.026) and negatively with HIV viral set points (P = 0.014 and P = 0.002). Kaplan-Meier survival analysis showed that high baseline B-cell counts/percentages were associated with a slow CD4-cell decline. B-cell kinetics indicated the baseline B-cell counts/percentages could be factors distinguishing between TPs and RPs. The combination of the baseline B-cell counts and percentages was associated with rapid disease progression (a 80.7% predictive value as measured by the area under the curve). These results indicate that the baseline B-cell counts/percentages might be associated with HIV disease progression. PMID- 26436093 TI - Using PET/CT Bone Scan Dynamic Data to Evaluate Tibia Remodeling When a Taylor Spatial Frame Is Used: Short and Longer Term Differences. AB - Eighteen consecutive patients, treated with a Taylor Spatial Frame for complex tibia conditions, gave their informed consent to undergo Na(18)F(-) PET/CT bone scans. We present a Patlak-like analysis utilizing an approximated blood time activity curve eliminating the need for blood aliquots. Additionally, standardized uptake values (SUV) derived from dynamic acquisitions were compared to this Patlak-like approach. Spherical volumes of interest (VOIs) were drawn to include broken bone, other (normal) bone, and muscle. The SUV m (t) (m = max, mean) and a series of slopes were computed as (SUV m (t i ) - SUV m (t j ))/(t i t j ), for pairs of time values t i and t j . A Patlak-like analysis was performed for the same time values by computing ((VOI p (t i )/VOI e (t i ))-(VOI p (t j )/VOI e (t j )))/(t i - t j ), where p = broken bone, other bone, and muscle and e = expected activity in a VOI. Paired comparisons between Patlak-like and SUV m slopes showed good agreement by both linear regression and correlation coefficient analysis (r = 84%, r s = 78%-SUVmax, r = 92%, and r s = 91%-SUVmean), suggesting static scans could substitute for dynamic studies. Patlak-like slope differences of 0.1 min(-1) or greater between examinations and SUVmax differences of ~5 usually indicated good remodeling progress, while negative Patlak-like slope differences of -0.06 min(-1) usually indicated poor remodeling progress in this cohort. PMID- 26436094 TI - Efficacy Study of Broken Rice Maltodextrin in In Vitro Wound Healing Assay. AB - Maltodextrins that contain both simple sugars and polymers of saccharides have been widely used as ingredients in food products and pharmaceutical delivery systems. To date, no much work has been reported on the applications of maltodextrin from broken rice (RB) sources. Therefore, the objective of this work was to investigate the in vitro wound healing efficacy of RB maltodextrin at different conditions. Wounds treated with lower dextrose equivalent (DE) range (DE 10-14) of maltodextrins at a concentration of 10% obtained from RB were found to be able to heal the wounds significantly faster (p < 0.01) than maltodextrin with higher DE ranges (DE 15-19 and DE 20-24) and concentrations of 5% and 20%. The findings from both BrdU and MTT assay further confirmed its wound healing properties as the NIH 3T3 fibroblast wounded cells were able to proliferate without causing cytotoxic effect when wounded cell was treated with maltodextrin. All these findings indicated that the RB maltodextrin could perform better than the commercial maltodextrin at the same DE range. This study showed that RB maltodextrins had better functionality properties than other maltodextrin sources and played a beneficial role in wound healing application. PMID- 26436095 TI - Bioinformatics Methods and Biological Interpretation for Next-Generation Sequencing Data. PMID- 26436096 TI - The Effect of Covalently Immobilized FGF-2 on Biphasic Calcium Phosphate Bone Substitute on Enhanced Biological Compatibility and Activity. AB - The purpose of this research was to covalently graft fibroblast growth factor 2 (FGF-2) onto biphasic calcium phosphate (BCP) via a bifunctional cross-linker technique and to estimate the optimal dose of FGF-2 resulting in the best osteogenic differentiation of human mesenchymal stem cells (hMSCs). SEM observation revealed that the surface of the 100 ng FGF-2 coated BCP was completely covered with the nanoparticles expected to be from the silane coupling agent. XRD, FT-IR, and XPS analysis showed that silane treatment, bifunctional cross-linker coating, and FGF-2 covalent grafts were conducted successfully without deforming the crystalline structure of BCP. An MTT assay demonstrated that FGF-2 coated BCP had good biocompatibility, regardless of the concentration of FGF-2, after 24 or 48 h of incubation. An alkaline phosphatase (ALP) activity assay (14 days of incubation) and the ALP gene expression level of real-time PCR analysis (7 days of incubation) revealed that 50, 100, and 200 ng FGF-2 coated BCP induced the highest activities among all experimental groups and control group (P < 0.05). Thus, low concentrations of FGF-2 facilitated excellent osteogenesis and were effective at enhancing osteogenic potential. Also, the bifunctional cross-linker technique is expected to be a more feasible way to induce osteogenic differentiation while minimizing the risk of FGF-2 overdose. PMID- 26436097 TI - Surface Modifications and Their Effects on Titanium Dental Implants. AB - This review covers several basic methodologies of surface treatment and their effects on titanium (Ti) implants. The importance of each treatment and its effects will be discussed in detail in order to compare their effectiveness in promoting osseointegration. Published literature for the last 18 years was selected with the use of keywords like titanium dental implant, surface roughness, coating, and osseointegration. Significant surface roughness played an important role in providing effective surface for bone implant contact, cell proliferation, and removal torque, despite having good mechanical properties. Overall, published studies indicated that an acid etched surface-modified and a coating application on commercial pure titanium implant was most preferable in producing the good surface roughness. Thus, a combination of a good surface roughness and mechanical properties of titanium could lead to successful dental implants. PMID- 26436098 TI - Ultrastructural Morphology of Sperm from Human Globozoospermia. AB - Globozoospermia is a rare disorder characterized by the presence of sperm with round head, lacking acrosome. Coiling tail around the nucleus has been reported since early human studies, but no specific significance has conferred it. By contrast, studies on animal models suggest that coiling tail around the nucleus could represent a crucial step of defective spermatogenesis, resulting in round headed sperm. No observations, so far, support the transfer of this hypothesis to human globozoospermia. The purpose of this work was to compare ultrastructural morphology of human and mouse model globozoospermic sperm. Sperm have been investigated by using scanning and transmission electron microscopy. The images that we obtained show significant similarities to those described in GOPC knockout mice, an animal model of globozoospermia. By using this model as reference, we were able to identify the probable steps of the tail coiling process in human globozoospermia. Although we have no evidence that there is the same pathophysiology in man and knocked-out mouse, the similarities between these ultrastructural observations in human and those in the experimental model are very suggestive. This is the first demonstration of the existence of relevant morphological homologies between the tail coiling in animal model and human globozoospermia. PMID- 26436099 TI - Anodisation Increases Integration of Unloaded Titanium Implants in Sheep Mandible. AB - Spark discharge anodic oxidation forms porous TiO2 films on titanium implant surfaces. This increases surface roughness and concentration of calcium and phosphate ions and may enhance early osseointegration. To test this, forty 3.75 mm * 13 mm titanium implants (Megagen, Korea) were placed into healed mandibular postextraction ridges of 10 sheep. There were 10 implants per group: RBM surface (control), RBM + anodised, RBM + anodised + fluoride, and titanium alloy + anodised surface. Resonant frequency analysis (RFA) was measured in implant stability quotient (ISQ) at surgery and at sacrifice after 1-month unloaded healing. Mean bone-implant contact (% BIC) was measured in undemineralised ground sections for the best three consecutive threads. One of 40 implants showed evidence of failure. RFA differed between groups at surgery but not after 1 month. RFA values increased nonsignificantly for all implants after 1 month, except for controls. There was a marked difference in BIC after 1-month healing, with higher values for alloy implants, followed by anodised + fluoride and anodised implants. Anodisation increased early osseointegration of rough-surfaced implants by 50-80%. RFA testing lacked sufficient resolution to detect this improvement. Whether this gain in early bone-implant contact is clinically significant is the subject of future experiments. PMID- 26436102 TI - Utility and limitations of animal models for the functional validation of human sequence variants. PMID- 26436103 TI - Medical genetics and genomic medicine in Greece: achievements and challenges. PMID- 26436100 TI - In Vitro Selection of Cancer Cell-Specific Molecular Recognition Elements from Amino Acid Libraries. AB - Differential cell systematic evolution of ligands by exponential enrichment (SELEX) is an in vitro selection method for obtaining molecular recognition elements (MREs) that specifically bind to individual cell types with high affinity. MREs are selected from initial large libraries of different nucleic or amino acids. This review outlines the construction of peptide and antibody fragment libraries as well as their different host types. Common methods of selection are also reviewed. Additionally, examples of cancer cell MREs are discussed, as well as their potential applications. PMID- 26436101 TI - The Clinical Relevance of IL-17-Producing CD4+CD161+ Cell and Its Subpopulations in Primary Sjogren's Syndrome. AB - OBJECTIVE: Th17 cells have been demonstrated to play an important role in the onset and development of primary Sjogren's syndrome (pSS). In this study, we evaluated the expansion and clinical significance of circulating CD4+CD161+ T cell and its "effector" (CD4+CD25-CD161+ T cell) and "regulatory" (CD4+CD25+CD161+ T cell) subpopulations. METHODS: Fifty-eight pSS patients and 16 healthy controls (HCs) were recruited in our study. The cell populations and intracellular IL-17 expression were analyzed by flow cytometry. The disease activity was evaluated by the EULAR-SS Disease Activity Index (ESSDAI). Autoantibodies were measured by ELISA or indirect immunofluorescence assay. RESULTS: The CD161+ T cell fractions showed higher proportions of IL-17-producing cells. The frequencies of the overall CD4+CD161+ T cell population and its effector subset were positively correlated with disease activity parameters and more severe disease manifestations. A significant elevation of the CD4+CD25+CD161+ T cell subpopulation was observed in the peripheral blood of pSS patients compared to HCs and this subset showed decreased regulatory functions compared with the CD4+CD25+CD161- population. CONCLUSION: Circulating CD4+CD161+ T cell populations associated with pSS disease activity and severity. These cells might be involved in the development of pSS and could be potential therapeutic targets in the treatment of pSS. PMID- 26436104 TI - Familial adenomatous polyposis in an adolescent with coexisting schizophrenia: treatment strategies and implications. AB - Schizophrenia is associated with high mortality and morbidity. The etiology of schizophrenia remains unclear, studies implicate a multifactorial origin with genetic and environmental factors. The adenomatous polyposis coli (APC) gene has been associated with FAP (familial adenomatous polyposis), and studies have linked it to schizophrenia. However, there are few studies which examine the association between FAP and schizophrenia. Limited data exist regarding recommendations for genetic counseling of adolescents with comorbid psychiatric illness. A case of an adolescent with FAP who developed psychotic symptoms is presented. This case hopes to add to the literature about mental illness in those with FAP. A review of literature about the role of APC in schizophrenia as well as implications of genetic counseling on those who suffer with mental illness will be discussed. PMID- 26436105 TI - Validation of a semiconductor next-generation sequencing assay for the clinical genetic screening of CFTR. AB - Genetic testing for cystic fibrosis and CFTR-related disorders mostly relies on laborious molecular tools that use Sanger sequencing to scan for mutations in the CFTR gene. We have explored a more efficient genetic screening strategy based on next-generation sequencing (NGS) of the CFTR gene. We validated this approach in a cohort of 177 patients with previously known CFTR mutations and polymorphisms. Genomic DNA was amplified using the Ion AmpliSeqTM CFTR panel. The DNA libraries were pooled, barcoded, and sequenced using an Ion Torrent PGM sequencer. The combination of different robust bioinformatics tools allowed us to detect previously known pathogenic mutations and polymorphisms in the 177 samples, without detecting spurious pathogenic calls. In summary, the assay achieves a sensitivity of 94.45% (95% CI: 92% to 96.9%), with a specificity of detecting nonvariant sites from the CFTR reference sequence of 100% (95% CI: 100% to 100%), a positive predictive value of 100% (95% CI: 100% to 100%), and a negative predictive value of 99.99% (95% CI: 99.99% to 100%). In addition, we describe the observed allelic frequencies of 94 unique definitely and likely pathogenic, uncertain, and neutral CFTR variants, some of them not previously annotated in the public databases. Strikingly, a seven exon spanning deletion as well as several more technically challenging variants such as pathogenic poly-thymidine guanine and poly-thymidine (poly-TG-T) tracts were also detected. Targeted NGS is ready to substitute classical molecular methods to perform genetic testing on the CFTR gene. PMID- 26436106 TI - Novel recruitment strategy to enrich for LRRK2 mutation carriers. AB - The LRRK2 G2019S mutation is found at higher frequency among Parkinson disease (PD) patients of Ashkenazi Jewish (AJ) ancestry. This study was designed to test whether an internet-based approach could be an effective approach to screen and identify mutation carriers. Individuals with and without PD of AJ ancestry were recruited and consented through an internet-based study website. An algorithm was applied to a series of screening questions to identify individuals at increased risk to carry the LRRK2 G2019S mutation. About 1000 individuals completed the initial screening. Around 741 qualified for mutation testing and 650 were tested. Seventy-two individuals carried at least one LRRK2 G2019S mutation; 38 with PD (12.5%) and 34 without (10.1%). Among the AJ PD participants, each affected first degree relative increased the likelihood the individual was LRRK2+ [OR = 4.7; 95% confidence interval = (2.4-9.0)]. The same was not observed among the unaffected AJ subjects (P = 0.11). An internet-based approach successfully screened large numbers of individuals to identify those with risk factors increasing the likelihood that they carried a LRRK2 G2019S mutation. A similar approach could be implemented in other disorders to identify individuals for clinical trials, biomarker analyses and other types of research studies. PMID- 26436107 TI - Inherited CHST11/MIR3922 deletion is associated with a novel recessive syndrome presenting with skeletal malformation and malignant lymphoproliferative disease. AB - Glycosaminoglycans (GAGs) such as chondroitin are ubiquitous disaccharide carbohydrate chains that contribute to the formation and function of proteoglycans at the cell membrane and in the extracellular matrix. Although GAG modifying enzymes are required for diverse cellular functions, the role of these proteins in human development and disease is less well understood. Here, we describe two sisters out of seven siblings affected by congenital limb malformation and malignant lymphoproliferative disease. Using Whole-Genome Sequencing (WGS), we identified in the proband deletion of a 55 kb region within chromosome 12q23 that encompasses part of CHST11 (encoding chondroitin-4 sulfotransferase 1) and an embedded microRNA (MIR3922). The deletion was homozygous in the proband but not in each of three unaffected siblings. Genotyping data from the 1000 Genomes Project suggest that deletions inclusive of both CHST11 and MIR3922 are rare events. Given that CHST11 deficiency causes severe chondrodysplasia in mice that is similar to human limb malformation, these results underscore the importance of chondroitin modification in normal skeletal development. Our findings also potentially reveal an unexpected role for CHST11 and/or MIR3922 as tumor suppressors whose disruption may contribute to malignant lymphoproliferative disease. PMID- 26436108 TI - Limb body wall complex, amniotic band sequence, or new syndrome caused by mutation in IQ Motif containing K (IQCK)? AB - Limb body wall complex (LBWC) and amniotic band sequence (ABS) are multiple congenital anomaly conditions with craniofacial, limb, and ventral wall defects. LBWC and ABS are considered separate entities by some, and a continuum of severity of the same condition by others. The etiology of LBWC/ABS remains unknown and multiple hypotheses have been proposed. One individual with features of LBWC and his unaffected parents were whole exome sequenced and Sanger sequenced as confirmation of the mutation. Functional studies were conducted using morpholino knockdown studies followed by human mRNA rescue experiments. Using whole exome sequencing, a de novo heterozygous mutation was found in the gene IQCK: c.667C>G; p.Q223E and confirmed by Sanger sequencing in an individual with LBWC. Morpholino knockdown of iqck mRNA in the zebrafish showed ventral defects including failure of ventral fin to develop and cardiac edema. Human wild type IQCK mRNA rescued the zebrafish phenotype, whereas human p.Q223E IQCK mRNA did not, but worsened the phenotype of the morpholino knockdown zebrafish. This study supports a genetic etiology for LBWC/ABS, or potentially a new syndrome. PMID- 26436109 TI - Actionable clinical decisions based on comprehensive genomic evaluation in asymptomatic adults. AB - Whole-exome sequencing (WES) arises as a new approach in diagnosing individuals affected by multigenic and complex phenotypes. Herein, we aim to examine whether WES is useful in screening asymptomatic individuals for actionable interventions, which has not yet been established. Twenty-five healthy adults underwent WES, bioinformatics, and manual curation of their exomes. Six participants (24%) harbored significant, management-changing variants in cancer predisposition genes, American College of Medical Genetics, and genomics reportable cardiac diseases and pharmacogenomic biomarkers that have led to clinical recommendations and interventions. Furthermore, more than 80% of the participants (21) carried 1 3 genetic variants with an associated clinical guideline for an altered drug dosing or administration based on the FDA's table of pharmacogenomics. These results support WES potential not only to answer specific diagnostic questions presented by the relevant personal and/or family history but also to uncover clinically important genetic findings unrelated to the primary indication for sequencing. PMID- 26436110 TI - Regulatory variant in FZD6 gene contributes to nonsyndromic cleft lip and palate in an African-American family. AB - Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect affecting 135,000 newborns worldwide each year. While a multifactorial etiology has been suggested as the cause, despite decades of research, the genetic underpinnings of NSCLP remain largely unexplained. In our previous genome wide linkage study of a large NSCLP African-American family, we identified a candidate locus at 8q21.3-24.12 (LOD = 2.98). This region contained four genes, Frizzled-6 (FZD6), Matrilin-2 (MATN2), Odd-skipped related 2 (OSR2) and Solute Carrier Family 25, Member 32 (SLC25A32). FZD6 was located under the maximum linkage peak. In this study, we sequenced the coding and noncoding regions of these genes in two affected family members, and identified a rare variant in intron 1 of FZD6 (rs138557689; c.-153 + 432A>C). The variant C allele segregated with NSCLP in this family, through affected and unaffected individuals, and was found in one other NSCLP African-American family. Functional assays showed that this allele creates an allele-specific protein-binding site and decreases promoter activity. We also observed that loss and gain of fzd6 in zebrafish contributes to craniofacial anomalies. FZD6 regulates the WNT signaling pathway, which is involved in craniofacial development, including midfacial formation and upper labial fusion. We hypothesize, therefore, that alteration in FZD6 expression contributes to NSCLP in this family by perturbing the WNT signaling pathway. PMID- 26436111 TI - EGFR mutations cause a lethal syndrome of epithelial dysfunction with progeroid features. AB - The epidermal growth factor receptor (EGFR) is part of a large family of receptors required for communicating extracellular signals through internal tyrosine kinases. Epidermal growth factor (EGF) signaling is required for tissue development, whereas constitutive activation of this signaling pathway is associated with oncogenic transformation. We identified homozygous c.1283G>A (p.Gly428Asp) mutations in the extracellular domain of EGFR in two siblings. The children were born prematurely, had abnormalities in skin and hair, suffered multisystem organ failure, and died in the neonatal period from intestinal perforation. EGF failed to induce mutated receptor phosphorylation in patient derived fibroblasts and activation of downstream targets was suppressed. The heterologously expressed extracellular domain was impaired in stability and the binding of EGF. Cells from the affected patient undergo early senescence with accelerated expression of beta-galactosidase and shortened telomeres at all passages when compared to controls. A comparison of homozygous inherited regions from a separate report of a patient from the same ethnic background and EGFR genotype confirms the pathogenicity of EGFR mutations in congenital disease. PMID- 26436112 TI - Multigene panel analysis identified germline mutations of DNA repair genes in breast and ovarian cancer. AB - Approximately 5-10% of all breast and/or ovarian cancer cases are considered as inherited. BRCA1 and BRCA2 tumor suppressor genes account for a high penetrance of hereditary cases, but familial cases without mutations in these genes can also occur. Despite their low penetrance, other hereditary cancer-related genes are known to be associated with breast and ovarian cancer risk. However, the extent to which these genes prevail in breast and ovarian cancer remains to be elucidated. To estimate the frequency of mutations in these predisposition genes, we analyzed the germline mutations of 25 hereditary cancer-related genes in 155 patients using targeted next-generation sequencing. These subjects included 11 BRCA1/2 mutation-positive cases and 144 negative cases. Of these, three patients (1.9%) had pathogenic mutations in ATM, MRE11A, or MSH6, all of which have a central role in DNA repair and the mismatch repair pathway. The MSH6 splice-site mutation (IVS6+1G>T) was predicted to be pathogenic, as demonstrated by in vitro and immunohistochemical analyses. These results suggested deficiencies in cellular DNA repair functions result in the development of breast and ovarian cancer. PMID- 26436113 TI - Mutations in CDK5RAP2 cause Seckel syndrome. AB - Seckel syndrome is a heterogeneous, autosomal recessive disorder marked by prenatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic facial features. Here, we describe the novel homozygous splice-site mutations c.383+1G>C and c.4005-9A>G in CDK5RAP2 in two consanguineous families with Seckel syndrome. CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly. We establish CDK5RAP2 as a disease-causing gene for Seckel syndrome and show that loss of functional CDK5RAP2 leads to severe defects in mitosis and spindle organization, resulting in cells with abnormal nuclei and centrosomal pattern, which underlines the important role of centrosomal and mitotic proteins in the pathogenesis of the disease. Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations in CDK5RAP2 and CEP152. This finding points toward a potential additive genetic effect of mutations in CDK5RAP2 and CEP152. PMID- 26436114 TI - Communicating with School Staff About Sexual Identity, Health and Safety: An Exploratory Study of the Experiences and Preferences of Black and Latino Teen Young Men Who Have Sex with Men. AB - PURPOSE: This exploratory study examined the experiences of black and Latino teen young men who have sex with men (YMSM) and their preferences for communication with school staff about matters related to sexual orientation. METHODS: Participants for this study were recruited in three urban centers in the United States and by multiple community-based organizations serving black and Latino YMSM. Eligible youth were male, black and Latino, ages 13-19, enrolled in 90 days of school in the previous 18 months, and reported attraction to or sexual behavior with other males, or identified as gay or bisexual. Participants completed web-based questionnaires (n=415) and/or in-depth interviews (n=32). RESULTS: Questionnaire participants reported willingness to talk to at least one school staff member about: safety, dating and relationships, and feeling attracted to other guys (63.4%, 58.4%, and 55.9%, respectively). About one-third of the sample reported they would not talk with any school staff about these topics. Exploratory analyses revealed youth who experienced feeling unsafe at school and who had higher levels of trust in the information provided by school staff were more likely to be willing to talk with school staff about safety issues, dating, or same sex attraction (adjusted odds ratio [AOR]=2.80 and AOR=4.85, respectively). Interview participants reported being most willing to talk to staff who were able and willing to help them, who would keep discussions confidential, and who expressed genuine care. Preferences for confiding in school staff perceived to be lesbian, gay, bisexual, and transgender (LGBT) and having similar racial/ethnic background were also noted. CONCLUSION: Findings suggest school staff can serve as points of contact for reaching YMSM and professional development and interventions can be tailored to reach YMSM and connect them to services they need. Additional research is needed to understand how to increase YMSM comfort talking with school staff about sexual health or sexual identity concerns. PMID- 26436115 TI - Hepatitis B virus infection: An insight into infection outcomes and recent treatment options. AB - Hepatitis B virus (HBV) currently infects an estimated population of 2 billion individuals in the world, including 400 million people with chronic HBV infection. HBV virology, replication and the host's immune response to HBV infection contribute to different infection outcomes. Acute hepatitis HBV infection is self-limiting but it leaves a residual infection that can become active in an individual during immunosuppression. In chronic HBV infection, the virus persistently replicates in hepatocytes leading to immune mediated hepatocellular damage. Despite the inability to remove the virus in more than 70 % of patients, current treatments for chronic HBV infection, interferon alpha and antiviral nucleotide/nucleoside analogues, aim to reduce viral replication to prevent or at least delay the progression to cirrhosis and hepatocellular carcinoma. In both self resolved acute and persistent HBV infection, the long term existence of chromatinised covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes cannot be targeted by current treatments to eliminate these templates to eradicate the viral persistence. Identifying the mechanisms involve in the removal of infected hepatocytes will be useful as treatment options. In this context, DNA based novel therapeutic and immunization strategies might help to remove stable cccDNA and thus viral persistence. PMID- 26436116 TI - Gene expression profiling in gill tissues of White spot syndrome virus infected black tiger shrimp Penaeus monodon by DNA microarray. AB - White spot syndrome virus (WSSV) continues to be the most devastating viral pathogen infecting penaeid shrimp the world over. The genome of WSSV has been deciphered and characterized from three geographical isolates and significant progress has been made in developing various molecular diagnostic methods to detect the virus. However, the information on host immune gene response to WSSV pathogenesis is limited. Microarray analysis was carried out as an approach to analyse the gene expression in black tiger shrimp Penaeus monodon in response to WSSV infection. Gill tissues collected from the WSSV infected shrimp at 6, 24, 48 h and moribund stage were analysed for differential gene expression. Shrimp cDNAs of 40,059 unique sequences were considered for designing the microarray chip. The Cy3-labeled cRNA derived from healthy and WSSV-infected shrimp was subjected to hybridization with all the DNA spots in the microarray which revealed 8,633 and 11,147 as up- and down-regulated genes respectively at different time intervals post infection. The altered expression of these numerous genes represented diverse functions such as immune response, osmoregulation, apoptosis, nucleic acid binding, energy and metabolism, signal transduction, stress response and molting. The changes in gene expression profiles observed by microarray analysis provides molecular insights and framework of genes which are up- and down regulated at different time intervals during WSSV infection in shrimp. The microarray data was validated by Real Time analysis of four differentially expressed genes involved in apoptosis (translationally controlled tumor protein, inhibitor of apoptosis protein, ubiquitin conjugated enzyme E2 and caspase) for gene expression levels. The role of apoptosis related genes in WSSV infected shrimp is discussed herein. PMID- 26436117 TI - Evaluation of thermo-stability of bluetongue virus recombinant VP7 antigen in indirect ELISA. AB - This study shows the thermo-stability of lyophilized and purified recombinant VP7 bluetongue virus (BTV) protein in the presence of two sugar stabilizers (trehalose and mannitol) at different temperature. Truncated VP7 protein purified by nickel affinity column was lyophilized in the presence of trehalose and mannitol at 60 mM final concentration and then exposed to different temperature like 4, 25, 37 and 45 degrees C for various periods like 5 months, 7 weeks, 7 days and 48 h, respectively. After thermal treatment, the reactivity of the protein was evaluated in indirect ELISA. At 4 and 25 degrees C, the protein was stable up to 5 months and 7 weeks, respectively, irrespective of stabilizers used. At 37 degrees C, it was stable up to 3 days with both the stabilizers, after which it lost its stability and reactivity. At 45 degrees C, the protein was stable up to 30 and 24 h with trehalose and mannitol stabilizers, respectively. Both stabilizers found suitable for stability of the protein. However, trehalose appeared to have better stabilizing effect, particularly at higher temperatures than the mannitol. Trehalose could be used as stabilizer for freeze-drying the recombinant VP7 protein if an indirect ELISA kit based on the purified rVP7 protein is supplied to different laboratories of the country for detection of BTV antibody in sheep. PMID- 26436118 TI - In-silico structural analysis of the influenza A subtype H7N9 neuraminidase and molecular docking with different neuraminidase inhibitors. AB - Human infection with H7 influenza subtypes usually resulted in mild disease with a rare mortalities, however, human infection with the avian low pathogenic H7N9 influenza virus resulted in about 38.6 % human fatality. Due to the new cross species barrier of this virus subtype, there is an urgent need to better understand the susceptibility to commercially available antivirals and their relation to the structural changes of the viral neuraminidase. Neuraminidases derived from 2013 H7N9, H5N1 and H1N1 were subjected to a structural analysis of their catalytic and framework binding sites. The modeling structure of selected neuraminidases from H7N9 and influenza A subtypes were solved and the docking studies with oseltamivir, zanamivir, laninamivir and peramivir were conducted. The active site residues that are responsible for both binding and cleavage of the terminally linked sialic acid receptors were found conserved. Docking studies with oseltamivir, zanamivir, laninamivir and peramivir revealed that the laninamivir and peramivir showed superior energy binding activities in comparison to the commonly used oseltamivir and zanamivir. The results presented in the current study provide data that are useful for the future treatment of different influenza A subtypes including the recently emerged H7N9. PMID- 26436119 TI - First genome analysis and molecular characterization of Chickpea chlorotic dwarf virus Egyptian isolate infecting squash. AB - This study aims to identifying and characterizing some molecular properties of geminiviruses co-infection in squash field crop cultivated in Egypt. Squash crops observed to be heavily infected with several insect vectors, also severe chlorosis and stunting was observed. Electron microscopic analysis has revealed geminate capsid particles which indicate the infection of Geminiviruses, especially SqLCV which represent an economic problem to squash filed crop in Egypt. We have investigated possible mixed infections with different plant viruses associated with chlorotic stunt diseases and or other genus groups of geminiviruses. The main objective of this study is to investigate the recombination events, possible recombinants and variants among these genera in the same family differing in vector transmission. This is the first report of the molecular characterization, phylogenetic analysis and putative recombination events of the full length genome of the Chickpea Chlorotic Dwarf Mastrevirus in Egypt. And the first report of co-infection with another begomovirus infecting squash plants. A full length clone of both viruses were isolated and characterized at the molecular level. The complete nucleotide sequence of DNA-A was determined (2,572 bp) and submitted to the genbank under accession no. KF692356. The isolate from Egypt has about 97.8 % homology with the Chickpea chlorotic dwarf virus (CpCDV) isolate from Syria DNA-A isolate FR687959, a 83.2 % homology with the Sudan isolate AM933134 and a 82.7 % homology with Pakistan isolate FR687960. To best of our knowledge this is the first report of complete genome of CpCDV that infect squash plants in Egypt and worldwide. PMID- 26436120 TI - Isolation and molecular characterization of nephropathic infectious bronchitis virus isolates of Gujarat state, India. AB - Infectious bronchitis (IB) is a common, highly contagious, acute, and economically important viral disease of chickens caused by Infectious bronchitis virus (IBV, sp. Avian coronavirus). Five pooled tissue suspensions of 50 layer birds and one reference Massachusetts vaccine strain were inoculated into specific pathogen free (SPF) chicken egg for isolation of IBV. Reverse transcription polymerase chain reaction (RT-PCR) was carried out using post inoculated allontoic fluid to amplify the spike (S) glycoprotein of S1 subunit of IBV. All the eggs inoculated with five pooled tissue samples and vaccine sample showed dwarfing and curling of SPF embryos indicative of IBV. All the five samples and the vaccine sample produced the expected amplicons of 466 bp by RT PCR. The sequencing of five isolates revealed that all the five sequences were 99.09-100 % similar among themselves and showed 99.10-100 % nucleotide identity with the vaccine strain. On multiple sequence alignment it was found that our isolates were more similar at S1 subunit nucleotide level with the reference Ma5 and H120 vaccine strains than the reference Mass41 strain. The sequences of Anand isolates revealed further genetic changes in the circulating IBV in comparison to previous isolate of Gujarat as well as higher differences with the strains isolated in other states showing substantial changes at genetic level in Indian IBV isolates, which may partially explain the increasing incidences of IB in the country in spite of the vaccination. PMID- 26436121 TI - Heterozygosity at the SNP (rs136500299) of ITGB6 receptor gene possibly influences the susceptibility among crossbred bull to foot and mouth disease infection. AB - Zebu (Bos indicus) cattle are known to be resistant against foot and mouth disease virus (FMDV) compared to taurine (Bos taurus). To understand the susceptibility of two cattle species to FMDV infection in terms of viral receptors, the present study reports the cloning, characterization and sequence analysis of Zebu ITGB6 gene. The complete CDS of zebu ITGB6 was 2367 basepair in length with 788 amino acid residues. The zebu integrin shares common structural and functional elements with taurine and other species. We identified an amino substitution (S665 to F665) presents in ITGB6 gene among zebu and taurine as SNP (rs136500299). Further, we determined and compared the structural differences of ITGB6 receptor gene among zebu and taurine species. To elucidate the influence of the SNP on the susceptibility of cattle to FMDV infection, a tetra ARMS PCR based genetic screening was performed among Zebu and crossbred cattle. Our observation revealed that, the targeted SNP are strongly (P < 0.05) associated with FMD susceptibility among Frieswal (HF X Sahiwal) crossbred cattle. PMID- 26436122 TI - Transgenic tobacco plants expressing siRNA targeted against the Mungbean yellow mosaic virus transcriptional activator protein gene efficiently block the viral DNA accumulation. AB - Mungbean yellow mosaic virus (MYMV) is a bipartite begomovirus that infects many pulse crops such as blackgram, mungbean, mothbean, Frenchbean, and soybean. We tested the efficacy of the transgenically expressed intron-spliced hairpin RNA gene of the transcriptional activator protein (hpTrAP) in reducing MYMV DNA accumulation. Tobacco plants transformed with the MYMV hpTrAP gene accumulated 21 22 nt siRNA. Leaf discs of the transgenic plants, agroinoculated with the partial dimers of MYMV, displayed pronounced reduction in MYMV DNA accumulation. Thus, silencing of the TrAP gene, a suppressor of gene silencing, emerged as an effective strategy to control MYMV. PMID- 26436123 TI - Modulation of gene expression in CD4+ T lymphocytes following in vitro HIV infection: a comparison between human and chimpanzee. AB - Chimpanzees are susceptible to experimental infection by human deficiency virus (HIV)-1, but unlike humans, they exceptionally develop an immunodeficiency syndrome after HIV-1 inoculation. To explore the difference between human and chimpanzee, we analyzed the expression of 1547 genes of various functions in human or chimpanzee CD4+ lymphoblasts inoculated in vitro with HIV-1. We observed that, 1 day after HIV inoculation, fifty-eight genes were up-regulated in lymphoblasts of the three humans while their expression remained unchanged in lymphoblasts of the three chimpanzees. One gene is involved in adhesion of HIV (catenin-alpha), three in the immune response (semaphorin 4D, placental growth factor, IL-6), three in apoptosis (deleted in colorectal carcinoma, caspase 9 and FOXO1A). No difference between species was revealed for the expression of 373 genes related to glycosylation pathways. The in vitro human/chimpanzee comparison reveals new candidate genes up-regulated after inoculation with HIV-1 only in human lymphoblasts and which could be related to the higher sensitivity of human to HIV-induced AIDS. PMID- 26436124 TI - Characterization of cytopathogenicity of classical swine fever virus isolate induced by Newcastle disease virus. AB - Classical swine fever virus (CSFV), the causative agent of classical swine fever, belongs to the family Flaviviridae and genus Pestivirus. Some pestiviruses exhibit cytopathic effect in cell culture but exact phenomenon is unknown. Over expression of NS2-3 gene, presence of defective interfering particle and exaltation of Newcastle disease virus (END) phenomenon could be the reasons of cytopathogenicity. In the present study, a CSFV isolate exhibiting cytopathic effect (CPE) in Madin-Darby Canine Kidney (MDCK) cell line was characterized. To characterize cytopathogenicity of such isolate, END test was carried out. Interference of Newcastle disease virus (NDV) in MDCK adapted CSFV was confirmed by RT-PCR and virus neutralization test. Absence of CPE and NDV specific nucleic acid after neutralization confirmed the induction of CPE by NDV. Further, identity of the CSFV isolate in MDCK cell line by immunoperoxidase test, immunoblotting and RT-PCR post NDV neutralization established the virus replication without CPE (non-cytopathic isolate). Findings suggest that, there could be a chance of mixed infection of both CSFV and NDV in the piglet from which the sample was collected for virus isolation. PMID- 26436125 TI - Lower respiratory tract infections among HIV positive and control group in Nepal. AB - Lower respiratory tract infections (LRTIs) are the most frequent respiratory diseases among HIV infected patients and are frequently the first clinical manifestations of the HIV infections. LRTIs are common not only among the HIV seropositive cases but also the commonest domiciliary and nosocomial infections among the general population. The present study was carried out to determine the comparative prevalence of common bacterial and fungal organism among the HIV positive and control population. This cross sectional study was conducted among 220 people attending National Public Health Laboratory, Kathmandu, Nepal. Out of them 120 were HIV sero-positive and rest were HIV sero-negative. Sputum samples were collected and processed soon after its collection. Macroscopic examination was done to determine the sample integrity. Gram stain, AFB stain and KOH preparation was performed for preliminary identification of the pathogens. Culture was carried out for bacterial and fungal pathogens. Antibiotic susceptibility test (Kirby-Bauer disc diffusion method) was performed from the isolated organisms. The 85 out of 120 HIV sero-positive patients were found to be infected with one or more microbial pathogens. The overall infection rate was found to be significantly lower in HIV seronegative people (27 %). Among HIV seropositive cases prevalence of LRTIs was strongly associated with lower CD4 counts (<200/mm(3)). The prevalence of mycobacterium tuberculosis was found to be 10 % among HIV/AIDS patients which was significantly higher than among the non HIV cases (3 %). The bacterial pathogens was observed among 46.6 % of HIV positive and 22.0 % of HIV negative people. Among the positive cases, K. pneumoniae was the predominant bacterial pathogens, followed by E. coli and S. pneumoniae. C. albicans was found to be predominant fungal pathogen followed by Aspergillus spp. germ tube negative Candida spp. and Penicillium spp. Similar types of organisms were found to be associated with LRTIs among HIV positive and negative people. The prevalence of both fungal and bacterial infections was significantly higher among HIV seropositive people than HIV seronegative people. All in all, lower respiratory tract illness is significantly higher in HIV/AIDS cases than in HIV seronegative cases. PMID- 26436126 TI - Isolation and molecular characterization of Orf virus from natural outbreaks in goats of Assam. AB - Outbreaks of contagious ecthyma (caused by a Parapox virus) in goats were investigated in 6 districts of Assam, a north eastern state of India. Diagnosis of the disease was carried out employing both standard virological as well as molecular methods. Four representative isolates from different places were selected for phylogenetic analysis. The major envelop protein (B2L) of Orf virus was targeted for molecular analysis. The sequencing and phylogenetic analysis of the selected sequences at nucleotide level revealed that the Orf virus isolates were closely related to each other (97.6-100 %) and showed highest similarity to the Orf virus isolate 82/04 (98.4 %), reported from Shahjahanpur, India. The data will provide an insight in transmission of the virus from northern to North eastern part of the country. PMID- 26436127 TI - Safety of inoculation of bovine parainfluenza virus 3 as potential vaccine vector in pigs. AB - Bovine parainfluenza virus 3 (BPIV3) is one of the most important respiratory pathogens in cattle. One BPIV3, named NM09, was isolated from cattle suffering from severe respiratory diseases in 2009. BPIV3 is a potential recombinant vaccine vector. To investigate whether NM09 can infect pigs and determine BPIV3 defense in these animals, BPIV3 antibody-free pigs were inoculated intramuscularly with the BPIV3 NM09 strain in a continuous passage. Clinical signs were observed each day after inoculation. Viral nucleic acid was detected in nasal and anal secretions. Results showed that virus-inoculated pigs displayed few observable clinical signs related to respiratory diseases. The antibody was identified, but the virus could not be detected in the second continuous passage in pigs. Thus, BPIV3 is a potential vaccine vector for genetic engineering. PMID- 26436128 TI - Malus pumila 'Spy 227' and Apple stem pitting virus: graft incompatibility and epinasty. AB - Apple stem pitting foveavirus (ASPV) is one of the most important and widespread virus infecting apples in the world. Of late, the virus has been found to be invariably associated with most of the apple plantations of Shimla district of Himachal Pradesh based on DAS-ELISA results. Bioassay of viruses in vegetatively propagated crops including apple is considered to be an essential component in indexing programmes for the production of virus free propagating material. Woody indicator Malus pumila 'Spy 227' was used for the detection of ASPV through double grafting method. Graft incompatibility and epinasty symptoms were observed on Malus pumila Spy 227 indicator plants. Further, molecular identification of the virus isolate was done by cloning and sequencing of the test isolate. Partial sequence analysis of the coat protein gene showed 89 % nucleotide identity in BLASTN analysis with ASPV isolate from China (Accession No. JF895517). This is the first record of ASPV producing Graft incompatibility on Spy 227 indicator plants. PMID- 26436129 TI - Ionising radiation and risk of death from leukaemia and lymphoma in radiation monitored workers (INWORKS): an international cohort study. AB - BACKGROUND: There is much uncertainty about the risks of leukaemia and lymphoma after repeated or protracted low-dose radiation exposure typical of occupational, environmental, and diagnostic medical settings. We quantified associations between protracted low-dose radiation exposures and leukaemia, lymphoma, and multiple myeloma mortality among radiation-monitored adults employed in France, the UK, and the USA. METHODS: We assembled a cohort of 308,297 radiation monitored workers employed for at least 1 year by the Atomic Energy Commission, AREVA Nuclear Cycle, or the National Electricity Company in France, the Departments of Energy and Defence in the USA, and nuclear industry employers included in the National Registry for Radiation Workers in the UK. The cohort was followed up for a total of 8.22 million person-years. We ascertained deaths caused by leukaemia, lymphoma, and multiple myeloma. We used Poisson regression to quantify associations between estimated red bone marrow absorbed dose and leukaemia and lymphoma mortality. FINDINGS: Doses were accrued at very low rates (mean 1.1 mGy per year, SD 2.6). The excess relative risk of leukaemia mortality (excluding chronic lymphocytic leukaemia) was 2.96 per Gy (90% CI 1.17-5.21; lagged 2 years), most notably because of an association between radiation dose and mortality from chronic myeloid leukaemia (excess relative risk per Gy 10.45, 90% CI 4.48-19.65). INTERPRETATION: This study provides strong evidence of positive associations between protracted low-dose radiation exposure and leukaemia. FUNDING: Centers for Disease Control and Prevention, Ministry of Health, Labour and Welfare of Japan, Institut de Radioprotection et de Surete Nucleaire, AREVA, Electricite de France, National Institute for Occupational Safety and Health, US Department of Energy, US Department of Health and Human Services, University of North Carolina, Public Health England. PMID- 26436131 TI - Examining Racial/Ethnic Disparities in the Association between Adolescent Sleep and Alcohol or Marijuana Use. AB - OBJECTIVES: The current study examines the association between self-reported measures of trouble sleeping, total sleep time (TST), and bedtimes and odds of past month alcohol and marijuana (AM) use in a racially/ethnically diverse sample of adolescents. DESIGN: Web-based cross-sectional survey. SETTING: Los Angeles (LA) County, California. PARTICIPANTS: The sample is comprised of 2539 youth representing four distinct racial/ethnic categories (Non-Hispanic White, Hispanic, Asian, and "Other"; mean age= 15.54; 54.23% female) from Los Angeles. MEASUREMENTS: The survey assessed TST and bedtimes (weekdays and weekends), trouble sleeping, and past month AM use, as well as relevant covariates (sociodemographics and mental health symptoms). RESULTS: Although there were significant racial/ethnic differences in the prevalence of sleep problems and AM use, the associations between sleep problems and AM use were consistent across racial/ethnic groups. Specifically, shorter TST, later bedtimes, and trouble sleeping, were each associated with significantly higher odds of past month alcohol use, whereas later bedtimes and shorter TST were also associated with increased odds of past month marijuana use, even after adjusting for other known risk factors. CONCLUSIONS: Sleep problems are associated with increased AM use in teens, even after controlling for sociodemographics and mental health symptoms. Further longitudinal research on sleep and AM use is critical to identify novel prevention and intervention efforts to reduce disparities in the relationship between sleep and AM use. PMID- 26436130 TI - Ponatinib as first-line treatment for patients with chronic myeloid leukaemia in chronic phase: a phase 2 study. AB - BACKGROUND: Ponatinib has shown efficacy in patients with refractory chronic myeloid leukaemia (CML) and in those with CML with a Thr315Ile mutation. We aimed to investigate the activity and safety of ponatinib as first-line treatment for patients with chronic-phase CML. METHODS: We did a single-arm, phase 2 trial at MD Anderson Cancer Center in Houston, TX, USA. Between May 3, 2012, and Sept 24, 2013, we enrolled patients with early (<6 months) chronic-phase CML and treated them with oral ponatinib once a day. Patients enrolled before July 25, 2013, were given a starting dose of 45 mg per day; we lowered this due to tolerability issues and patients enrolled after this date were given a starting dose of 30 mg per day. After a warning by the US Food and Drug Administration (FDA) in Oct 6, 2013, for vascular complications with ponatinib, we started all patients on aspirin 81 mg daily and reduced the dose of ponatinib to 30 mg or 15 mg per day for all patients. The primary endpoint was the proportion of patients who achieved complete cytogenetic response by 6 months in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01570868. FINDINGS: We enrolled 51 patients. Median follow-up was 20.9 months (IQR 14.9 25.2). 43 patients were started on 45 mg ponatinib every day; eight patients were started on 30 mg per day. 43 (94%) of 46 evaluable patients achieved complete cytogenetic response at 6 months. Most frequent toxicities included skin-related effects (n=35; 69%) and elevated lipase (n=32; 63%). Cardiovascular events (mainly hypertension) occurred in 25 (49%) patients. Grade 3-4 myelosuppression occurred in 15 (29%) patients. Five (10%) patients developed cerebrovascular or vaso-occlusive disease. 43 (85%) patients needed treatment interruptions at some time and 45 (88%) needed dose reductions. The study was terminated June 18, 2014, at the recommendation of the FDA due to concern about the increased risk of thromboembolism with ponatinib. INTERPRETATION: Patients with newly diagnosed CML in chronic phase respond well to treatment with ponatinib, with most achieving a complete cytogenetic response. Dose adjustment, extensive monitoring, and counselling of the patients for thromboembolic events is needed for patients on ponatinib therapy. However, due to the risk of vascular thrombotic events and the availability of alternative options for these patients, other drugs should be considered first in the frontline setting. FUNDING: MD Anderson Cancer Center, National Cancer Institute, ARIAD Pharmaceutical. PMID- 26436132 TI - Novel Strategy to Improve the Performance of Localization in WSN. AB - A novel strategy of discrete energy consumption model for WSN based on quasi Monte Carlo and crude Monte Carlo method is developed. In our model the discrete hidden Markov process plays a major role in analyzing the node location in heterogeneous media. In this energy consumption model we use both static and dynamic sensor nodes to monitor the optimized energy of all sensor nodes in which every sensor state can be considered as the dynamic Bayesian network. By using this method the power is assigned in terms of dynamic manner to each sensor over discrete time steps to control the graphical structure of our network. The simulation and experiment result shows that our proposed methods are better in terms of localization accuracy and possess minimum computational time over existing localization method. PMID- 26436133 TI - NADPH Oxidases in Chronic Liver Diseases. AB - Oxidative stress is a common feature observed in a wide spectrum of chronic liver diseases including viral hepatitis, alcoholic, and nonalcoholic steatohepatitis. The nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are emerging as major sources of reactive oxygen species (ROS). Several major isoforms are expressed in the liver, including NOX1, NOX2, and NOX4. While the phagocytic NOX2 has been known to play an important role in Kupffer cell and neutrophil phagocytic activity and inflammation, the nonphagocytic NOX homologues are increasingly recognized as key enzymes in oxidative injury and wound healing. In this review, we will summarize the current advances in knowledge on the regulatory pathways of NOX activation, their cellular distribution, and their role in the modulation of redox signaling in liver diseases. PMID- 26436136 TI - Recruitment and Retention of Smokers Versus Nonsmokers in an rTMS Study. AB - Repetitive transcranial magnetic stimulation (rTMS) is a new frontier in the examination of addictive behaviors and perhaps the development of new interventions. This study examined differences in recruitment, eligibility, and retention among smokers and nonsmokers in an rTMS study. We modeled participant eligibility and study completion among eligible participants accounting for demographic differences between smokers and nonsmokers. Nonsmokers were more likely than smokers to remain eligible for the study after the in-person screen (84.2% versus 57.4%; OR 4.0 CI: 1.0, 15.4, p=0.05) and to complete the study (87.5% versus 59.3%; OR=43.9 CI: 2.8, 687.2, p=0.007). The preliminary findings suggest that careful screening for drugs of abuse and brain abnormalities among smokers prior to administering rTMS is warranted. More research is needed concerning the prevalence of brain abnormalities in smokers. Smokers might need to be informed about a higher risk of incidental MRI findings. PMID- 26436134 TI - Pediatric cancer gone viral. Part II: potential clinical application of oncolytic herpes simplex virus-1 in children. AB - Oncolytic engineered herpes simplex viruses (HSVs) possess many biologic and functional attributes that support their use in clinical trials in children with solid tumors. Tumor cells, in an effort to escape regulatory mechanisms that would impair their growth and progression, have removed many mechanisms that would have protected them from virus infection and eventual virus-mediated destruction. Viruses engineered to exploit this weakness, like mutant HSV, can be safely employed as tumor cell killers, since normal cells retain these antiviral strategies. Many preclinical studies and early phase trials in adults demonstrated that oncolytic HSV can be safely used and are highly effective in killing tumor cells that comprise pediatric malignancies, without generating the toxic side effects of nondiscriminatory chemotherapy or radiation therapy. A variety of engineered viruses have been developed and tested in numerous preclinical models of pediatric cancers and initial trials in patients are underway. In Part II of this review series, we examine the preclinical evidence to support the further advancement of oncolytic HSV in the pediatric population. We discuss clinical advances made to date in this emerging era of oncolytic virotherapy. PMID- 26436135 TI - Pediatric cancer gone viral. Part I: strategies for utilizing oncolytic herpes simplex virus-1 in children. AB - Progress for improving outcomes in pediatric patients with solid tumors remains slow. In addition, currently available therapies are fraught with numerous side effects, often causing significant life-long morbidity for long-term survivors. The use of viruses to kill tumor cells based on their increased vulnerability to infection is gaining traction, with several viruses moving through early and advanced phase clinical testing. The prospect of increased efficacy and decreased toxicity with these agents is thus attractive for pediatric cancer. In part I of this two-part review, we focus on strategies for utilizing oncolytic engineered herpes simplex virus (HSV) to target pediatric malignancies. We discuss mechanisms of action, routes of delivery, and the role of preexisting immunity on antitumor efficacy. Challenges to maximizing oncolytic HSV in children are examined, and we highlight how these may be overcome through various arming strategies. We review the preclinical and clinical evidence demonstrating safety of a variety of oncolytic HSVs. In Part II, we focus on the antitumor efficacy of oncolytic HSV in pediatric tumor types, pediatric clinical advances made to date, and future prospects for utilizing HSV in pediatric patients with solid tumors. PMID- 26436137 TI - Partial Saturation of Menaquinone in Mycobacterium tuberculosis: Function and Essentiality of a Novel Reductase, MenJ. AB - Menaquinone (MK) with partially saturated isoprenyl moieties is found in a wide range of eubacteria and Archaea. In many Gram-positive organisms, including mycobacteria, it is the double bond found in the beta-isoprene unit that is reduced. Mass spectral characterization of menaquinone from mycobacterial knockout strains and heterologous expression hosts demonstrates that Rv0561c (designated menJ) encodes an enzyme which reduces the beta-isoprene unit of menaquinone in Mycobacterium tuberculosis, forming the predominant form of menaquinone found in mycobacteria. MenJ is highly conserved in mycobacteria species but is not required for growth in culture. Disruption of menJ reduces mycobacterial electron transport efficiency by 3-fold, but mycobacteria are able to maintain ATP levels by increasing the levels of the total menaquinone in the membrane; however, MenJ is required for M. tuberculosis survival in host macrophages. Thus, MK with partially hydrogenated isoprenyl moieties represents a novel virulence factor and MenJ is a contextually essential enzyme and a potential drug target in pathogenic mycobacteria and other Gram-positive pathogens. PMID- 26436138 TI - Structure-Based Design of Dendritic Peptide Bolaamphiphiles for siRNA Delivery. AB - Development of safe and effective delivery vectors is a critical challenge for the application of RNA interference (RNAi)-based biotechnologies. In this study we show the rational design of a series of novel dendritic peptide bolaamphiphile vectors that demonstrate high efficiency for the delivery of small interfering RNA (siRNA) while exhibiting low cytotoxicity and hemolytic activity. Systematic investigation into structure-property relationships revealed an important correlation between molecular design, self-assembled nanostructure, and biological activity. The unique bolaamphiphile architecture proved a key factor for improved complex stability and transfection efficiency. The optimal vector contains a fluorocarbon core and exhibited enhanced delivery efficiency to a variety of cell lines and improved serum resistance when compared to hydrocarbon analogues and lipofectamine RNAiMAX. In addition to introducing a promising new vector system for siRNA delivery, the structure-property relationships and "fluorocarbon effect" revealed herein offer critical insight for further development of novel materials for nucleic acid delivery and other biomaterial applications. PMID- 26436139 TI - Assessing Systemic Stress in Otolaryngology: Methodology and Feasibility of Hair and Salivary Cortisol Testing. AB - OBJECTIVE: Elevated systemic stress is a predictor of adverse health outcomes, and stress can be objectively quantified by cortisol concentration. Despite its utility, such testing is rarely performed in otolaryngology. This manuscript provides details on the principles, methodology, and feasibility of performing laboratory assessments of hair and salivary cortisol to inform researchers wishing to incorporate these novel tests in future otolaryngologic studies. METHODS: Participants were older adults with hearing impairment. One hair sample and eight saliva samples were collected. Feasibility of study design was assessed through rates of participation in hair and saliva sampling and protocol adherence for saliva collection. Area under the curve (AUC) was used to evaluate overall secretion, and cortisol awakening response (CAR) was used to evaluate the dynamic secretion response. RESULTS: From 9/1/2013 to 12/31/2013, 26/30 (86.7%) eligible participants agreed to hair sampling. All 30 subjects agreed to collect saliva, with 29 (96.7%) adhering to the collection protocol. Mean AUC was 401.2 nmol/L per hour, and CAR was 4.5 nmol/L. CONCLUSIONS: Evaluating systemic stress in an otolaryngologic population using hair and saliva is feasible with acceptable participation and adherence. Repeat measurements over time will allow for evaluation of changes in systemic stress in relation to treatment. PMID- 26436140 TI - Entropy-scaling search of massive biological data. AB - Many data sets exhibit well-defined structure that can be exploited to design faster search tools, but it is not always clear when such acceleration is possible. Here we introduce a framework for similarity search based on characterizing a data set's entropy and fractal dimension. We prove that searching scales in time with metric entropy (number of covering hyperspheres), if the fractal dimension of the data set is low, and scales in space with the sum of metric entropy and information-theoretic entropy (randomness of the data). Using these ideas, we present accelerated versions of standard tools, with no loss in specificity and little loss in sensitivity, for use in three domains-high throughput drug screening (Ammolite, 150x speedup), metagenomics (MICA, 3.5x speedup of DIAMOND (3700x BLASTX)), and protein structure search (esFragBag, 10x speedup of FragBag). Our framework can be used to achieve 'compressive omics,' and the general theory can be readily applied to data science problems outside of biology. Source code: http://gems.csail.mit.edu. PMID- 26436141 TI - Brevetoxin Degradation and By-Product Formation via Natural Sunlight. AB - We investigated the effects of solar radiation on brevetoxin (PbTx2). Our findings suggest that natural sunlight mediates brevetoxin (PbTx2) degradation and results in brevetoxin by-product formation via photochemical processes. PMID- 26436142 TI - Competitive ELISA: An Accurate, Quick and Effective Tool to Monitor Brevetoxins in Environmental and Biological Sample. AB - A competitive Enzyme-Linked Immuno-Sorbent Assay (competitive ELISA) has been developed for analyzing brevetoxins (PbTxs). Antibodies to brevetoxins were used in combination with a multi-step signal amplification procedure for the detection of toxins. This procedure minimizes non-specific signals and background noise often observed in complex matrices. Therefore, analysis can be performed with various samples (seawater, air filter, mammalian body fluids, shellfish, etc.) without the need for extensive extraction and/or purification steps. Brevetoxin analysis in liquid samples like seawater, urine and serum can be performed without pretreatment, dilution or purification. The limit of quantification of PbTxs is 2 ng mL-1 in any of the liquid sample matrices tested. For shellfish monitoring, analyses are performed after homogenization of shellfish meat (5 g) with brevetoxin-ELISA buffer (200 mL) and can be performed on tissue from a single mollusk as well as on a pool of shellfish meat. Comparative quantification of PbTxs achieved in buffer, seawater, mammalian body fluid and shellfish homogenate spiked with equal amounts of toxin (10 ng mL-1 sample) varied by no more than 5%. These data suggest that the matrix composition of the sample does not affect the performance of the assay. Because this assay is not affected by matrix composition and can be performed in shellfish homogenate, this procedure can be used to prevent or diagnose human exposure to PbTxs and has the potential to replace the currently used mouse bioassay for monitoring PbTxs in shellfish. PMID- 26436143 TI - Multi-Laboratory Study of Five Methods for the Determination of Brevetoxins in Shellfish Tissue Extracts. AB - A thirteen-laboratory comparative study tested the performance of four methods as alternatives to mouse bioassay for the determination of brevetoxins in shellfish. The methods were N2a neuroblastoma cell assay, two variations of the sodium channel receptor binding assay, competitive ELISA, and LC/MS. Three to five laboratories independently performed each method using centrally prepared spiked and naturally incurred test samples. Competitive ELISA and receptor binding (96 well format) compared most favorably with mouse bioassay. Between-laboratory relative standard deviations (RSDR) ranged from 10 to 20% for ELISA and 14 to 31% for receptor binding. Within-laboratory (RSDr) ranged from 6 to 15% for ELISA, and 5 to 31% for receptor binding. Cell assay was extremely sensitive but data variation rendered it unsuitable for statistical treatment. LC/MS performed as well as ELISA on spiked test samples but was inordinately affected by lack of toxin-metabolite standards, uniform instrumental parameters, or both, on incurred test samples. The ELISA and receptor binding assay are good alternatives to mouse bioassay for the determination of brevetoxins in shellfish. PMID- 26436144 TI - Florida Red Tide: Inhalation Toxicity of Karenia brevis Extract in Rats. AB - Brevetoxins are neurotoxins produced by the marine dinoflagellate Karenia brevis. Histopathologic examination of marine mammals dying following repeated exposure of brevetoxins during red tide events suggests that the respiratory tract, nervous, hematopoietic, and immune systems are potential targets for toxicity in repeatedly exposed individuals. The purpose of this experiment was to evaluate the effects of repeated inhalation of K. brevis extract on these potential target systems in rats. Male Sprague-Dawley rats were exposed four hours/day, five days/week for up to four weeks to target concentrations of 200 and 1000 MUg/L K. brevis extract (approximately 50 and 200 MUg/L brevetoxin-like compounds; positive neurotoxicity in a fish bioassay). Control rats were sham exposed to air. Immunohistochemical staining of pulmonary macrophages indicated deposition of brevetoxin-like compound within the lung. However, exposure resulted in no clinical signs of toxicity or behavioral changes. There were no adverse effects on hematology or serum chemistry. No histopathological changes were observed in the nose, lung, liver, kidneys, lymph nodes, spleen, or brain of exposed rats. Immune suppression was suggested by reduced responses of spleen cells in the IgM specific antibody-forming plaque cell response assay and reduced responses of lymphocytes to mitogen stimulation in vitro. Differences between responses observed in rats in this study and those observed in manatees may be a function of dose or species differences in sensitivity. PMID- 26436145 TI - An Epidemiologic Approach to the Study of Aerosolized Florida Red Tides. AB - Very little has been published in the scientific literature on the human health effects of Florida red tide, either as human clinical case reports or formal epidemiologic studies. In addition to the health effects associated with the ingestion of contaminated shellfish, there have been multiple anecdotal reports of respiratory irritation and possible immunologic effects associated with the inhalation of aerosolized Florida red tide. To investigate the human health effects from environmental exposure to red tide toxins, we have formed an interdisciplinary team of scientists. We have created a network of public and environmental health workers who periodically report local conditions as a red tide develops. In addition, we have access to environmental monitoring data as well as data from a surveillance program supported through the Florida Poison Information Network. When a red tide moves onshore where people might be exposed, the team rapidly assembles at the site to collect environmental samples and epidemiologic data. To assess the more long-term effects from environmental exposure to red tide toxins, we are conducting epidemiologic studies involving occupational and sensitive populations who live in areas that are regularly impacted by red tides. Other scientists are evaluating the acute and chronic respiratory effects of red tides and brevetoxins in both rat and sheep models as well as refinement of toxin measurement methodology. These models are being used to refine and validate the biomarkers of brevetoxins exposure as well as explore the pathophysiology of health effects from brevetoxins respiratory exposure. Bolstered by the additional research in rat and sheep models, this interdisciplinary scientific team is exploring the acute and chronic exposures and health effects of aerosolized Florida red tides in animal models and various human populations. In the future, this research can be applied to the understanding of exposure and effects of other aerosolized natural toxins such as cyanobacterial toxins. PMID- 26436146 TI - Fenton reaction-mediated fluorescence quenching of N-acetyl-L-cysteine-protected gold nanoclusters: analytical applications of hydrogen peroxide, glucose, and catalase detection. AB - Given the importance of hydrogen peroxide (H2O2) in many biological processes and its wide application in various industries, the demand for sensitive, accurate, and economical H2O2 sensors is high. In this study, we used Fenton reaction stimulated fluorescence quenching of N-acetyl-L-cysteine-protected gold nanoclusters (NAC-AuNCs) as a reporter system for the determination of H2O2. After the experimental conditions were optimized, the sensing platform enabled the analysis of H2O2 with a limit of detection (LOD) as low as 0.027 MUM. As the glucose oxidase cascade leads to the generation of H2O2 and catalase catalyzes the decomposition of H2O2, these two biocatalytic procedures can be probed by the Fenton reaction-mediated quenching of NAC-AuNCs. The LOD for glucose was found to be 0.18 MUM, and the linear range was 0.39-27.22 MUM. The LOD for catalase was 0.002 U mL(-1), and the linear range was 0.01-0.3 U mL(-1). Moreover, the proposed sensing methods were successfully applied for human serum glucose detection and the non-invasive determination of catalase activity in human saliva, demonstrating their great potential for practical applications. PMID- 26436147 TI - Rapid and efficient pesticide detection via cyclodextrin-promoted energy transfer. AB - Cyclodextrins facilitate non-covalent fluorescence energy transfer from a variety of pesticides to high quantum-yield fluorophores, resulting in a rapid, sensitive detection scheme for these compounds with detection limits as low as two micromolar. Such a facile detection tool has significant potential applications in agriculture and public health research. PMID- 26436148 TI - Cross-linked supramolecular polymer metallogels constructed via a self-sorting strategy and their multiple stimulus-response behaviors. AB - Novel cross-linked supramolecular polymer metallogels were successfully constructed from four components via a self-sorting strategy, and feature interesting multiple stimulus-response behaviors under various external stimuli, including halide, base, and competitive guests. PMID- 26436149 TI - A high stiffness bio-inspired hydrogel from the combination of a poly(amido amine) dendrimer with DOPA. AB - A robust biodegradable hydrogel is constructed from two components containing G4.0 PAMAM and DOPA, which displays excellent interconnected porous 3D networks, higher mechanical strength, low and stable swelling and good biocompatibility. A mouse CSD model in vivo evidences that moderate bone-like tissue and extensive bony tissue are observed when the hydrogel is implanted. PMID- 26436150 TI - Retractions. PMID- 26436151 TI - Preface: Selected papers from the 30th SEGH Conference on Environmental Geochemistry and Health. PMID- 26436152 TI - Reflections: neurology and the humanities: Clarity. PMID- 26436153 TI - Long sleep duration in elders without dementia increases risk of dementia mortality (NEDICES). PMID- 26436154 TI - Author response. PMID- 26436155 TI - Commentary on "Pregnancy week at delivery and the risk of shoulder dystocia: A population study of 2,014,956 deliveries". PMID- 26436156 TI - Editorial: big data for health. PMID- 26436158 TI - Predictive modeling in health informatics. PMID- 26436157 TI - EMBC 2014. PMID- 26436159 TI - Unobtrusive assessment of the mechanical aspects of cardiovascular function. PMID- 26436160 TI - Corticosteroids: out of fashion? PMID- 26436161 TI - Rituximab (MABTHERA) and severe polyangiitis. An option for patients informed of the uncertainties. AB - Granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis are two types of rapidly fatal necrotizing vasculitis. The standard induction therapy consists of cyclophosphamide (an immunosuppressant) plus a corticosteroid. This treatment significantly prolongs survival but has burdensome adverse effects. After an induction phase lasting 3 to 6 months, cyclophosphamide is replaced by another immunosuppressant such as azathioprine for 2 to 5 years in order to prevent relapse. There is no consensus on an alternative treatment for patients who cannot receive cyclophosphamide. Rituximab, a monoclonal antibody already approved in oncology and rheumatology, is now authorised in the European Union for induction therapy in adult patients with granulomatosis with polyangiitis and microscopic polyangiitis. A randomised, double-blind, non inferiority trial in 197 patients compared intravenous rituximab infusion once a week for 4 weeks, versus oral cyclophosphamide given for 3 to 6 months, followed by azathioprine for 12 months. During the 18-month follow-up period, 2% of patients in each group died. Rituximab was at least as effective as cyclophosphamide in terms of complete remission rate by 6 months (primary endpoint), which was respectively 64% and 55%. At 18 months, about one-third of patients in both arms were still in remission, despite the absence of maintenance therapy in the rituximab arm. Uncertainties concerning the use of rituximab in this setting include its longer-term impact on survival, possible advantage in patients who relapse, efficacy in patients with life-threatening disease, and optimal dose. During 18 months of follow-up, about 42% of patients in the rituximab group and 70% of those in the cyclophosphamide and azathioprine group had at least one treatment-related adverse effect. The following adverse effects were more frequent with rituximab than with sequential treatment with cyclophosphamide followed by azathioprine: infections, thrombocytopenia, diarrhoea, peripheral oedema, cough and cardiovascular disorders, while the following effects were more frequent with cyclophosphamide followed by azathioprine: leukopenia, venous thromboembolism, nausea, vomiting, transaminase elevation and hair loss. Rituximab should be avoided during pregnancy because it can cause lymphopenia in the unborn child. Its effects on fertility are poorly documented. In practice, in patients with severe granulomatosis with polyangiitis or microscopic polyangiitis, rituximab is as effective at 18 months as cyclophosphamide followed by azathioprine; in addition, it has different and less frequent adverse effects. Rituximab is therefore an alternative when the standard treatment is likely to be problematic, but patients should be informed that longer-term efficacy is uncertain and that the optimal dose remains to be established. PMID- 26436162 TI - INN COMMON STEM: -tide. PMID- 26436164 TI - Ranibizumab(Lucentis) in high myopia with neovascularization. Better short-term visual acuity but serious adverse effects. AB - In a trial versus verteporfin photodynamic therapy, ranibizumab improved visual acuity after 3 months of treatment but had more adverse effects. PMID- 26436165 TI - Dabigatran (Pradaxa): deep vein thrombosis and pulmonary embolism. Warfarin remains the standard drug. AB - Not more effective than warfarin in three "non-inferiority" trials. Less bleeding but more acute coronary events with dabigatran, and still no antidote. PMID- 26436166 TI - omalizumab (Xolair) and chronic spontaneous urticaria. Too many adverse effects and uncertainties. AB - Omalizumab has only modest and transient symptomatic efficacy when an antihistamine is ineffective. Its adverse effects can be severe, and its safety during long-term use is uncertain. Omalizumab is not better than a corticosteroid. PMID- 26436167 TI - Febuxostat (Adenuric). Toxic epidermal necrolysis and severe hypersensitivity reactions added to the EU SPC. AB - This hypouricaemic drug does not have a better adverse effect profile than allopurinol. PMID- 26436168 TI - Methylphenidate: pulmonary hypertension and heart valve disease. AB - Several amphetamine-like appetite suppressants are known to have cardiovascular adverse effects, in particular pulmonary arterial hypertension and cardiac valve disease. Is this also the case with methylphenidate, an amphetamine-like psychostimulant used in attention-deficit hyperactivity disorder (especially in children) and also in narcolepsy? Cases of pulmonary hypertension and heart valve disease have been reported with methylphenidate, including in children. The risk appears to be low, but epidemiological studies are needed to estimate the incidence. This risk should be minimised by only using methylphenidate to treat serious disorders, at the lowest effective dose. Attention should be paid to warning signs such as dyspnoea. PMID- 26436169 TI - Mechanisms of action of amphetamine-like drugs. PMID- 26436170 TI - Red yeast rice: muscle and liver disorders. PMID- 26436171 TI - Hydroxychloroquine: hypoglycaemia. PMID- 26436172 TI - Efavirenz: suicides. PMID- 26436173 TI - Smoking cessation during pregnancy. PMID- 26436174 TI - Epicondylitis and corticosteroid injection: fewer cures at one year. AB - Corticosteroid injection provides short-term relief for patients with epicondylitis. However, in a trial lasting one year, corticosteroid injection resulted in a lower complete recovery rate and higher recurrence rate. Physiotherapy appears to improve symptoms in the short-term without affecting outcome at one year. PMID- 26436175 TI - How INNs are created. Making drug names safer by contributing to INN selection. AB - The international nonproprietary names (INNs) of drugs proposed by the World Health Organization (WHO) are released for public consultation. These consultations provide an opportunity to identify any risks associated with INNs that could lead to confusion. Prescrire has submitted numerous comments since it began participating in the WHO's public consultations on proposed INNs in 2007. The WHO INN programme has occasionally taken our objections into account. It is easier to replace a proposed INN when a risk of confusion is identified early, before the drug is introduced to the market and the INN enters into use. Regular analysis of the INNs proposed by the WHO reveals some of the challenges of naming drugs and the influence exerted by pharmaceutical companies and the US drug nomenclature committee (USANC) in particular. The lack of an identifiable common stem in certain INNs, sometimes perceived as an obstacle to INN comprehensibility, is a consequence of the procedure for assigning INNs, because the INN programme wants to ensure that new common stems are not created prematurely. Critical analysis of proposed INNs during WHO public consultations offers an insight into the challenges involved in devising common stems. This analysis is useful for improving the quality and safety of INNs. PMID- 26436176 TI - The finances of Association Mieux Prescrire: 2014 Prescrire annual report. PMID- 26436177 TI - For the Future. PMID- 26436178 TI - The Advantage of a General Journal. PMID- 26436179 TI - Results From Wisconsin Medical Society's Physician Satisfaction Survey Are Cause for Concern. PMID- 26436180 TI - Dissatisfaction Among Wisconsin Physicians Is Part of Serious National Trend. PMID- 26436181 TI - Factors Affecting Physician Satisfaction and Wisconsin Medical Society Strategies to Drive Change. AB - Physicians' dissatisfaction in their work is increasing, which is affecting the stability of health care in America. The Wisconsin Medical Society (Society) surveyed 1016 Wisconsin physicians to determine the source of their dissatisfaction. The survey results indicate Wisconsin physicians are satisfied when it comes to practice environment, work-life balance, and income. In addition, they are extremely satisfied when it comes to rating their ability to provide high quality care, and they have identified some benefits related to the adoption of electronic health records. However, they are feeling burned out, very unsatisfied with the amount of time spent in direct patient care compared to indirect patient care, and that they are spending too much time on administrative and data entry tasks. In terms of future workforce, many physicians are either unsure or would not recommend the profession to a prospective medical student. Electronic health records serve as both a satisfier and dissatisfier and as a potential driver for future physician satisfaction interventions. Changes at the institutional, organizational, and individual levels potentially could address the identified dissatisfiers and build upon the satisfiers. The Society identifies 12 strategies to improve upon the physician experience. PMID- 26436183 TI - Assessment of Food Insecurity in Children's Hospital of Wisconsin's Emergency Department. AB - IMPORTANCE: Food insecurity is associated with adverse health outcomes and the emergency department may be an ideal location to identify food insecure children and families. OBJECTIVE: To determine the prevalence of food insecurity in families with children that present to an urban pediatric emergency department (ED) in Milwaukee, Wisconsin. DESIGN: We conducted a cross-sectional survey of caregivers of children 0-18 years between June and August, 2013. The questionnaire included 2 validated statements about food insecurity and demographic and community resource questions. Participant rooms were approached during predefined shifts in an order determined by random number generation. OUTCOMES: The primary outcome was the prevalence of caregivers who identified as food insecure. A secondary outcome was the percentage of food insecure caregivers who accessed community resources. RESULTS: We enrolled 309 caregivers; 141 (45.6%) reported food insecurity. Nearly 60% (56.8%) of nonwhite caregivers were food insecure compared to 27.4% of non-Hispanic white caregivers (P < 0.0001). Among caregivers who identified as food insecure, 82% reported using at least 1 community resource for food. CONCLUSIONS: Almost half of caregivers presenting to the ED reported food insecurity. The ED is an excellent location for targeted intervention to identify and link food insecure families with community resources. PMID- 26436182 TI - Association Between Alcohol Use Among College Students and Alcohol Outlet Proximity and Densities. AB - BACKGROUND: Alcohol consumption is common on college campuses and is associated with negative consequences. Factors associated with availability of alcohol are not completely understood. OBJECTIVE: To describe how proximity and density of alcohol outlets are associated with any drinking and binge drinking in students at the University of Wisconsin-Madison. METHODS: Participants were full-time students enrolled in the Young Adults Eating and Active for Health, a multisite, randomized intervention that assessed a variety of health behaviors. Geographic information systems were used to calculate proximity and enumerate alcohol outlet densities. Participants were categorized as "drinkers" or "nondrinkers" based on self-reported alcohol consumption. Binge drinking was categorized as "non-binge drinker," "frequent binge drinker," and "excessive binge drinker." Analysis included regression, t tests, and chi-square tests. RESULTS. Among the 166 participants, 126 (76%) were drinkers. Among drinkers, 80 (63%) were either frequent or excessive binge drinkers. Drinkers lived closer to an alcohol outlet than non-drinkers (0.18 +/- 0.15 vs. 0.61 +/- 1.59 miles, respectively, P=0.005). Within a 1-mile walking radius, there were 47% more establishments for drinkers (153 +/- 47 compared to 104 +/- 55 outlets for nondrinkers, P<0.0001). At distances of 0.10-0.25 and 0.25-0.50 miles, twice as many outlets were available to drinkers (19 +/- 19 and 43 +/- 25, respectively) compared to nondrinkers (7 +/ 11 and 20 +/- 22, respectively), P<0.001. Proximity and density were hot associated with binge drinking frequency. CONCLUSION: Drinkers lived closer to alcohol outlets and had significantly more outlets available at a distance of up to 1 mile. Municipal and college administrators could consider limiting alcohol license distributions in municipalities with high alcohol consumption. PMID- 26436184 TI - The Emergence of Clinically Relevant Babesiosis in Southwestern Wisconsin. AB - OBJECTIVE: To determine the frequency and characteristics of babesiosis cases, and to assess the impact of the introduction of a tick-borne infection diagnostic panel on babesiosis diagnosis in the region surrounding La Crosse, Wisconsin, where babesiosis in non-travelers was previously rare. METHODS: In the spring of 2013, we conducted a point-in-time survey of Ixodes scopuloris ticks for the presence of Babesia microti. We also conducted a retrospective study of all babesiosis cases diagnosed in our health system between January 1, 2004, and November 1, 2013. Finally, we compared the number of babesiosis cases diagnosed during the study period before and after the June 1, 2012, introduction of a tick borne infection diagnostic panel in our organization. RESULTS: Babesia microti was present in 5% of ticks surveyed in our region. Twenty-two cases. of babesiosis were diagnosed in our organization during the study period-19 since 2010. The tick-borne infection diagnostic panel was used widely by clinicians, with an attendant increase in babesiosis diagnoses. CONCLUSION: Babesiosis should be considered endemic in southwestern Wisconsin, and testing should be considered for patients with compatible clinical and laboratory features. PMID- 26436185 TI - The Savant Syndrome Registry: A Preliminary Report. AB - A registry has been established to document certain characteristics on a sizeable worldwide sample of individuals with savant syndrome, a rare but remarkable condition in which persons with developmental disabilities, brain injury, or brain disease have some spectacular "islands" of skill or ability that stand in jarring, marked contrast to overall handicap. Of the 319 savants included in the registry, 90% are congenital savants, while 10% are acquired savants. The registry includes individuals from 33 countries, with 70% from the United States or Canada. Sex distribution was 79% male vs. 21% female (4:1). This report summarizes the findings in the congenital savant syndrome category of the registry. Among the individuals with congenital savant syndrome, the most common underlying disability was Autistic Spectrum Disorder (75%); various other central nervous system (CNS) disorders were present in the other 25%. Fifty-five percent possessed a single special skill, while 45% had multiple skills. Music was the most frequent principal skill followed by art, memory, mathematics, calendar calculating, language, visual-spatial/mechanical, athletic, computer, extrasensory perception, and other skills. PMID- 26436186 TI - Hypocalcemia Secondary to Zoledronate Therapy in a Patient With Low Vitamin D Level. AB - Zoledronate (ZDA) is a bisphosphonate used to treat hypercalcemia that commonly occurs with malignancy, multiple myeloma, and bone metastases from solid tumors. It acts primarily by decreasing osteoclastic activity, thereby slowing the release of skeletal calcium. However, a potential adverse effect of ZDA is hypocalcemia that can be symptomatic, especially in patients with risk factors such as hypomagnesemia, hypoparathyroidism, renal failure, and vitamin D deficiency. We report the case of a patient with extensive stage small cell lung cancer with multiple osseous and visceral metastases who developed symptomatic hypocalcemia following ZDA administration. Significant clinical improvement occurred following administration of calcium and vitamin D, and his calcium levels returned to normal within a few days. Due to the high incidence of vitamin D deficiency and the low accuracy of clinical risk factors to predict vitamin D deficiency, screening for vitamin D deficiency before administration of ZDA may be appropriate. PMID- 26436187 TI - Medical Training in the Fitbit, Google Glass and Personal Information Era. PMID- 26436188 TI - Implementing Heart Health Strategies With Point-of Care and Population Management. PMID- 26436189 TI - ANMF priorities. What's in store for 2015. PMID- 26436190 TI - Curriculum in unis needed to protect students from violence. PMID- 26436191 TI - Scope of practice and cancer care. PMID- 26436193 TI - Cancer mapped out globally. PMID- 26436192 TI - Rotating night shift increases risk of disease. PMID- 26436194 TI - Nurses' role essential at end-of-life. PMID- 26436195 TI - Incidental exercises could save lives. PMID- 26436196 TI - Heart condition twice as common in Indigenous Australians. PMID- 26436198 TI - Exploration of new functional endpoints in neuro-2a cells for the detection of the marine biotoxins saxitoxin, palytoxin and tetrodotoxin. AB - Marine neurotoxins accumulate in seafood and therewith represent a threat for consumers. At the European level, the use of in vivo bioassays is banned from 2015 onwards, except for the control of production areas. Cytotoxicity in the neuro-2a assay has been shown a promising in vitro alternative. However, given that cytotoxicity may be sensitive to confounding factors the current study investigates the suitability of functional endpoints as alternatives to cytotoxicity for the detection of marine neurotoxins. Microarray analyses were performed following exposure of neuro-2a cells to three marine neurotoxins (palytoxin (PlTx), saxitoxin (STX) and tetrodotoxin (TTX)) to identify genes up- or down-regulated that can be used as biomarkers for screening purposes. In addition to microarrays, the voltage dependent fluorescent probe bisoxonol was used to assess changes in cellular membrane potential. Biomarkers based on mRNA expression were detected for PlTx but not for STX and TTX. STX and TTX decreased the fluorescence of bisoxonol while PlTx showed no effect. When using cytotoxicity as the read out the neuro-2a assay detects these three neurotoxins at similar concentrations. Therefore it is concluded that the newly investigated endpoints in the neuro-2a assay are not preferred over cytotoxicity in a suitable broad and sensitive bioassay for the detection of marine neurotoxins in real practice. PMID- 26436199 TI - Lead-Free Piezoceramics: Revealing the Role of the Rhombohedral-Tetragonal Phase Coexistence in Enhancement of the Piezoelectric Properties. AB - Until now, lead zirconate titanate (PZT) based ceramics are the most widely used in piezoelectric devices. However, the use of lead is being avoided due to its toxicity and environmental risks. Indeed, the attention in piezoelectric devices has been moved to lead-free ceramics, especially on (K,Na)NbO3-based materials, due to growing environmental concerns. Here we report a systematic evaluation of the effects of the compositional modifications induced by replacement of the B sites with Sb(5+) ions in 0.96[(K0.48Na0.52)0.95Li0.05Nb1-xSbxO3]-0.04[BaZrO3] lead-free piezoceramics. We show that this compositional design is the driving force for the development of the high piezoelectric properties. So, we find that this phenomenon can be explained by the stabilization of a Rhombohedral Tetragonal (R-T) phase boundary close to room temperature, that facilities the polarization process of the system and exhibits a significantly high piezoelectric response with a d33 value as high as ~400 pC/N, which is comparable to part soft PZTs. As a result, we believe that the general strategy and design principles described in this study open the possibility of obtaining (K,Na)NbO3 based lead-free ceramics with enhanced properties, expanding their application range. PMID- 26436197 TI - Observing the overall rocking motion of a protein in a crystal. AB - The large majority of three-dimensional structures of biological macromolecules have been determined by X-ray diffraction of crystalline samples. High-resolution structure determination crucially depends on the homogeneity of the protein crystal. Overall 'rocking' motion of molecules in the crystal is expected to influence diffraction quality, and such motion may therefore affect the process of solving crystal structures. Yet, so far overall molecular motion has not directly been observed in protein crystals, and the timescale of such dynamics remains unclear. Here we use solid-state NMR, X-ray diffraction methods and MUs long molecular dynamics simulations to directly characterize the rigid-body motion of a protein in different crystal forms. For ubiquitin crystals investigated in this study we determine the range of possible correlation times of rocking motion, 0.1-100 MUs. The amplitude of rocking varies from one crystal form to another and is correlated with the resolution obtainable in X-ray diffraction experiments. PMID- 26436200 TI - Drinking behavior among older adults in a planned retirement community: results from The Villages survey. AB - OBJECTIVES: Research indicates increasing trends among older adults toward heavy and abusive drinking, often associated with depressive symptoms. Possible exceptions are residents of planned retirement communities, whose drinking may be associated with social activities. To better understand these relationships, this study examined the relationship of depressive symptoms and drinking in a large retirement community. METHODS: The Villages, a retirement community in central Florida with a focus on healthy, active living, has almost 90,000 residents. In 2012, a population-based needs assessment was conducted in partnership with University of South Florida Health. In the present study, 11,102 surveys were completed and returned. A structural equation model was utilized to analyze the relationship between depressive symptoms and alcohol use as measured by the three item Alcohol Use Disorders Identification Test (AUDIT-C). RESULTS: Hazardous drinking was reported in 15.4% of respondents, somewhat higher than the general population of older adults (around 10%). Variables of depressive symptoms, physical activity, total health problems, and poor general health loaded significantly into the factor of depression indicators, which was shown to have a significant, negative correlation with risk of hazardous drinking (lambda = 0.16, p < 0.000, R(2) = 0.02). CONCLUSIONS: Results suggest at-risk drinking among respondents was not associated with depression, in contrast to studies of older adults living alone where alcohol abuse was often associated with depression. Implications for successful aging are discussed. PMID- 26436201 TI - Epidemiological trends among the population with chronic HCV infection in the Netherlands. AB - BACKGROUND: As the field of antiviral therapy for chronic HCV infection is rapidly evolving, this study aimed to assess the epidemiological changes in patient and disease characteristics among individuals with chronic HCV infection. METHODS: This study included all consecutive patients with chronic HCV monoinfection who were referred between 1990 and 2013 to the Erasmus MC University Medical Center Rotterdam, a large tertiary centre in the Netherlands. To identify trends over time, the study population was divided into six equal eras based on date of first visit to the outpatient clinic. RESULTS: A total of 1,779 patients were diagnosed with chronic HCV infection. Mean age increased over time from 43.6 (sd 13.8) years to 51.7 (sd 11.2) years (P<0.001). The number of patients who were referred with cirrhosis increased over time, from 31 (25%) patients in Era 1 to 118 (42%) patients in Era 6 (P<0.001), respectively. More patients were referred with HCV genotype 1a and 3 in the last era, with 27 (48.2%) and 15 (14.0%) patients in Era 1 and 58 (54.2%) and 60 (21.8%) patients in Era 6 (P<0.001 both), respectively. The vast majority of patients (69.5%) were born between 1950 to 1975, with 62.5% of the patients being born between 1945 and 1965. CONCLUSIONS: The HCV-infected population is ageing and is more often referred with severe liver disease. This study stresses the importance of urgently implementing national HCV screening programmes in order to be able to decrease the future burden of chronic HCV infection in the Netherlands. PMID- 26436202 TI - My epilepsy story--The Anita Kaufmann Foundation. PMID- 26436203 TI - Dynamic acousto-optic control of a strongly coupled photonic molecule. AB - Strongly confined photonic modes can couple to quantum emitters and mechanical excitations. To harness the full potential in quantum photonic circuits, interactions between different constituents have to be precisely and dynamically controlled. Here, a prototypical coupled element, a photonic molecule defined in a photonic crystal membrane, is controlled by a radio frequency surface acoustic wave. The sound wave is tailored to deliberately switch on and off the bond of the photonic molecule on sub-nanosecond timescales. In time-resolved experiments, the acousto-optically controllable coupling is directly observed as clear anticrossings between the two nanophotonic modes. The coupling strength is determined directly from the experimental data. Both the time dependence of the tuning and the inter-cavity coupling strength are found to be in excellent agreement with numerical calculations. The demonstrated mechanical technique can be directly applied for dynamic quantum gate operations in state-of-the-art coupled nanophotonic, quantum cavity electrodynamic and optomechanical systems. PMID- 26436204 TI - Microfluidic Foaming: A Powerful Tool for Tailoring the Morphological and Permeability Properties of Sponge-like Biopolymeric Scaffolds. AB - Ordered porous polymeric materials can be engineered to present highly ordered pore arrays and uniform and tunable pore size. These features prompted a number of applications in tissue engineering, generation of meta materials, and separation and purification of biomolecules and cells. Designing new and efficient vistas for the generation of ordered porous materials is an active area of research. Here we investigate the potential of microfluidic foaming within a flow-focusing (FF) geometry in producing 3D regular sponge-like polymeric matrices with tailored morphological and permeability properties. The challenge in using microfluidic systems for the generation of polymeric foams is in the high viscosity of the continuous phase. We demonstrate that as the viscosity of the aqueous solution increases, the accessible range of foam bubble fraction (Phib) and bubble diameter (Db) inside the microfluidic chip tend to narrow progressively. This effect limits the accessible range of geometric properties of the resulting materials. We further show that this problem can be rationally tackled by appropriate choice of the concentration of the polymer. We demonstrate that via such optimization, the microfluidic assisted synthesis of porous materials becomes a facile and versatile tool for generation of porous materials with a wide range of pore size and pore volume. Moreover, we demonstrate that the size of interconnects among pores-for a given value of the gas fraction-can be tailored through the variation of surfactant concentration. This, in turn, affects the permeability of the materials, a factor of key importance in flow through applications and in tissue engineering. PMID- 26436205 TI - The application of CD73 in minimal residual disease monitoring using flow cytometry in B-cell acute lymphoblastic leukemia. AB - The expression of CD73 by flow cytometry (FC) in bone marrow (BM) specimens of B cell acute lymphoblastic leukemia (B-ALL) with or without minimal residual disease (MRD) was studied, and its advantages were evaluated using the MRD assay. This study also detected the expression profile of CD73 in hematogones and mature B cells in BM specimens of 18 healthy donors. Results showed that the mean value of CD73 expression in MRD-positive B cells was 6-fold greater than that in the MRD negative ones. Also, 41.82% MRD-positive B-ALL cases expressed high CD73 and the sensitivity of CD73-based MRD detection reached 10(-4). Since the expression of CD73 increases with the maturation of normal B cells, it is better to mix it with CD34, CD10 and CD20 in one tube to prevent the disturbance of mature B cells. CD73 is recommended as an optional MRD marker for B-ALL patients by using FC. PMID- 26436206 TI - Trichostatin A and Tamoxifen inhibit breast cancer cell growth by miR-204 and ERalpha reducing AKT/mTOR pathway. AB - MicroRNAs (miRs) are small non-coding RNAs aberrantly expressed in human tumors. Increasing evidence suggests that miRNAs are functionally important in cancers. We demonstrated miR-204 exerts its function by targeting gene involved in tumor growth and chemotherapy drugs reactivity. Here, we show that Trichostatin A (TSA) could increase ERalpha expression in MCF-7 and MDA-MB-231 cells by reducing miR204. Analysis of tumors growth inhibition shows that TSA promotes ERalpha expression, which could be reversed by miR-204 mimic transfection. When miR-204 is down regulated, the inhibition of TAM on breast cancer cells is enhanced. Caspase 3 activity is also increased. TSA and TAM combination inhibits Mcl-1 expression by decreasing phosphorylation of AKT induced by ERalpha increase in vivo and in vitro. PMID- 26436209 TI - Remote Ischemic Preconditioning in Cardiac Surgery--Ineffective and Risky? PMID- 26436208 TI - A Multicenter Trial of Remote Ischemic Preconditioning for Heart Surgery. AB - BACKGROUND: Remote ischemic preconditioning (RIPC) is reported to reduce biomarkers of ischemic and reperfusion injury in patients undergoing cardiac surgery, but uncertainty about clinical outcomes remains. METHODS: We conducted a prospective, double-blind, multicenter, randomized, controlled trial involving adults who were scheduled for elective cardiac surgery requiring cardiopulmonary bypass under total anesthesia with intravenous propofol. The trial compared upper limb RIPC with a sham intervention. The primary end point was a composite of death, myocardial infarction, stroke, or acute renal failure up to the time of hospital discharge. Secondary end points included the occurrence of any individual component of the primary end point by day 90. RESULTS: A total of 1403 patients underwent randomization. The full analysis set comprised 1385 patients (692 in the RIPC group and 693 in the sham-RIPC group). There was no significant between-group difference in the rate of the composite primary end point (99 patients [14.3%] in the RIPC group and 101 [14.6%] in the sham-RIPC group, P=0.89) or of any of the individual components: death (9 patients [1.3%] and 4 [0.6%], respectively; P=0.21), myocardial infarction (47 [6.8%] and 63 [9.1%], P=0.12), stroke (14 [2.0%] and 15 [2.2%], P=0.79), and acute renal failure (42 [6.1%] and 35 [5.1%], P=0.45). The results were similar in the per-protocol analysis. No treatment effect was found in any subgroup analysis. No significant differences between the RIPC group and the sham-RIPC group were seen in the level of troponin release, the duration of mechanical ventilation, the length of stay in the intensive care unit or the hospital, new onset of atrial fibrillation, and the incidence of postoperative delirium. No RIPC-related adverse events were observed. CONCLUSIONS: Upper-limb RIPC performed while patients were under propofol-induced anesthesia did not show a relevant benefit among patients undergoing elective cardiac surgery. (Funded by the German Research Foundation; RIPHeart ClinicalTrials.gov number, NCT01067703.). PMID- 26436211 TI - In silico prediction and characterization of protein post-translational modifications. AB - This review outlines the computational approaches and procedures for predicting post translational modification (PTM)-induced changes in protein conformation and their influence on protein function(s), the latter being assessed as differential affinity in interaction with either low (ligands for receptors or transporters, substrates for enzymes) or high molecular mass molecules (proteins or nucleic acids in supramolecular assemblies). The scope for an in silico approach is discussed against a summary of the in vitro evidence on the structural and functional outcome of protein PTM. PMID- 26436212 TI - Real-World Patterns of Care for the Overactive Bladder Syndrome in the United States. AB - OBJECTIVE: To examine the "real-world" overactive bladder (OAB) practice patterns using national data in the United States. MATERIALS AND METHODS: The Humedica EHR database was queried. This database consists of de-identified patient records from a network of organizations treating approximately over 30 million patients across states in the United States. The entire study period was from July 1, 2008, to September 30, 2013. Patients with a diagnosis of OAB between July 1, 2009, and June 30, 2012 were included and followed. Patient comorbidities, demographics, diagnostic testing, and medication usage were analyzed. RESULTS: Of 19,309,600 subjects enrolled during the study period, 46,648 adults had a diagnosis of OAB, with follow-up of at least 6 months, and met the inclusion criteria. There were 35,315 women and 11,333 men. Compared with women, men with OAB were more likely to undergo post-void residual measurement (32% vs 22%) and diagnostic cystoscopy (10% vs 7%). Women were more likely than men to undergo urodynamics (7% vs 3%). Overall, 34% of women and 19% of men diagnosed with OAB were prescribed medication. CONCLUSION: Few patients with OAB underwent invasive diagnostic testing. Anticholinergic medication was prescribed to a minority of patients diagnosed with OAB, indicating possible underuse of a potentially effective therapy. Men were less likely than women to receive medical therapy, despite the fact that OAB is common in both sexes. PMID- 26436213 TI - The Clinical and Urodynamic Results of Percutaneous Posterior Tibial Nerve Stimulation on Neurogenic Detrusor Overactivity in Patients With Parkinson's Disease. AB - OBJECTIVE: To investigate the effect of percutaneous posterior tibial nerve stimulation (PTNS) treatment after 12 weeks on urodynamic and clinical findings in patients with Parkinson's disease (PD) with neurogenic detrusor overactivity. METHODS: A total of 47 patients with PD with neurogenic detrusor overactivity were enrolled in the study. Urodynamic studies before and after 12-week PTNS treatment were performed. International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF), Overactive Bladder Questionnaire (OAB-V8), and Overactive Bladder Questionnaire Short Form (OAB-q SF) have been assessed before and after PTNS treatment. RESULTS: The mean first involuntary detrusor contraction volume (1st IDCV) on standard cystometry was 133.2 +/- 48.1 (24-265) mL, whereas it was 237.3 +/- 43.1 (145-390) mL after PTNS. The mean maximum cystometric capacity (MCC) on standard cystometry was 202.2 +/- 36.5 (115-320) mL, whereas it was 292.1 +/- 50.6 (195-395) mL after stimulation. The improvements in the first involuntary detrusor contraction volume and maximum cystometric capacity were statistically significant after stimulation. The mean Pdetmax at first involuntary detrusor contraction, maximal detrusor pressure at maximum cystometric capacity, PdetQmax, Qmax, and post-void residual volume were statistically significant after 12-week stimulation. Mean parametric improvements at 12-week PTNS treatment from baseline included daytime frequency decreased by 5.6 voids daily, urge incontinence decreased by 3.1 episodes daily, urgency episodes decreased by 6.3 episodes daily, nocturia decreased by 2.7 voids, and voided volume improved by a mean of 92.6 mL. The change from baseline on the ICIQ SF, OABv8, and OAB-q at 12-week PTNS treatment demonstrated statistically significant improvements. CONCLUSION: These results have demonstrated that PTNS improves the lower urinary tract symptoms and urodynamic parameters in patients with PD. PMID- 26436214 TI - Metal release from coffee machines and electric kettles. AB - The release of elemental ions from 8 coffee machines and 11 electric kettles into food simulants was investigated. Three different types of coffee machines were tested: portafilter espresso machines, pod machines and capsule machines. All machines were tested subsequently on 3 days before and on 3 days after decalcification. Decalcification of the machines was performed with agents according to procedures as specified in the respective manufacturer's manuals. The electric kettles showed only a low release of the elements analysed. For the coffee machines decreasing concentrations of elements were found from the first to the last sample taken in the course of 1 day. Metal release on consecutive days showed a decreasing trend as well. After decalcification a large increase in the amounts of elements released was encountered. In addition, the different machine types investigated clearly differed in their extent of element release. By far the highest leaching, both quantitatively and qualitatively, was found for the portafilter machines. With these products releases of Pb, Ni, Mn, Cr and Zn were in the range and beyond the release limits as proposed by the Council of Europe. Therefore, a careful rinsing routine, especially after decalcification, is recommended for these machines. The comparably lower extent of release of one particular portafilter machine demonstrates that metal release at levels above the threshold that triggers health concerns are technically avoidable. PMID- 26436215 TI - A Rare Mechanism of Hyponatremia in HIV Disease. AB - BACKGROUND: Hyponatremia is the most common disorder of body fluid and electrolyte balance in clinical practice. It is associated with increased morbidity, mortality, and length of hospital stay. Little is known about the relationship between hyponatremia and HIV disease. It is thought that hyponatremia in HIV is associated with a syndrome of inappropriate ADH secretion (SIADH), volume depletion, and adrenal insufficiency. Another common association is with Pneumocystis jirovecii (PCP). In early 1990s, there were several reports linking hyponatremia and HIV disease. It was found that these patients with acquired immune deficiency syndrome (AIDS) had abnormal adrenal cortical function. Additionally, these patients showed an abnormally elevated baseline cortisol level and a blunted response to cosyntropin. CASE REPORT: Here, we present the case of an HIV patient presenting with hyponatremia and a physical examination suggestive of hypovolemia. Laboratory tests revealed urinary loss of sodium in the setting of normal serum cortisol level. The patient responded well to the administration of a mineralocorticoid hormone. CONCLUSIONS: Glucocorticoid resistance is an unusual cause of hyponatremia, and needs to be identified and treated accordingly. PMID- 26436217 TI - Investigation of Child Restraint System (CRS) Compatibility in the Vehicle Seat Environment. AB - OBJECTIVE: Child restraint system (CRS) misuse is common and can have serious consequences to child safety. Physical incompatibilities between CRS and vehicles can complicate the installation process and may worsen CRS misuse rates. This study aims to identify the most common sources of incompatibility between representative groups of CRS and vehicles. METHODS: Detailed dimensional data were collected from 59 currently marketed CRS and 61 late model vehicles. Key dimensions were compared across all 3,599 theoretical CRS/vehicle combinations and the most common predicted incompatibilities were determined. A subset of 34 physical installations was analyzed to validate the results. RESULTS: Only 58.2% of rear-facing (RF) CRS/vehicle combinations were predicted to have proper agreement between the vehicle's seat pan angle and the CRS manufacturers' required base angle. The width of the base of the CRS was predicted to fit snugly between the vehicle's seat pan bolsters in 63.3% of RF CRS/vehicle combinations and 62.2% of forward-facing (FF) CRS/vehicle combinations. FF CRS were predicted to be free of interaction with the vehicle's head restraint in 66.4% of combinations. Roughly 90.0% of RF CRS/vehicle combinations were predicted to have enough horizontal clearance space to set the front seat in the middle its fore/aft slider track. Compatibility rates were above 98% regarding the length of the CRS base compared to the length of the vehicle seat pan and the ability of the top tether to reach the tether anchor. Validation studies revealed that the predictions of RF CRS base angle range vs. seat pan angle compatibility were accurate within 6%, and head restraint interference and front row clearance incompatibilities may be more common than the dimensional analysis approach has predicted. CONCLUSIONS: The results of this study indicate that RF CRS base angles and front row clearance space, as well as FF CRS head restraint interference, are frequent compatibility concerns. These results enable manufacturers, researchers, and consumers to focus their attention on the most relevant CRS/vehicle incompatibility issues in today's market. PMID- 26436218 TI - Injury Outcome in Crashes with Guardrail End Terminals. AB - OBJECTIVE: The goal of this study is to evaluate the crash performance of guardrail end terminals in real-world crashes. Guardrail end terminals are installed at the ends of guardrail systems to prevent the rail from spearing through the car in an end-on collision. Recently, there has been a great deal of controversy as to the safety of certain widely used end terminal designs, partly because there is surprisingly little real-world crash data for end terminals. Most existing studies of end terminal crashes used data from prior to the mid 1990s. Since then, there have been large improvements to vehicle crashworthiness and seat belt usage rates, as well as new roadside safety hardware compliant with National Cooperative Highway Research Program (NCHRP) Report 350, "Recommended Procedures for the Safety Performance Evaluation of Highway Features." Additionally, most existing studies of injury in end terminal crashes do not account for factors such as the occurrence of rollover. This analysis uses more recent crash data that represent post-1990s vehicle fleet changes and account for a number of factors that may affect driver injury outcome and rollover occurrence. METHODS: Passenger vehicle crashes coded as involving guardrail end terminals were identified in the set of police-reported crashes in Michigan in 2011 and 2012. End terminal performance was expected to be a function of end terminal system design. State crash databases generally do not identify specific end terminal systems. In this study, the coded crash location was used to obtain photographs of the crash site prior to the crash from Google Street View. These site photographs were manually inspected to identify the particular end terminal system involved in the crash. Multiple logistic regression was used to test for significant differences in the odds of driver injury and rollover between different terminal types while accounting for other factors. RESULTS: A total of 1,001 end terminal crashes from the 2011-2012 Michigan State crash data were manually inspected to identify the terminal that had been struck. Four hundred fifty-one crashes were found to be suitable for analysis. Serious to fatal driver injury occurred in 3.8% of end terminal crashes, moderate to fatal driver injury occurred in 11.8%, and 72.3% involved property damage only. No significant difference in moderate to fatal driver injury odds was observed between NCHRP 350 compliant end terminals and noncompliant terminals. Car drivers showed odds of moderate to fatal injury 3.6 times greater than LTV drivers in end terminal crashes. Rollover occurrence was not significantly associated with end terminal type. CONCLUSIONS: Car drivers have greater potential for injury in end terminal crashes than light truck/van/sport utility vehicle drivers. End terminal designs compliant with NCHRP 350 did not appear to carry different odds of moderate driver injury than noncompliant end terminals. The findings account for driver seat belt use, rollover occurrence, terminal orientation (leading/trailing), control loss, and the number of impact events. Rollover and nonuse of seat belts carried much larger increases in injury potential than end terminal type. Rollover did not appear to be associated with NCHRP 350 compliance. PMID- 26436219 TI - Comparison of Expected Crash and Injury Reduction from Production Forward Collision and Lane Departure Warning Systems. AB - OBJECTIVES: The U.S. New Car Assessment Program (NCAP) now tests for forward collision warning (FCW) and lane departure warning (LDW). The design of these warnings differs greatly between vehicles and can result in different real-world field performance in preventing or mitigating the effects of collisions. The objective of this study was to compare the expected number of crashes and injured drivers that could be prevented if all vehicles in the fleet were equipped with the FCW and LDW systems tested under the U.S. NCAP. METHODS: To predict the potential crashes and serious injury that could be prevented, our approach was to computationally model the U.S. crash population. The models simulated all rear end and single-vehicle road departure collisions that occurred in a nationally representative crash database (NASS-CDS). A sample of 478 single-vehicle crashes from NASS-CDS 2012 was the basis for 24,822 simulations for LDW. A sample of 1,042 rear-end collisions from NASS-CDS years 1997-2013 was the basis for 7,616 simulations for FCW. For each crash, 2 simulations were performed: (1) without the system present and (2) with the system present. Models of each production safety system were based on 54 model year 2010-2014 vehicles that were evaluated under the NCAP confirmation procedure for LDW and/or FCW. NCAP performed 40 LDW and 45 FCW tests of these vehicles. RESULTS: The design of the FCW systems had a dramatic impact on their potential to prevent crashes and injuries. Between 0 and 67% of crashes and 2 and 69% of moderately to fatally injured drivers in rear-end impacts could have been prevented if all vehicles were equipped with the FCW systems. Earlier warning times resulted in increased benefits. The largest effect on benefits, however, was the lower operating speed threshold of the systems. Systems that only operated at speeds above 20 mph were less than half as effective as those that operated above 5 mph with similar warning times. The production LDW systems could have prevented between 11 and 23% of drift-out-of lane crashes and 13 and 22% of seriously to fatally injured drivers. A majority of the tested LDW systems delivered warnings near the point when the vehicle first touched the lane line, leading to similar benefits. Minimum operating speed also greatly affected LDW effectiveness. CONCLUSIONS: The results of this study show that the expected field performance of FCW and LDW systems are highly dependent on the design and system limitations. Systems that delivered warnings earlier and operated at lower speeds may prevent far more crashes and injuries than systems that warn late and operate only at high speeds. These results suggest that future FCW and LDW evaluation should prioritize early warnings and full-speed range operation. A limitation of this study is that additional crash avoidance features that may also mitigate collisions-for example, brake assist, automated braking, or lane-keeping assistance-were not evaluated during the NCAP tests or in our benefits models. The potential additional mitigating effects of these systems were not quantified in this study. PMID- 26436220 TI - Real-World Rib Fracture Patterns in Frontal Crashes in Different Restraint Conditions. AB - OBJECTIVE: The purpose of this study was to use the detailed medical injury information in the Crash Injury Research and Engineering Network (CIREN) to evaluate patterns of rib fractures in real-world crash occupants in both belted and unbelted restraint conditions. Fracture patterns binned into rib regional levels were examined to determine normative trends associated with belt use and other possible contributing factors. METHODS: Front row adult occupants with Abbreviated Injury Scale (AIS) 3+ rib fractures, in frontal crashes with a deployed frontal airbag, were selected from the CIREN database. The circumferential location of each rib fracture (with respect to the sternum) was documented using a previously published method (Ritchie et al. 2006) and digital computed tomography scans. Fracture patterns for different crash and occupant parameters (restraint use, involved physical component, occupant kinematics, crash principal direction of force, and occupant age) were compared qualitatively and quantitatively. RESULTS: There were 158 belted and 44 unbelted occupants included in this study. For belted occupants, fractures were mainly located near the path of the shoulder belt, with the majority of fractures occurring on the inboard (with respect to the vehicle) side of the thorax. For unbelted occupants, fractures were approximately symmetric and distributed across both sides of the thorax. There were negligible differences in fracture patterns between occupants with frontal (0 degrees ) and near side (330 degrees to 350 degrees for drivers; 10 degrees to 30 degrees for passengers) crash principal directions of force but substantial differences between groups when occupant kinematics (and contacts within the vehicle) were considered. Age also affected fracture pattern, with fractures tending to occur more anteriorly in older occupants and more laterally in younger occupants (both belted and unbelted). CONCLUSIONS: Results of this study confirmed with real-world data that rib fracture patterns in unbelted occupants were more distributed and symmetric across the thorax compared to belted occupants in crashes with a deployed frontal airbag. Other factors, such as occupant kinematics and occupant age, also produced differing patterns of fractures. Normative data on rib fracture patterns in real-world occupants can contribute to understanding injury mechanisms and the role of different causation factors, which can ultimately help prevent fractures and improve vehicle safety. PMID- 26436207 TI - Remote Ischemic Preconditioning and Outcomes of Cardiac Surgery. AB - BACKGROUND: Whether remote ischemic preconditioning (transient ischemia and reperfusion of the arm) can improve clinical outcomes in patients undergoing coronary-artery bypass graft (CABG) surgery is not known. We investigated this question in a randomized trial. METHODS: We conducted a multicenter, sham controlled trial involving adults at increased surgical risk who were undergoing on-pump CABG (with or without valve surgery) with blood cardioplegia. After anesthesia induction and before surgical incision, patients were randomly assigned to remote ischemic preconditioning (four 5-minute inflations and deflations of a standard blood-pressure cuff on the upper arm) or sham conditioning (control group). Anesthetic management and perioperative care were not standardized. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization, or stroke, assessed 12 months after randomization. RESULTS: We enrolled a total of 1612 patients (811 in the control group and 801 in the ischemic-preconditioning group) at 30 cardiac surgery centers in the United Kingdom. There was no significant difference in the cumulative incidence of the primary end point at 12 months between the patients in the remote ischemic preconditioning group and those in the control group (212 patients [26.5%] and 225 patients [27.7%], respectively; hazard ratio with ischemic preconditioning, 0.95; 95% confidence interval, 0.79 to 1.15; P=0.58). Furthermore, there were no significant between-group differences in either adverse events or the secondary end points of perioperative myocardial injury (assessed on the basis of the area under the curve for the high sensitivity assay of serum troponin T at 72 hours), inotrope score (calculated from the maximum dose of the individual inotropic agents administered in the first 3 days after surgery), acute kidney injury, duration of stay in the intensive care unit and hospital, distance on the 6-minute walk test, and quality of life. CONCLUSIONS: Remote ischemic preconditioning did not improve clinical outcomes in patients undergoing elective on-pump CABG with or without valve surgery. (Funded by the Efficacy and Mechanism Evaluation Program [a Medical Research Council and National Institute of Health Research partnership] and the British Heart Foundation; ERICCA ClinicalTrials.gov number, NCT01247545.). PMID- 26436221 TI - Driver Injury Risk Variability in Finite Element Reconstructions of Crash Injury Research and Engineering Network (CIREN) Frontal Motor Vehicle Crashes. AB - OBJECTIVE: A 3-phase real-world motor vehicle crash (MVC) reconstruction method was developed to analyze injury variability as a function of precrash occupant position for 2 full-frontal Crash Injury Research and Engineering Network (CIREN) cases. METHOD: Phase I: A finite element (FE) simplified vehicle model (SVM) was developed and tuned to mimic the frontal crash characteristics of the CIREN case vehicle (Camry or Cobalt) using frontal New Car Assessment Program (NCAP) crash test data. Phase II: The Toyota HUman Model for Safety (THUMS) v4.01 was positioned in 120 precrash configurations per case within the SVM. Five occupant positioning variables were varied using a Latin hypercube design of experiments: seat track position, seat back angle, D-ring height, steering column angle, and steering column telescoping position. An additional baseline simulation was performed that aimed to match the precrash occupant position documented in CIREN for each case. Phase III: FE simulations were then performed using kinematic boundary conditions from each vehicle's event data recorder (EDR). HIC15, combined thoracic index (CTI), femur forces, and strain-based injury metrics in the lung and lumbar vertebrae were evaluated to predict injury. RESULTS: Tuning the SVM to specific vehicle models resulted in close matches between simulated and test injury metric data, allowing the tuned SVM to be used in each case reconstruction with EDR-derived boundary conditions. Simulations with the most rearward seats and reclined seat backs had the greatest HIC15, head injury risk, CTI, and chest injury risk. Calculated injury risks for the head, chest, and femur closely correlated to the CIREN occupant injury patterns. CTI in the Camry case yielded a 54% probability of Abbreviated Injury Scale (AIS) 2+ chest injury in the baseline case simulation and ranged from 34 to 88% (mean = 61%) risk in the least and most dangerous occupant positions. The greater than 50% probability was consistent with the case occupant's AIS 2 hemomediastinum. Stress-based metrics were used to predict injury to the lower leg of the Camry case occupant. The regional-level injury metrics evaluated for the Cobalt case occupant indicated a low risk of injury; however, strain-based injury metrics better predicted pulmonary contusion. Approximately 49% of the Cobalt occupant's left lung was contused, though the baseline simulation predicted 40.5% of the lung to be injured. CONCLUSIONS: A method to compute injury metrics and risks as functions of precrash occupant position was developed and applied to 2 CIREN MVC FE reconstructions. The reconstruction process allows for quantification of the sensitivity and uncertainty of the injury risk predictions based on occupant position to further understand important factors that lead to more severe MVC injuries. PMID- 26436222 TI - Evaluation of Vehicle-Based Crash Severity Metrics. AB - OBJECTIVE: Vehicle change in velocity (delta-v) is a widely used crash severity metric used to estimate occupant injury risk. Despite its widespread use, delta-v has several limitations. Of most concern, delta-v is a vehicle-based metric which does not consider the crash pulse or the performance of occupant restraints, e.g. seatbelts and airbags. Such criticisms have prompted the search for alternative impact severity metrics based upon vehicle kinematics. The purpose of this study was to assess the ability of the occupant impact velocity (OIV), acceleration severity index (ASI), vehicle pulse index (VPI), and maximum delta-v (delta-v) to predict serious injury in real world crashes. METHODS: The study was based on the analysis of event data recorders (EDRs) downloaded from the National Automotive Sampling System / Crashworthiness Data System (NASS-CDS) 2000-2013 cases. All vehicles in the sample were GM passenger cars and light trucks involved in a frontal collision. Rollover crashes were excluded. Vehicles were restricted to single-event crashes that caused an airbag deployment. All EDR data were checked for a successful, completed recording of the event and that the crash pulse was complete. The maximum abbreviated injury scale (MAIS) was used to describe occupant injury outcome. Drivers were categorized into either non-seriously injured group (MAIS2-) or seriously injured group (MAIS3+), based on the severity of any injuries to the thorax, abdomen, and spine. ASI and OIV were calculated according to the Manual for Assessing Safety Hardware. VPI was calculated according to ISO/TR 12353-3, with vehicle-specific parameters determined from U.S. New Car Assessment Program crash tests. Using binary logistic regression, the cumulative probability of injury risk was determined for each metric and assessed for statistical significance, goodness-of-fit, and prediction accuracy. RESULTS: The dataset included 102,744 vehicles. A Wald chi-square test showed each vehicle-based crash severity metric estimate to be a significant predictor in the model (p < 0.05). For the belted drivers, both OIV and VPI were significantly better predictors of serious injury than delta-v (p < 0.05). For the unbelted drivers, there was no statistically significant difference between delta-v, OIV, VPI, and ASI. CONCLUSIONS: The broad findings of this study suggest it is feasible to improve injury prediction if we consider adding restraint performance to classic measures, e.g. delta-v. Applications, such as advanced automatic crash notification, should consider the use of different metrics for belted versus unbelted occupants. PMID- 26436223 TI - Implications of Functional Capacity Loss and Fatality for Vehicle Safety Prioritization. AB - OBJECTIVE: We investigate the use of the Functional Capacity Index (FCI) as a tool for establishing vehicle safety priorities by comparing the life year burden of injuries to the burden of fatality in frontal and side automotive crashes. We demonstrate FCI's utility by investigating in detail the resulting disabling injuries and their life year costs. METHODS: We selected occupants in the 2000 2013 NASS-CDS database involved in frontal and side crashes, merged their injuries with FCI, and then used the merged data to estimate each occupant's overall functional loss. Lifetime functional loss was assessed by combining this measure of impairment with the occupants' expected future life spans, estimated from the Social Security Administration's Actuarial Life Table. RESULTS: Frontal crashes produce a large number of disabling injuries, particularly to the lower extremities. In our population, these crashes are estimated to account for approximately 400,000 life years lost to disability in comparison with 500,000 life years lost to fatality. Victims of side crashes experienced a higher rate of fatality but a significantly lower rate of disabling injury (0.3 vs. 1.0%), resulting in approximately 370,000 life years lost to fatality versus 50,000 life years lost to disability. CONCLUSIONS: The burden of disabling injuries to car crash survivors should be considered when setting vehicle safety design priorities. In frontal crashes this burden in life years is similar to the burden attributable to fatality. PMID- 26436224 TI - Association Between NCAP Ratings and Real-World Rear Seat Occupant Risk of Injury. AB - OBJECTIVE: Several studies have evaluated the correlation between U.S. or Euro New Car Assessment Program (NCAP) ratings and injury risk to front seat occupants, in particular driver injuries. Conversely, little is known about whether NCAP 5-star ratings predict real-world risk of injury to restrained rear seat occupants. The NHTSA has identified rear seat occupant protection as a specific area under consideration for improvements to its NCAP. In order to inform NHTSA's efforts, we examined how NCAP's current 5-star rating system predicts risk of moderate or greater injury among restrained rear seat occupants in real-world crashes. METHODS: We identified crash-involved vehicles, model year 2004-2013, in NASS-CDS (2003-2012) with known make and model and nonmissing occupant information. We manually matched these vehicles to their NCAP star ratings using data on make, model, model year, body type, and other identifying information. The resultant linked NASS-CDS and NCAP database was analyzed to examine associations between vehicle ratings and rear seat occupant injury risk; risk to front seat occupants was also estimated for comparison. Data were limited to restrained occupants and occupant injuries were defined as any injury with a maximum Abbreviated Injury Scale (AIS) score of 2 or greater. RESULTS: We linked 95% of vehicles in NASS-CDS to a specific vehicle in NCAP. The 18,218 vehicles represented an estimated 6 million vehicles with over 9 million occupants. Rear seat passengers accounted for 12.4% of restrained occupants. The risk of injury in all crashes for restrained rear seat occupants was lower in vehicles with a 5 star driver rating in frontal impact tests (1.4%) than with 4 or fewer stars (2.6%, P =.015); results were similar for the frontal impact passenger rating (1.3% vs. 2.4%, P =.024). Conversely, side impact driver and passenger crash tests were not associated with rear seat occupant injury risk (driver test: 1.7% for 5-star vs. 1.8% for 1-4 stars; passenger test: 1.6% for 5 stars vs 1.8% for 1 4 stars). CONCLUSIONS: Current frontal impact test procedures provide some degree of discrimination in real-world rear seat injury risk among vehicles with 5 compared to fewer than 5 stars. However, there is no evidence that vehicles with a 5-star side impact passenger rating, which is the only crash test procedure to include an anthropomorphic test dummy (ATD) in the rear, demonstrate lower risks of injury in the rear than vehicles with fewer than 5 stars. These results support prioritizing modifications to the NCAP program that specifically evaluate rear seat injury risk to restrained occupants of all ages. PMID- 26436226 TI - Effects of LATCH versus Available Seatbelt Installation of Rear Facing Child Restraint Systems on Head Injury Criteria for 6 Month Old Infants in Rear End Collisions. AB - OBJECTIVE: The Lower Anchor and Tethers for CHildren (LATCH) system was introduced in vehicles made after September 1, 2002 and intended to make installation of rear and forward-facing child safety seats easier. Due to the lack of rear impact testing of RFCRS required per the Federal Motor Vehicle Safety Standards (FMVSS), the purpose of this study was to explore the effects, if any, of installation method of RFCRS on the performance of commonly purchased makes and models of RFCRS. Specifically, we hypothesize that in a 48 km/h (29.8 MPH) rear-end collision, installation of RFCRS using the LATCH system will result in higher Head Injury Criteria (HIC) values when compared to using the available lap/shoulder seatbelt (Emergency Locking Retractor - ELR or Automatic Locking Retractor - ALR). METHODS: The test matrix included 36 rear impact sled tests conducted using 3 installation methods on 3 models of RFCRS: the Graco SnugRide(r) with and without the base, the Britax Chaperone with base-mounted anti-rebound bar, and the Evenflo Tribute(r), a model of convertible rearward/forward facing restraint system used in the rearward facing mode. The seats were installed using the LATCH system, ELR lap/shoulder belts, or ALR lap/shoulder belts in seating positions 4 and 6 on a vehicle buck mounted to the sled test base. The infant seat and 6 month old CRABI anthropometric test device (ATD) installation methods were in accordance with standards set forth in the National Highway Traffic Safety Administration's (NHTSA) FMVSS No. 213, Child Restraint Systems. All tests were conducted on pneumatic controlled acceleration sled (HYGE, Inc., PA, USA) at 48 km/h. RESULTS: Installation of infant seat type RFCRS using the LATCH system resulted in higher HIC15 values when compared to using the available lap/shoulder seatbelt (ELR or ALR). The mean HIC15 values were most severe when infant seat type RFCRS were installed using LATCH (Graco SnugRide(r) HIC15 = 394 and Britax Chaperone HIC15 = 133) compared to using either ELR lap/shoulder belts (Graco SnugRide(r) HIC15 = 218 and Britax Chaperone HIC15 = 65) or ALR lap/shoulder belts (Graco SnugRide(r) HIC15 = 194 and Britax Chaperone HIC15 = 78). The installation method did not result in a statistically significant difference in HIC for the convertible type RFCRS (Evenflo Tribute(r)). In many of the tests, the ATD's head struck the seatback in which the RFCRS was installed. These head strikes resulted in the higher HIC15 scores recorded throughout the testing. CONCLUSIONS: The results of this study suggest that LATCH does not offer equal protection to lap/shoulder belts from head injuries in rear impacts when used with infant seat type RFCRS. PMID- 26436225 TI - Lumbar Bone Mineral Density Phantomless Computed Tomography Measurements and Correlation with Age and Fracture Incidence. AB - OBJECTIVE: Low bone quality is a contributing factor to motor vehicle crash (MVC) injury. Quantification of occupant bone mineral density (BMD) is important from an injury causation standpoint. The first aim of this study was to validate a technique for measuring lumbar volumetric BMD (vBMD) from phantomless computed tomography (CT) scans. The second aim was to apply the validated phantomless technique to quantify lumbar vBMD in Crash Injury Research and Engineering Network (CIREN) occupants for correlation with age, fracture incidence, and osteopenia/osteoporosis diagnoses. METHODS: Quantitative CT (qCT) and dual-energy X-ray absorptiometry (DXA) were collected prospectively for 50 subjects and used to validate a technique to measure vBMD from 281 phantomless CT scans of CIREN occupants. Hounsfield unit (HU) measurements were collected from the L1-L5 vertebrae, right psoas major muscle, and anterior subcutaneous fat for all subjects and from 3 phantom ports with known mg/cc calcium hydroxyapatite values for the validation group. qCT calibration was accomplished using regressions between the phantom HU and mg/cc values to convert L1-L5 HU values to mg/cc. A phantomless calibration technique was developed where the fat and muscle HU values were linearly regressed against fat (-69 mg/cc) and muscle (77 mg/cc) to establish a conversion for L1-L5 HU measurements to mg/cc. vBMD calculated from qCT versus the phantomless method was compared for the 50 subjects to assess agreement and a mg/cc osteopenia threshold was established using DXA T-scores. CIREN HU measurements were converted to mg/cc using the phantomless technique and the mg/cc osteopenia threshold was used to compare vBMD to age, fracture incidence, and osteopenia comorbidity classifications in CIREN. RESULTS: Linear regression of lumbar vBMD derived from the qCT versus phantomless calibrations showed excellent agreement (R(2) = 0.87, P <.0001). A 145 mg/cc threshold for osteopenia was established (sensitivity = 1, specificity = 0.57) and 44 CIREN occupants had vBMD below this threshold. Of these 44 occupants, 64% were not classified as osteopenic in CIREN, but vBMD suggested undiagnosed osteopenia. Age was negatively correlated with vBMD in both sexes (P <.0001) and CIREN occupants with less than 145 mg/cc vBMD sustained an average 1.7 additional rib/sternum fractures (P =.036). CONCLUSIONS: Because lumbar vBMD was estimated from phantomless CT scans with accuracy similar to qCT, the phantomless technique can be broadly applied to both prospectively and retrospectively assess patient bone quality for research and clinical studies related to MVCs, falls, and aging. PMID- 26436227 TI - Older Adults at Increased Risk as Pedestrians in Victoria, Australia: An Examination of Crash Characteristics and Injury Outcomes. AB - OBJECTIVES: Engaging in active transport modes (especially walking) is a healthy and environmentally friendly alternative to driving and may be particularly beneficial for older adults. However, older adults are a vulnerable group: they are at higher risk of injury compared with younger adults, mainly due to frailty and may be at increased risk of collision due to the effects of age on sensory, cognitive, and motor abilities. Moreover, our population is aging, and there is a trend for the current cohort of older adults to maintain mobility later in life compared with previous cohorts. Though these trends have serious implications for transport policy and safety, little is known about the contributing factors and injury outcomes of pedestrian collision. Further, previous research generally considers the older population as a homogeneous group and rarely considers the increased risks associated with continued ageing. METHOD: Collision characteristics and injury outcomes for 2 subgroups of older pedestrians (65-74 years and 75+ years) were examined by extracting data from the state police reported crash dataset and hospital admission/emergency department presentation data over the 10-year period between 2003 and 2012. Variables identified for analysis included pedestrian characteristics (age, gender, activity, etc.), crash location and type, injury characteristics and severity, and duration of hospital stay. A spatial analysis of crash locations was also undertaken to identify collision clusters and the contribution of environmental features on collision and injury risk. RESULTS: Adults over 65 years were involved in 21% of all pedestrian collisions. A high fatality rate was found among older adults, particularly for those aged 75 years and older: this group had 3.2 deaths per 100,000 population, compared to a rate of 1.3 for 65- to 74-year-olds and 0.7 for adults below 65 years of age. Older pedestrian injuries were most likely to occur while crossing the carriageway; they were also more likely to be injured in parking lots, at driveway intersections, and on sidewalks compared to younger cohorts. Spatial analyses revealed older pedestrian crash clusters on arterial roads in urban shopping precincts. Significantly higher rates of hospital admissions were found for pedestrians over the age of 75 years and for abdominal, head, and neck injuries; conversely, older adults were underrepresented in emergency department presentations (mainly lower and upper extremity injuries), suggesting an increased severity associated with older pedestrian injuries. Average length of hospital stay also increased with increasing age. CONCLUSION: This analysis revealed age differences in collision risk and injury outcomes among older adults and that aggregate analysis of older pedestrians can distort the significance of risk factors associated with older pedestrian injuries. These findings have implications that extend to the development of engineering, behavioral, and enforcement countermeasures to address the problems faced by the oldest pedestrians and reduce collision risk and improve injury outcomes. PMID- 26436228 TI - Biofidelity Corridors for Sternum Kinematics in Low-Speed Side Impacts. AB - OBJECTIVE: Field data show that side impact car crashes have become responsible for a greater proportion of the fatal crashes compared to frontal crashes, which suggests that the protection gained in frontal impact has not been matched in side impact. One of the reasons is the lack of understanding of the torso injury mechanisms in side impact. In particular, the deformation of the rib cage and how it affects the mechanical loading of the individual ribs have yet to be established. Therefore, the objective of this study was to characterize the ribcage deformation in side impacts by describing the kinematics of the sternum relative to the spine. METHODS: The 3D kinematics of the 1st and of the 5th or 6th thoracic vertebrae and of the sternum were obtained for three Post Mortem Human Subjects (PMHS) impacted laterally by a rigid wall traveling at 15 km/h. The experimental data were processed to express the kinematics of the sternum relative to the spine throughout the impact event. Methods were developed to interpolate the kinematics of the vertebrae for which experimental data were not available. RESULTS: The kinematics of the sternocostal junction for ribs 1 to 6 as well as the orientation of the sternum were expressed in the vertebra coordinate systems defined for each upper thoracic vertebra (T1 to T6). Corridors were designed for the motion of the sternum relative to each vertebra. In the experiments, the sternum moved upward for all rib levels (1 to 6), and away from the spine with an amplitude that increased with the decreasing rib level (from rib 1 to rib 6). None of the differences observed in the kinematics could be correlated to the occurrence of rib fractures. CONCLUSIONS: This study provides both qualitative and quantitative information for the ribcage skeletal kinematics in side impact. This data set provides the information required to better evaluate computational models of the thorax for side impact simulations. The corridors developed in this study provide new biofidelity targets for the impact response of the ribcage. This study contributes to augmenting the state of knowledge of the human chest deformation in side impact to better characterize the rib fracture mechanisms. PMID- 26436229 TI - Driver Behavior During Overtaking Maneuvers from the 100-Car Naturalistic Driving Study. AB - OBJECTIVE: Lane changes with the intention to overtake the vehicle in front are especially challenging scenarios for forward collision warning (FCW) designs. These overtaking maneuvers can occur at high relative vehicle speeds and often involve no brake and/or turn signal application. Therefore, overtaking presents the potential of erroneously triggering the FCW. A better understanding of driver behavior during lane change events can improve designs of this human-machine interface and increase driver acceptance of FCW. The objective of this study was to aid FCW design by characterizing driver behavior during lane change events using naturalistic driving study data. METHODS: The analysis was based on data from the 100-Car Naturalistic Driving Study, collected by the Virginia Tech Transportation Institute. The 100-Car study contains approximately 1.2 million vehicle miles of driving and 43,000 h of data collected from 108 primary drivers. In order to identify overtaking maneuvers from a large sample of driving data, an algorithm to automatically identify overtaking events was developed. The lead vehicle and minimum time to collision (TTC) at the start of lane change events was identified using radar processing techniques developed in a previous study. The lane change identification algorithm was validated against video analysis, which manually identified 1,425 lane change events from approximately 126 full trips. RESULTS: Forty-five drivers with valid time series data were selected from the 100-Car study. From the sample of drivers, our algorithm identified 326,238 lane change events. A total of 90,639 lane change events were found to involve a closing lead vehicle. Lane change events were evenly distributed between left side and right side lane changes. The characterization of lane change frequency and minimum TTC was divided into 10 mph speed bins for vehicle travel speeds between 10 and 90 mph. For all lane change events with a closing lead vehicle, the results showed that drivers change lanes most frequently in the 40-50 mph speed range. Minimum TTC was found to increase with travel speed. The variability in minimum TTC between drivers also increased with travel speed. CONCLUSIONS: This study developed and validated an algorithm to detect lane change events in the 100-Car Naturalistic Driving Study and characterized lane change events in the database. The characterization of driver behavior in lane change events showed that driver lane change frequency and minimum TTC vary with travel speed. The characterization of overtaking maneuvers from this study will aid in improving the overall effectiveness of FCW systems by providing active safety system designers with further understanding of driver action in overtaking maneuvers, thereby increasing system warning accuracy, reducing erroneous warnings, and improving driver acceptance. PMID- 26436230 TI - Analysis of Driver Evasive Maneuvering Prior to Intersection Crashes Using Event Data Recorders. AB - OBJECTIVE: Intersection crashes account for over 4,500 fatalities in the United States each year. Intersection Advanced Driver Assistance Systems (I-ADAS) are emerging vehicle-based active safety systems that have the potential to help drivers safely navigate across intersections and prevent intersection crashes and injuries. The performance of an I-ADAS is expected to be highly dependent upon driver evasive maneuvering prior to an intersection crash. Little has been published, however, on the detailed evasive kinematics followed by drivers prior to real-world intersection crashes. The objective of this study was to characterize the frequency, timing, and kinematics of driver evasive maneuvers prior to intersection crashes. METHODS: Event data recorders (EDRs) downloaded from vehicles involved in intersection crashes were investigated as part of NASS CDS years 2001 to 2013. A total of 135 EDRs with precrash vehicle speed and braking application were downloaded to investigate evasive braking. A smaller subset of 59 EDRs that collected vehicle yaw rate was additionally analyzed to investigate evasive steering. Each vehicle was assigned to one of 3 precrash movement classifiers (traveling through the intersection, completely stopped, or rolling stop) based on the vehicle's calculated acceleration and observed velocity profile. To ensure that any significant steering input observed was an attempted evasive maneuver, the analysis excluded vehicles at intersections that were turning, driving on a curved road, or performing a lane change. Braking application at the last EDR-recorded time point was assumed to indicate evasive braking. A vehicle yaw rate greater than 4 degrees per second was assumed to indicate an evasive steering maneuver. RESULTS: Drivers executed crash avoidance maneuvers in four-fifths of intersection crashes. A more detailed analysis of evasive braking frequency by precrash maneuver revealed that drivers performing complete or rolling stops (61.3%) braked less often than drivers traveling through the intersection without yielding (79.0%). After accounting for uncertainty in the timing of braking and steering data, the median evasive braking time was found to be between 0.5 to 1.5 s prior to impact, and the median initial evasive steering time was found to occur between 0.5 and 0.9 s prior to impact. The median average evasive braking deceleration for all cases was found to be 0.58 g. The median of the maximum evasive vehicle yaw rates was found to be 8.2 degrees per second. Evasive steering direction was found to be most frequently in the direction of travel of the approaching vehicle. CONCLUSIONS: The majority of drivers involved in intersection crashes were alert enough to perform an evasive action. Most drivers used a combination of steering and braking to avoid a crash. The average driver attempted to steer and brake at approximately the same time prior to the crash. PMID- 26436231 TI - On-Scene Injury Severity Prediction (OSISP) Algorithm for Truck Occupants. AB - OBJECTIVE: The aim of this study is to develop an on-scene injury severity prediction (OSISP) algorithm for truck occupants using only accident characteristics that are feasible to assess at the scene of the accident. The purpose of developing this algorithm is to use it as a basis for a field triage tool used in traffic accidents involving trucks. In addition, the model can be valuable for recognizing important factors for improving triage protocols used in Sweden and possibly in other countries with similar traffic environments and prehospital procedures. METHODS: The scope is adult truck occupants involved in traffic accidents on Swedish public roads registered in the Swedish Traffic Accident Data Acquisition (STRADA) database for calendar years 2003 to 2013. STRADA contains information reported by the police and medical data on injured road users treated at emergency hospitals. Using data from STRADA, 2 OSISP multivariate logistic regression models for deriving the probability of severe injury (defined here as having an Injury Severity Score [ISS] > 15) were implemented for light and heavy trucks; that is, trucks with weight up to 3,500 kg and ? 16,500 kg, respectively. A 10-fold cross-validation procedure was used to estimate the performance of the OSISP algorithm in terms of the area under the receiver operating characteristic curve (AUC). RESULTS: The rate of belt use was low, especially for heavy truck occupants. The OSISP models developed for light and heavy trucks achieved cross-validation AUC of 0.81 and 0.74, respectively. The AUC values obtained when the models were evaluated on all data without cross validation were 0.87 for both light and heavy trucks. The difference in the AUC values with and without use of cross-validation indicates overfitting of the model, which may be a consequence of relatively small data sets. Belt use stands out as the most valuable predictor in both types of trucks; accident type and age are important predictors for light trucks. CONCLUSIONS: The OSISP models achieve good discriminating capability for light truck occupants and a reasonable performance for heavy truck occupants. The prediction accuracy may be increased by acquiring more data. Belt use was the strongest predictor of severe injury for both light and heavy truck occupants. There is a need for behavior-based safety programs and/or other means to encourage truck occupants to always wear a seat belt. PMID- 26436232 TI - New Methodology for an Expert-Designed Map From International Classification of Diseases (ICD) to Abbreviated Injury Scale (AIS) 3+ Severity Injury. AB - OBJECTIVE: There has been a longstanding desire for a map to convert International Classification of Diseases (ICD) injury codes to Abbreviated Injury Scale (AIS) codes to reflect the severity of those diagnoses. The Association for the Advancement of Automotive Medicine (AAAM) was tasked by European Union representatives to create a categorical map classifying diagnoses codes as serious injury (Abbreviated Injury Scale [AIS] 3+), minor/moderate injury (AIS 1/2), or indeterminate. This study's objective was to map injury-related ICD-9-CM (clinical modification) and ICD-10-CM codes to these severity categories. METHODS: Approximately 19,000 ICD codes were mapped, including injuries from the following categories: amputations, blood vessel injury, burns, crushing injury, dislocations/sprains/strains, foreign body, fractures, internal organ, nerve/spinal cord injury, intracranial, laceration, open wounds, and superficial injury/contusion. Two parallel activities were completed to create the maps: (1) An in-person expert panel and (2) an electronic survey. The panel consisted of expert users of AIS and ICD from North America, the United Kingdom, and Australia. The panel met in person for 5 days, with follow-up virtual meetings to create and revise the maps. Additional qualitative data were documented to resolve potential discrepancies in mapping. The electronic survey was completed by 95 injury coding professionals from North America, Spain, Australia, and New Zealand over 12 weeks. ICD-to-AIS maps were created for: ICD-9-CM and ICD-10-CM. Both maps indicated whether the corresponding AIS 2005/Update 2008 severity score for each ICD code was AIS 3+, 1/2, or indeterminable. Though some ICD codes could be mapped to multiple AIS codes, the maximum severity of all potentially mapped injuries determined the final severity categorization. RESULTS: The in-person panel consisted of 13 experts, with 11 Certified AIS specialists (CAISS) with a median of 8 years and an average of 15 years of coding experience. Consensus was reached for AIS severity categorization for all injury-related ICD codes. There were 95 survey respondents, with a median of 8 years of injury coding experience. Approximately 15 survey responses were collected per ICD code. Results from the 2 activities were compared, and any discrepancies were resolved using additional qualitative and quantitative data from the in-person panel and survey results, respectively. CONCLUSIONS: Robust maps of ICD-9-CM and ICD-10-CM injury codes to AIS severity categories (3+ versus <3) were successfully created from an in person panel discussion and electronic survey. These maps provide a link between the common ICD diagnostic lexicons and the AIS severity coding system and are of value to injury researchers, public health scientists, and epidemiologists using large databases without available AIS coding. PMID- 26436233 TI - Mortality Risk in Pediatric Motor Vehicle Crash Occupants: Accounting for Developmental Stage and Challenging Abbreviated Injury Scale Metrics. AB - OBJECTIVE: Survival risk ratios (SRRs) and their probabilistic counterpart, mortality risk ratios (MRRs), have been shown to be at odds with Abbreviated Injury Scale (AIS) severity scores for particular injuries in adults. SRRs have been validated for pediatrics but have not been studied within the context of pediatric age stratifications. We hypothesized that children with similar motor vehicle crash (MVC) injuries may have different mortality risks (MR) based upon developmental stage and that these MRs may not correlate with AIS severity. METHODS: The NASS-CDS 2000-2011 was used to define the top 95% most common AIS 2+ injuries among MVC occupants in 4 age groups: 0-4, 5-9, 10-14, and 15-18 years. Next, the National Trauma Databank 2002-2011 was used to calculate the MR (proportion of those dying with an injury to those sustaining the injury) and the co-injury-adjusted MR (MRMAIS) for each injury within 6 age groups: 0-4, 5-9, 10 14, 15-18, 0-18, and 19+ years. MR differences were evaluated between age groups aggregately, between age groups based upon anatomic injury patterns and between age groups on an individual injury level using nonparametric Wilcoxon tests and chi-square or Fisher's exact tests as appropriate. Correlation between AIS and MR within each age group was also evaluated. RESULTS: MR and MRMAIS distributions of the most common AIS 2+ injuries were right skewed. Aggregate MR of these most common injuries varied between the age groups, with 5- to 9-year-old and 10- to 14-year-old children having the lowest MRs and 0- to 4-year-old and 15- to 18 year-old children and adults having the highest MRs (all P <.05). Head and thoracic injuries imparted the greatest mortality risk in all age groups with median MRMAIS ranging from 0 to 6% and 0 to 4.5%, respectively. Injuries to particular body regions also varied with respect to MR based upon age. For example, thoracic injuries in adults had significantly higher MRMAIS than such injuries among 5- to 9-year-olds and 10- to 14-year-olds (P =.04; P <.01). Furthermore, though AIS was positively correlated with MR within each age group, less correlation was seen for children than for adults. Large MR variations were seen within each AIS grade, with some lower AIS severity injuries demonstrating greater MRs than higher AIS severity injuries. As an example, MRMAIS in 0- to 18 year-olds was 0.4% for an AIS 3 radius fracture versus 1.4% for an AIS 2 vault fracture. CONCLUSIONS: Trauma severity metrics are important for outcome prediction models and can be used in pediatric triage algorithms and other injury research. Trauma severity may vary for similar injuries based upon developmental stage, and this difference should be reflected in severity metrics. The MR-based data-driven determination of injury severity in pediatric occupants of different age cohorts provides a supplement or an alternative to AIS severity classification for pediatric occupants in MVCs. PMID- 26436234 TI - Constrained Laboratory vs. Unconstrained Steering-Induced Rollover Crash Tests. AB - OBJECTIVE: The goal of this study was to evaluate how well an in-laboratory rollover crash test methodology that constrains vehicle motion can reproduce the dynamics of unconstrained full-scale steering-induced rollover crash tests in sand. METHODS: Data from previously-published unconstrained steering-induced rollover crash tests using a full-size pickup and mid-sized sedan were analyzed to determine vehicle-to-ground impact conditions and kinematic response of the vehicles throughout the tests. Then, a pair of replicate vehicles were prepared to match the inertial properties of the steering-induced test vehicles and configured to record dynamic roof structure deformations and kinematic response. RESULTS: Both vehicles experienced greater increases in roll-axis angular velocities in the unconstrained tests than in the constrained tests; however, the increases that occurred during the trailing side roof interaction were nearly identical between tests for both vehicles. Both vehicles experienced linear accelerations in the constrained tests that were similar to those in the unconstrained tests, but the pickup, in particular, had accelerations that were matched in magnitude, timing, and duration very closely between the two test types. Deformations in the truck test were higher in the constrained than the unconstrained, and deformations in the sedan were greater in the unconstrained than the constrained as a result of constraints of the test fixture, and differences in impact velocity for the trailing side. CONCLUSIONS: The results of the current study suggest that in-laboratory rollover tests can be used to simulate the injury-causing portions of unconstrained rollover crashes. To date, such a demonstration has not yet been published in the open literature. This study did, however, show that road surface can affect vehicle response in a way that may not be able to be mimicked in the laboratory. Lastly, this study showed that configuring the in-laboratory tests to match the leading-side touchdown conditions could result in differences in the trailing side impact conditions. PMID- 26436235 TI - Assessment of Bilateral Thoracic Loading on the Near-Side Occupant Due to Occupant-to-Occupant Interaction in Vehicle Crash Tests. AB - OBJECTIVE: This study aims, by means of the WorldSID 50th percentile male, to evaluate thoracic loading and injury risk to the near-side occupant due to occupant-to-occupant interaction in combination with loading from an intruding structure. METHOD: Nine vehicle crash tests were performed with a 50th percentile WorldSID male dummy in the near-side (adjacent to the intruding structure) seat and a THOR or ES2 dummy in the far-side (opposite the intruding structure) seat. The near-side seated WorldSID was equipped with 6 + 6 IR-Traccs (LH and RH) in the thorax/abdomen enabling measurement of bilateral deflection. To differentiate deflection caused by the intrusion, and the deflection caused by the neighboring occupant, time history curves were analyzed. The crash tests were performed with different modern vehicles, equipped with thorax side airbags and inflatable curtains, ranging from a compact car to a large sedan, and in different loading conditions such as car-to-car, barrier, and pole tests. Lateral delta V based on vehicle tunnel acceleration and maximum residual intrusion at occupant position were used as a measurement of crash severity to compare injury measurements. RESULT: In the 9 vehicle crash tests, thoracic loading, induced by the intruding structure as well as from the far-side occupant, varied due to the size and structural performance of the car as well as the severity of the crash. Peak deflection on the thoracic outboard side occurred during the first 50 ms of the event. Between 70 to 150 ms loading induced by the neighboring occupant occurred and resulted in an inboard-side peak deflection and viscous criterion. In the tests where the target vehicle lateral delta V was below 30 km/h and intrusion less than 200 mm, deflections were low on both the outboard (20-40 mm) and inboard side (10-15 mm). At higher crash severities, delta V 35 km/h and above as well as intrusions larger than 350 mm, the inboard deflections (caused by interaction to the far-side occupant) were of the same magnitude or even higher (30-70 mm) than the outboard deflections (30-50 mm). CONCLUSION: A WorldSID 50th percentile male equipped with bilateral IR-Traccs can detect loading to the thorax from a neighboring occupant making injury risk assessment feasible for this type of loading. At crash severities resulting in a delta V above 35 km/h and intrusions larger than 350 mm, both the inboard deflection and VC resulted in high risks of Abbreviated Injury Scale (AIS) 3+ injury, especially for a senior occupant. PMID- 26436237 TI - Short Communications from AAAM's 59th Annual Scientific Conference. PMID- 26436236 TI - Injuries in Full-Scale Vehicle Side Impact Moving Deformable Barrier and Pole Tests Using Postmortem Human Subjects. AB - OBJECTIVE: To conduct near-side moving deformable barrier (MDB) and pole tests with postmortem human subjects (PMHS) in full-scale modern vehicles, document and score injuries, and examine the potential for angled chest loading in these tests to serve as a data set for dummy biofidelity evaluations and computational modeling. METHODS: Two PMHS (outboard left front and rear seat occupants) for MDB and one PMHS (outboard left front seat occupant) for pole tests were used. Both tests used sedan-type vehicles from same manufacturer with side airbags. Pretest x-ray and computed tomography (CT) images were obtained. Three-point belt restrained surrogates were positioned in respective outboard seats. Accelerometers were secured to T1, T6, and T12 spines; sternum and pelvis; seat tracks; floor; center of gravity; and MDB. Load cells were used on the pole. Biomechanical data were gathered at 20 kHz. Outboard and inboard high-speed cameras were used for kinematics. X-rays and CT images were taken and autopsy was done following the test. The Abbreviated Injury Scale (AIS) 2005 scoring scheme was used to score injuries. RESULTS: MDB test: male (front seat) and female (rear seat) PMHS occupant demographics: 52 and 57 years, 177 and 166 cm stature, 78 and 65 kg total body mass. Demographics of the PMHS occupant in the pole test: male, 26 years, 179 cm stature, and 84 kg total body mass. Front seat PMHS in MDB test: 6 near-side rib fractures (AIS = 3): 160-265 mm vertically from suprasternal notch and 40-80 mm circumferentially from center of sternum. Left rear seat PMHS responded with multiple bilateral rib fractures: 9 on the near side and 5 on the contralateral side (AIS = 3). One rib fractured twice. On the near and contralateral sides, fractures were 30-210 and 20-105 mm vertically from the suprasternal notch and 90-200 and 55-135 mm circumferentially from the center of sternum. A fracture of the left intertrochanteric crest occurred (AIS = 3). Pole test PMHS had one near-side third rib fracture. Thoracic accelerations of the 2 occupants were different in the MDB test. Though both occupants sustained positive and negative x-accelerations to the sternum, peak magnitudes and relative changes were greater for the rear than the front seat occupant. Magnitudes of the thoracic and sternum accelerations were lower in the pole test. CONCLUSIONS: This is the first study to use PMHS occupants in MDB and pole tests in the same recent model year vehicles with side airbag and head curtain restraints. Injuries to the unilateral thorax for the front seat PMHS in contrast to the bilateral thorax and hip for the rear seat occupant in the MDB test indicate the effects of impact on the seating location and restraint system. Posterolateral locations of fractures to the front seat PMHS are attributed to constrained kinematics of occupant interaction with torso side airbag restraint system. Angled loading to the rear seat occupant from coupled sagittal and coronal accelerations of the sternum representing anterior thorax loading contributed to bilateral fractures. Inward bending initiated by the distal femur complex resulting in adduction of ipsilateral lower extremity resulted in intertrochanteric fracture to the rear seat occupant. These results serve as a data set for evaluating the biofidelity of the WorldSID and federalized side impact dummies and assist in validating human body computational models, which are increasingly used in crashworthiness studies. PMID- 26436238 TI - Evaluating the Effect of a Mechanical Adjunct to Improve the Installation of Child Restraint Systems to Vehicles. AB - OBJECTIVES: We explored if an alternative CRS design that utilized a mechanical adjunct to amplify the force applied to the adult seat belt (intervention CRS) results in more accurate and secure attachment between the CRS and the vehicle compared to similar CRS models that use LATCH or the existing adult seat belt. We conducted three separate studies to address this question and additionally explored: (1) the contribution of prior CRS installation experience (Study 1), (2) the value-added of CRS labeling (Study 2), and (3) paper-based vs. video instructions (Study 3). METHODS: In Studies 1 and 2 we assessed a forward facing combination CRS design (intervention CRS) compared to a commercially available LATCH equipped model (control CRS) and in Study 3 we conducted a similar study using a convertible model of both the intervention and control CRS. Participants installed both CRS in a contemporary minivan and could choose which type of attachment to use for the control CRS (LATCH or seat belt); order of installation was counter-balanced. Evaluators systematically examined installations for accuracy and security. RESULTS: Study 1: A greater proportion of participants in both the experienced and inexperienced groups was able to securely install the intervention CRS compared to the control CRS: (45% vs. 16%, p =.0001 for experienced) and (37% vs. 6%, p =.003 for inexperienced). No differences between the CRS were observed for accuracy of installation in either user group. Study 2: A greater proportion of participants were able to securely install the enhanced intervention CRS compared to the control CRS: (62% vs. 9%, p =.001). The intervention CRS demonstrated reduced installation accuracy: (30% vs. 61%, p =.001). Study 3: A greater proportion of participants was able to securely install the intervention CRS compared to the control CRS: 79% vs. 66% p =.03, but this effect was smaller than in the previous studies. Participants were less likely to achieve an accurate installation with the intervention CRS compared to the control CRS: 54% vs. 79%, p =.004. Common accuracy errors in each study included twisting or misrouting the seatbelt when installing the intervention CRS. CONCLUSIONS: Our results suggest that novel CRS designs that utilize mechanical advantage to facilitate attachment of the CRS to the vehicle result in a tighter installation compared to LATCH equipped models, but an increase in accuracy errors occurred. PMID- 26436240 TI - Did Child Restraint Laws Globally Converge? Examining 40 Years of Policy Diffusion. AB - OBJECTIVE: The objective of the current study is to determine what factors have been associated with the global adoption of mandatory child restraint laws (ChRLs) since 1975. METHODS: In order to determine what factors explained the global adoption of mandatory ChRLs, Weibull models were analyzed. To carry out this analysis, 170 countries were considered and the time risk corresponded to 5,146 observations for the period 1957-2013. The dependent variable was first time to adopt a ChRL. Independent variables representing global factors were the World Health Organization (WHO) and World Bank's (WB) road safety global campaign; the Geneva Convention on Road Traffic; and the United Nation's (UN) 1958 Vehicle Agreement. Independent variables representing regional factors were the creation of the European Transport Safety Council and being a Commonwealth country. Independent variables representing national factors were population; gross domestic product (GDP) per capita; political violence; existence of road safety nongovernmental organizations (NGOs); and existence of road safety agencies. Urbanization served as a control variable. To examine regional dynamics, Weibull models for Africa, Asia, Europe, North America, Latin America, the Caribbean, and the Commonwealth were also carried out. RESULTS: Empirical estimates from full Weibull models suggest that 2 global factors and 2 national factors are significantly associated with the adoption of this measure. The global factors explaining adoption are the WHO and WB's road safety global campaign implemented after 2004 (P <.01), and the UN's 1958 Vehicle Agreement (P <.001). National factors were GDP (P <.01) and existence of road safety agencies (P <.05). The time parameter rho for the full Weibull model was 1.425 (P <.001), suggesting that the likelihood of ChRL adoption increased over the observed period of time, confirming that the diffusion of this policy was global. Regional analysis showed that the UN's Convention on Road Traffic was significant in Asia, the creation of the European Transport Safety Council was significant in Europe and North America, and the global campaign was in Africa. In Commonwealth and European and North American countries, the existence of road safety agencies was also positively associated with ChRL adoption. CONCLUSIONS: Results of the world models suggest that the WHO and WB's global road safety campaign was effective in disseminating ChRLs after 2004. Furthermore, regions such as Asia and Europe and North America were early adopters since specific regional and national characteristics anticipated the introduction of this policy before 2004. In this particular case, the creation of the European Transport Safety Council was fundamental in promoting ChRLs. Thus, in order to introduce conditions to more rapidly diffuse road safety measures across lagging regions, the maintenance of global efforts and the creation of road safety regional organizations should be encouraged. Lastly, the case of ChRL convergence illustrates how mechanisms of global and regional diffusion need to be analytically differentiated in order better to assess the process of policy diffusion. PMID- 26436241 TI - Reasons for Child Passenger Nonrestraint in Motor Vehicles. AB - OBJECTIVE: Although child passenger restraint use in motor vehicles has increased, there is an important minority of children who remain unrestrained. The goal of this study was to identify the frequency of and under what circumstances parents keep their children unrestrained. METHODS: A cross sectional, online survey was distributed to parents and caregivers of children 10 years old and younger. Survey participants were asked about child restraint practices, including frequency of and reasons for nonuse of restraints. Parents were specifically asked how acceptable it would be to keep their child unrestrained in certain situations. RESULTS: One thousand two hundred eighty-five parents and guardians responded to the survey and 1,002 completed it; 23.8% (95% confidence interval [CI], 21.3-26.6%) of respondents said they had driven with their child not fully restrained on at least one occasion. Approximately 1 in 5 parents strongly or somewhat agreed that it would be acceptable to keep their child unrestrained in certain situations, including a short drive, in a rush, an inadequate number of restraints, riding in a taxi, if somebody was holding the child, and as a reward for a child. Parents were more likely to agree that it was acceptable to keep their child unrestrained under nearly all circumstances listed if they were male, ages 18-29, with a graduate school education, in the $100,000+ income bracket, or Latino. CONCLUSIONS: There are certain situations for which parents find it acceptable to leave their children unrestrained. This has implications for targeted child passenger safety efforts designed to maximize consistent restraint use. PMID- 26436242 TI - Children's and Adults' Comfort Experience of Extra Seat Belts When Riding in the Rear Seat of a Passenger Car. AB - OBJECTIVE: The objective of this study was to explore passengers' comfort experience of extra seat belts during on-road driving in the rear seat of a passenger car and to investigate how the use of extra belts affects children's and adults' attitudes to the product. METHODS: Two different seat belt systems were tested, criss-cross (CC) and backpack (BP), consisting of the standard 3 point belt together with an additional 2-point belt. In total, 32 participants (15 children aged 6-10, 6 youths aged 11-15, and 11 adults aged 20-79, who differed considerably in size, shape, and proportions) traveled for one hour with each system, including city traffic and highway driving. Four video cameras monitored the test subject during the drive. Subjective data regarding emotions and perceived discomfort were collected in questionnaires every 20 min. A semistructured interview was held afterwards. RESULTS: All participant groups accepted the new products and especially the increased feeling of safety (P <.01); 56% preferred CC and 44% preferred BP but the difference was not significant. In total, 81% wanted to have extra seat belts in their family car. CC was appreciated for its symmetry, comfort, and the perceived feeling of safety. Some participants found CC unpleasant because the belts tended to slip close to the neck, described as a strangling feeling. BP was simpler to use and did not cause annoyance to the neck in the way CC did. Instead, it felt asymmetric and to some extent less safe than CC. Body size and shape affected seat belt fit to a great extent, which in turn affected the experience of comfort, both initially and over time. Perceived safety benefit and experienced comfort were the most determinant factors for the attitude toward the extra seat belts. The extra seat belts were perceived as being better than the participants had expected before the test, and they became more used to them over time. CONCLUSION: This exploratory study provided valuable knowledge from a user perspective for further development of new seat belt systems in cars. In addition to an increased feeling of safety, seat belt fit and comfort are supplementary influencing factors when it comes to gaining acceptance of new seat belt systems. PMID- 26436243 TI - Teen Drivers' Perceptions of Inattention and Cell Phone Use While Driving. AB - OBJECTIVE: Inattention to the roadway, including cell phone use while driving (cell phone calls, sending and reading texts, mobile app use, and Internet use), is a critical problem for teen drivers and increases risk for crashes. Effective behavioral interventions for teens are needed in order to decrease teen driver inattention related to cell phone use while driving. However, teens' perceptions of mobile device use while driving is a necessary component for theoretically driven behavior change interventions. The purpose of this study was to describe teen drivers' perceptions of cell phone use while driving in order to inform future interventions to reduce risky driving. METHODS: We conducted 7 focus groups with a total of 30 teen drivers, ages 16-18, licensed for <= 1 year in Pennsylvania. The focus group interview guide and analysis were based on the Theory of Planned Behavior, identifying the attitudes, perceived behavioral control, and norms about inattention to the roadway. Directed descriptive content analysis was used to analyze the focus group interviews. All focus groups were coded by 2 research team members and discrepancies were reconciled. Themes were developed based on the data. RESULTS: Teens had a mean age of 17.39 (SD = 0.52), mean length of licensure of 173.7 days (SD = 109.2; range 4-364), were 50% male and predominately white (90%) and non-Hispanic (97%). From the focus group data, 3 major themes emerged: (1) Recognizing the danger but still engaging; (2) Considering context; and (3) Formulating safer behaviors that might reduce risk. Despite recognizing that handheld cell phone use, texting, and social media app use are dangerous and distracting while driving, teens and their peers often engaged in these behaviors. Teens described how the context of the situation contributed to whether a teen would place or answer a call, write or respond to a text, or use a social media app. Teens identified ways in which they controlled their behaviors, although some still drew attention away from the roadway. CONCLUSIONS: Cell phone use while driving is a contributor to motor vehicle crashes in teens, and effective interventions to decrease risks are needed. Teens viewed some types of cell phone use as unsafe and describe methods in which they control their behaviors. However, some of their methods still take attention off the primary task of driving. Teens could benefit from behavior change interventions that propose strategies to promote focused attention on the roadway at all times during the driving trip. PMID- 26436245 TI - An Analysis of Young Driver Crash Types and the Associated Lifetime Care Cost in Victoria, Australia. AB - OBJECTIVE: The elevated crash involvement rate of young drivers is well documented. Given the higher crash risk of young drivers and the need for innovative policy and programs, it remains important to fully understand the type of crashes young drivers are involved in, and knowledge of the lifetime care cost of crashes can support effective policy development. The aim of this article is to document the number and type of young driver crashes, as well as the associated lifetime care cost over a 9-year period (2005-2013) in Victoria, Australia. METHODS: In Victoria, Australia, the Transport Accident Commission (TAC) has legislated responsibility for road safety and the care of persons injured in road crashes, irrespective of fault. TAC claims data for the period 2005-2013 were used to document the number and type of young driver crashes. Lifetime care costs (past and future payment liabilities) were calculated by Taylor Fry actuarial consultancy. License and population data were used to define the crash involvement rate of young drivers. RESULTS: Over the 9-year period, 16,817 claims were lodged to the TAC by drivers 18-25 years of age following a crash. There were 646 fewer drivers aged 18-25 killed and injured in 2013, compared to 2005, representing an unadjusted change of -28.7% (-29.8% males; 28.4% females). The total lifetime care cost of young drivers killed and injured in Victoria for the period 2005-2013 was estimated to be AU$634 million (US$493 million). Differences between males and females, single- and multivehicle crashes, and fatalities and injuries were found to be statistically significant. Run-off-road crashes and crashes from opposing direction were overrepresented in the lifetime care costs for young driver claimants. Twenty-eight injured drivers were classified as high-severity claims. These 28 claimants require additional long-term care, which was estimated to be AU$219 million; of these 28, 24 were male (85.7%). The long-term care costs for these 28 drivers (0.16%) accounts for 34.5% of the total lifetime care cost of all 18- to 25-year-old injured drivers. CONCLUSIONS: By using no-fault lifetime care costs that account for medical and like expenses, rehabilitation, and social reintegration costs, a more accurate understanding of the cost of young driver crashes can be determined. Application of these costs to specific crash types highlights new priorities and opportunities for developing programs to reduce young driver crashes. PMID- 26436244 TI - Effects of Dram Shop, Responsible Beverage Service Training, and State Alcohol Control Laws on Underage Drinking Driver Fatal Crash Ratios. AB - OBJECTIVES: In this study, we aimed to determine whether three minimum legal drinking age 21 (MLDA-21) laws-dram shop liability, responsible beverage service (RBS) training, and state control of alcohol sales-have had an impact on underage drinking and driving fatal crashes using annual state-level data, and compared states with strong laws to those with weak laws to examine their effect on beer consumption and fatal crash ratios. METHODS: Using the Fatality Analysis Reporting System, we calculated the ratio of drinking to nondrinking drivers under age 21 involved in fatal crashes as our key outcome measure. We used structural equation modeling to evaluate the three MLDA-21 laws. We controlled for covariates known to impact fatal crashes including: 17 additional MLDA-21 laws; administrative license revocation; blood alcohol concentration limits of.08 and.10 for driving; seat belt laws; sobriety checkpoint frequency; unemployment rates; and vehicle miles traveled. Outcome variables, in addition to the fatal crash ratios of drinking to nondrinking drivers under age 21 included state per capita beer consumption. RESULTS: Dram shop liability laws were associated with a 2.4% total effect decrease (direct effects: beta =.019, p =.018). Similarly, RBS training laws were associated with a 3.6% total effect decrease (direct effect: beta =.048, p =.001) in the ratio of drinking to nondrinking drivers under age 21 involved in fatal crashes. There was a significant relationship between dram shop liability law strength and per capita beer consumption, F (4, 1528) = 24.32, p <.001, partial eta(2) =.016, showing states with strong dram shop liability laws (Mean (M) = 1.276) averaging significantly lower per capita beer consumption than states with weak laws (M = 1.340). CONCLUSIONS: Dram shop liability laws and RBS laws were both associated with significantly reduced per capita beer consumption and fatal crash ratios. In practical terms, this means that dram shop liability laws are currently associated with saving an estimated 64 lives in the 45 jurisdictions that currently have the law. If the remaining 6 states adopted the dram shop law, an additional 9 lives could potentially be saved annually. Similarly, RBS training laws are associated with saving an estimated 83 lives in the 37 jurisdictions that currently have the laws. If the remaining 14 states adopted these RBS training laws, we estimate that an additional 28 lives could potentially be saved. PMID- 26436246 TI - Improving the Chest Protection of Elderly Occupants in Frontal Crashes Using SMART Load Limiters. AB - OBJECTIVE: To determine whether varying the seat belt load limiter (SBL) according to crash and occupant characteristics could have real-world injury reduction benefits in frontal impacts and, if so, to quantify those benefits. METHODS: Real-world UK accident data were used to identify the target population of vehicle occupants and frontal crash scenarios where improved chest protection could be most beneficial. Generic baseline driver and front passenger numerical models using a 50th percentile dummy were developed with MADYMO software. Simulations were performed where the load limiter threshold was varied in selected frontal impact scenarios. For each SBL setting, restraint performance, dummy kinematics, and injury outcome were studied in 5 different frontal impact types. Thoracic injury predictions were converted into injury probability values using Abbreviated Injury Scale (AIS) 2+ age-dependent thoracic risk curves developed and validated based on a methodology proposed by Laituri et al. (2005). Real-world benefit was quantified using the predicted AIS 2+ risk and assuming that an appropriate adaptive system was fitted to all the cars in a real-world sample of recent frontal crashes involving European passenger cars. RESULTS: From the accident data sample the chest was the most frequently injured body region at an AIS 2+ level in frontal impacts (7% of front seat occupants). The proportion of older vehicle front seat occupants (>64 years) with AIS 2+ injury was also greater than the proportion of younger occupants. Additionally, older occupants were more likely to sustain seat belt-induced serious chest injury in low- and moderate-speed frontal crashes. In both front seating positions, the low SBL provided the best chest injury protection, without increasing the risk to other body regions. In severe impacts, the low SBL allowed the driver to move dangerously close to the steering wheel. Compared to the driver side, greater ride-down space on the passenger side gave a higher potential for using the low SBLs. When applying the AIS 2+ risk reduction findings to the weighted accident data sample, the risk of sustaining an AIS 2+ seat belt injury changed to 0.9, 4.9, and 8.1% for young, mid, and older occupants, respectively, from their actual injury risk of 1.3, 7.6, and 13.1%. CONCLUSIONS: These results suggest the potential for improving the safety of older occupants with the development of smarter restraint systems. This is an important finding because the number of older users is expected to increase rapidly over the next 20 years. The greatest benefits were seen at lower crash severities. This is also important because most real-world crashes occur at lower speeds. PMID- 26436247 TI - The Contribution of Pre-impact Posture on Restrained Occupant Finite Element Model Response in Frontal Impact. AB - OBJECTIVE: The objective of this study was to discuss the influence of the pre impact posture to the response of a finite element human body model (HBM) in frontal impacts. METHODS: This study uses previously published cadaveric tests (PMHS), which measured six realistic pre-impact postures. Seven postured models were created from the THUMS occupant model (v4.0): one matching the standard UMTRI driving posture as it was the target posture in the experiments, and six matching the measured pre-impact postures. The same measurements as those obtained during the cadaveric tests were calculated from the simulations, and biofidelity metrics based on signals correlation (CORA) were established to compare the response of the seven models to the experiments. RESULTS: The HBM responses showed good agreement with the PMHS responses for the reaction forces (CORA = 0.80 +/- 0.05) and the kinematics of the lower part of the torso but only fair correlation was found with the head, the upper spine, rib strains (CORA= 0.50 +/- 0.05) and chest deflections (CORA = 0.67 +/- 0.08). All models sustained rib fractures, sternal fracture and clavicle fracture. The average number of rib fractures for all the models was 5.3 +/- 1.0, lower than in the experiments (10.8 +/- 9.0). Variation in pre-impact posture greatly altered the time histories of the reaction forces, deflections and the rib strains, mainly in terms of time delay, but no definite improvement in HBM response or injury prediction was observed. By modifying only the posture of the HBM, the variability in the impact response was found to be equivalent to that observed in the experiments. The postured HBM sustained from 4 to 8 rib fractures, confirming that the pre-impact posture influenced the injury outcome predicted by the simulation. CONCLUSIONS: This study tries to answer an important question: what is the effect of occupant posture on kinematics and kinetics. Significant differences in kinematics observed between HBM and PMHS suggesting more coupling between the pelvis and the spine for the models which makes the model response very sensitive to any variation in the spine posture. Consequently, the findings observed for the HBM cannot be extended to PMHS. Besides, pre-impact posture should be carefully quantified during experiments and the evaluation of HBM should take into account the variation in the predicted impact response due to the variation in the model posture. PMID- 26436248 TI - The Influence of Enhanced Side Impact Protection on Kinematics and Injury Measures of Far- or Center-Seated Children in Forward-Facing Child Restraints. AB - OBJECTIVE: To evaluate the influence of forward-facing child restraint systems' (FFCRSs) side impact structure, such as side wings, on the head kinematics and response of a restrained, far- or center-seated 3-year-old anthropomorphic test device (ATD) in oblique sled tests. METHODS: Sled tests were conducted utilizing an FFCRS with large side wings and with the side wings removed. The CRS were attached via LATCH on 2 different vehicle seat fixtures-a small SUV rear bench seat and minivan rear bucket seat-secured to the sled carriage at 20 degrees from lateral. Four tests were conducted on each vehicle seat fixture, 2 for each FFCRS configuration. A Q3s dummy was positioned in FFCRS according to the CRS owner's manual and FMVSS 213 procedures. The tests were conducted using the proposed FMVSS 213 side impact pulse. Three-dimensional motion cameras collected head excursion data. Relevant data collected during testing included the ATD head excursions, head accelerations, LATCH belt loads, and neck loads. RESULTS: Results indicate that side wings have little influence on head excursions and ATD response. The median lateral head excursion was 435 mm with side wings and 443 mm without side wings. The primary differences in head response were observed between the 2 vehicle seat fixtures due to the vehicle seat head restraint design. The bench seat integrated head restraint forced a tether routing path over the head restraint. Due to the lateral crash forces, the tether moved laterally off the head restraint reducing tension and increasing head excursion (477 mm median). In contrast, when the tether was routed through the bucket seat's adjustable head restraint, it maintained a tight attachment and helped control head excursion (393 mm median). CONCLUSION: This testing illustrated relevant side impact crash circumstances where side wings do not provide the desired head containment for a 3-year-old ATD seated far-side or center in FFCRS. The head appears to roll out of the FFCRS even in the presence of side wings, which may expose the occupant to potential head impact injuries. We postulate that in a center or far-side seating configuration, the absence of door structure immediately adjacent to the CRS facilitates the rotation and tipping of the FFCRS toward the impact side and the roll-out of the head around the side wing structure. Results suggest that other prevention measures, in the form of alternative side impact structure design, FFCRS vehicle attachment, or shared protection between the FFCRS and the vehicle, may be necessary to protect children in oblique side impact crashes. PMID- 26436249 TI - Survival Model for Foot and Leg High Rate Axial Impact Injury Data. AB - OBJECTIVES: Understanding how lower extremity injuries from automotive intrusion and underbody blast (UBB) differ is of key importance when determining whether automotive injury criteria can be applied to blast rate scenarios. This article provides a review of existing injury risk analyses and outlines an approach to improve injury prediction for an expanded range of loading rates. This analysis will address issues with existing injury risk functions including inaccuracies due to inertial and potential viscous resistance at higher loading rates. METHODS: This survival analysis attempts to minimize these errors by considering injury location statistics and a predictor variable selection process dependent upon failure mechanisms of bone. Distribution of foot/ankle/leg injuries induced by axial impact loading at rates characteristic of UBB as well as automotive intrusion was studied and calcaneus injuries were found to be the most common injury; thus, footplate force was chosen as the main predictor variable because of its proximity to injury location to prevent inaccuracies associated with inertial differences due to loading rate. A survival analysis was then performed with age, sex, dorsiflexion angle, and mass as covariates. This statistical analysis uses data from previous axial postmortem human surrogate (PMHS) component leg tests to provide perspectives on how proximal boundary conditions and loading rate affect injury probability in the foot/ankle/leg (n = 82). RESULTS: Tibia force-at-fracture proved to be up to 20% inaccurate in previous analyses because of viscous resistance and inertial effects within the data set used, suggesting that previous injury criteria are accurate only for specific rates of loading and boundary conditions. The statistical model presented in this article predicts 50% probability of injury for a plantar force of 10.2 kN for a 50th percentile male with a neutral ankle position. Force rate was found to be an insignificant covariate because of the limited range of loading rate differences within the data set; however, compensation for inertial effects caused by measuring the force-at-fracture in a location closer to expected injury location improved the model's predictive capabilities for the entire data set. CONCLUSIONS: This study provides better injury prediction capabilities for both automotive and blast rates because of reduced sensitivity to inertial effects and tibia-fibula load sharing. Further, a framework is provided for future injury criteria generation for high rate loading scenarios. This analysis also suggests key improvements to be made to existing anthropomorphic test device (ATD) lower extremities to provide accurate injury prediction for high rate applications such as UBB. PMID- 26436251 TI - Microbial Transport and Fate in the Subsurface Environment: Introduction to the Special Section. AB - Microorganisms constitute an almost exclusive form of life in the earth's subsurface environment (not including caves), particularly at depths exceeding the soil horizon. While of broad interest to ecology and geology, scientific interest in the fate and transport of microorganisms, particularly those introduced through the anthropogenic environment, has focused on understanding the subsurface environment as a pathway for human pathogens and on optimizing the use of microbial organisms for remediation of potable groundwater. This special section, inspired by the 2014 Ninth International Symposium for Subsurface Microbiology, brings together recent efforts to better understand the spatiotemporal occurrence of anthropogenic microbial groundwater contamination and the fate and transport of microbes in the subsurface environment: in soils, deep unsaturated zones, and within aquifer systems. Work includes field reconnaissance, controlled laboratory studies to improve our understanding of specific fate and transport processes, and the development and application of improved mechanistic understanding of microbial fate and transport processes in the subsurface environment. The findings confirm and also challenge the limitations of our current understanding of highly complex microbial fate and transport processes across spatiotemporal scales in the subsurface environment; they also add to the increasing knowledge base to improve our ability to protect drinking water resources and perform in situ environmental remediation. PMID- 26436250 TI - Contractility Measurements on Isolated Papillary Muscles for the Investigation of Cardiac Inotropy in Mice. AB - Papillary muscle isolated from adult mouse hearts can be used to study cardiac contractility during different physiological/pathological conditions. The contractile characteristics can be evaluated independently of external influences such as vascular tonus or neurohumoral status. It depicts a scientific approach between single cell measurements with isolated cardiac myocytes and in vivo studies like echocardiography. Thus, papillary muscle preparations serve as an excellent model to study cardiac physiology/pathophysiology and can be used for investigations like the modulation by pharmacological agents or the exploration of transgenic animal models. Here, we describe a method of isolating the murine left anterior papillary muscle to investigate cardiac contractility in an organ bath setup. In contrast to a muscle strip preparation isolated from the ventricular wall, the papillary muscle can be prepared in toto without damaging the muscle tissue severely. The organ bath setup consists of several temperature controlled, gassed and electrode-equipped organ bath chambers. The isolated papillary muscle is fixed in the organ bath chamber and electrically stimulated. The evoked twitch force is recorded using a pressure transducer and parameters such as twitch force amplitude and twitch kinetics are analyzed. Different experimental protocols can be performed to investigate the calcium- and frequency dependent contractility as well as dose-response curves of contractile agents such as catecholamines or other pharmaceuticals. Additionally, pathologic conditions like acute ischemia can be simulated. PMID- 26436252 TI - Release and Removal of Microorganisms from Land-Deposited Animal Waste and Animal Manures: A Review of Data and Models. AB - Microbial pathogens present a leading cause of impairment to rivers, bays, and estuaries in the United States, and agriculture is often viewed as the major contributor to such contamination. Microbial indicators and pathogens are released from land-applied animal manure during precipitation and irrigation events and are carried in overland and subsurface flow that can reach and contaminate surface waters and ground water used for human recreation and food production. Simulating the release and removal of manure-borne pathogens and indicator microorganisms is an essential component of microbial fate and transport modeling regarding food safety and water quality. Although microbial release controls the quantities of available pathogens and indicators that move toward human exposure, a literature review on this topic is lacking. This critical review on microbial release and subsequent removal from manure and animal waste application areas includes sections on microbial release processes and release-affecting factors, such as differences in the release of microbial species or groups; bacterial attachment in turbid suspensions; animal source; animal waste composition; waste aging; manure application method; manure treatment effect; rainfall intensity, duration, and energy; rainfall recurrence; dissolved salts and temperature; vegetation and soil; and spatial and temporal scale. Differences in microbial release from liquid and solid manures are illustrated, and the influential processes are discussed. Models used for simulating release and removal and current knowledge gaps are presented, and avenues for future research are suggested. PMID- 26436253 TI - Bacterial Pathogen Indicator Transport from Livestock Mortality Biopiles. AB - Biopiles can be used to dispose of slaughterhouse residuals (SLRs); however, the fate of pathogenic bacteria (e.g., pathogenic strains of , ) in these systems is not well understood. The transport of these bacteria in water leaching from the biopile could represent a significant contamination source. This research examined the transport of Enterobacteriaceae and Enterococcaceae indicator bacteria from SLR biopiles. Three biopiles (2.6 m wide by 4.6 m long by 1.8 m high) were formed on soil layers in concrete cells that allowed for real-time monitoring of environmental parameters, hydrologic flux, and indicator bacteria levels in effluent leaching from the piles. In biopile effluent, indicator bacteria populations decreased exponentially following biopile formation. Indicator bacteria loads in effluent constituted <0.01% of the initial indicator bacteria levels in the biopiles, which was attributed to retention, inactivation, and death. Nearly 90% of the total indicator bacteria loads coincided with large precipitation events (>15 mm d). Movement of the indicator bacteria through the biopiles and underlying soil appeared to be consistent with preferential flow phenomena. The populations of the Enterobacteriaceae indicators remained low in conditions of higher soil water content and lower biopile temperatures, whereas the Enterococcaceae indicator appeared to regrow in these conditions. This indicated that bacterial pathogen transport from a biopile could be a concern after the disappearance of conventional bacterial indicators, such as . Management considerations should attempt to divert excess water from entering a biopile, such as locating a biopile under a roof. Unsaturated biopile and soil conditions should be maintained to impede water flow through preferential pathways in the soil underneath a biopile. PMID- 26436254 TI - Swimming Motility Reduces Deposition to Silica Surfaces. AB - The transport and fate of bacteria in porous media is influenced by physicochemical and biological properties. This study investigated the effect of swimming motility on the attachment of cells to silica surfaces through comprehensive analysis of cell deposition in model porous media. Distinct motilities were quantified for different strains using global and cluster-based statistical analyses of microscopic images taken under no-flow condition. The wild-type, flagellated strain DJ showed strong swimming as a result of the actively swimming subpopulation whose average speed was 25.6 MUm/s; the impaired swimming of strain DJ77 was attributed to the lower average speed of 17.4 MUm/s in its actively swimming subpopulation; and both the nonflagellated JZ52 and chemically treated DJ cells were nonmotile. The approach and deposition of these bacterial cells were analyzed in porous media setups, including single-collector radial stagnation point flow cells (RSPF) and two-dimensional multiple-collector micromodels under well-defined hydrodynamic conditions. In RSPF experiments, both swimming and nonmotile cells moved with the flow when at a distance >=20 MUm above the collector surface. Closer to the surface, DJ cells showed both horizontal and vertical movement, limiting their contact with the surface, while chemically treated DJ cells moved with the flow to reach the surface. These results explain how wild-type swimming reduces attachment. In agreement, the deposition in micromodels was also lowest for DJ compared with those for DJ77 and JZ52. Wild-type swimming specifically reduced deposition on the upstream surfaces of the micromodel collectors. Conducted under environmentally relevant hydrodynamic conditions, the results suggest that swimming motility is an important characteristic for bacterial deposition and transport in the environment. PMID- 26436255 TI - Pore-Scale Study of Flow Rate on Colloid Attachment and Remobilization in a Saturated Micromodel. AB - Colloid attachment is an important retention mechanism. It is influenced by colloid size, pore size, and flow rate, among other factors. In this work, we studied colloid attachment experimentally under various flow rates, as well as colloid release in response to a rapid change of flow rate. Colloid transport experiments under saturated conditions and with different flow rates were conducted in a physical micromodel. The micromodel was made of polydimethylsiloxane (PDMS), which is a hydrophobic polymer. Colloids were hydrophilic fluorescent carboxylate-modified polystyrene latex microspheres with a mean diameter of 300 nm. We could directly observe the movement of colloids within the pores using a confocal microscope. We also obtained concentration breakthrough curves by measuring the fluorescence intensity at the outlet of the micromodel. In addition, our experiments were simulated using a pore-network modeling, PoreFlow, based on the pore structure of the micromodel. Local colloid concentrations were calculated by solving local mass balance equations for all network elements and then averaging resulting concentrations over the whole micromodel. The measured breakthrough curves were successfully simulated using PoreFlow. Observed and calculated breakthrough curves showed that colloid attachment rate was smaller for larger flow rate. Temporally enhance colloid release (remobilization of attached colloids) was observed when the flow rate was increased by a factor of 10. But no colloid remobilization was observed when the flow rate decreased by a factor of 10. PMID- 26436256 TI - Efficacy of Coral Sand for Removal of and Bacteriophage under Saturated Flow Conditions. AB - Knowledge of how effectively microbes are transported through porous media is useful for water resource/wastewater management. Despite much research having been done to characterize microbial contaminant transport through various sedimentary materials, very little study has been made on coral sand, such as constitutes the primary substrate of many Pacific atolls. We conducted a set of laboratory column experiments as a preliminary examination of how effective coral sand is at attenuating model pathogens J6-2 and MS2 bacteriophage (phage) under saturated flow conditions mildly representative of field conditions at the Bonriki freshwater lens, South Tarawa, Kiribati. The very poorly sorted gravelly sand coral substrate tested proved very effective at attenuating the bacterial tracer, and spatial removal rates of between 0.02 and 0.07 log cm were determined for J6-2. The ability to determine precise removal rates for MS2 phage was compromised by the use of a plastic apparatus, although the evidence weights toward coral sand being less effective at attenuating MS2 phage than it is . Further research is required to fully assess the ability of coral sand to remove pathogens and to explore how this medium could be engineered into cost-effective water/wastewater treatment solutions on Pacific atolls. The phage data from this work highlight the limitations of using plastic apparatus in experiments targeted at characterizing the fate and transport of viruses. PMID- 26436257 TI - Attachment and Detachment Behavior of Human Adenovirus and Surrogates in Fine Granular Limestone Aquifer Material. AB - The transport of human adenovirus, nanoparticles, and PRD1 and MS2 bacteriophages was tested in fine granular limestone aquifer material taken from a borehole at a managed aquifer recharge site in Adelaide, South Australia. Comparison of transport and removal of virus surrogates with the pathogenic virus is necessary to understand the differences between the virus and surrogate. Because experiments using pathogenic viruses cannot be done in the field, laboratory tests using flow-through soil columns were used. Results show that PRD1 is the most appropriate surrogate for adenovirus in an aquifer dominated by calcite material but not under high ionic strength or high pH conditions. It was also found that straining due to size and the charge of the colloid were not dominant removal mechanisms in this system. Implications of this study indicate that a certain surrogate may not represent a specific pathogen solely based on similar size, morphology, and/or surface charge. Moreover, if a particular surrogate is representative of a pathogen in one aquifer system, it may not be the most appropriate surrogate in another porous media system. This was apparent in the inferior performance of MS2 as a surrogate, which is commonly used in virus transport studies. PMID- 26436258 TI - Pathogen Decay during Managed Aquifer Recharge at Four Sites with Different Geochemical Characteristics and Recharge Water Sources. AB - Recycling of stormwater water and treated effluent via managed aquifer recharge (MAR) has often been hampered because of perceptions of low microbiological quality of recovered water and associated health risks. The goal of this study was to assess the removal of selected pathogens in four large-scale MAR schemes and to determine the influence of aquifer characteristics, geochemistry, and type of recharge water on the pathogen survival times. Bacterial pathogens tested in this study had the shortest one log removal time (, <3 d), followed by oocysts (, <120 d), with enteric viruses having the biggest variability in removal times (, 18 to >200 d). Human adenovirus and rotavirus were relatively persistent under anaerobic conditions (, >200 d). Human adenovirus survived longer than all the other enteric virus tested in the study and hence could be used as a conservative indicator for virus removal in groundwater during MAR. The results suggest that site-specific subsurface conditions such as groundwater chemistry can have considerable influence on the decay rates of enteric pathogens and that viruses are likely to be the critical pathogens from a public health perspective. PMID- 26436259 TI - Importance of the Colmation Layer in the Transport and Removal of Cyanobacteria, Viruses, and Dissolved Organic Carbon during Natural Lake-Bank Filtration. AB - This study focused on the importance of the colmation layer in the removal of cyanobacteria, viruses, and dissolved organic carbon (DOC) during natural bank filtration. Injection-and-recovery studies were performed at two shallow (0.5 m deep), sandy, near-shore sites at the southern end of Ashumet Pond, a waste impacted, kettle pond on Cape Cod, MA, that is subject to periodic blooms of cyanobacteria and continuously recharges a sole-source drinking-water aquifer. The experiment involved assessing the transport behaviors of bromide (conservative tracer), sp. IU625 (cyanobacterium, 2.6 +/- 0.2 um), AS-1 (tailed cyanophage, 110 nm long), MS2 (coliphage, 26 nm diameter), and carboxylate modified microspheres (1.7 um diameter) introduced to the colmation layer using a bag-and-barrel (Lee-type) seepage meter. The injectate constituents were tracked as they were advected across the pond water-groundwater interface and through the underlying aquifer sediments under natural-gradient conditions past push-point samplers placed at ~30-cm intervals along a 1.2-m-long, diagonally downward flow path. More than 99% of the microspheres, IU625, MS2, AS-1, and ~44% of the pond DOC were removed in the colmation layer (upper 25 cm of poorly sorted bottom sediments) at two test locations characterized by dissimilar seepage rates (1.7 vs. 0.26 m d). Retention profiles in recovered core material indicated that >82% of the attached IU625 were in the top 3 cm of bottom sediments. The colmation layer was also responsible for rapid changes in the character of the DOC and was more effective (by three orders of magnitude) at removing microspheres than was the underlying 20-cm-thick segment of sediment. PMID- 26436260 TI - Transport of through a Thick Vadose Zone. AB - Livestock manure applications on fields can be a source of contamination in water resources, including groundwater. Although fecal indicators like have often been detected in tile drainage systems, few studies have monitored groundwater at depth after manure treatments, especially at sites with a deep, heterogeneous vadose zone. Our hypothesis was that microbial transport through a thick vadose zone would be limited or nonexistent due to attenuation processes, subsurface thickness, and heterogeneity. This study tested this hypothesis by monitoring concentrations beneath a 12-m-thick vadose zone of coarse, heterogeneous glacial sediments after surface application of liquid swine manure. was detected on all 23 sample dates over the 5-mo period (4 Apr. 2012-13 Aug. 2012), with particularly elevated concentrations 1 wk after application and lasting for 5 wk. Variable low-level concentrations before and after the elevated period suggest remobilization and delayed transport of microorganisms to the water table without additional loadings within the flow field. These findings suggest preferential flow pathways allowing deep infiltration of manure bacteria as well as a continued source of bacteria, with variable retention and travel times, over several months. Preferential flow pathways at this site include soil macropores, depression focused infiltration, and pathways related to subsurface heterogeneity and/or fracture flow through finer-grained diamict beds. Further research is needed to confirm the relative contribution of sources, constrain travel times, and define specific transport pathways. PMID- 26436261 TI - Fecal Indicator and Pathogenic Bacteria and Their Antibiotic Resistance in Alluvial Groundwater of an Irrigated Agricultural Region with Dairies. AB - Surveys of microbiological groundwater quality were conducted in a region with intensive animal agriculture in California, USA. The survey included monitoring and domestic wells in eight concentrated animal feeding operations (CAFOs) and 200 small (domestic and community supply district) supply wells across the region. was not detected in groundwater, whereas O157:H7 and were each detected in 2 of 190 CAFO monitoring well samples. Nonpathogenic generic and spp. were detected in 24.2% (46/190) and 97.4% (185/190) groundwater samples from CAFO monitoring wells and in 4.2% (1/24) and 87.5% (21/24) of CAFO domestic wells, respectively. Concentrations of both generic and spp. were significantly associated with well depth, season, and the type of adjacent land use in the CAFO. No pathogenic bacteria were detected in groundwater from 200 small supply wells in the extended survey. However, 4.5 to 10.3% groundwater samples were positive for generic and . Concentrations of generic were not significantly associated with any factors, but concentrations of were significantly associated with proximity to CAFOs, seasons, and concentrations of potassium in water. Among a subset of and isolates from both surveys, the majority of (63.6%) and (86.1%) isolates exhibited resistance to multiple (>=3) antibiotics. Findings confirm significant microbial and antibiotic resistance loading to CAFO groundwater. Results also demonstrate significant attenuative capacity of the unconfined alluvial aquifer system with respect to microbial transport. PMID- 26436262 TI - Characterizing Aquifer Heterogeneity Using Bacterial and Bacteriophage Tracers. AB - Gravel aquifers act as important potable water sources in central western Europe, yet they are subject to numerous contamination pressures. Compositional and textural heterogeneity makes protection zone delineation around groundwater supplies in these units challenging; artificial tracer testing aids characterization. This paper reappraises previous tracer test results in light of new geological and microbiological data. Comparative passive gradient testing, using a fluorescent solute (Uranine), virus (H40/1 bacteriophage), and comparably sized bacterial tracers and , was used to investigate a calcareous gravel aquifer's ability to remove microbiological contaminants at a test site near Munich, Germany. Test results revealed relative recoveries could exceed those of H40/1 at monitoring wells, 10 m and 20 m from an injection well, by almost four times; recoveries varied by a factor of up to three between wells. Application of filtration theory suggested greater attenuation of H40/1 relative to similarly charged occurred due to differences in microorganism size, while estimated collision efficiencies appeared comparable. By contrast, more positively charged experienced greater attenuation at one monitoring point, while lower attenuation rates at the second location indicated the influence of geochemical heterogeneity. Test findings proved consistent with observations from nearby fresh outcrops that suggested thin open framework gravel beds dominated mass transport in the aquifer, while discrete intervals containing stained clasts reflect localized geochemical heterogeneity. Study results highlight the utility of reconciling outcrop observations with artificial tracer test responses, using microbiological tracers with well-defined properties, to characterize aquifer heterogeneity. PMID- 26436263 TI - Bacteria Transport in a Soil-Based Wastewater Treatment System under Simulated Operational and Climate Change Conditions. AB - Bacteria removal efficiencies in a conventional soil-based wastewater treatment system (OWTS) have been modeled to elucidate the fate and transport of bacteria under environmental and operational conditions that might be expected under changing climatic conditions. The HYDRUS 2D/3D software was used to model the impact of changing precipitation patterns, bacteria concentrations, hydraulic loading rates (HLRs), and higher subsurface temperatures at different depths and soil textures. Modeled effects of bacteria concentration shows that greater depth of treatment was required in coarser soils than in fine-textured ones to remove . The initial removal percentage was higher when HLR was lower, but it was greater when HLR was higher. When a biomat layer was included in the transport model, the performance of the system improved by up to 12.0%. Lower bacteria removal (<5%) was observed at all depths under the influence of precipitation rates ranging from 5 to 35 cm, and 35-cm rainfall combined with a 70% increase in HLR. Increased subsurface temperature (23 degrees C) increased bacteria removal relative to a lower temperature range (5-20 degrees C). Our results show that the model is able to effectively simulate bacteria removal and the effect of precipitation and temperature in different soil textures. It appears that the performance of OWTS may be impacted by changing climate. PMID- 26436264 TI - Langmuirian Blocking of Irreversible Colloid Retention: Analytical Solution, Moments, and Setback Distance. AB - Soil and aquifer materials have a finite capacity for colloid retention. Blocking of the limited number of available retention sites further decreases the rate of retention with time and enhances risks (e.g., pathogens or colloid-associated contaminants) or benefits (e.g., remediation by microorganisms or nanoparticles) of colloid migration. Our objective was to use a straightforward procedure, based on variable transformation and Laplace transform, to solve the problem of advective colloid transport with irreversible retention and Langmuirian blocking for a pulse-type condition. Formulas for the mean breakthrough time and retardation factor were obtained using zero- and first-order time moments of the breakthrough curves. Equations for the time and position (setback distance) for a particular colloid concentration were obtained from this information. D21 g breakthrough curves and retention profiles in fine sand at four ionic strengths were well described by the model when parameters were optimized. Illustrative simulations demonstrated that blocking becomes more important for smaller retention capacity () and for larger retention rate coefficient (), input concentration (), and pulse duration. Blocking tended to delay colloid arrival time at a particular location relative to a conservative tracer, and produced larger setback distances for smaller and /. PMID- 26436265 TI - Long-Term Impacts of Bacteria-Sediment Interactions in Watershed-Scale Microbial Fate and Transport Modeling. AB - Elevated levels of fecal indicator bacteria (FIB) remain the leading cause of surface water-quality impairments in the United States. Under the Clean Water Act, basin-specific total maximum daily load (TMDL) restoration plans are responsible for bringing identified water impairments in compliance with applicable standards. Watershed-scale model predictions of FIB concentrations that facilitate the development of TMDLs are associated with considerable uncertainty. An increasingly cited criticism of existing modeling practice is the common strategy that assumes bacteria behave similarly to "free-phase" contaminants, although many field evidence indicates a nontrivial number of cells preferentially associate with particulates. Few attempts have been made to evaluate the impacts of sediment on the predictions of in-stream FIB concentrations at the watershed scale, with limited observational data available for model development, calibration, and validation. This study evaluates the impacts of bacteria-sediment interactions in a continuous, watershed-scale model widely used in TMDL development. In addition to observed FIB concentrations in the water column, streambed sediment-associated FIB concentrations were available for model calibration. While improved model performance was achieved compared with previous studies, model performance under a "sediment-attached" scenario was essentially equivalent to the simpler "free-phase" scenario. Watershed-specific characteristics (e.g., steep slope, high imperviousness) likely contributed to the dominance of wet-weather pollutant loading in the water column, which may have obscured sediment impacts. As adding a module accounting for bacteria sediment interactions would increase the model complexity considerably, site evaluation preceding modeling efforts is needed to determine whether the additional model complexity and effort associated with partitioning phases of FIB is sufficiently offset by gains in predictive capacity. PMID- 26436267 TI - Implementing Effects-Based Water Quality Criteria for Eutrophication in Beaver Lake, Arkansas: Linking Standard Development and Assessment Methodology. AB - To address water quality standards needed to prevent accelerated eutrophication, many states in the United States have developed effects-based standards related to nutrients. In many cases, this has resulted in specific standards for Secchi transparency (ST) and phytoplankton biomass measured as sestonic chlorophyll (chl ). The state of Arkansas recently adopted its first effects-based water quality criteria for Beaver Lake in northwestern Arkansas, which was a growing-season geometric mean chl- <8 MUg L and an annual average ST >1.1 m. However, the adopted standard did not have a predefined assessment methodology that outlined the frequency and duration of potential exceedances. This study used hydrologic frequency analysis to estimate the risk of exceeding these water quality standards using measured and modeled data from Beaver Lake from 2001 to 2014. Beaver Lake conformed to common models in reservoir limnology in that ST was least and chl- was greatest in the river-reservoir transition zone and decreased in the downstream direction toward the dam. Greater chl- and lesser ST was clearly related to total phosphorus concentrations along this gradient. Thus, the risk of exceeding the water quality criteria decreased in a downstream direction. There were substantial differences in the probability of exceeding the adopted water quality criteria based on both spatial and temporal variation in the potential assessment periods. Based on the way the standard was developed and the risk of exceeding these standards derived from data collected before the standards were in place, we recommend that a minimum of half of the years assessed be necessary to result in a water quality violation. A number of other assessment considerations are presented that could provide flexibility to regulatory agencies in assessing water quality standards. PMID- 26436268 TI - An Improved Indirect Procedure for Estimating Pesticide Volatility from Field Trials. AB - Conventional indirect approaches for estimating pesticide volatility from agricultural fields require an air dispersion model and near-field, temporal air concentration measurements. The model pesticide flux profile is chosen such that field observations are recovered. Ross et al. (1996) first proposed a back calculation method (BCM) using a single iteration of the Industrial Source Complex Short Term (ISCST) parameterized by a unit source flux. The unit flux is updated by scaling with the slope of a linear regression line between model predictions and actual field observations at each measured time point and location, yielding an estimate for the field flux that occurred over the sampling period. The BCM is expanded using a downhill simplex optimization procedure requiring many ISCST iterations to consecutively adjust the volatility flux rate such that the sum of the squared residuals between predicted and measured air concentrations is minimized (denoted as BCMO). The BCMO is ideally suited for comparing the volatility of different pesticide formulations of the same active from field studies performed simultaneously. Comparison of the BCM and BCMO from field trials containing single (Texas) and multiple simultaneously treated fields (Indiana) are provided for pesticides ranging from low to high volatility. The advanced BCMO is a better alternative than the original BCM, as shown by closer model predictions to measured air concentrations. A major advantage of the BCMO is the ability to extract unique flux source strengths for each field when multiple fields are present and treated consecutively and contiguously with each field emitting pesticide mass at different rates. PMID- 26436266 TI - QMRAcatch: Microbial Quality Simulation of Water Resources including Infection Risk Assessment. AB - Given the complex hydrologic dynamics of water catchments and conflicts between nature protection and public water supply, models may help to understand catchment dynamics and evaluate contamination scenarios and may support best environmental practices and water safety management. A catchment model can be an educative tool for investigating water quality and for communication between parties with different interests in the catchment. This article introduces an interactive computational tool, QMRAcatch, that was developed to simulate concentrations in water resources of , a human-associated microbial source tracking (MST) marker, enterovirus, norovirus, , and as target microorganisms and viruses (TMVs). The model domain encompasses a main river with wastewater discharges and a floodplain with a floodplain river. Diffuse agricultural sources of TMVs that discharge into the main river are not included in this stage of development. The floodplain river is fed by the main river and may flood the plain. Discharged TMVs in the river are subject to dilution and temperature dependent degradation. River travel times are calculated using the Manning Gauckler-Strickler formula. Fecal deposits from wildlife, birds, and visitors in the floodplain are resuspended in flood water, runoff to the floodplain river, or infiltrate groundwater. Fecal indicator and MST marker data facilitate calibration. Infection risks from exposure to the pathogenic TMVs by swimming or drinking water consumption are calculated, and the required pathogen removal by treatment to meet a health-based quality target can be determined. Applicability of QMRAcatch is demonstrated by calibrating the tool for a study site at the River Danube near Vienna, Austria, using field TMV data, including a sensitivity analysis and evaluation of the model outcomes. PMID- 26436269 TI - Impact of Storage Conditions on the Stability of Volatile Sulfur Compounds in Sampling Bags. AB - Odorous emissions from agricultural and waste management operations can cause annoyance to local populations. Volatile sulfur compounds (VSCs) are dominant odorants that are often lost during collection using sample bags. The degree of VSC losses depends on factors such as storage time, bag materials, temperature, sample relative humidity (RH), light exposure, and the presence of volatile organic compounds (VOCs). To assess the impact of those factors on the stability of 10 VSCs (hydrogen sulfide, methanethiol, ethanethiol, dimethyl sulfide, tert butanethiol, ethyl methyl sulfide, 1-butanethiol, dimethyl disulfide, diethyl disulfide, and dimethyl trisulfide), laboratory-based experiments were conducted according to a factorial experimental design. Linear mixed-effects models were constructed for loss predictions. The estimated recovery of HS in Tedlar bag was 8 to 10% higher than in Mylar and Nalophan between 6 and 30 h. At <=20 degrees C and without being exposed to light, at least 75% relative recovery of the 10 VSCs in Tedlar bags can be achieved after 18 h, whereas, a maximum of 12 h of storage should not be exceeded to ensure a minimum of 74% relative recovery of the VSCs in Mylar and Nalophan bags. PMID- 26436270 TI - Effect of Alum Additions to Poultry Litter on In-House Ammonia and Greenhouse Gas Concentrations and Emissions. AB - Alum [Al(SO4) .14HO] addition to poultry litter has been shown to reduce ammonia (NH) concentrations in poultry houses; however, its effects on greenhouse gas (GHG; NO, CH, and CO) emissions is unknown. The objectives of this study were to determine the effects of alum additions on (i) in-house NH and GHG concentrations, (ii) NH and GHG emissions, and (iii) litter chemical properties. Two identical broiler houses located in northwest Arkansas were used for this study: one house was a control and the other was treated with alum between each flock of birds. Ventilation rates were coupled with in-house NH and GHG measurements to determine emission rates. Overall, alum additions significantly reduced the daily average in-house NH concentration by 42% (8.9 vs. 15.4 MUL L), and the overall NH emission rate was reduced by 47% (7.2 vs. 13.4 kg d house). The average cumulative NH emission for the three flocks was 330 kg house flock for the alum-treated house and 617 kg house flock for the control. Concentrations and emissions of nitrous oxide (NO) and methane (CH) from the alum-treated house were not significantly different than the untreated house. However, carbon dioxide (CO) emissions were significantly higher from the untreated house than the alum-treated house. Alum also significantly increased litter N content and reduced the C/N ratio. These results indicate that the addition of alum to poultry litter is not only an effective management practice for reducing in-house NH concentrations and emissions but also significantly reduces CO emissions from poultry facilities. PMID- 26436271 TI - Biomass, Nutrient, and Trace Element Accumulation and Partitioning in Cattail ( L.) during Wetland Phytoremediation of Municipal Biosolids. AB - Biomass and contaminant accumulation and partitioning in plants determine the harvest stage for optimum contaminant uptake during phytoremediation of municipal biosolids. This wetland microcosm bioassay characterized accumulation and partitioning of biomass, nutrients (N and P), and trace elements (Zn, Cu, Cr, and Cd) in cattail ( L.) in a growth room. Four cattail seedlings were transplanted into each 20-L plastic pail containing 3.9 kg (dry wt.) biosolids from an end-of life municipal lagoon. A 10-cm-deep water column was maintained above the 12-cm thick biosolids layer. Plants were harvested every 14 d over a period of 126 d for determination of aboveground biomass (AGB) and belowground biomass (BGB) yields, along with contaminant concentrations in these plant tissues. Logistic model fits to biomass yield data indicated no significant difference in asymptotic yield between AGB and BGB. Aboveground biomass accumulated significantly greater amounts of N and P and lower amounts of trace elements than BGB. Maximum N accumulation in AGB occurred 83 d after transplanting (DAT), and peak P uptake occurred at 86 DAT. Harvesting at maximum aboveground accumulation removed (percent of the initial element concentration in the biosolids) 4% N, 3% P, 0.05% Zn, 0.6% Cu, 0.1% Cd, and 0.2% Cr. Therefore, under the conditions of this study, phytoremediation would be most effective if cattail is harvested at 86 DAT. These results contribute toward the identification of the harvest stage that will optimize contaminant uptake and enhance in situ phytoremediation of biosolids using cattail. PMID- 26436272 TI - Detection of Purple Sulfur Bacteria in Purple and Non-purple Dairy Wastewaters. AB - The presence of purple bacteria in manure storage lagoons is often associated with reduced odors. In this study, our objectives were to determine the occurrence of purple sulfur bacteria (PSB) in seven dairy wastewater lagoons and to identify possible linkages between wastewater properties and purple blooms. Community DNA was extracted from composited wastewater samples, and a conservative 16S rRNA gene sequence within and genes found in both purple sulfur and nonsulfur bacteria was amplified. Analysis of the genes indicated that all of the lagoons contained sequences that were 92 to 97% similar with . Sequences from a few lagoons were also found to be similar with other PSB, such as sp. (97%), (93-100%), and (95-98%). sequences amplified from enrichment and pure cultures were most similar to (93-96%). Carotenoid pigment concentrations, which were used as an indirect measure of purple bacteria levels in the wastewaters, were found to be positively correlated with salinity, nitrogen, total and volatile solids, and chemical oxygen demand; however, salinity could be the dominant factor influencing purple blooms. Due to the detection of PSB sequences in all lagoons, our findings suggest that the non-purple lagoons may have been purple in the past or may have the potential to become purple in the future. PMID- 26436273 TI - Fecal Contamination in the Surface Waters of a Rural- and an Urban-Source Watershed. AB - Surface waters are commonly used as source water for drinking water and irrigation. Knowledge of sources of fecal pollution in source watersheds benefits the design of effective source water protection plans. This study analyzed the relationships between enteric pathogens ( O157:H7, spp., and spp. [, and ]), water quality (turbidity, temperature, and ), and human and ruminant-cow and mitochondrial DNA (mtDNA)-based fecal source tracking (FST) markers in two source watersheds. Water samples ( = 329) were collected at 10 sites (five in each watershed) over 18 mo. The human marker (HF183) occurred in 9 to 10% of the water samples at nine sampling sites; while a forested site in the urban watershed tested negative. Ruminant-cow markers (BacR and CowM2) only appeared in the rural watershed (6%). The mtDNA markers (HcytB and AcytB) showed the same pattern but were less sensitive due to lower fecal concentrations. Higher prevalences ( < 0.05) of spp. (41 vs. 16% for the rural and urban watershed, respectively) and O157:H7 (12 vs. 3%) were observed in the rural watershed, while spp. levels were comparable (23-28%). Densities of >=100 colony-forming units (CFU) 100 mL increased the odds ( < 0.05) of detecting the enteric bacterial pathogens. The water turbidity levels (nephelometric turbidity units [NTU] >= 1.0) similarly predicted ( < 0.05) pathogen presence. Storm events increased ( < 0.01) pathogen and fecal marker concentrations in the waterways. The employment of multiple FST methods suggested failing onsite wastewater systems contribute to human fecal pollution in both watersheds. PMID- 26436274 TI - Evaluation of AGRO-2014 for Predicting Hydrophobic Organic Chemical Concentrations in Ponds. AB - Highly hydrophobic organic chemicals (HOCs), like pyrethroids, adsorb strongly to eroded soil and suspended sediment. Therefore, total suspended solids (TSS) concentration in the water column of receiving waters is important for determining the proportion of chemical in the sediment-sorbed vs. the dissolved (bioavailable) state. However, most current regulatory exposure models, such as the Exposure Analysis Modeling System (EXAMS) and Variable Volume Water Model (VVWM), do not include dynamic modeling of TSS. The objective of this study is to compare the performance of those models for simulating observed pesticide concentrations in small water bodies with an updated version of the AGRO model, called AGRO-2014, which includes dynamic sediment processes. The paper also evaluates the importance of explicitly modeling sediment dynamics for HOCs. We calibrated AGRO-2014 for small, static, water bodies using published pyrethroid mesocosm data. To improve the basis for intermodel comparison, AGRO-2014 includes the same algorithm for temperature-dependent degradation found in EXAMS and VVWM, direct acceptance of organic C partition coefficient () inputs, and acceptance of user-defined pesticide loading durations. Differences in sediment processes in AGRO-2014, EXAMS, and VVWM significantly affected predicted concentrations of high- compounds for standardized loading scenarios, whereas differences between the models were less evident for compounds with lower sorption to sediments. AGRO 2014 simulations of drift and slurry pyrethroid applications to ponds closely matched observed concentrations, while EXAMS and VVWM simulations underestimated the observations. The publicly available AGRO-2014 model offers improvements over other models for predicting concentrations of HOC compounds in small water bodies. PMID- 26436275 TI - Benefits of the Use of Sewage Sludge over EDTA to Remediate Soils Polluted with Heavy Metals. AB - Sewage sludges from urban wastewater treatment plants are often used to remediate degraded soils. However, the benefits of their use in metal-polluted soils remain unclear and need to be assessed in terms of factors besides soil fertility. This study examines the use of thermal-dried sewage sludge (TDS) as an amendment for heavy metal-polluted soil in terms of its effects on soil chemical properties, leachate composition, and the growth of native plant communities. To assess the response of the soil and its plant community to an increase in metal mobilization, the effects of TDS amendment were compared with those of the addition of a chelating agent (ethylenediaminetetraacetic acid [EDTA]). The experimental design was based on a real-case scenario in which soils from of an abandoned mine site were used in a greenhouse bioassay. Two doses of TDS and EDTA were applied to a soil containing high Pb, Zn, Cu, and Cd levels (4925, 5675, 404, and 25 mg kg, respectively). Soil pH was 6.4, and its organic matter content was 5.53%. The factors examined after soil amendment were soil fertility and heavy metal contents, leachate element losses, the plant community arising from the seed bank (plant cover, species richness and biodiversity, above/below ground biomass), and phytotoxic effects (chemical contents of abundant species). Thermal dried sewage sludge emerged as a good phytostabilizer of Pb, Zn, Cu, and Cd given its capacity to reduce the plant uptake of metals and achieve rapid plant cover. This amendment also enhanced the retention of other elements in the plant root system and overall showed a better capacity to remediate soils polluted with several heavy metals. The addition of EDTA led to plant productivity losses and nutritional imbalances because it increased the mobility of several elements in the soil and its leachates. PMID- 26436276 TI - Long-Term Observations of Nitrogen and Phosphorus Export in Paired-Agricultural Watersheds under Controlled and Conventional Tile Drainage. AB - Controlled tile drainage (CTD) regulates water and nutrient export from tile drainage systems. Observations of the effects of CTD imposed en masse at watershed scales are needed to determine the effect on downstream receptors. A paired-watershed approach was used to evaluate the effect of field-to-field CTD at the watershed scale on fluxes and flow-weighted mean concentrations (FWMCs) of N and P during multiple growing seasons. One watershed (467-ha catchment area) was under CTD management (treatment [CTD] watershed); the other (250-ha catchment area) had freely draining or uncontrolled tile drainage (UCTD) (reference [UCTD] watershed). The paired agricultural watersheds are located in eastern Ontario, Canada. Analysis of covariance and paired tests were used to assess daily fluxes and FWMCs during a calibration period when CTD intervention on the treatment watershed was minimal (2005-2006, when only 4-10% of the tile-drained area was under CTD) and a treatment period when the treatment (CTD) watershed had prolific CTD intervention (2007-2011 when 82% of tile drained fields were controlled, occupying >70% of catchment area). Significant linear regression slope changes assessed using ANCOVA ( <= 0.1) for daily fluxes from upstream and downstream monitoring sites pooled by calibration and treatment period were -0.06 and -0.20 (stream water) (negative values represent flux declines in CTD watershed), -0.59 and -0.77 (NH-N), -0.14 and -0.15 (NO-N), -1.77 and -2.10 (dissolved reactive P), and -0.28 and 0.45 (total P). Total P results for one site comparison contrasted with other findings likely due to unknown in-stream processes affecting total P loading, not efficacy of CTD. The FWMC results were mixed and inconclusive but suggest physical abatement by CTD is the means by which nutrient fluxes are predominantly reduced at these scales. Overall, our study results indicate that CTD is an effective practice for reducing watershed scale fluxes of stream water, N, and P during the growing season. PMID- 26436277 TI - Selecting Color-based Tracers and Classifying Sediment Sources in the Assessment of Sediment Dynamics Using Sediment Source Fingerprinting. AB - The use of sediment color as a fingerprint property to determine sediment sources is an emerging technique that can provide a rapid and inexpensive means of investigating sediment sources. The present study aims to test the feasibility of color fingerprint properties to apportion sediment sources within the South Tobacco Creek Watershed (74 km) in Manitoba, Canada. Suspended sediment from 2009 to 2011 at six monitoring stations and potential source samples along the main stem of the creek were collected. Reflectance spectra of sediments and source materials were quantified using a diffuse reflectance spectrometry, and 16 color coefficients were derived from several color space models. Canonical discriminant analysis was used to reclassify and downsize sediment source groups. After the linear additive test and stepwise discriminant function analysis, four color coefficients were chosen to fit the Stable Isotope Analysis in R model. Consistent with the conventional fingerprinting approach, the color fingerprint results demonstrated a switch in the dominant sediment source between the headwaters and the outlet of the watershed, with the main sources being topsoil in the upper reaches, whereas outcrop shale and stream bank materials dominated in the lower reaches. The color fingerprinting approach can be integrated with conventional fingerprints (e.g., geochemical and fallout radionuclide properties) to improve source discrimination, which is a key component for source ascription modeling. We concluded that the use of color fingerprints is a promising, cost effective technique for sediment source fingerprinting. PMID- 26436278 TI - A Methodological Approach for Spatiotemporally Analyzing Water-Polluting Effluents in Agricultural Landscapes Using Partial Triadic Analysis. AB - Multivariate techniques for two-dimensional data matrices are normally used in water quality studies. However, if the temporal dimension is included in the analysis, other statistical techniques are recommended. In this study, partial triadic analysis was used to investigate the spatial and temporal variability in water quality variables sampled in a northeastern Spain river basin. The results highlight the spatiality of the physical and chemical properties of water at different sites along a river over 1 yr. Partial triadic analysis allowed us to clearly identify the presence of a stable spatial structure that was common to all sampling dates across the entire catchment. Variables such as electrical conductivity and Na and Cl ions were associated with agricultural sources, whereas total dissolved nitrogen, NH-N concentrations, and NO-N concentrations were linked to polluted urban sites; differences were observed between irrigated and nonirrigated periods. The concentration of NO-N was associated with both agricultural and urban land uses. Variables associated with urban and agricultural pollution sources were highly influenced by the seasonality of different activities conducted in the study area. In analyzing the impact of land use and fertilization management on water runoff and effluents, powerful statistical tools that can properly identify the causes of pollution in watersheds are important. Partial triadic analysis can efficiently summarize site specific water chemistry patterns in an applied setting for land- and water monitoring schemes at the landscape level. The method is recommended for land-use decision-making processes to reduce harmful environmental effects and promote sustainable watershed management. PMID- 26436279 TI - Degradation of Herbicide Mesotrione in Three Soils with Differing Physicochemical Properties from China. AB - The movement and fate of herbicides in soils under various environmental factors are important in evaluating their mobility and ecological impact. The effects of sterilization, solarization, and soil physicochemical properties on the degradation of herbicide mesotrione in three soils from China were evaluated using laboratory incubation method, and the degradation kinetics were also simulated using pseudo first-order reaction model. The calculated half-lives () of mesotrione were found to be 3.78- to 5.24-fold increased in sterilized soils than nonsterilized soils, which indicated that the degradation of mesotrione was strongly affected by soil microbial activity. A certain role of promoting degradation effect of natural light was found, and the values appeared to be only 7.90, 15.89, and 25.29 d in the surface of paddy soil, sandy loess, and silt clay loam, respectively. Correlation analysis between the observed first-order reaction rate constant () values and the selected soil properties revealed that the degradation of mesotrione was highly dependent on soil pH value ( > 0.992) and organic matter content ( > 0.932), but less related with clay content (<0.02 mm) with < 0.761 and nonrelated with cation exchange capacity (CEC) ( < 0.164). Data obtained in this study are helpful for further research on the prediction of the movement and fate of mesotrione in soils in limiting its environmental impact. PMID- 26436280 TI - Subsurface Drainage Nitrate and Total Reactive Phosphorus Losses in Bioenergy Based Prairies and Corn Systems. AB - We compare subsurface-drainage NO-N and total reactive phosphorus (TRP) concentrations and yields of select bioenergy cropping systems and their rotational phases. Cropping systems evaluated were grain-harvested corn-soybean rotations, grain- and stover-harvested continuous corn systems with and without a cover crop, and annually harvested reconstructed prairies with and without the addition of N fertilizer in an Iowa field. Drainage was monitored when soils were unfrozen during 2010 through 2013. The corn-soybean rotations without residue removal and continuous corn with residue removal produced similar mean annual flow-weighted NO-N concentrations, ranging from 6 to 18.5 mg N L during the 4-yr study. In contrast, continuous corn with residue removal and with a cover crop had significantly lower NO-N concentrations of 5.6 mg N L when mean annual flow weighted values were averaged across the 4 yr. Prairies systems with or without N fertilization produced significantly lower concentrations below <1 mg NO-N L than all the row crop systems throughout the study. Mean annual flow-weighted TRP concentrations and annual yields were generally low, with values <0.04 mg TRP L and <0.14 kg TRP ha, and were not significantly affected by any cropping systems or their rotational phases. Bioenergy-based prairies with or without N fertilization and continuous corn with stover removal and a cover crop have the potential to supply bioenergy feedstocks while minimizing NO-N losses to drainage waters. However, subsurface drainage TRP concentrations and yields in bioenergy systems will need further evaluation in areas prone to higher levels of P losses. PMID- 26436281 TI - Characterizing the Performance of Denitrifying Bioreactors during Simulated Subsurface Drainage Events. AB - The need to mitigate nitrate export from corn and soybean fields with subsurface (tile) drainage systems, a major environmental issue in the midwestern United States, has made the efficacy of field-edge, subsurface bioreactors an active subject of research. This study of three such bioreactors located on the University of Illinois South Farms during their first 6 mo of operation (July Dec. 2012) focused on the interactions of seasonal temperature changes and hydraulic retention times (HRTs), which were subject to experimental manipulation. Changes in nitrate, phosphate, oxygen, and dissolved organic carbon were monitored in influent and effluent to assess the benefits and the potential harmful effects of bioreactors for nearby aquatic ecosystems. On average, bioreactors reduced nitrate loads by 63%, with minimum and maximum reductions of 20 and 98% at low and high HRTs, respectively. The removal rate per unit reactor volume averaged 11.6 g NO-N m d (range, 5-30 g NO-N m d). Multiple regression models with exponential dependencies on influent water temperature and on HRT explained 73% of the variance in NO-N load reduction and 43% of the variance in its removal rate. Although concentrations of dissolved reactive phosphorus and dissolved organic carbon in the bioreactor effluent increased relative to the influent by an order of magnitude during initial tests, within 1 mo of operation they stabilized at nearly equal values. PMID- 26436282 TI - Alum and Rainfall Effects on Ionophores in Runoff from Surface-Applied Broiler Litter. AB - Polyether ionophores, monensin, and salinomycin are commonly used as antiparasitic drugs in broiler production and may be present in broiler litter (bird excreta plus bedding material). Long-term application of broiler litter to pastures may lead to ionophore contamination of surface waters. Because polyether ionophores break down at low pH, we hypothesized that decreasing litter pH with an acidic material such as aluminum sulfate (alum) would reduce ionophore losses to runoff (i.e., monensin and salinomycin concentrations, loads, or amounts lost). We quantified ionophore loss to runoff in response to (i) addition of alum to broiler litter and (ii) length of time between litter application and the first simulated rainfall event. The factorial experiment consisted of unamended (~pH 9) vs. alum-amended litters (~pH 6), each combined with simulated rainfall at 0, 2, or 4 wk after litter application. Runoff from alum-amended broiler litter had 33% lower monensin concentration ( < 0.01), 57% lower monensin load ( < 0.01), 48% lower salinomycin concentration ( < 0.01), and 66% lower salinomycin load ( < 0.01) than runoff from unamended broiler litter when averaged across all events of rainfall. Ionophore losses to runoff were also less when rainfall was delayed for 2 or 4 wk after litter application relative to applying rainfall immediately after litter application. While the weather is difficult to predict, our data suggest that ionophore losses in runoff can be reduced if broiler litter applications are made to maximize dry time after application. PMID- 26436283 TI - Leaching of Glyphosate and Aminomethylphosphonic Acid through Silty Clay Soil Columns under Outdoor Conditions. AB - Glyphosate [-(phosphono-methyl)-glycine] is the main herbicide used in the Chianti vineyards. Considering the pollution risk of the water table and that the vineyard tile drain may deliver this pollutant into nearby streams, the objective of the present study was to estimate the leaching losses of glyphosate under natural rainfall conditions in a silty clay soil in the Chianti area. The leaching of glyphosate and its metabolite (aminomethylphosphonic acid [AMPA]) through soils was studied in 1-m-deep soil columns under outdoor conditions over a 3-yr period. Glyphosate was detected in the leachates for up to 26 d after treatments at concentrations ranging between 0.5 and 13.5 MUg L. The final peak (0.28 MUg L) appeared in the leachates approximately 319 d after the first annual treatment. Aminomethylphosphonic acid first appeared (21.3 MUg L) in the soil leachate 6.8 d after the first annual treatment. Aminomethylphosphonic acid detection frequency and measured concentration in the leachates were more than that observed for the glyphosate. Aminomethylphosphonic acid was detected in 20% of the soil leachates at concentrations ranging from 1 to 24.9 MUg L. No extractable glyphosate was detected in the soil profile. However, the AMPA content in the lowest layer ranged from 13.4 to 21.1 mg kg, and on the surface layer, it ranged from 86.7 to 94 mg kg. Overall, these results indicate that both glyphosate and AMPA leaching through a 1-m soil column may be potential groundwater contaminants. PMID- 26436284 TI - Use of Zeolite with Alum and Polyaluminum Chloride Amendments to Mitigate Runoff Losses of Phosphorus, Nitrogen, and Suspended Solids from Agricultural Wastes Applied to Grassed Soils. AB - Diffuse pollutant losses containing phosphorus (P), nitrogen (N), and suspended solids (SS) can occur when agricultural wastes are applied to soil. This study aimed to mitigate P, N, and SS losses in runoff from grassed soils, onto which three types of agricultural wastes (dairy slurry, pig slurry, and dairy-soiled water [DSW]), were applied by combining amendments of either zeolite and polyaluminum chloride (PAC) with dairy and pig slurries or zeolite and alum with DSW. Four treatments were investigated in rainfall simulation studies: (i) control soil, (ii) agricultural wastes, (iii) dairy and pig slurries amended with PAC and DSW amended with alum, and (iv) dairy and pig slurries amended with zeolite and PAC and DSW amended with zeolite and alum. Our data showed that combined amendments of zeolite and PAC applied to dairy and pig slurries reduced total P (TP) in runoff by 87 and 81%, respectively, compared with unamended slurries. A combined amendment of zeolite and alum applied to DSW reduced TP in runoff by 50% compared with unamended DSW. The corresponding reductions in total N (TN) were 56% for dairy slurry and 45% for both pig slurry and DSW. Use of combined amendments reduced SS in runoff by 73 and 44% for dairy and pig slurries and 25% for DSW compared with unamended controls, but these results were not significantly different from those using chemical amendments only. The findings of this study are that combined amendments of zeolite and either PAC or alum reduce TP and TN losses in runoff to a greater extent than the use of single PAC or alum amendments and are most effective when used with dairy slurry and pig slurry but less effective when used with DSW. PMID- 26436285 TI - Beaver Ponds: Resurgent Nitrogen Sinks for Rural Watersheds in the Northeastern United States. AB - Beaver-created ponds and dams, on the rise in the northeastern United States, reshape headwater stream networks from extensive, free-flowing reaches to complexes of ponds, wetlands, and connecting streams. We examined seasonal and annual rates of nitrate transformations in three beaver ponds in Rhode Island under enriched nitrate-nitrogen (N) conditions through the use of N mass balance techniques on soil core mesocosm incubations. We recovered approximately 93% of the nitrate N from our mesocosm incubations. Of the added nitrate N, 22 to 39% was transformed during the course of the incubation. Denitrification had the highest rates of transformation (97-236 mg N m d), followed by assimilation into the organic soil N pool (41-93 mg N m d) and ammonium generation (11-14 mg N m d). Our denitrification rates exceeded those in several studies of freshwater ponds and wetlands; however, rates in those ecosystems may have been limited by low concentrations of nitrate. Assuming a density of 0.7 beaver ponds km of catchment area, we estimated that in nitrate-enriched watersheds, beaver pond denitrification can remove approximately 50 to 450 kg nitrate N km catchment area. In rural watersheds of southern New England with high N loading (i.e., 1000 kg km), denitrification from beaver ponds may remove 5 to 45% of watershed nitrate N loading. Beaver ponds represent a relatively new and substantial sink for watershed N if current beaver populations persist. PMID- 26436286 TI - Prevalence of and Relationship between Two Human-Associated DNA Biomarkers for Bacteroidales in an Urban Watershed. AB - Human-associated fecal biomarkers offer potent tools for the detection and control of human fecal pollution in watersheds. In some cases, the probability of false-negative findings may call for using a less specific biomarker that is present in higher quantities as long as it can be related to the more specific indicator. The objective of this study is to investigate the relationship between two previously published human-associated biomarkers for Bacteroidales bacteria in an urban watershed influenced by human fecal pollution and to determine if the less specific marker may be used to identify the locations of broken or leaking sewer lines. Samples were collected from 19 stream locations on 10 dates. Sample DNA was extracted and qPCR analysis was conducted for the HuBac and qHF183 biomarkers. The HuBac biomarker was detected more frequently than the qHF183 biomarker and in greater quantities when both were detected. A strong linear relationship ( = 0.91) between the two markers was observed in 219 samples taken from both the watershed and inlet sewage. The relationship between the two biomarkers showed less variance at higher concentrations. However, even when the inlet sewage samples were excluded from the dataset, a clear linear relationship remained ( = 0.74). The results indicate that use of a less specific, but more sensitive, biomarker may provide greater utility when the prevention of false negatives is necessary and the primary fecal source is known, as in spatial distribution studies of human fecal pollution in an urban watershed. PMID- 26436288 TI - Prototype Sodium-Ion Batteries Using an Air-Stable and Co/Ni-Free O3-Layered Metal Oxide Cathode. AB - A prototype rechargeable sodium-ion battery using an O3-Na0.90[Cu0.22 Fe0.30 Mn0.48]O2 cathode and a hard carbon anode is demonstrated to show an energy density of 210 W h kg(-1) , a round-trip energy efficiency of 90%, a high rate capability (up to 6C rate), and excellent cycling stability. PMID- 26436287 TI - Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice. AB - Osmotic pumps continuously deliver compounds at a constant rate into small animals. This article introduces a standard protocol used to induce aortic aneurysms via subcutaneous infusion of angiotensin II (AngII) from implanted osmotic pumps. This protocol includes calculation of AngII amount and dissolution, osmotic pump filling, implantation of osmotic pumps subcutaneously, observation after pump implantation, and harvest of aortas to visualize aortic aneurysms in mice. Subcutaneous infusion of AngII through osmotic pumps following this protocol is a reliable and reproducible technique to induce both abdominal and thoracic aortic aneurysms in mice. Infusion durations range from a few days to several months based on the purpose of the study. AngII 1,000 ng/kg/min is sufficient to provide maximal effects on abdominal aortic aneurysmal formation in male hypercholesterolemic mouse models such as apolipoprotein E deficient or low density lipoprotein receptor deficient mice. Incidence of abdominal aortic aneurysms induced by AngII infusion via osmotic pumps is 5-10 times lower in female hypercholesterolemic mice and also lower in both genders of normocholesterolemic mice. In contrast, AngII-induced thoracic aortic aneurysms in mice are not hypercholesterolemia or gender-dependent. Importantly, multiple features of this mouse model recapitulate those of human aortic aneurysms. PMID- 26436289 TI - Enhancement in the excitonic spontaneous emission rates for Si nanocrystal multi layers covered with thin films of Au, Ag, and Al. AB - The enhancement in the spontaneous emission rate (SER) for Ag, Au, and Al films on multilayer Si nanocrystals (SiNCs) was probed with time-resolved cathodoluminescence (CL). The SiNCs were grown on Si(100) using plasma enhanced chemical vapor deposition. Electron-hole pairs were generated in the metal covered SiNCs by injecting a pulsed high-energy electron beam through the thin metal films, which is found to be an ideal method of excitation for plasmonic quantum heterostructures and nanostructures that are opaque to laser or light excitation. Spatially, spectrally, and temporally resolved CL was used to measure the excitonic lifetime of the SiNCs in metal-covered and bare regions of the same samples. The observed enhancement in the SER for the metal-covered SiNCs, relative to the SER for the bare sample, is attributed to a coupling of the SiNC excitons with surface plasmon polaritons (SPPs) of the thin metal films. A maximum SER enhancement of ~2.0, 1.4 and 1.2 was observed for the Ag, Au, and Al films, respectively, at a temperature of 55 K. The three chosen plasmonic metals of Ag, Au, and Al facilitate an interesting comparison of the exciton-SPP coupling for metal films that exhibit varying differences between the surface plasmon energy, omega(sp), and the SiNC excitonic emission energy. A modeling of the temperature dependence of the Purcell enhancement factor, Fp, was performed and included the temperature dependence of the dielectric properties of the metals. PMID- 26436290 TI - Impact of visceral metastases on outcome to abiraterone after docetaxel in castration-resistant prostate cancer patients. AB - BACKGROUND: The objective of this study was to analyze the impact of visceral metastases in castration-resistant prostate cancer (CRPC) treated with abiraterone. MATERIALS & METHODS: All CRPC patients received abiraterone 1000 mg daily plus prednisone 10 mg orally daily. Liver and lung metastases were considered as visceral metastases. RESULTS: Of 265 CRPC patients, 49 had visceral metastases. Results on progression-free survival were not significantly different in patients with or without visceral metastases. Conversely, the median overall survival between the two groups was 12.4 and 18.5 months (p = 0.01), respectively, and median overall survival of patients with liver-only disease versus other sites was 10.5 versus 18.5 months (p = 0.006), respectively. CONCLUSION: Visceral disease appears to be an important predictor of clinical outcome in CRPC patients treated with abiraterone. PMID- 26436291 TI - beta-Blocker-Associated Risks in Patients With Uncomplicated Hypertension Undergoing Noncardiac Surgery. AB - IMPORTANCE: Perioperative beta-blocker strategies are important to reduce risks of adverse events. Effectiveness and safety may differ according to patients' baseline risk. OBJECTIVE: To determine the risk of major adverse cardiovascular events (MACEs) associated with long-term beta-blocker therapy in patients with uncomplicated hypertension undergoing noncardiac surgery. DESIGN, SETTING, AND PARTICIPANTS: Association study based on in-hospital records and out-of-hospital pharmacotherapy use using a Danish nationwide cohort of patients with uncomplicated hypertension treated with at least 2 antihypertensive drugs (beta blockers, thiazides, calcium antagonists, or renin-angiotensin system [RAS] inhibitors) undergoing noncardiac surgery between 2005 and 2011. INTERVENTIONS: Various antihypertensive treatment regimens, chosen as part of usual care. MAIN OUTCOMES AND MEASURES: Thirty-day risk of MACEs (cardiovascular death, nonfatal ischemic stroke, nonfatal myocardial infarction) and all-cause mortality, assessed using multivariable logistic regression models and adjusted numbers needed to harm (NNH). RESULTS: The baseline characteristics of the 14,644 patients who received beta-blockers (65% female, mean [SD] age, 66.1 [12.0] years) were similar to those of the 40,676 patients who received other antihypertensive drugs (57% female, mean [SD] age, 65.9 [11.8] years). Thirty-day MACEs occurred in 1.3% of patients treated with beta-blockers compared with 0.8% of patients not treated with beta-blockers (P < .001). beta-Blocker use was associated with increased risks of MACEs in 2-drug combinations with RAS inhibitors (odds ratio [OR], 2.16 [95% CI, 1.54-3.04]), calcium antagonists (OR, 2.17 [95% CI, 1.48-3.17]), and thiazides (OR, 1.56 [95% CI, 1.10-2.22]), compared with the reference combination of RAS inhibitors and thiazides. Results were similar for all-cause mortality. Risk of MACEs associated with beta-blocker use seemed especially pronounced for patients at least 70 years old (number needed to harm [NNH], 140 [95% CI, 86-364]), for men (NNH, 142 [95% CI, 93-195]), and for patients undergoing acute surgery (NNH, 97 [95% CI, 57-331]), compared with patients younger than 70 years, women, and patients undergoing elective surgery, respectively. CONCLUSIONS AND RELEVANCE: Antihypertensive treatment with a beta blocker may be associated with increased risks of perioperative MACEs and all cause mortality in patients with uncomplicated hypertension. PMID- 26436292 TI - Multiphase Oscillatory Flow Strategy for in Situ Measurement and Screening of Partition Coefficients. AB - Taking advantage of the difference between the surface energies of aqueous and organic solvents on a Teflon substrate, a fully automated small-scale strategy is developed on the basis of gas-driven oscillatory motion of a biphasic slug for high-throughput in situ measurement and screening of partition coefficients of organic substances between aqueous and organic phases. The developed oscillatory flow strategy enables single partition coefficient data point measurement within 8 min (including the sample preparation time) which is 360 times faster than the conventional "shake-flask" method, while using less than a 30 MUL volume of the two phases and 9 nmol of the target organic substance. The developed multiphase strategy is validated using a conventional shake-flask technique. Finally, the developed strategy is extended to include automated screening of partition coefficients at physiological temperature. PMID- 26436294 TI - A conversation for the holidays: part II "what matters to you". PMID- 26436293 TI - Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis. AB - NCOA4 is a selective cargo receptor for the autophagic turnover of ferritin, a process critical for regulation of intracellular iron bioavailability. However, how ferritinophagy flux is controlled and the roles of NCOA4 in iron-dependent processes are poorly understood. Through analysis of the NCOA4-FTH1 interaction, we demonstrate that direct association via a key surface arginine in FTH1 and a C terminal element in NCOA4 is required for delivery of ferritin to the lysosome via autophagosomes. Moreover, NCOA4 abundance is under dual control via autophagy and the ubiquitin proteasome system. Ubiquitin-dependent NCOA4 turnover is promoted by excess iron and involves an iron-dependent interaction between NCOA4 and the HERC2 ubiquitin ligase. In zebrafish and cultured cells, NCOA4 plays an essential role in erythroid differentiation. This work reveals the molecular nature of the NCOA4-ferritin complex and explains how intracellular iron levels modulate NCOA4-mediated ferritinophagy in cells and in an iron-dependent physiological setting. PMID- 26436295 TI - Overcoming resistance to family-witnessed resuscitation. AB - Giving family members the option of being present during resuscitation has been shown to be beneficial for both family and staff. However, only a small percentage of intensive care units have policies promoting family-witnessed resuscitation. This article reviews current research showing the benefits of family-witnessed resuscitation, outlines how to successfully integrate a family facilitator during resuscitation, and includes research that has been effective in changing the prevailing attitudes of staff. The authors also argue for the resuscitation team to practice ethical and cultural humility when involving family members so that all resuscitation efforts are a success, whether the patient lives or dies. PMID- 26436296 TI - Pronation therapy case report: nurse's perspective and lessons learned. AB - This article describes a brief review of prone therapy and its efficacy and effect on mortality in the treatment of acute respiratory distress syndrome. Furthermore, the situational background and clinical events that transpired prior to, during, and after the institution of pronation therapy for Elkhart General Hospital's Critical Care Center's first pronation patient using the RotoProne Therapy System are described from the nurse's perspective. The lessons learned from this first experience have led to the formation of several practice-based recommendations for future patient care. PMID- 26436297 TI - Facilitating palliative care referrals in the intensive care unit: a pilot project. AB - BACKGROUND: Palliative care in intensive care units (ICUs) reduces costs and improves outcomes yet is consistently underused; studies suggest that screening tools increase the use of palliative services. AIMS: This project piloted the use of the Palliative Performance Scale, version 2 (PPSv2), as a trigger for palliative care referrals in a 12-bed medical ICU. METHODS: Using a preintervention-postintervention design, the authors measured the effect of the intervention on nurses' comfort and knowledge in assessing palliative care needs, number of palliative care referrals, and number of days between ICU admission and palliative care referral. The authors also measured uptake of the scale over 12 weeks of implementation and asked nurses to share their thoughts about using the PPSv2. RESULTS: Over 610 observations, the rate of uptake increased over time and use of the scale ranged from 24.2% to 85.6%. The nurses' (n = 26) comfort with palliative care issues increased from preintervention to postintervention, albeit not significantly. Knowledge items did not change. There was a 110% increase in the number of palliative care referrals between preintervention and postintervention and a nearly 1-day decrease in the number of days between medical ICU admission and palliative care referral; this reduction was not statistically significant. A majority of nurses (n = 22 [84.5%]) voted to retain the PPSv2 as an official process of care, stating that the tool facilitated assessment of patient needs that might have been previously overlooked. CONCLUSION: Data suggest that the PPSv2 was well received by the bedside nurses and changed practice patterns with regard to facilitating palliative care services. PMID- 26436299 TI - Care of the patient with pulmonary arterial hypertension. AB - Patients presenting with pulmonary arterial hypertension (PAH), the rarest of the groups of pulmonary hypertension diagnoses, are infrequently seen in the critical care arena. However, when patients with PAH present in the intensive care unit, it is generally related to an exhaustion of treatments. This article focuses on the current state of the literature addressing the group designation, pathophysiology, symptom expression, and treatment modalities of the patient with PAH. PMID- 26436301 TI - Promotion of progressive mobility activities with ventricular assist and extracorporeal membrane oxygenation devices in a cardiothoracic intensive care unit. AB - BACKGROUND: Progressive mobility (PM) is a clinical intervention that influences complications experienced throughout critical illness. Early PM is a relevant topic in critical care practice literature and was principle to introducing a PM care guideline in an acute cardiothoracic/cardiovascular intensive care unit. PURPOSE: A noted challenge in the cardiothoracic/cardiovascular intensive care unit is caring for acute cardiac and pulmonary failure. Often, these patients require prolonged mechanical circulatory support via extracorporeal mechanical oxygenation or a ventricular assist device. This article describes safe and effective progressive mobilization for patients experiencing MCS in a case study format. This article also highlights how a multidisciplinary clinical team supports mobility practice in specific critical care roles. CONCLUSIONS: Post intensive care syndrome is composed of various health implications that occur following critical illness. Recent data suggest improved care outcomes when critically ill patients are awake and participate in active physical rehabilitation as early as clinically possible. The case studies presented indicate that mobility, to the point of ambulation, is a feasible clinical expectation when patients present with substantial acute respiratory and cardiac failure and are managed with MCS. CLINICAL IMPLICATIONS: Development of a PM guideline uses a critical appraisal of practice evidence, highlights multidisciplinary collaboration, and increases progression to ambulation. Mobility for complex patients is attainable, as demonstrated in the postguideline outcomes. The PM guideline provides structure to primary caregivers and promotes safe practices. The PM guideline facilitates an advanced level of care, promotes safe practices, champions holistic recovery, and encourages active patient involvement, goals satisfying to both patients and staff. PMID- 26436302 TI - Qualitative research: the "what," "why," "who," and "how"! AB - There has been a general view of qualitative research as a lower level form of inquiry and the diverse conceptualizations of what it is, its use or utility, its users, the process of how it is conducted, and its scientific merit. This fragmented understanding and varied ways in which qualitative research is conceived, synthesized, and presented have a myriad of implications in demonstrating and enhancing the utilization of its findings and the ways and skills required in transforming knowledge gained from it. The purpose of this article is to define qualitative research and discuss its significance in research, the questions it addresses, its characteristics, methods and criteria for rigor, and the type of results it can offer. A framework for understanding the "what," "why," "who," and "how" of qualitative research; the different approaches; and the strategies to achieve trustworthiness are presented. Qualitative research provides insights into health-related phenomena and seeks to understand and interpret subjective experience and thus humanizes health care and can enrich further research inquiries and be made clearer and more rigorous as it is relevant to the perspective and goals of nursing. PMID- 26436303 TI - Letter to the editor, re: better pain management for elders in the intensive care unit. PMID- 26436304 TI - Authors' response. PMID- 26436305 TI - The INANE experience. PMID- 26436306 TI - Prevalence and risk factors of coronary artery disease in patients with chronic viral hepatitis. AB - OBJECTIVES: Patients with chronic viral hepatitis usually present metabolic abnormalities and hemodynamic changes, which are known factors associated with the development of coronary artery disease (CAD). This study aims to determine the risk factors of incident CAD in these patients. METHODS: We identified 193 patients who subsequently developed CAD amongst 37,840 cases diagnosed as chronic viral hepatitis from January 2007 through December 2013. RESULTS: In these patients, 141 had hepatitis B virus infections and 52 had hepatitis C virus infections. There was a male preponderance (65.9%). The median age at the diagnosis of hepatitis was 51 years. In the univariate analysis, patients aged >= 51 years had shorter median periods from the diagnosis of hepatitis to the onset of CAD than patients aged < 51 years (50 versus 96 months, p < 0.001), and patients with hypertension had shorter median durations compared to those without hypertension (48 versus 96 months, p < 0.001). Statistical significance also existed between patients with different etiologies (p = 0.004). In the multivariate analysis by Cox regression, age at the diagnosis of hepatitis (p < 0.001; hazard ratio (HR), 1.041; 95% CI, 1.027-1.056) and hypertension (with versus without, p < 0.001; HR, 1.925; 95% CI, 1.419-2.611) were revealed. CONCLUSIONS: Age at diagnosis of hepatitis and hypertension appeared to be independent risk factors of incident CAD in these patients. This topic deserves further studies. PMID- 26436307 TI - Mercury speciation and selenium in toothed-whale muscles. AB - Mercury accumulates at high levels in marine mammal tissues. However, its speciation is poorly understood. The main goal of this investigation was to establish the relationships among mercury species and selenium (Se) concentrations in toothed-whale muscles at different mercury levels. The concentrations of total mercury (T-Hg), methylmercury (MeHg), inorganic mercury (I-Hg) and Se were determined in the muscles of four toothed-whale species: bottlenose dolphins (n=31), Risso's dolphins (n=30), striped dolphins (n=29), and short-finned pilot whales (n=30). In each species, the MeHg concentration increased with increasing T-Hg concentration, tending to reach a plateau. In contrast, the proportion of MeHg in T-Hg decreased from 90-100% to 20-40%. The levels of T-Hg and Se showed strong positive correlations. Se/I-Hg molar ratios rapidly decreased with the increase of I-Hg and reached almost 1 in all species. These results suggested that the demethylated MeHg immediately formed Se/I-Hg equimolar complex of mercury selenide (HgSe) in their muscles. In addition, an X ray absorption fine structure analysis (XAFS) of a bottlenose dolphin muscle confirmed that the dominant chemical form of the Se/I-Hg equimolar complex was HgSe. HgSe was mainly localized in cells near the endomysium using electron probe microanalysis (EPMA). These results suggested that the demethylated MeHg finally deposits within muscle cells of bottlenose dolphin as an inert HgSe. PMID- 26436309 TI - The cytochrome c oxidase biogenesis factor AtCOX17 modulates stress responses in Arabidopsis. AB - COX17 is a soluble protein from the mitochondrial intermembrane space that participates in the transfer of copper for cytochrome c oxidase (COX) assembly in eukaryotic organisms. In this work, we studied the function of both Arabidopsis thaliana AtCOX17 genes using plants with altered expression levels of these genes. Silencing of AtCOX17-1 in a cox17-2 knockout background generates plants with smaller rosettes and decreased expression of genes involved in the response of plants to different stress conditions, including several genes that are induced by mitochondrial dysfunctions. Silencing of either of the AtCOX17 genes does not affect plant development or COX activity but causes a decrease in the response of genes to salt stress. In addition, these plants contain higher reactive oxygen and lipid peroxidation levels after irrigation with high NaCl concentrations and are less sensitive to abscisic acid. In agreement with a role of AtCOX17 in stress and abscisic acid responses, both AtCOX17 genes are induced by several stress conditions, abscisic acid and mutation of the transcription factor ABI4. The results indicate that AtCOX17 is required for optimal expression of a group of stress-responsive genes, probably as a component of signalling pathways that link stress conditions to gene expression responses. PMID- 26436310 TI - Conceptual and methodological issues in research on mindfulness and meditation. AB - Both basic science and clinical research on mindfulness, meditation, and related constructs have dramatically increased in recent years. However, interpretation of these research results has been challenging. The present article addresses unique conceptual and methodological problems posed by research in this area. Included among the key topics is the role of first-person experience and how it can be best studied, the challenges posed by intervention research designs in which true double-blinding is not possible, the nature of control and comparison conditions for research that includes mindfulness or other meditation-based interventions, issues in the adequate description of mindfulness and related trainings and interventions, the question of how mindfulness can be measured, questions regarding what can and cannot be inferred from self-report measures, and considerations regarding the structure of study design and data analyses. Most of these topics are germane to both basic and clinical research studies and have important bearing on the future scientific understanding of mindfulness and meditation. PMID- 26436312 TI - When mindfulness is therapy: Ethical qualms, historical perspectives. AB - In the past 20 years, mindfulness therapeutic programs have moved firmly into the mainstream of clinical practice and beyond. As they have, we have also seen the development of an increasingly vocal critique. At issue is often less whether or not these mindfulness practices "work," and more whether there is a danger in dissociating them from the ethical frameworks for which they were originally developed. Mindfulness, the argument goes, was never supposed to be about weight loss, better sex, helping children perform better in school, helping employees be more productive in the workplace, or even improving the functioning of anxious, depressed people. It was never supposed to be a merchandized commodity to be bought and sold. The larger clinical and religious community, however, has not always been troubled by the idea that (PsycINFO Database Record PMID- 26436314 TI - Beyond the confines of culture: Reflections of two non-American psychologists. AB - Comments on the original article by Christopher et al. (see record 2014-20055 001) regarding "culturally situated" psychology. In this commentary, the current authors articulate a few points of contention and words of caution to be borne in mind when attempting to cultivate critical cultural awareness. PMID- 26436315 TI - Revisiting cultural awareness and cultural relevancy. AB - Comments on the original article by Christopher et al. (see record 2014-20055 001) regarding critical cultural awareness. The more insights and exploration of the meaning and influence of culture we receive, the better. There is no single treatment of any personal or collective culture(s) that can be inherently complete or totally exhaustive. New hermeneutics and skills are always needed, appreciated, and refreshing. PMID- 26436311 TI - Prospects for a clinical science of mindfulness-based intervention. AB - Mindfulness-based interventions (MBIs) are at a pivotal point in their future development. Spurred on by an ever-increasing number of studies and breadth of clinical application, the value of such approaches may appear self-evident. We contend, however, that the public health impact of MBIs can be enhanced significantly by situating this work in a broader framework of clinical psychological science. Utilizing the National Institutes of Health stage model (Onken, Carroll, Shoham, Cuthbert, & Riddle, 2014), we map the evidence base for mindfulness-based cognitive therapy and mindfulness-based stress reduction as exemplars of MBIs. From this perspective, we suggest that important gaps in the current evidence base become apparent and, furthermore, that generating more of the same types of studies without addressing such gaps will limit the relevance and reach of these interventions. We offer a set of 7 recommendations that promote an integrated approach to core research questions, enhanced methodological quality of individual studies, and increased logical links among stages of clinical translation in order to increase the potential of MBIs to impact positively the mental health needs of individuals and communities. PMID- 26436313 TI - Investigating the phenomenological matrix of mindfulness-related practices from a neurocognitive perspective. AB - There has been a great increase in literature concerned with the effects of a variety of mental training regimes that generally fall within what might be called contemplative practices, and a majority of these studies have focused on mindfulness. Mindfulness meditation practices can be conceptualized as a set of attention-based, regulatory, and self-inquiry training regimes cultivated for various ends, including wellbeing and psychological health. This article examines the construct of mindfulness in psychological research and reviews recent, nonclinical work in this area. Instead of proposing a single definition of mindfulness, we interpret it as a continuum of practices involving states and processes that can be mapped into a multidimensional phenomenological matrix which itself can be expressed in a neurocognitive framework. This phenomenological matrix of mindfulness is presented as a heuristic to guide formulation of next-generation research hypotheses from both cognitive/behavioral and neuroscientific perspectives. In relation to this framework, we review selected findings on mindfulness cultivated through practices in traditional and research settings, and we conclude by identifying significant gaps in the literature and outline new directions for research. PMID- 26436316 TI - Cultural humility: The cornerstone of positive contact with culturally different individuals and groups? AB - Comments on the original article by Christopher et al. (see record 2014-20055 001) regarding cultural and folk psychologies. As noted by Christopher, Wendt, Marecek, and Goodman (2014), "U.S. psychology remains not only overwhelmingly U.S.- centric but also largely unaware of how its cultural roots shape theory and research. PMID- 26436317 TI - Culture revisited: A reply to comments. AB - Replies to comments by Winston & Maher (see record 2015-45553-005), Abi-Hashem (see record 2015-45553-006), and Hook & Watkins (see record 2015-45553-007), on the original article by Christopher et al. (see record 2014-20055-001). In this brief response, the authors clarify some elements of their thinking and address some misconceptions put forward by the commentators. PMID- 26436318 TI - The gender similarities hypothesis is untestable as formulated. AB - Comments on the original article by Zell et al. (see record 2015-00137-002) regarding gender similarities and differences using a metasynthesis approach. The authors concluded that the average difference between males and females across psychological domains is relatively small (d = 0.21), with the majority of effects being either small or very small, thereby supporting Hyde's (2005) gender similarities hypothesis that males and females are similar on most psychological dimensions. Unfortunately, their study suffers from the same flaw as nearly all studies testing that hypothesis, namely that it does not provide a metric for either the psychological importance or relevance of the dimensions considered nor does it supply an individuation rule for counting dimensions. PMID- 26436319 TI - Global gender differences can be operationalized and tested. AB - Replies to comments by Zuriff (see record 2015-45553-009) on the original article by Zell et al. (see record 2015-00137-002). The authors appreciate the commentary on their report by Zuriff (2015, this issue) and welcome the opportunity to discuss several important issues that he raises. PMID- 26436320 TI - Validity and completeness of colorectal cancer diagnoses in a primary care database in the United Kingdom. AB - PURPOSE: To validate the recorded diagnoses of colorectal cancer (CRC) and identify false negatives in The Health Improvement Network (THIN) primary care database. METHODS: We conducted a validation study of incident CRC cases in THIN among patients aged 40-89 years from 2000-2011. CRC Read code entries (N = 3805) were verified by manual review of patients' electronic medical records (EMRs) including free-text comments. Incident CRC cases in THIN ascertained following manual review were validated against two data sources deemed gold standards: (i) questionnaires sent to primary care practitioners (PCPs; for a random sample of 100 potential CRC cases), and (ii) Hospital Episode Statistics (HES) among linked practices. False negatives in THIN were identified by searching for International Classification of Diseases-10 codes related to CRC in HES. RESULTS: Of 3805 CRC cases identified in THIN via Read codes, 3033 patients (80.0%) were considered definite cases after manual review of EMRs. The positive predictive value (PPV) of CRC Read codes was 86.0% after removing patients identified from THIN via a Read code for 'fast track referral for suspected CRC'. The response rate from PCPs was 87.0% (n = 87), and the PPV of CRC in THIN was 100% based on PCP questionnaires. Using HES, the PPV for CRC in THIN was 97.9% (556/568), and false negative rate was 6.1% (36/592). CONCLUSIONS: CRC diagnostic Read codes in THIN have a high PPV, which is increased further following manual review of free-text comments. The false negative rate of CRC diagnoses in THIN is low. PMID- 26436321 TI - Adherence to airway clearance therapy in pediatric cystic fibrosis: Socioeconomic factors and respiratory outcomes. AB - OBJECTIVES: The evidence linking socioeconomic status (SES) and adherence in cystic fibrosis (CF) is inconclusive and focused on medication uptake. We examined associations between SES, adherence to airway clearance therapy (ACT), and CF respiratory outcomes. STUDY DESIGN: Socioeconomic, clinical, and adherence data of CF patients (N = 110) at a single CF Center were evaluated in this cross sectional observational study. SES was operationalized as maternal and paternal education and household income. Adherence to ACT was measured with utilization data from the high-frequency chest wall oscillation (HFCWO) device over 4-6 weeks. Statistical modeling was used to test three hypotheses: (H1) Higher SES is associated with higher ACT adherence; (H2) Higher SES is associated with better respiratory outcomes; and (H3) ACT adherence mediates the relationship between SES and respiratory outcomes. RESULTS: In multinomial logistic regression, maternal college education, annual income >$50,000, and more adults in the household were independently related to better adherence (P < 0.05). Paternal college education, income >$100,000, and lack of exposure to smoking were independently related to higher lung function (P < 0.05). Current adherence to ACT with HFCWO was not associated with lung function over 12 months. CONCLUSIONS: SES is associated both with ACT adherence and respiratory outcomes in pediatric CF patients. However, the link between SES and respiratory outcomes in this study was not mediated by adherence to ACT with HFCWO. These data emphasize the importance of socioeconomic resources and household environment for CF health. Family socio-demographic profiles can help identify patients at increased risk for ACT nonadherence. PMID- 26436322 TI - Internalized Homonegativity: A Systematic Mapping Review of Empirical Research. AB - Internalized homonegativity (IH) is an important variable affecting the wellbeing of lesbian, gay, and bisexual (LGB) persons. We included 201 studies in a systematic mapping review of IH. Most studies were conducted in North America and examined IH as a predictor of poor health. The primary focus of 14 studies was IH scale measurement, and, in total, these studies detailed nine distinct scales. Eighteen studies compared levels of IH in LGB populations, four described prevention programs, and one investigated IH using qualitative methods. Our review indicates that further research is needed, particularly qualitative research and ways to ameliorate IH. PMID- 26436323 TI - Pancreas After Islet Transplantation: A First Report of the International Pancreas Transplant Registry. AB - Pancreas after islet (PAI) transplantation is a treatment option for patients seeking insulin independence through a whole-organ transplant after a failed cellular transplant. This report from the International Pancreas Transplant Registry (IPTR) and the United Network for Organ Sharing (UNOS) studied PAI transplant outcomes over a 10-year time period. Forty recipients of a failed alloislet transplant subsequently underwent pancreas transplant alone (50%), pancreas after previous kidney transplant (22.5%), or simultaneous pancreas and kidney (SPK) transplant (27.5%). Graft and patient survival rates were not statistically significantly different compared with matched primary pancreas transplants. Regardless of the recipient category, overall 1- and 5-year PAI patient survival rates for all 40 cases were 97% and 83%, respectively; graft survival rates were 84% and 65%, respectively. A failed previous islet transplant had no negative impact on kidney graft survival in the SPK category: It was the same as for primary SPK transplants. According to this IPTR/UNOS analysis, a PAI transplant is a safe procedure with low recipient mortality, high graft-function rates in both the short and long term and excellent kidney graft outcomes. Patients with a failed islet transplant should know about this alternative in their quest for insulin independence through transplantation. PMID- 26436324 TI - Thermodynamic Analysis of the Two-Liquid Model for Anomalies of Water, HDL-LDL Fluctuations, and Liquid-Liquid Transition. AB - After reviewing the protocol-dependent properties of HDA, which thermally anneals to LDA, and the data gap over an unusually large T-range between HDA, LDA, and water, we investigate whether or not, despite HDA's ill-defined state and distinction from a glass, the HDL-LDL fluctuations view of the two-liquid model can explain water's anomalous behavior. An analysis of the density, rho, compressibility, beta, heat capacity, Cp, and thermal conductivity, kappa, of water over a monotonic (continuous) path bridging this data gap shows the following: (i) Such a path between rhowater at 320 K and rhoHDA yields an untenable thermal expansion coefficient of water. (ii) There is neither a continuous path between betawater at 353 K and betaHDA, nor between Cp,water at 363 K and Cp,HDA. (iii) The same value of rhowater, of betawater, or of Cp,water at two temperatures separated by a maxima or a minima is incompatible with the HDL-LDL fluctuations view. (iv) kappaLDA at ~140 K is about twice that of kappa water at 253 K. (v) kappaHDA at 120 K is incompatible with kappawater at T > 320 K. Thus, there is an internal inconsistency between the thermodynamics of HDA seen as a glass and that of water seen as an HDL-LDL mixture, which is incompatible with both the HDL-LDL fluctuations view and the liquid-liquid transition. PMID- 26436325 TI - A sensitive and label-free photoelectrochemical aptasensor using Co-doped ZnO diluted magnetic semiconductor nanoparticles. AB - Co-doped ZnO diluted magnetic semiconductor as a novel photoelectric beacon was first constructed for photoelectrochemical (PEC) aptasensor of acetamiprid. The fabricated PEC sensing is based on the specific binding of acetamiprid and its aptamer, which induces the decreasement of enhanced photocurrent produced by the electron donor of quercetin. Co(2+) doping has a beneficial effect in extending the band width of light absorption of ZnO into the visible region and to promote the separation of the photoinduced carriers due to the sp-d exchange interactions existing between the band electrons and the localized d electrons of Co(2+). The fabricated aptasensor was linear with the concentration of acetamiprid in the range of 0.5-800 nmolL(-1) with the detection limit of 0.18 nmolL(-1). The presence of same concentration of other conventional pesticides did not interfere in the detection of acetamiprid and the recovery is between 96.2% and 103.7%. This novel PEC aptasensor has good performances with high sensitivity, good selectivity, low cost and portable features. The strategy of Co-doped ZnO diluted magnetic semiconductor paves a new way to improve the performances of PEC aptasensor. PMID- 26436326 TI - Real-time concentration monitoring in microfluidic system via plasmonic nanocrescent arrays. AB - In this work, on-chip bio/chemical sensor was reported based on localized surface plasmon resonance of nanocrescent patterns fabricated via electron beam lithography. The nanocrescent arrays with different dimensional features exhibited controllable plasmonic properties in accordance with the simulation results based on the finite-difference time-domain model. The highest refractive index sensitivity of the fabricated samples was achieved to be ~699.2 nm/RIU with a figure of merit of ~3.1 when the two opposite crescents own a gap of ~43.3 nm. Such obtained plasmonic sensor was further integrated into the microfluidic system which can simply control the specific analyte concentrations via tuning the flow rate ratios between two injecting microstreams. Our method has successfully demonstrated the capability of the nanocrescent patterns as on-chip plasmonic bio/chemical sensor for real-time monitoring of dynamic concentrations in the microchannel. PMID- 26436327 TI - Biomimetic sensor based on molecularly imprinted polymer with nitroreductase-like activity for metronidazole detection. AB - The utility of molecularly imprinted polymer (MIP) as electrochemical sensor often suffers from its limited catalytic efficiency. Here, we proposed an alternative approach by combining the concept of MIP with the use of mimetic enzyme. A metronidazole imprinted polymer with nitroreductase-like activity was successfully achieved via an electrochemical method, where melamine served two purposes: functional monomer of MIP and component of mimetic enzyme. During the imprinting process, the redox-active center, which is responsible for catalysis, was introduced into the imprinted cavities. Accordingly, the imprinted polymer, having both catalysis centers and recognition sites, exhibited enhanced electrocatalytic activity and selectivity. The sensing performances of this metronidazole imprinted biomimetic sensor were evaluated in detail. Results revealed that the response to metronidazole was linear in the concentration range of 0.5-1000 MUM, and the detection limit was 0.12 MUM (S/N=3). In addition, we applied the proposed sensor to detect metronidazole in an injection solution and the results implied its feasibility for practical application. PMID- 26436328 TI - A novel diagnostic biosensor for distinguishing immunoglobulin mutated and unmutated types of chronic lymphocytic leukemia. AB - In chronic lymphocytic leukemia (CLL), the immunoglobulin heavy-chain variable (IgVH) region may be mutated (Ig-mutated CLL) or unmutated (Ig-unmutated CLL); and the presence or absence of mutations in this region of CLL cells distinguishes two clinically distinct forms. It is important for physicians to distinguish between patients with Ig-unmutated CLL, where typically have more indolent disease with median survivals close to 25 years, and Ig-mutated CLL, where have more aggressive disease with median survivals around eight years. In this work, a biosensor capable of diagnosis and distinguishing between these two types of CLL was reported. The biosensor was fabricated by modifying a gold electrode with gold nanoparticles (AuNPS) followed by coating of ZAP70 oligonucleotide probe on the surface to detect specific sequence of ZAP70 gene. ZAP70 could predict the IgVH mutation status and is a good marker for differentiating Ig-mutated and Ig-unmutated CLL and serve as prognostic marker. First, we focused on achieving hybridization between probe and its complementary sequence. Hybridization between probe and target was determined with electrochemical impedance spectroscopy (EIS). Then, our efforts turned to optimize the conditions for the detection of any point mutation and also to maximize the selectivity. Under optimal conditions, the biosensor has a good calibration range between 2.0 * 10(-14) and 1.0 * 10(-9)molL(-1), with ZAP70 DNA sequence detection limit of 4.0 * 10(-15)molL(-1). We successfully detect hybridization first in synthetic samples, and ultimately in blood samples from patients. Experimental results illustrated that the nanostructured biosensor clearly discriminates between mutated and non-mutated CLL and predict the IgVH mutation status, which it has been considered as the single most informative stage independent prognostic factor in CLL. PMID- 26436329 TI - Dasatinib-induced nephrotic syndrome. PMID- 26436330 TI - Dimethylfumarate Impairs Neutrophil Functions. AB - Host defense against pathogens relies on neutrophil activation. Inadequate neutrophil activation is often associated with chronic inflammatory diseases. Neutrophils also constitute a significant portion of infiltrating cells in chronic inflammatory diseases; eg psoriasis and multiple sclerosis. Fumarates improve the latter diseases, which so far has been attributed to effects on lymphocytes and dendritic cells. Here, we focused on effects of dimethyl fumarate (DMF) on neutrophils. In vitro, DMF inhibited neutrophil activation, including changes in surface marker expression, reactive oxygen species production, formation of neutrophil extracellular traps and migration. Phagocytic ability and autoantibody-induced, neutrophil-dependent tissue injury ex vivo was also impaired by DMF. Regarding the mode of action, DMF modulates -in a stimulus dependent manner- neutrophil activation using the PI3K/Akt-p38 MAPK- and ERK 1/2 pathways. For in vivo validation, mouse models of epidermolysis bullosa acquisita (EBA), an organ-specific autoimmune disease caused by autoantibodies to type VII collagen (COL7), were employed. In the presence of DMF, blistering induced by injection of anti-COL7 antibodies into mice was significantly impaired. DMF treatment of mice with clinically already manifested EBA led to disease improvement. Collectively, we demonstrate a profound inhibitory activity of DMF on neutrophil functions. These findings encourage wider use of DMF in patients with neutrophil-mediated diseases.Journal of Investigative Dermatology accepted article preview online, 05 October 2015. doi:10.1038/jid.2015.361. PMID- 26436331 TI - Perampanel in the treatment of focal and idiopathic generalized epilepsies and of status epilepticus. AB - Perampanel is the latest approved antiepileptic drug in focal and generalized epilepsies and has a distinct and selective mode of action on AMPA-receptors. Several thousand patients have received perampanel within randomized placebo controlled trials, open-label extension trials and post-marketing observational studies. Significant median partial-onset seizure reduction rates of 23% for 4 mg/day, 26-31% for 8 mg/day and 18-35% for 12 mg/day were reported. Likewise 50 percent responder rates were 29% for 4 mg/day, 33-38% for 8 mg/day and 34-36% for 12 mg/day. Primary generalized tonic-clonic seizures were reduced by 76.5% (8 mg) vs 38.4% (placebo) in a recent controlled trial. Overall, perampanel is well tolerated and the main adverse events are dizziness, somnolence and fatigue. There are also anecdotal reports on use in progressive myoclonic epilepsies and status epilepticus. Perampanel will likely remain an important, possibly broad spectrum AED with a significant market share, especially in patients with drug refractory epilepsies. PMID- 26436333 TI - Gender-responsiveness in corrections: Estimating female inmate misconduct risk using the Personality Assessment Inventory (PAI). AB - Proper inmate assessment is critical to correctional management and institutional security. While many instruments have been developed to assist with this process, most of these tools have not been validated using samples of female inmates although distinct gender differences have been identified in the inmate population in terms of adaptation and misconduct. The Personality Assessment Inventory (PAI) is a multiscale measure of psychopathology that is being increasingly utilized in the correctional setting to assist with the inmate classification process. The current study contributes to the dearth of literature surrounding gender-responsive inmate classification by utilizing a sample of 2,000 female inmates to examine the incremental and predictive validity of the PAI in association with general and assaultive disciplinary infractions. Findings from this study reveal that the PAI scales presenting the strongest relationship to general and assaultive disciplinary infractions among this female sample included Aggression (AGG), Antisocial Features (ANT), Paranoia (PAR), and the Violence Potential Index (VPI). Moreover, findings derived from this study suggest that certain PAI measures, specifically ARD-T, DRU, and more general substance abuse and mental health indicators may be useful in gender-responsive assessments during the female inmate classification process. PMID- 26436332 TI - Visualization of miniSOG Tagged DNA Repair Proteins in Combination with Electron Spectroscopic Imaging (ESI). AB - The limits to optical resolution and the challenge of identifying specific protein populations in transmission electron microscopy have been obstacles in cell biology. Many phenomena cannot be explained by in vitro analysis in simplified systems and need additional structural information in situ, particularly in the range between 1 nm and 0.1 um, in order to be fully understood. Here, electron spectroscopic imaging, a transmission electron microscopy technique that allows simultaneous mapping of the distribution of proteins and nucleic acids, and an expression tag, miniSOG, are combined to study the structure and organization of DNA double-strand break repair foci. PMID- 26436334 TI - Holistic face processing can inhibit recognition of forensic facial composites. AB - Facial composite systems help eyewitnesses to show the appearance of criminals. However, likenesses created by unfamiliar witnesses will not be completely accurate, and people familiar with the target can find them difficult to identify. Faces are processed holistically; we explore whether this impairs identification of inaccurate composite images and whether recognition can be improved. In Experiment 1 (n = 64) an imaging technique was used to make composites of celebrity faces more accurate and identification was contrasted with the original composite images. Corrected composites were better recognized, confirming that errors in production of the likenesses impair identification. The influence of holistic face processing was explored by misaligning the top and bottom parts of the composites (cf. Young, Hellawell, & Hay, 1987). Misalignment impaired recognition of corrected composites but identification of the original, inaccurate composites significantly improved. This effect was replicated with facial composites of noncelebrities in Experiment 2 (n = 57). We conclude that, like real faces, facial composites are processed holistically: recognition is impaired because unlike real faces, composites contain inaccuracies and holistic face processing makes it difficult to perceive identifiable features. This effect was consistent across composites of celebrities and composites of people who are personally familiar. Our findings suggest that identification of forensic facial composites can be enhanced by presenting composites in a misaligned format. PMID- 26436335 TI - Memory and the operational witness: Police officer recall of firearms encounters as a function of active response role. AB - Investigations after critical events often depend on accurate and detailed recall accounts from operational witnesses (e.g., law enforcement officers, military personnel, and emergency responders). However, the challenging, and often stressful, nature of such events, together with the cognitive demands imposed on operational witnesses as a function of their active role, may impair subsequent recall. We compared the recall performance of operational active witnesses with that of nonoperational observer witnesses for a challenging simulated scenario involving an armed perpetrator. Seventy-six police officers participated in pairs. In each pair, 1 officer (active witness) was armed and instructed to respond to the scenario as they would in an operational setting, while the other (observer witness) was instructed to simply observe the scenario. All officers then completed free reports and responded to closed questions. Active witnesses showed a pattern of heart rate activity consistent with an increased stress response during the event, and subsequently reported significantly fewer correct details about the critical phase of the scenario. The level of stress experienced during the scenario mediated the effect of officer role on memory performance. Across the sample, almost one-fifth of officers reported that the perpetrator had pointed a weapon at them although the weapon had remained in the waistband of the perpetrator's trousers throughout the critical phase of the encounter. These findings highlight the need for investigator awareness of both the impact of operational involvement and stress-related effects on memory for ostensibly salient details, and reflect the importance of careful and ethical information elicitation techniques. PMID- 26436336 TI - Surface Acidity as Descriptor of Catalytic Activity for Oxygen Evolution Reaction in Li-O2 Battery. AB - Unraveling the descriptor of catalytic activity, which is related to physical properties of catalysts, is a major objective of catalysis research. In the present study, the first-principles calculations based on interfacial model were performed to study the oxygen evolution reaction mechanism of Li2O2 supported on active surfaces of transition-metal compounds (TMC: oxides, carbides, and nitrides). Our studies indicate that the O2 evolution and Li(+) desorption energies show linear and volcano relationships with surface acidity of catalysts, respectively. Therefore, the charging voltage and desorption energies of Li(+) and O2 over TMC could correlate with their corresponding surface acidity. It is found that certain materials with an appropriate surface acidity can achieve the high catalytic activity in reducing charging voltage and activation barrier of rate-determinant step. According to this correlation, CoO should have as active catalysis as Co3O4 in reducing charging overpotential, which is further confirmed by our comparative experimental studies. Co3O4, Mo2C, TiC, and TiN are predicted to have a relatively high catalytic activity, which is consistent with the previous experiments. The present study enables the rational design of catalysts with greater activity for charging reactions of Li-O2 battery. PMID- 26436337 TI - Assessing personal financial management in patients with bipolar disorder and its relation to impulsivity and response inhibition. AB - INTRODUCTION: Impulsivity and risk-taking behaviours are reported in bipolar disorder (BD). We examined whether financial management skills are related to impulsivity in patients with BD. METHODS: We assessed financial management skills using the Executive Personal Finance Scale (EPFS), impulsivity using the Barratt Impulsiveness Scale (BIS) and response inhibition using an emotional go/no-go task in bipolar individuals (N = 21) and healthy controls (HC; N = 23). RESULTS: Patients had fewer financial management skills and higher levels of impulsivity than HC. In patients and controls, increased impulsivity was associated with poorer personal financial management. Patients and HC performed equally on the emotional go/no-go task. Higher BIS scores were associated with faster reaction times in HC. In patients, however, higher BIS scores were associated with slower reaction times, possibly indicating compensatory cognitive strategies to counter increased impulsivity. CONCLUSIONS: Patients with BD may have reduced abilities to manage personal finances, when compared against healthy participants. Difficulty with personal finance management may arise in part as a result of increased levels of impulsivity. Patients may learn to compensate for increased impulsivity by modulating response times in our experimental situations although whether such compensatory strategies generalize to real-world situations is unknown. PMID- 26436338 TI - Changes in hydration following haemodialysis estimated with bioimpedance spectroscopy. AB - INTRODUCTION: Bioelectrical impedance devices are being more frequently used as an aid to clinical assessment in helping to determine normo-hydrated weight, or target weight for haemodialysis patients. Pre-dialysis measurements are more convenient in clinical practice for patients and staff. We wished to determine the value of pre-dialysis measurements of over-hydration by comparing post dialysis values with actual weight loss. METHODS: We measured bioimpedance using bioimpedance spectroscopy pre-dialysis and then post-dialysis. RESULTS: Bioimpedance spectroscopy was measured pre-dialysis and post-dialysis in 49 haemodialysis patients, 70% male; mean age 63.9 +/- 17.9 years. Weight fell from 69.5 +/- 17.3 to 67.7 +/- 16.9 kg, P < 0.001, with a fall in mean over-hydration (OH) from 2.1 +/- 3.4 to 1.3 +/- 2.8 L, P < 0.017, and extracellular water (ECW) from 17.0 +/- 5.2 to 16.5 +/- 5.0 L, P = 0.03. The change in OH underestimated weight change (mean bias -1. 1). Change in OH did not correlate with measured weight loss on univariate analysis (r = 0.26, P = 0.07) but positively correlated with the change in ECW (r = 0.29, P = 0.046) and negatively with intracellular water (r = -0.58, P < 0.001). SUMMARY: Although more convenient to make bioimpedance measurements of hydration status pre-dialysis, we did not find that changes in OH post-dialysis mirrored the changes in measured weight. As such, single pre-dialysis bioimpedance measurements of hydration status may not accurately predict post-dialysis hydration status. PMID- 26436339 TI - Convergence of multi-valley bands as the electronic origin of high thermoelectric performance in CoSb3 skutterudites. AB - Filled skutterudites R(x)Co4Sb12 are excellent n-type thermoelectric materials owing to their high electronic mobility and high effective mass, combined with low thermal conductivity associated with the addition of filler atoms into the void site. The favourable electronic band structure in n-type CoSb3 is typically attributed to threefold degeneracy at the conduction band minimum accompanied by linear band behaviour at higher carrier concentrations, which is thought to be related to the increase in effective mass as the doping level increases. Using combined experimental and computational studies, we show instead that a secondary conduction band with 12 conducting carrier pockets (which converges with the primary band at high temperatures) is responsible for the extraordinary thermoelectric performance of n-type CoSb3 skutterudites. A theoretical explanation is also provided as to why the linear (or Kane-type) band feature is not beneficial for thermoelectrics. PMID- 26436340 TI - Understanding and predicting the orientation of heteroleptic phosphors in organic light-emitting materials. AB - Controlling the alignment of the emitting molecules used as dopants in organic light-emitting diodes is an effective strategy to improve the outcoupling efficiency of these devices. To explore the mechanism behind the orientation of dopants in films of organic host materials, we synthesized a coumarin-based ligand that was cyclometalated onto an iridium core to form three phosphorescent heteroleptic molecules, (bppo)2Ir(acac), (bppo)2Ir(ppy) and (ppy)2Ir(bppo) (bppo represents benzopyranopyridinone, ppy represents 2-phenylpyridinate, and acac represents acetylacetonate). Each emitter was doped into a 4,4'-bis(N-carbazolyl) 1,1'-biphenyl host layer, and the resultant orientation of their transition dipole moment vectors was measured by angle-dependent p-polarized photoluminescent emission spectroscopy. In solid films, (bppo)2Ir(acac) is found to have a largely horizontal transition dipole vector orientation relative to the substrate, whereas (ppy)2Ir(bppo) and (bppo)2Ir(ppy) are isotropic. We propose that the inherent asymmetry at the surface of the growing film promotes dopant alignment in these otherwise amorphous films. Modelling the net orientation of the transition dipole moments of these materials yields general design rules for further improving horizontal orientation. PMID- 26436341 TI - Three-dimensional macroporous nanoelectronic networks as minimally invasive brain probes. AB - Direct electrical recording and stimulation of neural activity using micro fabricated silicon and metal micro-wire probes have contributed extensively to basic neuroscience and therapeutic applications; however, the dimensional and mechanical mismatch of these probes with the brain tissue limits their stability in chronic implants and decreases the neuron-device contact. Here, we demonstrate the realization of a three-dimensional macroporous nanoelectronic brain probe that combines ultra-flexibility and subcellular feature sizes to overcome these limitations. Built-in strains controlling the local geometry of the macroporous devices are designed to optimize the neuron/probe interface and to promote integration with the brain tissue while introducing minimal mechanical perturbation. The ultra-flexible probes were implanted frozen into rodent brains and used to record multiplexed local field potentials and single-unit action potentials from the somatosensory cortex. Significantly, histology analysis revealed filling-in of neural tissue through the macroporous network and attractive neuron-probe interactions, consistent with long-term biocompatibility of the device. PMID- 26436342 TI - The negative piezoelectric effect of the ferroelectric polymer poly(vinylidene fluoride). AB - Piezoelectricity describes interconversion between electrical charge and mechanical strain. As expected for lattice ions displaced in an electric field, the proportionality constant is positive for all piezoelectric materials. The exceptions are poly(vinylidene fluoride) (PVDF) and its copolymers with trifluoroethylene (P(VDF-TrFE)), which exhibit a negative longitudinal piezoelectric coefficient. Reported explanations exclusively consider contraction with applied electric field of either the crystalline or the amorphous part of these semi-crystalline polymers. To distinguish between these conflicting interpretations, we have performed in situ dynamic X-ray diffraction measurements on P(VDF-TrFE) capacitors. We find that the piezoelectric effect is dominated by the change in lattice constant but, surprisingly, it cannot be accounted for by the polarization-biased electrostrictive contribution of the crystalline part alone. Our quantitative analysis shows that an additional contribution is operative, which we argue is due to an electromechanical coupling between the intermixed crystalline lamellae and amorphous regions. Our findings tie the counterintuitive negative piezoelectric response of PVDF and its copolymers to the dynamics of their composite microstructure. PMID- 26436343 TI - Cell and Protein Recognition at a Supported Bilayer Interface via In Situ Cavitand-Mediated Functional Polymer Growth. AB - Water-soluble deep cavitands embedded in a supported lipid bilayer are capable of anchoring ATRP initiator molecules for the in situ synthesis of primary amine containing polymethacrylate patches at the water:membrane interface. These polymers can be derivatized in situ to incorporate fluorescent reporters, allow selective protein recognition, and can be applied to the immobilization of nonadherent cells at the bilayer interface. PMID- 26436344 TI - Structural Properties and UV-Visible Absorption Spectroscopy of Retinal-pyridyl CN Re(I) Carbonyl Bipyridine Complex: A Theoretical Study. AB - The structural, electronic, and optical properties of the all-trans and five cis conformers of [Re(CO)3(bpy)(ret-pyr-CN)](+) (bpy = 2,2'-bipyridine; ret-pyr-CN = pyridyl-CN-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-2-n)-none-(2,4,6,8-tetraen) were studied in solvent by means of density functional theory (DFT) and time dependent DFT. The isolated retinal-like chromophore ret-pyr-CN was investigated as well for comparison. By coordination to the complex the two lowest intraligand (IL) states localized on the retinal group are slightly red-shifted from 627 to 690 nm and from 415 to 450 nm, respectively. Several isomerization pathways are open upon irradiation of the Re(I) complex by visible light (400-450 nm), especially to two cis conformers corresponding to the isomerization of the two double bonds of the retinal-like ligand close to the pyridyl group linked to the Re(I) fragment. The metal-to-ligand charge transfer states localized either on the retinal group or on the bpy ligand should play a minor role in the isomerization process itself but could improve its efficiency via ultra-fast intersystem crossing. PMID- 26436346 TI - Speaker Abstracts. PMID- 26436348 TI - Pearls for optimizing biomedical manuscripts. PMID- 26436349 TI - Meeting the Eastern perspective in hepatitis B related ACLF. PMID- 26436350 TI - The treatment of diabetes mellitus of patients with chronic liver disease. AB - About 80% of patients with liver cirrhosis may have glucose metabolism disorders, 30% show overt diabetes mellitus (DM). Prospective studies have demonstrated that DM is associated with an increased risk of hepatic complications and death in patients with liver cirrhosis. DM might contribute to liver damage by promoting inflammation and fibrosis through an increase in mitochondrial oxidative stress mediated by adipokines. Based on the above mentioned the effective control of hyperglycemia may have a favorable impact on the evolution of these patients. However, only few therapeutic studies have evaluated the effectiveness and safety of antidiabetic drugs and the impact of the treatment of DM on morbidity and mortality in patients with liver cirrhosis. In addition, oral hypoglycemic agents and insulin may produce hypoglycemia and lactic acidosis, as most of these agents are metabolized by the liver. This review discusses the clinical implications of DM in patients with chronic liver disease. In addition the effectiveness and safety of old, but particularly the new antidiabetic drugs will be described based on pharmacokinetic studies and chronic administration to patients. Recent reports regarding the use of the SGLT2 inhibitors as well as the new incretin based therapies such as injectable glucagon-like peptide-1 (GLP-1) receptor agonists and oral inhibitors of dipeptidylpeptidase-4 (DPP-4) will be discussed. The establishment of clear guidelines for the management of diabetes in patients with CLD is strongly required. PMID- 26436351 TI - Drug-induced fatty liver disease: An overview of pathogenesis and management. AB - Over the past decades, many drugs have been identified, that can potentially induce steatohepatitis in the predisposed individual. Classically this has been incriminated to amiodarone, perhexiline, and 4,4'-diethylaminoethoxyhexestrol (DH), all of which have been found to independently induce the histologic picture of non-alcoholic steatohepatitis (NASH). Pathogenetic mechanisms of hepatotoxicity although still evolving, demonstrate that mitochondrial dysfunction, deranged ATP production and fatty acid catabolism likely play an important role. Drugs like steroid hormones can exacerbate the pathogenetic mechanisms that lead to NASH, and other drugs like tamoxifen, cisplatin and irenotecan have been shown to precipitate latent fatty liver as well. Further research aiming to elucidate the pathogenesis of drug-induced steatosis and steatohepatitis is needed in order to better design therapeutic targets. PMID- 26436352 TI - Prevalence of hepatitis C virus infection among patients undergoing haemodialysis in Latin America. AB - Hepatitis C infection is a worldwide problem. The global prevalence of the hepatitis C virus (HCV) averages 3%. Moreover, its prevalence among patients undergoing haemodialysis (HD) varies worldwide, ranging from as low as 1% to up to 70%. There are few data on its prevalence in developing countries, and even less information is available on HD patients. A literature review revealed that the prevalence of HCV infection among patients undergoing HD in Latin America ranges from 4.2 to 83.9%, with most data stemming from Argentina, Brazil, Mexico, Peru, Chile, Venezuela and Cuba. The most common genotype was genotype 1, and subtype 1b was the most frequent. The risk factors associated with this condition were the duration of the HD treatment and blood transfusion before hepatitis C screening. In addition, HCV RNA detection by polymerase chain reaction is crucial for the diagnosis of HCV infection in HD patients. Trials using combinations of new oral antiviral drugs, such as sofosbuvir and combo (ombitasvir, paritaprevir, ritonavir and dasabuvir), should be the next step in the improvement of care among HD patients with HCV, because these therapeutic agents apparently do not require dose adjustment according to renal function. Finally, information on this subgroup of patients remains unavailable in some countries; therefore, additional studies are needed to determine the prevalence trend of HCV infection in these populations. PMID- 26436353 TI - Prevalence of hepatitis B and C markers in a population of an urban university in Rio de Janeiro, Brazil: a cross-sectional study. AB - BACKGROUND AND RATIONALE: Epidemics of hepatitis B and C are a public health burden, and their prevalence in Brazil varies among regions. We determined the prevalence of hepatitis markers in an urban university population in order to support the development of a comprehensive program for HBV immunization and HBV/HCV diagnosis. Students, employees, and visitors (n = 2,936, 31 years IQR 24.5-50, female = 69.0% and 81.1% with at least 12 years of education) were enrolled from May to November 2013. Antibodies against hepatitis B surface antigen (anti-HBs), against hepatitis B core antigen (anti-HBc), and hepatitis B surface antigen (HBsAg) were detected with enzyme immunoassays and anti-hepatitis C virus (anti-HCV) antibodies with a chemiluminescence immunoassay. The results were confirmed with polymerase chain reaction for HCV and nucleic acid amplification test for hepatitis B virus (HBV). RESULTS: The overall prevalence of markers among the participants was 0.136% (95% confidence interval [CI]: 0.003 0.270) for HBsAg, 6.44% (95% CI: 5.55-7.33%) for anti-HBc, 50.8% (95% CI: 48.9 52.7%) for anti-HBs > 10 mIU/mL, and 0.44% (95% CI: 0.20-0.68) for anti-HCV. Almost 30.4% had anti-HBs titers > 100 mIU/mL. Participants with a detectable HCV viral load (n = 9) were infected with genotype 1a. CONCLUSIONS: In an urban university population, in which 80% of participants had > 11 years of education, prevalence increased with age, and self-declared ethnicity for anti-HBc and with age, marital status and professional activity for anti-HCV antibodies. A periodical offer of HCV rapid testing should be implemented, and HBsAg rapid testing should be offered to individuals above 20 years of age. PMID- 26436354 TI - Diagnostic performance of controlled attenuation parameter for predicting steatosis grade in chronic hepatitis B. AB - BACKGROUND & AIMS: A novel controlled attenuation parameter (CAP) using the signals acquired by the FibroScan(r) has been developed as a method for evaluating steatosis. The aim of this study is to assess the performance of the CAP for the detection and quantification of steatosis in patients with chronic hepatitis B (CHB). MATERIAL AND METHODS: 136 subjects with CHB underwent liver biopsy and FibroScan(r) within 60 days. CAP was evaluated retrospectively using raw FibroScan(r) data. Steatosis was graded as follows: S0 (steatosis < 10% of hepatocytes), S1 (10 to < 30%), S2 (30 to < 60%) or S3 (>= 60%). Performance was evaluated by area under the receiver operating characteristic (AUROC) curve. RESULTS: Proportions of each steatosis grade (S0-S3) were 78, 10, 9 and 3%, respectively. Using univariate analysis, liver stiffness measurement (LMS) significantly correlated with fibrosis (tau = 0.43; P < 10-10), sex, necro inflammatory activity, steatosis, age, NASH, and perisinusoidal fibrosis, and with liver fibrosis (P < 10-8) and perisinusoidal fibrosis (P = 0.008) using multivariate analysis. CAP correlated with steatosis (tau = 0.38, P < 10-7), body mass index, NASH, fibrosis and perisinusoidal fibrosis using univariate analysis, but only steatosis (P < 10-10) and perisinusoidal fibrosis (P = 0.002) using multivariate analysis. AUROCs for LSM were: 0.77 (0.69-0.85), 0.87 (0.80-0.95), and 0.93 (0.83-1.00), respectively, for fibrosis stages F >= 2, F >= 3 and F = 4. AUROCs for CAP were: 0.82 (0.73-0.92), 0.82 (0.69-0.95), and 0.97 (0.84-1.00) for >= S1, >= S2 and S3 steatosis, respectively. CONCLUSIONS: In conclusion CAP is a novel, accurate non-invasive tool and may be suitable for detecting and quantifying steatosis in CHB patients. PMID- 26436355 TI - Correlation between serum cytokeratin-18 and the progression or regression of non alcoholic fatty liver disease. AB - BACKGROUND: Diagnosis of non-alcoholic fatty liver disease (NAFLD) is limited by the need for liver biopsies. Serum cytokeratin 18 (CK-18) levels have been investigated as potential biomarkers for the presence of NAFLD and non-alcoholic steatohepatitis (NASH). Herein, we assessed the correlation between CK-18 levels and NAFLD progression. MATERIAL AND METHODS: Serum CK-18 levels were estimated using the M30 antibody enzyme-linked immunosorbent assay in 147 patients diagnosed with NAFLD. In 72 patients, disease progression was evaluated by repeated liver biopsy, which was conducted after 4.3 +/- 2.6 years. The relationship between the CK-18 levels and liver histological findings was assessed. RESULTS: The CK-18 levels were useful for identifying NAFLD patients with NAFLD activity scores (NAS) >= 5 (NAS >= 5 vs. <= 4: 675.1 U/L vs. 348.7 U/L; p < 0.0001). A cut-off value of 375 U/L was calculated using the receiver operating characteristic curve approach, with a specificity and sensitivity of 81.5 and 65%, respectively, for the diagnosis of NASH. Among the 72 patients who underwent repeated liver biopsy, 11 patients with a progressed NAS also had significantly increased serum CK-18 levels (p < 0.01); in 30 patients with an improved NAS, there was a significant improvement in the mean CK-18 levels (p < 0.0001). The 31 patients with static NAS had static CK-18 levels. CONCLUSIONS: In conclusion, serum CK-18 levels can predict NAS >= 5 in NAFLD patients. In NAFLD patients, serum CK-18 levels reflect NAS values and correlate with histological changes, and they appear to be useful indicators of progression and improvement. PMID- 26436356 TI - Predicting early discharge from hospital after liver transplantation (ERDALT) at a single center: a new model. AB - BACKGROUND & RATIONALE: Limited information related to Liver Transplantation (LT) costs in South America exists. Additionally, costs analysis from developed countries may not provide comparable models for those in emerging economies. We sought to evaluate a predictive model of Early Discharge from Hospital after LT (ERDALT = length of hospital stay <= 8 days). A predictive model was assessed based on the odds ratios (OR) from a multivariate regression analysis in a cohort of consecutively transplanted adult patients in a single center from Argentina and internally validated with bootstrapping technique. RESULTS: ERDALT was applicable in 34 of 289 patients (11.8%). Variables independently associated with ERDALT were MELD exception points OR 1.9 (P = 0.04), surgery time < 4 h OR 3.8 (P = 0.013), < 5 units of blood products consumption (BPC) OR 3.5 (P = 0.001) and early weaning from mechanical intubation OR 6.3 (P = 0.006). Points in the predictive scoring model were allocated as follows: MELD exception points (absence = 0 points, presence = 1 point), surgery time < 4 h (0-2 points), < 5 units of BPC (0-2 points), and early weaning (0-3 points). Final scores ranged from 0 to 8 points with a c-statistic of 0.83 (95% CI 0.77-0.90; P < 0.0001). Transplant costs were significantly lower in patients with ERDALT (median $23,078 vs. $28,986; P < 0.0001). Neither lower patient and graft survival, nor higher rates of short-term re-hospitalization and acute rejection events after discharge were observed in patients with ERDALT. In conclusion, the ERDALT score identifies patients suitable for early discharge with excellent outcomes after transplantation. This score may provide applicable models particularly for emerging economies. PMID- 26436357 TI - Evaluation the value of markers for prediction of portal vein thrombosis after devascularization. AB - AIM: To evaluate the value of D-dimer and P-selectin in cirrhotic portal hypertension (PHT) patients for prediction of portal vein thrombosis (PVT) after devascularization. MATERIAL AND METHODS: 137 patients with cirrhotic PHT who undergone devascularization from January 2012 to April 2014 were retrospectively reviewed, all of them were divided into two groups (PVT group and non-PVT group) by Doppler ultrasonography (DU) examination. The level of D-dimer and P-selectin was tested during the peri-operative period. RESULTS: 38 patients (27.7%) were found PVT by DU examination post-operatively. In contrast to the non- PVT group, the level of D-dimer and P-selectin in the PVT group was much higher significantly at 1, 3 and 7 days after devascularization (P < 0.05). However, in the 15 days after surgery, the difference of P-selectin between the two groups was not significant (P = 0.260). It was shown that the higher sensitivity of the two markers for PVT was D-dimer, the higher specificity belonged to P-selectin. The area under receiver operating characteristic (ROC) curve of P-selectin was the bigger of the two markers. When the two markers were combined to be used to diagnose PVT, the sensitivity was increased to 0.911, with a slight drop of specificity to 0.715, the area under ROC curve was 0.919. CONCLUSION: The level of D-dimer and P-selectin might be good candidate predictive markers for PVT in patients with cirrhotic PHT after devascularization. The combined test of the two markers can increase the value of prediction. PMID- 26436358 TI - The burden of cirrhosis and impact of universal coverage public health care system in Thailand: Nationwide study. AB - BACKGROUND AND RATIONALE: Cirrhosis is responsible for significant health-care costs and morbidity. This study aims to evaluate the burden of illness associated with cirrhosis, its impact on the universal coverage public health care system in Thailand. MATERIAL AND METHODS: We used data from the 2010 Nationwide Hospital Admission Data, the National Health Security Office (NHSO), Thailand. Their baseline characteristics, hospital costs, and outcomes were analyzed according to national health insurance categories including medical welfare scheme (MWFS), social security scheme (SSS) and civil servant medical benefit scheme (CSMBS). RESULTS: 92,301 admissions were eligible for analysis. The mean age was 55 +/- 12.8 years, and 63.3% of patients were above 50 years old. The majority of patients (79%) belonged to the MWFS group. The MWFS group incurred the lowest medical expense and had the shortest hospital stay compared to the SSS and CSMBS groups. Overall in-hospital mortality was 10.7%. Cirrhosis complications include bleeding esophageal varices, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, and hepatocellular carcinoma. These complications significantly increased mortality rates compared to patients without complications (26 vs. 8.9%, p < 0.001). In-hospital mortality of patients with cirrhosis complications did not differ among the three national health insurance groups. Respiratory failure and septicemia were associated with the highest risk of death (HR 5.4; 95% CI: 4.8-5.9 and HR 5.2; 95% CI: 4.9-5.6 respectively; P < 0.001). CONCLUSIONS: Illness associated with cirrhosis is a significant public health problem in Thailand. Outcomes of cirrhosis complications did not differ between universal public health care coverage systems in Thailand. PMID- 26436359 TI - A simple diagnostic index comprising epithelial membrane antigen and fibronectin for hepatocellular carcinoma. AB - Background and rationale for the study. Continuing search for suitable tumor markers is of clinical value in managing patients with various malignancies. These markers may be presented as intracellular substances in tissues or may be released into the circulation and appear in serum. Therefore, this work is concerned with identification and quantitative determination of epithelial membrane antigen (EMA) and fibronectin and estimating their performances as surrogate markers for identifying hepatocellular carcinoma (HCC). RESULTS: A total of 627 individuals constituted this study [fibrosis (F1-F3) = 217; cirrhosis = 191; HCC = 219]. Western-blot was used for identifying EMA and fibronectin in sera. As a result, a single immunoreactive band was shown at 130 kDa and 90-kDa corresponding to EMA and fibronectin, respectively. They were quantified using ELISA providing values in HCC higher than fibrosis or cirrhosis with a significant difference (P < 0.0001). For identifying HCC, EMA showed 0.82 area under receiver-operating characteristic curve (AUC) with sensitivity = 70% and specificity = 78% while fibronectin yielded AUC = 0.70 with sensitivity = 67% and specificity = 82%. FEBA-Test comprising fibronectin and EMA together with total-bilirubin and AFP was constructed yielding AUC = 0.92 for identifying HCC from cirrhosis with sensitivity = 89% and specificity = 85%. FEBA-Test was then tested for differentiating HCC from fibrosis showing AUC = 0.97 with sensitivity = 90% and specificity = 89%. FEBA-Test enabled the correct identification of HCC patients with CLIP 0-1 and size <= 3 cm with AUC = 0.80 and AUC = 0.84, respectively, indicating its ability in identifying early HCC. CONCLUSIONS: A four-marker index may improve the early detection of HCC with a high degree of accuracy. PMID- 26436360 TI - Evaluation of alpha-fetoprotein as a screening marker for hepatocellular carcinoma in hepatitis prevalent areas. AB - The objective of this study was to establish modified cutoff values of serum alpha-fetoprotein (AFP) according to hepatitis status. While AFP is used as a serum marker in the diagnosis or monitoring of hepatocellular carcinoma (HCC), its use as a screening method to the general population is controversial. We evaluated its screening performance in a hepatitis prevalent East Asian population, and suggest different cutoff values according to the individual's hepatitis status. We evaluated the performance of AFP as a screening test in 48,123 consecutive Koreans during the period from March, 2012 to August, 2013 who underwent routine health checks at a single institution. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated with fixed cutoff and with modified cutoffs according the individual's hepatitis status. A total of 24 out of 48,123 subject (0.05%) were newly diagnosed with HCC after screening. Among the 1,874 subject with positive hepatitis B virus surface antigen (HBsAg), 17 (0.91%) developed HCC, compared with two out of 393 (0.51%) individuals with hepatitis C virus antibody (anti HCV). Five out of 45,855 (0.01%) subject with neither HBsAg nor anti-HCV developed HCC. Compared to the performance of a fixed cutoff, specificity, PPV, and NPV improved without sacrificing sensitivity when applying modified cutoff. In conclusion, our findings suggest that AFP with modified cutoffs according to the individual's hepatitis status might be a useful screening marker for HCC in hepatitis prevalent areas. PMID- 26436361 TI - Drug-induced liver injury in hospitalized HIV patients: high incidence and association with drugs for tuberculosis. AB - BACKGROUND: The evaluation of liver disease in HIV patients is cumbersome because may result from a number of different causes. The aim of this retrospective study was to estimate the incidence of severe drug induced liver injury (DILI) in a group of HIV inpatients and investigate potential risk factors. MATERIAL AND METHODS: We performed a retrospective analysis of data from HIV-infected patients hospitalized between August 2010 and August 2011 in a tertiary hospital in Sao Paulo, Brazil. Severe hepatotoxicity was defined as grade 3 (5.1 to 10 x ULN) or 4 (> 10 x ULN) of ALT and AST levels. Factors analyzed included demographics, infection with hepatitis viruses, alcohol history and use of hepatotoxic drugs prior to or during hospital admission. RESULTS: A total of 149 patients with HIV were hospitalized during the study period. The majority were male over 42 years of age and 82 (55%) were taking HAART initiated prior to admission. Mean CD4 counts were 164 cells/mm3. Thirty three patients (22.1%) developed severe DILI during hospital stay, which had a mean duration of 26 days. Factors associated with severe DILI in the multivariate analysis were abnormal baseline ALT levels [OR 2.02 (95%CI 1.13-3.59); p = 0.017] and tuberculosis therapy [OR 2.31 (95% CI 1.27-4.19); p = 0.006]. In conclusion, in this group of HIV patients admitted to a tertiary hospital in Brazil, we found a high incidence (22.1%) of severe DILI. The use of anti-tuberculosis drugs and baseline liver injury were independent factors associated with severe DILI during hospital stay. PMID- 26436362 TI - Contrast-induced acute kidney injury in cirrhotic patients. A retrospective analysis. AB - BACKGROUND: The nephrotoxic potential of intravenous iodinated contrast (IC) is controversial. Cirrhotic patients are often submitted to imaging procedures involving IC and small changes in renal function may have detrimental effects. MATERIAL AND METHODS: Retrospective analysis of hospitalized patients with elective imaging by either contrast-enhanced CT or MRI. Contrast induced acute kidney injury (CI-AKI) was diagnosed if there was either an increase of SCr by 25% or by 44 MUmol/L or a decrease of estimated glomerular filtration rate by 25% by day 3. RESULTS: Between 2004 and 2012 152 patients (female: 30.3%, age: 60 +/- 10.8 years, MELD 13 +/- 6) were included in this study of which 84 (55.3%) had received IC and 68 (44,7%), who served as controls, MRI with gadolinium based contrast (non-IC). Baseline parameters were well matched except for age (61.7 vs. 56.9) years in the IC vs. non-IC groups, p = 0.005). 15 patients (17.9%) receiving IC and 4 patients (5.9%) not receiving IC (p = 0.026) reached the composite end-point for CI-AKI. In multivariable regression analysis INR [B = 0.252 (95% CI: 0.108-0.397), p = 0.001]; IC [B = 0.136 (95% CI: 0.023-0.248), p = 0.019] and serum sodium [B = 0.011 (95% CI: 0.001-0.023); p = 0.080] were independently associated with changes of SCr. In conclusion IC may cause renal dysfunction in cirrhotic patients. Patients subjected to imaging using IC should be closely monitored. PMID- 26436363 TI - The limited prognostic value of liver histology in children with biliary atresia. AB - Background and rationale for the study. The aim of the study was to determine the prognostic value of histopathological findings with special care to the severity of liver fibrosis at the moment of hepatoportoenterostomy (HPE) in children with biliary atresia (BA). We performed analysis of 142 wedge liver biopsies taken at the time of HPE. All patients were operated by the same surgical team between 1995 and 2007. According to the outcome 6 months after HPE patients were divided into prognostic groups: group 1-bilirubin level < 2 mg% (n = 65), group 2 bilirubin level > 2 mg% (n = 77). Liver biopsies were re-evaluated according to the extended histopathological protocol and then were compared between the prognostic groups. Survival with native liver (SNL) estimates were performed in regard to severity of liver fibrosis. RESULTS: Survival with native liver estimates after 2, 5 and 10 years in patients after successful operation were 96%, 91%, 75% vs. 30%, 11%, and 5% if operation failed (p < 0.001). There was no difference between groups in the following variables: fibrosis (p = 0.69), portal inflammation (p = 0.99), lobular inflammation (p = 0.95), cholangiolitis (p = 0.23), accumulation of bile pigments (zone 1:p = 0.49; zone 2:p = 0.51; zone 3:p = 0.48), bile plugs in canaliculi (p = 0.12), bile plugs in ducts (p = 0.32), bilirubinostasis in hepatocytes (p = 0.45), bile ductular proliferation (p = 0.59), ductal plate malformation (p = 0.12), focal necrosis (p = 0.44), giant cell transformation (p = 0.45), haematopoesis (p = 0.52), ductopenia (p = 0.46), microabscesses (p = 0.49), ballooning of hepatocytes (p = 0.08). The actuarial 5/10-year SNL was not dependent on severity of liver fibrosis (log-rank test p = 0.84). The severity of fibrosis corresponded neither with the age at HPE nor with the laboratory findings before operation but increased the risk of portal hypertension. CONCLUSION: Liver histology at the time of HPE is of limited value in prognosis making in BA. PMID- 26436364 TI - Maternal separation on the ethanol-preferring adult rat liver structure. AB - Background and rationale for the study. We designed to test whether there is interaction of maternal separation (MS) on the ethanol-preferring rats liver structure. The UCh rat pups were separated daily from their mothers during the stress hyporesponsive period (SHRP), between four and 14 days-old, always at the same time for four hours in a cage containing eight subdivisions, one for each pup. Subsequently, rats that presented the highest (UChB) and the lowest (UChA) ethanol (EtOH) consumption were selected to the study. Both UChB and UChA rats received 10% (v/v) EtOH and distilled water ad libitum until the end of the experiment (120 days-old). The liver was collected to histological routine for morphometric and stereological analyses, and immunohistochemistry. RESULTS: There was an interaction of MS and EtOH on the liver: increased liver mass, peritubular vessels, stellate cell numbers, steatosis and cell death, decreased necrosis, sinusoidal capillary diameters and cell proliferation. While there was a decrease in FSH, testosterone and 5alpha-di-hidrotestosterone, and increasing corticosterone and cholesterol. CONCLUSIONS: There is interaction of MS and EtOH on the liver structure, dependent on the amount of EtOH intake. Furthermore, the interaction of stress and drugs can increase or decrease their effects on the liver or indirectly via hypothalamic-pituitary-adrenal (HPA) and hypothalamic pituitary-gonadal (HPG) axes. PMID- 26436365 TI - Congenital double intrahepatic portosystemic shunt: Imaging findings and endovascular closure. PMID- 26436366 TI - Severe hypercholesterolemia mediated by lipoprotein X in a patient with cholestasis. AB - Lipoprotein X (LpX) is an abnormal lipoprotein associated with cholestasis. It is a significant cause of severe hypercholesterolemia and should always be considered in patients with cholestatic liver disease. This case highlights the significance of LpX as a cause of severe hypercholesterolemia in a patient with cholestasis secondary to a granulomatous hepatitis attributed to tuberculosis. Lipoprotein agarose gel electrophoresis and gradient gel electrophoresis were performed for the detection of LpX. The liver function tests, electrolytes, lipid profile and bile acids were also determined. Anti-tuberculous therapy was initiated and the liver functions improved with normalisation of the lipid profile. PMID- 26436367 TI - Peritoneal ultrafiltration for refractory fluid overload and ascites due to pulmonary arterial hypertension. AB - Pulmonary hypertension is a common finding in patients with advanced liver disease. Similarly, among patients with advanced pulmonary arterial hypertension, right heart failure leads to congestive hepatopathy. Diuretic resistant fluid overload in both advanced pulmonary hypertension and chronic liver disease is a demanding challenge for physicians. Venous congestion and ascites-induced increased intra-abdominal pressure are essential regarding recurrent hospitalization, morbidity and mortality. Due to impaired right-ventricular function, many patients cannot tolerate extracorporeal ultrafiltration. Peritoneal dialysis, a well-established, hemodynamically tolerated treatment for outpatients may be a good alternative to control fluid status. We present a patient with pulmonary arterial hypertension and congestive hepatopathy hospitalized for over 3 months due to ascites induced refractory volume overload treated with peritoneal ultrafiltration. We report the treatment benefits on fluid balance, cardiorenal and pulmonary function, as well as its safety. In conclusion, we report a case in which peritoneal ultrafiltration was an efficient treatment option for refractory ascites in patients with congestive hepatopathy. PMID- 26436368 TI - Isolated liver disease in a patient with a CFTR genotype F508del/12TG-5T and 470MV: A new face of an old disease. AB - Today the knowledge of genotype-phenotype correlation in cystic fibrosis is enriched by the growing discoveries of new mutations of the CFTR gene. Although the combination of two severe mutations usually leads to the classic disease (pulmonary and pancreatic insufficiency, sterility, nasal polyposis), the presence of a complex genotype characterized by severe and milder mutations or polymorphism can cause a hidden disease, which is often asymptomatic at early ages. We report on a case of a 15 years old boy, in whom the only clinical signs of CF were chronic hypertransaminasemia and hyperbilirubinemia, and in whom it was demonstrated the presence of the mutations F508del associated with TG11-9T 470M in one allele and TG12-5T-470V in the other allele. Although a clear genotype-phenotype correlation for liver disease is still missing for CF patients, it is possible to state that this isolated clinical presentation could represent an unusual phenotype of CF, related to a complex genotype characterized by a severe mutation and one (or more) polymorphism. PMID- 26436369 TI - Assessing risk factors of acute kidney injury after liver transplantation. PMID- 26436370 TI - Acute kidney injury after liver transplantation is associated with viral hepatitis, prolonged warm ischemia, serum lactate and higher mortality. PMID- 26436371 TI - Nonalcoholic fatty liver disease and polycystic ovary syndrome. PMID- 26436372 TI - Slow growth of the overexploited milk shark Rhizoprionodon acutus affects its sustainability in West Africa. AB - Age and growth of Rhizoprionodon acutus were estimated from vertebrae age bands. From December 2009 to November 2010, 423 R. acutus between 37 and 112 cm total length (LT ) were sampled along the Senegalese coast. Marginal increment ratio was used to check annual band deposition. Three growth models were adjusted to the length at age and compared using Akaike's information criterion. The Gompertz growth model with estimated size at birth appeared to be the best and resulted in growth parameters of Linfinity = 139.55 (LT ) and K = 0.17 year(-1) for females and Linfinity = 126.52 (LT ) and K = 0.18 year(-1) for males. The largest female and male examined were 8 and 9 years old, but the majority was between 1 and 3 years old. Ages at maturity estimated were 5.8 and 4.8 years for females and males, respectively. These results suggest that R. acutus is a slow-growing species, which render the species particularly vulnerable to heavy fishery exploitation. The growth parameters estimated in this study are crucial for stock assessments and for demographic analyses to evaluate the sustainability of commercial harvests. PMID- 26436373 TI - Macroecological analysis of the fish fauna inhabiting Cymodocea nodosa seagrass meadows. AB - In this study, patterns in the taxonomic richness and composition of the fish fauna inhabiting Cymodocea nodosa seagrass meadows were described across their entire distribution range in the Mediterranean Sea and adjacent Atlantic Ocean. Specifically, the study tested whether there are differences in the composition of fish assemblages between those ecoregions encompassed by the distribution range of C. nodosa, and whether these differences in composition are connected with differences in bioclimatic affinities of the fish faunas. A literature review resulted in a total of 19 studies, containing 22 fish assemblages at 18 locations. The ichthyofauna associated with C. nodosa seagrass meadows comprises 59 families and 188 species. The western Mediterranean (WM) Sea has the highest species richness (87 species). Fish assemblages from the Macaronesia-Canary Islands, the Sahelian Upwelling, South European Atlantic Shelf and the WM differ, in terms of assemblage composition, relative to other ecoregions. In contrast, the composition of the fish fauna from the central and eastern Mediterranean overlaps. There is a significant serial correlation in fish assemblage composition between adjacent ecoregions along the distribution range of C. nodosa. Dissimilarities in assemblage composition are connected with the geographical separation between locations, and the mean minimum annual seawater temperature is the environmental factor that explains most variation in fish assemblage composition. PMID- 26436375 TI - Genetic diversity and genetic structure of consecutive breeding generations of golden mandarin fish (Siniperca scherzeri Steindachner) using microsatellite markers. AB - In this study, 12 polymorphic microsatellites were inves-tigated to determine the genetic diversity and structure of 5 consecu-tive selected populations of golden mandarin fish (Siniperca scherzeri Steindachner). The total numbers of alleles, average heterozyosity, and average polymorphism information content showed that the genetic diversity of these breeding populations was decreasing. Additionally, pairwise fixation index FST values among populations and Da values in-creased from F1 generation to subsequent generations (FST values from 0.0221-0.1408; Da values from 0.0608-0.1951). Analysis of molecular variance indicated that most genetic variations arise from individuals within populations (about 92.05%), while variation among populations accounted for only 7.95%. The allele frequency of the loci SC75-220 and SC101-222 bp changed regularly in the 5 breeding generations. Their frequencies were gradually increased and showed an enrichment trend, indicating that there may be genetic correlations between these 2 loci and breeding traits. Our study indicated that microsatellite markers are effective for assessing the genetic variability in the golden mandarin fish breeding program. PMID- 26436374 TI - Differential submitochondrial localization of PINK1 as a molecular switch for mediating distinct mitochondrial signaling pathways. AB - Mutations in mitochondrial kinase PINK1 cause Parkinson disease (PD), but the submitochondrial site(s) of PINK1 action remains unclear. Here, we report that three-dimensional structured illumination microscopy (3D-SIM) enables super resolution imaging of protein submitochondrial localization. Dual-color 3D-SIM imaging analysis revealed that PINK1 resides in the cristae membrane and intracristae space but not on the outer mitochondrial membrane (OMM) of healthy mitochondria. Under normal physiological conditions, PINK1 colocalizes with its substrate TRAP1 in the cristae membrane and intracristae space. In response to mitochondrial depolarization, PINK1, but not TRAP1, translocates to the OMM. The PINK1 translocation to the OMM of depolarized mitochondria is independent of new protein synthesis and requires combined action of PINK1 transmembrane domain and C-terminal region. We found that mitochondrial depolarization-induced PINK1 OMM translocation is required for recruitment of parkin to the OMM of damaged mitochondria. Our findings suggest that differential submitochondrial localization of PINK1 serves as a molecular switch for mediating two distinct mitochondrial signaling pathways in maintenance of mitochondrial homeostasis. Furthermore, our study provides evidence for the involvement of deregulated PINK1 submitochondrial localization in PD pathogenesis. PMID- 26436376 TI - Changes and clinical significance of serum vaspin levels in patients with type 2 diabetes. AB - We investigated serum visceral adipose tissue-derived serpin (vaspin) levels in patients with normal glucose regulation and recently diagnosed type 2 diabetes (T2DM) and explored the association between vaspin and body mass index, age, gender, glucose, lipid metabolism, and insulin sensitivity. Fasting serum vaspin levels in 66 patients with T2DM and 48 normal subjects were detected using enzyme linked immunosorbent assay. We found that serum vaspin levels in the DM group were 0.65 +/- 0.13 mg/L in non-obese patients and 1.13 +/- 0.25 mg/L in obese patients. Serum vaspin levels in the control group were 0.38 +/- 0.18 mg/L in non obese patients and 0.95 +/- 0.11 mg/L in obese patients. Average serum vaspin levels were significantly higher in obese patients than in non-obese patients in both the DM group and control group. In the DM group, the serum vaspin level was 0.76 +/- 0.22 mg/L in males and 0.92 +/- 0.35 mg/L in females. In the control group, the serum vaspin level was 0.48 +/- 0.14 mg/L in males and 1.05 +/- 0.21 mg/L in females. Association analysis showed that serum vaspin levels were significantly associated with body mass index, waist-to-rip ratio (WHR), fat percentage, triglyceride, fasting plasma insulin, and insulin sensitivity index. Stepwise multiple regression analysis showed that gender, insulin sensitivity index, and WHR were the most significant independent factors affecting vaspin. Therefore, serum vaspin levels were significantly elevated in obese people and were independently associated with WHR, gender, and index sensitivity index. PMID- 26436377 TI - Effect of RAGE polymorphisms on susceptibility to and severity of osteoarthritis in a Han Chinese population: a case-control study. AB - Recent studies have revealed that the inflammatory process plays a role in the pathogenesis of osteoarthritis (OA). The S100 family and receptor for advanced glycation end products (RAGE) participate in regulating inflammation, even in the production of matrix metalloproteinases (MMPs). MMP-1 degrades cartilage, which may result in OA development. Moreover, polymorphisms in RAGE, S100A8, and MMP-1 have a marked effect on ligand binding and transcription regulating. In this study, we investigated the potential genetic contribution of the RAGE, S100A8, and MMP-1 genes to OA. We performed a matched case-control association study and genotyped OA patients and healthy controls, who were analyzed by polymerase chain reaction-restriction fragment length polymorphism assays. A total of 207 patients were diagnosed with knee OA and underwent total knee replacement. The control group included 207 individuals who had standard X-rays of the knee joints to confirm K/L < 2 and were matched by age and gender. Single-nucleotide polymorphisms in RAGE (-429T/C, -374T/A, and 557G/A), S100A8 (rs3795391A/G), and MMP-1 (-1607 1G/2G, -755G/T, and -519A/G) were evaluated. RAGE -374T/A, S100A8 rs3795391A/G, MMP-1 -1607 1G/2G, -755G/T, and -519A/G showed no significant difference between OA patients and healthy controls. RAGE -429T/C and 557G/A showed a significant association between OA patients and healthy controls (P = 0.016 and 0.047, respectively). In haplotype analyses, no RAGE and MMP-1 haplotypes showed associations with OA. Our results suggest that the investigated polymorphism in the RAGE gene play a role in OA in the Han Chinese population. PMID- 26436378 TI - Expressional analysis of immune-related miRNAs in breast milk. AB - Immune-related miRNAs in breast milk are extracellular miRNAs that are related to immune organ development and regulation of the immune function in infants and young animals. The goal of this study was to compare the expression levels of five immune-related miRNAs in breast milk in black goats, humans, and dairy cattle. The miRNAs from milk were extracted and the expression levels were assessed using quantitive RT-PCR methods. MiR-146, miR-155, miR-181a, miR-223, and miR-150 were all detected in Dazu black goat milk, and these miRNAs were significantly more highly expressed in colostrum than in mature milk of goats (P < 0.01), except for miR-150. Further, all five miRNAs were expressed in human colostrum, but patterns differed from those in goats: miR-146 and miR-155 were highly expressed (P < 0.01) in human colostrum, whereas miR-223 was abundant in goat colostrum (P < 0.01). In addition, five miRNAs were significantly higher in bovine mature milk than in goat milk (P < 0.01). Taken together, these results confirm that immune-related miRNAs are rich in breast milk with different expression levels depending on the lactation phase and species. PMID- 26436379 TI - Identification of single nucleotide polymorphisms in the ASB15 gene and their associations with chicken growth and carcass traits. AB - ASB15 is a member of the ankyrin repeat and suppressor of cytokine signaling box family, and is predominantly expressed in skeletal muscle. In the present study, an F2 resource population of Gushi chickens crossed with Anka broilers was used to investigate the genetic effects of the chicken ASB15 gene. Two single nucleotide polymorphisms (SNPs) (rs315759231 A>G and rs312619270 T>C) were identified in exon 7 of the ASB15 gene using forced chain reaction-restriction fragment length polymorphism and DNA sequencing. One was a missense SNP (rs315759231 A>G) and the other was a synonymous SNP (rs312619270 T>C). The rs315759231 A>G polymorphism was significantly associated with body weight at birth, 12-week body slanting length, semi-evisceration weight, evisceration weight, leg muscle weight, and carcass weight (P < 0.05). The rs312619270 T>C polymorphism was significantly associated with body weight at birth, 4, 8, and 12 week body weight, 8-week shank length, 12-week breast bone length, 8 and 12-week body slanting length, breast muscle weight, and carcass weight (P < 0.05). Our results suggest that the ASB15 gene profoundly affects chicken growth and carcass traits. PMID- 26436380 TI - Molecular typing of Salmonella from Sergipe, Northeastern Brazil, showing the epidemiological relationship between poultry and human infection. AB - Randomly amplified polymorphic DNA (RAPD) has been widely used for epidemiological and phylogenetic purposes ow-ing to its rapidity and efficiency. The aim of this study was to perform genome typing of Salmonella samples isolated from different sources by RAPD profiling. Thirty-three Salmonella samples from the bacterial collection of the Laboratorio de Virologia Comparada, Departamento de Morfologia, Universidade Federal de Sergipe, Brazil, and two standard samples were used. RAPD profiling was conducted using six primers of the Ready-To-Go RAPD system. The amplified products were electro-phoresed on 5% polyacrylamide gel and silver-stained. RAPD analysis resulted in reproducible and stable banding patterns and showed high genetic diversity among the isolated strains. The Primer P1-generated dendrogram showed an epidemiologic relationship between the human and poultry isolated samples, highlighting the usefulness of RAPD for molecular typing and epidemiological studies. PMID- 26436381 TI - Effects of glucose and disorders in lipid metabolism on cytokine levels and cognitive impairment in the olanzapine-induced obesity rat model. AB - The aim of the study was to explore the effects of increased levels of blood sugar and cytokines on impaired cognitive function in the olanzapine-induced obesity rat model. A total of 40 rats were randomly divided into 2 groups; the control and olanzapine groups (N = 20 per group). The control rats were fed regular food, while the olanzapine rats received olanzapine-enriched (1.2 mg/kg) food by gavage for 4 weeks to establish the olanzapine-induced obese rat model. Enzyme-linked immunosorbent assays were used to measure the serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and C-reactive protein (CRP). Serum glucose content was measured by biochemical colorimetry. Learning and memory capacity was measured using a Y-maze, and the time before escape from a Morris water maze was recorded. Body weight and levels of blood glucose, lipids, TNF-alpha, IL-6, and CRP increased in the olanzapine group. In addition, the number of shocks received before reaching the learning and memory standard and the time before escape from the Morris water maze were higher in the olanzapine group than in the control group. Olanzapine causes disorders in glucose and lipid metabolism. Increase in blood glucose promotes the toxicity of cytokines and leads to cognitive dysfunction in rats. PMID- 26436382 TI - Sequence variation in ROP8 gene among Toxoplasma gondii isolates from different hosts and geographical localities. AB - The protozoan parasite Toxoplasma gondii has a worldwide distribution; it can cause serious diseases in humans and almost all other warm-blooded animals. Different genotypes of T. gondii result in different lesions in the same host. T. gondii rhoptry protein 8 (TgROP8) is a major factor of T. gondii acute virulence. We examined sequence variation in the TgROP8 gene among T. gondii isolates from different hosts and geographical localities. The TgROP8 gene was amplified from individual isolates and sequenced. A phylogenetic tree was constructed using Bayesian inference, maximum parsimony, and maximum likelihood based on the sequences obtained plus TgME49 from the ToxoDB database. The TgROP8 gene was 1728 bp in length for all the examined T. gondii strains, and their A+T contents were 45.37-45.95%. Sequence analysis detected 140 (0.06-5.56%) variable nucleotide positions resulting in 96 (0-10.78%) amino acid substitutions. Sequence variations in the TgROP8 gene resulted in polymorphic restriction sites for endonucleases BstBI, BsaI, and XhoI, which allowed the differentiation of the three classical genotype strains (types I, II, and III) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). However, phylogenetic analyses indicated that the TgROP8 gene is not a suitable genetic marker for population studies of T. gondii. PMID- 26436383 TI - Evaluation of microsatellite loci from libraries derived from the wild diploid 'Calcutta 4' and 'Ouro' banana cultivars. AB - Microsatellite markers have been widely used in the quantification of genetic variability and for genetic breeding in Musa spp. The objective of the present study was to evaluate the discriminatory power of microsatellite markers derived from 'Calcutta 4' and 'Ouro' genomic libraries, and to analyze the genetic variability among 30 banana accessions. Thirty-eight markers were used: 15 from the 'Ouro' library and 23 from the 'Calcutta 4' library. Genetic diversity was evaluated by considering SSR markers as both dominant markers because of the presence of triploid accessions, and co-dominant markers. For the dominant analysis, polymorphism information content (PIC) values for 44 polymorphic markers ranged from 0.063 to 0.533, with a mean value of 0.24. A dendrogram analysis separated the BGB-Banana accessions into 4 groups: the 'Ouro' and 'Muisa Tia' accessions were the most dissimilar (93% dissimilarity), while the most similar accessions were 'Pacovan' and 'Walha'. The mean genetic distance between samples was 0.74. For the analysis considering SSR markers as co-dominants, using only diploid accessions, two groups were separated based on their genome contents (A and B). The PIC values for the markers from the 'Calcutta 4' library varied from 0.4836 to 0.7886, whereas those from the 'Ouro' library ranged from 0.3800 to 0.7521. Given the high PIC values, the markers from both the libraries showed high discriminatory power, and can therefore be widely applied for analysis of genetic diversity, population structures, and linkage mapping in Musa spp. PMID- 26436384 TI - Apoptosis induced by lipid-associated membrane proteins from Mycoplasma hyopneumoniae in a porcine lung epithelial cell line with the involvement of caspase 3 and the MAPK pathway. AB - Lipid-associated membrane proteins (LAMPs) are important in the pathogenicity of the Mycoplasma genus of bacteria. We investigated whether Mycoplasma hyopneumoniae LAMPs have pathogenic potential by inducing apoptosis in a St. Jude porcine lung epithelial cell line (SJPL). LAMPs from a pathogenic strain of M. hyopneumoniae (strain 232) were used in the research. Our investigation made use of diamidino-phenylindole (DAPI) and acridine orange/ethidium bromide (AO/EB) staining, terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) analysis, and Annexin-V-propidium iodide staining. After LAMP treatment for 24 h, typical changes were induced, chromosomes were concentrated, apoptotic bodies were observed, the 3'-OH groups of cleaved genomes were exposed, and the percentage of apoptotic cells reached 36.5 +/- 11.66%. Caspase 3 and caspase 8 were activated and cytochrome c (cyt c) was released from the mitochondria into the cytoplasm; poly ADP ribose polymerase (PARP) was digested into two fragments; p38 mitogen-activated protein kinase (MAPK) was phosphorylated; and the expression of pro-apoptosis protein Bax increased while the anti-apoptosis protein Bcl-2 decreased. LAMPs also stimulated SJPL cells to produce nitric oxide (NO) and superoxide. This study demonstrated that LAMPs from M. hyopneumoniae can induce apoptosis in SJPL cells through the activation of caspase 3, caspase 8, cyt c, Bax, and p38 MAPK, thereby contributing to our understanding of the pathogenesis of M. hyopneumoniae, which should improve the treatment of M. hyopneumoniae infections. PMID- 26436385 TI - Suppression of lentivirus-mediated transgenic dendritic cells in graft-versus host disease after allogeneic bone marrow transplantation in mice. AB - We determined whether genetically engineered immature dendritic cells (imDCs) mediated by lentiviral vectors alleviate acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT) in mice. We introduced the mouse chemokine receptor 7 (Ccr7) gene into the bone marrow-derived imDCs of C57BL/6 mice to construct genetically engineered imDCs. A 1:1 mixture of bone marrow and spleen cells from the donors was injected into the recipients, which were divided into four groups: radiation, transplantation, empty vector, and transgenic imDC groups. Symptoms, clinical scores, GVHD pathological changes, and survival times and rates of recipients were recorded; secretion of IFN-gamma and IL-4, and allogeneic chimerism rates were detected. The survival time of the transgenic imDC group (27.5 +/- 7.55 days) was significantly longer than in the other three groups (P < 0.01). The GVHD score of the imDC group mice was significantly lower than in the transplantation and empty vector groups (P < 0.05), which meant that mice in the transgenic imDC group had the lightest pathology damage in the target organs. In the transplantation group, IFN-gamma increased while IL-4 decreased. In contrast, IFN-gamma decreased and IL-4 increased in both empty vector and trans-imDC groups, and the difference was significant in the latter (P < 0.01). Thirty days or more following transplantation, the allogeneic chimerism rate was still 95-100%, suggesting complete donor type implantation. Ccr7 transfection into imDCs suppressed occurrence and severity of acute GVHD after allo-BMT in mice; the mechanism might be associated with IFN-gamma decrease and IL-4 increase. PMID- 26436386 TI - Resistance of Castanea mollissima Shuhe-WYL strain to Dryocosmus kuriphilus and its molecular mechanism. AB - The resistance of Castanea mollissima Shuhe-WYL strain to Dryocosmus kuriphilus and its molecular mechanism were examined. The larvae of D. kuriphilus were inoculated on the Shuhe-WYL and Qingzha strains, and mortality was observed and compared; the relative mRNA content of the OsCDPK2, receptor-like protein, OsNAC6 protein, KH domain protein, RNA-binding protein, and the bHLH genes was detected using real-time polymerase chain reaction, and then compared between the Shuhe WYL and Qingzha strains. Phenylalanine ammonia-lyase content was detected by western blotting and compared between the inoculated Shuhe-WYL, non-inoculated Shuhe-WYL, and inoculated Qingzha strains. The mortalities of larvae inoculated on the bud, bracteal leaf, and cardiac lobe were lower in Shuhe-WYL than Qingzha at 48 and 96 h after inoculation; the contents of OsCDPK2, receptor-like protein, OsNAC6 protein, and bHLH in the cardiac lobe were higher in Shuhe-WYL than in Qingzha at 96 h after inoculation, but KH domain protein and RNA-binding protein were not significantly different. The content of phenylalanine ammonia-lyase in the cardiac lobe was higher in inoculated and non-inoculated Shuhe-WYL compared to inoculated Qingzha at 15, 30, 45, and 60 days, and higher in inoculated Shuhe WYL than in non-inoculated Shuhe-WYL at 15, 30, 45, and 60 days. The content of phenylalanine ammonia-lyase in the cardiac lobe of inoculated Shuhe-WYL had no significant difference between at 60 and at 45 days; and was higher at 60 and 45 days than at 30 and 15 days; and was higher at 30 days than at 15 days (60~45?30?15 days). The C. mollissima Shuhe-WYL strain was resistant to D. kuriphilus; high expression of OsCDPK2, receptor-like protein, OsNAC6 protein, and bHLH and phenylalanine ammonia-lyase may explain the mechanism. PMID- 26436387 TI - A new method of QTL identification for undersaturated maps. AB - In many species, low levels of polymorphism prevent the assembly of linkage maps that are used to identify genetic markers related to the expression of quantitative trait loci (QTLs). This study compared two methods of locating QTLs in association studies that do not require a previous estimation of linkage maps. Method I (MI) was a Bayesian multiple marker regression and Method II (MII) combined multiple QTL mapping and "moving away from markers". In this method, markers are not directly regressed to the phenotype, but are used as pivots to search for QTLs along the genome. To compare methods, we simulated 300 individuals from an F2 progeny with two levels of marker loss (20 and 80%). A total of 165 markers and seven QTLs were spread along 11 chromosomes (roughly emulating the genetic structure of the common bean, Phaseolus vulgaris). A real data example with 186 progenies of a F2:4 generation of the species was analyzed using 59 markers (17 simple sequence repeats, 31 amplified fragment length polymorphisms, and 11 sequence-related amplified polymorphisms). MII was more precise than MI for both levels of marker loss. For real data, MII detected 17 candidate positions for QTLs, whereas MI did not detect any. MII is a powerful method that requires further studies with actual data and other designs such as crossover, and genome-wide studies. PMID- 26436388 TI - Establishment and rapid detection of a heterozygous missense mutation in the CACNA1F gene by ARMS technique with double-base mismatched primers. AB - Retinitis pigmentosa (RP) is a retinal degenerative disorder that often causes complete blindness. Mutations of more than 50 genes have been identified as associated with RP, including the CACNA1F gene. In a recent study, by employing next-generation sequencing, we identified a novel mutation in the CACNA1F gene. In this study, we used the amplification refractory mutation system (ARMS) and identified a single nucleotide change c.1555C>T in exon 13 of the CACNA1F gene, leading to the substitution of arginine by tryptophan (p.R519W) in a Chinese individual affected by RP. This study actually confirms this novel mutation, and establishes the ARMS technique for the detection of mutations in RP. PMID- 26436389 TI - Correlation between polymorphisms in the IL-17A and IL-17F genes and development of coronary artery disease. AB - A case-control study was conducted to investigate the association between genetic variants of IL-17A rs2275913 and IL-17F rs763780 and the development of coronary artery disease (CAD) in a Chinese population. A total of 306 individuals with CAD and 306 unaffected individuals were enrolled from the Zhengzhou People's Hospital between May 2012 and May 2014. The IL-17A rs2275913 and IL-17F rs763780 genes were genotyped by polymerase chain reaction combined with a restriction fragment length polymorphism (PCR-RFLP). Logistic regression analysis revealed that individuals with the AA genotype of rs2275913 were associated with increased risk of CAD, compared to those with the GG genotype in a codominant model [adjusted odds ratio (OR) = 1.96; 95% confidence interval (CI) = 1.10-3.53]. On the other hand, the AA genotype of rs2275913 was correlated with moderately increased risk of CAD compared to the GG + GA genotype (adjusted OR = 1.76; 95%CI = 1.02-3.07) in a recessive model. However, no significant differences were observed between polymorphisms at the IL-17F rs763780 locus and CAD risk, in codominant, dominant, and recessive models. In conclusion, the results of our study suggested that the IL-17A rs2275913 polymorphism may affect the development of CAD; however, no significant association was observed between the IL-17F rs763780 polymorphism and risk of CAD. PMID- 26436390 TI - Effects of Pax3 and Pax7 expression on muscle mass in the Pekin duck (Anas platyrhynchos domestica). AB - This study aimed to investigate whether the differential expression of muscle development-related genes is one of the reasons why muscle development differs between Pekin, Jianchang, and Heiwu ducks, which are all domesticated duck breeds (Anas platyrhynchos domestica) breeds. At 2 weeks of age, the RNA expression of paired box 7 (Pax7), paired box 3 (Pax3), myogenic differentiation antigen (MYOD), and myogenin (MYOG) genes were measured by quantitative polymerase chain reaction, and Pax3 and Pax7 protein levels were detected by western blot assay. Myofiber morphology was investigated using paraffin-embedded muscle sections. At 8 weeks of age, 30 ducks of each breed were slaughtered for meat quality determination. The results revealed that Pax3 and Pax7 expression levels at both the RNA and protein levels were high in the Pekin duck. In addition, MYOG expression levels in the Jianchang duck were significantly higher than in the other two duck breeds (P < 0.05). There were no significant differences in MYOD expression levels between the breeds (P > 0.05). Myofiber diameter and cross sectional area were the largest in the Pekin duck and the smallest in the Heiwu duck. There were significant differences in slaughter data between these breeds, and muscle content was greatest in the Pekin duck. The results indicate that the muscle content of three different duck breeds is associated with the expression of satellite-cell marker genes. PMID- 26436391 TI - Protective effects of bifidobacteria on intestines in newborn rats with necrotizing enterocolitis and its regulation on TLR2 and TLR4. AB - We established a necrotizing enterocolitis (NEC) rat model and explored the role of bifidobacteria in the intestines of the rats and its regulation on intestinal Toll-like receptors (TLRs). Seventy-five newborn Sprague-Dawley rats were randomly divided into 5 groups (15 rats/group): group A, artificial feeding group (formula-fed); group B, NEC model (LPS + formula-fed); group C, bifidobacterium (LPS + formula-fed + bifidobacterium microcapsules, intragastric administration); group D, artificial feeding + bifidobacterium (formula-fed + bifidobacterium microcapsules gavage); group E, rat breast-feeding group (rat breast-feeding). After 3 days of feeding, rats were placed in incubators, fasted for 12 h, and killed by decapitation. The ileocecal proximal segment ileum was fixed and sliced; pathological examination was conducted, and TLR2, TLR4, and nuclear factor-kB p65 protein expression in the intestinal tissue was detected by immunohistochemistry. There was a statistically significant difference in pathological scores between groups C and B (H = 21.789, P = 0.000), and the former was lower than the latter. TLR2, TLR4, and nuclear factor-kB p65 expression in intestinal tissue was determined in groups A-E. There were statistically significant differences between groups C and B (P = 0.001; P = 0.000; P = 0.000). Bifidobacteria had a protective effect on the intestines of newborn rats with NEC, which showed reduced NEC and intestinal damage severity. This observation may be related to the reduced levels of TLR2, TLR4, and nuclear factor-kB P65 observed during the inflammatory response. PMID- 26436392 TI - Potential of hypocotyl diameter in family selection aiming at plant architecture improvement of common bean. AB - Cultivars of common bean with more erect plant architecture and greater tolerance to degree of lodging are required by producers. Thus, to evaluate the potential of hypocotyl diameter (HD) in family selection for plant architecture improvement of common bean, the HDs of 32 F2 plants were measured in 3 distinct populations, and the characteristics related to plant architecture were analyzed in their progenies. Ninety-six F2:3 families and 4 controls were evaluated in a randomized block design, with 3 replications, analyzing plant architecture grade, HD, and grain yield during the winter 2010 and drought 2011 seasons. We found that the correlation between the HD of F2 plants and traits related to plant architecture of F2:3 progenies were of low magnitude compared to the estimates for correlations considering the parents, indicating a high environmental influence on HD in bean plants. There was a predominance of additive genetic effects on the determination of hypocotyl diameter, which showed higher precision and accuracy compared to plant architecture grade. Thus, this characteristic can be used to select progenies in plant architecture improvement of common beans; however, selection must be based on the means of at least 39 plants in the plot, according to the results of repeatability analysis. PMID- 26436393 TI - Isolation and characterization of novel microsatellite markers from the sika deer (Cervus nippon) genome. AB - Microsatellite markers are widely and evenly distributed, and are highly polymorphic. Rapid and convenient detection through automated analysis means that microsatellite markers are widely used in the construction of plant and animal genetic maps, in quantitative trait loci localization, marker-assisted selection, identification of genetic relationships, and genetic diversity and phylogenetic tree construction. However, few microsatellite markers remain to be isolated. We used streptavidin magnetic beads to affinity-capture and construct a (CA)n microsatellite DNA-enriched library from sika deer. We selected sequences containing more than six repeats to design primers. Clear bands were selected, which were amplified using non-specific primers following PCR amplification to screen polymorphisms in a group of 65 unrelated sika deer. The positive clone rate reached 82.9% by constructing the enriched library, and we then selected positive clones for sequencing. There were 395 sequences with CA repeats, and the CA repeat number was 4-105. We selected sequences containing more than six repeats to design primers, of which 297 pairs were designed. We next selected clear bands and used non-specific primers to amplify following PCR amplification. In total, 245 pairs of primers were screened. We then selected 50 pairs of primers to randomly screen for polymorphisms. We detected 47 polymorphic and 3 monomorphic loci in 65 unrelated sika deer. These newly isolated and characterized microsatellite loci can be used to construct genetic maps and for lineage testing in deer. In addition, they can be used for comparative genomics between Cervidae species. PMID- 26436394 TI - Effect of pulsed electromagnetic field therapy on the osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells. AB - We investigated the effects of pulsed electromagnetic fields (PEMFs) of 20 Hz/2 mT on the osteogenic and adipogenic differentiation of bone marrow stem cells (BMSCs). Sprague Dawley rat BMSCs were isolated and cultured in vitro. The BMSCs of the third passage were obtained and stimulated by PEMFs of 20 Hz/2 mT. The alkaline phosphatase (ALP) activity was measured according to the ALP assay kit manufacturer instructions, the BMSC osteogenic and adipogenic indicators were detected by semi-quantitative reverse transcription polymerase chain reaction (RT PCR), and oil red O staining was used to observe the adipose-induced adipogenic differentiation of BMSCs. PEMFs of 20 Hz/2 mT significantly promoted the activity of ALP in the BMSCs (P < 0.01) and mRNA expression of osteogenic proteins (osteocalcin and osteopontin). The PEMFs inhibited the expression of adipogenic transcription factors such as adipokines and adipocyte-binding protein-2, and the adipogenic differentiation of BMSCs. PEMFs of 20 Hz/2 mT can promote osteogenic differentiation and inhibit adipogenic differentiation in BMSCs. PMID- 26436395 TI - Lack of clinical significance of the ImmuKnow(TM)-Cylex assay for the detection of cellular immune function in patients with renal cell carcinoma. AB - This study aimed to explore the clinical value of the CD4(+) T cell ATP levels in patients with renal cell carcinoma through the application of the ImmuKnow(TM) Cylex((r)) assay. We recruited 104 patients with renal cancer who had undergone surgery at Fuzhou General Hospital from March 2009 to June 2012, and were subsequently treated by dendritic cell and cytokine-induced killer cell bio therapy or interferon-alpha therapy. The changes in CD4(+) T cell ATP levels were detected at the perioperative period and at 10 days, 1 month, 3 months, and 1 year after the surgery using the ImmuKnow assay. In addition, the differences in ATP levels in different therapy groups were compared and the prognosis conditions were analyzed. Our results demonstrated that no significant difference in the ATP levels occurred at different time points; furthermore, there were no obviously different ATP levels between the different therapy groups, and the ATP levels were found to have no clinical significance for the assessment of renal cancer prognosis. Overall, this study suggested that CD4(+) T cell ATP levels as detected by the ImmuKnow assay have no obvious clinical value in patients with renal cancer. PMID- 26436396 TI - Analysis of skin color change and related gene expression after crossing of Dongxiang black chicken and ISA layer. AB - This study evaluated the effects of the autosomal domi-nant Fm gene in conjunction with the sex-linked Id gene on skin color and related gene expression. Ten Dongxiang black cocks were selected to build ten families by mating 60 individuals of ISA B-line layers. The skin color of the F1 generation was observed at different time points. At 126 days, 36 chickens were slaughtered, and gene expression of TYRP1, TYRP2, MC1R, and EDNRB in breast skin was assessed by quantitative RT-PCR. The ratio of Dongxiang black chickens with white skin chicks in the F1 generation to that of non-white was 3:7 (HoFF: HeFf). At 126 days, all F1 generation cocks showed white skin (115/115), while the percentages of hens with black skin were 100% (HoFF, 27/27) and 53.75% (HeFf, 43/80). The change in skin color peaked between 42 and 84 days. The offspring of HoFF displayed significantly higher expres-sion of MC1R, compared with those of HeFf (P < 0.05). The "L" value of hen's skin was significantly lower, and TYRP1 and TYRP2 expres-sion was significantly higher (P < 0.05) than in cocks with the same Fm/fm genotype. These findings indicate the presence of homozygous and heterozygous Fm in Dongxiang black chickens, with the offspring of homozygous birds showing a higher percentage of black skin percentage. The expression of the four genes studied was correlated with skin color, with TYRP1 and TYRP2 representing the most suitable molecular markers. PMID- 26436397 TI - Correlation between single nucleotide polymorphisms in hypoxia-related genes and susceptibility to acute high-altitude pulmonary edema. AB - This study aimed to explore the relationship between genetic changes and high altitude pulmonary edema (HAPE) susceptibility, and to screen for the key single nucleotide polymorphism (SNP) loci in the HAPE-susceptibility gene, by investigating the SNPs occurring in hypoxia-related genes in HAPE-susceptible and control (non-susceptible) populations. This research was conducted on Han recruits, who travelled to the Lhasa plateau (altitude, 3658 m). Ten loci located on ten genes extracted from the HAPE and healthy populations were amplified by polymerase chain reaction, and subsequently sequenced. The investigated genes included those coding for aldosterone synthase 2 (CYP11B2), angiotensin converting enzyme (ACE), heat-shock protein 70 (HSP70), nuclear factor kappa B (NF-kappaB), surfactant protein A2 (SP-A2), plasminogen activator inhibitor-1 (PAI-1), nitric oxide synthetase (NOS), vascular endothelial growth factor (VEGF), prolyl hydroxylase (EGLN1), and zinc finger protein A20. The gene distribution of each SNP loci and its correlation with HAPE was analyzed. Statistical analyses of the genotype frequencies of the SNPs revealed significant differences in the ACE (rs4309), EGLN1 (rs480902), SP-A2 (rs1965708), HSP70 (rs1008438), PAI-1 (rs1799889), and NOS (rs199983) expressions between the HAPE and healthy control groups (P < 0.05); therefore, these SNP loci were believed to indicate HAPE susceptibility. HAPE is correlated with multiple- SNP loci. A correlation analysis between genetic polymorphism and HAPE susceptibility revealed that 6 hypoxia-related genes were key sites accounting for HAPE. These findings could help assess the risk of HAPE in populations expressing different genotypes, in order to reduce the occurrence of HAPE. PMID- 26436398 TI - Investigation of the value of miR-21 in the diagnosis of early stage HCC and its prognosis: a meta-analysis. AB - The diagnostic and prognostic value of miR-21 has been examined for hepatocellular carcinoma (HCC), with inconsistent results. Present meta-analysis summarized the diagnostic accuracy and the predictive role for survival of miR-21 in patients with HCC. All eligible studies were searched using PubMed, EMBASE, and Chinese National Knowledge Infrastructure (CNKI) databases up to October 2014. For the diagnostic meta-analysis, the indices of miR-21 in the diagnosis of HCC were pooled using bivariate random-effect approach models. For the prognostic meta-analysis, data were synthesized with a random effect model, and the hazard ratio (HR) or odd ratio (OR) with its 95% confidence interval (95%CI) was used as the effect size estimate. Ten studies dealing with HCC were included. The overall pooled results for sensitivity, specificity, and the area under the curve (AUC) for the diagnostic meta-analysis (five studies) were 74.0 (95%CI = 61.0-85.0), 78.0 (95%CI = 67.0-86.0), and 0.83 (95%CI = 0.80-0.86), respectively. The combined data for the prognostic meta-analysis (seven studies) suggested that miR 21 overexpression in HCC correlated with poor overall survival [HR = 1.19 (95%CI = 0.44-1.94)], and higher miR-21 expression was associated with tumor, node, metastases (TNM) stage [OR = 0.34 (95%CI = 0.13-0.91)]. We concluded that miR-21 might be complementary to alpha fetal protein in HCC diagnosis, and might serve as an attractive estimator of HCC. We also demonstrated that miR-21 overexpression was associated with HCC TNM stage and with poor survival. As our study was limited, additional prospective studies are needed to validate these results. PMID- 26436399 TI - Hypoxia-related gene expression in porcine skeletal muscle tissues at different altitude. AB - Hypoxia influences many physiological processes, such as respiration, cardiovascular, neurophysiology, and digestion. Skeletal muscle is an important motor organ, which relies on oxygen of oxidation; however, the study of hypoxia in skeletal muscle is lacking. In order to understand the effect of hypoxia on skeletal muscle, we determined the expression level of four hypoxia-related genes (ADAM17, ARG2, MMP, and HIF1A) in two distinct skeletal muscle tissues from Tibetan pigs that live at different altitudes (500 and 3650 m). Consistent with the well-characterized role of four hypoxia-related genes in the adaptation to high altitude, we found that, compared with the plain pigs, the plateau pigs had higher mRNA abundances of the four genes and lower myofiber ratio in skeletal muscle. The negative correlation between the myofiber ratio and mRNA abundance of the four hypoxia-related genes highlights their critical roles in skeletal muscle. These findings may be important for understanding skeletal muscle adaptation to high altitude and hypoxia-related muscle diseases in humans. PMID- 26436400 TI - Decreased expression of humanized Fat-1 in porcine fetal fibroblasts following deletion of PGK-neomycin resistance. AB - The neomycin-resistance (neo(r)) gene is widely used as a selectable marker in eukaryotic expression vectors; however, its expression often affects that of target genes. Cre recombinase recognizes LoxP sites, leading to site-specific recombination and deletion of DNA and RNA between two LoxP sites. In the present study, a humanized Fat-1 gene (hFat-1) was generated by DNA Works and used to construct a pC-PGK-neo(r)-hfat-1 expression vector, in which PGK-neo(r) was flanked by two LoxP sites. The pC-PGK-neo(r)-hfat-1 plasmids were transfected into porcine fetal fibroblasts using liposomes, and three transgenic cell lines were obtained by culturing with 400 MUg/mL G418 for 7 days. Next, these cell lines were transfected with a Cre recombinase expression plasmid, which contains a puromycin resistance gene, in order to delete neo(r), which was integrated into the genome. hFat-1-neo(r) negative cells were obtained following puromycin selection. Real-time quantitative polymerase chain reaction data indicated that neomycin-resistant cells had higher hFat-1 expression than neomycin-sensitive cells. High performance gas chromatography data suggested that the n-6/n-3 ratio was significantly lower in transfected cells than in wild-type cells. The n-6/n-3 ratio in Cre-treated hFat-1-transfected cells was higher than that in untreated cells, suggesting that deletion of PGK-neo(r) decreased hFat-1 expression. PMID- 26436401 TI - Isolation and characterization of yeasts capable of efficient utilization of hemicellulosic hydrolyzate as the carbon source. AB - Few yeasts have shown the potential to efficiently utilize hemicellulosic hydrolyzate as the carbon source. In this study, microorganisms isolated from the Manaus region in Amazonas, Brazil, were characterized based on their utilization of the pentoses, xylose, and arabinose. The yeasts that showed a potential to assimilate these sugars were selected for the better utilization of lignocellulosic biomass. Two hundred and thirty seven colonies of unicellular microorganisms grown on hemicellulosic hydrolyzate, xylose, arabinose, and yeast nitrogen base selective medium were analyzed. Of these, 231 colonies were subjected to sugar assimilation tests. One hundred and twenty five of these were shown to utilize hydrolyzed hemicellulose, xylose, or arabinose as the carbon source for growth. The colonies that showed the best growth (N = 57) were selected, and their internal transcribed spacer-5.8S rDNA was sequenced. The sequenced strains formed four distinct groups in the phylogenetic tree, and showed a high percentage of similarity with Meyerozyma caribbica, Meyerozyma guilliermondii, Trichosporon mycotoxinivorans, Trichosporon loubieri, Pichia kudriavzevii, Candida lignohabitans, and Candida ethanolica. The discovery of these xylose-fermenting yeasts could attract widespread interest, as these can be used in the cost-effective production of liquid fuel from lignocellulosic materials. PMID- 26436402 TI - Genetic diversity of wild soybean populations in Dongying, China, by simple sequence repeat analysis. AB - Annual wild soybean (Glycine soja Sieb. et Zucc.), the ancestor of cultivated soybean (G. max), is believed to be a potential gene source for further improvement of soybean to cope with environmental stress. In this study, 10 simple sequence repeat (SSR) markers were used to evaluate the genetic diversity and population genetic structure in five wild soybean populations using 195 accessions collected from Dongying, China. Ten SSR markers yielded 90 bands, with an average of nine bands per marker. The percentage of polymorphic loci (P) was 97.78%, the distribution of expected heterozygosity (HE) was 0.1994-0.4460 with an average of 0.3262, and the distribution from Shannon's information index (I) was 0.3595-0.6506 with an average of 0.5386. The results showed that wild soybean had a high degree of genetic diversity at the species level. Nei's differentiation coefficient (FST) was 0.1533, and gene flow (Nm) was 1.3805, which indicated that genetic variation mainly existed within populations and that there was a certain level of gene exchange between populations. Some genetic differentiation occurred among populations, although this was not significant. Cluster analysis indicated that there was no significant correlation between the genetic structure of wild soybean populations and their geographic distribution, and the clustering results may be relatively consistent with the habitats of the accessions. In the present study, the genetic diversity of wild soybeans showed a broad genetic base and enables suggestions for the conservation of this plant to be made. PMID- 26436403 TI - Microvascular remodeling of nasal mucosa in allergic rhinitis induced by an allergen in Sprague-Dawley rats. AB - This study aimed to observe microvascular changes in the nasal mucosa of Sprague Dawley (SD) rats with allergic rhinitis (AR) after persistent exposure to an allergen with fluticasone propionate (FP) treatment. Ninety healthy SD rats were randomly distributed into the control group (A, N = 30), the group with continued exposure to an allergen (B, N = 30), and FP treatment group (C, N = 30). The animals of the persistence group were subjected to persistent exposure to an allergen after 7 weeks of modeling of ovalbumin (OVA) provocation in the nasal mucosa for 16 weeks. At the 8th, 12th, and 16th week after OVA provocation, each group was euthanized at each time point: the FP treatment after OVA provocation, and animals of the control group were not stimulated with OVA and were sacrificed at the same time point. The nasal mucosa of 5 animals from each group was analyzed for the expression of vascular endothelial growth factor (VEGF), and another 5 animals were used to make micro vascular corrosion casts for a scanning electron microscope. The results demonstrate that FP has a strong inhibitory effect on angiogenesis in AR. Inhalation of FP had an antiangiogenic effect through inhibition of VEGF expression but does not completely reverse the remodeling of the nasal mucosa in the short term nor does it have complete control over the expression of VEGF mRNA. PMID- 26436404 TI - Analysis of the association between polymorphisms in the vitamin D receptor (VDR) gene and dental caries in a Chinese population. AB - Environmental influences on the development and progression of dental caries are well known; however, there is little evidence of a genetic component imparting susceptibility to dental caries. The aim of this study was to investigate the relationship between a single nucleotide polymorphism in the vitamin D receptor TaqI locus and dental caries susceptibility in a Chinese population. This case control study was conducted with a case group (264 patients with dental caries from northwestern China) and a control group (219 individuals without dental caries or systemic disease from the same area). DNA was extracted from the peripheral venous blood of the study participants; the distribution of TaqI locus genotypes and allele frequencies was determined via polymerase chain reaction restriction fragment length polymorphism. The data obtained were statistically analyzed using the Hardy-Weinberg equilibrium and Chi-square test. The frequency of the Tt genotype in the case group (14.0%) was significantly higher than that in the control group (4.3%), as determined using the genotype TT as the reference. The risk of dental caries was increased 3.8-fold in individuals with the heterozygous Tt genotype compared to that in the individuals with the TT genotype. The proportion of the 't' allele in the case group (7.0%) and the control group (2.1%) was observed to be significantly different [P = 0.0003; OR = 3.592, confidence interval 95% (1.790-7.208)]. Our results therefore suggested that the allele 't' might be a genetic factor determining dental caries susceptibility in individuals from the northwest of China. PMID- 26436405 TI - Morphological analysis and muscle-associated gene expression during different muscle growth phases of Megalobrama amblycephala. AB - Skeletal muscle growth is regulated by both positive and negative factors, such as myogenic regulatory factors (MRFs) and myostatin (MSTN), and involves both hyperplasia and hypertrophy. In the present study, morphological changes during muscle development in Megalobrama amblycephala were characterized and gene expression levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR) analysis in juvenile [60, 90, 120, and 180 days post-hatching (dph)] and adult fish. Our results show that during muscle development, the frequency of muscle fibers with a diameter <20 MUm dramatically decreased in both red and white muscles, with a concomitant increase in the frequency of >30 MUm fibers in red muscle and >50 MUm fibers in white muscle. At 90-120 dph, the ratio of hyperplastic to hypertrophic areas in red and white muscles increased, but later decreased at 120-180 dph. The effect of hypertrophy was significantly larger than hyperplasia during these phases. qRT-PCR indicated MRF and MSTN (MSTNa and MSTNb) genes had similar expression patterns that peaked at 120 dph, with the exception of MSTNa. This new information on the molecular regulation of muscle growth and rapid growth phases will be of value to the cultivation of M. amblycephala. PMID- 26436406 TI - Genetic variability of genes involved in DNA repair influence treatment outcome in osteosarcoma. AB - We conducted a perspective study to investigate the role of ERCC1 (rs11615), ERCC2 (rs13181 and rs1799793), ERCC4 (rs1800067), and ERCC5 (rs17655) in NER pathway in the prognosis of osteosarcoma patients. In total, 146 osteosarcoma patients were recruited between 2008 and 2013. ERCC1 rs11615, ERCC2 rs13181 and rs1799793, ERCC4 rs1800067, and ERCC5 rs17655 gene polymorphisms were assessed by polymerase chain reaction-restriction fragment length polymorphism assay. By multivariate Cox proportional hazards models, we found that carriers of ERCC1 rs11615 TT genotype showed significantly favorable survival compared to wide-type CC genotype, and the adjusted OR (95%CI) was 0.24 (0.08-0.96). Moreover, we found that subjects with ERCC2 rs1799793 AA genotype were associated with decreased hazards of death in multivariate analysis (HR = 0.22, 95%CI = 0.12-0.93). In conclusion, our results suggest that ERCC1 rs11615 and ERCC2 rs1799793 may be useful genetic prognostic markers for osteosarcoma in a Chinese population. PMID- 26436407 TI - Function Clustering Self-Organization Maps (FCSOMs) for mining differentially expressed genes in Drosophila and its correlation with the growth medium. AB - The central task of this study was to mine the gene-to-medium relationship. Adequate knowledge of this relationship could potentially improve the accuracy of differentially expressed gene mining. One of the approaches to differentially expressed gene mining uses conventional clustering algorithms to identify the gene-to-medium relationship. Compared to conventional clustering algorithms, self organization maps (SOMs) identify the nonlinear aspects of the gene-to-medium relationships by mapping the input space into another higher dimensional feature space. However, SOMs are not suitable for huge datasets consisting of millions of samples. Therefore, a new computational model, the Function Clustering Self Organization Maps (FCSOMs), was developed. FCSOMs take advantage of the theory of granular computing as well as advanced statistical learning methodologies, and are built specifically for each information granule (a function cluster of genes), which are intelligently partitioned by the clustering algorithm provided by the DAVID_6.7 software platform. However, only the gene functions, and not their expression values, are considered in the fuzzy clustering algorithm of DAVID. Compared to the clustering algorithm of DAVID, these experimental results show a marked improvement in the accuracy of classification with the application of FCSOMs. FCSOMs can handle huge datasets and their complex classification problems, as each FCSOM (modeled for each function cluster) can be easily parallelized. PMID- 26436408 TI - Accuracy of enzyme-linked immunospot assay for diagnosis of pleural tuberculosis: a meta-analysis. AB - Current methods for diagnosing tuberculous pleurisy are poor. Some studies have explored the diagnostic value of a pleural effusion enzyme-linked immunospot (ELISPOT) assay, but its accuracy remains controversial. Therefore, we performed a meta-analysis of the existing evidence on the ability of the ELISPOT assay to diagnose tuberculous pleurisy. We systematically searched PubMed, Google Scholar, and EMBASE databases for studies measuring the sensitivity, specificity, and other measures of accuracy of the pleural effusion ELISPOT assay for diagnosis of tuberculous pleurisy. A total of nine studies were identified and subjected to meta-analysis, giving the following pooled values for diagnostic accuracy: sensitivity, 0.93 [95% confidence intervals (95%CI) = 0.90 to 0.95]; specificity, 0.90 (95%CI = 0.86 to 0.93); positive likelihood ratio, 8.21 (95%CI = 4.00 to 16.84); negative likelihood ratio, 0.11 (95%CI = 0.06 to 0.19); diagnostic odds ratio, 88.26 (95%CI = 33.81 to 230.43); and the area under the curve, 0.9599 (standard error of the mean, 0.0134). The available evidence suggests that pleural effusion ELISPOT assay is sufficiently accurate to diagnose tuberculous pleurisy as a stand-alone technique. In fact, it appears to be superior to assays based on adenosine deaminase and gamma interferon for screening patients and confirming the diagnosis of tuberculous pleurisy. PMID- 26436409 TI - Weak Hydrogen Bonding Enables Hard, Strong, Tough, and Elastic Hydrogels. AB - A new type of "rigid and tough" hydrogel with excellent elasticity is designed by dense clustering of hydrogen bonds within a loose chemical network. The resultant hydrogel exhibits a good combination of high modulus (28 MPa), toughness (9300 J m(-3) ), extensibility (800%), and tensile stress (2 MPa). Furthermore, the gel displays good fatigue-resistance and complete and extremely fast recovery of shape and mechanical properties (3 min at 37 degrees C). PMID- 26436410 TI - An Atmospheric Constraint on the NO2 Dependence of Daytime Near-Surface Nitrous Acid (HONO). AB - Recent observations suggest a large and unknown daytime source of nitrous acid (HONO) to the atmosphere. Multiple mechanisms have been proposed, many of which involve chemistry that reduces nitrogen dioxide (NO2) on some time scale. To examine the NO2 dependence of the daytime HONO source, we compare weekday and weekend measurements of NO2 and HONO in two U.S. cities. We find that daytime HONO does not increase proportionally to increases in same-day NO2, i.e., the local NO2 concentration at that time and several hours earlier. We discuss various published HONO formation pathways in the context of this constraint. PMID- 26436411 TI - Cronobacter sakazakii bacteremia in a heart transplant patient with polycystic kidney disease. AB - Infections with Cronobacter sakazakii are mainly described among neonates and infants, with contaminated powdered infant formulas most often incriminated as the cause. We describe here a case of C. sakazakii bacteremia secondary to a suspected cyst infection in a heart-and-kidney transplant patient with polycystic kidney disease. PMID- 26436412 TI - Chronic lichen sclerosus successfully treated with intralesional adalimumab. PMID- 26436413 TI - Acute Ischemic Stroke Therapy: The Way Forward. PMID- 26436415 TI - Supraspinal Transient Receptor Potential Subfamily V Member 1 (TRPV1) in Pain and Psychiatric Disorders. AB - The transient receptor potential subfamily V member 1 (TRPV1) belongs to the diverse transient receptor potential (TRP) family of cation channels. It was first characterized in primary afferent fibres as a receptor for capsaicin. Peripheral TRPV1 has a very well-described role in nociception. However, TRPV1 is now recognized to have a broader distribution and function, with supraspinal/brain TRPV1 known to modulate pain processing. Recently, studies employing histological, genetic and pharmacological approaches have provided evidence that supraspinal TRPV1 also modulates brain neurobiology and behaviours related to anxiety, depression and schizophrenia. Key brain regions involved in TRPV1-mediated modulation of pain and affect include the periaqueductal grey, hippocampus and medial prefrontal cortex. Thus, TRPV1 in the brain is emerging as an important molecular substrate which is dually implicated in both pain and psychiatric disorders, and represents a novel therapeutic target for these conditions and their comorbidity. PMID- 26436414 TI - Root Effect Haemoglobins in Fish May Greatly Enhance General Oxygen Delivery Relative to Other Vertebrates. AB - The teleost fishes represent over half of all extant vertebrates; they occupy nearly every body of water and in doing so, occupy a diverse array of environmental conditions. We propose that their success is related to a unique oxygen (O2) transport system involving their extremely pH-sensitive haemoglobin (Hb). A reduction in pH reduces both Hb-O2 affinity (Bohr effect) and carrying capacity (Root effect). This, combined with a large arterial-venous pH change (DeltapHa-v) relative to other vertebrates, may greatly enhance tissue oxygen delivery in teleosts (e.g., rainbow trout) during stress, beyond that in mammals (e.g., human). We generated oxygen equilibrium curves (OECs) at five different CO2 tensions for rainbow trout and determined that, when Hb-O2 saturation is 50% or greater, the change in oxygen partial pressure (DeltaPO2) associated with DeltapHa-v can exceed that of the mammalian Bohr effect by at least 3-fold, but as much as 21-fold. Using known DeltapHa-v and assuming a constant arterial venous PO2 difference (Pa-vO2), Root effect Hbs can enhance O2 release to the tissues by 73.5% in trout; whereas, the Bohr effect alone is responsible for enhancing O2 release by only 1.3% in humans. Disequilibrium states are likely operational in teleosts in vivo, and therefore the DeltapHa-v, and thus enhancement of O2 delivery, could be even larger. Modeling with known Pa-vO2 in fish during exercise and hypoxia indicates that O2 release from the Hb and therefore potentially tissue O2 delivery may double during exercise and triple during some levels of hypoxia. These characteristics may be central to performance of athletic fish species such as salmonids, but may indicate that general tissue oxygen delivery may have been the incipient function of Root effect Hbs in fish, a trait strongly associated with the adaptive radiation of teleosts. PMID- 26436417 TI - Correction: When Less Is More: Non-monotonic Spike Sequence Processing in Neurons. PMID- 26436416 TI - Effects of Very Low Dose Fast Neutrons on Cell Membrane And Secondary Protein Structure in Rat Erythrocytes. AB - The effects of ionizing radiation on biological cells have been reported in several literatures. Most of them were mainly concerned with doses greater than 0.01 Gy and were also concerned with gamma rays. On the other hand, the studies on very low dose fast neutrons (VLDFN) are rare. In this study, we have investigated the effects of VLDFN on cell membrane and protein secondary structure of rat erythrocytes. Twelve female Wistar rats were irradiated with neutrons of total dose 0.009 Gy (241Am-Be, 0.2 mGy/h) and twelve others were used as control. Blood samples were taken at the 0, 4th, 8th, and 12th days postirradiation. Fourier transform infrared (FTIR) spectra of rat erythrocytes were recorded. Second derivative and curve fitting were used to analysis FTIR spectra. Hierarchical cluster analysis (HCA) was used to classify group spectra. The second derivative and curve fitting of FTIR spectra revealed that the most significant alterations in the cell membrane and protein secondary structure upon neutron irradiation were detected after 4 days postirradiation. The increase in membrane polarity, phospholipids chain length, packing, and unsaturation were noticed from the corresponding measured FTIR area ratios. This may be due to the membrane lipid peroxidation. The observed band shift in the CH2 stretching bands toward the lower frequencies may be associated with the decrease in membrane fluidity. The curve fitting of the amide I revealed an increase in the percentage area of alpha-helix opposing a decrease in the beta-structure protein secondary structure, which may be attributed to protein denaturation. The results provide detailed insights into the VLDFN effects on erythrocytes. VLDFN can cause an oxidative stress to the irradiated erythrocytes, which appears clearly after 4 days postirradiation. PMID- 26436419 TI - Correction: Attenuation of High-Frequency (50-200 Hz) Thalamocortical EEG Rhythms by Propofol in Rats Is More Pronounced for the Thalamus than for the Cortex. PMID- 26436418 TI - Andrographolide Analogue Induces Apoptosis and Autophagy Mediated Cell Death in U937 Cells by Inhibition of PI3K/Akt/mTOR Pathway. AB - BACKGROUND: Current chemotherapeutic agents based on apoptosis induction are lacking in desired efficacy. Therefore, there is continuous effort to bring about new dimension in control and gradual eradication of cancer by means of ever evolving therapeutic strategies. Various forms of PCD are being increasingly implicated in anti-cancer therapy and the complex interplay among them is vital for the ultimate fate of proliferating cells. We elaborated and illustrated the underlying mechanism of the most potent Andrographolide analogue (AG-4) mediated action that involved the induction of dual modes of cell death-apoptosis and autophagy in human leukemic U937 cells. PRINCIPAL FINDINGS: AG-4 induced cytotoxicity was associated with redox imbalance and apoptosis which involved mitochondrial depolarisation, altered apoptotic protein expressions, activation of the caspase cascade leading to cell cycle arrest. Incubation with caspase inhibitor Z-VAD-fmk or Bax siRNA decreased cytotoxic efficacy of AG-4 emphasising critical roles of caspase and Bax. In addition, AG-4 induced autophagy as evident from LC3-II accumulation, increased Atg protein expressions and autophagosome formation. Pre-treatment with 3-MA or Atg 5 siRNA suppressed the cytotoxic effect of AG-4 implying the pro-death role of autophagy. Furthermore, incubation with Z VAD-fmk or Bax siRNA subdued AG-4 induced autophagy and pre-treatment with 3-MA or Atg 5 siRNA curbed AG-4 induced apoptosis-implying that apoptosis and autophagy acted as partners in the context of AG-4 mediated action. AG-4 also inhibited PI3K/Akt/mTOR pathway. Inhibition of mTOR or Akt augmented AG-4 induced apoptosis and autophagy signifying its crucial role in its mechanism of action. CONCLUSIONS: Thus, these findings prove the dual ability of AG-4 to induce apoptosis and autophagy which provide a new perspective to it as a potential molecule targeting PCD for future cancer therapeutics. PMID- 26436420 TI - Mortality Prediction in Patients Undergoing Non-Invasive Ventilation in Intermediate Care. AB - BACKGROUND: Intermediate Care Units (ImCU) have become an alternative scenario to perform Non-Invasive Ventilation (NIV). The limited number of prognostic studies in this population support the need of mortality prediction evaluation in this context. OBJECTIVE: The objective of this study is to analyze the performance of Simplified Acute Physiology Score (SAPS) II and 3 in patients undergoing NIV in an ImCU. Additionally, we searched for new variables that could be useful to customize these scores, in order to improve mortality prediction. DESIGN: Cohort study with prospectively collected data from all patients admitted to a single center ImCU who received NIV. The SAPS II and 3 scores with their respective predicted mortality rates were calculated. Discrimination and calibration were evaluated by calculating the area under the receiver operating characteristic curve (AUC) and with the Hosmer-Lemeshow goodness of fit test for the models, respectively. Binary logistic regression was used to identify new variables to customize the scores for mortality prediction in this setting. PATIENTS: The study included 241 patients consecutively admitted to an ImCU staffed by hospitalists from April 2006 to December 2013. KEY RESULTS: The observed in hospital mortality was 32.4% resulting in a Standardized Mortality Ratio (SMR) of 1.35 for SAPS II and 0.68 for SAPS 3. Mortality discrimination based on the AUC was 0.73 for SAPS II and 0.69 for SAPS 3. Customized models including immunosuppression, chronic obstructive pulmonary disease (COPD), acute pulmonary edema (APE), lactic acid, pCO2 and haemoglobin levels showed better discrimination than old scores with similar calibration power. CONCLUSIONS: These results suggest that SAPS II and 3 should be customized with additional patient risk factors to improve mortality prediction in patients undergoing NIV in intermediate care. PMID- 26436421 TI - The Undecided Have the Key: Interaction-Driven Opinion Dynamics in a Three State Model. AB - The effects of interpersonal interactions on individual's agreements result in a social aggregation process which is reflected in the formation of collective states, as for instance, groups of individuals with a similar opinion about a given issue. This field, which has been a longstanding concern of sociologists and psychologists, has been extended into an area of experimental social psychology, and even has attracted the attention of physicists and mathematicians. In this article, we present a novel model of opinion formation in which agents may either have a strict preference for a choice, or be undecided. The opinion shift emerges, in a threshold process, as a consequence of a cumulative persuasion for either one of the two opinions in repeated interactions. There are two main ingredients which play key roles in determining the steady states: the initial fraction of undecided agents and the change in agents' persuasion after each interaction. As a function of these two parameters, the model presents a wide range of solutions, among which there are consensus of each opinion and bi-polarization. We found that a minimum fraction of undecided agents is not crucial for reaching consensus only, but also to determine a dominant opinion in a polarized situation. In order to gain a deeper comprehension of the dynamics, we also present the theoretical framework of the model. The master equations are of special interest for their nontrivial properties and difficulties in being solved analytically. PMID- 26436422 TI - Prey Preference and Life Table of Amblyseius orientalis on Bemisia tabaci and Tetranychus cinnabarinus. AB - Amblyseius orientalis (Ehara) (Acari: Phytoseiidae) is a native predatory mite species in China. It used to be considered as a specialist predator of spider mites. However, recent studies show it also preys on other small arthropod pests, such as Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae). Experiments were conducted to investigate (1) prey preference of A. orientalis between Tetranychus cinnabarinus (Boisd.) (Acari: Tetranychidae) and B. tabaci, and (2) development, consumption and life table parameters of A. orientalis when reared on T. cinnabarinus, B. tabaci or a mix of both prey species. When preying on different stages of T. cinnabarinus, A. orientalis preferred protonymphs, whereas when preying on different stages of B. tabaci, A. orientalis preferred eggs. When these two most preferred stages were provided together (T. cinnabarinus protonymphs and B. tabaci eggs), A. orientalis randomly selected its prey. Amblyseius orientalis was able to complete its life cycle on B. tabaci eggs, T. cinnabarinus protonymphs, or a mix of both prey. However, its developmental duration was 53.9% and 30.0% longer when reared on B. tabaci eggs than on T. cinnabarinus and a mix of both prey, respectively. In addition, it produced only a few eggs and its intrinsic rate of increase was negative when reared on B. tabaci eggs, which indicates that B. tabaci is not sufficient to maintain A. orientalis population. The intrinsic rates of increase were 0.16 and 0.23 when A. orientalis was fed on the prey mix and T. cinnabarinus, respectively. These results suggest that although B. tabaci is a poor food resource for A. orientalis in comparison to T. cinnabarinus, A. orientalis is able to sustain its population on a mix of both prey. This predatory mite may thus be a potential biological control agent of B. tabaci when this pest co-occurs with the alternative minor pest T. cinnabarinus. PMID- 26436425 TI - Effect of Stone-Wales defects on the thermal conductivity of graphene. AB - The problem of phonon scattering by strain fields caused by Stone-Wales (SW) defects in graphene is studied in the framework of the deformation potential approach. An explicit form of the phonon mean free path due to phonon-SW scattering is obtained within the Born approximation. The mean free path demonstrates a specific q-dependence varying as q (-3) at low wavevectors and taking a constant value at large q. The thermal conductivity of graphene nanoribbons (GNRs) is calculated with the three-phonon umklapp, SW and rough edge scatterings taken into account. A pronounced decrease of the thermal conductivity due to SW defects is found at low temperatures whereas at room temperatures and above the phonon-phonon umklapp scattering becomes dominant. A comparison with the case of vacancy defects shows that they play more important role in the reduction of the thermal conductivity in GNRs over a wide temperature range. PMID- 26436424 TI - Weighted Score Tests Implementing Model-Averaging Schemes in Detection of Rare Variants in Case-Control Studies. AB - Multi-locus effect modeling is a powerful approach for detection of genes influencing a complex disease. Especially for rare variants, we need to analyze multiple variants together to achieve adequate power for detection. In this paper, we propose several parsimonious branching model techniques to assess the joint effect of a group of rare variants in a case-control study. These models implement a data reduction strategy within a likelihood framework and use a weighted score test to assess the statistical significance of the effect of the group of variants on the disease. The primary advantage of the proposed approach is that it performs model-averaging over a substantially smaller set of models supported by the data and thus gains power to detect multi-locus effects. We illustrate these proposed approaches on simulated and real data and study their performance compared to several existing rare variant detection approaches. The primary goal of this paper is to assess if there is any gain in power to detect association by averaging over a number of models instead of selecting the best model. Extensive simulations and real data application demonstrate the advantage the proposed approach in presence of causal variants with opposite directional effects along with a moderate number of null variants in linkage disequilibrium. PMID- 26436423 TI - A Retrospective Study on Genetic Heterogeneity within Treponema Strains: Subpopulations Are Genetically Distinct in a Limited Number of Positions. AB - BACKGROUND: Pathogenic uncultivable treponemes comprise human and animal pathogens including agents of syphilis, yaws, bejel, pinta, and venereal spirochetosis in rabbits and hares. A set of 10 treponemal genome sequences including those of 4 Treponema pallidum ssp. pallidum (TPA) strains (Nichols, DAL 1, Mexico A, SS14), 4 T. p. ssp. pertenue (TPE) strains (CDC-2, Gauthier, Samoa D, Fribourg-Blanc), 1 T. p. ssp. endemicum (TEN) strain (Bosnia A) and one strain (Cuniculi A) of Treponema paraluisleporidarum ecovar Cuniculus (TPLC) were examined with respect to the presence of nucleotide intrastrain heterogeneous sites. METHODOLOGY/PRINCIPAL FINDINGS: The number of identified intrastrain heterogeneous sites in individual genomes ranged between 0 and 7. Altogether, 23 intrastrain heterogeneous sites (in 17 genes) were found in 5 out of 10 investigated treponemal genomes including TPA strains Nichols (n = 5), DAL-1 (n = 4), and SS14 (n = 7), TPE strain Samoa D (n = 1), and TEN strain Bosnia A (n = 5). Although only one heterogeneous site was identified among 4 tested TPE strains, 16 such sites were identified among 4 TPA strains. Heterogeneous sites were mostly strain-specific and were identified in four tpr genes (tprC, GI, I, K), in genes involved in bacterial motility and chemotaxis (fliI, cheC-fliY), in genes involved in cell structure (murC), translation (prfA), general and DNA metabolism (putative SAM dependent methyltransferase, topA), and in seven hypothetical genes. CONCLUSIONS/SIGNIFICANCE: Heterogeneous sites likely represent both the selection of adaptive changes during infection of the host as well as an ongoing diversifying evolutionary process. PMID- 26436426 TI - The hows and whys of face processing: Level of construal influences the holistic processing of human faces. AB - Face recognition and identification are optimized by holistic processing. Various visual-spatial manipulations appear to have transfer effects on holistic face processing. The present experiment tests the effects of a semantic manipulation- of construal level--on holistic processing as measured by composite congruency effects. Participants completed two blocks of trials. The first served as a baseline, whereas the second included a manipulation of construal level. High level construal resulted in stronger congruency effects, indicative of greater holistic processing (relative to baseline and to low-level construal). These results have implications for conceptualizations of both construal level and holistic processing. PMID- 26436427 TI - Any effects of social orientation priming on object-location memory are smaller than initially reported. AB - It has previously been reported that priming a collectivistic social orientation (compared with an individualistic one) boosts object-location memory (Kuhnen & Oyserman, 2002; Oyserman, Sorensen, Reber, & Chen, 2009). We conducted 4 experiments to replicate this reported effect, using the same methods as in those initial reports. In Experiment 1 (n = 145), we found a hint of a priming effect on object-location memory, but also an unanticipated interaction between priming and gender. In Experiment 2 (n = 90), we included gender as a formal factor and doubled the "dosage" of the priming, yet did not see any priming effects on memory. In Experiment 3 (n = 101), we octupled the priming "dosage" and again saw no significant effects on memory. Finally, in Experiment 4 (n = 102), we performed an exact replication of the methods of the original reports and again found no priming effects on memory. Any effects of this type of social orientation priming on object-location memory appear to be smaller and/or less robust than initially thought. PMID- 26436428 TI - The role of action readiness in motivated behavior. AB - According to many theories of motivation and decision making, the principal driver of human behavior is the valuation of actions. Action value is computed as the difference between stimulus value (the benefits and costs inherent in the stimulus that is the target of the action) and action costs (the effort required to perform the action). In the present work, we propose that action costs are crucially influenced by the readiness to perform a given action. We define action readiness as the ease with which an action may be initiated given the preaction launch state of the individual. An action that has been frequently or recently performed or rehearsed has a high level of action readiness, whereas an action that has not been frequently or recently performed or rehearsed has a low level of action readiness. By our account, if action readiness levels are high for a given action, decreased action costs may result in action even when the stimulus value is relatively low. Conversely, if action readiness levels are low for a given action, even action costs that appear negligible can dominate positive stimulus values, resulting in seemingly puzzling instances of inaction. We develop and test these ideas in 3 studies across 233 participants using an image viewing decision context and a logistic prediction model. PMID- 26436429 TI - On the Utility of Spinel Oxide Hosts for Magnesium-Ion Batteries. AB - There is immense interest to develop Mg-ion batteries, but finding suitable cathode materials has been a challenge. The spinel structure has many advantages for ion insertion and has been successfully used in Li-ion batteries. We present here findings on the attempts to extract Mg from MgMn2O4-based spinels with acid (H2SO4) and with NO2BF4. The acid treatment was able to fully remove all Mg from MgMn2O4 by following a mechanism involving the disproportionation of Mn(3+), and the extraction rate decreased with increasing cation disorder. Samples with additional Mg(2+) ions in the octahedral sites (e.g., Mg1.1Mn1.9O4 and Mg1.5Mn1.5O4) also exhibit complete or near complete demagnesiation due to an additional mechanism involving ion exchange of Mg(2+) by H(+), but no Mg could be extracted from MgMnAlO4 due to the disruption of Mn-Mn interaction/contact across shared octahedral edges. In contrast, no Mg could be extracted with the oxidizing agent NO2BF4 from MgMn2O4 or Mg1.5Mn1.5O4 as the electrostatic repulsion between the divalent Mg(2+) ions prevents Mg(2+) diffusion through the 16c octahedral sites, unlike Li(+) diffusion, suggesting that spinels may not serve as potential hosts for Mg-ion batteries. The ability to extract Mg with acid in contrast to that with NO2BF4 is attributed to Mn dissolution from the lattice and the consequent reduction in electrostatic repulsion. The findings could provide insights toward the design of Mg hosts for Mg-ion batteries. PMID- 26436430 TI - Aqueous-Processed Inorganic Thin-Film Solar Cells Based on CdSe(x)Te(1-x) Nanocrystals: The Impact of Composition on Photovoltaic Performance. AB - Aqueous processed nanocrystal (NC) solar cells are attractive due to their environmental friendliness and cost effectiveness. Controlling the bandgap of absorbing layers is critical for achieving high efficiency for single and multijunction solar cells. Herein, we tune the bandgap of CdTe through the incorporation of Se via aqueous process. The photovoltaic performance of aqueous CdSexTe1-x NCs is systematically investigated, and the impacts of charge generation, transport, and injection on device performance for different compositions are deeply discussed. We discover that the performance degrades with the increasing Se content from CdTe to CdSe. This is mainly ascribed to the lower conduction band (CB) of CdSexTe1-x with higher Se content, which reduces the driving force for electron injection into TiO2. Finally, the performance is improved by mixing CdSexTe1-x NCs with conjugated polymer poly(p phenylenevinylene) (PPV), and power conversion efficiency (PCE) of 3.35% is achieved based on ternary NCs. This work may provide some information to further optimize the aqueous-processed NC and hybrid solar cells. PMID- 26436431 TI - Electrical behaviour of dendritic spines as revealed by voltage imaging. AB - Thousands of dendritic spines on individual neurons process information and mediate plasticity by generating electrical input signals using a sophisticated assembly of transmitter receptors and voltage-sensitive ion channel molecules. Our understanding, however, of the electrical behaviour of spines is limited because it has not been possible to record input signals from these structures with adequate sensitivity and spatiotemporal resolution. Current interpretation of indirect data and speculations based on theoretical considerations are inconclusive. Here we use an electrochromic voltage-sensitive dye which acts as a transmembrane optical voltmeter with a linear scale to directly monitor electrical signals from individual spines on thin basal dendrites. The results show that synapses on these spines are not electrically isolated by the spine neck to a significant extent. Electrically, they behave as if they are located directly on dendrites. PMID- 26436432 TI - Discovery of stable skyrmionic state in ferroelectric nanocomposites. AB - Non-coplanar swirling field textures, or skyrmions, are now widely recognized as objects of both fundamental interest and technological relevance. So far, skyrmions were amply investigated in magnets, where due to the presence of chiral interactions, these topological objects were found to be intrinsically stabilized. Ferroelectrics on the other hand, lacking such chiral interactions, were somewhat left aside in this quest. Here we demonstrate, via the use of a first-principles-based framework, that skyrmionic configuration of polarization can be extrinsically stabilized in ferroelectric nanocomposites. The interplay between the considered confined geometry and the dipolar interaction underlying the ferroelectric phase instability induces skyrmionic configurations. The topological structure of the obtained electrical skyrmion can be mapped onto the topology of domain-wall junctions. Furthermore, the stabilized electrical skyrmion can be as small as a few nanometers, thus revealing prospective skyrmion based applications of ferroelectric nanocomposites. PMID- 26436433 TI - Immediate Effects of Traditional Thai Massage on Psychological Stress as Indicated by Salivary Alpha-Amylase Levels in Healthy Persons. AB - BACKGROUND Stress can cause psychological and physiological changes. Many studies revealed that massage can decrease stress. However, traditional Thai massage has not been well researched in this regard. The purpose of this study was to investigate the immediate effects of traditional Thai massage (TTM) on salivary alpha-amylase levels (sAA), heart rate variability (HRV), autonomic nervous system (ANS) function, and plasma renin activity (PRA). MATERIAL AND METHODS Twenty-nine healthy participants were randomly allocated into either a traditional Thai massage (TTM) group or Control (C) group, after which they were switched to the other group with a 2-week wash-out period. Each of them was given a 10-minute mental arithmetic test to induce psychological stress before a 1-hour session of TTM or rest. RESULTS Within-groups comparison revealed that sAA was significantly decreased (p<0.05) in the TTM group but not in the C group. HRV and ANS function were significantly increased (p<0.05) and PRA was significantly decreased (p<0.05) in both groups. However, low frequency per high frequency ratio (LF/HF ratio) and ANS balance status were not changed. Only sAA was found to be significantly different between groups (p<0.05). CONCLUSIONS We conclude that both TTM and rest can reduce psychological stress, as indicated by decreased sAA levels, increased parasympathetic activity, decreased sympathetic activity, and decreased PRA. However, TTM may have a modest effect on stress reduction as indicated by a reduced sAA. PMID- 26436434 TI - Ferromagnetic Bare Metal Stent for Endothelial Cell Capture and Retention. AB - Rapid endothelialization of cardiovascular stents is needed to reduce stent thrombosis and to avoid anti-platelet therapy which can reduce bleeding risk. The feasibility of using magnetic forces to capture and retain endothelial outgrowth cells (EOC) labeled with super paramagnetic iron oxide nanoparticles (SPION) has been shown previously. But this technique requires the development of a mechanically functional stent from a magnetic and biocompatible material followed by in-vitro and in-vivo testing to prove rapid endothelialization. We developed a weakly ferromagnetic stent from 2205 duplex stainless steel using computer aided design (CAD) and its design was further refined using finite element analysis (FEA). The final design of the stent exhibited a principal strain below the fracture limit of the material during mechanical crimping and expansion. One hundred stents were manufactured and a subset of them was used for mechanical testing, retained magnetic field measurements, in-vitro cell capture studies, and in-vivo implantation studies. Ten stents were tested for deployment to verify if they sustained crimping and expansion cycle without failure. Another 10 stents were magnetized using a strong neodymium magnet and their retained magnetic field was measured. The stents showed that the retained magnetism was sufficient to capture SPION-labeled EOC in our in-vitro studies. SPION-labeled EOC capture and retention was verified in large animal models by implanting 1 magnetized stent and 1 non-magnetized control stent in each of 4 pigs. The stented arteries were explanted after 7 days and analyzed histologically. The weakly magnetic stents developed in this study were capable of attracting and retaining SPION-labeled endothelial cells which can promote rapid healing. PMID- 26436435 TI - Microperfusion Technique to Investigate Regulation of Microvessel Permeability in Rat Mesentery. AB - Experiments to measure the permeability properties of individually perfused microvessels provide a bridge between investigation of molecular and cellular mechanisms regulating vascular permeability in cultured endothelial cell monolayers and the functional exchange properties of whole microvascular beds. A method to cannulate and perfuse venular microvessels of rat mesentery and measure the hydraulic conductivity of the microvessel wall is described. The main equipment needed includes an intravital microscope with a large modified stage that supports micromanipulators to position three different microtools: (1) a beveled glass micropipette to cannulate and perfuse the microvessel; (2) a glass micro-occluder to transiently block perfusion and enable measurement of transvascular water flow movement at a measured hydrostatic pressure, and (3) a blunt glass rod to stabilize the mesenteric tissue at the site of cannulation. The modified Landis micro-occlusion technique uses red cells suspended in the artificial perfusate as markers of transvascular fluid movement, and also enables repeated measurements of these flows as experimental conditions are changed and hydrostatic and colloid osmotic pressure difference across the microvessels are carefully controlled. Measurements of hydraulic conductivity first using a control perfusate, then after re-cannulation of the same microvessel with the test perfusates enable paired comparisons of the microvessel response under these well-controlled conditions. Attempts to extend the method to microvessels in the mesentery of mice with genetic modifications expected to modify vascular permeability were severely limited because of the absence of long straight and unbranched microvessels in the mouse mesentery, but the recent availability of the rats with similar genetic modifications using the CRISPR/Cas9 technology is expected to open new areas of investigation where the methods described herein can be applied. PMID- 26436436 TI - Ethnic, Racial, and Socioeconomic Disparities in Retinoblastoma. AB - IMPORTANCE: Most children with retinoblastoma in the United States are diagnosed as having a large intraocular tumor burden that requires intensive ocular-salvage treatment or enucleation. OBJECTIVE: To investigate the effect of socioeconomic status, race, and ethnicity on the extent of disease and the outcomes of retinoblastoma. DESIGN, SETTING, AND PARTICIPANTS: A population-based review of 18 Surveillance, Epidemiology, and End Results (SEER) registries. From January 1, 2000, through December 31, 2010, 830 cases of retinoblastoma were recorded for children aged 0 to 9 years. Data were collected and analyzed from January 1, 2000, through December 31, 2010, with the last follow-up on December 31, 2010. EXPOSURES: County-based socioeconomic variables analyzed included poverty level, educational attainment, language isolation, crowding, unemployment, and percentage of immigrants. MAIN OUTCOMES AND MEASURES: Extent of disease, ocular outcome, and children's survival. RESULTS: Of the 830 individuals included, Hispanic children had a higher percentage of extraocular disease (86 of 261 [33.0%] vs. 102 of 510 non-Hispanic children [20.0%]; odds ratio [OR], 1.97 [95% CI, 1.38-2.79]). The percentage of extraocular cases was also higher in counties with the following low socioeconomic status indicators: higher vs. lower poverty status (115 of 413 [27.8%] vs. 73 of 358 [20.4%]; OR, 1.51; 95% CI, 1.06-2.14); lower vs. higher educational attainment (115 of 400 [28.7%] vs. 73 of 371 [19.7%]; OR, 1.65; 95% CI, 1.16-2.34); higher vs. lower levels of crowding (124 of 398 [31.2%] vs. 64 of 373 [17.2%]; OR, 2.18; 95% CI, 1.53-3.13); higher vs. lower unemployment (119 of 411 [28.9%] vs. 69 of 360 [19.2%]; OR, 1.72; 95% CI, 1.21-2.45); higher vs. lower language isolation (117 of 388 [30.2%] vs. 71 of 383 [18.5%]; OR, 1.89; 95% CI, 1.34-2.70); and higher vs. lower percentage of immigrants (109 of 386 [28.2%] vs. 79 of 385 [20.5%]; OR, 1.52; 95% CI, 1.08 2.16). Higher rates of enucleation were associated with low educational attainment (265 of 401 [66.1%] vs 309 of 421 [73.4%]; OR, 1.42; 95% CI, 1.04 1.93), a higher level of crowding (316 of 416 [76.0%] vs. 258 of 406 [63.5%]; OR, 1.81; 95% CI, 1.32-2.48), and Hispanic origin (202 of 271 [74.5%]; OR, 1.41; 95% CI, 1.01-1.98). Relative survival at 5 years was lower among black compared with non-Hispanic white children (92.7% vs. 99.2%; P < .001). CONCLUSIONS AND RELEVANCE: Significant disparities exist in the care and outcomes of children with retinoblastoma. A low socioeconomic status negatively affects disease extent and ocular outcomes, presumably by limiting access to primary and cancer-directed care. Hispanic children in particular have more advanced disease and higher rates of enucleation. PMID- 26436438 TI - Selectivity of Terahertz Gas-Phase Spectroscopy. AB - Analytical potential of terahertz (THz) spectroscopy is assessed by comparing selectivity for a set of eight environmentally important gases over THz and infrared (IR) optical frequencies. Selectivity coefficients are determined over selected spectral regions for acetaldehyde, acetonitrile, ethanol, water, methanol, ammonia, propionaldehyde, and propionitrile. These selectivity coefficients quantify the magnitude of the net analyte signal for each test compound relative to the other seven. In addition to the THz spectral range (2 125 cm(-1)), selectivity coefficients are determined for the following IR regions 600-1300, 1300-2000, 2600-3100, 3100-4000, and 4000-6500 cm(-1). Highest selectivity is afforded over the THz frequencies for six of the eight test compounds and THz selectivity coefficients for the other two gases (water and acetonitrile) are acceptable for environmental measurements. PMID- 26436437 TI - Letter to the Editor. PMID- 26436439 TI - Enhanced stability of black phosphorus field-effect transistors with SiO2 passivation. AB - Few-layer black phosphorus (BP) has attracted much attention due to its high mobility and suitable band gap for potential applic5ations in optoelectronics and flexible devices. However, its instability under ambient conditions limits its practical applications. Our investigations indicate that by passivation of the mechanically exfoliated BP flakes with a SiO2 layer, the fabricated BP field effect transistors (FETs) exhibit greatly enhanced environmental stability. Compared to the unpassivated BP devices, which show a fast drop of on/off current ratio by a factor of 10 after one week of ambient exposure, the SiO2-passivated BP devices display a high retained on/off current ratio of over 600 after one week of exposure, just a little lower than the initial value of 810. Our investigations provide an effective route to passivate the few-layer BPs for enhancement of their environmental stability. PMID- 26436440 TI - How and why do interviewers try to make impressions on applicants? A qualitative study. AB - To remain viable in today's highly competitive business environments, it is crucial for organizations to attract and retain top candidates. Hence, interviewers have the goal not only of identifying promising applicants but also of representing their organization. Although it has been proposed that interviewers' deliberate signaling behaviors are a key factor for attracting applicants and thus for ensuring organizations' success, no conceptual model about impression management (IM) exists from the viewpoint of the interviewer as separate from the applicant. To develop such a conceptual model on how and why interviewers use IM, our qualitative study elaborates signaling theory in the interview context by identifying the broad range of impressions that interviewers intend to create on applicants, what kinds of signals interviewers deliberately use to create their intended impressions, and what outcomes they pursue. Following a grounded theory approach, multiple raters analyzed in-depth interviews with interviewers and applicants. We also observed actual employment interviews and analyzed memos and image brochures to generate a conceptual model of interviewer IM. Results showed that the spectrum of interviewers' IM intentions goes well beyond what has been proposed in past research. Furthermore, interviewers apply a broad range of IM behaviors, including verbal and nonverbal as well as paraverbal, artifactual, and administrative behaviors. An extensive taxonomy of interviewer IM intentions, behaviors, and intended outcomes is developed, interrelationships between these elements are presented, and avenues for future research are derived. PMID- 26436441 TI - The long road to employment: Incivility experienced by job seekers. AB - This study addresses how job seekers' experiences of rude and discourteous treatment--incivility--can adversely affect self-regulatory processes underlying job searching. Using the social-cognitive model (Zimmerman, 2000), we integrate social-cognitive theory with the goal orientation literature to examine how job search self-efficacy mediates the relationship between incivility and job search behaviors and how individual differences in learning goal orientation and avoid performance goal orientation moderate that process. We conducted 3 studies with diverse methods and samples. Study 1 employed a mixed-method design to understand the nature of incivility within the job search context and highlight the role of attributions in linking incivility to subsequent job search motivation and behavior. We tested our hypotheses in Study 2 and 3 employing time-lagged research designs with unemployed job seekers and new labor market entrants. Across both Study 2 and 3 we found evidence that the negative effect of incivility on job search self-efficacy and subsequent job search behaviors are stronger for individuals low, rather than high, in avoid-performance goal orientation. Theoretical implications of our findings and practical recommendations for how to address the influence of incivility on job seeking are discussed. PMID- 26436442 TI - Self-Assembled Smart Nanocarriers for Targeted Drug Delivery. AB - Nanostructured drug-carrier systems promise numerous benefits for drug delivery. They can be engineered to precisely control drug-release rates or to target specific sites within the body with a specific amount of therapeutic agent. However, to achieve the best therapeutic effects, the systems should be designed for carrying the optimum amount of a drug to the desired target where it should be released at the optimum rate for a specified time. Despite numerous attempts, fulfilling all of these requirements in a synergistic way remains a huge challenge. The trend in drug delivery is consequently directed toward integrated multifunctional carrier systems, providing selective recognition in combination with sustained or triggered release. Capsules as vesicular systems enable drugs to be confined for controlled release. Furthermore, carriers modified with recognition groups can enhance the capability of encapsulated drug efficacy. Here, recent advances are reviewed regarding designing and preparing assembled capsules with targeting ligands or size controllable for selective recognition in drug delivery. PMID- 26436444 TI - Metabolic and body composition changes in first year following traumatic amputation. AB - Body composition and metabolism may change considerably after traumatic amputation because of muscle atrophy and an increase in adiposity. The purpose of this study was to quantify changes in weight, body composition, and metabolic rate during the first year following traumatic amputation in military servicemembers. Servicemembers without amputation were included for comparison. Participants were measured within the first 12 wk after amputation (baseline) and at 6, 9, and 12 mo after amputation. Muscle mass, fat mass, weight, and metabolic rate were measured at each time point. There was a significant increase in weight and body mass index in the unilateral group between baseline and all follow-up visits (p < 0.01). Over the 12 mo period, total fat mass and trunk fat mass increased in both unilateral and bilateral groups; however, these changes were not statistically significant over time. Muscle mass increased in both the unilateral and bilateral group despite percent of lean mass decreasing. No changes in resting metabolism or walking energy expenditure were observed in any group. The results of this study conclude that weight significantly increased because of an increase in both fat mass and muscle mass in the first year following unilateral and bilateral amputation. PMID- 26436445 TI - Wheat leaf lipids during heat stress: II. Lipids experiencing coordinated metabolism are detected by analysis of lipid co-occurrence. AB - Identifying lipids that experience coordinated metabolism during heat stress would provide information regarding lipid dynamics under stress conditions and assist in developing heat-tolerant wheat varieties. We hypothesized that co occurring lipids, which are up-regulated or down-regulated together through time during heat stress, represent groups that can be explained by coordinated metabolism. Wheat plants (Triticum aestivum L.) were subjected to 12 days of high day and/or night temperature stress, followed by a 4-day recovery period. Leaves were sampled at four time points, and 165 lipids were measured by electrospray ionization-tandem mass spectrometry. Correlation analysis of lipid levels in 160 leaf samples from each of two wheat genotypes revealed 13 groups of lipids. Lipids within each group co-occurred through the high day and night temperature stress treatments. The lipid groups can be broadly classified as groups containing extraplastidic phospholipids, plastidic glycerolipids, oxidized glycerolipids, triacylglycerols, acylated sterol glycosides and sterol glycosides. Current knowledge of lipid metabolism suggests that the lipids in each group co-occur because they are regulated by the same enzyme(s). The results suggest that increases in activities of desaturating, oxidizing, glycosylating and acylating enzymes lead to simultaneous changes in levels of multiple lipid species during high day and night temperature stress in wheat. PMID- 26436446 TI - Multiple breath washout cannot be used for tidal breath parameter analysis in infants. AB - BACKGROUND: Multiple breath washout (MBW) testing with SF6 gas mixture is routinely used to assess ventilation distribution in infants. It is currently unknown whether SF6 changes tidal breathing parameters during MBW in infants. We investigated if SF6 does change tidal breathing parameters in infants and whether a separate tidal breathing trace prior to MBW testing is necessary. METHODS: Tidal breathing during MBW was compared to standard tidal breathing in room air in healthy infants (n = 38), preterm infants (n = 41), and infants with cystic fibrosis (n = 41). Outcomes included inspiratory and expiratory times (TI and TE ), time to peak tidal inspiratory and expiratory flow (tPTIF and tPTEF), tidal volume (VT ), respiratory rate (f), and minute ventilation (VE ). RESULTS: Breath times were all significantly increased for both healthy (TE : -0.0790 [-0.10566, 0.05217]; mean difference [95% confidence intervals]) and CF (-0.109 [-0.15235, 0.06607]) infants during the MBW wash-in (P < 0.001). Healthy infants and those with CF showed decreased f during MBW wash-in (P < 0.001); however, no change in VT, resulting in a decreased VE (0.154 (0.086, 0.222) and 0.128 (0.069, 0.186) for healthy and CF infants, respectively, P < 0.001). Preterm infants experienced a decreased VE during both wash-in (0.134 [0.061, 0.207]; P < 0.001) and wash-out phases of MBW (P < 0.05). CONCLUSION: There are differences in tidal breathing parameters during MBW testing with SF6 in infants. It is, therefore, important to measure a separate tidal breathing trace in room air, prior to MBW testing to ensure rigour of tidal breath indices derived from analysis. PMID- 26436447 TI - Natural antioxidants for non-alcoholic fatty liver disease: molecular targets and clinical perspectives. AB - Non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD), is emerging as a main health problem in industrialized countries. Lifestyle modifications are effective in the treatment of NAFLD; however, the long-term compliance is low. Therefore, several pharmacological treatments have been proposed but none has shown significant efficacy or long term safety. Natural polyphenols are a heterogeneous class of polyphenolic compounds contained in vegetables, which are being proposed for the treatment of different metabolic disorders. Although the beneficial effect of these compounds has traditionally related to their antioxidant properties, they also exert several beneficial effects on hepatic and extra-hepatic glucose and lipid homeostasis. Furthermore, natural polyphenols exert antifibrogenic and antitumoural effects in animal models, which appear relevant from a clinical point of view because of the association of NASH with cirrhosis and hepatocellular carcinoma. Several polyphenols, such anthocyanins, curcumin and resveratrol and those present in coffee, tea, soy are available in the diet and their consumption can be proposed as part of a healthy diet for the treatment of NAFLD. Other phenolic compounds, such as silymarin, are commonly consumed worldwide as nutraceuticals or food supplements. Natural antioxidants are reported to have beneficial effects in preclinical models of NAFLD and in pilot clinical trials, and thus need clinical evaluation. In this review, we summarize the existing evidence regarding the potential role of natural antioxidants in the treatment of NAFLD and examine possible future clinical applications. PMID- 26436449 TI - Transferable ab Initio Dipole Moment for Water: Three Applications to Bulk Water. AB - We recently reported a second-generation, ab initio dipole moment surface (DMS) for water and applied it successfully to the IR spectrum of liquid water at 300 K. Here the transferability of this DMS is demonstrated in three applications. One is the distribution of monomer dipole moments, considering two definitions, and effective atomic charges of liquid water at 300 K and also for a model of ice Ih at 0 K. The second one is a calculation of the dielectric constant of liquid water at 280, 300, 320, 340, 360 K, and the third one is correcting the intensities of the IR spectrum of liquid water at 300 K, obtained using the q TIP4P/F potential, bringing them into much improved agreement with experiment. For the purpose of obtaining statistical ensembles we use molecular dynamics simulations with the TIP4P+E3B water model developed by Skinner and co-workers. The average monomer dipole moments for 300 K water and 0 K ice Ih are 2.94 and 3.54 D, respectively, in good agreement with literature values. Effective monomer charge distributions are derived from the monomer dipoles and give average values of -1.02 e for O and 0.51 e for H in liquid water, which are also in agreement with values reported from experiment. The calculated dielectric constant of liquid water at the above five temperatures is compared to experiment and is roughly 10-15% lower than experiment. PMID- 26436450 TI - Synthesis of highly strained bicyclic[3.n.1]alkenes by a metal-catalyzed Conia ene reaction. AB - A high yielding metal-catalysed Conia-ene reaction of 2-acetylenic ketones for the synthesis of bicyclo[3.n.1]alkenes has been developed. This simple and efficient 6-endo-dig-cyclization protocol enables the synthesis of a wide variety of bicyclic systems, present in many natural products. PMID- 26436448 TI - Postdepletion Lymphocyte Reconstitution During Belatacept and Rapamycin Treatment in Kidney Transplant Recipients. AB - Belatacept is used to prevent allograft rejection but fails to do so in a sizable minority of patients due to inadequate control of costimulation-resistant T cells. In this study, we report control of costimulation-resistant rejection when belatacept was combined with perioperative alemtuzumab-mediated lymphocyte depletion and rapamycin. To assess the means by which the alemtuzumab, belatacept and rapamycin (ABR) regimen controls belatacept-resistant rejection, we studied 20 ABR-treated patients and characterized peripheral lymphocyte phenotype and functional responses to donor, third-party and viral antigens using flow cytometry, intracellular cytokine staining and carboxyfluorescein succinimidyl ester-based lymphocyte proliferation. Compared with conventional immunosuppression in 10 patients, lymphocyte depletion evoked substantial homeostatic lymphocyte activation balanced by regulatory T and B cell phenotypes. The reconstituted T cell repertoire was enriched for CD28(+) naive cells, notably diminished in belatacept-resistant CD28(-) memory subsets and depleted of polyfunctional donor-specific T cells but able to respond to third-party and latent herpes viruses. B cell responses were similarly favorable, without alloantibody development and a reduction in memory subsets-changes not seen in conventionally treated patients. The ABR regimen uniquely altered the immune profile, producing a repertoire enriched for CD28(+) T cells, hyporesponsive to donor alloantigen and competent in its protective immune capabilities. The resulting repertoire was permissive for control of rejection with belatacept monotherapy. PMID- 26436451 TI - Projections from neocortex mediate top-down control of memory retrieval. AB - Top-down prefrontal cortex inputs to the hippocampus have been hypothesized to be important in memory consolidation, retrieval, and the pathophysiology of major psychiatric diseases; however, no such direct projections have been identified and functionally described. Here we report the discovery of a monosynaptic prefrontal cortex (predominantly anterior cingulate) to hippocampus (CA3 to CA1 region) projection in mice, and find that optogenetic manipulation of this projection (here termed AC-CA) is capable of eliciting contextual memory retrieval. To explore the network mechanisms of this process, we developed and applied tools to observe cellular-resolution neural activity in the hippocampus while stimulating AC-CA projections during memory retrieval in mice behaving in virtual-reality environments. Using this approach, we found that learning drives the emergence of a sparse class of neurons in CA2/CA3 that are highly correlated with the local network and that lead synchronous population activity events; these neurons are then preferentially recruited by the AC-CA projection during memory retrieval. These findings reveal a sparsely implemented memory retrieval mechanism in the hippocampus that operates via direct top-down prefrontal input, with implications for the patterning and storage of salient memory representations. PMID- 26436453 TI - A two-qubit logic gate in silicon. AB - Quantum computation requires qubits that can be coupled in a scalable manner, together with universal and high-fidelity one- and two-qubit logic gates. Many physical realizations of qubits exist, including single photons, trapped ions, superconducting circuits, single defects or atoms in diamond and silicon, and semiconductor quantum dots, with single-qubit fidelities that exceed the stringent thresholds required for fault-tolerant quantum computing. Despite this, high-fidelity two-qubit gates in the solid state that can be manufactured using standard lithographic techniques have so far been limited to superconducting qubits, owing to the difficulties of coupling qubits and dephasing in semiconductor systems. Here we present a two-qubit logic gate, which uses single spins in isotopically enriched silicon and is realized by performing single- and two-qubit operations in a quantum dot system using the exchange interaction, as envisaged in the Loss-DiVincenzo proposal. We realize CNOT gates via controlled phase operations combined with single-qubit operations. Direct gate-voltage control provides single-qubit addressability, together with a switchable exchange interaction that is used in the two-qubit controlled-phase gate. By independently reading out both qubits, we measure clear anticorrelations in the two-spin probabilities of the CNOT gate. PMID- 26436452 TI - Cryo-electron microscopy structure of the Slo2.2 Na(+)-activated K(+) channel. AB - Na(+)-activated K(+) channels are members of the Slo family of large conductance K(+) channels that are widely expressed in the brain, where their opening regulates neuronal excitability. These channels fulfil a number of biological roles and have intriguing biophysical properties, including conductance levels that are ten times those of most other K(+) channels and gating sensitivity to intracellular Na(+). Here we present the structure of a complete Na(+)-activated K(+) channel, chicken Slo2.2, in the Na(+)-free state, determined by cryo electron microscopy at a nominal resolution of 4.5 angstroms. The channel is composed of a large cytoplasmic gating ring, in which resides the Na(+)-binding site and a transmembrane domain that closely resembles voltage-gated K(+) channels. In the structure, the cytoplasmic domain adopts a closed conformation and the ion conduction pore is also closed. The structure reveals features that can explain the unusually high conductance of Slo channels and how contraction of the cytoplasmic gating ring closes the pore. PMID- 26436454 TI - Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration. AB - Postnatal tissue quiescence is thought to be a default state in the absence of a proliferative stimulus such as injury. Although previous studies have demonstrated that certain embryonic developmental programs are reactivated aberrantly in adult organs to drive repair and regeneration, it is not well understood how quiescence is maintained in organs such as the lung, which displays a remarkably low level of cellular turnover. Here we demonstrate that quiescence in the adult lung is an actively maintained state and is regulated by hedgehog signalling. Epithelial-specific deletion of sonic hedgehog (Shh) during postnatal homeostasis in the murine lung results in a proliferative expansion of the adjacent lung mesenchyme. Hedgehog signalling is initially downregulated during the acute phase of epithelial injury as the mesenchyme proliferates in response, but returns to baseline during injury resolution as quiescence is restored. Activation of hedgehog during acute epithelial injury attenuates the proliferative expansion of the lung mesenchyme, whereas inactivation of hedgehog signalling prevents the restoration of quiescence during injury resolution. Finally, we show that hedgehog also regulates epithelial quiescence and regeneration in response to injury via a mesenchymal feedback mechanism. These results demonstrate that epithelial-mesenchymal interactions coordinated by hedgehog actively maintain postnatal tissue homeostasis, and deregulation of hedgehog during injury leads to aberrant repair and regeneration in the lung. PMID- 26436455 TI - Electrophysiological Motor Unit Number Estimation (MUNE) Measuring Compound Muscle Action Potential (CMAP) in Mouse Hindlimb Muscles. AB - Compound muscle action potential (CMAP) and motor unit number estimation (MUNE) are electrophysiological techniques that can be used to monitor the functional status of a motor unit pool in vivo. These measures can provide insight into the normal development and degeneration of the neuromuscular system. These measures have clear translational potential because they are routinely applied in diagnostic and clinical human studies. We present electrophysiological techniques similar to those employed in humans to allow recordings of mouse sciatic nerve function. The CMAP response represents the electrophysiological output from a muscle or group of muscles following supramaximal stimulation of a peripheral nerve. MUNE is an electrophysiological technique that is based on modifications of the CMAP response. MUNE is a calculated value that represents the estimated number of motor neurons or axons (motor control input) supplying the muscle or group of muscles being tested. We present methods for recording CMAP responses from the proximal leg muscles using surface recording electrodes following the stimulation of the sciatic nerve in mice. An incremental MUNE technique is described using submaximal stimuli to determine the average single motor unit potential (SMUP) size. MUNE is calculated by dividing the CMAP amplitude (peak-to peak) by the SMUP amplitude (peak-to-peak). These electrophysiological techniques allow repeated measures in both neonatal and adult mice in such a manner that facilitates rapid analysis and data collection while reducing the number of animals required for experimental testing. Furthermore, these measures are similar to those recorded in human studies allowing more direct comparisons. PMID- 26436456 TI - Do cherished children age successfully? Longitudinal findings from the Veterans Affairs Normative Aging Study. AB - Although early adversity has been linked to worse mental and physical health in adulthood, few studies have investigated the pathways through which positive and negative dimensions of early experiences can jointly influence psychological well being in later life. This study examined: (a) profiles of early experiences across multiple domains, (b) the relations of these profiles to hedonic and eudaimonic well-being in later life, and (c) whether midlife social support mediated these relations. We first conducted latent class analysis of early experiences using data from 1,076 men in the VA Normative Aging Study who completed the Childhood Experiences Scale (age: M = 69, SD = 7). Analyses yielded 3 profiles of early experiences, labeled as cherished (strong support and some losses), harshly disciplined (harsh parental discipline, low positive reinforcement, and nonnormative stressors), and ordinary (few stressors and low parental attention). Next, we applied structural equation modeling to data on a subset of this sample assessed 7 years later on hedonic and eudaimonic well-being (n = 496; age: M = 76, SD = 7). In general, the cherished group reported stronger qualitative social support in midlife than the harshly disciplined and ordinary groups, which in turn was related to greater hedonic (life satisfaction, positive affect) and eudaimonic (competence, positive relations with others) well-being in later life. The cherished group also reported higher autonomy than the ordinary group, but this association was independent of midlife social support. Our findings suggest that experiencing adversity in the context of a nurturing early environment can promote successful aging through the maintenance of supportive relationships in midlife. PMID- 26436457 TI - Gene Positioning Effects on Expression in Eukaryotes. AB - The packaging and organization of the genome within the eukaryotic interphase nucleus directly influence how the genes are expressed. An underappreciated aspect of genome structure is that it is highly dynamic and that the physical positioning of a gene can impart control over its transcriptional status. In this review, we assess the current knowledge of how gene positioning at different levels of genome organization can directly influence gene expression during interphase. The levels of organization discussed include chromatin looping, topologically associated domains, chromosome territories, and nuclear compartments. We discuss specific studies demonstrating that gene positioning is a dynamic and highly regulated feature of the eukaryotic genome that allows for the essential spatiotemporal regulation of genes. PMID- 26436459 TI - Population Genomics for Understanding Adaptation in Wild Plant Species. AB - Darwin's theory of evolution by natural selection is the foundation of modern biology. However, it has proven remarkably difficult to demonstrate at the genetic, genomic, and population level exactly how wild species adapt to their natural environments. We discuss how one can use large sets of multiple genome sequences from wild populations to understand adaptation, with an emphasis on the small herbaceous plant Arabidopsis thaliana. We present motivation for such studies; summarize progress in describing whole-genome, species-wide sequence variation; and then discuss what insights have emerged from these resources, either based on sequence information alone or in combination with phenotypic data. We conclude with thoughts on opportunities with other plant species and the impact of expected progress in sequencing technology and genome engineering for studying adaptation in nature. PMID- 26436460 TI - Chromosome-Membrane Interactions in Bacteria. AB - Prokaryotes, by definition, do not segregate their genetic material from the cytoplasm. Thus, there is no barrier preventing direct interactions between chromosomal DNA and the plasma membrane. The possibility of such interactions in bacteria was proposed long ago and supported by early electron microscopy and cell fractionation studies. However, the identification and characterization of chromosome-membrane interactions have been slow in coming. Recently, this subject has seen more progress, driven by advances in imaging techniques and in the exploration of diverse cellular processes. A number of loci have been identified in specific bacteria that depend on interactions with the membrane for their function. In addition, there is growing support for a general mechanism of DNA membrane contacts based on transertion-concurrent transcription, translation, and insertion of membrane proteins. This review summarizes the history and recent results of chromosome-membrane associations and discusses the known and theorized consequences of these interactions in the bacterial cell. PMID- 26436458 TI - Nonsense-Mediated mRNA Decay: Degradation of Defective Transcripts Is Only Part of the Story. AB - Nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance mechanism that monitors cytoplasmic mRNA translation and targets mRNAs undergoing premature translation termination for rapid degradation. From yeasts to humans, activation of NMD requires the function of the three conserved Upf factors: Upf1, Upf2, and Upf3. Here, we summarize the progress in our understanding of the molecular mechanisms of NMD in several model systems and discuss recent experiments that address the roles of Upf1, the principal regulator of NMD, in the initial targeting and final degradation of NMD-susceptible mRNAs. We propose a unified model for NMD in which the Upf factors provide several functions during premature termination, including the stimulation of release factor activity and the dissociation and recycling of ribosomal subunits. In this model, the ultimate degradation of the mRNA is the last step in a complex premature termination process. PMID- 26436462 TI - ClC-3 chloride channel functions as a mechanically sensitive channel in osteoblasts. AB - Mechanical stimulation usually causes the volume changes of osteoblasts. Whether these volume changes could be sensed by the ClC-3 chloride channel, a volume sensitive ion channel, and further promote the osteodifferentiation in osteoblasts has not been determined. In this study, we applied persistent static compression on MC3T3-E1 cells to detect the expression changes of ClC-3, osteogenic markers, as well as some molecules related with signaling transduction pathway. We tested the key role of ClC-3 in transferring the mechanical signal to osteoinduction by ClC-3 overexpressing and siRNA technique. We found that ClC-3 level was up-regulated by mechanical stimulation in MC3T3-E1 cells. Mechanical force also up-regulated the mRNA level of osteogenic markers such as alkaline phosphatase (Alp), bone sialoprotein (Bsp), and osteocalcin (Oc), which could be blocked or strengthened by Clcn3 siRNA or overexpressing, and Alp expression was more sensitive to the changes of ClC-3 level. We also found that runt-related transcription factor 2 (Runx2), transforming growth factor beta 1 (TGF-beta1), and Wnt pathway might be involved in ClC-3 mediated mechanical transduction in osteoblasts. The data from the current study suggest that the ClC-3 chloride channel acts as a mechanically sensitive channel to regulate osteodifferentiation in osteoblasts. PMID- 26436463 TI - The role of cardiorespiratory fitness on plasma lipid levels. AB - Dyslipidemia is a treatable risk factor for cardiovascular disease. Epidemiological studies have demonstrated the importance of treatment for abnormalities in total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides. Aside from pharmacotherapy, exercise and cardio-respiratory fitness have been shown to have beneficial effects on decreasing cardiovascular disease risk. Even though previous data regarding the benefits of exercise on plasma lipids have been somewhat conflicting, numerous studies have demonstrated that exercise increases HDL-cholesterol and reduces the triglyceride levels. Also, smaller, more atherogenic LDL particles seem to decrease with increases in cardio-respiratory fitness and exercise, and favorable blood lipid profiles seem to persist longer through the adult life span. PMID- 26436464 TI - The Interactive Effects of Impulsivity and Negative Emotions on Adolescent Nonsuicidal Self-injury: A Latent Growth Curve Analysis. AB - This study employed latent growth curve analysis to evaluate the interactive effects of two specific facets of impulsivity (i.e., negative urgency [NU] and premeditation [PRE]) and negative emotions (NE) on the developmental trajectory of nonsuicidal self-injury (NSSI) among 3,453 (57% females) Chinese community adolescents. Participants completed questionnaires assessing NSSI, NU, PRE, and NE (i.e., depression, anxiety, and stress) at three waves of time. The initial levels of NE and NU significantly predicted the initial level of NSSI. Changes in NE and NU significantly predicted change in NSSI. Moreover, the initial levels of NU and PRE significantly moderated the relationship between the initial levels of NE and NSSI, such that among individuals with higher NU or less PRE, the three NE were associated with a higher level of NSSI. Additionally, among individuals with a faster increase in NU, depression and anxiety were associated with a faster increase in NSSI. These findings suggest that adolescents with trait impulsivity, especially in the form of NU, are more vulnerable to the engagement in NSSI. PMID- 26436461 TI - Eukaryotic Mismatch Repair in Relation to DNA Replication. AB - Three processes act in series to accurately replicate the eukaryotic nuclear genome. The major replicative DNA polymerases strongly prevent mismatch formation, occasional mismatches that do form are proofread during replication, and rare mismatches that escape proofreading are corrected by mismatch repair (MMR). This review focuses on MMR in light of increasing knowledge about nuclear DNA replication enzymology and the rate and specificity with which mismatches are generated during leading- and lagging-strand replication. We consider differences in MMR efficiency in relation to mismatch recognition, signaling to direct MMR to the nascent strand, mismatch removal, and the timing of MMR. These studies are refining our understanding of relationships between generating and repairing replication errors to achieve accurate replication of both DNA strands of the nuclear genome. PMID- 26436465 TI - A Dual-Ion Battery Cathode via Oxidative Insertion of Anions in a Metal-Organic Framework. AB - A redox-active metal-organic framework, Fe2(dobpdc) (dobpdc(4-) = 4,4' dioxidobiphenyl-3,3'-dicarboxylate), is shown to undergo a topotactic oxidative insertion reaction with a variety of weakly coordinating anions, including BF4(-) and PF6(-). The reaction results in just a minor lattice contraction, and a broad intervalence charge-transfer band emerges, indicative of charge mobility. Although both metal- and ligand-based oxidations can be accessed, only the former were found to be fully reversible and, importantly, proceed stoichiometrically under both chemical and electrochemical conditions. Electrochemical measurements probing the effects of nanoconfinement on the insertion reaction revealed strong anion size and solvent dependences. Significantly, the anion insertion behavior of Fe2(dobpdc) enabled its use in the construction of a dual-ion battery prototype incorporating a sodium anode. As a cathode, the material displays a particularly high initial reduction potential and is further stable for at least 50 charge/discharge cycles, exhibiting a maximum specific energy of 316 Wh/kg. PMID- 26436466 TI - Regulatory systemic effect of postsurgical polychromatic light (480-3400 nm) irradiation of breast cancer patients on the proliferation of tumor and normal cells in vitro. AB - OBJECTIVE: The aim of this work was to study the effect of phototherapy (PT) with percutaneous exposures to polychromatic visible and IR light (pVIS + pIR) on breast cancer (BC) patients at the early postmastectomy period, on the growth promoting (GP) properties of their blood serum, by evaluating its capability to support proliferation of normal and tumor human cells in vitro. MATERIAL AND METHODS: After mastectomy, one group of patients was treated daily for 1 week on the sacral area with pVIS + pIR light (480-3400 nm, 40 mW/cm(2), 95% polarization, 24 J/cm(2)). The second group used as a control was sham irradiated. Blood serum samples collected before surgery, and 1 and 8 days after surgery, were added (2.5%) into nutrition media for cells instead of 10% of fetal calf serum. Cell targets were cultures of human fibroblasts (FBs), keratinocytes (KCs), three lines of the human BC cells (BT-474, HBL-100, Hs 578T) and cells of human epidermoid carcinoma (A-431). Cell number was evaluated by staining cell nuclei with crystal violet and a spectrometric assay of the extracted dye. RESULTS: The day after mastectomy there were no significant changes in the GP activity of sera. After a 7-day PT course, an increase of this activity was recorded for normal FBs and KCs by 18% and 24%, respectively, in comparison with presurgical levels. GP activity of the same patients' sera for all tumor cells, BT-474, HBL-100, Hs 578T and A-431, decreased by 32%, 17%, 11%, and 7% respectively. As a result, enhancement of proliferation of KCs and FBs and inhibition of proliferation of tumor cells was seen. CONCLUSIONS: The results suggest an effect at the systemic level where pVIS + pIR light may stimulate growth of human skin cells and simultaneously downregulate the proliferation of tumor cells, including BC cells. This argues in favor of the oncological safety of PT for BC patients postsurgically. PMID- 26436467 TI - Gene Editing Versus Morphants. PMID- 26436469 TI - Prevalence and spatial distribution of cattle herds infected with Theileria orientalis in New Zealand between 2012 and 2013. AB - AIM: To describe the prevalence and spatial distribution of cattle herds infected with Ikeda and non-Ikeda types of Theileria orientalis in New Zealand between November 2012 and June 2013. METHODS: Pooled serum samples collected historically between November 2012 and June 2013 were obtained from cattle herds throughout New Zealand. Each pooled sample consisted of approximately 20 individual cattle samples from that herd, and was provided with details of the spatial location of the herd (n=722). DNA from all samples was tested using two quantitative PCR assays for the detection of T. orientalis (all types) and the Ikeda type. The proportion of herds that were positive for T. orientalis and Ikeda type, or that were positive for T. orientalis but negative for Ikeda type (non-Ikeda positive) was determined for different regions of New Zealand. RESULTS: The highest prevalence of herds infected with Ikeda type was detected in the Northland (33/35; 94%) and Auckland and the Waikato (63/191; 33%) regions. Only 2/204 (1%) herds were positive for the Ikeda type in the South Island. A high percentage of herds that were positive for non-Ikeda types was detected in the Gisborne and Hawkes Bay (23 (95%CI=13-37)%), Auckland and Waikato (22 (95%CI=16-29)%) and Bay of Plenty (24 (95%CI=10-44)%) regions. CONCLUSIONS AND CLINICAL RELEVANCE: The high prevalence of Ikeda type detected in cattle herds in the Northland, Auckland and Waikato regions represents a risk to naive cattle being introduced into these regions. There is also the potential for resident cattle herds in the Gisborne and Hawkes Bay, Auckland, Waikato and Bay of Plenty regions to experience increased infection with the Ikeda type. The overall impact experienced by regions will depend on other factors such as the number of herds present and the predominant type of farming, as well as the interplay between tick ecology, cattle immunity and movement patterns of cattle. PMID- 26436470 TI - Dipeptidyl peptidase-4 inhibitor use in patients with type 2 diabetes and cardiovascular disease or risk factors. AB - OBJECTIVES: Management of cardiovascular (CV) risk is an essential aspect of diabetes care, and acceptable CV risk is a requirement for antidiabetes medications. Dipeptidyl peptidase-4 (DPP-4) inhibitors effectively reduce glycated hemoglobin, with a low risk of hypoglycemia and weight gain. The purpose of this review is to discuss the use of DPP-4 inhibitors in patients with type 2 diabetes mellitus (T2DM) and CV disease or risk factors. METHODS: A PubMed search (January 2013-June 2015) was conducted to identify prospective trials, meta analyses, pooled analyses and cohort studies evaluating CV outcomes with DPP-4 inhibitors. RESULTS: Meta-analyses, pooled analyses and retrospective cohort studies in patients with T2DM suggest no increased CV risk and possible CV benefit compared with some antidiabetes medications. The three published, long term, prospective, randomized, double-blind CV outcomes trials in patients with CV disease or risk factors found no increased rate of major CV events in patients treated with alogliptin, saxagliptin or sitagliptin versus placebo as add-on to standard-of-care. However, the analysis of the components of the secondary end point of the saxagliptin study showed an increased number of hospitalizations for heart failure (HF) in treated patients versus placebo. A post hoc analysis of the alogliptin study showed no increase in HF hospitalization in treated patients with a history of HF versus placebo, but did show an increase in alogliptin treated patients with no baseline HF history. Sitagliptin showed no increased risk for HF hospitalization versus placebo in the overall cohort. Two CV outcomes trials for linagliptin are ongoing. CONCLUSION: The majority of available data from CV outcomes trials suggest a neutral effect of DPP-4 inhibitors on major CV events. PMID- 26436471 TI - Erratum. PMID- 26436472 TI - Structure of n-Alkyltrichlorosilane Monolayers on Si(100)/SiO2. AB - The structure of n-alkyltrichlorosilane self-assembled monolayers (SAMs) of alkyl chain lengths n = 12, 14, 18, and 22 formed on the amorphous native oxide of silicon (100) has been investigated via angstrom-resolution surface X-ray scattering techniques, with particular focus on the proliferation of lateral order along the molecules' long axis. Grazing incidence diffraction shows that the monolayer is composed of hexagonally packed crystalline-like domains for n = 14, 18, and 22 with a lateral size of about 60 A. However, Bragg rod analysis shows that ~12 of the CH2 units are not included in the crystalline-like domains. We assign this, and the limited lateral crystallites' size, to strain induced by the size mismatch between the optimal chain-chain and headgroup-headgroup spacings. Analysis of X-ray reflectivity profiles for n = 12, 14, and 22 shows that the density profile used to successfully model n = 18 provides an excellent fit where the analysis-derived parameters provide complementary structural information to the grazing incidence results. PMID- 26436474 TI - Serum ferritin predicted prognosis in patients with locally advanced pancreatic cancer. AB - AIM: The present study evaluated the value of serum ferritin (SF) level for the prognosis of patients with locally advanced pancreatic cancer (LAPC). PATIENTS & METHODS: A total of 79 patients with LAPC treated by chemoradiotherapy were reviewed retrospectively. Pretreatment and post-treatment levels of SF were obtained. RESULTS: Median progression-free survival (PFS) was 11.8 months; median overall survival was 18.3 months. A total of 36 patients with elevated SF level showed significantly worse overall survival and PFS than patients with low SF level (p = 0.002 and p = 0.004, respectively). In total, 17 patients showed normal SF level after chemoradiotherapy, and their median PFS was 3.2 months longer than that of patients whose SF levels were not restored after chemoradiotherapy. CONCLUSION: SF may serve as a valuable tool to assess prognosis and monitor chemoradiotherapy response in patients with LAPC. PMID- 26436475 TI - Ab Initio Unimolecular Reaction Kinetics of CH2C(?O)OCH3 and CH3C(?O)OCH2 Radicals. AB - The unimolecular dissociation and isomerization kinetics of the methyl ester combustion intermediates methoxycarbonylmethyl (CH2C(?O)OCH3) and acetyloxylmethyl (CH3C(?O)OCH2) are theoretically investigated using high-level ab initio methods and the Rice-Ramsperger-Kassel-Marcus (RRKM)/master equation (ME) theory. Potential energy surfaces (PESs) are obtained using coupled cluster singles and doubles with perturbative triples correction (CCSD(T)), multireference singles and doubles configuration interaction (MRSDCI) with the Davidson-Silver (DS) correction, and multireference averaged coupled pair functional (MRACPF2) theory. The transition states exhibit high T1 diagnostics in coupled cluster calculations, suggesting the need for a multireference correlated wave function treatment. MRSDCI+DS and MRACPF2 capture their multiconfigurational character well, yielding lower barrier heights than CCSD(T) for these reactions. The rate coefficients are computed using the RRKM/ME theory over a 500-2500 K temperature range and at a pressure range of 0.01 atm to the high-pressure limit. The temperature- and pressure-dependent rate coefficients are given in modified Arrhenius expressions. The beta-scission of CH2C(?O)OCH3 is predicted to have a much higher barrier than the corresponding isomerization reaction and the beta scission of CH3C(?O)OCH2. Consequently, the rate coefficients for beta-scission of CH2C(?O)OCH3 are the smallest among the three reactions and the isomerization followed by decomposition to CH3C(?O) and HCHO is the dominant reaction pathway for CH2C(?O)OCH3. Both radicals CH2C(?O)OCH3 and CH3C(?O)OCH2 are predicted to mainly decompose to CH3C(?O) + HCHO rather than to the bimolecular product CH2C(?O) + CH3O. A newly developed MA combustion mechanism, using our theoretical rate coefficients for the MA-related reactions, predicts combustion properties in good agreement with available experimental data. PMID- 26436476 TI - Assessment of chronic effects of tebuconazole on survival, reproduction and growth of Daphnia magna after different exposure times. AB - The effect of the fungicide tebuconazole (0.41, 0.52, 0.71 and 1.14mg/L) on survival, reproduction and growth of Daphnia magna organisms was monitored using 14 and 21 days exposure tests. A third experiment was performed by exposing D. magna to the fungicide for 14 days followed by 7 days of recovery (14+7). In order to test fungicide effects on D. magna, parameters as survival, mean whole body length, mean total number of neonates per female, mean number of broods per female, mean brood size per female, time to first brood/reproduction and intrinsic rate of natural increase (r) were used. Reproduction was seriously affected by tebuconazole. All tebuconazole concentrations tested affected the number of broods per female and day to first brood. At 14-days test, number of neonates per female and body size decreased by concentrations of tebuconazole higher than 0.52mg/L, whereas at 21-days test both parameters were affected at all the concentrations tested. Survival of the daphnids after 14 days fungicide exposure did not exhibited differences among experimental and control groups. In this experiment r value was reduced (in a 22%) when animals were exposed to concentrations of 0.71mg/L and 1.14mg/L. Survival of daphnids exposed during 21 days to 1.14mg/L declined, and the intrinsic rate of natural increase (r) decreased in a 30 % for tebuconazole concentrations higher than 0.41mg/L. Longevity of daphnids pre-exposed to tebuconazole for 14 days and 7 days in clean water did not show differences from control values and all of them survived the 21 days of the test. However, after 7 days in fungicide free medium animals were unable to restore control values for reproductive parameters and length. The maximum acceptable toxicant concentration (MATC) was calculated using the r values as parameter of evaluation. MATC estimations were 0.61mg/L and 0.46mg/L for 14 and 21 days, respectively. Results showed that the number of neonates per female was the highest sensitive parameter to the effects of tebuconazole on D. magna. On the other hand, a recovery period of 7 days in a free toxicant medium would not be longer enough to reestablish normal reproduction parameters in pre exposed tebuconazole daphnids. PMID- 26436477 TI - General stress, detoxification pathways, neurotoxicity and genotoxicity evaluated in Ruditapes philippinarum exposed to human pharmaceuticals. AB - A battery of biomarkers was evaluated on Ruditapes philippinarum exposed during 14 days to caffeine, ibuprofen, carbamazepine and novobiocin (0.1, 1, 5, 10, 15, and 50ugL(-1)). The battery included general stress (lysosomal membrane stability - LMS) analysed in the hemolymph, and biochemical biomarkers analysed in digestive gland tissues including: biomarkers of phase I (etoxyresorufin O deethylase - EROD, dibenzylfluorescein dealkylase - DBF), phase II (gluthathione S-transferase - GST), oxidative stress (gluthathione reductase - GR, gluthathione peroxidase - GPX, lipid peroxidation - LPO), neurotoxicity (acetylcholinesterase activity - AChE), and genotoxicity (DNA damage). Pharmaceuticals tested induced the sublethal responses (even at the environmental range 0.1ugL(-1)). At this low concentration; caffeine, ibuprofen and carbamazepine decreased the LMS significantly compared with controls (p<0.05). The four compounds induced significantly the detoxification metabolism and oxidative stress (p<0.05). Neurotoxicity was noticed in clams exposed to caffeine and carbamazepine (p<0.05). Ibuprofen, carbamazepine and novobiocin produced genotoxic effects (p<0.05). Results from this research validate the use of biomarkers when assessing the effects of pharmaceuticals within a marine environmental risk assessment framework, using as a laboratory bioassay model the species R. philippinarum. PMID- 26436473 TI - Acetaminophen for Fever in Critically Ill Patients with Suspected Infection. AB - BACKGROUND: Acetaminophen is a common therapy for fever in patients in the intensive care unit (ICU) who have probable infection, but its effects are unknown. METHODS: We randomly assigned 700 ICU patients with fever (body temperature, >=38 degrees C) and known or suspected infection to receive either 1 g of intravenous acetaminophen or placebo every 6 hours until ICU discharge, resolution of fever, cessation of antimicrobial therapy, or death. The primary outcome was ICU-free days (days alive and free from the need for intensive care) from randomization to day 28. RESULTS: The number of ICU-free days to day 28 did not differ significantly between the acetaminophen group and the placebo group: 23 days (interquartile range, 13 to 25) among patients assigned to acetaminophen and 22 days (interquartile range, 12 to 25) among patients assigned to placebo (Hodges-Lehmann estimate of absolute difference, 0 days; 96.2% confidence interval [CI], 0 to 1; P=0.07). A total of 55 of 345 patients in the acetaminophen group (15.9%) and 57 of 344 patients in the placebo group (16.6%) had died by day 90 (relative risk, 0.96; 95% CI, 0.66 to 1.39; P=0.84). CONCLUSIONS: Early administration of acetaminophen to treat fever due to probable infection did not affect the number of ICU-free days. (Funded by the Health Research Council of New Zealand and others; HEAT Australian New Zealand Clinical Trials Registry number, ACTRN12612000513819.). PMID- 26436478 TI - Defining the risk threshold for risk reducing salpingo-oophorectomy for ovarian cancer prevention in low risk postmenopausal women. AB - OBJECTIVE: To define risk thresholds for cost-effectiveness of risk-reducing salpingo-oophorectomy (RRSO) for ovarian cancer (OC) prevention in low/intermediate risk postmenopausal women. METHODS: A decision-analytic model compares lifetime costs-&-effects of offering 'RRSO' with 'no RRSO' to postmenopausal women >=50years for different lifetime OC-risk thresholds: 2%, 4%, 5%, 6%, 8% and 10%. Well established data from the literature are used to estimate total costs, effects in terms of Quality-Adjusted-Life-Years(QALYs), cancer incidence, incremental cost-effectiveness ratio(ICER) and impact. Costs are reported at 2012 prices; costs/outcomes discounted at 3.5%. Deterministic/probabilistic sensitivity analysis (PSA) evaluate model uncertainty. RESULTS: RRSO does not save QALYs and is not cost-effective at the 2% general population lifetime OC-risk. At 4% OC-risk RRSO saves QALYs but is not cost-effective. At risk thresholds >=5%, RRSO saves more life-years and QALYs and is highly cost-effective. The ICERs for OC-risk levels 5%, 6%, 8% and 10% are L15,247, L9958, L4584, and L1864 respectively. The gain in life-years from RRSO equates to 29.2, 40.1, 62.1 and 80.3days at risk thresholds of 5%, 6%, 8% and 10% respectively. The results are not sensitive to treatment costs of RRSO/OC/cardiovascular events but are sensitive to utility-scores for RRSO. On PSA, 67%, 80%, 84%, 91% and 94% of simulations at risk thresholds of 4%, 5%, 6%, 8% and 10% respectively are cost-effective for RRSO. CONCLUSION: RRSO is highly cost-effective in postmenopausal women aged >50 with >=5% lifetime OC-risk and increases life-expectancy by >=29.2days. The results could have significant clinical implications given the improvements in risk prediction and falling costs of genotyping. PMID- 26436479 TI - Bayesian cluster identification in single-molecule localization microscopy data. AB - Single-molecule localization-based super-resolution microscopy techniques such as photoactivated localization microscopy (PALM) and stochastic optical reconstruction microscopy (STORM) produce pointillist data sets of molecular coordinates. Although many algorithms exist for the identification and localization of molecules from raw image data, methods for analyzing the resulting point patterns for properties such as clustering have remained relatively under-studied. Here we present a model-based Bayesian approach to evaluate molecular cluster assignment proposals, generated in this study by analysis based on Ripley's K function. The method takes full account of the individual localization precisions calculated for each emitter. We validate the approach using simulated data, as well as experimental data on the clustering behavior of CD3zeta, a subunit of the CD3 T cell receptor complex, in resting and activated primary human T cells. PMID- 26436481 TI - Group-DIA: analyzing multiple data-independent acquisition mass spectrometry data files. PMID- 26436480 TI - A strategy for dissecting the architectures of native macromolecular assemblies. AB - It remains particularly problematic to define the structures of native macromolecular assemblies, which are often of low abundance. Here we present a strategy for isolating complexes at endogenous levels from GFP-tagged transgenic cell lines. Using cross-linking mass spectrometry, we extracted distance restraints that allowed us to model the complexes' molecular architectures. PMID- 26436484 TI - Mean platelet volume is elevated in exacerbated and convalescent COPD patients. AB - BACKGROUND: Mean platelet volume (MPV), reflecting the platelet production rate and stimulation, is an inflammatory marker for cardiovascular disease, inflammatory bowel disease, and rheumatoid arthritis. However, the associations between MPV and chronic obstructive pulmonary disease (COPD) are not in agreement. METHODS: Ninety participants with an exacerbation of COPD were investigated, and were reassessed when convalescent. Ninety controls were matched for age, gender, body mass index, smoking index, and medication use. Blood samples were collected for measurements of MPV and other laboratory data, and pulmonary function was also assessed. RESULTS: MPV is significantly increased in convalescent COPD patients compared with healthy controls, and further increased in COPD patients with an acute exacerbation. MPV was positively correlated with high-sensitivity C-reactive protein both in the exacerbation and convalescence periods of COPD, and negatively correlated with FEV1 % predicted and FEV1/FVC in the convalescent COPD patients. CONCLUSIONS: MPV may be regarded as a quick and reliable tool in the assessment of inflammatory response in the progression of COPD. PMID- 26436482 TI - Noncontact three-dimensional mapping of intracellular hydromechanical properties by Brillouin microscopy. AB - Current measurements of the biomechanical properties of cells require physical contact with cells or lack subcellular resolution. Here we developed a label-free microscopy technique based on Brillouin light scattering that is capable of measuring an intracellular longitudinal modulus with optical resolution. The 3D Brillouin maps we obtained of cells in 2D and 3D microenvironments revealed mechanical changes due to cytoskeletal modulation and cell-volume regulation. PMID- 26436483 TI - Apelin/APJ signaling in hypoxia-related diseases. AB - The regulatory peptide apelin is the endogenous ligand for the orphan G protein coupled receptor APJ. Apelin and APJ exist in a variety of tissues, with special status in the heart, lung and tumors. Consequently, the apelin/APJ system exerts a broad range of activities that affect multiple organ systems. Accumulating evidence indicates that the expressions of apelin and APJ are significantly augmented by hypoxia through the hypoxia-inducible factor-1 alpha (HIF-1alpha) signaling pathway. Increased apelin promotes cellular proliferation, migration and survival, therefore regulating angiogenesis. In addition, the pre administration of exogenous apelin is involved in the occurrence and development of hypoxia-induced pathological diseases. The purpose of this article is to review the properties of the apelin/APJ system, which is affected by hypoxic conditions, and the regulation of apelin/APJ signaling in hypoxia-associated disorders. Thus, the apelin/APJ system may be a potential therapeutic target in hypoxia-related diseases. PMID- 26436485 TI - An efficient and robust fatty acid profiling method for plasma metabolomic studies by gas chromatography-mass spectrometry. AB - BACKGROUND: Targeted metabolomic analysis of fatty acids has linked the dysregulation of fatty acids to many diseases. This study selected five frequently used fatty acid derivatization methods for comparison. METHODS: We compared the method precisions and derivatization efficiencies, the most economical and best performing method was subjected to method validation. Twenty four fatty acid standards were used to validate the method, which was later applied to the investigation of potential fatty acid markers of breast cancer. RESULTS: The acetyl chloride method was demonstrated to provide the best derivatization efficiency and lowest cost for plasma samples. The ionic liquid column successfully separated positional and geometric fatty acid isomers within 26 min under the optimized conditions. Intra-day and inter-day CVs for most of the fatty acids were <10%. Over 90% of the results showed recoveries within 85% 115%. The validated method was applied to investigate potential fatty acid markers of breast cancer. The fatty acid profiling results revealed that 3 fatty acids (C22:0, C24:0, C18:2n6) were significantly lower in both pre- and post menopausal breast cancer patients (P<0.05). CONCLUSIONS: We demonstrated that the proposed method is an accurate, efficient and economical method for plasma metabolomic studies of fatty acids. PMID- 26436487 TI - Can electronic stability control replace studded tyres? AB - Based on recent studies, this paper examines whether an increased use of electronic stability control can replace studded tyres. A re-analysis of a study that evaluated the effects on accidents of changes in the use of studded tyres in major cities in Norway is presented. It is found that if all cars have electronic stability control, the use of studded tyres can be reduced to about 15 percent before any increase in the number of accidents occurs. Even if studded tyres were eliminated entirely, any increase in the number of accidents is likely to be considerably smaller than it would have been if electronic stability control had never been invented. PMID- 26436488 TI - Estimating the human recovery costs of seriously injured road crash casualties. AB - Road crashes result in substantial trauma and costs to societies around the world. Robust costing methods are an important tool to estimate costs associated with road trauma, and are key inputs into policy development and cost-benefit analysis for road safety programmes and infrastructure projects. With an expanding focus on seriously injured road crash casualties, in addition to the long standing focus on fatalities, methods for costing seriously injured casualties are becoming increasingly important. Some road safety agencies are defining a seriously injured casualty as an individual that was admitted to hospital following a road crash, and as a result, hospital separation data provide substantial potential for estimating the costs associated with seriously injured road crash casualties. The aim of this study is to establish techniques for estimating the human recovery costs of (non-fatal) seriously injured road crash casualties directly from hospital separation data. An individuals' road crash-related hospitalisation record and their personal injury insurance claim were linked for road crashes that occurred in New South Wales, Australia. These records provided the means for estimating all of the costs to the casualty directly related to their recovery from their injuries. A total of 10,897 seriously injured road crash casualties were identified and four methods for estimating their recovery costs were examined, using either unit record or aggregated hospital separation data. The methods are shown to provide robust techniques for estimating the human recovery costs of seriously injured road crash casualties, that may prove useful for identifying, implementing and evaluating safety programmes intended to reduce the incidence of road crash related serious injuries. PMID- 26436489 TI - A quarter century of the Pacific Basin Consortium: looking back to move forward. AB - The Pacific Basin Consortium (PBC) was formed 25 years ago to address significant public health challenges to vulnerable populations imposed by environmental threats in the region, including areas surrounding the rim of and in the Pacific Ocean. Originally focused on toxic waste pollution, the PBC has broadened its efforts over the years, embracing a health focus and more of a balance between engineering and public health. This move was informed by the PBC's close relationship with the National Institutes of Health (NIH) National Institute of Environmental Health Sciences (NIEHS) Superfund Hazardous Substances Basic Research and Training Program (Superfund Research Program, or SRP), which played a dynamic role in the PBC from its early days. In addition, a sub-focus on children's environmental health emerged, which helped set the agenda for children's environmental health research in the region. Progress has also been made in reducing harm from some threats, particularly via extensive interventions to remediate arsenic in drinking water in Bangladesh, western Thailand, and Vietnam. However, many of the environmental health problems in the Pacific Basin region persist, including air pollution, inadequate safe drinking water, undernutrition, and a growing electronic waste problem. In the Pacific Basin and elsewhere, people with the lowest incomes often live in areas with the worst pollution. Although it is difficult to implement, dynamic strategic networking efforts are vital to understanding and correcting the inequities that persist in global environmental health. The PBC can help accomplish this by continuing and expanding its work to foster and enhance collaborations and communications between environmental health and engineering investigators and to integrate investigator-initiated research. As the PBC looks forward, there is also a need to exert increased effort to establish and maintain partnerships, to develop community-based primary-care and health services for vulnerable populations, as well as to connect with researchers in the eastern side of the Pacific basin and those in smaller island states. PMID- 26436490 TI - Robust decoding of selective auditory attention from MEG in a competing-speaker environment via state-space modeling. AB - The underlying mechanism of how the human brain solves the cocktail party problem is largely unknown. Recent neuroimaging studies, however, suggest salient temporal correlations between the auditory neural response and the attended auditory object. Using magnetoencephalography (MEG) recordings of the neural responses of human subjects, we propose a decoding approach for tracking the attentional state while subjects are selectively listening to one of the two speech streams embedded in a competing-speaker environment. We develop a biophysically-inspired state-space model to account for the modulation of the neural response with respect to the attentional state of the listener. The constructed decoder is based on a maximum a posteriori (MAP) estimate of the state parameters via the Expectation Maximization (EM) algorithm. Using only the envelope of the two speech streams as covariates, the proposed decoder enables us to track the attentional state of the listener with a temporal resolution of the order of seconds, together with statistical confidence intervals. We evaluate the performance of the proposed model using numerical simulations and experimentally measured evoked MEG responses from the human brain. Our analysis reveals considerable performance gains provided by the state-space model in terms of temporal resolution, computational complexity and decoding accuracy. PMID- 26436491 TI - The impact of transoral robotic surgery on the overall treatment of oropharyngeal cancer patients. AB - OBJECTIVES/HYPOTHESIS: To assess adjuvant therapy in patients undergoing surgical management of oropharyngeal squamous cell carcinoma (OPSCCA) with transoral robotic surgery (TORS) and neck dissection. STUDY DESIGN: A prospective, nonrandomized, consecutive patient series from two separate protocols in a tertiary academic medical center. METHODS: Patients undergoing treatment for OPSCCA were selected from a prospective protocol evaluating functional and oncologic outcomes following TORS with a comparator group of OPSCCA patients receiving definitive chemoradiotherapy (CRT) participating in a separate prospective protocol. RESULTS: Forty-two patients represented the TORS group and 38 the CRT group. Twenty (48%) of the TORS patients received surgery only, whereas nine (21%) underwent adjuvant radiotherapy and 13 (31%) adjuvant CRT. Adjuvant therapy patients had a higher overall T (P =.0007) and N (P < .0001) stage than the TORS-only group. Surgery resulted in stage changes in 18 (43%) patients, leading to alteration in therapy for nine (21%) patients. The 3-year overall survival (OS), disease-specific survival (DSS), and locoregional control was 74% versus 90% (P = .30), 94% versus 94% (P = .91), and 72% versus 91% (P = .19) for the TORS-alone versus TORS plus adjuvant therapy groups, respectively. Comparison with the CRT group revealed a survival benefit in the TORS group approaching significance, with a 3-year OS of 83% versus 57% (P = .06) and DSS of 94% versus 85% (P = .08), respectively. CONCLUSIONS: Primary surgical management of OPSCCA with TORS and neck dissection provides accurate staging information, which can lead to the appropriate selection of subsequent therapy. This approach does not compromise survival and warrants additional investigation. LEVEL OF EVIDENCE: 3b. PMID- 26436492 TI - Relationship between polymorphisms in the proline dehydrogenase gene and schizophrenia risk. AB - Previous studies have suggested that an association exists between the proline dehydrogenase gene (PRODH) and increased schizophrenia risk. We examined the prevalence of the PRODH 757C/T (Arg185Trp), 1766A/G (Gly521Arg), and 1852G/A (intronic mutation) polymorphisms in 175 patients with schizophrenia and 185 control subjects. All subjects were of Iranian ancestry. The PRODH 757TT, 1852AA, and 1766GG genotypes were associated with an increased risk of schizophrenia (odds ratio = 1.38, 95% confidence interval: 0.88-2.16, P = 0.001, P = 0.001, respectively). The activity alleles in the PRODH genotype combinations were associated with an increased risk of schizophrenia (haplotype analysis, TAG genotype P = 0.007). Our findings support a major role for the PRODH 757TT, 1766GG, and 1852AA genotypes alone and in combination for schizophrenia susceptibility. PMID- 26436493 TI - Risk factors associated with aortic remodeling in patients with Stanford type B aortic dissection after thoracic endovascular aortic repair. AB - To determine the risk factors associated with adverse aortic remodeling after thoracic endovascular aortic repair (TEVAR) in patients with Stanford type B aortic dissection, we performed a retrospective analysis of 54 patients between January 2009 and June 2012 at the First Affiliated Hospital of Soochow University. All patients underwent TEVAR of the descending thoracic aorta. Multiple-logistic regression analyses were performed to identify risk factors associated with aortic remodeling. True-lumen and false-lumen volumes were increased (P < 0.001) and decreased (P < 0.001) after surgery, respectively. Therefore, the remodeling index increased after surgery (1.04 +/- 0.6 to 2.06 +/- 1.12, P < 0.001). Remodeling index and true-lumen volume were higher in the favorable aortic remodeling group compared to the adverse aortic remodeling group (P < 0.001), while the false-lumen volume was lower in the favorable aortic remodeling group (P < 0.001). Multivariate analyses revealed a branch originating from the false lumen (OR = 39.9, P < 0.01) and multiple tears (OR = 27.4, P < 0.01) to be independent risk factors for adverse aortic remodeling. Therefore, a branch originating from the false lumen and multiple tears were determined to be independent risk factors for adverse aortic remodeling after TEVAR in patients with Stanford type B aortic dissection. PMID- 26436494 TI - Effect of p53 gene polymorphism on functions of prostate cancer cells. AB - Prostate cancer cells were transfected with plasmids [empty plasmids, wild-type pcDNA3.1-p53 (V/V), mutant type pcDNA3.1- p53 (G/G)] to analyze the effect of p53 gene polymorphisms on the proliferation, cycle, and apoptosis of prostatic cancer cells. Empty plasmids containing wild-type pcDNA3.1-p53 (V/V) and mutant type pcDNA3.1- p53 (G/G) were used to transfect PC3 and LNCaP cells, respectively. Cell proliferation was detected at 0, 24, 48, and 72 h using the MTT method. Cells were collected at 24 and 72 h. The distribution of cell cycles in various groups was detected using flow cytometry (propidium iodide staining method) and the apoptosis rate was detected using annexin V + propidium iodide double staining. Compared with the control group, wild-type pcDNA3.1-p53 (V/V) and mutant type pcDNA3.1-p53 (G/G) showed a significant inhibitory effect on cell proliferation (P < 0.05); the inhibitory effect of the mutant type was stronger than that of the wild-type. There was no significant difference between PC3 cells and LNCaP cells. After transfection with wild-type pcDNA3.1-p53 (V/V) and mutant type pcDNA3.1-p53 (G/G), PC3 and LNCaP cells were arrested in the G0/G1 stage. Transfection with pcDNA3.1-p53 (G/G) showed a more significant effect than transfection with pcDNA3.1-p53 (V/V). Both the wild-type pcDNA3.1-p53 (V/V) and mutant-type pcDNA3.1-p53 (G/G) led to an increased apoptosis rate of PC3 and LNCaP cells. The p53 gene polymorphism affects the proliferation, apoptosis, and cycle of prostate cancer cells and may serve as a reliable index for the diagnosis and treatment of prostate cancer. PMID- 26436495 TI - Prevalence of CCR5-Delta32 and CCR2-V64I polymorphisms in a mixed population from northeastern Brazil. AB - Chemokines are low-molecular weight proteins that play a key role in inflammatory processes. Genomic variations in chemokine receptors are associated with the susceptibility to various diseases. Polymorphisms in chemokine receptor type 5 (CCR5)-Delta32 and CCR2-V64I are related to human immunodeficiency virus infection resistance, which has led to genetic association studies for several other diseases. Given the heterogeneous distribution of these polymorphisms in different global populations and within Brazilian populations, we analyzed the prevalence of CCR5-Delta32 and CCR2-V64I polymorphisms in a mixed population from northeastern Brazil. The study included 223 individuals from the general population of the city of Parnaiba, Piaui, who had a mean age of 73 years. Of these individuals, 37.2% were men and 62.8% were women. Polymorphisms were analyzed using DNA extracted from peripheral blood leukocytes by using polymerase chain reaction alone (CCR5-Delta32) or accompanied by restriction endonuclease digestion (CCR2-V64I). In both cases, the genotypes were determined using 8% polyacrylamide gel electrophoresis and silver nitrate staining. The population conformed to Hardy-Weinberg equilibrium for both the loci studied. No individuals were homozygous for allele-Delta32, which was present in 1.8% of the population, whereas allele-64I was present in 13.9% of the participants studied; 74.9% were homozygous for the wild-type allele, while 22.4 and 2.7% were heterozygous and homozygous for the mutant allele, respectively. Additional studies are needed to investigate the relationship between these polymorphisms and disease etiopathogenesis in reference populations. PMID- 26436496 TI - Endo-beta-mannanase and beta-tubulin gene expression during the final phases of coffee seed maturation. AB - Coffee seeds begin to develop shortly after fertilization and can take 6 to 8 months to complete their formation, a period during which all the characteristics of the mature seed are determined, directly influencing physiological quality. However, little is known about the molecular mechanisms that act during coffee seed maturation. The objective of the current study was to analyze expression of the beta-tubulin (TUB) and endo-beta-mannanase (MAN) genes during different phases at the end of development and in different tissues of Coffea arabica seeds. The transcription levels of the TUB and MAN genes were quantified in a relative manner using qRT-PCR in whole seeds, and dissected into embryos and endosperms at different developmental stages. Greater expression of MAN was observed in whole seeds and in endosperms during the green stage, and in the embryo during the over-ripe stage. High TUB gene expression was observed in whole seeds during the green stage and, in the embryos, there were peaks in expression during the over-ripe stage. In endosperms, the peak of expression occurred in both the green stage and in the cherry stage. These results suggest participation of endo-beta-mannanase during the initial seed developmental stages, and in the stages of physiological maturity in the embryo tissues. TUB gene expression varied depending on the developmental stage and section of seed analyzed, indicating the participation of beta-tubulin during organogenesis and coffee seed maturation. PMID- 26436497 TI - Screening of crucial long non-coding RNAs in oral epithelial dysplasia by serial analysis of gene expression. AB - Oral epithelial dysplasia (OED) is a premalignant lesion of the oral mucosa. Considering the poor 5-year survival rate of oral cancer, further investigation is needed in order to determine the pathogenesis of OED. In the present study, serial analysis of gene expression (SAGE) data from patients with OED were compared to normal controls to identify differentially expressed genes (DEGs). SAGE data were obtained from the Gene Expression Omnibus, and included samples from patients with mild, moderate, or severe dysplasia. The DEGs were identified using the edgeR software package and functional-enrichment analysis was performed with the DAVID (https://david.ncifcrf.gov/) software program. The co-expression network was constructed using the CoExpress software and target genes of long non coding RNAs (lncRNAs) were predicted according to the proximity between the lncRNAs and mRNAs in the genome. A total of 517 DEGs were identified, including 409 mRNAs and 108 lncRNAs. Functional-enrichment analysis showed that mRNAs and lncRNAs involved in epithelial cell differentiation, epithelium development, and epidermal cell differentiation were significantly enriched in the DEGs. Thirty eight potential regulatory relationships were unveiled between lncRNAs and mRNAs, and two subnetworks were discovered by analyzing the topological properties of the co-expression network. In conclusion, we have identified key mRNAs and lncRNAs in OED, and these findings may aid in understanding the pathogenesis of OED and advance potential future treatments. PMID- 26436498 TI - Molecular identification of Fusarium species isolated from transgenic insect resistant cotton plants in Mexicali valley, Baja California. AB - Cotton production in the Mexicali valley is adversely affected by wilt and root rot disease associated with Fusarium species. In the present study, we sought to isolate and identify the Fusarium species in the rhizosphere of transgenic insect resistant cotton plants grown in the Mexicali valley. Our analyses isolated four native fungi from the rhizosphere of cotton plants, namely, T-ICA01, T-ICA03, T ICA04, and T-ICA08. These fungal isolates were categorized as belonging to Fusarium solani using their phenotypic characteristics and ITS region sequence data. Examination of the infection index showed that T-ICA03 and T-ICA04 caused systemic colonization (90%) of seeds followed by the occurrence of radicle and coleoptile decay. In contrast, T-ICA08 strain was less pathogenic against seed tissues (40%) in comparison to the other strains isolated. Our study showed that in transgenic insect-resistant cotton the disease "Fusarium wilt" is caused by the fungus, F. solani. Future studies are necessary to characterize the F. solani populations to determine whether phenological stages might influence the genetic diversity of the fungal populations present. PMID- 26436499 TI - Male-specific association of the APC rs383830 T allele with the risk of coronary heart disease. AB - APC is a tumor suppressor gene that is involved in the processes of cell migration and adhesion, transcriptional activation, and apoptosis. The goal of this study was to evaluate the contribution of the APC rs383830 polymorphism to coronary heart disease (CHD) in Han Chinese. A total of 783 patients with CHD and 737 controls were tested in the current association study. Although our study did not identify an association between the APC rs383830 polymorphism and CHD, a breakdown analysis by gender indicated there was a significant contribution of the rs383830 T allele to the risk of CHD in males (P = 0.046, odds ratio = 1.267, 95% confidence interval = 1.004-1.598). In conclusion, our study suggested a male specific association of the APC rs383830 polymorphism with CHD. PMID- 26436500 TI - Unraveling systematic inventory of Echinops (Asteraceae) with special reference to nrDNA ITS sequence-based molecular typing of Echinops abuzinadianus. AB - The present study explored the systematic inventory of Echinops L. (Asteraceae) of Saudi Arabia, with special reference to the molecular typing of Echinops abuzinadianus Chaudhary, an endemic species to Saudi Arabia, based on the internal transcribed spacer (ITS) sequences (ITS1-5.8S-ITS2) of nuclear ribosomal DNA. A sequence similarity search using BLAST and a phylogenetic analysis of the ITS sequence of E. abuzinadianus revealed a high level of sequence similarity with E. glaberrimus DC. (section Ritropsis). The novel primary sequence and the secondary structure of ITS2 of E. abuzinadianus could potentially be used for molecular genotyping. PMID- 26436501 TI - Effectiveness evaluation of dendritic cell immunotherapy for osteosarcoma on survival rate and in vitro immune response. AB - The aim of this study was to investigate the effects of dendritic cell (DC) therapy in osteosarcoma. Bone marrow DCs from Wistar (allograft group) and Sprague Dawley (SD) (homograft group) rats were electrically fused with the SD derived osteosarcoma cell line UMR106 to generate a DC-osteosarcoma fusion (DOF) tumor vaccine, which was co-incubated with SD T lymphocytes to stimulate T cell proliferation. CD8+ and CD4+ cell percentages were measured by flow cytometry; tumor-cytotoxic effects of cytotoxic T lymphocytes (CTLs) were measured by the MTT assay. Active immunotherapy was applied to SD osteosarcoma model rats via subcutaneous injection of the tumor vaccine. Significant potentiation of T lymphocyte proliferation was observed in both groups. In the homograft group, the CD8+/CD4+ ratio was elevated to 78.2 from 55.1% after stimulation (P < 0.05) whereas the CD4+ cell percentage was reduced from 61.3 to 21.2% (P < 0.05). Similarly, in the allograft group the CD8+ and CD4+ cell percentages significantly increased (33.8 to 69.6%) or decreased (61.3 to 28.1%) after stimulation, respectively (P < 0.05). The preferential homograft group response was not significant (P > 0.05). Induced UMR106- specific CTLs showed a significantly higher tumor-cytotoxic effect after stimulation (P < 0.05). After DOF active immunotherapy, tumor bodies displayed atrophy or disappearance, leading to higher survival times and rates (60 and 70% in the allograft and homograft groups) (P < 0.05). This study demonstrated that osteosarcoma immunotherapy using a DC-fused tumor vaccine can effectively stimulate T lymphocyte proliferation and induce the tumor-cytotoxic activity of CTLs. PMID- 26436502 TI - Thermotherapy-induced reduction in glioma invasiveness is mediated by tumor necrosis factor-alpha. AB - Thermotherapy has been proven to be effective for the treatment of various tumors, including glioma. We determined whether tumor necrosis factor-alpha (TNF alpha) is involved in the regulation of the biological processes of glioma development. Reverse transcription-polymerase chain reaction (RT-PCR) and immunocytochemistry were used to investigate the levels of TNF-alpha mRNA and heat shock factor-1 (HSF1) protein, respectively, in glioma cells. Radioimmunoassay was used to dynamically monitor the contents of TNF-alpha in the nutrient fluid of C6 cells after thermotherapy treatment. Crystal violet staining was used to determine glioma invasiveness. The most obvious increases in HSF1 protein and TNF-alpha mRNA in C6 cells were observed at 30 and 60 min after thermotherapy, respectively. In addition, the radioactivity of TNF-alpha in the culture fluid of the C6 cells reached a peak after 120 min of thermotherapy. In addition, glioma invasiveness decreased and the concentration of TNF-alpha reached a maximum after 120 min of thermotherapy. Our results show that the decrease in thermotherapy-mediated glioma invasiveness is due to the accelerated release of TNF-alpha, which could promote the release of HSF1 from neurospongioma cells. PMID- 26436503 TI - Identification of natural recombinants derived from PCV2a and PCV2b. AB - Porcine circovirus type 2 (PCV2) is considered to be the main pathogen in PC associated diseases, and significantly affects the global pig-producing industry. PCV2 continuously evolves by point mutations and genome recombinations. In the present study, we aimed to further identify recombinant PCV2 strains. We used polymerase chain reaction to detect PCV2 in the carcasses of pigs with suspected infections from different regions of Guangdong Province in China. DNA was extracted from samples with confirmed infection and full- genome amplification, sequencing, phylogenetic tree construction, gene recombination detection, and sequence alignment were performed in gene recombination analysis. Our results show that recombination occurred between the strains SHC (DQ104421) and ZhuJi2003 (AY579893). The recombination resulted in three recombinants: GD003 (KM503044), GD005 (KM487708), and GD008 (KM487709). Further analyses revealed that these novel recombinants appeared to result from recombination between the PCV2a and PCV2b strains, with crossover regions located in ORF2. This study was a comprehensive analysis that used several different methods, which demonstrated that a cluster of PCV2 strains resulted from the same type of inter-genotypic recombination pattern, with a breakpoint in the structural protein coding region. The results of our study provide both information on the recombination mechanism and disease pathogenesis and useful data for the prevention of PCV2 in the swine industry. PMID- 26436504 TI - Prediction of protein-protein interactions using chaos game representation and wavelet transform via the random forest algorithm. AB - Studying the network of protein-protein interactions (PPIs) will provide valuable insights into the inner workings of cells. It is vitally important to develop an automated, high-throughput tool that efficiently predicts protein-protein interactions. This study proposes a new model for PPI prediction based on the concept of chaos game representation and the wavelet transform, which means that a considerable amount of sequence-order effects can be incorporated into a set of discrete numbers. The advantage of using chaos game representation and the wavelet transform to formulate the protein sequence is that it can more effectively reflect its overall sequence-order characteristics than the conventional correlation factors. Using such a formulation frame to represent the protein sequences means that the random forest algorithm can be used to conduct the prediction. The results for a large-scale independent test dataset show that the proposed model can achieve an excellent performance with an accuracy value of about 0.86 and a geometry mean value of about 0.85. The model is therefore a useful supplementary tool for PPI predictions. The predictor used in this article is freely available at http://www.jci-bioinfo.cn/PPI. PMID- 26436505 TI - DNA genetic artificial fish swarm constant modulus blind equalization algorithm and its application in medical image processing. AB - This study proposes use of the DNA genetic artificial fish swarm constant modulus blind equalization algorithm (DNA-G-AFS-CMBEA) to overcome the local convergence of the CMBEA. In this proposed algorithm, after the fusion of the fast convergence of the AFS algorithm and the global search capability of the DNA-G algorithm to drastically optimize the position vector of the artificial fish, the global optimal position vector is obtained and used as the initial optimal weight vector of the CMBEA. The result of application of this improved method in medical image processing demonstrates that the proposed algorithm outperforms the CMBEA and the AFS-CMBEA in removing the noise in a medical image and improving the peak signal to noise ratio. PMID- 26436506 TI - Expression of claudin-1 and its relationship with lymphatic microvessel generation in hypopharyngeal squamous cell carcinoma. AB - We investigated the relationship between claudin-1 and micro-lymphatic vessel density (MLVD) by detecting claudin-1 and protein D2-40 expression in cancer tissue specimens obtained from 97 patients with hypopharyngeal squamous cell carcinoma (HSCC). We also explored the correlation between the expression of these proteins and clinical tumor stage, pathological grading, and clinical prognosis in the patients. Moreover, we studied the mechanism of lymph node metastasis in HSCC, thereby providing information for treating HSCC and inhibiting lymph node metastasis. We detected levels of claudin-1 and protein D2 40 expression in cancer tissue from 97 patients with HSCC and para-tumor tissue from 90 patients by immunohistochemistry; we analyzed the correlation between markers and clinicopathological features by using the Pearson chi-square test and conducted survival analysis by the log-rank test. Claudin-1 expression was high in HSCC and was related to tumor differentiation and lymph node metastasis; Kaplan-Meier analysis showed that claudin-1 expression was related to patient survival rate (P = 0.012). There was a significant relationship between MLVD in the tissues adjacent to the carcinoma and the indices of histopathological grade, clinical stage, and lymph node metastasis. There was also a positive correlation between claudin-1 expression and MLVD. High expression of claudin-1 might induce the generation of tumor lymphatic vessels, which increases metastasis in the lymph node. Because claudin-1 is related to patient survival rate, it may be useful as a monitoring index for postoperative HSCC and might be a new target for treating the disease. PMID- 26436507 TI - Identification of genes involved in spontaneous leaf color variation in Pseudosasa japonica. AB - Spontaneous leaf color variation in bamboo provides the opportunity to study the mechanisms of leaf color formation and the breeding of ornamental bamboos. Despite the fact that many genes are known to be involved in leaf color variation in model plants, molecular mechanisms governing natural leaf color variation in bamboo have remained obscure. This study aimed to identify the genes responsible for the occurrence of such phenomena in bamboo using the suppression subtractive hybridization (SSH) method between green and albino leaves in Pseudosasa japonica f. A total of 1062 and 1004 differentially expressed transcripts were obtained from the forward and reverse SSH libraries, respectively. Subsequently, 59 differentially expressed unigenes with potential roles in leaf color formation, predicted via computational analysis of their functional relevance, were selected for further analysis using qPCR. Ten genes, involved in photosynthesis, plastid development, and cation signal transduction, showed 2-fold changes in expression levels between green and albino leaves. Further expression pattern analyses of these genes at three developmental stages revealed much lower expression abundance of Lhca1-encoded chlorophyll a/b binding protein in the albino leaves than in the green leaves. Our results suggest that, together with the concatenated negative pressure for subsequent photosynthetic processes, the albino phenotype is at least partly attributable to chloroplast inner membrane damage or to the impairment of photosynthetic pigment accumulation, which results from low Lhca1 expression. PMID- 26436508 TI - High yield of functional metagenomic library from mangroves constructed in fosmid vector. AB - In the present study, metagenomic technique and fosmid vectors were used to construct a library of clones for exploring the biotechnological potential of mangrove soils by isolation of functional genes encoding hydrolytic enzymes. The library was built with genomic DNA from the soil samples of mangrove sediments and the functional screening of 1824 clones (~64 Mbp) was performed to detect the hydrolytic activity specific for cellulases, amylases (at acidic, neutral and basic pH), lipases/esterases, proteases, and nitrilases. Significant numbers of clones, positive for the tested enzyme activities were obtained. Our results indicate the importance and biotechnological potential of mangrove soils especially when compared to those obtained using other soil metagenomic libraries. PMID- 26436509 TI - Genome-wide identification of copy number variations in Holstein cattle from Baja California, Mexico, using high-density SNP genotyping arrays. AB - Copy number variations (CNVs) are an important source of genomic structural variation, and can be used as markers to investigate phenotypic and economic traits. CNVs also have functional effects on gene expression and can contribute to disease susceptibility in mammals. Currently, single nucleotide polymorphism genotyping arrays (SNP chips) are the technology of choice for identifying CNV variations. Microarray technologies have recently been used to study the bovine genome. The objective of the present study was to develop CNVs in Holstein cows from the Northwest of Mexico using the Affymetrix Axiom Genome-Wide BOS 1 Array, which assays 648,315 SNPs and provides a wide coverage for genome-wide studies. We applied the two most widely used algorithms for the discovery of CNVs (PennCNV and QuantiSNP) and found 56 CNV regions (CNVRs) representing 0.33% of the bovine genome (8.46 Mb). These CNVRs ranged from 1.5 to 970.8 kb with an average length of 151 kb. They involved 103 genes and showed a 28% overlap with CNVRs already reported. Of the 56 CNVRs found, 20 were novel. In this study we present the first genomic analysis of CNVs in Mexican cattle using high-density SNP data. Our results provide a new reference basis for future genomic variation and association studies between CNVs and phenotypes, especially in Mexican cattle. PMID- 26436510 TI - Significance of Ebp1 and p53 protein expression in cervical cancer. AB - In this study, the ErbB3-binding protein (Ebp1) and p53 protein expression in cervical cancer tissues, and its significance in the prognosis of the disease was investigated. Ebp1 and p53 protein expression was detected by immunohistochemical analysis in cervical cancer tissues (N = 60) and normal tissues adjacent to the cancer tissues (N = 60). The rates of positive Ebp1 and p53 protein expression were 35.0 and 60.0%, respectively. Ebp1 and p53 were overexpressed in cervical cancer tissues, compared to normal tissues (P < 0.05). Ebp1 and p53 protein expression was not correlated with age, tumor size, or family tumor history (P > 0.05). However, high levels of expression of Ebp1 and p53 were positively correlated with the TNM stage and lymphatic metastasis in cervical cancer patients (P < 0.05). The combined determination of Ebp1 and p53 expression levels in cervical cancer patients could support the effective prediction of metastatic potential and patient prognosis. PMID- 26436511 TI - Short Communication: Elucidation of bacterial community structure on thin-spined porcupine (Chaetomys subspinosus) spines by denaturing. AB - Thin-spined porcupines (Chaetomys subspinosus) are threatened with extinction and are categorized as vulnerable. This is because of alteration to and loss of their habitat and possible hunting activities in their distribution area. Their spines constitute one of their defense mechanisms, which can be fomites for pathogens to humans. However, little is known about such pathogens. The present study aimed to detect bacteria on spines of C. subspinosus, from the Una Biological Reserve, South of Bahia, northeastern Brazil, by analyzing metagenomic DNA, isolating bacterial culture, using the denaturing gradient gel electrophoresis (DGGE) technique, and sequencing. Six anatomical points were selected for withdrawing spine samples from an individual C. subspinosus. At all sample points, bacteria were detected by bacteriological culture and/or DGGE and sequencing of excised bands. When all samples were combined, standard PCR-DGGE analysis of bacteria present in the spines identified 15 distinct bands, thereby revealing a distinct bacterial community. The main pathogens identified through sequencing were Bacillus cereus, B. thuringiensis, B. anthracis, and B. pumilus. The present study demonstrated the isolation and identification of non-pathogenic and pathogenic bacteria on the spines of C. subspinosus. PMID- 26436512 TI - Iron-Catalyzed Decarboxylation of Trifluoroacetate and Its Application to the Synthesis of Trifluoromethyl Thioethers. AB - Nucleophilic CF3 has been generated by decarboxylation of potassium trifluoroacetate, arguably the most easy-to-handle, inexpensive, and sustainable source of trifluoromethyl groups. Simple iron(II) chloride catalyzes the decarboxylation as well as a subsequent trifluoromethylation of organothiocyanates, resulting in a straightforward synthesis of trifluoromethyl thioethers. The KCN byproduct is absorbed by iron(II) with formation of nontoxic potassium hexacyanoferrate. An analogous trifluoromethylation of aldehydes with trifluoroacetate underlines the synthetic potential of such iron-catalyzed decarboxylative trifluoromethylations. PMID- 26436513 TI - Concentrations, Trends, and Air-Water Exchange of PAHs and PBDEs Derived from Passive Samplers in Lake Superior in 2011. AB - Polycyclic aromatic hydrocarbons (PAHs) and polybrominated diphenylethers (PBDEs) are both currently released into the environment from anthropogenic activity. Both are hence primarily associated with populated or industrial areas, although wildfires can be an important source of PAHs, as well. Polyethylene passive samplers (PEs) were simultaneously deployed in surface water and near surface atmosphere to determine spatial trends and air-water gaseous exchange of 21 PAHs and 11 PBDEs at 19 sites across Lake Superior in 2011. Surface water and atmospheric PAH concentrations were greatest at urban sites (up to 65 ng L(-1) and 140 ng m(-3), respectively, averaged from June to October). Near populated regions, PAHs displayed net air-to-water deposition, but were near equilibrium off-shore. Retene, probably depositing following major wildfires in the region, dominated dissolved PAH concentrations at most Lake Superior sites. Atmospheric and dissolved PBDEs were greatest near urban and populated sites (up to 6.8 pg L( 1) and 15 pg m(-3), respectively, averaged from June to October), dominated by BDE-47. At most coastal sites, there was net gaseous deposition of BDE-47, with less brominated congeners contributing to Sault Ste. Marie and eastern open lake fluxes. Conversely, the central open lake and Eagle Harbor sites generally displayed volatilization of PBDEs into the atmosphere, mainly BDE-47. PMID- 26436516 TI - Metal-ligand cooperation. AB - Metal-ligand cooperation (MLC) has become an important concept in catalysis by transition metal complexes both in synthetic and biological systems. MLC implies that both the metal and the ligand are directly involved in bond activation processes, by contrast to "classical" transition metal catalysis where the ligand (e.g. phosphine) acts as a spectator, while all key transformations occur at the metal center. In this Review, we will discuss examples of MLC in which 1) both the metal and the ligand are chemically modified during bond activation and 2) bond activation results in immediate changes in the 1st coordination sphere involving the cooperating ligand, even if the reactive center at the ligand is not directly bound to the metal (e.g. via tautomerization). The role of MLC in enabling effective catalysis as well as in catalyst deactivation reactions will be discussed. PMID- 26436518 TI - Measuring Carbapenem-Resistant Enterobacteriaceae in the United States: A Critical Step for Control. PMID- 26436519 TI - Adjusting for Confounding in Early Postlaunch Settings: Going Beyond Logistic Regression Models. AB - BACKGROUND: Postlaunch data on medical treatments can be analyzed to explore adverse events or relative effectiveness in real-life settings. These analyses are often complicated by the number of potential confounders and the possibility of model misspecification. METHODS: We conducted a simulation study to compare the performance of logistic regression, propensity score, disease risk score, and stabilized inverse probability weighting methods to adjust for confounding. Model misspecification was induced in the independent derivation dataset. We evaluated performance using relative bias confidence interval coverage of the true effect, among other metrics. RESULTS: At low events per coefficient (1.0 and 0.5), the logistic regression estimates had a large relative bias (greater than -100%). Bias of the disease risk score estimates was at most 13.48% and 18.83%. For the propensity score model, this was 8.74% and >100%, respectively. At events per coefficient of 1.0 and 0.5, inverse probability weighting frequently failed or reduced to a crude regression, resulting in biases of -8.49% and 24.55%. Coverage of logistic regression estimates became less than the nominal level at events per coefficient <=5. For the disease risk score, inverse probability weighting, and propensity score, coverage became less than nominal at events per coefficient <=2.5, <=1.0, and <=1.0, respectively. Bias of misspecified disease risk score models was 16.55%. CONCLUSION: In settings with low events/exposed subjects per coefficient, disease risk score methods can be useful alternatives to logistic regression models, especially when propensity score models cannot be used. Despite better performance of disease risk score methods than logistic regression and propensity score models in small events per coefficient settings, bias, and coverage still deviated from nominal. PMID- 26436521 TI - On-line preconcentration strategy for the simultaneous quantification of three local anesthetics in human urine using CZE. AB - The simultaneous determination of usually employed anesthetics (procaine, lidocaine, and bupivacaine) has been developed and validated using CE with ultraviolet detection at 212 nm. The separation of these three drugs has been achieved in less than 7 min, using a temperature of 25oC and 25 kV, with a 150 mM citrate buffer (pH 2.5) as BGE. Field-amplified sample injection (FASI) has been used for on-line sample preconcentration. Ultrapure water and ACN 50/50 (v/v) mixture gave the greatest enhancement factor when it was employed as an injection solvent. Injection voltage and time were optimized, being 13 kV and 13 s, the optimum values, respectively. To avoid the possible irreproducibility associated with the electrokinetic injection, an internal standard such as tetracaine, was employed. The instrumental detection limits (LOD S/N = 3) for the compounds ranged between 2.6 and 7.0 MUg L(-1) and the quantitation limits (LOQ S/N = 10) between 37.8 and 55.9 MUg L(-1) . The detection limits obtained in real human urine samples ranged between 55.2 and 83.6 MUg L(-1) and the quantitation limits between 196.0 and 276.0 MUg L(-1) . The proposed method has demonstrated its applicability to the analysis of these local anesthetics in urine samples without any pretreatment, allowing the rapid determination of these target analytes. PMID- 26436520 TI - The syndemic of HIV, HIV-related risk and multiple co-morbidities among women who use drugs in Malaysia: Important targets for intervention. AB - BACKGROUND: Substance use and HIV are syndemic public health problems in Malaysia. Harm reduction efforts to reduce HIV transmission have primarily focused on men with substance use disorders. OBJECTIVES: To explore HIV risk behaviors, substance use, and social factors associated with poor health outcomes among women who use drugs in Malaysia. METHODS: A cross-sectional survey of 103 drug-using women in Kuala Lumpur, Malaysia were recruited to assess their medical, psychiatric and social comorbidity as well as their engagement in nationally recommended HIV testing and monitoring activities. RESULTS: One-third reported having ever injected drugs, with most (68.2%) having recently shared injection paraphernalia. Sex work (44.7%) and infrequent condom use (42.4%) were common as was underlying psychiatric illness and physical and sexual violence during childhood and adulthood. Most women (62.1%) had unstable living situations and suffered from an unmet need for social support and health services. HIV prevalence was high (20%) with only two thirds of women eligible for antiretroviral therapy having received it. Suboptimal HIV testing and/or monitoring was positively associated with interpersonal violence (AOR 2.73; 95% CI 1.04-7.14) and negatively associated with drug injection (AOR 0.28; 95% CI 0.10-0.77). CONCLUSIONS/IMPORTANCE: Women who use drugs in Malaysia demonstrate considerable medical, psychiatric and social co-morbidity, which negatively contributes to optimal and crucial engagement in HIV treatment-as-prevention strategies. Mental health and social support may be key targets for future public health interventions aimed at drug-using women in Malaysia. PMID- 26436522 TI - Keratinocytes and neutrophils are important sources of proinflammatory molecules in hidradenitis suppurativa. AB - BACKGROUND: The pathogenesis of the chronic inflammatory skin disease hidradenitis suppurativa (HS, also known as acne inversa) involves epidermal alterations such as psoriasiform epidermal hyperplasia and keratin plugging. Keratinocytes are an important source of proinflammatory molecules in inflammatory skin diseases and can be stimulated by interleukin (IL)-17(+) cells. OBJECTIVES: To explore the possible role of the epithelium in the pathogenesis of HS. METHODS: We performed immunohistochemical stainings and Western blot experiments to investigate the localization and expression of inflammation associated molecules, including the cytokine IL-17, components of the inflammasome including caspase-1, and the endogenous danger-associated molecular pattern molecules S100A8 and S100A9 (calprotectin). To examine a possible effect of upregulated proinflammatory cytokines on the inflammatory infiltrate, differences in the cellular composition of perifollicular and deep dermal infiltrates were analysed. RESULTS: The number of IL-17(+) cells is increased in lesional and perilesional HS skin. The epidermis produces proinflammatory molecules and shows an upregulated expression of components of the NLRP3 inflammasome, activated caspase-1 and expression of S100A8/S100A9. Additionally, the course of the inflammatory process in HS involves influx of innate immune cells, particularly IL-17-expressing neutrophils. CONCLUSIONS: IL-17-producing cells are present in lesional and perilesional HS skin and may contribute to the initiation of inflammatory processes. Furthermore, the epidermis is a source of proinflammatory cytokines, shows inflammasome activation and expresses S100A8/S100A9, thereby possibly contributing to the propagation of inflammation. A massive influx of IL-17-expressing neutrophils is observed in the deep infiltrate. PMID- 26436524 TI - Phase evolution of the two-dimensional Kondo lattice model near half-filling. AB - Within a mean-field approximation, the ground state and finite temperature phase diagrams of the two-dimensional Kondo lattice model have been carefully studied as functions of the Kondo coupling J and the conduction electron concentration [Formula: see text]. In addition to the conventional hybridization between local moments and itinerant electrons, a staggered hybridization is proposed to characterize the interplay between the antiferromagnetism and the Kondo screening effect. As a result, a heavy fermion antiferromagnetic phase is obtained and separated from the pure antiferromagnetic ordered phase by a first-order Lifshitz phase transition, while a continuous phase transition exists between the heavy fermion antiferromagnetic phase and the Kondo paramagnetic phase. We have developed an efficient theory to calculate these phase boundaries. As [Formula: see text] decreases from the half-filling, the region of the heavy fermion antiferromagnetic phase shrinks and finally disappears at a critical point [Formula: see text], leaving a first-order critical line between the pure antiferromagnetic phase and the Kondo paramagnetic phase for [Formula: see text]. At half-filling limit, a finite temperature phase diagram is also determined on the Kondo coupling and temperature (J-T) plane. Notably, as the temperature is increased, the region of the heavy fermion antiferromagnetic phase is reduced continuously, and finally converges to a single point, together with the pure antiferromagnetic phase and the Kondo paramagnetic phase. The phase diagrams with such triple point may account for the observed phase transitions in related heavy fermion materials. PMID- 26436523 TI - Risk of Aortic Dissection and Aortic Aneurysm in Patients Taking Oral Fluoroquinolone. AB - IMPORTANCE: Fluoroquinolones have been associated with collagen degradation, raising safety concerns related to more serious collagen disorders with use of these antibiotics, including aortic aneurysm and dissection. OBJECTIVE: To examine the relationship between fluoroquinolone therapy and the risk of developing aortic aneurysm and dissection. DESIGN, SETTING, AND PARTICIPANTS: We conducted a nested case-control analysis of 1477 case patients and 147 700 matched control cases from Taiwan's National Health Insurance Research Database (NHIRD) from among 1 million individuals longitudinally observed from January 2000 through December 2011. Cases patients were defined as those hospitalized for aortic aneurysm or dissection. One hundred control patients were matched for each case based on age and sex. EXPOSURES: Current, past, or any prior-year use of fluoroquinolone. Current use was defined as a filled fluoroquinolone prescription within 60 days of the aortic aneurysm or dissection; past use refers to a filled fluoroquinolone prescription between 61 and 365 days prior to the aortic aneurysm; and any prior-year use refers to having a fluoroquinolone prescription filled for 3 or more days any time during the 1-year period before the aortic aneurysm or dissection. MAIN OUTCOMES AND MEASURES: Risk of developing aortic aneurysm or dissection. RESULTS: A total of 1477 individuals who experienced aortic aneurysm or dissection were matched to 147 700 controls. After propensity score adjustment, current use of fluoroquinolones was found to be associated with increased risk for aortic aneurysm or dissection (rate ratio [RR], 2.43; 95% CI, 1.83-3.22), as was past use, although this risk was attenuated (RR, 1.48; 95% CI, 1.18-1.86). Sensitivity analysis focusing on aortic aneurysm and dissection requiring surgery also demonstrated an increased risk associated with current fluoroquinolone use, but the increase was not statistically significant (propensity score-adjusted RR, 2.15; 95% CI, 0.97-4.60). CONCLUSIONS AND RELEVANCE: Use of fluoroquinolones was associated with an increased risk of aortic aneurysm and dissection. While these were rare events, physicians should be aware of this possible drug safety risk associated with fluoroquinolone therapy. PMID- 26436525 TI - Social influence protects collective decision making from equality bias. AB - A basic tenet of research on wisdom of the crowds-and key assumption of Condercet's (1785) Jury Theorem-is the independence of voters' opinions before votes are aggregated. However, we often look for others' opinions before casting our vote. Such social influence can push groups toward herding, leading to "madness of the crowds." To investigate the role of social influence in joint decision making, in Experiment 1 we had dyads of participants perform a visual oddball search task together. In the Independent (IND) condition participants initially made a private decision. If they disagreed, discussion and collective decision ensued. In the Influence (INF) condition no private decisions were made and collective decision was immediately negotiated. Dyads that did not accrue collective benefit under the IND condition improved with added social influence under the INF condition. In Experiment 2, covertly, we added noise to 1 of the dyad members' visual search display. The resulting increased heterogeneity in dyad members' performances impaired the dyadic performance under the IND condition (Bahrami et al., 2010). Importantly, dyadic performance improved with social influence under the INF condition, replicating results in Experiment 1. Further analyses revealed that under the IND condition, dyads exercised equality bias (Mahmoodi et al., 2015) by granting undue credit to the less-reliable partner. Under the INF condition, however, the more-reliable partner (correctly) dominated the joint decisions. Although social influence may impede collective success under ideal conditions, our results demonstrate how it can help the group members overcome factors such as equality bias, which could potentially lead to catastrophic failure. (PsycINFO Database Record PMID- 26436526 TI - Perceived heaviness in the context of Newton's Second Law: Combined effects of muscle activity and lifting kinematics. AB - Researchers generally agree that perceived heaviness is based on the actions associated with unsupported holding. Psychophysical research has supported this idea, as has psychophysiological research connecting muscle activity to the perceptions of heaviness and effort. However, the role of muscle activity in the context of the resulting motions has not been investigated. In the present study, perceptions of heaviness were recorded along with the electromyogram (EMG) of the lifting muscle and peak acceleration of the lift. Consistent with predictions derived from Newton's Second Law of motion (Force=Mass * Acceleration), normal and illusory perceptions of heaviness were a function of the ratio of muscle activity to lifting acceleration. These results identify a psychophysiological mechanism for heaviness perception based on the forces and motions associated with unsupported holding. PMID- 26436527 TI - Task-irrelevant memories rapidly gain attentional control with learning. AB - Although many of our perceptual biases stem from long-term, repeated exposure, current theories of visual search assume a central role for visual working memory (VWM) in guiding attention to target information. Crucially, whether a VWM representation guides attention depends on the relative priority that the memory has within VWM. Here, in a combined visual search/VWM task, we used attentional guidance by irrelevant memories to measure how long a target representation remains prioritized in VWM when observers repeatedly search for the same target. Irrelevant memories started guiding attention already when the target was repeated once, indicating that the target representation rapidly lost priority within VWM as it moved to long-term memory. By showing that training can lead to interference from irrelevant memories, the findings resolve a long-standing paradox on why VWM appears central to, yet at the same time not sufficient nor necessary for attentional guidance. PMID- 26436528 TI - High-Performance Small Molecule/Polymer Ternary Organic Solar Cells Based on a Layer-By-Layer Process. AB - The layer-by-layer process method, which had been used to fabricate a bilayer or bulk heterojunction organic solar cell, was developed to fabricate highly efficient ternary blend solar cells in which small molecules and polymers act as two donors. The active layer could be formed by incorporating the small molecules into the polymer based active layer via a layer-by-layer method: the small molecules were first coated on the surface of poly(3,4-ethylenedioxy thiophene):poly(styrenesulfonate) ( PEDOT: PSS), and then the mixed solution of polymer and fullerene derivative was spin-coated on top of a small molecule layer. In this method, the small molecules in crystalline state were effectively mixed in the active layer. Without further optimization of the morphology of the ternary blend, a high power conversion efficiency (PCE) of 8.76% was obtained with large short-circuit current density (Jsc) (17.24 mA cm(-2)) and fill factor (FF) (0.696). The high PCE resulted from not only enhanced light harvesting but also more balanced charge transport by incorporating small molecules. PMID- 26436529 TI - Surface/Interface Effects on High-Performance Thin-Film All-Solid-State Li-Ion Batteries. AB - The further development of all-solid-state batteries is still limited by the understanding/engineering of the interfaces formed upon cycling. Here, we correlate the morphological, chemical, and electrical changes of the surface of thin-film devices with Al negative electrodes. The stable Al-Li-O alloy formed at the stress-free surface of the electrode causes rapid capacity fade, from 48.0 to 41.5 MUAh/cm(2) in two cycles. Surprisingly, the addition of a Cu capping layer is insufficient to prevent the device degradation. Nevertheless, Si electrodes present extremely stable cycling, maintaining >92% of its capacity after 100 cycles, with average Coulombic efficiency of 98%. PMID- 26436530 TI - Eomesodermin-expressing T-helper cells are essential for chronic neuroinflammation. AB - Development of acute experimental autoimmune encephalomyelitis (EAE) depends on Th17 cells expressing the nuclear factor NR4A2. However, in mice lacking NR4A2 in T cells, a late-onset disease is still inducible, despite a great reduction in acute inflammation. We here reveal that development of this late onset disease depends on cytotoxic T-cell-like CD4(+) T cells expressing the T-box transcription factor Eomesodermin (Eomes). T-cell-specific deletion of the Eomes gene remarkably ameliorates the late-onset EAE. Strikingly, similar Eomes(+) CD4(+) T cells are increased in the peripheral blood and cerebrospinal fluid from patients in a progressive state of multiple sclerosis. Collective data indicate an involvement of granzyme B and protease-activated receptor-1 in the neuroinflammation mediated by Eomes(+) CD4(+) T cells. PMID- 26436531 TI - Effect of Inducible Co-Stimulatory Molecule siRNA in Cerebral Infarction Rat Models. AB - BACKGROUND: T cell-induced inflammatory response and related cytokine secretion at the injury site may participate in the pathogenesis of cerebral infarction. Recent studies established inducible co-stimulatory molecule (ICOS) as a novel T cell-related factor for its activation and functions. We thus investigate the role of ICOS in cerebral infarction. MATERIAL AND METHODS: The siRNA of ICOS was first used to suppress the gene expression in cultured lymphocytes. An in vivo study was then performed by intravenous application of ICOS siRNA in cerebral infarction rats. Survival rates, neurological scores, serum tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and IL-17 levels were observed. RESULTS: The expression of ICOS in cultured lymphocytes was significantly suppressed by siRNA. In the in vivo study, the application of siRNA effectively lowered mortality rates of rats, in addition to the improvement of neurological behaviors and amelioration of cerebral tissue damage. Serum levels of TNF-alpha, IL-1 and IL-17 were all significantly suppressed after siRNA injection. CONCLUSIONS: ICOS siRNA can protect brain tissues from ischemia injuries after cerebral infarction, improve limb movement and coordination, lower the mortality rate of rats, and inhibit T cell-induced cytokines. These results collectively suggest the potential treatment efficacy of ICOS siRNA against cerebral infarction. PMID- 26436533 TI - Adaptive truncated weighting for improving marginal structural model estimation of treatment effects informally censored by subsequent therapy. AB - Randomized clinical trials are designed to estimate the direct effect of a treatment by randomly assigning patients to receive either treatment or control. However, in some trials, patients who discontinued their initial randomized treatment are allowed to switch to another treatment. Therefore, the direct treatment effect of interest may be confounded by subsequent treatment. Moreover, the decision on whether to initiate a second-line treatment is typically made based on time-dependent factors that may be affected by prior treatment history. Due to these time-dependent confounders, traditional time-dependent Cox models may produce biased estimators of the direct treatment effect. Marginal structural models (MSMs) have been applied to estimate causal treatment effects even in the presence of time-dependent confounders. However, the occurrence of extremely large weights can inflate the variance of the MSM estimators. In this article, we proposed a new method for estimating weights in MSMs by adaptively truncating the longitudinal inverse probabilities. This method provides balance in the bias variance trade-off when large weights are inevitable, without the ad hoc removal of selected observations. We conducted simulation studies to explore the performance of different methods by comparing bias, standard deviation, confidence interval coverage rates, and mean square error under various scenarios. We also applied these methods to a randomized, open-label, phase III study of patients with nonsquamous non-small cell lung cancer. PMID- 26436532 TI - Systematic analysis of somatic mutations impacting gene expression in 12 tumour types. AB - We present a novel hierarchical Bayes statistical model, xseq, to systematically quantify the impact of somatic mutations on expression profiles. We establish the theoretical framework and robust inference characteristics of the method using computational benchmarking. We then use xseq to analyse thousands of tumour data sets available through The Cancer Genome Atlas, to systematically quantify somatic mutations impacting expression profiles. We identify 30 novel cis-effect tumour suppressor gene candidates, enriched in loss-of-function mutations and biallelic inactivation. Analysis of trans-effects of mutations and copy number alterations with xseq identifies mutations in 150 genes impacting expression networks, with 89 novel predictions. We reveal two important novel characteristics of mutation impact on expression: (1) patients harbouring known driver mutations exhibit different downstream gene expression consequences; (2) expression patterns for some mutations are stable across tumour types. These results have critical implications for identification and interpretation of mutations with consequent impact on transcription in cancer. PMID- 26436535 TI - In Search of Lost Springs: A Protocol for Locating Active and Inactive Springs. AB - Groundwater springs are significant landscape features for humans and the biota that occupies their habitat. Many springs become inactive where groundwater exploitation by humans has lowered the water table or artesian pressure. In order to assess this impact, it is important to identify and locate active, and with more difficulty, inactive springs. Using a variety of archival, environmental and field-based data, this study presents a protocol for the determination of the location and status of springs across the Great Artesian Basin of Australia. This protocol underpins a database of springs, which is not only important for the assessment of spring ecosystems, but also contributes to understand groundwater extraction impacts and hydrogeological processes. The database indicates that 30.0% of discharge (artesian) springs in the Great Artesian Basin are entirely inactive and another 11.8% are partially inactive. For the outcrop (gravity) springs of the Basin, only 1.9% are entirely inactive and 7.4% partially inactive, and for the outcrop springs in the Tertiary sandstone overlying the Basin 30.9% are inactive and 18.2% are partially inactive. PMID- 26436534 TI - Quantification of Colonic Stem Cell Mutations. AB - The ability to measure stem cell mutations is a powerful tool to quantify in a critical cell population if, and to what extent, a chemical can induce mutations that potentially lead to cancer. The use of an enzymatic assay to quantify stem cell mutations in the X-linked glucose-6-phosphate dehydrogenase gene has been previously reported.(1) This method requires the preparation of frozen sections and incubation of the sectioned tissue with a reaction mixture that yields a blue color if the cells produce functional glucose-6-phosphate dehydrogenase (G6PD) enzyme. If not, the cells appear whitish. We have modified the reaction mixture using Optimal Cutting Temperature Compound (OCT) medium in place of polyvinyl alcohol. This facilitates pH measurement, increases solubilization of the G6PD staining components and restricts diffusion of the G6PD enzyme. To demonstrate that a mutation occurred in a stem cell, the entire crypt must lack G6PD enzymatic activity. Only if a stem cell harbors a phenotypic G6PD mutation will all of the progeny in the crypt lack G6PD enzymatic activity. To identify crypts with a stem cell mutation, four consecutive adjacent frozen sections (a level) were cut at 7 um thicknesses. This approach of making adjacent cuts provides conformation that a crypt was fully mutated since the same mutated crypt will be observed in adjacent sections. Slides with tissue samples that were more than 50 um apart were prepared to assess a total of >10(4) crypts per mouse. The mutation frequency is the number of observed mutated (white) crypts/by the number of wild type (blue) crypts in a treatment group. PMID- 26436536 TI - Interaction of Thermus thermophilus ArsC enzyme and gold nanoparticles naked-eye assays speciation between As(III) and As(V). AB - The thermophilic bacterium Thermus thermophilus HB27 encodes chromosomal arsenate reductase (TtArsC), the enzyme responsible for resistance to the harmful effects of arsenic. We report on adsorption of TtArsC onto gold nanoparticles for naked eye monitoring of biomolecular interaction between the enzyme and arsenic species. Synthesis of hybrid biological-metallic nanoparticles has been characterized by transmission electron microscopy (TEM), ultraviolet-visible (UV vis), dynamic light scattering (DLS) and phase modulated infrared reflection absorption (PM-IRRAS) spectroscopies. Molecular interactions have been monitored by UV-vis and Fourier transform-surface plasmon resonance (FT-SPR). Due to the nanoparticles' aggregation on exposure to metal salts, pentavalent and trivalent arsenic solutions can be clearly distinguished by naked-eye assay, even at 85 MUM concentration. Moreover, the assay shows partial selectivity against other heavy metals. PMID- 26436537 TI - The Battle Hymn of the Tiger Child. PMID- 26436538 TI - Thinking styles and decision making: A meta-analysis. AB - This meta-analysis examined whether tendencies to use reflective and intuitive thinking styles predicted decision performance (normatively correct responding) and decision experience (e.g., speed, enjoyment) on a range of decision-making tasks. A pooled sample of 17,704 participants (Mage = 25 years) from 89 samples produced small but significant weighted average effects for reflection on performance (r = .11) and experience (r = .14). Intuition was negatively associated with performance (r = -.09) but positively associated with experience (r = .06). Moderation analyses using 499 effect sizes revealed heterogeneity across task-theory match/mismatch, task type, description-based versus experience based decisions, time pressure, age, and measure type. Effects of both thinking styles were strongest when the task matched the theoretical strengths of the thinking style (up to r = .29). Specific tasks that produced the largest thinking style effects (up to r = .35) were also consistent with system characteristics. Time pressure weakened the effects of reflection, but not intuition, on performance. Effect sizes for reflection on performance were largest for individuals aged either 12 to 18 years or 25+ (up to r = .18), and the effects of both reflection and intuition on experience were largest for adults aged 25+ (up to r = .27). Overall, our results indicate that associations between thinking styles and decision outcomes are context dependent. To improve decision performance and experience, decision architects and educators should carefully consider both individual differences in the decision maker and the nature of the decision task. PMID- 26436539 TI - Visible-light Induced Reduction of Graphene Oxide Using Plasmonic Nanoparticle. AB - Present work demonstrates the simple, chemical free, fast, and energy efficient method to produce reduced graphene oxide (r-GO) solution at RT using visible light irradiation with plasmonic nanoparticles. The plasmonic nanoparticle is used to improve the reduction efficiency of GO. It only takes 30 min at RT by illuminating the solutions with Xe-lamp, the r-GO solutions can be obtained by completely removing gold nanoparticles through simple centrifugation step. The spherical gold nanoparticles (AuNPs) as compared to the other nanostructures is the most suitable plasmonic nanostructure for r-GO preparation. The reduced graphene oxide prepared using visible light and AuNPs was equally qualitative as chemically reduced graphene oxide, which was supported by various analytical techniques such as UV-Vis spectroscopy, Raman spectroscopy, powder XRD and XPS. The reduced graphene oxide prepared with visible light shows excellent quenching properties over the fluorescent molecules modified on ssDNA and excellent fluorescence recovery for target DNA detection. The r-GO prepared by recycled AuNPs is found to be of same quality with that of chemically reduced r-GO. The use of visible light with plasmonic nanoparticle demonstrates the good alternative method for r-GO synthesis. PMID- 26436540 TI - SubClonal Hierarchy Inference from Somatic Mutations: Automatic Reconstruction of Cancer Evolutionary Trees from Multi-region Next Generation Sequencing. AB - Recent improvements in next-generation sequencing of tumor samples and the ability to identify somatic mutations at low allelic fractions have opened the way for new approaches to model the evolution of individual cancers. The power and utility of these models is increased when tumor samples from multiple sites are sequenced. Temporal ordering of the samples may provide insight into the etiology of both primary and metastatic lesions and rationalizations for tumor recurrence and therapeutic failures. Additional insights may be provided by temporal ordering of evolving subclones--cellular subpopulations with unique mutational profiles. Current methods for subclone hierarchy inference tightly couple the problem of temporal ordering with that of estimating the fraction of cancer cells harboring each mutation. We present a new framework that includes a rigorous statistical hypothesis test and a collection of tools that make it possible to decouple these problems, which we believe will enable substantial progress in the field of subclone hierarchy inference. The methods presented here can be flexibly combined with methods developed by others addressing either of these problems. We provide tools to interpret hypothesis test results, which inform phylogenetic tree construction, and we introduce the first genetic algorithm designed for this purpose. The utility of our framework is systematically demonstrated in simulations. For most tested combinations of tumor purity, sequencing coverage, and tree complexity, good power (>= 0.8) can be achieved and Type 1 error is well controlled when at least three tumor samples are available from a patient. Using data from three published multi-region tumor sequencing studies of (murine) small cell lung cancer, acute myeloid leukemia, and chronic lymphocytic leukemia, in which the authors reconstructed subclonal phylogenetic trees by manual expert curation, we show how different configurations of our tools can identify either a single tree in agreement with the authors, or a small set of trees, which include the authors' preferred tree. Our results have implications for improved modeling of tumor evolution and the importance of multi-region tumor sequencing. PMID- 26436541 TI - Aptamer Recognition Induced Target-Bridged Strategy for Proteins Detection Based on Magnetic Chitosan and Silver/Chitosan Nanoparticles Using Surface-Enhanced Raman Spectroscopy. AB - Poor selectivity and biocompability remain problems in applying surface-enhanced Raman spectroscopy (SERS) for direct detection of proteins due to similar spectra of most proteins and overlapping Raman bands in complex mixtures. To solve these problems, an aptamer recognition induced target-bridged strategy based on magnetic chitosan (MCS) and silver/chitosan nanoparticles (Ag@CS NPs) using SERS was developed for detection of protein benefiting from specific affinity of aptamers and biocompatibility of chitosan (CS). In this process, one aptamer (or antibody) modified MCS worked as capture probes through the affinity binding site of protein. The other aptamer modified Raman report molecules encapsulated Ag@CS NPs were used as SERS sensing probes based on the other binding site of protein. The sandwich complexes of aptamer (antibody)/protein/aptamer were separated easily with a magnet from biological samples, and the concentration of protein was indirectly reflected by the intensity variation of SERS signal of Raman report molecules. To explore the universality of the strategy, three different kinds of proteins including thrombin, platelet derived growth factor BB (PDGF BB) and immunoglobulin E (lgE) were investigated. The major advantages of this aptamer recognition induced target-bridged strategy are convenient operation with a magnet, stable signal expressing resulting from preventing loss of report molecules with the help of CS shell, and the avoidance of slow diffusion-limited kinetics problems occurring on a solid substrate. To demonstrate the feasibility of the proposed strategy, the method was applied to detection of PDGF BB in clinical samples. The limit of detection (LOD) of PDGF BB was estimated to be 3.2 pg/mL. The results obtained from human serum of healthy persons and cancer patients using the proposed strategy showed good agreement with that of the ELISA method but with wider linear range, more convenient operation, and lower cost. The proposed strategy holds great potential in highly sensitive and selective analysis of target proteins in complex biological samples. PMID- 26436542 TI - Effects of renal denervation on renal pelvic contractions and connexin expression in rats. AB - AIMS: The renal pelvis shows spontaneous rhythmic contractile activity. We assessed to what extent this activity depends on renal innervation and studied the role of connexins in pelvic contractions. METHODS: Rats underwent unilateral renal denervation or renal transplantation. Renal pelvic pressure and diuresis were measured in vivo. Spontaneous and agonist-induced contractions of isolated renal pelves were investigated by wire myography. Rat and human renal pelvic connexin mRNA abundances and connexin localization were studied by real-time PCR and immunofluorescence respectively. RESULTS: Renal denervation or transplantation increased renal pelvic pressure in vivo by about 60 and 150%, respectively, but did not significantly affect pelvic contraction frequency. Under in vitro conditions, isolated pelvic preparations from innervated or denervated kidneys showed spontaneous contractions. Pelves from denervated kidneys showed about 50% higher contraction frequencies than pelves from innervated kidneys, whereas contraction force was similar in pelves from denervated and innervated kidneys. There was no denervation-induced supersensitivity to noradrenaline or endothelin-1. Renal denervation did not increase pelvic connexin37, 40, 43 or 45 mRNA abundances. Gap junction blockade had no effect on spontaneous pelvic contractile activity. CONCLUSIONS: The denervation-induced effect on pelvic pressure may be the consequence of the enhanced diuresis. The mechanisms underlying the denervation-induced effects on pelvic contraction frequency remain unknown. Our data rule out a major role for two important candidates, by showing that renal denervation neither induced supersensitivity to contractile agonists nor increased connexin mRNA abundance in the pelvic wall. PMID- 26436543 TI - Engineering Proteins for Thermostability with iRDP Web Server. AB - Engineering protein molecules with desired structure and biological functions has been an elusive goal. Development of industrially viable proteins with improved properties such as stability, catalytic activity and altered specificity by modifying the structure of an existing protein has widely been targeted through rational protein engineering. Although a range of factors contributing to thermal stability have been identified and widely researched, the in silico implementation of these as strategies directed towards enhancement of protein stability has not yet been explored extensively. A wide range of structural analysis tools is currently available for in silico protein engineering. However these tools concentrate on only a limited number of factors or individual protein structures, resulting in cumbersome and time-consuming analysis. The iRDP web server presented here provides a unified platform comprising of iCAPS, iStability and iMutants modules. Each module addresses different facets of effective rational engineering of proteins aiming towards enhanced stability. While iCAPS aids in selection of target protein based on factors contributing to structural stability, iStability uniquely offers in silico implementation of known thermostabilization strategies in proteins for identification and stability prediction of potential stabilizing mutation sites. iMutants aims to assess mutants based on changes in local interaction network and degree of residue conservation at the mutation sites. Each module was validated using an extensively diverse dataset. The server is freely accessible at http://irdp.ncl.res.in and has no login requirements. PMID- 26436544 TI - Arterial Expression of the Calcium-Sensing Receptor Is Maintained by Physiological Pulsation and Protects against Calcification. AB - Vascular calcification (VC) is common in chronic kidney disease (CKD) and contributes to cardiovascular mortality. The calcium-sensing receptor (CaSR) is present in human artery, senses extracellular calcium and may directly modulate VC. OBJECTIVE: to investigate the association between arterial cyclic strain, CaSR expression and VC. METHODS AND RESULTS: human aortic smooth muscle cells (HAoSMC) were cultured under static or strained conditions, with exposure to CaSR agonists, the calcimimetic R568, and after CaSR silencing and over-expression. High extracellular calcium reduced CaSR expression and promoted osteochondrogenic transformation and calcium deposition. This was partially prevented by cyclic strain and exposure to R568. CaSR silencing enhanced calcification and osteochondrogenic transformation, whereas CaSR over-expression attenuated this procalcific response, demonstrating a central role for the CaSR in the response to cyclic strain and regulation of VC. In arterial explants from CKD patients (n = 11) and controls (n = 9), exposure to R568 did not significantly alter calcium deposition, osteochondrogenic markers or total artery calcium content. CONCLUSIONS: physiological mechanical strain is important for arterial homeostasis and may protect arteries from VC. The beneficial effects of cyclic strain may be mediated via the CaSR. PMID- 26436545 TI - Estimating the Sensitivity and Specificity of Real-Time Quantitative PCR of Fecal Samples for Diagnosis of Rhodococcus equi Pneumonia in Foals. AB - BACKGROUND: Real-time, quantitative PCR (qPCR) methods for detecting Rhodococcus equi in feces have been developed as a noninvasive, rapid diagnostic test for R. equi pneumonia, but have not been evaluated in a large population of foals. OBJECTIVE: The objective of this study was to evaluate the clinical utility of fecal PCR as a diagnostic test for R. equi pneumonia in foals using receiver operating characteristic (ROC) methods. ANIMALS: 186 foals born in 2011 at an R. equi-endemic ranch in Texas. METHODS: Fecal samples were collected at the time of onset of clinical signs for pneumonic foals (n = 31). Foals with pneumonia were matched by age and birth date to healthy (n = 31) and subclinical (n = 124) control foals; fecal samples were collected from these controls. DNA was extracted from feces using commercial kits and concentration of virulent R. equi in feces was determined by qPCR. RESULTS: Concentration of R. equi in feces differed significantly (P < .05) among groups. The area under the ROC curve for fecal qPCR for diagnosis of R. equi pneumonia was 89% (95% CI, 83-99), with a sensitivity of 94% and specificity of 72%. CONCLUSIONS AND CLINICAL IMPORTANCE: qPCR of feces can be useful as an alternative to tracheobronchial aspiration for the diagnosis of R. equi in foals with clinical signs of pneumonia. Caution should be used in extrapolating results of this study to other populations because fecal concentration of R. equi might vary by geographic location or management practices. PMID- 26436546 TI - The Role of Crowding Forces in Juxtaposing beta-Globin Gene Domain Remote Regulatory Elements in Mouse Erythroid Cells. AB - The extremely high concentration of macromolecules in a eukaryotic cell nucleus indicates that the nucleoplasm is a crowded macromolecular solution in which large objects tend to gather together due to crowding forces. It has been shown experimentally that crowding forces support the integrity of various nuclear compartments. However, little is known about their role in control of chromatin dynamics in vivo. Here, we experimentally addressed the possible role of crowding forces in spatial organization of the eukaryotic genome. Using the mouse beta globin domain as a model, we demonstrated that spatial juxtaposition of the remote regulatory elements of this domain in globin-expressing cells may be lost and restored by manipulation of the level of macromolecular crowding. In addition to proving the role of crowding forces in shaping interphase chromatin, our results suggest that the folding of the chromatin fiber is a major determinant in juxtaposing remote genomic elements. PMID- 26436547 TI - Generation of an Enhancer-Trapping Vector for Insertional Mutagenesis in Zebrafish. AB - Enhancer trapping (ET) is a powerful approach to establish tissue- or cell specific reporters and identify expression patterns of uncharacterized genes. Although a number of enhancer-trapping vectors have been developed and a large library of fish lines with distinct tissue- or cell-specific expression of reporter genes have been generated, the specificity and efficiency of trapping vectors need to be improved because of the bias interaction of minimal promoters with genomic enhancers. Accordingly, we generated an enhancer-trapping vector pTME that contains a minimal mouse metallothionein gene (mMTI) promoter upstream of EGFP reporter. In the first round of screening, twelve zebrafish lines that carry a single copy of ET cassettes were characterized to have tissue- or cell specific EGFP expression. One of the highly conserved noncoding elements near an insertion site of trapping cassettes was characterized as an enhancer that can specifically regulate the expression of EGFP in cells of the central nervous system. In addition, the pTME vector contains a mutation-cassette that is able to effectively block the transcription of an endogenous gene in an ET line with ubiquitous EGFP expression. Thus, the pTME vector can be used as an alternative tool for both enhancer trapping and mutagenesis across a target genome. PMID- 26436548 TI - Involvement of Neuroactive Steroids in Pain, Depression and Anxiety. AB - Comorbidity between major depressive disorder (MDD), anxiety (generalized anxiety, panic disorder, social anxiety disorder) and pain is a major complicating factor in the diagnosis and treatment of psychiatric and neurological disorders. Although numerous neurotransmitters and/or neuromodulators may be involved, abnormalities in the GABAergic and glutamatergic systems seem to be a common factor in all these disorders. Neuroactive steroids (NASs) have been the object of considerable interest in this area in recent years since they appear to act predominantly on GABA-A and glutamate NMDA receptors. An overview of the possible involvement of NASs in MDD, anxiety and pain is provided in this chapter. PMID- 26436549 TI - Correction: Visualization of Glutamine Transporter Activities in Living Cells Using Genetically Encoded Glutamine Sensors. PMID- 26436550 TI - Is Cryotherapy Friend or Foe for Symptomatic Cervical Ectopy? AB - OBJECTIVE: To evaluate the success rates and clinical outcomes of cervical cryotherapy applied to cervical ectopy for symptomatic relief. SUBJECTS AND METHODS: A total of 124 women who underwent cryotherapy for symptomatic treatment of cervical ectopy were included in this study. Indications for treatment were: abundant leucorrhoea (n = 114), post-coital bleeding (n = 22), recurrent cervicitis (n = 30) and pelvic pain (n = 12). Cryotherapy consisted of the use of carbon dioxide at -89 degrees C to destroy the ectopic columnar epithelium by freezing, and it was transmitted to the ectopy through a flat cryoprobe. No routine anaesthesia or analgesia was administered. All patients were questioned about the status of their symptoms after 6 weeks of treatment. RESULTS: The highest success rate was obtained in patients with abundant leucorrhoea (n = 102; 89.5%), while the lowest success rate was achieved in subjects with pelvic pain (n = 7; 58%). After treatment, no severe complications were observed, except for hydrorrhoea for a few days. Success rates were 9 times lower in patients who had 3 or more cervicitis episodes per 6 months. CONCLUSION: In this study, the success rate of cryotherapy was highest in patients with abundant leucorrhoea and lowest in patients with pelvic pain and recurrent cervicitis. Hence, we recommend that clinicians perform the procedure in such patients without much delay. PMID- 26436551 TI - Dynamic Membrane Formation in Anaerobic Dynamic Membrane Bioreactors: Role of Extracellular Polymeric Substances. AB - Dynamic membrane (DM) formation in dynamic membrane bioreactors plays an important role in achieving efficient solid-liquid separation. In order to study the contribution of extracellular polymeric substances (EPS) to DM formation in anaerobic dynamic membrane bioreactor (AnDMBR) processes, EPS extraction from and re-addition to bulk sludge were carried out in short-term filtration tests. DM formation behaviors could be well simulated by cake filtration model, and sludge with EPS re-addition showed the highest resistance coefficient, followed by sludge after EPS extraction. The DM layers exhibited a higher resistance and a lower porosity for the sludge sample after EPS extraction and for the sludge with EPS re-addition. Particle size of sludge flocs decreased after EPS extraction, and changed little with EPS re-addition, which was confirmed by interaction energy analysis. Further investigations by confocal laser scanning microscopy (CLSM) analysis and batch tests suggested that the removal of in-situ EPS stimulated release of soluble EPS, and re-added EPS were present as soluble EPS rather than bound EPS, which thus improved the formation of DM. The present work revealed the role of EPS in anaerobic DM formation, and could facilitate the operation of AnDMBR processes. PMID- 26436552 TI - Nanoarchitectonics for Dynamic Functional Materials from Atomic-/Molecular-Level Manipulation to Macroscopic Action. AB - Objects in all dimensions are subject to translational dynamism and dynamic mutual interactions, and the ability to exert control over these events is one of the keys to the synthesis of functional materials. For the development of materials with truly dynamic functionalities, a paradigm shift from "nanotechnology" to "nanoarchitectonics" is proposed, with the aim of design and preparation of functional materials through dynamic harmonization of atomic /molecular-level manipulation and control, chemical nanofabrication, self organization, and field-controlled organization. Here, various examples of dynamic functional materials are presented from the atom/molecular-level to macroscopic dimensions. These systems, including atomic switches, molecular machines, molecular shuttles, motional crystals, metal-organic frameworks, layered assemblies, gels, supramolecular assemblies of biomaterials, DNA origami, hollow silica capsules, and mesoporous materials, are described according to their various dynamic functions, which include short-term plasticity, long-term potentiation, molecular manipulation, switchable catalysis, self-healing properties, supramolecular chirality, morphological control, drug storage and release, light-harvesting, mechanochemical transduction, molecular tuning molecular recognition, hand-operated nanotechnology. PMID- 26436553 TI - Colonization of Lutzomyia verrucarum and Lutzomyia longipalpis Sand Flies (Diptera: Psychodidae) by Bartonella bacilliformis, the Etiologic Agent of Carrion's Disease. AB - Bartonella bacilliformis is a pathogenic bacterium transmitted to humans presumably by bites of phlebotomine sand flies, infection with which results in a bi-phasic syndrome termed Carrion's disease. After constructing a low-passage GFP labeled strain of B. bacilliformis, we artificially infected Lutzomyia verrucarum and L. longipalpis populations, and subsequently monitored colonization of sand flies by fluorescence microscopy. Initially, colonization of the two fly species was indistinguishable, with bacteria exhibiting a high degree of motility, yet still confined to the abdominal midgut. After 48 h, B. bacilliformis transitioned from bacillus-shape to a non-motile, small coccoid form and appeared to be digested along with the blood meal in both fly species. Differences in colonization patterns became evident at 72 h when B. bacilliformis was observed at relatively high density outside the peritrophic membrane in the lumen of the midgut in L. verrucarum, but colonization of L. longipalpis was limited to the blood meal within the intra-peritrophic space of the abdominal midgut, and the majority of bacteria were digested along with the blood meal by day 7. The viability of B. bacilliformis in L. longipalpis was assessed by artificially infecting, homogenizing, and plating for determination of colony-forming units in individual flies over a 13-d time course. Bacteria remained viable at relatively high density for approximately seven days, suggesting that L. longipalpis could potentially serve as a vector. The capacity of L. longipalpis to transmit viable B. bacilliformis from infected to uninfected meals was analyzed via interrupted feeds. No viable bacteria were retrieved from uninfected blood meals in these experiments. This study provides significant information toward understanding colonization of sand flies by B. bacilliformis and also demonstrates the utility of L. longipalpis as a user-friendly, live-vector model system for studying this severely neglected tropical disease. PMID- 26436554 TI - Construction of a Genetic Linkage Map and Identification of QTLs for Seed Weight and Seed Size Traits in Lentil (Lens culinaris Medik.). AB - Seed weight and seed size both are quantitative traits and have been considered as important components of grain yield, thus identification of quantitative trait loci (QTL) for seed traits in lentil (Lens culinaris) would be beneficial for the improvement of grain yield. Hence the main objective of this study was to identify QTLs for seed traits using an intraspecific mapping population derived from a cross between L. culinaris cv. Precoz (seed weight-5.1g, seed size-5.7mm) and L. culinaris cv. L830 (seed weight-2.2g, seed size-4mm) comprising 126 F8 RILs. For this, two microsatellite genomic libraries enriched for (GA/CT) and (GAA/CTT) motif were constructed which resulted in the development of 501 new genomic SSR markers. Six hundred forty seven SSR markers (including 146 previously published) were screened for parental polymorphism and 219 (33.8%) were found to be polymorphic among the parents. Of these 216 were mapped on seven linkage groups at LOD4.0 spanning 1183.7cM with an average marker density of 5.48cM. Phenotypic data from the RILs was used to identify QTLs for the seed weight and seed size traits by single marker analysis (SMA) followed by composite interval mapping (CIM) which resulted in one QTL each for the 2 traits (qSW and qSS) that were co-localized on LG4 and explained 48.4% and 27.5% of phenotypic variance respectively. The current study would serve as a strong foundation for further validation and fine mapping for utilization in lentil breeding programs. PMID- 26436555 TI - Maternal Lineage of Warmblood Mares Contributes to Variation of Gestation Length and Bias of Foal Sex Ratio. AB - Maternal lineage influences performance traits in horses. This is probably caused by differences in mitochondrial DNA (mtDNA) transferred to the offspring via the oocyte. In the present study, we investigated if reproductive traits with high variability-gestation length and fetal sex ratio-are influenced by maternal lineage. Data from 142 Warmblood mares from the Brandenburg State Stud at Neustadt (Dosse), Germany, were available for the study. Mares were grouped according to their maternal lineage. Influences on the reproduction parameters gestation length and sex ratio of offspring were analyzed by simple and multiple analyses of variance. A total of 786 cases were included. From the 142 mares, 119 were assigned to six maternal lineages with n>=10 mares per lineage, and 23 mares belonged to smaller maternal lineages. The mean number of live foals produced per mare was 4.6+/-3.6 (+/-SD). Live foal rate was 83.5%. Mean gestation length was 338.5+/-8.9 days (+/-SD) with a range of 313 to 370 days. Gestation length was affected by maternal lineage (p<0.001). Gestation length was also significantly influenced by the individual mare, age of the mare, year of breeding, month of breeding and sex of the foal (p<0.05). Of the 640 foals born alive at term, 48% were male and 52% female. Mare age group and maternal lineage significantly influenced the sex ratio of the foals (p<0.05). It is concluded that maternal lineage influences reproductive parameters with high variation such as gestation length and foal sex ratio in horses. In young primiparous and aged mares, the percentage of female offspring is higher than the expected 1:1 ratio. PMID- 26436556 TI - Emerging treatments for recurrent prostate cancer. AB - Despite radical treatment, many men with prostate cancer will develop recurrence of their disease. In an exciting era of new therapies for prostate cancer in general, we focus on how these will specifically benefit those men with recurrent disease. We consider salvage treatments aimed at those with local recurrence confined to the prostate gland, therapies for those presenting with metastatic recurrence and the approach to men presenting with a rising prostate-specific antigen but no demonstrable disease (M0). In general, men with recurrent disease are often under-represented in randomized clinical trials. Consequently, evidence to guide treatment for these men is often lacking and this needs to be addressed in order to improve and better define our approach to this problem in the future. PMID- 26436557 TI - Products and Mechanism of the Reaction of 1-Pentadecene with NO3 Radicals and the Effect of a -ONO2 Group on Alkoxy Radical Decomposition. AB - The linear C15 alkene, 1-pentadecene, was reacted with NO3 radicals in a Teflon environmental chamber and yields of secondary organic aerosol (SOA) and particulate beta-hydroxynitrates, beta-carbonylnitrates, and organic peroxides (beta-nitrooxyhydroperoxides + dinitrooxyperoxides) were quantified using a variety of methods. Reaction occurs almost solely by addition of NO3 to the C?C double bond and measured yields of beta-hydroxynitrate isomers indicate that 92% of addition occurs at the terminal carbon. Molar yields of reaction products determined from measurements, a proposed reaction mechanism, and mass-balance considerations were 0.065 for beta-hydroxynitrates (0.060 and 0.005 for 1 nitrooxy-2-hydroxypentadecane and 1-hydroxy-2-nitrooxypentadecane isomers), 0.102 for beta-carbonylnitrates, 0.017 for organic peroxides, 0.232 for beta nitrooxyalkoxy radical isomerization products, and 0.584 for tetradecanal and formaldehyde, the volatile C14 and C1 products of beta-nitrooxyalkoxy radical decomposition. Branching ratios for decomposition and isomerization of beta nitrooxyalkoxy radicals were 0.716 and 0.284 and should be similar for other linear 1-alkenes >= C6 whose alkyl chains are long enough to allow for isomerization to occur. These branching ratios have not been measured previously, and they differ significantly from those estimated using structure-activity relationships, which predict >99% isomerization. It appears that the presence of a -ONO2 group adjacent to an alkoxy radical site greatly enhances the rate of decomposition relative to isomerization, which is otherwise negligible, and that the effect is similar to that of a -OH group. The results provide insight into the effects of molecular structure on mechanisms of oxidation of volatile organic compounds and should be useful for improving structure-activity relationships that are widely used to predict the fate of these compounds in the atmosphere and for modeling SOA formation and aging. PMID- 26436558 TI - Skin Necrosis and Purpura Fulminans in Children With and Without Thrombophilia--A Tertiary Center's Experience. AB - Purpura fulminans (PF) is a very rare clinicopathologic skin disorder comprising dermal microvascular thrombosis associated with perivascular hemorrhage of multiple origins. It may occur as the presenting symptom of severe congenital deficiency of protein C (PC) or protein S (PS) during the newborn period, or later in life following oral anticoagulant therapy with vitamin K antagonists, or of sepsis that may be associated with disseminated intravascular coagulation. Treatment consists of anticoagulants and PC concentrates during acute episodes. We report our experience in the diagnosis and management of pediatric PF. The medical records of the 6 children aged 2-16 years (median: 5 years) who presented with PF to our tertiary care center between 1996 and 2013 were studied. The thrombophilia workup revealed either the presence of congenital homozygous PC deficiency, prothrombotic polymorphisms (factor V Leiden and FIIG20210A heterozygosity), acquired PC/PS deficiency, or no discernible thrombophilia. The skin necrosis resolved following conservative fresh-frozen plasma/anticoagulant therapy in 2 cases, whereas 3 children required interventional plastic surgery. The sixth case, a 10-year-old child with severe PC deficiency, heterozygous factor V Leiden, and FIIG20210A, received recombinant activated PC. PF in childhood is rare and has multiple etiologies. Understanding of the variable pathogenesis and risk factors will facilitate diagnosis and appropriate clinical management. PMID- 26436559 TI - Effect of Splinting on Dimensional Accuracy of Impressions Made of Implants with Different Subgingival Alignments. AB - PURPOSE: Placement of implants at deeper levels of gingiva is sometimes inevitable because of issues like esthetics or bone availability. The accuracy of impressions may be affected in these situations. The aim of this in vitro study was to evaluate the effects of splinting and length of impression copings on the accuracy of impressions made of deeply placed implants. MATERIALS AND METHODS: A metal model with two parallel implants (Implantium; Dentium) was fabricated. One hundred and twenty impressions were made using the direct impression technique with and without splinting the impression copings (using short and long impression copings). Impressions were made of implants at three subgingival levels (1, 3, and 6 mm) using regular viscosity poly(vinyl siloxane). The impressions were poured with type IV dental stone. Displacements in the x, y, and z axes, as well as rotational discrepancies and interimplant distances were measured with a coordinate measuring machine. Data were analyzed with Kruskal Wallis, Mann-Whitney, and nonparametric adjusted rank transform tests. RESULTS: There was less rotational displacement using longer impression copings at different subgingival positions of the implants, either with splinted or nonsplinted direct technique (p < 0.05). Also, the nonsplinted technique produced more accurate impressions at different apico-coronal levels of implants than the splinted technique using short impression copings (p < 0.05). CONCLUSIONS: According to the findings of this study, longer impression copings yielded better results than shorter ones in both splinted and nonsplinted techniques. Also, nonsplinted short impression copings produced more accurate impressions than splinted short impression copings. PMID- 26436561 TI - Photoelectron Spectroscopy of BiAu(-) and BiBO(-): Further Evidence of the Analogy between Au and Boronyl. AB - Boronyl (BO) is a monovalent sigma radical with a B=O triple bond. Its chemistry has remained relatively unknown, though analogy has been established for BO with monovalent atoms, such as H or Au. Here we report a photoelectron spectroscopic study of BiAu(-) and BiBO(-), showing further evidence of the analogy between Au and BO. The photoelectron spectra of BiAu(-) and BiBO(-) are found to be similar, suggesting that they possess similar electronic structure and chemical bonding. The electron affinities of BiAu and BiBO are measured to be 1.38(4) and 1.84(3) eV, respectively. The ground states of both BiAu and BiBO are shown to be a triplet (X (3)Sigma(-)). In addition, vibrational structures are resolved in the spectra of BiBO(-). Two vibrational frequencies at 320(30) and 1860(50) cm(-1) are measured for the ground state of BiBO, corresponding to the Bi-B and B-O stretching modes, respectively. The low-lying electronic excited states of BiAu and BiBO are also found to be similar: their first four excited states are A (1)Delta, B (1)Sigma(+), C (3)Pi, and D (1)Pi, with excitation energies at 0.71, 1.29, 2.54, and 2.67 eV for BiAu and 0.63, 1.26, 3.68, and 3.82 eV for BiBO, respectively, above the (3)Sigma(-) ground state. Weak photoelectron features related to two-electron detachment transitions are also observed for both anions because of strong electron correlation effects in the ground state of the anions. PMID- 26436560 TI - Zinc pyrithione inhibits caspase-3 activity, promotes ErbB1-ErbB2 heterodimerization and suppresses ErbB2 downregulation in cardiomyocytes subjected to ischemia/reperfusion. AB - Heart tissue becomes zinc-depleted and the capacity to mobilize labile zinc is diminished, indicating zinc dyshomeostasis during ischemia/reperfusion (I/R). Apparently, zinc pyrithione restores the basal zinc levels during I/R and prevents apoptosis by activating phosphatidyl inositol-3-kinase/Akt and targeting mitochondrial permeability transition. Receptor tyrosine kinases of the ErbB family (ErbB1 to ErbB4) are cell surface proteins that can regulate cell growth, proliferation and survival. Previous studies have shown that zinc pyrithione induced activation of PI3kinase/Akt requires ErbB2 expression. On the other hand, while I/R decreases ErbB2 levels causing cardiomyocyte dysfunction and cell death, zinc pyrithione restores ErbB2 levels and maintains cardiomyocyte function. H9c2 cells expressed all the four ErbBs, although the expression of ErbB1 and ErbB2 were higher compared to ErbB3 and ErbB4. Hypoxia/Reoxygenation (H/R) had opposing effects on the mRNA expression of ErbB1 and ErbB2. ErbB2 mRNA levels were enhanced, but corresponding ErbB2 protein levels decreased after reoxygenation. H/R induced the degradation of ErbB2 in caspase-3 dependent manner, with the formation of a 25kDa fragment. This fragment could be detected after H/R only upon treatment of the cells with a proteasomal inhibitor, ALLN, suggesting that caspase-mediated cleavage of 185kDa ErbB2 results in C-terminal cleavage and formation of 25kDa fragment, which is further degraded by proteasome. Heterodimerization and phosphorylation of ErbB2/ErbB1 which decreased upon reoxygenation, was promoted by zinc pyrithione. Zinc pyrithione effectively suppressed the caspase activation, decreased the proteolytic cleavage of ErbB2, enhanced the phosphorylation and activation of ErbB1-ErbB2 complexes and improved the cell survival after hypoxia/reoxygenation. PMID- 26436562 TI - Nicotine intake and problem solving strategies are modified during a cognitively demanding water maze task in rats. AB - BACKGROUND: Nicotine is the major addictive component in tobacco, and despite well-established adverse health effects of tobacco addiction, some smokers have difficulty quitting. The acute cognitive enhancement and/or the amelioration of the cognitive disruption during withdrawal that some smokers experience after smoking are among important factors that hinder quit attempts. The animal model presented in the current study is comparable to the human smoking condition although nicotine intake routes are different. Rats were exposed to a free choice of oral nicotine starting at adolescence, and given a water maze (WM) task as adults. This design allowed us to see if rats alter their nicotine intake during the WM task and if nicotine preference and intake modify abilities and strategies rats use for problem solving. METHODS: Male and female rats were exposed to a free choice of oral nicotine/water for 24weeks, starting at five weeks of age. After this period, they were selected based on their nicotine intake and, together with control animals that received only water, were subjected to a place learning task in the WM. Free-choice nicotine exposure continued during WM testing. Following acquisition, the probe trial presented the rats with a choice between using two different strategies for problem solving. RESULTS: Nicotine supported acquisition and rats increased their nicotine intake during WM testing; this effect was more pronounced in male rats with minimum nicotine preference and intake. Furthermore, nicotine modified the "female type" strategy in solving the place-learning task and nicotine treated female rats, unlike control females, behaved like males. CONCLUSIONS: The increase in nicotine intake during mental engagement, and the sexually dimorphic effect of nicotine on problem solving strategies that we have observed in rats, may suggest that implementing sex specific smoking cessation approaches, especially under stressful and cognitively demanding conditions, may be useful in helping smokers quit. PMID- 26436563 TI - Electrical detection of magnetic skyrmions by tunnelling non-collinear magnetoresistance. AB - Magnetic skyrmions are localized non-collinear spin textures with a high potential for future spintronic applications. Skyrmion phases have been discovered in a number of materials and a focus of current research is to prepare, detect and manipulate individual skyrmions for implementation in devices. The local experimental characterization of skyrmions has been performed by, for example, Lorentz microscopy or atomic-scale tunnel magnetoresistance measurements using spin-polarized scanning tunnelling microscopy. Here we report a drastic change of the differential tunnel conductance for magnetic skyrmions that arises from their non-collinearity: mixing between the spin channels locally alters the electronic structure, which makes a skyrmion electronically distinct from its ferromagnetic environment. We propose this tunnelling non-collinear magnetoresistance as a reliable all-electrical detection scheme for skyrmions with an easy implementation into device architectures. PMID- 26436564 TI - Skyrmions: Detection with unpolarized currents. PMID- 26436566 TI - Heterogeneous sub-continuum ionic transport in statistically isolated graphene nanopores. AB - Graphene and other two-dimensional materials offer a new class of ultrathin membranes that can have atomically defined nanopores with diameters approaching those of hydrated ions. These nanopores have the smallest possible pore volumes of any ion channel, which, due to ionic dehydration and electrokinetic effects, places them in a novel transport regime and allows membranes to be created that combine selective ionic transport with ultimate permeance and could lead to separations and sensing applications. However, experimental characterization and understanding of sub-continuum ionic transport in nanopores below 2 nm is limited. Here we show that isolated sub-2 nm pores in graphene exhibit, in contrast to larger pores, diverse transport behaviours consistent with ion transport over a free-energy barrier arising from ion dehydration and electrostatic interactions. Current-voltage measurements reveal that the conductance of graphene nanopores spans three orders of magnitude and that they display distinct linear, voltage-activated or rectified current-voltage characteristics and different cation-selectivity profiles. In rare cases, rapid, voltage-dependent stochastic switching is observed, consistent with the presence of a dissociable group in the pore vicinity. A modified Nernst-Planck model incorporating ion hydration and electrostatic effects quantitatively matches the observed behaviours. PMID- 26436565 TI - Picosecond photoresponse in van der Waals heterostructures. AB - Two-dimensional crystals such as graphene and transition-metal dichalcogenides demonstrate a range of unique and complementary optoelectronic properties. Assembling different two-dimensional materials in vertical heterostructures enables the combination of these properties in one device, thus creating multifunctional optoelectronic systems with superior performance. Here, we demonstrate that graphene/WSe2/graphene heterostructures ally the high photodetection efficiency of transition-metal dichalcogenides with a picosecond photoresponse comparable to that of graphene, thereby optimizing both speed and efficiency in a single photodetector. We follow the extraction of photoexcited carriers in these devices using time-resolved photocurrent measurements and demonstrate a photoresponse time as short as 5.5 ps, which we tune by applying a bias and by varying the transition-metal dichalcogenide layer thickness. Our study provides direct insight into the physical processes governing the detection speed and quantum efficiency of these van der Waals heterostuctures, such as out of-plane carrier drift and recombination. The observation and understanding of ultrafast and efficient photodetection demonstrate the potential of hybrid transition-metal dichalcogenide-based heterostructures as a platform for future optoelectronic devices. PMID- 26436567 TI - Complete mitochondrial genome of Drabescoides nuchalis (Hemiptera: Cicadellidae). AB - The complete mitochondrial genome (mitogenome) of Drabescoides nuchalis (Hemiptera: Cicadellidae) was sequenced. It is 15 309 bp in length with 75.62% (A + T) content and comprises 13 protein-coding genes, 22 transfer RNAs, two ribosomal RNA genes, and a non-coding region (GenBank accession no. KR349344). Gene order is identical to that of the inferred ancestral insect genome. All PCGs start with an ATN codon and terminate with TAA except ND4, which has an incomplete stop codon (T). The anticodons are identical to those of Drosophila yakuba. The phylogenetic tree confirms D. nuchalis and two Cicadellidae species are clustered into a clade, and Cicadellidae is a monophyletic group and provides support for the sister relationship of leafhopper and treehopper. PMID- 26436568 TI - Interventions at the laboratory level to reduce laboratory test ordering by family physicians: Systematic review. AB - OBJECTIVES: To assess the effectiveness of interventions by laboratories and to increase rational and reduce unnecessary family physician test ordering. DESIGN AND METHODS: MEDLINE [1946-present], EMBASE [1980-present], EBM Reviews [1991 present](Cochrane Database of Systematic Reviews, ACP Journal Club, Database of Abstracts of Reviews of Effects, - Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Health Technology Assessment, NHS Economic Evaluation Database), PubMed [1966-present], PubMed Central [1900-present], Scopus [1960-present], Web of Science [1900-present] and CINAHL [1982-present] were searched with no language or publication limits. Non-randomised studies were assessed with the Newcastle-Ottawa scale. RESULTS: The search identified 9282 titles and abstracts, 238 were read in full-text and 3 cohort and 7 before- and after-studies were included. Most focused on changing a few tests and evaluated the interventions over several months. Seven changed laboratory forms (the two largest involved 5.2 million and 3.2 million tests), one negotiated a test ordering protocol with family physicians, and two required laboratory approval. They achieved an average 35% reduction in the 19 targeted tests, with a wide range (0%-100% reduction). CONCLUSIONS: Ten studies were identified which tested interventions by laboratories to reduce test ordering by family physicians, and achieved an average 35% reduction in the 19 targeted tests. The rationale for choosing specific tests for intervention was often not explained, most studies targeted a few tests for several months, the tests and test volumes differed widely across studies, no author improved the results of previous interventions or asked participants their opinions about the intervention or assessed factors impeding change. PMID- 26436569 TI - Different forms of Hb Le Lamentin. An unexpected finding in Hba1c quantification. AB - OBJECTIVES: Glycated hemoglobin (HbA1c) is accepted as the most trusted marker for monitoring patients with diabetes mellitus. Ion-exchange high-performance liquid chromatography (HPLC) is one of the most widely used methods for HbA1c analysis. The presence of a hemoglobin variant can interfere with HbA1c quantification, requiring other analyses to clarify the results.Herein, we present two cases of Hb Le Lamentin, which, although they were the same variant, were thought to correspond to different hemoglobinopathies because of their percentages. DESIGN AND METHODS: Two male patients presented with an anomalous peak between HbA1c and HbA0 during a routine analysis of HbA1c using ion-exchange HPLC (VariantTM II Turbo).The hemoglobin variants were studied using capillary zone electrophoresis with the Sebia system, and the globin chains were analyzed by reverse-phase HPLC. A genetic analysis was performed using automated sequencing of the alpha2 and beta genes. RESULTS: In this work, we describe the first case of homozygous Hb Le Lamentin and the first double-heterozygous case of Hb Le Lamentin/Hb City of Hope. CONCLUSIONS: Although the presence of these variants does not lead to clinical anomalies, it also does not affect hematologic parameters. The variants have an impact on the determination of glycated hemoglobin levels using ion-exchange HPLC because the retention time interferes with the elution time of HbA1c, resulting in a falsely reduced value. Therefore, it is necessary to either recalculate the result or use another measurement method. PMID- 26436570 TI - Polymorphisms rs144723656, rs2268574, and rs2268575 of the glucokinase gene are not associated with obese women with type 2 diabetes mellitus. PMID- 26436571 TI - Oncolytic Newcastle disease virus as a prospective anti-cancer therapy. A biologic agent with potential to break therapy resistance. AB - INTRODUCTION: Oncolytic viruses (OVs) selectively replicate in tumor cells and cause cancer cell death. Most OVs in clinical studies are genetically engineered. In contrast, the avian Newcastle disease virus (NDV) is a naturally oncolytic RNA virus. While anti-viral immunity is considered a major problem in achieving maximal tumor cell killing by OVs, this review discusses the importance of NDV immunogenic cell death (ICD) and how anti-viral immune responses can be integrated to induce maximal post-oncolytic T-cell-mediated anti-tumor immunity. Since replication of NDV is independent of host cell DNA replication (which is the target of many cytostatic drugs and radiotherapy) and because of other findings, oncolytic NDV is a candidate agent to break therapy resistance of tumor cells. AREAS COVERED: Properties of this avian paramyxovirus are summarized with special emphasis to its anti-neoplastic and immune-stimulatory properties. The review then discusses prospective anti-cancer therapies, including treatments with NDV alone, and combinations with an autologous NDV-modified tumor cell vaccine or with a viral oncolysate pulsed dendritic cell vaccine. Various combinatorial approaches between these and with other modalities are also reviewed. EXPERT OPINION: Post-oncolytic anti-tumor immunity based on ICD is in the expert's opinion of greater importance for long-term therapeutic effects than maximal tumor cell killing. Of the various combinatorial approaches discussed, the most promising and feasible for clinical practice appears to be the combination of systemic NDV pre-treatment with anti-tumor vaccination. PMID- 26436573 TI - Addendum. PMID- 26436572 TI - Hepatocyte nuclear factor-alpha genetic mutation in a Chinese pedigree with maturity-onset diabetes of the young (MODY3). PMID- 26436574 TI - Fluorine-controlled C-H borylation of arenes catalyzed by a PSiN-pincer platinum complex. AB - An efficient, regioselective synthesis of fluorine-substituted arylboronic esters was achieved through fluorine-controlled C-H borylation of arenes with diboron catalyzed by a PSiN-platinum complex. The promising utility of the PSiN-platinum catalyst and its unique regioselectivity were demonstrated for the first time, which would complement the well-developed Ir-catalyzed C-H borylation. PMID- 26436575 TI - Orthogonal gene knockout and activation with a catalytically active Cas9 nuclease. AB - We have developed a CRISPR-based method that uses catalytically active Cas9 and distinct single guide (sgRNA) constructs to knock out and activate different genes in the same cell. These sgRNAs, with 14- to 15-bp target sequences and MS2 binding loops, can activate gene expression using an active Streptococcus pyogenes Cas9 nuclease, without inducing double-stranded breaks. We use these 'dead RNAs' to perform orthogonal gene knockout and transcriptional activation in human cells. PMID- 26436576 TI - Simple Bulk Readout of Digital Nucleic Acid Quantification Assays. AB - Digital assays are powerful methods that enable detection of rare cells and counting of individual nucleic acid molecules. However, digital assays are still not routinely applied, due to the cost and specific equipment associated with commercially available methods. Here we present a simplified method for readout of digital droplet assays using a conventional real-time PCR instrument to measure bulk fluorescence of droplet-based digital assays. We characterize the performance of the bulk readout assay using synthetic droplet mixtures and a droplet digital multiple displacement amplification (MDA) assay. Quantitative MDA particularly benefits from a digital reaction format, but our new method applies to any digital assay. For established digital assay protocols such as digital PCR, this method serves to speed up and simplify assay readout. Our bulk readout methodology brings the advantages of partitioned assays without the need for specialized readout instrumentation. The principal limitations of the bulk readout methodology are reduced dynamic range compared with droplet-counting platforms and the need for a standard sample, although the requirements for this standard are less demanding than for a conventional real-time experiment. Quantitative whole genome amplification (WGA) is used to test for contaminants in WGA reactions and is the most sensitive way to detect the presence of DNA fragments with unknown sequences, giving the method great promise in diverse application areas including pharmaceutical quality control and astrobiology. PMID- 26436577 TI - Helium Ion Microscopy Visualizes Lipid Nanodomains in Mammalian Cells. AB - Cell membranes are composed of 2D bilayers of amphipathic lipids, which allow a lateral movement of the respective membrane components. These components are arranged in an inhomogeneous manner as transient micro- and nanodomains, which are believed to be crucially involved in the regulation of signal transduction pathways in mammalian cells. Because of their small size (diameter 10-200 nm), membrane nanodomains cannot be directly imaged using conventional light microscopy. Here, direct visualization of cell membrane nanodomains by helium ion microscopy (HIM) is presented. It is shown that HIM is capable to image biological specimens without any conductive coating and that HIM images clearly allow the identification of nanodomains in the ultrastructure of membranes with 1.5 nm resolution. The shape of these nanodomains is preserved by fixation of the surrounding unsaturated fatty acids while saturated fatty acids inside the nanodomains are selectively removed. Atomic force microscopy, fluorescence microscopy, 3D structured illumination microscopy, and direct stochastic optical reconstruction microscopy provide additional evidence that the structures in the HIM images of cell membranes originate from membrane nanodomains. The nanodomains observed by HIM have an average diameter of 20 nm and are densely arranged with a minimal nearest neighbor distance of ~ 15 nm. PMID- 26436578 TI - Mentalization in borderline personality disorder: From bench to bedside. AB - The current special issue focuses on the potential of mentalizing as a translational construct for the understanding and treatment of borderline personality disorder (BPD). Mentalizing, which provides the central construct around which mentalization-based therapy (MBT) and theory is organized, refers to the capacity to meaningfully reflect on the mind of others as well as the self. In this introductory article to the special issue, we begin by discussing the need for and nature of translational research. We contend that translational research in mental health and personality disorder, in particular, lags behind that of other medical disorders because of the challenges inherent in meeting translational criteria. We discuss these criteria and we demonstrate the potential of the construct of mentalizing to meet translational criteria in the context of BPD. This article thereby provides the context for the other 3 papers in this special issue which each represent a different point along the translational spectrum. In all, our aim is to provide a foundation for the further evaluation of the usefulness and potential of mentalizing as translational construct in the context of BPD. PMID- 26436579 TI - The mind in the making: Developmental and neurobiological origins of mentalizing. AB - Tracing the development of mentalizing is central to understanding how we come to learn about the mind. Barring significant biological or developmental abnormalities, we all come to form an understanding of the mind and mental states. But how does this happen, and what accounts for individual differences in abilities to reason about mental states (i.e., desires, feelings, intentions)? The first section of the present article brings together relevant developmental research to outline the normative developmental trajectory of mentalizing. The second section delves into attachment research to drive home the point that this fundamental human capacity develops in tandem with early attachment relationships, and underscores the fact that suboptimal attachment contexts can hinder the developmental progression of mentalizing. Biobehavioral mechanisms that have been proposed to mediate this developmental process are discussed in the third section, with a particular focus on the neuropeptide oxytocin. PMID- 26436580 TI - The neurobiology of mentalizing. AB - Mentalizing is the capacity to understand ourselves and others in terms of intentional mental states, such as feelings, desires, wishes, attitudes, and goals. It is a fundamental capacity in our complex social environment. This article reviews our current understanding of the neurobiology of mentalizing. We first summarize the key assumptions of the mentalizing approach to normal and disrupted development. This is followed by discussion of the multiple dimensions of mentalizing and our emerging knowledge of the neural circuits that underlie these dimensions. We then consider the neurobiology of attachment and arousal regulation in relation to mentalizing, and summarize relevant studies in this area. Finally, we discuss the limitations of extant research and outline implications for future research. PMID- 26436581 TI - Translation: Mentalizing as treatment target in borderline personality disorder. AB - The role of mentalizing in relation to borderline personality disorder (BPD) is examined with a view to achieving improved levels of mentalizing in BPD patients as a therapeutic target. The article seeks to explain why mentalizing works as a treatment target for BPD, and suggests that a mentalizing approach to BPD may be at the core of any successful intervention. PMID- 26436582 TI - Mentalization as a common process in treatments for borderline personality disorder: Commentary on the special issue on mentalization in borderline personality disorder. AB - Chapman and Dixon-Gordon were invited to write this commentary, they were concerned that they did not know enough about mentalization to make coherent comments on this interesting series. As it turns out, they were among a shrinking minority, as the past decade has witnessed a surge research on mentalization. Work in this field has been pioneered, in no small part, by the authors of the present issue. Collectively, this set of articles provides a useful summary of the state of mentalization research for the uninitiated and makes a compelling case for mentalization as a key translational construct, particularly with regard to borderline personality disorder (BPD). Mentalization deserves attention in further translational research as well as in treatment refinement for BPD and other clinical problems. Future work should also involve the development of effective, objective ways to assess mentalization. Ultimately, the use of translational constructs to loosen the boundaries between evidence-based treatment approaches may help us move toward more refined, accessible, and effective treatment for BPD and other complex mental health problems. PMID- 26436583 TI - Bringing research findings to the clinic and back: Commentary on the special issue on mentalization in borderline personality disorder. AB - The articles assembled in this special issue demonstrate the broadening acceptance that a failure of "mentalization" is central in borderline personality disorder (BPD). This idea has emerged from a number of places, from astute clinicians who recognized that individuals with BPD were often limited in their ability to recognize and describe their own emotions to empirical work on emotion recognition in BPD. These articles provide a compelling argument that mentalization, with its relatively distinct and testable cognitive components, is a fertile ground for translational research. They also suggest a pathway by which empirical studies can illuminate clinical understanding. To highlight this point, it is now the routine to explain the laboratory evidence for deficits in emotional interoception to patients with BPD. This has been useful in helping to explain the internal and nuanced nature of patients' difficulties (apparent in laboratory testing but not obvious in casual encounters. This translational discussion with patients maps very closely onto an approach the editors argue for in this special issue. PMID- 26436584 TI - A framework for all seasons: Commentary on the special issue on mentalization in borderline personality disorder. AB - It is interesting to consider whether impairment in the capacity to mentalize might be a persuasive way to describe the core pathology in most patients with a personality disorder (PD). It has long been recognized that a dimensional approach to understanding PDs is more useful than the traditional categorical diagnostic model. Studies are pointing to an underlying general factor as a latent dimension of borderline personality disorder (BPD), perhaps reflecting shared or common genetic endophenotypes as risk factors for the development of BPD or other PDs. With regard to the focus on mentalizing in particular, however one thinks about impairment in mentalizing as a core reflection of personality pathology, it is helpful to drill down to deeper levels. In these pages, the authors do a remarkable job of unpacking, to the granular level, the many components of mentalization and the attachment process. PMID- 26436585 TI - Vulnerabilities of the mentalization-based models of vulnerability: A rejoinder to commentaries on the special issue on mentalization in borderline personality disorder. AB - Fonagy and Sharp read the commentaries with interest, respect, and deep gratitude. Interest, because, consistent with their mentalization-based approach, they discover most about themselves through the eyes of others. Respect, because all the commentators are major contributors to the field whose contributions deserve special issues in their own right. And finally, deep gratitude for the time and effort they took to review our contributions with thoughtfulness and insight. Fonagy and Sharp hope that the set of articles that they have brought together for this special section, in combination with the thoughtful commentaries previously discussed, will further stimulate constructive dialogue around the potential of mentalizing as a translational target. They are grateful to the editors of this journal for their assistance in laying the foundation for this continued dialogue. PMID- 26436586 TI - Maternal effect and speciation: maternal effect contributes to the evolution of hybrid inviability between Drosophila simulans and Drosophila mauritiana. AB - Haldane's rule has been the basis of speciation research during the last 30 years. Most studies have focused on the nature of incompatibilities in the hybrid male, but not much attention has been given to the genetic basis of fertility and inviability in hybrid females. Hybridizations between Drosophila simulans and Drosophila mauritiana produce fertile females and sterile males. Here, we re examined the level of fertility in reciprocal F1 females of these two species and looked for the presence of maternal effects. Our results show that the reciprocal F1 females of D. simulans and D. mauritiana hybridizations are fully fertile and in fact show a significant level of heterosis in the rate of oviposition but display reduced egg hatching in one direction. Reduced egg hatching was observed in the progenies of F1 hybrid females with D. mauritiana as mother, the same cross that showed a stronger negative effect on F1 male fertility. A review of the literature on the hybridizations in Lepidoptera also showed a maternal effect on inviability when reciprocal crosses produced asymmetric results. Our findings point to the importance of maternal effects in the evolution of embryo inviability and thus enhancing the process of speciation through the evolution of hybrid inviability. PMID- 26436587 TI - On the relative contributions of multisensory integration and crossmodal exogenous spatial attention to multisensory response enhancement. AB - Two processes that can give rise to multisensory response enhancement (MRE) are multisensory integration (MSI) and crossmodal exogenous spatial attention. It is, however, currently unclear what the relative contribution of each of these is to MRE. We investigated this issue using two tasks that are generally assumed to measure MSI (a redundant target effect task) and crossmodal exogenous spatial attention (a spatial cueing task). One block of trials consisted of unimodal auditory and visual targets designed to provide a unimodal baseline. In two other blocks of trials, the participants were presented with spatially and temporally aligned and misaligned audiovisual (AV) targets (0, 50, 100, and 200ms SOA). In the integration block, the participants were instructed to respond to the onset of the first target stimulus that they detected (A or V). The instruction for the cueing block was to respond only to the onset of the visual targets. The targets could appear at one of three locations: left, center, and right. The participants were instructed to respond only to lateral targets. The results indicated that MRE was caused by MSI at 0ms SOA. At 50ms SOA, both crossmodal exogenous spatial attention and MSI contributed to the observed MRE, whereas the MRE observed at the 100 and 200ms SOAs was attributable to crossmodal exogenous spatial attention, alerting, and temporal preparation. These results therefore suggest that there may be a temporal window in which both MSI and exogenous crossmodal spatial attention can contribute to multisensory response enhancement. PMID- 26436588 TI - Breastfeeding: An Unknown Factor to Reduce Heart Disease Risk Among Breastfeeding Women. AB - BACKGROUND: Breastfeeding confers many health benefits not only to babies but also to their lactating mothers. Breastfeeding is a notable protective factor in the Gail model for breast cancer and is protective for heart disease. Although individuals in the Appalachian region have lower risk of developing breast cancer, their risk of heart disease is elevated compared with the national value for the United States. SUBJECTS AND METHODS: We surveyed 155 predominantly breastfeeding mothers of toddlers under 3 years old, recruited through parenting groups, daycares, and county extension in Appalachian West Virginia. Participants were asked their perceived comparative risks for breast cancer and heart disease and why they felt their risk was higher, same, or lower than that of the general population. RESULTS: For breast cancer, 29.7% felt their risk was lower than the general population. For heart disease, 26.5% felt their risk was lower than the general population. Although these risks were highly correlated (p=0.006), there was considerable variability in responses (p<0.03). Qualitative responses for breast cancer risk frequently included breastfeeding (30.3%) and family history (30.3%). Qualitative responses for heart disease noted family history (36.1%) but did not include breastfeeding. A regression analysis found that greater family history, shorter duration of breastfeeding, and fewer pregnancies were associated with greater breast cancer risk perceptions. Family history, lower household income, and current smoking were associated with greater heart disease risk perceptions. CONCLUSIONS: These well-educated, predominantly lactating women did not know the protective effects of breastfeeding for heart disease. Increased educational efforts about heart disease may be helpful to encourage more women to breastfeed. PMID- 26436589 TI - PRMT6 increases cytoplasmic localization of p21CDKN1A in cancer cells through arginine methylation and makes more resistant to cytotoxic agents. AB - p21(CDKN1A) is known as a potent inhibitor of cyclin-dependent kinase (CDK), which regulates cell cycle in response to various stimuli, including DNA damage, on the p53-dependent manner. Here we demonstrate that protein arginine methyltransferase 6 (PRMT6) methylates p21 at arginine 156 and promotes phosphorylation of threonine 145 on p21, resulting in the increase of cytoplasmic localization of p21. The cytoplasmic presence of p21 makes cancer cells more resistant to cytotoxic agents. Our results indicate that PRMT6 appears to be one of the key proteins to dysregulate p21 functions in human cancer, and targeting this pathway may be an appropriate strategy for development of anticancer drugs. PMID- 26436591 TI - Lysosomal mTORC2/PHLPP1/Akt axis: a new point of control of chaperone-mediated autophagy. PMID- 26436590 TI - The lincRNA HOTAIRM1, located in the HOXA genomic region, is expressed in acute myeloid leukemia, impacts prognosis in patients in the intermediate-risk cytogenetic category, and is associated with a distinctive microRNA signature. AB - Long non-coding RNAs (lncRNAs) are deregulated in several tumors, although their role in acute myeloid leukemia (AML) is mostly unknown.We have examined the expression of the lncRNA HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) in 241 AML patients. We have correlated HOTAIRM1 expression with a miRNA expression profile. We have also analyzed the prognostic value of HOTAIRM1 expression in 215 intermediate-risk AML (IR-AML) patients.The lowest expression level was observed in acute promyelocytic leukemia (P < 0.001) and the highest in t(6;9) AML (P = 0.005). In 215 IR-AML patients, high HOTAIRM1 expression was independently associated with shorter overall survival (OR:2.04;P = 0.001), shorter leukemia free survival (OR:2.56; P < 0.001) and a higher cumulative incidence of relapse (OR:1.67; P = 0.046). Moreover, HOTAIRM1 maintained its independent prognostic value within the favorable molecular subgroup (OR: 3.43; P = 0.009). Interestingly, HOTAIRM1 was overexpressed in NPM1-mutated AML (P < 0.001) and within this group retained its prognostic value (OR: 2.21; P = 0.01). Moreover, HOTAIRM1 expression was associated with a specific 33-microRNA signature that included miR-196b (P < 0.001). miR-196b is located in the HOX genomic region and has previously been reported to have an independent prognostic value in AML. miR 196b and HOTAIRM1 in combination as a prognostic factor can classify patients as high-, intermediate-, or low-risk (5-year OS: 24% vs 42% vs 70%; P = 0.004).Determination of HOTAIRM1 level at diagnosis provided relevant prognostic information in IR-AML and allowed refinement of risk stratification based on common molecular markers. The prognostic information provided by HOTAIRM1 was strengthened when combined with miR-196b expression. Furthermore, HOTAIRM1 correlated with a 33-miRNA signature. PMID- 26436593 TI - Transcriptome asymmetry in synthetic and natural allotetraploid wheats, revealed by RNA-sequencing. AB - Allopolyploidization has occurred frequently within the Triticum-Aegilops complex which provides a suitable system to investigate how allopolyploidization shapes the expression patterns of duplicated homeologs. We have conducted transcriptome profiling of leaves and young inflorescences in wild and domesticated tetraploid wheats, Triticum turgidum ssp. dicoccoides (BBAA) and ssp. durum (BBAA), an extracted tetraploid (BBAA), and a synthetic tetraploid (S(l) S(l) AA) wheat together with its diploid parents, Aegilops longissima (S(l) S(l) ) and Triticum urartu (AA). The two diploid species showed tissue-specific differences in genome wide ortholog expression, which plays an important role in transcriptome shock mediated homeolog expression rewiring and hence transcriptome asymmetry in the synthetic tetraploid. Further changes of homeolog expression apparently occurred in natural tetraploid wheats, which led to novel transcriptome asymmetry between the two subgenomes. In particular, our results showed that extremely biased homeolog expression can occur rapidly upon the allotetraploidzation and this trend is further enhanced in the course of domestication and evolution of polyploid wheats. Our results suggest that allopolyploidization is accompanied by distinct phases of homeolog expression changes, with parental legacy playing major roles in the immediate rewiring of homeolog expression upon allopolyploidization, while evolution and domestication under allotetraploidy drive further homeolog-expression changes toward re-established subgenome expression asymmetry. PMID- 26436594 TI - I Can Stomach That! Fearlessness About Death Predicts Attenuated Facial Electromyography Activity in Response to Death-Related Images. AB - Objective measures of suicide risk can convey life-saving information to clinicians, but few such measures exist. This study examined an objective measure of fearlessness about death (FAD), testing whether FAD relates to self-reported and physiological aversion to death. Females (n = 87) reported FAD and disgust sensitivity, and facial electromyography was used to measure physiological facial responses consistent with disgust while viewing death-related images. FAD predicted attenuated expression of physiological death aversion, even when controlling for self-reported death-related disgust sensitivity. Diminished physiological aversion to death-related stimuli holds promise as an objective measure of FAD and suicide risk. PMID- 26436595 TI - Surface and Bulk Effects in Photochemical Reactions and Photomechanical Effects in Dynamic Molecular Crystals. AB - The increasing number of reports on photomechanical effects in molecular crystals necessitates systematic studies to understand the intrinsic and external effectors that determine and have predictive power of their type and magnitude. Differential light absorption and product gradient between the surface and the bulk of the crystal are often invoked to qualitatively explain the mechanical response of crystals to light; however, the details on how this difference in photochemical response accounts for macroscopic effects such as surface modification, deformation, or disintegration of crystals are yet to be established. Using both bulk- and surface-sensitive analytical techniques, a rare instance of benzylidenefuranone crystals is studied here, and it is capable of several distinct types of photomechanical response including surface striation and delamination, photosalient effect (ballistic disintegration and motion), and photoinduced bending by dimerization. The results provide a holistic view on these effects and set the stage for the development of overarching theoretical models to describe the photomechanics in the ordered solid state. PMID- 26436596 TI - Role of diode lasers (800-980 nm) as adjuncts to scaling and root planing in the treatment of chronic periodontitis: a systematic review. AB - OBJECTIVE: The purpose of this study was to systematically review currently available evidence regarding the role of diode lasers (810-980 nm) as adjuncts to scaling and root planing (SRP) in the treatment of chronic periodontitis (CP). BACKGROUND DATA: Mechanical instrumentation of periodontal tissues followed by diode laser application leads to complete removal of pocket epithelium compared with conventional SRP. MATERIALS AND METHODS: To address the focused question "Is SRP with adjunct diode lasers (810-980 nm) therapy more effective in the treatment of CP than when CP is treated by SRP alone?" databases were searched using the following key words: chronic periodontitis, diode laser, surgical, AND scaling and root planing, periodontal diseases, periodontal therapy, AND periodontal treatment. Original studies were included. Letters to the editor, case reports, commentaries, and reviews were excluded. RESULTS: Ten clinical studies were included. In all studies, patients were systemically healthy, and cigarette smokers were included in two studies. In five studies, SRP plus diode laser application was more effective in the treatment of CP than SRP, and three studies showed no difference. In two studies, there was a moderate reduction in periodontal inflammation using SRP plus diode laser. The diameter of optic fiber, laser wavelengths, power, pulse repetition rate, and duration of laser exposure ranged between 300 MUm and 2 mm, 810-980 nm, 0.8-2.5 W, 10-60 Hz, and 10-100 ms, respectively. CONCLUSIONS: In CP patients with probing depths <=5 mm, diode lasers, SRP plus diode laser (800-980 nm) is more effective in the treatment of CP than when SRP is used alone. PMID- 26436597 TI - Parasympathomimetic drugs for the treatment of salivary gland dysfunction due to radiotherapy. AB - BACKGROUND: This is an updated version of the original Cochrane review on parasympathomimetic drugs for the treatment of salivary gland dysfunction due to radiotherapy (published in Issue 3, 2007). Salivary gland dysfunction is a predictable side effect of radiotherapy to the head and neck region. Pilocarpine hydrochloride (a choline ester) is licensed in many countries for the treatment of radiation-induced salivary gland dysfunction. Other parasympathomimetics have also been used 'off licence' in the treatment of this condition. OBJECTIVES: To determine the efficacy and tolerability of parasympathomimetic drugs in the treatment of radiation-induced salivary gland dysfunction (specifically radiation induced xerostomia). SEARCH METHODS: For this update, we ran searches of the Cochrane Oral Health Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 6), MEDLINE, EMBASE, and CINAHL in July 2015. We checked the reference lists of retrieved articles for additional studies, contacted experts in the field for unpublished and ongoing trials, and contacted relevant pharmaceutical companies for unpublished and ongoing trials. SELECTION CRITERIA: The selection criteria for the review were: 1) randomised controlled trials; 2) people suffering from radiation-induced salivary gland dysfunction; 3) people treated with parasympathomimetic drugs; and 4) assessable data available on primary outcome measure. DATA COLLECTION AND ANALYSIS: The two review authors independently collected data from the full-text version of relevant papers including: 1) citation details; 2) participants; 3) interventions; 4) assessments; 5) outcomes (that is efficacy, tolerability); and 6) quality issues.Due to a lack of appropriate data, we were unable to perform a meta-analysis. MAIN RESULTS: In the original review, three studies, including a total of 298 participants, fulfilled the inclusion criteria. All three studies involved the use of pilocarpine hydrochloride. We have included no additional studies in the update of the review; we have excluded eight additional studies.The data suggest that pilocarpine hydrochloride is more effective than placebo and at least as effective as artificial saliva. The response rate was 42% to 51%. The time to response was up to 12 weeks. The overall side effect rate was high, and side effects were the main reason for withdrawal (6% to 15% of participants taking 5 mg three times a day had to withdraw). The side effects were usually the result of generalised parasympathomimetic stimulation (for example sweating, headaches, urinary frequency, vasodilatation). Response rates were not dose dependent, but side effect rates were dose dependent. AUTHORS' CONCLUSIONS: There is limited evidence to support the use of pilocarpine hydrochloride in the treatment of radiation-induced xerostomia. Currently, there is little evidence to support the use of other parasympathomimetic drugs in the treatment of radiation-induced xerostomia. Available studies suggest that approximately half of patients will respond, but side effects can be problematic. The conclusions of the update are the same as the conclusions of the original review, since no new relevant studies have been published in the interim. PMID- 26436598 TI - High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma. AB - BACKGROUND: Despite the development of new treatment options, the prognosis of high-risk neuroblastoma patients is still poor; more than half of patients experience disease recurrence. High-dose chemotherapy and haematopoietic stem cell rescue (i.e. myeloablative therapy) might improve survival. This review is the second update of a previously published Cochrane review. OBJECTIVES: Primary objectiveTo compare the efficacy, that is event-free and overall survival, of high-dose chemotherapy and autologous bone marrow or stem cell rescue with conventional therapy in children with high-risk neuroblastoma. Secondary objectivesTo determine adverse effects (e.g. veno-occlusive disease of the liver) and late effects (e.g. endocrine disorders or secondary malignancies) related to the procedure and possible effects of these procedures on quality of life. SEARCH METHODS: We searched the electronic databases The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, issue 11), MEDLINE/PubMed (1966 to December 2014) and EMBASE/Ovid (1980 to December 2014). In addition, we searched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (SIOP) (from 2002 to 2014), American Society for Pediatric Hematology and Oncology (ASPHO) (from 2002 to 2014), Advances in Neuroblastoma Research (ANR) (from 2002 to 2014) and American Society for Clinical Oncology (ASCO) (from 2008 to 2014). We searched for ongoing trials by scanning the ISRCTN register (www.isrct.com) and the National Institute of Health Register (www.clinicaltrials.gov). Both registers were screened in April 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the efficacy of myeloablative therapy with conventional therapy in high-risk neuroblastoma patients. DATA COLLECTION AND ANALYSIS: Two authors independently performed study selection, data extraction and risk of bias assessment. If appropriate, we pooled studies. The risk ratio (RR) and 95% confidence interval (CI) was calculated for dichotomous outcomes. For the assessment of survival data, we calculated the hazard ratio (HR) and 95% CI. We used Parmar's method if hazard ratios were not reported in the study. We used a random-effects model. MAIN RESULTS: We identified three RCTs including 739 children. They all used an age of one year as the cut-off point for pre-treatment risk stratification. The first updated search identified a manuscript reporting additional follow-up data for one of these RCTs, while the second update identified an erratum of this study. There was a significant statistical difference in event-free survival in favour of myeloablative therapy over conventional chemotherapy or no further treatment (three studies, 739 patients; HR 0.78, 95% CI 0.67 to 0.90). There was a significant statistical difference in overall survival in favour of myeloablative therapy over conventional chemotherapy or no further treatment (two studies, 360 patients; HR 0.74, 95% CI 0.57 to 0.98). However, when additional follow-up data were included in the analyses the difference in event-free survival remained statistically significant (three studies, 739 patients; HR 0.79, 95% CI 0.70 to 0.90), but the difference in overall survival was no longer statistically significant (two studies, 360 patients; HR 0.86, 95% CI 0.73 to 1.01). The meta-analysis of secondary malignant disease and treatment-related death did not show any significant statistical differences between the treatment groups. Data from one study (379 patients) showed a significantly higher incidence of renal effects, interstitial pneumonitis and veno-occlusive disease in the myeloablative group compared to conventional chemotherapy, whereas for serious infections and sepsis no significant difference between the treatment groups was identified. No information on quality of life was reported. In the individual studies we evaluated different subgroups, but the results were not univocal in all studies. All studies had some methodological limitations. AUTHORS' CONCLUSIONS: Based on the currently available evidence, myeloablative therapy seems to work in terms of event-free survival. For overall survival there is currently no evidence of effect when additional follow-up data are included. No definitive conclusions can be made regarding adverse effects and quality of life, although possible higher levels of adverse effects should be kept in mind. A definitive conclusion regarding the effect of myeloablative therapy in different subgroups is not possible. This systematic review only allows a conclusion on the concept of myeloablative therapy; no conclusions can be made regarding the best treatment strategy. Future trials on the use of myeloablative therapy for high-risk neuroblastoma should focus on identifying the most optimal induction and/or myeloablative regimen. The best study design to answer these questions is a RCT. These RCTs should be performed in homogeneous study populations (e.g. stage of disease and patient age) and have a long-term follow up. Different risk groups, using the most recent definitions, should be taken into account.It should be kept in mind that recently the age cut-off for high risk disease was changed from one year to 18 months. As a result it is possible that patients with what is now classified as intermediate-risk disease have been included in the high-risk groups. Consequently the relevance of the results of these studies to the current practice can be questioned. Survival rates may be overestimated due to the inclusion of patients with intermediate-risk disease. PMID- 26436599 TI - Noninvasive positive pressure ventilation for acute respiratory failure following upper abdominal surgery. AB - BACKGROUND: Each year, more than four million abdominal surgeries are performed in the US and over 250,000 in England. Acute respiratory failure, a common complication that can affect 30% to 50% of people after upper abdominal surgery, can lead to significant morbidity and mortality. Noninvasive ventilation has been associated with lower rates of tracheal intubation in adults with acute respiratory failure, thus reducing the incidence of complications and mortality. This review compared the effectiveness and safety of noninvasive positive pressure ventilation (NPPV) versus standard oxygen therapy in the treatment of acute respiratory failure after upper abdominal surgery. OBJECTIVES: To assess the effectiveness and safety of noninvasive positive pressure ventilation (NPPV), that is, continuous positive airway pressure (CPAP) or bilevel NPPV, in reducing mortality and the rate of tracheal intubation in adults with acute respiratory failure after upper abdominal surgery, compared to standard therapy (oxygen therapy), and to assess changes in arterial blood gas levels, hospital and intensive care unit (ICU) length of stay, gastric insufflation, and anastomotic leakage. SEARCH METHODS: The date of the last search was 12 May 2015. We searched the following databases: the Cochrane Handbook for Systematic Reviews of Interventions (CENTRAL) (2015, Issue 5), MEDLINE (Ovid SP, 1966 to May 2015), EMBASE (Ovid SP, 1974 to May 2015); the physiotherapy evidence database (PEDro) (1999 to May 2015); the Cumulative Index to Nursing and Allied Health Literature (CINAHL, EBSCOhost, 1982 to May 2015), and LILACS (BIREME, 1986 to May 2015). We reviewed reference lists of included studies and contacted experts. We also searched grey literature sources. We checked databases of ongoing trials such as www.controlled-trials.com/ and www.trialscentral.org/. We did not apply language restrictions. SELECTION CRITERIA: We selected randomized or quasi-randomized controlled trials involving adults with acute respiratory failure after upper abdominal surgery who were treated with CPAP or bilevel NPPV with, or without, drug therapy as standard medical care, compared to adults treated with oxygen therapy with, or without, standard medical care. DATA COLLECTION AND ANALYSIS: Two authors independently selected and abstracted data from eligible studies using a standardized form. We evaluated study quality by assessing allocation concealment; random sequence generation; incomplete outcome data; blinding of participants, personnel, and outcome assessors; selective reporting; and adherence to the intention-to-treat (ITT) principle. MAIN RESULTS: We included two trials involving 269 participants. The participants were mostly men (67%); the mean age was 65 years. The trials were conducted in China and Italy (one was a multicentre trial). Both trials included adults with acute respiratory failure after upper abdominal surgery. We judged both trials at high risk of bias. Compared to oxygen therapy, CPAP or bilevel NPPV may reduce the rate of tracheal intubation (risk ratio (RR) 0.25; 95% confidence interval (CI) 0.08 to 0.83; low quality evidence) with a number needed to treat for an additional beneficial outcome of 11. There was very low quality evidence that the intervention may also reduce ICU length of stay (mean difference (MD) -1.84 days; 95% CI -3.53 to 0.15). We found no differences for mortality (low quality evidence) and hospital length of stay. There was insufficient evidence to be certain that CPAP or NPPV had an effect on anastomotic leakage, pneumonia-related complications, and sepsis or infections. Findings from one trial of 60 participants suggested that bilevel NPPV, compared to oxygen therapy, may improve blood gas levels and blood pH one hour after the intervention (partial pressure of arterial oxygen (PaO2): MD 22.5 mm Hg; 95% CI 17.19 to 27.81; pH: MD 0.06; 95% CI 0.01 to 0.11; partial pressure of arterial carbon dioxide (PCO2) levels (MD -9.8 mm Hg; 95% CI -14.07 to -5.53). The trials included in this systematic review did not present data on the following outcomes that we intended to assess: gastric insufflation, fistulae, pneumothorax, bleeding, skin breakdown, eye irritation, sinus congestion, oronasal drying, and patient-ventilator asynchrony. AUTHORS' CONCLUSIONS: The findings of this review indicate that CPAP or bilevel NPPV is an effective and safe intervention for the treatment of adults with acute respiratory failure after upper abdominal surgery. However, based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, the quality of the evidence was low or very low. More good quality studies are needed to confirm these findings. PMID- 26436600 TI - Preoperative inspiratory muscle training for postoperative pulmonary complications in adults undergoing cardiac and major abdominal surgery. AB - BACKGROUND: Postoperative pulmonary complications (PPCs) have an impact on the recovery of adults after surgery. It is therefore important to establish whether preoperative respiratory rehabilitation can decrease the risk of PPCs and to identify adults who might benefit from respiratory rehabilitation. OBJECTIVES: Our primary objective was to assess the effectiveness of preoperative inspiratory muscle training (IMT) on PPCs in adults undergoing cardiac or major abdominal surgery. We looked at all-cause mortality and adverse events. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 10), MEDLINE (1966 to October 2014), EMBASE (1980 to October 2014), CINAHL (1982 to October 2014), LILACS (1982 to October 2014), and ISI Web of Science (1985 to October 2014). We did not impose any language restrictions. SELECTION CRITERIA: We included randomized controlled trials that compared preoperative IMT and usual preoperative care for adults undergoing cardiac or major abdominal surgery. DATA COLLECTION AND ANALYSIS: Two or more review authors independently identified studies, assessed trial quality, and extracted data. We extracted the following information: study characteristics, participant characteristics, intervention details, and outcome measures. We contacted study authors for additional information in order to identify any unpublished data. MAIN RESULTS: We included 12 trials with 695 participants; five trials included participants awaiting elective cardiac surgery and seven trials included participants awaiting elective major abdominal surgery. All trials contained at least one domain judged to be at high or unclear risk of bias. Of greatest concern was the risk of bias associated with inadequate blinding, as it was impossible to blind participants due to the nature of the study designs. We could pool postoperative atelectasis in seven trials (443 participants) and postoperative pneumonia in 11 trials (675 participants) in a meta-analysis. Preoperative IMT was associated with a reduction of postoperative atelectasis and pneumonia, compared with usual care or non-exercise intervention (respectively; risk ratio (RR) 0.53, 95% confidence interval (CI) 0.34 to 0.82 and RR 0.45, 95% CI 0.26 to 0.77). We could pool all cause mortality within postoperative period in seven trials (431 participants) in a meta-analysis. However, the effect of IMT on all-cause postoperative mortality is uncertain (RR 0.40, 95% CI 0.04 to 4.23). Eight trials reported the incidence of adverse events caused by IMT. All of these trials reported that there were no adverse events in both groups. We could pool the mean duration of hospital stay in six trials (424 participants) in a meta-analysis. Preoperative IMT was associated with reduced length of hospital stay (MD -1.33, 95% CI -2.53 to 0.13). According to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) Working Group guidelines for evaluating the impact of healthcare interventions, the overall quality of studies for the incidence of pneumonia was moderate, whereas the overall quality of studies for the incidence of atelectasis, all-cause postoperative death, adverse events, and duration of hospital stay was low or very low. AUTHORS' CONCLUSIONS: We found evidence that preoperative IMT was associated with a reduction of postoperative atelectasis, pneumonia, and duration of hospital stay in adults undergoing cardiac and major abdominal surgery. The potential for overestimation of treatment effect due to lack of adequate blinding, small-study effects, and publication bias needs to be considered when interpreting the present findings. PMID- 26436601 TI - Oral nonsteroidal anti-inflammatory drugs for neuropathic pain. AB - BACKGROUND: Although often considered to be lacking adequate evidence, nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the management of neuropathic pain. Previous surveys found 18% to 47% of affected people reported using NSAIDs specifically for their neuropathic pain, although possibly not in the United Kingdom (UK). OBJECTIVES: To assess the analgesic efficacy of oral NSAIDs for chronic neuropathic pain in adults, when compared to placebo or another active intervention, and the adverse events associated with its use in clinical trials. SEARCH METHODS: We searched CENTRAL, MEDLINE, and EMBASE from inception to 29 May 2015, together with reference lists of retrieved papers and reviews, and an online trials registry. SELECTION CRITERIA: We included randomised, double-blind studies of two weeks duration or longer, comparing any oral NSAID with placebo or another active treatment in chronic neuropathic pain. DATA COLLECTION AND ANALYSIS: Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality. We did not carry out any pooled analysis. MAIN RESULTS: We included two studies involving 251 participants with chronic low back pain with a neuropathic component or postherpetic neuralgia; 209 of these participants were involved in a study of an experimental NSAID not used in clinical practice, and of the remaining 42, only 16 had neuropathic pain. This represented only third tier evidence, and was of very low quality. There was no indication of any significant pain reduction with NSAIDs. Adverse event rates were low, with insufficient events for any analysis. AUTHORS' CONCLUSIONS: There is no evidence to support or refute the use of oral NSAIDs to treat neuropathic pain conditions. PMID- 26436602 TI - Comparison of a restrictive versus liberal red cell transfusion policy for patients with myelodysplasia, aplastic anaemia, and other congenital bone marrow failure disorders. AB - BACKGROUND: Bone marrow failure disorders include a heterogenous group of disorders, of which myelodysplastic syndrome (MDS), forms the largest subgroup. MDS is predominantly a disease of the elderly, with many elderly people managed conservatively with regular allogeneic red blood cell (RBC) transfusions to treat their anaemia. However, RBC transfusions are not without risk. Despite regular transfusions playing a central role in treating such patients, the optimal RBC transfusion strategy (restrictive versus liberal) is currently unclear. OBJECTIVES: To assess the efficacy and safety of a restrictive versus liberal red blood cell transfusion strategy for patients with myelodysplasia, acquired aplastic anaemia, and other inherited bone marrow failure disorders. SEARCH METHODS: We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2015, Issue 4), Ovid MEDLINE (from 1946), Ovid EMBASE (from 1974), EBSCO CINAHL (from 1937), the Transfusion Evidence Library (from 1980) and ongoing trial databases to 26th May 2015. SELECTION CRITERIA: RCTs including patients with long-term bone marrow failure disorders that require allogeneic blood transfusion, who are not being actively treated with a haematopoietic stem cell transplant, or intensive chemotherapy. DATA COLLECTION AND ANALYSIS: We used standard Cochrane review methodology. One author initially screened all references, and excluded any that were clearly irrelevant or duplicates. Two authors then independently screened all abstracts of articles, identified by the review search strategy, for relevancy. Two authors independently assessed the full text of all potentially relevant articles for eligibility, completed the data extraction and assessed the studies for risk of bias using The Cochrane Collaboration's 'Risk of bias' tool. MAIN RESULTS: We included one trial (13 participants) and identified three ongoing trials that assess RBC transfusion strategies in people with MDS.The quality of the evidence was very low across different outcomes according to GRADE methodology.The one included study randomised participants to a restrictive [haemoglobin (Hb) transfusion trigger < 72 g/L, 8 participants] or liberal [Hb trigger < 96 g/L, 5 participants] transfusion policy. There was insufficient evidence to determine a difference in all-cause mortality (1 RCT; 13 participants; RR 0.13, 95% CI 0.01 to 2.32; very low quality evidence). There was insufficient evidence to determine a difference in the number of red blood cell transfusions (1 RCT; 13 participants; 1.8 units per patient per month in the liberal group, compared to 0.8 in the restrictive arm, no standard deviation was reported; very low quality evidence). There were no anaemia-related complications reported (cardiac failure) and no reported effect on activity levels (no statistics provided). The study did not report: mortality due to bleeding/infection/transfusion reactions or iron overload, quality of life, frequency and length of hospital admissions, serious infections (requiring admission to hospital), or serious bleeding (e.g. WHO/CTCAE grade 3 (or equivalent) or above). AUTHORS' CONCLUSIONS: This review indicates that there is currently a lack of evidence for the recommendation of a particular transfusion strategy for bone marrow failure patients undergoing supportive treatment only. The one RCT included in this review was only published as an abstract and contained only 13 participants. Further randomised trials with robust methodology are required to develop the optimal transfusion strategy for such patients, particularly as the incidence of the main group of bone marrow failure disorders, MDS, rises with an ageing population. PMID- 26436603 TI - Predicting non-familial major physical violent crime perpetration in the US Army from administrative data. AB - BACKGROUND: Although interventions exist to reduce violent crime, optimal implementation requires accurate targeting. We report the results of an attempt to develop an actuarial model using machine learning methods to predict future violent crimes among US Army soldiers. METHOD: A consolidated administrative database for all 975 057 soldiers in the US Army in 2004-2009 was created in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). Of these soldiers, 5771 committed a first founded major physical violent crime (murder-manslaughter, kidnapping, aggravated arson, aggravated assault, robbery) over that time period. Temporally prior administrative records measuring socio demographic, Army career, criminal justice, medical/pharmacy, and contextual variables were used to build an actuarial model for these crimes separately among men and women using machine learning methods (cross-validated stepwise regression, random forests, penalized regressions). The model was then validated in an independent 2011-2013 sample. RESULTS: Key predictors were indicators of disadvantaged social/socioeconomic status, early career stage, prior crime, and mental disorder treatment. Area under the receiver-operating characteristic curve was 0.80-0.82 in 2004-2009 and 0.77 in the 2011-2013 validation sample. Of all administratively recorded crimes, 36.2-33.1% (male-female) were committed by the 5% of soldiers having the highest predicted risk in 2004-2009 and an even higher proportion (50.5%) in the 2011-2013 validation sample. CONCLUSIONS: Although these results suggest that the models could be used to target soldiers at high risk of violent crime perpetration for preventive interventions, final implementation decisions would require further validation and weighing of predicted effectiveness against intervention costs and competing risks. PMID- 26436608 TI - Multinuclear Magnetic Resonance Investigation of Crystalline Alkali Molybdates. AB - A variety of crystalline alkali molybdate phases are characterized by (23)Na, (133)Cs, and (95)Mo magic-angle-spinning nuclear magnetic resonance (MAS NMR) to provide spectroscopic handles for studies of devitrification products in borosilicate nuclear waste glasses. The NMR parameters obtained from line-shape simulations are plotted as a function of various structural parameters to discern trends that may prove useful in the determination of unknown phases. These are applied to Cs3Na(MoO4)2, the most common precipitate found in cesium- and molybdenum-bearing model nuclear waste glasses, the crystal structure of which has not yet been determined, to provide structural constraints that may guide the refinement of powder X-ray diffraction data. PMID- 26436605 TI - A mixed-method investigation of patient monitoring and enhanced feedback in routine practice: Barriers and facilitators. AB - OBJECTIVE: To investigate the barriers and facilitators of an effective implementation of an outcome monitoring and feedback system in a UK National Health Service psychological therapy service. METHOD: An outcome monitoring system was introduced in two services. Enhanced feedback was given to therapists after session 4. Qualitative and quantitative methods were used, including questionnaires for therapists and patients. Thematic analysis was carried out on written and verbal feedback from therapists. Analysis of patient outcomes for 202 episodes of therapy was compared with benchmark data of 136 episodes of therapy for which feedback was not given to therapists. RESULTS: Themes influencing the feasibility and acceptability of the feedback system were the extent to which therapists integrated the measures and feedback into the therapy, availability of administrative support, information technology, and complexity of the service. There were low levels of therapist actions resulting from the feedback, including discussing the feedback in supervision and with patients. CONCLUSIONS: The findings support the feasibility and acceptability of setting up a routine system in a complex service, but a number of challenges and barriers have to be overcome and therapist differences are apparent. More research on implementation and effectiveness is needed in diverse clinical settings. PMID- 26436609 TI - Synthesis and Characterization of Chitosan-Based Polyelectrolyte Complexes Doped with Xanthene Dyes. AB - Biocompatible chitosan-based polyelectrolyte complexes (PECs) doped with xanthene dyes (fluorescein, eosin Y, erythrosin B, rhodamine 6G) were synthesized and characterized by scanning electron microscopy, dynamic light scattering, zeta potential measurements, and absorption and luminescence (including polarized, time-resolved, and phosphorescence) spectroscopy. The results are discussed in terms of the mechanism and rigidity of dye-PEC binding, the heavy-atom effect in dyes and PEC stability. Eosin Y is found to be the optimal dopant, providing both a high dye content in PECs and a high quantum yield of fluorescence. PMID- 26436610 TI - Serum miR-122 may serve as a biomarker for response to direct acting antivirals: effect of paritaprevir/R with dasabuvir or ombitasvir on miR-122 in HCV-infected subjects. AB - Circulating microRNAs (miRNA) have been intensely investigated as biomarkers in disease and therapy. Several studies have identified miR-122 as an important regulator of HCV replication. The effect of new therapies that directly target the HCV replication life cycle on circulating microRNA levels has not been elucidated. We performed expression profiling of circulating miRNA in serum in subjects treated with HCV direct-acting antiviral agents (DAAs). Serum miRNA levels were evaluated from two studies in HCV GT1-infected treatment-naive subjects and prior nonresponders to pegylated interferon (pegIFN) and ribavirin (RBV) who received paritaprevir/ritonavir + dasabuvir + RBV for 12 weeks, and in treatment-naive genotype (GT)1-3-infected subjects who received paritaprevir/ritonavir + ombitasvir +/- RBV for 12 weeks. Over 100 different miRNA species were detected in serum. Of these, levels of miR-122 showed the most consistent change in response to treatment across all HCV genotypes. In all subjects, miR-122 showed an average four-fold reduction between baseline and week 2, and remained below baseline through post-treatment week 12 in subjects who achieved sustained virological response. In contrast, in subjects who did not achieve SVR, miR-122 levels began to return to baseline levels after the second week of treatment. The change in miR-122 levels was similar across genotypes, and was comparable with or without RBV. This is the first report comparing expression levels of circulating miRNA in HCV GT1-3 subjects treated with IFN-free combinations of DAAs. The results suggest that serum levels of miR-122 are reduced following treatment in subjects who achieve SVR, and correlate with HCV RNA levels across genotypes. PMID- 26436612 TI - Subnanometer Control of Mean Core Size during Mesofluidic Synthesis of Small (D(core) < 10 nm) Water-Soluble, Ligand-Stabilized Gold Nanoparticles. AB - A convenient, single-step synthesis is reported that produces ligand-stabilized, water-soluble gold nanoparticles (AuNPs) with subnanometer-level precision of the mean core diameter over a range of 2-9 nm for a series of desired surface chemistries. The synthesis involves the reduction of a Au(III) species with sodium borohydride in the presence of a functionalized alkyl thiosulfate (Bunte salt) to yield thiolate-protected AuNPs. A key advantage of this synthesis is that simply adjusting the pH of the gold salt solution leads to control over the AuNP core size. The speciation of Au(III), and therefore the kinetics for its reduction and the core size produced, depends upon pH. The use of pH as the sole variable to control core size is a more reliable and convenient method than traditional approaches that rely on adjusting the concentrations and ratios of ligand, metal salt, and reducing agent. The average core size increased as the pH was raised for each ligand studied. Because the influence of pH was different for each of the ligands, working curves were plotted for each ligand to identify conditions to synthesize particles with specific, targeted core diameters. Using this approach, reaction conditions can be rapidly optimized using a combination of a mesofluidic reactor and small-angle X-ray scattering (SAXS) size analysis. The use of the mesofluidic reactor was needed to ensure fast mixing given the rapid kinetics for core formation. Using the reactor, it is possible to obtain reproducible sizes across multiple syntheses (<1-2% core size variation) and subnanometer control of the mean core dimensions. The synthetic method demonstrated here provides an attractive alternative to two-step syntheses involving ligand exchange because it is more efficient and eliminates the possibility of nanoparticle core size changes during exchange steps. This approach enables the development of "size ladders" of particles with the same surface chemistry for investigations of structure-function relationships. PMID- 26436611 TI - Association Between Hospitalization With Community-Acquired Laboratory-Confirmed Influenza Pneumonia and Prior Receipt of Influenza Vaccination. AB - IMPORTANCE: Few studies have evaluated the relationship between influenza vaccination and pneumonia, a serious complication of influenza infection. OBJECTIVE: To assess the association between influenza vaccination status and hospitalization for community-acquired laboratory-confirmed influenza pneumonia. DESIGN, SETTING, AND PARTICIPANTS: The Etiology of Pneumonia in the Community (EPIC) study was a prospective observational multicenter study of hospitalizations for community-acquired pneumonia conducted from January 2010 through June 2012 at 4 US sites. In this case-control study, we used EPIC data from patients 6 months or older with laboratory-confirmed influenza infection and verified vaccination status during the influenza seasons and excluded patients with recent hospitalization, from chronic care residential facilities, and with severe immunosuppression. Logistic regression was used to calculate odds ratios, comparing the odds of vaccination between influenza-positive (case) and influenza negative (control) patients with pneumonia, controlling for demographics, comorbidities, season, study site, and timing of disease onset. Vaccine effectiveness was estimated as (1 - adjusted odds ratio) * 100%. EXPOSURE: Influenza vaccination, verified through record review. MAIN OUTCOMES AND MEASURES: Influenza pneumonia, confirmed by real-time reverse-transcription polymerase chain reaction performed on nasal/oropharyngeal swabs. RESULTS: Overall, 2767 patients hospitalized for pneumonia were eligible for the study; 162 (5.9%) had laboratory-confirmed influenza. Twenty-eight of 162 cases (17%) with influenza-associated pneumonia and 766 of 2605 controls (29%) with influenza negative pneumonia had been vaccinated. The adjusted odds ratio of prior influenza vaccination between cases and controls was 0.43 (95% CI, 0.28-0.68; estimated vaccine effectiveness, 56.7%; 95% CI, 31.9%-72.5%). CONCLUSIONS AND RELEVANCE: Among children and adults hospitalized with community-acquired pneumonia, those with laboratory-confirmed influenza-associated pneumonia, compared with those with pneumonia not associated with influenza, had lower odds of having received influenza vaccination. PMID- 26436614 TI - Instruments for the evaluation of motor abilities for children with severe multiple disabilities: A systematic review of the literature. AB - Based on a systematic review, psychometric characteristics of currently available instruments on motor abilities of children with disabilities were evaluated, with the aim to identify candidates for use in children with severe multiple (intellectual and motor) disabilities. In addition, motor abilities are essential for independent functioning, but are severely compromised in these children. The methodological quality of all studies was evaluated with the Consensus Based Standards for the Selection of Health Status Measurement Instruments (COSMIN) Checklist; overall levels of evidence per instrument were based on the Cochrane Back Review Group strategy. As a result, 18 studies with a total of eight instruments, developed for children with cerebral palsy (CLA, GMFM-88 and LE85), spinal muscular atrophy (MHFMS), neuromuscular diseases (MFM), disabilities 0-6 years (VAB, WeeFIM), and one developed specifically for children with severe multiple disabilities (TDMMT) were found. Strong levels of evidence were found for construct validity of LE85 and MFM and for responsiveness of WeeFIM, but reliability studies of these instruments had a limited methodological quality. Up to now studies of the TDMMT resulted in limited and unknown evidence for structural validity due to the poor methodological quality of reliability studies. In a next step, the clinical suitability of the instruments for children with severe multiple disabilities will be evaluate. PMID- 26436613 TI - Influence of Hepatitis C Virus Sustained Virological Response on Immunosuppressive Tryptophan Catabolism in ART-Treated HIV/HCV Coinfected Patients. AB - BACKGROUND: We previously reported an association between tryptophan (Trp) catabolism and immune dysfunction in HIV monoinfection. Coinfection with HIV is associated with more rapid evolution of hepatitis C virus (HCV)-associated liver disease despite antiretroviral therapy (ART), possibly due to immune dysregulation. We hypothesized that liver fibrosis in HIV/HCV coinfection would be associated with immune dysfunction and alterations in Trp metabolism. METHODS: Trp catabolism and inflammatory soluble markers were assessed in plasma samples from ART-treated HIV/HCV-coinfected patients (n = 90) compared with ART-treated HIV-monoinfected patients and noninfected subjects. Furthermore, 17 additional coinfected patients with sustained virological response (SVR) were assessed longitudinally 6 months after completion of interferon-alpha/ribavirin treatment. RESULTS: HIV/HCV patients had higher Trp catabolism compared with HIV monoinfected and healthy individuals. Elevated kynurenine levels in HIV/HCV patients with liver fibrosis correlated with the prognostic aspartate aminotransaminase to platelet ratio (APRI scores) and insulin levels. Furthermore, HIV/HCV patients had elevated levels of disease progression markers interleukin-6 and induced protein 10 and shared similar levels of markers of microbial translocation (intestinal fatty acid-binding protein, soluble CD14 and lipopolysaccharide-binding protein) compared with HIV-monoinfected and healthy individuals. Successful HCV treatment improved APRI score and markers of disease progression and microbial translocation although elevated Trp catabolism remained unchanged 6 months after SVR. CONCLUSION: ART-treated HIV/HCV-coinfected patients had elevated immunosuppressive Trp catabolism when compared with monoinfected HIV treated patients, which did not normalize after SVR. These findings suggest that a necroinflammatory liver syndrome persists through inflammation by Trp catabolism after 6 month of SVR. PMID- 26436615 TI - Solid organ transplant in individuals with monoclonal B-cell lymphocytosis and chronic lymphocytic leukaemia. PMID- 26436618 TI - Screening Pelvic Examinations in Adult Women: Grand Rounds Discussion From the Beth Israel Deaconess Medical Center. AB - Pelvic examinations have historically been a part of regular preventive care. However, because women can now be screened for cervical cancer at intervals up to every 5 years, the question of whether women need to be seen annually for routine pelvic examinations has arisen. In July 2014, the American College of Physicians (ACP) issued a guideline presenting the available evidence on screening for pathologic conditions using pelvic examination in adult, asymptomatic women at average risk. The American College of Obstetricians and Gynecologists (ACOG) Committee on Gynecologic Practice had previously issued a committee opinion in August 2012 on the need for annual examinations and provided guidelines on important elements of this procedure, including when to examine asymptomatic women. ACOG reaffirmed its initial position after publication of the ACP guideline. The guidelines differ-the ACP guideline recommends against and the ACOG committee opinion recommends in favor of routine annual pelvic examination. This paper summarizes a discussion between an internist and a gynecologist on how they would balance these recommendations in general and what they would suggest for an individual patient. PMID- 26436619 TI - Guidelines International Network: Principles for Disclosure of Interests and Management of Conflicts in Guidelines. AB - Conflicts of interest (COIs) have been defined by the American Thoracic Society as "a divergence between an individual's private interests and his or her professional obligations such that an independent observer might reasonably question whether the individual's professional actions or decisions are motivated by personal gain, such as direct financial, academic advancement, clinical revenue streams, or community standing." In the context of guideline development, the concerns are not simply about identifying and disclosing direct financial or indirect COIs. Despite this recognition, the management of COIs in guidelines is often unsatisfactory. In response to requests from its international membership and informed by existing syntheses of the evidence and policies of international organizations, the Guidelines International Network Board of Trustees developed guidance on the disclosure of interests and management of COIs. Current approaches are relatively similar throughout the guideline development community, with an increasing recognition of the importance of disclosing and managing indirect COIs. Although there are differences in detail among the approaches, the similarities allow for the formulation of 9 core principles for managing COIs. In formulating these principles, the Guidelines International Network Board of Trustees recognizes that COIs cannot be totally avoided when panel members are being chosen for certain guidelines or in certain settings; thus, the important issue is the management of COIs in a fair, judicious, transparent manner. PMID- 26436621 TI - Celebrating the ACP Centennial: From the Annals Archive-Malaria Treatment. PMID- 26436622 TI - The Tyranny of Guidelines. PMID- 26436624 TI - Screening for Thyroid Dysfunction. PMID- 26436625 TI - Screening for Thyroid Dysfunction. PMID- 26436616 TI - Cumulative Incidence of Cancer Among Persons With HIV in North America: A Cohort Study. AB - BACKGROUND: Cancer is increasingly common among persons with HIV. OBJECTIVE: To examine calendar trends in cumulative cancer incidence and hazard rate by HIV status. DESIGN: Cohort study. SETTING: North American AIDS Cohort Collaboration on Research and Design during 1996 to 2009. PARTICIPANTS: 86 620 persons with HIV and 196 987 uninfected adults. MEASUREMENTS: Cancer type-specific cumulative incidence by age 75 years and calendar trends in cumulative incidence and hazard rates, each by HIV status. RESULTS: Cumulative incidences of cancer by age 75 years for persons with and without HIV, respectively, were as follows: Kaposi sarcoma, 4.4% and 0.01%; non-Hodgkin lymphoma, 4.5% and 0.7%; lung cancer, 3.4% and 2.8%; anal cancer, 1.5% and 0.05%; colorectal cancer, 1.0% and 1.5%; liver cancer, 1.1% and 0.4%; Hodgkin lymphoma, 0.9% and 0.09%; melanoma, 0.5% and 0.6%; and oral cavity/pharyngeal cancer, 0.8% and 0.8%. Among persons with HIV, calendar trends in cumulative incidence and hazard rate decreased for Kaposi sarcoma and non-Hodgkin lymphoma. For anal, colorectal, and liver cancer, increasing cumulative incidence, but not hazard rate trends, were due to the decreasing mortality rate trend (-9% per year), allowing greater opportunity to be diagnosed. Despite decreasing hazard rate trends for lung cancer, Hodgkin lymphoma, and melanoma, cumulative incidence trends were not seen because of the compensating effect of the declining mortality rate. LIMITATION: Secular trends in screening, smoking, and viral co-infections were not evaluated. CONCLUSION: Cumulative cancer incidence by age 75 years, approximating lifetime risk in persons with HIV, may have clinical utility in this population. The high cumulative incidences by age 75 years for Kaposi sarcoma, non-Hodgkin lymphoma, and lung cancer support early and sustained antiretroviral therapy and smoking cessation. PMID- 26436626 TI - Pain, Opioids, and Addiction. PMID- 26436627 TI - Pain, Opioids, and Addiction. PMID- 26436628 TI - The PRISMA Extension Statement. PMID- 26436629 TI - The PRISMA Extension Statement. PMID- 26436630 TI - Medicare's Annual Wellness Visit in a Large Health Care Organization: Who Is Using It? PMID- 26436632 TI - Web Exclusives. Annals Graphic Medicine: Sign Out. PMID- 26436631 TI - In the Clinic: Community-Acquired Pneumonia. PMID- 26436633 TI - Short-term and long-term effects on visual word recognition. AB - Effects of lexical and sublexical variables on visual word recognition are often treated as homogeneous across participants and stable over time. In this study, we examine the modulation of frequency, length, syllable and bigram frequency, orthographic neighborhood, and graphophonemic consistency effects by (a) individual differences, and (b) item repetition. A group of 129 participants performed lexical decision and naming, in counterbalanced order, using a set of 150 Greek words in which these variables were decorrelated. Frequency, length, and syllable frequency effects were reduced by a preceding task. Length effects were inversely related to years of education. Neighborhood effects depended on the metric used. There were no significant effects or interactions of bigram frequency or consistency. The results suggest that exposure to a word causes transient effects that may cumulatively develop into permanent individual differences. Models of word recognition must incorporate item-specific learning to account for these findings. PMID- 26436634 TI - Phonological activation of word meanings in grade 5 readers. AB - Three experiments examined the role of phonology in the activation of word meanings in Grade 5 students. In Experiment 1, homophone and spelling control errors were embedded in a story context and participants performed a proofreading task as they read for meaning. For both good and poor readers, more homophone errors went undetected than spelling control errors. In Experiments 2 and 3, homophone and spelling control errors were in sentence contexts. Experiment 2 used an online sentence verification task, and found that both good and poor readers were less accurate when sentences contained a homophone error than a spelling control error. Furthermore, a difference between the 2 types of sentences was observed even when participants were concurrently performing an articulation task. In Experiment 3, initial reading times were shorter on homophone errors than on spelling controls, and participants were less likely to make a regression from homophone errors than spelling controls. These experiments provide clear evidence that phonology makes an important contribution to the activation of word meanings in Grade 5 readers. PMID- 26436635 TI - Observation of S = 1/2 quasi-1D magnetic and magneto-dielectric behavior in a cubic SrCuTe2O6. AB - We investigate the magnetic, thermal, and dielectric properties of SrCuTe2O6, which is isostructural to PbCuTe2O6, a recently found, Cu-based 3D frustrated magnet with a corner-sharing triangular spin network having dominant first and second nearest neighbor (nn) couplings (Koteswararao et al 2014 Phys. Rev. B 90 035141). Although SrCuTe2O6 has a structurally similar spin network, the magnetic data exhibit the characteristic features of a typical quasi-1D magnet, which mainly resulted from the magnetically dominant third nn coupling, uniform chains. The magnetic properties of this system are studied via magnetization (M), heat capacity (C p ), dielectric constant ([Formula: see text]), and measurements along with ab initio band structure calculations. The magnetic susceptibility [Formula: see text] data show a broad maximum at 32 K and the system orders at low temperatures [Formula: see text] K and [Formula: see text] K, respectively. The analysis of the [Formula: see text] data gives an intra-chain coupling, [Formula: see text], to be about ~ - 42 K with non-negligible frustrated inter chain couplings ([Formula: see text] and [Formula: see text]). The hopping parameters obtained from the LDA band structure calculations also suggest the presence of coupled uniform chains. The observation of simultaneous anomalies in [Formula: see text] at [Formula: see text] and [Formula: see text] suggests the presence of a magneto-dielectric effect in SrCuTe2O6. A magnetic phase diagram is also built based on the M, C p , and [Formula: see text] results. PMID- 26436636 TI - Deoxygenative C-C Bond-Forming Processes via a Net Four-Electron Reductive Coupling. AB - The nickel-catalyzed coupling of enones or enals with alkynes in the presence of silane and titanium alkoxide reductants provides direct access to skipped diene products. The process involves a net four-electron reductive coupling and proceeds with deoxygenation of the starting enone or enal. A new class of well defined nickel(0) precatalysts bearing an unhindered N-heterocyclic carbene ligand, which was developed in optimization of the process, is essential for the efficiency of the transformation. The strategy allows the high reactivity of alpha,beta-unsaturated carbonyl substrates to be utilized in couplings with simultaneous extrusion of the oxygen atom, thus enabling a traceless strategy for alkene installation. PMID- 26436637 TI - Spontaneous Packaging and Hypothermic Storage of Mammalian Cells with a Cell Membrane-Mimetic Polymer Hydrogel in a Microchip. AB - Currently, continuous culture/passage and cryopreservation are two major, well established methods to provide cultivated mammalian cells for experiments in laboratories. Due to the lack of flexibility, however, both laboratory-oriented methods are unable to meet the need for rapidly growing cell-based applications, which require cell supply in a variety of occasions outside of laboratories. Herein, we report spontaneous packaging and hypothermic storage of mammalian cells under refrigerated (4 degrees C) and ambient conditions (25 degrees C) using a cell-membrane-mimetic methacryloyloxyethyl phosphorylcholine (MPC) polymer hydrogel incorporated within a glass microchip. Its capability for hypothermic storage of cells was comparatively evaluated over 16 days. The results reveal that the cytocompatible MPC polymer hydrogel, in combination with the microchip structure, enabled hypothermic storage of cells with quite high viability, high intracellular esterase activity, maintained cell membrane integrity, and small morphological change for more than 1 week at 4 degrees C and at least 4 days at 25 degrees C. Furthermore, the stored cells could be released from the hydrogel and exhibited the ability to adhere to a surface and achieve confluence under standard cell culture conditions. Both hypothermic storage conditions are ordinary flexible conditions which can be easily established in places outside of laboratories. Therefore, cell packaging and storage using the hydrogel incorporated within the microchip would be a promising miniature and portable solution for flexible supply and delivery of small amounts of cells from bench to bedside. PMID- 26436638 TI - Self-assembled hybrid metal oxide base catalysts prepared by simply mixing with organic modifiers. AB - Multidentate materials formed by simply mixing heterogeneous and homogeneous components are promising for construction of versatile active sites on the surface of heterogeneous compounds, however, to the best of our knowledge, there are no reports on such materials. Self-assembly of hetero-hybrid catalytic materials occurs when heterogeneous catalysts having adjacent Lewis acid-Lewis base sites are mixed with an organic modifier that contains at least two Lewis base functional groups. Here we demonstrate the strategy by combining cerium oxide and 2-cyanopyridine that self-assembles to form a charge-transfer complex in methanol that exhibits a 2,000-fold increase in reaction rate for hydromethoxylation of acrylonitrile with high selectivity compared with cerium oxide or 2-cyanopyridine alone. The catalytic system is applied to the transesterification and Knoevenagel condensation affording 14-fold and 11-fold higher activity, respectively, than cerium oxide alone. These results demonstrate the potential versatility of the catalytic system and the generality of the catalyst preparation strategy. PMID- 26436639 TI - Transsynaptic Tracing from Peripheral Targets with Pseudorabies Virus Followed by Cholera Toxin and Biotinylated Dextran Amines Double Labeling. AB - Transsynaptic tracing has become a powerful tool used to analyze central efferents that regulate peripheral targets through multi-synaptic circuits. This approach has been most extensively used in the brain by utilizing the swine pathogen pseudorabies virus (PRV)(1). PRV does not infect great apes, including humans, so it is most commonly used in studies on small mammals, especially rodents. The pseudorabies strain PRV152 expresses the enhanced green fluorescent protein (eGFP) reporter gene and only crosses functional synapses retrogradely through the hierarchical sequence of synaptic connections away from the infection site(2,3). Other PRV strains have distinct microbiological properties and may be transported in both directions (PRV-Becker and PRV-Kaplan)(4,5). This protocol will deal exclusively with PRV152. By delivering the virus at a peripheral site, such as muscle, it is possible to limit the entry of the virus into the brain through a specific set of neurons. The resulting pattern of eGFP signal throughout the brain then resolves the neurons that are connected to the initially infected cells. As the distributed nature of transsynaptic tracing with pseudorabies virus makes interpreting specific connections within an identified network difficult, we present a sensitive and reliable method employing biotinylated dextran amines (BDA) and cholera toxin subunit b (CTb) for confirming the connections between cells identified using PRV152. Immunochemical detection of BDA and CTb with peroxidase and DAB (3, 3'-diaminobenzidine) was chosen because they are effective at revealing cellular processes including distal dendrites(6-11). PMID- 26436640 TI - Deterministic processes vary during community assembly for ecologically dissimilar taxa. AB - The continuum hypothesis states that both deterministic and stochastic processes contribute to the assembly of ecological communities. However, the contextual dependency of these processes remains an open question that imposes strong limitations on predictions of community responses to environmental change. Here we measure community and habitat turnover across multiple vertical soil horizons at 183 sites across Scotland for bacteria and fungi, both dominant and functionally vital components of all soils but which differ substantially in their growth habit and dispersal capability. We find that habitat turnover is the primary driver of bacterial community turnover in general, although its importance decreases with increasing isolation and disturbance. Fungal communities, however, exhibit a highly stochastic assembly process, both neutral and non-neutral in nature, largely independent of disturbance. These findings suggest that increased focus on dispersal limitation and biotic interactions are necessary to manage and conserve the key ecosystem services provided by these assemblages. PMID- 26436642 TI - Design and analysis of field studies with bees: A critical review of the draft EFSA guidance. AB - The specific protection goal, primary assessment endpoints, acceptable effect thresholds, and experimental design proposed in the European Food Safety Authority (EFSA) update of the bee guidance document are subjected to critical review. It is concluded that the negligible effect criteria were established without sufficient regulatory definition and without convincing scientific argumentation. For the assessment endpoints, effects on hive strength lack temporal definition and the reduction to numbers of bees is inappropriate to evaluate effects. Restricting mortality assessments to homing failure is not theoretically justified and specific criteria were incorrectly derived. The combination of acute effect estimates with models for chronic stressors is biased risk assessment and a temporal basis for the acceptability of effects is missing. Effects on overwintering success cannot be experimentally assessed using the proposed criteria. The experimental methodology proposed is inappropriate and the logistical consequences, in particular those related to replication and land use are such that field studies are no longer a feasible option for the risk assessment. It may be necessary to explore new lines of thought for the set-up of field studies and to clearly separate experimentation from monitoring. Integr Environ Assess Manag 2016;12:422-428. (c) 2015 SETAC. PMID- 26436641 TI - Cell Sorting of Neural Stem and Progenitor Cells from the Adult Mouse Subventricular Zone and Live-imaging of their Cell Cycle Dynamics. AB - Neural stem cells (NSCs) in the subventricular zone of the lateral ventricles (SVZ) sustain olfactory neurogenesis throughout life in the mammalian brain. They successively generate transit amplifying cells (TACs) and neuroblasts that differentiate into neurons once they integrate the olfactory bulbs. Emerging fluorescent activated cell sorting (FACS) techniques have allowed the isolation of NSCs as well as their progeny and have started to shed light on gene regulatory networks in adult neurogenic niches. We report here a cell sorting technique that allows to follow and distinguish the cell cycle dynamics of the above-mentioned cell populations from the adult SVZ with a LeX/EGFR/CD24 triple staining. Isolated cells are then plated as adherent cells to explore in details their cell cycle progression by time-lapse video microscopy. To this end, we use transgenic Fluorescence Ubiquitination Cell Cycle Indicator (FUCCI) mice in which cells are red-fluorescent during G1 phase due to a G1 specific red-Cdt1 reporter. This method has recently revealed that proliferating NSCs progressively lengthen their G1 phase during aging, leading to neurogenesis impairment. This method is easily transposable to other systems and could be of great interest for the study of the cell cycle dynamics of brain cells in the context of brain pathologies. PMID- 26436643 TI - Bringing GRACE Down to Earth. PMID- 26436644 TI - Toward Adenotonsillectomy in Children: A Review for the General Pediatrician. AB - Adenotonsillectomy is one of the most common surgical procedures performed in children, with more than half a million procedures performed annually. We provide a review of the procedure, including indications, contraindications, perioperative issues, and current controversies. A more in-depth discussion of indications for sleep-disordered breathing and recurrent throat infections is performed. We provide a reasonable approach to these conditions for the general pediatrician. Finally, we discuss selected areas of current controversies: the role of preoperative polysomnogram, postoperative weight gain, and effects on immune function. PMID- 26436645 TI - The relationship between session frequency and psychotherapy outcome in a naturalistic setting. AB - OBJECTIVE: The dose-response relationship in psychotherapy has been examined extensively, but few studies have included session frequency as a component of psychotherapy "dose." Studies that have examined session frequency have indicated that it may affect both the speed and the amount of recovery. No studies were found examining the clinical significance of this construct in a naturalistic setting, which is the aim of the current study. METHOD: Using an archival database of session-by-session Outcome Questionnaire 45 (OQ-45) measures over 17 years, change trajectories of 21,488 university counseling center clients (54.9% female, 85.0% White, mean age = 22.5) were examined using multilevel modeling, including session frequency at the occasion level. Of these clients, subgroups that attended therapy approximately weekly or fortnightly were compared to each other for differences in speed of recovery (using multilevel Cox regression) and clinically significant change (using multilevel logistic regression). RESULTS: Results indicated that more frequent therapy was associated with steeper recovery curves (Cohen's f2 = 0.07; an effect size between small and medium). When comparing weekly and fortnightly groups, clinically significant gains were achieved faster for those attending weekly sessions; however, few significant differences were found between groups in total amount of change in therapy. CONCLUSIONS: Findings replicated previous session frequency literature and supported a clinically significant effect, where higher session frequency resulted in faster recovery. Session frequency appears to be an impactful component in delivering more efficient psychotherapy, and it is important to consider in individual treatment planning, institutional policy, and future research. PMID- 26436646 TI - Investigating Functional Regeneration in Organotypic Spinal Cord Co-cultures Grown on Multi-electrode Arrays. AB - Adult higher vertebrates have a limited potential to recover from spinal cord injury. Recently, evidence emerged that propriospinal connections are a promising target for intervention to improve functional regeneration. So far, no in vitro model exists that grants the possibility to examine functional recovery of propriospinal fibers. Therefore, a representative model that is based on two organotypic spinal cord sections of embryonic rat, cultured next to each other on multi-electrode arrays (MEAs) was developed. These slices grow and, within a few days in vitro, fuse along the sides facing each other. The design of the used MEAs permits the performance of lesions with a scalpel blade through this fusion site without inflicting damage on the MEAs. The slices show spontaneous activity, usually organized in network activity bursts, and spatial and temporal activity parameters such as the location of burst origins, speed and direction of their propagation and latencies between bursts can be characterized. Using these features, it is also possible to assess functional connection of the slices by calculating the amount of synchronized bursts between the two sides. Furthermore, the slices can be morphologically analyzed by performing immunohistochemical stainings after the recordings. Several advantages of the used techniques are combined in this model: the slices largely preserve the original tissue architecture with intact local synaptic circuitry, the tissue is easily and repeatedly accessible and neuronal activity can be detected simultaneously and non-invasively in a large number of spots at high temporal resolution. These features allow the investigation of functional regeneration of intraspinal connections in isolation in vitro in a sophisticated and efficient way. PMID- 26436647 TI - MicroRNA-223 is a crucial mediator of PPARgamma-regulated alternative macrophage activation. AB - Polarized activation of adipose tissue macrophages (ATMs) is crucial for maintaining adipose tissue function and mediating obesity-associated cardiovascular risk and metabolic abnormalities; however, the regulatory network of this key process is not well defined. Here, we identified a PPARgamma/microRNA 223 (miR-223) regulatory axis that controls macrophage polarization by targeting distinct downstream genes to shift the cellular response to various stimuli. In BM-derived macrophages, PPARgamma directly enhanced miR-223 expression upon exposure to Th2 stimuli. ChIP analysis, followed by enhancer reporter assays, revealed that this effect was mediated by PPARgamma binding 3 PPARgamma regulatory elements (PPREs) upstream of the pre-miR-223 coding region. Moreover, deletion of miR-223 impaired PPARgamma-dependent macrophage alternative activation in cells cultured ex vivo and in mice fed a high-fat diet. We identified Rasa1 and Nfat5 as genuine miR-223 targets that are critical for PPARgamma-dependent macrophage alternative activation, whereas the proinflammatory regulator Pknox1, which we reported previously, mediated miR-223 regulated macrophage classical activation. In summary, this study provides evidence to support the crucial role of a PPARgamma/miR-223 regulatory axis in controlling macrophage polarization via distinct downstream target genes. PMID- 26436648 TI - Intravital imaging of intestinal lacteals unveils lipid drainage through contractility. AB - Lacteals are lymphatic vessels located at the center of each intestinal villus and provide essential transport routes for lipids and other lipophilic molecules. However, it is unclear how absorbed molecules are transported through the lacteal. Here, we used reporter mice that express GFP under the control of the lymphatic-specific promoter Prox1 and a custom-built confocal microscope and performed intravital real-time visualization of the absorption and transport dynamics of fluorescence-tagged fatty acids (FAs) and various exogenous molecules in the intestinal villi in vivo. These analyses clearly revealed transepithelial absorption of these molecules via enterocytes, diffusive distribution over the lamina propria, and subsequent transport through lacteals. Moreover, we observed active contraction of lacteals, which seemed to be directly involved in dietary lipid drainage. Our analysis revealed that the smooth muscles that surround each lacteal are responsible for contractile dynamics and that lacteal contraction is ultimately controlled by the autonomic nervous system. These results indicate that the lacteal is a unique organ-specific lymphatic system and does not merely serve as a passive conduit but as an active pump that transports lipids. Collectively, using this efficient imaging method, we uncovered drainage of absorbed molecules in small intestinal villus lacteals and the involvement of lacteal contractibility. PMID- 26436649 TI - Sialylation of IgG Fc domain impairs complement-dependent cytotoxicity. AB - IgG molecules exert both pro- and antiinflammatory effector functions based on the composition of the fragment crystallizable (Fc) domain glycan. Sialylated IgG Fc domains have antiinflammatory properties that are attributed to their ability to increase the activation threshold of innate effector cells to immune complexes by stimulating the upregulation of the inhibitory Fcgamma receptor IIB (FcgammaRIIB). Here, we report that IgG Fc sialylation of human monoclonal IgG1 molecules impairs their efficacy to induce complement-mediated cytotoxicity (CDC). Fc sialylation of a CD20-targeting antibody had no impact on antibody dependent cellular cytotoxicity and did not change the affinity of the antibody for activating Fcgamma receptors. In contrast, the presence of sialic acid abrogated the increased binding of C1q to Fc-galactosylated IgG1 and resulted in decreased levels of C3b deposition on the cell surface. Similar to monoclonal antibodies, sialic acid inhibited the increased C1q binding to galactosylated Fc fragments in human polyclonal IgG. In sera derived from patients with chronic inflammatory demyelinating polyneuropathy, an autoimmune disease of the peripheral nervous system in which humoral immune responses mediate tissue damage, induction of IgG Fc sialylation was associated with clinical disease remission. Thus, impairment of CDC represents an FcgammaR-independent mechanism by which Fc-sialylated glycovariants might limit proinflammatory IgG effector functions. PMID- 26436650 TI - MicroRNA-30 family members regulate calcium/calcineurin signaling in podocytes. AB - Calcium/calcineurin signaling is critical for normal cellular physiology. Abnormalities in this pathway cause many diseases, including podocytopathy; therefore, understanding the mechanisms that underlie the regulation of calcium/calcineurin signaling is essential. Here, we showed that critical components of calcium/calcineurin signaling, including TRPC6, PPP3CA, PPP3CB, PPP3R1, and NFATC3, are the targets of the microRNA-30 family (miR-30s). We found that these 5 genes are highly expressed as mRNA, but the level of the proteins is low in normal podocytes. Conversely, protein levels were markedly elevated in podocytes from rats treated with puromycin aminonucleoside (PAN) and from patients with focal segmental glomerulosclerosis (FSGS). In both FSGS patients and PAN-treated rats, miR-30s were downregulated in podocytes. In cultured podocytes, PAN or a miR-30 sponge increased TRPC6, PPP3CA, PPP3CB, PPP3R1, and NFATC3 expression; calcium influx; intracellular Ca2+ concentration; and calcineurin activity. Moreover, NFATC3 nuclear translocation, synaptopodin degradation, integrin beta3 (ITGB3) activation, and actin fiber loss, which are downstream of calcium/calcineurin signaling, were induced by miR-30 reduction but blocked by the calcineurin inhibitor FK506. Podocyte-specific expression of the miR-30 sponge in mice increased calcium/calcineurin pathway component protein expression and calcineurin activity. The mice developed podocyte foot process effacement and proteinuria, which were prevented by FK506. miR-30s also regulated calcium/calcineurin signaling in cardiomyocytes. Together, our results identify miR-30s as essential regulators of calcium/calcineurin signaling. PMID- 26436653 TI - Statistical Models for the Analysis and Design of Digital Polymerase Chain Reaction (dPCR) Experiments. AB - Statistical methods for the analysis and design of experiments using digital PCR (dPCR) have received only limited attention and have been misused in many instances. To address this issue and to provide a more general approach to the analysis of dPCR data, we describe a class of statistical models for the analysis and design of experiments that require quantification of nucleic acids. These models are mathematically equivalent to generalized linear models of binomial responses that include a complementary, log-log link function and an offset that is dependent on the dPCR partition volume. These models are both versatile and easy to fit using conventional statistical software. Covariates can be used to specify different sources of variation in nucleic acid concentration, and a model's parameters can be used to quantify the effects of these covariates. For purposes of illustration, we analyzed dPCR data from different types of experiments, including serial dilution, evaluation of copy number variation, and quantification of gene expression. We also showed how these models can be used to help design dPCR experiments, as in selection of sample sizes needed to achieve desired levels of precision in estimates of nucleic acid concentration or to detect differences in concentration among treatments with prescribed levels of statistical power. PMID- 26436652 TI - Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis. AB - Cardiomyopathy is a common human disorder that is characterized by contractile dysfunction and cardiac remodeling. Genetic mutations and altered expression of genes encoding many signaling molecules and contractile proteins are associated with cardiomyopathy; however, how cardiomyocytes sense pathophysiological stresses in order to then modulate cardiac remodeling remains poorly understood. Here, we have described a regulator in the heart that harmonizes the progression of cardiac hypertrophy and dilation. We determined that expression of the myocyte enriched protein cardiac ISL1-interacting protein (CIP, also known as MLIP) is reduced in patients with dilated cardiomyopathy. As CIP is highly conserved between human and mouse, we evaluated the effects of CIP deficiency on cardiac remodeling in mice. Deletion of the CIP-encoding gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models. Conversely, transgenic and AAV-mediated CIP overexpression prevented pathologic remodeling and preserved cardiac function. CIP deficiency combined with lamin A/C deletion resulted in severe dilated cardiomyopathy and cardiac dysfunction in the absence of stress. Transcriptome analyses of CIP-deficient hearts revealed that the p53- and FOXO1-mediated gene networks related to homeostasis are disturbed upon pressure overload stress. Moreover, FOXO1 overexpression suppressed stress induced cardiomyocyte hypertrophy in CIP-deficient cardiomyocytes. Our studies identify CIP as a key regulator of cardiomyopathy that has potential as a therapeutic target to attenuate heart failure progression. PMID- 26436651 TI - Proteinase 3 on apoptotic cells disrupts immune silencing in autoimmune vasculitis. AB - Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis that is associated with granulomatous inflammation and the presence of anti-neutrophil cytoplasmic antibodies (ANCAs) directed against proteinase 3 (PR3). We previously determined that PR3 on the surface of apoptotic neutrophils interferes with induction of antiinflammatory mechanisms following phagocytosis of these cells by macrophages. Here, we demonstrate that enzymatically active membrane-associated PR3 on apoptotic cells triggered secretion of inflammatory cytokines, including granulocyte CSF (G-CSF) and chemokines. This response required the IL-1R1/MyD88 signaling pathway and was dependent on the synthesis of NO, as macrophages from animals lacking these pathways did not exhibit a PR3-associated proinflammatory response. The PR3-induced microenvironment facilitated recruitment of inflammatory cells, such as macrophages, plasmacytoid DCs (pDCs), and neutrophils, which were observed in close proximity within granulomatous lesions in the lungs of GPA patients. In different murine models of apoptotic cell injection, the PR3-induced microenvironment instructed pDC-driven Th9/Th2 cell generation. Concomitant injection of anti-PR3 ANCAs with PR3-expressing apoptotic cells induced a Th17 response, revealing a GPA-specific mechanism of immune polarization. Accordingly, circulating CD4+ T cells from GPA patients had a skewed distribution of Th9/Th2/Th17. These results reveal that PR3 disrupts immune silencing associated with clearance of apoptotic neutrophils and provide insight into how PR3 and PR3-targeting ANCAs promote GPA pathophysiology. PMID- 26436654 TI - Recruitment, response rates and characteristics of 5511 people enrolled in a prospective clinical cohort study: head and neck 5000. PMID- 26436656 TI - Fate of Carbohydrates and Lignin during Composting and Mycelium Growth of Agaricus bisporus on Wheat Straw Based Compost. AB - In wheat straw based composting, enabling growth of Agaricus bisporus mushrooms, it is unknown to which extent the carbohydrate-lignin matrix changes and how much is metabolized. In this paper we report yields and remaining structures of the major components. During the Phase II of composting 50% of both xylan and cellulose were metabolized by microbial activity, while lignin structures were unaltered. During A. bisporus' mycelium growth (Phase III) carbohydrates were only slightly consumed and xylan was found to be partially degraded. At the same time, lignin was metabolized for 45% based on pyrolysis GC/MS. Remaining lignin was found to be modified by an increase in the ratio of syringyl (S) to guaiacyl (G) units from 0.5 to 0.7 during mycelium growth, while fewer decorations on the phenolic skeleton of both S and G units remained. PMID- 26436655 TI - Genome-Wide Detection and Analysis of Multifunctional Genes. AB - Many genes can play a role in multiple biological processes or molecular functions. Identifying multifunctional genes at the genome-wide level and studying their properties can shed light upon the complexity of molecular events that underpin cellular functioning, thereby leading to a better understanding of the functional landscape of the cell. However, to date, genome-wide analysis of multifunctional genes (and the proteins they encode) has been limited. Here we introduce a computational approach that uses known functional annotations to extract genes playing a role in at least two distinct biological processes. We leverage functional genomics data sets for three organisms--H. sapiens, D. melanogaster, and S. cerevisiae--and show that, as compared to other annotated genes, genes involved in multiple biological processes possess distinct physicochemical properties, are more broadly expressed, tend to be more central in protein interaction networks, tend to be more evolutionarily conserved, and are more likely to be essential. We also find that multifunctional genes are significantly more likely to be involved in human disorders. These same features also hold when multifunctionality is defined with respect to molecular functions instead of biological processes. Our analysis uncovers key features about multifunctional genes, and is a step towards a better genome-wide understanding of gene multifunctionality. PMID- 26436657 TI - An Improved Approach of Mesh Segmentation to Extract Feature Regions. AB - The objective of this paper is to extract concave and convex feature regions via segmenting surface mesh of a mechanical part whose surface geometry exhibits drastic variations and concave-convex features are equally important when modeling. Referring to the original approach based on the minima rule (MR) in cognitive science, we have created a revised minima rule (RMR) and presented an improved approach based on RMR in the paper. Using the logarithmic function in terms of the minimum curvatures that are normalized by the expectation and the standard deviation on the vertices of the mesh, we determined the solution formulas for the feature vertices according to RMR. Because only a small range of the threshold parameters was selected from in the determined formulas, an iterative process was implemented to realize the automatic selection of thresholds. Finally according to the obtained feature vertices, the feature edges and facets were obtained by growing neighbors. The improved approach overcomes the inherent inadequacies of the original approach for our objective in the paper, realizes full automation without setting parameters, and obtains better results compared with the latest conventional approaches. We demonstrated the feasibility and superiority of our approach by performing certain experimental comparisons. PMID- 26436658 TI - Improvement in B1+ Homogeneity and Average Flip Angle Using Dual-Source Parallel RF Excitation for Cardiac MRI in Swine Hearts. AB - Cardiac MRI may benefit from increased polarization at high magnetic field strength of 3 Tesla but is challenged by increased field inhomogeneity. Initial human studies have shown that the radiofrequency (RF) excitation field (B1+) used for signal excitation in the heart is both inhomogeneous and significantly lower than desired, potentially leading to image artifacts and biased quantitative measures. Recently, multi-channel transmit systems have been introduced allowing localized patient specific RF shimming based on acquired calibration B1+ maps. Some prior human studies have shown lower than desired mean flip angles in the hearts of large patients even after RF shimming. Here, 100 cardiac B1+ map pairs before and after RF shimming were acquired in 55 swine. The mean flip angle and the coefficient of variation (CV) of the flip angle in the heart were determined before and after RF shimming. Mean flip angle, CV, and RF shim values (power ratio and phase difference between the two transmit channels) were tested for correlation with cross sectional body area and the Right-Left/Anterior-Posterior ratio. RF shimming significantly increased the mean flip angle in swine heart from 74.4+/-6.7% (mean +/- standard deviation) to 94.7+/-4.8% of the desired flip angle and significantly reduced CV from 0.11+/-0.03 to 0.07+/-0.02 (p<<1e-10 for both). These results compare well with several previous human studies, except that the mean flip angle in the human heart only improved to 89% with RF shimming, possibly because the RF shimming routine does not consider safety constraints in very large patients. Additionally, mean flip angle decreased and CV increased with larger cross sectional body area, however, the RF shimming parameters did not correlate with cross sectional body area. RF shim power ratio correlated weakly with Right-Left/Anterior-Posterior ratio but phase difference did not, further substantiating the need for subject specific cardiac RF shimming. PMID- 26436660 TI - Fabrication and Doping Methods for Silicon Nano- and Micropillar Arrays for Solar Cell Applications: A Review. AB - Silicon is one of the main components of commercial solar cells and is used in many other solar-light-harvesting devices. The overall efficiency of these devices can be increased by the use of structured surfaces that contain nanometer to micrometer-sized pillars with radial p/n junctions. High densities of such structures greatly enhance the light-absorbing properties of the device, whereas the 3D p/n junction geometry shortens the diffusion length of minority carriers and diminishes recombination. Due to the vast silicon nano- and microfabrication toolbox that exists nowadays, many versatile methods for the preparation of such highly structured samples are available. Furthermore, the formation of p/n junctions on structured surfaces is possible by a variety of doping techniques, in large part transferred from microelectronic circuit technology. The right choice of doping method, to achieve good control of junction depth and doping level, can contribute to an improvement of the overall efficiency that can be obtained in devices for energy applications. A review of the state-of-the-art of the fabrication and doping of silicon micro and nanopillars is presented here, as well as of the analysis of the properties and geometry of thus-formed 3D structured p/n junctions. PMID- 26436659 TI - Phosphorylation of Threonine 794 on Tie1 by Rac1/PAK1 Reveals a Novel Angiogenesis Regulatory Pathway. AB - The endothelial receptor tyrosine kinase (RTK) Tie1 was discovered over 20 years ago, yet its precise function and mode of action remain enigmatic. To shed light on Tie1's role in endothelial cell biology, we investigated a potential threonine phosphorylation site within the juxtamembrane domain of Tie1. Expression of a non phosphorylatable mutant of this site (T794A) in zebrafish (Danio rerio) significantly disrupted vascular development, resulting in fish with stunted and poorly branched intersomitic vessels. Similarly, T794A-expressing human umbilical vein endothelial cells formed significantly shorter tubes with fewer branches in three-dimensional Matrigel cultures. However, mutation of T794 did not alter Tie1 or Tie2 tyrosine phosphorylation or downstream signaling in any detectable way, suggesting that T794 phosphorylation may regulate a Tie1 function independent of its RTK properties. Although T794 is within a consensus Akt phosphorylation site, we were unable to identify a physiological activator of Akt that could induce T794 phosphorylation, suggesting that Akt is not the physiological Tie1-T794 kinase. However, the small GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1), which is required for angiogenesis and capillary morphogenesis, was found to associate with phospho-T794 but not the non-phosphorylatable T794A mutant. Pharmacological activation of Rac1 induced downstream activation of p21-activated kinase (PAK1) and T794 phosphorylation in vitro, and inhibition of PAK1 abrogated T794 phosphorylation. Our results provide the first demonstration of a signaling pathway mediated by Tie1 in endothelial cells, and they suggest that a novel feedback loop involving Rac1/PAK1 mediated phosphorylation of Tie1 on T794 is required for proper angiogenesis. PMID- 26436661 TI - Visceral Pain and Psychiatric Disorders. AB - The high comorbidity existing between visceral pain and psychiatric disorders such as depression and anxiety is well documented and it is gaining increasing interest among scientists. When visceral pain and psychiatric disorders are comorbid, they present a more debilitating condition than each disorder alone, impacting significantly on the quality of life of these patients. Despite several groups having shown that an overlapping pathophysiology exists between visceral pain and stress-related disorders the link between them is not clear yet. Moreover, it still remains to be elucidated if psychiatric conditions predispose the individual to develop visceral hypersensitivity or vice versa. The brain-gut microbiome axis is the bidirectional communication between the CNS and the gastrointestinal tract. Alterations at different levels of this axis have been implicated in both visceral hypersensitivity and psychiatric disorders. Here we give an overview of what it is known about comorbid visceral pain and psychiatric disorders and provide evidence of potential overlapping pathophysiological mechanisms involved. Preclinical models of comorbid visceral pain and stress related disorders are also discussed. PMID- 26436662 TI - Correction: Fractal Feature of Particle-Size Distribution in the Rhizospheres and Bulk Soils during Natural Recovery on the Loess Plateau, China. PMID- 26436663 TI - Sclerosing Mesenteritis Presenting as a Pseudotumor of the Greater Omentum. AB - OBJECTIVE: The aim was to demonstrate a diagnostic challenge of sclerosing mesenteritis initially considered as liposarcoma. CLINICAL PRESENTATION AND INTERVENTION: A 45-year-old man was admitted with a painful abdominal mass. Abdominal computed tomography demonstrated a well- demarcated tumor in his left hemiabdomen, with a large fat component and areas of soft tissue attenuation suggestive of liposarcoma. Intraoperative findings showed a tumor arising from the greater omentum. The tumor was completely removed, and histopathology confirmed a pseudotumorous type of sclerosing mesenteritis with dominant mesenteric lipodystrophy. CONCLUSION: This case showed that a pseudotumorous type of sclerosing mesenteritis should be considered in the differential diagnosis of the mesenteric tumors. PMID- 26436665 TI - Regional variations in US cancer imaging data: a warning for imaging overuse. AB - Danil V Makarov speaks to Gemma Westcott, Commissioning Editor: Danil V Makarov is an Assistant Professor and Director of Surgical Research in the Department of Urology at NYU Langone Medical Center (NY, USA). In addition, he is an Assistant Professor in the Department of Population Health. His clinical areas of expertise include prostate cancer, benign prostatic hyperplasia, erectile dysfunction, kidney cancer, urinary tract infections, genitourinary neoplasm, elevated prostate-specific antigen and testicular cancer. In addition, his research interests are in the areas of prostate cancer, health policy and quality of care. An alumnus of the Johns Hopkins University School of Medicine (MD, USA), he completed his residency in urology at Johns Hopkins Hospital and a research fellowship at Yale University School of Medicine (CT, USA). PMID- 26436666 TI - Systematic review of effects of current transtibial prosthetic socket designs Part 1: Qualitative outcomes. AB - This review is an attempt to untangle the complexity of transtibial prosthetic socket fit, determine the most important characteristic for a successful fitting, and perhaps find some indication of whether a particular prosthetic socket type might be best for a given situation. Further, it is intended to provide directions for future research. We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and used medical subject headings and standard key words to search for articles in relevant databases. No restrictions were made on study design or type of outcome measure. From the obtained search results (n = 1,863), 35 articles were included. The relevant data were entered into a predefined data form that incorporated the Downs and Black risk of bias assessment checklist. Results for the qualitative outcomes (n = 19 articles) are synthesized. Total surface bearing sockets lead to greater activity levels and satisfaction in active persons with amputation, those with a traumatic cause of amputation, and younger persons with amputation than patellar tendon bearing sockets. Evidence on vacuum-assisted suction and hydrostatic sockets is inadequate, and further studies are much needed. To improve the scientific basis for prescription, comparison of and correlation between mechanical properties of interface material, socket designs, user characteristics, and outcome measures should be conducted and reported in future studies. PMID- 26436664 TI - Purification and Characterization of Recombinant N-Terminally Pyroglutamate Modified Amyloid-beta Variants and Structural Analysis by Solution NMR Spectroscopy. AB - Alzheimer's disease (AD) is the leading cause of dementia in the elderly and is characterized by memory loss and cognitive decline. Pathological hallmark of AD brains are intracellular neurofibrillary tangles and extracellular amyloid plaques. The major component of these plaques is the highly heterogeneous amyloid beta (Abeta) peptide, varying in length and modification. In recent years pyroglutamate-modified amyloid-beta (pEAbeta) peptides have increasingly moved into the focus since they have been described to be the predominant species of all N-terminally truncated Abeta. Compared to unmodified Abeta, pEAbeta is known to show increased hydrophobicity, higher toxicity, faster aggregation and beta sheet stabilization and is more resistant to degradation. Nuclear magnetic resonance (NMR) spectroscopy is a particularly powerful method to investigate the conformations of pEAbeta isoforms in solution and to study peptide/ligand interactions for drug development. However, biophysical characterization of pEAbeta and comparison to its non-modified variant has so far been seriously hampered by the lack of highly pure recombinant and isotope-enriched protein. Here we present, to our knowledge, for the first time a reproducible protocol for the production of pEAbeta from a recombinant precursor expressed in E. coli in natural isotope abundance as well as in uniformly [U-15N]- or [U-13C, 15N] labeled form, with yields of up to 15 mg/l E. coli culture broth. The chemical state of the purified protein was evaluated by RP-HPLC and formation of pyroglutamate was verified by mass spectroscopy. The recombinant pyroglutamate modified Abeta peptides showed characteristic sigmoidal aggregation kinetics as monitored by thioflavin-T assays. The quality and quantity of produced pEAbeta40 and pEAbeta42 allowed us to perform heteronuclear multidimensional NMR spectroscopy in solution and to sequence-specifically assign the backbone resonances under near-physiological conditions. Our results suggest that the presented method will be useful in obtaining cost-effective high-quality recombinant pEAbeta40 and pEAbeta42 for further physiological and biochemical studies. PMID- 26436667 TI - Franck-Condon-like Progressions in Infrared Spectra of Biological Molecules. AB - Infrared spectra in the NH stretch region are often used for structure determination of gas-phase biological molecules. Vibrational couplings complicate the structure determination process by giving rise to additional vibrational bands along with the expected fundamental transitions. We present an example of a strong anharmonic coupling in a biological molecule, Ac-Phe-Ala-LysH(+), which causes the appearance of long vibrational progressions in the infrared spectrum. By analyzing the spectra of the ground and the electronically excited state, we determined that the coupling occurs between the NH stretch (omegaNH) and a low frequency torsion of the phenyl ring (omegatau). We describe the vibrational progressions using a Born-Oppenheimer-like separation of the high-frequency stretch and low-frequency torsion with a quartic Taylor expansion for the potential energy surface that accounts for the equilibrium distance and frequency change of the torsional vibration upon the NH stretch excitation. We also demonstrate that small conformational changes in the peptide are sufficient to break this coupling. PMID- 26436668 TI - Validating chest MRI to detect and monitor cystic fibrosis lung disease in a pediatric cohort. AB - BACKGROUND: Computed Tomography (CT) is the gold standard to assess bronchiectasis and trapped air in cystic fibrosis (CF) lung disease, but has the disadvantage of radiation exposure. Magnetic Resonance Imaging (MRI) is a radiation free alternative. OBJECTIVE: To validate MRI as outcome measure by: correlating MRI scores for bronchiectasis and trapped air with clinical parameters, and by comparing those MRI scores with CT scores. METHODS: In patients with CF (aged 5.6-17.4 years), MRI and CT were alternated annually during routine annual check-ups between July 2007 and January 2010. Twenty-three children had an MRI performed 1 year prior to CT, 34 children had a CT 1 year prior to MRI. Bronchiectasis and trapped air were scored using the CF-MRI and CF CT scoring system. CF-MRI scores were correlated with clinical parameters: FEV1 , Pseudomonas aeruginosa, pulmonary exacerbations and patient-reported respiratory symptoms measured on the Cystic Fibrosis Questionnaire-Revised (CFQ-R), using Spearman's correlation coefficient. MRI and CT scores were compared using intra class correlation coefficients (ICC) and Bland-Altman plots. RESULTS: Fifty-seven patients who had an MRI, CT and CFQ-R during the study period were included. CF MRI bronchiectasis correlated with FEV1 , Pseudomonas aeruginosa, pulmonary exacerbations and patient-reported respiratory symptoms. CF-MRI trapped air only correlated with FEV1 and Pseudomonas aeruginosa. ICCs between MRI and CT bronchiectasis and trapped air were 0.41 and 0.35 respectively. MRI tended to overestimate bronchiectasis compared to CT. CONCLUSION: The associations between CF-MRI scores and several important clinical parameters further contributes to the validation of MRI. MRI provides different information than CT. PMID- 26436669 TI - Aggregation of Cricket Activity in Response to Resource Addition Increases Local Diversity. AB - Crickets are often found feeding on fallen fruits among forest litter. Fruits and other sugar-rich resources are not homogeneously distributed, nor are they always available. We therefore expect that crickets dwelling in forest litter have a limited supply of sugar-rich resource, and will perceive this and displace towards resource-supplemented sites. Here we evaluate how sugar availability affects cricket species richness and abundance in old-growth Atlantic forest by spraying sugarcane syrup on leaf litter, simulating increasing availability, and collecting crickets via pitfall trapping. We found an asymptotic positive association between resource addition and species richness, and an interaction between resource addition and species identity on cricket abundance, which indicates differential effects of resource addition among cricket species. Our results indicate that 12 of the 13 cricket species present in forest litter are maintained at low densities by resource scarcity; this highlights sugar-rich resource as a short-term driver of litter cricket community structure in tropical forests. When resource was experimentally increased, species richness increased due to behavioral displacement. We present evidence that the density of many species is limited by resource scarcity and, when resources are added, behavioral displacement promotes increased species packing and alters species composition. Further, our findings have technical applicability for increasing sampling efficiency of local cricket diversity in studies aiming to estimate species richness, but with no regard to local environmental drivers or species-abundance characteristics. PMID- 26436673 TI - A mixed treatment comparison for short- and long-term outcomes of bare-metal and drug-eluting coronary stents. AB - BACKGROUND: The increasing use of drug eluting stents in interventional cardiology calls for assessment of their efficacy and safety, both among drug eluting and bare-metal stents, in the context of rational decision making. METHODS: We searched for papers that compared any of the sirolimus-eluting stent, paclitaxel-eluting stent, drug- eluting stent, biodegradable stent, everolimus eluting stent, zotarolimus-resolute eluting stent, biolimus- eluting stent, bare metal stent and zotarolimus-eluting stent. The search was contacted through Medline, the Cochrane database, Embase, TCTMD, ClinicalTrials.gov, Clinical Trial Results, CardioSource, abstracts and presentations from major cardiovascular meetings. We also searched for further articles cited by selected papers. Furthermore, important conferences and relevant proceedings and abstracts, such as the American Heart Association, American College of Cardiology, Transcatheter Cardiovascular Therapeutics, Society of Cardiovascular Angiography and Intervention, European Society of Cardiology, and Euro-PCR, were also searched. Inclusion criteria were: randomised controlled trials (RCTs), size of study (>=100 patients), duration more than 6 months and definition of reported endpoints (target vessel revascularization, thrombosis, myocardial infarction and cardiac death). Analysis of the data was performed for short-term (less than a year) and long-term outcomes (more than a year). A mixed treatment comparison approach was utilised for the data analysis. CONCLUSIONS: Based on the rankings of each treatment, a distinct difference between the 2nd and 1st generation stents was identified. We can conclude that everolimus, zotarolimus-resolute and biolimus eluting stents carry the highest probabilities of being superior for all endpoints. PMID- 26436672 TI - Attenuation of reflected waves in man during retrograde propagation from femoral artery to proximal aorta. AB - BACKGROUND: Wave reflection may be an important influence on blood pressure, but the extent to which reflections undergo attenuation during retrograde propagation has not been studied. We quantified retrograde transmission of a reflected wave created by occlusion of the left femoral artery in man. METHODS: 20 subjects (age 31-83 years; 14 male) underwent invasive measurement of pressure and flow velocity with a sensor-tipped intra-arterial wire at multiple locations distal to the proximal aorta before, during and following occlusion of the left femoral artery by thigh cuff inflation. A numerical model of the circulation was also used to predict reflected wave transmission. Wave reflection was measured as the ratio of backward to forward wave energy (WRI) and the ratio of peak backward to forward pressure (Pb/Pf). RESULTS: Cuff inflation caused a marked reflection which was largest at 5-10 cm from the cuff (change (Delta) in WRI=0.50 (95% CI 0.38, 0.62); p<0.001, DeltaPb/Pf=0.23 (0.18-0.29); p<0.001). The magnitude of the cuff-induced reflection decreased progressively at more proximal locations and was barely discernible at sites>40 cm from the cuff including in the proximal aorta. Numerical modelling gave similar predictions to those observed experimentally. CONCLUSIONS: Reflections due to femoral artery occlusion are markedly attenuated by the time they reach the proximal aorta. This is due to impedance mismatches of bifurcations traversed in the backward direction. This degree of attenuation is inconsistent with the idea of a large discrete reflected wave arising from the lower limb and propagating back into the aorta. PMID- 26436674 TI - Personalized ADP-receptor inhibition strategy and outcomes following primary PCI for STEMI (PASTOR study). AB - BACKGROUND: Adequate antiplatelet therapy in patients with myocardial infarction with ST-elevation (STEMI) is vital in order to avoid ischemic complications. However, especially with the novel potent oral drugs, bleeding is a major concern. We aimed to investigate whether STEMI patients switched to novel ADP receptor inhibitors due to high platelet reactivity (HPR) on clopidogrel have similar outcomes compared to patients with adequate response to clopidogrel. METHODS: A prospective cohort of 175 STEMI patients (mean age 62.3 years) undergoing primary PCI were included in the PASTOR study. Patients were loaded with 600 mg clopidogrel before the index PCI procedure. Bedside VerifyNow P2Y12 platelet function testing was performed the following morning. RESULTS: 46 patients (26.3%) were found to have HPR on clopidogrel (PRU>235) and were switched to novel ADP receptor antagonists. The remaining 129 patients were treated with clopidogrel. The mean duration of dual antiplatelet therapy (DAPT) was 6.7 months. Duration of entire follow-up of patients was approximately 2 years. Major adverse cardiac events (MACE) while patients were on DAPT occurred in 7.0% in the clopidogrel group compared to 8.7% in the novel ADP receptor antagonist group (p=0.70). No differences were observed between groups off-DAPT either. CONCLUSIONS: Following primary PCI for STEMI, patients with adequate response to clopidogrel show similar outcomes compared to patients switched to novel ADP receptor antagonists due to HPR on clopidogrel. Platelet reactivity testing can be used to guide the choice of antiplatelet therapy in patients with STEMI treated by primary PCI. PMID- 26436670 TI - Oral TNFalpha Modulation Alters Neutrophil Infiltration, Improves Cognition and Diminishes Tau and Amyloid Pathology in the 3xTgAD Mouse Model. AB - Cytokines such as TNFalpha can polarize microglia/macrophages into different neuroinflammatory types. Skewing of the phenotype towards a cytotoxic state is thought to impair phagocytosis and has been described in Alzheimer's Disease (AD). Neuroinflammation can be perpetuated by a cycle of increasing cytokine production and maintenance of a polarized activation state that contributes to AD progression. In this study, 3xTgAD mice, age 6 months, were treated orally with 3 doses of the TNFalpha modulating compound isoindolin-1,3 dithione (IDT) for 10 months. We demonstrate that IDT is a TNFalpha modulating compound both in vitro and in vivo. Following long-term IDT administration, mice were assessed for learning & memory and tissue and serum were collected for analysis. Results demonstrate that IDT is safe for long-term treatment and significantly improves learning and memory in the 3xTgAD mouse model. IDT significantly reduced paired helical filament tau and fibrillar amyloid accumulation. Flow cytometry of brain cell populations revealed that IDT increased the infiltrating neutrophil population while reducing TNFalpha expression in this population. IDT is a safe and effective TNFalpha and innate immune system modulator. Thus small molecule, orally bioavailable modulators are promising therapeutics for Alzheimer's disease. PMID- 26436675 TI - Selection of the appropriate binary effect measure for the correct interpretation in meta-analysis. PMID- 26436676 TI - Impact of intraprocedural thrombotic events on short- and long-term outcomes following percutaneous coronary intervention. Evidence from a meta-analysis. AB - BACKGROUND: Data regarding the effects of intraprocedural thrombotic events (IPTE) are scarce. Hence we aim to perform a meta-analysis to examine the outcomes of IPTE compared to non-IPTE during PCI. METHODS: We performed a literature search of all published full-length articles of studies that reported data on patients with IPTE compared with non-IPTE during PCI. We calculated odd ratios via random effects model. RESULTS: A total of 26,697 patients, of which 1572 patients had IPTE, were included in this analysis. In-hospital, IPTE was associated with higher mortality (odds ratio (OR) 5.36, 95% confidence interval (CI) [2.31, 12.41]; p<0.0001), myocardial infarction (MI) and major bleeding compared to non-IPTE. At 30 days, IPTE was also associated with higher mortality (OR 4.57, 95% CI [2.43, 8.60]; p<0.0001), MI, repeat revascularization, stent thrombosis and major bleeding compared to non-IPTE group. IPTE was also associated with higher long-term mortality (OR 2.19, 95% CI [1.35, 3.53]; p=0.001). Among IPTE patients, intraprocedural stent thrombosis was associated with greater odds of MI compared to both no reflow and distal embolization events. CONCLUSION: IPTE during PCI is associated with more adverse ischemic events, including mortality, during the index hospitalization, at 30 days and long-term. PMID- 26436677 TI - Full-Arch, Implant-Supported Monolithic Zirconia Rehabilitations: Pilot Clinical Evaluation of Wear Against Natural or Composite Teeth. AB - PURPOSE: To clinically evaluate the amount of contact wear generated between full arch monolithic zirconia implant-supported restorations and natural or composite antagonists, over a 1-year period. MATERIALS AND METHODS: Forty-seven teeth from clinically functional, full-arch monolithic zirconia screw-retained implant prostheses (FDPs) and their antagonists were investigated. The first group ("Zirconia-E") was opposed to natural teeth ("Enamel"), whereas the other one ("Zirconia-CR") was opposed to nano-hybrid composite teeth ("Composite Resin"). Replicas of the restorations and their antagonists were obtained immediately after delivery (T0 ) and after 1 year of clinical service (T1 ). Each tooth surface was individually evaluated three-dimensionally by software to quantify the vertical distance between the two scans (Hausdorff distance), which was considered as contact wear. Data obtained for each arch were subjected to one-way ANOVA test and a post hoc analysis (Tukey's test) at a 5% level of significance. Furthermore, the influence of the location of the teeth (anterior or posterior) was analyzed. Minimum post hoc statistical power between statistically different groups was 99.6%. RESULTS: Mean values were 63 +/- 23 MUm for Zirconia-E, 76 +/- 29 MUm for enamel, 70 +/- 38 MUm for composite resin; Zirconia-CR had a mean value of 19 +/- 4 MUm and significantly differed from the other groups. Contact wear between anterior and posterior teeth differed significantly only in the composite resin arch, with a mean of 39 +/- 22 MUm for anterior teeth versus 101 +/- 19 MUm for posterior ones. CONCLUSIONS: Within the limitations of this preliminary evaluation, monolithic zirconia full-arch rehabilitations induced a clinically acceptable wear on natural and composite antagonists over a 1-year period; they might be considered a viable solution for implant-supported rehabilitations. PMID- 26436680 TI - Temperature Determination by EPR at 275 GHz and the Detection of Temperature Jumps in Aqueous Samples. AB - Second-moment analysis along two dimensions of continuous-wave EPR spectra of nitroxides enables EPR thermometry in a broad temperature range. Simulations show that the temperature can be derived in both the slow-motion and the fast-motion regime, which is experimentally verified at 275 GHz for H2O/glycerol (50/50% by volume) and pure water. We demonstrate that this tool allows the calibration of temperature jumps induced by infrared laser irradiation of a submicroliter sample in the single-mode cavity of a 275 GHz spectrometer, which prepares for kinetic studies of processes involving paramagnetic species. PMID- 26436678 TI - Course of Chronic Trypanosoma cruzi Infection after Treatment Based on Parasitological and Serological Tests: A Systematic Review of Follow-Up Studies. AB - BACKGROUND: Chagas disease is caused by the flagellate protozoan Trypanosoma cruzi (T. cruzi). It is endemic in Latin American countries outside the Caribbean. The current criterion for cure in the chronic phase of the disease is the negativization of at least two serological tests such as enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence assay (IIF) and indirect hemagglutination assay (IHA). The serological evolution of treated subjects with chronic T. cruzi infection is variable. Treatment failure is indicated by a positive parasitological and/or molecular test (persistence of parasitemia). OBJECTIVES: To summarize the pattern of response to treatment of parasitological, molecular and serological tests performed during the follow-up of subjects with chronic T. cruzi infection. METHODS: Electronic searches in relevant databases and screening of citations of potentially eligible articles were accomplished. Organizations focusing on neglected infectious diseases were asked for help in identifying relevant studies. Included studies were randomized controlled trials (RCTs), quasi-RCTs, and cohort studies involving adults and children with chronic infection who received trypanocidal treatment (benznidazole or nifurtimox) and were followed over time. The assessment of risk of bias was performed separately for each study design. The Cochrane Collaboration's tool and the guidelines developed by Hayden et al. were used. Two reviewers extracted all data independently. A third review author was consulted in case of discordant opinion. Additional analyses were defined in ad-hoc basis. Scatter plots for percentage of positive parasitological and molecular tests and for negative serological tests were developed by using the lowess curve technique. Heterogeneity was measured by I2. The protocol was registered in PROSPERO, an international prospective register of systematic review protocols (Registration Number CRD42012002162). RESULTS: Out of 2,136 citations screened, 54 studies (six RCTs and 48 cohort studies) were included. The smoothed curves for positive xenodiagnosis and positive polymerase chain reaction (PCR) were characterized by a sharp decrease at twelve month posttreatment. Afterwards, they reached 10-20% and 40% for xenodiagnosis and PCR, respectively. The smoothed curves for negative conventional serological tests increased up to 10% after 48 months of treatment. In the long-term, the rate of negativization was between 20% and 45%. The main sources of bias identified across cohort studies were the lack of control for confounding and attrition bias. In general, RCTs were judged as low risk of bias in all domains. The level of heterogeneity across included studies was moderate to high. Additional analysis were incomplete because of the limited availability of data. In this regard, the country of origin of study participants might affect the results of parasitological and molecular tests, while the level of risk of bias might affect serological outcomes. Subgroup analysis suggested that seronegativization occurs earlier in children compared to adults. CONCLUSIONS: We acknowledge that there is a dynamic pattern of response based on parasitological, molecular and serological tests in subjects chronically infected with T. cruzi after treatment. Our findings suggest a trypanocidal effect in the long-term follow-up. Further research is needed to explore potential sources of heterogeneity and to conduct reliable subgroup analysis. PMID- 26436679 TI - Wheat leaf lipids during heat stress: I. High day and night temperatures result in major lipid alterations. AB - Understanding how wheat (Triticum aestivum L.) plants under high temperature (HT) regulate lipid composition is critical to developing climate-resilient varieties. We measured 165 glycerolipids and sterol derivatives under optimum and high day and night temperatures in wheat leaves using electrospray ionization-tandem mass spectrometry. Levels of polar lipid fatty acyl chain unsaturation were lower in both heat-tolerant genotype Ventnor and susceptible genotype Karl 92 under HT, compared with optimum temperature. The lower unsaturation was predominantly because of lower levels of 18:3 acyl chains and higher levels of 18:1 and 16:0 acyl chains. Levels of 18:3-containing triacylglycerols increased threefold/more under HT, consistent with their possible role in sequestering fatty acids during membrane lipid remodelling. Phospholipids containing odd-numbered or oxidized acyl chains accumulated in leaves under HT. Sterol glycosides (SG) and 16:0 acylated sterol glycosides (ASG) were higher under HT than optimum temperatures. Ventnor had lower amounts of phospholipids with oxidized acyl chains under HT and higher amounts of SG and 16:0-ASG than Karl 92. Taken together, the data demonstrate that wheat leaf lipid composition is altered by HT, in which some lipids are particularly responsive to HT, and that two wheat genotypes, chosen for their differing physiological responses to HT, differ in lipid profile under HT. PMID- 26436681 TI - Complete mitochondrial genome and phylogenic analysis of the mudskipper Scartelaos gigas (Perciformes, Gobiidae). AB - In this paper, the complete mitochondrial genome sequence of Scartelaos gigas was firstly determined. The circular genome (16 717 bp) comprises 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and 1 control region. The overall base composition of S. gigas is 28.9% for C, 28.3% for A, 26.4% for T, 16.4% for G, with a slight A + T bias of 54.7%. In the control region, the termination associated sequence and conserved sequence block domains were found, but the tandem repeat structure was not found. It has the typical vertebrate mitochondrial gene arrangement. The phylogenic analysis using the Neighbor Joining method showed that the fishes belonging to Gobiidae, Odontoburidae, and Eleotridae formed three branches grouped with other fishes into one clade which separated from the mammals. We hope that the results from the present study will provide useful molecular information for the further studies on genetic structure and demographic history of S. gigas. PMID- 26436682 TI - Patterns of sun protective behaviors among Hispanic children in a skin cancer prevention intervention. AB - BACKGROUND: Invasive melanoma is becoming more common in U.S. Hispanics, yet little is known about the sun protection behaviors in this population, particularly children and adolescents who incur high ultraviolet (UV) exposures. METHODS: We used latent class analysis to examine patterns of sun protective behaviors in a cross-sectional survey of Hispanic elementary students participating in a sun safety intervention in Los Angeles from 2013- to 2014 (N=972). Five behavior indicators in two environments (school and home) representing multiple methods of sun protection were selected for the model. RESULTS: Results suggested a four-class model best fit the data. Classes were labeled in order of increasing risk as multiple protective behaviors (28%), clothing and shade (32%), pants only (15%), and low/inconsistent protective behaviors (25%). Children who reported high parental engagement with sun protection were significantly more likely to be classified in high overall protective categories (odds ratio (OR)=4.77). Girls were more likely than boys to be classified in the highest protecting class (OR=3.46), but were also more likely to be in the "pants only" class (OR=2.65). Sensitivity to sunburn was associated with less likelihood of being in the "clothing and shade" class (OR=0.53). CONCLUSION: The differences among these classes and their predictors reveal the heterogeneity and complexity of Hispanic children's sun protective behaviors. These findings have implications for the design and delivery of future sun protection interventions targeting Hispanic children, as strategies tailored to specific subgroups may be more effective in achieving meaningful behavioral changes. PMID- 26436683 TI - Effects of a multi-component camp-based intervention on inflammatory markers and adipokines in children: A randomized controlled trial. AB - OBJECTIVE: To examine the effects of a multi-component camp-based intervention on inflammatory markers and adipokines in children. METHODS: One hundred and fifteen children were recruited in Odense, Denmark (2012-2014). The participants were randomly allocated to either the day camp intervention arm (DCIA) or the standard intervention arm (SIA). The intervention for the DCIA consisted of a 6-week camp based intervention and a 46-week family-based intervention. The SIA was offered one weekly physical activity session for 6 weeks and one educational meeting. C reactive protein (CRP), monocyte chemoattractant protein-1 (MCP1), leptin, and adiponectin were measured in serum at baseline, 6 weeks and 52 weeks. RESULTS: In comparison with the SIA, the reductions in CRP (P=0.003) and leptin (p<0.001) were larger in the DCIA at 6 weeks. The intervention effects on leptin were significantly mediated by the changes in body fat mass. No intervention effects on CRP and leptin were seen at 52 weeks. No between-group differences in changes in MCP1 and adiponectin were observed at 6 weeks or 52 weeks. CONCLUSIONS: The 6 week camp intervention resulted in reductions in CRP and leptin. The intervention effects did not persist to 52 weeks. The intervention effect on leptin was explained by changes in body fat mass. PMID- 26436684 TI - Smoking, heavy drinking, and depression among U.S. middle-aged and older adults. AB - OBJECTIVE: To examine the relationship between smoking, heavy drinking and depression among U.S. middle-aged and older adults. METHOD: Individual-level data came from 1992-2012 waves of the Health and Retirement Study. Smoking was ascertained from self-reported cigarette smoking status at the time of interview. Heavy drinking was defined as one or more drinks per day on average or four or more drinks on any occasion in the past three months for women, and two or more drinks per day on average or four or more drinks on any occasion in the past three months for men. Depression was defined as scoring three and above on the eight-item Center for Epidemiologic Studies Depression Scale. Cox proportional hazards regressions were performed to examine the relationship between smoking, heavy drinking and depression. RESULTS: Compared to non-smokers, smokers free from depression and heavy drinking at baseline were 20% (95% confidence interval: 12-28%) and 34% (20-50%) more likely to develop depression and engage in heavy drinking during follow-up period, respectively. Compared to non-depressed participants, participants with depression who were nonsmokers and non-heavy drinkers at baseline were 41% (14-74%) and 18% (6-31%) more likely to smoke and engage in heavy drinking during follow-up, respectively. Compared to non-heavy drinkers, heavy drinkers who were nonsmokers at baseline were 60% (26-104%) more likely to smoke during follow-up. CONCLUSION: Health promotion programs in midlife and older age should be mindful of the associations between smoking, heavy drinking and depression in order to improve intervention effectiveness. PMID- 26436685 TI - Smoking-attributable medical expenditures: Time biases and smokers' social role. PMID- 26436687 TI - Brainstem node for loss of consciousness due to GABA(A) receptor-active anesthetics. AB - The molecular agents that induce loss of consciousness during anesthesia are classically believed to act by binding to cognate transmembrane receptors widely distributed in the CNS and critically suppressing local processing and network connectivity. However, previous work has shown that microinjection of anesthetics into a localized region of the brainstem mesopontine tegmentum (MPTA) rapidly and reversibly induces anesthesia in the absence of global spread. This implies that functional extinction is determined by neural pathways rather than vascular distribution of the anesthetic agent. But does clinical (systemic-induced) anesthesia employ MPTA-linked circuitry? Here we show that cell-selective lesioning of the MPTA in rats does not, in itself, induce anesthesia or coma. However, it increases the systemic dose of pentobarbital required to induce anesthesia, in a manner proportional to the extent of the lesion. Such lesions also affect emergence, extending the duration of anesthesia. Off-target and sham lesions were ineffective. Combined with the prior microinjection data, we conclude that drug delivery to the MPTA is sufficient to induce loss-of consciousness and that neurons in this locus are necessary for anesthetic induction at clinically relevant doses. Together, the results support an architecture for anesthesia with the MPTA serving as a key node in an endogenous network of dedicated pathways that switch between wake and unconsciousness. As such, the MPTA might also play a role in syncope, concussion and sleep. PMID- 26436688 TI - High Cycling Stability and Extreme Rate Performance in Nanoscaled LiMn2O4 Thin Films. AB - Ultrathin LiMn2O4 electrode layers with average crystal size of ~15 nm were fabricated by means of radio frequency sputtering. Cycling behavior and rate performance was evaluated by galvanostatic charge and discharge measurements. The thinnest films show the highest volumetric capacity and best cycling stability, retaining the initial capacity over 70 (dis)charging cycles when manganese dissolution is prevented. The increased stability for film thicknesses below 50 nm allows cycling in both the 4 and 3 V potential regions, resulting in a high volumetric capacity of 1.2 Ah/cm3. It is shown that the thinnest films can be charged to 75% of their full capacity within 18 s (200 C), the best rate performance reported for LiMn2O4. This is explained by the short diffusion lengths inherent to thin films and the absence of phase transformation. PMID- 26436686 TI - Gender differences in incidence and outcomes of urothelial and kidney cancer. AB - A gender discrepancy exists in the incidence of both urothelial and kidney carcinomas, with more men presenting with these cancers than women. Men have a threefold greater risk of developing bladder cancer than women, but female gender has been identified as an independent adverse prognostic factor for both recurrence and progression of this disease. In particular, women with bladder cancer are often diagnosed with a higher tumour stage than men. Conclusive data on the influence of gender on outcomes of patients with upper tract urothelial carcinoma are currently lacking, although men seem to have a higher disease incidence, whereas survival outcomes might be independent of gender. Patients with renal cell carcinoma are more often men and they typically have larger tumours and higher stage and grade disease than women with this cancer. Smoking habits, tumour biology, occupational risk factors and sex steroid hormones and their receptors could have a role in these observed gender disparities. The majority of data support the theory that gender influences incidence and prognosis of urothelial and kidney cancers; men and women are different genetically and socially, making the consideration of gender a key factor in the clinical decision-making process. Thus, the inclusion of this variable in validated prognostic tables and nomograms should be discussed as a matter of importance. PMID- 26436689 TI - The safety of liposome bupivacaine 2 years post-launch: a look back and a look forward. AB - The need for better post-surgical pain management continues to be unmet, despite clinicians' awareness and concern for many years. Opioids remain the standard of care because of their analgesic efficacy; however, opioid use is often associated with adverse effects and poor patient outcomes. Multimodal analgesic regimens have recently been endorsed as a way to provide adequate post-surgical pain control while reducing opioid consumption. Liposome bupivacaine is a liposomal formulation of bupivacaine indicated for a single administration into the surgical site. Based on the available clinical trial data compiled to date, as well as the author's review of publicly available post-marketing safety information, liposome bupivacaine may be a viable addition to currently available therapeutic options for post-surgical analgesia while reducing potential risks associated with use of opioid analgesics, and may represent a useful addition to the multimodal analgesic modalities currently used for post-operative pain management. The potential for its use in other areas is also being investigated. The purpose of this review is to examine the currently available post-marketing safety information on liposome bupivacaine. PMID- 26436691 TI - Experiments on Ultrasonic Lubrication Using a Piezoelectrically-assisted Tribometer and Optical Profilometer. AB - Friction and wear are detrimental to engineered systems. Ultrasonic lubrication is achieved when the interface between two sliding surfaces is vibrated at a frequency above the acoustic range (20 kHz). As a solid-state technology, ultrasonic lubrication can be used where conventional lubricants are unfeasible or undesirable. Further, ultrasonic lubrication allows for electrical modulation of the effective friction coefficient between two sliding surfaces. This property enables adaptive systems that modify their frictional state and associated dynamic response as the operating conditions change. Surface wear can also be reduced through ultrasonic lubrication. We developed a protocol to investigate the dependence of friction force reduction and wear reduction on the linear sliding velocity between ultrasonically lubricated surfaces. A pin-on-disc tribometer was built which differs from commercial units in that a piezoelectric stack is used to vibrate the pin at 22 kHz normal to the rotating disc surface. Friction and wear metrics including effective friction force, volume loss, and surface roughness are measured without and with ultrasonic vibrations at a constant pressure of 1 to 4 MPa and three different sliding velocities: 20.3, 40.6, and 87 mm/sec. An optical profilometer is utilized to characterize the wear surfaces. The effective friction force is reduced by 62% at 20.3 mm/sec. Consistently with existing theories for ultrasonic lubrication, the percent reduction in friction force diminishes with increasing speed, down to 29% friction force reduction at 87 mm/sec. Wear reduction remains essentially constant (49%) at the three speeds considered. PMID- 26436692 TI - Interparticle Forces Underlying Nanoparticle Self-Assemblies. AB - Studies on the self-assembly of nanoparticles have been a hot topic in nanotechnology for decades and still remain relevant for the present and future due to their tunable collective properties as well as their remarkable applications to a wide range of fields. The novel properties of nanoparticle assemblies arise from their internal interactions and assemblies with the desired architecture key to constructing novel nanodevices. Therefore, a comprehensive understanding of the interparticle forces of nanoparticle self-assemblies is a pre-requisite to the design and control of the assembly processes, so as to fabricate the ideal nanomaterial and nanoproducts. Here, different categories of interparticle forces are classified and discussed according to their origins, behaviors and functions during the assembly processes, and the induced collective properties of the corresponding nanoparticle assemblies. Common interparticle forces, such as van der Waals forces, electrostatic interactions, electromagnetic dipole-dipole interactions, hydrogen bonds, solvophonic interactions, and depletion interactions are discussed in detail. In addition, new categories of assembly principles are summarized and introduced. These are termed template mediated interactions and shape-complementary interactions. A deep understanding of the interactions inside self-assembled nanoparticles, and a broader perspective for the future synthesis and fabrication of these promising nanomaterials is provided. PMID- 26436690 TI - Integrin endosomal signalling suppresses anoikis. AB - Integrin-containing focal adhesions transmit extracellular signals across the plasma membrane to modulate cell adhesion, signalling and survival. Although integrins are known to undergo continuous endo/exocytic traffic, the potential impact of endocytic traffic on integrin-induced signals is unknown. Here, we demonstrate that integrin signalling is not restricted to cell-ECM adhesions and identify an endosomal signalling platform that supports integrin signalling away from the plasma membrane. We show that active focal adhesion kinase (FAK), an established marker of integrin-ECM downstream signalling, localizes with active integrins on endosomes. Integrin endocytosis positively regulates adhesion induced FAK activation, which is early endosome antigen-1 and small GTPase Rab21 dependent. FAK binds directly to purified endosomes and becomes activated on them, suggesting a role for endocytosis in enhancing distinct integrin downstream signalling events. Finally, endosomal integrin signalling contributes to cancer related processes such as anoikis resistance, anchorage independence and metastasis. PMID- 26436693 TI - "Healing is a Done Deal": Temporality and Metabolic Healing Among Evangelical Christians in Samoa. AB - Drawing on fieldwork in independent Samoa, in this article, I analyze the temporal dimensions of evangelical Christian healing of metabolic disorders. I explore how those suffering with metabolic disorders draw from multiple time based notions of healing, drawing attention to the limits of biomedicine in contrast with the effectiveness of Divine healing. By simultaneously engaging evangelical and biomedical temporalities, I argue that evangelical Christians create wellness despite sickness and, in turn, re-signify chronic suffering as a long-term process of Christian healing. Positioning biomedical temporality and evangelical temporality as parallel yet distinctive ways of practicing healing, therefore, influences health care choices. PMID- 26436694 TI - Changes in exposure temperature lead to changes in pesticide toxicity to earthworms: A preliminary study. AB - The occurring climate changes will have direct consequences to all ecosystems, including the soil ecosystems. The effects of climate change include, among other, the changes in temperature and greater frequency and intensity of extreme weather conditions. Temperature is an important factor in ecotoxicological investigations since it can act as a stressor and influence the physiological status of organisms, as well as affect the fate and transport of pollutants present in the environment. However, most of so far conducted (eco)toxicological investigations neglected the possible effects of temperature and focused solely on the effects of toxicants on organisms. Considering that temperature can contribute to the toxicity of pollutants, it is of immense importance to investigate whether the change in the exposure temperature will impact the strength of the toxic effects of pollutants present in soil ecosystems. Therefore, in the present study the toxicity of several commonly used pesticides to earthworms was assessed under different exposure temperatures (15, 20 and 25 degrees C). The results showed that changes in exposure temperature lead to changes in susceptibility of earthworms to particular pesticides. Namely, exposures to the same pesticide concentration at different temperatures lead to different toxicity responses. Increase in exposure temperature in most cases caused increase in toxicity, whereas decrease in temperature mostly caused decrease in toxicity. This preliminary study points to need for an in-depth investigation of mechanisms by which temperature affects the toxicity of pesticides and also provides important data for future research on the effects of temperature change on the soil ecosystems. PMID- 26436695 TI - Discovery of Compound A--a selective activator of the glucocorticoid receptor with anti-inflammatory and anti-cancer activity. AB - Glucocorticoids are among the most effective anti-inflammatory drugs, and are widely used for cancer therapy. Unfortunately, chronic treatment with glucocorticoids results in multiple side effects. Thus, there was an intensive search for selective glucocorticoid receptor (GR) activators (SEGRA), which retain therapeutic potential of glucocorticoids, but with fewer adverse effects. GR regulates gene expression by transactivation (TA), by binding as homodimer to gene promoters, or transrepression (TR), via diverse mechanisms including negative interaction between monomeric GR and other transcription factors. It is well accepted that metabolic and atrophogenic effects of glucocorticoids are mediated by GR TA. Here we summarized the results of extensive international collaboration that led to discovery and characterization of Compound A (CpdA), a unique SEGRA with a proven "dissociating" GR ligand profile, preventing GR dimerization and shifting GR activity towards TR both in vitro and in vivo. We outlined here the unusual story of compound's discovery, and presented a comprehensive overview of CpdA ligand properties, its anti-inflammatory effects in numerous animal models of inflammation and autoimmune diseases, as well as its anti-cancer effects. Finally, we presented mechanistic analysis of CpdA and glucocorticoid effects in skin, muscle, bone, and regulation of glucose and fat metabolism to explain decreased CpdA side effects compared to glucocorticoids. Overall, the results obtained by our and other laboratories underline translational potential of CpdA and its derivatives for treatment of inflammation, autoimmune diseases and cancer. PMID- 26436696 TI - A novel far-red fluorescent xenograft model of ovarian carcinoma for preclinical evaluation of HER2-targeted immunotoxins. AB - We have created a novel fluorescent model of a human ovarian carcinoma xenograft overexpressing receptor HER2, a promising molecular target of solid tumors. The model is based on a newly generated SKOV-kat cell line stably expressing far-red fluorescent protein Katushka. Katushka is most suitable for the in vivo imaging due to an optimal combination of high brightness and emission in the "window of tissue transparency". The relevance of the fluorescent model for the in vivo monitoring of tumor growth and response to treatment was demonstrated using a newly created HER2-targeted recombinant immunotoxin based on the 4D5scFv antibody and a fragment of the Pseudomonas exotoxin A. PMID- 26436697 TI - c-Met inhibitors attenuate tumor growth of small cell hypercalcemic ovarian carcinoma (SCCOHT) populations. AB - A cellular model (SCCOHT-1) of the aggressive small cell hypercalcemic ovarian carcinoma demonstrated constitutive chemokine and growth factor production including HGF. A simultaneous presence of c-Met in 41% SCCOHT-1 cells suggested an autocrine growth mechanism. Expression of c-Met was also observed at low levels in the corresponding BIN-67 cell line (6.5%) and at high levels in ovarian adenocarcinoma cells (NIH:OVCAR-3 (84.4%) and SK-OV-3 (99.3%)). Immunohistochemistry of c-Met expression in SCCOHT tumors revealed a heterogeneous distribution between undetectable levels and 80%. Further characterization of SCCOHT-1 and BIN-67 cells by cell surface markers including CD90 and EpCAM demonstrated similar patterns with differences to the ovarian adenocarcinoma cells. HGF stimulation of SCCOHT-1 cells was associated with c-Met phosphorylation at Tyr1349 and downstream Thr202/Tyr204 phosphorylation of p44/42 MAP kinase. This HGF-induced signaling cascade was abolished by the c-Met inhibitor foretinib. Cell cycle analysis after foretinib treatment demonstrated enhanced G2 accumulation and increasing apoptosis within 72 h. Moreover, the IC50 of foretinib revealed 12.4 nM in SCCOHT-1 cells compared to 411 nM and 481 nM in NIH:OVCAR-3 and SK-OV-3 cells, respectively, suggesting potential therapeutic effects. Indeed, SCCOHT-1 and BIN-67 tumor xenografts in NODscid mice exhibited an approximately 10-fold and 5-fold reduced tumor size following systemic application of foretinib, respectively. Furthermore, foretinib-treated tumors revealed a significantly reduced vascularization and little if any c-Met-mediated signal transduction. Similar findings of reduced proliferative capacity and declined tumor size were observed after siRNA-mediated c-Met knock-down in SCCOHT 1 cells demonstrating that in vivo inhibition of these pathways contributed to an attenuation of SCCOHT tumor growth. PMID- 26436698 TI - Depletion of mucin in mucin-producing human gastrointestinal carcinoma: Results from in vitro and in vivo studies with bromelain and N-acetylcysteine. AB - Aberrant expression of membrane-associated and secreted mucins, as evident in epithelial tumors, is known to facilitate tumor growth, progression and metastasis, and to provide protection against adverse growth conditions, chemotherapy and immune surveillance. Emerging evidence provides support for the oncogenic role of MUC1 in gastrointestinal carcinomas and relates its expression to an invasive phenotype. Similarly, mucinous differentiation of gastrointestinal tumors, in particular increased or de novo expression of MUC2 and/or MUC5AC, is widely believed to imply an adverse clinicopathological feature. Through formation of viscous gels, too, MUC2 and MUC5AC significantly contribute to the biology and pathogenesis of mucin-secreting gastrointestinal tumors. Here, we investigated the mucin-depleting effects of bromelain (BR) and N-acetylcysteine (NAC), in nine different regimens as single or combination therapy, in in vitro (MKN45, KATOIII and LS174T cell lines) and in vivo (female nude mice bearing intraperitoneal MKN45 and LS174T) settings. The inhibitory effects of the treatment on cancer cell growth and proliferation were also evaluated in vivo. Our results suggest that a combination of BR and NAC with dual effects on growth and mucin products of mucin-expressing tumor cells is a promising candidate towards the development of novel approaches to gastrointestinal malignancies with the involvement of mucin pathology. This capability supports the use of this combination formulation in locoregional approaches for reducing the adverse effects of the aberrantly secreted gel-forming mucins, as in pseudomyxoma peritonei and similar pathologies with ectopic production of mucin. PMID- 26436699 TI - Identification of high risk anaplastic gliomas by a diagnostic and prognostic signature derived from mRNA expression profiling. AB - Anaplastic gliomas are characterized by variable clinical and genetic features, but there are few studies focusing on the substratification of anaplastic gliomas. To identify a more objective and applicable classification of anaplastic gliomas, we analyzed whole genome mRNA expression profiling of four independent datasets. Univariate Cox regression, linear risk score formula and receiver operating characteristic (ROC) curve were applied to derive a gene signature with best prognostic performance. The corresponding clinical and molecular information were further analyzed for interpretation of the different prognosis and the independence of the signature. Gene ontology (GO), Gene Set Variation Analysis (GSVA) and Gene Set Enrichment Analysis (GSEA) were performed for functional annotation of the differences. We found a three-gene signature, by applying which, the anaplastic gliomas could be divided into low risk and high risk groups. The two groups showed a high concordance with grade II and grade IV gliomas, respectively. The high risk group was more aggressive and complex. The three-gene signature showed diagnostic and prognostic value in anaplastic gliomas. PMID- 26436700 TI - Recombinant rabies virus expressing dog GM-CSF is an efficacious oral rabies vaccine for dogs. AB - Developing efficacious oral rabies vaccines is an important step to increase immunization coverage for stray dogs, which are not accessible for parenteral vaccination. Our previous studies have demonstrated that recombinant rabies virus (RABV) expressing cytokines/chemokines induces robust protective immune responses after oral immunization in mice by recruiting and activating dendritic cells (DCs) and B cells. To develop an effective oral rabies vaccine for dogs, a recombinant attenuated RABV expressing dog GM-CSF, designated as LBNSE-dGM-CSF was constructed and used for oral vaccination in a dog model. Significantly more DCs or B cells were activated in the peripheral blood of dogs vaccinated orally with LBNSE-dGM-CSF than those vaccinated with the parent virus LBNSE, particularly at 3 days post immunization (dpi). As a result, significantly higher levels of virus neutralizing antibodies (VNAs) were detected in dogs immunized with LBNSE-dGM-CSF than with the parent virus. All the immunized dogs were protected against a lethal challenge with 4500 MICLD50 of wild-type RABV SXTYD01. LBNSE-dGM-CSF was found to replicate mainly in the tonsils after oral vaccination as detected by nested RT-PCR and immunohistochemistry. Taken together, our results indicate that LBNSE-dGM-CSF could be a promising oral rabies vaccine candidate for dogs. PMID- 26436701 TI - Length of paternal lifespan is manifested in the DNA methylome of their nonagenarian progeny. AB - The heritability of lifespan is 20-30%, but only a few genes associated with longevity have been identified. To explain this discrepancy, the inheritance of epigenetic features, such as DNA methylation, have been proposed to contribute to the heritability of lifespan.We investigated whether parental lifespan is associated with DNA methylation profile in nonagenarians. A regression model, adjusted for differences in blood cell proportions, identified 659 CpG sites where the level of methylation was associated with paternal lifespan. However, no association was observed between maternal lifespan and DNA methylation. The 659 CpG sites associated with paternal lifespan were enriched outside of CpG islands and were located in genes associated with development and morphogenesis, as well as cell signaling. The largest difference in the level of methylation between the progeny of the shortest-lived and longest-lived fathers was identified for CpG sites mapping to CXXC5. In addition, the level of methylation in three Notch genes (NOTCH1, NOTCH3 and NOTCH4) was also associated with paternal lifespan.There are implications for the inheritance of acquired traits via epigenetic mechanisms in mammals. Here we describe DNA methylation features that are associated with paternal lifespan, and we speculate that the identified CpG sites may represent intergenerational epigenetic inheritance. PMID- 26436702 TI - Inheritance in MGUS and MM. PMID- 26436704 TI - Mini-gut organoids: reconstitution of the stem cell niche. AB - In the adult mammalian body, self-renewal of tissue stem cells is regulated by extracellular niche environments in response to the demands of tissue organization. Intestinal stem cells expressing Lgr5 constantly self-renew in their specific niche at the crypt bottom to maintain rapid turnover of the epithelium. Niche-regulated stem cell self-renewal is perturbed in several mouse genetic models and during human tumorigenesis, suggesting roles for EGF, Wnt, BMP/TGF-beta, and Notch signaling. In vitro niche reconstitution capitalizing on this knowledge has enabled the growth of single intestinal stem cells into mini gut epithelial organoids comprising Lgr5(+) stem cells and all types of differentiated lineages. The mini-gut organoid culture platform is applicable to various types of digestive tissue epithelium from multiple species. The mechanism of self-renewal in organoids provides novel insights for organogenesis, regenerative medicine, and tumorigenesis of the digestive system. PMID- 26436705 TI - The hepatitis B virus receptor. AB - Hepatitis B virus (HBV) infection affects 240 million people worldwide. A liver specific bile acid transporter named the sodium taurocholate cotransporting polypeptide (NTCP) has been identified as the cellular receptor for HBV and its satellite, the hepatitis D virus (HDV). NTCP likely acts as a major determinant for the liver tropism and species specificity of HBV and HDV at the entry level. NTCP-mediated HBV entry interferes with bile acid transport in cell cultures and has been linked with alterations in bile acid and cholesterol metabolism in vivo. The human liver carcinoma cell line HepG2, complemented with NTCP, now provides a valuable platform for studying the basic biology of the viruses and developing treatments for HBV infection. This review summarizes critical findings regarding NTCP's role as a viral receptor for HBV and HDV and discusses important questions that remain unanswered. PMID- 26436703 TI - Sculpting neural circuits by axon and dendrite pruning. AB - The assembly of functional neural circuits requires the combined action of progressive and regressive events. Regressive events encompass a variety of inhibitory developmental processes, including axon and dendrite pruning, which facilitate the removal of exuberant neuronal connections. Most axon pruning involves the removal of axons that had already made synaptic connections; thus, axon pruning is tightly associated with synapse elimination. In many instances, these developmental processes are regulated by the interplay between neurons and glial cells that act instructively during neural remodeling. Owing to the importance of axon and dendritic pruning, these remodeling events require precise spatial and temporal control, and this is achieved by a range of distinct molecular mechanisms. Disruption of these mechanisms results in abnormal pruning, which has been linked to brain dysfunction. Therefore, understanding the mechanisms of axon and dendritic pruning will be instrumental in advancing our knowledge of neural disease and mental disorders. PMID- 26436707 TI - Modulation of host cell biology by plant pathogenic microbes. AB - Plant-pathogen interactions can result in dramatic visual changes in the host, such as galls, phyllody, pseudoflowers, and altered root-system architecture, indicating that the invading microbe has perturbed normal plant growth and development. These effects occur on a cellular level but range up to the organ scale, and they commonly involve attenuation of hormone homeostasis and deployment of effector proteins with varying activities to modify host cell processes. This review focuses on the cellular-reprogramming mechanisms of filamentous and bacterial plant pathogens that exhibit a biotrophic lifestyle for part, if not all, of their lifecycle in association with the host. We also highlight strategies for exploiting our growing knowledge of microbial host reprogramming to study plant processes other than immunity and to explore alternative strategies for durable plant resistance. PMID- 26436708 TI - Milk and dairy consumption correlates with cerebral cortical as well as cerebral white matter volume in healthy young adults. AB - The objective of this study was to investigate the relation between habitual milk and dairy consumption and brain morphology as assessed by magnetic resonance imaging (MRI) investigations in 119 young healthy university students. MRI measurements were performed on a Siemens Magnetom Trio Tim (3T) system while FreeSurfer software suite was used for volumetric segmentation. Dietary habits related to milk and dairy consumption were assessed by a structured questionnaire. Total cerebral cortex, total cerebral white matter, and total cerebral parenchyma were significantly related with cottage cheese and total protein intake from milk and dairy also when controlled for age and gender in the multivariate model. Our results indicate that dietary habits related with milk and dairy are proportionally associated with volumes of both cerebral cortex and cerebral white matter. PMID- 26436709 TI - Choline Chloride Assisted Synthesis of N and Metal Codoped TiO2 and their Photocatalytic Activity under Visible Light. AB - A few nanocrystalline N,metal codoped TiO2 (metal = Cr, Mn, Fe, Co, Ni, Cu and Zn) have been synthesized by a simple sol-gel method using choline chloride which is biodegradable, low cost, nontoxic ionic salt both as a structure directing agent and source of nitrogen. The prepared samples were well characterized by XRD, HRTEM, FTIR, DRS, EDX, XPS and BET techniques. The photocatalytic activity of all synthesized N, metal codoped TiO2 has been carried out for the degradation of Reactive Black 5 dye under visible light irradiation and among them, N, Fe codoped TiO2 was found to be the best for the degradation of Reactive Black 5 dye. The effect of incorporated metals on the photocatalytic activity of the various modified TiO2 has been discussed in detail based on the mechanism involved in the degradation of dye and their physico-chemical properties which includes surface area, particle size, defect sites, phase, band gap and electron hole recombination effect. PMID- 26436710 TI - Ventral fronto-parietal contributions to the disruption of visual working memory storage. AB - The ability to maintain information in visual working memory (VWM) in the presence of ongoing visual input allows for flexible goal-directed behavior. Previous evidence suggests that categorical overlap between visual distractors and the contents of VWM is associated with both the degree to which distractors disrupt VWM performance and activation among fronto-parietal regions of cortex. While within-category distractors have been shown to elicit a greater response in ventral fronto-parietal regions, to date, no study has linked distractor-evoked response of these regions to VWM performance costs. Here we examined the contributions of ventral fronto-parietal cortex to the disruption of VWM storage by manipulating memoranda-distractor similarity. Our results revealed that the degree of activation across cortex was graded in a manner suggesting that similarity between the contents of VWM and visual distractors influenced distractor processing. While abrupt visual onsets failed to engage ventral fronto parietal regions during VWM maintenance, objects sharing categorical- (Related objects) and feature-overlap (Matched objects) with VWM elicited a significant response in the right TPJ and right AI. Of central relevance, the magnitude of activation in the right AI elicited by both types of distractor objects subsequently predicted costs to binding change detection accuracy. In addition, Related and Matched distractors differentially affected ventral-dorsal connectivity between the right AI and dorsal parietal regions, uniquely contributing to disruption of VWM storage. Together, our current results implicate activation of ventral fronto-parietal cortex in disruption of VWM storage, and disconnection between ventral frontal and dorsal parietal cortices as a mechanism to protect the contents of VWM. PMID- 26436711 TI - Modality-independent reduction mechanisms of primary sensory evoked fields in a one-back task. AB - Attentional modulation of early, primary sensory components is still a topic of debate, as studies have produced conflicting results concerning the existence of a modulation within the primary somatosensory cortex and its direction. We previously showed that attention to tactile stimuli in a stream with visual stimuli leads to a reduction of primary somatosensory components when discrimination of different stimulus locations is requested. The question arises whether this effect is universal and independent from the distracting or attended modality. To test this, we compared the magnitude of primary somatosensory evoked fields (somatosensory P50m) in a one-back task after tactile finger stimulation during attention to tactile stimuli vs. auditory distraction in 28 volunteers. In comparison to acoustic distraction, we found a significantly decreased primary somatosensory activity when attending to tactile stimuli. Strikingly, similar results were produced within the auditory modality: when attention was focused on acoustic targets, primary auditory (auditory P50m) fields were lower as compared to the situation when attention was directed to the tactile stimulation. Our results clearly indicate that the type of task, independent from the modality, is actually the crucial factor for the direction of modulation of early sensory components by attention. Therefore, our finding of reduced primary sensory components in a discrimination task represents a universal effect independent from the distracting or attended modality. PMID- 26436712 TI - Differential processing of melodic, rhythmic and simple tone deviations in musicians--an MEG study. AB - Rhythm and melody are two basic characteristics of music. Performing musicians have to pay attention to both, and avoid errors in either aspect of their performance. To investigate the neural processes involved in detecting melodic and rhythmic errors from auditory input we tested musicians on both kinds of deviations in a mismatch negativity (MMN) design. We found that MMN responses to a rhythmic deviation occurred at shorter latencies than MMN responses to a melodic deviation. Beamformer source analysis showed that the melodic deviation activated superior temporal, inferior frontal and superior frontal areas whereas the activation pattern of the rhythmic deviation focused more strongly on inferior and superior parietal areas, in addition to superior temporal cortex. Activation in the supplementary motor area occurred for both types of deviations. We also recorded responses to similar pitch and tempo deviations in a simple, non musical repetitive tone pattern. In this case, there was no latency difference between the MMNs and cortical activation was smaller and mostly limited to auditory cortex. The results suggest that prediction and error detection of musical stimuli in trained musicians involve a broad cortical network and that rhythmic and melodic errors are processed in partially different cortical streams. PMID- 26436713 TI - Facilitation and inhibition in attention: Functional dissociation of pre-stimulus alpha activity, P1, and N1 components. AB - Attention--the ability to attend to some things while ignoring others - can be best described as an emergent property of many neural mechanisms, facilitatory and inhibitory, working together to resolve competition for processing resources and control of behavior. Previous EEG and MEG studies examining the neural mechanisms underlying facilitation and inhibition of stimulus processing typically used paradigms requiring alternating shifts of attention in the spatial domain, with stimuli occurring at both attended and unattended locations. These studies generally observed greater pre-stimulus alpha oscillations over task irrelevant vs. relevant posterior regions and bilateral attentional modulations of early sensory processing. In contrast, in the current series of experiments, participants continuously attended to only one hemifield and stimuli were only presented at the attended location, affording us an opportunity to elucidate the inhibitory and facilitatory effects of attention in the brain in a context in which spatial relevance was fixed. We found that continuous attention to one hemifield did not modulate prestimulus alpha activity in ipsilateral regions but did result in a perfectly lateralized P1 attention effect to ipsilateral posterior regions. Moreover, we found a bilateral N1 effect. These findings suggest that pre-stimulus alpha activity, the P1 and the N1 reflect qualitatively different aspects of attention; While pre-stimulus alpha-band activity may reflect a top-down inhibitory mechanism that critically depends on functional competition between task-relevant and irrelevant sensory regions, the ipsilateral P1 effect may reflect stimulus-triggered blocking of sensory processing in irrelevant networks, and the N1 effect facilitation of task-relevant processing. PMID- 26436706 TI - Mechanism and regulation of cytoplasmic dynein. AB - Until recently, dynein was the least understood of the cytoskeletal motors. However, a wealth of new structural, mechanistic, and cell biological data is shedding light on how this complicated minus-end-directed, microtubule-based motor works. Cytoplasmic dynein-1 performs a wide array of functions in most eukaryotes, both in interphase, in which it transports organelles, proteins, mRNAs, and viruses, and in mitosis and meiosis. Mutations in dynein or its regulators are linked to neurodevelopmental and neurodegenerative diseases. Here, we begin by providing a synthesis of recent data to describe the current model of dynein's mechanochemical cycle. Next, we discuss regulators of dynein, with particular focus on those that directly interact with the motor to modulate its recruitment to microtubules, initiate cargo transport, or activate minus-end directed motility. PMID- 26436714 TI - Examining impacts of current-use pesticides in Southern Ontario using in situ exposures of the amphipod Hyalella azteca. AB - In situ exposures with Hyalella azteca were used to assess impacts of current-use pesticides in Southern Ontario, Canada. Exposures were conducted over 2 growing seasons within areas of high pesticide use: 1 site on Prudhomme Creek and 3 sites on Twenty Mile Creek. Three sites on Spencer Creek, an area of low pesticide use, were added in the second season. Surface water samples were collected every 2 wk to 3 wk and analyzed for a suite of pesticides. Hyalella were exposed in situ for 1 wk every 4 wk to 6 wk, and survival and acetylcholinesterase (AChE) activity were measured. Pesticides in surface waters reflected seasonal use patterns: lower concentrations in spring and fall and higher concentrations during summer months. Organophosphate insecticides (chlorpyrifos, azinphos methyl, diazinon) and acid herbicides (2,4-dichlorophenoxyacetic acid [2,4-D], mecoprop) were routinely detected in Prudhomme Creek, whereas neutral herbicides (atrazine, metolachlor) dominated the pesticide signature of Twenty Mile Creek. Spencer Creek contained fewer pesticides, which were measured at lower concentrations. In situ effects also followed seasonal patterns: higher survival and AChE activity in spring and fall, and lower survival and AChE activity during summer months. The highest toxicity was observed at Prudhomme Creek and was primarily associated with organophosphates. The present study demonstrated that current-use pesticides in Southern Ontario were linked to in situ effects and identified sites of concern requiring further investigation. PMID- 26436715 TI - The [NiFe]-Hydrogenase of Pyrococcus furiosus Exhibits a New Type of Oxygen Tolerance. AB - We report the first direct electrochemical characterization of the impact of oxygen on the hydrogen oxidation activity of an oxygen-tolerant, group 3, soluble [NiFe]-hydrogenase: hydrogenase I from Pyrococcus furiosus (PfSHI), which grows optimally near 100 degrees C. Chronoamperometric experiments were used to probe the sensitivity of PfSHI hydrogen oxidation activity to both brief and prolonged exposure to oxygen. For experiments between 15 and 80 degrees C, following short (<200 s) exposure to 14 MUM O2 under oxidizing conditions, PfSHI always maintains some fraction of its initial hydrogen oxidation activity; i.e., it is oxygen tolerant. Reactivation experiments show that two inactive states are formed by interaction with oxygen and both can be quickly (<150 s) reactivated. Analogous experiments, in which the interval of oxygen exposure is extended to 900 s, reveal that the response is highly temperature-dependent. At 25 degrees C, under sustained 1% O2/ 99% H2 exposure, the H2oxidation activity drops nearly to zero. However, at 80 degrees C, up to 32% of the enzyme's oxidation activity is retained. Reactivation of PfSHI following sustained exposure to oxygen occurs on a much longer time scale (tens of minutes), suggesting that a third inactive species predominates under these conditions. These results stand in contrast to the properties of oxygen-tolerant, group 1 [NiFe]-hydrogenases, which form a single state upon reaction with oxygen, and we propose that this new type of hydrogenase should be referred to as oxygen-resilient. Furthermore, PfSHI, like other group 3 [NiFe]-hydrogenases, does not possess the proximal [4Fe3S] cluster associated with the oxygen tolerance of some group 1 enzymes. Thus, a new mechanism is necessary to explain the observed oxygen tolerance in soluble, group 3 [NiFe]-hydrogenases, and we present a model integrating both electrochemical and spectroscopic results to define the relationships of these inactive states. PMID- 26436716 TI - Vocational Psychology: Agency, Equity, and Well-Being. AB - The present review organizes the vocational psychology literature published between 2007 and 2014 into three overarching themes: Promoting (a) agency in career development, (b) equity in the work force, and (c) well-being in work and educational settings. Research on career adaptability, self-efficacy beliefs, and work volition is reviewed in the agency section, with the goal of delineating variables that promote or constrain the exercise of personal agency in academic and occupational pursuits. The equity theme covers research on social class and race/ethnicity in career development; entry and retention of women and people of color in science, technology, engineering, and math (STEM) fields; and the career service needs of survivors of domestic violence and of criminal offenders. The goal was to explore how greater equity in the work force could be promoted for these groups. In the well-being section, we review research on hedonic (work, educational, and life satisfaction) and eudaimonic (career calling, meaning, engagement, and commitment) variables, with the goal of understanding how well being might be promoted at school and at work. Future research needs related to each theme are also discussed. PMID- 26436718 TI - WITHDRAWN: Psychosocial and pharmacological treatments for deliberate self harm. PMID- 26436721 TI - The Folic Acid Rescue Strategy: High-Dose Folic Acid Supplementation in Early Pregnancy. PMID- 26436720 TI - Staphylococcal enterotoxin IgE sensitization in late-onset severe eosinophilic asthma in the elderly. AB - BACKGROUND: Asthma in the elderly (aged >= 65 years old) is a significant concern with high morbidity, but the pathophysiology remains unclear particularly in late onset asthma. Recent studies suggest staphylococcal enterotoxin IgE (SE-IgE) sensitization to be a risk factor for asthma in general populations; however, the associations have not been examined in late-onset elderly asthma. OBJECTIVE: We aimed to examine the associations of SE-IgE sensitization with late-onset asthma in the elderly, using a database of elderly asthma cohort study. METHODS: A total of 249 elderly patients with asthma and 98 controls were analysed. At baseline, patients were assessed for demographics, atopy, induced sputum profiles and comorbidities including chronic rhinosinusitis (CRS). Serum total IgE and SE-IgE levels were measured. Asthma severity was assessed on the basis of asthma outcomes during a 12-month follow-up period. RESULTS: At baseline, serum SE-IgE concentrations were significantly higher in patients with asthma than in controls [median 0.16 (interquartile range 0.04-0.53) vs. 0.10 (0.01-0.19), P < 0.001]. Elderly asthma patients with high SE-IgE levels had specific characteristics of having more severe asthma, sputum eosinophilia and CRS, compared to those with lower SE-IgE levels. In multivariate logistic regression analyses, the associations between serum SE-IgE concentrations and severe asthma were significant, independently of covariables [SE-IgE-high (>= 0.35 kU/L) vs. negative (< 0.10 kU/L) group: odds ratio 7.47, 95% confidence interval 1.86 30.03, P = 0.005]. Multiple correspondence analyses also showed that high serum SE-IgE level had close relationships with severe asthma, CRS and sputum eosinophilia together. CONCLUSIONS AND CLINICAL RELEVANCE: This is the first report on the significant associations of SE-IgE sensitization with late-onset asthma in the elderly, particularly severe eosinophilic asthma with CRS comorbidity. Our findings indicate a potential implication of SE in the high morbidity burden of elderly asthma and suggest clues to the pathogenesis of severe late-onset eosinophilic asthma in the elderly. PMID- 26436717 TI - The Affective Neuroscience of Aging. AB - Although aging is associated with clear declines in physical and cognitive processes, emotional functioning fares relatively well. Consistent with this behavioral profile, two core emotional brain regions, the amygdala and ventromedial prefrontal cortex, show little structural and functional decline in aging, compared with other regions. However, emotional processes depend on interacting systems of neurotransmitters and brain regions that go beyond these structures. This review examines how age-related brain changes influence processes such as attending to and remembering emotional stimuli, regulating emotion, and recognizing emotional expressions, as well as empathy, risk taking, impulsivity, behavior change, and attentional focus. PMID- 26436723 TI - Understanding the gender gap: Social cognitive changes during an introductory stem course. AB - Despite robust support for the basic theoretical model of social cognitive career theory (Lent, Brown, & Hackett, 1994) and predictions that, for example, increases (or declines) in self-efficacy would lead to subsequent increases (or declines) in interest, there has been surprisingly little longitudinal research that has directly examined the extent to which members of different groups (e.g., women and men) actually do experience changes in critical social-cognitive variables over time early in their curricula in the fields of science, technology, engineering, and mathematics (STEM). Knowing the extent to which such changes occur in typical introductory undergraduate courses is important for targeting interventions to increase persistence of underrepresented groups in STEM. We measured social-cognitive-career-theory-relevant variables near the middle and at the end of the 1st semester of a gateway introductory chemistry course and found that women had lower STEM self-efficacy, coping self-efficacy, and STEM interest than did men, even after controlling for actual course performance. Although there were no detrimental changes across the semester for women or men, men experienced a small but significant increase in their perceived support for pursuing a STEM degree, whereas women did not. PMID- 26436722 TI - Toll-IL1 receptor-mediated innate immune responses vary across HBV genotype and predict treatment response to pegylated-IFN in HBeAg-positive CHB patients. AB - Patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) have suppressed TLR2 expression, function and cytokine production. The aim of this study was to explore the importance of hepatitis B virus (HBV) genotype in innate immune responses and investigate whether Toll-like receptor (TLR) expression/function has potential roles as predictive biomarkers of successful therapy with pegylated interferon (Peg-IFN) therapy of HBeAg seroconversion in HBeAg-positive patients. We showed that as early as 4 weeks after initiation of Peg-IFN, future HBeAg seroconverters had significantly elevated levels of TLR2 expression on monocytes. TLR2-associated IL-6 production at baseline and week 4 of therapy and TLR4 IL-6 production at week 4 were also markedly elevated in HBeAg seroconverters. HBV genotype also influenced treatment response, with genotypes A and B more likely to seroconvert than D. We were able to demonstrate that these differences were due in part to the interaction of the specific HBeAg proteins with TLR pathway adaptor molecules, and these interactions were genotype dependent. HBeAg-mediated modulation of TLR signalling was also observed in Huh7 cells, following stimulation with Pam3Cys. Importantly, the addition of IFN-alpha to TLR2-stimulated cells cotransfected with an HBeAg expression plasmid reversed HBeAg-mediated suppression of hepatocytes. These findings demonstrate that patients with an activated inflammatory response are much more likely to respond to IFN therapy, with TLR responses showing promise as potential biomarkers of HBeAg seroconversion in this setting. Furthermore, our findings suggest there is differential genotype-specific HBeAg suppression of innate signalling pathways which may account for some of the clinical differences observed across the CHB spectrum. PMID- 26436724 TI - A dyadic study of multicultural counseling competence. AB - Using the Kenny, Kashy, and Cook (2006) one-with-many method, we investigated client and counselor reports of counselors' level of multicultural counseling competence (MCC) across 4 therapy sessions at a university counseling center. Specifically, we analyzed the association between counselor MCC and client psychological well-being among 133 clients of color receiving psychotherapy from 24 counselors. We found that both client and counselor perspectives suggested that some counselors possessed generally higher MCC than others. Counselors' self assessments of MCC, however, did not relate with their clients' assessments of counselor MCC-replicating findings from past studies of MCC. On average, counselors whose clients generally perceived them as more multiculturally competent did not report improved psychological well-being at the fourth session. Likewise, counselors who generally reported more MCC did not have clients who improved more in psychological well-being than would be expected over 4 sessions. Notably, at the dyad-level, clients who rated their counselor more highly on MCC than their counselors' other clients tended to report greater improvement in well being. Suggestions for future MCC research involving dyadic analytic designs are described. (PsycINFO Database Record PMID- 26436725 TI - Characterization of Intrinsic Properties of Promoters. AB - Accurate characterization of promoter behavior is essential for the rational design of functional synthetic transcription networks such as logic gates and oscillators. However, transcription rates observed from promoters can vary significantly depending on the growth rate of host cells and the experimental and genetic contexts of the measurement. Furthermore, in vivo measurement methods must accommodate variation in translation, protein folding, and maturation rates of reporter proteins, as well as metabolic load. The external factors affecting transcription activity may be considered to be extrinsic, and the goal of characterization should be to obtain quantitative measures of the intrinsic characteristics of promoters. We have developed a promoter characterization method that is based on a mathematical model for cell growth and reporter gene expression and exploits multiple in vivo measurements to compensate for variation due to extrinsic factors. First, we used optical density and fluorescent reporter gene measurements to account for the effect of differing cell growth rates. Second, we compared the output of reporter genes to that of a control promoter using concurrent dual-channel fluorescence measurements. This allowed us to derive a quantitative promoter characteristic (rho) that provides a robust measure of the intrinsic properties of a promoter, relative to the control. We imposed different extrinsic factors on growing cells, altering carbon source and adding bacteriostatic agents, and demonstrated that the use of rho values reduced the fraction of variance due to extrinsic factors from 78% to less than 4%. This is a simple and reliable method to quantitatively describe promoter properties. PMID- 26436726 TI - Polysomnographic findings after adenotonsillectomy for obstructive sleep apnoea in obese and non-obese children: a systematic review and meta-analysis. AB - BACKGROUND: Use of polysomnography (PSG) is the gold standard of diagnosis and measurement of treatment effectiveness for paediatric obstructive sleep apnoea (OSA). Although adenotonsillectomy (T&A) is effective in diminishing the apnoea hypopnoea index (AHI), a meta-analysis of postoperative changes for all other PSG parameters and outcome comparisons between obese and non-obese children following T&A have never been conducted. OBJECTIVE OF REVIEW: To comprehensively review polysomnographic findings after surgery for obese and non-obese children with OSA. SEARCH STRATEGY: Study protocol was registered on PROSPERO (CRD42013004737). Two authors independently searched databases including PubMed, MEDLINE, EMBASE and Cochrane Review from January 1997 to July 2014. The keywords used included the following: sleep apnea, OSA, sleep apnea syndromes, tonsillectomy, adenoidectomy, infant, child, adolescent, and Humans. EVALUATION METHOD: A comprehensive systematic review and meta-analysis for literature for OSA children treated by T&A with polysomnography data. Random-effects model was applied to determine postoperative sleep parameter changes and the surgical success rate between obese and non-obese groups. The quality of studies was assessed using the Newcastle-Ottawa Scale. RESULTS: In total, 51 studies with 3413 subjects were enrolled. After surgery, sleep architecture was altered by a significant decrease in sleep stage 1, and an increase in slow-wave sleep and the rapid eye movement stage, and enhanced sleep efficiency. The mean difference between pre- and postoperative was a significant reduction of 12.4 event/h in AHI, along with a reduction of obstructive index, hypopnoea index, central index and arousal index. Mean and minimum oxygen saturation increased significantly after surgery. The overall success rate was 51% for postoperative AHI <1 (obese versus non-obese versus combined, 34% versus 49% versus 56%), and 81% for AHI <5 (obese versus non obese versus combined, 61% versus 87% versus 84%). Meta-regression analyses demonstrate that postoperative AHI was positively correlated with AHI and body mass index z score before surgery. CONCLUSIONS: Meta-analysis of current literature shows T&A offers prominent improvement in a variety of sleep parameters. Improvements in non-obese children exceeded those for obese children. Postoperative residual OSA remained in roughly half of the children, especially those with severe disease and obesity, making additional treatment strategies and/or long-term follow-up highly desirable. PMID- 26436727 TI - Retroactive application of the new kidney allocation system to renal transplants performed in the ECD/SCD era. AB - The kidney allocation system (KAS) aims to improve deceased donor kidney transplant outcomes by matching of donor allografts and kidney recipients using the kidney donor risk index (KDRI) and recipient estimated post-transplant survival (EPTS) indices. In this single-center study, KAS was retroactively applied to 573 adult deceased donor kidney transplants (2004-2012) performed in the extended criteria/standard criteria donor (ECD/SCD) era. Donor KDRI and recipient EPTS were calculated, and transplants were analyzed to identify KAS fits. These were defined as allocation of top 20% allografts to top 20% recipients and bottom 80% allografts to bottom 80% recipients. On retroactive calculation, 70.2% of all transplants fit the KAS. Transplants that fit the KAS had inferior 1- and 5-yr patient survival (95.5% vs. 98.8%, p = 0.048, and 83.4% vs. 91.7%, p = 0.018) and similar 1- and 5-yr graft survival compared to transplants that did not fit the KAS (91.3% vs. 94.1%, p = 0.276, and 72.7% vs. 73.9%, p = 0.561). While EPTS correlated with recipient survival (HR = 2.96, p < 0.001), KDRI correlated with both recipient (HR = 3.56, p < 0.001) and graft survival (HR = 3.23, p < 0.001). Overall, retroactive application of the KAS to transplants performed in the ECD/SCD era did not identify superior patient survival for kidneys allocated in accordance with the KAS. PMID- 26436728 TI - Common Polymorphisms within Genes Encoding Platelet Receptors: Still a Way to Go. PMID- 26436729 TI - Experimental Research Examining How People Can Cope with Uncertainty Through Soft Haptic Sensations. AB - Human beings are constantly surrounded by uncertainty and change. The question arises how people cope with such uncertainty. To date, most research has focused on the cognitive strategies people adopt to deal with uncertainty. However, especially when uncertainty is due to unpredictable societal events (e.g., economical crises, political revolutions, terrorism threats) of which one is unable to judge the impact on one's future live, cognitive strategies (like seeking additional information) is likely to fail to combat uncertainty. Instead, the current paper discusses a method demonstrating that people might deal with uncertainty experientially through soft haptic sensations. More specifically, because touching something soft creates a feeling of comfort and security, people prefer objects with softer as compared to harder properties when feeling uncertain. Seeking for softness is a highly efficient and effective tool to deal with uncertainty as our hands are available at all times. This protocol describes a set of methods demonstrating 1) how environmental (un)certainty can be situationally activated with an experiential priming procedure, 2) that the quality of the softness experience (what type of softness and how it is experienced) matters and 3) how uncertainty can be reduced using different methods. PMID- 26436730 TI - Remanagement of Singlet and Triplet Excitons in Single-Emissive-Layer Hybrid White Organic Light-Emitting Devices Using Thermally Activated Delayed Fluorescent Blue Exciplex. AB - A high-performance hybrid white organic light-emitting device (WOLED) is demonstrated based on an efficient novel thermally activated delayed fluorescence (TADF) blue exciplex system. This device shows a low turn-on voltage of 2.5 V and maximum forward-viewing external quantum efficiency of 25.5%, which opens a new avenue for achieving high-performance hybrid WOLEDs with simple structures. PMID- 26436732 TI - Speciation Progress: A Case Study on the Bushcricket Poecilimon veluchianus. AB - Different mechanisms such as selection or genetic drift permitted e.g. by geographical isolation can lead to differentiation of populations and could cause subsequent speciation. The two subspecies of Poecilimon veluchianus, a bushcricket endemic to central Greece, show a parapatric distribution and are partially reproductively isolated. Therefore, P. veluchianus is suitable to investigate an ongoing speciation process. We based our analysis on sequences of the internal transcribed spacer (ITS) and the mitochondrial control region (CR). The population genetic analysis based on the nuclear marker ITS revealed a barrier to gene flow within the range of Poecilimon veluchianus, which corresponds well to the described subspecies. In contrast to the results based on the nuclear ITS marker, the mitochondrial CR marker does not clearly support the separation into two subspecies with restricted gene flow and a clear contact zone. Furthermore, we could identify isolation by distance (IBD) as one important mechanism responsible for the observed genetic structure (based on the ITS marker). The population genetic analysis based on the nuclear marker ITS also suggests the existence of hybrids in the wild. Furthermore, the simultaneous lack of strong prezygotic barriers and the presence of postzygotic mating barriers, observed in previous laboratory experiments, suggest that a secondary contact after an allopatric phase is more likely than parapatric speciation. PMID- 26436731 TI - Cortical Composition Hierarchy Driven by Spine Proportion Economical Maximization or Wire Volume Minimization. AB - The structure and quantitative composition of the cerebral cortex are interrelated with its computational capacity. Empirical data analyzed here indicate a certain hierarchy in local cortical composition. Specifically, neural wire, i.e., axons and dendrites take each about 1/3 of cortical space, spines and glia/astrocytes occupy each about (1/3)(2), and capillaries around (1/3)(4). Moreover, data analysis across species reveals that these fractions are roughly brain size independent, which suggests that they could be in some sense optimal and thus important for brain function. Is there any principle that sets them in this invariant way? This study first builds a model of local circuit in which neural wire, spines, astrocytes, and capillaries are mutually coupled elements and are treated within a single mathematical framework. Next, various forms of wire minimization rule (wire length, surface area, volume, or conduction delays) are analyzed, of which, only minimization of wire volume provides realistic results that are very close to the empirical cortical fractions. As an alternative, a new principle called "spine economy maximization" is proposed and investigated, which is associated with maximization of spine proportion in the cortex per spine size that yields equally good but more robust results. Additionally, a combination of wire cost and spine economy notions is considered as a meta-principle, and it is found that this proposition gives only marginally better results than either pure wire volume minimization or pure spine economy maximization, but only if spine economy component dominates. However, such a combined meta-principle yields much better results than the constraints related solely to minimization of wire length, wire surface area, and conduction delays. Interestingly, the type of spine size distribution also plays a role, and better agreement with the data is achieved for distributions with long tails. In sum, these results suggest that for the efficiency of local circuits wire volume may be more primary variable than wire length or temporal delays, and moreover, the new spine economy principle may be important for brain evolutionary design in a broader context. PMID- 26436733 TI - Systematic review of effects of current transtibial prosthetic socket designs- Part 2: Quantitative outcomes. AB - This review is an attempt to untangle the complexity of transtibial prosthetic socket fit and perhaps find some indication of whether a particular prosthetic socket type might be best for a given situation. In addition, we identified knowledge gaps, thus providing direction for possible future research. We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta Analyses) guidelines, using medical subject headings and standard key words to search for articles in relevant databases. No restrictions were made on study design and type of outcome measure used. From the obtained search results (n = 1,863), 35 articles were included. The relevant data were entered into a predefined data form that included the Downs and Black risk of bias assessment checklist. This article presents the results from the systematic review of the quantitative outcomes (n = 27 articles). Trends indicate that vacuum-assisted suction sockets improve gait symmetry, volume control, and residual limb health more than other socket designs. Hydrostatic sockets seem to create less inconsistent socket fittings, reducing a problem that greatly influences outcome measures. Knowledge gaps exist in the understanding of clinically meaningful changes in socket fit and its effect on biomechanical outcomes. Further, safe and comfortable pressure thresholds under various conditions should be determined through a systematic approach. PMID- 26436734 TI - Temporal Monitoring of Differentiated Human Airway Epithelial Cells Using Microfluidics. AB - The airway epithelium is exposed to a variety of harmful agents during breathing and appropriate cellular responses are essential to maintain tissue homeostasis. Recent evidence has highlighted the contribution of epithelial barrier dysfunction in the development of many chronic respiratory diseases. Despite intense research efforts, the responses of the airway barrier to environmental agents are not fully understood, mainly due to lack of suitable in vitro models that recapitulate the complex in vivo situation accurately. Using an interdisciplinary approach, we describe a novel dynamic 3D in vitro model of the airway epithelium, incorporating fully differentiated primary human airway epithelial cells at the air-liquid interface and a basolateral microfluidic supply of nutrients simulating the interstitial flow observed in vivo. Through combination of the microfluidic culture system with an automated fraction collector the kinetics of cellular responses by the airway epithelium to environmental agents can be analysed at the early phases for the first time and with much higher sensitivity compared to common static in vitro models. Following exposure of primary differentiated epithelial cells to pollen we show that CXCL8/IL-8 release is detectable within the first 2h and peaks at 4-6h under microfluidic conditions, a response which was not observed in conventional static culture conditions. Such a microfluidic culture model is likely to have utility for high resolution temporal profiling of toxicological and pharmacological responses of the airway epithelial barrier, as well as for studies of disease mechanisms. PMID- 26436738 TI - The Link Between Sauna Bathing and Mortality May Be Noncausal. PMID- 26436739 TI - The Link Between Sauna Bathing and Mortality May Be Noncausal. PMID- 26436740 TI - The Link Between Sauna Bathing and Mortality May Be Noncausal-Reply. PMID- 26436741 TI - Study Design for Vitamin D Randomized Clinical Trials. PMID- 26436742 TI - Study Design for Vitamin D Randomized Clinical Trials-Reply. PMID- 26436743 TI - Another Report of Familial Spontaneous Coronary Artery Dissection. PMID- 26436744 TI - Another Report of Familial Spontaneous Coronary Artery Dissection-Reply. PMID- 26436745 TI - Physical Function and Hospital Readmissions. PMID- 26436746 TI - Vitamin D Supplements and the Risk of Falls. PMID- 26436747 TI - Physical Function and Hospital Readmissions-Reply. PMID- 26436748 TI - Selecting the Optimal Design for Drug Discontinuation Trials in a Setting of Advanced, Life-Limiting Illness. PMID- 26436749 TI - Vitamin D Supplements and the Risk of Falls-Reply. PMID- 26436750 TI - Selecting the Optimal Design for Drug Discontinuation Trials in a Setting of Advanced, Life-Limiting Illness. PMID- 26436751 TI - Selecting the Optimal Design for Drug Discontinuation Trials in a Setting of Advanced, Life-Limiting Illness-Reply. PMID- 26436752 TI - Diet and Colorectal Cancer Incidence. PMID- 26436753 TI - Noninvasive Testing in Patients With Chest Pain. PMID- 26436754 TI - Diet and Colorectal Cancer Incidence-Reply. PMID- 26436756 TI - Error in Figure. PMID- 26436755 TI - Noninvasive Testing in Patients With Chest Pain-Reply. PMID- 26436757 TI - Microwave, r0 Structural Parameters, Conformational Stability, and Vibrational Assignment of (Chloromethyl)fluorosilane. AB - The FT-microwave spectrum (6.5-26 GHz) of (chloromethyl)fluorosilane (ClCH2 SiH2F) has been recorded and 250 transitions for the parent species along with (13)C, (37)Cl, (29)Si, and (30)Si isotopologues have been assigned for trans conformer. Infrared spectra (3100 to 400 cm(-1)) of gas, solid, and the variable temperature (-100 to -60 degrees C) studies of the infrared spectra of the sample dissolved in xenon have been recorded. Additionally, the variable temperature (-153 to -133 degrees C) studies of the Raman spectra of the sample dissolved in krypton have been recorded. The enthalpy difference between the trans and gauche conformers in xenon solutions has been determined to be 109 +/- 15 cm(-1) (1.47 +/- 0.16 kJ mol(-1)), and in krypton solution, the enthalpy difference has been determined to be 97 +/- 16 cm(-1) (1.16 +/- 0.19 kJ mol(-1)) with the trans conformer as the more stable form. Approximately 46 +/- 2% of the trans form is present at ambient temperature. By utilizing the microwave rotational constants of five isotopologues for trans and the structural parameters predicted from MP2(full)/6-311+G(d,p) calculations, adjusted r0 parameters have been obtained for trans conformer. The r0 structural parameter values for the trans form are for the heavy atom distances (A): Si-F = 1.608 (3); C-Cl = 1.771 (3); Si-C = 1.884 (3); and angles (deg): ?FSiC = 108.9 (5); ?ClCSi = 104.9 (5). The results are discussed and compared to some related molecules. PMID- 26436759 TI - A Patient-Centered Understanding of the Referral System in Ethiopian Primary Health Care Units. AB - BACKGROUND: Primary healthcare systems in sub-Saharan Africa have undergone substantial development in an effort to expand access to appropriate facilities through a well-functioning referral system. The objective of this study was to evaluate the current patterns of seeking prior care before arriving at a health center or a hospital as a key aspect of the referral system of the primary health care unit (PHCU) in three regions in Ethiopia. We examined what percentage of patients had either sought prior care or had been referred to the present facility and identified demographic and clinical factors associated with having sought prior care or having been referred. METHODS AND FINDINGS: We conducted a cross-sectional study using face-to-face interviews in the local language with 796 people (99% response rate) seeking outpatient care in three primary health care units serving approximately 100,000 people each and reflecting regional and ethnic diversity; 53% (N = 418) of the sample was seeking care at hospital outpatient departments, and 47% of the sample was seeking care at health centers (N = 378). We used unadjusted and adjusted logistic regression to identify factors associated with having been referred or sought prior care. Our findings indicated that only 10% of all patients interviewed had been referred to their current place of care. Among those in the hospital population, 14% had been referred; among those in the health center population, only 6% had been referred. Of those who had been referred to the hospital, most (74%) had been referred by a health center. Among those who were referred to the health center, the plurality portion (32%) came from a nearby hospital (most commonly for continued HIV treatment or early childhood vaccinations); only 18% had come from a health post. Among patients who had not been formally referred, an additional 25% in the hospital sample and 10% in the health center sample had accessed some prior source of care for their present health concern. In the adjusted analysis, living a longer distance from the source of care and needing more specialized care were correlated with having sought prior care in the hospital sample. We found no factors significantly associated with having sought prior care in the health center sample. CONCLUSIONS: The referral system among health facilities in Ethiopia is used by a minority of patients, suggesting that intended connections between health posts, health centers, and hospitals may need strengthening to increase the efficiency of primary care nationally. PMID- 26436758 TI - Thinking Forward: Future-oriented Thinking among Patients with Tobacco-associated Thoracic Diseases and Their Surrogates. AB - RATIONALE: The goal of shared decision making is to match patient preferences, including evaluation of potential future outcomes, with available management options. Yet, it is unknown how patients with smoking-related thoracic diseases or their surrogates display future-oriented thinking. OBJECTIVES: To document prevalent themes in patients' and potential surrogate decision makers' future oriented thinking when facing preference-sensitive choices. METHODS: We conducted 44 scenario-based semistructured interviews among a diverse group of outpatients with smoking-associated thoracic diseases and potential surrogates for whom one of three preference-sensitive decisions would be medically relevant. Using content analysis, we documented prevalent themes to understand how these individuals display future-oriented thinking. MEASUREMENTS AND MAIN RESULTS: Patients and potential surrogates generally expressed expectations for future outcomes but also acknowledged their limitations in doing so. When thinking about potential outcomes, decision makers relied on past experiences, including those only loosely related; perceived familiarity with treatment options; and spirituality. The content of these expectations included effects on family, emotional predictions, and prognostication. For surrogates, a tension existed between hope-based and fact-based expectations. CONCLUSIONS: Patients and surrogates may struggle to generate expectations, and these future-oriented thoughts may be based on loosely related past experiences or unrealistic optimism. These tendencies may lead to errors, preventing selection of treatments that promote true preferences. Clinicians should explore how decision makers engage in future-oriented thinking and what their expectations are as a component of the shared decision-making process. Future research should evaluate whether targeted guidance in future-oriented thinking may improve outcomes important to patients. PMID- 26436761 TI - Genetic and Epigenetic Mechanisms Linking Pain and Psychiatric Disorders. AB - The neurophysiological link between neuropathic pain and depression remains unknown despite evident high comorbidity of these two disorders. However, there is convincing evidence that genotype plays a role in both pain and depression. Using various types of genetic analysis - population genetics, cytogenetics and molecular technologies - specific genes have been implicated in mediating almost all aspects of nociception and mood disorders. The current review attempts to identify specific genes and epigenetic mechanisms common to both disorders. It is concluded that external and internal factors (inflammation, stress, gender, etc.) that contribute to the pathologies may do so through epigenetic mechanisms that may affect expression of these particular genes. The possible involvement of epigenetic regulation in pain and psychiatric disorders suggests that treatments targeting epigenetic mechanisms that mediate adverse life events should be considered. PMID- 26436762 TI - Conductance of graphene flakes contacted at their corners. AB - Linear conductance of junctions formed by graphene flakes with the order of the nanometer-thick electrodes attached at the corners of the flakes is studied. The explored structures have sizes up to 20,000 atoms and the conductance is studied as a function of applied gate voltage varied around the Fermi level. The finding, obtained computationally, is that junctions formed by armchair-edge flakes with the electrodes connected at the acute-angle corners block the electron transport while only junctions with such electrodes at the obtuse-angle corners tend to provide the high electrical conductance typical for metallic GNRs. The finding in the case of zig-zag edges is similar with the exception of a relatively narrow gate voltage interval in which each studied junction is highly conductive as mediated by the edge states. The contrast between the conductive and insulating setups is typically several orders of magnitude in terms of ratio of their conductances. The main results of the paper also remain to a large extent valid in the presence of edge disorder. PMID- 26436760 TI - GPR55 promotes migration and adhesion of colon cancer cells indicating a role in metastasis. AB - BACKGROUND AND PURPOSE: Tumour cell migration and adhesion constitute essential features of metastasis. G-protein coupled receptor 55 (GPR55), a lysophospholipid receptor, has been shown to play an important role in carcinogenesis. Here, we investigated the involvement of GPR55 in migration and metastasis of colon cancer cells. EXPERIMENTAL APPROACH: Adhesion and migration assays using the highly metastatic colon cancer cell line HCT116 and an in vivo assay of liver metastasis were performed. The GPR55 antagonist CID16020046, cannabidiol, a putative GPR55 antagonist and GPR55 siRNA were used to block GPR55 activity in HCT116 colon cancer cells. KEY RESULTS: HCT116 cells showed a significant decrease in adhesion to endothelial cells and in migration after blockade with CID16020046 or cannabidiol. The inhibitory effects of CID16020046 or cannabidiol were averted by GPR55 siRNA knock down in cancer cells. The integrity of endothelial cell monolayers was increased after pretreatment of HCT116 cells with the antagonists or after GPR55 siRNA knockdown while pretreatment with lysophosphatidylinositol (LPI), the endogenous ligand of GPR55, decreased integrity of the monolayers. LPI also induced migration in GPR55 overexpressing HCT116 cells that was blocked by GPR55 antagonists. In a mouse model of metastasis, the arrest of HCT116 cancer cells in the liver was reduced after treatment with CID16020046 or cannabidiol. Increased levels of LPI (18:0) were found in colon cancer patients when compared with healthy individuals. CONCLUSIONS AND IMPLICATIONS: GPR55 is involved in the migratory behaviour of colon carcinoma cells and may serve as a pharmacological target for the prevention of metastasis. (c) 2015 The British Pharmacological Society. PMID- 26436764 TI - Will modern immunotherapies become the standard of care for advanced synchronous or metachronous cancers? PMID- 26436763 TI - Spatial clusters of child lower respiratory illnesses associated with community level risk factors. AB - Identifying geographic areas with increased incidence of disease may elucidate community-level risk factors for intervention development. Lower respiratory illnesses (LRIs) are the leading cause of death in children and are associated with other morbidities. We assessed geographic clustering of LRIs and evaluated if these spatial patterns and associated risk factors differed by phenotype. Participants enrolled at birth in the Tucson Children's Respiratory Study were followed through age three for physician diagnosed LRIs. Spatial clustering analysis, based upon each participant's birth address, was performed for four LRI phenotypes. We conducted principal component analysis at the census tract level to generate indices for lower socioeconomic status (SES), poorer housing conditions, and increased air pollution. Enrollment addresses were mapped for 812 subjects, of whom 58.4%, 33.5%, 34.2%, and 23.4% had any LRI, a wheezing LRI, a viral LRI, and a respiratory syncytial virus (RSV) LRI, respectively. Patterns of spatial clustering and associated risk factors differed by LRI phenotype. Multivariable regression analyses showed that wheezing LRI clusters were associated with increased air pollution (OR = 1.18, P = 0.01). Being in a viral cluster was associated with poorer housing conditions (OR = 1.28, P = 0.01), while being in a RSV cluster was associated with increased air pollution (OR = 1.14, P = 0.006), poorer housing conditions (OR = 1.54, P = 0.003), and higher SES (OR = 0.77, P = 0.001). Our use of social and environmental indices allowed us to identify broad contextual factors that may contribute to increased incidence of LRIs in specific geographic regions. To reduce LRI incidence, multifaceted interventions should be developed at the community level. Pediatr Pulmonol. 2016;51:633-642. (c) 2015 Wiley Periodicals, Inc. PMID- 26436765 TI - Age-related motor dysfunction: Manual slowing in Gorilla gorilla gorilla. AB - Aging in humans and rhesus monkeys is commonly associated with motor function decrements including dexterity, speed, and strength. Despite their longevity and phylogenetic relatedness to humans, the effects of aging on motor function in non human apes have been minimally studied. We conducted two experiments with western lowland gorillas (11-54 years of age) to determine whether aged gorillas exhibit motor deficits similar to those seen in other species. In experiment one, gorillas extracted up to 12 food rewards lodged in holes of a Lexan board. Extraction rates were calculated for eight test sessions. A repeated measures ANOVA revealed no main effects of session or sex on extraction rate, but a significant main effect of age. Comparisons between the first and last sessions showed that experience significantly improved extraction rates in young but not aged gorillas. In experiment two, gorillas retrieved a hex nut from three differently shaped rods with each hand for a reward. Latencies of retrieval were calculated for 16 test sessions. A repeated measures ANOVA revealed significant main effects of age class, sex, and session. There were significant interactions between session and sex, session and age, and session, sex, and age. These findings held when analyzing each rod shape separately. Post hoc comparisons revealed that young gorillas were significantly faster at the task than aged gorillas, and females were faster than males. This finding held only for the question mark shaped rod when analyzing each rod shape separately. Comparisons between the first and last sessions showed that experience did not significantly improve latencies in either age or sex class. The direction of these results are congruent with previous findings in humans and monkeys and suggest that aged gorillas experience deficits in bimanual coordination compared to younger gorillas and that age and sex influence fine motor ability in gorillas. PMID- 26436766 TI - Myeloid Cell Arg1 Inhibits Control of Arthritogenic Alphavirus Infection by Suppressing Antiviral T Cells. AB - Arthritogenic alphaviruses, including Ross River virus (RRV) and chikungunya virus (CHIKV), are responsible for explosive epidemics involving millions of cases. These mosquito-transmitted viruses cause inflammation and injury in skeletal muscle and joint tissues that results in debilitating pain. We previously showed that arginase 1 (Arg1) was highly expressed in myeloid cells in the infected and inflamed musculoskeletal tissues of RRV- and CHIKV-infected mice, and specific deletion of Arg1 from myeloid cells resulted in enhanced viral control. Here, we show that Arg1, along with other genes associated with suppressive myeloid cells, is induced in PBMCs isolated from CHIKV-infected patients during the acute phase as well as the chronic phase, and that high Arg1 expression levels were associated with high viral loads and disease severity. Depletion of both CD4 and CD8 T cells from RRV-infected Arg1-deficient mice restored viral loads to levels detected in T cell-depleted wild-type mice. Moreover, Arg1-expressing myeloid cells inhibited virus-specific T cells in the inflamed and infected musculoskeletal tissues, but not lymphoid tissues, following RRV infection in mice, including suppression of interferon-gamma and CD69 expression. Collectively, these data enhance our understanding of the immune response following arthritogenic alphavirus infection and suggest that immunosuppressive myeloid cells may contribute to the duration or severity of these debilitating infections. PMID- 26436768 TI - Nasopalpebral Schwannomas and Human Immunodeficiency Virus Infection. AB - OBJECTIVE: To report a case of a schwannoma of nasopalpebral location, occurring in a human immunodeficiency virus (HIV)-positive patient. CLINICAL PRESENTATION AND INTERVENTION: A 55-year-old man presented with a nasopalpebral painless tumefaction, pneumopathy and HIV-related immunodepression after stopping combination antiretroviral therapy. Magnetic resonance imaging showed subcutaneous masses, with contrast enhancement of the left nose pyramid, internal cantus and inferior palpebral area, suspicious of Kaposi sarcoma. The resected specimen showed schwannoma histology, with tumor cells expressing S100 protein and WT1. CONCLUSION: The features of a rare case of facial schwannoma of nasopalpebral location in an HIV-positive patient are reported. The diagnosis may be difficult before microscopic examination, with imaging features suggesting a Kaposi sarcoma. PMID- 26436769 TI - Three-Dimensional Heterostructures of MoS2 Nanosheets on Conducting MoO2 as an Efficient Electrocatalyst To Enhance Hydrogen Evolution Reaction. AB - Molybdenum disulfide (MoS2) is a promising catalyst for hydrogen evolution reaction (HER) because of its unique nature to supply active sites in the reaction. However, the low density of active sites and their poor electrical conductivity have limited the performance of MoS2 in HER. In this work, we synthesized MoS2 nanosheets on three-dimensional (3D) conductive MoO2 via a two step chemical vapor deposition (CVD) reaction. The 3D MoO2 structure can create structural disorders in MoS2 nanosheets (referred to as 3D MoS2/MoO2), which are responsible for providing the superior HER activity by exposing tremendous active sites of terminal disulfur of S2(-2) (in MoS2) as well as the backbone conductive oxide layer (of MoO2) to facilitate an interfacial charge transport for the proton reduction. In addition, the MoS2 nanosheets could protect the inner MoO2 core from the acidic electrolyte in the HER. The high activity of the as synthesized 3D MoS2/MoO2 hybrid material in HER is attributed to the small onset overpotential of 142 mV, a largest cathodic current density of 85 mA cm(-2), a low Tafel slope of 35.6 mV dec(-1), and robust electrochemical durability. PMID- 26436767 TI - Interleukin-4 receptor-targeted liposomal doxorubicin as a model for enhancing cellular uptake and antitumor efficacy in murine colorectal cancer. AB - Our previous studies showed that colorectal tumor has high interleukin-4 receptor alpha (IL-4Ralpha) expression, whereas adjacent normal tissue has low or no IL 4Ralpha expression. We also observed that human atherosclerotic plaque-specific peptide-1 (AP1) can specifically target to IL-4Ralpha. In this study, we investigated the therapeutic efficacy and systemic toxicity of AP1-conjuagted liposomal doxorubicin. AP1 bound more strongly to and was more efficiently internalized into IL-4Ralpha-overexpressing CT26 cells than CT26 control cells. Selective cytotoxicity experiment revealed that AP1-conjugated liposomal doxorubicin preferentially killed IL-4Ralpha-overexpressing CT26 cells. AP1 conjugated liposomal doxorubicin administered intravenously into mice produced significant inhibition of tumor growth and showed decreased cardiotoxicity of doxorubicin. These results indicated that AP1-conjugated liposomal doxorubicin has a potent and selective anticancer potential against IL-4Ralpha-overexpressing colorectal cancer cells, thus providing a model for targeted anticancer therapy. PMID- 26436770 TI - Wave-driven butterfly distribution of Van Allen belt relativistic electrons. AB - Van Allen radiation belts consist of relativistic electrons trapped by Earth's magnetic field. Trapped electrons often drift azimuthally around Earth and display a butterfly pitch angle distribution of a minimum at 90 degrees further out than geostationary orbit. This is usually attributed to drift shell splitting resulting from day-night asymmetry in Earth's magnetic field. However, direct observation of a butterfly distribution well inside of geostationary orbit and the origin of this phenomenon have not been provided so far. Here we report high resolution observation that a unusual butterfly pitch angle distribution of relativistic electrons occurred within 5 Earth radii during the 28 June 2013 geomagnetic storm. Simulation results show that combined acceleration by chorus and magnetosonic waves can successfully explain the electron flux evolution both in the energy and butterfly pitch angle distribution. The current provides a great support for the mechanism of wave-driven butterfly distribution of relativistic electrons. PMID- 26436771 TI - Reduced Gut Acidity Induces an Obese-Like Phenotype in Drosophila melanogaster and in Mice. AB - In order to identify genes involved in stress and metabolic regulation, we carried out a Drosophila P-element-mediated mutagenesis screen for starvation resistance. We isolated a mutant, m2, that showed a 23% increase in survival time under starvation conditions. The P-element insertion was mapped to the region upstream of the vha16-1 gene, which encodes the c subunit of the vacuolar-type H+ ATPase. We found that vha16-1 is highly expressed in the fly midgut, and that m2 mutant flies are hypomorphic for vha16-1 and also exhibit reduced midgut acidity. This deficit is likely to induce altered metabolism and contribute to accelerated aging, since vha16-1 mutant flies are short-lived and display increases in body weight and lipid accumulation. Similar phenotypes were also induced by pharmacological treatment, through feeding normal flies and mice with a carbonic anhydrase inhibitor (acetazolamide) or proton pump inhibitor (PPI, lansoprazole) to suppress gut acid production. Our study may thus provide a useful model for investigating chronic acid suppression in patients. PMID- 26436772 TI - Correlating Gene-specific DNA Methylation Changes with Expression and Transcriptional Activity of Astrocytic KCNJ10 (Kir4.1). AB - DNA methylation serves to regulate gene expression through the covalent attachment of a methyl group onto the C5 position of a cytosine in a cytosine guanine dinucleotide. While DNA methylation provides long-lasting and stable changes in gene expression, patterns and levels of DNA methylation are also subject to change based on a variety of signals and stimuli. As such, DNA methylation functions as a powerful and dynamic regulator of gene expression. The study of neuroepigenetics has revealed a variety of physiological and pathological states that are associated with both global and gene-specific changes in DNA methylation. Specifically, striking correlations between changes in gene expression and DNA methylation exist in neuropsychiatric and neurodegenerative disorders, during synaptic plasticity, and following CNS injury. However, as the field of neuroepigenetics continues to expand its understanding of the role of DNA methylation in CNS physiology, delineating causal relationships in regards to changes in gene expression and DNA methylation are essential. Moreover, in regards to the larger field of neuroscience, the presence of vast region and cell-specific differences requires techniques that address these variances when studying the transcriptome, proteome, and epigenome. Here we describe FACS sorting of cortical astrocytes that allows for subsequent examination of a both RNA transcription and DNA methylation. Furthermore, we detail a technique to examine DNA methylation, methylation sensitive high resolution melt analysis (MS-HRMA) as well as a luciferase promoter assay. Through the use of these combined techniques one is able to not only explore correlative changes between DNA methylation and gene expression, but also directly assess if changes in the DNA methylation status of a given gene region are sufficient to affect transcriptional activity. PMID- 26436773 TI - Deep-Sea, Deep-Sequencing: Metabarcoding Extracellular DNA from Sediments of Marine Canyons. AB - Marine sediments are home to one of the richest species pools on Earth, but logistics and a dearth of taxonomic work-force hinders the knowledge of their biodiversity. We characterized alpha- and beta-diversity of deep-sea assemblages from submarine canyons in the western Mediterranean using an environmental DNA metabarcoding. We used a new primer set targeting a short eukaryotic 18S sequence (ca. 110 bp). We applied a protocol designed to obtain extractions enriched in extracellular DNA from replicated sediment corers. With this strategy we captured information from DNA (local or deposited from the water column) that persists adsorbed to inorganic particles and buffered short-term spatial and temporal heterogeneity. We analysed replicated samples from 20 localities including 2 deep sea canyons, 1 shallower canal, and two open slopes (depth range 100-2,250 m). We identified 1,629 MOTUs, among which the dominant groups were Metazoa (with representatives of 19 phyla), Alveolata, Stramenopiles, and Rhizaria. There was a marked small-scale heterogeneity as shown by differences in replicates within corers and within localities. The spatial variability between canyons was significant, as was the depth component in one of the canyons where it was tested. Likewise, the composition of the first layer (1 cm) of sediment was significantly different from deeper layers. We found that qualitative (presence absence) and quantitative (relative number of reads) data showed consistent trends of differentiation between samples and geographic areas. The subset of exclusively benthic MOTUs showed similar patterns of beta-diversity and community structure as the whole dataset. Separate analyses of the main metazoan phyla (in number of MOTUs) showed some differences in distribution attributable to different lifestyles. Our results highlight the differentiation that can be found even between geographically close assemblages, and sets the ground for future monitoring and conservation efforts on these bottoms of ecological and economic importance. PMID- 26436774 TI - Siaalpha2-3Galbeta1- Receptor Genetic Variants Are Associated with Influenza A(H1N1)pdm09 Severity. AB - Different host genetic variants may be related to the virulence and transmissibility of pandemic Influenza A(H1N1)pdm09, influencing events such as binding of the virus to the entry receptor on the cell of infected individuals and the host immune response. In the present study, two genetic variants of the ST3GAL1 gene, which encodes the Siaalpha2-3Galbeta1- receptor to which influenza A(H1N1)pdm09 virus binds for entry into the host cell, were investigated in an admixed Brazilian population. First, the six exons encoding the ST3GAL1 gene were sequenced in 68 patients infected with strain A(H1N1)pdm09. In a second phase of the study, the rs113350588 and rs1048479 polymorphisms identified in this sample were genotyped in a sample of 356 subjects from the northern and northeastern regions of Brazil with a diagnosis of pandemic influenza. Functional analysis of the polymorphisms was performed in silico and the influence of these variants on the severity of infection was evaluated. The results suggest that rs113350588 and rs1048479 may alter the function of ST3GAL1 either directly through splicing regulation alteration and/or indirectly through LD with SNP with regulatory function. In the study the rs113350588 and rs1048479 polymorphisms were in linkage disequilibrium in the population studied (D' = 0.65). The GC haplotype was associated with an increased risk of death in subjects with influenza (OR = 4.632, 95% CI = 2.10;1.21). The AT haplotype was associated with an increased risk of severe disease and death (OR = 1.993, 95% CI = 1.09;3.61 and OR 4.476, 95% CI = 2.37;8.44, respectively). This study demonstrated for the first time the association of ST3GAL1 gene haplotypes on the risk of more severe disease and death in patients infected with Influenza A(H1N1)pdm09 virus. PMID- 26436775 TI - Indirect Energy Flows in Niche Model Food Webs: Effects of Size and Connectance. AB - Indirect interactions between species have long been of interest to ecologists. One such interaction type takes place when energy or materials flow via one or more intermediate species between two species with a direct predator-prey relationship. Previous work has shown that, although each such flow is small, their great number makes them important in ecosystems. A new network analysis method, dynamic environ approximation, was used to quantify the fraction of energy flowing from prey to predator over paths of length greater than 1 (flow indirectness or FI) in a commonly studied food web model. Web structure was created using the niche model and dynamics followed the Yodzis-Innes model. The effect of food web size (10 to 40 species) and connectance (0.1 to 0.48) on FI was examined. For each of 250 model realizations run for each pair of size and connectance values, the FI of every predator-prey interaction in the model was computed and then averaged over the whole network. A classification and regression tree (CART) analysis was then used to find the best predictors of FI. The mean FI of the model food webs is 0.092, with a standard deviation of 0.0279. It tends to increase with system size but peaks at intermediate connectance levels. Of 27 potential predictor variables, only five (mean path length, dominant eigenvalue of the adjacency matrix, connectance, mean trophic level and fraction of species belonging to intermediate trophic levels) were selected by the CART algorithm as best accounting for variation in the data; mean path length and the dominant eigenvalue of the adjacency matrix were dominant. PMID- 26436776 TI - A quantum dot single-photon source with on-the-fly all-optical polarization control and timed emission. AB - Sources of single photons are key elements for applications in quantum information science. Among the different sources available, semiconductor quantum dots excel with their integrability in semiconductor on-chip solutions and the potential that photon emission can be triggered on demand. Usually, the photon is emitted from a single-exciton ground state. Polarization of the photon and time of emission are either probabilistic or pre-determined by electronic properties of the system. Here, we study the direct two-photon emission from the biexciton. The two-photon emission is enabled by a laser pulse driving the system into a virtual state inside the band gap. From this intermediate state, the single photon of interest is then spontaneously emitted. We show that emission through this higher-order transition provides a versatile approach to generate a single photon. Through the driving laser pulse, polarization state, frequency and emission time of the photon can be controlled on-the-fly. PMID- 26436777 TI - Bisphenol A and other bisphenol analogues including BPS and BPF in surface water samples from Japan, China, Korea and India. AB - Concentrations of eight bisphenol analogues (BPs) including BPA, BPS, and BPF were determined in surface waters collected from select rivers in Japan, Korea, China, and India. BPA was found at a concentration in the range of several tens to several hundreds of nanograms per liter in most of the rivers surveyed and some of the highest concentrations (54-1950 ng/L) were found in rivers in Chennai, India. Concentrations of BPF were one to two orders of magnitude higher than those of BPA in river and sea waters collected from Japan, Korea and China, which suggested that BPF is a major contaminant in surface waters in several Southeast Asian countries. BPF concentrations as high as 2850 ng/L were found in the Tamagawa River in Japan. The flux of BPs through riverine discharges into Tokyo Bay was calculated to be approximately 5.5 t per year. Based on the flux estimates and the mass of BPF found in water column and sediment in Tokyo Bay, it was found that BPF degrades faster than BPA in the environment. Elevated concentrations of BPF found in surface waters suggest the need for further studies to determine the fate and toxicity of this compound. PMID- 26436778 TI - Synthesis of Tricyclic Spiranoid Lactones via I2/Sm(II)- and I2/Pd(0)-Mediated Cyclizations of a Common Cycloalkylmethylene Precursor. AB - A general synthesis of phylogenetically and structurally different tricyclic angularly fused spiranoid lactones, frequently observed as scaffold segments of various biochemical compounds and drugs of natural origin, is demonstrated via controlled cyclization of simple and easily accessible cycloalkylmethylene key precursors. The rapid composition of the key architecture yields an assembly of stable bicyclic iodolactones, which are converted to form a wide range of angularly fused tricyclic scaffolds. PMID- 26436779 TI - Tomato yellow leaf curl virus differentially influences plant defence responses to a vector and a non-vector herbivore. AB - Plants frequently engage in simultaneous interactions with diverse classes of biotic antagonists. Differential induction of plant defence pathways by these antagonists, and interactions between pathways, can have important ecological implications; however, these effects are currently not well understood. We explored how Tomato yellow leaf curl virus (TYLCV) influenced the performance of its vector (Bemisia tabaci) and a non-vector herbivore (Tetranychus urticae) occurring separately or together on tomato plants (Solanum lycopersicum). TYLCV enhanced the performance of B. tabaci, although this effect was statistically significant only in the absence of T. urticae, which adversely affected B. tabaci performance regardless of infection status. In contrast, the performance of T. urticae was enhanced (only) by the combined presence of TYLCV and B. tabaci. Analyses of phytohormone levels and defence gene expression in wild-type tomatoes and various plant-defence mutants indicate that the enhancement of herbivore performance (for each species) entails the disruption of downstream defences in the jasmonic acid (JA) pathway. For T. urticae, this disruption appears to involve antagonistic effects of salicylic acid (SA), which is cumulatively induced to high levels by B. tabaci and TYLCV. In contrast, TYLCV was found to suppress JA-mediated responses to B. tabaci via mechanisms independent of SA. PMID- 26436780 TI - [Controversy regarding the use of thimerosal in vaccines: evidence for decision making]. PMID- 26436781 TI - [Primary resistance to anti tuberculosis drugs in Chile 2011-2012]. AB - This publication presents the results of the Chilean initial study of resistance to first line anti-tuberculous drugs. The study was carried out between 2011 and 2012 by the National Reference Laboratory of the Institute of Public Health, as part of the Drug Surveillance Resistance in tuberculosis (TB) promoted by the World Health Organization. METHODOLOGY: Cross-sectional study performed using cluster sampling, representative of the entire country as recommended by the World Health Organization. Susceptibility testing to isoniazid, rifampicin, streptomycin, ethambutol and pyrazinamide was performed through the proportion method or Wayne's enzymatic method, as appropriate. RESULTS: 594 susceptibility tests were performed, showing an overall level of TB drug resistance of 8.6% and a prevalence of multidrug resistance of 1.3%. Indeed, the study showed a decrease in streptomycin resistance and an increase of isoniazid resistance in both mono resistance and accumulated resistance compared to previous studies. No cases of mono-resistance to rifampicin were detected. CONCLUSION: An increased resistance to anti-TB drugs in Chile is observed, which despite being still low, is no less worrisome. Since 2014 the monitoring of drug resistance to TB is universally performed to avoid sub - diagnosis and treat each case according to the susceptibility profile. PMID- 26436782 TI - [Risk factor of intestinal colonization with vancomycin resistant Enterococcus spp in hospitalized pediatric patients with oncological disease]. AB - BACKGROUND: The isolation of vancomycin-resistant Enterococcus spp (ERV) has increased significantly within the last few years, along with the risk of infection and dissemination of these bacteria. Our aim was to determine risk factors (RF) for intestinal colonization in hospitalized pediatric patients with oncological disease at Hospital de Ninos Roberto del Rio. METHODS: Between January 2012 and December 2013 a transversal study was performed with 107 rectal swabs and processed with a PCR for ERV. The patients were classified as "colonized with ERV" and "not colonized with ERV" and we evaluated possible RF for intestinal colonization in both groups. RESULTS: VRE colonization was found in 51 patients (52%). The median of time elapsed between oncological diagnosis and VRE colonization was 35 days. The significant RF associated with VRE colonization were days of hospitalization prior to study, neutropenia and treatment with antibiotics within 30 days prior to study and mucositis. CONCLUSIONS: According to the RF revealed in this study we may suggest prevention standards to avoid ERV colonization. This is the first investigation in our country in hospitalized pediatric patients with oncological disease and processed with a multiplex PCR for ERV, therefore it is a great contribution about this subject in Chile. PMID- 26436783 TI - [Use of mass spectrometry for rapid diagnosis of positive blood cultures: Validation of a local algorythm]. AB - Mass spectrometry (MS) is used in identification of positive blood culture, a contribution in the clinical management of septic patients. The protocol is labor intensive and disrupts the normal workflow in a clinical laboratory. We intended to make rapid diagnosis by using MS directly from shortly incubated blood agar plates (4 to 6 hours) comparing with results of the conventional method (MC). We worked in parallel 145 positive blood cultures, with correct identification by short method in 79% of cases. We observed better yield with non carbon bottles and with gramnegative rods. With this information we designed a rapid identification algorithm using MS, which allows advancing diagnosis in 12-16 hours, without increasing to the costs or work load, since extraction protocol is not used. PMID- 26436784 TI - [Parasites of zoonotic importance in dog feces collected in parks and public squares of the city of Los Angeles, Bio-Bio, Chile]. AB - INTRODUCTION: The contamination of public squares and parks with dog feces poses a risk to the population, since it may contain parasitic elements of zoonotic importance. AIM: To identify human pathogenic parasites in samples of dog feces collected from parks and public squares. METHODS: 452 fecal dog samples collected from 65 squares and public parks were analyzed using the technique of Burrows. RESULTS: 60% (39/65) of the samples contained some parasitic forms with a zoonotic potential. Parasitic taxa with zoonotic risk were Toxocara sp., Ancylostoma sp., Dipylidium caninum, Giardia sp., Taenia sp., Toxascaris sp., Strongyloides sp., and Uncinaria sp. CONCLUSION: The detected parasites present a risk to human health, so it seems necessary to implement health education activities in the community, develop deworming plans, and control the canine overpopulation. PMID- 26436785 TI - [Effects in the adherence treatment and psychological adjustment after the disclosure of HIV/AIDS diagnosis with the "DIRE" clinical model in Colombian children under 17]. AB - BACKGROUND: A study in five Colombian cities in 2006, confirms the findings of other international studies: the majority of HIV-positive children not know their diagnosis, caregivers are reluctant to give this information because they believe that the news will cause emotional distress to the child becoming primary purpose of this study to validate a model of revelation. MATERIALS AND METHODS: We implemented a clinical model, referred to as: "DIRE" that hypothetically had normalizing effects on psychological adjustment and adherence to antiretroviral treatment of HIV seropositive children, using a quasi-experimental design. Test were administered (questionnaire to assess patterns of disclosure and non disclosure of the diagnosis of VIH/SIDA on children in health professionals and participants caregivers, Family Apgar, EuroQol EQ- 5D, MOS Social Support Survey Questionnaire Information treatment for VIH/SIDA and child Symptom Checklist CBCL/6-18 adapted to Latinos) before and after implementation of the model to 31 children (n: 31), 30 caregivers (n: 30) and 41 health professionals. Data processing was performed using the Statistical Package for the Social Science version 21 by applying parametric tests (Friedman) and nonparametric (t Student). RESULTS: No significant differences in adherence to treatment (p=0.392), in the psychological adjustment were found positive significant differences at follow ups compared to baseline 2 weeks (p: 0.001), 3 months (p: 0.000) and 6 months (p: 0.000). CONCLUSIONS: The clinical model demonstrated effectiveness in normalizing of psychological adjustment and maintaining treatment compliance. The process also generated confidence in caregivers and health professionals in this difficult task. PMID- 26436786 TI - [Measles: the disease, epidemiology, history and vaccination programs in Chile]. AB - Measles, one of most important inmuno-preventable diseases, remains as a worldwide concern issue with an important morbidity and mortality. Particularly in the America region declared free of measles in 2010 by WHO, they still appear imported cases that origin outbreaks of variable magnitude in susceptible subjects usually none vaccinated which is the current situation in Santiago, the capital city of Chile. In this review we present characteristics of the etiological agent, the disease, epidemiological aspects with national historical focus, impact of immunization programs and outbreaks in Chile, in order to contribute to knowledge and management of this always present public health problem. PMID- 26436787 TI - [Streptococcus gallolyticus (ex S. bovis) bacteremia and its relationship with colonic or hepatobiliary disease and endocarditis]. AB - BACKGROUND: Bacteremia due to Streptococcus bovis (now S. gallolyticus) has been traditionally associated to colon or hepatobiliar disease and endocarditis but there is no information on this matter in Chile. AIMS: To describe clinical features of adult patients suffering bacteremia by S. bovis/S. gallolyticus, identify the source of the bacteremia and the frequency of endocarditis. METHODS: Retrospective-descriptive study using laboratory records. RESULTS: Between January 2003 and August 2014, 23 S. bovis/S. gallolyticus bacteremic events were identified among 22 patients. Mean age was 72.7 years (range 46-96). Co morbidities were frequent (9.1 to 47.6%). The primary source of bacteremia was intestinal in 52.2%; hepatobiliar in 17.4% and in 34.8% it was not elucidated. Six patients had infective endocarditis (26.1%) and one patient had espondylodiscitis (4.3%). S. bovis represented 39.1% of isolates (all until 2008), S. gallolyticus subsp pasteurianus 39.1% and, S. gallolyticus subsp infantarius and S. gallolyticus subsp gallolyticus 8.7% each one, respectively. Association studies between the bacteremic source or endocarditis with specific S. gallolyticus subspecies were limited by the small number of isolates. Seven patients (30.4%) underwent surgical interventions. In-hospital mortality reached 21.7% (n=5). CONCLUSIONS: Although infrequent, bacteremic events by S. gallolyticus/S. bovis have increased in-hospital mortality, require surgical intervention and affect older patients with co-morbidities. Near two-thirds suffer from colonic or hepatobiliary disease that act as the primary source of bacteremia. In addition, near one fourth is affected by infective endocarditis. Detection of S. gallolyticus/S. bovis in blood cultures prompts a thorough clinical evaluation in order to clarify the source of the bloodstream infection and the presence of complications. PMID- 26436788 TI - [Prognostic factors in adult patients hospitalized for pneumonia caused by Legionella pneumophila]. AB - INTRODUCTION: Legionellosis is a multisystem bacterial disease, which causes pneumonia with high mortality in patients with comorbidity and admitted in intensive care units (ICU). OBJECTIVE: Determine predictors of mortality or ICU admission. METHODS: Retrospective follow-up of patients diagnosed with Legionella pneumophila pneumonia in Complexo Hospitalario Universitario de A Coruna. Period 2000-2013 (n=240). Analysis of multivariate logistic regression was performed. RESULTS: Mean age was 57.2+/-15.4 years old, 88.3% were male. Average score of comorbidity (Charlson score) was 2.3+/-2.3. There was a clear seasonal variation. Predominant symptoms were fever (92.5%), dry cough (38.1%) and dyspnea (33.9%). Creatinine clearance was lower than 60 mL/min/1.73 m2 in 29.7% and sodium<135 mEq/l in 58.3%. Admission to ICU rate was 16.3% and 10.8% needs mechanical ventilation. Inhospital mortality rate was 4.6%, rising to 23.1% in patients admitted to ICU. Variables associated to predict ICU admission were age (OR=0.96), liver disease (OR=7.13), dyspnea (OR=4.33), delirium (OR=5.86) and high levels of lactatedehydrogenase (OR=1.002). Variables associated with inhospital mortality were Charlson index (OR=1.70), mechanical ventilation (OR=31.44) and high levels of lactatedehydrogenase (OR=1.002). DISCUSSION: Younger patients with liver disease, dyspnea and confusion are more likely to be admitted to ICU. Comorbidity, mechanical ventilation and elevated LDH levels are associated with higher mortality rate. PMID- 26436789 TI - [Pseudomonas (Flavimonas) oryzihabitans]. PMID- 26436790 TI - [Early neonatal sepsis, incidence and associated risk factors in a public hospital in western Mexico]. AB - BACKGROUND: Early neonatal sepsis (EOS) is the second leading cause of death in the first week of life. Epidemiology differs in developed and developing countries. AIM: To describe the epidemiology of EOS among newborn patients in a public hospital in western Mexico. METHODS: A prospective cohort study was performed in newborns of Nuevo Hospital Civil de Guadalajara "Dr. Juan I Menchaca". EOS was diagnosed with blood cultures or cultures of cerebrospinal fluid within the first 72 h of life. We analyzed risk factors (RF) by multivariate analysis with logistic regression. RESULTS: We identified an EOS incidence of 4.7 events per 1,000 live births. Seventy two percent of the isolated bacteria were gram negative bacilli. Factors associated with EOS were maternal age<=15 years (OR 3.50; 95% CI 1.56-7.85), rupture of membranes>18 h (OR 2.65; 95% CI 1.18-5.92), maternal fever (OR 6.04; 95% CI 1.54-23.6), birth weight<=2,500 g (OR 4.82; 95% CI 2.38-9.75) and gestational age<37 weeks (OR 3.14; 95% CI 1.58-6.22). CONCLUSIONS: In addition to the RF known for EOS an independent association was observed with maternal age<=15 years. PMID- 26436791 TI - [Beginning of the Microbiology education in Chile: formation centers]. AB - The first Chair of Microbiology in Chile was created in the School of Medicine of the Canadilla at the University of Chile in 1892. Dr. Alejandro del Rio Soto Aguilar was its first Professor. For almost three decades it was the only educational center for microbiologists in Chile. Among them were the first Professors of the new School of Medicine of the Catholic University of Chile and of the University of Concepcion. PMID- 26436792 TI - [Stereotactic aspiration of Spirometra mansonides larvae]. AB - Brain sparganosis is a non-common parasite infection by Diphyllobothrium or Spirometra mansonoides larvae. This last one is responsible for most of the infestations in humans. We report a 19 years male patient bearer of a brain sparganosis. The patient presented with headache and left hemiparesis. CT diagnosis of right thalamic lesions was made and aspiration biopsy was performed using stereotactic system, obtaining a whole and death larvae. Histopathology confirms a CNS parasitism and it was treated initially with albendazol. ELISA test confirmed Spirometra spp. infestation. The patient developed asymptomatic with total remission of the lesions. It constitutes the second report in Cuba of brain sparganosis. PMID- 26436793 TI - [The sparganosis]. PMID- 26436794 TI - [Successful treatment of a persistent rhino-cerebral mucormycosis in a pediatric patient with a debut of acute lymphoblastic leukemia]. AB - The fungi of the order Mucorales cause mucormycosis, which usually presents as an invasive fungal disease with rapid angioinvasion in immunocompromised patients. Rhinocerebral is the most common presentation. The lipid formulations of amphotericin B are used as primary treatment in invasive mucormycosis; the combined use of posaconazole could allow a reduction in the dose of amphotericin B improving tolerance and adherence to treatment. Caspofungin and amphotericin B association has been shown to be synergistic in vitro and effective in murine models. We present the case of a preschool patient that during the debut of acute lymphoblastic leukemia developed a rhinocerebral mucormycosis successfully responding to antifungal treatment with the combination of liposomal amphotericin and caspofungin. PMID- 26436795 TI - [Listeria monocytogenes meningitis in immunocompetent children: unpasteurized cheese likely cause of infection]. AB - Listeria meningoencephalitis is a rare condition, occurring mainly in immunocompromised patients. We present two cases of Listeria monocytogenes meningoencephalitis in immunocompetent children, with successful treatment with betalactam/aminoglycoside combination. Unpasteurized cheese was postulated as the source of infection. PMID- 26436796 TI - [Cutaneous loxoscelism mainly edematous: a case report]. AB - In Chile, loxoscelism is caused by the bite of the Loxosceles laeta spider. The clinical presentation has two different forms: cutaneous loxoscelism (CL) and vicero-cutaneous loxoscelism, which is less frequent. Cutaneous loxoscelism includes an uncommon clinical variation (4%), called CL with edematous predominance (CLEP). We present a 5-year-old patient with sudden pain and edema on his right eyelid associated with fever, which progressed rapidly involving the right hemifacial area, frontal region, and left eyelid. Angioedema and pre orbital cellulitis were discarded and CLEP was suspect. Cutaneous loxoscelism with an edematous predominance is self-limited, benign and with little or no necrotic injury due to the edema, which dilutes the toxin-induced enzymatic process causing necrosis. As in the reported cases it usually responds well to medical treatment and does not cause visceral involvement. PMID- 26436797 TI - [Pulmonary non invasive infection by Scedosporium apiospermum]. AB - We reported a case of non-invasive pulmonary infection by Scedosporium apiospermum in 67 years old female with bronchiectasis and caverns secondary to tuberculosis. Diagnosis was made with lung CT and bronchial lavage cultures. The patient was initially treated with itraconazole for six weeks without success and then voriconazole for 16 weeks, with good clinical response. PMID- 26436798 TI - [Severe acute disseminated encephalomyelitis associated with parainfluenza 3 infection: Case report]. AB - Disseminated encephalomyelitis (ADEM) is an infrequent condition with considerable morbidity and mortality in adult patients. It requires a high level of suspicion and diagnosis emerges by gathering clinical information, laboratory exams and images studies. ADEM is related to an immunological phenomena occurring after a bacterial/viral infection or recent vaccination. Glucocorticoids are the first line treatment, reserving immunoglobulins and plasmapheresis to refractory cases. We report a male patient aged 25, with ADEM associated to parainfluenza 3 virus respiratory infection that required mechanical ventilation and that had a complete recovery only after plasmapheresis. PMID- 26436799 TI - [Hepatitis E virus seroprevalence: a reappraisal]. AB - Reported seroprevalence of hepatitis E virus (HEV) in developed countries is between 0.3-53%. Published data relies on the assays used and its technical performance. Sensitivity on new available tests has improved, which has changed HEV seroprevalence around the world. We re-evaluated retrospectively, 178 serum samples of patients with previous anti HEV IgG determination between 2009 and 2012. Initial analysis was performed with ELISA kit Genelabs (Singapore), with 7.3% positivity. The reevaluation was done with ELISA kit AccuDiag TM HEV-IgG (Diagnostic Automation, United States), with reported sensitivity and specificity over 99.8%. With the new assay, 32.6% positive samples were found, significantly greater to the previous result (p<0.001) (4.5 times more). There were no differences in gender but a significant association between age and HEV IgG seropositivity was found (p<0.001). This suggests that previous testing might have underestimated HEV seroprevalence in Chile, which should be reevaluated using the new available test. PMID- 26436800 TI - [Erratum]. PMID- 26436801 TI - [Thimerosal into vaccines: the law and the evidence]. PMID- 26436802 TI - [Elite controller cured of hepatitis C virus after 14 weeks of telaprevir-based triple therapy]. PMID- 26436803 TI - [Acquisition of multi-resistant enterobacteriaceae in travelers to tropical zones]. PMID- 26436804 TI - The Foraging Ecology of the Endangered Cape Verde Shearwater, a Sentinel Species for Marine Conservation off West Africa. AB - Large Marine Ecosystems such as the Canary Current system off West Africa sustains high abundance of small pelagic prey, which attracts marine predators. Seabirds are top predators often used as biodiversity surrogates and sentinel species of the marine ecosystem health, thus frequently informing marine conservation planning. This study presents the first data on the spatial (GPS loggers) and trophic (stable isotope analysis) ecology of a tropical seabird-the endangered Cape Verde shearwater Calonectris edwardsii-during both the incubation and the chick-rearing periods of two consecutive years. This information was related with marine environmental predictors (species distribution models), existent areas of conservation concern for seabirds (i.e. marine Important Bird Areas; marine IBAs) and threats to the marine environment in the West African areas heavily used by the shearwaters. There was an apparent inter-annual consistency on the spatial, foraging and trophic ecology of Cape Verde shearwater, but a strong alteration on the foraging strategies of adult breeders among breeding phases (i.e. from incubation to chick-rearing). During incubation, birds mostly targeted a discrete region off West Africa, known by its enhanced productivity profile and thus also highly exploited by international industrial fishery fleets. When chick-rearing, adults exploited the comparatively less productive tropical environment within the islands of Cape Verde, at relatively close distance from their breeding colony. The species enlarged its trophic niche and increased the trophic level of their prey from incubation to chick-rearing, likely to provision their chicks with a more diversified and better quality diet. There was a high overlap between the Cape Verde shearwaters foraging areas with those of European shearwater species that overwinter in this area and known areas of megafauna bycatch off West Africa, but very little overlap with existing Marine Important Bird Areas. Further investigation on the potential nefarious effects of fisheries on seabird communities exploiting the Canary Current system off West Africa is needed. Such negative effects could be alleviated or even dissipated if the 'fisheries-conservation hotspots' identified for the region, would be legislated as Marine Protected Areas. PMID- 26436805 TI - Biliary/Pancreas. PMID- 26436806 TI - Stomach. PMID- 26436809 TI - Clinical Vignettes/Case Reports - Biliary/Pancreas. PMID- 26436811 TI - Colorectal Cancer Prevention. PMID- 26436810 TI - Colon. PMID- 26436812 TI - Endoscopy. PMID- 26436813 TI - Endoscopy Video Forum. PMID- 26436814 TI - Esophagus. PMID- 26436815 TI - Functional Bowel Disease. PMID- 26436816 TI - Inflammatory Bowel Disease. PMID- 26436817 TI - Liver. PMID- 26436818 TI - Outcomes Research. PMID- 26436819 TI - Pediatrics. PMID- 26436820 TI - Small Intestine/Unclassified. PMID- 26436821 TI - Effect of Jig Design and Assessment of Stress Distribution in Testing Metal Ceramic Adhesion. AB - PURPOSE: In testing adhesion using shear bond test, a combination of shear and tensile forces occur at the interface, resulting in complex stresses. The jig designs used for this kind of test show variations in published studies, complicating direct comparison between studies. This study evaluated the effect of different jig designs on metal-ceramic bond strength and assessed the stress distribution at the interface using finite element analysis (FEA). MATERIALS AND METHODS: Metal-ceramic (Metal: Ni-Cr, Wiron 99, Bego; Ceramic: Vita Omega 900, Vita) specimens (N = 36) (diameter: 4 mm, veneer thickness: 4 mm; base diameter: 5 mm, thickness: 1 mm) were fabricated and randomly divided into three groups (n = 12 per group) to be tested using one of the following jig designs: (a) chisel (CH) (ISO 11405), (b) steel strip (SS), (c) piston (PI). Metal-ceramic interfaces were loaded under shear until debonding in a universal testing machine (0.5 mm/min). Failure types were evaluated using scanning electron microscopy (SEM). FEA was used to study the stress distribution using different jigs. Metal-ceramic bond strength data (MPa) were analyzed using ANOVA and Tukey's tests (alpha = 0.05). RESULTS: The jig type significantly affected the bond results (p = 0.0001). PI type of jig presented the highest results (MPa) (p < 0.05) (58.2 +/- 14.8), followed by CH (38.7 +/- 7.6) and SS jig type (23.3 +/- 4.2) (p < 0.05). Failure types were exclusively a combination of cohesive failure in the opaque ceramic and adhesive interface failure. FEA analysis indicated that the SS jig presented slightly more stress formation than with the CH jig. The PI jig presented small stress concentration with more homogeneous force distribution compared to the CH jig where the stress concentrated in the area where the force was applied. CONCLUSION: Metal-ceramic bond strength was affected by the jig design. Accordingly, the results of in vitro studies on metal-ceramic adhesion should be evaluated with caution. CLINICAL SIGNIFICANCE: When adhesion of ceramic materials to metals is evaluated in in vitro studies, it should be noted that the loading jig type affects the results. Clinical observations should report on the location and type of ceramic fractures in metal-ceramic reconstructions so that the most relevant test method can be identified. PMID- 26436822 TI - Use of terrestrial field studies in the derivation of bioaccumulation potential of chemicals. AB - Field-based studies are an essential component of research addressing the behavior of organic chemicals, and a unique line of evidence that can be used to assess bioaccumulation potential in chemical registration programs and aid in development of associated laboratory and modeling efforts. To aid scientific and regulatory discourse on the application of terrestrial field data in this manner, this article provides practical recommendations regarding the generation and interpretation of terrestrial field data. Currently, biota-to-soil-accumulation factors (BSAFs), biomagnification factors (BMFs), and bioaccumulation factors (BAFs) are the most suitable bioaccumulation metrics that are applicable to bioaccumulation assessment evaluations and able to be generated from terrestrial field studies with relatively low uncertainty. Biomagnification factors calculated from field-collected samples of terrestrial carnivores and their prey appear to be particularly robust indicators of bioaccumulation potential. The use of stable isotope ratios for quantification of trophic relationships in terrestrial ecosystems needs to be further developed to resolve uncertainties associated with the calculation of terrestrial trophic magnification factors (TMFs). Sampling efforts for terrestrial field studies should strive for efficiency, and advice on optimization of study sample sizes, practical considerations for obtaining samples, selection of tissues for analysis, and data interpretation is provided. Although there is still much to be learned regarding terrestrial bioaccumulation, these recommendations provide some initial guidance to the present application of terrestrial field data as a line of evidence in the assessment of chemical bioaccumulation potential and a resource to inform laboratory and modeling efforts. PMID- 26436823 TI - Spectral Inspections on Molecular Configurations of Nile Blue A Adsorbed on the Elementary Clay Sheets. AB - Studies on the configuration of dye molecules are of great importance in revealing origins of the electronic bands as well as understanding their transitions. In this work, we utilized dye molecules named Nile blue A, which are a type of oxazine dyes, to study the molecular configurations when they are transferred from solutions to a solid surface. The Langmuir-Blodgett (LB) technique was employed to construct such an interface where the interaction between the dye molecules and solid supports can be pursued. Hybrid films were prepared via the LB depositions, and the dye molecules were assembled on the elementary clay sheets (laponite, saponite). The configuration of Nb reflected by the molecular orientation, packing density, phase behavior, and variances of the surface tension has been derived. The ex situ spectroscopy characterizations such as UV-vis absorption, fluorescence emission, and excitation spectra were carried out on these LB films to reveal the fact that the adsorbed Nb molecules are mainly assembled in two types of configurations. Adsorbed state I was found to be achieved at high concentrations (1-10 ppm) of clay dispersions and low surface pressure (~5 mN/m). In this state the anionic oxazine rings of Nb are adsorbed on clay sheets sharing a large lift-off area. This configuration gives allowable fluorescence (lambda = 550 nm). Lower clay concentration (<1 ppm) and high surface pressure (10-30 mN/m) yield the adsorbed state II in which the oxazine chromophores were arranged in a side-by-side style, and the dye molecules stand perpendicularly to the clay sheets. This conformation exhibits no photoluminescence. PMID- 26436824 TI - Imazamox-clay complexes with chitosan- and iron(III)-modified smectites and their use in nanoformulations. AB - BACKGROUND: Imazamox is an ionisable herbicide, weakly retained and with high soil vertical mobility, that is used for the control of the root-parasitic plants Orobanche spp. A natural smectite (SW) modified with the biopolymer chitosan (Ch) or with Fe(3+) cation was assayed as adsorbent or carrier for imazamox controlled release formulations (CRFs). RESULTS: The greatest adsorption (74%) was observed for SWFe at high initial concentration (500 uM) and low pH (4.3). The interaction mechanism of imazamox on SWFe implies interlayer polar adsorption, followed by protonation of the imidazolinone ring, whereas ionic, polar and hydrophobic interactions seemed to occur in imazamox adsorption on SWCh. The herbicide release into water was inversely related to the strength of the imazamox-clay interactions and ranged in the first 10 min for imazamox-SWFe and imazamox-SWCh complexes from 27 to 75%, whereas commercial imazamox released 86%. The imazamox SWCh weak complex (SWCh6 WC) showed similar herbicidal activity to the commercial formulation but produced a reduction of 15% in the total soil leaching losses and a reduction of 40% in the peak maximum concentration in soil column leachates. CONCLUSION: The imazamox-clay weak complex (WC) of SWFe and SWCh and the strong complex (SC) with SWCh showed appropriate behaviour as nanopesticides or smart delivery systems to be incorporated in CRFs. (c) 2015 Society of Chemical Industry. PMID- 26436825 TI - Complete mitochondrial genome of Coregonus cluncaformis. AB - The complete mitochondrial genome of Coregonus cluncaformis was determined in this study. The mitogenome is 16 736 bp in length and contains 1D-loop region, 2 ribosomal RNA genes, 22 transfer RNA genes, and 13 protein-coding genes. The overall base composition of the heavy strand is 26.79% for A, 29.49% for C, 18.07% for G and 25.66% for T, The percentage of G + C content is 47.56%. This is the first time of the mitochondrial genome sequencing for C. cluncaformis in this study. PMID- 26436826 TI - Polymerase delta replicates both strands after homologous recombination-dependent fork restart. AB - To maintain genetic stability, DNA must be replicated only once per cell cycle, and replication must be completed even when individual replication forks are inactivated. Because fork inactivation is common, passive convergence of an adjacent fork is insufficient to rescue all inactive forks. Thus, eukaryotic cells have evolved homologous recombination-dependent mechanisms to restart persistent inactive forks. Completing DNA synthesis via homologous recombination restarted replication (HoRReR) ensures cell survival, but at a cost. One such cost is increased mutagenesis because HoRReR is more error prone than canonical replication. This increased error rate implies the HoRReR mechanism is distinct from that of a canonical fork. Here we demonstrate, in Schizosaccharomyces pombe, that a DNA sequence duplicated by HoRReR during S phase is replicated semiconservatively, but both the leading and lagging strands are synthesized by DNA polymerase delta. PMID- 26436827 TI - Rif1 binds to G quadruplexes and suppresses replication over long distances. AB - Rif1 regulates replication timing and repair of double-strand DNA breaks. Using a chromatin immunoprecipitation-sequencing method, we identified 35 high-affinity Rif1-binding sites in fission yeast chromosomes. Binding sites tended to be located near dormant origins and to contain at least two copies of a conserved motif, CNWWGTGGGGG. Base substitution within these motifs resulted in complete loss of Rif1 binding and in activation of late-firing or dormant origins located up to 50 kb away. We show that Rif1-binding sites adopt G quadruplex-like structures in vitro, in a manner dependent on the conserved sequence and on other G tracts, and that purified Rif1 preferentially binds to this structure. These results suggest that Rif1 recognizes and binds G quadruplex-like structures at selected intergenic regions, thus generating local chromatin structures that may exert long-range suppressive effects on origin firing. PMID- 26436828 TI - Structural basis of template-boundary definition in Tetrahymena telomerase. AB - Telomerase is required to maintain repetitive G-rich telomeric DNA sequences at chromosome ends. To do so, the telomerase reverse transcriptase (TERT) subunit reiteratively uses a small region of the integral telomerase RNA (TER) as a template. An essential feature of telomerase catalysis is the strict definition of the template boundary to determine the precise TER nucleotides to be reverse transcribed by TERT. We report the 3-A crystal structure of the Tetrahymena TERT RNA-binding domain (tTRBD) bound to the template boundary element (TBE) of TER. tTRBD is wedged into the base of the TBE RNA stem-loop, and each of the flanking RNA strands wraps around opposite sides of the protein domain. The structure illustrates how the tTRBD establishes the template boundary by positioning the TBE at the correct distance from the TERT active site to prohibit copying of nontemplate nucleotides. PMID- 26436829 TI - Excited-State Deactivation of Branched Phthalocyanine Compounds. AB - The excited-state relaxation dynamics and chromophore interactions in two phthalocyanine compounds (bis- and trisphthalocyanines) are studied by using steady-state and femtosecond transient absorption spectral measurements, where the excited-state energy-transfer mechanism is explored. By exciting phthalocyanine compounds to their second electronically excited states and probing the subsequent relaxation dynamics, a multitude of deactivation pathways are identified. The transient absorption spectra show the relaxation pathway from the exciton state to excimer state and then back to the ground state in bisphthalocyanine (bis-Pc). In trisphthalocyanine (tris-Pc), the monomeric and dimeric subunits are excited and the excitation energy transfers from the monomeric vibrationally hot S1 state to the exciton state of a pre-associated dimer, with subsequent relaxation to the ground state through the excimer state. The theoretical calculations and steady-state spectra also show a face-to-face conformation in bis-Pc, whereas in tris-Pc, two of the three phthalocyanine branches form a pre-associated face-to-face dimeric conformation with the third one acting as a monomeric unit; this is consistent with the results of the transient absorption experiments from the perspective of molecular structure. The detailed structure-property relationships in phthalocyanine compounds is useful for exploring the function of molecular aggregates in energy migration of natural photosynthesis systems. PMID- 26436830 TI - Strain ZP - the first bacterial conjugation-based "kill"-"anti-kill" antimicrobial system. AB - As multidrug resistant bacteria pose one of the greatest risks to human health new alternative antibacterial agents are urgently needed. One possible mechanism that can be used as an alternative to traditional antibiotic therapy is transfer of killing agents via conjugation. Our work was aimed at providing a proof of principle that conjugation-based antimicrobial systems are possible. We constructed a bacterial conjugation-based "kill"-"anti-kill" antimicrobial system employing the well known Escherichia coli probiotic strain Nissle 1917 genetically modified to harbor a conjugative plasmid carrying the "kill" gene (colicin ColE7 activity gene) and a chromosomally encoded "anti-kill" gene (ColE7 immunity gene). The constructed strain acts as a donor in conjugal transfer and its efficiency was tested in several types of conjugal assays. Our results clearly demonstrate that conjugation-based antimicrobial systems can be highly efficient. PMID- 26436832 TI - Stable and High-Performance Flexible ZnO Thin-Film Transistors by Atomic Layer Deposition. AB - Passivation is a challenging issue for the oxide thin-film transistor (TFT) technologies because it requires prolonged high-temperature annealing treatments to remedy defects produced in the process, which greatly limits its manufacturability as well as its compatibility with temperature-sensitive materials such as flexible plastic substrates. This study investigates the defect formation mechanisms incurred by atomic layer deposition (ALD) passivation processes on ZnO TFTs, based on which we demonstrate for the first time degradation-free passivation of ZnO TFTs by a TiO2/Al2O3 nanolaminated (TAO) film deposited by a low-temperature (110 degrees C) ALD process. By combining the TAO passivation film with ALD dielectric and channel layers into an integrated low temperature ALD process, we successfully fabricate flexible ZnO TFTs on plastics. Thanks to the exceptional gas-barrier property of the TAO film (water vapor transmission rate (WVTR)<10(-6) g m(-2) day(-1)) as well as the defect-free nature of the ALD dielectric and ZnO channel layers, the TFTs exhibit excellent device performance with high stability and flexibility: field-effect mobility>20 cm2 V(-1) s(-1), subthreshold swing<0.4 V decade(-1) after extended bias stressing (>10,000 s), air-storage (>1200 h), and bending (1.3 cm radius for 1000 times). PMID- 26436831 TI - Epidemiology of Carbapenem-Resistant Enterobacteriaceae in 7 US Communities, 2012 2013. AB - IMPORTANCE: Carbapenem-resistant Enterobacteriaceae (CRE) are increasingly reported worldwide as a cause of infections with high-mortality rates. Assessment of the US epidemiology of CRE is needed to inform national prevention efforts. OBJECTIVE: To determine the population-based CRE incidence and describe the characteristics and resistance mechanism associated with isolates from 7 US geographical areas. DESIGN, SETTING, AND PARTICIPANTS: Population- and laboratory based active surveillance of CRE conducted among individuals living in 1 of 7 US metropolitan areas in Colorado, Georgia, Maryland, Minnesota, New Mexico, New York, and Oregon. Cases of CRE were defined as carbapenem-nonsusceptible (excluding ertapenem) and extended-spectrum cephalosporin-resistant Escherichia coli, Enterobacter aerogenes, Enterobacter cloacae complex, Klebsiella pneumoniae, or Klebsiella oxytoca that were recovered from sterile-site or urine cultures during 2012-2013. Case records were reviewed and molecular typing for common carbapenemases was performed. EXPOSURES: Demographics, comorbidities, health care exposures, and culture source and location. MAIN OUTCOMES AND MEASURES: Population-based CRE incidence, site-specific standardized incidence ratios (adjusted for age and race), and clinical and microbiological characteristics. RESULTS: Among 599 CRE cases in 481 individuals, 520 (86.8%; 95% CI, 84.1%-89.5%) were isolated from urine and 68 (11.4%; 95% CI, 8.8%-13.9%) from blood. The median age was 66 years (95% CI, 62.1-65.4 years) and 284 (59.0%; 95% CI, 54.6%-63.5%) were female. The overall annual CRE incidence rate per 100<000 population was 2.93 (95% CI, 2.65-3.23). The CRE standardized incidence ratio was significantly higher than predicted for the sites in Georgia (1.65 [95% CI, 1.20 2.25]; P < .001), Maryland (1.44 [95% CI, 1.06-1.96]; P = .001), and New York (1.42 [95% CI, 1.05-1.92]; P = .048), and significantly lower than predicted for the sites in Colorado (0.53 [95% CI, 0.39-0.71]; P < .001), New Mexico (0.41 [95% CI, 0.30-0.55]; P = .01), and Oregon (0.28 [95% CI, 0.21-0.38]; P < .001). Most cases occurred in individuals with prior hospitalizations (399/531 [75.1%; 95% CI, 71.4%-78.8%]) or indwelling devices (382/525 [72.8%; 95% CI, 68.9%-76.6%]); 180 of 322 (55.9%; 95% CI, 50.0%-60.8%) admitted cases resulted in a discharge to a long-term care setting. Death occurred in 51 (9.0%; 95% CI, 6.6%-11.4%) cases, including in 25 of 91 cases (27.5%; 95% CI, 18.1%-36.8%) with CRE isolated from normally sterile sites. Of 188 isolates tested, 90 (47.9%; 95% CI, 40.6%-55.1%) produced a carbapenemase. CONCLUSIONS AND RELEVANCE: In this population- and laboratory-based active surveillance system in 7 states, the incidence of CRE was 2.93 per 100<000 population. Most CRE cases were isolated from a urine source, and were associated with high prevalence of prior hospitalizations or indwelling devices, and discharge to long-term care settings. PMID- 26436833 TI - Photonic Crystal Hydrogel Enhanced Plasmonic Staining for Multiplexed Protein Analysis. AB - Plasmonic nanoparticles are commonly used as optical transducers in sensing applications. The optical signals resulting from the interaction of analytes and plamsonic nanoparticles are influenced by surrounding physical structures where the nanoparticles are located. This paper proposes inverse opal photonic crystal hydrogel as 3D structure to improve Raman signals from plasmonic staining. By hybridization of the plasmonic nanoparticles and photonic crystal, surface enhanced Raman spectroscopy (SERS) analysis of multiplexed protein is realized. It benefits the Raman analysis by providing high-density "hot spots" in 3D and extra enhancement of local electromagnetic field at the band edge of PhC with periodic refractive index distribution. The strong interaction of light and the hybrid 3D nanostructure offers new insights into plasmonic nanoparticle applications and biosensor design. PMID- 26436834 TI - Aims and approaches of Web-RADR: a consortium ensuring reliable ADR reporting via mobile devices and new insights from social media. AB - INTRODUCTION: Advent of new technologies in mobile devices and software applications is leading to an evolving change in the extent, geographies and modes for use of internet. Today, it is used not only for information gathering but for sharing of experiences, opinions and suggestions. Web-Recognizing Adverse Drug Reactions (RADR) is a groundbreaking European Union (EU) Innovative Medicines Innovation funded 3-year initiative to recommend policies, frameworks, tools and methodologies by leveraging these new developments to get new insights in drug safety. AREAS COVERED: Data were gathered from prior surveys, previous initiatives and a review of relevant literature was done. New technologies provide an opportunity in the way safety information is collected, helping generate new knowledge for safety profile of drugs as well as unique insights into the evolving pharmacovigilance system in general. It is critical that these capabilities are harnessed in a way that is ethical, compliant with regulations, respecting data privacy and used responsibly. At the same time, the process for managing and interpreting this new information must be efficient and effective for sustenance, thoughtful use of resources and valuable return of knowledge. These approaches should complement the ongoing progress toward personalized medicine. EXPERT OPINION: This Web-RADR initiative should provide some directions on 'what and how' to use social media to further proactive pharmacovigilance and protection of public health. It is expected to also show how a multipronged expert consortium group comprising regulators, industry and academia can leverage new developments in technology and society to bring innovation in process, operations, organization and scientific approaches across its boundaries and beyond the normal realms of individual research units. These new approaches should bring insights faster, earlier, specific, actionable and moving toward the target of AE prevention. The possibilities of a blended targeted pharmacovigilance (PV) approach where boundaries between stakeholders blur and cultures mix point to very different future for better, healthier and longer lives. PMID- 26436837 TI - Synthesis of Inert Homo- and Heterodinuclear Rare-Earth Cryptates. AB - A new ditopic cryptand based on two tris(biaryl)-based binding pockets bridged by a 2,2'-bipyrimidine unit enables the selective synthesis of homo- and heterodinuclear rare-earth cryptates, which are kinetically inert under challenging conditions and can even be purified by preparative high-performance liquid chromatography. PMID- 26436836 TI - Age Impacts Pulmonary Inflammation and Systemic Bone Response to Inhaled Organic Dust Exposure. AB - Agricultural workers have high rates of airway and skeletal health disease. Studies recently demonstrated that inhaled agricultural organic dust extract (ODE)-induced airway injury is associated with bone deterioration in an animal model. However, the effect of age in governing these responses to organic dusts is unclear, but might be important in future approaches. Young (7-9 wk) and older (12-14,o) male C57BL/6 mice received intranasal (i.n.) inhalation exposure to ODE from swine confinement facilities once or daily for 3 wk. Acute ODE-induced neutrophil influx and cytokine and chemokine (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6, keratinocyte chemoattractant [CXCL1], macrophage inflammatory protein-2 [CXCL2]) airway production were reduced in older compared to young mice. Repetitive ODE treatment, however, increased lymphocyte recruitment and alveolar compartment histopathologic inflammatory changes in older mice. Whole lung cell infiltrate analysis revealed that young, but not older, mice repetitively treated with ODE demonstrated an elevated CD4:CD8 lymphocyte response. Acute inhalant ODE exposure resulted in a 4-fold and 1.5-fold rise in blood neutrophils in young and older mice, respectively. Serum IL-6 and CXCL1 levels were elevated in young and older mice i.n. exposed once to ODE, with increased CXCL1 levels in younger compared to older mice. Although older mice displayed reduced bone measurements compared to younger mice, younger rodents demonstrated ODE-induced decrease in bone mineral density, bone volume, and bone microarchitecture quality as determined by computed tomography (CT) analysis. Collectively, age impacts the airway injury and systemic inflammatory and bone loss response to inhalant ODE, suggesting an altered and enhanced immunologic response in younger as compared to older counterparts. PMID- 26436835 TI - Effects of developmental exposure to bisphenol A on spatial navigational learning and memory in rats: A CLARITY-BPA study. AB - Bisphenol A (BPA) is a ubiquitous industrial chemical used in the production of a wide variety of items. Previous studies suggest BPA exposure may result in neuro disruptive effects; however, data are inconsistent across animal and human studies. As part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA), we sought to determine whether female and male rats developmentally exposed to BPA demonstrated later spatial navigational learning and memory deficits. Pregnant NCTR Sprague-Dawley rats were orally dosed from gestational day 6 to parturition, and offspring were directly orally dosed until weaning (postnatal day 21). Treatment groups included a vehicle control, three BPA doses (2.5MUg/kg body weight (bw)/day-[2.5], 25MUg/kg bw/day-[25], and 2500MUg/kg bw/day-[2500]) and a 0.5MUg/kg/day ethinyl estradiol (EE)-reference estrogen dose. At adulthood, 1/sex/litter was tested for seven days in the Barnes maze. The 2500 BPA group sniffed more incorrect holes on day 7 than those in the control, 2.5 BPA, and EE groups. The 2500 BPA females were less likely than control females to locate the escape box in the allotted time (p value=0.04). Although 2.5 BPA females exhibited a prolonged latency, the effect did not reach significance (p value=0.06), whereas 2.5 BPA males showed improved latency compared to control males (p value=0.04), although the significance of this result is uncertain. No differences in serum testosterone concentration were detected in any male or female treatment groups. Current findings suggest developmental exposure of rats to BPA may disrupt aspects of spatial navigational learning and memory. PMID- 26436838 TI - Cardiac Pressure-Volume Loop Analysis Using Conductance Catheters in Mice. AB - Cardiac pressure-volume loop analysis is the "gold-standard" in the assessment of load-dependent and load-independent measures of ventricular systolic and diastolic function. Measures of ventricular contractility and compliance are obtained through examination of cardiac response to changes in afterload and preload. These techniques were originally developed nearly three decades ago to measure cardiac function in large mammals and humans. The application of these analyses to small mammals, such as mice, has been accomplished through the optimization of microsurgical techniques and creation of conductance catheters. Conductance catheters allow for estimation of the blood pool by exploiting the relationship between electrical conductance and volume. When properly performed, these techniques allow for testing of cardiac function in genetic mutant mouse models or in drug treatment studies. The accuracy and precision of these studies are dependent on careful attention to the calibration of instruments, systematic conduct of hemodynamic measurements and data analyses. We will review the methods of conducting pressure-volume loop experiments using a conductance catheter in mice. PMID- 26436841 TI - "Bitten By Shyness": Menstrual Hygiene Management, Sanitation, and the Quest for Privacy in South Africa. AB - Little is known about how menstruation is managed in low-income settings and whether existing sanitation systems meet women's needs. Using the 'Photovoice' method with 21 women in participatory workshops and in-depth interviews, we collected data on menstrual hygiene management in three sites in Durban, South Africa. All women reported using disposable sanitary pads. Although they were aware that disposable pads were nonbiodegradable, incompatible with waterborne flush systems, and fill up pit latrines, they had little experience with reusable products. Considerable energy was devoted to concealing and containing 'menstrual waste,' and women expressed concern about inadequate privacy during menstruation. All sites lacked discreet disposal options and reliable water access, while outdoor sanitation facilities were considered unsafe. Findings highlight the need for advocacy to improve safety and privacy of facilities for women in this setting. PMID- 26436840 TI - Determinants of amyloid fibril degradation by the PDZ protease HTRA1. AB - Excessive aggregation of proteins has a major impact on cell fate and is a hallmark of amyloid diseases in humans. To resolve insoluble deposits and to maintain protein homeostasis, all cells use dedicated protein disaggregation, protein folding and protein degradation factors. Despite intense recent research, the underlying mechanisms controlling this key metabolic event are not well understood. Here, we analyzed how a single factor, the highly conserved serine protease HTRA1, degrades amyloid fibrils in an ATP-independent manner. This PDZ protease solubilizes protein fibrils and disintegrates the fibrillar core structure, allowing productive interaction of aggregated polypeptides with the active site for rapid degradation. The aggregate burden in a cellular model of cytoplasmic tau aggregation is thus reduced. Mechanistic aspects of ATP independent proteolysis and its implications in amyloid diseases are discussed. PMID- 26436839 TI - New IDH1 mutant inhibitors for treatment of acute myeloid leukemia. AB - Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo. Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in the cells of individuals with AML. Our study provides proof of concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in leukemia. PMID- 26436842 TI - Spousal similarity in life satisfaction before and after divorce. AB - Previous research has explored possible origins of individual differences in subjective well-being, focusing largely on stable, internal characteristics of traits as predictors of life satisfaction (Diener & Lucas, 1999). Although past work has demonstrated that life satisfaction is largely stable over the life span, other evidence has also demonstrated the lasting impact of life events. In this study, we use married couples as a test of the impact of life circumstances on life satisfaction, focusing on similarity in life satisfaction before and after divorce. If life satisfaction is impacted by shared life circumstances, married couples (who share life circumstances) should show greater similarity in life satisfaction before divorce than after. We tested this possibility using a dyadic latent-state-trait model that examined cross-spouse similarity in the stable and changing components of life satisfaction. Using a nationally representative panel study from Germany (Wagner, Frick & Schupp, 2007), we showed that similarity declined substantially following divorce. This suggests that life satisfaction is related to shared life circumstances. PMID- 26436843 TI - Do people's world views matter? The why and how. AB - Over the past decades, personality and social psychologists have extensively investigated the role of self-views in individual functioning. Research on world views, however, has been less well studied due to overly specific conceptualizations, and little research about how and why they impact life outcomes. To answer why and how world views matter, we conducted 7 studies to examine the functions, antecedents, and consequences of generalized beliefs about the world, operationalized as social axioms (Leung et al., 2002). This research focused on 2 axiom factors, namely, social cynicism and reward for application. These axioms were found to explain individual differences in self-views over and above personality traits in Hong Kong and U.S. samples (Study 1) and to explain cultural differences in self-views in addition to self-construals among Mainland Chinese, Hong Kong Chinese, East Asian Canadians, and European Canadians (Study 2). Endorsement of social axioms by participants, their parents, and close friends was collected from Mainland China, Hong Kong, and Canada to infer parental and peer influences on world views (Study 3). World views affected psychological well-being through the mediation of positive self-views across 3 age groups, including children, adolescents, and young adults (Study 4) and over time (Study 5). The mediation of negative self-views was through comparative self criticism rather than internalized self-criticism (Study 6). Holistic thinking moderated the effect of social cynicism on self-views and psychological well being (Study 7). These results converge to show that world views as a distal force and self-views as a proximal force matter in people's subjective evaluation of their lives. (PsycINFO Database Record PMID- 26436844 TI - Comparative evaluation of Bis(thiosemicarbazone)- Biotin and Met-ac-TE3A for tumor imaging. AB - 2,2',2"-(11-(2-((4-mercapto-1-methoxy-1-oxobutan-2-yl)amino)-2-oxoethyl)-1,4,8,11 tetraaza cyclotetradecane-1,4,8-triyl)triacetic acid, Met-ac-TE3A and (E)-N methyl-2-((E)-3-(2-(2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4 yl)pentanoyl)hydrazinecarbono-thioyl)hydrazonobutan-2 ylidene)hydrazinecarbothioamide, Bis(thiosemicarbazone)- Biotin were synthesized and evaluated for imaging application. The pharmacokinetics of these ligands were determined by tracer methods. In vitro human serum stability of (99m)Tc Met-ac TE3A/(99m)Tc Bis(thiosemicarbazone)-Biotin after 24h was found to be 96.5% and 97.0% respectively. Blood kinetics of both ligands in normal rabbits showed biphasic clearance pattern. Ex vivo biodistribution study revealed significant initial tumor uptake and high tumor/muscles ratio which is a pre-requisite condition for a ligand to work as SPECT-radiopharmaceutical for tumor imaging. PMID- 26436845 TI - Modeling techniques and fluorescence imaging investigation of the interactions of an anthraquinone derivative with HSA and ctDNA. AB - A new anthraquinone derivative (AORha) was synthesized. Its interactions with human serum albumin (HSA) and calf thymus DNA (ctDNA) were investigated by fluorescence spectroscopy, UV-visible absorption spectroscopy and molecular modeling. Cell viability assay and cell imaging experiment were performed using cervical cancer cells (HepG2 cells). The fluorescence results revealed that the quenching mechanism was static quenching. At different temperatures (290, 300, 310 K), the binding constants (K) and the number of binding sites (n) were determined, respectively. The positive DeltaH and DeltaS values showed that the binding of AORha with HSA was hydrophobic force, which was identical with the molecular docking result. Studying the fluorescence spectra, UV spectra and molecular modeling also verified that the binding mode of AORha and ctDNA might be intercalative. When HepG2 cells were treated with AORha, the fluorescence became brighter and turned green, which could be used for bioimaging. PMID- 26436846 TI - Spectroscopic investigation on cocrystal formation between adenine and fumaric acid based on infrared and Raman techniques. AB - As an important component of double-stranded DNA, adenine has powerful hydrogen bond capability, due to rich hydrogen bond donors and acceptors existing within its molecular structure. Therefore, it is easy to form cocrystal between adenine and other small molecules with intermolecular hydrogen-bond effect. In this work, cocrystal of adenine and fumaric acid has been characterized as model system by FT-IR and FT-Raman spectral techniques. The experimental results show that the cocrystal formed between adenine and fumaric acid possesses unique spectroscopical characteristic compared with that of starting materials. Density functional theory (DFT) calculation has been performed to optimize the molecular structures and simulate vibrational modes of adenine, fumaric acid and the corresponding cocrystal. Combining the theoretical and experimental vibrational results, the characteristic bands corresponding to bending and stretching vibrations of amino and carbonyl groups within cocrystal are shifted into lower frequencies upon cocrystal formation, and the corresponding bond lengths show some increase due to the effect of intermolecular hydrogen bonding. Different vibrational modes shown in the experimental spectra have been assigned based on the simulation DFT results. The study could provide experimental and theoretical benchmarks to characterize cocrystal formed between active ingredients and cocrystal formers and also the intermolecular hydrogen-bond effect within cocrystal formation process by vibrational spectroscopic techniques. PMID- 26436847 TI - Discrimination of genetically modified sugar beets based on terahertz spectroscopy. AB - The objective of this paper was to apply terahertz (THz) spectroscopy combined with chemometrics techniques for discrimination of genetically modified (GM) and non-GM sugar beets. In this paper, the THz spectra of 84 sugar beet samples (36 GM sugar beets and 48 non-GM ones) were obtained by using terahertz time-domain spectroscopy (THz-TDS) system in the frequency range from 0.2 to 1.2 THz. Three chemometrics methods, principal component analysis (PCA), discriminant analysis (DA) and discriminant partial least squares (DPLS), were employed to classify sugar beet samples into two groups: genetically modified organisms (GMOs) and non GMOs. The DPLS method yielded the best classification result, and the percentages of successful classification for GM and non-GM sugar beets were both 100%. Results of the present study demonstrate the usefulness of THz spectroscopy together with chemometrics methods as a powerful tool to distinguish GM and non GM sugar beets. PMID- 26436848 TI - Can statistical linkage of missing variables reduce bias in treatment effect estimates in comparative effectiveness research studies? AB - AIM: Missing data, particularly missing variables, can create serious analytic challenges in observational comparative effectiveness research studies. Statistical linkage of datasets is a potential method for incorporating missing variables. Prior studies have focused upon the bias introduced by imperfect linkage. METHODS: This analysis uses a case study of hepatitis C patients to estimate the net effect of statistical linkage on bias, also accounting for the potential reduction in missing variable bias. RESULTS: The results show that statistical linkage can reduce bias while also enabling parameter estimates to be obtained for the formerly missing variables. CONCLUSION: The usefulness of statistical linkage will vary depending upon the strength of the correlations of the missing variables with the treatment variable, as well as the outcome variable of interest. PMID- 26436849 TI - Association Study of Matrix Metalloproteinases Gene Polymorphisms with Susceptibility to Rheumatoid Arthritis: A Meta-Analysis. AB - OBJECTIVE: Association of matrix metalloproteinases (MMPs) gene polymorphisms with rheumatoid arthritis is controversial. We conduct a meta-analysis to clarify this dispute. METHODS: We systematically searched the electronic PUBMED, EMBASE and CNKI databases for research articles about MMPs (MMP-1, MMP-2, MMP-3, MMP-9) gene polymorphisms and rheumatoid arthritis (RA) up to January 2015. According to the heterogeneity, fixed-effects or random-effects models were used to calculate crude odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: A total of 11 articles involving 2143 cases and 2049 controls were included in this meta analysis. Overall, no significant associations were observed between MMP-1-1607 1G/2G polymorphism and RA. Stratification by ethnicity, no significant associations were observed in Caucasian populations. Similarly, no significant associations were observed between MMP-3-1171 5A/6A, MMP-9-1562 C/T polymorphisms and RA in overall and Caucasian populations, respectively. However, a weak association was found between MMP-2-1306 C/T polymorphism and RA (C vs. T, OR = 0.813, 95%CI = 0.694-0.953, p = 0.010) in overall populations. CONCLUSIONS: The present meta-analysis suggests that MMP-1-1607 1G/2G, MMP-3-1171 5A/6A, MMP-9 1562 C/T polymorphisms are not associated with the susceptibility of RA, but MMP 2 -1306 C/T is weakly associated with susceptibility to RA. Further studies with more sample size are needed for definitive conclusions. PMID- 26436850 TI - Relation of interleukin-10 Promoter Polymorphisms to Adult Chronic Immune Thrombocytopenic Purpura in a Cohort of Egyptian Population. AB - BACKGROUND: Adult chronic immune thrombocytopenic purpura (chronic ITP) is an autoimmune multifactorial bleeding disorder that occurs because of enhanced peripheral platelet destruction. Treatment decisions can be challenging because the goal of treatment is to prevent severe bleeding, but the risk of bleeding can be difficult to estimate for any individual patient. OBJECTIVE: This case-control study was planned to investigate the relationship of interleukin (IL)-10 promoter (IL-10-1082, -819 and -592) polymorphisms with the susceptibility, severity and outcome of adult chronic ITP in a cohort of Egyptian population. SUBJECTS AND METHODS: Typing of IL-10 promoter polymorphisms was done using restriction fragment length polymorphism for 62 adult patients with chronic ITP and 73 age- and sex-matched healthy controls. RESULTS: No significant differences were found between ITP patients and controls regarding the frequency of IL-10 promoter genotypes, alleles or haplotypes. IL-10-592 AA genotype and ATA (IL-10-1082, -819 and -592) haplotype were associated with severe ITP (p = 0.003, 0.043, respectively). CONCLUSION: Our findings suggest that the IL-10 promoter polymorphisms are unlikely to affect the development or treatment outcome of chronic adult ITP in Egyptian population, but IL-10-592 AA genotype and IL-10 ( 1082, -819 and -592) ATA haplotype may be associated with disease severity. Because ITP is a complex disease, it is recommended that a multicenter study should be done with large sample size and unified typing technique. PMID- 26436851 TI - Comparing Antibody Responses in Chickens Against Plasmodium falciparum Lactate Dehydrogenase and Glyceraldehyde-3-phosphate Dehydrogenase with Freund's and Pheroid(r) Adjuvants. AB - Pheroid(r) technology was assessed as an alternative to Freund's adjuvant to raise antibodies in experimental animals. Chickens were immunized with two recombinantly expressed Plasmodium falciparum proteins, lactate dehydrogenase (PfLDH) and glyceraldehyde-3-phosphate dehydrogenase (PfGAPDH), alone or in combination with Freund's adjuvant or Pheroid(r). Chicken egg yolk antibodies (IgY) were isolated and compared for specificity, sensitivity and yield. Freund's adjuvant and Pheroid(r) stimulated prolonged antibody responses in chickens against both antigens. Affinity purified antibodies had specificity for the recombinant and the native proteins on Western blots. Antibodies generated in the presence of Freund's adjuvant had high sensitivity for both antigens. Pheroid(r) generated antibodies that detected the lowest concentration of recombinant PfLDH. Freund's adjuvant and Pheroid(r) both improved chicken IgY yields, with Pheroid(r) showing a 2-fold increase relative to controls. Pheroid(r) was well tolerated in chickens and has potential for development as a safe adjuvant for testing alternative stimulatory factors to improve adjuvant formulations. PMID- 26436852 TI - Circulating CD4(+)CXCR5(+) T Cells Exacerbate B Cell Antibody Production in Crohn's Disease Through IL-21 Secretion. AB - Interleukin-21 (IL-21) upregulation was observed in Crohn's disease (CD) patients and was shown to contribute to ongoing mucosal inflammation in CD patients through stabilizing Th1 cell differentiation and IFN-gamma production. Given the role of IL-21 in mediating adaptive B cell antibody responses in healthy individuals, we examined the effect of IL-21 upregulation in B cell responses in patients with active CD, including ileum, ileocolonic and colon subtypes, defined by the primary site of CD involvement. We first observed an upregulation of blood plasma IL-21 concentration and IL-21 production from CD4(+) T cells in CD patients compared to healthy individuals. The IL-21-expressing T cells were more concentrated in the CD4(+)CXCR5(+) compartment, both in unstimulated medium and after stimulation with SEB. ICOS and PD-1 expressions were also concentrated in the CD4(+)CXCR5(+) subset in CD patients. Since peripheral blood CD4(+)CXCR5(+) T cell-mediated antibody secretion is IL-21-dependent, we examined the plasma antibody concentration in CD patients and healthy controls. We found that CD patients had significantly higher plasma Ig level than healthy patients, with no significant differences between different CD subtypes. Higher plasma IL-21 concentration and increased IL-21 production from CD4(+) T cells were directly correlated with higher plasma antibody levels. Moreover, we found that IL-21 and CD4(+)CXCR5(+) T cells can directly enhance B cell antibody response in CD patients. Depletion of secreted IL-21 by sIL-21R addition compromised the CD4(+)CXCR5(+) T cell-mediated increase in antibody production. Together, our results demonstrated a novel role of IL-21 in mediating B cell inflammation in CD development. PMID- 26436853 TI - Short-Chain Fatty Acids Regulate Secretion of IL-8 from Human Intestinal Epithelial Cell Lines in vitro. AB - Short-chain fatty acids (SCFAs) including acetate, propionate and butyrate play an important role in the physiological functions of epithelial cells and colonocytes, such as immune response regulation. Human intestinal epithelial cells (IECs) contribute in intestinal immune response via different ways, such as production of different immune factors including Interleukin (IL) IL-8, which act as chemoattractant for neutrophils, and subsequently enhance inflammation. Therefore, we aimed to evaluate the effects of SCFAs on IECs viability and production of IL-8 in vitro. SCFAs were co-cultured with either normal intestinal epithelial (T4056) or adenocarcinoma derived (HT-29) cell lines for 24-96 h in the presence of E.coli lipopolysaccharides (LPS). Cell viability, proliferation, production of IL-8 and expression of IL-8 mRNA were determined in the cell cultures. The result showed that 20 mM of SCFAs was non-cytotoxic to T4056 and enhanced their growth, whereas the growth of HT-29 was inhibited. The SCFAs down regulated LPS-stimulated IL-8 secretion with different response patterns, but no obvious effects on the release of IL-8 from non LPS- stimulated cells. In conclusion, SCFAs showed regulatory effect on release of LPS-stimulated IL-8 as well as the expression of mRNA of IL-8; these might explain the anti-inflammatory and anti-carcinogenic mechanism of SCFAs. PMID- 26436854 TI - Prophylactic Effect of BIO-1211 Small-Molecule Antagonist of VLA-4 in the EAE Mouse Model of Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: Some functional limitations and economic burden of therapeutic antibodies indicated that introducing of alternative therapeutic compounds with same or different mechanism of action could be worthwhile. In this regard small-molecule antagonists can have a wide range of impacts, so in this research, we examine the prophylactic effects of BIO-1211 [Very Late Antigen-4 (VLA4) blocker], in experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis in comparison with commercial available medicine, Natalizumab (NTZ)]. METHODS: EAE was induced by subcutaneous immunization of myelin oligodendrocyte glycoprotein (MOG35-55) in 8-week-old C57BL/6 mice. During EAE induction, mice were separated to distinct groups and provided either BIO 1211 (5 and 10 mg/kg) or NTZ (5 mg/kg) and co-administration of these two compounds. After 21 days, neuro-inflammatory responses were analyzed using qRT PCR, western blot, and ELISA methods. Pervade of immune cells to brain was examined by Evans blue staining and immunohistochemistry (IHC) analysis of specific markers of microglia/monocytes (CD11b) and leukocytes (CD45). RESULTS: Targeted disruption of VLA4/VCAM1 interactions, by BIO-1211 agonist in mice, results in reduced cytokines expression, leukocyte trafficking, and inhibition of inflammatory responses in EAE (p < 0.01) in a dose-independent manner (data not shown). Mice treated with both BIO-1211 and NTZ exhibited a considerable depletion in the EAE clinical score, which correlated with decreased expression of TNF-alpha, IL-17, IFN-gamma and pervade of CD11b(+) and CD45(+) cells into the cerebral cortex. CONCLUSION: Our results indicated that BIO12-11 compound would be an useful tool to further understand the biological roles of VLA4/VCAM1 interactions, and could also be considered as EAE-suppressing agent. PMID- 26436855 TI - UV-induced DNA Damage: The Role of Electronic Excited States. AB - The knowledge of the fundamental processes induced by the direct absorption of UV radiation by DNA allows extrapolating conclusions drawn from in vitro studies to the in-vivo DNA photoreactivity. In this respect, the characterization of the DNA electronic excited states plays a key role. For a long time, the mechanisms of DNA lesion formation were discussed in terms of generic "singlet" and "triplet" excited state reactivity. However, since the beginning of the 21(st) century, both experimental and theoretical studies revealed the existence of "collective" excited states, i.e. excited states delocalized over at least two bases. Two limiting cases are distinguished: Frenkel excitons (delocalized pipi* states) and charge-transfer states in which positive and negative charges are located on different bases. The importance of collective excited states in photon absorption (in particular in the UVA spectral domain), the redistribution of the excitation energy within DNA, and the formation of dimeric pyrimidine photoproducts is discussed. The dependence of the behavior of the collective excited states on conformational motions of the nucleic acids is highlighted. PMID- 26436856 TI - Reactions of superoxide dismutases with HS(-)/H2S and superoxide radical anion: An in vitro EPR study. AB - Interactions of hydrogen sulfide (HS(-)/H2S), a reducing signaling species, with superoxide dimutases (SOD) are poorly understood. We applied low-T EPR spectroscopy to examine the effects of HS(-)/H2S and superoxide radical anion O2. on metallocenters of FeSOD, MnSOD, and CuZnSOD. HS(-)/H2S did not affect FeSOD, whereas active centers of MnSOD and CuZnSOD were open to this agent. Cu(2+) was reduced to Cu(1+), while manganese appears to be released from MnSOD active center. Untreated and O2.- treated FeSOD and MnSOD predominantly show 5 d electron systems, i.e. Fe(3+) and Mn(2+). Our study provides new details on the mechanisms of (patho)physiological effects of HS(-)/H2S. PMID- 26436857 TI - Coronary blood flow in the anesthetized American alligator (Alligator mississippiensis). AB - Coronary circulation of the heart evolved early within ectothermic vertebrates and became of vital importance to cardiac performance in some teleost fish, mammals and birds. In contrast, the role and function of the coronary circulation in ectothermic reptiles remains largely unknown. Here, we investigated the systemic and coronary arterial responses of five anesthetized juvenile American alligators (Alligator mississippiensis) to hypoxia, acetylcholine, adenosine, sodium nitroprusside, isoproterenol, and phenylephrine. We recorded electrocardiograms, monitored systemic blood pressure, blood flows in both aortae, and blood flow in a major coronary artery supplying most of the right ventricle. Coronary arterial blood flow was generally forward, but there was a brief retrograde flow during a ventricular contraction. Blood pressure was significantly changed in all conditions. Acetylcholine decreased coronary forward flow, but this response was confounded by the concomitant lowered work of the ventricles due to decreased heart rate and blood pressure. Coronary forward flow was poorly correlated with heart rate and mean arterial pressure across treatments. Overall changes in coronary forward flow, significant and not significant, were generally in the same direction as mean arterial pressure and ventricular power, approximated as the product of systemic cardiac output and mean arterial pressure. PMID- 26436858 TI - In vivo biomechanical properties of heavy versus light weight monofilament polypropylene meshes. Does the knitting pattern matter? AB - AIMS: This work evaluated the post-implant biomechanical properties of light weight (LW) and heavy-weight (HW) monofilament polypropylene (PP) meshes with different knitting patterns in an animal model in vivo. METHODS: Forty-five adult female Wistar rats were divided into three groups and randomly implanted with 32 * 32 mm HW-PP (62 gm-2 ) orLW-PP (16 gm-2 ) in the lower abdomen. LW-PPwas tested orthogonally (called LWL and LWT) to reproduce the longitudinal and transverse planes of the vaginal wall, respectively. Abdominal walls were removed at 7, 30, and 60 days, and then tested for tensile load (maximum load until avulsion from the tissue), deflection, and stiffness to maximum load. Explants were compared over time and between groups. RESULTS: LW-PP meshes implanted in the LWT fashion (vaginal transverse plane) showed comparable maximum load and stiffness to HW-PP meshes, and LW-PP meshes implanted in the LWL fashion (vaginal longitudinal plane) presented lower maximum load and stiffness than the HW-PP meshes. There were no significant differences in the values of deflection at maximum load between the studied meshes as a function of time. CONCLUSIONS: The final mechanical behavior of PP mesh can be changed by its weight and knitting pattern. These properties may be useful in making more biocompatible prostheses for pelvic organ prolapse (POP) with less foreign material to maintain longitudinal vaginal elasticity and minimize sexual symptoms while maintaining transverse resistance (i.e., between vaginal fornixes) to prevent POP recurrence. Neurourol. Urodynam. 36:73-79, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26436859 TI - WITHDRAWN: Drugs for preventing malaria in travellers. PMID- 26436860 TI - Evaluation of Quantitative PET/MR Enterography Biomarkers for Discrimination of Inflammatory Strictures from Fibrotic Strictures in Crohn Disease. AB - PURPOSE: To retrospectively evaluate positron emission tomography (PET)/magnetic resonance (MR) enterography for the differentiation of fibrotic strictures from inflammatory strictures in patients with Crohn disease. MATERIALS AND METHODS: This HIPAA-compliant retrospective study was approved by the institutional review board. Patients gave their written informed consent for study enrollment. PET/MR enterography images were evaluated in 19 patients with Crohn disease who had strictures that underwent surgical resection with pathologic confirmation. Two radiologists and a nuclear medicine physician in consensus evaluated the following bowel wall PET/MR enterography biomarkers: signal intensity (SI) on T2 weighted images, apparent diffusion coefficient (ADC), PET maximum standardized uptake value (SUVmax), SI on T2-weighted images * SUVmax, and ADC * SUVmax values at levels that corresponded to pathologic specimens. MR, PET, and hybrid PET/MR biomarkers were compared, and the performance for differentiation of inflammatory strictures from fibrotic strictures was assessed. Mixed-model regression analysis was used to compare the mean imaging parameters between groups; the P values were corrected for the five comparisons by using the Bonferroni method. RESULTS: Three of the PET/MR enterography biomarkers, SUVmax, SI on T2-weighted images * SUVmax, and ADC * SUVmax, showed significant differences in the fibrosis group compared with the fibrosis with active inflammation group and the active inflammation only group. The best discriminator between fibrosis and active inflammation was the combined PET/MR enterography biomarker ADC * SUVmax cutoff of less than 3000, which was associated with accuracy, sensitivity, and specificity values of 0.71, 0.67, and 0.73, respectively. CONCLUSION: PET/MR enterography offers a potential noninvasive technique for the differentiation of purely fibrotic strictures from mixed or inflammatory strictures. A hybrid biomarker that incorporates both MR and PET information performed better for stricture evaluation than either modality alone. PMID- 26436861 TI - Asymptomatic Progressive Multifocal Leukoencephalopathy Associated with Natalizumab: Diagnostic Precision with MR Imaging. AB - PURPOSE: To determine diagnostic precision with magnetic resonance (MR) imaging of the brain, the most predictive MR imaging features, and the added value of comparison with previous data for the diagnosis of asymptomatic progressive multifocal leukoencephalopathy (PML) associated with natalizumab (NTZ). MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and written informed consent was obtained. Eleven consecutive patients with multiple sclerosis (MS) who had received a definitive diagnosis of asymptomatic NTZ-associated PML (NTZ PML, 18 brain lesions) underwent 3-T MR imaging. The control group included 40 patients with MS but without PML who were treated with NTZ. Three readers independently performed blinded analysis of MR images. First, the readers were asked to detect NTZ PML lesions without comparing current images with previously obtained MR imaging data by evaluating MR images for the following features: U fiber and/or cortex involvement, lesion signal intensity and borders, and occurrence of punctate lesions. Second, they reassessed NTZ PML lesions with all the previous MR imaging data available. Diagnostic precision with MR imaging was assessed with and without comparison with previously obtained data. Logistic regression analyses were performed to identify the association of MR imaging features with NTZ PML. RESULTS: Overall interobserver agreement was good (kappa = 0.76; 95% confidence interval [CI]: 0.71, 0.81). Hyperintensity on diffusion-weighted images and involvement of U fibers were the most predictive features (odds ratio, 33.7; 95% CI: 4.9, 229.7 [P < .0001] and odds ratio, 8.7; 95% CI: 1.2, 61.4 [P = .03], respectively), while punctate lesions were exclusively observed in patients with NTZ PML. Comparison with previous MR imaging data improved specificity of MR imaging for the detection of NTZ PML lesions (from 88% to 100%, P = .05). CONCLUSION: Recognition of the most predictive imaging features and comparison with previous MR imaging data may facilitate the detection of asymptomatic NTZ PML. PMID- 26436862 TI - Human Norovirus prevalence in Africa: a review of studies from 1990 to 2013. AB - OBJECTIVES: To assess the contribution of Human Norovirus to diarrhoeal diseases in Africa. METHODS: We conducted a systematic review of the PubMed and EMBASE databases for published articles of Human Norovirus in Africa between 1990 and 2013. Data were extracted from selected studies and analysed. RESULTS: A total of 208 eligible studies were identified, of which 55 (from 19 countries) met the inclusion criteria. Many cases were of sporadic gastroenteritis (70.9%) in children (82%), 65.4% of which were seen in an outpatient setting. Over half (59.4%) of the affected children were under 5 years of age. The pooled prevalence rate of Human NoV was 11% (95% CI 8-14%), and the meta-analysis indicated significant heterogeneity between the studies. However, the conditional negative binomial regression could not clearly find the factors affecting the Human NoV prevalence rates reported. A close relationship was found between Human Norovirus strains from environmental and clinical samples. CONCLUSION: Unreported sporadic gastroenteritis cases of Human Norovirus are common in Africa. Most are community associated infections. Possible environmental transmission routes have been documented. Combined environmental and clinical studies are required for targeted actions to control transmission of Human Norovirus in Africa. Systematic surveillance of Human Norovirus is needed to measure the burden of Norovirus induced gastroenteritis in Africa and support any requirements for vaccine development. PMID- 26436863 TI - Dismantling Limb-Girdle Muscular Dystrophy: The Role of Whole-Exome Sequencing. PMID- 26436864 TI - Uncertainty and Possible Subclinical Valve Leaflet Thrombosis. PMID- 26436866 TI - Stuttering Associated With the Use of Short-Acting Oral Methylphenidate. PMID- 26436865 TI - Distinct modulation of allergic T cell responses by subcutaneous vs. sublingual allergen-specific immunotherapy. AB - BACKGROUND: Allergen-specific immunotherapy is the only curative treatment for type I allergy. It can be administered subcutaneously (SCIT) or sublingually (SLIT). The clinical efficacy of these two treatment modalities appears to be similar, but potential differences in the immunological mechanisms involved have not been fully explored. OBJECTIVE: To compare changes in the allergen-specific T cell response induced by subcutaneous vs. sublingual administration of allergen specific immunotherapy (AIT). METHODS: Grass pollen-allergic patients were randomized into groups receiving either SCIT injections or SLIT tablets or neither. PBMCs were tested for Timothy grass (TG)-specific cytokine production by ELISPOT after in vitro expansion with TG-peptide pools. Phenotypic characterization of cytokine-producing cells was performed by FACS. RESULTS: In the SCIT group, decreased IL-5 production was observed starting 10 months after treatment commenced. At 24 months, T cell responses showed IL-5 levels significantly below the before-treatment baseline. No significant reduction of IL 5 was observed in the SLIT or untreated group. However, a significant transient increase in IL-10 production after 10 months of treatment compared to baseline was detected in both treatment groups. FACS analysis revealed that IL-10 production was associated with CD4(+) T cells that also produced IFNgamma and therefore may be associated with an IL-10-secreting type 1 cell phenotype. CONCLUSION AND CLINICAL RELEVANCE: The most dominant immunological changes on a cellular level were a decrease in IL-5 in the SCIT group and a significant, transient increase of IL-10 observed after 10 months of treatment in both treated groups. The distinct routes of AIT administration may induce different immunomodulatory mechanisms at the cellular level. PMID- 26436867 TI - Surfactant-free green synthesis of Fe3O4 nanoparticles capped with 3,4 dihydroxyphenethylcarbamodithioate: stable recyclable magnetic nanoparticles for the rapid and efficient removal of Hg(II) ions from water. AB - Mercury is considered one of the most notorious global pollutants due to its high toxicity and widespread use in industry. Although many materials have been developed for the removal of mercury for water purification, most of these materials are difficult to reuse, which may lead to an increase in the mercury handling expense. Therefore, new sustainable materials that can be easily recycled and are highly efficient for the removal of mercury are required. Herein, we report the surfactant-free green synthesis of Fe3O4 magnetic nanoparticles (MNPs) using a watermelon (Citrullus lanatus) rind extract. The Fe3O4 MNPs were further functionalized with 3,4 dihydroxyphenethylcarbamodithioate (DHPCT) and applied to the removal of Hg(ii). Evaluation of the mercury removal efficiency and the amount adsorbed by DHPCT@Fe3O4 MNPs demonstrated a high Hg(ii) removal efficiency (98%) with a maximum Hg(ii) adsorption capacity of 52.1 mg g(-1). Systematic studies of the adsorption mechanism and selectivity suggest that the soft ligand (DHPCT) can preferentially coordinate with the soft metal ion (Hg(ii)) resulting in selective mercury removal. The developed DHPCT@Fe3O4 MNPs were readily recycled several times using an external magnet by exploiting their ferromagnetic character, without a significant decline in the Hg(ii) removal efficiency. This study provides a new insight into the preparation of a highly efficient adsorbent for Hg(ii) removal by an eco-friendly method. PMID- 26436868 TI - Developmental trajectories of form perception: A story of attention. AB - The developmental trajectories of selective and divided attention were examined in relation to the processing of hierarchically integrated stimuli. The participants included children in 4 age groups (6, 8, 10, and 12 years) and a group of young adults (24 years) who completed 2 computer-based attention tasks. In the selective attention task, the participants were instructed to attend to only 1 level of analysis and ignore the other. In the divided attention task, participants were told that the target could appear at either level, and the probability that a target would appear at either the global or local level was manipulated. For both of the tasks, distinct and qualitative developmental shifts were evident both between 6 and 8 years of age and between 8 and 10 years of age. Attention to the global form developed prior to, and may have been a prerequisite of, attention to the local form. These gains in attentional control occurred in terms of selective attention, sensitivity to the probability of bias, and relative efficiency in processing global and local targets. The clear developmental trajectory is consistent with the emergent role of voluntary attention in the processing of these types of stimuli. PMID- 26436869 TI - The magic shrinking machine revisited: The presence of props at recall facilitates memory in 3-year-olds. AB - In a seminal study Simcock and Hayne (2002) showed that 3-year-olds were unable to use newly acquired words to describe a "magic" event experienced 6 or 12 months earlier. In the reference study the children's verbal recall was tested without props being present. Inspired by recent evidence, the original design was replicated, testing 33-and 39-month-olds (n = 180), but with props present at recall while controlling for potential online reasoning. The results revealed that the children did use newly acquired words to describe their preverbal memory. Thus, the present study shows that nonverbal memories can be verbalized if the recall setting provides a high level of contextual support, a finding relevant to researchers investigating the offset of childhood amnesia. PMID- 26436871 TI - The nonlinear relations of the approximate number system and mathematical language to early mathematics development. AB - Both mathematical language and the approximate number system (ANS) have been identified as strong predictors of early mathematics performance. Yet, these relations may be different depending on a child's developmental level. The purpose of this study was to evaluate the relations between these domains across different levels of ability. Participants included 114 children who were assessed in the fall and spring of preschool on a battery of academic and cognitive tasks. Children were 3.12 to 5.26 years old (M = 4.18, SD = .58) and 53.6% were girls. Both mixed-effect and quantile regressions were conducted. The mixed-effect regressions indicated that mathematical language, but not the ANS, nor other cognitive domains, predicted mathematics performance. However, the quantile regression analyses revealed a more nuanced relation among domains. Specifically, it was found that mathematical language and the ANS predicted mathematical performance at different points on the ability continuum. These dual nonlinear relations indicate that different mechanisms may enhance mathematical acquisition dependent on children's developmental abilities. PMID- 26436870 TI - Does school mobility place elementary school children at risk for lower math achievement? The mediating role of cognitive dysregulation. AB - Children growing up in poverty have a higher likelihood of exposure to multiple forms of adversity that jeopardize their chances of academic success. The current paper identifies school mobility, or changing schools, as 1 such poverty-related risk. Using a sample of low-income, predominantly ethnic-minority children (n = 381) in Chicago, this study tests the hypothesis that repeatedly changing schools during the 5-year period between Head Start (preschool) and third grade is a potent predictor of children's math achievement in fourth grade and that children's cognitive dysregulation serves as a mechanism through which school mobility may negatively affect children's math achievement. Hierarchical linear models controlling for baseline child and family characteristics (including children's early math and dysregulation measured during Head Start) revealed an inverse relation between the number of times low-income children changed schools between preschool and third grade and children's math achievement on state standardized tests in fourth grade. Furthermore, frequently changing schools (3 or 4 school changes over the same time period) was positively associated with teacher-reported cognitive dysregulation in third grade and negatively associated with children's math achievement in fourth grade. Evidence for the role of children's cognitive dysregulation as a partial statistical mediator was found for the relation between frequently changing schools and math achievement, even after accounting for baseline risk. Results are discussed in terms of school policies, practices, and intervention strategies to prevent the disruptive and potentially stressful experiences of school mobility for young, low-income children. PMID- 26436872 TI - Visuomotor integration and inhibitory control compensate for each other in school readiness. AB - Visuomotor integration (VMI), or the ability to copy designs, and 2 measures of executive function were examined in a predominantly low-income, typically developing sample of children (n = 467, mean age 4.2 years) from 5 U.S. states. In regression models controlling for age and demographic variables, we tested the interaction between visuomotor integration (design copying) and inhibitory control (pencil-tap) or verbal working memory (digit span) on 4 directly assessed academic skills and teacher-reported approaches to learning. Compared with children with both poor visuomotor integration and low inhibitory control, those on the higher end of the continuum in at least 1 of these 2 skills performed better across several dependent variables. This compensatory pattern was evident for longitudinal improvement in print knowledge on the Test of Preschool Early Literacy (TOPEL), with similar though marginally significant findings for improvement in phonological awareness (TOPEL) and teacher-rated approaches to learning on the Preschool Learning Behaviors Scale (PLBS). Of note, the same compensatory pattern emerged for concurrently measured receptive vocabulary on the Peabody Picture Vocabulary Test (PPVT), expressive vocabulary on the Woodcock Johnson III (WJ), TOPEL phonological awareness, and teacher-rated approaches to learning. The consistent pattern of results suggests that strong visuomotor integration skills are an important part of school readiness, and merit further study. PMID- 26436873 TI - De Novo Biosynthesis of beta-Valienamine in Engineered Streptomyces hygroscopicus 5008. AB - The C7N aminocyclitol beta-valienamine is a lead compound for the development of new biologically active beta-glycosidase inhibitors as chemical chaperone therapeutic agents for lysosomal storage diseases. Its chemical synthesis is challenging due to the presence of multichiral centers in the structure. Herein, we took advantage of a heterogeneous aminotransferase with stereospecificity and designed a novel pathway for producing beta-valienamine in Streptomyces hygroscopicus 5008, a validamycin producer. The aminotransferase BtrR from Bacillus circulans was able to convert valienone to beta-valienamine with an optical purity of up to >99.9% enantiomeric excess value in vitro. When the aminotransferase gene was introduced into a mutant of S. hygroscopicus 5008 accumulating valienone, 20 mg/L of beta-valienamine was produced after 96 h cultivation in shaking flasks. This work provides a powerful alternative for preparing the chiral intermediates for pharmaceutical development. PMID- 26436874 TI - The Prognostic Significance of Right Bundle Branch Block: A Meta-analysis of Prospective Cohort Studies. AB - BACKGROUND: The prognostic significance of right bundle branch block (RBBB) is inconsistent across studies. We aimed to assess the association between RBBB (in general population and patients with heart disease) and risk of all-cause mortality, cardiac death, acute myocardial infarction (MI), and heart failure (HF). HYPOTHESIS: RBBB may be associated with increased risk of death. METHODS: PubMed, EMBASE, and the Cochrane Library up to February 2015 were searched for prospective cohort studies that reported RBBB at baseline and all-cause mortality, cardiac death, MI, and HF at follow-up. A meta-analysis of published data was undertaken primarily by means of fixed-effects models. RESULTS: Nineteen cohort studies including 201 437 participants were included with a mean follow-up period ranging from 1 to 246 months. For general population with RBBB, the pooled adjusted hazard ratio (HR) for all-cause mortality was 1.17 (95% confidence interval [CI]: 1.03-1.33) compared with no BBB. General population with RBBB had an increased risk of cardiac death (HR: 1.43, 95% CI: 1.17-1.74). For patients with RBBB and acute MI, the pooled risk ratio was 2.31 (95% CI: 2.13-2.49) for in hospital mortality, 2.85 (95% CI: 2.46-3.30) for 30-day mortality, and 1.96 (95% CI: 1.59-2.42) for longer-term mortality. For acute HF patients, the pooled risk ratio of all-cause mortality was 1.11 (95% CI: 1.06-1.16), and for chronic HF patients it was 1.75 (95% CI: 1.38-2.22). CONCLUSIONS: Right bundle branch block is associated with an increased risk of mortality in general population and patients with heart disease. PMID- 26436875 TI - Copy number increase of oncoprotein CIP2A is associated with poor patient survival in human head and neck squamous cell carcinoma. AB - BACKGROUND: CIP2A, an inhibitor of PP2A tumour suppressor function, is a widely overexpressed biomarker of aggressive disease and poor therapy response in multiple human cancer types. METHODS: CIP2A and DPPA4 copy number alterations and expression were analysed by fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) in different cell lines and a tissue microarray of 52 HNSCC patients. Results were correlated with patient survival and other clinicopathological data. RESULTS: CIP2A and DPPA4 copy number increase occurred at a relatively high frequency in human HNSCC patient samples. CIP2A but not DPPA4 FISH status was significantly associated with patient survival. CIP2A detection by combining IHC with FISH yielded superior resolution in the prognostication of HNSCC. CONCLUSIONS: CIP2A copy number increase is associated with poor patient survival in human HNSCC. We suggest that the reliability and prognostic value of CIP2A detection can be improved by performing FISH analysis to CIP2A IHC positive tumours. PMID- 26436876 TI - The role of pectoralis major flap in reducing the incidence of pharyngocutaneous fistula following total laryngectomy: a single-centre experience with 102 patients. PMID- 26436877 TI - Viability of Bioprinted Cellular Constructs Using a Three Dispenser Cartesian Printer. AB - Tissue engineering has centralized its focus on the construction of replacements for non-functional or damaged tissue. The utilization of three-dimensional bioprinting in tissue engineering has generated new methods for the printing of cells and matrix to fabricate biomimetic tissue constructs. The solid freeform fabrication (SFF) method developed for three-dimensional bioprinting uses an additive manufacturing approach by depositing droplets of cells and hydrogels in a layer-by-layer fashion. Bioprinting fabrication is dependent on the specific placement of biological materials into three-dimensional architectures, and the printed constructs should closely mimic the complex organization of cells and extracellular matrices in native tissue. This paper highlights the use of the Palmetto Printer, a Cartesian bioprinter, as well as the process of producing spatially organized, viable constructs while simultaneously allowing control of environmental factors. This methodology utilizes computer-aided design and computer-aided manufacturing to produce these specific and complex geometries. Finally, this approach allows for the reproducible production of fabricated constructs optimized by controllable printing parameters. PMID- 26436879 TI - Co(OH)2 @PANI Hybrid Nanosheets with 3D Networks as High-Performance Electrocatalysts for Hydrogen Evolution Reaction. AB - Hybrid electrocatalysts with excellent electrocatalytic activity for hydrogen reduction are fabricated using an efficient and facile electrochemical route. The electronic and synergistic effects between Co(OH)2 and polyaniline (PANI) in the composite structure are the key factors that generate the high electrocatalytic activity and excellent stability. A highly efficient, non-precious metal-based flexible electrocatalyst for high-performance electrocatalysts is shown, which reveals a novel route for the design and synthesis of electrocatalysts. PMID- 26436880 TI - Metabolic Capacity of Mitochondrion-related Organelles in the Free-living Anaerobic Stramenopile Cantina marsupialis. AB - Functionally and morphologically degenerate mitochondria, so-called mitochondrion related organelles (MROs), are frequently found in eukaryotes inhabiting hypoxic or anoxic environments. In the last decade, MROs have been discovered from a phylogenetically broad range of eukaryotic lineages and these organelles have been revealed to possess diverse metabolic capacities. In this study, the biochemical characteristics of an MRO in the free-living anaerobic protist Cantina marsupialis, which represents an independent lineage in stramenopiles, were inferred based on RNA-seq data. We found transcripts for proteins known to function in one form of MROs, the hydrogenosome, such as pyruvate:ferredoxin oxidoreductase, iron-hydrogenase, acetate:succinate CoA-transferase, and succinyl CoA synthase, along with transcripts for acetyl-CoA synthetase (ADP-forming). These proteins possess putative mitochondrial targeting signals at their N termini, suggesting dual ATP generation systems through anaerobic pyruvate metabolism in Cantina MROs. In addition, MROs in Cantina were also shown to share several features with canonical mitochondria, including amino acid metabolism and an "incomplete" tricarboxylic acid cycle. Transcripts for all four subunits of complex II (CII) of the electron transport chain were detected, while there was no evidence for the presence of complexes I, III, IV, or F1Fo ATPase. Cantina MRO biochemistry challenges the categories of mitochondrial organelles recently proposed. PMID- 26436881 TI - Dr. Ninan T. Mathew--A "Tribute" (1937-2015). PMID- 26436882 TI - Understanding contextual influences of community reintegration among injured servicemembers. AB - As part of a larger mixed-methods research project investigating the influence of contextual factors on community reintegration (CR), this qualitative study sought to understand the subjective experiences of injured servicemembers and their perception of how contextual factors influenced their CR. More specifically, this article addresses how the influences of contextual factors differ between injured servicemembers with different levels of CR. Using a phenomenological framework, semistructured interviews were conducted with nine injured, community-dwelling servicemembers with low, moderate, and high levels of CR (three per category). Participants provided in-depth descriptions of the contextual barriers and facilitators of CR. Thematic analysis indicated the importance of social support and personal factors (e.g., self-efficacy, personal motivation) as the primary means for being reintegrated into their homes and communities. Other themes indicated factors that had an indirect but important influence on CR, including adapted sports, recreation, and other social programs; rehabilitation programs and therapists; school, work, and volunteering; and organizations and policies in developing social supports and personal factors. Comparisons between servicemembers indicated participants with low CR described many more contextual barriers and far fewer contextual facilitators to reintegration than those with high CR. Those with moderate CR were unique in that they described many facilitators and barriers to reintegration. PMID- 26436884 TI - Influence of the Retinal Blood Vessel Topography on the Variability of the Retinal Nerve Fiber Bundle Trajectories in the Human Retina. AB - PURPOSE: To determine the relationship between the retinal blood vessel topography and the retinal nerve fiber bundle (RNFB) trajectories in the human retina. METHODS: A previously collected dataset comprising 28 fundus photographs with traced RNFB trajectories was used. For all traced trajectories, the departure from our previously published RNFB trajectory model was calculated. Subsequently, we calculated, per subject, a "mean departure" for the superior temporal and inferior-temporal region. We measured angles between a line connecting the optic nerve head (ONH) center and the fovea and lines connecting the ONH center and the crossings of the superior and inferior temporal arteries (arterial angles) and veins (venous angles) with circles around the ONH; circle radii were 25%, 50%, and 100% of the ONH center-to-fovea distance. We also defined two angles based on the location of the first arteriovenous crossing. Multiple linear regression analysis was performed with mean departure as dependent variable and refraction, ONH inclination, and vessel angles as independent variables. RESULTS: In the superior-temporal region, refraction (P = 0.017), ONH inclination (P = 0.021), and the arterial angle corresponding to the middle circle (P < 0.001) were significant determinants of mean departure. Explained variance was 0.54. In the inferior-temporal region, the arterial angle corresponding to the largest circle (P = 0.002) was significant. Explained variance was 0.32. CONCLUSIONS: The retinal blood vessel topography explains a significant part of the RNFB trajectory variability but only if (1) the vessel topography is assessed at an appropriate distance from the ONH and (2) the superior and inferior hemifield are addressed independently. PMID- 26436883 TI - Cell Invasion Dynamics into a Three Dimensional Extracellular Matrix Fibre Network. AB - The dynamics of filopodia interacting with the surrounding extracellular matrix (ECM) play a key role in various cell-ECM interactions, but their mechanisms of interaction with the ECM in 3D environment remain poorly understood. Based on first principles, here we construct an individual-based, force-based computational model integrating four modules of 1) filopodia penetration dynamics; 2) intracellular mechanics of cellular and nuclear membranes, contractile actin stress fibers, and focal adhesion dynamics; 3) structural mechanics of ECM fiber networks; and 4) reaction-diffusion mass transfers of seven biochemical concentrations in related with chemotaxis, proteolysis, haptotaxis, and degradation in ECM to predict dynamic behaviors of filopodia that penetrate into a 3D ECM fiber network. The tip of each filopodium crawls along ECM fibers, tugs the surrounding fibers, and contracts or retracts depending on the strength of the binding and the ECM stiffness and pore size. This filopodium ECM interaction is modeled as a stochastic process based on binding kinetics between integrins along the filopodial shaft and the ligands on the surrounding ECM fibers. This filopodia stochastic model is integrated into migratory dynamics of a whole cell in order to predict the cell invasion into 3D ECM in response to chemotaxis, haptotaxis, and durotaxis cues. Predicted average filopodia speed and that of the cell membrane advance agreed with experiments of 3D HUVEC migration at r(2) > 0.95 for diverse ECMs with different pore sizes and stiffness. PMID- 26436885 TI - Previous Driving Experience, but Not Vision, Is Associated With Motor Vehicle Collision Rate in Bioptic Drivers. AB - PURPOSE: Bioptic telescopic spectacles (BTS) consist of a small telescope (or telescopes) mounted high in a pair of spectacle lenses. More than 40 states allow for some form of bioptic driving licensure for people with decreased central vision. The purpose of this study was to determine significant associations among previous driving experience, vision, and motor vehicle collisions (MVCs) for bioptic drivers in Ohio. METHODS: We conducted a retrospective study of patients who received a vision examination and subsequently obtained bioptic licensure. We obtained driving records from the Ohio Bureau of Motor Vehicles in order to determine MVC involvement. Relationships among vision measures, age, sex, previous experience, and MVCs were investigated using time-to-event analysis and the Cox proportional hazards regression model. RESULTS: We identified 237 bioptic drivers (65% male). Age at initial exam ranged from 16 to 81 years, and mean visual acuity was approximately 20/120. The number of MVCs per driver ranged from 0 to 11, with 124 (52%) drivers having had at least one MVC. Visual acuity and contrast sensitivity were not significant predictors of MVC. Drivers without previous driving experience were significantly more likely to have been involved in an MVC (P < 0.001), and this association remained significant after adjusting for age and sex (P = 0.01). The rate of MVC per year decreased steadily over a 10 year period for drivers without previous experience. CONCLUSIONS: Previous nonbioptic driving experience, but not visual acuity or contrast sensitivity, was associated with yearly MVC rate in bioptic drivers. PMID- 26436886 TI - Neurodegeneration in Type 2 Diabetes: Evidence From Spectral-Domain Optical Coherence Tomography. AB - PURPOSE: The purpose of this study was to assess changes in the neural retina in eyes with different stages of diabetic retinopathy (DR) in comparison to age matched healthy subjects. METHODS: Retrospective analysis of spectral-domain optical coherence tomography (SD-OCT) scans of 76 naive eyes of 62 subjects with diabetes was performed. Key exclusion criteria included presence of diabetic macular edema, any other retinal disease, history of any treatment for DR, or incorrect segmentation of the retinal layers on SD-OCT scans. Eyes from diabetic patients were divided into three groups, including no DR, nonproliferative DR (NPDR), and proliferative DR (PDR). A control group of 67 eyes of 66 age-matched healthy volunteers was included for comparison. Average, minimum, and sectoral thicknesses for the ganglion cell-inner plexiform layer (GCIPL) and retinal nerve fiber layer (RNFL) were collected from both groups and compared using an ANOVA test. RESULTS: Among the 76 included eyes, 43 had NPDR, 13 had PDR, and 20 had no signs of DR. Average and minimum GCIPL showed significant thinning in diabetic subjects compared with controls in all stages of DR (P < 0.05), especially involving the papillo-macula bundle. However, GCIPL thickness was similar between diabetic groups. There was no significant difference in average or sectoral RNFL thicknesses among groups; however, the minimum RNFL thickness was lower in diabetics compared with controls (P < 0.05). No relationship between GCIPL and RNFL thicknesses and duration of diabetes was present. CONCLUSIONS: Early thinning on the inner retina happens in type 2 diabetes, even before visible vascular signs of DR. This supports the presence of a neurodegenerative process in eyes of patients with diabetes and warrants neuroprotective intervention to prevent chronic neurodegeneration. The SD-OCT may represent an indispensable tool for identifying early signs of neurodegeneration in diabetic patients. PMID- 26436887 TI - Residual and Dynamic Range of Retinal Nerve Fiber Layer Thickness in Glaucoma: Comparison of Three OCT Platforms. AB - PURPOSE: To estimate visual field (VF) sensitivity at which retinal nerve fiber layer (RNFL) thinning reaches the measurement floor and at which RNFL stops thinning (change points), the dynamic range of RNFL thickness, and the number of steps from normal to RNFL floor among three optical coherence tomography (OCT) devices. METHODS: Glaucomatous patients (n = 58) and healthy subjects (n = 55-60) prospectively underwent VF testing and RNFL thickness measurement with Cirrus, Spectralis, and RTVue. Change points and corresponding RNFL thicknesses were estimated with simple linear regression (SLR) and Bayesian change point (BCP) analyses. The dynamic range and number of steps to RNFL floor were determined. RESULTS: The average VF change points and corresponding residual thickness at the time RNFL stopped thinning were -22.2 dB and 57.0 MUm (Cirrus), -25.3 dB and 49.2 MUm (Spectralis), and -24.6 dB and 64.7 MUm (RTVue). The RNFL dynamic ranges derived from SLR values were wider on Spectralis (52.6 MUm) than on Cirrus (35.4 MUm) and RTVue (35.5 MUm); the corresponding number of steps to reach the RNFL floor were 9.0 on Cirrus, 10.6 on Spectralis, and 8.3 on RTVue. CONCLUSIONS: The relative VF sensitivity at which average RNFL thickness reaches the measurement floor, the residual layer thickness, and RNFL dynamic measurement range differ among the three devices. However, the number of steps from normal to the RNFL thickness floor is comparable. PMID- 26436888 TI - Therapeutic Effect of Resveratrol on Oxidative Stress in Graves' Orbitopathy Orbital Fibroblasts. AB - PURPOSE: Multiple causative factors complicate the pathogenesis in Graves' orbitopathy (GO). It has been suggested that oxidative stress contributes to the development and progression of GO. Therefore, we investigated the therapeutic effect of resveratrol, a potent antioxidant, upon oxidative stress levels in GO orbital fibroblasts in vitro. METHODS: Orbital fibroblasts were cultured from orbital connective tissues obtained from GO patients. Intracellular reactive oxygen species (ROS) levels and the expression of heme oxygenase-1 (HO-1), superoxide dismutase (SOD), catalase, and thioredoxin (Trx), were measured after resveratrol treatment. Adipogenesis was induced, and ROS levels were examined during adipogenic differentiation. Western blot assay was performed to evaluate the effects of resveratrol on the expression of antioxidants levels and transcriptional regulators. RESULTS: Treatment with 30 or 50 MUM resveratrol reduced ROS production and HO-1 level induced by oxidative stress. Levels of Cu/Zn-SOD, catalase, and Trx were also reduced, while Mn-SOD increased with 50 MUM resveratrol treatment. Resveratrol suppressed adipogenesis, reducing the number of adipocytes and suppressing the accumulation of lipid droplets. Treatment with 50 MUM resveratrol also decreased ROS levels during adipogenesis. Expression of the transcriptional regulators phosphor-extracellular signal regulated kinase and phospho-c-Jun NH(2)-terminal kinase significantly increased after treatment with 50 MUM resveratrol, and decreased in response to inhibitors of each protein. Phosphonuclear factor kappa-light-chain-enhancer of activated B cells p65 levels also increased after treatment with 50 MUM resveratrol. CONCLUSIONS: Resveratrol reduced ROS levels and inhibited adipogenesis in GO orbital fibroblasts in vitro. This study supports the potential use of resveratrol in GO treatment. PMID- 26436890 TI - Erratum. PMID- 26436889 TI - Allele-Specific Inhibition of Rhodopsin With an Antisense Oligonucleotide Slows Photoreceptor Cell Degeneration. AB - PURPOSE: To preserve photoreceptor cell structure and function in a rodent model of retinitis pigmentosa with P23H rhodopsin by selective inhibition of the mutant rhodopsin allele using a second generation antisense oligonucleotide (ASO). METHODS: Wild-type mice and rats were treated with ASO by intravitreal (IVT) injection and rhodopsin mRNA and protein expression were measured. Transgenic rats expressing the murine P23H rhodopsin gene (P23H transgenic rat Line 1) were administered either a mouse-specific P23H ASO or a control ASO. The contralateral eye was injected with PBS and used as a comparator control. Electroretinography (ERG) measurements and analyses of the retinal outer nuclear layer were conducted and correlated with rhodopsin mRNA levels. RESULTS: Rhodopsin mRNA and protein expression was reduced after a single ASO injection in wild-type mice with a rhodopsin-specific ASO. Transgenic rat eyes that express a murine P23H rhodopsin gene injected with a murine P23H ASO had a 181 +/- 39% better maximum amplitude response (scotopic a-wave) as compared with contralateral PBS-injected eyes; the response in control ASO eyes was not significantly different from comparator contralateral eyes. Morphometric analysis of the outer nuclear layer showed a significantly thicker nuclear layer in eyes injected with murine P23H ASO (18%) versus contralateral PBS-injected eyes. CONCLUSIONS: Allele-specific ASO-mediated knockdown of mutant P23H rhodopsin expression slowed the rate of photoreceptor degeneration and preserved the function of photoreceptor cells in eyes of the P23H rhodopsin transgenic rat. Our data indicate that ASO treatment is a potentially effective therapy for the treatment of retinitis pigmentosa. PMID- 26436891 TI - Coupled 3D Time-Dependent Wave-Packet Approach in Hyperspherical Coordinates: The D(+)+H2 Reaction on the Triple-Sheeted DMBE Potential Energy Surface. AB - We implement a coupled three-dimensional (3D) time-dependent wave packet formalism for the 4D reactive scattering problem in hyperspherical coordinates on the accurate double many body expansion (DMBE) potential energy surface (PES) for the ground and first two singlet states (1(1)A', 2(1)A', and 3(1)A') to account for nonadiabatic processes in the D(+) + H2 reaction for both zero and nonzero values of the total angular momentum (J). As the long-range interactions in D(+) + H2 contribute significantly due to nonadiabatic effects, the convergence profiles of reaction probabilities for the reactive noncharge transfer (RNCT), nonreactive charge transfer (NRCT), and reactive charge transfer (RCT) processes are shown for different collisional energies with respect to the helicity (K) and total angular momentum (J) quantum numbers. The total and state-to-state cross sections are presented as a function of the collision energy for the initial rovibrational state v = 0, j = 0 of the diatom, and the calculated cross sections compared with other theoretical and experimental results. PMID- 26436893 TI - Molecular Factors Underlying the Deposition of Intramuscular Fat and Collagen in Skeletal Muscle of Nellore and Angus Cattle. AB - Studies have shown that intramuscular adipogenesis and fibrogenesis may concomitantly occur in skeletal muscle of beef cattle. Thus, we hypothesized that the discrepancy of intramuscular fat content in beef from Nellore and Angus was associated with differences in intramuscular adipogenesis and fibrogenesis during the finishing phase. To test our hypothesis, longissimus muscle samples of Nellore (n = 6; BW = 372.5 +/- 37.3 kg) and Angus (n = 6; BW = 382.8 +/- 23.9 kg) cattle were collected for analysis of gene and protein expression, and quantification of intramuscular fat and collagen. Least-squares means were estimated for the effect of Breed and differences were considered at P <= 0.05. A greater intramuscular fat content was observed in skeletal muscle of Angus compared to Nellore cattle (P<=0.05). No differences were observed for mRNA expression of lipogenic and lipolytic markers ACC, FAS, FABP4, SERBP-1, CPT-2, LPL, and ACOX (P > 0.05) in skeletal muscle of Nellore and Angus cattle. Similarly, no differences were observed in mRNA expression of adipogenic markers Zfp423, PPARgamma, and C/EBPalpha (P>0.05) However, a greater PPARgamma protein content was observed in skeletal muscle of Angus compared to Nellore cattle (P<=0.05). A greater abundance of adipo/fibrogenic cells, evaluated by the PDGFRalpha content, was observed in skeletal muscle of Angus than Nellore cattle (P<=0.05). No differences in fibrogenesis were observed in skeletal muscle of Angus and Nellore cattle, which is in accordance with the lack of differences in intramuscular collagen content in beef from both breeds (P>0.05). These findings demonstrate that difference in intramuscular fat content is associated with a slightly enhanced adipogenesis in skeletal muscle of Angus compared to Nellore cattle, while no difference in fibrogenesis. PMID- 26436892 TI - Antisense Oligonucleotide-Mediated Transcript Knockdown in Zebrafish. AB - Antisense oligonucleotides (ASOs) are synthetic, single-strand RNA-DNA hybrids that induce catalytic degradation of complementary cellular RNAs via RNase H. ASOs are widely used as gene knockdown reagents in tissue culture and in Xenopus and mouse model systems. To test their effectiveness in zebrafish, we targeted 20 developmental genes and compared the morphological changes with mutant and morpholino (MO)-induced phenotypes. ASO-mediated transcript knockdown reproduced the published loss-of-function phenotypes for oep, chordin, dnd, ctnnb2, bmp7a, alk8, smad2 and smad5 in a dosage-sensitive manner. ASOs knocked down both maternal and zygotic transcripts, as well as the long noncoding RNA (lncRNA) MALAT1. ASOs were only effective within a narrow concentration range and were toxic at higher concentrations. Despite this drawback, quantitation of knockdown efficiency and the ability to degrade lncRNAs make ASOs a useful knockdown reagent in zebrafish. PMID- 26436894 TI - Immune Modulation of the T Cell Response in Asthma through Wnt10b. AB - Asthma is a chronic inflammatory disease, which is characterized by activation of CD4(+) T helper 2 cells orchestrating an allergic airway response. Whereas the role of Wnt family members in regulating T cell maintenance and maturation is established, their contribution to T cell activation in allergic asthma is not known. We hypothesized that Wnt10b plays a role in the modulation of the allergic airway response and affects T cell activation and polarization. Using an in vivo house dust mite asthma model, Wnt10b-deficient (Wnt10b(-/-)) mice were allergen sensitized and inflammation, as well as T cell activation, was studied in vivo and in vitro. Wnt10b(-/-) mice exhibited an augmented inflammatory phenotype with an increase in eosinophils in the bronchoalveolar lavage and IL-4 and IL-13 in the lungs when compared with wild-type mice. In vitro studies confirmed an increased T helper type 2 polarization and increased T cell activation of Wnt10b( /-) cells. Accordingly, the percentage of naive T cells was elevated by the addition of recombinant Wnt10b protein. Finally, Wnt10b(-/-) mice exhibited an increase in the percentage of effector T cells in the lungs after house dust mite sensitization, which indicated a heightened activation state, measured by an increased percentage of CD69(hi)CD11a(hi) cells. These findings suggest that Wnt10b plays an important role in regulating asthmatic airway inflammation through modification of the T cell response and is a prospective target in the disease process. PMID- 26436895 TI - Are Structural Changes Induced by Lithium in the HIV Brain Accompanied by Changes in Functional Connectivity? AB - Lithium therapy has been shown to affect imaging measures of brain function and microstructure in human immunodeficiency virus (HIV)-infected subjects with cognitive impairment. The aim of this proof-of-concept study was to explore whether changes in brain microstructure also entail changes in functional connectivity. Functional MRI data of seven cognitively impaired HIV infected individuals enrolled in an open-label lithium study were included in the connectivity analysis. Seven regions of interest (ROI) were defined based on previously observed lithium induced microstructural changes measured by Diffusion Tensor Imaging. Generalized partial directed coherence (gPDC), based on time variant multivariate autoregressive models, was used to quantify the degree of connectivity between the selected ROIs. Statistical analyses using a linear mixed model showed significant differences in the average node strength between pre and post lithium therapy conditions. Specifically, we found that lithium treatment in this population induced changes suggestive of increased strength in functional connectivity. Therefore, by exploiting the information about the strength of functional interactions provided by gPDC we can quantify the connectivity changes observed in relation to a given intervention. Furthermore, in conditions where the intervention is associated with clinical changes, we suggest that this methodology could enable an interpretation of such changes in the context of disease or treatment induced modulations in functional networks. PMID- 26436897 TI - Emotional and Cognitive Influences on Pain Experience. AB - Multiple emotional and cognitive factors impact on the experience of pain. This chapter will review some of the most important emotional and cognitive determinants of the pain experience as found in experimental and clinical studies with human participants. Emotional factors that may increase pain perception are anxiety, depression and anger. Positive emotions usually decrease perceived pain. The cognitive factors attention, expectancy and appraisal can either increase or decrease pain experiences depending on their specific focus and content. Many brain regions are involved in nociceptive processing and bringing pain into awareness. There are profound interconnections between areas processing sensory, emotional and cognitive information. Descending pathways from cortical areas to the midbrain and spinal levels can facilitate or inhibit spinal nociceptive information and thereby afferent nociceptive input to the brain. The underlying mechanisms of the various emotional and cognitive modulatory influences may partly overlap, but also have some unique aspects. What becomes clear is that pain is not merely a reflection of the nociceptive input, but should be considered as a complex experience shaped by psychological factors that may be unique for each individual. PMID- 26436898 TI - Potential-Modulated Electrochemiluminescence of Carbon Nitride Nanosheets for Dual-Signal Sensing of Metal Ions. AB - As an emerging semiconductor, graphite-phase polymeric carbon nitride (GPPCN) has drawn much attention not only in photocatalysis but also in optical sensors such as electrochemiluminescence (ECL) sensing of metal ions. However, when the concentrations of interfering metal ions are several times higher than that of the target metal ion, it is almost impossible to distinguish which metal ion changes the ECL signals in real sample detection. Herein, we report that the dual ECL signals could be actuated by different ECL reactions merely from GPPCN nanosheets at anodic and cathodic potentials, respectively. Interestingly, the different metal ions exhibited distinct quenching/enhancement of the ECL signal at different driven potentials, presumably ascribed to the diversity of energy level matches between the metal ions and GPPCN nanosheets and catalytic interactions of the intermediate species in ECL reactions. On this basis, without any labeling and masking reagents, the accuracy and reliability of sensors based on the ECL of GPPCN nanosheets toward metal ions were largely improved; thus, the false-positive result caused by interferential metal ions could be effectively avoided. As an example, the proposed GPPCN ECL sensor with a detection limit of 1.13 nM was successfully applied for the detection of trace Ni(2+) ion in tap and lake water. PMID- 26436896 TI - Quetiapine and its metabolite norquetiapine: translation from in vitro pharmacology to in vivo efficacy in rodent models. AB - BACKGROUND AND PURPOSE: Quetiapine has a range of clinical activity distinct from other atypical antipsychotic drugs, demonstrating efficacy as monotherapy in bipolar depression, major depressive disorder and generalized anxiety disorder. The neuropharmacological mechanisms underlying this clinical profile are not completely understood; however, the major active metabolite, norquetiapine, has been shown to have a distinct in vitro pharmacological profile consistent with a broad therapeutic range and may contribute to the clinical profile of quetiapine. EXPERIMENTAL APPROACH: We evaluated quetiapine and norquetiapine, using in vitro binding and functional assays of targets known to be associated with antidepressant and anxiolytic drug actions and compared these activities with a representative range of established antipsychotics and antidepressants. To determine how the in vitro pharmacological properties translate into in vivo activity, we used preclinical animal models with translational relevance to established antidepressant-like and anxiolytic-like drug action. KEY RESULTS: Norquetiapine had equivalent activity to established antidepressants at the noradrenaline transporter (NET), while quetiapine was inactive. Norquetiapine was active in the mouse forced swimming and rat learned helplessness tests. In in vivo receptor occupancy studies, norquetiapine had significant occupancy at NET at behaviourally relevant doses. Both quetiapine and norquetiapine were agonists at 5-HT1A receptors, and the anxiolytic-like activity of norquetiapine in rat punished responding was blocked by the 5-HT1A antagonist, WAY100635. CONCLUSIONS AND IMPLICATIONS: Quetiapine and norquetiapine have multiple in vitro pharmacological actions, and results from preclinical studies suggest that activity at NET and 5-HT1A receptors contributes to the antidepressant and anxiolytic effects in patients treated with quetiapine. PMID- 26436899 TI - Cup tool use by squirrel monkeys. AB - Captive-born male and female squirrel monkeys spontaneously 'invented' a cup tool use technique to Contain (i.e., hold and control) food they reduced into fragments for consumption and to Contain water collected from a valve to drink. Food cup use was observed more frequently than water cup use. Observations indicate that 68% (n = 39/57) of monkeys in this population used a cup (a plastic slip cap) to Contain food, and a subset of these monkeys, 10% (n = 4/39), also used a cup to Contain water. Cup use was optional and did not replace, but supplemented, the hand/arm-to-mouth eating and direct valve drinking exhibited by all members of the population. Strategies monkeys used to bring food and cups together for food processing activity at preferred upper-level perching areas, in the arboreal-like environment in which they lived, provides evidence that monkeys may plan food processing activity with the cups. Specifically, prior to cup use monkeys obtained a cup first before food, or obtained food and a cup from the floor simultaneously, before transporting both items to upper-level perching areas. After food processing activity with cups monkeys rarely dropped the cups and more often placed the cups onto perching. Monkeys subsequently returned to use cups that they previously placed on perching after food processing activity. The latter behavior is consistent with the possibility that monkeys may keep cups at preferred perching sites for future food processing activity and merits experimental investigation. Reports of spontaneous tool use by squirrel monkeys are rare and this is the first report of population-level tool use. These findings offer insights into the cognitive abilities of squirrel monkeys and provide a new context for behavior studies with this genus and for comparative studies with other primates. PMID- 26436900 TI - Human mutant huntingtin disrupts vocal learning in transgenic songbirds. AB - Speech and vocal impairments characterize many neurological disorders. However, the neurogenetic mechanisms of these disorders are not well understood, and current animal models do not have the necessary circuitry to recapitulate vocal learning deficits. We developed germline transgenic songbirds, zebra finches (Taneiopygia guttata) expressing human mutant huntingtin (mHTT), a protein responsible for the progressive deterioration of motor and cognitive function in Huntington's disease (HD). Although generally healthy, the mutant songbirds had severe vocal disorders, including poor vocal imitation, stuttering, and progressive syntax and syllable degradation. Their song abnormalities were associated with HD-related neuropathology and dysfunction of the cortical-basal ganglia (CBG) song circuit. These transgenics are, to the best of our knowledge, the first experimentally created, functional mutant songbirds. Their progressive and quantifiable vocal disorder, combined with circuit dysfunction in the CBG song system, offers a model for genetic manipulation and the development of therapeutic strategies for CBG-related vocal and motor disorders. PMID- 26436901 TI - Negligible fronto-parietal BOLD activity accompanying unreportable switches in bistable perception. AB - The human brain's executive systems have a vital role in deciding and selecting among actions. Selection among alternatives also occurs in the perceptual domain; for instance, when perception switches between interpretations during perceptual bistability. Whether executive systems also underlie this functionality remains debated, with known fronto-parietal concomitants of perceptual switches being variously interpreted as reflecting the switches' cause or as reflecting their consequences. We developed a procedure in which the two eyes receive different inputs and perception demonstrably switches between these inputs, yet the switches themselves are so inconspicuous as to become unreportable, minimizing their executive consequences. Fronto-parietal fMRI BOLD responses that accompanied perceptual switches were similarly minimized in this procedure, indicating that these reflect the switches' consequences rather than their cause. We conclude that perceptual switches do not always rely on executive brain areas and that processes responsible for selection among alternatives may operate outside the brain's executive systems. PMID- 26436902 TI - Flexible gating of contextual influences in natural vision. AB - Identical sensory inputs can be perceived as markedly different when embedded in distinct contexts. Neural responses to simple stimuli are also modulated by context, but the contribution of this modulation to the processing of natural sensory input is unclear. We measured surround suppression, a quintessential contextual influence, in macaque primary visual cortex with natural images. We found that suppression strength varied substantially for different images. This variability was not well explained by existing descriptions of surround suppression, but it was predicted by Bayesian inference about statistical dependencies in images. In this framework, surround suppression was flexible: it was recruited when the image was inferred to contain redundancies and substantially reduced in strength otherwise. Thus, our results reveal a gating of a basic, widespread cortical computation by inference about the statistics of natural input. PMID- 26436903 TI - Perceptual learning in autism: over-specificity and possible remedies. AB - Inflexible behavior is a core characteristic of autism spectrum disorder (ASD), but its underlying cause is unknown. Using a perceptual learning protocol, we observed initially efficient learning in ASD that was followed by anomalously poor learning when the location of the target was changed (over-specificity). Reducing stimulus repetition eliminated over-specificity. Our results indicate that inflexible behavior may be evident ubiquitously in ASD, even in sensory learning, but can be circumvented by specifically designed stimulation protocols. PMID- 26436905 TI - High-resolution high-sensitivity elemental imaging by secondary ion mass spectrometry: from traditional 2D and 3D imaging to correlative microscopy. AB - Secondary ion mass spectrometry (SIMS) constitutes an extremely sensitive technique for imaging surfaces in 2D and 3D. Apart from its excellent sensitivity and high lateral resolution (50 nm on state-of-the-art SIMS instruments), advantages of SIMS include high dynamic range and the ability to differentiate between isotopes. This paper first reviews the underlying principles of SIMS as well as the performance and applications of 2D and 3D SIMS elemental imaging. The prospects for further improving the capabilities of SIMS imaging are discussed. The lateral resolution in SIMS imaging when using the microprobe mode is limited by (i) the ion probe size, which is dependent on the brightness of the primary ion source, the quality of the optics of the primary ion column and the electric fields in the near sample region used to extract secondary ions; (ii) the sensitivity of the analysis as a reasonable secondary ion signal, which must be detected from very tiny voxel sizes and thus from a very limited number of sputtered atoms; and (iii) the physical dimensions of the collision cascade determining the origin of the sputtered ions with respect to the impact site of the incident primary ion probe. One interesting prospect is the use of SIMS-based correlative microscopy. In this approach SIMS is combined with various high resolution microscopy techniques, so that elemental/chemical information at the highest sensitivity can be obtained with SIMS, while excellent spatial resolution is provided by overlaying the SIMS images with high-resolution images obtained by these microscopy techniques. Examples of this approach are given by presenting in situ combinations of SIMS with transmission electron microscopy (TEM), helium ion microscopy (HIM) and scanning probe microscopy (SPM). PMID- 26436906 TI - Targeted alpha therapy for cancer: where we are today and where we are heading. PMID- 26436904 TI - Depletion of microglia and inhibition of exosome synthesis halt tau propagation. AB - Accumulation of pathological tau protein is a major hallmark of Alzheimer's disease. Tau protein spreads from the entorhinal cortex to the hippocampal region early in the disease. Microglia, the primary phagocytes in the brain, are positively correlated with tau pathology, but their involvement in tau propagation is unknown. We developed an adeno-associated virus-based model exhibiting rapid tau propagation from the entorhinal cortex to the dentate gyrus in 4 weeks. We found that depleting microglia dramatically suppressed the propagation of tau and reduced excitability in the dentate gyrus in this mouse model. Moreover, we demonstrate that microglia spread tau via exosome secretion, and inhibiting exosome synthesis significantly reduced tau propagation in vitro and in vivo. These data suggest that microglia and exosomes contribute to the progression of tauopathy and that the exosome secretion pathway may be a therapeutic target. PMID- 26436907 TI - A new chapter. PMID- 26436909 TI - Air pollution and children's respiratory health. PMID- 26436910 TI - Empowering family physicians to impart proper inhaler teaching to patients with chronic obstructive pulmonary disease and asthma. AB - BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) and asthma depend on inhalers for management, but critical errors committed during inhaler use can limit drug effectiveness. Outpatient education in inhaler technique remains inconsistent due to limited resources and inadequate provider knowledge. OBJECTIVE: To determine whether a simple, two-session inhaler education program can improve physician attitudes toward inhaler teaching in primary care practice. METHODS: An inhaler education program with small-group hands-on device training was instituted for family physicians (FP) in British Columbia and Alberta. Sessions were spaced one to three months apart. All critical errors were corrected in the first session. Questionnaires surveying current inhaler teaching practices and attitudes toward inhaler teaching were distributed to physicians before and after the program. RESULTS: Forty-one (60%) of a total 68 participating FPs completed both before and after program questionnaires. Before the program, only 20 (49%) reported providing some form of inhaler teaching in their practices, and only four (10%) felt fully competent to teach patients inhaler technique. After the program, 40 (98%) rated their inhaler teaching as good to excellent. Thirty-four (83%) reported providing inhaler teaching in their practices, either by themselves or by an allied health care professional they had personally trained. All stated they could teach inhaler technique within 5 min. Observation of FPs during the second session by certified respiratory educators found that none made critical errors and all had excellent technique. CONCLUSION: A physician inhaler education program can improve attitudes toward inhaler teaching and facilitate implementation in clinical practices. PMID- 26436911 TI - Corticosteroid therapy in critical illness due to seasonal and pandemic influenza. AB - BACKGROUND: Survey data suggest that Canadian intensivists administer corticosteroids to critically ill patients primarily in response to airway obstruction, perceived risk for adrenal insufficiency and hemodynamic instability. OBJECTIVE: To describe variables independently associated with systemic corticosteroid therapy during an influenza outbreak. METHODS: The present analysis was retrospective cohort study involving critically ill patients with influenza in two Canadian cities. Hospital records were reviewed for critically ill patients treated in the intensive care units (ICUs) of eight hospitals in Canada during the 2008 to 2009 and 2009 to 2010 influenza outbreaks. Abstracted data included demographic information, symptoms at disease onset, chronic comorbidities and baseline illness severity scores. Corticosteroid use data were extracted for every ICU day and expressed as hydrocortisone dose equivalent in mg. Multivariable regression models were constructed to identify variables independently associated with corticosteroid therapy in the ICU. RESULTS: The study cohort included 90 patients with a mean (+/- SD) age of 55.0 +/- 17.3 years and Acute Physiology and Chronic Health Evaluation II score of 19.8 +/- 8.3. Patients in 2009 to 2010 were younger with more severe lung injury but similar exposure to corticosteroids. Overall, 54% of patients received corticosteroids at a mean daily dose of 343 +/- 330 mg of hydrocortisone for 8.5 +/- 4.8 days. Variables independently associated with corticosteroid therapy in the ICU were history of airway obstruction (OR 4.8 [95% CI 1.6 to 14.9]) and hemodynamic instability (OR 4.6 [95% CI 1.2 to 17.8]). CONCLUSION: Observational data revealed that hemodynamic instability and airway obstruction were associated with corticosteroid therapy in the critical care setting, similar to a recent survey of stated practice. Efforts to determine the effects of corticosteroids in the ICU for these specific clinical situations are warranted. PMID- 26436912 TI - Past, present and future of respiratory research: A survey of Canadian health care professionals. AB - BACKGROUND: The Canadian Respiratory Health Professionals (CRHP) is the multidisciplinary health care professional group of the Canadian Lung Association. Although the CRHP has a growing number of highly qualified researchers, the landscape of their research in Canada has not been described. OBJECTIVES: To describe the level of respiratory research engagement; identify barriers and facilitators to research engagement; describe the experience and interest in developing research skills; and identify priority areas of future respiratory research among health care professionals. METHODS: An online survey of CRHP members was used to collect demographic information; barriers and facilitators to conducting research; future directions in respiratory research; and research funding and mentorship. Experience with and interest in 'upskilling' research skills were also evaluated. RESULTS: A total of 119 surveys were completed (22% response rate), of which 69 (58%) respondents were engaged in respiratory research. Reasons for not being involved in respiratory research were lack of mentorship, support and funding. The top research areas were chronic obstructive pulmonary disease (74%) and asthma (41%). The top facilitators for research engagement were amount of funding (29%) and mentorship (28%). Respondents in research positions rated their experience in research skills as high; those in nonresearch positions as low. However, both groups expressed interest in improving their research skills. CONCLUSIONS: Areas of development, such as research skills, greater funding opportunities and mentorship to increase the research capacity of health care professionals in respiratory health were identified. Health professional researchers have an important role in the national respiratory research strategy to increase interdisciplinary engagement and build collaborative teams. PMID- 26436913 TI - Povidone Iodine Rectal Preparation at Time of Prostate Needle Biopsy is a Simple and Reproducible Means to Reduce Risk of Procedural Infection. AB - Single institution and population-based studies highlight that infectious complications following transrectal ultrasound guided prostate needle biopsy (TRUS PNB) are increasing. Such infections are largely attributable to quinolone resistant microorganisms which colonize the rectal vault and are translocated into the bloodstream during the biopsy procedure. A povidone iodine rectal preparation (PIRP) at time of biopsy is a simple, reproducible method to reduce rectal microorganism colony counts and therefore resultant infections following TRUS PNB. All patients are administered three days of oral antibiotic therapy prior to biopsy. The PIRP technique involves initially positioning the patient in the standard manner for a TRUS PNB. Following digital rectal examination, 15 ml of a 10% solution of commercially available povidone iodine is mixed with 5 ml of 1% lidocaine jelly to create slurry. A 4 cmx4 cm sterile gauze is soaked in this slurry and then inserted into the rectal vault for 2 min after which it is removed. Thereafter, a disposable cotton gynecologic swab is used to paint both the perianal area and the rectal vault to a distance of 3 cm from the anus. The povidone iodine solution is then allowed to dry for 2-3 min prior to proceeding with standard transrectal ultrasonography and subsequent biopsy. This PIRP technique has been in practice at our institution since March of 2012 with an associated reduction of post-biopsy infections from 4.3% to 0.6% (p=0.02). The principal advantage of this prophylaxis regimen is its simplicity and reproducibility with use of an easily available, inexpensive agent to reduce infections. Furthermore, the technique avoids exposing patients to additional systemic antibiotics with potential further propagation of multi-drug resistant organisms. Usage of PIRP at TRUS PNB, however, is not applicable for patients with iodine or shellfish allergies. PMID- 26436914 TI - Animal Models for the Study of Comorbid Pain and Psychiatric Disorders. AB - Animal models of chronic pain have provided valuable information on the mechanisms of initiation and maintenance of the disease. Much of the research effort has targeted sensory abnormalities like hyperalgesia and allodynia. However, in the past 15 years a significant number of research groups have focused their attention on comorbid anxiety, depression and cognitive impairments that frequently emerge in chronic pain conditions. A myriad of paradigms have since then been introduced in the field to tackle multiple dimensions of rodents' behavior. Concerning emotional behavior, these include the elevated plus (and zero) maze and dark/light box for anxiety, the forced swimming and tail suspension tests for depression, and the spontaneous burrowing behavior for general well-being. Regarding the cognitive dimension, several water mazes (spatial-reference memory), attentional set-shifting test (attention and reversal learning), novel object recognition (memory), 5-choice serial reaction time task (sustained attention) and variable delay-to-signal task (impulsivity) are among the most commonly employed paradigms. The construct of some of these paradigms in the context of chronic pain will be reviewed in this chapter, with special emphasis on mood and cognitive alterations that are associated with the development of neuropathic and arthritic pain. PMID- 26436915 TI - Assessing Biases in the Evaluation of Classification Assays for HIV Infection Recency. AB - Identifying recent HIV infection cases has important public health and clinical implications. It is essential for estimating incidence rates to monitor epidemic trends and evaluate the effectiveness of interventions. Detecting recent cases is also important for HIV prevention given the crucial role that recently infected individuals play in disease transmission, and because early treatment onset can improve the clinical outlook of patients while reducing transmission risk. Critical to this enterprise is the development and proper assessment of accurate classification assays that, based on cross-sectional samples of viral sequences, help determine infection recency status. In this work we assess some of the biases present in the evaluation of HIV recency classification algorithms that rely on measures of within-host viral diversity. Particularly, we examine how the time since infection (TSI) distribution of the infected subjects from which viral samples are drawn affect performance metrics (e.g., area under the ROC curve, sensitivity, specificity, accuracy and precision), potentially leading to misguided conclusions about the efficacy of classification assays. By comparing the performance of a given HIV recency assay using six different TSI distributions (four simulated TSI distributions representing different epidemic scenarios, and two empirical TSI distributions), we show that conclusions about the overall efficacy of the assay depend critically on properties of the TSI distribution. Moreover, we demonstrate that an assay with high overall classification accuracy, mainly due to properly sorting members of the well represented groups in the validation dataset, can still perform notoriously poorly when sorting members of the less represented groups. This is an inherent issue of classification and diagnostics procedures that is often underappreciated. Thus, this work underscores the importance of acknowledging and properly addressing evaluation biases when proposing new HIV recency assays. PMID- 26436916 TI - Under What Circumstances Do Wood Products from Native Forests Benefit Climate Change Mitigation? AB - Climate change mitigation benefits from the land sector are not being fully realised because of uncertainty and controversy about the role of native forest management. The dominant policy view, as stated in the IPCC's Fifth Assessment Report, is that sustainable forest harvesting yielding wood products, generates the largest mitigation benefit. We demonstrate that changing native forest management from commercial harvesting to conservation can make an important contribution to mitigation. Conservation of native forests results in an immediate and substantial reduction in net emissions relative to a reference case of commercial harvesting. We calibrated models to simulate scenarios of native forest management for two Australian case studies: mixed-eucalypt in New South Wales and Mountain Ash in Victoria. Carbon stocks in the harvested forest included forest biomass, wood and paper products, waste in landfill, and bioenergy that substituted for fossil fuel energy. The conservation forest included forest biomass, and subtracted stocks for the foregone products that were substituted by non-wood products or plantation products. Total carbon stocks were lower in harvested forest than in conservation forest in both case studies over the 100-year simulation period. We tested a range of potential parameter values reported in the literature: none could increase the combined carbon stock in products, slash, landfill and substitution sufficiently to exceed the increase in carbon stock due to changing management of native forest to conservation. The key parameters determining carbon stock change under different forest management scenarios are those affecting accumulation of carbon in forest biomass, rather than parameters affecting transfers among wood products. This analysis helps prioritise mitigation activities to focus on maximising forest biomass. International forest-related policies, including negotiations under the UNFCCC, have failed to recognize fully the mitigation value of native forest conservation. Our analyses provide evidence for decision-making about the circumstances under which forest management provides mitigation benefits. PMID- 26436917 TI - Application of LogitBoost Classifier for Traceability Using SNP Chip Data. AB - Consumer attention to food safety has increased rapidly due to animal-related diseases; therefore, it is important to identify their places of origin (POO) for safety purposes. However, only a few studies have addressed this issue and focused on machine learning-based approaches. In the present study, classification analyses were performed using a customized SNP chip for POO prediction. To accomplish this, 4,122 pigs originating from 104 farms were genotyped using the SNP chip. Several factors were considered to establish the best prediction model based on these data. We also assessed the applicability of the suggested model using a kinship coefficient-filtering approach. Our results showed that the LogitBoost-based prediction model outperformed other classifiers in terms of classification performance under most conditions. Specifically, a greater level of accuracy was observed when a higher kinship-based cutoff was employed. These results demonstrated the applicability of a machine learning based approach using SNP chip data for practical traceability. PMID- 26436919 TI - Review of bioaerosols in indoor environment with special reference to sampling, analysis and control mechanisms. AB - Several tiny organisms of various size ranges present in air are called airborne particles or bioaerosol which mainly includes live or dead fungi and bacteria, their secondary metabolites, viruses, pollens, etc. which have been related to health issues of human beings and other life stocks. Bio-terror attacks in 2001 as well as pandemic outbreak of flue due to influenza A H1N1 virus in 2009 have alarmed us about the importance of bioaerosol research. Hence characterization i.e. identification and quantification of different airborne microorganisms in various indoor environments is necessary to identify the associated risks and to establish exposure threshold. Along with the bioaerosol sampling and their analytical techniques, various literatures revealing the concentration levels of bioaerosol have been mentioned in this review thereby contributing to the knowledge of identification and quantification of bioaerosols and their different constituents in various indoor environments (both occupational and non occupational sections). Apart from recognition of bioaerosol, developments of their control mechanisms also play an important role. Hence several control methods have also been briefly reviewed. However, several individual levels of efforts such as periodic cleaning operations, maintenance activities and proper ventilation system also serve in their best way to improve indoor air quality. PMID- 26436918 TI - Progestins Upregulate FKBP51 Expression in Human Endometrial Stromal Cells to Induce Functional Progesterone and Glucocorticoid Withdrawal: Implications for Contraceptive- Associated Abnormal Uterine Bleeding. AB - Use of long-acting progestin only contraceptives (LAPCs) offers a discrete and highly effective family planning method. Abnormal uterine bleeding (AUB) is the major side effect of, and cause for, discontinuation of LAPCs. The endometria of LAPC-treated women display abnormally enlarged, fragile blood vessels, decreased endometrial blood flow and oxidative stress. To understanding to mechanisms underlying AUB, we propose to identify LAPC-modulated unique gene cluster(s) in human endometrial stromal cells (HESCs). Protein and RNA isolated from cultured HESCs treated 7 days with estradiol (E2) or E2+ medroxyprogesterone acetate (MPA) or E2+ etonogestrel (ETO) or E2+ progesterone (P4) were analyzed by quantitative Real-time (q)-PCR and immunoblotting. HSCORES were determined for immunostained paired endometria of pre-and 3 months post-Depot MPA (DMPA) treated women and ovariectomized guinea pigs (GPs) treated with placebo or E2 or MPA or E2+MPA for 21 days. In HESCs, whole genome analysis identified a 67 gene group regulated by all three progestins, whereas a 235 gene group was regulated by E2+ETO and E2+MPA, but not E2+P4. Ingenuity pathway analysis identified glucocorticoid receptor (GR) activation as one of upstream regulators of the 235 MPA and ETO specific genes. Among these, microarray results demonstrated significant enhancement of FKBP51, a repressor of PR/GR transcriptional activity, by both MPA and ETO. q-PCR and immunoblot analysis confirmed the microarray results. In endometria of post-DMPA versus pre-DMPA administered women, FKBP51 expression was significantly increased in endometrial stromal and glandular cells. In GPs, E2+MPA or MPA significantly increased FKBP51 immunoreactivity in endometrial stromal and glandular cells versus placebo- and E2-administered groups. MPA or ETO administration activates GR signaling and increases endometrial FKBP51 expression, which could be one of the mechanisms causing AUB by inhibiting PR and GR-mediated transcription. The resultant PR and/or GR-mediated functional withdrawal may contribute to associated endometrial inflammation, aberrant angiogenesis, and bleeding. PMID- 26436921 TI - Regioselective Substitution at the 1,3- and 6,8-Positions of Pyrene for the Construction of Small Dipolar Molecules. AB - This article presents a novel asymmetrical functionalization strategy for the construction of dipolar molecules via efficient regioselective functionalization along the Z-axis of pyrene at both the 1,3- and 6,8-positions. Three asymmetrically substituted 1,3-diphenyl-6,8-R-disubsituted pyrenes were fully characterized by X-ray crystallography, photophysical properties, electrochemistry, and density functional theory calculations. PMID- 26436922 TI - Mosaic deletion of 20pter due to rescue by somatic recombination. AB - We report on a unique case of a mosaic 20pter-p13 deletion due to a somatic repair event identified by allele differentiating single nucleotide polymorphism (SNP) probes on chromosomal microarray. Small terminal deletions of 20p have been reported in a few individuals and appear to result in a variable phenotype. This patient was a 24-month-old female who presented with failure to thrive and speech delay. Chromosomal microarray analysis (CMA) performed on peripheral blood showed a 1.6 Mb deletion involving the terminus of 20p (20pter-20p13). This deletion appeared mosaic by CMA and this suspicion was confirmed by fluorescence in situ hybridization (FISH) analysis. Additionally, the deletion interval at 20p was directly adjacent to 15 Mb of mosaic copy-neutral loss of heterozygosity (LOH). The pattern of SNP probes was highly suggestive of a somatic repair event that resulted in rescue of the deleted region using the non-deleted homologue as a template. Structural mosaicism is rare and most often believed to be due to a postzygotic mechanism. This case demonstrates the additional utility of allele patterns to help distinguish mechanisms and in this case identified the possibility of either a post-zygotic repair of a germline deletion or a post zygotic deletion with somatic recombination repair in a single step. PMID- 26436920 TI - miR-142-5p and miR-130a-3p are regulated by IL-4 and IL-13 and control profibrogenic macrophage program. AB - Macrophages play a pivotal role in tissue fibrogenesis, which underlies the pathogenesis of many end-stage chronic inflammatory diseases. MicroRNAs are key regulators of immune cell functions, but their roles in macrophage's fibrogenesis have not been characterized. Here we show that IL-4 and IL-13 induce miR-142-5p and downregulate miR-130a-3p in macrophages; these changes sustain the profibrogenic effect of macrophages. In vitro, miR-142-5p mimic prolongs STAT6 phosphorylation by targeting its negative regulator, SOCS1. Blocking miR-130a relieves its inhibition of PPARgamma, which coordinates STAT6 signalling. In vivo, inhibiting miR-142-5p and increasing miR-130a-3p expression with locked nucleic acid-modified oligonucleotides inhibits CCL4-induced liver fibrosis and bleomycin-induced lung fibrosis in mice. Furthermore, macrophages from the tissue samples of patients with liver cirrhosis and idiopathic pulmonary fibrosis display increased miR-142-5p and decreased miR-130a-3p expression. Therefore, miR 142-5p and miR-130a-3p regulate macrophage profibrogenic gene expression in chronic inflammation. PMID- 26436923 TI - [Influence of weight gain during the first year after kidney transplantation in the survival of grafts and patients]. AB - BACKGROUND: After receiving a kidney allograft, patients tend to gain weight acquiring the risk associated with overweight and obesity. AIM: To compare the evolution during 10 years after transplantation of patients who gained more than 15% of their initial weight during the first year after receiving the graft with those who did not experience this increase. MATERIAL AND METHODS: Cohort study of 182 patients transplanted in a single hospital between 1981 and 2003. Demographic data, weight gain during the first year, drugs used, complications and evolution of patients and grafts were recorded. RESULTS: Seventy two patients gained more than 15% of their weight during the first year. These were discharged after receiving the graft with a lower serum creatinine than their counterparts (1.46 +/- 0.71 and 1.97 +/- 1.74 mg/dl respectively, p = 0.02). Ten years mortality with a functioning kidney was higher among weight gainers (25 and 12.7% respectively, p = 0.03). No other differences were observed between groups. CONCLUSIONS: Patients who gained more than 15% of their initial weight during the first year after receiving a kidney graft have a higher 10 years mortality with a functioning kidney. PMID- 26436924 TI - [Effects of an intervention to reduce cardiovascular risk factors in university students]. AB - BACKGROUND: Interventions aiming to reduce obesity and sedentary behaviors in young adults could be a feasible and effective approach to prevent cardiovascular diseases. AIM: To evaluate the effect of a lifestyle-based intervention on reducing cardiovascular risk factors in university students. MATERIAL AND METHODS: Sixty university students aged 21 +/- 1 years (n = 44 females) took part on a 17 weeks lifestyle intervention consisting in education about healthy lifestyles and physical training, during a curricular course about health promotion and healthy lifestyles. At baseline and at the end of the intervention participants completed a lifestyles questionnaire and provided fasting blood samples to quantify glucose and lipids profile. RESULTS: After the intervention significant reductions in the prevalence of hyperglycemia (-10.0%), high blood pressure (-16.7%) and physical inactivity (-26.7%) were observed. Moreover, a significant reduction in body weight, waist circumference, blood pressure, total cholesterol, triglycerides and an increase in HDL cholesterol were observed after intervention. CONCLUSIONS: The implementation of an intervention to promote healthy lifestyles is an effective way of reducing cardiovascular risk factors in university students. PMID- 26436925 TI - [An analysis of Chilean biomedical publications in PubMed in the years 2008 2009]. AB - BACKGROUND: During the years 2008 and 2009, 1,191 biomedical articles authored by Chilean investigators working in Chile were indexed in PubMed. AIMS: To evaluate the potential visibility of those articles, according to scientometric indexes of the journals where they were published. METHODS: Those journals where the articles had been published were identified and each journal?s Impact Factor (JIF), 5-year JIF, SCImago Journal Rank (SJR), SCImago Quartiles (Q) for 2010 and the Source Normalized Impact per Paper (SNIP) for 2008-2009 were identified. RESULTS: Three hundred and twelve articles (26,2%) were dedicated to experimental studies in animals, tissues or cells and they were classified as ?Biomedicine?, while 879 (73,8%) were classified as ?Clinical Medicine?; in both areas the main type of articles were original reports (90% and 73.6%, respectively). Revista Medica de Chile and Revista Chilena de Infectologia concentrated the greater number of publications. Articles classified in Biomedicine were published more frequently in English and in journals with higher scientometric indexes than those classified in Clinical Medicine. CONCLUSIONS: Biomedical articles dealing with clinical topics, particularly case reports, were published mostly in national journals or in foreign journals with low scientometric indexes. It can be partly attributable to the authors? interest in reaching local readers. The evaluation of research productivity should combine several scientometric indexes, selected according to the field of research, the institution's and investigators? interests, with a qualitative and multifactorial assessment. PMID- 26436926 TI - [Social security and labor absenteeism in a regional health service]. AB - BACKGROUND: Absenteism can generate important economic costs. AIM: To analyze the determinants of the time off work for sick leaves granted to workers of a regional health service. MATERIAL AND METHODS: Information about 2033 individuals, working at a health service, that were granted at least one sick leave during 2012, was analyzed. Personal identification was censored. Special emphasis was given to the type of health insurance system of the workers (public or private). RESULTS: Workers ascribed to the Chilean public health insurance system (FONASA) had 11 days more off work than their counterparts ascribed to private health insurance systems. A higher amount of time off work was observed among older subjects and women. CONCLUSIONS: Age, gender and the type of health insurance system influence the number of day off work due to sick leaves. PMID- 26436927 TI - [Association of grip strength with gender age and handedness in 116 older people]. AB - BACKGROUND: Hand grip strength could be influenced by gender, age and handedness. AIM: To describe differences in grip strength for age, gender and upper extremity handedness in non-disabled community-dwelling older adults. MATERIAL AND METHODS: We studied 47 males aged 72.3 +/- 5.6 years and 69 females 72.4 +/- 6.0 years who were divided in two age groups (65-70 and >= 71 years old). Grip strength was determined by a standardized protocol using a hand dynamometer. RESULTS: There was an inverse correlation between grip strength and age in both hands only among men (p <= 0.05). When analyzing both genders, there was a significant inverse correlation between grip strength and age only in the dominant hand (p <= 0.05). Strength was higher in the dominant hand in both genders (p <= 0.05). It was also higher in men, compared to women in the two age groups studied (p <= 0.05). CONCLUSIONS: Grip strength is higher in men than women, it decreases with age and is higher in the dominant hand. PMID- 26436928 TI - [Usefulness of antimicrobial prophylaxis with ciprofloxacin prior to flexible cystoscopy]. AB - BACKGROUND: Flexible cystoscopy is a common test in clinical practice done with or without antibiotic prophylaxis. AIM: To evaluate the efficacy of antibiotic prophylaxis with ciprofloxacin to reduce the incidence of urinary infection. MATERIAL AND METHODS: Prospective, non-randomized observational study that included 60 patients divided into two groups. Group 1 received prophylactic ciprofloxacin 500 mg, one hour prior to the procedure and group 2 did not receive prophylaxis. The presence of bacteriuria, symptoms or signs of urinary infection or attending Emergency rooms or primary care for these symptoms were recorded during the seven days after the cystoscopy. RESULTS: In groups 1 and 2, four and one patients had a positive urine culture, respectively. Only one patient in group 1 consulted in primary care for symptoms. No significant differences in symptoms or signs of urinary infection between groups were observed. CONCLUSIONS: In this group of patients, antibiotic prophylaxis with ciprofloxacin 500 mg prior to cystoscopy had no benefit. PMID- 26436929 TI - [Development of MEDUC-PG14 survey to assess postgraduate teaching in medical specialties]. AB - BACKGROUND: Feedback is one of the most important tools to improve teaching in medical education. AIM: To develop an instrument to assess the performance of clinical postgraduate teachers in medical specialties. MATERIAL AND METHODS: A qualitative methodology consisting in interviews and focus-groups followed by a quantitative methodology to generate consensus, was employed. After generating the instrument, psychometric tests were performed to assess the construct validity (factor analysis) and reliability (Cronbach?s alpha). RESULTS: Experts in medical education, teachers and residents of a medical school participated in interviews and focus groups. With this information, 26 categories (79 items) were proposed and reduced to 14 items (Likert scale 1-5) by an expert?s Delphi panel, generating the MEDUC-PG14 survey, which was answered by 123 residents from different programs of medical specialties. Construct validity was carried out. Factor analysis showed three domains: Teaching and evaluation, respectful behavior towards patients and health care team, and providing feedback. The global score was 4.46 +/- 0.94 (89% of the maximum). One teachers? strength, as evaluated by their residents was ?respectful behavior? with 4.85 +/- 0.42 (97% of the maximum). ?Providing feedback? obtained 4.09 +/- 1.0 points (81.8% of the maximum). MEDUC-PG14 survey had a Cronbach?s alpha coefficient of 0.947. CONCLUSIONS: MEDUC-PG14 survey is a useful and reliable guide for teacher evaluation in medical specialty programs. Also provides feedback to improve educational skills of postgraduate clinical teachers. PMID- 26436930 TI - [Legal recognition of transsexuality in Chile through the judicial procedure for name change]. AB - Do transsexual people in Chile have a right to have their gender identity or their sex reassignment legally recognized? The absence of any legislation on gender identity or transsexualism could lead us to believe that it is not the case. However, a quantitative review of decisions issued by Chilean courts during the last years on name-and sex-change requests filed by transsexual people reveals that most of these courts have accepted these requests. From the perspective of the well-being of transsexual people, this is a positive result. However, the fact that a few rejections exist reminds us of the need to enact an explicit legislation in this issue. Lastly, a qualitative analysis of those decisions suggests that the traditional reluctance of courts to interpret the law in a creative way has been overcome in these cases by the use of knowledge and discourses belonging to healthcare sciences. This is an example of an epistemological complementariness between medicine and law. PMID- 26436931 TI - [Opinions of medical students about complementary therapies]. AB - BACKGROUND: There is increasing national and worldwide interest on complementary therapies (CT). AIM: To describe and analyze the opinions and interest about CT among medical students. MATERIAL AND METHODS: An anonymous and voluntary survey with questions used in previous studies, was applied to students from first to fifth year. RESULTS: The survey was answered by 526 medical students, corresponding to 86% of the target population. The students knew about an average of 4.7 therapies, out of 12 displayed. The better known therapy was acupuncture, followed by homeopathy and reiki, which raised the greater interest. The knowledge and interest was higher among women, who also had a more favorable opinion about CT. The interest decreases and the proportion of unfavorable opinions increases among students of upper level courses. Forty nine percent of respondents have used CT for themselves and 22% had no experience whatsoever with them. CONCLUSIONS: In general, there is an appreciable knowledge, experience, interest and positive opinions toward CT. This favorable attitude is higher in women and decreases as career progresses. Medical students consider that they should have some approach to CT during their career. PMID- 26436932 TI - [Job satisfaction and organizational culture as predictors of absenteeism]. AB - BACKGROUND: Absenteeism caused by sick leaves generates an important economic burden. AIM: To determine if job satisfaction, psychological climate, hierarchic level and age are predictors of absenteeism caused by sick leaves. MATERIAL AND METHODS: FOCUS-93 survey that measures organizational culture and the satisfaction scale of Warr, Cook and Wall were distributed to 1387 workers of a hospital and answered by 874. Absenteeism data was obtained from the justified absenteeism registry of the Chilean Health Services. RESULTS: Absenteeism is influenced by job satisfaction and organizational culture. Age has no influence. Hierarchic level has a negative influence on absenteeism among men and a negligible effect among women. CONCLUSIONS: Those workers that are not satisfied with their work have higher rates of absenteeism. PMID- 26436933 TI - [Graves? orbitopathy in pediatrics]. AB - Graves? orbitopathy (GO) is rare in pediatric patients, however is the most common extrathyroid manifestation of Graves? disease (GD), being present in 30 67% of patients. GO is an autoimmune inflammatory disorder involving orbital connective and fatty tissues as well as the extraocular muscles. In children, GO is less common and less severe than in adults. The most common symptoms are upper eyelid retraction, conjunctival injection, and proptosis and periorbital edema. Severe complications include dysthyroid optic neuropathy, corneal ulceration and eyeball subluxation. The diagnosis is established by clinical, laboratory and imaging findings. There are no management guidelines for GO in children but adult recommendations include the assessment of clinical activity and its severity, to implement the best treatment. Supportive therapies are intended to relieve symptoms and prevent corneal damage in mild cases. Tobacco exposure should also be avoided. The first line of treatment is systemic administration of corticosteroids in active and severe cases. Other options as somatostatin use and retrobulbar radiation have not been used in children, therefore their use is not recommended. PMID- 26436934 TI - [Autoimmune diseases in type 1A diabetes mellitus]. AB - Type 1A diabetes (DM1A) is an autoimmune disease that comprises 10% of patients with diabetes mellitus. Its frequency is gradually increasing in countries like Mexico. Patients with DM1A commonly have hypothyroidism, Addison disease, celiac disease and less common diseases such as polyglandular syndrome. These diseases are related to susceptibility genes such as HLA, CTLA-4 and PTPN22, which induce central and peripheral immunologic tolerance. This review article emphasizes the importance of searching other autoimmune diseases in patients with DM1A, to improve their prognosis and quality of life. PMID- 26436935 TI - [Therapeutic monitoring of antibiotics: New methodologies: biosensors]. AB - The pharmacokinetics of antibiotics, especially in severely ill patients, may be profoundly altered due to multiple pathophysiological changes. Recent studies have shown that empiric dosing recommendations for ICU patients are inadequate to effectively treat a broad range of susceptible organisms and need to be reconsidered. Therapeutic drug monitoring (TDM) is an important mean for optimizing drug utilization and doses for the purpose of improving the clinical effectiveness. However, it is very challenging to quantify plasma antibiotic concentrations in clinical situations as a routine practice, because of the high costs and complexities associated with advanced instrumental techniques. Currently there are not routine and low cost methods to determine the presence and concentration of beta-lactam antibiotics in plasma patients in a clinical setup. Indeed, such analytical methods are based on chromatographic techniques mainly used in research. Here we describe and comment different techniques, focusing on our preliminary experience using biosensors. PMID- 26436936 TI - [A standardized practical examination for title revalidation of graduates of foreign medical schools]. AB - BACKGROUND: The University of Chile, backed by its extensive experience in Objective Structured Clinical Examinations (OSCEs), performs the practical exam to graduates of foreign medical school in this format. This test format would give more guarantees of validity and fairness as compared with the previous oral examination that was required for title revalidation. AIM: To compare the performance of graduates of foreign medical schools and last year medical students of the University of Chile in the same internal medicine OSCE. MATERIAL AND METHODS: Seventy-seven last year medical students and thirty-three graduates of foreign medical schools participated in the same Internal Medicine OSCE, but in different moments. At the end of the examination, graduates of foreign medical schools answered a questionnaire about their prior experience with OSCEs and about their perception about this type of examination. RESULTS: The performance of graduates of foreign medical schools was lower than those of our last year medical students in four of the eight stations of the examination. Graduates of foreign medical schools considered the examination objective, fair, and that it assessed skills adequately and that the degree difficulty was homogeneous for all examinees. CONCLUSIONS: The possibility of obtaining comparable results in a transparent process makes the OSCE the assessment tool of choice for title revalidation of physicians migrating from foreign countries. PMID- 26436937 TI - [A biographical sketch of Albert Szent-Gyorgyi]. AB - Albert Szent-Gyorgyi was a Hungarian biochemist and physiologist. He identified the structure and function of vitamin C, naming it as ascorbic acid. His research on cellular respiration and oxidation provided the basis for Krebs' citric acid cycle. He was awarded the Nobel Prize in 1937. With his collaborators, he discovered the biochemical basis of muscle contractility, isolating the basic proteins, giving them the name myosin and actin. Later on, he worked on the theory of carcinogenesis, linked to electron movements. He was one of the first researchers to describe the connection between free radicals and cancer. He lived a long, very complete life, defending always his opinion and freedom. PMID- 26436938 TI - [Invasive disease due to Streptococcus pyogenes in a patient with A H1N1 influenza infection. Report of one case]. AB - Bacterial superinfection is a known complication among patients affected by viral respiratory tract infections. Streptococcus pyogenes, a major bacterial agent involved in acute tonsillopharyngitis, skin and soft tissue infections, was reported as a co-infecting microorganism during the 2009 A H1N1 influenza pandemic. We report a 65-year-old male patient who evolved with multifocal pneumonia and multiple organ failure with a fatal outcome. Influenza A H1N1 was detected by a polymerase chain reaction-based technique from a tracheal aspirate sample. S. pyogenes was identified by a rapid test from a nasopharyngeal sample and isolated afterwards from a positive blood culture. PMID- 26436939 TI - [Intravascular lymphoma: Report of one case]. AB - Intravascular lymphoma is a rare subtype of extranodal diffuse large B-cell lymphoma characterized by clonal proliferation of lymphocytes inside of small and medium caliber vessels. Its incidence is estimated at one case per million. The clinical picture is very variable, but frequently has skin and central nervous system involvement. It is diagnosed by demonstrating pathological blood vessel infiltration by lymphoma cells. We report a 44 years old male presenting with fever, malaise and erythematous lesions in the abdominal wall. An abdominal wall biopsy showed dilated vascular vessels with atypical cells in their lumen, compatible with large B-cell intravascular lymphoma. He was treated with rituximab, cyclophosphamide, adriamycin, vincristine and prednisone and an autologous hematopoietic stem cell transplantation, achieving a complete remission that has lasted two years. PMID- 26436940 TI - Type I persistent proatlantal artery associated with fusiform subclavian artery aneurysm: Report of one case. AB - We report a 61 years old male presenting with a right cerebral infarction, along with a type I persistent left proatlantal artery (PA), which is a form of primitive carotid-basilar anastomosis. The patient had an absence of the ipsilateral vertebral artery (VA) and hypoplasia of the contralateral VA, while the basilar artery was supplied by the PA. Other vascular anomalies present were a fusiform aneurysm of the right subclavian artery, and an A1 segment aplasia of the hypoplastic anterior right cerebral artery, which originated from the anterior communicating artery. To our knowledge these anomalies were not described previously. PMID- 26436941 TI - [Recurrence of Tako-Tsubo syndrome. Case report]. PMID- 26436942 TI - [The BRAIN initiative: Is it only studied in computers?]. PMID- 26436943 TI - [Sedentary behaviour and physical inactivity is not the same!: An update of concepts oriented towards the prescription of physical exercise for health]. PMID- 26436945 TI - Impact of neonicotinoid seed treatment of cotton on the cotton leafhopper, Amrasca devastans (Hemiptera: Cicadellidae), and its natural enemies. AB - BACKGROUND: Neonicotinoid seed treatments suppress populations of pest insects efficiently and can enhance crop growth, but they may have negative effects on beneficial arthropods. We evaluated the effects of either imidacloprid or thiamethoxam on the abundances of a sucking pest, the cotton leafhopper (Amrasca devastans), and its arthropod predators under field conditions. We also evaluated the impact of seed treatment on transgenic cotton plant growth, with pests and natural enemies present or absent. RESULTS: Imidacloprid and thiamethoxam reduced pest abundance, with greater effects when dosages were higher. Treatment at recommended doses delayed the pest in reaching the economic damage threshold by around 10-15 days (thiamethoxam) and 20 days (imidacloprid). Recommended doses also enhanced plant growth under all tested conditions; growth is affected directly as well as via pest suppression. Neonicotinoid applications reduced abundance of beneficial arthropods, with lower populations after higher doses, but negative effects of imidacloprid were not apparent unless the manufacturer recommended dose was exceeded. CONCLUSION: Imidacloprid applied at the recommended dose of 5 g kg(-1) seed is effective against A. devastans and appears to be safer than thiamethoxam for natural enemies, and also enhances plant growth directly. We caution, however, that possible sublethal negative effects on individual beneficial arthropods were not evaluated. (c) 2015 Society of Chemical Industry. PMID- 26436944 TI - Comparative Proteomic Analysis of Aminoglycosides Resistant and Susceptible Mycobacterium tuberculosis Clinical Isolates for Exploring Potential Drug Targets. AB - Aminoglycosides, amikacin (AK) and kanamycin (KM) are second line anti tuberculosis drugs used to treat tuberculosis (TB) and resistance to them affects the treatment. Membrane and membrane associated proteins have an anticipated role in biological processes and pathogenesis and are potential targets for the development of new diagnostics/vaccine/therapeutics. In this study we compared membrane and membrane associated proteins of AK and KM resistant and susceptible Mycobacterium tuberculosis isolates by 2DE coupled with MALDI-TOF/TOF-MS and bioinformatic tools. Twelve proteins were found to have increased intensities (PDQuest Advanced Software) in resistant isolates and were identified as ATP synthase subunit alpha (Rv1308), Trigger factor (Rv2462c), Dihydrolipoyl dehydrogenase (Rv0462), Elongation factor Tu (Rv0685), Transcriptional regulator MoxR1(Rv1479), Universal stress protein (Rv2005c), 35kDa hypothetical protein (Rv2744c), Proteasome subunit alpha (Rv2109c), Putative short-chain type dehydrogenase/reductase (Rv0148), Bacterioferritin (Rv1876), Ferritin (Rv3841) and Alpha-crystallin/HspX (Rv2031c). Among these Rv2005c, Rv2744c and Rv0148 are proteins with unknown functions. Docking showed that both drugs bind to the conserved domain (Usp, PspA and SDR domain) of these hypothetical proteins and GPS-PUP predicted potential pupylation sites within them. Increased intensities of these proteins and proteasome subunit alpha might not only be neutralized/modulated the drug molecules but also involved in protein turnover to overcome the AK and KM resistance. Besides that Rv1876, Rv3841 and Rv0685 were found to be associated with iron regulation signifying the role of iron in resistance. Further research is needed to explore how these potential protein targets contribute to resistance of AK and KM. PMID- 26436946 TI - Controlling the Nanoscale Rotational Behaviors of Nanoparticles on the Cell Membranes: A Computational Model. AB - Nanoparticles prefer to bind to a membrane with a surface coated by short or rigid ligands, as shown by computer simulations. To realize such a preferred configuration, the nanoparticle can spontaneously spin itself on the membrane surface, no matter what its initial orientation is. PMID- 26436947 TI - Charge Separation and Catalytic Activity of Fe3 O4 @Ag "Nanospheres". AB - Nanospheres of Ag-coated Fe3 O4 were successfully synthesized and characterized. Photocatalytic properties of Fe3 O4 @Ag composites have been investigated using steady-state studies and laser pulse excitations. Accumulation of the electrons in the Ag shell was detected from the shift in the surface plasmon band from 430 to 405 nm, which was discharged when an electron acceptor such as O2 , Thionine (TH) or C60 was introduced into the system. Charge equilibration with redox couple such as C60 (?-) /C60 indicated the ability of these core-shell structures to carry out photocatalytic reduction reactions. As well, outer Ag layer could boost charge separation in magnetic core through dual effects of Schottky junction and localized surface plasmonic resonance (LSPR)-powered band gap breaking effect under sunlight irradiation; resulted in higher photocatalytic degradation of diphenylamine (DPA). The maximum photocatalytic degradation rate was achieved at optimum amount of Ag-NP loading to products. Adsorption studies confirmed that degradation of DPA dominantly occurred in solution. Moderately renewability of the nanocatalysts under sunlight was due to oxidation and dissolution of the outer Ag layer. PMID- 26436948 TI - Development and Characterization of Nanoembedded Microparticles for Pulmonary Delivery of Antitubercular Drugs against Experimental Tuberculosis. AB - The foremost objective of the present research study was to develop and evaluate the potential of rifampicin (RIF) and isoniazid (INH) loaded spray dried nanoembedded microparticles against experimental tuberculosis (TB). In this study, RIF-INH loaded various formulations (chitosan, guar gum, mannan, and guar gum coated chitosan) were prepared by spray drying and characterized on the basis of in vitro as well as in vivo studies. Results showed that guar gum spray dried particles showed uniform size distribution with smooth surface as compare to mannan formulations. Guar gum batches exhibited excellent flow ability attributed to their optimum moisture content and uniform size distribution. The drug release showed the biphasic pattern of release, i.e., initial burst followed by a sustained release pattern. The preferential uptake of guar gum coated formulations suggested the presence and selective uptake capability of mannose moiety to the specific cell surface of macrophages. In vivo lung distribution study showed that guar gum coated chitosan (GCNP) batches demonstrated prolonged residence at the target site and thereby improve the therapeutic utility of drug with a significant reduction in systemic toxicity. Optimized drug loaded GCNP formulation has resulted in almost 5-fold reduction of the number of bacilli as compared to control group. Histopathology study also demonstrated that none of the treated groups show any evidence of lung tissue abnormality. Hence, GCNPs could be a promising carrier for selective delivery of antitubercular drugs to alveolar macrophages with the interception of minimal side effects, for efficient management of TB. PMID- 26436949 TI - Incidence and management of myelosuppression in patients with chronic- and accelerated-phase chronic myeloid leukemia treated with omacetaxine mepesuccinate. AB - Omacetaxine mepesuccinate (Synribo) is an inhibitor of protein synthesis indicated for the treatment of patients with chronic- or accelerated-phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors. Myelosuppression is the most common and clinically significant toxicity experienced by patients treated with omacetaxine. Here, we further examine the patterns of hematologic toxicity observed in clinical trials and describe the approach to management as well as resolution of events. Omacetaxine-related myelosuppression typically occurs more frequently during induction cycles. In general, the myelosuppression observed with omacetaxine treatment is manageable and reversible, and long-term administration is feasible. Careful monitoring, dose delays and reduction in administration days, and appropriate supportive care are critical for successful management of hematologic toxicity. Concerns regarding myelosuppression, observed with many cancer treatments, should not prevent eligible patients from receiving omacetaxine, particularly CML patients with unsatisfactory responses to multiple lines of prior treatment. PMID- 26436950 TI - Regulation of triple-negative breast cancer cell metastasis by the tumor suppressor liver kinase B1. AB - Liver kinase B1 (LKB1), also known as serine/threonine kinase 11 (STK11), has been identified as a tumor suppressor in many cancers including breast. Low LKB1 expression has been associated with poor prognosis of breast cancer patients, and we report here a significant association between loss of LKB1 expression and reduced patient survival specifically in the basal subtype of breast cancer. Owing to the aggressive nature of the basal subtype as evidenced by high incidences of metastasis, the purpose of this study was to determine if LKB1 expression could regulate the invasive and metastatic properties of this specific breast cancer subtype. Induction of LKB1 expression in basal-like breast cancer (BLBC)/triple-negative breast cancer cell lines, MDA-MB-231 and BT-549, inhibited invasiveness in vitro and lung metastatic burden in an orthotopic xenograft model. Further analysis of BLBC cells overexpressing LKB1 by unbiased whole transcriptomics (RNA-sequencing) revealed striking regulation of metastasis associated pathways, including cell adhesion, extracellular matrix remodeling, and epithelial-to-mesenchymal transition (EMT). In addition, LKB1 overexpression inhibited EMT-associated genes (CDH2, Vimentin, Twist) and induced the epithelial cell marker CDH1, indicating reversal of the EMT phenotype in the MDA-MB-231 cells. We further demonstrated marked inhibition of matrix metalloproteinase 1 expression and activity via regulation of c-Jun through inhibition of p38 signaling in LKB1-expressing cells. Taken together, these data support future development of LKB1 inducing therapeutics for the suppression of invasion and metastasis of BLBC. PMID- 26436951 TI - PIK3CA mutations can initiate pancreatic tumorigenesis and are targetable with PI3K inhibitors. AB - Aberrations in the phosphoinositide 3-kinase (PI3K) signaling pathway have a key role in the pathogenesis of numerous cancers by altering cell growth, metabolism, proliferation and apoptosis. Interest in targeting the PI3K signaling cascade continues, as new agents are being clinically evaluated. PIK3CA mutations result in a constitutively active PI3K and are present in a subset of pancreatic cancers. Here we examine mutant PIK3CA-mediated pancreatic tumorigenesis and the response of PIK3CA mutant pancreatic cancers to dual PI3K/mammalian target of rapamycin (mTOR) inhibition. Two murine models were generated expressing a constitutively active PI3K within the pancreas. An increase in acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasms (PanINs) was identified. In one model these lesions were detected as early as 10 days of age. Invasive pancreatic ductal adenocarcinoma developed in these mice as early as 20 days of age. These cancers were highly sensitive to treatment with dual PI3K/mTOR inhibition. In the second model, PanINs and invasive cancer develop with a greater latency owing to a lesser degree of PI3K pathway activation in this murine model. In addition to PI3K pathway activation, increased ERK1/2 signaling is common in human pancreatic cancers. Phosphorylation of ERK1/2 was also investigated in these models. Phosphorylation of ERK1/2 is demonstrated in the pre-neoplastic lesions and invasive cancers. This activation of ERK1/2 is diminished with dual PI3K/mTOR inhibition. In summary, PIK3CA mutations can initiate pancreatic tumorigenesis and these cancers are particularly sensitive to dual PI3K/mTOR inhibition. Future studies of PI3K pathway inhibitors for patients with PIK3CA mutant pancreatic cancers are warranted. PMID- 26436952 TI - MiR expression profiles of paired primary colorectal cancer and metastases by next-generation sequencing. AB - MicroRNAs (miRs) have been recognized as promising biomarkers. It is unknown to what extent tumor-derived miRs are differentially expressed between primary colorectal cancers (pCRCs) and metastatic lesions, and to what extent the expression profiles of tumor tissue differ from the surrounding normal tissue. Next-generation sequencing (NGS) of 220 fresh-frozen samples, including paired primary and metastatic tumor tissue and non-tumorous tissue from 38 patients, revealed expression of 2245 known unique mature miRs and 515 novel candidate miRs. Unsupervised clustering of miR expression profiles of pCRC tissue with paired metastases did not separate the two entities, whereas unsupervised clustering of miR expression profiles of pCRC with normal colorectal mucosa demonstrated complete separation of the tumor samples from their paired normal mucosa. Two hundred and twenty-two miRs differentiated both pCRC and metastases from normal tissue samples (false discovery rate (FDR) <0.05). The highest expressed tumor-specific miRs were miR-21 and miR-92a, both previously described to be involved in CRC with potential as circulating biomarker for early detection. Only eight miRs, 0.5% of the analysed miR transcriptome, were differentially expressed between pCRC and the corresponding metastases (FDR <0.1), consisting of five known miRs (miR-320b, miR-320d, miR-3117, miR-1246 and miR-663b) and three novel candidate miRs (chr 1-2552-5p, chr 8-20656-5p and chr 10-25333-3p). These results indicate that previously unrecognized candidate miRs expressed in advanced CRC were identified using NGS. In addition, miR expression profiles of pCRC and metastatic lesions are highly comparable and may be of similar predictive value for prognosis or response to treatment in patients with advanced CRC. PMID- 26436953 TI - Using community-based participatory research in patient-centered outcomes research to address health disparities in under-represented communities. AB - The emergence of patient-centered outcomes research (PCOR) has created a paradigm shift in the way health outcomes research is designed, conducted and disseminated. While PCOR expands the potential for patients to play a key advisory role in every aspect of the research process, community-based participatory research (CBPR) has long provided this opportunity for engaging communities in research. CBPR is an excellent tool for achieving PCOR goals of improving the health of all people by providing them with evidence-based information for making informed healthcare decisions. We propose ways by which PCOR can effectively use CBPR principles to engage patients in general, and specifically patients from underserved communities. The hope is that this will help to reduce and eventually eliminate health disparities. PMID- 26436955 TI - Disappearing bone disease of the humerus and the cervico-thoracic spine: a case report with 42-year follow-up. AB - BACKGROUND CONTEXT: Disappearing bone disease (DBD) is a rare idiopathic musculoskeletal disorder that is distinguished by bone resorption without bone formation, vascular or lymphatic vessel proliferation, and soft-tissue swelling. Long-term follow-up of a patient with DBD has rarely been reported in the literature. PURPOSE: The following is a case report of a female patient with DBD of the humerus and the spine who was followed for 42 years, documenting the progression of the disease and outcomes. STUDY DESIGN: Case report. METHODS: A review of the medical records since the time of initial hospital admission throughout follow-up was performed. RESULTS: A female patient was first seen at our institution at the age of 14. She later developed DBD of the humerus and the spine. The initial difficulty encountered was reaching the diagnosis, and later on with management of the patient as the disease progressed. The case was complicated by syrinx and arachnoid cyst formation, which caused neurologic changes leading to tetraplegia and shunt infection. The patient's inability to form a solid fusion mass led to repeated implant loosening and progressive deformity despite efforts made to stabilize both the humerus and the spine. The treatment modalities used were oral bisphosphonates, rhBMP, repeated surgeries, and instrumentation with adjunct bone graft and substitutes. At the age of 56 years, the patient died because of septicemia secondary to urinary tract infection from tetraplegia. CONCLUSIONS: To our knowledge, this is the first report documenting a 42-year follow-up of a patient with DBD of the humerus and the spine. Our report showed that DBD greatly affects the quality of life of the patient. Close follow-up, a multidisciplinary approach, and supportive care are stressed when managing patients with DBD. PMID- 26436956 TI - Is dysphagia an orthopedic problem?--Yes, it could be! PMID- 26436954 TI - Transcriptome profiling reveals divergent expression shifts in brown and white adipose tissue from long-lived GHRKO mice. AB - Mice lacking the growth hormone receptor (GHRKO) exhibit improved lifespan and healthspan due to loss of growth hormone signaling. Both the distribution and activity of brown and white adipose tissue (BAT and WAT) are altered in GHRKO mice, but the contribution of each tissue to age-related phenotypes has remained unclear. We therefore used whole-genome microarrays to evaluate transcriptional differences in BAT and WAT depots between GHRKO and normal littermates at six months of age. Our findings reveal a unique BAT transcriptome as well as distinctive responses of BAT to Ghr ablation. BAT from GHRKO mice exhibited elevated expression of genes associated with mitochondria and metabolism, along with reduced expression of genes expressed by monocyte-derived cells (dendritic cells [DC] and macrophages). Largely the opposite was observed in WAT, with increased expression of DC-expressed genes and reduced expression of genes associated with metabolism, cellular respiration and the mitochondrial inner envelope. These findings demonstrate divergent response patterns of BAT and WAT to loss of GH signaling in GHRKO mice. These patterns suggest both BAT and WAT contribute in different ways to phenotypes in GHRKO mice, with Ghr ablation blunting inflammation in BAT as well as cellular metabolism and mitochondrial biogenesis in WAT. PMID- 26436957 TI - Radiofrequency ablation of a rare pathology: vertebral intraosseous lipoma. PMID- 26436958 TI - The complete mitochondrial genome sequence of Nemateleotris decora (gobiiformes, gobiidae). AB - We determined the mitochondrial genome (mitogenome) sequence of Nemateleotris decora by using a long polymerase chain reaction (PCR) method and next-generation sequence (NGS) technology. The total length of N. decora mitogenome is 16 502 bp, consisting of 13 protein-coding genes, 22 transfer RNAs, two ribosomal RNAs genes, and a non-coding control region. The overall base composition of N. decora is 25.22% for A, 25.90% for T, 30.69% for G, and 18.19% for C. Our results showed the complete mitogenome is a good marker for the phylogenetic study. PMID- 26436959 TI - Workplace interventions to prevent work disability in workers on sick leave. AB - BACKGROUND: Work disability has serious consequences for individuals as well as society. It is possible to facilitate resumption of work by reducing barriers to return to work (RTW) and promoting collaboration with key stakeholders. This review was first published in 2009 and has now been updated to include studies published up to February 2015. OBJECTIVES: To determine the effectiveness of workplace interventions in preventing work disability among sick-listed workers, when compared to usual care or clinical interventions. SEARCH METHODS: We searched the Cochrane Work Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO databases on 2 February 2015. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of workplace interventions that aimed to improve RTW for disabled workers. We only included studies where RTW or conversely sickness absence was reported as a continuous outcome. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias of the studies. We performed meta-analysis where possible, and we assessed the quality of evidence according to GRADE criteria. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 14 RCTs with 1897 workers. Eight studies included workers with musculoskeletal disorders, five workers with mental health problems, and one workers with cancer. We judged six studies to have low risk of bias for the outcome sickness absence.Workplace interventions significantly improved time until first RTW compared to usual care, moderate-quality evidence (hazard ratio (HR) 1.55, 95% confidence interval (CI) 1.20 to 2.01). Workplace interventions did not considerably reduce time to lasting RTW compared to usual care, very low-quality evidence (HR 1.07, 95% CI 0.72 to 1.57). The effect on cumulative duration of sickness absence showed a mean difference of -33.33 (95% CI -49.54 to -17.12), favouring the workplace intervention, high-quality evidence. One study assessed recurrences of sick leave, and favoured usual care, moderate-quality evidence (HR 0.42, 95% CI 0.21 to 0.82). Overall, the effectiveness of workplace interventions on work disability showed varying results.In subgroup analyses, we found that workplace interventions reduced time to first and lasting RTW among workers with musculoskeletal disorders more than usual care (HR 1.44, 95% CI 1.15 to 1.82 and HR 1.77, 95% CI 1.37 to 2.29, respectively; both moderate-quality evidence). In studies of workers with musculoskeletal disorders, pain also improved (standardised mean difference (SMD) -0.26, 95% CI -0.47 to -0.06), as well as functional status (SMD -0.33, 95% CI 0.58 to -0.08). In studies of workers with mental health problems, there was a significant improvement in time until first RTW (HR 2.64, 95% CI 1.41 to 4.95), but no considerable reduction in lasting RTW (HR 0.79, 95% CI 0.54 to 1.17). One study of workers with cancer did not find a considerable reduction in lasting RTW (HR 0.88, 95% CI 0.53 to 1.47).In another subgroup analysis, we did not find evidence that offering a workplace intervention in combination with a cognitive behavioural intervention (HR 1.93, 95% CI 1.27 to 2.93) is considerably more effective than offering a workplace intervention alone (HR 1.35, 95% CI 1.01 to 1.82, test for subgroup differences P = 0.17).Workplace interventions did not considerably reduce time until first RTW compared with a clinical intervention in workers with mental health problems in one study (HR 2.65, 95% CI 1.42 to 4.95, very low-quality evidence). AUTHORS' CONCLUSIONS: We found moderate-quality evidence that workplace interventions reduce time to first RTW, high-quality evidence that workplace interventions reduce cumulative duration of sickness absence, very low-quality evidence that workplace interventions reduce time to lasting RTW, and moderate-quality evidence that workplace interventions increase recurrences of sick leave. Overall, the effectiveness of workplace interventions on work disability showed varying results. Workplace interventions reduce time to RTW and improve pain and functional status in workers with musculoskeletal disorders. We found no evidence of a considerable effect of workplace interventions on time to RTW in workers with mental health problems or cancer.We found moderate-quality evidence to support workplace interventions for workers with musculoskeletal disorders. The quality of the evidence on the effectiveness of workplace interventions for workers with mental health problems and cancer is low, and results do not show an effect of workplace interventions for these workers. Future research should expand the range of health conditions evaluated with high-quality studies. PMID- 26436960 TI - Self-reported symptoms and risk factors for digital ischaemia among international world-class beach volleyball players. AB - The prevalence of ischaemia-related symptoms is remarkably high among elite indoor volleyball players. Since the exposure to sport-specific demands may be higher in beach volleyball compared to indoor volleyball, the aim of this study was to assess the prevalence of ischaemia-related symptoms and associated risk factors among world-class beach volleyball players. Therefore, a questionnaire survey was performed among beach volleyball players active during the 2013 Grand Slam Beach Volleyball in the Netherlands. In total, 60 of the 128 beach volleyball players (47%) participated: 26 males and 34 females from 17 countries. The self-reported prevalence of cold or blue or pale digits in the dominant hand during or immediately after practice or competition was 38% (n = 23). Two risk factors were independently associated with symptoms of blue or pale digits: more than 14 years playing volleyball (odds ratio (OR) 4.42, 90% confidence interval (90% CI) 1.30-15.07) and sex (female) (OR 4.62, 90% CI 1.15-18.57). In conclusion, the prevalence of symptoms associated with digital ischaemia is high among international world-class beach volleyball players. Female sex and the length of the volleyball career were independently associated with an increased risk of ischaemia-related symptoms. The high prevalence of these seemingly innocuous symptoms and possible associated risk factors warrant regular monitoring since early detection can potentially prevent thromboembolic complications and irreversible tissue damage. PMID- 26436961 TI - VBN-based nomograms provide critical voiding parameters which can be used for invasive or non-invasive flow interpretation of women at risk of obstruction over time. AB - AIMS: To design a simple office-based method to evaluate characteristic parameters from free uroflowmetries (FF) or pressure flow studies (PFs). This method can be applied by any physician to any recording, for instance in the follow-up of women at risk of developing outflow obstruction over time after surgical interventions. METHOD: Using pressure-flow studies (PFs), a reliable evaluation of urethral obstruction (U) and detrusor contractility (k) parameters could be obtained from the maximum flow rate and detrusor pressure at maximum flow rate. Nomograms for these parameters were derived from theoretical computations using the VBN model. Then, to allow an evaluation of the real urethral obstruction, a protocol was designed incorporating FF data in the follow up of women suspected of urethral obstruction. RESULTS: Two nomograms were obtained: (1) A urethral obstruction nomogram allowing to define a Woman Obstruction Index (WOI = pdet.Qmax - 0.5*Qmax ) which has the same structure than the A-G number in men. (2) A detrusor contractility nomogram which was generalized to all initial bladder volumes. The curves were fitted by algebraic equations easily programmable on any handheld device. CONCLUSION: Using a mathematical model of micturition and data extracted from PFs, two nomograms on urethral obstruction and detrusor contractility were designed. This tool offers a rapid and practical method for the clinician to follow women at risk of obstruction over time. Its applications will be the purpose of further studies. Neurourol. Urodynam. 36:37-42, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26436962 TI - Use of Whole-Exome Sequencing for Diagnosis of Limb-Girdle Muscular Dystrophy: Outcomes and Lessons Learned. AB - IMPORTANCE: To our knowledge, the efficacy of transferring next-generation sequencing from a research setting to neuromuscular clinics has never been evaluated. OBJECTIVE: To translate whole-exome sequencing (WES) to clinical practice for the genetic diagnosis of a large cohort of patients with limb-girdle muscular dystrophy (LGMD) for whom protein-based analyses and targeted Sanger sequencing failed to identify the genetic cause of their disorder. DESIGN, SETTING, AND PARTICIPANTS: We performed WES on 60 families with LGMDs (100 exomes). Data analysis was performed between January 6 and December 19, 2014, using the xBrowse bioinformatics interface (Broad Institute). Patients with LGMD were ascertained retrospectively through the Institute for Neuroscience and Muscle Research Biospecimen Bank between 2006 and 2014. Enrolled patients had been extensively investigated via protein studies and candidate gene sequencing and remained undiagnosed. Patients presented with more than 2 years of muscle weakness and with dystrophic or myopathic changes present in muscle biopsy specimens. MAIN OUTCOMES AND MEASURES: The diagnostic rate of LGMD in Australia and the relative frequencies of the different LGMD subtypes. Our central goals were to improve the genetic diagnosis of LGMD, investigate whether the WES platform provides adequate coverage of known LGMD-related genes, and identify new LGMD-related genes. RESULTS: With WES, we identified likely pathogenic mutations in known myopathy genes for 27 of 60 families. Twelve families had mutations in known LGMD-related genes. However, 15 families had variants in disease-related genes not typically associated with LGMD, highlighting the clinical overlap between LGMD and other myopathies. Common causes of phenotypic overlap were due to mutations in congenital muscular dystrophy-related genes (4 families) and collagen myopathy-related genes (4 families). Less common myopathies included metabolic myopathy (2 families), congenital myasthenic syndrome (DOK7), congenital myopathy (ACTA1), tubular aggregate myopathy (STIM1), myofibrillar myopathy (FLNC), and mutation of CHD7, usually associated with the CHARGE syndrome. Inclusion of family members increased the diagnostic efficacy of WES, with a diagnostic rate of 60% for "trios" (an affected proband with both parents) vs 40% for single probands. A follow-up screening of patients whose conditions were undiagnosed on a targeted neuromuscular disease-related gene panel did not improve our diagnostic yield. CONCLUSIONS AND RELEVANCE: With WES, we achieved a diagnostic success rate of 45.0% in our difficult-to-diagnose cohort of patients with LGMD. We expand the clinical phenotypes associated with known myopathy genes, and we stress the importance of accurate clinical examination and histopathological results for interpretation of WES, with many diagnoses requiring follow-up review and ancillary investigations of biopsy specimens or serum samples. PMID- 26436963 TI - Possible Subclinical Leaflet Thrombosis in Bioprosthetic Aortic Valves. AB - BACKGROUND: A finding of reduced aortic-valve leaflet motion was noted on computed tomography (CT) in a patient who had a stroke after transcatheter aortic valve replacement (TAVR) during an ongoing clinical trial. This finding raised a concern about possible subclinical leaflet thrombosis and prompted further investigation. METHODS: We analyzed data obtained from 55 patients in a clinical trial of TAVR and from two single-center registries that included 132 patients who were undergoing either TAVR or surgical aortic-valve bioprosthesis implantation. We obtained four-dimensional, volume-rendered CT scans along with data on anticoagulation and clinical outcomes (including strokes and transient ischemic attacks [TIAs]). RESULTS: Reduced leaflet motion was noted on CT in 22 of 55 patients (40%) in the clinical trial and in 17 of 132 patients (13%) in the two registries. Reduced leaflet motion was detected among patients with multiple bioprosthesis types, including transcatheter and surgical bioprostheses. Therapeutic anticoagulation with warfarin, as compared with dual antiplatelet therapy, was associated with a decreased incidence of reduced leaflet motion (0% and 55%, respectively, P=0.01 in the clinical trial; and 0% and 29%, respectively, P=0.04 in the pooled registries). In patients who were reevaluated with follow-up CT, restoration of leaflet motion was noted in all 11 patients who were receiving anticoagulation and in 1 of 10 patients who were not receiving anticoagulation (P<0.001). There was no significant difference in the incidence of stroke or TIA between patients with reduced leaflet motion and those with normal leaflet motion in the clinical trial (2 of 22 patients and 0 of 33 patients, respectively; P=0.16), although in the pooled registries, a significant difference was detected (3 of 17 patients and 1 of 115 patients, respectively; P=0.007). CONCLUSIONS: Reduced aortic-valve leaflet motion was shown in patients with bioprosthetic aortic valves. The condition resolved with therapeutic anticoagulation. The effect of this finding on clinical outcomes including stroke needs further investigation. (Funded by St. Jude Medical and Cedars-Sinai Heart Institute; Portico-IDE ClinicalTrials.gov number, NCT02000115; SAVORY registry, NCT02426307; and RESOLVE registry, NCT02318342.). PMID- 26436964 TI - Adverse drug reactions in Ghanaian children: review of reports from 2000 to 2012 in VigiBase. AB - OBJECTIVE: The aim of this article is to describe adverse drug reactions (ADRs) reported for children aged 0 - 17 years in Ghana. METHODS: Paediatric reports submitted by the Ghana National Centre for Pharmacovigilance to the World Health Organisation (WHO) Global ADR database, VigiBase up to December 2012 were extracted. The data were analysed for number of reports per year, types of reporters and suspected ADRs and drugs. RESULTS: A total of 343 reports for children were received during the period. The drug classes most frequently reported were vaccines (115, 31%), antimalarials (106, 28%) and antibiotics (57, 15%). Of the top 20 individual drugs, 19 were anti-infectives. The most frequently reported ADRs were injection site infection, fever and rash. There were 23 deaths reported, and antimalarials were implicated in 12 cases. CONCLUSIONS: Vaccines, antimalarials and antibiotics are the leading medicines reported to cause ADRs in Ghanaian children. There was a high mortality rate, with many of the deaths due to causes explained in the individual case safety reports. PMID- 26436965 TI - Psoriasis disease severity affects patient satisfaction with treatment. AB - BACKGROUND: Patients with psoriasis are often dissatisfied with available treatments, but contributing factors are not well defined. OBJECTIVE: Examine relationships between psoriasis severity, patient characteristics, and treatment satisfaction. METHODS: Patients with psoriasis were classified into mild and moderate-to-severe groups based on self-reported data. Demographics, comorbidities, symptoms, and multiple treatment satisfaction outcomes were compared between groups. Predictors of patient satisfaction with treatment were examined using linear regression models. RESULTS: The analyses included 773 patients (407 mild; 366 moderate-to-severe). The percentage of patients reporting satisfaction with treatment was low overall, ranging from 8.6% to 61.7% for the mild and 13.9% to 49.5% for the moderate-to-severe group. Satisfaction among biologics users was also low (<=53%; 50% of satisfaction rates <40%). Regression results consistently showed greater dissatisfaction with current treatment among moderately to severely affected patients. CONCLUSION: Many psoriasis patients were dissatisfied with their treatment; moderate-to-severe patients expressed significantly less satisfaction than mild patients. PMID- 26436966 TI - Beta blocker treatment for infantile hemangiomas. AB - Infantile hemangiomas (IH) are common childhood vascular tumors. Treatment of IH has undergone rapid change in recent years. Since 2008, oral propranolol has been used to treat complicated IH and has proven superior to previously used therapies. More recently, the efficacy of other systemic beta blockers, specifically atenolol and nadolol, has been reported. In addition, topical timolol solution has been effective for treatment of smaller, more superficial IH. The purpose of this article is to review the current literature of beta blocker therapy for IH. PMID- 26436967 TI - Successful treatment of psoriasis with ustekinumab in patients with multiple sclerosis. AB - Psoriasis is a chronic inflammatory disease, evolving from a complex interplay of genetic and environmental factors. In the recent years, we have seen much progress in understanding the immunopathogenesis of psoriasis, paving the way for new therapies with biologics. Currently, the most commonly used biologics in psoriasis are TNF inhibitors etanercept, infliximab and adalimumab, and the IL 12/23 inhibitor ustekinumab. As TNF inhibitors are contraindicated in patients with multiple sclerosis, ustekinumab remained the only biologic available for these patient before the recent approval of Secukinumab, an IL-17A inhibitor. Herein we report two patients with multiple sclerosis and comorbid psoriasis successfully treated with ustekinumab without progression of their multiple sclerosis. Our cases demonstrate that ustekinumab is a reasonably safe choice in this patient population. We also briefly reviewed new therapies currently under investigation, which will undoubtedly further expand our armamentarium for the treatment of psoriasis in patients with neuromuscular diseases. PMID- 26436968 TI - Acquired cutis laxa associated with cutaneous mastocytosis. AB - Cutis laxa is characterized by dramatic wrinkling of skin that is lacking in elasticity due to inherent defects in dermal elastic fibers. Cutis laxa can be caused by genetic and metabolic disorders. It can also be acquired, possibly resulting from inflammatory processes with destruction of elastic fibers. This report describes a 26-year old woman who developed acquired cutis laxa and cutaneous mastocytosis leading to premature aging. She represents a unique co occurrence of these two separate disease entities. To our knowledge, there has been only one published case report of acquired cutis laxa occurring in association with urticaria pigmentosa in a 4-year old girl. Our case would be a second case that exhibits the coexistence of these two disorders in an adult female. PMID- 26436969 TI - Alopecia as the Presenting Symptom of Syphilis. AB - Alopecia can be one of the many symptoms of secondary syphilis and the clinical presentations include essential syphilitic alopecia or symptomatic syphilitic alopecia. In this report, we present a case of a patient with essential syphilitic alopecia whose sole presenting symptom of syphilis was alopecia. Despite an initial negative rapid plasma reagin (RPR) test, he was ultimately found to have syphilis on scalp biopsy. His alopecia improved following treatment with benzathine penicillin. This presentation serves as a reminder to clinicians to be cognizant of alopecia as a presenting sign of syphilis. A review of the specificity and sensitivity of the typical tests used for the diagnosis is presented. PMID- 26436970 TI - Elevated levels of antibodies against phosphatidylserine/prothrombin complex and/or cardiolipin associated with infection and recurrent purpura in a child: a forme fruste of antiphospholipid syndrome? AB - Antiphospholipid syndrome is an autoimmune disorder characterized by the occurrence of venous and arterial thrombosis, as well as morbidity in pregnancy, in the presence of anti-phospholipid antibodies. The diagnosis of antiphospholipid syndrome is usually established based on clinical and laboratory findings by strictly following the 2006 Sapporo classification. However, the diagnosis remains challenging owing to the ongoing debates on the serological criteria. We report a case we describe as forme fruste antiphospholipid syndrome in which these criteria were not fulfilled. Purpura appeared repeatedly in a female infant starting from the age of 6 months and following episodes of upper respiratory infections and vaccinations. The levels of anti-cardiolipin IgG antibodies and anti-phosphatidylserine/prothrombin complex antibodies were elevated in accordance with these events. Histopathological evaluation revealed multiple small vessel thrombi in the dermis and adipose tissue. After 2 weeks of treatment with aspirin and heparin, the cutaneous symptoms subsided. Infection has long been associated with antiphospholipid syndrome, and anti phosphatidylserine/prothrombin antibodies are considered a new marker for the diagnosis of antiphospholipid syndrome. Forme fruste antiphospholipid syndrome should be considered even if the antiphospholipid syndrome diagnostic criteria are not completely fulfilled, especially in the presence of elevated levels of anti-phosphatidylserine/prothrombin antibodies and known preceding infections. PMID- 26436971 TI - A case of hair re-pigmentation from a scalp melanoma. AB - Hair re-pigmentation in adults is a rare phenomenon. We describe a 58-year-old woman who developed hair re-pigmentation on her vertex scalp as a marker of underlying melanoma. Histopathology revealed a nodular melanoma that was surrounding but not invading follicular epithelium. To our knowledge, there have only been 4 other previously published cases describing hair re-pigmentation in the setting of scalp melanoma. Focal hair re-pigmentation in adults should prompt a thorough evaluation for an underlying melanoma. PMID- 26436972 TI - Linear acral pseudolymphomatous angiokeratoma of children with associated nail dystrophy. AB - Acral pseudolymphomatous angiokeratoma of children (APACHE) is a rare entity that typically occurs on the extremities of young females. Although linear arrangement of cutaneous lesions has been rarely reported, accompanying nail dystrophy has not been linked with this condition to our knowledge. We describe a case of linearly-oriented infiltrative papules and nodules on the index finger of a young female with associated onychodystrophy. Histology demonstrated a heavy lymphocytic infiltrate with plasma cells and proliferation of blood vessels consistent with APACHE. Our case is unique given the linear array of cutaneous lesions and associated nail dystrophy. PMID- 26436973 TI - "Cyrano nose" associated with hepatic hemangiomas successfully treated with propranolol. AB - Hemangioma of the nasal tip is commonly described as "Cyrano nose" and his treatment is extremely difficult because of its location and possible severe aesthetic complications like definitive nasal deformation. We describe a patient who presented at two months of age with a "Cyrano nose" associated with multiple hepatic and cutaneous hemangiomas, which completely resolved after therapy with propranolol. Treatment was well tolerated and aesthetic result was excellent. PMID- 26436974 TI - Blue rubber bleb nevus syndrome: a rare multisystem affliction. AB - About 200 cases of blue rubber bleb nevus syndrome (BRBNS) have been reported in the literature. The disorder affects both sexes equally and the occurrence is mostly sporadic except for a few reports of cases with autosomal dominant inheritance pattern. Herein we report an 11-year-old girl with progressive BRBNS and onset at 5 years of age. PMID- 26436975 TI - A case of acanthosis nigricans coexisting with mycosis fungoides. AB - Acanthosis nigricans maligna (ANM) is a paraneoplastic phenomenon most commonly associated with visceral adenocarcinoma, in particular, gastric adenocarcinoma. Clinically, AMN is characterized by rapidly progressive symmetrical skin thickening and hyperpigmentation of the intertriginous areas with peripheral acrochorda. The diagnosis is made by a detailed medical work-up for occult malignancies with particular emphasis on endocrinological diseases. We report a 67-year-old man that presented clinically with acanthosis nigricans, in which a subsequent diagnosis of mycosis fungoides was made. PMID- 26436976 TI - [Not Available]. AB - Graham-Little-Piccardi-Lassueur syndrome is a rare lichenoid dermatosis. It is characterized by the triad of scarring alopecia of the scalp, alopecia of the axilla and or groin, and keratotic follicular papules of the body. The present paper reports on two cases affecting young women. Histopathological findings suggest the disorder represents a generalized form of lichen planus follicularis. PMID- 26436977 TI - Histiocytoid Sweet syndrome treated with azathioprine: a case report. AB - Histiocytoid Sweet syndrome (HSS) is a rare histologic variation of Sweet syndrome (SS) predominantly exhibiting mononuclear histiocytoid cells instead of neutrophils. We report a 22-year-old woman with HSS, who, after minimal improvement with colchicine and dapsone, had significant improvement of her cutaneous eruption and systemic symptoms following empiric treatment with azathioprine. Since azathioprine has historically been known to cause SS, this case highlights a previously unreported treatment response for the histiocytoid variant. PMID- 26436978 TI - A fibrous papule with abundant CD34-immunoreactive ganglion-like multinucleated giant cells: a case report and review of the literature. AB - Fibrous papules present clinically as benign, asymptomatic, dome-shaped, flesh colored papules on the face. Histologically, fibrous papules are characterized by fibrous stroma with fibroblasts and dilated blood vessels. Multiple variants of fibrous papules have been reported. Although scattered multinucleated cells in fibrous papules have been well described, we report a fibrous papule with abundant multinucleated ganglion-like giant cells that were immunoreactive with CD34. Recognition of such fibrous papule variants is important to avoid misdiagnosis as potentially more worrisome and/or aggressive melanocytic, soft tissue, or neural lesions that may require more aggressive treatment. Indeed, fibrous papules do not commonly appear on the differential diagnosis for lesions with multinucleated giant cells or ganglion-like cells and consideration should be given to their inclusion in the appropriate clinical setting. PMID- 26436979 TI - Jejunal adenocarcinoma with cutaneous metastasis. AB - Small bowel adenocarcinoma (SBA) is a rare primary gastrointestinal malignancy. We present a 60-year old man who developed a cutaneous metastasis of jejunal adenocarcinoma to his neck. This case highlights the clinicopathologic and immunophenotypic features of this uncommon cutaneous metastasis. PMID- 26436980 TI - Unilateral hyperkeratotic plaques along blaschko lines. AB - Epidermolytic ichthyosis (or epidermolytic hyperkeratosis) classically presents with erythroderma and increased fragility (blistering) at birth or soon thereafter. In later life, erythroderma and blistering improve gradually and the clinical picture is dominated by hyperkeratotic plaques in flexures and around joints. Linear epidermolytic hyperkeratosis is a unique, uncommon clinical variant and the absence of erythroderma and blistering are its hallmark. Linear lesions may be localized or generalized andunilateral or bilateral. Herein we report a 6-year-old girl with unilateral epidermolytic ichthyosis. PMID- 26436981 TI - [Not Available]. AB - Pityriasis rotunda disorder of keratinization clinically described as persistent, large, sharply defined circular patches of ichthyosiform scaling with no inflammatory changes. Patients with pityriasis rotunda may be classified into one of two groups, which are based on ethnicity, number of lesions, family history, and association with systemic diseases. A 45-year-old woman presented with asymptomatic, sharply-demarcated, round, scaly, hyperpigmented lesions on her leg that had been present for several years. Our patient did not have systemic disease or malignancy and so does not fit into groups already described. PMID- 26436982 TI - Early diagnosis of subungual squamous cell carcinoma of the hallux. AB - Primary subungual squamous cell carcinoma (SCC) of the toe is rare in the literature and frequently late or misdiagnosed. Lack of awareness among physicians of the specific clinical findings, the indolent course of the disease, and the high prevalence of benign conditions of the nail unit may account for delays in diagnosis. In addition to difficulties in identifying the true incidence of this tumor, a standardized therapeutic approach does not currently exist. We present a case of subungual SCC of the first toe without bone invasion. The tumor was diagnosed early, treated with conservative surgical excision, and showed no recurrence or metastasis after 2 years of follow-up. PMID- 26436983 TI - Monitoring in real time the cytotoxic effect of Clostridium difficile upon the intestinal epithelial cell line HT29. AB - The incidence and severity of Clostridium difficile infections (CDI) has been increased not only among hospitalized patients, but also in healthy individuals traditionally considered as low risk population. Current treatment of CDI involves the use of antibiotics to eliminate the pathogen, although recurrent relapses have also been reported. For this reason, the search of new antimicrobials is a very active area of research. The strategy to use inhibitors of toxin's activity has however been less explored in spite of being a promising option. In this regard, the lack of fast and reliable in vitro screening methods to search for novel anti-toxin drugs has hampered this approach. The aim of the current study was to develop a method to monitor in real time the cytotoxicity of C. difficile upon the human colonocyte-like HT29 line, since epithelial intestinal cells are the primary targets of the toxins. The label-free, impedance based RCTA (real time cell analyser) technology was used to follow overtime the behaviour of HT29 in response to C. difficile LMG21717 producing both A and B toxins. Results obtained showed that the selection of the medium to grow the pathogen had a great influence in obtaining toxigenic supernatants, given that some culture media avoided the release of the toxins. A cytotoxic dose- and time dependent effect of the supernatant obtained from GAM medium upon HT29 and Caco2 cells was detected. The sigmoid-curve fit of data obtained with HT29 allowed the calculation of different toxicological parameters, such as EC50 and LOAEL values. Finally, the modification in the behaviour of HT29 reordered in the RTCA was correlated with the cell rounding effect, typically induced by these toxins, visualized by time-lapsed captures using an optical microscope. Therefore, this RTCA method developed to test cytotoxicity kinetics of C. difficile supernatants upon IEC could be a valuable in vitro model for the screening of new anti-CDI agents. PMID- 26436984 TI - Normal and high eNOS levels are detrimental in both mild and severe cardiac pressure-overload. AB - Nitric oxide (NO) produced by endothelial NO synthase (eNOS) exerts beneficial effects in a variety of cardiovascular disease states. Studies on the benefit of eNOS activity in pressure-overload cardiac hypertrophy and dysfunction produced by aortic stenosis are equivocal, which may be due to different expression levels of eNOS or different severities of pressure-overload. Consequently, we investigated the effects of eNOS-expression level on cardiac hypertrophy and dysfunction produced by mild or severe pressure-overload. To unravel the impact of eNOS on pressure-overload cardiac dysfunction we subjected eNOS deficient, wildtype and eNOS overexpressing transgenic (eNOS-Tg) mice to 8weeks of mild or severe transverse aortic constriction (TAC) and studied cardiac geometry and function at the whole organ and tissue level. In both mild and severe TAC, lack of eNOS ameliorated, whereas eNOS overexpression aggravated, TAC-induced cardiac remodeling and dysfunction. Moreover, the detrimental effects of eNOS in severe TAC were associated with aggravation of TAC-induced NOS-dependent oxidative stress and by further elevation of eNOS monomer levels, consistent with enhanced eNOS uncoupling. In the presence of TAC, scavenging of reactive oxygen species with N-acetylcysteine reduced eNOS S-glutathionylation, eNOS monomer and NOS dependent superoxide levels in eNOS-Tg mice to wildtype levels. Accordingly, N acetylcysteine improved cardiac function in eNOS-Tg but not in wildtype mice with TAC. In conclusion, independent of the severity of TAC, eNOS aggravates cardiac remodeling and dysfunction, which appears due to TAC-induced eNOS uncoupling and superoxide production. PMID- 26436985 TI - Long-chain polyunsaturated fatty acids amend palmitate-induced inflammation and insulin resistance in mouse C2C12 myotubes. AB - Intramuscular lipid accumulation results in inflammation, which is correlated with impaired insulin action in the skeletal muscle, an important organ for glucose uptake in the body. In this study, we explored the effects of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), arachidonic acid (AA), and long-chain polyunsaturated fatty acids (PUFAs) on palmitic acid (PA)-induced inflammatory responses and insulin resistance in C2C12 myotubes. The mRNA expression of the pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha in PA-treated myotubes was suppressed by these three test long-chain PUFAs. Moreover, the addition of long-chain PUFAs decreased PA-induced insulin resistance as evidenced by increases in phosphorylated AKT and glucose uptake. In PA-treated myotubes, long-chain PUFAs improved glucose transporter 4 expression, basal glucose uptake without insulin, and the AMP-activated protein kinase pathway. Of note, the long-chain PUFAs obstructed the effects of PA on the activation of extracellular-signal-regulated kinase and protein kinase C-theta as well as nuclear factor-kappaB (NF-kappaB) and activator protein-1. The inhibitory effect of AA but not of DHA and EPA on PA-induced inflammation and impaired insulin action was cancelled in C2C12 myotubes transfected with a constitutively active mutant IkappaB kinase-beta plasmid. These data suggest that long-chain PUFAs may be useful in the management of PA-induced inflammation and insulin resistance in myotubes. In addition to the NF-kappaB pathway, other mechanisms are involved in the health benefits of DHA and EPA in PA-treated myotubes. PMID- 26436987 TI - Optic Neuropathy Due to Chronic Lymphocytic Leukemia Proven With Optic Nerve Sheath Biopsy. AB - Central nervous system involvement from chronic lymphocytic leukemia (CLL) occurs infrequently, and manifestations include cognitive and cerebellar dysfunction and cranial nerve palsies. We report a 45-year-old man with CLL believed to be in clinical remission, who presented with vision loss and bilateral optic disc edema. His optic neuropathy due to CLL was proven by optic nerve sheath biopsy, and he experienced visual recovery after treatment with ibrutinib and intrathecal methotrexate. PMID- 26436988 TI - Theranos promises a new era of preventive health care - but where's the physician? PMID- 26436986 TI - Assessment of Neuromuscular Function Using Percutaneous Electrical Nerve Stimulation. AB - Percutaneous electrical nerve stimulation is a non-invasive method commonly used to evaluate neuromuscular function from brain to muscle (supra-spinal, spinal and peripheral levels). The present protocol describes how this method can be used to stimulate the posterior tibial nerve that activates plantar flexor muscles. Percutaneous electrical nerve stimulation consists of inducing an electrical stimulus to a motor nerve to evoke a muscular response. Direct (M-wave) and/or indirect (H-reflex) electrophysiological responses can be recorded at rest using surface electromyography. Mechanical (twitch torque) responses can be quantified with a force/torque ergometer. M-wave and twitch torque reflect neuromuscular transmission and excitation-contraction coupling, whereas H-reflex provides an index of spinal excitability. EMG activity and mechanical (superimposed twitch) responses can also be recorded during maximal voluntary contractions to evaluate voluntary activation level. Percutaneous nerve stimulation provides an assessment of neuromuscular function in humans, and is highly beneficial especially for studies evaluating neuromuscular plasticity following acute (fatigue) or chronic (training/detraining) exercise. PMID- 26436989 TI - Relationship between emotion and forgetting. AB - A major determinant of forgetting in memory is the presence of interference in the retrieval context. Previous research has shown that proactive interference has less impact for emotional than neutral study material (Levens & Phelps, 2008). However, it is unclear how emotional content affects the impact of interference in memory. Emotional content could directly affect the buildup of interference, leading to reduced levels of interference. Alternatively, emotional content could affect the controlled processes that resolve interference. The present study employed the response deadline speed-accuracy trade-off procedure to independently test these hypotheses. Participants studied 3-item lists consisting of emotional or neutral images, immediately followed by a recognition probe. Results indicated a slower rate of accrual for interfering material (lures from previous study list) and lower levels of interference for emotional than neutral stimuli, suggesting a direct impact of emotion on the buildup of interference. In contrast to this beneficiary effect, resolution of interference for emotional material was less effective than neutral material. These findings can provide insight into the interactions of emotion and memory processes. PMID- 26436990 TI - The quantitative genetics of disgust sensitivity. AB - [Correction Notice: An Erratum for this article was reported in Vol 16(1) of Emotion (see record 2015-57029-001). In the article, the name of author Joshua M. Tybur was misspelled as Joshua M. Tyber. All versions of this article have been corrected.] Response sensitivity to common disgust elicitors varies considerably among individuals. The sources of these individual differences are largely unknown. In the current study, we use a large sample of female identical and nonidentical twins (N = 1,041 individuals) and their siblings (N = 170) to estimate the proportion of variation due to genetic effects, the shared environment, and other (residual) sources across multiple domains of disgust sensitivity. We also investigate the genetic and environmental influences on the covariation between the different disgust domains. Twin modeling revealed that approximately half of the variation in pathogen, sexual, and moral disgust is due to genetic effects. An independent pathways twin model also revealed that sexual and pathogen disgust sensitivity were influenced by unique sources of genetic variation, while also being significantly affected by a general genetic factor underlying all 3 disgust domains. Moral disgust sensitivity, in contrast, did not exhibit domain-specific genetic variation. These findings are discussed in light of contemporary evolutionary approaches to disgust sensitivity. PMID- 26436991 TI - Innovations 'Out of Place': Controversies Over IVF Beginnings in India Between 1978 and 2005. AB - In 1978, the year the first in vitro fertilization (IVF) baby was born in the United Kingdom, a research team in Kolkata reported that it too had successfully produced an IVF baby in India. However, the claim was dismissed at the time, because the experiment was conducted outside authorized institutions and recognized centers of innovation--in short, because it was an innovation 'out of place.' Tracing controversies over the case between 1978 and 2005, I show the importance of space or place in processes of knowledge production and recognition. Further, I explain the initial repudiation and subsequent partial recognition of the claim through shifts in the landscape of legitimate spaces of innovation. By discussing this specific case of the production of science and technology in the Global South, I challenge conventional narratives of diffusion that are prevalent in studies on the worldwide proliferation of reproductive technologies. PMID- 26436992 TI - Misconceptions about traumatic brain injury among U.S. Army behavioral health professionals. AB - PURPOSE/OBJECTIVE: To investigate the knowledge and misconceptions about traumatic brain injury (TBI) held by behavioral health care professionals providing services to an active-duty military population. RESEARCH METHOD/DESIGN: Active duty U.S. Army psychologists, psychiatrists, social workers, and psychiatric nurses from locations across the Department of Defense, and behavioral health professionals from a major military hospital (N = 181) were surveyed on 19 common myths and misconceptions about TBI (Gouvier, Prestholdt, & Warner, 1988). Eight new items were added to the survey to more specifically assess misconceptions pertaining to mild TBI (mTBI). RESULTS: Mean percentages for the subcomponents of the questionnaire suggested that responses were generally accurate for general information about brain damage (83.61% correct) but less accurate for unconsciousness (45.81%), amnesia or memory loss (53%), and recovery items (64.8%). The total percent correct was 51% on the new mTBI items with a sizable minority of the sample viewing mTBI as being associated with lengthier recovery and poorer outcome than what has been indicated by recent research. CONCLUSION/IMPLICATIONS: Overall, misconceptions, particularly about mTBI, are prevalent among U.S. Army behavioral health providers. These findings raise concern about the dissemination of TBI information to health care professionals in the U.S. Army and to military personnel who may not be receiving accurate information about TBI recovery. PMID- 26436993 TI - Functional recovery from neuroinvasive West Nile Virus: A tale of two courses. AB - OBJECTIVE: In 2012, the highest numbers of West Nile Virus (WNV) cases were reported by the Center for Disease Control since 2003. This outbreak included over half of the identified patients being classified with one of the more debilitating neuroinvasive subtypes of WNV. Despite improvements in diagnosis and treatment options in symptom management, longitudinal research on WNV neurocognitive and functional outcomes is limited by sample size, retrospective review, and/or reliance on self-report measures for cognitive status and level of independence. This study describes the cases of 2 patients diagnosed with WNV as they complete rehabilitation across the continuum of care. RESEARCH METHOD: Review of two cases that experience different rehabilitation outcomes 4-18 months post diagnosis. RESULTS: The cases presented here demonstrate the potentially differential courses of recovery and outcomes for physical (e.g., balance, ambulation, upper extremity function), cognitive (e.g., attention, executive functions, memory, language, visuospatial), and emotional functioning, as assessed via measures administered by the patient's physical therapists and neuropsychologists. These patients were evaluated as part of the standard clinical practice to monitor changes, track recovery, and provide recommendations across the continuum of care from admission to discharge from acute inpatient rehabilitation, during outpatient day neurorehabilitation, and while receiving outpatient neuropsychology services. CONCLUSIONS: These cases highlight the variability in rehabilitative course for individuals diagnosed with WNV. Consistent follow-up with patients is recommended to ensure management of remitting and chronic symptoms. PMID- 26436994 TI - Unprecedented Phthalocyanines Bearing Eight Di-butylamino Peripheral Substituents: Synthesis, Spectroscopy, and Structure. AB - Unprecedented 2,3,9,10,16,17,23,24-octakis(di-butylamino)phthalocyanine compounds M{Pc[N(C4H9)2]8} (M = 2H, Mg, Cu, Zn) (1-4) were prepared and structurally characterized on the basis of single-crystal X-ray diffraction analysis, representing the first structurally characterized alkylamino-substituted phthalocyanine examples. These novel phthalocyanine derivatives have also been characterized by a wide range of spectroscopic methods including MALDI-TOF mass spectra, NMR, electronic absorption, and IR spectroscopy in addition to elemental analysis. Their electrochemistry was also studied by cyclic voltammetry. PMID- 26436995 TI - Evaluation of Cytotoxicity and Cell Death Induced In Vitro by Saxitoxin in Mammalian Cells. AB - Since the cyanotoxin saxitoxin (STX) is a neurotoxin and induces ecological changes in aquatic environments, a potential risk to public and environmental health exists. However, data on STX-mediated cytotoxic and genotoxic effects are still scare. In order to gain a better understanding of the effects of this toxin, the cytotoxic and genotoxic potential of STX was examined in two mammalian cell lines. Neuro 2A (N2A), a neuroblastoma mouse cell line, and Vero cell line, derived from Vero green monkey kidney cells, were exposed to several concentrations of STX ranging from 0.5 to 64 nM to determine cell viability, induction of apoptosis (DNA fragmentation assay), and formation of micronuclei (MN) (cytokinesis-block micronucleus assay; CBMN) following 24 h of incubation. The half maximal effective concentration (EC50) values for STX calculated in cell viability tests were 1.01 nM for N2A and 0.82 nM for Vero cells. With increasing STX concentration there was evidence of DNA fragmentation indicating apoptosis induction in Vero cells with a 50% increase in DNA fragmentation compared to control at the highest STX concentration tested (3 nM). The results demonstrated no significant changes in the frequency of micronucleated binucleated cells in N2A and Vero cells exposed to STX, indicating the absence of genotoxicity under these test conditions. There was no apparent cellular necrosis as evidenced by a lack of formation of multinucleated cells. In conclusion, data reported herein demonstrate that STX produced death of both cell types tested through an apoptotic process. PMID- 26436996 TI - A Decad(e) of Reasons to Contribute to a PLOS Community-Run Journal. PMID- 26436998 TI - Tuning the Upconversion Luminescence Lifetimes of KYb2 F7 :Ho(3+) Nanocrystals for Optical Multiplexing. AB - Conventional luminescent color coding is limited by spectral overlap and the interference of background fluorescence, thus restricting the number of distinguishable identities that can be used in practice. Here, we demonstrate the possibility of generating diverse time-domain codes, specially designed for a single emission band, using lanthanide-doped upconversion nanocrystals. Based on the knowledge of concentration quenching, the upconversion luminescence kinetics of KYb2 F7 : Ho(3+) nanocrystals can be precisely controlled by modifying the dopant concentration of Ho(3+) ions, resulting in a tunable emission lifetime from 75.8 to 1944.5 MUs, which suggests the practicality of these time-domain codes for optical multiplexing. PMID- 26436999 TI - A Case Study of Fixed-Effects and Random-Effects Meta-Analysis Models for Genome Wide Association Studies in Celiac Disease. AB - BACKGROUND/AIMS: Amongst the many approaches to genome-wide association study (GWAS) meta-analysis (MA), the most popular methods are based on fixed-effects (FE) modeling because it tends to be the statistically most powerful approach in the absence of heterogeneity. However, FE-based MA ignores the potential heterogeneity that may exist between studies. The purpose of our analysis was to test whether results from random effects (RE)-based methods that account for heterogeneity differed significantly from the results that were originally published. METHODS: We reanalyzed two GWAS FE-based MAs of celiac disease with RE based methods: (1) a two-stage GWAS MA that includes 9,451 celiac disease cases and 16,434 controls from 12 collections and (2) a single-stage GWAS MA using a custom dense genotyping platform to capture low-frequency and rare variants in 12,041 cases and 12,228 controls from 7 collections. RESULTS: We present evidence that SNPs at loci that were previously reported to be genome-wide significant (GWS; p < 5 * 10(-8)) in either the two-stage GWAS MA or the single-stage GWAS MA were not GWS when heterogeneity was accounted for by an RE MA method. CONCLUSION: This case study highlights the strengths of RE MA methods in the presence of heterogeneity and of pooled FE methods. PMID- 26436997 TI - 'Emergency exit' of bone-marrow-resident CD34(+)DNAM-1(bright)CXCR4(+)-committed lymphoid precursors during chronic infection and inflammation. AB - During chronic inflammatory disorders, a persistent natural killer (NK) cell derangement is observed. While increased cell turnover is expected, little is known about whether and how NK-cell homeostatic balance is maintained. Here, flow cytometric analysis of peripheral blood mononuclear cells in chronic inflammatory disorders, both infectious and non-infectious, reveals the presence of a CD34(+)CD226(DNAM-1)(bright)CXCR4(+) cell population displaying transcriptional signatures typical of common lymphocyte precursors and giving rise to NK-cell progenies with high expression of activating receptors and mature function and even to alpha/beta T lymphocytes. CD34(+)CD226(bright)CXCR4(+) cells reside in bone marrow, hardly circulate in healthy donors and are absent in cord blood. Their proportion correlates with the degree of inflammation, reflecting lymphoid cell turnover/reconstitution during chronic inflammation. These findings provide insight on intermediate stages of NK-cell development, a view of emergency recruitment of cell precursors, and upgrade our understanding and monitoring of chronic inflammatory conditions. PMID- 26437000 TI - Geographically Modified PageRank Algorithms: Identifying the Spatial Concentration of Human Movement in a Geospatial Network. AB - A network approach, which simplifies geographic settings as a form of nodes and links, emphasizes the connectivity and relationships of spatial features. Topological networks of spatial features are used to explore geographical connectivity and structures. The PageRank algorithm, a network metric, is often used to help identify important locations where people or automobiles concentrate in the geographical literature. However, geographic considerations, including proximity and location attractiveness, are ignored in most network metrics. The objective of the present study is to propose two geographically modified PageRank algorithms-Distance-Decay PageRank (DDPR) and Geographical PageRank (GPR)-that incorporate geographic considerations into PageRank algorithms to identify the spatial concentration of human movement in a geospatial network. Our findings indicate that in both intercity and within-city settings the proposed algorithms more effectively capture the spatial locations where people reside than traditional commonly-used network metrics. In comparing location attractiveness and distance decay, we conclude that the concentration of human movement is largely determined by the distance decay. This implies that geographic proximity remains a key factor in human mobility. PMID- 26437001 TI - A novel glycobiomarker, Wisteria floribunda agglutinin macrophage colony stimulating factor receptor, for predicting carcinogenesis of liver cirrhosis. AB - Recently, we identified a novel liver fibrosis glycobiomarker, Wisteria floribunda agglutinin (WFA)-reactive colony stimulating factor 1 receptor (WFA(+) -CSF1R), using a glycoproteomics-based strategy. The aim of this study was to assess the value of measuring WFA(+) -CSF1R levels for the prognosis of carcinogenesis and outcome in liver cirrhosis (LC) patients with hepatitis C virus (HCV). WFA(+) -CSF1R and Total-CSF1R levels were measured in serum samples from 214 consecutive HCV-infected patients to evaluate their impact on carcinogenesis and the survival of LC patients. Serum WFA(+) -CSF1R levels were significantly higher in LC patients than chronic hepatitis (CH) patients (p < 0.001). The AUC of WFA(+) -CSF1R for predicting overall survival, calculated by time-dependent ROC analysis, was 0.691 and the HR (per 1-SD increase) was 1.80 (95% CI, 1.23-2.62, p < 0.001). Furthermore, the survival rate of LC patients with high WFA(+) -CSF1R levels (>= 310 ng/ml) was significantly worse than those with lower levels (p < 0.01). The AUC of WFA(+) /total-CSF1R percentage (WFA(+) CSF1R%) for predicting the cumulative carcinogenesis rate was 0.760, with an HR of 1.66 (95% CI 1.26-2.20, p < 0.001). In fact, the carcinogenesis rate was significantly higher in LC patients with a high WFA(+) -CSF1R% (>= 35%, p = 0.006). Assessing serum levels of WFA(+) -CSF1R has diagnostic value for predicting carcinogenesis and the survival of LC patients. PMID- 26437002 TI - Hybrid Modulation-Doping of Solution-Processed Ultrathin Layers of ZnO Using Molecular Dopants. AB - An alternative doping approach that exploits the use of organic donor/acceptor molecules for the effective tuning of the free electron concentration in quasi-2D ZnO transistor channel layers is reported. The method relies on the deposition of molecular dopants/formulations directly onto the ultrathin ZnO channels. Through careful choice of materials combinations, electron transfer from the dopant molecule to ZnO and vice versa is demonstrated. PMID- 26437003 TI - Characterizing effects of mild traumatic brain injury and posttraumatic stress disorder on balance impairments in blast-exposed servicemembers and Veterans using computerized posturography. AB - The high rate of blast exposures experienced by U.S. servicemembers (SMs) during the recent conflicts in Iraq and Afghanistan has resulted in frequent combat related mild traumatic brain injuries (mTBIs). Dizziness and postural instability can persist after mTBI as a component of postconcussion syndrome, but also occur among the somatic complaints of posttraumatic stress disorder (PTSD). The goals of this study were to examine the use of computerized posturography (CPT) to objectively characterize chronic balance deficits after mTBI and to explore the utility of CPT in distinguishing between combat and blast-exposed participants with and without mTBI and PTSD. Data were analyzed from a subject pool of 166 combat-exposed SMs and Veterans who had a blast experience within the past 2 yr while deployed. Using nonparametric tests and measures of impairment, we found that balance was deficient in participants diagnosed with mTBI with posttraumatic amnesia (PTA) or PTSD versus those with neither and that deficits were amplified for participants with both diagnoses. In addition, unique deficiencies were found using CPT for individuals having isolated mTBI with PTA and isolated PTSD. Computerized balance assessment offers an objective technique to examine the physiologic effects and provide differentiation between participants with combat associated mTBI and PTSD. PMID- 26437004 TI - Color Pattern on the Forewing of Micropterix (Lepidoptera: Micropterigidae): Insights into the Evolution of Wing Pattern and Wing Venation in Moths. AB - Wing patterns are key taxonomic characters that have long been used in descriptions of Lepidoptera; however, wing pattern homologies are not understood among different moth lineages. Here, we examine the relationship between wing venation and wing pattern in the genus Micropterix, among the most basal extant Lepidoptera, in order to evaluate the two existing predictive models that have the potential to establish wing pattern element homologies for the order. The location of wing pattern elements along the costal margin of the wing in Micropterix is consistent with the predictions of the model proposed for Tortricidae by Brown and Powell in 1991, later modified by Baixeras in 2002. The predictive power of this model for such distantly related taxa suggests that the model may hold across various superfamilies within Lepidoptera, and supports the long-held notion that fasciae, not spots, are the most likely primitive wing pattern elements for the order. In addition, the location of wing pattern elements suggests that the wing vein commonly termed Sc1 may in fact be a different vein, which Comstock identified in Trichoptera and referred to as "a." PMID- 26437007 TI - Quantum Dynamics of the (18)O + (36)O2 Collision Process. AB - We report full quantum cross sections and rate constants for the (18)O + (36)O2 > (36)O2 + (18)O collision process. This constitutes to the best of our knowledge the first dynamical study of the (18)O(18)O(18)O system, with three identical (18)O oxygen atoms. We emphasize the comparison with the (16)O + (32)O2 collision as this latter presents the exact same features as the one treated here, except the consistent change of mass for all three atoms. We find very similar behaviors in the cross sections, and we confirm that the rates are faster when three identical nuclei are involved. In particular, we cannot dynamically study this system with classical trajectory methods, and we have to include properly the indistinguishability of the three (18)O nuclei; however, we note some slight differences with the (16)O(16)O(16)O benchmark system, and we focus our analysis on their origin. PMID- 26437006 TI - High-throughput Screening of Recalcitrance Variations in Lignocellulosic Biomass: Total Lignin, Lignin Monomers, and Enzymatic Sugar Release. AB - The conversion of lignocellulosic biomass to fuels, chemicals, and other commodities has been explored as one possible pathway toward reductions in the use of non-renewable energy sources. In order to identify which plants, out of a diverse pool, have the desired chemical traits for downstream applications, attributes, such as cellulose and lignin content, or monomeric sugar release following an enzymatic saccharification, must be compared. The experimental and data analysis protocols of the standard methods of analysis can be time consuming, thereby limiting the number of samples that can be measured. High throughput (HTP) methods alleviate the shortcomings of the standard methods, and permit the rapid screening of available samples to isolate those possessing the desired traits. This study illustrates the HTP sugar release and pyrolysis molecular beam mass spectrometry pipelines employed at the National Renewable Energy Lab. These pipelines have enabled the efficient assessment of thousands of plants while decreasing experimental time and costs through reductions in labor and consumables. PMID- 26437005 TI - Effective intra-S checkpoint responses to UVC in primary human melanocytes and melanoma cell lines. AB - The objective of this study was to assess potential functional attenuation or inactivation of the intra-S checkpoint during melanoma development. Proliferating cultures of skin melanocytes, fibroblasts, and melanoma cell lines were exposed to increasing fluences of UVC and intra-S checkpoint responses were quantified. Melanocytes displayed stereotypic intra-S checkpoint responses to UVC qualitatively and quantitatively equivalent to those previously demonstrated in skin fibroblasts. In comparison with fibroblasts, primary melanocytes displayed reduced UVC-induced inhibition of DNA strand growth and enhanced degradation of p21Waf1 after UVC, suggestive of enhanced bypass of UVC-induced DNA photoproducts. All nine melanoma cell lines examined, including those with activating mutations in BRAF or NRAS oncogenes, also displayed proficiency in activation of the intra-S checkpoint in response to UVC irradiation. The results indicate that bypass of oncogene-induced senescence during melanoma development was not associated with inactivation of the intra-S checkpoint response to UVC induced DNA replication stress. PMID- 26437010 TI - A 6-Year-Old Boy With Fever, Emesis, Rash, and an Acute Abdomen. PMID- 26437011 TI - Glyburide vs Insulin and Adverse Pregnancy Outcomes. PMID- 26437012 TI - Glyburide vs Insulin and Adverse Pregnancy Outcomes. PMID- 26437013 TI - Glyburide vs Insulin and Adverse Pregnancy Outcomes--Reply. PMID- 26437014 TI - Kidney Stones in Children and Adolescents. PMID- 26437015 TI - Associations Between Antibullying Policies and Bullying in 25 States. AB - IMPORTANCE: Bullying is the most widespread form of peer aggression in schools. In an effort to address school bullying, 49 states have passed antibullying statutes. Despite the ubiquity of these policies, there has been limited empirical examination of their effectiveness in reducing students' risk of being bullied. OBJECTIVE: To evaluate the effectiveness of antibullying legislation in reducing students' risk of being bullied and cyberbullied, using data from 25 states in the United States. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional observational study was conducted using a population-based survey of 63 635 adolescents in grades 9 to 12 from 25 states participating in the 2011 Youth Risk Behavior Surveillance System study (September 2010-December 2011). Data on antibullying legislation were obtained from the US Department of Education (DOE), which commissioned a systematic review of state laws in 2011. The report identified 16 key components that were divided into the following 4 broad categories: purpose and definition of the law, district policy development and review, school district policy components (eg, responsibilities for reporting bullying incidents), and additional components (eg, how policies are communicated). Policy variables from 25 states were linked to individual-level data from the Youth Risk Behavior Surveillance System on experiencing bullying and cyberbullying. Analyses were conducted between March 1, 2014, and December 1, 2014. EXPOSURE: State antibullying legislation. MAIN OUTCOMES AND MEASURES: Exposure to bullying and cyberbullying in the past 12 months. RESULTS: There was substantial variation in the rates of bullying and cyberbullying across states. After controlling for relevant state-level confounders, students in states with at least 1 DOE legislative component in the antibullying law had a 24% (95% CI, 15%-32%) reduced odds of reporting bullying and 20% (95% CI, 9%-29%) reduced odds of reporting cyberbullying compared with students in states whose laws had no DOE legislative components. Three individual components of antibullying legislation were consistently associated with decreased odds of exposure to both bullying and cyberbullying: statement of scope, description of prohibited behaviors, and requirements for school districts to develop and implement local policies. CONCLUSIONS AND RELEVANCE: Antibullying policies may represent effective intervention strategies for reducing students' risk of being bullied and cyberbullied in schools. PMID- 26437016 TI - Total Direct Medical Expenses and Characteristics of Privately Insured Adolescents Who Incur High Costs. AB - IMPORTANCE: Accountable care payment models aim to reduce total direct medical expenses for high-cost patients through improved quality of care and preventive health services. Little is known about health care expenditures of privately insured adolescents, especially those who incur high costs. OBJECTIVES: To assess health care expenditures for high-cost adolescents and to describe the patient characteristics associated with high medical costs. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort analysis was conducted of data from January 1 to December 31, 2012, of 13,103 privately insured adolescents aged 13 to 21 years (mean [SD] age, 16.3 [2.4] years; 6764 [51.6%] males) at 82 independent pediatric primary care practices in Massachusetts. Analysis was conducted from April 1, 2014, to April 1, 2015. MAIN OUTCOMES AND MEASURES: We compared demographic (age, sex, median income by zip code) and clinical (obesity, behavioral health problem, complex chronic condition) characteristics between high-cost (top 1%) and non-high-cost adolescents. We assigned high-cost adolescents to clinical categories using software from the Agency for Healthcare Research and Quality to describe clinically relevant patterns of spending. RESULTS: Total direct medical expenses were $41.2 million for the entire cohort and a median $1167 per patient. A total of 132 (1.0%) patients with the highest costs accounted for 23.6% of expenses of the cohort, with a median $52,577 per patient. Mental health disorders were the most common diagnosis in high-cost patients; 78 (59.1%) of these patients had at least 1 behavioral health diagnosis. Pharmacy costs accounted for 28.4% of total direct medical expenses of high-cost patients; primary care accounted for 1.0%. Characteristics associated with being a high-cost patient included having 1 complex chronic condition (relative risk [RR], 6.5; 95% CI, 4.7-9.0), having 2 or more complex chronic conditions (RR, 23.5; 95% CI, 14.2-39.1), having any behavioral health diagnosis (RR, 3.6; 95% CI, 2.6-5.1), and obesity (RR, 2.0; 95% CI, 1.3-3.0). CONCLUSIONS AND RELEVANCE: Total direct medical expenses for privately insured high-cost adolescents are associated with medical complexity, mental health conditions, and obesity. Cost reduction strategies in similar populations should be tailored to these cost drivers. PMID- 26437017 TI - Difficult laparoscopic total mesorectal excision after preoperative colonoscopic tattooing. PMID- 26437018 TI - Burden of vaccine preventable diseases at large events. AB - BACKGROUND: Large events or mass gatherings (MGs) are known to amplify the risk of infectious diseases, many of which can be prevented by vaccination. In this review we have evaluated the burden of vaccine preventable diseases (VPDs) in MGs. METHODS: Major databases like PubMed and Embase, Google Scholar and pertinent websites were searched by using MeSH terms and text words; this was supplemented by hand searching. Following data abstraction, the pooled estimate of the burden of VPDs was calculated when possible; otherwise a narrative synthesis was conducted. RESULTS: In the past, at religious MGs like Hajj and Kumbh Mela, cholera caused explosive outbreaks; but currently respiratory infections, notably influenza, are the commonest diseases not only at Hajj but also at World Youth Day and Winter Olympiad. The recent cumulative attack rate of influenza at Hajj is 8.7% (range 0.7-15.8%), and the cumulative prevalence is 3.6% (range: 0.3-38%). Small outbreaks of measles (13-42 cases per event) have been reported at sport, entertainment and religious events. A sizeable outbreak (>200 cases) was reported following a special Easter Festival in Austria. An outbreak of hepatitis A occurred following the 'Jam bands' music festival. Other VPDs including pneumococcal disease, pertussis and tuberculosis have been reported in relation to MG attendance. CONCLUSION: VPDs not only affect the participants of MGs but also their contacts; vaccine uptake is variable and vaccine implementation is likely to have beneficial effects. Research to address the knowledge gaps surrounding VPDs at MGs is needed. PMID- 26437019 TI - Reversible High-Grade Atrioventricular Block Associated With Cocaine Use. PMID- 26437020 TI - Quantitative Phosphoproteomics Revealed Glucose-Stimulated Responses of Islet Associated with Insulin Secretion. AB - As central tissue of glucose homeostasis, islet has been an important focus of diabetes research. Phosphorylation plays pivotal roles in islet function, especially in islet glucose-stimulated insulin secretion. A systematic view on how phosphorylation networks were coordinately regulated in this process remains lacking, partially due to the limited amount of islets from an individual for a phosphoproteomic analysis. Here we optimized the in-tip and best-ratio phosphopeptide enrichment strategy and a SILAC-based workflow for processing rat islet samples. With limited islet lysates from each individual rat (20-47 MUg), we identified 8539 phosphosites on 2487 proteins. Subsequent quantitative analyses uncovered that short-term (30 min) high glucose stimulation induced coordinate responses of islet phosphoproteome on multiple biological levels, including insulin secretion related pathways, cytoskeleton dynamics, protein processing in ER and Golgi, transcription and translation, and so on. Furthermore, three glucose-responsive phosphosites (Prkar1a pT75pS77 and Tagln2 pS163) from the data set were proved to be correlated with insulin secretion. Overall, we initially gave an in-depth map of islet phosphoproteome regulated by glucose on individual rat level. This was a significant addition to our knowledge about how phosphorylation networks responded in insulin secretion. Also, the list of changed phosphosites was a valuable resource for molecular researchers in diabetes field. PMID- 26437022 TI - Catalytic Protein Film Electrochemistry Provides a Direct Measure of the Tetrathionate/Thiosulfate Reduction Potential. AB - The tetrathionate/thiosulfate interconversion is a two-electron process: S4O6(2-) + 2 e(-) <-> 2 S2O3(2-). Both transformations can support bacterial growth since S2O3(2-) provides an energy source, while S4O6(2-) serves as respiratory electron acceptor. Interest in the corresponding S2O3(2-) oxidation also arises from its widespread use in volumetric analysis of oxidizing agents and bleach neutralization during water treatment. Here we report protein film electrochemistry that defines the reduction potential of the S4O6(2-)/S2O3(2-) couple. The relevant interconversion is not reversible at inert electrodes. However, facile reduction of S4O6(2-) to S2O3(2-) and the reverse reaction are catalyzed by enzymes of the thiosulfate dehydrogenase, TsdA, family adsorbed on graphite electrodes. Zero-current potentials measured with different enzymes, at three pH values, and multiple S4O6(2-) and S2O3(2-) concentrations together with the relevant Nernst equation resolved the tetrathionate/thiosulfate reduction potential as +198 +/- 4 mV versus SHE. This potential lies in the ~250 mV window encompassing previously reported values calculated from parameters including the free energy of formation. However, the value is considerably more positive than widely used in discussions of bacterial bioenergetics. As a consequence anaerobic respiration by tetrathionate reduction is likely to be more prevalent than presently thought in tetrathionate-containing environments such as marine sediments and the human gut. PMID- 26437021 TI - Bik Mediates Caspase-Dependent Cleavage of Viral Proteins to Promote Influenza A Virus Infection. AB - Influenza virus induces apoptosis in infected cells to promote viral replication by manipulating the host cell death signaling pathway. Although some Bcl-2 family proteins play a role in the replication of influenza A virus (IAV), the role of cell death pathways in the viral replication cycle is unclear. We investigated whether deficiency of the proapoptotic Bcl-2 family protein, Bik, plays a role in IAV replication. IAV replication was attenuated in mouse airway epithelial cells (MAECs) from bik(-/-) compared with bik(+/+) mice, as indicated by reduced viral titers. Bik(-/-) MAECs showed more stable transepithelial resistance after infection than did bik(+/+) MAECs, were less sensitive to infection-induced cell death, and released fewer copies of viral RNA. Similar results were obtained when Bik expression was suppressed in human airway epithelial cells (HAECs). Bik(+/+) mice lost weight drastically and died within 8 days of infection, whereas 75% of bik(-/-) mice survived infection for 14 days and were 10-fold less likely to die from infection compared with bik(+/+) mice. IAV infection activated caspase 3 in bik(+/+) but not in bik(-/-) MAECs. Cleavage of viral nucleoprotein and M2 proteins were inhibited in bik(-/-) MAECs and when caspase activation was inhibited in HAECs. Furthermore, Bik deficiency impaired cytoplasmic export of viral ribonucleoprotein. These studies suggest a link between Bik-mediated caspase activation and cleavage of viral proteins. Thus, inhibition of proapoptotic host factors such as Bik and downstream mediators of cell death may represent a novel approach to influenza treatment. PMID- 26437023 TI - Chemically Crushed Wood Cellulose Fiber towards High-Performance Sodium-Ion Batteries. AB - Carbon materials have attracted great interest as an anode for sodium-ion batteries (SIBs) due to their high performance and low cost. Here, we studied natural wood fiber derived hard carbon anodes for SIBs considering the abundance and low cost of wood. We discovered that a thermal carbonization of wood fiber led to a porous carbon with a high specific surface area of 586 m(2) g(-1), while a pretreatment with 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) could effectively decrease it to 126 m(2) g(-1). When evaluating them as anodes for SIBs, we observed that the low surface area carbon resulted in a high initial Coulombic efficiency of 72% compared to 25% of the high surface area carbon. More importantly, the low surface area carbon exhibits an excellent cycling stability that a desodiation capacity of 196 mAh g(-1) can be delivered over 200 cycles at a current density of 100 mA g(-1), indicating a promising anode for low-cost SIBs. PMID- 26437024 TI - Hospital of diagnosis and likelihood of surgical treatment for pancreatic cancer. AB - BACKGROUND: Surgical resection for pancreatic cancer offers the only chance of cure. Assessment of the resectability of a pancreatic tumour is therefore of great importance. The aim of the study was to investigate whether centre of diagnosis influences the likelihood of surgery and whether this affects long-term survival. METHODS: Patients diagnosed with non-metastasized pancreatic cancer (M0) between 2005 and 2013 in the Netherlands were selected from the Netherlands Cancer Registry. Hospitals were classified as a pancreatic centre (at least 20 resections/year) or a non-pancreatic centre (fewer than 20 resections/year). The relationship between centre of diagnosis and likelihood of surgery was analysed by multivariable logistic regression. Influence of centre on overall survival was assessed by means of multivariable Cox regression analysis. RESULTS: Some 8141 patients were diagnosed with non-metastasized pancreatic cancer, of whom 3123 (38.4 per cent) underwent surgery. Of the 2712 patients diagnosed in one of 19 pancreatic centres, 52.4 per cent had exploratory laparotomy compared with 31.4 per cent of 5429 patients diagnosed in one of 74 non-pancreatic centres (P < 0.001). A pancreatectomy was performed in 42.8 and 24.6 per cent of the patients respectively (P < 0.001). Multivariable analysis revealed that patients diagnosed in a pancreatic centre had a higher chance of undergoing surgery (odds ratio 2.21, 95 per cent c.i. 1.98 to 2.47). Centre of diagnosis was not associated with improved long-term survival (hazard ratio 0.95, 95 per cent c.i. 0.91 to 1.00). CONCLUSION: Patients with non-metastasized pancreatic cancer had a greater likelihood of having surgical treatment when the diagnosis was established in a pancreatic centre. PMID- 26437025 TI - Reticulocyte hemoglobin content does not differentiate true from functional iron deficiency in dogs. AB - BACKGROUND: True and functional iron deficiency can result in anemia. Current tests to assess iron status often do not allow differentiation between these entities, which can affect optimal treatment. Previous work suggested low reticulocyte hemoglobin content (CHr) may be an early indicator of iron deficiency. OBJECTIVE: This study aimed to correlate several inflammation markers with CHr values in dogs. We hypothesize that dogs with low CHr values have hematologic and biochemical evidence of inflammation. METHODS: Animals with CHr values below the reference interval were included in the low CHr group, while dogs with normal or increased CHr were included in the control group. HCT, MCV, CHr, reticulocyte mean cell volume (MCVr), concentrations of serum iron, C reactive protein (CRP), ferritin, and ceruloplasmin, and total iron-binding capacity (TIBC), percent transferrin saturation (% sat), and total WBC, neutrophil, and monocyte counts were determined. Nonparametric tests were performed; median values and percentage of abnormalities between each group were compared. RESULTS: Relative to control dogs, animals in the low CHr group had higher median values for CRP, ferritin, ceruloplasmin, and WBC concentration (P <= .05), and lower median values for HCT and MCV (P <= .0001). Higher frequencies of abnormalities for CRP, ferritin, WBC, neutrophil, and monocyte concentrations (P <= .02) were present in the low CHr group. CONCLUSIONS: Dogs with low CHr values often have evidence of inflammation, but low CHr did not reliably predict Fe deficiency. Additional diagnostic tests are needed to differentiate true and functional iron deficiency. PMID- 26437026 TI - Ethanol and High-Value Terpene Co-Production from Lignocellulosic Biomass of Cymbopogon flexuosus and Cymbopogon martinii. AB - Cymbopogon flexuosus, lemongrass, and C. martinii, palmarosa, are perennial grasses grown to produce essential oils for the fragrance industry. The objectives of this study were (1) to evaluate biomass and oil yields as a function of nitrogen and sulfur fertilization, and (2) to characterize their utility for lignocellulosic ethanol compared to Panicum virgatum (switchgrass). Mean biomass yields were 12.83 Mg lemongrass ha-1 and 15.11 Mg palmarosa ha-1 during the second harvest year resulting in theoretical biofuel yields of 2541 and 2569 L ethanol ha-1 respectively compared to reported 1749-3691 L ethanol ha 1 for switchgrass. Pretreated lemongrass yielded 198 mL ethanol (g biomass)-1 and pretreated palmarosa yielded 170 mL ethanol (g biomass)-1. Additionally, lemongrass yielded 85.7 kg essential oil ha-1 and palmarosa yielded 67.0 kg ha-1 with an estimated value of USD $857 and $1005 ha-1. These data suggest that dual use crops such as lemongrass and palmarosa may increase the economic viability of lignocellulosic biofuels. PMID- 26437027 TI - Magnetic Sphincter Augmentation for Gastroesophageal Reflux at 5 Years: Final Results of a Pilot Study Show Long-Term Acid Reduction and Symptom Improvement. AB - BACKGROUND: As previously reported, the magnetic sphincter augmentation device (MSAD) preserves gastric anatomy and results in less severe side effects than traditional antireflux surgery. The final 5-year results of a pilot study are reported here. PATIENTS AND METHODS: A prospective, multicenter study evaluated safety and efficacy of the MSAD for 5 years. Prior to MSAD placement, patients had abnormal esophageal acid and symptoms poorly controlled by proton pump inhibitors (PPIs). Patients served as their own control, which allowed comparison between baseline and postoperative measurements to determine individual treatment effect. At 5 years, gastroesophageal reflux disease (GERD)-Health Related Quality of Life (HRQL) questionnaire score, esophageal pH, PPI use, and complications were evaluated. RESULTS: Between February 2007 and October 2008, 44 patients (26 males) had an MSAD implanted by laparoscopy, and 33 patients were followed up at 5 years. Mean total percentage of time with pH <4 was 11.9% at baseline and 4.6% at 5 years (P < .001), with 85% of patients achieving pH normalization or at least a 50% reduction. Mean total GERD-HRQL score improved significantly from 25.7 to 2.9 (P < .001) when comparing baseline and 5 years, and 93.9% of patients had at least a 50% reduction in total score compared with baseline. Complete discontinuation of PPIs was achieved by 87.8% of patients. No complications occurred in the long term, including no device erosions or migrations at any point. CONCLUSIONS: Based on long-term reduction in esophageal acid, symptom improvement, and no late complications, this study shows the relative safety and efficacy of magnetic sphincter augmentation for GERD. PMID- 26437028 TI - MMP21 is mutated in human heterotaxy and is required for normal left-right asymmetry in vertebrates. AB - Heterotaxy results from a failure to establish normal left-right asymmetry early in embryonic development. By whole-exome sequencing, whole-genome sequencing and high-throughput cohort resequencing, we identified recessive mutations in MMP21 (encoding matrix metallopeptidase 21) in nine index cases with heterotaxy. In addition, Mmp21-mutant mice and mmp21-morphant zebrafish displayed heterotaxy and abnormal cardiac looping, respectively, suggesting a new role for extracellular matrix remodeling in the establishment of laterality in vertebrates. PMID- 26437029 TI - Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. AB - Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes. PMID- 26437030 TI - DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control. AB - Although Burkitt lymphomas and follicular lymphomas both have features of germinal center B cells, they are biologically and clinically quite distinct. Here we performed whole-genome bisulfite, genome and transcriptome sequencing in 13 IG-MYC translocation-positive Burkitt lymphoma, nine BCL2 translocation positive follicular lymphoma and four normal germinal center B cell samples. Comparison of Burkitt and follicular lymphoma samples showed differential methylation of intragenic regions that strongly correlated with expression of associated genes, for example, genes active in germinal center dark-zone and light-zone B cells. Integrative pathway analyses of regions differentially methylated in Burkitt and follicular lymphomas implicated DNA methylation as cooperating with somatic mutation of sphingosine phosphate signaling, as well as the TCF3-ID3 and SWI/SNF complexes, in a large fraction of Burkitt lymphomas. Taken together, our results demonstrate a tight connection between somatic mutation, DNA methylation and transcriptional control in key B cell pathways deregulated differentially in Burkitt lymphoma and other germinal center B cell lymphomas. PMID- 26437032 TI - Intron retention is a widespread mechanism of tumor-suppressor inactivation. AB - A substantial fraction of disease-causing mutations are pathogenic through aberrant splicing. Although genome profiling studies have identified somatic single-nucleotide variants (SNVs) in cancer, the extent to which these variants trigger abnormal splicing has not been systematically examined. Here we analyzed RNA sequencing and exome data from 1,812 patients with cancer and identified ~900 somatic exonic SNVs that disrupt splicing. At least 163 SNVs, including 31 synonymous ones, were shown to cause intron retention or exon skipping in an allele-specific manner, with ~70% of the SNVs occurring on the last base of exons. Notably, SNVs causing intron retention were enriched in tumor suppressors, and 97% of these SNVs generated a premature termination codon, leading to loss of function through nonsense-mediated decay or truncated protein. We also characterized the genomic features predictive of such splicing defects. Overall, this work demonstrates that intron retention is a common mechanism of tumor suppressor inactivation. PMID- 26437031 TI - Integrated molecular analysis of adult T cell leukemia/lymphoma. AB - Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV 1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-kappaB signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor. PMID- 26437034 TI - Hedgehog- and mTOR-targeted therapies for advanced basal cell carcinomas. AB - Basal cell carcinomas (BCCs) are the most frequent human cancer. Over 90% of all BCCs have a mutation in PTCH1 or smoothened, two conducting proteins of the Hedgehog pathway. They rarely progress deeply and metastasize; however, if they do, these advanced basal cell carcinoma become amenable to treatment by inhibiting the Hedgehog and the P13K-mTOR pathways. Such innovative drugs include vismodegib, cyclopamine, itraconazole, everolimus and a few other agents that are in early clinical development. PMID- 26437035 TI - The effect of ALD-grown Al2O3 on the refractive index sensitivity of CVD gold coated optical fiber sensors. AB - The combined effect of nanoscale dielectric and metallic layers prepared by atomic layer deposition (ALD) and chemical vapor deposition (CVD) on the refractometric properties of tilted optical fiber Bragg gratings (TFBG) is studied. A high index intermediate layer made up of either 50 nm or 100 nm layers of Al2O3 (refractive index near 1.62) was deposited by ALD and followed by thin gold layers (30-65 nm) deposited from a known single-source gold (I) iminopyrrolidinate CVD precursor. The fabricated devices were immersed in different surrounding refractive indices (SRI) and the spectral transmission response of the TFBGs was measured. Preliminary results indicate that the addition of the dielectric Al2O3 pre-coating enhances the SRI sensitivity by up to 75% but this enhancement is highly dependent on the polarization and dielectric thickness. In fact, the sensitivity decreases by up to 50% for certain cases. These effects are discussed with support from TFBG simulations and models, by quantifying the penetration of the evanescently coupled light out of the fiber through the various coating layers. Additional characterization studies have been carried out on these samples to further correlate the optical behaviour of the coated TFBGs with the physical properties of the gold and Al2O3 layers, using atomic force microscopy x-ray photoelectron spectroscopy and an ensemble of other optical and x-ray absorption spectroscopy techniques. The purity, roughness, and morphology of gold thin films deposited by CVD onto the dielectric-TFBG surface are also provided. PMID- 26437033 TI - Genomic landscapes of breast fibroepithelial tumors. AB - Breast fibroepithelial tumors comprise a heterogeneous spectrum of pathological entities, from benign fibroadenomas to malignant phyllodes tumors. Although MED12 mutations have been frequently found in fibroadenomas and phyllodes tumors, the landscapes of genetic alterations across the fibroepithelial tumor spectrum remain unclear. Here, by performing exome sequencing of 22 phyllodes tumors followed by targeted sequencing of 100 breast fibroepithelial tumors, we observed three distinct somatic mutation patterns. First, we frequently observed MED12 and RARA mutations in both fibroadenomas and phyllodes tumors, emphasizing the importance of these mutations in fibroepithelial tumorigenesis. Second, phyllodes tumors exhibited mutations in FLNA, SETD2 and KMT2D, suggesting a role in driving phyllodes tumor development. Third, borderline and malignant phyllodes tumors harbored additional mutations in cancer-associated genes. RARA mutations exhibited clustering in the portion of the gene encoding the ligand-binding domain, functionally suppressed RARA-mediated transcriptional activation and enhanced RARA interactions with transcriptional co-repressors. This study provides insights into the molecular pathogenesis of breast fibroepithelial tumors, with potential clinical implications. PMID- 26437036 TI - Generalized Anxiety Disorder and Pain. AB - In this article, the co-occurrence of anxiety disorders (in particular generalized anxiety disorder) and pain conditions is described, characteristics of chronic pain are explained, and data on the prevalence of co-comorbidity of both conditions are reviewed. Further, hypotheses on the possible psychosocial and neurobiological backgrounds of the high rate of co-occurrence are discussed. This review will also focus on the role of 'unexplained' pain syndromes (e.g. somatic symptom disorder and fibromyalgia) and anxiety. Finally, we address possible treatment strategies for patients with both conditions. There is a need for a rigorous assessment of pain syndromes in generalized anxiety disorder and anxiety in chronic pain conditions in order to prevent subsequent mortality by early treatment of both conditions. PMID- 26437038 TI - The same but completely different. PMID- 26437037 TI - Xenopus laevis as a Model to Identify Translation Impairment. AB - Protein synthesis is a fundamental process to gene expression impacting diverse biological processes notably adaptation to environmental conditions. The initiation step, which involves the assembly of the ribosomal subunits at the mRNA initiation codon, involved initiation factor including eIF4G1. Defects in this rate limiting step of translation are linked to diverse disorders. To study the potential consequences of such deregulations, Xenopus laevis oocytes constitute an attractive model with high degrees of conservation of essential cellular and molecular mechanisms with human. In addition, during meiotic maturation, oocytes are transcriptionally repressed and all necessary proteins are translated from preexisting, maternally derived mRNAs. This inexpensive model enables exogenous mRNA to become perfectly integrated with an effective translation. Here is described a protocol for assessing translation with a factor of interest (here eIF4G1) using stored maternal mRNA that are the first to be polyadenylated and translated during oocyte maturation as a physiological readout. At first, mRNA synthetized by in vitro transcription of plasmids of interest (here eIF4G1) are injected in oocytes and kinetics of oocyte maturation by Germinal Vesicle Breakdown detection is determined. The studied maternal mRNA target is the serine/threonine-protein-kinase mos. Its polyadenylation and its subsequent translation are investigated together with the expression and phosphorylation of proteins of the mos signaling cascade involved in oocyte maturation. Variations of the current protocol to put forward translational defects are also proposed to emphasize its general applicability. In light of emerging evidence that aberrant protein synthesis may be involved in the pathogenesis of neurological disorders, such a model provides the opportunity to easily assess this impairment and identify new targets. PMID- 26437039 TI - Erratum: Viewpoint article in our March 2015 issue--author details. AB - The Viewpoint article entitled 'Peer support workers: an untapped resource in primary mental health care' was published with incorrect author details as supplied. The first author of the paper is Juan J Tellez. The paper should be correctly cited as: Tellez JJ, Kidd J. Peer support workers: an untapped resource in primary mental health care. J Prim Health Care. 2015;7(1):84-87. PMID- 26437040 TI - General practitioners gatekeepers for referral but neurosurgeons gatekeepers for investigations. PMID- 26437041 TI - The distribution and frequency of blood lipid testing by sociodemographic status among adults in Auckland, New Zealand. AB - INTRODUCTION: National cardiovascular disease (CVD) guidelines recommend that adults have cholesterol levels monitored regularly. However, little is known about the extent and equity of cholesterol testing in New Zealand. AIM: To investigate the distribution and frequency of blood lipid testing by sociodemographic status in Auckland, New Zealand. METHODS: We anonymously linked five national health datasets (primary care enrolment, laboratory tests, pharmaceuticals, hospitalisations and mortality) to identify adults aged >=25 years without CVD or diabetes who had their lipids tested in 2006-2010, by age, gender, ethnicity and area of residence and deprivation. Multivariate logistic regression was used to estimate the likelihood of testing associated with these factors. RESULTS: Of the 627 907 eligible adults, 66.3% had at least one test between 2006 and 2010. Annual testing increased from 24.7% in 2006 to 35.1% in 2010. Testing increased with age similarly for men and women. Indian people were 87% more likely than New Zealand European and Others (NZEO) to be tested, Pacific people 8% more likely, but rates for Maori were similar to NZEO. There was marked variation within the region, with residents of the most deprived areas less likely to be tested than residents in least deprived areas. DISCUSSION: Understanding differences within and between population groups supports the development of targeted strategies for better service utilisation. While lipid testing has increased, sociodemographic variations persist by place of residence, and deprivation. Of the high CVD risk populations, lipid testing for Maori and Pacific is not being conducted according to need. PMID- 26437042 TI - The Green Prescription Active Families programme in Taranaki, New Zealand 2007 2009: Did it reach children in need? AB - INTRODUCTION: The Green Prescription Active Families (GRxAF) programme focuses on overweight/obese children and adolescents, and is family/whanau based. It is an intervention supporting lifestyle changes through weekly sessions (nutrition advice and/or physical activity), and goal setting for the family/whanau for up to 12 months. AIMS: To describe the GRxAF programme in Taranaki and evaluate its reach and engagement, especially for those most at risk of obesity. METHODS: Participant files for each referred child from May 2007 to December 2009 were reviewed. Baseline demographic data, programme graduation information, and weekly activity session attendance were collected. RESULTS: Of the 109 participants during the audit period, 39% were Maori , 57% New Zealand European (NZE), 3% Pacific, and 1% Other ethnicity. Mean age at entry was 10 (range 4-17) years. Mean duration of programme involvement was five (range 0-12) months. Overall, 33/60 (55%) of the participants completing the programme during the audit period graduated, having made steps towards healthy lifestyle change. In comparison with NZE (68%), a smaller proportion of Maori (40%) graduated (p=0.04). In comparison with those who attended no sessions, participants who attended any sessions were more likely to make positive changes (OR=3.65, 95% CI 1.24-10.8). DISCUSSION: GRxAF in Taranaki met a need for some obese/overweight children, but not for all families/whanau, especially those over-represented in childhood obesity statistics. Programme delivery for Maori requires improvement, and assessment of readiness to make lifestyle change as an enrolment criteria for all participants is recommended. PMID- 26437043 TI - Optimising neurosurgical outpatient care: a paradigm shift? AB - INTRODUCTION: The Wellington Regional Hospital (WRH) neurosurgical service has noted a substantial increase in patient volumes over the last decade, with referrals to the neurosurgical outpatient clinic appearing to have increased even more substantially. AIM: To quantify the increase in referrals to the WRH neurosurgical outpatient service and to determine whether this has translated into an increase in the number of neurosurgical procedures performed. METHODS: All referrals to the WRH neurosurgical department from the lower North and upper South Islands of New Zealand spanning 10 years were collected. Key outcome data were the number of interventions performed. In addition to GP referrals, all specialist referrals to the WRH neurosurgical outpatient service were also analysed as a comparison. RESULTS: In total, 19 201 patients were referred to the WRH neurosurgical service over the 10 years of the study. Within this timeframe, 7105 patients were referred by GPs and 12 096 were referred by specialist teams. Only 348 patients (4.9%) referred by GPs underwent some form of therapeutic intervention, compared to 3489 patients (28.8%) referred by specialist teams. DISCUSSION: Our data shows that specialist referrals result in a proportionally greater number of therapeutic interventions than GP referrals. This is in part due to the wider array of diagnostic tests available to specialists compared to GPs. The development of relevant guidelines for primary care referral to a neurosurgical service appears warranted and could facilitate initiation of appropriate investigations in primary care. PMID- 26437044 TI - General practitioner awareness of sexual orientation among a community and internet sample of gay and bisexual men in New Zealand. AB - INTRODUCTION: General practitioners (GPs) can improve HIV and sexually transmitted infection (STI) screening, vaccination and wellbeing among gay, bisexual and other men who have sex with men (GBM) if they are aware of a patient's sexual orientation. AIM: To estimate GP awareness of their GBM patients' sexual orientation and examine whether HIV and STI screening was associated with this. METHODS: We analysed anonymous, self-completed data from 3168 GBM who participated in the community-based Gay Auckland Periodic Sex Survey (GAPSS) and Internet-based Gay men's Online Sex Survey (GOSS) in 2014. Participants were asked if their usual GP was aware of their sexual orientation or that they had sex with men. RESULTS: Half (50.5%) believed their usual GP was aware of their sexual orientation/behaviour, 17.0% were unsure, and 32.6% believed he/she was unaware. In multivariate analysis, GP awareness was significantly lower if the respondent was younger, Asian or an 'Other' ethnicity, bisexual-identified, had never had anal intercourse or had first done so very recently or later in life, and had fewer recent male sexual partners. GBM whose GP was aware of their sexual orientation were more likely to have ever had an HIV test (91.5% vs 57.9%; p<0.001), specific STI tests (91.7% vs 68.9%; p<0.001), and were twice as likely to have had an STI diagnosed. DISCUSSION: Lack of sexual orientation disclosure is resulting in missed opportunities to reduce health inequalities for GBM. More proactive, inclusive and safe environments surrounding the care of sexual orientation minorities are needed in general practice to encourage disclosure. PMID- 26437045 TI - The patient perspective on a first raised PSA test. AB - INTRODUCTION: Approximately 350 000 prostate-specific antigen (PSA) tests are undertaken in New Zealand on a quarter of a million men each year. A number of studies have looked at PSA testing done by general practitioners (GPs) and subsequent outcomes. Few have looked at the patient perspective after a raised PSA result. AIM: To explore patient experiences up to and following a raised PSA test. METHODS: Thirty-one general practices within the Midland region were recruited. Community laboratory databases were used to identify all men with a first raised PSA test during 2010. Questionnaires were sent to these men. RESULTS: One hundred and ninety-four (63%) eligible responses were received from 307 eligible men delivered questionnaires. For 54% of men this was their first PSA test. Most men (66%) identified that their PSA test was initiated by their GP. Forty-three percent of men identified having symptoms at the time of their first raised PSA test. A digital rectal examination (DRE) was performed on 73% of men at the time of the test. Fifty-eight percent of men were referred to see a specialist. Maori men were less likely to be referred after a raised PSA. Of all men referred, 61% received a biopsy. DISCUSSION: PSA testing is predominantly initiated by GPs. We found the care pathway is variable for men after an elevated PSA result. Standardisation of the pathway prior to and post diagnosis would assist patients in knowing what to expect and would aid in GP management of men being investigated for prostate cancer. PMID- 26437046 TI - The impact of non-motor manifestations of Parkinson's disease on partners: understanding and application of chronic sorrow theory. AB - INTRODUCTION: Parkinson's disease (PD) can cause many emotions, including grief and a sense of isolation for both the person with PD (referred to as Parkinsonian) and their partner. Such ongoing grief and emotional turmoil can be termed chronic sorrow. The aim of this research is to present accounts of partners' perspectives, analysed in the context of chronic sorrow theory, to offer health professionals an insight into the impact of non-motor PD symptoms on partners. METHODS: A group of partners of Parkinsonians provided the data through individual stories. These stories were subjected to thematic analysis, using a seven-step process leading to the establishment of themes. FINDINGS: Caregiver burden and chronic sorrow is not related to providing physical care, but the emotional care of attempting to minimise the effect of PD, coping with disturbance to sleep, and helping the Parkinsonian to maintain as much independence as possible. Contributors to this article found chronic sorrow theory provided a framework for understanding their emotions. Sharing their experiences with others provided an opportunity to be heard, and enabled them to make sense of individual situations. CONCLUSION: Chronic sorrow theory provides a useful framework for both partners of Parkinsonians in understanding their emotional responses, and for health professionals in considering the challenges partners face in coping with living with a person with PD. PMID- 26437047 TI - Culturally and linguistically diverse patients' views of multimorbidity and general practice care. AB - INTRODUCTION: It is recognised that patients who are culturally and linguistically diverse (CALD) have challenges in accessing health care and understanding health advice or instructions. Those with multimorbidity (MM) are likely to have additional difficulties. In New Zealand, little is known about how this patient group view their health and general practice health care. This study examined the views of multimorbid CALD patients about MM and the health care available in a Very Low Cost Access general practice. METHODS: This qualitative study recruited Samoan, Cook Island Ma-ori , and Cambodian patients with diabetes and more than three other long-term conditions. Two individual interviews and two language-specific focus groups were undertaken to yield themes representing the experience of these CALD patients with MM. FINDINGS: Participants described MM as having considerable impact on their life. They reported feeling responsible for supporting their own health and many detailed self-management techniques. However, they also expressed confusion, lack of information and limited understanding of MM, in particular about managing medication. Not all patients were aware of the range of available general practice services and some described difficulties in accessing general practice care. CONCLUSION: Despite being motivated to self-manage, this patient group report challenges in understanding their conditions and how to manage them, which may also be influenced by health beliefs. Available general practice services are not well known by CALD patients with MM. There is likely to be value in developing a specific structured, yet patient-centred, model of care for this group of patients. PMID- 26437048 TI - Nursing roles and responsibilities in general practice: three case studies. AB - INTRODUCTION: Primary care nursing teams may now comprise registered nurses (usually termed practice nurses), nurse practitioners, physician assistants, enrolled nurses, and primary care practice assistants, clinical assistants, or nursing assistants. There is a need to understand how practitioners in the different roles work with patients in the changed environment. The aim of this study was to describe the different configurations of health professionals' skill mix in three dissimilar primary care practices, their inter- and intra professional collaboration and communication, and to explore the potential of expanded nursing scopes and roles to improve patient access. METHODS: Document review, observation and interviews with key stakeholders were used to explore how health practitioners in three practice settings work together, including their delegation, substitution, enhancement and innovation in roles and interdisciplinary interactions in providing patient care. A multiphase integrative, qualitative and skill-mix framework analysis was used to compare findings related to nursing skill-mix across case studies. FINDINGS: Three models of primary care provision, utilising different nursing skill-mix and innovations were apparent. These illustrate considerable flexibility and responsiveness to local need and circumstances. CONCLUSION: Enabling nurses to work to the full extent of their scope, along with some adjustments to the models of care, greater multidisciplinary cooperation and coordination could mitigate future workforce shortages and improve patient access to care. PMID- 26437049 TI - Doctors' attitudes and confidence towards providing nutrition care in practice: Comparison of New Zealand medical students, general practice registrars and general practitioners. AB - INTRODUCTION: Improvements in individuals' nutrition behaviour can improve risk factors and outcomes associated with lifestyle-related chronic diseases. AIM: This study describes and compares New Zealand medical students, general practice registrars and general practitioners' (GPs') attitudes towards incorporating nutrition care into practice, and self-perceived skills in providing nutrition care. METHODS: A total of 183 New Zealand medical students, 51 general practice registrars and 57 GPs completed a 60-item questionnaire investigating attitudes towards incorporating nutrition care into practice and self-perceived skills in providing nutrition care. Items were scored using a 5-point Likert scale. Factor analysis was conducted to group questionnaire items and a generalised linear model compared differences between medical students, general practice registrars and GPs. RESULTS: All groups indicated that incorporating nutrition care into practice is important. GPs displayed more positive attitudes than students towards incorporating nutrition in routine care (p<0.0001) and performing nutrition recommendations (p<0.0001). General practice registrars were more positive than students towards performing nutrition recommendations (p=0.004), specified practices (p=0.037), and eliciting behaviour change (p=0.024). All groups displayed moderate confidence towards providing nutrition care. GPs were more confident than students in areas relating to wellness and disease (p<0.0001); macronutrients (p=0.030); micronutrients (p=0.010); and women, infants and children (p<0.0001). DISCUSSION: New Zealand medical students, general practice registrars and GPs have positive attitudes and moderate confidence towards incorporating nutrition care into practice. It is possible that GPs' experience providing nutrition care contributes to greater confidence. Strategies to facilitate medical students developing confidence in providing nutrition care are warranted. PMID- 26437050 TI - General practitioners should allow use of anonymised patient records for research: Yes. PMID- 26437051 TI - General practitioners should allow use of anonymised patient records for research: No. Confidentiality is not a decrepit concept. PMID- 26437052 TI - Challenges in the doctor-patient relationship: 12 tips for more effective peer group discussion. AB - In New Zealand, almost all general practitioners are members of peer groups, which provide opportunities for both clinical discussion and collegial support. This article proposes that peer groups can also be a useful medium for exploring specific challenges within the doctor-patient relationship. However, the peer group culture needs to be receptive to this particular goal. Structured discussion can help peer group members explore interpersonal issues more thoroughly. PMID- 26437054 TI - Effects of dry-aging on meat quality attributes and metabolite profiles of beef loins. AB - The objectives of this study were to evaluate different dry-aging regimes and their impacts on quality attributes and metabolite profiles of beef loins. Thirty loins (M. longissimus lumborum) from 15 beef carcasses at 2 days post-mortem were obtained. Each loin was cut in half yielding 60 sections, which were randomly assigned to six treatments including 4 dry-aging (2 temperatures (1 or 3 degrees C) * 2 air-velocities (0.2 or 0.5 m/s)) and 2 wet-aging regimes for 3 weeks; n=10/treatment. The sensory panel found that dry-aged loins had better flavour and overall liking (P<0.05), but there were no differences in tenderness and juiciness. No differences in drip/cook-loss and colour were observed. Metabolite analysis showed that 7 metabolites, including several flavour precursors, were more abundant in the dry-aged beef compared to the wet-aged beef, which may contribute to the enhanced flavours of the dry-aged beef. Overall, dry-aging loins at 3 degrees C with 0.2m/s resulted in the greatest improvement in beef palatability. PMID- 26437053 TI - A nanobuffer reporter library for fine-scale imaging and perturbation of endocytic organelles. AB - Endosomes, lysosomes and related catabolic organelles are a dynamic continuum of vacuolar structures that impact a number of cell physiological processes such as protein/lipid metabolism, nutrient sensing and cell survival. Here we develop a library of ultra-pH-sensitive fluorescent nanoparticles with chemical properties that allow fine-scale, multiplexed, spatio-temporal perturbation and quantification of catabolic organelle maturation at single organelle resolution to support quantitative investigation of these processes in living cells. Deployment in cells allows quantification of the proton accumulation rate in endosomes; illumination of previously unrecognized regulatory mechanisms coupling pH transitions to endosomal coat protein exchange; discovery of distinct pH thresholds required for mTORC1 activation by free amino acids versus proteins; broad-scale characterization of the consequence of endosomal pH transitions on cellular metabolomic profiles; and functionalization of a context-specific metabolic vulnerability in lung cancer cells. Together, these biological applications indicate the robustness and adaptability of this nanotechnology enabled 'detection and perturbation' strategy. PMID- 26437055 TI - Pain, Depression and Inflammation: Are Interconnected Causative Factors Involved? AB - Co-morbid depression and chronic pain are highly prevalent. The purpose of this review is to examine the role of chronic inflammation as a common mediator of these co-morbidities. Dysfunctional bidirectional pathways between the brain and the immune, endocrine and neurotransmitter systems have been extensively described and implicated in pain and psychiatric disorders. This short review therefore accesses the evidence in favour of the psychoneuroendocrine hypothesis of psychiatric disorders under three main headings: (1) by illustrating how different types of stress play a crucial role in initiating chronic inflammation in major depression, (2) by accessing the evidence that pain is frequently an important component of, and an initiator of, depression, and (3) considering the evidence that chronic inflammation provides an important link between chronic pain and depression, and the possible cellular mechanisms involved in this process. By understanding the critical role that chronic inflammation plays in pain and depression, novel approaches to the development of drugs may emerge that offer improvements in treatment. PMID- 26437056 TI - A randomized phase II study of stem cell mobilization with cyclophosphamide+G-CSF or G-CSF alone after lenalidomide-based induction in multiple myeloma. AB - The most common means of mobilizing autologous stem cells is G-CSF alone or combined with cyclophosphamide (CY) to obtain sufficient CD34+ cells for one to two transplants. There are few prospective, randomized studies investigating mobilization regimens in multiple myeloma (MM), especially after lenalidomide based induction. We designed this prospective, randomized study to compare low dose CY 2 g/m2 +G-CSF (arm A) and G-CSF alone (arm B) after lenalidomide-based up front induction in MM. Of the 80 initially randomized patients, 69 patients were evaluable, 34 and 35 patients in arms A and B, respectively. The primary end point was the proportion of patients achieving a yield of ?3 * 10(6)/kg CD34+ cells with 1-2 aphereses, which was achieved in 94% and 77% in arms A and B, respectively (P=0.084). The median number of aphereses needed to reach the yield of ?3 * 10(6)/kg was lower in arm A than in arm B (1 vs. 2, P=0.035). Two patients needed plerixafor in arm A and five patients in arm B (P=0.428). Although CY-based mobilization was more effective, G-CSF alone was successful in a great majority of patients to reach the defined collection target after three cycles of lenalidomide-based induction. PMID- 26437057 TI - Second reduced intensity conditioning allogeneic transplant as a rescue strategy for acute leukaemia patients who relapse after an initial RIC allogeneic transplantation: analysis of risk factors and treatment outcomes. AB - Limited therapeutic options are available after relapse of acute leukaemia following first reduced intensity conditioning haematopoietic stem cell transplantation (RIC1). A retrospective study on European Society for Blood and Marrow Transplantation (EBMT) registry data was performed on 234 adult patients with acute leukaemia who received a second RIC transplantation (RIC2) from 2000 to 2012 as a salvage treatment for relapse following RIC1. At the time of RIC2, 167 patients (71.4%) had relapsed or refractory disease, 49 (20.9%) were in second CR and 18 (7.7%) in third or higher CR. With a median follow-up of 21 (1.5 79) months after RIC2, 51 patients are still alive. At 2 years, the cumulative incidence of non-relapse mortality (NRM), relapse incidence (RI), leukaemia-free survival (LFS) and overall survival (OS) were 22.4% (95% confidence interval (CI): 17-28.4), 63.9% (56.7-70.1), 14.6% (8.8-18.5) and 20.5% (14.9-26.1), respectively. In patients with acute myelogenous, biphenotypic and undifferentiated leukaemia (representing 89.8% of all patients), duration of remission following RIC1 >225 days, presence of CR at RIC2, patient's Karnofsky performance status >80 at RIC2 and non-myeloablative conditioning were found to be the strongest predictors of patients' favourable outcome. PMID- 26437058 TI - Cerebrospinal fluid chimerism analysis in patients with neurological symptoms after allogeneic cell transplantation. AB - Central nervous system (CNS) complications have been described in patients undergoing allogeneic hematopoietic cell transplantation (alloHCT). Cerebrospinal fluid (CSF) analysis is included in the diagnostic workup in patients with neurological symptoms after alloHCT. CSF donor-recipient chimerism analysis usually is not used to evaluate patients with neurological complications after alloHCT. To assess the potential contribution of CSF donor-recipient chimerism in patients with neurological complications, we analyzed 85 CSF samples from 50 patients with neurological complications after alloHCT. After alloHCT, 21 patients showed the presence of recipient-derived DNA. In 13 of these patients, recurrence of the underlying disease was detected in CSF. There was a moderate correlation between the recipient DNA percentage as detected by short tandem repeat (STR) amplification and the cell concentration in CSF (Spearmann r: 0.66 P=0.004). The percentage of cells with immunophenotypic abnormalities from patients relapsing in the CNS detected by flow cytometry showed a strong correlation with the percentage of recipient-derived DNA in CSF assessed by STR analysis (Spearmann r: 0.83 P=0.0008). Donor-recipient chimerism analysis in CSF in patients with neurological symptoms after alloHCT is a practical, feasible and useful complementary method to the already established methodologies included in the diagnostic workup. PMID- 26437059 TI - The impact of pre-transplant body weight on short- and long-term outcomes after allogeneic hematopoietic cell transplantation in adults using different weight classification tools. PMID- 26437060 TI - Long-term results of adjuvant donor lymphocyte transfusion in AML after allogeneic stem cell transplantation. AB - Adjuvant transfusion of donor lymphocytes (aDLT) may reduce the risk of relapse after allogeneic stem cell transplantation in high-risk AML. We performed a retrospective analysis on the safety and efficacy of aDLT in a cohort of 46 patients. To be eligible for aDLT, patients had to be in CR for at least 120 days from transplantation, off immunosuppression for ?30 days and free of GvHD. Thirty four patients with similar disease characteristics and fulfilling the same selection criteria served as controls. Median follow-up among aDLT recipients was 7.2 years. Ten patients (22%) relapsed inspite of aDLT, as compared with 53% in the control group. Induction of GvHD was the main complication. However, non relapse mortality was low with patients dying from infection (n=2), severe chronic GvHD (n=1) and secondary malignancy (n=2). At the time of analysis, 31/46 aDLT recipients were alive in CR at a median of 5.7 years after first aDLT. Overall survival at 7 years after transplant was 67% as compared with 31% in the control group (P<0.001). In conclusion, aDLT is safe, when given in escalating doses to a well predefined group of patients. Long-term survival can be achieved. PMID- 26437061 TI - Clinically significant adverse events after major ABO mismatch BMT. PMID- 26437062 TI - Long-term survival outcomes of reduced-intensity allogeneic or autologous transplantation in relapsed grade 3 follicular lymphoma. AB - Grade 3 follicular lymphoma (FL) has aggressive clinical behavior. To evaluate the optimal first transplantation approach in relapsed/refractory grade 3 FL patients, we compared the long-term outcomes after allogeneic (allo-) vs autologous hematopoietic cell transplantation (auto-HCT) in the rituximab era. A total of 197 patients undergoing first reduced-intensity conditioning (RIC) allo HCT or first auto-HCT during 2000-2012 were included. Rituximab-naive patients were excluded. Allo-HCT recipients were younger, more heavily pretreated and had a longer interval between diagnosis and HCT. The 5-year probabilities of non relapse mortality (NRM), relapse/progression, PFS and overall survival (OS) for auto-HCT vs allo-HCT groups were 4% vs 27% (P<0.001), 61% vs 20% (P<0.001), 36% vs 51% (P=0.07) and 59% vs 54% (P=0.7), respectively. On multivariate analysis, auto-HCT was associated with reduced risk of NRM (relative risk (RR)=0.20; P=0.001). Within the first 11 months post HCT, auto- and allo-HCT had similar risks of relapse/progression and PFS. Beyond 11 months, auto-HCT was associated with higher risk of relapse/progression (RR=21.3; P=0.003) and inferior PFS (RR=3.2; P=0.005). In the first 24 months post HCT, auto-HCT was associated with improved OS (RR=0.42; P=0.005), but in long-time survivors (beyond 24 months) it was associated with inferior OS (RR=3.6; P=0.04). RIC allo-HCT as the first transplant approach can provide improved PFS and OS, in long-term survivors. PMID- 26437063 TI - A randomized controlled trial of cyclosporine and tacrolimus with strict control of blood concentrations after unrelated bone marrow transplantation. AB - Previous studies have suggested that tacrolimus (TAC) is more potent than cyclosporine (CSA) for prophylaxis against acute GVHD after allogeneic hematopoietic stem cell transplantation (HSCT). However, the target blood concentrations of these drugs in these studies were not consistent with the current recommendations. Therefore, we performed a randomized controlled trial to compare CSA and TAC with target blood concentrations of 500 and 15 ng/ml, respectively, to prevent acute GVHD after unrelated HSCT. A total of 107 patients were randomized into a CSA group (n=53) or a TAC group (n=54). During the first 4 weeks after HSCT, more than 90% of the patients achieved a mean blood concentration of between 80 and 120% of the target concentration. The incidences of grade II-IV and grade III-IV acute GVHD were 39.6 and 7.5% for the CSA group and 33.3 and 9.4% for the TAC group, respectively (P=0.41 and P=0.76). Other clinical outcomes, including overall survival, disease-free survival and the incidences of relapse, non-relapse mortality, and organ toxicities, were also equivalent. We concluded that the combinations of CSA and TAC with strict dose adjustment showed similar efficacies and toxicities as prophylaxis against acute GVHD after unrelated HSCT. PMID- 26437064 TI - Influence of melphalan plus fludarabine-conditioning regimen in elderly patients aged ?55 years with hematological malignancies. PMID- 26437065 TI - Diffuse large B-cell lymphoma: is salvage possible after failure of second-line treatment? PMID- 26437066 TI - The bone marrow microenvironment is similarly impaired in allogeneic hematopoietic stem cell transplantation patients with early and late poor graft function. AB - Poor graft function (PGF), including early and late PGF, is a serious complication following allotransplant. We recently reported that bone marrow microenvironment abnormalities may occur in cases of late PGF. Whether these abnormalities occur in early PGF remains unknown. To answer this question, we performed a nested case-control study comparing cellular elements of the bone marrow microenvironment in 10 subjects with early PGF, 30 subjects with late PGF and 40 subjects without PGF. Bone marrow endosteal cells, perivascular cells and endothelial cells were analyzed by flow cytometry and by hematoxylin-eosin and immunohistochemical staining in situ. Subjects with early and late PGF had similar abnormalities in these cell types compared with transplant recipients without PGF. However, none of the aforementioned elements of the bone marrow microenvironment were significantly different between early and late PGF patients. Our data suggest that similar abnormalities in the bone marrow microenvironment may occur in early and late PGF post allotransplant. Cellular approaches, such as the administration of mesenchymal stem cells, promise to be beneficial therapeutic strategies in patients with early or late PGF. PMID- 26437067 TI - Allogeneic hematopoietic cell transplantation for severe aplastic anemia: similar long-term overall survival after transplantation with related donors compared to unrelated donors. PMID- 26437068 TI - Decreased pulmonary function in asymptomatic long-term survivors after allogeneic hematopoietic stem cell transplant. PMID- 26437069 TI - Exacerbation of IgA nephropathy following G-CSF administration for PBSC collection: suggestions for better donor screening. PMID- 26437070 TI - Physician-diagnosed depression and suicides in pediatric hematopoietic cell transplant survivors with up to 40 years of follow-up. PMID- 26437071 TI - Early post-transplant contrast-enhanced abdominopelvic CT scan predicts the risk of subsequent acute GvHD. PMID- 26437072 TI - Skeletal Muscle Depletion Predicts the Prognosis of Patients with Advanced Pancreatic Cancer Undergoing Palliative Chemotherapy, Independent of Body Mass Index. AB - INTRODUCTION: Body composition has emerged as a prognostic factor in cancer patients. We investigated whether sarcopenia at diagnosis and loss of skeletal muscle during palliative chemotherapy were associated with survival in patients with pancreatic cancer. METHODS: We retrospectively reviewed the clinical outcomes of pancreatic cancer patients receiving palliative chemotherapy between 2003 and 2010. The cross-sectional area of skeletal muscle at L3 by computed tomography was analyzed with Rapidia 3D software. We defined sarcopenia as a skeletal muscle index (SMI)< 42.2 cm2/m2 (male) and < 33.9 cm2/m2 (female) using ROC curve. RESULTS: Among 484 patients, 103 (21.3%) patients were sarcopenic at diagnosis. Decrease in SMI during chemotherapy was observed in 156 (60.9%) male and 65 (40.6%) female patients. Decrease in body mass index (BMI) was observed in 149 patients (37.3%), with no gender difference. By multivariate analysis, sarcopenia (P< 0.001), decreasedBMI and SMI during chemotherapy (P = 0.002, P = 0.004, respectively) were poor prognostic factors for overall survival (OS). While the OS of male patients was affected with sarcopenia (P< 0.001) and decreased SMI (P = 0.001), the OS of female patients was influenced with overweight at diagnosis (P = 0.006), decreased BMI (P = 0.032) and decreased SMI (P = 0.014). Particularly, while the change of BMI during chemotherapy did not have impact on OS within the patients with maintained SMI (P = 0.750), decrease in SMI was associated with poor OS within the patients with maintained BMI (HR 1.502; P = 0.002). CONCLUSIONS: Sarcopenia at diagnosis and depletion of skeletal muscle, independent of BMI change, during chemotherapy were poor prognostic factors in advanced pancreatic cancer. PMID- 26437073 TI - Verbal Short-Term Memory Deficits in Chinese Children with Dyslexia may not be a Problem with the Activation of Phonological Representations. AB - This study explored the underlying mechanism of the verbal short-term memory deficit in Chinese children with developmental dyslexia. Twenty-four children with dyslexia and 28 age-matched normal readers participated in the study. They were required to memorize a visually presented series of six Chinese characters and identify them from a list also including code-specific distracters and non code-specific distracters. Error rates were recorded and were higher for code specific distracters in all three conditions, revealing phonological, visual, and semantic similarity effects respectively. Group comparisons showed a stronger phonological similarity effect in dyslexic group, suggesting intact activation of phonological representations of target characters. Children with dyslexia also exhibited a greater semantic similarity effect, revealing stronger activation of semantic representations, while visual similarity effects were equivalent to controls. These results suggest that the verbal short-term memory deficit in Chinese dyslexics might not stem from insufficient activation of phonological information. Based the semantic activation of target characters in dyslexics is greater than in controls, it is possible that the memory deficit of dyslexia is related with deficient inhibition of target semantic representations in short term memory. PMID- 26437074 TI - First fetal case of the 8q24.3 contiguous genes syndrome. AB - Molecular cytogenetics, particularly array-CGH, opened the way to the " genotype first approach " and for the discovery of new micro rearrangement syndromes. This was the case for the 8q24.3 microdeletion syndrome. Here, we describe the phenotype of a fetus with a 8q24.3 deletion. This rare condition has to be considered as a contiguous genes syndrome because its phenotype is generated by the SCRIB and PUF60 adjacent gene endophenotypes. The fetus presented atrioventricular septal defect and hypoplastic aortic arch, facial dysmorphism, microretrognathia, dysmorphic ears, clinodactyly of the 5th digit on both hands, mild rocker bottom feet and abnormal third sacral vertebra. This fetus is the first case where the endophenotype produced by SCRIB gene is absent. This case is compared with the previous published cases. PMID- 26437075 TI - Assessing the Power of Exome Chips. AB - Genotyping chips for rare and low-frequent variants have recently gained popularity with the introduction of exome chips, but the utility of these chips remains unclear. These chips were designed using exome sequencing data from mainly American-European individuals, enriched for a narrow set of common diseases. In addition, it is well-known that the statistical power of detecting associations with rare and low-frequent variants is much lower compared to studies exclusively involving common variants. We developed a simulation program adaptable to any exome chip design to empirically evaluate the power of the exome chips. We implemented the main properties of the Illumina HumanExome BeadChip array. The simulated data sets were used to assess the power of exome chip based studies for varying effect sizes and causal variant scenarios. We applied two widely-used statistical approaches for rare and low-frequency variants, which collapse the variants into genetic regions or genes. Under optimal conditions, we found that a sample size between 20,000 to 30,000 individuals were needed in order to detect modest effect sizes (0.5% < PAR > 1%) with 80% power. For small effect sizes (PAR <0.5%), 60,000-100,000 individuals were needed in the presence of non-causal variants. In conclusion, we found that at least tens of thousands of individuals are necessary to detect modest effects under optimal conditions. In addition, when using rare variant chips on cohorts or diseases they were not originally designed for, the identification of associated variants or genes will be even more challenging. PMID- 26437076 TI - Screening for the Most Suitable Reference Genes for Gene Expression Studies in Equine Milk Somatic Cells. AB - Apart from the well-known role of somatic cell count as a parameter reflecting the inflammatory status of the mammary gland, the composition of cells isolated from milk is considered as a valuable material for gene expression studies in mammals. Due to its unique composition, in recent years an increasing interest in mare's milk consumption has been observed. Thus, investigating the genetic background of horse's milk variability presents and interesting study model. Relying on 39 milk samples collected from mares representing three breeds (Polish Primitive Horse, Polish Cold-blooded Horse, Polish Warmblood Horse) we aimed to investigate the utility of equine milk somatic cells as a source of mRNA and to screen the best reference genes for RT-qPCR using geNorm and NormFinder algorithms. The results showed that despite relatively low somatic cell counts in mare's milk, the amount and the quality of the extracted RNA are sufficient for gene expression studies. The analysis of the utility of 7 potential reference genes for RT-qPCR experiments for the normalization of equine milk somatic cells revealed some differences between the outcomes of the applied algorithms, although in both cases the KRT8 and TOP2B genes were pointed as the most stable. Analysis by geNorm showed that the combination of 4 reference genes (ACTB, GAPDH, TOP2B and KRT8) is required for apropriate RT-qPCR experiments normalization, whereas NormFinder algorithm pointed the combination of KRT8 and RPS9 genes as the most suitable. The trial study of the relative transcript abundance of the beta-casein gene with the use of various types and numbers of internal control genes confirmed once again that the selection of proper reference gene combinations is crucial for the final results of each real-time PCR experiment. PMID- 26437077 TI - Analysing Local Sparseness in the Macaque Brain Network. AB - Understanding the network structure of long distance pathways in the brain is a necessary step towards developing an insight into the brain's function, organization and evolution. Dense global subnetworks of these pathways have often been studied, primarily due to their functional implications. Instead we study sparse local subnetworks of the pathways to establish the role of a brain area in enabling shortest path communication between its non-adjacent topological neighbours. We propose a novel metric to measure the topological communication load on a vertex due to its immediate neighbourhood, and show that in terms of distribution of this local communication load, a network of Macaque long distance pathways is substantially different from other real world networks and random graph models. Macaque network contains the entire range of local subnetworks, from star-like networks to clique-like networks, while other networks tend to contain a relatively small range of subnetworks. Further, sparse local subnetworks in the Macaque network are not only found across topographical super areas, e.g., lobes, but also within a super-area, arguing that there is conservation of even relatively short-distance pathways. To establish the communication role of a vertex we borrow the concept of brokerage from social science, and present the different types of brokerage roles that brain areas play, highlighting that not only the thalamus, but also cingulate gyrus and insula often act as "relays" for areas in the neocortex. These and other analysis of communication load and roles of the sparse subnetworks of the Macaque brain provide new insights into the organisation of its pathways. PMID- 26437078 TI - Novel Mn3 [Co(CN)6]2@SiO2@Ag Core-Shell Nanocube: Enhanced Two-Photon Fluorescence and Magnetic Resonance Dual-Modal Imaging-Guided Photothermal and Chemo-therapy. AB - The versatile Mn3[Co(CN)6]2@SiO2@Ag core-shell NCs are prepared by a simple coprecipitation method. Ag nanoparticles with an average diameter of 12 nm deposited on the surface of Mn3[Co(CN)6]2@SiO2 through S-Ag bonding are fabricated in ethanol solution by reducing silver nitrate (AgNO3 ) with NaBH4 . The NCs possess T1 -T2 dual-modal magnetic resonance imaging ability. The inner Prussian blue analogs (PBAs) Mn3[Co(CN)6]2 exhibit bright two-photon fluorescence (TPF) imaging when excited at 730 nm. Moreover, the TPF imaging intensity displays 1.85-fold enhancement after loading of Ag nanoparticles. Besides, the sample also has multicolor fluorescence imaging ability under 403, 488, and 543 nm single photon excitation. The as-synthesized Mn3[Co(CN)6]2@SiO2@Ag NCs show a DOX loading capacity of 600 mg g(-1) and exhibit an excellent ability of near infrared (NIR)-responsive drug release and photothermal therapy (PTT) which is induced from the relative high absorbance in NIR region. The combined chemotherapy and PTT against cancer cells in vitro test shows high therapeutic efficiency. The multimodal treatment and imaging could lead to this material a potential multifunctional system for biomedical diagnosis and therapy. PMID- 26437079 TI - The SET Domain Is Essential for Metnase Functions in Replication Restart and the 5' End of SS-Overhang Cleavage. AB - Metnase (also known as SETMAR) is a chimeric SET-transposase protein that plays essential role(s) in non-homologous end joining (NHEJ) repair and replication fork restart. Although the SET domain possesses histone H3 lysine 36 dimethylation (H3K36me2) activity associated with an improved association of early repair components for NHEJ, its role in replication restart is less clear. Here we show that the SET domain is necessary for the recovery from DNA damage at the replication forks following hydroxyurea (HU) treatment. Cells overexpressing the SET deletion mutant caused a delay in fork restart after HU release. Our In vitro study revealed that the SET domain but not the H3K36me2 activity is required for the 5' end of ss-overhang cleavage with fork and non-fork DNA without affecting the Metnase-DNA interaction. Together, our results suggest that the Metnase SET domain has a positive role in restart of replication fork and the 5' end of ss-overhang cleavage, providing a new insight into the functional interaction of the SET and the transposase domains. PMID- 26437081 TI - Oral Health-Related Quality of Life and Self-Rated Speech in Children With Existing Fistulas in Mid-Childhood and Adolescence. AB - OBJECTIVE: To report the associations of oro-nasal fistulae on the patient centered outcomes oral health-related quality of life and self-reported speech outcomes in school aged-children. DESIGN: Prospective, nonrandomized multicenter design. SETTING: Six ACPA-accredited cleft centers. PARTICIPANTS: Patients with cleft palate at the age of mixed dentition. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Prevalence of fistula and location of fistula (Pittsburgh Classification System). Patients were placed into one of three groups based on the following criteria: alveolar cleft present, no previous repair (Group 1); alveolar cleft present, previously repaired (Group 2); no congenital alveolar cleft (Group 3). Presence of fistula and subgroup classification were correlated to oral health-related quality of life (Child Oral Health Impact Profile [COHIP]) and perceived speech outcomes. RESULTS: The fistula rate was 5.52% (62 of 1198 patients). There was a significant difference in fistula rate between the three groups: Group 1 (11.15%), Group 2 (4.44%), Group 3 (1.90%). Patients with fistula had significantly lower COHIP scores (F1,1188 = 4.79; P = .03) and worse self reported speech scores (F1,1197 = 4.27; P = .04). Group 1 patients with fistula had the lowest COHIP scores (F5,1188 = 4.78, P =.02) and the lowest speech scores (F5,1188 = 3.41, P = .003). CONCLUSIONS: Presence of palatal fistulas was associated with lower oral health-related quality of life and perceived speech among youth with cleft. The poorest outcomes were reported among those with the highest fistula rates, including an unrepaired alveolar cleft. PMID- 26437080 TI - Diffuse large B-cell lymphoma cell-of-origin classification using the Lymph2Cx assay in the context of BCL2 and MYC expression status. PMID- 26437082 TI - The Psychosocial Impact of Cleft Lip and/or Palate on Unaffected Siblings. AB - BACKGROUND: Sibling relationships are among the most unique social connections, significantly affecting psychosocial adjustment. Previous reviews in the fields of chronic illness and disability have concluded that unaffected siblings of children with long-term conditions are at risk of poorer psychological functioning as a consequence. Much research has investigated the psychosocial impact of CL/P on affected individuals and their parents, yet comparatively little is known about the impact on other close family members. OBJECTIVE: To gain a better understanding of the experience of unaffected siblings of children born with CL/P, with a view to informing service provision and support. DESIGN: Individual qualitative interviews conducted over the telephone/Internet with five siblings and eight parents, including five sibling-parent pairs from the same family. RESULTS: Thematic analysis identified three key themes applicable across both parent and sibling interviews: perceptions of positive and negative impacts, factors affecting the degree of impact, and support for families. CONCLUSIONS: This study provides insight into a population that is often overlooked in the context of cleft care. The analysis identified a number of sibling support and information needs, along with suggestions of how to incorporate support for siblings in practice. The findings suggest that an inclusive approach to health care encompassing all members of the family is essential for optimal familial adjustment. PMID- 26437084 TI - A Young and Gifted Scientist. PMID- 26437085 TI - Meta-Analysis of Soybean-based Biodiesel. AB - Biofuel policy changes in the United States have renewed interest in soybean [ (L.) Merr.] biodiesel. Past studies with varying methodologies and functional units can provide valuable information for future work. A meta-analysis of nine peer-reviewed soybean life cycle analysis (LCA) biodiesel studies was conducted on the northern Great Plains in the United States. Results of LCA studies were assimilated into a standardized system boundary and functional units for global warming (GWP), eutrophication (EP), and acidification (AP) potentials using biodiesel conversions from peer-reviewed and government documents. Factors not fully standardized included variations in NO accounting, mid- or end-point impacts, land use change, allocation, and statistical sampling pools. A state-by state comparison of GWP lower and higher heating values (LHV, HHV) showed differences attributable to variations in spatial sampling and agricultural practices (e.g., tillage, irrigation). The mean GWP of LHV was 21.1 g.CO-eq MJ including outliers, and median EP LHV and AP LHV was 0.019 g.PO-eq MJ and 0.17 g.SO-eq MJ, respectively, using the limited data available. An LCA case study of South Dakota soybean-based biodiesel production resulted in GWP estimates (29 or 31 g.CO-eq MJ; 100% mono alkyl esters [first generation] biodiesel or 100% fatty acid methyl ester [second generation] biodiesel) similar to meta-analysis results (30.1 g.CO-eq MJ). Meta-analysis mean results, including outliers, resemble the California Low Carbon Fuel Standard for soybean biodiesel default value without land use change of 21.25 g.CO-eq MJ. Results were influenced by resource investment differences in water, fertilizer (e.g., type, application), and tillage. Future biofuel LCA studies should include these important factors to better define reasonable energy variations in regional agricultural management practices. PMID- 26437083 TI - New insights into the impact of Lactobacillus population on host-bacteria metabolic interplay. AB - We aimed at evaluating the association between intestinal Lactobacillus sp. composition and their metabolic activity with the host metabolism in adult and elderly individuals. Faecal and plasma metabolites were measured and correlated to the Lactobacillus species distribution in healthy Estonian cohorts of adult (n = 16; < 48 y) and elderly (n = 33; > 65 y). Total cholesterol, LDL, C-reactive protein and glycated hemoglobin were statistically higher in elderly, while platelets, white blood cells and urinary creatinine were higher in adults. Aging was associated with the presence of L. paracasei and L. plantarum and the absence of L. salivarius and L. helveticus. High levels of intestinal Lactobacillus sp. were positively associated with increased concentrations of faecal short chain fatty acids, lactate and essential amino acids. In adults, high red blood cell distribution width was positively associated with presence of L. helveticus and absence of L. ruminis. L. helveticus was correlated to lactate and butyrate in faecal waters. This indicates a strong relationship between the composition of the gut Lactobacillus sp. and host metabolism. Our results confirm that aging is associated with modulations of blood biomarkers and intestinal Lactobacillus species composition. We identified specific Lactobacillus contributions to gut metabolic environment and related those to blood biomarkers. Such associations may prove useful to decipher the biological mechanisms underlying host-gut microbial metabolic interactions in an ageing population. PMID- 26437086 TI - The Pivotal Role of Phosphorus in a Resilient Water-Energy-Food Security Nexus. AB - We make the case that phosphorus (P) is inextricably linked to an increasingly fragile, interconnected, and interdependent nexus of water, energy, and food security and should be managed accordingly. Although there are many other drivers that influence water, energy, and food security, P plays a unique and under recognized role within the nexus. The P paradox derives from fundamental challenges in meeting water, energy, and food security for a growing global population. We face simultaneous dilemmas of overcoming scarcity of P to sustain terrestrial food and biofuel production and addressing overabundance of P entering aquatic systems, which impairs water quality and aquatic ecosystems and threatens water security. Historical success in redistributing rock phosphate as fertilizer to enable modern feed and food production systems is a grand societal achievement in overcoming inequality. However, using the United States as the main example, we demonstrate how successes in redistribution of P and reorganization of farming systems have broken local P cycles and have inadvertently created instability that threatens resilience within the nexus. Furthermore, recent expansion of the biofuels sector is placing further pressure on P distribution and availability. Despite these challenges, opportunities exist to intensify and expand food and biofuel production through recycling and better management of land and water resources. Ultimately, a strategic approach to sustainable P management can help address the P paradox, minimize tradeoffs, and catalyze synergies to improve resilience among components of the water, energy, and food security nexus. PMID- 26437087 TI - Dietary Nitrate for Methane Mitigation Leads to Nitrous Oxide Emissions from Dairy Cows. AB - Nitrate supplements to cattle diets can reduce enteric CH emissions. However, if NO metabolism stimulates NO emissions, the effectiveness of dietary NO for CH mitigation will be reduced. We quantified NO emissions as part of a dairy cow feeding experiment in which urea was substituted in nearly iso-N diets with 0, 5, 14 or 21 g NO kg dry matter (DM). The feeding experiment was a Latin square with repetition of Period 1. Each period lasted 4 wk, with CH emission measurements in Week 4 using respiration chambers. During Period 3, NO concentrations in chamber outlet air were monitored semicontinuously during 48 h. High, but fluctuating, NO concentrations were seen at the two highest NO levels (up to between 2 and 5 MUL L), and dynamics were linked with recent feed intake. In Periods 4 and 5, NO concentrations and feed intake were determined from all four respiration chambers during two 7-h periods. Emissions of NO coincided with feed intake, again with NO concentrations in the microliter per liter range at the two highest NO intake levels. Neither feed nor excretion of NO via urine were significant sources of NO, indicating that emissions came from the animals. Leakages due to rumen fistulation could also not account for NO emissions. The possibility that NO is produced in the oral cavity is discussed. Nitrous oxide emission factors ranged between 0.7 and 1.0% except in one case at 21 g NO kg DM, where it was 3.4%. When accounting for NO emissions at the highest NO intake level, the overall GHG mitigation effect in two different animal-diet combinations changed from -47 to 40%, and from -19 to -17%, respectively, due to NO emissions. PMID- 26437088 TI - Methane and Nitrous Oxide Emissions from Flooded Rice Systems following the End of-Season Drain. AB - Large CH and NO fluxes can occur from flooded rice ( L.) systems following end-of season drainage, which contribute significantly to the total growing-season greenhouse gas (GHG) emissions. Field and laboratory studies were conducted to determine under what soil water conditions these emissions occur. In three field studies, GHG fluxes and dissolved CH in the soil pore water were measured before and after drainage. Across all fields, approximately 10% of the total seasonal CH emissions and 27% of the total seasonal NO emissions occurred following the final drain, confirming the importance of quantifying postdrainage CH and NO emissions. Preplant fertilizer N had no effect on CH emissions or dissolved CH; however, increased postdrainage NO fluxes were observed at higher N rates. To determine when postdrainage sampling needs to take place, our laboratory incubation study measured CH and NO fluxes from intact soil cores from these fields as the soil dried. Across fields, maximum CH emissions occurred at approximately 88% water filled pore space (WFPS), but emissions were observed between 47 and 156% WFPS. In contrast, maximum NO emissions occurred between 45 and 71% WFPS and were observed between 16 and 109% WFPS. For all fields, gas samplings between 76 and 100% WFPS for CH emissions and between 43 and 78% WFPS for NO emissions was necessary to capture 95% of these postdrainage emissions. We recommend that frequent gas sampling following drainage be included in the GHG protocol of total GHG emissions. PMID- 26437089 TI - Soil Methane and Carbon Dioxide Fluxes from Cropland and Riparian Buffers in Different Hydrogeomorphic Settings. AB - Riparian buffers contribute to the mitigation of nutrient pollution in agricultural landscapes, but there is concern regarding their potential to be hot spots of greenhouse gas production. This study compared soil CO and CH fluxes in adjacent crop fields and riparian buffers (a flood-prone forest and a flood protected grassland along an incised channel) and examined the impact of water table depth (WTD) and flood events on the variability of gas fluxes in riparian zones. Results showed significantly ( < 0.001) higher CO emission in riparian areas than in adjoining croplands (6.8 +/- 0.6 vs. 3.6 +/- 0.5 Mg CO-C ha yr; mean +/- SE). Daily flux of CO and soil temperature were significantly related ( < 0.002), with Q values ranging between 1.75 and 2.53. Significant relationships ( < 0.05) were found between CH daily flux and WTD. Flood events resulted in enhanced CH emission (up to +44.5 mg CH-C m d in a swale) under warm soil conditions (>22 degrees C), but the effect of flooding was less pronounced in early spring (emission <1.06 mg CH-C m d), probably due to low soil temperature. Although CH flux direction alternated at all sites, overall the croplands and the flood-affected riparian forest were CH sources, with annual emission averaging +0.04 +/- 0.17 and +0.92 +/- 1.6 kg CH-C ha, respectively. In the riparian forest, a topographic depression (<8% of the total area) accounted for 78% of the annual CH emission, underscoring the significance of landscape heterogeneity on CH dynamics in riparian buffers. The nonflooded riparian grassland, however, was a net CH sink (-1.08 +/- 0.22 kg CH-C ha yr), probably due to the presence of subsurface tile drains and a dredged/incised channel at that study site. Although these hydrological alterations may have contributed to improvement in the CH sink strength of the riparian grassland, this must be weighed against the water quality maintenance functions and other ecological services provided by riparian buffers. PMID- 26437090 TI - Simulation of Birch and Pine Litter Influence on Early Stage of Reclaimed Soil Formation Process under Controlled Conditions. AB - The impact of litter decomposition on chemical substrate properties and element leaching during early soil formation in afforested post-mine sites and the influence of different tree species are key issues in new ecosystem development. Scots pine ( L.) and common birch ( Roth) are important pioneering species used in afforestation of post-mine sites in central and eastern Europe. The aim of this study was to assess the impact of litter decomposition of these species on the chemical properties of mine soil substrates. The impact of litter decomposition on soil properties was tested on quaternary and neogene substrates with different textures (sands, loams, and mixtures of clays and sands) in a controlled incubation experiment using PVC columns. Simulation of precipitation and leaching was undertaken for 10 wk at a temperature of 16 degrees C with distilled water (200 mL wk) through cylinders with litter, substrate + litter, and control substrate (no litter). Filtrated water solution was collected once a week for laboratory analysis, and the concentrations of dissolved organic C, total N, K, Ca, Mg, and P were determined. The study results indicate a stronger impact of the common birch on the chemical properties of reclaimed mine soils compared with pine. After the experiment, birch litter caused significant changes in pH in quaternary sands, concentration of P in quaternary loams (Ql) and mixtures of neogene clays and quaternary sands (QsNc), exchangeable Ca in QsNc, and Mg in Ql and QsNc compared with pine litter. Birch, in comparison to pine, may affect the intensity of early-stage soil-forming processes by increasing nutrient availability and transport into the soil profile, which may affect the development of soil microbial communities. This process results in different soil properties under the two tree species. PMID- 26437091 TI - Sensitivity Analysis of the Agricultural Policy/Environmental eXtender (APEX) for Phosphorus Loads in Tile-Drained Landscapes. AB - Numerical modeling is an economical and feasible approach for quantifying the effects of best management practices on dissolved reactive phosphorus (DRP) loadings from agricultural fields. However, tools that simulate both surface and subsurface DRP pathways are limited and have not been robustly evaluated in tile drained landscapes. The objectives of this study were to test the ability of the Agricultural Policy/Environmental eXtender (APEX), a widely used field-scale model, to simulate surface and tile P loadings over management, hydrologic, biologic, tile, and soil gradients and to better understand the behavior of P delivery at the edge-of-field in tile-drained midwestern landscapes. To do this, a global, variance-based sensitivity analysis was performed, and model outputs were compared with measured P loads obtained from 14 surface and subsurface edge of-field sites across central and northwestern Ohio. Results of the sensitivity analysis showed that response variables for DRP were highly sensitive to coupled interactions between presumed important parameters, suggesting nonlinearity of DRP delivery at the edge-of-field. Comparison of model results to edge-of-field data showcased the ability of APEX to simulate surface and subsurface runoff and the associated DRP loading at monthly to annual timescales; however, some high DRP concentrations and fluxes were not reflected in the model, suggesting the presence of preferential flow. Results from this study provide new insights into baseline tile DRP loadings that exceed thresholds for algal proliferation. Further, negative feedbacks between surface and subsurface DRP delivery suggest caution is needed when implementing DRP-based best management practices designed for a specific flow pathway. PMID- 26437092 TI - Uncovering the Minor Contribution of Land-Cover Change in Upland Forests to the Net Carbon Footprint of a Boreal Hydroelectric Reservoir. AB - Hydropower in boreal conditions is generally considered the energy source emitting the least greenhouse gas per kilowatt-hour during its life cycle. The purpose of this study was to assess the relative contribution of the land-use change on the modification of the carbon sinks and sources following the flooding of upland forested territories to create the Eastmain-1 hydroelectric reservoir in Quebec's boreal forest using Carbon Budget Model of the Canadian Forest Sector. Results suggest a carbon sink loss after 100 yr of 300,000 +/- 100,000 Mg CO equivalents (COe). A wildfire sensitivity analysis revealed that the ecosystem would have acted as a carbon sink as long as <75% of the territory had burned over the 100-yr-long period. Our long-term net carbon flux estimate resulted in emissions of 4 +/- 2 g COe kWh as a contribution to the carbon footprint calculation, one-eighth what was obtained in a recent study that used less precise and less sensitive estimates. Consequently, this study significantly reduces the reported net carbon footprint of this reservoir and reveals how negligible the relative contribution of the land-use change in upland forests to the total net carbon footprint of a hydroelectric reservoir in the boreal zone can be. PMID- 26437093 TI - Sludge-Derived Biochar for Arsenic(III) Immobilization: Effects of Solution Chemistry on Sorption Behavior. AB - Recycling sewage sludge by pyrolysis has attracted increasing attention for pollutant removal from wastewater and soils. This study scrutinized As(III) sorption behavior on sludge-derived biochar (SDBC) under different pyrolysis conditions and solution chemistry. The SDBC pyrolyzed at a higher temperature showed a lower As(III) sorption capacity and increasingly nonlinear isotherm due to loss of surface sites and deoxygenation-dehydrogenation. The Langmuir sorption capacity on SDBC (3.08-6.04 mg g) was comparable to other waste-derived sorbents, with the highest As(III) sorption on SDBC pyrolyzed at 400 degrees C for 2 h. The As(III) sorption kinetics best fit with the pseudo-second-order equation, thus suggesting the significance of the availability of surface sites and initial concentration. Sorption of As(III) was faster than that of Cr(VI) but slower than that of Pb(II), which was attributed to their differences in molar volume (correlated to diffusion coefficients) and sorption mechanisms. The X-ray photoelectron spectra revealed an increase of oxide oxygen (O) with a decrease of sorbed water, indicative of ligand exchange with hydroxyl groups on SDBC surfaces. The As(III) sorption was not pH dependent in acidic-neutral range (pH < 8) due to the buffering capacity and surface characteristics of the SDBC; however, sorption was promoted by increasing pH in the alkaline range (pH > 8) because of As(III) speciation in solution. An increasing ionic strength (0.001 0.1 mol L) facilitated As(III) sorption, indicating the predominance of ligand exchange over electrostatic interactions, while high concentrations (0.1 mol L) of competing anions (fluoride, sulfate, carbonate, and phosphate) inhibited As(III) sorption. These results suggest that SDBC is applicable for As(III) immobilization in most environmentally relevant conditions. PMID- 26437094 TI - Phosphate Treatment of Lead-Contaminated Soil: Effects on Water Quality, Plant Uptake, and Lead Speciation. AB - Water quality threats associated with using phosphate-based amendments to remediate Pb-contaminated soils are a concern, particularly in riparian areas. This study investigated the effects of P application rates to a Pb-contaminated alluvial soil on Pb and P loss via surface water runoff, Pb accumulation in tall fescue ( Schreb; Kentucky 31), and Pb speciation. An alluvial soil was treated with triple superphosphate at P to Pb molar ratios of 0:1 (control), 4:1, 8:1, and 16:1. After a 6-mo reaction period, rainfall simulation (RFS) studies were conducted, followed by tall fescue establishment and a second set of RFS studies (1 yr after treatment). Results from the first RFS study (unvegetated) demonstrated that the total Pb and P concentrations in the effluents of 8:1 and 16:1 (P:Pb molar ratio) treatment levels were significantly greater ( < 0.05) than the control. One year after P treatment and 6 mo after vegetation establishment, total P and Pb concentrations of the effluents from a second RFS decreased by one to three orders of magnitude. Total and dissolved P concentration in runoff from the 16:1 P:Pb treatment remained significantly greater than all other treatments. However, total Pb concentration in the runoff was comparable among the treatments. Phosphorus treatment also reduced Pb uptake into tall fescue by >55%. X-ray absorption near-edge structure spectroscopy data showed that pyromorphite [Pb(PO)OH,Cl,F] abundance ranged from 0% (control) to 32% (16:1 P:Pb; 1 yr after treatment) of the total soil Pb. Although P treatment stimulated pyromorphite formation, pyromorphite abundance was comparable between the P-treated soils. These findings suggest that a 4:1 (P:Pb molar ratio) P treatment may be a sufficient means of reducing Pb bioavailability while minimizing concerns related to P loss in an alluvial setting. PMID- 26437095 TI - Nitrogen Runoff Losses during Warm-Season Turfgrass Sod Establishment. AB - Concern exists over the potential loss of nitrogen (N) and phosphorus (P) in runoff from newly established and fertilized lawns. Nutrient losses can be higher from turf when shoot density and surface cover are low and root systems are not fully developed. This study was conducted to evaluate fertilizer source and timing effects on nutrient losses from newly sodded lawns of St. Augustinegrass [ (Walt.) Kuntze]. For each study, 12 33.6-m plots were established on an undisturbed Alfisol having a 3.7% slope. Each plot was equipped with a runoff collection system, instrumentation for runoff flow rate measurement, and automated samplers. A 28-d establishment study was initiated on 8 Aug. 2012 and repeated on 9 Sept. 2012. Treatments included unfertilized plots, fertilized plots receiving 4.88 g N m as urea 6 d after planting, fertilized plots receiving 4.88 g N m as sulfur-coated urea 6 d after planting, and fertilized plots receiving 4.88 g N m as urea 19 d after planting. Runoff events were created by irrigating with 17 mm of water over 27 min. Runoff water samples were collected after every 37.8 L and analyzed for NO-N, NH-N, dissolved organic N (DON), and PO P. Increases of approximately 2 to 4 mg L NO-N and 8 to 12 mg L PO-P occurred in runoff 1 d after fertilization, which returned to background levels within 7 d. Total fertilizer N lost to runoff was 0.6 to 4.2% of that applied. Delaying fertilizer application until 19 d after planting provided no reduction in nutrient loss compared with a similar application 6 d after planting. Approximately 33% of the N lost in runoff was as DON. This large amount of DON suggests significant N loss from decomposing organic matter may occur during sod establishment. PMID- 26437096 TI - Patch-Burn Grazing Effects on the Ecological Integrity of Tallgrass Prairie Streams. AB - Conversion to agriculture, habitat fragmentation, and the loss of native grazers have made tallgrass prairie one of the most endangered ecosystems. One management option for the remaining prairie parcels, patch-burn grazing (PBG), applies a controlled burn to a portion of the prairie to attract cattle, creating a mosaic of more- and less-grazed patches. Although beneficial to cattle and grassland birds, the potential impacts of PBG on streams have not been studied, and a holistic approach is needed to ensure against adverse effects. We used a Before After-Control-Impact design to assess potential impacts of PBG with and without riparian protection on tallgrass prairie headwater streams. We sampled stream macroinvertebrates and benthic organic matter 2 yr before and 2 yr during PBG treatments on two grazed watersheds with riparian fencing (fenced), two unfenced grazed watersheds (unfenced), and two ungrazed (control) watersheds. Very fine benthic organic matter increased significantly (51%) in unfenced streams compared with controls ( < 0.007), and fine particulate organic matter (<1 mm and >250 um) increased 3-fold in the unfenced streams compared with controls ( = 0.008). The contribution of fine inorganic sediments to total substrata increased 28% in unfenced streams during PBG, which was significantly different from controls ( = 0.03). Additionally, the abundance of Ephemeroptera, Plecoptera, and Trichoptera taxa decreased from 7635 to 687 individuals m in unfenced streams, which was significantly lower than in control streams ( = 0.008). Our results indicate that PBG adversely influences prairie streams through sediment inputs and reductions in sensitive invertebrate taxa, but riparian fencing can alleviate these impacts. PMID- 26437097 TI - The Effect of the Moisture Regime on the Interaction of Fluorene with Porous Media. AB - Movement and persistence of organic molecules in porous media is strongly influenced by their interactions with the solid phase. Understanding these interactions is important for the execution of reliable risk assessments and for proper handling and disposal of toxic organic chemicals. Transport and attenuation models often assume rapid adsorption-desorption equilibration and neglect the role of the ever-changing moisture regime at the top of the vadose zone. Adsorption of the polyaromatic hydrocarbon fluorene (CH), both from hexane and from water, on a cattle manure compost and on two soils-Dor (montmorillonitic, 1.9% organic matter [OM]) and Maagan-Michael (kaolinitic, 5.2% OM)-was studied. Adsorption from hexane mimics interactions with surfaces exposed to a gas phase or to an apolar liquid. Desorption was measured after loading the sorbents with fluorene dissolved in hexane, evaporating the solvent, and incubation in the wet state (above saturation of the porous medium), air-dried, or while undergoing wetting-drying cycles. Although good correlation was observed between the adsorption coefficient of fluorene from water and OM content, adsorption from hexane highly correlated with the surface charge density of the sorbent (its cation exchange capacity or its polarity). When added to the sorbents from hexane and then desorbed into water, less fluorene desorbed than predicted by its aqueous adsorption isotherms. Desorption from all sorbents decreased as the duration of incubation at air dryness increased. Thus, fluorene exhibited adsorption-desorption hysteresis, and a particularly strong adsorption desorption hysteresis was exhibited by fluorene-loaded Maagan-Michael soil after undergoing wetting-drying cycles. PMID- 26437098 TI - The Role of Hydrology in the Polychlorinated Dibenzo--dioxin and Dibenzofuran Distributions in a Lowland River. AB - Persistent organic pollutants such as polychlorinated dibenzo--dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) are environmental contaminants that have widespread distribution and pose a serious threat to aquatic ecosystems. We conducted a study to quantify the distribution, patterns, and transport of PCDDs and PCDFs along the Pilica River in central Poland under different hydrological conditions to estimate the loads of these compounds and understand their fate in aquatic systems. Water samples were collected at five sampling points along the river that represent a range of hydrological conditions including flooding and stable and low water flows. Reduced river water flow was associated with lower average total and toxic equivalent (TEQ) concentrations of PCDDs plus PCDFs: 33.6 pg L and 4.21 pg TEQ L for flooding; 28.3 pg L and 3.6 pg TEQ L for stable flow; 18.4 pg L and 1.0 pg TEQ L for low-water flow. Similar results were observed for daily loadings of total and TEQ concentrations: the highest values were observed during flooding (331.1-839.4 mg d and 27.8-110.7 mg TEQ d), medium under stable hydrological conditions (55.8-121.0 mg d and 7.7-15.3 mg TEQ d), and the lowest values during low water flow (30.9 and 40.3 mg d and 1.4-2.4 mg TEQ d). The results demonstrate that diffuse sources of pollution play a key role during periods of high water flow (i.e., flooding season), whereas point sources of pollution, including municipal and industrial wastewater treatment plant discharges, mainly determine the PCDD and PCDF concentrations seen during low water periods. PMID- 26437099 TI - Adsorption of Sulfamethazine from Environmentally Relevant Aqueous Matrices onto Hypercrosslinked Adsorbent MN250. AB - Four hundred tons of sulfamethazine are fed to livestock annually in North America for disease prevention and growth promotion, but the majority is excreted unmetabolized into the environment. Due to its slow degradation and high mobility, sulfamethazine contaminates groundwater and causes aquatic ecosystem damage. Sulfamethazine remediation methods are not universally effective, necessitating newer techniques. Hypercrosslinked polystyrene adsorbents show promise because of high surface areas, durability, and regenerable properties. Using batch techniques, sulfamethazine adsorption onto Purolite MN250 was evaluated in the presence of dissolved humic acid and under variable pH and ionic strength. The adsorption capacity () of MN250 for sulfamethazine with humic acid was 109.3 mg g. In simulated groundwater, at pH 5 was 51 to 62% higher than at pH 9. The maximum at pH 7 (144.0 mg g) exceeded pH 5 performance (128.3 mg g). In 0.005 M KCl, was 181.0 mg g, which decreased by 34% in 0.05 M KCl. In 0.5 M, KCl, (153.4 mg g) increased 26% over 0.05 M KCl. For all matrices, equilibration was attained between 120 and 168 h, best fit by Ho's pseudo-second-order model. Overall, is pH dependent because the sulfamethazine speciation and the zeta potential of MN250 vary as a function of pH. Increasing ionic strength initially decreases by altering the activity coefficient of sulfamethazine and by altering the properties of the electrical double layer, while salting-out becomes prominent at seawater concentration. MN250's high sulfamethazine capacity in environmentally relevant aqueous matrices highlights its potential for groundwater remediation. PMID- 26437100 TI - Occurrence and Fate of Trace Contaminants during Aerobic and Anaerobic Sludge Digestion and Dewatering. AB - Digestion of municipal wastewater biosolids is a necessary prerequisite to their beneficial use in land application, in order to protect public health and the receiving environment. In this study, 13 pharmaceuticals and personal care products (PPCPs), 11 musks, and 17 polybrominated diphenyl ethers were analyzed in 84 samples including primary sludge, waste activated sludge, digested biosolids, dewatered biosolids, and dewatering centrate or filtrate collected from five wastewater treatment plants with aerobic or anaerobic digestion. Aerobic digestion processes were sampled during both warm and cold temperatures to analyze seasonal differences. Among the studied compounds, triclosan, triclocarban, galaxolide, and BDE-209 were the substances most frequently detected under different treatment processes at levels up to 30,000 ng/g dry weight. Comparing aerobic and anaerobic digestion, it was observed that the levels of certain PPCPs and musks were significantly higher in anaerobically digested biosolids, relative to the residues from aerobic digestion. Therefore, aerobic digestion has the potential advantage of reducing levels of PPCPs and musks. On the other hand, anaerobic digestion has the advantage of recovering energy from the biosolids in the form of combustible gases while retaining the nutrient and soil conditioning value of this resource. PMID- 26437101 TI - Phytoextraction of DDT-Contaminated Soil at Point Pelee National Park, Leamington, ON, Using Cultivar Howden and Native Grass Species. AB - A field investigation was conducted at three dichlorodiphenyltrichloroethane (DDT)-contaminated areas in Point Pelee National Park (PPNP), Leamington, ON. cultivar Howden and three native grass species, (Michx.) Nash (little bluestem), L. (switchgrass), and (Torr.) A. Gray (sand dropseed) were grown at three different sites in the PPNP having low (291 ng/g), moderate (5083 ng/g), and high (10,192 ng/g) soil DDT contamination levels. A threshold soil DDT concentration was identified at ~5000 ng/g where the DDT uptake into was maximized, resulting in plant shoot and root DDT concentrations of 16,600 and 45,000 ng/g, respectively. Two native grass species ( and ) were identified as potential phytoextractors, with higher shoot extraction capabilities than that of the known phytoextractor when optimal planting density was taken into account. PMID- 26437102 TI - Can Coarse Woody Debris Be Used for Carbon Storage in Open Grazed Woodlands? AB - Carbon dioxide off-setting policy in the agricultural sector is focused on manipulating the terrestrial carbon cycle by reafforestation and increasing the retention of carbon within agricultural soils. We quantified the amount of carbon stored in the living and dead biomass and the surface soils of a previously grazed woodland ecosystem. We demonstrate that modification of coarse woody debris management could potentially store 8 to 15 t C ha. This large carbon pool raises the prospect that appropriate management of temperate woodlands to retain coarse woody debris and increase its volume into the future could achieve increased landscape carbon storage. PMID- 26437103 TI - Dissolved Phosphorus Retention in Buffer Strips: Influence of Slope and Soil Type. AB - Phosphorus (P) contributes to eutrophication of surface waters and buffer strips may be implemented to reduce its transfer from agricultural sources to watercourses. This study was conducted to test the hypothesis that soil type and slope influence the retention of dissolved organic P and inorganic orthophosphate in agricultural runoff in 2-m-wide buffer strip soils. A solution, comprised of dissolved orthophosphate and the organic P compounds glucose-1-phosphate, RNA, and inositol hexakisphosphate (1.8 mg L total P) and a chloride tracer, was applied as simulated overland flow to grassland soil blocks (2 m long * 0.5 m wide * 0.35 m deep), containing intact clay or loam soils, at slope angles of 2, 5, and 10 degrees . Phosphorus forms were determined in the surface and subsurface flow from the soil blocks. Slope had no significant effect on the hydrological behavior of the soil blocks or on the retention of any form of P at the water application rate tested. The clay soil retained 60% of the unreactive P and 21% of the reactive P applied. The loam soil retained 74% of the unreactive P applied but was a net source of reactive P (the load increased by 61%). This indicates leaching of native soil P or hydrolysis of organic compounds and complicates our understanding of P retention in buffer strip soils. Our results suggest that a 2-m buffer strip may be more effective for reducing dissolved unreactive P transfers to surface waters than for reducing the eutrophication risk posed by dissolved reactive P. PMID- 26437104 TI - A Nitrogen-Saturated Plantation of and in Japan Is a Large Nonpoint Nitrogen Source. AB - Japanese cedar () and Japanese cypress () plantations account for approximately 30% of the total forested area in Japan. Both are arbuscular mycorrhizal trees that leach more NO in response to nitrogen (N) deposition than do forests of ectomycorrhizal trees. However, little information is available about the size of N exports from these plantations. The aim of this study was to evaluate nonpoint source N exports from a N-saturated plantation. We collected stream water samples in base-flow (25 samples) and storm-flow conditions (20 events) in a watershed (2.98 ha) where Japanese cypress and Japanese cedar were planted in 1969 (41 yr old). The annual NO export was calculated from load-discharge relationships. Atmospheric N deposition was also determined. The stream water contained high NO concentrations (160 and 165 MUmol L during base flow and storm flow, respectively), indicating N saturation in the watershed. High bulk atmospheric N deposition (16.5 kg N ha yr) could explain the N saturation. There were only small variations in NO concentrations in stream water in response to discharge volume, because of the N saturation of the forest ecosystem. Consequently, there were only small errors in estimating annual NO exports from the studied watershed. The annual NO export was high (36.1 kg N ha yr), comparable to values reported for agricultural and urbanized areas. These results suggest that N saturated forest plantations can become important nonpoint N sources. Our results also suggest that N exports from forest plantations across Japan should be quantified to evaluate nonpoint source N accurately. PMID- 26437105 TI - Monitoring Fipronil and Degradates in California Surface Waters, 2008-2013. AB - The phenylpyrazole insecticide fipronil has become a popular replacement pest management tool as organophosphorus insecticides have been phased out for residential use and pyrethroids have come under scrutiny as a surface water contaminant. There has been an increasing concern of offsite transport of fipronil to surrounding surface waters and a corresponding increase in potential toxicity to aquatic organisms. The California Department of Pesticide Regulation Environmental Monitoring Program has collected over 500 urban surface water samples throughout California since 2008 to determine the presence and concentrations of fipronil and five degradate products. Statewide, fipronil was detected at high frequency (49%), as were the sulfone (43%) and desulfinyl (33%) degradates. Data collected at long-term monitoring stations indicate higher concentrations in southern California, corresponding to a higher use pattern in the region. There is a clear pattern of increased transport of fipronil with higher flow associated with rain events. However, the lack of seasonality effects on degradates' concentrations suggest a constant source of fipronil with a corresponding lag time of transport to surface waters during the dry season. Receiving waters had a diluting effect on concentrations; however, a significant proportion (46%) of receiving water samples had associated fipronil concentrations above USEPA aquatic life chronic benchmark values. Total mass loading estimates from a long-term monitoring site suggest that the annual fipronil loading is greater in the dry season than during storm events. This could have implications for future mitigation efforts because most runoff during this period was generated from irrigation and outdoor residential use. PMID- 26437106 TI - Heavy Rainfall Impacts on Trihalomethane Formation in Contrasting Northwestern European Potable Waters. AB - There is emerging concern over the impact of extreme events such as heavy rainfall on the quality of water entering the drinking water supply from aboveground sources, as such events are expected to increase in magnitude and frequency in response to climate change. We compared the impact of rainfall events on streamwater quality in four contrasting upland (peatland and mineral soil) and lowland agricultural catchments used to supply drinking water in France (Brittany) and the United Kingdom (North Wales) by analyzing water samples collected before, during, and after specific events. At all four streams, heavy rainfall led to a considerable rise in organic matter concentration ranging from 48 to 158%. Dissolved organic carbon (DOC) quality, as determined using specific ultraviolet absorbance, changed consistently at all sites during rainfall events, with a greater proportion of aromatic and higher molecular weight compounds following the onset of rainfall. However, the change in DOC quality and quantity did not significantly alter the trihalomethane formation potential. We observed small increases in trihalomethane (THM) generation only at the Welsh peatland and agricultural sites and a small decrease at the Brittany agricultural site. The proportion of brominated THMs in chlorinated waters was positively correlated with bromide/DOC ratio in raw waters for all sites and hydrological conditions. These results provide a first indication of the potential implications for surface-based drinking water resources resulting from expected future increases in rainfall event intensity and extension of dry periods with climate changes. PMID- 26437107 TI - Phosphorus Mobilization from Manure-Amended and Unamended Alkaline Soils to Overlying Water during Simulated Flooding. AB - Anaerobic soil conditions resulting from flooding often enhance release of phosphorus (P) to overlying water. Enhanced P release is well documented for flooded acidic soils; however, there is little information for flooded alkaline soils. We examined the effect of flooding and anaerobic conditions on P mobilization using 12 alkaline soils from Manitoba that were either unamended or amended with solid cattle manure. Pore water and floodwater were analyzed over 8 wk of simulated flooding for dissolved reactive P (DRP), Ca, Mg, Fe, and Mn. As expected, manured soils had significantly greater pore and floodwater DRP concentrations than unamended. Flooding increased pore water DRP concentrations significantly in all soils and treatments except one manured clay in which concentrations increased initially and then decreased. Floodwater DRP concentrations increased significantly by two- to 15-fold in 10 soils regardless of amendment treatment but remained relatively stable in the two soils with greatest clay content. Phosphorus release at the onset of flooding was associated with the release of Ca, Mg, and Mn, suggesting that P release may be controlled by the dissolution of Mg and Ca phosphates and reductive dissolution of Mn phosphates. Thereafter, P release was associated with release of Fe, suggesting the reductive dissolution of Fe phosphates. Differences in pore water and floodwater DRP concentrations among soils and amendment treatments and the high variability in P mobilization from pore water to floodwater among soils indicate the need to further investigate chemical reactions responsible for P release and mobility under anaerobic conditions. PMID- 26437108 TI - Effects of Site Preparation for Pine Forest/Switchgrass Intercropping on Water Quality. AB - A study was initiated to investigate the sustainability effects of intercropping switchgrass ( L.) in a loblolly pine ( L.) plantation. This forest-based biofuel system could possibly provide biomass from the perennial energy grass while maintaining the economics and environmental benefits of a forest managed for sawtimber. Operations necessary for successful switchgrass establishment and growth, such as site preparation, planting, fertilizing, mowing and baling, may affect hydrology and nutrient runoff. The objectives of this study were (i) to characterize the temporal effects of management on nutrient concentrations and loadings and (ii) to use pretreatment data to predict those treatment effects. The study watersheds (~25 ha each) in the North Carolina Atlantic Coastal Plain were a pine/switchgrass intercropped site (D1), a midrotation thinned pine site with natural understory (D2), and a switchgrass-only site (D3). Rainfall, drainage, water table elevation, nitrogen (total Kjedahl N, NH-N, and NO-N), and phosphate were monitored for the 2007-2008 pretreatment and the 2009-2012 treatment periods. From 2010 to 2011 in site D1, the average NO-N concentration effects decreased from 0.18 to -0.09 mg L, and loads effects decreased from 0.86 to 0.49 kg ha. During the same period in site D3, the average NO-N concentration effects increased from 0.03 to 0.09 mg L, and loads effects increased from -0.26 to 1.24 kg ha. This study shows the importance of considering water quality effects associated with intensive management operations required for switchgrass establishment or other novel forest-based biofuel systems. PMID- 26437109 TI - Effect of Biochar on Nutrient Leaching in a Young Apple Orchard. AB - Nutrient leaching from agricultural soils is a worldwide problem that has been implicated in deleterious impacts on the environment. Application of biochar to soil has been proposed as a means to reduce nutrient leaching and improve fertilizer use efficiency. The potential for biochar to reduce nutrient leaching and increase fertilizer use efficiency was tested by applying 47 Mg ha hardwood biochar before replanting a commercial apple () orchard, in the Huon Valley, Tasmania. Passive wick flux meters were installed at the base of the A1 horizon at a depth of 25 cm to monitor leachate volume and the concentration of nutrients leached below the A1 soil horizon over a 38 mo period. Biochar application significantly increased the concentration of phosphorous in the leachate, while having no significant effect on nitrate or potassium concentration. The volume of leachate collected in the flux meters was significantly higher in the biochar treatment, which resulted in significantly higher amounts of potassium and phosphorous being leaching from the biochar treatment than the control. Biochar application had no significant effect on either the concentration or the flux of nitrate leached from the A1 horizon. Nonetheless, nutrient application was well in excess of tree requirements, such that between 53 to 78% of the applied nitrogen, 5 to 11% of the applied phosphate, and 69 to 112% of the applied potassium were leached below the A1 horizon. PMID- 26437110 TI - Titration and Spectroscopic Measurements of Poultry Litter pH Buffering Capacity. AB - The pH value of poultry litter is affected by nitrification, mineralization, and the addition of acidifying chemicals, all acting on the poultry litter pH buffering capacity (pHBC). Increased understanding of poultry litter pHBC will aid in modeling NH volatilization from surface-applied poultry litter as well as estimating rates of alum applications. Our objectives were to (i) determine the pHBC of a wide range of poultry litters; (ii) assess the accuracy of near infrared reflectance spectroscopy (NIRS) for determining poultry litter pHBC; and (iii) demonstrate the use of poultry litter pHBC to increase the accuracy of alum additions. Litter pHBC was determined by titration and calculated from linear and sigmoidal curves. For the 37 litters measured, linear pHBC ranged from 187 to 537 mmol (pH unit) kg dry litter. The linear and sigmoidal curves provided accurate predictions of pHBC, with most > 0.90. Results from NIRS analysis showed that the linear pHBC expressed on an "as is" water content basis had a NIRS coefficient of calibration (developed using a modified partial least squares procedure) of 0.90 for the 37 poultry litters measured. Using the litter pHBC, an empirical model was derived to determine the amount of alum needed to create a target pH. The model performed well in the range of pH 6.5 to 7.5 (RMSE = 0.07) but underpredicted the amount of alum needed to reach pH <6. The lack of model performance at pH <6 was probably due to Al reacting with organic matter in the poultry litter, which prevented its hydrolysis. PMID- 26437111 TI - Nitrogen and Phosphorus Loss Potential from Biosolids-Amended Soils and Biotic Response in the Receiving Water. AB - Application of municipal biosolids to agricultural soil can improve soil quality and improve crop yields. However, runoff or tile leachate from biosolids-applied fields may contribute to localized eutrophication of surface water. A laboratory experiment was conducted to determine loss potential of nutrients from soils amended with two different biosolids (anaerobically digested and chemically stabilized) relative to loss from a reference soil and to determine response in freshwater microcosms to nutrients lost from soils. Total phosphorus (TP) and total nitrogen (TN) were measured in runoff, and equivalent amounts were added to reference microcosms to determine if aquatic systems would respond similarly to TN and TP loading in bioavailable forms (PO, NH, NO) simulating loading related to inorganic fertilizer application. Nutrient concentrations (TP, TN, PO, NH, NO, and organic P and N) were similar in the runoff from the two biosolids-amended soils and higher than those in the runoff from the reference soil. Runoff from biosolids-amended soils stimulated algal growth and production (chlorophyll a and dissolved oxygen) relative to runoff from reference soil, but the response was weaker than in microcosms receiving equivalent amounts of inorganic N and P. Nutrient runoff from land-applied biosolids does have potential to increase algal production in receiving waters; however, this experiment suggests receiving waters may absorb a single large nutrient loading event associated with runoff from biosolids-amended soil without substantial impact. Moreover, the response to N and P in biosolids versus inorganic nutrient additions suggests biosolids may contribute relatively less to eutrophication than inorganic fertilizers, assuming equivalent TN and TP loading to aquatic systems. PMID- 26437112 TI - Contrasting Nutrient Mitigation and Denitrification Potential of Agricultural Drainage Environments with Different Emergent Aquatic Macrophytes. AB - Remediation of excess nitrogen (N) in agricultural runoff can be enhanced by establishing wetland vegetation, but the role of denitrification in N removal is not well understood in drainage ditches. We quantified differences in N retention during experimental runoff events followed by stagnant periods in mesocosms planted in three different vegetation treatments: unvegetated, cutgrass [ (L.) Sw.], and common cattail ( L.). We also quantified denitrification rates using membrane inlet mass spectrometry from intact cores extracted from each mesocosm treatment. All treatments retained 60% or more of NO-N loads during the 6-h experimental runoff event, but mesocosms planted with cutgrass had significantly higher (68%) retention than the cattail (60%) or unvegetated (61%) treatments. After the runoff event, mesocosms planted in cattail reduced NO-N concentrations by >95% within 24 h and cutgrass achieved similar reductions within 48 h, whereas reductions in the unvegetated mesocosms were significantly less (65%). Cores from cutgrass mesocosms had significantly higher average denitrification rates (5.93 mg m h), accounting for as much as 56% of the immobilized NO-N within 48 h, whereas denitrification rates were minimal in cores from the unvegetated (-0.19 mg m h) and cattail (0.2 mg m h) mesocosms. Our findings have implications for mitigating excess NO-N in agricultural runoff. While vegetated treatments removed excess NO-N from the water column at similar and significantly higher rates than unvegetated treatments, the high denitrification rates observed for cutgrass highlight the potential for permanent removal of excess N from agricultural runoff in vegetated ditches and wetlands. PMID- 26437113 TI - Biochar Soil Amendment Effects on Arsenic Availability to Mountain Brome (). AB - Biochar is a renewable energy byproduct that shows promise for remediating contaminated mine sites. A common contaminant at mine sites is arsenic (As). In this study, the effects of biochar amendments to a mine-contaminated soil on As concentrations in mountain brome ( Nees ex Steud.) were investigated. In the biochar-amended soil, mountain brome had greater root biomass and decreased root and shoot As concentrations. X-ray absorption near-edge structure spectroscopy results showed that arsenate [As(V)] is the predominant species in both the nonamended and biochar-amended soils. Soil extraction tests that measure phosphate and arsenate availability to plants failed to accurately predict plant tissue As concentrations, suggesting the arsenate bioavailability behavior in the soils is distinct from phosphate. Results from this study indicate that biochar will be a beneficial amendment to As-contaminated mine sites for remediation. PMID- 26437114 TI - Chemical Fouling Reduction of a Submersible Steel Spectrophotometer in Estuarine Environments Using a Sacrificial Zinc Anode. AB - The availability of in situ spectrophotometers, such as the S::CAN spectro::lyser, has expanded the possibilities for high-frequency water quality data collection. However, biological and chemical fouling can degrade the performance of in situ spectrophotometers, especially in saline environments with rapid flow rates. A complex freshwater washing system has been previously designed to reduce chemical fouling for the S::CAN spectro::lyser spectrophotometer. In the current study, we present a simpler, cheaper alternative: the attachment of a sacrificial zinc anode. Results are presented detailing the S::CAN spectro::lyser performance with and without the addition of the sacrificial anode. Attachment of the zinc anode provided efficient corrosion protection during 2-wk deployments in a highly dynamic (average tidal range, 2.5 m) saline tidal saltmarsh creek at Groves Creek, Skidaway Institute of Oceanography, Savannah, GA. PMID- 26437115 TI - Chemical and Isotopic Tracers Illustrate Pathways of Nitrogen Loss in Cranberry Floodwaters. AB - Limited research exists on the sources of nitrogen (N) in cranberry floodwaters, which have been identified as a prominent cause of concern to watershed N loading in the cranberry-producing region of southeastern Massachusetts. In this study, we used naturally occurring chemical and isotopic tracers to infer the sources of N transported by harvest floodwaters. In 2012, the cranberry bed was a net source of total N (TN), exporting 0.8 kg N ha (primarily as organic N) to a nearby lake. Systematic increases in TN concentration were associated with increasing fractions of pre-event soil water and groundwater ("porewater") in discharge. Results showed that N concentrations in porewater generally derive from the natural mixing of soil water and perched groundwater within the cranberry bed but locally display a connection to deep groundwater where the underlying peat is absent. These findings illustrate the environmental significance of stored pools of porewater in cranberry beds and the ability to focus on moments of disproportionate N transfer to most efficiently curtail floodwater N losses (i.e., 58% of N export occurred in only 22% of floodwater discharge). PMID- 26437116 TI - Prognostic biomarkers for renal amyloid. PMID- 26437118 TI - Two-Color Single Hybrid Plasmonic Nanoemitters with Real Time Switchable Dominant Emission Wavelength. AB - We demonstrate two-color nanoemitters that enable the selection of the dominant emitting wavelength by varying the polarization of excitation light. The nanoemitters were fabricated via surface plasmon-triggered two-photon polymerization. By using two polymerizable solutions with different quantum dots, emitters of different colors can be positioned selectively in different orientations in the close vicinity of the metal nanoparticles. The dominant emission wavelength of the metal/polymer anisotropic hybrid nanoemitter thus can be selected by altering the incident polarization. PMID- 26437119 TI - The relationship between adolescents' physical activity, fundamental movement skills and weight status. AB - The aim of this study was to determine if a potential relationship among physical activity (PA), fundamental movement skills and weight status exists amongst early adolescent youth. Participants were a sample of 85 students; 54 boys (mean age = 12.94 +/- 0.33 years) and 31 girls (mean age = 12.75 +/- 0.43 years). Data gathered during physical education class included PA (accelerometry), fundamental movement skills and anthropometric measurements. Standard multiple regression revealed that PA and total fundamental movement skill proficiency scores explained 16.5% (P < 0.001) of the variance in the prediction of body mass index. Chi-square tests for independence further indicated that compared with overweight or obese adolescents, a significantly higher proportion of adolescents classified as normal weight achieved mastery/near-mastery in fundamental movement skills. Results from the current investigation indicate that weight status is an important correlate of fundamental movement skill proficiency during adolescence. Aligned with most recent research, school- and community-based programmes that include developmentally structured learning experiences delivered by specialists can significantly improve fundamental movement skill proficiency in youth. PMID- 26437120 TI - Modeling the Effects of Hydrodynamic Regimes on Microbial Communities within Fluvial Biofilms: Combining Deterministic and Stochastic Processes. AB - To fully understand the effects of hydrodynamics on a microbial community, the roles of niche-based and neutral processes must be considered in a mathematical model. To this end, a two-dimensional model combining mechanisms of immigration, dispersal, and niche differentiation was first established to describe the effects of hydrodynamics on bacterial communities within fluvial biofilms. Deterministic factors of the model were identified via the calculation of Spearman's rank correlation coefficients between parameters of hydrodynamics and the bacterial community. It was found that turbulent kinetic energy and turbulent intensity were considered as a set of reasonable predictors of community composition, whereas flow velocity and turbulent intensity can be combined together to predict biofilm bacterial biomass. According to the modeling result, the bacterial community could get its favorable assembly condition with a flow velocity ranging from 0.041 to 0.061 m/s. However, the driving force for biofilm community assembly changed with the local hydrodynamics. Individuals reproduction within the biofilm was the main driving force with flow velocity less than 0.05 m/s, while cell migration played a much more important role with velocity larger than 0.05 m/s. The developed model could be considered as a useful tool for improving the technologies of water environment protection and remediation. PMID- 26437117 TI - Synaptotagmin-1 and -7 Are Redundantly Essential for Maintaining the Capacity of the Readily-Releasable Pool of Synaptic Vesicles. AB - In forebrain neurons, Ca(2+) triggers exocytosis of readily releasable vesicles by binding to synaptotagmin-1 and -7, thereby inducing fast and slow vesicle exocytosis, respectively. Loss-of-function of synaptotagmin-1 or -7 selectively impairs the fast and slow phase of release, respectively, but does not change the size of the readily-releasable pool (RRP) of vesicles as measured by stimulation of release with hypertonic sucrose, or alter the rate of vesicle priming into the RRP. Here we show, however, that simultaneous loss-of-function of both synaptotagmin-1 and -7 dramatically decreased the capacity of the RRP, again without altering the rate of vesicle priming into the RRP. Either synaptotagmin-1 or -7 was sufficient to rescue the RRP size in neurons lacking both synaptotagmin 1 and -7. Although maintenance of RRP size was Ca(2+)-independent, mutations in Ca(2+)-binding sequences of synaptotagmin-1 or synaptotagmin-7--which are contained in flexible top-loop sequences of their C2 domains--blocked the ability of these synaptotagmins to maintain the RRP size. Both synaptotagmins bound to SNARE complexes; SNARE complex binding was reduced by the top-loop mutations that impaired RRP maintenance. Thus, synaptotagmin-1 and -7 perform redundant functions in maintaining the capacity of the RRP in addition to nonredundant functions in the Ca(2+) triggering of different phases of release. PMID- 26437121 TI - Associated extrarenal vascular diseases may complicate the treatment and outcome of renovascular hypertension. AB - AIM: This studied reviewed renovascular hypertension (RVH) due to renal artery stenosis (RAS) in two Serbian paediatric centres from 2001 to 2013. METHODS: The patients' demographic data, underlying syndromes, blood pressure (BP), antihypertensive treatments and outcomes were reviewed. RESULTS: The incidence of RVH was 1.9 per million children per year during the study period, and there were 25 patients with RAS, aged 10.4 +/- 5.2 years. At presentation, their mean blood pressure (BP) standard deviation scores were 6.9 +/- 3.4 systolic and 5.2 +/- 2.6 diastolic. BP loads on 24-hour ambulatory BP were 88 +/- 14% systolic and 80 +/- 29% diastolic. We found that 72% had fibromuscular dysplasia and 28% had underlying syndromes. RAS was unilateral in 64% and bilateral in 28%, and 8% had RAS of a single kidney. Antihypertensive treatment included antihypertensive drugs (100%), percutaneous transluminal angioplasty (92%), renal auto transplantation (16%), surgical revascularisation (12%) and nephrectomy (12%). After 4.4 +/- 3.6 years of follow-up, high BP was cured in 40% of the patients and 39.4% of the kidneys and improved in 48% (75.7%), with BP decreases of 20.3 +/- 3.7% systolic and 16.3 +/- 6.2% diastolic. CONCLUSION: Fibromuscular dysplasia was the most common cause of RVH in this study, and hypertension was cured or improved in 88% of the patients. PMID- 26437122 TI - Liver fluke-infested graft used for living-donor liver transplantation: case report and review of the literature. AB - Clonorchiasis is a cholangiopathy caused by foodborne trematode parasites, also known as liver flukes. Clonorchiasis is endemic in a wide geographical area extending from Eastern Europe to Southeast Asia. Infested hosts may remain asymptomatic for decades and consequently their liver can become available as a graft. To date, 20 liver transplantations with liver fluke-infested grafts have been reported in the literature. All of them occurred in Asian countries. We, here, report the first case to our knowledge in the Western world of living-donor liver transplantation (LDLT) with an Opisthorchis felineus-infested graft, and present a review of the literature. A 6-month-old girl with decompensated secondary biliary cirrhosis underwent an LDLT with a left lateral graft infested with O. felineus. After prompt diagnosis and adequate therapy, both donor and recipient had an uneventful postoperative course and long-term follow-up. Liver grafts infested with liver flukes do not pose a contraindication to liver donation from deceased or living donors, provided that a correct diagnosis and treatment are performed in a timely fashion. PMID- 26437123 TI - Role of beta-Amyloidosis and Neurodegeneration in Subsequent Imaging Changes in Mild Cognitive Impairment. AB - IMPORTANCE: To understand how a model of Alzheimer disease pathophysiology based on beta-amyloidosis and neurodegeneration predicts the regional anatomic expansion of hypometabolism and atrophy in persons with mild cognitive impairment (MCI). OBJECTIVE: To define the role of beta-amyloidosis and neurodegeneration in the subsequent progression of topographic cortical structural and metabolic changes in MCI. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal, observational study with serial brain imaging conducted from March 28, 2006, to January 6, 2015, using a population-based cohort. A total of 96 participants with MCI (all aged >70 years) with serial imaging biomarkers from the Mayo Clinic Study of Aging or Mayo Alzheimer's Disease Research Center were included. Participants were characterized initially as having elevated or not elevated brain beta amyloidosis (A+ or A-) based on 11C-Pittsburgh compound B positron emission tomography. They were further characterized initially by the presence or absence of neurodegeneration (N+ or N-), where the presence of neurodegeneration was defined by abnormally low hippocampal volume or hypometabolism in an Alzheimer disease-like pattern on 18fluorodeoxyglucose (FDG)-positron emission tomography. MAIN OUTCOMES AND MEASURES: Regional FDG standardized uptake value ratio (SUVR) and gray matter volumes in medial temporal, lateral temporal, lateral parietal, and medial parietal regions. RESULTS: In the primary regions of interest (ROI), the A+N+ group (n = 45) had lower FDG SUVR at baseline compared with the A+N- group (n = 17) (all 4 ROIs; P < .001). The A+N+ group also had lower FDG SUVR at baseline (all 4 ROIs; P < .01) compared with the A-N- group (n = 12). The A+N+ group had lower medial temporal gray matter volume at baseline (P < .001) compared with either the A+N- group or A-N- group. The A+N+ group showed large longitudinal declines in FDG SUVR (P < .05 for medial temporal, lateral temporal, and medial parietal regions) and gray matter volumes (P < .05 for medial temporal and lateral temporal regions) compared with the A-N+ group (n = 22). The A+N+ group also showed large longitudinal declines compared with the A-N- group on FDG SUVR (P < .05 for medial temporal and lateral parietal regions) and gray matter volumes (all 4 ROIs; P < .05) compared with the A+N- group. The A-N+ group did not show declines in FDG SUVR or gray matter volume compared with the A+N- or A-N groups. CONCLUSIONS AND RELEVANCE: Persons with MCI who were A+N+ demonstrated volumetric and metabolic worsening in temporal and parietal association areas, consistent with the expectation that the MCI stage in the Alzheimer pathway heralds incipient isocortical involvement. The A-N+ group, those with suspected non-Alzheimer pathophysiology, lacked a distinctive longitudinal volumetric or metabolic profile. PMID- 26437124 TI - Complete mitochondrial genome of Bombus terrestris (Hymenoptera: Apidae). AB - In this study, complete mitochondrial genome of the large earth bumblebee, Bombus terrestris, was first determined. The mitochondrial genome is 174 000 bp in length, and encodes 1 D-loop region, 2 ribosomal RNA genes, 13 protein-coding genes and 20 transfer RNA genes. Average GC content of this genome is 15%. nad6 and cob are overlapped with 12 bp, while atp8 and atp6 are overlapped with 18 bp. Phylogeny analysis indicates Bombus species exhibit closer genetic distance with Melipona species than with Apis species. PMID- 26437125 TI - Amphibian molecular ecology and how it has informed conservation. AB - Molecular ecology has become one of the key tools in the modern conservationist's kit. Here we review three areas where molecular ecology has been applied to amphibian conservation: genes on landscapes, within-population processes, and genes that matter. We summarize relevant analytical methods, recent important studies from the amphibian literature, and conservation implications for each section. Finally, we include five in-depth examples of how molecular ecology has been successfully applied to specific amphibian systems. PMID- 26437126 TI - Effects of vagus nerve stimulation on pupillary function. AB - BACKGROUND: Chronic vagus nerve stimulation (VNS) is a recognized treatment for refractory epilepsy and depression. The vagus nerve projects to several brainstem autonomic structures. As pupillary measures are an easy and non-invasive method to evaluate autonomic functioning, we used resting diameter and light reflex measures to investigate the influence of VNS on the human central autonomic nervous system. METHOD: We studied 21 patients (7 with major depression, 14 with epilepsy) treated with chronic VNS (30s ON, 5 min OFF stimulation trains). Resting pupil size and light reflex measures were compared in consecutive intervals with (ON) and without stimulation (OFF). RESULTS: Compared to the OFF condition, the ON condition was associated with a significant increase in resting pupil diameter, but did not affect light reflex measures. There was no group difference between the two populations of patients (depression and epilepsy) on any of the pupil measures. CONCLUSION: VNS at clinically significant levels increases resting pupil diameter. PMID- 26437127 TI - Reduced Leaflet Motion in Bioprosthetic Aortic Valves--The FDA Perspective. PMID- 26437128 TI - Statins and their increased risk of inducing diabetes. AB - INTRODUCTION: Statins are evidence-based drugs to prevent cardiovascular (CV) disease. However, their benefits have been disputed by a statin-related increased risk of new onset diabetes (NOD) in randomized controlled trials and meta analyses. AREAS COVERED: This review provides an update based on recent outstanding evidence on the statin effect on the risk of diabetes. It also describes mechanisms potentially explaining adverse effects of statins on glucose homeostasis. PubMed was searched for original articles and reviews published from January 2010 (inclusive) to May 2015 (inclusive), which include the Search terms statins, diabetes, glucose, and insulin. NOD risk seems to be more relevant with high-intensity rather than with low-intensity statin treatment. Also, this risk is particularly increased in patients at risk for the development of diabetes. It appears that statins adversely affect glucose homeostasis in parallel with their 3-hydroxy-3-methylglutaryl-coenzyme A inhibition capacity. It was suggested that lipophilic statins are more diabetogenic than the hydrophilic ones. Mechanisms explaining statin diabetogeneicity include impaired insulin secretion by pancreatic beta cells together with increased insulin resistance of various tissues. EXPERT OPINION: The CV outcome benefits from statin use outweigh the diabetes menace. However, patients at risk for the development of diabetes should be prescribed statins with caution. PMID- 26437129 TI - ResQ: An Approach to Unified Estimation of B-Factor and Residue-Specific Error in Protein Structure Prediction. AB - Computer-based structure prediction becomes a major tool to provide large-scale structure models for annotating biological function of proteins. Information of residue-level accuracy and thermal mobility (or B-factor), which is critical to decide how biologists utilize the predicted models, is however missed in most structure prediction pipelines. We developed ResQ for unified residue-level model quality and B-factor estimations by combining local structure assembly variations with sequence-based and structure-based profiling. ResQ was tested on 635 non redundant proteins with structure models generated by I-TASSER, where the average difference between estimated and observed distance errors is 1.4A for the confidently modeled proteins. ResQ was further tested on structure decoys from CASP9-11 experiments, where the error of local structure quality prediction is consistently lower than or comparable to other state-of-the-art predictors. Finally, ResQ B-factor profile was used to assist molecular replacement, which resulted in successful solutions on several proteins that could not be solved from constant B-factor settings. PMID- 26437130 TI - Phenolic compounds from red wine and coffee are associated with specific intestinal microorganisms in allergic subjects. AB - The dietary modulation of gut microbiota, suggested to be involved in allergy processes, has recently attracted much interest. While several studies have addressed the use of fibres to modify intestinal microbial populations, information about other components, such as phenolic compounds, is scarce. The aim of this work was to identify the dietary components able to influence the microbiota in 23 subjects suffering from rhinitis and allergic asthma, and 22 age and sex-matched controls. The food intake was recorded by means of an annual food frequency questionnaire. Dietary fibre tables were obtained from Marlett et al., and the Phenol-Explorer database was used to assess the phenolic compound intake. The quantification of microbial groups was performed using an Ion Torrent 16S rRNA gene-based analysis. The results showed a direct association between the intake of red wine, a source of stilbenes, and the relative abundance of Bacteroides, and between the intake of coffee, rich in phenolic acids, and the abundance of Clostridium, Lactococcus and Lactobacillus genera. Despite epidemiological analyses not establishing causality, these results support the association between polyphenol-rich beverages and faecal microbiota in allergic patients. PMID- 26437132 TI - To Make a Difference. AB - Disengagement causes a host of problematic behaviors that can lead to poor staff performance and patient safety or quality issues. There are 2 broad kinds of engagement: individual and organizational; this Editorial is about individual engagement. PMID- 26437131 TI - Rodent Brain Microinjection to Study Molecular Substrates of Motivated Behavior. AB - Brain microinjection can aid elucidation of the molecular substrates of complex behaviors, such as motivation. For this purpose rodents can serve as appropriate models, partly because the response to behaviorally relevant stimuli and the circuitry parsing stimulus-action outcomes is astonishingly similar between humans and rodents. In studying molecular substrates of complex behaviors, the microinjection of reagents that modify, augment, or silence specific systems is an invaluable technique. However, it is crucial that the microinjection site is precisely targeted in order to aid interpretation of the results. We present a method for the manufacture of surgical implements and microinjection needles that enables accurate microinjection and unlimited customizability with minimal cost. Importantly, this technique can be successfully completed in awake rodents if conducted in conjunction with other JoVE articles that covered requisite surgical procedures. Additionally, there are many behavioral paradigms that are well suited for measuring motivation. The progressive ratio is a commonly used method that quantifies the efficacy of a reinforcer to maintain responding despite an (often exponentially) increasing work requirement. This assay is sensitive to reinforcer magnitude and pharmacological manipulations, which allows reinforcing efficacy and/ or motivation to be determined. We also present a straightforward approach to program operant software to accommodate a progressive ratio reinforcement schedule. PMID- 26437133 TI - What Case Managers Should Know About Their Roles and Functions: A National Study From the Commission for Case Manager Certification: Part 1. AB - PURPOSE: The purpose of this national role and function study was to identify the essential activities and necessary knowledge areas for effective case manager practice from the perspective of those currently functioning in various care settings and across diverse professional disciplines. PRIMARY PRACTICE SETTING(S): The national study covered all case management practices and/or work settings across the full continuum of health care. METHODOLOGY AND SAMPLE: This cross-sectional descriptive study used the practice analysis method and online survey research design. It employed a purposive sample of case managers, in which 52,370 individuals received an invitation to participate. Data collection completed over a 4-week period, resulting in 7,668 useable survey responses (nearly a 15% response rate). RESULTS: The study identified the common activities and knowledge areas necessary for competent and effective performance of case managers, as is highlighted in this article, which is the first of a 2-part series on the role and function study. The results informed the needed update of the test specifications for the Certified Case Manager (CCM) certification examination, as will be delineated in Part 2 of the article series, to ensure that it continues to be substantiated in current practice. Of special note are the emergence of specific activity and knowledge domains in the area of case management ethical, legal, and practice standards, and an increase in the number of employers requiring certified case managers to fill vacant positions and compensating them financially for such qualifications. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: This study helps keep the CCM credentialing examination evidence-based and maintain its validity for evaluating competency of case managers. Specifically, the study identified essential activities and knowledge domains that define competent case management practice. Findings can be used for developing programs and curricula for the training and development of case managers. The study instrument also can be used for further research of case management practice. PMID- 26437135 TI - Interdisciplinary Rounds: The Key to Communication, Collaboration, and Agreement on Plan of Care. AB - PURPOSE/OBJECTIVES: In the era of Pay for Performance, multiple auditing entities, and shorter length of stays, Interdisciplinary Rounds are the future of hospital care. This article seeks to take a broad look at this tool in its current and historical perspective and examine how it can provide a stable foundation for improved physician-nurse communication, agreement on the plan of care, successful care transitions, and improvements in quality metrics, and reduced length of stay. These rounds reflect the changing attitudes of nurses and physicians toward a more collaborative cooperation, and teamwork, in the delivery of patient care. When supported by strong, visible leadership, they can transform not only direct patient care, but the perception of that care by the patient, families, and caregivers. PRIMARY PRACTICE SETTING: Acute care hospitals. FINDINGS AND CONCLUSIONS: Properly executed, Interdisciplinary Rounds improve communication among the health care team and provide a basis for agreement upon the plan of care. IMPLICATIONS FOR CASE MANAGEMENT: Case management is a logical and frequent choice for a leadership role in Interdisciplinary Rounds. Creating a sustainable culture that drives improved clinical care delivery and reduces readmissions and length of stay requires efforts to ensure clear, concise care transitions. With hospitalist programs and nursing care shifts spanning 12 hr, and several days' off between work days, case management continues to be one of the few constant members of the health care team-often with more knowledge of the episode of care than even the current attending physician. Embracing rounds is a change for the better. PMID- 26437137 TI - Monitoring Resource Utilization in a Health Care Coordination Program. AB - PURPOSE OF THE STUDY: This initial article describes the development of a health care coordination intervention and documentation system designed using the Agency for Healthcare Research and Quality (AHRQ) Care Coordination Atlas framework for Centers for Medicare & Medicaid-funded innovation project, Leveraging Information Technology to Guide High-Tech, High-Touch Care (LIGHT). PRIMARY PRACTICE SETTING(S): The study occurred at an academic medical center that serves 114 counties. Twenty-five registered nurse care managers (NCMs) were hired to work with 137 providers in 10 family community and internal medicine clinics. METHODOLOGY AND SAMPLE: Patients were allocated into one of the four tiers on the basis of their chronic medical conditions and health care utilization. Using a documentation system on the basis of the AHRQ domains developed for this study, time and touch data were calculated for 8,593 Medicare, Medicaid, or dual eligible patients. RESULTS: We discovered through the touch and time analysis that the majority of health care coordination activity occurred in the AHRQ domains of communication, assess needs and goals, and facilitate transitions, accounting for 79% of the NCM time and 61% of the touches. As expected, increasing tier levels resulted in increased use of NCM resources. Tier 3 accounted for roughly 16% of the patients and received 159 minutes/member (33% of total minutes), and Tier 4 accounted for 4% of patients and received 316 minutes/member (17% of all minutes). In contrast Tier 2, which did not require routine touches per protocol, had 5,507 patients (64%), and those patients received 5,246 hours of health care coordination, or 57 minutes/member, and took 48% of NCM time. IMPLICATIONS FOR CASE MANAGEMENT: 1. The AHRQ Care Coordination Atlas offered a systematic way to build a documentation system that allowed for the extraction of data that was used to calculate the amount of time and the number of touches that NCMs delivered per member. 2. Using a framework to systematically guide the work of health care coordination helped NCMs to think strategically about the care being delivered, and has implications for improving coordination of care. 3. For the purpose of reimbursement and communication with payers about quality metrics, it is vital that the type of touches and amount of time spent in delivering care coordination be documented in a manner that can be easily retrieved to guide practice decisions. PMID- 26437138 TI - The Importance of Saying What We Mean. PMID- 26437139 TI - The Affordable Care Act: Impact on Case Managers. PMID- 26437140 TI - What the CCMC Role and Function Study Tells You About Changes in Case Management. PMID- 26437141 TI - Caring for the Uninsured, Undocumented Population: Challenges of Chronic Disease Management and Access to Care. PMID- 26437142 TI - Relational closeness moderates the association between maternal overcontrol and children's depressive symptoms. AB - Though numerous studies have examined the relationship between parental overcontrol (OC) and child anxiety, few have examined the association between OC and children's depressive symptoms. However, there are conceptual reasons to believe that overcontrolling parenting may also be relevant to depressive symptomatology, as well as to anticipate that other aspects of the parent-child relationship may moderate the association between the two. In this study we examine the association between self-reported maternal OC and child depressive symptoms, as moderated by multiple indicators of closeness within the parent child relationship. An ethnically and socioeconomically diverse sample of children (N = 106, M(age) = 10.27 years) and their mothers participated in this cross-sectional study. Mothers reported on their overcontrolling parenting and children reported on their depressive symptoms. Children and mothers participated in structured interviews that were analyzed for we-talk, a behavioral measure of closeness; they also self-reported their closeness. Results indicated that child we-talk, child self-reported closeness, and maternal we-talk moderated the association between maternal OC and child depressive symptoms, such that OC and depressive symptoms were positively associated only at low levels of relational closeness. The results provide initial evidence for an association between parental OC and child depressive symptoms, and point to the need for more research on the role of children's perceptions in moderating the association between parenting and child depressive symptoms. PMID- 26437143 TI - Determinants of father involvement with young children: Evidence from the Early Childhood Longitudinal Study-Birth Cohort. AB - The current study used data from the Early Childhood Longitudinal Study-Birth Cohort (ECLS-B; Snow et al., 2007) to explore determinants of resident father involvement. Families (N = 2,900) were measured at 3 time points (9 months, 2 years, and 4 years of age). Father, mother, and child factors were examined in relation to father caregiving and play. Latent change score models indicated that fathers engaged in more caregiving and play behaviors and increased at a faster rate when they more strongly identified with their role as a father. Fathers engaged in more caregiving when mothers reported higher depressive symptoms and increased in play more slowly when marital conflict was higher. In addition, a Mother Depressive Symptoms * Marital Conflict interaction emerged indicating that fathers differed in their levels of caregiving depending on mothers' report of depressive symptoms, but only when marital conflict was low. Fathers also increased in caregiving at a faster rate with girls than boys. A comprehensive framework for examining resident father involvement is presented. PMID- 26437145 TI - The effects of parental sensitivity and involvement in caregiving on mother infant and father-infant attachment in a Portuguese sample. AB - In the present longitudinal study, we investigated attachment quality in Portuguese mother-infant and in father-infant dyads, and evaluated whether attachment quality was related to parental sensitivity during parent-infant social interaction or to the amount of time each parent spent with the infant during play and in routine caregiving activities (e.g., feeding, bathing, play). The sample consisted of 82 healthy full-term infants (30 girls, 53 boys, 48 first born), and their mothers and fathers from mostly middle-class households. To assess parental sensitivity, mothers and fathers were independently observed during free play interactions with their infants when infants were 9 and 15 months old. The videotaped interactions were scored by masked coders using the Crittenden's CARE-Index. When infants were 12 and 18 months old, mother-infant and father-infant dyads were videotaped during an adaptation of Ainsworth's Strange Situation. Parents also described their level of involvement in infant caregiving activities using a Portuguese version of the McBride and Mills Parent Responsibility Scale. Mothers were rated as being more sensitive than fathers during parent-infant free play at both 9 and 15 months. There also was a higher prevalence of secure attachment in mother-infant versus father-infant dyads at both 12 and 18 months. Attachment security was predicted by the amount of time mothers and fathers were involved in caregiving and play with the infant, and with parents' behavior during parent-infant free play. PMID- 26437144 TI - Relationship of service members' deployment trauma, PTSD symptoms, and experiential avoidance to postdeployment family reengagement. AB - This research examined whether military service members' deployment-related trauma exposure, posttraumatic stress disorder (PTSD) symptoms, and experiential avoidance are associated with their observed levels of positive social engagement, social withdrawal, reactivity-coercion, and distress avoidance during postdeployment family interaction. Self reports of deployment related trauma, postdeployment PTSD symptoms, and experiential avoidance were collected from 184 men who were deployed to the Middle East conflicts, were partnered, and had a child between 4 and 13 years of age. Video samples of parent-child and partner problem solving and conversations about deployment issues were collected, and were rated by trained observers to assess service members' positive engagement, social withdrawal, reactivity-coercion, and distress avoidance, as well as spouse and child negative affect and behavior. Service members' experiential avoidance was reliably associated with less observed positive engagement and more observed withdrawal and distress avoidance after controlling for spouse and child negative affect and behavior during ongoing interaction. Service members' experiential avoidance also diminished significant associations between service members' PTSD symptoms and their observed behavior. The results are discussed in terms of how service members' psychological acceptance promotes family resilience and adaption to the multiple contextual challenges and role transitions associated with military deployment. Implications for parenting and marital interventions are described. PMID- 26437146 TI - Manifestations of Insomnia in Sleep Apnea: Implications for Screening and Treatment. AB - The aims of this study were to examine the presence, type, and severity of insomnia complaints in obstructive sleep apnea (OSA) patients and to assess the utility of the Sleep Symptom Checklist (SSC) for case identification in primary care. Participants were 88 OSA patients, 57 cognitive-behavioral therapy for insomnia (CBT-I) patients, and 14 healthy controls (Ctrl). Each completed a sleep questionnaire as well as the SSC, which includes insomnia, daytime functioning, psychological, and sleep disorder subscales. Results showed that OSA patients could be grouped according to 3 insomnia patterns: no insomnia (OSA), n = 21; insomnia (OSA-I), n = 30, with a subjective complaint and disrupted sleep; and noncomplaining poor sleepers (OSA-I-NC), n = 37. Comparisons among the OSA, CBT I, and Ctrl groups demonstrate distinct profiles on the SSC subscales, indicating its potential utility for both case identification and treatment planning. PMID- 26437147 TI - Transactive goal dynamics. AB - Transactive goal dynamics (TGD) theory conceptualizes 2 or more interdependent people as 1 single self-regulating system. Six tenets describe the nature of goal interdependence, predict its emergence, predict when it will lead to positive goal outcomes during and after the relationship, and predict the consequences for the relationship. Both partners in a TGD system possess and pursue self-oriented, partner-oriented, and system-oriented goals, and all of these goals and pursuits are interdependent. TGD theory states that relationship partners' goals, pursuit, and outcomes affect each other in a dense network of goal interdependence, ultimately becoming so tightly linked that the 2 partners are most accurately conceptualized as components within a single self-regulating system. PMID- 26437148 TI - Rehearsal in serial recall: An unworkable solution to the nonexistent problem of decay. AB - We examine the explanatory roles that have been ascribed to various forms of rehearsal or refreshing in short-term memory (STM) and working memory paradigms, usually in conjunction with the assumption that memories decay over time if they are not rehearsed. Notwithstanding the popularity of the rehearsal notion, there have been few detailed examinations of its underlying mechanisms. We explicitly implemented rehearsal in a decay model and explored its role by simulation in several benchmark paradigms ranging from immediate serial recall to complex span and delayed recall. The results show that articulatory forms of rehearsal often fail to counteract temporal decay. Rapid attentional refreshing performs considerably better, but so far there is scant empirical evidence that people engage in refreshing during STM tasks. Combining articulatory rehearsal and refreshing as 2 independent maintenance processes running in parallel leads to worse performance than refreshing alone. We conclude that theoretical reliance on articulatory rehearsal as a causative agent in memory may be unwise and that explanatory appeals to rehearsal are insufficient unless buttressed by quantitative modeling. PMID- 26437149 TI - An improved probabilistic account of counterfactual reasoning. AB - When people want to identify the causes of an event, assign credit or blame, or learn from their mistakes, they often reflect on how things could have gone differently. In this kind of reasoning, one considers a counterfactual world in which some events are different from their real-world counterparts and considers what else would have changed. Researchers have recently proposed several probabilistic models that aim to capture how people do (or should) reason about counterfactuals. We present a new model and show that it accounts better for human inferences than several alternative models. Our model builds on the work of Pearl (2000), and extends his approach in a way that accommodates backtracking inferences and that acknowledges the difference between counterfactual interventions and counterfactual observations. We present 6 new experiments and analyze data from 4 experiments carried out by Rips (2010), and the results suggest that the new model provides an accurate account of both mean human judgments and the judgments of individuals. (PsycINFO Database Record PMID- 26437150 TI - Impaired integration in psychopathy: A unified theory of psychopathic dysfunction. AB - This article introduces a novel theoretical framework for psychopathy that bridges dominant affective and cognitive models. According to the proposed impaired integration (II) framework of psychopathic dysfunction, topographical irregularities and abnormalities in neural connectivity in psychopathy hinder the complex process of information integration. Central to the II theory is the notion that psychopathic individuals are "'wired up' differently" (Hare, Williamson, & Harpur, 1988, p. 87). Specific theoretical assumptions include decreased functioning of the Salience and Default Mode Networks, normal functioning in executive control networks, and less coordination and flexible switching between networks. Following a review of dominant models of psychopathy, we introduce our II theory as a parsimonious account of behavioral and brain irregularities in psychopathy. The II theory provides a unified theoretical framework for understanding psychopathic dysfunction and integrates principle tenets of affective and cognitive perspectives. Moreover, it accommodates evidence regarding connectivity abnormalities in psychopathy through its network theoretical perspective. (PsycINFO Database Record PMID- 26437151 TI - A joint model of word segmentation and meaning acquisition through cross situational learning. AB - Human infants learn meanings for spoken words in complex interactions with other people, but the exact learning mechanisms are unknown. Among researchers, a widely studied learning mechanism is called cross-situational learning (XSL). In XSL, word meanings are learned when learners accumulate statistical information between spoken words and co-occurring objects or events, allowing the learner to overcome referential uncertainty after having sufficient experience with individually ambiguous scenarios. Existing models in this area have mainly assumed that the learner is capable of segmenting words from speech before grounding them to their referential meaning, while segmentation itself has been treated relatively independently of the meaning acquisition. In this article, we argue that XSL is not just a mechanism for word-to-meaning mapping, but that it provides strong cues for proto-lexical word segmentation. If a learner directly solves the correspondence problem between continuous speech input and the contextual referents being talked about, segmentation of the input into word-like units emerges as a by-product of the learning. We present a theoretical model for joint acquisition of proto-lexical segments and their meanings without assuming a priori knowledge of the language. We also investigate the behavior of the model using a computational implementation, making use of transition probability-based statistical learning. Results from simulations show that the model is not only capable of replicating behavioral data on word learning in artificial languages, but also shows effective learning of word segments and their meanings from continuous speech. Moreover, when augmented with a simple familiarity preference during learning, the model shows a good fit to human behavioral data in XSL tasks. These results support the idea of simultaneous segmentation and meaning acquisition and show that comprehensive models of early word segmentation should take referential word meanings into account. (PsycINFO Database Record PMID- 26437152 TI - Sequential processes and the shapes of reaction time distributions. AB - It is sometimes suggested that reaction time (RT) distributions have the same shape across conditions or groups. In this note we show that this is highly unlikely if the RT is the sum of the stochastically independent durations of 2 or more stages (sequential processes) (a) that are influenced selectively by different factors, or (b) 1 of which is influenced selectively by some factor. We provide an example of substantial shape differences in RT data from a flash detection experiment, data that have been shown to satisfy requirement (a). Ignoring these requirements, we also note that in a large range of instances reviewed by Matzke and Wagenmakers (2009) in which the ex-Gaussian distribution was fitted to RT data from different conditions in the same experiment, most sets of distributions fail to satisfy even a weak requirement for shape invariance. In the Appendix we describe the Summation Test for selectively influenced stages with independent durations (Roberts & Sternberg, 1993), and provide an example of its application. (PsycINFO Database Record PMID- 26437153 TI - Examining the mechanisms underlying contextual preference reversal: Comment on Trueblood, Brown, and Heathcote (2014). AB - Trueblood, Brown, and Heathcote (2014) provide a new model of multiattribute choice, which accounts for 3 contextual reversal effects (similarity, attraction and compromise). We review the details of the model and highlight some novel predictions. First, we show that the model works by setting a "fine balance" between 2 opposing factors that influence choice. As a result, small changes in the attributes of choice alternatives can disturb this balance. Second, we show that the model gives a partial account of the compromise effect. We describe a number of experiments that could distinguish the MLBA from other models of multiattribute choice. PMID- 26437154 TI - The fragile nature of contextual preference reversals: Reply to Tsetsos, Chater, and Usher (2015). AB - Trueblood, Brown, and Heathcote (2014) developed a new model, called the multiattribute linear ballistic accumulator (MLBA), to explain contextual preference reversals in multialternative choice. MLBA was shown to provide good accounts of human behavior through both qualitative analyses and quantitative fitting of choice data. Tsetsos, Chater, and Usher (2015) investigated the ability of MLBA to simultaneously capture 3 prominent context effects (attraction, compromise, and similarity). They concluded that MLBA must set a "fine balance" of competing forces to account for all 3 effects simultaneously and that its predictions are sensitive to the position of the stimuli in the attribute space. Through a new experiment, we show that the 3 effects are very fragile and that only a small subset of people shows all 3 simultaneously. Thus, the predictions that Tsetsos et al. generated from the MLBA model turn out to match closely real data in a new experiment. Support for these predictions provides strong evidence for the MLBA. A corollary is that a model that can "robustly" capture all 3 effects simultaneously is not necessarily a good model. Rather, a good model captures patterns found in human data, but cannot accommodate patterns that are not found. PMID- 26437155 TI - Dermatology consultations in a tertiary care hospital: A retrospective study of 243 cases. AB - BACKGROUND: The practice of dermatology remains mainly outpatient, although dermatologic consultations often have a large impact on inpatient care. OBJECTIVE: To analyze the reasons for dermatologic consultation and the impact of dermatologic evaluation at a major teaching hospital. METHODS: Retrospective chart review of 243 consecutive dermatologic consultations from primary ward teams between July 2012, and August 2013. RESULTS: Sixty-seven percent of the dermatologic consults were requested by the internal medicine, intensive care units, and hematology/oncology departments. Common skin conditions accounted for a large majority of consultations including: infectious (24.0%), drug-related (22.3%), and inflammatory skin conditions (21.0%). Most consultations required only one visit for resolution (60.9%). The primary team submitted a correct dermatologic diagnosis in 48.9% of cases. Dermatology consultation resulted in a change in or addition to treatment in 72.4% of patients. LIMITATIONS: Our analysis was limited by the data capture of the consulting physicians and the reliability of the patient historian. CONCLUSIONS: Our results revealed that common dermatoses account for a majority of dermatologic consultations. Modern ward teams continue to struggle with promptly recognizing and appropriately managing common skin conditions. Further training of ward physicians on common dermatologic conditions will improve recognition and treatment of skin conditions in hospitalized patients. PMID- 26437156 TI - Zoledronic acid-associated symmetrical drug-related intertriginous and flexural exanthema (SDRIFE): report of baboon syndrome in a woman with recurrent metastatic breast cancer after receiving zoledronic acid. AB - BACKGROUND: Baboon syndrome is a distinctive skin reaction in which the patient typically develops erythematous buttocks that appear similar to those of a baboon. The non-contact allergenic variant of baboon syndrome is also referred to as symmetrical drug-related intertriginous and flexural exanthema (SDRIFE). Zoledronic acid is a bisphosphonate that is used in patients with metastatic cancer to prevent bone complications. PURPOSE: Zoledronic acid-associated baboon syndrome is described in a woman with recurrent metastatic breast cancer. METHODS: PubMed was used to search the following terms, separately and in combination: baboon syndrome, breast cancer, symmetrical drug-related intertriginous and flexural exanthema, and zoledronic acid. All papers were reviewed and relevant manuscripts, along with their reference citations, were evaluated. RESULTS: Zoledronic acid has infrequently been associated with mucocutaneous adverse reactions. However, baboon syndrome has not previously been observed in patients receiving zoledronic acid. The reported woman developed baboon syndrome after her initial exposure to zoledronic acid. CONCLUSIONS: Non contact allergenic drug-induced baboon syndrome has most commonly been associated with antibiotics such as beta-lactams and penicillins. Zoledronic acid-associated baboon syndrome has not previously been observed in cancer patients. Baboon syndrome (SDRIFE variant) was observed in a woman with recurrent metastatic breast cancer after her first exposure to zoledronic acid. In summary, SDRIFE can occur in oncology patients receiving zoledronic acid and zoledronic acid should be added to the list of medications associated with the potential to cause non contact allergenic drug-induced baboon syndrome. PMID- 26437157 TI - Subcorneal pustular dermatosis associated with Coccidioides immitis. AB - Coccidioidomycosis (AKA "Valley fever") is a primary pulmonary infection via airborne spores released from coccidioides immitis in the soil. Reactive cutaneous eruptions resulting from the pulmonary infection are difficult to diagnose because skin biopsies do not contain the organism. We present an adolescent male with primary pulmonary C.immitis infection manifesting with biopsy proven subcorneal pustular dermatosis. Serological studies revealed increasingly positive titers for coccidioidomycosis and symptoms resolved promptly following initiation of systemic antifungal therapy. Our unique case presentation illustrates subcorneal pustular dermatosis as a reactive eruption owing to primary pulmonary coccidioidomycosis. An association between the two conditions warrants further investigation. PMID- 26437158 TI - Verruciform Genital-Associated (Vegas) Xanthoma: report of a patient with verruciform xanthoma of the scrotum and literature review. AB - BACKGROUND: Verruciform xanthoma is a benign verrucous lesion characterized by epithelial acanthosis and lipid-laden foamy histiocytes in the connective tissue papillae. It typically presents as a papillomatous, polypoid, or sessile lesion. Verruciform xanthoma is most commonly observed within the oral cavity. However, albeit less frequently, it develops on the penis, scrotum, or vulva. PURPOSE: We describe the clinical and pathologic findings of a man who developed a verruciform xanthoma on his scrotum. We also summarize the associated conditions, the differential diagnosis, the postulated pathogenesis, and the treatment options for this tumor. MATERIALS AND METHODS: The features of a man with a scrotal verruciform xanthoma are presented. Using PubMed, the following terms were searched and relevant citations assessed: anogenital, foam cells, penis, scrotum, verruciform, verruciform xanthoma, vulva, and xanthoma. In addition, the literature on verruciform xanthoma is reviewed. RESULTS: Our patient developed an asymptomatic, exophytic, red filiform papule on his scrotum. A shave biopsy, attempting to remove the entire lesion, was performed. Based on correlation of the clinical presentation and histopathologic findings, a diagnosis of verruciform xanthoma was established. The patient applied mupirocin 2% ointment to the biopsy site, which subsequently healed without complication or recurrence. CONCLUSION: Verruciform xanthoma is a benign tumor commonly located within the oral cavity and characterized by the development of a small verrucous, papillomatous, polypoid, or sessile growth. Extraoral sites of verruciform xanthoma often include the penis, scrotum, or vulva; we introduce the term 'Vegas' (Verruciform Genital-Associated) xanthoma for these lesions. The lesions are often mistaken for viral warts or malignancies. Although the mechanism of pathogenesis is unknown, verruciform xanthoma may have a multifactorial etiology involving inflammation, local immunosuppression, and/or metabolic dysfunction. It has also been postulated that verruciform xanthoma is a secondary reaction to trauma-induced epithelial damage or degeneration. A biopsy for histopathologic examination is required to diagnose verruciform xanthoma. The treatment of verruciform xanthoma typically involves simple surgical excision. PMID- 26437159 TI - Vesicular erythema migrans: an atypical and easily misdiagnosed form of Lyme disease. AB - Erythema migrans is the initial sign in the majority of patients infected with Borrelia, the genus of spirochetes that causes Lyme disease. Early identification and treatment decrease the risk of progression to later stages of disease. Although a "bull's eye" appearance owing to lesional clearing is considered classic for erythema migrans, this feature is surprisingly often lacking among patients in the United States. Furthermore, cutaneous Lyme disease can exhibit a wide range of morphologic variability in a minority of patients. Herein, we describe the case of a patient with Lyme disease in which the presence of atypical vesicular features, in conjunction with the initial absence of clearing, resulted in multiple misdiagnoses and delayed treatment. We also review the literature on the epidemiology and management of erythema migrans for cases in which the diagnosis may pose a challenge. PMID- 26437160 TI - Mycophenolate mofetil therapy for pediatric bullous pemphigoid. AB - Bullous pemphigoid (BP) is a common autoimmune blistering disease in the adult population, but extremely rare in the pediatric population. Childhood BP usually has a favorable prognosis and responds well to topical and oral steroids. However, for patients that do not respond to corticosteroids, therapeutic alternatives are scarce. We report a case of a toddler with recalcitrant BP who was successfully treated with mycophenolate mofetil (MMF). PMID- 26437161 TI - Pitted keratolysis: successful management with mupirocin 2% ointment monotherapy. AB - BACKGROUND: Pitted keratolysis is a benign dermatosis that occurs on plantar skin. PURPOSE: We describe a man with pitted keratolysis that was successfully treated with mupirocin 2% ointment monotherapy. METHODS AND MATERIALS: We reviewed PubMed for the following terms: mupirocin, ointment, pitted keratolysis, treatment. We also reviewed papers containing these terms and their references. RESULTS: Complete resolution of pitted keratolysis occurred following monotherapy with twice daily application of mupirocin 2% ointment for a duration of three weeks. There was no recurrence at a follow-up visit eight weeks later. CONCLUSIONS: Several topical and oral treatments are available to successfully manage pitted keratolysis. Our patient confirms previous reports of pitted keratolysis resolving with mupirocin 2% ointment treatment. Monotherapy with mupirocin 2% ointment should be considered as a primary treatment alternative for pitted keratolysis. PMID- 26437162 TI - A case report of primary cutaneous marginal zone lymphoma treated with intralesional steroids. AB - IMPORTANCE: Primary cutaneous marginal zone lymphoma (PCMZL) is a low-grade malignant B-cell lymphoma that appears in the skin without any extracutaneous manifestations. Therapeutic mainstays for PCMZL have primarily included radiotherapy and surgery. Intralesional steroids have been found to resolve the lesions caused by PCMZL, but there is a dearth of literature regarding this therapy indicating that this is not a commonly favored treatment option. OBSERVATIONS: We present a case of 60-year-old woman who presented with PCMZL on her right eyebrow. Three years later, after two courses of radiation and one relapse, the patient presented with new lesions on both arms, consistent once again with PCMZL. At this time, therapy with nine rounds of intralesional triamcinolone was attempted. After each round of triamcinolone, gradual improvement of the lesions was noted until complete resolution occurred. CONCLUSIONS AND RELEVANCE: This case reminds practitioners that intralesional corticosteroids can be effectively and safely used to treat localized PCMZL. Intralesional steroids are less invasive, cheaper, and easier to administer than the majority of other recommended therapies for PCMZL. Thus, although they are often overlooked, intralesional corticosteroids should be more often considered when developing a treatment plan for localized PCMZL. PMID- 26437163 TI - Atypical propylthiouracil-induced ANCA-positive vasculitis: report of a case with unusual clinical and histopathologic findings. AB - The side effects of propylthiouracil, including cytopenia and vasculitis, are well established. We present an interesting case in which cytopenia and cutaneous vasculopathy occurred concomitantly in a critically ill patient. The patient was initially treated for suspected infection until dermatologic and rheumatologic workup revealed ANCA-positivity and vasculopathy on histopathology, most consistent with an atypical presentation of ANCA-positive vasculitis. Upon initiation of immunosuppressive therapy, the patient's condition rapidly improved emphasizing the importance of early recognition of this condition. PMID- 26437165 TI - Primary care providers' perceptions of mobile store-and-forward teledermatology. AB - INTRODUCTION: Although teledermatology offers promise as a tool to increase access to care, adoption has been limited. Understanding the perspectives and experiences of key stakeholders, such as primary care providers (PCPs) and patients, is important to identify opportunities to reduce barriers to adoption and to improve teledermatology programs. Although many studies have examined patients' experiences and satisfaction with teledermatology, few have examined referring PCPs' perspectives. OBJECTIVE: To identify PCPs' perceptions on the strengths and limitations of teledermatology in order to identify opportunities to improve teledermatology programs. METHODS: We distributed an anonymous, web based survey to 30 PCPs involved in a two-year study evaluating a mobile app based teledermatology platform. RESULTS: 100% (18/18) agreed or strongly agreed that teledermatology increases access to dermatologic care, improves patient care, and is acceptable to patients. 100% (18/18) agreed or strongly agreed that teledermatology provides educational benefit to the PCP. Only 6% (1/18) agreed that teledermatology increases medical liability and 11% (2/18) agreed that it increases risk of a breach in privacy or confidentiality. CONCLUSIONS: Our findings highlight that PCPs are highly satisfied with mobile app-based, store and-forward teledermatology and that they believe teledermatology offers synergistic educational benefit. We hope these results will help guide the development of teledermatology programs to increase access to timely, cost effective care. PMID- 26437164 TI - Leukemia cutis with lymphoglandular bodies: a clue to acute lymphoblastic leukemia cutis. AB - Leukemia cutis describes cutaneous lesions produced by infiltrates of leukemic cells. It usually manifests contemporaneously with the initial diagnosis of systemic leukemia, but may also precede or follow systemic leukemia. Most cases are associated with acute myeloid leukemia. Adult B-cell lymphoblastic leukemia cutis is very rare. We report a 59-year-old woman with a history of B-cell acute lymphoblastic leukemia who relapsed with aleukemic lymphoblastic leukemia cutis. Lymphoglandular bodies were conspicuous on biopsy and may serve as a morphologic clue to lymphocytic differentiation while molecular and immunophenotypic studies are pending. The patient was successfully treated with local radiation therapy and oral ponatinib. PMID- 26437166 TI - A rare case of trigeminal trophic syndrome with an extensive scalp, forehead, and upper eyelid ulceration in a patient with undiagnosed Alzheimer disease. AB - BACKGROUND: Trigeminal Trophic Syndrome (TTS) is a rare presentation of facial ulceration, which is characterized by the triad of anesthesia, paraesthesia, and damage of trigeminal sensory branches. MAIN OBSERVATIONS: We report a unique case of TTS as an extensive forehead and scalp ulceration in a patient with undiagnosed Alzheimer disease. CONCLUSIONS: Treatment options for trigeminal trophic syndrome are limited and disappointing especially in older patients with dementia. Family education and behavioral modification therapies may be well tolerated option in this population. PMID- 26437167 TI - A case report of crusted scabies in an adult patient with Down syndrome. AB - IMPORTANCE: Crusted (Norwegian) scabies is a severe manifestation of the contagious skin infection caused by Sarcoptes scabiei. Crusted scabies has been well described in patients with known immunocompromised states. Treatment may be complicated by delayed diagnosis and/or inadequate treatment. This infection may not rank highly on one's differential diagnosis in the absence of an immunocompromised state, highlighting the uniqueness of the case being presented. Several papers describe immunocompromised children with Down syndrome who are infected with crusted scabies. We present a case of infection in an adult with Down syndrome without evidence of an immunocompromised state. OBSERVATIONS: Our patient came to us with a 13-month history of progressively worsening symptoms, the last 4-6 weeks of that time period being most dramatic, despite various treatments. We performed tissue biopsy, culture, and laboratory evaluations, which revealed numerous mites and bacterial superinfection. CONCLUSIONS AND RELEVANCE: Crusted scabies infection may occur in adult age individuals with Down syndrome regardless of immune status, leading us to encourage practitioners to consider this condition when presented with patients of this population. We also highlight the need for further exploration of disease prevalence in this patient population. PMID- 26437168 TI - Successful treatment of palmoplantar pustulosis with isotretinoin. AB - IMPORTANCE: Variably considered as a localized subtype of pustular psoriasis, palmoplantar pustulosis (PPP) is commonly treated with topical steroids, acitretin, and local phototherapy with oral or topical psoralen (PUVA). The utility of acitretin for PPP is limited by adverse effects such as myalgias and an extended risk of teratogenicity in female patients. Isotretinoin is a more tolerable retinoid with a shorter teratogenic window, but to date its effectiveness in PPP has not been reported. Herein we present two patients with PPP who responded well to isotretinoin treatment. OBSERVATIONS: Two patients with PPP refractory to topical therapies were started on acitretin. Both patients developed adverse effects (including headache, myalgias, and mood alterations) leading to acitretin discontinuation. Isotretinoin monotherapy was started in one patient resulting in significant clearing of palmar plaques and scale, and the addition of isotretinoin to UVA therapy resulted in near-complete clearing of recalcitrant plantar plaques in the second patient. CONCLUSIONS AND RELEVANCE: Acitretin represents an important treatment for PPP, but is limited by adverse effects and extended teratogenicity. Our experience supports the utility of isotretinoin as a potential therapeutic alternative, which may be particularly beneficial in patients who are poor candidates for or unable to tolerate acitretin therapy. PMID- 26437169 TI - Acne isolated within a Becker nevus of a 14 year-old girl. AB - Becker nevus (BN) is a common benign condition occurring most often in young men, much more often than in women. Acne isolated within a BN is a rare phenomenon hypothesized to occur, at least in part, due to increased androgen sensitivity within the nevus. We present a rare case of papular acne with in a BN of a 14 year-old girl. PMID- 26437170 TI - Nicolau syndrome following intramuscular injection of oxytocin in pregnant women: report of two cases. AB - Nicolau syndrome, also known as embolia cutis medicamentosa, is a well known but very rare complication occuring after intramuscular drug injections and presenting with local intense pain. Immediately after injection the skin blanches and within minutes to hours an erythematous macule develops, which evolves into a livedoid violaceous patch with dendrites. This condition is initially hemorrhagic, then it ulcerates, and eventually heals with an atrophic scar. Many different drugs have been reported to cause Nicolau syndrome . To date there have been no reports of Nicolau syndrome caused by intramuscular oxytocin injection. We would like to report two cases that occured after intramuscular injection of oxytocin. PMID- 26437171 TI - Flagellate shiitake mushroom dermatitis. AB - An 84-year-old woman presented with 5 days of a pruritic skin eruption that formed arciform and linear patterns. She was diagnosed with flagellate shiitake mushroom dermatitis related to shiitake mushroom consumption the day prior symptom onset. PMID- 26437172 TI - Isolation of Leclercia adecarboxylata from a patient with a subungual splinter. AB - Leclercia adecarboxylata is a rarely described motile, aerobic, gram-negative bacillus reported to cause clinically significant solitary infections in immunocompromised patients and polymicrobial wound infections in immunocompetent patients [1-5]. We present a case of a polymicrobial infection including L. adecarboxylata in a healthy female patient with a subungual splinter, to increase awareness and aid in the diagnosis and treatment of cutaneous L. adecarboxylata infections. To our knowledge, this is the first reported case of trauma-related subungual L. adecarboxylata infection reported in the dermatology literature. PMID- 26437173 TI - Phosphorescent Zinc Probe for Reversible Turn-On Detection with Bathochromically Shifted Emission. AB - Phosphorescent molecules are attractive complements to fluorescent compounds for bioimaging. Time-gated acquisition of the long-lived phosphorescence signals provides an effective means to eliminate unwanted background noises due to short lived autofluorescence. We have previously investigated the molecular principles governing modulation of photoinduced electron transfer in phosphorescence zinc probes that were based on biscyclometalated Ir(III) complexes (Woo, H. et al. J. Am. Chem. Soc. 2013, 135, 4771-4787). The studies established that phosphorescence turn-on responses would be attainable for Ir(III) complexes with high triplet-state energies. This sets an upper limit to an emission wavelength, restricting the development of red- or near-IR-phosphorescence turn-on probes. To address this challenge, we designed and synthesized a new phosphorescent probe having an electron-deficient 2-(2-pyridyl)pyrazine diimine ligand tethering a di(2-picolyl)amine (DPA) zinc receptor. This ligand control led to red phosphorescence emission (lambda(ems) = 596 nm), with an excited-state reduction potential (E*(red)) retained as high as 1.44 V versus standard calomel electrode (SCE). The E*(red) value was more positive than the ground-state oxidation potential of DPA (1.05 V vs SCE), permitting an occurrence of photoinduced electron transfer at a rate of 2 * 10(7) s(-1). Zinc binding at DPA abolished the electron transfer to produce phosphorescence turn-on signaling. The probe was capable of detecting zinc ions selectively over other competing biological metal ions in aqueous buffer solutions (pH 7.4, 20 mM piperazine-N,N'-bis(2 ethanesulfonic aid)) with the zinc dissociation constant of 109 pM. Finally, bioimaging utility of the probe has been successfully demonstrated by visualizing exogenously supplied zinc ions in live HeLa cells. The research described in this paper demonstrates that judicious ligand control enables retention of turn-on responses in the low-energy phosphorescence region. PMID- 26437174 TI - Postapplication Fipronil Exposure Following Use on Pets. AB - Fipronil is a pyrazole acaricide and insecticide that may be used for insect, tick, lice, and mite control on pets. Residents' short-term and long-term postapplication exposures to fipronil, including secondary environmental exposures, were estimated using data from chemical-specific studies. Estimations of acute (24-h) absorbed doses for residents were based on U.S. Environmental Protection Agency (U.S. EPA) 2012 standard operating procedures (SOPs) for postapplication exposure. Chronic exposures were not estimated for residential use, as continuous, long-term application activities were unlikely to occur. Estimated acute postapplication absorbed doses were as high as 0.56 MUg/kg-d for toddlers (1-2 yr) in households with treated pets based on current U.S. EPA SOPs. Acute toddler exposures estimated here were fivefold larger in comparison to adults. Secondary exposure from the household environment in which a treated pet lives that is not from contacting the pet, but from contacting the house interior to which pet residues were transferred, was estimated based on monitoring socks worn by pet owners. These secondary exposures were more than an order of magnitude lower than those estimated from contacting the pet and thus may be considered negligible. PMID- 26437176 TI - Sharpshooting in sport science and elite sports training. PMID- 26437175 TI - Brightness-equalized quantum dots. AB - As molecular labels for cells and tissues, fluorescent probes have shaped our understanding of biological structures and processes. However, their capacity for quantitative analysis is limited because photon emission rates from multicolour fluorophores are dissimilar, unstable and often unpredictable, which obscures correlations between measured fluorescence and molecular concentration. Here we introduce a new class of light-emitting quantum dots with tunable and equalized fluorescence brightness across a broad range of colours. The key feature is independent tunability of emission wavelength, extinction coefficient and quantum yield through distinct structural domains in the nanocrystal. Precise tuning eliminates a 100-fold red-to-green brightness mismatch of size-tuned quantum dots at the ensemble and single-particle levels, which substantially improves quantitative imaging accuracy in biological tissue. We anticipate that these materials engineering principles will vastly expand the optical engineering landscape of fluorescent probes, facilitate quantitative multicolour imaging in living tissue and improve colour tuning in light-emitting devices. PMID- 26437177 TI - The Cyclooctadepsipeptide Anthelmintic Emodepside Differentially Modulates Nematode, Insect and Human Calcium-Activated Potassium (SLO) Channel Alpha Subunits. AB - The anthelmintic emodepside paralyses adult filarial worms, via a mode of action distinct from previous anthelmintics and has recently garnered interest as a new treatment for onchocerciasis. Whole organism data suggest its anthelmintic action is underpinned by a selective activation of the nematode isoform of an evolutionary conserved Ca2+-activated K+ channel, SLO-1. To test this at the molecular level we compared the actions of emodepside at heterologously expressed SLO-1 alpha subunit orthologues from nematode (Caenorhabditis elegans), Drosophila melanogaster and human using whole cell voltage clamp. Intriguingly we found that emodepside modulated nematode (Ce slo-1), insect (Drosophila, Dm slo) and human (hum kcnma1)SLO channels but that there are discrete differences in the features of the modulation that are consistent with its anthelmintic efficacy. Nematode SLO-1 currents required 100 MUM intracellular Ca2+ and were strongly facilitated by emodepside (100 nM; +73.0 +/- 17.4%; n = 9; p < 0.001). Drosophila Slo currents on the other hand were activated by emodepside (10 MUM) in the presence of 52 nM Ca2+ but were inhibited in the presence of 290 nM Ca2+ and exhibited a characteristic loss of rectification. Human Slo required 300 nM Ca2+ and emodepside transiently facilitated currents (100 nM; +33.5 +/- 9%; n = 8; p<0.05) followed by a sustained inhibition (-52.6 +/- 9.8%; n = 8; p < 0.001). This first cross phyla comparison of the actions of emodepside at nematode, insect and human channels provides new mechanistic insight into the compound's complex modulation of SLO channels. Consistent with whole organism behavioural studies on C. elegans, it indicates its anthelmintic action derives from a strong activation of SLO current, not observed in the human channel. These data provide an important benchmark for the wider deployment of emodepside as an anthelmintic treatment. PMID- 26437178 TI - Stimuli-Responsive Cubosomes Formed from Blue Phase Liquid Crystals. AB - Cubosomes formed from blue phase liquid crystals (BPs) dispersed in aqueous media exhibit optical responses to biological amphiphiles. In this study, the formation of aqueous dispersions of BPs is reported, and the effects of confinement and lipids on the phase behavior, optical appearance, and morphology of BP droplets are characterized. PMID- 26437180 TI - Geographical diffusion of prazosin across Veterans Health Administration: Examination of regional variation in daily dosing and quality indicators among veterans with posttraumatic stress disorder. AB - Posttraumatic stress disorder (PTSD) is a high-priority treatment area for the Veterans Health Administration (VHA), and dissemination patterns of innovative, efficacious therapies can inform areas for potential improvement of diffusion efforts and quality prescribing. In this study, we replicated a prior examination of the period prevalence of prazosin use as a function of distance from Puget Sound, Washington, where prazosin was first tested as an effective treatment for PTSD and where prazosin use was previously shown to be much greater than in other parts of the United States. We tested the following three hypotheses related to prazosin geographic diffusion: (1) a positive geographical correlation exists between the distance from Puget Sound and the proportion of users treated according to a guideline recommended minimum therapeutic target dose (>/=6 mg/d), (2) an inverse geographic correlation exists between prazosin and benzodiazepine use, and (3) no geographical correlation exists between prazosin use and serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) use. Among a national sample of veterans with PTSD, overall prazosin utilization increased from 5.5 to 14.8% from 2006 to 2012. During this time period, rates at the Puget Sound VHA location declined from 34.4 to 29.9%, whereas utilization rates at locations a minimum of 2,500 miles away increased from 3.0 to 12.8%. Rates of minimum target dosing fell from 42.6 to 34.6% at the Puget Sound location. In contrast, at distances of at least 2,500 miles from Puget Sound, minimum threshold dosing rates remained stable (range, 18.6 to 17.7%). No discernible association was demonstrated between SSRI/SNRI or benzodiazepine utilization and the geographic distance from Puget Sound. Minimal threshold dosing of prazosin correlated positively with increased diffusion of prazosin use, but there was still a distance diffusion gradient. Although prazosin adoption has improved, geographic differences persist in both prescribing rates and minimum target dosing. Importantly, these regional disparities appear to be limited to prazosin prescribing and are not meaningfully correlated with SSRI/SNRI and benzodiazepine use as indicators of PTSD prescribing quality. PMID- 26437179 TI - Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status. AB - Targeted molecular therapy is an effective anticancer strategy. Anti-EGFR monoclonal antibodies such as cetuximab (CTX) have been approved for the treatment of various malignancies, including colorectal cancer (CRC) with wild type KRAS. However, their efficacy in patients with KRAS mutations has not been established. Therefore, we investigated whether CTX treatment was effective as a single agent or in combination with zoledronic acid (ZOL) in human CRC cell lines with different KRAS status. CRC cell lines SW48 (wild-type KRAS) and LS174T (mutant KRAS) were treated with ZOL, CTX and a combination of both drugs. Cytotoxicity was measured using the MTT assay. Changes in the levels of intracellular signaling proteins were evaluated using western blot analysis. Finally, we evaluated the efficacy of the combination treatment in an in vivo xenograft model. We observed that ZOL apparently inhibited growth in both cell lines, whereas CTX showed little effect. ZOL also increased the levels of unprenylated RAS. Combined ZOL and CTX treatment was synergistic in both cell lines and was associated with inhibition of the RAS-MAPK and AKT-mTOR signaling pathways. Furthermore, the combination treatment was more effective in suppressing the growth of xenografts derived from both SW48 and LS174T cells; this effect was associated with increased apoptosis. These results demonstrate that ZOL inhibits the growth of colon cancer cells regardless of KRAS status, and combination therapy using ZOL and CTX enhances this growth suppression. These findings suggest a novel strategy for the treatment of CRC independent of KRAS mutational status. PMID- 26437181 TI - Bet v 1- and Bet v 2-Associated Plant Food Sensitization in Uganda and Germany: Differences and Similarities. AB - BACKGROUND: Birch pollen allergy and concomitant plant food sensitization are well documented in Europe. However, there are currently no data available on pollen-associated plant food sensitization or even pollen allergy in tropical Africa. Our study aimed to investigate Bet v 1- and Bet v 2-associated plant food sensitization in atopic patients from Uganda and compare it with sensitization rates in German patients. METHODS: Sera from 83 Ugandan and 97 German atopic patients were analysed using UniCAP100TM for allergen-specific IgE against the birch tree pollen allergens Bet v 1 and Bet v 2 as well as the plant foods hazelnut, apple, kiwi, pea, peach, cherry, litchi, peanut, and soy. RESULTS: As expected, sensitization to Bet v 1 and cross-reactive plant food allergens was more common in German atopic patients. In contrast, the prevalence of sensitization against Bet v 2 was remarkably similar in Ugandan and German patients. Interestingly, in Ugandan patients we found IgE-mediated sensitization against plant foods such as hazelnut, pea, peach, cherry, and litchi that are neither cultivated nor consumed in Uganda. CONCLUSIONS: For Ugandan atopic patients, sensitization against the Bet v 2 allergen (a plant profilin) may explain cross-reactivity to several plant foods which are not consumed in Uganda. Additionally, it is probable that sensitization of Ugandan atopics to alder pollen (Alnus acuminata, plant family Betulaceae) caused serological cross reactivity with Betula verrucosa-related allergens. PMID- 26437182 TI - Rapid In Situ Hybridization using Oligonucleotide Probes on Paraformaldehyde prefixed Brain of Rats with Serotonin Syndrome. AB - 3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) toxicity may cause region specific changes in serotonergic mRNA expression due to acute serotonin (5 hydroxytryptamine; 5-HT) syndrome. This hypothesis can be tested using in situ hybridization to detect the serotonin 5-HT2A receptor gene htr2a. In the past, such procedures, utilizing radioactive riboprobe, were difficult because of the complicated workflow that needs several days to perform and the added difficulty that the technique required the use of fresh frozen tissues maintained in an RNase-free environment. Recently, the development of short oligonucleotide probes has simplified in situ hybridization procedures and allowed the use of paraformaldehyde-prefixed brain sections, which are more widely available in laboratories. Here, we describe a detailed protocol using non-radioactive oligonucleotide probes on the prefixed brain tissues. Hybridization probes used for this study include dapB (a bacterial gene coding for dihydrodipicolinate reductase), ppiB (a housekeeping gene coding for peptidylprolyl isomerase B), and htr2a (a serotonin gene coding for 5-HT2A receptors). This method is relatively simply, cheap, reproducible and requires less than two days to complete. PMID- 26437183 TI - Anharmonic Vibrational Analysis of the Infrared and Raman Gas-Phase Spectra of s trans- and s-gauche-1,3-Butadiene. AB - A quantum-mechanical (hybrid MP2/cc-pVTZ and CCSD(T)/cc-pVTZ) full quartic potential energy surface (PES) in rectilinear normal coordinates and the second order operator canonical Van Vleck perturbation theory (CVPT2) are employed to predict the anharmonic vibrational spectra of s-trans- and s-gauche-butadiene (BDE). These predictions are used to interpret their infrared and Raman scattering spectra. New high-temperature Raman spectra in the gas phase are presented in support of assignments for the gauche conformer. The CVPT2 solution is based on a PES and electro-optical properties (EOP; dipole moment and polarizability) expanded in Taylor series. Higher terms than those routinely available from Gaussian09 software were calculated by numerical differentiation of quadratic force fields and EOP using the MP2/cc-pVTZ model. The integer coefficients of the polyad quantum numbers were derived for both conformers of BDE. Replacement of harmonic frequencies by their counterparts from the CCSD(T)/cc-pVTZ model significantly improved the agreement with experimental data for s-trans-BDE (root-mean-square deviation ~ 5.5 cm(-1)). The accuracy in predicting the rather well-studied spectrum of fundamentals of s-trans-BDE assures good predictions of the spectrum of s-gauche-BDE. A nearly complete assignment of fundamentals was obtained for the gauche conformer. Many nonfundamental transitions of the BDE conformers were interpreted as well. The predictions of multiple Fermi resonances in the complex CH-stretching region correlate well with experiment. It is shown that solving a vibrational anharmonic problem through a numerical-analytic implementation of CVPT2 is a straightforward and computationally advantageous approach for medium-size molecules in comparison with the standard second-order vibrational perturbation theory (VPT2) based on analytic expressions. PMID- 26437186 TI - Correction: Rhinos in the Parks: An Island-Wide Survey of the Last Wild Population of the Sumatran Rhinoceros. PMID- 26437184 TI - Statistical Analysis of Zebrafish Locomotor Response. AB - Zebrafish larvae display rich locomotor behaviour upon external stimulation. The movement can be simultaneously tracked from many larvae arranged in multi-well plates. The resulting time-series locomotor data have been used to reveal new insights into neurobiology and pharmacology. However, the data are of large scale, and the corresponding locomotor behavior is affected by multiple factors. These issues pose a statistical challenge for comparing larval activities. To address this gap, this study has analyzed a visually-driven locomotor behaviour named the visual motor response (VMR) by the Hotelling's T-squared test. This test is congruent with comparing locomotor profiles from a time period. Different wild-type (WT) strains were compared using the test, which shows that they responded differently to light change at different developmental stages. The performance of this test was evaluated by a power analysis, which shows that the test was sensitive for detecting differences between experimental groups with sample numbers that were commonly used in various studies. In addition, this study investigated the effects of various factors that might affect the VMR by multivariate analysis of variance (MANOVA). The results indicate that the larval activity was generally affected by stage, light stimulus, their interaction, and location in the plate. Nonetheless, different factors affected larval activity differently over time, as indicated by a dynamical analysis of the activity at each second. Intriguingly, this analysis also shows that biological and technical repeats had negligible effect on larval activity. This finding is consistent with that from the Hotelling's T-squared test, and suggests that experimental repeats can be combined to enhance statistical power. Together, these investigations have established a statistical framework for analyzing VMR data, a framework that should be generally applicable to other locomotor data with similar structure. PMID- 26437187 TI - Internship and Empathy: Variations Across Time and Specialties. AB - OBJECTIVES: To assess whether any differences exist in Interpersonal Reactivity Index (IRI) scores among postgraduate year 1 (PGY-1) residents across specialties. METHODS: PGY-1 residents representing 11 specialties at our academic institution were invited to take a Web-based IRI survey at three time points. The specialties were condensed into several binary groups for analysis: internal medicine (IM) versus non-IM; primary care (IM, family medicine) versus nonprimary care; emergency medicine (EM, including the combined IM/EM) versus non-EM; surgical specialties (general surgery, obstetrics and gynecology, otolaryngology, orthopedics, urology) versus nonsurgical specialties (EM, family medicine, IM, neurology, pathology, and psychiatry); men versus women; and age groups. A repeated-measures generalized-estimating equations approach was taken to analyze the effect of specialty and time on each of the four IRI subscales. RESULTS: Of 94 PGY-1 residents invited to participate at each time point, 74 (77.1%) completed the survey at least once. Response rates at each time point were similar (mean 47.9%). When comparing the IM (n=35) and non-IM (n=39) groups, the perspective-taking subscale was found to be significantly lower in the non-IM group (P=0.006). Among male (n=46) versus female residents (n=26), the personal distress subscale was significantly different overall (P=0.041) but not among time points. No other significant differences were found between groups. The conglomerate subscale scores throughout the year did not show a dramatic change. CONCLUSIONS: Our study of IRI subscales in PGY-1 residents showed no major difference among specialties across 1 year except for IM residents, who scored significantly higher (more favorably) in the perspective-taking subscale. Contrary to previous studies, we did not observe a substantial decline in the empathic concern subscale IM residents over their first year. PMID- 26437188 TI - Analysis of a Guideline-Derived Resident Educational Program on Inpatient Glycemic Control. AB - OBJECTIVES: To determine the effects of a guideline-derived resident educational program on inpatient glycemic control and length of hospital stay (LOS). METHODS: We compared the following variables before and after resident education: percentage of patients on basal-plus-bolus regimens, mean fingerstick glucose (FSG), LOS, and rates of hypoglycemia (FSG<70 mg/dL) and severe hypoglycemia (FSG<40 mg/dL). A two-tailed t test was used for all continuous data and P<0.05 was considered statistically significant. RESULTS: After education, more patients (23% vs 8%; P=0.024) were placed on basal-plus-bolus regimens. We observed a decrease in mean FSG (158.7 mg/dL vs 165.1 mg/dL; P=0.028) and LOS (5.03 days vs 6.98 days; P=0.042). Rates of hypoglycemia (4.6% vs 1.5%; P<0.001) and severe hypoglycemia (0.71% vs 0.24%; P=0.089) increased. CONCLUSIONS: Our resident educational program significantly increased the number of patients receiving guideline-based inpatient insulin therapy and was associated with a reduction in mean FSG and LOS. Rates of hypoglycemia showed a statistically significant increase, whereas rates of severe hypoglycemia did not. Larger multicenter studies with adjustment for potential confounders are needed to further assess the impact of educational interventions on inpatient glycemic control. PMID- 26437189 TI - How Does Legalization of Physician-Assisted Suicide Affect Rates of Suicide? AB - OBJECTIVES: Several US states have legalized or decriminalized physician-assisted suicide (PAS) while others are considering permitting PAS. Although it has been suggested that legalization could lead to a reduction in total suicides and to a delay in those suicides that do occur, to date no research has tested whether these effects can be identified in practice. The aim of this study was to fill this gap by examining the association between the legalization of PAS and state level suicide rates in the United States between 1990 and 2013. METHODS: We used regression analysis to test the change in rates of nonassisted suicides and total suicides (including assisted suicides) before and after the legalization of PAS. RESULTS: Controlling for various socioeconomic factors, unobservable state and year effects, and state-specific linear trends, we found that legalizing PAS was associated with a 6.3% (95% confidence interval 2.70%-9.9%) increase in total suicides (including assisted suicides). This effect was larger in the individuals older than 65 years (14.5%, CI 6.4%-22.7%). Introduction of PAS was neither associated with a reduction in nonassisted suicide rates nor with an increase in the mean age of nonassisted suicide. CONCLUSIONS: Legalizing PAS has been associated with an increased rate of total suicides relative to other states and no decrease in nonassisted suicides. This suggests either that PAS does not inhibit (nor acts as an alternative to) nonassisted suicide, or that it acts in this way in some individuals but is associated with an increased inclination to suicide in other individuals. PMID- 26437190 TI - Social Contagion Effects of Physician-Assisted Suicide: Commentary on "How Does Legalization of Physician-Assisted Suicide Affect Rates of Suicide?". PMID- 26437191 TI - Academic Health Centers and Diversity "Readiness". PMID- 26437192 TI - Commentary on "Academic Health Centers and Diversity 'Readiness'". PMID- 26437193 TI - Chronic Pain Visits and Academic Medicine for Underrepresented Minorities: The Surprising Parallel. PMID- 26437194 TI - Waiting in the Accident and Emergency Department: Exploring Problematic Experiences. AB - OBJECTIVES: To investigate the relation between perceived waiting times and patients' overall ratings of accident and emergency departments (A&Es) and to explore which patients view waiting times as problematic. METHODS: A cross sectional survey was held in 21 A&Es in the Netherlands. From each A&E, a random sample of patients was investigated. Patients younger than 18 years and patients who had arrived by ambulance were excluded. Respondents' perceived waiting times and overall quality ratings of their A&E visit were collected and correlated. Respondents were divided into a "no problem" or "problem" group on the basis of the perceived waiting time before treatment. Logistic regression analyses were performed to explore factors potentially related to problematic waiting experiences, such as the amount of information received while waiting and perceived pain and acuity. RESULTS: The study included 3483 patients. Longer perceived waiting time was associated with a decrease in overall rating and increased reports of problematic experiences. Multivariate analysis showed that problematic waiting experiences were significantly associated with perceived pain (odds ratio [OR] 1.1), higher perceived acuity (emergency/urgent/nonurgent ORs: 2.7/2.2/1.0) and limited information before treatment. The OR for patients who did not receive any information about what to expect during a visit to the A&E versus patients who were completely informed was 3.3. For uninformed versus completely informed patients, the OR for information about how quickly patients needed to be helped with their health problem was 3.4. CONCLUSIONS: Providing information before treatment, controlling the perception of pain, and managing perceived acuity not only reduced problematic experiences concerning perceived waiting time but also improved experienced quality of care. PMID- 26437195 TI - Differentiating Bipolar Disorder from Attention-Deficit/Hyperactivity Disorder in Children. PMID- 26437196 TI - Virtual and Peer Reviews of Grant Applications at the Agency for Healthcare Research and Quality. AB - OBJECTIVES: This study documents the first six unplanned virtual review (VR) sessions conducted during the 2012 hurricane season at the Agency for Healthcare Research and Quality and their effects on review outcomes. It also compares these VR sessions with five face-to-face (FF) sessions. METHODS: In the first part of this study, six VR sessions are analyzed in terms of feasibility, reproducibility, and reviewers' responses to a questionnaire about VR. In the second part, the VR sessions are compared with five other FF meetings in terms of costs and duration per discussed application. RESULTS: Despite their technical novelty, all of the VR sessions have been successfully conducted to the satisfaction of reviewers and agency organizers. Special emphasis panel reviewers are more receptive to the new technology than study section reviewers: 75% versus 42%, respectively (P<0.05). Although the duration per discussed application is comparable to FF, the cost per reviewer is much lower for VR sessions than FF sessions. CONCLUSIONS: VR has successfully been used in six review sessions with a maximum of 34 discussed applications per session, special emphasis panel reviewers are more receptive to VR than SS reviewers, VR is a duplicable and low cost method of review, and practitioners and scientists are urged to serve as reviewers because doing so may assist them in receiving funding. PMID- 26437197 TI - Achieving Excellence in Pharmaceutical Care. PMID- 26437198 TI - SMJ Response. PMID- 26437199 TI - An Investigation of the Variety and Complexity of Statistical Methods Used in Current Internal Medicine Literature. AB - OBJECTIVES: Accreditation Council for Graduate Medical Education guidelines require internal medicine residents to develop skills in the interpretation of medical literature and to understand the principles of research. A necessary component is the ability to understand the statistical methods used and their results, material that is not an in-depth focus of most medical school curricula and residency programs. Given the breadth and depth of the current medical literature and an increasing emphasis on complex, sophisticated statistical analyses, the statistical foundation and education necessary for residents are uncertain. METHODS: We reviewed the statistical methods and terms used in 49 articles discussed at the journal club in the Department of Internal Medicine residency program at Texas Tech University between January 1, 2013 and June 30, 2013. We collected information on the study type and on the statistical methods used for summarizing and comparing samples, determining the relations between independent variables and dependent variables, and estimating models. We then identified the typical statistics education level at which each term or method is learned. RESULTS: A total of 14 articles came from the Journal of the American Medical Association Internal Medicine, 11 from the New England Journal of Medicine, 6 from the Annals of Internal Medicine, 5 from the Journal of the American Medical Association, and 13 from other journals. Twenty reported randomized controlled trials. Summary statistics included mean values (39 articles), category counts (38), and medians (28). Group comparisons were based on t tests (14 articles), chi2 tests (21), and nonparametric ranking tests (10). The relations between dependent and independent variables were analyzed with simple regression (6 articles), multivariate regression (11), and logistic regression (8). Nine studies reported odds ratios with 95% confidence intervals, and seven analyzed test performance using sensitivity and specificity calculations. These papers used 128 statistical terms and context-defined concepts, including some from data analysis (56), epidemiology-biostatistics (31), modeling (24), data collection (12), and meta-analysis (5). Ten different software programs were used in these articles. Based on usual undergraduate and graduate statistics curricula, 64.3% of the concepts and methods used in these papers required at least a master's degree-level statistics education. CONCLUSIONS: The interpretation of the current medical literature can require an extensive background in statistical methods at an education level exceeding the material and resources provided to most medical students and residents. Given the complexity and time pressure of medical education, these deficiencies will be hard to correct, but this project can serve as a basis for developing a curriculum in study design and statistical methods needed by physicians-in training. PMID- 26437200 TI - Commentary on "An Investigation of the Variety and Complexity of Statistical Methods Used in Current Internal Medicine Literature". PMID- 26437201 TI - Effect of Body Weight on Dose of Vitamin K Antagonists. AB - OBJECTIVES: Numerous factors are well documented to affect the response to vitamin K antagonists (VKA), including dietary vitamin K, other drugs, age, pharmacogenetics, and disease states. Body weight is perhaps not as well known as a variable affecting VKA dose. Our aim was to review the literature regarding body weight and VKA dose requirements. METHODS: We reviewed the English-language literature via PubMed and Scopus using the search terms VKA, warfarin, acenocoumarol, phenprocoumon, fluindione, AND body weight. RESULTS: Among 32 studies conducted since the widespread use of the international normalized ratio, 29 found a correlation with body weight or body surface area and VKA dose requirement. Warfarin was evaluated in 27 studies and acenocoumarol, phenprocoumon, or fluindione were assessed in 5 investigations. CONCLUSIONS: Because of varying study methodologies, further study is warranted. Based on current evidence, clinicians should include body weight, along with other established variables when dosing VKA. Most important, obese and morbidly obese patients may require a 30% to 50% increase with the initial dosing of VKA. PMID- 26437202 TI - Global Drug Safety Insights From Taiwan. PMID- 26437203 TI - Azole Resistance in Dermatophytes: Prevalence and Mechanism of Action. AB - Azole antifungal agents (eg, fluconazole and itraconazole) have been widely used to treat superficial fungal infections caused by dermatophytes and, unlike the allylamines (such as terbinafine and naftifine), have been associated with resistance development. Although many published manuscripts describe resistance to azoles among yeast and molds, reports describing resistance of dermatophytes are starting to appear. In this review, I discuss the mode of action of azole antifungals and mechanisms underlying their resistance compared with the allylamine class of compounds. Data from published and original studies were compared and summarized, and their clinical implications are discussed. In contrast to the cidal allylamines, static drugs such as azoles permit the occurrence of mutations in enzymes involved in ergosterol biosynthesis, and the ergosterol precursors accumulating as a consequence of azole action are not toxic. Azole antifungals, unlike allylamines, potentiate resistance development in dermatophytes. PMID- 26437204 TI - Erratum: Stock W, Johnson JL, Stone RM, Kolitz JE, Powell BL, Wetzler M, Westervelt P, Marcucci G, DeAngelo DJ, Vardiman JW, McDonnell D, Mrozek K, Bloomfield CD and Larson R A. Dose intensification of daunorubicin and cytarabine during treatment of adult acute lymphoblastic leukemia. Cancer. 2013;119:90-8. PMID- 26437206 TI - What is your diagnosis? Urine crystals in a dog. PMID- 26437208 TI - Tracking the Effect of Adatom Electronegativity on Systematically Modified AlGaN/GaN Schottky Interfaces. AB - The influence of surface modifications on the Schottky barrier height for gallium nitride semiconductor devices is frequently underestimated or neglected in investigations thereof. We show that a strong dependency of Schottky barrier heights for nickel/aluminum-gallium nitride (0001) contacts on the surface terminations exists: a linear correlation of increasing barrier height with increasing electronegativity of superficial adatoms is observed. The negatively charged adatoms compete with the present nitrogen over the available gallium (or aluminum) orbital to form an electrically improved surface termination. The resulting modification of the surface dipoles and hence polarization of the surface termination causes observed band bending. Our findings suggest that the greatest Schottky barrier heights are achieved by increasing the concentration of the most polarized fluorine-gallium (-aluminum) bonds at the surface. An increase in barrier height from 0.7 to 1.1 eV after a 15% fluorine termination is obtained with ideality factors of 1.10 +/- 0.05. The presence of surface dipoles that are changing the surface energy is proven by the sessile drop method as the electronegativity difference and polarization influences the contact angle. The extracted decrease in the Lifshitz-van-der-Waals component from 48.8 to 40.4 mJ/m(2) with increasing electronegativity and concentration of surface adatoms confirms the presence of increasing surface dipoles: as the polarizability of equally charged anions decreases with increasing electronegativity, the diiodomethane contact angles increase significantly from 14 degrees up to 39 degrees after the 15% fluorine termination. Therefore, a linear correlation between increasing anion electronegativity of the (Al)GaN termination and total surface energy within a 95% confidence interval is obtained. Furthermore, our results reveal a generally strong Lewis basicity of (Al)GaN surfaces explaining the high chemical inertness of the surfaces. PMID- 26437207 TI - Management of periorbital basal cell carcinoma with orbital invasion. AB - Basal cell carcinoma (BCC) is the most common eyelid malignancy; however, orbital invasion by periocular BCC is rare, and management remains challenging. Established risk factors for orbital invasion by BCC include male gender, advanced age, medial canthal location, previous recurrences, large tumor size, aggressive histologic subtype and perineural invasion. Management requires a multidisciplinary approach with orbital exenteration remaining the treatment of choice. Globe-sparing treatment may be appropriate in selected patients and radiotherapy and chemotherapy are often used as adjuvant therapies for advanced or inoperable cases, although the evidence remains limited. We aim to summarize the presentation and treatment of BCC with orbital invasion to better guide the management of this complex condition. PMID- 26437209 TI - No association between schizophrenia susceptibility variants and macroscopic structural brain volume variation in healthy subjects. AB - Previous studies have suggested that genetic variants for schizophrenia susceptibility might contribute to structural brain volume variations in schizophrenia patients, including total brain volume, hippocampal volume, and amygdalar volume. However, whether these schizophrenia susceptibility variants are associated with macroscopic structural brain volume (i.e., intracranial volume, total brain volume, and hippocampal volume) in healthy subjects is still unclear. In this study, we investigated the associations between 47 schizophrenia susceptibility variants (from 25 well-characterized schizophrenia susceptibility genes) and cranial volume variation in a healthy Chinese sample (N = 1,013). We also extracted the association between these 47 schizophrenia risk variants and the macroscopic structural brain volume (intracranial volume, total brain volume and hippocampal volume) in a large healthy sample of European ancestry (ENIGMA sample, N = 5,775). We identified several single-nucleotide polymorphisms (SNPs) nominally associated with intracranial volume, total brain volume, and hippocampal volume at P < 0.05 (uncorrected). However, after Bonferroni corrections for multiple testing, no SNP showed significant association. Hence, our results do not support previous observations that schizophrenia susceptibility variants are associated with brain structure (e.g., hippocampal volume) in healthy individuals, and indicate that single schizophrenia risk variant may not contribute significantly to macroscopic brain structure (e.g., intracranial volume or hippocampal volume) variation in healthy subjects. PMID- 26437210 TI - miRNA-mediated auxin signalling repression during Vat-mediated aphid resistance in Cucumis melo. AB - Resistance to Aphis gossypii in melon is attributed to the presence of the single dominant R gene virus aphid transmission (Vat), which is biologically expressed as antibiosis, antixenosis and tolerance. However, the mechanism of resistance is poorly understood at the molecular level. Aphid-induced transcriptional changes, including differentially expressed miRNA profiles that correspond to resistance interaction have been reported in melon. The potential regulatory roles of miRNAs in Vat-mediated aphid resistance were further revealed by identifying the specific miRNA degradation targets. A total of 70 miRNA:target pairs, including 28 novel miRNA:target pairs, for the differentially expressed miRNAs were identified: 11 were associated with phytohormone regulation, including six miRNAs that potentially regulate auxin interactions. A model for a redundant regulatory system of miRNA-mediated auxin insensitivity is proposed that incorporates auxin perception, auxin modification and auxin-regulated transcription. Chemically inhibiting the transport inhibitor response-1 (TIR-1) auxin receptor in susceptible melon tissues provides in vivo support for the model of auxin mediated impacts on A. gossypii resistance. PMID- 26437212 TI - Apoptosis- and cell cycle-related genes methylation profile in myeloproliferative neoplasms. PMID- 26437211 TI - Biochemical Characterization of Human Anti-Hepatitis B Monoclonal Antibody Produced in the Microalgae Phaeodactylum tricornutum. AB - Monoclonal antibodies (mAbs) represent actually the major class of biopharmaceuticals. They are produced recombinantly using living cells as biofactories. Among the different expression systems currently available, microalgae represent an emerging alternative which displays several biotechnological advantages. Indeed, microalgae are classified as generally recognized as safe organisms and can be grown easily in bioreactors with high growth rates similarly to CHO cells. Moreover, microalgae exhibit a phototrophic lifestyle involving low production costs as protein expression is fueled by photosynthesis. However, questions remain to be solved before any industrial production of algae-made biopharmaceuticals. Among them, protein heterogeneity as well as protein post-translational modifications need to be evaluated. Especially, N-glycosylation acquired by the secreted recombinant proteins is of major concern since most of the biopharmaceuticals including mAbs are N glycosylated and it is well recognized that glycosylation represent one of their critical quality attribute. In this paper, we assess the quality of the first recombinant algae-made mAbs produced in the diatom, Phaeodactylum tricornutum. We are focusing on the characterization of their C- and N-terminal extremities, their signal peptide cleavage and their post-translational modifications including N-glycosylation macro- and microheterogeneity. This study brings understanding on diatom cellular biology, especially secretion and intracellular trafficking of proteins. Overall, it reinforces the positioning of P. tricornutum as an emerging host for the production of biopharmaceuticals and prove that P. tricornutum is suitable for producing recombinant proteins bearing high mannose type N-glycans. PMID- 26437213 TI - PATIENTS' PERCEPTION ON CLINICAL OUTCOME AND QUALITY OF LIFE AFTER A DIAGNOSIS OF CUSHING SYNDROME. AB - OBJECTIVE: Excess cortisol production (Cushing syndrome, CS) is a chronic disease affecting many organ systems and impacting quality of life (QoL). This study analyzed factors associated with self-reported QoL, including aspects related to the diagnosis and treatment modalities of CS. METHODS: In collaboration with the Cushing's Support and Research Foundation (CSRF), surveys using a validated QoL instrument were sent to CSRF members. Data were analyzed for associations between QoL and demographic, treatment, and disease factors. RESULTS: A total of 269 patients completed the survey. Respondents were 89.9% female, and the mean age was 48 years (SD 12, range 16-76). Respondents visited a median of 4 physicians (range 1-40) prior to the diagnosis of CS, with a median of 5 years (mean 7, SD 5, range 1-30) to obtain a diagnosis, showing a statistically significant negative correlation (P<.001). In one-quarter of cases, someone other than a physician suggested the diagnosis. Multiple regression analysis demonstrated that remission status, time to diagnosis, radiation therapy, and hypopituitarism were significant predictors of QoL. There was no association between QoL and patient's sex, age, replacement steroid use, having follow-up with an endocrinologist, or surgical approach. CONCLUSION: This is one of the largest QoL studies of CS patients and provides information for treatment and education goals. It is notable that early diagnosis and treatment was the major predictor of better QoL after achieving remission from disease, highlighting the need for awareness about the disorder. Patients in remission had better QoL, emphasizing the importance of disease control. PMID- 26437214 TI - LIMITATIONS OF CURRENT APPROACHES FOR THE TREATMENT OF ACROMEGALY. AB - OBJECTIVE: Acromegaly is a rare disease characterized by hypersecretion of growth hormone (GH), typically from a benign pituitary somatotroph adenoma, that leads to subsequent hypersecretion of insulin-like growth factor 1 (IGF-1). Patients with acromegaly have an increased risk of mortality and progressive worsening of comorbidities. Surgery, medical therapy, and radiotherapy are currently available treatment approaches for patients with acromegaly, with overall therapeutic goals of lowering GH levels and achieving normal IGF-1 levels, reducing tumor size, improving comorbidities, and minimizing mortality risk. Although surgery can lead to biochemical remission in some patients with acromegaly, many patients will continue to have uncontrolled disease and require additional treatment. METHODS: We reviewed recently published reports and present a summary of the safety and efficacy of current treatment modalities for patients with acromegaly. RESULTS: A substantial proportion of patients who receive medical therapy or radiotherapy will have persistently elevated GH and/or IGF-1. Because of the serious health consequences of continued elevation of GH and IGF-1, there is a need to improve therapeutic approaches to optimize biochemical control, particularly in high-need patient populations for whom current treatment options provide limited benefit. CONCLUSION: This review discusses current treatment options for patients with acromegaly, limitations associated with each treatment approach, and areas within the current treatment algorithm, as well as patient populations for which improved therapeutic options are needed. Novel agents in development were also highlighted, which have the potential to improve management of patients with uncontrolled or persistent acromegaly. PMID- 26437215 TI - INCREASING PREVALENCE OF ADDISON DISEASE: RESULTS FROM A NATIONWIDE STUDY. AB - OBJECTIVE: Primary adrenal insufficiency is a life-threatening endocrine disease unless properly treated. However, few studies on the prevalence, concomitances of the disease, and prescribing of drugs have been published. The goal of the study was to establish the prevalence of primary adrenal insufficiency in Iceland and additionally, to study the most common concomitant diseases in patients with primary adrenal insufficiency, as well as the mode of glucocorticoid replacement therapies. METHODS: To achieve this, the medical records of all patients in Iceland who had received the International Classification of Diseases and Related Health Problems, 10th Revision, diagnosis code E27, were evaluated for true primary adrenal insufficiency. Additionally, these records were evaluated for concomitant diseases, as well as the mode of glucocorticoid replacement therapy. The study covered the whole population of Iceland over 18 years of age. It was thus a nationwide study. The records were retrieved from large hospitals and clinics and every practicing specialist in endocrinology. RESULTS: Primary adrenal insufficiency was found in 53 individuals, 26 women and 27 men, yielding a prevalence of 22.1 per 100,000 population. Hypothyroidism was by far the most common concomitant disease. Most patients had their glucocorticoid deficiency replaced with short-acting glucocorticoids. CONCLUSION: The prevalence of primary adrenal insufficiency in Iceland is higher than in earlier reports, with comorbidities being in line with recent studies. Treatment is according to the latest protocols. PMID- 26437216 TI - OUTCOME OF IMPLEMENTATION OF A MULTIDISCIPLINARY TEAM APPROACH TO THE CARE OF PATIENTS AFTER TRANSSPHENOIDAL SURGERY. AB - OBJECTIVE: Transsphenoidal surgery (TS) for sellar lesions is an established and safe procedure, but complications can occur, particularly involving the neuroendocrine system. We hypothesized that postoperative care of TS patients would be optimized when performed by a coordinated team including a pituitary neurosurgeon, endocrinologists, and a specialty nurse. METHODS: We implemented a formalized, multidisciplinary team approach and standardized postoperative protocols for the care of adult patients undergoing TS by a single surgeon (J.N.B.) at our institution beginning in July 2009. We retrospectively compared the outcomes of 214 consecutive TS-treated cases: 113 cases prior to and 101 following the initiation of the team approach and protocol implementation. Outcomes assessed included the incidence of neurosurgical and endocrine complications, length of stay (LOS), and rates of hospital readmission and unscheduled clinical visits. RESULTS: The median LOS decreased from 3 days preteam to 2 days postteam (P<.01). Discharge occurred on postoperative day 2 in 46% of the preteam group patients compared to 69% of the postteam group (P<.01). Rates of early postoperative diabetes insipidus (DI) and readmissions within 30 days for syndrome of inappropriate antidiuretic hormone (SIADH) or other complications did not differ between groups. CONCLUSION: Implementation of a multidisciplinary team approach was associated with a reduction of LOS. Despite earlier discharge, postoperative outcomes were not compromised. The endocrinologist is central to the success of this team approach, which could be successfully applied to care of patients undergoing TS, as well as other types of endocrine surgery at other centers. PMID- 26437217 TI - HISTORICAL RESPONSE RATES OF SOMATOSTATIN ANALOGUES IN THE TREATMENT OF ACROMEGALY: A SYSTEMATIC REVIEW. AB - OBJECTIVE: In a completed phase III study (C2305, Clinicaltrials.gov identifier: NCT00600886), the reported rate of biochemical control with octreotide long acting release (LAR) was lower than rates historically reported in patients pretreated and/or selected for response with somatostatin analogue (SSA) therapy. To assess whether lower efficacy rates of octreotide LAR in C2305 were influenced by study design, a systematic review of the literature was performed to evaluate response rates in previously published studies in acromegaly with similar design characteristics. METHODS: PubMed was used to search for English-language clinical studies of acromegaly published through May 2014. Prospective studies of medically naive patients (>=20) treated with SSAs for <=12 months that reported efficacy rates using composite endpoint measures (growth hormone [GH] and insulin like growth factor 1 [IGF-1]) were included. Two separate authors independently screened abstracts and full-length articles of each study to determine eligibility. All authors met to review and reach consensus when primary reviewers disagreed on the inclusion or exclusion of specific studies. RESULTS: A total of 9 studies (N = 354 patients) were identified, with reported mean efficacy rates of 31% (range, 20-54%). Of note, reported mean efficacy rates were lower in studies enrolling patients naive to any form of treatment (surgery, medical, and/or radiation) than in studies that enrolled only medically naive patients. A limitation of this analysis was that inclusion criteria restricted the number of studies analyzed. CONCLUSION: Interpretation of biochemical response rates with SSAs is critically dependent on the context of the study and should be evaluated across clinical trials with similar study design characteristics. PMID- 26437218 TI - IS IT TIME TO EMANCIPATE PLASMA CORTISOL? PMID- 26437219 TI - SELECTION OF ENDOCRINOLOGY SUBSPECIALTY TRAINEES: WHICH APPLICANT CHARACTERISTICS ARE ASSOCIATED WITH PERFORMANCE DURING FELLOWSHIP TRAINING? AB - OBJECTIVE: To determine which residency characteristics are associated with performance during endocrinology fellowship training as measured by competency based faculty evaluation scores and faculty global ratings of trainee performance. METHODS: We performed a retrospective review of interview applications from endocrinology fellows who graduated from a single academic institution between 2006 and 2013. Performance measures included competency-based faculty evaluation scores and faculty global ratings. The association between applicant characteristics and measures of performance during fellowship was examined by linear regression. RESULTS: The presence of a laudatory comparative statement in the residency program director's letter of recommendation (LoR) or experience as a chief resident was significantly associated with competency-based faculty evaluation scores (beta = 0.22, P = .001; and beta = 0.24, P = .009, respectively) and faculty global ratings (beta = 0.85, P = .006; and beta = 0.96, P = .015, respectively). CONCLUSION: The presence of a laudatory comparative statement in the residency program director's LoR or experience as a chief resident were significantly associated with overall performance during subspecialty fellowship training. Future studies are needed in other cohorts to determine the broader implications of these findings in the application and selection process. PMID- 26437220 TI - LEVOTHYROXINE REPLACEMENT IN OBESE HYPOTHYROID FEMALES AFTER TOTAL THYROIDECTOMY. AB - OBJECTIVE: Levothyroxine (LT4) replacement in hypothyroid obese patients is poorly understood. We assessed whether the LT4 regimen required to achieve euthyroidism differs between nonobese and obese hypothyroid females. METHODS: We retrospectively identified nonobese and obese females who received LT4 starting with a standard dose of 1.6 MUg/kg after total thyroidectomy for preoperative diagnosis of benign goiter. We examined the association between LT4 dosage required to achieve euthyroid state (thyroid-stimulating hormone [TSH] 0.4-2.5 mIU/L) and patient characteristics using linear regression models with and without adjustment for age, ethnicity, medication use, and postoperative hypoparathyroidism. RESULTS: We identified 32 females (15 nonobese/17 obese) who achieved euthyroid state. Obese patients weighed more (104.1 +/- 22.5 vs. 64.9 +/ 10.0 kg, P<.0001) and required a higher final LT4 than nonobese (146 +/- 38 vs. 102 +/- 12 MUg, P = .0002) but LT4 requirements per kg total body weight (TBW) were similar (1.60 +/- 0.29 vs. 1.42 +/- 0.38 MUg/kg, P = .15). LT4 dose per kg ideal body weight (IBW) was higher in obese than in nonobese females (2.62 +/- 0.67 vs. 1.88 +/- 0.28 MUg/kg, P = .0004) and this difference persisted after adjustments (P<.05). During LT4 titration, 47% and 20% of obese and nonobese patients had subnormal TSH episodes, respectively (P = .11). After taking LT4 compliance, malabsorption, and competing medication use into consideration, we found marked LT4 dose variability in obese patients. Patients who needed a mean daily LT4 dose <=150 mg (124 +/- 16 MUg/day) compared with >150 MUg (198 +/- 4 MUg/day) demonstrated lower LT4 per TBW (1.25 +/- 0.18 vs. 1.84 +/- 0.43 MUg/kg, P = .03) and IBW (2.28 +/- 0.47 vs. 3.44 +/- 0.18 MUg/kg, P<.0001), respectively. CONCLUSION: The standard approach to LT4 replacement in obese and nonobese females after thyroidectomy is imprecise. Mean daily LT4 doses in obese and nonobese patients were similar if expressed per kg TBW, though there was variability in the final LT4 among obese patients. We suggest initiating LT4 at a dose lower than that routinely recommended in obese females. PMID- 26437222 TI - Cetuximab promotes epithelial to mesenchymal transition and cancer associated fibroblasts in patients with head and neck cancer. AB - PURPOSE: To investigate if cetuximab induces epithelial to mesenchymal transition (EMT) and activation of cancer associated fibroblast (CAF) in the tumors of patients with squamous cell carcinoma of the head and neck (SCCHN). METHODS: Cetuximab was administered for two weeks prior to surgery to 20 treatment-naive patients. Five untreated patients were included as controls. Tumor biopsies were performed at baseline and before surgery. Gene expression profiles and quantitative real-time PCR (qRT-PCR) analysis of the pre-and post-treatment biopsies were compared. To further investigate EMT and CAF, correlations between previously described EMT and CAF markers and our microarray data set were calculated. RESULTS: Gene expression profile analyses and qRT-PCR showed that some of the genes modified by cetuximab were related to CAFs and EMT (ZNF521, CXCL12, ASPN, OLFML3, OLFM1, TWIST1, LEF1, ZEB1, FAP). We identified 2 patient clusters with different EMT and CAF characteristics. Whereas one cluster showed clear upregulation of expression of genes implicated in CAF and EMT including markers of embryologic pathways like NOTCH and Wnt, the other did not. CONCLUSIONS: Even if EMT and CAFs are implicated in cetuximab resistance in pre clinical models, we demonstrate for the first time that these molecular processes may occur clinically early on. PMID- 26437221 TI - Induction of KIAA1199/CEMIP is associated with colon cancer phenotype and poor patient survival. AB - Genes induced in colon cancer provide novel candidate biomarkers of tumor phenotype and aggressiveness. We originally identified KIAA1199 (now officially called CEMIP) as a transcript highly induced in colon cancer: initially designating the transcript as Colon Cancer Secreted Protein 1. We molecularly characterized CEMIP expression both at the mRNA and protein level and found it is a secreted protein induced an average of 54-fold in colon cancer. Knockout of CEMIPreduced the ability of human colon cancer cells to form xenograft tumors in athymic mice. Tumors that did grow had increased deposition of hyaluronan, linking CEMIP participation in hyaluronan degradation to the modulation of tumor phenotype. We find CEMIP mRNA overexpression correlates with poorer patient survival. In stage III only (n = 31) or in combined stage II plus stage III colon cancer cases (n = 73), 5-year overall survival was significantly better (p = 0.004 and p = 0.0003, respectively) among patients with low CEMIP expressing tumors than those with high CEMIP expressing tumors. These results demonstrate that CEMIP directly facilitates colon tumor growth, and high CEMIP expression correlates with poor outcome in stage III and in stages II+III combined cohorts. We present CEMIP as a candidate prognostic marker for colon cancer and a potential therapeutic target. PMID- 26437223 TI - miR-135b suppresses tumorigenesis in glioblastoma stem-like cells impairing proliferation, migration and self-renewal. AB - Glioblastoma multiforme (GBM) is the most common and fatal malignant adult primary brain tumor. Currently, the overall prognosis for GBM patients remains poor despite advances in neurosurgery and adjuvant treatments. MicroRNAs (miRNAs) contribute to the pathogenesis of various types of tumor, including GBM. In this study we analyzed the expression of a panel of miRNAs, which are known to be differentially expressed by the brain and GBM tumor, in a collection of patient derived GBM stem-like cells (GSCs). Notably, the average expression level of miR 135b, was the most downregulated compared to its normal counterpart, suggesting a potential role as anti-oncogene.Restoration of miR-135b in GSCs significantly decreased proliferation, migration and clonogenic abilities. More importantly, miR-135b restoration was able to significantly reduce brain infiltration in mouse models of GBM obtained by intracerebral injection of GSC lines. We identified ADAM12 and confirmed SMAD5 and GSK3beta as miR-135b targets and potential mediators of its effects. The whole transcriptome analysis ascertained that the expression of miR-135b downmodulated additional genes driving key pathways in GBM survival and infiltration capabilities.Our results identify a critical role of miR-135b in the regulation of GBM development, suggesting that miR-135b might act as a tumor-suppressor factor and thus providing a potential candidate for the treatment of GBM patients. PMID- 26437224 TI - Serine protease inhibitor Kazal type 1 (SPINK1) drives proliferation and anoikis resistance in a subset of ovarian cancers. AB - Ovarian cancer represents the most lethal tumor type among malignancies of the female reproductive system. Overall survival rates remain low. In this study, we identify the serine protease inhibitor Kazal type 1 (SPINK1) as a potential therapeutic target for a subset of ovarian cancers. We show that SPINK1 drives ovarian cancer cell proliferation through activation of epidermal growth factor receptor (EGFR) signaling, and that SPINK1 promotes resistance to anoikis through a distinct mechanism involving protease inhibition. In analyses of ovarian tumor specimens from a Mayo Clinic cohort of 490 patients, we further find that SPINK1 immunostaining represents an independent prognostic factor for poor survival, with the strongest association in patients with nonserous histological tumor subtypes (endometrioid, clear cell, and mucinous). This study provides novel insight into the fundamental processes underlying ovarian cancer progression, and also suggests new avenues for development of molecularly targeted therapies. PMID- 26437225 TI - Chemogenetic profiling identifies RAD17 as synthetically lethal with checkpoint kinase inhibition. AB - Chemical inhibitors of the checkpoint kinases have shown promise in the treatment of cancer, yet their clinical utility may be limited by a lack of molecular biomarkers to identify specific patients most likely to respond to therapy. To this end, we screened 112 known tumor suppressor genes for synthetic lethal interactions with inhibitors of the CHEK1 and CHEK2 checkpoint kinases. We identified eight interactions, including the Replication Factor C (RFC)-related protein RAD17. Clonogenic assays in RAD17 knockdown cell lines identified a substantial shift in sensitivity to checkpoint kinase inhibition (3.5-fold) as compared to RAD17 wild-type. Additional evidence for this interaction was found in a large-scale functional shRNA screen of over 100 genotyped cancer cell lines, in which CHEK1/2 mutant cell lines were unexpectedly sensitive to RAD17 knockdown. This interaction was widely conserved, as we found that RAD17 interacts strongly with checkpoint kinases in the budding yeast Saccharomyces cerevisiae. In the setting of RAD17 knockdown, CHEK1/2 inhibition was found to be synergistic with inhibition of WEE1, another pharmacologically relevant checkpoint kinase. Accumulation of the DNA damage marker gammaH2AX following chemical inhibition or transient knockdown of CHEK1, CHEK2 or WEE1 was magnified by knockdown of RAD17. Taken together, our data suggest that CHEK1 or WEE1 inhibitors are likely to have greater clinical efficacy in tumors with RAD17 loss of-function. PMID- 26437226 TI - Identification of novel, in vivo active Chk1 inhibitors utilizing structure guided drug design. AB - Chk1 kinase is a critical component of the DNA damage response checkpoint especially in cancer cells and targeting Chk1 is a potential therapeutic opportunity for potentiating the anti-tumor activity of DNA damaging chemotherapy drugs. Fragment elaboration by structure guided design was utilized to identify and develop a novel series of Chk1 inhibitors culminating in the identification of V158411, a potent ATP-competitive inhibitor of the Chk1 and Chk2 kinases. V158411 abrogated gemcitabine and camptothecin induced cell cycle checkpoints, resulting in the expected modulation of cell cycle proteins and increased cell death in cancer cells. V158411 potentiated the cytotoxicity of gemcitabine, cisplatin, SN38 and camptothecin in a variety of p53 deficient human tumor cell lines in vitro, p53 proficient cells were unaffected. In nude mice, V158411 showed minimal toxicity as a single agent and in combination with irinotecan. In tumor bearing animals, V158411 was detected at high levels in the tumor with a long elimination half-life; no pharmacologically significant in vivo drug-drug interactions with irinotecan were identified through analysis of the pharmacokinetic profiles. V158411 potentiated the anti-tumor activity of irinotecan in a variety of human colon tumor xenograft models without additional systemic toxicity. These results demonstrate the opportunity for combining V158411 with standard of care chemotherapeutic agents to potentiate the therapeutic efficacy of these agents without increasing their toxicity to normal cells. Thus, V158411 would warrant further clinical evaluation. PMID- 26437227 TI - Simultaneous PET/MRI Imaging During Mouse Cerebral Hypoxia-ischemia. AB - Dynamic changes in tissue water diffusion and glucose metabolism occur during and after hypoxia in cerebral hypoxia-ischemia reflecting a bioenergetics disturbance in affected cells. Diffusion weighted magnetic resonance imaging (MRI) identifies regions that are damaged, potentially irreversibly, by hypoxia-ischemia. Alterations in glucose utilization in the affected tissue may be detectable by positron emission tomography (PET) imaging of 2-deoxy-2-(18F)fluoro-?-glucose ([18F]FDG) uptake. Due to the rapid and variable nature of injury in this animal model, acquisition of both modes of data must be performed simultaneously in order to meaningfully correlate PET and MRI data. In addition, inter-animal variability in the hypoxic-ischemic injury due to vascular differences limits the ability to analyze multi-modal data and observe changes to a group-wise approach if data is not acquired simultaneously in individual subjects. The method presented here allows one to acquire both diffusion-weighted MRI and [18F]FDG uptake data in the same animal before, during, and after the hypoxic challenge in order to interrogate immediate physiological changes. PMID- 26437228 TI - Time Out-of-Home and Cognitive, Physical, and Emotional Wellbeing of Older Adults: A Longitudinal Mixed Effects Model. AB - BACKGROUND: Time out-of-home has been linked with numerous health outcomes, including cognitive decline, poor physical ability and low emotional state. Comprehensive characterization of this important health metric would potentially enable objective monitoring of key health outcomes. The objective of this study is to determine the relationship between time out-of-home and cognitive status, physical ability and emotional state. METHODS AND FINDINGS: Participants included 85 independent older adults, age 65-96 years (M = 86.36; SD = 6.79) who lived alone, from the Intelligent Systems for Assessing Aging Changes (ISAAC) and the ORCATECH Life Laboratory cohorts. Factors hypothesized to affect time out-of-home were assessed on three different temporal levels: yearly (cognitive status, loneliness, clinical walking speed), weekly (pain and mood) or daily (time out-of home, in-home walking speed, weather, and season). Subject characteristics including age, race, and gender were assessed at baseline. Total daily time out of-home in hours was assessed objectively and unobtrusively for up to one year using an in-home activity sensor platform. A longitudinal tobit mixed effects regression model was used to relate daily time out-of-home to cognitive status, physical ability and emotional state. More hours spend outside the home was associated with better cognitive function as assessed using the Clinical Dementia Rating (CDR) Scale, where higher scores indicate lower cognitive function (betaCDR = -1.69, p<0.001). More hours outside the home was also associated with superior physical ability (betaPain = -0.123, p<0.001) and improved emotional state (betaLonely = -0.046, p<0.001; betaLow mood = -0.520, p<0.001). Weather, season, and weekday also affected the daily time out-of-home. CONCLUSIONS: These results suggest that objective longitudinal monitoring of time out-of-home may enable unobtrusive assessment of cognitive, physical and emotional state. In addition, these results indicate that the factors affecting out-of-home behavior are complex, with factors such as living environment, weather and season significantly affecting time out-of-home. Studies investigating the relationship between time out-of-home and health outcomes may be optimized by taking into account the environment and life factors presented here. PMID- 26437230 TI - Duloxetine enters the brain - But why is it not found in the cerebrospinal fluid. AB - BACKGROUND: Antidepressants enter the brain to reach their site of action in a different extent. However, there has been no study to date about duloxetine's ability to enter the brain and cerebrospinal fluid. Aim of this study was to measure blood and cerebrospinal fluid concentrations of duloxetine and to account for the distribution between the two compartments. METHODS: Concentrations of duloxetine were measured in blood serum and cerebrospinal fluid of 19 patients treated with daily doses of 30-120mg. Daily doses were correlated with serum and cerebrospinal fluid concentrations and serum concentrations were correlated with concentrations in cerebrospinal fluid. RESULTS: Serum concentrations of duloxetine showed a moderate but significant correlation with the applied daily dose, r=+0.473, p=0.04. Duloxetine concentrations in the cerebrospinal fluid above the designated limit of quantification of 2.0ng/mL were only found in three of the 19 patients. CONCLUSIONS AND LIMITATIONS: Contrasting to own preceding studies on venlafaxine, mirtazapine and citalopram with comparably high concentrations in cerebrospinal fluid, the here presented findings indicate that duloxetine shows a very different distribution pattern. Very low concentrations in the cerebrospinal fluid may be due to the fact that the drug crosses the blood cerebrospinal fluid barrier much worse than other antidepressants do, suggesting a low ability of duloxetine to enter the brain. Alternatively, low drug concentrations may be interpreted in a sense of a missing residence time in cerebrospinal fluid due to active transport mechanisms out of this environment either back into the bloodstream or into the brain. PMID- 26437229 TI - Optimizing Production of Antigens and Fabs in the Context of Generating Recombinant Antibodies to Human Proteins. AB - We developed and optimized a high-throughput project workflow to generate renewable recombinant antibodies to human proteins involved in epigenetic signalling. Three different strategies to produce phage display compatible protein antigens in bacterial systems were compared, and we found that in vivo biotinylation through the use of an Avi tag was the most productive method. Phage display selections were performed on 265 in vivo biotinylated antigen domains. High-affinity Fabs (<20nM) were obtained for 196. We constructed and optimized a new expression vector to produce in vivo biotinylated Fabs in E. coli. This increased average yields up to 10-fold, with an average yield of 4 mg/L. For 118 antigens, we identified Fabs that could immunoprecipitate their full-length endogenous targets from mammalian cell lysates. One Fab for each antigen was converted to a recombinant IgG and produced in mammalian cells, with an average yield of 15 mg/L. In summary, we have optimized each step of the pipeline to produce recombinant antibodies, significantly increasing both efficiency and yield, and also showed that these Fabs and IgGs can be generally useful for chromatin immunoprecipitation (ChIP) protocols. PMID- 26437231 TI - Emotion-relevant impulsivity predicts sustained anger and aggression after remission in bipolar I disorder. AB - Recent evidence suggests that anger and aggression are of concern even during remission for persons with bipolar I disorder, although there is substantial variability in the degree of anger and aggression across individuals. Little research is available to examine psychological models of anger and aggression for those with remitted bipolar disorder, and that was the goal of this study. Participants were 58 persons diagnosed with bipolar I disorder using the Structured Clinical Interview for DSM-IV, who were followed with monthly symptom severity interviews until they achieved remission, and then assessed using the Aggression-Short Form. We examined traditional predictors of clinical parameters and trauma exposure, and then considered three trait domains that have been shown to be elevated in bipolar disorder and have also been linked to aggression outside of bipolar disorder: emotion-relevant impulsivity, approach motivation, and dominance-related constructs. Emotion-relevant impulsivity was related to anger, hostility, verbal aggression, and physical aggression, even after controlling for clinical variables. Findings extend the importance of emotion relevant impulsivity to another important clinical outcome and suggest the promise of using psychological models to understand the factors driving aggression and anger problems that persist into remission among persons with bipolar disorder. PMID- 26437232 TI - White matter microstructural characteristics in Bipolar I and Bipolar II Disorder: A diffusion tensor imaging study. AB - BACKGROUND: Diffusion tensor imaging (DTI) studies of bipolar disorder (BD) report contrasting results and are mainly focused on bipolar I (BD-I) samples. We aimed at investigating how and where DTI parameters differ between BD-I and bipolar II (BD-II) and between BD and healthy control subjects (HC). METHODS: We conducted a tract-based spatial statistics analysis of DTI derived parameters, namely fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) in a matched sample of 50 BD (25 BD-I and 25 BD-II) during the chronic course of the illness and 50 HC. RESULTS: Compared to BD-I and HC, BD-II showed lower FA but no significant AD or RD differences in the right inferior longitudinal fasciculus (ILF). Both patient groups showed lower AD and RD in the left internal capsule and lower AD across the left ILF, the cortico-spinal tract within the right hemisphere and bilaterally in the cerebellum with respect to HC. LIMITATIONS: Patients were medicated at the time of scanning; the BD-II group had higher Hamilton Rating Scale for Depression scores than the BD-I group. CONCLUSIONS: BD-II patients differ from BD-I in the ILF. Both BD subtypes showed widespread white matter (WM) changes in the internal capsule, cortico-spinal tract and cerebellum. The loss of WM integrity in BD-II might be due to demyelination whereas WM changes common to both subgroups could be attributable to axonal damage. PMID- 26437233 TI - Computerized cognitive training and functional recovery in major depressive disorder: A meta-analysis. AB - OBJECTIVE: Depression is common, frequently resistant to antidepressant treatment, and associated with impairments in cognition and everyday functioning. Computerized cognitive training (CCT) paradigms offer potential to improve cognition, mood and everyday functioning, but their effectiveness is not well established. The goal of this article was to conduct a systematic review and meta analysis to determine the efficacy of CCT in depressive disorders. METHOD: A search was conducted to identify high quality randomized controlled CCT trials per PRISMA guidelines using PsycINFO and MEDLINE with the keywords "Cognitive training" or "Cognitive remediation" or "Cognitive rehabilitation" and "Depression". 9 randomized trials for depressed adults met inclusion criteria. Effect sizes (Hedge's g) were calculated for key outcome measures of mood symptom severity, daily functioning, and cognition. A 3-level Bayesian hierarchical linear model was used to estimate effect sizes for each domain and study. Publication bias was assessed using Classic Fail Safe N's and homogeneity was evaluated using Q and I(2) indexes. RESULTS: Significant small-moderate effects for Symptom Severity (0.43) and Daily Functioning (0.72), and moderate-large effects for Attention (0.67), Working Memory (0.72), and Global Functioning (1.05) were found. No significant effects were found for Executive Functioning or Verbal Memory. Moderator variable analysis revealed decreased effect of CCT with age. Gender and concurrent medication treatment did not affect the results. LIMITATIONS: Small sample size, short duration, pseudo-specificity, and high heterogeneity for Verbal Memory measures. CONCLUSIONS: CCT is associated with improvement in depressive symptoms and everyday functioning, though produces inconsistent effects on cognition. PMID- 26437234 TI - Steroids for chronic inflammatory demyelinating polyradiculoneuropathy: evidence base and clinical practice. AB - Evidence-based therapies for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) consist of corticosteroids, intravenous immunglobulins (IVIg), and plasma exchange. Steroids represent the oldest treatment used historically. In countries where readily available and affordable, IVIg tends to be favored as first-line treatment. The reason for this preference, despite substantially higher costs, is the perception that IVIg is more efficacious and safer than corticosteroids. However, the unselected use of IVIg as a first-line treatment option in all cases of CIDP raises issues of cost effectiveness in the long-term. Furthermore, serious although rare, particularly thromboembolic side effects may result from their use. Recent data from randomized trials suggest pulsed corticosteroids to have a higher potential in achieving therapy-free remission or longer remission-free periods compared with IVIg, as well as relatively low rates of serious side effects when given as pulsed intravenous infusions during short periods of time. These specific advantages suggest that pulsed steroids could in many cases be used, as the first, rather than second choice of treatment when initiating immunomodulation in CIDP, primarily in hopes of achieving a remission after the short-term use. This article reviews the evidence base for the use of corticosteroids in its various forms in CIDP and factors that may influence clinicians' choice between IVIg and pulsed steroid treatment. The issue of efficacy, relapse rate and time, and side effect profile are analyzed, and some aspects from the authors' experience are discussed in relation to the possibility of using the steroid option as first line therapy in a large proportion of patients with CIDP. PMID- 26437235 TI - A systems approach to understanding human rhinovirus and influenza virus infection. AB - Human rhinovirus and influenza virus infections of the upper airway lead to colds and the flu and can trigger exacerbations of lower airway diseases including asthma and chronic obstructive pulmonary disease. Novel diagnostic and therapeutic targets are still needed to differentiate between the cold and the flu, since the clinical course of influenza can be severe while that of rhinovirus is usually more mild. In our investigation of influenza and rhinovirus infection of human respiratory epithelial cells, we used a systems approach to identify the temporally changing patterns of host gene expression from these viruses. After infection of human bronchial epithelial cells (BEAS-2B) with rhinovirus, influenza virus or co-infection with both viruses, we studied the time-course of host gene expression changes over three days. We modeled host responses to these viral infections with time and documented the qualitative and quantitative differences in innate immune activation and regulation. PMID- 26437236 TI - PCB Food Web Dynamics Quantify Nutrient and Energy Flow in Aquatic Ecosystems. AB - Measuring in situ nutrient and energy flows in spatially and temporally complex aquatic ecosystems represents a major ecological challenge. Food web structure, energy and nutrient budgets are difficult to measure, and it is becoming more important to quantify both energy and nutrient flow to determine how food web processes and structure are being modified by multiple stressors. We propose that polychlorinated biphenyl (PCB) congeners represent an ideal tracer to quantify in situ energy and nutrient flow between trophic levels. Here, we demonstrate how an understanding of PCB congener bioaccumulation dynamics provides multiple direct measurements of energy and nutrient flow in aquatic food webs. To demonstrate this novel approach, we quantified nitrogen (N), phosphorus (P) and caloric turnover rates for Lake Huron lake trout, and reveal how these processes are regulated by both growth rate and fish life history. Although minimal nutrient recycling was observed in young growing fish, slow growing, older lake trout (>5 yr) recycled an average of 482 Tonnes.yr(-1) of N, 45 Tonnes.yr(-1) of P and assimilated 22 TJ yr(-1) of energy. Compared to total P loading rates of 590 Tonnes.yr(-1), the recycling of primarily bioavailable nutrients by fish plays an important role regulating the nutrient states of oligotrophic lakes. PMID- 26437237 TI - Direct Observation of Highly Ordered Dendrimer Soft Building Blocks over a Large Area. AB - Developing large-area, single domain of organic soft-building blocks such as block copolymers, colloids, and supramolecular materials is one of the most important issues in the materials science and nanotechnology. Owing to their small sizes, complex molecular architectures, and high mobility, supramolecular materials are not well-suited for building large area, single domain structures. In the described study, a single domain of supramolecular columnar dendrimers was created over large area. The columnar structures in these domains have smaller (4.5 nm) diameters, higher area densities (ca. 36 Tera-dots/in(2)) and larger domains (>0.1 * 0.1 mm(2)) than those of all existing BCP and colloidal assemblies. By simply annealing dendrimer thin films between two flat solid surfaces, single domains of hexagonal columnar structures are created over large macroscopic areas. Observations made in this effort should serve as the foundation for the design of new routes for bottom-up lithography based on supramolecular building blocks. PMID- 26437238 TI - Stonin1 mediates endocytosis of the proteoglycan NG2 and regulates focal adhesion dynamics and cell motility. AB - Cellular functions, ranging from focal adhesion (FA) dynamics and cell motility to tumour growth, are orchestrated by signals cells receive from outside via cell surface receptors. Signalling is fine-tuned by the exo-endocytic cycling of these receptors to control cellular responses such as FA dynamics, which determine cell motility. How precisely endocytosis regulates turnover of the various cell surface receptors remains unclear. Here we identify Stonin1, an endocytic adaptor of unknown function, as a regulator of FA dynamics and cell motility, and demonstrate that it facilitates the internalization of the oncogenic proteoglycan NG2, a co-receptor of integrins and platelet-derived growth factor receptor. Embryonic fibroblasts obtained from Stonin1-deficient mice display a marked surface accumulation of NG2, increased cellular signalling and defective FA disassembly as well as altered cellular motility. These data establish Stonin1 as a specific adaptor for the endocytosis of NG2 and as an important factor for FA dynamics and cell migration. PMID- 26437239 TI - North American tree squirrels and ground squirrels with overlapping ranges host different Cryptosporidium species and genotypes. AB - Wildlife-associated Cryptosporidium are an emerging cause of cryptosporidiosis in humans. The present study was undertaken to determine the extent to which North American tree squirrels and ground squirrels host zoonotic Cryptosporidium species and genotypes. Fragments of the Cryptosporidium 18S rRNA and actin genes were amplified and sequenced from fecal samples obtained from three tree squirrel and three ground squirrel species. In tree squirrels, Cryptosporidium was identified in 40.5% (17/42) of American red squirrels (Tamiasciurus hudsonicus), 40.4% (55/136) of eastern gray squirrels (Sciurus carolinensis), and 28.6% (2/7) of fox squirrels (Sciurus niger). Human-pathogenic Cryptosporidium ubiquitum and Cryptosporidium skunk genotype were the most prevalent species/genotypes in tree squirrels. Because tree squirrels live in close proximity to humans and are frequently infected with potentially zoonotic Cryptosporidium species/genotypes, they may be a significant reservoir of infection in humans. In ground squirrels, Cryptosporidium was detected in 70.2% (33/47) of 13-lined ground squirrels (Ictidomys tridecemlineatus), 35.1% (27/77) of black-tailed prairie dogs (Cynomys ludovicianus), and the only golden-mantled ground squirrel (Callospermophilus lateralis) that was sampled. Cryptosporidium rubeyi and ground squirrel genotypes I, II, and III were identified in isolates from these ground squirrel species. In contrast to the Cryptosporidium infecting tree squirrels, these species/genotypes appear to be specific for ground squirrels and are not associated with human disease. PMID- 26437240 TI - Drosha controls dendritic cell development by cleaving messenger RNAs encoding inhibitors of myelopoiesis. AB - To investigate if the microRNA (miRNA) pathway is required for dendritic cell (DC) development, we assessed the effect of ablating Drosha and Dicer, the two enzymes central to miRNA biogenesis. We found that while Dicer deficiency had some effect, Drosha deficiency completely halted DC development and halted myelopoiesis more generally. This indicated that while the miRNA pathway did have a role, it was a non-miRNA function of Drosha that was particularly critical. Drosha repressed the expression of two mRNAs encoding inhibitors of myelopoiesis in early hematopoietic progenitors. We found that Drosha directly cleaved stem loop structure within these mRNAs and that this mRNA degradation was necessary for myelopoiesis. We have therefore identified a mechanism that regulates the development of DCs and other myeloid cells. PMID- 26437241 TI - The microRNA miR-22 inhibits the histone deacetylase HDAC4 to promote T(H)17 cell dependent emphysema. AB - Smoking-related emphysema is a chronic inflammatory disease driven by the T(H)17 subset of helper T cells through molecular mechanisms that remain obscure. Here we explored the role of the microRNA miR-22 in emphysema. We found that miR-22 was upregulated in lung myeloid dendritic cells (mDCs) of smokers with emphysema and antigen-presenting cells (APCs) of mice exposed to smoke or nanoparticulate carbon black (nCB) through a mechanism that involved the transcription factor NF kappaB. Mice deficient in miR-22, but not wild-type mice, showed attenuated T(H)17 responses and failed to develop emphysema after exposure to smoke or nCB. We further found that miR-22 controlled the activation of APCs and T(H)17 responses through the activation of AP-1 transcription factor complexes and the histone deacetylase HDAC4. Thus, miR-22 is a critical regulator of both emphysema and T(H)17 responses. PMID- 26437242 TI - Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling. AB - Receptors of the Notch family direct the differentiation of helper T cell subsets, but their influence on regulatory T cell (T(reg) cell) responses is obscure. We found here that lineage-specific deletion of components of the Notch pathway enhanced T(reg) cell-mediated suppression of type 1 helper T cell (T(H)1 cell) responses and protected against their T(H)1 skewing and apoptosis. In contrast, expression in T(reg) cells of a gain-of-function transgene encoding the Notch1 intracellular domain resulted in lymphoproliferation, exacerbated T(H)1 responses and autoimmunity. Cell-intrinsic canonical Notch signaling impaired T(reg) cell fitness and promoted the acquisition by T(reg) cells of a T(H)1 cell like phenotype, whereas non-canonical Notch signaling dependent on the adaptor Rictor activated the kinase AKT-transcription factor Foxo1 axis and impaired the epigenetic stability of Foxp3. Our findings establish a critical role for Notch signaling in controlling peripheral T(reg) cell function. PMID- 26437243 TI - Regulation of bifurcating B cell trajectories by mutual antagonism between transcription factors IRF4 and IRF8. AB - Upon recognition of antigen, B cells undertake a bifurcated response in which some cells rapidly differentiate into plasmablasts while others undergo affinity maturation in germinal centers (GCs). Here we identified a double-negative feedback loop between the transcription factors IRF4 and IRF8 that regulated the initial developmental bifurcation of activated B cells as well as the GC response. IRF8 dampened signaling via the B cell antigen receptor (BCR), facilitated antigen-specific interaction with helper T cells, and promoted antibody affinity maturation while antagonizing IRF4-driven differentiation of plasmablasts. Genomic analysis revealed concentration-dependent actions of IRF4 and IRF8 in regulating distinct gene-expression programs. Stochastic modeling suggested that the double-negative feedback was sufficient to initiate bifurcation of the B cell developmental trajectories. PMID- 26437248 TI - CORRIGENDUM: Whole-exome sequencing reveals diverse modes of inheritance in sporadic mild to moderate sensorineural hearing loss in a pediatric population. PMID- 26437244 TI - T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex. AB - Central to adaptive immunity is the interaction between the alphabeta T cell receptor (TCR) and peptide presented by the major histocompatibility complex (MHC) molecule. Presumably reflecting TCR-MHC bias and T cell signaling constraints, the TCR universally adopts a canonical polarity atop the MHC. We report the structures of two TCRs, derived from human induced T regulatory (iT(reg)) cells, complexed to an MHC class II molecule presenting a proinsulin derived peptide. The ternary complexes revealed a 180 degrees polarity reversal compared to all other TCR-peptide-MHC complex structures. Namely, the iT(reg) TCR alpha-chain and beta-chain are overlaid with the alpha-chain and beta-chain of MHC class II, respectively. Nevertheless, this TCR interaction elicited a peptide reactive, MHC-restricted T cell signal. Thus TCRs are not 'hardwired' to interact with MHC molecules in a stereotypic manner to elicit a T cell signal, a finding that fundamentally challenges our understanding of TCR recognition. PMID- 26437245 TI - Ensemble Methods Enable a New Definition for the Solution to Gas-Phase Transfer of Intrinsically Disordered Proteins. AB - Intrinsically disordered proteins (IDPs) are important for health and disease, yet their lack of net structure precludes an understanding of their function using classical methods. Gas-phase techniques provide a promising alternative to access information on the structure and dynamics of IDPs, but the fidelity to which these methods reflect the solution conformations of these proteins has been difficult to ascertain. Here we use state of the art ensemble techniques to investigate the solution to gas-phase transfer of a range of different IDPs. We show that IDPs undergo a vast conformational space expansion in the absence of solvent to sample a conformational space 3-5 fold broader than in solution. Moreover, we show that this process is coupled to the electrospray ionization process, which brings about the generation of additional subpopulations for these proteins not observed in solution due to competing effects on protein charge and shape. Ensemble methods have permitted a new definition of the solution to gas phase transfer of IDPs and provide a roadmap for future investigations into flexible systems by mass spectrometry. PMID- 26437250 TI - Microsphaeropsis arundinis skin and soft tissue infection in renal transplant recipients: three case reports and a review of the literature. AB - Microsphaeropsis arundinis, a dematiaceous mold, is emerging as a cause of skin and soft tissue infection in immunocompromised hosts. Diagnosis is challenging because of the difficulty in identifying Microsphaeropsis species morphologically and few data are available to guide optimal management. We report 3 renal transplant recipients with M. arundinis soft tissue infection, where the etiological agent was diagnosed using DNA sequencing, and who were successfully treated with prolonged courses of extended-spectrum triazole antifungal agents. PMID- 26437252 TI - The role of junior doctors in medical education. PMID- 26437251 TI - The Importance of Rare Subtypes in Diagnosis and Treatment of Peripheral Neuropathy: A Review. AB - IMPORTANCE: Peripheral neuropathy is a prevalent condition that usually warrants a thorough history and examination but has limited diagnostic evaluation. However, rare localizations of peripheral neuropathy often require more extensive diagnostic testing and different treatments. OBJECTIVE: To describe rare localizations of peripheral neuropathy, including the appropriate diagnostic evaluation and available treatments. EVIDENCE REVIEW: References were identified from PubMed searches conducted on May 29, 2015, with an emphasis on systematic reviews and randomized clinical trials. Articles were also identified through the use of the authors' own files. Search terms included common rare neuropathy localizations and their causes, as well as epidemiology, pathophysiology, diagnosis, and treatment. FINDINGS: Diffuse, nonlength-dependent neuropathies, multiple mononeuropathies, polyradiculopathies, plexopathies, and radiculoplexus neuropathies are rare peripheral neuropathy localizations that often require extensive diagnostic testing. Atypical neuropathy features, such as acute/subacute onset, asymmetry, and/or motor predominant signs, are frequently present. The most common diffuse, nonlength-dependent neuropathies are Guillain Barre syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and amyotrophic lateral sclerosis. Effective disease-modifying therapies exist for many diffuse, nonlength-dependent neuropathies including Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and some paraprotein-associated demyelinating neuropathies. Vasculitic neuropathy (multiple mononeuropathy) also has efficacious treatment options, but definitive evidence of a treatment effect for IgM anti-MAG neuropathy and diabetic amyotrophy (radiculoplexus neuropathy) is lacking. CONCLUSIONS AND RELEVANCE: Recognition of rare localizations of peripheral neuropathy is essential given the implications for diagnostic testing and treatment. Electrodiagnostic studies are an important early step in the diagnostic evaluation and provide information on the localization and pathophysiology of nerve injury. PMID- 26437253 TI - Dual-Function Exocytosis Regulator Has Yet Another Job. AB - A new study shows that synaptotagmins, known to regulate the fusion of neurotransmitter vesicles with synaptic membranes, are also needed for the prior tethering and priming of vesicles. Read the Research Article. PMID- 26437254 TI - Silica nanoparticles inhibit brown adipocyte differentiation via regulation of p38 phosphorylation. AB - Nanoparticles are of great interest due to their wide variety of biomedical and bioengineering applications. However, they affect cellular differentiation and/or intracellular signaling when applied and exposed to target organisms or cells. The brown adipocyte is a cell type important in energy homeostasis and thus closely related to obesity. In this study, we assessed the effects of silica nanoparticles (SNPs) on brown adipocyte differentiation. The results clearly showed that brown adipocyte differentiation was significantly repressed by exposure to SNPs. The brown adipocyte-specific genes as well as mitochondrial content were also markedly reduced. Additionally, SNPs led to suppressed p38 phosphorylation during brown adipocyte differentiation. These effects depend on the size of SNPs. Taken together, these results lead us to suggest that SNP has anti-brown adipogenic effect in a size-dependent manner via regulation of p38 phosphorylation. PMID- 26437255 TI - Neuroinflammatory Mechanisms Linking Pain and Depression. AB - Depression and chronic pain have been estimated to co-occur in up to 80% of patients suffering from these disorders, with this co-morbidity being more disabling and more expensive to both patients and society than either disorder alone. A number of neural substrates have been proposed to underlie this association; however, there has been increased interest and support for a role of neuroimmune and neuroinflammatory mechanisms as key players in this dyad. This chapter will provide an overview of the clinical and preclinical data supporting a role for neuroimmune alterations in depression-pain co-morbidity. We propose that such changes may impact on the functioning of key brain regions modulating emotional and nociceptive processing, thus resulting in the behavioural, psychological and physical symptoms observed in patients exhibiting depression and co-morbid pain. PMID- 26437256 TI - Synthesis of Amylose-b-P2 VP Block Copolymers. AB - A new class of rod-coil block copolymers is synthesized by chemoenzymatic polymerization. In the first step, maltoheptaose, which acts as a primer for the synthesis of amylose, is attached to poly(2-vinyl pyridine) (P2 VP). The enzymatic polymerization of maltoheptaose is carried out by phosphorylase to obtain amylose-b-P2 VP block copolymers. The block copolymer is characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance, gel permeation chromatography, and wide-angle X-ray scattering techniques. The designed molecules combine the inclusion complexation ability of amylose with the supramolecular complexation ability of P2 VP and therefore this kind of rod-coil block copolymers can be used to generate well-organized novel self-assembled structures. PMID- 26437258 TI - Pain in Borderline Personality Disorder. AB - Pain processing in patients with borderline personality disorder (BPD) is abnormal primarily with respect to pain thresholds which are typically elevated or perception of phasic nociceptive stimuli which is reduced. In spite of this common finding, nonsuicidal self-injury (NSSI), often expressed as cutting, is a hallmark sign of the disease and serves to release aversive inner tension. The question thus arises, how does a painful stimulus release inner tension when these patients feel less pain than healthy people? However, intensity discrimination is normal in these patients. Imaging data have provided evidence that inhibitory top-down modulation is increased in BPD patients, and that processing of the affective-emotional pain component is altered. Recent studies have focused on the role of pain, tissue injury and seeing blood in the context of NSSI. Preliminary findings suggest a significant role of pain irrespective of concomitant tissue injury, and of seeing blood expressed as a stronger immediate stress release. Taken together, BPD patients exhibit altered pain processing that can be assigned to altered processing of nociceptive stimuli in prefrontal and limbic brain areas, which may help to mechanistically explain the clinical behavior. PMID- 26437257 TI - Clinical and Molecular Characterization of Brazilian Patients Suspected to Have Lynch Syndrome. AB - Lynch syndrome (LS) accounts for 3-5% of all colorectal cancers (CRC) and is inherited in an autosomal dominant fashion. This syndrome is characterized by early CRC onset, high incidence of tumors in the ascending colon, excess of synchronous/metachronous tumors and extra-colonic tumors. Nowadays, LS is regarded of patients who carry deleterious germline mutations in one of the five mismatch repair genes (MMR), mostly in MLH1 and MSH2, but also in MSH6, PMS1 and PMS2. To comprehensively characterize 116 Brazilian patients suspected for LS, we assessed the frequency of germline mutations in the three minor genes MSH6, PMS1 and PMS2 in 82 patients negative for point mutations in MLH1 and MSH2. We also assessed large genomic rearrangements by MLPA for detecting copy number variations (CNVs) in MLH1, MSH2 and MSH6 generating a broad characterization of MMR genes. The complete analysis of the five MMR genes revealed 45 carriers of pathogenic mutations, including 25 in MSH2, 15 in MLH1, four in MSH6 and one in PMS2. Eleven novel pathogenic mutations (6 in MSH2, 4 in MSH6 and one in PMS2), and 11 variants of unknown significance (VUS) were found. Mutations in the MLH1 and MSH2 genes represented 89% of all mutations (40/45), whereas the three MMR genes (MSH6, PMS1 and PMS2) accounted for 11% (5/45). We also investigated the MLH1 p.Leu676Pro VUS located in the PMS2 interaction domain and our results revealed that this variant displayed no defective function in terms of cellular location and heterodimer interaction. Additionally, we assessed the tumor phenotype of a subset of patients and also the frequency of CRC and extra-colonic tumors in 2,365 individuals of the 116 families, generating the first comprehensive portrait of the genetic and clinical aspects of patients suspected of LS in a Brazilian cohort. PMID- 26437259 TI - Self-assembled 20-nm (64)Cu-micelles enhance accumulation in rat glioblastoma. AB - There is an urgent need to develop nanocarriers for the treatment of glioblastoma multiforme (GBM). Using co-registered positron emission tomography (PET) and magnetic resonance (MR) images, here we performed systematic studies to investigate how a nanocarrier's size affects the pharmacokinetics and biodistribution in rodents with a GBM xenograft. In particular, highly stable, long-circulating three-helix micelles (3HM), based on a coiled-coil protein tertiary structure, were evaluated as an alternative to larger nanocarriers. While the circulation half-life of the 3HM was similar to 110-nm PEGylated liposomes (t1/2=15.5 and 16.5h, respectively), the 20-nm micelles greatly enhanced accumulation within a U87MG xenograft in nu/nu rats after intravenous injection. After accounting for tumor blood volume, the extravasated nanoparticles were quantified from the PET images, yielding ~0.77%ID/cm(3) for the micelles and 0.45%ID/cm(3) for the liposomes. For GBM lesions with a volume greater than 100mm(3), 3HM accumulation was enhanced both within the detectable tumor and in the surrounding brain parenchyma. Further, the nanoparticle accumulation was shown to extend to the margins of the GBM xenograft. In summary, 3HM provides an attractive nanovehicle for carrying treatment to GBM. PMID- 26437262 TI - IgG-loaded hyaluronan-based dissolving microneedles for intradermal protein delivery. AB - Dissolving microneedles are an attractive approach for non-invasive delivery of drugs via the skin, particularly when the doses are in the microgram or low milligram range. The aim of the study was to develop hyaluronan-based, monoclonal IgG-loaded microneedles for intradermal delivery enabling efficient penetration and rapid dissolution in the skin while preserving protein stability. Microscopic analysis showed successful preparation of sharp microneedles with the tip length of ~280 MUm and with up to 10% (w/w) of IgG content. The water content of the microneedles was ~12% and was not affected by the protein content. The protein distribution was uniform within microneedle tips and individual arrays but some array-to-array variation of IgG level within a single preparation batch was detected. After dissolution of microneedle arrays in PBS, N80% of protein was recovered and no conformational changes were detected by fluorescence spectroscopy. At submicron level, only weak and reversible interaction between HA and IgG was found by asymmetric flow field flow fractionation analysis after the dissolution of prepared microneedles. Although, the formation of insoluble micron size particles was detected by flow imaging microscopy the IgG amount incorporated into these particles was negligible (b5%). Finally, microneedles were able to penetrate into the epidermis of ex vivo human skin followed by the rapid dissolution of the microneedle tips in the skin. After 10 min of application, the majority of the original tip length was dissolved and IgG and hyaluronan were co-deposited until a depth of 150-200 MUm in the skin. In conclusion, developed hyaluronan-based dissolving microneedles allow rapid noninvasive intradermal protein delivery. PMID- 26437261 TI - Hepatoma targeting peptide conjugated bio-reducible polymer complexed with oncolytic adenovirus for cancer gene therapy. AB - Despite adenovirus (Ad) vector's numerous advantages for cancer gene therapy, such as high ability of endosomal escape, efficient nuclear entry mechanism, and high transduction, and therapeutic efficacy, tumor specific targeting and antiviral immune response still remain as a critical challenge in clinical setting. To overcome these obstacles and achieve cancer-specific targeting, we constructed tumor targeting bioreducible polymer, an arginine grafted bio reducible polymer (ABP)-PEG-HCBP1, by conjugating PEGylated ABP with HCBP1 peptides which has high affinity and selectivity towards hepatoma. The ABP-PEG HCBP1-conjugated replication incompetent GFP-expressing ad, (Ad/GFP)-ABP-PEG HCBP1, showed a hepatoma cancer specific uptake and transduction compared to either naked Ad/GFP or Ad/GFP-ABP. Competition assays demonstrated that Ad/GFP ABP-PEG-HCBP1-mediated transduction was specifically inhibited by HCBP1 peptide rather than coxsackie and adenovirus receptor specific antibody. In addition, ABP PEG-HCBP1 can protect biological activity of Ad against serum, and considerably reduced both innate and adaptive immune response against Ad. shMet-expressing oncolytic Ad (oAd; RdB/shMet) complexed with ABP-PEG-HCBP1 delivered oAd efficiently into hepatoma cancer cells. The oAd/ABP-PEG-HCBP1 demonstrated enhanced cancer cell killing efficacy in comparison to oAd/ABP complex. Furthermore, Huh7 and HT1080 cancer cells treated with oAd/shMet-ABP-PEG-HCBP1 complex had significantly decreased Met and VEGF expression in hepatoma cancer, but not in non-hepatoma cancer. In sum, these results suggest that HCBP1 conjugated bioreducible polymer could be used to deliver oncolytic Ad safely and efficiently to treat hepatoma. PMID- 26437263 TI - Shape and size-dependent immune response to antigen-carrying nanoparticles. AB - The immune system has evolved to recognize and respond to a wide variety of pathogens and produce distinct immune responses against diverse pathogenic structures. Despite remarkable advances, the general mechanisms by which the immune system differentiates the structure of antigen presenting particulates have yet to be elucidated. Using particles of various sizes and shapes, we assessed the role of morphological features of particles in antigen presentation and subsequent processing by the immune cells. Ovalbumin was used as a model antigen. Spherical polystyrene particles of 193 nm and 521 nm diameters were successfully stretched to form rod-shaped particles of 376 nm and 1530 nm in length, respectively. Ovalbumin conjugation to these different particle types was optimized to achieve ~50 MUg of ovalbumin conjugation per mg of particle. In vivo immunization study results revealed that small spherical particles (193 nm in diameter) produced a Th1-biased response whereas rod-shaped particles (1530 nm in length) produced a Th2-biased response against ovalbumin. Among different particle types, smaller spherical (193 nm) particles generated stronger Th1 and Th2 immune responses compared to the other particle types. In vitro studies with dendritic cells indicated that spherical (193 nm) and rod (1530 nm) shaped particles were internalized by dendritic cells and delivered ovalbumin. These results provide evidence for size- and shape-dependent modulation of immune responses and this knowledge can be leveraged to rationally design and develop next generation vaccines against a wide range of pathogens. PMID- 26437260 TI - Design of smart HPMA copolymer-based nanomedicines. AB - The state-of-the art in water-soluble macromolecular therapeutics has been reviewed. First the design principles for polymer-drug conjugates are discussed followed by two recent developments in the field: a) The design, synthesis and properties of backbone degradable N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates. The enhanced intravascular half-life of such conjugates creates a concentration gradient (blood vs. tumor) for an extended time interval resulting in increased solid tumor accumulation by enhanced permeability and retention (EPR) effect with concomitant increase in efficacy. b) Drug-free macromolecular therapeutics is a new paradigm in macromolecular therapeutics. Apoptosis in malignant cell is induced by crosslinking of cell surface non-internalizing receptors. Crosslinking of receptors is mediated by the biorecognition of two nanoconjugates containing high-fidelity complementary motifs (peptides or oligonucleotides). Results for the treatment of B cell lymphomas in animal models and patient cells demonstrate the high translational potential of this approach. PMID- 26437264 TI - Degradation of Triazine-2-(14)C Metsulfuron-Methyl in Soil from an Oil Palm Plantation. AB - Triazine-2-(14)C metsulfuron-methyl is a selective, systemic sulfonylurea herbicide. Degradation studies in soils are essential for the evaluation of the persistence of pesticides and their breakdown products. The purpose of the present study was to investigate the degradation of triazine-2-(14)C metsulfuron methyl in soil under laboratory conditions. A High Performance Liquid Chromatograph (HPLC) equipped with an UV detector and an on-line radio-chemical detector, plus a Supelco Discovery column (250 x 4.6 mm, 5 MUm), and PRP-1 column (305 x 7.0 mm, 10 MUm) was used for the HPLC analysis. The radioactivity was determined by a Liquid Scintillation Counter (LSC) in scintillation fluid. The soil used was both sterilized and non-sterilized in order to observe the involvement of soil microbes. The estimated DT50 and DT90 values of metsulfuron methyl in a non-sterile system were observed to be 13 and 44 days, whereas in sterilized soil, the DT50 and DT90 were 31 and 70 days, respectively. The principal degradation product after 60 days was CO2. The higher cumulative amount of (14)CO2 in (14)C-triazine in the non-sterilized soil compared to that in the sterile system suggests that biological degradation by soil micro-organisms significantly contributes to the dissipation of the compound. The major routes of degradation were O-demethylation, sulfonylurea bridge cleavage and the triazine "ring-opened." PMID- 26437265 TI - Treatment discontinuation with peg-interferon: what to consider. AB - Eradication of chronic hepatitis C virus infection improves the outcome of both liver and extrahepatic-related diseases and interferon-based regimens represented, for years, the standard of care to achieve this goal. Several baseline and on-treatment predictors of response, associated with a lower chance to achieve sustained virological response after interferon-based treatment, were developed. In the past few years, the advent of direct acting antivirals has dramatically modified the landscape of antiviral therapy, leading to an evolution from interferon-based to interferon-free therapies. This review will focus on the usefulness of futility stopping rules that allow the discontinuation of therapy in patients with a reduced chance to obtain sustained virological response if treated with interferon-containing regimens. PMID- 26437266 TI - Changes in liver acceptance patterns after implementation of Share 35. AB - The Share 35 policy was implemented June 2013. We sought to evaluate liver offer acceptance patterns of centers under this policy. We compared three 1-year eras (1, 2, and 3) before and 1 era (4) after the implementation date of the Share 35 policy (June 18, 2013). We evaluated all offers for liver-only recipients including only those offers for livers that were ultimately transplanted. Logistic regression was used to develop a liver acceptance model. In era 3, there were 4809 offers for Model for End-Stage Liver Disease (MELD) score >= 35 patients with 1071 acceptances (22.3%) and 10,141 offers and 1652 acceptances (16.3%) in era 4 (P < 0.001). In era 3, there were 42,954 offers for MELD score < 35 patients with 4181 acceptances (9.7%) and 44,137 offers and 3882 acceptances (8.8%) in era 4 (P < 0.001). The lower acceptance rate persisted across all United Network for Organ Sharing regions and was significantly less in regions 2, 3, 4, 5, and 7. Mean donor risk index was the same (1.3) for all eras for MELD scores >= 35 acceptances and the same (1.4) for MELD score < 35 acceptances. Refusal reasons did not vary throughout the eras. The adjusted odds ratio of accepting a liver for a MELD score of 35 + compared to a MELD score < 35 patient was 1.289 before the policy and 0.960 after policy implementation. In conclusion, the Share 35 policy has resulted in more offers to patients with MELD scores >= 35. Overall acceptance rates were significantly less compared to the same patient group before the policy implementation. Centers are less likely to accept a liver for a patient with a MELD score of 35 + after the policy change. Decreased donor acceptance rates could reflect more programmatic selectivity and ongoing donor and recipient matching. PMID- 26437268 TI - Method of Studying Palatal Fusion using Static Organ Culture. AB - Cleft lip and palate are among the most common of all birth defects. The secondary palate forms from mesenchymal shelves covered with epithelium that adheres to form the midline epithelial seam (MES). The theories suggest that MES cells follow an epithelial to mesenchymal transition (EMT), apoptosis and migration, making a fused palate (1). Complete disintegration of the MES is the final essential phase of palatal confluence with surrounding mesenchymal cells. We provide a method for palate organ culture. The developed in vitro protocol allows the study of the biological and molecular processes during fusion. The applications of this technique are numerous, including evaluating responses to exogenous chemical agents, effects of regulatory and growth factors and specific proteins. Palatal organ culture has a number of advantages including manipulation at different stages of development that is not possible using in vivo studies. PMID- 26437267 TI - INFLUENCE OF STUDY DESIGN ON TREATMENT RESPONSE IN ANXIETY DISORDER CLINICAL TRIALS. AB - OBJECTIVE: The influence of study design variables and publication year on response to medication and placebo was investigated in clinical trials for social anxiety disorder (SAD), generalized anxiety disorder (GAD), and panic disorder (PD). METHOD: Hierarchical linear modeling determined whether publication year, treatment assignment (medication vs. placebo), study type (placebo-controlled or active comparator), study duration, and the number of study visits affected the mean change associated with medication and placebo. RESULTS: In the 66 trials examined, the change associated with both medication and placebo increased over time (t = 4.23, df = 39, P < .001), but average drug-placebo differences decreased over time (t = -2.04, df = 46, P = .047). More severe baseline illness was associated with greater drug-placebo differences for serotonin norepinephrine reuptake inhibitors (SNRIs, t = 3.46, df = 106, P = .001) and selective serotonin reuptake inhibitors (SSRI, t = 10.37, df = 106, P < .001). Improvement with medication was significantly greater in active-comparator studies compared to placebo-controlled trials (t = 3.41, df = 39, P = .002). A greater number of study visits was associated with greater symptom improvement in PD trials relative to SAD (t = 2.83, df = 39, P = .008) and GAD (t = 2.16, df = 39, P = .037). CONCLUSIONS: Placebo response is substantial in SAD, GAD, and PD trials, and its rise over time has been associated with diminished drug-placebo differences. Study design features that influence treatment response in anxiety disorder trials include patient expectancy, frequency of follow-up visits, and baseline illness severity. PMID- 26437269 TI - Enhanced permeability of ferulic acid loaded nanoemulsion based gel through skin against UVA mediated oxidative stress. AB - AIMS: The study was aimed to develop a ferulic acid (FA) loaded nanoemulsion based gel in order to ensure the enhanced permeability and maximum antioxidant activity against UVA induced oxidative stress in rat. MAIN METHODS: The optimized ferulic acid loaded nanoemulsion 3 (FA-NE3) was prepared by spontaneous nano emulsification method with an appropriate ratio (20:30:50% w/w) of the oil (isostearyl isostearate), aqueous system and Smix [surfactant (labrasol) and co surfactant (plurol isostearique)] respectively. FA-NE3 was characterized by measuring their droplet size, zeta potential, refractive index, transmission electron microscopy (TEM), ultraviolet (UV), fourier transform infrared spectroscopy (FTIR) and rheological characteristics. Ex vivo skin permeation and in vivo UVA protection activity of FA-NE3 based nano-gels (FA-NG3) along with placebo were studied through the rat skin. KEY FINDINGS: FA-NE3 exhibited sustained-release profile, better permeability and ultraviolet A (UVA) protection activity as compared to conventional dosage form. This phenomenon may be attributed towards increased solubility of the drug and enhanced permeability from nanoemulsion. FA-NE3 based nanogel (FA-NG3) could elevate the level of skin marker enzymes against oxidative stress mediated by UVA. SIGNIFICANCE: The gel formulation exhibited significant (P<0.01) skin permeability and antioxidant activity in the current investigations. The nanogel could be promising nanocarriers for topical delivery of FA in response to better skin protection activity against UVA rays in a sustained manner. PMID- 26437270 TI - Mechanistic evidence of Passiflora edulis (Passifloraceae) anxiolytic activity in relation to its metabolite fingerprint as revealed via LC-MS and chemometrics. AB - Passiflora edulis Sims F. flavicarpa along with several other plants belonging to the genus Passiflora have been reported as sedatives and for treatment or prevention of central disorders. This study evaluated the anxiolytic effect of P. edulis ethanol extract and its fractions (viz. chloroform, ethyl acetate and butanol) using the elevated plus-maze model of anxiety and assessment of gamma aminobutyric acid levels. The results revealed that butanol and chloroform extracts exhibit the strongest effect followed by ethyl acetate suggesting that a combination of different classes of metabolites is likely to mediate for P. edulis anxiolytic effect in these fractions. To further pinpoint bioactive agents in fractions, ultra-performance liquid chromatography (UPLC) coupled to high resolution qTOF-MS was used for secondary metabolite profiling. A total of 65 metabolites were characterized including O-flavonoids, C-flavonoids, cyanogenic glycosides and fatty acids. Harman type alkaloids found in P. incarnata were not detected in P. edulis ethanol extract or any of its fractions suggesting that they do not mediate for its CNS modulating effects. Multivariate data analysis (PCA) was further applied to identify metabolite markers for fractions and revealed that enrichment of C-glycoside type flavonoids in chloroform/ethyl acetate fractions versus the exclusive presence of cyanogenic glycosides in its butanol fraction. PMID- 26437275 TI - Diagnostic Accuracies of Glycated Hemoglobin, Fructosamine, and Homeostasis Model Assessment of Insulin Resistance in Predicting Impaired Fasting Glucose, Impaired Glucose Tolerance, or New Onset Diabetes After Transplantation. AB - BACKGROUND: New onset diabetes after transplantation (NODAT) is associated with a 3-fold greater risk of cardiovascular disease events, with early identification and treatment potentially attenuating this risk. The optimal screening test to identify those with NODAT remains unclear, and the aim of this study was to examine the diagnostic accuracies of 4 screening tests in identifying impaired fasting glucose, impaired glucose tolerance (IGT), and NODAT. METHODS: This is a single-center prospective cohort study of 83 nondiabetic kidney transplant recipients between 2008 and 2011. Oral glucose tolerance test was considered the gold standard in identifying IFG/IGT or NODAT. Diagnostic accuracies of random blood glucose, glycated hemoglobin (HBA1c), fructosamine, and Homeostasis Model Assessment-Insulin Resistance in predicting IFG/IGT or NODAT were assessed using the area under the receiver operating characteristic curve. RESULTS: Forty (48%) recipients had IFG/IGT or NODAT. Compared with HBA1c with adjusted area under the curve (AUC) of 0.88 (95% confidence interval [95% CI], 0.77-0.93), fructosamine was the most accurate test with adjusted AUC of 0.92 (95% CI, 0.83-0.96). The adjusted AUCs of random blood glucose and Homeostasis Model Assessment-Insulin Resistance in identifying IFG/IGT were between 0.81 and 0.85. Restricting to identifying IGT/NODAT using 2-hour oral glucose tolerance test (n = 66), fructosamine was the most accurate diagnostic test with adjusted AUC of 0.93 (95% CI, 0.84-0.99), but not statistically different to HBA1c with adjusted AUC of 0.88 (95% CI, 0.76-0.96). CONCLUSIONS: Although HBA1c is an acceptable and widely used screening test in detecting IFG/IGT or NODAT, fructosamine may be a more accurate diagnostic test but this needs to be further examined in larger cohorts. PMID- 26437278 TI - Evans Enolates: Solution Structures of Lithiated Oxazolidinone-Derived Enolates. AB - The results of a combination of (6)Li and (13)C NMR spectroscopic and computational studies of oxazolidinone-based lithium enolates-Evans enolates-in tetrahydrofuran (THF) solution revealed a mixture of dimers, tetramers, and oligomers (possibly ladders). The distribution depended on the structure of the oxazolidinone auxiliary, substituent on the enolate, and THF concentration (in THF/toluene mixtures). The unsolvated tetrameric form contained a D(2d)-symmetric core structure, whereas the dimers were determined experimentally and computationally to be trisolvates with several isomeric forms. PMID- 26437279 TI - Generalized linear IgA dermatosis with palmar involvement. AB - Linear IgA bullous dermatosis (LABD) is a sub-epidermal blistering disorder characterized by deposition of IgA along the basement membrane zone (BMZ) as detected by immunofluorescence microscopy. The diagnosis is made by clinicopathologic correlation with immunofluorescence confirmation. Differentiation from other bullous dermatoses is important because therapeutic measures differ. Prompt initiation of the appropriate therapies can have a major impact on outcomes. We present three cases with prominent palmar involvement to alert the clinician of this potential physical exam finding and to consider LABD in the right context. PMID- 26437277 TI - Mfa4, an Accessory Protein of Mfa1 Fimbriae, Modulates Fimbrial Biogenesis, Cell Auto-Aggregation, and Biofilm Formation in Porphyromonas gingivalis. AB - Porphyromonas gingivalis, a gram-negative obligate anaerobic bacterium, is considered to be a key pathogen in periodontal disease. The bacterium expresses Mfa1 fimbriae, which are composed of polymers of Mfa1. The minor accessory components Mfa3, Mfa4, and Mfa5 are incorporated into these fimbriae. In this study, we characterized Mfa4 using genetically modified strains. Deficiency in the mfa4 gene decreased, but did not eliminate, expression of Mfa1 fimbriae. However, Mfa3 and Mfa5 were not incorporated because of defects in posttranslational processing and leakage into the culture supernatant, respectively. Furthermore, the mfa4-deficient mutant had an increased tendency to auto-aggregate and form biofilms, reminiscent of a mutant completely lacking Mfa1. Notably, complementation of mfa4 restored expression of structurally intact and functional Mfa1 fimbriae. Taken together, these results indicate that the accessory proteins Mfa3, Mfa4, and Mfa5 are necessary for assembly of Mfa1 fimbriae and regulation of auto-aggregation and biofilm formation of P. gingivalis. In addition, we found that Mfa3 and Mfa4 are processed to maturity by the same RgpA/B protease that processes Mfa1 subunits prior to polymerization. PMID- 26437280 TI - Opioid associated intravenous and cutaneous microvascular drug abuse (skin popping) masquerading as Degos disease (malignant atrophic papulosis) with multiorgan involvement. AB - BACKGROUND: In 2012, a nephrologist reported the development of a multiorgan thrombotic syndromic complex resembling thrombotic thrombocytopenic purpura (TTP) in patients who were abusing long acting oxymorphone hydrochloride; all patients had hemolytic anemia and thrombocytopenia. OBJECTIVE: Herein, we report another case involving a 31-year-old woman who self intravenously administered dissolved oral oxymorphone resulting in thrombotic sequelae resembling Degos disease. METHODS: Formalin-fixed and paraffin embedded skin biopsies were prepared according to standard protocols for H&E and immunohistochemistry. RESULTS: The clinical presentation and biopsy findings were held to be indicative of Degos disease/malignant atrophic papulosis (MAP) but with unusual clinical features including renal failure and severe respiratory insufficiency. Given the efficacy of eculizumab in the treatment of the acute thrombotic phase of Degos disease/MAP, the patient received this drug, resulting in rapid resolution of signs and symptoms associated with her multiorgan failure. Although she developed recurrent cutaneous ulcers despite complete complement inhibition with eculizumab., her other extracutaneous manifestations did not recur. The patient's pre and post eculizumab skin biopsies showed a striking pauci-inflammatory thrombogenic vasculopathy associated with marked endothelial cell injury along with deposits of C3d and C4d within the cutaneous vasculature; the C5b-9 deposits were limited to the pre-eculizumab biopsy. We discovered that her syndromic complex was a self-inflicted one related to the localized administration of dissolved oxymorphone. CONCLUSION: Our patient's biopsy along with the rapid response to eculizumab indicates that this distinct thrombotic microangiopathy is another complement mediated thrombotic microangiopathy syndrome. Opioid thrombotic microangiopathy has a varied clinical presentation and can mimic other catastrophic microangiopathy syndromes, all of which have in common a responsiveness to complement inhibition. PMID- 26437281 TI - A 7-year-old with indurated skin and unilateral progressive joint immobility: A case of stiff skin syndrome. AB - Stiff skin syndrome is a rare sclerotic condition that presents during infancy or early childhood. It has an insidious chronic course and may lead to significant co-morbidity and reduced quality of life. Often, affected individuals experience impaired ambulation and immobilization related to joint involvement. Clinically, it may resemble other sclerotic diseases, so histopathological evaluation is necessary to establish a diagnosis. As it is a condition with limited treatment options, prompt diagnosis and early initiation of physical therapy is crucial to prevent joint restriction and maintain quality of life. We describe a case of a 7 year-old with stiff skin syndrome, and review the literature to discuss the clinical presentation, histological findings, and management of this condition. PMID- 26437282 TI - Sporotrichoid granuloma annulare-like dermatitis associated with systemic B-cell lymphoma. AB - IMPORTANCE: Granuloma annulare is typically a benign, self-limited disease. Atypical presentations have been reported in association with systemic disease, including malignancy. Such patients may require additional diagnostic studies to assess for underlying malignancy. We report a patient with extensive sporotrichoid granuloma annulare-like dermatitis in association with systemic B cell lymphoma. OBSERVATIONS: An 83-year-old man with a three-year history of progressive sporotrichoid annular plaques and nodules on the arm developed ipsilateral retroauricular palpable lymphadenopathy, the latter consistent with B cell lymphoma. Multiple skin biopsies of the plaques and nodules revealed granuloma annulare-like dermatitis. Lesions were unresponsive to intralesional and intramuscular corticosteroids, antibiotics, and antifungal agents, but rapidly improved following initiation of rituximab to treat his underlying lymphoma. CONCLUSIONS AND RELEVANCE: Atypical presentations of granuloma annulare including granuloma annulare-like dermatitis warrant evaluation for systemic malignancy in a subset of patients. PMID- 26437283 TI - Scleromyxedema secondary to hepatitis C virus and successfully treated with antiviral therapy. AB - Scleromyxedema (SM) is a chronic and progressive fibromucinous disease with no known etiology. We report a patient with scleromyxedema associated with hepatitis C virus, successfully treated with interferon and ribavirin therapy. PMID- 26437284 TI - Phacomatosis cesiomarmorata with hypospadias and phacomatosis cesioflammea with Sturge-Weber syndrome, Klippel-Trenaunay syndrome and aplasia of veins -- case reports with rare associations. AB - Phacomatosis pigmentovascularis (PPV) is a rare genodermatosis characterized by the co-existence of an extensive vascular and a pigmentary nevus with or without extracutaneous manifestations. We report two such rare cases. The first is a 3 year-old boy exhibiting a rare association of cutis marmorata telangiectatica congenita with aberrant dermal melanocytosis along with hypospadias and melanosis oculi (traditionally classified as PPV type Vb or phacomatosis cesiomarmorata - Happle's classification). The other patient is a 5-year-old boy with Sturge-Weber syndrome, Klippel-Trenaunay syndrome, aplasia of iliac, femoral, and popliteal veins and congenital heart disease, associated with aberrant dermal melanocytosis and melanosis oculi (also classified as PPV type IIb or phacomatosis cesioflammea). These sporadic cases display a unique constellation of additional, previously unreported systemic associations, which will further expand the clinical spectrum of phacomatosis pigmentovascularis. PMID- 26437285 TI - Eruptive milia and comedones during treatment with dovitinib. AB - Dovitinib (TKI258) is a multi-targeted receptor tyrosine kinase inhibitor currently under clinical trials for a wide variety of cancers. Well-known side effects include nausea, vomiting, diarrhea, and fatigue. To date, there have only been only two reported cases with skin manifestations as a side effect. We report a case of eruptive facial milia and comedones in the setting of dovitinib treatment for metastatic gastrointestinal cancer. This case is unique as the clinical presentation was more rapid in onset and showed an absence of inflammatory lesions. Although the pathogenesis for skin manifestations is presently unknown, we present this case to increase awareness of potentially under-reported cutaneous side effects. PMID- 26437286 TI - Trichophytum rubrum endonyx onychomycosis resistant to standard oral and topical therapies. AB - We present a 45 year-old man with an eight-year history of discoloration of the nail plate on his left hallux. He had been treated with two courses of oral terbinafine and topical 8% ciclopirox for presumed onychomycosis. On exam, his left great toenail contained a wide yellow-white longitudinal band involving a majority of the nail plate. No subungual debris, hyperkeratosis, or paronychial inflammation was present in the affected nail. Histopathology of the nail plate revealed numerous fungal elements arranged transversely and longitudinally, solely within the keratin layers of the nail plate; these were highlighted with periodic acid-Schiff (PAS) stain confirming endonyx onychomycosis. Cultures grew Trichophyton rubrum. All types of onychomycosis under the new classification system proposed by Hay et al. have now been associated with T. rubrum. Endonyx related to T. rubrum may be a particularly difficult infection to treat with oral or topical agents owing to the absence of robust local immune response and limited drug penetration to the interior nail plate. Physicians should be aware that this type of infection may require treatment with dual-agent therapy or alternative modalities including chemical or surgical plate avulsion or photodynamic therapy. PMID- 26437287 TI - Generalized lentiginosis in an 11 year old boy. AB - Generalized lentiginosis refers to generalized lentigines without systemic abnormalities, characterized by multiple brown or black macules owing to increased proliferation of melanocytes. There are also lentiginosis syndromes associated with systemic abnormalities such as Peutz-Jeghers syndrome, Leopard syndrome, and Carney complex. Generalized lentiginosis can be diagnosis by patient's history, physical and laboratory examination, and histopathology. We report an 11-year-old boy who presented with multiple dark brown macules, varying in size, but less than 0.5 cm, with no abnormalities of other systemic organs. PMID- 26437288 TI - Bullous pilomatricoma: a rarely reported variant of pilomatricoma. AB - Pilomatricomas are cutaneous adnexal tumors with matrical differentiation. We report and describe a rare variant called bullous pilomatricoma. PMID- 26437289 TI - Two sisters with Reed's syndrome: treatment with pregabalin. AB - Cutaneous leiomyomas, which originate in the arrector pili muscles of the skin are rarely seen benign cutaneous tumors. Sometimes familial cutaneous and uterine leiomyomatosis can occur together, an autosomal dominant genetic condition called Reed syndrome or familial leiomyomatosis cutis et uteri. This disorder can be accompanied by malignancies, particularly by renal carcinoma. In this paper, two sisters with Reed syndrome are presented in view of the rarity of the disorder and good response to pregabalin therapy. PMID- 26437290 TI - Localized and linear lichen planopilaris over the face and scalp with associated alopecia - clinical and dermoscopy pattern. AB - A case of localized lichen planopilaris over the face, extending to the scalp is presented.This case highlights the different variations, which can occur in the presentation of localized lichen planus. The case was unique because of the extension of the lesions into the scalp. We also wanted to demonstrate the peculiar dermoscopic patterns of active lichen planopilaris when occurring over the face. PMID- 26437291 TI - What is the prognostic significance of acrometastases? AB - In contrast with bone metastasis, acrometastases are uncommon and are associated with advanced cancer. We report the cases of two patients with atypical lesions of the fingers in a context of cancer, in which biopsies confirmed a metastasis. Patients died rapidly before treatment was initiated. We discuss the characteristics of these atypical metastatic sites, associated with a generally poor prognosis. PMID- 26437292 TI - Immediate resolution of severe bullous chronic regional pain syndrome with onset of spinal paralysis. AB - Complex regional pain syndrome (CRPS) is an incompletely understood disorder characterized by progressive regional pain and sensory changes, with fluctuating cutaneous edema and erythema. We describe a patient with a rarely reported severe bullous CRPS variant on the left lower extremity, which resolved immediately upon developing spinal paralysis. PMID- 26437293 TI - Even well-controlled psoriasis patients have unmet treatment needs regardless of disease severity. AB - BACKGROUND: Though psoriasis is chronic and recurring, current options can help many patients achieve good disease control. New treatments could provide greater improvement in objective disease, but it is not clear that there is room for improving subjective outcomes, particularly for patients who are already "well controlled." OBJECTIVE: To analyze treatment satisfaction of well-controlled patients with psoriasis in two patient populations of very different disease severity. METHODS: Patients with well-controlled psoriasis on topicals (mild psoriasis) only or on biologics (moderate-to-severe psoriasis) were queried by telephone about perceptions of disease control, improvement level, overall treatment satisfaction, and consideration for trying new treatments. Satisfaction scores and feedback were analyzed to assess treatment type and satisfaction level associations. RESULTS: The majority of patients, regardless of disease severity, would consider trying new treatments for psoriasis, though patients with mild psoriasis were less satisfied with their disease control, level of improvement, and overall treatment. Patient feedback revealed widespread treatment dissatisfaction, non-adherence, and inconvenience. LIMITATIONS: The patient population was from one university setting. CONCLUSION: 16% of patients with psoriasis meet study definition for "well-controlled" disease. Less than 20% of these well- controlled patients with psoriasis are satisfied with their current level of control and clearance and would not consider trying new treatments, suggesting the majority of well-controlled patients, regardless of disease severity, still have unmet needs. Stronger patient-physician communication may contribute to patient-based, comprehensive care in concordance with a health system that is headed towards financial incentives for better patient satisfaction. PMID- 26437294 TI - Additional evidence that rosacea pathogenesis may involve demodex: new information from the topical efficacy of ivermectin and praziquantel. AB - Additional evidence that Demodex folliculorum may contribute to the pathogenesis of papulopustular rosacea are new studies of two topical antiparasitic agents. Ivermectin and praziquantel have recently been shown to be effective in decreasing the severity of papulopustular rosacea. These two agents significantly differ in molecular structure, but yield similar antiparasitic mechanisms of action. Higher numbers of Demodex mites are found in the skin of patients with rosacea than in people with normal skin. If Demodex play a role in pathogenesis, then hypersensitivity to the mites, their flora, or their products could explain the observed efficacy of antidemodectic therapy. PMID- 26437295 TI - Generalized pruritus in dysmetabolic hyperferritinemia treated by phlebotomy. AB - This paper describes a case of pruritus caused by dysmetabolic hyperferritinemia treated by multiple phlebotomies. A 63-year-old man was followed for generalized pruritus, which was resistant to the usual treatments. He presented with metabolic syndrome. Physical examination showed only excoriations and lichenification on the skin. The serum ferritin was high at 1043 ng/ml, with transferrin saturation at 67%. The other biological investigations and genetic tests for hemochromatosis were negative. In spite of the dietary measures, the ferritin level was still high (853 ng/ml). Magnetic resonance imaging confirmed hepatic iron overload.The association of hyperferritinemia, hepatic iron overload, and metabolic syndrome led to the diagnosis of dysmetabolic hyperferritinemia. Phlebotomies are an unusual treatment, but because the pruritus and hyperferritinemia were still present, phlebotomy was initiated. After 19 months, the patient reported improvement of his pruritus and normalization of ferritin levels. PMID- 26437297 TI - Exploring three-dimensional orbital imaging with energy-dependent photoemission tomography. AB - Recently, it has been shown that experimental data from angle-resolved photoemission spectroscopy on oriented molecular films can be utilized to retrieve real-space images of molecular orbitals in two dimensions. Here, we extend this orbital tomography technique by performing photoemission initial state scans as a function of photon energy on the example of the brickwall monolayer of 3,4,9,10-perylene tetracarboxylic dianhydride (PTCDA) on Ag(110). The overall dependence of the photocurrent on the photon energy can be well accounted for by assuming a plane wave for the final state. However, the experimental data, both for the highest occupied and the lowest unoccupied molecular orbital of PTCDA, exhibits an additional modulation attributed to final state scattering effects. Nevertheless, as these effects beyond a plane wave final state are comparably small, we are able, with extrapolations beyond the attainable photon energy range, to reconstruct three-dimensional images for both orbitals in agreement with calculations for the adsorbed molecule. PMID- 26437299 TI - Continuous Fabrication of Hierarchical and Asymmetric Bijel Microparticles, Fibers, and Membranes by Solvent Transfer-Induced Phase Separation (STRIPS). AB - Continuous generation of hierarchical and asymmetric bijels based on solvent transfer-induced phase separation (STRIPS) is demonstrated. In STRIPS, phase separation is induced by solvent extraction from an initially homogeneous ternary mixture, and bicontinuous morphology is stabilized by inter-facial attachment of nano-particles, which are functionalized in situ. STRIPS allows stable bijel formation from a wide variety of liquids and particles. PMID- 26437296 TI - A mechanical argument for the differential performance of coronary artery grafts. AB - Coronary artery bypass grafting (CABG) acutely disturbs the homeostatic state of the transplanted vessel making retention of graft patency dependent on chronic remodeling processes. The time course and extent to which remodeling restores vessel homeostasis will depend, in part, on the nature and magnitude of the mechanical disturbances induced upon transplantation. In this investigation, biaxial mechanical testing and histology were performed on the porcine left anterior descending artery (LAD) and analogs of common autografts, including the internal thoracic artery (ITA), radial artery (RA), great saphenous vein (GSV) and lateral saphenous vein (LSV). Experimental data were used to quantify the parameters of a structure-based constitutive model enabling prediction of the acute vessel mechanical response pre-transplantation and under coronary loading conditions. A novel metric Xi was developed to quantify mechanical differences between each graft vessel in situ and the LAD in situ, while a second metric Omega compares the graft vessels in situ to their state under coronary loading. The relative values of these metrics among candidate autograft sources are consistent with vessel-specific variations in CABG clinical success rates with the ITA as the superior and GSV the inferior graft choices based on mechanical performance. This approach can be used to evaluate other candidate tissues for grafting or to aid in the development of synthetic and tissue engineered alternatives. PMID- 26437300 TI - Differential senescence capacities in meibomian gland carcinoma and basal cell carcinoma. AB - Meibomian gland carcinoma (MGC) and basal cell carcinoma (BCC) are common eyelid carcinomas that exhibit highly dissimilar degrees of proliferation and prognoses. We address here the question of the differential mechanisms between these two eyelid cancers that explain their different outcome. A total of 102 confirmed MGC and 175 diagnosed BCC cases were analyzed. Twenty confirmed MGC and twenty diagnosed BCC cases were collected to determine the telomere length, the presence of senescent cells, and the expression levels of the telomere capping shelterin complex, P53, and the E3 ubiquitin ligase Siah1. Decreased protein levels of the shelterin subunits, shortened telomere length, over-expressed Ki-67, and Bcl2 as well as mutations in P53 were detected both in MGC and BCC. It suggests that the decreased protein levels of the shelterin complex and the shortened telomere length contribute to the tumorigenesis of MGC and BCC. However, several parameters distinguish MGC from BCC samples: (i) the mRNA level of the shelterin subunits decreased in MGC but it increased in BCC; (ii) P53 was more highly mutated in MGC; (iii) Siah1 mRNA was over-expressed in BCC; (iv) BCC samples contain a higher level of senescent cells; (v) Ki-67 and Bcl2 expression were lower in BCC. These results support a model where a preserved P53 checkpoint in BCC leads to cellular senescence and reduced tumor proliferation as compared to MGC. PMID- 26437301 TI - Foot placement control and gait instability among people with stroke. AB - Gait instability is a common problem following stroke, as evidenced by increases in fall risk and fear of falling. However, the mechanism underlying gait instability is currently unclear. We recently found that young, healthy humans use a consistent gait stabilization strategy of actively controlling their mediolateral foot placement based on the concurrent mechanical state of the stance limb. In the present work, we tested whether people with stroke (n = 16) and age-matched controls (n = 19) used this neuromechanical strategy. Specifically, we used multiple linear regressions to test whether (1) swing phase gluteus medius (GM) activity was influenced by the simultaneous state of the stance limb and (2) mediolateral foot placement location was influenced by swing phase GM activity and the mechanical state of the swing limb at the start of the step. We found that both age-matched controls and people with stroke classified as having a low fall risk (Dynamic Gait Index [DGI] score >19) essentially used the stabilization strategy previously described in young controls. In contrast, this strategy was disrupted for people with stroke classified as higher fall risk (DGI =6-repeats) in their core promoter, which may be of selective advantage in this species. At the top of that list, SCGB2B2 (also known as SCGBL), contains one of the longest CA-repeat STRs identified in a human gene core promoter, at 25-repeats. In the study reported here, we analyzed the conservation status of this CA-STR across evolution. The functional implication of this STR to alter gene expression activity was also analyzed in the HEK-293 cell line. We report that the SCGB2B2 core promoter CA repeat reaches exceptional lengths, ranging from 9- to 25-repeats, across Apes (Hominoids) and the Old World monkeys (CA>2-repeats were not detected in any other species). The longest CA-repeats and highest identity in the SCGB2B2 protein sequence were observed between human and bonobo. A trend for increased gene expression activity was observed from the shorter to the longer CA-repeats (p<0.009), and the CA-repeat increased gene expression activity, per se (p<0.02). We propose that the SCGB2B2 gene core promoter CA-repeat functions as an expression code for the evolution of Apes and the Old World monkeys. PMID- 26437310 TI - Drugs, Substance Use Disorder and Driving: Intervention of Health Professionals in the Treatment of Addictions. AB - Editorial of vol 27-3. PMID- 26437311 TI - A group intervention to reduce intimate partner violence among female drug users. Results from a randomized controlled pilot trial in a community substance-abuse center. AB - BACKGROUND: A greater proportion of drug dependent women are victims of intimate partner violence (IPV) than women in the general population; however, few interventions have been developed to reduce IPV among drug dependent women. METHODS: An adapted version of the Women's Wellness Treatment, to address IPV and depressive symptoms, was piloted in a randomized controlled trial conducted in outpatient treatment program in Barcelona, Spain among 14 women receiving outpatient treatment for a drug use disorder who screened positive for IPV in the previous month. Participants were randomly assigned to receive the 10 session cognitive behavioral therapy (IPaViT-CBT) group intervention or treatment as usual. The frequency of IPV, depressive symptoms, substance use, quality of life and health status were assessed at baseline and 1, 3 and 12 months post intervention. Intention to treat analysis was performed. RESULTS: Moderate effects for the intervention were found in reducing psychological maltreatment, increasing assertiveness of IPV and reducing aggressiveness in the partner relationship, and in reducing the frequency of drinking up to 3 months post intervention. The intervention did not significantly reduce the likelihood of any IPV, depressive symptoms, quality of life or self-reported health status, up to 12-months post intervention. CONCLUSION: This pilot trial suggests some initial support for the 10-session CBT group intervention among IPV victims who received treatment for drug use. Study findings indicate that it is feasible to deliver the intervention in a community substance abuse center. An adequately powered trial is required to replicate these results. PMID- 26437312 TI - Management of opioid-dependent patients: comparison of the cost associated with use of buprenorphine/naloxone or methadone, and their interactions with concomitant treatments for infectious or psychiatric comorbidities. AB - The objective was to estimate the annual interaction management cost of agonist opioid treatment (AOT) for opioid-dependent (OD) patients with buprenorphine naloxone (Suboxone(r)) (B/N) or methadone associated with concomitant treatments for infectious (HIV) or psychiatric comorbidities. A costs analysis model was developed to calculate the associated cost of AOT and interaction management. The AOT cost included pharmaceutical costs, drug preparation, distribution and dispensing, based on intake regimen (healthcare center or take-home) and type and frequency of dispensing (healthcare center or pharmacy), and medical visits. The cost of methadone also included single-dose bottles, monthly costs of custody at pharmacy, urine toxicology drug screenings and nursing visits. Potential interactions between AOT and concomitant treatments (antivirals, antibacterials/antifungals, antipsychotics, anxiolytics, antidepressant and anticonvulsants), were identified to determine the additional use of healthcare resources for each interaction management. The annual cost per patient of AOT was ?1,525.97 for B/N and ?1,467.29 for methadone. The average annual cost per patient of interaction management was ?257.07 (infectious comorbidities), ?114.03 (psychiatric comorbidities) and ?185.55 (double comorbidity) with methadone and ?7.90 with B/N in psychiatric comorbidities. Total annual costs of B/N were ?1,525.97, ?1,533.87 and ?1,533.87 compared to ?1,724.35, ?1,581.32 and ?1,652.84 for methadone per patient with infectious, psychiatric or double comorbidity respectively.Compared to methadone, the total cost per patient with OD was lower with B/N (?47.45-?198.38 per year). This is due to the differences in interaction management costs associated with the concomitant treatment of infectious and/or psychiatric comorbidities. PMID- 26437313 TI - Online Gambling Advertising Regulations in Spain. A Study on the Protection of Minors. AB - This article examines the online gambling advertising regulations in Spain currently in effect to assess the actual protection of underage youth. In recent years, online gambling among youth has increased. Through advertising, online gambling companies incite and encourage an involvement that can be harmful for vulnerable audiences. Some studies have demonstrated that advertising influences youths' assessment of gambling by increasing its appeal. We demonstrate that the shortcomings of the legal framework in force results in effective vulnerability of minors. We claim that society should seek to implement a regulatory framework to protect children from the risk of developing an addiction. PMID- 26437314 TI - Polydrug use and its relationship with the familiar and social context amongst young college students. AB - The prevalence of polydrug use continues to grow among Spanish college students. The European Observatory for Drugs and Addictions establishes three different types of polydrug use: Pattern A (consumers of alcohol and tobacco), Pattern B (consumers of cannabis plus alcohol and/or tobacco) and Pattern C (consumers of cannabis plus alcohol plus tobacco plus at least one other kind of illegal drug). The objectives are: 1) to study the frequency of substance consumption among a sample of young Spanish undergradudates studying health and sports science according to their sex; 2) to describe the patterns of polydrug use; 3) to study the relationship between the polydrug use of the participants and polydrug use within their closest environment (parents, sisters or brothers, best friend and partner). The sample was composed of 480 Spanish undergraduates (43.7% females) aged 18 to 36. The level of drug consumption of students and their closest reference persons was evaluated by means of a self-report measure. A total of 46% of the participants reported consumption of two or more substances; among them 29.4% corresponded to Pattern A, 50.7% to Pattern B and 16.7% to Pattern C, while 3.2% corresponded to other multiple consumption patterns (alcohol + cocaine; alcohol + cocaine + tobacco; alcohol + inhalants; amphetamines + hallucinogens + Spice). An important correlation was observed concerning polydrug use between participants and their closest reference persons: the more the reference person is a multiple consumer, the more the participant tends to consume. Polydrug use within the closest environment emerges as one of the key elements to be taken into account in further prevention programs. PMID- 26437315 TI - Opioid Receptor Antagonists in the Treatment of Alcoholism. AB - OBJECTIVES: On the basis of the recent advances in drug therapy of alcoholism, we conducted a review on opioid receptor antagonist drugs with approved indication for the treatment of alcoholism, such as naltrexone and nalmefene. METHODS: We reviewed over 100 publications on peptides and opioid receptors, as well as studies conducted in experimental animals and in humans on the effect of opioid receptor antagonists on alcohol consumption in the treatment of alcoholism. We also reviewed the pharmacological characteristics of naltrexone and nalmefene, and the usefulness of these drugs in clinical practice. RESULTS: Much evidence has demonstrated the efficacy of naltrexone and nalmefene for the reduction of alcohol consumption, in experimental animals as well as in humans examined under experimental bar conditions; however, due to its different receptor profile, nalmefene has been associated with higher efficacy levels in reducing alcohol consumption in alcohol-dependent rats. In addition, a great number of controlled clinical trials have demonstrated the efficacy of naltrexone for relapse prevention in patients with an alcohol dependence disorder. Recent controlled clinical trials have demonstrated the efficacy of nalmefene "as-needed" in the reduction of alcohol consumption in subjects with mild alcohol dependence. CONCLUSIONS: Both naltrexone and nalmefene have proved to be safe, well tolerated, easy to manage, and efficient drugs for the treatment of alcohol dependence disorder (currently known as alcohol use disorder). On the basis of recent controlled clinical trials, nalmefene has been shown to result in a significant reduction of alcohol consumption, thereby representing a new objective that extends the therapeutic possibilities for those patients who do not wish for a continuous abstinence, but rather a reduction of alcohol consumption. PMID- 26437316 TI - New Psychoactive Drugs. PMID- 26437317 TI - Alcohol consumption in college students from the pharmacy faculty. AB - Alcohol consumption is highly prevalent in university students. Early detection in future health professionals is important: their consumption might not only influence their own health but may determine how they deal with the implementation of preventive strategies in the future. The aim of this paper is to detect the prevalence of risky alcohol consumption in first- and last-degree year students and to compare their drinking patterns.Risky drinking in pharmacy students (n=434) was assessed and measured with the AUDIT questionnaire (Alcohol Use Disorders Identification Test). A comparative analysis between college students from the first and fifth years of the degree in pharmacy, and that of a group of professors was carried to see differences in their alcohol intake patterns.Risky drinking was detected in 31.3% of students. The highest prevalence of risky drinkers, and the total score of the AUDIT test was found in students in their first academic year. Students in the first academic level taking morning classes had a two-fold risk of risky drinking (OR=1.9 (IC 95%1.1-3.1)) compared with students in the fifth level. The frequency of alcohol consumption increases with the academic level, whereas the number of alcohol beverages per drinking occasion falls.Risky drinking is high during the first year of university. As alcohol consumption might decrease with age, it is important to design preventive strategies that will strengthen this tendency. PMID- 26437319 TI - No Time to Wait. PMID- 26437318 TI - HPV Prevalence in Multiple Anatomical Sites among Men Who Have Sex with Men in Peru. AB - BACKGROUND: Human Papilloma Virus (HPV) infection is the most common sexually transmitted viral infection worldwide. HPV is highly prevalent in sexually active men who have sex with men (MSM) and has been associated with anal cancer, penile cancer, and oropharyngeal cancer. METHODS: From March to September 2011, we conducted a cross-sectional study of HPV prevalence among MSM above age 18 years. Participants were recruited using respondent driven sampling at Clinica Cayetano Heredia. All participants provided anal, genital, and oral samples for HPV DNA testing, and blood for HIV and HPV antibody testing. RESULTS: A total of 200 MSM were recruited in the study. The mean age was 34 years (range 18-59 years, SD = 9.4) and101 participants were HIV negative (99 HIV positive). HPV 6/11/16/18 or quadrivalent HPV vaccine (HPV4) genotype seroprevalence among HIV negative and positive MSM was 64.3% (55%-75.9%) and 93.8% (87.6%-99.2%) respectively (p<0.001). HIV positivity was associated with a higher prevalence of HPV4 and HPV 16/18 DNA at external genital sites and the anal canal. HPV4 DNA prevalence at external genital sites among HIV negative and positive MSM was 14.9% and 28.7% (p = 0.02) respectively, at anal canal was 50.9% and 79.0% (p = 0.001), and at the oral cavity was 9.9% and 8.5% (p = 0.6). CONCLUSIONS: HPV4 seroprevalence was high in our study among both HIV positives and negatives, with HPV DNA prevalence much lower, and the anal canal being the anatomical site with the highest HPV DNA prevalence. HPV prevention interventions are needed among MSM at high-risk for HIV infection. PMID- 26437320 TI - Anti-inflammatory Effects of Clostridial Collagenase Results from In Vitro and Clinical Studies. AB - BACKGROUND: Digestion of collagen with clostridial collagenase (CC) produces peptides that can induce cellular responses consistent with wound healing in vivo. However, nonhealing human wounds are typically in a state of chronic inflammation. We evaluated the effects of CC on markers of inflammation in cell culture and wound fluid from diabetic patients. METHODS: Lipopolysaccharide induced release of tumor necrosis factor-alpha and interleukin-6 from interferon gamma-activated THP-1 monocytes was measured in the presence or absence of CC or CC collagen digests. In the clinical study, 17 individuals with mildly inflamed diabetic foot ulcers were randomized to receive CC ointment (CCO) or hydrogel. Weekly assessments included wound appearance and measurements. Wound exudate was collected at baseline and at 2 and 4 weeks of treatment. A multiplex assay was used to measure levels of analytes, including those associated with inflammation and with inflammation resolution. RESULTS: Lower levels of tumor necrosis factor alpha and interleukin-6 were found in media of cells cultured with CC or CC digests of collagen type I or III than for untreated lipopolysaccharide controls (P < .05). Clinically, CCO and hydrogel resulted in improvement in wound appearance and a decrease in mean wound area. The CCO, but not the hydrogel, was found to increase the level of analytes associated with resolution of inflammation while decreasing those associated with inflammation. There was a general correlation between resolution of inflammation and healing. CONCLUSIONS: These results support a hypothesis that debridement with CCO is associated with decreased inflammation and greater progress toward healing. PMID- 26437321 TI - Correction: Characterization of Carriage Isolates of Neisseria meningitidis in the Adolescents and Young Adults Population of Bogota (Colombia). PMID- 26437324 TI - Docetaxel rechallenge in metastatic castration-resistant prostate cancer: any place in the modern treatment scenario? An intention to treat evaluation. AB - BACKGROUND: We evaluated the possible advantages of a docetaxel (DCT) rechallenge strategy in metastatic castration-resistant prostate cancer (mCRPC) patients, also given the possible earlier positioning of this treatment option in the modern scenario. PATIENTS & METHODS: All mCRPC patients planned for DCT chemotherapy rechallenge in our institutions were evaluated. RESULTS: Of 128 patients, 98 achieved disease control on the initial DCT round. After a treatment holiday of 8.3 months, the 98 responsive patients underwent a second DCT round, with 56 cases achieving again disease control. After a 5.7-month off-treatment period, 32 of these cases underwent a third DCT round, and 16 responded. Lastly, after a further 4.2-month treatment holiday, eight patients underwent a fourth DCT round and two responded. Median time to definitive disease progression for the whole population was 16.4 months. CONCLUSIONS: Rechallenge with DCT may be considered a suitable treatment option for mCRPC patients recurring after a successful DCT chemotherapy. The interest in this strategy may be increased because of the showed efficacy of early DCT chemotherapy in patients with bulky disease (CHAARTED study) and the potential lower efficacy of the new hormonal agents abiraterone acetate and enzalutamide when used in a immediate sequencing. PMID- 26437325 TI - Preparation of a Superhydrophobic and Peroxidase-like Activity Array Chip for H2O2 Sensing by Surface-Enhanced Raman Scattering. AB - In this paper, we propose a novel and simple method for preparing a dual biomimetic functional array possessing both superhydrophobic and peroxidase-like activity that can be used for hydrogen peroxide (H2O2) sensing. The proposed method is an integration innovation that combines the above two properties and surface-enhanced Raman scattering (SERS). We integrated a series of well-ordered arrays of Au points (d = 1 mm) onto a superhydrophobic copper (Cu)/silver (Ag) surface by replicating an arrayed molybdenum template. Instead of using photoresists and the traditional lithography method, we utilized a chemical etching method (a substitution reaction between Cu and HAuCl4) with a Cu/Ag superhydrophobic surface as the barrier layer, which has the benefit of water repellency. The as-prepared Au points were observed to possess peroxidase-like activity, allowing for catalytic oxidation of the chromogenic molecule o phenylenediamine dihydrochloride (OPD). Oxidation was evidenced by a color change in the presence of H2O2, which allows the array chip to act as an H2O2 sensor. In this study, the water repellency of the superhydrophobic surface was used to fabricate the array chip and increase the local reactant concentration during the catalytic reaction. As a result, the catalytic reaction occurred when only 2 MUL of an aqueous sample (OPD/H2O2) was placed onto the Au point, and the enzymatic product, 2,3-diaminophenazine, showed a SERS signal distinguishable from that of OPD after mixing with 2 MUL of colloidal Au. Using the dual-biomimetic functional array chip, quantitative analysis of H2O2 was performed by observing the change in the SERS spectra, which showed a concentration-dependent behavior for H2O2. This method allows for the detection of H2O2 at concentrations as low as 3 pmol per 2 MUL of sample, which is a considerable advantage in H2O2 analysis. The as prepared substrate was convenient for H2O2 detection because only a small amount of sample was required in each analysis. Highly sensitive detection was realized using SERS. Therefore, this chip was shown to exhibit significant potential for applications in bioanalysis. PMID- 26437326 TI - En Bloc Multivisceral and Kidney Transplantation in an HIV Patient: First Case Report. AB - The continual improvement in outcome with highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV) infection and visceral transplantation for gut failure stimulated our interest in lifting HIV infection as a contraindication for intestinal and multivisceral transplantation. This report is the first to describe visceral transplantation in a patient with HIV infection. A HAART regimen was introduced in the setting of short-gut syndrome with successful suppression of HIV viral load. The indication for en bloc multivisceral and kidney transplantation was end-stage liver failure with portomesenteric venous thrombosis and chronic renal insufficiency. The underlying hepatic pathology was alcoholic and home parenteral nutrition-associated cirrhosis. Surgery was complicated due to technical difficulties with excessive blood loss and long operative time. The complex posttransplant course included multiple exploratory laparotomies due to serious intra-abdominal and systemic infections. Heavy immunosuppression was required to treat recurrent episodes of severe allograft rejection. Posttransplant oral HAART successfully sustained undetectable viral load. Unfortunately, the patient succumbed to sepsis 3 months posttransplant. With new insights into the biology of gut immunity, mechanisms of allograft tolerance, and HIV-associated immune dysregulation, successful outcome is anticipated, particularly in patients who are in need of isolated intestinal and less-organ-contained visceral allografts. PMID- 26437327 TI - Rooting depth, water relations and non-structural carbohydrate dynamics in three woody angiosperms differentially affected by an extreme summer drought. AB - In 2012, an extreme summer drought induced species-specific die-back in woody species in Northeastern Italy. Quercus pubescens and Ostrya carpinifolia were heavily impacted, while Prunus mahaleb was largely unaffected. By comparing seasonal changes in isotopic composition of xylem sap, rainfall and deep soil samples, we show that P. mahaleb has a deeper root system than the other two species. This morphological trait allowed P mahaleb to maintain higher water potential (Psi), gas exchange rates and non-structural carbohydrates content (NSC) throughout the summer, when compared with the other species. More favourable water and carbon states allowed relatively stable maintenance of stem hydraulic conductivity (k) throughout the growing season. In contrast, in Quercus pubescens and Ostrya carpinifolia, decreasing Psi and NSC were associated with significant hydraulic failure, with spring-to-summer k loss averaging 60%. Our data support the hypothesis that drought-induced tree decline is a complex phenomenon that cannot be modelled on the basis of single predictors of tree status like hydraulic efficiency, vulnerability and carbohydrate content. Our data highlight the role of rooting depth in seasonal progression of water status, gas exchange and NSC, with possible consequences for energy-demanding mechanisms involved in the maintenance of vascular integrity. PMID- 26437328 TI - [Comparison of the Biochemical Recurrence risk between Radical Prostatectomy and Brachytherapy in the treatment of low- and intermediate-risk prostate cancer]. AB - OBJECTIVES: To evaluate the results of patients treated with Radical Prostatectomy (RP) and Brachytherapy for low- and intermediate-risk localized prostate cancer and to determine the Biochemical Recurrence (BCR) risk according to the treatment performed. METHODS: The study included 129 patients treated with iodine-125 seeds Brachytherapy, 98 patients treated with Laparoscopic RP (LRP), and 61 patients treated with Robotic RP (RRP) at our institution between December 1999 and January 2010, who had a low-risk disease according to D'Amico criteria (PSA <10 ng/mL, Gleason < or = 6, cT1c-T2a), or an intermediate-risk disease (PSA = or >10 and < 20 ng/mL, Gleason = 7, cT2b), but with a tumor burden of up to 30%. Follow-up was conducted with PSA at 1, 3, and 6 months, and then every six months. As for Brachytherapy, annual digital rectal examinations were also performed. A PSA level increase of 2 ng/mL above the nadir in Brachytherapy (confirmed in 2 cases) and a PSA value greater than 0.2 ng/mL after RP were considered BCR. RESULTS: Overall mean follow-up was 60.5 months (R:1-152), with a mean time for BCR of 51.7 months (R:1-138). Estimated 5-year Biochemical Recurrence-free Survival (BCRFS) in patients with D'Amico low-risk was 85.7%, 77.2% and 90.7% (p 0.336), while for intermediate-risk it was 75.8%, 68.1% and 65.1% (p 0.114), for Brachytherapy, LRP and RRP respectively. In the univariate analysis, the Gleason score 7, a clinical stage T2b, and a D'Amico intermediate risk were associated with an increased BCR risk, and treatment with Brachytherapy was associated with a decreased BCR risk, all these being statistically significant. In the multivariate analysis, only the Gleason score 7 was significant; treatment with LRP, RRP or Brachytherapy was not associated with a greater BCR risk. CONCLUSION: Brachytherapy and Laparoscopic or Robotic Radical Prostatectomy showed no difference in terms of Biochemical Recurrence risk in patients treated for low-risk or intermediate-risk tumors, with low tumor volume. PMID- 26437329 TI - [Optimization and improvement of surgical indicators in the urology department of a regional hospital of the ministry of health of the Junta de Andalucia]. AB - OBJECTIVES: To improve the rates of surgical activity and average waiting times for surgery, and to optimize the number of surgical indications in the Urology Department of a Regional Hospital. METHODS: A study and analysis of the surgical activity and different indexes in 2014 was performed comparing the first half of the year and the second half after implementation of improvement measures. STUDY VARIABLES: operating room occupancy rate, average hospital stay, cancellations, surgical complexity, average number of surgeries per operative room, average global waiting time and waiting time by 120 and 180 days guarantee decrees following the Junta de Andalucia standards. RESULTS: In comparison with the first half of 2014, in the second half the operating room occupancy rate increased from 79% to 85%, the average stay decreased from 6 to 3 days, and a decrease in cancellations from 9% to 6% was observed. Moreover, a decrease in the mean waiting times was observed for surgeries subject to both the 120 days and 180 days guarantee decree and a decrease in the number of surgical indications in urology through the implementation of protocols based on clinical practice guidelines. CONCLUSIONS: Despite the limitations of the study, and being a small Department in a district hospital, we observed that optimization of resources, implementation of protocols, and clinical pathways can improve and optimize different indicators of surgical activity. PMID- 26437331 TI - [Testicular epidermoid cyst: A rare entity]. AB - OBJECTIVE: Testicular epidermoid cyst is a rare clinical entity that accounts for 1% of testicular neoplasias. METHODS AND RESULTS: We report two cases of testicular epidermoid cysts in a 18 and 19 year old males with a painless testicular lesion. Testicular US was carried out showing a hypoechoic nodule in both cases. With the suspicion of testicular neoplasm inguinal orchiectomy was carried out with placement of testicular prostheses in the same act. The pathology report was testicular epidermoid cyst in both cases. CONCLUSIONS: Testicular epidermoid cysts are an uncommon benign entity. When there is a suspicion of this diagnosis, based on tumor markers and ultrasound or MRI images, testicular parenchyma-sparing surgery must be attempted. PMID- 26437330 TI - Thermochemotherapy in adjuvant treatment of primary high risk non muscle invasive bladder cancers: Single center results. AB - OBJECTIVE: To evaluate the results of Thermochemotherapy in adjuvant treatment of primary high risk non-muscle invasive bladder cancer in our center. METHODS: The study included 26 patients with an age of 51-78 years (mean: 62.4 years). All patients had transurethral tumor resection (TURB) after being diagnosed with a primary bladder tumor and were pathologically diagnosed with non-muscle invasive urothelial carcinoma. Thermochemotherapy (TCT) applications were performed via the Synergo(r) system SB-TS 101. RESULTS: Of the study participants, 13 patients had T1 Grade III, six patients had T1Grade III CIS (+), four patients had Ta Grade III, and three patients Ta Grade II multiple > 5 cm tumor. In all patients, six weeks plus six months protocol were completed. All patients completed the follow-up protocol. With a median follow-up time of 16.4 months (range: 6 - 48 months), recurrent urothelial carcinoma was identified in three patients. With a median follow-up time of 16.4 months, the recurrence-free survival was 88.4% in 26 patients included in the study. CONCLUSIONS: The obtained data suggest that the TCT method can be used effectively and safely in non-muscle invasive bladder cancers of primary high-risk. Prospective randomized studies will shed light on this subject which are BCG vs TCT in primary high risk patients and second course BCG vs TCT in the BCG insufficient patients. PMID- 26437332 TI - [Prostate Specific Antigen (PSA) use in a national health department]. AB - OBJECTIVES: PSA is a frequently used marker in the daily clinical practice for the diagnosis and management of prostate cancer. We analysed the use of PSA in our health department in patients with and without prostate cancer diagnosis. METHODS: The registry of all PSA petitions in our health department during 2011 and 2012 was used. Demographic data were used to establish each year's population and the data corresponding to the prevalence of prostate cancer patients, performing a descriptive study. Thus, the use of PSA in patients with or without prostate cancer was studied. RESULTS: 25.700 PSA petitions are issued annually in our department over a total of 67.000 males older than 45. This entails a cost of 332.815 Euros annually. Within the group of patients with no prostate cancer diagnosis, it was noticed that the percentage of individuals with at least one annual PSA petition per decade of age is of 23% in males in their fifties, 40% in their sixties, 46% in their seventies, and 36% in their eighties or successive decades. Furthermore, in these cancer-free patients, around 3.800 annual petitions fall on individuals over 75 and with PSA under 4 ng/ml, from which 20% are repeated petitions over the same individual in the same year. Over 1100 males under 45 have an annual PSA. Regarding the average PSA value for decade of age in cancer-free patients, it is of 0.89 +/- 0.4 ng/ml in the forties decade, 1.26 +/- 1.07 ng/ml in the fifties, 1.67 +/- 1.38 ng/ml in the sixties, 1.96 +/- 1.78 ng/ml in the seventies, and 2.24 +/- 2.16 ng/ml in the eighties. We ascertained, also, that for every 144 PSA petitions one prostate cancer case is diagnosed. Regarding the use of this marker in cancer patients, 1.800 petitions are destined to patients follow up annually, and over 200 fall on the newly diagnosed cases. CONCLUSIONS: Even though annually less than 50% of males get PSA petitions in any decade of age, its use is sometimes incorrect, including repeated petitions in a short period of time or in individuals of extreme age. PMID- 26437333 TI - [Metastatic urinary bladder involvement in breast cancer]. AB - OBJECTIVE: To contribute to the literature with three unusual cases of primary breast tumor with metastasis to the urinary bladder. METHODS: Presentation of the three clinical cases and bibliographic review. RESULTS: Three women, with an average age of 49.3 years, were diagnosed with invasive lobular breast carcinoma. Two of them suffered from hematuria after being diagnosed with breast cancer. The third patient was diagnosed incidentally after a routine CT scan. Upon diagnosis of the bladder metastases, they already had metastasis in other locations. The treatment of the three cases was palliative. The cause of death was due to additional pathologies. CONCLUSIONS: The presence of bladder metastases due to breast cancer is infrequent. The appearance of urinary tract symptoms in these patients requires a diagnostic study in order to rule out metastases. PMID- 26437334 TI - An Aquatic Microbial Metaproteomics Workflow: From Cells to Tryptic Peptides Suitable for Tandem Mass Spectrometry-based Analysis. AB - Meta-omic technologies such as metagenomics, metatranscriptomics and metaproteomics can aid in the understanding of microbial community structure and metabolism. Although powerful, metagenomics alone can only elucidate functional potential. On the other hand, metaproteomics enables the description of the expressed in situ metabolism and function of a community. Here we describe a protocol for cell lysis, protein and DNA isolation, as well as peptide digestion and extraction from marine microbial cells collected on a cartridge filter unit (such as the Sterivex filter unit) and preserved in an RNA stabilization solution (like RNAlater). In mass spectrometry-based proteomics studies, the identification of peptides and proteins is performed by comparing peptide tandem mass spectra to a database of translated nucleotide sequences. Including the metagenome of a sample in the search database increases the number of peptides and proteins that can be identified from the mass spectra. Hence, in this protocol DNA is isolated from the same filter, which can be used subsequently for metagenomic analysis. PMID- 26437335 TI - A Hybrid CPU/GPU Pattern-Matching Algorithm for Deep Packet Inspection. AB - The large quantities of data now being transferred via high-speed networks have made deep packet inspection indispensable for security purposes. Scalable and low cost signature-based network intrusion detection systems have been developed for deep packet inspection for various software platforms. Traditional approaches that only involve central processing units (CPUs) are now considered inadequate in terms of inspection speed. Graphic processing units (GPUs) have superior parallel processing power, but transmission bottlenecks can reduce optimal GPU efficiency. In this paper we describe our proposal for a hybrid CPU/GPU pattern matching algorithm (HPMA) that divides and distributes the packet-inspecting workload between a CPU and GPU. All packets are initially inspected by the CPU and filtered using a simple pre-filtering algorithm, and packets that might contain malicious content are sent to the GPU for further inspection. Test results indicate that in terms of random payload traffic, the matching speed of our proposed algorithm was 3.4 times and 2.7 times faster than those of the AC CPU and AC-GPU algorithms, respectively. Further, HPMA achieved higher energy efficiency than the other tested algorithms. PMID- 26437336 TI - Continued pregnancy and vaginal delivery after 32 weeks of gestation for monoamniotic twins. AB - OBJECTIVE: To report the outcomes of 38 monoamniotic twin pregnancies managed homogeneously to assess whether continuing the pregnancy past 32 weeks of gestation and vaginal delivery are reasonable options. STUDY DESIGN: Single centre retrospective study including all monoamniotic pregnancies managed over a 20-year period at Port-Royal Obstetrics Department, Paris, France. METHODS: In the study department, both continuation of the pregnancy up to 36 weeks of gestation and vaginal delivery are allowed for monoamniotic pregnancies in some conditions. Perinatal outcomes are described and then compared according to mode of delivery for patients who gave birth at or after 32 weeks of gestation. RESULTS: Three of the 38 pregnancies included fetal malformations; in two of these cases, both fetuses died in utero at 26 weeks of gestation. In cases without malformations, one twin died in utero in two women at 28.0 and 29.2 weeks of gestation, and both fetuses died in two other women at 24.0 and 24.5 weeks of gestation. Mean gestational age at delivery was 32.9 weeks (range 24.0-36.3). Five women gave birth between 22 and 26 weeks of gestation, six women gave birth between 27 and 31 weeks of gestation, and 27 women gave birth at or after 32 weeks of gestation (26 after excluding those with fetal malformations). No intrauterine or neonatal deaths were observed at or after 32 weeks of gestation. The 28 infants delivered vaginally did not differ significantly from the 22 infants born by caesarean section in terms of umbilical artery pH or 5-min Apgar scores. CONCLUSION: Continuation of monoamniotic pregnancies beyond 32 weeks of gestation and trial of vaginal delivery are both reasonable options if the parents agree, and optimal surveillance is provided. PMID- 26437337 TI - Detection of Candida spp. in the vagina of a cohort of nulliparous pregnant women by culture and molecular methods: Is there an association between maternal vaginal and infant oral colonisation? AB - BACKGROUND: Most studies describing vaginal Candida spp. in pregnancy focus on symptomatic vaginitis, rather than asymptomatic colonisation, and solely utilise microbiological culture. The extent to which asymptomatic vaginal carriage may represent a reservoir for infant oral colonisation has been highly debated. MATERIALS AND METHODS: This study formed part of the Candida and Staphylococcus Transmission Longitudinal Evaluation (CASTLE) study, in Melbourne, Australia, from 2009 to 2011 and used culture and molecular methods to examine vaginal swabs collected late in the third trimester of pregnancy for Candida spp. Oral swabs from infants were also examined using culture methods. RESULTS: Overall, 80 of 356 (22%) women were positive for Candida spp; the majority being Candida albicans (83%). Candida glabrata and other Candida spp. were also identified, but in much lower numbers. Molecular analysis identified numerous positive samples not detected by culture, including 13 cases of C. albicans. In addition, some positive samples only recorded to genus level by culture were accurately identified as either C. albicans or C. glabrata following molecular analyses. Eighteen infants recorded positive Candida spp. cultures, predominantly C. albicans. However, there were only four (25%) mother/infant dyads where C. albicans was detected. CONCLUSIONS: This study provides valuable data on asymptomatic colonisation rates of Candida spp. within an asymptomatic population of women late in pregnancy. The utilisation of molecular methods improved the rate of detection and provided a more accurate means for identification of non albicans Candida spp. The low mother/infant colonisation rate suggests that non maternal sources are likely involved in determining infant oral colonisation status. PMID- 26437338 TI - lncRScan-SVM: A Tool for Predicting Long Non-Coding RNAs Using Support Vector Machine. AB - Functional long non-coding RNAs (lncRNAs) have been bringing novel insight into biological study, however it is still not trivial to accurately distinguish the lncRNA transcripts (LNCTs) from the protein coding ones (PCTs). As various information and data about lncRNAs are preserved by previous studies, it is appealing to develop novel methods to identify the lncRNAs more accurately. Our method lncRScan-SVM aims at classifying PCTs and LNCTs using support vector machine (SVM). The gold-standard datasets for lncRScan-SVM model training, lncRNA prediction and method comparison were constructed according to the GENCODE gene annotations of human and mouse respectively. By integrating features derived from gene structure, transcript sequence, potential codon sequence and conservation, lncRScan-SVM outperforms other approaches, which is evaluated by several criteria such as sensitivity, specificity, accuracy, Matthews correlation coefficient (MCC) and area under curve (AUC). In addition, several known human lncRNA datasets were assessed using lncRScan-SVM. LncRScan-SVM is an efficient tool for predicting the lncRNAs, and it is quite useful for current lncRNA study. PMID- 26437340 TI - Spatial and temporal relationships among watershed mining, water quality, and freshwater mussel status in an eastern USA river. AB - The Powell River of southwestern Virginia and northeastern Tennessee, USA, drains a watershed with extensive coal surface mining, and it hosts exceptional biological richness, including at-risk species of freshwater mussels, downstream of mining-disturbed watershed areas. We investigated spatial and temporal patterns of watershed mining disturbance; their relationship to water quality change in the section of the river that connects mining areas to mussel habitat; and relationships of mining-related water constituents to measures of recent and past mussel status. Freshwater mussels in the Powell River have experienced significant declines over the past 3.5 decades. Over that same period, surface coal mining has influenced the watershed. Water-monitoring data collected by state and federal agencies demonstrate that dissolved solids and associated constituents that are commonly influenced by Appalachian mining (specific conductance, pH, hardness and sulfates) have experienced increasing temporal trends from the 1960s through ~2008; but, of those constituents, only dissolved solids concentrations are available widely within the Powell River since ~2008. Dissolved solids concentrations have stabilized in recent years. Dissolved solids, specific conductance, pH, and sulfates also exhibited spatial patterns that are consistent with dilution of mining influence with increasing distance from mined areas. Freshwater mussel status indicators are correlated negatively with dissolved solids concentrations, spatially and temporally, but the direct causal mechanisms responsible for mussel declines remain unknown. PMID- 26437339 TI - Down-Regulation of miR-92 in Breast Epithelial Cells and in Normal but Not Tumour Fibroblasts Contributes to Breast Carcinogenesis. AB - BACKGROUND: MicroRNA (miR) expression is commonly dysregulated in many cancers, including breast. MiR-92 is one of six miRs encoded by the miR-17-92 cluster, one of the best-characterised oncogenic miR clusters. We examined expression of miR 92 in the breast epithelium and stroma during breast cancer progression. We also investigated the role of miR-92 in fibroblasts in vitro and showed that down regulation in normal fibroblasts enhances the invasion of breast cancer epithelial cells. METHODOLOGY/PRINCIPAL FINDINGS: We used laser microdissection (LMD) to isolate epithelial cells from matched normal, DCIS and invasive tissue from 9 breast cancer patients and analysed miR-92 expression by qRT-PCR. Expression of ERbeta1, a direct miR-92 target, was concurrently analysed for each case by immunohistochemistry. LMD was also used to isolate matched normal (NFs) and cancer-associated fibroblasts (CAFs) from 14 further cases. Effects of miR-92 inhibition in fibroblasts on epithelial cell invasion in vitro was examined using a MatrigelTM assay. miR-92 levels decreased in microdissected epithelial cells during breast cancer progression with highest levels in normal breast epithelium, decreasing in DCIS (p<0.01) and being lowest in invasive breast tissue (p<0.01). This was accompanied by a shift in cell localisation of ERbeta1 from nuclear expression in normal breast epithelium to increased cytoplasmic expression during progression to DCIS (p = 0.0078) and invasive breast cancer (p = 0.031). ERbeta1 immunoreactivity was also seen in stromal fibroblasts in tissues. Where miR-92 expression was low in microdissected NFs this increased in matched CAFs; a trend also seen in cultured primary fibroblasts. Down-regulation of miR-92 levels in NFs but not CAFs enhanced invasion of both MCF-7 and MDA-MB-231 breast cancer epithelial cells. CONCLUSIONS: miR-92 is gradually lost in breast epithelial cells during cancer progression correlating with a shift in ERbeta1 immunoreactivity from nuclei to the cytoplasm. Our data support a functional role in fibroblasts where modification of miR-92 expression can influence the invasive capacity of breast cancer epithelial cells. However in silico analysis suggests that ERbeta1 may not be the most important miR-92 target in breast cancer. PMID- 26437341 TI - De-oiled two-phase olive mill waste may reduce water contamination by metribuzin. AB - The impact of de-oiled two-phase olive mill waste (DW) on the behavior of metribuzin in Mediterranean agricultural soils is evaluated, and the effects of the transformation of organic matter from this waste under field conditions are assessed. Four soils were selected and amended in the laboratory with DW at the rates of 2.5% and 5%. One of these soils was also amended in the field with 27 and 54 Mg ha(-1) of DW for 9 years. Significant increases in metribuzin sorption were observed in all the amended soils. In the laboratory, the 5% DW application rate increased the t1/2 values of metribuzin from 22.9, 35.8, 29.1, and 20.0 d for the original soils to 59.2, 51.1, 45.7, and 29.4d, respectively. This was attributable mainly to the inhibitory effect of the amendment on microbial activity. However, the addition of DW transformed naturally under field conditions decreased the persistence down to 3.93 d at the greater application rate. Both amendments (fresh and field-aged DW) significantly reduced the amount of metribuzin leached. This study showed that DW amendment may be an effective and sustainable management practice for controlling groundwater contamination by metribuzin. PMID- 26437343 TI - Origin of high ammonium, arsenic and boron concentrations in the proximity of a mine: Natural vs. anthropogenic processes. AB - High ammonium (NH4), arsenic (As) and boron (B) concentrations are found in aquifers worldwide and are often related to human activities. However, natural processes can also lead to groundwater quality problems. High NH4, As and B concentrations have been identified in the confined, deep portion of the Niebla Posadas aquifer, which is near the Cobre Las Cruces (CLC) mining complex. The mine has implemented a Drainage and Reinjection System comprising two rings of wells around the open pit mine, were the internal ring drains and the external ring is used for water reinjection into the aquifer. Differentiating geogenic and anthropogenic sources and processes is therefore crucial to ensuring good management of groundwater in this sensitive area where groundwater is extensively used for agriculture, industry, mining and human supply. No NH4, As and B are found in the recharge area, but their concentrations increase with depth, salinity and residence time of water in the aquifer. The increased salinity down flow is interpreted as the result of natural mixing between infiltrated meteoric water and the remains of connate waters (up to 8%) trapped within the pores. Ammonium and boron are interpreted as the result of marine solid organic matter degradation by the sulfate dissolved in the recharge water. The light delta(15)NNH4 values confirm that its origin is linked to marine organic matter. High arsenic concentrations in groundwater are interpreted as being derived from reductive dissolution of As-bearing goethite by dissolved organic matter. The lack of correlation between dissolved Fe and As is explained by the massive precipitation of siderite, which is abundantly found in the mineralization. Therefore, the presence of high arsenic, ammonium and boron concentrations is attributed to natural processes. Ammonium, arsenic, boron and salinity define three zones of groundwater quality: the first zone is close to the recharge area and contains water of sufficient quality for human drinking; the second zone is downflow and contains groundwater suitable for continuous irrigation but not drinkable due to high ammonium concentrations; and the third zone contains groundwater of elevated salinity (up to 5940 MUS cm(-1)) and is not useable due to high ammonium, arsenic and boron concentrations. PMID- 26437344 TI - Distribution of virulence factors in ESBL-producing Escherichia coli isolated from the environment, livestock, food and humans. AB - In this study, extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli isolates recovered from the following sources were characterized with regard to the occurrence and distribution of uropathogenic and enteric pathogenic virulence factors: surface waters (rivers and lakes, n=60), the intestines of freshwater fish (n=33), fresh vegetables (n=26), retail poultry meat (n=13) and the fecal samples of livestock (n=28), healthy humans (n=34) and primary care patients (n=13). Among the 207 isolates, 82% tested positive by PCR for one or more of the virulence factors (VF) that predict uropathogenicity, TraT, fyuA, chuA, PAI, yfcv or vat. Uropathogenic E. coli (UPEC) were detected in each of the analyzed sources. Regarding virulence factors for intestinal pathogenic E. coli, these were found more rarely and predominantly associated with the aquatic environment, with aagR (EAEC) found in isolates from surface waters and STp (porcine heat stable enterotoxin) and LT (heat-labile enterotoxin) associated with isolates from fish. Aggregate VF scores (the number of unique virulence factors detected for each isolate) were lowest among isolates belonging to phylogenetic group B1 and highest among group B2. Clustering of the isolates by phylogenetic group, multilocus sequence type (MLST) and ESBL-types revealed clonal overlaps of A:ST10(CTX-M-1) and D:ST350(CTX-M-1) between the sources of livestock, poultry meat and healthy humans, suggesting livestock, in particular poultry, represents a potential reservoir for these particular UPEC clones. The clones A:ST10(CTX-M 55) and B2:ST131(CTX-M-27), harboring uropathogenic virulence factors were significantly associated with fresh vegetables and with fish, respectively. Further clonal complexes with source overlaps included D:ST38(CTX-M-14), D:ST69(CTX-M-15), D:ST405(CTX-M-15) and D:ST648(CTX-M-15), which were found in surface water and healthy humans. Identifying potential reservoirs of UPEC in the environment, animals, food and humans is important in order to assess routes of transmission and risk factors for acquiring UPEC. PMID- 26437345 TI - Cooling and eutrophication of southern Chilean lakes. AB - Understanding the impacts of global warming and human-disturbances on lakes is required for implementing management strategies aimed at mitigating the decline of the quality and availability of water for humans. We assessed temporal trends in water parameters, and the contribution of land use to the eutrophication of the largest lakes of central-southern Chile. The mean values of water parameters varied seasonally, with lakes Chapo and Caburgua exhibiting lower pH, temperature, and N/P ratio values. Over the assessed period (19 years), we found a temporal reduction in water conductivity and temperature of the lakes. The concentration of NO3(-)-N, PO4(3-)-P and dissolved oxygen increased in all the lakes, but pH increased in eight out of the ten lakes. The negative temporal trend in temperature was more pronounced as the depth level increased. Lakes whose basins had a higher percentage of forest plantation and urban areas had larger values of Chlorophyll a and pH, as well as, smaller values of dissolved oxygen. Lakes whose basins included larger percentages of native forest had smaller nutrient (NO3(-)-N, PO4(3-)-P) concentrations. Our findings suggest that decreased rainfall in central-southern Chile due to climate change may cause a decrease of particulate material that is carried by tributaries into the lakes. The observed temporal decrease in temperature, especially at the deeper levels, may be explained by the rapid melting of glaciers. Although the studied lakes are classified as oligotrophic, deforestation and expansion of urban areas around the lakes have led to increased nutrient input, thus accelerating their eutrophication. PMID- 26437342 TI - Environmental exposure to manganese in air: Associations with tremor and motor function. AB - BACKGROUND: Manganese (Mn) inhalation has been associated with neuropsychological and neurological sequelae in exposed workers. Few environmental epidemiologic studies have examined the potentially neurotoxic effects of Mn exposure in ambient air on motor function and hand tremor in adult community residents. Mn exposed residents were recruited in two Ohio towns: Marietta, a town near a ferro manganese smelter, and East Liverpool, a town adjacent to a facility processing, crushing, screening, and packaging Mn products. METHODS: Chronic (>= 10 years) exposure to ambient air Mn in adult residents and effects on neuropsychological and neurological outcomes were investigated. Participants from Marietta (n=100) and East Liverpool (n=86) were combined for analyses. AERMOD dispersion modeling of fixed-site outdoor air monitoring data estimated Mn inhalation over a ten year period. Adult Mn-exposed residents' psychomotor ability was assessed using Finger Tapping, Hand Dynamometer, Grooved Pegboard, and the Computerized Adaptive Testing System (CATSYS) Tremor system. Bayesian structural equation modeling was used to assess associations between air-Mn and motor function and tremor. RESULTS: Air-Mn exposure was significantly correlated in bivariate analyses with the tremor test (CATSYS) for intensity, center frequency and harmonic index. The Bayesian path analysis model showed associations of air-Mn with the CATSYS non dominant center frequency and harmonic index; while the Bayesian structural equation model revealed associations between air-Mn and lower Finger Tapping scores. Household income was significantly associated with motor dysfunction but not with tremor. CONCLUSION: Tremor and motor function were associated with higher exposure to airborne Mn. PMID- 26437346 TI - Direct and indirect effects of an invasive omnivore crayfish on leaf litter decomposition. AB - Invasive alien species (IAS) can disrupt important ecological functions in aquatic ecosystems; however, many of these effects are not quantified and remain speculative. In this study, we assessed the effects of the invasive crayfish Procambarus clarkii (Girard, 1852) on leaf litter decomposition (a key ecosystem process) and associated invertebrates using laboratory and field manipulative experiments. The crayfish had significant impacts on leaf decomposition due to direct consumption of leaf litter and production of fine particulate organic matter, and indirectly due to consumption of invertebrate shredders. The invertebrate community did not appear to recognize P. clarkii as a predator, at least in the first stages after its introduction in the system; but this situation might change with time. Overall, results suggested that the omnivore invader P. clarkii has the potential to affect detritus-based food webs through consumption of basal resources (leaf litter) and/or consumers. Recognizing that this IAS is widespread in Europe, Asia and Africa, and may attain high density and biomass in aquatic ecosystems, our results are important to develop strategies for improving stream ecosystem functioning and to support management actions aiming to control the invasive omnivore P. clarkii. PMID- 26437347 TI - An epidemiological assessment of stomatal ozone flux-based critical levels for visible ozone injury in Southern European forests. AB - Southern forests are at the highest ozone (O3) risk in Europe where ground-level O3 is a pressing sanitary problem for ecosystem health. Exposure-based standards for protecting vegetation are not representative of actual field conditions. A biologically-sound stomatal flux-based standard has been proposed, although critical levels for protection still need to be validated. This innovative epidemiological assessment of forest responses to O3 was carried out in 54 plots in Southeastern France and Northwestern Italy in 2012 and 2013. Three O3 indices, namely the accumulated exposure AOT40, and the accumulated stomatal flux with and without an hourly threshold of uptake (POD1 and POD0) were compared. Stomatal O3 fluxes were modeled (DO3SE) and correlated to measured forest-response indicators, i.e. crown defoliation, crown discoloration and visible foliar O3 injury. Soil water content, a key variable affecting the severity of visible foliar O3 injury, was included in DO3SE. Based on flux-effect relationships, we developed species-specific flux-based critical levels (CLef) for forest protection against visible O3 injury. For O3 sensitive conifers, CLef of 19 mmol m(-2) for Pinus cembra (high O3 sensitivity) and 32 mmol m(-2) for Pinus halepensis (moderate O3 sensitivity) were calculated. For broadleaved species, we obtained a CLef of 25 mmol m(-2) for Fagus sylvatica (moderate O3 sensitivity) and of 19 mmol m(-2) for Fraxinus excelsior (high O3 sensitivity). We showed that an assessment based on PODY and on real plant symptoms is more appropriated than the concentration-based method. Indeed, POD0 was better correlated with visible foliar O3 injury than AOT40, whereas AOT40 was better correlated with crown discoloration and defoliation (aspecific indicators). To avoid an underestimation of the real O3 uptake, we recommend the use of POD0 calculated for hours with a non-null global radiation over the 24-h O3 accumulation window. PMID- 26437348 TI - Impact of biosolids and wastewater effluent application to agricultural land on corticosterone content in lettuce plants. AB - We studied corticosterone occurrence in lettuce plants grown on three biosolids amended soils under irrigation with either tap water or secondary wastewater effluent. Corticosterone was examined as it has possible implications for human health. It is a major glucocorticoid, and as such has an effect on regulation of metabolism, immune functions and stress response. The plants were grown in 220-L lysimeters packed with 3 soils which represent a wide range of physicochemical properties. Lettuce was grown in cycles (two in summer and two in winter) during 3 years, and in every spring season the sludges were re-applied. Corticosterone was quantified using ELISA and LCMS, and was found in the biosolids, tap water, wastewater effluent and lettuce plants. The respective ranges of concentrations were: 11-92 ng g(-1), 0.5-1.6 ng L(-1), 4.2-4.7 ng L(-1); and 1-900 ng g(-1) dry weight. A positive relationship was found between corticosterone concentrations in winter-grown lettuces and the plants fresh weight. The corticosterone content of the plants did not correspond with either the type of irrigation water or the biosolids type and rate of application or the soil properties. PMID- 26437349 TI - Maize yield gaps caused by non-controllable, agronomic, and socioeconomic factors in a changing climate of Northeast China. AB - Closing the gap between current and potential yields is one means of increasing agricultural production to feed the globally increasing population. Therefore, investigation of the geographic patterns, trends and causes of crop yield gaps is essential to identifying where yields might be increased and quantifying the contributions of yield-limiting factors that may provide us potentials to enhance crop productivity. In this study, the changes in potential yields, attainable yields, potential farmers' yields, and actual farmers' yields during the past five decades in Northeast China (NEC) were investigated. Additionally the yield gaps caused by non-controllable, agronomic, and socioeconomic factors were determined. Over the period 1961 to 2010 the estimated regional area-weighted mean maize potential yield, attainable yield, and potential farmers' yield were approximately 12.3 t ha(-1), 11.5 t ha(-1), and 6.4 t ha(-1) which showed a decreasing tendency. The actual farmers' yield over NEC was 4.5 t ha(-1), and showed a tendency to increase (p<0.01) by 1.27 t ha(-1) per decade. The regional mean total yield gap (YGt), weighted by the area in each county dedicated to maize crop, was 64% of potential yield. Moreover, 8, 40, and 16% reductions in potential yields were due to non-controllable factors (YGI), agronomic factors (YGII), and socioeconomic factors (YGIII), respectively. Therefore, the exploitable yield gap, considered here as the difference between the potential yield and what one can expect considering non-controllable factors (i.e. YGt YGI), of maize in NEC was about 56%. The regional area-weighted averages of YGt, and YGIII were found to have significant decreases of 11.0, and 10.7% per decade. At the time horizon 2010, the exploitable yield gaps were estimated to equal 36% of potential yield. This led to the conclusion that the yield gap could be deeply reduced by improving local agronomic management and controlling socioeconomic factors. PMID- 26437350 TI - Carbon based secondary compounds do not provide protection against heavy metal road pollutants in epiphytic macrolichens. AB - Lichens are useful monitoring organisms for heavy metal pollution. They are high in carbon based secondary compounds (CBSCs) among which some may chelate heavy metals and thus increase metal accumulation. This study quantifies CBSCs in four epiphytic lichens transplanted for 6months on stands along transects from a highway in southern Norway to search for relationships between concentrations of heavy metals and CBSCs along a gradient in heavy metal pollutants. Viability parameters and concentrations of 21 elements including nutrients and heavy metals in these lichen samples were reported in a separate paper. Medullary CBSCs in fruticose lichens (Ramalina farinacea, Usnea dasypoga) were reduced in the most polluted sites, but not in foliose ones (Parmelia sulcata, Lobaria pulmonaria), whereas cortical CBSC did not change with distance from the road in any species. Strong positive correlations only occurred between the major medullary compound stictic acid present in L. pulmonaria and most heavy metals, consistent with a chelating role of stictic acid, but not of other studied CBSCs or in other species. However, heavy metal chelating did not protect L. pulmonaria against damage because this species experienced the strongest reduction in viability in the polluted sites. CBSCs with an accumulation potential for heavy metals should be quantified in lichen biomonitoring studies of heavy metals because they, like stictic acid, could overshadow pollutant inputs in some species rendering biomonitoring data less useful. In the two fruticose lichen species, CBSCs decreased with increasing heavy metal concentration, probably because heavy metal exposure impaired secondary metabolism. Thus, we found no support for a heavy metal protection role of any CBSCs in studied epiphytic lichens. No intraspecific relationships occurred between CBSCs versus N or C/N-ratio. Interspecifically, medullary CBSCs decreased and cortical CBSCs increased with increasing C/N-ratio. PMID- 26437351 TI - Nitrate source identification in groundwater of multiple land-use areas by combining isotopes and multivariate statistical analysis: A case study of Asopos basin (Central Greece). AB - Nitrate (NO3) is one of the most common contaminants in aquatic environments and groundwater. Nitrate concentrations and environmental isotope data (delta(15)N NO3 and delta(18)O-NO3) from groundwater of Asopos basin, which has different land-use types, i.e., a large number of industries (e.g., textile, metal processing, food, fertilizers, paint), urban and agricultural areas and livestock breeding facilities, were analyzed to identify the nitrate sources of water contamination and N-biogeochemical transformations. A Bayesian isotope mixing model (SIAR) and multivariate statistical analysis of hydrochemical data were used to estimate the proportional contribution of different NO3 sources and to identify the dominant factors controlling the nitrate content of the groundwater in the region. The comparison of SIAR and Principal Component Analysis showed that wastes originating from urban and industrial zones of the basin are mainly responsible for nitrate contamination of groundwater in these areas. Agricultural fertilizers and manure likely contribute to groundwater contamination away from urban fabric and industrial land-use areas. Soil contribution to nitrate contamination due to organic matter is higher in the south-western part of the area far from the industries and the urban settlements. The present study aims to highlight the use of environmental isotopes combined with multivariate statistical analysis in locating sources of nitrate contamination in groundwater leading to a more effective planning of environmental measures and remediation strategies in river basins and water bodies as defined by the European Water Frame Directive (Directive 2000/60/EC). PMID- 26437352 TI - Performance evaluation of conventional and water saving taps. AB - The rapid pace of urbanisation comes with considerable environmental implications including pressures on already stressed limited water resources. In urban areas, most of the water use is associated with water consumption in buildings. The second largest use of water is via taps. It is often assumed that water taps with low flow rates can contribute to reduced per capita water consumption. However, this is based on very little evidence. This paper presents the synthesis of a 13,000 high resolution observations made to investigate the actual water consumption of innovative (water saving) electronic taps and conventional mixer taps. High resolution flow-meters and data loggers were fitted into two washrooms in two different buildings of a higher education institution to record the water use through the basin taps. The recorded data provided information on duration, frequency of use and volume of water consumption per use. The data was helpful in identifying trends in hot and cold water use and therefore can be useful in estimating energy for producing hot water and associated greenhouse gas emissions. Analysis of the observed data suggests that the low flow taps have greater mean water consumption per event than the conventional taps and water consumption is more influenced by user behaviour rather than the technology. PMID- 26437353 TI - Risk assessment of down-the-drain chemicals at large spatial scales: Model development and application to contaminants originating from urban areas in the Saint Lawrence River Basin. AB - Chemicals released into freshwater systems threaten ecological functioning and may put aquatic life and the health of humans at risk. We developed a new contaminant fate model (CFM) that follows simple, well-established methodologies and is unique in its cross-border, seamless hydrological and geospatial framework, including lake routing, a critical component in northern environments. We validated the model using the pharmaceutical Carbamazepine and predicted eco toxicological risk for 15 pharmaceuticals in the Saint-Lawrence River Basin, Canada. The results indicated negligible to low environmental risk for the majority of tested chemicals, while two pharmaceuticals showed elevated risk in up to 13% of rivers affected by municipal effluents. As an integrated model, our CFM is designed for application at very large scales with the primary goal of detecting high risk zones. In regulatory frameworks, it can help screen existing or new chemicals entering the market regarding their potential impact on human and environmental health. Due to its high geospatial resolution, our CFM can also facilitate the prioritization of actions, such as identifying regions where reducing contamination sources or upgrading treatment plants is most pertinent to achieve targeted pollutant removal or to protect drinking water resources. PMID- 26437354 TI - Analysis of the effects of meteorology on aircraft exhaust dispersion and deposition using a Lagrangian particle model. AB - The risk of air quality degradation is of considerable concern particularly for those airports that are located near urban areas. The ability to quantitatively predict the effects of air pollutants originated by airport operations is important for assessing air quality and the related impacts on human health. Current emission regulations have focused on local air quality in the proximity of airports. However, an integrated study should consider the effects of meteorological events, at both regional and local level, that can affect the dispersion and the deposition of exhausts. Rigorous scientific studies and extensive experimental data could contribute to the analysis of the impacts of airports expansion plans. This paper is focused on the analysis of the effects of meteorology on aircraft emission for the Marco Polo Airport in Venice. This is the most important international airport in the eastern part of the Po' Valley, one of the most polluted area in Europe. Air pollution is exacerbated by meteorology that is a combination of large and local scale effects that do not allow significant dispersion. Moreover, the airport is located near Venice, a city of noteworthy cultural and architectural relevance, and nearby the lagoon that hosts several areas of outstanding ecological importance at European level (Natura 2000 sites). Dispersion and deposit of the main aircraft exhausts (NOx, HC and CO) have been evaluated by using a Lagrangian particle model. Spatial and temporal aircraft exhaust dispersion has been analyzed for LTO cycle. Aircraft taxiing resulted to be the most impacting aircraft operation especially for the airport working area and its surroundings, however occasionally peaks may be observed even at high altitudes when cruise mode starts. Mixing height can affect concentrations more significantly than the concentrations in the exhausts themselves. An increase of HC and CO concentrations (15-50%) has been observed during specific meteorological events. PMID- 26437355 TI - Cadmium and phosphate variability during algal blooms of the dinoflagellate Lingulodinium polyedrum in Todos Santos Bay, Baja California, Mexico. AB - Dinoflagellate algal blooms (DABs), with Lingulodinium polyedrum as the dominant species, have increased over the past few years in coastal areas off Baja California, Mexico. Vertical and temporal variability of particulate cadmium (Cdp), dissolved Cd (Cdd), PO4(3-) and Cdd/PO4(3-) were investigated during two intense DABs of L. polyedrum that occurred during the fall of 2011 and 2012 in Todos Santos Bay. Results were then, compared with data gathered in the absence of algal blooms during the autumn of 2013. In both algal blooms, L. polyedrum tended to be concentrated near the surface throughout the duration; however, during DAB 2011 the number of cells was twice as abundant ([10.0 +/- 8.0] * 10(5) cells L(-1)) as in DAB 2012 ([5.0 +/- 4.4] * 10(5) cells L(-1)). During DAB 2011, Cdp increased significantly (up to 1.02 +/- 0.99 nmol kg(-1)) and was positively correlated with the cell abundance of L. polyedrum, suggesting that this dinoflagellate is able to assimilate and concentrate Cdd. Likewise, Cdd (up to 0.71 +/- 0.17 nM) increased in the days of highest cell abundance, which could be attributed to uptake and subsequent regeneration of Cdd resulting from the remineralization of organic particulate matter produced during the bloom, as well as with the presence of organic ligands secreted by L. polyedrum that could keep Cdd in solution. During DAB 2011, dissolved Cdd/PO4(3-) ratios exhibited high vertical and temporal variability in the upper 5 m of the water column, but remained virtually constant near the bottom, suggesting a depth-dependent decoupling between these two dissolved components during the bloom development. Given the observed differences in the vertical and temporal variability of Cdd, Cdp, and PO4(3-) between these two intense DABs, we propose the existence of an abundance threshold of approximately 10(6) cells L(-1) of L. polyedrum above which Cd and PO4(3-) significantly increased due to remineralization in coastal waters during the bloom development. PMID- 26437356 TI - The influence of environmental and physiological factors on the litter size of wild boar (Sus scrofa) in an agriculture dominated area in Germany. AB - The wild boar population has increased enormously in all of Europe over the last decades and caused problems like crop damage, transmission of diseases, and vehicle accidents. Therefore, it is necessary to investigate the underlying causes of this increase in order to be able to manage populations effectively. The purpose of this study was to analyse how environmental (food and climate) and physiological factors (maternal weight and age) as well as hunting and population density influence the litter size of wild boar populations in Northern Germany. The mean litter size in the studied population for the whole period was 6.6 (range 1-12), which is one of the highest in all of Europe. Litter size was positively influenced by maternal body weight, higher mast yield of oak as well as higher temperature in combination with higher precipitation in summer. Only higher temperature or only higher precipitation in summer however had a negative effect on litter size production. Probably,weather and food conditions act via maternal bodyweight on the litter size variation in wild boar. Hunting as well a s population density did not affect the litter size variation in this study which might indicate that wild boar population did not reach carrying capacity yet. PMID- 26437357 TI - Reconstruction of centennial-scale fluxes of chemical elements in the Australian coastal environment using seagrass archives. AB - The study of a Posidonia australis sedimentary archive has provided a record of changes in element concentrations (Al, Fe, Mn, Pb, Zn, Cr, Cd, Co, As, Cu, Ni and S) over the last 3000 years in the Australian marine environment. Human-derived contamination in Oyster Harbor (SW Australia) started ~100 years ago (AD ~1900) and exponentially increased until present. This appears to be related to European colonization of Australia and the subsequent impact of human activities, namely mining, coal and metal production, and extensive agriculture. Two contamination periods of different magnitude have been identified: Expansion period (EXP, AD ~1900-1970) and Establishment period (EST, AD ~1970 to present). Enrichments of chemical elements with respect to baseline concentrations (in samples older than ~115 cal years BP) were found for all elements studied in both periods, except for Ni, As and S. The highest enrichment factors were obtained for the EST period (ranging from 1.3-fold increase in Cu to 7.2-fold in Zn concentrations) compared to the EXP period (1.1-fold increase for Cu and Cr to 2.4-fold increase for Pb). Zinc, Pb, Mn and Co concentrations during both periods were 2- to 7-fold higher than baseline levels. This study demonstrates the value of Posidonia mats as long term archives of element concentrations and trends in coastal ecosystems. We also provide preliminary evidence on the potential for Posidonia meadows to act as significant long-term biogeochemical sinks of chemical elements. PMID- 26437358 TI - Examining within-person and between-person effects of victimization and social risk on cannabis use among emerging adults in substance-use treatment. AB - The goals of this study were to examine associations between within- and between person social risk and victimization and cannabis use among emerging adults in substance-use treatment. We also tested gender differences for both victimization and social risk. Participants consisted of 3,052 emerging adults (M(age) = 20.0 years; SD = 2.21) entering substance-use treatment in a wide range of treatment centers across the United States. Individuals were assessed on all measures at baseline 3, 6, and 12 months. We fitted a taxonomy of multilevel growth curve models to test main effects, and interactive relations between within- and between-person social risk, victimization, and gender on cannabis use. Several significant interactions were evident. Irrespective of gender, within-person increases in social risk were associated with contemporaneous increases in cannabis use; however, the magnitude of this relation was comparatively more pronounced for men. Similar gender differences emerged between individuals. Males experiencing heightened social risk over time tended to show high levels of early cannabis use. Simple slope analyses revealed that reporting more (+1 SD) social risk than one's own mean resulted in significant increases in cannabis use for both men and women. Cross-level simple slope analyses revealed no differences in cannabis use among individuals reporting low (-1 SD) social risk and victimization, but significant increases in cannabis use for individuals reporting high (+ 1 SD) victimization and social risk. Results demonstrate support for gender differences in social risk on cannabis use and the importance of considering within-person effects. (PsycINFO Database Record PMID- 26437360 TI - Islands contribute disproportionately high amounts of evolutionary diversity in passerine birds. AB - Island systems generally have fewer species than continental areas due to their small size and geographical isolation. Low island diversity reduces the possibility of exportation of island lineages and island systems are not thought to have a major influence on the build-up of continental diversity. However, the view that islands represent the end of the colonization road has recently been challenged and islands do represent the origin of some specific continental lineages. Here we assess the net contribution of island systems to global diversity patterns of passerine birds, using a complete phylogeny (5,949 species), biogeographical regionalization and null-model comparisons. We show that, in contrast to major continental regions, island regions export relatively more evolutionary lineages than would be expected based on current distributional patterns. This result challenges a central paradigm in island biogeography and changes our perception of the relative importance of islands for the build-up of global diversity. PMID- 26437359 TI - Change over time in adolescent and friend alcohol use: Differential associations for youth with and without childhood attention-deficit/hyperactivity disorder (ADHD). AB - Individuals with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for experiencing alcohol-related problems by adulthood. However, few studies have examined contextual factors that may contribute to this risk. The current study examined 1 widely investigated social-contextual risk factor, friend alcohol use, in a sample of adolescents with and without a history of ADHD. One hundred and 59 adolescents (14-17 years old) with childhood ADHD and 117 demographically similar youth without ADHD were interviewed annually in the Pittsburgh ADHD Longitudinal Study. Adolescents reported the frequency of their own alcohol use in the prior 12 months and the number of friends who used alcohol regularly or occasionally (perceived friend alcohol use). Multiple-group parallel process models indicated that increases in friend alcohol use were more strongly associated with increases in adolescent alcohol use over time for individuals with ADHD (r = .15, SE = 0.04; 95% confidence interval [CI] = [0.08, 0.22]) than for those without ADHD (r = .06, SE = 0.03; 95% CI [0.00, 0.11]). These results suggest that social factors are an important part of escalating alcohol use among adolescents with ADHD histories, and they highlight the possibility that interventions focused on the peer context could be important for these at-risk youth. Additional social network research on adolescent alcohol use within the larger context of other relationships (e.g., family and romantic relationships) is indicated. PMID- 26437361 TI - Quantifying Neonicotinoid Insecticide Residues Escaping during Maize Planting with Vacuum Planters. AB - Neonicotinoid residues escaping in vacuum-planter exhaust during maize planting were measured in 25 fields in southwestern Ontario in 2013-2014 using filter bags to collect planter exhaust dust and horizontal and vertical sticky traps to collect planter operation-generated dust. Atrazine residues were used to differentiate between neonicotinoid residues originating from seed or from disturbed soil. Recovery rates of seed-applied neonicotinoids in exhaust were 0.014 and 0.365% in 2013 and 2014, respectively, calculated on the basis of neonicotinoid concentrations in preplant soil and seed application rates. Neonicotinoid exhaust emission rates were 0.0036 and 0.1104 g/ha for 2013 and 2014, respectively, with 99.9472 and 99.7820% originating from treated seed in 2013 and 2014, respectively, calculated on the basis of the atrazine marker. Rates of recovery of seed-applied neonicotinoid residues by exhaust filter bags were 0.015 and 0.437% for 2013 and 2014, respectively. Neonicotinoid residues captured on horizontal and vertical traps were 1.10 ng/cm2 (0.1104 g/ha) and 1.45 ng/cm2 (0.0029 g/ha), respectively, with 92.31 and 93.03% originating from treated seed, respectively, representing 0.3896% of the original active ingredient applied to the seed planted. Exposure to pollinators can be best reduced by strategies to keep active ingredient on the seed, below the soil surface, and in the field where applied. PMID- 26437362 TI - Enantioselective 1,2-Difunctionalization of Dienes Enabled by Chiral Palladium Complex-Catalyzed Cascade Arylation/Allylic Alkylation Reaction. AB - A Pd-catalyzed highly enantioselective three-component coupling of 1,3-dienes with aryl iodines and sodium dialkyl malonates has been successfully established by using a H8-BINOL-based phosphoramidite ligand. This reaction proceeded via a Pd-catalyzed cascade arylation and asymmetric allylic alkylation reaction, providing an efficient strategy for the enantioselective 1,2-difunctionalization of 1,3-dienes. PMID- 26437363 TI - Mitoepigenetics: The different shades of grey. AB - Epigenetic modifications of the nuclear genome have been well studied and it is established that these modifications play a key role in nuclear gene expression. However, the status of mitochondrial epigenetic modifications has not been delved in detail. The recent technological advancements in the genome analyzing tools and techniques, have helped in investigating mitochondrial epigenetic modifications with greater resolution and studies have indicated a regulatory role of the mitochondrial epigenome. Association of mitochondrial DNA methylation with various disease conditions, drug treatment, aging, exposure to environmental pollutants etc. has lent credence to this belief. Herein, we have reviewed studies on mitochondrial epigenetic modifications with a focus to comprehend its regulatory role in gene expression and disease association. PMID- 26437364 TI - Regulation of mitochondrial biogenesis through TFAM-mitochondrial DNA interactions: Useful insights from aging and calorie restriction studies. AB - Mitochondrial biogenesis is regulated to adapt mitochondrial population to cell energy demands. Mitochondrial transcription factor A (TFAM) performs several functions for mtDNA and interactions between TFAM and mtDNA participate to regulation of mitochondrial biogenesis. Such interactions are modulated through different mechanisms: regulation of TFAM expression and turnover, modulation of TFAM binding activity to mtDNA through post-translational modifications and differential affinity of TFAM, occurrence of TFAM sliding on mtDNA filaments and of cooperative binding among TFAM molecules, modulation of protein-protein interactions. The tissue-specific regulation of mitochondrial biogenesis in aging and calorie restriction (CR) highlights the relevance of modulation of TFAM-mtDNA interactions. PMID- 26437367 TI - A lab-on-a-chip-based multiplex platform to detect potential fraud of introducing pig, dog, cat, rat and monkey meat into the food chain. AB - Food forgery has posed considerable risk to public health, religious rituals, personal budget and wildlife. Pig, dog, cat, rat and monkey meat are restricted in most religions, but their sporadic adulteration are rampant. Market controllers need a low-cost but reliable technique to track and trace suspected species in the food chain. Considering the need, here we documented a lab-on-a chip-based multiplex polymerase chain reaction (PCR) assay for the authentication of five non-halal meat species in foods. Using species-specific primers, 172, 163, 141, 129 and 108-bp sites of mitochondrial ND5, ATPase 6 and cytochrome b genes were amplified to detect cat, dog, pig, monkey and rat species under complex matrices. Species-specificity was authenticated against 20 different species with the potential to be used in food. The targets were stable under extreme sterilisation (121 degrees C at 45 psi for 2.5 h) which severely degrades DNA. The assay was optimised under the backgrounds of various commercial meat products and validated for the analysis of meatballs, burgers and frankfurters, which are popular fast food items across the globe. The assay was tested to detect 0.1% suspected meats under commercial backgrounds of marketed foods. Instead of simplex PCR which detects only one species at a time, such a multiplex platform can reduce cost by at least fivefolds by detecting five different species in a single assay platform. PMID- 26437368 TI - Meta-analysis of problem solving therapy for the treatment of major depressive disorder in older adults. AB - OBJECTIVE: Major depressive disorder (MDD) affects many older adults and is associated with poor medical and mental health outcomes. Problem Solving Therapy (PST) has emerged as a promising psychotherapy for MDD in older adults, although the efficacy of PST in this population has not been well described. We examined the effectiveness of PST for the treatment of MDD in older adults in a systematic review and meta-analysis. METHODS: We searched electronic databases to identify randomized controlled trials comparing PST to a control condition or other treatment for MDD in adults with an average age of 60 years or older. We used meta-analysis to arrive at pooled summary measures of the efficacy of PST when compared to control conditions on the change in depressive symptoms and other outcomes. RESULTS: Nine studies with a total of 569 participants (290 PST, 279 control) met inclusion criteria. Most studies administered PST in person and were between 6 and 12 weeks in duration. Meta-analysis of six studies evaluating the effect of PST on depression using the Hamilton Rating Scale for Depression identified a significant reduction in depression associated with PST (pooled mean difference = -6.94, 95%CI -10.91 to -2.97, d = 1.15, P = 0.0006). PST was also effective in reducing disability in studies reporting this outcome. CONCLUSIONS: Our review supports the existing research literature on PST suggesting that it is an effective treatment for older people with MDD. Further study is required to understand long-term outcomes associated with PST and its efficacy when compared to other treatments. PMID- 26437366 TI - Loss of BAP1 function leads to EZH2-dependent transformation. AB - The tumor suppressors BAP1 and ASXL1 interact to form a polycomb deubiquitinase complex that removes monoubiquitin from histone H2A lysine 119 (H2AK119Ub). However, BAP1 and ASXL1 are mutated in distinct cancer types, consistent with independent roles in regulating epigenetic state and malignant transformation. Here we demonstrate that Bap1 loss in mice results in increased trimethylated histone H3 lysine 27 (H3K27me3), elevated enhancer of zeste 2 polycomb repressive complex 2 subunit (Ezh2) expression, and enhanced repression of polycomb repressive complex 2 (PRC2) targets. These findings contrast with the reduction in H3K27me3 levels seen with Asxl1 loss. Conditional deletion of Bap1 and Ezh2 in vivo abrogates the myeloid progenitor expansion induced by Bap1 loss alone. Loss of BAP1 results in a marked decrease in H4K20 monomethylation (H4K20me1). Consistent with a role for H4K20me1 in the transcriptional regulation of EZH2, expression of SETD8-the H4K20me1 methyltransferase-reduces EZH2 expression and abrogates the proliferation of BAP1-mutant cells. Furthermore, mesothelioma cells that lack BAP1 are sensitive to EZH2 pharmacologic inhibition, suggesting a novel therapeutic approach for BAP1-mutant malignancies. PMID- 26437365 TI - MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. AB - The hepatic low-density lipoprotein receptor (LDLR) pathway is essential for clearing circulating LDL cholesterol (LDL-C). Whereas the transcriptional regulation of LDLR is well characterized, the post-transcriptional mechanisms that govern LDLR expression are just beginning to emerge. Here we develop a high throughput genome-wide screening assay to systematically identify microRNAs (miRNAs) that regulate LDLR activity in human hepatic cells. From this screen we identified and characterized miR-148a as a negative regulator of LDLR expression and activity and defined a sterol regulatory element-binding protein 1 (SREBP1) mediated pathway through which miR-148a regulates LDL-C uptake. In mice, inhibition of miR-148a increased hepatic LDLR expression and decreased plasma LDL C. Moreover, we found that miR-148a regulates hepatic expression of ATP-binding cassette, subfamily A, member 1 (ABCA1) and circulating high-density lipoprotein cholesterol (HDL-C) levels in vivo. These studies uncover a role for miR-148a as a key regulator of hepatic LDL-C clearance through direct modulation of LDLR expression and demonstrate the therapeutic potential of inhibiting miR-148a to ameliorate an elevated LDL-C/HDL-C ratio, a prominent risk factor for cardiovascular disease. PMID- 26437369 TI - JC polyomavirus viremia and progressive multifocal leukoencephalopathy in human leukocyte antigen-sensitized kidney transplant recipients desensitized with intravenous immunoglobulin and rituximab. AB - BACKGROUND: Desensitization (DES) with intravenous immunoglobulin (IVIG) + rituximab is effective, safe, and increases the transplantation rate in human leukocyte antigen-sensitized patients. However, reports of progressive multifocal leukoencephalopathy (PML) caused by JC polyomavirus (JCPyV) in autoimmune patients treated with rituximab is concerning. Here, we report on the JCPyV viremia and PML status in kidney transplant patients with/without DES (non-DES). METHODS: In total 1195 and 699 DNA samples from plasma in 117 DES (78% lymphocyte depleting [LyD] induction) and 100 non-DES patients (45% LyD), respectively, were submitted for JCPyV-polymerase chain reaction. Results were compared in both groups. RESULTS: No patients in either DES or non-DES developed PML or presented with any neurological symptoms. The JCPyV viremia rate was similar in DES and non DES patients (3/117 vs. 9/100, P = 0.07). The JCPyV levels were low (median peak levels, 1025 copies/mL) and JCPyV viremia was observed only once during the study period in most patients. All 3 DES patients with JCPyV(+) received 1 dose rituximab and no DES patients with >1 dose rituximab showed JCPyV(+). All 3 JCPyV(+) DES patients received LyD induction, while only 2 of 9 JCPyV(+) non-DES patients did so, and the remaining 7 received non-LyD or no induction. JCPyV in leukocyte was mostly negative in DES and non-DES patients. Immunosuppression in patients with or without JCPyV(+) was similar. BK polyomavirus viremia was observed more commonly in patients with JCPyV(+) than in those without (P < 0.02). CONCLUSIONS: Patients with IVIG + rituximab DES followed by transplantation with LyD induction and additional rituximab rarely show JCPyV viremia and appear at low risk for PML. PMID- 26437370 TI - CT-Based Morphological Analysis of Isolated Inferior and Medial Blow-out Orbital Fractures in Korean Adults. AB - PURPOSE: To evaluate morphologic differences in isolated inferior medial orbital wall fractures (OWF) based on computed tomography scans. METHODS: This was a retrospective observational case study of 22 patients with an isolated inferior OWF and 32 patients with an isolated medial fracture between January 2008 and August 2010. We analyzed patient demographics and bony radiologic characteristics on CT scans, including the length and height of the lamina papyracea, the number of ethmoid air cell septa, the length of the anterior and posterior border of the orbital floor, the thickness of the orbital floor maxillary bone, and the axial length of the eyeball. RESULTS: There were no significant differences in sex, laterality, or concomitant intraocular injury between the two groups. The anteroposterior length (p = 0.391), the number of ethmoid septa (p = 0.869), and the thickness of the orbital floor (p = 0.419) did not differ significantly. The anterior (p < 0.001) or posterior (p = 0.014) height of the lamina papyracea, the lamina papyracea area (p < 0.001), and the lamina papyracea area/ethmoid air cell septa (p = 0.024) were significantly higher in the medial OWF group, while the anterior (p = 0.026) or posterior (p < 0.001) border length of the orbital floor and the axial length (p = 0.047) and volume (p = 0.034) of the eyeball were longer and smaller, respectively, in the inferior OWF group. CONCLUSIONS: Patients with a longer anterior or posterior border of the orbital floor, a shorter axial length, and a smaller eyeball volume are more likely to incur an isolated inferior OWF than an isolated medial OWF. PMID- 26437371 TI - Nonpolar m-plane GaN/AlGaN heterostructures with intersubband transitions in the 5-10 THz band. AB - This paper assesses intersubband (ISB) transitions in the 1-10 THz frequency range in nonpolar m-plane GaN/AlGaN multi-quantum-wells deposited on free standing semi-insulating GaN substrates. The quantum wells (QWs) were designed to contain two confined electronic levels, decoupled from the neighboring wells. Structural analysis reveals flat and regular QWs in the two perpendicular in plane directions, with high-angle annular dark-field scanning transmission electron microscopy images showing inhomogeneities of the Al composition in the barriers along the growth axis. We do not observe extended structural defects (stacking faults or dislocations) introduced by the epitaxial process. Low temperature ISB absorption from 1.5 to 9 THz (6.3-37.4 meV) is demonstrated, covering most of the 7-10 THz band forbidden to GaAs-based technologies. PMID- 26437373 TI - The effect of antiepileptic drugs on thyroid hormonal function: causes and implications. AB - Epilepsy is a chronic disease and its treatment is lifelong in one-third of patients. Data from cross-sectional and prospective studies have reviewed the influence of antiepileptic drugs (AEDs) on thyroid hormones. Thyroid abnormalities were reported in one-third of the patients on AEDs. Subclinical hypothyroidism, reduced thyroxine, triiodothyronine, free thyroxine, free triiodothyronine and thyroid binding globulin concentrations were reported with phenobarbital, phenytoin, carbamazepine, valproate and oxcarbazepine, but not with lamotrigine, levitracetam, tiagabine and vigabatrine. All reported patients were clinically euthyroid and hormonal changes were reversible after AED withdrawal. The mechanisms for thyroid dysfunction with AEDs include enhanced metabolism and/or altered protein binding or interference of hypothalamic pituitary-thyroid axis function. This review focuses on the evidence, mechanisms of thyroid abnormalities with AEDs and their clinical implications. The associations between subclinical hypothyroidism and metabolic risks due to AEDs are also discussed. PMID- 26437372 TI - Reconciling Estimates of Cell Proliferation from Stable Isotope Labeling Experiments. AB - Stable isotope labeling is the state of the art technique for in vivo quantification of lymphocyte kinetics in humans. It has been central to a number of seminal studies, particularly in the context of HIV-1 and leukemia. However, there is a significant discrepancy between lymphocyte proliferation rates estimated in different studies. Notably, deuterated (2)H2-glucose (D2-glucose) labeling studies consistently yield higher estimates of proliferation than deuterated water (D2O) labeling studies. This hampers our understanding of immune function and undermines our confidence in this important technique. Whether these differences are caused by fundamental biochemical differences between the two compounds and/or by methodological differences in the studies is unknown. D2 glucose and D2O labeling experiments have never been performed by the same group under the same experimental conditions; consequently a direct comparison of these two techniques has not been possible. We sought to address this problem. We performed both in vitro and murine in vivo labeling experiments using identical protocols with both D2-glucose and D2O. This showed that intrinsic differences between the two compounds do not cause differences in the proliferation rate estimates, but that estimates made using D2-glucose in vivo were susceptible to difficulties in normalization due to highly variable blood glucose enrichment. Analysis of three published human studies made using D2-glucose and D2O confirmed this problem, particularly in the case of short term D2-glucose labeling. Correcting for these inaccuracies in normalization decreased proliferation rate estimates made using D2-glucose and slightly increased estimates made using D2O; thus bringing the estimates from the two methods significantly closer and highlighting the importance of reliable normalization when using this technique. PMID- 26437374 TI - Anxiety and retrieval inhibition: support for an enhanced inhibition account. AB - Retrieval inhibition of negative associations is important for exposure therapy for anxiety, but the relationship between memory inhibition and anxiety is not well understood-anxiety could either be associated with enhanced or deficient inhibition. The present study tested these two competing hypotheses by measuring retrieval inhibition of negative stimuli by related neutral stimuli. Non clinically anxious undergraduates completed measures of trait and state anxiety and completed a retrieval induced forgetting task. Adaptive forgetting varied with state anxiety. Low levels of state anxiety were associated with no evidence for retrieval inhibition for either threatening or non-threatening categories. Participants in the middle tertile of state anxiety scores exhibited retrieval inhibition for non-threatening categories but not for threatening categories. Participants in the highest tertile of state anxiety, however, exhibited retrieval inhibition for both threatening and non-threatening categories with the magnitude of retrieval inhibition being greater for threatening than non threatening categories. The data are in line with the avoidance aspect of the vigilance-avoidance theory of anxiety and inhibition. Implications for cognitive behavioural therapy practices are discussed. PMID- 26437375 TI - Cytokines in Neuropathic Pain and Associated Depression. AB - Neuropathic pain occurs as a result of lesion or disease affecting the somatosensory nervous system and is present in a diverse set of peripheral and central pathologies such as nerve trauma, diabetic neuropathy, post-herpetic neuralgia, chemotherapy-induced peripheral neuropathy, spinal cord injury and multiple sclerosis. Debilitating symptoms including allodynia, hyperalgesia and spontaneous pain have a substantial negative impact on patients' quality of life. The currently available therapeutic treatments are generally ineffective and characterised by poor response rates. Accumulating evidence suggests that neuroinflammation and cytokine signalling play a critical role in neuropathic pain. Numerous experimental studies have demonstrated that certain pro inflammatory cytokines are elevated in neuropathic pain conditions, and administration of these cytokines can elicit pain hypersensitivity in the absence of injury or disease. This phenomenon is also apparent in the 'sickness response', which encompasses a broad inflammatory response to disease and injury and involves a series of physiological and behavioural changes including pain hypersensitivity. Interestingly, the 'sickness response' is also similar in nature to some of the defining characteristics of the depressed state of affective disorder. In this review, we explore links that may relate the co existence of depression in neuropathic pain patients with the activity of cytokines and discuss the role of several key pro-inflammatory and anti inflammatory cytokines in neuropathic pain. PMID- 26437376 TI - Effect of scavenger receptor class B type I antagonist ITX5061 in patients with hepatitis C virus infection undergoing liver transplantation. AB - Hepatitis C virus (HCV) entry inhibitors have been hypothesized to prevent infection of the liver after transplantation. ITX5061 is a scavenger receptor class B type I antagonist that blocks HCV entry and infection in vitro. We assessed the safety and efficacy of ITX5061 to limit HCV infection of the graft. The study included 23 HCV-infected patients undergoing liver transplantation. The first 13 "control" patients did not receive drug. The subsequent 10 patients received 150 mg of ITX5061 immediately before and after transplant and daily for 1 week thereafter. ITX5061 pharmacokinetics and plasma HCV RNA were quantified. Viral genetic diversity was measured by ultradeep pyrosequencing (UDPS). ITX5061 was well tolerated with measurable plasma concentrations during therapy. Although the median HCV RNA reduction was greater in ITX-treated patients at all time points in the first week after transplantation, there was no difference in the overall change in the area over the HCV RNA curve in the 7-day treatment period. However, in genotype (GT) 1-infected patients, treatment was associated with a sustained reduction in HCV RNA levels compared to the control group (area over the HCV RNA curve analysis, P = 0.004). UDPS revealed a complex and evolving pattern of HCV variants infecting the graft during the first week. ITX5061 significantly limited viral evolution where the median divergence between day 0 and day 7 was 3.5% in the control group compared to 0.1% in the treated group. In conclusion, ITX5061 reduces plasma HCV RNA after transplant notably in GT 1 infected patients and slows viral evolution. Following liver transplantation, the likely contribution of extrahepatic reservoirs of HCV necessitates combining entry inhibitors such as ITX5061 with inhibitors of replication in future studies. PMID- 26437378 TI - Enzyme-Powered Hollow Mesoporous Janus Nanomotors. AB - The development of synthetic nanomotors for technological applications in particular for life science and nanomedicine is a key focus of current basic research. However, it has been challenging to make active nanosystems based on biocompatible materials consuming nontoxic fuels for providing self-propulsion. Here, we fabricate self-propelled Janus nanomotors based on hollow mesoporous silica nanoparticles (HMSNPs), which are powered by biocatalytic reactions of three different enzymes: catalase, urease, and glucose oxidase (GOx). The active motion is characterized by a mean-square displacement (MSD) analysis of optical video recordings and confirmed by dynamic light scattering (DLS) measurements. We found that the apparent diffusion coefficient was enhanced by up to 83%. In addition, using optical tweezers, we directly measured a holding force of 64 +/- 16 fN, which was necessary to counteract the effective self-propulsion force generated by a single nanomotor. The successful demonstration of biocompatible enzyme-powered active nanomotors using biologically benign fuels has a great potential for future biomedical applications. PMID- 26437377 TI - Effect of Roux-en-Y Gastric Bypass on the NLRP3 Inflammasome in Adipose Tissue from Obese Rats. AB - OBJECTIVE: Obesity is associated with low-grade chronic inflammation. We hypothesized that Roux-en-Y gastric bypass (RYGB) surgery would reduce activation of the NLRP3 inflammasome in metabolically active adipose tissue (AT) of obese rats, and this change would be related to decreases in body weight and improved glycemic control. METHODS: Omental, mesenteric and subcutaneous fat depots were collected from Sprague-Dawley rats: Sham control and RYGB; 90-days after surgery. NLRP3, caspase-1, apoptosis-associated speck-like protein (ASC), IL-1beta, IL-18, IL-6 and MCP-1 gene and protein expression were quantified. Glucose metabolism was assessed by oral glucose tolerance test (OGTT). RESULTS: Compared to Sham surgery controls, RYGB surgery decreased IL-6, MCP-1, NLRP3, IL-18, caspase-1 and ASC in omental fat, and decreased IL-6, MCP1, IL-1beta, IL-18, caspase-1 and ASC gene expression in mesenteric fat. We observed differential gene expression between visceral and subcutaneous fat for IL-6 and IL-1beta, both being downregulated by RYGB in visceral, and upregulated in subcutaneous depots. These changes in gene expression were accompanied by a decrease in NLRP3, ASC, IL-18, caspase-1 and IL-1beta protein expression in omental tissue. We found a positive correlation between caspase-1, ASC, MCP-1, IL-18 and IL-6 gene expression following surgery and glucose AUC response in omental fat, while the change in glucose AUC response correlated with caspase-1 gene expression in subcutaneous fat. CONCLUSION: This study demonstrates that bariatric surgery reverses inflammation in visceral adipose tissue by suppressing NLRP3 inflammasome activation. These are the first data to implicate the NLRP3 inflammasome in diabetes remission after RYGB surgery. PMID- 26437379 TI - Neuroprotective effects of crocin against oxidative stress induced by ischemia/reperfusion injury in rat retina. AB - AIMS: Crocin, a pharmacologically active component of Crocus sativus L. (saffron), has been reported to be useful in the treatment of oxidative stress injury. In the present study, we investigated the antioxidative effect of crocin and the change of the ERK signaling pathway on rat retina induced by ischemia/reperfusion (IR) injury. METHODS: Crocin was pretreated 30 min before and once daily after retinal IR injury by intraperitoneal injection. The retinal morphological damage was observed by hematoxylin and eosin (HE) staining. The number of retinal ganglion cells (RGCs) was counted by Brn-3a immunofluorescence staining. The antiapoptotic effect of crocin was determined by detecting cleaved caspase-3 protein levels by means of Western blot and immunohistochemical analysis. Furthermore, retinas were also used for the determination of malondialdehyde (MDA) levels, glutathione (GSH) levels, total superoxide dismutase (T-SOD), and reactive oxygen species (ROS). The phosphorylated ERK (p ERK) protein level was determined by Western blot and immunohistochemical analysis. RESULTS: Our results showed that crocin treatment (50 mg/kg) significantly inhibited the decrease of retinal thickness through HE staining and protected RGCs from decreasing. Compared with the IR + vehicle group, crocin treatment significantly decreased cleaved caspase-3 and p-ERK protein expression by Western blot analysis and immunohistochemistry. Immunohistochemical staining for cleaved caspase-3 and p-ERK in the retinal sections showed positive cells were present in the RGC layer and inner nuclear layer after IR injury. Similarly, crocin (50 mg/kg) treatment also significantly increased the level of activity of GSH, enhanced the activity of T-SOD, and decreased the activity level of ROS and MDA after IR injury. CONCLUSIONS: These findings demonstrated that crocin treatment could notably protect the retina from damage induced by IR. It might be related to crocin antioxidant and antiapoptotic properties in the retina. PMID- 26437381 TI - Mesenchymal stem cells as novel micro-ribonucleic acid delivery vehicles in kidney disease. AB - MicroRNAs (miRNAs) are short single strands of RNA responsible for post transcriptional regulation of gene expression and have been implicated in the pathogenesis of chronic kidney disease (CKD). Emerging evidence reports that miRNAs can reduce kidney fibrosis through regulation of targets associated with collagen and extracellular matrix accumulation. However, the development of miRNA therapies has been hampered by the lack of targeted and sustainable methods of systemic miRNA delivery. Mesenchymal stem cells (MSCs) provide a promising miRNA delivery platform to overcome toxicity, the potential for insertional mutations and the low efficiency of previous methods. MSCs are endogenously immunoprivileged and home to sites of inflammation. They also release trophic growth factors to modulate the immune system, alter the polarization of macrophages and provide renal protection and repair. The potential to engineer MSCs to express or overexpress miRNAs, released by exosomes, may enhance their natural functions. Clinical studies are already being conducted individually for the use of miRNAs in cancer and MSCs in diseases associated with CKD. Hence, the combination of miRNAs and MSCs may provide an unparalleled cell-based therapy for treating CKD. PMID- 26437380 TI - Anti-Apoptotic Effects of 3,3',5-Triiodo-L-Thyronine in the Liver of Brain-Dead Rats. AB - BACKGROUND: Thyroid hormone treatment in brain-dead organ donors has been extensively studied and applied in the clinical setting. However, its clinical applicability remains controversial due to a varying degree of success and a lack of mechanistic understanding about the therapeutic effects of 3,3',5-Triiodo-L thyronine (T3). T3 pre-conditioning leads to anti-apoptotic and pro-mitotic effects in liver tissue following ischemia/reperfusion injury. Therefore, we aimed to study the effects of T3 pre-conditioning in the liver of brain-dead rats. METHODS: Brain death (BD) was induced in mechanically ventilated rats by inflation of a Fogarty catheter in the epidural space. T3 (0.1 mg/kg) or vehicle was administered intraperitoneally 2 h prior to BD induction. After 4 h of BD, serum and liver tissue were collected. RT-qPCR, routine biochemistry, and immunohistochemistry were performed. RESULTS: Brain-dead animals treated with T3 had lower plasma levels of AST and ALT, reduced Bax gene expression, and less hepatic cleaved Caspase-3 activation compared to brain-dead animals treated with vehicle. Interestingly, no differences in the expression of inflammatory genes (IL-6, MCP-1, IL-1beta) or the presence of pro-mitotic markers (Cyclin-D and Ki 67) were found in brain-dead animals treated with T3 compared to vehicle-treated animals. CONCLUSION: T3 pre-conditioning leads to beneficial effects in the liver of brain-dead rats as seen by lower cellular injury and reduced apoptosis, and supports the suggested role of T3 hormone therapy in the management of brain-dead donors. PMID- 26437382 TI - Modification of a Colliculo-thalamocortical Mouse Brain Slice, Incorporating 3-D printing of Chamber Components and Multi-scale Optical Imaging. AB - The ability of the brain to process sensory information relies on both ascending and descending sets of projections. Until recently, the only way to study these two systems and how they interact has been with the use of in vivo preparations. Major advances have been made with acute brain slices containing the thalamocortical and cortico-thalamic pathways in the somatosensory, visual, and auditory systems. With key refinements to our recent modification of the auditory thalamocortical slice(1), we are able to more reliably capture the projections between most of the major auditory midbrain and forebrain structures: the inferior colliculus (IC), medial geniculate body (MGB), thalamic reticular nucleus (TRN), and the auditory cortex (AC). With portions of all these connections retained, we are able to answer detailed questions that complement the questions that can be answered with in vivo preparations. The use of flavoprotein autofluorescence imaging enables us to rapidly assess connectivity in any given slice and guide the ensuing experiment. Using this slice in conjunction with recording and imaging techniques, we are now better equipped to understand how information processing occurs at each point in the auditory forebrain as information ascends to the cortex, and the impact of descending cortical modulation. 3-D printing to build slice chamber components permits double-sided perfusion and broad access to networks within the slice and maintains the widespread connections key to fully utilizing this preparation. PMID- 26437383 TI - Extinction and spontaneous recovery of spatial behavior in pigeons. AB - We investigated extinction and spontaneous recovery of spatial associations using a landmark-based appetitive search task in a touchscreen preparation with pigeons. Four visual landmarks (A, B, C, and D) were separately established as signals of a hidden reinforced target among an 8 * 7 array of potential target locations. The target was located above landmarks (LM) A and C and below B and D. After conditioning, A and B were extinguished. Responding to A and C was assessed on probe tests 2 days following extinction, whereas, B and D were tested 14 days after extinction. We observed spontaneous recovery from spatial extinction following a 14-day, but not a 2-day, postextinction retention interval. Furthermore, by plotting the spatial distribution of responding across the X and Y axes during testing, we found that spontaneous recovery of responding to the target in our task was due to enhanced spatial control (i.e., a change in the overall distribution of responses) following the long delay to testing. These results add spatial extinction and spontaneous recovery to the list of findings supporting the assertion that extinction involves new learning that attenuates the originally acquired response, and that original learning of the spatial relationship between paired events survives extinction. (PsycINFO Database Record PMID- 26437384 TI - Responses compete and collaborate, shaping each others' distributions: Commentary on Boakes, Patterson, Kendig, and Harris (2015). AB - Boakes, Patterson, Kendig, and Harris (2015) showed that schedule-induced drinking (SID), typically concentrated in the first half of the interpellet interval, is not moved there exclusively by competition from magazine entries, and that not all arbitrary responses can be maintained by adventitious reinforcement. They attribute such inferences to Killeen and Pellon (2013) and Patterson and Boakes (2012), and on that basis reject their explanation for the excessive nature of many adjunctive responses as a result of reinforcement. It is a mistaken attribution, as Killeen and Pellon emphasized that reinforcers act on many competing interim and terminal responses. That attribution is a minor oversight on the authors' part; their return to a discredited motivational account is, however, a major blunder. It discards the seminal recent advances in understanding the nature of schedule-induced responses (e.g., those of Patterson and Boakes), and even the positive contributions of their own article: Their data show very strong correlations between magazine entries and drinking, providing much more evidence for response competition than their microanalysis provides against it. PMID- 26437385 TI - Reply to Pellon and Killeen's (2015) commentary on Boakes, Patterson, Kendig, and Harris (2015). AB - This reply notes the importance of data from variable-time schedules for resolving the issue of whether competition from magazine approach behavior is a major factor responsible for the concentration of schedule-induced drinking early in interpellet intervals. Pellon and Killeen propose that this temporal distribution of schedule-induced drinking reflects the effectiveness of adventitious reinforcement of this behavior over a delay, as detailed in their model. However, there is no evidence to support either of their key assumptions: (a) that schedule-induced behaviors are maintained by adventitious reinforcement ("are operants") and (b) that behaviors vary in their sensitivity to a delay before the subsequent occurrence of a reinforcer. PMID- 26437386 TI - Disparities in Time Spent Seeking Medical Care in the United States. PMID- 26437387 TI - Amyotrophic lateral sclerosis progression: Iran-ALS clinical registry, a multicentre study. AB - This study was designed to evaluate ALS progression among different subgroups of Iranian patients. Three hundred and fifty-eight patients from centres around the country were registered and their progression rate was evaluated using several scores including Manual Muscle Test scoring (MMT) and the revised ALS Functional Rating Scale (ALSFRS-R). Progression rate was analysed separately in subgroups regarding gender, onset site, stage of disease and riluzole consumption. A significant difference in MMT deterioration rate (p = 0.01) was noted between those who used riluzole and those who did not. No significant difference was observed in progression rates between male/female and bulbar-onset/limb-onset groups using riluzole. In conclusion, riluzole has a significant effect on muscle force deterioration rate but not functional scale. Progression rate was not influenced by site of onset or gender. PMID- 26437389 TI - Ionic Liquid-Based Ultrasonic-Assisted Extraction of Secoisolariciresinol Diglucoside from Flaxseed (Linum usitatissimum L.) with Further Purification by an Aqueous Two-Phase System. AB - In this work, a two-step extraction methodology of ionic liquid-based ultrasonic assisted extraction (IL-UAE) and ionic liquid-based aqueous two-phase system (IL ATPS) was developed for the extraction and purification of secoisolariciresinol diglucoside (SDG) from flaxseed. In the IL-UAE step, several kinds of ILs were investigated as the extractants, to identify the IL that affords the optimum extraction yield. The extraction conditions such as IL concentration, ultrasonic irradiation time, and liquid-solid ratio were optimized using response surface methodology (RSM). In the IL-ATPS step, ATPS formed by adding kosmotropic salts to the IL extract was used for further separation and purification of SDG. The most influential parameters (type and concentration of salt, temperature, and pH) were investigated to obtain the optimum extraction efficiency. The maximum extraction efficiency was 93.35% under the optimal conditions of 45.86% (w/w) IL and 8.27% (w/w) Na2SO4 at 22 degrees C and pH 11.0. Thus, the combination of IL UAE and IL-ATPS makes up a simple and effective methodology for the extraction and purification of SDG. This process is also expected to be highly useful for the extraction and purification of bioactive compounds from other important medicinal plants. PMID- 26437390 TI - Therapeutic Oligonucleotides Targeting Liver Disease: TTR Amyloidosis. AB - The liver has become an increasingly interesting target for oligonucleotide therapy. Mutations of the gene encoding transthyretin (TTR), expressed in vast amounts by the liver, result in a complex degenerative disease, termed familial amyloid polyneuropathy (FAP). Misfolded variants of TTR are linked to the establishment of extracellular protein deposition in various tissues, including the heart and the peripheral nervous system. Recent progress in the chemistry and formulation of antisense (ASO) and small interfering RNA (siRNA) designed for a knockdown of TTR mRNA in the liver has allowed to address the issue of gene specific molecular therapy in a clinical setting of FAP. The two therapeutic oligonucleotides bind to RNA in a sequence specific manner but exploit different mechanisms. Here we describe major developments that have led to the advent of therapeutic oligonucleotides for treatment of TTR-related disease. PMID- 26437391 TI - Comparative Studies on Phenolic Composition, Antioxidant, Wound Healing and Cytotoxic Activities of Selected Achillea L. Species Growing in Turkey. AB - Turkey is one of the most important centers of diversity for the genus Achillea L. in the world. Keeping in mind the immense medicinal importance of phenols, in this study, three species growing in Turkey, A. coarctata Poir. (AC), A. kotschyi Boiss. subsp. kotschyi (AK) and A. lycaonica Boiss. & Heldr. (AL) were evaluated for their phenolic compositions, total phenolic contents (TPC), antioxidant properties, wound healing potencies on NIH-3T3 fibroblasts and cytotoxic effects on MCF-7 human breast cancer cells. Comprehensive LC-MS/MS analysis revealed that AK was distinctively rich in chlorogenic acid, hyperoside, apigenin, hesperidin, rutin, kaempferol and luteolin (2890.6, 987.3, 797.0, 422.5, 188.1, 159.4 and 121.2 ug analyte/g extract, respectively). The findings exhibited a strong correlation between TPC and both free radical scavenging activity and total antioxidant capacity (TAC). Among studied species, the highest TPC (148.00 mg GAE/g extract) and TAC (2.080 UAE), the strongest radical scavenging (EC50 = 32.63 MUg/mL), the most prominent wound healing and most abundant cytotoxic activities were observed with AK. The results suggested that AK is a valuable source of flavonoids and chlorogenic acid with important antioxidant, wound healing and cytotoxic activities. These findings warrant further studies to assess the potential of AK as a bioactive source that could be exploited in pharmaceutical, cosmetics and food industries. PMID- 26437392 TI - Cucurbitacins from the Leaves of Citrullus colocynthis (L.) Schrad. AB - Two new tetracyclic cucurbitane-type triterpene glycosides were isolated from an ethyl acetate extract of Citrullus colocynthis leaves together with four known cucurbitacins. Their structures were established on the basis of their spectroscopic data (mainly NMR and mass spectrometry). Evaluation of the in vitro cytotoxic activity of the isolated compounds against two human colon cancer cell lines (HT29 and Caco-2) and one normal rat intestine epithelial cell line (IEC6), revealed that one of the isolated compounds presented interesting specific cytotoxic activity towards colorectal cell lines. PMID- 26437393 TI - Treatment Efficiency of Free and Nanoparticle-Loaded Mitoxantrone for Magnetic Drug Targeting in Multicellular Tumor Spheroids. AB - Major problems of cancer treatment using systemic chemotherapy are severe side effects. Magnetic drug targeting (MDT) employing superparamagnetic iron oxide nanoparticles (SPION) loaded with chemotherapeutic agents may overcome this dilemma by increasing drug accumulation in the tumor and reducing toxic side effects in the healthy tissue. For translation of nanomedicine from bench to bedside, nanoparticle-mediated effects have to be studied carefully. In this study, we compare the effect of SPION, unloaded or loaded with the cytotoxic drug mitoxantrone (MTO) with the effect of free MTO, on the viability and proliferation of HT-29 cells within three-dimensional multicellular tumor spheroids. Fluorescence microscopy and flow cytometry showed that both free MTO, as well as SPION-loaded MTO (SPION(MTO)) are able to penetrate into tumor spheroids and thereby kill tumor cells, whereas unloaded SPION did not affect cellular viability. Since SPION(MTO) has herewith proven its effectivity also in complex multicellular tumor structures with its surrounding microenvironment, we conclude that it is a promising candidate for further use in magnetic drug targeting in vivo. PMID- 26437394 TI - Plasma Pharmacokinetics of Polyphenols in a Traditional Japanese Medicine, Jumihaidokuto, Which Suppresses Propionibacterium acnes-Induced Dermatitis in Rats. AB - Most orally administered polyphenols are metabolized, with very little absorbed as aglycones and/or unchanged forms. Metabolic and pharmacokinetic studies are therefore necessary to understand the pharmacological mechanisms of polyphenols. Jumihaidokuto (JHT), a traditional Japanese medicine, has been used for treatment of skin diseases including inflammatory acne. Because JHT contains various types of bioactive polyphenols, our aim was to clarify the metabolism and pharmacokinetics of the polyphenols in JHT and identify active metabolites contributing to its antidermatitis effects. Orally administered JHT inhibited the increase in ear thickness in rats induced by intradermal injection of Propionibacterium acnes. Quantification by LC-MS/MS indicated that JHT contains various types of flavonoids and is also rich in hydrolysable tannins, such as 1,2,3,4,6-penta-O-galloyl glucose. Pharmacokinetic and antioxidant analyses showed that some flavonoid conjugates, such as genistein 7-O-glucuronide and liquiritigenin 7-O-glucuronide, appeared in rat plasma and had an activity to inhibit hydrogen peroxide-dependent oxidation. Furthermore, 4-O-methylgallic acid, a metabolite of Gallic acid, appeared in rat plasma and inhibited the nitric oxide reaction. JHT has numerous polyphenols; it inhibited dermatitis probably via the antioxidant effect of its metabolites. Our study is beneficial for understanding in vivo actions of orally administered polyphenol drugs. PMID- 26437395 TI - Metabolic Profiling of Alpine and Ecuadorian Lichens. AB - Non-targeted 1H-NMR methods were used to determine metabolite profiles from crude extracts of Alpine and Ecuadorian lichens collected from their natural habitats. In control experiments, the robustness of metabolite detection and quantification was estimated using replicate measurements of Stereocaulon alpinum extracts. The deviations in the overall metabolite fingerprints were low when analyzing S. alpinum collections from different locations or during different annual and seasonal periods. In contrast, metabolite profiles observed from extracts of different Alpine and Ecuadorian lichens clearly revealed genus- and species specific profiles. The discriminating functions determining cluster formation in principle component analysis (PCA) were due to differences in the amounts of genus-specific compounds such as sticticin from the Sticta species, but also in the amounts of ubiquitous metabolites, such as sugar alcohols or trehalose. However, varying concentrations of these metabolites from the same lichen species e.g., due to different environmental conditions appeared of minor relevance for the overall cluster formation in PCA. The metabolic clusters matched phylogenetic analyses using nuclear ribosomal DNA (nrDNA) internal transcribed spacer (ITS) sequences of lichen mycobionts, as exemplified for the genus Sticta. It can be concluded that NMR-based non-targeted metabolic profiling is a useful tool in the chemo-taxonomy of lichens. The same approach could also facilitate the discovery of novel lichen metabolites on a rapid and systematical basis. PMID- 26437396 TI - Meta-Analysis of Multiple Sclerosis Microarray Data Reveals Dysregulation in RNA Splicing Regulatory Genes. AB - Abnormalities in RNA metabolism and alternative splicing (AS) are emerging as important players in complex disease phenotypes. In particular, accumulating evidence suggests the existence of pathogenic links between multiple sclerosis (MS) and altered AS, including functional studies showing that an imbalance in alternatively-spliced isoforms may contribute to disease etiology. Here, we tested whether the altered expression of AS-related genes represents a MS specific signature. A comprehensive comparative analysis of gene expression profiles of publicly-available microarray datasets (190 MS cases, 182 controls), followed by gene-ontology enrichment analysis, highlighted a significant enrichment for differentially-expressed genes involved in RNA metabolism/AS. In detail, a total of 17 genes were found to be differentially expressed in MS in multiple datasets, with CELF1 being dysregulated in five out of seven studies. We confirmed CELF1 downregulation in MS (p=0.0015) by real-time RT-PCRs on RNA extracted from blood cells of 30 cases and 30 controls. As a proof of concept, we experimentally verified the unbalance in alternatively-spliced isoforms in MS of the NFAT5 gene, a putative CELF1 target. In conclusion, for the first time we provide evidence of a consistent dysregulation of splicing-related genes in MS and we discuss its possible implications in modulating specific AS events in MS susceptibility genes. PMID- 26437397 TI - Mutagenic Effects of Iron Oxide Nanoparticles on Biological Cells. AB - In recent years, there has been an increased interest in the design and use of iron oxide materials with nanoscale dimensions for magnetic, catalytic, biomedical, and electronic applications. The increased manufacture and use of iron oxide nanoparticles (IONPs) in consumer products as well as industrial processes is expected to lead to the unintentional release of IONPs into the environment. The impact of IONPs on the environment and on biological species is not well understood but remains a concern due to the increased chemical reactivity of nanoparticles relative to their bulk counterparts. This review article describes the impact of IONPs on cellular genetic components. The mutagenic impact of IONPs may damage an organism's ability to develop or reproduce. To date, there has been experimental evidence of IONPs having mutagenic interactions on human cell lines including lymphoblastoids, fibroblasts, microvascular endothelial cells, bone marrow cells, lung epithelial cells, alveolar type II like epithelial cells, bronchial fibroblasts, skin epithelial cells, hepatocytes, cerebral endothelial cells, fibrosarcoma cells, breast carcinoma cells, lung carcinoma cells, and cervix carcinoma cells. Other cell lines including the Chinese hamster ovary cells, mouse fibroblast cells, murine fibroblast cells, Mytilus galloprovincialis sperm cells, mice lung cells, murine alveolar macrophages, mice hepatic and renal tissue cells, and vero cells have also shown mutagenic effects upon exposure to IONPs. We further show the influence of IONPs on microorganisms in the presence and absence of dissolved organic carbon. The results shed light on the OPEN ACCESS Int. J. Mol. Sci. 2015, 16 23483 transformations IONPs undergo in the environment and the nature of the potential mutagenic impact on biological cells. PMID- 26437398 TI - Systematic Analysis of the Maize PHD-Finger Gene Family Reveals a Subfamily Involved in Abiotic Stress Response. AB - Plant homeodomain (PHD)-finger proteins were found universally in eukaryotes and known as key players in regulating transcription and chromatin structure. Many PHD-finger proteins have been well studied on structure and function in animals. Whereas, only a few of plant PHD-finger factors had been characterized, and majority of PHD-finger proteins were functionally unclear. In this study, a complete comprehensive analysis of maize PHD family is presented. Sixty-seven PHD finger genes in maize were identified and further divided into ten groups according to phylogenetic analysis that was supported by motif and intron/exon analysis. These genes were unevenly distributed on ten chromosomes and contained 12 segmental duplication events, suggesting that segmental duplications were the major contributors in expansion of the maize PHD family. The paralogous genes mainly experienced purifying selection with restrictive functional divergence after the duplication events on the basis of the Ka/Ks ratio. Gene digital expression analysis showed that the PHD family had a wide expression profile in maize development. In addition, 15 potential stress response genes were detected by promoter cis-element and expression analysis. Two proteins ZmPHD14 and ZmPHD19 were located in the nucleus. These results provided a solid base for future functional genome study of the PHD-finger family in maize and afforded important clues for characterizing and cloning potentially important candidates in response to abiotic stresses. PMID- 26437399 TI - A Large-Scale Analysis of the Relationship of Synonymous SNPs Changing MicroRNA Regulation with Functionality and Disease. AB - Historically, owing to not changing amino acid composition of protein sequences, synonymous mutations are commonly assumed to be neutral during evolution and therefore have no effect on the phenotype and disease. Here, based on observations from large-scale analysis of genomic data, we predicted the putative synonymous SNPs that could result in functional consequences and disease risk through changing the microRNA-mediated gene regulation. We found that nearly half of the synonymous SNPs could affect protein expression by changing microRNA regulation in human genome and these SNPs significantly prefer to be associated with human diseases and traits. The synonymous SNPs changing microRNA-mediated gene regulation tend to be more under recent positive selection, prefer to affect gene expression, and implicate in human disease. We conclude that the miRNA mediated regulation changes could be a potential mechanism for the contributions of synonymous SNPs to protein functions and disease risks. PMID- 26437400 TI - Systemically Administered, Target Organ-Specific Therapies for Regenerative Medicine. AB - Growth factors and other agents that could potentially enhance tissue regeneration have been identified, but their therapeutic value in clinical medicine has been limited for reasons such as difficulty to maintain bioactivity of locally applied therapeutics in the protease-rich environment of regenerating tissues. Although human diseases are treated with systemically administered drugs in general, all current efforts aimed at enhancing tissue repair with biological drugs have been based on their local application. The systemic administration of growth factors has been ruled out due to concerns about their safety. These concerns are warranted. In addition, only a small proportion of systemically administered drugs reach their intended target. Selective delivery of the drug to the target tissue and use of functional protein domains capable of penetrating cells and tissues could alleviate these problems in certain circumstances. We will present in this review a novel approach utilizing unique molecular fingerprints ("Zip/postal codes") in the vasculature of regenerating tissues that allows target organ-specific delivery of systemically administered therapeutic molecules by affinity-based physical targeting (using peptides or antibodies as an "address tag") to injured tissues undergoing repair. The desired outcome of targeted therapies is increased local accumulation and lower systemic concentration of the therapeutic payload. We believe that the physical targeting of systemically administered therapeutic molecules could be rapidly adapted in the field of regenerative medicine. PMID- 26437401 TI - Identification and Validation of Aspartic Acid Semialdehyde Dehydrogenase as a New Anti-Mycobacterium Tuberculosis Target. AB - Aspartic acid semialdehyde dehydrogenase (ASADH) lies at the first branch point in the essential aspartic acid biosynthetic pathway that is found in bacteria and plants but is absent from animals. Mutations in the asadh gene encoding ASADH produce an inactive enzyme, which is lethal. Therefore, in this study, we investigated the hypothesis that ASADH represents a new anti-Mycobacterium tuberculosis (MTB) target. An asadh promoter-replacement mutant MTB, designated MTB::asadh, in which asadh gene expression is regulated by pristinamycin, was constructed to investigate the physiological functions of ASADH in the host bacteria. Bacterial growth was evaluated by monitoring OD600 and ASADH expression was analyzed by Western blotting. The results showed that the growth and survival of MTB::asadh was completely inhibited in the absence of the inducer pristinamycin. Furthermore, the growth of the mutant was rigorously dependent on the presence of the inducer in the medium. The starved mutant exhibited a marked reduction (approximately 80%) in the cell wall materials compared to the wild type, in addition to obvious morphological differences that were apparent in scanning electron microscopy studies; however, with the addition of pristinamycin, the cell wall contents and morphology similar to those of the wild type strain were recovered. The starved mutant also exhibited almost no pathogenicity in an in vitro model of infection using mouse macrophage J774A.1 cells. The mutant showed a concentration-dependent recovery of pathogenicity with the addition of the inducer. These findings implicate ASADH as a promising target for the development of novel anti-MTB drugs. PMID- 26437402 TI - Streamlining the Pipeline for Generation of Recombinant Affinity Reagents by Integrating the Affinity Maturation Step. AB - Often when generating recombinant affinity reagents to a target, one singles out an individual binder, constructs a secondary library of variants, and affinity selects a tighter or more specific binder. To enhance the throughput of this general approach, we have developed a more integrated strategy where the "affinity maturation" step is part of the phage-display pipeline, rather than a follow-on process. In our new schema, we perform two rounds of affinity selection, followed by error-prone PCR on the pools of recovered clones, generation of secondary libraries, and three additional rounds of affinity selection, under conditions of off-rate competition. We demonstrate the utility of this approach by generating low nanomolar fibronectin type III (FN3) monobodies to five human proteins: ubiquitin-conjugating enzyme E2 R1 (CDC34), COP9 signalosome complex subunit 5 (COPS5), mitogen-activated protein kinase kinase 5 (MAP2K5), Splicing factor 3A subunit 1 (SF3A1) and ubiquitin carboxyl terminal hydrolase 11 (USP11). The affinities of the resulting monobodies are typically in the single-digit nanomolar range. We demonstrate the utility of two binders by pulling down the targets from a spiked lysate of HeLa cells. This integrated approach should be applicable to directed evolution of any phage displayed affinity reagent scaffold. PMID- 26437404 TI - Fully Integrated Biopotential Acquisition Analog Front-End IC. AB - A biopotential acquisition analog front-end (AFE) integrated circuit (IC) is presented. The biopotential AFE includes a capacitively coupled chopper instrumentation amplifier (CCIA) to achieve low input referred noise (IRN) and to block unwanted DC potential signals. A DC servo loop (DSL) is designed to minimize the offset voltage in the chopper amplifier and low frequency respiration artifacts. An AC coupled ripple rejection loop (RRL) is employed to reduce ripple due to chopper stabilization. A capacitive impedance boosting loop (CIBL) is designed to enhance the input impedance and common mode rejection ratio (CMRR) without additional power consumption, even under an external electrode mismatch. The AFE IC consists of two-stage CCIA that include three compensation loops (DSL, RRL, and CIBL) at each CCIA stage. The biopotential AFE is fabricated using a 0.18 MUm one polysilicon and six metal layers (1P6M) complementary metal oxide semiconductor (CMOS) process. The core chip size of the AFE without input/output (I/O) pads is 10.5 mm2. A fourth-order band-pass filter (BPF) with a pass-band in the band-width from 1 Hz to 100 Hz was integrated to attenuate unwanted signal and noise. The overall gain and band-width are reconfigurable by using programmable capacitors. The IRN is measured to be 0.94 MUVRMS in the pass band. The maximum amplifying gain of the pass-band was measured as 71.9 dB. The CIBL enhances the CMRR from 57.9 dB to 67 dB at 60 Hz under electrode mismatch conditions. PMID- 26437403 TI - Genome Editing Using Mammalian Haploid Cells. AB - Haploid cells are useful for studying gene functions because disruption of a single allele can cause loss-of-function phenotypes. Recent success in generating haploid embryonic stem cells (ESCs) in mice, rats, and monkeys provides a new platform for simple genetic manipulation of the mammalian genome. Use of haploid ESCs enhances the genome-editing potential of the CRISPR/Cas system. For example, CRISPR/Cas was used in haploid ESCs to generate multiple knockouts and large deletions at high efficiency. In addition, genome-wide screening is facilitated by haploid cell lines containing gene knockout libraries. PMID- 26437405 TI - Hyperbolic Positioning with Antenna Arrays and Multi-Channel Pseudolite for Indoor Localization. AB - A hyperbolic positioning method with antenna arrays consisting of proximately located antennas and a multi-channel pseudolite is proposed in order to overcome the problems of indoor positioning with conventional pseudolites (ground-based GPS transmitters). A two-dimensional positioning experiment using actual devices is conducted. The experimental result shows that the positioning accuracy varies centimeter- to meter-level according to the geometric relation between the pseudolite antennas and the receiver. It also shows that the bias error of the carrier-phase difference observables is more serious than their random error. Based on the size of the bias error of carrier-phase difference that is inverse calculated from the experimental result, three-dimensional positioning performance is evaluated by computer simulation. In addition, in the three dimensional positioning scenario, an initial value convergence analysis of the non-linear least squares is conducted. Its result shows that initial values that can converge to a right position exist at least under the proposed antenna setup. The simulated values and evaluation methods introduced in this work can be applied to various antenna setups; therefore, by using them, positioning performance can be predicted in advance of installing an actual system. PMID- 26437406 TI - A Context-Aware Model to Provide Positioning in Disaster Relief Scenarios. AB - The effectiveness of the work performed during disaster relief efforts is highly dependent on the coordination of activities conducted by the first responders deployed in the affected area. Such coordination, in turn, depends on an appropriate management of geo-referenced information. Therefore, enabling first responders to count on positioning capabilities during these activities is vital to increase the effectiveness of the response process. The positioning methods used in this scenario must assume a lack of infrastructure-based communication and electrical energy, which usually characterizes affected areas. Although positioning systems such as the Global Positioning System (GPS) have been shown to be useful, we cannot assume that all devices deployed in the area (or most of them) will have positioning capabilities by themselves. Typically, many first responders carry devices that are not capable of performing positioning on their own, but that require such a service. In order to help increase the positioning capability of first responders in disaster-affected areas, this paper presents a context-aware positioning model that allows mobile devices to estimate their position based on information gathered from their surroundings. The performance of the proposed model was evaluated using simulations, and the obtained results show that mobile devices without positioning capabilities were able to use the model to estimate their position. Moreover, the accuracy of the positioning model has been shown to be suitable for conducting most first response activities. PMID- 26437408 TI - A High Performance LIA-Based Interface for Battery Powered Sensing Devices. AB - This paper proposes a battery-compatible electronic interface based on a general purpose lock-in amplifier (LIA) capable of recovering input signals up to the MHz range. The core is a novel ASIC fabricated in 1.8 V 0.18 um CMOS technology, which contains a dual-phase analog lock-in amplifier consisting of carefully designed building blocks to allow configurability over a wide frequency range while maintaining low power consumption. It operates using square input signals. Hence, for battery-operated microcontrolled systems, where square reference and exciting signals can be generated by the embedded microcontroller, the system benefits from intrinsic advantages such as simplicity, versatility and reduction in power and size. Experimental results confirm the signal recovery capability with signal-to-noise power ratios down to -39 dB with relative errors below 0.07% up to 1 MHz. Furthermore, the system has been successfully tested measuring the response of a microcantilever-based resonant sensor, achieving similar results with better power-bandwidth trade-off compared to other LIAs based on commercial off-the-shelf (COTS) components and commercial LIA equipment. PMID- 26437407 TI - Fiber-Optic Chemical Sensors and Fiber-Optic Bio-Sensors. AB - This review summarizes principles and current stage of development of fiber-optic chemical sensors (FOCS) and biosensors (FOBS). Fiber optic sensor (FOS) systems use the ability of optical fibers (OF) to guide the light in the spectral range from ultraviolet (UV) (180 nm) up to middle infrared (IR) (10 MUm) and modulation of guided light by the parameters of the surrounding environment of the OF core. The introduction of OF in the sensor systems has brought advantages such as measurement in flammable and explosive environments, immunity to electrical noises, miniaturization, geometrical flexibility, measurement of small sample volumes, remote sensing in inaccessible sites or harsh environments and multi sensing. The review comprises briefly the theory of OF elaborated for sensors, techniques of fabrications and analytical results reached with fiber-optic chemical and biological sensors. PMID- 26437409 TI - Auto Regressive Moving Average (ARMA) Modeling Method for Gyro Random Noise Using a Robust Kalman Filter. AB - To solve the problem in which the conventional ARMA modeling methods for gyro random noise require a large number of samples and converge slowly, an ARMA modeling method using a robust Kalman filtering is developed. The ARMA model parameters are employed as state arguments. Unknown time-varying estimators of observation noise are used to achieve the estimated mean and variance of the observation noise. Using the robust Kalman filtering, the ARMA model parameters are estimated accurately. The developed ARMA modeling method has the advantages of a rapid convergence and high accuracy. Thus, the required sample size is reduced. It can be applied to modeling applications for gyro random noise in which a fast and accurate ARMA modeling method is required. PMID- 26437410 TI - Depth Estimation of Submerged Aquatic Vegetation in Clear Water Streams Using Low Altitude Optical Remote Sensing. AB - UAVs and other low-altitude remote sensing platforms are proving very useful tools for remote sensing of river systems. Currently consumer grade cameras are still the most commonly used sensors for this purpose. In particular, progress is being made to obtain river bathymetry from the optical image data collected with such cameras, using the strong attenuation of light in water. No studies have yet applied this method to map submergence depth of aquatic vegetation, which has rather different reflectance characteristics from river bed substrate. This study therefore looked at the possibilities to use the optical image data to map submerged aquatic vegetation (SAV) depth in shallow clear water streams. We first applied the Optimal Band Ratio Analysis method (OBRA) of Legleiter et al. (2009) to a dataset of spectral signatures from three macrophyte species in a clear water stream. The results showed that for each species the ratio of certain wavelengths were strongly associated with depth. A combined assessment of all species resulted in equally strong associations, indicating that the effect of spectral variation in vegetation is subsidiary to spectral variation due to depth changes. Strongest associations (R2-values ranging from 0.67 to 0.90 for different species) were found for combinations including one band in the near infrared (NIR) region between 825 and 925 nm and one band in the visible light region. Currently data of both high spatial and spectral resolution is not commonly available to apply the OBRA results directly to image data for SAV depth mapping. Instead a novel, low-cost data acquisition method was used to obtain six band high spatial resolution image composites using a NIR sensitive DSLR camera. A field dataset of SAV submergence depths was used to develop regression models for the mapping of submergence depth from image pixel values. Band (combinations) providing the best performing models (R2-values up to 0.77) corresponded with the OBRA findings. A 10% error was achieved under sub-optimal data collection conditions, which indicates that the method could be suitable for many SAV mapping applications. PMID- 26437411 TI - A Low Noise Amplifier for Neural Spike Recording Interfaces. AB - This paper presents a Low Noise Amplifier (LNA) for neural spike recording applications. The proposed topology, based on a capacitive feedback network using a two-stage OTA, efficiently solves the triple trade-off between power, area and noise. Additionally, this work introduces a novel transistor-level synthesis methodology for LNAs tailored for the minimization of their noise efficiency factor under area and noise constraints. The proposed LNA has been implemented in a 130 nm CMOS technology and occupies 0.053 mm-sq. Experimental results show that the LNA offers a noise efficiency factor of 2.16 and an input referred noise of 3.8 MUVrms for 1.2 V power supply. It provides a gain of 46 dB over a nominal bandwidth of 192 Hz-7.4 kHz and consumes 1.92 MUW. The performance of the proposed LNA has been validated through in vivo experiments with animal models. PMID- 26437412 TI - GPS Cycle Slip Detection Considering Satellite Geometry Based on TDCP/INS Integrated Navigation. AB - This paper presents a means of carrier phase cycle slip detection for an inertial aided global positioning system (GPS), which is based on consideration of the satellite geometry. An integrated navigation solution incorporating a tightly coupled time differenced carrier phase (TDCP) and inertial navigation system (INS) is used to detect cycle slips. Cycle-slips are detected by comparing the satellite-difference (SD) and time-difference (TD) carrier phase measurements obtained from the GPS satellites with the range estimated by the integrated navigation solution. Additionally the satellite geometry information effectively improves the range estimation performance without a hardware upgrade. And the covariance obtained from the TDCP/INS filter is used to compute the threshold for determining cycle slip occurrence. A simulation and the results of a vehicle based experiment verify the cycle slip detection performance of the proposed algorithm. PMID- 26437413 TI - Development of a Cost-Effective Airborne Remote Sensing System for Coastal Monitoring. AB - Coastal lands and nearshore marine areas are productive and rapidly changing places. However, these areas face many environmental challenges related to climate change and human-induced impacts. Space-borne remote sensing systems may be restricted in monitoring these areas because of their spatial and temporal resolutions. In situ measurements are also constrained from accessing the area and obtaining wide-coverage data. In these respects, airborne remote sensing sensors could be the most appropriate tools for monitoring these coastal areas. In this study, a cost-effective airborne remote sensing system with synthetic aperture radar and thermal infrared sensors was implemented to survey coastal areas. Calibration techniques and geophysical model algorithms were developed for the airborne system to observe the topography of intertidal flats, coastal sea surface current, sea surface temperature, and submarine groundwater discharge. PMID- 26437414 TI - Analysis of Surface Plasmon Resonance Curves with a Novel Sigmoid-Asymmetric Fitting Algorithm. AB - The present study introduces a novel curve-fitting algorithm for surface plasmon resonance (SPR) curves using a self-constructed, wedge-shaped beam type angular interrogation SPR spectroscopy technique. Previous fitting approaches such as asymmetric and polynomial equations are still unsatisfactory for analyzing full SPR curves and their use is limited to determining the resonance angle. In the present study, we developed a sigmoid-asymmetric equation that provides excellent curve-fitting for the whole SPR curve over a range of incident angles, including regions of the critical angle and resonance angle. Regardless of the bulk fluid type (i.e., water and air), the present sigmoid-asymmetric fitting exhibited nearly perfect matching with a full SPR curve, whereas the asymmetric and polynomial curve fitting methods did not. Because the present curve-fitting sigmoid-asymmetric equation can determine the critical angle as well as the resonance angle, the undesired effect caused by the bulk fluid refractive index was excluded by subtracting the critical angle from the resonance angle in real time. In conclusion, the proposed sigmoid-asymmetric curve-fitting algorithm for SPR curves is widely applicable to various SPR measurements, while excluding the effect of bulk fluids on the sensing layer. PMID- 26437415 TI - Design and Performance Evaluation of a Dual Antenna Joint Carrier Tracking Loop. AB - In order to track the carrier phases of Global Navigation Satellite Systems (GNSS) signals in signal degraded environments, a dual antenna joint carrier tracking loop is proposed and evaluated. This proposed tracking loop processes inputs from two antennas, namely the master antenna and the slave antenna. The master antenna captures signals in open-sky environments, while the slave antenna capture signals in degraded environments. In this architecture, a Phase Lock Loop (PLL) is adopted as a master loop to track the carrier phase of the open-sky signals. The Doppler frequency estimated by this master loop is utilized to assist weak carrier tracking in the slave loop. As both antennas experience similar signal dynamics due to satellite motion and clock frequency variations, a much narrower loop bandwidth and possibly a longer coherent integration can be adopted to track the weak signals in slave channels, by utilizing the Doppler aid from master channels. PLL tracking performance is affected by the satellite/user dynamics, clock instability, and thermal noise. In this paper, their impacts on the proposed phase tracking loop are analyzed and verified by both simulation and field data. Theoretical analysis and experimental results show that the proposed loop structure can track degraded signals (i.e., 18 dB-Hz) with a very narrow loop bandwidth (i.e., 0.5 Hz) and a TCXO clock. PMID- 26437416 TI - Does Laser Surgery Interfere with Optical Nerve Identification in Maxillofacial Hard and Soft Tissue?--An Experimental Ex Vivo Study. AB - The protection of sensitive structures (e.g., nerves) from iatrogenic damage is of major importance when performing laser surgical procedures. Especially in the head and neck area both function and esthetics can be affected to a great extent. Despite its many benefits, the surgical utilization of a laser is therefore still limited to superficial tissue ablation. A remote feedback system which guides the laser in a tissue-specific way would provide a remedy. In this context, it has been shown that nerval structures can be specifically recognized by their optical diffuse reflectance spectra both before and after laser ablation. However, for a translation of these findings to the actual laser ablation process, a nerve protection within the laser pulse is of utmost significance. Thus, it was the aim of the study to evaluate, if the process of Er:YAG laser surgery--which comes with spray water cooling, angulation of the probe (60 degrees ) and optical process emissions--interferes with optical tissue differentiation. For the first time, no stable conditions but the ongoing process of laser tissue ablation was examined. Therefore, six different tissue types (nerve, skin, muscle, fat, cortical and cancellous bone) were acquired from 15 pig heads. Measurements were performed during Er:YAG laser ablation. Diffuse reflectance spectra (4500, wavelength range: 350-650 nm) where acquired. Principal component analysis (PCA) and quadratic discriminant analysis (QDA) were calculated for classification purposes. The clinical highly relevant differentiation between nerve and bone was performed correctly with an AUC of 95.3% (cortial bone) respectively 92.4% (cancellous bone). The identification of nerve tissue against the biological very similar fat tissue yielded good results with an AUC value of 83.4% (sensitivity: 72.3%, specificity: of 82.3%). This clearly demonstrates that nerve identification by diffuse reflectance spectroscopy works reliably in the ongoing process of laser ablation in spite of the laser beam, spray water cooling and the tissue alterations entailed by tissue laser ablation. This is an essential step towards a clinical utilization. PMID- 26437417 TI - Mitochondrial Dysfunction and Disturbed Coherence: Gate to Cancer. AB - Continuous energy supply, a necessary condition for life, excites a state far from thermodynamic equilibrium, in particular coherent electric polar vibrations depending on water ordering in the cell. Disturbances in oxidative metabolism and coherence are a central issue in cancer development. Oxidative metabolism may be impaired by decreased pyruvate transfer to the mitochondrial matrix, either by parasitic consumption and/or mitochondrial dysfunction. This can in turn lead to disturbance in water molecules' ordering, diminished power, and coherence of the electromagnetic field. In tumors with the Warburg (reverse Warburg) effect, mitochondrial dysfunction affects cancer cells (fibroblasts associated with cancer cells), and the electromagnetic field generated by microtubules in cancer cells has low power (high power due to transport of energy-rich metabolites from fibroblasts), disturbed coherence, and a shifted frequency spectrum according to changed power. Therapeutic strategies restoring mitochondrial function may trigger apoptosis in treated cells; yet, before this step is performed, induction (inhibition) of pyruvate dehydrogenase kinases (phosphatases) may restore the cancer state. In tumor tissues with the reverse Warburg effect, Caveolin-1 levels should be restored and the transport of energy-rich metabolites interrupted to cancer cells. In both cancer phenotypes, achieving permanently reversed mitochondrial dysfunction with metabolic-modulating drugs may be an effective, specific anti-cancer strategy. PMID- 26437419 TI - Immunostimulative Activity of Low Molecular Weight Chitosans in RAW264.7 Macrophages. AB - Chitosan and its derivatives such as low molecular weight chitosans (LMWCs) have been reported to exert many biological activities, such as antioxidant and antitumor effects. However, complex and molecular weight dependent effects of chitosan remain controversial and the mechanisms that mediate these complex effects are still poorly defined. This study was carried out to investigate the immunostimulative effect of different molecular weight chitosan in RAW264.7 macrophages. Our data suggested that two LMWCs (molecular weight of 3 kDa and 50 kDa) both possessed immunostimulative activity, which was dependent on dose and, at the higher doses, also on the molecular weight. LMWCs could significantly enhance the the pinocytic activity, and induce the production of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), interferon-gamma (IFN-gamma), nitric oxide (NO) and inducible nitric oxide synthase (iNOS) in a molecular weight and concentration-dependent manner. LMWCs were further showed to promote the expression of the genes including iNOS, TNF-alpha. Taken together, our findings suggested that LMWCs elicited significantly immunomodulatory response through up-regulating mRNA expression of proinflammatory cytokines and activated RAW264.7 macrophage in a molecular weight- and concentration-dependent manner. PMID- 26437420 TI - Marine Carotenoids against Oxidative Stress: Effects on Human Health. AB - Carotenoids are lipid-soluble pigments that are produced in some plants, algae, fungi, and bacterial species, which accounts for their orange and yellow hues. Carotenoids are powerful antioxidants thanks to their ability to quench singlet oxygen, to be oxidized, to be isomerized, and to scavenge free radicals, which plays a crucial role in the etiology of several diseases. Unusual marine environments are associated with a great chemical diversity, resulting in novel bioactive molecules. Thus, marine organisms may represent an important source of novel biologically active substances for the development of therapeutics. In this respect, various novel marine carotenoids have recently been isolated from marine organisms and displayed several utilizations as nutraceuticals and pharmaceuticals. Marine carotenoids (astaxanthin, fucoxanthin, beta-carotene, lutein but also the rare siphonaxanthin, sioxanthin, and myxol) have recently shown antioxidant properties in reducing oxidative stress markers. This review aims to describe the role of marine carotenoids against oxidative stress and their potential applications in preventing and treating inflammatory diseases. PMID- 26437421 TI - Mycemycins A-E, New Dibenzoxazepinones Isolated from Two Different Streptomycetes. AB - Five new dibenzoxazepinone derivatives, mycemycins A-E (1-5), were isolated from the ethanol extracts of mycelia of two different streptomycetes. 1 and 2 were isolated from an acidic red soil-derived strain, Streptomyces sp. FXJ1.235, and 3 5 from a gntR gene-disrupted deep-sea strain named Streptomyces olivaceus FXJ8.012Delta1741. The structures of mycemycins were elucidated by a combination of spectroscopic analyses, including 1D- and 2D-NMR techniques. PMID- 26437422 TI - Important Variables When Screening for Students at Suicidal Risk: Findings from the French Cohort of the SEYLE Study. AB - Due to early detection of mental ill-health being an important suicide preventive strategy, the multi-centre EU funded "Saving and Empowering Young Lives in Europe" (SEYLE) study compared three school-based mental health promotion programs to a control group. In France, 1007 students with a mean age of 15.2 years were recruited from 20 randomly assigned schools. This paper explores the French results of the SEYLE's two-stage screening program (ProfScreen) and of the cross-program suicidal emergency procedure. Two-hundred-thirty-five ProfScreen students were screened using 13 psychopathological and risk behaviour scales. Students considered at risk because of a positive finding on one or more scales were offered a clinical interview and, if necessary, referred for treatment. A procedure for suicidal students (emergency cases) was set up to detect emergencies in the whole cohort (n = 1007). Emergency cases were offered the same clinical interview as the ProfScreen students. The interviewers documented their reasons for referrals in a short report. 16,2% of the ProfScreen students (38/235) were referred to treatment and 2,7% of the emergency cases (27/1007) were also referred to treatment due to high suicidal risk. Frequent symptoms in those students referred for evaluation were depression, alcohol misuse, non suicidal self-injuries (NSSI), and suicidal behaviours. According to the multivariate regression analysis of ProfScreen, the results show that the best predictors for treatment referral were NSSI (OR 2.85), alcohol misuse (OR 2.80), and depressive symptoms (OR 1.13). Analysis of the proportion for each scale of students referred to treatment showed that poor social relationships (60%), anxiety (50%), and suicidal behaviours (50%) generated the highest rate of referrals. Qualitative analysis of clinician's motivations to refer a student to mental health services revealed that depressive symptoms (51%), anxiety (38%), suicidal behaviours (40%), and negative life events (35%) were the main reasons for referrals. Thus, not only the classical psychopathological symptoms, such as depression, anxiety, and suicidal behaviours, but also negative life events and poor social relationships (especially isolation) motivate referrals for treatment. PMID- 26437423 TI - Early Substance Use Initiation and Suicide Ideation and Attempts among School Aged Adolescents in Four Pacific Island Countries in Oceania. AB - This study aimed to investigate the correlations between early initiation (<12 years) of smoking cigarettes, alcohol use, and drug use (cannabis) with suicidal ideation and suicide attempts in school-aged adolescents in four Pacific Island countries in Oceania. The sample included 6540 adolescents (<=13 to >=16 years old) from Kiribati, Samoa, Solomon Islands, and Vanuatu. Bivariate and multivariable analyses were conducted to assess the association between pre adolescent substance use initiation and suicidal ideation and suicide attempts. Results indicate a prevalence of 25.8% suicidal ideation in the past 12 months (ranging from 17.2% in Vanuatu to 34.7% in Kiribati) and 34.9% suicide attempts in the past 12 months (ranging from 23.5% in Vanuatu to 62.0% in Samoa). The prevalence of early cigarette smoking initiation was 15.7%, early alcohol initiation 13.8%, and early drug use initiation was 12.9%. Students who reported pre-adolescent substance use initiation, compared with non-substance users, were more likely reporting suicidal ideation and suicide attempts. The concurrent initiation of cigarette smoking, alcohol, and drug use should be targeted in early prevention programmes in order to prevent possible subsequent suicidal behaviours. PMID- 26437424 TI - Noise in the Sea and Its Impacts on Marine Organisms. AB - With the growing utilization and exploration of the ocean, anthropogenic noise increases significantly and gives rise to a new kind of pollution: noise pollution. In this review, the source and the characteristics of noise in the sea, the significance of sound to marine organisms, and the impacts of noise on marine organisms are summarized. In general, the studies about the impact of noise on marine organisms are mainly on adult fish and mammals, which account for more than 50% and 20% of all the cases reported. Studies showed that anthropogenic noise can cause auditory masking, leading to cochlear damage, changes in individual and social behavior, altered metabolisms, hampered population recruitment, and can subsequently affect the health and service functions of marine ecosystems. However, since different sampling methodologies and unstandarized measurements were used and the effects of noise on marine organisms are dependent on the characteristics of the species and noise investigated, it is difficult to compare the reported results. Moreover, the scarcity of studies carried out with other species and with larval or juvenile individuals severely constrains the present understanding of noise pollution. In addition, further studies are needed to reveal in detail the causes for the detected impacts. PMID- 26437418 TI - Bioactive Compounds Isolated from Microalgae in Chronic Inflammation and Cancer. AB - The risk of onset of cancer is influenced by poorly controlled chronic inflammatory processes. Inflammatory diseases related to cancer development include inflammatory bowel disease, which can lead to colon cancer, or actinic keratosis, associated with chronic exposure to ultraviolet light, which can progress to squamous cell carcinoma. Chronic inflammatory states expose these patients to a number of signals with tumorigenic effects, including nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinases (MAPK) activation, pro-inflammatory cytokines and prostaglandins release and ROS production. In addition, the participation of inflammasomes, autophagy and sirtuins has been demonstrated in pathological processes such as inflammation and cancer. Chemoprevention consists in the use of drugs, vitamins, or nutritional supplements to reduce the risk of developing or having a recurrence of cancer. Numerous in vitro and animal studies have established the potential colon and skin cancer chemopreventive properties of substances from marine environment, including microalgae species and their products (carotenoids, fatty acids, glycolipids, polysaccharides and proteins). This review summarizes the main mechanisms of actions of these compounds in the chemoprevention of these cancers. These actions include suppression of cell proliferation, induction of apoptosis, stimulation of antimetastatic and antiangiogenic responses and increased antioxidant and anti-inflammatory activity. PMID- 26437425 TI - Lifetime Effective Dose Assessment Based on Background Outdoor Gamma Exposure in Chihuahua City, Mexico. AB - Determining ionizing radiation in a geographic area serves to assess its effects on a population's health. The aim of this study was to evaluate the spatial distribution of the background environmental outdoor gamma dose rates in Chihuahua City. This study also estimated the annual effective dose and the lifetime cancer risks of the population of this city. To determine the outdoor gamma dose rate in air, the annual effective dose and the lifetime cancer risk, 48 sampling points were randomly selected in Chihuahua City. Outdoor gamma dose rate measurements were carried out by using a Geiger-Muller counter. Outdoor gamma dose rates ranged from 113 to 310 nGy.h(-1). At the same sites, 48 soil samples were taken to obtain the activity concentrations of (226)Ra, (232)Th and (40)K and to calculate their terrestrial gamma dose rates. Radioisotope activity concentrations were determined by gamma spectrometry. Calculated gamma dose rates ranged from 56 to 193 nGy.h(-1). Results indicated that the lifetime effective dose of the inhabitants of Chihuahua City is on average 19.8 mSv, resulting in a lifetime cancer risk of 0.001. In addition, the mean of the activity concentrations in soil were 52, 73 and 1097 Bq.kg(-1), for (226)Ra, (232)Th and (40)K, respectively. From the analysis, the spatial distribution of (232)Th, (226)Ra and (40)K is to the north, to the north-center and to the south of city, respectively. In conclusion, the natural background gamma dose received by the inhabitants of Chihuahua City is high and mainly due to the geological characteristics of the zone. From the radiological point of view, this kind of study allows us to identify the importance of manmade environments, which are often highly variable and difficult to characterize. PMID- 26437426 TI - The Effects of Leptin on Breastfeeding Behaviour. AB - Breastfed infants have a reduced risk of becoming overweight and/or obese later in life. This protective effect has been partly attributed to leptin present in breastmilk. This study investigated 24-h variations of skim milk leptin and its relationship with breastmilk macronutrients and infant breastfeeding patterns. Exclusive breastfeeding mothers of term singletons (n = 19; age 10 +/- 5 weeks) collected pre- and post-feed breastmilk samples for every breastfeed over a 24-h period and test-weighed their infants to determine milk intake at every breastfeed over a 24-h period. Samples (n = 454) were analysed for leptin, protein, lactose and fat content. Skim milk leptin concentration did not change with feeding (p = 0.184). However, larger feed volumes (>105 g) were associated with a decrease in post-feed leptin levels (p = 0.009). There was no relationship between the change in leptin levels and change in protein (p = 0.313) or lactose levels (p = 0.587) between pre- and post-feed milk, but there was a trend for a positive association with changes in milk fat content (p = 0.056). Leptin concentration significantly increased at night (p < 0.001) indicating a possible 24-h pattern. Leptin dose (ng) was not associated with the time between feeds (p = 0.232). Further research should include analysis of whole breastmilk and other breastmilk fractions to extend these findings. PMID- 26437427 TI - Construction of Specific Primers for Rapid Detection of South African Exportable Vegetable Macergens. AB - Macergens are bacteria causing great damages to the parenchymatous tissues of vegetable both on the field and in transit. To effectively and rapidly investigate the diversity and distribution of these macergens, four specific primers were designed by retrieving 16S rDNA sequences of pectolytic bacteria from GenBank through the National Center for Biotechnology Information (NCBI). These were aligned using ClusterW via BioEdit and primers were designed using Primer3Plus platform. The size and primer location of each species and PCR product size were accurately defined. For specificity enhancement, DNA template of known macergens (Pectobacterium chrysanthermi) and fresh healthy vegetable were used. These primers yielded expected size of approximately 1100 bp product only when tested with known macergens and no amplicon with fresh healthy vegetable was detected. Rapid detection of macergens in rotten vegetable samples was then carried out using these primers. Nucleotide sequences of macergens identified were deposited into the GenBank and were assigned accession numbers. Hence, with these specific primers, macergens can be identified with minimal quantities of the vegetable tissues using molecular techniques, for future use of the quarantine section of the Agricultural Department of the country for quick and rapid detection of macergens before exportation. PMID- 26437428 TI - Isolation and Genome Characterization of the Virulent Staphylococcus aureus Bacteriophage SA97. AB - A novel bacteriophage that infects S. aureus, SA97, was isolated and characterized. The phage SA97 belongs to the Siphoviridae family, and the cell wall teichoic acid (WTA) was found to be a host receptor of the phage SA97. Genome analysis revealed that SA97 contains 40,592 bp of DNA encoding 54 predicted open reading frames (ORFs), and none of these genes were related to virulence or drug resistance. Although a few genes associated with lysogen formation were detected in the phage SA97 genome, the phage SA97 produced neither lysogen nor transductant in S. aureus. These results suggest that the phage SA97 may be a promising candidate for controlling S. aureus. PMID- 26437429 TI - Vitamin D Deficiency Increases the Risk of Gestational Diabetes Mellitus: A Meta Analysis of Observational Studies. AB - The results investigating the relationship between vitamin D levels and gestational diabetes mellitus (GDM) are inconsistent. Thus, we focused on evaluating the association of vitamin D deficiency with GDM by conducting a meta analysis of observed studies. A systematic literature search was conducted via PubMed, MEDLINE, and Cochrane library to identify eligible studies before August 2015. The meta-analysis of 20 studies including 9209 participants showed that women with vitamin D deficiency experienced a significantly increased risk for developing GDM (odds ratio (OR) = 1.53; 95% confidence intervals (CI), 1.33, 1.75) with a little heterogeneity (I2 = 16.20%, p = 0.252). A noteworthy decrease of 4.93 nmol/L (95% CI, -6.73, -3.14) in serum 25(OH)D was demonstrated in the participants with GDM, and moderate heterogeneity was observed (I2 = 61.40%, p = 0.001). Subgroup analysis with study design showed that there were obvious heterogeneities in nested case-control studies (I2 > 52.5%, p < 0.07). Sensitivity analysis showed that exclusion of any single study did not materially alter the overall combined effect. In summary, the evidence from this meta analysis indicates a consistent association between vitamin D deficiency and an increased risk of GDM. However, well-designed randomized controlled trials are needed to elicit the clear effect of vitamin D supplementation on prevention of GDM. PMID- 26437431 TI - Measurement Issues in Anthropometric Measures of Limb Volume Change in Persons at Risk for and Living with Lymphedema: A Reliability Study. AB - Understanding whether a true change has occurred during the process of care is of utmost importance in lymphedema management secondary to cancer treatments. Decisions about when to order a garment, start an exercise program, and begin or end therapy are based primarily on measurements of limb volume, based on circumferences taken by physiotherapists using a flexible tape. This study aimed to assess intra-rater and inter-rater reliability of measurements taken by physiotherapists of legs and arms with and without lymphedema and to evaluate whether there is a difference in reliability when measuring a healthy versus a lymphedematous limb. The intra-rater reliability of arm and leg measurements by trained physiotherapist is very high (scaled standard error of measurements (SEMs) for an arm and a leg volume were 0.82% and 0.64%, respectively) and a cut point of 1% scaled SEM may be recommended as a threshold for acceptable reliability. Physiotherapists can rely on the same error when assessing lymphedematous or healthy limbs. For those who work in teams and share patients, practice is needed in synchronizing the measurements and regularly monitoring their inter-rater reliability. PMID- 26437430 TI - Impact of Chromatin on HIV Replication. AB - Chromatin influences Human Immunodeficiency Virus (HIV) integration and replication. This review highlights critical host factors that influence chromatin structure and organization and that also impact HIV integration, transcriptional regulation and latency. Furthermore, recent attempts to target chromatin associated factors to reduce the HIV proviral load are discussed. PMID- 26437432 TI - A Real-Time Magnetoencephalography Brain-Computer Interface Using Interactive 3D Visualization and the Hadoop Ecosystem. AB - Ecumenically, the fastest growing segment of Big Data is human biology-related data and the annual data creation is on the order of zetabytes. The implications are global across industries, of which the treatment of brain related illnesses and trauma could see the most significant and immediate effects. The next generation of health care IT and sensory devices are acquiring and storing massive amounts of patient related data. An innovative Brain-Computer Interface (BCI) for interactive 3D visualization is presented utilizing the Hadoop Ecosystem for data analysis and storage. The BCI is an implementation of Bayesian factor analysis algorithms that can distinguish distinct thought actions using magneto encephalographic (MEG) brain signals. We have collected data on five subjects yielding 90% positive performance in MEG mid- and post-movement activity. We describe a driver that substitutes the actions of the BCI as mouse button presses for real-time use in visual simulations. This process has been added into a flight visualization demonstration. By thinking left or right, the user experiences the aircraft turning in the chosen direction. The driver components of the BCI can be compiled into any software and substitute a user's intent for specific keyboard strikes or mouse button presses. The BCI's data analytics OPEN ACCESS Brain. Sci. 2015, 5 420 of a subject's MEG brainwaves and flight visualization performance are stored and analyzed using the Hadoop Ecosystem as a quick retrieval data warehouse. PMID- 26437433 TI - Interaction Study of Phospholipid Membranes with an N-Glucosylated beta-Turn Peptide Structure Detecting Autoantibodies Biomarkers of Multiple Sclerosis. AB - The interaction of lipid environments with the type I' beta-turn peptide structure called CSF114 and its N-glucosylated form CSF114(Glc), previously developed as a synthetic antigenic probe recognizing specific autoantibodies in a subpopulation of multiple sclerosis patients' serum, was investigated by fluorescence spectroscopy and electrochemical experiments using large unilamellar vesicles, mercury supported lipid self-assembled monolayers (SAMs) and tethered bilayer lipid membranes (tBLMs). The synthetic antigenic probe N-glucosylated peptide CSF114(Glc) and its unglucosylated form interact with the polar heads of lipid SAMs of dioleoylphosphatidylcholine at nonzero transmembrane potentials, probably establishing a dual electrostatic interaction of the trimethylammonium and phosphate groups of the phosphatidylcholine polar head with the Glu5 and His8 residues on the opposite ends of the CSF114(Glc) beta-turn encompassing residues 6-9. His8 protonation at pH 7 eliminates this dual interaction. CSF114(Glc) is adsorbed on top of SAMs of mixtures of dioleoylphosphatidylcholine with sphingomyelin, an important component of myelin, whose proteins are hypothesized to undergo an aberrant N-glucosylation triggering the autoimmune response. Incorporation of the type I' beta-turn peptide structure CSF114 into lipid SAMs by potential scans of electrochemical impedance spectroscopy induces defects causing a slight permeabilization toward cadmium ions. The N-glucopeptide CSF114(Glc) does not affect tBLMs to a detectable extent. PMID- 26437434 TI - Cancer Metabolism and Drug Resistance. AB - Metabolic alterations, driven by genetic and epigenetic factors, have long been known to be associated with the etiology of cancer. Furthermore, accumulating evidence suggest that cancer metabolism is intimately linked to drug resistance, which is currently one of the most important challenges in cancer treatment. Altered metabolic pathways help cancer cells to proliferate at a rate higher than normal, adapt to nutrient limited conditions, and develop drug resistance phenotypes. Application of systems biology, boosted by recent advancement of novel high-throughput technologies to obtain cancer-associated, transcriptomic, proteomic and metabolomic data, is expected to make a significant contribution to our understanding of metabolic properties related to malignancy. Indeed, despite being at a very early stage, quantitative data obtained from the omics platforms and through applications of (13)C metabolic flux analysis (MFA) in in vitro studies, researchers have already began to gain insight into the complex metabolic mechanisms of cancer, paving the way for selection of molecular targets for therapeutic interventions. In this review, we discuss some of the major findings associated with the metabolic pathways in cancer cells and also discuss new evidences and achievements on specific metabolic enzyme targets and target directed small molecules that can potentially be used as anti-cancer drugs. PMID- 26437436 TI - New Insights into the Biological Role of Mammalian ADARs; the RNA Editing Proteins. AB - The ADAR proteins deaminate adenosine to inosine in double-stranded RNA which is one of the most abundant modifications present in mammalian RNA. Inosine can have a profound effect on the RNAs that are edited, not only changing the base-pairing properties, but can also result in recoding, as inosine behaves as if it were guanosine. In mammals there are three ADAR proteins and two ADAR-related proteins (ADAD) expressed. All have a very similar modular structure; however, both their expression and biological function differ significantly. Only two of the ADAR proteins have enzymatic activity. However, both ADAR and ADAD proteins possess the ability to bind double-strand RNA. Mutations in ADARs have been associated with many diseases ranging from cancer, innate immunity to neurological disorders. Here, we will discuss in detail the domain structure of mammalian ADARs, the effects of RNA editing, and the role of ADARs in human diseases. PMID- 26437437 TI - RNA-Binding Proteins in the Regulation of miRNA Activity: A Focus on Neuronal Functions. AB - Posttranscriptional modifications of messenger RNAs (mRNAs) are key processes in the fine-tuning of cellular homeostasis. Two major actors in this scenario are RNA binding proteins (RBPs) and microRNAs (miRNAs) that together play important roles in the biogenesis, turnover, translation and localization of mRNAs. This review will highlight recent advances in the understanding of the role of RBPs in the regulation of the maturation and the function of miRNAs. The interplay between miRNAs and RBPs is discussed specifically in the context of neuronal development and function. PMID- 26437435 TI - 4-Hydroxy-nonenal-A Bioactive Lipid Peroxidation Product. AB - This review on recent research advances of the lipid peroxidation product 4 hydroxy-nonenal (HNE) has four major topics: I. the formation of HNE in various organs and tissues, II. the diverse biochemical reactions with Michael adduct formation as the most prominent one, III. the endogenous targets of HNE, primarily peptides and proteins (here the mechanisms of covalent adduct formation are described and the (patho-) physiological consequences discussed), and IV. the metabolism of HNE leading to a great number of degradation products, some of which are excreted in urine and may serve as non-invasive biomarkers of oxidative stress. PMID- 26437438 TI - The Role of the COP9 Signalosome and Neddylation in DNA Damage Signaling and Repair. AB - The maintenance of genomic integrity is an important process in organisms as failure to sense and repair damaged DNA can result in a variety of diseases. Eukaryotic cells have developed complex DNA repair response (DDR) mechanisms to accurately sense and repair damaged DNA. Post-translational modifications by ubiquitin and ubiquitin-like proteins, such as SUMO and NEDD8, have roles in coordinating the progression of DDR. Proteins in the neddylation pathway have also been linked to regulating DDR. Of interest is the COP9 signalosome (CSN), a multi-subunit metalloprotease present in eukaryotes that removes NEDD8 from cullins and regulates the activity of cullin-RING ubiquitin ligases (CRLs). This in turn regulates the stability and turnover of a host of CRL-targeted proteins, some of which have established roles in DDR. This review will summarize the current knowledge on the role of the CSN and neddylation in DNA repair. PMID- 26437439 TI - Rho GTPases: Novel Players in the Regulation of the DNA Damage Response? AB - The Ras-related C3 botulinum toxin substrate 1 (Rac1) belongs to the family of Ras-homologous small GTPases. It is well characterized as a membrane-bound signal transducing molecule that is involved in the regulation of cell motility and adhesion as well as cell cycle progression, mitosis, cell death and gene expression. Rac1 also adjusts cellular responses to genotoxic stress by regulating the activity of stress kinases, including c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38 kinases as well as related transcription factors. Apart from being found on the inner side of the outer cell membrane and in the cytosol, Rac1 has also been detected inside the nucleus. Different lines of evidence indicate that genotoxin-induced DNA damage is able to activate nuclear Rac1. The exact mechanisms involved and the biological consequences, however, are unclear. The data available so far indicate that Rac1 might integrate DNA damage independent and DNA damage dependent cellular stress responses following genotoxin treatment, thereby coordinating mechanisms of the DNA damage response (DDR) that are related to DNA repair, survival and cell death. PMID- 26437441 TI - Molecular Process Producing Oncogene Fusion in Lung Cancer Cells by Illegitimate Repair of DNA Double-Strand Breaks. AB - Constitutive activation of oncogenes by fusion to partner genes, caused by chromosome translocation and inversion, is a critical genetic event driving lung carcinogenesis. Fusions of the tyrosine kinase genes ALK (anaplastic lymphoma kinase), ROS1 (c-ros oncogene 1), or RET (rearranged during transfection) occur in 1%-5% of lung adenocarcinomas (LADCs) and their products constitute therapeutic targets for kinase inhibitory drugs. Interestingly, ALK, RET, and ROS1 fusions occur preferentially in LADCs of never- and light-smokers, suggesting that the molecular mechanisms that cause these rearrangements are smoking-independent. In this study, using previously reported next generation LADC genome sequencing data of the breakpoint junction structures of chromosome rearrangements that cause oncogenic fusions in human cancer cells, we employed the structures of breakpoint junctions of ALK, RET, and ROS1 fusions in 41 LADC cases as "traces" to deduce the molecular processes of chromosome rearrangements caused by DNA double-strand breaks (DSBs) and illegitimate joining. We found that gene fusion was produced by illegitimate repair of DSBs at unspecified sites in genomic regions of a few kb through DNA synthesis-dependent or -independent end joining pathways, according to DSB type. This information will assist in the understanding of how oncogene fusions are generated and which etiological factors trigger them. PMID- 26437440 TI - Physicochemical Properties of Ion Pairs of Biological Macromolecules. AB - Ion pairs (also known as salt bridges) of electrostatically interacting cationic and anionic moieties are important for proteins and nucleic acids to perform their function. Although numerous three-dimensional structures show ion pairs at functionally important sites of biological macromolecules and their complexes, the physicochemical properties of the ion pairs are not well understood. Crystal structures typically show a single state for each ion pair. However, recent studies have revealed the dynamic nature of the ion pairs of the biological macromolecules. Biomolecular ion pairs undergo dynamic transitions between distinct states in which the charged moieties are either in direct contact or separated by water. This dynamic behavior is reasonable in light of the fundamental concepts that were established for small ions over the last century. In this review, we introduce the physicochemical concepts relevant to the ion pairs and provide an overview of the recent advancement in biophysical research on the ion pairs of biological macromolecules. PMID- 26437445 TI - Estimating Sustainable Live-Coral Harvest at Kamiali Wildlife Management Area, Papua New Guinea. AB - Live coral is harvested throughout the Indo-West Pacific to make lime, used in the consumption of the world's fourth-most consumed drug, betel nut. Coral harvesting is an environmental concern; however, because lime-making is one of the few sources of income in some areas of Papua New Guinea (PNG), the practice is unlikely to stop. To better manage coral harvest, we used standard fishery yield methods to generate sustainable-harvest guidelines for corymbose Acropora species found on the reef flat and crest at Lababia, PNG. We constructed a yield curve (weight-specific net annual-dry-weight production) by: 1) describing the allometric relationship between colony size and dry weight, and using that relationship to estimate the dry weight of Acropora colonies in situ; 2) estimating annual growth of Acropora colonies by estimating in situ, and describing the relationship between, colony dry weight at the beginning and end of one year; and 3) conducting belt-transect surveys to describe weight frequencies and ultimately to predict annual weight change per square meter for each weight class. Reef habitat covers a total 2,467,550 m2 at Lababia and produces an estimated 248,397 kg/y (dry weight) of corymbose Acropora, of which 203,897 kg is produced on the reef flat/crest. We conservatively estimate that 30,706.6 kg of whole, dry, corymbose, Acropora can be sustainably harvested from the reef flat/crest habitat each year provided each culled colony weighs at least 1805 g when dry (or is at least 46 cm along its major axis). Artisanal lime makers convert 24.8% of whole-colony weight into marketable lime, thus we estimate 7615.2 g of lime can be sustainably produced annually from corymbose Acropora. This value incorporates several safety margins, and should lead to proper management of live coral harvest. Importantly, the guideline recognizes village rights to exploit its marine resources, is consistent with village needs for income, and balances an equally strong village desire to conserve its marine resources for future generations. PMID- 26437443 TI - MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway. AB - The Hippo pathway plays a central role in tissue homoeostasis, and its dysregulation contributes to tumorigenesis. Core components of the Hippo pathway include a kinase cascade of MST1/2 and LATS1/2 and the transcription co activators YAP/TAZ. In response to stimulation, LATS1/2 phosphorylate and inhibit YAP/TAZ, the main effectors of the Hippo pathway. Accumulating evidence suggests that MST1/2 are not required for the regulation of YAP/TAZ. Here we show that deletion of LATS1/2 but not MST1/2 abolishes YAP/TAZ phosphorylation. We have identified MAP4K family members--Drosophila Happyhour homologues MAP4K1/2/3 and Misshapen homologues MAP4K4/6/7-as direct LATS1/2-activating kinases. Combined deletion of MAP4Ks and MST1/2, but neither alone, suppresses phosphorylation of LATS1/2 and YAP/TAZ in response to a wide range of signals. Our results demonstrate that MAP4Ks act in parallel to and are partially redundant with MST1/2 in the regulation of LATS1/2 and YAP/TAZ, and establish MAP4Ks as components of the expanded Hippo pathway. PMID- 26437444 TI - Interleukin-23 Facilitates Thyroid Cancer Cell Migration and Invasion by Inhibiting SOCS4 Expression via MicroRNA-25. AB - Interleukin-23 (IL-23) is a conventional proinflammatory cytokine that plays a role in tumor progression by inducing inflammation in the tumor microenvironment. However, the role of IL-23 in thyroid cancer migration and invasion remains unclear. In the present study, we observed that the treatment with IL-23, induced migration and invasion in human thyroid cancer cells. Additional data demonstrate that SOCS4 negatively regulates IL-23-mediated migration and invasion. On investigating the mechanisms involved in IL-23 mediated migration and invasion, we observed that miR-25 promotes the migration and invasion of thyroid cancer cells by directly binding to the 3'-UTR of SOCS4 that leads to the inhibition of SOCS4. In addition, we also demonstrated that IL-23 increases miR-25 expression levels, and overexpressed miR-25 is involved in IL-23-associated SOCS4 inhibition and cell migration and invasion. Together, our data suggest that IL-23 induces migration and invasion in thyroid cancer cells by mediating the miR-25/SOCS4 signaling pathway. PMID- 26437442 TI - Potential Role of the Gut/Liver/Lung Axis in Alcohol-Induced Tissue Pathology. AB - Both Alcoholic Liver Disease (ALD) and alcohol-related susceptibility to acute lung injury are estimated to account for the highest morbidity and mortality related to chronic alcohol abuse and, thus, represent a focus of intense investigation. In general, alcohol-induced derangements to both organs are considered to be independent and are often evaluated separately. However, the liver and lung share many general responses to damage, and specific responses to alcohol exposure. For example, both organs possess resident macrophages that play key roles in mediating the immune/inflammatory response. Additionally, alcohol induced damage to both organs appears to involve oxidative stress that favors tissue injury. Another mechanism that appears to be shared between the organs is that inflammatory injury to both organs is enhanced by alcohol exposure. Lastly, altered extracellular matrix (ECM) deposition appears to be a key step in disease progression in both organs. Indeed, recent studies suggest that early subtle changes in the ECM may predispose the target organ to an inflammatory insult. The purpose of this chapter is to review the parallel mechanisms of liver and lung injury in response to alcohol consumption. This chapter will also explore the potential that these mechanisms are interdependent, as part of a gut-liver-lung axis. PMID- 26437446 TI - Hydroxyflutamide affects connexin 43 via the activation of PI3K/Akt-dependent pathway but has no effect on the crosstalk between PI3K/Akt and ERK1/2 pathways at the Raf-1 kinase level in primary rat Sertoli cells. AB - We investigated the effects of 2-hydroxyflutamide (HF), an active metabolite of the anti-androgen flutamide, on the activation of the phosphoinositide-3 kinase/protein kinase B (PI3K/Akt) in rat Sertoli cells. Sertoli cells, isolated from 20-day-old rat testes, were cultured in vitro and treated with HF, testosterone, or HF+testosterone. Studies by western blotting demonstrated that HF inhibited the testosterone-mediated increase in c-Src activity (p<0.05). In contrast, Akt phosphorylation was augmented within 5 min after HF treatment (p<0.01). This effect was accompanied by a rapid upregulation in PTEN phosphorylation (p<0.001). Despite no changes in Raf-1 phosphorylation, HF increased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation (p<0.001), indicating that the effect of the anti-androgen on ERK1/2 was independent of PI3K/Akt-pathway activation at this level. Since HF inhibited the testosterone-mediated increase in c-Src activity, it is likely that activation of both Akt and ERK1/2 occurred in a p-Src independent manner. Activation of PI3K/Akt-pathway by HF resulted in the reduced level of Sertoli cell functional marker, connexin 43 (p<0.01). Collectively, these data provide evidence that HF rapidly and transiently affects the protein kinase-dependent signaling pathways, acting both as an antagonist and agonist. Moreover, using testes of flutamide treated rats for 7 days, we demonstrated that the anti-androgen can modulate the protein kinase-dependent pathways in long term by enhancing Akt and ERK1/2 protein expression (p<0.05). PMID- 26437448 TI - Impact of Michelangelo prosthetic hand: Findings from a crossover longitudinal study. AB - This work explores the functional and psychosocial impact of the multigrip Michelangelo (M) prosthetic hand. Transradial myoelectric prosthesis users (6 men, median age: 47 y) participated in a crossover longitudinal study. A multifactorial assessment protocol was applied before the application of M and after 3 mo (functional assessment) and 6 mo (psychosocial assessment) of home use. Functional assessment included both practical tests (i.e., Southampton Hand Assessment Procedure [SHAP], Box and Blocks Test [BBT], and Minnesota Manual Dexterity Test [MMDT]) and self-report functional scales. Psychosocial assessment consisted of a clinical interview and a battery of self-report questionnaires concerning current anxious-depressive symptoms and health-related quality of life, body image concerns, adjustment and satisfaction with prosthesis, social support, coping style, and personality. Increased manual dexterity was observed after 3 mo based on improvements in the SHAP, BBT, and MMDT. Two important themes emerged from the clinical interviews at the 6 mo follow-up: (1) the enhanced functionality and (2) the "like a real hand" aspect of the M, which further increased prosthesis integration to the Self. A few patients expressed concerns about M dimension, noise, and weight. The M appeared to restore hand function and natural appearance. The present findings provide preliminary evidence, and additional studies are needed. PMID- 26437447 TI - Discovery of a Novel Mutation (X8Del) Resulting in an 8-bp Deletion in the Hepatitis B Virus X Gene Associated with Occult Infection in Korean Vaccinated Individuals. AB - Universal infantile hepatitis B virus (HBV) vaccination may lead to an increase in vaccine escape variants, which may pose a threat to the long-term success of massive vaccination. To determine the prevalence of occult infections in Korean vaccinated individuals, 87 vaccinated subjects were screened for the presence of HBV DNA using both the nested PCR protocol and the VERSANT HBV DNA 3.0 assay. The mutation patterns of variants were analyzed in full-length HBV genome sequences. Their HBsAg secretion and replication capacities were investigated using both in vitro transient transfection and in vivo hydrodynamic injection. The presence of HBV DNA was confirmed in 6 subjects (6.9%). All six variants had a common mutation type (X8Del) composed of an 8-bp deletion in the C-terminal region of the HBV X gene (HBxAg). Our in vitro and in vivo analyses using the full-length HBV genome indicated that the X8Del HBxAg variant reduced the secretion of HBsAg and HBV virions compared to the wild type. In conclusion, our data suggest that a novel mutation (X8Del) may contribute to occult HBV infection in Korean vaccinated individuals via a reduced secretion of HBsAg and virions, possibly by compromising HBxAg's transacting capacity. PMID- 26437450 TI - Prioritizing Clinically Relevant Copy Number Variation from Genetic Interactions and Gene Function Data. AB - It is becoming increasingly necessary to develop computerized methods for identifying the few disease-causing variants from hundreds discovered in each individual patient. This problem is especially relevant for Copy Number Variants (CNVs), which can be cheaply interrogated via low-cost hybridization arrays commonly used in clinical practice. We present a method to predict the disease relevance of CNVs that combines functional context and clinical phenotype to discover clinically harmful CNVs (and likely causative genes) in patients with a variety of phenotypes. We compare several feature and gene weighing systems for classifying both genes and CNVs. We combined the best performing methodologies and parameters on over 2,500 Agilent CGH 180k Microarray CNVs derived from 140 patients. Our method achieved an F-score of 91.59%, with 87.08% precision and 97.00% recall. Our methods are freely available at https://github.com/compbio UofT/cnv-prioritization. Our dataset is included with the supplementary information. PMID- 26437449 TI - Effect of a Multi-Dimensional and Inter-Sectoral Intervention on the Adherence of Psychiatric Patients. AB - BACKGROUND: In psychiatry, hospital stays and transitions to the ambulatory sector are susceptible to major changes in drug therapy that lead to complex medication regimens and common non-adherence among psychiatric patients. A multi dimensional and inter-sectoral intervention is hypothesized to improve the adherence of psychiatric patients to their pharmacotherapy. METHODS: 269 patients from a German university hospital were included in a prospective, open, clinical trial with consecutive control and intervention groups. Control patients (09/2012 03/2013) received usual care, whereas intervention patients (05/2013-12/2013) underwent a program to enhance adherence during their stay and up to three months after discharge. The program consisted of therapy simplification and individualized patient education (multi-dimensional component) during the stay and at discharge, as well as subsequent phone calls after discharge (inter sectoral component). Adherence was measured by the "Medication Adherence Report Scale" (MARS) and the "Drug Attitude Inventory" (DAI). RESULTS: The improvement in the MARS score between admission and three months after discharge was 1.33 points (95% CI: 0.73-1.93) higher in the intervention group compared to controls. In addition, the DAI score improved 1.93 points (95% CI: 1.15-2.72) more for intervention patients. CONCLUSION: These two findings indicate significantly higher medication adherence following the investigated multi-dimensional and inter-sectoral program. TRIAL REGISTRATION: German Clinical Trials Register DRKS00006358. PMID- 26437451 TI - Black-white differences in cancer risk in Harare, Zimbabwe, during 1991-2010. AB - Data from 20 years of cancer registration in Harare (Zimbabwe) are used to investigate the risk of cancer in the white population of the city (of European origin), relative to that in blacks (of African origin). In the absence of information on the respective populations-at-risk, we calculated odds of each major cancer among all cancers, and took the odds ratios of whites to blacks. Some major differences reflect obvious phenotypic differences (the very high incidence of skin cancer-melanoma and nonmelanoma--in the white population), whereas others (high rates of liver cancer, Kaposi sarcoma and conjunctival cancers in blacks) are the result of differences in exposure to infectious agents. Of particular interest are cancers related to lifestyle factors, and how the differences in risk are changing over time, as a result of evolving lifestyles. Thus, the high risk of cancers of the esophagus and cervix uteri in blacks (relative to whites) and colorectal cancers in whites show little change over time. Conversely, the odds of breast cancer, on average four times higher in whites than blacks, has shown a significant decrease in the differential over time. Cancer of the prostate, with the odds initially (1991-1997) 15% higher in whites had become 33% higher in blacks by 2004-2010. PMID- 26437453 TI - Correction: DNA damage induces nuclear actin filament assembly by Formin-2 and Spire-1/2 that promotes efficient DNA repair. PMID- 26437452 TI - Nanoparticulate carbon black in cigarette smoke induces DNA cleavage and Th17 mediated emphysema. AB - Chronic inhalation of cigarette smoke is the major cause of sterile inflammation and pulmonary emphysema. The effect of carbon black (CB), a universal constituent of smoke derived from the incomplete combustion of organic material, in smokers and non-smokers is less known. In this study, we show that insoluble nanoparticulate carbon black (nCB) accumulates in human myeloid dendritic cells (mDCs) from emphysematous lung and in CD11c(+) lung antigen presenting cells (APC) of mice exposed to smoke. Likewise, nCB intranasal administration induced emphysema in mouse lungs. Delivered by smoking or intranasally, nCB persisted indefinitely in mouse lung, activated lung APCs, and promoted T helper 17 cell differentiation through double-stranded DNA break (DSB) and ASC-mediated inflammasome assembly in phagocytes. Increasing the polarity or size of CB mitigated many adverse effects. Thus, nCB causes sterile inflammation, DSB, and emphysema and explains adverse health outcomes seen in smokers while implicating the dangers of nCB exposure in non-smokers. PMID- 26437455 TI - Reactive Charged Droplets for Reduction of Matrix Effects in Electrospray Ionization Mass Spectrometry. AB - A new quantitative contained-electrospray (ES) process is described here that employs a movable ES emitter to control the reactivity of charged microdroplets by varying their exposure time with acid vapor. The method allows elimination of ion suppression effects caused by the presence of various surface active compounds that coelute with the analyte. For mixtures, contained-ESI mass spectrometric analysis produces relative ion intensities that reflect the true concentrations of analytes in solution. The mechanism for this effect has been elucidated and ascribed to the generation of fine initial droplets in the presence of a high abundance of protons; together, these two factors eliminate competition for charge and space during ion formation. Examples of analytes tested include steroids, phospholipids, phosphopeptides, and sialylated glycans. At least 1 order of magnitude improvement in detection limits, sensitivity, and accuracy of detection was observed when compared to conventional electrospray. PMID- 26437454 TI - Using Social Media for Actionable Disease Surveillance and Outbreak Management: A Systematic Literature Review. AB - OBJECTIVE: Research studies show that social media may be valuable tools in the disease surveillance toolkit used for improving public health professionals' ability to detect disease outbreaks faster than traditional methods and to enhance outbreak response. A social media work group, consisting of surveillance practitioners, academic researchers, and other subject matter experts convened by the International Society for Disease Surveillance, conducted a systematic primary literature review using the PRISMA framework to identify research, published through February 2013, answering either of the following questions: Can social media be integrated into disease surveillance practice and outbreak management to support and improve public health?Can social media be used to effectively target populations, specifically vulnerable populations, to test an intervention and interact with a community to improve health outcomes?Examples of social media included are Facebook, MySpace, microblogs (e.g., Twitter), blogs, and discussion forums. For Question 1, 33 manuscripts were identified, starting in 2009 with topics on Influenza-like Illnesses (n = 15), Infectious Diseases (n = 6), Non-infectious Diseases (n = 4), Medication and Vaccines (n = 3), and Other (n = 5). For Question 2, 32 manuscripts were identified, the first in 2000 with topics on Health Risk Behaviors (n = 10), Infectious Diseases (n = 3), Non infectious Diseases (n = 9), and Other (n = 10). CONCLUSIONS: The literature on the use of social media to support public health practice has identified many gaps and biases in current knowledge. Despite the potential for success identified in exploratory studies, there are limited studies on interventions and little use of social media in practice. However, information gleaned from the articles demonstrates the effectiveness of social media in supporting and improving public health and in identifying target populations for intervention. A primary recommendation resulting from the review is to identify opportunities that enable public health professionals to integrate social media analytics into disease surveillance and outbreak management practice. PMID- 26437457 TI - Morpho-syntactic processing of Arabic plurals after aphasia: dissecting lexical meaning from morpho-syntax within word boundaries. AB - Within the domain of inflectional morpho-syntax, differential processing of regular and irregular forms has been found in healthy speakers and in aphasia. One view assumes that irregular forms are retrieved as full entities, while regular forms are compiled on-line. An alternative view holds that a single mechanism oversees regular and irregular forms. Arabic offers an opportunity to study this phenomenon, as Arabic nouns contain a consonantal root, delivering lexical meaning, and a vocalic pattern, delivering syntactic information, such as gender and number. The aim of this study is to investigate morpho-syntactic processing of regular (sound) and irregular (broken) Arabic plurals in patients with morpho-syntactic impairment. Three participants with acquired agrammatic aphasia produced plural forms in a picture-naming task. We measured overall response accuracy, then analysed lexical errors and morpho-syntactic errors, separately. Error analysis revealed different patterns of morpho-syntactic errors depending on the type of pluralization (sound vs broken). Omissions formed the vast majority of errors in sound plurals, while substitution was the only error mechanism that occurred in broken plurals. The dissociation was statistically significant for retrieval of morpho-syntactic information (vocalic pattern) but not for lexical meaning (consonantal root), suggesting that the participants' selective impairment was an effect of the morpho-syntax of plurals. These results suggest that irregular plurals forms are stored, while regular forms are derived. The current findings support the findings from other languages and provide a new analysis technique for data from languages with non-concatenative morpho-syntax. PMID- 26437456 TI - Urban Market Gardening and Rodent-Borne Pathogenic Leptospira in Arid Zones: A Case Study in Niamey, Niger. AB - Leptospirosis essentially affects human following contact with rodent urine contaminated water. As such, it was mainly found associated with rice culture, recreational activities and flooding. This is also the reason why it has mainly been investigated in temperate as well as warm and humid regions, while arid zones have been only very occasionally monitored for this disease. In particular, data for West African countries are extremely scarce. Here, we took advantage of an extensive survey of urban rodents in Niamey, Niger, in order to look for rodent-borne pathogenic Leptospira species presence and distribution across the city. To do so, we used high throughput bacterial 16S-based metabarcoding, lipL32 gene-targeting RT-PCR, rrs gene sequencing and VNTR typing as well as GIS-based multivariate spatial analysis. Our results show that leptospires seem absent from the core city where usual Leptospira reservoir rodent species (namely R. rattus and M. natalensis) are yet abundant. On the contrary, L. kirschneri was detected in Arvicanthis niloticus and Cricetomys gambianus, two rodent species that are restricted to irrigated cultures within the city. Moreover, the VNTR profiles showed that rodent-borne leptospires in Niamey belong to previously undescribed serovars. Altogether, our study points towards the importance of market gardening in maintain and circulation of leptospirosis within Sahelian cities. In Africa, irrigated urban agriculture constitutes a pivotal source of food supply, especially in the context of the ongoing extensive urbanization of the continent. With this in mind, we speculate that leptospirosis may represent a zoonotic disease of concern also in arid regions that would deserve to be more rigorously surveyed, especially in urban agricultural settings. PMID- 26437458 TI - Penetrative Injury to the Face Resulting in Delayed Death After Rupture of a Cavernous Sinus Aneurysm on the Contralateral Side. AB - Delayed deaths after assault give rise to medicolegal issues such as whether the assault was directly responsible, did it contribute or was it totally unrelated to the death. We present the case of a patient who sustained penetrative trauma to the face resulting in the formation of a contralateral, carotid-cavernous fistula, which resulted in aneurysm formation, delayed rupture, and death. A literature search failed to find a similar case. PMID- 26437459 TI - Biogenic Amines and the Amino Acids GABA and Glutamate: Relationships with Pain and Depression. AB - Although it is well known that there is a high degree of comorbidity between chronic pain and mood and anxiety disorders, the mechanisms involved in these co occurrences are not clear. It appears that numerous neurotransmitters and neuromodulators are involved, and this chapter focuses on the monoamine neurotransmitters noradrenaline, 5-hydroxytryptamine (5-HT, serotonin), and dopamine and the amino acid neurotransmitters GABA (gamma-aminobutyric acid) and glutamate in chronic pain and depression. Numerous preclinical and clinical neurochemical, neuroanatomical, pharmacological and molecular biological studies as well as clinical pharmacological treatment investigations implicate noradrenaline, 5-HT and, to a lesser extent, dopamine in the etiology of pain and depression. Similarly, preclinical and clinical studies on GABAergic and glutamatergic mechanisms as well as reports on the actions of neuroactive steroids suggest that GABA and glutamate play an important role in the etiology of pain and depression and may contribute to comorbidity. PMID- 26437460 TI - Predicting Neuroinflammation in Morphine Tolerance for Tolerance Therapy from Immunostaining Images of Rat Spinal Cord. AB - Long-term morphine treatment leads to tolerance which attenuates analgesic effect and hampers clinical utilization. Recent studies have sought to reveal the mechanism of opioid receptors and neuroinflammation by observing morphological changes of cells in the rat spinal cord. This work proposes a high-content screening (HCS) based computational method, HCS-Morph, for predicting neuroinflammation in morphine tolerance to facilitate the development of tolerance therapy using immunostaining images for astrocytes, microglia, and neurons in the spinal cord. HCS-Morph first extracts numerous HCS-based features of cellular phenotypes. Next, an inheritable bi-objective genetic algorithm is used to identify a minimal set of features by maximizing the prediction accuracy of neuroinflammation. Finally, a mathematic model using a support vector machine with the identified features is established to predict drug-treated images to assess the effects of tolerance therapy. The dataset consists of 15 saline controls (1 MUl/h), 15 morphine-tolerant rats (15 MUg/h), and 10 rats receiving a co-infusion of morphine (15 MUg/h) and gabapentin (15 MUg/h, Sigma). The three individual models of astrocytes, microglia, and neurons for predicting neuroinflammation yielded respective Jackknife test accuracies of 96.67%, 90.00%, and 86.67% on the 30 rats, and respective independent test accuracies of 100%, 90%, and 60% on the 10 co-infused rats. The experimental results suggest that neuroinflammation activity expresses more predominantly in astrocytes and microglia than in neuron cells. The set of features for predicting neuroinflammation from images of astrocytes comprises mean cell intensity, total cell area, and second-order geometric moment (relating to cell distribution), relevant to cell communication, cell extension, and cell migration, respectively. The present investigation provides the first evidence for the role of gabapentin in the attenuation of morphine tolerance from phenotypic changes of astrocytes and microglia. Based on neuroinflammation prediction, the proposed computer-aided image diagnosis system can greatly facilitate the development of tolerance therapy with anti-inflammatory drugs. PMID- 26437461 TI - Risk of Demyelinating Diseases in the Central Nervous System in Patients With Inflammatory Bowel Disease Treated With Tumor Necrosis Factor Inhibitors. PMID- 26437464 TI - Snoring-Induced Vibratory Angioedema. AB - BACKGROUND: Vibratory angioedema (VA) is a rare physical urticaria, with symptoms of itching and swelling of the skin or mucosa when it is exposed to vibration. Avoidance of vibration is the best way to manage this condition. This case report will assist physicians to diagnose this rare condition. Here, a previously unpublished potential successful treatment modality is being presented, with good symptom control, along with some photographs taken during an acute attack. A literature review points towards potential undiagnosed cases. CASE REPORT: A 70 year-old woman had multiple emergency department visits for tongue and throat swelling over 3 years. The episodes always happened at night. Detailed history elicited some episodes of itching and swelling of hands when driving as well as significant snoring while sleeping. Physical examination was unremarkable except for morbid obesity. Complement factor 4 and C1esterase inhibitor level were within normal limits. A tentative diagnosis of angioedema induced by oropharyngeal vibration from snoring was made. A sleep study confirmed sleep apnea with severe snoring. After CPAP (continuous positive airway pressure) treatment, she had successful symptom control. CONCLUSIONS: Snoring-induced VA is very likely an under-diagnosed condition in the community. The typical history is the key to the diagnosis. This condition could be confirmed by vibration test or by the resolution of symptoms with elimination of vibration. Effective symptom control is possible by avoidance of oropharyngeal vibration from snoring with the administration of CPAP therapy, making it a potential novel indication for this condition. PMID- 26437463 TI - Development of a Radiolabeled Peptide-Based Probe Targeting MT1-MMP for Breast Cancer Detection. AB - Breast cancer is one of the most frequent and aggressive primary tumors among women of all races. Matrix metalloproteinase (MMPs), a family of zinc- and calcium-dependent secreted or membrane anchored endopeptidases, is overexpressed in varieties of diseases including breast cancer. Therefore, noninvasive visualization and quantification of MMP in vivo are of great interest in basic research and clinical application for breast cancer early diagnosis. Herein, we developed a 99mTc labeled membrane type I matrix metalloproteinase (MT1-MMP) specific binding peptide, [99mTc]-(HYNIC-AF7p)(tricine)(TPPTS), for in vivo detection of MDA-MB-231 breast tumor by single photon emission computed tomography (SPECT). [99mTc]-(HYNIC-AF7p)(tricine)(TPPTS) demonstrated nice biostability and high MT1-MMP binding affinity in vitro and in vivo. Tumor-to muscle ratio was found to reach to the highest (4.17+/-0.49) at 2 hour after intravenously administration of [99mTc]-(HYNIC-AF7P)(tricine)(TPPTS) into MDA-MB 231 tumor bearing mice. Overall, [99mTc]-(HYNIC-AF7P)(tricine)(TPPTS) demonstrated great potential for MT1-MMP targeted detection in vivo and it would be a promising molecular imaging probe that are probably beneficial to breast cancer early diagnoses. PMID- 26437462 TI - Familial Dysautonomia (FD) Human Embryonic Stem Cell Derived PNS Neurons Reveal that Synaptic Vesicular and Neuronal Transport Genes Are Directly or Indirectly Affected by IKBKAP Downregulation. AB - A splicing mutation in the IKBKAP gene causes Familial Dysautonomia (FD), affecting the IKAP protein expression levels and proper development and function of the peripheral nervous system (PNS). Here we found new molecular insights for the IKAP role and the impact of the FD mutation in the human PNS lineage by using a novel and unique human embryonic stem cell (hESC) line homozygous to the FD mutation originated by pre implantation genetic diagnosis (PGD) analysis. We found that IKBKAP downregulation during PNS differentiation affects normal migration in FD-hESC derived neural crest cells (NCC) while at later stages the PNS neurons show reduced intracellular colocalization between vesicular proteins and IKAP. Comparative wide transcriptome analysis of FD and WT hESC-derived neurons together with the analysis of human brains from FD and WT 12 weeks old embryos and experimental validation of the results confirmed that synaptic vesicular and neuronal transport genes are directly or indirectly affected by IKBKAP downregulation in FD neurons. Moreover we show that kinetin (a drug that corrects IKBKAP alternative splicing) promotes the recovery of IKAP expression and these IKAP functional associated genes identified in the study. Altogether, these results support the view that IKAP might be a vesicular like protein that might be involved in neuronal transport in hESC derived PNS neurons. This function seems to be mostly affected in FD-hESC derived PNS neurons probably reflecting some PNS neuronal dysfunction observed in FD. PMID- 26437466 TI - Reply to the Editorial published in this issue on breastfeeding and ECC. PMID- 26437465 TI - Effect of smoke-free legislation on perinatal and child health: a systematic review and meta-analysis. PMID- 26437467 TI - Reply to the Editorial published in issue 2/2005 on nutrition and dentistry. PMID- 26437468 TI - [Proceeding of 44th annual meeting of the Japanese Society of Neuropsychopharmacology. Nagoya, Japan. November 20-22, 2014. Abstracts]. PMID- 26437469 TI - [The patient-user-citizen revolution continues]. PMID- 26437470 TI - On Fifty-Plus Shades of graying Patients and Their Needs for Special Dentists. PMID- 26437471 TI - Age and Frailty in Prosthodontics. PMID- 26437472 TI - [Abstracts of the 45th Eastern/Western Regional Meeting, Japanese Society of Nephrology. 2015. Japan]. PMID- 26437474 TI - [Abstracts of the 99th Congress of the Japanese Society of Legal Medicine. June 10-12, 2015, Kouchi, Japan]. PMID- 26437473 TI - Erratum. PMID- 26437475 TI - [Abstracts of the 27th Annual Meeting of the Japanese Society of Clinical Toxicology. July 4, 2015. Kanazawa, Japan]]. PMID- 26437476 TI - [A Grand Lady and two self-made men: testimony of a patient-investigator]. AB - The psychological distress of a person, a parent in this case, can have very significant impact on family dynamics and the fate of all family members. They may become unwitting experts of mental health, by accompanying necessity and with their own vulnerabilities, sometimes trying to understand misunderstanding. This story is that of a patient-investigator who questioned the impact that mental illness has had on his professional life and his career choices. Going back to distant childhood memories, this exercise has proved to be an introspective work or observation of an individual conscience by itself. The fruit of this reflection is the story of a double conversion, spiritual and scientific, and this attempt to find sense and meaning to this personal journey becomes a socially engaged ethics of research in mental health and psychiatry. PMID- 26437477 TI - [In Process Citation]. PMID- 26437478 TI - [In Process Citation]. PMID- 26437479 TI - [In Process Citation]. PMID- 26437480 TI - [In Process Citation]. PMID- 26437481 TI - Beyond the Walls: Moving To Population Health. PMID- 26437482 TI - Strategies and Vision: Looking Back from 2015. PMID- 26437483 TI - Expanded Business View Benefits Catholic Systems. PMID- 26437484 TI - THE FUTURE HAS ARRIVED: Shared, Collaborative and Sustainable. PMID- 26437485 TI - TODAY'S TRANSFORMATIONAL MISSION: Opportunity Abounds to Bring More People Better Care. PMID- 26437486 TI - How Collaboration Becomes Partnership. PMID- 26437487 TI - INTERVIEW WITH KEVIN E. LOFTON: Umbrella of Approaches Keeps Focus on Growth. PMID- 26437488 TI - Sustaining the Mission through Mergers, Alliances, Partnerships. PMID- 26437489 TI - SPEAKING IN A UNIFIED VOICE: The Power of 'We'. PMID- 26437490 TI - Catholic Identity and the Reshaping of Health Care. PMID- 26437491 TI - Taking an Untraditional View of Partnerships. PMID- 26437492 TI - Investment in Innovation Can Bring Transformative Change. PMID- 26437494 TI - THE CHALLENGES OF PRECISION MEDICINE. PMID- 26437493 TI - MISSION LEADER SUCCESSION PLANNING: What If We Acted as One Ministry? PMID- 26437495 TI - Using the Voice of the Church. PMID- 26437496 TI - CHILDHOOD OBESITY: Report from the First Round of CHNAs and Implementation Strategies. PMID- 26437497 TI - Physical effects of non-cavitated explorer probing on enamel smooth-surface carious lesions. AB - PURPOSE: To assess the physical effects of explorer probing on non-cavitated smooth-surface enamel carious lesions. METHODS: Extracted teeth with white enamel decalcification (ICDAS 2) were used. Indentations were made in decalcified and non-decalcified regions with a #23 explorer using "scratch" or "poke" application and 100g, 300g or 600g force. Specimens were imaged with SEM and polarizing light microscopy. Indentation widths were measured digitally. Two-way ANOVA with pair wise comparisons was used to assess interactions of force and enamel condition (normal or carious) on indentation groove width. RESULTS: No or minimal effect was seen on normal enamel surface morphology. For the decalcified regions, defects were seen in SEM and polarizing light images. Findings included a smear layer, open clefts, lateral debris and micro-fractures. Two-way ANOVA for effects of force and enamel quality on mean groove width showed statistically significant differences for both variables for all teeth tested. PMID- 26437498 TI - Confirmation of efficacy in providing relief from the pain of dentin hypersensitivity of an anhydrous dentifrice containing 0.454% with or without stannous fluoride in an 8-week randomized clinical trial. AB - PURPOSE: To compare the efficacy of an anhydrous dentifrice containing 0.454% w/w stannous fluoride and a negative control dentifrice containing 1,000 ppm fluoride, as sodium monofluorophosphate, at reducing dentin hypersensitivity over 8 weeks with twice-daily brushing. METHODS: This was a randomized, examiner blind, parallel, two treatment group, stratified (by maximum baseline Schiff sensitivity score), 8-week clinical study carried out at a single site in 119 healthy subjects with at least two sensitive teeth, who met all study criteria at the screening and baseline visits. Clinical assessments of sensitivity to evaporative (air) [with Schiff sensitivity score and visual analogue scale (VAS)] and tactile (Yeaple probe) stimuli were employed to compare the efficacy of the test dentifrice containing 0.454% w/w stannous fluoride to the negative control dentifrice at reducing sensitivity after 4 and 8 weeks treatment. RESULTS: Of the 119 subjects randomized to study treatment, 113 completed the study. At 4 and 8 weeks, between treatment analyses found the test dentifrice to be significantly better than the negative control dentifrice in relieving dentin hypersensitivity for all measures (Schiff: P < 0.0001 at 4 and 8 weeks; VAS score: P = 0.0003 at 4 weeks, P < 0.0001 at 8 weeks; tactile threshold: P = 0.0138 at 4 weeks, P < 0.0001 at 8 weeks). PMID- 26437499 TI - Gingival health benefits of essential oil, 0.075% cetylpyridinium chloride and control mouthrinses: A 4-week randomized clinical study. AB - PURPOSE: This randomized, single center, examiner-blind, controlled, parallel group, 4-week clinical study compared the antiplaque/anti-gingivitis efficacy of an essential oil (EO) containing mouthrinse versus a 0.075% cetylpyridinium chloride (CPC) containing mouthrinse. A 5% hydroalcohol solution was included as a control group. METHODS: 165 systemically healthy volunteers (18-72 years of age), with mild to moderate plaque-related gingivitis were enrolled in this clinical trial; 162 subjects completed the study. At baseline and 4-week visits, subjects received an oral examination, gingivitis (MGI), gingival bleeding (BI) and plaque (PI) assessments. Following randomization, subjects began rinsing with 20 mL of the assigned mouthrinse for 30 seconds, in conjunction with their usual oral hygiene, twice daily for the duration of the study. RESULTS: All rinses were well tolerated by the subjects. EO was statistically significantly superior to CPC with a reduction in mean MGI of 5.9%, and in mean PI of 6.4%. Statistically significant reductions in gingivitis, bleeding and plaque were observed for both EO and CPC when compared to the negative control; mean MGI and mean PI were reduced by 13.0% and 18.9% for EO and by 7.6% and 13.3% for CPC. EO also statistically significantly reduced the proportion of gingival bleeding sites compared to CPC by 7.6% (P = 0.012) and compared to control by 10.6% (P < 0.001). For the post hoc sitewise analyses, at 4 weeks, the mean percentage of healthy sites for EO, CPC and Control were 7.4%, 1.1% and 0.8%, respectively and the mean percentage of virtually plaque free sites for EO, CPC and control were 5.4%, 3.8% and 0.4% respectively. The mean percentages of more inflamed gingival sites for EO, CPC and control were 20.4%, 26.2% and 45.7%, respectively. The mean percentage of tooth surfaces with heavier accumulations of plaque (PI scores >= 3) was 50.9% for EO, 56.1% for CPC and 81.1% for control. Reduction of gingival inflammation and dental plaque was statistically significantly superior for EO compared to both 0.075% CPC and negative control. Both marketed antimicrobial mouthrinses showed a beneficial result in gingival health and in reducing plaque accumulation as early as 4 weeks. PMID- 26437501 TI - Radiolucent halos beneath composite restorations do not justify restoration replacement. AB - PURPOSE: To determine the correlation between the presence of radiolucent areas (RA) beneath composite restorations and gaps and remaining demineralized tissue (RDT). METHODS: 50 extracted teeth (sound and carious) were studied. After caries removal, cavities were filled. Artificial cavities were created and filled in the sound teeth. Samples were sectioned and analyzed with stereomicroscopy. RESULTS: Gap/RDT was observed in 38.9% [95% confidence interval (CI) =28.2-50.5] and 68.9% (95% CI = 57-78.6) of sound and carious teeth, respectively, (P = 0.001). Gap/RDT was associated with RA (P < 0.001). Sensitivity, specificity, predictive positive values (PPV), predictive negative value, and accuracy for carious teeth were 77.1% (95% CI = 63.7-87.3), 54.5% (95% CI = 33.8-74.1), 78.7% (95% CI = 65.3- 88.7), 52.2% (95% CI = 32.1-71.7), and 70% (95% CI = 58.5-79.8), and for sound teeth were 73.7% (95% CI = 62.9-82.6), 59.1% (95% CI = 47.0-70.4), 67.5% (95% CI = 56.9-76.9), 66.1% (95% CI = 53.4-77.3), and 66.9% (95% CI = 58.9-74.3). Only the PPV differed between the sound and carious teeth (P = 0.024).There was a correlation between radiolucency and gap/RDT, but a high number of false positives were found. PMID- 26437500 TI - Does refurbishing composites lead to short-term effects or long-lasting improvement? AB - PURPOSE: To evaluate the clinical performance of refurbished resin composite restorations compared to untreated (negative control) restorations over a period of 10 years. METHODS: 26 subjects (having a total of 52 composite restorations) were recruited. All restorations in the refurbished group showed clinical features rated bravo according to modified USPHS criteria. Untreated restorations were those that had been deemed acceptable (alpha or bravo rated); these were used as controls. Two examiners performed assessments at baseline and during the 5th and 10th years after the intervention. Wilcoxon tests were performed for within-group comparisons, Friedman tests were used for multiple within-group comparisons, and Mann Whitney tests were used for between-groups comparisons. Kaplan-Meier survival curves were calculated, and the Mantel-Cox test was used to compare curves. P < 0.05 was considered statistically significant. RESULTS: In both groups, 10-year scores were significantly different from baseline scores in all clinical parameters except secondary caries. There were no statistically significant differences in the survival analysis of groups (log-rank test, P = 0.376). Refurbishing treatment improved the anatomy, roughness, luster, and marginal adaptation of restorations with a short-term effect, with most properties rated acceptable after 10 years of clinical service. The clinical characteristics were similar for all groups at the 10th year. PMID- 26437502 TI - Influence of multi-step etch-and-rinse versus self-etch adhesive systems on the post-operative sensitivity in medium-depth carious lesions: An in vivo study. AB - PURPOSE: To evaluate the influence of a three-step etch-and-rinse versus a two step self-etch adhesive system on immediate post-operative sensitivity. METHODS: In total, 204 subjects with one posterior tooth affected by a primary carious lesion were recruited. The subjects were randomly divided into two groups, based on the two multi-step adhesive systems used: Group A (All Bond 3) and Group B (Clearfil Protect Bond). The same skilled operator carried out the restorations using a nano-hybrid composite (Venus Diamond) in oblique stratification. Each increment was light-cured for 20 seconds with a LED lamp (Translux Power Blue). Subjects received a three-level thermal sensitivity questionnaire for post operative sensitivity ratings. The evaluations were recorded daily for 7 days. Scores were analyzed using the McNemar test and postoperative trends were analyzed with the Friedman test (P < 0.05). All (100%) enrolled subjects completed the follow-up visits. There was no statistically significant difference between the two groups in post-operative sensitivity trends. In both groups, increased post-operative sensitivity was found at D1, which then decreased significantly during the observation period. RESULTS: The results of this in vivo study showed that both of the tested adhesives, etch-and-rinse or self-etch, provided effective dentin sealing, preventing subjects from experiencing post operative sensitivity in the treatment of medium-depth cavities. PMID- 26437503 TI - Influence of colorant solutions in properties of indirect resin composites. AB - PURPOSE: To evaluate the influence of colorant solutions on color stability and surface roughness of indirect resin composites submitted to prior immersion in mouthwashes. METHODS: Five brands of indirect resin composites were assessed: Adoro, Resilab, Cristobal, Sinfony and Epricord. The specimens were immersed in five different solutions (n = 10): four mouthwashes (Listerine, Oral-B, Plax, Periogard) and artificial saliva (control). 60 hours after immersion in mouthwashes, the specimens were exposed to coffee solution. Shade stability and surface roughness were tested by a spectrophotometer and by a profilometer, respectively. A three-way repeated-measures ANOVA was performed. Differences between the values were compared by the Tukey-Kramer test (P < 0.05). RESULTS: The majority of the specimens showed human-perceptible color change. Greater color change was observed after immersion in coffee, except for Cristobal. The color change was even higher for specimens previously immersed in mouthwashes. The Epricord resin showed the lowest roughness value and the Cristobal showed the highest value, regardless of the period. The highest roughness change occurred after immersion in Listerine. PMID- 26437505 TI - Shear bond strength of two adhesives to bovine dentin contaminated with various astringents. AB - PURPOSE: To investigate the in vitro shear bond strength of two adhesives to bovine dentin contaminated with various astringents. METHODS: 120 adult bovine incisors were collected and cut to obtain 240 specimens. The specimens were randomly divided into a self-etch adhesive group (N = 120) and a total-etch adhesive group (N = 120). Both of the groups were divided into the following six subgroups: the non-contamination group and the contamination groups 25% Al2(SO4)3 (Orbat sensitive), 25% AlCl3 (Racestyptine), 10% AlCl3 (Roeko Gingiva Liquid), 15.5% Fe2(SO4)3 (Astringedent) and AlCl3 Paste (Astringent Retraction Paste, N = 20 in each subgroup). Each astringent was applied for 1 minute to the dentin surface before rinsing with water spray for 20 seconds. The respective adhesive was then applied according to the manufacturer's instructions. Two composite cylinders were shaped with a mold, cured on the dentin surface of each specimen and sheared off after 1 day and 1 week storage. The shear bond strengths (MPa) were recorded and analyzed with ANOVA. Results: In the self-etching adhesive group, all astringents showed negative effects on dentin bonding (P < 0.05). Astringent contamination did not have a negative effect on dentin bonding in the total-etch adhesive group (P > 0.05). PMID- 26437504 TI - Application of ethanol improves the resin-dentin bond strength of a two-bottle, self-etching primer-adhesive. AB - PURPOSE: To investigate whether the application of ethanol to a two-step self etching adhesive can improve its resin-dentin bond performance. METHODS: Four different ethanol concentrations were added to the adhesive of Clearfil SE Bond to create four ethanol primers (40, 60, 80 or 100% ethanol). 24 extracted third molars were divided into four groups. Each group corresponded to one of the four hydrophobic ethanol primer concentrations. The teeth in the control group were bonded with Clearfil SE Bond according to the manufacturer's instructions. The primed teeth in the experimental groups were treated with the ethanol primer prior to application of the solvent-free adhesive. Microtensile bond strengths (mTBS) were tested 24 hours after specimen preparation. Another 14 teeth were bonded using the same methods to evaluate mTBS after 1 year. Nanoleakage was evaluated under field-emission scanning electron microscopy before and after aging. RESULTS: In the 24-hour group, the mTBS in the 60% ethanol/40% adhesive primer group increased significantly (21.6%, P < 0.05) over the no ethanol control. After 12-month water storage, the bond strength of that experimental group was still higher than that of the control group (19.5%, P < 0.05). Before aging, the nanoleakage was clearly seen in the control group but hardly any was seen in the experimental group. After aging, the nanoleakage increase in the experimental group was much less than that in the control group. PMID- 26437506 TI - Short-term clinical performance of zirconia single crowns with different framework designs: 3-year clinical trial. AB - PURPOSE: The present prospective clinical study evaluated the influence of coping design on the fracture resistance of CAD/CAM zirconia single crowns layered with dedicated ceramics. METHODS: 56 subjects were provided with 90 zirconia single crowns in posterior regions. Tooth preparations were standardized and the abutment teeth were randomly distributed into three groups, according to three different coping designs (flat design, FD; porcelain-fused-to-metal-like crowns, PFM; anatomically-guided, AG). The zirconia cores were produced using a CAD/CAM software and then were hand-layered with dedicated ceramics. All crowns were cemented with a self-adhesive resin luting agent and the patients were recalled for follow-up visits after 1 month, 6 months, 1, 2 and 3 years of clinical service. The function, esthetics and marginal adaptation of the restorations were evaluated. Statistical analyses were performed to evaluate survival and success of the restorations. RESULTS: Success rates of 100% were reported in Group 2 and Group 3 while the percentage was 80% in Group 1. Three chippings were noticed in Group 1 (FD) and two crowns needed to be replaced after 3 years, resulting in a survival rate of 93.3%. Group 2 and Group 3 had significantly higher 3-year success rates than Group 1 (P < 0.05). Based on the present clinical results, the following conclusions were drawn: the porcelain-fused-to-metal-like and the anatomically-guided frameworks for zirconia single crowns performed better clinically than the flat designed cores in posterior regions after 3 years; standardized tooth preparations achieved even thicknesses of the bilayered restorations; the proper support given to the veneering ceramic by the correct design of the zirconia framework could significantly reduce the risk of chipping during function. PMID- 26437507 TI - Temperature changes in bulk-fill resin composite during photopolymerization. AB - PURPOSE: To investigate the temperature changes at multiple sites within bulk fill resin composites and in the pulp chamber during photopolymerization in the tooth cavity. METHODS: Class 1 cavities (n = 5) prepared in extracted third molars were filled with SureFil SDR Flow, a newly developed bulk-fill composite. After securing the specimens in a water bath at 36.5 degrees C, eight thermocouples were used to measure the temperature at the bottom center (BC), middle center (MC), top center (TC), bottom edge (BE), middle edge (ME), and top edge (TE) of the restoration; the pulpal aspect of the dentin (PD); and the center of the curing light tip (CL) during photopolymerization. RESULTS: The maximum temperature values (degrees C) differed among the measurement sites. TC exhibited the greatest temperature increase (72.3 +/- 2.4), followed by MC, BC, TE, TE, ME, CL, and BE. The lowest temperature was observed at PD (41.1 +/- 1.9). The peak temperatures within the composite were observed during the early stage of light-curing, while CL and PD exhibited the highest temperature at the end stage of light-curing. PMID- 26437509 TI - Mixed Beds. Beyond the Frontiers of Classical Chromatography for Proteins. PMID- 26437510 TI - Mechanistic Studies of Chiral Discrimination in Polysaccharide Phases. PMID- 26437511 TI - Chromatographic Separation and NMR An Integrated Approach in Pharmaceutical Development. AB - Over the past 10 years, major improvements in the performance of LC-NMR have been realized. The addition of postcolumn SPE, advances in probe technology including cryogenic probes and microcoil probes, improved solvent suppression pulse sequences, and shielded magnets with better homogeneity have all contributed to rapid advancements in this technology. Application of LC-NMR to problems in pharmaceutical development has had a major impact on structure elucidation studies. LC-NMR has been successfully applied to determine the structures of degradation products, impurities, mixtures of compounds, and metabolites. Use of stop flow techniques with LC-NMR experiments has been a critical means of identifying unstable compounds and studying conformational kinetics. The integration of SPE as an intermediate step between the LC unit and the NMR spectrometer has vastly improved the power of the hyphenated technique in trace analysis applications. Online postcolumn enrichment of chromatographic peaks by SPE dramatically reduces the NMR acquisition times by allowing repeated injections to be trapped onto the same cartridge or different cartridges. Because protonated solvents can be easily removed with a drying procedure, solvents and buffers may be freely chosen for maximizing chromatographic separation without compromising NMR spectral quality. The compound of interest may then be eluted from an SPE cartridge using deuterated organic solvent, which helps to reduce dynamic range issues. When combined with cryogenically cooled microcapillary probes, the sensitivity of the NMR signal increases about 10-fold over conventional room temperature probes, enabling full structure characterization at the microgram level. Heteronuclear experiments with concentrations previously only possible in a limited number of cases have now become standard experiments. The availability of HSQC and HMBC experiments and microcoil/cryogenic technology opens the possibility of using LC-(SPE) NMR for the structural elucidation of complete unknowns on a microgram scale. To enable significant future downscaling beyond the current capabilities, improved performance of the LC-NMR interface and improved SPE cartridge retention need to be addressed. In addition, the active volume of the NMR flow cell or capillary tube will have to shrink along with the corresponding detection coils in order not to lose filling factor. As the size of the NMR probes become more efficient with respect to mass sensitivity, techniques such as CE or capillary electrochromatography (CEC) may be interfaced more successfully with NMR spectroscopy. Overall, the current state of the art in LC NMR has demonstrated proven utility in a variety of applications. When combined with SPE and cryotechnology, LC-NMR has become an extremely valuable tool for mass limited samples, enabling structure elucidation without the need for laborious serial isolation and purification procedures. PMID- 26437512 TI - Principles of Online Comprehensive Multidimensional Liquid Chromatography. PMID- 26437513 TI - Organic Monolith Column Technology for Capillary Liquid Chromatography. PMID- 26437514 TI - A Brief History of Superficially Porous Particles. PMID- 26437515 TI - The Hydrophobic-Subtraction Model of Reversed-Phase Column Selectivity. PMID- 26437517 TI - Recent Developments and Applications in Nonlinear Reversed Phase Liquid Chromatography. PMID- 26437516 TI - Chromatographic Hydrophobicity Index (CHI). PMID- 26437518 TI - [Tribute to Maurice Rochaix]. PMID- 26437519 TI - [Questions regarding secularism of the public hospital]. PMID- 26437520 TI - [Abandoned children at the general hospital of Laon, 1780-1789]. PMID- 26437521 TI - [Religious orders and hospitals of Seine-Maritime]. PMID- 26437522 TI - [Organizing the photography collection of the hospitals of Rouen]. PMID- 26437523 TI - [The general hospital of Rouen. Its origins and its architectural evolution from the 17th to the 19th century]. PMID- 26437524 TI - [Communicable diseases and their impact on the Rouen Hospital architecture]. PMID- 26437525 TI - [From the Saint-Nicolas hospice to the central hospital of Haguenau: 1180-2012]. PMID- 26437526 TI - [Bicetre Hospital - the Valley Foundation, 1890-1919]. PMID- 26437527 TI - [A half century of interns in the hospitals of Bordeaux]. PMID- 26437528 TI - Comparison of Clinical Manifestations and Survival Outcomes between Neuroendocrine Tumor and Squamous Cell Carcinoma of the Uterine Cervix: Results from a Tertiary Center in Southern Thailand. AB - OBJECTIVE: To study the clinical manifestations and survival outcomes of neuroendocrine tumor of the uterine cervix (NTUC) and compare them with those of squamous cell carcinoma (SCCA) MATERIAL AND METHOD: A case-control study was conducted. In the study group, we included patients whose tumors were described in the original pathology reports as NTUC. For the control group, we calculated the sample size based on a formula according to survival rate. The ratio of cases to controls was 1:4. Patients with a diagnosis of SCCA of the uterine cervix and treated between January 2003 and December 2011 in Son gklanagarind Hospital were included in the control group according to stage and year of NT UC diagnos is. The patients 'characteristics, method of treatment, treatment outcomes, and survival of the two groups were compared. The prognostic factors among patients with NTUC were analyzed using the Cox regression. RESULTS: Of the 2,835 cervical carcinoma cases studied, 44 (1.6%) were NTUC. NTUC patients had a lower mean age at diagnosis, received more multimodality treatments, had a lower complete response rate, a higher recurrence rate, and more distant metastasis than their SCCA counterparts. A significantly lower 2-year and 5-year survival was detected in NTUC compared with SCCA (62% and 52% vs. 97% and 85%, respectively, p < 0.01). In the univariate analysis, the number of sexual partners, stage of disease, surgery treatment, status of response, and site of recurrence predicted a poorer overall survival in NTUC. However, these factors were not found to be statistically significant prognostic factors on multivariate analysis. CONCLUSION: A poorer treatment outcome and prognosis were found in NTUC compared with SCCA. Moreover a poorer prognosis was observed in NTUC patients with an advanced-stage disease, non-surgery treatment, progressive disease, and distant metastasis recurrence than in those with SCCA patients. Multimodality treatments should be considered in NTUC to improve survival. Additionally close monitoring may be necessary in this group of patients. PMID- 26437529 TI - Reducing Pain and Anxiety during Second Trimester Genetic Amniocentesis Using Aromatic Therapy: A Randomized Trial. AB - OBJECTIVE: To evaluate the benefit of aromatic therapy using menthol for decrease pain perception during amniocentesis. MATERIAL AND METHOD: A prospective randomized study was conducted to compare pain level between groups ofpregnant women who underwent amniocentesis with and without aromatic therapy using menthol. Visual analogue scale (VAS) was usedfor pain assessment. The participants were askedfor their anticipated pain and anxiety level and level ofpain before and immediately after the procedure. RESULTS: Three hundred seventeen pregnant women were recruited into the present study, 158 in the menthol group and 159 in the non-menthol group. Mean VAS score of the post procedure pain and anxiety did not differ significantly between the two groups. Mean VAS score of the anticipated pain influenced the mean VAS score of the pre procedure anxiety and post-procedure pain and anxiety irrespective of the group. Mean VAS score of the pre-procedure anxiety and post-procedure pain and anxiety increased about 0.3 cm for each 1 cm of increasing mean VAS score of anticipated pain. CONCLUSION: Aromatic therapy using menthol was not significantly effective in reducing pain and anxiety during second trimester genetic amniocentesis. PMID- 26437530 TI - Association between Socioeconomic Status and Major Risk Factors of Stroke: Thai Epidemiologic Stroke (TES) Study. AB - OBJECTIVE: To investigate the association of socioeconomic status (SES) (education, personal income, and occupation) with four major risk factors of stroke, those are diabetes, hypertension, hypercholesterolemia, and current smoker MATERIAL AND METHOD: The Thai Epidemiologic Stroke Study is a community based cohort study, which recruitedparticipants from the general population from five geographic regions around the country. Cross-sectional baseline data of 19,997 (6,803 men and 13,194 women) participants, aged 45 to 80 years were included in the present analysis. Multiple logistic regression analysis was used to estimate association ofsocioeconomic indicators with the major risk factors of stroke. RESULTS: SES was associated with a major risk factor of stroke. Among three indicators ofsocioeconomic status, education was more consistently associated with the risk factors than personal income and occupation, particularly in women. Education significantly inversely associated with diabetes (p = 0.015 in men and 0.002 in women, respectively), and current smoker in both sexes (p < 0.001), and with hypertension in women (p = 0.011). By contrast, education was significantly positively associated with hypercholesterolemia in women (p < 0.001). CONCLUSION: The differences in the prevalence of the major risk factors of stroke between SES groups were important, and should be considered in the development ofpolicies or tailored strategies for prevention of stroke. PMID- 26437531 TI - Ramathibodi Language Development Questionnaire: A Newly Developed Screening Tool for Detection of Delayed Language Development in Children Aged 18-30 Months. AB - OBJECTIVE: To develop a parental questionnaire for screening children with delayed language development in primary care settings. MATERIAL AND METHOD: Ramathibodi Language Development (RLD) questionnaire was developed and completed by groups of 40 typically developing children age 18 to 30 months old and 30 children with delayed language development. RESULTS: The mean score was significantly lower in the delay language group (6.7 +/- 1.9), comparing with the typically developing group (9.6 +/- 0.7). The optimal ROC curve cut-off score was 8 with corresponding sensitivity and specificity were 98% and 72%, respectively. The corresponding area under the curve was 0.96 (95% CI = 0.92-0.99). CONCLUSION: The RLD questionnaire was the promising language developmental screening instrument that easily utilized in well-child examination settings. PMID- 26437532 TI - Randomized Controlled Trial of Azithromycin versus Doxycycline or Chloramphenicol for Treatment of Uncomplicated Pediatric Scrub Typhus. AB - OBJECTIVE: To evaluate the efficacy and safety of azithromycinfor treatment of uncomplicated pediatric scrub typhus. MATERIAL AND METHOD: A randomized controlled trial was performed. We compared azithromycin with doxycycline or chloramphenicol in uncomplicated pediatric scrub typhus from inpatient pediatric department of Chiangrai Prachanukroh Hospital. The primary outcome was cure rate at day 3. The secondary outcomes were timing to defervescence within 72 hours, side effects, and relapsed rate. We compared data between both groups with Fisher's exact test or Mann-Whitney U test, and failure rate was demonstrated by Kaplan-Meier survival curve and Log-rank test. RESULTS: We included 57 patients, ofwhom, 28 were assigned to doxycycline or chloramphenicol (control group) and 29 to azithromycin (study group). The baseline characteristics of both groups were similar The cure rate was 85.7% in the doxycycline or chloramphenicol group, as compared to 79.3% in the azithromycin group (p = 0.73), and a median time to defervescence was 30 hours (IQR 21, 48) vs. 36 hours (IQR 20, 68) respectively (p = 0.166). There was a little minor side effect in azithromycin group. No relapsed was found in either groups. CONCLUSION: Azithromycin was as effective as doxycycline or chloramphenicol in treatment of uncomplicated pediatric scrub typhus. PMID- 26437533 TI - The Profile of Pediatric Patients Visit Emergency Department at Urban University Hospital in Thailand. AB - BACKGROUND: There is an absence of data describing pediatric patients who visit Emergency Department (ED) in Thailand. Therefore, this report creates a profile of pediatric emergency room visit at a university hospital in Thailand. MATERIAL AND METHOD: The retrospective data of the pediatric patient aged less than 15 years that visited ED at Ramathibodi Hospital, Mahidol University, Bangkok, Thailand between fiscal year (FY) 2002 and 2011 were reviewed. The Electronic Medical Record Tracking was extracted. Demographic characteristic, acuity level, timing, and presumptive diagnosis were reviewed. RESULTS: During the 10 years of the data collection, 122,037 pediatric patient visited ED, thus, approximately 12,000 visits per year Pediatric patients account for an average of 18% of hospital patients. Medical condition accounted for 95.21% of the visits followed by trauma at 4.77%, and death at 0.02%. The triage categorized patients into critical, emergency, urgency, and non-emergency, consisting of 0.6% as critical patients, 37.6% as emergency patients, 52.5% as acute illness, and 9.3% as non emergency patients. The three most common diagnosis were upper respiratory tract infection, acute febrile illness, and acute gastroenteritis. Patient usually visited ED in the evening shift 44% (4 p.m. to midnight), followed by morning shift 40% (8 a.m. to 4 p.m.), and overnight shift 16% (midnight to 8 a.m.). There were two highest peaks of ED visit, in June, during the rainy season, and in January, during the winter. CONCLUSION: Pediatric patients attending the emergency service were mostly for medical conditions. Acute illnesses were the major group ofpediatric patients. A small proportion of visits in ED were true emergencies. PMID- 26437534 TI - The Short Stem THA Provides Promising Results in Patients with Osteonecrosis of the Femoral Head. AB - BACKGROUND: The short stem prosthesis showed good results in patients with primary osteoarthritis. However there were afew studies about the short stem total hip arthroplasty (THA) in patients with osteonecrosis of thefemoral head (ONFH). OBJECTIVE: To evaluate the clinical and radiographic results of the short stem THA in patients with ONFH. The authors hypothesized that the short stem THA would be a promising procedure for patients with ONFH. MATERIAL AND METHOD: The authors reviewed 120 osteonecrotic hips in 93 patients who underwent THA with Metha(r) short stem between November 2010 and February 2013. The appearance of bone trabeculae development and radiolucent line was reviewed using Gruen's classification. The Harris hip score (HHS) was recorded at 6, 12, 24, and 36 monthspostoperative for evaluating the clinical results. RESULTS: The mean age of patients was 44.4 years (18-68) with the mean BMI of 22.7 (15.1-32.5, SD 3.5). The average follow-up period was 29.2 months (20-47). The mean HHS was significantly improved from 43.9 (22.7-74, SD 7.7) preoperatively to 97.7 (85.9 100, SD 2.7) at 6-month postoperatively (p < 0.01). The radiographic change around the stems showed bone trabeculae development at zone 1 (77 cases, 64.2%), 2 (27 cases, 22.5%), 3 (106 cases, 88.3%), 6 (120 cases, 100%), and 7 (115 cases, 95.8%). There was one case (0.8%) of 5 mm subsidence and the radiolucent line was observed in zone 1. There were six cases (5%) of intraoperativefemoralfractures and were treated with cerclage wires with nofurther subsidence observed There was one case (0.8%) of distal stem perforation that had stable bone ingrowth. No revision was required. CONCLUSION: The clinical and radiographic results of the short stem THA in patients with ONFH are generally satisfactory. Its design enables preservation of the bone stock and the bone trabeculae appear to confirm the assumption of proximal force transmission. The authors believe that the short stem THA is a promising procedure for patients with ONFH. PMID- 26437535 TI - The Changes in Cortisol Levels during Cardiac Surgery: A Randomized Double Blinded Study between Two Induction Agents Etomidate and Thiopentone. AB - OBJECTIVE: To study the changes in cortisol levels during and after cardiac surgery after an inductive dose of either etomidate or thiopentone and their consequences. MATERIAL AND METHOD: A prospective, randomized, double-blinded study was conducted in 26 patients undergoing elective cardiac surgery. They received either etomidate or thiopentone for induction. Serum cortisol levels were measured preoperatively, and then at 2-, 4-, 8-, and 24-hour All of the patients received standard anesthesia and surgery. The data also included patients perioperative management and outcome. RESULTS: There is no difference in patients' characteristics. The baseline plasma morning cortisols in the two groups were comparable (11.7 +/- 7.5 mcg/dL in etomidate group vs. 12.0 +/- 8.2 mcg/dL in thiopentone group). In both groups, during surgery, the cortisol levels rose to higher levels and reached peak levels at four to eight hours and related to surgical stress. At all times, the etomidate group had lower cortisol levels but only at 8-hour the etomidate group had significantly lower cortisol level (39.9 +/- 14.2 vs. 65.9 +/- 20.0 mcg/dL). At 24 hours, in both groups, cortisol levels were lower than at 8-hour but did not return to normal baseline levels. There were no differences in the dose of inotropic use and ICU stay. However surprisingly the etomidate group had shorter hospital stay. CONCLUSION: A single dose of etomidate usedfor induction in elective cardiac patients can partially and reversibly inhibit of the cortisol synthesis for, at least, 24 hours, but its association with any hemodynamic consequences cannot be concluded. REGISTRATION: ClinicalTrials.gov as NCT01495949. PMID- 26437536 TI - The Montreal Cognitive Assessment as a Screening Tool for Preoperative Cognitive Impairment in Geriatric Patients. AB - OBJECTIVE: Study the prevalence of cognitive impairment using the Montreal Cognitive Assessment (MoCA), its relationship to physiologic age-related change, and the preoperative drugs used in geriatric patients. MATERIAL AND METHOD: At the preoperative visit, the co-researchers invited 322 general/vascular patients (190 male, 132 female) and 260 urological patients (220 male, 40 female) who met the inclusion criteria and were scheduled for elective surgery to join the study. They went for the MoCA interview, and their preoperative drugs used were recorded in a medication reconciliation file. A cut-off score 24 or above was considered normal. RESULTS: Ninety-two general/vascular and 126 urological patients had taken drugs before admission, but those did not show any correlation with the MoCA score. There were 231 and 91 general/vascular patients and 175 and 85 urological patients with formal education of less than six years and equal/more than six years respectively. The 286 and 36 general/vascular patients and 212 and 48 urological patients posted scores of less than 24 and equal/more than 24 respectively. Gender and education correlated positively and significantly with the score; however age proved negatively significant. CONCLUSION: The prevalence of cognitive impairment featured highly in preoperative geriatric patients. The gender age, and education but not preoperative drugs used affected cognitive function. PMID- 26437537 TI - Epidemiology of Age-Related Macular Degeneration among the Elderly Population in Thailand. AB - OBJECTIVE: To estimate the prevalence and associated factors of age-related macular degeneration (AMD) in Thailand. MATERIAL AND METHOD: This cross-sectional survey was undertaken in 2010. Five provinces were selected and people aged 50 years and over were invited for eye examination. Demographic and health behaviors and data from eye examination equipment were registered. Ophthalmologists graded AMD as early or late based on fundus color photograph and image from optical coherence tomography. Logistic regressions were analyzed to establish associationfactorsfor AMD. RESULTS: Of the 7,043 participants, AMD wasfound in 862 people (12.2%), with more than half (53.1%) found in both eyes. Most cases (94.3%) were early dry, 1.8% early wet, 3.4% late dry, and 0.7% late wet AMD. Factors positively associated with AMD were age (OR 1.03, 95% CI 1.02-1.04), diabetes mellitus (OR 1.20, 95% CI 1.03-1.39), and consumption of yellow vegetable (OR 2.32, 95% CI 1.23-4.39). Factors that conversely associated with AMD were consumption of green vegetable (OR 0.51, 95% CI 0.33-0.79), physical exercise (OR 0.67, 95% CI 0.51-0.87), high bloodpressure (OR 0.75,95% CI 0.63 0.89), and heavy drinking habit (OR 0.45, 95% CI 0.26-0.75). CONCLUSION: The prevalence of AMD in Thai population age 50 and over was 12.2%. More than half (53.1%) of the cases were found in both eyes, but few at severe stages. The present study confirmed age and DM as positive associated factors, and green vegetable, exercise as negative associated factors. Further research should investigate the effects of hypertension, yellow vegetable, and alcohol drinking on AMD. PMID- 26437538 TI - Stability of Bevacizumab Divided in Multiple Doses for Intravitreal Injection. AB - OBJECTIVE: To investigate the stability of bevacizumab in multiple doses divided from a single-use vial for intravitreal injection after storage at 4 degrees C for up to six months and under drug transfer condition in tropical climate. MATERIAL AND METHOD: Five syringes (0.1 mL, 2.5 mg) of bevacizumab were withdrawn each from five new bevacizumab single-use vials (4 mL, 100 mg) under sterile technique. The concentration of bevacizumab in each syringe was measured at two dilutions (2 x 10(6) and 4 x 10(6) fold) using enzyme-linked immunosorbent assay at baseline and after storage at 4 degrees C for 1-, 3-, and 6-month. Each assay was performed at least twice. To simulate the drug transfer condition, bevacizumab was placed in a brown plastic bag and put in another transfer plastic bag with an ice cube for 30 minutes prior to the assay at 1-, 3-, and 6-month. RESULTS: The concentrations of bevacizumab (mean +/- standard deviation) at baseline, 1-, 3-, and 6-month were 26.24 +/- 1.95, 25.43 +/- 3.80, 27.87 +/- 2.81, and 24.25 +/- 2.00 mg/mL, respectively. The lowest lower limit of 95% confidence interval for the mean concentration was 23.32 mg/mL at 6-month storage, which was 89% of the mean baseline concentration and considered to be non-inferior to the baseline concentration. CONCLUSION: Bevacizumab in a single use vial could be divided into multiple small doses for intravitreal injection with sufficient stability when refrigerated at 4 degrees C for up to six months and under the drug transfer condition in tropical climate. PMID- 26437539 TI - Computerized Tomographic Angiography for Detection of Cerebral Vasospasm after Ruptured Intracranial Aneurysm. AB - OBJECTIVE: Digital subtraction angiography (DSA) is the gold standard to diagnose cerebral vasospasm but it is usually not available due to lack of expertise and proper equipment. The present study aimed to compare the diagnostic accuracy of brain computerized tomographic angiography (CTA) in detecting cerebral vasospasm after intracranial aneurysmal rupture. MATERIAL AND METHOD: Between January 2011 and October 2014, 20 patients who were suspected of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) were prospectively enrolled. All patients underwent brain CTA andDSA within 24 hours after clinical onset ofvasospasm. Separate reviewers independently reviewed the CTA and DSA. RESULTS: Twenty patients were enrolled, including 7 males and 13 females. The patient characteristics did not have any relationship to the incidence of cerebral vasospasm. The CTA finding of vasospasm was well correlated to the DSA finding (Kappa 0.793). Diagnostic accuracy and false negative of the CTA were 90% and 5%, respectively. Sensitivity of the CTA was 94% and specificity was 100%. Positive predictive value ofthe CTA was 100% and negative predictive value was 66%. The vessels that showed the most correlation between the CTA and DSA findings were left A1 (Kappa 0.684) and left A2 (Kappa 0.663) segments of anterior cerebral artery, and left M1 (Kappa 0.503) segment of middle cerebral artery. Both CTA and DSA can detect mild vasospasm (< 50% luminal stenosis) located proximal to the circle of Willis. CONCLUSION: Compared to the DSA, the CTA can be used for detecting cerebral vasospasm in patients with ruptured intracranial aneurysms with high sensitivity, specificity, and diagnostic accuracy. PMID- 26437540 TI - The Diagnosis of Acute Cholecystitis: Sensitivity of Sonography, Cholescintigraphy and Computed Tomography. AB - OBJECTIVE: To compare the sensitivity of sonographic, cholescintigraphic, and computed tomographic examination of acute cholecystitis to the pathology result, which is considered the Gold Standard. MATERIAL AND METHOD: A retrospective analytic study was conducted among 412 patients, aged between 15 and 98 years, who underwent cholecystectomy surgeries, and whose pathology results indicated acute cholecystitis between July 2004 and May 2013. The sensitivity and the differences between sensitivity of the three methods were calculated in all patients. Complicated acute cholecystitis cases were analyzed separately. RESULTS: The three methods demonstrated statistically significant differences in sensitivity (p-value = 0.017), with the cholescintigraphy as the most sensitive method (84.2%), followed by computed tomography (67.3%), and sonography (59.8%). Concerning the samples with the pathology result indicating complicated acute cholecystitis, computed tomography was statistically significantly more sensitive than sonography in detecting acute cholecystitis, whether or not the complications were identified (100% and 63.6%, respectively, with p-value = 0.0055). None of the patients with the pathology result of complicated acute cholecystitis case was examined by cholescintigraphy, thus, no calculation was possible. Regarding the ability to detect the complications of acute cholecystitis, computed tomography had a sensitivity of 35.71% (5 in 14 patients), while sonographic examinations could not detect any of the complications. CONCLUSION: Cholescintigraphy is a more sensitive method than computed tomography and sonography, but the three methods have its own advantages, disadvantages, and limitations, which must be consideredfor each individual patient. PMID- 26437541 TI - Clinicopathological Features and Prognostic Factors of Malignant Melanoma: A Retrospective Analysis of Thai Patients in Ramathibodi Hospital. AB - OBJECTIVE: To present the clinicopathological characteristics of cutaneous melanoma in Thai patients and to define the possible clinicopathological prognostic factors. MATERIAL AND METHOD: A retrospective study of primary cutaneous melanoma in Thai patients in Ramathibodi Hospital between January 2007 and December 2012 was conducted. All medical records and skin biopsies were reviewed for demographic data and histopathologicalfeatures. Univariate and multivariate analysis for overall survival, and prognostic factors, according to clinical and histopathological features were performed. RESULTS: Fourty-three patients with pathologically confirmed primary cutaneous melanoma were identified and reviewed. The median age of onset was 58 years, with male:female ratio was 1:1.05. Acral lentiginous melanoma (ALM) was the most common type (76.7%). The majority of patients had clinical stage 11 (56.1%). Histologically, the median tumor thickness was 2.9 mm, 88.2% had Clark's level IV and V, 47.1% were ulcerated, and 76.5% had dermal mitotic rate of >= 1 mitoses/mm. The 5-year overall survival rates was 38.3%. Univariate analysis demonstrated that clinical stage IV Breslow's thickness of > 3 mm, and dermal mitotic rate of >= 3 mitoses/mm2 were bad prognostic factors. Multivariate analysis demonstrated that advanced clinical staging (stage III and IV), Breslow's thickness of > 3 mm, ulceration, palmoplantar or subungual site, and histologic subtype of ALM were the independent risk factors for poor prognosis. CONCLUSION: Most patients with cutaneous melanoma in Thai patients had the histologic subtype of ALM and were diagnosed with locally advanced disease (stage II). The prognosis depends on clinical staging, Breslow's thickness, ulceration, primary location of tumor and histologic subtype. PMID- 26437542 TI - Metastatic Neuroendocrine Carcinoma of the Breast Identified by Tc-99m-HYNIC-TOC SPECT/CT: A Rare Case Report. AB - The authors reported an uncommon presentation of metastatic neuroendocrine carcinoma to the breast detected by Tc-99m-HYNIC-TOC SPECT/CT in a 49 years old woman who, previously, had carcinoid tumor of left main bronchus and invasive ductal carcinoma of the right breast. Later, the patient developed left breast mass. Core needle biopsy of the mass revealed poorly differentiated invasive ductal carcinoma. The disease remained stable for 12 years without any treatment on that left breast (due to patient's rejection). On the later investigation using Tc-99m-HYNIC-TOC scintigraphy examination, rather than invasive ductal carcinoma, metastatic neuroendocrine cancer was suggested. The final diagnosis was confirmed by pathological examination after surgical excision. Multiple metastatic lesions of neuroendocrine carcinoma at lung, liver, ovaries, and bones were also depicted. Due to the good behavior of the disease, patient had been doing well for eight months, without specific treatment. This report confirmed the advantage and the accuracy of Tc-99m-HYNIC-TOC scintigraphy in detection of neuroendocrine carcinoma. Furthermore, metastatic neuroendocrine tumor should be in differential diagnosis for patient with breast mass together with history of neuroendocrine tumor PMID- 26437543 TI - [Constant Performance]. PMID- 26437545 TI - [Strategy for Determining the Appropriate Dose of Sugammadex with Monitoring Train-of-four (TOF) Responses at the End of Surgery]. AB - BACKGROUND: Intraoperative monitoring of train-of-four (TOF) response is recommended to avoid inadequate dose of muscle relaxant and its antagonist. We have standardized monitoring of TOF response at the end of surgery in all the patients undergoing general anesthesia with rocuronium since October 2013. METHODS: TOF group comprised of 113 consecutive patients just after the standardization and we investigated the relationship between the dose of sugammadex and TOF count and also compared anesthetic factors in TOF group with those in control group which included 104 consecutive patients just before the standardization without TOF monitoring. RESULTS: Rate of the patients with TOF count 4 in TOF group approximately reached 70% and mean TOF ratio resulted in 0.56 +/- 0.28. Mean dose of sugammadex in patients with TOF count 2-4 was 2.5 +/- 0.9 mg x kg(-1), while the dose in patients with TOF count 0-1 was 3.6 +/- 0.9 mg x kg(-1) and 6 patients among 11 patients with TOF count 0 was given less than 4 mg x kg(-1) of sugammadex. The percentage of the patients given 200 mg of sugammadex significantly decreased from 78% in control group to 48% in TOF group. CONCLUSIONS: We conclude that standardization of TOF response at the end of surgery reduces dose of sugammadex in patients with slight residual neuromuscular block though the dose in patients under deep muscle relaxation seems to be insufficient. PMID- 26437544 TI - [The Interaction of Low-dose Droperidol, Propofol, and Sevoflurane on QTc Prolongation]. AB - BACKGROUND: Droperidol is an effective antiemetic, but its use is limited because of the warning of drug-induced QT prolongation. Some reports showed that low-dose droperidol does not significantly probing QT interval. This study was aimed to determine the effect of low-dose droperidol (1.25 and 2.5 mg) on QTc interval, and the interaction among droperidol, propofol and sevoflurane. METHODS: Patients received either 1.25 mg (group L : n = 25) or 2.5 mg (group H : n = 25) droperidol, and fentanyl (3 MUg x kg(-1)) was administered 2.5 min later. One minute after fentanyl administration, anesthesia was induced using propofol (1.5 mg x kg(-1)) and vecuronium. One minute after propofol administration, sevoflurane (3%) was started. Tracheal intubation was performed 3 min after propofol administration, and then sevoflurane was reduced to 1%. RESULTS: Compared to baseline, the QTc interval in group L was unchanged by droperidol. In group H, the QTc interval was significantly prolonged after droperidol injection, but recovered after propofol injection. After tracheal intubation, QTc interval was significantly prolonged in both groups. CONCLUSIONS: Droperidol's effect on QTc prolongation was shown at the dose of 2.5 mg but not 1.25 mg. This prolongation effect was offset by propofol, and was unchanged by sevoflurane. PMID- 26437546 TI - [Risk Factors for Poor Prognosis after Emergency Surgery for Acute Abdomen]. AB - BACKGROUND: Risk factors associated with poor outcome were investigated in patients receiving emergency surgery. METHODS: Patients' characteristics, surgical information, postoperative complication and 30-days mortality were reviewed in 226 adult consecutive patients undergoing emergency abdominal surgery. Postoperative complication was defined as surgical site infection, anastomotic leakage, intraperitoneal abscess and formation or requirement of renal replacement therapy. Multivariate logistic regression was performed to identify the parameters associated with 30-day mortality and postoperative complication. RESULTS: Mortality rate was 7.1%. Complication occurred in 41.2%. Multivariate logistic regression revealed surgical Apgar score (SAS) as independent predictor of the death. SAS, duration of the surgery and preoperative SOFA were identified as independent predictors of the complication. CONCLUSIONS: SAS and preoperative SOFA are useful to predict poor prognosis after emergency surgery due to acute abdomen. PMID- 26437547 TI - [Incidence, Risk Factors, and Effects on Outcome of Postoperative Delirium in Patients Undergoing Esophagectomy]. AB - BACKGROUND: Postoperative delirium (POD) is a common but serious complication after major surgery. The aim of this study was to investigate the incidence and effects on outcome of POD in esophagectomy patients, and to identify risk factors for developing POD. METHODS: A retrospective medical record review was conducted for all patients who had received esophagectomy for esophageal cancer during a three-year period. RESULTS: In a total of 71 patients, the overall incidence of POD was 20%. Multivariable regression analysis identified two independent risk factors for POD: older age (70) and preoperative electrolyte abnormalities. Patients with delirium had a higher incidence of respiratory complications and longer hospital stays compared with the non-delirium patients. CONCLUSIONS: The incidence of POD in patients undergoing esophagectomy is 20%. The risk factors of POD are older age and preoperative electrolyte abnormalities. POD negatively impacts postoperative respiratory complications and hospital stay. PMID- 26437548 TI - [Transient Femoral Nerve Palsy after Ilioinguinal-Iliohypogastric Nerve Block: Comparison of Ultrasound-guided and Landmark-based Techniques in Adult Inguinal Hernia Surgery]. AB - BACKGROUND: Transient femoral nerve palsy (TFNP) is a well-known complication associated with ilioinguinal-iliohypogastric nerve block (IINB). We compared the incidence of TFNP after ultrasound-guided IINB and that after anatomical landmark based IINB. METHODS: We reviewed medical records of adult patients (ASA-PS 1-3, Age 21-87) who had received inguinal hernia surgery under general anesthesia and LINB retrospectively. IINB was performed using 0.5% ropivacaine either by ultrasound-guidance (US group, n = 16) or by landmark-based technique (LM group, n =17). TFNP was defined as sensory loss in the anterior aspect of the thigh or weakness of quadriceps femoris muscle in the nerve-blocked side. RESULTS: The frequency of TFNP in US group (6%) was lower than that in LM group (41%) in the post-anesthesia care unit (P = 0.019). TFNP symptom was resolved completely on the morning after surgery. The incidence of severe-intermediate postoperative pain and analgesic requirement were not different between the two groups. CONCLUSIONS: This study revealed that ultrasound-guided technique is effective to lower the incidence of TFNP after IINB in adult inguinal hernia surgery. PMID- 26437549 TI - [Serratus-Intercostal Plane Block for Brest Surgery]. AB - BACKGROUND: Serratus-intercostal plane block (SIPB) is a novel ultrasound-guided thoracic wall nerve block reported recently. We performed SIPB for perioperative analgesia together with general anesthesia in patients undergoing partial mastectomy. METHODS: We chose the patients with breast cancer of upper to lower lateral quadrant or subareolar region. The patients received general anesthesia followed by ultrasound-guided SIPB. The needle was introduced in the midaxillary line at the level of the fourth or fifth rib. Under continuous ultrasound guidance, we injected 30 ml of ropivacaine 0.375-0.5% between the serratus anterior and the external intercostal muscles. RESULTS: After the partial mastectomy, the area of sensory loss obtained by skin prick was extended from five to six as the number of intercostal spaces. Analgesic effect was obtained for 12 to 24 hours. The cephalad dermatomal paresthesia was T2. More than 20 patients received SIPB, and no one acquired the sensory loss at T1 of dermatomal distribution. CONCLUSIONS: SIPB provides effective analgesia for breast surgery of upper to lower lateral quadrant and/or subareolar region. However, it should be administered with other additional analgesic agents when axillary dissection is performed, because sensory loss of T1 is difficult to achieve. PMID- 26437551 TI - [A Biphasic Anaphylactic Attack from Sugammadex with a Severe Second Attack]. AB - A 74-year-old man was scheduled for transurethral resection of the prostate under general anesthesia. Anesthesia was induced by propofol, rocuronium, remifentanil and maintained with sevoflurane. The operation was finished in 56 minutes without trouble. After operation, sugammadex was administered, and after about 2 minutes, redness, tachycardia, hypotension and itchiness appeared. Treatment was initiated using steroids, adrenaline, and antihistamine upon diagnosis of anaphylaxis caused by sugammadex. Reaction to the treatment was good and the general condition improved to normal; however, the patient was moved to the intensive care unit for follow-up observation. Furthermore, no upper respiratory tract symptoms were observed during the follow-up along with no decline in SpO2. The condition progressed without any particularly major abnormalities after entering the intensive care unit; however, a sudden decline in blood pressure and dyspnea occurred again 3 hours following entering the intensive care unit. These were considered to be biphasic reactions due to anaphylaxis, and treatment was carried out again with intravenous injection of adrenaline, steroids and inhalation of beta-agonist. No symptoms were observed since and the patient was discharged from the intensive care unit the following day. PMID- 26437550 TI - [The Hemodynamics and Bispectral Index Score during Lower Abdominal Surgery under Balanced Anesthesia with the Two Different Combination Doses of Desflurane and Remifentanil]. AB - BACKGROUND: The purpose of this study was to examine the hemodynamics and bispectral index score during lower abdominal surgery under balanced anesthesia with the two different combination doses of desflurane and remifentanil. METHODS: Twenty patients undergoing total hysterectomy were allocated into two groups; 1) 10 patients received 4.5% end-tidal concentration of desflurane combined with remifentanil 0.125 MUg x kg(-1) x min(-1) (H group) and 2) 10 patients received 3.0% end-tidal concentration of desflurane combined with remifentanil 0.2 MUg x kg(-1) X min(-1) (L group). Mean arterial pressure (MAP), heart rate (HR) and BIS were recorded 5 times (on admission to operating room, immediately before surgery, 5 minutes after the skin incision, at the moment of uterine extraction and during retroperitoneal closure). RESULTS: MAP and HR during surgery did not increase compared with those on admission to operating room, and BIS was unchanged throughout the study in both two groups. CONCLUSIONS: The patients could be anesthetized adequately during lower abdominal surgery under balanced anesthesia with the two different combination doses of desflurane and remifentanil. PMID- 26437552 TI - [A Case of Repetitive Cardiac Arrest due to Coronary Vasospasm after Sugammadex Administration]. AB - A 58-year-old man with no history of cardiac disease was scheduled for a cerebral aneurysm clipping surgery. Anesthesia was administered with propofol, rocuronium, fentanyl, and remifentanil. At the end of the surgery, extubation was performed 3 min after the administration of 200 mg sugammadex, along with a simultaneous blood-pressure decrease with ST elevation on lead II. Cardiopulmonary resuscitation was per- formed owing to the occurrence of lethal arrhythmia, and the patient was successfully resuscitated. Subsequent emergent coronary angiography revealed normal coronary arteries. Twelve days after the first surgery, a tracheostomy was performed owing to persistent disturbance of consciousness. Anesthesia was administered with sevoflurane, fentanyl, and rocuronium. Sugammadex 200 mg was administered after the insertion of a tracheal cannula, and 5 min later, the blood pressure were gradually decreased with ST depression on lead V5. Finally, cardiopulmonary resuscitation was required, and the patient recovered again. An acetylcholine provocation test performed later showed positive results. We suspect sugammadex to be the cause of coronary vasospasm, because the time courses of the two cardiac arrest episodes after sugammadex administration were very similar. Therefore, clinicians should consider sugammadex as one of the causative agents of cardiac arrest in the operating room. PMID- 26437553 TI - [Anesthesia Management for Primary Cleft Lip Closure in an Infant with Congenital Total Length Complete Tracheal Rings]. AB - Complete tracheal ring causes congenital tracheal stenosis in neonates and infants. We have to prevent further tracheal stenosis in perioperative period. This is a case report of an infant with congenital tracheal stenosis due to complete tracheal ring who underwent primary cleft lip closure under general anesthesia. An 8 month-old boy was scheduled for bilateral cleft lip closure. His first operation at two months was canceled because of unsuccessful intubation in previous hospital. He came to our hospital to seek a second opinion. His CT scan showed long segment stenosis of the trachea below glottis. The tracheobronchial endoscopy showed complete tracheal rings 1.5 cm below glottis to the bifurcation. Considering his aspiration episode, we decided to do the cleft lip closure promptly after examinations. We chose an ID 3.0 mm RAE tracheal tube, which is commercially narrowest We intubated 2 cm below glottis, and confirmed that the tip did not touch narrowed trachea with endoscope. This tube was fixed in the center of the mandible and packed with gauze. He was discharged on 8 POD without complication. CT scan and its integrated 3 D image of the trachea were useful to understand the approximate structure. However endoscopic examination allowed more detailed structure-measurement below glottis. PMID- 26437554 TI - [Rapid Sequence Intubation with the McGRATH MAC Videolaryngoscope in the Sitting Position for a Patient with Restricted Mouth Opening]. AB - Here we report successful rapid-sequence inubation with the McGRATH MAC videolaryngscope (McGRATH) in the face to face sitting position for a patient with severe ileus and restricted mouse opening. A 46-year-old woman with advanced bladder cancer had developed ileus. Ileus tube and octreotide did not relieve her symptoms, and emergency colostomy was planned. Due to the invasion of cancer to the spine and interior of the pelvis, she could not keep supine position and always kept sitting position. We decided to perform rapid-sequence intubation in the sitting position. First an anesthesiologist stood at face to face position to the patients, and the second anesthesiologist kept the head of the patient from the cranial side. After thiamylal and fentanyl administration, cricoid pressure was applied by the third anesthesiologist. Under the guide of the McGRATH's monitor, we could successfully insert the 7.0 mm internal diameter tracheal tube with a stylet uneventfully in the face to face sitting position. PMID- 26437555 TI - [Reexpansion Pulmonary Edema during Emergency Surgery in a Patient with Spontaneous Hemopneumothorax]. AB - A 43-year-old male patient with spontaneous hemopneumothorax of the right lung underwent emergency video-assisted thoracoscopic surgery for drainage, hemostasis and bullae resection. Fifteen minutes after reexpansion of the right lung, we found bubbly sputum coming out from the right tracheal tube and cloudy shadow in the right field of his chest X-ray. The occurrence of reexpansion pulmonary edema (RPE) was considered. Subsequent mechanical ventilation with PEEP and administration of steroid and diuretic was done as his treatment. His respiratory state was stabiized in the next two days. As the lung collapse following spontaneous hemopneumothorax often becomes more severe, we should pay attention to the occurrence of RPE after expansion of affected side lung. And, if it occurred, appropriate and prompt treatment as above should be done because of its high mortality. PMID- 26437556 TI - [Anesthetic Management of Two Patients with Chilaiditi Syndrome]. AB - Chilaiditi syndrome is assosiated with hepatodiaphragmatic interposition of the colon and the small intestines. We anesthetized 2 patients with Chilaiditi syndrome. A 62-year-old woman with interposition of the intestine was scheduled for right femoral fibrosarcoma resection. She had been medicated for schizophrenia. Total intravenous anesthesia was induced and maintained. Another patient an 81-year-old man with interposition of the colon, was scheduled for transurethral resection of a bladder tumor. He was anesthetized with spinal anesthesia. In both cases, there was no cardiovascular complication or digestive disorder during the perioperative period. PMID- 26437557 TI - [Usefullness of Beta-blocker for Hemodynamic Changes Induced by Uterotonic Drug in a Patient with Hypertrophic Obstructive Cardiomyopathy Undergoing Elective Cesarean Section]. AB - Combined spinal-epidural anesthesia (CSEA) was given to a 27-year-old woman with hypertrophic obstructive cardiomyopathy (HOCM) for a selective cesarean section. After the injection of uterotonic drug via uterine muscle and a vein after delivery, the patient developed dyspnea, tachycardia, ST-change on elecrocardiogram and hypotension. It is important in HOCM patients to control heart rate and left ventricular contractile force. We started to infuse beta blocker (landiolol, 10 MUg x kg(-1) x min(-1)) and improved these symptoms of the patient. This case demonstrates that CSEA is safe for HOCM patients and beta blocker is effective to improve hemodynamic changes induced by uterotonic drug in these patients. PMID- 26437558 TI - [A Case Report of the Postoperative Epidural Hematoma the Cause of Which Was Thought to Be the Spinal Abnormality]. AB - Although an 84-year-old patient did not have any coagulopathy and there was no vascular injury at the time of epidural puncture, epidural hematoma developed late in onset Ossification of the posterior longitudinal ligament of the spine was suspected as a potential cause. The vascular hyperplasia in the epidural space is possible in a case of ossification of the posterior longitudinal ligament of the spine. A careful observation is necessary after the epidural catheter insertion in a patient with ossification of the posterior longitudinal ligament. PMID- 26437559 TI - [Persistent Bilateral Vocal Cord Paralysis after General Anesthesia in a Patient with Multiple System Atrophy: A Case Report]. AB - We report a case of persistent bilateral vocal cord paralysis which developed after spine surgery under general anesthesia in a patient with multiple system atrophy. A 64-year-old woman was scheduled to receive spinal fusion surgery for kyphoscoliosis. She did not have apparent symptoms of vocal cord paralysis such as hoarseness before surgery. The surgery was performed smoothly under general anesthesia with endotracheal intubation. However, immediately after extubation, the patient developed severe upper airway obstruction and was re-intubated. Fiberoptic laryngoscopy revealed bilateral vocal cord abductor paralysis. Vocal cord paralysis did not improve and she received tracheotomy on the 12th day after surgery. She also showed symptoms of autonomic nervous system dysfunction and cerebellar ataxia, and was diagnosed as multiple system atrophy on postoperative day 64. We discuss differential diagnosis of persistent vocal cord paralysis after general anesthesia, and anesthetic management of a patient with multiple system atrophy. PMID- 26437560 TI - [Cytoreductive Surgery Performed Twice for Pseudomyxoma Peritonei with Pleural Extension of Mucinous Tumor]. AB - Pseudomyxoma peritonei (PMP) is a condition characterized by production of a large amount of mucopolysaccharides by neoplastic epithelium, with intraabdominal cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) known to be viable treatment options. Pleural extension from an PMP is unusual and thought to be related to diaphragmatic perforation during surgery or transdiaphragmatic spreading of the disease through the lymphatic lacunae. Here, we report a patient with PMP with pleural extension of a mucinous tumor for whom CRS was performed twice. A 57-year-old female with PMP infiltrating the right chest cavity was scheduled for two separate CRS and hyperthermic chemotherapy procedures, because of the highly invasive characteristics of the surgery. For the first operation, we performed intra-abdominal surgery under general anesthesia combined with epidural anesthesia. To assess fluid and blood transfusion responsiveness, and reactions to vasoactive medication, we utilized an arterial pressure-based cardiac output monitor and central venous oximetry catheter. The second operation was performed 5 months later under general anesthesia with differential lung ventilation combined with epidural anesthesia. The operation and anesthesia for both surgical procedures were uneventful. PMID- 26437561 TI - [A Case of Suspected Delayed Postoperative Malignant Hyperthermia]. AB - Malignant hyperthermia occurred 10 hours after surgery in a 72-year-old man who had received emergency laparoscopic cholecystectomy for severe acute cholecystitis with cholelethiasis. He had a high fever (39.4 degrees C) with liver damage before surgery. Anesthesia was induced with propofol and fentanyl and maintained with sevoflurane and epidural block using ropivacaine. Rocuronium was used as a muscle relaxant During surgery, body temperature decreased by cooling the body surface, but tachycardia continued. Ten hours after surgery, body temperature increased to the maximum of 40.6 degrees C and he went into shock. Then another 10 hours later, he developed cardiac arrest He recovered, but 22 hours later, second cardiac arrest occurred. After his second recovery, dantrolene was administered and body temperature decreased. He had hypoxic brain damage, but was dischanged from the hospital after tracheostomy on the 150th hospital day. From his clinical course, especially decrease in body temperature by dantrolene, he was suspected to have developed malignant hyperthermia. We should consider malignant hyperthermia when patient had a severe high fever postoperatively. PMID- 26437562 TI - [Ultrasound-guided Sciatic Nerve Block (Pulsed Radiofrequency) for Intractable Cancer Pain Caused by Sacral Bone Metastasis]. AB - We report a case of successful pulsed radiofrequency stimulation of the sciatic nerve for intractable cancer pain caused by sacral bone metastasis of non-small cell lung cancer. A 57-year-old man who suffered from intractable left femoral pain was diagnosed with cancer metastasis to the sacral bone and lumbar spine. Oral oxycodone relieved the pain at rest but he could not walk or remain sitting due to the pain during exercise. Oxycodone rescue or increase did not relieve the pain, but induced drowsiness. Given that sciatic nerve block with mepivacaine was effective, we performed pulsed radiofrequency with ultrasound guidance twice. Pulsed radiofrequency relieved the left femoral pain and he could sit for hours and walk uneventfully. Our finding suggest that ultrasound-guided pulsed radiofrequency of the sciatic nerve effectively relieves intractable left femoral pain caused by sacral bone metastasis. PMID- 26437563 TI - [Successful Anesthetic Management of a Patient with Critical Bleeding during Hepatectomy Using Recombinant Activated Factor VII and Intraoperative Blood Salvage]. AB - A 58-year-old 79 kg male with metastatic liver cancer was scheduled for hepatectomy. Preoperative examination did not reveal any hemostatic abnormalities. Nine hours into the surgery, a vascular clip attached to the middle hepatic vein was disconnected and rapid bleeding followed. Unscheduled intraoperative cell salvage was employed. Despite surgical hemostasis as well as transfusion with fresh frozen plasma and platelets, significant oozing persisted for 10 hours, and cumulative blood loss amounted to 30,000 ml. Therefore, we administered fibrinogen products and recombinant activated factor VLL (rFVIIa, NovoSeven), a potent hemostatic initiator used in treating congenital factor VII deficient patients. After injecting 5 mg of rFVIIa, the bleeding was controlled almost immediately, and the surgery was completed within an hour. Although postoperative computed tomography detected subclinical but extensive thrombosis in the middle hepatic vein, the inferior vena cava, and the deep femoral veins, the thrombus spontaneously dissolved within seven months postoperatively. There was no evidence of metastatic disease 24 months postoperatively. Off-label use of rFVIIa and intraoperatively salvaged autologous blood transfusions are life saving procedures for cancer patients who have massive bleeding during surgery, although we cannot completely exclude the possibility of serious postoperative thrombotic events and/or hematogenous cancer dissemination. PMID- 26437564 TI - [A New Teaching Model for Practicing Ultrasound-guided Regional Anesthesia Techniques]. AB - We developed a simulator using "slime" composed of polyvinyl alcohol (PVA) and borax to evaluate this new ultrasound-guided nerve block training model. Seventeen subjects used the training model in the present study. They had no previous experience in performing ultrasound-guided nerve block. A plastic case measuring 25 x 18 x 12 cm was filled with 8 cm of slime. Three pieces of gauze were placed between the slime layers at 2 cm intervals. An in-plane approach was used to visualize the needle for the nerve block, and the amount of time required to stop the needle on the second gauze was measured 5 times for each subject. Significant differences were observed between the times for the first experiment and those for the third experiment to the fifth experiment In the fourth and fifth experiments, all subjects visualized the nerve block needle clearly above the target layer and were able to stop the needle at the target layer. The present simulation using our proposed ultrasound-guided nerve block training model was useful in terms of the amount of time required to perform the procedure and as well as in terms of its safety. PMID- 26437565 TI - [Several Issues before and after the Recognition of "Anesthesiology" as "Specially Approved Specialty"]. PMID- 26437566 TI - Does Mode of Contact with Different Types of Social Relationships Predict Depression in Older Adults? Evidence from a Nationally Representative Survey. AB - OBJECTIVES: To determine associations between use of three different modes of social contact (in person, telephone, written or e-mail), contact with different types of people, and risk of depressive symptoms in a nationally representative, longitudinal sample of older adults. DESIGN: Population-based observational cohort. SETTING: Urban and suburban communities throughout the contiguous United States. PARTICIPANTS: Individuals aged 50 and older who participated in the Health and Retirement Survey between 2004 and 2010 (N = 11,065). MEASUREMENTS: Frequency of participant use of the three modes of social contact with children, other family members, and friends at baseline were used to predict depressive symptoms (measured using the eight-item Center for Epidemiologic Studies Depression Scale) 2 years later using multivariable logistic regression models. RESULTS: Probability of having depressive symptoms steadily increased as frequency of in-person-but not telephone or written or e-mail contact-decreased. After controlling for demographic, clinical, and social variables, individuals with in-person social contact every few months or less with children, other family, and friends had a significantly higher probability of clinically significant depressive symptoms 2 years later (11.5%) than those having in-person contact once or twice per month (8.1%; P < .001) or once or twice per week (7.3%; P < .001). Older age, interpersonal conflict, and depression at baseline moderated some of the effects of social contact on depressive symptoms. CONCLUSION: Frequency of in-person social contact with friends and family independently predicts risk of subsequent depression in older adults. Clinicians should consider encouraging face-to-face social interactions as a preventive strategy for depression. PMID- 26437567 TI - Comprehensive treatments for social cognitive deficits in schizophrenia: A critical review and effect-size analysis of controlled studies. AB - Recent advances in psychosocial treatments for schizophrenia have targeted social cognitive deficits. A critical literature review and effect-size (ES) analysis was conducted to investigate the efficacy of comprehensive programs of social cognitive training in schizophrenia. Results revealed 16 controlled studies consisting of seven models of comprehensive treatment with only three of these treatment models investigated in more than one study. The effects of social cognitive training were reported in 11/15 studies that included facial affect recognition skills (ES=.84) and 10/13 studies that included theory-of-mind (ES=.70) as outcomes. Less than half (4/9) of studies that measured attributional style as an outcome reported effects of treatment, but effect sizes across studies were significant (ESs=.30-.52). The effect sizes for symptoms were modest, but, with the exception of positive symptoms, significant (ESs=.32-.40). The majority of trials were randomized (13/16), selected active control conditions (11/16) and included at least 30 participants (12/16). Concerns for this area of research include the absence of blinded outcome raters in more than 50% of trials and low rates of utilization of procedures for maintaining treatment fidelity. These findings provide preliminary support for the broader use of comprehensive social cognitive training procedures as a psychosocial intervention for schizophrenia. PMID- 26437568 TI - Sargaquinoic Acid Inhibits TNF-alpha-Induced NF-kappaB Signaling, Thereby Contributing to Decreased Monocyte Adhesion to Human Umbilical Vein Endothelial Cells (HUVECs). AB - Sargaquinoic acid (SQA) has been known for its antioxidant and anti-inflammatory properties. This study investigated the effects of SQA isolated from Sargassum serratifolium on the inhibition of tumor necrosis factor (TNF)-alpha-induced monocyte adhesion to human umbilical vein endothelial cells (HUVECs). SQA decreased the expression of cell adhesion molecules such as intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 as well as chemotactic cytokines such as interleukin-8 and monocyte chemoattractant protein-1 in TNF alpha-treated HUVECs. As a result, SQA prevented monocyte adhesion to TNF-alpha induced adhesion. SQA also inhibited TNF-alpha-induced nuclear factor kappa B (NF kappaB) translocation into the nucleus by preventing proteolytic degradation of inhibitor kappaB-alpha. Overall, SQA protects against TNF-alpha-induced vascular inflammation through inhibition of the NF-kappaB pathway in HUVECs. These data suggest that SQA may be used as a therapeutic agent for vascular inflammatory diseases such as atherosclerosis. PMID- 26437569 TI - Through-Space 1,4-Palladium Migration and 1,2-Aryl Shift: Direct Access to Dibenzo[a,c]carbazoles through a Triple C-H Functionalization Cascade. AB - A palladium-catalyzed expeditious synthesis of dibenzofused carbazoles from readily available 2-arylindoles and diaryliodonium salts is reported. Interestingly, after the electrophilic C3 palladation of indole, an unexpected "through-space" 1,4-palladium migration to the 2-aryl moiety, by remote C-H bond activation followed by C-H arylation with diaryliodonium salt, and an unprecedented 1,2-aryl shift take place. Finally, an intramolecular cross dehydrogenative coupling (CDC) at the C2 position affords dibenzo[a,c]carbazoles in high yields. Remarkably, the present migratory annulation occurs through three C-H bond activation one C-C bond cleavage, and the simultaneous construction of three new C-C bonds in a single operation. PMID- 26437570 TI - Time-dependent stabilization of the +1 nucleosome is an early step in the transition to stable cold-induced repression of FLC. AB - In vernalized Arabidopsis, the extent of FLC repression and promotion of flowering are correlated with the length of winter (low temperature exposure), but how plants measure the duration of winter is unknown. Repression of FLC occurs in two phases: establishment and maintenance. This study investigates the early events in the transition between establishment and maintenance of repression. Initial repression was rapid but transient; within 24 h of being placed at low temperatures FLC transcription was reduced by 40% and repression was complete after 5 days in the cold. The extent to which repression was maintained depended on the length of the cold treatment. Occupancy of the +1 nucleosome in FLC chromatin increased in a time-dependent manner over a 4-week low temperature treatment concomitant with decreased histone acetylation and increased trimethylation of histone H3 lysine 27 (H3K27me3). Mutant analyses showed that increased nucleosome occupancy occurred independent of histone deacetylation and increased H3K27me3, suggesting that it is an early step in the switch between transient and stable repression. Both altered histone composition and deacetylation contributed to increased nucleosome occupancy. The time dependency of the steps required for the switch between transient and stable repression suggests that the duration of winter is measured by the chromatin state at FLC. A chromatin-based switch is consistent with finding that each FLC allele in a cell undergoes this transition independently. PMID- 26437571 TI - Oxidative status in treatment-naive essential thrombocythemia: a pilot study in a single center. AB - Oxidative stress (OS), due to pro-oxidant species [reactive oxygen species (ROS)] excess not counterbalanced by endogenous antioxidant molecules [e.g., reduced glutathione (GSH)], is involved in the pathogenesis of human cancers, but few data are available on essential thrombocythemia (ET). This study aims to investigate OS in ET off-therapy patients. Thirty ET treatment-naive patients were compared with 26 age-matched and gender-matched controls. Serum ROS, urinary 8-hydroxydeoxyguanosine, full blood GSH levels, and reduced/oxidized GSH ratio (GSH/GSSG) were measured. Data were adjusted for gender, age, JAK2 mutational status, smoking, dyslipidemia, or hypercholesterolemia requiring drug therapy, antiplatelet therapy, treatment with acetylsalicylic acid, high-sensitive C reactive protein levels, and absolute monocyte count. ROS and GSH levels were increased in both patients and controls. Patients showed increased GSSG (p = 0.05), reduced GSH/GSSG ratio (p = 0.08), and similar 8-hydroxydeoxyguanosine levels when compared with controls. No differences in OS parameters were found between JAK2-positive and JAK2-negative patients. Confounding factors did not modify the results. Our study suggests an OS condition in a cohort of treatment naive ET patients, not associated with JAK2 mutational status or with chronic inflammation situation. GSH/GSSG ratio, altered in ET patients because of increased GSSG levels, showed the presence of higher GSH levels in ET than controls as a possible compensatory mechanism of an excess of pro-oxidant production. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26437573 TI - Regulatory Mechanism of the Enantioselective Intramolecular Enone [2+2] Photocycloaddition Reaction Mediated by a Chiral Lewis Acid Catalyst Containing Heavy Atoms. AB - The asymmetric catalysis of the intramolecular enone [2+2] photocycloaddition has been subject of extensive experimental studies, however theoretical insight to its regulatory mechanism is still sparse. Accurate quantum chemical calculations at the CASPT2//CASSCF level of theory associated with energy-consistent relativistic pseudopotentials provide a basis for the first regulation theory that the enantioselective reaction is predominantly controlled by the presence of relativistic effects, that is, spin-orbit coupling resulting from heavy atoms in the chiral Lewis acid catalyst. PMID- 26437572 TI - MicroRNA-34a Promotes Hepatic Stellate Cell Activation via Targeting ACSL1. AB - BACKGROUND: The incidence of liver fibrosis remains high due to the lack of effective therapies. Our previous work found that microRNA (miR)-34a expression was increased, while acy1-CoA synthetase long-chain family member1 (ACSL1) was decreased, in a dimethylnitrosamine (DNS)-induced hepatic fibrosis rat model. We hypothesized that miR-34a may play a role in the process of hepatic fibrosis by targeting ACSL1. MATERIAL AND METHODS: From days 2 to 14, cultured primary hepatic stellate cells (HSCs) underwent cell morphology, immunocytochemical staining, and quantitative reverse transcription PCR (RT-qPCR) for alpha smooth muscle actin (a-SMA), desmin, rno-miR-34a, and ACSL1 expression. Wild-type and mutant luciferase reporter plasmids were constructed according to the predicted miR-34a binding site on the 3'-untranslated region (UTR) of the ACSL1 mRNA and then transfected into HEK293 cells. rno-miR-34a was silenced in HSCs to confirm that rno-miR-34a negatively regulates ACSL1 expression. mRNA and protein expression of alpha-SMA, type I collagen, and desmin were assayed in miR-34a silenced HSCs. RESULTS: HSCs were deemed quiescent during the first 3 days and activated after 10 days. rno-miR-34a expression increased, and ACSL1 expression decreased, from day 2 to 7 to 14. rno-miR-34a was shown to specifically bind to the 3'-UTR of ACSL1. miR-34a-silenced HSCs showed higher ACSL1and lower alpha SMA, type I collagen, and desmin expression than that of matching negative controls and non-transfected cells. CONCLUSIONS: miR-34a appears to play an important role in the process of liver fibrosis by targeting ACSL1 and may show promise as a therapeutic molecular target for hepatic fibrosis. PMID- 26437574 TI - Altered EEG resting-state effective connectivity in drug-naive childhood absence epilepsy. AB - OBJECTIVE: We investigated interictal EEG activity in patients with childhood absence seizures with the aim of detecting markers of network defects generating "idiopathic" hyperexcitability in this form of epilepsy. METHODS: We included 11 drug-naive patients with childhood absence epilepsy (CAE), and 11 age matched controls (CTRL). We analyzed interictal EEG using partial directed coherence (PDC), a connectivity estimator in frequency domain based on autoregressive multivariate (MVAR) modeling giving the advantage of indicating the direction and strength of the interactions between multiple variables. RESULTS: Our results revealed the presence of an abnormal cortico-cortical network occurring in the interictal condition in CAE and involving a large span of frequencies, with prominence in the alpha band; the most evident finding was a highly significant increase of out-going connectivity involving frontal and central cortical areas in CAE patients compared to CTRL subjects. CONCLUSIONS: Our observation indicates that, in interictal conditions, a distorted network characterizes CAE, and a hyperconnected network is already detectable under resting conditions in the delta, theta and alpha bands. SIGNIFICANCE: The increased interictal EEG connectivity demonstrated here provides support for a persistent abnormal relationship between the thalamus and a hyperexcitable cortex outside the ictal phase. PMID- 26437575 TI - Thermoelectricity in polymer composites due to fluctuation-induced tunneling. AB - Transport in heavily-doped polymer composites, characterized by localized charge regions, is examined in light of the recent interest in polymers for thermoelectric applications. The developed fundamental transport theory describes carrier tunneling between charged localizations by taking into account thermally induced fluctuations of the applied potential. A range of characteristic behaviors corresponding to experimental data are described. Deviations from the Wiedemann-Franz law are also identified. This novel theory enables the determination of factors dominating the transport in polymers and a comparison to tunneling without thermal fluctuations is also provided. The obtained asymptotic expressions for the conductivity, Seebeck coefficient, and carrier thermal conductivity are particularly useful for elucidating possible routes for thermoelectric transport control and optimization. PMID- 26437576 TI - Role of postoperative radiation therapy (PORT) in pT1-T2 N0 deep tongue cancers. AB - OBJECTIVE: Carcinoma of tongue is associated with a high risk of occult metastasis and mortality despite early-stage detection and therapy; the critical tumor thickness at which this risk increases has been demonstrated as 4 mm or greater. There are no sufficient data in the published literature to evaluate the role of postoperative radiation therapy (PORT) in the treatment of pT1-T2 N0 oral tongue cancers with depth of invasion 4 mm or greater. STUDY DESIGN: Historical cohorts of patients with primary pT1-T2 N0 oral tongue cancer of depth of invasion 4 mm or greater treated surgically from January 2010 to December 2012 were included in the study, and negative margins on initial resection were filtered. Locoregional recurrence and death were analyzed among the patients who received PORT and those who did not. RESULTS: A total of 103 patients fulfilled the above-mentioned criteria, with 62 patients receiving PORT and 41 patients not receiving PORT; median period of follow-up was 41.3 months. Logistic and Cox regression models showed no significant difference in locoregional recurrences (P = .078) and survival (P = .339) between patients who received PORT and those who did not receive PORT. CONCLUSIONS: PORT did not influence survival of patients with stage I and stage II deep tongue cancers, with 4 mm or greater tumor invasion depth. PMID- 26437577 TI - Chronic Contusion Spinal Cord Injury Impairs Ejaculatory Reflexes in Male Rats: Partial Recovery by Systemic Infusions of Dopamine D3 Receptor Agonist 7OHDPAT. AB - Chronic spinal cord injury (SCI) causes major disruption of ejaculatory function in men. Ejaculation is a reflex and the spinal generator for ejaculatory reflexes in the rat has been located in the lumbosacral spinal cord. The effects of SCI on the rat spinal ejaculation generator and ejaculatory reflexes remain understudied. The first goal of the current study was to establish the effects of chronic SCI on the function of the spinal ejaculation generator. Male rats received a contusion injury of the spinal cord at spinal level T6-T7. Ejaculatory reflexes elicited by electrical stimulation of the dorsal penile nerve (DPN) were evaluated in injured and control rats at 4-6 weeks following SCI. SCI males demonstrated significant reductions in bursting of the bulbocavernosus muscle (BCM), an indicator for expulsion phase of ejaculation, and in seminal vesicle pressure (SVP) increases, an indicator for the emission phase of ejaculation, following DPN stimulation. Thus, contusion SCI resulted in long-term impairment of ejaculatory reflexes. The D3 agonist 7-hydroxy-2-(di-N-propylamino) tetralin (7OHDPAT) facilitates ejaculation in spinal cord intact rats, thus the second goal of the current study was to test whether subcutaneous infusions of 7OHDPAT can facilitate ejaculatory reflexes in rats with chronic SCI. Male rats received a contusion injury at T6-T7 and effects of systemic administration of 7OHDPAT (1 mg/kg) were tested 4-5 weeks following injury. Results showed that 7OHDPAT administration facilitated ejaculatory reflexes in SCI males with or without DPN stimulation, provided that supraspinal inputs to the lumbar cord were severed by transection just prior to evaluating the reflex. Thus, 7OHDPAT administration in SCI males was able to overcome the detrimental effects of SCI on ejaculatory reflexes. PMID- 26437578 TI - The 127th Regional Meeting (Kinki Area). PMID- 26437579 TI - The 132th Regional Meeting (Kanto Area). PMID- 26437580 TI - A combined omics approach to evaluate the effects of dietary curcumin on colon inflammation in the Mdr1a(-/-) mouse model of inflammatory bowel disease. AB - The aim of this study was to provide insight into how curcumin reduces colon inflammation in the Mdr1a(-/-) mouse model of human inflammatory bowel disease using a combined transcriptomics and proteomics approach. Mdr1a(-/-) and FVB control mice were randomly assigned to an AIN-76A (control) diet or AIN-76A+0.2% curcumin. At 21 or 24weeks of age, colonic histological injury score (HIS) was determined, colon mRNA transcript levels were assessed using microarrays and colon protein expression was measured using 2D gel electrophoresis and LCMS protein identification. Colonic HIS of Mdr1a(-/-) mice fed the AIN-76A diet was higher (P<.001) than FVB mice fed the same diet; the curcumin-supplemented diet reduced colonic HIS (P<.05) in Mdr1a(-/-) mice. Microarray and proteomics analyses combined with new data analysis tools, such as the Ingenuity Pathways Analysis regulator effects analysis, showed that curcumin's antiinflammatory activity in Mdr1a(-/-) mouse colon may be mediated by activation of alpha catenin, which has not previously been reported. We also show evidence to support curcumin's action via multiple molecular pathways including reduced immune response, increased xenobiotic metabolism, resolution of inflammation through decreased neutrophil migration and increased barrier remodeling. Key transcription factors and other regulatory molecules (ERK, FN1, TNFSF12 and PI3K complex) activated in inflammation were down-regulated by dietary intervention with curcumin. PMID- 26437582 TI - Antimicrobial activity of iron oxide nanoparticle upon modulation of nanoparticle bacteria interface. AB - Investigating the interaction patterns at nano-bio interface is a key challenge for safe use of nanoparticles (NPs) to any biological system. The study intends to explore the role of interaction pattern at the iron oxide nanoparticle (IONP) bacteria interface affecting antimicrobial propensity of IONP. To this end, IONP with magnetite like atomic arrangement and negative surface potential (n-IONP) was synthesized by co-precipitation method. Positively charged chitosan molecule coating was used to reverse the surface potential of n-IONP, i.e. positive surface potential IONP (p-IONP). The comparative data from fourier transform infrared spectroscope, XRD, and zeta potential analyzer indicated the successful coating of IONP surface with chitosan molecule. Additionally, the nanocrystals obtained were found to have spherical size with 10-20 nm diameter. The BacLight fluorescence assay, bacterial growth kinetic and colony forming unit studies indicated that n-IONP (<50 MUM) has insignificant antimicrobial activity against Bacillus subtilis and Escherichia coli. However, coating with chitosan molecule resulted significant increase in antimicrobial propensity of IONP. Additionally, the assay to study reactive oxygen species (ROS) indicated relatively higher ROS production upon p-IONP treatment of the bacteria. The data, altogether, indicated that the chitosan coating of IONP result in interface that enhances ROS production, hence the antimicrobial activity. PMID- 26437581 TI - Innervation and neuromuscular control in ageing skeletal muscle. AB - Changes in the neuromuscular system affecting the ageing motor unit manifest structurally as a reduction in motor unit number secondary to motor neuron loss; fibre type grouping due to repeating cycles of denervation-reinnervation; and instability of the neuromuscular junction that may be due to either or both of a gradual perturbation in postsynaptic signalling mechanisms necessary for maintenance of the endplate acetylcholine receptor clusters or a sudden process involving motor neuron death or traumatic injury to the muscle fibre. Functionally, these changes manifest as a reduction in strength and coordination that precedes a loss in muscle mass and contributes to impairments in fatigue. Regular muscle activation in postural muscles or through habitual physical activity can attenuate some of these structural and functional changes up to a point along the ageing continuum. On the other hand, regular muscle activation in advanced age (>75 years) loses its efficacy, and at least in rodents may exacerbate age-related motor neuron death. Transgenic mouse studies aimed at identifying potential mechanisms of motor unit disruptions in ageing muscle are not conclusive due to many different mechanisms converging on similar motor unit alterations, many of which phenocopy ageing muscle. Longitudinal studies of ageing models and humans will help clarify the cause and effect relationships and thus, identify relevant therapeutic targets to better preserve muscle function across the lifespan. PMID- 26437583 TI - Photopolymer Electrolytes for Sustainable, Upscalable, Safe, and Ambient Temperature Sodium-Ion Secondary Batteries. AB - The first example of a photopolymerized electrolyte for a sodium-ion battery is proposed herein. By means of a preparation process free of solvents, catalysts, purification steps, and separation steps, it is possible to obtain a three dimensional polymeric network capable of efficient sodium-ion transport. The thermal properties of the resulting solid electrolyte separator, characterized by means of thermogravimetric and calorimetric techniques, are excellent for use in sustainable energy systems conceived for safe large-scale grid storage. The photopolymerized electrolyte shows a wide electrochemical stability window up to 4.8 V versus Na/Na(+) along with the highest ionic conductivity (5.1 mS cm(-1) at 20 degrees C) obtained in the field of Na-ion polymer batteries so far and stable long-term constant-current charge/discharge cycling. Moreover, the polymeric networks are also demonstrated for the in situ fabrication of electrode/electrolyte composites with excellent interfacial properties, which are ideal for all-solid-state, safe, and easily upscalable device assembly. PMID- 26437584 TI - Ubiquitin-Dependent And Independent Signals In Selective Autophagy. AB - Selective autophagy regulates the abundance of specific cellular components via a specialized arsenal of factors, termed autophagy receptors, that target protein complexes, aggregates, and whole organelles into lysosomes. Autophagy receptors bind to LC3/GABARAP proteins on phagophore and autophagosome membranes, and recognize signals on cargoes to deliver them to autophagy. Ubiquitin (Ub), a well known signal for the degradation of polypeptides in the proteasome, also plays an important role in the recognition of cargoes destined for selective autophagy. In addition, a variety of cargoes are committed to selective autophagy pathways by Ub-independent mechanisms employing protein-protein interaction motifs, Ub-like modifiers, and sugar- or lipid-based signals. In this article we summarize Ub dependent and independent selective autophagy pathways, and discuss regulatory mechanisms and challenges for future studies. PMID- 26437585 TI - Ligand-Independent Mechanisms of Notch Activity. AB - Interaction between the Notch receptor and Delta-Serrate-Lag2 (DSL) ligands is generally deemed to be the starting point of the Notch signaling cascade, after which, Notch is cleaved and the intracellular domain acts as a transcriptional coactivator. By contrast, Notch protein can become activated independent of ligand stimulus through recently identified endosomal trafficking routes as well as through aberrant regulation of Notch components during Notch trafficking, ubiquitination, and degradation. In this review, we summarize genes implicated in ligand-independent Notch activity and remark on the mechanisms by which this process could occur. PMID- 26437586 TI - Repair Pathway Choices and Consequences at the Double-Strand Break. AB - DNA double-strand breaks (DSBs) are cytotoxic lesions that threaten genomic integrity. Failure to repair a DSB has deleterious consequences, including genomic instability and cell death. Indeed, misrepair of DSBs can lead to inappropriate end-joining events, which commonly underlie oncogenic transformation due to chromosomal translocations. Typically, cells employ two main mechanisms to repair DSBs: homologous recombination (HR) and classical nonhomologous end joining (C-NHEJ). In addition, alternative error-prone DSB repair pathways, namely alternative end joining (alt-EJ) and single-strand annealing (SSA), have been recently shown to operate in many different conditions and to contribute to genome rearrangements and oncogenic transformation. Here, we review the mechanisms regulating DSB repair pathway choice, together with the potential interconnections between HR and the annealing-dependent error-prone DSB repair pathways. PMID- 26437587 TI - Types or States? Cellular Dynamics and Regenerative Potential. AB - Many of our organs can maintain and repair themselves during homeostasis and injury, as a result of the action of tissue-specific, multipotent stem cells. However, recent evidence from mammalian systems suggests that injury stimulates dramatic plasticity, or transient changes in cell potential, in both stem cells and more differentiated cells. Planarian flatworms possess abundant stem cells, making them an exceptional model for understanding the cellular behavior underlying homeostasis and regeneration. Recent discoveries of cell lineages and regeneration-specific events provide an initial framework for unraveling the complex cellular contributions to regeneration. In this review, we discuss the concept of cellular plasticity in the context of planarian regeneration, and consider the possibility that pluripotency may be a transient, probabilistic state exhibited by stem cells. PMID- 26437588 TI - The Functions of MicroRNAs: mRNA Decay and Translational Repression. AB - MicroRNAs (miRNAs) are a class of endogenous small noncoding RNAs, which regulate complementary mRNAs by inducing translational repression and mRNA decay. Although this dual repression system seems to operate in both animals and plants, genetic and biochemical studies suggest that the mechanism underlying the miRNA-mediated silencing is different in the two kingdoms. Here, we review the recent progress in our understanding of how miRNAs mediate translational repression and mRNA decay, and discuss the contributions of the two silencing modes to the overall silencing effect in both kingdoms. PMID- 26437590 TI - The Material Basis of Life. AB - The manner by which the organization and behaviors of cells arise from the activities of their constituent molecules remains poorly understood. Approaches from the physical sciences for studying collective properties may help with this difficult problem, but they must be adapted to account for the specific attributes of biological molecules. PMID- 26437589 TI - Epithelial-Mesenchymal Plasticity: A Central Regulator of Cancer Progression. AB - The epithelial-mesenchymal transition (EMT) program has emerged as a central driver of tumor malignancy. Moreover, the recently uncovered link between passage through an EMT and acquisition of stem-like properties indicates that activation of the EMT programs serves as a major mechanism for generating cancer stem cells (CSCs); that is, a subpopulation of cancer cells that are responsible for initiating and propagating the disease. In this review, we summarize the evidence supporting the widespread involvement of the EMT program in tumor pathogenesis and attempt to rationalize the connection between the EMT program and acquisition of stem cell traits. We propose that epithelial-mesenchymal plasticity is likely controlled by multiple varients of the core EMT program, and foresee the need to resolve the various programs and the molecular mechanisms that underlie them. PMID- 26437592 TI - Beyond the Linear Genome: Paired-End Sequencing as a Biophysical Tool. AB - Paired-end sequencing has enabled a variety of new methods for high-throughput interrogation of both genome structure and chromatin architecture. Here, we discuss how the paired-end paradigm can be used to interpret sequencing data as biophysical measurements of in vivo chromatin structure that report on single molecules in single cells. PMID- 26437591 TI - Border Safety: Quality Control at the Nuclear Envelope. AB - The unique biochemical identity of the nuclear envelope confers its capacity to establish a barrier that protects the nuclear compartment and directly contributes to nuclear function. Recent work uncovered quality control mechanisms employing the endosomal sorting complexes required for transport (ESCRT) machinery and a new arm of endoplasmic reticulum-associated protein degradation (ERAD) to counteract the unfolding, damage, or misassembly of nuclear envelope proteins and ensure the integrity of the nuclear envelope membranes. Moreover, cells have the capacity to recognize and triage defective nuclear pore complexes to prevent their inheritance and preserve the longevity of progeny. These mechanisms serve to highlight the diverse strategies used by cells to maintain nuclear compartmentalization; we suggest they mitigate the progression and severity of diseases associated with nuclear envelope malfunction such as the laminopathies. PMID- 26437593 TI - After the Greeting: Realizing the Potential of Physical Models in Cell Biology. AB - Biophysics is increasingly taking center stage in cell biology as the tools for precise quantifications of cellular behaviors expand. Interdisciplinary approaches, combining quantitative physical modeling with cell biology, are of growing interest to journal editors, funding agencies, and hiring committees. However, despite an ever-increasing emphasis on the importance of interdisciplinary research, the student trained in biology may still be at a loss as to what it actually means. I discuss here some considerations on how to achieve meaningful and high-quality interdisciplinary work. PMID- 26437594 TI - An Apoptotic 'Eat Me' Signal: Phosphatidylserine Exposure. AB - Apoptosis and the clearance of apoptotic cells are essential processes in animal development and homeostasis. For apoptotic cells to be cleared, they must display an 'eat me' signal, most likely phosphatidylserine (PtdSer) exposure, which prompts phagocytes to engulf the cells. PtdSer, which is recognized by several different systems, is normally confined to the cytoplasmic leaflet of the plasma membrane by a 'flippase'; apoptosis activates a 'scramblase' that quickly exposes PtdSer on the cell surface. The molecules that flip and scramble phospholipids at the plasma membrane have recently been identified. Here we discuss recent findings regarding the molecular mechanisms of apoptotic PtdSer exposure and the clearance of apoptotic cells. PMID- 26437595 TI - Nuclear Reprogramming by Defined Factors: Quantity Versus Quality. AB - The generation of induced pluripotent stem cells (iPSCs) and directly converted cells holds great promise in regenerative medicine. However, after in-depth studies of the murine system, we know that the current methodologies to produce these cells are not ideal and mostly yield cells of poor quality that might hold a risk in therapeutic applications. In this review we address the duality found in the literature regarding the use of 'quality' as a criterion for the clinic. We discuss the elements that influence reprogramming quality, and provide evidence that safety and functionality are directly linked to cell quality. Finally, because most of the available data come from murine systems, we speculate about what aspects can be applied to human cells. PMID- 26437596 TI - How Cells Measure Length on Subcellular Scales. AB - Cells are not just amorphous bags of enzymes, but precise and complex machines. With any machine, it is important that the parts be of the right size, yet our understanding of the mechanisms that control size of cellular structures remains at a rudimentary level in most cases. One problem with studying size control is that many cellular organelles have complex 3D structures that make their size hard to measure. Here we focus on linear structures within cells, for which the problem of size control reduces to the problem of length control. We compare and contrast potential mechanisms for length control to understand how cells solve simple geometry problems. PMID- 26437597 TI - Fibroblasts Lead the Way: A Unified View of 3D Cell Motility. AB - Primary human fibroblasts are remarkably adaptable, able to migrate in differing types of physiological 3D tissue and on rigid 2D tissue culture surfaces. The crawling behavior of these and other vertebrate cells has been studied intensively, which has helped generate the concept of the cell motility cycle as a comprehensive model of 2D cell migration. However, this model fails to explain how cells force their large nuclei through the confines of a 3D matrix environment and why primary fibroblasts can use more than one mechanism to move in 3D. Recent work shows that the intracellular localization of myosin II activity is governed by cell-matrix interactions to both force the nucleus through the extracellular matrix (ECM) and dictate the type of protrusions used to migrate in 3D. PMID- 26437598 TI - A Unified Material Description for Light Induced Deformation in Azobenzene Polymers. AB - Complex light-matter interactions in azobenzene polymers have limited our understanding of how photoisomerization induces deformation as a function of the underlying polymer network and form of the light excitation. A unified modeling framework is formulated to advance the understanding of surface deformation and bulk deformation of polymer films that are controlled by linear or circularly polarized light or vortex beams. It is shown that dipole forces strongly respond to polarized light in contrast to higher order quadrupole forces that are often used to describe surface relief grating deformation through a field gradient constitutive law. The modeling results and comparisons with a broad range of photomechanical data in the literature suggest that the molecular structure of the azobenzene monomers dramatically influences the photostrictive behavior. The results provide important insight for designing azobenzene monomers within a polymer network to achieve enhanced photo-responsive deformation. PMID- 26437599 TI - Competition between global warming and an abrupt collapse of the AMOC in Earth's energy imbalance. AB - A collapse of the Atlantic Meridional Overturning Circulation (AMOC) leads to global cooling through fast feedbacks that selectively amplify the response in the Northern Hemisphere (NH). How such cooling competes with global warming has long been a topic for speculation, but was never addressed using a climate model. Here it is shown that global cooling due to a collapsing AMOC obliterates global warming for a period of 15-20 years. Thereafter, the global mean temperature trend is reversed and becomes similar to a simulation without an AMOC collapse. The resulting surface warming hiatus lasts for 40-50 years. Global warming and AMOC-induced NH cooling are governed by similar feedbacks, giving rise to a global net radiative imbalance of similar sign, although the former is associated with surface warming, the latter with cooling. Their footprints in outgoing longwave and absorbed shortwave radiation are very distinct, making attribution possible. PMID- 26437600 TI - Nondestructive Quantification of Local Plasticizer Concentration in PVC by (1)H NMR Relaxometry. AB - The properties of plasticized poly(vinyl chloride) (PVC) , one of the most important polymers today, are strongly dictated by the concentration of plasticizer. Yet, it has been impossible to quantify this concentration at different positions inside a PVC product without its destruction because of a lack of suitable analytical methods. Thus, this paper introduces a simple, fast, and efficient way to determine truly nondestructively the concentration of plasticizer in PVC by single-sided nuclear magnetic resonance (NMR). With the help of correlation curves between the concentration of plasticizer inside nonaged PVC samples and the corresponding volume-averaged NMR parameters, single sided NMR allows the quantification of the local concentration of plasticizer in aged PVC plates at different depths by spatially resolved relaxation measurements. The presented approach represents a fundamental step toward in situ characterization of plasticized PVC. PMID- 26437601 TI - Human rights in maternity care. PMID- 26437602 TI - Global Phosphoproteomic Analysis of Human Skeletal Muscle Reveals a Network of Exercise-Regulated Kinases and AMPK Substrates. AB - Exercise is essential in regulating energy metabolism and whole-body insulin sensitivity. To explore the exercise signaling network, we undertook a global analysis of protein phosphorylation in human skeletal muscle biopsies from untrained healthy males before and after a single high-intensity exercise bout, revealing 1,004 unique exercise-regulated phosphosites on 562 proteins. These included substrates of known exercise-regulated kinases (AMPK, PKA, CaMK, MAPK, mTOR), yet the majority of kinases and substrate phosphosites have not previously been implicated in exercise signaling. Given the importance of AMPK in exercise regulated metabolism, we performed a targeted in vitro AMPK screen and employed machine learning to predict exercise-regulated AMPK substrates. We validated eight predicted AMPK substrates, including AKAP1, using targeted phosphoproteomics. Functional characterization revealed an undescribed role for AMPK-dependent phosphorylation of AKAP1 in mitochondrial respiration. These data expose the unexplored complexity of acute exercise signaling and provide insights into the role of AMPK in mitochondrial biochemistry. PMID- 26437605 TI - Oxygen Sensing by Arterial Chemoreceptors Depends on Mitochondrial Complex I Signaling. AB - O2 sensing is essential for mammalian homeostasis. Peripheral chemoreceptors such as the carotid body (CB) contain cells with O2-sensitive K(+) channels, which are inhibited by hypoxia to trigger fast adaptive cardiorespiratory reflexes. How variations of O2 tension (PO2) are detected and the mechanisms whereby these changes are conveyed to membrane ion channels have remained elusive. We have studied acute O2 sensing in conditional knockout mice lacking mitochondrial complex I (MCI) genes. We inactivated Ndufs2, which encodes a protein that participates in ubiquinone binding. Ndufs2-null mice lose the hyperventilatory response to hypoxia, although they respond to hypercapnia. Ndufs2-deficient CB cells have normal functions and ATP content but are insensitive to changes in PO2. Our data suggest that chemoreceptor cells have a specialized succinate dependent metabolism that induces an MCI state during hypoxia, characterized by the production of reactive oxygen species and accumulation of reduced pyridine nucleotides, which signal neighboring K(+) channels. PMID- 26437603 TI - Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy. AB - Chronic kidney disease (CKD) is a worldwide public health threat that increases risk of death due to cardiovascular complications, including left ventricular hypertrophy (LVH). Novel therapeutic targets are needed to design treatments to alleviate the cardiovascular burden of CKD. Previously, we demonstrated that circulating concentrations of fibroblast growth factor (FGF) 23 rise progressively in CKD and induce LVH through an unknown FGF receptor (FGFR) dependent mechanism. Here, we report that FGF23 exclusively activates FGFR4 on cardiac myocytes to stimulate phospholipase Cgamma/calcineurin/nuclear factor of activated T cell signaling. A specific FGFR4-blocking antibody inhibits FGF23 induced hypertrophy of isolated cardiac myocytes and attenuates LVH in rats with CKD. Mice lacking FGFR4 do not develop LVH in response to elevated FGF23, whereas knockin mice carrying an FGFR4 gain-of-function mutation spontaneously develop LVH. Thus, FGF23 promotes LVH by activating FGFR4, thereby establishing FGFR4 as a pharmacological target for reducing cardiovascular risk in CKD. PMID- 26437606 TI - Pregnancy outcome after blastocyst stage transfer comparing to early cleavage stage embryo transfer. AB - Blastocyst transfer has been introduced as an alternative for improving the chance for in vitro fertilizations (IVF) implantation. The present study was to evaluate pregnancy rates when embryo transfer was performed either on day 2-3 (cleavage stage) or on day 4-5 (blastocyst stage). This randomized clinical trial included 118 infertile women. All the study subjects underwent controlled ovarian stimulation using a long protocol and randomized into two groups. BS group (n = 57), the culture was extended to day 5 (blastocyst stage) and in the CS-group (n = 61), embryo culture was continued to day 3 (cleavage stage). Ongoing pregnancies, abortion, implantation rate were evaluated. No significant differences were seen in the pregnancy rate between the two groups (33.3% in the BS group versus 27.9% in the CS group; p = 0.519). Abortion, implantation rate in two groups are not significant. Despite the lack of statistical difference between the two study groups, our data suggest that blastocyst transfer may be associated with a higher pregnancy and an overall better implantation rates. However, further studies with larger sample size are mandatory to confirm these findings. PMID- 26437607 TI - Optimization of silver nanowire-based transparent electrodes: effects of density, size and thermal annealing. AB - Silver nanowire (AgNW) networks are efficient as flexible transparent electrodes, and are cheaper to fabricate than ITO (Indium Tin Oxide). Hence they are a serious competitor as an alternative to ITO in many applications such as solar cells, OLEDs, transparent heaters. Electrical and optical properties of AgNW networks deposited on glass are investigated in this study and an efficient method to optimize them is proposed. This paper relates network density, nanowire dimensions and thermal annealing directly to the physical properties of the nanowire networksusing original physical models. A fair agreement is found between experimental data and the proposed models. Moreover thermal stability of the nanowires is a key issue in thermal optimization of such networks and needs to be studied. In this work the impact of these four parameters on the networks physical properties are thoroughly investigated via in situ measurements and modelling, such a method being also applicable to other metallic nanowire networks. We demonstrate that this approach enables the optimization of both optical and electrical properties through modification of the junction resistance by thermal annealing, and a suitable choice of nanowire dimensions and network density. This work reports excellent optical and electrical properties of electrodes fabricated from AgNW networks with a transmittance T = 89.2% (at 550 nm) and a sheet resistance of Rs = 2.9 Omega ?(-1), leading to the highest reported figure of merit. PMID- 26437604 TI - Ironing out Ferroportin. AB - Maintaining physiologic iron concentrations in tissues is critical for metabolism and host defense. Iron absorption in the duodenum, recycling of iron from senescent erythrocytes, and iron mobilization from storage in macrophages and hepatocytes constitute the major iron flows into plasma for distribution to tissues, predominantly for erythropoiesis. All iron transfer to plasma occurs through the iron exporter ferroportin. The concentration of functional membrane associated ferroportin is controlled by its ligand, the iron-regulatory hormone hepcidin, and fine-tuned by regulatory mechanisms serving iron homeostasis, oxygen utilization, host defense, and erythropoiesis. Fundamental questions about the structure and biology of ferroportin remain to be answered. PMID- 26437608 TI - 2D NMR Trace Analysis by Continuous Hyperpolarization at High Magnetic Field. AB - Nuclear magnetic resonance is often the technique of choice in chemical analysis because of its sensitivity to molecular structure, quantitative character, and straightforward sample preparation. However, determination of trace analytes in complex mixtures is generally limited by low sensitivity and extensive signal overlap. Here, we present an approach for continuous hyperpolarization at high magnetic field that is based on signal amplification by reversible exchange (SABRE) and can be straightforwardly incorporated in multidimensional NMR experiments. This method was implemented in a 2D correlation experiment that allows detection and quantification of analytes at nanomolar concentration in complex solutions. PMID- 26437609 TI - Surface toughness of silicon nitride bioceramics: II, Comparison with commercial oxide materials. AB - Raman microprobe-assisted indentation, a micromechanics method validated in a companion paper, was used to compare the surface toughening behaviors of silicon nitride (Si3N4) and alumina-based bioceramics employed in joint arthroplasty (i.e., monolithic alumina, Al2O3, and yttria-stabilized zirconia (ZrO2)-toughened alumina, ZTA). Quantitative assessments of microscopic stress fields both ahead and behind the tip of Vickers indentation cracks propagated under increasing indentation loads were systematically made using a Raman microprobe with spatial resolution on the order of a single micrometer. Concurrently, crack opening displacement (COD) profiles were monitored on the same microcracks screened by Raman spectroscopy. The Raman eye clearly visualized different mechanisms operative in toughening Si3N4 and ZTA bioceramics (i.e., crack-face bridging and ZrO2 polymorphic transformation, respectively) as compared to the brittle behavior of monolithic Al2O3. Moreover, emphasis was placed on assessing not only the effectiveness but also the durability of such toughening effects when the biomaterials were aged in a hydrothermal environment. A significant degree of embrittlement at the biomaterial surface was recorded in the transformation toughened ZTA, with the surface toughness reduced by exposure to the hydrothermal environment. Conversely, the Si3N4 biomaterial experienced a surface toughness value independent of hydrothermal attack. Crack-face bridging thus appears to be a durable surface toughening mechanism for biomaterials in joint arthroplasty. PMID- 26437610 TI - Transient behavior and relaxation of microcapsules with a cross-linked human serum albumin membrane. AB - Capsules consist of droplets enclosed by a membrane with shear resistant properties especially when fabricated by interfacial cross-linking. In many applications, the protection and release of the internal medium need to be strictly controlled. It is possible to tune the membrane mechanical properties by changing the physico-chemical conditions of the fabrication process, but a good control of the production requires their characterization, which is a scientific challenge, since the objects are a few tens of microns in size at most. One advantageous approach is to resort to microfluidic techniques. We study the transient response of capsules having a cross-linked human serum albumin (HSA) membrane, as they flow through a sudden expansion. We determine the characteristic time scales of the capsule relaxation and compare them to the ones predicted by a full numerical model of the relaxation of a capsule flowing in a rectangular channel, for which the membrane is assumed to be purely elastic. We show that the membrane is viscoelastic and that the relaxation is solely a function of the ratio of the relaxation time to the convective time. PMID- 26437611 TI - The Utility of Positron Emission Tomography in Epilepsy. AB - The role of fludeoxyglucose F 18 positron emission tomography (PET) in the presurgical evaluation of patients with medically intractable epilepsy continues to be refined. The purpose of this study was to systematically review the literature to assess the diagnostic accuracy and utility of PET in this setting. Thirty-nine studies were identified through MEDLINE and EMBASE databases that met the inclusion criteria. In adult patients, PET hypometabolism showed a 56 to 90% agreement with seizure onset localized by intracranial electroencephalogram (pediatric: 21 to 86%). In temporal lobe epilepsy patients with good surgical outcome, PET displayed moderate to high sensitivity in localizing the seizure focus (range: 71 to 89%). The sensitivity increased by 8 to 23% when PET results were combined with magnetic resonance imaging or electroencephalogram. PET has been shown to affect patient management by improving the guidance of intracranial electrodes placement, altering the decision to perform surgery, or excluding patients from further evaluation. PMID- 26437612 TI - Toward a personalized calorie prescription. PMID- 26437613 TI - Chamomile tea improves glycemic indices and antioxidants status in patients with type 2 diabetes mellitus. AB - OBJECTIVES: Oxidative stress is a major factor in the pathogenesis of diabetes complications. The objectives were to investigate the effects of chamomile tea consumption on glycemic control and antioxidant status in subjects with type 2 diabetes mellitus (T2 DM). METHODS: This single-blind randomized controlled clinical trial was conducted on 64 subjects with T2 DM (males and females) ages 30 to 60 y. The intervention group (n = 32) consumed chamomile tea (3 g/150 mL hot water) 3 times per day immediately after meals for 8 wk. The control group (n = 32) followed a water regimen for same intervention period. Fasting blood samples, anthropometric measurements, and 3-d, 24-h dietary recalls were collected at the baseline and at the end of the trial. Data were analyzed by independent t test, paired t test, and analysis of covariance. RESULTS: Chamomile tea significantly decreased concentration of glycosylated hemoglobin, serum insulin levels, homeostatic model assessment for insulin resistance, and serum malondialdehyde, compared with control group (all P < 0.05). Total antioxidant capacity, superoxide dismutase, glutathione peroxidase, and catalase activities were significantly increased by 6.81%, 26.16 %, 36.71 % and 45.06% respectively in chamomile group compared with these variables in control group at the end of the intervention (all P < 0.05). CONCLUSIONS: Short term intake of chamomile tea has beneficial effects on glycemic control and antioxidant status in patients with T2 DM. A larger sample population and a longer intervention period may be required to show significant clinical improvements. PMID- 26437615 TI - Ruthenium-Grafted Vinylhelicenes: Chiroptical Properties and Redox Switching. AB - The properties of mono- and bis-Ru-vinyl[6]helicene complexes (2 a and 2 b, respectively), recently synthesized by using molecular engineering of helicenes based on the grafting of lateral organometallic substituents on the pi-helical backbone through a vinyl bridge, are presented. These helicene derivatives are thoroughly characterized, with special attention given to their chiroptical properties and redox switching activity. The UV/Vis and electronic circular dichroism (ECD) spectra of P and M enantiopure species, both in the neutral and oxidized states ([2 a](.+), [2 b](.+), and [2 b](2+)), are analyzed with the aid of quantum-chemical calculations. The extended pi-conjugation facilitated by the vinyl moiety, clearly visible in the electronic structures of 2 a,b, introduces new active bands in the ECD spectra that consequently lead to a significant increase in optical rotation of Ru-vinylhelicenes compared with the organic precursors. The vibrational circular dichroism (VCD) spectra were measured and calculated for both the organic and organometallic species and constitute the first examples of VCD for metal-based helicene derivatives. Finally, the redox triggered chiroptical switching activity of 2 a,b is examined in detail by using ECD spectroscopy. The modifications of the ECD spectra in the UV/Vis and NIR region are well reproduced and rationalized by calculations. PMID- 26437614 TI - Respiratory syncytial virus induces phosphorylation of mTOR at ser2448 in CD8 T cells from nasal washes of infected infants. AB - Respiratory syncytial virus (RSV)-specific CD8(+) T cell responses do not protect against reinfection. Activation of mammalian target of rapamycin (mTOR) impairs memory CD8(+) T cell differentiation. Our hypothesis was that RSV inhibits the formation of CD8(+) T cells memory responses through mTOR activation. To explore this, human and mouse T cells were used. RSV induced mTOR phosphorylation at Ser2448 in CD8 T cells. mTOR activation by RSV was completely inhibited using rapamycin. RSV-infected children presented higher mTOR gene expression on nasal washes comparing to children infected with metapneumovirus and rhinovirus. In addition, RSV-infected infants presented a higher frequency of CD8(+) pmTORser2448(+) T cells in nasal washes compared to RSV-negative infants. Rapamycin treatment increased the frequency of mouse CD8 RSV-M282-90 pentamer positive T cells and the frequency of RSV-specific memory T cells precursors. These data demonstrate that RSV is activating mTOR directly in CD8 T cells, indicating a role for mTOR during the course of RSV infection. PMID- 26437617 TI - Obesity: Beige adipocytes-will they beat obesity? PMID- 26437618 TI - Bone: Irisin boosts bone mass. PMID- 26437622 TI - Decade in review-thyroid disease: The endocrinology of thyroid disease from 2005 to 2015. PMID- 26437621 TI - Short and tall stature: a new paradigm emerges. AB - In the past, the growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis was often considered to be the main system that regulated childhood growth and, therefore, determined short stature and tall stature. However, findings have now revealed that the GH-IGF-1 axis is just one of many regulatory systems that control chondrogenesis in the growth plate, which is the biological process that drives height gain. Consequently, normal growth in children depends not only on GH and IGF-1 but also on multiple hormones, paracrine factors, extracellular matrix molecules and intracellular proteins that regulate the activity of growth plate chondrocytes. Mutations in the genes that encode many of these local proteins cause short stature or tall stature. Similarly, genome-wide association studies have revealed that the normal variation in height seems to be largely due to genes outside the GH-IGF-1 axis that affect growth at the growth plate through a wide variety of mechanisms. These findings point to a new conceptual framework for understanding short and tall stature that is centred not on two particular hormones but rather on the growth plate, which is the structure responsible for height gain. PMID- 26437624 TI - Fit the operation to the patient, not the patient to the operation. PMID- 26437625 TI - Efficacy of gadoxetic acid-enhanced magnetic resonance cholangiography compared with T2-weighted magnetic resonance cholangiography in patients with liver cirrhosis. AB - BACKGROUND: Gadoxetic acid is one of the hepatobiliary-specific agents and so can be used for contrast-enhanced magnetic resonance cholangiography (CE-MRC). The aim of our study was to compare the performance of CE-MRC with that of T2 weighted magnetic resonance cholangiography (T2W-MRC), and also to ascertain the effectiveness of both modalities combined for visualizing anatomic structures of the biliary tree in patients with liver cirrhosis. METHODS: Fifty-six patients underwent CE-MRC and T2W-MRC imaging. In the CE-MRC studies, hepatobiliary phase images were acquired 20 minutes after contrast injection. Two radiologists first evaluated the T2W-MRC and CE-MRC images separately in random order, and then they reviewed both images together 8 weeks later. The readers graded the quality of visualization of each biliary duct and the entire biliary tree (overall rating) using a five-point scale. Images with a grade of 3 or 4 were considered to provide sufficient visualization for clinical application, and those with a grade of 2 or less were considered to provide insufficient visualization. Laboratory data, Child-Pugh classification, and model for end-stage liver disease score were also recorded. RESULTS: The overall rating of T2W-MRC was significantly higher than that of CE-MRC (p < 0.001), although combined T2W/CE-MRC provided better visualization of biliary segments than T2W-MRC alone (p = 0.025). There were no significant differences between liver function and the overall rating of CE-MRC. CONCLUSION: CE-MRC is not superior to conventional T2W-MRC with respect to biliary visualization in patients with liver cirrhosis. However, a combination of T2W-MRC and CE-MRC provides significantly better visualization of biliary structures than T2W-MRC alone. PMID- 26437623 TI - Hormonal control of T-cell development in health and disease. AB - The physiology of the thymus, the primary lymphoid organ in which T cells are generated, is controlled by hormones. Data from animal models indicate that several peptide and nonpeptide hormones act pleiotropically within the thymus to modulate the proliferation, differentiation, migration and death by apoptosis of developing thymocytes. For example, growth hormone and prolactin can enhance thymocyte proliferation and migration, whereas glucocorticoids lead to the apoptosis of these developing cells. The thymus undergoes progressive age dependent atrophy with a loss of cells being generated and exported, therefore, hormone-based therapies are being developed as an alternative strategy to rejuvenate the organ, as well as to augment thymocyte proliferation and the export of mature T cells to peripheral lymphoid organs. Some hormones (such as growth hormone and progonadoliberin-1) are also being used as therapeutic agents to treat immunodeficiency disorders associated with thymic atrophy, such as HIV infection. In this Review, we discuss the accumulating data that shows the thymus gland is under complex and multifaceted hormonal control that affects the process of T-cell development in health and disease. PMID- 26437626 TI - Mycobacterium tuberculosis nucleic acid amplification tests reduce nosocomial tuberculosis exposure in intensive care units: A nationwide cohort study. AB - BACKGROUND AND OBJECTIVE: This retrospective national surveillance study investigated the burden of and risk factors for nosocomial exposure of pulmonary tuberculosis (TB) in intensive care units. METHODS: Patients admitted to intensive care units were identified from the National Health Insurance Research Database. During 2004-2009, there were 1 387 707 intensive care unit admissions of 900 562 adult patients. Pulmonary tuberculosis association was considered if the patient was diagnosed with pulmonary tuberculosis during admission or within 3 months after discharge. Nosocomial transmissible period was calculated based on the length of anti-tuberculosis treatment and negative-pressure isolation during admission. RESULTS: Pulmonary tuberculosis was associated with 1.20% of all intensive care unit admissions and 6731 (38.9%) started anti-TB treatment during admission. For the other 10 583 admissions, the diagnosis was made after discharge and anti-TB treatment was not prescribed during admission. The probability paralleled the regional tuberculosis incidence. On average, 2794 pulmonary tuberculosis associated intensive care unit admissions contributed to 42 999-44 062 days of nosocomial exposure per year. The length of nosocomial transmissible period decreased with the gradual implementation of Mycobacterium tuberculosis nucleic acid amplification tests in intensive care practice. Multivariate linear regression analysis revealed that the length of nosocomial transmissible period was inversely associated with male gender, airway symptoms prior to admission and performing M. tuberculosis nucleic acid amplification tests and mycobacterial culture. CONCLUSIONS: Nosocomial tuberculosis exposure is not uncommon in intensive care units. Performing rapid molecular diagnostic tests in those suspected of tuberculosis is recommended to reduce the risk of nosocomial exposure. PMID- 26437627 TI - Trapping, entrainment and synchronization of semiflexible polymers in narrow, asymmetric confinements. AB - The physical properties of polymeric actin facilitate many mechanical processes within the cell, including cellular deformation and locomotion, whereby the polymers can be confined to a range of different geometries. As actin polymers often form entangled solutions in the cell, we have investigated the effect of confinement on the evolution of entangled semiflexible polymer solutions. Using a microfluidic platform, we examined the physical dynamics of actin polymers confined within narrow (2-4 MUm) rectangular channels. Focusing on the entanglement process of two actin polymers, we found that their prolonged entrainment leads to synchronized horizontal undulations and decreased translational diffusion. In the absence of cross-linking molecules or proteins, the long-range entrainment interactions are predominantly controlled by the geometric boundaries. We directly measure the deflection length Lambda for an individual polymer, either solitarily confined within a channel or confined in the presence of a second filament, enabling the determination of the change in free energy associated with polymer entanglement. Our results indicate that geometrical confinement can serve as a solitary variable influencing the physical dynamics of entangled semiflexible polymers. PMID- 26437628 TI - Cytomegalovirus antiviral drug resistance: future prospects for prevention, detection and management. PMID- 26437629 TI - How to use mechanistic effect models in environmental risk assessment of pesticides: Case studies and recommendations from the SETAC workshop MODELINK. AB - Mechanistic effect models (MEMs) are useful tools for ecological risk assessment of chemicals to complement experimentation. However, currently no recommendations exist for how to use them in risk assessments. Therefore, the Society of Environmental Toxicology and Chemistry (SETAC) MODELINK workshop aimed at providing guidance for when and how to apply MEMs in regulatory risk assessments. The workshop focused on risk assessment of plant protection products under Regulation (EC) No 1107/2009 using MEMs at the organism and population levels. Realistic applications of MEMs were demonstrated in 6 case studies covering assessments for plants, invertebrates, and vertebrates in aquatic and terrestrial habitats. From the case studies and their evaluation, 12 recommendations on the future use of MEMs were formulated, addressing the issues of how to translate specific protection goals into workable questions, how to select species and scenarios to be modeled, and where and how to fit MEMs into current and future risk assessment schemes. The most important recommendations are that protection goals should be made more quantitative; the species to be modeled must be vulnerable not only regarding toxic effects but also regarding their life history and dispersal traits; the models should be as realistic as possible for a specific risk assessment question, and the level of conservatism required for a specific risk assessment should be reached by designing appropriately conservative environmental and exposure scenarios; scenarios should include different regions of the European Union (EU) and different crops; in the long run, generic MEMs covering relevant species based on representative scenarios should be developed, which will require EU-level joint initiatives of all stakeholders involved. The main conclusion from the MODELINK workshop is that the considerable effort required for making MEMs an integral part of environmental risk assessment of pesticides is worthwhile, because it will make risk assessments not only more ecologically relevant and less uncertain but also more comprehensive, coherent, and cost effective. PMID- 26437630 TI - Adverse Events Associated with Fosfomycin Use: Review of the Literature and Analyses of the FDA Adverse Event Reporting System Database. AB - INTRODUCTION: The growing problem of antibacterial resistance resulted in an increased interest in fosfomycin, especially its parenteral formulation. We reviewed fosfomycin safety profile using the Food and Drug Administration Adverse Event (AE) Reporting System (FAERS) and published literature. METHODS: We conducted a FAERS search and disproportionality analysis of all fosfomycin associated AEs. We also conducted a FAERS search for AEs implicating fosfomycin as the primary suspect and a search of reports of fosfomycin-associated bone marrow toxicity. We then review the literature for publications reporting AEs associated with fosfomycin by conducting PubMed searches. RESULTS: The disproportionality analysis of all FAERS reports of fosfomycin-associated AEs produced a higher than expected frequency of agranulocytosis, liver injury, severe skin reactions, and pseudomembranous colitis. Subsequent search for AEs where fosfomycin was the primary suspect and the literature review did not suggest a higher association of fosfomycin with these AEs. The search of bone marrow toxicity reports did not demonstrate an association between aplastic anemia and fosfomycin. The literature review selected 23 trials of parenteral administration of fosfomycin in 1242 patients including 8 comparative and 15 non comparative trials. For oral fosfomycin, only prospective comparative trials (n = 28) in 2743 patients were included. The most frequent AEs associated with parenteral fosfomycin included rash, peripheral phlebitis, hypokalemia, and gastrointestinal disorders. Serious AEs such as aplastic anemia, anaphylaxis, and liver toxicities were reported infrequently. Gastrointestinal disorders were the most common AEs associated with oral fosfomycin. CONCLUSION: The identified AEs were consistent with the safety profile of fosfomycin. No new safety signals related to either parenteral or oral fosfomycin were identified. PMID- 26437632 TI - Have Ecosystem Services Been Oversold? AB - The concept of ecosystem services (ES) neatly encapsulates the ways in which human society depends upon the existence and functioning of nature, but also draws power by chiming with dominant neoliberal ideology. Scientific paradigms such as this have an inherent tendency to stop adherents from recognizing alternative approaches. It is high time to examine whether the concept is being oversold with potentially damaging consequences. Many authors have questioned the monetization of ES, but the origin of the problem lies deeper in anthropocentrism. By illustration with alternatives, I attempt to show how the ES paradigm has constrained thought, particularly towards the monetization and financialization of nature, even when many ecologists and others oppose this trend. PMID- 26437631 TI - Identification of a FOXP3(+)CD3(+)CD56(+) population with immunosuppressive function in cancer tissues of human hepatocellular carcinoma. AB - The liver resident lymphoid population is featured by the presence of a large number of CD3(+)CD56(+) cells referred as natural T cells. In human hepatocellular carcinoma (HCC) patients, the natural T cells were found to be sharply decreased in tumor (5.871 +/- 3.553%) versus non-tumor (14.02 +/- 6.151%) tissues. More intriguingly, a substantial fraction of the natural T cells (22.76 +/- 18.61%) assumed FOXP3 expression. These FOXP3-expressing CD3(+)CD56(+) cells lost the expression of IFN-gamma and perforin, which are critical for the effector function of natural T cells. On the other hand, they acquired surface expression of CD25 and CTLA-4 typically found in regulatory T (Treg) cells. Consistent with the phenotypic conversion, they imposed an inhibitory effect on anti-CD3-induced proliferation of naive T cells. Further studies demonstrated that transforming growth factor beta1 (TGF-beta1) could effectively induce FOXP3 expression in CD3(+)CD56(+) cells and the cells were thus endowed with a potent immunosuppressive capacity. Finally, Kaplan-Meier analysis revealed that the relative abundance of FOXP3-expressing CD3(+)CD56(+) cells in tumor tissues was significantly correlated with the survival of HCC patients. In conclusion, the present study identified a new type of regulatory immune cells whose emergence in liver cancer tissues may contribute to tumor progression. PMID- 26437633 TI - Biodiversity and Resilience of Ecosystem Functions. AB - Accelerating rates of environmental change and the continued loss of global biodiversity threaten functions and services delivered by ecosystems. Much ecosystem monitoring and management is focused on the provision of ecosystem functions and services under current environmental conditions, yet this could lead to inappropriate management guidance and undervaluation of the importance of biodiversity. The maintenance of ecosystem functions and services under substantial predicted future environmental change (i.e., their 'resilience') is crucial. Here we identify a range of mechanisms underpinning the resilience of ecosystem functions across three ecological scales. Although potentially less important in the short term, biodiversity, encompassing variation from within species to across landscapes, may be crucial for the longer-term resilience of ecosystem functions and the services that they underpin. PMID- 26437634 TI - Misconceptions of Fragmentation's Effects on Ecosystem Services: A Response to Mitchell et al. PMID- 26437635 TI - Landscape Fragmentation and Ecosystem Services: A Reply to Andrieu et al. PMID- 26437636 TI - Emerging Technologies to Conserve Biodiversity. AB - Technologies to identify individual animals, follow their movements, identify and locate animal and plant species, and assess the status of their habitats remotely have become better, faster, and cheaper as threats to the survival of species are increasing. New technologies alone do not save species, and new data create new problems. For example, improving technologies alone cannot prevent poaching: solutions require providing appropriate tools to the right people. Habitat loss is another driver: the challenge here is to connect existing sophisticated remote sensing with species occurrence data to predict where species remain. Other challenges include assembling a wider public to crowdsource data, managing the massive quantities of data generated, and developing solutions to rapidly emerging threats. PMID- 26437637 TI - Pre-alcoholic fermentation acidification of red grape must using Lactobacillus plantarum. AB - Red grape musts from overripe grapes are characterised by high pH and sugar concentration. Corrections with organic acids are commonly used to secure the alcoholic fermentation and improve the organoleptic characteristics of the wine. In this study we test an alternative biological acidification method using the ability of Lactobacillus plantarum to produce high concentrations of lactic acid. The time course of sugars, organic acids and pH were measured. Available sugars were consumed by L. plantarum producing up to 8.3 g L(-1) of lactic acid. Lactic acid changed the pH from 3.9 to 3.4 after 14 days post-inoculation without yielding a relevant concentration of acetic acid (0.34 g L(-1)). PMID- 26437639 TI - [Not Available]. PMID- 26437638 TI - Taxonomic characterisation of Proteus terrae sp. nov., a N2O-producing, nitrate ammonifying soil bacterium. AB - In the context of studying the influence of N-fertilization on N2 and N2O flux rates in relation to the soil bacterial community composition in fen peat grassland, a group of bacterial strains was isolated that performed dissimilatory nitrate reduction to ammonium and concomitantly produced N2O. The amount of nitrous oxide produced was influenced by the C/N ratio of the medium. The potential to generate nitrous oxide was increased by higher availability of nitrate-N. Phylogenetic analysis based on the 16S rRNA and the rpoB gene sequences demonstrated that the investigated isolates belong to the genus Proteus, showing high similarity with the respective type strains of Proteus vulgaris and Proteus penneri. DNA-DNA hybridization studies revealed differences at the species level. These differences were substantiated by MALDI-TOF MS analysis and several distinct physiological characteristics. On the basis of these results, it was concluded that the soil isolates represent a novel species for which the name Proteus terrae sp. nov. (type strain N5/687(T) =DSM 29910(T) =LMG 28659(T)) is proposed. PMID- 26437640 TI - Basigin-mediated redistribution of CD98 promotes cell spreading and tumorigenicity in hepatocellular carcinoma. AB - BACKGROUND: Dysregulated endocytosis of membrane proteins contributes significantly to several hallmarks of cancer. Basigin can enhance cancer progression, but its precise mechanism remains unclear. CD98 promotes cell spreading and tumorigenicity by triggering integrin clustering and enhancing cell adhesion to the extracellular matrix. The endocytosis and recyle of basigin and CD98 might play critical roles in cancer. METHODS: The role of CD98 was confirmed in liver cancer cells by cell spreading in vitro and tumorigenicity by nude mice xenograft tumor assay in vivo; membrane expression of basigin and CD98 in SMMC 7721 was measured by FCAS; pull down and SPR analysis were uses to reveal the direct association between basigin and CD98; DsRed1 tagged CD98 was blocked in the cytoplasm in K7721 (whose basigin was knockn out) and had a well colocalization with ER and Rab5a positive recycling endosomes under co-focal; finally, by FRET imaging and FCAS we observed the internalization of basigin and CD98 was flotillin-1-regulated, and their recycle at early steps was Arf6 mediated. RESULTS: Basigin and CD98 were highly expressed and co-localized on the human hepatocellular carcinoma (HCC) cell membrane; basigin can directly bind to CD98, mediating CD98 redistribution on the HCC cell membrane and activating the downstream integrin signaling pathway. Internalization of basigin and CD98 was flotillin-1 regulated the and their recycling was mediated by Arf6. This recycling process for basigin and CD98 promotes cell spreading and tumor growth in liver cancer xenografts. CONCLUSION: Basigin, as a redistribution chaperone of CD98, plays a critical role in promoting cell spreading and the progression of hepatocellular carcinoma. PMID- 26437641 TI - Mass-Up: an all-in-one open software application for MALDI-TOF mass spectrometry knowledge discovery. AB - BACKGROUND: Mass spectrometry is one of the most important techniques in the field of proteomics. MALDI-TOF mass spectrometry has become popular during the last decade due to its high speed and sensitivity for detecting proteins and peptides. MALDI-TOF-MS can be also used in combination with Machine Learning techniques and statistical methods for knowledge discovery. Although there are many software libraries and tools that can be combined for these kind of analysis, there is still a need for all-in-one solutions with graphical user friendly interfaces and avoiding the need of programming skills. RESULTS: Mass Up, an open software multiplatform application for MALDI-TOF-MS knowledge discovery is herein presented. Mass-Up software allows data preprocessing, as well as subsequent analysis including (i) biomarker discovery, (ii) clustering, (iii) biclustering, (iv) three-dimensional PCA visualization and (v) classification of large sets of spectra data. CONCLUSIONS: Mass-Up brings knowledge discovery within reach of MALDI-TOF-MS researchers. Mass-Up is distributed under license GPLv3 and it is open and free to all users at http://sing.ei.uvigo.es/mass-up. PMID- 26437643 TI - Recent advance in molecular angiogenesis in glioblastoma: the challenge and hope for anti-angiogenic therapy. AB - Glioblastoma (GBM) is the most highly malignant brain tumor in the human central nerve system. In this paper, we review new and significant molecular findings on angiogenesis and possible resistance mechanisms. Expression of a number of genes and regulators has been shown to be upregulated in GBM microvessel cells, such as interleukin-8, signal transducer and activator of transcription 3, Tax interacting protein-1, hypoxia induced factor-1 and anterior gradient protein 2. The regulator factors that may strongly promote angiogenesis by promoting endothelial cell metastasis, changing the microenvironment, enhancing the ability of resistance to anti-angiogenic therapy, and that inhibit angiogenesis are reviewed. Based on the current knowledge, several potential targets and strategies are proposed for better therapeutic outcomes, such as its mRNA interference of DII4-Notch signaling pathway and depletion of b1 integrin expression. We also discuss possible mechanisms underlying the resistance to anti angiogenesis and future directions and challenges in developing new targeted therapy for GBM. PMID- 26437644 TI - Are commercial probiotics and prebiotics effective in the treatment and prevention of honeybee nosemosis C? AB - The study was conducted to investigate the effect of Lactobacillus rhamnosus (a commercial probiotic) and inulin (a prebiotic) on the survival rates of honeybees infected and uninfected with Nosema ceranae, the level of phenoloxidase (PO) activity, the course of nosemosis, and the effect on the prevention of nosemosis development in bees. The cells of L. rhamnosus exhibited a high rate of survival in 56.56 % sugar syrup, which was used to feed the honeybees. Surprisingly, honeybees fed with sugar syrup supplemented with a commercial probiotic and a probiotic + prebiotic were more susceptible to N. ceranae infection, and their lifespan was much shorter. The number of microsporidian spores in the honeybees fed for 9 days prior to N. ceranae infection with a sugar syrup supplemented with a commercial probiotic was 25 times higher (970 million spores per one honeybee) than in a control group fed with pure sucrose syrup (38 million spores per one honeybee). PO activity reached its highest level in the hemolymph of this honeybee control group uninfected with N. ceranae. The addition of probiotics or both probiotics and prebiotics to the food of uninfected bees led to the ~2-fold decrease in the PO activity. The infection of honeybees with N. ceranae accompanied an almost 20-fold decrease in the PO level. The inulin supplemented solely at a concentration of 2 MUg/mL was the only administrated factor which did not significantly affect honeybees' survival, the PO activity, or the nosemosis infection level. In conclusion, the supplementation of honeybees' diet with improperly selected probiotics or both probiotics and prebiotics does not prevent nosemosis development, can de-regulate insect immune systems, and may significantly increase bee mortality. PMID- 26437646 TI - New insights into diagnosis of Platynosomum fastosum (Trematoda: Dicrocoeliidae) in cats. AB - Platynosomum fastosum is a hepatic trematode which causes the so-called lizard poisoning in cats. This parasite is reported in tropical and sub-tropical areas infecting the liver, gallbladder, and bile ducts of cats. Despite its clinical importance, the diagnosis of P. fastosum has been poorly investigated so far. In this study, three cases of infection by P. fastosum in cats are reported. The FLOTAC technique was utilized for the first time in the detection of eggs of this parasite. Three cats (two males and one female), being one of them with a history of diarrhea and vomiting, were diagnosed positive for the presence of P. fastosum eggs through the FLOTAC technique. In conclusion, this study provides important and new insights into the diagnosis of P. fastosum in cats, expanding the geographical knowledge of this parasite in Brazil. PMID- 26437645 TI - Molecular cloning and characterization of a Spirometra erinacei casein kinase I. AB - The Spirometra erinacei casein kinase I (SeCKI) gene was cloned and expressed in Escherichia coli, and its characteristics were investigated in this study. The recombinant SeCP protein (rSeCKI) was purified. The vaccination of mice with rSeCKI induced the Th1/Th2-mixed type of immune response with Th2 predominant (high levels of IgG1). Western blotting analysis showed that rSeCP was recognized by the sera of plerocercoid-infected mice, and anti-rSeCP serum recognized the native SeCP protein of plerocercoid crude antigens. Transcription and expression of SeCP was observed at the plerocercoid and adult stages of S. erinacei. Immunolocalization identified SeCKI in the tegument and parenchymal tissues of plerocercoids and in the teguments of adults. SeCKI appeared to be essential indispensable for the S. erinacei development and survival in host, but its biological functions need to be further investigated. PMID- 26437647 TI - Magnetic resonance examination to predict pathological complete response following neoadjuvant chemotherapy: when is it appropriate for HER2-positive and triple-negative breast cancers? AB - BACKGROUND: To clarify appropriate timing for magnetic resonance examination to predict pathological complete response to neoadjuvant chemotherapy for patients with human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancers in terms of tumor volume change. METHODS: Between September 2009 and December 2014, 113 women with HER2-positive (n = 51) and triple-negative (n = 62) invasive breast cancers undergoing neoadjuvant chemotherapy were enrolled. Patients with HER2-positive tumors underwent neoadjuvant chemotherapy with an anthracycline-based regimen followed by docetaxel with trastuzumab. Patients with triple-negative tumors underwent neoadjuvant chemotherapy with anthracycline based (first in most cases) and taxane-based regimens. Magnetic resonance imaging was performed before neoadjuvant chemotherapy, between the regimens (midpoint examination), and after neoadjuvant chemotherapy (final examination). Response ratio of tumor volume was calculated and receiver-operating characteristic analyses for them for both subtypes were performed at the midpoint and final examinations. RESULTS: Twenty-eight women with HER2-positive tumors (54.9 %) and 29 women with triple-negative tumors (46.8 %) had pathological complete response. The response ratios were better in cases with pathological complete response than in those without (p = 0.0341, p < 0.0001). The area under the curve at the final examination was higher than that at the midpoint examination for HER2-positive tumors (p = 0.039); whereas for the triple-negative tumors, no significant difference between the two examinations was shown (p = 0.5218). CONCLUSIONS: Magnetic resonance examination to predict pathological complete response would be feasible after completion of a regimen including trastuzumab for HER2-positive tumors and at the midpoint of neoadjuvant chemotherapy for triple-negative tumors. PMID- 26437648 TI - A dense SNP genetic map constructed using restriction site-associated DNA sequencing enables detection of QTLs controlling apple fruit quality. AB - BACKGROUND: Genetic map based quantitative trait locus (QTL) analysis is an important method for studying important horticultural traits in apple. To facilitate molecular breeding studies of fruit quality traits in apple, we aim to construct a high density map which was efficient for QTL mapping and possible to search for candidate genes directly in mapped QTLs regions. METHODS: A total of 1733 F1 seedlings derived from 'Jonathan' * 'Golden Delicious' was used for the map constructionand QTL analysis. The SNP markers were developed by restriction site-associated DNA sequencing (RADseq). Phenotyping data of fruit quality traits were calculated in 2008-2011. Once QTLs were mapped, candidate genes were searched for in the corresponding regions of the apple genome sequence underlying the QTLs. Then some of the candidate genes were validated using real-time PCR. RESULTS: A high-density genetic map with 3441 SNP markers from 297 individuals was generated. Of the 3441 markers, 2017 were mapped to 'Jonathan' with a length of 1343.4 cM and the average distance between markers was 0.67 cM, 1932 were mapped to 'Golden Delicious' with a length of 1516.0 cM and the average distance between markers was 0.78 cM. Twelve significant QTLs linked to the control of fruit weight, fruit firmness, sugar content and fruit acidity were mapped to seven linkage groups. Based on gene annotation, 80, 64 and 17 genes related to fruit weight, fruit firmness and fruit acidity, respectively, were analyzed.Among the 17 candidate genes associated with control of fruit acidity, changes in the expression of MDP0000582174 (MdMYB4) were in agreement with the pattern of changes in malic acid content in apple during ripening, and the relative expression of MDP0000239624 (MdME) was significantly correlated withfruit acidity. CONCLUSIONS: We demonstrated the construction of a dense SNP genetic map in apple using next generation sequencing and that the increased resolution enabled the detection of narrow interval QTLs linked to the three fruit quality traits assessed. The candidate genes MDP0000582174 and MDP0000239624 were found to be related to fruit acidity regulation. We conclude that application of RADseq for genetic map construction improved the precision of QTL detection and should be utilized in future studies on the regulatory mechanisms of important fruit traits in apple. PMID- 26437650 TI - Transdifferentiation of differentiated stem cells contributes to remyelination. AB - Evidence suggests that transdifferentiation of mesenchymal stem cells (MSCs) into various neuronal cells contributes to functional recovery after experimental spinal cord injury. Qiu et al. have recently published an exciting article in Stem Cell Research & Therapy demonstrating the transdifferentiation of already differentiated MSCs that contributes to remyelination of injured/regenerating axons, and thereby to functional recovery of spinal cord injured animals. The authors highlight the importance of interaction between neurotrophin-3 and tropomyosin receptor kinase C for the observed effects. This study provided important evidence that manipulation of rat bone marrow-derived MSCs before transplantation could enhance the therapeutic benefit of cell-based treatment. PMID- 26437649 TI - Abdominal fat depots associated with insulin resistance and metabolic syndrome risk factors in black African young adults. AB - BACKGROUND: Individuals of black African ethnicity tend to have less visceral adipose tissue (VAT) but more subcutaneous-abdominal adipose tissue (SCAT) than white Caucasians. However, it is unclear whether such distribution of abdominal fat is beneficial for metabolic disease risk in black individuals. Here we compared the associations between these specific abdominal fat depots, insulin sensitivity and metabolic syndrome risk. METHODS: A cross-sectional analysis of 76 black South African young adults (36 men; 40 women) aged 18-19 years participating in the Birth to Twenty Cohort Study had VAT and SCAT measured by MRI. The metabolic syndrome traits (blood pressure, lipid profile, fasting glucose and insulin) were measured and the values were combined into a metabolic syndrome risk score. Fasting glucose and insulin were used to derive the HOMA index of insulin resistance (HOMA-IR). RESULTS: Compared to men, women had greater VAT (mean: 16.6 vs. 12.5 cm(2)) and SCAT (median 164.0 vs. 59.9 cm(2)). In men, SCAT (r = 0.50) was more strongly correlated to the metabolic syndrome score (MetS) than was VAT (r = 0.23), and was associated with both MetS (P = 0.001) and HOMA-IR (P = 0.001) after adjustment for VAT and total fat mass. In women, both abdominal fat compartments showed comparable positive correlations with MetS (r = 0.26 to 0.31), although these trends were weaker than in men. CONCLUSIONS: In young black South African adults, SCAT appears to be more relevant than VAT to metabolic syndrome traits. PMID- 26437651 TI - Blood cultures taken from patients attending emergency departments in South Africa are an important antibiotic stewardship tool, which directly influences patient management. AB - BACKGROUND: Febrile illness with suspected blood stream infection (BSI) is a common reason for admission to hospital in Africa and blood cultures are therefore an important investigation. Data on the prevalence and causes of community acquired BSI in Africa are scarce and there are no studies from South Africa. There are no validated clinical prediction rules for use of blood cultures in Africa. METHODS: A prospective observational cohort study of patients attending 2 urban emergency departments in Cape Town, South Africa. The decision to take a blood culture was made by the attending clinician and information available at the time of blood draw was collected. Bottles were weighed to measure volume of blood inoculated. RESULTS: 500 blood culture sets were obtained from 489 patients. 39 (7.8 %) were positive for pathogens and 13 (2.6 %) for contaminants. Significant independent predictors of positive cultures were diastolic blood pressure <60 mmHg, pulse >120 bpm, diabetes and a suspected biliary source of infection, but not HIV infection. Positive results influenced patient management in 36 of 38 (95 %) cases with the organism being resistant to the chosen empiric antibiotic in 9 of 38 (24 %). Taking <8 ml of blood was predictive of a negative culture. The best clinical prediction rule had a negative predictive value (NPV) of 92 % which is unlikely to be high enough to be clinically useful. DISCUSSION: Blood cultures taken from patients attending emergency departments in a high HIV prevalent city in South Africa are frequently positive and almost always influence patient management. At least 8 ml of blood should be inoculated into each bottle. CONCLUSION: Blood cultures should be taken from all patients attending EDs in South Africa suspected of having BSI particularly if diabetic, with hypotension, tachycardia or if biliary sepsis is suspected. PMID- 26437653 TI - MBE Growth of AlN Nanowires on Si Substrates by Aluminizing Nucleation. AB - By introducing an aluminization process to achieve nucleation of nanowires (NWs), spontaneous growth of AlN NWs on Si substrates has been realized by plasma assisted molecular beam epitaxy. The AlN NWs are grown from the nuclei formed by the aluminization process, and the NW density and diameter can be controlled by the aluminization parameters. The influence of growth conditions on the morphologies of AlN NWs is carefully investigated. Island-like films are found to grow between the NWs due to poor migration ability of Al adatoms. The films are proved to be Al-polar different from the N-polar AlN NWs, which can explain the absence of newly formed NWs. Increasing the V/III ratio can efficiently suppress the growth of Al-polar AlN films. PMID- 26437652 TI - Simian malaria in wild macaques: first report from Hulu Selangor district, Selangor, Malaysia. AB - BACKGROUND: Malaria is a vector-borne parasitic disease which is prevalent in many developing countries. Recently, it has been found that Plasmodium knowlesi, a simian malaria parasite can be life-threatening to humans. Long-tailed macaques, which are widely distributed in Malaysia, are the natural hosts for simian malaria, including P. knowlesi. The aim of the present study was to determine the prevalence of simian malaria parasites in long-tailed macaques in the district of Hulu Selangor, Selangor, Malaysia. METHODS: A total of 70 blood samples were collected from Macaca fascicularis dwelling in the forest of Hulu Selangor by the Department of Wildlife and National Parks Peninsular Malaysia, Kuala Lumpur, Malaysia. DNA was extracted using PureLinkTM Genomic DNA Kits. Conventional and nested PCR were used to detect the genus and species of Plasmodium parasites respectively. In addition, phylogenetic analysis was carried out to confirm the species of Plasmodium parasites. RESULTS: Thirty-five (50 %) of the 70 samples were positive for Plasmodium using genus-specific primers. These positive samples were then subjected to nested PCR targeting the 18S ribosomal RNA genes to detect all five simian malaria parasites: namely, P. knowlesi, Plasmodium inui, Plasmodium cynomolgi, Plasmodium fieldi, and Plasmodium coatneyi. All five species of simian malaria parasites were detected. Of these, P. inui was the predominant (65.7 %), followed by P. knowlesi (60 %), P. cynomolgi (51.4 %) P. coatneyi (45.7 %) and P. fieldi (2.9 %). A total of nine macaques had mono-infection with P. knowlesi (four), P. cynomolgi (two), P. coatneyi (two) and P. fieldi (one). Eleven of the macaques had dual infections while 12 had triple infections. Three macaques were infected with four species of Plasmodium. Molecular and phylogenetic analysis confirmed the five species of Plasmodium parasites. CONCLUSION: This study has provided evidence to elucidate the presence of transmission of malaria parasites among the local macaques in Hulu Selangor. Since malaria is a zoonosis, it is important to determine the new control strategies for the control of malaria. PMID- 26437654 TI - Fabrication and Characterization of Monodisperse Magnetic Porous Nickel Microspheres as Novel Catalysts. AB - A facile and efficient hard-templating strategy is reported for the preparation of porous nickel microspheres with excellent uniformity and strong magnetism. The strategy involves impregnation of porous polymer microspheres with nickel precursors, calcination to remove the template, followed by thermal reduction. The morphology, structure, and the property of the Ni microspheres were characterized by scanning electron microscopy, X-ray powder diffraction, N2 adsorption-desorption isotherms, thermogravimetric analysis, and magnetic hysteresis measurement. The obtained porous nickel microspheres were monodispersed with a particle size of 0.91 MUm and crystallite size of 52 nm. Their saturation magnetization was much higher than that of Ni nanoparticles. The unique porous nanostructured Ni microspheres possess catalytic activity and excellent recyclability, as demonstrated in the catalytic reduction of 4 nitrophenol to 4-aminophenol. The micropherical Ni catalysts could be easily separated either by an external magnetic field or by simple filtration. PMID- 26437655 TI - Synthesis of BiPO4/Bi2S3 Heterojunction with Enhanced Photocatalytic Activity under Visible-Light Irradiation. AB - BiPO4/Bi2S3 photocatalysts were successfully synthesized by a simple two-step hydrothermal process, which involved the initial formation of BiPO4 rod and then the attachment of Bi2S3 through ion exchange. The as-synthesized products were characterized by X-ray diffraction (XRD), scanning electron microscope (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and UV-vis diffuse reflectance spectra (UV-vis DRS). It was found that BiPO4 was regular rods with smooth surfaces. However, BiPO4/Bi2S3 heterojunction had a rough surface, which could be attributed to the attachment of Bi2S3 on the surface of BiPO4 rods. The BiPO4/Bi2S3 composite exhibited better photocatalytic performance than that of pure BiPO4 and Bi2S3 for the degradation of methylene blue (MB) and Rhodamine B (RhB) under visible light. The enhanced photocatalytic performance could be ascribed to synergistic effect of BiPO4/Bi2S3 heterojunction, in which the attached Bi2S3 nanoparticles could improve visible light absorption and the BiPO4/Bi2S3 heterojunction suppressed the recombination of photogenerated electron-hole pairs. Our work suggested that BiPO4/Bi2S3 heterojunction could be a potential photocatalyst under visible light. PMID- 26437656 TI - Conductivity of PEDOT:PSS on Spin-Coated and Drop Cast Nanofibrillar Cellulose Thin Films. AB - Aqueous dispersion of conductive polymer poly(3,4-ethylenedioxythiophene) poly(styrenesulfonate) ( PEDOT: PSS) was deposited on spin-coated and drop cast nanofibrillar cellulose (NFC)-glycerol (G) matrix on a glass substrate. A thin glycerol film was utilized on plasma-treated glass substrate to provide adequate adhesion for the NFC-glycerol (NFC-G) film. The effects of annealing temperature, the coating method of NFC-G, and the coating time intervals on the electrical performance of the PEDOT: PSS were characterized. PEDOT: PSS on drop cast NFC-G resulted in 3 orders of magnitude increase in the electrical conductivity compared to reference PEDOT: PSS film on a reference glass substrate, whereas the optical transmission was only slightly decreased. The results point out the importance of the interaction between the PEDOT: PSS and the NFC-G for the electrical and barrier properties for thin film electronics applications. PMID- 26437657 TI - Mechanism of Electrochemical Deposition and Coloration of Electrochromic V2O5 Nano Thin Films: an In Situ X-Ray Spectroscopy Study. AB - Electrochromic switching devices have elicited considerable attention because these thin films are among the most promising materials for energy-saving applications. The vanadium oxide system is simple and inexpensive because only a single-layer film of this material is sufficient for coloration. Vanadium dioxide thin films are fabricated by electrochemical deposition and cyclic voltammetry. Chronoamperometric analyses have indicated that the thin V2O5 film demonstrates faster intercalation and deintercalation of lithium ions than those of the thick V2O5 film, benefiting the coloration rate. Despite substantial research on the synthesis of vanadium oxides, the monitoring of electronic and atomic structures during growth and coloration of such material has not been thoroughly examined. In the present study, in situ X-ray absorption spectroscopy (XAS) is employed to determine the electronic and atomic structures of V2O5 thin films during electrochemical growth and then electrochromic coloration. In situ XAS results demonstrate the growth mechanism of the electrodeposited V2O5 thin film and suggest that its electrochromic performance strongly depends on the local atomic structure. This study improves our understanding of the electronic and atomic properties of the vanadium oxide system grown by electrochemical deposition and enhances the design of electrochromic materials for potential energy-saving applications. PMID- 26437658 TI - Relationship between probability of future shoulder arthroplasty and outcomes of arthroscopic debridement in patients with advanced osteoarthritis of glenohumeral joint. AB - BACKGROUND: Arthroscopic glenohumeral debridement for symptom control has shown promising short term results in the young active population, when arthroplasty may not be a practical option due to the recommended activity restrictions, potential for complications and/or early wear, and a need for revision. The purpose of this study was twofold: 1) to examine the impact of arthroscopic debridement with or without subacromial decompression on clinical outcomes in patients with severe glenohumeral osteoarthritis (OA), and 2) to explore the differences in post-debridement outcomes between patients who eventually progressed to arthroplasty vs. those who did not. The role of an active worker's compensation claim was examined. METHODS: Prospectively collected data of patients who were not good candidates for shoulder arthroplasty and had subsequently undergone arthroscopic shoulder debridement were used for analysis. Disability was measured using the relative Constant-Murley score (CMS), the American Shoulder and Elbow Surgeon's (ASES) assessment form, pain free range of motion (ROM), and strength. RESULTS: Fifty-six patients were included in the final analysis. Eighteen (32 %) patients underwent arthroplasty surgery (arthroplasty group) over a period of 11 years. The arthroplasty group was comparable with the non-arthroplasty group prior to debridement but was more disabled at post-debridement surgery follow-up, functioning at less than 50 % of normal based on ASES, relative CMS, and active painfree ROM. In the multivariable analysis, the post-debridement relative CMS was affected by having a compensation claim and having a future arthroplasty. CONCLUSION: Arthroscopic debridement improved clinical outcome in 68 % of patients suffering from advanced OA of glenohumeral joint. Having less than 50 % of normal score in ASES, relative CMS and painfree ROM post- debridement within a period of two years may be an indication for future arthroplasty. Role of worker's compensation claims should not be underestimated. PMID- 26437660 TI - [Not Available]. PMID- 26437661 TI - Bioinformatic Characterization of Genes and Proteins Involved in Blood Clotting in Lampreys. AB - Lampreys and hagfish are the earliest diverging of extant vertebrates and are obvious targets for investigating the origins of complex biochemical systems found in mammals. Currently, the simplest approach for such inquiries is to search for the presence of relevant genes in whole genome sequence (WGS) assemblies. Unhappily, in the past a high-quality complete genome sequence has not been available for either lampreys or hagfish, precluding the possibility of proving gene absence. Recently, improved but still incomplete genome assemblies for two species of lamprey have been posted, and, taken together with an extensive collection of short sequences in the NCBI trace archive, they have made it possible to make reliable counts for specific gene families. Particularly, a multi-source tactic has been used to study the lamprey blood clotting system with regard to the presence and absence of genes known to occur in higher vertebrates. As was suggested in earlier studies, lampreys lack genes for coagulation factors VIII and IX, both of which are critical for the "intrinsic" clotting system and responsible for hemophilia in humans. On the other hand, they have three each of genes for factors VII and X, participants in the "extrinsic" clotting system. The strategy of using raw trace sequence "reads" together with partial WGS assemblies for lampreys can be used in studies on the early evolution of other biochemical systems in vertebrates. PMID- 26437662 TI - Comparative study between M. oleifera and aluminum sulfate for water treatment: case study Colombia. AB - The world has a water deficit, mostly located in developing countries. For example, in Colombia, water deficit is a major concern and it increases in rural areas, where the rate of accessibility to drinking water is of 33.26% in 2005. Since the 1970s, the most used technology for water purification is the conventional physicochemical process. The most common coagulant used in this process is aluminum sulfate (alum). This study focuses on a comparison between Moringa oleifera seeds and alum for water treatment in different natural waters. Results showed that M. oleifera removed 90% turbidity and alum 96% from water samples from the tested natural brook. However, color removal for M. oleifera was 95 and 80.3% for alum. For water-polluted samples, both coagulants have shown high efficiency (100%) in color and turbidity removal. Usage of natural coagulants (i.e., M. oleifera) instead of chemical ones (i.e., alum) are more convenient in rural areas where the economic situation and accessibility of those products are key elements to maintain fresh water treatment standards. Additionally, results demonstrated that high dosages M. oleifera did not affect the optimal value in terms of color and turbidity removal. In rural and developing countries, this is important because it does not require a sophisticated dosing equipment. PMID- 26437663 TI - Identification and characterization of a maize-associated mastrevirus in China by deep sequencing small RNA populations. AB - BACKGROUND: Maize streak Reunion virus (MSRV) is a member of the Mastrevirus genus in the family Geminiviridae. Of the diverse and increasing number of mastrevirus species found so far, only Wheat dwarf virus and Sweetpotato symptomless virus 1 have been discovered in China. Recently, a novel, unbiased approach based on deep sequencing of small interfering RNAs followed by de novo assembly of siRNA, has greatly offered opportunities for plant virus identification. METHODS: Samples collected from maize leaves was deep sequencing for virus identification. Subsequently, the assay of PCR, rolling circle amplification and Southern blot were used to confirm the presence of a mastrevirus. RESULTS: Maize streak Reunion virus Yunnan isolate (MSRV [China:Yunnan 06:2014], abbreviated to MSRV-YN) was identified from maize collected from Yunnan Province, China, by small RNA deep sequencing. The complete genome of this virus was ascertained as 2,880 nucleotides long by conventional sequencing. A phylogenetic analysis showed it shared 96.3 % nucleotide sequence identity with the isolate of Maize streak Reunion virus from La Reunion Island. To our knowledge, this is the first identification of MSRV in China. Analyses of the viral derived small interfering RNAs (vsiRNAs) profile showed that the most abundant MSRV-YN vsiRNAs were 21, 22 and 24 nt long and biased for A and G at their 5' terminal residue. There was a slightly higher representation of MSRV-YN siRNAs derived from the virion-sense strand genome than the complementary-sense strand genome. Moreover, MSRV-YN vsiRNAs were not uniformly distributed along the genome, and hotspots were detected in the movement protein and coat protein coding region. CONCLUSIONS: A mastrevirus MSRV-YN collected in Yunnan Province, China, was identified by small RNA deep sequencing. This vsiRNAs profile derived from MSRV-YN was characterized, which might contribute to get an insight into the host RNA silencing defense induced by MSRV-YN, and provide guidelines on designing antiviral strategies using RNAi against MSRV-YN. PMID- 26437665 TI - Sympatric ecological divergence associated with a color polymorphism. AB - BACKGROUND: Color polymorphisms are a conspicuous feature of many species and a way to address broad ecological and evolutionary questions. Three potential major evolutionary fates of color polymorphisms are conceivable over time: maintenance, loss, or speciation. However, the understanding of color polymorphisms and their evolutionary implications is frequently impaired by sex-linkage of coloration, unknown inheritance patterns, difficulties in phenotypic characterization, and a lack of evolutionary replicates. Hence, the role of color polymorphisms in promoting ecological and evolutionary diversification remains poorly understood. In this context, we assessed the ecological and evolutionary consequences of a color polymorphic study system that is not hampered by these restrictions: the repeated adaptive radiations of the gold/dark Midas cichlid fishes (the Amphilophus citrinellus species complex) from the great lakes and crater lakes of Nicaragua, Central America. RESULTS: We conducted multi-trait morphological and ecological analyses from ten populations of this young adaptive radiation (<6,000 years old), which revealed sympatric ecological differentiation associated with the conspicuous binary (gold/dark) color polymorphism. Varying degrees of intraspecific ecological divergence were observed across the ten color morph pairs, but most pairs exhibited a consistently parallel ecological and evolutionary trajectory across populations. Specifically, gold Midas cichlids are frequently deeper-bodied, have more robust pharyngeal jaws, and feed at a lower trophic level compared to conspecific, sympatric dark individuals. A common garden experiment suggests there is a genetic correlation of color and eco morphological traits. CONCLUSIONS: We demonstrate unprecedented ecological and evolutionary consequences of color polymorphism in this adaptive radiation. Across the species complex, sympatric conspecific individuals differed in eco morphology depending on color morph (gold/dark) and the axis of differentiation tended to be consistent across replicates. The consistent divergence across wild populations and the common garden experiment suggests that color is genetically correlated to ecology. Because Midas cichlids are known to mate color assortatively, the putative genetic correlation of this color polymorphism with an eco-morphological divergence suggests an innate potential to promote ecological and evolutionary divergence across this species complex. However, there are to date no examples of speciation based on color in this radiation, suggesting long-term maintenance of this color polymorphism. PMID- 26437666 TI - Is Noninvasive Brachial Systolic Blood Pressure an Accurate Estimate of Central Aortic Systolic Blood Pressure? AB - OBJECTIVES: Noninvasive brachial systolic blood pressure (nSBP-B) usually approaches invasive central systolic blood pressure (iSBP-C) with a high correlation. Whether nSBP-B is an accurate estimate of iSBP-C remained to be investigated. Thus, this study aimed to compare the errors of nSBP-B and noninvasive central systolic blood pressure (nSBP-C) with different techniques in estimating iSBP-C. METHODS: Simultaneous invasive high-fidelity central aortic pressure waveforms and the noninvasive left brachial pulse volume recording (PVR) waveform were recorded in a Generation group ( N = 40) and a Validation group ( N = 100). The accuracy of the noninvasive estimates of iSBP-C obtained from analysis of the calibrated PVR waveform using the generalized transfer function (GTF), pulse waveform analysis (PWA), and N-point moving average (NPMA) methods was examined in the Validation group by calculating the mean absolute error (MAE). RESULTS: In Generation group, the MAE was 4.6+/-4.1mm Hg between nSBP-B and invasive brachial SBP, and 6.8+/-5.5mm Hg between nSBP-B and iSBP-C. In comparison, the MAE of between iSBP-C and nSBP-C with PWA, NPMA, and GTF were 5.5+/-4.5, 5.8+/-4.9, and 5.9+/-5.0mm Hg, respectively. In Validation group, the MAE of nSBP-B (6.9+/-4.6mm Hg) for estimating iSBP-C was significantly greater than that of PWA (5.0+/-3.4mm Hg) and NPMA (6.1+/-4.4mm Hg), and GTF (6.1+/-4.9mm Hg). The percentage of absolute band error <=5mm Hg was 62% for nSBP-B, 69% for GTF, 83% for PWA, and 69% for NPMA. CONCLUSIONS: The accuracy of nSBP-B was inferior to the n SBP-C measures in estimating iSBP-C. PMID- 26437664 TI - Moderate-to-vigorous physical activity as a mediator between sedentary behavior and cardiometabolic risk in Spanish healthy adults: a mediation analysis. AB - BACKGROUND: Public health strategies for cardiovascular prevention highlight the importance of physical activity, but do not consider the additional potentially harmful effects of sedentary behavior. This study was conducted between 2010 and 2012 and analyzed between 2013 and 2014. The aim of the study was to analyze the relationship between sedentary behavior and cardiometabolic risk factors in the Spanish adult population and to examine whether this relationship is mediated by moderate-to-vigorous physical activity (MVPA). METHODS: The cross-sectional study included 1122 healthy subjects belonging to the EVIDENT study. Sedentary behavior was objectively measured over 7 days using Actigraph accelerometers. We assessed waist circumference (WC), triglycerides-to-HDL-C ratio (TG/HDL-C), and mean arterial pressure (MAP), and undertook homeostasis model assessment (HOMA-IR). Linear regression models were fitted according to Baron and Kenny procedures for mediation analysis. RESULTS: TG/HDL-C and HOMA-IR were significantly higher in adults who spent more minutes in sedentary activities after adjusting for potential covariates. However when MVPA was added to the ANCOVA models as covariate the effect of sedentary time on HOMA-IR disappeared. In addition, MVPA acted as a full mediator of the relationship between sedentary time and HOMA-IR. In contrast, subjects with lower levels of MVPA presented worse cardiometabolic profiles than those from higher MVPA categories, even after controlling for sedentary time and other potential confounders. CONCLUSIONS: These results suggest that both MVPA and sedentary time should be considered when developing cardiometabolic risk guidelines. TRIAL REGISTRATION: NCT01083082 . PMID- 26437667 TI - Management and Outcomes of Esophageal Perforation: A National Study of 2,564 Patients in England. AB - OBJECTIVES: Traditionally esophageal perforation is a rare clinical emergency that confers a high rate of mortality and major morbidity. The objective of this study was to establish the annual rate and mortality from esophageal perforation and determine the effect of hospital volume on clinical outcomes. METHODS: Hospital Episode Statistics database was used for the identification of patients admitted to hospitals within England with esophageal perforation between 2001 and 2012. The influence of hospital volume and treatment approach upon clinical outcomes was analyzed using multivariable analysis to control for patient age and medical comorbidities that may influence outcome. RESULTS: Over the 12-year study period 2,564 patients with esophageal perforation were treated at 158 hospitals. The 30- and 90-day mortality rates were 30.0 and 38.8%, respectively. Esophageal perforation etiology was spontaneous in 81.9% and iatrogenic in 5.9% of cases. There was a significant increase in the percentage of patients managed supportively and a reduction in surgical management over time. Furthermore there were significant reductions in 30-day (36.6% to 24.9%; P<0.001) and 90-day mortality (44.1% to 35.4%; P=0.006) over the 12-year study period. Important patient demographics associated with 30- and 90-day mortality included age >=70 years, preoperative congestive cardiac failure, ischemic heart, liver, and renal disease. High hospital volume was associated with significant reductions in 30- (odds ratio (OR)=0.68; P=0.001) and 90-day mortality (OR=0.69; P=0.001). In a subset analysis of patients undergoing endoscopic intervention, hospital volume was identified as an important factor associated with mortality. CONCLUSIONS: This study provides evidence for the centralization of management of esophageal perforation to high volume centers with appropriate multi-disciplinary infrastructure to treat these complex patients. PMID- 26437668 TI - Charity condemns attack on Afghan hospital as "war crime". PMID- 26437670 TI - Randomised comparison of two neonatal resuscitation bags in manikin ventilation. AB - OBJECTIVE: To compare ventilation properties and user preference of a new upright neonatal resuscitator developed for easier cleaning, reduced complexity, and possibly improved ventilation properties, with the standard Laerdal neonatal resuscitator. DESIGN: Eighty-seven Tanzanian and Norwegian nursing and medical students without prior knowledge of newborn resuscitation were briefly trained in bag-mask ventilation. The two resuscitators were used in random order on a manikin connected to a test lung with normal or low lung compliance. Data were collected with the Laerdal Newborn Resuscitation Monitor. The students graded mask seal and ease of air entry on a four-point scale ranging from 1 ('difficult') to 4 ('easy') and stated which device they preferred. (Equipment from Laerdal Global Health and Laerdal Medical). RESULTS: For upright versus standard resuscitator and normal lung compliance, mean expiratory lung volume was 15.5 mL vs 13.9 mL (p=0.001), mean mask leakage 48% vs 58% (p<0.001), and mean airway pressure 20 cm H2O vs 19 cm H2O (p=0.003), respectively. For low lung compliance, mean expiratory lung volume was 8.6 mL vs 8.1 mL (p=0.045), mean mask leakage 53% vs 62% (p<0.001), and mean airway pressure 21 cm H2O vs 20 cm H2O (p=0.004) for upright versus standard. The upright resuscitator was preferred by 82% and 68% of students during ventilation with normal and low lung compliance, respectively (p=0.001). CONCLUSIONS: Expiratory volumes were higher, mask leakage lower, and mean airway pressure slightly higher with upright versus standard resuscitator when ventilating a manikin. The majority of students preferred the upright resuscitator. PMID- 26437669 TI - Global analysis of physical and functional RNA targets of hnRNP L reveals distinct sequence and epigenetic features of repressed and enhanced exons. AB - HnRNP L is a ubiquitous splicing-regulatory protein that is critical for the development and function of mammalian T cells. Previous work has identified a few targets of hnRNP L-dependent alternative splicing in T cells and has described transcriptome-wide association of hnRNP L with RNA. However, a comprehensive analysis of the impact of hnRNP L on mRNA expression remains lacking. Here we use next-generation sequencing to identify transcriptome changes upon depletion of hnRNP L in a model T-cell line. We demonstrate that hnRNP L primarily regulates cassette-type alternative splicing, with minimal impact of hnRNP L depletion on transcript abundance, intron retention, or other modes of alternative splicing. Strikingly, we find that binding of hnRNP L within or flanking an exon largely correlates with exon repression by hnRNP L. In contrast, exons that are enhanced by hnRNP L generally lack proximal hnRNP L binding. Notably, these hnRNP L enhanced exons share sequence and context features that correlate with poor nucleosome positioning, suggesting that hnRNP may enhance inclusion of a subset of exons via a cotranscriptional or epigenetic mechanism. Our data demonstrate that hnRNP L controls inclusion of a broad spectrum of alternative cassette exons in T cells and suggest both direct RNA regulation as well as indirect mechanisms sensitive to the epigenetic landscape. PMID- 26437671 TI - Efficacy of 1-methylcyclopropene on the mitigation of storage disorders of "Rocha" pear under normal refrigerated and controlled atmospheres. AB - Alternatives are needed for long-term preservation of European pears (Pyrus communis L.) after the ban on diphenylamine. "Rocha" pear fruit harvested at commercial maturity were treated with 1-methylcyclopropene (1-methylcyclopropene, SmartFreshTM) and diphenylamine and stored at 0 C, 90-95% relative humidity, under normal atmosphere for up to six months or under controlled atmosphere (controlled atmosphere, 3 kPa O2 + 0.7 kPa CO2) for up to 9.4 months. At 312 nl l(-1), 1-methylcyclopropene reduced softening and yellowing, and increased soluble solids content during shelf life in comparison with fruit treated with diphenylamine. 1-Methylcyclopropene at 312 nl l(-1) was also more effective than diphenylamine in reducing superficial scald and internal browning disorders. 1 Methylcyclopropene at 150 nl l(-1) had little effect on ripening-related changes but was effective against physiological disorders of pears stored in regular atmosphere or under controlled atmosphere. Delayed controlled atmosphere slightly reduced internal browning disorders but increased superficial scald. 1 Methylcyclopropene at 312 nl l(-1) reduced physiological disorders in "Rocha" pear under refrigerated storage and delayed ripening-related softening and color changes during shelf life. At 150 nl l(-1), 1-methylcyclopropene is as effective as diphenylamine against storage disorders without ripening impairment. PMID- 26437672 TI - Effects of nonthermal preservation technologies on antioxidant activity of fruits and vegetables: A review. AB - Consumer demand for safe and nutritious fruits and vegetables has given rise to the development of a number of nonthermal food preservation techniques. Recent studies have highlighted that antioxidant activity of fruits and vegetables plays an important role in human health. In this paper, the influences of nonthermal preservation technologies, including pulsed electric field, radiation processing, dense phase carbon dioxide, ozone processing, and edible coatings, on the antioxidant capacity and related compounds in fruits and vegetables are reviewed. The proposed mechanisms and future trends are also discussed to accelerate the further commercialization and exploration of these novel technologies, which will, in turn, help to promote human health. PMID- 26437673 TI - Interprotein Coupling Enhances the Electrocatalytic Efficiency of Tobacco Peroxidase Immobilized at a Graphite Electrode. AB - Covalent immobilization of enzymes at electrodes via amide bond formation is usually carried out by a two-step protocol, in which surface carboxylic groups are first activated with the corresponding cross-coupling reagents and then reacted with protein amine groups. Herein, it is shown that a modification of the above protocol, involving the simultaneous incubation of tobacco peroxidase and the pyrolytic graphite electrode with the cross-coupling reagents produces higher and more stable electrocatalytic currents than those obtained with either physically adsorbed enzymes or covalently immobilized enzymes according to the usual immobilization protocol. The remarkably improved electrocatalytic properties of the present peroxidase biosensor that operates in the 0.3 V <= E <= 0.8 V (vs SHE) potential range can be attributed to both an efficient electronic coupling between tobacco peroxidase and graphite and to the formation of intra- and intermolecular amide bonds that stabilize the protein structure and improve the percentage of anchoring groups that provide an adequate orientation for electron exchange with the electrode. The optimized tobacco peroxidase sensor exhibits a working concentration range of 10-900 MUM, a sensitivity of 0.08 A M( 1) cm(-2) (RSD 0.05), a detection limit of 2 MUM (RSD 0.09), and a good long-term stability, as long as it operates at low temperature. These parameter values are among the best reported so far for a peroxidase biosensor operating under simple direct electron transfer conditions. PMID- 26437674 TI - Effect of normal sperm morphology rate (NSMR) on clinical outcomes and fertilization methods selection in the ultra-short-term GnRH-a protocol. AB - PURPOSE: To investigate whether intracytoplasmic sperm injection (ICSI) can improve the clinical outcomes of the male patients with teratozoospermia in the ultra-short term GnRH-a protocol. METHODS: Based on different normal sperm morphology rate (NSMR), the patients were divided into three groups as follows: NSMR = 0% group, 1% <=NSMR <4% group and NSMR >=4% group. Each group was compared with two fertilization type of in-vitro fertilization (IVF) and ICSI separately. Main outcomes compared were normal fertilization, high-quality embryo, transferrable embryo, implantation, pregnancy and abortion rate. RESULTS: We observed that the total clinical pregnancy rate in single cleavage-stage embryo transfer (SET) group was significantly lower compared with double cleavage-stage embryo transfer (DET) group (23.87% versus 40.08%; p < 0.001). There was no significant difference in the aspects of female age, endometrial thickness, infertility duration and the number of retrieved oocytes among three groups (p > 0.05). The normal fertilization, high-quality embryo, transferrable embryo, implantation, pregnancy and abortion rate of IVF and ICSI showed no significant difference among three groups (p > 0.05). CONCLUSION: ICSI cannot improve clinical outcomes of the patients with teratozoospermia in the ultra-short term GnRH-a protocol. PMID- 26437675 TI - Recovery from Mild Traumatic Brain Injury in Previously Healthy Adults. AB - This prospective longitudinal study reports recovery from mild traumatic brain injury (MTBI) across multiple domains in a carefully selected consecutive sample of 74 previously healthy adults. The patients with MTBI and 40 orthopedic controls (i.e., ankle injuries) completed assessments at 1, 6, and 12 months after injury. Outcome measures included cognition, post-concussion symptoms, depression, traumatic stress, quality of life, satisfaction with life, resilience, and return to work. Patients with MTBI reported more post-concussion symptoms and fatigue than the controls at the beginning of recovery, but by 6 months after injury, did not differ as a group from nonhead injury trauma controls on cognition, fatigue, or mental health, and by 12 months, their level of post-concussion symptoms and quality of life was similar to that of controls. Almost all (96%) patients with MTBI returned to work/normal activities (RTW) within the follow-up of 1 year. A subgroup of those with MTBIs and controls reported mild post-concussion-like symptoms at 1 year. A large percentage of the subgroup who had persistent symptoms had a modifiable psychological risk factor at 1 month (i.e., depression, traumatic stress, and/or low resilience), and at 6 months, they had greater post-concussion symptoms, fatigue, insomnia, traumatic stress, and depression, and worse quality of life. All of the control subjects who had mild post-concussion-like symptoms at 12 months also had a mental health problem (i.e., depression, traumatic stress, or both). This illustrates the importance of providing evidence-supported treatment and rehabilitation services early in the recovery period. PMID- 26437676 TI - Porcine 2', 5'-oligoadenylate synthetases inhibit Japanese encephalitis virus replication in vitro. AB - The 2', 5'-oligoadenylate synthetases (OAS) are antiviral proteins and several isoforms have been identified as flavivirus-resistance biomarkers in human and mouse. The expression kinetics and antiviral functions of porcine OAS family (OAS1, OAS2, and OASL) in PK-15 cells following infection by Japanese encephalitis virus (JEV) were evaluated in the present study. The endogenous expression of the three OAS genes was efficiently induced by IFN-alpha treatment in PK-15 cells. However, expression of pOAS1 and pOAS2 responded more quickly than pOASL. Infection by JEV also induced the expression of the pOAS isoforms, but at a significantly lower level than that observed following IFN-alpha stimulation. Transient overexpression of pOASL and pOAS1 inhibited JEV replication more efficiently than OAS2 overexpression. Interestingly, knockdown of pOAS2 expression by siRNA treatment led to the highest increase in JEV multiplication. Co-silencing of RNase L and each pOAS revealed that the anti-JEV function of pOAS1 and pOAS2 were RNase L dependent, while the antiviral activity of pOASL was not. In conclusion, all pOAS isoforms play a significant role in the response to JEV infection, and are differentially induced by different stimuli. The alternative pathways of antiviral activity stimulated by OASL require further study. PMID- 26437677 TI - Resveratrol Stimulates Hydrogen Sulfide (H2 S) Formation to Relax Murine Corpus Cavernosum. AB - INTRODUCTION: Resveratrol (RVT) found in red wine protects against erectile dysfunction and relaxes penile tissue (corpus cavernosum) via a nitric oxide (NO) independent pathway. However, the mechanism remains to be elucidated. Hydrogen sulfide (H2 S) is a potent vasodilator and neuromodulator generated in corpus cavernosum. AIMS: We investigated whether RVT caused the relaxation of mice corpus cavernosum (MCC) through H2 S. METHODS: H2 S formation is measured by methylene blue assay and vascular reactivity experiments have been performed by DMT strip myograph in CD1 MCC strips. MAIN OUTCOME MEASURES: Endothelial NO synthase (eNOS) inhibitor Nomega-Nitro-L-arginine (L-NNA, 0.1 mM) or H2 S inhibitor aminooxyacetic acid (AOAA, 2 mM) which inhibits both cystathionine-beta synthase (CBS) and cystathionine-gamma-lyase (CSE) enzyme or combination of AOAA with PAG (CSE inhibitor) has been used in the presence/absence of RVT (0.1 mM, 30 min) to elucidate the role of NO or H2 S pathways on the effects of RVT in MCC. Concentration-dependent relaxations to RVT, L-cysteine, sodium hydrogen sulfide (NaHS) and acetylcholine (ACh) were studied. RESULTS: Exposure of murine corpus cavernosum to RVT increased both basal and L-cysteine-stimulated H2 S formation. Both of these effects were reversed by AOAA but not by L-NNA. RVT caused concentration-dependent relaxation of MCC and that RVT-induced relaxation was significantly inhibited by AOAA or AOAA + PAG but not by L-NNA. L-cysteine caused concentration-dependent relaxations, which are inhibited by AOAA or AOAA + PAG significantly. Incubation of MCC with RVT significantly increased L-cysteine induced relaxation, and this effect was inhibited by AOAA + PAG. However, RVT did not alter the effect of exogenous H2 S (NaHS) or ACh-induced relaxations. CONCLUSIONS: These results demonstrate that RVT-induced relaxation is at least partly dependent on H2 S formation and acts independent of eNOS pathway. In phosphodiesterase 5 inhibitor (PDE-5i) nonresponder population, combination therapy with RVT may reverse erectile dysfunction via stimulating endogenous H2 S formation. PMID- 26437678 TI - Outcomes of total hip arthroplasty in patients with primary immune thrombocytopenia. AB - BACKGROUND: Immune thrombocytopenia (ITP) is an immune-mediated acquired disease that is characterized by a decrease in the platelet count and an increased risk of bleeding. There is little information in the literature about the results of major joint replacement surgery in patients with ITP. The aim of this study was to report on the results of total hip arthroplasty (THA) in patients with primary ITP. METHODS: We retrospectively identified 15 THAs performed in 11 patients with primary ITP. The study group was matched (1:2) to a non-ITP control group of 30 THAs in 22 patients. According to the perioperative hematologic evaluation, blood management interventions were performed. All procedures were performed by a single surgeon and all patients received cementless components with ceramic-on ceramic bearing. Mean duration of follow-up was 7.1 years (range, 2-13). RESULTS: No significant differences were found between the two groups with regard to mean operative time, intraoperative blood loss, amount of closed suction drainage, length of hospital stay, and readmission rate. However, the proportion of patients requiring transfusion of packed red blood cells and/or platelet concentrate was higher in the ITP group when compared to the non-ITP group. Mean Harris hip score improved from 49.5 points preoperatively to 93.4 points at the final follow-up and no hips were revised for loosening or osteolysis in the ITP group. No significant differences were found between the two groups with respect to mean postoperative Harris hip scores and complication rates. CONCLUSIONS: Our study showed encouraging clinical and radiographic results of THA in patients with ITP without increased risk of adverse events compared to those in patients without ITP. On the basis of these findings, we suggest that modern cementless THA might be a viable treatment for achieving functional improvement in patients with ITP and end-stage hip disease. PMID- 26437679 TI - Discrete Rectangles, Prisms, and Heterometallic Cages from a Conjugated Cp*Rh Based Building Block. AB - By carefully selecting an existing synthetic strategy and suitable coordination subunits, constructing desired coordination geometries is no longer that difficult to accomplish. Herein, a new strategy to construct a series of unprecedented structures by using conjugated Cp*Rh-based complex BN-OTf (Cp* = eta(5)-C5Me5) as the building block is proposed. DFT calculations revealed extensive delocalized pi bonds in the subunit. With BN-OTf, rectangular macrocycles TN-bpy and TN-bpe were controllably synthesized. Single-crystal XRD studies confirmed one-dimensional stacking channels for the tetranuclear structure. Notably, the starting ligand imidazole-4,5-dicarboxylate was found to act not only as a tetradentate but also as a hexadentate ligand that can coordinate to further metal ions. Subsequently, [4 Rh+1 M] heterometallic complexes HMZ (M = Cu and Zn) were accessed by chelating borderline hard/soft Lewis acids. With TN-Linker or HMZ, two routes resulted in the [8 Rh+2 M] heterometallic cages HMC (M = Cu and Zn) with excellent crystallinity and stability. Surprisingly, when BN-OTf bonded to rhodium itself, triangular prisms TP-Linker were obtained with high solubility after being linked by bipyridine linkers. Both the X-ray structure and (1)H NMR spectrum confirmed the novel isomerization of the triangular structures. All of the compounds were obtained in high yields and were fully characterized by (1)H NMR spectroscopy, elemental analysis, IR spectroscopy, and in most cases single-crystal X-ray structure determination. PMID- 26437680 TI - Determination of the potential gold electrowinning from an ammoniacal thiosulphate solution applied to recycling of printed circuit board scraps. AB - The use of electrochemical techniques in the selective recovery of gold from a solution containing thiosulphate, ammonia, and copper, obtained from the leaching of printed circuit boards from mobile phones using ammoniacal thiosulphate, are shown in this work. First, cyclic voltammetry tests were performed to determine the potential of electrodeposition of gold and copper, and then, electrowinning tests at different potentials for checking the rates of recovery of these metals were performed. The results of the cyclic voltammetry show that copper deposition occurs at potentials more negative than -600 mV (Ag/AgCl), whereas the gold deposition can be performed at potentials more positives than -600 mV (Ag/AgCl). The results of electrowinning show that 99% of the gold present in solutions containing thiosulphate and copper can be selectively recovered in a potential range between -400 mV (vs Ag/AgCl) and -500 mV (vs Ag/AgCl). Furthermore, 99% of copper can be recovered in potentials more negative than -700 mV (vs Ag/AgCl). PMID- 26437681 TI - Developing models for the prediction of hospital healthcare waste generation rate. AB - An increase in the number of health institutions, along with frequent use of disposable medical products, has contributed to the increase of healthcare waste generation rate. For proper handling of healthcare waste, it is crucial to predict the amount of waste generation beforehand. Predictive models can help to optimise healthcare waste management systems, set guidelines and evaluate the prevailing strategies for healthcare waste handling and disposal. However, there is no mathematical model developed for Ethiopian hospitals to predict healthcare waste generation rate. Therefore, the objective of this research was to develop models for the prediction of a healthcare waste generation rate. A longitudinal study design was used to generate long-term data on solid healthcare waste composition, generation rate and develop predictive models. The results revealed that the healthcare waste generation rate has a strong linear correlation with the number of inpatients (R(2) = 0.965), and a weak one with the number of outpatients (R(2) = 0.424). Statistical analysis was carried out to develop models for the prediction of the quantity of waste generated at each hospital (public, teaching and private). In these models, the number of inpatients and outpatients were revealed to be significant factors on the quantity of waste generated. The influence of the number of inpatients and outpatients treated varies at different hospitals. Therefore, different models were developed based on the types of hospitals. PMID- 26437682 TI - The relationship between the Five-Factor Model personality traits and peptic ulcer disease in a large population-based adult sample. AB - The current study examined the relationship between the Five-Factor Model personality traits and physician-confirmed peptic ulcer disease (PUD) diagnosis in a large population-based adult sample, controlling for the relevant behavioral and sociodemographic factors. Personality traits were assessed by participants themselves and by knowledgeable informants using the NEO Personality Inventory-3 (NEO PI-3). When controlling for age, sex, education, and cigarette smoking, only one of the five NEO PI-3 domain scales - higher Neuroticism - and two facet scales - lower A1: Trust and higher C1: Competence - made a small, yet significant contribution (p < 0.01) to predicting PUD in logistic regression analyses. In the light of these relatively modest associations, our findings imply that it is certain behavior (such as smoking) and sociodemographic variables (such as age, gender, and education) rather than personality traits that are associated with the diagnosis of PUD at a particular point in time. Further prospective studies with a longitudinal design and multiple assessments would be needed to fully understand if the FFM personality traits serve as risk factors for the development of PUD. PMID- 26437684 TI - Strong and superplastic nanoglass. AB - The strength-ductility tradeoff has been a common long-standing dilemma in materials science. For example, superplasticity with a tradeoff in strength has been reported for Cu50Zr50 nanoglass (NG) with grain sizes below 5 nm. Here we report an improvement in strength without sacrificing superplasticity in Cu50Zr50 NG by using a bimodal grain size distribution. Our results reveal that large grains impart high strength, which is in striking contrast to the physical origin of the improvement in strength reported in the traditional nanostructured metals/alloys. Furthermore, the mechanical properties of NG with a bimodal nanostructure depend critically upon the fraction of large grains. By increasing the fraction of the large grains, a transition from superplastic flow to failure by shear banding is clearly observed. We expect that these results will be useful in the development of a novel strong and superplastic NG. PMID- 26437683 TI - Epidemiology and genetics of cystic fibrosis in Asia: In preparation for the next generation treatments. AB - Cystic fibrosis (CF) in the Asian population is less frequently reported due to under-diagnosis and lack of centralized CF patient registries. Clinical studies on CF cases from Asia have documented a severe course of the disease. The spectrum of the cystic fibrosis transmembrane conductance regulator (CFTR) variants in this population is quite heterogeneous. In total, 166 variants have been reported on approximately 3700 Asian CF chromosomes. The frequency of F508del among Asians is low compared with Caucasians. Recent in vitro studies have shown promise of small molecule correction and potentiation of 45 different CFTR variants. Of these variants, 16 (including G551D and F508del) have also been observed among Asian CF individuals. We suggest undertaking molecular studies extensively to annotate CFTR variants that will help Asian CF individuals to benefit from the precision medicine gaining momentum in the Western countries. PMID- 26437685 TI - Stability of unstimulated and stimulated whole saliva flow rates in children. AB - OBJECTIVE: To analyze the stability of the unstimulated saliva flow rate (USFR) and the stimulated saliva flow rate (SSFR) in children followed from age 7 to 12 years old. METHODS: Longitudinal study. Whole saliva samples were collected from school children (50 girls and 50 boys). Forty-four girls and 32 boys remained in this cohort for 6 years (dropout rate 24%). Variables that could influence USFR or SSFR patterns were analyzed in a repeated-measures manova. RESULTS: Over a 6 year follow-up, the children's USFR ranged from 0.41 to 0.46 mL/min in the initial and final observation, respectively, and showed no significant differences (P = 0.4455) during the follow-up. The children consistently belonged to one of three distinct SSFR groups (P < 0.0001). A repeated-measures manova model showed that USFR and SSFR were not associated with sex, body mass index, or indoor temperature during sampling. CONCLUSION: These results indicate that USFR and SSFR patterns were stable from 7 to 12 years old. This finding may be useful in oral health prevention or treatment and in the search for biomarkers in saliva for screening or diagnostic purposes. PMID- 26437686 TI - Improved molecular diagnosis of the common recurrent intragenic deletion mutation in IKBKG in a Filipino family with incontinentia pigmenti. AB - Incontinentia pigmenti is a rare, multisystem X-linked dominant genetic disorder caused by mutations in IKBKG, the encoding inhibitor of kappa light polypeptide gene enhancer in B-cells. Almost 80% of all cases result from a recurrent intragenic deletion mutation that removes exon 4-10. At present, this mutation can be detected by a multi-primer polymerase chain reaction (PCR) technique although current protocols may preferentially amplify the wild-type allele and miss the deletion. Here, we report a female infant with incontinentia pigmenti that also affected her mother and sister, and two spontaneously aborted male siblings. We developed a modified PCR amplification method that provides more robust detection of the exon 4-10 deletion mutation, which was demonstrated in all affected females in this pedigree. PMID- 26437687 TI - 'A short time but a lovely little short time': Bereaved parents' experiences of having a child with spinal muscular atrophy type 1. AB - AIM: Spinal muscular atrophy (SMA) type 1 is a relatively common, untreatable and invariably fatal neuromuscular disorder of early childhood. Psychosocial care is vital in management of families affected by this disease. There are few studies examining the impact of having a family member with a neuromuscular disorder, and none describing parents' experiences of having a child with SMA type 1. This study explored parents' perspectives of having a child with SMA type 1, from diagnosis to bereavement, in order to inform clinical practice by identifying aspects most meaningful to parents and to aid development of support strategies. METHODS: This qualitative study undertook thematic analysis of 11 in-depth interviews with 13 bereaved parents of children with SMA type 1. RESULTS: While individuals' experiences were unique, common themes emerging from the data include: experiencing shock and anticipatory grief, processing feelings of responsibility and helplessness, experiencing multiple losses including the loss of future reproductive freedom, feeling supported, regaining a sense of control by making decisions about the child's life and death, and finding peace in the dying process. CONCLUSION: These findings highlight the importance of a multidisciplinary approach to the care of such families, including psychosocial support beginning from the time of diagnosis and continuing to bereavement. We suggest areas for further exploration, with a goal to develop family-centred and evidence-based psychosocial care guidelines to complement the current Standards of Care for Spinal Muscular Atrophy. PMID- 26437688 TI - Picosecond melting of peptide nanotubes using an infrared laser: a nonequilibrium simulation study. AB - Self-assembled functional peptide biomaterials are emerging with a wide range of envisioned applications in the field of nanotechnology. Currently, methods and tools have been developed to control and manipulate as well as to explore new properties of self-assembled structures. However, considerably fewer studies are being devoted to developing efficient methods to degrade or recycle such extremely stable biomaterials. With this in mind, here we suggest a theoretical framework, inspired by the recent developed mid-infrared free-electron laser pulse technology, to dissociate peptide nanotubes. Adopting a diphenylalanine channel as a prototypical example, we find that the primary step in the dissociation process occurs due to the strong resonance between the carboxylate bond vibrations of the diphenylalanine peptides and the tuned laser frequencies. The effects of laser irradiation are determined by a balance between tube formation and dissociation. Our work shows a proof of concept and should provide a motivation for future experimental developments with the final aim to open a new and efficient way to cleave or to recycle bio-inspired materials. PMID- 26437689 TI - Streptocollin, a Type IV Lanthipeptide Produced by Streptomyces collinus Tu 365. AB - Lanthipeptides are ribosomally synthesized and post-translationally modified microbial secondary metabolites. Here, we report the identification and isolation of streptocollin from Streptomyces collinus Tu 365, a new member of class IV lanthipeptides. Insertion of the constitutive ermE* promoter upstream of the lanthipeptide synthetase gene stcL resulted in peptide production. The streptocollin gene cluster was heterologously expressed in S. coelicolor M1146 and M1152 with 3.5- and 5.5-fold increased yields, respectively. The structure and ring topology of streptocollin were determined by high resolution MS/MS analysis. Streptocollin contains four macrocyclic rings, with one lanthionine and three methyllanthionine residues. To the best of our knowledge, this is the first report on the isolation of a class IV lanthipeptide in preparative amounts, and on the successful heterologous expression of a class IV lanthipeptide gene cluster. PMID- 26437690 TI - Developing ecological scenarios for the prospective aquatic risk assessment of pesticides. AB - The prospective aquatic environmental risk assessment (ERA) of pesticides is generally based on the comparison of predicted environmental concentrations in edge-of-field surface waters with regulatory acceptable concentrations derived from laboratory and/or model ecosystem experiments with aquatic organisms. New improvements in mechanistic effect modeling have allowed a better characterization of the ecological risks of pesticides through the incorporation of biological trait information and landscape parameters to assess individual, population and/or community-level effects and recovery. Similarly to exposure models, ecological models require scenarios that describe the environmental context in which they are applied. In this article, we propose a conceptual framework for the development of ecological scenarios that, when merged with exposure scenarios, will constitute environmental scenarios for prospective aquatic ERA. These "unified" environmental scenarios are defined as the combination of the biotic and abiotic parameters that are required to characterize exposure, (direct and indirect) effects, and recovery of aquatic nontarget species under realistic worst-case conditions. Ideally, environmental scenarios aim to avoid a potential mismatch between the parameter values and the spatial-temporal scales currently used in aquatic exposure and effect modeling. This requires a deeper understanding of the ecological entities we intend to protect, which can be preliminarily addressed by the formulation of ecological scenarios. In this article we present a methodological approach for the development of ecological scenarios and illustrate this approach by a case-study for Dutch agricultural ditches and the example focal species Sialis lutaria. Finally, we discuss the applicability of ecological scenarios in ERA and propose research needs and recommendations for their development and integration with exposure scenarios. Integr Environ Assess Manag 2016;12:510-521. (c) 2015 SETAC. PMID- 26437691 TI - Mechanistic Insight into a Sugar-Accelerated Tin-Catalyzed Cascade Synthesis of alpha-Hydroxy-gamma-butyrolactone from Formaldehyde. AB - Applications of the formose reaction, which involves the formation of sugars from formaldehyde, have previously been confined to the selective synthesis of unprotected sugars. Herein, it is demonstrated that alpha-hydroxy-gamma butyrolactone (HBL), which is one of the most important intermediates in pharmaceutical syntheses, can be produced from paraformaldehyde. In the developed reaction system, homogeneous tin chloride exhibits high catalytic activity and the addition of mono- and disaccharides accelerates the formation of HBL. These observations suggest that the formose reaction may serve as a feasible pathway for the synthesis of important chemicals. PMID- 26437692 TI - Mechanistic Insight into the Facilitation of beta-Lactam Fragmentation through Metal Assistance. AB - The mechanism of OsH6(PiPr3)2-mediated fragmentation of a 4-(2 pyridyl)-2 azetidinone has been investigated by DFT calculations. The addition of the C4-H bond of the substrate to OsH2(PiPr3)2 allows the active participation of an osmium lone pair in the B-type beta-lactam fragmentation process. This new mechanism makes the N1-C4/C2-C3 fragmentation of the lactamic core thermally accessible through a stepwise process. PMID- 26437693 TI - Synchronous del5q myelodysplastic syndrome (del5qMDS) and adult B-cell acute lymphoblastic leukemia (B-ALL) with TET2 and TP53 mutations. PMID- 26437694 TI - Fusion and planarization of bisBODIPY: a new family of photostable near infrared dyes. AB - We have synthesized a new family of directly-fused bisBODIPY BBP 1 through a key FeCl3-mediated intramolecular oxidative cyclodehydrogenation reaction and its derivatives 2 and 3 from the Knoevenagel reaction. These dyes display effective expansion of pi-conjugation over the two BODIPYs due to their locked coplanar conformation, showing intriguing electrochemical and spectroscopic properties, such as intensive absorption/emission bands ranging from 676 to 877 nm and high photostability. PMID- 26437696 TI - [Stability of mortality from thyroid cancer in a developing country]. AB - OBJECTIVE: To establish characteristics and the trend of mortality from thyroid cancer in Colombia. MATERIAL AND METHODS: This is a study of mortality from thyroid cancer in Colombia using official national mortality databases (1998 2010). Year of death, sex, age and department of residence were analyzed. Proportions, arithmetic mean and median were used. The p-value for statistical significance was 0.05. Crude, specific and age-adjusted rates were calculated. RESULTS: Overall, 2 570 people died of thyroid cancer; 1 827 (71.1 %) deaths occurred in women. Median age at death was 68 years for men and 70 years for women. The age-adjusted average annual mortality rate (2006-2010) for thyroid cancer was 0.52 cancer deaths per 100 000 (both sexes), 0.32 deaths per 100 000 men and 0.70 per 100 000 women. CONCLUSIONS: Further studies showing potential factors associated with earlier age at death among Colombian women should be made. PMID- 26437695 TI - Evaluation of a novel automated allergy microarray platform compared with three other allergy test methods. AB - Microarray platforms, enabling simultaneous measurement of many allergens with a small serum sample, are potentially powerful tools in allergy diagnostics. We report here the first study comparing a fully automated microarray system, the Microtest allergy system, with a manual microarray platform, Immuno-Solid phase Allergen Chip (ISAC), and two well-established singleplex allergy tests, skin prick test (SPT) and ImmunoCAP, all tested on the same patients. One hundred and three adult allergic patients attending the allergy clinic were included into the study. All patients were tested with four allergy test methods (SPT, ImmunoCAP, Microtest and ISAC 112) and a total of 3485 pairwise test results were analysed and compared. The four methods showed comparable results with a positive/negative agreement of 81-88% for any pair of test methods compared, which is in line with data in the literature. The most prevalent allergens (cat, dog, mite, timothy, birch and peanut) and their individual allergen components revealed an agreement between methods with correlation coefficients between 0.73 and 0.95. All four methods revealed deviating individual patient results for a minority of patients. These results indicate that microarray platforms are efficient and useful tools to characterize the specific immunoglobulin (Ig)E profile of allergic patients using a small volume of serum sample. The results produced by the Microtest system were in agreement with diagnostic tests in current use. Further data collection and evaluation are needed for other populations, geographical regions and allergens. PMID- 26437697 TI - Healthcare plans and consumer perceptions of healthcare institutions. AB - OBJECTIVE: This study evaluates the effect of healthcare insurance plans on consumer perception of trust in a healthcare institution, and the mediating effect of trust on consumer loyalty towards an institution. METHOD: The study was conducted at a healthcare institution in Colombia where a total of 841 patients responded to a questionnaire. RESULTS: A structural equation model shows that individuals who have a pre-paid healthcare plan have a stronger evaluation of trust compared to those who hold a regulated healthcare plan (i.e., subsidized and contributory plans). In turn, trust positively predicts consumers' loyalty towards an institution. The relationship between the patients' healthcare plans and their degree of loyalty towards healthcare institutions is completely mediated by their perception of trust towards the institution. DISCUSSION: A greater perception of trust is explained by having a medical plan that provides consumers with more flexibility, allowing them to select their health provider at a premium price. Although health institutions do not control healthcare regimes, these affect consumers' trust in their service. Institutions cannot modify characteristics of the regime, but they can promote a trustworthy environment to strengthen consumers' loyalty to the institution. PMID- 26437698 TI - Hazards for Women and Children in Rural Settings. AB - OBJECTIVES: a) To identify possible risk factors associated with rural accidents in women, b) to describe women's knowledge about zoonosis, c) to describe women's risk perception about farming, d) to describe mothers' risk perception about children's activities in rural settings, e) to estimate the initial age of exposure to the rural setting and its dangers, and f) to identify possible risk factors associated with rural accidents in children. MATERIALS AND METHODS: Cross sectional design. Women with children that live in the countryside were surveyed (n=24). Structured questionnaire. STATISTICAL ANALYSES: chi2, Student's t-test, Pearson's correlation coefficient and logistic regression. RESULTS: Many women had suffered an accident in the countryside (65.6 %). Farm worker usually did not use personal protective equipment (PPE). Hearing protection, gloves, and safety goggles were rarely used. Working women showed a high risk perception for urban driving, the handling of agrochemicals, and driving on main roads (85.7 %, 70 % and 66.7 %). There was no significant association between risk perception and PPE use. Most mothers (87.5 %) thought that was good for children to learn how to perform farm chores starting at a young age. Children started to drive tractors at 9 years of age; 12.23 years on average. More than 7 % of the children (7.14 %) have suffered an accident on the farm. The most frequent accidents were being trapped in machinery (60 %). No association was found between the independent variables and the dependent variable; farm-related accidents in children (p>0.2). CONCLUSIONS: Risk communication is necessary to inform people involved and to reduce exposure. PMID- 26437699 TI - [Analysis of the performance of the assessment battery related to psychosocial factors in Colombia]. AB - OBJECTIVE: The goal of this study is to analyze the performance of the three questionnaires and the file of general information that comprise the Set of Instruments for the Assessment of Psychosocial Factors in six companies from different economic sectors in Colombia, with regard to: (a) content of the instruments, (b) application methodology, and (c) the response from workers and employers. METHODOLOGY: This research was performed through the study of multiple instances. It was based on the processing of: (1) the observation logs with regard to the application of the questionnaires, (2) workers' annotations about their questionnaires and (3) minutes of meetings with representatives of the workers. A reclassification into more specific subcategories was done taking into consideration some particular and common elements found between companies. RESULTS: Regarding the "Content" category, there are significant limitations in the questionnaires about both outside and inside-of-work factors. This is because some items cannot be applied under specific working conditions such as outsourcing or field work. In "Methodology" it was observed that some practices could decrease the reliability of the assessments, such as not having adequate schedules or locations. In the "Reception" category, it was found that even though this assessment is deemed desirable by most workers and employers, there are, however, some actions taken by companies that could affect this perception. CONCLUSIONS: It is positive to implement the assessment of psychosocial working conditions in companies of this country, even though this assessment, with a universal assessment tool, has difficulties in a changing and increasingly complex working world. It is advisable to complement these assessments with qualitative methods. PMID- 26437700 TI - [The interaction in clinical nursing education: reflections on care of the person with hypertension]. AB - OBJECTIVE: To identify the knowledge and attitudes about self-care in health among users who received clinical nursing education for hypertension based on the level of knowledge and attitudes of the hypertensive patient through interactive care interventions with patients and relatives in the therapeutic context, with the goal of developing health education. METHOD: This study represents action research with a qualitative approach on hypertensive patients hospitalized for stroke. Hypertension as a risk factor is most strongly associated with the development of this health problem. RESULTS: Participants were interviewed about their knowledge about the illness before and after the realization of individualized health education activities on the basis of the theory of symbolic interactionism. CONCLUSION: It was found that the respondents, after participating in the educational process, demonstrated a broader knowledge of hypertension, which motivated them to seek changes in habits that could improve their quality of life. Through the use of symbolic interactionism, health education proved to be a strategy for empowerment and autonomy of the hypertensive subject with respect to their treatment and can be integrated into nursing care. PMID- 26437701 TI - [Information technology in learning sign language]. AB - OBJECTIVE: To develop a technological tool that improves the initial learning of sign language in hearing impaired children. METHODS: The development of this research was conducted in three phases: the lifting of requirements, design and development of the proposed device, and validation and evaluation device. Through the use of information technology and with the advice of special education professionals, we were able to develop an electronic device that facilitates the learning of sign language in deaf children. This is formed mainly by a graphic touch screen, a voice synthesizer, and a voice recognition system. Validation was performed with the deaf children in the Filadelfia School of the city of Bogota. RESULTS: A learning methodology was established that improves learning times through a small, portable, lightweight, and educational technological prototype. CONCLUSIONS: Tests showed the effectiveness of this prototype, achieving a 32 % reduction in the initial learning time for sign language in deaf children. PMID- 26437702 TI - [Risk factors related with pediatric accidents in a children's hospital in Bogota]. AB - OBJECTIVE: To describe the biophysical and sociocultural risk factors related to the accident rate in pediatric patients. METHOD: Cross-sectional descriptive study. Data collection through the direct application of surveys. RESULTS: 308 surveys were analyzed, obtained between the months of february and april, 2010. Adolescents were the most affected group (33.5 %); the male gender registered the highest number of traumas (64.7 %). The main family type was nuclear 52 %, 34.9 % of patients belonged to stratum 2 and 46,6 % were under the care of their mothers when the accident occurred. 84 % of caretakers had over 5 years study, 47 % considered that the most unsafe place for a child is a public road, and 76.8 % stated having never received information on accident prevention. The most frequent accident was a fall from a height (54.7 %) and home was the place with highest number of traumas (51 %). DISCUSSION: Demographic features and sociocultural factors of this study differ from reports from large studies of non intentional lesions. PMID- 26437703 TI - [Medicinal herbs used in the care for diseases of the digestive system in the city of Taxco, Guerrero, Mexico]. AB - OBJECTIVE: This study shows a) the empirical use, b) the properties proven scientifically and c), doses of the main medicinal herbs that are used in the care for disease of the digestive system (and/or its signs and symptoms) in the city of Taxco, Guerrero, Mexico. METHODS: The study was qualitative. Approaches regarding sampling in qualitative research were taken into account. This specifically was with regard to homogeneous samples. We interviewed six recognized traditional practitioners that had deep knowledge of the subject. A questionnaire interview with open questions was designed regarding the characteristics of the major herbs, the most common diseases of the digestive system, and the doses and parts used. RESULTS: The main findings reflect about 20 plants that are used to heal these conditions, as well as their real scientifically proven health properties. CONCLUSIONS: Medicinal plants continue to be part of a complex local medical structure. This knowledge and the set of specialized therapeutic techniques and treatments are valid today. PMID- 26437704 TI - [Tuberculosis and drug-resistance tuberculosis in prisoners. Colombia, 2010 2012]. AB - OBJECTIVE: To characterize tuberculosis drug-resistance using anti-tuberculosis drug-sensitivity tests in Colombian prisoners. METHODS: Descriptive-retrospective analyses were performed on cases of tuberculosis in prisoners. Samples were evaluated by the National Reference Laboratory. Conditions like gender, TB/VIH co infection and drug-resistance were evaluated. RESULTS: Anti-tuberculosis drug sensitivity tests were carried out on 72 prisoners. Results showed a distribution of 90.7 % of cases in males and 9.3 % of cases in females. 12 % of cases were TB/VIH co-infections, 94 % of the cases had not received any anti-tuberculosis treatment before, six isolates were drug-resistant corresponding to 8.8 % of total cases, and two cases were multi drug-resistant representing 1.3 % of the cases. Of the drug-resistant cases, 83.3 % were TB/VIH co-infected. Previously treated cases corresponded to 5.6 % of the total cases analyzed. One case with TB/VIH co-infection and rifampicin resistance was observed, representing 1.3 % of the total cases. CONCLUSION: The government must create a clear policy for prisoners in Colombia, because a high rate of disease in prisoners was observed. In addition, the results showed an association between drug-resistance and TB/VIH co-infection. Overcrowding and low quality of life in penitentiaries could become an important public health problem. PMID- 26437705 TI - [Antimicrobial susceptibility of Salmonella enterica isolated during the pre harvest period in swine in Colombia]. AB - OBJECTIVE: To determine the antimicrobial susceptibility of isolates of Salmonella enterica isolated from animals and during the pre-slaughter period. METHOD: Antimicrobial susceptibility tests were performed using the agar diffusion method on 333 isolates of Salmonella enterica obtained from the pre harvest period represented by transport trucks and pens. From the animals, isolates were obtained from the animals' feces in transport trucks and pens, mesenteric lymph nodes, and cecal content. The specimens were obtained from four slaughtering facilities. RESULTS: The antimicrobial susceptibility tests were performed obtaining the following results: 99.6 % (n=332) of isolates showed resistance to at least one antimicrobial agent. The following resistance percentages were found: amoxicillin-clavulanic acid 15.9 % (n=53), ampicillin 33.9 % (n=113), ceftiofur 41.4 % (n=138), ciprofloxacin 9 % (n=30 ), chloramphenicol 19.2 % (n=64), florfenicol 33 % (n=110), gentamicin 22.8 % (n=76), sulfamethoxazole-trimethoprim 24.9 % (n=83), tetracycline 93.1 % (n=310) and tilmicosin 73.8 % (n=246). CONCLUSION: The results show that it is essential to reinforce containment measures to prevent the development of antimicrobial resistances and improve training of the operators, workers, and veterinarians in Colombia involved in the primary production, product processing, distribution, and sale to the consumer, thereby guaranteeing a safe food product and the effectiveness of antimicrobial agents in human and veterinary medicine. PMID- 26437706 TI - Efficacy of the prescription of physical activity in the obese child population. AB - OBJECTIVE: To determine the effectiveness of prescribing physical activity to the population of overweight and obese children, in accordance with the levels of evidence. METHODS: To find literature pertaining to the intervention of physical activity in overweight and obese children. four electronic databases were used: Pubmed, Embase, Cochrane and Lilacs. The search was conducted with a cut-off date of June 2012. Randomized controlled clinical trials of intervention programs involving physical activity for both overweight and obese children were selected. Two independent researchers reviewed and evaluated the quality of the studies, and extracted intervention and result data. RESULTS: A total of 204 studies were identified. 19 randomized controlled studies which complied with inclusion and exclusion criteria were included. These studies evaluated the impact of physical activity among obese children and compared different types of intervention based on exercise and diet or both with the objective of reducing weight in obese children. CONCLUSIONs: It is necessary to conduct studies on obese children with bigger sample sizes to determine the effects of the treatment, and more importantly, to devise comprehensive programs that include a structured exercise program complemented by a dietary program. Likewise, the development of public health policies that allow for the development of national programs for weight and obesity control in Colombian children and adults should be developed, taking into account that the causes of obesity are multiple, including social, familiar, metabolic, and dietary aspects. PMID- 26437707 TI - [The value of dental imaging in the teaching and promotion of oral health]. AB - In the context of the great diversity of oral microflora, including over 600 species, we highlight the educational value of electron micrographs and images of dental plaque cultures in dental models made with culture media, showing the bacterial colonies in the anatomic sites of the teeth that were most abundantly colonized. Such images allow for an easy understanding of the magnitude of the oral microbiome for students of biomedical careers--especially dentistry--and for the general public. As such, these images can be used in teaching programs and oral health campaigns. PMID- 26437708 TI - [The decade of action for road safety in Medellin, Colombia, to 2015]. AB - Road safety (RS) is key in the study and intervention of human mobility. It is a determining priority in international public health and in the development of communities and nations. The declaration of a global RS crisis in the 1990s by the United Nations urged the social, political and technical processes to propose the Decade of Action for Road Safety 2010-2020 (DARS). The DARS has a global action plan structured around five pillars; the first refers to institutional management. The article describes the background, framework, evidence, and effects of poor management during first half of the DARS in Medellin, Colombia up to 2015. PMID- 26437709 TI - Impact of sympathetic nervous system activity on post-exercise flow-mediated dilatation in humans. AB - Transient reduction in vascular function following systemic large muscle group exercise has previously been reported in humans. The mechanisms responsible are currently unknown. We hypothesised that sympathetic nervous system activation, induced by cycle ergometer exercise, would contribute to post-exercise reductions in flow-mediated dilatation (FMD). Ten healthy male subjects (28 +/- 5 years) undertook two 30 min sessions of cycle exercise at 75% HR(max). Prior to exercise, individuals ingested either a placebo or an alpha1-adrenoreceptor blocker (prazosin; 0.05 mg kg(-1)). Central haemodynamics, brachial artery shear rate (SR) and blood flow profiles were assessed throughout each exercise bout and in response to brachial artery FMD, measured prior to, immediately after and 60 min after exercise. Cycle exercise increased both mean and antegrade SR (P < 0.001) with retrograde SR also elevated under both conditions (P < 0.001). Pre exercise FMD was similar on both occasions, and was significantly reduced (27%) immediately following exercise in the placebo condition (t-test, P = 0.03). In contrast, FMD increased (37%) immediately following exercise in the prazosin condition (t-test, P = 0.004, interaction effect P = 0.01). Post-exercise FMD remained different between conditions after correction for baseline diameters preceding cuff deflation and also post-deflation SR. No differences in FMD or other variables were evident 60 min following recovery. Our results indicate that sympathetic vasoconstriction competes with endothelium-dependent dilator activity to determine post-exercise arterial function. These findings have implications for understanding the chronic impacts of interventions, such as exercise training, which affect both sympathetic activity and arterial shear stress. PMID- 26437710 TI - How Cryptococcus interacts with the blood-brain barrier. AB - Cryptococcus demonstrates predilection for invasion of the brain, but the mechanism by which Cryptococcus crosses the blood-brain barrier (BBB) to cause brain invasion is largely unknown. In order for Cryptococcus to cross the BBB, there must be a way to either cross human brain microvascular endothelial cells, which are the main constitute of the BBB, or go in between tight junctions. Recent evidence of human brain microvascular endothelial cell responses to transcellular brain invasions includes membrane rearrangements, intracellular signaling pathways and cytoskeletal activations. Several Cryptococcal genes related to the traversal of BBB have been identified, including CPS1, ITR1a, ITR3c, PLB1, MPR1, FNX1 and RUB1. In addition, Cryptococcus neoformans-derived microvesicles may contribute to cryptococcal brain invasion. Paracellularly, Cryptococcus may traverse across BBB using either routes utilizing plasmin, ammonia or macrophages in a Trojan horse mechanism. PMID- 26437711 TI - The Unexpected Influence of Precursor Conversion Rate in the Synthesis of III-V Quantum Dots. AB - Control of quantum dot (QD) precursor chemistry has been expected to help improve the size control and uniformity of III-V QDs such as indium phosphide and indium arsenide. Indeed, experimental results for other QD systems are consistent with the theoretical prediction that the rate of precursor conversion is an important factor controlling QD size and size distribution. We synthesized and characterized the reactivity of a variety of group-V precursors in order to determine if precursor chemistry could be used to improve the quality of III-V QDs. Despite slowing down precursor conversion rate by multiple orders of magnitude, the less reactive precursors do not yield the expected increase in size and improvement in size distribution. This result disproves the widely accepted explanation for the shortcoming of current III-V QD syntheses and points to the need for a new generalizable theoretical picture for the mechanism of QD formation and growth. PMID- 26437712 TI - Long-term immunogenicity and safety after a single dose of the quadrivalent meningococcal serogroups A, C, W, and Y tetanus toxoid conjugate vaccine in adolescents and adults: 5-year follow-up of an open, randomized trial. AB - BACKGROUND: Long-term protection against meningococcal disease is associated with persistence of post-vaccination antibodies at protective levels. We evaluated the bactericidal antibody persistence and safety of the quadrivalent meningococcal serogroups A, C, W and Y tetanus-toxoid conjugate vaccine (MenACWY-TT) and the meningococcal polysaccharide serogroups A, C, W, and Y vaccine (MenACWY-PS) up to 5 years post-vaccination. METHODS: This phase IIb, open, randomized, controlled study conducted in the Philippines and Saudi Arabia consisted of a vaccination phase and a long-term persistence phase. Healthy adolescents and adults aged 11 55 years were randomized (3:1) to receive a single dose of MenACWY-TT (ACWY-TT group) or MenACWY-PS (Men-PS group). Primary and persistence results up to 3 years post-vaccination have been previously reported. Antibody responses against meningococcal serogroups A, C, W, and Y were assessed by a serum bactericidal antibody assay using rabbit complement (rSBA, cut-off titers 1:8 and 1:128) at Year 4 and Year 5 post-vaccination. Vaccine-related serious adverse events (SAEs) and cases of meningococcal disease were assessed up to Year 5. RESULTS: Of the 500 vaccinated participants, 404 returned for the Year 5 study visit (Total Cohort Year 5). For the Total Cohort Year 5, 71.6-90.0 and 64.9-86.3 % of MenACWY TT recipients had rSBA titers >=1:8 and >=1:128, respectively, compared to 24.8 74.3 and 21.0-68.6 % of MenACWY-PS recipients. The rSBA geometric mean titers (GMTs) remained above the pre-vaccination levels in both treatment groups. Exploratory analyses suggested that both rSBA GMTs as well as the percentages of participants with rSBA titers above the cut-offs were higher in the ACWY-TT than in the Men-PS group for serogroups A, W and Y, with no apparent difference for MenC. No SAEs related to vaccination or cases of meningococcal disease were reported up to Year 5. CONCLUSION: These results suggest that a single dose of MenACWY-TT could protect at least 72 % of vaccinated adolescents and adults against meningococcal disease at least 5 years post-vaccination. TRIAL REGISTRATION: ClinicalTrials.gov NCT00356369. PMID- 26437713 TI - Protocol for a systematic review of the impact of resuscitation fluids on the microcirculation after haemorrhagic shock in animal models. AB - BACKGROUND: Modern resuscitation strategies following haemorrhagic shock are influenced by global haemodynamic parameters such as blood pressure and cardiac output. Microcirculatory dysfunction in this context may persist even after restoration of satisfactory global parameters. Additional monitoring of the microcirculatory function may therefore be warranted in order to facilitate goal directed therapy at a tissue oxygenation level. Although such a phenomenon is recognised in the case of sepsis, clinical evidence regarding the behaviour of the microcirculation following the delivery of resuscitation fluids after haemorrhagic shock is sparse. A summation of the current state of pre-clinical evidence is justified in order to direct avenues for future clinical research. METHODS/DESIGN: Systematic review methodology will be utilised in order to identify relevant studies, assess for bias, and extract data for analysis. Medical databases will be searched to find pre-clinical studies that monitor the microcirculatory function following haemorrhagic shock and subsequent fluid resuscitation. Different fluid types (e.g. blood products, crystalloid, and colloid fluids) will be compared. The search strategy will combine terms for the animal model, resuscitation fluid, and microcirculatory parameters. Randomised and non-randomised experiments, as well as case series, will be eligible for inclusion. Specific quality assessment tools for pre-clinical research will be used depending on study design. A combination of narrative and meta-analysis techniques will be used for the synthesis of data. DISCUSSION: The choice of type, sequence, and quantity of resuscitation fluid following haemorrhagic shock is controversial, and the optimal strategy for restoration of microcirculatory function is yet unknown. A detailed examination of pre-clinical data regarding the microcirculation is timely and will enable a focussed approach to clinical research for the improvement of resuscitation following haemorrhagic shock. SYSTEMATIC REVIEW REGISTRATION: Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies ( CAMARADES). PMID- 26437714 TI - Interlog protein network: an evolutionary benchmark of protein interaction networks for the evaluation of clustering algorithms. AB - BACKGROUND: In the field of network science, exploring principal and crucial modules or communities is critical in the deduction of relationships and organization of complex networks. This approach expands an arena, and thus allows further study of biological functions in the field of network biology. As the clustering algorithms that are currently employed in finding modules have innate uncertainties, external and internal validations are necessary. METHODS: Sequence and network structure alignment, has been used to define the Interlog Protein Network (IPN). This network is an evolutionarily conserved network with communal nodes and less false-positive links. In the current study, the IPN is employed as an evolution-based benchmark in the validation of the module finding methods. The clustering results of five algorithms; Markov Clustering (MCL), Restricted Neighborhood Search Clustering (RNSC), Cartographic Representation (CR), Laplacian Dynamics (LD) and Genetic Algorithm; to find communities in Protein Protein Interaction networks (GAPPI) are assessed by IPN in four distinct Protein Protein Interaction Networks (PPINs). RESULTS: The MCL shows a more accurate algorithm based on this evolutionary benchmarking approach. Also, the biological relevance of proteins in the IPN modules generated by MCL is compatible with biological standard databases such as Gene Ontology, KEGG and Reactome. CONCLUSION: In this study, the IPN shows its potential for validation of clustering algorithms due to its biological logic and straightforward implementation. PMID- 26437715 TI - Intranasal administration of poly-gamma glutamate induced antiviral activity and protective immune responses against H1N1 influenza A virus infection. AB - BACKGROUND: The global outbreak of a novel swine-origin strain of the 2009 H1N1 influenza A virus and the sudden, worldwide increase in oseltamivir-resistant H1N1 influenza A viruses highlight the urgent need for novel antiviral therapy. METHODS: Here, we investigated the antiviral efficacy of poly-gamma glutamate (gamma-PGA), a safe and edible biomaterial that is naturally synthesized by Bacillus subtilis, against A/Puerto Rico/8/1934 (PR8) and A/California/04/2009 (CA04) H1N1 influenza A virus infections in C57BL/6 mice. RESULTS: Intranasal administration of gamma-PGA for 5 days post-infection improved survival, increased production of antiviral cytokines including interferon-beta (IFN-beta) and interleukin-12 (IL-12), and enhanced activation of natural killer (NK) cells and influenza antigen-specific cytotoxic T lymphocytes (CTL) activity. CONCLUSIONS: These results suggest that gamma-PGA protects mice against H1N1 influenza A virus by enhancing antiviral immune responses. PMID- 26437717 TI - 2-Aminoethanol Extraction as a Method for Purifying Sc3N@C80 and for Differentiating Classes of Endohedral Fullerenes on the Basis of Reactivity. AB - Extraction with 2-aminoethanol is an inexpensive method for removing empty cage fullerenes from the soluble extract from electric-arc-generated fullerene soot that contains endohedral metallofullerenes of the type Sc3N@C2n (n = 34, 39, 40). Our method of separation exploits the fact that C60, C70, and other larger, empty cage fullerenes are more susceptible to nucleophilic attack than endohedral fullerenes and that these adducts can be readily extracted into 2-aminoethanol. This methodology has also been employed to examine the reactivity of the mixture of soluble endohedral fullerenes that result from doping graphite rods used in the Kratschmer-Huffman electric-arc generator with the oxides of Y, Lu, Dy, Tb, and Gd. For example, with Y2O3, we were able to detect by mass spectrometry several new families of endohedral fullerenes, namely Y3C108 to Y3C126, Y3C107 to Y3C125, Y4C128 to Y4C146, that resisted reactivity with 2-aminoethanol more than the empty cage fullerenes and the mono- and dimetallo fullerenes. The discovery of the family Y3C107 to Y3C125 with odd numbers of carbon atoms is remarkable, since fullerene cages must involve even numbers of carbon atoms. The newly discovered families of endohedral fullerenes with the composition M4C2n (M = Y, Lu, Dy, Tb, and Gd) are unusually resistant to reaction with 2-aminoethanol. Additionally, the individual endohedrals, Y3C112 and M3C102 (M = Lu, Dy, Tb and Gd), were remarkably less reactive toward 2-aminoethanol. PMID- 26437716 TI - An investigation of the added value of an ACPA multiplex assay in an early rheumatoid arthritis setting. AB - INTRODUCTION: Recently, arrays have become available that allow the simultaneous analysis of several anti-citrullinated protein antibody (ACPA) reactivities using distinct citrullinated peptides. Such assays are designed for exploratory studies. The interpretation of positive antibody reactivities can best be made if the diagnostic and prognostic value of a multiplex array in an early arthritis setting is known and if the multiplex-positive patients who are negative according to three commonly used commercial ACPA assays are characterized. METHODS: Using Thermo Scientific's ImmunoCap ISAC (Immuno Solid-phase Allergen Chip) system, a multiplexed array that determines reactivities to 11 citrullinated peptides, we analysed serum/plasma of 195 healthy controls and 1282 early arthritis patients from two independent cohorts: the Leiden Early Arthritis Clinic (n = 1013) and the IMPROVED (n = 269) cohort. Findings were compared with results primarily of the anti-citrullinated cyclic peptide 2 (anti-CCP-2) assay but also with anti- CCP-3 and anti-mutated citrullinated vimentin (anti-MCV) assays. The associations between ACPA reactivities and patient characteristics, risk factors (shared epitope, smoking) and disease outcomes (progression of undifferentiated arthritis to rheumatoid arthritis (RA) and severity of joint destruction) were assessed. RESULTS: Thirty-one percent of anti-CCP-2-negative RA patients displayed reactivity toward citrullinated peptides in the multiplex assay. These patients had a positive signal toward a more restricted peptide repertoire than anti-CCP-2-positive RA patients (median of 1 versus 5). Within anti-CCP-2-negative patients, ACPA reactivity as detected by multiplex array was not significantly associated with known risk factors or clinical or prognostic parameters. The frequency of sera from anti-CCP-2-negative RA patients who were positive for the multiplexed peptides was comparable to the frequency in non-RA arthritic patients (27 %). CONCLUSIONS: Additive citrulline peptide reactivities detected by the current multiplex system did not reach significant power to be RA specific. The presence of residual citrulline reactivities detected by this multiplex system in arthritis patients who are negative in commercial ACPA assays needs to be interpreted with caution. PMID- 26437718 TI - Mitotically active cellular fibroma of the ovary: a case report and literature review. AB - BACKGROUND: The ovarian cellular fibrous tumor with mitotic figure >4 per 10 high power field without moderate to severe atypia is defined as mitotically active cellular fibroma according to the 2014 World Health Organization classification. As this category is new and rare now, we described here a case of MACF and reviewed the literature. CASE: We present a case of mitotically active cellular fibroma of the ovary with 10-year history that was treated with laparoscopic surgery. METHODS: We reviewed the relevant literature using PubMed search system and analyzed the previous cases. RESULTS: To date, only 5 cases of mitotically active cellular fibroma have been reported. Our patient is the first case of mitotically active cellular fibroma of the ovary treated with laparoscopic surgery. CONCLUSION: MACF of the ovary is a newly defined category and few cases have been reported, while prognostic factors have also not yet been fully characterized. Long-term clinical follow-up is necessary. PMID- 26437719 TI - Food environment and fruit and vegetable intake in a urban population: a multilevel analysis. AB - BACKGROUND: Environmental, social and individual factors influence eating patterns, which in turn affect the risk of many chronic diseases. This study aimed to estimate associations between environmental factors and the consumption of fruit and vegetables among adults in a Brazilian urban context. METHODS: Data from the surveillance system for risk factors for chronic diseases (VIGITEL) of Brazilian Ministry of Health were used. A cross-sectional telephone survey (VIGITEL - 2008-2010) was carried out with 5826 adults in the urban area of Belo Horizonte. Individual variables were collected. The frequency of fruit and vegetables consumption was assessed from number of servings, weekly frequency and an intake score was calculated. Georeferenced variables were used to characterize the food environment. The density of healthy food outlets (stores specialized in selling fruit and vegetables), unhealthy food outlets (bars, snack bars and food trucks/trailers) and the neighborhood family income were investigated and associated with fruit and vegetables intake score. Weighted multilevel linear regression was used to evaluate the associations between the environment variables and the fruit and vegetables intake score. RESULTS: Higher fruit and vegetables intake scores were observed in neighborhoods with higher density of healthy food outlets and higher income. Lower scores were observed in neighborhood with higher density of unhealthy food outlets. These associations were adjusted by individual variables such as gender, age, physical activity, sugar sweetened beverages consumption, education level and smoking. DISCUSSION: The food environment might explain some of the socioeconomic disparities with respect to healthy food intake and health outcomes. Healthy food stores are less common in socially disadvantaged neighborhoods, and therefore, healthy foods such as fruits and vegetables are less available or are of a lower quality in lower income areas. CONCLUSION: Food environment characteristics and neighborhood socioeconomic level had significant associations with fruit and vegetable intake score. These are initial findings that require further investigation within the middle income world populations and the role of the environment with respect to both healthy and unhealthy food acquisition and intake. PMID- 26437721 TI - Real men are made, not born! Incidental exposure to energy drinks may promote men's tolerance of physical pain. AB - The energy drink market has grown exponentially since the debut of Red Bull. Advertising of energy drinks tends to reinforce an emphasis on masculine identification. However, no previous study has addressed the symbolic effect of energy drinks on pain tolerance, that is, a particular masculine characteristic. We conducted a priming-based experiment to show that energy drink primes elevated men's pain tolerance. Induced conformity to masculinity norms mediated the priming effect of energy drinks on pain tolerance. These findings suggest that mere reminders of masculinity-related products can lead men to behave accordingly in seemingly irrelevant domains (i.e., pain tolerance). Besides distraction and placebo treatment, the connection between a symbolic masculinity prime and greater tolerance of pain may shed lights on an alternative route for pain control. PMID- 26437720 TI - Effect and cost of an after-school dance programme on the physical activity of 11 12 year old girls: The Bristol Girls Dance Project, a school-based cluster randomised controlled trial. AB - BACKGROUND: The aim of this study was to examine the effectiveness and cost of an after-school dance intervention at increasing the physical activity levels of Year 7 girls (age 11-12). METHODS: A cluster randomised controlled trial was conducted in 18 secondary schools. Participants were Year 7 girls attending a study school. The Bristol Girls Dance Project (BGDP) intervention consisted of up to forty, 75-minute dance sessions delivered in the period immediately after school by experienced dance instructors over 20-weeks. The pre-specified primary outcome was accelerometer assessed mean minutes of weekday moderate to vigorous physical activity (MVPA) at time 2 (52 weeks are T0 baseline assessments). Secondary outcomes included accelerometer assessed mean minutes of weekday MVPA at time 1 (while the intervention was still running) and psychosocial outcomes. Intervention costs were assessed. RESULTS: 571 girls participated. Valid accelerometer data were collected from 549 girls at baseline with 508 girls providing valid accelerometer data at baseline and time 2. There were no differences between the intervention and control group for accelerometer assessed physical activity at either time 1 or time 2. Only one third of the girls in the intervention arm met the pre-set adherence criteria of attending two thirds of the dance sessions that were available to them. Instrumental variable regression analyses using complier average causal effects provided no evidence of a difference between girls who attended the sessions and the control group. The average cost of the intervention was L73 per girl, which was reduced to L63 when dance instructor travel expenses were excluded. CONCLUSION: This trial showed no evidence that an after-school dance programme can increase the physical activity of Year 7 girls. The trial highlighted the difficulty encountered in maintaining attendance in physical activity programmes delivered in secondary schools. There is a need to find new ways to help adolescent girls to be physically active via identifying ways to support and encourage sustained engagement in physical activity over the life course. TRIAL REGISTRATION: ISRCTN52882523. PMID- 26437722 TI - Cancers in Australia in 2010 attributable to modifiable factors: introduction and overview. AB - OBJECTIVE: To describe the approach underpinning a national project to estimate the numbers and proportions of cancers occurring in Australia in 2010 that are attributable to modifiable causal factors. METHODS: We estimated the population attributable fraction (PAF) (or prevented fraction) of cancers associated with exposure to causal (or preventive) factors using standard formulae. Where possible, we also estimated the potential impact on cancer incidence resulting from changes in prevalence of exposure. Analyses were restricted to factors declared causal by international agencies: tobacco smoke; alcohol; solar radiation; infectious agents; obesity; insufficient physical activity; insufficient intakes of fruits, vegetables and fibre; red and processed meat; menopausal hormone therapy (MHT); oral contraceptive pill (OCP); and insufficient breast feeding. Separately, we estimated numbers of cancers prevented by: aspirin; sunscreen; MHT; and OCP use. We discuss assumptions pertaining to latent periods between exposure and cancer onset, choices of prevalence data and risk estimates, and approaches to sensitivity analyses. RESULTS: Numbers and population attributable fractions of cancer are presented in accompanying papers. CONCLUSIONS: This is the first systematic assessment of population attributable fractions of cancer in Australia. PMID- 26437723 TI - Cancers in Australia in 2010 attributable to the consumption of alcohol. AB - OBJECTIVE: To estimate the proportion and numbers of cancers occurring in Australia in 2010 that are attributable to alcohol consumption. METHODS: We estimated the population attributable fraction (PAF) of cancers causally associated with alcohol consumption using standard formulae incorporating prevalence of alcohol consumption and relative risks associated with consumption and cancer. We also estimated the proportion change in cancer incidence (potential impact fraction [PIF]) that might have occurred under the hypothetical scenario that an intervention reduced alcohol consumption, so that no-one drank >2 drinks/day. RESULTS: An estimated 3,208 cancers (2.8% of all cancers) occurring in Australian adults in 2010 could be attributed to alcohol consumption. The greatest numbers were for cancers of the colon (868) and female breast cancer (830). The highest PAFs were for squamous cell carcinomas of the oral cavity/pharynx (31%) and oesophagus (25%). The incidence of alcohol associated cancer types could have been reduced by 1,442 cases (4.3%)--from 33,537 to 32,083--if no Australian adult consumed >2 drinks/day. CONCLUSIONS: More than 3,000 cancers were attributable to alcohol consumption and thus were potentially preventable. IMPLICATIONS: Strategies that limit alcohol consumption to guideline levels could prevent a large number of cancers in Australian adults. PMID- 26437724 TI - Cancers prevented in Australia in 2010 through the consumption of aspirin. AB - OBJECTIVES: To estimate the proportion and number of cancers in Australia in 2010 that may have been prevented from occurring due to daily use of aspirin in the population. METHODS: We calculated the Prevented Fraction (PF) of colorectal and oesophageal cancers using standard formulae. The PF is the proportion of the hypothetical total load of cancer in the population that was prevented by exposure to aspirin. The formula incorporates estimates of the prevalence of aspirin use in Australian adult populations, the relative risks associated with aspirin use and cancer incidence. RESULTS: An estimated 335 colorectal cancers, 22 oesophageal adenocarcinomas and 29 oesophageal squamous cell carcinomas (SCC) were potentially prevented due to daily aspirin use. These figures equate to 2.2%, 3.1% and 5.4% of all colorectal cancers, oesophageal adenocarcinomas and oesophageal SCCs, respectively, that would otherwise have occurred but were potentially avoided due to the daily use of aspirin pertaining in the Australian population. CONCLUSIONS: At current levels of consumption, a small but measurable reduction in cancer incidence can be attributed to daily aspirin use. IMPLICATIONS: Assuming the benefits outweigh the harms of known gastrointestinal toxicity and other hazards, aspirin use may be considered for some people to prevent the development of particular gastrointestinal cancers. PMID- 26437725 TI - Cancers in Australia in 2010 attributable to total breastfeeding durations of 12 months or less by parous women. AB - OBJECTIVES: To estimate the proportion and number of cancers occurring in Australia in 2010 attributable to parous women having breastfed for total durations of <=12 months. METHODS: We estimated the population attributable fraction (PAF) of breast cancers (the only cancer site with convincing evidence of causal association) associated with women breastfeeding for <=12 months in total, using standard formulae incorporating breastfeeding prevalence data, relative risks associated with breastfeeding and cancer incidence. We also estimated the proportion change in disease incidence (potential impact fraction [PIF]) that might have occurred under two hypothetical scenarios of women breastfeeding for longer durations. RESULTS: An estimated 235 (1.7%) breast cancer cases that occurred in Australian in 2010 could be attributed to women breastfeeding for total durations of <=12 months. Assuming a hypothetical increase in breastfeeding, we estimated that the number of breast cancers prevented would range from 36 to 51 (prevented fraction = 0.3% to 0.4%). CONCLUSIONS: More than 200 breast cancers were attributable to women breastfeeding for total durations of <=12 months. IMPLICATIONS: Policies to increase breastfeeding duration may help prevent breast cancers in the future. PMID- 26437726 TI - Cancers in Australia in 2010 attributable to inadequate consumption of fruit, non starchy vegetables and dietary fibre. AB - OBJECTIVES: To estimate the number and proportion of cancers occurring in Australia in 2010 attributable to consumption deficits in fruit, non-starchy vegetables and dietary fibre. METHODS: We estimated the population attributable fraction (PAF) for cancers causally associated with inadequate intake of fruit and non-starchy vegetables (oral cavity, pharynx, oesophageal squamous cell carcinoma, stomach, larynx); inadequate intake of fruit (lung); and insufficient intake of fibre (colorectum). We used standard formulae incorporating prevalence of exposure (1995 National Nutrition Survey) and relative risks from independent studies. RESULTS: Overall, 1,555 (1.4% of all) and 311 (0.3% of all) cancers were attributable to inadequate intakes of fruit and non-starchy vegetables, respectively. A further 2,609 colorectal cancers (18% of colorectal) were attributable to insufficient fibre intake. If Australians increased their fibre intake by eating the recommended daily intakes of fruit and vegetables, an estimated 1,293 (8.8%) colorectal cancers could be prevented. CONCLUSIONS: One in six colorectal cancer cases was attributable to inadequate intake of dietary fibre and about 1,800 cancers at other sites were attributable to insufficient fruit and non-starchy vegetable consumption. IMPLICATIONS: Increasing the proportion of Australians who consume the recommended intake of fruit, vegetables and fibre could prevent up to 4% of all cancers. PMID- 26437727 TI - Cancers in Australia in 2010 attributable to the consumption of red and processed meat. AB - OBJECTIVES: To estimate the proportion and numbers of cancers in Australia in 2010 attributable to consuming red/processed meat. METHODS: We estimated the population attributable fraction (PAF) for cancers causally associated with red/processed meat consumption (colon, rectum) using standard formulae incorporating prevalence of consumption (1995 National Nutrition Survey), relative risks associated with consumption and cancer incidence. We also estimated the proportion change in cancer incidence (potential impact fraction [PIF]) that might have occurred under two hypothetical interventions whereby Australian adults reduced their consumption of red/processed meat from prevailing levels to <=100 g or <=65 g per day, respectively. RESULTS: An estimated 2,614 cases (18%) of colorectal cancer occurring in Australians in 2010 were attributable to red/processed meat consumption (16% of colon cancers; 23% of rectal cancers). We estimated that if all Australian adults had consumed <=65 g/day or <=100 g/day of red/processed meat, then the incidence of colorectal cancer would have been 5.4% (798 cancers) or 1.4% (204 cancers) lower, respectively. CONCLUSIONS: About one in six colorectal cancers in Australians in 2010 were attributable to red/processed meat consumption. IMPLICATIONS: Reducing red/processed meat intake may reduce colorectal cancer incidence, but must be balanced against nutritional benefits of modest lean meat consumption. PMID- 26437728 TI - Cancers in Australia in 2010 attributable to and prevented by the use of menopausal hormone therapy. AB - OBJECTIVES: To estimate the proportion and number of cancers occurring in Australia in 2010 attributable to menopausal hormone therapy (MHT) use. METHODS: We estimated the population attributable fraction for cancers causally associated with MHT (breast, endometrium, ovary), and the proportion of colorectal cancers prevented by MHT. We used standard formulae incorporating Australian prevalence data, relative risks of cancer associated with MHT and cancer incidence. We also estimated potential change in cancer incidence under two hypothetical scenarios whereby 25% fewer Australian women used MHT, or women exclusively used oestrogen only MHT. RESULTS: An estimated 539 cancers in Australia in 2010 were attributable to MHT: 453 breast, 67 endometrial and 19 ovarian cancers equating to 3.4%, 3.1% and 1.6% of each cancer type, respectively. In contrast, MHT may have prevented 52 colorectal cancers. If 25% fewer women used MHT, then 141 cancers may have been avoided. If women exclusively used oestrogen-only MHT then 240 cancers may have been avoided. CONCLUSIONS: MHT use caused more than 500 cancers in Australian women in 2010 and prevented ~50 colorectal cancers. IMPLICATIONS: MHT use continues to cause an excess of cancers. The risks, benefits, regimen and treatment duration should be carefully considered for each woman before MHT is commenced. PMID- 26437729 TI - Cancers in Australia in 2010 attributable to and prevented by the use of combined oral contraceptives. AB - OBJECTIVES: To estimate the proportion and number of cancers occurring in Australia in 2010 attributable to combined oral contraceptive pill (OCP) use. METHODS: We estimated the population attributable fraction (PAF) for cancers causally associated with combined OCP use (breast, cervix), and the proportion of endometrial and ovarian cancers prevented (prevented fraction [PF]). We used standard formulae incorporating prevalence of combined OCP use in the Australian population, relative risks of cancer associated with this exposure and cancer incidence. RESULTS: An estimated 105 breast and 52 cervical cancers (0.7% and 6.4% of each cancer, respectively) in Australia in 2010 were attributable to current use of combined OCP. Past combined OCP use was estimated to have prevented 1,032 endometrial and 308 ovarian cancers in 2010, reducing the number of cancers that would otherwise have occurred by 31% and 19%, respectively. CONCLUSIONS: A small proportion of breast and cervical cancers is attributable to combined OCP use; OCP use is likely to have prevented larger numbers of endometrial and ovarian cancers. IMPLICATIONS: Women seeking contraceptive advice should be told of potential adverse effects, but should also be told that - along with reproductive health benefits - combined OCP use can reduce long-term risks of ovarian and endometrial cancers. PMID- 26437730 TI - Cancers in Australia in 2010 attributable to infectious agents. AB - OBJECTIVES: To estimate the proportion and numbers of cancers in Australia in 2010 attributable to infectious agents. METHODS: The population attributable fraction (PAF) and number of cancers caused by hepatitis B and C viruses (HBV, HCV), Helicobacter pylori and human immunodeficiency virus (HIV) were calculated using standard formulae incorporating prevalence of infection in the Australian population, the relative risks associated with that infection and cancer incidence. For cancers with very strong associations to the infectious agent (Epstein-Barr virus [EBV], human papillomavirus [HPV] and HIV/Kaposi's sarcoma herpes virus [KSHV]), calculations were based on viral prevalence in the tumour. RESULTS: An estimated 3,421 cancers (2.9% of all cancers) in Australia in 2010 were attributable to infections. Infectious agents causing the largest numbers of cancers were HPV (n=1,706), H. pylori (n=793) and HBV/HCV (n=518). Cancer sites with the greatest number of cancers caused by infections were cervix (n=818), stomach (n=694) and liver (n=483). Cancers with highest proportions attributable to infectious agents were Kaposi's sarcoma (100%), cervix (100%), nasopharynx (87%), anus (84%) and vagina (70%). CONCLUSIONS: Infectious agents cause more than 3,000 cancers annually in Australia. IMPLICATIONS: Opportunities for cancer prevention through infection control are considerable, even in a 'first world' nation like Australia. PMID- 26437731 TI - Cancers in Australia in 2010 attributable to overweight and obesity. AB - OBJECTIVES: To estimate the proportion and number of cancers occurring in Australia in 2010 attributable to overweight/obesity. METHODS: We estimated the population attributable fraction (PAF) and number of cancers causally associated with overweight/obesity. We used standard formulae incorporating Australian prevalence data for body mass index (BMI), relative risks associated with BMI and cancer. We also estimated the proportion change in cancer incidence (potential impact fraction [PIF]) that may have occurred assuming that the prevalence of overweight/obesity had remained at 1990 levels. RESULTS: An estimated 3,917 cancer cases (3.4% of all cancers) diagnosed in 2010 were attributable to overweight/obesity, including 1,101 colon cancers, 971 female post-menopausal breast cancers and 595 endometrial cancers (PAFs of 10%, 8% and 26%, respectively). Highest PAFs were observed for oesophageal adenocarcinoma (31%), endometrial cancer (26%) and kidney cancer (19%). If the prevalence of overweight/obesity in Australia had remained at levels prevailing in 1990, we estimate there would have been 820 fewer cancers diagnosed in 2010 (PIF 2%). CONCLUSIONS: Overweight/obesity causes a substantial number of cancers in Australia. IMPLICATIONS: Public health strategies to reduce the prevalence of overweight and obesity will reduce the incidence of cancer, particularly of the colon, breast and endometrium. PMID- 26437732 TI - Cancers in Australia in 2010 attributable to insufficient physical activity. AB - OBJECTIVES: To estimate the proportion and numbers of cancers occurring in Australia in 2010 attributable to insufficient levels of physical activity. METHODS: We estimated the population attributable fraction (PAF) of cancers causally associated with insufficient physical activity (colon, post-menopausal breast and endometrium) using standard formulae incorporating prevalence of insufficient physical activity (<60 minutes at least 5 days/week), relative risks associated with physical activity and cancer incidence. We also estimated the proportion change in cancer incidence (potential impact fraction [PIF]) that may have occurred assuming that everyone with insufficient activity levels increased their exercise by 30 minutes/week. RESULTS: An estimated 1,814 cases of colon, post-menopausal breast and endometrial cancer were attributable to insufficient levels of physical activity: 707 (6.5%) colon; 971 (7.8%) post-menopausal breast; and 136 (6.0%) endometrial cancers. If those exercising below the recommended level had increased their activity level by 30 minutes/week, we estimate 314 fewer cancers (17% of those attributable to insufficient physical activity) would have occurred in 2010. CONCLUSIONS: More than 1,500 cancers were attributable to insufficient levels of physical activity in the Australian population. IMPLICATIONS: Increasing the proportion of Australians who exercise could reduce the incidence of several common cancers. PMID- 26437733 TI - Cancers in Australia in 2010 attributable to tobacco smoke. AB - OBJECTIVES: To estimate the population attributable fraction (PAF) and numbers of cancers occurring in Australia in 2010 attributable to tobacco smoking, both personal and by a partner. METHODS: We used a modified Peto-Lopez approach to calculate the difference between the number of lung cancer cases observed and the number expected assuming the entire population developed lung cancer at the same rate as never smokers. For cancers other than lung, we applied the standard PAF formula using relative risks from a large cohort and derived notional smoking prevalence. To estimate the PAF for partners' smoking, we used the standard formula incorporating the proportion of non-smoking Australians living with an ever-smoking partner and relative risks associated with partner smoking. RESULTS: An estimated 15,525 (13%) cancers in Australia in 2010 were attributable to tobacco smoke, including 8,324 (81%) lung, 1,973 (59%) oral cavity and pharynx, 855 (60%) oesophagus and 951 (6%) colorectal cancers. Of these, 136 lung cancers in non-smokers were attributable to partner tobacco smoke. CONCLUSIONS: More than one in eight cancers in Australia is attributable to tobacco smoking and would be avoided if nobody smoked. IMPLICATIONS: Strategies to reduce the prevalence of smoking remain a high priority for cancer control. PMID- 26437734 TI - Cancers in Australia attributable to exposure to solar ultraviolet radiation and prevented by regular sunscreen use. AB - OBJECTIVES: To estimate the proportion and numbers of cancers occurring in Australia attributable to solar ultraviolet radiation (UVR) and the proportion and numbers prevented by regular sun protection factor (SPF) 15+ sunscreen use. METHODS: We estimated the population attributable fraction (PAF) and numbers of melanomas and keratinocyte cancers (i.e. basal cell carcinomas and squamous cell carcinomas) due to exposure to ambient UVR resulting from residing in Australia versus residing in the UK (for melanoma) or Scandinavia (for keratinocyte cancers). We also estimated the prevented fraction (PF): the proportion of cancers that would have occurred but were likely prevented by regular sunscreen use. RESULTS: An estimated 7,220 melanomas (PAF 63%) and essentially all keratinocyte cancers occurring in Australia were attributable to high ambient UVR levels in Australia. We estimated that regular sunscreen use prevented around 14,190 (PF 9.3%) and 1,730 (PF 14%) people from developing SCC and melanoma, respectively. CONCLUSIONS: Although our approach was conservative, a high proportion of skin cancers in Australia are attributable to high ambient levels of UVR. Prevailing levels of sunscreen use probably reduced skin cancer incidence by 10-15%. IMPLICATIONS: Most skin cancers are preventable. Sunscreen should be a component of a comprehensive sun protection strategy. PMID- 26437736 TI - Addendum. AB - Swinburn B, Moore M. Urgently needed: voices for integrity in public policy making. Aust NZ J Public Health 2014;38:505.It has been brought to our attention that following the publication of this Editorial, the Office of the Auditor General investigated and found no conflict of interest between Katherine Rich's role as a member of the board of the Health Promotion Agency and her role as chief executive of the New Zealand Food & Grocery Council. PMID- 26437737 TI - New GP contract will replace targets with seven day working. PMID- 26437735 TI - Cancers in Australia in 2010 attributable to modifiable factors: summary and conclusions. AB - OBJECTIVE: To estimate the numbers and proportions of cancers occurring in Australia in 2010 attributable to modifiable causal factors. METHODS: We estimated the population attributable fraction (PAF) of cancers associated with exposure to 13 causal factors using standard formulae incorporating exposure prevalence and relative risk data. We also calculated the potential impact of changing exposure to some factors. RESULTS: A total of 32% of all cancers diagnosed in Australia in 2010 (excluding keratinocyte cancers) were attributable to the 13 factors assessed (men 33%; women 31%). Leading factors were tobacco smoke (PAF all cancers: 13.4%), solar radiation (6.2%), inadequate diet (6.1%) and overweight/obesity (3.4%). Factors conferring highest PAFs differed by sex: highest PAFs for men were tobacco smoke (15.8%), solar radiation (7.1%) and alcohol (3.0%); while highest PAFs for women were tobacco smoke (10.1%), solar radiation (5.0%) and overweight/obesity (4.5%). Sites with the highest counts of potentially preventable cancers were lung (8,569), colorectal (7,404), melanoma of the skin (7,220) and breast (3,233). CONCLUSIONS: At least one in three cancers in Australia is attributable to exposure to known modifiable factors. IMPLICATIONS: Up to 37,000 cancers could be prevented in Australia each year if the population avoided exposure to 13 common factors known or strongly suspected to cause cancer. PMID- 26437738 TI - Rational design of nanomaterials for water treatment. AB - The ever-increasing human demand for safe and clean water is gradually pushing conventional water treatment technologies to their limits. It is now a popular perception that the solutions to the existing and future water challenges will hinge upon further developments in nanomaterial sciences. The concept of rational design emphasizes on 'design-for-purpose' and it necessitates a scientifically clear problem definition to initiate the nanomaterial design. The field of rational design of nanomaterials for water treatment has experienced a significant growth in the past decade and is poised to make its contribution in creating advanced next-generation water treatment technologies in the years to come. Within the water treatment context, this review offers a comprehensive and in-depth overview of the latest progress in rational design, synthesis and applications of nanomaterials in adsorption, chemical oxidation and reduction reactions, membrane-based separation, oil-water separation, and synergistic multifunctional all-in-one nanomaterials/nanodevices. Special attention is paid to the chemical concepts related to nanomaterial design throughout the review. PMID- 26437739 TI - Deep Learning for Drug-Induced Liver Injury. AB - Drug-induced liver injury (DILI) has been the single most frequent cause of safety-related drug marketing withdrawals for the past 50 years. Recently, deep learning (DL) has been successfully applied in many fields due to its exceptional and automatic learning ability. In this study, DILI prediction models were developed using DL architectures, and the best model trained on 475 drugs predicted an external validation set of 198 drugs with an accuracy of 86.9%, sensitivity of 82.5%, specificity of 92.9%, and area under the curve of 0.955, which is better than the performance of previously described DILI prediction models. Furthermore, with deep analysis, we also identified important molecular features that are related to DILI. Such DL models could improve the prediction of DILI risk in humans. The DL DILI prediction models are freely available at http://www.repharma.cn/DILIserver/DILI_home.php. PMID- 26437740 TI - A study on the association between serum amyloid A and sperm concentration. AB - Our aim was to compare peripheral blood and seminal fluid serum amyloid A (SAA) protein levels in men classified on the basis of sperm concentration and investigate whether SAA protein is an important marker of male infertility. A total of 74 first-attempt IVF male partners of infertile couples classified as azoospermic (n = 25), oligozoospermic (n = 25) and normozoospermic group (n = 24) were recruited for this cross-sectional study. There was no difference with respect to age, BMI, infertility period and smoking ratio. No difference in haematologic parameters including white blood cell count, neutrophil ratio, lymphocyte ratio, neutrophil-to-lymphocyte ratio and blood SAA level was found between the groups. Seminal fluid SAA level was 17.85 +/- 2.21 ng ml(-1) in azoospermics, 16.13 +/- 3.58 ng ml(-1) in oligozoospermics and 15.67 +/- 4.77 ng ml(-1) in normozoospermics, showing no significant difference. Seminal SAA level was found to be not correlated with blood SAA levels. Therefore, we could not find any associations between these parameters at all. However, further studies with more participants are needed to address the exact action of SAA on spermatogenesis. PMID- 26437741 TI - Assessment of gene expression levels of proopiomelanocortin (POMC) and melanocortin-1 receptor (MC1R) in vitiligo. AB - Proopiomelanocortin (POMC) and melanocortin 1 receptor (MC1R) are regulators of melanogenesis and pigmentation. Our objective was to estimate their levels, searching for a possible role of the melanocortin system in vitiligo. This study included 40 vitiligo patients and 40 controls. Skin biopsies were taken from lesional and non-lesional skin of patients and from the non-sun exposed skin of controls to detect the expression of POMC and MC1R using quantitative real-time polymerase chain reaction. Both factors were significantly lower in lesional than non-lesional skin and controls, while they were significantly higher in non lesional skin than in controls. There was a statistically significant positive correlation between lesional levels of POMC and MC1R, as well as between non lesional levels of POMC and MC1R in the patients. On the other hand, we found a statistically significant negative correlation between the lesional and non lesional levels of POMC, as well as between the lesional and non-lesional levels of MC1R in the patients. As a conclusion, the melanocortin system could play a role in the pathogenesis of vitiligo or could be affected as the end result of the disease. PMID- 26437742 TI - Diagnosing appendicitis: What works, what does not and where to go from here? AB - Although acute appendicitis is the most common reason for emergency abdominal surgery in children, diagnosis is far from straightforward. Delays in diagnosis can result in significant complications, whereas over-diagnosis can result in costly inter-hospital transfers and unnecessary surgery. This article aims to describe current evidence-based assessment of children with possible appendicitis presenting to the emergency department. We provide an overview of the literature relating to the various available diagnostic approaches, including the application of history, examination, pathology tests, imaging, and clinical decision rules. PMID- 26437743 TI - CSL regulates AKT to mediate androgen independence in prostate cancer progression. AB - BACKGROUND: Aberrant signaling pathways leads to cancer initiation and progression. Both Notch and PI3K/AKT signaling pathways are believed to be involved in prostate cancer. How the interaction between the two pathways contributes to prostate cancer progression to androgen independence is still elusive. METHODS: Prostate cancer cells were grown in RPMI 1,640 supplemented with 10% heat-inactivated fetal bovine serum (FBS) or 10% charcoal-stripped heat inactivated fetal bovine serum (FCS), 1% penicillin-streptomycin in 75 cm2 polystyrene flasks, and maintained at 37 degrees C in a humidified atmosphere with 5% CO2 . Cell proliferation, invasion were performed with cell counting, matrigel assay in vitro. Dual luciferase assays were performed using reporter plasmids with ARE (Androgen Response Element, ARE). RNA interference was applied to gene silence. Tumorigenicity of cancer cells was evaluated by mouse xenograft in vivo. RESULTS: A subpopulation of casodex resistant prostate cancer cells were identified with an overexpressed androgen receptor (AR) and aggressive phenotypes, characterized with high proliferation, invasion in vitro and enhanced tumorigenesis in vivo. Gene profiling for androgen-dependent LNCaP and androgen independent LNCaP-CR revealed that both CSL and AKT gave the similar expressional pattern upon casodex treatment. Immunoblot demonstrated that CSL and AKT were dramatically suppressed in androgen dependent LNCaP cells, but slightly inhibited in LNCaP-CR cells as well as other androgen independent prostate cancer cells. Further studies indicated that CSL regulates AKT, and subsequently AR in prostate cancer cells. AKT mediates casodex resistance and androgen independence through regulation of cyclin D1. CONCLUSION: CSL-AKT-AR axis might play an important role in prostate cancer progression. Targeting CSL depleted the casodex resistant population through inhibition of the AKT, suggesting a more effective therapeutic strategy for abrogating casodex resistance in advanced prostate cancer. PMID- 26437744 TI - Regiocomplementary O-Methylation of Catechols by Using Three-Enzyme Cascades. AB - S-Adenosylmethionine (SAM)-dependent enzymes have great potential for selective alkylation processes. In this study we investigated the regiocomplementary O methylation of catechols. Enzymatic methylation is often hampered by the need for a stoichiometric supply of SAM and the inhibitory effect of the SAM-derived byproduct on most methyltransferases. To counteract these issues we set up an enzyme cascade. Firstly, SAM was generated from l-methionine and ATP by use of an archaeal methionine adenosyltransferase. Secondly, 4-O-methylation of the substrates dopamine and dihydrocaffeic acid was achieved by use of SafC from the saframycin biosynthesis pathway in 40-70 % yield and high selectivity. The regiocomplementary 3-O-methylation was catalysed by catechol O-methyltransferase from rat. Thirdly, the beneficial influence of a nucleosidase on the overall conversion was demonstrated. The results of this study are important milestones on the pathway to catalytic SAM-dependent alkylation processes. PMID- 26437746 TI - The role of size polydispersity in magnetic fluid hyperthermia: average vs. local infra/over-heating effects. AB - An efficient and safe hyperthermia cancer treatment requires the accurate control of the heating performance of magnetic nanoparticles, which is directly related to their size. However, in any particle system the existence of some size polydispersity is experimentally unavoidable, which results in a different local heating output and consequently a different hyperthermia performance depending on the size of each particle. With the aim to shed some light on this significant issue, we have used a Monte Carlo technique to study the role of size polydispersity in heat dissipation at both the local (single particle) and global (macroscopic average) levels. We have systematically varied size polydispersity, temperature and interparticle dipolar interaction conditions, and evaluated local heating as a function of these parameters. Our results provide a simple guide on how to choose, for a given polydispersity degree, the more adequate average particle size so that the local variation in the released heat is kept within some limits that correspond to safety boundaries for the average-system hyperthermia performance. All together we believe that our results may help in the design of more effective magnetic hyperthermia applications. PMID- 26437745 TI - Thrombocytopenia and Cornelia de Lange syndrome: Still an enigma? AB - Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder caused by mutations in the cohesion complex and its regulators. The syndrome is characterized by multiple organ system abnormalities, pre- and post-natal growth retardation and typical facial features. Thrombocytopenia is a reduction in platelet count to <150 * 10(9) L. It can be caused by congenital or acquired decreased production, increased destruction, or sequestration of platelets. In recent years, several papers reported thrombocytopenia and immune thrombocytopenia in patients affected by CdLS. In 2011, Lambert et al. estimated the risk of idiopathic thrombocytopenia purpura in CdLS patients to be 31-633 times greater than in the general population. We describe the incidence of thrombocytopenia in 127 Italian CdLS patients, identifying patients with transient or persistent thrombocytopenia, but a lower incidence of true idiopathic thrombocytopenic purpura (ITP). PMID- 26437747 TI - Molecular Catalyst Immobilized Photocathodes for Water/Proton and Carbon Dioxide Reduction. AB - As one of the components in a tandem photoelectrochemical cell for solar-fuel production, the photocathode carries out the reduction reaction to convert solar light and the corresponding substrate (e.g., proton and CO2) into target fuels. Immobilizing molecular catalysts onto the photocathode is a promising strategy to enhance the interfacial electron/hole-transfer process and to improve the stability of the catalysts. Furthermore, the molecular catalysts are beneficial in improving the selectivity of the reduction reaction, particularly for CO2 reduction. On the photocathode, the binding mode of the catalysts and the arrangement between the photosensitizer and the catalyst also play crucial roles in the performance and stability of the final device. How to firmly and effectively immobilize the catalyst on the photoelectrode is now becoming a scientific question. Recent publications on molecular catalyst immobilized photocathodes are therefore surveyed. PMID- 26437748 TI - Stereospecific Pd-Catalyzed Intermolecular C(sp(3))-C(sp) Cross-Coupling of Diarylmethyl Carbonates and Terminal Alkynes Under Base-Free Conditions. AB - A palladium-catalyzed intermolecular decarboxylative C(sp(3))-C(sp) coupling of diarylmethyl carbonates and terminal alkynes has been developed. The reaction proceeds smoothly under external base-free conditions to deliver the corresponding alkynylated diarylmethanes with the liberation of CO2 and MeOH as the sole byproducts. Moreover, enantioenriched diarylmethyl carbonates are stereospecifically converted to optically active cross-coupling products with inversion of configuration. Thus, the stereospecific palladium catalysis can provide new and unique access to the alkynylated chiral tertiary stereocenters, which are relatively difficult to construct by conventional methods. PMID- 26437749 TI - Laboratory tests for disorders of complement and complement regulatory proteins. AB - The complement pathway is a cascade of proteases that is involved in immune surveillance and innate immunity, as well as adaptive immunity. Dysfunction of the complement cascade may be mediated by aberrations in the pathways of activation, complement regulatory proteins, or complement deficiencies, and has been linked to a number of hematologic disorders, including paroxysmal noctural hemoglobinuria (PNH), hereditary angioedema (HAE), and atypical hemolytic-uremic syndrome (aHUS). Here, current laboratory tests for disorders of the complement pathway are reviewed, and their utility and limitations in hematologic disorders and systemic diseases are discussed. Current therapeutic advances targeting the complement pathway in treatment of complement-mediated hematologic disorders are also reviewed. PMID- 26437750 TI - Consideration surrounding incidental findings throughout multigene panel testing in cancer genetics. PMID- 26437751 TI - Reactivity differences of Sc3N@C(2n) (2n = 68 and 80). Synthesis of the first methanofullerene derivatives of Sc3N@D(5h)-C80. AB - Using a purification method introduced earlier based on redox properties it was possible to isolate Sc3N@I(h)-C80 and Sc3N@D(3h)-C78 and a mixture of Sc3N@D(5h) C80 and Sc3N@D3-C68. Taking advantage of their chemical reactivity differences, Sc3N@D(5h)-C80 was isolated from Sc3N@D3-C68 followed by further functionalization, giving rise to five new methano-derivatives of Sc3N@D(5h)-C80. PMID- 26437752 TI - [Noma/Cancrum oris: a neglected disease]. AB - Noma is an aggressive orofacial gangrenous pathology that damages hard and soft tissues of the mouth and the face. Throughout the centuries it has been present around the globe, but nowadays it has practically disappeared from developed countries and mainly affects children from the most disadvantaged places, especially in Africa. Noma disease is a multifactorial process; malnutrition, debilitating diseases (bacterial or viral systemic diseases, HIV-associated immunosuppression, etc.) and intraoral infections are some of the factors implied. The characteristic tissue necrosis is produced by a polymicrobial infection. Fusobacterium necrophorum, Prevotella intermedia, Prevotella melaninogenica, Fusobacterium nucleatum, Bacteroides fragilis, Bacillus cereus, Trueperella pyogenes, spyrochetes, etc, are some of the species that have been isolated from the affected areas. Without treatment, noma is lethal in a short period of time, and the patients that survive show severe sequelae that hinder their life and interpersonal relationships. The aim of this paper is to unify the existing information and to promote wider knowledge and awareness among the population. PMID- 26437753 TI - [Boosted protease inhibitor monotherapy in HIV-infected patients: results of a study in a real life setting]. AB - BACKGROUND: Boosted protease inhibitor monotherapy may offer antiviral efficacy while reducing drug interactions, costs and toxicity. The aim of this study was to assess the efficacy of darunavir/ritonavir (DRV/r) and lopinavir/ritonavir (LPV/r) monotherapy in a real life setting. METHODS: A retrospective analysis of all HIV infected patients, who had initiated DRV/r or LPV/r monotherapy, was performed. Patients whose HIV viral load had remained undetectable for at least two consecutive follow-up visits and who had no neurocognitive disorder or hepatitis B co-infection, were included. RESULTS: Sixty patients were included. The median (IQR) time to follow-up was 66 (33-118) weeks. The proportions (CI95%) of patients with virological failure were 6.3% (1.7- 20.2) and 25.0% (12.7-43.4), respectively, in the DRV/r and LPV/r groups (p= 0.0424). The proportions (CI95%) of patients with therapeutic success were 90.6% (80.5-100) in the DRV/r group and 60.7% (42.6-78.8) in the LPV/r group (p=0.0063). No protease inhibitor mutations were detected. During the follow-up, 6 patients with dyslipidemia normalized their lipid values. The median monthly cost was 410 (IQR 242-416) euros per person lower for the monotherapy than for the combined antiretroviral therapy. CONCLUSIONS: Boosted protease inhibitor monotherapy was effective in a real life setting. This study showed differences in favour of DRV/r as compared with LPV/r in terms of therapeutic success; however prospective studies are needed to confirm these results. Finally, although this study was not specifically designed to detect benefits in terms of costs and lipid profile, it shows evidence of a positive impact of monotherapy in these fields. PMID- 26437754 TI - Vitek MS matrix-assisted laser desorption ionization-time of flight mass spectrometry for identifying respiratory bacterial pathogens: a fast and efficient method. AB - Mass spectrometry has become a reference resource for identifying microorganisms in clinical microbiology services. One hundred and fifty one clinical isolates were selected from respiratory specimens routinely identified as Streptococcus pneumoniae (43), Haemophilus influenzae (64) and Moraxella catarrhalis (44). These identifications were compared with other phenotypical methods and mass spectrometry (MALDI-TOF-MS Vitek). Result discrepancies were assessed by 16S rRNA sequencing. Thirty-eight of the 43 strains of S. pneumoniae (86%) were identified as such using phenotypical methods and spectrometry. In 5 cases, MALDI-TOF identified 4 of them as Streptococcus pseudopneumoniae and 1 as S. mitis/oralis. Forty-eight of the 64 strains were identified as H. influenzae (75%) using biochemical identification systems and automated identification systems, whereas MALDI-TOF-MS Vitek identified 51 strains (79%) as such. Conventional methods and spectrometry identified all the 40 strains tested (100%) as M. catarrhalis. All strains with discrepant results were sequenced, and in all cases, the identification obtained by spectrometry was confirmed. The results obtained in this study show that mass spectrometry provides identification of these bacteria faster and in a more reliable way than those based on conventional phenotypical methods. PMID- 26437755 TI - A two-hour procedure for determining the susceptibility of enterococci and staphylococci to antibiotics by a colourimetric method. AB - INTRODUCTION: Rapid determination of the antibiotic susceptibility test in bacteria remains a challenge for Clinical Microbiology laboratories. METHODS: An improvement in the colorimetric antimicrobial susceptibility testing performed with resazurin in enterococci and staphylococci has been carried out. The design of method was performed using two collection strains, which have a known susceptibility. This procedure was then validated against standard commercial methods on 15 strains of staphylococci and 15 strains of enterococci from patients. RESULTS: The essential agreement between the colorimetric method and commercial methods (E-test, MicroScan and VITEK2) was 100%. CONCLUSION: Resazurin allows us to obtain a reliable antibiotic susceptibility test in staphylococci and enterococci in less than two hours. PMID- 26437756 TI - [Bacteraemia due to extended-spectrum beta-lactamases (ESBL) and other beta lactamases (ampC and carbapenemase) producing Enterobacteriaceae: association with health-care and cancer]. AB - INTRODUCTION: Bloodstream infections due to multire-sistant Enterobacteriaceae are a major matter of concern nowadays. The present study evaluated the impact of these infections in our area. METHODS: Prospective observational study of a cohort of patients with bacteraemia due to extended-spectrum beta-lactamases (ESBL) and other beta-lactamases producing organisms among hospitalized patients in Cruces Hospital for 2 years. We conducted a descriptive analysis, a subgroup analysis (cancer vs. non-cancer patients) and a mortality analysis. RESULTS: During the study period, 3409 episodes of bacteraemia were diagnosed, of which 124 (3.6%) were ESBL and other beta-lactamases producing Enterobacteriaceae. 40.3% of the cases were nosocomial, 15.3% community acquired and 44.4% were health-care associated. 44.4% of the cohort had cancer as underlying disease. The most commonly isolated organism was E. coli (83% of cases), regardless of the source of infection. 58.1% of patients received inadequate empirical therapy. 7 day-mortality was 10.5% and 30 day-mortality was 21.8%. None of the analyzed variables showed association with 7 and 14 day-mortality, but the presence of solid cancer (p= 0.032) and advanced HIV infection (p = 0.027), were significantly associated with higher 30 day-mortality. CONCLUSIONS: More than half of bacteraemia episodes affected outpatients and most of them were health care associated episodes. Even though more than half of the patients received inadequate empirical treatment, this was not related to higher mortality. We only found an association between 30 day-mortality and the presence of underlying solid malignancy or advanced HIV infection. PMID- 26437757 TI - [Evaluation of antibiotic resistance of Escherichia coli in urinary tract infections in Primary Care Barbastro Sector (Huesca)]. AB - OBJECTIVES: Evaluate the resistance of community-uropathogen, Escherichia coli to several antibiotics in our health sector and deduce empirical treatment options. METHODS: E. coli strains isolated from urine cultures of patients from Primary Care Barbastro Sector, between January 2011 and December 2013, were studied. The resistances rates for nine common antibiotics were determined, and differences in sensitivity were analyzed, comparing confidence intervals for proportions by the method of Wilson. RESULTS: E. coli was the most frequently isolated bacteria (61.08% of positive urine cultures sent from Primary Care). Overall, there has been an increase in resistance of E. coli isolates in all antimicrobials studied. Still, resistance has remained below 4% compared to fosfomycin and nitrofurantoin and below 10% in cephalosporins second and third generation. Resistance to amoxicillin-clavulanate has increased progressively reaching 21.5% in 2013; only this antibiotic has presented a statistically significant increase. The maximum levels of resistance (over 30%) were found in the antibiotics administered orally and often indicated in uncomplicated urinary tract infections: trimethoprim sulfamethoxazole, ciprofloxacin and ampicillin. CONCLUSIONS: Update knowledge susceptibility patterns of microorganisms most commonly isolated in urine samples in each health area allows to choose the most suitable and effective treatments trough empirical knowledge. PMID- 26437758 TI - [Carotid mycotic pseudoaneurysm. Case report and review]. PMID- 26437759 TI - [Bacteraemia by Staphylococcus aureus from respiratory origin and mortality]. PMID- 26437760 TI - [Yersinia pseudotuberculosis septicemia. Case report]. PMID- 26437762 TI - Consensus statement: patient safety, healthcare-associated infections and hospital environmental surfaces. AB - Healthcare-associated infections have serious implications for both patients and hospitals. Environmental surface contamination is the key to transmission of nosocomial pathogens. Routine manual cleaning and disinfection eliminates visible soil and reduces environmental bioburden and risk of transmission, but may not address some surface contamination. Automated area decontamination technologies achieve more consistent and pervasive disinfection than manual methods, but it is challenging to demonstrate their efficacy within a randomized trial of the multiple interventions required to reduce healthcare-associated infection rates. Until data from multicenter observational studies are available, automated area decontamination technologies should be an adjunct to manual cleaning and disinfection within a total, multi-layered system and risk-based approach designed to control environmental pathogens and promote patient safety. PMID- 26437763 TI - Yield Point of Semiconducting Polymer Films on Stretchable Substrates Determined by Onset of Buckling. AB - Mechanical buckling of thin films on elastomeric substrates is often used to determine the mechanical properties of polymers whose scarcity precludes obtaining a stress-strain curve. Although the modulus and crack-onset strain can readily be obtained by such film-on-elastomer systems, information critical to the development of flexible, stretchable, and mechanically robust electronics (i.e., the range of strains over which the material exhibits elastic behavior) cannot be measured easily. This paper describes a new technique called laser determination of yield point (LADYP), in which a polymer film on an elastic substrate is subjected to cycles of tensile strain that incrementally increase in steps of 1% (i.e., 0% -> 1% -> 0% -> 2% -> 0% -> 3% -> 0%, etc.). The formation of buckles manifests as a diffraction pattern obtained using a laser, and represents the onset of plastic deformation, or the yield point of the polymer. In the series of conjugated polymers poly(3-alkylthiophene), where the alkyl chain is pentyl, hexyl, heptyl, octyl, and dodecyl, the yield point is found to increase with increasing length of the side chain (from approximately 5% to 15% over this range when holding the thickness between ~200 and 300 nm). A skin-depth effect is observed in which films of <150 nm thickness exhibit substantially greater yield points, up to 40% for poly(3-dodecylthiophene). Along with the tensile modulus obtained by the conventional analysis of the buckling instability, knowledge of the yield point allows one to calculate the modulus of resilience. Combined with knowledge of the crack-onset strain, one can estimate the total energy absorbed by the film (i.e., the modulus of toughness). PMID- 26437761 TI - Sodium nitrate alleviates functional muscle ischaemia in patients with Becker muscular dystrophy. AB - Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. BMD is caused by in-frame mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the sarcolemma. Among these is neuronal nitric oxide synthase mu (nNOSMU), which requires specific spectrin-like repeats (SR16/17) in dystrophin's rod domain and the adaptor protein alpha-syntrophin for sarcolemmal targeting. When healthy skeletal muscle is exercised, sarcolemmal nNOSMU-derived nitric oxide (NO) attenuates alpha-adrenergic vasoconstriction, thus optimizing perfusion. In the mdx mouse model of dystrophinopathy, this protective mechanism (functional sympatholysis) is defective, resulting in functional muscle ischaemia. Treatment with a NO-donating non-steroidal anti-inflammatory drug (NSAID) alleviates this ischaemia and improves the murine dystrophic phenotype. In the present study, we report that, in 13 men with BMD, sympatholysis is defective mainly in patients whose mutations disrupt sarcolemmal targeting of nNOSMU, with the vasoconstrictor response measured as a decrease in muscle oxygenation (near infrared spectroscopy) to reflex sympathetic activation. Then, in a single-arm, open-label trial in 11 BMD patients and a double-blind, placebo controlled cross-over trial in six patients, we show that acute treatment with oral sodium nitrate, an inorganic NO donor without a NSIAD moiety, restores sympatholysis and improves post-exercise hyperaemia (Doppler ultrasound). By contrast, sodium nitrate improves neither sympatholysis, nor hyperaemia in healthy controls. Thus, a simple NO donor recapitulates the vasoregulatory actions of sarcolemmal nNOS in BMD patients, and constitutes a putative novel therapy for this disease. PMID- 26437764 TI - Diverting Hydrogenations with Wilkinson's Catalyst towards Highly Reactive Rhodium(I) Species. AB - The addition of Barton's base has a dramatic effect on the classic rhodium(III) mediated hydrogenations promoted by Wilkinson's catalyst. Following the initial oxidative addition, a barrierless reductive elimination of HCl from the traditional rhodium(III) intermediates instantly produces a rhodium(I) monohydride species, which is remarkably reactive in the hydrogenation of several internal alkynes and functionalized trisubstituted alkenes. The direct formation of this species is unprecedented upon addition of molecular hydrogen and its catalytic potential has been hitherto barely explored. PMID- 26437766 TI - SCExV: a webtool for the analysis and visualisation of single cell qRT-PCR data. AB - BACKGROUND: Single cell gene expression assays have become a powerful tool with which to dissect heterogeneous populations. While methods and software exist to interrogate such data, what has been lacking is a unified solution combining analysis and visualisation which is also accessible and intuitive for use by non bioinformaticians, as well as bioinformaticians. RESULTS: We present the Single cell expression visualiser (SCExV), a webtool developed to expedite the analysis of single cell qRT-PCR data. SCExV is able to take any data matrix of Ct values as an input, but can handle files exported by the Fluidigm Biomark platform directly. In addition, SCExV also accepts and automatically integrates cell surface marker intensity values which are measured during index sorting. This allows the user to directly visualise relationships between a single cell gene expression profile and the immunophenotype of the interrogated cell. CONCLUSIONS: SCExV is a freely available webtool created to import, filter, analyse, and visualise single cell gene expression data whilst being able to simultaneously consider cellular immunophenotype. SCExV is designed to be intuitive to use whilst maintaining advanced functionality and flexibility in how analyses are performed. PMID- 26437765 TI - Angiogenesis related genes NOS3, CD14, MMP3 and IL4R are associated to VEGF gene expression and circulating levels in healthy adults. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis. The aim was to assess the genetic connections between the angiogenesis-related NOS3, CD14, MMP3, IL4R, IL4 genes and VEGF expression and plasma levels. METHODS: The associations between VEGF plasma levels with the polymorphisms of NOS3, CD14, MMP3, IL4R, and IL4 were assessed in 403 healthy unrelated adults. The epistatic and environmental interactions were explored, including four VEGF-related polymorphisms previously identified. The VEGF expression in peripheral blood mononuclear cells was quantified (n = 65) for the VEGF121, VEGF145, VEGF165, and VEGF189 isoforms. RESULTS: The polymorphism rs1799983 of NOS3 was associated with the sum of all VEGF isoforms mRNA levels (P = 0.032) and VEGF145 (P = 0.033). Rs1800779 of NOS3 interacted with rs3918226 of the same gene and with the rs2569190 of CD14 (P = 0.022, P = 0.042, respectively) for VEGF plasma levels. Other epistatic interactions included the rs1801275 of IL4R with the rs6921438 (VEGF-related variant) and rs3025058 of MMP3 (P = 0.042, P = 0.010 respectively) and the rs2569190 of CD14 with the rs3025058 of MMP3 (P = 0.0119). We also identified an interaction of rs1800779 with obesity, high density lipoprotein cholesterol and triglycerides (P = 0.018, P = 0.005, P = 0.043, respectively) as well as the interaction of rs6921438 with hypertension (P = 0.028). CONCLUSIONS: Our findings indicated that genetic variants of NOS3, CD14, MMP3 and IL4R are implicated in the determination of VEGF expression and plasma levels. Thus, they support the hypothesis that in physiological conditions there are complex biological relationships between pathways (such as angiogenesis and inflammation), which are involved in the development of chronic diseases. PMID- 26437767 TI - Epilepsy is a possible feature in Williams-Beuren syndrome patients harboring typical deletions of the 7q11.23 critical region. AB - Seizures are rarely reported in Williams-Beuren syndrome (WBS)--a contiguous-gene deletion disorder caused by a 7q11.23 heterozygous deletion of 1.5-1.8 Mb--and no previous study evaluated electro-clinical features of epilepsy in this syndrome. Furthermore, it has been hypothesized that atypical deletion (e.g., larger than 1.8 Mb) may be responsible for a more pronounced neurological phenotypes, especially including seizures. Our objectives are to describe the electro clinical features in WBS and to correlate the epileptic phenotype with deletion of the 7q11.23 critical region. We evaluate the electro-clinical features in one case of distal 7q11.23 deletion syndrome and in eight epileptic WBS (eWBS) patients. Additionally, we compare the deletion size-and deleted genes-of four epileptic WBS (eWBS) with that of four non-epileptic WBS (neWBS) patients. Infantile spasms, focal (e.g., motor and dyscognitive with autonomic features) and generalized (e.g., tonic-clonic, tonic, clonic, myoclonic) seizures were encountered. Drug-resistance was observed in one patient. Neuroimaging discovered one case of focal cortical dysplasia, one case of fronto-temporal cortical atrophy and one case of periventricular nodular heterotopia. Comparison of deletion size between eWBS and neWBS patients did not reveal candidate genes potentially underlying epilepsy. This is the largest series describing electro clinical features of epilepsy in WBS. In WBS, epilepsy should be considered both in case of typical and atypical deletions, which do not involve HIP1, YWHAG or MAGI2. PMID- 26437768 TI - Drosophila innate immunity: regional and functional specialization of prophenoloxidases. AB - BACKGROUND: The diversification of immune systems during evolution involves the expansion of particular gene families in given phyla. A better understanding of the metazoan immune system requires an analysis of the logic underlying such immune gene amplification. This analysis is now within reach due to the ease with which we can generate multiple mutations in an organism. In this paper, we analyze the contribution of the three Drosophila prophenoloxidases (PPOs) to host defense by generating single, double and triple mutants. PPOs are enzymes that catalyze the production of melanin at the site of infection and around parasites. They are the rate-limiting enzymes that contribute to the melanization reaction, a major immune mechanism of arthropods. The number of PPO-encoding genes is variable among insects, ranging from one in the bee to ten in the mosquito. RESULTS: By analyzing mutations alone and in combination, we ascribe a specific function to each of the three PPOs of Drosophila. Our study confirms that two PPOs produced by crystal cells, PPO1 and PPO2, contribute to the bulk of melanization in the hemolymph, upon septic or clean injury. In contrast, PPO3, a PPO restricted to the D. melanogaster group, is expressed in lamellocytes and contributes to melanization during the encapsulation process. Interestingly, another overlapping set of PPOs, PPO2 and PPO3, achieve melanization of the capsule upon parasitoid wasp infection. CONCLUSIONS: The use of single or combined mutations allowed us to show that each PPO mutant has a specific phenotype, and that knocking out two of three genes is required to abolish fully a particular function. Thus, Drosophila PPOs have partially overlapping functions to optimize melanization in at least two conditions: following injury or during encapsulation. Since PPO3 is restricted to the D. melanogaster group, this suggests that production of PPO by lamellocytes emerged as a recent defense mechanism against parasitoid wasps. We conclude that differences in spatial localization, immediate or late availability, and mode of activation underlie the functional diversification of the three Drosophila PPOs, with each of them having non-redundant but overlapping functions. PMID- 26437769 TI - Pore-formation by adenylate cyclase toxoid activates dendritic cells to prime CD8+ and CD4+ T cells. AB - The adenylate cyclase toxin-hemolysin (CyaA) of Bordetella pertussis is a bi functional leukotoxin. It penetrates myeloid phagocytes expressing the complement receptor 3 and delivers into their cytosol its N-terminal adenylate cyclase enzyme domain (~400 residues). In parallel, ~1300 residue-long RTX hemolysin moiety of CyaA forms cation-selective pores and permeabilizes target cell membrane for efflux of cytosolic potassium ions. The non-enzymatic CyaA-AC(-) toxoid, has repeatedly been successfully exploited as an antigen delivery tool for stimulation of adaptive T-cell immune responses. We show that the pore forming activity confers on the CyaA-AC(-) toxoid a capacity to trigger Toll-like receptor and inflammasome signaling-independent maturation of CD11b-expressing dendritic cells (DC). The DC maturation-inducing potency of mutant toxoid variants in vitro reflected their specifically enhanced or reduced pore-forming activity and K(+) efflux. The toxoid-induced in vitro phenotypic maturation of DC involved the activity of mitogen activated protein kinases p38 and JNK and comprised increased expression of maturation markers, interleukin 6, chemokines KC and LIX and granulocyte-colony-stimulating factor secretion, prostaglandin E2 production and enhancement of chemotactic migration of DC. Moreover, i.v. injected toxoids induced maturation of splenic DC in function of their cell permeabilizing capacity. Similarly, the capacity of DC to stimulate CD8(+) and CD4(+) T-cell responses in vitro and in vivo was dependent on the pore-forming activity of CyaA-AC(-). This reveals a novel self-adjuvanting capacity of the CyaA-AC(-) toxoid that is currently under clinical evaluation as a tool for delivery of immunotherapeutic anti-cancer CD8(+) T-cell vaccines into DC. PMID- 26437770 TI - mTORC1 signaling is crucial for regulatory T cells to suppress macrophage mediated inflammatory response after acute myocardial infarction. AB - Post-infarction inflammatory response results in worse remodeling and dysfunction following myocardial infarction (MI). Supression of post-infarction inflammation would be a logical approach of alleviating post-infarction injury and promoting cardiac repair. In this study, we investigated the significance of mTORC1 signaling in the anti-inflammatory activity of regulatory T cells (Tregs) after MI. Using the murine MI model with wild type and Rag1(-/-) mice, we found that the mechanistic target of rapamycin compex 1 (mTORC1) signaling was upregulated in Tregs infiltrating into the infarcted myocardium, rather than in circulating Tregs after MI. The anti-inflammatory activity of infiltrating Tregs was significantly stronger than that of circulating Tregs. This was demonstrated by a higher expression of anti-inflammatory cytokines in the infiltrating Tregs and a robust suppression of proinflammatory cytokine production by macrophages. In an adoptive transfer analysis, compared with normal splenic Tregs, rapamycin-treated splenic Tregs ineffectively suppressed the post-infarction inflammatory response of infiltrating macrophages. In addition, in vitro cultured primary cardiomyocytes treated with mild oxygen glucose deprivation induced mTORC1 activation and a higher anti-inflammatory activity of Tregs in a coculture assay. Our study identified a new mechanism by which infiltrating Tregs subdue post infarction inflammation. Understanding and utilizing this information would be helpful for designing new therapeutic interventions for MI. PMID- 26437771 TI - Functional development of the adult ovine mammary gland--insights from gene expression profiling. AB - BACKGROUND: The mammary gland is a dynamic organ that undergoes dramatic physiological adaptations during the transition from late pregnancy to lactation. Investigation of the molecular basis of mammary development and function will provide fundamental insights into tissue remodelling as well as a better understanding of milk production and mammary disease. This is important to livestock production systems and human health. Here we use RNA-seq to identify differences in gene expression in the ovine mammary gland between late pregnancy and lactation. RESULTS: Between late pregnancy (135 days of gestation +/- 2.4 SD) and lactation (15 days post partum +/- 1.27 SD) 13 % of genes in the sheep genome were differentially expressed in the ovine mammary gland. In late pregnancy, cell proliferation, beta-oxidation of fatty acids and translation were identified as key biological processes. During lactation, high levels of milk fat synthesis were mirrored by enrichment of genes associated with fatty acid biosynthesis, transport and lipogenesis. Protein processing in the endoplasmic reticulum was enriched during lactation, likely in support of active milk protein synthesis. Hormone and growth factor signalling and activation of signal transduction pathways, including the JAK-STAT and PPAR pathways, were also differently regulated, indicating key roles for these pathways in functional development of the ovine mammary gland. Changes in the expression of epigenetic regulators, particularly chromatin remodellers, indicate a possible role in coordinating the large-scale transcriptional changes that appear to be required to switch mammary processes from growth and development during late pregnancy to synthesis and secretion of milk during lactation. CONCLUSIONS: Coordinated transcriptional regulation of large numbers of genes is required to switch between mammary tissue establishment during late pregnancy, and activation and maintenance of milk production during lactation. Our findings indicate the remarkable plasticity of the mammary gland, and the coordinated regulation of multiple genes and pathways to begin milk production. Genes and pathways identified by the present study may be important for managing milk production and mammary development, and may inform studies of diseases affecting the mammary gland. PMID- 26437772 TI - New users of antipsychotic medication: A population-based cohort study of occupational outcome measures in relation to antipsychotic on-label and off-label prescribing practices. AB - BACKGROUND: Treatment with antipsychotic medication is thoroughly investigated in schizophrenia and bipolar disorder but is also widely applied for a diversity of off-label conditions, despite an uncertain risk-benefit ratio. This study examined the relationship between antipsychotic prescribing patterns and labor market affiliation, considering both authority approved and off-label prescriptions and the relation to polypharmacy. METHODS: Register-based cohort study using a dataset of 71,254 new antipsychotic users with a psychiatric diagnosis. Labor market affiliation and duration of welfare payments were analyzed using linear regression models and duration analysis. The analyses were adjusted for the following confounding variables: age, gender, diagnosis, marital status, length of education, and utilization of mental health care services. RESULTS: The majority of new antipsychotic users received welfare payments for prolonged periods of time during the observation period, even more so for individuals treated with antipsychotic polypharmacy or other antipsychotic combination regimens. The risk of permanently leaving the labor market was also associated with antipsychotic combination regimen. CONCLUSIONS: Antipsychotic treatment, especially in combination with other antipsychotics or other psychotropic drugs, could serve as a marker of subjects with increased need for support to maintain the labor market affiliation. However, causality cannot be inferred from an observational study because of residual confounding that could not be adjusted for in this study. PMID- 26437773 TI - Archaeal ancestors of eukaryotes: not so elusive any more. AB - The origin of eukaryotes is one of the hardest problems in evolutionary biology and sometimes raises the ominous specter of irreducible complexity. Reconstruction of the gene repertoire of the last eukaryotic common ancestor (LECA) has revealed a highly complex organism with a variety of advanced features but no detectable evolutionary intermediates to explain their origin. Recently, however, genome analysis of diverse archaea led to the discovery of apparent ancestral versions of several signature eukaryotic systems, such as the actin cytoskeleton and the ubiquitin network, that are scattered among archaea. These findings inspired the hypothesis that the archaeal ancestor of eukaryotes was an unusually complex form with an elaborate intracellular organization. The latest striking discovery made by deep metagenomic sequencing vindicates this hypothesis by showing that in phylogenetic trees eukaryotes fall within a newly identified archaeal group, the Lokiarchaeota, which combine several eukaryotic signatures previously identified in different archaea. The discovery of complex archaea that are the closest living relatives of eukaryotes is most compatible with the symbiogenetic scenario for eukaryogenesis. PMID- 26437774 TI - The effect of local variation in malaria transmission on the prevalence of sulfadoxine-pyrimethamine resistant haplotypes and selective sweep characteristics in Malawi. AB - BACKGROUND: Persistence of sulfadoxine-pyrimethamine (SP) resistance has been described in an urban setting in Malawi where malaria transmission is relatively low. Higher malaria transmission is associated with greater genetic diversity and more frequent genetic recombination, which could lead to a more rapid re emergence of SP-sensitive parasites, as well as more rapid degradation of selective sweeps. In this study, the impact of local variation in malaria transmission on the prevalence of SP-resistant haplotypes and selective sweep characteristics was investigated at an urban site with low parasite prevalence and two rural sites with moderate and high parasite prevalence. METHODS: Samples from three sites with different parasite prevalence were genotyped for resistance markers within pfdhfr-ts and pfdhps and at microsatellites flanking these genes. Expected heterozygosity (He) was estimated to evaluate genetic diversity. RESULTS: No difference in the prevalence of highly resistant DHFR 51I/59R/108N and DHPS 437G/540E was found between sites. Small differences in He flanking pfdhfr-ts and pfdhps were seen between rural-moderate and the other sites, as well as some shared haplotypes between the rural-high and urban-low sites. CONCLUSIONS: The results do not show an effect of local variation in malaria transmission, as inferred from parasite prevalence, on SP-resistant haplotype prevalence. PMID- 26437775 TI - Identification of H2S3 and H2S produced by 3-mercaptopyruvate sulfurtransferase in the brain. AB - Hydrogen polysulfides (H2Sn) have a higher number of sulfane sulfur atoms than hydrogen sulfide (H2S), which has various physiological roles. We recently found H2Sn in the brain. H2Sn induced some responses previously attributed to H2S but with much greater potency than H2S. However, the number of sulfur atoms in H2Sn and its producing enzyme were unknown. Here, we detected H2S3 and H2S, which were produced from 3-mercaptopyruvate (3 MP) by 3-mercaptopyruvate sulfurtransferase (3MST), in the brain. High performance liquid chromatography with fluorescence detection (LC-FL) and tandem mass spectrometry (LC-MS/MS) analyses showed that H2S3 and H2S were produced from 3 MP in the brain cells of wild-type mice but not 3MST knockout (3MST-KO) mice. Purified recombinant 3MST and lysates of COS cells expressing 3MST produced H2S3 from 3 MP, while those expressing defective 3MST mutants did not. H2S3 was localized in the cytosol of cells. H2S3 was also produced from H2S by 3MST and rhodanese. H2S2 was identified as a minor H2Sn, and 3 MP did not affect the H2S5 level. The present study provides new insights into the physiology of H2S3 and H2S, as well as novel therapeutic targets for diseases in which these molecules are involved. PMID- 26437776 TI - A functional polymorphism in the CEBPE gene promoter influences acute lymphoblastic leukemia risk through interaction with the hematopoietic transcription factor Ikaros. PMID- 26437778 TI - Retraction: The onset of thalamic hemorrhage in Rivaroxaban in oral IX factor complex formulation administration, but showed a hematoma expansion case. AB - This article released online on July 11, 2015 as advance publication was retracted by author's request. PMID- 26437777 TI - A simple one-tube assay for immunophenotypical quantification of leukemic stem cells in acute myeloid leukemia. AB - Relapses after initial successful treatment in acute myeloid leukemia are thought to originate from the outgrowth of leukemic stem cells. Their flow cytometrically assessed frequency is of importance for relapse prediction and is therefore assumed to be implemented in future risk group profiling. Since current detection methods are complex, time- and bone marrow consuming (multiple-tubes approach), it would be advantageous to have a broadly applicable approach that enables to quantify leukemia stem cells both at diagnosis and follow-up. We compared 15 markers in 131 patients concerning their prevalence, usefulness and stability in CD34(+)CD38(-) leukemic stem cell detection in healthy controls, acute myeloid leukemia diagnosis and follow-up samples. Ultimately, we designed a single 8 color detection tube including common markers CD45, CD34 and CD38, and specific markers CD45RA, CD123, CD33, CD44 and a marker cocktail (CLL-1/TIM 3/CD7/CD11b/CD22/CD56) in one fluorescence channel. Validation analyses in 31 patients showed that the single tube approach was as good as the multiple-tube approach. Our approach requires the least possible amounts of bone marrow, and is suitable for multi-institutional studies. Moreover, it enables detection of leukemic stem cells both at time of diagnosis and follow-up, thereby including initially low-frequency populations emerging under therapy pressure. PMID- 26437779 TI - Serum levels of inflammatory cytokines in Rift Valley fever patients are indicative of severe disease. AB - BACKGROUND: Rift Valley fever (RVF) is a mosquito-borne viral zoonosis affecting domestic and wild ruminants, camels and humans. Outbreaks of RVF are characterized by a sudden onset of abortions and high mortality amongst domestic ruminants. Humans develop disease ranging from a mild flu-like illness to more severe complications including hemorrhagic syndrome, ocular and neurological lesions and death. During the RVF outbreak in South Africa in 2010/11, a total of 278 human cases were laboratory confirmed, including 25 deaths. The role of the host inflammatory response to RVF pathogenesis is not completely understood. METHODS: Virus load in serum from human fatal and non-fatal cases was determined by standard tissue culture infective dose 50 (TCID50) titration on Vero cells. Patient serum concentration of chemokines and cytokines involved in inflammatory responses (IL-8, RANTES, CXCL9, MCP-1, IP-10, IL-1beta, IL-6, IL-10, TNF and IL 12p70) was determined using cytometric bead assays and flow cytometry. RESULTS: Fatal cases had a 1-log10 higher TCID50/ml serum concentration of RVF virus (RVFV) than survivors (p < 0.05). There were no significant sequence differences between isolates recovered from fatal and non-fatal cases. Chemokines and pro- and anti-inflammatory cytokines were detected at significantly increased (IL-8, CXCL9, MCP-1, IP-10, IL-10) or decreased (RANTES) levels when comparing fatal cases to infected survivors and uninfected controls, or when comparing combined infected patients to uninfected controls. CONCLUSIONS: The results suggest that regulation of the host inflammatory responses plays an important role in the outcome of RVFV infection in humans. Dysregulation of the inflammatory response contributes to a fatal outcome. The cytokines and chemokines identified in this study that correlate with fatal outcomes warrant further investigation as markers for disease severity. PMID- 26437780 TI - PLD1 participates in BDNF-induced signalling in cortical neurons. AB - The brain-derived neurotrophic factor BDNF plays a critical role in neuronal development and the induction of L-LTP at glutamatergic synapses in several brain regions. However, the cellular and molecular mechanisms underlying these BDNF effects have not been firmly established. Using in vitro cultures of cortical neurons from knockout mice for Pld1 and Rsk2, BDNF was observed to induce a rapid RSK2-dependent activation of PLD and to stimulate BDNF ERK1/2-CREB and mTor-S6K signalling pathways, but these effects were greatly reduced in Pld1(-/-) neurons. Furthermore, phospho-CREB did not accumulate in the nucleus, whereas overexpression of PLD1 amplified the BDNF-dependent nuclear recruitment of phospho-ERK1/2 and phospho-CREB. This BDNF retrograde signalling was prevented in cells silenced for the scaffolding protein PEA15, a protein which complexes with PLD1, ERK1/2, and RSK2 after BDNF treatment. Finally PLD1, ERK1/2, and RSK2 partially colocalized on endosomal structures, suggesting that these proteins are part of the molecular module responsible for BDNF signalling in cortical neurons. PMID- 26437783 TI - Paroxysmal nocturnal hemoglobinuria induced by the occurrence of BCR-ABL in a PIGA mutant hematopoietic progenitor cell. PMID- 26437782 TI - Frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the European ENEST1st study. AB - The Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study included 1089 patients with newly diagnosed chronic myeloid leukemia in chronic phase. The rate of deep molecular response (MR(4) (BCR-ABL1?0.01% on the International Scale or undetectable BCR-ABL1 with ?10,000 ABL1 transcripts)) at 18 months was evaluated as the primary end point, with molecular responses monitored by the European Treatment and Outcome Study network of standardized laboratories. This analysis was conducted after all patients had completed 24 months of study treatment (80.9% of patients) or discontinued early. In patients with typical BCR-ABL1 transcripts and ?3 months of prior imatinib therapy, 38.4% (404/1052) achieved MR(4) at 18 months. Six patients (0.6%) developed accelerated or blastic phase, and 13 (1.2%) died. The safety profile of nilotinib was consistent with that of previous studies, although the frequencies of some nilotinib-associated adverse events were lower (for example, rash, 21.4%). Ischemic cardiovascular events occurred in 6.0% of patients. Routine monitoring of lipid and glucose levels was not mandated in the protocol. These results support the use of frontline nilotinib, particularly when achievement of a deep molecular response (a prerequisite for attempting treatment-free remission in clinical trials) is a treatment goal. PMID- 26437784 TI - Prospective molecular monitoring of minimal residual disease after non myeloablative allografting in newly diagnosed multiple myeloma. PMID- 26437781 TI - A20 targets caspase-8 and FADD to protect HTLV-I-infected cells. AB - Adult T-cell leukemia (ATL) arises from a human T-cell leukemia virus type I (HTLV-I)-infected cell and has few therapeutic options. Here, we have uncovered a previously unrecognized role for a ubiquitin-editing enzyme A20 in the survival of HTLV-I-infected cells. Unlike in lymphomas of the B-cell lineage, A20 is abundantly expressed in primary ATL cells without notable mutations. Depletion of A20 in HTLV-I-infected cells resulted in caspase activation, cell death induction and impaired tumorigenicity in mouse xenograft models. Mechanistically, A20 stably interacts with caspase-8 and Fas-associated via death domain (FADD) in HTLV-I-infected cells. Mutational studies revealed that A20 supports the growth of HTLV-I-infected cells independent of its catalytic functions and that the zinc finger domains are required for the interaction with and regulation of caspases. These results indicate a pivotal role for A20 in the survival of HTLV-I-infected cells and implicate A20 as a potential therapeutic target in ATL. PMID- 26437785 TI - Oncogenic activation of MPL/thrombopoietin receptor by 17 mutations at W515: implications for myeloproliferative neoplasms. PMID- 26437786 TI - Profiling serum antibodies to Mycobacterium tuberculosis proteins in rhesus monkeys with nontuberculous Mycobacteria. AB - Recent evidence indicates that the prevalence of diseases caused by nontuberculous mycobacteria (NTM) has been increasing in both human and animals. In this study, antibody profiles of NTM in rhesus monkeys (Macaca mulatta) were determined and compared with those of monkeys infected with Mycobacterium tuberculosis complex (MTBC). Antibodies against 10 M. tuberculosis proteins, purified protein derivative (PPD), and mammalian old tuberculin (MOT) were detected in 14 monkeys naturally infected with NTM by indirect ELISA. Sera from 10 monkeys infected with MTBC and 10 healthy monkeys were set as controls. All antigens showed high serological reactivities to MTBC infections and low reactivities in healthy monkeys. NTM infections showed strong antibody responses to MOT and PPD; moderate antibody responses to 16kDa, U1, MPT64L, 14kDa, and TB16.3; and low antibody responses to 38kDa, Ag85b, CFP10, ESAT-6, and CFP10-ESAT 6. According to the criteria of MTBC, only CFP10, ESAT-6, and CFP10-ESAT-6 showed negative antibody responses in all NTM infections. Taken together, these results suggest that positive results of a PPD/MOT-based ELISA in combination with results of antibodies to M. tuberculosis-specific antigens, such as CFP10 and ESAT-6, could discriminate NTM and MTBC infections. Two positive results indicate an MTBC infection, and a negative result for an M. tuberculosis-specific antigen may preliminarily predict an NTM infection. PMID- 26437787 TI - Construction and evaluation of the novel DNA vaccine harboring the inhibin alpha (1-32) and the RF-amide related peptide-3 genes for improving fertility in mice. AB - To further improve fertility of animals, a novel gene RFRP-3 (RF-amide related peptide-3, RFRP-3) was used to construct DNA vaccines with INH alpha (1-32) (inhibin, INH) fragment for the first time. The aim of this study was to evaluate the effects of novel DNA vaccines on fertility in mice. Synthesized SINH and SRFRP (INH and RFRP genes were separately ligated to the C-terminus of the small envelope protein of the hepatitis B virus (HBV-S) gene) fragments were inserted into multiple cloning site of pIRES vector to develop p-SINH/SRFRP. The synthesized tissue plasminogen activator (TPA) signal sequence was then inserted into the p-SINH/SRFRP to construct p-TPA-SINH/TPA-SFRFP. Meanwhile, p-SINH was prepared and considered as positive control. Forty Kunming mice were equally divided into four groups and respectively immunized by electroporation with p SINH, p-SINH/SRFRP and p-TPA-SINH/TPA-SRFRP vaccine (three times at 2 weeks interval) and saline as control. Results showed that the average antibodies (P/N value) of anti-INH and anti-RFRP in mice inoculated with p-TPA-SINH/TPA-SFRFP were significantly higher (P<0.05) than those inoculated with p-SINH/SRFRP and the positive rates were 100% (anti-INH) and 90% (anti-RFRP) respectively, at 2 weeks after the third immunization. Litter size of mice immunized with the three recombinant plasmids was higher (P<0.05) than that of the control, and litter size of mice immunized with p-TPA-SINH/TPA-SRFRP significantly increased (P<0.05) compared with p-SINH. These results suggested that the p-TPA-SINH/TPA-SRFRP harboring INH and RFRP genes was successfully constructed and had good immunogenicity, and might effectively increase litter size. PMID- 26437788 TI - What's happening to cheap generic drugs? PMID- 26437789 TI - CNOT3 suppression promotes necroptosis by stabilizing mRNAs for cell death inducing proteins. AB - The CCR4-NOT complex is conserved in eukaryotes and is involved in mRNA metabolism, though its molecular physiological roles remain to be established. We show here that CNOT3-depleted mouse embryonic fibroblasts (MEFs) undergo cell death. Levels of other complex subunits are decreased in CNOT3-depleted MEFs. The death phenotype is rescued by introduction of wild-type (WT), but not mutated CNOT3, and is not suppressed by the pan-caspase inhibitor, zVAD fluoromethylketone. Gene expression profiling reveals that mRNAs encoding cell death-related proteins, including receptor-interacting protein kinase 1 (RIPK1) and RIPK3, are stabilized in CNOT3-depleted MEFs. Some of these mRNAs bind to CNOT3, and in the absence of CNOT3 their poly(A) tails are elongated. Inhibition of RIPK1-RIPK3 signaling by a short-hairpin RNA or a necroptosis inhibitor, necrostatin-1, confers viability upon CNOT3-depleted MEFs. Therefore, we conclude that CNOT3 targets specific mRNAs to prevent cells from being disposed to necroptotic death. PMID- 26437790 TI - Correlation of single-breath count test and neck flexor muscle strength with spirometry in myasthenia gravis. AB - INTRODUCTION: Although formal spirometry is the gold standard for monitoring respiratory function in patients with myasthenia gravis (MG), such testing is often delayed or unavailable. There is a need for a simple bedside test that can accurately measure respiratory function. METHODS: We conducted a prospective, cross-sectional, single-blind study in adults with acetylcholine receptor antibody positive MG. Participants performed the single breath count test (SBCT) and underwent manual muscle strength testing, and a respiratory therapist performed spirometry blinded to SBCT and strength results. RESULTS: Thirty-one patients, aged 57 +/- 19 years participated. SBCT showed significant correlations with forced vital capacity (FVC), negative inspiratory force, and neck flexor strength (P < 0.01). FVC showed significant correlation with neck flexor strength (P = 0.02) but no correlation with shoulder abductor strength. CONCLUSIONS: These data suggest that the SBCT and neck flexor strength testing are valuable tools for bedside assessment of respiratory function in MG patients. PMID- 26437791 TI - Screening for Down syndrome in the second trimester of pregnancy. AB - Antenatal screening for fetal anomalies has provided women and their partners with information to make reproductive choices based on the risk of serious chromosomal or structural defects since the 1990s. Alternative tests include first-trimester screening (combined ultrasound and maternal serum markers), second-trimester maternal serum markers and noninvasive cell-free DNA testing. The recent recommendations by the Royal Australian and New Zealand College of Obstetrics and Gynaecology and the Human Genetics Society of Australasia against second-trimester triple testing are based on unsound performance criteria, raise several contestable issues around access and equity and challenge the principles of governments providing affordable options. PMID- 26437792 TI - Safety assessment of the Clostridium butyricum MIYAIRI 588(r) probiotic strain including evaluation of antimicrobial sensitivity and presence of Clostridium toxin genes in vitro and teratogenicity in vivo. AB - Probiotics are live microorganisms ingested for the purpose of conferring a health benefit on the host. Development of new probiotics includes the need for safety evaluations that should consider factors such as pathogenicity, infectivity, virulence factors, toxicity, and metabolic activity. Clostridium butyricum MIYAIRI 588((r)) (CBM 588((r))), an anaerobic spore-forming bacterium, has been developed as a probiotic for use by humans and food animals. Safety studies of this probiotic strain have been conducted and include assessment of antimicrobial sensitivity, documentation of the lack of Clostridium toxin genes, and evaluation of CBM 588((r)) on reproductive and developmental toxicity in a rodent model. With the exception of aminoglycosides, to which anaerobes are intrinsically resistant, CBM 588((r)) showed sensitivity to all antibiotic classes important in human and animal therapeutics. In addition, analysis of the CBM 588((r)) genome established the absence of genes for encoding for alpha, beta, or epsilon toxins and botulin neurotoxins types A, B, E, or F. There were no deleterious reproductive and developmental effects observed in mice associated with the administration of CBM 588((r)) These data provide further support for the safety of CBM 588((r)) for use as a probiotic in animals and humans. PMID- 26437793 TI - Lipid emulsion attenuates apoptosis induced by a toxic dose of bupivacaine in H9c2 rat cardiomyoblast cells. AB - The goal of this in vitro study was to investigate the effect of lipid emulsion on apoptosis induced by a toxic dose of bupivacaine (BPV) in H9c2 rat cardiomyoblast cell lines. The effect of lipid emulsion on the decreased cell viability and count induced by BPV or mepivacaine (MPV) in the H9c2 cells was assessed using an 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide assay or a cell count assay. The effect of BPV or lipid emulsion combined with BPV on cleaved caspase 3, caspase 8, and Bax in H9c2 cells was investigated using Western blotting. A terminal deoxynucleotidyl transferase dUTP2'-deoxyuridine 5' triphosphate nick end-labeling (TUNEL) assay was performed to detect apoptosis of H9c2 cells treated with BPV alone or lipid emulsion combined with BPV. The magnitude of lipid emulsion-mediated attenuation of decreased cell viability induced by BPV was higher than that of lipid emulsion-mediated attenuation of decreased cell viability induced by MPV. Lipid emulsion attenuated the increases in cleaved caspase 3, caspase 8 and Bax induced by BPV. Lipid emulsion attenuated the increases in TUNEL-positive cells induced by BPV. These results suggest that lipid emulsion attenuates a toxic dose of BPV-induced apoptosis via inhibition of the extrinsic and intrinsic apoptotic pathways. The protective effect of lipid emulsion may be partially associated with the relatively high lipid solubility of BPV. PMID- 26437795 TI - An Infected Aneurysm of the Vertebral Artery Treated with a Stent-graft: A Case Report. AB - In a 75-year-old man, a growing vertebral artery aneurysm at the C3/4 intervertebral level was found at postoperative evaluation of cervical abscess, which was diagnosed as a complication of sepsis subsequent to cholangitis. Even after a successful antibiotic treatment and a surgical drainage, the aneurysm grew enough to cause compression of esophagus and trachea. The aneurysm was judged to be infection-related, based on the clinical course and the anatomical vicinity to the abscess. Following a dual antiplatelet treatment (clopidogrel 75 mg and aspirin 100 mg per day) for a week, the patient underwent endovascular treatment of the aneurysm with a stent-graft. Postoperative angiography showed complete obliteration of the aneurysm with preserving patency of the vertebral artery. A dual antiplatelet treatment was continued for 6 months and was changed to a single antiplatelet treatment (clopidogrel 75 mg per day) thereafter. Neither recurrence of the aneurysm nor stent-graft infection was observed for 4 years of follow-up. This case illustrates the potential use of a stent-graft in the treatment of an infected aneurysm. PMID- 26437794 TI - Proteolysis of MDA5 and IPS-1 is not required for inhibition of the type I IFN response by poliovirus. AB - BACKGROUND: The type I interferon (IFN) response is a critical component of the innate immune response to infection by RNA viruses and is initiated via recognition of viral nucleic acids by RIG-like receptors (RLR). Engagement of these receptors in the cytoplasm initiates a signal transduction pathway leading to activation of the transcription factors NF-kappaB, ATF-2 and IRF-3 that coordinately upregulate transcription of type I IFN genes, such as that encoding IFN-beta. In this study the impact of poliovirus infection on the type I interferon response has been examined. METHODS: The type I IFN response was assessed by measuring IFN-beta mRNA levels using qRT-PCR and normalizing to levels of beta-actin mRNA. The status of host factors involved in activation of the type I IFN response was examined by immunoblot, immunofluorescence microcopy and qRT-PCR. RESULTS: The results show that poliovirus infection results in induction of very low levels of IFN-beta mRNA despite clear activation of NF kappaB and ATF-2. In contrast, analysis of IRF-3 revealed no transcriptional induction of an IRF-3-responsive promoter or homodimerization of IRF-3 indicating it is not activated in poliovirus-infected cells. Exposure of poliovirus-infected cells to poly(I:C) results in lower levels of IFN-beta mRNA synthesis and IRF-3 activation compared to mock-infected cells. Analysis of MDA-5 and IPS-1 revealed that these components of the RLR pathway were largely intact at times when the type I IFN response was suppressed. CONCLUSIONS: Collectively, these results demonstrate that poliovirus infection actively suppresses the host type I interferon response by blocking activation of IRF-3 and suggests that this is not mediated by cleavage of MDA-5 or IPS-1. PMID- 26437796 TI - Retreatment of Recurrent Internal Carotid-Posterior Communicating Artery Aneurysm after Coil Embolization. AB - Internal carotid-posterior communicating artery (IC-PC) aneurysms account for more than 20% of all intracranial aneurysms. As a result of the increase in coiling, there has also been an increase in recurrent IC-PC aneurysms after coiling. We present our experience of 10 recurrent IC-PC aneurysms after coiling that were retreated using surgical or endovascular techniques in order to discuss the choice of treatment and the points of clipping without removal of coils. From 2007 to 2014, 10 recurrent IC-PC aneurysms after coiling were retreated. When the previous frames covered the aneurysms all around or almost around except a part of the neck, coiling was chosen. In other cases, clipping was chosen. Clipping was attempted without removal of coils when it was technically feasible. Among the 10 IC-PC aneurysms retreated, 3 were retreated with coiling and 7 were retreated with clipping. In all three cases retreated with coiling, almost complete occlusion was accomplished. In the seven cases retreated with clipping, coil extrusion was observed during surgery in six cases. In most of them, it was necessary to dissect strong adhesions around the coiled aneurysms and to utilize temporary occlusion of the internal carotid artery. In all seven cases, neck clipping was accomplished without the removal of coils. There were no neurological complications in any cases. The management of recurrent lesions of embolized IC-PC aneurysms requires appropriate choice of treatment using both coiling and clipping. Clipping, especially without the removal of coils, plays an important role in safe treatment. PMID- 26437797 TI - Toll-like Receptor 4 (TLR4) is Associated with Cerebral Vasospasm and Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage. AB - In the present prospective study, the Toll-like receptor 4 (TLR4) levels on peripheral blood mononuclear cells (PBMCs) were investigated in 30 patients with aneurysmal subarachnoid hemorrhage (aSAH) and in 20 healthy controls (HCs). The relationship between TLR4 levels and the occurrence of cerebral vasospasm (CVS) was also analyzed. TLR4 expression level on cell surface of PBMCs on days 1, 3, and 7 after admission was determined by flow cytometry. Results showed that patients with aSAH presented a significantly higher TLR4 levels. For patients with Hunt-Hess grades IV-V, higher TLR4 levels were also observed; higher TLR4 levels have already been seen in patients developing CVS and/or delayed cerebral ischemia (DCI). Higher TLR4 levels were also associated with modified Fisher score, occurrence of dCVS, DCI, cerebral infarction (CT), and poor neurological functional recovery. Binary logistic regression analysis indicated that high TLR4 expression on blood monocytes was an independent predictive factor of the occurrence of dCVS, DCI, and poor neurological functional recovery. Taken together, TLR4 levels on PBMCs is significantly altered in the early stage of aSAH, especially in those patients experiencing CVS and DCI. Furthermore, higher TLR4 levels in the early stage of aSAH is also associated with the neurological function outcome. As far as we know, this is the first clinical study about TLR4's significance for patients with aSAH. PMID- 26437798 TI - Distribution of malaria exposure in endemic countries in Africa considering country levels of effective treatment. AB - BACKGROUND: Malaria prevalence, clinical incidence, treatment, and transmission rates are dynamically interrelated. Prevalence is often considered a measure of malaria transmission, but treatment of clinical malaria reduces prevalence, and consequently also infectiousness to the mosquito vector and onward transmission. The impact of the frequency of treatment on prevalence in a population is generally not considered. This can lead to potential underestimation of malaria exposure in settings with good health systems. Furthermore, these dynamical relationships between prevalence, treatment, and transmission have not generally been taken into account in estimates of burden. METHODS: Using prevalence as an input, estimates of disease incidence and transmission [as the distribution of the entomological inoculation rate (EIR)] for Plasmodium falciparum have now been made for 43 countries in Africa using both empirical relationships (that do not allow for treatment) and OpenMalaria dynamic micro-simulation models (that explicitly include the effects of treatment). For each estimate, prevalence inputs were taken from geo-statistical models fitted for the year 2010 by the Malaria Atlas Project to all available observed prevalence data. National level estimates of the effectiveness of case management in treating clinical attacks were used as inputs to the estimation of both EIR and disease incidence by the dynamic models. RESULTS AND CONCLUSIONS: When coverage of effective treatment is taken into account, higher country level estimates of average EIR and thus higher disease burden, are obtained for a given prevalence level, especially where access to treatment is high, and prevalence relatively low. These methods provide a unified framework for comparison of both the immediate and longer-term impacts of case management and of preventive interventions. PMID- 26437799 TI - Cancer Cell Imaging Using in Situ Generated Gold Nanoclusters. AB - In situ generated fluorescent gold nanoclusters (Au-NCs) are used for bio-imaging of three human cancer cells, namely, lung (A549), breast (MCF7), and colon (HCT116), by confocal microscopy. The amount of Au-NCs in non-cancer cells (WI38 and MCF10A) is 20-40 times less than those in the corresponding cancer cells. The presence of a larger amount of glutathione (GSH) capped Au-NCs in the cancer cell is ascribed to a higher glutathione level in cancer cells. The Au-NCs exhibit fluorescence maxima at 490-530 nm inside the cancer cells. The fluorescence maxima and matrix-assisted laser desorption ionization (MALDI) mass spectrometry suggest that the fluorescent Au-NCs consist of GSH capped clusters with a core structure (Au8-13). Time-resolved confocal microscopy indicates a nanosecond (1-3 ns) lifetime of the Au-NCs inside the cells. This rules out the formation of aggregated Au-thiolate complexes, which typically exhibit microsecond (~1000 ns) lifetimes. Fluorescence correlation spectroscopy (FCS) in live cells indicates that the size of the Au-NCs is ~1-2 nm. For in situ generation, we used a conjugate consisting of a room-temperature ionic liquid (RTIL, [pmim][Br]) and HAuCl4. Cytotoxicity studies indicate that the conjugate, [pmim][AuCl4], is non toxic for both cancer and non-cancer cells. PMID- 26437800 TI - Experiencing Functional Electrical Stimulation Roots on Education, and Clinical Developments in Paraplegia and Tetraplegia With Technological Innovation. AB - Cybernetics-based concepts can allow for complete independence for paralyzed individuals, including sensory motor recovery. Spinal cord injuries are responsible for a huge stress on health and a financial burden to society. This article focuses on novel procedures such as functional diagnosis for paraplegics and tetraplegics, cybertherapies toward lessening comorbidities such as cardiovascular diseases, osteoporosis, etc., and the production of new technology for upper and lower limb control. Functional electrical stimulation reflects a unique opportunity for bipedal gait to be achieved by paraplegics and tetraplegics. Education and training of undergraduates and postgraduates in engineering and life sciences have also been a major aim of this work. PMID- 26437802 TI - Spontaneous Heterotopic Pregnancy Presenting with Hemoperitoneum. AB - BACKGROUND: Heterotopic pregnancy is a condition in which intra- and extrauterine pregnancies occur at the same time. Spontaneous heterotopic pregnancy is a rare event, with incidences ranging from 1 in 30,000 pregnancies to as high as 1 in 6 pregnancies assisted by reproductive technology. CASE REPORT: A 34-year-old woman presented with a 10-week history of amenorrhea, pelvic pain, and generally feeling unwell. Ultrasonography revealed a 10-week intrauterine viable pregnancy and free fluid in the abdominal cavity. Emergency laparotomy was performed and a ruptured tubal ectopic pregnancy was encountered on the right tube with hemoperitoneum. Salpingectomy was performed. Her intrauterine pregnancy was intact with positive fetal cardiac activity when she was discharged. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Heterotopic pregnancy should be kept in the differential diagnosis of any patient with an intrauterine pregnancy presenting with abdominal pain, abdominal tenderness, or free fluid in the abdominal cavity. PMID- 26437803 TI - Spontaneous Adrenal Hemorrhage in Pregnancy Presenting as a Pulmonary Embolism. PMID- 26437805 TI - Acute Basilar Artery Thrombosis. PMID- 26437804 TI - Mad Honey Poisoning-Related Hypothermia: A Case Series. AB - BACKGROUND: Mad honey-related intoxication frequently leads to bradycardia, hypotension, and syncope. Hypothermia is a potentially life-threatening condition if not identified early and treated appropriately. CASE REPORT: Three patients are reviewed. Patient 1 was a 66-year-old man who presented to the emergency department with nausea, vomiting, and faintness beginning 2 h after consuming honey. His temperature was 34 degrees C, his blood pressure was 70/40 mm Hg, and his heart rate was 30 beats/min. Patient 2, a 57-year-old man, presented to the emergency department with headache, feeling cold, and faintness beginning 3 h after consuming honey. His temperature was 35 degrees C, his blood pressure was 60/40 mm Hg, and his heart rate was 46 beats/min. Patient 3 was a 79-year-old woman who presented with nausea, vomiting, and headache 2 h after consuming honey. Her temperature was 35 degrees C, her blood pressure was 70/40 mm Hg, and her heart rate was 40 beats/min. All 3 patients were discharged in good condition after appropriate therapy. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Bradycardia and hypotension are frequently encountered in mad honey intoxication. However, intoxication accompanied by hypothermia has attracted little attention to date. PMID- 26437801 TI - Copper Transport Protein Antioxidant-1 Promotes Inflammatory Neovascularization via Chaperone and Transcription Factor Function. AB - Copper (Cu), an essential micronutrient, plays a fundamental role in inflammation and angiogenesis; however, its precise mechanism remains undefined. Here we uncover a novel role of Cu transport protein Antioxidant-1 (Atox1), which is originally appreciated as a Cu chaperone and recently discovered as a Cu dependent transcription factor, in inflammatory neovascularization. Atox1 expression is upregulated in patients and mice with critical limb ischemia. Atox1 deficient mice show impaired limb perfusion recovery with reduced arteriogenesis, angiogenesis, and recruitment of inflammatory cells. In vivo intravital microscopy, bone marrow reconstitution, and Atox1 gene transfer in Atox1(-/-) mice show that Atox1 in endothelial cells (ECs) is essential for neovascularization and recruitment of inflammatory cells which release VEGF and TNFalpha. Mechanistically, Atox1-depleted ECs demonstrate that Cu chaperone function of Atox1 mediated through Cu transporter ATP7A is required for VEGF induced angiogenesis via activation of Cu enzyme lysyl oxidase. Moreover, Atox1 functions as a Cu-dependent transcription factor for NADPH oxidase organizer p47phox, thereby increasing ROS-NFkappaB-VCAM-1/ICAM-1 expression and monocyte adhesion in ECs inflamed with TNFalpha in an ATP7A-independent manner. These findings demonstrate a novel linkage between Atox1 and NADPH oxidase involved in inflammatory neovascularization and suggest Atox1 as a potential therapeutic target for treatment of ischemic disease. PMID- 26437806 TI - Solitary Extramedullary Multiple Myeloma Presenting with Small Bowel Obstruction. PMID- 26437807 TI - Venolymphatic Malformation of the Labia in a 12-Year-Old Child. PMID- 26437809 TI - Can state ownership of the tobacco industry really advance tobacco control? PMID- 26437808 TI - Estimating the 'consumer surplus' for branded versus standardised tobacco packaging. AB - BACKGROUND: Tobacco companies question whether standardised (or 'plain') packaging will change smokers' behaviour. We addressed this question by estimating how standardised packaging compared to a proven tobacco control intervention, price increases through excise taxes, thus providing a quantitative measure of standardised packaging's likely effect. METHODS: We conducted an online study of 311 New Zealand smokers aged 18 years and above that comprised a willingness-to-pay task comparing a branded and a standardised pack at four different price levels, and a choice experiment. The latter used an alternative specific design, where the alternatives were a branded pack or a standardised pack, with warning theme and price varied for each pack. RESULTS: Respondents had higher purchase likelihoods for the branded pack (with a 30% warning) than the standardised pack (with a 75% warning) at each price level tested, and, on average, were willing to pay approximately 5% more for a branded pack. The choice experiment produced a very similar estimate of 'consumer surplus' for a branded pack. However, the size of the 'consumer surplus' varied between warning themes and by respondents' demographic characteristics. CONCLUSIONS: These two experiments suggest standardised packaging and larger warning labels could have a similar overall effect on adult New Zealand smokers as a 5% tobacco price increase. The findings provide further evidence for the efficacy of standardised packaging, which focuses primarily on reducing youth initiation, and suggest this measure will also bring notable benefits to adult smokers. PMID- 26437810 TI - Production of Recombinant Adeno-associated Virus Vectors Using Suspension HEK293 Cells and Continuous Harvest of Vector From the Culture Media for GMP FIX and FLT1 Clinical Vector. AB - Adeno-associated virus (AAV) has shown great promise as a gene therapy vector in multiple aspects of preclinical and clinical applications. Many developments including new serotypes as well as self-complementary vectors are now entering the clinic. With these ongoing vector developments, continued effort has been focused on scalable manufacturing processes that can efficiently generate high titer, highly pure, and potent quantities of rAAV vectors. Utilizing the relatively simple and efficient transfection system of HEK293 cells as a starting point, we have successfully adapted an adherent HEK293 cell line from a qualified clinical master cell bank to grow in animal component-free suspension conditions in shaker flasks and WAVE bioreactors that allows for rapid and scalable rAAV production. Using the triple transfection method, the suspension HEK293 cell line generates greater than 1 * 10(5) vector genome containing particles (vg)/cell or greater than 1 * 10(14) vg/l of cell culture when harvested 48 hours post transfection. To achieve these yields, a number of variables were optimized such as selection of a compatible serum-free suspension media that supports both growth and transfection, selection of a transfection reagent, transfection conditions and cell density. A universal purification strategy, based on ion exchange chromatography methods, was also developed that results in high-purity vector preps of AAV serotypes 1-6, 8, 9 and various chimeric capsids tested. This user-friendly process can be completed within 1 week, results in high full to empty particle ratios (>90% full particles), provides postpurification yields (>1 * 10(13) vg/l) and purity suitable for clinical applications and is universal with respect to all serotypes and chimeric particles. To date, this scalable manufacturing technology has been utilized to manufacture GMP phase 1 clinical AAV vectors for retinal neovascularization (AAV2), Hemophilia B (scAAV8), giant axonal neuropathy (scAAV9), and retinitis pigmentosa (AAV2), which have been administered into patients. In addition, we report a minimum of a fivefold increase in overall vector production by implementing a perfusion method that entails harvesting rAAV from the culture media at numerous time-points post transfection. PMID- 26437812 TI - "Difficult asthma": not as easy as you think. PMID- 26437811 TI - Full-length nucleotide sequences of 30 common SLC44A2 alleles encoding human neutrophil antigen-3. AB - BACKGROUND: Human neutrophil antigen-3a (HNA-3a) alloantibodies can cause severe transfusion-related acute lung injury. The frequencies of the single-nucleotide polymorphisms (SNPs) indicative of the two clinically relevant HNA-3a/b antigens are known in many populations. In this study, we determined the full-length nucleotide sequence of common SLC44A2 alleles encoding the choline transporter like protein-2 that harbors HNA-3a/b antigens. STUDY DESIGN AND METHODS: A method was devised to determine the full-length coding sequence (CDS) and adjacent intron sequences from genomic DNA by eight polymerase chain reaction amplifications covering all 22 SLC44A2 exons. Samples from 200 African American, 96 Caucasian, two Hispanic, and four Asian blood donors were analyzed. We developed a decision tree to determine alleles (confirmed haplotypes) from the genotype data. RESULTS: A total of 10 SNPs were detected in the SLC44A2 CDS. The noncoding sequences harbored an additional 28 SNPs (one in the 5'-untranslated region [UTR]; 23 in the introns; and four in the 3'-UTR). No SNP indicative of a nonfunctional allele was detected. The nucleotide sequences for 30 SLC44A2 alleles (haplotypes) were confirmed. There may be 66 haplotypes among the 604 chromosomes screened. CONCLUSIONS: We found 38 SNPs, including one novel SNP, in 8192 nucleotides covering the CDS of the SLC44A2 gene among 302 blood donors. Population frequencies of these SNPs were established for African Americans and Caucasians. Because alleles encoding HNA-3b are more common than non-functional SLC44A2 alleles, we confirmed our previous postulate that African American donors are less likely to form HNA-3a antibodies compared to Caucasians. PMID- 26437813 TI - Is the eosinophil a leading villain in lung function decline? PMID- 26437814 TI - Visceral pleural invasion: crossing a (thin) line. PMID- 26437815 TI - Prostacyclin and oral vasodilator therapy in sarcoidosis-associated pulmonary hypertension: a retrospective case series. AB - BACKGROUND: It is unclear whether recent advances in pulmonary arterial hypertension therapy can be safely applied to sarcoidosis-associated pulmonary hypertension (SAPH). Evidence for prostacyclin (PG) therapy in SAPH is limited. METHODS: We conducted a single-center, retrospective review of 46 patients with sarcoidosis, 26 of whom had SAPH. Thirteen received PG as monotherapy or in combination with oral vasodilators. RESULTS: Follow-up right-sided heart catheterization at a mean of 12.7 months revealed improved cardiac output, cardiac index, and pulmonary vascular resistance. Functional class and N-terminal pro-brain natriuretic peptide levels also improved in patients treated with PG. No significant change in oxygen requirement was seen with vasodilator therapy initiation. At 2 years, 15 patients with SAPH survived, including eight on PG, and at 5 years, seven survived, including five on PG. Survival was significantly reduced in patients with SAPH compared with patients who had sarcoidosis without pulmonary hypertension. Multivariate analysis demonstrated that the use of PG therapy in SAPH is not associated with increased mortality. CONCLUSIONS: Many patients with severe SAPH showed significant hemodynamic and clinical improvement on long-term IV or subcutaneous PG therapy and had survival outcomes similar to patients with moderate SAPH on oral vasodilator therapy. PMID- 26437817 TI - A man in his 50s with septic shock from an occult source. PMID- 26437816 TI - Three-dimensional modeled T-tube design and insertion in a patient with tracheal dehiscence. AB - A 68-year-old man with recurrent medullary thyroid cancer underwent cervical tracheal resection and reconstruction. His course was complicated by tracheal anastomotic dehiscence, right carotid blowout, and ultimately cervical tracheoplasty with AlloDerm. Given the complex vascular interventions and upper airway anatomy, a custom-designed Montgomery T-tube was designed for him. Three dimensional digital reconstruction of his upper airways was obtained from a CT scan. The T-tube was designed and fabricated based on the digital trachea model and was subsequently placed successfully. Follow-up CT scan and bronchoscopy confirmed placement and revealed no granulation tissue at 4 weeks. The patient was discharged to home with the ability to phonate. To our knowledge, this is the first demonstration of three-dimensional modeling of an upper-airway defect with subsequent T-tube design using engineering software. The success of this case demonstrates a possible avenue for personalized airway prosthesis design and manufacturing in the future. PMID- 26437818 TI - A 33-year-old man with multiple bilateral pulmonary pseudoaneurysms. AB - A 33-year-old man, never smoker, presented with acute-onset dyspnea secondary to bilateral pulmonary emboli. Echocardiography at the time revealed a right atrial myxoma, for which he underwent resection, followed by anticipated lifelong therapeutic anticoagulation therapy. PMID- 26437819 TI - A 44-year-old man with bilateral pneumothorax. AB - A 44-year-old man presented with a 3-day history of persistent upper-back pain, chest discomfort, and dyspnea. He denied any precipitating events such as trauma or vigorous activity before the presentation of symptoms. His exercise capacity had been excellent. He is a lifetime nonsmoker and never had significant lung problems apart from intermittent asthma for which he had several ED visits in the past. Chest CT scan performed during an asthma exacerbation 2 years earlier demonstrated two left-side lung blebs. He had no prior surgical procedures. PMID- 26437820 TI - A 60-year-old woman with cough, dyspnea, and atelectasis 19 years after liver transplant. AB - A 60-year-old black woman presented with nonproductive cough of 1-month duration. She had also experienced rapidly progressive dyspnea for 1 week and one bout of vomiting a day before presentation. Her symptoms had failed to improve with a course of amoxicillin-clavulanate. Her medical history was significant for diabetes mellitus and liver transplant 19 years earlier for hepatitis C cirrhosis, for which she was receiving tacrolimus and mycophenolate. She was a current smoker with 40 pack-years of smoking history. PMID- 26437821 TI - Therapy for pulmonary arterial hypertension: approved dosages should be prescribed in clinical practice. PMID- 26437822 TI - High-flow nasal cannula can be used outside the ICU. PMID- 26437823 TI - Response. PMID- 26437824 TI - Endosonography: esophagus is better! PMID- 26437825 TI - Response. PMID- 26437826 TI - Does circulating IL-17 identify a subset of patients with idiopathic pulmonary arterial hypertension? PMID- 26437827 TI - Response. PMID- 26437828 TI - Using clinical pathways to assess interventions to prevent COPD readmissions. PMID- 26437829 TI - Response. PMID- 26437830 TI - Cognitive effects following acute wild blueberry supplementation in 7- to 10-year old children. AB - PURPOSE: Previously, anthocyanin-rich blueberry treatments have shown positive effects on cognition in both animals and human adults. However, little research has considered whether these benefits transfer to children. Here we describe an acute time-course and dose-response investigation considering whether these cognitive benefits extend to children. METHODS: Using a double-blind cross-over design, on three occasions children (n = 21; 7-10 years) consumed placebo (vehicle) or blueberry drinks containing 15 or 30 g freeze-dried wild blueberry (WBB) powder. A cognitive battery including tests of verbal memory, word recognition, response interference, response inhibition and levels of processing was performed at baseline, and 1.15, 3 and 6 h following treatment. RESULTS: Significant WBB-related improvements included final immediate recall at 1.15 h, delayed word recognition sustained over each period, and accuracy on cognitively demanding incongruent trials in the interference task at 3 h. Importantly, across all measures, cognitive performance improved, consistent with a dose-response model, with the best performance following 30 g WBB and the worst following vehicle. CONCLUSION: Findings demonstrate WBB-related cognitive improvements in 7 to 10-year-old children. These effects would seem to be particularly sensitive to the cognitive demand of task. PMID- 26437831 TI - Digestion-resistant maltodextrin effects on colonic transit time and stool weight: a randomized controlled clinical study. AB - PURPOSE: Increased awareness of the importance of dietary fibre has led to increased interest in "functional" fibre components like digestion-resistant maltodextrin (RMD). This randomized, placebo-controlled, double-blind study assessed the effects of RMD in the colonic transit time (CTT) and defecation characteristics (frequency, stool volume and consistency). METHODS: Sixty-six healthy adult volunteers (32 men) who did not have a daily defecation habit had a 7-day run-in period before the 21-day intervention period with RMD or placebo. CTT and segmental CTT (SCTT) were assessed by a single abdominal X-ray film taken at the end of both periods after radiopaque marker ingestion. Defecation characteristics and intestinal functions were also assessed, which were self reported by patients. Intragroup comparisons were evaluated by Student's paired t test, Bonferroni test and Chi-square test, while time comparisons by analysis of variance (ANOVA) and time-by-treatment interaction by repeated-measures ANOVA. RESULTS: Fifty-seven subjects were assessed for CTT (placebo, n = 28; RMD, n = 29). In the RMD group, the total CTT, left SCTT and rectosigmoidal SCTT decreased significantly compared to baseline (p < 0.01 each; -13.3, -4.7, -8.7 h, respectively). Significant differences between groups were observed in total CTT and left SCTT. Significant time-by-treatment interaction was observed in the RMD group for stool volume (p = 0.014), increasing 56 % compared to baseline (p < 0.01), while remained unchanged in the placebo group. Stool consistency was improved only in the RMD group (p < 0.01). No adverse effects related to study products were observed. CONCLUSIONS: The results show that RMD improved CTT, stool volume, stool consistency and some intestinal functions in a healthy population. PMID- 26437832 TI - Intake and sources of gluten in 20- to 75-year-old Danish adults: a national dietary survey. AB - PURPOSE: Celiac disease, an immunological response triggered by gluten, affects ~1 % of the Western population. Information concerning gluten intake in the general population is scarce. We determined intake of gluten from wheat, barley, rye and oat in the Danish National Survey of Diet and Physical Activity 2005 2008. The study population comprised a random cross-sectional sample of 1494 adults 20-75 years, selected from the Danish Civil Registration System. METHODS: Protein content in wheat, rye, barley and oat was determined from the National Danish Food Composition Table and multiplied with the amount of cereal used in recipes. Amount of gluten was calculated as amount of cereal protein *0.80 for wheat and oat, *0.65 for rye and *0.50 for barley. Dietary intake was recorded daily during seven consecutive days in pre-coded food diaries with open-answer possibilities. RESULTS: Mean total gluten intake was 10.4 +/- 4.4 g/day (10th 90th percentiles; 5.4-16.2 g/day), in men 12.0 +/- 4.6 g/day and 9.0 +/- 3.4 g/day in women. It was higher among men than among women in all age groups (20-75 years; P < 0.0001); however, this difference was eliminated when adjusting for energy intake. Intake of different gluten sources tended to be higher in men than in women with the exception of gluten from barley. Total gluten intake decreased with increasing age (P < 0.0001) as did gluten intake from wheat (P < 0.0001), whereas intake of gluten from rye (P < 0.0001) and barley (P = 0.001) increased with increasing age, also when adjusted for energy intake or body weight. CONCLUSION: This study presents representative population-based data on gluten intake in Danish adults. Total gluten intake decreased with increasing age. PMID- 26437833 TI - High resolution structure of an M23 peptidase with a substrate analogue. AB - LytM is a Staphylococcus aureus autolysin and a homologue of the S. simulans lysostaphin. Both enzymes are members of M23 metallopeptidase family (MEROPS) comprising primarily bacterial peptidoglycan hydrolases. LytM occurs naturally in a latent form, but can be activated by cleavage of an inhibitory N-terminal proregion. Here, we present a 1.45 A crystal structure of LytM catalytic domain with a transition state analogue, tetraglycine phosphinate, bound in the active site. In the electron density, the active site of the peptidase, the phosphinate and the "diglycine" fragment on the P1' side of the transition state analogue are very well defined. The density is much poorer or even absent for the P1 side of the ligand. The structure is consistent with the involvement of His260 and/or His291 in the activation of the water nucleophile and suggests a possible catalytic role for Tyr204, which we confirmed by mutagenesis. Possible mechanisms of catalysis and the structural basis of substrate specificity are discussed based on the structure analysis. PMID- 26437834 TI - Choosing Wisely? "It's Complicated!". PMID- 26437835 TI - Minimising harm in the early pregnancy population. PMID- 26437836 TI - [The life cycle of Rubella Virus]. AB - Rubella virus (RV), an infectious agent of rubella, is the sole member of the genus Rubivirus in the family of Togaviridae. RV has a positive-stranded sense RNA as a genome. A natural host of RV is limited to human, and rubella is considered to be a childhood disease in general. When woman is infected with RV during early pregnancy, her fetus may develop severe birth defects known as congenital rubella syndrome. In this review, the RV life cycle from the virus entry to budding is illustrated in comparison with those of member viruses of the genus alphavirus in the same family. The multiple functions of the RV capsid protein are also introduced. PMID- 26437837 TI - [Application of artificial DNA-binding proteins and artificial nucleases to prevention of virus infection: development of virus-resistant plants and protein based anti-viral drugs]. AB - Various DNA viruses are known to cause severe infectious diseases in both plants and mammals, including humans. For many of these infectious diseases, we have yet to find an effective prevention or treatment. Therefore, new methodologies for the prevention of virus infections in both agricultural crops and humans have been vigorously sought for a long time. One attractive approach to the prevention is inhibition of virus replication. We first inhibited virus replication by blocking binding of a viral replication protein, which initiates virus replication, to its replication origin, with using an artificial DNA-binding protein. We demonstrated that this new methodology was very effective in plants and mammalian cells: especially, we created transgenic plants that were immune to a geminivirus. We also developed novel protein-based antiviral drugs by fusing a cell-penetrating peptide to an artificial DNA-binding protein. Furthermore, we successfully generated a more effective protein-based antiviral, which was one hundred thousand times more active than the antiviral chemical drug Cidofovia, by alternatively fusing an DNA-cleaving enzyme to an artificial DNA-binding protein. Since this artificial protein has little cytotoxicity, it is expected that it will be used as a new antiviral drug. PMID- 26437838 TI - [Membrane Binding of Retroviral Gag Proteins]. AB - Location of virus assembly in infected cells has major influences on efficiencies of virus assembly and release and on post-assembly processes including cell-to cell transmission. Therefore, for better understanding of virus spread and for developing new antiviral strategies, it is important to elucidate mechanisms by which the subcellular site of virus particle assembly is determined. Retrovirus particle assembly is driven by viral structural protein Gag. In the case of HIV 1, Gag binds to the plasma membrane (PM) via the N-terminal MA domain and forms nascent particles at this location. Recent studies reveled that PM-specific phospholipid PI(4,5)P2 plays an important role in directing Gag to the PM through its interaction with MA. In this review, I will summarize our current understanding of relationships between retroviral MA domains and phospholipids in cellular membranes and discuss possible mechanisms by which lipids and other factors regulate membrane binding and subcellular localization of retroviral Gag proteins. PMID- 26437839 TI - [The multifunctional RNA polymerase L protein of non-segmented negative strand RNA viruses catalyzes unique mRNA capping]. AB - Non-segmented negative strand RNA viruses belonging to the Mononegavirales order possess RNA-dependent RNA polymerase L proteins within viral particles. The L protein is a multifunctional enzyme catalyzing viral RNA synthesis and processing (i.e., mRNA capping, cap methylation, and polyadenylation). Using vesicular stomatitis virus (VSV) as a prototypic model virus, we have shown that the L protein catalyzes the unconventional mRNA capping reaction, which is strikingly different from the eukaryotic reaction. Furthermore, co-transcriptional pre-mRNA capping with the VSV L protein was found to be required for accurate stop?start transcription to synthesize full-length mRNAs in vitro and virus propagation in host cells. This article provides a review of historical and present studies leading to the elucidation of the molecular mechanism of VSV mRNA capping. PMID- 26437840 TI - [Rotaviruses]. AB - Rotavirus, a member of the family Reoviridae, was identified as the leading etiological agent of severe gastroenteritis in infants and young children in 1973. The rotavirus genome is composed of 11 gene segments of double-stranded (ds)RNA. During the last 40 years, a large amount of basic research on rotavirus structure, genome, antigen, replication, pathogenesis, epidemiology, immune responses, and evolution has been accumulated. This article reviews the fundamental aspects of rotavirology including recent important achievements in research. PMID- 26437841 TI - [Orthoreoviruses]. AB - Members of the genus Orthoreovirus in the family Reoviridae are nonenveloped, icosahedral viruses. Their genomes contain 10 segments of double-stranded RNA (dsRNA). The orthoreoviruses are divided into two subgroups, the fusogenic and nonfusogenic reoviruses, based on the ability of the virus to induce cell-to-cell fusion. The fusogenic subgroup consists of the avian reovirus, baboon reovirus, pteropine reovirus, and reptilian reovirus, whereas the nonfusogenic subgroup consists of the prototypical mammalian reovirus (MRV) species. MRVs are highly tractable experimental models for studies of segmented dsRNA virus replication and pathogenesis. Moreover, MRVs can selectively kill tumor cells and have been evaluated as oncolytic agents in clinical trials. This review provides a brief overview of current knowledge on the virological features of MRVs. PMID- 26437842 TI - [Reverse genetics systems for orbiviruses reveal the essential mechanisms in their replication]. AB - The members of Orbivirus genus within the family Reoviridae cause severe arthropod-born diseases mainly in ruminants and equids. In addition, the orbiviruses, which can infect humans, have been reported. In the last decade, the molecular and structural studies for orbiviruses, including Bluetongue virus (BTV), has made a great progress. Especially, a reverse genetics system (RG) for BTV, developed soon after Orhoreovirus and Rotavirus, is a major breakthrough. Here, I introduced the recent findings in orbivirus replication, especially the function of an enzymatic protein, VP6. PMID- 26437843 TI - [Plant-infecting reoviruses]. AB - The family Reoviridae separates two subfamilies and consists of 15 genera. Fourteen viruses in three genera (Phytoreovirus, Oryzavirus, and Fijivirus) infect plants. The outbreaks of the plant-infecting reoviruses cause sometime the serious yield loss of rice and maize, and are a menace to safe and efficient food production in the Southeast Asia. The plant-infecting reoviruses are double shelled icosahedral particles, from 50 to 80nm in diameter, and include from 10 to 12 segmented double-stranded genomic RNAs depending on the viruses. These viruses are transmitted in a persistent manner by the vector insects and replicated in both plants and in their vectors. This review provides a brief overview of the plant-infecting reoviruses and their recent research progresses including the strategy for viral controls using transgenic rice plants. PMID- 26437844 TI - [Diverse double-stranded RNA viruses infecting fungi]. AB - Most of reported fungal viruses (mycoviruses) have double-stranded RNA (dsRNA) genomes. This may reflect the simple, easy method for mycovirus hunting that entails detection of dsRNAs as a sign of viral infections. There are an increasing number of screens of various fungi, particularly phytopathogenic fungi for viruses pathogenic to host fungi or able to confer hypovirulence to them. This bases on an attractive research field of biological control of fungal plant diseases using viruses (virocontrol), mainly targeting important phytopathogenic fungi. While isolated viruses usually induce asymptomatic symptoms, they show a considerably high level of diversity. As of 2014, fungal dsRNA viruses are classified into six families: Reoviridae, Totiviridae, Chrysoviridae, Partitiviridae, Megabirnaviridae and Quadriviridae. These exclude unassigned mycoviruses which will definitely be placed into distinct families and/or genera. In this review article, dsRNA viruses isolated from the kingdom Fungi including as-yet-unclassified taxa are overviewed. Some recent achievements in the related field are briefly introduced as well. PMID- 26437845 TI - Transoral robotic surgery for carcinoma of unknown primary in the head and neck. AB - Multiple diagnostic and treatment paradigms exist for the management of carcinoma of unknown primary (CUP) metastatic to cervical lymph nodes. Transoral robotic surgery (TORS) has emerged as a modality for diagnosis and treatment of CUP, optimizing identification and resection of the primary tumor, although also preventing chemotherapy in a subset of patients. This article presents the authors' treatment paradigm and reviews the literature supporting the use of TORS in the management of CUP. PMID- 26437846 TI - Localization-triggered bacterial pathogenesis. AB - Bacterial infections are becoming an increasing problem worldwide and there is a need for a deeper understanding of how bacteria turn pathogenic. Here, we suggest that one answer may be found by taking into account the localization of the bacteria, both at an anatomical level and at a microenvironment level. Both commensals and traditional pathogens alter their interaction with the human host depending on the local surroundings--turning either more or less virulent. These localization effects could derive from the characteristics of different anatomical sites but also from local differences within a microenvironment. In order to understand the adaptive functions of bacterial virulence factors, we need to study the bacteria in the environments where they have evolved. PMID- 26437847 TI - A first-principles study of orthorhombic CN as a potential superhard material. AB - Using first-principles calculations, we have investigated the structural, electronic, dynamical and mechanical properties of a recently synthesized Pnnm CN. Phonon dispersion and elastic constant calculations were carried out to demonstrate the dynamical and mechanical stabilities of the Pnnm structure of CN at ambient pressure. The electronic band structure suggests that Pnnm-CN is an insulator with an indirect band gap of about 3.7 eV. First-principles strain stress relationships at large strains were also simulated to examine the structural and mechanical properties of Pnnm-CN. The established ideal tensile strength of ~41 GPa in the <100> direction suggests that CN is a potential superhard material. The present results provide deep insights for understanding the mechanical properties of CN and thus are helpful to explore the potential industrial applications of CN. PMID- 26437848 TI - Highly Selective Artificial Cholesteryl Crown Ether K(+)-Channels. AB - The bacterial KcsA channel conducts K(+) cations at high rates while excluding Na(+) cations. Herein, we report an artificial ion-channel formed by H-bonded stacks of crown-ethers, where K(+) cation conduction is highly preferred to Na(+) cations. The macrocycles aligned along the central pore surround the K(+) cations in a similar manner to the water around the hydrated cation, compensating for the energetic cost of their dehydration. In contrast, the Na(+) cation does not fit the macrocyclic binding sites, so its dehydration is not completely compensated. The present highly K(+)-selective macrocyclic channel may be regarded as a biomimetic of the KcsA channel. PMID- 26437849 TI - Meckel's diverticulum as a cause of persistent anaemia. PMID- 26437851 TI - Treatment of keloid scars with a 1210-nm diode laser in an animal model. AB - BACKGROUND AND OBJECTIVE: A temperature increase can improve wound healing by activation of heat shock protein 70 and stimulation of fibroblasts. Since keloids are a dysfunction of collagen fiber synthesis and organization, this study aimed to evaluate if a 1,210 nm diode laser could have effects in a new animal model of keloid scars. STUDY DESIGN/MATERIALS AND METHODS: A total of 39 nude mice were used for this study. Phototypes IV and V human keloids were grafted into their backs and after 1 month of healing, the mice were divided into four groups: Control, Laser, Resection, Resection/Laser. In the Laser group, the keloids were treated with a 1,210-nm diode-laser with the following parameters: 4 W; 10 seconds; fluence: 51 J/cm(2) ; spot: 18.9 * 3.7 mm(2) . In the Resection group, surgical intra-lesional excision was performed. In the Resection/Laser group, keloids were treated with the 1,210-nm laser-diode after surgical intra-lesional excision. Temperature measurements were made during the laser treatment. Clinical examination and histological study were performed on the day of treatment and 1 month, 2 months, and 3 months later. RESULTS: Mean temperature measurement was of 44.8 degrees C (42-48 degrees ) in the Laser groups. No healing complications or keloid proliferation was observed in any group. Keloid histologic characters were confirmed in all grafts. No histologic particularity was observed in the laser groups in comparison with the Control and Resection groups. CONCLUSION: First, this keloid animal model appears to be adapted for laser study. Secondly, the 1,210-nm diode laser does not induce keloid thermal damage in vivo. Further studies with different 1,210-nm laser diode parameters should be performed in order to observe significant effects on keloids. PMID- 26437850 TI - Next-generation-based targeted sequencing as an efficient tool for the study of the genetic background in Hirschsprung patients. AB - BACKGROUND: The development of next-generation sequencing (NGS) technologies has a great impact in the human variation detection given their high-throughput. These techniques are particularly helpful for the evaluation of the genetic background in disorders of complex genetic etiology such as Hirschsprung disease (HSCR). The purpose of this study was the design of a panel of HSCR associated genes as a rapid and efficient tool to perform genetic screening in a series of patients. METHODS: We have performed NGS-based targeted sequencing (454-GS Junior) using a panel containing 26 associated or candidate genes for HSCR in a group of 11 selected HSCR patients. RESULTS: The average percentage of covered bases was of 97%, the 91.4% of the targeted bases were covered with depth above 20X and the mean coverage was 422X. In addition, we have found a total of 13 new coding variants and 11 new variants within regulatory regions among our patients. These outcomes allowed us to re-evaluate the genetic component associated to HSCR in these patients. CONCLUSIONS: Our validated NGS panel constitutes an optimum method for the identification of new variants in our patients. This approach could be used for a fast, reliable and more thorough genetic screening in future series of patients. PMID- 26437852 TI - One in four GP appointments can be avoided, says report. PMID- 26437853 TI - Effect of adjuvant chemotherapy on recurrence-free survival varies by neo adjuvant treatment in patients with stage III rectal cancer. AB - INTRODUCTION: Adjuvant chemotherapy still is a controversial therapy for rectal cancer patients. The aim of this study was to analyze the effect of adjuvant chemotherapy on recurrence-free survival (RFS) for patients with stage III rectal cancer treated in clinical practice, taking into account which neo-adjuvant treatment patients received. METHODS: Patients from regions in the Netherlands diagnosed between 1996 and 2013 with pathological stage III rectal cancer who received short-course radiotherapy, chemoradiation or no neo-adjuvant treatment and who underwent surgery were included. After stratification by neo-adjuvant treatment, 5-year RFS according to adjuvant chemotherapy receipt was calculated using Kaplan-Meier curves. Cox regression was used to discriminate the independent effect of adjuvant chemotherapy on the risk of recurrence/death. RESULTS: The study population consisted of 829 patients, of whom 537 (65%) patients received short-course radiotherapy, 128 (15%) patients received chemoradiation and 164 (20%) patients received no neo-adjuvant treatment. Adjuvant chemotherapy was administered to 152 (18%) patients. Adjuvant chemotherapy was associated with improved 5-year RFS for patients who received short-course radiotherapy (61% vs. 46%, p = 0.005) and for patients who did not receive any neo-adjuvant treatment (70% vs. 28%, p < 0.0001). In multivariable analyses, adjuvant chemotherapy was associated with a reduced risk of recurrence/death for patients treated with short-course radiotherapy (HR 0.65, 95% CI 0.46-0.93) and for patients without neo-adjuvant treatment (HR 0.35, 95% CI 0.18-0.71), but not for patients treated with chemoradiation (HR 1.11, 95% CI 0.51-2.41). CONCLUSION: Among patients with stage III rectal cancer, the effect of adjuvant chemotherapy on RFS seems to vary by neo-adjuvant treatment. PMID- 26437854 TI - Reply to: "Is there a role for axillary reverse mapping in the current management of breast cancer treatment?". PMID- 26437855 TI - Is radiofrequency ablation of lung metastases the most radical treatment? PMID- 26437856 TI - Intraspinal serotonergic neurons consist of two, temporally distinct populations in developing zebrafish. AB - Zebrafish intraspinal serotonergic neuron (ISN) morphology and distribution have been examined in detail at different ages; however, some aspects of the development of these cells remain unclear. Although antibodies to serotonin (5 HT) have detected ISNs in the ventral spinal cord of embryos, larvae, and adults, the only tryptophan hydroxylase (tph) transcript that has been described in the spinal cord is tph1a. Paradoxically, spinal tph1a is only expressed transiently in embryos, which brings the source of 5-HT in the ISNs of larvae and adults into question. Because the pet1 and tph2 promoters drive transgene expression in the spinal cord, we hypothesized that tph2 is expressed in spinal cords of zebrafish larvae. We confirmed this hypothesis through in situ hybridization. Next, we used 5-HT antibody labeling and transgenic markers of tph2-expressing neurons to identify a transient population of ISNs in embryos that was distinct from ISNs that appeared later in development. The existence of separate ISN populations may not have been recognized previously due to their shared location in the ventral spinal cord. Finally, we used transgenic markers and immunohistochemical labeling to identify the transient ISN population as GABAergic Kolmer-Agduhr double-prime (KA") neurons. Altogether, this study revealed a novel developmental paradigm in which KA" neurons are transiently serotonergic before the appearance of a stable population of tph2-expressing ISNs. PMID- 26437857 TI - Multicopper oxidase-1 is required for iron homeostasis in Malpighian tubules of Helicoverpa armigera. AB - Multicopper oxidases (MCOs) are enzymes that contain 10 conserved histidine residues and 1 cysteine residue. MCO1 has been extensively investigated in the midgut because this MCO is implicated in ascorbate oxidation, iron homeostasis and immune responses. However, information regarding the action of MCO1 in Malpighian tubules is limited. In this study, Helicoverpa armigera was used as a model to investigate the function of MCO1 in Malpighian tubules. Sequence analysis results revealed that HaMCO1 exhibits typical MCO characteristics, with 10 histidine and 1 cysteine residues for copper ion binding. HaMCO1 was also found to be highly abundant in Malpighian tubules. Temporal expression patterns indicated that HaMCO1 is mainly expressed during larval molting stages. Hormone treatments [the molting hormone 20-hydroxyecdysone (20E) and juvenile hormone (JH)] revealed that 20E inhibits HaMCO1 transcript expression via its heterodimer receptor, which consists of ecdysone receptor (EcR) and ultraspiracle (USP), and that JH counteracts the action of 20E to activate HaMCO1 transcript expression via its intracellular receptor methoprene-tolerant (Met). HaMCO1 knockdown caused a significant decrease in iron accumulation and also significantly reduced transferrin and ferritin transcript expression. Therefore, HaMCO1 is coordinately regulated by 20E and JH and is required for iron homeostasis in Malpighian tubules. PMID- 26437858 TI - Model of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells. AB - The aetiology of human fibrolamellar hepatocellular carcinomas (hFL-HCCs), cancers occurring increasingly in children to young adults, is poorly understood. We present a transplantable tumour line, maintained in immune-compromised mice, and validate it as a bona fide model of hFL-HCCs by multiple methods. RNA-seq analysis confirms the presence of a fusion transcript (DNAJB1-PRKACA) characteristic of hFL-HCC tumours. The hFL-HCC tumour line is highly enriched for cancer stem cells as indicated by limited dilution tumourigenicity assays, spheroid formation and flow cytometry. Immunohistochemistry on the hFL-HCC model, with parallel studies on 27 primary hFL-HCC tumours, provides robust evidence for expression of endodermal stem cell traits. Transcriptomic analyses of the tumour line and of multiple, normal hepatic lineage stages reveal a gene signature for hFL-HCCs closely resembling that of biliary tree stem cells--newly discovered precursors for liver and pancreas. This model offers unprecedented opportunities to investigate mechanisms underlying hFL-HCCs pathogenesis and potential therapies. PMID- 26437859 TI - Genetic identification of cytomegaloviruses in a rural population of Cote d'Ivoire. AB - BACKGROUND: Cytomegaloviruses (CMVs) are herpesviruses that infect many mammalian species, including humans. Infection generally passes undetected, but the virus can cause serious disease in individuals with impaired immune function. Human CMV (HCMV) is circulating with high seroprevalence (60-100 %) on all continents. However, little information is available on HCMV genoprevalence and genetic diversity in subsaharan Africa, especially in rural areas of West Africa that are at high risk of human-to-human HCMV transmission. In addition, there is a potential for zoonotic spillover of pathogens through bushmeat hunting and handling in these areas as shown for various retroviruses. Although HCMV and nonhuman CMVs are regarded as species-specific, potential human infection with CMVs of non-human primate (NHP) origin, shown to circulate in the local NHP population, has not been studied. FINDINGS: Analysis of 657 human oral swabs and fecal samples collected from 518 individuals living in 8 villages of Cote d'Ivoire with generic PCR for identification of human and NHP CMVs revealed shedding of HCMV in 2.5 % of the individuals. Determination of glycoprotein B sequences showed identity with strains Towne, AD169 and Toledo, respectively. NHP CMV sequences were not detected. CONCLUSIONS: HCMV is actively circulating in a proportion of the rural Cote d'Ivoire human population with circulating strains being closely related to those previously identified in non-African countries. The lack of NHP CMVs in human populations in an environment conducive to cross species infection supports zoonotic transmission of CMVs to humans being at most a rare event. PMID- 26437860 TI - Malaria ecology along the Thailand-Myanmar border. AB - BACKGROUND: Malaria in Southeast Asia frequently clusters along international borders. For example, while most of Thailand is malaria free, the border region shared with Myanmar continues to have endemic malaria. This spatial pattern is the result of complex interactions between landscape, humans, mosquito vectors, and malaria parasites. An understanding of these complex ecological and socio cultural interactions is important for designing and implementing malaria elimination efforts in the region. This article offers an ecological perspective on the malaria situation along the Thailand-Myanmar border. DISCUSSION: This border region is long (2000 km), mountainous, and the environment ranges from thick forests to growing urban settlements and wet-rice fields. It is also a biologically diverse region. All five species of malaria known to naturally infect humans are present. At least three mosquito vector species complexes, with widely varying behavioural characteristics, exist in the area. The region is also a hub for ethnic diversity, being home to over ten different ethnolinguistic groups, several of which have been engaged in conflict with the Myanmar government now for over half a century. Given the biological and ethnic diversity, as well as the complex socio-political context, malaria control and elimination in the region is challenging. CONCLUSION: Despite these complexities, multipronged approaches including collaborations with multiple local organizations, quick access to diagnosis and treatment, prevention of mosquito bites, radical cure of parasites, and mass drug administration appear to be drastically decreasing Plasmodium falciparum infections. Such approaches remain crucial as the region moves toward elimination of P. falciparum and potentially Plasmodium vivax. PMID- 26437861 TI - Chemomodulatory Potential of Flaxseed Oil Against DMBA/Croton Oil-Induced Skin Carcinogenesis in Mice. AB - The present study was conducted to evaluate the potential of flaxseed oil to prevent chemically induced skin cancer in mice. Cancer was induced on 2-stage skin carcinogenesis model by single topical application of 7,12 dimethylbenz [a]anthracene (DMBA), as, initiator, and two weeks later it was promoted by croton oil treatment thrice a week on the dorsal surface of mice for 16 weeks. Flaxseed oil (FSO; 100uL/animal/d) was orally administered 1 week before and 1 week after DMBA application (Peri-initiation stage). The animals of the FSO administered group showed a significant reduction in tumor incidence (76.67%), cumulative number of tumors (37), tumor yield (3.7), and tumor burden (4.81) when compared with the carcinogen-treated control animals. Biochemical parameters in skin and liver tissue such as LPO and phase I enzymes were significantly (P < .01) reduced in the FSO-treated experimental group, whereas the phase II enzymes (GST, DT-diaphorase) and antioxidant parameters (GSH, GPx, SOD, catalase, and vitamin C) exhibited a significant (P < .01) elevation when compared with the animals of the carcinogen-treated control group. Histopathological alterations in the carcinogen-treated control animals were also observed in the form of epidermal hyperplasia, keratinized pearl formation, and acanthosis in skin and tumors, whereas these were found to be reduced after FSO administration. The results of the present study demonstrate that the oral administration of FSO has the potential to modulate the levels of LPO, antioxidants, and detoxification enzymes in the DMBA-croton oil-induced skin carcinogenesis in mice. PMID- 26437863 TI - Wisdom at the End of Life: An Analysis of Mediating and Moderating Relations Between Wisdom and Subjective Well-Being. AB - OBJECTIVES: Several studies have shown that wisdom, measured as an integration of cognitive, reflective, and compassionate dimensions, is positively related to subjective well-being in old age. This study investigated whether wisdom might be particularly beneficial for people at the end of life, when extrinsic means to increase well-being largely disappear, and whether the association between wisdom and well-being is mediated by mastery and purpose in life. METHODS: Samples of 156 older community residents (M = 71 years) and 41 older hospice patients and nursing home residents (M = 77 years) were analyzed, using a moderated and mediated path model. RESULTS: (a) Wisdom was positively related to subjective well-being in the later years, even after controlling for physical health, socioeconomic status, financial situation, social involvement, age, gender, race, and marital status. (b) The association between wisdom and well-being was significantly stronger in the nursing home and hospice sample than the community sample. (c) The relation between wisdom and well-being was partially mediated by purpose in life, both directly and via a sense of mastery. CONCLUSION: Aging well at the end of life might depend to a larger extent on psychosocial growth across the life course than on present circumstances. PMID- 26437862 TI - Associations Among Individuals' Perceptions of Future Time, Individual Resources, and Subjective Well-Being in Old Age. AB - Objectives: Perceptions of future time are of key interest to aging research because of their implications for subjective well-being. Interestingly, perceptions about future time are only moderately associated with age when looking at the second half of life, pointing to a vast heterogeneity in future time perceptions among older adults. We examine associations between future time perceptions, age, and subjective well-being across two studies, including moderations by individual resources. Method: Using data from the Berlin Aging Study (N = 516; Mage = 85 years), we link one operationalization (subjective nearness to death) and age to subjective well-being. Using Health and Retirement Study data (N = 2,596; Mage = 77 years), we examine associations of another future time perception indicator (subjective future life expectancy) and age with subjective well-being. Results: Consistent across studies, perceptions of limited time left were associated with poorer subjective well-being (lower life satisfaction and positive affect; more negative affect and depressive symptoms). Importantly, individual resources moderated future time perception-subjective well-being associations with those of better health exhibiting reduced future time perception-subjective well-being associations. Discussion: We discuss our findings in the context of the Model of Strength and Vulnerability Integration. PMID- 26437864 TI - Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS. AB - The nuclear transactive response DNA-binding protein 43 (TDP-43) undergoes relocalization to the cytoplasm with formation of cytoplasmic deposits in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Pathogenic mutations in the TDP-43-encoding TARDBP gene in familial ALS as well as non-mutant human TDP-43 have been utilized to model FTD/ALS in cell culture and animals, including mice. Here, we report novel A315T mutant TDP-43 transgenic mice, iTDP-43(A315T), with controlled neuronal over-expression. Constitutive expression of human TDP-43(A315T) resulted in pronounced early-onset and progressive neurodegeneration, which was associated with compromised motor performance, spatial memory and disinhibition. Muscle atrophy resulted in reduced grip strength. Cortical degeneration presented with pronounced astrocyte activation. Using differential protein extraction from iTDP-43(A315T) brains, we found cytoplasmic localization, fragmentation, phosphorylation and ubiquitination and insolubility of TDP-43. Surprisingly, suppression of human TDP-43(A315T) expression in mice with overt neurodegeneration for only 1 week was sufficient to significantly improve motor and behavioral deficits, and reduce astrogliosis. Our data suggest that functional deficits in iTDP-43(A315T) mice are at least in part a direct and transient effect of the presence of TDP-43(A315T). Furthermore, it illustrates the compensatory capacity of compromised neurons once transgenic TDP 43 is removed, with implications for future treatments. PMID- 26437866 TI - Predictive factors for perioperative blood transfusions in partial nephrectomy for renal masses. AB - BACKGROUND: Allogeneic perioperative blood transfusions (PBT) have been associated with higher rates of postoperative complications and tumour recurrence in a number of malignancies. This study evaluates the risk factors for PBT in patients undergoing partial nephrectomy (PN), in order to identify patients who could benefit from alternatives to allogenic blood. METHODS: Data on 822 patients who underwent elective PN between 1988 and 2013 were analysed. Patient demographics and clinicopathologic variables were collected retrospectively. PBT was defined as transfusion of allogeneic red blood cells during PN (in the operating-room) or postoperative hospitalization. RESULTS: Of the 822 patients, 122 (14.8%) received PBT. Of these, 45.9% were transfused intraoperatively and 47.5% in the postoperative period. Only 14.3% of the patients who were transfused intraoperatively required additional postoperative transfusions. On multivariable analysis, age >=65 (P < 0.01), lower preoperative haemoglobin levels (P < 0.001), larger renal masses (P < 0.001), central lesions (P < 0.01) and cumulative surgical experience (P < 0.001) were found to be associated with higher rate of PBT. CONCLUSIONS: Age, low preoperative haemoglobin level, lesion size, surgeons' experience and central renal lesions are independent pre-operative risk factors for PBT in patients undergoing PN. Evaluation of these risk factors prior to surgery may be helpful in constituting guidelines for a more responsible use of allogeneic blood and its alternatives. PMID- 26437865 TI - Novel clinical associations with specific C9ORF72 transcripts in patients with repeat expansions in C9ORF72. AB - The loss of chromosome 9 open reading frame 72 (C9ORF72) expression, associated with C9ORF72 repeat expansions, has not been examined systematically. Three C9ORF72 transcript variants have been described thus far; the GGGGCC repeat is located between two non-coding exons (exon 1a and exon 1b) in the promoter region of transcript variant 2 (NM_018325.4) or in the first intron of variant 1 (NM_145005.6) and variant 3 (NM_001256054.2). We studied C9ORF72 expression in expansion carriers (n = 56) for whom cerebellum and/or frontal cortex was available. Using quantitative real-time PCR and digital molecular barcoding techniques, we assessed total C9ORF72 transcripts, variant 1, variant 2, variant 3, and intron containing transcripts [upstream of the expansion (intron 1a) and downstream of the expansion (intron 1b)]; the latter were correlated with levels of poly(GP) and poly(GA) proteins aberrantly translated from the expansion as measured by immunoassay (n = 50). We detected a decrease in expansion carriers as compared to controls for total C9ORF72 transcripts, variant 1, and variant 2: the strongest association was observed for variant 2 (quantitative real-time PCR cerebellum: median 43 %, p = 1.26e-06, and frontal cortex: median 58 %, p = 1.11e 05; digital molecular barcoding cerebellum: median 31 %, p = 5.23e-10, and frontal cortex: median 53 %, p = 5.07e-10). Importantly, we revealed that variant 1 levels greater than the 25th percentile conferred a survival advantage [digital molecular barcoding cerebellum: hazard ratio (HR) 0.31, p = 0.003, and frontal cortex: HR 0.23, p = 0.0001]. When focusing on intron containing transcripts, analysis of the frontal cortex revealed an increase of potentially truncated transcripts in expansion carriers as compared to controls [digital molecular barcoding frontal cortex (intron 1a): median 272 %, p = 0.003], with the highest levels in patients pathologically diagnosed with frontotemporal lobar degeneration. In the cerebellum, our analysis suggested that transcripts were less likely to be truncated and, excitingly, we discovered that intron containing transcripts were associated with poly(GP) levels [digital molecular barcoding cerebellum (intron 1a): r = 0.33, p = 0.02, and (intron 1b): r = 0.49, p = 0.0004] and poly(GA) levels [digital molecular barcoding cerebellum (intron 1a): r = 0.34, p = 0.02, and (intron 1b): r = 0.38, p = 0.007]. In summary, we report decreased expression of specific C9ORF72 transcripts and provide support for the presence of truncated transcripts as well as pre-mRNAs that may serve as templates for RAN translation. We further show that higher C9ORF72 levels may have beneficial effects, which warrants caution in the development of new therapeutic approaches. PMID- 26437867 TI - Cross-sectional Examination of Long-term Access to Sit-Stand Desks in a Professional Office Setting. AB - INTRODUCTION: Prolonged sedentary behavior is an independent risk factor for many negative health outcomes. Although many employers have begun introducing sit stand desks as means of reducing employee's occupational sitting time, few studies have examined the impact of prolonged access to such desks on sitting/standing time or cardiometabolic outcomes. The present study compared occupational sedentary/physical activity behaviors and cardiometabolic biomarkers among employees with long-term access to traditional sitting and sit-stand desks. METHODS: This study used a naturalistic, cross-sectional study design. Occupational sedentary and physical activity behaviors and cardiometabolic health outcomes were collected in a controlled laboratory between February and June 2014. Data were analyzed in September 2014. Adults working in full-time sedentary desk jobs who reported having either a sit-stand desk (n=31) or standard sitting desk (n=38) for a minimum of 6 months were recruited. RESULTS: Employees with sit stand desks sat less (p=0.02) and stood more at work (p=0.01) compared with employees with sitting desks. Significant inverse correlations were observed between several occupational physical activity outcomes (walking time, steps at work) and cardiometabolic risk factors (systolic blood pressure, weight, lean mass, BMI) over the entire sample. CONCLUSIONS: Employees with long-term access to sit-stand desks sat less and stood more compared with employees with sitting desks. These findings hold public health significance, as sit-stand desks represent a potentially sustainable approach for reducing sedentary behavior among the large, growing number of sedentary workers at increased risk for sedentariness-related pathologies. PMID- 26437868 TI - The Nutrient Content of U.S. Household Food Purchases by Store Type. AB - INTRODUCTION: Little is known about where households shop for packaged foods, what foods and beverages they purchase, and the nutrient content of these purchases. This study describes volume trends and nutrient content (nutrient profiles, food and beverage groups) of household packaged foods purchases (PFPs) by store type. METHODS: Cross-sectional analysis of U.S. households' PFPs (Nielsen Homescan) from 2000 to 2012 (N=652,023 household-year observations) with survey weights used for national representativeness. Household PFP trends (% volume), household purchases of key food and beverage groups based on caloric contribution, and mean caloric and nutrient densities (sugars, saturated fat, and sodium) of household PFPs were analyzed by store type. Data were collected from 2000 to 2012. Analyses were conducted in 2014-2015. RESULTS: The proportion of total volume of household PFPs significantly increased from 2000 to 2012 for mass merchandisers (13.1% to 23.9%), convenience stores (3.6% to 5.9%), and warehouse clubs (6.2% to 9.8%), and significantly decreased for grocery chains (58.5% to 46.3%) and non-chain grocers (10.3% to 5.2%). Top common sources of calories (%) from household PFPs by food/beverage group included: savory snacks, grain-based desserts, and regular soft drinks. The energy, total sugar, sodium, and saturated fat densities of household PFPs from mass merchandisers, warehouse clubs, and convenience stores were higher compared with grocery stores. CONCLUSIONS: PFPs from stores with poorer nutrient density (more energy, total sugar, sodium, and saturated fat-dense), such as warehouse clubs, mass merchandisers, and convenience stores are growing, representing a potential U.S. public health concern. PMID- 26437869 TI - Association Between Sedentary Work and BMI in a U.S. National Longitudinal Survey. AB - INTRODUCTION: Technological advancements have made life and work more sedentary, and long hours of sitting are known to be associated with many health concerns. Several studies have reported an association between prolonged sitting time at work and weight gain, but the results are inconsistent. This study examined the relationship between sitting time at work and BMI using data from a large prospective cohort of U.S. men and women from 2002 to 2010. Initial analyses were performed in 2013, with additional analyses in 2014 and 2015. METHODS: The sample size at the base year (2002) was 5,285 and the age range 38-45 years. The outcome, BMI, was based on self-reported measures of height and weight. Estimates of workplace sitting time were linked from an external database (Occupational Information Network), and the occupation-wide rating for sitting time was linked to survey participants by occupation. Fixed-effects models controlling for time invariant effects of all time-invariant characteristics were employed to examine the association, controlling for age, education, work hours, and hours of vigorous and light/moderate physical activities. RESULTS: Longer sitting time was significantly associated with higher BMI for the overall sample (beta = 0.054; p<0.05) and men (beta = 0.086; p<0.01). For women, the association was not statistically significant. CONCLUSIONS: The findings provide further support for initiatives to reduce workplace sitting time as a means of reducing the risk of weight gain and related health conditions. PMID- 26437870 TI - Acidity of two-dimensional zeolites. AB - Hybrid quantum mechanics:molecular mechanics (QM/MM) calculations of absolute deprotonation energies are performed with periodic boundary conditions for Bronsted sites of aluminosilicate bilayers with various Al/Si ratios (two dimensional zeolite). The supercell method is applied and density functional theory is used. Much lower values are obtained (1042, 1069 and 1091 kJ mol(-1) for Al/Si = 1/63, 1/7 and 1/3, respectively) than those for bulk zeolites (1233 kJ mol(-1) for H-chabazite with Al/Si = 1/11). We ascribe the much lower deprotonation energy to the smaller effective dielectric constant (1.6-1.9) of an ultra-thin dielectric in a vacuum compared to that of the corresponding bulk systems (3.0 for H-chabazite), which leads to a better stabilization of the charge created upon deprotonation. PMID- 26437871 TI - Efficacy of Azacitidine in De Novo and Relapsed Acute Myeloid Leukemia: A Retrospective Comparative Study. AB - INTRODUCTION: Azacitidine is a therapeutic alternative to low-dose cytarabine in patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. PATIENTS AND METHODS: We retrospectively analyzed all AML patients treated with azacitidine at the University Hospital Zurich and the Kantonsspital Munsterlingen between January 2005 and December 2011. The primary end point was overall survival (OS). RESULTS: Thirty-eight patients were included in the analysis. Twenty-one (55%) patients had newly diagnosed AML, 14 (37%) had relapsed AML, and 3 (8%) underwent bridging therapy before allogeneic stem-cell transplantation. Age at diagnosis was 72 years in the newly diagnosed cohort and 58 years in the relapsed cohort, 19 (50%) patients were female, 20 (53%) patients were transfusion dependent, and bone marrow blast count was 43% (interquartile range, 26-80). Most patients (58%) had poor or very poor risk AML. Patients received a median (range) of 7 (3-13) therapy cycles. The median (range) OS in the newly diagnosed and previously treated patient groups were 308 (175-580) days and 346 (293-628) days, respectively (P = .94). Median OS in the 3 patients treated before allogeneic stem-cell transplantation has not been reached. Sixty day mortality was 7.9%, with no difference between the 2 groups. Ongoing or increasing transfusion dependency was associated with adverse outcome (hazard ratio, 3.09; 95% confidence interval, 1.29-7.37, P = .011). CONCLUSION: Treatment with azacitidine led to a median OS of 10 months in both a previously untreated and a previously treated frail AML patient cohort. A positive effect in transfusion dependency was observed in 29% of these patients and was associated with better survival. PMID- 26437872 TI - Clinical development of RTS,S/AS malaria vaccine: a systematic review of clinical Phase I-III trials. AB - The first clinical Phase III trial evaluating a malaria vaccine was completed in December 2013 at 11 sites from seven sub-Saharan African countries. This systematic review assesses data of Phase I-III trials including malaria-naive adults and adults, children and infants from malaria endemic settings in sub Saharan Africa. The main endpoint of this systematic review was an analysis of the consistency of efficacy and immunogenicity data from respective Phase I-III trials. In addition, safety data from a pooled analysis of RTS/AS Phase II trials and RTS,S/AS01 Phase III trial were reviewed. The RTS,S/AS01 malaria vaccine may become available on the market in the coming year. If so, further strategies should address challenges on how to optimize vaccine efficacy and implementation of RTS,S/AS01 vaccine within the framework of established malaria control measures. PMID- 26437873 TI - Femtosecond X-ray absorption study of electron localization in photoexcited anatase TiO2. AB - Transition metal oxides are among the most promising solar materials, whose properties rely on the generation, transport and trapping of charge carriers (electrons and holes). Identifying the latter's dynamics at room temperature requires tools that combine elemental and structural sensitivity, with the atomic scale resolution of time (femtoseconds, fs). Here, we use fs Ti K-edge X-ray absorption spectroscopy (XAS) upon 3.49 eV (355 nm) excitation of aqueous colloidal anatase titanium dioxide nanoparticles to probe the trapping dynamics of photogenerated electrons. We find that their localization at Titanium atoms occurs in <300 fs, forming Ti(3+) centres, in or near the unit cell where the electron is created. We conclude that electron localization is due to its trapping at pentacoordinated sites, mostly present in the surface shell region. The present demonstration of fs hard X-ray absorption capabilities opens the way to a detailed description of the charge carrier dynamics in transition metal oxides. PMID- 26437874 TI - [The Convention on Biological Diversity and the Nagoya Protocol- Beware of and prevent their possible side effects on virus research and public health measures]. PMID- 26437875 TI - Slow intestinal transit contributes to elevate urinary p-cresol level in Italian autistic children. AB - The uremic toxin p-cresol (4-methylphenol) is either of environmental origin or can be synthetized from tyrosine by cresol-producing bacteria present in the gut lumen. Elevated p-cresol amounts have been previously found in the urines of Italian and French autism spectrum disorder (ASD) children up until 8 years of age, and may be associated with autism severity or with the intensity of abnormal behaviors. This study aims to investigate the mechanism producing elevated urinary p-cresol in ASD. Urinary p-cresol levels were thus measured by High Performance Liquid Chromatography in a sample of 53 Italian ASD children assessed for (a) presence of Clostridium spp. strains in the gut by means of an in vitro fecal stool test and of Clostridium difficile-derived toxin A/B in the feces, (b) intestinal permeability using the lactulose/mannitol (LA/MA) test, (c) frequent use of antibiotics due to recurrent infections during the first 2 years of postnatal life, and (d) stool habits with the Bristol Stool Form Scale. Chronic constipation was the only variable significantly associated with total urinary p cresol concentration (P < 0.05). No association was found with presence of Clostridium spp. in the gut flora (P = 0.92), augmented intestinal permeability (P = 0.18), or frequent use of antibiotics in early infancy (P = 0.47). No ASD child was found to carry C. difficile in the gut or to release toxin A/B in the feces. In conclusion, urinary p-cresol levels are elevated in young ASD children with increased intestinal transit time and chronic constipation. Autism Res 2016, 9: 752-759. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26437876 TI - Special issue on computer-aided drug discovery. PMID- 26437877 TI - Kinesin-5 is a microtubule polymerase. AB - Kinesin-5 slides antiparallel microtubules during spindle assembly, and regulates the branching of growing axons. Besides the mechanical activities enabled by its tetrameric configuration, the specific motor properties of kinesin-5 that underlie its cellular function remain unclear. Here by engineering a stable kinesin-5 dimer and reconstituting microtubule dynamics in vitro, we demonstrate that kinesin-5 promotes microtubule polymerization by increasing the growth rate and decreasing the catastrophe frequency. Strikingly, microtubules growing in the presence of kinesin-5 have curved plus ends, suggesting that the motor stabilizes growing protofilaments. Single-molecule fluorescence experiments reveal that kinesin-5 remains bound to the plus ends of static microtubules for 7 s, and tracks growing microtubule plus ends in a manner dependent on its processivity. We propose that kinesin-5 pauses at microtubule plus ends and enhances polymerization by stabilizing longitudinal tubulin-tubulin interactions, and that these activities underlie the ability kinesin-5 to slide and stabilize microtubule bundles in cells. PMID- 26437878 TI - To Transfer or Not to Transfer? Development of a Dinitrosyl Iron Complex as a Nitroxyl Donor for the Nitroxylation of an Fe(III) -Porphyrin Center. AB - A positive myocardial inotropic effect achieved using HNO/NO(-) , compared with NO?, triggered attempts to explore novel nitroxyl donors for use in clinical applications in vascular and myocardial pharmacology. To develop M-NO complexes for nitroxyl chemistry and biology, modulation of direct nitroxyl-transfer reactivity of dinitrosyl iron complexes (DNICs) is investigated in this study using a Fe(III) -porphyrin complex and proteins as a specific probe. Stable dinuclear {Fe(NO)2 }(9) DNIC [Fe(MU-(Me) Pyr)(NO)2 ]2 was discovered as a potent nitroxyl donor for nitroxylation of Fe(III) -heme centers through an associative mechanism. Beyond the efficient nitroxyl transfer, transformation of DNICs into a chemical biology probe for nitroxyl and for pharmaceutical applications demands further efforts using in vitro/in vivo studies. PMID- 26437879 TI - The effects of phylogenetic relatedness on invasion success and impact: deconstructing Darwin's naturalisation conundrum. AB - Darwin's naturalisation conundrum describes the paradox that the relatedness of exotic species to native residents could either promote or hinder their success through opposing mechanisms: niche pre-adaptation or competitive interactions. Previous studies focusing on single snapshots of invasion patterns have provided support to both sides of the conundrum. Here, by examining invasion dynamics of 480 plots over 40 years, we show that exotic species more closely related to native species were more likely to enter, establish and dominate the resident communities, and that native residents more closely related to these successful exotics were more likely to go locally extinct. Therefore, non-random displacement of natives during invasion could weaken or even reverse the negative effects of exotic-native phylogenetic distances on invasion success. The scenario that exotics more closely related to native residents are more successful, but tend to eliminate their closely related natives, may help to reconcile the 150 year-old conundrum. PMID- 26437880 TI - Controlled mud-crack patterning and self-organized cracking of polydimethylsiloxane elastomer surfaces. AB - Exploiting pattern formation - such as that observed in nature - in the context of micro/nanotechnology could have great benefits if coupled with the traditional top-down lithographic approach. Here, we demonstrate an original and simple method to produce unique, localized and controllable self-organised patterns on elastomeric films. A thin, brittle silica-like crust is formed on the surface of polydimethylsiloxane (PDMS) using oxygen plasma. This crust is subsequently cracked via the deposition of a thin metal film - having residual tensile stress. The density of the mud-crack patterns depends on the plasma dose and on the metal thickness. The mud-crack patterning can be controlled depending on the thickness and shape of the metallization - ultimately leading to regularly spaced cracks and/or metal mesa structures. Such patterning of the cracks indicates a level of self-organization in the structuring and layout of the features - arrived at simply by imposing metallization boundaries in proximity to each other, separated by a distance of the order of the critical dimension of the pattern size apparent in the large surface mud-crack patterns. PMID- 26437881 TI - Clinical and molecular delineation of dysequilibrium syndrome type 2 and profound sensorineural hearing loss in an inbred Arab family. PMID- 26437883 TI - 360 degrees versus localized demarcation laser photocoagulation for macular sparing retinal detachment in silicone oil-filled eyes with undetected breaks: A retrospective, comparative, interventional study. AB - BACKGROUND AND OBJECTIVE: Recurrent retinal detachment (RD) in silicone oil filled eyes is a serious condition. At the initial stage, it usually spares the macular and is localized in the inferior retina. The inability to locate the retinal breaks has been reported to be associated with a poor prognosis and has limited the use of conventional vitreoretinal surgeries. Demarcation laser photocoagulation (DLP) is widely accepted for treating macular-sparing RDs. For laser treatments to be effective, an adequate extent and the correct placement of the laser is of great importance. The purpose of this research was to compare the efficacy of 360 degrees and localized DLP in the management of macular-sparing RD in silicone oil-filled eyes with no detected retinal breaks. MATERIALS AND METHODS: This is a retrospective, comparative, interventional study. The medical records of 48 consecutive eyes with macular-sparing RD in silicone oil-filled eyes with no detected retinal breaks were reviewed. Twenty-six patients (group I) received 360 degrees DLP, and the remaining 22 patients (group II) underwent localized DLP. The anatomical and visual outcomes of the two groups were compared. RESULTS: The mean follow-up period was 12.54 +/- 1.17 months. No significant difference was identified in the baseline characteristics. The single operation success rate of 92.31% was achieved in group I, which was significantly higher than that of group II (59.09%, P = 0.01), and this trend was not weakened after adjusting for confounding factors (odds ratio: 0.002, P = 0.02). After salvage management of vitreoretinal surgeries, both groups had equivalent visual outcomes with silicone oil removal. Multivariate logistic regression also indicated that the radial extent of RD (odds ratio: 11.10, P = 0.04) was an independent predictor for laser treatment failure. Significant complications sufficient to require further operations included proliferative vitreoretinopathy in two (4.17%) eyes and epiretinal membrane in four (8.33%) eyes. CONCLUSIONS: The 360 degrees DLP achieved a better primary success rate and equivalent visual outcomes with localized DLP for macular-sparing RD in silicone oil-filled eyes with no detected retinal breaks. PMID- 26437884 TI - Fitness consequences of short- and long-distance pollinations in Phlox hirsuta, an endangered species. AB - PREMISE OF THE STUDY: The persistence of rare and endangered plant species may depend on the distance pollinators travel when dispersing pollen. Pollinations between adjacent plants, which are often genetically similar, can decrease seed set, germination, and/or progeny vigor due to shared S-alleles or inbreeding depression. Interpopulation pollen dispersal is often suggested as a management tool to increase genetic diversity; however, long-distance pollinations also have the potential to decrease fitness. METHODS: We performed experimental hand pollinations in the field and germination experiments in a growth chamber to determine the effect of intrapopulation pollination distance (1 m, 10 m, and 100 m) on seed set, seed germination, progeny growth, and progeny reproduction in Phlox hirsuta. In addition, we included interpopulation pollinations (6740 m) to determine whether artificial gene flow is a viable management option for this endangered species. KEY RESULTS: Although pollination distance did not affect the number of healthy seeds produced or the likelihood of radicle emergence, it did significantly affect the ability of germinating seeds to successfully produce cotyledons. Outbreeding depression was observed during seed germination and early seedling development. Seedlings resulting from interpopulation pollinations developed more slowly and were less likely to survive to produce cotyledons than seedlings resulting from all three intrapopulation pollination distances. CONCLUSIONS: Our results suggest that the success of P. hirsuta does not depend on the distance pollinators travel within populations and that conservation strategies that involve transporting genes between populations can be counterproductive. PMID- 26437882 TI - Targeting mosquito FREP1 with a fungal metabolite blocks malaria transmission. AB - Inhibiting Plasmodium development in mosquitoes will block malaria transmission. Fibrinogen-related protein 1 (FREP1) is critical for parasite infection in Anopheles gambiae and facilitates Plasmodium invasion in mosquitoes through interacting with gametocytes and ookinetes. To test the hypothesis that small molecules that disrupt this interaction will prevent parasites from infecting mosquitoes, we developed an ELISA-based method to screen a fungal extract library. We obtained a candidate fungal extract of Aspergillus niger that inhibited the interaction between FREP1 and P. falciparum infected cells by about 92%. The inhibition specificity was confirmed by immunofluorescence assays. Notably, feeding mosquitoes with the candidate fungal extract significantly inhibited P. falciparum infection in the midgut without cytotoxicity or inhibition of the development of P. falciparum gametocytes or ookinetes. A bioactive natural product that prevents FREP1 from binding to gametocytes or ookinetes was isolated and identified as P-orlandin. Importantly, the nontoxic orlandin significantly reduced P. falciparum infection intensity in mosquitoes. Therefore, disruption of the interaction between FREP1 and parasites effectively reduces Plasmodium infection in mosquitoes. Targeting FREP1 with small molecules is thus an effective novel approach to block malaria transmission. PMID- 26437885 TI - Pleistocene climatic oscillations rather than recent human disturbance influence genetic diversity in one of the world's highest treeline species. AB - PREMISE OF THE STUDY: Biological responses to climatic change usually leave imprints on the genetic diversity and structure of plants. Information on the current genetic diversity and structure of dominant tree species has facilitated our general understanding of phylogeographical patterns. METHODS: Using amplified fragment length polymorphism (AFLPs), we compared genetic diversity and structure of 384 adults of P. tarapacana with those of 384 seedlings across 32 forest sites spanning a latitudinal gradient of 600 km occurring between 4100 m and 5000 m a.s.l. in Polylepis tarapacana (Rosaceae), one of the world's highest treeline species endemic to the central Andes. KEY RESULTS: Moderate to high levels of genetic diversity and low genetic differentiation were detected in both adults and seedlings, with levels of genetic diversity and differentiation being almost identical. Four slightly genetically divergent clusters were identified that accorded to differing geographical regions. Genetic diversity decreased from south to north and with increasing precipitation for adults and seedlings, but there was no relationship to elevation. CONCLUSIONS: Our study shows that, unlike the case for other Andean treeline species, recent human activities have not affected the genetic structure of P. tarapacana, possibly because its inhospitable habitat is unsuitable for agriculture. The current genetic pattern of P. tarapacana points to a historically more widespread distribution at lower altitudes, which allowed considerable gene flow possibly during the glacial periods of the Pleistocene epoch, and also suggests that the northern Argentinean Andes may have served as a refugium for historical populations. PMID- 26437886 TI - Functional and environmental determinants of bark thickness in fire-free temperate rain forest communities. AB - PREMISE OF THE STUDY: In fire-prone ecosystems, variation in bark thickness among species and communities has been explained by fire frequency; thick bark is necessary to protect cambium from lethal temperatures. Elsewhere this investment is deemed unnecessary, and thin bark is thought to prevail. However, in rain forest ecosystems where fire is rare, bark thickness varies widely among species and communities, and the causes of this variation remain enigmatic. We tested for functional explanations of bark thickness variation in temperate rain forest species and communities. METHODS: We measured bark thickness in 82 tree species throughout New Zealand temperate rain forests that historically have experienced little fire and applied two complementary analyses. First, we examined correlations between bark traits and leaf habit, and leaf and stem traits. Second, we calculated community-weighted mean (CWM) bark thickness for 272 plots distributed throughout New Zealand to identify the environments in which thicker barked communities occur. KEY RESULTS: Conifers had higher size-independent bark thickness than evergreen angiosperms. Species with thicker bark or higher bark allocation coefficients were not associated with "slow economic" plant traits. Across 272 forest plots, communities with thicker bark occurred on infertile soils, and communities with thicker bark and higher bark allocation coefficients occurred in cooler, drier climates. CONCLUSIONS: In non-fire-prone temperate rain forest ecosystems, investment in bark is driven by soil resources, cool minimum temperatures, and seasonal moisture stress. The role of these factors in fire prone ecosystems warrants testing. PMID- 26437887 TI - Vicariance, long-distance dispersal, and regional extinction-recolonization dynamics explain the disjunct circumpolar distribution of the arctic-alpine plant Silene acaulis. AB - PREMISE OF THE STUDY: Many arctic-alpine species have vast geographic ranges, but these may encompass substantial gaps whose origins are poorly understood. Here we address the phylogeographic history of Silene acaulis, a perennial cushion plant with a circumpolar distribution except for a large gap in Siberia. METHODS: We assessed genetic variation in a range-wide sample of 103 populations using plastid DNA (pDNA) sequences and AFLPs (amplified fragment length polymorphisms). We constructed a haplotype network and performed Bayesian phylogenetic analyses based on plastid sequences. We visualized AFLP patterns using principal coordinate analysis, identified genetic groups using the program structure, and estimated genetic diversity and rarity indices by geographic region. KEY RESULTS: The history of the main pDNA lineages was estimated to span several glaciations. AFLP data revealed a distinct division between Beringia/North America and Europe/East Greenland. These two regions shared only one of 17 pDNA haplotypes. Populations on opposite sides of the Siberian range gap (Ural Mountains and Chukotka) were genetically distinct and appear to have resulted from postglacial leading-edge colonizations. We inferred two refugia in North America (Beringia and the southern Rocky Mountains) and two in Europe (central-southern Europe and northern Europe/East Greenland). Patterns in the East Atlantic region suggested transoceanic long-distance dispersal events. CONCLUSIONS: Silene acaulis has a highly dynamic history characterized by vicariance, regional extinction, and recolonization, with persistence in at least four refugia. Long-distance dispersal explains patterns across the Atlantic Ocean, but we found no evidence of dispersal across the Siberian range gap. PMID- 26437888 TI - Ploidy and domestication are associated with genome size variation in Palms. AB - PREMISE OF THE STUDY: The genome size of a species (C-value) is associated with growth, development and adaptation to environmental changes. Angiosperm C-values range 1200-fold and frequently vary within species, although little is known about the impacts of domestication on genome size. Genome size variation among related species of palms is of evolutionary significance because changes characterize clades and may be associated with polyploidy, transposon amplifications, deletions, or rearrangements. Further knowledge of genome size will provide crucial information needed for planning of whole genome sequencing and accurate annotations. We studied the genome size of Cocos nucifera and its variation among cultivars, and compared it to values for related palms from the Attaleinae subtribe. METHODS: Flow cytometric analysis of isolated nuclei from young palm leaves was used to estimate genome sizes of 23 coconut cultivars (Talls, Dwarfs, and hybrids) worldwide and 17 Cocoseae species. Ancestral genome size was reconstructed on a maximum likelihood phylogeny of Attaleinae from seven WRKY loci. KEY RESULTS: The coconut genome is large-averaging 5.966 pg-and shows intraspecific variation associated with domestication. Variation among Tall coconuts was significantly greater than among Dwarfs. Attaleinae genomes showed moderate size variation across genera, except polyploids Jubaeopsis caffra, Voanioala gerardii, Beccariophoenix alfredii, and Allagoptera caudescens, which had larger genomes. CONCLUSIONS: Our results contribute to the understanding of the relationship between domestication and genome size in long-lived tree crops and provide a basis for whole-genome sequencing of the coconut and other domesticated plants. Polyploidy evolved independently in two clades within Attaleinae. PMID- 26437889 TI - Structural Characterization of Sm(III)(EDTMP). AB - Samarium-153 ethylenediamine-N,N,N',N'-tetrakis(methylenephosphonic acid) ((153)Sm-EDTMP, or samarium lexidronam), also known by its registered trademark name Quadramet, is an approved therapeutic radiopharmaceutical used in the palliative treatment of painful bone metastases. Typically, patients with prostate, breast, or lung cancer are most likely to go on to require bone pain palliation treatment due to bone metastases. Sm(EDTMP) is a bone-seeking drug which accumulates on rapidly growing bone, thereby delivering a highly region specific dose of radiation, chiefly through beta particle emission. Even with its widespread clinical use, the structure of Sm(EDTMP) has not yet been characterized at atomic resolution, despite attempts to crystallize the complex. Herein, we prepared a 1:1 complex of the cold (stable isotope) of Sm(EDTMP) under alkaline conditions and then isolated and characterized the complex using conventional spectroscopic techniques, as well as with extended X-ray absorption fine structure (EXAFS) spectroscopy and density functional structure calculations, using natural abundance Sm. We present the atomic resolution structure of [Sm(III)(EDTMP)-8H](5-) for the first time, supported by the EXAFS data and complementary spectroscopic techniques, which demonstrate that the samarium coordination environment in solution is in agreement with the structure that has long been conjectured. PMID- 26437890 TI - Implementation of High-Quality Warm-White Light-Emitting Diodes by a Model Experimental Feedback Approach Using Quantum Dot-Salt Mixed Crystals. AB - In this work, a model-experimental feedback approach is developed and applied to fabricate high-quality, warm-white light-emitting diodes based on quantum dots (QDs) as color-conversion materials. Owing to their unique chemical and physical properties, QDs offer huge potential for lighting applications. Nevertheless, both emission stability and processability of the QDs are limited upon usage from solution. Incorporating them into a solid ionic matrix overcomes both of these drawbacks, while preserving the initial optical properties. Here borax (Na2B4O7.10H2O) is used as a host matrix because of its lower solubility and thereby reduced ionic strength in water in comparison with NaCl. This guarantees the stability of high-quality CdSe/ZnS QDs in the aqueous phase during crystallization and results in a 3.4 times higher loading amount of QDs within the borax crystals compared to NaCl. All steps from the synthesis via mixed crystal preparation to the warm-white LED preparation are verified by applying the model-experimental feedback, in which experimental data and numerical results provide feedback to each other recursively. These measures are taken to ensure a high luminous efficacy of optical radiation (LER) and a high color rendering index (CRI) of the final device as well as a correlated color temperature (CCT) comparable to an incandescent bulb. By doing so, a warm-white LED with a LER of 341 lm/Wopt, a CCT of 2720 K and a CRI of 91.1 is produced. Finally, we show that the emission stability of the QDs within the borax crystals on LEDs driven at high currents is significantly improved. These findings indicate that the proposed warm-white light-emitting diodes based on QDs-in-borax hold great promise for quality lighting. PMID- 26437891 TI - Coronary artery perforation: don't rush, IVUS may be useful. AB - Coronary artery perforation (CAP) is a rare but potentially fatal complication of percutaneous coronary intervention. Polytetrafluoroethylene-covered stents prevent blood leakage between struts with a high rate of success. However, they lack elasticity and rapid and correct deployment is difficult. They have also a higher rate of stent restenosis and thrombosis. For these reasons, optimal deployment is essential. Although severe CAP needs an emergent solution, after stabilizing the patient, intracoronary imaging techniques may be useful to ensure correct expansion and reduce further adverse events. We present a case that shows the potential role of intravascular ultrasound in the resolution of a CAP. PMID- 26437893 TI - Preoperative neutrophil to lymphocyte ratio predicts survival in patients with T1 2N0 colorectal cancer. AB - PURPOSE: Neutrophil to lymphocyte ratio (NLR) is reported to be associated with prognosis of colorectal cancer. The aim of this study is to determine whether the NLR is a predictor of oncological outcomes in patients with stage I colorectal cancer who underwent curative surgery. METHODS: Two hundred sixty-nine patients with stage I colorectal cancer who underwent surgical resection between December 2003 and December 2011 were retrospectively reviewed. The cutoff for NLR was defined as three by maximizing log-rank test statistics. We compared patients with a low NLR and those with a high NLR in terms of survival. RESULTS: The 5 year disease-free survival (DFS) and cancer-specific survival (CSS) rates were lower in patients with a high NLR compared to those with a low NLR in stage I colorectal cancer (89.5% vs. 97.4%, P = 0.006; 94.0% vs. 98.9%, P = 0.022). Cox multivariate analysis demonstrated that preoperative NLR was independently associated with DFS (HR, 5.216; 95%CI, 1.400-19.431; P = 0.014) and CSS (HR, 6.190; 95%CI, 1.034-37.047; P = 0.046) in patients with stage I colorectal cancer. CONCLUSION: The preoperative NLR is a prognostic factor predicting DFS and CSS in patients with stage I colorectal cancer who underwent curative surgery. PMID- 26437892 TI - Effects of prenatal inhalation exposure to copper nanoparticles on murine dams and offspring. AB - BACKGROUND: Increasing numbers of individuals may be exposed to nanomaterials during pregnancy. The overarching goal of this investigation was to determine if prenatal inhalation exposure to copper nanoparticles (Cu NPs) has an effect on dams and offspring, including an analysis of inflammatory markers (Th1/Th2 cytokine profiles). METHODS: Physicochemical characterization of Cu NPs was performed. Pregnant and non-pregnant mice (C57Bl/6 J) were exposed to Cu NPs or laboratory air in the whole-body chamber for 4 hrs/day on gestation days (GD) 3 19 (3.5 mg/m(3)). Animals were euthanized on GD 19 (0 week) or 7 weeks later. Bronchoalveolar lavage (BAL) fluid was analyzed for total and differential cells. Cytokine/chemokine concentrations were determined in the BAL fluid and the plasma of dams/non-pregnant mice and pups. Cu content was determined in the lungs and the blood of dams/non-pregnant mice and pups, in the placentas as well as in the whole bodies of pups immediately after delivery. Lungs and placentas were evaluated for histopathological changes. Gene expression of the Th1/Th2 profiles were analyzed in spleens of pups. RESULTS: The survival rate of 7 week old pups exposed to Cu NPs was significantly lower than control pups (73 vs. 97 %). The average litter size, male/female ratio, body weight and lenght at birth were not different between Cu NP-exposed and control mice. Both pregnant and non-pregnant mice exposed to Cu NPs had significant pulmonary inflammation with increased number of neutrophils in the BAL fluid compared to controls. Perivascular lymphoplasmacytic cuffing was found in the lungs of exposed mice and was more pronounced in the non-pregnant group. Similarly, levels of inflammatory cytokines/chemokines IL-12(p40), G-CSF, GM-CSF, KC, MCP-1, MIP-1alpha, MIP-1beta, RANTES and TNF-alpha in BAL fluid were significantly higher in non-pregnant than pregnant exposed mice. Histopathology evaluation of placentas did not identify any pathological changes. No translocation of Cu into the placenta or the fetus was found by inductively coupled plasma-mass spectroscopy. Expression of several Th1/Th2 or other immune response genes in pups' spleens were found to be significantly up- or down-regulated. CONCLUSIONS: Prenatal exposure to Cu NPs caused a profound pulmonary inflammation in dams and strong immunomodulatory effects in offspring. There was no clear polarization of genes expressed in pups' spleens towards Th1 or Th2 type of response. PMID- 26437895 TI - Embodied simulation of emotional valence: Facial muscle responses to abstract and concrete words. AB - Semantic knowledge is thought to be at least partially grounded in sensory, motor, and affective information, acquired through experiences in our inner and outer world. The reactivation of experience-related information during meaning access is called simulation. In the affective simulation account, it is assumed that the grounding information depends on the concepts' concreteness. Whereas abstract concepts are thought to be mainly represented through affective experiential information, concrete words rely more on sensory-motor experiential information. To test this hypothesis, we measured facial muscle activity as an indicator of affective simulation during visual word recognition. Words varied on the dimensions of concreteness and valence. Behavioral and electromyographic data were analyzed with linear mixed-effects models with maximal random effect structure to optimize generalization over participants and word samples. Contrary to this hypothesis, we found a valence effect in the m. corrugator supercilii only in response to concrete but not to abstract words. Our data show that affective simulation as measured with facial muscle activity occurs in response to concrete rather than to abstract words. More concrete words are supposed to have higher context availability and richer visual imagery, which might promote affective simulation on the expressive level of facial muscle activity. The results are in line with embodied accounts of semantic representation but speak against its predominant role for representing affective information in abstract concepts. PMID- 26437894 TI - A potential role for interleukin-33 and gamma-epithelium sodium channel in the pathogenesis of human malaria associated lung injury. AB - BACKGROUND: The pathogenesis of pulmonary oedema (PE) in patients with severe malaria is still unclear. It has been hypothesized that lung injury depends, in addition to microvascular obstruction, on an increased pulmonary capillary pressure and altered alveolar-capillary membrane permeability, causing pulmonary fluid accumulation. METHODS: This study compared the histopathological features of lung injury in Southeast Asian patients (n = 43) who died from severe Plasmodium falciparum malaria, and correlated these with clinical history in groups with or without PE. To investigate the expression of mediators that may influence fluid accumulation in PE, immunohistochemistry and image analysis were performed on controls and sub-sets of patient with or without PE. RESULTS: The expression of leukocyte sub-set antigens, bronchial interleukin (IL)-33, gamma epithelium sodium channel (ENaC), aquaporin (AQP)-1 and -5, and control cytokeratin staining was quantified in the lung tissue of severe malaria patients. Bronchial IL-33 expression was significantly increased in severe malaria patients with PE. Malaria patients with shock showed significantly increased bronchial IL-33 compare to other clinical manifestations. Bronchial IL 33 levels were positively correlated with CD68+ monocyte and elastase + neutrophil, septal congestion and hyaline membrane formation. Moreover, the expression of both vascular smooth muscle cell (VSMC) and bronchial gamma-ENaC significantly decreased in severe malaria patients with PE. Both VSMC and bronchial gamma-ENaC were negatively correlated with the degree of parasitized erythrocyte sequestration, alveolar thickness, alveolar expansion score, septal congestion score, and malarial pigment score. In contrast AQP-1 and -5 and pan cytokeratin levels were similar between groups. CONCLUSIONS: The results suggest that IL-33 may play a role in lung injury during severe malaria and lead to PE. Both VSMC and bronchial gamma-ENaC downregulation may explain pulmonary fluid disturbances and participate in PE pathogenesis in severe malaria patients. PMID- 26437896 TI - A facile method of activating graphitic carbon nitride for enhanced photocatalytic activity. AB - Activated graphitic carbon nitride (g-C3N4) with enhanced photocatalytic capability under visible light irradiation was fabricated by using a facile chemical activation treatment method. In the chemical activation, a mixed solution of hydrogen peroxide and ammonia was employed. The yield can reach as high as 90% after the activation process. The activation process did not change the crystal structure, functional group, morphology and specific surface area of pristine g-C3N4, but it introduced H and O elements into the CN framework of g C3N4, resulting in a broader optical absorption range, higher light absorption capability and more efficient separation of photogenerated electrons and holes. The photoactivity was investigated by the degradation of rhodamine B (RhB) under visible light irradiation. As compared to the pristine g-C3N4, the activated g C3N4 exhibited a distinct and efficient two-step degradation process. It was found that the RhB dye in the activated g-C3N4 was mainly oxidized by the photogenerated holes. It is believed that sufficient holes account for the two step degradation process because they would significantly improve the efficiency of the N-de-ethylation reaction of RhB. PMID- 26437897 TI - Lipid droplets and associated proteins in the skin: basic research and clinical perspectives. AB - Lipid droplets (LDs), the major organelles handling fat storage, comprise a hydrophobic neutral lipid core surrounded by a phospholipid monolayer embedded with a protein miscellany. Although lipids of the stratum corneum are essential for the skin barrier, and progressive lipid accumulation culminating in cell disruption is the hallmark of sebaceous differentiation, only a few studies touched on skin LD and associated proteins so far. Here, after briefly introducing the basic facts about LD and associated proteins, we discuss how forthcoming studies may unveil novel players in skin lipid metabolism and candidate target proteins for treating skin diseases. PMID- 26437898 TI - Cone-beam evaluation of pharyngeal airway space in class I, II, and III patients. AB - OBJECTIVES: The purpose of this study is to make a 3-dimensional (3-D) evaluation of the pharyngeal airway space (PAS) in patients with class I, II, and III malocclusion. STUDY DESIGN: Sixty patients were evaluated. The patients were divided in 3 groups according to their occlusion classification. The volume and area of PAS were evaluated using the software Dolphin 3-D Imaging in the preoperative period for orthognathic surgery. RESULTS: PAS volume and area were influenced by different patterns of malocclusion. The mean volume and area for class III patients were statistically bigger than for classes I and II patients (P < .001). There was also a significant difference for volume values between class I and II patients, being the bigger volume for the class I patients (P < .05). CONCLUSIONS: It was possible to conclude that the class III patients presented a bigger PAS compared with classes I and II patients. PMID- 26437899 TI - Correlation of deglutition in subacute ischemic stroke patients with peripheral blood adaptive immunity: Essential amino acid improvement. AB - We aimed to document in stroke patients peripheral blood immune cell profiles, their relations with neuro-functional tests, and any possible influence of supplemented essential amino acids (EAAs) may have on both the immune system and the relationship of the latter with neuro-function.Forty-two dysphagic stroke patients (27 men; 71+/-9 years) underwent bio-humoral measurements, neuro functional tests, including Functional Independence Measure (FIM) and Dysphagia Outcome and Severity Scale (DOSS), and were randomized to receive EAAs 8 g/d (EAA group) or isocaloric maltodextrin (placebo group).At discharge all measurements were repeated 38+/-1 days after randomization.At admission, total white cell (TWC), neutrophil (N), and lymphocyte (Lymph) counts were normal and the N/Lymph ratio was higher than normal values (<3.0). At discharge, both TWC and N decreased while Lymph increased significantly. As a result, the N/Lymph ratio significantly decreased (P <0.001) returning to normal levels. Absolute Lymph counts and Lymph % TWC correlated positively with DOSS (r = +0.235, P = 0.04 and r = +0.224, P = 0.05, respectively), negatively with C-reactive protein natural logarithm (ln CRP) (P = 0.02 and P = 0.0001, respectively), which is an inflammation marker. N correlated positively with ln CRP (P = 0.001) and had a slight negative association with FIM (P = 0.07). The N/Lymph ratio was inversely related to FIM (r = -0.262, P = 0.02) and DOSS (r = -0.279, P = 0.01). Finally, FIM correlated with DOSS (r = +0.35, P = 0.05).For the regression analysis, the overtime changes of Lymph % TWC correlated significantly with DOSS (P = 0.01). There was a positive correlation between Lymph % TWC and DOSS for the entire stroke population (P = 0.015). While this correlation was not important for the placebo group (P = 0.27), it was significant in the EAA subgroup (P = 0.018).In the sub-acute stroke stage, there may be slight alterations of peripheral blood immune cells. Lymph cells are associated with improved neuro-function tests with evidence that this association is enhanced by supplementing EAAs. PMID- 26437900 TI - Metallic Co4N Porous Nanowire Arrays Activated by Surface Oxidation as Electrocatalysts for the Oxygen Evolution Reaction. AB - Designing highly efficient electrocatalysts for oxygen evolution reaction (OER) plays a key role in the development of various renewable energy storage and conversion devices. In this work, we developed metallic Co4N porous nanowire arrays directly grown on flexible substrates as highly active OER electrocatalysts for the first time. Benefiting from the collaborative advantages of metallic character, 1D porous nanowire arrays, and unique 3D electrode configuration, surface oxidation activated Co4N porous nanowire arrays/carbon cloth achieved an extremely small overpotential of 257 mV at a current density of 10 mA cm(-2), and a low Tafel slope of 44 mV dec(-1) in an alkaline medium, which is the best OER performance among reported Co-based electrocatalysts to date. Moreover, in-depth mechanistic investigations demonstrate the active phases are the metallic Co4N core inside with a thin cobalt oxides/hydroxides shell during the OER process. Our finding introduces a new concept to explore the design of high-efficiency OER electrocatalysts. PMID- 26437901 TI - Molecular essence and endocrine responsiveness of estrogen receptor-negative, progesterone receptor-positive, and HER2-negative breast cancer. AB - BACKGROUND: The clinical significance of progesterone receptor (PgR) expression in estrogen receptor-negative (ER-) breast cancer is controversial. Herein, we systemically investigate the clinicopathologic features, molecular essence, and endocrine responsiveness of ER-/PgR+/HER2- phenotype. METHODS: Four study cohorts were included. The first and second cohorts were from the Surveillance, Epidemiology, and End Results database (n = 67,932) and Fudan University Shanghai Cancer Center (n = 2,338), respectively, for clinicopathologic and survival analysis. The third and fourth cohorts were from two independent publicly available microarray datasets including 837 operable cases and 483 cases undergoing neoadjuvant chemotherapy, respectively, for clinicopathologic and gene expression analysis. Characterized genes defining subgroups within the ER /PgR+/HER2- phenotype were determined and further validated. RESULTS: Clinicopathologic features and survival outcomes of the ER-/PgR+ phenotype fell in between the ER+/PgR+ and ER-/PgR- phenotypes, but were more similar to ER-/PgR . Among the ER-/PgR+ phenotype, 30% (95% confidence interval [CI] 17-42%, pooled by a fixed-effects method) were luminal-like and 59% (95% CI 45-72%, pooled by a fixed-effects method) were basal-like. We further refined the characterized genes for subtypes within the ER-/PgR+ phenotype and developed an immunohistochemistry based method that could determine the molecular essence of ER-/PgR+ using three markers, TFF1, CK5, and EGFR. Either PAM50-defined or immunohistochemistry defined basal-like ER-/PgR+ cases have a lower endocrine therapy sensitivity score compared with luminal-like ER-/PgR+ cases (P <0.0001 by Mann-Whitney test for each study set and P <0.0001 for pooled standardized mean difference in meta analysis). Immunohistochemistry-defined basal-like ER-/PgR+ cases might not benefit from adjuvant endocrine therapy (log-rank P = 0.61 for sufficient versus insufficient endocrine therapy). CONCLUSIONS: The majority of ER-/PgR+/HER2- phenotype breast cancers are basal-like and associated with a lower endocrine therapy sensitivity score. Additional studies are needed to validate these findings. PMID- 26437903 TI - The multicomponent meningococcal serogroup B vaccine (4CMenB): origin, composition, health impact and unknown aspects. AB - Neisseria meningitidis serogroup B is the main cause for meningococcal invasive disease in many parts of the world. Since 2013, a new multicomponent vaccine against meningococcal serogroup B (4CMenB) has been licensed in Europe, Australia, Canada, Chile, Uruguay, USA and Brazil with different immunization schedules. Clinical trials involving adults, adolescents, children and infants showed 4CMenB has a good immunogenicity and safety profile. Strain coverage estimates are similar to or better than other recently approved vaccines, ranging from 66% in Canada to 91% in Unites States. Some points still remain to be clarified such as the best immunization strategy, the effect of 4CMenB on carriage, the long-term persistence of protective bactericidal antibodies titers, long-term safety outcomes, the possible emergence of N. meningitidis escape mutants and the vaccine cost-effectiveness. In this review, we focus on the vaccine composition, clinical trials and suggested schedules, safety data, potential strain coverage and future challenges. PMID- 26437902 TI - Phylum-wide analysis of genes/proteins related to the last steps of assembly and export of extracellular polymeric substances (EPS) in cyanobacteria. AB - Many cyanobacteria produce extracellular polymeric substances (EPS) with particular characteristics (e.g. anionic nature and presence of sulfate) that make them suitable for industrial processes such as bioremediation of heavy metals or thickening, suspending or emulsifying agents. Nevertheless, their biosynthetic pathway(s) are still largely unknown, limiting their utilization. In this work, a phylum-wide analysis of genes/proteins putatively involved in the assembly and export of EPS in cyanobacteria was performed. Our results demonstrated that most strains harbor genes encoding proteins related to the three main pathways: Wzy-, ABC transporter-, and Synthase-dependent, but often not the complete set defining one pathway. Multiple gene copies are mainly correlated to larger genomes, and the strains with reduced genomes (e.g. the clade of marine unicellular Synechococcus and Prochlorococcus), seem to have lost most of the EPS-related genes. Overall, the distribution of the different genes/proteins within the cyanobacteria phylum raises the hypothesis that cyanobacterial EPS production may not strictly follow one of the pathways previously characterized. Moreover, for the proteins involved in EPS polymerization, amino acid patterns were defined and validated constituting a novel and robust tool to identify proteins with similar functions and giving a first insight to which polymer biosynthesis they are related to. PMID- 26437904 TI - Does the Rewarmed Heart Restore the Myocardial Proteome to That of the Pre-Cooled State?--A Proteomic Analysis of Surgical Samples. AB - BACKGROUND: Hypothermia is utilized in cardiac and aortic surgery to protect organs from ischemic reperfusion injury. Although the cooled body is invariably rewarmed after the procedure, it is still unknown whether the rewarmed body regains its former biological state. This study determined the modulatory effects of hypothermia on the human myocardial proteome and whether subsequent rewarming restores the proteome to the state prior to cooling. METHODS AND RESULTS: A quantitative proteomic analysis was performed using isobaric tags for relative and absolute quantification labeling tandem mass spectrometry. Right atrial samples were taken 3 times (pre, during and post cooling) during deep hypothermic cardiopulmonary bypass (CPB) from 8 patients with aortic arch aneurysms and 3 corresponding time points during normothermic CPB from 8 patients with ascending aortic or valsalva aneurysms. In total, 697 proteins were identified, with 222 proteins having high protein confidence. Bioinformatic analyses revealed significant downregulation of 19 proteins associated with energy production at hypothermic cardioplegic arrest. On rewarmed beating, 10 proteins remained downregulated, including those regulating cardiac contraction and adaptor proteins, although levels of the aforementioned 19 downregulated proteins returned to their initial values. Additional echocardiographic evaluation demonstrated that hypothermia preserved the variables of diastolic function to a greater extent than normothermic surgery. CONCLUSIONS: Rewarming restores the human myocardial proteome to the pre-cooled state, except for proteins regulating cardiac contraction and adaptor proteins. PMID- 26437905 TI - Recent progress and next challenges in the treatment of symptomatic heart failure in Japan. PMID- 26437906 TI - Long-term outcomes after St. Jude Medical mechanical valve implantation. PMID- 26437908 TI - How often does the embryo implant at the location to which it was transferred? AB - OBJECTIVE: To determine how often the embryo implants exactly at the site of transfer and what additional factors may affect the eventual site of implantation in assisted reproductive technology (ART) cycles. METHODS: This was a prospective observational study of women undergoing ART treatment in a tertiary university unit. Several factors inherent to the embryo transfer (ET), such as the location of the air bubbles and uterine contractility at 1 and at 60 min after ET were assessed with two-dimensional and three-dimensional (3D) ultrasound. In women in whom there was a resulting pregnancy, the position of the gestational sac (i.e. right, left, center or low) was subsequently assessed using 3D ultrasound, and predictors of its location were evaluated. RESULTS: Of 239 recruited women with visualization of air bubbles at ET, 71 singleton gestational sacs were subsequently observed on 3D ultrasound. Overall, 40.8% (29/71) of embryos implanted at the location where the air bubbles were visualized at 1 min after ET, and 50.7% (36/71) implanted where the air bubbles were visualized at 60 min after ET (Cohen's kappa coefficients 0.21 and 0.37, respectively; comparison of agreement values: P = 0.28). Specifically, at 1 min the correspondence between the location of the air bubble and embryo implantation was 37.5% (6/16), 57.1% (8/14), 36.8% (7/19) and 36.4% (8/22) for right, left, central and lower uterus, respectively (4 * 4 contingency table, P < 0.01); at 60 min, the correspondence was 72.2% (13/18), 50.0% (9/18), 33.3% (8/24) and 85.7% (6/7), respectively (5 * 4 contingency table, P < 0.001). In addition, higher vs lower frequency of uterine contractions at 60 min was associated with different sites of implantation (5.6% (1/18), 11.1% (2/18), 27.8% (5/18) and 55.6% (10/18) vs 34.0% (18/53), 24.5% (13/53), 13.2% (7/53) and 28.3% (15/53) for right, left, central and lower uterus, respectively, P < 0.05). In particular, a high uterine contraction frequency following ET was associated with a twofold increased chance of the pregnancy implanting in the lower part of the uterine cavity (relative risk, 1.96 (95% CI, 1.08-3.56), P < 0.05). CONCLUSIONS: The position of the air bubbles within the first 60 min of ET appears to predict the site of implantation in approximately half of cases, denoting an overall poor agreement. This implies significant embryo migration, and has important clinical implications, as it demonstrates that other factors such as uterine contractility may dictate where the embryo will eventually implant following transfer. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26437907 TI - Autism screening and diagnosis in low resource settings: Challenges and opportunities to enhance research and services worldwide. AB - Most research into the epidemiology, etiology, clinical manifestations, diagnosis and treatment of autism is based on studies in high income countries. Moreover, within high income countries, individuals of high socioeconomic status are disproportionately represented among participants in autism research. Corresponding disparities in access to autism screening, diagnosis, and treatment exist globally. One of the barriers perpetuating this imbalance is the high cost of proprietary tools for diagnosing autism and for delivering evidence-based therapies. Another barrier is the high cost of training of professionals and para professionals to use the tools. Open-source and open access models provide a way to facilitate global collaboration and training. Using these models and technologies, the autism scientific community and clinicians worldwide should be able to work more effectively and efficiently than they have to date to address the global imbalance in autism knowledge and at the same time advance our understanding of autism and our ability to deliver cost-effective services to everyone in need. PMID- 26437909 TI - Utilization of Systemic Chemotherapy in Advanced Urothelial Cancer: A Retrospective Collaborative Study by the Hellenic Genitourinary Cancer Group (HGUCG). AB - BACKGROUND: Advanced urothelial cancer (AUCa) is associated with poor long-term survival. Two major concerns are related to nonexposure to cisplatin-based chemotherapy and poor outcome after relapse. Our purpose was to record patterns of practice in AUCa in Greece, focusing on first-line treatment and management of relapsed disease. METHODS: Patients with AUCa treated from 2011 to 2013 were included in the analysis. Fitness for cisplatin was assessed by recently established criteria. RESULTS: Of 327 patients treated with first-line chemotherapy, 179 (55%) did not receive cisplatin. Criteria for unfitness for cisplatin were: Eastern Cooperative Oncology Group (ECOG) performance status (PS) >= 2, 21%; creatinine clearance <= 60 mL/min, 55%; hearing impairment, 8%; neuropathy, 1%; and cardiac failure, 5%. Forty-six patients (27%) did not fulfill any criterion for unfitness for cisplatin. The main reasons for these deviations were comorbidities (28%) and advanced age (32%). Seventy-four (68%) of 109 patients who experienced a relapse received second-line chemotherapy. The most frequent reason for not offering second-line chemotherapy was poor PS or limited life expectancy (66%). CONCLUSION: In line with international data, approximately 50% of Greek patients with AUCa do not receive cisplatin-based chemotherapy, although 27% of them were suitable for such treatment. In addition, about one third of patients with relapse did not receive second-line chemotherapy because of poor PS or short life expectancy. Enforcing criteria for fitness for cisplatin and earlier diagnosis of relapse represent 2 targets for improvement in current treatment practice for AUCa. PMID- 26437912 TI - Pd(II)-Catalyzed C-H Activation of Styrylindoles: Short, Efficient, and Regioselective Synthesis of Functionalized Carbazoles. AB - A novel Pd(II)-catalyzed approach for the direct synthesis of highly functionalized carbazoles from unprotected styrylindoles has been developed. The reaction features a variety of olefin substrates, which are readily switchable by subtle tuning of the reaction conditions. Investigations of the mechanism suggest that the C-H activation proceeds via enamine formation. PMID- 26437911 TI - Measuring fast stochastic displacements of bio-membranes with dynamic optical displacement spectroscopy. AB - Stochastic displacements or fluctuations of biological membranes are increasingly recognized as an important aspect of many physiological processes, but hitherto their precise quantification in living cells was limited due to a lack of tools to accurately record them. Here we introduce a novel technique--dynamic optical displacement spectroscopy (DODS), to measure stochastic displacements of membranes with unprecedented combined spatiotemporal resolution of 20 nm and 10 MUs. The technique was validated by measuring bending fluctuations of model membranes. DODS was then used to explore the fluctuations in human red blood cells, which showed an ATP-induced enhancement of non-Gaussian behaviour. Plasma membrane fluctuations of human macrophages were quantified to this accuracy for the first time. Stimulation with a cytokine enhanced non-Gaussian contributions to these fluctuations. Simplicity of implementation, and high accuracy make DODS a promising tool for comprehensive understanding of stochastic membrane processes. PMID- 26437910 TI - The extended trajectory of hippocampal development: Implications for early memory development and disorder. AB - Hippocampus has an extended developmental trajectory, with refinements occurring in the trisynaptic circuit until adolescence. While structural change should suggest a protracted course in behavior, some studies find evidence of precocious hippocampal development in the first postnatal year and continuity in memory processes beyond. However, a number of memory functions, including binding and relational inference, can be cortically supported. Evidence from the animal literature suggests that tasks often associated with hippocampus (visual paired comparison, binding of a visuomotor response) can be mediated by structures external to hippocampus. Thus, a complete examination of memory development will have to rule out cortex as a source of early memory competency. We propose that early memory must show properties associated with full function of the trisynaptic circuit to reflect "adult-like" memory function, mainly (1) rapid encoding of contextual details of overlapping patterns, and (2) retention of these details over sleep-dependent delays. A wealth of evidence suggests that these functions are not apparent until 18-24 months, with behavioral discontinuities reflecting shifts in the neural structures subserving memory beginning approximately at this point in development. We discuss the implications of these observations for theories of memory and for identifying and measuring memory function in populations with typical and atypical hippocampal function. PMID- 26437913 TI - Enhanced interannual precipitation variability increases plant functional diversity that in turn ameliorates negative impact on productivity. AB - Although precipitation interannual variability is projected to increase due to climate change, effects of changes in precipitation variance have received considerable less attention than effects of changes in the mean state of climate. Interannual precipitation variability effects on functional diversity and its consequences for ecosystem functioning are assessed here using a 6-year rainfall manipulation experiment. Five precipitation treatments were switched annually resulting in increased levels of precipitation variability while maintaining average precipitation constant. Functional diversity showed a positive response to increased variability due to increased evenness. Dominant grasses decreased and rare plant functional types increased in abundance because grasses showed a hump-shaped response to precipitation with a maximum around modal precipitation, whereas rare species peaked at high precipitation values. Increased functional diversity ameliorated negative effects of precipitation variability on primary production. Rare species buffered the effect of precipitation variability on the variability in total productivity because their variance decreases with increasing precipitation variance. PMID- 26437914 TI - Changes in Aortoiliac Anatomy After Elective Treatment of Infrarenal Abdominal Aortic Aneurysms with a Sac Anchoring Endoprosthesis. AB - OBJECTIVE: Endovascular aortic sealing (EVAS) with the Nellix endosystem (Endologix, Irvine, CA, USA) is a new concept to treat infrarenal abdominal aortic aneurysms (AAAs). By sealing the aneurysm, potential endoleaks may be avoided. Early results of EVAS are good, but no data have been published regarding peri-procedural changes in aortoiliac anatomy. In this study, 27 consecutive patients who underwent elective EVAS repair of an AAA were reviewed. METHOD: Specific AAA (diameter, length from renal arteries to aortic bifurcation, supra- and infrarenal neck angulation, AAA volume, thrombus volume, and flow lumen volume), and iliac artery characteristics (length, angulation, location of most severe angulation with reference to the origin of the common iliac artery) were determined from pre- and post-procedural reconstructed computed tomography angiograms. RESULTS: No type I or II endoleaks were seen at 30 day follow up. Total AAA volume, suprarenal and infrarenal angulation, as well as aortic neck diameter did not change significantly post-EVAS. AAA flow lumen increased significantly (mean difference -4.4 mL, 95% CI 2.0 to -8.6 mL) and AAA thrombus volume decreased (mean difference 3.2 mL, 95% CI 2.0 to -1.1 mL). AAA length (125.7 mm vs. 123.1 mm), left common iliac artery length (57.6 mm vs. 55.3 mm), and right and left maximum iliac artery angulation (right 37.4 degrees vs. 32.2 degrees ; left: 43.9 degrees vs. 38.4 degrees ) were reduced significantly and the location of maximum angulation was further from the iliac artery origin post EVAS, suggesting slight straightening of the aortoiliac anatomy. CONCLUSION: Most aortoiliac anatomic characteristics remained unchanged post-EVAS. Filling of the endobags to a pressure of 180 mmHg may lead to lost thrombus volume in some patients, probably because liquid is squeezed into lumbar or the inferior mesenteric artery. The absolute differences in pre- and post-EVAS aortoiliac lengths were small, so pre-operative sizing is accurate for determining stent length. PMID- 26437915 TI - A novel dual EGFR/HER2 inhibitor KU004 induces cell cycle arrest and apoptosis in HER2-overexpressing cancer cells. AB - Human epidermal growth factor receptor 2 (HER2) is a validated therapeutic target in cancer therapy, and HER2 protein-tyrosine kinase inhibitors have attracted considerable attention in the field of searching for novel anticancer drug candidates. In this study, we investigated the anticancer effect of KU004, a novel dual EGFR and HER2 inhibitor in vitro and in vivo. In vitro, KU004 preferentially inhibited the growth of HER2-overexpressing breast and gastric cell lines and HER2 expression level significantly correlated with response to KU004. It blocked activation of EGFR, HER2 and downstream Akt and Erk and induced G0/G1 arrest which was associated with downregulation of p53, p21, cyclin D1 and CDK4 along with increase of p27 and dephosphorylation of pRb. Apoptosis occurred in a caspase-dependent manner mainly via the extrinsic apoptotic pathway after KU004 treatment. The in vitro efficacy of KU004 was comparable to that of lapatinib. Moreover, KU004 suppressed the growth of NCI-N87 tumor and induced apoptosis without causing apparent weight loss or obvious toxicity. Tumor volume was significantly smaller in KU004-treated group than that in lapatinib-treated group at comparable dose levels. Taken together, these findings demonstrate KU004 can be expected to be a promising anti-HER2 candidate. PMID- 26437916 TI - Apoptotic and autophagic cell death induced by glucolaxogenin in cervical cancer cells. AB - The antiproliferative and cytotoxic activity of glucolaxogenin and its ability to induce apoptosis and autophagy in cervical cancer cells are reported. We ascertained that glucolaxogenin exerts an inhibitory effect on the proliferation of HeLa, CaSki and ViBo cells in a dose-dependent manner. Analysis of DNA distribution in the cell-cycle phase of tumor cells treated with glucolaxogenin suggests that the anti-proliferative activity of this steroid is not always dependent on the cell cycle. Cytotoxic activity was evaluated by detection of the lactate dehydrogenase enzyme in supernatants from tumor cell cultures treated with the steroid. Glucolaxogenin exhibited null cytotoxic activity. With respect to the apoptotic activity, the generation of apoptotic bodies, the presence of active caspase-3 and annexin-V, as well as the DNA fragmentation observed in all tumor lines after treatment with glucolaxogenin suggests that this compound does indeed induce cell death by apoptosis. Also, a significantly increased presence of the LC3-II, LC3 and Lamp-1 proteins was evidenced with the ultrastructural existence of autophagic vacuoles in cells treated with this steroidal glycoside, indicating that glucolaxogenin also induces autophagic cell death. It is important to note that this compound showed no cytotoxic effect and did not affect the proliferative capacity of mononuclear cells obtained from normal human peripheral blood activated by phytohaemagglutinin. Thus, glucolaxogenin is a compound with anti-proliferative properties that induces programmed cell death in cancer cell lines, though it is selective with respect to normal lymphocytic cells. These findings indicate that this glycoside could have a selective action on tumor cells and, therefore, be worthy of consideration as a therapeutic candidate with anti-tumor potential. PMID- 26437918 TI - Prediction of Drug Clearance in Premature and Mature Neonates, Infants, and Children <=2 Years of Age: A Comparison of the Predictive Performance of 4 Allometric Models. AB - The objective of this study was to evaluate the predictive performance of 4 allometric models to predict clearance in pediatric ages ranging from premature neonates to children <=2 years of age. Four allometric models were used to predict clearances of 28 drugs in children from preterm neonates to 2 years of age (n = 564). The 4 models are (1) basal metabolic rate-dependent model; (2) age dependent exponent model; (3) an allometric model based on kidney and liver weights as well as kidney and liver blood flow; and (4) an allometric model based on a fixed exponent of 0.75. The predictive performance of these models was evaluated by comparing the predicted clearance of the studied drugs with the observed clearance in an individual child. The results of the study indicated that the 3 new proposed models predicted the mean clearance of the drugs with reasonable accuracy (<=50% prediction error). On the other hand, the exponent of 0.75 produced substantial prediction error. Predicted individual clearance values were >=50% in approximately 30% of the children by the proposed 3 methods and 73% by exponent 0.75. The 3 new proposed allometric models can predict mean clearances of drugs in children from premature neonates to <=2 years of age with reasonable accuracy and are of practical value during pediatric drug development. PMID- 26437919 TI - Genome-wide identification of long noncoding RNA genes and their potential association with fecundity and virulence in rice brown planthopper, Nilaparvata lugens. AB - BACKGROUND: The functional repertoire of long noncoding RNA (lncRNA) has been characterized in several model organisms, demonstrating that lncRNA plays important roles in fundamental biological processes. However, they remain largely unidentified in most species. Understanding the characteristics and functions of lncRNA in insects would be useful for insect resources utilization and sustainable pest control. METHODS: A computational pipeline was developed to identify lncRNA genes in the rice brown planthopper, Nilaparvata lugens, a destructive rice pest causing huge yield losses. Strand specific RT-PCR were used to determine the transcription orientation of lncRNAs. RESULTS: In total, 2,439 lncRNA transcripts corresponding to 1,882 loci were detected from 12 whole transcriptomes (RNA-seq) datasets, including samples from high fecundity (HFP), low fecundity (LFP), I87i and C89i populations, in addition Mudgo and TN1 virulence strains. The identified N. lugens lncRNAs had low sequence similarities with other known lncRNAs. However, their structural features were similar with mammalian counterparts. N. lugens lncRNAs had shorter transcripts than protein coding genes due to the lower exon number though their exons and introns were longer. Only 19.9% of N. lugens lncRNAs had multiple alternatively spliced isoforms. We observed biases in the genome location of N. lugens lncRNAs. More than 30% of the lncRNAs overlapped with known protein-coding genes. These lncRNAs tend to be co-expressed with their neighboring genes (Pearson correlation, p < 0.01, T-test) and might interact with adjacent protein-coding genes. In total, 19 148 lncRNAs were specifically-expressed in the samples of HFP, LFP, Mudgo, TN1, I87i and C89i populations. Three lncRNAs specifically expressed in HFP and LFP populations overlapped with reproductive-associated genes. DISCUSSION: The structural features of N. lugens lncRNAs are similar to mammalian counterparts. Coexpression and function analysis suggeste that N. lugens lncRNAs might have important functions in high fecundity and virulence adaptability. CONCLUSIONS: This study provided the first catalog of lncRNA genes in rice brown planthopper. Gene expression and genome location analysis indicated that lncRNAs might play important roles in high fecundity and virulence adaptation in N. lugens. PMID- 26437920 TI - Luteimonas soli sp. nov., isolated from farmland soil. AB - A yellow-pigmented bacterial strain, designated Y2T, was isolated from farmland soil in Bengbu, Anhui province, China. Cells of strain Y2T were Gram-stain negative, strictly aerobic, non-motile and rod-shaped. Strain Y2T grew optimally at pH 7.0, 30 degrees C and in the presence of 2 % (w/v) NaCl. The DNA G+C content was 68.9 mol%. The major fatty acids (>5 %) were iso-C15 : 0, iso-C17 : 0, summed feature 9 (C16 : 0 10-methyl and/or iso-C17 : 1omega9c), iso-C11 : 0 3 OH and iso-C11 : 0. The major respiratory quinone was ubiquinone-8 (Q-8), and the major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. Phylogenetic analysis of the 16S rRNA gene sequences showed that strain Y2T was most closely related to Luteimonas mephitis B1953/27.1T (99.1 % 16S rRNA gene sequence similarity), followed by Luteimonas lutimaris G3T (98.6 %), Luteimonas abyssi XH031T (96.2 %) and Luteimonas aquatica RIB1-20T (96.0 %). Strain Y2T exhibited low DNA-DNA relatedness with Luteimonas mephitis B1953/27.1T (43.6 +/- 0.5 %) and Luteimonas lutimaris G3T (43.9 +/- 2.1 %). On the basis of phenotypic, genotypic and phylogenetic evidence, strain Y2T represents a novel species of the genus Luteimonas, for which the name Luteimonas soli sp. nov. is proposed. The type strain is Y2T ( = ACCC 19799T = KCTC 42441T). PMID- 26437922 TI - Impact of parental weight status on a school-based weight management programme designed for Mexican-American children. AB - BACKGROUND: While overweight and obese children are more likely to have overweight or obese parents, less is known about the effect of parental weight status on children's success in weight management programmes. OBJECTIVES: This study was a secondary data analysis of a randomized controlled trial and investigated the impact of having zero, one or two obese parents on children's success in a school-based weight management programme. METHODS: Sixty-one Mexican American children participated in a 24-week school-based weight management intervention which took place in 2005-2006. Children's heights and weights were measured at baseline, 3, 6 and 12 months. Parental weight status was assessed at baseline. Repeated measures anova and ancova were conducted to compare changes in children's weight within and between groups, respectively. RESULTS: Within-group comparisons revealed that the intervention led to significant decreases in standardized body mass index (zBMI) for children with zero (F = 23.16, P < .001) or one obese (F = 4.99, P < .05) parent. Between-group comparisons indicated that children with zero and one obese parents demonstrated greater decreases in zBMI compared to children with two obese parents at every time point. CONCLUSIONS: The school-based weight management programme appears to be most efficacious for children with one or no obese parents compared to children with two obese parents. These results demonstrate the need to consider parental weight status when engaging in childhood weight management efforts. PMID- 26437921 TI - Contribution of BDNF and DRD2 genetic polymorphisms to continued opioid use in patients receiving methadone treatment for opioid use disorder: an observational study. AB - BACKGROUND: The heritability of opioid use disorder has been widely investigated; however, the influence of specific genes on methadone treatment outcomes is not well understood. The association between response to methadone treatment and genes that are involved in substance use behaviors and reward mechanisms is poorly understood, despite evidence suggesting their contribution to opioid use disorder. The aim of this study was to investigate the effect of brain-derived neurotrophic factor (BDNF) and dopamine receptor D2 (DRD2) polymorphisms on continued opioid use among patients on methadone treatment for opioid use disorder. METHODS: BDNF 196G>A (rs6265) and DRD2-241A>G (rs1799978) genetic variants were examined in patients with opioid use disorder who were recruited from methadone treatment clinics across Southern Ontario, Canada. We collected demographic information, substance use history, blood for genetic analysis, and urine to measure opioid use. We used regression analysis to examine the association between continued opioid use and genetic variants, adjusting for age, sex, ethnicity, methadone dose, duration in treatment, and number of urine screens. RESULTS: Among 240 patients treated with methadone for opioid use disorder, 36.3 percent (n = 87) and 11.3 percent (n = 27) had at least one risk allele for rs6265 and rs1799978, respectively. These genetic variants were not significantly associated with continued opioid use while on methadone maintenance treatment [rs6265: odds ratio (OR) = 1.37, 95 % confidence interval (CI) = 0.792, 2.371, p = 0.264; rs1799978: OR 1.27, 95 % CI 0.511, 3.182, p = 0.603]. CONCLUSIONS: Despite an association of BDNF rs6265 and DRD2 rs1799978 with addictive behaviors, these variants were not associated with continued illicit opioid use in patients treated with methadone. Problematic use of opioids throughout treatment with methadone may be attributed to nongenetic factors or a polygenic effect requiring further exploration. Additional research should focus on investigating these findings in larger samples and different populations. PMID- 26437923 TI - Biodistribution and toxicity of spherical aluminum oxide nanoparticles. AB - With the rapid development of the nano-industry, concerns about their potential adverse health effects have been raised. Thus, ranking accurately their toxicity and prioritizing for in vivo testing through in vitro toxicity test is needed. In this study, we used three types of synthesized aluminum oxide nanoparticles (AlONPs): gamma-aluminum oxide hydroxide nanoparticles (gamma-AlOHNPs), gamma- and alpha-AlONPs. All three AlONPs were spherical, and the surface area was the greatest for gamma-AlONPs, followed by the alpha-AlONPs and gamma-AlOHNPs. In mice, gamma-AlOHNPs accumulated the most 24 h after a single oral dose. Additionally, the decreased number of white blood cells (WBC), the increased ratio of neutrophils and the enhanced secretion of interleukin (IL)-8 were observed in the blood of mice dosed with gamma-AlOHNPs (10 mg kg(-1)). We also compared their toxicity using four different in vitro test methods using six cell lines, which were derived from their potential target organs, BEAS-2B (lung), Chang (liver), HACAT (skin), H9C2 (heart), T98G (brain) and HEK-293 (kidney). The results showed gamma-AlOHNPs induced the greatest toxicity. Moreover, separation of particles was observed in a transmission electron microscope (TEM) image of cells treated with gamma-AlOHNPs, but not gamma-AlONPs or alpha-AlONPs. In conclusion, our results suggest that the accumulation and toxicity of AlONPs are stronger in gamma-AlOHNPs compared with gamma-AlONPs and alpha-AlONPs owing their low stability within biological system, and the presence of hydroxyl group may be an important factor in determining the distribution and toxicity of spherical AlONPs. PMID- 26437924 TI - Vitamin D deficiency and its characteristics among patients with acute stroke at a national referral hospital in Kampala Uganda. AB - BACKGROUND: Vitamin D deficiency has been associated with acute stroke and other cardiovascular diseases in the developed world. Low 25-hydroxyvitamin D (25OHD) has been described in some populations in Sub-Saharan Africa (SSA) in spite of adequate sunshine all year round. There is no information on the magnitude of vitamin D deficiency among patients with stroke and other cardiovascular diseases in Uganda or SSA. The aim of this study was to determine the burden and characteristics of vitamin D deficiency among patients with acute stroke, the most common form of cardiovascular events in SSA. METHODS: We conducted a cross sectional study between October 2012 and March 2013. We consecutively recruited 142 subjects with acute stroke admitted to the medical wards of Mulago hospital. We administered a pre-tested questionnaire to the study participants, and did a detailed physical examination and laboratory evaluation. Serum levels of 25OHD were determined using an electrochemiluminescence assay. Data were analyzed using STATA version 12 software. RESULTS: The prevalence of vitamin D deficiency (25OHD < 20 ng/ml) was 15 %. Longer hours of sunshine exposure decreased the likelihood vitamin D deficiency significantly (adjusted OR 0.85, p = 0.03). Higher HDL cholesterol had a significant inverse association with vitamin D deficiency (adjusted OR 0.15, p = 0.02). In addition, the likelihood of vitamin D deficiency increased with rising age (adjusted OR 1.03, p = 0.05). CONCLUSIONS: There was a relatively low burden of vitamin D deficiency among patients with acute stroke in Uganda. With increasing longevity and indoor lifestyles vitamin D deficiency may assume a greater role in stroke and other cardiovascular diseases in tropical sub Saharan Africa. Future studies on the mechanisms of vitamin D deficiency and its relationship to outcomes among patients with stroke may be necessary. PMID- 26437925 TI - Resolving Anomalies in Predicting Electrokinetic Energy Conversion Efficiencies of Nanofluidic Devices. AB - We devise a new approach for capturing complex interfacial interactions over reduced length scales, towards predicting electrokinetic energy conversion efficiencies of nanofluidic devices. By embedding several aspects of intermolecular interactions in continuum based formalism, we show that our simple theory becomes capable of representing complex interconnections between electro mechanics and hydrodynamics over reduced length scales. The predictions from our model are supported by reported experimental data, and are in excellent quantitative agreement with molecular dynamics simulations. The present model, thus, may be employed to rationalize the discrepancies between low energy conversion efficiencies of nanofluidic channels that have been realized from experiments, and the impractically high energy conversion efficiencies that have been routinely predicted by the existing theories. PMID- 26437926 TI - In Situ Transmission Electron Microscopy Observation of the Lithiation Delithiation Conversion Behavior of CuO/Graphene Anode. AB - The electrochemical conversion behavior of metal oxides as well as its influence on the lithium-storage performance remains unclear. In this paper, we studied the dynamic electrochemical conversion process of CuO/graphene as anode by in situ transmission electron microscopy. The microscopic conversion behavior of the electrode was further correlated with its macroscopic lithium-storage properties. During the first lithiation, the porous CuO nanoparticles transformed to numerous Cu nanograins (2-3 nm) embedded in Li2O matrix. The porous spaces were found to be favorable for accommodating the volume expansion during lithium insertion. Two types of irreversible processes were revealed during the lithiation-delithiation cycles. First, the nature of the charge-discharge process of CuO anode is a reversible phase conversion between Cu2O and Cu nanograins. The delithiation reaction cannot recover the electrode to its pristine structure (CuO), which is responsible for about ~55% of the capacity fading in the first cycle. Second, there is a severe nanograin aggregation during the initial conversion cycles, which leads to low Coulombic efficiency. This finding could also account for the electrochemical behaviors of other transition metal oxide anodes that operate with similar electrochemical conversion mechanism. PMID- 26437927 TI - Selection of reference genes for analysis of stress-responsive genes after challenge with viruses and temperature changes in the silkworm Bombyx mori. AB - Viruses and high temperature (HT) are the primary threats to silkworms. Changes in the expression of stress-response genes can be measured using quantitative polymerase chain reaction (qPCR) after exposure to viruses or HT. However, appropriate reference genes (RGs) for qPCR data normalization have not been established in this organism. In this study, we summarized the RGs used in the previous silkworm studies after infection with Bombyx mori nucleopolyhedrovirus (BmNPV), B. mori cytoplasmic polyhedrosis virus (BmCPV), or B. mori densovirus (BmDNV) or after HT treatment. The expression levels of these RGs were extracted from silkworm transcriptome data to screen for candidate RGs that were unaffected by the experimental conditions. Actin-1 (A1), actin-3 (A3), glyceraldehyde-3 phosphate dehydrogenase (GAPDH), and translation initiation factor 4a (TIF-4A) were selected for further qPCR verification. The results of RNA-seq and qPCR showed that GAPDH and TIF-4A were suitable RGs after BmNPV challenge or HT stress, whereas TIF-4A was an appropriate RG for BmCPV or BmDNV-Z challenge in silkworms. These results suggested that TIF-4A may be the most appropriate RG for gene expression analysis after challenge with viruses or HT in silkworms. PMID- 26437928 TI - Erratum to: Identification and characterization of microRNAs at different flowering developmental stages in moso bamboo (Phyllostachys edulis) by high throughput sequencing. PMID- 26437929 TI - Muscle Ultrasound in Patients with Glycogen Storage Disease Types I and III. AB - In glycogen storage diseases (GSDs), improved longevity has resulted in the need for neuromuscular surveillance. In 12 children and 14 adults with the "hepatic" (GSD-I) and "myopathic" (GSD-III) phenotypes, we cross-sectionally assessed muscle ultrasound density (MUD) and muscle force. Children with both "hepatic" and "myopathic" GSD phenotypes had elevated MUD values (MUD Z-scores: GSD-I > 2.5 SD vs. GSD-III > 1 SD, p < 0.05) and muscle weakness (GSD-I muscle force; p < 0.05) of myopathic distribution. In "hepatic" GSD-I adults, MUD stabilized (GSD-I adults vs. GSD-I children, not significant), concurring with moderate muscle weakness (GSD-I adults vs. healthy matched pairs, p < 0.05). In "myopathic" GSD III adults, MUD increased with age (MUD-GSD III vs. age: r = 0.71-0.83, GSD-III adults > GSD-III children, p < 0.05), concurring with pronounced muscle weakness (GSD-III adults vs. GSD-I adults, p < 0.05) of myopathic distribution. Children with "hepatic" and "myopathic" GSD phenotypes were both found to have myopathy. Myopathy stabilizes in "hepatic" GSD-I adults, whereas it progresses in "myopathic" GSD-III adults. Muscle ultrasonography provides an excellent, non invasive tool for neuromuscular surveillance per GSD phenotype. PMID- 26437931 TI - Physico-chemical and bacteriological quality of drinking water of different sources, Jimma zone, Southwest Ethiopia. AB - BACKGROUND: The quality of drinking water has always been a major health concern, especially in developing countries, where 80% of the disease cases are attributed to inadequate sanitation and use of polluted water. The inaccessibility of potable water to large segment of a population in the rural communities is the major health concern in most part of developing countries. This study was designed to evaluate the physico-chemical and bacteriological qualities of drinking water of different sources in the study area. METHODS: The study was conducted at Serbo town and selected kebeles around the same town in Kersa district of Jimma Zone, southwest Ethiopia. Socio-demographic characteristics of the study populations were gathered using structured and pre-tested questionnaires. Standard microbiological methods were employed for determination of bacterial load and detection of coliforms. Physico-chemical analyses [including total dissolved substances (TDS), total suspended substances (TSS), biological oxygen demand (BOD), nitrate and phosphate concentrations, turbidity and electrical conductivities] were conducted following guidelines of American Public Health Association and WHO. Correlations among measured parameters of water samples collected from different water sources were computed using SPSS software (version 20). RESULT: Only 18.1% (43/237) of the study population had access to tap water in the study area. More than 50% of the community relies on open field waste disposal. Members of the family Enterobacteriaceae, Bacillus and Pseudomonas were among dominant bacterial isolates in the water samples. All water samples collected from unprotected water sources were positive for total coliforms and fecal coliforms (FC). Accordingly, FC were detected in 80% of the total samples with counts ranging between 0.67 and 266.67 CFU/100 ml although 66.67% of tap water samples were negative for FC. The recorded temperature and pH ranged between 20.1-29.90 degrees C and 5.64-8.14, respectively. The lowest and highest mean TDS were 116 and 623 mg/l, respectively. Furthermore, the mean concentration of TSS ranged between 2.07 and 403.33 mg/l. Turbidity, electric conductivity, and nitrate concentration of the water samples ranged, respectively, between 0.01-65.4 NTU, 30.6-729 MUS/cm, and below detection limit to 95.80 mg/l. In addition, the mean dissolved oxygen values were found to be between 1.62 and 10.71 mg/l; whereas BOD was within the range of 8-77 mg/l. In all water samples, the concentrations of zinc were within the WHO maximum permissible limits (3 mg/l) although the lead concentration in about 66.7% of the samples exceeded the maximum permissible limit (0.01 mg/l). CONCLUSION: The present study has revealed that some of the bacteriological data and physico chemical parameters of the different water sources had values beyond the maximum tolerable limits recommended by WHO. Thus, it calls for appropriate intervention, including awareness development work and improving the existing infrastructure in order to minimize the potential health problems of those communities currently realizing of the available water sources. PMID- 26437930 TI - Effect of oral administration of low-dose follicle stimulating hormone on hyperandrogenized mice as a model of polycystic ovary syndrome. AB - BACKGROUND: Polycystic Ovary Syndrome (PCOS) is a widespread reproductive disorder characterized by a disruption of follicular growth and anovulatory infertility. In women with PCOS, follicular growth and ovulation can be induced by subcutaneous injections of low doses of follicle stimulating hormone (FSH). The aim of this study was to determine the effect of oral administration of recombinant human FSH (rhFSH) on follicle development in a PCOS murine model. Moreover, since it is unlikely that intact rhFSH is present into the circulation after oral administration, the biological activity of a peptide fragment, derived from the predicted enzymatic cleavage sites with the FSH molecule, was investigated in vitro on cumulus-enclosed oocytes (COCs). METHODS: Female peripubertal mice were injected with dehydroepiandrosterone (DHEA) diluted in sesame oil for 20 consecutive days and orally treated with a saline solution of rhFSH. A control group received only sesame oil and saline solution. At the end of treatments, blood was analyzed for hormone concentrations and ovaries were processed for morphological analysis. The presumptive bioactive peptide was added during in vitro maturation of bovine COCs and the effects on cumulus expansion and on maturation rate were evaluated. RESULTS: DHEA treatment increased serum levels of testosterone, estradiol and progesterone as well as the percentage of cystic follicles. Orally administered rhFSH restored estradiol level and reduced the percentage of cystic follicles. Despite these results indicating a reduction of the severity of PCOS in the mouse model, the presumptive bioactive peptide did not mimic the effect of rhFSH and failed to induce bovine cumulus expansion and oocyte maturation in vitro. CONCLUSIONS: Although further studies are needed, the present data supports the concept that orally administrated FSH could attenuate some of the characteristic of PCOS in the mouse model. PMID- 26437932 TI - A novel homozygous MPV17 mutation in two families with axonal sensorimotor polyneuropathy. AB - BACKGROUND: Mutations in MPV17 cause the autosomal recessive disorder mitochondrial DNA depletion syndrome 6 (MTDPS6), also called Navajo neurohepatopathy (NNH). Clinical features of MTDPS6 is infantile onset of progressive liver failure with seldom development of progressive neurologic involvement. METHODS: Whole exome sequencing (WES) was performed to isolate the causative gene of two unrelated neuropathy patients (9 and 13 years of age) with onset of the syndrome. Clinical assessments and biochemical analysis were performed. RESULTS: A novel homozygous mutation (p.R41Q) in MPV17 was found by WES in both patients. Both showed axonal sensorimotor polyneuropathy without liver and brain involvement, which is neurophysiologically similar to axonal Charcot-Marie-Tooth disease (CMT). A distal sural nerve biopsy showed an almost complete loss of the large and medium-sized myelinated fibers compatible with axonal neuropathy. An in vitro assay using mouse motor neuronal cells demonstrated that the abrogation of MPV17 significantly affected cell integrity. In addition, the expression of the mutant protein affected cell proliferation. These results imply that both the loss of normal function of MPV17 and the gain of detrimental effects of the mutant protein might affect neuronal function. CONCLUSION: We report a novel homozygous mutation in MPV17 from two unrelated patients harboring axonal sensorimotor polyneuropathy without hepatoencephalopathy. This report expands the clinical spectrum of diseases caused by mutations of MPV17, and we recommend MPV17 gene screening for axonal peripheral neuropathies. PMID- 26437933 TI - An accurate and efficient experimental approach for characterization of the complex oral microbiota. AB - BACKGROUND: Currently, taxonomic interrogation of microbiota is based on amplification of 16S rRNA gene sequences in clinical and scientific settings. Accurate evaluation of the microbiota depends heavily on the primers used, and genus/species resolution bias can arise with amplification of non-representative genomic regions. The latest Illumina MiSeq sequencing chemistry has extended the read length to 300 bp, enabling deep profiling of large number of samples in a single paired-end reaction at a fraction of the cost. An increasingly large number of researchers have adopted this technology for various microbiome studies targeting the 16S rRNA V3-V4 hypervariable region. RESULTS: To expand the applicability of this powerful platform for further descriptive and functional microbiome studies, we standardized and tested an efficient, reliable, and straightforward workflow for the amplification, library construction, and sequencing of the 16S V1-V3 hypervariable region using the new 2 * 300 MiSeq platform. Our analysis involved 11 subgingival plaque samples from diabetic and non-diabetic human subjects suffering from periodontitis. The efficiency and reliability of our experimental protocol was compared to 16S V3-V4 sequencing data from the same samples. Comparisons were based on measures of observed taxonomic richness and species evenness, along with Procrustes analyses using beta(beta)-diversity distance metrics. As an experimental control, we also analyzed a total of eight technical replicates for the V1-V3 and V3-V4 regions from a synthetic community with known bacterial species operon counts. We show that our experimental protocol accurately measures true bacterial community composition. Procrustes analyses based on unweighted UniFrac beta-diversity metrics depicted significant correlation between oral bacterial composition for the V1-V3 and V3-V4 regions. However, measures of phylotype richness were higher for the V1-V3 region, suggesting that V1-V3 offers a deeper assessment of population diversity and community ecology for the complex oral microbiota. CONCLUSION: This study provides researchers with valuable experimental evidence for the selection of appropriate 16S amplicons for future human oral microbiome studies. We expect that the tested 16S V1-V3 framework will be widely applicable to other types of microbiota, allowing robust, time-efficient, and inexpensive examination of thousands of samples for population, phylogenetic, and functional crossectional and longitutidal studies. PMID- 26437934 TI - Cranioplasty complications and risk factors associated with bone flap resorption. AB - BACKGROUND: Decompressive craniectomy (DC) may be performed in patients with acutely raised intracranial pressure due to traumatic brain injury or stroke. It is later followed by a cranioplasty procedure (CP) in the surviving patients. This procedure is associated with a high frequency of post-operative complications. Identifying risk factors for these adverse events is important in order to improve the clinical outcome. This study examines possible predictive parameters for post-operative complications in CP. METHODS: Retrospective, single institution review of all patients undergoing a DC for acutely raised intracranial pressure over a 10 year period at Oslo University Hospital Ulleval, Norway. Subsequent CP using autologous bone flaps or synthetic implants were registered along with all post-operative complications. Predictors of post operative complications were identified using uni -and multivariable regression analyses. RESULTS: A DC was carried out in 125 patients, of whom 33 died, 4 were lost to follow-up, and 1 (an infant) later underwent cranial remodeling. A CP was performed in the remaining 87 patients. Post-operative complications were recorded in 31 (36 %) patients of whom 22 lost their primary implant. Surgical site infection (SSI) and bone flap resorption (BFR) were the two most common complications, affecting 8 (9.2 %) and 14 (19.7 %) patients, respectively. Only BFR was associated with some of the recorded variables. Using multivariable logistic regression analysis, young age (OR = 0.94, 95 % CI 0.88-1.00, p = 0.04), bone flap fragmentation (OR = 14.3, 95 % CI 2.26-89, p = 0.005), long storage time (OR = 1.03, 95 % CI 1.00-1.04, p = 0.02) and Glasgow Outcome Scale at the time of cranioplasty (OR = 2.55, 95 % CI 1.04-6.23, p = 0.04) were found to be significant risk factors for bone flap resorption. CONCLUSIONS: Cranioplasty after decompressive craniectomy carries a high rate of complications. In this study, SSI and BFR were the two most common complications of which predictive clinical parameters could be identified for BFR only. The results indicate that synthetic implants may be considered in pediatric patients and in cases with fragmented bone flaps or delayed time to cranioplasty. Although the rate of complications was high, 73 % had a successful reinsertion of the autologous graft at a low cost. We feel this result justifies the continued use of cryopreserved bone flaps. PMID- 26437935 TI - Health status among black African-born women in Kansas City: a preliminary assessment. AB - BACKGROUND: Health information and statistics for Black foreign-born women in the United States are under-reported or not available. Black foreign-born women typically are classified under the general category of African American, ignoring the heterogeneity that exists in the United States Black population. It is important to identify health issues and behaviors of African-born women to effectively address health disparities. METHODS: Black African-born women (N = 29), 20 years or older completed a survey about general and women's health, health history, acculturation, lifestyle, social and health challenges, beliefs about breast cancer. Data were analyzed using SPSS 14.0 software. Categorical variables were summarized with frequencies and percentages and continuous variables were summarized with means and standard variation. A Likert scale (strongly agree, agree, disagree, and strongly disagree) was used to assess beliefs about breast cancer. RESULTS: Most (71.4%) participants had a high school education or more, 70% were employed, and 50% had health insurance. Two-thirds received health care from primary care doctors, 20.7% from health departments, and 39.3% got annual checkups. Lack of jobs, healthcare cost, language barrier, discrimination, and child care were the top social issues faced by participants. High blood pressure, obesity, oral health, HIV/AIDS, and diabetes were indicated as the most common health problems. The percent of participants (60%) that had not had a mammogram within the previous 2 years was more than the state average (24%) for women 40 years and older reported by the Kansas Department of Health and Environment. The percent of participants (40%) that had a mammogram within the previous 2 years was lower than the national average (73.2%) for African American women. CONCLUSIONS: Study provides a snapshot of social concerns and health issues in an African population residing in Midwestern United States. Understanding the socio-cultural characteristics of this population is necessary to address health disparities. PMID- 26437936 TI - Palliative surgical intervention in metastatic colorectal carcinoma: a prospective analysis of quality of life. AB - AIM: Quality of life (QOL) was assessed after palliative surgery for incurable metastatic colorectal cancer (CRC). METHOD: Newly diagnosed patients with incurable metastatic CRC who were offered elective palliative surgical intervention were included. The European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR29 questionnaire was used for the assessment of QOL at baseline and at 3 and 6 months after surgery. Generalized estimating equations were used to estimate the mean change in the QOL score from baseline. RESULTS: Twenty-four patients formed the study group. Sixteen underwent resection of the primary tumour and eight had a proximal diversion or bypass. The Global Health (GH) score and Social Functioning (SF) score improved at 3 and 6 months after intervention respectively (GH +11, P = 0.021; SF +15, P = 0.005). Mean anxiety scores were markedly improved from the baseline of 51 to 71 (P = 0.004, 3 months) and 76 (P = 0.002, 6 months). Weight concerns also improved significantly when compared with baseline (3 months, +20, P < 0.001; 6 months, +14, P = 0.012). Symptoms of diarrhoea (3 months, --17, P = 0.007; 6 months,--16, P = 0.008) and nausea (--8, P = 0.032) improved. CONCLUSION: In patients with incurable metastatic CRC, surgery improved QOL. PMID- 26437937 TI - Advances in the anatomic study of the interscapular region of the cat. AB - BACKGROUND: New clinical oriented approaches are supported by the integration of advanced imaging techniques, e.g. computed tomography and magnetic resonance, with gross anatomy imaging. The interscapular region of the cat is a typical site of a highly invasive infiltrative pathology, i.e. Feline Injection-Site Sarcoma. Even if chemotherapy and radiotherapy have been considered as pre-surgical therapies, extensive surgery is still the recommended treatment. Evidence suggested that the relationships between muscles, infiltrative mass and adjacent musculoskeletal structures could change according to the forelimb positions: a fact to be duly considered while planning the surgical approach. Anatomic and tomographic atlases provide only images of the interscapular region from cats positioned with their forelimbs extended cranially, which means that, they do not record musculoskeletal modifications due to the forelimb movements. Aim of this study was to provide detailed images of the changes occurring in the musculoskeletal structures of the interscapular region of cats according to their forelimb position by comparing cross-sectional gross anatomy, computed tomography and magnetic resonance imaging. RESULTS: We provide an atlas of normal cross sectional anatomy, computed tomography and magnetic resonance imaging of the interscapular region of the cat, from the fifth cervical vertebra to the fifth thoracic vertebra. We compare and couple the slices obtained both in flexed and extended forelimb positioning with the animal maintained in sternal recumbency. CONCLUSION: This study shows a new and dynamic way to investigate the interscapular region of the cat and provides anatomical references for in vivo computed tomography and magnetic resonance imaging, considering changes in the muscular form according to the forelimb positioning. We believe that an in-depth anatomical knowledge of the interscapular region may be helpful to approach the study of any pathology located there and, in particular, to set up an appropriate therapy for the feline injection-site sarcoma. PMID- 26437938 TI - A case of Listeria monocytogenes endophthalmitis with recurrent inflammation and novel management. AB - BACKGROUND: Listeria monocytogenes is a rare cause of endogenous endophthalmitis. In the limited number of reported Listeria endophthalmitis cases, visual acuity outcomes have been very poor. FINDINGS: Here, we report a case of Listeria endophthalmitis that was complicated by recurrent inflammation. The patient required treatment with both intravitreal and long-term systemic antibiotics. An anterior chamber washout was necessary for the patient to regain 20/20 visual acuity. CONCLUSIONS: This case highlights the importance of considering Listeria early in the disease course, as it has low sensitivity to standard empiric antibiotic therapy. It also stresses the importance of addressing damaging inflammation in infectious conditions. PMID- 26437939 TI - Family planning to promote physical activity: a randomized controlled trial protocol. AB - BACKGROUND: Physical activity is associated with the reduction of several chronic conditions in adults. Additionally, physical activity is extremely important for children for their development and cognitive functioning and also to create a physically active lifestyle that continues into adulthood. Despite the known benefits of physical activity, only one in five adults are achieving the public health recommendations of 150 minutes of moderate-to-vigorous physical activity per week and only 13 % of boys and 6 % of girls between the ages of 5 and 17 years are meeting the guidelines of 60 minutes per day. This study aims to evaluate whether a planning condition improves adherence to regular physical activity compared to an education-only control condition among families. Families are eligible if there is at least one child between the ages of 6 and 12 years who is not meeting the Canadian Physical Activity Guidelines. METHODS/DESIGN: A six-month longitudinal randomized controlled trial will be used to compare the two conditions. Materials will be delivered at baseline with 'booster' sessions at six weeks and three months. Participants will be assessed at baseline and at six months with a fitness test, as well as questionnaires and accelerometery at baseline, six weeks, three months and six months. A total of 137 families have been recruited thus far from Greater Victoria. This study is ongoing and recruitment will continue until December 2015 with the target goal of reaching 160 families. DISCUSSION: This protocol describes the implementation of a randomized controlled trial that utilizes planning strategies to try and increase physical activity among families. Research findings could be useful in public health in providing effective strategies to families to help decrease sedentary lifestyles. Additionally, findings may help to inform future interventions aimed at increasing physical activity among families. TRIAL REGISTRATION: This trial was registered on June 5, 2012 with the Clinical Trials Registry maintained by the National Library of Medicine at the National Institutes of Health. The registration ID is NCT01882192. PMID- 26437942 TI - Behavior Genetics Association 45th Annual Meeting Abstracts. PMID- 26437940 TI - Placental vascularization alterations in hypertensive disorders complicating pregnancy (HDCP) and small for gestational age with HDCP using three-dimensional power doppler in a prospective case control study. AB - BACKGROUND: Hypertensive disorders complicating pregnancy (HDCP) continues to be a leading cause of maternal and neonatal mortality and morbidity. The clinical value of placental three-dimensional power Doppler (3DPD) in assessing HDCP requires further confirmation. The research was developed to assess changes of placental vascularity in HDCP using 3DPD and to investigate the placental vascularity in small for gestational age (SGA) compared with not-SGA in patients with HDCP. METHODS: There were 126 normotensive and 128 hypertensive pregnant women included in this prospective case-control study from March 2011 to March 2013. Pregnant women underwent 3DPD. Vascularization index (VI), flow index (FI) and vascularization flow index (VFI) were obtained. The placental 3DPD indices, umbilical artery systolic and diastolic ratio (S/D) and pregnancy outcomes were compared between the groups. RESULTS: The placental VI and VFI were significantly lower in hypertensive women compared with normotensive women (P < 0.001 and P = 0.014, respectively), and these parameters were significantly reduced in severe preeclampsia (P < 0.001 and P = 0.003, respectively). A weak correlation was found between VI and umbilical artery S/D in HDCP group (r = -0.277, P = 0.001). In HDCP population, neonates who were postnatally diagnosed with SGA had lower VI (P = 0.041) and higher S/D (P < 0.001). DISCUSSION: The placental vascularity indices decreased in hypertensive women and the reduction inplacental perfusion was consistent with the severity of the hypertensive disorder. The associations betweenplacental vascularization and umbilical artery impedance may be valuable for further researches and arerequired confirmation. The significant differences in the 3DPD placental vascularization between SGA andnot-SGA in hypertensive pregnancy population may show some clinical importance that we could use tobetter assess or predict the progression and adverse outcomes in the future. Although 3DPD quantificationhas been widely used in multiple publications, we have to acknowledge its limitations. CONCLUSIONS: The intraplacental vascularization was poor in HDCP, and especially in severe preeclampsia. Neonates with SGA had poor placental vascularization and higher umbilical artery S/D. Further studies should focus on the clinical assessment of placental 3DPD as well as a combination of placental 3DPD and other fetal Doppler indices to better predict the development and outcomes of preeclampsia. PMID- 26437943 TI - Phylogenetic approaches to microbial community classification. AB - BACKGROUND: The microbiota from different body sites are dominated by different major groups of microbes, but the variations within a body site such as the mouth can be more subtle. Accurate predictive models can serve as useful tools for distinguishing sub-sites and understanding key organisms and their roles and can highlight deviations from expected distributions of microbes. Good classification depends on choosing the right combination of classifier, feature representation, and learning model. Machine-learning procedures have been used in the past for supervised classification, but increased attention to feature representation and selection may produce better models and predictions. RESULTS: We focused our attention on the classification of nine oral sites and dental plaque in particular, using data collected from the Human Microbiome Project. A key focus of our representations was the use of phylogenetic information, both as the basis for custom kernels and as a way to represent sets of microbes to the classifier. We also used the PICRUSt software, which draws on phylogenetic relationships to predict molecular functions and to generate additional features for the classifier. Custom kernels based on the UniFrac measure of community dissimilarity did not improve performance. However, feature representation was vital to classification accuracy, with microbial clade and function representations providing useful information to the classifier; combining the two types of features did not yield increased prediction accuracy. Many of the best performing clades and functions had clear associations with oral microflora. CONCLUSIONS: The classification of oral microbiota remains a challenging problem; our best accuracy on the plaque dataset was approximately 81 %. Perfect accuracy may be unattainable due to the close proximity of the sites and intra-individual variation. However, further exploration of the space of both classifiers and feature representations is likely to increase the accuracy of predictive models. PMID- 26437944 TI - The 14-3-3 Gene Function of Cryptococcus neoformans Is Required for its Growth and Virulence. AB - Cryptococcus neoformans is a life-threatening pathogenic yeast that causes devastating meningoencephalitis. The mechanism of cryptococcal brain invasion is largely unknown, and recent studies suggest that its extracellular microvesicles may be involved in the invasion process. The 14-3-3 protein is abundant in the extracellular microvesicles of C. neoformans, and the 14-3-3-GFP fusion has been used as the microvesicle's marker. However, the physiological role of 14-3-3 has not been explored. In this report, we have found that C. neoformans contains a single 14-3-3 gene that apparently is an essential gene. To explore the functions of 14-3-3, we substituted the promoter region of the 14-3-3 with the copper controllable promoter CTR4. The CTR4 regulatory strain showed an enlarged cell size, drastic changes in morphology, and a decrease in the thickness of the capsule under copper-enriched conditions. Furthermore, the mutant cells produced a lower amount of total proteins in their extracellular microvesicles and reduced adhesion to human brain microvascular endothelial cells in vitro. Proteomic analyses of the protein components under 14-3-3-overexpressed and -suppressed conditions revealed that the 14-3-3 function(s) might be associated with the microvesicle biogenesis. Our results support that 14-3-3 has diverse pertinent roles in both physiology and pathogenesis in C. neoformans. Its gene functions are closely relevant to the pathogenesis of this fungus. PMID- 26437945 TI - Bacterial Community Structure Shifted by Geosmin in Granular Activated Carbon System of Water Treatment Plants. AB - We investigated the relation between the presence of geosmin in water and the bacterial community structure within the granular activated carbon (GAC) system of water treatment plants in South Korea. GAC samples were collected in May and August of 2014 at three water treatment plants (Sungnam, Koyang, and Yeoncho in Korea). Dissolved organic carbon and geosmin were analyzed before and after GAC treatment. Geosmin was found in raw water from Sungnam and Koyang water treatment plants but not in that from Yeoncho water treatment plant. Interestingly, but not surprisingly, the 16S rRNA clone library indicated that the bacterial communities from the Sungnam and Koyang GAC systems were closely related to geosmin-degrading bacteria. Based on the phylogenetic tree and multidimensional scaling plot, bacterial clones from GAC under the influence of geosmin were clustered with Variovorax paradoxus strain DB 9b and Comamonas sp. DB mg. In other words, the presence of geosmin in water might have inevitably contributed to the growth of geosmin degraders within the respective GAC system. PMID- 26437946 TI - A Color-Reaction-Based Biochip Detection Assay for RIF and INH Resistance of Clinical Mycobacterial Specimens. AB - The widespread occurrence of drug-resistant Mycobacterium tuberculosis places importance on the detection of TB (tuberculosis) drug susceptibility. Conventional drug susceptibility testing (DST) is a lengthy process. We developed a rapid enzymatic color-reaction-based biochip assay. The process included asymmetric multiplex PCR/templex PCR, biochip hybridization, and an enzymatic color reaction, with specific software for data operating. Templex PCR (tem- PCR) was applied to avoid interference between different primers in conventional multiplex- PCR. We applied this assay to 276 clinical specimens (including 27 sputum, 4 alveolar lavage fluid, 2 pleural effusion, and 243 culture isolate specimens; 40 of the 276 were non-tuberculosis mycobacteria specimens and 236 were M. tuberculosis specimens). The testing process took 4.5 h. A sensitivity of 50 copies per PCR was achieved, while the sensitivity was 500 copies per PCR when tem-PCR was used. Allele sequences could be detected in mixed samples at a proportion of 10%. Detection results showed a concordance rate of 97.46% (230/236) in rifampicin resistance detection (sensitivity 95.40%, specificity 98.66%) and 96.19% (227/236) in isoniazid (sensitivity 93.59%, specificity 97.47%) detection with those of DST assay. Concordance rates of testing results for sputum, alveolar lavage fluid, and pleural effusion specimens were 100%. The assay provides a potential choice for TB diagnosis and treatment. PMID- 26437947 TI - Enzyme-Catalyzed Henry Reaction in Choline Chloride-Based Deep Eutectic Solvents. AB - The enzyme-catalyzed Henry reaction was realized using deep eutectic solvents (DESs) as a reaction medium. The lipase from Aspergillus niger (lipase AS) showed excellent catalytic activity toward the substrates aromatic aldehydes and nitromethane in choline chloride:glycerol at a molar ratio of 1:2. Addition of 30 vol% water to DES further improved the lipase activity and inhibited DES catalyzed transformation. A final yield of 92.2% for the lipase AS-catalyzed Henry reaction was achieved under optimized reaction conditions in only 4 h. In addition, the lipase AS activity was improved by approximately 3-fold in a DES water mixture compared with that in pure water, which produced a final yield of only 33.4%. Structural studies with fluorescence spectroscopy showed that the established strong hydrogen bonds between DES and water may be the main driving force that affects the spatial conformation of the enzyme, leading to a change in lipase activity. The methodology was also extended to the aza-Henry reaction, which easily occurred in contrast to that in pure water. The enantioselectivity of both Henry and aza-Henry reactions was not found. However, the results are still remarkable, as we report the first use of DES as a reaction medium in a lipase-catalyzed Henry reaction. PMID- 26437948 TI - Anticancer Effect of Thymol on AGS Human Gastric Carcinoma Cells. AB - Numerous plants have been documented to contain phenolic compounds. Thymol is one among these phenolic compounds that possess a repertoire of pharmacological activities, including anti-inflammatory, anticancer, antioxidant, antibacterial, and antimicrobial effects. Despite of the plethora of affects elicited by thymol, its activity profile on gastric cancer cells is not explored. In this study, we discovered that thymol exerts anticancer effects by suppressing cell growth, inducing apoptosis, producing intracellular reactive oxygen species, depolarizing mitochondrial membrane potential, and activating the proapoptotic mitochondrial proteins Bax, cysteine aspartases (caspases), and poly ADP ribose polymerase in human gastric AGS cells. The outcomes of this study displayed that thymol, via an intrinsic mitochondrial pathway, was responsible for inducing apoptosis in gastric AGS cells. Hence, thymol might serve as a tentative agent in the future to treat cancer. PMID- 26437949 TI - Melanin Biosynthesis Inhibition Effects of Ginsenoside Rb2 Isolated from Panax ginseng Berry. AB - Ginsenoside Rb2 (Gin-Rb2) was purified from the fruit extract of Panax ginseng. Its chemical structure was measured by spectroscopic analysis, including HR-FAB MS, (1)H-NMR, and IR spectroscopy. Gin-Rb2 decreased potent melanogenesis in melan-a cells, with 23.4% at 80 MUM without cytotoxicity. Gin-Rb2 also decreased tyrosinase and MITF protein expression in melan-a cells. Furthermore, Gin-Rb2 presented inhibition of the body pigmentation in the zebrafish in vivo system and reduced melanin contents and tyrosinase activity. These results show that Gin-Rb2 isolated from P. ginseng may be an effective skin-whitening agent via the in vitro and in vivo systems. PMID- 26437950 TI - Identifying Desistance Pathways in a Higher Education Program for Formerly Incarcerated Individuals. AB - The link between education and crime is a topic that requires special attention with respect to the converging influence of individual, social, and environmental factors. This article will investigate the educational pathways followed by students in a higher education program for formerly incarcerated individuals at a large state university in the northeastern United States. Specifically, it will explore the extent to which their postincarceration educational experiences served as a "hook for change" and also related impediments tied to street influences, financial constraints, stigma, academic and social development. Data were collected from a sample of 34 current and former students in the program, each of whom participated in a face-to-face interview. The higher education program played a key role in propelling the desistance process for research participants. This article will discuss how personal agency can be sustained through participation in higher education post release and the implications for future research on crime avoidance. PMID- 26437951 TI - Teachers of various school grades and representations of epilepsy: problems, relational aspects and perspectives of life quality. AB - INTRODUCTION: The analysis of the representations of the health of their students by teachers is key to the understanding of the attitudes and behaviors that, in general, take place inside the school community and the educational processes. In fact, social attitudes by teachers and individual within the school environment are often the result of simple categorization and stereotypes, which hinder the process of evolutionary change. AIMS: On these premises it was necessary to investigate the level of knowledge of the epilepsy syndrome, the representations by a group of teachers of the quality of life of people with epilepsy and the representations of the interpersonal relationships between students with epilepsy and their classmates. METHODOLOGY: We used an ad hoc questionnaire, with 33 multiple choice answers, focusing on these variables: work seniority, experience with epileptic students, special education or main teacher. PARTICIPANTS: The sample consisted of 113 female teachers with a mean age of 44.4. RESULTS: There aren't significant differences between the answers of special education and main teachers: a) teachers with work seniority > 11 years showed a more than adequate knowledge of information about epilepsy. Moreover, in case of seizure in the classroom, first aid is to call an ambulance rather than administering rescue drugs; b) teachers, who have had a real experience, represent the epileptic student as more limited in the possibilities of getting married, having children, finding a job, and practising a sport; c) teachers, who have had a student with epilepsy don't report interpersonal relationships with his/her classmates as being difficult. Moreover, they claim to have inadequate knowledge of the educational strategies needed to integrate the epileptic student with his/her classmates; d) there are some different answers for primary school teachers and for secondary school teachers. CONCLUSIONS: Teachers demonstrate inaccurate information about epilepsy, its impact in educational contexts and management of seizures in the classroom. Also, critical areas have emerged indicating efforts should focus on education, sharing the role of teacher, awareness and integration in the class group. PMID- 26437952 TI - Chitinophaga dinghuensis sp. nov., isolated from soil. AB - A Gram-reaction-negative, aerobic, non-motile bacterial strain, DHOC24T, was isolated from the forest soil of Dinghushan Biosphere Reserve, Guangdong Province, PR China. Strain DHOC24T underwent a shape change during the course of culture from long filamentous cells (10-30 * 0.4-0.5 MUm) at 2 days to coccobacilli (0.5-1.0 * 0.7-1.0 MUm) at 15 days after inoculation. It grew optimally at 28-33 degrees C and pH 6.5-7.5. The major quinone of strainDHOC24T was MK-7, the main fatty acids were iso-C15 : 0, C16 : 1omega5c and iso-C17 : 0 3 OH and the DNA G+C content was 43.1 mol%. On the basis of 16S rRNA gene sequence analysis, the strain was found to be affiliated with members of the genus Chitinophaga, but was clearly separated from established species of the genus. Strain DHOC24T was most closely related to Chitinophaga jiangningensis JN53T (98.3 % 16S rRNA gene sequence similarity) and Chitinophaga terrae KP01T (97.9 %). DNA-DNA hybridization study showed relatively low relatedness values (32.1 %) of strain DHOC24T with C. jiangningensis JN53T. The phenotypic, chemotaxonomic and phylogenetic data showed that strain DHOC24T represents a novel species of the genus Chitinophaga, for which the name Chitinophaga dinghuensis sp. nov. is proposed. The type strain is DHOC24T ( = CGMCC 1.12995T = DSM 29821T). PMID- 26437954 TI - Erratum to: congenital HCMV and assisted reproduction: why not use the chance for primary screening? PMID- 26437953 TI - Prognostic factors and genes associated with endometrial cancer based on gene expression profiling by bioinformatics analysis. AB - BACKGROUND: Endometrial cancer (EC) is the most prevalent malignancy worldwide. Although several efforts had been made to explore the molecular mechanism responsible for EC progression, it is still not fully understood. AIM OF THE STUDY: To evaluate the clinical characteristics and prognostic factors of patients with EC, and further to search for novel genes associated with EC progression. METHODS: We recruited 328 patients with EC and analyzed prognostic factors using Cox proportional hazard regression model. Further, a gene expression profile of EC was used to identify the differentially expressed genes (DEGs) between normal samples and tumor samples. Subsequently, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis ( http://www.genome.jp/kegg/ ) for DEGs were performed, and then protein-protein interaction (PPI) network of DEGs as well as the subnetwork of PPI were constructed with plug-in, MCODE by mapping DEGs into the Search Tool for the Retrieval of Interacting Genes database. RESULTS: Our results showed that body mass index (BMI), hypertension, myometrial invasion, pathological type, and Glut4 positive expression were prognostic factors in EC (P < 0.05). Bioinformatics analysis showed that upregulated DEGs were associated with cell cycle, and downregulated DEGs were related to MAPK pathway. Meanwhile, PPI network analysis revealed that upregulated CDK1 and CCNA2 as well as downregulated JUN and FOS were listed in top two nodes with high degrees. CONCLUSIONS: Patients with EC should be given more focused attentions in respect of pathological type, BMI, hypertension, and Glut4-positive expression. In addition, CDK1, CCNA2, JUN, and FOS might play important roles in EC development. PMID- 26437955 TI - Predictors for a successful external cephalic version: a single centre experience. AB - PURPOSE: The external cephalic version (ECV) is one of the options patients presenting with a breech pregnancy should be offered. Various fetal, maternal and other predictors for a successful ECV have been published in the past. METHODS: This is a retrospective multivariate analysis of our ECV patient database at the Department of Obstetrics and Gynaecology at the University Hospital Ulm. In an outpatient setting, patients with fetal breech position were routinely offered an ECV attempt after 36 weeks of gestation if the patient was willing to consent. Contraindications for ECV were placental abruption, placenta praevia, uterus malformations, regular contractions, premature rupture of membranes, and non reassuring fetal heart rate patterns. RESULTS: From January 1st 2010 to July 31st 2013, 444 patients with a minimum of 36 weeks gestational age (i.e. >35 + 6 weeks) attended our clinic with a breech presentation. Of those 118 had an ECV attempt and an extended ultrasound examination within 21 days. In 33 patients the procedure was successful (success rate 28 %). A multivariate binary logistic regression analysis revealed that an increased Amniotic Fluid Index (AFI; p < 0.001), at least one prior vaginal delivery (p = 0.002) or a high estimated fetal weight (p = 0.045) were significant independent predictors for a successful ECV. In our series no delivery occurred within 48 h after the ECV. CONCLUSIONS: An ECV is a safe procedure. ECV should be offered as an option for the mother-to-be on the basis of an informed consent. Identified fetal and maternal factors can help to estimate the chances of success and in particular multi-parity and increased amniotic fluid seem to be associated with successful ECV. PMID- 26437956 TI - Double-balloon catheter and sequential vaginal prostaglandin E2 versus vaginal prostaglandin E2 alone for induction of labor after previous cesarean section. AB - PURPOSE: To evaluate the efficacy of inducing labor using a double-balloon catheter and vaginal prostaglandin E2 (PGE2) sequentially, in comparison with vaginal PGE2 alone after previous cesarean section. METHODS: A total of 264 pregnant women with previous cesarean section undergoing labor induction at term were included in this prospective multicentre cohort study. Induction of labor was performed either by vaginal PGE2 gel or double-balloon catheter followed by vaginal PGE2. The primary outcome measure was the cesarean section rate. RESULTS: The cesarean section rate was 37 % without any statistically significant difference between the two groups (PGE2: n = 41, 37 % vs. balloon catheter/PGE2: n = 41, 42 %; P = 0.438). The median (range) number of applications of PGE2 [2 (1 10) versus 1 (0-8), P < 0.001] and the total amount of PGE2 used in median (range) mg [2 (1-15) vs. 1 (0-14), P = 0.001] was less in the balloon catheter/PGE2 group. Factors significantly increasing risk for cesarean section were "no previous vaginal delivery" (OR 5.391; CI 2.671-10.882) and "no oxytocin augmentation during childbirth" (OR 2.119; CI 1.215-3.695). CONCLUSIONS: The sequential application of double-balloon catheter and vaginal PGE2 is as effective as the sole use of vaginal PGE2 with less applications and total amount of PGE2. PMID- 26437957 TI - Comparison of citalopram and venlafaxine's role in treating sleep disturbances in menopausal women, a randomized, double-blind, placebo-controlled trial. AB - INTRODUCTION: Sleep disturbance is a common complaint in postmenopausal women. Few studies compared symptom improvement taking antidepressants versus placebo. This study aims to evaluate the efficacy of venlafaxine and Citalopram compared to placebo in treatment of sleep disturbance in healthy postmenopausal women. METHOD: This randomized, double-blind, placebo-controlled clinical trial was conducted in three groups of 20 postmenopausal women. The patients took venlafaxine 75 mg/daily (group I) or citalopram 20 mg/d (group II) or placebo (group III). Each patient filled Pittsburgh sleep quality index (PSQI) and Pittsburgh and Beck depression questionnaires. The frequency of hot flashes in a day and its severity were measured through diaries. Somatic symptoms and adverse side effects were evaluated. Follow-up visit was conducted after 3 months. The prior and the later results were compared. RESULTS: The PSQI scores in three placebo, venlafaxine, and citalopram groups before treatment were 14.25 +/- 3.85, 11.55 +/- 3.96, and 13.50 +/- 3.56, respectively (p = 0.076). These values after treatment reached 9.95 +/- 5.07, 8 +/- 3.06, and 6.95 +/- 1.84, respectively. PSQI score in citalopram and venlafaxine group was not significantly different (p = 0.19) but the score in both groups was significantly lower compared with placebo group after treatment (p = 0.01). The frequency of hot flashes in a day was reduced significantly by both citalopram and venlafaxine (p < 0.05), although it was more reduced by citalopram than venlafaxine (p = 0.03). Severity of hot flashes in both venlafaxine and citalopram was significantly lower in comparison with placebo group (p = 0.02), and there was no significant difference between two drugs, though (p = 0.84). Beck score decreased more in venlafaxine group in comparison with other groups but it did not reach significant (p = 0.06). CONCLUSION: Citalopram and venlafaxine are equally more effective than placebo in reducing sleep disturbance and severity of hot flashes, while citalopram is more effective in reducing frequency of hot flashes than venlafaxine. Meanwhile, venlafaxine is more effective than citalopram in treatment of depression in postmenopausal women. TRIAL REGISTRATION: Iranian Registry of Clinical Trials 201210152576N6. PMID- 26437958 TI - External quality assessment for acid fast bacilli smear microscopy in eastern part of Ethiopia. AB - BACKGROUND: External quality assessment (EQA) of sputum smear microscopy is essential and indispensable component of any tuberculosis program. This study assessed the EQA of acid fast bacilli (AFB) smear microscopy through onsite evaluation, blinded rechecking and panel test. A one year study was conducted on eight health institution laboratories from December 2011 to December 2012. Onsite evaluation, blinded rechecking and panel tests were used to collect data. Data were analyzed using SPSS version 16. Sensitivity, specificity, predictive values, and proportions of false readings were calculated. The level of agreement was measured using Kappa (kappa) value. RESULTS: Problems observed during onsite evaluation include shortages of materials, disinfectant, and poor storage and working condition. A total of 578 slides were collected for blinded rechecking, of which 102 (17.6%) were reported as positive by peripheral laboratories. The panel test revealed an overall error of 17 (25.25%) of which 14 (17.5%) were minor errors [low false negative 6 (7.5%) and low false positive 8 (10%)], and 3 (3.75%) were major errors (high false positive). The sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV) of the peripheral laboratories were 83.5, 97.8, 91.7, and 95.7, respectively. The false readings at the peripheral laboratories were 32 (5.5%). Agreement on reading the slides was observed on 546 (94.5%) slides (K = 0.84, SE = 0.054). CONCLUSIONS: Lack of reagents, supplies, favorable working environment and AFB related technical problems were identified in the peripheral laboratories. High false negative error was found to be the predominant major error. A continuous and strong EQA scheme should be implemented to avoid reporting errors and produce quality sputum results. PMID- 26437959 TI - The biogeographic origin of a radiation of trees in Madagascar: implications for the assembly of a tropical forest biome. AB - BACKGROUND: Madagascar's rain forests are characterized by extreme and uneven patterns of species richness and endemicity, the biogeographic and evolutionary origins of which are poorly understood. METHODS: Here we use a time-calibrated phylogeny of a dominant group of trees in Madagascar's eastern rain forests, Canarium, and related Burseraceae (Canarieae), to test biogeographic hypotheses regarding the origin and radiation of the flora of this unique biome. RESULTS: Our findings strongly support the monophyly of Malagasy Canarium, suggesting that this clade represents a previously undocumented in situ radiation. Contrary to expectations of dispersal from Africa during the Oligocene, concurrent with the formation of Madagascar's rain forest biome, our analyses support a late Miocene origin for Malagasy Canarium, probably by long distance dispersal from Southeast Asia. DISCUSSION: Our study illustrates the importance of considering long distance dispersal as a viable explanation for clades with pantropical distributions diversifying subsequent to the Oligocene, and it highlights the formation of the Indo-Australian Archipelago and associated fast-moving equatorial surface currents, suggesting an under-appreciated evolutionary link among tropical centers of endemism. CONCLUSIONS: We postulate that the relatively recent establishment and radiation of Canarium in Madagascar may have been facilitated by the highly stochastic climates associated with these forest ecosystems. PMID- 26437960 TI - Systematic literature review of determinants of sedentary behaviour in older adults: a DEDIPAC study. AB - BACKGROUND: Older adults are the most sedentary segment of society and high sedentary time is associated with poor health and wellbeing outcomes in this population. Identifying determinants of sedentary behaviour is a necessary step to develop interventions to reduce sedentary time. METHODS: A systematic literature review was conducted to identify factors associated with sedentary behaviour in older adults. Pubmed, Embase, CINAHL, PsycINFO and Web of Science were searched for articles published between 2000 and May 2014. The search strategy was based on four key elements: (a) sedentary behaviour and its synonyms; (b) determinants and its synonyms (e.g. correlates, factors); (c) types of sedentary behaviour (e.g. TV viewing, sitting, gaming) and (d) types of determinants (e.g. environmental, behavioural). Articles were included in the review if specific information about sedentary behaviour in older adults was reported. Studies on samples identified by disease were excluded. Study quality was rated by means of QUALSYST. The full review protocol is available from PROSPERO (PROSPERO 2014: CRD42014009823). The analysis was guided by the socio ecological model framework. RESULTS: Twenty-two original studies were identified out of 4472 returned by the systematic search. These included 19 cross-sectional, 2 longitudinal and 1 qualitative studies, all published after 2011. Half of the studies were European. The study quality was generally high with a median of 82 % (IQR 69-96 %) using Qualsyst tool. Personal factors were the most frequently investigated with consistent positive association for age, negative for retirement, obesity and health status. Only four studies considered environmental determinants suggesting possible association with mode of transport, type of housing, cultural opportunities and neighbourhood safety and availability of places to rest. Only two studies investigated mediating factors. Very limited information was available on contexts and sub-domains of sedentary behaviours. CONCLUSION: Few studies have investigated determinants of sedentary behaviour in older adults and these have to date mostly focussed on personal factors, and qualitative studies were mostly lacking. More longitudinal studies are needed as well as inclusion of a broader range of personal and contextual potential determinants towards a systems-based approach, and future studies should be more informed by qualitative work. PMID- 26437961 TI - Influence of social experiences in shaping perceptions of the Ebola virus among African residents of Hong Kong during the 2014 outbreak: a qualitative study. AB - INTRODUCTION: The outbreak of Ebola virus disease (EVD) in Africa in 2014 attracted worldwide attention. Because of the high mortality rate, marginalised social groups are vulnerable to disease-associated stigmatisation and discrimination, according to the literature. In Hong Kong, ethnic minorities such as Africans are often disadvantaged groups because of their low position in the social hierarchy. In 2011, approximately 1700 Africans were residing in Hong Kong. Their overseas experiences during the EVD outbreak were not well documented. Therefore, this study investigated the EVD-associated stigmatisation experiences of African residents of Hong Kong with chronic illnesses, and how these experiences shaped their perceptions of EVD. METHODS: A qualitative design with 30 in-depth semistructured interviews was conducted with chronically ill African residents of Hong Kong. RESULTS: The interview data showed that the sampled Africans often experienced stigmatisation in their workplaces and in the community during the EVD outbreak. Their experiences of EVD-associated stigma were correlated to the embedded social and cultural values regarding ethnic minorities in Hong Kong. These experiences of being stigmatised shaped the perceptions of the Africans of EVD, leading them to view EVD as shameful and horrifying. They also perceived EVD as retribution and was introduced by Westerners. The participants' perceptions of EVD influenced their responses to and behaviour towards EVD, which may have posed potential threats to Hong Kong's public health. CONCLUSIONS: The EVD outbreak was not the only cause of the participants' stigmatisation; rather, their EVD-associated experiences were a continuation and manifestation of the embedded social and cultural values regarding ethnic minorities in Hong Kong. The experiences of being stigmatised shaped the participants' perceptions of EVD. Because of their marginalised social position and isolation from the main community, the participants had extremely limited access to reliable information about EVD. As a result, they used their own cultural beliefs to understand EVD, which might have ultimately influenced their health behaviours. The experiences of the participants showed that ethnic minorities in Hong Kong were in need of more culturally responsive social and health care support to obtain reliable information about the nature of and preventive measures against EVD. PMID- 26437962 TI - Activating PI3Kdelta mutations in a cohort of 669 patients with primary immunodeficiency. AB - The gene PIK3CD codes for the catalytic subunit of phosphoinositide 3-kinase delta (PI3Kdelta), and is expressed solely in leucocytes. Activating mutations of PIK3CD have been described to cause an autosomal dominant immunodeficiency that shares clinical features with common variable immunodeficiency (CVID). We screened a cohort of 669 molecularly undefined primary immunodeficiency patients for five reported mutations (four gain-of-function mutations in PIK3CD and a loss of function mutation in PIK3R1) using pyrosequencing. PIK3CD mutations were identified in three siblings diagnosed with CVID and two sporadic cases with a combined immunodeficiency (CID). The PIK3R1 mutation was not identified in the cohort. Our patients with activated PI3Kdelta syndrome (APDS) showed a range of clinical and immunological findings, even within a single family, but shared a reduction in naive T cells. PIK3CD gain of function mutations are more likely to occur in patients with defective B and T cell responses and should be screened for in CVID and CID, but are less likely in patients with a pure B cell/hypogammaglobulinaemia phenotype. PMID- 26437963 TI - Web-Based Malignancy Risk Estimation for Thyroid Nodules Using Ultrasonography Characteristics: Development and Validation of a Predictive Model. AB - BACKGROUND: To establish a practical and simplified method for analyzing thyroid nodules in a clinical setting, the development of a new practical prediction model was required. This study aimed to construct and validate a simple and reliable web-based predictive model using the ultrasonography characteristics of thyroid nodules to stratify the risk of malignancy. METHODS: To analyze ultrasonography images, radiologists were asked to assess thyroid nodules according to the following criteria: internal content, echogenicity of the solid portion, shape, margin, and calcifications. Multivariate logistic regression was performed to predict whether nodules were diagnosed as malignant or benign. The developmental data set included 849 nodules (January-June 2003). The validation set included different data (n = 453, June 2008-February 2009). RESULTS: Ultrasonography features, including solid content, taller-than-wide shape, spiculated margin, ill-defined margin, hypoechogenicity, marked hypoechogenicity, microcalicifications, and rim calcifications, were selected as predictors for malignant nodules in the development set. A 14-point risk scoring system was developed. Malignancy risk ranged from 3.8% to 97.4%, and the risk of malignancy was positively associated with increases in risk scores. The areas under the receiver operating characteristic curve of the development and validation sets were 0.903 and 0.897, respectively. CONCLUSION: A simple and reliable web-based predictive model was designed using ultrasonography characteristics to stratify thyroid nodules according to the probability of malignancy. PMID- 26437964 TI - Towards in vivo estimation of reaction kinetics using high-throughput metabolomics data: a maximum likelihood approach. AB - BACKGROUND: High-throughput assays such as mass spectrometry have opened up the possibility for large-scale in vivo measurements of the metabolome. This data could potentially be used to estimate kinetic parameters for many metabolic reactions. However, high-throughput in vivo measurements have special properties that are not taken into account in existing methods for estimating kinetic parameters, including significant relative errors in measurements of metabolite concentrations and reaction rates, and reactions with multiple substrates and products, which are sometimes reversible. A new method is needed to estimate kinetic parameters taking into account these factors. RESULTS: A new method, InVEst (In Vivo Estimation), is described for estimating reaction kinetic parameters, which addresses the specific challenges of in vivo data. InVEst uses maximum likelihood estimation based on a model where all measurements have relative errors. Simulations show that InVEst produces accurate estimates for a reversible enzymatic reaction with multiple reactants and products, that estimated parameters can be used to predict the effects of genetic variants, and that InVEst is more accurate than general least squares and graphic methods on data with relative errors. InVEst uses the bootstrap method to evaluate the accuracy of its estimates. CONCLUSIONS: InVEst addresses several challenges of in vivo data, which are not taken into account by existing methods. When data have relative errors, InVEst produces more accurate and robust estimates. InVEst also provides useful information about estimation accuracy using bootstrapping. It has potential applications of quantifying the effects of genetic variants, inference of the target of a mutation or drug treatment and improving flux estimation. PMID- 26437965 TI - Kinetics and model development for enzymatic synthesis of fructo-oligosaccharides using fructosyltransferase. AB - Experimental investigations were made to synthesize fructo-oligosaccharides (FOS) from sucrose using fructosyltransferase. The influence of various parameters such as temperature (45-55 degrees C), pH (4-5), initial sucrose concentration (ISC: 300-500 g/L) and enzyme concentration (4-32 U/mL) were varied. A maximum FOS yield of 60% was observed at ISC 500 g/L, pH 4.5 with enzyme activity 32 U/mL and at 55 degrees C. It was confirmed that 1-kestose (tri-) was the major product of FOS as compared to nystose (tetra-) and fructosylnystose (penta-saccharides). Further, the reaction rate increases with increase in temperature. From separate sets of experiments, it was observed that FOS formation was affected by glucose inhibition. Apart from the increase in the rate of FOS formation with increasing enzyme activity, the final values of FOS yield increase though till 16 U/mL and thereafter attain plateau. A kinetic model was also developed, based on Michaelis Menten kinetics, and a five-step ten-parameter model, including glucose inhibition, was obtained. Model was solved using COPASI((r)) (version 4.8) solver for kinetic parameter estimations followed by time course simulations. PMID- 26437966 TI - Laccases for biorefinery applications: a critical review on challenges and perspectives. AB - Modern biorefinery concepts focus on lignocellulosic biomass as a feedstock for the production of next generation biofuels and platform chemicals. Lignocellulose is a recalcitrant composite consisting of several tightly packed components which are stuck together by the phenolic polymer lignin hampering the access to the carbohydrate compounds of biomass. Certain saprophytic organisms are able to degrade lignin by the use of an enzymatic cocktail. Laccases have been found to play a major role during lignin degradation and have therefore been intensively researched with regard to potential applications for biomass processing. Within this review, we go along the process chain of a third generation biorefinery and highlight the process steps which could benefit from laccase applications. Laccases can assist the pretreatment of biomass and promote the subsequent enzymatic hydrolysis of cellulose by the oxidative modification of residual lignin on the biomass surface. In combination with mediator molecules laccases are often reported being able to catalyze the depolymerization of lignin. Studies with lignin model compounds confirm the chemical possibility of a laccase catalyzed cleavage of lignin bonds, but the strong polymerization activity of laccase counters the decomposition of lignin by repolymerizing the degradation products. Therefore, it is a key challenge to shift the catalytic performance of laccase towards lignin cleavage by optimizing the process conditions. Another field of application for laccases is the detoxification of biomass hydrolyzates by the oxidative elimination of lignin-derived phenolics which inhibit hydrolytic enzymes and are toxic for fermentation organisms. This review critically discusses the potential applications for laccases in biorefinery processes and emphasizes the challenges and perspectives which go along with the use of this enzyme for the technical utilization of lignocellulose. PMID- 26437968 TI - The tricky charm of the radial access. PMID- 26437967 TI - A cross-sectional analysis of the relationship between tobacco and alcohol outlet density and neighbourhood deprivation. AB - BACKGROUND: There is a strong socio-economic gradient in both tobacco-and alcohol related harm. One possible factor contributing to this social gradient may be greater availability of tobacco and alcohol in more socially-deprived areas. A higher density of tobacco and alcohol outlets is not only likely to increase supply but also to raise awareness of tobacco/alcohol brands, create a competitive local market that reduces product costs, and influence local social norms relating to tobacco and alcohol consumption. This paper examines the association between the density of alcohol and tobacco outlets and neighbourhood level income deprivation. METHODS: Using a national tobacco retailer register and alcohol licensing data this paper calculates the density of alcohol and tobacco retail outlets per 10,000 population for small neighbourhoods across the whole of Scotland. Average outlet density was calculated for neighbourhoods grouped by their level of income deprivation. Associations between outlet density and deprivation were analysed using one way analysis of variance. RESULTS: There was a positive linear relationship between neighbourhood deprivation and outlets for both tobacco (p <0.001) and off-sales alcohol (p <0.001); the most deprived quintile of neighbourhoods had the highest densities of both. In contrast, the least deprived quintile had the lowest density of tobacco and both off-sales and on-sales alcohol outlets. CONCLUSIONS: The social gradient evident in alcohol and tobacco supply may be a contributing factor to the social gradient in alcohol- and tobacco-related disease. Policymakers should consider such gradients when creating tobacco and alcohol control policies. The potential contribution to public health, and health inequalities, of reducing the physical availability of both alcohol and tobacco products should be examined in developing broader supply side interventions. PMID- 26437969 TI - Upper-extremity dysfunction following transradial percutaneous procedures: an overlooked and disregarded complication? PMID- 26437970 TI - Revealing the impact of local access-site complications and upper extremity dysfunction post transradial percutaneous coronary procedures. AB - OBJECTIVES: Little is known about local access-site complications and upper extremity dysfunction after transradial percutaneous coronary procedures (TR PCP). This systematic review study aimed to summarise the current knowledge on the incidences of access-site complications and upper extremity dysfunction after TR-PCP. METHODS: Two independent, trained investigators searched MEDLINE, EMBASE and CENTRAL for eligible studies published before 1 January 2015. Also, they hand searched the conference proceedings of the annual scientific sessions of the American College of Cardiology, the American Heart Association, European Society of Cardiology, and the Trans-catheter Cardiovascular Therapeutics. Inclusion criteria were cohort studies and clinical trials discussing the incidence of access-site complications and upper extremity function after transradial percutaneous coronary intervention (TR-PCI) and/or transradial coronary angiography (TR-CAG) as endpoints. RESULTS: 176 articles described access-site complications. The incidence is up to 9.6 %. Fourteen articles described upper extremity dysfunction, with an incidence of up to 1.7 %. Upper extremity dysfunction was rarely investigated, hardly ever as primary endpoint, and if investigated not thoroughly enough. CONCLUSION: Upper extremity dysfunction in TR PCP has never been properly investigated and is therefore underestimated. Further studies are needed to investigate the magnitude, prevention and best treatment of upper extremity dysfunction. Optimising TR-PCP might be achieved by using slender techniques, detection of upper extremity dysfunction and early referral to a hand rehabilitation centre. PMID- 26437971 TI - An Autocatalytic System of Photooxidation-Driven Substitution Reactions on a Fe(II)4L6 Cage Framework. AB - The functions of life are accomplished by systems exhibiting nonlinear kinetics: autocatalysis, in particular, is integral to the signal amplification that allows for biological information processing. Novel synthetic autocatalytic systems provide a foundation for the design of artificial chemical networks capable of carrying out complex functions. Here we report a set of Fe(II)4L6 cages containing BODIPY chromophores having tuneable photosensitizing properties. Electron-rich anilines were observed to displace electron-deficient anilines at the dynamic-covalent imine bonds of these cages. When iodoaniline residues were incorporated, heavy-atom effects led to enhanced (1)O2 production. The incorporation of (methylthio)aniline residues into a cage allowed for the design of an autocatalytic system: oxidation of the methylthio groups into sulfoxides make them electron-deficient and allows their displacement by iodoanilines, generating a better photocatalyst and accelerating the reaction. PMID- 26437972 TI - The association between pelvic girdle pain and sick leave during pregnancy; a retrospective study of a Norwegian population. AB - BACKGROUND: The incidence of pelvic girdle pain (PGP) in pregnancy is wide ranged depending on definition, the utilised diagnostic means, and the design of the studies. PGP during pregnancy has negative effects on activities of daily living and causes long sick leave, which makes it a major public health issue. Our objectives were to explore the frequency of sick leave in pregnancy due to PGP, assess the relationship between different types of pain-related activities of daily living, examine physical workload, type of work in relation to sick leave, and to explore factors that make women less likely to take sick leave for PGP. METHODS: All women giving birth at the maternity ward of Stavanger University Hospital, Norway, were asked to participate and complete a questionnaire on demographic features, PGP, pain-related activities of daily living, sick leave in general and for PGP, frequency of exercising before and during pregnancy. Drawings of pelvic girdle and low back area were used for the localization of pain. PGP intensity was then rated retrospectively on a numerical rating scale. Non-parametric tests, multinomial logistic regression and sequential linear regression analysis were used in the statistical analysis. RESULTS: PGP is a frequent and major cause of sick leave during pregnancy among Norwegian women, which is also reflected in activities of daily living as measured with scores on all Oswestry disability index items. In the multivariate analysis of factors related to sick leave and PGP we found that work satisfaction, problems with lifting and sleeping, and pain intensity were risk factors for sick leave. In addition, women with longer education, higher work satisfaction and fewer problems with sitting, walking and standing, were less likely to take sick leave in pregnancy, despite the same pain intensity as women being on sick leave. CONCLUSIONS: A coping factor in pregnant women with PGP was discovered, most likely dependant on education, associated with work situation and/or work posture, which decreases sick leave. We recommend these issues to be further examined in a prospective longitudinal study since it may have important implications for sick leave frequency during pregnancy. PMID- 26437973 TI - Recent research progress with phospholipase C from Bacillus cereus. AB - Phospholipase C (PLC) catalyzes the hydrolysis of phospholipids to produce phosphate monoesters and diacylglycerol. It has many applications in the enzymatic degumming of plant oils. PLC Bc , a bacterial PLC from Bacillus cereus, is an optimal choice for this activity in terms of its wide substrate spectrum, high activity, and approved safety. Unfortunately, its large-scale production and reliable high-throughput screening of PLC Bc remain challenging. Herein, we summarize the research progress regarding PLC Bc with emphasis on the screening methods, expression systems, catalytic mechanisms and inhibitor of PLC Bc . This review hopefully will inspire new achievements in related areas, to promote the sustainable development of PLC Bc and its application. PMID- 26437975 TI - Prevention of post-operative recurrence in Crohn's disease. Are we ready for a treat-to-target strategy? PMID- 26437974 TI - Immunomodulatory effect of hypertonic saline in hemorrhagic shock. AB - Multiple organ dysfunction syndrome (MODS) and nosocomial infection following trauma-hemorrhage are among the most important causes of mortality in hemorrhagic shock patients. Dysregulation of the immune system plays a central role in MODS and a fluid having an immunomodulatory effect could be advantageous in hemorrhagic shock resuscitation. Hypertonic saline (HS) is widely used as a resuscitation fluid in trauma-hemorrhagic patients. Besides having beneficial effects on the hemodynamic parameters, HS has modulatory effects on various functions of immune cells such as degranulation, adhesion molecules and cytokines expression, as well as reactive oxygen species production. This article reviews clinical evidence for decreased organ failure and mortality in hemorrhagic shock patients resuscitated with HS. Despite promising results in animal models, results from pre-hospital and emergency department administration in human studies did not show improvement in survival, organ failure, or a reduction in nosocomial infection by HS resuscitation. Further post hoc analysis showed some benefit from HS resuscitation for severely-injured patients, those who received more than ten units of blood by transfusion, patients who underwent surgery, and victims of traumatic brain injury. Several reasons are suggested to explain the differences between clinical and animal models. PMID- 26437976 TI - Impact of endoscopic monitoring in postoperative Crohn's disease patients already receiving pharmacological prevention of recurrence. AB - BACKGROUND: Current guidelines address the initiation of treatment to prevent postoperative recurrence (PR) after ileo-cecal resection in Crohn's disease (CD), but appropriate management of postoperative CD patients who are already receiving treatment to prevent PR is yet to be defined. Usefulness of endoscopic monitoring in this scenario remains uncertain. AIMS: To evaluate the usefulness of endoscopy based management of postoperative CD patients who are already under pharmacological prevention of PR. METHODS: Retrospective review of clinical outcome of all CD patients with ileo-cecal resection who underwent postoperative colonoscopy between 2004 and 2013 at our centre. Postoperative endoscopic findings were classified as no endoscopic recurrence (Rutgeerts i0-i1) or endoscopic recurrence (Rutgeerts i2-i4). Patients with endoscopic recurrence were classified as "endoscopy-based management (EBM)" if treatment step-up after endoscopy, or "non EBM (N-EBM)". Clinical recurrence was considered if re operation, CD related hospitalization or treatment change. Time until clinical recurrence or the end of the follow up was considered. RESULTS: One hundred sixty six patients initially identified. One hundred twenty nine (77%) under pharmacological prevention of PR at the time of colonoscopy were analyzed: 34% were receiving aminosalicylates, 50% thiopurines, 11% anti-TNF, 5% combo. Colonoscopy showed endoscopic recurrence in 57% of patients; those with N-EBM were more likely to have clinical recurrence than patients with EBM along the follow up (p = 0.01). Conclussions: Endoscopic monitoring could be useful in postoperative CD patients also in patients already receiving pharmacological treatment to prevent PR. PMID- 26437977 TI - Efficacy and safety of simeprevir in combination with peginterferon and ribavirin for patients with hepatitis C genotype 1 infection: a meta-analysis of randomized trials. AB - BACKGROUND AND AIM: A simeprevir (SMV)-based regimen has shown promising results in treating chronic hepatitis C virus (HCV) infection. This meta-analysis aimed to assess the efficacy and safety of simeprevir for treating HCV genotype 1 infection. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched, along with the reference lists of retrieved articles. The meta-analysis only included randomized controlled trials (RCTs) that compared the efficacy and safety of addition of SMV to peginterferon (PegIFN) and ribavirin (RBV) (triple regimen) with PegIFN/RBV alone (dual regimen) in treating chronic HCV genotype 1 infection. RESULTS: A total of seven RCTs involving 2,301 patients were included. The triple regimen had a higher pooled sustained virologic response (SVR) rate [odds ratio (OR) = 4.57; 95% confidence interval (CI): 3.34-6.27; p < 0.001)] and lower pooled relapse rate [relative risk (RR) = 0.41; 95% CI: 0.33-0.50; p < 0.001] than the dual regimen had. The pooled incidence of adverse events (AEs) was comparable between the two regimens (RR = 1.01; 95% CI: 0.99-1.03; p = 0.339), whereas the incidence of serious AEs in the triple regimen was lower (RR = 0.7; 95% CI: 0.50-0.98; p < 0.05). CONCLUSIONS: The meta-analysis demonstrates that the addition of SMV to pegIFN and RBV is effective and well-tolerated in treating chronic HCV genotype 1 infection, with a low incidence of AEs. PMID- 26437978 TI - Screening of enzymatic synthesis and expression of Lewis determinants in human colorectal carcinoma. AB - BACKGROUND: Although colorectal carcinogenesis has been intensively studied, the published investigations do not provide a consistent description of how different carbohydrate determinants of colorectal epithelium are modified in colorectal cancer (CRC). OBJECTIVE: This study is an attempt to characterize the terminal fucosylation steps responsible for the synthesis of mono- Le(a)/Le(x)- and difucosylated -Le(b)/Le(y)- Lewis antigens in healthy and tumour CRC tissue. METHODS: An immunohistochemical study of Lewis antigens' expression was undertaken, along with screening of the fucosyltransferase (FT) activities involved in their synthesis, on healthy and tumour samples from 18 patients undergoing CRC. RESULTS: Analysis of alpha(1,2/3/4)FT activities involved in the sequential fucosylation of cores 1 and 2 showed significant increases in tumour tissue. Expressed as microU/mg and control vs. tumour activity (pfrom Wilcoxon's test), the FT activities for Le(a)/Le(b) synthesis were: lacto-N-biose alpha(1,2)/alpha(1,4)FT, 65.4 +/- 19.0 vs. 186 +/- 35.1 (p< 0.005); lacto-N fucopentaose 1 alpha(1,4)FT, 64.9 +/- 11.9 vs. 125.4 +/- 20.7 (p< 0.005); Le(a) alpha(1,2)FT, 56.2 +/- 7.2 vs. 130.5 +/- 15.6 (p< 0.001). Similarly, for Le(x)/Le(y) synthesis were: N-acetyllactosamine alpha(1,2)-/alpha(1,3)FT, 53.4 +/ 12.2 vs. 108.1 +/- 18.9 (p< 0.001); 2'-Fucosyl-N-acetyllactosamine alpha(1,3)FT, 61.3 +/- 10.7 vs. 126.4 +/- 22.9 (p< 0.001); 2'-Fucosyllactose alpha(1,3)FT, 38.9 +/- 10.9 vs. 143.6 +/- 28.9 (p< 0.001); 2'-Methyllactose alpha(1,3)FT, 30.9 +/- 4.8 vs. 66.1 +/- 8.1 (p< 0.005); and Le(x) alpha(1,2)FT, 54.3 +/- 11.9 vs. 88.2 +/- 14.4 (p< 0.001). Immunohistochemical Le(y) expression was increased (p< 0.01 according to Wilcoxon's test) in tumour tissue, with 84.6% of specimens being positive: 7.7% weak, 15.4% moderate and 61.5% high intensity. CONCLUSIONS: Results suggest the activation of the biosynthesis pathways of mono- and difucosylated Lewis histo-blood antigens in tumour tissue from CRC patients, leading to the overexpression of Le(y), probably at the expense of Le(x). PMID- 26437980 TI - Impact of the age of diagnosis on the natural history of ulcerative colitis. AB - BACKGROUND: Ulcerative colitis (UC) has a recognized phenotypic heterogeneity. Some studies suggest that age at diagnosis may influence features and natural history of the disease. AIM: This study aimed to compare patients', disease's and treatment's features between Portuguese patients diagnosed before and after the age of 40-years-old. METHODS: Retrospective single-center study that included 310 patients with UC, divided in two groups: Those diagnosed before the age of 40 years-old (early onset UC) and those diagnosed later than that (late onset UC). In each group features of the patients (gender, family history, smoking), of the disease (duration, extension, severity, clinical course, hospitalization, extraintestinal manifestations), and of treatment (oral aminosalicylates, systemic steroids or immunomodulators) were analyzed. Statistical analysis was performed using SPSSv22.0. Univariate and multivariate analyses were performed to assess factors associated with early and late onset UC. RESULTS: From the analyzed patients, 207 had UC diagnosed before the age of 40 years old (43.5% men; mean age at diagnosis 29.4 +/- 6.9 years) and 103 were diagnosed after that age (61.2% men; mean age at diagnosis 51.8 +/- 8.1 years). In the group diagnosed before 40 years old, female gender (p = 0.003), severe disease (p = 0.002), chronic intermittent clinical course (p = 0.026), and hospitalizations (p = 0.001) were significantly more frequent. The use of oral aminosalicylates (p = 0.032), systemic steroids (p = 0.003) and immunomodulators (p = 0.012) were also more common in the early onset UC group. No differences between groups were found in family history, smoking, disease's extension, extraintestinal manifestations, and use of biological agents. Multivariate analysis pointed early onset UC to be significantly associated with female gender (odds ratio [OR], 1.77; 95% confidence interval [CI], 1.08-2.91; p = 0.024), chronic intermittent symptoms (OR, 2.34; 95% CI, 1.17-4.70; p = 0.016), and need of hospitalization (OR, 2.89; 95% CI, 1.46-5.72; p = 0.002). CONCLUSIONS: When diagnosed before the age of 40 years-old, UC preferably affects women and manifests as a more severe disease, with more frequent hospitalizations and chronic intermittent symptoms. These facts might have implications in planning timely and individualized future therapeutic strategies. PMID- 26437979 TI - Fully covered metal stents for the treatment of leaks after gastric and esophageal surgery. AB - OBJECTIVE: The use of fully covered metal stents (FCMS) for the treatment of benign conditions is increasing. The aim of our study was to assess the efficacy of FCMS in the management of post-operative leaks after gastric or esophageal surgery. MATERIAL AND METHODS: During a three year period (2011-2013), patients who underwent a surgery related with esophageal or gastric cancer and developed a postoperative anastomotic leak treated with FCMS were prospectively included. RESULTS: Fourteen patients were included (11 men, 3 women), with median age of 65 years. Placement of at least one stent was achieved in 13 patients (93% of cases), with initial closure of the leak in 12 of these 13 cases (92.3%). A final success (after removal of the stent) could be demonstrated in 9 cases (69.2%, intention to treat analysis); stent failed only in one case (7.7%) and there were 3 patients (23.1%) not evaluated because death before stent retrieval (not related with the endoscopic procedure). One stent were used in 9 cases (69.2%), and two in 4 (30.8%). Migration was observed in two cases (15.3%). There were no major complications related with the use of stents. There were no complications related with retrieval. CONCLUSIONS: The placement of FCMS to achieve the leak closure after esophageal or gastric surgery is an effective and probably safe alternative feasible with minor risks. PMID- 26437981 TI - Impaired esophageal motor function in eosinophilic esophagitis. AB - Eosinophilic esophagitis is a chronic immunoallergic inflammatory disease of the esophagus that represents a major cause of digestive morbidity among the pediatric and young adult populations. Despite the fact that key symptoms in adults include dysphagia and food impaction, many patients lack structural changes in the esophagus to account for their complaints, which suggests the presence of underlying motor disorders and esophageal distensibility impairment. In the last few years the esophageal motility of these patients has been studied using various approaches, most particularly high-resolution manometry, ambulatory manometry, and impedance planimetry. This review focuses on the most relevant findings and scientific evidence regarding esophageal motor disorders in eosinophilic esophagitis. PMID- 26437982 TI - Solitary fibrous tumor of the liver. Case report and review of the literature. AB - Solitary fibrous tumor (SFT) is a rare mesenchymal tumor. Given its origin, it can appear in almost any location. In the literature, only 50 cases of SFT in the liver parenchyma have been reported. Despite its rarity, this entity should be included in the differential diagnosis of liver masses. We report the first case with imaging data from five years prior to diagnosis, which was treated by right portal embolization and arterial tumor embolization, and subsequent liver resection. We also present an exhaustive review of the cases described to date. PMID- 26437984 TI - Spanish in international bibliography. AB - Comments related to a review article about percutaneous gastrostomies written by Lucendo et al. in REED. PMID- 26437983 TI - Duodenal involvement by seminomatous tumors. AB - Testicular germ cell tumors, though rare (1%), represent the most common neoplasm among young men. Gastrointestinal involvement from these malignancies usually presents as bowel obstruction and digestive bleeding, but their frequency is low (5%). The patterns of this involvement are: infiltration from affected retroperitoneal lymph nodes or, less frequently, by peritoneal seeding and direct hematogenous spread. Particularly, infiltration of duodenum is also rare, though its real frequency is not well defined. Moreover, the affinity for GI tract differs among the histological types of GCT, being seminomatous tumors an exceedingly unfrequent cause of duodenal infiltration. We herein present a recent case in our institution of severe anemia due to gastrointestinal bleeding in the context of giant retroperitoneal bulky metastatic mass infiltrating duodenum as first manifestation of a testicular pure seminoma. PMID- 26437985 TI - Synchronic gastric and pancreatic ductal adenocarcinoma. A case report. AB - Simultaneous gastric and pancreatic ductal adenocarcinoma is an exceptional situation with short literature review. The accumulated risk throughout life in women is 0.8% for gastric cancer and 0.6% for pancreas cancer. We report a case where both tumors are demonstrated. The patient was surgically intervened removing both tumors and achieving total recovery, with no signs of tumor recurrence after four months. This is to remind us that simultaneous tumors do exist, especially when suggestive images of neoplasia appear in a patient previously diagnosed of tumor in another location. PMID- 26437986 TI - Mucinous hepatic cystic neoplasm: an uncommon cystic lesion in the liver. AB - Invasive hepatic mucinous neoplasms, previously referred to as cystoadenomas, are rare tumours of the liver. Many patients are asymptomatic and the lessions are found incidentally. Tha aim of this paper is to present a clinic case about a asymptomatic 78 years-old-man with a cystic neoplasm of the liver, founded incidentanlly and treated by surgery. PMID- 26437987 TI - Leiomyoma of the round ligament of the liver: report of one case. AB - Tumoral conditions in the round ligament of the liver are very uncommon and exhibit nonspecific manifestations, hence a high level of suspicion is necessary for their diagnosis. We report the case of a 47-year-old female patient who presented with abdominal pain for several months; imaging studies showed a lesion of indeterminate nature likely connected with the falciform ligament, and only intraoperative findings acknowledged the presence of an apparently benign tumor in the round ligament of the liver, which biopsy confirmed. Following the excision of the round ligament the patient had a favorable course. As this is a pathologically benign lesion we deem its surgical management both advisable and sufficient. However, because of its small prevalence and the scarcity of literature involving this condition, further studies would be needed to provide information on natural history, treatment, and long-term prognosis. PMID- 26437988 TI - Sprue-like enteropathy due to olmesartan. AB - A case of spue-like enteropathy due to olmesartan is reported to draw attention to this disease, given the high frequency of use of this drug and the difficulty of diagnosis if the entity if it is not known. In his journal one case was published as Clinical Note in 2014 and we wish to emphasize the importance of knowledge about this relatively new entity. PMID- 26437989 TI - Choosing a Hyperacute Stroke Imaging Protocol for Proper Patient Selection and Time Efficient Endovascular Treatment: Lessons from Recent Trials. AB - Recently, several prospective randomized control trials regarding endovascular treatment for patients with intracranial large artery occlusions causing acute ischemic stroke have been successfully reported. Effort to minimize time delays to endovascular treatment, patient selection and the use of retrievable stent were important factors for the success of these trials. The inclusion and exclusion criteria for each of these trials did include differences in imaging protocols. In this review, we focus on the importance of baseline non-invasive angiography prior to deciding endovascular treatment. Then imaging protocols are described for each trial according to measurement of infarct volume and collateral grading. PMID- 26437990 TI - Patent Foramen Ovale and Stroke-Current Status. AB - Patent foramen ovale (PFO) is growing in clinical interest because of a renewed focus on embolic stroke of undetermined source (ESUS), the PFO attributable fraction (the 10-point Risk of Paradoxical Embolism score), technical advances in PFO diagnosis, and the emergence of endovascular device closure as a treatment option. However, recent randomized controlled trials of the management of patients with ESUS and PFO failed to demonstrate the superiority of closure over medical treatment. The mechanisms of stroke other than paradoxical embolism may be important in patients with ESUS and PFO. This paper reviews the current understanding of the pathophysiology of stroke and therapeutic options in patients with PFO and ESUS. PMID- 26437992 TI - Stroke Connectome and Its Implications for Cognitive and Behavioral Sequela of Stroke. AB - Systems-based approaches to neuroscience, using network analysis and the human connectome, have been adopted by many researchers by virtue of recent progress in neuroimaging and computational technologies. Various neurological disorders have been evaluated from a network perspective, including stroke, Alzheimer's disease, Parkinson's disease, and traumatic brain injury. Until now, dynamic processes after stroke and during recovery were investigated through multimodal neuroimaging techniques. Many studies have shown disruptions in structural and functional connectivity, including in large-scale neural networks, in patients with stroke sequela such as motor weakness, aphasia, hemianopia, neglect, and general cognitive dysfunction. A connectome-based approach might shed light on the underlying mechanisms of stroke sequela and the recovery process, and could identify candidates for individualized rehabilitation programs. In this review, we briefly outline the basic concepts of structural and functional connectivity, and the connectome. Then, we explore current evidence regarding how stroke lesions cause changes in connectivity and network architecture parameters. Finally, the clinical implications of perspectives on the connectome are discussed in relation to the cognitive and behavioral sequela of stroke. PMID- 26437991 TI - Vessel Wall Imaging of the Intracranial and Cervical Carotid Arteries. AB - Vessel wall imaging can depict the morphologies of atherosclerotic plaques, arterial walls, and surrounding structures in the intracranial and cervical carotid arteries beyond the simple luminal changes that can be observed with traditional luminal evaluation. Differentiating vulnerable from stable plaques and characterizing atherosclerotic plaques are vital parts of the early diagnosis, prevention, and treatment of stroke and the neurological adverse effects of atherosclerosis. Various techniques for vessel wall imaging have been developed and introduced to differentiate and analyze atherosclerotic plaques in the cervical carotid artery. High-resolution magnetic resonance imaging (HR-MRI) is the most important and popular vessel wall imaging technique for directly evaluating the vascular wall and intracranial artery disease. Intracranial artery atherosclerosis, dissection, moyamoya disease, vasculitis, and reversible cerebral vasoconstriction syndrome can also be diagnosed and differentiated by using HR-MRI. Here, we review the radiologic features of intracranial artery disease and cervical carotid artery atherosclerosis on HR-MRI and various other vessel wall imaging techniques (e.g., ultrasound, computed tomography, magnetic resonance, and positron emission tomography-computed tomography). PMID- 26437993 TI - Endovascular Recanalization Therapy in Acute Ischemic Stroke: Updated Meta analysis of Randomized Controlled Trials. AB - BACKGROUND AND PURPOSE: Recent randomized clinical trials (RCTs) have demonstrated benefits of endovascular recanalization therapy (ERT) contrary to earlier trials. We aimed to estimate the benefits of ERT added to standard therapy in acute ischemic stroke. METHODS: From a literature search of RCTs testing ERT, we performed a meta-analysis to estimate an overall efficacy and safety of ERT for all trials, stent-retriever trials, and RCTs comparing ERT and intravenous tissue plasminogen activator (IV-TPA). RESULTS: We identified 15 relevant RCTs including 2,899 patients. For all trials, ERT was associated with increased good outcomes (odds ratio [OR] 1.79; 95% confidence interval [CI] 1.34, 2.40; P<0.001) compared to the control. ERT also increased no or minimal disability outcomes, good neurological recovery, good activity of daily living, and recanalization. ERT did not significantly increase symptomatic intracranial hemorrhage (SICH) (OR 1.19; 95% CI 0.83, 1.69; P=0.345) or death (OR 0.87; 95% CI 0.71, 1.05; P=0.151). In contrast, ERT significantly reduced extreme disability or death (OR 0.77; 95% CI 0.61, 0.97; P=0.025). Restricting to five stent retriever trials comparing ERT plus IV-TPA vs. IV-TPA alone, the benefit was even greater for good outcome (OR 2.39; 95% CI 1.88, 3.04; P<0.001) and extreme disability or death (OR 0.57; 95% CI 0.41, 0.78; P=0.001). Restricting to eight RCTs comparing ERT (plus IV-TPA in six trials) with IV-TPA alone showed similar efficacy and safety. CONCLUSIONS: This updated meta-analysis shows that ERT substantially improves clinical outcomes and reduces extreme disability or death without significantly increasing SICH compared to standard therapy. PMID- 26437994 TI - Statins in Acute Ischemic Stroke: A Systematic Review. AB - BACKGROUND AND PURPOSE: Statins have pleiotropic effects of potential neuroprotection. However, because of lack of large randomized clinical trials, current guidelines do not provide specific recommendations on statin initiation in acute ischemic stroke (AIS). The current study aims to systematically review the statin effect in AIS. METHODS: From literature review, we identified articles exploring prestroke and immediate post-stroke statin effect on imaging surrogate markers, initial stroke severity, functional outcome, and short-term mortality in human AIS. We summarized descriptive overview. In addition, for subjects with available data from publications, we conducted meta-analysis to provide pooled estimates. RESULTS: In total, we identified 70 relevant articles including 6 meta analyses. Surrogate imaging marker studies suggested that statin might enhance collaterals and reperfusion. Our updated meta-analysis indicated that prestroke statin use was associated with milder initial stroke severity (odds ratio [OR] [95% confidence interval], 1.24 [1.05-1.48]; P=0.013), good functional outcome (1.50 [1.29-1.75]; P<0.001), and lower mortality (0.42 [0.21-0.82]; P=0.0108). In hospital statin use was associated with good functional outcome (1.31 [1.12 1.53]; P=0.001), and lower mortality (0.41 [0.29-0.58]; P<0.001). In contrast, statin withdrawal was associated with poor functional outcome (1.83 [1.01-3.30]; P=0.045). In patients treated with thrombolysis, statin was associated with good functional outcome (1.44 [1.10-1.89]; P=0.001), despite an increased risk of symptomatic hemorrhagic transformation (1.63 [1.04-2.56]; P=0.035). CONCLUSIONS: The current study findings support the use of statin in AIS. However, the findings were mostly driven by observational studies at risk of bias, and thereby large randomized clinical trials would provide confirmatory evidence. PMID- 26437995 TI - Identifying Target Risk Factors Using Population Attributable Risks of Ischemic Stroke by Age and Sex. AB - BACKGROUND AND PURPOSE: Estimating age- and sex-specific population attributable risks (PARs) of major risk factors for stroke may be a useful strategy to identify risk factors for targeting preventive strategies. METHODS: For this case control matched study, consecutive patients aged 18-90 years and admitted to nine nationwide hospitals with acute ischemic stroke between December 2008 and June 2010, were enrolled as cases. Controls, individually matched by age and sex, were chosen from the 4th Korean National Health & Nutrition Examination Survey (2008 2010). Based on odds ratios and prevalence, standardized according to the age and sex structure of the Korean population, PARs of major risk factors were estimated according to age (young, <= 45; middle-aged, 46-65; and elderly, >= 66 years) and sex subgroups. RESULTS: In 4,743 matched case-control sets, smoking (PAR, 45.1%) was the greatest contributing risk factor in young men, followed by hypertension (28.5%). In middle-aged men, the greatest contributing factors were smoking (37.4%), hypertension (22.7%), and diabetes (14.6%), whereas in women the greatest factors were hypertension (22.7%) and stroke history (10.6%). In the elderly, hypertension was the leading factor in men (23.7%) and women (23.4%). Other noticeable factors were stroke history (men, 19.7%; women, 17.3%) and diabetes (men, 12.5%; women, 15.1%). In young women, risk factors with a PAR greater than 10% were not found. CONCLUSIONS: Smoking cessation in young people and hypertension and diabetes control in older people may be effective in reducing the burden of stroke on the population. In the elderly, secondary prevention could also be emphasized. PMID- 26437996 TI - Relation between Left Atrial Remodeling in Young Patients with Cryptogenic Stroke and Normal Inter-atrial Anatomy. AB - BACKGROUND AND PURPOSE: To investigate an association between left atrial (LA) structural and P wave dispersion (PWD) during sinus rhythm, and electrical remodeling in cryptogenic stroke (CS) patients. METHODS: Forty CS patients and 40 age- and sex-matched healthy controls were enrolled. P wave calculations were based on 12-lead electrocardiography (ECG) at a 50-mm/s-paper speed with an amplitude of 10 mm/mV. Difference between the maximum and minimum P wave duration was the P wave dispersion (PWD=Pmax-Pmin). LA deformation was evaluated by speckle tracking echocardiography within 3 days of the acute event. RESULTS: PWD was 30.1+/-7.0 ms and 27.4+/-3.5 ms in CS and control group (P=0.02), whereas LA maximum volume index [LAVImax] was 20.4+/-4.5 mL/m(2) and 19.9+/-2.4 mL/m(2) in CS and control group, respectively (P = 0.04). While global peak LA strain was [pLA-S] (LA reservoir function) 41.4 +/- 6.3% and 44.5 +/- 7.1% in CS and control group, (P = 0.04), global peak late diastolic strain rate values [pLA-SRa] (LA pump function) were 2.5 +/- 0.4% and 2.9 +/- 0.5% in CS and control group, respectively (P = 0.001). A mild and a strong negative correlation between global pLA-S and LAVImax (r=-0.49; P<0.01), and between PWD and global pLA-S (r = -0.52; P < 0.01), respectively, was observed in CS. CONCLUSIONS: Increased PWD is associated with impaired LA mechanical functions and enlargement, and involved in the pathophysiology of AF or an AF-like physiology in CS. PMID- 26437997 TI - Quantitative Magnetic Resonance Angiography in Internal Carotid Artery Occlusion with Primary Collateral Pathway. AB - BACKGROUND AND PURPOSE: Quantitative magnetic resonance angiography (Q-MRA) enables direct measurement of volume flow rate (VFR) of intracranial arteries. We aimed to evaluate the collateral flows in internal carotid artery (ICA) occlusion with primary collateral pathway via circle of Willis using Q-MRA, and to compare them between patients who recently developed ipsilateral symptomatic ischemia and those who did not. METHODS: Between 2012 and 2014, 505 patients underwent Q-MRA in our institution. Among these, 33 patients who had unilateral ICA occlusion with primary collateral pathway were identified, and grouped into asymptomatic patients, stable patients with chronic infarction, and symptomatic patients with acute/subacute infarction. Mean VFR (mVFR) in intracranial arteries was measured and compared between the patients' groups. Kruskal-Wallis test was used for statistical analysis. RESULTS: Six patients were asymptomatic, fifteen with chronic infarction were stable, and twelve with acute/subacute infarction were symptomatic. The mVFR of ipsilateral middle cerebral artery in symptomatic patients was significantly lower than those in stable or asymptomatic patients (73.7+/-45.6 mL/min vs. 119.9+/-36.1 mL/min vs. 121.8+/-42.0 mL/min; P = 0.04). Total sum of the mVFR of ipsilateral anterior, middle, and posterior cerebral arteries was significantly lower in symptomatic patients than those in other groups (229.3 +/- 51.3 mL/min vs. 282.0+/-68.6 mL/min vs. 314.0+/-44.4 mL/min; P = 0.02). CONCLUSIONS: Q-MRA could be helpful to demonstrate the difference in the degree of primary collateral flow in ICA occlusion between the patients with recent symptomatic ischemia and those without. PMID- 26437998 TI - Intravenous Tissue Plasminogen Activator Improves the Outcome in Very Elderly Korean Patients with Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: In a recent pooled analysis of randomized clinical trials (RCTs), intravenous tissue plasminogen activator (TPA) improves the outcome in patients aged >=80 years. However, it is uncertain whether the findings are applicable to clinical practice in Asian populations. METHODS: From a multicenter stroke registry database of Korea, we identified patients with acute ischemic stroke who were aged >= 80 years. Using multivariable analysis and propensity score (PS)-matched analyses, we assessed the effectiveness and safety of intravenous TPA within 4.5 hours. RESULTS: Among 2,334 patients who met the eligible criteria, 236 were treated with intravenous TPA (mean age, 83+/-5; median NIHSS, 13 [IQR, 8-17]). At discharge, the TPA group compared to the no-TPA group had a favorable shift on the modified Rankin Scale (mRS) score (multivariable analysis, OR [95% CI], 1.51 [1.17-1.96], P=0.002; PS-matched analysis, 1.54 [1.17-2.04], P=0.002) and was more likely to achieve mRS 0-1 outcome (multivariable analysis, 2.00 [1.32-3.03], P=0.001; PS-matched analysis, 1.59 [1.04-2.42], P=0.032). TPA treatment was associated with an increased risk of symptomatic intracranial hemorrhage (multivariable analysis, 5.45 [2.80 10.59], P<0.001; PS-matched analysis, 4.52 [2.24-9.13], P<0.001), but did not increase the in-hospital mortality (multivariable analysis, 0.86 [0.50-1.48], P=0.58; PS-matched analysis, 0.88 [0.52-1.47], P=0.61). CONCLUSIONS: In the setting of clinical practice, intravenous TPA within 4.5 hours improved the functional outcome despite an increased risk of symptomatic intracranial hemorrhage in very elderly Korean patients. The findings, consistent with those from pooled analysis of RCTs, strongly support the use of TPA for this population. PMID- 26437999 TI - Endovascular Management of Long-Segmental Petrocavernous Internal Carotid Artery (Carotid S) Occlusion. AB - BACKGROUND AND PURPOSE: Long-segmental thrombotic occlusion of the distal internal carotid artery (ICA) sparing the cervical segment proximally and the supraclinoid segment distally, which could be termed 'Carotid S occlusion', has an unusual clinical presentation. However, endovascular management of this lesion is challenging. The purpose of our study is to report our endovascular treatment clinical experience of the disease. METHODS: From March 2008 to June 2013, we could identify 14 patients (average age: 62.1, median age: 62, range: 50-79) with 'Carotid S occlusion', who underwent endovascular recanalization procedures. Patient's clinical presentations were collected and the imaging findings also analyzed. The technical success rate, 24-hour and follow-up imaging outcome, and the clinical outcome using the 90-day mRS (modified Rankin scale) score were evaluated. RESULTS: Patients presented with gradually progressing (n = 8), fluctuating (n = 3), transient ischemic attack (n = 2) and stationary (n = 1) symptoms. DWI showed internal and external border-zone lesions in six patients, only internal ICA border-zone lesions in three patients, and only external border zone lesions in two patients. Underlying distal ICA stenosis was noted in 12 patients. The technical success rate was 92.8% (13/14). Luminal patency was noted in all patients (100%) after 24 hours and in nine of 10 (90%) on long-term follow up (median: 6.5, average: 15.1, range: 1-39 months). A 90-day, good functional outcome (mRS <= 2) was noted in 13 of 14 patients (92.8%). CONCLUSIONS: 'Carotid S occlusion' usually presented with border-zone infarction and endovascular management of the lesions was feasible. A relatively successful clinical outcome could be achieved after successful revascularization. PMID- 26438002 TI - Carotid Stump as a Cause of Recurrent Embolism-Endovascular Treatment in a Case of Congenital Carotid Stump Syndrome. PMID- 26438000 TI - Anterior Optic Pathway Compression Due to Internal Carotid Artery Aneurysms: Neurosurgical Management and Outcomes. AB - BACKGROUND AND PURPOSE: Compression of the anterior optic pathway results in visual deficits that can lead to the detection of unruptured aneurysms in the internal carotid artery (ICA). The general types of treatment modalities for aneurysms and visual deficits include surgery and endosaccular coiling. This study retrospectively analyzed and compared the resolution of visual deficits following surgery or endosaccular coiling. METHODS: We reviewed data on 33 patients with unruptured ICA aneurysms who presented with visual field deficits caused by mass effects over the anterior optic pathway. Statistical analyses were performed to identify the variables associated with the recovery of visual symptoms. RESULTS: Eighteen patients underwent aneurysm clipping, 2 underwent bypass surgery with endovascular trapping, and 2 underwent endovascular trapping without bypass surgery (group A). Ten patients received endosaccular coiling (group B). The visual outcomes included the following: in group A, 17 patients (73.9%) demonstrated improvement and 6 patients (26.1%) demonstrated no changes or worse outcomes; in group B, 2 patients (20.0%) demonstrated improvement and 8 patients (80.0%) demonstrated no changes or worse outcomes. Group A was associated with a higher rate of favorable outcome than group B (P = 0.007). According to the multivariate analysis, treatment without endosaccular coiling (group A) was the only variable significantly associated with improvement of visual outcome (P = 0.005; OR = 28.523; 95% CI = 2.683-303.171). CONCLUSIONS: Treatment modality was the only predictor of improvement in visual deficits. Treatment without endosaccular coiling resulted in visual improvement significantly more often in comparison with endosaccular coiling. PMID- 26438001 TI - The Effects of Transcranial Direct-Current Stimulation on Cognition in Stroke Patients. AB - BACKGROUND AND PURPOSE: To investigate whether transcranial direct-current stimulation (tDCS) can improve cognition in stroke patients. METHODS: Forty-five stroke patients (20 males and 25 females, average age: 62.7 years) with cognitive dysfunction were included in this prospective, double-blinded, randomized case control study. All patients were right-handed and the mean elapsed time after stroke was 39.3 days. Three different treatments groups were used: (1) anodal stimulation of the left anterior temporal lobe, (2) anodal stimulation of the right anterior temporal lobe, and (3) sham stimulation. tDCS was delivered for 30 minutes at 2 mA with 25 cm(2) electrodes, five times/week, for a total of 3 weeks, using a Phoresor II Auto Model PM 850 (IOMED((r))). The evaluation of cognitive impairment was based on a Computerized Neuropsychological Test (CNT), Korean Mini-Mental State Examination (K-MMSE). The Korean version of the Modified Barthel Index (K-MBI) was used to assess activities of daily living functionality. These evaluations were conducted in all patients before and after treatment. RESULTS: Each group included 15 patients. Pre-treatment evaluation showed no significant differences between the three groups for any of the parameters. There was significant improvement in the verbal learning test on the CNT in the left anodal stimulation group (P < 0.05). There were, however, no significant differences in the K-MMSE or K-MBI scores among the three groups. CONCLUSIONS: These results demonstrated the beneficial effects of anodal tDCS on memory function. Thus, tDCS can successfully be used as a treatment modality for patients with cognitive dysfunction after stroke. PMID- 26438003 TI - Malignant Cerebral Venous Sinus Thrombosis in Polycythemia. PMID- 26438004 TI - Dabigatran Effect on Left Ventricular Thrombus in a Patient with Acute Ischemic Stroke. PMID- 26438005 TI - Updated Korean Clinical Practice Guidelines on Decompressive Surgery for Malignant Middle Cerebral Artery Territory Infarction. PMID- 26438006 TI - ERRATUM: Table Correction: Case Characteristics, Hyperacute Treatment, and Outcome Information from the Clinical Research Center for Stroke-Fifth Division Registry in South Korea. PMID- 26438007 TI - ERRATUM: Author's Name Correction: Evolution of Endovascular Therapy in Acute Stroke: Implications of Device Development. PMID- 26438008 TI - Biliary strictures and recurrence after liver transplantation for primary sclerosing cholangitis: A retrospective multicenter analysis. AB - Liver transplantation (LT) is the only definitive treatment for patients with end stage liver disease due to primary sclerosing cholangitis (PSC), but a high rate of biliary strictures (BSs) and of recurrent primary sclerosing cholangitis (recPSC) has been reported. In this multicenter study, we analyzed a large patient cohort with a long follow-up in order to evaluate the incidence of BS and recPSC, to assess the impact on survival after LT, and to identify risk factors. We collected clinical, surgical, and laboratory data and records on inflammatory bowel disease (IBD), immunosuppression, recipient and graft outcome, and biliary complications (based on cholangiography and histology) of all patients who underwent LT for PSC in 10 German transplant centers between January 1990 and December 2006; 335 patients (68.4% men; mean age, 38.9 years; 73.5% with IBD) underwent transplantation 8.8 years after PSC diagnosis with follow-up for 98.8 months. The 1-, 5-, and 10-year recipient and graft survival was 90.7%, 84.8%, 79.4% and 79.1%, 69.0%, 62.4%, respectively. BS was diagnosed in 36.1% after a mean time of 3.9 years, and recPSC was diagnosed in 20.3% after 4.6 years. Both entities had a significant impact on longterm graft and recipient survival. Independent risk factors for BS were donor age, ulcerative colitis, chronic ductopenic rejection, bilirubin, and international normalized ratio (INR) at LT. Independent risk factors for recPSC were donor age, IBD, and INR at LT. These variables were able to categorize patients into risk groups for BS and recPSC. In conclusion, BS and recPSC affect longterm graft and patient survival after LT for PSC. Donor age, IBD, and INR at LT are independent risk factors for BS and recPSC and allow for risk estimation depending on the recipient-donor constellation. PMID- 26438009 TI - Streptobacillus notomytis sp. nov., isolated from a spinifex hopping mouse (Notomys alexis Thomas, 1922), and emended description of Streptobacillus Levaditi et al. 1925, Eisenberg et al. 2015 emend. AB - A pleomorphic, Gram-negative, rod-shaped, indole-, oxidase- and catalase negative, non-spore-forming, non-motile bacterium was isolated in 1979 from the heart of a spinifex hopping mouse (Notomys alexis Thomas, 1922) with septicaemia and stored as Streptobacillus moniliformis in the strain collection of the Animal Health Laboratory, South Perth, Western Australia (AHL 370-1), as well as under CCUG 12425. On the basis of 16SrRNA gene sequence analyses, the strain was assigned to the genus Streptobacillus, with 99.4 % sequence similarity to the type strain of Streptobacillus moniliformis, 95.6 %sequence similarity to the type strain of Streptobacillus hongkongensis and 99.0 %sequence similarity to the type strain of Streptobacillus felis. The clear differentiation of strain AHL 370 1T from Streptobacillus moniliformis, Streptobacillus hongkongensis and Streptobacillus felis was also supported by rpoB, groEL and recA nucleotide and amino acid sequence analysis. Average nucleotide identity was 87.16 % between strain AHL 370-1T and Streptobacillus moniliformis DSM 12112T. Physiological data confirmed the allocation of strain AHL 370-1T to the family Leptotrichiaceae, considering the very similar profiles of enzyme activities and fatty acids compared to closely related species. Within the genus Streptobacillus,isolate AHL 370-1T could also be separated unambiguously from the type strains of Streptobacillus moniliformis, Streptobacillus hongkongensis and Streptobacillus felis by MALDI-TOF mass spectrometry. Two further strains (KWG2 and KWG24) isolated from asymptomatic black rats in Japan were highly similar to AHL 370-1T. On the basis of these data, we propose the novel species Streptobacillus notomytis sp. nov., with the type strain AHL370-1T (=CCUG 12425T=DSM 100026T=CCM 8593T=EF 12425T). PMID- 26438010 TI - The intraindividual impact of ADHD on the transition of adulthood to old age. AB - The aim of the study was to explore whether the individual burden of ADHD is the same in the elderly as in younger ages even though the symptomatological impact of ADHD seems to remain stable over the lifespan. To assess ADHD symptoms and ADHD-associated problems in daily life, standardised questionnaires were conducted. To assess the subjectively experienced course of disease over the lifespan, all participants were interviewed regarding symptoms of ADHD in childhood as well as before and after the fiftieth year of life. In the sample of 296 respondents with a mean age of 69.55 years, 11 fulfilled the criteria of adult ADHD. Retrospectively, the ADHD subjects reported negative impacts due to ADHD-associated behaviour over the life span. These impairments remained stable over time with 18 % of subjects reporting impairments in family life, 46 % in social relationships, 18 % in dealing with money, and 36 % in organisation of daily life in the presence. Thus, the ADHD subjects reported problems with stability over time caused by low self-confidence, being quick-tempered, and due to defiantness. Although this is pilot study, our results reflect the burden of ADHD not only in young and middle adulthood, but also in seniority. The findings indicate the lifelong impact of ADHD as the explored seniors with ADHD reported the negative impact of ADHD remaining stable over the lifespan. PMID- 26438011 TI - Deeply divergent sympatric mitochondrial lineages of the earthworm Lumbricus rubellus are not reproductively isolated. AB - BACKGROUND: The accurate delimitation of species is essential to numerous areas of biological research. An unbiased assessment of the diversity, including the cryptic diversity, is of particular importance for the below ground fauna, a major component of global biodiversity. On the British Isles, the epigeic earthworm Lumbricus rubellus, which is a sentinel species in soil ecotoxicology, consists of two cryptic taxa that are differentiated in both the nuclear and the mitochondrial (mtDNA) genomes. Recently, several deeply divergent mtDNA lineages were detected in mainland Europe, but whether these earthworms also constitute cryptic species remains unclear. This information is important from an evolutionary perspective, but it is also essential for the interpretation and the design of ecotoxicological projects. In this study, we used genome-wide RADseq data to assess the reproductive isolation of the divergent mitochondrial lineages of L. rubellus that occur in sympatry in multiple localities in Central Europe. RESULTS: We identified five divergent (up to 16 % net p-distance) mitochondrial lineages of L. rubellus in sympatry. Because the clustering of the RADseq data was according to the population of origin and not the mtDNA lineage, reproductive isolation among the mtDNA lineages was not likely. Although each population contained multiple mtDNA lineages, subdivisions within the populations were not observed for the nuclear genome. The lack of fixed differences and sharing of the overwhelming majority of nuclear polymorphisms between localities, indicated that the populations did not constitute allopatric species. The nucleotide diversity within the populations was high, 0.7-0.8 %. CONCLUSIONS: The deeply divergent mtDNA sympatric lineages of L. rubellus in Central Europe were not reproductively isolated groups. The earthworm L. rubellus, which is represented by several mtDNA lineages in continental Europe, apparently is a single highly polymorphic species rather than a complex of several cryptic species. This study demonstrated the critical importance of the use of multilocus nuclear data for the unbiased assessment of cryptic diversity and for the delimitation of species in soil invertebrates. PMID- 26438012 TI - Dehydroepiandrosterone sulphate: diabolical hormone or epiphenomenon in aneurysmal subarachnoid hemorrhage? AB - Inflammation is purported to play an important role in the clinical course of subarachnoid hemorrhage. The current study by Hollig et al. entails using dehydroepiandrosterone sulfate, a hormone that inhibits key inflammatory pathways, as a predictor of functional outcome in these patients. PMID- 26438013 TI - A cross-sectional investigation of parenting style and friendship as mediators of the relation between social class and mental health in a university community. AB - INTRODUCTION: This study tested a novel explanation for the positive relation between social class and mental health among university students. Students with a higher social class were expected to have experienced more authoritative and less authoritarian parenting styles; these parenting styles were expected to lead to greater friendship and social integration at university; and greater friendship and integration were expected to lead to better mental health. METHOD: To test this model, the researchers asked 397 Australian undergraduate students to complete an online survey. The research used a cross-sectional correlational design, and the data was analysed using bootstrapped multiple serial mediation tests. RESULTS: Consistent with predictions, parenting style, general friendship and support, and social integration at university mediated the relation between social class and mental health. CONCLUSIONS: The present results suggest that working-class parenting styles may inhibit the development of socially-supportive friendships that protect against mental health problems. The potential effectiveness of interventions based on (a) social integration and (b) parenting style is discussed. Future research in this area should employ a longitudinal research design in order to arrive at clearer causal conclusions about the relations between social class, parenting styles, friendship, social integration, and mental health. PMID- 26438014 TI - Meta-analysis comparing doublet and single cytotoxic agent therapy as first-line treatment in elderly patients with advanced nonsmall-cell lung cancer. AB - OBJECTIVE: To perform a systematic review and meta-analysis comparing doublet versus single agent therapy in elderly patients with advanced nonsmall-cell lung cancer (NSCLC). METHODS: PubMed(r) and Cochrane databases, and American Society of Clinical Oncology, World Congress of Lung Cancer, and European Society of Medical Oncology abstracts were searched. Endpoints were overall survival (OS), 1 year survival rate (1-year SR), overall response rate (ORR), and grade 3/4 adverse events. Subgroup analyses were based on chemotherapy regimens and race. RESULTS: Out of 11 studies (13 randomized trials; n = 2782), doublet therapy was associated with significantly increased OS (hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.83, 0.95), 1-year SR (risk ratio [RR] 1.15, 95% CI 1.04, 1.28), and ORR (RR 1.39, 95% CI 1.39, 1.86) versus single-agents. Chemotherapy regimen-based subgroup analyses favoured platinum-based doublet therapy for OS (RR 0.71, 95% CI 0.60, 0.84), 1-year SR (RR 1.28, 95% CI 1.11, 1.47), and ORR (RR 1.88, 95% CI 1.49, 2.38). Race-based subgroup analyses revealed increased benefit from doublet therapy in Asian populations for ORR (RR 1.70, 95% CI 1.29, 2.23) but not increased survival benefit. Higher incidences of grade 3/4 anaemia (RR 2.23, 95% CI 1.61, 3.09), thrombocytopenia (RR 2.47, 95% CI 1.17, 5.20), and fatigue (RR 1.36, 95% CI 1.06, 1.74) were observed with doublet versus single-agent therapy. CONCLUSIONS: Doublet therapy was associated with significantly increased OS, 1-year SR and ORR compared with single agent therapy. Race may be considered when choosing doublet versus single-agent therapy as first line treatment of NSCLC in elderly patients. PMID- 26438015 TI - Arthroplasty and postoperative antimicrobial prophylaxis. PMID- 26438016 TI - UN goals trigger calls for reforming Canadian aid. PMID- 26438017 TI - Bones of contention. PMID- 26438018 TI - Artificial scents have no place in our hospitals. PMID- 26438019 TI - A 29-year-old woman with Crohn disease considering pregnancy. PMID- 26438020 TI - Nunavut suicides a "public health emergency". PMID- 26438021 TI - Expect little, demand more from feds on health. PMID- 26438022 TI - Election 2015: closing the Aboriginal health gap. PMID- 26438023 TI - Maternal and child health: gains, but a long journey ahead. PMID- 26438024 TI - Medicine by design. PMID- 26438025 TI - Tools for translational epigenetic studies involving formalin-fixed paraffin embedded human tissue: applying the Infinium HumanMethyation450 Beadchip assay to large population-based studies. AB - BACKGROUND: Large population-based translational epigenetic studies are emerging due to recent technological advances that have made molecular analyses possible. For example, the Infinium HumanMethylation450 Beadchip (HM450K) has enabled studies of genome-wide methylation on a scale not previously possible. However, application of the HM450K to DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour material has been more challenging than application to high quality DNA extracted from blood. To facilitate the application of this assay consistently across a large number of FFPE tumour-enriched DNA samples we have devised a modification to the HM450K protocol for FFPE that includes an additional quality control (QC) checkpoint. RESULTS: QC checkpoint 3 was designed to assess the presence of DNA after bisulfite conversion and restoration, just prior to application of the HM450K assay. DNA was extracted from 474 archival FFPE breast tumour material. Five samples did not have a detectable amount of DNA with an additional 42 failing to progress past QC checkpoint 3. Genome-wide methylation was measured for the remaining 428 tumour-enriched DNA. Of these, only 4 samples failed our stringent HM450K data criteria thus representing a 99% success rate. Using prior knowledge about methylation marks associated with breast cancer we further explored the quality of the data. Twenty probes in the BRCA1 promoter region showed increased methylation in triple-negative breast cancers compared to Luminal A, Luminal B and HER2-positive breast cancer subtypes. Validation of this observation in published data from The Cancer Genome Atlas (TCGA) Network (obtained from DNA extracted from fresh frozen tumour samples) confirms the quality of the data obtained from the improved protocol. CONCLUSIONS: The modified protocol is suitable for the analysis of FFPE tumour enriched DNA and can be systematically applied to hundreds of samples. This protocol will have utility in population-based translational epigenetic studies and is applicable to a wide variety of translated studies interested in analysis of methylation and its role in the predisposition to disease and disease progression. PMID- 26438026 TI - Human Anthrax Transmission at the Urban-Rural Interface, Georgia. AB - Human anthrax has increased dramatically in Georgia and was recently linked to the sale of meat in an urban market. We assessed epidemiological trends and risk factors for human anthrax at the urban-rural interface. We reviewed epidemiologic records (2000-2012) that included the place of residence (classified as urban, peri-urban, or rural), age, gender, and self-reported source of infection (handling or processing animal by-products and slaughtering or butchering livestock). To estimate risk, we used a negative binomial regression. The average incidence per 1 million population in peri-urban areas (24.5 cases) was > 2-fold higher compared with rural areas and > 3-fold higher compared with urban area. Risk from handling or purchasing meat was nearly 2-fold higher in urban areas and > 4-fold higher in peri-urban areas compared with rural area. Our findings suggest a high risk of anthrax in urban and peri-urban areas likely as a result of spillover from contaminated meat and animal by-products. Consumers should be warned to purchase meat only from licensed merchants. PMID- 26438027 TI - Hepatitis E Virus Exposure is Increased in Pork Butchers from Burkina Faso. AB - We conducted the first survey of zoonotic risk of Hepatitis E virus (HEV) transmissions in Ouagadougou, Burkina Faso, through the direct contact with pork meat during professional activity. Anti-HEV antibodies were more prevalent in pork butchers, 76% than in the general population, which was 47.8% in 2013 (odds ratio = 3.46, 95% CI = 2.85-4.21, P < 0.001). Among slaughter-aged swine, HEV seroprevalence was of 80%, and HEV RNA was detected in 1% of pork livers. Phylogenetic analysis pointed out HEV genotype 3. Thus, in addition to possible HEV contamination through the water source, as in endemic region, zoonotic transmissions of HEV probably occur in west Africa. PMID- 26438028 TI - Does Poor Water Quality Cause Diarrheal Disease? PMID- 26438029 TI - Knowledge, Attitudes, and Practices Associated with Brucellosis in Livestock Owners in Jordan. AB - We evaluated livestock owners' knowledge, attitudes, and practices regarding brucellosis in Jordan. A questionnaire was administered and biological samples were examined to verify the serological status of animals. Seroprevalence estimates indicated that 18.1% (95% CI: 11-25.3) of cattle herds and 34.3% (95% CI: 28.4-40.4) of small ruminant flocks were seropositive. The results showed that 100% of the interviewed livestock keepers were aware of brucellosis: 87% indicated a high risk of infection if unpasteurized milk is consumed and 75% indicated a high risk if unpasteurized dairy products are consumed. Awareness of the risk of infection through direct contact with fetal membranes or via physical contact with infected livestock is considerably lower, 19% and 13%, respectively. These knowledge gaps manifest in a high frequency of high-risk practices such as assisting in animal parturition (62%), disposing aborted fetuses without protective gloves (71.2%) or masks (65%), and not boiling milk before preparation of dairy products (60%). When brucellosis is suspected, basic hygiene practices are often disregarded and suspect animals are freely traded. Public health education should be enhanced as the disease is likely to remain endemic in the ruminant reservoir as long as a suitable compensation program is not established and trust on available vaccines is regained. PMID- 26438030 TI - A Cost-Effectiveness Analysis of Plasmodium falciparum Malaria Elimination in Hainan Province, 2002-2012. AB - In Hainan Province, China, great achievements in elimination of falciparum malaria have been made since 2010. There have been no locally acquired falciparum malaria cases since that time. The cost-effectiveness of elimination of falciparum malaria has been analyzed in Hainan Province. There were 4,422 falciparum malaria cases reported from 2002 to 2012, more cases occurred in males than in females. From 2002 to 2012, a total of 98.5 disability-adjusted life years (DALYs) were reported because of falciparum malaria. Populations in the age ranges of 15-25 and 30-44 years had higher incidences and DALYs than other age groups. From 2002 to 2012, malaria-related costs for salaries of staff, funds from the provincial government, national government, and the GFATM were US$3.02, US$2.24, US$1.44, and US$5.08 million, respectively. An estimated 9,504 falciparum malaria cases were averted during the period 2003-2012. The estimated cost per falciparum malaria case averted was US$116.5. The falciparum malaria elimination program in Hainan was highly effective and successful. However, funding for maintenance is still needed because of imported cases. PMID- 26438031 TI - Microbiological Contamination of Drinking Water Associated with Subsequent Child Diarrhea. AB - We used a prospective, longitudinal cohort enrolled as part of a program evaluation to assess the relationship between drinking water microbiological quality and child diarrhea. We included 50 villages across rural Bangladesh. Within each village field-workers enrolled a systematic random sample of 10 households with a child under the age of 3 years. Community monitors visited households monthly and recorded whether children under the age of 5 years had diarrhea in the preceding 2 days. Every 3 months, a research assistant visited the household and requested a water sample from the source or container used to provide drinking water to the child. Laboratory technicians measured the concentration of Escherichia coli in the water samples using membrane filtration. Of drinking water samples, 59% (2,273/3,833) were contaminated with E. coli. Of 12,192 monthly follow-up visits over 2 years, mothers reported that their child had diarrhea in the preceding 2 days in 1,156 (9.5%) visits. In a multivariable general linear model, the log10 of E. coli contamination of the preceding drinking water sample was associated with an increased prevalence of child diarrhea (prevalence ratio = 1.14, 95% CI = 1.05, 1.23). These data provide further evidence of the health benefits of improved microbiological quality of drinking water. PMID- 26438032 TI - Hospital-Based Surveillance for Infectious Etiologies Among Patients with Acute Febrile Illness in Georgia, 2008-2011. AB - Information on the infectious causes of undifferentiated acute febrile illness (AFI) in Georgia is essential for effective treatment and prevention. In May 2008, a hospital-based AFI surveillance was initiated at six hospitals in Georgia. Patients aged >= 4 years with fever >= 38 degrees C for >= 48 hours were eligible for surveillance. Blood culture and serologic testing were conducted for Leptospira spp., Brucella spp., West Nile virus (WNV), Crimean-Congo hemorrhagic fever virus, Coxiella burnetii, tick-borne encephalitis virus (TBEV), hantavirus, Salmonella enterica serovar Typhi (S. Typhi), and Rickettsia typhi. Of 537 subjects enrolled, 70% were outpatients, 54% were males, and the mean age was 37 years. Patients reported having fatigue (89%), rigors (87%), sweating (83%), pain in joints (49%), and sleep disturbances (42%). Thirty-nine (7%) patients were seropositive for R. typhi, 37 (7%) for Brucella spp., 36 (7%) for TBEV, 12 (2%) for Leptospira spp., 10 (2%) for C. burnetii, and three (0.6%) for S. Typhi. None of the febrile patients tested positive for WNV antibodies. Of the patients, 73% were negative for all pathogens. Our results indicate that most of the targeted pathogens are present in Georgia, and highlight the importance of enhancing laboratory capacity for these infectious diseases. PMID- 26438034 TI - Effect of interfaces on the nearby Brownian motion. AB - Near-boundary Brownian motion is a classic hydrodynamic problem of great importance in a variety of fields, from biophysics to micro-/nanofluidics. However, owing to challenges in experimental measurements of near-boundary dynamics, the effect of interfaces on Brownian motion has remained elusive. Here we report a computational study of this effect using MUs-long large-scale molecular dynamics simulations and our newly developed Green-Kubo relation for friction at the liquid-solid interface. Our computer experiment unambiguously reveals that the t(-3/2) long-time decay of the velocity autocorrelation function of a Brownian particle in bulk liquid is replaced by a t(-5/2) decay near a boundary. We discover a general breakdown of traditional no-slip boundary condition at short time scales and we show that this breakdown has a profound impact on the near-boundary Brownian motion. Our results demonstrate the potential of Brownian-particle-based micro-/nanosonar to probe the local wettability of liquid-solid interfaces. PMID- 26438033 TI - Relationship between ITPA polymorphisms and hemolytic anemia in HCV-infected patients after ribavirin-based therapy: a meta-analysis. AB - BACKGROUND: There is growing evidence that variations in the gene encoding inosine triphosphate pyrophosphohydrolase (ITPase), known as inosine triphosphatase (ITPA), are related to hemolytic anemia, which is frequently observed among hepatitis C virus (HCV)-infected patients receiving ribavirin (RBV)-based therapy. We performed a meta-analysis of all eligible studies assessing ITPA gene polymorphisms related to RBV-induced hemolytic anemia in HCV infected patients published in PubMed, Embase and the Cochrane library prior to the end of 2014. METHODS: Three outcomes were evaluated: (1) hemoglobin decline, (2) severe anemia, and (3) RBV dose reduction or treatment discontinuation. Pooled odds ratio (OR) and 95 % confidence interval (95 % CI) were estimated by either fixed or random effects models. RESULTS: Twenty-nine studies were selected from the literature search: 20 references involving 6533 individuals for hemoglobin decline, 13 references on 3764 patients for severe anemia, and 16 references on 3918 patients for RBV dose reduction or discontinuation. Significant associations with hemoglobin decline were found for rs1127354 CC [OR = 12.84 (95 % CI 7.44; 22.17)], rs7270101 AA [OR = 3.41 (95 % CI 2.08; 5.59)] and rs6051702 AA [OR = 4.43 (95 % CI 2.80; 7.00)] genotypes. Moreover, significant associations with hemoglobin decline were also found for absent [OR = 6.01 (95 % CI 4.84; 7.46)] and mild [OR = 4.68 (95 % CI 2.83; 7.74)] ITPase deficiency haplotypes. The ITPA rs1127354 CC genotype and absent ITPase deficiency haplotype were also associated with severe anemia {[OR = 7.77 (95 % CI 5.03; 12.00)] and [OR = 4.79 (95 % CI 1.69; 13.56)], respectively}. Additionally, the rs1127354 CC genotype showed significant association with RBV dose reduction or stopping treatment (OR = 2.24; 95 % CI 1.79; 2.81). CONCLUSIONS: ITPA polymorphisms increase the likelihood of developing hemolytic anemia for HCV-infected patients on RBV-based therapy, particularly rs1127354 CC and rs7270101 AA genotypes, suggesting the utility of screening for ITPA polymorphisms to avoid hematological toxicity and increase adherence to RBV-based therapy. PMID- 26438035 TI - Extracts from Aralia elata (Miq) Seem alleviate hepatosteatosis via improving hepatic insulin sensitivity. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common liver disease that is strongly associated with obesity and dysregulation of insulin in the liver. However, currently no pharmacological agents have been established for the treatment of NAFLD. In this regard, we sought to evaluate the anti-NAFLD effects of Aralia elata (Miq) Seem (AE) extract and its ability to inhibit hepatic lipid accumulation and modulate cellular signaling in a high fat diet (HFD)-induced obese mouse model. METHODS: A model of hepatic steatosis in the HepG2 cells was induced by oleic acid. Intracellular lipid droplets were detected by Oil-Red-O staining, and the expression of sterol regulatory element-binding protein 1(SREBP 1), Fatty acid synthase (FAS), Acetyl-CoA carboxylase (ACC) 1 and 2, Peroxisome proliferator activated receptor-alpha (PPARalpha), and carnitine palmitoyl transferase 1(CPT-1) was analyzed by real time reverse transcription-Polymerase chain reaction (qRT-PCR). And glucose consumption was measured with commercial kit. Furthermore, Male C57BL/6 J mice were fed with HFD to induce NAFLD. Groups of mice were given plant extracts orally at 100 and 300 mg/kg at daily for 4 weeks. After 3 weeks of AE extract treatment, we performed oral glucose tolerance test (OGTT). Liver tissue was procured for histological examination, Phosphoinositide 3-kinase (PI3K) and Protein kinase B (PKB/Akt) activity. RESULTS: In the present study, AE extract was shown to reduce hepatic lipid accumulation and significantly downregulate the level of lipogenic genes and upregulate the expression of lipolysis genes in HepG2 cells. And also, AE extract significantly increased the glucose consumption, indicating that AE extract improved insulin resistance. Subsequently, we confirmed the inhibitory activity of AE extract on NAFLD, in vivo. Treatment with AE extract significantly decreased body weight and the fasting glucose level, alleviated hyperinsulinism and hyperlipidemia, and reduced glucose levels, as determined by OGTT. Additionally, AE extract decreased PI3K and Akt activity. CONCLUSIONS: Our results suggest that treatment with AE extract ameliorated NAFLD by inhibiting insulin resistance through activation of the Akt/GLUT4 pathway. PMID- 26438037 TI - Intersubjectivity, otherness, and thirdness: A necessary relationship. AB - The author proposes an interplay among the notions of otherness, intersubjectivity and thirdness with its coincidences and oppositions. Its polysemic nature is analyzed in this paper. The relation internal world-external world is at stake and concerns both the construction of subjectivity as well as the way the analytic relation is deemed to assume. This review focuses on the psychoanalytic developments from Freud to posfreudian and contemporary authors plus, at the same time, interdisciplinary proposals are also included. It is also revisited the notion of "analytic field", proposed by Willy and Madeleine Baranger who, early as 1961-62, underlined the transition from "the unipersonal to the intersubjective", emphasizing that this was an expression of a change in the understanding of the analytic treatment. In this paper, the author argues that the concept of otherness introduces a symbolic aspect of decentring into the seeming interactive symmetry of intersubjectivity. At the same time, it is stressed that thirdness places a wedge into the between-subjects, which opens the way from and to recognition of the other and others. PMID- 26438036 TI - Maternal and Child's Thyroid Function and Child's Intellect and Scholastic Performance. AB - BACKGROUND: Maternal hypothyroidism and/or hypothyroxinemia have been associated with child's poor neuropsychological development, but the results have been inconsistent. METHODS: The Northern Finland Birth Cohort 1986 included all expected births within a year (9362 women, 9479 children) from the two northernmost provinces of Finland. Maternal serum samples (n = 5791) were obtained in early pregnancy (M +/- SD = 10.7 +/- 2.8 weeks' gestation), and serum samples from their children were obtained at 16 years of age (n = 5829). All samples were analyzed for thyrotropin, free thyroxine (fT4), and thyroid peroxidase antibodies. The children's school performance was evaluated by their main teachers at eight years of age, as well as by the adolescents themselves at 16 years of age. Data on possible severe intellectual deficiency and mild cognitive limitation were collected from healthcare records and registries for all children. Logistic regression estimated the odds of poor school performance or severe intellectual deficiency/mild cognitive limitation associated with exposure to maternal thyroid dysfunction. The odds of poor school performance associated with the adolescents' own thyroid function at age 16 were also estimated. Results are presented as odds ratios (OR) with confidence intervals (CI), adjusted for maternal/family covariates and child's sex. RESULTS: Girls of mothers with subclinical hypothyroidism had more self-evaluated difficulties in mathematics than did girls of euthyroid mothers (OR 1.62 [CI 1.06-2.49]). Boys of hypothyroxinemic mothers repeated a school class more often than did boys of euthyroid mothers (OR 5.46 [CI 1.19-25.06]). Adolescents of hyperthyroid mothers had increased odds of poor self-evaluated performance in mathematics (OR 1.61 [CI 1.01-2.49]). Maternal thyroid dysfunction did not increase the odds of a child having severe intellectual deficiency/mild cognitive limitation. At 16 years of age, girls with hyperthyroidism by laboratory measurements had more difficulties in Finnish language (OR 2.82 [CI 1.42-5.61]) than did euthyroid girls. Boys with hypothyroxinemia by laboratory measurement had higher odds of having difficulties in Finnish and/or mathematics (OR 2.13 [CI 1.26-3.62]) than did euthyroid boys. CONCLUSIONS: Maternal thyroid dysfunction during early pregnancy was associated with poorer scholastic performance of the adolescent. Additionally, adolescents' own thyroid dysfunction was associated with difficulties in school performance assessed by self-evaluation. PMID- 26438038 TI - Efficacy and safety of iota-carrageenan nasal spray versus placebo in early treatment of the common cold in adults: the ICICC trial. AB - Iota-carrageenan (I-C) is active against respiratory viruses in vitro and was effective as nasal spray in three previous clinical trials. The current trial served to further investigate I-C in patients with early common cold symptoms. METHODS: This randomized, placebo-controlled, double-blind phase IV trial was conducted in 200 adult patients with self-diagnosed colds of <48 h' duration that were confirmed by baseline cold symptom scores. Patients were to self-administer 0.12 % I-C or placebo spray (NaCl 0.5 %) four times daily for four to ten days and record symptom information for ten days. Common respiratory viruses were quantified by RT-PCR during pretreatment and on Day 3 or 4. The primary endpoint was the mean total symptom score (TSS) of eight cold symptoms on Days 2-4 (TSS2 4). RESULTS: Patients in both treatment groups had similar baseline TSSs (mean TSS: 6.75 for I-C and 6.79 for placebo). Viruses were detected in baseline samples from 53 of 98 I-C patients (54.1 %) and 54 of 97 placebo patients (55.7 %). Mean +/- SE for TSS2-4 was 5.78 +/- 0.25 for I-C patients and 6.39 +/- 0.25 for placebo (p = 0.0895). Exploratory analyses after unblinding (TSS2-4 excluding a patient with aberrantly high symptom scores [TSS2-4, ex 1pt]; mean of TSS over Days 1-4 [TSS1-4]; change in TSS1-4 relative to baseline [TSS1-4, rel]) demonstrated treatment differences in favor of I-C (p = 0.0364, p = 0.0495 and p = 0.0421, respectively). For patients with quantifiable rhinovirus/enterovirus at baseline, there was a trend towards greater reduction of virus load at Day 3 or 4 (p = 0.0958; I-C: 90.2 % reduction in viral load; placebo: 72.0 %). Treatments were well tolerated with no differences in adverse event rates. CONCLUSIONS: The primary endpoint did not demonstrate a statistically significant difference between I-C and placebo but showed a trend towards I-C benefit. Exploratory analyses indicated significant reduction of cold symptoms in the I-C group relative to placebo during the first four days when symptoms were most severe, and also substantiated I-C's activity against rhinovirus/enterovirus. TRIAL REGISTRATION: NCT01944631 (clinicaltrials.gov). PMID- 26438039 TI - Long-term hemodialysis therapy in neonates and infants with end-stage renal disease: a 16-year experience and outcome. AB - BACKGROUND: Peritoneal dialysis is the preferred mode of renal replacement therapy in infants with end-stage renal disease (ESRD). Hemodialysis (HD) is seldom used in neonates and infants due to the risk of major complications in the very young. METHODS: Demographic, clinical, laboratory, and imaging data on all infants younger than 12 months with ESRD who received HD in our Pediatric Dialysis Unit between January 1997 and June 2013 were analyzed. RESULTS: Eighteen infants (n = 6 male) with ESRD (median age 3 months; median weight 4.06 kg) received HD through a central venous catheter (CVC) for a total of 543 months (median duration per infant 16 months). Seven of the infants (39%) were neonates, and five (28%) had serious comorbidities. There were five episodes of CVC infection, which is a rate of 0.3/1000 CVC days. Median catheter survival time was 320 days. Most infants had good oral intake, and only four (22%) required a gastric tube; 14 (78%) infants displayed normal growth. Fourteen (78%) infants had hypertension, of whom four (22%) had severe cardiac complications; eight (44%) showed delayed psychomotor development. Eleven (61%) of the infants, including six (86%) of the neonates, survived. Five (28%) infants underwent renal transplantation; 10-year graft survival was 80%. CONCLUSIONS: Based on these results, long-term HD in neonates and infants with ESRD is technically feasible, can be implemented without major complications, carries a very low rate of CVC infection and malfunction, and results in adequate nutrition, good growth, as well as good kidney graft and patient survivals. Future efforts should aim to prevent hypertension and its cardiac sequelae, improve neurodevelopmental outcome, and lower mortality rate in these infants. PMID- 26438040 TI - Epidemiology of infections by HIV, Syphilis, Gonorrhea and Lymphogranuloma Venereum in Barcelona City: a population-based incidence study. AB - BACKGROUND: The aim of this study was to determine the evolution of HIV infection, gonorrhea, syphilis and lymphogranuloma venereum (LGV), and their epidemiological characteristics in Barcelona city. METHODS: Population-based incidence study of all newly occurring diagnoses of HIV infection, syphilis, gonorrhea and LGV detected in Barcelona between January 2007 and December 2011. A descriptive analysis was performed. The annual incidence rates per 100,000 inhabitants were calculated by sex, sexual conduct and educational level. To estimate global sex-specific rates we used the Barcelona city census; for the calculation of rates by sexual conduct and educational level we used estimates of the Barcelona Health Interview Survey. Trends were analysed using the chi-squared test for linear trend. RESULTS: HIV. 66.8 % of the HIV cases were men who had sex with men (MSM). The incidence rates in MSM over the study period were from 692.67/100,000 to 909.88/100,000 inh. Syphilis. 74.2 % of the syphilis cases were MSM. The incidence rates in MSM were from 224.9/100,000 to 891.97/100,000 inh. and the MSM with a university education ranged from 196.3/100,000 to 1020.8/100,000. Gonorrhea. 45.5 % of the gonorrhea cases were MSM. The incidence rates in MSM were from 164.24/100,000 to 404.79/100,000 inh. and the MSM with university education ranged from 176.7/100,000 to 530.1/100,000 inh.. Lymphogranuloma venereum (LGV). 95.3 % of the LGV cases are MSM. The incidence rates in MSM were from 24.99/100,000 to 282.99/100,000 inh. and the MSM with university education ranged from 9.3/100,000 to 265/100,000 inh. CONCLUSION: An increase in cases of STI was observed. These STI mainly affected MSM with a university education. Continuing to monitor changes in the epidemiology of STI, and identifying the most affected groups should permit redesigning preventive programs, with the goal of finding the most efficient way to reach these population groups. PMID- 26438041 TI - Changes in equity of maternal, newborn, and child health care practices in 115 districts of rural Ethiopia: implications for the health extension program. AB - BACKGROUND: Reducing within-country inequities in the coverage of maternal, newborn, and child health (MNCH) interventions is essential to improving a country's maternal and child health and survival rates. The community-based health extension program (HEP) of Ethiopia, launched in 2003, aims to provide equitable primary health care services. Since 2008 the Last Ten Kilometers Project (L10K) has been supporting the HEP in promoting equitable MNCH interventions in 115 districts covering about 14 million people. We report the inequities in MNCH programmatic indicators in 2008 and in 2010 in the L10K areas, along with changes in equity between the two survey periods, and the implications of these results for the national program. METHODS: The study used cross sectional surveys of 3932 and 3867 women from 129 representative kebeles (communities) conducted in December 2008 and December 2010, respectively. Nineteen HEP outreach activity coverage and MNCH care practice indicators were calculated for each survey period, stratified by the inequity factors considered (i.e. age, education, wealth and distance from the nearest health facility). We calculated relative inequities using concentration indices for each of the indicators and inequity factors. Ninety-five percent confidence intervals and survey design adjusted Wald's statistics were used to assess differentials in equity. RESULTS: Education and age related inequities in the MNCH indicators were the most prominent (observed for 13 of the 19 outcomes analyzed), followed in order by wealth inequity (observed for eight indicators), and inequity due to distance from the nearest health facility (observed for seven indicators). Age inequities in six of the indicators increased between 2008 and 2010; nevertheless, there was no consistent pattern of changes in inequities during that period. Some related issues such as inequities due to wealth in household visits by the health extension workers and prevalence of modern family household; and inequities due to education in household visits by community health promoters showed improvement. CONCLUSIONS: Addressing these inequities in MNCH interventions by age, education and wealth will contribute significantly toward achieving Ethiopia's maternal health targets for the Millennium Development Goals and beyond. HEP will require more innovative strategies to achieve equitable MNCH services and outcomes and to routinely monitor the effectiveness of those strategies. PMID- 26438042 TI - Training Cambodian Village Health Support Guides in Diabetes Prevention: Effects on Guides' Knowledge and Teaching Activities Over 6 Months. AB - BACKGROUND: Type 2 diabetes is a pressing public health concern in Cambodia, a country with limited human resource capacity due to genocide. Cambodian village health support guides (Guides) promote health at the local level. PURPOSE: This paper reports preliminary results of training Guides in diabetes prevention. METHOD: The curriculum, called Eat, Walk, Sleep was delivered to Guides in Siem Reap province once over 3 h. Participants completed a pretest and posttest on diabetes knowledge. Guides were offered continuing education through Eat, Walk, Sleep resources and were encouraged to teach Eat, Walk, Sleep in their villages. For each of 6 months following their training, Guides completed a checklist regarding their activities. RESULTS: One hundred eighty-five Guides attended one of ten trainings. Knowledge scores increased significantly from pretest to posttest. During 6 months of follow-up, n = 159 Guides (85 %) completed at least one monthly checklist. Guides reported high rates of uptake and delivery of the Eat, Walk, Sleep curriculum and moderate rates of continuing education about diabetes. CONCLUSION: Diabetes prevention in Cambodia is nascent. Guides show excellent uptake and dissemination of the curriculum. Future research should examine effect of support for Guide activities and the effect of the curriculum on villager health behaviors, and ultimately, on rates of type 2 diabetes. PMID- 26438043 TI - Evaluation of microbial transport during aerobic bioaugmentation of an RDX contaminated aquifer. AB - In situ bioaugmentation with aerobic hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX)-degrading bacteria is being considered for treatment of explosives contaminated groundwater at Umatilla Chemical Depot, Oregon (UMCD). Two forced gradient bacterial transport tests of site groundwater containing chloride or bromide tracer and either a mixed culture of Gordonia sp. KTR9 (xplA (+)Km(R)), Rhodococcus jostii RHA1 (pGKT2 transconjugant; xplA (+)Km(R)) and Pseudomonas fluorescens I-C (xenB (+)), or a single culture of Gordonia sp. KTR9 (xplA (+); i.e. wild-type) were conducted at UMCD. Groundwater monitoring evaluated cell viability and migration in the injection well and downgradient monitoring wells. Enhanced degradation of RDX was not evaluated in these demonstrations. Quantitative PCR analysis of xplA, the kanamycin resistance gene (aph), and xenB indicated that the mixed culture was transported at least 3 m within 2 h of injection. During a subsequent field injection of bioaugmented groundwater, strain KTR9 (wild-type) migrated up to 23-m downgradient of the injection well within 3 days. Thus, the three RDX-degrading strains were effectively introduced and transported within the UMCD aquifer. This demonstration represents an innovative application of bioaugmentation to potentially enhance RDX biodegradation in aerobic aquifers. PMID- 26438044 TI - Genomic dissection of the 1994 Cronobacter sakazakii outbreak in a French neonatal intensive care unit. AB - BACKGROUND: Cronobacter sakazakii is a member of the genus Cronobacter that has frequently been isolated from powdered infant formula (PIF) and linked with rare but fatal neonatal infections such as meningitis and necrotising enterocolitis. The Cronobacter MLST scheme has reported over 400 sequence types and 42 clonal complexes; however C. sakazakii clonal complex 4 (CC4) has been linked strongly with neonatal infections, especially meningitis. There have been a number of reported Cronobacter outbreaks over the last three decades. The largest outbreak of C. sakazakii was in a neonatal intensive care unit (NICU) in France (1994) that lasted over 3 months and claimed the lives of three neonates. The present study used whole genome sequencing data of 26 isolates obtained from this outbreak to reveal their relatedness. This study is first of its kind to use whole genome sequencing data to analyse a Cronobacter outbreak. METHODS: Whole genome sequencing data was generated for 26 C. sakazakii isolates on the Illumina MiSeq platform. The whole genome phylogeny was determined using Mugsy and RaxML. SNP calls were determined using SMALT and SAMtools, and filtered using VCFtools. RESULTS: The whole genome phylogeny suggested 3 distant clusters of C. sakazakii isolates were associated with the outbreak. SNP typing and phylogeny indicate the source of the C. sakazakii could have been from extrinsic contamination of reconstituted infant formula from the NICU environment and personnel. This pool of strains would have contributed to the prolonged duration of the outbreak, which was up to 3 months. Furthermore 3 neonates were co-infected with C. sakazakii from two different genotype clusters. CONCLUSION: The genomic investigation revealed the outbreak consisted of an heterogeneous population of C. sakazakii isolates. The source of the outbreak was not identified, but probably was due to environmental and personnel reservoirs resulting in extrinsic contamination of the neonatal feeds. It also indicated that C. sakazakii isolates from different genotype clusters have the ability to co-infect neonates. PMID- 26438045 TI - High evolutionary turnover of satellite families in Caenorhabditis. AB - BACKGROUND: The high density of tandem repeat sequences (satellites) in nematode genomes and the availability of genome sequences from several species in the group offer a unique opportunity to better understand the evolutionary dynamics and the functional role of these sequences. We take advantage of the previously developed SATFIND program to study the satellites in four Caenorhabditis species and investigate these questions. METHODS: The identification and comparison of satellites is carried out in three steps. First we find all the satellites present in each species with the SATFIND program. Each satellite is defined by its length, number of repeats, and repeat sequence. Only satellites with at least ten repeats are considered. In the second step we build satellite families with a newly developed alignment program. Satellite families are defined by a consensus sequence and the number of satellites in the family. Finally we compare the consensus sequence of satellite families in different species. RESULTS: We give a catalog of individual satellites in each species. We have also identified satellite families with a related sequence and compare them in different species. We analyze the turnover of satellites: they increased in size through duplications of fragments of 100-300 bases. It appears that in many cases they have undergone an explosive expansion. In C. elegans we have identified a subset of large satellites that have strong affinity for the centromere protein CENP-A. We have also compared our results with those obtained from other species, including one nematode and three mammals. CONCLUSIONS: Most satellite families found in Caenorhabditis are species-specific; in particular those with long repeats. A subset of these satellites may facilitate the formation of kinetochores in mitosis. Other satellite families in C. elegans are either related to Helitron transposons or to meiotic pairing centers. PMID- 26438046 TI - Downregulation of ASPP2 in pancreatic cancer cells contributes to increased resistance to gemcitabine through autophagy activation. AB - BACKGROUND: Apoptosis-stimulating of p53 protein 2 (ASPP2) is one of the ASPP family members and it has been reported to be associated with human cancer. However, the role of it in pancreatic cancer is still not clear. METHODS: We analyzed the expression level of ASPP2 in cancer tissue samples with RT-qPCR, Western Blotting assay and immunohistochemistry staining. We studied the biological function of ASPP2 and its mechanism with gene overexpression and gene silencing technologies. We determined the sensitivity of pancreatic cells with differential ASPP2 level to gemcitabine and whether autophagy inhibition affected the gemcitabine resistance, both in vitro and in vivo. RESULTS: Expression of ASPP2 was downregulated in cancerous tissues in comparison with para-cancerous tissues. ASPP2 expression was linked to clinical outcomes in patients and down regulation of ASPP2 increased cell proliferation, autophagic flux, the activity of AMP Kinase of pancreatic cancer cells and vice versa. Knockdown of ASPP2 results in increased resistance to gemcitabine, which was attributed to the enhanced autophagy. CONCLUSIONS: ASSP2 expression is lower in cancerous tissues and decreased ASPP2 lead to higher cancer cells proliferation and autophagic flux, which contribute to the gemcitabine resistance. PMID- 26438047 TI - Genetics analysis of 38 STR loci in Uygur population from Southern Xinjiang of China. AB - The allele frequencies and statistical parameters of 38 autosomal short tandem repeat (STR) loci were analyzed in the Uygur population from Southern Xinjiang of China with 290 unrelated individuals. The results show these 38 STR loci have high or medium power of discrimination and probabilities of exclusion. All loci are in Hardy-Weinberg equilibrium. The genetic distances between the Uygur population and other Chinese populations were also estimated. PMID- 26438048 TI - Tumor-induced inflammation alters neutrophil phenotype and disease progression. AB - Neutrophils are essential to combat infectious agents but contribute to collateral inflammatory damage. Likewise, neutrophils can kill cancer cells and have been shown to promote malignant growth and metastasis through immunosuppressive functions. Two articles in a recent issue of Nature reveal new mechanisms by which tumors induce changes in neutrophil phenotype through production of inflammatory cytokines. Although the two studies report different outcomes on the effects of neutrophils on tumor growth and metastasis, they delineate novel molecular pathways influencing neutrophil phenotype that may provide new approaches to harnessing neutrophil functions in the treatment of cancer. PMID- 26438049 TI - Isoferulic acid prevents methylglyoxal-induced protein glycation and DNA damage by free radical scavenging activity. AB - BACKGROUND: Isoferulic acid (IFA), a naturally occurring cinnamic acid derivative, is a main active ingredient of the rhizoma of Cimicifuga dahurica. It has been shown various pharmacological activities. The aim of the study was to investigate the effect of IFA against MG-induced protein glycation and oxidative DNA damage. Free radical scavenging activity and the MGO-trapping abilities of IFA were also investigated. METHODS: The fluorescent MG-derived AGEs and non fluorescent N(epsilon)-(carboxymethyl) lysine (N(epsilon)-CML) was measured using a spectrofluorometer and an enzyme linked immunosorbant assay (ELISA). Protein carbonyl content was used to detect protein oxidation. Gel electrophoresis was used to determine DNA damage. Superoxide anion radicals and hydroxyl radicals were determined using cytochrome c reduction assay and thiobarbituric acid reactive 2-deoxy-D-ribose oxidation products, respectively. The MG-trapping capacity was performed by HPLC. RESULTS: IFA (1.25-5 mM) inhibited the formation of fluorescent MG-derived AGEs, and N(epsilon)-CML, and protein carbonyl in bovine serum albumin. In addition, IFA (0.1-1 mM) also prevented MG/lysine mediated oxidative DNA damage in the presence and absence of copper ion. The protective ability of IFA was directly correlated to inhibition of hydroxyl and superoxide anion radical generation during the reaction of MG and lysine. Most notably, IFA had no the directly trapping ability to MG. CONCLUSIONS: The present results highlighted that free radical scavenging activity, but not the MG trapping ability, is the mechanism of IFA for preventing MG-induced protein glycation and DNA damage. PMID- 26438051 TI - Balloon protection of the Labbe vein during transarterial embolization of a dural arterio-venous fistula. AB - INTRODUCTION: Endovascular treatment of type III dural arterio-venous fistulas can be challenging if the fistulous point is close to a functionally important cortical vein. METHODS: A technique is described for temporary balloon protection of the vein of Labbe during transarterial Onyx embolization of a type III dural arterio-venous fistula. One illustrative case is presented. Careful anatomic consideration of the concerned venous segment (at the insertion point into the lateral sinus) and the choice of balloon minimized the risk of venous rupture. RESULTS: Using this method, satisfactory progression of Onyx was obtained within the arterio-venous shunt while preserving the patency of the Labbe vein. CONCLUSION: Temporary balloon protection of the Labbe vein is a feasible option to preserve its patency during embolization of dural arterio-venous fistulas. To the authors' knowledge, this is the first report on the use of temporary balloon protection of a cortical vein. PMID- 26438050 TI - Immunopathogenic Background of Pars Planitis. AB - Pars planitis is defined as an intermediate uveitis of unknown background of systemic disease with characteristic formations such as vitreous snowballs, snowbanks and changes in peripheral retina. The incidence of pars planitis varies 2.4-15.4 % of the uveitis patients. The pathogenesis of the disease is to be determined in future. Clinical and histopathological findings suggest an autoimmune etiology, most likely as a reaction to endogenous antigen of unknown source, with T cells predominant in both vitreous and pars plana infiltrations. T cells subsets play an important role as a memory-effector peripheral cell. Snowbanks are formed as an effect of post inflammatory glial proliferation of fibrous astrocytes. There is also a genetic predisposition for pars planitis by human leukocyte antigen and several other genes. A coexistence of multiple sclerosis and optic neuritis has been described in numerous studies. Epiretinal membrane, cataract, cystoid macular edema, retinal detachment, retinal vasculitis, neovascularization, vitreous peripheral traction, peripheral hole formation, vitreous hemorrhage, disc edema are common complications observed in pars planitis. There is a need to expand the knowledge of the pathogenic and immunologic background of the pars planitis to create an accurate pharmacological treatment. PMID- 26438052 TI - Simple SNP-based minimal marker genotyping for Humulus lupulus L. identification and variety validation. AB - BACKGROUND: Hop is an economically important crop for the Pacific Northwest USA as well as other regions of the world. It is a perennial crop with rhizomatous or clonal propagation system for varietal distribution. A big concern for growers as well as brewers is variety purity and questions are regularly posed to public agencies concerning the availability of genotype testing. Current means for genotyping are based upon 25 microsatellites that provides relatively accurate genotyping but cannot always differentiate sister-lines. In addition, numerous PCR runs (25) are required to complete this process and only a few laboratories exist that perform this service. A genotyping protocol based upon SNPs would enable rapid accurate genotyping that can be assayed at any laboratory facility set up for SNP-based genotyping. The results of this study arose from a larger project designed for whole genome association studies upon the USDA-ARS hop germplasm collection consisting of approximately 116 distinct hop varieties and germplasm (female lines) from around the world. RESULTS: The original dataset that arose from partial sequencing of 121 genotypes resulted in the identification of 374,829 SNPs using TASSEL-UNEAK pipeline. After filtering out genotypes with more than 50% missing data (5 genotypes) and SNP markers with more than 20% missing data, 32,206 highly filtered SNP markers across 116 genotypes were identified and considered for this study. Minor allele frequency (MAF) was calculated for each SNP and ranked according to the most informative to least informative. Only those markers without missing data across genotypes as well as 60% or less heterozygous gamete calls were considered for further analysis. Genetic distances among individuals in the study were calculated using the marker with the highest MAF value, then by using a combination of the two markers with highest MAF values and so on. This process was reiterated until a set of markers was identified that allowed for all genotypes in the study to be genetically differentiated from each other. Next, we compared genetic matrices calculated from the minimal marker sets [(Table 2; 6-, 7-, 8-, 10- and 12-marker set matrices] and that of a matrix calculated from a set of markers with no missing data across all 116 samples (1006 SNP markers). The minimum number of markers required to meet both specifications was a set of 7-markers (Table 3). These seven SNPs were then aligned with a genome assembly, and DNA sequence both upstream and downstream were used to identify primer sequences that can be used to develop seven amplicons for high resolution melting curve PCR detection or other SNP-based PCR detection methods. CONCLUSIONS: This study identifies a set of 7 SNP markers that may prove useful for the identification and validation of hop varieties and accessions. Variety validation of unknown samples assumes that the variety under question has been included a priori in a discovery panel. These results are based upon in silica studies and markers need to be validated using different SNP marker technology upon a differential set of hop genotypes. The marker sequence data and suggested primer sets provide potential means to fingerprint hop varieties in most genetic laboratories utilizing SNP-marker technology. PMID- 26438053 TI - Alveolar macrophages support interferon gamma-mediated viral clearance in RSV infected neonatal mice. AB - BACKGROUND: Poor interferon gamma (IFNgamma) production during respiratory syncytial virus (RSV) is associated with prolonged viral clearance and increased disease severity in neonatal mice and humans. We previously showed that intra nasal delivery of IFNgamma significantly enhances RSV clearance from neonatal lungs prior to observed T-lymphocyte recruitment or activation, suggesting an innate immune mechanism of viral clearance. We further showed that alveolar macrophages dominate the RSV-infected neonatal airways relative to adults, consistent with human neonatal autopsy data. Therefore, the goal of this work was to determine the role of neonatal alveolar macrophages in IFNgamma-mediated RSV clearance. METHODS: Clodronate liposomes, flow cytometry, viral plaque assays, and histology were used to examine the role of alveolar macrophages (AMs) and the effects of intra-nasal IFNgamma in RSV infected neonatal Balb/c mice. The functional outcomes of AM depletion were determined quantitatively by viral titers using plaque assay. Illness was assessed by measuring reduced weight gain. RESULTS: AM activation during RSV infection was age-dependent and correlated tightly with IFNgamma exposure. Higher doses of IFNgamma more efficiently stimulated AM activation and expedited RSV clearance without significantly affecting weight gain. The presence of AMs were independently associated with improved RSV clearance, whereas AM depletion but not IFNgamma exposure, significantly impaired weight gain in RSV-infected neonates. CONCLUSION: We show here for the first time, that IFNgamma is critical for neonatal RSV clearance and that it depends, in part, on alveolar macrophages (AMs) for efficient viral clearing effects. Early reductions in viral burden are likely to have profound short- and long-term immune effects in the vulnerable post-natally developing lung environment. Studies are ongoing to elucidate the pathologic effects associated with early versus delayed RSV clearance in developing neonatal airways. PMID- 26438055 TI - A series of abnormal climatic conditions caused the most severe outbreak of first generation adults of the meadow moth (Loxostege sticticalis L.) in China. AB - The meadow moth, Loxostege sticticalis L., is a destructive migratory pest in the northern temperate zone. The outbreak mechanism of first-generation adults in China remains unclear. In 2008, the density of first-generation larvae was very low or even negligible in most sites in China. However, a great number of first generation adults appeared unexpectedly in late July, and their offspring caused the most severe infestation on record. The present study aims to determine where the large influx of immigrant adults originated from and how this unprecedented population was established. Source areas were explored by trajectory analysis, and climatic patterns related to the population increase were investigated. Results showed that the outbreak population mainly immigrated from Northeast Mongolia and the Chita State of Russia, and the buildup of such a large population could be attributed to an exceptional northward migration of overwintered adults from North China to East Mongolia in the spring of 2007 and unusually favourable climatic conditions in the next two growth seasons. These results indicated that the population dynamics of meadow moth in Northeast Asia would be difficult to predict when only considering local climatic factors and population size within one country. International joint monitoring and information sharing related to this pest between China, Mongolia and Russia should be implemented. PMID- 26438054 TI - Neuregulin1-beta decreases interleukin-1beta-induced RhoA activation, myosin light chain phosphorylation, and endothelial hyperpermeability. AB - Neuregulin-1 (NRG1) is an endogenous growth factor with multiple functions in the embryonic and postnatal brain. The NRG1 gene is large and complex, transcribing more than twenty transmembrane proteins and generating a large number of isoforms in tissue and cell type-specific patterns. Within the brain, NRG1 functions have been studied most extensively in neurons and glia, as well as in the peripheral vasculature. Recently, NRG1 signaling has been found to be important in the function of brain microvascular endothelial cells, decreasing IL-1beta-induced increases in endothelial permeability. In the current experiments, we have investigated the pathways through which the NRG1-beta isoform acts on IL-1beta induced endothelial permeability. Our data show that NRG1-beta increases barrier function, measured by transendothelial electrical resistance, and decreases IL 1beta-induced hyperpermeability, measured by dextran-40 extravasation through a monolayer of brain microvascular endothelial cells plated on transwells. An investigation of key signaling proteins suggests that the effect of NRG1-beta on endothelial permeability is mediated through RhoA activation and myosin light chain phosphorylation, events which affect filamentous actin morphology. In addition, AG825, an inhibitor of the erbB2-associated tyrosine kinase, reduces the effect of NRG1-beta on IL-1beta-induced RhoA activation and myosin light chain phosphorylation. These data add to the evidence that NRG1-beta signaling affects changes in the brain microvasculature in the setting of neuroinflammation. We propose the following events for neuregulin-1-mediated effects on Interleukin-1 beta (IL-1beta)-induced endothelial hyperpermeability: IL-1beta leads to RhoA activation, resulting in an increase in phosphorylation of myosin light chain (MLC). Phosphorylation of MLC is known to result in actin contraction and alterations in the f-actin cytoskeletal structure. These changes are associated with increased endothelial permeability. Neuregulin-1beta acts through its transmembrane receptors to activate intracellular signaling pathways which inhibit IL-1beta-induced RhoA activation and MLC phosphorylation, thereby preserving the f-actin cytoskeletal structure and endothelial barrier function. PMID- 26438056 TI - Rationale and methods for a randomized controlled trial of a movement-to-music video program for decreasing sedentary time among mother-child pairs. AB - BACKGROUND: Measured objectively, under a quarter of adults and fewer than half of preschool children meet the criteria set in the aerobic physical activity recommendations of the Centers for Disease Control and Prevention. Moreover, adults reportedly are sedentary (seated or lying down) for most of their waking hours. Importantly, greater amounts of sedentary time on parents' part are associated with an increased risk of more sedentary time among their children. A randomized controlled trial targeting mother-child pairs has been designed, to examine whether a movement-to-music video program may be effective in reducing sedentary time and increasing physical activity in the home environment. METHODS: Mother-child pairs (child age of 4-7 years) will be recruited from among NELLI lifestyle-modification study five-year follow-up cohort participants, encompassing 14 municipalities in Pirkanmaa region, Finland. Accelerometer and exercise diary data are to be collected for intervention and control groups at the first, second and eighth week after the baseline measurements. Background factors, physical activity, screen time, motivation to exercise, and self reported height and weight, along with quality of life, will be assessed via questionnaires. After the baseline and first week measurements, the participants of the intervention group will receive a movement-to-music video program designed to reduce sedentary time and increase physical activity. Intervention group mother-child pairs will be instructed to exercise every other day while watching the video program over the next seven weeks. Information on experiences of the use of the movement-to-music video program will be collected 8 weeks after baseline. Effects of the intervention will be analyzed in line with the intention to-treat principle through comparison of the changes in the main outcomes between intervention and control group participants. The study has received ethics approval from the Pirkanmaa Ethics Committee in Human Sciences. DISCUSSION: The study will yield information on the effectiveness of movement-to-music video exercise in reducing sedentary behavior. Intervention-based methods have proven effective in increasing physical activity in home environments. Music may improve exercise adherence, which creates a possibility of achieving long-term health benefits. TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov, as NCT02270138. It was registered on October 2, 2014. PMID- 26438057 TI - Core domain mutant Y220C of p53 protein has a key role in copper homeostasis in case of free fatty acids overload. AB - Nonalcoholic fatty liver disease (NAFLD) is a pathology that includes a wide variety of clinical conditions ranging from simple steatosis to end-stage liver diseases. Despite the huge amount of researches, the molecular basis of NAFLD are still not fully understood. Recently, it was suggested a role for p53 in NAFLD pathogenesis. Among its targets there is Synthesis of Cytochrome c Oxidase 2 (SCO2), a copper chaperone, involved in both aerobic respiration and metal cellular excretion. Copper seems to play a role in NAFLD. It was demonstrated a low hepatic copper content in NAFLD patients, which correlates with metabolic syndrome parameters. Copper homeostasis deregulation, in fact, seems to be related to lipid metabolism alteration and insulin resistance. Here we provide evidence on the role of p53 in the modulation of copper homeostasis, in an experimental model of NAFLD. We used two different hepatoma cell lines, HepG2 and Huh 7.5.1, characterized by the presence of wt p53 and its Y220C mutant, respectively, treated with a free fatty acids (FFAs) solution. Interestingly, p53 activation correlated with the intracellular copper level maintenance. We demonstrated that, in hepatoma cell lines, core domain mutant Y220C of p53 affects the modulation of SCO2 and Copper transporter 1 (CTR1), influencing, in this way, intracellular copper homeostasis in presence of FFAs accumulation, and that the 220 residue of the protein is crucial for such control. The role of p53 we highlighted may have deep implications in clinical conditions where copper homeostasis is deregulated. PMID- 26438058 TI - Maternal risk factors and perinatal outcomes among pacific islander groups in Hawaii: a retrospective cohort study using statewide hospital data. AB - BACKGROUND: Studies suggest Pacific Islander women have disparate rates of preterm birth, primary cesarean delivery, preeclampsia, gestational diabetes, and low birthweight infants. However, data is limited. In order to improve the health of Pacific Islanders, it is essential to better understand differences in obstetric outcomes in this diverse population METHODS: This study compared perinatal outcomes between Pacific Islander (9,646) and White (n = 5,510) women who delivered a singleton liveborn in any Hawaii hospital from January 2010 to December 2011 using the Hawaii Health Information Corporation (HHIC) database. Pacific Islanders were disaggregated into the following groups: Native Hawaiian, Samoan, Micronesian, and Other Pacific Islanders. Perinatal outcomes (e.g. hypertensive diseases, birthweight, mode of delivery) were compared using multivariable logistic models controlling for relevant sociodemographic and health risk factors (e.g. age and payer type). RESULTS: Significant differences in perinatal outcomes between Pacific Islander and White women and newborns were noted. All Pacific Islander groups had an increased risk of hypertension. Outcome differences were also seen between Pacific Islanders groups. Native Hawaiians had the highest risk of low birthweight infants, Samoans had the highest risk of macrosomic infants and Micronesians had the highest risk of cesarean delivery. CONCLUSIONS: Important differences in perinatal outcomes among Pacific Islanders exist. It is important to examine Pacific Islander populations separately in future research, public health interventions, and policy. PMID- 26438059 TI - Diagnostic value of soluble receptor-binding cancer antigen expressed on SiSo cells and carcinoembryonic antigen in differentiating malignant from benign pleural effusion. AB - Diagnosis of malignant pleural effusion (MPE) remains a major clinical challenge. The aim of this study was to evaluate the diagnostic value of combined detection of receptor-binding cancer antigen expressed on SiSo cells (RCAS1) and carcinoembryonic antigen (CEA) in patients with MPE and benign pleural effusion (BPE). The serum and pleural fluid samples were collected from 53 patients diagnosed with MPE and 49 patients with BPE. Enzyme-linked immunosorbent assay was used to detect the concentration of RCAS1 in serum and pleural effusion. The clinical data and laboratory information, including CEA levels, were gathered from these cases. The concentration of RCAS1 in MPE was significantly higher than that of BPE (P < 0.001). There was no significant difference between the two serum groups. The diagnostic sensitivity and specificity of pleural fluid RCAS1 were 67.92 and 81.63 %, respectively, at the optimized cutoff value of 7.326 U/mL; meanwhile, the sensitivity and specificity of pleural fluid CEA were 83.02 and 91.84 % at the cutoff value of 3.93 ng/mL. The specificity could be elevated to 98.50 % in serial detection, while the sensitivity may be improved to 94.55 % in parallel detection. Serum RCAS1 concentration was only detected in 53 serum samples out of the 102 samples, indicating that serum RCAS1 may not be a better option in differential diagnosis of malignancies compared with serum CEA, of which the diagnostic sensitivity and specificity were 64.15 and 83.67 % at the cutoff value of 3.90 ng/mL. No significant differences were found in pleural fluid RCAS1 concentration in MPE patients with different ages, gender, and pathological types of lung cancers. The detection of RCAS1 concentration in pleural fluid is informative for the diagnosis of MPE. Joint detection of RCAS1 and CEA can improve the diagnostic sensitivity and specificity. However, the diagnostic value of RCAS1 is not higher than that of CEA. PMID- 26438060 TI - Polymorphisms of 5,10-methylenetetrahydrofolate reductase and thymidylate synthase, dietary folate intake, and the risk of leukemia in adults. AB - The 5,10-methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) are critical enzymes in folate metabolism. Previous studies have reported conflicting results on the associations between MTHFR/TS polymorphisms and adult leukemia risk, which may due to the lack of information on folate intake. We investigated the risks of adult leukemia with genetic polymorphisms of folate metabolic enzymes (MTHFR C677T, A1298C, and TS) and evaluated if the associations varied by dietary folate intake from a multicenter case-control study conducted in Chinese. This study comprised 442 incident adult leukemia cases and 442 outpatient controls, individually matched to cases by gender, birth quinquennium, and study site. Genotypes were determined by a polymerase chain reaction (PCR) or PCR-based restriction fragment length polymorphism assay. Dietary folate intake was assessed by face-to-face interviews using a validated food-frequency questionnaire. The MTHFR 677TT genotype conferred a significant higher risk of leukemia in males than in females and exhibited an increased risk of acute myeloid leukemia (AML) but a decreased risk of acute lymphoblastic leukemia (ALL). The MTHFR 1298AC genotype appeared to decrease the risks of leukemia in both genders, in AML and ALL. Stratified analysis by dietary folate intake showed the increased risks of leukemia with the MTHFR 677TT and TS 2R3R/2R2R genotypes were only significant in individuals with low folate intake. A significant interaction between TS polymorphism and dietary folate intake was observed (P = 0.03). This study suggests that dietary folate intake and gender may modify the associations between MTHFR/TS polymorphisms and adult leukemia risk. PMID- 26438061 TI - Significance of Onodera's prognostic nutritional index in patients with colorectal cancer: a large cohort study in a single Chinese institution. AB - The preoperative nutritional and immunological statuses have an important impact in predicting the survival outcome of patients with various types of malignant tumors. Our study aimed to explore the clinical significance and predictive prognostic potential of Onodera's prognostic nutritional index (PNI) in patients with colorectal carcinoma. This retrospective study included a total of 1321 patients who were diagnosed with colorectal cancer and who had been surgically treated between January 1994 and December 2007. The PNI level was determined according the following formula: 10 * serum albumin (g/dL) + 0.005 * total lymphocyte count (per mm(3)). The impact of PNI on clinicopathological features and overall survival (OS) was determined. The optimal cutoff value of PNI was set at 45. Patients in the low-PNI group had a greater potential to have aggressive histological features, advanced tumors (T), nodal involvement (N), metastasis (M), and TNM stage than those in the high-PNI group. The low-PNI group had a worse OS than the high-PNI group (5-year survival rate 56.1 vs 64.8 %, respectively; P < 0.05). Furthermore, the PNI value was an independent prognostic factor for colorectal cancer in this study. The OS was significantly lower in the low-PNI group than in the high-PNI group in patients with TNM stage II and III diseases. Preoperative PNI is a simple and useful marker to predict clinicopathological features and long-term survival outcome in patients with colorectal carcinoma. PNI analysis should be included in the routine assessment of patients with locally advanced colorectal cancer. PMID- 26438062 TI - Increased expression of C-C motif ligand 2 associates with poor prognosis in patients with gastric cancer after gastrectomy. AB - Previous studies have demonstrated the clinical significance of polarized tumor associated macrophages (TAMs) in gastric cancer whereas the cytokines orchestrating TAM polarization remain elusive. This study aims to evaluate the prognostic value of C-C motif ligand 2 (CCL2) expression in gastric cancer patients after surgery. We examined CCL2 expression in tumor tissues by immunohistochemical staining in retrospectively enrolled 414 gastric cancer patients receiving gastrectomy at Zhongshan Hospital during 2008. We used Kaplan Meier analysis and Cox regression models to assess the prognostic value of CCL2 expression. We generated a predictive nomogram from integrating CCL2 expression with the TNM staging system to evaluate 3- and 5-year overall survival. High intratumor CCL2 expression associated with adverse clinical outcome. Intratumor CCL2 expression provided additional prognostic value in gastric cancer patients. CCL2 expression, as well as well-established TNM staging parameters, was identified as independent prognostic factor for overall survival. The generated nomogram corresponded well with the ideal model in predicting the 3- and 5-year overall survival of gastric cancer patients. CCL2, an identified potential independent adverse prognosticator, could be integrated with TNM staging system to improve the predictive accuracy for overall survival in gastric cancer patients especially with advanced stages. PMID- 26438063 TI - Fibronectin-, vitronectin- and laminin-binding proteins at the cell walls of Candida parapsilosis and Candida tropicalis pathogenic yeasts. AB - BACKGROUND: Candida parapsilosis and C. tropicalis increasingly compete with C. albicans-the most common fungal pathogen in humans-as causative agents of severe candidiasis in immunocompromised patients. In contrast to C. albicans, the pathogenic mechanisms of these two non-albicans Candida species are poorly understood. Adhesion of Candida yeast to host cells and the extracellular matrix is critical for fungal invasion of hosts. METHODS: The fungal proteins involved in interactions with extracellular matrix proteins were isolated from mixtures of beta-1,3-glucanase- or beta-1,6-glucanase-extractable cell wall-associated proteins by use of affinity chromatography and chemical cross-linking methods, and were further identified by liquid chromatography-coupled tandem mass spectrometry. RESULTS: In the present study, we characterized the binding of three major extracellular matrix proteins--fibronectin, vitronectin and laminin- to C. parapsilosis and C. tropicalis pseudohyphae. The major individual compounds of the fungal cell wall that bound fibronectin, vitronectin and laminin were found to comprise two groups: (1) true cell wall components similar to C. albicans adhesins from the Als, Hwp and Iff/Hyr families; and (2) atypical (cytoplasm-derived) surface-exposed proteins, including malate synthase, glucose 6-phosphate isomerase, 6-phosphogluconate dehydrogenase, enolase, fructose-1,6 bisphosphatase, transketolase, transaldolase and elongation factor 2. DISCUSSION: The adhesive abilities of two investigated non-albicans Candida species toward extracellular matrix proteins were comparable to those of C. albicans suggesting an important role of this particular virulence attribute in the pathogenesis of infections caused by C. tropicalis and C. parapsilosis. CONCLUSIONS: Our results reveal new insight into host-pathogen interactions during infections by two important, recently emerging, fungal pathogens. PMID- 26438064 TI - Weathering the storm: parental effort and experimental manipulation of stress hormones predict brood survival. AB - BACKGROUND: Unpredictable and inclement weather is increasing in strength and frequency, challenging organisms to respond adaptively. One way in which animals respond to environmental challenges is through the secretion of glucocorticoid stress hormones. These hormones mobilize energy stores and suppress non-essential physiological and behavioral processes until the challenge passes. To investigate the effects of glucocorticoids on reproductive decisions, we experimentally increased corticosterone levels (the primary glucocorticoid in birds) in free living female tree swallows, Tachycineta bicolor, during the chick-rearing stage. Due to an unprecedented cold and wet breeding season, 90 % of the nests in our study population failed, which created a unique opportunity to test how challenging environmental conditions interact with the physiological mechanisms underlying life-history trade-offs. RESULTS: We found that exogenous corticosterone influenced the regulation of parental decisions in a context dependent manner. Control and corticosterone-treated females had similar brood failure rates under unfavorable conditions (cold and rainy weather), but corticosterone treatment hastened brood mortality under more favorable conditions. Higher female nest provisioning rates prior to implantation were associated with increased probability of brood survival for treatment and control groups. However, higher pre-treatment male provisioning rates were associated with increased survival probability in the control group, but not the corticosterone-treated group. CONCLUSIONS: These findings reveal complex interactions between weather, female physiological state, and partner parental investment. Our results also demonstrate a causal relationship between corticosterone concentrations and individual reproductive behaviors, and point to a mechanism for why naturally disturbed populations, which experience multiple stressors, could be more susceptible and unable to respond adaptively to changing environmental conditions. PMID- 26438066 TI - Standing genetic variation as a major contributor to adaptation in the Virginia chicken lines selection experiment. AB - BACKGROUND: Artificial selection provides a powerful approach to study the genetics of adaptation. Using selective-sweep mapping, it is possible to identify genomic regions where allele-frequencies have diverged during selection. To avoid false positive signatures of selection, it is necessary to show that a sweep affects a selected trait before it can be considered adaptive. Here, we confirm candidate, genome-wide distributed selective sweeps originating from the standing genetic variation in a long-term selection experiment on high and low body weight of chickens. RESULTS: Using an intercross between the two divergent chicken lines, 16 adaptive selective sweeps were confirmed based on their association with the body weight at 56 days of age. Although individual additive effects were small, the fixation for alternative alleles across the loci contributed at least 40 % of the phenotypic difference for the selected trait between these lines. The sweeps contributed about half of the additive genetic variance present within and between the lines after 40 generations of selection, corresponding to a considerable portion of the additive genetic variance of the base population. CONCLUSIONS: Long-term, single-trait, bi-directional selection in the Virginia chicken lines has resulted in a gradual response to selection for extreme phenotypes without a drastic reduction in the genetic variation. We find that fixation of several standing genetic variants across a highly polygenic genetic architecture made a considerable contribution to long-term selection response. This provides new fundamental insights into the dynamics of standing genetic variation during long-term selection and adaptation. PMID- 26438067 TI - Hypovolemic men and women regulate blood pressure differently following exposure to artificial gravity. AB - PURPOSE: In addition to serious bone, vestibular, and muscle deterioration, space flight leads to cardiovascular dysfunction upon return to gravity. In seeking a countermeasure to space flight-induced orthostatic intolerance, we previously determined that exposure to artificial gravity (AG) training in a centrifuge improved orthostatic tolerance of ambulatory subjects. This protocol was more effective in men than women and more effective when subjects exercised. METHODS: We now determine the orthostatic tolerance limit (OTL) of cardiovascularly deconditioned (furosemide) men and women on one day following 90 min of AG compared to a control day (90 min of head-down bed rest, HDBR). RESULTS: There were three major findings: a short bout of artificial gravity improved orthostatic tolerance of hypovolemic men (30 %) and women (22 %). Men and women demonstrated different mechanisms of cardiovascular regulation on AG and HDBR days; women maintained systolic blood pressure the same after HDBR and AG exposure while men's systolic pressure dropped (11 +/- 2.9 mmHg) after AG. Third, as presyncopal symptoms developed, men's and women's cardiac output and stroke volume dropped to the same level on both days, even though the OTL test lasted significantly longer on the AG day, indicating cardiac filling as a likely variable to trigger presyncope. CONCLUSIONS: (1) Even with gender differences, AG should be considered as a space flight countermeasure to be applied to astronauts before reentry into gravity, (2) men and women regulate blood pressure during an orthostatic stress differently following exposure to artificial gravity and (3) the trigger for presyncope may be cardiac filling. PMID- 26438065 TI - P-cadherin and the journey to cancer metastasis. AB - P-cadherin is a classical cell-to-cell adhesion molecule with a homeostatic function in several normal tissues. However, its behaviour in the malignant setting is notably dependent on the cellular context. In some tumour models, such as melanoma and oral squamous cell carcinoma, P-cadherin acts as a tumour suppressor, since its absence is associated with a more aggressive cancer cell phenotype; nevertheless, the overexpression of this molecule is linked to significant tumour promoting effects in the breast, ovarian, prostate, endometrial, skin, gastric, pancreas and colon neoplasms. Herein, we review the role of P-cadherin in cancer cell invasion, as well as in loco-regional and distant metastatic dissemination. We focus in P-cadherin signalling pathways that are activated to induce invasion and metastasis, as well as cancer stem cell properties. The signalling network downstream of P-cadherin is notably dependent on the cellular and tissue context and includes the activation of integrin molecules, receptor tyrosine kinases, small molecule GTPases, EMT transcription factors, and crosstalk with other cadherin family members. As new oncogenic molecular pathways mediated by P-cadherin are uncovered, putative therapeutic options can be tested, which will allow for the targeting of invasion or metastatic disease, depending on the tumour model. PMID- 26438069 TI - Editorial: From Extended Spectrum beta-Lactamases to Carbapenemase: The Never Ending Challenge Against Gram-Negative Bacteria. PMID- 26438068 TI - The effect of prior walking on coronary heart disease risk markers in South Asian and European men. AB - PURPOSE: Heart disease risk is elevated in South Asians possibly due to impaired postprandial metabolism. Running has been shown to induce greater reductions in postprandial lipaemia in South Asian than European men, but the effect of walking in South Asians is unknown. METHODS: Fifteen South Asian and 14 white European men aged 19-30 years completed two, 2-day trials in a randomised crossover design. On day 1, participants rested (control) or walked for 60 min at approximately 50 % maximum oxygen uptake (exercise). On day 2, participants rested and consumed two high-fat meals over a 9-h period during which 14 venous blood samples were collected. RESULTS: South Asians exhibited higher postprandial triacylglycerol [geometric mean (95 % confidence interval) 2.29 (1.82 to 2.89) vs. 1.54 (1.21 to 1.96) mmol L(-1) h(-1)], glucose [5.49 (5.21 to 5.79) vs. 5.05 (4.78 to 5.33) mmol L(-1) h(-1)], insulin [32.9 (25.7 to 42.1) vs. 18.3 (14.2 to 23.7) uU mL(-1) h(-1)] and interleukin-6 [2.44 (1.61 to 3.67) vs. 1.04 (0.68 to 1.59) pg mL(-1) h(-1)] than Europeans (all ES >= 0.72, P <= 0.03). Between-group differences in triacylglycerol, glucose and insulin were not significant after controlling for age and percentage body fat. Walking reduced postprandial triacylglycerol [1.79 (1.52 to 2.12) vs. 1.97 (1.67 to 2.33) mmol L(-1) h(-1)] and insulin [21.0 (17.0 to 26.0) vs. 28.7 (23.2 to 35.4) uU mL(-1) h(-1)] (all ES >= 0.23. P <= 0.01), but group differences were not significant. CONCLUSIONS: Healthy South Asians exhibited impaired postprandial metabolism compared with white Europeans, but these differences were diminished after controlling for potential confounders. The small-moderate reduction in postprandial triacylglycerol and insulin after brisk walking was not different between the ethnicities. PMID- 26438070 TI - Acute liver failure and seizures as a consequence of regorafenib exposure in advanced rectal cancer. AB - BACKGROUND: Regorafenib is a multi-targeted tyrosine kinase inhibitor approved for use in refractory colorectal cancer. We report the first case of seizures secondary to acute liver failure, shortly after initiation of regorafenib in a patient with advanced rectal carcinoma. CASE PRESENTATION: A 64 year-old Caucasian female presented with confusion and generalized tonic-clonic seizures, 5 days after initiation of regorafenib for advanced rectal cancer. Investigations revealed significant elevations in bilirubin and alanine aminotransferase. No other cause for seizures and liver dysfunction were found. After interruption of regorafenib, no further seizures occurred, the symptoms of confusion resolved and liver function returned to normal. CONCLUSIONS: We report the first case of regorafenib-induced acute liver failure resulting in seizures. We suggest early monitoring for side effects, both clinically and biochemically after initiation of regorafenib. PMID- 26438071 TI - IMRT and 3D conformal radiotherapy with or without elective nodal irradiation in locally advanced NSCLC: A direct comparison of PET-based treatment planning. AB - AIM: The potential of intensity-modulated radiation therapy (IMRT) as opposed to three-dimensional conformal radiotherapy (3D-CRT) is analyzed for two different concepts of fluorodeoxyglucose positron emission tomography (FDG PET)-based target volume delineation in locally advanced non-small cell lung cancer (LA NSCLC): involved-field radiotherapy (IF-RT) vs. elective nodal irradiation (ENI). METHODS: Treatment planning was performed for 41 patients with LA-NSCLC, using four different planning approaches (3D-CRT-IF, 3D-CRT-ENI, IMRT-IF, IMRT-ENI). ENI included a boost irradiation after 50 Gy. For each plan, maximum dose escalation was calculated based on prespecified normal tissue constraints. The maximum prescription dose (PD), tumor control probability (TCP), conformal indices (CI), and normal tissue complication probabilities (NTCP) were analyzed. RESULTS: IMRT resulted in statistically significant higher prescription doses for both target volume concepts as compared with 3D-CRT (ENI: 68.4 vs. 60.9 Gy, p < 0.001; IF: 74.3 vs. 70.1 Gy, p < 0.03). With IMRT-IF, a PD of at least 66 Gy was achieved for 95 % of all plans. For IF as compared with ENI, there was a considerable theoretical increase in TCP (IMRT: 27.3 vs. 17.7 %, p < 0.00001; 3D CRT: 20.2 vs. 9.9 %, p < 0.00001). The esophageal NTCP showed a particularly good sparing with IMRT vs. 3D-CRT (ENI: 12.3 vs. 30.9 % p < 0.0001; IF: 15.9 vs. 24.1 %; p < 0.001). CONCLUSION: The IMRT technique and IF target volume delineation allow a significant dose escalation and an increase in TCP. IMRT results in an improved sparing of OARs as compared with 3D-CRT at equivalent dose levels. PMID- 26438072 TI - Reaching their potential: Perceived impact of a collaborative academic-clinical partnership programme for early career nurses in New Zealand. AB - BACKGROUND: The dynamic nature of healthcare ensures that early career nurses enter an uncertain and complex world of practice and consequently require support to develop their practice, build confidence and reach their potential. The New Zealand Nurse Entry to Practice programme for registered nurses in their first year of practice has been operating since 2005 to enable safe and confident practice, improve the quality of care, and positively impact on recruitment and retention. This academic and clinical programme was offered as a partnership between a university and a clinical provider with postgraduate academic credits gained. AIM: The aim of this study was to explore the perceived impact of postgraduate university education for early career nurses in one regional health area of New Zealand. METHODS: Participants were registered nurses who had completed the early career nurse programme and their clinical preceptors. The research was conducted via an online survey of 248 nurses and three focus groups to explore how the programme was experienced and its impact on knowledge and practice. RESULTS: Early career nurses and their preceptors found that the programme enables improved knowledge and skills of patient assessment, application of critical thinking to clinical practice, perceived improvement in patient care delivery and outcomes, enhanced interprofessional communication and knowledge sharing, and had a positive impact on professional awareness and career planning. CONCLUSIONS: This clinical-academic partnership positively impacted on the clinical practice and transition experience of early career nurses and was closely aligned to an organization's strategic plan for nursing workforce development. PMID- 26438073 TI - An evaluation of the effectiveness of a planned training program for nurses on administering intramuscular injections into the ventrogluteal site. AB - BACKGROUND: Nurses commonly use the dorsogluteal area for administering intramuscular injections. Since the dorsogluteal area has the potential of leading to serious complications, the ventrogluteal area is recommended as the best alternative. OBJECTIVE: This study was carried out to determine the level of knowledge nurses have about the ventrogluteal site and the effects of the training provided in this context. METHOD AND DESIGN: The study was of quasi experimental design with a single group based on a pre-test/post-test time sequence and was conducted with 81 nurses who consented to participate in the research at a University Hospital. Data in the research were collected with a questionnaire on the identifying features of the nurses and a questionnaire that contained statements about the ventrogluteal area. RESULTS: The results of the study revealed that before the training, 76.5% of the nurses most commonly used the dorsogluteal area and 7.4% the ventrogluteal region. Four months after the training, however, it was found that the rate of nurses using the dorsogluteal area had fallen (48.1%) while the rate of using the ventrogluteal site rose (34.6%). It was seen that there was a significant difference between the nurses' pre-training and post-training knowledge scores and their scores four months after the training. CONCLUSION: It was concluded that the training offered the nurses about the ventrogluteal area had a positive impact on their knowledge and practices and that the nurses came away from the training with raised awareness about the subject and an increased level of knowledge. PMID- 26438074 TI - Atlas-based analysis of 4D flow CMR: automated vessel segmentation and flow quantification. AB - BACKGROUND: Flow volume quantification in the great thoracic vessels is used in the assessment of several cardiovascular diseases. Clinically, it is often based on semi-automatic segmentation of a vessel throughout the cardiac cycle in 2D cine phase-contrast Cardiovascular Magnetic Resonance (CMR) images. Three dimensional (3D), time-resolved phase-contrast CMR with three-directional velocity encoding (4D flow CMR) permits assessment of net flow volumes and flow patterns retrospectively at any location in a time-resolved 3D volume. However, analysis of these datasets can be demanding. The aim of this study is to develop and evaluate a fully automatic method for segmentation and analysis of 4D flow CMR data of the great thoracic vessels. METHODS: The proposed method utilizes atlas-based segmentation to segment the great thoracic vessels in systole, and registration between different time frames of the cardiac cycle in order to segment these vessels over time. Additionally, net flow volumes are calculated automatically at locations of interest. The method was applied on 4D flow CMR datasets obtained from 11 healthy volunteers and 10 patients with heart failure. Evaluation of the method was performed visually, and by comparison of net flow volumes in the ascending aorta obtained automatically (using the proposed method), and semi-automatically. Further evaluation was done by comparison of net flow volumes obtained automatically at different locations in the aorta, pulmonary artery, and caval veins. RESULTS: Visual evaluation of the generated segmentations resulted in good outcomes for all the major vessels in all but one dataset. The comparison between automatically and semi-automatically obtained net flow volumes in the ascending aorta resulted in very high correlation (r (2)=0.926). Moreover, comparison of the net flow volumes obtained automatically in other vessel locations also produced high correlations where expected: pulmonary trunk vs. proximal ascending aorta (r (2)=0.955), pulmonary trunk vs. pulmonary branches (r (2)=0.808), and pulmonary trunk vs. caval veins (r (2)=0.906). CONCLUSIONS: The proposed method allows for automatic analysis of 4D flow CMR data, including vessel segmentation, assessment of flow volumes at locations of interest, and 4D flow visualization. This constitutes an important step towards facilitating the clinical utility of 4D flow CMR. PMID- 26438075 TI - Prospectively defined murine mesenchymal stem cells inhibit Klebsiella pneumoniae induced acute lung injury and improve pneumonia survival. AB - BACKGROUND: Numerous studies have described the immunosuppressive capacity of mesenchymal stem cells (MSC) but these studies use mixtures of heterogeneous progenitor cells for in vitro expansion. Recently, multipotent MSC have been prospectively identified in murine bone marrow (BM) on the basis of PDFGRa(+) SCA1(+) CD45(-) TER119(-) (PalphaS) expression but the immunomodulatory capacity of these MSC is unknown. METHODS: We isolated PalphaS MSC by high-purity FACS sorting of murine BM and after in vitro expansion we analyzed the in vivo immunomodulatory activity during acute pneumonia. PalphaS MSC (1 * 10(6)) were applied intratracheally 4 h after acute respiratory Klebsiella pneumoniae induced infection. RESULTS: PalphaS MSC treatment resulted in significantly reduced alveolitis and protein leakage in comparison to mock-treated controls. PalphaS MSC-treated mice exhibited significantly reduced alveolar TNF-alpha and IL-12p70 expression, while IL-10 expression was unaffected. Dissection of respiratory dendritic cell (DC) subsets by multiparameter flow cytometry revealed significantly reduced lung DC infiltration and significantly reduced CD86 costimulatory expression on lung CD103(+) DC in PalphaS MSC-treated mice. In the post-acute phase of pneumonia, PalphaS MSC-treated animals exhibited significantly reduced respiratory IL-17(+) CD4(+) T cells and IFN-gamma(+) CD4(+) T cells. Moreover, PalphaS MSC treatment significantly improved overall pneumonia survival and did not increase bacterial load. CONCLUSION: In this study we demonstrated for the first time the feasibility and in vivo immunomodulatory capacity of prospectively defined MSC in pneumonia. PMID- 26438076 TI - The anti-aging properties of a human placental hydrolysate combined with dieckol isolated from Ecklonia cava. AB - BACKGROUNDS: In the present study, we aimed to examine the anti-aging properties of human placental hydrolysate (HPE) and dieckol (DE) from Ecklonia cava against free radical scavenging, muscle hypertrophy-related follistatin mRNA expression, amelioration of cognition-related genes and proteins, inhibition of collagenase regulating genes, and elastinase activity. METHODS: The anti-aging effects were examined in human fibroblast (CCD986sk), mouse myoblast (C2C12), and neuroblastoma (N2a) cell models, by employing various assays such as 2,2-diphenyl 1-picrylhydrazyl hydrate (DPPH) scavenging, hydroxyl radical-mediated oxidation, quantitative real-time polymerase chain reaction, enzyme activity, and immunocytochemistry observation. RESULTS: Our results show that HPE combined with DE (HPE:DE) strongly scavenged DPPH radicals and protected proteins against degradation by hydroxyl radical attack. HPE:DE effectively inhibited matrix metalloproteinase-1 expression, protein kinase C alpha expression, and elastinase activity. Furthermore, HPE:DE improved the expression of cognition-related genes (choline acetyltransferase and vesicular acetylcholine transporter). These events may proactively contribute to retard the aging processes and the abrupt physiological changes probably induced by mitochondrial dysfunction with aging. CONCLUSIONS: Based on these findings, we conclude that the combined treatment of HPE:DE may be useful for anti-aging therapy in which the accumulation of oxidative damage is the main driving force. PMID- 26438077 TI - Development of a bead-based Luminex assay using lipopolysaccharide specific monoclonal antibodies to detect biological threats from Brucella species. AB - BACKGROUND: Brucella, a Gram-negative bacterium, is classified as a potential bioterrorism agent mainly due to the low dose needed to cause infection and the ability to transmit the bacteria via aerosols. Goats/sheep, cattle, pigs, dogs, sheep and rodents are infected by B. melitensis, B. abortus, B. suis, B. canis, B. ovis and B. neotomae, respectively, the six classical Brucella species. Most human cases are caused by B. melitensis and B. abortus. Our aim was to specifically detect Brucellae with 'smooth' lipopolysaccharide (LPS) using a highly sensitive monoclonal antibody (mAb) based immunological assay. METHODS: To complement molecular detection systems for potential bioterror agents, as required by international biodefense regulations, sets of mAbs were generated by B cell hybridoma technology and used to develop immunological assays. The combination of mAbs most suitable for an antigen capture assay format was identified and an immunoassay using the Luminex xMAP technology was developed. RESULTS: MAbs specific for the LPS O-antigen of Brucella spp. were generated by immunising mice with inactivated B. melitensis or B. abortus cells. Most mAbs recognised both B. melitensis and B. abortus and antigen binding was not impeded by inactivation of the bacterial cells by gamma irradiation, formalin or heat treatment, a step required to analyse the samples immunologically under biosafety level two conditions. The Luminex assay recognised all tested Brucella species with 'smooth' LPS with detection limits of 2*10(2) to 8*10(4) cells per mL, depending on the species tested. Milk samples spiked with Brucella spp. cells were identified successfully using the Luminex assay. In addition, the bead-based immunoassay was integrated into a multiplex format, allowing for simultaneous, rapid and specific detection of Brucella spp., Bacillus anthracis, Francisella tularensis and Yersinia pestis within a single sample. CONCLUSION: Overall, the robust Luminex assay should allow detection of Brucella spp. in both natural outbreak and bio-threat situations. PMID- 26438078 TI - Oral albuterol to treat symptomatic bradycardia in acute spinal cord injury. PMID- 26438080 TI - Children's implicit recall of junk food, alcohol and gambling sponsorship in Australian sport. AB - BACKGROUND: In Australia, sport is saturated by the promotion of junk food, alcohol and gambling products. This is particularly evident on player jerseys. The effect of this advertising on children, who are exposed to these messages while watching sport, has not been thoroughly investigated. The aim of this research study was to investigate: (1) the extent to which children implicitly recalled shirt sponsors with the correct sporting team; (2) whether children associated some types of sponsors with certain sporting codes more than others; and (3) whether age of the children influenced the correct recall of sponsoring brands and teams. METHOD: This experimental study conducted in New South Wales, Australia used projective techniques to measure the implicit recall of team sponsorship relationships of 85 children aged 5-12 years. Participants were asked to arrange two sets of magnets - one which contained sporting teams and one which contained brand logos - in the manner deemed most appropriate by them. Children were not given any prompts relating to sporting sponsorship relationships. RESULTS: Three quarters (77 %) of the children were able to identify at least one correct shirt sponsor. Children associated alcohol and gambling brands more highly with the more popular sporting code, the National Rugby League compared to the Australian Football League sporting code. Results showed that age had an effect on number of shirt sponsors correctly recalled with 9-12 year olds being significantly more likely than 5-8 year olds to correctly identify team sponsors. CONCLUSIONS: Given children's ability to implicitly recall shirt sponsors in a sporting context, Australian sporting codes should examine their current sponsorship relationships to reduce the number of unhealthy commodity shirt sponsors. While there is some regulation that protects children from the marketing of unhealthy commodity products, these findings suggest that children are still exposed to and recall these sponsorship relationships. Results suggest that the promotion of unhealthy commodity products during sporting matches is contributing to increased awareness amongst children of unhealthy commodity brands. Further investigation is required to examine the extent and impact of marketing initiatives during televised sporting matches on children. PMID- 26438079 TI - ABCB1 C3435T polymorphism and the lipid-lowering response in hypercholesterolemic patients on statins: a meta-analysis. AB - BACKGROUND: A number of researches have evaluated the association between the ABCB1 polymorphism and the lipid-lowering response of statins, but the results have been inconclusive. To examine the lipid-lowering efficacy and safety associated with the ABCB1 C3435T polymorphism in hypercholesterolemic patients receiving statin, all available studies were included in this meta-analysis. METHODS: A systematic search for eligible studies in the Cochrane library database, Scopus and PubMed was performed. Articles meeting the inclusion criteria were comprehensively reviewed, and the available data were accumulated by the meta-analysis. RESULTS: The results indicated that the comparisons of CC+CT vs. TT were associated with a significant elevation of the serum HDL-C levels after statin treatment (CC+CT vs. TT: MD, 2.46; 95 % CI, 0.36 to 4.55; P = 0.02), and the ABCB1 C3435T variant in homozygotes was correlated with decreases in LDL-C (CC vs. TT: MD, 2.29; 95 % CI, 0.37 to 4.20; P = 0.02) as well as TC (CC vs. TT: MD, 3.05; 95 % CI, 0.58 to 5.53; P = 0.02) in patients treated with statin. However, we did not observe a significant association in the TG group or an association between other genetic models serum lipid parameters. In addition, statin treatment more than 5 months led to a higher risk of muscle toxicity. CONCLUSIONS: The evidence from the meta-analysis demonstrated that the ABCB1 C3435T polymorphism may represent a pharmacogenomic biomarker for predicting treatment outcomes in patients on statins and that statin treatment for more than 5 months can increase the risk of myopathy. PMID- 26438081 TI - Standardization of hernia surgery. PMID- 26438082 TI - Minimally invasive surgery for congenital diaphragmatic hernia: a meta-analysis. AB - OBJECTIVES: To compare the safety and efficacy of minimally invasive surgery (MIS) with traditional open surgical approach for congenital diaphragmatic hernia (CDH). METHODS: A literature search was performed using the PubMed database, Embase, and the Cochrane central register of controlled trials using a defined set of criteria. The outcomes, which include post-operative mortality, incidence of hernia recurrence, rates of patch use and complications, were analyzed. RESULTS: We investigated nine studies, which included 507 patients. All studies were non-randomized historical control trials. The MIS group had a significantly lower rate of post-operative death with a risk ratio of 0.26 [95% confidence interval (CI) 0.10-0.68; p = 0.006] but a greater incidence of hernia recurrence with a risk ratio of 3.42 (95% CI 1.98-5.88; p < 0.00001). Rates of prosthetic patch use were similar between the two groups. Fewer cases of surgical complications were found in the MIS group with a risk ratio of 0.66 (95% CI 0.47 0.94; p = 0.02). CONCLUSIONS: MIS for CDH repair is associated with lower post operative mortality and morbidity compared with traditional open repair. Although rate of patch use appears to be comparable, the increased risk of CDH recurrence should not be ignored. The lack of well-controlled prospective trials still limits strong evaluations of the two surgical techniques. PMID- 26438085 TI - Challenges, progress, and new directions in stem cell therapies: a new section launched in Clinical and Translational Medicine. PMID- 26438084 TI - Analogue peptides for the immunotherapy of human acute myeloid leukemia. AB - The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies. PMID- 26438083 TI - Association of Hearing Impairment With Incident Frailty and Falls in Older Adults. AB - OBJECTIVE: We aimed to determine whether hearing impairment (HI) in older adults is associated with the development of frailty and falls. METHOD: Longitudinal analysis of observational data from the Health, Aging and Body Composition study of 2,000 participants aged 70 to 79 was conducted. Hearing was defined by the pure-tone-average of hearing thresholds at 0.5, 1, 2, and 4 kHz in the better hearing ear. Frailty was defined as a gait speed of <0.60 m/s and/or inability to rise from a chair without using arms. Falls were assessed annually by self report. RESULTS: Older adults with moderate-or-greater HI had a 63% increased risk of developing frailty (adjusted hazard ratio [HR] = 1.63, 95% confidence interval [CI] = [1.26, 2.12]) compared with normal-hearing individuals. Moderate or-greater HI was significantly associated with a greater annual percent increase in odds of falling over time (9.7%, 95% CI = [7.0, 12.4] compared with normal hearing, 4.4%, 95% CI = [2.6, 6.2]). DISCUSSION: HI is independently associated with the risk of frailty in older adults and with greater odds of falling over time. PMID- 26438086 TI - Cell surface interaction of annexin A2 and galectin-3 modulates epidermal growth factor receptor signaling in Her-2 negative breast cancer cells. AB - Overexpression and activation of tyrosine kinase receptors like EGFR and Src regulate the progression and metastasis of Her-2 negative breast cancer. Recently we have reported the role of cell membrane interaction of phospholipid-binding protein annexin A2 (AnxA2) and EGFR in regulating cellular signaling in the activation of angiogenesis, matrix degradation, invasion, and cancer metastasis. Beta-galactoside-specific animal lectin galectin-3 is an apoptosis inhibitor, and cell surface-associated extracellular galectin-3 also has a role in cell migration, cancer progression, and metastasis. Similar expression pattern and membrane co-localization of these two proteins made us to hypothesize in the current study that galectin-3 and AnxA2 interaction is critical for Her-2 negative breast cancer progression. By various experimental analyses, we confirm that glycosylated AnxA2 at the membrane surface interacts with galectin-3. N linked glycosylation inhibitor tunicamycin treatment convincingly blocked AnxA2 membrane translocation and its association with galectin-3. To analyze whether this interaction has any functional relevance, we tried to dissociate this interaction with purified plant lectin from chickpea (Cicer arietinum agglutinin). This highly specific 30 kDa plant lectin could dissociate AnxA2 from endogenous lectin galectin-3 interaction at the cell surface. This dissociation could down-regulate Bcl-2 family proteins, cell proliferation, and migration simultaneously triggering cell apoptosis. Targeting this interaction of membrane surface glycoprotein and its animal lectin in Her-2 negative breast cancer may be of therapeutic value. PMID- 26438087 TI - Comparative analysis of four disease prediction models of Parkinson's disease. AB - Parkinson's disease (PD) is a multi-factorial disorder with high-penetrant mutations accounting for small percentage of PD. Our previous studies demonstrated individual association of genetic variants in folate, xenobiotic, and dopamine metabolic pathways with PD risk. The rational of the study was to develop a risk prediction model for PD using these genetic polymorphisms along with synuclein (SNCA) polymorphism. We have generated additive, multifactor dimensionality reduction (MDR), recursive partitioning (RP), and artificial neural network (ANN) models using 21 SNPs as inputs and disease outcome as output. The clinical utility of all these models was assessed by plotting receiver operating characteristics curves where in area under the curve (AUC) was used as an index of diagnostic utility of the model. The additive model was the simplest and exhibited an AUC of 0.72. The MDR model showed significant gene-gene interactions between SNCA, DRD4VNTR, and DRD2A polymorphisms. The RP model showed SHMT C1420T as important determinant of PD risk. This variant allele was found to be protective and this protection was nullified by MTRR A66G. Inheritance of SHMT wild allele and SNCA intronic polymorphism was shown to increase the risk of PD. The ANN model showed higher diagnostic utility (AUC = 0.86) compared to all the models and was able to explain 56.6% cases of sporadic PD. To conclude, the ANN model developed using SNPs in folate, xenobiotic, and dopamine pathways along with SNCA has higher clinical utility in predicting PD risk compared to other models. PMID- 26438088 TI - Percutaneous dilatational tracheostomy (PDT) in trauma patients: a safe procedure. AB - PURPOSE: Percutaneous dilatational tracheostomy (PDT) is a standard procedure routinely performed on intensive care units. While complication rates and long term outcomes have been studied in different patient populations, there are few studies known to these authors involving PDT in trauma patients and the complications which may result. METHODS: Between March 2007 and August 2013, all instances and peri-procedural complications during PDT occurring on the trauma intensive care unit, a unit specialized in the care of injured patients and especially polytrauma patients, were documented. PDTs were performed by a surgeon with the assistance and supervision of another, using bronchoscopic guidance performed by the respiratory medicine department. RESULTS: 289 patients were included in the study, 225 men and 64 women with a mean age of 49 +/- 21 years. Complications occurred in 37.4 % of cases. The most common complication, bleeding, occurred in 26.3 % of patients ranging from little to severe bleeding. Fracture of tracheal cartilage occurred in 6 % of PDT cases. Additional complications such as dislocation of the guidewire, hypotension, and oxygen desaturation were observed. Most complications did not require treatment. The second tracheal intercartilaginous space was successfully intubated in 82 % of cases. CONCLUSIONS: PDT is a safe procedure in trauma patients. When considering the severity of complications such as major blood loss, pneumothorax, or death, this evidence suggests that PDT is safer in trauma patients compared to other patient cohorts. PMID- 26438089 TI - Twenty years of experience with perineal injury in children. AB - PURPOSE: The aim of this study was to review our 20 years of experience determining the common mechanisms of perineal trauma and initial management to evaluate the effects of classification for treatment. METHODS: A total of 75 children with perineal injuries were reviewed retrospectively, including patient demographics, mechanism of injury, associated injuries, injury severity score, presenting symptoms and methods of diagnosis and treatment. RESULTS: Amongst the 75 children (55 females and 20 males; mean age, 8 years), fall from height, followed by motor vehicle crash and sexual abuse were the most common reasons for injury. The most common symptom on presentation was bleeding, followed by abdominopelvic pain and tenderness. Eleven patients were allowed to heal secondarily, and 64 were examined under general anaesthesia. The affected area was repaired in 48, further diagnostic tools were needed in 20 and 11 cystoscopic, 10 rectoscopic, and 5 vaginoscopic evaluations were performed. Six patients with full-thickness injuries that extended to the peritoneum were treated with colostomy, and all were victims of motor vehicle crashes. CONCLUSION: The genital injury score is a useful genital trauma scale for predicting anogenital injury severity. Identifying the mechanism and severity of perineal and associated injuries under general anaesthesia may facilitate appropriate classification and management. PMID- 26438090 TI - [Ultrasound elastography]. AB - Noninvasive, ultrasound-based methods for visualizing and measuring tissue elasticity are becoming more and more common in routine practice. Using hepatic shear wave elastography, cut-off levels can help to detect the degree of relevant fibrosis (F >= 2) with a diagnostic accuracy using the area under the reader operating characteristic (AUROC) of 87 % and cirrhosis (F = 4, AUROC 93 %). Normal values virtually exclude liver cirrhosis (negative predictive value up to 97 %) and high shear wave velocities predict complications in the course of primary sclerosing cholangitis, liver cirrhosis and chronic hepatitis B or C. Elastography is of no relevant help in the differentiation of the dignity of hepatic lesions. Concerning thyroid or breast lesions, low shear wave velocities are indicative of benign lesions and in contrast, high velocities of malignant lesions. A differentiation between benign and malignant thyroid nodules is performed by elastography with a sensitivity of 89 % and a specificity of 82 %. In breast lesions a differentiation of nodes can be improved with elastography compared to B-mode ultrasound alone with a sensitivity of 97 % and a specificity of 83 %. Invasive biopsy punctures can therefore be specifically performed or can be omitted. Due to several influencing factors, in particular during liver elastography, the measurements need to be interpreted in the clinical context. In summary, ultrasound-based elastography provides helpful information for the detection of hepatic fibrosis and for further characterization of thyroid or breast lesions in addition to classical techniques, such as B-mode imaging and color Doppler. PMID- 26438091 TI - [Optoacoustic imaging]. AB - CLINICAL/METHODICAL ISSUE: Imaging modalities play an increasing role in today's medical diagnostics. Among them, ultrasound (US) is one the most widespread techniques although it has relatively poor soft tissue contrast. Furthermore, US is poorly suited as a modality for molecular imaging (MI). STANDARD RADIOLOGICAL METHODS: Methods such as Doppler and contrast-enhanced US (CEUS) allow functional imaging of the vasculature; however, ultrasound-based MI remains limited to the vascular network due to the size of available contrast agents. METHODICAL INNOVATIONS: Optoacoustic imaging combines the benefits of optics (high contrast) with those of acoustics (low scattering and high resolution). In this technique, signals are generated in tissue with high contrast depending on the local optical absorption coefficient and detected with an acoustic procedure. PERFORMANCE: Optoacoustic imaging can intrinsically be scaled in terms of resolution and is therefore usable in various applications from in vitro microscopy, to preclinical small animal imaging up to clinical imaging. With a resolution in the range of clinical ultrasound systems (100-400 um), highly scattering tissue can be imaged up to several centimeters in depth. ACHIEVEMENTS: In contrast to conventional ultrasound imaging, optoacoustic techniques are highly suitable for MI. Various contrast agents as well as different technical implementations of the approach have already been preclinically evaluated. The technique is currently close to being transferred to clinical implementation and the first studies have already been started. PRACTICAL RECOMMENDATIONS: Clinical studies are ongoing with respect to early diagnosis of breast cancer and arthritis. Furthermore, the suitability of the technique for skin imaging is currently being investigated. PMID- 26438092 TI - [Transcranial focused ultrasound: Neurological applications of magnetic resonance guided high-intensity focused ultrasound]. AB - BACKGROUND: Ultrasound surgery uses the thermal effects of the absorption of high intensity focused ultrasound to induce localized thermal ablation of diseased tissue. The clinical introduction in recent years was made possible by a better understanding of the interactions of ultrasound with biological structures and the resulting physiological changes, major advances in the design of ultrasound applicators and the development of imaging modalities for reliable guiding the interventions. METHODS: Magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS) is especially appealing for applications in the brain where target volumes have to be accessed with high precision without inflicting collateral damage to surrounding healthy tissue. In 2013 a MRgFUS system was CE certified for the treatment of functional neurological disorders, such as chronic neuropathic pain and movement disorders. Currently, some 400 patients have been treated worldwide using this system, which is also undergoing clinical testing for the treatment of primary brain tumors and brain metastases. CONCLUSION: This article describes the technical basis of transcranial focused ultrasound neurosurgery and summarizes the current clinical experience of this new class of image-guided, non-invasive interventions. PMID- 26438093 TI - [Ultrasound motion tracking for radiation therapy]. AB - BACKGROUND: In modern radiotherapy the radiation dose can be applied with an accuracy in the range of 1-2 mm provided that the exact position of the target is known. If, however, the target (the tumor) is located in the lungs or the abdomen, respiration or peristalsis can cause substantial movement of the target. METHODS: Various methods for intrafractional motion detection and compensation are currently under consideration or are already applied in clinical practice. Sonography is one promising option, which is now on the brink of clinical implementation. Ultrasound is particularly suited for this purpose due to the high soft tissue contrast, real-time capability, the absence of ionizing radiation and low acquisition costs. Ultrasound motion tracking is an image-based approach, i.e. the target volume or an adjacent structure is directly monitored and the motion is tracked automatically on the ultrasound image. Diverse algorithms are presently available that provide the real-time target coordinates from 2D as well as 3D images. Definition of a suitable sonographic window is not, however, trivial and a gold standard for positioning and mounting of the transducer has not yet been developed. Furthermore, processing of the coordinate information in the therapy unit and the dynamic adaptation of the radiation field are challenging tasks. CONCLUSION: It is not clear whether ultrasound motion tracking will become established in the clinical routine although all technical prerequisites can be considered as fulfilled, such that exciting progress in this field of research is still to be expected. PMID- 26438094 TI - [Molecular ultrasound imaging: Clinical applications]. AB - BACKGROUND: Contrast-enhanced ultrasound imaging is increasingly being used in clinical applications, particularly for cardiovascular and liver diagnostics. In this context the availability of new molecular contrast agents and the initiation of clinical translation promises new options for pathomechanistic diagnostics. MATERIAL AND METHODS: Analysis of the current literature on the development of molecular ultrasound contrast agents, the detection methods as well as the applications in preclinical and clinical studies. RESULTS: Molecular contrast agents have become established in preclinical research for the detection of inflammation and angiogenesis and have been continuously refined over recent years. They consist of gas filled microbubbles with a diameter of 1-5 um and the gas core is stabilized by a shell made of lipids, proteins or polymers to which biomolecules are conjugated that determine the target specificity. The agent BR55 is the first clinically evaluated molecular ultrasound contrast agent. It binds to the angiogenesis marker vascular endothelial growth factor receptor 2 (VEGFR2) and has been studied in several preclinical and clinical phase I and II studies on tumor diagnostics and characterization. CONCLUSION: Molecular ultrasound imaging is rapidly evolving in preclinical research for a broad field of applications. Translation to clinical practice is conceivable for many indications and is already ongoing for BR55. PMID- 26438095 TI - Cerebellum-inspired neural network solution of the inverse kinematics problem. AB - The demand today for more complex robots that have manipulators with higher degrees of freedom is increasing because of technological advances. Obtaining the precise movement for a desired trajectory or a sequence of arm and positions requires the computation of the inverse kinematic (IK) function, which is a major problem in robotics. The solution of the IK problem leads robots to the precise position and orientation of their end-effector. We developed a bioinspired solution comparable with the cerebellar anatomy and function to solve the said problem. The proposed model is stable under all conditions merely by parameter determination, in contrast to recursive model-based solutions, which remain stable only under certain conditions. We modified the proposed model for the simple two-segmented arm to prove the feasibility of the model under a basic condition. A fuzzy neural network through its learning method was used to compute the parameters of the system. Simulation results show the practical feasibility and efficiency of the proposed model in robotics. The main advantage of the proposed model is its generalizability and potential use in any robot. PMID- 26438096 TI - Real-time aortic pulse wave velocity measurement during exercise stress testing. AB - BACKGROUND: Pulse wave velocity (PWV), a measure of arterial stiffness, has been demonstrated to be an independent predictor of adverse cardiovascular outcomes. This can be derived non-invasively using cardiovascular magnetic resonance (CMR). Changes in PWV during exercise may reveal further information on vascular pathology. However, most known CMR methods for quantifying PWV are currently unsuitable for exercise stress testing. METHODS: A velocity-sensitive real-time acquisition and evaluation (RACE) pulse sequence was adapted to provide interleaved acquisition of two locations in the descending aorta (at the level of the pulmonary artery bifurcation and above the renal arteries) at 7.8 ms temporal resolution. An automated method was used to calculate the foot-to-foot transit time of the velocity pulse wave. The RACE method was validated against a standard gated phase contrast (STD) method in flexible tube phantoms using a pulsatile flow pump. The method was applied in 50 healthy volunteers (28 males) aged 22-75 years using a MR-compatible cycle ergometer to achieve moderate work rate (38 +/- 22 W, with a 31 +/- 12 bpm increase in heart rate) in the supine position. Central pulse pressures were estimated using a MR-compatible brachial device. Scan-rescan reproducibility was evaluated in nine volunteers. RESULTS: Phantom PWV was 22 m/s (STD) vs. 26 +/- 5 m/s (RACE) for a butyl rubber tube, and 5.5 vs. 6.1 +/- 0.3 m/s for a latex rubber tube. In healthy volunteers PWV increased with age at both rest (R(2) = 0.31 p < 0.001) and exercise (R(2) = 0.40, p < 0.001). PWV was significantly increased at exercise relative to rest (0.71 +/- 2.2 m/s, p = 0.04). Scan-rescan reproducibility at rest was -0.21 +/- 0.68 m/s (n = 9). CONCLUSIONS: This study demonstrates the validity of CMR in the evaluation of PWV during exercise in healthy subjects. The results support the feasibility of using this method in evaluating of patients with systemic aortic disease. PMID- 26438097 TI - Butylidenephthalide antagonizes cromakalim-induced systolic pressure reduction in conscious normotensive rats. AB - BACKGROUND: Butylidenephthalide (Bdph), a main constituent of Ligusticum chuanxiong Hort., was reported to have selective antianginal effect without changing blood pressure in conscious rat. Recently, we have observed that Bdph antagonized cromakalim, an ATP-dependent K(+) channel opener, in guinea-pig trachea. Thus, we were interested in investigating whether Bdph at the dose without changing blood pressure antagonized cromakalim-induced systolic pressure reduction in conscious rats. METHODS: Systolic arterial pressures of conscious rats were determined by using the indirect tail-cuff method. RESULTS: Bdph (30 mg/kg, i.p.) did not affect baseline systolic pressure in conscious normotensive and spontaneous hypertensive rats. Bdph (30 mg/kg, i.p.) also did not affect log dose-response curves of prazosin, clonidine and Bay K 8644, a Ca(2+) channel activator, in normotensive rats. However, Bdph (30 mg/kg, i.p.) similar to 4 aminopyridine (4-AP, 0.4 mg/kg, i.p.), a K(+) channel blocker, non-parallelly but surmountably, and partially similar to glibenclamide (GBC, 10 mg/kg, i.v.), an ATP-sensitive K(+) channel blocker, surmountably but not parallelly rightward shifted the log dose-systolic pressure reduction curve of cromakalim, an ATP sensitive K(+) channel opener, in normotensive rats, respectively. DISCUSSION: The antagonistic effect of Bdph against cromakalim was similar to that of 4-AP, a K+ channel blocker of Kv1 family, and partially similar to that of GBC, an ATP sensitive K+ channel blocker. Thus, Bdph may be a kind of K+ channel blockers, which have been reviewed to have a potential clinical use for Alzheimer disease. Indeed, Bdph has also been reported to reverse the deficits of inhibitory avoidance performance and improve memory in rats. Recently, 4-AP was reported to treat Episodic ataxia type 2 (EA2) which is a form of hereditary neurological disorder. Consistently, Bdph was recently reported to have antihyperglycemic activity in mice, since GBC is a powerful oral hypoglycemic drug. CONCLUSIONS: Bdph similar to 4-AP and partially similar to GBC may block Kv1 family and ATP sensitive K(+) channels in conscious normotensive rats. PMID- 26438098 TI - Discovery of a Novel Linoleate Dioxygenase of Fusarium oxysporum and Linoleate Diol Synthase of Colletotrichum graminicola. AB - Fungal pathogens constitute serious threats for many forms of life. The pathogenic fungi Fusarium and Colletotrichum and their formae speciales (f. spp.) infect many types of crops with severe consequences and Fusarium oxysporum can also induce keratitis and allergic conditions in humans. These fungi code for homologues of dioxygenase-cytochrome P450 (DOX-CYP) fusion proteins of the animal heme peroxidase (cyclooxygenase) superfamily. The objective was to characterize the enzymatic activities of the DOX-CYP homologue of Colletotrichum graminicola (EFQ34869) and the DOX homologue of F. oxysporum (EGU79548). The former oxidized oleic and linoleic acids in analogy with 7,8-linoleate diol synthases (LDSs), but with the additional biosynthesis of 8,11-dihydroxylinoleic acid. The latter metabolized fatty acids to hydroperoxides with broad substrate specificity. It oxidized 20:4n-6 and 18:2n-6 to hydroperoxides with an R configuration at the (n 10) positions, and other n-6 fatty acids in the same way. [11S-(2)H]18:2n-6 was oxidized with retention and [11R-(2)H]18:2n-6 with loss of deuterium, suggesting suprafacial hydrogen abstraction and oxygen insertion. Fatty acids of the n-3 series were oxidized less efficiently and often to hydroperoxides with an R configuration at both (n-10) and (n-7) positions. The enzyme spans 1426 amino acids with about 825 residues in the N-terminal domain with DOX homology and 600 residues at the C-terminal domain without homology to other enzymes. We conclude that fungal oxylipins can be formed by two novel subfamilies of cyclooxygenase related DOX. PMID- 26438099 TI - Involvement of Subcortical Brain Structures During Olfactory Stimulation in Multiple Chemical Sensitivity. AB - Multiple chemical sensitivity (MCS) patients usually react to odour compounds and the majority of neuroimaging studies assessed, especially at the cortical level, many olfactory-related correlates. The purpose of the present study was to depict sub-cortical metabolic changes during a neutral (NC) and pure (OC) olfactory stimulation by using a recently validated (18)F-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography/computer tomography procedure in 26 MCS and 11 healthy (HC) resting subjects undergoing a battery of clinical tests. Twelve subcortical volumes of interest were identified by the automated anatomical labeling library and normalized to thalamus FDG uptake. In both groups, when comparing OC to NC, the within-subjects ANOVA demonstrated a relative decreased metabolism in bilateral putamen and hippocampus and a relative increased metabolism in bilateral amygdala, olfactory cortex (OLF), caudate and pallidum. The between-groups ANOVA demonstrated in MCS a significant higher metabolism in bilateral OLF during NC. As in HC subjects negative correlations were found in OC between FDG uptake in bilateral amygdala and hippocampus and odor pleasantness scale, the latter positively correlated with MCS subjects' bilateral putamen FDG uptake in OC. Besides FDG uptake resemblances in both groups were found, for the first time a relative higher metabolism increase in OLF in MCS subjects at rest with respect to HC was found. When merging this aspect to the different subcortical FDG uptake correlations patterns in the two groups, the present study demonstrated to describe a peculiar metabolic index of behavioral and neurological aspects of MCS complaints. PMID- 26438100 TI - Brachial artery endothelial function is stable across the morning in young men. AB - BACKGROUND: The morning hours are associated with increased cardiovascular (CV) risk, and vascular endothelial function (VEF) is a strong predictor of CV disease. A diurnal rhythm in VEF has been established but the morning variation in VEF is not well-documented. Thus, we tested if VEF is impaired across the vulnerable morning period. METHODS: After overnight fasts, eight healthy men (age 26.3 +/- 3 yr) underwent assessments of VEF under standardized testing conditions every 2 h from 0700 to 1300 h on two separate days. VEF was estimated following 5 min brachial artery occlusions by hyperemic flow-mediated dilation (FMD). RESULTS: There was no significant change in FMD or hyperemic shear stimulus across the 6 h vulnerable period on either day, despite changes in physical activity and meals across these periods. CONCLUSION: In this healthy group of young men, VEF is stable across the vulnerable morning period when typical behaviors occurred (breakfast and physical activity). Future research should focus on the roles of sleep, physical inactivity during sleep and endogenous circadian rhythm in VEF. PMID- 26438102 TI - Acute dyspnea caused by a giant spindle cell lipoma of the larynx. AB - BACKGROUND: The spindle cell lipoma (SCL) is a special type of lipoma and this is very rare in the head and neck regions. There are only five reported cases exist, which describes the occurrence of a SCL in the hypopharynx. METHODS: Our case report presents a case of a very large SCL in the larynx. We want to describe that how we treated the patients and compared the situation with other reported cases. RESULTS: Intraoperatively, we found a tumor mass of 7 * 5 cm. It was successfully removed with the carbon dioxide laser. No postoperative complications occurred. CONCLUSIONS: Although SCL is a very rare diagnosis in the larynx/hypopharynx, it should be included in the differential diagnosis of larynx/hypopharynx tumors. Our case is the first report of such a large SCL in the larynx. The clinical symptoms occurred relatively late and ended up in an acute situation of stridor and dyspnea. PMID- 26438101 TI - Influence of adult role modeling on child/adolescent helmet use in recreational sledging: an observational study. AB - BACKGROUND: During recreational sledging (tobogganing), the head represents the most frequent injured body region with approximately one-third of all sledging injuries among children and adolescents. Whether children are wearing a helmet or not might be influenced on parental encouragement and role modeling of helmet use. Therefore, the aim of this study was to evaluate the impact of adult helmet use on child/adolescent helmet use in recreational sledging. METHODS: More than 500 adults sitting together with another adult or child/adolescent on a two seater sledge were interviewed during two winter seasons at the bottom of six sledging tracks on demographics, mean frequency of sledging per season, self estimated skill level, risk-taking behavior, and the use of a helmet. RESULTS: Total helmet use of all observed persons was 41.0 %. Helmet use among interviewed adults significantly increased with increasing age up to 45 years, frequency of sledging, and skill level, respectively. Helmet use of interviewed adults was 46.5 % if a child/adolescent was sitting on the same sledge and 29.8 % (odds ratios (OR): 2.1, 95 % confidence intervals (CI): 1.4-2.9, p < 0.001) when sledging together with another adult. Helmet use was 71.3 % among children/adolescents and 26.7 % among adults (OR: 6.8, 95 % CI: 4.6-10.1, p < 0.001) sitting on the same sledge as the interviewed person, respectively. CONCLUSION: Adults were wearing more often a helmet during recreational sledging when sitting together with a child/adolescent on the sledge. However, helmet use during sledging is clearly below 50 %. Thus, more intense educational campaigns on helmet use are urgently needed for tobogganists. PMID- 26438103 TI - Assessment of smoking for low bone mineral density in postmenopausal Turkish women. AB - OBJECTIVE: To investigate the effect of cigarette smoking on bone mineral density (BMD) in postmenopausal Turkish women. STUDY DESIGN: A total of 175 postmenopausal Turkish women admitted to Tepecik Training and Research Hospital for a routine menopausal checkup were included in this study. All participants completed a questionnaire regarding their age, educational status, parity, number of abortus, time since menopause, caffeine intake, tobacco use, alcohol consumption, history of a previous fracture related to trauma, and taking any medication for menopause and osteoporosis. Of all subjects, 23.3% (n = 39) were smokers and 77.7% (n = 136) were nonsmokers. T-scores and Z-scores of vertebra and femur neck were assessed using dual energy X-ray absorptiometry (DXA). For analyzing the results, Student t-test, one-way ANOVA, Mann-Whitney U test, Pearson correlation, and Kruskal-Wallis test were performed. RESULTS: Femur T scores (- 0.78 +/- 1.07 vs. - 0.32 +/- 1.56) and vertebra T-scores (- 2.26 +/- 1.23 vs. - 1.82 +/- 1.04) were significantly lower in smoking women than nonsmoking women (p < 0.05). However, there were no significant difference between duration of smoking, number of cigarettes consumed per day, and BMD (p > 0.05) CONCLUSION: Cigarette smoking is one of the modifiable risk factors influencing bone density in postmenopausal Turkish women. "Cessation of cigarette" should be recommended for lifestyle modifications to prevent postmenopausal osteoporosis. PMID- 26438104 TI - Characterising atypical Candida albicans clinical isolates from six third-level hospitals in Bogota, Colombia. AB - BACKGROUND: Candida species are the most frequently found fungal pathogens causing nosocomial disease in a hospital setting. Such species must be correctly identified to ensure that appropriate control measures are taken and that suitable treatment is given for each species. Candida albicans is causing most fungal disease burden worldwide; the challenge lies in differentiating it from emerging atypical, minor and related species such as Candida dubliniensis and Candida africana. The purpose of this study was to compare identification based on MALDI-TOF MS to standard identification systems using a set of nosocomial isolates. METHODS: Eleven nosocomial samples were collected from 6 third-level hospitals in Bogota, Colombia. All the samples were identified by combining MALDI TOF MS with morphological characters, carbohydrate assimilation and molecular markers (D1/D2 and HWP1). RESULTS: The present work describes the first collection of atypical Colombian Candida clinical isolates; these were identified as Candida albicans/Candida africana by their MALDI-TOF MS profile. Phenotypical characteristics showed that they were unable to produce chlamydospores, assimilate trehalose, glucosamine, N- acetyl-glucosamine and barely grew at 42 degrees C, as would be expected for Candida africana. The molecular identification of the D1/D2 region of large subunit ribosomal RNA and HWP1 hyphal cell wall protein 1 sequences from these isolates was consistent with those for Candida albicans. The mass spectra obtained by MALDI-TOF MS were analysed by multi-dimensional scaling (MDS) and cluster analysis, differences being revealed between Candida albicans, Candida africana, Candida dubliniensis reference spectra and two clinical isolate groups which clustered according to the clinical setting, one of them being clearly related to C. albicans. CONCLUSION: This study highlights the importance of using MALDI-TOF MS in combination with morphology, substrate assimilation and molecular markers for characterising Candida albicans related and atypical C. albicans species, thereby overcoming conventional identification methods. This is the first report of hospital-obtained isolates of this type in Colombia; the approach followed might be useful for gathering knowledge regarding local epidemiology which could, in turn, have an impact on clinical management. The findings highlight the complexity of distinguishing between typical and atypical Candida albicans isolates in hospitals. PMID- 26438105 TI - A de novo microdeletion in NRXN1 in a Dutch patient with mild intellectual disability, microcephaly and gonadal dysgenesis. AB - This report is regarding a Dutch female with microcephaly, mild intellectual disability (ID), gonadal dysgenesis and dysmorphic facial features with synophrys. Upon genotyping, an ~455 kb de novo deletion encompassing the first exon of NRXN1 was found. Bidirectional sequencing of the coding exons of the NRXN1 alpha isoform was subsequently performed to investigate the possibility of a pathogenic mutation on the other allele, but we could not find any other mutation. Previously, many heterozygous mutations as well as microdeletions in NRXN1 were shown to be associated with ID, autism, schizophrenia, and other psychiatric and psychotic disorders. Our results are in agreement with other reports that show that NRXN1 deletions can lead to ID, microcephaly and mild dysmorphic features. However, this is the first report of gonadal dysgenesis being associated with such deletions. It is not clear whether there is a causal relationship between the NRXN1 deletion and gonadal dysgenesis, but it is of interest that the FSHR gene, which encodes the follicle-stimulating hormone receptor causative correlation that is mutated in ovarian dysgenesis, is located proximal to the NRXN1 gene. Given that most of the females carrying NRXN1 deletions have been diagnosed at a prepubertal age, gynecologic screening of female carriers of a NRXN1 deletion is warranted. PMID- 26438106 TI - Erratum to: Early Glycemic Response Predicts Achievement of Subsequent Treatment Targets in the Treatment of Type 2 Diabetes: A Post hoc Analysis. PMID- 26438107 TI - Characterization of Sitagliptin Use in Patients with Type 2 Diabetes and Chronic Kidney Disease by Cross-Sectional Analysis of a Medical Insurance Claims Database. AB - INTRODUCTION: Chronic kidney disease (CKD) is common in patients with type 2 diabetes (T2DM) and makes them particularly susceptible to safety/tolerability issues related to many classes of oral antihyperglycemic agents (OAHA). Dipeptidyl peptidase-4 inhibitors (DPP-4is) like sitagliptin are generally well tolerated in patients with T2DM and renal disease and therefore may be preferentially used in patients with CKD. To assess the extent of this preference, the characteristics of sitagliptin users with T2DM and CKD were compared with those of other (non-DPP-4i) OAHA users with T2DM and CKD. METHODS: Patients with T2DM and CKD with claims between 2006 and 2012 were identified from a United States insurance claims database. Patients starting sitagliptin or another OAHA as mono, dual, or triple therapy were compared. Demographic and clinical characteristics within 5 years before starting or escalating to new therapies were assessed. RESULTS: Compared to patients with CKD starting other OAHAs, patients with CKD starting sitagliptin as mono or dual therapy were older, had more physician visits, were more likely to have a history of heart failure and to use loop diuretics. In triple therapy patients, the differences between groups were not as pronounced, but the overall prevalences of comorbidities was higher. CONCLUSION: Similar to prior observations in a general T2DM population, patients with T2DM and CKD prescribed sitagliptin tend to be older and have more comorbidities than those prescribed other classes of OAHA. If not recognized and analyzed appropriately, this channeling could lead to biased treatment effect estimates in comparative analyses that include users of sitagliptin. FUNDING: Merck & Co., Inc., Kenilworth, NJ, USA. PMID- 26438108 TI - Repetitive Transcranial Magnetic Stimulation (rTMS) for the cognitive rehabilitation of traumatic brain injury (TBI) victims: study protocol for a randomized controlled trial. AB - BACKGROUND: Repetitive Transcranial Magnetic Stimulation (rTMS) has been proposed as a new tool in neurological rehabilitation of victims of traumatic brain injury (TBI). However, its usefulness to treat this condition has never been tested rigorously. The primary goal is to conduct a study protocol to determine whether rTMS used to cognitive rehabilitation of victims of TBI with diffuse axonal injury (DAI) is a safe instrument and if it enhances cognitive function recovery. METHODS: Double-blind randomized controlled trial of patients with diffuse axonal injury. Thirty-six patients will be randomized to either an active coil group or sham group in a 1:1 ratio. rTMS protocol: 10 sessions of high-frequency rTMS (10 Hz) over the left dorsolateral prefrontal cortex (DLPFC). Cortical Excitability measures will be obtained. Neuropsychological evaluations will be performed 1 week before, 1 week and 3 months after rTMS. There are 2 study hypotheses: (1) rTMS over the left DLPFC in patients with DAI will improve cognitive function and (2) whether rTMS is safe in TBI patients. DISCUSSION: This study evaluates the immediate and delayed effects of rTMS over the DLPFC on the cognitive domain of patients with DAI following TBI. rTMS has shown good results in treating major depression and may be promising for patients with TBI. As such, the results of this study can greatly modify the cognitive rehabilitation strategies. TRIAL REGISTRATION: This trial was registered in clinicaltrials.gov ( NCT02167971 ) on 17 June 2014. PMID- 26438109 TI - Prevalence and factors associated with musculoskeletal disorders and rheumatic diseases in indigenous Maya-Yucateco people: a cross-sectional community-based study. AB - This study aimed to estimate the prevalence of musculoskeletal disorders and rheumatic diseases in indigenous Maya-Yucateco communities using Community Oriented Program for Control of Rheumatic Diseases (COPCORD) methodology. The study population comprised subjects aged >=18 years from 11 communities in the municipality of Chankom, Yucatan. An analytical cross-sectional study was performed, and a census was used. Subjects positive for musculoskeletal (MSK) pain were examined by trained physicians. A total of 1523 community members were interviewed. The mean age was 45.2 years (standard deviation (SD) 17.9), and 917 (60.2 %) were women. Overall, 592 individuals (38.8 %; 95 % CI 36.3-41.3 %) had experienced MSK pain in the last 7 days. The pain intensity was reported as "strong" to "severe" in 43.4 %. The diagnoses were rheumatic regional pain syndromes in 165 (10.8 %; 95 % CI 9.4-12.5), low back pain in 153 (10.0 %; 95 % CI 8.5-11.6), osteoarthritis in 144 (9.4 %; 95 % CI 8.0-11.0), fibromyalgia in 35 (2.2 %; 95 % CI 1.6-3.1), rheumatoid arthritis in 17 (1.1 %; 95 % CI 0.6-1.7), undifferentiated arthritis in 8 (0.5 %; 95 % CI 0.2-0.8), and gout in 1 (0.06 %; 95 % CI 0.001-0.3). Older age, being female, disability, and physically demanding work were associated with a greater likelihood of having a rheumatic disease. In conclusion, MSK pain and rheumatic diseases were highly prevalent. The high impact of rheumatic diseases on daily activities in this indigenous population suggests the need to organize culturally-sensitive community interventions for the prevention of disabilities caused by MSK disorders and diseases. PMID- 26438110 TI - Genetic analysis of enteropathogenic Escherichia coli (EPEC) adherence factor (EAF) plasmid reveals a new deletion within the EAF probe sequence among O119 typical EPEC strains. AB - BACKGROUND: Enteropathogenic Escherichia coli (EPEC) are classified into typical and atypical strains based on the presence of the E. coli adherence factor (EAF) plasmid. The EAF plasmid contains the bfp (bundle-forming pilus) operon and the perABC (plasmid encoded regulator) gene cluster. A 1-kb cryptic region of EAF plasmid has been widely used as a genetic probe for EPEC detection. However, some EPEC strains may harbor an EAF plasmid lacking the EAF probe sequence, which makes the differentiation between typical and atypical a complex task. In this study, we report the genetic analysis of the EAF plasmid-encoded genes in a collection of EPEC clinical isolates. METHODS: A total of 222 EPEC clinical isolates, which were previously classified as typical (n=70) or atypical (n=152) by EAF probe reactivity, were screened for the presence of different EAF sequences by PCR and DNA hybridization. RESULTS: All typical strains possessed intact bfpA and perA genes, and most of them were positive in the PCR for EAF probe sequence. However, a subset of 30 typical strains, 22 of which belonged to O119 serogroup, presented a 1652 pb deletion in the region between 1093-bp downstream perC and 616-bp of the EAF fragment. The bfpA, bfpG, and per genes were found in all typical strains. In addition, 32 (21%) atypical strains presented the perA gene, and 20 (13.2%) also presented the bfpA gene. Among the 32 strains, 16 belonged to the O119:H2, O119:HND, and ONT:HND serotypes. All 32 atypical strains contained perA mutation frameshifts and possessed an IS1294 element upstream of the per operon as detected by PCR followed by restriction fragment length polymorphism (RFLP) typing and multiplex PCR. Among the 20 bfpA probe-positive strains, eight O119 strains possessed deletion in the bfp operon at the 3'end of bfpA due to an IS66 element. CONCLUSION: Our data show that typical O119 strains may contain a deletion within the EAF probe sequence not previously reported. This new finding suggests that care should be taken when using the previously described EAF PCR assay in epidemiological studies for the detection of typical O119 strains. In addition, we were able to confirm that some atypical strains carry vestiges of the EAF plasmid. PMID- 26438111 TI - Extended RAS Gene Mutation Testing in Metastatic Colorectal Carcinoma to Predict Response to Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update 2015. AB - PURPOSE: An American Society of Clinical Oncology Provisional Clinical Opinion (PCO) offers timely clinical direction after publication or presentation of potentially practice-changing data from major studies. This PCO update addresses the utility of extended RAS gene mutation testing in patients with metastatic colorectal cancer (mCRC) to detect resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) therapy. CLINICAL CONTEXT: Recent results from phase II and III clinical trials in mCRC demonstrate that patients whose tumors harbor RAS mutations in exons 2 (codons 12 and 13), 3 (codons 59 and 61), and 4 (codons 117 and 146) are unlikely to benefit from therapy with MoAbs directed against EGFR, when used as monotherapy or combined with chemotherapy. RECENT DATA: In addition to the evidence reviewed in the original PCO, 11 systematic reviews with meta-analyses, two retrospective analyses, and two health technology assessments based on a systematic review were obtained. These evaluated the outcomes for patients with mCRC with no mutation detected or presence of mutation in additional exons in KRAS and NRAS. PCO: All patients with mCRC who are candidates for anti-EGFR antibody therapy should have their tumor tested in a Clinical Laboratory Improvement Amendments-certified laboratory for mutations in both KRAS and NRAS exons 2 (codons 12 and 13), 3 (codons 59 and 61), and 4 (codons 117 and 146). The weight of current evidence indicates that anti EGFR MoAb therapy should only be considered for treatment of patients whose tumor is determined to not have mutations detected after such extended RAS testing. PMID- 26438112 TI - Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors As Adjuvant Therapy in Completely Resected Non-Small-Cell Lung Cancer. PMID- 26438113 TI - To Treat or Not to Treat: The Use of Hormone Replacement Therapy in Patients With Ovarian Cancer. PMID- 26438115 TI - Routine Imaging for Diffuse Large B-Cell Lymphoma in First Complete Remission Does Not Improve Post-Treatment Survival: A Danish-Swedish Population-Based Study. AB - PURPOSE: Routine imaging for diffuse large B-cell lymphoma (DLBCL) in first complete remission (CR) is controversial and plays a limited role in detecting relapse. This population-based study compared the survival of Danish and Swedish patients with DLBCL for whom traditions for routine imaging have been different. PATIENTS AND METHODS: Patients from the Danish and Swedish lymphoma registries were included according to the following criteria: newly diagnosed DLBCL from 2007 to 2012, age 18 to 65 years, and CR after R-CHOP/CHOEP. Follow-up for Swedish patients included symptom assessment, clinical examinations, and blood tests at 3- to 4-month intervals for 2 years, with longer intervals later in follow-up. Imaging was only recommended when relapse was clinically suspected. Follow-up for Danish patients was similar but included routine imaging (usually computed tomography every 6 months for 2 years). RESULTS: Danish (n = 525) and Swedish (n = 696) patients with DLBCL had comparable baseline characteristics. Cumulative 2-year progression rate after CR was 6% (95% CI, 4 to 9) for International Prognostic Index (IPI) <= 2 versus 21% (95% CI, 13 to 28) for IPI > 2. Age > 60 years (hazard ratio [HR], 2.3; 95% CI, 1.6 to 3.4), elevated lactate dehydrogenase (HR, 2.3; 95% CI, 1.4 to 3.8), B symptoms (HR, 1.7; 95% CI, 1.1 to 2.5), and Eastern Cooperative Oncology Group performance status >= 2 (HR, 1.8; 95% CI, 1.0 to 3.0) were associated with worse post-CR survival. Imaging-based follow-up strategy had no impact on survival, neither for all patients nor for IPI-specific subgroups. CONCLUSION: DLBCL relapse after first CR is infrequent, and the widespread use of routine imaging in Denmark did not translate into better survival. This favors follow-up without routine imaging and, more generally, a shift of focus from relapse detection to improved survivorship. PMID- 26438116 TI - To Surveil or Not to Surveil. PMID- 26438118 TI - You've Lived a Good Life. PMID- 26438117 TI - Extended Survival and Prognostic Factors for Patients With ALK-Rearranged Non Small-Cell Lung Cancer and Brain Metastasis. AB - PURPOSE: We performed a multi-institutional study to identify prognostic factors and determine outcomes for patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and brain metastasis. PATIENTS AND METHODS: A total of 90 patients with brain metastases from ALK-rearranged NSCLC were identified from six institutions; 84 of 90 patients received radiotherapy to the brain (stereotactic radiosurgery [SRS] or whole-brain radiotherapy [WBRT]), and 86 of 90 received tyrosine kinase inhibitor (TKI) therapy. Estimates for overall (OS) and intracranial progression-free survival were determined and clinical prognostic factors were identified by Cox proportional hazards modeling. RESULTS: Median OS after development of brain metastases was 49.5 months (95% CI, 29.0 months to not reached), and median intracranial progression-free survival was 11.9 months (95% CI, 10.1 to 18.2 months). Forty-five percent of patients with follow-up had progressive brain metastases at death, and repeated interventions for brain metastases were common. Absence of extracranial metastases, Karnofsky performance score >= 90, and no history of TKIs before development of brain metastases were associated with improved survival (P = .003, < .001, and < .001, respectively), whereas a single brain metastasis or initial treatment with SRS versus WBRT were not (P = .633 and .666, respectively). Prognostic factors significant by multivariable analysis were used to describe four patient groups with 2-year OS estimates of 33%, 59%, 76%, and 100%, respectively (P < .001). CONCLUSION: Patients with brain metastases from ALK-rearranged NSCLC treated with radiotherapy (SRS and/or WBRT) and TKIs have prolonged survival, suggesting that interventions to control intracranial disease are critical. The refinement of prognosis for this molecular subtype of NSCLC identifies a population of patients likely to benefit from first-line SRS, close CNS observation, and treatment of emergent CNS disease. PMID- 26438119 TI - Randomized Multicenter Phase II Study of Modified Docetaxel, Cisplatin, and Fluorouracil (DCF) Versus DCF Plus Growth Factor Support in Patients With Metastatic Gastric Adenocarcinoma: A Study of the US Gastric Cancer Consortium. AB - PURPOSE: Docetaxel, cisplatin, and fluorouracil (DCF) is a standard first-line three-drug chemotherapy regimen for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma and is associated with significant toxicity. We examined the safety and efficacy of a modified DCF (mDCF) regimen in a randomized multicenter phase II study. PATIENTS AND METHODS: Previously untreated patients with metastatic gastric or GEJ adenocarcinoma were randomly assigned to receive either mDCF (fluorouracil 2,000 mg/m2 intravenously [IV] over 48 hours, docetaxel 40 mg/m2 IV on day 1, cisplatin 40 mg/m2 IV on day 3, every 2 weeks) or parent DCF (docetaxel 75 mg/m2, cisplatin 75 mg/m2, and fluorouracil 750 mg/m2 IV over 5 days with granulocyte colony-stimulating factor, every 3 weeks). The study had 90% power to differentiate between 6-month progression-free survival of 26% and 43%, with type I and II error rates of 10% each. An early stopping rule for toxicity was included, defined as grade 3 to 4 adverse event rate > 70% in the first 3 months. RESULTS: From November 2006 to June 2010, 85 evaluable patients were enrolled (male, n = 61; female, n = 24; median age, 58 years; Karnofsky performance status, 90%; GEJ, n = 28; gastric, 57). mDCF (n = 54) toxicity rates included 54% grade 3 to 4 toxicity (22% hospitalized) within the first 3 months and 76% grade 3 to 4 toxicity over the course of treatment. The DCF arm (n = 31) closed early because of toxicity, with rates of 71% grade 3 to 4 toxicity (52% hospitalized) within 3 months and 90% grade 3 to 4 toxicity over the course of treatment. Six-month PFS was 63% (95% CI, 48% to 75%) for mDCF and 53% (95% CI, 34% to 69%) for DCF. Median overall survival was improved for mDCF (18.8 v 12.6 months; P = .007). CONCLUSION: mDCF is less toxic than parent DCF, even when supported with growth factors, and is associated with improved efficacy. mDCF should be considered a standard first-line option for patients with metastatic gastric or GEJ adenocarcinoma. PMID- 26438122 TI - Towards a balanced approach to identifying conflicts of interest faced by institutional review boards. AB - The welfare and protection of human subjects is critical to the integrity of clinical investigation and research. Institutional review boards (IRBs) were thus set up to be impartial reviewers of research protocols in clinical research. Their main role is to stand between the investigator and her human subjects in order to ensure that the welfare of human subjects are protected. While there is much literature on the conflicts of interest (CIs) faced by investigators and researchers in clinical investigations, an area that is less explored is CIs that may affect members of IRBs during the institutional ethics review of clinical investigations. This article examines the notion of CIs in clinical research and attempts to develop a framework for a clearer and more balanced approach to identifying CIs that may influence members of IRBs and impede their independence. It will also apply the proposed framework to demonstrate how IRBs possess, or at least may appear to possess, forms of financial CIs and non-financial CIs. The proper identification and management of these CIs is critical to preserving the integrity of clinical investigations and achieving the primary aim of human subjects protection. PMID- 26438121 TI - Outcomes of Prognostic Disclosure: Associations With Prognostic Understanding, Distress, and Relationship With Physician Among Patients With Advanced Cancer. AB - PURPOSE: To determine how prognostic conversations influence perceptions of life expectancy (LE), distress, and the patient-physician relationship among patients with advanced cancer. PATIENTS AND METHODS: This was a multicenter observational study of 590 patients with metastatic solid malignancies with progressive disease after >= one line of palliative chemotherapy, undergoing follow-up to death. At baseline, patients were asked whether their oncologist had disclosed an estimate of prognosis. Patients also estimated their own LE and completed assessments of the patient-physician relationship, distress, advance directives, and end-of-life care preferences. RESULTS: Among this cohort of 590 patients with advanced cancer (median survival, 5.4 months), 71% wanted to be told their LE, but only 17.6% recalled a prognostic disclosure by their physician. Among the 299 (51%) of 590 patients willing to estimate their LE, those who recalled prognostic disclosure offered more realistic estimates as compared with patients who did not (median, 12 months; interquartile range, 6 to 36 months v 48 months; interquartile range, 12 to 180 months; P < .001), and their estimates were less likely to differ from their actual survival by > 2 (30.2% v 49.2%; odds ratio [OR], 0.45; 95% CI, 0.14 to 0.82) or 5 years (9.5% v 35.5%; OR, 0.19; 95% CI, 0.08 to 0.47). In adjusted analyses, recall of prognostic disclosure was associated with a 17.2-month decrease (95% CI, 6.2 to 28.2 months) in patients' LE self-estimates. Longer LE self-estimates were associated with lower likelihood of do-not-resuscitate order (adjusted OR, 0.439; 95% CI, 0.296 to 0.630 per 12-month increase in estimate) and preference for life-prolonging over comfort-oriented care (adjusted OR, 1.493; 95% CI, 1.091 to 1.939). Prognostic disclosure was not associated with worse patient-physician relationship ratings, sadness, or anxiety in adjusted analyses. CONCLUSION: Prognostic disclosures are associated with more realistic patient expectations of LE, without decrements to their emotional well-being or the patient-physician relationship. PMID- 26438123 TI - Linear atrophoderma of Moulin: an underrecognized entity. AB - Linear atrophoderma of Moulin (LAM) is an acquired skin condition that manifests in early childhood and adolescence. It likely represents a form of cutaneous mosaicism that presents with linear, hyperpigmented and atrophic lesions appearing on the trunk and limbs. Its clinical appearance varies and may closely resemble that of atrophoderma of Pasini and Pierini (APP) and linear scleroderma. LAM usually follows a benign course and no effective treatment options exist. We present a case of a young and healthy patient that developed such lesions on her upper and lower extremities over 5 years. The initial clinical impression of linear scleroderma was reviewed in favor of LAM following histological examination of the lesions which revealed no significant inflammatory changes. LAM remains a rare and possibly under recognized entity with reports confined only to the dermatologic literature. This case highlights the importance of recognizing LAM and distinguishing it from linear scleroderma given the significant differences in management and prognosis. PMID- 26438120 TI - Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and Sezary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model. AB - PURPOSE: Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sezary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. PATIENTS AND METHODS: Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). RESULTS: Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). CONCLUSION: To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients. PMID- 26438124 TI - Photofragmentation of the Gas-Phase Lanthanum Isopropylcyclopentadienyl Complex: Computational Modeling vs Experiment. AB - Photofragmentation of the lanthanum isopropylcyclopentadienyl complex, La(iCp), was explored through time-dependent excited-state molecular dynamics (TDESMD), excited-state molecular dynamics (ESMD), and thermal molecular dynamics (MD). Simulated mass spectra were extracted from ab initio molecular dynamics simulations through a new and simple method and compared to experimental photoionization time-of-flight (PI-TOF) mass spectra. The computational results indicate that the value of excitation energy and mechanism of excitation determine the dissociation process. PMID- 26438125 TI - Proteomic analysis of the influence of Cu(2+) on the crystal protein production of Bacillus thuringiensis X022. AB - BACKGROUND: Bacillus thuringiensis X022, a novel strain isolated from soil in China, produces diamond-shaped parasporal crystals. Specific mineral nutrients, such as Mg, Cu, and Mn, influence insecticidal crystal proteins (ICP) expression and the effects of these elements vary significantly. However, the molecular mechanisms of the effects caused by mineral elements have yet to be reported. RESULTS: The ICP are mainly composed of Cry1Ca, Cry1Ac, and Cry1Da, which have molecular weights of about 130 kDa. ICP production was most efficient when Cu(2+) was added at concentrations ranging from 10(-6) to 10(-4) mol/L at an initial pH of 8.0. Addition of Cu(2+) also evidently increased the toxicity of fermentation broth to Spodoptera exigua and Helicoverpa armigera. After analyzing changes in proteome and fermentation parameters caused by Cu(2+) addition, we propose that Cu(2+) increases PhaR expression and consequently changes the carbon flow. More carbon sources was used to produce intracellular poly-beta-hydroxybutyrate (PHB). Increases in PHB as a storage material bring about increases of ICP production. CONCLUSIONS: Bacillus thuringiensis X022 mainly expresses Cry1Ca, Cry1Ac, and Cry1Da. Cu(2+) increases the expression of Cry1Da, Cry1Ca, and also enhances the toxicity of fermentation broth to S. exigua and H. armigera. PMID- 26438126 TI - High Throughput In Situ DDA Analysis of Neuropeptides by Coupling Novel Multiplex Mass Spectrometric Imaging (MSI) with Gas-Phase Fractionation. AB - Matrix-assisted laser desorption/ionization (MALDI) mass spectrometric imaging (MSI) is a powerful tool to map the spatial distribution of biomolecules on tissue sections. Recent developments of hybrid MS instruments allow combination of different types of data acquisition by various mass analyzers into a single MSI analysis, which reduces experimental time and sample consumptions. Here, using the well-characterized crustacean nervous system as a test-bed, we explore the utility of high resolution and accurate mass (HRAM) MALDI Orbitrap platform for enhanced in situ characterization of the neuropeptidome with improved chemical information. Specifically, we report on a multiplex-MSI method, which combines HRAM MSI with data dependent acquisition (DDA) tandem MS analysis in a single experiment. This method enables simultaneous mapping of neuropeptide distribution, sequence validation, and novel neuropeptide discovery in crustacean neuronal tissues. To enhance the dynamic range and efficiency of in situ DDA, we introduced a novel approach of fractionating full m/z range into several sub-mass ranges and embedding the setup using the multiplex-DDA-MSI scan events to generate pseudo fractionation before MS/MS scans. The division of entire m/z into multiple segments of m/z sub-ranges for MS interrogation greatly decreased the complexity of molecular species from tissue samples and the heterogeneity of the distribution and variation of intensities of m/z peaks. By carefully optimizing the experimental conditions such as the dynamic exclusion, the multiplex-DDA-MSI approach demonstrates better performance with broader precursor coverage, less biased MS/MS scans towards high abundance molecules, and improved quality of tandem mass spectra for low intensity molecular species. Graphical Abstract ?. PMID- 26438127 TI - Focus on Mass Spectrometry-Based Strategies for Neuroproteomics and Peptidomics, Honoring Dr. Lingjun Li, Recipient of the 2014 ASMS Biemann Medal. PMID- 26438128 TI - Benzylammonium Thermometer Ions: Internal Energies of Ions Formed by Low Temperature Plasma and Atmospheric Pressure Chemical Ionization. AB - The extent of internal energy deposition upon ion formation by low temperature plasma and atmospheric pressure chemical ionization was investigated using novel benzylammonium thermometer ions. C-N heterolytic bond dissociation enthalpies of nine 4-substituted benzylammoniums were calculated using CAM-B3LYP/6-311++G(d,p), which was significantly more accurate than B3LYP/6-311++G(d,p), MP2/6 311++G(d,p), and CBS-QB3 for calculating the enthalpies of 20 heterolytic dissociation reactions that were used to benchmark theory. All 4-substituted benzylammonium thermometer ions fragmented by a single pathway with comparable dissociation entropies, except 4-nitrobenzylammonium. Overall, the extent of energy deposition into ions formed by low temperature plasma was significantly lower than those formed by atmospheric pressure chemical ionization under these conditions. Because benzylamines are volatile, this new suite of thermometer ions should be useful for investigating the extent of internal energy deposition during ion formation for a wide range of ionization methods, including plasma, spray and laser desorption-based techniques. Graphical Abstract ?. PMID- 26438130 TI - Paramedicine students' perception of preparedness for clinical placement in Australia and New Zealand. AB - BACKGROUND: Clinical placement is an essential element of paramedicine education and training as the profession completes the transition from vocational training to a pre-employment, university based model. The objective of this study was to survey pre-employment paramedicine students at Universities in Victoria, Australia and Auckland, New Zealand to measure their self-assessed preparedness for clinical placement. METHODS: This was a cross-sectional study involving paper based questionnaires employing a convenience sample of 682 undergraduate paramedicine students (years 1-4) who had completed at least one clinical placement. Student perceptions of preparedness for clinical placement were measured using an adaptation of the 'Preparedness for Hospital Practice' questionnaire. RESULTS: There are significant differences in students' perception of preparedness for clinical placement, which reflects the differences between universities in relation to structure of their paramedicine programs, the timing of clinical education and the number of hours of clinical placement. DISCUSSION: There needs to be clinical placement agreements between the ambulance services and universities that clearly describe the standards and expected elements of a quality clinical placement. CONCLUSIONS: In order to improve the preparedness for placement for paramedicine students, a united approach is required by all stakeholders, including ambulance services, students and universities. PMID- 26438129 TI - Perioperative smoking cessation in vascular surgery: challenges with a randomized controlled trial. AB - BACKGROUND: The effect of intensive smoking cessation programs on postoperative complications has never before been assessed in soft tissue surgery when smoking cessation is initiated on the day of surgery. METHODS: A single-blinded randomized clinical trial conducted at two vascular surgery departments in Denmark. The intervention group was offered the Gold Standard Program (GSP) for smoking cessation intervention. The control group was offered the departments' standard care. Inclusion criteria were patients with planned open peripheral vascular surgery and who were daily smokers. According to the power calculation a total of 144 patients were needed in the trial. RESULTS: Due to slow patient inclusion, the trial was terminated prior to fulfilling the power calculation. Thirty-two patients were included in the trial from March 2011 to September 2012. Of these, 11 were randomized to the GSP intervention and 21 as controls. There was no difference in 30-day complication rates or 6-week abstinence rates between the two groups. CONCLUSIONS: A trial assessing the effect of smoking cessation on postoperative complications on the day of soft tissue surgery is still needed. If another trial is to be planned it must be more pragmatic with less extended inclusion criteria and conducted nationally or internationally to ensure enough patients for the trial. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01469091 ). Registration date: 27 October 2011. PMID- 26438131 TI - Construction of the BAC Library of Small Abalone (Haliotis diversicolor) for Gene Screening and Genome Characterization. AB - The small abalone (Haliotis diversicolor) is one of the most important aquaculture species in East Asia. To facilitate gene cloning and characterization, genome analysis, and genetic breeding of it, we constructed a large-insert bacterial artificial chromosome (BAC) library, which is an important genetic tool for advanced genetics and genomics research. The small abalone BAC library includes 92,610 clones with an average insert size of 120 Kb, equivalent to approximately 7.6* of the small abalone genome. We set up three-dimensional pools and super pools of 18,432 BAC clones for target gene screening using PCR method. To assess the approach, we screened 12 target genes in these 18,432 BAC clones and identified 16 positive BAC clones. Eight positive BAC clones were then sequenced and assembled with the next generation sequencing platform. The assembled contigs representing these 8 BAC clones spanned 928 Kb of the small abalone genome, providing the first batch of genome sequences for genome evaluation and characterization. The average GC content of small abalone genome was estimated as 40.33%. A total of 21 protein-coding genes, including 7 target genes, were annotated into the 8 BACs, which proved the feasibility of PCR screening approach with three-dimensional pools in small abalone BAC library. One hundred fifty microsatellite loci were also identified from the sequences for marker development in the future. The BAC library and clone pools provided valuable resources and tools for genetic breeding and conservation of H. diversicolor. PMID- 26438132 TI - Prognostic impact of neutrophil gelatinase-associated lipocalin and B-type natriuretic in patients with ST-elevation myocardial infarction treated by primary PCI: a prospective observational cohort study. AB - OBJECTIVES: Neutrophil gelatinase-associated lipocalin (NGAL) from a pathophysiological perspective connects various pathways that affect the prognosis after myocardial infarction. The objective was to evaluate the benefits of measuring NGAL for prognostic stratification in addition to the Thrombolysis in Myocardial Infarction (TIMI) score, and to compare it with the prognostic value of B-type natriuretic peptide (BNP). DESIGN: Prospective observational cohort study. SETTING: One university/tertiary centre. PARTICIPANTS: A total of 673 patients with ST segment elevation myocardial infarction were treated by primary percutaneous coronary intervention. NGAL and BNP were assessed on hospital admission. OUTCOMES: PRIMARY OUTCOME: 1-year mortality. SECONDARY OUTCOMES: 1-year hospitalisation due to acute heart failure, unplanned revascularisation, reinfarction, stroke and combined end point of 1-year mortality and hospitalisation due to heart failure. STATISTICAL METHODS: Using the c-statistic, the ability of NGAL, BNP and TIMI score to predict 1-year mortality alone and in combination with readmission for heart failure was evaluated. The addition of the predictive value of biomarkers to the score was assessed by category free net reclassification improvement (cfNRI) and the integrated discrimination index (IDI). RESULTS: The NGAL level was significantly higher in non-survivors (67 vs 115 pg/mL; p<0.001). The area under the curve (AUC) values for mortality prediction for NGAL, BNP and TIMI score were 75.5, 78.7 and 74.4, respectively (all p<0.001) with optimal cut-off values of 84 pg/mL for NGAL and 150 pg/mL for BNP. The addition of NGAL and BNP to the TIMI score significantly improved risk stratification according to cfNRI and IDI. A BNP and the combination of the TIMI score with NGAL predicted the occurrence of the combined end point with an AUC of 80.6 or 82.2, respectively. NGAL alone is a simple tool to identify very high-risk patients. NGAL >110 pg/mL was associated with a 1-year mortality of 20%. CONCLUSIONS: The measurement of NGAL together with the TIMI score results in a strong prognostic model for the 1-year mortality rate in patients with STEMI. PMID- 26438133 TI - Studying the time trend of Methicillin-resistant Staphylococcus aureus (MRSA) in Norway by use of non-stationary gamma-Poisson distributions. AB - OBJECTIVES: Study the time development of methicillin-resistant Staphylococcus aureus (MRSA) and forecast future behaviour. The major question: Is the number of MRSA isolates in Norway increasing and will it continue to increase? DESIGN: Time trend analysis using non-stationary gamma-Poisson distributions. SETTING: Two data sets were analysed. The first data set (data set I) consists of all MRSA isolates collected in Oslo County from 1997 to 2010; the study area includes the Norwegian capital of Oslo and nearby surrounding areas, covering approximately 11% of the Norwegian population. The second data set (data set II) consists of all MRSA isolates collected in Health Region East from 2002 to 2011. Health Region East consists of Oslo County and four neighbouring counties, and is the most populated area of Norway. PARTICIPANTS: Both data sets I and II consist of all persons in the area and time period described in the Settings, from whom MRSA have been isolated. PRIMARY AND SECONDARY OUTCOME MEASURES: MRSA infections have been mandatory notifiable in Norway since 1995, and MRSA colonisation since 2004. In the time period studied, all bacterial samples in Norway have been sent to a medical microbiological laboratory at the regional hospital for testing. In collaboration with the regional hospitals in five counties, we have collected all MRSA findings in the South-Eastern part of Norway over long time periods. RESULTS: On an average, a linear or exponential increase in MRSA numbers was observed in the data sets. A Poisson process with increasing intensity did not capture the dispersion of the time series, but a gamma-Poisson process showed good agreement and captured the overdispersion. The numerical model showed numerical internal consistency. CONCLUSIONS: In the present study, we find that the number of MRSA isolates is increasing in the most populated area of Norway during the time period studied. We also forecast a continuous increase until the year 2017. PMID- 26438134 TI - A systematic review protocol for reporting deficiencies within surgical case series. AB - INTRODUCTION: Case series are an important and common study type in surgical literature. There is evidence that key data are excluded from published case series, and currently no reporting guideline exists for case series. There is, therefore, the potential to change practices and improve the reporting of case series. Reporting guidelines have been shown to be efficacious in raising the bar for reporting quality. We present our protocol for the first stage of guideline development--a systematic review of previously identified deficiencies in how surgical case series are reported. METHODS AND ANALYSIS: Electronic searches will be conducted on MEDLINE, EMBASE, Cochrane Methods Register, Science Citation Index and Conference Proceedings Citation Index, from the start of indexing until 5 November 2014. The electronic search strategy was developed with an information specialist. Two independent researchers will identify articles for inclusion, specifically those that describe reporting deficiencies within surgical case series. Data will be extracted to specifically focus on the deficiencies of reporting. These will be categorised according to their type, and other identified issues will also be presented. Data will be presented with descriptive statistics to determine frequently missing types of data, and the commonest reporting issues tabulated. ETHICS AND DISSEMINATION: The authors hope to disseminate the findings as widely as possible, irrespective of results, as these will add to the wider corpora of information on this subject. The systematic review will be published in a peer-reviewed journal and will be presented at a wide range of national and international conferences. Ultimately, this will inform a Delphi process for the development of a surgical case series reporting guideline. PROTOCOL REGISTRATION: CRD42015016145. PMID- 26438135 TI - Willingness to pay per quality-adjusted life year for life-saving treatments in Thailand. AB - OBJECTIVE: To estimate the willingness to pay (WTP) per quality-adjusted life year (QALY) value for life-saving treatments and to determine factors affecting the WTP per QALY value. DESIGN: A cross-sectional survey with multistage sampling and face-to-face interviews. SETTING: General population in the southern part of Thailand. PARTICIPANTS: A total of 600 individuals were included in the study. Only 554 (92.3%) responses were usable for data analyses. OUTCOME MEASURE: Participants were asked for the maximum amount of WTP value for life-saving treatments by an open-ended question. EQ-5D-3L and visual analogue scale (VAS) were used to estimate additional QALY. RESULTS: The amount of WTP values varied from 0 to 720,000 Baht/year (approximately 32 Baht=US$1). The averages of additional QALY obtained from VAS and EQ-5D-3L were only slightly different (0.872 and 0.853, respectively). The averages of WTP per QALY obtained from VAS and EQ-5D-3L were 244,720 and 243,120 Baht/QALY, respectively. As compared to male participants, female participants were more likely to pay less for an additional QALY (p=0.007). In addition, participants with higher household incomes tended to have higher WTP per QALY values (p<0.001). CONCLUSIONS: Our study added another WTP per QALY value specifically for life-saving treatments, which would complement the current cost-effectiveness threshold used in Thailand and optimise patient access to innovative treatments or technologies. PMID- 26438136 TI - Association between COX-2 gene polymorphisms and risk of hepatocellular carcinoma development: a meta-analysis. AB - OBJECTIVE: To investigate the association between cyclo-oxygenase-2 (COX-2) polymorphism and the risk of hepatocellular carcinoma (HCC) development. DESIGN: Systematic review and meta-analysis of COX-2 polymorphism and risk of HCC development among people with or without HCC. DATA SOURCES: EMBASE, PubMed, Public Library of Science, SCOPUS, Web of Knowledge and Chinese National Knowledge Infrastructure were searched for all clinical and experimental case control studies of COX-2 polymorphism and HCC risk. Studies published up to March 2015 were included. REVIEW METHOD: Ten studies were included for data extraction, which were mainly from Asian countries. RESULTS: 2538 people with HCC and 3714 without HCC were found to satisfy the inclusion criteria and included in the review. The associations of specific genotypes in the eight polymorphic variants of COX-2 and the risk of HCC development were analysed. GG genotype at the A 1195G polymorphism may be associated with a reduced risk of HCC development: the OR across all studies was 0.87 (95% CI 0.75 to 1.02) for the G allele versus the A allele, 0.72 (0.53 to 0.97) for GG versus AA, 0.72 (0.57 to 0.92) for GG versus GA+AA and 1.05 (0.77 to 1.44) for AA versus GA+GG. Similar results were found when the meta-analysis was repeated separately for the Chinese subgroup. However, more reliable data are needed to demonstrate associations between variants in G 765C, T+8473C, A-1290G, G-899C and introns 1, 5 and 6 polymorphisms and the risk of HCC development. CONCLUSIONS: Only the COX-2 A-1195G gene polymorphism may be associated with a decreased risk of HCC development. These conclusions should be verified in further studies. PMID- 26438137 TI - Micronutrient deficiencies and developmental delays among infants: evidence from a cross-sectional survey in rural China. AB - OBJECTIVES: Research increasingly indicates the importance of the nutritional programming that occurs in the first 2-3 years of life. Quality nutrition during this brief window has been shown to have large and significant effects on health and development throughout childhood and even into adulthood. Despite the widespread understanding of this critical window, and the long-term consequences of leaving nutritional deficiencies unaddressed, little is known about the status of infant nutrition in rural China, or about the relationship between infant nutrition and cognitive development in rural China. DESIGN, SETTING AND PARTICIPANTS: In April 2013 and October 2013, we conducted a survey of 1808 infants aged 6-12 months living in 351 villages across 174 townships in nationally designated poverty counties in rural areas of southern Shaanxi Province, China. MAIN OUTCOME MEASURES: Infants were administered a finger prick blood test for haemoglobin and assessed according to the Bayley Scales of Infant Development. They were also measured for length and weight. Caregivers were administered a survey of demographic characteristics and feeding practices. RESULTS: We found that 48.8% of sample infants were anaemic, 3.7% were stunted, 1.2% were underweight and 1.6% were wasted. Approximately 20.0% of the sample infants were significantly delayed in their cognitive development, while just over 32.3% of the sample infants were significantly delayed in their psychomotor development. After controlling for potential confounders, infants with lower haemoglobin counts were significantly more likely to be delayed in both their cognitive (p<0.01) and psychomotor development (p<0.01). CONCLUSIONS: The anaemia rates that we identify in this study classify anaemia as a 'severe' public health problem according to the WHO. In contrast, there is virtually no linear growth failure among this population. We find that low haemoglobin levels among our sample population are associated with significant cognitive and psychomotor delays that could eventually affect children's schooling performance and labour force outcomes. TRIAL REGISTRATION NUMBER: ISRCTN44149146. PMID- 26438138 TI - Self-reported sleep in late pregnancy in relation to birth size and fetal distress: the E Moe, Mama prospective cohort study. AB - OBJECTIVES: To explore associations between features of sleep during pregnancy and adverse outcomes for the infant. SETTING: E Moe, Mama is a cohort study in Aotearoa/New Zealand that investigates self-reported sleep and maternal health in late pregnancy and the postpartum period. PARTICIPANTS: Women (N=633; 194 Maori) reported detailed information on their sleep duration, quality, disturbances, disorders (snoring, breathing pauses, twitching legs, restless legs) and daytime sleepiness between 35 and 37 weeks gestation. OUTCOME MEASURES: Birthweight and fetal distress during labour were extracted from medical records. Associations between each sleep variable and small or large for gestational age (SGA/LGA) using customised birthweight centile or fetal distress were estimated using multinomial/logistic regression, controlling for potential confounders. Secondary analyses considered differences in associations between Maori and non-Maori women. RESULTS: There was some indication that breathing pauses (a measure of sleep apnoea) were associated with both SGA (OR 2.8, 95% CI 0.9 to 9.0, p=0.08) and LGA (OR 2.0, 95% CI 0.7 to 5.7, p=0.20), with the association for LGA being stronger when only pregnancy-onset breathing pauses were considered (OR 3.5, 95% CI 1.3 to 9.6, p=0.01). There was also some evidence that pregnancy-onset leg twitching (OR 3.3, 95% CI 1.1 to 10.0, p=0.03) and frequent sleep disturbance due to feeling too hot or too cold (OR 1.7, 95% CI 0.9 to 3.6, p=0.13) were associated with higher risk of fetal distress. Other sleep measures, including snoring, were not associated with SGA, LGA or fetal distress. Many of the associations we observed were considerably stronger in Maori compared with non Maori women. CONCLUSIONS: We did not find evidence of previously reported associations between snoring and SGA. Our findings tentatively suggest that self reported breathing pauses and leg twitching in late pregnancy are associated with infant outcomes, and highlight ethnic inequalities. PMID- 26438139 TI - Assessment of mental health literacy using a multifaceted measure among a Chinese rural population. AB - OBJECTIVES: The present study aims to assess mental health literacy (MHL) using a standardised multifaceted 20-item instrument called Mental Health Knowledge Questionnaire (MHKQ) developed by the Chinese Ministry of Health, among a rural Chinese population. SETTING: Four villages in Liuyang county of Hunan province, China. PARTICIPANTS: This was a cross-sectional study. A multistage cluster sampling method was adopted, leading to a final sampling frame of 2377 residents aged 18-60 years from four villages of Liuyang county. Included in the study were residents aged 18-60 years living in their village for at least half a year; excluded were those not living in the areas during the research period, those with difficulty in communication due to serious physical or mental illness and those who were cognitively impaired or actively psychotic. Finally, 2052 participants completed the survey. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was correct response rate of the MHKQ; secondary outcome measures were association between sociodemographics and MHL, and association between MHL and health outcomes. RESULTS: Correct response rates for the 20 MHKQ items ranged from 19% to 94%, with a mean rate of 58%. Younger age (r=-0.02, p<0.01), higher education (r: 1.38-2.69, p<0.01) and higher income (r=0.41, p<0.01), were independently associated with higher MHL. MHL was independently associated with self-rated general health (r=2.31, p<0.01), depression (r=-0.09, p<0.01) and anxiety (r=-0.07, p<0.05). CONCLUSIONS: MHL in the rural areas of Liuyang is lower than that reported in urban areas of China. There is much room for improvement with regard to MHL promotion in rural areas of China. Younger age, higher education and higher income are the three robust factors related to higher MHL, so cohort-specific educational intervention efforts may be indicated. PMID- 26438140 TI - Increased planned delivery contributes to declining rates of pregnancy hypertension in Australia: a population-based record linkage study. AB - OBJECTIVE: Since the 1990s, pregnancy hypertension rates have declined in some countries, but not all. Increasing rates of early planned delivery (before the due date) have been hypothesised as the reason for the decline. The aim of this study was to explore whether early planned delivery can partly explain the declining pregnancy hypertension rates in Australia. DESIGN: Population-based record linkage study utilising linked birth and hospital records. SETTING AND PARTICIPANTS: A cohort of 1,076,122 deliveries in New South Wales, Australia, 2001-2012. OUTCOME MEASURES: Pregnancy hypertension (including gestational hypertension, pre-eclampsia and eclampsia) was the main outcome; pre-eclampsia was a secondary outcome. RESULTS: From 2001 to 2012, pregnancy hypertension rates declined by 22%, from 9.9% to 7.7%, and pre-eclampsia by 27%, from 3.3% to 2.4% (trend p<0.0001). At the same time, planned deliveries increased: prelabour caesarean section by 43% (12.9-18.4%) and labour inductions by 10% (24.8-27.2%). Many maternal risk factors for pregnancy hypertension significantly increased (p<0.01) over the study period including nulliparity, age >=35 years, diabetes, overweight and obesity, and use of assisted reproductive technologies; some risk factors decreased including multifetal pregnancies, age <20 years, autoimmune diseases and previous pregnancy hypertension. Given these changes in risk factors, the pregnancy hypertension rate was predicted to increase to 10.5%. Examination of annual gestational age distributions showed that pregnancy hypertension rates actually declined from 38 weeks gestation and were steepest from 41 weeks; at least 36% of the decrease could be attributed to planned deliveries. The risk factors for pregnancy hypertension were also risk factors for planned delivery. CONCLUSIONS: It appears that an unanticipated consequence of increasing early planned deliveries is a decline in the incidence of pregnancy hypertension. Women with risk factors for hypertension were relatively more likely to be selected for early delivery. PMID- 26438141 TI - Prognostic and functional importance of the engraftment-associated genes in the patient-derived xenograft models of triple-negative breast cancers. AB - We aimed to identify the factors affecting the successful tumor engraftment in breast cancer patient-derived xenograft (PDX) models. Further, we investigated the prognostic significance and the functional importance of the PDX engraftment related genes in triple-negative breast cancers (TNBC). The clinico-pathologic features of 81 breast cancer patients whose tissues were used for PDX transplantation were analyzed to identify the factors affecting the PDX engraftment. A gene signature associated with the PDX engraftment was discovered and its clinical importance was tested in a publicly available dataset and in vitro assays. Nineteen out of 81 (23.4 %) transplanted tumors were successfully engrafted into the PDX models. The engraftment rate was highest in TNBC when compared to other subtypes (p = 0.001) and in recurrent or chemotherapy-resistant tumors compared to newly diagnosed primary tumors (p = 0.024). PDX tumors originated from the TNBC cases showed more rapid tumor growth in mice. Gene expression profiling showed that down-regulation of genes involved in the tumor immune interaction was significantly associated with the successful PDX engraftment. The engraftment gene signature was associated with worse survival outcome when tested in publicly available mRNA datasets of TNBC cases. Among the engraftment-related genes, PHLDA2, TKT, and P4HA2 showed high expression in triple-negative breast cancer cell lines, and siRNA-based gene silencing resulted in reduced cell invasion and proliferation in vitro. Our results show that the PDX engraftment may reflect the aggressive phenotype in breast cancer. Genes associated with the PDX engraftment may provide a novel prognostic biomarker and therapeutic targets in TNBC. PMID- 26438142 TI - Comparison of methods to detect the in vitro activity of silver nanoparticles (AgNP) against multidrug resistant bacteria. AB - BACKGROUND: Multidrug resistant microorganisms are a growing challenge and new substances that can be useful to treat infections due to these microorganisms are needed. Silver nanoparticle may be a future option for treatment of these infections, however, the methods described in vitro to evaluate the inhibitory effect are controversial. RESULTS: This study evaluated the in vitro activity of silver nanoparticles against 36 susceptible and 54 multidrug resistant Gram positive and Gram-negative bacteria from clinical sources. The multidrug resistant bacteria were oxacilin-resistant Staphylococcus aureus, vancomycin resistant Enterococcus spp., carbapenem- and polymyxin B-resistant A. baumannii, carbapenem-resistant P. aeruginosa and carbapenem-resistant Enterobacteriaceae. We analyzed silver nanoparticles stabilized with citrate, chitosan and polyvinyl alcohol and commercial silver nanoparticle. Silver sulfadiazine and silver nitrate were used as control. Different methods were used: agar diffusion, minimum inhibitory concentration, minimum bactericidal concentration and time kill. The activity of AgNPs using diffusion in solid media and the MIC methods showed similar effect against MDR and antimicrobial-susceptible isolates, with a higher effect against Gram-negative isolates. The better results were achieved with citrate and chitosan silver nanoparticle, both with MIC90 of 6.75 MUg mL( 1), which can be due the lower stability of these particles and, consequently, release of Ag(+) ions as revealed by X-ray diffraction (XRD). The bactericidal effect was higher against antimicrobial-susceptible bacteria. CONCLUSION: It seems that agar diffusion method can be used as screening test, minimum inhibitory concentration/minimum bactericidal concentration and time kill showed to be useful methods. The activity of commercial silver nanoparticle and silver controls did not exceed the activity of the citrate and chitosan silver nanoparticles. The in vitro inhibitory effect was stronger against Gram-negative than Gram-positive, and similar against multidrug resistant and susceptible bacteria, with best result achieved using citrate and chitosan silver nanoparticles. The bactericidal effect of silver nanoparticle may, in the future, be translated into important therapeutic and clinical options, especially considering the shortage of new antimicrobials against the emerging antimicrobial resistant microorganisms, in particular against Gram-negative bacteria. PMID- 26438143 TI - Defining cancer-related fatigue for biomarker discovery. PMID- 26438144 TI - Cancer patients' respect experiences in relation to perceived communication behaviours from hospital staff: analysis of the 2012-2013 National Cancer Patient Experience Survey. AB - PURPOSE: Respect experiences are poorly understood despite respect being central to professionalism in health care and patient well-being, and needed for optimal patient care. This study explores which patient-perceived communication behaviours from hospital staff contribute most to cancer patients' respect experiences and account for variation in their experience by socio-demographic and clinical characteristics. METHODS: We present a secondary analysis of data from the 2012-2013 National Cancer Patient Experience Survey of 45,191 patients with a primary cancer diagnosis treated in English National Health Service trusts providing adult acute cancer services who provided data on experienced respect and dignity. RESULTS: Both autonomy-supportive and caring/emotionally sensitive behaviours were associated with reported respect, although the latter showed stronger associations and accounted for most differences in reports of respect between patient groups. Differences in respect were found by gender, race/ethnicity, age, the presence of long-standing conditions, treatment response, time since first treated for cancer (p < .001), employment and type of cancer (p < .05). CONCLUSIONS: The study questions the tendency to conceptualise respect primarily in terms of autonomy-supportive behaviours and shows the relative contribution of autonomy-supportive and caring/emotionally sensitive behaviours in explaining disparities in respect experiences. More attention should be paid to affective communication behaviours from hospital staff to reduce disparities in respect experiences. PMID- 26438145 TI - Breakthrough pain and its treatment: critical review and recommendations of IOPS (Italian Oncologic Pain Survey) expert group. AB - Controversies exist about the definition and epidemiology of breakthrough cancer pain (BTcP), the pharmacological treatment options, drug dosing, and how to select the medications for BTcP among the new fentanyl products. Existing data were critically evaluated to provide recommendations by an expert group. An algorithm to diagnose BTcP should be used followed by a careful assessment. Fentanyl products provide efficacy and rapidity of action to counteract the temporal pattern of BTcP. The doses of opioids used for background pain should guide the choice of the doses of fentanyl products. The choice of fentanyl products should be based on individual clinical conditions. PMID- 26438147 TI - Psychological distress, optimism and general health in breast cancer survivors: a data linkage study using the Scottish Health Survey. AB - PURPOSE: The aim of this study is to examine the association between optimism and psychological distress in women with breast cancer after taking into account their self-rated general health. METHODS: Data were aggregated from the Scottish Health Survey (2008 to 2011) to derive a nationally representative sample of 12,255 women (11,960 cancer-free controls, and 295 breast cancer cases identified from linked cancer registry data). The explanatory variables were optimism and general health, and the outcome variable was symptoms of psychological distress. Logistic regression analyses were conducted, with optimism entered in step 1 and general health entered in step 2. RESULTS: In an unadjusted model, higher levels of optimism were associated with lower odds of psychological distress in both the control group (OR = 0. 57, 95 % CI = 0.51-0.60) and breast cancer group (OR = 0. 64, 95 % CI = 0.47-0.88). However, in a model adjusting for general health, optimism was associated with lower odds of psychological distress only in the control group (OR = 0.50, 95 % CI = 0.44-0.57), but not significantly in the breast cancer group (OR = 1.15, 95 % CI = 0.32-4.11). In the breast cancer group, poor general health was a stronger associate of psychological distress (OR = 4. 98, 95 % CI = 1.32-18.75). Results were consistent after adjusting for age, years since breast cancer diagnosis, survey year, socioeconomic status, education, marital status, body mass index, smoking status, and alcohol consumption. CONCLUSION: This research confirms the value of multicomponent supportive care interventions for women with breast cancer. Specifically, it suggests that following breast cancer diagnosis, health care professionals need to provide advice and signpost to services that assist women to maintain or improve both their psychological and general health. PMID- 26438148 TI - A telephone survey of factors affecting willingness to participate in health research surveys. AB - BACKGROUND: In recent years, reduced participation has been encountered across all epidemiological study designs, both in terms of non-response as well as refusal. A low response rate may reduce the statistical power but, more importantly, results may not be generalizable to the wider community. METHODS: In a telephone survey of 1413 randomly selected members of the Australian general population and of 690 participants sourced from previous studies, we examined factors affecting people's stated willingness to participate in health research. RESULTS: The majority of participants (61 %) expressed willingness to participate in health research in general but the percentage increased when provided with more specific information about the research. People were more willing if they have personal experience of the disease under study, and if the study was funded by government or charity rather than pharmaceutical companies. Participants from previous studies, older people and women were the groups most willing to participate. Younger men preferred online surveys, older people a written questionnaire, and few participants in any age and sex groups preferred a telephone questionnaire. CONCLUSION: Despite a trend toward reduced participation rates, most participants expressed their willingness to participate in health research. However, when seeking participants, researchers should be concrete and specific about the nature of the research they want to carry out. The preferred method of recommended contact varies with the demographic characteristics. PMID- 26438146 TI - Effect of patient navigation on satisfaction with cancer-related care. AB - PURPOSE: Despite growing popularity of patient navigation (PN) as a means to improve cancer care quality and reduce cancer-related disparities, there are few well-designed controlled trials assessing the impact of PN on patient outcomes like satisfaction with care. The present controlled study examined effect of PN on satisfaction with cancer-related care. METHODS: Patients who presented with a symptom or abnormal screening test (n = 1788) or definitive diagnosis (n = 445) of breast, cervical, colorectal, or prostate cancer from eight Patient Navigator Research Program sites were included in one of two groups: intervention (PN) or comparison (usual care or usual care plus cancer educational materials). Trained patient navigators met with intervention group participants to help them assess and identify resources to address barriers to cancer diagnostic or treatment care. Using a validated instrument, we assessed participants' satisfaction with their cancer diagnostic or treatment care up to 3 months after diagnostic resolution of a cancer-related abnormality or within 3 months of initiation of cancer treatment. RESULTS: Overall, patients reported high satisfaction with diagnostic care and cancer treatment. There were no statistically significant differences between PN and control groups in satisfaction with cancer-related care (p > 0.05). Hispanic and African American participants were less likely to report high satisfaction with cancer care when compared to White patients. Middle aged participants with higher education, higher household income, private insurance, owning their own home, working full-time, and those whose primary language is English had higher satisfaction with cancer-related diagnostic care. CONCLUSIONS: PN had no statistically significant effect on patients' satisfaction with cancer-related care. Further research is needed to define the patient populations who might benefit from PN, content of PN that is most useful, and services that might enhance PN. TRIAL REGISTRATIONS: clinicaltrials.gov identifiers: NCT00613275 , NCT00496678 , NCT00375024 , NCT01569672. PMID- 26438149 TI - Low temperature-induced DNA hypermethylation attenuates expression of RhAG, an AGAMOUS homolog, and increases petal number in rose (Rosa hybrida). AB - BACKGROUND: Flower development is central to angiosperm reproduction and is regulated by a broad range of endogenous and exogenous stimuli. It has been well documented that ambient temperature plays a key role in controlling flowering time; however, the mechanisms by which temperature regulates floral organ differentiation remain largely unknown. RESULTS: In this study, we show that low temperature treatment significantly increases petal number in rose (Rosa hybrida) through the promotion of stamen petaloidy. Quantitative RT-PCR analysis revealed that the expression pattern of RhAG, a rose homolog of the Arabidopsis thaliana AGAMOUS C-function gene, is associated with low temperature regulated flower development. Silencing of RhAG mimicked the impact of low temperature treatments on petal development by significantly increasing petal number through an increased production of petaloid stamens. In situ hybridization studies further revealed that low temperature restricts its spatial expression area. Analysis of DNA methylation level showed that low temperature treatment enhances the methylation level of the RhAG promoter, and a specific promoter region that was hypermethylated at CHH loci under low temperature conditions, was identified by bisulfite sequencing. This suggests that epigenetic DNA methylation contributes to the ambient temperature modulation of RhAG expression. DISCUSSION: Our results provide highlights in the role of RhAG gene in petal number determination and add a new layer of complexity in the regulation of floral organ development. CONCLUSIONS: We propose that RhAG plays an essential role in rose flower patterning by regulating petal development, and that low temperatures increase petal number, at least in part, by suppressing RhAG expression via enhancing DNA CHH hypermethylation of the RhAG promoter. PMID- 26438151 TI - The common NOD2/CARD15 variant P268S in patients with non-infectious uveitis: a cohort study. AB - BACKGROUND: The etiology of Autoimmune chronic uveitis (ACU) is still unknown; NOD2/CARD15 gene mutations are responsible for the Blau Syndrome and can induce uveitis in animal models. PRESENTATION OF THE HYPOTHESIS: Aim of our study was to assess if NOD2/CARD15 variants have a role in the etiology or in the clinical course of patients with ACU, either idiopathic or associated with other inflammatory diseases. TESTING THE HYPOTHESIS: We consecutively enrolled 25 patients (19 pediatric and 6 adults) affected with ACU. For each patient medical history was reviewed and clinical data were recorded. Allelic and genotypic frequencies of NOD2/CARD15 variations were calculated in patients and matched with those of 25 healthy controls. The statistical analysis was performed. Fifteen patients showed the polymorphism P268S/SNP5 (SNP rs2066842) as heterozygous carriers while two patients were homozygous for the same polymorphism; one patient carried also the variant c647 18-16 TCT on intron 3, not previously reported in the literature. Statistical analysis for NOD2/CARD15 genotyping showed significant differences between patients and controls for allelic frequencies (p = 0.04, OR: 4.03, 95 %; CI = 1.2-13.5) but not for genotypic frequencies. We could not identify a significant phenotype-genotype correlation. IMPLICATIONS OF THE HYPOTHESIS: In our cohort of Italian patients, the NOD2/CARD15 common variant P268S/SNP5 could potentially be significantly associated with ACU. PMID- 26438150 TI - Neuroprotection Against Diisopropylfluorophosphate in Acute Hippocampal Slices. AB - Diisopropylfluorophosphate (DFP) is an irreversible inhibitor of acetylcholine esterase and a surrogate of the organophosphorus (OP) nerve agent sarin. The neurotoxicity of DFP was assessed as a reduction of population spike (PS) area elicited by synaptic stimulation in acute hippocampal slices. Two classical antidotes, atropine, and pralidoxime, and two novel antidotes, 4R-cembranotriene diol (4R) and a caspase nine inhibitor, were tested. Atropine, pralidoxime, and 4R significantly protected when applied 30 min after DFP. The caspase inhibitor was neuroprotective when applied 5-10 min before or after DFP, suggesting that early synaptic apoptosis is responsible for the loss of PSs. It is likely that apoptosis starts at the synapses and, if antidotes are not applied, descends to the cell bodies, causing death. The acute slice is a reliable tool for mechanistic studies, and the assessment of neurotoxicity and neuroprotection with PS areas is, in general, pharmacologically congruent with in vivo results and predicts the effect of drugs in vivo. 4R was first found to be neuroprotective in slices and later we demonstrated that 4R is neuroprotective in vivo. The mechanism of neurotoxicity of OPs is not well understood, and there is a need for novel antidotes that could be discovered using acute slices. PMID- 26438153 TI - Assessment of BRAF V600E Status in Colorectal Carcinoma: Tissue-Specific Discordances between Immunohistochemistry and Sequencing. AB - Although sequencing provides the gold standard for identifying colorectal carcinoma with BRAF V600E mutation, immunohistochemistry (IHC) with the recently developed mouse monoclonal antibody VE1 for BRAF V600E protein has shown promise as a more widely available and rapid method. However, we identified anecdotal discordance between VE1 IHC and sequencing results and therefore analyzed VE1 staining by two different IHC methods (Leica Bond and Ventana BenchMark) in whole tissue sections from 480 colorectal carcinomas (323 BRAF wild-type, 142 BRAF V600E mutation, and 15 BRAF non-V600E mutation). We also compared the results with melanomas and papillary thyroid carcinomas (PTC). With the Bond method, among 142 BRAF V600E-mutated colorectal carcinomas, 77 (54%) had diffuse VE1 staining and 48 (33%) had heterogeneous staining, but 17 (12%) were negative. Among 323 BRAF wild-type colorectal carcinomas, 196 (61%) were negative, but 127 (39%) had staining, including 7 with diffuse staining. When positivity was defined as staining in >= 20% of tumor cells, VE1 IHC had sensitivity of 75% and specificity of 93% for BRAF V600E mutation. With the Ventana method, among 57 BRAF V600E-mutated colorectal carcinomas, 36 (63%) had diffuse VE1 staining, whereas 6 (11%) had no or weak (<20% of tumor cells) staining. Among 33 BRAF wild type colorectal carcinomas, 16 (48%) had no or weak staining, whereas 15 (45%) had heterogeneous staining. In contrast with colorectal carcinoma, Bond and Ventana VE1 IHC in melanoma and PTC were highly concordant with sequencing results. We conclude that VE1 IHC produces suboptimal results in colorectal carcinoma and should not be used to guide patient management. PMID- 26438152 TI - Functional analyses of ATM, ATR and Fanconi anemia proteins in lung carcinoma : ATM, ATR and FA in lung carcinoma. AB - BACKGROUND: ATM and ATR are kinases implicated in a myriad of DNA-damage responses. ATM kinase inhibition radiosensitizes cells and selectively kills cells with Fanconi anemia (FA) gene mutations. ATR kinase inhibition sensitizes cells to agents that induce replication stress and selectively kills cells with ATM and TP53 mutations. ATM mutations and FANCF promoter-methylation are reported in lung carcinomas. METHODS: We undertook functional analyses of ATM, ATR, Chk1 and FA proteins in lung cancer cell lines. We included Calu6 that is reported to be FANCL-deficient. In addition, the cancer genome atlas (TCGA) database was interrogated for alterations in: 1) ATM, MRE11A, RAD50 and NBN; 2) ATR, ATRIP and TOPBP1; and 3) 15 FA genes. RESULTS: No defects in ATM, ATR or Chk1 kinase activation, or FANCD2 monoubiquitination were identified in the lung cancer cell lines examined, including Calu6, and major alterations in these pathways were not identified in the TCGA database. Cell lines were radiosensitized by ATM kinase inhibitor KU60019, but no cell killing by ATM kinase inhibitor alone was observed. While no synergy between gemcitabine or carboplatin and ATR kinase inhibitor ETP-46464 was observed, synergy between gemcitabine and Chk1 kinase inhibitor UCN-01 was observed in 54 T, 201 T and H460, and synergy between carboplatin and Chk1 kinase inhibitor was identified in 201 T and 239 T. No interactions between ATM, ATR and FA activation were observed by either ATM or ATR kinase inhibition in the lung cancer cell lines. CONCLUSIONS: Analyses of ATM serine 1981 and Chk1 serine 345 phosphorylation, and FANCD2 monoubiquitination revealed that ATM and ATR kinase activation and FA pathway signaling are intact in the lung cancer cell lines examined. As such, these posttranslational modifications may have utility as biomarkers for the integrity of DNA damage signaling pathways in lung cancer. Different sensitization profiles between gemcitabine and carboplatin and ATR kinase inhibitor ETP-46464 and Chk1 kinase inhibitor UCN-01 were observed and this should be considered in the rationale for Phase I clinical trial design with ATR kinase inhibitors. PMID- 26438154 TI - BI 885578, a Novel IGF1R/INSR Tyrosine Kinase Inhibitor with Pharmacokinetic Properties That Dissociate Antitumor Efficacy and Perturbation of Glucose Homeostasis. AB - Inhibition of the IGF1R, INSRA, and INSRB receptor tyrosine kinases represents an attractive approach of pharmacologic intervention in cancer, owing to the roles of the IGF1R and INSRA in promoting cell proliferation and survival. However, the central role of the INSRB isoform in glucose homeostasis suggests that prolonged inhibition of this kinase could result in metabolic toxicity. We describe here the profile of the novel compound BI 885578, a potent and selective ATP competitive IGF1R/INSR tyrosine kinase inhibitor distinguished by rapid intestinal absorption and a short in vivo half-life as a result of rapid metabolic clearance. BI 885578, administered daily per os, displayed an acceptable tolerability profile in mice at doses that significantly reduced the growth of xenografted human GEO and CL-14 colon carcinoma tumors. We found that treatment with BI 885578 is accompanied by increases in circulating glucose and insulin levels, which in turn leads to compensatory hyperphosphorylation of muscle INSRs and subsequent normalization of blood glucose within a few hours. In contrast, the normalization of IGF1R and INSR phosphorylation in GEO tumors occurs at a much slower rate. In accordance with this, BI 885578 led to a prolonged inhibition of cell proliferation and induction of apoptosis in GEO tumors. We propose that the remarkable therapeutic window observed for BI 885578 is achieved by virtue of the distinctive pharmacokinetic properties of the compound, capitalizing on the physiologic mechanisms of glucose homeostasis and differential levels of IGF1R and INSR expression in tumors and normal tissues. PMID- 26438155 TI - Systemic Administration and Targeted Radiosensitization via Chemically Synthetic Aptamer-siRNA Chimeras in Human Tumor Xenografts. AB - Radiation therapy is a highly effective tool for treating all stages of prostate cancer, from curative approaches in localized disease to palliative care and enhanced survival for patients with distant bone metastases. The therapeutic index of these approaches may be enhanced with targeted radiation-sensitizing agents. Aptamers are promising nucleic acid delivery agents for short interfering RNAs (siRNA) and short hairpin RNAs (shRNA). We have previously developed a radiation-sensitizing RNA aptamer-shRNA chimera that selectively delivers DNA-PK targeting shRNAs to prostate-specific membrane antigen (PSMA) positive cells in the absence of transfection reagents. Although these chimera are effective, their synthesis requires in vitro transcription and their evaluation was limited to intratumoral administration. Here, we have developed a second-generation aptamer siRNA chimera that can be assembled through the annealing of three separate chemically synthesized components. The resulting chimera knocked down DNA-PK in PSMA-positive prostate cancer cells, without the need of additional transfection reagents, and enhanced the efficacy of radiation-mediated cell death. Following intravenous injection, the chimera effectively knocked down DNA-PK in established subcutaneous PSMA-positive tumors. Systemic treatment with these radiation sensitizing agents selectively enhanced the potency of external beam radiation therapy for established PSMA-positive tumors. PMID- 26438156 TI - A TORC2-Akt Feed-Forward Topology Underlies HER3 Resiliency in HER2-Amplified Cancers. AB - The requisite role of HER3 in HER2-amplified cancers is beyond what would be expected as a dimerization partner or effector substrate and it exhibits a substantial degree of resiliency that mitigates the effects of HER2-inhibitor therapies. To better understand the roots of this resiliency, we conducted an in depth chemical-genetic interrogation of the signaling network downstream of HER3. A unique attribute of these tumors is the deregulation of TORC2. The upstream signals that ordinarily maintain TORC2 signaling are lost in these tumors, and instead TORC2 is driven by Akt. We find that in these cancers HER3 functions as a buffering arm of an Akt-TORC2 feed-forward loop that functions as a self perpetuating module. This network topology alters the role of HER3 from a conditionally engaged ligand-driven upstream physiologic signaling input to an essential component of a concentric signaling throughput highly competent at preservation of homeostasis. The competence of this signaling topology is evident in its response to perturbation at any of its nodes. Thus, a critical pathophysiologic event in the evolution of HER2-amplified cancers is the loss of the input signals that normally drive TORC2 signaling, repositioning it under Akt dependency, and fundamentally altering the role of HER3. This reprogramming of the downstream network topology is a key aspect in the pathogenesis of HER2 amplified cancers and constitutes a formidable barrier in the targeted therapy of these cancers. PMID- 26438158 TI - PARP Inhibitors Sensitize Ewing Sarcoma Cells to Temozolomide-Induced Apoptosis via the Mitochondrial Pathway. AB - Ewing sarcoma has recently been reported to be sensitive to poly(ADP)-ribose polymerase (PARP) inhibitors. Searching for synergistic drug combinations, we tested several PARP inhibitors (talazoparib, niraparib, olaparib, veliparib) together with chemotherapeutics. Here, we report that PARP inhibitors synergize with temozolomide (TMZ) or SN-38 to induce apoptosis and also somewhat enhance the cytotoxicity of doxorubicin, etoposide, or ifosfamide, whereas actinomycin D and vincristine show little synergism. Furthermore, triple therapy of olaparib, TMZ, and SN-38 is significantly more effective compared with double or monotherapy. Mechanistic studies revealed that the mitochondrial pathway of apoptosis plays a critical role in mediating the synergy of PARP inhibition and TMZ. We show that subsequent to DNA damage-imposed checkpoint activation and G2 cell-cycle arrest, olaparib/TMZ cotreatment causes downregulation of the antiapoptotic protein MCL-1, followed by activation of the proapoptotic proteins BAX and BAK, mitochondrial outer membrane permeabilization (MOMP), activation of caspases, and caspase-dependent cell death. Overexpression of a nondegradable MCL 1 mutant or BCL-2, knockdown of NOXA or BAX and BAK, or the caspase inhibitor N benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) all significantly reduce olaparib/TMZ-mediated apoptosis. These findings emphasize the role of PARP inhibitors for chemosensitization of Ewing sarcoma with important implications for further (pre)clinical studies. PMID- 26438157 TI - Efficacy of PARP Inhibitor Rucaparib in Orthotopic Glioblastoma Xenografts Is Limited by Ineffective Drug Penetration into the Central Nervous System. AB - PARP inhibition can enhance the efficacy of temozolomide and prolong survival in orthotopic glioblastoma (GBM) xenografts. The aim of this study was to evaluate the combination of the PARP inhibitor rucaparib with temozolomide and to correlate pharmacokinetic and pharmacodynamic studies with efficacy in patient derived GBM xenograft models. The combination of rucaparib with temozolomide was highly effective in vitro in short-term explant cultures derived from GBM12, and, similarly, the combination of rucaparib and temozolomide (dosed for 5 days every 28 days for 3 cycles) significantly prolonged the time to tumor regrowth by 40% in heterotopic xenografts. In contrast, the addition of rucaparib had no impact on the efficacy of temozolomide in GBM12 or GBM39 orthotopic models. Using Madin Darby canine kidney (MDCK) II cells stably expressing murine BCRP1 or human MDR1, cell accumulation studies demonstrated that rucaparib is transported by both transporters. Consistent with the influence of these efflux pumps on central nervous system drug distribution, Mdr1a/b(-/-)Bcrp1(-/-) knockout mice had a significantly higher brain to plasma ratio for rucaparib (1.61 +/- 0.25) than wild-type mice (0.11 +/- 0.08). A pharmacokinetic and pharmacodynamic evaluation after a single dose confirmed limited accumulation of rucaparib in the brain is associated with substantial residual PARP enzymatic activity. Similarly, matrix assisted laser desorption/ionization mass spectrometric imaging demonstrated significantly enhanced accumulation of drug in flank tumor compared with normal brain or orthotopic tumors. Collectively, these results suggest that limited drug delivery into brain tumors may significantly limit the efficacy of rucaparib combined with temozolomide in GBM. PMID- 26438159 TI - ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor. AB - Drugs that target specific gene alterations have proven beneficial in the treatment of cancer. Because cancer cells have multiple resistance mechanisms, it is important to understand the downstream pathways of the target genes and monitor the pharmacodynamic markers associated with therapeutic efficacy. We performed a transcriptome analysis to characterize the response of various cancer cell lines to a selective fibroblast growth factor receptor (FGFR) inhibitor (CH5183284/Debio 1347), a mitogen-activated protein kinase kinase (MEK) inhibitor, or a phosphoinositide 3-kinase (PI3K) inhibitor. FGFR and MEK inhibition produced similar expression patterns, and the extracellular signal regulated kinase (ERK) gene signature was altered in several FGFR inhibitor sensitive cell lines. Consistent with these findings, CH5183284/Debio 1347 suppressed phospho-ERK in every tested FGFR inhibitor-sensitive cell line. Because the mitogen-activated protein kinase (MAPK) pathway functions downstream of FGFR, we searched for a pharmacodynamic marker of FGFR inhibitor efficacy in a collection of cell lines with the ERK signature and identified dual-specificity phosphatase 6 (DUSP6) as a candidate marker. Although a MEK inhibitor suppressed the MAPK pathway, most FGFR inhibitor-sensitive cell lines are insensitive to MEK inhibitors and we found potent feedback activation of several pathways via FGFR. We therefore suggest that FGFR inhibitors exert their effect by suppressing ERK signaling without feedback activation. In addition, DUSP6 may be a pharmacodynamic marker of FGFR inhibitor efficacy in FGFR-addicted cancers. PMID- 26438160 TI - Longitudinal assessment of fractional anisotropy alterations caused by simian immunodeficiency virus infection: a preliminary diffusion tensor imaging study. AB - Previous diffusion tensor imaging (DTI) studies found that human immunodeficiency virus (HIV) infection led to white matter (WM) microstructure degeneration. Most of the DTI studies were cross-sectional and thus merely investigated only one specific point in the disease. In order to systematically study the WM impairments caused by HIV infection, more longitudinal studies are needed. However, longitudinal studies on HIV patients are very difficult to conduct. To address this question, we employed the simian immunodeficiency virus (SIV) infected rhesus monkeys model to carry out a longitudinal DTI study. We aimed to longitudinally access the WM abnormalities of SIV-infected rhesus monkeys by studying the fractional anisotropy (FA) alterations with Tract Based Spatial Statistic (TBSS) analysis. Four rhesus monkeys inoculated intravenously with SIVmac239 were utilized in the study. DTI scans and peripheral blood CD4(+) and CD8(+) T cell counts were acquired prior to virus inoculation (as the baseline) and in the 12th and 24th week postvirus inoculation. Significant FA alterations were found in the two areas of the inferotemporal regions (iTE), respectively located in the ventral subregion of posterior iTE (iTEpv) and the dorsal subregion of iTE (iTEpd). The decreased FA values in iTEpd were found significantly negatively correlated with the elevated peripheral blood CD4(+)/CD8(+) ratios. It might suggest that WM in iTEpd was still impaired even though the immune dysfunction alleviated temporally. PMID- 26438161 TI - Cytokine inhibition in chronic fatigue syndrome patients: study protocol for a randomized controlled trial. AB - BACKGROUND: Chronic fatigue syndrome (CFS) is a medically unexplained syndrome for which no somatic or pharmacological treatment has been proven effective. Dysfunction of the cytokine network has been suspected to play a role in the pathophysiology of CFS. The disturbances of the cytokine network detected in CFS patients are highly variable, in part due to the lack of adequate controls in many studies. Furthermore, all studies have been performed on peripheral venous blood of patients. As cytokines mainly act in tissues, for example, the brain, the information that can be derived from peripheral blood cells is limited. The information regarding the possible role of cytokines in the pathophysiology could come from intervention studies in which the activities of relevant cytokines are reduced, for example, reducing interleukin-1, interleukin-6 or tumor necrosis factor. In this study, the clinical usefulness of anakinra, an IL-1 antagonist, will be assessed in patients with CFS. METHODS/DESIGN: A randomized placebo controlled, double-blind trial will be conducted. Fifty adult female patients meeting the Centers for Disease Control (CDC) criteria for CFS and without psychiatric co-morbidity will be included. After inclusion, patients will be randomized between treatment with anakinra (recombinant human interleukin-1 receptor antagonist) or placebo. Each group will be treated for 4 weeks. Outcome measures will be assessed at baseline, after 4 weeks of intervention, and 6 months after baseline assessment. The primary outcome measure will be fatigue severity at 4 weeks, measured with the validated Checklist of Individual Strength (CIS). Secondary outcome measures are functional impairment, physical and social functioning, psychological distress, pain severity, presence of accompanying symptoms, and cytokine and cortisol concentrations. DISCUSSION: This is the first randomized placebo-controlled trial that will evaluate the effect of interference with IL-1 on the experience of fatigue in patients with CFS. The results of this study may expand treatment options for patients with CFS, for whom graded exercise therapy and cognitive behavioral therapy are the only evidence-based interventions that exist at this moment. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02108210 . Clinicaltrials.gov registration date: 8 April 2014. EudraCT: 2013 005466-19. PMID- 26438162 TI - Enhancement of 3-hydroxypropionic acid production from glycerol by using a metabolic toggle switch. AB - BACKGROUND: 3-hydroxypropionic acid (3-HP) is an important platform for the production of C3 chemicals, including acrylic acid, methyl acrylate, and acrylamide. Microbial production of 3-HP is mainly due to glycerol metabolism. In this study, in order to improve microbial 3-HP production, we applied a metabolic toggle switch for controlling the glycerol metabolism to redirect the excess metabolic flux of central metabolic pathway toward an exogenous 3-HP producing pathway in Escherichia coli. RESULTS: The metabolic toggle switch enables conditional repression of the expression of a target gene during the fermentation. We individually performed conditional repression of glpK, tpiA, and gapA, which are involved in glycerol metabolism. The conditional repression of glpK and tpiA was not effective for 3-HP production under our experimental conditions. However, gapA conditional repression contributed to improve 3-HP production (titer, 54.2 +/- 1.5 mM; yield, 32.1 +/- 1.3 %) compared with that for the wild type strain. Additional deletion of endogenous yqhD, which is responsible for the production of a major byproduct, 1,3-propandiol, further increased 3-HP production (titer, 67.3 +/- 2.1 mM; yield, 51.5 +/- 3.2 %). The titer and yield were 80 and 94 % higher than those of the wild type strain, respectively. The obtained 3-HP yield from glycerol is comparable with the highest yield ever reported for microbial 3-HP production using glycerol as a sole carbon source. The measurement of intracellular metabolites showed the metabolic toggle switch successfully controlled the metabolic flux. CONCLUSION: The conditional repression of gapA by using the metabolic toggle switch combined with deletion of endogeneous yqhD increased 3-HP production approximately twofold from glycerol. This result indicates the metabolic toggle switch can be applied in various bio-production using diverse substrates. PMID- 26438163 TI - Factors important in the choice of a medical career: a Finnish national study. AB - BACKGROUND: Applying for medical school is the first and also one of the most important career choices a physician makes. It is important to understand the reasons behind this decision if we are to choose the best applicants for medical schools and enable them to pursue satisfying careers. METHODS: Respondents to the Finnish Junior Physician 88, Physician 1998 and Physician 2008 studies were asked: "To what extent did the following factors influence your decision to apply for medical school?" In 1998 and 2008 the respondents were also asked: "If you were starting your studies now, would you start studying medicine?" and had to answer "Yes" or "No". The odds ratios for the answer "No" were tested using logistic regression models. RESULTS: "Interest in people" was the main motive for starting to study medicine. "Good salary" and "Prestigious profession" were more important motives for males and "Vocation" and "Interest in people" for females. There were some significant changes in the motives for entering medicine in the 20-year period between studies. "Vocation" and "Wide range of professional opportunities" as important motives for entering medicine predicted satisfaction with the medical profession. DISCUSSION: Strong inner motivation may indicate the ability to adapt to the demands of work as a physician. CONCLUSIONS: Medical schools should try to select those applicants with the greatest vocational inclination towards a medical career. PMID- 26438164 TI - A single gene all3940 (Dps) overexpression in Anabaena sp. PCC 7120 confers multiple abiotic stress tolerance via proteomic alterations. AB - DNA-binding proteins (Dps) induced during starvation play an important role in gene regulation and maintaining homeostasis in bacteria. The nitrogen-fixing cyanobacterium, Anabaena PCC7120, has four genes annotated as coding for Dps; however, the information on their physiological roles is limiting. One of the genes coding for Dps, 'all3940' was found to be induced under different abiotic stresses in Anabaena and upon overexpression enhanced the tolerance of Anabaena to a multitude of stresses, which included salinity, heat, heavy metals, pesticide, and nutrient starvation. On the other hand, mutation in the gene resulted in decreased growth of Anabaena. The modulation in the levels of All3940 in Anabaena, achieved either by overexpression of the protein or mutation of the gene, resulted in changes in the proteome, which correlated well with the physiological changes observed. Proteins required for varied physiological activities, such as photosynthesis, carbon-metabolism, oxidative stress alleviation, exhibited change in protein profile upon modulation of All3940 levels in Anabaena. This suggested a direct or an indirect effect of All3940 on the expression of the above stress-responsive proteins, thereby enhancing tolerance in Anabaena PCC7120. Thus, All3940, though categorized as a Dps, is possibly a general stress protein having a global role in regulating tolerance to multitude of stresses in Anabaena. PMID- 26438165 TI - MicroRNAs in the oriental fruit fly, Bactrocera dorsalis: extending Drosophilid miRNA conservation to the Tephritidae. AB - BACKGROUND: The oriental fruit fly, Bactrocera dorsalis, is an important plant pest species in the family Tephritidae. It is a phytophagous species with broad host range, and while not established in the mainland United States, is a species of great concern for introduction. Despite the vast amount of information available from the closely related model organism Drosophila melanogaster, information at the genome and transcriptome level is still very limited for this species. Small RNAs act as regulatory molecules capable of determining transcript levels in the cells. The most studied small RNAs are micro RNAs, which may impact as much as 30 % of all protein coding genes in animals. RESULTS: We have sequenced small RNAs (sRNAs) from the Tephritid fruit fly, B. dorsalis (oriental fruit fly), specifically sRNAs corresponding to the 17 to 28 nucleotides long fraction of total RNA. Sequencing yielded more than 16 million reads in total. Seventy five miRNAs orthologous to known miRNAs were identified, as well as five additional novel miRNAs that might be specific to the genera, or to the Tephritid family. We constructed a gene expression profile for the identified miRNAs, and used comparative analysis with D. melanogaster to support our expression data. In addition, several miRNA clusters were identified in the genome that show conservancy with D. melanogaster. Potential targets for the identified miRNAs were also searched. CONCLUSIONS: The data presented here adds to our growing pool of information concerning the genome structure and characteristics of true fruit flies. It provides a basis for comparative studies with other Dipteran and within Tephritid species, and can be used for applied research such as in the development of new control strategies based on gene silencing and transgenesis. PMID- 26438166 TI - Morbidity associated with anterior iliac crest bone graft harvesting in children undergoing orthopaedic surgery: a prospective review. AB - PURPOSE: Autologous iliac crest bone grafting is an integral part of many orthopaedic surgical procedures. Several studies have documented morbidity and prolonged pain following iliac crest bone graft harvesting in adults; however, in children there is a paucity of information. The purpose of the present study was to quantify the degree of pain and morbidity associated with anterior iliac crest graft harvesting in children undergoing non-spinal orthopaedic surgery. METHODS: Patients were prospectively enrolled prior to orthopaedic surgery. A patient self reported visual analogue score was used to record pain at specified time points following surgery. In addition, the patients were reviewed at 2 and 6 weeks, 3 months and 1 year after surgery to record any complications. RESULTS: Data was collected on 33 patients (34 graft sites). Only one patient (2.94 %) had a complication, namely an injury to the lateral femoral cutaneous nerve. This resolved 3 months after surgery. 89 % of patients had no pain at the iliac crest graft harvest site 3 months after surgery. The three patients who had pain at 3 months had visual analogue scores of 1.0, 1.1 and 1.3, respectively. CONCLUSION: This series reveals a very low complication rate and minimal iliac crest graft harvest site pain in children undergoing non-spinal orthopaedic surgery. In addition, the pain experienced is short-lived. PMID- 26438168 TI - Topical issue: multimodality imaging in atherosclerosis. PMID- 26438167 TI - Mapping and direct valuation: do they give equivalent EQ-5D-5L index scores? AB - OBJECTIVE: Utility values of health states defined by health-related quality of life instruments can be derived from either direct valuation ('valuation derived') or mapping ('mapping-derived'). This study aimed to compare the utility based EQ-5D-5L index scores derived from the two approaches as a means to validating the mapping function developed by van Hout et al for the EQ-5D-5L instrument. METHODS: This was an observational study of 269 breast cancer patients whose EQ-5D-5L index scores were derived from both methods. For comparing discriminatory ability and responsiveness to change, multivariable regression models were used to estimate the effect sizes of various health indicators on the index scores. Agreement and test-retest reliability were examined using intraclass correlation coefficient (ICC). Whenever appropriate, the 90% confidence intervals (90% CI) were compared to predefined equivalence margins. RESULTS: The mean difference in and ICC between the valuation- and mapping-derived EQ-5D-5L index scores were 0.015 (90% CI = 0.006 to 0.024) and 0.915, respectively. Discriminatory ability and responsiveness of the two indices were equivalent in 13 of 15 regression analyses. However, the mapping-derived index score was lower than the valuation-derived index score in patients experiencing extreme health problems, and the test-retest reliability of the former was lower than the latter, for example, their ICCs differed by 0.121 (90% CI = 0.051 to 0.198) in patients who reported no change in performance status in the follow-up survey. CONCLUSION: This study provided the first evidence supporting the validity of the mapping function for converting EQ-5D-5L profile data into a utility-based index score. PMID- 26438169 TI - Posterior decompression and stabilisation of a spondylodiscitis L4/5. PMID- 26438170 TI - Percutaneous posterior stabilisation of L1 to L5 with microsurgical decompression of L3/4, and percutaneous L3 biopsy, in a spinal metastasis. PMID- 26438171 TI - Posterior stabilization of the cervical spine with lateral mass screws. PMID- 26438172 TI - Vertebral body replacement in the thoracolumbar spine via a mini-open, thoracoscopically assisted transthoracic approach. PMID- 26438173 TI - Is it possible to preserve lumbar lordosis after hybrid stabilization? Preliminary results of a novel rigid-dynamic stabilization system in degenerative lumbar pathologies. AB - PURPOSE OF THE STUDY: To evaluate the results of a novel rigid-dynamic stabilization technique in lumbar degenerative segment diseases (DSD), expressly pointing out the preservation of postoperative lumbar lordosis (LL). MATERIALS AND METHODS: Forty-one patients with one level lumbar DSD and initial disc degeneration at the adjacent level were treated. Circumferential lumbar arthrodesis and posterior hybrid instrumentation were performed to preserve an initial disc degeneration above the segment that has to be fused. Clinical and spino-pelvic parameters were evaluated pre- and postoperatively. RESULTS: At 2 year follow-up, a significant improvement of clinical outcomes was reported. No statistically significant difference was noted between postoperative and 2-year follow-up in LL and in disc/vertebral body height ratio at the upper adjacent fusion level. CONCLUSIONS: When properly selected, this technique leads to good results. A proper LL should be achieved after any hybrid stabilization to preserve the segment above the fusion. PMID- 26438174 TI - Head repositioning accuracy in patients with neck pain and asymptomatic subjects: concurrent validity, influence of motion speed, motion direction and target distance. AB - BACKGROUND: Cervicocephalic kinesthetic deficiencies have been demonstrated in patients with chronic neck pain (NP). On the other hand, authors emphasized the use of different motion speeds for assessing functional impairment of the cervical spine. PURPOSE: The objectives of this study were (1) to investigate the head repositioning accuracy in NP patients and control subjects and (2) to assess the influence of target distance, motion speed, motion direction and pain. MATERIALS AND METHODS: Seventy-one subjects (36 healthy subjects and 35 NP patients; age 30-55 years) performed the head repositioning test (HRT) at two different speeds for horizontal and vertical movements and at two different distances. For each condition, six consecutive trials were sampled. RESULTS: The study showed the validity and reproducibility of the HRT, confirming a dysfunctional threshold of 4.5 degrees . Normative values of head repositioning error up to 3.6 degrees and 7.1 degrees were identified for healthy and NP subjects, respectively. A distance of 180 cm from the target and a natural motion speed increased HRT accuracy. Repositioning after extension movement showed a significantly larger error in both groups. Intensity, duration of pain as well as pain level did not significantly alter head repositioning error. CONCLUSIONS: The assessment of proprioceptive performance in healthy and NP subjects allowed the validation of the HRT. The HRT is a simple, not expensive and fast test, easily implementable in daily practice to assess and monitor treatment and evolution of proprioceptive cervical deficits. PMID- 26438175 TI - Variation of Stable Carbon and Nitrogen Isotopic Composition of PM10 at Urban Sites of Indo Gangetic Plain (IGP) of India. AB - This paper presents the variation of elemental concentrations of total carbon (TC), total nitrogen (TN) and isotopic ratios of delta13C and delta15N along with delta13OC and OC of PM10 mass over Delhi, Varanasi and Kolkata of the Indo Gangetic Plain (IGP), India. For Delhi, the average concentrations of TC and TN of PM10 were 53.0+/-33.6 and 14.9+/-10.8 ug m(-3), whereas delta13C and delta15N of PM10 were -25.5+/-0.5 and 9.6+/-2.80/00, respectively. For Varanasi, the average values of delta13C and delta15N of PM10 were -25.4+/-0.8 and 6.8+/ 2.40/00, respectively. For Kolkata, TC and TN values for PM10 ranged from 9.1 98.2 to 1.4-25.9 ug m(-3), respectively with average values of 32.6+/-24.9 and 9.3+/-8.2 ug m(-3), respectively. The average concentrations of delta13C and delta15N were -26.0+/-0.4 and 7.4+/-2.70/00, respectively over Kolkata with ranges of -26.6 to -24.90/00 and 2.8+/-11.50/00, respectively. The isotopic analysis revealed that biomass burning, vehicular emission and secondary inorganic aerosols were likely sources of PM10 mass over IGP, India. PMID- 26438176 TI - Magnetic Graphene-Dispersive Solid-Phase Extraction for Preconcentration and Determination of Lead and Cadmium in Dairy Products and Water Samples. AB - A magnetic-dispersive solid-phase extraction (MDSPE) was used for precocentration of Pb(II) and Cd(II) in milk, yoghurt and water samples. An appropriate amount of suspension containing the magnetic graphene and Triton X-114 was injected rapidly into the aqueous sample by a syringe. Triton X-114 was used to achieve stable suspension of graphene in solution. The structure of the resulting products was confirmed by Fourier transform infrared (FT-IR) spectra, X-ray diffraction (XRD) spectrometry. The effects of various parameters were studied. A detection limit of 0.16 and 0.50 ug L(-1) for Cd(II) and Pb(II) was obtained, respectively. The relative standard deviations (RSDs, n = 10) of 50 ug L(-1) of Pb and Cd were 3.3 % and 2.1 %, respectively. The results indicated that the present method can be reliably used for determination of Pb(II) and Cd(II) in dairy products and water samples with good recoveries. PMID- 26438177 TI - Mercury Inhibits Soil Enzyme Activity in a Lower Concentration than the Guideline Value. AB - Three soil types - neutral, alkaline and acidic were experimentally contaminated with nine different concentrations of inorganic mercury (0, 5, 10, 50, 100, 150, 200, 250, 300 mg/kg) to derive effective concentrations of mercury that exert toxicity on soil quality. Bioavailability of mercury in terms of water solubility was lower in acidic soil with higher organic carbon. Dehydrogenase enzyme activity and nitrification rate were chosen as indicators to assess soil quality. Inorganic mercury significantly inhibited (p < 0.001) microbial activities in the soils. The critical mercury contents (EC10) were found to be less than the available safe limits for inorganic mercury which demonstrated inadequacy of existing guideline values. PMID- 26438178 TI - Temporal evolution of brain cancer incidence in the municipalities of Navarre and the Basque Country, Spain. AB - BACKGROUND: Brain cancer incidence rates in Spain are below the European's average. However, there are two regions in the north of the country, Navarre and the Basque Country, ranked among the European regions with the highest incidence rates for both males and females. Our objective here was two-fold. Firstly, to describe the temporal evolution of the geographical pattern of brain cancer incidence in Navarre and the Basque Country, and secondly, to look for specific high risk areas (municipalities) within these two regions in the study period (1986-2008). METHODS: A mixed Poisson model with two levels of spatial effects is used. The model also included two levels of spatial effects (municipalities and local health areas). Model fitting was carried out using penalized quasi likelihood. High risk regions were detected using upper one-sided confidence intervals. RESULTS: Results revealed a group of high risk areas surrounding Pamplona, the capital city of Navarre, and a few municipalities with significant high risks in the northern part of the region, specifically in the border between Navarre and the Basque Country (Gipuzkoa). The global temporal trend was found to be increasing. Differences were also observed among specific risk evolutions in certain municipalities. CONCLUSIONS: Brain cancer incidence in Navarre and the Basque Country (Spain) is still increasing with time. The number of high risk areas within those two regions is also increasing. Our study highlights the need of continuous surveillance of this cancer in the areas of high risk. However, due to the low percentage of cases explained by the known risk factors, primary prevention should be applied as a general recommendation in these populations. PMID- 26438179 TI - Effect-site concentration of propofol required for LMA-SupremeTM insertion with and without remifentanil: a randomized controlled trial. AB - BACKGROUND: A new supraglottic device, the LMA-SupremeTM, has recently become available for clinical use. Information on anaesthetic and co-adjuvant requirements for insertion of the LMA-SupremeTM is limited. The present study aimed to evaluate the optimal effect-site concentration of propofol in 50 % (EC50) of adults necessary for successful insertion of the LMA-SupremeTM and to examine remifentanil's effect on propofol requirements. METHODS: Fifty-eight elective patients (aged 18-60 years; ASA (American Society Anaesthesiologists) physical status classification I and II) scheduled for day surgery were randomly assigned to one of two groups: propofol with saline or propofol with remifentanil. Anaesthesia was induced by target-controlled infusion according to predetermined effect-site concentrations of propofol and remifentanil (5 ng.mL( 1)). The EC50 was calculated using Dixon's up-and-down method. Ten minutes following drug administration, LMA-SupremeTM insertion was attempted without the use of muscle relaxant drugs. RESULTS: In the propofol + saline group, the EC50 of propofol required for LMA-SupremeTM insertion was 6.32 +/- 0.67 MUg.mL(-1) (95 % CI, 5.69-6.94 MUg.mL(-1)). With the addition of remifentanil at an effect-site concentration of 5 ng.mL(-1), the EC50 of propofol required for LMA-SupremeTM insertion was 2.50 +/- 0.80 MUg.mL(-1) (95 % CI, 1.82-3.17 MUg.mL(-1); p < 0.0001). CONCLUSIONS: The propofol requirement for smooth insertion of the LMA SupremeTM was 60 % less when remifentanil (5 ng.mL(-1)) was co-administered. CLINICAL TRIAL REGISTRATION: Identified as NCT01974648 at www.clinicaltrials.gov . PMID- 26438180 TI - Role of glial 14-3-3 gamma protein in autoimmune demyelination. AB - BACKGROUND: The family of 14-3-3 proteins plays an important role in the regulation of cell survival and death. Here, we investigate the role of the 14-3 3 gamma (14-3-3 gamma) subunit for glial responses in autoimmune demyelination. METHODS: Expression of 14-3-3 gamma in glial cell culture was investigated by reverse transcription polymerase chain reaction (RT-PCR) and immunocytochemistry. 14-3-3 gamma knockout mice were subjected to murine myelin oligodendrocyte induced experimental autoimmune encephalomyelitis (MOG-EAE), an animal model mimicking inflammatory features and neurodegenerative aspects of multiple sclerosis (MS). RESULTS: Expression studies in cell culture confined expression of 14-3-3 gamma to both, oligodendrocytes (OL) and astrocytes. RT-PCR analysis revealed an increased expression of 14-3-3 gamma mRNA in the spinal cord during the late chronic phase of MOG-EAE. At that stage, EAE was more severe in 14-3-3 gamma knockout mice as compared to age- and gender-matched controls. Histopathological analyses on day 56 post immunization (p.i.) revealed significantly enhanced myelin damage as well as OL injury and secondary, an increase in axonal injury and gliosis in 14-3-3 gamma -/- mice. At the same time, deficiency in 14-3-3 gamma protein did not influence the immune response. Further histological studies revealed an increased susceptibility towards apoptosis in 14 3-3 gamma-deficient OL in the inflamed spinal cord. CONCLUSION: These data argue for a pivotal role of 14-3-3 gamma-mediated signalling pathways for OL protection in neuroinflammation. PMID- 26438181 TI - Folate-Conjugated pH-Responsive Nanocarrier Designed for Active Tumor Targeting and Controlled Release of Gemcitabine. AB - PURPOSE: The prime end of this study was to design a novel pH-sensitive as well as a PEGylated dendritic nanocarrier for both controllable and traceable gemcitabine delivery to cancerous cells. To accomplish this goal, we took advantage of a hybrid of nanoparticles including: mesoporous silica, graphene oxide and magnetite. METHODS: The nanocarrier was prepared in a multi-step synthesis route. First, magnetite mesoporous silica was deposited on the graphene oxide matrix. Then, polyamidoamine dendrimers (up to generation 1.5) with pentaethylene hexamine end groups were grafted on the surface of the nanoparticles. In order to enhance the biostability, and as the next step, the nanocarrier was modified by polyethylene glycol. Finally, these particles were functionalized by folic acid as tumor targeting agents. RESULTS: According to the dynamic light scattering results, the hydrodynamic diameter of magnetic mesoporous silica graphene oxide hybrid nanoparticle was 152 +/- 3 nm, while for the supramolecular hybrid nanoparticles it was about 324 +/- 12 nm. Attained through the adsorption branch, the average pore diameter of these nanoparticles was 7.6 nm. Zeta potential test indicated -27.1 mV value for hybrid nanoparticles and +7.35 mV for supramolecular hybrid nanoparticles. Besides, cytotoxicity assay showed enhanced cytotoxicity of epidermoid carcinoma cell line A431 in the presence of folate conjugated carriers. The maximum release occurred at the pH 5.5, because the dendritic structure was in the open state rather than compact state. CONCLUSIONS: The enhanced cytotoxicity of the epidermoid carcinoma cell line A431 in the presence of folate conjugated carriers, confirmed the improved cancerous cells uptake. Also, the positive surface potential would be a good property for the biological applications because the inherent negative-charged surface of cell membranes facilitates the uptake of positive particles by electrostatic interactions. PMID- 26438182 TI - Comment on Roessler et al.: Short-term follow up after implantation of a cell free collagen type I matrix for the treatment of large cartilage defects of the knee. PMID- 26438183 TI - "Fatigue meniscal tears": a description of the lesion and the results of arthroscopic partial meniscectomy. AB - PURPOSE: The purpose of this study was to describe the clinical outcomes of partial meniscectomy in patients with "fatigue meniscal tear", which presents as a non-traumatic tear with abrupt onset of symptoms of a radial tear in the transition between the middle and posterior thirds of the meniscus. METHODS: We prospectively followed 71 patients with "fatigue meniscal tear" (41 women and 30 men, mean age of 63 years, SD 6.9 years) recruited among 497 patients with isolated medial meniscal lesions treated between January 2006 and June 2011. Inclusion criteria were spontaneous abrupt onset knee pain, minor or no trauma, no radiographic or MRI osteoarthritis, no bone oedema, pre-operative magnetic resonance image of medial meniscus tear, and arthroscopic evaluation demonstrating radial or vertical flap tear in the body to posterior horn junction of the medial meniscus. We followed all patients for a minimum of two years and reviewed their clinical symptoms, physical exam, functional outcome, and patient satisfaction at last follow-up. RESULTS: The average follow-up was 4.2 years, with a minimum follow-up of two years. Among the 71 patients, there were 59 (83.1 %) good or excellent results and 12 (16.9 %) poor results. These 12 patients demanded further treatment because of persistent pain, with three of the patients developing subchondral bone fracture. All patient complaints and poor outcomes could be identified in the initial six months after surgery. There was no gender difference in the subgroup analysis. CONCLUSION: Our findings indicate that patients with "fatigue meniscal tear" benefit from arthroscopic partial meniscectomy, with only 16.9 % reporting unfavourable results. LEVEL OF EVIDENCE: IV, Cohort study or case series. PMID- 26438185 TI - Attitudes and practice patterns for maintaining relative dose intensity of chemotherapy in outpatient clinics: results of a Japanese web-based survey. AB - BACKGROUND: This analysis was undertaken to evaluate the practice patterns of Japanese physicians regarding curative-intent chemotherapy, especially in outpatient settings, and to define factors negatively affecting the maintenance of relative dose intensity (RDI). METHODS: We performed a web-based questionnaire survey of Japanese physicians involved in malignant lymphoma chemotherapy (Group ML) or in breast cancer chemotherapy (Group BC). The questionnaire inquired how they manage low-risk febrile neutropenia (FN) caused by initial chemotherapy for diffuse large B-cell lymphoma(DLBCL) or by adjuvant chemotherapy for breast cancer in an outpatient setting. RESULTS: Valid responses were obtained from 185 physicians in Group ML and 160 in Group BC. In Group ML, 76 % (n = 141) of the physicians were board-certified hematologists, while 82 % (n = 131) of the physicians in Group BC were board-certified surgeons. A significantly higher proportion of physicians in Group ML responded that "dose reduction is not required for the subsequent course of chemotherapy after the first episode of FN" than in Group BC (ML versus BC; 77 % versus 31 %; P < 0.001). Significantly higher proportions of physicians in Group ML were more likely to prophylactically administer antibiotics or granulocyte-colony stimulating factor (G-CSF; ML versus BC; antibiotics: 36 % versus 26 %, P = 0.049; G-CSF: 25 % versus 16 %, P = 0.047). Eighty six percent (n = 159) of Group ML and 70 % (n = 112) of Group BC responded that "emergency outpatient unit is open at all hours". CONCLUSIONS: Japanese physicians are more likely to administer reduced doses of chemotherapy to patients with breast cancer than to patients with malignant lymphoma. Supportive infrastructures should be improved to ensure the provision of adequate chemotherapy to all cancer patients. PMID- 26438184 TI - Effects of Intermittent Fasting, Caloric Restriction, and Ramadan Intermittent Fasting on Cognitive Performance at Rest and During Exercise in Adults. AB - The aim of this review was to highlight the potent effects of intermittent fasting on the cognitive performance of athletes at rest and during exercise. Exercise interacts with dietary factors and has a positive effect on brain functioning. Furthermore, physical activity and exercise can favorably influence brain plasticity. Mounting evidence indicates that exercise, in combination with diet, affects the management of energy metabolism and synaptic plasticity by affecting molecular mechanisms through brain-derived neurotrophic factor, an essential neurotrophin that acts at the interface of metabolism and plasticity. The literature has also shown that certain aspects of physical performance and mental health, such as coping and decision-making strategies, can be negatively affected by daylight fasting. However, there are several types of intermittent fasting. These include caloric restriction, which is distinct from fasting and allows subjects to drink water ad libitum while consuming a very low-calorie food intake. Another type is Ramadan intermittent fasting, which is a religious practice of Islam, where healthy adult Muslims do not eat or drink during daylight hours for 1 month. Other religious practices in Islam (Sunna) also encourage Muslims to practice intermittent fasting outside the month of Ramadan. Several cross-sectional and longitudinal studies have shown that intermittent fasting has crucial effects on physical and intellectual performance by affecting various aspects of bodily physiology and biochemistry that could be important for athletic success. Moreover, recent findings revealed that immunological variables are also involved in cognitive functioning and that intermittent fasting might impact the relationship between cytokine expression in the brain and cognitive deficits, including memory deficits. PMID- 26438186 TI - A Mechanistic Neural Field Theory of How Anesthesia Suppresses Consciousness: Synaptic Drive Dynamics, Bifurcations, Attractors, and Partial State Equipartitioning. AB - With the advances in biochemistry, molecular biology, and neurochemistry there has been impressive progress in understanding the molecular properties of anesthetic agents. However, there has been little focus on how the molecular properties of anesthetic agents lead to the observed macroscopic property that defines the anesthetic state, that is, lack of responsiveness to noxious stimuli. In this paper, we use dynamical system theory to develop a mechanistic mean field model for neural activity to study the abrupt transition from consciousness to unconsciousness as the concentration of the anesthetic agent increases. The proposed synaptic drive firing-rate model predicts the conscious-unconscious transition as the applied anesthetic concentration increases, where excitatory neural activity is characterized by a Poincare-Andronov-Hopf bifurcation with the awake state transitioning to a stable limit cycle and then subsequently to an asymptotically stable unconscious equilibrium state. Furthermore, we address the more general question of synchronization and partial state equipartitioning of neural activity without mean field assumptions. This is done by focusing on a postulated subset of inhibitory neurons that are not themselves connected to other inhibitory neurons. Finally, several numerical experiments are presented to illustrate the different aspects of the proposed theory. PMID- 26438187 TI - Spatial spillover effects of a community action programme targeting on-licensed premises on violent assaults: evidence from a natural experiment. AB - BACKGROUND: Spatial dependencies may influence the success of community action strategies to prevent and reduce harmful alcohol use. This study examined the effectiveness of a multicomponent Responsible Beverage Service (RBS) programme targeting on-licensed premises on police-recorded assaults in Swedish municipalities. It was expected that the implementation of the programme within any given municipality had an indirect effect by reducing violent assaults in adjacent municipalities. METHODS: This study was a natural experiment exploiting the temporal and spatial variation in the implementation of the RBS programme to predict change in the rate of violent assaults in all Swedish municipalities during 1996-2009 (n=288; T=14; N=4 032). Yearly police-recorded violent assaults per 100,000 inhabitants aged 15 and above committed on weekend nights were used as a dependent variable. Programme fidelity was identified by means of survey data. A semilogarithmic fixed-effects spatial panel regression model was used to estimate the direct, indirect and total effects of the programme. RESULTS: The direct, indirect and total effects were -1.8% (95% CI -4.4% to 0.8%), -5.8% (95% CI -11.5% to -0.1%) and -7.6% (95% CI -13.2% to -2.2%), respectively. Averaged over time and across all municipalities, implementing one additional programme component in all municipalities will thus reduce violent assaults in one typical municipality by nearly 8%. CONCLUSIONS: The indirect effect of the programme was three times larger than its direct effect. Failing to account for such local spillover effects can result in a considerable underestimation of the programme's total impact and may lead to erroneous policy recommendations. PMID- 26438188 TI - Ebola, jobs and economic activity in Liberia. AB - BACKGROUND: The 2014 Ebola virus disease (EVD) outbreak in the neighbouring West African countries of Guinea, Liberia and Sierra Leone represents the most significant setback to the region's development in over a decade. This study provides evidence on the extent to which economic activity declined and jobs disappeared in Liberia during the outbreak. METHODS: To estimate how the level of activity and number of jobs in a given set of firms changed during the outbreak, we use a unique panel data set of registered firms surveyed by the business development non-profit organisation, Building Markets. We also compare the change in economic activity during the outbreak, across regions of the country that had more versus fewer Ebola cases in a difference-in-differences approach. FINDINGS: We find a large decrease in economic activity and jobs in all of Liberia during the Ebola outbreak, and an especially large decline in Monrovia. Outside of Monrovia, the restaurants, and food and beverages sectors have suffered the most among the surveyed sectors, and in Monrovia, the construction and restaurant sectors have shed the most employees, while the food and beverages sectors experienced the largest drop in new contracts. We find little association between the incidence of Ebola cases and declines in economic activity outside of Monrovia. CONCLUSIONS: If the large decline in economic activity that occurred during the Ebola outbreak persists, a focus on economic recovery may need to be added to the efforts to rebuild and support the healthcare system in order for Liberia to regain its footing. PMID- 26438189 TI - The Candida albicans agglutinin-like sequence family of adhesins: functional insights gained from structural analysis. AB - Candida albicans colonizes many host sites suggesting its interaction with diverse ligands. Candida albicans adhesion is mediated by a number of proteins including those in the Als (agglutinin-like sequence) family, which have been studied intensively. The recent solution of the Als binding domain structure ended years of speculation regarding the molecular mechanism for Als adhesive function. Als adhesins bind flexible C termini from a broad collection of proteins, providing the basis for adhesion to various cell types and perhaps for C. albicans broad tissue tropism. Understanding adhesive functions at the molecular level will reveal the sequence of events in C. albicans pathogenesis, from host recognition to complex interactions such as development of polymicrobial biofilms or disseminated disease. PMID- 26438190 TI - T-wave Right Slope Provides a New Angle in the Prediction of Drug-Induced Ventricular Arrhythmias : Editorial to: "Electrocardiographic Predictors of Torsadogenic Risk During Dofetilide or Sotalol Initiation: Utility of a Novel T Wave Analysis Program" by Sugrue A. et al. PMID- 26438191 TI - Cellular volume regulation by anoctamin 6: Ca2+, phospholipase A2 and osmosensing. AB - During cell swelling, Cl(-) channels are activated to lower intracellular Cl(-) concentrations and to reduce cell volume, a process termed regulatory volume decrease (RVD). We show that anoctamin 6 (ANO6; TMEM16F) produces volume regulated anion currents and controls cell volume in four unrelated cell types. Volume regulation is compromised in freshly isolated intestinal epithelial cells from Ano6-/- mice and also in lymphocytes from a patient lacking expression of ANO6. Ca(2+) influx is activated and thus ANO6 is stimulated during cell swelling by local Ca(2+) increase probably in functional nanodomains near the plasma membrane. This leads to stimulation of phospholipase A2 (PLA2) and generation of plasma membrane lysophospholipids, which activates ANO6. Direct application of lysophospholipids also activates an anion current that is inhibited by typical ANO6 blocker. An increase in intracellular Ca(2+) supports activation of ANO6, but is not required when PLA2 is fully activated, while re-addition of arachidonic acid completely blocked ANO6. Moreover, ANO6 is activated by low intracellular Cl(-) concentrations and may therefore operate as a cellular osmosensor. High intracellular Cl(-) concentration inhibits ANO6 and activation by PLA2. Taken together, ANO6 supports volume regulation and volume activation of anion currents by action as a Cl(-) channel or by scrambling membrane phospholipids. Thereby, it may support the function of LRRC8 proteins. PMID- 26438192 TI - Unexpected dependence of RyR1 splice variant expression in human lower limb muscles on fiber-type composition. AB - The skeletal muscle ryanodine receptor Ca(2+) release channel (RyR1), essential for excitation-contraction (EC) coupling, demonstrates a known developmentally regulated alternative splicing in the ASI region. We now find unexpectedly that the expression of the splice variants is closely related to fiber type in adult human lower limb muscles. We examined the distribution of myosin heavy chain isoforms and ASI splice variants in gluteus minimus, gluteus medius and vastus medialis from patients aged 45 to 85 years. There was a strong positive correlation between ASI(+)RyR1 and the percentage of type 2 fibers in the muscles (r = 0.725), and a correspondingly strong negative correlation between the percentages of ASI(+)RyR1 and percentage of type 1 fibers. When the type 2 fiber data were separated into type 2X and type 2A, the correlation with ASI(+)RyR1 was stronger in type 2X fibers (r = 0.781) than in type 2A fibers (r = 0.461). There was no significant correlation between age and either fiber-type composition or ASI(+)RyR1/ASI(-)RyR1 ratio. The results suggest that the reduced expression of ASI(-)RyR1 during development may reflect a reduction in type 1 fibers during development. Preferential expression of ASI(-) RyR1, having a higher gain of in Ca(2+) release during EC coupling than ASI(+)RyR1, may compensate for the reduced terminal cisternae volume, fewer junctional contacts and reduced charge movement in type 1 fibers. PMID- 26438193 TI - Parapatric distribution and sexual competition between two tick species, Amblyomma variegatum and A. hebraeum (Acari, Ixodidae), in Mozambique. AB - BACKGROUND: Amblyomma variegatum and A. hebraeum are two ticks of veterinary and human health importance in south-east Africa. In Zimbabwe they occupy parapatric (marginally overlapping and juxtaposed) distributions. Understanding the mechanisms behind this parapatry is essential for predicting the spatio-temporal dynamics of Amblyomma spp. and the impacts of associated diseases. It has been hypothesized that exclusive competition between these species results from competition at the levels of male signal reception (attraction-aggregation attachment pheromones) or sexual competition for mates. This hypothesis predicts that the parapatry described in Zimbabwe could also be present in other countries in the region. METHODS: To explore this competitive exclusion hypothesis we conducted field surveys at the two species' range limits in Mozambique to identify areas of sympatry (overlapping areas) and to study potential interactions (communicative and reproductive interference effects) in those areas. At sympatric sites, hetero-specific mating pairs were collected and inter specific attractiveness/repellent effects acting at long and short distances were assessed by analyzing species co-occurrences on co-infested herds and co-infested hosts. RESULTS: Co-occurrences of both species at sampling sites were infrequent and localized in areas where both tick and host densities were low. At sympatric sites, high percentages of individuals of both species shared attachment sites on hosts and inter-specific mating rates were high. Although cross-mating rates were not significantly different for A. variegatum and A. hebraeum females, attraction towards hetero-specific males was greater for A. hebraeum females than for A. variegatum females and we observed small asymmetrical repellent effects between males at attachment sites. CONCLUSIONS: Our observations suggest near-symmetrical reproductive interference between A. variegatum and A. hebraeum, despite between species differences in the strength of reproductive isolation barriers acting at the aggregation, fixation and partner contact levels. Theoretical models predict that sexual competition coupled with hybrid inviability, greatly reduces the probability of one species becoming established in an otherwise suitable location when the other species is already established. This mechanism can explain why the parapatric boundary in Mozambique has formed within an area of low tick densities and relatively infrequent host-mediated dispersal events. PMID- 26438194 TI - Cost of illness of the prostate cancer in Japan--a time-trend analysis and future projections. AB - BACKGROUND: The majority of patients with prostate cancer (International Classification of Diseases, 10th edition, code C61) are elderly. With Japan's rapidly society aging, both the prevalence and mortality of prostate cancer are expected to increase in the future. The objective of this study was to estimate and predict the cost of illness (COI) associated with prostate cancer in Japan. METHODS: Using a COI method based on available data from government office statistics, we estimated the COI for 2002, 2005, 2008, and 2011. We then predicted the COI for 2014, 2017, and 2020 using fixed model estimation and variable model estimation. With fixed model estimation, only estimated future population was used as a variable. Variable model estimation considered the time trend of health-related indicators in the past 15 years. We derived the COI from the sum of direct and indirect costs (morbidity and mortality). RESULTS: We found the predicted future COI of prostate cancer to be 354.7-378.3 billion yen in 2014, 370.8-421.0 billion yen in 2017, and 385.3-474.1 billion yen in 2020. Regardless of the estimation model, we found that COI would increase compared with the baseline year 2011 (307.3 billion yen). The direct costs for inpatient and outpatient treatment, laboratory tests, and drugs accounted for 60-75% of the COI of prostate cancer. CONCLUSIONS: The results of this study suggest that the COI of prostate cancer in Japan has steadily increased and is expected to rise in the future. Direct costs comprised the largest proportion of the COI and are anticipated to continue expanding; this will result in increased burden on public funds in Japan, where a universal public insurance system operates. These trends differ from those with other forms of cancer. PMID- 26438195 TI - Opportunities for involving men and families in chronic disease management: a qualitative study from Chiapas, Mexico. AB - BACKGROUND: A healthy lifestyle intervention was implemented in primary care health centers in urban parts of Tuxtla Gutierrez, Chiapas, Mexico with an aim of reducing cardiovascular disease risk for patients with type 2 diabetes and/or hypertension. During implementation, research questions emerged. Considerably fewer men participated in the intervention than women, and an opportunity was identified to increase the reach of activities aimed at improving disease self management through strategies involving family members. A qualitative study was conducted to identify strategies to involve men and engage family members in disease management and risk reduction. METHODS: Nine men with hypertension and/or type 2 diabetes with limited to no participation in disease self-management and health promotion activities, six families in which at least one family member had a diagnosis of one or both conditions, and nine health care providers from four different government health centers were recruited for the study. Participants took part in semi-structured interviews. During interviews with families, genograms and eco-maps were used to diagram family composition and structure, and capture the nature of patients' relationships to the extended family and community resources. Transcripts were coded and a general inductive analytic approach was used to identify themes related to men's limited participation in health promotion activities, family support and barriers to disease management, and health care providers' recommendations. RESULTS: Participants reported barriers to men's participation in chronic disease management and healthy lifestyle education activities that can be grouped into two categories: internal and external factors. Internal factors are those for which they are able to make the decision on their own and external factors are those that are not related solely to their decision to take part or not. Four primary aspects were identified related to families' relationships with disease: different roles within the family, types of support provided to patients, the opportunity to prevent disease among family members without a diagnosis, and - in some cases - lack of family support or stress-induced by other family members. There was an overlap in recommended strategies for engaging men and family members in chronic disease management activities. CONCLUSIONS: There is an opportunity to increase the reach of interventions aimed at improving disease self-management by engaging men and family members. The proposed strategies presented by patients, family members, and providers have implications for health education and service provision at primary care health centers and for future research. PMID- 26438196 TI - [Should metal alloy discs be used for patch testing in suspected metal implant intolerance reaction?]. AB - Intolerance reactions to metal implants may be caused by metal allergy. However, prior to implantation, patch testing should not be done in a prophylactic prophetic approach. Pre-implant patch testing should only be performed to verify or exclude metal allergy in patients with a reported respective history. In the case of implant-in particular arthroplasty-related complications like, for example, pain, effusion, skin changes, reduced range of motion, or loosening, orthopedic-surgical differential diagnostics should be performed first. Allergological workup of suspected metal implant allergy should be done with the DKG baseline series which contains nickel-, cobalt- and chromium-preparations. Various studies assessing the usefulness of metal alloy discs for patch testing proved that this approach does not give reliable information about metal allergy. Positive patch test reactions to the discs cannot be assigned to a specific metal within the disc alloy components. Furthermore, availability of such metal discs might be an invitation to uncritical testing. Accordingly, due to lack of benefit in comparison to patch testing with standardized metal salt preparations, we do not recommend patch testing with metal alloy discs. PMID- 26438197 TI - Frontotemporal epi- and subdural approach to a cavernous sinus tumor for sphenobasal vein preservation--technical case report. AB - In cavernous sinus (CS) surgery, venous complication may occur in some types of venous drainage. The sphenobasal vein (SBV) drains from the superficial middle cerebral vein (SMCV) to the pterygoid venous plexus at the temporal skull base. A frontotemporal epi- and interdural approach (Dolenc approach), which is one of the CS approaches, may damage the SBV's route. We report a case of intracavernous trigeminal schwannoma that contained the SBV and discuss our modified surgical procedure that combined epi- and subdural approaches to preserve the SBV. A 64 year-old man complained of right progressive oculomotor palsy and was referred to our hospital for surgery. MR images revealed a hemorrhagic tumor in the right CS. Three-dimensional venography revealed that the SMCV drained into the pterygoid venous plexus via the SBV. After identifying the first branch of the trigeminal nerve epidurally, we incised the dura linearly along the sylvian fissure and entered the subdural space to visualize the SBV. The incision was continued to the meningeal dura of the lateral wall of the CS along the superior margin of the first branch of the trigeminal nerve, and the Parkinson's triangle was opened from the subdural side. The tumor was grossly totally removed, and the SBV was preserved. In conclusion, a frontotemporal epi- and subdural approach to the intracavernous trigeminal schwannoma can effectively preserve the SBV. PMID- 26438198 TI - Endoscopic submucosal dissection for early gastric cancer in elderly patients: a meta-analysis. AB - BACKGROUND: The effectiveness of endoscopic submucosal dissection (ESD) has been increasingly reported. However, studies addressing the safety and application value of ESD in elderly patients with early gastric cancer (EGC) were still lacking. This meta-analysis was intended to evaluate the feasibility and safety of ESD in elderly patients with EGC. METHODS: A systematic search was conducted in PubMed, EBSCO, Cochrane Library, EMBASE, and Web of Science. Studies were screened out if data of elderly and non-elderly gastric cancer patients were reported separately. The qualities of included studies were assessed using Newcastle-Ottawa Quality Assessment Scale. The pooled odd ratios (ORs) with 95 % confidence intervals (CIs) were calculated. Statistical analysis was conducted using the Review Manager 5.2 (Cochrane Collaboration, Oxford, UK). RESULTS: Nine studies (eight in Japan, one in China), including a total of 30,100 lesions, met the inclusion criteria. The "en bloc" and histological complete resection rates of the elderly and non-elderly groups were similar [OR, 0.98, 95 % CI, 0.56 to 1.71; P = 0.93 and OR, 0.79, 95 % CI, 0.58 to 1.07; P = 0.13, respectively]. As for procedure-related complications, similar perforation rates [OR, 1.19, 95 % CI, 0.94 to 1.51; P = 0.15], and bleeding rates [OR, 1.13, 95 % CI, 0.83 to 1.56); P = 0.43] between the elderly and non-elderly groups were observed. Whereas, the elderly patients had a higher procedure-related pneumonia rate compared with non-elderly ones [OR, 2.18, 95 % CI, 1.55 to 3.08; P < 0.01]. CONCLUSIONS: The ESD procedure appears to be a safe technique in elderly patients with EGC while appropriate approach should be taken to avoid procedure-related pneumonia. PMID- 26438200 TI - Influence of nutritional status on the therapeutic effect of infliximab in patients with Crohn's disease. AB - PURPOSE: Crohn's disease (CD) is a refractory inflammatory bowel disease of unknown etiology, frequently complicated by malnutrition. It is thought that the delayed wound healing associated with this malnutrition in CD patients might adversely affect the therapeutic benefits of infliximab (IFX). Therefore, we investigated the effects of nutritional status on IFX treatment. METHODS: We assessed nutritional status and CD activity when IFX therapy was initiated and following the third dose, 6 weeks later. Nutritional status was assessed using the body mass index (BMI) and nutritional risk index (NRI), whereas CD activity was assessed using the CD activity index (CDAI). RESULTS: All patients with a BMI >= 18.5 kg/m(2) at the time of IFX therapy met the effective criteria for the CDAI, and IFX treatment was considered responsive in these patients. Furthermore, IFX treatment was responsive, with a high level of effectiveness, in all five subjects (31.3 %) with NRI scores of 97.5 and above with no risk of malnutrition (p = 0.037). CONCLUSIONS: Our results suggest that nutritional status does influence the therapeutic effect of IFX in CD patients. The response rate to IFX treatment thus could be improved by optimizing the nutritional status. We recommend comprehensive nutritional assessment and intervention prior to IFX treatment schedules. PMID- 26438201 TI - Clinical implications of carotid artery intima media thickness assessment on cardiovascular risk stratification in hyperlipidemic Korean adults with diabetes: the ALTO study. AB - BACKGROUND: The primary objective was to investigate prevalence of subclinical atherosclerosis in Korean individuals with diabetes and hyperlipidemia. Association of subclinical atherosclerosis with cardiovascular risk was assessed. METHODS: Assessments of carotid artery intima media thickness (cIMT) and atheromatous plaque were done using B-mode ultrasonography. Subclinical atherosclerosis was diagnosed based on presence of plaque, and/or increased cIMT versus mean cIMT reference values for Korean healthy controls. Atherosclerosis risk factors were analyzed using United Kingdom Prospective Diabetes Study (UKPDS) risk engine and Framingham Risk Score. RESULTS: In total, 355 patients were included; increased mean cIMT was observed in 15.3 % of patients, 69 % had >1 carotid artery plaque, and 72.7 % were diagnosed with subclinical atherosclerosis. In total, 60 % of subjects were taking statins, with low-density lipoprotein cholesterol level maintained ~80 mg/dL at enrollment. Carotid artery measures were well correlated with UKPDS and Framingham risk scores. Prevalence of subclinical atherosclerosis in the low risk group (<15 % 10-year UKPDS predicted coronary heart disease risk) was 64.7 %; higher than predicted in previous studies. In multivariate analysis, advanced age was a significant risk factor for subclinical atherosclerosis in men and women, while increased waist circumference and longer diabetes duration were independent predictors only in women. CONCLUSION: Subclinical atherosclerosis is more prevalent among individuals with both diabetes and hyperlipidemia than in diabetic patients without additional cardiovascular risk factors. As conventional risk engines, based on modifiable risk factors may underestimate cardiovascular risk, early non invasive carotid artery imaging screening may be warranted for patients with diabetes and hyperlipidemia, especially if they are elderly, have central obesity or have long duration of diabetes. TRIAL REGISTRATION: www.clinicaltrials.gov NCT01264263. PMID- 26438202 TI - [Full thickness resection device (FTRD). Experience and outcome for benign neoplasms of the rectum and colon]. AB - BACKGROUND: The diagnostic validity of a full-thickness resection is higher compared to endoscopic mucosal resection (EMR) or endoscopic mucosal dissection (ESD). Whereas transanal endoscopic microsurgery techniques (TEM, TAMIS) are established therapeutic procedures in the rectum no established and safe minimally invasive or endoscopic procedure exists in the colon. AIM: In this study the novel endoscopic full thickness resection device (FTRD, Ovesco, Germany) was investigated concerning success rates with histologically proven full thickness resections, R0 status as well as patient and device safety for the rectum and colon. METHOD: In the period from November 2014 to June 2015 full thickness resections in the rectum and colon were performed with the FTRD in 20 patients. Data on technical success, R0 resection rate and histologically confirmed full thickness resections were retrospectively analyzed. RESULTS: The following indications were treated in the rectum (n = 11) and colon (n = 9): T1 carcinoma (n = 6) and neuroendocrine tumors (n = 2), untreated and nonlifting adenomas (n = 3) and incomplete resection of adenomas with low and high grade dysplasia (n = 9). The technical success rate was 75 %, 3 technical failures made a conventional polypectomy necessary in 2 patients and in 1 patient an operative resection of the duplicated intestinal wall had to be performed. The median endoscopic follow-up time was 61.5 days (n = 10) and in 7 patients the clip had dislodged at the first follow-up. A thermal perforation in one case of conventional polypectomy gave rise to indications for a partial resection of the colon. In one patient the lesion in the cecum could be reached but not treated for technical reasons. The histological R0 rate was 80 %, whereas the full thickness resection rate was 60 % (85.7 % in the colon and 54.6 % in the rectum). In two patients with carcinoma and incomplete FTRD, surgical treatment was performed. The median size of the resection specimen was 5 cm(2) (range 1.6-12.9 cm(2)). CONCLUSION: The results show that FTRD is a safe and effective instrument for use in the lower gastrointestinal tract. Limitations of the FTRD system concerning full thickness resection are scarring, fibrosis and thickness of the intestinal wall, especially in the lower rectum; therefore, it is suggested that a simulation with a tube similar in size to the FTRD should be performed during the screening colonoscopy in order to establish whether an endoscopic resection with FTRD is possible. PMID- 26438204 TI - Special Issue on Pan American Biofuel and Bioenergy Sustainability. PMID- 26438203 TI - Microglia processes associate with diffusely injured axons following mild traumatic brain injury in the micro pig. AB - BACKGROUND: Mild traumatic brain injury (mTBI) is an all too common occurrence that exacts significant personal and societal costs. The pathophysiology of mTBI is complex, with reports routinely correlating diffuse axonal injury (DAI) with prolonged morbidity. Progressive chronic neuroinflammation has also recently been correlated to morbidity, however, the potential association between neuroinflammatory microglia and DAI is not well understood. The majority of studies exploring neuroinflammatory responses to TBI have focused on more chronic phases of injury involving phagocytosis associated with Wallerian change. Little, however, is known regarding the neuroinflammatory response seen acutely following diffuse mTBI and its potential relationship to early DAI. Additionally, while inflammation is drastically different in rodents compared to humans, pigs and humans share very similar inflammatory profiles and responses. METHODS: In the current study, we employed a modified central fluid percussion model in micro pigs. Using this model of diffuse mTBI, paired with various immunohistological endpoints, we assessed the potential association between acute thalamic DAI and neuroinflammation 6 h following injury. RESULTS: Injured micro pigs displayed substantial axonal damage reflected in the presence of APP+ proximal axonal swellings, which were particularly prominent in the thalamus. In companion, the same thalamic sites displayed extensive neuroinflammation, which was observed using Iba-1 immunohistochemistry. The physical relationship between microglia and DAI, assessed via confocal 3D analysis, revealed a dramatic increase in the number of Iba-1+ microglial processes that contacted APP+ proximal axonal swellings compared to uninjured myelinated thalamic axons in sham animals. CONCLUSIONS: In aggregate, these studies reveal acute microglial process convergence on proximal axonal swellings undergoing DAI, an interaction not previously recognized in the literature. These findings transform our understanding of acute neuroinflammation following mTBI and may suggest its potential as a diagnostic and/or a therapeutic target. PMID- 26438205 TI - The impact of an unpredictable context and intolerance of uncertainty on the electrocortical response to monetary gains and losses. AB - There is growing evidence that unpredictability and uncertainty can alter reward system functioning. The present study examined the impact of (1) a task irrelevant unpredictable relative to predictable context and (2) individual differences in intolerance of uncertainty (IU) on the reward-related positivity (RewP), an event-related potential (ERP) response to monetary gains relative to losses. Specifically, 64 participants listened to predictable and unpredictable tone sequences while electroencephalography was recorded during a monetary gambling task. Participants also completed the Intolerance of Uncertainty Scale, which measures both cognitive distress (prospective IU) and behavioral inhibition (inhibitory IU) elicited by uncertainty, in addition to the Depression Anxiety Stress Scale-21 and Penn State Worry Questionnaire. Results indicated that the RewP was reduced during the unpredictable relative to the predictable context. Greater self-reported anxiety elicited by the unpredictable context was associated with a decreased RewP, and a decreased RewP was associated with poorer lose-shift behavioral adjustment. Furthermore, the RewP mediated the relationship between self-reported anxiety elicited by the unpredictable context and lose shift behavioral adjustment. The IU subscales demonstrated the opposite relationship with the RewP across both contexts-inhibitory IU was associated with an attenuated RewP and prospective IU was associated with an enhanced RewP. In contrast, anxiety, depression, stress, and worry symptomatology were not associated with the RewP. This is the first study to demonstrate that an unpredictable context and individual differences in the degree to which people cannot tolerate uncertainty impact an ERP measure of reward system functioning. PMID- 26438206 TI - Assessing the utility of ICU admission for octogenarians. AB - BACKGROUND: Advanced age is associated with increased severity of acute critical illnesses and admission to ICU. Despite advances in the support for older critically ill patients, the short- and long-term mortality rates remain substantial. The purpose of this study is to analyze the factors influencing the outcome of a geriatric population admitted to the ICU. METHODS: A single-center, prospective, observational study was conducted among all geriatric patients, 80 years or older, admitted to ICU during a 6-month study period. RESULTS: Fifty-two patients were admitted. Mean age was 85.1 years (range 80-96), mean APACHE-II score was 24.7 (range 11-40), and mean frailty score was 5.8 (range 3-8). Thirty nine (75 %) patients received mechanical ventilation, and 31 (59.7 %) were on vasoactive therapy. Twenty-four (46.3 %) patients died during their hospital admission, and 13 (25 %) of them expired in ICU. DISCUSSION: Advanced age, needs for vasopressor therapy, and mechanical ventilation are independent predictive factors of adverse outcome. Pre-admission functional status was not independently associated with unfavorable outcome. PMID- 26438207 TI - Serum gamma-glutamyltranspeptidase and oxidative stress in subjectively healthy women: an association with menopausal stages. AB - BACKGROUND: Gamma-glutamyltransferase (gamma-GT) is used as a marker of alcohol related pathology, while gamma-GT is recently considered to be an oxidative stress marker. AIM: The present study aimed to investigate the correlation between the oxidative status and gamma-GT levels, in association with menopausal stages. METHODS: In total, 252 women, who were subjectively healthy, were divided into three groups: premenopausal, perimenopausal, and postmenopausal. The circulating oxidative status was evaluated by the diacron-reactive oxygen metabolite (d-ROM) test. In addition to serum gamma-GT, routine blood investigations, including lipid, glucose, and inflammatory parameters, were performed. RESULTS: The median gamma-GT level was 17 U/L and the mean d-ROM level was 335 Carr U in all subjects. On multiple regression analysis, independent significant positive correlations were observed between d-ROM and high sensitivity CRP levels in three groups, while there was a significant positive correlation between d-ROM and gamma-GT levels only in the premenopausal group but not in the perimenopausal and postmenopausal groups. DISCUSSION: The significant relationship between d-ROM and gamma-GT at active estrogen stage may indicate a different oxidative stress condition by memopausal stage. The reasons of this relationship should be further explored. CONCLUSION: A positive relationship between d-ROM and gamma-GT levels, both as known as oxidative stress-related markers, could exist in premenopausal women. PMID- 26438208 TI - Response to Letter to the Editor, "Impact of Overloading on Temporomandibular Joint Osteoarthritis". PMID- 26438209 TI - Letter to the Editor: Impact of Overloading on Temporomandibular Joint Osteoarthritis. PMID- 26438210 TI - Preventing Childhood Caries: A Review of Recent Behavioral Research. AB - The etiology of dental caries reflects a complex interplay of biochemical, microbial, genetic, social and physical environmental, and health-influencing behavioral factors. This review updates the literature on the efficacy of behavioral approaches to caries prevention for children up to 18 y of age. Included were studies of behavioral interventions implemented at individual, family, and community levels that assessed results in terms of reductions in caries increments. Only those reports published since 2011 were considered. Outcomes were variable, although motivational interviewing, which involves individuals in decisions about oral health within the context of their respective life circumstances, proved effective in 3 of 4 reported studies, and more definitive trials are underway. Recommendations for future research include examinations of the cost-effectiveness of interventions, as well as work focused on understanding the mechanisms underlying oral health behavior change and variables that may mediate or moderate responses to interventions. PMID- 26438212 TI - Molecular Basis for Differential Sensitivity of alpha-Conotoxin RegIIA at Rat and Human Neuronal Nicotinic Acetylcholine Receptors. AB - alpha-Conotoxins, as nicotinic acetylcholine receptor (nAChR) antagonists, are powerful tools for dissecting biologic processes and guiding drug development. The alpha3beta2 and alpha3beta4 nAChR subtypes are expressed in the central and peripheral nervous systems and play a critical role in various pathophysiological conditions ranging from nicotine addiction to the development and progression of lung cancer. Here we used the alpha4/7-conotoxin RegIIA, a disulfide-bonded peptide from the venom of Conus regius, and its analog [N11A,N12A]RegIIA to probe the specific pharmacological properties of rat and human nAChR subtypes. nAChR subtypes were heterologously expressed in Xenopus oocytes and two-electrode voltage clamp recordings used to investigate the effects of the peptides on nAChR activity. RegIIA potently inhibited currents evoked by acetylcholine (ACh) at rat alpha3beta2 (IC50 = 10.7 nM), whereas a 70-fold lower potency was observed at human alpha3beta2 nAChR (IC50 = 704.1 nM). Conversely, there were no species specific differences in sensitivity to RegIIA at the alpha3beta4 nAChR. Receptor mutagenesis and molecular dynamics studies revealed that this difference can be attributed primarily to a single amino acid change: Glu198 on the rat alpha3 subunit corresponding to a proline on the human subunit. These findings reveal a novel species- and subunit-specific receptor-antagonist interaction. PMID- 26438211 TI - Microbial Nucleic Acid Sensing in Oral and Systemic Diseases. AB - One challenge in studying chronic infectious and inflammatory disorders is understanding how host pattern recognition receptors (PRRs), specifically toll like receptors (TLRs), sense and respond to pathogen- or damage-associated molecular patterns, their communication with each other and different components of the immune system, and their role in propagating inflammatory stages of disease. The discovery of innate immune activation through nucleic acid recognition by intracellular PRRs such as endosomal TLRs (TLR3, TLR7, TLR8, and TLR9) and cytoplasmic proteins (absent in melanoma 2 and DNA-dependent activator of interferon regulatory factor) opened a new paradigm: Nucleic acid sensing is now implicated in multiple immune and inflammatory conditions (e.g., atherosclerosis, cancer), viral (e.g., human papillomavirus, herpes virus) and bacterial (e.g., Helicobacter pylori, pneumonia) diseases, and autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis). Clinical investigations reveal the overexpression of specific nucleic acid sensors in diseased tissues. In vivo animal models show enhanced disease progression associated with receptor activation. The involvement of nucleic acid sensors in various systemic conditions is further supported by studies reporting receptor knockout mice being either protected from or prone to disease. TLR9-mediated inflammation is also implicated in periodontal diseases. Considering that persistent inflammation in the oral cavity is associated with systemic diseases and that oral microbial DNA is isolated at distal sites, nucleic acid sensing may potentially be a link between oral and systemic diseases. In this review, we discuss recent advances in how intracellular PRRs respond to microbial nucleic acids and emerging views on the role of nucleic acid sensors in various systemic diseases. We also highlight new information on the role of intracellular PRRs in the pathogenesis of oral diseases including periodontitis and oral cavity cancer, which might offer future possibilities for disease prevention and therapy. PMID- 26438213 TI - Long-Range Inhibitor-Induced Conformational Regulation of Human IRE1alpha Endoribonuclease Activity. AB - Activation of the inositol-requiring enzyme-1 alpha (IRE1alpha) protein caused by endoplasmic reticulum stress results in the homodimerization of the N-terminal endoplasmic reticulum luminal domains, autophosphorylation of the cytoplasmic kinase domains, and conformational changes to the cytoplasmic endoribonuclease (RNase) domains, which render them functional and can lead to the splicing of X box binding protein 1 (XBP 1) mRNA. Herein, we report the first crystal structures of the cytoplasmic portion of a human phosphorylated IRE1alpha dimer in complex with (R)-2-(3,4-dichlorobenzyl)-N-(4-methylbenzyl)-2,7 diazaspiro(4.5)decane-7-carboxamide, a novel, IRE1alpha-selective kinase inhibitor, and staurosporine, a broad spectrum kinase inhibitor. (R)-2-(3,4 dichlorobenzyl)-N-(4-methylbenzyl)-2,7-diazaspiro(4.5)decane-7-carboxamide inhibits both the kinase and RNase activities of IRE1alpha. The inhibitor interacts with the catalytic residues Lys599 and Glu612 and displaces the kinase activation loop to the DFG-out conformation. Inactivation of IRE1alpha RNase activity appears to be caused by a conformational change, whereby the alphaC helix is displaced, resulting in the rearrangement of the kinase domain-dimer interface and a rotation of the RNase domains away from each other. In contrast, staurosporine binds at the ATP-binding site of IRE1alpha, resulting in a dimer consistent with RNase active yeast Ire1 dimers. Activation of IRE1alpha RNase activity appears to be promoted by a network of hydrogen bond interactions between highly conserved residues across the RNase dimer interface that place key catalytic residues poised for reaction. These data implicate that the intermolecular interactions between conserved residues in the RNase domain are required for activity, and that the disruption of these interactions can be achieved pharmacologically by small molecule kinase domain inhibitors. PMID- 26438214 TI - Elevated Serum Levels of SCUBE1, a Marker for Coagulation, in Patients with Breast Cancer. AB - Breast cancer (BC) is the most common cancer among women and a major cause of death. Signal Peptide-Cub-Epidermal growth factor domain-containing protein-1 (SCUBE1) is secreted under hypoxia and inflammatory conditions from platelet alpha granules. Its biological function is uncertain, although it may be a procoagulant substance in cancer patients. SCUBE1 is useful for identifying thrombotic diseases, including cancers and acute coronary syndromes. D-dimer reflects the relationship between coagulation activation and fibrinolysis; namely, thrombosis and D-dimer levels are closely linked. This is the first investigation of the potential diagnostic and prognostic value of SCUBE1 levels in patients with BC. Fifty patients and 33 age-matched and body mass index matched healthy controls were enrolled. Blood samples were collected before chemotherapy regimens commenced. Serum SCUBE1 and D-dimer levels were measured before adjuvant chemotherapy and were compared to the healthy controls. SCUBE1 levels were determined using an enzyme-linked immunosorbent assay (ELISA) method. SCUBE1 and D-dimer levels were significantly higher in patients than in the controls (p = 0.03 and p < 0.001, respectively). A cut-off value of 1.55 ng/mL for SCUBE1 was associated with 62% sensitivity and 72.7% specificity and with positive predictive value of 77.5% and negative predictive value of 55.8%. Two patients with high SCUBE1 and D-dimer levels also developed pulmonary embolism. SCUBE1 may indicate hypercoagulability in patients with BC and thus help identify patients at greater risk of thrombosis and requiring anti-thrombosis treatment. SCUBE1 may also be used as an assistant test for identifying patients at risk of BC. PMID- 26438215 TI - Intragel photoreduction of aryl halides by green-to-blue upconversion under aerobic conditions. AB - The first proof of concept for the application of intragel green-to-blue photon upconversion to a chemical reaction is reported. The developed method allows the photoreduction of aryl halides at room temperature under aerobic conditions. PMID- 26438216 TI - Label-free blood serum detection by using surface-enhanced Raman spectroscopy and support vector machine for the preoperative diagnosis of parotid gland tumors. AB - BACKGROUND: It is difficult for the parotid gland neoplasms to make an accurate preoperative diagnosis due to the restriction of biopsy in the parotid gland neoplasms. The aim of this study is to apply the surface-enhanced Raman spectroscopy (SERS) method for the blood serum biochemical detection and use the support vector machine for the analysis in order to develop a simple but accurate blood serum detection for preoperative diagnosis of the parotid gland neoplasms. METHODS: The blood serums were collected from four groups: the patients with pleomorphic adenoma, the patients with Warthin's tumor, the patients with mucoepidermoid carcinoma and the volunteers without parotid gland neoplasms. Au nanoparticles (Au NPs) were mixed with the blood serum as the SERS active nanosensor to enhance the Raman scattering signals produced by the various biochemical materials and high quality SERS spectrum were obtained by using the Raman microscope system. Then the support vector machine was utilized to analyze the differences of the SERS spectrum from the blood serum of different groups and established a diagnostic model to discriminate the different groups. RESULTS: It was demonstrated that there were different intensities of SERS peaks assigned to various biochemical changes in the blood serum between the parotid gland tumor groups and normal control group. Compared with the SERS spectra of the normal serums, the intensities of peaks assigned to nucleic acids and proteins increased in the SERS spectra of the parotid gland tumor serums, which manifested the differences of the biochemical metabolites in the serum from the patients with parotid gland tumors. When the leave-one-sample-out method was used, support vector machine (SVM) played an outstanding performance in the classification of the SERS spectra with the high accuracy (84.1 % ~ 88.3 %), sensitivity (82.2 % ~ 97.4 %) and specificity (73.7 % ~ 86.7 %). Though the accuracy, sensitivity and specificity decreased in the leave-one-patient-out cross validation, the mucoepidermoid carcinoma was still easier to diagnose than other tumors. DISCUSSION: The specific molecular differences of parotid gland tumors and normal serums were significantly demonstrated through the comparison between the various SERS spectra.But compared with the serum SERS spectra reported in the other studies, some differences exist between the spectra in this study and the ones reported in the lietratures. These differences may result from the various nano particles, the different preparation of serum and equipment parameters, and we could need a further research to find an exact explanation.Based on the SERS spectra of the serum samples, SVM have shown a giant potential to diagnose the parotid gland tumors in our preliminary study. However, different cross validaiton methods could effect the accuracy and a further study involing a great number of samples should be needed. CONCLUSIONS: This exploratory research demonstrated the great potential of SERS combined with SVM into a non-invasive clinical diagnostic method for preoperative diagnosis of parotid gland tumors. And the internal relation between the spectra and patients should be established in the further study. PMID- 26438217 TI - Treatment Concerns and Functional Impairment in Pediatric Anxiety. AB - Although there are efficacious, evidence-based treatments for anxiety disorders, youth often experience delays in seeking therapy. Myriad reasons may contribute to this lag in treatment initiation, with some youth possessing concerns about therapy. Treatment concerns are broadly characterized by worries/ambivalence about seeking treatment, including concerns about the negative reactions, consequences, and inconvenience of treatment. As no studies exist for youth with anxiety disorders, this study examined the phenomenology of treatment concerns in 119 treatment-seeking, anxious youth and utilized a structural equation model to examine the relationship between child anxiety, depressive symptoms, treatment concerns, and anxiety-related functional impairment. Over 90 % of the children positively endorsed some type of treatment-related fear, with the most frequently expressed concern being that therapy would take too much time (50.4 %). Based on the model, both child anxiety and depressive symptoms predicted functional impairment, and treatment concerns mediated the relationship between child anxiety and functional impairment. PMID- 26438218 TI - Relationship between endodormancy, FLOWERING LOCUS T and cell cycle genes in Vitis vinifera. AB - MAIN CONCLUSION: In grapevines, the increased expression of VvFT , genes involved in the photoperiodic control of seasonal growth ( VvAP1, VvAIL2 ) and cell cycle genes ( VvCDKA, VvCDKB2, VvCYCA1, VvCYCB, VvCYCD3.2 ) in the shoot apex relative to the latent bud, suggests a high mitotic activity of the apex which could prevent them to enter into endodormancy. Additionally, the up-regulation of these genes by the dormancy-breaking compound hydrogen cyanamide (H 2 CN 2 ) strongly suggests that VvFT plays a key role in regulating transcriptionally cell cycle genes. At the end of the growing season, short-day (SD) photoperiod induces the transition of latent grapevine buds (Vitis vinifera L) from paradormancy (PD) to endodormancy (ED), which allows them to survive the cold temperatures of winter. Meanwhile, the shoot apex gradually decreases its growth without entering into ED, and as a result of the fall of temperatures at the beginning of autumn, dies. To understand developmental differences and contrasting responses to environmental cues between both organs, the expression of cell cycle genes, and of genes involved in photoperiodic control of seasonal growth in trees, such as FLOWERING LOCUS T (FT), APETALA1 (AP1) and AINTEGUMENTA-like (AIL) was analyzed at the shoot apex and latent buds of vines during the transition from PD to ED. After shift to SD photoperiod, increased expression of cell cycle genes in the shoot apex suggests a high mitotic activity in this organ which could prevent them from entering into ED. Additionally, the increased expression of VvFT, VvAP1and VvAIL2 in the shoot apex, and the up-regulation of VvFT, VvAP1and cell cycle genes VvCDKA, VvCDKB2, VvCYCA.1, by the dormancy-breaking compound hydrogen cyanamide (H2CN2), strongly suggests that VvFT plays a key role in regulating transcriptionally cell cycle genes, giving thus, more support to the model for photoperiodic control of seasonal growth in trees. Furthermore, downregulation of VvFT by the SD photoperiod detected in leaves and buds of grapevines highlights the importance of VvFT in the induction of growth cessation and in ED development, probably by regulating the expression of cell cycle genes. PMID- 26438219 TI - Limited transpiration under high vapor pressure deficits of creeping bentgrass by application of Daconil-Action. AB - MAIN CONCLUSION: First observation that chemical spray can induce limited transpiration rate under high vapor pressure deficit. It appears that acibenzolar may be key in inducing this water conservation trait. Irrigation and water use have become major issues in management of turfgrasses. Plant health products that have been introduced into the turfgrass market have been observed to improve plant performance in water stress conditions. In this study, we evaluated whether a selection of common plant health products alter the ability of creeping bentgrass (Agrostis stolonifera L.) to control transpiration under high vapor pressure deficit (VPD). The plant health treatments--Daconil Action, Insignia, and Signature--were applied to plots on golf course putting greens located in Raleigh NC and in Scottsdale, AZ. Using intact cores removed from the putting greens, transpiration rates were measured over a range of VPDs in controlled conditions. In all cases stretching over a 3-year period, bentgrass cores from field plots treated with Daconil-Action limited transpiration under high VPD conditions, while check treatments with water, and others treated with Insignia or Signature did not. Transpiration control became engaged when VPDs reached values ranging from 1.39 to 2.50 kPa, and was not strongly influenced by the field temperature at which the bentgrass was growing. Because all plots in NC had been treated with chlorothalonil-the key ingredient in Daconil Action to control diseases-it was concluded that the likely chemical ingredient in Daconil Action triggering the transpiration control response was acibenzolar. This is the first evidence that the limited-transpiration trait can be induced by a chemical application, and it implies significant potential for ameliorating drought vulnerability in cool-season turfgrasses, and likely other plant species. PMID- 26438220 TI - The Impact of Medical and Surgical Treatment for Benign Prostatic Hypertrophy on Erectile Function. AB - There is a well-known link between treatment for lower urinary tract symptoms (LUTS) and erectile dysfunction. Surgical and medical management of LUTS all have side effect profiles which may affect erectile dysfunction, ejaculatory dysfunction, or libido. These should be taken into consideration during patient counseling. This article reviews the common side effects of the medical and surgical treatments of LUTS. PMID- 26438221 TI - Clocks do not tick in unison: isolation of Clock and vrille shed new light on the clockwork model of the sand fly Lutzomyia longipalpis. AB - BACKGROUND: Behavior rhythms of insect vectors directly interfere with the dynamics of pathogen transmission to humans. The sand fly Lutzomyia longipalpis is the main vector of visceral leishmaniasis in America and concentrates its activity around dusk. Despite the accumulation of behavioral data, very little is known about the molecular bases of the clock mechanism in this species. This study aims to characterize, within an evolutionary perspective, two important circadian clock genes, Clock and vrille. FINDINGS: We have cloned and isolated the coding sequence of L. longipalpis' genes Clock and vrille. The former is structured in eight exons and encodes a protein of 696 amino acids, and the latter comprises three exons and translates to a protein of 469 amino acids. When compared to other insects' orthologues, L. longipalpis CLOCK shows a high degree of conservation in the functional domains bHLH and PAS, but a much shorter glutamine-rich (poly-Q) C-terminal region. As for L. longipalpis VRILLE, a high degree of conservation was found in the bZIP domain. To support these observations and provide an elegant view of the evolution of both genes in insects, phylogenetic analyses based on maximum-likelihood and Bayesian inferences were performed, corroborating the previously known insect systematics. CONCLUSIONS: The isolation and phylogenetic analyses of Clock and vrille orthologues in L. longipalpis bring novel and important data to characterize this species' circadian clock. Interestingly, the poly-Q shortening observed in CLOCK suggests that its transcription activity might be impaired and we speculate if this effect could be compensated by other clock factors such as CYCLE. PMID- 26438222 TI - Did studies on HFOV fail to improve ARDS survival because they did not decrease VILI? On the potential validity of a physiological concept enounced several decades ago. AB - High frequency oscillatory ventilation (HFOV) has been the subject of extensive physiological research for 30 years and even more so of an intense debate on its potential usefulness in the treatment of acute respiratory distress syndrome (ARDS). This technique has been enthusiastically promoted by some teams until two high-quality randomized clinical trials in adults with ARDS showed that HFOV did not decrease and might have even increased mortality. As a consequence of these results, physiological concepts such as atelectrauma and biotrauma on which ARDS management with HFOV were based should be reexamined. In contrast, the concept of volutrauma, i.e., end-inspiratory overdistension, as the cause for ventilator induced lung injury might help explain excess mortality during mechanical ventilation of ARDS when inspiratory volumes are too high. This is what might have happened during one of the recent studies on HFOV. Failure of this complex technique must be put in perspective with the dramatic improvement of ARDS prognosis with very simple interventions such as tidal volume reduction, early pharmacological paralysis, and prone positioning which all limited end inspiratory volume. PMID- 26438223 TI - Effects of packed red blood cell storage duration on post-transfusion clinical outcomes: a meta-analysis and systematic review. AB - PURPOSE: There is substantial conjecture regarding the clinical significance of packed red blood cell (PRBC) changes that occur during in vitro storage. Here, we present a meta- and systematic analysis of adult studies published between 1994 and 2015 with the aim of updating existing quantitative reviews and providing a comprehensive cover of the six most commonly studied outcomes-mortality, infection, renal dysfunction, multiple organ dysfunction syndrome (MODS), thrombotic complications and prolonged hospital length of stay. METHODS: Computerised searches of Pubmed and EMBASE identified publications that reported target outcomes and PRBC storage duration prior to transfusion. Bibliographies of relevant literature were manually searched to incorporate missed studies. Randomised controlled trial (RCT) data was meta-analysed using a random effects model with Cochrane Collaboration Review Manager (RevMan) version 5.1 software. Observational investigations were systematically reviewed. RESULTS: Sixty-four papers were selected covering 462,581 patients with the majority of studies being observational in nature. Meta-analysis of eight RCTs demonstrated a trend towards decreased mortality with stored PRBC transfusion; albeit this effect was not statistically significant (OR 0.91, 95 % CI 0.78-1.05, p = 0.20). In a small subset of intensive care unit (ICU), cardiac surgery and trauma patients; observational studies suggested that prolonged storage may be correlated with increased mortality. Trauma and cardiac surgery patients appeared to be most susceptible to the potential infectious complications of stored PRBCs. Stored PRBCs were unlikely to affect thrombotic complications or hospital length of stay. There were inadequate data to determine whether stored PRBCs had clinically relevant effects on renal dysfunction and MODS. CONCLUSION: Although literature presents a concerning picture of potential storage complications, current findings are too inconsistent to drive changes in clinical practice. Results from current RCTs will likely play a role in PRBC age guidelines for cardiac surgery and ICU patients. However, these studies may be less efficacious at detecting small effects that are limited to specific subpopulations. PMID- 26438225 TI - TaylorActive--Examining the effectiveness of web-based personally-tailored videos to increase physical activity: a randomised controlled trial protocol. AB - BACKGROUND: Physical inactivity levels are unacceptably high and effective interventions that can increase physical activity in large populations at low cost are urgently needed. Web-based interventions that use computer-tailoring have shown to be effective, though people tend to 'skim' and 'scan' text on the Internet rather than thoroughly read it. The use of online videos is, however, popular and engaging. Therefore, the aim of this 3-group randomised controlled trial is to examine whether a web-based physical activity intervention that provides personally-tailored videos is more effective when compared with traditional personally-tailored text-based intervention and a control group. METHODS/DESIGN: In total 510 Australians will be recruited through social media advertisements, e-mail and third party databases. Participants will be randomised to one of three groups: text-tailored, video-tailored, or control. All groups will gain access to the same web-based platform and a library containing brief physical activity articles. The text-tailored group will additionally have access to 8 sessions of personalised physical activity advice that is instantaneously generated based on responses to brief online surveys. The theory-based advice will be provided over a period of 3 months and address constructs such as self efficacy, motivation, goal setting, intentions, social support, attitudes, barriers, outcome expectancies, relapse prevention and feedback on performance. Text-tailored participants will also be able to complete 7 action plans to help them plan what, when, where, who with, and how they will become more active. Participants in the video-tailored group will gain access to the same intervention content as those in the text-tailored group, however all sessions will be provided as personalised videos rather than text on a webpage. The control group will only gain access to the library with generic physical activity articles. The primary outcome is objectively measured physical activity. Secondary outcomes include website engagement and retention, quality of life, depression, anxiety, stress, sitting time, sleep and psychosocial correlates of physical activity. Outcomes will be measured at baseline, 3, and 9 months. DISCUSSION: This study presents an ideal opportunity to study the effectiveness of an isolated feature within a web-based physical activity intervention and the knowledge generated from this study will help to increase intervention effectiveness. TRIAL REGISTRATION: Australian New-Zealand Clinical Trial Registry: ACTRN12615000057583 . Registered 22 January 2015. CQUniversity Ethics Project Number: H14/07-163. PMID- 26438226 TI - The impacts of withdrawal and replacement of general practitioner services on aeromedical service trends: a 13-year interrupted time-series study in Tennant Creek, Northern Territory. AB - BACKGROUND: The Royal Flying Doctor Service (RFDS) provides aeromedical care to patients during fixed-wing transport over vast distances to healthcare unavailable in rural or remote communities. This study examined the relationship between changes in local accessibility to primary healthcare services and rates of aeromedical service use over time. METHODS: This was a 13-year interrupted time-series study (1999-2012) in Tennant Creek, Northern Territory. Quarterly aeromedical service use for primary care sensitive conditions were calculated and exposure to general practice (GP) services was characterised over time with events modelled as intervention variables: (a) GP service withdrawal (Nov-2004); and (b) GP service replacement (Dec-2006). Intervention effects were estimated using PROC ARIMA in SAS after examination of the time-series structure. RESULTS: GP withdrawal resulted in an immediate and sustained doubling in quarterly aeromedical service use (+11.8 services per quarter) and GP service replacement had no significant effect. DISCUSSION: Large and immediate increases in aeromedical service use result from the loss of local GPservices yet, in this case, replacement with a new GP service, 2-years hence, did not ameliorate that effect after six years. CONCLUSIONS: These findings demonstrate the immediate impact of GP-service loss on the rates ofaeromedical transfer of patients from this remote community and lend caution to expectations about thetimeline over which newly implemented primary health care services in such contexts can mitigate the impact of such a loss. PMID- 26438227 TI - Deep brain stimulation of the subthalamic nucleus: histological verification and 9.4-T MRI correlation. AB - BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) using an MRI-guided and MRI-verified technique without microelectrode recording is an effective and safe surgical treatment for patients with Parkinson's disease (PD). OBJECTIVES: To assess the anatomical accuracy of lead placement after MRI-guided, MRI-verified STN DBS using post-mortem histology and high-field MRI at 9.4 T. METHODS: We conducted post-mortem analysis of a patient's brain who had had MRI guided, MRI-verified STN DBS for PD, using 9.4-T MRI and histology. After death, the brain was retrieved and a block including the electrode tracks down to the mesencephalon was examined with high-field MRI at 9.4 T and histological analysis. RESULTS: High-field MRI images and corresponding histological examination showed that each electrode track ended within the intended target area, and that DBS did not cause significant neuroparenchymal tissue damage. CONCLUSIONS: This study supports the anatomical accuracy of the MRI-guided and MRI-verified method of STN DBS. PMID- 26438224 TI - Task force on management and prevention of Acinetobacter baumannii infections in the ICU. AB - INTRODUCTION: Acinetobacter baumannii constitutes a dreadful problem in many ICUs worldwide. The very limited therapeutic options available for these organisms are a matter of great concern. No specific guidelines exist addressing the prevention and management of A. baumannii infections in the critical care setting. METHODS: Clinical microbiologists, infectious disease specialists and intensive care physicians were invited by the Chair of the Infection Section of the ESICM to participate in a multidisciplinary expert panel. After the selection of clinically relevant questions, this document provides recommendations about the use of microbiological techniques for identification of A. baumannii in clinical laboratories, antibiotic therapy for severe infections and recommendations to control this pathogen in outbreaks and endemic situations. Evidence supporting each statement was graded according to the European Society of Clinical Microbiology and Infection Diseases (ESCMID) grading system. RESULTS: Empirical coverage of A. baumannii is recommended in severe infections (severe sepsis or septic shock) occurring during an A. baumannii outbreak, in an endemic setting, or in a previously colonized patient. For these cases, a polymyxin is suggested as part of the empirical treatment in cases of a high suspicion of a carbapenem resistant (CR) A. baumannii strain. An institutional program including staff education, promotion of hand hygiene, strict contact and isolation precautions, environmental cleaning, targeted active surveillance, and antimicrobial stewardship should be instituted and maintained to combat outbreaks and endemic situations. CONCLUSIONS: Specific recommendations about prevention and management of A. baumannii infections in the ICU were elaborated by this multidisciplinary panel. The paucity of randomized controlled trials is noteworthy, so these recommendations are mainly based on observational studies and pharmacodynamics modeling. PMID- 26438228 TI - Transdiscal C6-C7 contralateral C7 nerve root transfer in the surgical repair of brachial plexus avulsion injuries. AB - BACKGROUND: Repair of complete brachial plexus avulsion injuries may require contralateral C7 nerve root transfer. The available techniques might allow direct neuroraphy in about 50 % of cases but the others require interposing nerve grafts or humeral shaft shortening. We aimed to see if transdiscal C6-C7 contralateral C7 nerve root transfer is technically feasible and if it allows direct coaptation with the contralateral nerve roots in 100 % of cases. METHODS: In ten fresh frozen adult cadavers, the C7 nerve root was sectioned just before it connects with other brachial plexus branches and re-routed though the C6-C7 disc space to the contralateral side. A complete C6-C7 discectomy was performed and the disc space kept open with the aid of an autologous iliac crest bone graft. RESULTS: Transdiscal C6-C7 contralateral C7 nerve root transfer is technically feasible. In our cadavers, it provided 5.3 +/- 1.2 SDcm of extra length that allowed direct coaptation with the contralateral nerve roots, mainly C8 and T1. CONCLUSIONS: Transdiscal C6-C7 contralateral C7 nerve root transfer is technically feasible. In our dissections it lengthens the available C7 nerve root stump by 5.3 +/- 1.2SDcm. The increase was 4 cm versus the retropharyngeal route making direct coaptation with the contralateral C8 and T1 nerve roots possible. PMID- 26438229 TI - Metastasis of an occult pulmonary carcinoma into meningioma: a case report. AB - Tumour-to-tumour metastasis is an infrequent pathological phenomenon. Meningioma is the most common intracranial tumour where metastatic deposits may be found, the majority of which arise from breast and lung cancers. We describe an unusual case of occult pulmonary carcinoma metastasis into the intracranial meningioma. A 77-year old lady presented with acutely deteriorating hemiparesis. Her previous medical history was unremarkable. Radiological imaging revealed an expansive lesion, classified as meningioma, which was located parasagittally in the right premotor area. A well-capsulated tumour attached to the dura was removed surgically. The pathological examination demonstrated a mixture of angiomatous meningioma and pulmonary adenocarcinoma. Possible explanations for the development of a composite tumour and pathophysiology are described. PMID- 26438230 TI - Radical hysterectomy with or without para-aortic lymphadenectomy for patients with stage IB2, IIA2, and IIB cervical cancer: outcomes for a series of 308 patients. AB - BACKGROUND: Although many studies have already shown that lymph node metastasis is one of the major prognostic factors for cervical cancer, the therapeutic significance of para-aortic lymphadenectomy for the surgical treatment of cervical cancer remains controversial. METHODS: A total of 308 patients diagnosed with stage IB2, IIA2, or IIB cervical cancer and treated with radical hysterectomy were retrospectively investigated to assess the incidence of para aortic lymph node metastasis and the clinicopathological factors linked to cervical cancer prognosis. RESULTS: Para-aortic lymph node metastases were pathologically confirmed in 13 of the 136 patients (9.6 %) who underwent para aortic lymphadenectomy. The incidence of para-aortic lymph node metastasis was significantly higher in the patients who had common iliac lymph node metastases (odds ratio 31.5, p < 0.001) according to logistic regression analysis. Common iliac lymph node metastasis was related to risk of recurrence (hazard ratio 2.43, p = 0.003) and death (hazard ratio 2.62, p = 0.007) in Cox regression analysis. Kaplan-Meier analysis and Cox regression analysis showed that para-aortic lymphadenectomy did not have a positive impact on survival in 308 patients or 140 pN1 patients, but para-aortic lymphadenectomy was related to better overall survival with a marginal trend toward significance (p = 0.053) in 30 patients with common iliac lymph node metastasis. CONCLUSIONS: Indication for para-aortic lymphadenectomy in the surgical treatment of stage IB2, IIA2, or IIB cervical cancer needs to be individualized. Patients with common iliac lymph node metastasis are possible candidates, and a prospective study is needed to clarify this issue. PMID- 26438232 TI - Prophage recombinases-mediated genome engineering in Lactobacillus plantarum. AB - BACKGROUND: Lactobacillus plantarum is a food-grade microorganism with industrial and medical relevance belonging to the group of lactic acid bacteria (LAB). Traditional strategies for obtaining gene deletion variants in this organism are mainly vector-based double-crossover methods, which are inefficient and laborious. A feasible possibility to solve this problem is the recombineering, which greatly expands the possibilities for engineering DNA molecules in vivo in various organisms. RESULTS: In this work, a double-stranded DNA (dsDNA) recombineering system was established in L. plantarum. An exonuclease encoded by lp_0642 and a potential host-nuclease inhibitor encoded by lp_0640 involved in dsDNA recombination were identified from a prophage P1 locus in L. plantarum WCFS1. These two proteins, combined with the previously characterized single strand annealing protein encoded by lp_0641, can perform homologous recombination between a heterologous dsDNA substrate and host genomic DNA. Based on this, we developed a method for marker-free genetic manipulation of the chromosome in L. plantarum. CONCLUSIONS: This Lp_0640-41-42-mediated recombination allowed easy screening of mutants and could serve as an alternative to other genetic manipulation methods. We expect that this method can help for understanding the probiotic functionality and physiology of LAB. PMID- 26438231 TI - Protein repair L-isoaspartyl methyltransferase 1 (PIMT1) in rice improves seed longevity by preserving embryo vigor and viability. AB - Damaged proteins containing abnormal isoaspartyl (isoAsp) accumulate as seeds age and the abnormality is thought to undermine seed vigor. Protein-L-isoaspartyl methyltransferase (PIMT) is involved in isoAsp-containing protein repair. Two PIMT genes from rice (Oryza sativa L.), designated as OsPIMT1 and OsPIMT2, were isolated and investigated for their roles. The results indicated that OsPIMT2 was mainly present in green tissues, but OsPIMT1 largely accumulated in embryos. Confocal visualization of the transient expression of OsPIMTs showed that OsPIMT2 was localized in the chloroplast and nucleus, whereas OsPIMT1 was predominately found in the cytosol. Artificial aging results highlighted the sensitivity of the seeds of OsPIMT1 mutant line when subjected to accelerated aging. Overexpression of OsPIMT1 in transgenic seeds reduced the accumulation of isoAsp-containing protein in embryos, and increased embryo viability. The germination percentage of transgenic seeds overexpressing OsPIMT1 increased 9-15% compared to the WT seeds after 21-day of artificial aging, whereas seeds from the OsPIMT1 RNAi lines overaccumulated isoAsp in embryos and experienced rapid loss of seed germinability. Taken together, these data strongly indicated that OsPIMT1-related seed longevity improvement is probably due to the repair of detrimental isoAsp containing proteins that over accumulate in embryos when subjected to accelerated aging. PMID- 26438233 TI - Unskilled but subjectively aware: Metacognitive monitoring ability and respective awareness in low-performing students. AB - Two studies were conducted to further examine the unskilled-and-unaware effect and to test whether low-performing students are indeed unaware of their (expected) lower metacognitive monitoring abilities. Postdicted judgments of performance and second-order judgments (SOJs) were solicited to test students' metacognitive awareness. Given that global and local judgments tend to differ (the confidence-frequency effect), we investigated whether students' (un)awareness pertains to both types of judgments. A first study focusing on global judgments was conducted in a regular exam setting with 196 undergraduate education students. A second study with 115 undergraduate education students examined both global and local judgments. Local judgments were analyzed on an average level and according to different signal detection theory categories (hits, correct rejections, misses, and false alarms). In both studies, students were grouped in four performance quartiles. The results showed that low performing students highly overestimated their performance (they were functionally overconfident). However, their SOJs indicated that they were less confident in their judgments than the other students, and thus seemed to be aware of their low ability to estimate their own performance (they were not subjectively overconfident). This was observed for global as well as for averaged local SOJs. Moreover, an analysis of the local judgments revealed that students' SOJs varied depending not only on whether their judgments were accurate but also on whether or not they thought they knew the answer to an item. In sum, SOJs provide valuable information about students' metacognitive awareness. PMID- 26438234 TI - Activation and selection of arithmetic facts: The role of numerical format. AB - We examined the role of numerical format in the activation and selection of arithmetic facts. We also explored the inhibitory nature of this mechanism. To this end, in two experiments we manipulated the format of the operations (digit format and word format) while participants decided whether simple additions were correct or not. In Experiment 1, when an addition was incorrect but the result was that of multiplying the operands (e.g., 2 + 4 = 8), participants took more time to respond relative to a control condition where the addition's result was incorrect but unrelated. Afterward, participants took more time to respond when the result of multiplying the operands was presented again in a correct addition problem (e.g., 2 + 6 = 8), suggesting that the related multiplication result in the previous trial (e.g., 8) was inhibited to select the correct response (e.g., 6); thus, when it was presented again in the next problem, additional time was necessary to reactivate it. These effects were found in the digit format but not in the word format. In Experiment 2, we considered the degree to which participants used memory retrieval to perform the task. In participants with high retrieval usage, the interference effects in the first and second trials were larger for the digit format than for the word format. However, the participants with low retrieval usage showed interference effects only for problems with digits. These findings are discussed in terms of automaticity in retrieving arithmetic facts to perform simple arithmetic. PMID- 26438236 TI - The Problem with Education in Global Mental Health. PMID- 26438235 TI - Sample selection, recruitment and participation rates in health examination surveys in Europe--experience from seven national surveys. AB - BACKGROUND: Health examination surveys (HESs), carried out in Europe since the 1950's, provide valuable information about the general population's health for health monitoring, policy making, and research. Survey participation rates, important for representativeness, have been falling. International comparisons are hampered by differing exclusion criteria and definitions for non-response. METHOD: Information was collected about seven national HESs in Europe conducted in 2007-2012. These surveys can be classified into household and individual-based surveys, depending on the sampling frames used. Participation rates of randomly selected adult samples were calculated for four survey modules using standardised definitions and compared by sex, age-group, geographical areas within countries, and over time, where possible. RESULTS: All surveys covered residents not just citizens; three countries excluded those in institutions. In two surveys, physical examinations and blood sample collection were conducted at the participants' home; the others occurred at examination clinics. Recruitment processes varied considerably between surveys. Monetary incentives were used in four surveys. Initial participation rates aged 35-64 were 45% in the Netherlands (phase II), 54% in Germany (new and previous participants combined), 55% in Italy, and 65% in Finland. In Ireland, England and Scotland, household participation rates were 66%, 66% and 63% respectively. Participation rates were generally higher in women and increased with age. Almost all participants attending an examination centre agreed to all modules but surveys conducted in the participants' home had falling responses to each stage. Participation rates in most primate cities were substantially lower than the national average. Age standardized response rates to blood pressure measurement among those aged 35-64 in Finland, Germany and England fell by 0.7-1.5 percentage points p.a. between 1998-2002 and 2010-2012. Longer trends in some countries show a more marked fall. CONCLUSIONS: The coverage of the general population in these seven national HESs was good, based on the sampling frames used and the sample sizes. Pre notification and reminders were used effectively in those with highest participation rates. Participation rates varied by age, sex, geographical area, and survey design. They have fallen in most countries; the Netherlands data shows that they can be maintained at higher levels but at much higher cost. PMID- 26438237 TI - The effects of short-term fasting on tolerance to (neo) adjuvant chemotherapy in HER2-negative breast cancer patients: a randomized pilot study. AB - BACKGROUND: Preclinical evidence shows that short-term fasting (STF) protects healthy cells against side effects of chemotherapy and makes cancer cells more vulnerable to it. This pilot study examines the feasibility of STF and its effects on tolerance of chemotherapy in a homogeneous patient group with early breast cancer (BC). METHODS: Eligible patients had HER2-negative, stage II/III BC. Women receiving (neo)-adjuvant TAC (docetaxel/doxorubicin/cyclophosphamide) were randomized to fast 24 h before and after commencing chemotherapy, or to eat according to the guidelines for healthy nutrition. Toxicity in the two groups was compared. Chemotherapy-induced DNA damage in peripheral blood mononuclear cells (PBMCs) was quantified by the level of gamma-H2AX analyzed by flow cytometry. RESULTS: Thirteen patients were included of whom seven were randomized to the STF arm. STF was well tolerated. Mean erythrocyte- and thrombocyte counts 7 days post chemotherapy were significantly higher (P = 0.007, 95 % CI 0.106-0.638 and P = 0.00007, 95 % CI 38.7-104, respectively) in the STF group compared to the non-STF group. Non-hematological toxicity did not differ between the groups. Levels of gamma-H2AX were significantly increased 30 min post-chemotherapy in CD45 + CD3- cells in non-STF, but not in STF patients. CONCLUSIONS: STF during chemotherapy was well tolerated and reduced hematological toxicity of TAC in HER2-negative BC patients. Moreover, STF may reduce a transient increase in, and/or induce a faster recovery of DNA damage in PBMCs after chemotherapy. Larger studies, investigating a longer fasting period, are required to generate more insight into the possible benefits of STF during chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01304251 , March 2011. PMID- 26438238 TI - Cost of illness of breast cancer in Japan: trends and future projections. AB - BACKGROUND: Breast cancer is a major cause of death for women in Japan. The objectives of this study were to estimate and project the economic burden associated with breast cancer in Japan and identify the key factors that drive the change of the economic burden of breast cancer. METHODS: We calculated the cost of illness (COI) every 3 years from 1996 to 2020 using governmental statistics. COI was calculated by summing the direct costs, morbidity costs, and mortality costs. RESULTS: From 1996 to 2011 COI was trending upward. COI in 2011 (697 billion yen) was 1.7-times greater than that in 1996 (407 billion yen). The mortality costs accounted for approximately 65-70% of the total COI and were a major contributing factor to increase in COI. It was predicted that COI would continue to trend upwards until 2020 (699.4-743.8 billion yen depending on the model), but the rate of increase would decline. CONCLUSIONS: COI of breast cancer has been steadily increasing since 1996. While the rate of increase is expected to plateau, the average age at death from breast cancer is still less than that from other cancers, and the relative economic burden of breast cancer will continue to increase in the foreseeable future. PMID- 26438239 TI - Diffuse cortical calcification of failed kidney allograft. PMID- 26438240 TI - Social inequalities in a population based colorectal cancer screening programme in the Basque Country. AB - BACKGROUND: While it is known that a variety of factors (biological, behavioural and interventional) play a major role in the health of individuals and populations, the importance of the role of social determinants is less clear. The effect of social inequality on population-based screening for colorectal cancer (CRC) could limit the value of such programmes. The present study aims to determine whether such inequalities exist. METHODS: Data was obtained from the population-based screening programme administered in the Autonomous Community of the Basque Country, Spain, with a target population aged 50 to 69, first invited to participate between 2009 and 2011. The magnitude of inequality was analysed using the odds ratio (taking the least disadvantaged socioeconomic quintile as the reference population), the population attributable risk and the relative index of inequality, based on the regression, which is the ratio of the rates in the most and least disadvantaged socioeconomic groups. RESULTS: The target population comprised 242,394 people, with the test kit successfully sent to 95.1 % (230,510). The overall response rate was 64.3 % (67.1 in women and 61.4 % men). Among women, the highest participation was in the third quintile (71.5 %) and the lowest in the first - the least disadvantaged (65.7 %). The lowest and highest rates of people with identified lesions were in the second and fourth quintiles (14.7/1000 and 17.0/1000 respectively). Among men, the response rate was lowest in the fifth - most disadvantaged - quintile (60.2 %). The highest rate of identified lesions was in the fifth quintile; 38 % higher than the first (55.7/1000 compared to 41.0/1000). CONCLUSIONS: Sex and socioeconomic group influence the rate of participation in the CRC programme and the rate of lesions found in the participants. Any public health programme is morally and ethically obliged to strive for equity and effectiveness. Improving participation of men and socially disadvantaged groups should be taken in account. PMID- 26438241 TI - The Overwhelming Majority but not All Motor Fibers of the Bifid Recurrent Laryngeal Nerve are Located in the Anterior Extralaryngeal Branch. AB - BACKGROUND: Few small studies reported that motor fibers are located exclusively in the anterior branch of the bifid recurrent laryngeal nerve (RLN). The aim of this study was to investigate the location of the motor fibers to the intrinsic muscles of the larynx among the bifid RLNs, and assess the prevalence of RLN injury with respect to nerve branching in a pragmatic trial. METHODS: This was a prospective cohort study of 1250 patients who underwent total thyroidectomy with intraoperative neural monitoring. The primary outcome was the position of the motor fibers in the bifid nerves. Adduction of the vocal folds was detected by the endotracheal tube electromyography and abduction by finger palpation of muscle contraction in the posterior cricoarytenoid. The secondary outcomes were the prevalence of the RLN branching and the prevalence of RLN injury in bifid versus non-bifid nerves. RESULTS: The bifid RLNs were identified in 613/2500 (24.5%) nerves at risk, including 92 (7.4%) patients with bilateral bifurcations. The motor fibers were present exclusively in the anterior branch in 605/613 (98.7%) bifid nerves, and in both the RLN branches in 8/613 (1.3%) bifid nerves. Prevalence of RLN injury was 5.2 versus 1.6% for the bifid versus non-bifid nerves (p < 0.001), odds ratio 2.98 (95% confidence interval 1.79-4.95; p < 0.001). CONCLUSIONS: The motor fibers of the RLN are located in the anterior extralaryngeal branch in the vast majority of but not in all patients. In rare cases, the motor fibers for adduction or abduction are located in the posterior branch of the RLN. As the bifid nerves are more prone to injury than non-branched nerves, meticulous dissection is recommended to assure preservation of all the branches of the RLN during thyroidectomy. PMID- 26438242 TI - Genotype-Phenotype Correlation in Indian Patients with MEN2-Associated Pheochromocytoma and Comparison of Clinico-Pathological Attributes with Apparently Sporadic Adrenal Pheochromocytoma. AB - INTRODUCTION: Pheochromocytoma (PCC) manifests in up to 50% of MEN2 patients. We correlated the clinico-pathological features of MEN2-associated PCC (MEN-PCC) with RET mutations and compared them with non-MEN adrenal-PCCs. METHODS: In this retrospective single institution study on a large PCC database (n = 208, 1997 2014) 24 MEN-PCC patients with known RET mutations were reviewed. Excluding 7 with incomplete data, the study cohort of 17 MEN-PCC patients from 11 kindreds (M:F::7:10) was identified. Clinical, biochemical, pathological attributes, and outcomes in the MEN-PCC group were correlated with the genotype, and further compared with non-MEN, apparently sporadic adrenal-PCCs (n = 132, excluding 37 extra-adrenal and 15 VHL/NF1/SDH-associated PCC). RESULTS: Components of MEN2 encountered included MTC in 13(76.5%), Marfanoid habitus in 2, and PHPT, cutaneous lichen amyloidosis and mucosal neuromas in 1 patient each. In 11(64.7%), PCC was the first detected MEN2 component (Symptomatic:8, Incidentaloma:3). Four (23.5%) were normotensive; 8(47.1%) had bilateral PCC (7 synchronous, 1 metachronous). Surgery for PCC included laparoscopic adrenalectomy in 12; and cortical-sparing adrenalectomy in 2 of 8 bilateral PCC patients. Mean MEN-PCC tumor size was 6.9 +/- 3.9 cm, and 6(35%) had additional adrenal medullary hyperplasia. Four different genotypes were encountered, commonest involving codon 634, others being 804 and 918. Mean age in MEN-PCC (27.7 +/- 12.2 years) was lower than non-MEN PCC (39.4 +/- 15.7, p = 0.018). Proportion of pediatric patients (35.3% in MEN-PCC vs. 12.9% in non-MEN-PCC, p = 0.007), bilateral tumors (47.1% in MEN-PCC, 4.5% in non-MEN-PCC, p < 0.001), and adrenal medullary hyperplasia (35.2% in MEN-PCC, 0.7% in non-MEN-PCC, p < 0.001) were different. Median 24-hour urinary metanephrines was significantly higher in index MEN-PCC patients, than non-MEN-PCC (634 vs. 214 mcg/24 h, p value = 0.006), but was non-significantly higher in non-index MEN-PCC patients. Mean tumor sizes were comparable in the two groups. None of MEN-PCC patients had malignant PCC, compared to 7(5.3%) in non-MEN-PCC. CONCLUSIONS: In this cohort of MEN-PCC from India, the commonest causative RET mutations for MEN-PCC involved codon 634. MEN PCC patients were younger, and more frequently had bilateral PCC than non-MEN disease. MEN-PCC patients in India are diagnosed with large tumors and extremely high catecholamine/metanephrine levels. PMID- 26438243 TI - A particular silent codon exchange in a recombinant gene greatly influences host cell metabolic activity. AB - BACKGROUND: Recombinant protein production using Escherichia coli as expression host is highly efficient, however, it also induces strong host cell metabolic burden. Energy and biomass precursors are withdrawn from the host's metabolism as they are required for plasmid replication, heterologous gene expression and protein production. Rare codons in a heterologous gene may be a further drawback. This study aims to investigate the influence of particular silent codon exchanges within a heterologous gene on host cell metabolic activity. Silent mutations were introduced into the coding sequence of a model protein to introduce all synonymous arginine or leucine codons at two randomly defined positions, as well as substitutions leading to identical amino acid exchanges with different synonymous codons. The respective E. coli clones were compared during cultivation in a mineral autoinduction medium using specialized online and offline measuring techniques to quantitatively analyze effects on respiration, biomass and protein production, as well as on carbon source consumption, plasmid copy number, intracellular nucleobases and mRNA content of each clone. RESULTS: Host stain metabolic burden correlates with recombinant protein production. Upon heterologous gene expression, tremendous differences in respiration, biomass and protein production were observed. According to their different respiration activity the E. coli clones could be classified into two groups, Type A and Type B. Type A clones tended to higher product formation, Type B clones showed stronger biomass formation. Whereas codon usage and intracellular nucleobases had no influence on the Type-A-Type-B-behavior, plasmid copy number, mRNA content and carbon source consumption strongly differed between the two groups. CONCLUSIONS: Particular silent codon exchanges in a heterologous gene sequence led to differences in initial growth of Type A and Type B clones. Thus, the biomass concentration at the time point of induction varied. In consequence, not only plasmid copy number and expression levels differed between the two groups, but also the kinetics of lactose and glycerol consumption. Even though the underlying molecular mechanisms are not yet identified we observed the astonishing phenomenon that particular silent codon exchanges within a heterologous gene tremendously affect host cell metabolism and recombinant protein production. This could have great impact on codon optimization of heterologous genes, screening procedures for improved variants, and biotechnological protein production processes. PMID- 26438244 TI - Unraveling the evolution and regulation of the alternative oxidase gene family in plants. AB - Alternative oxidase (AOX) is a diiron carboxylate protein present in all plants examined to date that couples the oxidation of ubiquinol with the reduction of oxygen to water. The predominant structure of AOX genes is four exons interrupted by three introns. In this study, by analyzing the genomic sequences of genes from different plant species, we deduced that intron/exon loss/gain and deletion of fragments are the major mechanisms responsible for the generation and evolution of AOX paralogous genes. Integrating gene duplication and structural information with expression profiles for various AOXs revealed that tandem duplication/block duplication contributed greatly to the generation and maintenance of the AOX gene family. Notably, the expression profiles based on public microarray database showed highly diverse expression patterns among AOX members in different developmental stages and tissues and that both orthologous and paralogous genes did not have the same expression profiles due to their divergence in regulatory regions. Comparative analysis of genes in six plant species under various perturbations indicated a large number of protein kinases, transcription factors and antioxidant enzymes are co-expressed with AOX. Of these, four sets of transcription factors--WRKY, NAC, bZIP and MYB--are likely involved in the regulating the differential responses of AOX1 genes to specific stresses. Furthermore, divergence of AOX1 and AOX2 subfamilies in regulation might be the main reason for their differential stress responses. PMID- 26438245 TI - Osteotomy configuration of the proximal wedge and analysis of the affecting factors in the medial open-wedge high tibial osteotomy. AB - PURPOSE: The purposes of this study were (1) to confirm the disparity of the measured thickness at the lateral hinge between anterior-posterior (AP) radiograph and 3D CT image, (2) to evaluate the affecting factors, and (3) to evaluate the differences between uniplanar and biplanar osteotomies. METHODS: From 2012 to 2014, a prospective comparative study was performed with 30 patients who received uniplanar osteotomy (group I) and 35 patients who received biplanar osteotomy (group II). For measurement of the proximal wedge, postoperative AP radiograph and 3D CT images were used. In the AP radiograph, medial and lateral bony bridge thicknesses were measured. In the 3D CT, the anterior and posterior images parallel to the coronal plane were selected for the evaluation. Coronal osteotomy slope was measured with the anterior image of the 3D CT scan. Sagittal osteotomy slope was measured with the sagittal section of the CT scan. RESULTS: Differences between the lateral bony bridge thicknesses measured in AP radiograph and the posterolateral posterolateral bony bridge thicknesses measured in 3D CT were statistically significant in both groups. Negative correlation was observed in the biplanar osteotomy group. Differences of the sagittal osteotomy slope from the native tibial slope showed negative correlation in the biplanar osteotomy group. CONCLUSION: Thickness of the posterolateral bony bridge was smaller compared to the observed thickness on the AP radiograph image that is routinely used for the follow-up. The thickness would be getting smaller if osteotomy is performed with an abrupt angle on the coronal plane and reverse slope on the sagittal plane. Therefore, osteotomy with abrupt angle on the coronal plane and reverse slope on the sagittal plane should be avoided for the proper thickness of the posterolateral bony bridge. LEVEL OF EVIDENCE: III. PMID- 26438246 TI - Changes in the orientation of knee functional flexion axis during passive flexion and extension movements in navigated total knee arthroplasty. AB - PURPOSE: Recently, the functional flexion axis has been considered to provide a proper rotational alignment of the femoral component in total knee arthroplasty. Several factors could influence the identification of the functional flexion axis. The purpose of this study was to analyse the estimation of the functional flexion axis by separately focusing on passive flexion and extension movements and specifically assessing its orientation compared to the transepicondylar axis, in both the axial plane and the frontal plane. METHODS: Anatomical and kinematic acquisitions were performed using a commercial navigation system on 79 patients undergoing total knee arthroplasty with cruciate substituting prosthesis design. The functional flexion axis was estimated from passive movements, between 0 degrees and 120 degrees of flexion and back. Intra-observer agreement and reliability, internal-external rotation and the angle with the surgical transepicondylar axis, in axial and frontal planes, were separately analysed for flexion and extension, in pre- and post-implant conditions. RESULTS: The analysis of reliability and agreement showed good results. The identification of the functional flexion axis showed statistically significant differences both in relation to flexion and extension and to pre- and post-implant conditions, both in frontal plane and in axial plane. The analysis of internal-external rotation confirmed these differences in kinematics (p < 0.05, between 25 degrees and 35 degrees of flexion). CONCLUSIONS: The identification of the functional flexion axis changed in relation to passive flexion and extension movements, above all in frontal plane, while it resulted more stable and reliable in axial plane. These findings supported the possible clinical application of the functional flexion axis in the surgical practice by implementing navigated procedures. However, further analyses are required to better understand the factors affecting the identification of the functional flexion axis. LEVEL OF EVIDENCE: IV. PMID- 26438247 TI - Return to sport following acute lateral ligament repair of the ankle in professional athletes. AB - PURPOSE: Recent literature supports early reconstruction of severe acute lateral ligament injuries in professional athletes, suggesting earlier rehabilitation and reduced recurrent instability incidence. Not previously reported, predicting the time to return to training and play is important to both athlete and club. We evaluate the effectiveness and complications of lateral ligament reconstruction in professional athletes. We aim to estimate the time to return to training and sports in both isolated injuries and patients with additional injuries. METHODS: A consecutive series of 42 athletes underwent modified Brostrom repair for clinically and radiologically confirmed acute grade III lateral ligament injury. Of 42, 30 had isolated complete rupture of ATFL and CFL. Of 42, 12 had additional injuries (osteochondral lesions, deltoid ligament injuries). All patients received minimum of 2 years post-operative assessment. RESULTS: The median return to training and sports for isolated injuries was 63 days (49-110) and 77 days (56 127), respectively. However, for concomitant injury results were 86 days (63-152) and 105 days (82-178). This delay was significant (p < 0.001). Despite no difference in pre- and post-op VAS scores between the groups, those with combined injuries had significantly lower FAOS pain and symptoms sub-scores post operatively (p = 0.027, p < 0.001). Two superficial infections responded to oral antibiotics. No patient developed recurrent instability. All returned to their pre-injury level of professional sports. CONCLUSION: Lateral ligament reconstruction is a safe and effective treatment for acute severe ruptures providing a stable ankle and expected return to sports at approximately 10 weeks. Despite return to the same level of competition, club and player should be aware that associated injuries may delay return and symptoms may continue. These results may act as a guide to predict the expected time to return to training and to sport after surgical repair of acute injuries and also the influence of associated injuries in prolonging rehabilitation. LEVEL OF EVIDENCE: III. PMID- 26438248 TI - Engineering Nanomedicines to Overcome Multidrug Resistance in Cancer Therapy. AB - Drug resistance to conventional antitumor drugs represents one of the major causes of treatment failure in patients affected by tumors. Two main types of drug resistance to anticancer drugs are found in tumors, namely intrinsic resistance, in which tumor cells are inherently resistant to chemotherapy, and acquired resistance, which results from previous drug exposure. Tumor cells resistant to a chemotherapeutic agent become cross-resistant to both similar and structurally unrelated classes of antitumor drugs, a biological mechanism known as multi drug resistance (MDR). Among the strategies considered to overcome MDR, nanovector-mediated drug administration represents an innovative and promising alternative. In this review, we report a number of nanovectors including polymer drug conjugates, polymeric micelles, nanotubes, LbL nanocapsules, and silica and gold nanoparticles. These systems are designed for the efficient delivery of anthracyclines, vinca alkaloids, taxanes, and others drugs. The development of these nanovectos to specifically overcome MDR and their mechanisms of action are covered and discussed. Finally, we discuss challenges and opportunities for further development of nanodevices-based chemotherapies to circumvent MDR through the design of nanovectors for the delivery of multiple cargoes. PMID- 26438249 TI - A Review of Bisindolylmethane as an Important Scaffold for Drug Discovery. AB - Bisindolylmethane and its derivatives are pharmacologically active and applicable in the field of pharmaceutical chemistry. Bisindolylmethanes have a variety of biological activities such as antihyperglycemic, antiinflammatory, antibacterial, anticancer, and antileishmanial activities, including enzyme inhibition activity. They play a crucial role in many diseases especially anticancer activity. Modifying their structure had proven to be useful in the search of new therapeutic agents. Extensive research carried out on bisindolylmethane and its derivatives shows that they are pharmacologically significant. The present review focuses on the pharmacological profile of bisindolylmethane derivatives. This review includes the current literature with an update of research findings as well as the perspectives that they hold for future research. PMID- 26438250 TI - Biological and chemical diversity of coral-derived microorganisms. AB - Coral-derived microorganisms have been a major focus of many research efforts on marine ecology in recent decades. Importantly, research on bioactive compounds from these diverse microorganisms, which include fungi and bacteria, has experienced an explosive growth during the past five years. This has unveiled the ecological roles of these microorganisms, which prevent antifouling, inhibit pathogenic bacteria, and deter predators in ocean ecosystems. Moreover, the structural diversity and pharmacological activity of the compounds produced by these microorganisms have also been studied extensively, leading not only to an understanding their roles within ecosystems, but also the potential value of their use in human health. In this review, 258 marine natural products, including polyketides, terpenoids, meroterpenoids, alkaloids, peptides, shikimates and lipids, all discovered in the past 24 years, are presented. 146 references are cited. PMID- 26438251 TI - ROS1 Kinase Inhibitors for Molecular-Targeted Therapies. AB - ROS1 is a pivotal transmembrane receptor protein tyrosine kinase which regulates several cellular processes like apoptosis, survival, differentiation, proliferation, cell migration, and transformation. There is increasing evidence supporting that ROS1 plays an important role in different malignancies including glioblastoma, colorectal cancer, gastric adenocarcinoma, inflammatory myofibroblastic tumor, ovarian cancer, angiosarcoma, and non small cell lung cancer; thus, ROS1 has become a potential drug discovery target. ROS1 shares about 49% sequence homology with ALK primary structure; therefore, wide range of ALK kinase inhibitors have shown in vitro inhibitory activity against ROS1 kinase. After Crizotinib approval by FDA for the management of ALK-rearranged lung cancer, ROS1-positive tumors have been focused. Although significant advancements have been achieved in understanding ROS1 function and its signaling pathways plus recent discovery of small molecules modulating ROS1 protein, a vital need of medicinal chemistry efforts is still required to produce selective and potent ROS1 inhibitors as an important therapeutic strategy for different human malignancies. This review focuses on the current knowledge about different scaffolds targeting ROS1 rearrangements, methods to synthesis, and some biological data about the most potent compounds that have delivered various scaffold structures. PMID- 26438252 TI - Diagnostic accuracy of WHO verbal autopsy tool for ascertaining causes of neonatal deaths in the urban setting of Pakistan: a hospital-based prospective study. AB - BACKGROUND: Globally, clinical certification of the cause of neonatal death is not commonly available in developing countries. Under such circumstances it is imperative to use available WHO verbal autopsy tool to ascertain causes of death for strategic health planning in countries where resources are limited and the burden of neonatal death is high. The study explores the diagnostic accuracy of WHO revised verbal autopsy tool for ascertaining the causes of neonatal deaths against reference standard diagnosis obtained from standardized clinical and supportive hospital data. METHODS: All neonatal deaths were recruited between August 2006 -February 2008 from two tertiary teaching hospitals in Province Sindh, Pakistan. The reference standard cause of death was established by two senior pediatricians within 2 days of occurrence of death using the International Cause of Death coding system. For verbal autopsy, trained female community health worker interviewed mother or care taker of the deceased within 2-6 weeks of death using a modified WHO verbal autopsy tool. Cause of death was assigned by 2 trained pediatricians. The performance was assessed in terms of sensitivity and specificity. RESULTS: Out of 626 neonatal deaths, cause-specific mortality fractions for neonatal deaths were almost similar in both verbal autopsy and reference standard diagnosis. Sensitivity of verbal autopsy was more than 93% for diagnosing prematurity and 83.5% for birth asphyxia. However the verbal autopsy didn't have acceptable accuracy for diagnosing the congenital malformation 57%. The specificity for all five major causes of neonatal deaths was greater than 90%. CONCLUSION: The WHO revised verbal autopsy tool had reasonable validity in determining causes of neonatal deaths. The tool can be used in resource limited community-based settings where neonatal mortality rate is high and death certificates from hospitals are not available. PMID- 26438253 TI - Turn of the screw--helicases everywhere. PMID- 26438254 TI - Does learning to read shape verbal working memory? AB - Many experimental studies have investigated the relationship between the acquisition of reading and working memory in a unidirectional way, attempting to determine to what extent individual differences in working memory can predict reading achievement. In contrast, very little attention has been dedicated to the converse possibility that learning to read shapes the development of verbal memory processes. In this paper, we present available evidence that advocates a more prominent role for reading acquisition on verbal working memory and then discuss the potential mechanisms of such literacy effects. First, the early decoding activities might bolster the development of subvocal rehearsal, which, in turn, would enhance serial order performance in immediate memory tasks. In addition, learning to read and write in an alphabetical system allows the emergence of phonemic awareness and finely tuned phonological representations, as well as of orthographic representations. This could improve the quality, strength, and precision of lexical representations, and hence offer better support for the temporary encoding of memory items and/or for their retrieval. PMID- 26438256 TI - Erratum to: Symptom attributions in patients with colorectal cancer. PMID- 26438255 TI - Re-examining selective adaptation: Fatiguing feature detectors, or distributional learning? AB - When a listener hears many good examples of a /b/ in a row, they are less likely to classify other sounds on, e.g., a /b/-to-/d/ continuum as /b/. This phenomenon is known as selective adaptation and is a well-studied property of speech perception. Traditionally, selective adaptation is seen as a mechanistic property of the speech perception system, and attributed to fatigue in acoustic-phonetic feature detectors. However, recent developments in our understanding of non linguistic sensory adaptation and higher-level adaptive plasticity in speech perception and language comprehension suggest that it is time to re-visit the phenomenon of selective adaptation. We argue that selective adaptation is better thought of as a computational property of the speech perception system. Drawing on a common thread in recent work on both non-linguistic sensory adaptation and plasticity in language comprehension, we furthermore propose that selective adaptation can be seen as a consequence of distributional learning across multiple levels of representation. This proposal opens up new questions for research on selective adaptation itself, and also suggests that selective adaptation can be an important bridge between work on adaptation in low-level sensory systems and the complicated plasticity of the adult language comprehension system. PMID- 26438257 TI - Circulating concentration of markers of angiogenic activity in patients with sarcoidosis and idiopathic pulmonary fibrosis. AB - BACKGROUND: Angiogenesis is an important process involved in the pathogenesis of diffuse parenchymal lung diseases. The aim of the study was to compare the angiogenic profile of patients with sarcoidosis and idiopathic pulmonary fibrosis (IPF) based on analysis of circulating factors. METHODS: Serum concentrations of angiopoietin-2 (Ang-2), follistatin, granulocyte-macrophage-colony stimulating factor (GM-CSF), interleukin-8 (IL-8), platelet derived growth factor-BB (PDGF BB), platelet endothelial cellular adhesion molecule-1 (PECAM-1) and vascular endothelial growth factors (VEGF) were measured in the patients and the healthy subjects. RESULTS: Serum concentrations of G-CSF, follistatin, PECAM-1 and IL-8 were significantly higher in the IPF patients in comparison with the control group and the sarcoid patients. PDGF-BB concentrations were also significantly higher in serum of IPF patients than in sarcoid patients, but not than in the controls. In contrast, Ang-2 and VEGF concentrations did not differ significantly between the three groups. In the sarcoid patients, irrespective of the disease activity or the radiological stage, serum concentrations of these cytokines were similar to the control group. CONCLUSIONS: These results indicate that differences may exist in angiogenic activity between patients with parenchymal lung diseases. In contrast to sarcoidosis, IPF is characterized by a higher serum concentration of different molecules involved in the angiogenic processes . PMID- 26438258 TI - The pla gene, encoding plasminogen activator, is not specific to Yersinia pestis. AB - Here we present evidence to show that the pla gene, previously thought to be specific to Yersinia pestis, occurs in some strains of Citrobacter koseri and Escherichia coli. This means that detection of this gene on its own can no longer be taken as evidence of detection of Y. pestis. PMID- 26438259 TI - Membrane Hydration: A Hint to a New Model for Biomembranes. AB - The classical view of a biological membrane is based on the Singer-Nicholson mosaic fluid model in which the lipid bilayer is the structural backbone. Under this paradigm, many studies of biological processes such as, permeability, active transport, enzyme activity and adhesion and fusion processes have been rationalized considering the lipid membrane as a low dielectric slab of hydrocarbon chains with polar head groups exposed to water at each side in which oil/water partition prevails. In spite of several analyses and evidence available in relation to membrane hydration, water is not taken into account as a functional component. For this purpose, new insights in the water organization in restricted environments and the thermodynamical and mechanical properties emerging from them are specifically analysed and correlated.This chapter summarizes the progress of the studies of water in membranes along the book in order to give a more realistic structural and dynamical picture accounting for the membrane functional properties. PMID- 26438260 TI - Use of X-Ray and Neutron Scattering Methods with Volume Measurements to Determine Lipid Bilayer Structure and Number of Water Molecules/Lipid. AB - In this chapter I begin with a historical perspective of membrane models, starting in the early twentieth century. As these membrane models evolved, so did experiments to characterize the structure and water content of purified lipid bilayers. The wide-spread use of the X-ray gravimetric, or Luzzati method, is critically discussed. The main motivation of the gravimetric technique is to determine the number of water molecules/lipid, n(W), and then derive other important structural quantities, such as area/lipid, A(L). Subsequent experiments from the Nagle/Tristram-Nagle laboratory using X-ray and neutron scattering, first determine A(L) and then calculate n(W), using molecular lipid V(L) and water V(W) volumes. This chapter describes the details of our volume experiments to carefully measure V(L). Our results also determine n(W)', the steric water associated with the lipid headgroup, and how our calculated value compares to many literature values of tightly-associated headgroup water. PMID- 26438261 TI - Water and Lipid Bilayers. AB - Water is crucial to the structure and function of biological membranes. In fact, the membrane's basic structural unit, i.e. the lipid bilayer, is self-assembled and stabilized by the so-called hydrophobic effect, whereby lipid molecules unable to hydrogen bond with water aggregate in order to prevent their hydrophobic portions from being exposed to water. However, this is just the beginning of the lipid-bilayer-water relationship. This mutual interaction defines vesicle stability in solution, controls small molecule permeation, and defines the spacing between lamella in multi-lamellar systems, to name a few examples. This chapter will describe the structural and dynamical properties central to these, and other water- lipid bilayer interactions. PMID- 26438262 TI - Hydration Forces Between Lipid Bilayers: A Theoretical Overview and a Look on Methods Exploring Dehydration. AB - Although, many biological systems fulfil their functions under the condition of excess hydration, the behaviour of bound water as well as the processes accompanying dehydration are nevertheless important to investigate. Dehydration can be a result of applied mechanical pressure, lowered humidity or cryogenic conditions. The effort required to dehydrate a lipid membrane at relatively low degree of hydration can be described by a disjoining pressure which is called hydration pressure or hydration force. This force is short-ranging (a few nm) and is usually considered to be independent of other surface forces, such as ionic or undulation forces. Different theories were developed to explain hydration forces that are usually not consistent with each other and which are also partially in conflict with experimental or numerical data.Over the last decades it has been more and more realised that one experimental method alone is not capable of providing much new insight into the world of such hydration forces. Therefore, research requires the comparison of results obtained from the different methods. This chapter thus deals with an overview on the theory of hydration forces, ranging from polarisation theory to protrusion forces, and presents a selection of experimental techniques appropriate for their characterisation, such as X-ray diffraction, atomic force microscopy and even calorimetry. PMID- 26438263 TI - Monitoring Membrane Hydration with 2-(Dimethylamino)-6-Acylnaphtalenes Fluorescent Probes. AB - A family of polarity sensitive fluorescent probes (2-(dimethylamino)-6 acylnaphtalenes, i.e. LAURDAN, PRODAN, ACDAN) was introduced by Gregorio Weber in 1979, with the aim to monitor solvent relaxation phenomena on protein matrices. In the following years, however, PRODAN and particularly LAURDAN, were used to study membrane lateral structure and associated dynamics. Once incorporated into membranes, the (nanosecond) fluorescent decay of these probes is strongly affected by changes in the local polarity and relaxation dynamics of restricted water molecules existing at the membrane/water interface. For instance, when glycerophospholipid containing membranes undertake a solid ordered (gel) to liquid disordered phase transition the fluorescence emission maximum of these probes shift ~ 50 nm with a significant change in their fluorescence lifetime. Furthermore, the fluorescence parameters of LAURDAN and PRODAN are exquisitely sensitive to cholesterol effects, allowing interpretations that correlate changes in membrane packing with membrane hydration. Different membrane model systems as well as innate biological membranes have been studied with this family of probes allowing interesting comparative studies. This chapter presents a short historical overview about these fluorescent reporters, discusses on different models proposed to explain their sensitivity to membrane hydration, and includes relevant examples from experiments performed in artificial and biological membranes. PMID- 26438264 TI - Long-Range Lipid-Water Interaction as Observed by ATR-FTIR Spectroscopy. AB - It is commonly assumed that the structure of water at a lipid-water interface is influenced mostly in the first hydration layer. However, recent results from different experimental methods show that perturbation extends through several hydration layers. Due to its low light penetration depth, attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy is specifically suited to study interlamellar water structure in multibilayers. Results obtained by this technique confirm the long-range water structure disturbance. Consequently, in confined membrane environments nearly all water molecules can be perturbed. It is important to note that the behavior of confined water molecules differs significantly in samples prepared in excess water and in partially hydrated samples. We show in what manner the interlamellar water perturbation is influenced by the hydration level and how it is sequentially modified with a step by-step dehydration of samples either by water evaporation or by osmotic pressure. Our results also indicate that besides different levels of hydration the lipid-water interaction is modulated by different lipid headgroups and different lipid phases as well. Therefore, modification of interlamellar water properties may clarify the role of water-mediated effects in biological processes. PMID- 26438265 TI - Hydration and Nanoconfined Water: Insights from Computer Simulations. AB - The comprehension of the structure and behavior of water at interfaces and under nanoconfinement represents an issue of major concern in several central research areas like hydration, reaction dynamics and biology. From one side, water is known to play a dominant role in the structuring, the dynamics and the functionality of biological molecules, governing main processes like protein folding, protein binding and biological function. In turn, the same principles that rule biological organization at the molecular level are also operative for materials science processes that take place within a water environment, being responsible for the self-assembly of molecular structures to create synthetic supramolecular nanometrically-sized materials. Thus, the understanding of the principles of water hydration, including the development of a theory of hydrophobicity at the nanoscale, is imperative both from a fundamental and an applied standpoint. In this work we present some molecular dynamics studies of the structure and dynamics of water at different interfaces or confinement conditions, ranging from simple model hydrophobic interfaces with different geometrical constraints (in order to single out curvature effects), to self assembled monolayers, proteins and phospholipid membranes. The tendency of the water molecules to sacrifice the lowest hydrogen bond (HB) coordination as possible at extended interfaces is revealed. This fact makes the first hydration layers to be highly oriented, in some situations even resembling the structure of hexagonal ice. A similar trend to maximize the number of HBs is shown to hold in cavity filling, with small subnanometric hydrophobic cavities remaining empty while larger cavities display an alternation of filled and dry states with a significant inner HB network. We also study interfaces with complex chemical and geometrical nature in order to determine how different conditions affect the local hydration properties. Thus, we show some results for protein hydration and, particularly, some preliminary studies on membrane hydration. Finally, calculations of a local hydrophobicity measure of relevance for binding and self assembly are also presented. We then conclude with a few words of further emphasis on the relevance of this kind of knowledge to biology and to the design of new materials by highlighting the context-dependent and non-additive nature of different non-covalent interactions in an aqueous nanoenvironment, an issue that is usually greatly overlooked. PMID- 26438266 TI - Aquaphotomics: Near Infrared Spectroscopy and Water States in Biological Systems. AB - Aquaphotomics is a new discipline that provides a framework for understanding changes in water molecular system presented as a water spectral pattern, to mirror the rest of the solution and to give a holistic description related to system functionality. One of its main purposes is to identify water bands as main coordinates of future absorbance patterns to be used as a system biomarker. This chapter presents the Aquaphotomics methodology and illustrates a way to identify specific water bands using temperature change and addition of solutions of different ionic strength as perturbations. Rapid and precise measurement of low concentration solutes has been given as a strong evidence of the vast information that "the water spectral pattern as molecular mirror" approach provides. Few applications using near infrared spectroscopy and multivariate analysis as main tools of Aquaphotomics have been presented. PMID- 26438267 TI - Hydration in Lipid Monolayers: Correlation of Water Activity and Surface Pressure. AB - In order to give a physical meaning to each region of the membrane we define the interphase as the region in a lipid membrane corresponding to the polar head groups imbibed in water with net different properties than the hydrocarbon region and the water phase. The interphase region is analyzed under the scope of thermodynamics of surface and solutions based on the definition of Defay Prigogine of an interphase and the derivation that it has in the understanding of membrane processeses in the context of biological response. In the view of this approach, the complete monolayer is considered as the lipid layer one molecule thick plus the bidimensional solution of the polar head groups inherent to it (the interphase region). Surface water activity appears as a common factor for the interaction of several aqueous soluble and surface active proteins with lipid membranes of different composition. Protein perturbation can be measured by changes in the surface pressure of lipid monolayers at different initial water surface activities. As predicted by solution chemistry, the increase of surface pressure is independent of the particle nature that dissolves. Therefore, membranes give a similar response in terms of the determined surface states given by water activity independent of the protein or peptide. PMID- 26438268 TI - Water at Biological Phase Boundaries: Its Role in Interfacial Activation of Enzymes and Metabolic Pathways. AB - Many life-sustaining activities in living cells occur at the membrane-water interface. The pertinent questions that we need to ask are, what are the evolutionary reasons in biology for choosing the membrane-water interface as the site for performing and/or controlling crucial biological reactions, and what is the key physical principle that is very singular to the membrane-water interface that biology exploits for regulating metabolic processes in cells? In this chapter, a hypothesis is developed, which espouses that cells control activities of membrane-bound enzymes through manipulation of the thermodynamic activity of water in the lipid-water interfacial region. The hypothesis is based on the fact that the surface pressure of a lipid monolayer is a direct measure of the thermodynamic activity of water at the lipid-water interface. Accordingly, the surface pressure-dependent activation or inactivation of interfacial enzymes is directly related to changes in the thermodynamic activity of interfacial water. Extension of this argument suggests that cells may manipulate conformations (and activities) of membrane-bound enzymes by manipulating the (re)activity of interfacial water at various locations in the membrane by localized compression or expansion of the interface. In this respect, cells may use the membrane-bound hormone receptors, lipid phase transition, and local variations in membrane lipid composition as effectors of local compression and/or expansion of membrane, and thereby local water activity. Several experimental data in the literature will be reexamined in the light of this hypothesis. PMID- 26438269 TI - Anhydrobiosis: An Unsolved Problem with Applications in Human Welfare. AB - Anhydrobiosis (Life Without Water) has been known for millennia, but the underlying mechanisms have not been understood until recent decades, and we have achieved only a partial understanding. One of the chief sites of damage from dehydration is membranes, and we and others have provided evidence that this damage may be obviated by the production of certain sugars, particularly trehalose. The sugar stabilizes membranes by preventing fusion and fluidizing the dry bilayers. The mechanism by which this is accomplished has been controversial, and I review that controversy here. In the past decade evidence is accumulating for a role of stress proteins in addition to or as a substitute for trehalose. Genomic studies on anhydrobiotes are yielding rapid progress. Also in the past decade, numerous uses for trehalose in treating human diseases have been proposed, some of which are in clinical testing. I conclude that the mechanisms underlying anhydrobiosis are more complex than we thought 20 years ago, but progress is being made towards elucidating those mechanisms. PMID- 26438270 TI - Up-regulated S100 calcium binding protein A8 in Plasmodium-infected patients correlates with CD4(+)CD25(+)Foxp3 regulatory T cell generation. AB - BACKGROUND: The pro-inflammatory S100 calcium binding protein A8 (S100A8) is elevated in the serum of patients with Plasmodium falciparum malaria, but its function in Plasmodium vivax malaria is not yet clear. This function was investigated in P. vivax-infected patients in this study. METHODS: The level of S100A8 in the serum was measured with ELISA. Full amino acids of S100A8 were synthesized to verify the functions for maturation of immature dendritic cell (iDC) and evaluation of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) generation by mature DC (mDC). RESULTS: A higher amount of S100A8 was detected in vivax infected patients (141.2 +/- 61.849 ng/ml, n = 40) compared with normal control group (48.1 +/- 27.384 ng/ml, n = 40). The level of S100A8 did not coincide with that of anti-malarial antibody measured by indirect fluorescent antibody test (IFAT) using parasite-infected red blood cells as antigen. Programmed death ligand 1 (PD-L1) was up-regulated on the surface of iDCs following treatment with synthetic S100A8, not with synthetic MSP-1, AMA-1 and CSP, as compared to the expression seen for non-treated iDCs. The addition of red blood cells of infected patients to iDCs also elevated their surface expression of CD86. However, the serum levels of S100A8 decreased with increase in parasitaemia. DCs matured by sera containing S100A8 generated Treg cells from naive T cells. The ratio of Treg cells generated was inversely proportional to the concentration of S100A8 in sera. CONCLUSIONS: Treg cells suppress the activity of cytotoxic T cells, which kill malaria parasites; therefore, the up-regulation of S100A8 in malaria patients may contribute to pathogen immune escape or tolerance. PMID- 26438272 TI - Marked lateral deviation of the phrenic nerve due to variant origin and course of the thyrocervical trunk: a cadaveric study. AB - Phrenic nerve impairment can often lead to serious respiratory disorders under various pathological conditions. During routine dissection of an 88-year-old Japanese male cadaver, a victim of heart failure, we recognized an extremely rare variation of the right thyrocervical trunk arising from the subclavian artery laterally to the anterior scalene muscle. In addition to that, the ipsilateral phrenic nerve was drawn and displaced remarkably laterad by this vessel. We examined all of the branches arising from subclavian arteries, phrenic nerves and diaphragm muscles. The embryological background of this arterial variation is considered. The marked displacement with prolonged strain had a potential to cause phrenic nerve impairment with an atrophic change of the diaphragm muscle. Recently many image diagnostic technologies have been developed and are often used. However, it is still possible that rare variations like this case may be overlooked and can only be recognized by intimate regional examination while keeping these rare variations in mind. PMID- 26438271 TI - Loss of Afferent Vestibular Input Produces Central Adaptation and Increased Gain of Vestibular Prosthetic Stimulation. AB - Implanted vestibular neurostimulators are effective in driving slow phase eye movements in monkeys and humans. Furthermore, increases in slow phase velocity and electrically evoked compound action potential (vECAP) amplitudes occur with increasing current amplitude of electrical stimulation. In intact monkeys, protracted intermittent stimulation continues to produce robust behavioral responses and preserved vECAPs. In lesioned monkeys, shorter duration studies show preserved but with somewhat lower or higher velocity behavioral responses. It has been proposed that such changes are due to central adaptive changes in the electrically elicited vestibulo-ocular reflex (VOR). It is equally possible that these differences are due to changes in the vestibular periphery in response to activation of the vestibular efferent system. In order to investigate the site of adaptive change in response to electrical stimulation, we performed transtympanic gentamicin perfusions to induce rapid changes in vestibular input in monkeys with long-standing stably functioning vestibular neurostimulators, disambiguating the effects of implantation from the effects of ototoxic lesion. Gentamicin injection was effective in producing a large reduction in natural VOR only when it was performed in the non-implanted ear, suggesting that the implanted ear contributed little to the natural rotational response before injection. Injection of the implanted ear produced a reduction in the vECAP responses in that ear, suggesting that the intact hair cells in the non-functional ipsilateral ear were successfully lesioned by gentamicin, reducing the efficacy of stimulation in that ear. Despite this, injection of both ears produced central plastic changes that resulted in a dramatically increased slow phase velocity nystagmus elicited by electrical stimulation. These results suggest that loss of vestibular afferent activity, and a concurrent loss of electrically elicited vestibular input, produces an increase in the efficacy of a vestibular neurostimulator by eliciting centrally adapted behavioral responses without concurrent adaptive increase of galvanic afferent activation in the periphery. PMID- 26438273 TI - Extension of the frontal sinus into the roof of the optic canal: a cadaveric case report. AB - This case reports a bilateral asymmetrical posterior extension of the frontal sinuses into the orbital roof with an unusual expansion into the roof of the optic canal in a 55-year-old male cadaver. The posterior extensions of the sinus were lined by mucoperiosteum and were separated from the underlying orbital contents and optic nerve by a thin plate of bone. This knowledge of an unusual anatomic variation of the frontal sinus may help understand better the ocular and intracranial complications associated with frontal sinus pathologies. PMID- 26438274 TI - Influence of the renal lower pole anatomy and mid-renal-zone classification in successful approach to the calices during flexible ureteroscopy. AB - PURPOSE: The aim of this paper is to analyze if the anatomy type of the collector system (CS) limits the accessibility of flexible ureteroscopy (FUR) in the lower pole. METHODS: We analyzed the pyelographies of 51 patients submitted to FUR and divided the CS into four groups: A1-kidney midzone (KM) drained by minor calices (Mc) that are dependent on the superior or on the inferior caliceal groups; A2-KM drained by crossed calices; B1-KM drained by a major caliceal group independent both of the superior and inferior groups, and B2-KM drained by Mc entering directly into the renal pelvis. We studied the number of calices, the angle between the lower infundibulum and renal pelvis, and the angle between the lower infundibulum and the inferior Mc. With the use of a flexible ureteroscope, the access attempt was made to all of lower pole calices. Averages were statistically compared using the ANOVA and Unpaired T test (p < 0.05). RESULTS: We found 14 kidneys of A1 (27.45 %); 4 of A2 (7.84 %); 17 of B1 (33.33 %); and 16 of B2 (31.37 %). The LIP was >90 degrees in 31 kidneys (60.78 %) and between 61 degrees and 90 degrees in 20 kidneys (39.22 %). We did not find angles smaller than 60 degrees . The group A1 presented 48 Mc and the UF was able to access 42 (87.5 %); the group A2 had 11 Mc and the UF was able to access 7 (63.64 %); the group B1 had 48 Mc and the UF was able to access 41 (85.42 %) and in group B2 we observed 41 Mc and the UF could access 35 (85.36 %). There was no statistical difference in the accessibility between the groups (p = 0.2610). CONCLUSIONS: Collecting system with kidney midzone drained by crossed calices presented the lower accessibility rate during FUR. PMID- 26438275 TI - Plasma copeptin for short term risk stratification in acute pulmonary embolism. AB - Copeptin (COP) was reported to have prognostic value in various cardiovascular diseases. We hypothesized that COP levels reflect the severity of acute pulmonary embolism (PE) and may be useful in prognostic assessment. Plasma COP concentrations were measured on the Kryptor Compact Plus platform (BRAHMS, Hennigsdorf, Germany). The study included 107 consecutive patients with diagnosed acute PE (47 males, 60 females), with median age of 65 years (range 20-88). High risk PE was diagnosed in 3 patients (2.8 %), intermediate risk in 69 (64.5 %), and low risk PE in 35 (32.7 %) patients. Control group included 64 subjects (25 males, 39 females; median age 52.5 year, range 17-87). Four patients (3.7 %) died during 30-day observation. Complicated clinical course (CCC) was experienced by 10 (9.3 %) patients. COP level was higher in PE patients than in controls [11.55 pmol/L (5.16-87.97), and 19.00 pmol/L (5.51-351.90), respectively, p < 0.0001], and reflected PE severity. COP plasma concentration in low risk PE was 14.67 nmol/L (5.51-59.61) and in intermediate/high risk PE 19.84 mol/L (5.64-351.90) p < 0.05. Median COP levels in nonsurvivors was higher than in survivors, 84.6 (28.48-351.9) pmol/L and 18.68 (5.512-210.1) pmol/L, respectively, p = 0.009. Subjects with CCC presented higher COP levels than patients with benign clinical course 53.1 (17.95-351.9) pmol/L and 18.16 (5.51-210.1) pmol/L, respectively, p = 0.001. Log-transformed plasma COP was the significant predictor of CCC, OR 16.5 95 % CI 23.2-111.9, p < 0.001. AUC-for prediction of CCC using plasma COP was 0.811 (95 % CI 0.676-0.927). The COP cut off value of 17.95 nmol/l had sensitivity of 100 %, specificity 49.5 %, positive predictive value of 16.9 % and negative predictive value of 100 %. We conclude that plasma COP levels can be regarded for promising marker of severity of acute PE and show potential in risk stratification of these patients. PMID- 26438277 TI - Feedbacks on climate in the Earth system: introduction. PMID- 26438276 TI - A simplified, data-constrained approach to estimate the permafrost carbon-climate feedback. AB - We present an approach to estimate the feedback from large-scale thawing of permafrost soils using a simplified, data-constrained model that combines three elements: soil carbon (C) maps and profiles to identify the distribution and type of C in permafrost soils; incubation experiments to quantify the rates of C lost after thaw; and models of soil thermal dynamics in response to climate warming. We call the approach the Permafrost Carbon Network Incubation-Panarctic Thermal scaling approach (PInc-PanTher). The approach assumes that C stocks do not decompose at all when frozen, but once thawed follow set decomposition trajectories as a function of soil temperature. The trajectories are determined according to a three-pool decomposition model fitted to incubation data using parameters specific to soil horizon types. We calculate litterfall C inputs required to maintain steady-state C balance for the current climate, and hold those inputs constant. Soil temperatures are taken from the soil thermal modules of ecosystem model simulations forced by a common set of future climate change anomalies under two warming scenarios over the period 2010 to 2100. Under a medium warming scenario (RCP4.5), the approach projects permafrost soil C losses of 12.2-33.4 Pg C; under a high warming scenario (RCP8.5), the approach projects C losses of 27.9-112.6 Pg C. Projected C losses are roughly linearly proportional to global temperature changes across the two scenarios. These results indicate a global sensitivity of frozen soil C to climate change (gamma sensitivity) of -14 to -19 Pg C degrees C(-1) on a 100 year time scale. For CH4 emissions, our approach assumes a fixed saturated area and that increases in CH4 emissions are related to increased heterotrophic respiration in anoxic soil, yielding CH4 emission increases of 7% and 35% for the RCP4.5 and RCP8.5 scenarios, respectively, which add an additional greenhouse gas forcing of approximately 10 18%. The simplified approach presented here neglects many important processes that may amplify or mitigate C release from permafrost soils, but serves as a data-constrained estimate on the forced, large-scale permafrost C response to warming. PMID- 26438279 TI - The inconstancy of the transient climate response parameter under increasing CO2. AB - In the Coupled Model Intercomparison Project Phase 5 (CMIP5), the model-mean increase in global mean surface air temperature T under the 1pctCO2 scenario (atmospheric CO(2) increasing at 1% yr(-1)) during the second doubling of CO(2) is 40% larger than the transient climate response (TCR), i.e. the increase in T during the first doubling. We identify four possible contributory effects. First, the surface climate system loses heat less readily into the ocean beneath as the latter warms. The model spread in the thermal coupling between the upper and deep ocean largely explains the model spread in ocean heat uptake efficiency. Second, CO(2) radiative forcing may rise more rapidly than logarithmically with CO(2) concentration. Third, the climate feedback parameter may decline as the CO(2) concentration rises. With CMIP5 data, we cannot distinguish the second and third possibilities. Fourth, the climate feedback parameter declines as time passes or T rises; in 1pctCO2, this effect is less important than the others. We find that T projected for the end of the twenty-first century correlates more highly with T at the time of quadrupled CO(2) in 1pctCO2 than with the TCR, and we suggest that the TCR may be underestimated from observed climate change. PMID- 26438278 TI - The impact of parametrized convection on cloud feedback. AB - We investigate the sensitivity of cloud feedbacks to the use of convective parametrizations by repeating the CMIP5/CFMIP-2 AMIP/AMIP + 4K uniform sea surface temperature perturbation experiments with 10 climate models which have had their convective parametrizations turned off. Previous studies have suggested that differences between parametrized convection schemes are a leading source of inter-model spread in cloud feedbacks. We find however that 'ConvOff' models with convection switched off have a similar overall range of cloud feedbacks compared with the standard configurations. Furthermore, applying a simple bias correction method to allow for differences in present-day global cloud radiative effects substantially reduces the differences between the cloud feedbacks with and without parametrized convection in the individual models. We conclude that, while parametrized convection influences the strength of the cloud feedbacks substantially in some models, other processes must also contribute substantially to the overall inter-model spread. The positive shortwave cloud feedbacks seen in the models in subtropical regimes associated with shallow clouds are still present in the ConvOff experiments. Inter-model spread in shortwave cloud feedback increases slightly in regimes associated with trade cumulus in the ConvOff experiments but is quite similar in the most stable subtropical regimes associated with stratocumulus clouds. Inter-model spread in longwave cloud feedbacks in strongly precipitating regions of the tropics is substantially reduced in the ConvOff experiments however, indicating a considerable local contribution from differences in the details of convective parametrizations. In both standard and ConvOff experiments, models with less mid-level cloud and less moist static energy near the top of the boundary layer tend to have more positive tropical cloud feedbacks. The role of non-convective processes in contributing to inter-model spread in cloud feedback is discussed. PMID- 26438280 TI - Insights into low-latitude cloud feedbacks from high-resolution models. AB - Cloud feedbacks are a leading source of uncertainty in the climate sensitivity simulated by global climate models (GCMs). Low-latitude boundary-layer and cumulus cloud regimes are particularly problematic, because they are sustained by tight interactions between clouds and unresolved turbulent circulations. Turbulence-resolving models better simulate such cloud regimes and support the GCM consensus that they contribute to positive global cloud feedbacks. Large-eddy simulations using sub-100 m grid spacings over small computational domains elucidate marine boundary-layer cloud response to greenhouse warming. Four observationally supported mechanisms contribute: 'thermodynamic' cloudiness reduction from warming of the atmosphere-ocean column, 'radiative' cloudiness reduction from CO2- and H2O-induced increase in atmospheric emissivity aloft, 'stability-induced' cloud increase from increased lower tropospheric stratification, and 'dynamical' cloudiness increase from reduced subsidence. The cloudiness reduction mechanisms typically dominate, giving positive shortwave cloud feedback. Cloud-resolving models with horizontal grid spacings of a few kilometres illuminate how cumulonimbus cloud systems affect climate feedbacks. Limited-area simulations and superparameterized GCMs show upward shift and slight reduction of cloud cover in a warmer climate, implying positive cloud feedbacks. A global cloud-resolving model suggests tropical cirrus increases in a warmer climate, producing positive longwave cloud feedback, but results are sensitive to subgrid turbulence and ice microphysics schemes. PMID- 26438281 TI - Shortwave forcing and feedbacks in Last Glacial Maximum and Mid-Holocene PMIP3 simulations. AB - Simulations of the climates of the Last Glacial Maximum (LGM), 21 000 years ago, and of the Mid-Holocene (MH), 6000 years ago, allow an analysis of climate feedbacks in climate states that are radically different from today. The analyses of cloud and surface albedo feedbacks show that the shortwave cloud feedback is a major driver of differences between model results. Similar behaviours appear when comparing the LGM and MH simulated changes, highlighting the fingerprint of model physics. Even though the different feedbacks show similarities between the different climate periods, the fact that their relative strength differs from one climate to the other prevents a direct comparison of past and future climate sensitivity. The land-surface feedback also shows large disparities among models even though they all produce positive sea-ice and snow feedbacks. Models have very different sensitivities when considering the vegetation feedback. This feedback has a regional pattern that differs significantly between models and depends on their level of complexity and model biases. Analyses of the MH climate in two versions of the IPSL model provide further indication on the possibilities to assess the role of model biases and model physics on simulated climate changes using past climates for which observations can be used to assess the model results. PMID- 26438282 TI - What does global mean temperature tell us about local climate? AB - The subject of climate feedbacks focuses attention on global mean surface air temperature (GMST) as the key metric of climate change. But what does knowledge of past and future GMST tell us about the climate of specific regions? In the context of the ongoing UNFCCC process, this is an important question for policy makers as well as for scientists. The answer depends on many factors, including the mechanisms causing changes, the timescale of the changes, and the variables and regions of interest. This paper provides a review and analysis of the relationship between changes in GMST and changes in local climate, first in observational records and then in a range of climate model simulations, which are used to interpret the observations. The focus is on decadal timescales, which are of particular interest in relation to recent and near-future anthropogenic climate change. It is shown that GMST primarily provides information about forced responses, but that understanding and quantifying internal variability is essential to projecting climate and climate impacts on regional-to-local scales. The relationship between local forced responses and GMST is often linear but may be nonlinear, and can be greatly complicated by competition between different forcing factors. Climate projections are limited not only by uncertainties in the signal of climate change but also by uncertainties in the characteristics of real world internal variability. Finally, it is shown that the relationship between GMST and local climate provides a simple approach to climate change detection, and a useful guide to attribution studies. PMID- 26438283 TI - Weighting climate model projections using observational constraints. AB - Projected climate change integrates the net response to multiple climate feedbacks. Whereas existing long-term climate change projections are typically based on unweighted individual climate model simulations, as observed climate change intensifies it is increasingly becoming possible to constrain the net response to feedbacks and hence projected warming directly from observed climate change. One approach scales simulated future warming based on a fit to observations over the historical period, but this approach is only accurate for near-term projections and for scenarios of continuously increasing radiative forcing. For this reason, the recent Fifth Assessment Report of the Intergovernmental Panel on Climate Change (IPCC AR5) included such observationally constrained projections in its assessment of warming to 2035, but used raw model projections of longer term warming to 2100. Here a simple approach to weighting model projections based on an observational constraint is proposed which does not assume a linear relationship between past and future changes. This approach is used to weight model projections of warming in 2081-2100 relative to 1986-2005 under the Representative Concentration Pathway 4.5 forcing scenario, based on an observationally constrained estimate of the Transient Climate Response derived from a detection and attribution analysis. The resulting observationally constrained 5-95% warming range of 0.8-2.5 K is somewhat lower than the unweighted range of 1.1-2.6 K reported in the IPCC AR5. PMID- 26438284 TI - Carbon cycle feedbacks and future climate change. AB - Climate and carbon cycle are tightly coupled on many timescales, from interannual to multi-millennial timescales. Observations always evidence a positive feedback, warming leading to release of carbon to the atmosphere; however, the processes at play differ depending on the timescales. State-of-the-art Earth System Models now represent these climate-carbon cycle feedbacks, always simulating a positive feedback over the twentieth and twenty-first centuries, although with substantial uncertainty. Recent studies now help to reduce this uncertainty. First, on short timescales, El Nino years record larger than average atmospheric CO2 growth rate, with tropical land ecosystems being the main drivers. These climate-carbon cycle anomalies can be used as emerging constraint on the tropical land carbon response to future climate change. Second, centennial variability found in last millennium records can be used to constrain the overall global carbon cycle response to climatic excursions. These independent methods point to climate-carbon cycle feedback at the low-end of the Earth System Models range, indicating that these models overestimate the carbon cycle sensitivity to climate change. These new findings also help to attribute the historical land and ocean carbon sinks to increase in atmospheric CO2 and climate change. PMID- 26438285 TI - Atmospheric and oceanic impacts of Antarctic glaciation across the Eocene Oligocene transition. AB - The glaciation of Antarctica at the Eocene-Oligocene transition (approx. 34 million years ago) was a major shift in the Earth's climate system, but the mechanisms that caused the glaciation, and its effects, remain highly debated. A number of recent studies have used coupled atmosphere-ocean climate models to assess the climatic effects of Antarctic glacial inception, with often contrasting results. Here, using the HadCM3L model, we show that the global atmosphere and ocean response to growth of the Antarctic ice sheet is sensitive to subtle variations in palaeogeography, using two reconstructions representing Eocene and Oligocene geological stages. The earlier stage (Eocene; Priabonian), which has a relatively constricted Tasman Seaway, shows a major increase in sea surface temperature over the Pacific sector of the Southern Ocean in response to the ice sheet. This response does not occur for the later stage (Oligocene; Rupelian), which has a more open Tasman Seaway. This difference in temperature response is attributed to reorganization of ocean currents between the stages. Following ice sheet expansion in the earlier stage, the large Ross Sea gyre circulation decreases in size. Stronger zonal flow through the Tasman Seaway allows salinities to increase in the Ross Sea, deep-water formation initiates and multiple feedbacks then occur amplifying the temperature response. This is potentially a model-dependent result, but it highlights the sensitive nature of model simulations to subtle variations in palaeogeography, and highlights the need for coupled ice sheet-climate simulations to properly represent and investigate feedback processes acting on these time scales. PMID- 26438286 TI - The $10 trillion value of better information about the transient climate response. AB - How much is better information about climate change worth? Here, I use PAGE09, a probabilistic integrated assessment model, to find the optimal paths of CO(2) emissions over time and to calculate the value of better information about one aspect of climate change, the transient climate response (TCR). Approximately halving the uncertainty range for TCR has a net present value of about $10.3 trillion (year 2005 US$) if accomplished in time for emissions to be adjusted in 2020, falling to $9.7 trillion if accomplished by 2030. Probabilistic integrated assessment modelling is the only method we have for making estimates like these for the value of better information about the science and impacts of climate change. PMID- 26438287 TI - Feedbacks, climate sensitivity and the limits of linear models. AB - The term 'feedback' is used ubiquitously in climate research, but implies varied meanings in different contexts. From a specific process that locally affects a quantity, to a formal framework that attempts to determine a global response to a forcing, researchers use this term to separate, simplify and quantify parts of the complex Earth system. We combine new model results with a historical and educational perspective to organize existing ideas around feedbacks and linear models. Our results suggest that the state- and forcing-dependency of feedbacks are probably not appreciated enough, and not considered appropriately in many studies. A non-constant feedback parameter likely explains some of the differences in estimates of equilibrium climate sensitivity from different methods and types of data. Clarifying the value and applicability of the linear forcing feedback framework and a better quantification of feedbacks on various timescales and spatial scales remains a high priority in order to better understand past and predict future changes in the climate system. PMID- 26438288 TI - Implementation and Outcomes of Forensic Housing First Programs. AB - This mixed-method study used administrative data from 68 supportive housing programs and evaluative and qualitative site visit data from a subset of four forensic programs to (a) compare fidelity to the Housing First model and residential client outcomes between forensic and nonforensic programs and (b) investigate whether and how providers working in forensic programs can navigate competing Housing First principles and criminal justice mandates. Quantitative findings suggested that forensic programs were less likely to follow a harm reduction approach to substance use and clients in those programs were more likely to live in congregate settings. Qualitative findings suggested that an interplay of court involvement, limited resources, and risk environments influenced staff decisions regarding housing and treatment. Existing mental health and criminal justice collaborations necessitate adaptation to the Housing First model to accommodate client needs. PMID- 26438289 TI - Estimation of Additive, Dominance, and Imprinting Genetic Variance Using Genomic Data. AB - Traditionally, exploration of genetic variance in humans, plants, and livestock species has been limited mostly to the use of additive effects estimated using pedigree data. However, with the development of dense panels of single-nucleotide polymorphisms (SNPs), the exploration of genetic variation of complex traits is moving from quantifying the resemblance between family members to the dissection of genetic variation at individual loci. With SNPs, we were able to quantify the contribution of additive, dominance, and imprinting variance to the total genetic variance by using a SNP regression method. The method was validated in simulated data and applied to three traits (number of teats, backfat, and lifetime daily gain) in three purebred pig populations. In simulated data, the estimates of additive, dominance, and imprinting variance were very close to the simulated values. In real data, dominance effects account for a substantial proportion of the total genetic variance (up to 44%) for these traits in these populations. The contribution of imprinting to the total phenotypic variance of the evaluated traits was relatively small (1-3%). Our results indicate a strong relationship between additive variance explained per chromosome and chromosome length, which has been described previously for other traits in other species. We also show that a similar linear relationship exists for dominance and imprinting variance. These novel results improve our understanding of the genetic architecture of the evaluated traits and shows promise to apply the SNP regression method to other traits and species, including human diseases. PMID- 26438290 TI - Reassignment of Drosophila willistoni Genome Scaffolds to Chromosome II Arms. AB - Drosophila willistoni is a geographically widespread Neotropical species. The genome of strain Gd-H4-1 from Guadeloupe Island (Caribbean) was sequenced in 2007 as part of the 12 Drosophila Genomes Project. The assembled scaffolds were joined based on conserved linkage and assigned to polytene chromosomes based on a handful of genetic and physical markers. This paucity of markers was particularly striking in the metacentric chromosome II, comprised two similarly sized arms, IIL and IIR, traditionally considered homologous to Muller elements C and B, respectively. In this paper we present the cytological mapping of 22 new gene markers to increase the number of markers mapped by in situ hybridization and to test the assignment of scaffolds to the polytene chromosome II arms. For this purpose, we generated, by polymerase chain reaction amplification, one or two gene probes from each scaffold assigned to the chromosome II arms and mapped these probes to the Gd-H4-1 strain's polytene chromosomes by nonfluorescent in situ hybridization. Our findings show that chromosome arms IIL and IIR correspond to Muller elements B and C, respectively, directly contrasting the current homology assignments in D. willistoni and constituting a major reassignment of the scaffolds to chromosome II arms. PMID- 26438291 TI - Joint Transcriptomic and Metabolomic Analyses Reveal Changes in the Primary Metabolism and Imbalances in the Subgenome Orchestration in the Bread Wheat Molecular Response to Fusarium graminearum. AB - Fusarium head blight is a prevalent disease of bread wheat (Triticum aestivum L.), which leads to considerable losses in yield and quality. Quantitative resistance to the causative fungus Fusarium graminearum is poorly understood. We integrated transcriptomics and metabolomics data to dissect the molecular response to the fungus and its main virulence factor, the toxin deoxynivalenol in near-isogenic lines segregating for two resistance quantitative trait loci, Fhb1 and Qfhs.ifa-5A. The data sets portrait rearrangements in the primary metabolism and the translational machinery to counter the fungus and the effects of the toxin and highlight distinct changes in the metabolism of glutamate in lines carrying Qfhs.ifa-5A. These observations are possibly due to the activity of two amino acid permeases located in the quantitative trait locus confidence interval, which may contribute to increased pathogen endurance. Mapping to the highly resolved region of Fhb1 reduced the list of candidates to few genes that are specifically expressed in presence of the quantitative trait loci and in response to the pathogen, which include a receptor-like protein kinase, a protein kinase, and an E3 ubiquitin-protein ligase. On a genome-scale level, the individual subgenomes of hexaploid wheat contribute differentially to defense. In particular, the D subgenome exhibited a pronounced response to the pathogen and contributed significantly to the overall defense response. PMID- 26438292 TI - The Role of Mms22p in DNA Damage Response in Candida albicans. AB - To ensure correct DNA replication, eukaryotes have signaling pathways that respond to replication-associated DNA damage and trigger repair. In both Saccharomyces cerevisiae and Schizosaccharomyces pombe, a complex of proteins, including the cullin protein Rtt101p and two adapter proteins Mms22p and Mms1p, is important for proper response to replication stress. We have investigated this system in Candida albicans. In this pathogen, Mms22p is important for recovery from DNA replication damage induced by agents including methylmethane sulfonate, camptothecin, and ionizing radiation. Although no clear ortholog of Mms1p has been identified in C. albicans, loss of either Mms22p or Rtt101p generates similar damage sensitivity, consistent with a common function. In S. cerevisiae, the Mrc1p-Csm3p-Tof1p complex stabilizes stalled replication forks and activates a replication checkpoint and interacts with Mms22p. A similar complex in S. pombe, consisting of the Tof1p and Csm3p orthologs Swi1p and Swi3p, along with the fission yeast Mrc1p, genetically also interacts with Mms22p. Intriguingly in C. albicans only Mrc1p and Csm3p appear involved in damage repair, and Mms22p is required for responding to DNA damage agents in MRC1 or CSM3 conditional mutants. In C. albicans, although the loss of RAD57 greatly impairs response in the pathogen to many DNA-damaging agents, lethality due to camptothecin damage requires concomitant loss of Rad57p and Mms22p, suggesting that Mms22p is only essential for homologous recombination induced by camptothecin. These results establish that although C. albicans uses conserved cellular modules to respond to DNA damage and replication blocks, the specific details of these modules differ significantly from the S. cerevisiae model. PMID- 26438294 TI - Drosophila melanogaster Natural Variation Affects Growth Dynamics of Infecting Listeria monocytogenes. AB - We find that in a Listeria monocytogenes/Drosophila melanogaster infection model, L. monocytogenes grows according to logistic kinetics, which means we can measure both a maximal growth rate and growth plateau for the microbe. Genetic variation of the host affects both of the pathogen growth parameters, and they can vary independently. Because growth rates and ceilings both correlate with host survival, both properties could drive evolution of the host. We find that growth rates and ceilings are sensitive to the initial infectious dose in a host genotype-dependent manner, implying that experimental results differ as we change the original challenge dose within a single strain of host. PMID- 26438293 TI - Markerless Escherichia coli rrn Deletion Strains for Genetic Determination of Ribosomal Binding Sites. AB - Single-copy rrn strains facilitate genetic ribosomal studies in Escherichia coli. Consecutive markerless deletion of rrn operons resulted in slower growth upon inactivation of the fourth copy, which was reversed by supplying transfer RNA genes encoded in rrn operons in trans. Removal of the sixth, penultimate rrn copy led to a reduced growth rate due to limited rrn gene dosage. Whole-genome sequencing of variants of single-copy rrn strains revealed duplications of large stretches of genomic DNA. The combination of selective pressure, resulting from the decreased growth rate, and the six identical remaining scar sequences, facilitating homologous recombination events, presumably leads to elevated genomic instability. PMID- 26438295 TI - Estimating Trait Heritability in Highly Fecund Species. AB - Increasingly, researchers are interested in estimating the heritability of traits for nonmodel organisms. However, estimating the heritability of these traits presents both experimental and statistical challenges, which typically arise from logistical difficulties associated with rearing large numbers of families independently in the field, a lack of known pedigree, the need to account for group or batch effects, etc. Here we develop both an empirical and computational methodology for estimating the narrow-sense heritability of traits for highly fecund species. Our experimental approach controls for undesirable culturing effects while minimizing culture numbers, increasing feasibility in the field. Our statistical approach accounts for known issues with model-selection by using a permutation test to calculate significance values and includes both fitting and power calculation methods. We further demonstrate that even with moderately high sample-sizes, the p-values derived from asymptotic properties of the likelihood ratio test are overly conservative, thus reducing statistical power. We illustrate our methodology by estimating the narrow-sense heritability for larval settlement, a key life-history trait, in the reef-building coral Orbicella faveolata. The experimental, statistical, and computational methods, along with all of the data from this study, are available in the R package multiDimBio. PMID- 26438297 TI - A Nonsense Variant in COL6A1 in Landseer Dogs with Muscular Dystrophy. AB - A novel canine muscular dystrophy in Landseer dogs was observed. We had access to five affected dogs from two litters. The clinical signs started at a few weeks of age, and the severe progressive muscle weakness led to euthanasia between 5 and 15 months of age. The pedigrees of the affected dogs suggested a monogenic autosomal-recessive inheritance of the trait. Linkage and homozygosity mapping indicated two potential genome segments for the causative variant on chromosomes 10 and 31 harboring a total of 4.8 Mb of DNA or 0.2% of the canine genome. Using the Illumina sequencing technology, we obtained a whole-genome sequence from one affected Landseer. Variants were called with respect to the dog reference genome and compared with the genetic variants of 170 control dogs from other breeds. The affected Landseer dog was homozygous for a single, private nonsynonymous variant in the critical intervals, a nonsense variant in the COL6A1 gene (Chr31:39,303,964G>T; COL6A1:c.289G>T; p.E97*). Genotypes at this variant showed perfect concordance with the muscular dystrophy phenotype in all five cases and more than 1000 control dogs. Variants in the human COL6A1 gene cause Bethlem myopathy or Ullrich congenital muscular dystrophy. We therefore conclude that the identified canine COL6A1 variant is most likely causative for the observed muscular dystrophy in Landseer dogs. On the basis of the nature of the genetic variant in Landseer dogs and their severe clinical phenotype these dogs represent a model for human Ullrich congenital muscular dystrophy. PMID- 26438296 TI - Sleeping Beauty Transposon Mutagenesis as a Tool for Gene Discovery in the NOD Mouse Model of Type 1 Diabetes. AB - A number of different strategies have been used to identify genes for which genetic variation contributes to type 1 diabetes (T1D) pathogenesis. Genetic studies in humans have identified >40 loci that affect the risk for developing T1D, but the underlying causative alleles are often difficult to pinpoint or have subtle biological effects. A complementary strategy to identifying "natural" alleles in the human population is to engineer "artificial" alleles within inbred mouse strains and determine their effect on T1D incidence. We describe the use of the Sleeping Beauty (SB) transposon mutagenesis system in the nonobese diabetic (NOD) mouse strain, which harbors a genetic background predisposed to developing T1D. Mutagenesis in this system is random, but a green fluorescent protein (GFP) polyA gene trap within the SB transposon enables early detection of mice harboring transposon-disrupted genes. The SB transposon also acts as a molecular tag to, without additional breeding, efficiently identify mutated genes and prioritize mutant mice for further characterization. We show here that the SB transposon is functional in NOD mice and can produce a null allele in a novel candidate gene that increases diabetes incidence. We propose that SB transposon mutagenesis could be used as a complementary strategy to traditional methods to help identify genes that, when disrupted, affect T1D pathogenesis. PMID- 26438298 TI - Tc1-like Transposase Thm3 of Silver Carp (Hypophthalmichthys molitrix) Can Mediate Gene Transposition in the Genome of Blunt Snout Bream (Megalobrama amblycephala). AB - Tc1-like transposons consist of an inverted repeat sequence flanking a transposase gene that exhibits similarity to the mobile DNA element, Tc1, of the nematode, Caenorhabditis elegans. They are widely distributed within vertebrate genomes including teleost fish; however, few active Tc1-like transposases have been discovered. In this study, 17 Tc1-like transposon sequences were isolated from 10 freshwater fish species belonging to the families Cyprinidae, Adrianichthyidae, Cichlidae, and Salmonidae. We conducted phylogenetic analyses of these sequences using previously isolated Tc1-like transposases and report that 16 of these elements comprise a new subfamily of Tc1-like transposons. In particular, we show that one transposon, Thm3 from silver carp (Hypophthalmichthys molitrix; Cyprinidae), can encode a 335-aa transposase with apparently intact domains, containing three to five copies in its genome. We then coinjected donor plasmids harboring 367 bp of the left end and 230 bp of the right end of the nonautonomous silver carp Thm1 cis-element along with capped Thm3 transposase RNA into the embryos of blunt snout bream (Megalobrama amblycephala; one- to two-cell embryos). This experiment revealed that the average integration rate could reach 50.6% in adult fish. Within the blunt snout bream genome, the TA dinucleotide direct repeat, which is the signature of Tc1 like family of transposons, was created adjacent to both ends of Thm1 at the integration sites. Our results indicate that the silver carp Thm3 transposase can mediate gene insertion by transposition within the genome of blunt snout bream genome, and that this occurs with a TA position preference. PMID- 26438300 TI - Unlike in clear cell renal cell carcinoma, KRAS is not mutated in multilocular cystic clear cell renal cell neoplasm of low potential. AB - The recent International Society Urological Pathology (ISUP) Vancouver classification of renal neoplasia distinguishes between clear cell renal cell carcinoma (CCRCC) and multilocular cystic clear cell renal cell neoplasm of low malignant potential (mcCCRCNLMP). Current data supports the latter being a low aggressive neoplasm which does not recur or metastasize after definitive surgical treatment. Therefore, differentiating mcCCRCNLMP from low-grade CCRCC with cystic changes is important for patient management. The role of the pathologist is crucial in distinguishing between both entities. Since these tumors have overlapping molecular features, including 3p deletion and VHL mutations, it would be potentially clinically relevant to identify other molecular differences which might help to differentiate between these entities. We studied six different codons of KRAS and six codons of NRAS in mcCCRCNLMP and CCRCC of low grade and stage. All cases of CCRCC had a mutation in one of the studied KRAS codons. In contrast, no mutations were found in mcCCRCNLMP. We provide preliminary data to support that CCRCC and mcCCRCNLMP, in spite of their histologic similarity, show a different pattern of KRAS gene mutation, which is consistent with the observed differences in disease progression between these tumors. PMID- 26438299 TI - HES-Mediated Repression of Pten in Caenorhabditis elegans. AB - The hairy/enhancer-of-split (HES) group of transcription factors controls embryonic development, often by acting downstream of the Notch signaling pathway; however, little is known about postembryonic roles of these proteins. In Caenorhabditis elegans, the six proteins that make up the REF-1 family are considered to be HES orthologs that act in both Notch-dependent and Notch independent pathways to regulate embryonic events. To further our understanding of how the REF-1 family works to coordinate postembryonic cellular events, we performed a functional characterization of the REF-1 family member, HLH-25. We show that, after embryogenesis, hlh-25 expression persists throughout every developmental stage, including dauer, into adulthood. Like animals that carry loss-of-function alleles in genes required for normal cell-cycle progression, the phenotypes of hlh-25 animals include reduced brood size, unfertilized oocytes, and abnormal gonad morphology. Using gene expression microarray, we show that the HLH-25 transcriptional network correlates with the phenotypes of hlh-25 animals and that the C. elegans Pten ortholog, daf-18, is one major hub in the network. Finally, we show that HLH-25 regulates C. elegans lifespan and dauer recovery, which correlates with a role in the transcriptional repression of daf-18 activity. Collectively, these data provide the first genetic evidence that HLH-25 may be a functional ortholog of mammalian HES1, which represses PTEN activity in mice and human cells. PMID- 26438301 TI - Deconvolution of the vestibular evoked myogenic potential using the power spectrum of the electromyogram. AB - BACKGROUND: The vestibular evoked myogenic potential (VEMP) can be modelled reasonably well by convolving two functions: one representing an average motor unit action potential (MUAP), the other representing the temporal modulation of the MUAP rate (rate modulation). It is the latter which contains the information of interest, and so it would be desirable to be able to estimate this function from a combination of the VEMP with some other data. As the VEMP is simply a stimulus-triggered average of the electromyogram (EMG), a supplementary, easily accessible source of information is the EMG power spectrum, which can be shown to be roughly proportional to the squared modulus of the Fourier transform of the MUAP. But no phase information is available for the MUAP so that a straightforward deconvolution is not possible. METHODS: To get around the problem of incomplete information, the rate modulation is described by a thoughtfully chosen function with just a few adjustable parameters. The convolution model is then used to make predictions as to the energy spectral density of the VEMP, and the parameters are optimized using a cost function that quantifies the difference between model prediction and data. RESULTS: The workability of the proposed approach is demonstrated by analysing Monte Carlo simulated data and exemplary data from patients who underwent VEMP testing as part of a clinical evaluation of their dizziness symptoms. CONCLUSIONS: The approach is suited, for example, to estimate the duration of the inhibition causing the VEMP or to disentangle a VEMP consisting of more than one component. PMID- 26438302 TI - Sharing data from MS clinical trials: Opportunities, challenges, and future directions. AB - The treatment of people affected by multiple sclerosis, particularly the relapsing forms of the disease, has been transformed by the availability of various therapeutic agents. This landmark progress is due to an enormous foundation of clinical research and, particularly, numerous phase II and III clinical trials. Although the research community has many reasons to take pride in this progress, a fundamental question remains about whether opportunities for additional research are being lost due to inadequate clinical trial data sharing. PMID- 26438303 TI - Multiple sclerosis relapse phenotype is an important, neglected, determinant of disease outcome - YES. PMID- 26438304 TI - Multiple sclerosis relapse phenotype is an important, neglected, determinant of disease outcome - NO. PMID- 26438305 TI - Multiple sclerosis relapse phenotype is an important, neglected determinant of disease-outcome: Commentary. PMID- 26438306 TI - The burden of multiple sclerosis variants in continental Italians and Sardinians. AB - BACKGROUND: Recent studies identified > 100 non-HLA (human leukocyte antigen) multiple sclerosis (MS) susceptibility variants in Northern European populations, but their role in Southern Europeans is largely unexplored. OBJECTIVE: We aimed to investigate the cumulative impact of those variants in two Mediterranean populations: Continental Italians and Sardinians. METHODS: We calculated four weighted Genetic Risk Scores (wGRS), using up to 102 non-HLA MS risk variants and 5 HLA MS susceptibility markers in 1691 patients and 2194 controls from continental Italy; and 2861 patients and 3034 controls from Sardinia. We then assessed the differences between populations using Nagelkerke's R(2) and the area under the Receiver Operating Characteristic (ROC) curves. RESULTS: As expected, the genetic burden (mean wGRS value) was significantly higher in MS patients than in controls, in both populations. Of note, the burden was significantly higher in Sardinians. Conversely, the proportion of variability explained and the predictive power were significantly higher in continental Italians. Notably, within the Sardinian patients, we also observed a significantly higher burden of non-HLA variants in individuals who do not carry HLA risk alleles. CONCLUSIONS: The observed differences in MS genetic burden between the two Mediterranean populations highlight the need for more genetic studies in South Europeans, to further expand the knowledge of MS genetics. PMID- 26438307 TI - Treatment of osteoporosis after alendronate or risedronate. AB - Alendronate (ALN) and risedronate (RIS) are ideal as first-choice therapy options in the treatment of postmenopausal osteoporosis. What to do for patients who do not respond adequately to bisphosphonates has not been conclusively determined, but transitioning to other therapies should be considered. The aim of this article is to describe potential alternatives for patients switching from ALN or RIS to other therapies for osteoporosis. A systematic search of PubMed was conducted to find papers that evaluate the effects of switching therapies on fractures, bone mineral density (BMD), or bone turnover markers. Results from 11 studies that prospectively assessed treatment after ALN or RIS in women with postmenopausal osteoporosis were reviewed. All studies are of short duration (all 24 months or less) and assess the topic of transitioning therapy from ALN or RIS. None of the studies had the statistical power to assess fracture-reduction efficacy. Transitioning from ALN to zoledronic acid maintains therapeutic effects for 12 months. Switching to strontium ranelate, denosumab, or teriparatide causes further increases in BMD. Specifically, transitioning to teriparatide could be used for a limited time for select patients but needs to be followed up with anti resorptive treatment to prevent a loss of the bone gained. There are only few studies-of short duration-that assess the topic of transitioning therapy from ALN or RIS, although this is a very frequent occurrence in clinical practice. This is especially true if the patient has not reached his/her therapy goal. Further long term studies are needed. PMID- 26438308 TI - Does salmon calcitonin cause cancer? A review and meta-analysis. AB - Recently an association between the use of calcitonin and cancer has been postulated. We reviewed the biological rationale and performed an additional analysis of historical data with respect to the possibility. An association cannot be excluded, but the relationship is weak and causality is unlikely. The purpose of the present study is to review the strength of association and likelihood of a causal relationship between use of calcitonin and cancer. We reviewed the evidence for this association, including the molecular signaling mechanisms of calcitonin, preclinical data, an "experiment of nature," and the results of a previous meta-analysis which showed a weak association. We performed an additional meta-analysis to incorporate the data from a novel investigational oral formulation of salmon calcitonin. Review of the literature did not identify a cellular signaling mechanism of action which might account for a causal relationship or toxicologic or postmarketing data to support the thesis. Additional clinical results incorporated into previous meta-analyses weakened but did not completely negate the possibility of association. A causal association between calcitonin use and malignancy is unlikely, as there is little biological plausibility. The preponderance of nonclinical and clinical evidence also does not favor a causal relationship. PMID- 26438309 TI - Non-hip and non-vertebral fractures: the neglected fracture sites. AB - SUMMARY: Non-hip, non-vertebral fractures (NHNVF) were compared with hip, vertebral and controls. NHNVF were younger and heavier than controls and hip/vertebral fractures in both men and women, respectively. Falls and prior fractures were less common in NHNVF than hip fractures. Glucocorticoid use was lower in NHNVF compared to vertebral fracture (VF) in men. INTRODUCTION: Although hip fracture (HF) and vertebral fractures (VF) receive the most attention in the literature and are the targeted sites for fracture prevention, non-hip, non vertebral fracture (NHNVF) sites account for a greater proportion of fractures than the hip or vertebrae. This study aimed to assess risk factors for NHNVF and compare them with those for HF, VF and controls. METHODS: Incident fractures during 2005-2007 for men and 1994-1996 for women were identified using computerised keyword searches of radiological reports, and controls were selected at random from electoral rolls for participation in the Geelong Osteoporosis Study. Participants aged 60+ years were included in this study. RESULTS: Compared to controls, men and women with NHNVF were younger (ORs, 0.90, 95% CI 0.86-0.94; and 0.96, 0.93-0.98, respectively) and had a lower femoral neck bone mineral density (BMD) T-score (age-adjusted; difference [men] 0.383, P = 0.002; [women] 0.287, P = 0.001). Compared to HF, men and women with NHNVF were heavier (difference [men] 9.0 kg, P = 0.01; [women] 7.6 kg, P < 0.001). Heavier weight was also a risk factor for women with NHNVF compared to VF (1.03, 1.01-1.06). In men with NHNVF, falls (0.37, 0.14-0.97) and prior fractures (0.38, 0.15-0.98) were less common compared to HF; and glucocorticoid use was less common for NHNVF (0.30, 0.11-0.85) compared to VF. CONCLUSIONS: Given the high numbers of NHNVF sustained by men and women in this study, fracture prevention strategies should focus on individuals with high risk of sustaining these types of fractures, as well as on individuals who are more likely to sustain a HF or VF. PMID- 26438310 TI - The effects of visceral obesity and androgens on bone: trenbolone protects against loss of femoral bone mineral density and structural strength in viscerally obese and testosterone-deficient male rats. AB - SUMMARY: In males, visceral obesity and androgen deficiency often present together and result in harmful effects on bone. Our findings show that both factors are independently associated with adverse effects on femoral bone structure and strength, and trenbolone protects rats from diet-induced visceral obesity and consequently normalises femoral bone structural strength. INTRODUCTION: In light of the rapidly increasing incidence of obesity and osteoporosis globally, and recent conjecture regarding the effects of visceral adiposity and testosterone deficiency on bone health, we investigated the effects of increased visceral adipose tissue (VAT) mass on femoral bone mineral density (BMD), structure and strength in normal weight rats with testosterone deficiency. METHODS: Male Wistar rats (n = 50) were fed either standard rat chow (CTRL, n = 10) or a high-fat/high-sugar diet (HF/HS, n = 40). Following 8 weeks of feeding, rats underwent sham surgery (CTRL, n = 10; HF/HS, n = 10) or orchiectomy (HF/HS + ORX, n = 30). Following a 4-week recovery period, mini-osmotic pumps containing either vehicle (CTRL, n = 10; HF/HS, n = 10; HF/HS + ORX, n = 10), 2.0 mg kg day( 1), testosterone (HF/HS + ORX + TEST, n = 10) or 2.0 mg kg day(-1) trenbolone (HF/HS + ORX + TREN, n = 10) were implanted for 8 weeks of treatment. Dual-energy X-ray absorptiometry and three-point bending tests were used to assess bone mass, structure and strength of femora. RESULTS: Diet-induced visceral obesity resulted in decreased bone mineral area (BMA) and content (BMC) and impaired femoral stiffness and strength. Orchiectomy further impaired BMA, BMC and BMD and reduced energy to failure in viscerally obese animals. Both TEST and TREN treatment restored BMA, BMC, BMD and energy to failure. Only TREN reduced visceral adiposity and improved femoral stiffness and strength. CONCLUSIONS: Findings support a role for both visceral adiposity and testosterone deficiency as independent risk factors for femoral osteoporosis, adverse bone geometry and impaired bone strength in male rats. Trenbolone may be a more effective candidate for androgen replacement therapy than testosterone in viscerally obese testosterone-deficient males. PMID- 26438311 TI - Development of a generic Ehrlichia FRET-qPCR and investigation of ehrlichioses in domestic ruminants on five Caribbean islands. AB - BACKGROUND: The Ehrlichia are obligate intracellular Gram-negative tick-borne bacteria that are important human and animal pathogens. There is a need for assays to rapidly and reliably detect and differentiate the five generally recognized species into groups in a single reaction: E. canis, E. chaffeensis, E. ewingii, E. muris and E. ruminantium. METHODS: We developed primers and probes against the 16S rRNA gene to enable us to reliably detect the five major Ehrlichia spp. in a single FRET-qPCR. We tested the Ehrlichia FRET-qPCR on reference strains and on DNA from the blood of domestic ruminants from five Caribbean islands. The Ehrlichia present were determined using melting point analysis and by sequencing the Ehrlichia FRET-qPCR products as well as those of a nested PCR against the citrate synthase gene (gltA). RESULTS: Our Ehrlichia FRET qPCR was negative for the closely related Anaplasma marginale and A. phagocytophilum but gave positive reactions with reference strains of the most generally recognized species and with other less characterized Ehrlichia of domestic ruminants, mainly E. ovina, the Panola Mountain Ehrlichia, and Ehrlichia sp. BOV2010. Melting point analysis revealed 4 distinct groups: E. ruminantium (T m ~55.8 degrees C); E. chaffeensis and E. ewingii (T m ~57.7 degrees C); E. canis, E. muris, E. ovina and Ehrlichia sp. BOV 2010 (T m ~62.0 degrees C); and the Panola Mountain Ehrlichia (T m ~65.5 degrees C). The detection limit of the FRET-qPCR was ~ 5 gene copies in a reaction and the sequences of the FRET-qPCR products were as expected. With DNA from domestic ruminants from the Caribbean we found 12.2 % (134/1,101) positive: cattle (76/385; 19.7 %), sheep (45/340; 13.2 %) and goats (13/376; 3.5 %). Melting point analysis and sequencing of the FRET qPCR and nested PCR gltA products showed the Ehrlichia we detected were E. canis or very closely related organisms. CONCLUSIONS: In a single reaction, our Ehrlichia FRET-qPCR can detect the Ehrlichia spp. we studied and differentiate them into four groups. Domestic ruminants in the Caribbean are not uncommonly exposed to Ehrlichia, possibly E. canis or very closely related organisms. PMID- 26438313 TI - Exploration of Peptide Inhibitors of Human Squalene Synthase through Molecular Modeling and Phage Display Technique. AB - Many studies have demonstrated the role of elevated levels of serum cholesterol in the pathogenesis of atherosclerosis and coronary heart disease. Various drugs targeting the key enzymes involved in the cholesterol biosynthesis pathway have been investigated for the treatment of hypercholesterolemia. Human squalene synthase has been one of the most important targets for therapeutic intervention. In the present study, we used the recombinant human squalene synthase as the lure for screening the peptide inhibitors from phage-displayed random peptide library. The tightly bound phages and their derived peptides were further evaluated based on their potential binding capabilities, molecular modeling characteristics and predicted absorption, distribution, metabolism, excretion, toxicity (ADMET) properties. Several hexa-peptides and tetra-peptides were finally synthesized to assay their inhibitory effects toward the recombinant human squalene synthase. The results demonstrated that the hexa-peptide FTACNW and tetra-peptide VACL can inhibit human squalene synthase effectively (with IC50 values near 100 MUM) and may have potential to develop further as future hypocholesterolemia agents. PMID- 26438314 TI - Efficient Cadmium Bioaccumulation by Displayed Hybrid CS3 Pili: Effect of Heavy Metal Binding Motif Insertion Site on Adsorption Capacity and Selectivity. AB - The objective of this study was to evaluate the influence of insertion site of the metal binding motif on the bioaccumulation capacity of the hybrid CS3 pili displayed on the surface of Escherichia coli using both computational and experimental methods. Two metal binding motifs (cadmium binding motif (cbm) and cadmium binding beta motif (cbbetam)), identified by searching against the PROSITE database, were inserted into five putative permissive sites of CstH protein (CS3 pili subunit) by using SOEing PCR technique. The expression and surface display of the hybrid pili were evaluated using dot and Western blotting methods and also immunofluorescence microscopy. The cadmium binding affinity and selectivity of the recombinant bacteria displaying various hybrid pili were evaluated using atomic absorption procedure. The results showed that the cadmium binding motifs enabled the cells to sequester cadmium 8- to 16-fold higher than the E.coli expressing native pili. The location of the metal binding motifs in the pili subunit had also a significant effect on the metal-binding properties of the hybrid pili. The insertion at positions 107-108 and 92-93 of the mature CstH showed the highest adsorption in comparison to other positions. PMID- 26438312 TI - Genome analyses of the sunflower pathogen Plasmopara halstedii provide insights into effector evolution in downy mildews and Phytophthora. AB - BACKGROUND: Downy mildews are the most speciose group of oomycetes and affect crops of great economic importance. So far, there is only a single deeply sequenced downy mildew genome available, from Hyaloperonospora arabidopsidis. Further genomic resources for downy mildews are required to study their evolution, including pathogenicity effector proteins, such as RxLR effectors. Plasmopara halstedii is a devastating pathogen of sunflower and a potential pathosystem model to study downy mildews, as several Avr-genes and R-genes have been predicted and unlike Arabidopsis downy mildew, large quantities of almost contamination-free material can be obtained easily. RESULTS: Here a high-quality draft genome of Plasmopara halstedii is reported and analysed with respect to various aspects, including genome organisation, secondary metabolism, effector proteins and comparative genomics with other sequenced oomycetes. Interestingly, the present analyses revealed further variation of the RxLR motif, suggesting an important role of the conservation of the dEER-motif. Orthology analyses revealed the conservation of 28 RxLR-like core effectors among Phytophthora species. Only six putative RxLR-like effectors were shared by the two sequenced downy mildews, highlighting the fast and largely independent evolution of two of the three major downy mildew lineages. This is seemingly supported by phylogenomic results, in which downy mildews did not appear to be monophyletic. CONCLUSIONS: The genome resource will be useful for developing markers for monitoring the pathogen population and might provide the basis for new approaches to fight Phytophthora and downy mildew pathogens by targeting core pathogenicity effectors. PMID- 26438315 TI - Cloning, Expression, and Purification of Xylanase Gene from Bacillus licheniformis for Use in Saccharification of Plant Biomass. AB - The xylanase gene (xynA) of Bacillus licheniformis 9945A was cloned and expressed in Escherichia coli BL21(DE3) using pET-22b(+) as an expression vector. The recombinant xylanase enzyme was purified by ammonium sulfate precipitation, followed by single-step immobilized metal ion affinity chromatography with a 57.58-fold purification having 138.2 U/mg specific activity and recovery of 70.08 %. Molecular weight of the purified xylanase, 23 kDa, was determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The enzyme was stable for up to 70 degrees C with a broad pH range of 4-9 pH units. The enzyme activity was increased in the presence of metal ions especially Ca(+2) and decreased in the presence of EDTA, indicating that the xylanase was a metalloenzyme. However, an addition of 1-4 % Tween 80, beta-mercaptoethanol, and DTT resulted in the increase of enzyme activity by 51, 52, and 5 %, respectively. Organic solvents with a concentration of 10-40 % slightly decreased the enzyme activity. The xylanase enzyme possesses the ability of bioconversion of plant biomasses like wheat straw, rice straw, and sugarcane bagasse. Among the different tested biomasses, the highest saccharification percentage was observed with 1 % sugarcane bagasse after 72 h of incubation at 50 degrees C with 20 units of enzyme. The results suggest that recombinant xylanase can be used in the bioconversion of natural biomasses into simple sugars which could be further used for the production of biofuel. PMID- 26438316 TI - GLP-1 Receptor Agonists and Type 1 Diabetes - Where Do We Stand? AB - Type 1 diabetes (T1DM) is a disease characterized by autoimmune mediated destruction of the insulin producing beta cells of endocrine pancreas. Beside insulin deficiency, T1DM is also characterized by abnormal suppression of glucagon secretion in response to hyperglycemia. All these abnormalities are likely to leave patients dependent upon exogenous insulin administration for survival. GLP-1 is a hormone secreted by L-cells of distal small intestine and colon. GLP-1 exerts its effects through the interaction with GLP-1 receptor expressed in the pancreatic islets, lung, hypothalamus, stomach, heart and kidney. It belongs to the group of incretin peptides and it stimulates insulin and inhibits glucagon secretion. Actions of GLP-1 also include delaying of gastric emptying, reduction of appetite and induction of satiety. On the other hand, evidences mainly collected from animal models, have indicated the role of GLP-1 in increasing beta cell proliferation and differentiation and in decreasing the rate of beta cell apoptosis. GLP-1 receptor agonists are approved for the treatment of type 2 diabetes where they have established very important position. However, they are still not approved for use in T1DM, although they could have beneficial effects in both new onset and longstanding T1DM patients, mainly as an adjunctive therapy to insulin in order to improve glycemic control and body weight management in longstanding disease or to reduce insulin requirements or even to delay the absolute dependence upon insulin administration in new onset T1DM. Randomized, long-term, placebo controlled clinical trials are warranted before the official implementation of GLP-1 receptor agonists in the treatment of T1DM. PMID- 26438317 TI - Integrating care for individuals with FASD: results from a multi-stakeholder symposium. AB - BACKGROUND: Fetal Alcohol Spectrum Disorder (FASD) has a significant impact on communities and systems such as health, education, justice and social services. FASD is a complex neurodevelopmental disorder that results in permanent disabilities and associated service needs that change across affected individuals' lifespans. There is a degree of interdependency among medical and non-medical providers across these systems that do not frequently meet or plan a coordinated continuum of care. Improving overall care integration will increase provider-specific and system capacity, satisfaction, quality of life and outcomes. METHODS: We conducted a consensus generating symposium comprised of 60 experts from different stakeholder groups: Allied & Mental Health, Education, First Nations & Metis Health, Advocates, Primary Care, Government Health Policy, Regional FASD Coordinators, Social Services, and Youth Justice. Research questions addressed barriers and solutions to integration across systems and group-specific and system-wide research priorities. Solutions and consensus on prioritized lists were generated by combining the Electronic Meeting System approach with a modified 'Nominal Group Technique'. RESULTS: FASD capacity (e.g., training, education, awareness) needs to be increased in both medical and non medical providers. Outcomes and integration will be improved by implementing: multidisciplinary primary care group practice models, FASD system navigators/advocates, and patient centred medical homes. Electronic medical records that are accessible to multiple medical and non-medical providers are a key tool to enhancing integration and quality. Eligibility criteria for services are a main barrier to integration across systems. There is a need for culturally and community-specific approaches for First Nations communities. CONCLUSIONS: There is a need to better integrate care for individuals and families living with FASD. Primary Care is well positioned to play a central and important role in facilitating and supporting increased integration. Research is needed to better address best practices (e.g., interventions, supports and programs) and long-term individual and family outcomes following a diagnosis of FASD. PMID- 26438318 TI - Do Targeted Stipend Programs Reduce Gender and Socioeconomic Inequalities in Schooling Attainment? Insights From Rural Bangladesh. AB - Social investment in schooling in low-income countries has increased greatly in the 1990s and 2000s because of the robust associations among schooling and demographic, economic, and health outcomes. This analysis investigates whether targeted school-attendance stipend programs succeeded in reducing gender and socioeconomic inequalities in school attainment among a sample of the rural poor in Bangladesh. Multivariate analyses find that targeted stipend programs helped to reduce the gender attainment gap. Females had an increased probability of participating in stipend programs, and returns to stipend participation were significantly higher for females. However, stipend programs failed to reduce the relative achievement gap between children of different socioeconomic backgrounds: low socioeconomic status (SES) was associated with a decreased probability of stipend participation, and stipend-related schooling gains for lower-SES females were matched by comparable gains for higher-SES females. Meanwhile, there was no significant association between stipend participation and schooling attainment for males. PMID- 26438319 TI - An Environmental Cause Common to Sex Determination and Infant Mortality. PMID- 26438320 TI - The role of serum osteoprotegerin and receptor-activator of nuclear factor-kappaB ligand in metabolic bone disease of women after obesity surgery. AB - Metabolic bone disease may appear as a complication of obesity surgery. Because an imbalance in the osteoprotegerin and receptor-activator of nuclear factor kappaB ligand system may underlie osteoporosis, we aimed to study this system in humans in the metabolic bone disease occurring after obesity surgery. In this study we included sixty women with a mean age of 47 +/- 10 years studied 7 +/- 2 years after bariatric surgery. The variables studied were bone mineral density, beta-isomer of C-terminal telopeptide of type I collagen cross-links (a bone resorption marker), the bone formation markers osteocalcin and N-terminal propeptide of procollagen 1, serum osteoprotegerin and receptor-activator of nuclear factor-kappaB ligand. Serum osteoprotegerin inversely correlated with the bone remodeling markers osteocalcin, beta-isomer of C-terminal telopeptide of type I collagen cross-links and N-terminal propeptide of procollagen 1. The osteoprotegerin and receptor-activator of nuclear factor-kappaB ligand ratio also correlated inversely with serum parathormone and osteocalcin. Bone mineral density at the lumbar spine was associated with age (beta = -0.235, P = 0.046), percentage of weight loss (beta = 0.421, P = 0.001) and osteoprotegerin and receptor-activator of nuclear factor-kappaB ligand ratio (beta = 0.259, P = 0.029) in stepwise multivariate analysis (R 2 = 0.29, F = 7.49, P < 0.001). Bone mineral density at the hip site was associated only with percentage of weight loss (beta = 0.464, P < 0.001) in stepwise multivariate regression (R 2 = 0.21, F = 15.1, P < 0.001). These data show that the osteoprotegerin and receptor activator of nuclear factor-kappaB ligand system is associated with bone markers and bone mineral density at the lumbar spine after obesity surgery. PMID- 26438322 TI - Identification of patients with suboptimal results after hip arthroplasty: development of a preliminary prediction algorithm. AB - BACKGROUND: The ability to predict preoperatively the identity of patients undergoing hip arthroplasty at risk of suboptimal outcomes could help implement interventions targeted at improving surgical results. The objective was to develop a preliminary prediction algorithm (PA) allowing the identification of patients at risk of unsatisfactory outcomes one to two years following hip arthroplasty. METHODS: Retrospective data on a cohort of 265 patients having undergone primary unilateral hip replacement (188 total arthroplasties and 77 resurfacing arthroplasties) from 2004 to 2010 were collected from our arthroplasty database. Hip pain and function, as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were collected, as well as self-reported hip joint perception after surgery. Demographic and clinical variables recorded at the time of the surgery were considered as potential predictors. Patients were considered as having a suboptimal surgical outcome if they were in the worst quartile of the postoperative total WOMAC score and perceived their operated hip as artificial with minimal or major limitations. The PA was developed using recursive partitioning. RESULTS: Mean postoperative surgical follow-up was 446 +/- 171 days. Forty patients (15.1 %) had a postoperative total WOMAC score in the worst quartile (>11.5/100) and perceived their joint as artificial with minimal or major restrictions. A PA consisting of the following variables achieved the most acceptable level of prediction: gender, age at the time of surgery, body mass index (BMI), and three items of the preoperative WOMAC (degree of pain with walking on a flat surface and during the night as well as degree of difficulty with putting socks or stockings). The rule had a sensitivity of 75.0 % (95 % CI: 59.8-85.8), a specificity of 77.8 % (95 % CI: 71.9-82.7), a positive predictive value of 37.5 % (95 % CI: 27.7-48.5), a negative predictive value of 94.6 % (95 % CI: 90.3-97.0) and positive and negative likelihood ratios of 3.38 (95 % CI: 2.49-4.57) and 0.34 (95 % CI: 0.19 0.55) respectively. CONCLUSIONS: The preliminary PA shows promising results at identifying patients at risk of significant functional limitations, increased pain and inadequate joint perception after hip arthroplasty. Clinical use should not be implemented before additional validation and refining. PMID- 26438321 TI - Factors associated with growth disturbance at celiac disease diagnosis in children: a retrospective cohort study. AB - BACKGROUND: Impaired growth is a well-known complication in celiac disease, but factors associated with it are poorly known. We investigated this issue in a large cohort of children. METHODS: 530 children with biopsy-proven celiac disease were included. The participants were divided into two groups on the basis of the presence (n = 182) or absence (n = 348) of growth disturbance at diagnosis. Histological, serological and clinical characteristics were compared between children with growth failure and those with normal growth. Further, patients with growth failure as the sole clinical presentation were compared to those with poor growth and concomitant other symptoms. RESULTS: Children with growth failure were younger (p < 0.001) and had lower hemoglobin (p = 0.016) and higher celiac antibody (p < 0.001), alanine aminotransferase (p = 0.035) and thyroid stimulating hormone values (p = 0.013) than those with normal growth. Significantly associated with growth failure at diagnosis were age <3 years (OR 4.3 (95 % CI 2.5-7.5) vs older age), diagnosis before the year 2000 and in 2000 09 (OR 3.1 (1.8-5.4) and OR 1.8 (1.1-2.8) vs diagnosis in 2010-2013), presence of total and subtotal villous atrophy (OR 4.2 (2.5-7.0) and OR 2.0 (1.3-3.2) vs partial atrophy), severe symptoms (OR 3.4 (1.8-6.7) vs mild symptoms) and vomiting (OR 3.1 (1.5-6.3). The presence of abdominal pain reduced the risk (OR 0.5 (0.3-0.7)), while there was no effect of gender, diarrhea, constipation, other chronic diseases and celiac disease in the family. Children evincing poor growth as the sole clinical presentation were older (p < 0.001) and had higher hemoglobin (P < 0.001) and total iron (p = 0.010) values and lower TG2ab values (p = 0.009) than those with growth disturbance and other symptoms. CONCLUSIONS: In particular young age and severe clinical and histological presentation were associated with growth disturbance at celiac disease diagnosis. Children with only poor growth are markedly different from those with other concomitant symptoms, suggesting different pathogenic mechanisms. PMID- 26438323 TI - Australian GP management of osteoarthritis following the release of the RACGP guideline for the non-surgical management of hip and knee osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) is a highly disabling and costly condition with an escalating prevalence in Australia due to the ageing and increasing obesity of the population. The general practitioner (GP) plays a central role in the management of this condition. The aim of this study was to examine opinions about the management of OA by Australian GPs following the release of the Royal Australian College of General Practitioners Guideline for the non-surgical management of hip and knee OA (RACGP OA CPG), and to compare the results with an earlier survey administered by the National Prescribing Service. METHODS: In January 2013, a self-administered questionnaire was sent to 228 GPs to determine their treatment approaches to OA management using a clinical vignette of a patient with OA. This was compared with results from a similar survey undertaken in 2006. RESULTS: Seventy-nine GPs returned questionnaires (response rate 35%). GP recommendations for paracetamol, a paracetamol/codeine compound, and oral non steroidal anti-inflammatory drugs (NSAIDs) were consistent with recommendations in the RACGP OA CPG, and varied little from the previous survey. Notably, there was a marked increase between surveys in GP recommendations for tramadol (p = 0.004) and more potent opioids (p < 0.001). Advice about the adverse effects of NSAIDs and codeine and how to manage them increased between surveys (p = 0.038 and 0.005, respectively). For all non-pharmacological treatments, there were only minor changes in the percentage of GP recommendations when compared with the previous survey, however they remain underutilised. CONCLUSIONS: GPs generally demonstrated a conservative approach to the treatment of OA, however, the increased recommendations for more potent opioids warrants further investigation. Patients should be made aware of the risks of medications through the use of decision aids, which can provide structured guidance to treatment. Non pharmacological interventions were not given the importance that is suggested by clinical practice guidelines. PMID- 26438325 TI - Direct inhibition of plasmatic renin activity with aliskiren: a promising but under-investigated therapeutic option for non-diabetic glomerulonephritis. AB - Non-diabetic glomerulonephritis is a frequent cause of end-stage renal disease. The use of renin-angiotensin-aldosterone system blockers is a fundamental therapeutic approach. However, converting enzyme inhibitors (ACE-is) and angiotensin receptor blockers do not always achieve the desired target of proteinuria. The induction of the prorenin and renin up-regulation is a possible explanation. Aliskiren is the first drug acting as direct inhibitor of plasmatic renin activity, also able to interfere with the prorenin and renin profibrotic escape. We aimed at reviewing the literature for the assessment of potential efficacy and safety of aliskiren in the treatment of non-diabetic glomerulonephritis. The data on this topic are limited; however, we concluded for a possible usefulness of aliskiren. The renal safety profile appears potentially acceptable in non-diabetic patients although extreme carefulness, particularly with respect to long-term renal and cardiovascular tolerability, is recommended. PMID- 26438326 TI - Comparing the efficacy and safety of 365- and 550-MUm laser fibers in semirigid ureteroscopic Ho:YAG lithotripsy. AB - PURPOSE: To compare the efficacy and safety of 365- and 550-MUm Ho:YAG laser fiber in semirigid ureteroscopic lithotripsy and to identify parameters that may affect laser energy and time during the procedure. METHODS: A database of 111 patients who undergone a semirigid ureteroscopy (SRURS) for ureteral stone lithotripsy was analyzed. A 365-MUm core fiber was used in 56 cases, and a multiple-uses 550-MUm laser fiber was used in 55 cases. A standard 6.4 W protocol (8 Hz, 0.8 J/pulse) was used in all cases. The association between laser fiber diameter and several preoperative, intraoperative and postoperative parameters was evaluated. RESULTS: Mean stone burden was 54.1 +/- 39.1 mm(2), and postoperative stone-free and complication rate was 100.0 and 16.2 %, respectively. The 550-MUm laser fiber diameter was significantly associated with lower laser energy (p = 0.01), energy/mm(3) (p = 0.031), number of pulses (p = 0.012), laser time (p = 0.012) and laser time/mm(3) (p = 0.043), while it did not affect postoperative outcomes. The multivariate analysis showed that shorter procedure duration, smaller stone burden and the 550-MUm laser fiber were all significant independent predictors for decreased laser energy consumption. CONCLUSION: The 550-MUm laser fiber may decrease laser energy and time during SRURS lithotripsy with Ho:YAG laser compared to the 365 MUm. Given its lower cost, it may represent the optimal choice for semirigid procedures. PMID- 26438324 TI - Pathology and immune reactivity: understanding multidimensionality in pulmonary tuberculosis. AB - Heightened morbidity and mortality in pulmonary tuberculosis (TB) are consequences of complex disease processes triggered by the causative agent, Mycobacterium tuberculosis (Mtb). Mtb modulates inflammation at distinct stages of its intracellular life. Recognition and phagocytosis, replication in phagosomes and cytosol escape induce tightly regulated release of cytokines [including interleukin (IL)-1, tumor necrosis factor (TNF), IL-10], chemokines, lipid mediators, and type I interferons (IFN-I). Mtb occupies various lung lesions at sites of pathology. Bacteria are barely detectable at foci of lipid pneumonia or in perivascular/bronchiolar cuffs. However, abundant organisms are evident in caseating granulomas and at the cavity wall. Such lesions follow polar trajectories towards fibrosis, encapsulation and mineralization or liquefaction, extensive matrix destruction, and tissue injury. The outcome is determined by immune factors acting in concert. Gradients of cytokines and chemokines (CCR2, CXCR2, CXCR3/CXCR5 agonists; TNF/IL-10, IL-1/IFN-I), expression of activation/death markers on immune cells (TNF receptor 1, PD-1, IL-27 receptor) or abundance of enzymes [arginase-1, matrix metalloprotease (MMP)-1, MMP-8, MMP 9] drive genesis and progression of lesions. Distinct lesions coexist such that inflammation in TB encompasses a spectrum of tissue changes. A better understanding of the multidimensionality of immunopathology in TB will inform novel therapies against this pulmonary disease. PMID- 26438327 TI - Open partial nephrectomy: ancient art or currently available technique? AB - Renal cell carcinoma (RCC) accounts for 3 % of adult solid tumors, with the highest incidence between 50 and 70 years of age. Nephron-sparing surgery was initially reserved to patients with small renal masses detected in anatomically or functionally solitary kidney or in the presence of multiple bilateral tumors or hereditary forms of RCC, which posed a high risk of developing a tumor in the contralateral kidney. Nowadays, partial nephrectomy (PN) has grown up to an established approach for the treatment of small renal masses. In patients with T1a-staged RCCs, PN has proven to be associated with better survival, long-term renal function preservation with lower dialysis need or renal transplantation. Currently, most of the kidney masses are incidentally detected, up to 40 %, with smaller size due to the widespread use of imaging modalities such as ultrasound, computed tomography and magnetic resonance. Here we review the role of open PN in the management of small renal masses particularly focusing on indications, oncological outcomes and comparison with laparoscopic and robotic PN. Recent studies demonstrate that PN confers better survival, oncologic equivalence and lower risk of severe chronic kidney disease compared to radical nephrectomy becoming then the gold-standard surgical technique, even if increasingly challenged by laparoscopic and/or robot-assisted partial nephrectomy which in the hands of experts seems to achieve comparable outcome results albeit with slightly higher complication rate. PMID- 26438329 TI - Prevalence of primary headache disorders in Fayoum Governorate, Egypt. AB - BACKGROUND: There is abundance of epidemiological studies of headache in developed and western countries; however, data in developing countries and in Egypt are still lacking. This study aims to detect the prevalence of primary headache disorders in both urban and rural sectors in Fayoum governorate, Egypt. METHODS: A total of 2600 subjects were included using multi-stage stratified systematic random sampling, with respondent rate of 91.3 %. A pre-designed Arabic version, interviewer-administered, pilot tested structured questionnaire was developed according to The International Classification of Headache Disorders, 3rd edition (beta version), and this questionnaire was validated and the strength of agreement in headache diagnosis was good. RESULTS: The 1-year headache prevalence was 51.4 %, which was more prevalent in urban dwellers. The most common primary headache type was episodic tension type headache (prevalence; 24.5 %), followed by episodic migraine (prevalence; 17.3 %), both types peaked in midlife. Headache disorders were more common in females with exception of cluster headache that showed the expected male dominance. The risk of chronic headache increased more than one fold and half when the participants were females, married, and in those with high education. More than 60 % of our participants did not seek medical advice for their headaches problem; this percentage was higher in rural areas. CONCLUSIONS: Primary headache disorders are common in Egypt; prevalence rate was comparable with western countries with exception of episodic tension headache. Still headache is under-estimated and under-recognized in Egypt and this problem should be targeted by health care providers. PMID- 26438328 TI - Diabetic nephropathy: What does the future hold? AB - The consensus management of diabetic nephropathy (DN) in 2015 involves good control of glycaemia, dyslipidaemia and blood pressure (BP). Blockade of the renin-angiotensin-aldosterone system using angiotensin-converting enzyme inhibitors, angiotensin-2 receptor blockers or mineralocorticoid inhibitors are key therapeutic approaches, shown to be beneficial once overt nephropathy is manifest, as either, or both, of albuminuria and loss of glomerular filtration rate. Some significant additional clinical benefits in slowing the progression of DN was reported from the Remission clinic experience, where simultaneous intensive control of BP, tight glycaemic control, weight loss, exercise and smoking cessation were prioritised in the management of DN. This has not proved possible to translate to more conventional clinical settings. This review briefly looks over the history and limitations of current therapy from landmark papers and expert reviews, and following an extensive PubMed search identifies the most promising clinical biomarkers (both established and proposed). Many challenges need to be addressed urgently as in order to obtain novel therapies in the clinic; we also need to examine what we mean by remission, stability and progression of DN in the modern era. PMID- 26438330 TI - Elevated blood pressure and headache disorders in China--associations, under treatment and implications for public health. AB - BACKGROUND: Both hypertension (HTN) and headache disorders are highly prevalent worldwide. Our purpose, in a nationwide study of the Chinese general population, was to evaluate any association between primary headache disorders and elevated blood pressure (eBP). We could not collect data on antihypertensive therapy, but took the view that, whatever such therapy might be taken, eBP was a sign that it was failing to meet treatment needs. Therefore, as a secondary purpose, important from the public-health perspective, we would present the prevalence of eBP (treated or not) as indicative of unmet health-care need in China. METHODS: This was a questionnaire-based nationwide cross-sectional door-to-door survey using cluster random-sampling, selecting one adult (18-65 years) per household. Headache was diagnosed by ICHD-II criteria and eBP as systolic blood pressure >=140 mmHg and/or diastolic blood pressure >=90 mmHg. Chi-squared test and multivariate logistic regression analysis were used to assess the strength and significance of associations. We set significance at P <= 0.05. RESULTS: Of 5,041 survey participants (participation rate 94.1 %), 154 were excluded because of missing BP data, leaving 4,987 for analysis [mean age: 43.6 +/- 12.8 years; male 2,532 (mean age: 43.4 +/- 12.9 years); female 2,455 (mean age 43.9 +/- 12.8 years)]. There were 466 participants with migraine, 535 with tension type headache (TTH) and 48 with all causes of headache on >=15 days/month. The prevalence of eBP was 22.1 % (males 22.9 %, females 21.3 %). No associations of eBP with any of the headache disorders survived multivariate adjusted analysis. The demographic and anthropometric variables most strongly associated with eBP were higher age (AOR 3.7) and being overweight (AOR 2.4), seen in both genders. Less strong were male gender, lower educational level and urban habitation. CONCLUSIONS: We found no clear-cut associations between eBP and any headache disorder. The associations with demographic and anthropometric variables may have acted as confounders in past reports to the contrary. We did find an alarmingly high prevalence of eBP, recognizing that this signals substantial under-treatment in China of a serious condition, and therefore a major public-health concern. PMID- 26438331 TI - Astrocyte/neuron ratio and its importance on glutamate toxicity: an in vitro voltammetric study. AB - The purpose of this study was to clarify the relationship between neuron cells and astrocyte cells in regulating glutamate toxicity on the 10th and 20th day in vitro. A mixed primary culture system from newborn rats that contain cerebral cortex neurons cells was employed to investigate the glutamate toxicity. All cultures were incubated with various glutamate concentrations, then viability tests and histological analyses were performed. The activities of glutamate transporters were determined by using in vitro voltammetry technique. Viable cell number was decreased significantly on the 10th day at 10(-7) M and at 10(-6) M glutamate applications, however, viable cell number was not decreased at 20th day. Astrocyte number was increased nearly six times on the 20th day as compared to the 10th day. The peak point of glutamate reuptake capacity was about 2 * 10( 4) M on the 10th day and 10(-3) M on the 20th day. According to our results, we suggested that astrocyte age was important to maintain neuronal survival against glutamate toxicity. Thus, we revealed activation or a trigger point of glutamate transporters on astrocytes due to time since more glutamate was taken up by astrocytes when glutamate transporters on the astrocyte were triggered with high exogenous glutamate concentrations. In conclusion, the present investigation is the first voltammetric study on the reuptake parameters of glutamate in vitro. PMID- 26438332 TI - Growth and refinement of excitatory synapses in the human auditory cortex. AB - We had earlier demonstrated a neurofilament-rich plexus of axons in the presumptive human auditory cortex during fetal development which became adult like during infancy. To elucidate the origin of these axons, we studied the expression of the vesicular glutamate transporters (VGLUT) 1 and 2 in the human auditory cortex at different stages of development. While VGLUT-1 expression predominates in intrinsic and cortico-cortical synapses, VGLUT-2 expression predominates in thalamocortical synapses. Levels of VGLUT-2 mRNA were higher in the auditory cortex before birth compared to postnatal development. In contrast, levels of VGLUT-1 mRNA were low before birth and increased during postnatal development to peak during childhood and then began to decrease in adolescence. Both VGLUT-1 and VGLUT-2 proteins were present in the human auditory cortex as early as 15GW. Further, immunohistochemistry revealed that the supra- and infragranular layers were more immunoreactive for VGLUT-1 compared to that in Layer IV at 34GW and this pattern was maintained until adulthood. As for VGLUT-1 mRNA, VGLUT-1 synapses increased in density between prenatal development and childhood in the human auditory cortex after which they appeared to undergo attrition or pruning. The adult pattern of VGLUT-2 immunoreactivity (a dense band of VGLUT-2-positive terminals in Layer IV) also began to appear in the presumptive Heschl's gyrus at 34GW. The density of VGLUT-2-positive puncta in Layer IV increased between prenatal development and adolescence, followed by a decrease in adulthood, suggesting that thalamic axons which innervate the human auditory cortex undergo pruning comparatively late in development. PMID- 26438333 TI - Dentatorubrothalamic tract localization with postmortem MR diffusion tractography compared to histological 3D reconstruction. AB - Diffusion-weighted imaging (DWI) tractography is a technique with great potential to characterize the in vivo anatomical position and integrity of white matter tracts. Tractography, however, remains an estimation of white matter tracts, and false-positive and false-negative rates are not available. The goal of the present study was to compare postmortem tractography of the dentatorubrothalamic tract (DRTT) by its 3D histological reconstruction, to estimate the reliability of the tractography algorithm in this specific tract. Recent studies have shown that the cerebellum is involved in cognitive, language and emotional functions besides its role in motor control. However, the exact working mechanism of the cerebellum is still to be elucidated. As the DRTT is the main output tract it is of special interest for the neuroscience and clinical community. A postmortem human brain specimen was scanned on a 7T MRI scanner using a diffusion-weighted steady-state free precession sequence. Tractography was performed with PROBTRACKX. The specimen was subsequently serially sectioned and stained for myelin using a modified Heidenhain-Woelke staining. Image registration permitted the 3D reconstruction of the histological sections and comparison with MRI. The spatial concordance between the two modalities was evaluated using ROC analysis and a similarity index (SI). ROC curves showed a high sensitivity and specificity in general. Highest measures were observed in the superior cerebellar peduncle with an SI of 0.72. Less overlap was found in the decussation of the DRTT at the level of the mesencephalon. The study demonstrates high spatial accuracy of postmortem probabilistic tractography of the DRTT when compared to a 3D histological reconstruction. This gives hopeful prospect for studying structure function correlations in patients with cerebellar disorders using tractography of the DRTT. PMID- 26438334 TI - Long, intrinsic horizontal axons radiating through and beyond rat barrel cortex have spatial distributions similar to horizontal spreads of activity evoked by whisker stimulation. AB - Stimulation of a single whisker evokes a peak of activity that is centered over the associated barrel in rat primary somatosensory cortex, and yet the evoked local field potential and the intrinsic signal optical imaging response spread symmetrically away from this barrel for over 3.5 mm to cross cytoarchitectonic borders into other "unimodal" sensory cortical areas. To determine whether long horizontal axons have the spatial distribution necessary to underlie this activity spread, we injected adeno-associated viral vectors into barrel cortex and characterized labeled axons extending from the injection site in transverse sections of flattened cortex. Combined qualitative and quantitative analyses revealed labeled axons radiating diffusely in all directions for over 3.5 mm from supragranular injection sites, with density declining over distance. The projection pattern was similar at four different cortical depths, including infragranular laminae. Infragranular vector injections produced patterns similar to the supragranular injections. Long horizontal axons were detected both using a vector with a permissive cytomegalovirus promoter to label all neuronal subtypes and using a calcium/calmodulin-dependent protein kinase II alpha vector to restrict labeling to excitatory cortical pyramidal neurons. Individual axons were successfully reconstructed from series of supragranular sections, indicating that they traversed gray matter only. Reconstructed axons extended from the injection site, left the barrel field, branched, and sometimes crossed into other sensory cortices identified by cytochrome oxidase staining. Thus, radiations of long horizontal axons indeed have the spatial characteristics necessary to explain horizontal activity spreads. These axons may contribute to multimodal cortical responses and various forms of cortical neural plasticity. PMID- 26438335 TI - The KT Jeang Retrovirology prize 2015: Paul Bieniasz. PMID- 26438337 TI - Erratum to: A Trial of Rectal Indomethacin to Prevent Post-ERCP Pancreatitis in Patients with Suspected Type 3 Sphincter of Oddi Dysfunction. PMID- 26438336 TI - The relationship between parenting stress and parent-child interaction with health outcomes in the youngest patients with type 1 diabetes (0-7 years). AB - To test whether parenting stress and the quality of parent-child interaction were associated with glycemic control and quality of life (QoL) in young children (0-7 years) with type 1 diabetes (T1DM), we videotaped 77 families with a young child with T1DM during mealtime (including glucose monitoring and insulin administration). Parent-child interactions were scored with a specifically designed instrument. Questionnaires assessed general and disease-related parenting stress and (diabetes-specific (DS)) QoL. HbA(1c) (glycemic control) was extracted from the medical records. Both general and disease-related parenting stress were associated with a lower (DS)QoL (r ranged from -0.39 to -0.70, p < 0.05), but not with HbA(1c) levels. Furthermore, with regard to the parent-child interaction, emotional involvement of parents (r = 0.23, p < 0.05) and expressed discomfort of the child (r = 0.23, p < 0.05) were related to suboptimal HbA(1c) levels. There was no clear pattern in the correlations between parent-child interaction and (DS)QoL. CONCLUSION: The results support the notion that diabetes does not only affect the child with T1DM: T1DM is a family disease, as parenting factors (like stress and parent-child interactions) are associated with important child outcomes. Therefore, it is important for health-care providers to not only focus on the child with T1DM, but also on the family system. PMID- 26438338 TI - Plasma pharmacokinetic profile of fluralaner (BravectoTM) and ivermectin following concurrent administration to dogs. AB - BACKGROUND: Fluralaner is a novel systemic ectoparasiticide for dogs providing immediate and persistent flea, tick and mite control after a single oral dose. Ivermectin has been used in dogs for heartworm prevention and at off label doses for mite and worm infestations. Ivermectin pharmacokinetics can be influenced by substances affecting the p-glycoprotein transporter, potentially increasing the risk of ivermectin neurotoxicity. This study investigated ivermectin blood plasma pharmacokinetics following concurrent administration with fluralaner. FINDINGS: Ten Beagle dogs each received a single oral administration of either 56 mg fluralaner (BravectoTM), 0.3 mg ivermectin or 56 mg fluralaner plus 0.3 mg ivermectin/kg body weight. Blood plasma samples were collected at multiple post treatment time points over a 12-week period for fluralaner and ivermectin plasma concentration analysis. Ivermectin blood plasma concentration profile and pharmacokinetic parameters Cmax, tmax, AUCinfinity and t1/2 were similar in dogs administered ivermectin only and in dogs administered ivermectin concurrently with fluralaner, and the same was true for fluralaner pharmacokinetic parameters. CONCLUSIONS: Concurrent administration of fluralaner and ivermectin does not alter the pharmacokinetics of either compound. Based on the plasma pharmacokinetic profile and the clinical observations, there is no evident interaction between fluralaner and ivermectin, and co-administration does not increase the risk of ivermectin associated neurotoxicity. PMID- 26438339 TI - Gene loss, adaptive evolution and the co-evolution of plumage coloration genes with opsins in birds. AB - BACKGROUND: The wide range of complex photic systems observed in birds exemplifies one of their key evolutionary adaptions, a well-developed visual system. However, genomic approaches have yet to be used to disentangle the evolutionary mechanisms that govern evolution of avian visual systems. RESULTS: We performed comparative genomic analyses across 48 avian genomes that span extant bird phylogenetic diversity to assess evolutionary changes in the 17 representatives of the opsin gene family and five plumage coloration genes. Our analyses suggest modern birds have maintained a repertoire of up to 15 opsins. Synteny analyses indicate that PARA and PARIE pineal opsins were lost, probably in conjunction with the degeneration of the parietal organ. Eleven of the 15 avian opsins evolved in a non-neutral pattern, confirming the adaptive importance of vision in birds. Visual conopsins sw1, sw2 and lw evolved under negative selection, while the dim-light RH1 photopigment diversified. The evolutionary patterns of sw1 and of violet/ultraviolet sensitivity in birds suggest that avian ancestors had violet-sensitive vision. Additionally, we demonstrate an adaptive association between the RH2 opsin and the MC1R plumage color gene, suggesting that plumage coloration has been photic mediated. At the intra-avian level we observed some unique adaptive patterns. For example, barn owl showed early signs of pseudogenization in RH2, perhaps in response to nocturnal behavior, and penguins had amino acid deletions in RH2 sites responsible for the red shift and retinal binding. These patterns in the barn owl and penguins were convergent with adaptive strategies in nocturnal and aquatic mammals, respectively. CONCLUSIONS: We conclude that birds have evolved diverse opsin adaptations through gene loss, adaptive selection and coevolution with plumage coloration, and that differentiated selective patterns at the species level suggest novel photic pressures to influence evolutionary patterns of more-recent lineages. PMID- 26438340 TI - NF-kappaB Blockade in Hypothalamic Paraventricular Nucleus Inhibits High-Salt Induced Hypertension Through NLRP3 and Caspase-1. AB - High-salt-induced inflammation and oxidative stress in the hypothalamic paraventricular nucleus (PVN) contribute to the pathogenesis of salt-sensitive hypertension. In this study, we hypothesized that chronic inhibition of nuclear factor-kappaB (NF-kappaB) activity in the PVN delays the progression of hypertension by upregulating anti-inflammatory cytokines, reducing NLRP3 (NOD like receptor family pyrin domain containing 3) and IL-1beta and attenuating p IKKbeta, NF-kappaB p65 activity and NAD(P)H oxidase in the PVN of salt-sensitive hypertensive rats. Dahl salt-sensitive rats received a high-salt diet (HS, 8 % NaCl) or a normal-salt diet (NS, 0.3 % NaCl) for 6 weeks and were treated with bilateral PVN infusion with either vehicle or pyrrolidine dithiocarbamate (PDTC, 5 MUg/h), a NF-kappaB inhibitor via osmotic minipump. The mean arterial pressure and plasma levels of norepinephrine (NE) and epinephrine (EPI) were significantly increased in high-salt-fed rats. In addition, rats with high-salt diet had higher levels of p-IKKbeta, NF-kappaB p65 activity, Fra-like (Fra-LI) activity (an indicator of chronic neuronal activation), NOX-4 (subunits of NAD(P)H oxidase), NLRP3 and IL-1beta, and lower levels of IL-10 in the PVN than normal diet rats. Bilateral PVN infusions of PDTC attenuated these high-salt-induced changes. These findings suggest that high-salt-induced NF-kappaB activation in the PVN caused hypertension via sympathoexcitation, which are associated with the increases of NLRP3, IL-1beta and oxidative stress in the PVN; PVN inhibition of NF-kappaB activity attenuates NLRP3, IL-1beta and oxidative stress in the PVN and thereby attenuates hypertension. PMID- 26438341 TI - Erratum to: Synchronization in the Heart Rate and the Vasomotion in Rat Aorta: Effect of Arsenic Trioxide. PMID- 26438342 TI - Diagnostics barriers and innovations in rural areas: insights from junior medical doctors on the frontlines of rural care in Peru. AB - BACKGROUND: Worldwide, rural communities face barriers when accessing health services. In response, numerous initiatives have focused on fostering technological innovations, new management approaches and health policies. Research suggests that the most successful innovations are those involving stakeholders at all levels. However, there is little evidence exploring the opinions of local health providers that could contribute with further innovation development and research. The aims of this study were to explore the perspectives of medical doctors (MDs) working in rural areas of Peru, regarding the barriers impacting the diagnostic process, and ideas for diagnostic innovations that could assist them. METHODS: Data gathered through three focus group discussions (FGG) and 18 individual semi-structured interviews (SSI) with MDs who had completed their medical service in rural areas of Peru in the last two years were analyzed using thematic analysis. RESULTS: Three types of barriers emerged. The first barrier was the limited access to point of care (POC) diagnostic tools. Tests were needed for: i) the differential diagnosis of malaria vs. pneumonia, ii) dengue vs. leptospirosis, iii) tuberculosis, iv) vaginal infections and cervical cancer, v) neurocysticercosis, and vi) heavy metal toxicity. Ultrasound was needed for the diagnosis of obstetric and intra-abdominal conditions. There were also health system-related barriers such as limited funding for diagnostic services, shortage of specialists, limited laboratory services and access to telecommunications, and lack of institutional support. Finally, the third type of barriers included patient related-barriers to follow through with diagnostic referrals. Ideas for innovations proposed included POC equipment and tests, and telemedicine. CONCLUSIONS: MDs at primary health facilities in rural Peru face diagnostic challenges that are difficult to overcome due to a limited access to diagnostic tools. Referrals to specialized facilities are constrained by deficiencies in the organization of health services and by barriers that impede the patients' travel to distant health facilities. Technological innovations suggested by the participants such as POC diagnostic tools and mobile-health (m health) applications could help address part of the problem. However, other types of innovation to address social, adaptation and policy issues should not be dismissed. PMID- 26438344 TI - Multifractal spectrum and lacunarity as measures of complexity of osseointegration. AB - OBJECTIVES: The goal of this study is to contribute to a better quantitative description of the early stages of osseointegration, by application of fractal, multifractal, and lacunarity analysis. MATERIALS AND METHODS: Fractal, multifractal, and lacunarity analysis are performed on scanning electron microscopy (SEM) images of titanium implants that were first subjected to different treatment combinations of i) sand blasting, ii) acid etching, and iii) exposition to calcium phosphate, and were then submersed in a simulated body fluid (SBF) for 30 days. All the three numerical techniques are applied to the implant SEM images before and after SBF immersion, in order to provide a comprehensive set of common quantitative descriptors. RESULTS: It is found that implants subjected to different physicochemical treatments before submersion in SBF exhibit a rather similar level of complexity, while the great variety of crystal forms after SBF submersion reveals rather different quantitative measures (reflecting complexity), for different treatments. In particular, it is found that acid treatment, in most combinations with the other considered treatments, leads to a higher fractal dimension (more uniform distribution of crystals), lower lacunarity (lesser variation in gap sizes), and narrowing of the multifractal spectrum (smaller fluctuations on different scales). CONCLUSION: The current quantitative description has shown the capacity to capture the main features of complex images of implant surfaces, for several different treatments. Such quantitative description should provide a fundamental tool for future large scale systematic studies, considering the large variety of possible implant treatments and their combinations. CLINICAL RELEVANCE: Quantitative description of early stages of osseointegration on titanium implants with different treatments should help develop a better understanding of this phenomenon, in general, and provide basis for further systematic experimental studies. Clinical practice should benefit from such studies in the long term, by more ready access to implants of higher quality. PMID- 26438343 TI - Longevity of resin-bonded fixed partial dental prostheses made with metal alloys. AB - OBJECTIVES: The purpose of this study was to evaluate the clinical performance of resin-bonded fixed partial dental prostheses (RBFPDPs) made with metal alloys. MATERIALS AND METHODS: The retention of 311 RBFPDPs from 226 patients fabricated from 1983 to 2013 using an adhesive resin was clinically evaluated. Partial or complete debonding of the RBFPDP or framework fracture was considered a treatment failure. All data were obtained from clinical examinations, and missing data were censored at the date of the last available information. The effect of the following factors on survival rate were investigated: patient gender, location (maxilla/mandible and anterior/posterior), number of missing teeth, number of abutment teeth, framework structure, type of metal alloy, patient age at the point of cementation, cement type, and distinction of the treating dentist. Data were analyzed with the Kaplan-Meier survival tests, log-rank tests, and Cox regression analyses (alpha = 0.05). RESULTS: The Kaplan-Meier survival rate was 41.2 % +/- 6.5 % (standard error) at 28.8 years (last outcome event). Significant differences were found for patient age and treating dentist (p < 0.05). The risk of failure in younger patients was 1.7 times greater than that in older patients and that of inexperienced dentists was 2.0 times greater than that of dentist experienced and specialized in adhesive dentistry. CONCLUSIONS: When fabricating RBFPDPs for younger patients, mechanical preparation for bonding may be necessary in consideration of the risk for debonding. Experienced dentists may achieve better results. CLINICAL RELEVANCE: Mastery of skills is necessary to ensure excellent prognoses for RBFPDPs. PMID- 26438345 TI - Mortality in Rheumatoid Arthritis (RA): factors associated with recording RA on death certificates. AB - BACKGROUND: Death certificates can be used to assess disease prevalence and incidence; however, rheumatoid arthritis (RA) often remains unreported in death certificates. We sought to determine to what extent RA is underreported and what demographic and clinical characteristics could predict mention of RA in the death certificate. METHODS: We recruited 1328 patients with RA from private, public and military rheumatology practices and followed them prospectively for yearly evaluations. A rheumatologist assessed clinical characteristics of RA and comorbidities at each evaluation. Deaths were identified through family members, other physicians, obituaries and public death databases. All were confirmed with state-issued death certificates. Patients with and without RA in death certificate were compared using bivariate and multivariate analyses. RESULTS: By December 2013, 326 deaths had occurred. We received and reviewed death certificates for all confirmed deaths, of which 58 (17.7 %) mentioned RA on the death certificate. Bivariate analysis revealed that younger age, a greater number of deformities, higher Sharp score and lower socioeconomic status were each associated with recording RA. Multivariable analyses revealed that comorbidity [OR (95 % CI) = 0.84 (0.73, 0.97); P = 0.022] was inversely associated with listing RA on the death certificate, while the number of deformities [OR (95 % CI) = 1.04 (1.00, 1.07); P = 0.033] and a certified physician's signature on the death certificate [OR (95 % CI) = 4.79 (1.35, 16.9); P = 0.015] increased likelihood of reporting RA. CONCLUSION: In this cohort, RA was not listed in over 80 % of death certificates. Younger patients with fewer comorbidities and more joint deformities were more likely to have RA reported. DISCUSSION: RA is often not included in death certificates. The findings of this study suggest that older patients may have a greater number of comorbidities, thus decreasing the likelihood that RA be included when completing the death certificate. PMID- 26438346 TI - "Short term surgical complications after subthalamic deep brain stimulation for Parkinson's disease: does old age matter?". AB - BACKGROUND: Patients aged 65 years and older are not traditionally considered optimal candidates for subthalamic deep brain stimulation (STN-DBS), mainly for their presumed increased incidence of surgical complications. The aim of this study was to assess STN-DBS surgery safety in relation to age. METHODS: A total of 107 consecutive patients undergoing bilateral STN-DBS at our institution between 2002 and 2014 were retrospectively stratified according to age in two groups (Young group < 65 years old; Elderly group >= 65 years old;). Rate of short-term surgical complications (within 90 days) was reviewed and compared between the two groups. RESULTS: Pre-operative baseline data were comparable between the two groups. The 90-days post-operative mortality rate was 0%. Overall incidence of complications related to surgery was 6,54%. In the Elderly group we observed 3 post-operative intra-cerebral haematomas (7,89%), 1 requiring urgent surgical evacuation. In the Young group we observed 2 post-operative asymptomatic intra-cerebral haematomas (2,89%) and 2 wound infections (2,89%), 1 requiring system removal. No others surgical complications were noticed in both groups. CONCLUSIONS: Chronological age >= 65 years old should not be considered alone as exclusion criteria to STN-DBS surgery. PMID- 26438347 TI - Inhomogeneous myocardial stress perfusion in SPECT studies predicts future allograft dysfunction in heart transplant recipients. AB - BACKGROUND: Myocardial perfusion gated single photon emission computed tomography (SPECT) can be used for non-invasive detection of coronary artery stenosis and cardiac allograft vasculopathy (CAV), which is a crucial factor for the long-term survival of heart transplant (HTx) recipients. A frequently observed finding in myocardial perfusion imaging of patients after HTx is inhomogeneous myocardial perfusion. This finding is not associated with epicardial CAV, but its prognostic relevance is unclear so far. We therefore evaluated the prognosis of patients with homogeneous versus inhomogeneous myocardial stress perfusion. METHODS: One hundred four HTx patients (mean 3.6 +/- 2.9 years after HTx) without significant stress-induced ischemia (summed stress score <=3) in gated SPECT and without CAV were included. Myocardial stress perfusion was visually assessed as homogeneous, moderately, or severely inhomogeneous. The mean follow-up period after SPECT was 9.4 +/- 3.1 years. End points were the diagnosis of CAV, major cardiac events (MACE) or death, and the development of allograft dysfunction (left ventricular ejection fraction, LVEF <45 %). RESULTS: Of all HTx patients, 24 % enrolled in this study (n = 25) presented with inhomogeneous myocardial perfusion. Compared to the patients with homogeneous perfusion, these patients were at higher risk for developing allograft dysfunction (multivariate hazard ratio, HR = 5.59). As to the development of CAV, the occurrence of MACE, or death, no statistical differences were observed between patients with homogenous and inhomogeneous perfusion. There was no correlation between myocardial perfusion pattern and prior cardiac allograft rejections. CONCLUSIONS: Inhomogeneous myocardial stress perfusion in SPECT studies predicts a higher risk for future development of allograft dysfunction in HTx patients (LVEF <45 %) but is not associated with future CAV, MACE, or overall survival. PMID- 26438348 TI - A longitudinal daily diary analysis of condom use during bleeding-associated vaginal sex among adolescent females. AB - OBJECTIVE: Sex during bleeding is a risk factor for sexually transmitted infection (STI) and other bloodborne viruses, including HIV. We examined daily predictors of adolescent women's male condom use during bleeding-associated vaginal sex. METHODS: Adolescent females (N=387; 14-17 years) were recruited from primary care clinics for a longitudinal cohort study of STIs and sexual behaviour. Data were daily partner-specific sexual diaries; generalised estimating equation logistic regression assessed the likelihood of condom use during bleeding-associated vaginal sex. RESULTS: Less than 30% of bleeding associated vaginal sex events were condom protected. Condom use during these events was less likely with younger age, higher partner support, higher partner negativity or past week bleeding-associated sex with a given partner; condom use was more likely with high individual mood and past week condom use during bleeding-associated vaginal sex with a given partner. CONCLUSIONS: Low condom rates during bleeding-associated vaginal sex can increase STI and bloodborne virus risk. Providers should consider integrating partner-specific and behavioural factors when they deliver sexual health messages to young women. PMID- 26438349 TI - Does integration of HIV and SRH services achieve economies of scale and scope in practice? A cost function analysis of the Integra Initiative. AB - OBJECTIVE: Policy-makers have long argued about the potential efficiency gains and cost savings from integrating HIV and sexual reproductive health (SRH) services, particularly in resource-constrained settings with generalised HIV epidemics. However, until now, little empirical evidence exists on whether the hypothesised efficiency gains associated with such integration can be achieved in practice. METHODS: We estimated a quadratic cost function using data obtained from 40 health facilities, over a 2-year-period, in Kenya and Swaziland. The quadratic specification enables us to determine the existence of economies of scale and scope. FINDINGS: The empirical results reveal that at the current output levels, only HIV counselling and testing services are characterised by service-specific economies of scale. However, no overall economies of scale exist as all outputs are increased. The results also indicate cost complementarities between cervical cancer screening and HIV care; post-natal care and HIV care and family planning and sexually transmitted infection treatment combinations only. CONCLUSIONS: The results from this analysis reveal that contrary to expectation, efficiency gains from the integration of HIV and SRH services, if any, are likely to be modest. Efficiency gains are likely to be most achievable in settings that are currently delivering HIV and SRH services at a low scale with high levels of fixed costs. The presence of cost complementarities for only three service combinations implies that careful consideration of setting-specific clinical practices and the extent to which they can be combined should be made when deciding which services to integrate. TRIAL REGISTRATION NUMBER: NCT01694862. PMID- 26438350 TI - Common Iliac Artery Aneurysm Repair Using a Sac-Anchoring Endograft to Preserve the Internal Iliac Artery. AB - PURPOSE: To report the application of the Nellix endovascular aneurysm sealing system to successfully treat a unilateral common iliac aneurysm and preserve the internal iliac artery. CASE REPORT: An 85-year-old man presented with right-sided necrosis of the third and fourth toe. Computed tomography angiography (CTA) showed a right 40-mm popliteal aneurysm and a 38-mm left fusiform common iliac artery aneurysm. After endovascular exclusion of the popliteal aneurysm, the Nellix device was positioned to exclude the common iliac artery aneurysm while preserving the internal iliac artery. Postoperative CTA showed no endoleak and a patent internal iliac artery. At 1 year, duplex ultrasound documented a common iliac aneurysm diameter of 32 mm without complications. CONCLUSION: Endovascular sealing using the Nellix device can be applied to exclude selected common iliac artery aneurysms with an adequate length and a minimal distal neck, with preservation of the internal iliac artery. The endobag can be positioned such that the aneurysm is completely excluded while the orifice of the side branch is not endangered. PMID- 26438351 TI - Five-Year Outcome of Self-Expanding Covered Stents for Superficial Femoral Artery Occlusive Disease and an Analysis of Factors Predicting Failure. AB - PURPOSE: To investigate the 5-year outcome of patients treated with self expanding covered stents for superficial femoral artery (SFA) occlusive disease and identify parameters that could predict loss of primary patency. METHODS: In a dual-center study, 315 consecutive patients (mean age 69.0+/-10.1 years; 232 men) treated for SFA occlusive disease in 334 limbs with Viabahn self-expanding covered stents between 2001 and 2014 were retrospectively analyzed. Mean lesion length was 11.7+/-8.8 cm, and half of the lesions were classified as TASC II C/D. Five-year patency rates were calculated, and Cox regression analyses were performed to assess potential factors affecting patency. RESULTS: All-cause mortality at 5 years was 14.1%. Primary patency rates at 1, 3, and 5 years were 72.2%, 51.8%, and 47.6%, respectively, with secondary patency rates of 86.2%, 78.7%, and 77.5%. Parameters predicting loss of primary patency in a univariate analysis were covered stent diameter (p=0.001), the number of covered stents per lesion (p=0.015), and TASC II D classification (p=0.007). Covered stent diameter was the only parameter predicting loss of primary patency in the multivariate regression analysis (p=0.001), with 7-mm covered stents having superior performance. CONCLUSION: Five-year patency rates of self-expanding covered stents inserted for SFA occlusive disease are within an acceptable range. Covered stent diameter is the most relevant factor in predicting loss of primary patency, and thus, an adequate diameter of the distal landing site seems to be among the most important factors in the decision-making process. In smaller vessels, one should not use covered stents but venous conduits, as oversizing may be detrimental. PMID- 26438352 TI - Relationship Between Primary Patency and Lesion Length Following Bare Nitinol Stent Placement for Femoropopliteal Disease. AB - PURPOSE: To evaluate the relationship between 1-year primary patency and lesion length in patients with femoropopliteal disease treated with bare nitinol stents. METHODS: The study was a retrospective analysis of a prospectively maintained multicenter database. Between January 2004 and December 2011, 1047 consecutive patients (mean age 72 years; 765 men) underwent femoropopliteal stenting with nitinol stents in 1373 limbs. The mean vessel diameter was 5.3+/-0.7 mm and the mean lesion length was 142+/-75 mm. One-year follow-up data were collected and analyzed to ascertain which lesion length would be expected to demonstrate a 1 year primary patency above the established 66% objective performance goal (OPG). RESULTS: The lower limit of the 95% confidence interval (CI) for the unadjusted 1 year primary patency was >66% when the lesion length was <=243 mm. After adjustment of the covariates to match those of the OPG-derived population, the 1 year primary patency decreased linearly with longer lesion length. The 1-year primary patency was 83.2% (95% CI 79.8% to 86.1%) for a 100-mm lesion length, 76.4% (95% CI 71.7% to 80.5%) for a 200-mm lesion length, and 70.7% (95% CI 62.4% to 77.7%) for a 300-mm lesion length. The maximum lesion length providing a 1 year primary patency significantly greater than 66% was calculated to be 263 mm. CONCLUSION: The 1-year primary patency of femoropopliteal lesions treated with bare nitinol stents decreased linearly with longer lesion length. The maximum lesion length providing a higher patency rate than the OPG of 66% was ~25 cm. PMID- 26438353 TI - Malignant teratoma in Klippel-Feil syndrome: a case report and review of the literature. AB - INTRODUCTION: Klippel-Feil syndrome is characterized by a congenital fusion of cervical vertebrae. Intracranial teratomas are nongerminomatous germ cell tumors and they account for 0.3 to 0.9% of all intracranial tumors. Teratomas with malignant transformation refer to lesions which give rise to malignant cancer of somatic type. The association between tumors of dermoid origin and Klippel-Feil malformation is extremely rare. Only 23 other cases have so far been reported, and only one case of dermoid tumor with areas of dedifferentiation on squamous cell carcinoma has been described. CASE PRESENTATION: We report the case of a 72 year-old white man with a 2-year history of gait and balance disturbances. A brain magnetic resonance imaging revealed a fourth ventricle neoplastic process with infiltrative features. He was operated through a suboccipital craniectomy with a C1 laminotomy and bilateral vertebral artery transposition. At 6-months follow-up, magnetic resonance imaging showed an early regrowth of the fourth ventricle tumor, with the same radiological features. CONCLUSIONS: Patients with Klippel-Feil malformation could develop posterior fossa dermoid tumors. The malignant potential of such tumors must be considered and surgery is recommended. Particular attention must be focused on the histopathological analysis in order to identify possible foci of malignant transformation. PMID- 26438354 TI - Uptake of risk-reducing salpingo-oophorectomy among female BRCA mutation carriers: experience at the National Cancer Center of Korea. AB - PURPOSE: The aim of this study was to identify the uptake rate of risk-reducing salpingo-oophorectomy (RRSO) and the factors affecting this rate among female BRCA1 or BRCA2 mutation carriers at the National Cancer Center of Korea. METHODS: Between April 2007 and December 2014, 450 women underwent BRCA gene testing, and 97 women were found to have BRCA1/2 mutations. Through the review of medical records, 42 candidates for RRSO were identified. Of these, 22 underwent RRSO. Demographic, clinical, and consultation-related factors were compared between the RRSO and non-RRSO groups. RESULTS: The uptake rate of RRSO was 52.4 %. The mean time interval between genetic testing and surgery in the RRSO group was 7.3 months (range 0.6-33.9). The prevalence of amenorrhea was greater in the RRSO group than in the non-RRSO group (59.1 % vs. 20.0 %; P = 0.010). More women in the RRSO group were consulted with gynecologic oncologists (95.5 % vs. 60.0 %; P = 0.008). In multivariate analyses, amenorrhea at the time of genetic counseling (OR 16.44; 95 % CI 1.16-232.82; P = 0.038) and consultation with gynecologic oncologists (OR 30.78; 95 % CI 1.34-707.21; P = 0.032) were identified as factors affecting the carrier's decision to undergo RRSO. One patient in the non-RRSO group (5.0 %) developed primary peritoneal carcinoma, which was diagnosed 4.6 years after genetic testing. CONCLUSIONS: The uptake rate of RRSO among BRCA1/2 mutation carriers was affected by the presence of amenorrhea and consultation with gynecologic oncologists. Gynecologic oncologists with clinical experience with ovarian cancer should play a major role in aiding carriers' decision-making concerning RRSO. PMID- 26438355 TI - Does acute lead (Pb) contamination influence membrane fatty acid composition and freeze tolerance in intertidal blue mussels in arctic Greenland? AB - In their natural habitats, organisms are exposed to multiple stressors. Heavy metal contamination stresses the cell membrane due to increased peroxidation of lipids. Likewise, sub-zero air temperatures potentially reduce membrane functionality in ectothermal animals. We tested if acute lead (Pb) exposure for 7 days would influence survival in intertidal blue mussels (Mytilus edulis) after exposure to realistic sub-zero air temperatures. A full factorial experiment with five tissue Pb concentrations between 0 and 3500 MUg Pb/g and six sub-zero temperatures from 0 to -17 degrees C were used to test the hypothesis that sub lethal effects of Pb may increase the lethality caused by freezing in blue mussels exposed to temperatures simulating Greenland winter conditions. We found a significant effect of temperature on mortality. However, the short-term exposure to Pb did not result in any effects of Pb, nor did we find interactions between Pb and temperature. We analysed the relative abundance of major phospholipid fatty acids (PLFAs) in the gill tissue, but we found no significant effect of Pb tissue concentration on PLFA composition. Results suggest that Pb accumulation has limited effects on freeze tolerance and does not induce membrane damage in terms of persistent lipid peroxidation. PMID- 26438356 TI - DNA oxidation and DNA repair in gills of zebra mussels exposed to cadmium and benzo(a)pyrene. AB - Freshwater bivalve molluscs are considered as effective indicators of environmental pollution. The comet assay allows the detection of DNA damage such as DNA strand breaks and alkali-labile sites. The main oxidative lesion, 8-oxo 7,8-dihydro-2'-deoxyguanosine (8-oxodG), which is a pre-mutagenic lesion, can be detected by the comet assay coupled with the hOGG1 DNA repair enzyme. With this modified assay we recently observed that BaP induced 8-oxodG lesions and with the modified comet-Fpg assay we observed that Cd induced oxidative DNA damage. The aim of this study was to determine the stability of DNA lesions in Cd and BaP exposed zebra mussels using the comet-hOGG1 assay. Mussels were exposed for 24 h to these two chemicals and then placed in clean water for 6 days. We observed that BaP (7, 12 and 18 ug/L) induced an increase of DNA strand break levels as soon as 6 h of exposure and that the two highest concentrations of BaP induced a low level of hOGG1-sensitive sites. After 2 days of depuration, BaP induced DNA lesions returned to the basal level, indicating an effective DNA repair. Cd (3, 32 and 81 ug/L) induced an increase of the DNA strand break levels and a low level of hOGG1-sensitive sites. This study revealed that BaP-induced DNA lesions are repaired more efficiently than Cd-induced DNA lesions. As the level of hOGG1 sensitive sites was increased in Cd and BaP exposed mussels, it seems that these chemicals induce 8-oxo-dG. PMID- 26438357 TI - [Small cell structured cell nests of endometrial stroma]. AB - Tissue from endometrial diagnostic curettage material may show small clumps of stromal cells, which are pushed together (stromal collapse) and present a picture of glandular and stromal breakdown. This can be misinterpreted as small cell structured carcinoma, possibly of neuroendocrine or basal cell origin. Immunohistochemical investigations (e.g. estrogen receptor, epithelial and neuroendocrine markers and proliferation markers) are helpful in identifying the correct differential diagnosis. PMID- 26438359 TI - Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms. AB - The cohesin complex (consisting of Rad21, Smc1a, Smc3, and Stag2 proteins) is critically important for proper sister chromatid separation during mitosis. Mutations in the cohesin complex were recently identified in a variety of human malignancies including acute myeloid leukemia (AML). To address the potential tumor-suppressive function of cohesin in vivo, we generated a series of shRNA mouse models in which endogenous cohesin can be silenced inducibly. Notably, silencing of cohesin complex members did not have a deleterious effect on cell viability. Furthermore, knockdown of cohesin led to gain of replating capacity of mouse hematopoietic progenitor cells. However, cohesin silencing in vivo rapidly altered stem cells homeostasis and myelopoiesis. Likewise, we found widespread changes in chromatin accessibility and expression of genes involved in myelomonocytic maturation and differentiation. Finally, aged cohesin knockdown mice developed a clinical picture closely resembling myeloproliferative disorders/neoplasms (MPNs), including varying degrees of extramedullary hematopoiesis (myeloid metaplasia) and splenomegaly. Our results represent the first successful demonstration of a tumor suppressor function for the cohesin complex, while also confirming that cohesin mutations occur as an early event in leukemogenesis, facilitating the potential development of a myeloid malignancy. PMID- 26438360 TI - Oxysterols and EBI2 promote osteoclast precursor migration to bone surfaces and regulate bone mass homeostasis. AB - Bone surfaces attract hematopoietic and nonhematopoietic cells, such as osteoclasts (OCs) and osteoblasts (OBs), and are targeted by bone metastatic cancers. However, the mechanisms guiding cells toward bone surfaces are essentially unknown. Here, we show that the Galphai protein-coupled receptor (GPCR) EBI2 is expressed in mouse monocyte/OC precursors (OCPs) and its oxysterol ligand 7alpha,25-dihydroxycholesterol (7alpha,25-OHC) is secreted abundantly by OBs. Using in vitro time-lapse microscopy and intravital two-photon microscopy, we show that EBI2 enhances the development of large OCs by promoting OCP motility, thus facilitating cell-cell interactions and fusion in vitro and in vivo. EBI2 is also necessary and sufficient for guiding OCPs toward bone surfaces. Interestingly, OCPs also secrete 7alpha,25-OHC, which promotes autocrine EBI2 signaling and reduces OCP migration toward bone surfaces in vivo. Defective EBI2 signaling led to increased bone mass in male mice and protected female mice from age- and estrogen deficiency-induced osteoporosis. This study identifies a novel pathway involved in OCP homing to the bone surface that may have significant therapeutic potential. PMID- 26438361 TI - Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis. AB - Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation; however, cohesin mutant leukemias do not show genomic instability. We hypothesized that reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic progenitors. We investigated the consequences of Smc3 deletion in normal and malignant hematopoiesis. Biallelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation and revealed an absolute requirement for cohesin in hematopoietic stem cell (HSC) function. In contrast, Smc3 haploinsufficiency increased self-renewal in vitro and in vivo, including competitive transplantation. Smc3 haploinsufficiency reduced coordinated transcriptional output, including reduced expression of transcription factors and other genes associated with lineage commitment. Smc3 haploinsufficiency cooperated with Flt3-ITD to induce acute leukemia in vivo, with potentiated Stat5 signaling and altered nucleolar topology. These data establish a dose dependency for cohesin in regulating chromatin structure and HSC function. PMID- 26438362 TI - The role of group IIF-secreted phospholipase A2 in epidermal homeostasis and hyperplasia. AB - Epidermal lipids are important for skin homeostasis. However, the entire picture of the roles of lipids, particularly nonceramide lipid species, in epidermal biology still remains obscure. Here, we report that PLA2G2F, a functionally orphan-secreted phospholipase A2 expressed in the suprabasal epidermis, regulates skin homeostasis and hyperplasic disorders. Pla2g2f(-/-) mice had a fragile stratum corneum and were strikingly protected from psoriasis, contact dermatitis, and skin cancer. Conversely, Pla2g2f-overexpressing transgenic mice displayed psoriasis-like epidermal hyperplasia. Primary keratinocytes from Pla2g2f(-) (/-) mice showed defective differentiation and activation. PLA2G2F was induced by calcium or IL-22 in keratinocytes and preferentially hydrolyzed ethanolamine plasmalogen-bearing docosahexaenoic acid secreted from keratinocytes to give rise to unique bioactive lipids (i.e., protectin D1 and 9S-hydroxyoctadecadienoic acid) that were distinct from canonical arachidonate metabolites (prostaglandins and leukotrienes). Ethanolamine lysoplasmalogen, a PLA2G2F-derived marker product, rescued defective activation of Pla2g2f(-/-) keratinocytes both in vitro and in vivo. Our results highlight PLA2G2F as a previously unrecognized regulator of skin pathophysiology and point to this enzyme as a novel drug target for epidermal-hyperplasic diseases. PMID- 26438363 TI - Resolvin E1 inhibits dendritic cell migration in the skin and attenuates contact hypersensitivity responses. AB - Resolvin E1 (RvE1) is a lipid mediator derived from omega3 polyunsaturated fatty acids that exerts potent antiinflammatory roles in several murine models. The antiinflammatory mechanism of RvE1 in acquired immune responses has been attributed to attenuation of cytokine production by dendritic cells (DCs). In this study, we newly investigated the effect of RvE1 on DC motility using two photon microscopy in a contact hypersensitivity (CHS) model and found that RvE1 impaired DC motility in the skin. In addition, RvE1 attenuated T cell priming in the draining lymph nodes and effector T cell activation in the skin, which led to the reduced skin inflammation in CHS. In contrast, leukotriene B4 (LTB4) induced actin filament reorganization in DCs and increased DC motility by activating Cdc42 and Rac1 via BLT1, which was abrogated by RvE1. Collectively, our results suggest that RvE1 attenuates cutaneous acquired immune responses by inhibiting cutaneous DC motility, possibly through LTB4-BLT1 signaling blockade. PMID- 26438364 TI - Influence of phosphate on toxicity and bioaccumulation of arsenic in a soil isolate of microalga Chlorella sp. AB - In this study, the toxicity, biotransformation and bioaccumulation of arsenite and arsenate in a soil microalga, Chlorella sp., were investigated using different phosphate levels. The results indicated that arsenate was highly toxic than arsenite to the alga, and the phosphate limitation in growth media greatly enhanced arsenate toxicity. The uptake of arsenate in algal cells was more than that of arsenite, and the predominant species in the growth media was arsenate after 8 days of exposure to arsenite or arsenate, indicating arsenite oxidation by this microalga. Arsenate reduction was also observed when the alga was incubated in a phosphate-limiting growth medium. Similar to the process of biotransformation, the alga accumulated more arsenic when it was exposed to arsenate and preferably more in a phosphate-limiting condition. Although phosphate significantly influences the biotransformation and bioaccumulation of arsenic, the oxidizing ability and higher accumulation capacity of this alga have great potential for its application in arsenic bioremediation. PMID- 26438365 TI - Accumulation patterns of Cr in Callitriche organs--qualitative and quantitative analysis. AB - The aims of this study were both the qualitative and quantitative analysis of chromium accumulation in the shoots of Callitriche cophocarpa. This globally distributed, submersed macrophyte exhibits outstanding Cr phytoremediation capacity in an aquatic environment. Cr was applied separately for 7 days at two stable forms as Cr(VI) and Cr(III), known from their diverse physicochemical properties and toxicities. The maps of Cr depositions in young leaves, mature leaves, and stems were obtained by micro X-ray fluorescence spectroscopy (MUXRF). The detailed analysis of XRF maps was done based on Image-Pro PLUS (Media Cybernetics) software. Cr was accumulated either in trichomes or vascular bundles in respect to the element speciation and the plant organ. The concentration of Cr significantly increased in the following order: Cr(VI) mature leaves < Cr(VI) young leaves = Cr(VI) stems < Cr(III) young leaves <= Cr(III) mature leaves <= Cr(III) stems. The observed differences in distribution and accumulation of Cr were correlated with the different reduction potential of Cr(VI) by particular plant organs. The reduction of Cr(VI) is considered the main detoxification mechanism of the highly toxic Cr(VI) form. The unique L-band electron resonance spectrometer (L-band EPR) was applied to follow the reduction of Cr(VI) to Cr(III) in the studied material. PMID- 26438366 TI - Temporal variation of nitrogen balance within constructed wetlands treating slightly polluted water using a stable nitrogen isotope experiment. AB - Slightly polluted water has become one of the main sources of nitrogen contaminants in recent years, for which constructed wetlands (CW) is a typical and efficient treatment. However, the knowledge about contribution of individual nitrogen removal pathways and nitrogen balance in constructed wetlands is still limited. In this study, a stable-isotope-addition experiment was performed in laboratory-scale constructed wetlands treating slightly polluted water to determine quantitative contribution of different pathways and temporal variation of nitrogen balance using Na(15)NO3 as tracer. Microbial conversion and substrate retention were found to be the dominant pathways in nitrogen removal contributing 24.4-79.9 and 8.9-70.7 %, respectively, while plant contributed only 4.6-11.1 % through direct assimilation but promoted the efficiency of other pathways. In addition, microbial conversion became the major way to remove N whereas nitrogen retained in substrate at first was gradually released to be utilized by microbes and plants over time. The findings indicated that N2 emission representing microbial conversion was not only the major but also permanent nitrogen removal process, thus keeping a high efficiency of microbial conversion is important for stable and efficient nitrogen removal in constructed wetlands. PMID- 26438367 TI - Removal of Cd, Cu, Pb, and Zn from aqueous solutions by biochars. AB - Sorption and desorption of heavy metals (Cd, Cu, Pb, and Zn) was evaluated in biochars derived from sugarcane bagasse (SB), eucalyptus forest residues (CE), castor meal (CM), green coconut pericarp (PC), and water hyacinth (WH) as candidate materials for the treatment of contaminated waters and soils. Solid liquid distribution coefficients depended strongly on the initial metal concentration, with K d,max values mostly within the range 10(3)-10(4) L kg(-1). For all biochars, up to 95 % removal of all the target metals from water was achieved. The WH biochar showed the highest K d,max values for all the metals, especially Cd and Zn, followed by CE (for Cd and Pb) and PC (for Cd, Pb, and Zn). Sorption data were fitted satisfactorily with Freundlich and linear models (in the latter case, for the low concentration range). The sorption appeared to be controlled by cationic exchange, together with specific surface complexation at low metal concentrations. The low desorption yields, generally less than 5 %, confirmed that the sorption process was largely irreversible and that the biochars could potentially be used in decontamination applications. PMID- 26438368 TI - A comparative study of the grain-size distribution of surface dust and stormwater runoff quality on typical urban roads and roofs in Beijing, China. AB - The deposition of pollutants on impervious surfaces is a serious problem associated with rapid urbanization, which results in non-point-source pollution. Characterizing the build-up and wash-off processes of pollutants in urban catchments is essential for urban planners. In this paper, the spatial variation and particle-size distributions of five heavy metals and two nutrients in surface dust were analyzed, and the runoff water first-flush effect (FF30) and event-mean concentrations (EMCs) of 10 common constituents were characterized. The relationships between runoff variables and stormwater characteristics were examined from three typical urban impervious surfaces in Beijing, China. Dust on road surfaces with smaller grain sizes had higher pollutant concentrations, whereas concentrations of Mn, Zn, Fe, and TP in roof surface dust increased with grain size. Particles with grain sizes of 38-74 and 125-300 MUm contributed most to the total pollutant load in roads, while particles with the smallest grain sizes (<38 MUm) contributed most on roofs (23.46-41.71 %). Event-mean concentrations (EMCs) and FF30 values for most runoff pollutants tended to be higher on roofs than on roads. The maximum intensity (I max) and the antecedent dry days (ADD) were critical parameters for EMCs in roads, while ADD was the only dominant parameter for EMCs on our studied roof. The rainfall intensity (RI) and maximum intensity (I max) were found to be the parameters with the strongest correlation to the first-flush effect on both roads and roofs. Significant correlations of total suspended solids (TSS) concentration in runoff with grain size fractions of surface dust indicated that coarser particles (74-300 MUm) are most likely to contribute to the solid-phase pollutants, and finer particles (<38 MUm) are likely the main source of dissolved pollutants. PMID- 26438369 TI - GC-MS analysis of bioactive components and biosynthesis of silver nanoparticles using Hybanthus enneaspermus at room temperature evaluation of their stability and its larvicidal activity. AB - Green synthesis of silver nanoparticles (AgNPs) using Hybanthus enneaspermus extract at room temperature that act as a reducing agent as well as capping agent has been investigated. The synthesized AgNPs were characterized by UV-visible spectroscopy, X-ray diffraction (XRD), Fourier transform infrared (FTIR), zeta potential, and dynamic light scattering (DLS) transmission electron microscopy (TEM) and energy-dispersive X-ray (EDX). The silver surface plasmon resonance was observed at 420 nm in the UV-visible spectrum. XRD peaks were observed at 2theta values in 38.20 degrees , 44.40 degrees , 64.60 degrees , and 77.50 degrees which are indexed as (111), (200), (220), and (311) bands of face-centered cubic (fcc) structures of silver. FTIR revealed the AgNPs were capped with plant compounds of alcohol, phenols, carbonyl, amines, and amide functional groups. TEM image shows that the particles were of spherical, hexagonal, and triangular in shape, and the size range was 16-26 nm. Further, DLS exhibits the average size of 25.2 nm and the zeta values were measured (-27.1 mV) which proves the stability of the AgNPs. The conversion of Ag(+) ions into Ag(0) was calculated using inductively coupled plasma atomic emission spectroscopy (ICP-MS) and was found to be 96 %. The biosynthesized AgNPs showed the larvicidal activity with the LC50 values of 17.24 and 13.12 mg/L against the fourth-instar larvae of Anopheles subpictus and Culex quinquefasciatus, respectively. The GC-MS analysis of the plant extract showed that 39 bioactive phytochemical compounds have been found to possess a wide range of activities, which may help in the protection against incurable diseases. PMID- 26438370 TI - Growth and efficiency of nutrient removal by Salix jiangsuensis J172 for phytoremediation of urban wastewater. AB - Willows are a group of versatile tree species that may have multiple environmental applications. In the present study, Salix jiangsuensis J172 plants were grown in the fixed mats as an economic plant-based treatment system to evaluate its potential for removing nutrients in wastewater. Plants grew normally in wastewater compared with those in Hoagland solution. However, wastewater containing a high concentration of chlorine ions was toxic to S. jiangsuensis J172 plants. The plants accumulated large amounts of nitrogen and phosphorus in aboveground tissues under conditions of abundant supply. The removal efficiency for raw wastewater was 82.18-87.78 % for nitrogen, 57.35-65.58 % for phosphorus, and 58.24-59.90 % for chemical oxygen demand. Nutrient removal efficiency was positively correlated with the initial nutrient supply. The results show that S. jiangsuensis J172 grown in the fixed mat economic plant-based treatment system with nutrient-rich, eutrophic water may be an effective, low-cost phytoremediation technology to treat water containing undesirable levels of wastewater. PMID- 26438371 TI - Mobilization of trace metals and PCBs from contaminated marine sediments of the Mar Piccolo in Taranto during simulated resuspension experiment. AB - The effects of sediment resuspension on the fate of metals and polychlorinated biphenyls (PCBs) were studied by using a short-term small reactor. Sediments and water were collected nearby the most contaminated site of the Mar Piccolo of Taranto. Contaminant partitioning was calculated between the solid and water phases and, in the latter, between the dissolved and particulate phases and related to physical-chemical variables. Before and after resuspension, metal concentrations in sediments did not vary remarkably. Except for Cd, all the analyzed metals exceeded by many folds both threshold effect level (TEL) and probable effect level (PEL) SQGs. Igeo index values for Hg designated the sediment quality as extremely polluted for Pb, Cu and moderately polluted for Zn. In the dissolved phase, Mn increased of about 70 times, Fe of about 7 times and Hg and Zn of 4 and 3 times, respectively. PCBs in sediments before and after resuspension did not vary for more than 15 %. PCB concentrations exceeded for more than ten times PEL values. After resuspension, PCBs increased from 0.82 to 4.82 ng L(-1) in the dissolved phase and from 0.22 to 202.21 ng L(-1) in the particulate one. The dissolved phase was initially enriched in light- to mid weight compounds. After resuspension, the particulate phase was enriched in heavier congeners. In particular, hexachlorobiphenyl-153, 149 and 138 together with heptachlorobiphenyl-180 and 187 accounted for 57 % of total PCBs. The dissolved organic carbon (DOC) that increased from 1.31 to 8.55 mg L(-1) likely influenced the fate of metals and PCBs in the dissolved and particulate phases. Despite that the residence time of the contaminated resuspended sediments in the water column is limited, they are still highly toxic for the pelagic trophic web. PMID- 26438372 TI - Sorption and degradation of carbaryl in soils amended with biochars: influence of biochar type and content. AB - Biochars that were produced from three different biomass materials were amended to a soil to elucidate their influence on the fate of carbaryl. Sorption and degradation of carbaryl in soils amended with the biochars were investigated. The results showed that the amendment of biochars to soil enhanced the sorption of carbaryl. The nonlinearity of sorption isotherm and sorption affinity of carbaryl increased with the content and pyrolytic temperature of the biochars. Both chemical and biological degradation of carbaryl were influenced by biochars. The biochars enhanced the chemical hydrolysis of carbaryl in soil, with biochars produced at 700 degrees C (BC700) exhibiting greater impact, due to their strong liming effect. In contrast, BC350 (produced at 350 degrees C) promoted the biodegradation of carbaryl in soil by different extents, while BC700 obviously reduced the biodegradation of carbaryl. The enhanced activities of natural microorganisms in the soil and the lowered bioavailability of carbaryl acted together to determine the biodegradation. PMID- 26438373 TI - Estimation of aerosol optical depth at different wavelengths by multiple regression method. AB - This study aims to investigate and establish a suitable model that can help to estimate aerosol optical depth (AOD) in order to monitor aerosol variations especially during non-retrieval time. The relationship between actual ground measurements (such as air pollution index, visibility, relative humidity, temperature, and pressure) and AOD obtained with a CIMEL sun photometer was determined through a series of statistical procedures to produce an AOD prediction model with reasonable accuracy. The AOD prediction model calibrated for each wavelength has a set of coefficients. The model was validated using a set of statistical tests. The validated model was then employed to calculate AOD at different wavelengths. The results show that the proposed model successfully predicted AOD at each studied wavelength ranging from 340 nm to 1020 nm. To illustrate the application of the model, the aerosol size determined using measure AOD data for Penang was compared with that determined using the model. This was done by examining the curvature in the ln [AOD]-ln [wavelength] plot. Consistency was obtained when it was concluded that Penang was dominated by fine mode aerosol in 2012 and 2013 using both measured and predicted AOD data. These results indicate that the proposed AOD prediction model using routine measurements as input is a promising tool for the regular monitoring of aerosol variation during non-retrieval time. PMID- 26438374 TI - Targeted deletion of Atg5 in chondrocytes promotes age-related osteoarthritis. AB - OBJECTIVES: It has been suggested that the lysosomal recycling process called macro-autophagy plays a role in osteoarthritis development. We thus decided to genetically ablate the autophagy-indispensable Atg5 gene specifically in chondrocytes and analyse the development of osteoarthritis upon aging and in a post-traumatic model. METHODS: Mice lacking the Atg5 gene in their chondrocytes (Atg5cKO) were generated by crossing Atg5-floxed mice with transgenic mice that expressed cre recombinase driven by the collagen type 2 promoter. Animals were analysed at the age of 2, 6 and 12 months for age-related osteoarthritis or underwent mini-open partial medial meniscectomy at 2 months of age and were analysed 1 or 2 months after surgery. We evaluated osteoarthritis using the Osteoarthritis Research Society International (OARSI) scoring on safranin-O stained samples. Cell death was evaluated by terminal deoxy-nucleotidyl transferase-mediated deoxy-UTP nick end labelling (TUNEL) and by immunostaining of cleaved caspases. RESULTS: We observed the development of osteoarthritis in Atg5cKO mice with aging including fibrillation and loss of proteoglycans, which was particularly severe in males. The ablation of Atg5 was associated with an increased cell death as assessed by TUNEL, cleaved caspase 3 and cleaved caspase 9. Surprisingly, no difference in the development of post-traumatic osteoarthritis was observed between Atg5cKO and control mice. CONCLUSIONS: Autophagy protects from age-related osteoarthritis by facilitating chondrocyte survival. PMID- 26438375 TI - Pathogen-regulated genes in wheat isogenic lines differing in resistance to brown rust Puccinia triticina. AB - BACKGROUND: Inoculation of wheat plants with Puccinia triticina (Pt) spores activates a wide range of host responses. Compatible Pt interaction with susceptible Thatcher plants supports all stages of the pathogen life cycle. Incompatible interaction with TcLr9 activates defense responses including oxidative burst and micronecrotic reactions associated with the pathogen's infection structures and leads to complete termination of pathogen development. These two contrasting host-pathogen interactions were a foundation for transcriptome analysis of incompatible wheat-Pt interaction. METHODS: A suppression subtractive hybridization (SSH) library was constructed using cDNA from pathogen-inoculated susceptible Thatcher and resistant TcLr9 isogenic lines. cDNA represented steps of wheat-brown rust interactions: spore germination, haustorium mother cell (HMC) formation and micronecrotic reactions. All ESTs were clustered and validated by similarity search to wheat genome using BLASTn and sim4db tools. qRT-PCR was used to determine transcript levels of selected ESTs after inoculation in both lines. RESULTS AND DISCUSSION: Out of 793 isolated cDNA clones, 183 were classified into 152 contigs. 89 cDNA clones and encoded proteins were functionally annotated and assigned to 5 Gene Ontology categories: catalytic activity 48 clones (54 %), binding 32 clones (36 %), transporter activity 6 clones (7 %), structural molecule activity 2 clones (2 %) and molecular transducer activity 1 clone (1 %). Detailed expression profiles of 8 selected clones were analyzed using the same plant-pathogen system. The strongest induction after pathogen infection and the biggest differences between resistant and susceptible interactions were detected for clones encoding wall-associated kinase (GenBank accession number JG969003), receptor with leucine-rich repeat domain (JG968955), putative serine/threonine protein kinase (JG968944), calcium mediated signaling protein (JG968925) and 14-3-3 protein (JG968969). CONCLUSIONS: The SSH library represents transcripts regulated by pathogen infection during compatible and incompatible interactions of wheat with P. triticina. Annotation of selected clones confirms their putative roles in successive steps of plant pathogen interactions. The transcripts can be categorized as defense-related due to their involvement in either basal defense or resistance through an R-gene mediated reaction. The possible involvement of selected clones in pathogen recognition and pathogen-induced signaling as well as resistance mechanisms such as cell wall enforcement, oxidative burst and micronecrotic reactions is discussed. PMID- 26438377 TI - Efficacy of a referral center for patient-centered care in multiple myeloma: a cohort study. AB - BACKGROUND: Within the Brazilian Unified Health System (SUS), Referral Centers (RCs) are care facilities that provide specialized services. The objective of this study was to evaluate the efficacy of care provided to patients with multiple myeloma (MM) at a specialized RC (Hospital de Clinicas de Porto Alegre Referral Center for Multiple Myeloma, CRMM-HCPA) and to compare quality of life between patients with MM treated at CRMM-HCPA and those treated at non-RC facilities. METHODS: A 6-month cohort study was conducted in patients with MM receiving thalidomide from the Rio Grande do Sul State Health Department and treated at CRMM-HCPA and patients receiving treatment at other, non-RC care facilities. Thirty-two patients were included in the study, 19 from CRMM-HCPA and 13 from other institutions. To analyze the efficacy of care provided at CRMM HCPA, the main outcome measure was the time from diagnosis to referral for autologous hematopoietic stem cell transplantation (HSCT). This outcome measure was assessed using questionnaires specifically designed for this study. Quality of life was also assessed, using the SF-36 questionnaire. RESULTS: Time from MM diagnosis to referral for autologous HSCT in each group was measured only in patients aged <= 65 years (n = 25); of these, 15 were recruited from CRMM-HCPA and 10 from other institutions. In this analysis, there was a significant difference (p = 0.036) in time elapsed between diagnosis and referral for autologous HSCT, which was significantly shorter for patients treated at CRMM HCPA (median, 9 months; IQR, 8.5-14.5) than for those treated elsewhere (median, 24 months; IQR, 16-24). On quality of life analysis, there was a significant difference in the Social Functioning domain of the SF-36 questionnaire, which relates to performance of social activities (p = 0.02). CONCLUSIONS: The Referral Center model provided seems to be a more efficient treatment strategy as compared with other health care facilities, as it enabled a reduction in time to transplantation. Patients treated at CRMM-HCPA demonstrated greater ease in performing social activities, with less interference from physical or emotional problems. PMID- 26438376 TI - Comparison of Human Primary with Human iPS Cell-Derived Dopaminergic Neuron Grafts in the Rat Model for Parkinson's Disease. AB - Neuronal degeneration within the substantia nigra and the loss of the dopaminergic nigro-striatal pathway are the major hallmarks of Parkinson's disease (PD). Grafts of foetal ventral mesencephalic (VM) dopaminergic (DA) neurons into the striatum have been shown to be able to restore striatal dopamine levels and to improve overall PD symptoms. However, human foetus-derived cell grafts are not feasible for clinical application. Autologous induced pluripotent stem cell (iPS cell)-derived DA neurons are emerging as an unprecedented alternative. In this review, we summarize and compare the efficacy of human iPS cell-derived DA neuron grafts to restore normal behaviour in a rat model for PD with that of human foetal primary DA neurons. The differences we observed in the efficacy to restore normal function between the 2 types of DA neuron grafts could be ascribed to intrinsic properties of the iPS cell-derived DA neurons that critically affected survival and proper neurite extension in the striatum after implantation. PMID- 26438378 TI - Halorubrum rutilum sp. nov. isolated from a marine solar saltern. AB - A halophilic archaeal strain, YJ-18-S1(T), was isolated from Yangjiang marine solar saltern, Guangxi Province, China. Cells were pleomorphic, stained Gram negative and formed red-pigmented colonies on agar plates. Strain YJ-18-S1(T) was able to grow at 20-55 degrees C (optimum 37 degrees C), at 0.9-4.8 M NaCl (optimum 2.6 M NaCl), at 0.005-1.0 M MgCl2 (optimum 0.3 MgCl2) and at pH 5.5-8.5 (optimum pH 7.0). The cells were lysed in distilled water, and the minimal NaCl concentration to prevent cell lysis was found to be 5 % (w/v). The major polar lipids of the strain were phosphatidic acid, phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, phosphatidylglycerol sulfate and sulfated mannosyl glucosyl diether. The 16S rRNA gene and rpoB' gene of strain YJ 18-S1(T) were phylogenetically related to the corresponding genes of Halorubrum members (94.3-98.0 and 86.7-96.1 % similarities, respectively). The DNA G+C content of strain YJ-18-S1(T) was 66.2 mol%. The phenotypic, chemotaxonomic and phylogenetic properties suggested that strain YJ-18-S1(T) (=CGMCC 1.12554(T) = JCM 30030(T)) represents a new species of Halorubrum, for which the name Halorubrum rutilum sp. nov. is proposed. PMID- 26438379 TI - Comparative study of serum proteomes in Legg-Calve-Perthes disease. AB - BACKGROUND: Legg-Calve-Perthes Disease (LCPD) is an idiopathic osteonecrosis of the developing femoral head complicated by pain and disability of the hip joint. To date, the pathological mechanisms of LCPD are not well-known. This study screened the changes in serum protein expression in patients with LCPD. METHODS: Age- and sex-matched serum samples from 10 control subjects and 10 patients with LCPD were compared using the isobaric tags for relative and absolute quantification (iTRAQ) technique. Gene ontology analyses, KEGG pathway and functional network analyses were performed. Proteins of interest with large differences in expression, S100-A8, alpha-1-acid glycoprotein 1, haptoglobin and apolipoprotein E, were compared by western blotting. RESULTS: The disease/control ratios showed 26 proteins were significantly differentially expressed (all p < 0.05). Including higher abundances of complement factor H (1.44), complement C4-B (1.45), isocitrate dehydrogenase [NAD] subunit alpha (2.7) alpha-1-acid glycoprotein 1 (1.87), heptoglobin (1.53) and Ig lambda-2 chain C regions (1.46), and lower levels of apolipoprotein E (0.50), apolipoprotein F (0.60), apolipoprotein C-III (0.69), S100-A8 (0.73), S100-A9 (0.75) and prothrombin (0.77) in LCPD than in controls. The alpha-1-acid glycoprotein 1 and haptoglobin increases, and apolipoprotein E and S100-A8 decreases were confirmed by western blot. KEGG pathway analysis revealed these proteins were related to the complement and coagulation cascades, Staphylococcus aureus infection, PPAR signaling, fat digestion and absorption, and vitamin digestion and absorption. Functional network analysis suggested that the proteins were involved in lipid regulation. CONCLUSIONS: The complement and coagulation cascades, and abnormal lipid metabolism may be involved in the pathogenesis of LCPD. PMID- 26438380 TI - Reported co-infection deaths are more common in early adulthood and among similar infections. AB - BACKGROUND: Many people have multiple infections at the same time, but the combined contribution of those infections to disease-related mortality is unknown. Registered causes of death offer a unique opportunity to study associations between multiple infections. METHODS: We analysed over 900,000 death certificates that reported infectious causes of death. We tested whether reports of multiple infections (i.e., co-infections) differed across individuals' age or sex. We also tested whether each pair of infections were reported together more or less often than expected by chance, and whether this co-reporting was associated with the number of biological characteristics they had in common. RESULTS: In England and Wales, and the USA, 10 and 6 % respectively of infection related deaths involved co-infection. Co-infection was reported reported most often in young adults; 30 % of infection-related deaths among those aged 25-44 from the USA, and 20 % of infection-related deaths among those aged 30-39 from England and Wales, reported multiple infections. The proportion of infection related deaths involving co-infection declined with age more slowly in males than females, to less than 10 % among those aged >65. Most associated pairs of infections co-occurred more often than expected from their frequency of being reported alone (488/683 [71 %] in the USA, 129/233 [55 %] in England and Wales), and tended to share biological characteristics (taxonomy, transmission mode, tropism or timescale). CONCLUSIONS: Age, sex, and biologically similar infections are associated with death from co-infection, and may help indicate patients at risk of severe co-infection. PMID- 26438381 TI - Randomized Questionnaire Based Case-Control Research Study on Evaluation of Sexual Function in Indian Patients Taking Oral Finasteride for Androgenetic Alopecia. AB - INTRODUCTION: Finasteride is one of the most common drugs used in androgenetic alopecia. The literature discusses the sexual side effects of the drug; however, in practice there is little evidence to support this. The aim of the present study was to investigate the sexual dysfunction in patients taking finasteride 1 mg for androgenetic alopecia. METHODS: A questionnaire, based on the International Index of Erectile Function, was given to approximately 586 patients with androgenetic alopecia who were being treated with finasteride 1 mg for an average of 16 weeks. These patients were compared to an age-related control group who were attending the Dermatology Out Patients Department for various other skin ailments not related to hair disorders. RESULTS: Statistical analysis of the results showed no significant difference in the scores between patients taking finasteride and the control group. CONCLUSION: Analysis showed no significant difference in sex-related problems with that of patients taking finasteride and age matched controls, suggesting that sex-related issues are not a side effect of finasteride. PMID- 26438383 TI - Metastasized pancreatic neuroendocrine tumor in a teenage girl: a case report. AB - INTRODUCTION: Metastasized pancreatic neuroendocrine tumors are extremely rare malignancies, especially in children. Therefore, therapeutic options are limited, and few standardized therapy regimens exist. CASE PRESENTATION: We report a case of a 14-year-old white girl. In 2011 she was diagnosed with a metastasized, well differentiated pancreatic neuroendocrine tumor with expression of synaptophysin and chromogranin A. We describe her clinical course with special attention to her individual therapeutic regimens while bringing together several disciplines of medicine. CONCLUSIONS: In patients such as ours, surgical intervention may be the only therapy that will lead to long-term survival. PMID- 26438382 TI - Cognitive flexibility and performance in children and adolescents with threshold and sub-threshold bipolar disorder. AB - Greater understanding of cognitive function in children and adolescents with bipolar disorder (BD) is of critical importance to improve our ability to design targeted treatments to help with real-world impairment, including academic performance. We sought to evaluate cognitive performance among children with either BD type I, II, or "not otherwise specified" (NOS) participating in multi site Course and Outcome of Bipolar Youth study compared to typically developing controls (TDC) without psychopathology. In particular, we sought to test the hypothesis that BD-I and BD-II youths with full threshold episodes of mania or hypomania would have cognitive deficits, including in reversal learning, vs. those BD-NOS participants with sub-threshold episodes and TDCs. N = 175 participants (BD-I = 81, BD-II = 11, BD-NOS = 28, TDC = 55) completed Cambridge Neuropsychological Automated Testing Battery (CANTAB) tasks. A priori analyses of the simple reversal stage of the CANTAB intra-/extra-dimensional shift task showed that aggregated BD-I/II participants required significantly more trials to complete the task than either BD-NOS participants with sub-syndromal manic/hypomanic symptoms or than TDCs. BD participants across sub-types had impairments in sustained attention and information processing for emotionally valenced words. Our results align with prior findings showing that BD-I/II youths with distinct episodes have specific alterations in reversal learning. More broadly, our study suggests that further work is necessary to see the interaction between neurocognitive performance and longitudinal illness course. Additional work is required to identify the neural underpinnings of these differences as targets for potential novel treatments, such as cognitive remediation. PMID- 26438384 TI - Subretinal heterotopic respiratory epithelium: a case report and literature review. AB - A 51-year-old female underwent vitrectomy surgery to remove a group of spherical subretinal tumors beneath the detached retina. Hematoxylin and eosin staining and immunohistochemical findings showed that the characteristics of the tumor were consistent with a subretinal heterotopic respiratory epithelium. This is the first report of a respiratory epithelial heterotopia located in the subretinal space. PMID- 26438385 TI - A proposed clinical and biological interpretation of mediated interaction. AB - Understanding of causal pathways in epidemiology involves the concepts of direct and indirect effects. Recently, causal mediation analysis has been formalized to quantify these direct and indirect effects in the presence of exposure-mediator interaction and even allows for four-way decomposition of the total effect: controlled direct effect, reference interaction, mediated interaction, pure indirect effect. Whereas the other three effects can be intuitively conceptualized, mediated interaction is often considered a nuisance in statistical analysis. In this paper, we focus on mediated interaction and contrast it against pure mediation. We also propose a clinical and biological interpretation of mediated interaction using three hypothetical examples. With these examples we aim to make researchers aware that mediated interaction can actually provide important clinical and biological information. PMID- 26438386 TI - Levels of interleukin-1 beta can predict response to tocilizumab therapy in rheumatoid arthritis: the PETITE (predictors of effectiveness of tocilizumab therapy) study. AB - Predicting the responses of patients with rheumatoid arthritis (RA) to tocilizumab is difficult, because inflammatory markers such as C-reactive protein rapidly normalize regardless of clinical efficacy. We aimed to identify factors that could predict response to tocilizumab. Sixty-five patients completed 52 weeks of tocilizumab therapy. Serum fibrinogen, D-dimer and interleukin (IL) 1beta levels were measured at baseline and after 4 weeks of therapy. Clinical responses to tocilizumab were assessed using disease activity score 28 erythrocyte sedimentation rate and the clinical disease activity index at baseline and after 52 weeks of therapy (UMIN Clinical Trials Registry No. UMIN000002246). Mean age was 60.5 years (range 22-85 years). Mean disease duration was 11.2 years (range 0-45 years). All patients had moderate-to-severe disease activity and were resistant to disease-modifying anti-rheumatic drugs and/or other biologics. Baseline IL-1beta levels were significantly lower in responders than in non-responders (p = 0.045), but multiple logistic regression analysis found no significant difference (adjusted odds ratio 2.74; 95 % confidence interval 0.84-8.95; p = 0.096). Low D-dimer and IL-1beta levels at 4 weeks predicted greater decrease in disease activity after 52 weeks of treatment (p = 0.005 and p < 0.001, respectively). Effects of tocilizumab at 52 weeks could be predicted from D-dimer and IL-1beta levels after 4 weeks of tocilizumab treatment. These markers might be more useful than current inflammatory markers for early-stage prediction of response to tocilizumab in RA. PMID- 26438387 TI - WDR1 and CLNK gene polymorphisms correlate with serum glucose and high-density lipoprotein levels in Tibetan gout patients. AB - Current evidence suggests heredity and metabolic syndrome contributes to gout progression. Specifically, the WDR1 and CLNK genes may play a role in gout progression in European ancestry populations. However, no studies have focused on Chinese populations, especially Tibetan individuals. This study aims to determine whether variations in these two genes correlate with gout-related indices in Chinese-Tibetan gout patients. Eleven single-nucleotide polymorphisms in the WDR1 and CLNK genes were detected in 319 Chinese-Tibetan gout patients and 318 controls. We used one-way analysis of variance to evaluate the polymorphisms' effects on gout based on mean serum levels of metabolism indicators, such as albumin, glucose (GLU), triglycerides, cholesterol, high-density lipoproteins (HDL-C), creatinine, and uric acid, from fasting venous blood samples. All p values were Bonferroni corrected. Polymorphisms of the WDR1 and CLNK genes affected multiple risk factors for gout development. Significant differences in serum GLU levels were detected between different genotypic groups with WDRI polymorphisms rs4604059 (p = 0.005) and rs12498927 (p = 0.005). In addition, significant differences in serum HDL-C levels were detected between different genotypic groups with the CLNK polymorphism rs2041215 (p = 0.001). Polymorphisms of CLNK also affected levels of albumin, triglycerides, and creatinine. This study is the first to investigate and identify positive correlations between WDR1 and CLNK gene polymorphisms in Chinese-Tibetan populations. Our findings provide significant evidence for the effect of genetic polymorphisms on gout-related factors in Chinese-Tibetan populations. PMID- 26438388 TI - Multidisciplinary dermatology-rheumatology management for patients with moderate to-severe psoriasis and psoriatic arthritis: a systematic review. AB - The aim of the study was to analyze the efficacy and satisfaction of multidisciplinary dermatology-rheumatology management for patients with moderate to-severe psoriasis and psoriatic arthritis (PsA). We conducted a systematic literature search in MEDLINE, EMBASE, and Cochrane Library up to September 2015. Selection criteria include (1) adult patients with moderate-to-severe psoriasis and PsA, (2) assessed in a multidisciplinary consultation, (3) comparison with routine separate consultations, and (4) outcome measures to evaluate efficacy and/or satisfaction. Meta-analyses, systematic reviews, clinical trials, cohort studies, and case series were included. The quality of the studies included was graded according to the Oxford Level of Evidence scale. Of 195 articles, three studies complied with the inclusion criteria: two case series and one descriptive study in which 506 patients were evaluated. Patients were referred to the multidisciplinary consultation from dermatology and rheumatology consultations in all but one study, in which primary care was also involved. The reason for the referral was to confirm the diagnosis and/or treatment. Patients were evaluated on a weekly and monthly basis in two and one study, respectively. The evidence obtained is scarce but suggests the efficacy of multidisciplinary consultations in terms of improved skin and joint symptoms after changing treatment (82-56 %), showing higher scores for this type of consultation compared to the usual [4.91 vs. 2.85 (0-5)] and a high level of satisfaction among patients (94 % "very satisfied"). However, waiting times were higher. With the limited evidence found, multidisciplinary management seems to be more effective and more satisfactory for patients with moderate-to-severe psoriasis and PsA than conventional consultations, though this could not be conclusively demonstrated. The results of this review support the benefit of implementing this type of consultation. PMID- 26438389 TI - On the computational implementation of forward and back-projection operations for cone-beam computed tomography. AB - Forward- and back-projection operations are the main computational burden in iterative image reconstruction in computed tomography. In addition, their implementation has to be accurate to ensure stable convergence to a high-quality image. This paper reviews and compares some of the variations in the implementation of these operations in cone-beam computed tomography. We compare four algorithms for computing the system matrix, including a distance-driven algorithm, an algorithm based on cubic basis functions, another based on spherically symmetric basis functions, and a voxel-driven algorithm. The focus of our study is on understanding how the choice of the implementation of the system matrix will influence the performance of iterative image reconstruction algorithms, including such factors as the noise strength and spatial resolution in the reconstructed image. Our experiments with simulated and real cone-beam data reveal the significance of the speed-accuracy trade-off in the implementation of the system matrix. Our results suggest that fast convergence of iterative image reconstruction methods requires accurate implementation of forward- and back-projection operations, involving a direct estimation of the convolution of the footprint of the voxel basis function with the surface of the detectors. The required accuracy decreases by increasing the resolution of the projection measurements beyond the resolution of the reconstructed image. Moreover, reconstruction of low-contrast objects needs more accurate implementation of these operations. Our results also show that, compared with regularized reconstruction methods, the behavior of iterative reconstruction algorithms that do not use a proper regularization is influenced more significantly by the implementation of the forward- and back-projection operations. PMID- 26438390 TI - Hybrid stent device of flow-diverting effect and stent-assisted coil embolization formed by fractal structure. AB - This paper presents a novel hybrid medical stent device. This hybrid stent device formed by fractal mesh structures provides a flow-diverting effect and stent assisted coil embolization. Flow-diverter stents decrease blood flow into an aneurysm to prevent its rupture. In general, the mesh size of a flow-diverter stent needs to be small enough to prevent blood flow into the aneurysm. Conventional flow-diverter stents are not available for stent-assisted coil embolization, which is an effective method for aneurysm occlusion, because the mesh size is too small to insert a micro-catheter for coil embolization. The proposed hybrid stent device is capable of stent-assisted coil embolization while simultaneously providing a flow-diverting effect. The fractal stent device is composed of mesh structures with fine and rough mesh areas. The rough mesh area can be used to insert a micro-catheter for stent-assisted coil embolization. Flow diverting effects of two fractal stent designs were composed to three commercially available stent designs. Flow-diverting effects were analyzed using computational fluid dynamics (CFD) analysis and particle image velocimetry (PIV) experiment. Based on the CFD and PIV results, the fractal stent devices reduce the flow velocity inside an aneurism just as much as the commercially available flow-diverting stents while allowing stent-assisted coil embolization. PMID- 26438391 TI - Morphologic variations of lip-print patterns in a Central Indian population: A preliminary study. AB - Lip prints can provide vital information that may be useful for the purposes of forensic investigations. The current study was undertaken with the aims of determining the distribution and predominant lip-print patterns in a Central Indian (Marathi) population and evaluating whether any sex differences exist. The study subjects were 400 healthy consenting volunteers - 200 males and 200 females - aged 18-25 years, from the Marathi community. A simpler and more convenient method of data collection - digital photography - was used. The central (most motile) 1 cm(2) portion of both upper and lower lips was analysed digitally. As per Suzuki and Tsuchihashi's classification, overall, Type IV (27.5%) and Type III (6.25%) were found to be the most and least prevalent patterns, respectively. The Type II (32%) lip-print pattern was found to be most predominant in males, while Type IV (32.5%) was found to be most commonly occurring in females. Statistically significant differences (p < .01) were observed between lip-print pattern types in males and females. PMID- 26438392 TI - Adult porcine genome-wide DNA methylation patterns support pigs as a biomedical model. AB - BACKGROUND: Pigs (Sus scrofa) provide relevant biomedical models to dissect complex diseases due to their anatomical, genetic, and physiological similarities with humans. Aberrant DNA methylation has been linked to many of these diseases and is associated with gene expression; however, the functional similarities and differences between porcine and human DNA methylation patterns are largely unknown. METHODS: DNA and RNA was isolated from eight tissue samples (fat, heart, kidney, liver, lung, lymph node, muscle, and spleen) from the adult female Duroc utilized for the pig genome sequencing project. Reduced representation bisulfite sequencing (RRBS) and RNA-seq were performed on an Illumina HiSeq2000. RRBS reads were aligned using BSseeker2, and only sites with a minimum depth of 10 reads were used for methylation analysis. RNA-seq reads were aligned using Tophat, and expression analysis was performed using Cufflinks. In addition, SNP calling was performed using GATK for targeted control and whole genome sequencing reads for CpG site validation and allelic expression analysis, respectively. RESULTS: Analysis on the influence of DNA variation in methylation calling revealed a reduced effectiveness of WGS datasets in covering CpG rich regions, as well as the usefulness of a targeted control library for SNP detection. Analysis of over 500,000 CpG sites demonstrated genome wide methylation patterns similar to those observed in humans, including reduced methylation within CpG islands and at transcription start sites (TSS), X chromosome inactivation, and anticorrelation of TSS CpG methylation with gene expression. In addition, a positive correlation between TSS CpG density and expression, and a negative correlation between TSS TpG density and expression were demonstrated. Low but non-random non-CpG methylation (<1%) was also detected in all non-neuronal somatic tissues, with differences in tissue clustering observed based on CpG and non-CpG methylation patterns. Finally, allele specific expression analysis revealed enrichment of genes involved in metabolic and regulatory processes. DISCUSSION: These results provide transcriptional and DNA methylation datasets for the biomedical community that are directly relatable to current genomic resources. In addition, the correlation between TSS CpG density and expression suggests increased mutation rates at CpG sites play a significant role in adaptive evolution by reducing CpG density at TSS over time, resulting in higher methylation levels in these regions and more permanent changes to lower gene expression. This is proposed to occur predominantly through deamination of 5-methylcytosine to thymidine, resulting in the replacement of CpG with TpG sites in these regions, as indicated by the increased TSS TpG density observed in non-expressed genes, resulting in a negative correlation between expression and TSS TpG density. CONCLUSIONS: This study provides baseline methylation and gene transcription profiles for a healthy adult pig, reports similar patterns to those observed in humans, and supports future porcine studies related to human disease and development. Additionally, the observed reduced CpG and increased TpG density at TSS of lowly expressed genes suggests DNA methylation plays a significant role in adaptive evolution through more permanent changes to lower gene expression. PMID- 26438393 TI - Temporal transcriptional response to latency reversing agents identifies specific factors regulating HIV-1 viral transcriptional switch. AB - BACKGROUND: Latent HIV-1 reservoirs are identified as one of the major challenges to achieve HIV-1 cure. Currently available strategies are associated with wide variability in outcomes both in patients and CD4(+) T cell models. This underlines the critical need to develop innovative strategies to predict and recognize ways that could result in better reactivation and eventual elimination of latent HIV-1 reservoirs. RESULTS AND DISCUSSION: In this study, we combined genome wide transcriptome datasets post activation with Systems Biology approach (Signaling and Dynamic Regulatory Events Miner, SDREM analyses) to reconstruct a dynamic signaling and regulatory network involved in reactivation mediated by specific activators using a latent cell line. This approach identified several critical regulators for each treatment, which were confirmed in follow-up validation studies using small molecule inhibitors. Results indicate that signaling pathways involving JNK and related factors as predicted by SDREM are essential for virus reactivation by suberoylanilide hydroxamic acid. ERK1/2 and NF-kappaB pathways have the foremost role in reactivation with prostratin and TNF alpha, respectively. JAK-STAT pathway has a central role in HIV-1 transcription. Additional evaluation, using other latent J-Lat cell clones and primary T cell model, also confirmed that many of the cellular factors associated with latency reversing agents are similar, though minor differences are identified. JAK-STAT and NF-kappaB related pathways are critical for reversal of HIV-1 latency in primary resting T cells. CONCLUSION: These results validate our combinatorial approach to predict the regulatory cellular factors and pathways responsible for HIV-1 reactivation in latent HIV-1 harboring cell line models. JAK-STAT have a role in reversal of latency in all the HIV-1 latency models tested, including primary CD4(+) T cells, with additional cellular pathways such as NF-kappaB, JNK and ERK 1/2 that may have complementary role in reversal of HIV-1 latency. PMID- 26438394 TI - Relationship between myostatin and irisin in type 2 diabetes mellitus: a compensatory mechanism to an unfavourable metabolic state? AB - Myostatin and irisin are two myokines related to energy metabolism, acting on skeletal muscle and recently suggested on adipose tissue in mice. However, the exact role of these myokines in humans has not been fully established. Our aim was to evaluate the relationship between serum levels of myostatin and irisin in type 2 diabetes mellitus patients and non-diabetic controls and to explore its links with metabolic parameters. Case-control study including 73 type 2 diabetes mellitus patients and 55 non-diabetic subjects as control group. Circulating myostatin and irisin levels were measured by enzyme-linked immunosorbent assays. Type 2 diabetes mellitus patients showed significantly lower myostatin levels (p = 0.001) and higher irisin levels (p = 0.036) than controls. An inverse relationship was observed between myostatin and irisin levels (p = 0.002). Moreover, in type 2 diabetes mellitus patients, after adjusting by confounder factors, myostatin was negatively related to fasting plasma glucose (p = 0.005) and to triglyceride levels (p = 0.028) while irisin showed a positive association with these variables (p = 0.017 and p = 0.006 respectively). A linear regression analysis showed that irisin and fasting plasma glucose levels were independently associated to myostatin levels and that myostatin and triglyceride levels were independently associated to irisin concentrations in type 2 diabetes mellitus patients. Our results suggest that serum levels of myostatin and irisin are related in patients with type 2 diabetes. Triglyceride and glucose levels could modulate myostatin and irisin concentrations as a compensatory mechanism to improve the metabolic state in these patients although further studies are needed to elucidate whether the action of these myokines represents an adaptative response. PMID- 26438395 TI - The activity of 11beta-hydroxysteroid dehydrogenase type 2 enzyme and cortisol secretion in patients with adrenal incidentalomas. AB - In adrenal incidentaloma (AI) patients, beside the cortisol secretion, a different 11beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) activity, measurable by 24-h urinary cortisol/cortisone ratio (R-UFF/UFE) (the higher R UFF/UFE the lower HSD11B2 activity), could influence the occurrence of the subclinical hypercortisolism (SH)-related complications (hypertension, type 2 diabetes, obesity). We evaluated whether in AI patients, UFF levels are associated to UFE levels, and the HSD11B2 activity to the complications presence. In 156 AI patients (93F, age 65.2 +/- 9.5 years), the following were measured: serum cortisol after 1 mg-dexamethasone test (1 mg-DST), ACTH, UFF, UFE levels, and R-UFF/UFE (by liquid chromatography-tandem mass spectrometry), the latter was also evaluated in 63 matched-controls. We diagnosed SH (n = 22) in the presence of >=2 among ACTH <2.2 pmol/L, increased UFF levels, and 1 mg-DST >83 nmol/L. Patients showed higher UFF levels and R-UFF/UFE than controls (75.9 +/- 43.1 vs 54.4 +/- 22.9 nmol/24 h and 0.26 +/- 0.12 vs 0.20 +/- 0.07, p < 0.005, respectively) but comparable UFE levels (291 +/- 91.1 vs 268 +/- 61.5, p = 0.069). The R-UFF/UFE was higher in patients with high (h-UFF, n = 28, 0.41 +/- 0.20) than in those with normal (n-UFF, 0.22 +/- 0.10, p < 0.005) UFF levels and in patients with SH than in those without SH (0.30 +/- 0.12 vs 0.25 +/- 0.12, p = 0.04). UFF levels were associated with R-UFF/UFE (r = 0.849, p < 0.001) in n-UFF, but not in h-UFF patients. Among h-UFF patients, the complications prevalence was not associated with R-UFF/UFE values. In AI patients, the UFF increase is not associated with a UFE increase. The HSD11B2 activity is inversely associated with UFF levels in n-UFF patients but not in h-UFF patients, and it is not associated with the SH complications. PMID- 26438396 TI - Increased thyroid cancer incidence in a basaltic volcanic area is associated with non-anthropogenic pollution and biocontamination. AB - The increased thyroid cancer incidence in volcanic areas suggests an environmental effect of volcanic-originated carcinogens. To address this problem, we evaluated environmental pollution and biocontamination in a volcanic area of Sicily with increased thyroid cancer incidence. Thyroid cancer epidemiology was obtained from the Sicilian Regional Registry for Thyroid Cancer. Twenty-seven trace elements were measured by quadrupole mass spectrometry in the drinking water and lichens (to characterize environmental pollution) and in the urine of residents (to identify biocontamination) in the Mt. Etna volcanic area and in adjacent control areas. Thyroid cancer incidence was 18.5 and 9.6/10(5) inhabitants in the volcanic and the control areas, respectively. The increase was exclusively due to the papillary histotype. Compared with control areas, in the volcanic area many trace elements were increased in both drinking water and lichens, indicating both water and atmospheric pollution. Differences were greater for water. Additionally, in the urine of the residents of the volcanic area, the average levels of many trace elements were significantly increased, with values higher two-fold or more than in residents of the control area: cadmium (*2.1), mercury (*2.6), manganese (*3.0), palladium (*9.0), thallium (*2.0), uranium (*2.0), vanadium (*8.0), and tungsten (*2.4). Urine concentrations were significantly correlated with values in water but not in lichens. Our findings reveal a complex non-anthropogenic biocontamination with many trace elements in residents of an active volcanic area where thyroid cancer incidence is increased. The possible carcinogenic effect of these chemicals on the thyroid and other tissues cannot be excluded and should be investigated. PMID- 26438397 TI - Statin reduces orbitopathy risk in patients with Graves' disease by modulating apoptosis and autophagy activities. AB - Statins use has been associated with reduced risk for developing orbitopathy among patients with Graves' disease. We hypothesize that statin reduces orbitopathy risk mainly by modulating both apoptosis and autophagy activities in patients with Graves' disease. PMID- 26438398 TI - "You cannot eat rights": a qualitative study of views by Zambian HIV-vulnerable women, youth and MSM on human rights as public health tools. AB - BACKGROUND: Human rights approaches now dominate the HIV prevention landscape across sub-Saharan Africa, yet little is known about how they are viewed by the populations they are designed to serve. Health interventions are most effective when they resonate with the worldviews and interests of target groups. This study examined local Zambian understandings of human rights approaches to HIV prevention among three highly HIV-vulnerable groups: women, youth, and men-who have-sex-with-men (MSM). METHODS: Focus groups included 23 women, youth, and MSM who had participated in activities organized by local non-governmental organizations (NGOs) using rights-based approaches, and interviews included 10 Zambian employees of these NGOs. Topics included participants' experiences and views of the utility of these activities. Thematic analysis mapped out diverse ways participants viewed the concept of human rights in relation to HIV prevention. RESULTS: Whilst NGO workers noted the need for human rights programs to address the complex drivers of the HIV epidemic, they struggled to tailor them to the Zambian context due to donor stipulations. Women program beneficiaries noted that the concept of human rights helped challenge harmful sexual practices and domestic abuse, and youth described rights-based approaches as more participatory than previous HIV-prevention efforts. However, they criticized the approach for conflicting with traditional values such as respect for elders and 'harmonious' marital relationships. They also critiqued it for threatening the social structures and relationships that they relied on for material survival, and for failing to address issues like poverty and unemployment. In contrast, MSM embraced the rights approach, despite being critical of its overly confrontational implementation. CONCLUSIONS: A rights-based approach seeks to tackle the symbolic drivers of HIV-its undeniable roots in cultural and religious systems of discrimination. Yet, it fails to resonate with youth and women's own understandings of their needs and priorities due to its neglect of material drivers of HIV such as poverty and unemployment. MSM, who suffer extreme stigma and discrimination, have less to lose and much to gain from an approach that challenges inequitable social systems. Developing effective HIV-prevention strategies requires careful dialogue with vulnerable groups and greater flexibility for context-specific implementation rather than a one-size-fits-all conceptualization of human rights. PMID- 26438399 TI - Multiple sclerosis: relapses, resource use, and costs. AB - BACKGROUND: Relapses can have a major impact on the lives of people with multiple sclerosis (MS), and yet relapse-related healthcare costs have received little attention. This has limited cost-effectiveness analyses of treatments for MS and hampered decision-making regarding the funding of MS healthcare services. OBJECTIVE: To describe health/social care resource use and costs according to the frequency, severity, and endurance of MS relapses. METHODS: Data from the prospective, longitudinal UK South West Impact of Multiple Sclerosis cohort were used. A total of 11,800 questionnaires from 1441 people with MS were available, including data on relapses, contacts with health/social care professionals, and other MS-related resource use. RESULTS: The mean (SD) 6-monthly MS-related health/social care cost for individuals who reported a relapse was L519 (L949), compared to L229 (L366) for those who had not did report a relapse. Care costs varied widely dependent on the characteristics of the relapse. The mean (SD) cost when a relapse was not treated with steroids was L381 (L780), whilst the equivalent cost was L3579 (L1727) when a relapse resulted in hospitalization. CONCLUSIONS: The impact of relapses on health and social care resources and costs differs according to their frequency, length, and severity. The data provided here can be used in cost-effectiveness analyses and to inform decision-making regarding healthcare provision for people with this condition. PMID- 26438401 TI - Blockade of KCa3.1 potassium channels protects against cisplatin-induced acute kidney injury. AB - Tubular cell apoptosis significantly contributes to cisplatin-induced acute kidney injury (AKI) pathogenesis. Although KCa3.1, a calcium-activated potassium channel, participates in apoptosis, its involvement in cisplatin-induced AKI is unknown. Here, we found that cisplatin treatment triggered an early induction of KCa3.1 expression associated with HK-2 cell apoptosis, the development of renal tubular damage, and apoptosis in mice. Treatment with the highly selective KCa3.1 blocker TRAM-34 suppressed cisplatin-induced HK-2 cell apoptosis. We further assessed whether KCa3.1 mediated cisplatin-induced AKI in genetic knockout and pharmacological blockade mouse models. KCa3.1 deficiency reduced renal function loss, renal tubular damage, and the induction of the apoptotic marker caspase-3 in the kidneys of cisplatin-treated KCa3.1 (-/-) mice. Pharmacological blockade of KCa3.1 by TRAM-34 similarly attenuated cisplatin-induced AKI in mice. Furthermore, we dissected the mechanisms underlying cisplatin-induced apoptosis reduction via KCa3.1 blockade. We found that KCa3.1 blockade attenuated cytochrome c release and the increase in the intrinsic apoptotic mediators Bax, Bak, and caspase-9 after cisplatin treatment. KCa3.1 blocking inhibited the cisplatin-induced activation of the endoplasmic reticulum (ER) stress mediator caspase-12, which is independent of calcium-dependent protease m-calpain activation. Taken together, KCa3.1 blockade protects against cisplatin-induced AKI through the attenuation of apoptosis by interference with intrinsic apoptotic and ER stress-related mediators, providing a potential target for the prevention of cisplatin-induced AKI. PMID- 26438402 TI - Oxidative DNA damage enhances the carcinogenic potential of in vitro chronic arsenic exposures. AB - Chronic exposure to arsenic is known to increase the incidence of cancer in humans. Our previous work demonstrated that environmentally relevant arsenic exposures generate an accelerated accumulation of pre-carcinogen 8-OH-dG DNA lesions under Ogg1-deficient backgrounds, but it remains unproved whether this observed arsenic-induced oxidative DNA damage (ODD) is certainly important in terms of cancer. Here, isogenic MEF Ogg1 (+/+) cells and MEF Ogg1 (-/-) cells unable to properly eliminate 8-OH-dG from DNA-were exposed to 0.5, 1 and 2 uM of sodium arsenite for 40 weeks. The acquisition of an in vitro cancer-like phenotype was assessed throughout the exposure; matrix metalloproteinase (MMP) activities were measured by zymography, colony formation and promotion were evaluated by soft agar assay, and cellular invasiveness was measured by the transwell assay. Alterations in cellular morphology, growth and differentiation status were also included as complementary measures of transformation. MEF Ogg1 ( /-) cells showed a cancer-associated phenotype after 30 weeks of exposure, as indicated by morphological changes, increased proliferation, deregulated differentiation status, increased MMPs secretion, anchorage-independent cell growth and enhancement of tumor growth and invasiveness. Conversely, MEF Ogg1 (+/+) cells did not present changes in morphology or proliferation, exhibited a milder degree of gene deregulation and needed 10 weeks of additional exposure to the highest arsenite doses to show tumor enhancing effects. Thus, Ogg1 genetic background and arsenic-induced 8-OH-dG proved relevant for arsenic-mediated carcinogenic effects. To our knowledge, this is the first study directly linking ODD with arsenic carcinogenesis. PMID- 26438403 TI - Boxplots for grouped and clustered data in toxicology. AB - The vast majority of toxicological papers summarize experimental data as bar charts of means with error bars. While these graphics are easy to generate, they often obscure essential features of the data, such as outliers or subgroups of individuals reacting differently to a treatment. In particular, raw values are of prime importance in toxicology; therefore, we argue they should not be hidden in messy supplementary tables but rather unveiled in neat graphics in the results section. We propose jittered boxplots as a very compact yet comprehensive and intuitively accessible way of visualizing grouped and clustered data from toxicological studies together with individual raw values and indications of statistical significance. A web application to create these plots is available online. PMID- 26438400 TI - Inflammation-associated extracellular beta-glucuronidase alters cellular responses to the chemical carcinogen benzo[a]pyrene. AB - Neutrophils infiltrate tissues during inflammation, and when activated, they release beta-glucuronidase. Since inflammation is associated with carcinogenesis, we investigated how extracellular beta-glucuronidase changed the in vitro cellular response to the chemical carcinogen benzo(a)pyrene (B[a]P). For this we exposed human liver (HepG2) and lung (A549) cells to B[a]P in the presence or absence of beta-glucuronidase. beta-Glucuronidase reduced B[a]P-induced expression of CYP1A1 and CYP1B1 at 6 h after exposure, which did not depend on beta-glucuronidase activity, because the inhibitor D-saccharic acid 1,4-lactone monohydrate did not antagonize the effect of beta-glucuronidase. On the other hand, the inhibitory effect of beta-glucuronidase on CYP expression was dependent on signalling via the insulin-like growth factor receptor (IGF2R, a known receptor for beta-glucuronidase), because co-incubation with the IGF2R inhibitor mannose-6-phosphate completely abolished the effect of beta-glucuronidase. Extracellular beta-glucuronidase also reduced the formation of several B[a]P metabolites and B[a]P-DNA adducts. Interestingly, at 24 h of exposure, beta glucuronidase significantly enhanced CYP expression, probably because beta glucuronidase de-glucuronidated B[a]P metabolites, which continued to trigger the aryl hydrocarbon receptor (Ah receptor) and induced expression of CYP1A1 (in both cell lines) and CYP1B1 (in A549 only). Consequently, significantly higher concentrations of B[a]P metabolites and DNA adducts were found in beta glucuronidase-treated cells at 24 h. DNA adduct levels peaked at 48 h in cells that were exposed to B[a]P and treated with beta-glucuronidase. Overall, these data show that beta-glucuronidase alters the cellular response to B[a]P and ultimately enhances B[a]P-induced DNA adduct levels. PMID- 26438404 TI - Effects of copper toxicity on response inhibition processes: a study in Wilson's disease. AB - Wilson's disease (WD) is a rare genetic disease causing copper deposits in various tissues. Given the specificity of the underlying pathology, it is a good model to investigate the effects of copper toxicity on cognitive functions in humans. If left untreated, WD results in neurodegeneration and organ failure, but irrespective of potential brain damage, the medication might reduce cortical norepinephrine (NE) levels. In line with this, dysexecutive symptoms including increased impulsivity have been reported for WD patients, but the underlying mechanisms have remained elusive. We investigated inhibition and the associated neurophysiological correlates in n = 26 WD patients with mild-to-moderate clinical symptoms and matched healthy controls who completed a Go/Nogo task, while an EEG was recorded. Although the behavioral data do not show increased impulsivity in WD, the neurophysiological data show that evaluative processing of successful inhibition (as reflected by the P3 component) was strongly compromised. This was reflected by a decrease in ACC activity which was positively correlated with the severity of WD symptoms, stressing the importance of copper (toxicity) for neurocognitive functioning and impulsivity. These changes are most likely due to a combination of NE deficiency induced by WD medication as well as WD-induced brain damage. The fact that changes were still evident on a neurophysiological level suggests that neurophysiological correlates of cognitive processes and functions provide a more sensitive index of toxicity and/or treatment efficiency than purely behavioral measures. PMID- 26438405 TI - Optimality in the zonation of ammonia detoxification in rodent liver. AB - The rodent liver eliminates toxic ammonia. In mammals, three enzymes (or enzyme systems) are involved in this process: glutaminase, glutamine synthetase and the urea cycle enzymes, represented by carbamoyl phosphate synthetase. The distribution of these enzymes for optimal ammonia detoxification was determined by numerical optimization. This in silico approach predicted that the enzymes have to be zonated in order to achieve maximal removal of toxic ammonia and minimal changes in glutamine concentration. Using 13 compartments, representing hepatocytes, the following predictions were generated: glutamine synthetase is active only within a narrow pericentral zone. Glutaminase and carbamoyl phosphate synthetase are located in the periportal zone in a non-homogeneous distribution. This correlates well with the paradoxical observation that in a first step glutamine-bound ammonia is released (by glutaminase) although one of the functions of the liver is detoxification by ammonia fixation. The in silico approach correctly predicted the in vivo enzyme distributions also for non physiological conditions (e.g. starvation) and during regeneration after tetrachloromethane (CCl4) intoxication. Metabolite concentrations of glutamine, ammonia and urea in each compartment, representing individual hepatocytes, were predicted. Finally, a sensitivity analysis showed a striking robustness of the results. These bioinformatics predictions were validated experimentally by immunohistochemistry and are supported by the literature. In summary, optimization approaches like the one applied can provide valuable explanations and high-quality predictions for in vivo enzyme and metabolite distributions in tissues and can reveal unknown metabolic functions. PMID- 26438406 TI - Infarction of the lingula following left upper lobe trisegmentectomy. AB - Anatomical segmentectomy has emerged as the procedure of choice for early-stage non-small-cell lung cancer, especially in the presence of poor cardiopulmonary reserve. The most common postoperative complications are pneumonia, persistent air leak, and rarely, vascular compromise of the remaining lobe. We report the case of a 74-year-old woman who underwent thoracotomy and left upper lobe trisegmentectomy for T1bN0Mo squamous cell carcinoma and subsequently developed infarction and hepatization of the remaining lingula. A completion left upper lobectomy was performed and the patient made a full recovery. PMID- 26438407 TI - Hypertension in pregnancy: An unresectable mediastinal pheochromocytoma. AB - Hypertension is a relatively common occurrence during pregnancy, which usually has a benign course with an excellent prognosis. However, physicians caring for pregnant women should have a high index of suspicion for underlying medical conditions that could lead to a more perilous outcome. Herein, we present the case of a pregnant woman who was found to have uncontrollable hypertension late in her pregnancy, secondary to a mediastinal pheochromocytoma, which was deemed unresectable at the time of exploration after her delivery. PMID- 26438408 TI - Combined 3D-QSAR, molecular docking, and molecular dynamics study of tacrine derivatives as potential acetylcholinesterase (AChE) inhibitors of Alzheimer's disease. AB - Acetylcholinesterase (AChE) is one of the key targets of drugs for treating Alzheimer's disease (AD). Tacrine is an approved drug with AChE-inhibitory activity. In this paper, 3D-QSAR, molecular docking, and molecular dynamics were carried out in order to study 60 tacrine derivatives and their AChE-inhibitory activities. 3D-QSAR modeling resulted in an optimal CoMFA model with q(2) = 0.552 and r(2) = 0.983 and an optimal CoMSIA model with q(2) = 0.581 and r(2) = 0.989. These QSAR models also showed that the steric and H-bond fields of these compounds are important influences on their activities. The interactions between these inhibitors and AChE were further explored through molecular docking and molecular dynamics simulation. A few key residues (Tyr70, Trp84, Tyr121, Trp279, and Phe330) at the binding site of AChE were identified. The results of this study improve our understanding of the mechanisms of AChE inhibitors and afford valuable information that should aid the design of novel potential AChE inhibitors. Graphical Abstract Superposition of backbone atoms of the lowest energy structure obtained from MD simulation (magenta) onto those of the structure of the initial molecular docking model (green). PMID- 26438409 TI - Specific Diversity of Metarhizium Isolates Infecting Aeneolamia spp. (Hemiptera: Cercopidae) in Sugarcane Plantations. AB - Spittlebugs from the genus Aeneolamia are important pests of sugarcane. Although the use of the entomopathogenic fungus Metarhizum anisopliae s.l. for control of this pest is becoming more common in Mexico, fundamental information regarding M. anisopliae in sugarcane plantations is practically non-existent. Using phylogenetic analysis, we determined the specific diversity of Metarhizium spp. infecting adult spittlebugs in sugarcane plantations from four Mexican states. We obtained 29 isolates of M. anisopliae s.str. Haplotype network analysis revealed the existence of eight haplotypes. Eight selected isolates, representing the four Mexican states, were grown at different temperatures in vitro; isolates from Oaxaca achieved the greatest growth followed by isolates from Veracruz, San Luis Potosi and Tabasco. No relationship was found between in vitro growth and haplotype diversity. Our results represent a significant contribution to the better understanding of the ecology of Metarhizum spp. in the sugarcane agroecosystem. PMID- 26438410 TI - Pharyngo-jugular fistula after "salvage" total laryngectomy: a case report. AB - INTRODUCTION: We present a rare case of pharyngo-jugular fistula in a patient who underwent salvage total laryngectomy after organ-sparing radiochemotherapy. CASE PRESENTATION: A 77-year-old Caucasian man underwent total laryngectomy and bilateral neck dissection as salvage surgery after the failure of radiochemotherapy at another hospital. Thirty-five days after surgery, he was admitted to our emergency room for fever and massive oral bleeding during meals. Videopanendoscopy showed the presence of a large clot at the base of his tongue, while a neck computed tomography scan showed a pharyngo-jugular fistula with the presence of air in the left internal jugular vein. Cervicotomy was performed: the internal jugular vein was ligated and sectioned, and the pharyngeal defect was repaired with a pectoralis major myocutaneous flap. The postoperative period was uneventful. Twenty-five days post surgery, videofluorography showed the fistula had disappeared. Our patient then began oral feeding without complications and was discharged. At present, 5 years after the operation, our patient is alive and shows no evidence of disease. CONCLUSIONS: Pharyngo-jugular fistula is an uncommon complication after total laryngectomy, especially in the chemoradiation era, which is potentially fatal if not promptly treated. PMID- 26438411 TI - Plant species introduced by foreigners according to folk tradition in Norway and some other European countries: xenophobic tales or not? AB - BACKGROUND: In their quest to understand and interpret nature, people have frequently sought religious or divine origins for plant species and their characteristics. Less often, historical events or persons are involved. This study comprises eleven cases of the latter kind, all claiming that plant species have been introduced by foreigners or at least from foreign lands. METHODS: Based on literature data and a few cases recorded during my own ethnobotanical field work, eleven European examples of pseudo-historical plant origins are presented here, including Cakile maritima, Cicuta virosa, Lathyrus japonicus, Leymus arenarius, Primula vulgaris, and Scopolia carniolica in Norway, Heracleum mantegazzianum and/or H. persicum in Denmark, Phoenix dactylifera and P. theophrastii in Greece, and Jacobaea vulgaris in Scotland. RESULTS: The only common trait in these stories is that foreigner or at least foreign lands are claimed as sources of the plant species. In most cases, the "historical" explanations given in folk tradition are demonstrably at odds with reality. In those cases that involve poisonous or potentially harmful species (Cicuta virosa, Heracleum mantegazzianum and/or H. persicum, Jacobaea vulgaris), or the "useless" Phoenix theophrastii, with its inedible fruits, the stories may be interpreted as xenophobic, blaming foreigners for introducing dangerous or worthless species. The remaining examples merely suggest a search for exotic and seemingly rational, if erroneous, origins for plant species and stands that people considered strange and unusual. CONCLUSION: The spreading vectors assumed in folk tradition are correct and well documented, e.g. ship cargos (including goods and packing materials), which are responsible for introducing ballast plants and other anthropochores, and wartime activities, introducing a broad range of species (polemochores). They do not, however, apply to the species included in this study, which are either indigenous plants or introduced ornamentals. The foreigners appearing in the folk tales serve mostly as suitably exotic explanations for what is perceived "alien" plants. PMID- 26438412 TI - Plant resistance against the parasitic nematode Heterodera schachtii is mediated by MPK3 and MPK6 kinases, which are controlled by the MAPK phosphatase AP2C1 in Arabidopsis. AB - Plant-parasitic cyst nematodes infect plants and form highly sophisticated feeding sites in roots. It is not known which plant cell signalling mechanisms trigger plant defence during the early stages of nematode parasitism. Mitogen activated protein kinases (MAPKs) are central components of protein phosphorylation cascades transducing extracellular signals to plant defence responses. MAPK phosphatases control kinase activities and the signalling outcome. The involvement and the role of MPK3 and MPK6, as well as the MAPK phosphatase AP2C1, is demonstrated during parasitism of the beet cyst nematode Heterodera schachtii in Arabidopsis. Our data reveal notable activation patterns of plant MAPKs and the induction of AP2C1 suggesting the attenuation of defence signalling in plant cells during early nematode infection. It is demonstrated that the ap2c1 mutant that is lacking AP2C1 is more attractive but less susceptible to nematodes compared with the AP2C1-overexpressing line. This implies that the function of AP2C1 is a negative regulator of nematode-induced defence. By contrast, the enhanced susceptibility of mpk3 and mpk6 plants indicates a positive role of stress-activated MAPKs in plant immunity against nematodes. Evidence is provided that phosphatase AP2C1, as well as AP2C1-targeted MPK3 and MPK6, are important regulators of plant-nematode interaction, where the co-ordinated action of these signalling components ensures the timely activation of plant defence. PMID- 26438413 TI - Transgenic rice seed expressing flavonoid biosynthetic genes accumulate glycosylated and/or acylated flavonoids in protein bodies. AB - Plant-specialized (or secondary) metabolites represent an important source of high-value chemicals. In order to generate a new production platform for these metabolites, an attempt was made to produce flavonoids in rice seeds. Metabolome analysis of these transgenic rice seeds using liquid chromatography-photodiode array-quadrupole time-of-flight mass spectrometry was performed. A total of 4392 peaks were detected in both transgenic and non-transgenic rice, 20-40% of which were only detected in transgenic rice. Among these, 82 flavonoids, including 37 flavonols, 11 isoflavones, and 34 flavones, were chemically assigned. Most of the flavonols and isoflavones were O-glycosylated, while many flavones were O glycosylated and/or C-glycosylated. Several flavonoids were acylated with malonyl, feruloyl, acetyl, and coumaroyl groups. These glycosylated/acylated flavonoids are thought to have been biosynthesized by endogenous rice enzymes using newly synthesized flavonoids whose biosynthesis was catalysed by exogenous enzymes. The subcellular localization of the flavonoids differed depending on the class of aglycone and the glycosylation/acylation pattern. Therefore, flavonoids with the intended aglycones were efficiently produced in rice seeds via the exogenous enzymes introduced, while the flavonoids were variously glycosylated/acylated by endogenous enzymes. The results suggest that rice seeds are useful not only as a production platform for plant-specialized metabolites such as flavonoids but also as a tool for expanding the diversity of flavonoid structures, providing novel, physiologically active substances. PMID- 26438414 TI - Impact of endobronchial coiling on segmental bronchial lumen in treated and untreated lung lobes: Correlation with changes in lung volume, clinical and pulmonary function tests. AB - OBJECTIVES: To assess the impact of endobronchial coiling on the segment bronchus cross-sectional area and volumes in patients with lung emphysema using quantitative chest-CT measurements. MATERIALS AND METHODS: Thirty patients (female = 15; median age = 65.36 years) received chest-CT before and after endobronchial coiling for lung volume reduction (LVR) between January 2010 and December 2014. Thin-slice (0.6 mm) non-enhanced image data sets were acquired both at end-inspiration and end-expiration using helical technique and 120 kV/100 150 mAs. Clinical response was defined as an increase in the walking distance (Six-minute walk test; 6MWT) after LVR-therapy. Additionally, pulmonary function test (PFT) measurements were used for clinical correlation. RESULTS: In the treated segmental bronchia, the cross-sectional lumen area showed significant reduction (p < 0.05) in inspiration and tendency towards enlargement in expiration (p > 0.05). In the ipsilateral lobes, the lumina showed no significant changes. In the contralateral lung, we found tendency towards increased cross sectional area in inspiration (p = 0.06). Volumes of the treated segments correlated with the treated segmental bronchial lumina in expiration (r = 0.80, p < 0.001). Clinical correlation with changes in 6MWT/PFT showed a significant decrease of the inspiratory volume of the treated lobe in responders only. CONCLUSION: Endobronchial coiling causes significant decrease in the cross sectional area of treated segment bronchi in inspiration and a slight increase in expiration accompanied by a volume reduction. KEY POINTS: * Endobronchial coiling has indirect impact on cross-sectional area of treated segment bronchi * Volume changes of treated lobes correlate with changes in bronchial cross-sectional area * Coil-induced effects reflect their stabilizing and stiffening impact on lung parenchyma * Endobronchial coiling reduces bronchial collapsing compensating the loss of elasticity. PMID- 26438415 TI - The Predictive Syndemic Effect of Multiple Psychosocial Problems on Health Care Costs and Utilization among Sexual Minority Women. AB - Previous studies documenting sexual minority women's disproportionate risk for a range of medical, mental health, and substance use disorders have not provided a predictive framework for understanding their interrelations and outcomes. The present study aimed to address this gap by testing the syndemic effect of co occurring psychosocial problems on 7-year health care costs and utilization among sexual minority women. The sample was comprised of sexual minority women (N = 341) who were seen at an urban LGBT-affirmative community health center. Medical and mental health care utilization and cost data were extracted from electronic medical records. Demographically adjusted regression models revealed that co occurring psychosocial problems (i.e., childhood sexual abuse, partner violence, substance use, and mental health distress [history of suicide attempt]) were all strongly interrelated. The presence of these indicators had a syndemic (additive) effect on medical costs and utilization and mental health utilization over 7-year follow-up, but no effect on 7-year mental health costs. These results suggest that the presence and additive effect of these syndemic conditions may, in part, explain increased medical costs and utilization (and higher medical morbidity) among sexual minority women. PMID- 26438417 TI - Acute Respiratory Distress Syndrome: Mortality in a Single Center According to Different Definitions. AB - BACKGROUND: Mortality in acute lung injury (ALI) remains high, with outcome data arising mostly from multicenter studies. We undertook this investigation to determine hospital mortality in patients with ALI in a single center. METHODS: We studied patients admitted between 2005 and 2012 with ALI and acute respiratory distress syndrome (ARDS) according to the American European Consensus Conference (AECC) criteria and recorded clinical variables. Thereafter, patients were classified as subgroups according to the AECC and Berlin definition in order to compare the clinical characteristics and outcomes. RESULTS: In the 93 patients comprising the study, hospital mortality was 38%. Mortality at 28 days was 36%. Multivariate analysis associated hospital mortality with age and Pao2/Fio2 on day 1 ( P < .001). Differences resulted between the subgroups of AECC (ALI vs ARDS) and Berlin (mild vs moderate vs severe ARDS) in the lung injury score, Pao2/Fio2, Pao2/PAo2, PaCo2 on day 1, and hospital mortality. CONCLUSION: The overall hospital mortality (38%) was similar to that of other studies and according to the presence of ARDS (Pao2/Fio2 <= 200), we found significant differences between ALI and ARDS (AECC) and between mild and moderate or severe ARDS (Berlin) in baseline respiratory variables and mortality. PMID- 26438416 TI - Substantial genome synteny preservation among woody angiosperm species: comparative genomics of Chinese chestnut (Castanea mollissima) and plant reference genomes. AB - BACKGROUND: Chinese chestnut (Castanea mollissima) has emerged as a model species for the Fagaceae family with extensive genomic resources including a physical map, a dense genetic map and quantitative trait loci (QTLs) for chestnut blight resistance. These resources enable comparative genomics analyses relative to model plants. We assessed the degree of conservation between the chestnut genome and other well annotated and assembled plant genomic sequences, focusing on the QTL regions of most interest to the chestnut breeding community. RESULTS: The integrated physical and genetic map of Chinese chestnut has been improved to now include 858 shared sequence-based markers. The utility of the integrated map has also been improved through the addition of 42,970 BAC (bacterial artificial chromosome) end sequences spanning over 26 million bases of the estimated 800 Mb chestnut genome. Synteny between chestnut and ten model plant species was conducted on a macro-syntenic scale using sequences from both individual probes and BAC end sequences across the chestnut physical map. Blocks of synteny with chestnut were found in all ten reference species, with the percent of the chestnut physical map that could be aligned ranging from 10 to 39 %. The integrated genetic and physical map was utilized to identify BACs that spanned the three previously identified QTL regions conferring blight resistance. The clones were pooled and sequenced, yielding 396 sequence scaffolds covering 13.9 Mbp. Comparative genomic analysis on a microsytenic scale, using the QTL associated genomic sequence, identified synteny from chestnut to other plant genomes ranging from 5.4 to 12.9 % of the genome sequences aligning. CONCLUSIONS: On both the macro- and micro-synteny levels, the peach, grape and poplar genomes were found to be the most structurally conserved with chestnut. Interestingly, these results did not strictly follow the expectation that decreased phylogenetic distance would correspond to increased levels of genome preservation, but rather suggest the additional influence of life-history traits on preservation of synteny. The regions of synteny that were detected provide an important tool for defining and cataloging genes in the QTL regions for advancing chestnut blight resistance research. PMID- 26438418 TI - Discretization of gene expression data revised. AB - Gene expression measurements represent the most important source of biological data used to unveil the interaction and functionality of genes. In this regard, several data mining and machine learning algorithms have been proposed that require, in a number of cases, some kind of data discretization to perform the inference. Selection of an appropriate discretization process has a major impact on the design and outcome of the inference algorithms, as there are a number of relevant issues that need to be considered. This study presents a revision of the current state-of-the-art discretization techniques, together with the key subjects that need to be considered when designing or selecting a discretization approach for gene expression data. PMID- 26438419 TI - Computational modelling of atherosclerosis. AB - Atherosclerosis is one of the principle pathologies of cardiovascular disease with blood cholesterol a significant risk factor. The World Health Organization estimates that approximately 2.5 million deaths occur annually because of the risk from elevated cholesterol, with 39% of adults worldwide at future risk. Atherosclerosis emerges from the combination of many dynamical factors, including haemodynamics, endothelial damage, innate immunity and sterol biochemistry. Despite its significance to public health, the dynamics that drive atherosclerosis remain poorly understood. As a disease that depends on multiple factors operating on different length scales, the natural framework to apply to atherosclerosis is mathematical and computational modelling. A computational model provides an integrated description of the disease and serves as an in silico experimental system from which we can learn about the disease and develop therapeutic hypotheses. Although the work completed in this area to date has been limited, there are clear signs that interest is growing and that a nascent field is establishing itself. This article discusses the current state of modelling in this area, bringing together many recent results for the first time. We review the work that has been done, discuss its scope and highlight the gaps in our understanding that could yield future opportunities. PMID- 26438420 TI - Vitamin D deficiency versus non-accidental trauma: comment on "Rickets or abuse? A histologic comparison of rickets and child abuse-related fractures". PMID- 26438421 TI - Drawing the line. AB - The pea aphid Acyrthosiphon pisum is an agriculturally important pest of leguminous plants including peas and broad beans. The widespread use of chemical pesticides impacts heavily on the environment, and increases pesticide-resistant pea aphid populations, so alternative strategies are being actively sought. Pseudomonas syringae bacteria are known to infect and kill the pea aphid, and offer a possible control strategy. In this study, the authors measured the effects of injecting P. syringae on the survival of pea aphid populations at 24 and 48 hours. The pea aphid population was killed more rapidly (98 % after 24 hours) with a higher concentration of injected bacteria than in the control or with lower concentrations, indicating that a P. syringae-based control strategy may be a useful alternative to conventional pesticides. PMID- 26438422 TI - Glycoside hydrolase family 32 is present in Bacillus subtilis phages. AB - BACKGROUND: Glycoside hydrolase family 32 (GH32) enzymes cleave the glycosidic bond between two monosaccharides or between a carbohydrate and an aglycone moiety. GH32 enzymes have been studied in prokaryotes and in eukaryotes but not in viruses. FINDINGS: This is the first analysis of GH32 enzymes in Bacillus subtilis phage SP10, phiNIT1 and SPG24. Phylogenetic analysis, molecular docking and secretability predictions suggest that phage GH32 enzymes function as levan (fructose homopolysaccharide) fructotransferase. CONCLUSIONS: We showed that viruses also contain GH32 enzymes and that our analyses in silico strongly suggest that these enzymes function as levan fructotransferase. PMID- 26438423 TI - Mobile Image Interpretation: Diagnostic Performance of CT Exams Displayed on a Tablet Computer in Detecting Abdominopelvic Hemorrhage. AB - To investigate whether abdominopelvic hemorrhage shown on computed tomography (CT) images can be diagnosed with the same accuracy on a tablet computer as on a dedicated reading display. One hundred patients with a clinical suspicion of abdominopelvic hemorrhage that underwent biphasic CT imaging were retrospectively read by two readers on a dedicated reading display (reference standard) and on a tablet computer (iPad Air). Reading was performed in a dedicated reading room with ambient light conditions. Image evaluation included signs of an active hemorrhage (extravasation of contrast media) and different signs indicating a condition after abdominopelvic hemorrhage (hematoma, intestinal clots, vessel stump, free abdominopelvic fluid with a mean Hounsfield unit value >20, and asymmetric muscle volume indicating intramuscular hemorrhage). Sensitivity, specificity, and positive and negative predictive values (PPV/NPV) were calculated for the tablet-based reading. Active abdominopelvic hemorrhage (n = 72) was diagnosed with the tablet computer with a sensitivity of 0.96, a specificity of 0.93, a PPV of 0.97, and an NPV of 0.90. The results for the detection of the signs indicating a condition after abdominopelvic hemorrhage range from 0.83 to 1.00 in the case of sensitivity, from 0.95 to 1.00 in the case of specificity, from 0.94 to 1.00 in the case of the PPV, and from 0.96 to 1.00 in the case of the NPV. Abdominopelvic hemorrhage shown on CT images can be diagnosed on a tablet computer with a high diagnostic accuracy allowing mobile on call diagnoses. This may be helpful because an early and reliable diagnosis at any time is crucial for an adequate treatment strategy. PMID- 26438424 TI - An Evaluation of Performance Characteristics of Primary Display Devices. AB - The aim of this study was to complete a full evaluation of the new EIZO RX850 liquid crystal display and compare it to two currently used medical displays in Australia (EIZO GS510 and Barco MDCG 5121). The American Association of Physicists in Medicine (AAPM) Task Group 18 Quality Control test pattern was used to assess the performance of three high-resolution primary medical displays: EIZO RX850, EIZO GS510, and Barco MDCG 5121. A Konica Minolta spectroradiometer (CS 2000) was used to assess luminance response, non-uniformity, veiling glare, and color uniformity. Qualitative evaluation of noise was also performed. Seven breast lesions were displayed on each monitor and photographed with a calibrated 5.5-MP Olympus E-1 digital SLR camera. ImageJ software was used to sample pixel information from each lesion and surrounding background to calculate their conspicuity index on each of the displays. All monitor fulfilled all AAPM acceptance criteria. The performance characteristics for EIZO RX850, Barco MDCG 5121, and EIZO GS510 respectively were as follows: maximum luminance (490, 500.5, and 413 cd/m(2)), minimum luminance (0.724, 1.170, and 0.92 cd/m(2)), contrast ratio (675:1, 428:1, 449:1), just-noticeable difference index (635, 622, 609), non-uniformity (20, 5.92, and 8.5 %), veiling glare (GR = 2465.6, 720.4, 1249.8), and color uniformity (Deltau'v' = +0.003, +0.002, +0.002). All monitors demonstrated low noise levels. The conspicuity index (chi) of the lesions was slightly higher in the EIZO RX850 display. All medical displays fulfilled AAPM performance criteria, and performance characteristics of EIZO RX850 are equal to or better than those of the Barco MDCG 5121 and EIZO GS510 displays. PMID- 26438425 TI - Phenomenologically distinct psychotomimetic effects of ketamine are associated with cerebral blood flow changes in functionally relevant cerebral foci: a continuous arterial spin labelling study. AB - RATIONALE: The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine provides a pragmatic approach to address the link between glutamate-mediated changes in brain function and psychosis-like experiences. Most studies using PET or BOLD fMRI have assessed these symptoms broadly, which may limit inference about specific mechanisms. OBJECTIVES: The objective of this study is to identify the cerebral blood flow (CBF) correlates of ketamine-induced psychopathology, focusing on individual psychotomimetic symptom dimensions, which may have separable neurobiological substrates. METHODS: We measured validated psychotomimetic symptom factors following intravenous ketamine administration in 23 healthy male volunteers (10 given a lower dose and 13 a higher dose) and correlated ketamine-induced changes in symptoms with regional changes in CBF, measured non-invasively using arterial spin labelling (ASL). RESULTS: The main effect of ketamine paralleled previous studies, with increases in CBF in anterior and subgenual cingulate cortex and decreases in superior and medial temporal cortex. Subjective effects were greater in the high-dose group. For this group, ketamine-induced anhedonia inversely related to orbitofrontal cortex CBF changes and cognitive disorganisation was positively correlated with CBF changes in posterior thalamus and the left inferior and middle temporal gyrus. Perceptual distortion was correlated with different regional CBF changes in the low- and high-dose groups. CONCLUSIONS: Here, we provide evidence for the sensitivity of ASL to the effects of ketamine and the strength of subjective experience, suggesting plausible neural mechanisms for ketamine-induced anhedonia and cognitive disorganisation. PMID- 26438426 TI - Rapid and high-efficiency generation of mature functional hepatocyte-like cells from adipose-derived stem cells by a three-step protocol. AB - The generation of functional hepatocytes is a major challenge for regenerative medicine and drug discovery. Here we show a method that facilitates generation of induced functional hepatocytes (iHeps) from adipose-derived stem cells (ADSCs) within 9 days. iHeps express hepatocytic gene programs and display functions characteristic of mature hepatocytes, including cytochrome P450 enzyme activity. Upon transplantation into mice with carbon tetrachloride (CCl4)-induced acute fulminant liver failure, iHeps restore the liver function and prolong survival. The work could contribute to the development of alternative strategies to obtain nonhepatic cell-derived mature hepatocytes with potential for biomedical and pharmaceutical applications. PMID- 26438427 TI - A computer simulation model of Wolbachia invasion for disease vector population modification. AB - BACKGROUND: Wolbachia invasion has been proved to be a promising alternative for controlling vector-borne diseases, particularly Dengue fever. Creating computer models that can provide insight into how vector population modification can be achieved under different conditions would be most valuable for assessing the efficacy of control strategies for this disease. METHODS: In this paper, we present a computer model that simulates the behavior of native mosquito populations after the introduction of mosquitoes infected with the Wolbachia bacteria. We studied how different factors such as fecundity, fitness cost of infection, migration rates, number of populations, population size, and number of introduced infected mosquitoes affect the spread of the Wolbachia bacteria among native mosquito populations. RESULTS: Two main scenarios of the island model are presented in this paper, with infected mosquitoes introduced into the largest source population and peripheral populations. Overall, the results are promising; Wolbachia infection spreads among native populations and the computer model is capable of reproducing the results obtained by mathematical models and field experiments. CONCLUSIONS: Computer models can be very useful for gaining insight into how Wolbachia invasion works and are a promising alternative for complementing experimental and mathematical approaches for vector-borne disease control. PMID- 26438428 TI - Identifying binary protein-protein interactions from affinity purification mass spectrometry data. AB - BACKGROUND: The identification of protein-protein interactions contributes greatly to the understanding of functional organization within cells. With the development of affinity purification-mass spectrometry (AP-MS) techniques, several computational scoring methods have been proposed to detect protein interactions from AP-MS data. However, most of the current methods focus on the detection of co-complex interactions and do not discriminate between direct physical interactions and indirect interactions. Consequently, less is known about the precise physical wiring diagram within cells. RESULTS: In this paper, we develop a Binary Interaction Network Model (BINM) to computationally identify direct physical interactions from co-complex interactions which can be inferred from purification data using previous scoring methods. This model provides a mathematical framework for capturing topological relationships between direct physical interactions and observed co-complex interactions. It reassigns a confidence score to each observed interaction to indicate its propensity to be a direct physical interaction. Then observed interactions with high confidence scores are predicted as direct physical interactions. We run our model on two yeast co-complex interaction networks which are constructed by two different scoring methods on a same combined AP-MS data. The direct physical interactions identified by various methods are comprehensively benchmarked against different reference sets that provide both direct and indirect evidence for physical contacts. Experiment results show that our model has a competitive performance over the state-of-the-art methods. CONCLUSIONS: According to the results obtained in this study, BINM is a powerful scoring method that can solely use network topology to predict direct physical interactions from AP-MS data. This study provides us an alternative approach to explore the information inherent in AP-MS data. The software can be downloaded from https://github.com/Zhangxf-ccnu/BINM. PMID- 26438429 TI - Are brief interventions to increase physical activity cost-effective? A systematic review. AB - OBJECTIVE: To determine whether brief interventions promoting physical activity are cost-effective in primary care or community settings. DESIGN: Systematic review of economic evaluations. METHODS AND DATA SOURCES: We searched MEDLINE, EMBASE, PsycINFO, CINAHL, EconLit, SPORTDiscus, PEDro, the Cochrane library, National Health Service Economic Evaluation Database and the Cost-Effectiveness Analysis Registry up to 20 August 2014. Web of Knowledge was used for cross reference search. We included studies investigating the cost-effectiveness of brief interventions, as defined by National Institute for Health and Care Excellence, promoting physical activity in primary care or the community. Methodological quality was assessed using Drummond's checklist for economic evaluations. Data were extracted from individual studies fulfilling selection criteria using a standardised pro forma. Comparisons of cost-effectiveness and cost-utility ratios were made between studies. RESULTS: Of 1840 identified publications, 13 studies fulfilled the inclusion criteria describing 14 brief interventions. Studies varied widely in the methods used, such as the perspective of economic analysis, intervention effects and outcome measures. The incremental cost of moving an inactive person to an active state, estimated for eight studies, ranged from L96 to L986. The cost-utility was estimated in nine studies compared with usual care and varied from L57 to L14 002 per quality-adjusted life year; dominant to L6500 per disability-adjusted life year; and L15 873 per life years gained. CONCLUSIONS: Brief interventions promoting physical activity in primary care and the community are likely to be inexpensive compared with usual care. Given the commonly accepted thresholds, they appear to be cost-effective on the whole, although there is notable variation between studies. PMID- 26438430 TI - Increased ethanol production by deletion of HAP4 in recombinant xylose assimilating Saccharomyces cerevisiae. AB - The Saccharomyces cerevisiae HAP4 gene encodes a transcription activator that plays a key role in controlling the expression of genes involved in mitochondrial respiration and reductive pathways. This work examines the effect of knockout of the HAP4 gene on aerobic ethanol production in a xylose-utilizing S. cerevisiae strain. A hap4-deleted recombinant yeast strain (B42-DHAP4) showed increased maximum concentration, production rate, and yield of ethanol compared with the reference strain MA-B42, irrespective of cultivation medium (glucose, xylose, or glucose/xylose mixtures). Notably, B42-DHAP4 was capable of producing ethanol from xylose as the sole carbon source under aerobic conditions, whereas no ethanol was produced by MA-B42. Moreover, the rate of ethanol production and ethanol yield (0.44 g/g) from the detoxified hydrolysate of wood chips was markedly improved in B42-DHAP4 compared to MA-B42. Thus, the results of this study support the view that deleting HAP4 in xylose-utilizing S. cerevisiae strains represents a useful strategy in ethanol production processes. PMID- 26438431 TI - Natural products as probes in pharmaceutical research. AB - From the start of the pharmaceutical research natural products played a key role in drug discovery and development. Over time many discoveries of fundamental new biology were triggered by the unique biological activity of natural products. Unprecedented chemical structures, novel chemotypes, often pave the way to investigate new biology and to explore new pathways and targets. This review summarizes the recent results in the area with a focus on research done in the laboratories of Novartis Institutes for BioMedical Research. We aim to put the technological advances in target identification techniques in the context to the current revival of phenotypic screening and the increasingly complex biological questions related to drug discovery. PMID- 26438433 TI - [Erratum to: Abstract-Band DOG 2015]. PMID- 26438432 TI - Rapid assay of stem cell functionality and potency using electric cell-substrate impedance sensing. AB - Regenerative medicine studies using autologous bone marrow mononuclear cells (BM MNCs) have shown improved clinical outcomes that correlate to in vitro BM-MNC invasive capacity. The current Boyden-chamber assay for testing invasive capacity is labor-intensive, provides only a single time point, and takes 36 hours to collect data and results, which is not practical from a clinical cell delivery perspective. To develop a rapid, sensitive and reproducible invasion assay, we employed Electric Cell-substrate Impedance Sensing (ECIS) technology. Chemokine directed BM-MNC cell invasion across a Matrigel-coated Transwell filter was measurable within minutes using the ECIS system we developed. This ECIS-Transwell chamber system provides a rapid and sensitive test of stem and progenitor cell invasive capacity for evaluation of stem cell functionality to provide timely clinical data for selection of patients likely to realize clinical benefit in regenerative medicine treatments. This device could also supply robust unambiguous, reproducible and cost effective data as a potency assay for cell product release and regulatory strategies. PMID- 26438434 TI - [Evaluation of the German version of the caregiver reaction assessment questionnaire for informal caregivers of patients with neovascular age-related macular degeneration]. AB - BACKGROUND: Informal caregivers of patients with loss of vision often have to give physical and emotional support because of the high level of dependence induced. Although it is known that these informal caregivers suffer a higher risk of being affected by burn-out syndrome or depression, the various dimensions of burden, especially of informal caregivers of patients with neovascular age related macular degeneration (nv-AMD) have not yet been investigated. OBJECTIVE: The objective of this study was the evaluation of the German version of the caregiver reaction assessment (CRA) questionnaire in a collective of informal caregivers of patients with nv-AMD. In this context the positive and negative influences on the informal caregivers were assessed. MATERIAL AND METHODS: Between January 2013 and July 2014 a total of 150 informal caregivers of patients with nv-AMD filled out the CRA independently using a questionnaire survey which had been translated into German. Based on this collective, the psychometric characteristics of the translated questionnaire were evaluated. RESULTS: The informal caregivers of the current collective reported a lower burden in the five subgroups disrupted schedule, lack of family support, self-esteem, health problems and financial problems, compared to the previous CRA studies with caregivers of patients with other diseases. The informal caregivers saw the greatest burden as the disruption of their schedule. Through a principal component analysis the five subgroups could be identified as five factors. It was shown that 19 out of the 24 items could be assigned to the same factors as in the original English version. The internal consistency of the five subgroups was acceptable except for the subscale on self-esteem. CONCLUSION: In this study the CRA has been confirmed as a suitable instrument to assess both positive and negative reactions of informal caregivers related to caregiving of patients with nv-AMD. The results provide support for a five subscale structure of the CRA in the original English version but five items of the questionnaire could be assigned to another subscale. PMID- 26438436 TI - Cost Analysis of Intraoperative Subareolar Frozen Section During Nipple-Sparing Mastectomy. AB - BACKGROUND: Permanent paraffin subareolar biopsy during nipple-sparing mastectomy (NSM) tests for occult cancer at the nipple-areolar complex. Intraoperative subareolar frozen section can provide earlier detection intraoperatively. Cost analysis for intraoperative subareolar frozen section has never been performed. METHODS: NSM cases from 2006-2013 were reviewed. Patient records including financial charges were analyzed. RESULTS: Of 480 subareolar biopsies for NSM from 2006-2013, 21 were abnormal (4.4 %). A total of 307 of the subareolar biopsies included intraoperative frozen section. Of the 307, 12 (3.9 %) were abnormal with 7 of 12 detected on intraoperative frozen section. The median baseline charge for an intraoperative subareolar frozen section was $309 for an estimated total cost of $94,863 in 307 breasts. The median baseline charge for interval operative resection of a nipple-areolar complex following an abnormal subareolar pathology result was $11,021. Intraoperative subareolar biopsy avoided an estimated six return trips to the operating room for savings of $66,126. At our institution, routine use of intraoperative frozen section resulted in an additional $28,737 in healthcare charges or $95 per breast. CONCLUSIONS: We present the first cost analysis to evaluate intraoperative subareolar frozen section in NSM. This practice obviated an estimated six return trips to the operating room. With our institutional frequency of abnormal subareolar pathology, intraoperative frozen sections resulted in a marginal increased charge per mastectomy. PMID- 26438437 TI - Single-Port Extra- and Transperitoneal Approach for Paraaortic Lymphadenectomy in Gynecologic Cancers: A Propensity-Adjusted Analysis. AB - BACKGROUND: Endoscopic paraaortic lymphadenectomy (PALN), an important step in the management of gynecologic cancers, is associated with low morbidity. However, some concerns exist about the completeness of PALN according to the route (transperitoneal vs. single-port extraperitoneal). METHODS: This study retrospectively reviewed the records of patients who had undergone an endoscopic PALN for a gynecologic cancer from May 2010 to August 2014 at the authors' center. The findings showed that 44 patients had a single-port extraperitoneal PALN and 56 had a transperitoneal PALN. The factors independently related to technical performances were tested with a multivariate model adjusted for a propensity score. RESULTS: A median of 16 lymph nodes were removed by the transperitoneal route and 12 by the extraperitoneal route (p = 0.04). No difference in the number of lymph nodes removed was observed after adjustment for the propensity score of patients who underwent the extraperitoneal approach (p = 0.9). The transperitoneal route was associated with more lymphocysts (20 vs. 2% for the extraperitoneal approach) (p = 0.008). The success rate for the extraperitoneal PALN was 91% (n = 40), with the three remaining patients requiring conversion to the transperitoneal route due to a peritoneal breach. CONCLUSION: This propensity-score-adjusted study supports the conclusion that the efficacy of the single-port extraperitoneal route is similar to that of the transperitoneal route for PALN. PMID- 26438438 TI - The Added Value of SPECT/CT in Sentinel Lymph Nodes Mapping for Endometrial Carcinoma. AB - OBJECTIVES: This study was designed to evaluate the detection rate (DR) and sensitivity of sentinel lymph node (SLN) mapping in patients with endometrial cancer using TC99m colloid and blue dye and to evaluate the contribution of preoperative planar lymphoscintigraphy (PLSG) and SPECT/CT. METHODS: A retrospective analysis of patients who underwent SLN mapping as part of their primary surgery for endometrial cancer. Patients underwent preoperative PLSG and later with additional SPECT/CT. Intraoperative detection was performed using TC99m colloid and blue dye by cervical injections. SLNs were sent separately for pathologic evaluation with ultrastaging. RESULTS: Fifty-three patients were included in this study. Successful preoperative mapping was achieved in 31 of 37 patients (84 %) who underwent SPECT/CT compared with only 30 of 45 patients (67 %) who underwent PLSG. SPECT/CT localizations of SLNs were anatomically accurate in 91 % of cases. Intraoperative DR of at least one SLN was 77 %, whilst the bilateral DR was 49 %. DR was significantly better using combined blue dye and TC99m colloid injections compared with blue dye alone: 81 versus 57 % for unilateral and 54 versus 28 % for bilateral mapping (P = 0.01, 0.009, respectively). Six cases of nodal metastasis were diagnosed: four by positive SLNs, and two cases were diagnosed using side-specific full dissection according to the SLN algorithm when SLN detection failed. There were no cases of false negative results. CONCLUSIONS: SLN detection using cervical injections of TC99m colloid and blue dye is feasible and sensitive for patients with endometrial cancer. SPECT/CT aids to accurate locating of the SLN. PMID- 26438435 TI - Genome-wide association study dissects genetic architecture underlying longitudinal egg weights in chickens. AB - BACKGROUND: As a major economic trait in chickens, egg weight (EW) receives widespread interests in breeding, production and consumption. However, limited information is available for underlying genetic architecture of longitudinal trend in EW. Herein, we measured EWs at nine time points from onset of laying to 60 week of age, and conducted comprehensive genome-wide association studies (GWAS) in 1,534 F2 hens derived from reciprocal crosses between White Leghorn and Dongxiang chickens. RESULTS: Egg weights at all ages except the first egg weight (FEW) exhibited high SNP-based heritability estimates (0.47~0.60). Strong pair wise genetic correlations (0.77~1.00) were found among all EWs. Nine separate univariate genome-wide screens suggested 73 signals showing significant associations with longitudinal EWs. After multivariate and conditional analyses, four variants on three chromosomes remained independent contributions. The minor alleles at two loci exerted consistent and positive substitution effects on EWs, and other two were negative. The four loci together accounted for 3.84 % of the phenotypic variance for FEW and 7.29~11.06 % for EWs from 32 to 60 week of age. We obtained five candidate genes, of which NCAPG harbors a non-synonymous SNP (rs14491030) causing a valine-to-alanine amino-acid substitution. Genome partitioning analysis indicated a strong linear correlation between the variance explained by each chromosome and its length, which provided evidence that EW follows a highly polygenic nature of inheritance. CONCLUSIONS: Identification of significant genetic causes that together implicate EWs at different ages will greatly advance our understanding of the genetic basis behind longitudinal EWs, and would be helpful to illuminate the future breeding direction on how to select desired egg size. PMID- 26438439 TI - Updated Evidence of Acellular Dermal Matrix Use for Implant-Based Breast Reconstruction: A Meta-analysis. AB - BACKGROUND: Although the use of acellular dermal matrix (ADM) has increased exponentially, debates regarding its safety are still ongoing. There have been several meta-analyses; however, potential learning curve effects of using ADM might affect their outcomes. The present meta-analysis reappraised the potential benefits and risks of ADM on the outcome of implant-based breast reconstruction using recent publications. METHODS: Electronic databases were searched to identify relevant studies comparing the outcome of ADM use with traditional submuscular technique, which were published from 2011 to 2014. The relative risks of postoperative complications and mean difference of expander dynamics between the two groups were computed. RESULTS: A total of 23 studies representing 6199 cases were analyzed. There was one randomized controlled study and three prospective cohort studies. The use of ADM significantly elevated the risks of infection, seroma, and mastectomy flap necrosis, but did not affect the risks of implant loss, unplanned reoperation, and total complications. The risks of capsular contracture and implant malposition were significantly reduced by the application of ADM. The ADM allows for significantly greater intraoperative expansion and reduced frequency of injection to complete expansion. CONCLUSIONS: According to this meta-analysis, the increasing risks for serious complication and overall morbidity related to ADM use might not be remarkable, while its benefits for preventing late complications and improving expander dynamics might be appreciable. Although future well-controlled studies would be required, the implant-based breast reconstruction using ADM may be reliable and advantageous. PMID- 26438440 TI - OSNA-Assisted Molecular Staging in Colorectal Cancer: A Prospective Multicenter Trial in Japan. AB - BACKGROUND: We previously reported that the one-step nucleic acid amplification (OSNA) assay provided a judgment performance for colorectal cancer equivalent to a 2-mm-interval histopathological examination of lymph nodes (concordance 97.1 %, n = 385 lymph nodes). In this prospective multicenter study, we uncovered an OSNA assisted pathology to detect lymph node metastasis. METHODS: A total of 204 (50 stage I, 74 stage II, and 80 stage III) colorectal cancer patients. All 4324 lymph nodes were examined by the standard histology (one-slice H&E staining) and 1925 lymph nodes (44.5 %) of them were also subject to the OSNA analysis. RESULTS: The concordance rate between 1 slice hematoxylin/eosin and OSNA assay was 95.7 % (1,842/1925 lymph nodes). The sensitivity and specificity of the OSNA assay were 86.2 % (125/145) and 96.5 % (1717/1780), respectively. Among 124 node negative patients (pN0), the respective upstaging rates of pStages I, IIA, IIB, and IIC were 2.0 % (1/50), 17.7 % (11/62), 12.5 % (1/8), and 25 % (1/4). OSNA positive patients had deeper invasion to the colonic wall and severe lymphatic invasion (P = 0.048 and P = 0.004, respectively). The sum of the quantitative results of OSNA and total tumor load increased as the number of metastasized lymph nodes increased: 1550 copies/MUL in pN0, 24,050 copies/MUL in pN1, and 90,600 copies/MUL in pN2. CONCLUSIONS: The present study on colorectal cancer provided fundamental data regarding OSNA-assisted pathology of lymph node metastasis in Japan. PMID- 26438441 TI - Complications and Postoperative Mortality Rate After Surgery for Pathological Femur Fracture Related to Bone Metastasis: Analysis of a Nationwide Database. AB - BACKGROUND: Currently, there are few reports regarding predictors of postoperative complications and short-term mortality after surgery for pathological femur fracture related to bone metastasis. METHODS: Using data from the Japanese Diagnosis Procedure Combination Database from 2007 to 2012, we retrospectively identified 1497 patients who underwent internal fixation (n = 1073) or proximal femur resection and endoprosthetic reconstruction of the proximal femur (n = 424) for pathological femur fracture related to bone metastasis. Multivariable logistic regression analysis was performed to examine the relationship of various factors with postoperative complications and 30-day mortality. RESULTS: The overall 30-day mortality after surgery was 2.6%, and the proportion of postoperative complications was 12.1%. Multivariable logistic regression analysis showed that postoperative complications overall were significantly associated with older age [odds ratio (OR), 2.15; 95% confidence interval (CI) 1.23-3.74 for age >=80 vs. <=59 years]; lung carcinoma (OR 2.05; 95% CI 1.47-2.86); esophageal carcinoma (OR 4.41; 95% CI 1.57-12.43); higher Charlson Comorbidity Index (OR 1.50; 95% CI 1.03-2.18 for >=9 vs. 8); and blood transfusion (OR 1.57; 95% CI 1.14-2.15). Thirty-day mortality also was significantly higher in patients with rapid-growth tumors, visceral metastasis, internal fixation, and no postoperative chemotherapy in the univariate analysis. CONCLUSIONS: Older age, type of primary tumor, higher Charlson Comorbidity Index, and blood transfusion were associated with higher morbidity. These findings can provide important information to assess perioperative risk in patients with pathological femur fracture related to bone metastasis. PMID- 26438442 TI - Enhanced Neurobehavioral Outcomes of Action Observation Prosthesis Training. AB - Background Previous studies have demonstrated improved neurobehavioral outcomes when prosthesis users learn task-specific behaviors by imitating movements of prosthesis users (matched limb) compared with intact limbs (mismatched limb). Objective This study is the first to use a unique combination of neurophysiological and task performance methods to investigate prosthetic device training strategies from a cognitive motor control perspective. Intact nonamputated prosthesis users (NAPUs) donned specially adapted prosthetic devices to simulate the wrist and forearm movement that persons with transradial limb loss experience. The hypothesis is that NAPUs trained with matched limb imitation would show greater engagement of parietofrontal regions and reduced movement variability compared with their counterparts trained with a mismatched limb. Methods Training elapsed over 3 days comprised alternating periods of video demonstration observation followed by action imitation. At the beginning and end of the training protocol, participants performed a cued movement paradigm while electroencephalography and electrogoniometry data were collected to track changes in cortical activity and movement variability, respectively. Results Matched limb participants showed greater engagement of motor-related areas while mismatched limb participants showed greater engagement of the parietooccipital system. Matched limb participants also showed lower movement variability. Conclusions These results indicate that the type of limb imitated influences neural and behavioral strategies for novel prosthetic device usage. This finding is important, as customary prosthetic rehabilitation with intact therapists involves mismatched limb imitation that may exacerbate challenges in adapting to new motor patterns demanded by prosthesis use. PMID- 26438443 TI - Innate Lymphoid Cells in Cancer. AB - The world of lymphocytes has recently expanded. A group of cells, innate lymphoid cells (ILC), has been defined. It includes lymphoid cells that have been known for decades, such as natural killer (NK) cells and lymphoid tissue-inducer (LTi) cells. NK cells recognize a vast array of tumor cells, which they help to eliminate through cytotoxicity and the production of cytokines, such as IFNgamma. Advances in our understanding of NK-cell biology have led to a growing interest in the clinical manipulation of these cells in cancer. The other ILCs are found mostly in the mucosae and mucosal-associated lymphoid tissues, where they rapidly initiate immune responses to pathogens without the need for specific sensitization. Here, we outline the basic features of ILCs and review the role of ILCs other than NK cells in cancer. Much of the role of these ILCs in cancer remains unknown, but several findings should lead to further efforts to dissect the contribution of different ILC subsets to the promotion, maintenance, or elimination of tumors at various anatomic sites. This will require the development of standardized reagents and protocols for monitoring the presence and function of ILCs in human blood and tissue samples. PMID- 26438444 TI - T-cell-based Immunotherapy: Adoptive Cell Transfer and Checkpoint Inhibition. AB - Tumor immunotherapy has had demonstrable efficacy in patients with cancer. The most promising results have been with T-cell-based therapies. These include adoptive cell transfer of tumor-infiltrating lymphocytes, genetically engineered T cells, and immune checkpoint inhibitor antibodies. In this review, we describe the different T-cell-based strategies currently in clinical trials and put their applications, present and future, into perspective. PMID- 26438445 TI - Theoretical and experimental studies on three new coordination complexes of Co(II), Ni(II), and Cu(II) with 2,4-dichloro-6-{(E)-[(5-chloro-2 sulfanylphenyl)imino]methyl}phenol Schiff base ligand. AB - Three mononuclear coordination complexes of Co(II), Ni(II), and Cu(II) have been synthesized from 2,4-dichloro-6-{(E)-[(5-chloro-2 sulfanylphenyl)imino]methyl}phenol ligand (H 2 L) obtained by simple condensation reaction of 3,5-dichloro-2-hydroxybenzaldehyde and 2-amino-4-chlorobenzenethiol and characterized by elemental analysis, spectral (FT-IR, electronic, and (1)H NMR), molar conductance, thermal, SEM, PXRD, and fluorescence studies. The PXRD analysis and SEM-EDX micrographs show the crystalline nature of complexes. The domain size and the lattice strain of synthesized compounds have been determined according to Williamson-Hall plot. TG of the synthesized complexes illustrates the general decomposition pattern of the complexes. The ligand exhibits an interesting fluorescence property which is suppressed after complex formation. The Co(II) complex adopted a distorted octahedral configuration while Ni(II) and Cu(II) complexes showed square planar geometry around metal center. The geometry optimization, HOMO-LUMO, molecular electrostatic potential map (MEP), and spin density of synthesized compounds have been performed by density functional theory (DFT) method using B3LYP/6-31G and B3LYP/LANL2DZ as basis set. Graphical abstract Three new coordination complexes of Co(II), Ni(II) and Cu(II) with 2,4-dichloro-6 {(E)-[(5-chloro-2 sulfanylphenyl)imino]methyl}phenol Schiff base ligand. PMID- 26438446 TI - The CO oxidation mechanism on small Pd clusters. A theoretical study. AB - CO is a pollutant that is removed by oxidation using Pd, Pt or Rh as catalysts in the exhaust pipes of vehicles. Here, a quantum chemistry study on the CO + O2 reaction catalyzed by small Pdn clusters (n <= 5) using the PBE/TZ2P/ZORA method is performed. The limiting step in this reaction at low temperature and coverage is the O2 dissociation. Pdn clusters catalyze the O=O bond breaking, reducing the energy barrier from 119 kcal mol(-1) without catalyst to ~35 kcal mol(-1). The charge transfer from Pd to the O2,ad antibonding orbital weakens, and finally breaks the O?O bond. The CO oxidation takes place by the Eley-Rideal (ER) mechanism or the Langmuir-Hinshelwood (LH) mechanism. The ER mechanism presents an energy barrier of 4.10-7.05 kcal mol(-1) and the formed CO2 is released after the reaction. The LH mechanism also shows barrier energies to produce CO2 (7-15 kcal mol(-1)) but it remains adsorbed on Pd clusters. An additional energy (7-25 kcal mol(-1)) is necessary to desorb CO2 and release the metal site. The triplet multiplicity is the ground states of studied Pdn clusters, with the following order of stability: triplet > singlet > quintet state. Graphical Abstract CO oxidation mechanism on small Pd clusters. PMID- 26438447 TI - Patchy Invasion of Stage-Structured Alien Species with Short-Distance and Long Distance Dispersal. AB - Understanding of spatiotemporal patterns arising in invasive species spread is necessary for successful management and control of harmful species, and mathematical modeling is widely recognized as a powerful research tool to achieve this goal. The conventional view of the typical invasion pattern as a continuous population traveling front has been recently challenged by both empirical and theoretical results revealing more complicated, alternative scenarios. In particular, the so-called patchy invasion has been a focus of considerable interest; however, its theoretical study was restricted to the case where the invasive species spreads by predominantly short-distance dispersal. Meanwhile, there is considerable evidence that the long-distance dispersal is not an exotic phenomenon but a strategy that is used by many species. In this paper, we consider how the patchy invasion can be modified by the effect of the long distance dispersal and the effect of the fat tails of the dispersal kernels. PMID- 26438448 TI - Non-invasive Characterization of Immune Responses to Biomedical Implants. AB - Biomedical implants play an important role in today's clinical practice. Unfortunately, biomedical implant-mediated host responses may lead to implant failure. Thus, all implants are tested for tissue compatibility prior to clinical trials. For that, after implantation in animals for different periods of time, the implants and surrounding tissues are isolated for histological analyses. Unfortunately, histological evaluation methods are labor intensive, time consuming, expensive and do not produce quantitative outcomes. With the advent of in vivo imaging technology, many imaging methods have been developed for evaluating biomedical implant-associated immune responses. In this review, we summarize the recent progress in the use of in vivo real-time imaging techniques for assessing acute phase foreign body reactions, including fibrin deposition, inflammatory cell recruitment and responses surrounding biomaterial implants. These new technologies may serve as powerful tools to characterize tissue compatibility of medical implants. PMID- 26438449 TI - Shrinking the Supply Chain for Implantable Coronary Stent Devices. AB - Stenting treatments for the management of disease in the heart, arterial and venous systems, biliary ducts, urethras, ureters, oesophageal tract and prostate have made enormous technical advances since their introduction into clinical use. The progression from metallic to polymer based bio-absorbable stents, coupled with the advances in additive manufacturing techniques, present a unique opportunity to completely re-envision the design, manufacture, and supply chain of stents. This paper looks at current stenting trends and proposes a future where the stent supply chain is condensed from ~150 days to ~20 min. The Cardiologist therefore has the opportunity to become a designer, manufacturer and user with patients receiving custom stents specific to their unique pathology that will be generated, delivered and deployed in the Cath-lab. The paper will outline this potentially revolutionary development and consider the technical challenges that will need to be overcome in order to achieve these ambitious goals. A high level overview of the generating eluting stents in situ program GENESIS-is outlined including some early experimental work. PMID- 26438450 TI - Fatigue of Metallic Stents: From Clinical Evidence to Computational Analysis. AB - The great success of stents in treating cardiovascular disease is actually undermined by their long-term fatigue failure. The high variability of stent failure incidence suggests that it is due to several correlated aspects, such as loading conditions, material properties, component design, surgical procedure, and patient functional anatomy. Numerical and experimental non-clinical assessments are included in the recommendations and requirements of several regulatory bodies and they are thus exploited in the analysis of stent fatigue performance. Optimization-based simulation methodologies have been developed as well, to improve the fatigue endurance of novel designs. This paper presents a review on the fatigue issue in metallic stents, starting from a description of clinical evidence about stent fracture up to the analysis of computational approaches available from the literature. The reported discussion on both the experimental and numerical framework aims at providing a general insight into stent lifetime prediction as well as at understanding the factors which affect stent fatigue performance for the design of novel components. PMID- 26438451 TI - Evaluation of the Early In Vivo Response of a Functionally Graded Macroporous Scaffold in an Osteochondral Defect in a Rabbit Model. AB - Cartilage tissue engineering is a multifactorial problem requiring a wide range of material property requirements from provision of biological cues to facilitation of mechanical support in load-bearing diarthrodial joints. The study aim was to design, fabricate and characterize a template to promote endogenous cell recruitment for enhanced cartilage repair. A polylactic acid poly-epsilon caprolactone (PLCL) support structure was fabricated using laser micromachining technology and thermal crimping to create a functionally-graded open pore network scaffold with a compressive modulus of 9.98 +/- 1.41 MPa and a compressive stress at 50% strain of 8.59 +/- 1.35 MPa. In parallel, rabbit mesenchymal stem cells were isolated and their growth characteristics, morphology and multipotency confirmed. Sterilization had no effect on construct chemical structure and cellular compatibility was confirmed. After four weeks implantation in an osteochondral defect in a rabbit model to assess biocompatibility, there was no evidence of inflammation or giant cells. Moreover, acellular constructs performed better than cell-seeded constructs with endogenous progenitor cells homing through microtunnels, differentiating to form neo-cartilage and strengthening integration with native tissue. These results suggest, albeit at an early stage of repair, that by modulating the architecture of a macroporous scaffold, pre seeding with MSCs is not necessary for hyaline cartilage repair. PMID- 26438452 TI - Emergency Neurologic Life Support (ENLS): Evolution of Management in the First Hour of a Neurological Emergency. AB - Emergency neurological life support (ENLS) is an educational program designed to provide users advisory instruction regarding management for the first few hours of a neurological emergency. The content of the course is divided into 14 modules, each addressing a distinct category of neurological injury. The course is appropriate for practitioners and providers from various backgrounds who work in environments of variable medical complexity. The focus of ENLS is centered on a standardized treatment algorithm, checklists to guide early patient care, and a structured format for communication of findings and concerns to other healthcare professionals. Certification and training in ENLS is hosted by the Neurocritical Care Society. This document introduces the concept of ENLS and describes the revisions that constitute this second version. PMID- 26438453 TI - Emergency Neurological Life Support: Acute Ischemic Stroke. AB - Acute ischemic stroke is a neurological emergency that can be treated with time sensitive interventions, including intravenous thrombolysis and endovascular approaches. Extensive study has demonstrated that rapid assessment and treatment are essential for improving neurological outcome. For this reason, acute ischemic stroke was chosen as an Emergency Neurological Life Support protocol. The protocol focuses on the first hour following the onset of neurological deficit. PMID- 26438454 TI - Emergency Neurological Life Support: Pharmacotherapy. AB - The appropriate use of medications during Emergency Neurological Life Support (ENLS) is essential to optimize patient care. Important considerations when choosing the appropriate agent include the patient's organ function and medication allergies, potential adverse drug effects, drug interactions, and critical illness and aging pathophysiologic changes. Critical medications used during ENLS include hyperosmolar therapy, anticonvulsants, antithrombotics, anticoagulant reversal and hemostatic agents, anti-shivering agents, neuromuscular blockers, antihypertensive agents, sedatives, vasopressors and inotropes, and antimicrobials. This article focuses on the important pharmacokinetic and pharmacodynamics characteristics, advantages and disadvantages, and clinical pearls of these therapies, providing practitioners with essential drug information to optimize pharmacotherapy in acutely ill neurocritical care patients. PMID- 26438455 TI - Emergency Neurological Life Support: Acute Non-traumatic Weakness. AB - Acute non-traumatic weakness may be life threatening if it involves the respiratory muscles or is associated with autonomic dysfunction. Most patients presenting with acute muscle weakness have a worsening neurological disorder that requires a rapid, systematic evaluation, and detailed neurological exam to localize the disorder. Urgent laboratory tests and neuroimaging are needed in many patients to make the diagnosis. Because acute weakness is a common presenting sign of neurological emergencies, it was chosen as an Emergency Neurological Life Support protocol. Causes of acute non-traumatic weakness are discussed by both presenting clinical signs and anatomical location. For each diagnosis, key features of the history, examination, investigations, and treatment are outlined in the included tables. PMID- 26438456 TI - Emergency Neurologic Life Support: Meningitis and Encephalitis. AB - Bacterial meningitis and viral encephalitis, particularly herpes simplex encephalitis, are severe neurological infections that, if not treated promptly and effectively, lead to poor neurological outcome or death. Because treatment is more effective if given early, the topic of meningitis and encephalitis was chosen as an Emergency Neurological Life Support protocol. This protocol provides a practical approach to recognition and urgent treatment of bacterial meningitis and encephalitis. Appropriate imaging, spinal fluid analysis, and early empiric treatment is discussed. Though uncommon in its full form, the typical clinical triad of headache, fever, and neck stiffness should alert the clinical practitioner to the possibility of a central nervous system infection. Early attention to the airway and maintaining normotension is crucial in treatment of these patients, as is rapid treatment with anti-infectives and, in some cases, corticosteroids. PMID- 26438458 TI - Emergency Neurologic Life Support: Spinal Cord Compression. AB - There are many causes of acute myelopathy including multiple sclerosis, systemic disease (SD), and acute spinal cord compression (SCC). SCC should be among the first potential causes considered given the significant permanent loss of neurologic function commonly associated with SCC. This impairment can occur over a short period of time, and may be avoided through rapid and acute surgical intervention. Patients with SCC typically present with a combination of motor and sensory dysfunction that has a distribution referable to a spinal level. Bowel and bladder dysfunction and neck or back pain may also be part of the clinical presentation, but are not uniformly present. Because interventions are critically time-sensitive, the recognition and treatment of SCC was chosen as an ENLS protocol. PMID- 26438457 TI - Emergency Neurological Life Support: Airway, Ventilation, and Sedation. AB - Airway management and ventilation are central to the resuscitation of the neurologically ill. These patients often have evolving processes that threaten the airway and adequate ventilation. Furthermore, intubation, ventilation, and sedative choices directly affect brain perfusion. Therefore, airway, ventilation, and sedation was chosen as an emergency neurological life support protocol. Topics include airway management, when and how to intubate with special attention to hemodynamics and preservation of cerebral blood flow, mechanical ventilation settings, and the use of sedative agents based on the patient's neurological status. PMID- 26438459 TI - Emergency Neurological Life Support: Intracranial Hypertension and Herniation. AB - Sustained intracranial hypertension and acute brain herniation are "brain codes," signifying catastrophic neurological events that require immediate recognition and treatment to prevent irreversible injury and death. As in cardiac arrest, a brain code mandates the organized implementation of a stepwise management algorithm. The goal of this emergency neurological life support protocol is to implement an evidence-based, standardized approach to the evaluation and management of patients with intracranial hypertension and/or herniation. PMID- 26438460 TI - Emergency Neurological Life Support: Traumatic Spine Injury. AB - Traumatic spine injuries (TSIs) carry significantly high risks of morbidity, mortality, and exorbitant health care costs from associated medical needs following injury. For these reasons, TSI was chosen as an ENLS protocol. This article offers a comprehensive review on the management of spinal column injuries using the best available evidence. Alhough the review focuses primarily on cervical spinal column injuries, thoracolumbar injuries are briefly discussed as well. The initial emergency department clinical evaluation of possible spinal fractures and cord injuries, along with the definitive early management of confirmed injuries, is also covered. PMID- 26438461 TI - Emergency Neurological Life Support: Intracerebral Hemorrhage. AB - Intracerebral hemorrhage (ICH) is a subset of stroke due to bleeding within the parenchyma of the brain. It is potentially lethal, and survival depends on ensuring an adequate airway, reversal of coagulopathy, and proper diagnosis. ICH was chosen as an Emergency Neurological Life Support protocol because intervention within the first critical hour may improve outcome, and it is critical to have site-specific protocols to drive care quickly and efficiently. PMID- 26438462 TI - Emergency Neurological Life Support: Status Epilepticus. AB - Patients with prolonged or rapidly recurring convulsions lasting more than 5 min are in status epilepticus (SE) and require immediate resuscitation. Although there are relatively few randomized clinical trials, available evidence and experience suggest that early and aggressive treatment of SE improves patient outcomes, for which reason this was chosen as an Emergency Neurological Life Support protocol. The current approach to the emergency treatment of SE emphasizes rapid initiation of adequate doses of first-line therapy, as well as accelerated second-line anticonvulsant drugs and induced coma when these fail, coupled with admission to a unit capable of neurological critical care and electroencephalography monitoring. This protocol will focus on the initial treatment of SE but also review subsequent steps in the protocol once the patient is hospitalized. PMID- 26438464 TI - Emergency Neurological Life Support: Approach to the Patient with Coma. AB - Coma is an acute failure of neuronal systems governing arousal and awareness and represents a medical emergency. When encountering a comatose patient, the clinician must have an organized approach to detect easily remediable causes, prevent ongoing neurologic injury, and determine a hierarchical plan for diagnostic tests, treatments, and neuromonitoring. Coma was chosen as an Emergency Neurological Life Support protocol because timely medical and surgical interventions can be life-saving, and the initial work-up of such patients is critical to establishing a correct diagnosis. PMID- 26438463 TI - Emergency Neurological Life Support: Resuscitation Following Cardiac Arrest. AB - Cardiac arrest is the most common cause of death in North America. Neurocritical care interventions, including targeted temperature management (TTM), have significantly improved neurological outcomes in patients successfully resuscitated from cardiac arrest. Therefore, resuscitation following cardiac arrest was chosen as an emergency neurological life support protocol. Patients remaining comatose following resuscitation from cardiac arrest should be considered for TTM. This protocol will review induction, maintenance, and re warming phases of TTM, along with management of TTM side effects. Aggressive shivering suppression is necessary with this treatment to ensure the maintenance of a target temperature. Ancillary testing, including electrocardiography, computed tomography and/or magnetic resonance imaging of the brain, continuous electroencephalography monitoring, and correction of electrolyte, blood gas, and hematocrit changes, are also necessary to optimize outcomes. PMID- 26438465 TI - Emergency Neurological Life Support: Subarachnoid Hemorrhage. AB - Subarachnoid hemorrhage (SAH) is a neurological emergency because it may lead to sudden neurological decline and death and, depending on the cause, has treatment options that can return a patient to normal. Because there are interventions that can be life-saving in the first hour of onset, SAH was chosen as an Emergency Neurological Life Support protocol. PMID- 26438466 TI - Emergency Neurological Life Support: Traumatic Brain Injury. AB - Traumatic Brain Injury (TBI) was chosen as an Emergency Neurological Life Support topic due to its frequency, the impact of early intervention on outcomes for patients with TBI, and the need for an organized approach to the care of such patients within the emergency setting. This protocol was designed to enumerate the practice steps that should be considered within the first critical hour of neurological injury. PMID- 26438467 TI - CSF Volumetric Analysis for Quantification of Cerebral Edema After Hemispheric Infarction. AB - BACKGROUND: Malignant cerebral edema (CED) complicates at least 20 % of large hemispheric infarcts (LHI) and may result in neurological deterioration or death. Midline shift (MLS) is a standard but crude measure of edema severity. We propose that volumetric analysis of shifts in cerebrospinal fluid (CSF) over time provides a reliable means of quantifying the spectrum of edema severity after LHI. METHODS: We identified 38 patients from 2008 to 2014 with NIHSS >=8, baseline CT <6 h after stroke onset, at least 1 follow-up (FU) CT, and no parenchymal hematoma. The volumes of CSF (sulci, ventricles, and cisterns) ipsilateral (IL) and contralateral (CL) to infarct on baseline and FU CTs were quantified by manually assisted outlining with MIPAV image analysis software, as was infarct volume and MLS on FU CTs. Percentage change in CSF volumes (?CSF) from baseline to FU scans was correlated with MLS and compared in those with vs. without malignant edema (defined as hemicraniectomy, osmotic therapy, or death/neurological deterioration with MLS >=5 mm). RESULTS: 11 of 38 subjects (29 %) developed malignant edema. Neither baseline NIHSS nor CSF volume differed between those with and without edema (median NIHSS 18 vs. 13, p = 0.12, CSF volume 102 vs. 124 ml, p = 0.16). Inter-rater reliability for CSF measurements was excellent (intraclass correlation coefficient 0.97). ?CSF correlated strongly with MLS at peak edema (r = -0.75), even adjusting for infarct volume (p = 0.009). ?CSF was also greater in those with malignant edema [-55 % (IQR -49 to 62) vs. -36 % (-27 to -45), p = 0.004]. ?CSF was the greatest within IL sulci [ 97 % (-86 to -99) vs. -71 % (-41 to -79), p = 0.002] but also significantly greater within CL sulci in those with malignant edema [-50 % (-29 to -65) vs. -25 % (0 to -31), p = 0.014]. More than half this CSF volume reduction occurred by the time of first FU CT around 24 h after stroke, while MLS rose later. CONCLUSIONS: Volumetric CSF analysis reliably quantifies CED and distinguishes those with malignant edema and MLS from those with a more benign course after LHI. ?CSF may provide an earlier and more sensitive indicator of edema severity across a broader dynamic range than MLS. PMID- 26438468 TI - Changes in Depression Subtypes Among Men in STAR*D: A Latent Transition Analysis. AB - The burden of depression in men is high. Current diagnostic criteria may not fully capture men's experience with depression. Descriptions of the heterogeneity in depression among men are lacking. The purpose of the study was to characterize latent subtypes of major depression and changes in these subtypes among men receiving citalopram in Level 1 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Latent transition analysis was applied to data from 387 men who completed baseline and Week 12 study visits in Level 1 of STAR*D. Items from the self-report version of the Quick Inventory of Depressive Symptomatology were used as indicators of latent depression subtypes. Four statuses were identified at baseline and Week 12. Baseline statuses were Mild (10% of men), Moderate (53%), Severe with Psychomotor Slowing (20%), and Severe with Psychomotor Agitation (17%). At Week 12, the statuses were Symptom Resolution (41%), Mild (36%), Moderate (18%), and Severe with Psychomotor Slowing (5%). Men in the Mild status were most likely to transition to Symptom Resolution (probability = 69%). Men in the Severe with Agitation status were least likely to transition to Symptom Resolution (probability = 0%). This work highlights the need to not focus solely on summary rating scores but to also consider patterns of symptoms when treating depression. PMID- 26438469 TI - Falls and Depression in Men: A Population-Based Study. AB - The link between falls and depression has been researched in the elderly; however, little information is available on this association in younger adults, particularly men. This study sought to investigate the link between major depressive disorder (MDD) and falls in a population-based sample of 952 men (24 97 years). MDD was diagnosed utilizing the Structured Clinical Interview for DSM IV-TR Research Version, Non-Patient edition, and categorized as 12 month/past/never. Body mass index and gait were measured; falls, smoking status, psychotropic medication use, and alcohol intake were self-reported as part of the Geelong Osteoporosis Study 5-year follow-up assessment. Thirty-four (3.6%) men met criteria for 12-month MDD, and 110 (11.6%) for past MDD. Of the 952 men, 175 (18.4%) reported falling at least once during the past 12 months. Fallers were older (66 [interquartile range: 48-79] vs. 59 [45-72] years, p = .001) and more likely to have uneven gait ( n = 16, 10% vs. n = 31, 4%, p = .003) than nonfallers. Participants with 12-month MDD had more than twice the odds of falling (age-adjusted odds ratio: 2.22, 95% confidence interval [1.03, 4.80]). The odds of falling were not associated with past depression ( p = .4). Further adjustments for psychotropic drug use, gait, body mass index, smoking status, blood pressure, and alcohol did not explain these associations. Given the 2.2 fold greater likelihood of falling associated with depression was not explained by age or psychotropic drug use, further research is warranted. PMID- 26438471 TI - The Effect of Testosterone Topical Solution in Hypogonadal Men With Suboptimal Response to a Topical Testosterone Gel. AB - This study evaluated the effect of axillary administration of a 2% testosterone solution (Axiron(r)) in hypogonadal (HGN) men who had had a suboptimal response to treatment with a commercially available topical testosterone gel. HGN men averaging 57 years old, with a mean body mass index of 31.9 kg/m2 and median baseline testosterone level (T-level) of 185.2 ng/dL, who had failed to reach normal T-levels with a topical testosterone gel (Androgel 1.62%, Androgel, Testim, or Fortesta) were treated with a 2% testosterone solution until T-levels reached a normal range (from >=300 to <=1,050 ng/dL) or for up to 9 weeks. Outcomes included the cumulative percentage of men with a serum T-level in the normal range during treatment with Axiron and improvement in symptoms of low energy level and low sexual drive. During the study, 95% of HGN men (72/78) attained a T-level in the normal range. The median T-level at endpoint was 495.7 ng/dL, a threefold increase over baseline, p < .001, 70% achieving normal T levels within the first 2 weeks of treatment. In a post hoc analysis, all subjects with baseline body mass indexes >35 kg/m2 ( n = 19) achieved T-levels in the normal range. Prior to treatment, over 61% of subjects (48/78) reported impairment in either energy level or sexual drive. After treatment (or testosterone normalization), energy level improved in 75% of subjects and sexual drive improved in 70%. Topical 2% testosterone solution is a safe and effective treatment for HGN men who have had a suboptimal response to previous treatment with topical testosterone gels. PMID- 26438470 TI - Transactional Sex With Regular and Casual Partners Among Young Men Who Have Sex With Men in the Detroit Metro Area. AB - Transactional sex refers to the commodification of the body in exchange for shelter, food, and other goods and needs. Transactional sex has been associated with negative health outcomes including HIV infection, psychological distress, and substance use and abuse. Compared with the body of research examining transactional sex among women, less is known about the prevalence and correlates of transactional sex among men. Using data from a cross-sectional survey of young men who have sex with men (ages 18-29) living in the Detroit Metro Area ( N = 357; 9% HIV infected; 49% Black, 26% White, 16% Latino, 9% Other race), multivariate logistic regression analyses examined the association between transactional sex with regular and casual partners and key psychosocial factors (e.g., race/ethnicity, education, poverty, relationship status, HIV status, prior sexually transmitted infections [STIs], mental health, substance use, and residential instability) previously identified in the transactional sex literature. Forty-four percent of the current sample reported engaging in transactional sex. Transactional sex was associated with age, employment status, relationship status, and anxiety symptoms. When stratified, transactional sex with a regular partner was associated with age, educational attainment, employment status, relationship status, anxiety, and alcohol use. Transactional sex with a casual partner was associated with homelessness, race/ethnicity, employment status, and hard drug use. The implications of these findings for HIV/STI prevention are discussed, including the notion that efforts to address HIV/STIs among young men who have sex with men may require interventions to consider experiences of transactional sex and the psychosocial contexts that may increase its likelihood. PMID- 26438472 TI - Comparative study of 13C composition in ethanol and bulk dry wine using isotope ratio monitoring by mass spectrometry and by nuclear magnetic resonance as an indicator of vine water status. AB - The potential of wine (13)C isotope composition (delta(13)C) is presented to assess vine water status during grape ripening. Measurements of delta(13)C have been performed on a set of 32 authentic wines and their ethanol recovered after distillation. The data, obtained by isotope ratio monitoring by mass spectrometry coupled to an elemental analyser (irm-EA/MS), show a high correlation between delta(13)C of the bulk wine and its ethanol, indicating that the distillation step is not necessary when the wine has not been submitted to any oenological treatment. Therefore, the ethanol/wine delta(13)C correlation can be used as an indicator of possible enrichment of the grape must or the wine with exogenous organic compounds. Wine ethanol delta(13)C is correlated to predawn leaf water potential (R(2) = 0.69), indicating that this parameter can be used as an indicator of vine water status. Position-specific (13)C analysis (PSIA) of ethanol extracted from wine, performed by isotope ratio monitoring by nuclear magnetic resonance (irm-(13)C NMR), confirmed the non-homogenous repartition of (13)C on ethanol skeleton. It is the delta(13)C of the methylene group of ethanol, compared to the methyl moiety, which is the most correlated to predawn leaf water potential, indicating that a phase of photorespiration of the vine during water stress period is most probably occurring due to stomata closure. However, position-specific (13)C analysis by irm-(13)C NMR does not offer a greater precision in the assessment of vine water status compared to direct measurement of delta(13)C on bulk wine by irm-EA/MS. PMID- 26438473 TI - Accelerated separation of GC-amenable lipid classes in plant oils by countercurrent chromatography in the co-current mode. AB - Triacylglycerols represent the major part (>90%) in most plant oils and have to be eliminated, when the minor compounds such as phytosterols or tocopherols should be analyzed. Here, we used an all liquid-liquid chromatographic technique, countercurrent chromatography (CCC), to fractionate the minor lipids before gas chromatography (GC) analysis. To cover the wide range of polarity of the minor compounds, we used the co-current mode, in which both mobile and stationary phase are pumped through the system. This allowed to elute substances which partitioned almost exclusively in the stationary phase within 90 min. After testing with standard compounds, the method was applied to the separation of sesame oil and sunflower oil samples. The abundant triacylglycerols could be effectively separated from tocopherols, phytosterols, diacylglycerols, and free fatty acids in the samples, and these compounds could be analyzed (after trimethylsilylation) by GC coupled with mass spectrometry. After the enrichment caused by the CCC fractionation, we were also able to identify the tocopherol derivative alpha tocomonoenol, which had not been described in sunflower oil before. Also, separation of sesame oil yielded a mixture of the polar compounds sesamin and sesamolin without further impurities. PMID- 26438475 TI - Introduction of regulations for arsenic in feed and food with emphasis on inorganic arsenic, and implications for analytical chemistry. PMID- 26438476 TI - Nanospectroscopy. PMID- 26438477 TI - MC ICP-MS delta(34)S(VCDT) measurement of dissolved sulfate in environmental aqueous samples after matrix separation by means of an anion exchange membrane. AB - Analysis of (34)S/(32)S of sulfate in rainwater and soil solutions can be seen as a powerful tool for the study of the sulfur cycle. Therefore, it is considered as a useful means, e.g., for amelioration and calibration of ecological or biogeochemical models. Due to several analytical limitations, mainly caused by low sulfate concentration in rainwater, complex matrix of soil solutions, limited sample volume, and high number of samples in ecosystem studies, a straightforward analytical protocol is required to provide accurate S isotopic data on a large set of diverse samples. Therefore, sulfate separation by anion exchange membrane was combined with precise isotopic measurement by multicollector inductively coupled plasma mass spectrometry (MC ICP-MS). The separation method proved to be able to remove quantitatively sulfate from matrix cations (Ca, K, Na, or Li) which is a precondition in order to avoid a matrix-induced analytical bias in the mass spectrometer. Moreover, sulfate exchange on the resin is capable of preconcentrating sulfate from low concentrated solutions (to factor 3 in our protocol). No significant sulfur isotope fractionation was observed during separation and preconcentration. MC ICP-MS operated at edge mass resolution has enabled the direct (34)S/(32)S analysis of sulfate eluted from the membrane, with an expanded uncertainty U (k = 2) down to 0.3 0/00 (a single measurement). The protocol was optimized and validated using different sulfate solutions and different matrix compositions. The optimized method was applied in a study on solute samples retrieved in a beech (Fagus sylvatica) forest in the Vienna Woods. Both rainwater (precipitation and tree throughfall) and soil solution delta (34)SVCDT ranged between 4 and 6 0/00, the ratio in soil solution being slightly lower. The lower ratio indicates that a considerable portion of the atmospherically deposited sulfate is cycled through the organic S pool before being released to the soil solution. Nearly the same trends and variations were observed in soil solution and rainwater delta (34)SVCDT values showing that sulfate adsorption/desorption are not important processes in the studied soil. PMID- 26438478 TI - Real-time cdPCR opens a window into events occurring in the first few PCR amplification cycles. AB - Polymerase chain reaction (PCR) end-point limiting dilution techniques, collectively termed "digital PCR (dPCR)", have been proposed as providing a potentially primary method for DNA quantification. We are evaluating several commercially available dPCR systems for use in certifying mass concentration in human genomic DNA reference materials. To better understand observed anomalies among results from chamber- and droplet-dPCR (cdPCR and ddPCR) systems, we have developed a graphical tool for evaluating and documenting the performance of PCR assays in real-time cdPCR systems: the ogive plot, the cumulative distribution of crossing threshold values. The ogive structure appears to embed information about early amplification events. We have successfully simulated ogives observed with different assays and reaction conditions using a four-stage amplification model parameterized by the probability of creating an intact 1) first generation "long" amplicon of indeterminate length from an original DNA target, 2) second generation defined-length amplicon from a long amplicon, and 3) defined-length amplicon from another defined-length amplicon. We are using insights from this model to optimize dPCR assay design and reaction conditions and to help validate assays proposed for use in value-assigning DNA reference materials. PMID- 26438479 TI - IL-1beta promotes ADAMTS enzyme-mediated aggrecan degradation through NF-kappaB in human intervertebral disc. AB - BACKGROUND: The purpose of this study is to investigate IL-1beta regulation of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-4 and ADAMTS 5) expression through nuclear factor kappa B (NF-kappaB) in human nucleus pulposus (NP) cells. METHODS: qRT-PCR and Western blot were used to measure ADAMTS expression. Transfections and gene silencing were used to determine the role of NF-kappaB on cytokine-mediated ADAMTS expression and its role in aggrecan degradation. RESULTS: IL-1beta increased ADAMTS expression in NP cells. Treatment with NF-kappaB inhibitors abolished the inductive effect of the cytokines on ADAMTS expression. Silencing of p65 confirmed their role in IL-1beta-dependent ADAMTS-4 and ADAMTS-5 expression and aggrecan degradation. CONCLUSIONS: By controlling the activation of NF-kappaB signaling, IL-1beta modulates the expression of ADAMTS in NP cells. To our knowledge, this is the first study that shows the contribution of both ADAMTS-4 and ADAMTS-5 to aggrecan degradation in human NP cells. PMID- 26438480 TI - Minimally Invasive Resection of Colorectal Cancer Liver Metastases Leads to an Earlier Initiation of Chemotherapy Compared to Open Surgery. AB - INTRODUCTION: Previous studies have shown benefit not only from postoperative chemotherapy but also from a short interval to initiation of treatment after resection of primary colorectal cancer. The aim of this study was to determine difference in timing to postoperative chemotherapy for minimally invasive resection (MIR) vs. open resection (OR) of colorectal cancer liver metastases (CRCLM). METHODS: This is a retrospective review of 1:1 matched patients undergoing MIR (n = 66) and OR (n = 66) for CRCLM at a single institution. RESULTS: Patients undergoing MIR of CRCLM had significantly shorter length of hospital stay, fewer major complications, and shorter interval to postoperative chemotherapy (median 42 vs. 63 days, p < 0.001). Univariable analysis showed that surgical approach, postoperative complications, blood loss, number of lesions, and length of stay were associated with timing to chemotherapy. On multivariable analysis, surgical approach was still associated with timing to chemotherapy, and postoperative complications resulted in a delay of chemotherapy among patients who underwent OR but not among those who underwent MIR. In addition, worse disease-free survival was seen among patients who received postoperative chemotherapy more than 60 days after surgery. CONCLUSION: By modifying the deleterious effects of postoperative complications on timing of postoperative chemotherapy, patients undergoing MIR for CRCLM are treated with chemotherapy sooner after surgery compared to those undergoing OR. PMID- 26438481 TI - Intra-gastric Ectopic Splenic Tissue. AB - A 40-year-old man presented with a 3-year duration of intermittent upper abdominal pain. Gastroscopy and endoscopic ultrasonography revealed a tumor in the bottom of the stomach with a homogenous low echogenicity that originated from the gastric serosa. An abdominal contrast-enhanced computed tomography (CT) scan showed that a well-marginated ovoid mass was obviously enhanced homogenously in the arterial period and weakened slightly in the venous period. The diagnosis of a gastric stromal tumor was made. Laparoscopic resection of the gastric tumor was subsequently performed. Surprisingly, postoperative pathological examination of the mass showed the typical structure of a normal splenic tissue. To our knowledge, ectopic splenic tissue originating from the gastric serosa is reported for the first time, showing important clinical significance for the identification of gastric malignant tumors. PMID- 26438482 TI - Prevention of Postoperative Bile Leak in Partial Cystectomy for Hydatid Liver Disease: Tricks of the Trade. AB - BACKGROUND: The presence of postoperative bile leak is the major outcome measure for the assessment of operative success in partial cystectomy for hydatid liver disease. However, the optimal operative strategy to reduce the postoperative bile leak rate is yet to be defined. METHODS: Medical records of patients who underwent partial cystectomy for hydatid liver disease between January 2013 and January 2015 were reviewed in this retrospective analysis. All patients were managed with a specific operative protocol. The primary outcome measure was the rate of persistent postoperative bile leak. The secondary outcome measures were the morbidity and mortality rate, and the length of hospital stay. RESULTS: Twenty-eight patients were included in the study. Only one patient (3.6 %) developed persistent postoperative bile leak. The overall morbidity and mortality rate was 17.8 and 0 %, respectively. The median length of hospital stay was 5 days. CONCLUSION: Aggressive preventative surgical measures have led to low persistent bile leak rates with low morbidity and mortality. PMID- 26438483 TI - Reply to the Letter to the Editor Regarding Manuscript Entitled: "Feasibility of Fast-Track Surgery in Gastrectomy for Elderly Patients with Gastric Cancer". PMID- 26438484 TI - Outcomes Improvement Is Not Continuous Along the Learning Curve for Pancreaticoduodenectomy at the Hospital Level. AB - BACKGROUND: Most studies on learning curves for pancreaticoduodenectomy have been based on single-surgeon series at tertiary academic centers or are inferred indirectly from volume-outcome relationships. Our aim is to describe mortality rates associated with cumulative surgical experience among non-teaching hospitals. STUDY DESIGN: Observational study of a statewide inpatient database. Analysis included hospitals that began performing pancreaticoduodenectomy between 1996 and 2010, as captured by the California Office of Statewide Health Planning and Development database. Cases were numbered sequentially within each hospital. The same sequential series (e.g., first 10 cases, 11th through 20th cases) were identified across hospitals. The outcome measure was in-hospital mortality. RESULTS: A total of 1210 cases from 143 non-teaching hospitals were analyzed. The average age was 63 years old, and the majority of patients were non-Hispanic white. The median overall mortality rate was 9.75 %. The mortality rate for the first 10 aggregated cases was 11.3 %. This improved for subsequent cases, reaching 7.1 % for the 21st-30th cases. However, the mortality rate then increased, reaching 16.7 % by the 41st-50th cases before falling to 0.0 % by the 61st-70th cases. CONCLUSIONS: Initial improvement in surgical outcomes relative to cumulative surgical experience is not sustained. It is likely that factors other than surgical experience affect outcomes, such as less rigorous assessment of comorbidities or changes in support services. Vigilance regarding outcomes should be maintained even after initial improvements. PMID- 26438485 TI - Hepatic Resection Improved the Long-Term Survival of Patients with BCLC Stage B Hepatocellular Carcinoma: a Letter to Response. PMID- 26438486 TI - Pain and Mortality Risk in a Cohort of HIV-Infected Persons with Alcohol Use Disorders. AB - Pain has been associated with increased risk for mortality in some studies. We analyzed data from a cohort study [HIV-longitudinal interrelationships of viruses and ethanol (HIV-LIVE)] of HIV-infected persons with alcohol use disorders enrolled 2001-2003 to explore whether reporting moderate or greater pain interference was associated with mortality. The main independent variable was pain that at least moderately interfered with work based on a single question from the SF-12. Primary analyses dichotomized at "moderately" or above. Cox proportional hazards models assessed the association between pain interference and death adjusting for demographics, substance use, CD4 count, HIV viral load and co-morbidities. Although significant in unadjusted models (HR = 1.58 (95 % CI 1.03-2.41; p value = 0.04)), after adjusting for confounders, >=moderate pain interference was not associated with an increased risk of death [aHR = 1.30 (95 % CI 0.81-2.11, p value = 0.28)]. Among HIV-infected persons with alcohol use disorders, we did not detect a statistically significant independent association between pain interference and risk of death after adjustment for potential confounders. PMID- 26438487 TI - Accuracy and Acceptability of Oral Fluid HIV Self-Testing in a General Adult Population in Kenya. AB - We evaluated performance, accuracy, and acceptability parameters of unsupervised oral fluid (OF) HIV self-testing (HIVST) in a general population in western Kenya. In a prospective validation design, we enrolled 240 adults to perform rapid OF HIVST and compared results to staff administered OF and rapid fingerstick tests. All reactive, discrepant, and a proportion of negative results were confirmed with lab ELISA. Twenty participants were video-recorded conducting self-testing. All participants completed a staff administered survey before and after HIVST to assess attitudes towards OF HIVST acceptability. HIV prevalence was 14.6 %. Thirty-six of the 239 HIVSTs were invalid (15.1 %; 95 % CI 11.1-20.1 %), with males twice as likely to have invalid results as females. HIVST sensitivity was 89.7 % (95 % CI 73-98 %) and specificity was 98 % (95 % CI 89-99 %). Although sensitivity was somewhat lower than expected, there is clear interest in, and high acceptability (94 %) of OF HIV self-testing. PMID- 26438488 TI - Molecular Cloning and Biochemical Characterization of the Iron Superoxide Dismutase from the Cyanobacterium Nostoc punctiforme ATCC 29133 and Its Response to Methyl Viologen-Induced Oxidative Stress. AB - Superoxide dismutase (SOD) detoxifies cell-toxic superoxide radicals and constitutes an important component of antioxidant machinery in aerobic organisms, including cyanobacteria. The iron-containing SOD (SodB) is one of the most abundant soluble proteins in the cytosol of the nitrogen-fixing cyanobacterium Nostoc punctiforme ATCC 29133, and therefore, we investigated its biochemical properties and response to oxidative stress. The putative SodB-encoding open reading frame Npun_R6491 was cloned and overexpressed in Escherichia coli as a C terminally hexahistidine-tagged protein. The purified recombinant protein had a SodB specific activity of 2560 +/- 48 U/mg protein at pH 7.8 and was highly thermostable. The presence of a characteristic iron absorption peak at 350 nm, and its sensitivity to H2O2 and azide, confirmed that the SodB is an iron containing SOD. Transcript level of SodB in nitrogen-fixing cultures of N. punctiforme decreased considerably (threefold) after exposure to an oxidative stress-generating herbicide methyl viologen for 4 h. Furthermore, in-gel SOD activity analysis of such cultures grown at increasing concentrations of methyl viologen also showed a loss of SodB activity. These results suggest that SodB is not the primary scavenger of superoxide radicals induced by methyl viologen in N. punctiforme. PMID- 26438489 TI - Comparison of the EUCAST and CLSI Broth Microdilution Methods for Testing Isavuconazole, Posaconazole, and Amphotericin B against Molecularly Identified Mucorales Species. AB - We compared EUCAST and CLSI antifungal susceptibility testing (AFST) methods for triazoles and amphotericin B against 124 clinical Mucorales isolates. The EUCAST method yielded MIC values 1- to 3-fold dilutions higher than those of the CLSI method for amphotericin B. The essential agreements between the two methods for triazoles were high, i.e., 99.1% (voriconazole), 98.3% (isavuconazole), and 87% (posaconazole), whereas it was significantly lower for amphotericin B (66.1%). Strategies for harmonization of the two methods for Mucorales AFST are warranted. PMID- 26438490 TI - Acquired Multidrug Antifungal Resistance in Candida lusitaniae during Therapy. AB - Candida lusitaniae is usually susceptible to echinocandins. Beta-1,3-glucan synthase encoded by FKS genes is the target of echinocandins. A few missense mutations in the C. lusitaniae FKS1 hot spot 1 (HS1) have been reported. We report here the rapid emergence of antifungal resistance in C. lusitaniae isolated during therapy with amphotericin B (AMB), caspofungin (CAS), and azoles for treatment of persistent candidemia in an immunocompromised child with severe enterocolitis and visceral adenoviral disease. As documented from restriction fragment length polymorphism (RFLP) and random amplified polymorphic DNA (RAPD) analysis, the five C. lusitaniae isolates examined were related to each other. From antifungal susceptibility and molecular analyses, 5 different profiles (P) were obtained. These profiles included the following: profile 1 (P1) (CAS MIC [MUg/ml], 0.5; fluconazole [FLC] MIC, 0.25), determined while the patient was being treated with liposomal AMB for 3 months; P2 (FLC MIC [MUg/ml], 0.25; CAS MIC, 4), while the patient was being treated with CAS for 2 weeks; P3 (CAS MIC [MUg/ml], 0.5; FLC MIC, 32), while the patient was being treated with azoles and CAS initially followed by azoles alone for a week; P4 (CAS MIC [MUg/ml], 8; FLC MIC, 8), while the patient was being treated with both drugs for 3 weeks; and P5 (AMB MIC [MUg/ml], 0.125; CAS MIC, 8), while the patient was being treated with AMB and FLC for 2 weeks. CAS resistance was associated with resistance not only to micafungin and anidulafungin but also to AMB. Analysis of CAS resistance revealed 3 novel FKS1 mutations in CAS-resistant isolates (S638Y in P2; S631Y in P4; S638P in P5). While S638Y and -P are within HS1, S631Y is in close proximity to this domain but was confirmed to confer candin resistance using a site directed mutagenesis approach. FLC resistance could be linked with overexpression of major facilitator gene 7 (MFS7) in C. lusitaniae P2 and P4 and was associated with resistance to 5-flurocytosine. This clinical report describes resistance of C. lusitaniae to all common antifungals. While candins or azole resistance followed monotherapy, multidrug antifungal resistance emerged during combined therapy. PMID- 26438491 TI - Roflumilast, a Type 4 Phosphodiesterase Inhibitor, Shows Promising Adjunctive, Host-Directed Therapeutic Activity in a Mouse Model of Tuberculosis. AB - With phosphodiesterase inhibitors (PDE-Is) showing significant promise in shortening tuberculosis treatment, we assessed the effect of roflumilast, an FDA approved type 4 PDE-I, in both acute and chronic murine models of tuberculosis. Alone, roflumilast had no effect on lung bacillary burden and mortality. However, when roflumilast was used in combination with isoniazid, a reduction in lung bacillary burden was observed. These data suggest that roflumilast may be a good candidate for tuberculosis host-directed therapy (HDT). PMID- 26438492 TI - Clonal Dissemination of Enterobacter cloacae Harboring blaKPC-3 in the Upper Midwestern United States. AB - Carbapenemase-producing, carbapenem-resistant Enterobacteriaceae, or CP-CRE, are an emerging threat to human and animal health, because they are resistant to many of the last-line antimicrobials available for disease treatment. Carbapenemase producing Enterobacter cloacae harboring blaKPC-3 recently was reported in the upper midwestern United States and implicated in a hospital outbreak in Fargo, North Dakota (L. M. Kiedrowski, D. M. Guerrero, F. Perez, R. A. Viau, L. J. Rojas, M. F. Mojica, S. D. Rudin, A. M. Hujer, S. H. Marshall, and R. A. Bonomo, Emerg Infect Dis 20:1583-1585, 2014, http://dx.doi.org/10.3201/eid2009.140344). In early 2009, the Minnesota Department of Health began collecting and screening CP-CRE from patients throughout Minnesota. Here, we analyzed a retrospective group of CP-E. cloacae isolates (n = 34) collected between 2009 and 2013. Whole genome sequencing and analysis revealed that 32 of the strains were clonal, belonging to the ST171 clonal complex and differing collectively by 211 single nucleotide polymorphisms, and it revealed a dynamic clone under positive selection. The phylogeography of these strains suggests that this clone existed in eastern North Dakota and western Minnesota prior to 2009 and subsequently was identified in the Minneapolis and St. Paul metropolitan area. All strains harbored identical IncFIA-like plasmids conferring a CP-CRE phenotype and an additional IncX3 plasmid. In a single patient with multiple isolates submitted over several months, we found evidence that these plasmids had transferred from the E. cloacae clone to an Escherichia coli ST131 bacterium, rendering it as a CP CRE. The spread of this clone throughout the upper midwestern United States is unprecedented for E. cloacae and highlights the importance of continued surveillance to identify such threats to human health. PMID- 26438493 TI - Esters of Pyrazinoic Acid Are Active against Pyrazinamide-Resistant Strains of Mycobacterium tuberculosis and Other Naturally Resistant Mycobacteria In Vitro and Ex Vivo within Macrophages. AB - Pyrazinamide (PZA) is active against major Mycobacterium tuberculosis species (M. tuberculosis, M. africanum, and M. microti) but not against M. bovis and M. avium. The latter two are mycobacterial species involved in human and cattle tuberculosis and in HIV coinfections, respectively. PZA is a first-line agent for the treatment of human tuberculosis and requires activation by a mycobacterial pyrazinamidase to form the active metabolite pyrazinoic acid (POA). As a result of this mechanism, resistance to PZA, as is often found in tuberculosis patients, is caused by point mutations in pyrazinamidase. In previous work, we have shown that POA esters and amides synthesized in our laboratory were stable in plasma (M. F. Simoes, E. Valente, M. J. Gomez, E. Anes, and L. Constantino, Eur J Pharm Sci 37:257-263, 2009, http://dx.doi.org/10.1016/j.ejps.2009.02.012). Although the amides did not present significant activity, the esters were active against sensitive mycobacteria at concentrations 5- to 10-fold lower than those of PZA. Here, we report that these POA derivatives possess antibacterial efficacy in vitro and ex vivo against several species and strains of Mycobacterium with natural or acquired resistance to PZA, including M. bovis and M. avium. Our results indicate that the resistance probably was overcome by cleavage of the prodrugs into POA and a long-chain alcohol. Although it is not possible to rule out that the esters have intrinsic activity per se, we bring evidence here that long-chain fatty alcohols possess a significant antimycobacterial effect against PZA-resistant species and strains and are not mere inactive promoieties. These findings may lead to candidate dual drugs having enhanced activity against both PZA-susceptible and PZA-resistant isolates and being suitable for clinical development. PMID- 26438494 TI - In Vitro Activity of Isavuconazole and Comparators against Clinical Isolates of the Mucorales Order. AB - The in vitro activity of isavuconazole against Mucorales isolates measured by EUCAST E.Def 9.2 and CLSI M38-A2 methodologies was investigated in comparison with those of amphotericin B, posaconazole, and voriconazole. Seventy-two isolates were included: 12 of Lichtheimia corymbifera, 5 of Lichtheimia ramosa, 5 of group I and 9 of group II of Mucor circinelloides, 9 of Rhizomucor pusillus, 26 of Rhizopus microsporus, and 6 of Rhizopus oryzae. Species identification was confirmed by internal transcribed spacer (ITS) sequencing. EUCAST MICs were read on day 1 (EUCAST-d1) and day 2 (EUCAST-d2), and CLSI MICs were read on day 2 (CLSI-d2). Isavuconazole MIC50s (range) (mg/liter) by EUCAST-d1, CLSI-d2, and EUCAST-d2 were 1 (0.125 to 16), 1 (0.125 to 2), and 4 (0.5 to >16), respectively, across all isolates. The similar values for comparator drugs were as follows: posaconazole, 0.25 (<= 0.03 to >16), 0.25 (0.06 to >16), and 1 (0.06 to >16); amphotericin, 0.06 (<= 0.03 to 0.5), 0.06 (<= 0.03 to 0.25), and 0.125 (<= 0.03 to 1); voriconazole, 16 (2 to >16), 8 (1 to >16), and >16 (8 to >16), respectively. Isavuconazole activity varied by species: Lichtheimia corymbifera, 1 (0.5 to 2), 1 (1 to 2), and 2 (1 to 4); Lichtheimia ramosa, 0.25 (0.125 to 0.5), 1 (0.5 to 2), and 2 (0.5 to 4); Rhizomucor pusillus, 0.5 (0.5 to 1), 1 (0.125 to 1), and 2 (1 to 2); Rhizopus microsporus, 1 (0.5 to 4), 0.5 (0.125 to 1), and 4 (1 to 8); and Rhizopus oryzae, 1 (0.5 to 4), 1 (0.125 to 2), and 4 (0.5 to 8), respectively, were more susceptible than Mucor circinelloides: group I, 8 (4 to 8), 4 (2 to 4), and 16 (2 to 16), respectively, and group II, 8 (1 to 16), 8 (1 to 8), and 16 (4 to >16), respectively. This was also observed for posaconazole. The essential agreement was best between EUCAST-d1 and CLSI-d2 (75% to 83%). Isavuconazole displayed in vitro activity against Mucorales isolates with the exception of Mucor circinelloides. The MICs were in general 1 to 3 steps higher than those for posaconazole. However, in the clinical setting this may be compensated for by the higher exposure at standard dosing. PMID- 26438496 TI - 3-Halo Chloroquine Derivatives Overcome Plasmodium falciparum Chloroquine Resistance Transporter-Mediated Drug Resistance in P. falciparum. AB - Polymorphism in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) was shown to cause chloroquine resistance. In this report, we examined the antimalarial potential of novel 3-halo chloroquine derivatives (3-chloro, 3 bromo, and 3-iodo) against chloroquine-susceptible and -resistant P. falciparum. All three derivatives inhibited the proliferation of P. falciparum; with 3-iodo chloroquine being most effective. Moreover, 3-iodo chloroquine was highly effective at potentiating and reversing chloroquine toxicity of drug-susceptible and -resistant P. falciparum. PMID- 26438495 TI - Generation and Characterization of ALX-0171, a Potent Novel Therapeutic Nanobody for the Treatment of Respiratory Syncytial Virus Infection. AB - Respiratory syncytial virus (RSV) is an important causative agent of lower respiratory tract infections in infants and elderly individuals. Its fusion (F) protein is critical for virus infection. It is targeted by several investigational antivirals and by palivizumab, a humanized monoclonal antibody used prophylactically in infants considered at high risk of severe RSV disease. ALX-0171 is a trimeric Nanobody that binds the antigenic site II of RSV F protein with subnanomolar affinity. ALX-0171 demonstrated in vitro neutralization superior to that of palivizumab against prototypic RSV subtype A and B strains. Moreover, ALX-0171 completely blocked replication to below the limit of detection for 87% of the viruses tested, whereas palivizumab did so for 18% of the viruses tested at a fixed concentration. Importantly, ALX-0171 was highly effective in reducing both nasal and lung RSV titers when delivered prophylactically or therapeutically directly to the lungs of cotton rats. ALX-0171 represents a potent novel antiviral compound with significant potential to treat RSV-mediated disease. PMID- 26438497 TI - Susceptibility Pattern of Microorganisms Isolated by Percutaneous Needle Biopsy in Nonbacteremic Pyogenic Vertebral Osteomyelitis. AB - Pyogenic vertebral osteomyelitis (VO) is diagnosed according to several lines of evidence: clinical, biological, radiological, and histological. Definitive diagnosis requires the isolation of a causative pathogen or histological confirmation. The aim of our study was to describe the microorganisms isolated by percutaneous needle biopsy (PNB) and to analyze their susceptibility patterns, in order to assess the possibility of empirical combination therapy for the treatment of nonbacteremic patients without resorting to PNB. Based on a French prospective multicenter study of 351 patients with VO, we compiled clinical, biological, and radiological findings for 101 patients with microbiologically confirmed VO. Based on antibiotic susceptibility testing of PNB isolated pathogens, the suitabilities of four antibiotic combinations were analyzed: ofloxacin plus rifampin, levofloxacin plus rifampin, ciprofloxacin plus clindamycin, and ciprofloxacin plus amoxicillin-clavulanate. The main causative pathogens identified were coagulase-negative Staphylococcus spp. (26% of isolates), followed by Staphylococcus aureus (21%), Streptoccocus spp. (13%), and enterobacteria (21%). Empirical antibiotic combination therapy was effective in nearly 75% of cases, and the different combinations gave similar results, except for ofloxacin-rifampin, which was effective in only 58% of cases. A "perfect" empirical antibiotic therapy does not exist. If PNB is not possible, a combination of a fluoroquinolone with clindamycin or rifampin can be used, but the high risk of microbiological failure does not allow the exclusion of PNB. (This study has been registered with EudraCT, number 2006-000951-18, and ClinicalTrials.gov, number NCT00764114.). PMID- 26438498 TI - Complex Regulation Pathways of AmpC-Mediated beta-Lactam Resistance in Enterobacter cloacae Complex. AB - Enterobacter cloacae complex (ECC), an opportunistic pathogen causing numerous infections in hospitalized patients worldwide, is able to resist beta-lactams mainly by producing the AmpC beta-lactamase enzyme. AmpC expression is highly inducible in the presence of some beta-lactams, but the underlying genetic regulation, which is intricately linked to peptidoglycan recycling, is still poorly understood. In this study, we constructed different mutant strains that were affected in genes encoding enzymes suspected to be involved in this pathway. As expected, the inactivation of ampC, ampR (which encodes the regulator protein of ampC), and ampG (encoding a permease) abolished beta-lactam resistance. Reverse transcription-quantitative PCR (qRT-PCR) experiments combined with phenotypic studies showed that cefotaxime (at high concentrations) and cefoxitin induced the expression of ampC in different ways: one involving NagZ (a N-acetyl beta-D-glucosaminidase) and another independent of NagZ. Unlike the model established for Pseudomonas aeruginosa, inactivation of DacB (also known as PBP4) was not responsible for a constitutive ampC overexpression in ECC, whereas it caused AmpC-mediated high-level beta-lactam resistance, suggesting a post transcriptional regulation mechanism. Global transcriptomic analysis by transcriptome sequencing (RNA-seq) of a dacB deletion mutant confirmed these results. Lastly, analysis of 37 ECC clinical isolates showed that amino acid changes in the AmpD sequence were likely the most crucial event involved in the development of high-level beta-lactam resistance in vivo as opposed to P. aeruginosa where dacB mutations have been commonly found. These findings bring new elements for a better understanding of beta-lactam resistance in ECC, which is essential for the identification of novel potential drug targets. PMID- 26438499 TI - Increased Hydrolysis of Oximino-beta-Lactams by CMY-107, a Tyr199Cys Mutant Form of CMY-2 Produced by Escherichia coli. AB - The cephalosporinase CMY-107, a Tyr199Cys mutant form of CMY-2 encoded by an IncI self-transferable plasmid carried by an Escherichia coli clinical strain, was characterized. The enzyme hydrolyzed oximino-cephalosporins and aztreonam more efficiently than CMY-2 did. PMID- 26438500 TI - Multiple Genetic Mutations Associated with Polymyxin Resistance in Acinetobacter baumannii. AB - We studied polymyxin B resistance in 10 pairs of clinical Acinetobacter baumannii isolates, two of which had developed polymyxin B resistance in vivo. All polymyxin B-resistant isolates had lower growth rates than and substitution mutations in the lpx or pmrB gene compared to their parent isolates. There were significant differences in terms of antibiotic susceptibility and genetic determinants of resistance in A. baumannii isolates that had developed polymyxin B resistance in vivo compared to isolates that had developed polymyxin B resistance in vitro. PMID- 26438501 TI - Low Frequency of Drug-Resistant Variants Selected by Long-Acting Rilpivirine in Macaques Infected with Simian Immunodeficiency Virus Containing HIV-1 Reverse Transcriptase. AB - Preexposure prophylaxis (PrEP) using antiretroviral drugs is effective in reducing the risk of human immunodeficiency virus type 1 (HIV-1) infection, but adherence to the PrEP regimen is needed. To improve adherence, a long-acting injectable formulation of the nonnucleoside reverse transcriptase (RT) inhibitor rilpivirine (RPV LA) has been developed. However, there are concerns that PrEP may select for drug-resistant mutations during preexisting or breakthrough infections, which could promote the spread of drug resistance and limit options for antiretroviral therapy. To address this concern, we administered RPV LA to macaques infected with simian immunodeficiency virus containing HIV-1 RT (RT SHIV). Peak plasma RPV levels were equivalent to those reported in human trials and waned over time after dosing. RPV LA resulted in a 2-log decrease in plasma viremia, and the therapeutic effect was maintained for 15 weeks, until plasma drug concentrations dropped below 25 ng/ml. RT mutations E138G and E138Q were detected in single clones from plasma virus in separate animals only at one time point, and no resistance mutations were detected in viral RNA isolated from tissues. Wild-type and E138Q RT-SHIV displayed similar RPV susceptibilities in vitro, whereas E138G conferred 2-fold resistance to RPV. Overall, selection of RPV-resistant variants was rare in an RT-SHIV macaque model despite prolonged exposure to slowly decreasing RPV concentrations following injection of RPV LA. PMID- 26438502 TI - Pharmacodynamic Profiling of a Siderophore-Conjugated Monocarbam in Pseudomonas aeruginosa: Assessing the Risk for Resistance and Attenuated Efficacy. AB - The objective of this study was to investigate the risk of attenuated efficacy due to adaptive resistance for the siderophore-conjugated monocarbam SMC-3176 in Pseudomonas aeruginosa by using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined in cation-adjusted Mueller-Hinton broth (MHB) and in Chelex-treated, dialyzed MHB (CDMHB). Spontaneous resistance was assessed at 2* to 16* the MIC and the resulting mutants sequenced. Efficacy was evaluated in a neutropenic mouse thigh model at 3.13 to 400 mg/kg of body weight every 3 h for 24 h and analyzed for association with free time above the MIC (fT>MIC). To closer emulate the conditions of the in vivo model, we developed a novel assay testing activity mouse whole blood (WB). All mutations were found in genes related to iron uptake: piuA, piuC, pirR, fecI, and pvdS. Against four P. aeruginosa isolates, SMC-3176 displayed predictable efficacy corresponding to the fT>MIC using the MIC in CDMHB (R(2) = 0.968 to 0.985), with stasis to 2-log kill achieved at 59.4 to 81.1%. Efficacy did not translate for P. aeruginosa isolate JJ 4-36, as the in vivo responses were inconsistent with fT>MIC exposures and implied a threshold concentration that was greater than the MIC. The results of the mouse WB assay indicated that efficacy was not predictable using the MIC for JJ 4-36 and four additional isolates, against which in vivo failures of another siderophore-conjugated beta-lactam were previously reported. SMC-3176 carries a risk of attenuated efficacy in P. aeruginosa due to rapid adaptive resistance preventing entry via the siderophore-mediated iron uptake systems. Substantial in vivo testing is warranted for compounds using the siderophore approach to thoroughly screen for this in vitro-in vivo disconnect in P. aeruginosa. PMID- 26438503 TI - Clinical Pharmacokinetics of Rifampin in Patients with Tuberculosis and Type 2 Diabetes Mellitus: Association with Biochemical and Immunological Parameters. AB - Tuberculosis (TB) remains a major public health issue due to the increasing incidence of type 2 diabetes mellitus (T2DM), which exacerbates the clinical course of TB and increases the risk of poor long-term outcomes. The aim of this study was to characterize the pharmacokinetics of rifampin (RIF) and its relationship with biochemical and immunological parameters in patients with TB and T2DM. The biochemical and immunological parameters were assessed on the same day that the pharmacokinetic evaluation of RIF was performed. Factors related to the metabolic syndrome that is characteristic of T2DM patients were not detected in the TB-T2DM group (where predominant malnutrition was present) or in the TB group. Percentages of CD8(+) T lymphocytes and NK cells were diminished in the TB and TB-T2DM patients, who had high tumor necrosis factor alpha (TNF-alpha) and low interleukin-17 (IL-17) levels compared to healthy volunteers. Delayed RIF absorption was observed in the TB and TB-T2DM patients; absorption was poor and slower in the latter group due to poor glycemic control. RIF clearance was also slower in the diabetic patients, thereby prolonging the mean residence time of RIF. There was a significant association between glycemic control, increased TNF alpha serum concentrations, and RIF pharmacokinetics in the TB-T2DM patients. These altered metabolic and immune conditions may be factors to be considered in anti-TB therapy management when TB and T2DM are concurrently present. PMID- 26438504 TI - Raltegravir Pharmacokinetics in Patients on Asunaprevir-Daclatasvir. AB - Raltegravir pharmacokinetics was studied in 20 patients included in the ANRS HC30 QUADRIH Study before and after addition of anti-hepatitis C virus (anti-HCV) quadritherapy, including pegylated-interferon-ribavirin and asunaprevir plus daclatasvir. Raltegravir pharmacokinetic parameters remained unchanged whether administered on or off anti-HCV therapy. In addition, concentrations of raltegravir, asunaprevir, and daclatasvir were not affected by liver cirrhosis. These data suggest that in human immunodeficiency virus (HIV)-HCV-coinfected patients, whether cirrhotic or not, asunaprevir and daclatasvir could be administered safely with raltegravir. PMID- 26438505 TI - Validation and Application of a Dried Blood Spot Ceftriaxone Assay. AB - Dried blood spot (DBS) antibiotic assays can facilitate pharmacokinetic/pharmacodynamic (PK/PD) studies in situations where venous blood sampling is logistically and/or ethically problematic. In this study, we aimed to develop, validate, and apply a DBS ceftriaxone assay. A liquid chromatography tandem mass spectroscopy (LC-MS/MS) DBS ceftriaxone assay was assessed for matrix effects, process efficiency, recovery, variability, and limits of quantification (LOQ) and detection (LOD). The effects of hematocrit, protein binding, red cell partitioning, and chad positioning were evaluated, and thermal stability was assessed. Plasma, DBS, and cell pellet ceftriaxone concentrations in 10 healthy adults were compared, and plasma concentration-time profiles of DBS and plasma ceftriaxone were incorporated into population PK models. The LOQ and LOD for ceftriaxone in DBS were 0.14 mg/liter and 0.05 mg/liter, respectively. Adjusting for hematocrit, red cell partitioning, and relative recovery, DBS-predicted plasma concentrations were comparable to measured plasma concentrations (r > 0.95, P < 0.0001), and Bland-Altman plots showed no significant bias. The final population PK estimates of clearance, volume of distribution, and time above threshold MICs for measured and DBS-predicted plasma concentrations were similar. At 35 degrees C, 21 degrees C, 4 degrees C, -20 degrees C, and -80 degrees C, ceftriaxone retained >95% initial concentrations in DBS for 14 h, 35 h, 30 days, 21 weeks, and >11 months, respectively. The present DBS ceftriaxone assay is robust and can be used as a surrogate for plasma concentrations to provide valid PK and PK/PD data in a variety of clinical situations, including in studies of young children and of those in remote or resource-poor settings. PMID- 26438506 TI - Parenteral Administration of Capsule Depolymerase EnvD Prevents Lethal Inhalation Anthrax Infection. AB - Left untreated, inhalation anthrax is usually fatal. Vegetative forms of Bacillus anthracis survive in blood and tissues during infection due to elaboration of a protective poly-gamma-D-glutamic acid (PDGA) capsule that permits uncontrolled bacterial growth in vivo, eventually leading to overwhelming bacillosis and death. As a measure to counter threats from multidrug-resistant strains, we are evaluating the prophylactic and therapeutic potential of the PDGA depolymerase EnvD, a stable and potent enzyme which rapidly and selectively removes the capsule from the surface of vegetative cells. Repeated intravenous administration of 10 mg/kg recombinant EnvD (rEnvD) to mice infected with lethal doses of B. anthracis Ames spores by inhalation prevented the emergence of symptoms of anthrax and death; all animals survived the 5-day treatment period, and 70% survived to the end of the 14-day observation period. In contrast to results in sham-treated animals, the lungs and spleen of rEnvD-dosed animals were free of gross pathological changes. We conclude that rEnvD has potential as an agent to prevent the emergence of inhalation anthrax in infected animals and is likely to be effective against drug-resistant forms of the pathogen. PMID- 26438507 TI - Effect of temporal stimulus properties on the nociceptive detection probability using intra-epidermal electrical stimulation. AB - Chronic pain disorders can be initiated and maintained by malfunctioning of one or several mechanisms underlying the nociceptive function. Although several quantitative sensory testing methods exist to characterize the nociceptive function, it remains difficult to distinguish the contributions of individual mechanisms. Intra-epidermal electrical stimulation of nociceptive fibers allows defining stimuli with temporal properties within the timescale of these mechanisms. Here, we studied the effect of stimulus properties on the psychophysical detection probability. A psychophysical detection experiment was conducted including 30 healthy human participants. Participants were presented with electrical stimuli having various temporal properties. The pulse-width was varied for single pulse stimuli (either 420 or 840 MUs), and the inter-pulse interval for double pulse stimuli (10, 50, or 100 ms). Generalized linear mixed models were used to obtain estimates of thresholds and slopes of the psychophysical function. The 840-MUs single pulse resulted in a lower threshold and steeper slope of the psychophysical function than the 420-MUs single pulse. Moreover, a double-pulse stimulus resulted in a lower threshold and steeper slope than single pulse stimuli. The slopes were similar between the double pulse stimuli, but thresholds slightly increased with increasing inter-pulse intervals. In the present study, it was demonstrated that varying the temporal properties of intra-epidermal electrical stimuli results in variations in nociceptive processing. The estimated thresholds and slopes corresponding to the selection of temporal properties suggest that contributions of peripheral and central nociceptive mechanisms can be reflected in psychophysical functions. PMID- 26438508 TI - Testing the concurrent validity of a naturalistic upper extremity reaching task. AB - Point-to-point reaching has been widely used to study upper extremity motor control. We have been developing a naturalistic reaching task that adds tool manipulation and object transport to this established paradigm. The purpose of this study was to determine the concurrent validity of a naturalistic reaching task in a sample of healthy adults. This task was compared to the criterion measure of standard point-to-point reaching. Twenty-eight adults performed unconstrained out-and-back movements in three different directions relative to constant start location along midline using their nondominant arm. In the naturalistic task, participants manipulated a tool to transport objects sequentially between physical targets anchored to the planar workspace. In the standard task, participants moved a digital cursor sequentially between virtual targets, veridical to the planar workspace. In both tasks, the primary measure of performance was trial time, which indicated the time to complete 15 reaches (five cycles of three reaches/target). Two other comparator tasks were also designed to test concurrent validity when components of the naturalistic task were added to the standard task. Spearman's rank correlation coefficients indicated minimal relationship between the naturalistic and standard tasks due to differences in progressive task difficulty. Accounting for this yielded a moderate linear relationship, indicating concurrent validity. The comparator tasks were also related to both the standard and naturalistic task. Thus, the principles of motor control and learning that have been established by the wealth of point-to-point reaching studies can still be applied to the naturalistic task to a certain extent. PMID- 26438510 TI - Concerning the publication: "Histological difference between pulsed wave laser and continuous wave laser in endovenous laser ablation" by Kansaku R, Sakakibara N, Amano A, Endo H, Shimabukuro T, Sueishi M. Phlebology 2015; 30: 429-434. PMID- 26438509 TI - Single-cell coding of sensory, spatial and numerical magnitudes in primate prefrontal, premotor and cingulate motor cortices. AB - The representation of magnitude information enables humans and animal species alike to successfully interact with the external environment. However, how various types of magnitudes are processed by single neurons to guide goal directed behavior remains elusive. Here, we recorded single-cell activity from the dorsolateral prefrontal (PFC), dorsal premotor (PMd) and cingulate motor (CMA) cortices in monkeys discriminating discrete numerical (numerosity), continuous spatial (line length) and basic sensory (spatial frequency) stimuli. We found that almost exclusively PFC neurons represented the different magnitude types during sample presentation and working memory periods. The frequency of magnitude-selective cells in PMd and CMA did not exceed chance level. The proportion of PFC neurons selectively tuned to each of the three magnitude types were comparable. Magnitude coding was mainly dissociated at the single-neuron level, with individual neurons representing only one of the three tested magnitude types. Neuronal magnitude discriminability, coding strength and temporal evolution were comparable between magnitude types encoded by PFC neuron populations. Our data highlight the importance of PFC neurons in representing various magnitude categories. Such magnitude representations are based on largely distributed coding by single neurons that are anatomically intermingled within the same cortical area. PMID- 26438512 TI - Minimal amounts of kindlin-3 suffice for basal platelet and leukocyte functions in mice. AB - Hematopoietic cells depend on integrin-mediated adhesion and signaling, which is induced by kindlin-3 and talin-1. To determine whether platelet and polymorphonuclear neutrophil (PMN) functions require specific thresholds of kindlin-3, we generated mouse strains expressing 50%, 10%, or 5% of normal kindlin-3 levels. We report that in contrast to kindlin-3-null mice, which die perinatally of severe bleeding and leukocyte adhesion deficiency, mice expressing as little as 5% of kindlin-3 were viable and protected from spontaneous bleeding and infections. However, platelet adhesion and aggregation were reduced in vitro and bleeding times extended. Similarly, leukocyte adhesion, extravasation, and bacterial clearance were diminished. Quantification of protein copy numbers revealed stoichiometric quantities of kindlin-3 and talin-1 in platelets and neutrophils, indicating that reduction of kindlin-3 in our mouse strains progressively impairs the cooperation with talin-1. Our findings show that very low levels of kindlin-3 enable basal platelet and neutrophil functions, whereas in stress situations such as injury and infection, platelets and neutrophils require a maximum of functional integrins that is achieved with high and stoichiometric quantities of kindlin-3 and talin-1. PMID- 26438513 TI - ETV3-NCOA2 in indeterminate cell histiocytosis: clonal translocation supports sui generis. PMID- 26438511 TI - Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse. AB - Acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologic malignancy with a grave prognosis. To identify the mutational spectrum associated with relapse, whole-exome sequencing was performed on 13 matched diagnosis, relapse, and remission trios followed by targeted sequencing of 299 genes in 67 FLT3-ITD patients. The FLT3-ITD genome has an average of 13 mutations per sample, similar to other AML subtypes, which is a low mutation rate compared with that in solid tumors. Recurrent mutations occur in genes related to DNA methylation, chromatin, histone methylation, myeloid transcription factors, signaling, adhesion, cohesin complex, and the spliceosome. Their pattern of mutual exclusivity and cooperation among mutated genes suggests that these genes have a strong biological relationship. In addition, we identified mutations in previously unappreciated genes such as MLL3, NSD1, FAT1, FAT4, and IDH3B. Mutations in 9 genes were observed in the relapse-specific phase. DNMT3A mutations are the most stable mutations, and this DNMT3A transformed clone can be present even in morphologic complete remissions. Of note, all AML matched trio samples shared at least 1 genomic alteration at diagnosis and relapse, suggesting common ancestral clones. Two types of clonal evolution occur at relapse: either the founder clone recurs or a subclone of the founder clone escapes from induction chemotherapy and expands at relapse by acquiring new mutations. Relapse-specific mutations displayed an increase in transversions. Functional assays demonstrated that both MLL3 and FAT1 exert tumor suppressor activity in the FLT3-ITD subtype. An inhibitor of XPO1 synergized with standard AML induction chemotherapy to inhibit FLT3-ITD growth. This study clearly shows that FLT3-ITD AML requires additional driver genetic alterations in addition to FLT3-ITD alone. PMID- 26438514 TI - The novel mechanism of lenalidomide activity. AB - Lenalidomide acts by a novel drug mechanism-modulation of the substrate specificity of the CRL4(CRBN) E3 ubiquitin ligase. In multiple myeloma, lenalidomide induces the ubiquitination of IKZF1 and IKZF3 by CRL4(CRBN). Subsequent proteasomal degradation of these transcription factors kills multiple myeloma cells. In del(5q) myelodysplastic syndrome, lenalidomide induces the degradation of CK1alpha, which preferentially affects del(5q) cells because they express this gene at haploinsufficient levels. In the future, modulation of ubiquitin ligase function may enable us to target previously "undruggable" proteins. PMID- 26438515 TI - The role of iatrogenic foraminal stenosis from lordotic correction in the development of C5 palsy after posterior laminectomy and fusion. AB - BACKGROUND: Post-operative C5 nerve root palsy is a known complication following cervical spine surgery. Although several theories have been proposed, there remains no consensus as to the etiology of the palsies. Multiple pre-operative radiographic measures have been assessed for utility in predicting palsy. The purpose of this study is to evaluate published radiographic parameters as well as specifically evaluate the effect of cervical lordosis in the development of C5 palsy to establish thresholds that reliably predict the incidence. METHODS: This study is a retrospective review of 54 consecutive multilevel cervical laminectomy and fusion surgeries performed by a single spine surgeon between June 2007 and February 2014. Pre-operative MRI and pre- and post-operative plain films were assessed to measure anteroposterior diameter (APD) of the spinal cord, cervical laminar angles, anteroposterior foraminal diameters (FD), cervical curvature index (Ishihara), cervical spine angle (C2-7), and C4-5 angle. Univariate analysis through independent t tests was used to compare differences between groups. Stepwise logistic regression was performed to identify pre-operative variables associated with C5 palsy. Receiver operating characteristic curves were created for significant variables to assess predictive accuracy through determining the area under the curve. RESULTS: There were 13 (24%) palsies in the 54 patients in the study. All palsies completely resolved within 6 months. Among pre-operative measures, FD and APD were significantly different between the palsy and non-palsy groups. The average post-operative C4-5 angle was significantly different between the groups, though the cervical spine angle and curvature index, as well as the change in these measures from pre-operative measurements, did not differ significantly between groups. CONCLUSIONS: Post-operative palsy is likely a result of iatrogenic nerve root compression from a decreased in cross sectional area of the neuroforamen in a patient with pre-operative narrowing of the foramen. However, spinal cord drift back may also play a role from the combined effect of posterior decompression from laminectomy and relative slack afforded by increased lordosis. Accordingly, increased post-operative lordosis would increase the likelihood of effect from both of these mechanisms. We recommended limited conservative lordotic correction in patients with pre operative foraminal narrowing. PMID- 26438516 TI - The Unbefriended Patient: An Exercise in Ethical Clinical Reasoning. PMID- 26438517 TI - Pharmacological identification of cholinergic receptor subtypes on Drosophila melanogaster larval heart. AB - The Drosophila melanogaster heart is a popular model in which to study cardiac physiology and development. Progress has been made in understanding the role of endogenous compounds in regulating cardiac function in this model. It is well characterized that common neurotransmitters act on many peripheral and non neuronal tissues as they flow through the hemolymph of insects. Many of these neuromodulators, including acetylcholine (ACh), have been shown to act directly on the D. melanogaster larval heart. ACh is a primary neurotransmitter in the central nervous system (CNS) of vertebrates and at the neuromuscular junctions on skeletal and cardiac tissue. In insects, ACh is the primary excitatory neurotransmitter of sensory neurons and is also prominent in the CNS. A full understanding regarding the regulation of the Drosophila cardiac physiology by the cholinergic system remains poorly understood. Here we use semi-intact D. melanogaster larvae to study the pharmacological profile of cholinergic receptor subtypes, nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs), in modulating heart rate (HR). Cholinergic receptor agonists, nicotine and muscarine both increase HR, while nAChR agonist clothianidin exhibits no significant effect when exposed to an open preparation at concentrations as low as 100 nM. In addition, both nAChR and mAChR antagonists increase HR as well but also display capabilities of blocking agonist actions. These results provide evidence that both of these receptor subtypes display functional significance in regulating the larval heart's pacemaker activity. PMID- 26438518 TI - Effect of Milk Powder Supplementation with Different Calcium Contents on Bone Mineral Density of Postmenopausal Women in Northern China: A Randomized Controlled Double-Blind Trial. AB - The objective of this study is to examine the effect of milk powder supplementation with different calcium contents on bone mineral density (BMD) in postmenopausal Chinese women, and to determine a more appropriate dose of calcium supplementation. A 2-year, randomized controlled double-blind trial. Postmenopausal women (n = 210) aged 50-65 years were recruited and assigned randomly into three calcium supplementation groups. All participants received milk powder supplementation with different calcium contents (300, 600, and 900 mg per day for groups A, B, and C, respectively) and all groups received 800 IU of vitamin D per day. During the follow-up period, BMD of the left hip and lumbar spine (as the main indicator) was measured using dual-energy X-ray absorptiometry at the baseline, 1 and 2 years. Both three BMD measures and the changes of BMD over 2 years were used to analyze. Before adjusting for covariates, BMD in group A of the lumbar spine and groups A and B of greater trochanter decreased significantly from the baseline over time but increased significantly in the rest groups of the lumbar spine and greater trochanter and in three groups of Ward's triangle. There were significant differences across the three groups for changes of BMD in the greater trochanter and Ward's triangle. When adjusting for covariates, there were significant decreases with time in group A of the spine (P = 0.001), groups A and B of greater trochanter (P = 0.0002 and P = 0.04, respectively) and increases in groups B and C of Ward's triangle (P = 0.03 and P = 0.004, respectively). BMD change in the greater trochanter was significantly different among three groups. For healthy postmenopausal women, high calcium milk powder supplementation was better in retarding bone loss than medium and low calcium in the greater trochanter. Considering the dietary calcium intake of postmenopausal women in north of China, a dose of 900 mg/day is considered as the most appropriate calcium supplementation for greater trochanter but not for other sites. PMID- 26438519 TI - NICE referral guidelines for suspected cancer: colorectal cancer and faecal occult blood testing. PMID- 26438520 TI - Serum and plasma 5-hydroxyindoleacetic acid as an alternative to 24-h urine 5 hydroxyindoleacetic acid measurement. AB - BACKGROUND: Neuroendocrine tumours are slow growing tumours known to secrete a variety of vasoactive peptides which give rise to symptoms of the carcinoid syndrome. The diagnosis and monitoring of patients with neuroendocrine tumours is undertaken in many centres using 24 h urinary measurement of 5 hydroxyindoleacetic acid. However, 5-hydroxyindoleacetic acid can also be quantified in plasma and serum. METHODS: We measured 5-hydroxyindoleacetic acid concentration in 134 paired EDTA plasma and urine samples from 108 patients with known neuroendocrine tumours and 26 healthy volunteers. We also compared 5 hydroxyindoleacetic acid concentrations in paired serum and plasma samples (n = 63), then analysed paired urine and serum samples (n = 97). Furthermore, we examined the impact of renal impairment on serum 5-hydroxyindoleacetic acid by analysing 5-hydroxyindoleacetic acid in patients without neuroendocrine tumours in different stages of chronic kidney disease, as indicated by the estimated glomerular filtration rate. RESULTS: Plasma and urine 5-hydroxyindoleacetic acid had very similar diagnostic sensitivities and specificities, with areas under the curve on ROC analysis of 0.917 and 0.920, respectively. Serum and plasma 5 hydroxyindoleacetic acid values showed good correlation but serum results demonstrated a positive bias, indicating the necessity for different serum and plasma reference intervals. There was an inverse correlation between estimated glomerular filtration rate and serum 5-hydroxyindoleacetic acid concentration, with 5-hydroxyindoleacetic acid increasing once the estimated glomerular filtration rate falls below 60 mL/min/1.73 m(2). CONCLUSION: The measurement of both serum and plasma 5-hydroxyindoleacetic acid can be used for the diagnosis and monitoring of patients with neuroendocrine tumours. Provided renal function is taken into consideration, either of these tests should be incorporated into standard practice as an alternative assay to urinary 5-hydroxyindoleacetic acid. PMID- 26438521 TI - A nicer approach to the use of 'faecal occult blood tests' in assessment of the symptomatic. PMID- 26438522 TI - Estimating age-specific trends in circulating testosterone and sex hormone binding globulin in males and females across the lifespan. AB - BACKGROUND: Age-specific trends of serum testosterone and sex hormone-binding globulin across the full lifespan have not been reported. METHODS: We deduced age specific trends in serum testosterone and sex hormone-binding globulin in males and females between ages 10 and 90 from a large sample of consecutive results from a single large pathology laboratory. Coded results of 110,712 consecutive blood samples requesting serum testosterone over seven years (2007-2013) comprising blood testosterone, sex hormone-binding globulin and calculated free testosterone together with gender and age were analysed create smoothed age specific centiles (2.5%, 5%, 25%, 50%, 75%, 95%, 97.5%) for males and females. RESULTS: These identified the pubertal increases in serum testosterone in males peaking at 20 years of age and remaining stable thereafter until the eighth decade. In females, circulating testosterone peaked in late adolescence and declined gradually over the next two decades but remained stable across menopause and beyond. After early childhood, serum sex hormone-binding globulin declines to a nadir in males at the age of 20 years and remains stable till the sixth decade with a gradual, progressive rise thereafter. In females, the sex hormone-binding globulin nadir is reached earlier with levels rising gradually and progressively with age thereafter and accelerating after the age of 70 years. Females also exhibit a second sex hormone-binding globulin peak during reproductive ages reflected only in upper centiles due to effects of pregnancy and oral contraceptive use in a significant minority of females. CONCLUSIONS: This large sample of clinical data provides a comprehensive profile of androgen status across the lifespan from early adolescence to late old age. PMID- 26438523 TI - Cellular Dynamics of Memory B Cell Populations: IgM+ and IgG+ Memory B Cells Persist Indefinitely as Quiescent Cells. AB - Despite their critical role in long-term immunity, the life span of individual memory B cells remains poorly defined. Using a tetracycline-regulated pulse-chase system, we measured population turnover rates and individual t1/2 of pre established Ag-induced Ig class-switched and IgM-positive memory B cells over 402 d. Our results indicate that, once established, both IgG-positive and less frequent IgM-positive memory populations are exceptionally stable, with little evidence of attrition or cellular turnover. Indeed, the vast majority of cells in both pools exhibited t1/2 that appear to exceed the life span of the mouse, contrasting dramatically with mature naive B cells. These results indicate that recall Ab responses are mediated by stable pools of extremely long-lived cells, and suggest that Ag-experienced B cells employ remarkably efficient survival mechanisms. PMID- 26438524 TI - UNC-45A Is a Nonmuscle Myosin IIA Chaperone Required for NK Cell Cytotoxicity via Control of Lytic Granule Secretion. AB - NK cell's killing is a tightly regulated process under the control of specific cytoskeletal proteins. This includes Wiskott-Aldrich syndrome protein, Wiskott Aldrich syndrome protein-interacting protein, cofilin, Munc13-4, and nonmuscle myosin IIA (NMIIA). These proteins play a key role in controlling NK-mediated cytotoxicity either via regulating the attachment of lytic granules to the actin based cytoskeleton or via promoting the cytoskeletal reorganization that is requisite for lytic granule release. UNC-45A is a highly conserved member of the UNC-45/CRO1/She4p family of proteins that act as chaperones for both conventional and nonconventional myosin. Although we and others have shown that in lower organisms and in mammalian cells NMIIA-associated functions, such as cytokinesis, cell motility, and organelle trafficking, are dependent upon the presence of UNC 45A, its role in NK-mediated functions is largely unknown. In this article, we describe UNC-45A as a key regulator of NK-mediated cell toxicity. Specifically we show that, in human NK cells, UNC-45A localize at the NK cell immunological synapse of activated NK cells and is part of the multiprotein complex formed during NK cell activation. Furthermore, we show that UNC-45A is disposable for NK cell immunological synapse formation and lytic granules reorientation but crucial for lytic granule exocytosis. Lastly, loss of UNC-45A leads to reduced NMIIA binding to actin, suggesting that UNC-45A is a crucial component in regulating human NK cell cytoskeletal dynamics via promoting the formation of actomyosin complexes. PMID- 26438526 TI - NK Cell Functional Impairment after Allogeneic Hematopoietic Stem Cell Transplantation Is Associated with Reduced Levels of T-bet and Eomesodermin. AB - NK cells play a major role in protection against tumor recurrence and infection after allogeneic hematopoietic stem cell transplantation (HSCT). It has been shown that NK cell function after HSCT is impaired, but underlying molecular mechanisms are not well-known. In this report we show that the level of T-bet and Eomesodermin (Eomes), two T-box transcription factors regulating lymphocyte effector functions, is strongly reduced in NK cells from HSCT recipients compared with healthy control subjects. Reduction of T-bet and Eomes expression appeared early and persisted for years after HSCT, affecting all peripheral blood NK cells independently of their differentiation status. Reduced T-bet levels in NK cells from allogeneic HSCT recipients significantly correlated with reduced perforin expression. Acute, but not chronic, graft-versus-host disease, as well as CMV reactivation, was associated with further downregulation of T-bet expression in NK cells. Lower levels of T-bet expression in NK cells were associated with less favorable outcome after HSCT as a result of increased nonrelapse mortality. Collectively, our results provide a possible molecular explanation for the previously reported functional exhaustion of NK cells after allogeneic HSCT and suggest an impact of the NK transcriptional machinery status on HSCT outcome. PMID- 26438527 TI - Short-term and longer-term survival after veno-arterial extracorporeal membrane oxygenation in an adult patient population: does older age matter? AB - BACKGROUND: Veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO) is increasingly being used for patients with refractory cardiopulmonary failure. This study evaluates the short-term (to discharge) and longer-term (1 year) survival among older (?65 years) versus younger (<65 years) adults, adjusted for comorbidities, in a diverse cohort of V-A ECMO patients. METHODS: This was a retrospective cohort analysis of 131 adult patients (28% ?65 years old) who received V-A ECMO at an academic medical center from 2004-2013. Demographics, comorbidities and surgical characteristics were abstracted from the medical records and verified. Mortality status at discharge and at one year post-ECMO were determined by the hospital clinical information system, updated monthly with Social Security Death Index data. Cox proportional hazard analyses were conducted to evaluate associations between age strata and mortality at discharge and at one year post ECMO initiation, adjusted for covariates. RESULTS: The survival rate following V-A ECMO was 48% (n=68/131) to discharge and 44% (n=58/131) to one year. Age ?65 versus <65 was significantly associated with increased mortality during hospitalization (HR:2.03; 95%CI=1.23-3.33) and at one year (HR:1.81; 95% CI=1.12-2.93); these associations were attenuated and did not retain statistical significance after adjustment for comorbidities (HR:1.61; 95%CI=0.90-2.88 and HR:1.42; 95% CI=0.81-2.50, respectively). Statistically significant predictors of mortality at discharge and one year included history of coronary artery bypass graft, peripheral vascular disease and renal failure/dialysis (p<0.05). CONCLUSIONS: Older age was not independently associated with short-term or longer term survival among V-A ECMO patients, but may reflect greater comorbidity, suggesting that age alone may not disqualify patients from V-A ECMO therapy. PMID- 26438525 TI - Ptpn22 and Cd2 Variations Are Associated with Altered Protein Expression and Susceptibility to Type 1 Diabetes in Nonobese Diabetic Mice. AB - By congenic strain mapping using autoimmune NOD.C57BL/6J congenic mice, we demonstrated previously that the type 1 diabetes (T1D) protection associated with the insulin-dependent diabetes (Idd)10 locus on chromosome 3, originally identified by linkage analysis, was in fact due to three closely linked Idd loci: Idd10, Idd18.1, and Idd18.3. In this study, we define two additional Idd loci- Idd18.2 and Idd18.4--within the boundaries of this cluster of disease-associated genes. Idd18.2 is 1.31 Mb and contains 18 genes, including Ptpn22, which encodes a phosphatase that negatively regulates T and B cell signaling. The human ortholog of Ptpn22, PTPN22, is associated with numerous autoimmune diseases, including T1D. We, therefore, assessed Ptpn22 as a candidate for Idd18.2; resequencing of the NOD Ptpn22 allele revealed 183 single nucleotide polymorphisms with the C57BL/6J (B6) allele--6 exonic and 177 intronic. Functional studies showed higher expression of full-length Ptpn22 RNA and protein, and decreased TCR signaling in congenic strains with B6-derived Idd18.2 susceptibility alleles. The 953-kb Idd18.4 locus contains eight genes, including the candidate Cd2. The CD2 pathway is associated with the human autoimmune disease, multiple sclerosis, and mice with NOD-derived susceptibility alleles at Idd18.4 have lower CD2 expression on B cells. Furthermore, we observed that susceptibility alleles at Idd18.2 can mask the protection provided by Idd10/Cd101 or Idd18.1/Vav3 and Idd18.3. In summary, we describe two new T1D loci, Idd18.2 and Idd18.4, candidate genes within each region, and demonstrate the complex nature of genetic interactions underlying the development of T1D in the NOD mouse model. PMID- 26438528 TI - Campaigners demand right to generic version of breast cancer drug. PMID- 26438530 TI - Higher visit-to-visit intra-dialytic blood pressure is associated with the progression of aortic valve stenosis in chronic hemodialysis patients. AB - Aortic valve stenosis (AS) is a frequent complication contributing to poor prognosis in chronic hemodialysis (CHD) patients. High blood pressure (BP) is known to be associated with AS progression in the general population. In CHD patients, however, BP varies during and between hemodialysis sessions with ultrafiltration volume or inter-dialytic weight gain; therefore it is difficult to characterize the BP status with a conventional single measurement. Our purpose was to clarify the BP variables affecting AS progression in CHD patients. We retrospectively enrolled 32 consecutive CHD patients with AS [aortic valve area (AVA), 1.3 +/- 0.3 cm(2); mean age 69 +/- 8 years] who had serial transthoracic echocardiographic studies at least 6 months apart (mean 23 +/- 9 months). AS progression was evaluated using absolute reduction in AVA per year. Pre-dialytic and intra-dialytic (every hour during sessions) BPs throughout the 3 consecutive visits were used to determine each patient's BP status. We calculated the mean values of pre-dialytic and intra-dialytic BPs and their variability. In univariate analysis, mean visit-to-visit pre-dialytic and intra-dialytic BP were associated with AS progression, whereas all variables of BP variability were not. Multiple regression analysis indicated that only mean visit-to-visit intra dialytic systolic and diastolic BP remained independently associated with AS progression after adjustment for age, sex, hypertension, hypercholesterolemia, diabetes mellitus, and serum parathyroid hormone (p < 0.05). Although BP regulation in CHD patients is complex and multifactorial, mean visit-to-visit intra-dialytic BP was independently associated with AS progression. Prospective studies are necessary before considering intra-dialytic BP as a potential target for therapy. PMID- 26438529 TI - Genetics ignite focus on microglial inflammation in Alzheimer's disease. AB - In the past five years, a series of large-scale genetic studies have revealed novel risk factors for Alzheimer's disease (AD). Analyses of these risk factors have focused attention upon the role of immune processes in AD, specifically microglial function. In this review, we discuss interpretation of genetic studies. We then focus upon six genes implicated by AD genetics that impact microglial function: TREM2, CD33, CR1, ABCA7, SHIP1, and APOE. We review the literature regarding the biological functions of these six proteins and their putative role in AD pathogenesis. We then present a model for how these factors may interact to modulate microglial function in AD. PMID- 26438531 TI - Increased IL18 mRNA levels in peripheral artery disease and its association with triglyceride and LDL cholesterol levels: a pilot study. AB - Peripheral artery disease (PAD) typically refers to lower limb vessel ischemia caused by atherosclerotic stenosis of lower extremity arteries. IL18 is a pleiotropic pro-inflammatory cytokine reported to function as an inflammatory biomarker in cardiovascular diseases. IL18 activity is balanced by high-affinity naturally occurring IL18-binding protein (IL18BP). This study aimed to determine whether IL18, IL18 BP mRNA levels and -137 G/C (rs187238) polymorphism, which was previously associated with IL18 gene transcriptional activity, were associated with PAD etiology. IL18, IL18BP mRNA levels from peripheral blood mononuclear cells and -137 G/C (rs187238) polymorphism were determined by quantitative real time polymerase chain reaction (qRT-PCR) and RT-PCR, respectively, in 55 PAD patients (26 aorta-iliac, 29 femoro-popliteal) and 61 disease-free controls. IL18 mRNA levels were increased in PAD patients compared with healthy controls (p = 0.09); however, did not reach a statistical significant level, also did not significantly differ between aorta-iliac and femoro-popliteal occlusive PAD subgroups (p = 0.285). However, IL18BP mRNA levels were significantly lower in PAD group compared with controls (p < 0.001). Genotype frequencies of rs187238 polymorphism did not significantly differ between PAD patients and controls (p = 0.385). IL18 mRNA levels were significantly correlated with triglycerides and LDL cholesterol levels in PAD patients (p = 0.003, p = 0.014, respectively). HDL cholesterol levels were negatively correlated with IL18 mRNA levels in controls (p = 0.05). This report is a preliminary study to show an association between IL18, IL18BP mRNA levels and PAD and suggests that the IL18 gene may have a significant relationship with triglyceride and LDL cholesterol levels in PAD patients. PMID- 26438532 TI - Use and outcome of thrombus aspiration in patients with primary PCI for acute ST elevation myocardial infarction: results from the multinational Euro Heart Survey PCI Registry. AB - The clinical benefit of thrombus aspiration (TA) in patients presenting with acute ST-elevation myocardial infarction (STEMI) and treated with primary percutaneous coronary intervention (PCI) is not well defined. Furthermore, there is a large variation in the use of TA in real-world registries. Between 2005 and 2008, a total of 7146 consecutive patients with acute STEMI undergoing primary PCI were prospectively enrolled into the PCI Registry of the Euro Heart Survey Programme. For the present analysis, patients treated additionally with TA (n = 897, 12.6 %) were compared with those without TA (n = 6249, 87.4 %). Patients with hemodynamic instability at initial presentation (15.1 vs. 11.0 %; p < 0.001) and resuscitation prior to PCI (10.4 vs. 7.4 %; p = 0.002) were more frequently treated with TA. TIMI flow grade 0/1 before PCI was more often found among those with TA (73.5 vs. 58.6 %; p < 0.001). After adjustment for confounding factors in the propensity score analysis, TA was not associated with improved in-hospital survival (risk difference -1.1 %, 95 % confidence interval -2.7 to 0.6 %). In this European real-world registry, the rate of TA use was low. Hemodynamically unstable patients were more likely to be treated with TA. Consistent with the results of the TASTE study and the TOTAL trial, TA was not associated with a significant reduction in short-term mortality. PMID- 26438533 TI - Plasma pharmacokinetics and synovial concentrations of S-flurbiprofen plaster in humans. AB - PURPOSE: The purpose of this study is to investigate the pharmacokinetics and deep tissue penetration capability of the newly developed S-flurbiprofen plaster (SFPP) in humans. METHODS: Study 1: SFPP tape-type patch (2-60 mg) was applied to the lower back for 24 h in healthy adult volunteers. S-flurbiprofen (SFP) plasma concentration was measured over time to examine SFP pharmacokinetics. Study 2: SFPP (20 mg) was applied for 12 h to the affected knee of osteoarthritis (OA) patients who were scheduled for total knee arthroplasty. Deep tissues (synovial tissue and synovial fluid) were collected during surgery to compare SFP concentrations after application of SFPP or a commercially available flurbiprofen (FP) gel-type patch. RESULTS: Study 1: The plasma concentration of SFP was sustained during 24-h topical application of the SFPP, showing a high percutaneous absorption ratio of 51.4-72.2 %. Cmax and AUC0-infinity were dose proportional. Study 2: After application of the SFPP for 12 h, SFP concentrations in the synovial tissue and synovial fluid were 14.8-fold (p = 0.002) and 32.7 fold (p < 0.001) higher, respectively, than those achieved by the FP patch. CONCLUSIONS: Sustained plasma concentration of SFP and high percutaneous absorption ratio was observed after 24-h topical application of the SFPP. Compared to the FP patch, the SFPP showed superior percutaneous absorption and greater tissue penetration of SFP into the synovial tissue. Greater tissue penetration of the SFPP seemed to be primarily due to its formulation. Thus, SFPP is expected to show higher efficacy for the treatment of knee OA. PMID- 26438534 TI - Insights into molecular plasticity in protein complexes from Trm9-Trm112 tRNA modifying enzyme crystal structure. AB - Most of the factors involved in translation (tRNA, rRNA and proteins) are subject to post-transcriptional and post-translational modifications, which participate in the fine-tuning and tight control of ribosome and protein synthesis processes. In eukaryotes, Trm112 acts as an obligate activating platform for at least four methyltransferases (MTase) involved in the modification of 18S rRNA (Bud23), tRNA (Trm9 and Trm11) and translation termination factor eRF1 (Mtq2). Trm112 is then at a nexus between ribosome synthesis and function. Here, we present a structure function analysis of the Trm9-Trm112 complex, which is involved in the 5 methoxycarbonylmethyluridine (mcm(5)U) modification of the tRNA anticodon wobble position and hence promotes translational fidelity. We also compare the known crystal structures of various Trm112-MTase complexes, highlighting the structural plasticity allowing Trm112 to interact through a very similar mode with its MTase partners, although those share less than 20% sequence identity. PMID- 26438535 TI - Influence of 5-N-carboxamide modifications on the thermodynamic stability of oligonucleotides. AB - We have recently shown that the incorporation of modified nucleotides such as 5-N carboxamide-deoxyuridines into random nucleic acid libraries improves success rates in SELEX experiments and facilitates the identification of ligands with slow off-rates. Here we report the impact of these modifications on the thermodynamic stability of both duplexes and intramolecular 'single-stranded' structures. Within duplexes, large, hydrophobic naphthyl groups were destabilizing relative to the all natural DNA duplex, while the hydrophilic groups exhibited somewhat improved duplex stability. All of the significant changes in stability were driven by opposing contributions from the enthalpic and entropic terms. In contrast, both benzyl and naphthyl modifications stabilized intramolecular single-stranded structures relative to their natural DNA analogs, consistent with the notion that intramolecular folding allows formation of novel, stabilizing hydrophobic interactions. Imino proton NMR data provided evidence that elements of the folded structure form at temperatures well below the Tm, with a melting transition that is distinctly less cooperative when compared to duplex DNA. Although there are no data to suggest that the unmodified DNA sequences fold into structures similar to their modified analogs, this still represents clear evidence that these modifications impart thermodynamic stability to the folded structure not achievable with unmodified DNA. PMID- 26438536 TI - Attomole quantification and global profile of RNA modifications: Epitranscriptome of human neural stem cells. AB - Exploration of the epitranscriptome requires the development of highly sensitive and accurate technologies in order to elucidate the contributions of the more than 100 RNA modifications to cell processes. A highly sensitive and accurate ultra-high performance liquid chromatography-tandem mass spectrometry method was developed to simultaneously detect and quantify 28 modified and four major nucleosides in less than 20 min. Absolute concentrations were calculated using extinction coefficients of each of the RNA modifications studied. A comprehensive RNA modifications database of UV profiles and extinction coefficient is reported within a 2.3-5.2 % relative standard deviation. Excellent linearity was observed 0.99227-0.99999 and limit of detection values ranged from 63.75 attomoles to 1.21 femtomoles. The analytical performance was evaluated by analyzing RNA modifications from 100 ng of RNA from human pluripotent stem cell-derived neural cells. Modifications were detected at concentrations four orders of magnitude lower than the corresponding parental nucleosides, and as low as 23.01 femtograms, 64.09 attomoles. Direct and global quantitative analysis of RNA modifications are among the advantages of this new approach. PMID- 26438537 TI - A novel transcriptional regulator of L-arabinose utilization in human gut bacteria. AB - Carbohydrate metabolism plays a crucial role in the ecophysiology of human gut microbiota. Mechanisms of transcriptional regulation of sugar catabolism in commensal and prevalent human gut bacteria such as Bacteroides thetaiotaomicron remain mostly unknown. By a combination of bioinformatics and experimental approaches, we have identified an NrtR family transcription factor (BT0354 in B. thetaiotaomicron, BtAraR) as a novel regulator controlling the arabinose utilization genes. L-arabinose was confirmed to be a negative effector of BtAraR. We have solved the crystal structures of the apo and L-arabinose-bound BtAraR proteins, as well as the complex of apo-protein with a specific DNA operator. BtAraR forms a homodimer with each subunit comprised of the ligand-binding Nudix hydrolase-like domain and the DNA-binding winged-helix-turn-helix (wHTH) domain. We have identified the residues involved in binding of L-arabinose and recognition of DNA. The majority of these residues are well conserved in the AraR orthologs in Bacteroidetes. In the structure of the BtAraR-DNA complex, we found the unique interaction of arginine intercalating its guanidinum moiety into the base pair stacking of B-DNA. L-arabinose binding induces movement of wHTH domains, resulting in a conformation unsuitable for DNA binding. Our analysis facilitates reconstruction of the metabolic and regulatory networks involved in carbohydrate utilization in human gut Bacteroides. PMID- 26438538 TI - dbSUPER: a database of super-enhancers in mouse and human genome. AB - Super-enhancers are clusters of transcriptional enhancers that drive cell-type specific gene expression and are crucial to cell identity. Many disease associated sequence variations are enriched in super-enhancer regions of disease relevant cell types. Thus, super-enhancers can be used as potential biomarkers for disease diagnosis and therapeutics. Current studies have identified super enhancers in more than 100 cell types and demonstrated their functional importance. However, a centralized resource to integrate all these findings is not currently available. We developed dbSUPER (http://bioinfo.au.tsinghua.edu.cn/dbsuper/), the first integrated and interactive database of super-enhancers, with the primary goal of providing a resource for assistance in further studies related to transcriptional control of cell identity and disease. dbSUPER provides a responsive and user-friendly web interface to facilitate efficient and comprehensive search and browsing. The data can be easily sent to Galaxy instances, GREAT and Cistrome web-servers for downstream analysis, and can also be visualized in the UCSC genome browser where custom tracks can be added automatically. The data can be downloaded and exported in variety of formats. Furthermore, dbSUPER lists genes associated with super enhancers and also links to external databases such as GeneCards, UniProt and Entrez. dbSUPER also provides an overlap analysis tool to annotate user-defined regions. We believe dbSUPER is a valuable resource for the biology and genetic research communities. PMID- 26438539 TI - CRISPRz: a database of zebrafish validated sgRNAs. AB - CRISPRz (http://research.nhgri.nih.gov/CRISPRz/) is a database of CRISPR/Cas9 target sequences that have been experimentally validated in zebrafish. Programmable RNA-guided CRISPR/Cas9 has recently emerged as a simple and efficient genome editing method in various cell types and organisms, including zebrafish. Because the technique is so easy and efficient in zebrafish, the most valuable asset is no longer a mutated fish (which has distribution challenges), but rather a CRISPR/Cas9 target sequence to the gene confirmed to have high mutagenic efficiency. With a highly active CRISPR target, a mutant fish can be quickly replicated in any genetic background anywhere in the world. However, sgRNA's vary widely in their activity and models for predicting target activity are imperfect. Thus, it is very useful to collect in one place validated CRISPR target sequences with their relative mutagenic activities. A researcher could then select a target of interest in the database with an expected activity. Here, we report the development of CRISPRz, a database of validated zebrafish CRISPR target sites collected from published sources, as well as from our own in-house large-scale mutagenesis project. CRISPRz can be searched using multiple inputs such as ZFIN IDs, accession number, UniGene ID, or gene symbols from zebrafish, human and mouse. PMID- 26438540 TI - Second primary osteosarcomas in patients with retinoblastoma. AB - OBJECTIVE: Second primary malignancies have become the leading cause of death in retinoblastoma survivors. Although osteosarcoma is the most common second malignancy, little is known about its clinical and therapeutic features. METHODS: We retrospectively reviewed a database of patients with retinoblastoma and osteosarcoma occurring as a second malignancy between 1964 and 2010 at the National Cancer Center Hospital of Japan. RESULTS: Among 857 patients with retinoblastoma registered in the database, 10 (1.1%) developed osteosarcoma as a second malignancy. The median age at the onset of retinoblastoma was 3 months, being bilateral in nine patients and unilateral in one. Systemic chemoreduction was performed in three patients and intra-arterial chemotherapy in six; all patients received external beam radiotherapy. The median age at the onset of second primary osteosarcoma was 11.2 years; four were radiation-related and six were located in an extremity. Among five patients treated at our institute, four patients with tumors on an extremity were treated by wide resection with neoadjuvant and adjuvant chemotherapy. Three of these four patients (75%) were good responders to high-dose methotrexate-based multi-agent chemotherapy and survived with no evidence of disease (median follow-up period, 17.3 years). One patient whose temporal bone was affected underwent radiotherapy with chemotherapy but died after local recurrence. CONCLUSIONS: The clinical outcomes of second primary osteosarcoma in an extremity occurring in retinoblastoma survivors may be more favorable than those of conventional osteosarcoma. Early diagnosis of radiation-related osteosarcoma arising in the craniofacial region should be made at a stage where complete resection is possible. PMID- 26438541 TI - Gait analysis in dogs with pelvic fractures treated conservatively using a pressure-sensing walkway. AB - BACKGROUND: This study aimed to evaluate dogs with pelvic fractures and treated conservatively during locomotion on a pressure-sensing walkway. The hypothesis was that dogs may present changes in kinetic and temporospatial parameters because of the fractures, which may interfere with the symmetry index. Thirty dogs were selected and divided into two groups: Group 1-healthy group (n = 15) and Group 2-conservatively treated group (n = 15). The dogs were of similar body size. The body weight distribution percentages and symmetry indices of the peak vertical force, vertical impulse, stance time, swing time, percentage of stance time, and percentage of swing time of the hind limbs were evaluated. RESULTS: In Group 2, the time interval between fracture occurrence and patient evaluation was between 4 and 87 months (mean of 20 months). Four dogs had lower percentage of body weight distribution on one of the hind limbs while three dogs had greater weight distributed toward both hind limbs. Four of these dogs had alterations in the temporospatial and/or kinetic symmetry indices. CONCLUSIONS: Dogs with pelvic fractures treated conservatively may present changes in percentage of body weight distribution and symmetry indices of the kinetic and temporospatial parameters. The conservative treatment can cause persistent abnormal gait. PMID- 26438542 TI - America and the age of genocide: labeling a third-party conflict "genocide" decreases support for intervention among ingroup-glorifying Americans because they down-regulate guilt and perceived responsibility to intervene. AB - Drawing on research on the collapse of compassion and group processes and interrelations, four experiments investigated how labeling a conflict "genocide" affects distant bystanders' support for intervention. The genocide label (compared with no label or the label "not a genocide") weakened Americans' support for intervention in a crisis analogous to Darfur. Ingroup glorification moderated this effect such that the genocide label decreased support at high levels of glorification (Studies 1-3). Ingroup attachment, if anything, moderated such that the genocide label increased support at high levels of attachment (Studies 1 and 3). Importantly, the effects occurred even when controlling for conservatism (Studies 1 and 3), gender, religion, military affiliation, and level of education (Study 2). Decreases in anticipated guilt over possible nonintervention (Studies 1 and 3) among high glorifiers, and a subsequent decrease in perceived obligation to intervene (Study 3), mediated the effect of the genocide label on support for intervention. PMID- 26438543 TI - Urologist is investigated by GMC after review by Royal College of Surgeons. PMID- 26438544 TI - Embryonal tumors with multilayered rosettes in children: the SFCE experience. AB - PURPOSES: The purpose of this study was to retrospectively study embryonal tumors with multilayered rosettes (ETMR), a rare new entity that gathers ETAN-TR (embryonal tumor with abundant neuropil and true rosettes), ependymoblastomas, and medulloepitheliomas, in order to improve their descriptions and try to better define therapeutic modalities. METHODS: Patients with ETMR, ETAN-TR, ependymoblastoma, and medulloepithelioma treated in SFCE centres (Societe Francaise de lutte contre les Cancers et les leucemies de l'Enfant et de l'adolescent) since 2000 were collected. Data were retrieved from clinical charts. RESULTS: Thirty-eight patients were included in the analysis. Seventeen had an ETAN-TR, 13 had a medulloepithelioma, and 8 had an ETMR. No ependymoblastoma was included. The median age at diagnosis was 31 months (range, 2.8-141 months). The predominant tumor location was supratentorial (66%); 18.4% patients had metastatic lesion. LIN28A expression was positive in 11/11 patients. Amplification of the locus 19q13.42 was positive in 10/12 patients. Thirty patients were treated according to the primitive neuroectodermal tumors of high risk (PNET-HR) protocol. The median time of follow-up was 0.9 years (range 0.1 to 15.3 years). The 1-year event-free survival (EFS) and overall survival (OS) were, respectively, 36% CI 95% (23-55) and 45% CI 95% (31-64). On multivariate analysis, complete surgical resection, radiotherapy, and high-dose chemotherapy were associated with a better overall survival with a relative risk of, respectively, 7.9 CI 95% (2.6-23.5) p < 0.0002, 41.8 CI 95% (9.4-186) p < 0.0001, and 3.5 CI 95% (1.3-9.5) p = 0.012. CONCLUSION: Prognosis of ETMR remains dismal despite multimodal therapy. LIN28A immunostaining and 19q13.42 amplification should be systematically done to secure the diagnosis. Complete surgical resection, radiotherapy, and high-dose chemotherapy are associated with better outcome. PMID- 26438546 TI - Posture and movement in very preterm infants at term age in and outside the nest. AB - OBJECTIVE: The objective of this study is to evaluate the use of nests on general movements (GM) and posture in very preterm infants at term age. METHOD: Seventeen high-risk preterm infants-less than 30 weeks of gestation (GA)-underwent a video recording, lying in supine position, with or without nest. Posture, GM quality, and movements made around the child's midline, as well as abrupt movements and frozen postures-in extension or flexion of the four limbs-were analyzed. RESULTS: Nest did not modify quality of GM. Children significantly adopted a curled-up position. The nest system was associated with an increase in movements toward or across the midline, as well as reduction of the hyperextension posture and head rotation movements. Frozen postures in flexion or extension, as well as abrupt movements of the four limbs, were reduced but not significantly. CONCLUSIONS: Nest helps very preterm infants to adopt semi-flexed posture and facilitates movements across the midline and reduces movements of spine hyperextension, without GM global quality modifications. PMID- 26438545 TI - Bilateral occlusion of the foramina of Monro after endoscopic third ventriculostomy for aqueductal stenosis--a case report. AB - CASE REPORT: Bilateral occlusion of the foramina of Monro is an extremely rare clinical condition. We present the case of a 10-year-old girl who complained of frequent headaches. METHODS: Magnetic resonance imaging showed triventricular hydrocephalus due to aqueductal stenosis, so endoscopic third ventriculostomy was performed successfully. The headaches subsequently disappeared, but the patient presented with exacerbation of headaches 32 months postoperatively. Magnetic resonance imaging demonstrated bilateral hydrocephalus of the lateral ventricles, implying bilateral occlusion of the foramina of Monro. We again performed endoscopic surgery, confirming bilateral occlusion of the foramina of Monro. RESULTS: The foramina of Monro were apparently obstructed by normal ependyma, and no tumor masses or other structures were detected around the foramina, so we diagnosed the occlusion of the foramina as secondary after endoscopic third ventriculostomy. We fenestrated the septum pellucidum using a monopolar micro endoscopic electrode, and a ventriculoperitoneal shunt was placed for the management of hydrocephalus. The postoperative course was uneventful, and the headaches were completely resolved. PMID- 26438548 TI - Pediatric gliosarcoma treated with adjuvant radiotherapy and temozolomide. AB - PURPOSE: Primary pediatric gliosarcoma (pPGS) is an extremely rare entity with only 25 cases reported in the English literature. The value of concurrent and adjuvant temozolomide is not known in this group of patient. METHODS: Five patients of pPGS treated from 2006 to 2011 were included in this retrospective analysis. All patients underwent maximal safe surgical resection. Adjuvant therapy included conformal radiation 60 Gy in 30 fractions (2 Gy daily for 5 days in a week) with concurrent temozolomide 75 mg/m(2) daily followed by six cycles of maintenance temozolomide 150-200 mg/m(2) (day 1 to day 5) every 4 weeks. We combined the survival data of 25 patients (already published) and five of our patients and analyzed them in terms of progression free survival (PFS) and overall survival (OS) using Kaplan-Meier method. RESULTS: Male to female ratio was 1:4 and median age was 12 years (range, 7-19 years). All but one patient underwent gross total resection and four patients completed adjuvant radiotherapy as well as concurrent and adjuvant temozolomide. At a median follow up of 22.6 months (range, 0 to 45.3 months), two patients were dead and two were alive without disease while one was lost to follow up. For the pooled data, estimated median PFS and OS of all 30 patients reported in literature were 12 and 43 months, respectively. Two years PFS and OS rate for all patients was 44.2 and 62.9%, respectively. CONCLUSION: Adjuvant radiotherapy and temozolomide is well tolerated and show an encouraging survival in pPGS. PMID- 26438550 TI - First trimester diagnosis of cervico-thoracic diastematomyelia and diplomyelia using three-dimensional ultrasound. AB - BACKGROUND: Diastematomyelia and diplomyelia are rare form of spinal cord malformations (SCM) characterized by sagittal cleft in the spinal cord, conus medullaris, and/or filum terminale with splaying of the posterior vertebral elements and duplication of the spinal cord into two twin cords. Prenatal diagnosis of these diseases by two-dimensional ultrasound has been reported usually late in pregnancy and only recently in the first trimester. OBJECTIVE: We describe the first case of cervico-thoracic diastematomyelia and diplomyelia diagnosed early in pregnancy using three-dimensional ultrasound. PMID- 26438547 TI - The role of simulation in neurosurgery. AB - PURPOSE: In an era of residency duty-hour restrictions, there has been a recent effort to implement simulation-based training methods in neurosurgery teaching institutions. Several surgical simulators have been developed, ranging from physical models to sophisticated virtual reality systems. To date, there is a paucity of information describing the clinical benefits of existing simulators and the assessment strategies to help implement them into neurosurgical curricula. Here, we present a systematic review of the current models of simulation and discuss the state-of-the-art and future directions for simulation in neurosurgery. METHODS: Retrospective literature review. RESULTS: Multiple simulators have been developed for neurosurgical training, including those for minimally invasive procedures, vascular, skull base, pediatric, tumor resection, functional neurosurgery, and spine surgery. The pros and cons of existing systems are reviewed. CONCLUSION: Advances in imaging and computer technology have led to the development of different simulation models to complement traditional surgical training. Sophisticated virtual reality (VR) simulators with haptic feedback and impressive imaging technology have provided novel options for training in neurosurgery. Breakthrough training simulation using 3D printing technology holds promise for future simulation practice, proving high-fidelity patient-specific models to complement residency surgical learning. PMID- 26438549 TI - Tonsillar contusion associated with benign tonsillar ectopia following minor head trauma. AB - PURPOSE: The relationship between tonsil position and symptomatic cerebellar contusion is unclear. To date, there are no reports of symptomatic traumatic brain injury associated with benign tonsillar ectopia. Reported cases are limited to prominent cerebellar tonsillar displacement by >=5 mm (i.e., Chiari malformations). METHODS: The authors describe a case of symptomatic concussion in a toddler with unusual computerized tomography (CT) presentation and incidental finding of benign tonsillar ectopia, hemorrhagic contusion of the tonsils, blood brain barrier (BBB) disruption and delayed atrophy shown using magnetic resonance imaging (MRI) studies. The radiological presentation and the clinical challenges are discussed through a review of the literature. CONCLUSION: This case suggests that damage to cerebellar structures is not limited only to overt tonsillar herniation. Benign tonsillar ectopia may predispose to cerebellar contusion even after minor concussion and thus has a clinical significance. The current paradigm viewing only noticeable tonsillar herniation as a risk factor for hindbrain injury should be revisited. PMID- 26438551 TI - Embolization of a giant hypervascularized choroid plexus papilloma with onyx by direct puncture: a case report. AB - BACKGROUND: Choroid plexus papilloma is a rare intracranial neoplasm derived from choroid plexus epithelium accounting for less than 1 % of all brain tumors. These tumors are highly vascularized, and tumor resection is difficult, especially in small children, due to severe intraoperative bleeding. Preoperative embolization is helpful to reduce intraoperative bleeding, but it may not be possible in small children or if the tumor has no suitable feeding vessels for embolization. METHODS: We present the case of a 2-year-old girl with a giant choroid plexus papilloma. An attempt of tumor resection was previously performed in another clinic, but the surgery was aborted due to massive intraoperative bleeding and only a biopsy was done. Angiography showed no suitable vessels for embolization. A new attempt of tumor removal was carried out, but again, severe intraoperative bleeding occurred and only a partial resection was possible. Intratumoral embolization with onyx through direct percutaneous puncture was performed. RESULTS: Radical tumor removal was possible after two additional surgeries. Intraoperative blood loss was 345 ml (first surgery = only partial removal), 250 ml (second procedure = 1/3 of tumor volume resected), and 250 ml (third surgery = total removal). The patient presented no additional deficits. CONCLUSIONS: Intratumoral percutaneous embolization with onyx was very helpful in reducing intraoperative bleeding in this case. Safe radical tumor resection was possible. This technique may be useful for those surgeons dealing with highly vascularized tumors, especially in small children. No report of intratumoral embolization with onyx in cases of intracerebral tumors could be found in the literature. PMID- 26438552 TI - Rosette-forming glioneuronal tumor outside the fourth ventricle: a case-based update. AB - INTRODUCTION: Rosette-forming glioneuronal tumors (RGNTs) that do not involve the fourth ventricle are rare. RGNTs were originally thought to be exclusively localized into the fourth ventricle but were found in various anatomical localizations. MATERIAL AND METHODS: We review the literature and found 32 cases of this particular RGNT. The outcome was excellent with no mortality reported after surgical treatment. Only two patients had received adjuvant therapy for progression. We added one case of a RGNT located in the cerebellar hemisphere. CASE AND CONCLUSION: She underwent a subtotal removal with no evidence of progression after. This WHO grade I tumor with a specific biphasic histopathology is of a good oncological outcome after surgical treatment. A long follow-up is needed as recurrence or metastatic progressions exist. PMID- 26438553 TI - No Evidence for Spontaneous Lipid Transfer at ER-PM Membrane Contact Sites. AB - Non-vesicular lipid transport steps play a crucial role in lipid trafficking and potentially include spontaneous exchange. Since membrane contact facilitates this lipid transfer, it is most likely to occur at membrane contact sites (MCS). However, to date it is unknown whether closely attached biological membranes exchange lipids spontaneously. We have set up a system for studying the exchange of lipids at MCS formed between the endoplasmic reticulum (ER) and the plasma membrane. Contact sites were stably anchored and the lipids cholesterol and phosphatidylcholine (PC) were not capable of transferring spontaneously into the opposed bilayer. We conclude that physical contact between two associated biological membranes is not sufficient for transfer of the lipids PC and cholesterol. PMID- 26438554 TI - Validation of the Modified Raymond-Roy classification for intracranial aneurysms treated with coil embolization. AB - BACKGROUND: The Raymond-Roy Occlusion Classification (RROC) qualitatively assesses intracranial aneurysm occlusion following endovascular coil embolization. The Modified Raymond-Roy Classification (MRRC) was developed as a refinement of this classification scheme, and dichotomizes RROC III occlusions into IIIa (opacification within the interstices of the coil mass) and IIIb (opacification between the coil mass and aneurysm wall) closures. METHODS: To demonstrate in an external cohort the predictive accuracy of the MRRC, the records of 326 patients with 345 intracranial aneurysms treated with endovascular coil embolization from January 2007 to December 2013 were retrospectively analyzed. RESULTS: Within this cohort, 84 (24.3%) and 83 aneurysms (24.1%) had MRRC IIIa and IIIb closures, respectively, during initial coil embolization. Progression to complete occlusion was more likely with IIIa than IIIb closures (53.6% vs 19.2%, p<=0.01), while recanalization was more likely with IIIb than IIIa closures (65.1% vs 27.4%, p<0.01). Kaplan-Meier estimates demonstrated a significant difference in the test of equality for progression to complete occlusion (p=0.02) and recurrence (p<0.01) between class IIIa and IIIb distributions. For the entire cohort, male gender (p<0.01), ruptured aneurysm (p=0.04), intraluminal thrombus (p<0.01), and MRRC IIIb closure (p<0.01) were identified as predictors of recanalization. For aneurysms with an initial RROC III occlusion, MRRC IIIa closure was found to be an independent predictor of progression to complete occlusion (p=0.02). CONCLUSIONS: This study confirms that the MRRC enhances the predictive accuracy of the RROC. PMID- 26438555 TI - Effect of electroacupuncture pretreatment at GB20 on behaviour and the descending pain modulatory system in a rat model of migraine. AB - BACKGROUND: While electroacupuncture (EA) pretreatment has been found to ameliorate migraine-like symptoms, the underlying mechanisms remain poorly understood. Emerging evidence suggests that the brainstem descending pain modulatory system, comprising the periaqueductal grey (PAG), raphe magnus nucleus (RMg), and trigeminal nucleus caudalis (TNC), may be involved in migraine pathophysiology. We hypothesised that EA would ameliorate migraine-like symptoms via modulation of this descending system. METHODS: We used a conscious rat model of migraine induced by repeated electrical stimulation of the dura. Forty male Sprague-Dawley rats were randomly assigned to one of four groups: an EA group, which received EA at GB20 following dural stimulation; a sham acupuncture (SA) group, which received manual acupuncture at a non-acupuncture point following dural stimulation; a Model group, which received dural stimulation but no acupuncture; and a Control group, which received neither dural stimulation nor acupuncture (electrode implantation only). HomeCageScan was used to measure effects on behaviour, and immunofluorescence staining was used to examine neural activation (c-Fos immunoreactivity) in the PAG, RMg, and TNC. RESULTS: Compared to the Model group, rats in the EA group showed a significant increase in exploratory, locomotor and eating/drinking behaviour (p<0.01) and a significant decrease in freezing-like resting and grooming behaviour (p<0.05). There was a significant increase in the mean number of c-Fos neurons in the PAG, RMg, and TNC in Model versus Control groups (p<0.001); however, this was significantly attenuated by EA treatment (p<0.001). There were no significant differences between the SA and Model groups in behaviour or c-Fos immunoreactivity. CONCLUSIONS: EA pretreatment ameliorates behavioural changes in a rat model of recurrent migraine, possibly via modulation of the brainstem descending pathways. PMID- 26438556 TI - Laser acupuncture before heel lancing for pain management in healthy term newborns: a randomised controlled trial. AB - BACKGROUND: Healthy term newborns commonly undergo painful procedures during routine follow-up visits. Non-pharmacological strategies have currently become more important than pharmacological analgesic agents in neonatal pain management. Acupuncture is a new non-pharmacological method for preventing pain in newborns. OBJECTIVE: We aimed to investigate the effect of laser acupuncture (LA) at the Yintang point before heel lancing as a non-pharmacological intervention for procedural pain management in infants. METHODS: Forty-two term newborns, who were undergoing heel lancing between postnatal days 3 to 8 as part of routine neonatal screening, were randomly assigned to the LA group or the oral sucrose group. In the LA group, 2 min before the heel lancing, 0.3 J of energy was applied to the Yintang point using a Laser PREMIO-30 unit for 30 s. In the sucrose group, each infant received 0.5 mL of 24% sucrose orally via syringe 2 min before the heel lancing. Each baby's behaviour was scored using the Neonatal Infant Pain Scale (NIPS), assessed blinded to group. RESULTS: There were no significant differences between the LA and oral sucrose groups with respect to means for gestational week of age at birth, birth weight, actual weight, or Apgar score. Mean procedure time was significantly shorter in the LA group; however, mean crying time was longer and NIPS score was lower compared to the oral sucrose group. CONCLUSIONS: Our results indicate that 0.3 J of LA at the Yintang point before heel lancing is less effective than oral sucrose for reducing the discomfort of this procedure. TRIAL REGISTRATION NUMBER: KA14/09. PMID- 26438557 TI - Auricular acupuncture for pre-exam anxiety in medical students: a prospective observational pilot investigation. AB - OBJECTIVE: Auricular acupuncture (AA) is effective for the treatment of preoperative anxiety. We aimed to study the feasibility and effects of AA on exam anxiety in a prospective observational pilot study. METHODS: Healthy medical students received bilateral AA using indwelling fixed needles at points MA-IC1, MA-TF1, MA-SC, MA-AH7, and MA-T on the day before an anatomy exam. The needles were removed after the exam. Anxiety levels were measured using the State-Trait Anxiety Inventory (STAI) and a 100 mm visual analogue scale (VAS-100) before and after the AA intervention and once again immediately before the exam. The duration of sleep on the night before the exam was recorded and compared to that over the preceding 1 week and 6 months (all through students' recollection). In addition, blood pressure, heart rate and the acceptability of AA to the students were recorded. RESULTS: Ten students (all female) were included in the final analysis. All tolerated the needles well and stated they would wish to receive AA again for exam anxiety in the future. Exam anxiety measured using both STAI and VAS-100 decreased by almost 20% after AA. CONCLUSIONS: AA was well accepted, the outcome measurement was feasible, and the results have facilitated the calculation of the sample size for a subsequent randomised controlled trial. PMID- 26438558 TI - Backbone chemical shift assignments for Xanthomonas campestris peroxiredoxin Q in the reduced and oxidized states: a dramatic change in backbone dynamics. AB - Peroxiredoxins (Prx) are ubiquitous enzymes that reduce peroxides as part of antioxidant defenses and redox signaling. While Prx catalytic activity and sensitivity to hyperoxidative inactivation depend on their dynamic properties, there are few examples where their dynamics has been characterized by NMR spectroscopy. Here, we provide a foundation for studies of the solution properties of peroxiredoxin Q from the plant pathogen Xanthomonas campestris (XcPrxQ) by assigning the observable (1)H(N), (15)N, (13)C(alpha), (13)C(beta), and (13)C' chemical shifts for both the reduced (dithiol) and oxidized (disulfide) states. In the reduced state, most of the backbone amide resonances (149/152, 98 %) can be assigned in the XcPrxQ (1)H-(15)N HSQC spectrum. In contrast, a remarkable 51 % (77) of these amide resonances are not visible in the (1)H-(15)N HSQC spectrum of the disulfide state of the enzyme, indicating a substantial change in backbone dynamics associated with the formation of an intramolecular C48-C84 disulfide bond. PMID- 26438559 TI - Endothelin-1 induces LIMK2-mediated programmed necrotic neuronal death independent of NOS activity. AB - BACKGROUND: Recently, we have reported that LIM kinase 2 (LIMK2) involves programmed necrotic neuronal deaths induced by aberrant cyclin D1 expression following status epilepticus (SE). Up-regulation of LIMK2 expression induces neuronal necrosis by impairment of dynamin-related protein 1 (DRP1)-mediated mitochondrial fission. However, we could not elucidate the upstream effecter for LIMK2-mediated neuronal death. Thus, we investigated the role of endothelin-1 (ET 1) in LIMK2-mediated neuronal necrosis, since ET-1 involves neuronal death via various pathways. RESULTS: Following SE, ET-1 concentration and its mRNA were significantly increased in the hippocampus with up-regulation of ETB receptor expression. BQ788 (an ETB receptor antagonist) effectively attenuated SE-induced neuronal damage as well as reduction in LIMK2 mRNA/protein expression. In addition, BQ788 alleviated up-regulation of Rho kinase 1 (ROCK1) expression and impairment of DRP1-mediated mitochondrial fission in CA1 neurons following SE. BQ788 also attenuated neuronal death and up-regulation of LIMK2 expression induced by exogenous ET-1 injection. CONCLUSION: These findings suggest that ET-1 may be one of the upstream effectors for programmed neuronal necrosis through abnormal LIMK2 over-expression by ROCK1. PMID- 26438560 TI - High-resolution blood-pool-contrast-enhanced MR angiography in glioblastoma: tumor-associated neovascularization as a biomarker for patient survival. A preliminary study. AB - INTRODUCTION: The objective of the study was to determine whether tumor associated neovascularization on high-resolution gadofosveset-enhanced magnetic resonance angiography (MRA) is a useful biomarker for predicting survival in patients with newly diagnosed glioblastomas. METHODS: Before treatment, 35 patients (25 men; mean age, 64 +/- 14 years) with glioblastoma underwent MRI including first-pass dynamic susceptibility contrast (DSC) perfusion and post contrast T1WI sequences with gadobutrol (0.1 mmol/kg) and, 48 h later, high resolution MRA with gadofosveset (0.03 mmol/kg). Volumes of interest for contrast enhancing lesion (CEL), non-CEL, and contralateral normal-appearing white matter were obtained, and DSC perfusion and DWI parameters were evaluated. Prognostic factors were assessed by Kaplan-Meier survival and Cox proportional hazards model. RESULTS: Eighteen (51.42 %) glioblastomas were hypervascular on high resolution MRA. Hypervascular glioblastomas were associated with higher CEL volume and lower Karnofsky score. Median survival rates for patients with hypovascular and hypervascular glioblastomas treated with surgery, radiotherapy, and chemotherapy were 15 and 9.75 months, respectively (P < 0.001). Tumor associated neovascularization was the best predictor of survival at 5.25 months (AUC = 0.794, 81.2 % sensitivity, 77.8 % specificity, 76.5 % positive predictive value, 82.4 % negative predictive value) and yielded the highest hazard ratio (P < 0.001). CONCLUSIONS: Tumor-associated neovascularization detected on high resolution blood-pool-contrast-enhanced MRA of newly diagnosed glioblastoma seems to be a useful biomarker that correlates with worse survival. PMID- 26438562 TI - Frequent Dilatation of the Descending Aorta in Children With Hypoplastic Left Heart Syndrome Relates to Decreased Aortic Arch Elasticity. AB - BACKGROUND: Patients with hypoplastic left heart syndrome after a Norwood operation show dilatation and reduced distensibility of the reconstructed proximal aorta. Cardiac magnetic resonance imaging (CMR) and angiographic examinations indicate that the native descending aorta (DAo) is also dilated, but this has not been studied in detail. METHODS AND RESULTS: Seventy-nine children with hypoplastic left heart syndrome in Fontan circulation (aged 6.3+/-3.2 years) and 18 control participants (aged 6.8+/-2.4 years) underwent 3.0-tesla CMR. Gradient-echo cine and phase-contrast imaging was applied to measure cross sectional areas (CSAs), distensibility, pulse wave velocity, and the incremental elastic modulus of the thoracic aorta. CSA of the DAo in patients was also compared with published percentiles for aortic CSA. Patients had significantly larger CSA of the DAo at the level of pulmonary artery bifurcation (229.1+/-97.2 versus 175.7+/-24.3 mm/m(2), P=0.04) and the diaphragm (196.2+/-66.0 versus 142.6+/-16.7 mm/m(2), P<0.01). In 41 patients (52%), CSA of the DAo was >95th percentile level for control participants, and the incremental elastic modulus of the aortic arch and the DAo was higher than in patients with normal CSAs (arch: 90.1+/-64.3 versus 45.6+/-38.9 m/s; DAo: 86.3+/-53.7 versus 47.1+/-47.6 m/s; P<0.01). Incremental elastic modulus of the aortic arch and the DAo correlated with the CSA of the DAo (arch: r=0.5; DAo: r=0.49; P<0.01). CONCLUSIONS: Children with hypoplastic left heart syndrome frequently show dilatation of their DAo associated with increased stiffness of the aortic arch. Higher aortic impedance increases the afterload of the systemic circulation and likely contributes to the burden of the systemic right ventricle. PMID- 26438561 TI - PGC-1alpha-mediated changes in phospholipid profiles of exercise-trained skeletal muscle. AB - Exercise training influences phospholipid fatty acid composition in skeletal muscle and these changes are associated with physiological phenotypes; however, the molecular mechanism of this influence on compositional changes is poorly understood. Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), a nuclear receptor coactivator, promotes mitochondrial biogenesis, the fiber-type switch to oxidative fibers, and angiogenesis in skeletal muscle. Because exercise training induces these adaptations, together with increased PGC 1alpha, PGC-1alpha may contribute to the exercise-mediated change in phospholipid fatty acid composition. To determine the role of PGC-1alpha, we performed lipidomic analyses of skeletal muscle from genetically modified mice that overexpress PGC-1alpha in skeletal muscle or that carry KO alleles of PGC-1alpha. We found that PGC-1alpha affected lipid profiles in skeletal muscle and increased several phospholipid species in glycolytic muscle, namely phosphatidylcholine (PC) (18:0/22:6) and phosphatidylethanolamine (PE) (18:0/22:6). We also found that exercise training increased PC (18:0/22:6) and PE (18:0/22:6) in glycolytic muscle and that PGC-1alpha was required for these alterations. Because phospholipid fatty acid composition influences cell permeability and receptor stability at the cell membrane, these phospholipids may contribute to exercise training-mediated functional changes in the skeletal muscle. PMID- 26438563 TI - Comparison between whole-body inhalation and nose-only inhalation on the deposition and health effects of nanoparticles. AB - OBJECTIVES: We performed the two inhalation exposures, whole-body inhalation and nose-only inhalation, to investigate the pulmonary deposition and health effects of the two inhalation methods. METHODS: In both methods, we exposed rats to the same TiO2 nanoparticles at almost the same exposure concentration for 6 h and compared the deposited amounts of nanoparticles and histopathological changes in the lungs. Rats were exposed to rutile-type TiO2 nanoparticles generated by the spray-dry method for 6 h. The exposure concentration in the whole-body chamber was 4.10 +/- 1.07 mg/m(3), and that in nose-only chamber was 4.01 +/- 1.11 mg/m(3). The particle sizes were 230 and 180 nm, respectively. A control group was exposed to fresh air. RESULTS: The amounts of TiO2 deposited in the lungs as measured by ICP-AES after acid digestion just after the exposure were: 42.6 +/- 3.5 MUg in the whole-body exposure and 46.0 +/- 7.7 MUg in the nose-only exposure groups. The histopathological evaluation was the same in both exposure groups: no infiltration of inflammatory cells in the alveolar space and interstitium, and no fibrosis. CONCLUSION: The two inhalation methods using the same material under the same exposure conditions resulted in the same particle deposition and histopathology in the lung. PMID- 26438566 TI - Evaluation of a ring enhancing lesion. PMID- 26438565 TI - Signet-ring cell carcinoma of the rectum and synchronous renal cell carcinoma in a young man. PMID- 26438564 TI - Indomethacin induced gene regulation in the rat hippocampus. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs such as indomethacin are widely used to treat inflammatory diseases and manage pain, fever and inflammation in several conditions, including neuropsychiatric disorders. Although they predominantly function by inhibiting cyclooxygenase (COX) activity, important COX independent actions also occur. These actions could be responsible for the adverse side effects associated with chronic and/or high dose usage of this popular drug class. RESULTS: We examined gene regulation in the hippocampus after peripheral administration of indomethacin by employing a microarray approach. Secondary confirmation and the brain expression pattern of regulated genes was examined by in situ hybridization and immunohistochemistry. Transglutaminase 2, serum glucocorticoid inducible kinase, Inhibitor of NF-kappa B and vascular endothelial growth factor were among genes that were prominently upregulated, while G-protein coupled receptor 56 and neuropeptide Y were among genes that were downregulated by indomethacin. Co-localization studies using blood vessel markers revealed that transglutaminase 2 was induced specifically in brain vasculature. CONCLUSIONS: The data demonstrate that COX-inhibitors can differentially regulate gene transcription in multiple, functionally distinctly cell types in the brain. The results provide additional insight into the molecular actions of COX inhibitors and indicate that their effects on vasculature could influence cerebral blood flow mechanisms. PMID- 26438567 TI - Celebrating 75 years of oestradiol. AB - Oestrogens exert important effects on the reproductive as well as many other organ systems in both men and women. The history of the discovery of oestrogens, the mechanisms of their synthesis, and their therapeutic applications are very important components of the fabric of endocrinology. These aspects provide the rationale for highlighting several key components of this story. Two investigators, Edward Doisy and Alfred Butenandt, purified and crystalized oestrone nearly simultaneously in 1929, and Doisy later discovered oestriol and oestradiol. Butenandt won the Nobel Prize for this work and Doisy's had to await his purification of vitamin K. Early investigators quickly recognized that oestrogens must be synthesized from androgens and later investigators called this process aromatization. The aromatase enzyme was then characterized, its mechanism determined, and its structure identified after successful crystallization. With the development of knock-out methodology, the precise effects of oestrogen in males and females were defined and clinical syndromes of deficiency and excess described. Their discovery ultimately led to the development of oral contraceptives, treatment of menopausal symptoms, therapies for breast cancer, and induction of fertility, among others. The history of the use of oestrogens for postmenopausal women to relieve symptoms has been characterized by cyclic periods of enthusiasm and concern. The individuals involved in these studies, the innovative thinking required, and the detailed understanding made possible by evolving biologic and molecular techniques provide many lessons for current endocrinologists. PMID- 26438568 TI - Non-coding genome functions in diabetes. AB - Most of the genetic variation associated with diabetes, through genome-wide association studies, does not reside in protein-coding regions, making the identification of functional variants and their eventual translation to the clinic challenging. In recent years, high-throughput sequencing-based methods have enabled genome-scale high-resolution epigenomic profiling in a variety of human tissues, allowing the exploration of the human genome outside of the well studied coding regions. These experiments unmasked tens of thousands of regulatory elements across several cell types, including diabetes-relevant tissues, providing new insights into their mechanisms of gene regulation. Regulatory landscapes are highly dynamic and cell-type specific and, being sensitive to DNA sequence variation, can vary with individual genomes. The scientific community is now in place to exploit the regulatory maps of tissues central to diabetes etiology, such as pancreatic progenitors and adult islets. This giant leap forward in the understanding of pancreatic gene regulation is revolutionizing our capacity to discriminate between functional and non functional non-coding variants, opening opportunities to uncover regulatory links between sequence variation and diabetes susceptibility. In this review, we focus on the non-coding regulatory landscape of the pancreatic endocrine cells and provide an overview of the recent developments in this field. PMID- 26438569 TI - Rhetorical functions of a 'language of uncertainty' in the mass media. AB - As linguists, we are interested in the way uncertainty, understood as a range of epistemic qualities related to not knowing, is dealt with linguistically in communicative contexts involving scientists, the mass media and the public. One of our central theses is that uncertainty in journalistic texts is not only reflected at different linguistic levels but that it also has various rhetorical functions. Through close analysis of a German newspaper article about geo engineering, we show which specific linguistic forms, categories and structures are used when dealing with uncertainty, and which rhetorical functions of uncertainty are identifiable in the text. We conclude from our analysis that a 'language of (un-)certainty' is always highly context sensitive, meaning that the linguistic resources used to express uncertainty are both multifaceted and multifunctional. PMID- 26438570 TI - Discourse over a contested technology on Twitter: A case study of hydraulic fracturing. AB - High-volume hydraulic fracturing, a drilling simulation technique commonly referred to as "fracking," is a contested technology. In this article, we explore discourse over hydraulic fracturing and the shale industry on the social media platform Twitter during a period of heightened public contention regarding the application of the technology. We study the relative prominence of negative messaging about shale development in relation to pro-shale messaging on Twitter across five hashtags (#fracking, #globalfrackdown, #natgas, #shale, and #shalegas). We analyze the top actors tweeting using the #fracking hashtag and receiving @mentions with the hashtag. Results show statistically significant differences in the sentiment about hydraulic fracturing and shale development across the five hashtags. In addition, results show that the discourse on the main contested hashtag #fracking is dominated by activists, both individual activists and organizations. The highest proportion of tweeters, those posting messages using the hashtag #fracking, were individual activists, while the highest proportion of @mention references went to activist organizations. PMID- 26438571 TI - Former Tory health minister attacks new junior doctor contract. PMID- 26438572 TI - A Checklist of Chigger Mites (Acari: Trombiculidae and Leeuwenhokiidae) From Taiwan, With Descriptions of Three New Species. AB - Scrub typhus is a lethal human disease transmitted by larval trombiculid mites (i.e., chiggers) that have been infected with the rickettsia Orientia tsutsugamushi. In total, 21 chigger species are known from Taiwan. We update the checklist of chiggers of Taiwan based on an intensive survey of shrew and rodent hosts in grasslands and agricultural fields in lowland Taiwan, coupled with surveys of forests in one mountainous site and an opportunistic examination of submitted host specimens. Three new species of chiggers, Gahrliepia (Gateria) lieni sp. n., Gahrliepia (Gateria) minuta sp. n., and Gahrliepia (Gateria) yilanensis sp. n., as well as 23 newly recorded chigger species, were discovered. Accordingly, recorded chigger species of Taiwan more than doubled from 21 to 47 species. Two new species and nine newly recorded chigger species were discovered in forests in one mountainous site in northeastern Taiwan, suggesting that many more chigger species may be uncovered, particularly in mountainous Taiwan. Further studies should also investigate O. tsutsugamushi infection in different chigger species to assess its risks to human health. PMID- 26438573 TI - NHS must reform to avoid "busting" public finances, says health secretary. PMID- 26438574 TI - Health and Economic Impact of Switching from a 4-Valent to a 9-Valent HPV Vaccination Program in the United States. AB - BACKGROUND: Randomized clinical trials have shown the 9-valent human papillomavirus (HPV) vaccine to be highly effective against types 31/33/45/52/58 compared with the 4-valent. Evidence on the added health and economic benefit of the 9-valent is required for policy decisions. We compare population-level effectiveness and cost-effectiveness of 9- and 4-valent HPV vaccination in the United States. METHODS: We used a multitype individual-based transmission-dynamic model of HPV infection and disease (anogenital warts and cervical, anogenital, and oropharyngeal cancers), 3% discount rate, and societal perspective. The model was calibrated to sexual behavior and epidemiologic data from the United States. In our base-case, we assumed 95% vaccine-type efficacy, lifelong protection, and a cost/dose of $145 and $158 for the 4- and 9-valent vaccine, respectively. Predictions are presented using the mean (80% uncertainty interval [UI] = 10(th) 90(th) percentiles) of simulations. RESULTS: Under base-case assumptions, the 4 valent gender-neutral vaccination program is estimated to cost $5500 (80% UI = 2400-9400) and $7300 (80% UI = 4300-11 000)/quality-adjusted life-year (QALY) gained with and without cross-protection, respectively. Switching to a 9-valent gender-neutral program is estimated to be cost-saving irrespective of cross protection assumptions. Finally, the incremental cost/QALY gained of switching to a 9-valent gender-neutral program (vs 9-valent girls/4-valent boys) is estimated to be $140 200 (80% UI = 4200->1 million) and $31 100 (80% UI = 2100->1 million) with and without cross-protection, respectively. Results are robust to assumptions about HPV natural history, screening methods, duration of protection, and healthcare costs. CONCLUSIONS: Switching to a 9-valent gender-neutral HPV vaccination program is likely to be cost-saving if the additional cost/dose of the 9-valent is less than $13. Giving females the 9-valent vaccine provides the majority of benefits of a gender-neutral strategy. PMID- 26438575 TI - Hospice Use Among Patients With Lymphoma: Impact of Disease Aggressiveness and Curability. AB - BACKGROUND: Little is known about factors that influence hospice use for patients with blood cancers. We aimed to characterize hospice enrollment in a large population of patients with B-cell non-Hodgkin lymphoma (NHL) and assess the impact of disease characteristics such as aggressiveness and curability. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified patients age 65 years and older who were diagnosed with indolent NHL, aggressive NHL, or mantle cell lymphoma (MCL, which is aggressive and incurable) and died between 1999 and 2009. We determined the prevalence of hospice use and predictors thereof, using multivariable logistic regression. All statistical tests were two-sided. RESULTS: Of 18 777 patients, 9645 had indolent NHL, 8226 had aggressive NHL, and 906 had MCL. Of the total cohort, 41.6% enrolled in hospice, and 34.3% enrolled three or more days before death. Compared with patients with indolent NHL, those with MCL were more likely to enroll (adjusted odds ratio [AOR] = 1.72, 95% confidence interval [CI] = 1.49 to 1.98), followed by patients with aggressive NHL (AOR = 1.41, 95% CI = 1.32 to 1.50). Other factors statistically significantly associated with hospice use included older age, female sex, white race, high socioeconomic status, and later year of death. CONCLUSIONS: In this large cohort of patients with lymphoma, hospice use was substantially lower than the national average for all cancers, suggesting either the need for improvement in enrollment or that the current hospice model is not meeting this population's end-of-life needs. Moreover, the fact that patients with MCL were most likely to enroll suggests that the end-of-life phase may be more easily determined in the context of cancers that are both aggressive and incurable. PMID- 26438576 TI - Margaret McCartney: Honesty, placebos, and pain care. PMID- 26438577 TI - Are neurofilaments heading for the ALS clinic? PMID- 26438578 TI - Does a popular documentary about a "life saving" heart scan promote overtreatment? PMID- 26438579 TI - Care Coordination and Transition of Men's Health Management. PMID- 26438580 TI - Training for contingency operations; a potential role for regional training days? PMID- 26438581 TI - Medical and DNBI admissions to the Role 3 field hospital at Camp Bastion during Operation Herrick. PMID- 26438582 TI - Angiotensin receptor blockers use and the risk of lung cancer: A meta-analysis. AB - BACKGROUND: Several reports suggest that the use of angiotensin receptor blockers (ARBs) is associated with lung cancer (LC) reduction. However, the results were contradictory. METHODS: Four online databases were searched. The strength of the association between ARB and the risk of LC was measured by odds ratio (OR) and 95% confidence interval (CI). OR was analyzed by random-effects model. RESULTS: Eight studies with 298000 subjects were included in this meta-analysis. Using of ARB was significantly associated with decreased LC risk (OR = 0.81; 95% CI 0.69 0.94; p = 0.005). In the subgroup analysis by race, Asians treated with ARB showed decreased LC risk (OR = 0.60; 95% CI 0.54-0.67; p < 0.00001). However, Caucasians treated with ARB did not show significantly decreased LC risk (OR = 0.90; 95% CI 0.79-1.02; p = 0.11). Subgroup analysis by duration of follow-up was conducted. The studies with less than 5 years showed significant result (OR = 0.79; 95% CI 0.64-0.97;p = 0.02). However, the studies with more than 5 years did not show significantly decreased LC risk (OR = 0.84; 95% CI 0.61-1.16; p = 0.29). CONCLUSIONS: This meta-analysis indicated that ARBs may be associated with decreased risk of LC. PMID- 26438583 TI - Experts call for snakebite to be re-established as a neglected tropical disease. PMID- 26438585 TI - PUS has gone global in documenting the local culture of science. PMID- 26438587 TI - Aspergillosis spores and medical marijuana. PMID- 26438584 TI - Celiac disease and non-celiac gluten sensitivity. AB - Celiac disease is a multisystem immune based disorder that is triggered by the ingestion of gluten in genetically susceptible individuals. The prevalence of celiac disease has risen in recent decades and is currently about 1% in most Western populations. The reason for this rise is unknown, although environmental factors related to the hygiene hypothesis are suspected. The pathophysiology of celiac disease involves both the innate and adaptive immune response to dietary gluten. Clinical features are diverse and include gastrointestinal symptoms, metabolic bone disease, infertility, and many other manifestations. Although a gluten-free diet is effective in most patients, this diet can be burdensome and can limit quality of life; consequently, non-dietary therapies are at various stages of development. This review also covers non-celiac gluten sensitivity. The pathophysiology of this clinical phenotype is poorly understood, but it is a cause of increasing interest in gluten-free diets in the general population. PMID- 26438588 TI - Clinical trial transparency. PMID- 26438589 TI - An epidemiological paradox. PMID- 26438590 TI - The art of medicine. PMID- 26438591 TI - Long-term use of diphenhydramine. PMID- 26438593 TI - What next for environmental health? AB - AIMS: The aim of the wider research was to explore Health and Wellbeing Boards (HWBs) during their early development stages, with a focus on health inequalities and the role of environmental health (EH). This article presents empirical findings relating to challenges facing the EH profession in the new English public health (PH) system and offers new practical suggestions as to how they might be overcome in relation to educating and training the new generation of EH practitioners (EHPs). METHODS: Four case study HWBs in the Midlands and North of England were followed for 18 months from early 2012. In addition, EHPs and managers from each English region were interviewed. In total, 50 semi-structured interviews were carried out, around 55 h of HWB meetings were observed, and documents associated with HWBs such as strategies and minutes of meetings were collected. Data were analysed thematically, both inductively and deductively, using Atlas.ti. RESULTS: EH is largely invisible in the new PH system due to a variety of internal and external factors, including existing skill sets and practices. There is a new imperative to move away from reliance on statutory functions for funding and to engage with wider PH issues and colleagues, requiring new skills of evaluation and a change in perception from being 'doers' to include a greater role as 'thinkers'. This is being recognised by EHPs and managers, who are seeking ways to adapt to these new expectations. CONCLUSION: Recent changes to the English PH system have led to a period of reflection and the beginnings of adaptation in EH to overcome new challenges. Linked to this is a need for graduate training to prepare new practitioners to think critically, to thrive and become high-level managers of the future, while being technically competent. We suggest a new, enhanced role for Chartered Institute of Environmental Health (CIEH)-accredited universities in securing the future of the profession by supporting new graduates. Specifically, a mentoring scheme could be introduced for the practical training element for new practitioners. This would help to embed criticality and evaluation in practice, provide consistency in training, and overcome the disconnect between academia and practice. PMID- 26438592 TI - Modulation of Breast Cancer Risk Biomarkers by High-Dose Omega-3 Fatty Acids: Phase II Pilot Study in Premenopausal Women. AB - Higher intakes of the omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to the omega-6 arachidonic acid (AA) have been variably associated with reduced risk of premenopausal breast cancer. The purpose of this pilot trial was to assess feasibility and explore the effects of high-dose EPA and DHA on blood and benign breast tissue risk biomarkers before design of a placebo-controlled phase IIB trial. Premenopausal women with evidence of hyperplasia +/- atypia by baseline random periareolar fine needle aspiration were given 1860 mg of EPA + 1500 mg of DHA ethyl esters daily for 6 months. Blood and benign breast tissue were sampled during the same menstrual cycle phase prestudy and a median of 3 weeks after last dose. Additional blood was obtained within 24 hours of last dose. Feasibility, which was predefined as 50% uptake, 85% retention, and 70% compliance, was demonstrated with 46% uptake, 94% completion, and 85% compliance. Cytologic atypia decreased from 77% to 38% (P = 0.002), and Ki-67 from a median of 2.1% to 1.0% (P = 0.021) with an increase in the ratio of EPA + DHA to AA in erythrocyte phospholipids but no change in blood hormones, adipokines, or cytokines. Exploratory breast proteomics assessment showed decreases in several proteins involved in hormone and cytokine signaling with mixed effects on those in the AKT/mTOR pathways. Further investigation of EPA plus DHA for breast cancer prevention in a placebo-controlled trial in premenopausal women is warranted. PMID- 26438594 TI - Multiple Myeloma Impairs Bone Marrow Localization of Effector Natural Killer Cells by Altering the Chemokine Microenvironment. AB - Natural killer (NK) cells are key innate immune effectors against multiple myeloma, their activity declining in multiple myeloma patients with disease progression. To identify the mechanisms underlying NK cell functional impairment, we characterized the distribution of functionally distinct NK cell subsets in the bone marrow of multiple myeloma-bearing mice. Herein we report that the number of KLRG1(-) NK cells endowed with potent effector function rapidly and selectively decreases in bone marrow during multiple myeloma growth, this correlating with decreased bone marrow NK cell degranulation in vivo. Altered NK cell subset distribution was dependent on skewed chemokine/chemokine receptor axes in the multiple myeloma microenvironment, with rapid downmodulation of the chemokine receptor CXCR3 on NK cells, increased CXCL9 and CXCL10, and decreased CXCL12 expression in bone marrow. Similar alterations in chemokine receptor/chemokine axes were observed in patients with multiple myeloma. Adoptive transfer experiments demonstrated that KLRG1(-) NK cell migration to the bone marrow was more efficient in healthy than multiple myeloma-bearing mice. Furthermore, bone marrow localization of transferred CXCR3-deficient NK cells with respect to wild type was enhanced in healthy and multiple myeloma-bearing mice, suggesting that CXCR3 restrains bone marrow NK cell trafficking. Our results indicate that multiple myeloma-promoted CXCR3 ligand upregulation together with CXCL12 downmodulation act as exit signals driving effector NK cells outside the bone marrow, thus weakening the antitumor immune response at the primary site of tumor growth. PMID- 26438595 TI - In Vitro Models for Neurogenesis. AB - The process of generating new neurons of different phenotype and function from undifferentiated stem and progenitor cells starts at very early stages of development and continues in discrete regions of the mammalian nervous system throughout life. Understanding mechanisms underlying neuronal cell development, biology, function, and interaction with other cells, especially in the neurogenic niche of fully developed adults, is important in defining and developing new therapeutic regimes in regenerative neuroscience. Studying these complex and dynamic processes in vivo is challenging because of the complexity of the nervous system and the presence of many known and unknown confounding variables. However, the challenges could be overcome with simple and robust in vitro models that more or less recapitulate the in vivo events. In this work, we will present an overview of present available in vitro cell-based models of neurogenesis. PMID- 26438597 TI - Matrix Metalloproteinase 1 Causes Vasoconstriction and Enhances Vessel Reactivity to Angiotensin II via Protease-Activated Receptor 1. AB - Matrix metalloproteinase 1 (MMP-1) is an activator of protease-activated receptor 1 (PAR-1), which is known to mediate the release of endothelin 1 (ET-1) in endothelial cells and activate the RhoA kinase (ROCK) pathway. Recently, we reported increased serum and vascular MMP-1 in women with preeclampsia and hypothesized that the action of MMP-1 on PAR-1 might have vasoconstrictive effects. Resistance-sized omental arteries obtained from normal pregnant women were mounted on a myograph system and perfused with MMP-1 in a dose range of 0.025 to 25 ng/mL or with angiotensin II (Ang II) in a dose range of 0.001 to 10 umol/L in the presence of intraluminal MMP-1 (2.5 ng/mL) perfusion. Angiotensin II dose response was also performed with omental arteries from women with preeclampsia. Matrix metalloproteinase 1 caused dose-dependent vasoconstriction in endothelium-intact, but not in endothelium-denuded, vessels from normal pregnant women, which was blocked by inhibitors of PAR-1 and ET-1 type A receptor blocker. Intraluminal perfusion with a constant amount of MMP-1 enhanced vessel reactivity to Ang II, which was blocked by inhibitors of PAR-1, ROCK, and ET-1. Enhanced vascular reactivity to Ang II was observed in endothelium-intact, but not in endothelium-denuded, arteries of women with preeclampsia. Inhibitors of PAR-1, ROCK, and ET-1 blocked enhanced vascular reactivity to Ang II in endothelium-intact preeclamptic arteries. These data demonstrate that MMP-1 has potent vasoconstrictor effects and the ability to enhance vascular reactivity to vasoconstrictor hormones, which are mediated by an endothelial PAR-1, ROCK, and ET-1 pathway. Increased circulating levels of MMP-1 and its increased expression in systemic vessels of women with preeclampsia may contribute to the development of maternal hypertension. PMID- 26438598 TI - Posttranscriptional Regulation of the Inflammatory Marker C-Reactive Protein by the RNA-Binding Protein HuR and MicroRNA 637. AB - C-reactive protein (CRP), an acute-phase plasma protein, is a major component of inflammatory reactions functioning as a mediator of innate immunity. It has been widely used as a validated clinical biomarker of the inflammatory state in trauma, infection, and age-associated chronic diseases, including cancer and cardiovascular disease (CVD). Despite this, the molecular mechanisms that regulate CRP expression are not well understood. Given that the CRP 3' untranslated region (UTR) is long and AU rich, we hypothesized that CRP may be regulated posttranscriptionally by RNA-binding proteins (RBPs) and by microRNAs. Here, we found that the RBP HuR bound directly to the CRP 3' UTR and affected CRP mRNA levels. Through this interaction, HuR selectively increased CRP mRNA stability and promoted CRP translation. Interestingly, treatment with the age associated inflammatory cytokine interleukin-6 (IL-6) increased binding of HuR to CRP mRNA, and conversely, HuR was required for IL-6-mediated upregulation of CRP expression. In addition, we identified microRNA 637 (miR-637) as a microRNA that potently inhibited CRP expression in competition with HuR. Taken together, we have uncovered an important posttranscriptional mechanism that modulates the expression of the inflammatory marker CRP, which may be utilized in the development of treatments for inflammatory processes that cause CVD and age related diseases. PMID- 26438596 TI - Memory Retrieval in Mice and Men. AB - Retrieval, the use of learned information, was until recently mostly terra incognita in the neurobiology of memory, owing to shortage of research methods with the spatiotemporal resolution required to identify and dissect fast reactivation or reconstruction of complex memories in the mammalian brain. The development of novel paradigms, model systems, and new tools in molecular genetics, electrophysiology, optogenetics, in situ microscopy, and functional imaging, have contributed markedly in recent years to our ability to investigate brain mechanisms of retrieval. We review selected developments in the study of explicit retrieval in the rodent and human brain. The picture that emerges is that retrieval involves coordinated fast interplay of sparse and distributed corticohippocampal and neocortical networks that may permit permutational binding of representational elements to yield specific representations. These representations are driven largely by the activity patterns shaped during encoding, but are malleable, subject to the influence of time and interaction of the existing memory with novel information. PMID- 26438599 TI - Cotargeting Polo-Like Kinase 1 and the Wnt/beta-Catenin Signaling Pathway in Castration-Resistant Prostate Cancer. AB - The Wnt/beta-catenin signaling pathway has been identified as one of the predominantly upregulated pathways in castration-resistant prostate cancer (CRPC). However, whether targeting the beta-catenin pathway will prove effective as a CRPC treatment remains unknown. Polo-like kinase 1 (Plk1) is a critical regulator in many cell cycle events, and its level is significantly elevated upon castration of mice carrying xenograft prostate tumors. Indeed, inhibition of Plk1 has been shown to inhibit tumor growth in several in vivo studies. Here, we show that Plk1 is a negative regulator of Wnt/beta-catenin signaling. Plk1 inhibition or depletion enhances the level of cytosolic and nuclear beta-catenin in human prostate cancer cells. Furthermore, inhibition of Wnt/beta-catenin signaling significantly potentiates the antineoplastic activity of the Plk1 inhibitor BI2536 in both cultured prostate cancer cells and CRPC xenograft tumors. Mechanistically, axin2, a negative regulator of the beta-catenin pathway, serves as a substrate of Plk1, and Plk1 phosphorylation of axin2 facilitates the degradation of beta-catenin by enhancing binding between glycogen synthase kinase 3beta (GSK3beta) and beta-catenin. Plk1-phosphorylated axin2 also exhibits resistance to Cdc20-mediated degradation. Overall, this study identifies a novel Plk1-Wnt signaling axis in prostate cancer, offering a promising new therapeutic option to treat CRPC. PMID- 26438600 TI - Lysine Acetylation of CREBH Regulates Fasting-Induced Hepatic Lipid Metabolism. AB - Cyclic AMP-responsive element-binding protein 3-like 3, hepatocyte specific (CREBH), is a hepatic transcription factor that functions as a key regulator of energy homeostasis. Here, we defined a regulatory CREBH posttranslational modification process, namely, lysine-specific acetylation, and its functional involvement in fasting-induced hepatic lipid metabolism. Fasting induces CREBH acetylation in mouse livers in a time-dependent manner, and this event is critical for CREBH transcriptional activity in regulating hepatic lipid homeostasis. The histone acetyltransferase PCAF-mediated acetylation and the deacetylase sirtuin-1-mediated deacetylation coexist to maintain CREBH acetylation states under fasting conditions. Site-directed mutagenesis and functional analyses revealed that the lysine (K) residue at position 294 (K294) within the bZIP domain of the CREBH protein is the site where fasting-induced acetylation/deacetylation occurs. Introduction of the acetylation-deficient (K294R) or acetylation-mimicking (K294Q) mutation inhibited or enhanced CREBH transcriptional activity, respectively. Importantly, CREBH acetylation at lysine 294 was required for the interaction and synergy between CREBH and peroxisome proliferator-activated receptor alpha (PPARalpha) in activating their target genes upon fasting or glucagon stimulation. Introduction of the CREBH lysine 294 mutation in the liver leads to hepatic steatosis and hyperlipidemia in animals under prolonged fasting. In summary, our study reveals a molecular mechanism by which fasting or glucagon stimulation modulates lipid homeostasis through acetylation of CREBH. PMID- 26438601 TI - The LSD1 Family of Histone Demethylases and the Pumilio Posttranscriptional Repressor Function in a Complex Regulatory Feedback Loop. AB - The lysine (K)-specific demethylase (LSD1) family of histone demethylases regulates chromatin structure and the transcriptional potential of genes. LSD1 is frequently deregulated in tumors, and depletion of LSD1 family members causes developmental defects. Here, we report that reductions in the expression of the Pumilio (PUM) translational repressor complex enhanced phenotypes due to dLsd1 depletion in Drosophila. We show that the PUM complex is a target of LSD1 regulation in fly and mammalian cells and that its expression is inversely correlated with LSD1 levels in human bladder carcinoma. Unexpectedly, we find that PUM posttranscriptionally regulates LSD1 family protein levels in flies and human cells, indicating the existence of feedback loops between the LSD1 family and the PUM complex. Our results highlight a new posttranscriptional mechanism regulating LSD1 activity and suggest that the feedback loop between the LSD1 family and the PUM complex may be functionally important during development and in human malignancies. PMID- 26438603 TI - Ablation of osteopontin suppresses N-methyl-N-nitrosourea and Helicobacter pylori induced gastric cancer development in mice. AB - Several clinical studies have reported increased expression of osteopontin (OPN) in various types of human cancer, including gastric cancer. However, the precise mechanisms underlying tumor development remain unclear. In the present study, we investigated the pathogenic roles of OPN in Helicobacter pylori-induced gastric cancer development. Wild-type (WT) and OPN knockout (KO) mice were treated with N methyl-N-nitrosourea (MNU) and infected with H.pylori. Mice were killed 50 weeks after treatment, and stomach tissues were assessed by histopathological examination, immunohistochemistry, quantitative real-time RT-PCR and western blotting. To clarify the carcinogenic effects of OPN, we also conducted an in vitro study using AGS human gastric cancer cell line and THP-1 human monocytic cell line. The overall incidence of gastric tumors was significantly decreased in OPN KO mice compared with WT mice. Apoptotic cell death was significantly enhanced in OPN KO mice and was accompanied by upregulation of signal transducer and activator of transcription 1 (STAT1) and inducible nitric oxide synthase (iNOS). In vitro study, OPN suppression also caused STAT1 upregulation and iNOS overexpression in AGS and THP-1 cells, which resulted in apoptosis of AGS cells. In addition, a negative correlation was clearly identified between expression of OPN and iNOS in human gastric cancer tissues. Our data demonstrate that loss of OPN decreases H.pylori-induced gastric carcinogenesis by suppressing proinflammatory immune response and augmenting STAT1 and iNOS-mediated apoptosis of gastric epithelial cells. An important implication of these findings is that OPN actually contributes to the development of gastric cancer. PMID- 26438604 TI - Trichomonas vaginalis infection in Nigerian pregnant women and risk factors associated with sexually transmitted infections. AB - Trichomoniasis poses a public health threat to pregnant women and neonatal health. This study evaluated Trichomonas vaginalis and other common sexually transmitted infections (STIs) status in pregnant women, and risk factors associated with them. The study was cross-sectional and descriptive and a total of 198 pregnant women were recruited for T. vaginalis screening by microscopic examination. Questionnaires were also administered to 108 pregnant women to access information related to socio-demography and other factors associated with STI transmission. The overall prevalence of T. vaginalis was 18.7%. While prevalence of T. vaginalis was neither age nor parity dependent (p > 0.05), women in their first trimester showed significantly higher prevalence of trichomoniasis compared to women in their second and third trimesters (p < 0.05). The frequency of STIs was lowest (18.2%) and highest (71.4%) in age groups >= 39 and 15-20 years, respectively. Low levels of education, multiple sexual partners, lack of knowledge on partners' STI history, and having sex under the influence of alcohol or drugs were risk factors of for STIs (p < 0.05). We found a high prevalence of T. vaginalis in pregnant women, with those at an early gestational age at greater risk. The improved education of women on safe sex and the need to know partners' STI status are advocated. PMID- 26438602 TI - Acetylation of Histone H2AX at Lys 5 by the TIP60 Histone Acetyltransferase Complex Is Essential for the Dynamic Binding of NBS1 to Damaged Chromatin. AB - The association and dissociation of DNA damage response (DDR) factors with damaged chromatin occurs dynamically, which is crucial for the activation of DDR signaling in a spatiotemporal manner. We previously showed that the TIP60 histone acetyltransferase complex acetylates histone H2AX, to facilitate H2AX exchange at sites of DNA damage. However, it remained unclear how the acetylation of histone H2AX by TIP60 is related to the DDR signaling. We found that the acetylation but not the phosphorylation of H2AX is essential for the turnover of NBS1 on damaged chromatin. The loss of H2AX acetylation at Lys 5 by TIP60 in cells disturbed the accumulation of NBS1 at sites of DNA damage. Although the phosphorylation of H2AX is also reportedly required for the retention of NBS1 at damage sites, our data indicated that the acetylation-dependent NBS1 turnover by TIP60 on damaged chromatin restricts the dispersal of NBS1 foci from the sites of DNA damage. These findings indicate the importance of the acetylation-dependent dynamic binding of NBS1 to damaged chromatin, created by histone H2AX exchange, for the proper accumulation of NBS1 at DNA damage sites. PMID- 26438605 TI - Potential Uses and Inherent Challenges of Using Genome-Scale Sequencing to Augment Current Newborn Screening. AB - Since newborn screening (NBS) began in the 1960s, technological advances have enabled its expansion to include an increasing number of disorders. Recent developments now make it possible to sequence an infant's genome relatively quickly and economically. Clinical application of whole-exome and whole-genome sequencing is expanding at a rapid pace but presents many challenges. Its utility in NBS has yet to be demonstrated and its application in the pediatric population requires examination, not only for potential clinical benefits, but also for the unique ethical challenges it presents. PMID- 26438608 TI - Corrigendum. PMID- 26438607 TI - Aquaporins: New Targets for Cancer Therapy. AB - Aquaporins are a family of integral membrane proteins that are expressed in all living organisms and play vital roles in transcellular and transepithelial water movement. Cell viability and motility are critical for progression of cancer. Cell survival requires the suitable concentration of water and solutes. The balance is largely maintained by aquaporins whose major function is the transport of water and small solutes across the plasma membrane. The important role of aquaporins has received more and more attention in the recent years. A number of recent studies have revealed that aquaporins may be involved in cell migration and angiogenesis. This review will highlight the expression of aquaporins in different malignant neoplasms. Remarkably, we will summarize the influence of drugs on aquaporins, not only the traditional Chinese medicine but also the Western medicine. Therapeutic targeting of aquaporins may thus be advantageous for blocking the mechanism common for a number of key cancer phenotypes. PMID- 26438606 TI - Epigenetics and Epilepsy. AB - Epigenetic processes in the brain involve the transfer of information arising from short-lived cellular signals and changes in neuronal activity into lasting effects on gene expression. Key molecular mediators of epigenetics include methylation of DNA, histone modifications, and noncoding RNAs. Emerging findings in animal models and human brain tissue reveal that epilepsy and epileptogenesis are associated with changes to each of these contributors to the epigenome. Understanding and influencing the molecular mechanisms controlling epigenetic change could open new avenues for treatment. DNA methylation, particularly hypermethylation, has been found to increase within gene body regions and interference with DNA methylation in epilepsy can change gene expression profiles and influence epileptogenesis. Posttranscriptional modification of histones, including transient as well as sustained changes to phosphorylation and acetylation, have been reported, which appear to influence gene expression. Finally, roles have emerged for noncoding RNAs in brain excitability and seizure thresholds, including microRNA and long noncoding RNA. Together, research supports strong effects of epigenetics influencing gene expression in epilepsy, suggesting future therapeutic approaches to manipulate epigenetic processes to treat or prevent epilepsy. PMID- 26438609 TI - Asna1/TRC40 Controls beta-Cell Function and Endoplasmic Reticulum Homeostasis by Ensuring Retrograde Transport. AB - Type 2 diabetes (T2D) is characterized by insulin resistance and beta-cell failure. Insulin resistance per se, however, does not provoke overt diabetes as long as compensatory beta-cell function is maintained. The increased demand for insulin stresses the beta-cell endoplasmic reticulum (ER) and secretory pathway, and ER stress is associated with beta-cell failure in T2D. The tail recognition complex (TRC) pathway, including Asna1/TRC40, is implicated in the maintenance of endomembrane trafficking and ER homeostasis. To gain insight into the role of Asna1/TRC40 in maintaining endomembrane homeostasis and beta-cell function, we inactivated Asna1 in beta-cells of mice. We show that Asna1(beta-/-) mice develop hypoinsulinemia, impaired insulin secretion, and glucose intolerance that rapidly progresses to overt diabetes. Loss of Asna1 function leads to perturbed plasma membrane-to-trans Golgi network and Golgi-to-ER retrograde transport as well as to ER stress in beta-cells. Of note, pharmacological inhibition of retrograde transport in isolated islets and insulinoma cells mimicked the phenotype of Asna1(beta-/-) beta-cells and resulted in reduced insulin content and ER stress. These data support a model where Asna1 ensures retrograde transport and, hence, ER and insulin homeostasis in beta-cells. PMID- 26438610 TI - Baroreflex Sensitivity Impairment During Hypoglycemia: Implications for Cardiovascular Control. AB - Studies have shown associations between exposure to hypoglycemia and increased mortality, raising the possibility that hypoglycemia has adverse cardiovascular effects. In this study, we determined the acute effects of hypoglycemia on cardiovascular autonomic control. Seventeen healthy volunteers were exposed to experimental hypoglycemia (2.8 mmol/L) for 120 min. Cardiac vagal baroreflex function was assessed using the modified Oxford method before the initiation of the hypoglycemic-hyperinsulinemic clamp protocol and during the last 30 min of hypoglycemia. During hypoglycemia, compared with baseline euglycemic conditions, 1) baroreflex sensitivity decreases significantly (19.2 +/- 7.5 vs. 32.9 +/- 16.6 ms/mmHg, P < 0.005), 2) the systolic blood pressure threshold for baroreflex activation increases significantly (the baroreflex function shifts to the right; 120 +/- 14 vs. 112 +/- 12 mmHg, P < 0.005), and 3) the maximum R-R interval response (1,088 +/- 132 vs. 1,496 +/- 194 ms, P < 0.001) and maximal range of the R-R interval response (414 +/- 128 vs. 817 +/- 183 ms, P < 0.001) decrease significantly. These findings indicate reduced vagal control and impaired cardiovascular homeostasis during hypoglycemia. PMID- 26438612 TI - RETRACTED: Simple versus branched pedal bypass in the treatment of critical limb ischemia. PMID- 26438611 TI - Relationship Between Left Ventricular Structural and Metabolic Remodeling in Type 2 Diabetes. AB - Concentric left ventricular (LV) remodeling is associated with adverse cardiovascular events and is frequently observed in patients with type 2 diabetes mellitus (T2DM). Despite this, the cause of concentric remodeling in diabetes per se is unclear, but it may be related to cardiac steatosis and impaired myocardial energetics. Thus, we investigated the relationship between myocardial metabolic changes and LV remodeling in T2DM. Forty-six nonhypertensive patients with T2DM and 20 matched control subjects underwent cardiovascular magnetic resonance to assess LV remodeling (LV mass-to-LV end diastolic volume ratio), function, tissue characterization before and after contrast using T1 mapping, and (1)H and (31)P magnetic resonance spectroscopy for myocardial triglyceride content (MTG) and phosphocreatine-to-ATP ratio, respectively. When compared with BMI- and blood pressure-matched control subjects, subjects with diabetes were associated with concentric LV remodeling, higher MTG, impaired myocardial energetics, and impaired systolic strain indicating a subtle contractile dysfunction. Importantly, cardiac steatosis independently predicted concentric remodeling and systolic strain. Extracellular volume fraction was unchanged, indicating the absence of fibrosis. In conclusion, cardiac steatosis may contribute to concentric remodeling and contractile dysfunction of the LV in diabetes. Because cardiac steatosis is modifiable, strategies aimed at reducing MTG may be beneficial in reversing concentric remodeling and improving contractile function in the hearts of patients with diabetes. PMID- 26438613 TI - Endovascular treatment of occluded and stenotic visceral vessels in patients with chronic mesenteric ischemia. AB - Objective Current evidence in the literature about endovascular treatment (ET) of visceral vessels in patients with chronic mesenterial ischemia (CMI) based on morphological characteristics is limited. The aim of this study was the evaluation of ET in occluded and stenotic visceral vessels. Methods Patients undergoing ET for CMI between November 2000 and November 2012 were included in this retrospective study. Primary measure outcome was the symptom-free survival (SFS). Secondary outcomes were primary (PPR), secondary patency (SPR) rates and technical success rate (TSR). A Cox-regression analysis identified risk factors for the primary and secondary measure outcomes. Results Forty patients were included in the present study (men: 21, mean age: 68). The overall number of vessels with intention-to-treat was 62. Fifty-two visceral arteries (18 occlusions and 34 stenoses) were successfully treated by endovascular means. The overall TSR was 84%. Visceral vessel occlusions and atherosclerotic disease of the superior mesenteric artery (SMA) were identified as independent risk factors for poorer TSR ( p < 0.05). The 12-month SFS was 60%. The overall 12-month PPR and SPR were 71% and 94%, respectively. No significant differences were observed between occluded and stenotic vessels ( p > 0.05) concerning the PPR. On the other hand, the subgroup analysis revealed higher SPR among occluded visceral vessels ( p < 0.001) and coeliac axis lesions ( p < 0.001). Conclusions ET was associated with high incidence of symptoms recurrence despite the satisfying patency rates in both occluded and stenotic vessels. Additionally, visceral vessel occlusion and presence of atherosclerotic lesions in the SMA were associated with poorer TSR. PMID- 26438617 TI - Does Type of Child Risk Affect Whether Mothers Seek Assistance for Intimate Partner Violence From Civil or Criminal Court? AB - We examined whether risks to children of intimate partner violence survivors affected the type of legal assistance accessed. We hypothesized that the level and type of perceived child risk would be associated with whether women sought a protection order in civil court or filed charges against a current or former intimate partner in criminal court. Using data from a sample of predominantly African American women (N=293), we found that some forms of child risk were positively associated with seeking a civil order of protection but negatively associated with pressing criminal charges. Implications for practice, policy, and future research are presented. PMID- 26438615 TI - Storytelling in the context of vaccine refusal: a strategy to improve communication and immunisation. AB - The December 2014 outbreak of measles in California impacted over 100 children and served as a reminder that this disease still plagues the USA, even 50 years following the first licensed vaccine. Refusal of vaccination is a complicated and multifaceted issue, one that clearly demands a closer look by paediatricians and public health officials alike. While medical doctors and scientists are trained to practice 'evidence-based medicine', and studies of vaccine safety and efficacy speak the language of statistics, there is reason to believe that this is not the most effective strategy for communicating with all groups of parents. Herein, we consider other methods such as narrative practices that employ stories and appeal more directly to parents. We also examine how doctors are trained to disseminate information and whether there are reasonable supplementary methods that could be used to improve vaccine communication and ultimately immunisation rates. PMID- 26438614 TI - Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations. AB - OBJECTIVE: Neonatal diabetes secondary to mutations in potassium-channel subunits is a rare disease but constitutes a paradigm for personalized genetics-based medicine, as replacing the historical treatment with insulin injections with oral sulfonylurea (SU) therapy has been proven beneficial. SU receptors are widely expressed in the brain, and we therefore evaluated potential effects of SU on neurodevelopmental parameters, which are known to be unresponsive to insulin. RESEARCH DESIGN AND METHODS: We conducted a prospective single-center study. Nineteen patients (15 boys aged 0.1-18.5 years) were switched from insulin to SU therapy. MRI was performed at baseline. Before and 6 or 12 months after the switch, patients underwent quantitative neurological and developmental assessments and electrophysiological nerve and muscle testing. RESULTS: At baseline, hypotonia, deficiencies in gesture conception or realization, and attention disorders were common. SU improved HbA1c levels (median change -1.55% [range -3.8 to 0.1]; P < 0.0001), intelligence scores, hypotonia (in 12 of 15 patients), visual attention deficits (in 10 of 13 patients), gross and fine motor skills (in all patients younger than 4 years old), and gesture conception and realization (in 5 of 8 older patients). Electrophysiological muscle and nerve tests were normal. Cerebral MRI at baseline showed lesions in 12 patients, suggesting that the impairments were central in origin. CONCLUSIONS: SU therapy in neonatal diabetes secondary to mutations in potassium-channel subunits produces measurable improvements in neuropsychomotor impairments, which are greater in younger patients. An early genetic diagnosis should always be made, allowing for a rapid switch to SU. PMID- 26438618 TI - Neurology Resident & Fellow Section: The second decade begins. PMID- 26438619 TI - Motor evoked potential polyphasia: A novel endophenotype of idiopathic generalized epilepsy. PMID- 26438621 TI - Pseudo-Foster-Kennedy syndrome with optic nerve compression by the gyrus rectus. PMID- 26438620 TI - Anti-MOG antibodies with longitudinally extensive transverse myelitis preceded by CLIPPERS. PMID- 26438622 TI - Clinical Reasoning: A 68-year-old man with a history of lung cancer presenting with right-sided weakness and aphasia. PMID- 26438623 TI - Teaching NeuroImages: Subacute encephalopathy in a young woman with THTR2 gene mutation. PMID- 26438624 TI - Implantation technique of the 50-cm3 SynCardia Total Artificial Heart: does size make a difference? AB - Despite downsizing, implantation technique of the 50-cm(3) SynCardia Total Artificial Heart and settings of the Companion driver remain unchanged. Owing to the absence of de-airing nipples, de-airing procedure is even more crucial and has to be performed carefully. PMID- 26438625 TI - Using data envelopment analysis for assessing the performance of pediatric emergency department physicians. AB - In attempting to measure the performance of providers in a service industry such as health care, it is crucial that the measurement tool recognize both the efficiency and quality of service provided. We develop a Data Envelopment Analysis (DEA) model to help assess the performance of emergency department (ED) physicians at a partner hospital. The model incorporates efficiency measures as inputs and quality measures as outputs. We demonstrate the importance of a nuanced approach that recognizes the heterogeneity of patients that an ED physician encounters and the important role s/he plays as a mentor for physicians in training. In the study, patients were grouped according to their presenting complaint and ED physicians were assessed on each group separately. Performance variations were evident between physicians within each complaint group as well as between groups. A secondary grouping divided patients based on whether the attending physician was assisted by a trainee. Almost all ED physicians showed better performance scores when not assisted by trainees or ED fellows. PMID- 26438627 TI - Elucidating the Mechanisms of Formation for Two Unusual Cytochrome P450-Mediated Fused Ring Metabolites of GDC-0623, a MAPK/ERK Kinase Inhibitor. AB - Two isomeric metabolites of GDC-0623 [5-((2-fluoro-4-iodophenyl)amino)-N-(2 hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide], a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) kinase inhibitor, were identified in radiolabeled mass balance studies in rats and dogs (approximately 5% in excreta) and were also observed in human circulation (nonradiolabeled). Mass spectrometric data indicated that both metabolites had formed a new ring structure fused to the imidazopyridine core. Given their unusual structures, we conducted experiments to elucidate their chemical structures and understand the mechanisms for their formation. For the first metabolite, M14, a pyrazol-3-ol ring was generated by N-N bond formation between the aniline and hydroxamate. For the second metabolite, M13, an imidazol-2-one was generated by a Hofmann-type rearrangement that involved C-C bond cleavage and C-N bond formation. Both reactions were catalyzed by CYP2C9 and CYP2C19. M14 was generated directly from GDC-0623 and we speculate that its formation was via oxidative activation of the hydroxamic ester by cytochrome P450 (P450) and intramolecular nucleophilic displacement of the ester side chain. M13 (the rearranged metabolite) formed from the N-reduced hydroxamate (amide) and not from GDC-0623 directly. We propose for M13 that a P450-mediated reaction formed a cationic amide intermediate, which enabled the molecular rearrangement of the imidazopyridine core migrating from the amide carbon to the nitrogen and subsequent cyclization reaction. Each of these metabolic pathways constitutes a novel biotransformation mediated by P450 enzymes. PMID- 26438626 TI - Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements. AB - The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but underinvestigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport, and/or metabolism of pharmaceutical agents. Clinical trials of drug-botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical studies. For example, phase 1 clinical trials have confirmed preclinical studies and clinical case reports that St. John's wort (Hypericum perforatum) induces CYP3A4/CYP3A5. However, clinical studies of most botanicals that were predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and/or CYP3A4. Here, we highlight discrepancies between preclinical and clinical data concerning drug-botanical interactions and critically evaluate why some preclinical models perform better than others in predicting the potential for drug-botanical interactions. Gaps in knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport, and metabolism. PMID- 26438628 TI - In Vitro and In Vivo Mechanistic Studies toward Understanding the Role of 1 Aminobenzotriazole in Rat Drug-Drug Interactions. AB - 1-Aminobenzotriazole (ABT) is regularly used in vivo as a nonspecific and irreversible cytochrome P450 inhibitor to elucidate the role of metabolism on the pharmacokinetic profile of xenobiotics. However, few reports have considered the recent findings that ABT can alter drug absorption or have investigated the possible differential inhibition of ABT on intestinal and hepatic metabolism. To address these uncertainties, pharmacokinetic studies under well controlled and defined ABT pretreatment conditions (50 mg/kg, 1 hour ABT i.v. and 16 hours ABT p.o.) were conducted prior to the oral administration of metoprolol, a permeable P450 probe that undergoes extensive intestinal and hepatic metabolism. The pharmacokinetic profile of metoprolol was affected differently by the two ABT pretreatments. An increase in area under the curve of 16-fold with ABT p.o. and 6.5-fold with ABT i.v. was observed compared with control. Based on in vitro studies, this difference could not be attributed to a differential inhibition of intestinal and hepatic metabolism. In the ABT i.v. pretreatment group, the increase in area under the curve was also associated with a prolonged time at maximal concentration (24-fold versus control), suggesting a delay in absorption. This was further confirmed by the administration of a charcoal meal, which resulted in a 7-fold increase in stomach weights in the 1-hour ABT pretreated groups compared with the untreated or 16-hour ABT pretreated rats. Based on these results, we recommend pretreating rats with ABT p.o. 16 hours before the administration of a test compound to preserve the inhibitory effect on intestinal and hepatic metabolism and avoid the confounding effect on drug absorption. PMID- 26438629 TI - The RNA-binding protein Sam68 regulates tumor cell viability and hepatic carcinogenesis by inhibiting the transcriptional activity of FOXOs. AB - Src associated in mitosis (Sam68; 68 kDa) is a KH domain RNA-binding protein that belongs to the signal transduction and activation of RNA family, and has been implicated in the oncogenesis and progression of several human cancers. Our study aimed to investigated the clinicopathologic significance of Sam68 expression and its role in cell proliferation and the underlying molecular mechanism in hepatocellular carcinoma (HCC). We demonstrated that Sam68 expression was significantly increased in HCC and high expression of Sam68 was significantly associated with Edmondson grade, tumor size, tumor nodule number, HBsAg status and Ki-67 expression. The Kaplan-Meier survival curves showed that increased expression of Sam68 was correlated with poor prognosis in HCC patients and served as an independent prognostic marker of overall survival in a multivariable analysis. In addition, through serum starvation and refeeding assay, we demonstrated that Sam68 was lowly expressed in serum-starved HCC cells, and was progressively increased after serum-additioning. Furthermore, siRNA knockdown of endogenous Sam68 inhibited cell proliferation and tumourigenicity of HCC cells in vitro, through blocking the G1 to S phase transition. Moreover, we reported that the anti-proliferative effect of silencing Sam68 was accompanied with up regulated expression of cyclin-dependent kinase inhibitors, p21(Cip1) and p27(Kip1), enhanced transactivation of FOXO factors (FOXO4), and dysreuglation of Akt/GSK-3beta signaling. Taken together, these findings provide a rational framework for the progression of HCC and thereby indicated that Sam68 might be a novel and useful prognostic marker and a potential target for human HCC treatment. PMID- 26438630 TI - Definition, epidemiology and registries of pulmonary hypertension. AB - Pulmonary arterial hypertension (PAH) is a subcategory of pulmonary hypertension (PH) that comprises a group of disorders with similar pulmonary vascular pathology. Though PH is common, the estimated incidence of IPAH is 1-3 cases per million, making it a rare disease. The hemodynamic definition of PAH is a mean pulmonary artery pressure at rest >OR = 25 mm Hg in the presence of a pulmonary capillary wedge pressure =2 seizure diagnoses before age 12 months and who were also prescribed anticonvulsants at 24 months. A child neurologist reviewed records to identify infants who met 4 of 5 criteria for clinical Dravet syndrome: normal development before seizure onset; >=2 seizures before age 12 months; myoclonic, hemiclonic, or generalized tonic-clonic seizures; >=2 seizures lasting >10 minutes; and refractory seizures after age 2 years. SCN1A gene sequencing was performed as part of routine clinical care. RESULTS: Eight infants met the study criteria for clinical Dravet syndrome, yielding an incidence of 1 per 15 700. Six of these infants (incidence of 1 per 20 900) had a de novo SCN1A missense mutation that is likely to be pathogenic. One infant had an inherited SCN1A variant that is unlikely to be pathogenic. All 8 experienced febrile seizures, and 6 had prolonged seizures lasting >10 minutes by age 1 year. CONCLUSIONS: Dravet syndrome due to an SCN1A mutation is twice as common in the United States as previously thought. Genetic testing should be considered in children with >=2 prolonged febrile seizures by 1 year of age. PMID- 26438701 TI - Hospital Variation in Health Care Utilization by Children With Medical Complexity. AB - BACKGROUND: Although children with medical complexity have high health care needs, little is known about the variation in care provided between centers. This information may be particularly useful in identifying opportunities to improve quality and reduce costs. METHODS: We conducted a retrospective population-based observational cohort study using all payer claims databases for children aged 30 days to <18 years residing in Maine, New Hampshire, and Vermont from 2007 to 2010. We identified hospital-affiliated cohorts (n = 6) of patients (n = 8216) with medical complexity by using diagnostic codes from both inpatient and outpatient claims. Children were assigned to the hospital where they received the most inpatient days, or their outpatient visits if no hospitalization occurred. Outcomes of interest included patient encounters, medical imaging, and diagnostic testing. Adjusted relative rates were calculated with overdispersed Poisson regression models. RESULTS: Adjusting for patient characteristics, the number of inpatient (relative rate 0.84 vs 2.28) and intensive care days (relative rate 0.45 vs 1.28) varied by more than twofold, whereas office (relative rate 0.77 vs 1.12) and emergency department visits (relative rate 0.71 vs 1.37) varied to a lesser extent. There was also marked variation in the use of imaging, and other diagnostic tests, with particularly high variation in electrocardiography (relative rate 0.35 vs 2.81) and head MRI (relative rate 0.72 vs 2.12). CONCLUSIONS: Depending on where they receive care, children with medical complexity experience widely different patterns of utilization. These findings indicate the need for identifying best practices for this growing patient population. PMID- 26438702 TI - Early Substance Use and Subsequent DUI in Adolescents. AB - OBJECTIVE: Little is known about risk factors in early adolescence that lead to driving under the influence (DUI) and riding with a drinking driver (RWDD). In a diverse group of adolescents, we longitudinally explored the influence of alcohol and marijuana (AM) use, AM beliefs, and peer and family factors (including familism) on DUI/RWDD in high school. METHODS: We conducted 3 surveys 2 years apart of 1189 students recruited from 16 middle schools in Southern California. We used multivariable models to evaluate the effects of AM use, AM beliefs, and peer and family factors at ages 12 and 14 on DUI/RWDD at age 16. RESULTS: At age 12, adolescents with more positive beliefs about marijuana (odds ratio [OR] = 1.63, 95% confidence interval [CI]: 1.20-2.20) and more ability to resist marijuana offers (OR = 1.89, 95% CI: 1.22-2.92) had significantly higher risk of DUI/RWDD 4 years later. At age 14, youth with more past month alcohol use (OR = 2.10, 95% CI: 1.07-4.11), positive beliefs about marijuana (OR = 1.67, 95% CI: 1.31-2.13), exposure to peer AM use (alcohol: OR = 1.01, 95% CI: 1.00-1.02; marijuana: OR = 2.41, 95% CI: 1.28-4.53), and family marijuana use (OR = 1.54, 95% CI: 1.12-2.11) had higher risk of DUI/RWDD at age 16. CONCLUSIONS: Findings indicate a need to target adolescents as young as sixth grade at multiple levels to help prevent DUI/RWDD in high school. Given recent changes in legislation in several states, research should begin to focus on the distinction between DUI/RWDD of AM. PMID- 26438703 TI - Effectiveness and Cost of Bidirectional Text Messaging for Adolescent Vaccines and Well Care. AB - OBJECTIVE: To evaluate the effectiveness and cost of bidirectional short messaging service in increasing rates of vaccination and well child care (WCC) among adolescents. METHODS: We included all adolescents needing a recommended adolescent vaccine (n = 4587) whose parents had a cell-phone number in 5 private and 2 safety-net pediatric practices. Adolescents were randomized to intervention (n = 2228) or control (n = 2359). Parents in the intervention group received up to 3 personalized short messaging services with response options 1 (clinic will call to schedule), 2 (parent will call clinic), or STOP (no further short messaging service). Primary outcomes included completion of all needed services, WCC only, all needed vaccinations, any vaccination, and missed opportunity for vaccination. RESULTS: Intervention patients were more likely to complete all needed services (risk ratio [RR] 1.31, 95% confidence interval [CI] 1.12-1.53), all needed vaccinations (RR 1.29, 95% CI 1.12-1.50), and any vaccination (RR 1.36, 95% CI 1.20-1.54). Seventy-five percent of control patients had a missed opportunity versus 69% of intervention (P = .002). There was not a significant difference for WCC visits. Responding that the clinic should call to schedule ("1") was associated with the highest effect size for completion of all needed services (RR 1.89, 95% CI 1.41-2.54). Net cost ranged from $855 to $3394 per practice. CONCLUSIONS: Bidirectional short messaging service to parents was effective at improving rates for all adolescent vaccinations and for all needed services, especially among parents who responded they desired a call from the practice. PMID- 26438705 TI - Testing for Abuse in Children With Sentinel Injuries. AB - OBJECTIVE: Child physical abuse is commonly missed, putting abused children at risk for repeated injury and death. Several so-called sentinel injuries have been suggested to be associated with high rates of abuse, and to imply the need for routine testing for other, occult traumatic injuries. Our objective was to determine rates of abuse evaluation and diagnosis among children evaluated at leading children's hospitals with these putative sentinel injuries. METHODS: This is a retrospective secondary analysis of the Pediatric Health Information System database. We identified 30 355 children with putative sentinel injuries. We measured rates of abuse diagnosis and rates of testing commonly used to identify occult injuries. RESULTS: Among all visits for children <24 months old to Pediatric Health Information System hospitals, the rate of abuse diagnosis was 0.17%. Rates of abuse diagnosis for children with at least 1 putative sentinel injury ranged from 3.5% for children <12 months old with burns to 56.1% for children <24 months with rib fractures. Rates of skeletal survey and other testing that can identify occult traumatic injury were highly variable between centers and for different injuries. CONCLUSIONS: Several putative sentinel injuries are associated with high rates of physical abuse. Among eligible children with rib fracture(s), abdominal trauma, or intracranial hemorrhage, rates of abuse were more than 20%. Future work is warranted to test whether routine testing for abuse in these children can improve early recognition of abuse. PMID- 26438704 TI - Stigma and Parenting Children Conceived From Sexual Violence. AB - BACKGROUND AND OBJECTIVES: Since armed conflict began in 1996, widespread sexual violence in eastern Democratic Republic of Congo has resulted in many sexual violence-related pregnancies (SVRPs). However, there are limited data on the relationships between mothers and their children from sexual violence. This study aimed to evaluate the nature and determinants of these maternal-child relationships. METHODS: Using respondent-driven sampling, 757 women raising children from SVRPs in South Kivu Province, Democratic Republic of Congo were interviewed. A parenting index was created from questions assessing the maternal child relationship. The influences of social stigma, family and community acceptance, and maternal mental health on the parenting index were assessed in univariate and multivariable analyses. RESULTS: The majority of mothers reported positive attitudes toward their children from SVRPs. Prevalence of perceived family or community stigma toward the women or their children ranged from 31.8% to 42.9%, and prevalence of perceived family or community acceptance ranged from 45.2% to 73.5%. In multivariable analyses, stigma toward the child, as well as maternal anxiety and depression, were associated with lower parenting indexes, whereas acceptance of the mother or child and presence of a spouse were associated with higher parenting indexes (all P <= .01). CONCLUSIONS: In this study with a large sample size, stigma and mental health disorders negatively influenced parenting attitudes, whereas family and community acceptance were associated with adaptive parenting attitudes. Interventions to reduce stigmatization, augment acceptance, and improve maternal mental health may improve the long-term well-being of mothers and children from SVRPs. PMID- 26438706 TI - Interpreting Variability in the Health Care Utilization of Children With Medical Complexity. PMID- 26438707 TI - Hospital Use in the Last Year of Life for Children With Life-Threatening Complex Chronic Conditions. AB - BACKGROUND AND OBJECTIVES: Although many adults experience resource-intensive and costly health care in the last year of life, less is known about these health care experiences in children with life-threatening complex chronic conditions (LT CCCs). We assessed hospital resource use in children by type and number of LT CCCs. METHODS: A retrospective analysis of 1252 children with LT-CCCs, ages 1 to 18 years, who died in 2012 within 40 US children's hospitals of the Pediatric Health Information System database. LT-CCCs were identified with International Classification of Diseases, 9th Revision, Clinical Modification codes. Using generalized linear models, we assessed hospital admissions, days, costs, and interventions (mechanical ventilation and surgeries) in the last year of life by type and number of LT-CCCs. RESULTS: In the last year of life, children with LT CCCs experienced a median of 2 admissions (interquartile range [IQR] 1-5), 27 hospital days (IQR 7-84), and $142 562 (IQR $45 270-$410 087) in hospital costs. During the terminal admission, 76% (n = 946) were mechanically ventilated; 36% (n = 453) underwent surgery. Hospital use was greatest (P < .001) among children with hematologic/immunologic conditions (99 hospital days [IQR 51-146]; cost = $504 145 [IQR $250 147-$879 331]) and children with >=3 LT-CCCs (75 hospital days [IQR 28-132]; cost = $341 222 [IQR $146 698-$686 585]). CONCLUSIONS: Hospital use for children with LT-CCCs in the last year of life varies significantly across the type and number of conditions. Children with hematologic/immunologic or multiple conditions have the greatest hospital use. This information may be useful for clinicians striving to improve care for children with LT-CCCs nearing the end of life. PMID- 26438708 TI - Antenatal Three-Dimensional Printing of Aberrant Facial Anatomy. AB - Congenital airway obstruction poses a life-threatening challenge to the newborn. We present the first case of three-dimensional (3D) modeling and 3D printing of complex fetal maxillofacial anatomy after prenatal ultrasound indicated potential upper airway obstruction from a midline mass of the maxilla. Using fetal MRI and patient-specific computer-aided modeling, the craniofacial anatomy of the fetus was manufactured using a 3D printer. This model demonstrated the mass to be isolated to the upper lip and maxilla, suggesting the oral airway to be patent. The decision was made to deliver the infant without a planned ex utero intrapartum treatment procedure. The neonate was born with a protuberant cleft lip and palate deformity, without airway obstruction, as predicted by the patient specific model. The delivery was uneventful, and the child was discharged without need for airway intervention. This case demonstrates that 3D modeling may improve prenatal evaluation of complex patient-specific fetal anatomy and facilitate the multidisciplinary approach to perinatal management of complex airway anomalies. PMID- 26438709 TI - Surgical Site Infection Reduction by the Solutions for Patient Safety Hospital Engagement Network. AB - OBJECTIVE: Surgical site infections (SSIs) negatively affect patients and the health care system. National standards for SSI prevention do not exist in pediatric settings. We sought to reduce SSI-related harm by implementing a prevention bundle through the Solutions for Patient Safety (SPS) national hospital engagement network. METHODS: Our study period was January 2011 to December 2013. We formed a national workgroup of content and quality improvement experts. We focused on 3 procedure types at high risk for SSIs: cardiothoracic, neurosurgical shunt, and spinal fusion surgeries. We used the Model for Improvement methodology and the Centers for Disease Control and Prevention SSI definition. After literature review and consultation with experts, we distributed a recommended bundle among network partners. Institutions were permitted to adopt all or part of the bundle and reported local bundle adherence and SSI rates monthly. Our learning network used webinars, discussion boards, targeted leader messaging, and in-person learning sessions. RESULTS: Recommended bundle elements encompassed proper preoperative bathing, intraoperative skin antisepsis, and antibiotic delivery. Within 6 months, the network achieved 96.7% reliability among institutions reporting adherence data. A 21% reduction in SSI rate was reported across network hospitals, from a mean baseline rate of 2.5 SSIs per 100 procedures to a mean rate of 1.8 SSIs per 100 procedures. The reduced rate was sustained for 15 months. CONCLUSIONS: Adoption of a SSI prevention bundle with concomitant reliability measurement reduced the network SSI rate. Linking reliability measurement to standardization at an institutional level may lead to safer care. PMID- 26438710 TI - Case Report: When an Induced Illness Looks Like a Rare Disease. AB - The recognition of fabricated illness (FI) in a child represents a diagnostic challenge. The suspicion of FI often arises from the discrepancy between laboratory tests and clinical history. For instance, (unnecessary) insulin injections by caregivers has been widely described as a common cause of factitious hypoglycemia that may be inferred from discrepancies between plasma insulin and c-peptide. However, contemporary administration of insulin with an insulin secretagogue (glyburide), and of additional drugs, can make the diagnostic pathway problematic. We report the case of a child 4 years and 11 months old, admitted for alternance of hypo- and hyperglycemia associated with hirsutism, hypokalemia, nephrocalcinosis, and neurodevelopmental delay. All these features were compatible with Rabson-Mendenhall syndrome, a rare disorder of severe insulin resistance linked to mutations of insulin receptor. At admission, plasma insulin levels were high during hypoglycemic episodes, but c-peptide was repeatedly in the normal range. The genetic analysis of insulin receptor was negative. The story of previous hospital admissions, inconsistency between insulin and c-peptide values, and association between hypoglycemic episodes in the child with the presence of the mother, raised the suspicion of FI. This hypothesis was confirmed by a video recording that revealed the administration by the mother of multiple drugs (insulin, glyburide, progesterone, and furosemide) that mimicked most of the features of Rabson-Mendenhall syndrome, including hirsutism and hypoglycemia with coincident, inappropriately normal c-peptide values due to the administration of the insulin secretagogue. Our case indicates that inconsistency among consecutive diagnostic tests should be regarded as a clue of FI. PMID- 26438711 TI - Deferred Consent for Randomized Controlled Trials in Emergency Care Settings. AB - BACKGROUND: There is limited experience in using deferred consent for studies involving children, which was legalized in the United Kingdom in 2008. We aimed to inform future studies by evaluating consent rates and reasons for nonconsent in a large randomized controlled trial in pediatric intensive care. METHODS: In the CATCH trial, eligible children from 14 PICUs in England and Wales were randomly assigned to 3 types of central venous catheters. To avoid delay in treatment, children admitted on an emergency basis were first randomly assigned to a trial central venous catheter, and we deferred seeking consent to use already collected data and blood samples until after stabilization. RESULTS: Consent was obtained for 984/1358 (72%) of children admitted on an emergency basis. Failure to obtain consent resulted mainly from a lack of opportunity (early discharge or transfer) for survivors and difficulties in seeking consent for children who died. For admissions where there was an opportunity to approach (n = 1298), inclusion rates differed according to survival status: 93/984 (9%) of consented patients died, compared with 58/314 (18%) of nonconsented patients. For children admitted on an emergency basis whose families were approached, 984/1178 (84%) provided deferred consent (n = 15 sites), compared with 441/641 (69%) of children admitted on an elective basis who were approached for prospective consent (n = 9 sites). CONCLUSIONS: Design of emergency randomized controlled trials should balance the potential burden that seeking consent in difficult situations may cause against risk of bias by disproportionately excluding children who die or are transferred. Ethics committees could consider approving the use of already collected data when best efforts to obtain deferred consent are unsuccessful. PMID- 26438712 TI - Risk Factors for Central Nervous System Tuberculosis. AB - OBJECTIVES: To describe the epidemiology and factors associated with pediatric central nervous system (CNS) tuberculosis (TB) in California from 1993 to 2011. METHODS: We analyzed California TB registry data for persons aged <=18 years, comparing CNS TB cases versus non-CNS TB cases reported from 1993 to 2011. Factors associated with CNS TB and TB deaths were identified by using multivariate logistic regression. RESULTS: A total of 200 CNS TB cases were reported. Compared with non-CNS TB case patients, CNS TB case patients were more likely to be aged <5 years (72.0% vs 43.6%; odds ratio [OR]: 3.8 [95% confidence interval (CI): 2.4-5.9]), US-born (82.0% vs 58.2%; OR: 3.3 [CI: 2.3-4.7]), and Hispanic (75.0% vs 63.2%; OR: 1.7 [CI: 1.3-2.4]). Among US-born CNS TB case patients (during 2010-2011), 76.5% had a foreign-born parent. Tuberculin skin test results were negative in 38.2% of 170 CNS TB cases tested. In multivariate analysis, age <5 years (adjusted odds ratio [aOR]: 3.3 [CI: 2.0-5.4]), US birth (aOR: 1.8 [CI 1.2-2.7]), and Hispanic ethnicity (aOR: 1.5 [CI: 1.1-2.1]) were associated with an increased risk of developing CNS TB. For deaths, CNS TB (aOR: 3.8 [CI: 1.4-9.9]) and culture positivity (aOR: 6.2 [CI: 2.2-17.3]) were associated with increased risk of death, whereas tuberculin skin test positivity (aOR: 0.1 [CI: 0.04-0.2]) was associated with decreased risk. CONCLUSIONS: Subsets of children are at increased risk for CNS TB in California and may benefit from additional prevention efforts. PMID- 26438713 TI - Taking Humanism Back to the Bedside. PMID- 26438714 TI - Mucosal Healing in Ulcerative Colitis--When Zero is Better. AB - BACKGROUND AND AIMS: Extensive evidence has underlined the importance of mucosal healing as a treatment aim for ulcerative colitis (UC). We aimed to assess differences in the incidence of clinical relapse at 12 months between UC patients with Mayo endoscopic scores (MES) 0 and 1. METHODS: This retrospective study included consecutive patients in corticosteroid-free remission between 2008 and 2013 and with follow-up of at least 1 year, with MES 0 or 1 in complete colonoscopy. Clinical relapse was defined as need for induction treatment, treatment escalation, hospitalization or surgery. A p value <0.05 was considered statistically significant. RESULTS: The study included 138 patients, 72 (52.2%) female, with mean age of 49 (+/-14) years. Inflammatory activity was classified as MES 0 in 61 (44.2%) patients and MES 1 in 77 (55.8%) patients. Clinical relapse during follow-up was significantly more frequent in patients with MES 1 than MES 0 (27.3 vs 11.5%, p = 0.022), and in the multivariate analysis MES 1 was the only factor significantly associated with an increased risk of relapse (odds ratio 2.89, 95% confidence interval 1.14-7.36, p = 0.026). This association was encountered in the subgroup of patients with left-sided/extensive colitis (29.7 vs 11.1%, p = 0.049), but not proctitis (25.0 vs 12.0%, p = 0.202). CONCLUSIONS: In patients with UC in corticosteroid-free remission, particularly those with left-sided colitis or extensive colitis, MES 1 was significantly associated with a 3-fold increased risk of relapse compared with endoscopic MES 0. Our results support the use of endoscopic MES 0 as the most suitable treatment endpoint to define mucosal healing in patients with UC. PMID- 26438715 TI - Variability in the detection of macro TSH in different immunoassay systems. AB - DESIGN: Macro TSH is a large molecular-sized TSH that is mostly a complex of TSH and IgG. Patients with macro TSH have elevated serum TSH and normal free thyroxine levels, mimicking subclinical hypothyroidism. The aim of this study was to clarify the degree of cross-reactivity of macro TSH to different commercial immunoassay systems. METHODS: Screening for macro TSH was done using a polyethylene glycol (PEG) method and confirmed with gel filtration chromatography in serum samples from 1901 patients with subclinical hypothyroidism. Interference due to human anti-mouse antibodies (HAMA) was examined using HAMA blockers. TSH was measured with an enzyme immunoassay for the analysis of macro TSH. Serum TSH values in patients with macro TSH were also determined with the widely used commercial immunoassay platforms Elecsys, Centaur and Architect, and the detectability of macro TSH was compared among them. RESULTS: Gel filtration chromatography was performed with 174 serum samples with PEG-precipitable TSH ratios >75%. Twenty serum samples were found to contain large molecular-sized TSH, five of which were due to interference by HAMA. The prevalence of macro TSH was eventually 0.79% (15/1901). Commercial immunoassay systems variably recognized macro TSH. The Architect TSH immunoassay platform was the least reactive to macro TSH, but still recognized it in 60% of macro TSH-containing serum samples. CONCLUSIONS: There were no commercial TSH immunoassay platforms that did not cross-react with macro TSH. Screening for macro TSH should be performed before hormone replacement therapy is initiated for subclinical hypothyroidism. PMID- 26438716 TI - Antioxidative Properties and Effect of Quercetin and Its Glycosylated Form (Rutin) on Acetylcholinesterase and Butyrylcholinesterase Activities. AB - This study sought to investigate the anticholinesterase and antioxidative properties of quercetin and its glycosylated conjugate, rutin. The in vitro inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities, inhibition of Fe(2+)-induced lipid peroxidation in rat's brain homogenates, radicals scavenging, and Fe(2+)-chelating abilities of the flavonoids were investigated in vitro with concentrations of the samples ranging from 0.06 to 0.6 mM. Quercetin had significantly higher AChE and BChE inhibitory abilities than rutin. Quercetin also had stronger inhibition of Fe(2+)-induced lipid peroxidation in rat's brain homogenates. Similarly, quercetin had higher radical scavenging abilities than rutin. Quercetin also had stronger Fe(2+) chelating ability than rutin. The inhibition of cholinesterases and antioxidative properties are possible mechanisms by which the flavonoids can be used in the management of oxidative stress-induced neurodegeneration. PMID- 26438717 TI - Spread of Traditional Medicines in India: Results of National Sample Survey Organization's Perception Survey on Use of AYUSH. AB - For the first time, we have a comprehensive database on usage of AYUSH (acronym for Ayurveda, naturopathy and Yoga, Unani, Siddha, and Homeopathy) in India at the household level. This article aims at exploring the spread of the traditional medical systems in India and the perceptions of people on the access and effectiveness of these medical systems using this database. The article uses the unit level data purchased from the National Sample Survey Organization, New Delhi. Household is the basic unit of survey and the data are the collective opinion of the household. This survey shows that less than 30% of Indian households use the traditional medical systems. There is also a regional pattern in the usage of particular type of traditional medicine, reflecting the regional aspects of the development of such medical systems. The strong faith in AYUSH is the main reason for its usage; lack of need for AYUSH and lack of awareness about AYUSH are the main reasons for not using it. With regard to source of medicines in the traditional medical systems, home is the main source in the Indian medical system and private sector is the main source in Homeopathy. This shows that there is need for creating awareness and improving access to traditional medical systems in India. By and large, the users of AYUSH are also convinced about the effectiveness of these traditional medicines. PMID- 26438718 TI - The Role of Date Palm (Phoenix dactylifera L) Pollen in Fertility: A Comprehensive Review of Current Evidence. AB - Date palm pollen (DPP) is the male reproductive dust of palm flowers used as dietary supplement especially as aphrodisiac and fertility enhancer in both women and men from ancient times. Although there are few clinical trials evaluating the beneficial effects of DPP in humans, various experimental studies have been conducted on the reproductive effects of DPP. Among the compounds isolated from DPP are amino acids, fatty acids, flavonoids, saponins, and estroles. The present review summarizes comprehensive information concerning the phytochemistry and pharmacological activities of DPP and its application in fertility disorders. PMID- 26438719 TI - Barriers to Implementing a Reporting and Learning Patient Safety System: Pediatric Chiropractic Perspective. AB - A reporting and learning system is a method of monitoring the occurrence of incidents that affect patient safety. This cross-sectional survey asked pediatric chiropractors about factors that may limit their participation in such a system. The list of potential barriers for participation was developed using a systematic approach. All members of the 2 pediatric councils associated with US national chiropractic organizations were invited to complete the survey (N = 400). The cross-sectional survey was created using an online survey tool (REDCap) and sent directly to member emails addressed by the respective executive committees. Of the 400 potential respondents, 81 responded (20.3%). The most common limitations to participating were identified as time pressure (96%) and patient concerns (81%). Reporting and learning systems have been utilized to increase safety awareness in many high-risk industries. To be successful, future patient safety studies with pediatric chiropractors need to ensure these barriers are understood and addressed. PMID- 26438720 TI - Incorporating an Exercise Detection, Grading, and Hormone Dosing Algorithm Into the Artificial Pancreas Using Accelerometry and Heart Rate. AB - In this article, we present several important contributions necessary for enabling an artificial endocrine pancreas (AP) system to better respond to exercise events. First, we show how exercise can be automatically detected using body-worn accelerometer and heart rate sensors. During a 22 hour overnight inpatient study, 13 subjects with type 1 diabetes wearing a Zephyr accelerometer and heart rate monitor underwent 45 minutes of mild aerobic treadmill exercise while controlling their glucose levels using sensor-augmented pump therapy. We used the accelerometer and heart rate as inputs into a validated regression model. Using this model, we were able to detect the exercise event with a sensitivity of 97.2% and a specificity of 99.5%. Second, from this same study, we show how patients' glucose declined during the exercise event and we present results from in silico modeling that demonstrate how including an exercise model in the glucoregulatory model improves the estimation of the drop in glucose during exercise. Last, we present an exercise dosing adjustment algorithm and describe parameter tuning and performance using an in silico glucoregulatory model during an exercise event. PMID- 26438721 TI - Inhibiting myostatin signaling prevents femoral trabecular bone loss and microarchitecture deterioration in diet-induced obese rats. AB - Besides resulting in a dramatic increase in skeletal muscle mass, myostatin (MSTN) deficiency has a positive effect on bone formation. However, the issue about whether blocking MSTN can inhibit obesity-induced bone loss has not been previously investigated. In the present study, we have evaluated the effects of MSTN blocking on bone quality in high-fat (HF), diet-induced obese rats using a prepared polyclonal antibody for MSTN (MsAb). Twenty-four rats were randomly assigned to the Control, HF and HF + MsAb groups. Rats in the HF + MsAb group were injected once a week with purified MsAb for eight weeks. The results showed that MsAb significantly reduced body and fat weight, and increased muscle mass and strength in the HF group. MicroCT analysis demonstrated that obesity-induced bone loss and architecture deterioration were significantly mitigated by MsAb treatment, as evidenced by increased bone mineral density, bone volume over total volume, trabecular number and thickness, and decreased trabecular separation and structure model index. However, neither HF diet nor MsAb treatment had an impact on femoral biomechanical properties including maximum load, stiffness, energy absorption and elastic modulus. Moreover, MsAb significantly increased adiponectin concentrations, and decreased TNF-alpha and IL-6 levels in diet induced obese rats. Taken together, blocking MSTN by MsAb improves bone quality in diet-induced obese rats through a mechanotransduction pathway from skeletal muscle, and the accompanying changes occurring in the levels of circulating adipokines and pro-inflammatory cytokines may also be involved in this process. It indicates that the administration of MSTN antagonists may be a promising therapy for treating obesity and obesity-induced bone loss. PMID- 26438722 TI - Phospholipid methylation controls Atg32-mediated mitophagy and Atg8 recycling. AB - Degradation of mitochondria via selective autophagy, termed mitophagy, contributes to mitochondrial quality and quantity control whose defects have been implicated in oxidative phosphorylation deficiency, aberrant cell differentiation, and neurodegeneration. How mitophagy is regulated in response to cellular physiology remains obscure. Here, we show that mitophagy in yeast is linked to the phospholipid biosynthesis pathway for conversion of phosphatidylethanolamine to phosphatidylcholine by the two methyltransferases Cho2 and Opi3. Under mitophagy-inducing conditions, cells lacking Opi3 exhibit retardation of Cho2 repression that causes an anomalous increase in glutathione levels, leading to suppression of Atg32, a mitochondria-anchored protein essential for mitophagy. In addition, loss of Opi3 results in accumulation of phosphatidylmonomethylethanolamine (PMME) and, surprisingly, generation of Atg8 PMME, a mitophagy-incompetent lipid conjugate of the autophagy-related ubiquitin like modifier. Amelioration of Atg32 expression and attenuation of Atg8-PMME conjugation markedly rescue mitophagy in opi3-null cells. We propose that proper regulation of phospholipid methylation is crucial for Atg32-mediated mitophagy. PMID- 26438723 TI - Alzheimer's disease-causing proline substitutions lead to presenilin 1 aggregation and malfunction. AB - Do different neurodegenerative maladies emanate from the failure of a mutual protein folding mechanism? We have addressed this question by comparing mutational patterns that are linked to the manifestation of distinct neurodegenerative disorders and identified similar neurodegeneration-linked proline substitutions in the prion protein and in presenilin 1 that underlie the development of a prion disorder and of familial Alzheimer's disease (fAD), respectively. These substitutions were found to prevent the endoplasmic reticulum (ER)-resident chaperone, cyclophilin B, from assisting presenilin 1 to fold properly, leading to its aggregation, deposition in the ER, reduction of gamma secretase activity, and impaired mitochondrial distribution and function. Similarly, reduced quantities of the processed, active presenilin 1 were observed in brains of cyclophilin B knockout mice. These discoveries imply that reduced cyclophilin activity contributes to the development of distinct neurodegenerative disorders, propose a novel mechanism for the development of certain fAD cases, and support the emerging theme that this disorder can stem from aberrant presenilin 1 function. This study also points at ER chaperones as targets for the development of counter-neurodegeneration therapies. PMID- 26438724 TI - H3K9 methylation extends across natural boundaries of heterochromatin in the absence of an HP1 protein. AB - Proteins of the conserved HP1 family are elementary components of heterochromatin and are generally assumed to play a central role in the creation of a rigid, densely packed heterochromatic network that is inaccessible to the transcription machinery. Here, we demonstrate that the fission yeast HP1 protein Swi6 exists as a single highly dynamic population that rapidly exchanges in cis and in trans between different heterochromatic regions. Binding to methylated H3K9 or to heterochromatic RNA decelerates Swi6 mobility. We further show that Swi6 is largely dispensable to the maintenance of heterochromatin domains. In the absence of Swi6, H3K9 methylation levels are maintained by a mechanism that depends on polymeric self-association properties of Tas3, a subunit of the RNA-induced transcriptional silencing complex. Our results disclose a surprising role for Swi6 dimerization in demarcating constitutive heterochromatin from neighboring euchromatin. Thus, rather than promoting maintenance and spreading of heterochromatin, Swi6 appears to limit these processes and appropriately confine heterochromatin. PMID- 26438725 TI - MED23: a new Mediator of H2B monoubiquitylation. AB - The Mediator multiprotein complex physically links transcription factors to RNA polymerase II and the basal transcription machinery. While the Mediator complex has been shown to be required for transcriptional initiation and elongation, the understanding of its interplay with histone modifying enzymes and post translational modifications remains elusive. In this issue of The EMBO Journal, Yao et al (2015) report that the MED23 subunit of the Mediator complex physically associates with the heterodimeric RNF20/40 E3-ligase complex to facilitate the monoubiquitylation of histone H2B on gene bodies of actively transcribed genes. PMID- 26438727 TI - Finding the fifth intercostal space for chest drain insertion: guidelines and ultrasound. AB - OBJECTIVES: International guidelines exist for chest drain insertion and recommend identifying the fifth intercostal space or above, around the midaxillary line. In a recent study, applying these guidelines in cadavers risked insertion in the 6th intercostal space or below in 80% of cases. However, there are limitations of cadaveric studies and this investigation uses ultrasound to determine the intercostal space identified when applying these guidelines in healthy adult volunteers. METHODS: On each side of the chest wall in 31 volunteers, the position for drain insertion was identified using the European Trauma Course method, Advanced Trauma Life Support (ATLS) method, British Thoracic Society's 'safe triangle' and the 'traditional' method of palpation. Ultrasound imaging was used to determine the relationship of the skin marks with the underlying intercostal spaces. RESULTS: Five methods were assessed on 60 sides. In contrast to the cadaveric study, 94% of skin marks lay over a safe intercostal space. However, the range of intercostal spaces found spanned the second to the seventh space. In 44% of women, the inferior boundary of the 'safe triangle' and the ATLS guidelines located the sixth intercostal space or below. CONCLUSIONS: Current guidelines often identify a safe site for chest drain insertion, although the same site is not reproducibly found. In addition, women appear to be at risk of subdiaphragmatic drain insertion when the nipple is used to identify the fifth intercostal space. Real-time ultrasonography can be used to confirm the intercostal space during this procedure, although a safe guideline is still needed for circumstances in which ultrasound is not possible. PMID- 26438726 TI - The balance of Id3 and E47 determines neural stem/precursor cell differentiation into astrocytes. AB - Adult neural stem/precursor cells (NSPCs) of the subventricular zone (SVZ) are an endogenous source for neuronal replacement in CNS disease. However, adult neurogenesis is compromised after brain injury in favor of a glial cell fate, which is mainly attributed to changes in the NSPC environment. Yet, it is unknown how this unfavorable extracellular environment translates into a transcriptional program altering NSPC differentiation. Here, we show that genetic depletion of the transcriptional regulator Id3 decreased the number of astrocytes generated from SVZ-derived adult NSPCs in the cortical lesion area after traumatic brain injury. Cortical brain injury resulted in rapid BMP-2 and Id3 up-regulation in the SVZ stem cell niche. Id3(-/-) adult NSPCs failed to differentiate into BMP-2 induced astrocytes, while NSPCs deficient for the Id3-controlled transcription factor E47 readily differentiated into astrocytes in the absence of BMP-2. Mechanistically, E47 repressed the expression of several astrocyte-specific genes in adult NSPCs. These results identify Id3 as the BMP-2-induced transcriptional regulator, promoting adult NSPC differentiation into astrocytes upon CNS injury and reveal a molecular link between environmental changes and NSPC differentiation in the CNS after injury. PMID- 26438728 TI - Celecoxib reduces glucocorticoids in vitro and in a mouse model with adrenocortical hyperplasia. AB - Primary pigmented nodular adrenocortical disease (PPNAD), whether in the context of Carney complex (CNC) or isolated, leads to ACTH-independent Cushing's syndrome (CS). CNC and PPNAD are caused typically by inactivating mutations of PRKAR1A, a gene coding for the type 1a regulatory subunit (R1alpha) of cAMP-dependent protein kinase (PKA). Mice lacking Prkar1a, specifically in the adrenal cortex (AdKO) developed CS caused by bilateral adrenal hyperplasia (BAH), which is formed from the abnormal proliferation of fetal-like adrenocortical cells. Celecoxib is a cyclooxygenase 2 (COX2) inhibitor. In bone, Prkar1a inhibition is associated with COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of bone stromal cells. We hypothesized that COX2 inhibition may have an effect in PPNAD. In vitro treatment of human cell lines, including one from a patient with PPNAD, with celecoxib resulted in decreased cell viability. We then treated AdKO and control mice with 1500 mg/kg celecoxib or vehicle. Celecoxib treatment led to decreased PGE2 and corticosterone levels, reduced proliferation and increased apoptosis of adrenocortical cells, and decreased steroidogenic gene expression. We conclude that, in vitro and in vivo, celecoxib led to decreased steroidogenesis. In a mouse model of PPNAD, celecoxib caused histological changes that, at least in part, reversed BAH and this was associated with a reduction of corticosterone levels. PMID- 26438730 TI - Subtle modulation of ongoing calcium dynamics in astrocytic microdomains by sensory inputs. AB - Astrocytes communicate with neurons through their processes. In vitro experiments have demonstrated that astrocytic processes exhibit calcium activity both spontaneously and in response to external stimuli; however, it has not been fully determined whether and how astrocytic subcellular domains respond to sensory input in vivo. We visualized the calcium signals in astrocytes in the primary visual cortex of awake, head-fixed mice. Bias-free analyses of two-photon imaging data revealed that calcium activity prevailed in astrocytic subcellular domains, was coordinated with variable spot-like patterns, and was dominantly spontaneous. Indeed, visual stimuli did not affect the frequency of calcium domain activity, but it increased the domain size, whereas tetrodotoxin reduced the sizes of spontaneous calcium domains and abolished their visual responses. The "evoked" domain activity exhibited no apparent orientation tuning and was distributed unevenly within the cell, constituting multiple active hotspots that were often also recruited in spontaneous activity. The hotspots existed dominantly in the somata and endfeet of astrocytes. Thus, the patterns of astrocytic calcium dynamics are intrinsically constrained and are subject to minor but significant modulation by sensory input. PMID- 26438731 TI - Renal stromal miRNAs are required for normal nephrogenesis and glomerular mesangial survival. AB - MicroRNAs are small noncoding RNAs that post-transcriptionally regulate mRNA levels. While previous studies have demonstrated that miRNAs are indispensable in the nephron progenitor and ureteric bud lineage, little is understood about stromal miRNAs during kidney development. The renal stroma (marked by expression of FoxD1) gives rise to the renal interstitium, a subset of peritubular capillaries, and multiple supportive vascular cell types including pericytes and the glomerular mesangium. In this study, we generated FoxD1(GC);Dicer(fl/fl) transgenic mice that lack miRNA biogenesis in the FoxD1 lineage. Loss of Dicer activity resulted in multifaceted renal anomalies including perturbed nephrogenesis, expansion of nephron progenitors, decreased renin-expressing cells, fewer smooth muscle afferent arterioles, and progressive mesangial cell loss in mature glomeruli. Although the initial lineage specification of FoxD1(+) stroma was not perturbed, both the glomerular mesangium and renal interstitium exhibited ectopic apoptosis, which was associated with increased expression of Bcl2l11 (Bim) and p53 effector genes (Bax, Trp53inp1, Jun, Cdkn1a, Mmp2, and Arid3a). Using a combination of high-throughput miRNA profiling of the FoxD1(+) derived cells and mRNA profiling of differentially expressed transcripts in FoxD1(GC);Dicer(fl/fl) kidneys, at least 72 miRNA:mRNA target interactions were identified to be suppressive of the apoptotic program. Together, the results support an indispensable role for stromal miRNAs in the regulation of apoptosis during kidney development. PMID- 26438729 TI - Immunity and immune modulation in Trypanosoma cruzi infection. AB - Chagas disease is caused by the protozoan Trypanosoma cruzi. The parasite reaches the secondary lymphoid organs, the heart, skeletal muscles, neurons in the intestine and esophagus among other tissues. The disease is characterized by mega syndromes, which may affect the esophagus, the colon and the heart, in about 30% of infected people. The clinical manifestations associated with T. cruzi infection during the chronic phase of the disease are dependent on complex interactions between the parasite and the host tissues, particularly the lymphoid system that may either result in a balanced relationship with no disease or in an unbalanced relationship that follows an inflammatory response to parasite antigens and associated tissues in some of the host organs and/or by an autoimmune response to host antigens. This review discusses the findings that support the notion of an integrated immune response, considering the innate and adaptive arms of the immune system in the control of parasite numbers and also the mechanisms proposed to regulate the immune response in order to tolerate the remaining parasite load, during the chronic phase of infection. This knowledge is fundamental to the understanding of the disease progression and is essential for the development of novel therapies and vaccine strategies. PMID- 26438734 TI - Erratum. PMID- 26438732 TI - The effects of intragastric infusion of umami solutions on amygdalar and lateral hypothalamic neurons in rats. AB - Previous behavioral studies have suggested that l-glutamate, an umami substance, is detected in the gut, and that this information regarding glutamate is conveyed from the gut to the amygdala and the lateral hypothalamus (LH) through the vagus nerve to establish glutamate preference. In this study, we investigated the roles of the amygdala and LH in the information processing of gut glutamate. We recorded the activity of amygdalar and LH neurons during the intragastric administration of five test solutions (monosodium l-glutamate [MSG, 60 mmol/L]; inosine monophosphate [IMP, 60 mmol/L]; a mixture of MSG and IMP; NaCl [60 mmol/L]; or physiological saline) in intact and subdiaphragmatic vagotomized awake rats. In intact rats, 349 and 189 neurons were recorded from the amygdala and LH, respectively, while in vagotomized rats, 104 and 90 neurons were recorded from the amygdala and LH, respectively. In intact rats, similar percentages of neurons (30-60%) in the amygdala and LH responded to the intragastric infusion of the solutions. Vagotomy significantly altered responses to the MSG and NaCl solutions. In particular, vagotomy suppressed the inhibitory responses to the NaCl solution. Furthermore, vagotomy increased the response similarity between the MSG and NaCl solutions, suggesting that vagotomy impaired the coding of the postingestive consequences of the MSG solution in the amygdala and LH, which are unique for glutamate. The present results provide the first neurophysiological evidence that amygdalar and LH neurons process glutamate signals from the gut. PMID- 26438735 TI - The Interplay Between Health And Social Supports. PMID- 26438733 TI - PGC-1 isoforms and their target genes are expressed differently in human skeletal muscle following resistance and endurance exercise. AB - The primary aim of the present study was to investigate the acute gene expression responses of PGC-1 isoforms and PGC-1alpha target genes related to mitochondrial biogenesis (cytochrome C), angiogenesis (VEGF-A), and muscle hypertrophy (myostatin), after a resistance or endurance exercise bout. In addition, the study aimed to elucidate whether the expression changes of studied transcripts were linked to phosphorylation of AMPK and MAPK p38. Nineteen physically active men were divided into resistance exercise (RE, n = 11) and endurance exercise (EE, n = 8) groups. RE group performed leg press exercise (10 * 10 RM, 50 min) and EE walked on a treadmill (~80% HRmax, 50 min). Muscle biopsies were obtained from the vastus lateralis muscle before, 30 min, and 180 min after exercise. EE and RE significantly increased the gene expression of alternative promoter originated PGC-1alpha exon 1b- and 1bxs'-derived isoforms, whereas the proximal promoter originated exon 1a-derived transcripts were less inducible and were upregulated only after EE. Truncated PGC-1alpha transcripts were upregulated both after EE and RE. Neither RE nor EE affected the expression of PGC-1beta. EE upregulated the expression of cytochrome C and VEGF-A, whereas RE upregulated VEGF-A and downregulated myostatin. Both EE and RE increased the levels of p-AMPK and p-MAPK p38, but these changes were not linked to the gene expression responses of PGC-1 isoforms. The present study comprehensively assayed PGC-1 transcripts in human skeletal muscle and showed exercise mode-specific responses thus improving the understanding of early signaling events in exercise-induced muscle adaptations. PMID- 26438736 TI - An Overdose Antidote Goes Mainstream. PMID- 26438737 TI - Connecticut's 'Money Follows The Person' Yields Positive Results For Transitioning People Out Of Institutions. AB - A centerpiece of federal and state efforts to rebalance long-term services and supports to enhance consumer choice and contain costs, the federal Money Follows the Person Rebalancing Demonstration helps qualified individuals living in institutions make the transition to life in the community. The Connecticut Money Follows the Person program is an unusually rich source of data, with information on the 2,262 people who transitioned to the community under that state's program during 2008-14. Responses to participant surveys completed before and six, twelve, and twenty-four months after transition indicate that, for the majority of respondents who remained in the community, quality of life and life satisfaction improved significantly after transition, and they stayed high. About half of the participants visited hospitals or emergency departments after transition; however, only 14 percent had returned to an institution one year after transition. Predictors of reinstitutionalization included some not previously observed: mental health disability, difficulties with family members before transition, and not exercising choice and control in daily life. These and other findings suggest multiple ways in which policy makers can target efforts to strengthen transition programs that can meaningfully improve people's lives while containing costs. PMID- 26438738 TI - US Prevalence And Predictors Of Informal Caregiving For Dementia. PMID- 26438739 TI - The Disproportionate Impact Of Dementia On Family And Unpaid Caregiving To Older Adults. AB - The number of US adults ages sixty-five and older who are living with dementia is substantial and expected to grow, raising concerns about the demands that will be placed on family members and other unpaid caregivers. We used data from the 2011 National Health and Aging Trends Study and its companion study, the National Study of Caregiving, to investigate the role of dementia in caregiving. We found that among family and unpaid caregivers to older noninstitutionalized adults, one third of caregivers, and 41 percent of the hours of help they provide, help people with dementia, who account for about 10 percent of older noninstitutionalized adults. Among older adults who receive help, the vast majority in both community and residential care settings other than nursing homes rely on family or unpaid caregivers (more than 90 percent and more than 80 percent, respectively), regardless of their dementia status. Caregiving is most intense, however, to older adults with dementia in community settings and from caregivers who are spouses or daughters or who live with the care recipient. PMID- 26438740 TI - Integrated Payment And Delivery Models Offer Opportunities And Challenges For Residential Care Facilities. AB - Under health care reform, new financing and delivery models are being piloted to integrate health and long-term care services for older adults. Programs using these models generally have not included residential care facilities. Instead, most of them have focused on long-term care recipients in the community or the nursing home. Our analyses indicate that individuals living in residential care facilities have similarly high rates of chronic illness and Medicare utilization when compared with matched individuals in the community and nursing home, and rates of functional dependency that fall between those of their counterparts in the other two settings. These results suggest that the residential care facility population could benefit greatly from models that coordinated health and long term care services. However, few providers have invested in the infrastructure needed to support integrated delivery models. Challenges to greater care integration include the private-pay basis for residential care facility services, which precludes shared savings from reduced Medicare costs, and residents' preference for living in a home-like, noninstitutional environment. PMID- 26438741 TI - Nearly Half Of US Adults Living With HIV Received Federal Disability Benefits In 2009. AB - The effects of HIV infection on national labor-force participation have not been rigorously evaluated. Using data from the Medical Monitoring Project and the National Health Interview Survey, we present nationally representative estimates of the receipt of disability benefits by adults living with HIV receiving care compared with the general US adult population. We found that in 2009, adults living with HIV were nine times more likely than adults in the general population to receive disability benefits. The risk of being on disability is also greater for younger and more educated adults living with HIV compared to the general population, which suggests that productivity losses can result from HIV infection. To prevent disability, early diagnosis and treatment of HIV are essential. This study offers a baseline against which to measure the impacts of recently proposed or enacted changes to Medicaid and private insurance markets, including the Affordable Care Act and proposed revisions to the Social Security Administration's HIV Infection Listings. PMID- 26438742 TI - Broad Hepatitis C Treatment Scenarios Return Substantial Health Gains, But Capacity Is A Concern. AB - Treatment of hepatitis C virus, the most common chronic viral infection in the United States, has historically suffered from challenges including serious side effects, low efficacy, and ongoing transmission and reinfection. Recent innovations have produced breakthrough therapies that are effective in more than 90 percent of patients. These treatments could dramatically reduce the virus's prevalence but are costly. To quantify the benefit of these treatments to society, including the value of reduced transmission, we estimated the effects of several hepatitis C treatment strategies on cost and population health. Treating patients at all disease stages could generate $610-$1,221 billion in additional quality-adjusted life-years, plus an additional $139 billion in saved medical expenditures over fifty years, and minimize the disease burden, but up-front treatment costs would exceed $150 billion. An intermediate scenario--treating 5 percent of the infected population annually, regardless of patients' disease stages--would also return substantial benefits and would be much more affordable under current financing schemes. PMID- 26438744 TI - Medicare's Part D Drug Benefit At 10 Years: Firmly Established But Still Evolving. PMID- 26438743 TI - High-Cost Patients Had Substantial Rates Of Leaving Medicare Advantage And Joining Traditional Medicare. AB - Medicare Advantage payment regulations include risk-adjusted capitated reimbursement, which was implemented to discourage favorable risk selection and encourage the retention of members who incur high costs. However, the extent to which risk-adjusted capitation has succeeded is not clear, especially for members using high-cost services not previously considered in assessments of risk selection. We examined the rates at which participants who used three high-cost services switched between Medicare Advantage and traditional Medicare. We found that the switching rate from 2010 to 2011 away from Medicare Advantage and to traditional Medicare exceeded the switching rate in the opposite direction for participants who used long-term nursing home care (17 percent versus 3 percent), short-term nursing home care (9 percent versus 4 percent), and home health care (8 percent versus 3 percent). These results were magnified among people who were enrolled in both Medicare and Medicaid. Our findings raise questions about the role of Medicare Advantage plans in serving high-cost patients with complex care needs, who account for a disproportionately high amount of total health care spending. PMID- 26438745 TI - California's Early ACA Expansion Increased Coverage And Reduced Out-Of-Pocket Spending For The State's Low-Income Population. AB - The Affordable Care Act (ACA) expanded eligibility for Medicaid to millions of low-income adults. While many expanding states implemented their expansion in 2014, five states and the District of Columbia expanded eligibility as early as 2010 by taking advantage of provisions in the ACA and Medicaid waivers. We used restricted data from the National Health Interview Survey to examine the impact of California's Low Income Health Program, an early expansion program that began in 2011. Our study demonstrates that the county-by-county rollout of expanded public insurance coverage in California significantly increased coverage, by 7 percentage points, and significantly reduced the likelihood of any family out-of pocket medical spending in the previous year, by 10 percentage points, among low income adults. PMID- 26438746 TI - Out-Of-Pocket Prescription Costs Under A Typical Silver Plan Are Twice As High As They Are In The Average Employer Plan. AB - The health insurance Marketplaces created under the Affordable Care Act have attracted nearly ten million enrollees, including many people who were previously insured by an employer-sponsored plan. The most popular Marketplace plan--the silver plan--has significantly higher cost sharing than does a typical employer sponsored plan, which may cause patients to reduce the use of cost-saving services that are essential for managing chronic conditions. We estimated the impact of higher cost sharing on drug and medical spending among patients with chronic conditions. Using national data, we compared cost sharing and prescription and medical spending for patients covered by employer-sponsored plans to the spending for those in a typical silver plan in the Marketplaces. Our results show that out-of-pocket expenses for medications in a typical silver plan are twice as high as they are in the average employer-sponsored plan, resulting in fewer prescriptions filled and refilled and in higher spending on other medical services. Maintaining the use of cost-effective prescription medications might require lower cost sharing for patients with chronic conditions than is currently found in the Marketplaces. PMID- 26438747 TI - Assessing Latin America's Progress Toward Achieving Universal Health Coverage. AB - Two commonly used metrics for assessing progress toward universal health coverage involve assessing citizens' rights to health care and counting the number of people who are in a financial protection scheme that safeguards them from high health care payments. On these metrics most countries in Latin America have already "reached" universal health coverage. Neither metric indicates, however, whether a country has achieved universal health coverage in the now commonly accepted sense of the term: that everyone--irrespective of their ability to pay- gets the health services they need without suffering undue financial hardship. We operationalized a framework proposed by the World Bank and the World Health Organization to monitor progress under this definition and then constructed an overall index of universal health coverage achievement. We applied the approach using data from 112 household surveys from 1990 to 2013 for all twenty Latin American countries. No country has achieved a perfect universal health coverage score, but some countries (including those with more integrated health systems) fare better than others. All countries except one improved in overall universal health coverage over the time period analyzed. PMID- 26438748 TI - Risk Selection Threatens Quality Of Care For Certain Patients: Lessons From Europe's Health Insurance Exchanges. AB - Experience in European health insurance exchanges indicates that even with the best risk-adjustment formulas, insurers have substantial incentives to engage in risk selection. The potentially most worrisome form of risk selection is skimping on the quality of care for underpriced high-cost patients--that is, patients for whom insurers are compensated at a rate lower than the predicted health care expenses of these patients. In this article we draw lessons for the United States from twenty years of experience with health insurance exchanges in Europe, where risk selection is a serious problem. Mistakes by European legislators and inadequate evaluation criteria for risk selection incentives are discussed, as well as strategies to reduce risk selection and the complex trade-off among selection (through quality skimping), efficiency, and affordability. Recommended improvements to the risk-adjustment process in the United States include considering the adoption of risk adjusters used in Europe, investing in the collection of data, using a permanent form of risk sharing, and replacing the current premium "band" restrictions with more flexible restrictions. Policy makers need to understand the complexities of regulating competitive health insurance markets and to prevent risk selection that threatens the provision of good-quality care for underpriced high-cost patients. PMID- 26438749 TI - Uncompensated Care Burden May Mean Financial Vulnerability For Rural Hospitals In States That Did Not Expand Medicaid. AB - The implementation of the Affordable Care Act has led to a large decrease in the number of uninsured people. Yet uncompensated care will still occur, particularly in states where eligibility for Medicaid is not expanded. We compared rural hospitals in Medicaid expansion and nonexpansion states in terms of the amount of uncompensated care they provided and their profitability and market characteristics in 2013. We found that rural hospitals in expansion states provided more dollars of uncompensated care than those in nonexpansion states and that the difference was at least partly driven by greater uncompensated costs associated with public programs such as Medicaid. We found higher dollar values of unrecoverable debt and charity care among non-critical access rural hospitals in nonexpansion states than among those in expansion states. Compared to hospitals in expansion states, those in nonexpansion states provided greater amounts of uncompensated care as a percentage of revenues and appeared to be more financially vulnerable; thus, these hospitals may be more likely to experience financial pressure or losses. Policy makers need to formulate strategies for maintaining access to care for rural populations residing in nonexpansion states. PMID- 26438750 TI - Observation Rates At Veterans' Hospitals More Than Doubled During 2005-13, Similar To Medicare Trends. AB - When neither inpatient admission nor prompt discharge is clearly indicated for a patient in the emergency department, physicians place the patient under observation in a hospital for diagnosis and treatment. The increasing prevalence of observation stays at hospitals reimbursed by Medicare is receiving considerable attention, but the prevalence remains unexplored in Veterans Health Administration (VHA) hospitals, which are subject to different payment policies. Using VHA data for fiscal years 2005-13, we identified trends and variations in observation rates across twenty-one Veteran Integrated Service Networks and 128 VHA hospitals nationwide. We found that observation rates across VHA hospitals more than doubled, from 6.5 percent to 13.8 percent, and that there was substantial variation across both Veteran Integrated Service Networks and hospitals. The most prevalent diagnoses accounted for an increasing share of observation stays over time. Despite different incentives within the VHA and Medicare, rates of observation have increased over time for both populations. PMID- 26438751 TI - Price Increases Were Much Lower In Ambulatory Surgery Centers Than Hospital Outpatient Departments In 2007-12. AB - Ambulatory surgery centers (ASCs) are freestanding facilities that provide services to patients who do not require an overnight stay. The number of ASCs has grown rapidly over the past fifteen years, as have the number of surgical procedures performed at them. ASCs now compete with hospital outpatient departments. This study examined the revenue side of ASC growth by using a large national claims database that contains information on actual prices paid. For six common outpatient surgical procedures, prices paid to ASCs on the whole grew in line with general medical care prices, while overall prices paid to hospital outpatient departments for the same procedures climbed sharply. This provides no evidence that ASCs are successfully pressuring hospital outpatient departments to lower their prices. Not unexpectedly, private insurers paid ASCs considerably more than Medicare paid ASCs for the same procedures. Medicare currently pays ASCs a legislated percentage of what it pays hospital outpatient departments for the same services, but there is a considerable discrepancy between this ratio and the ratio of payments by private insurers across provider types and procedures. This finding questions the wisdom of using a single ratio for ASC payments to hospital outpatient department payments. PMID- 26438752 TI - Payment Reform Pilot In Beijing Hospitals Reduced Expenditures And Out-Of-Pocket Payments Per Admission. AB - In 2009 China announced plans to reform provider payment methods at public hospitals by moving from fee-for-service (FFS) to prospective and aggregated payment methods that included the use of diagnosis-related groups (DRGs) to control health expenditures. In October 2011 health policy makers selected six Beijing hospitals to pioneer the first DRG payment system in China. We used hospital discharge data from the six pilot hospitals and eight other hospitals, which continued to use FFS and served as controls, from the period 2010-12 to evaluate the pilot's impact on cost containment through a difference-in differences methods design. Our study found that DRG payment led to reductions of 6.2 percent and 10.5 percent, respectively, in health expenditures and out-of pocket payments by patients per hospital admission. We did not find evidence of any increase in hospital readmission rates or cost shifting from cases eligible for DRG payment to ineligible cases. However, hospitals continued to use FFS payments for patients who were older and had more complications than other patients, which reduced the effectiveness of payment reform. Continuous evidence based monitoring and evaluation linked with adequate management systems are necessary to enable China and other low- and middle-income countries to broadly implement DRGs and refine payment systems. PMID- 26438753 TI - Less Physician Practice Competition Is Associated With Higher Prices Paid For Common Procedures. AB - Concentration among physician groups has been steadily increasing, which may affect prices for physician services. We assessed the relationship in 2010 between physician competition and prices paid by private preferred provider organizations for fifteen common, high-cost procedures to understand whether higher concentration of physician practices and accompanying increased market power were associated with higher prices for services. Using county-level measures of the concentration of physician practices and county average prices, and statistically controlling for a range of other regional characteristics, we found that physician practice concentration and prices were significantly associated for twelve of the fifteen procedures we studied. For these procedures, counties with the highest average physician concentrations had prices 8-26 percent higher than prices in the lowest counties. We concluded that physician competition is frequently associated with prices. Policies that would influence physician practice organization should take this into consideration. PMID- 26438754 TI - Exposure To Harmful Workplace Practices Could Account For Inequality In Life Spans Across Different Demographic Groups. AB - The existence of important socioeconomic disparities in health and mortality is a well-established fact. Many pathways have been adduced to explain inequality in life spans. In this article we examine one factor that has been somewhat neglected: People with different levels of education get sorted into jobs with different degrees of exposure to workplace attributes that contribute to poor health. We used General Social Survey data to estimate differential exposures to workplace conditions, results from a meta-analysis that estimated the effect of workplace conditions on mortality, and a model that permitted us to estimate the overall effects of workplace practices on health. We conclude that 10-38 percent of the difference in life expectancy across demographic groups can be explained by the different job conditions their members experience. PMID- 26438755 TI - Lesbian, Gay, And Bisexual Adults Making Gains In Health Insurance And Access To Care. PMID- 26438759 TI - The Safety Net: How Foundations Are Supporting It. PMID- 26438762 TI - Negative Ads: The Authors Reply. PMID- 26438761 TI - Negative Ads And Smoking Prevalence. PMID- 26438763 TI - Left Ventricular Assist Devices. PMID- 26438764 TI - Left Ventricular Assist Devices: The Authors Reply. PMID- 26438765 TI - Hospitals' Charity Care. PMID- 26438766 TI - Hospitals' Charity Care: The Authors Reply. PMID- 26438767 TI - Tax Exemptions For Nonprofit Hospitals. PMID- 26438768 TI - Cardiovascular Management in Pregnancy: Antithrombotic Agents and Antiplatelet Agents. PMID- 26438769 TI - ECG Response: October 6, 2015. PMID- 26438770 TI - Image Fusion Guided Device Closure of Left Ventricle to Right Atrium Shunt. PMID- 26438771 TI - Right Ventricular Hypertrophy Along With Malignant Ventricular Arrhythmias: An Uncommon Case of Sarcoidosis at Cardiac Magnetic Resonance Imaging. PMID- 26438772 TI - Cardiology Patient Page. Magnetic Resonance Imaging in Patients With Cardiac Implantable Electronic Devices. PMID- 26438773 TI - Letter by Lavine Regarding Article, "Cardiovascular, Bleeding, and Mortality Risks in Elderly Medicare Patients Treated With Dabigatran or Warfarin for Nonvalvular Atrial Fibrillation". PMID- 26438774 TI - Letter by Wheeler et al Regarding Article, "Recognition and Significance of Pathological T-Wave Inversions in Athletes". PMID- 26438775 TI - Response to Letter Regarding Article, "Recognition and Significance of Pathological T-Wave Inversions in Athletes". PMID- 26438776 TI - Letter by Almendro-Delia et al Regarding Article, "Association Between Surgical Indications, Operative Risk, and Clinical Outcome in Infective Endocarditis: A Prospective Study From the International Collaboration on Endocarditis". PMID- 26438777 TI - Response to Letter Regarding Article, "Association Between Surgical Indications, Operative Risk, and Clinical Outcome in Infective Endocarditis: A Prospective Study From the International Collaboration on Endocarditis". PMID- 26438778 TI - Letter by Barison et al Regarding Article, "Familial Clustering of Mitral Valve Prolapse in the Community". PMID- 26438779 TI - Response to Letter Regarding Article, "Familial Clustering of Mitral Valve Prolapse in the Community". PMID- 26438780 TI - Pneumonia's second wind? A case study of the global health network for childhood pneumonia. AB - Advocacy, policy, research and intervention efforts against childhood pneumonia have lagged behind other health issues, including malaria, measles and tuberculosis. Accelerating progress on the issue began in 2008, following decades of efforts by individuals and organizations to address the leading cause of childhood mortality and establish a global health network. This article traces the history of this network's formation and evolution to identify lessons for other global health issues. Through document review and interviews with current, former and potential network members, this case study identifies five distinct eras of activity against childhood pneumonia: a period of isolation (post WWII to 1984), the duration of WHO's Acute Respiratory Infections (ARI) Programme (1984 1995), Integrated Management of Childhood illness's (IMCI) early years (1995 2003), a brief period of network re-emergence (2003-2008) and recent accelerating progress (2008 on). Analysis of these eras reveals the critical importance of building a shared identity in order to form an effective network and take advantage of emerging opportunities. During the ARI era, an initial network formed around a relatively narrow shared identity focused on community-level care. The shift to IMCI led to the partial dissolution of this network, stalled progress on addressing pneumonia in communities and missed opportunities. Frustrated with lack of progress on the issue, actors began forming a network and shared identity that included a broad spectrum of those whose interests overlap with pneumonia. As the network coalesced and expanded, its members coordinated and collaborated on conducting and sharing research on severity and tractability, crafting comprehensive strategies and conducting advocacy. These network activities exerted indirect influence leading to increased attention, funding, policies and some implementation. PMID- 26438781 TI - Dose-Response Relationship Between Physical Activity and Risk of Heart Failure: A Meta-Analysis. AB - BACKGROUND: Prior studies have reported an inverse association between physical activity (PA) and risk of heart failure (HF). However, a comprehensive assessment of the quantitative dose-response association between PA and HF risk has not been reported previously. METHODS AND RESULTS: Prospective cohort studies with participants >18 years of age that reported association of baseline PA levels and incident HF were included. Categorical dose-response relationships between PA and HF risk were assessed with random-effects models. Generalized least-squares regression models were used to assess the quantitative relationship between PA (metabolic equivalent [MET]-min/wk) and HF risk across studies reporting quantitative PA estimates. Twelve prospective cohort studies with 20 203 HF events among 370 460 participants (53.5% women; median follow-up, 13 years) were included. The highest levels of PA were associated with significantly reduced risk of HF (pooled hazard ratio for highest versus lowest PA, 0.70; 95% confidence interval, 0.67-0.73). Compared with participants reporting no leisure time PA, those who engaged in guideline-recommended minimum levels of PA (500 MET min/wk; 2008 US federal guidelines) had modest reductions in HF risk (pooled hazard ratio, 0.90; 95% confidence interval, 0.87-0.92). In contrast, a substantial risk reduction was observed among individuals who engaged in PA at twice (hazard ratio for 1000 MET-min/wk, 0.81; 95% confidence interval, 0.77 0.86) and 4 times (hazard ratio for 2000 MET-min/wk, 0.65; 95% confidence interval, 0.58-0.73) the minimum guideline-recommended levels. CONCLUSIONS: There is an inverse dose-response relationship between PA and HF risk. Doses of PA in excess of the guideline-recommended minimum PA levels may be required for more substantial reductions in HF risk. PMID- 26438782 TI - Physical Activity in the Prevention of Heart Failure: Another Step Forward. PMID- 26438783 TI - Crizotinib Synergizes with Chemotherapy in Preclinical Models of Neuroblastoma. AB - PURPOSE: The presence of an ALK aberration correlates with inferior survival for patients with high-risk neuroblastoma. The emergence of ALK inhibitors such as crizotinib has provided novel treatment opportunities. However, certain ALK mutations result in de novo crizotinib resistance, and a phase I trial of crizotinib showed a lack of response in patients harboring those ALK mutations. Thus, understanding mechanisms of resistance and defining circumvention strategies for the clinic is critical. EXPERIMENTAL DESIGN: The sensitivity of human neuroblastoma-derived cell lines, cell line-derived, and patient-derived xenograft (PDX) models with varying ALK statuses to crizotinib combined with topotecan and cyclophosphamide (topo/cyclo) was examined. Cultured cells and xenografts were evaluated for effects of these drugs on proliferation, signaling, and cell death, and assessment of synergy. RESULTS: In neuroblastoma murine xenografts harboring the most common ALK mutations, including those mutations associated with resistance to crizotinib (but not in those with wild-type ALK), crizotinib combined with topo/cyclo enhanced tumor responses and mouse event-free survival. Crizotinib + topo/cyclo showed synergistic cytotoxicity and higher caspase-dependent apoptosis than crizotinib or topo/cyclo alone in neuroblastoma cell lines with ALK aberrations (mutation or amplification). CONCLUSIONS: Combining crizotinib with chemotherapeutic agents commonly used in treating newly diagnosed patients with high-risk neuroblastoma restores sensitivity in preclinical models harboring both sensitive ALK aberrations and de novo-resistant ALK mutations. These data support clinical testing of crizotinib and conventional chemotherapy with the goal of integrating ALK inhibition into multiagent therapy for ALK-aberrant neuroblastoma patients. PMID- 26438784 TI - Handheld echocardiographic screening for rheumatic heart disease by non-experts. AB - OBJECTIVES: Handheld echocardiography (HAND) has good sensitivity and specificity for rheumatic heart disease (RHD) when performed by cardiologists. However, physician shortages in RHD-endemic areas demand less-skilled users to make RHD screening practical. We examine nurse performance and interpretation of HAND using a simplified approach for RHD screening. METHODS: Two nurses received training on HAND and a simplified screening approach. Consented students at two schools in Uganda were eligible for participation. A simplified approach (HAND performed and interpreted by a non-expert) was compared with the reference standard (standard portable echocardiography, performed and interpreted by experts according to the 2012 World Heart Federation guidelines). Reasons for false-positive and false-negative HAND studies were identified. RESULTS: A total of 1002 children were consented, with 956 (11.1 years, 41.8% male) having complete data for review. Diagnoses included: 913 (95.5%) children were classified normal, 32 (3.3%) borderline RHD and 11 (1.2%) definite RHD. The simplified approach had a sensitivity of 74.4% (58.8% to 86.5%) and a specificity of 78.8% (76.0% to 81.4%) for any RHD (borderline and definite). Sensitivity improved to 90.9% (58.7% to 98.5%) for definite RHD. Identification and measurement of erroneous colour jets was the most common reason for false positive studies (n=164/194), while missed mitral regurgitation and shorter regurgitant jet lengths with HAND were the most common reasons for false-negative studies (n=10/11). CONCLUSIONS: Non-expert-led HAND screening programmes offer a potential solution to financial and workforce barriers that limit widespread RHD screening. Nurses trained on HAND using a simplified approach had reasonable sensitivity and specificity for RHD screening. Information on reasons for false negative and false-positive screening studies should be used to inform future training protocols, which could lead to improved screening performance. PMID- 26438785 TI - Adding point of care ultrasound to assess volume status in heart failure patients in a nurse-led outpatient clinic. A randomised study. AB - OBJECTIVES: Medical history, physical examination and laboratory testing are not optimal for the assessment of volume status in heart failure (HF) patients. We aimed to study the clinical influence of focused ultrasound of the pleural cavities and inferior vena cava (IVC) performed by specialised nurses to assess volume status in HF patients at an outpatient clinic. METHODS: HF outpatients were prospectively included and underwent laboratory testing, history recording and clinical examination by two nurses with and without an ultrasound examination of the pleural cavities and IVC using a pocket-size imaging device, in random order. Each nurse worked in a team with a cardiologist. The influence of the different diagnostic tests on diuretic dosing was assessed descriptively and in linear regression analyses. RESULTS: Sixty-two patients were included and 119 examinations were performed. Mean+/-SD age was 74+/-12 years, EF was 34+/-14%, and N-terminal pro-brain natriuretic peptide (NT-proBNP) value was 3761+/-3072 ng/L. Dosing of diuretics differed between the teams in 31 out of 119 consultations. Weight change and volume status assessed clinically with and without ultrasound predicted dose adjustment of diuretics at follow-up (p<0.05). Change of oedema, NT-proBNP, creatinine, and symptoms did not (p>=0.10). In adjusted analyses, only volume status based on ultrasound predicted dose adjustments of diuretics at first visit and follow-up (all ultrasound p<=0.01, all other p>=0.2). CONCLUSIONS: Ultrasound examinations of the pleural cavities and IVC by nurses may improve diagnostics and patient care in HF patients at an outpatient clinic, but more studies are needed to determine whether these examinations have an impact on clinical outcomes. TRIAL REGISTRATION NUMBER: NCT01794715. PMID- 26438786 TI - A Conserved Core of Programmed Cell Death Indicator Genes Discriminates Developmentally and Environmentally Induced Programmed Cell Death in Plants. AB - A plethora of diverse programmed cell death (PCD) processes has been described in living organisms. In animals and plants, different forms of PCD play crucial roles in development, immunity, and responses to the environment. While the molecular control of some animal PCD forms such as apoptosis is known in great detail, we still know comparatively little about the regulation of the diverse types of plant PCD. In part, this deficiency in molecular understanding is caused by the lack of reliable reporters to detect PCD processes. Here, we addressed this issue by using a combination of bioinformatics approaches to identify commonly regulated genes during diverse plant PCD processes in Arabidopsis (Arabidopsis thaliana). Our results indicate that the transcriptional signatures of developmentally controlled cell death are largely distinct from the ones associated with environmentally induced cell death. Moreover, different cases of developmental PCD share a set of cell death-associated genes. Most of these genes are evolutionary conserved within the green plant lineage, arguing for an evolutionary conserved core machinery of developmental PCD. Based on this information, we established an array of specific promoter-reporter lines for developmental PCD in Arabidopsis. These PCD indicators represent a powerful resource that can be used in addition to established morphological and biochemical methods to detect and analyze PCD processes in vivo and in planta. PMID- 26438787 TI - The Interplay between Sulfur and Iron Nutrition in Tomato. AB - Plant response mechanisms to deficiency of a single nutrient, such as sulfur (S) or iron (Fe), have been described at agronomic, physiological, biochemical, metabolomics, and transcriptomic levels. However, agroecosystems are often characterized by different scenarios, in which combined nutrient deficiencies are likely to occur. Soils are becoming depleted for S, whereas Fe, although highly abundant in the soil, is poorly available for uptake because of its insolubility in the soil matrix. To this end, earlier reports showed that a limited S availability reduces Fe uptake and that Fe deficiency results in the modulation of sulfate uptake and assimilation. However, the mechanistic basis of this interaction remains largely unknown. Metabolite profiling of tomato (Solanum lycopersicum) shoots and roots from plants exposed to Fe, S, and combined Fe and S deficiency was performed to improve the understanding of the S-Fe interaction through the identification of the main players in the considered pathways. Distinct changes were revealed under the different nutritional conditions. Furthermore, we investigated the development of the Fe deficiency response through the analysis of expression of ferric chelate reductase, iron-regulated transporter, and putative transcription factor genes and plant sulfate uptake and mobilization capacity by analyzing the expression of genes encoding sulfate transporters (STs) of groups 1, 2, and 4 (SlST1.1, SlST1.2, SlST2.1, SlST2.2, and SlST4.1). We identified a high degree of common and even synergistic response patterns as well as nutrient-specific responses. The results are discussed in the context of current models of nutrient deficiency responses in crop plants. PMID- 26438788 TI - Comparative Transcriptomics Unravel Biochemical Specialization of Leaf Tissues of Stevia for Diterpenoid Production. AB - Stevia (Stevia rebaudiana) produces not only a group of diterpenoid glycosides known as steviol glycosides (SGs), but also other labdane-type diterpenoids that may be spatially separated from SGs. However, their biosynthetic routes and spatial distribution in leaf tissues have not yet been elucidated. Here, we integrate metabolome and transcriptome analyses of Stevia to explore the biosynthetic capacity of leaf tissues for diterpenoid metabolism. Tissue-specific chemical analyses confirmed that SGs were accumulated in leaf cells but not in trichomes. On the other hand, Stevia leaf trichomes stored other labdane-type diterpenoids such as oxomanoyl oxide and agatholic acid. RNA sequencing analyses from two different tissues of Stevia provided a comprehensive overview of dynamic metabolic activities in trichomes and leaf without trichomes. These metabolite guided transcriptomics and phylogenetic and gene expression analyses clearly identified specific gene members encoding enzymes involved in the 2-C-methyl-d erythritol 4-phosphate pathway and the biosynthesis of steviol or other labdane type diterpenoids. Additionally, our RNA sequencing analysis uncovered copalyl diphosphate synthase (SrCPS) and kaurene synthase1 (SrKS1) homologs, SrCPS2 and KS-like (SrKSL), which were specifically expressed in trichomes. In vitro and in planta assays showed that unlike SrCPS and SrKS1, SrCPS2 synthesized labda-13-en 8-ol diphosphate and successively catalyzed the formation of manoyl oxide and epi manoyl oxide in combination with SrKSL. Our findings suggest that Stevia may have evolved to use distinct metabolic pathways to avoid metabolic interferences in leaf tissues for efficient production of diverse secondary metabolites. PMID- 26438789 TI - Phosphorylation of the Light-Harvesting Complex II Isoform Lhcb2 Is Central to State Transitions. AB - Light-harvesting complex II (LHCII) is a crucial component of the photosynthetic machinery, with central roles in light capture and acclimation to changing light. The association of an LHCII trimer with PSI in the PSI-LHCII supercomplex is strictly dependent on LHCII phosphorylation mediated by the kinase STATE TRANSITION7, and is directly related to the light acclimation process called state transitions. In Arabidopsis (Arabidopsis thaliana), the LHCII trimers contain isoforms that belong to three classes: Lhcb1, Lhcb2, and Lhcb3. Only Lhcb1 and Lhcb2 can be phosphorylated in the N-terminal region. Here, we present an improved Phos-tag-based method to determine the absolute extent of phosphorylation of Lhcb1 and Lhcb2. Both classes show very similar phosphorylation kinetics during state transition. Nevertheless, only Lhcb2 is extensively phosphorylated (>98%) in PSI-LHCII, whereas phosphorylated Lhcb1 is largely excluded from this supercomplex. Both isoforms are phosphorylated to different extents in other photosystem supercomplexes and in different domains of the thylakoid membranes. The data imply that, despite their high sequence similarity, differential phosphorylation of Lhcb1 and Lhcb2 plays contrasting roles in light acclimation of photosynthesis. PMID- 26438790 TI - Long-term survival of Borrelia burgdorferi lacking the hibernation promotion factor homolog in the unfed tick vector. AB - Borrelia burgdorferi, a causative agent of Lyme borreliosis, is a zoonotic pathogen that survives in nutrient-limited environments within a tick, prior to transmission to its mammalian host. Survival under these prolonged nutrient limited conditions is thought to be similar to survival during stationary phase, which is characterized by growth cessation and decreased protein production. Multiple ribosome-associated proteins are implicated in stationary-phase survival of Escherichia coli. These proteins include hibernation-promoting factor (HPF), which dimerizes ribosomes and prevents translation of mRNA. Bioinformatic analyses indicate that B. burgdorferi harbors an hpf homolog, the bb0449 gene. BB0449 protein secondary structure modeling also predicted HPF-like structure and function. However, BB0449 protein was not localized in the ribosome-associated protein fraction of in vitro-grown B. burgdorferi. In wild-type B. burgdorferi, bb0449 transcript and BB0449 protein levels are low during various growth phases. These results are inconsistent with patterns of synthesis of HPF-like proteins in other bacterial species. In addition, two independently derived bb0449 mutants successfully completed the mouse-tick infectious cycle, indicating that bb0449 is not required for prolonged survival in the nutrient-limited environment in the unfed tick or any other stage of infection by B. burgdorferi. We suggest either that BB0449 is associated with ribosomes under specific conditions not yet identified or that BB0449 of B. burgdorferi has a function other than ribosome conformation modulation. PMID- 26438791 TI - Global metabolomic analysis of a mammalian host infected with Bacillus anthracis. AB - Whereas DNA provides the information to design life and proteins provide the materials to construct it, the metabolome can be viewed as the physiology that powers it. As such, metabolomics, the field charged with the study of the dynamic small-molecule fluctuations that occur in response to changing biology, is now being used to study the basis of disease. Here, we describe a comprehensive metabolomic analysis of a systemic bacterial infection using Bacillus anthracis, the etiological agent of anthrax disease, as the model pathogen. An organ and blood analysis identified approximately 400 metabolites, including several key classes of lipids involved in inflammation, as being suppressed by B. anthracis. Metabolite changes were detected as early as 1 day postinfection, well before the onset of disease or the spread of bacteria to organs, which testifies to the sensitivity of this methodology. Functional studies using pharmacologic inhibition of host phospholipases support the idea of a role of these key enzymes and lipid mediators in host survival during anthrax disease. Finally, the results are integrated to provide a comprehensive picture of how B. anthracis alters host physiology. Collectively, the results of this study provide a blueprint for using metabolomics as a platform to identify and study novel host-pathogen interactions that shape the outcome of an infection. PMID- 26438792 TI - Role of B cells in host defense against primary Coxiella burnetii infection. AB - Despite Coxiella burnetii being an obligate intracellular bacterial pathogen, our recent study demonstrated that B cells play a critical role in vaccine-induced immunity to C. burnetii infection by producing protective antibodies. However, the role of B cells in host defense against primary C. burnetii infection remains unclear. In this study, we investigated whether B cells play an important role in host defense against primary C. burnetii infection. The results showed that peritoneal B cells were able to phagocytose virulent C. burnetii bacteria and form Coxiella-containing vacuoles (CCVs) and that C. burnetii can infect and replicate in peritoneal B1a subset B cells in vitro, demonstrating a potential role for peritoneal B cells in host defense against C. burnetii infection in vivo. In addition, the results showing that B1a cells secreted a high level of interleukin-10 (IL-10) in response to C. burnetii infection in vitro suggest that B1a cells may play an important role in inhibiting the C. burnetii infection induced inflammatory response. The observation that adoptive transfer of peritoneal B cells did not significantly affect the severity of C. burnetii infection-induced diseases in both severe combined immunity-deficient (SCID) and MUMT mice indicates that peritoneal B cells alone may not be able to control C. burnetii infection. In contrast, our finding that C. burnetii infection induced more-severe splenomegaly and a higher bacterial burden in the spleens of B1a cell deficient Bruton's tyrosine kinase x-linked immunity-deficient (BTK(xid)) mice than in their wild-type counterparts further suggests that B1a cells play an important role in host defense against primary C. burnetii infection. PMID- 26438794 TI - Impact of the Pla protease substrate alpha2-antiplasmin on the progression of primary pneumonic plague. AB - Many pathogens usurp the host hemostatic system during infection to promote pathogenesis. Yersinia pestis, the causative agent of plague, expresses the plasminogen activator protease Pla, which has been shown in vitro to target and cleave multiple proteins within the fibrinolytic pathway, including the plasmin inhibitor alpha2-antiplasmin (A2AP). It is not known, however, if Pla inactivates A2AP in vivo; the role of A2AP during respiratory Y. pestis infection is not known either. Here, we show that Y. pestis does not appreciably cleave A2AP in a Pla-dependent manner in the lungs during experimental pneumonic plague. Furthermore, following intranasal infection with Y. pestis, A2AP-deficient mice exhibit no difference in survival time, bacterial burden in the lungs, or dissemination from wild-type mice. Instead, we found that in the absence of Pla, A2AP contributes to the control of the pulmonary inflammatory response during infection by reducing neutrophil recruitment and cytokine production, resulting in altered immunopathology of the lungs compared to A2AP-deficient mice. Thus, our data demonstrate that A2AP is not significantly affected by the Pla protease during pneumonic plague, and although A2AP participates in immune modulation in the lungs, it has limited impact on the course or ultimate outcome of the infection. PMID- 26438793 TI - Outer surface protein OspC is an antiphagocytic factor that protects Borrelia burgdorferi from phagocytosis by macrophages. AB - Outer surface protein C (OspC) is one of the major lipoproteins expressed on the surface of Borrelia burgdorferi during tick feeding and the early phase of mammalian infection. OspC is required for B. burgdorferi to establish infection in both immunocompetent and SCID mice and has been proposed to facilitate evasion of innate immune defenses. However, the exact biological function of OspC remains elusive. In this study, we showed that the ospC-deficient spirochete could not establish infection in NOD-scid IL2rgamma(null) mice that lack B cells, T cells, NK cells, and lytic complement. The ospC mutant also could not establish infection in anti-Ly6G-treated SCID and C3H/HeN mice (depletion of neutrophils). However, depletion of mononuclear phagocytes at the skin site of inoculation in SCID and C3H/HeN mice allowed the ospC mutant to establish infection in vivo. In phagocyte-depleted mice, the ospC mutant was able to colonize the joints and triggered neutrophilia during dissemination. Furthermore, we found that phagocytosis of green fluorescent protein (GFP)-expressing ospC mutant spirochetes by murine peritoneal macrophages and human THP-1 macrophage-like cells, but not in PMN-HL60, was significantly higher than parental wild-type B. burgdorferi strains, suggesting that OspC has an antiphagocytic property. In addition, overproduction of OspC in spirochetes also decreased the uptake of spirochetes by murine peritoneal macrophages. Together, our findings provide evidence that mononuclear phagocytes play a key role in clearance of the ospC mutant and that OspC promotes spirochetes' evasion of macrophages during early Lyme borreliosis. PMID- 26438795 TI - Helicobacter pylori adaptation in vivo in response to a high-salt diet. AB - Helicobacter pylori exhibits a high level of intraspecies genetic diversity. In this study, we investigated whether the diversification of H. pylori is influenced by the composition of the diet. Specifically, we investigated the effect of a high-salt diet (a known risk factor for gastric adenocarcinoma) on H. pylori diversification within a host. We analyzed H. pylori strains isolated from Mongolian gerbils fed either a high-salt diet or a regular diet for 4 months by proteomic and whole-genome sequencing methods. Compared to the input strain and output strains from animals fed a regular diet, the output strains from animals fed a high-salt diet produced higher levels of proteins involved in iron acquisition and oxidative-stress resistance. Several of these changes were attributable to a nonsynonymous mutation in fur (fur-R88H). Further experiments indicated that this mutation conferred increased resistance to high-salt conditions and oxidative stress. We propose a model in which a high-salt diet leads to high levels of gastric inflammation and associated oxidative stress in H. pylori-infected animals and that these conditions, along with the high intraluminal concentrations of sodium chloride, lead to selection of H. pylori strains that are most fit for growth in this environment. PMID- 26438796 TI - Brucella canis is an intracellular pathogen that induces a lower proinflammatory response than smooth zoonotic counterparts. AB - Canine brucellosis caused by Brucella canis is a disease of dogs and a zoonotic risk. B. canis harbors most of the virulence determinants defined for the genus, but its pathogenic strategy remains unclear since it has not been demonstrated that this natural rough bacterium is an intracellular pathogen. Studies of B. canis outbreaks in kennel facilities indicated that infected dogs displaying clinical signs did not present hematological alterations. A virulent B. canis strain isolated from those outbreaks readily replicated in different organs of mice for a protracted period. However, the levels of tumor necrosis factor alpha, interleukin-6 (IL-6), and IL-12 in serum were close to background levels. Furthermore, B. canis induced lower levels of gamma interferon, less inflammation of the spleen, and a reduced number of granulomas in the liver in mice than did B. abortus. When the interaction of B. canis with cells was studied ex vivo, two patterns were observed, a predominant scattered cell-associated pattern of nonviable bacteria and an infrequent intracellular replicative pattern of viable bacteria in a perinuclear location. The second pattern, responsible for the increase in intracellular multiplication, was dependent on the type IV secretion system VirB and was seen only if the inoculum used for cell infections was in early exponential phase. Intracellular replicative B. canis followed an intracellular trafficking route undistinguishable from that of B. abortus. Although B. canis induces a lower proinflammatory response and has a stealthier replication cycle, it still displays the pathogenic properties of the genus and the ability to persist in infected organs based on the ability to multiply intracellularly. PMID- 26438797 TI - Pathophysiological changes induced by Pseudomonas aeruginosa infection are involved in MMP-12 and MMP-13 upregulation in human carcinoma epithelial cells and a pneumonia mouse model. AB - Pseudomonas aeruginosa infections persist in patients with cystic fibrosis (CF) and drive lung disease progression. P. aeruginosa potently activates the innate immune system mostly through the recognition of pathogen-associated molecular patterns, such as flagellin. Matrix metalloproteinases 12 and 13 (MMP-12 and MMP 13, respectively) exacerbate chronic lung infection and inflammation by promoting uncontrolled tissue rearrangements and fibrosis, yet the underlying molecular mechanisms by which this occurs remain largely unknown. In this study, we used quantitative bacteriology, histological examination, and proinflammatory cytokine levels to evaluate the effects of MMP-12 and MMP-13 on P. aeruginosa strain K induced infection and pneumonia in H292 epithelial cells and mice, respectively. Under inflammatory stimulation, mRNA and protein expression levels of proinflammatory mediators were higher in strain K-infected mice and cells than in uninfected counterparts, in which MMP-12 and MMP-13 expression reached levels similar to those observed in epithelial cells. Moreover, we also found that the NF-kappaB pathway might be involved in the induction of cytokines in response to strain K infection. Taken together, these data suggest that MMP-12 and MMP-13 alter strain K infection in mice and play a role in inflammatory regulation by modulating cytokine levels. PMID- 26438798 TI - Pancreatic amylase is an environmental signal for regulation of biofilm formation and host interaction in Campylobacter jejuni. AB - Campylobacter jejuni is a commensal bacterium in the intestines of animals and birds and a major cause of food-borne gastroenteritis in humans worldwide. Here we show that exposure to pancreatic amylase leads to secretion of an alpha dextran by C. jejuni and that a secreted protease, Cj0511, is required. Exposure of C. jejuni to pancreatic amylase promotes biofilm formation in vitro, increases interaction with human epithelial cell lines, increases virulence in the Galleria mellonella infection model, and promotes colonization of the chicken ileum. We also show that exposure to pancreatic amylase protects C. jejuni from stress conditions in vitro, suggesting that the induced alpha-dextran may be important during transmission between hosts. This is the first evidence that pancreatic amylase functions as an interkingdom signal in an enteric microorganism. PMID- 26438801 TI - "Power and Greed and the Corruptible Seed": Mental Disability, Prosecutorial Misconduct, and the Death Penalty. PMID- 26438800 TI - Gut Microbiota and Brain Function: An Evolving Field in Neuroscience. AB - There is a growing appreciation of the importance of gut microbiota to health and disease. This has been driven by advances in sequencing technology and recent findings demonstrating the important role of microbiota in common health disorders such as obesity. Moreover, the potential role of gut microbiota in influencing brain function, behavior, and mental health has attracted the attention of neuroscientists and psychiatrists. At the 29(th) International College of Neuropsychopharmacology (CINP) World Congress held in Vancouver, Canada, in June 2014, a group of experts presented the symposium, "Gut microbiota and brain function: Relevance to psychiatric disorders" to review the latest findings in how gut microbiota may play a role in brain function, behavior, and disease. The symposium covered a broad range of topics, including gut microbiota and neuroendocrine function, the influence of gut microbiota on behavior, probiotics as regulators of brain and behavior, and imaging the gut-brain axis in humans. This report provides an overview of these presentations. PMID- 26438799 TI - Leptin/LepRb in the Ventral Tegmental Area Mediates Anxiety-Related Behaviors. AB - BACKGROUND: Leptin, an adipose-derived hormone, has been implicated in emotional regulation. We have previously shown that systemic administration of leptin produces anxiolytic-like effects and deletion of the leptin receptor, LepRb, in midbrain dopamine neurons leads to an anxiogenic phenotype. This study investigated whether activation or deletion of LepRb in the ventral tegmental area of adult mice is capable of inducing anxiolytic and anxiogenic effects, respectively. METHODS: Mice were cannulated in the ventral tegmental area and received bilateral intra-ventral tegmental area infusions of leptin or the JAK2/STAT3 inhibitor AG490. Anxiety-like behaviors were assessed using the elevated plus-maze, light-dark box, and novelty suppressed feeding tests. Deletion of LepRb in the ventral tegmental area was achieved by bilateral injection of AAV-Cre into the ventral tegmental area of adult Lepr(flox/flox) mice. Anxiety-related behaviors were evaluated 3 weeks after viral injection. RESULTS: Intra-ventral tegmental area infusions of leptin reduced anxiety-like behaviors, as indicated by increased percent open-arm time and open-arm entries in the elevated plus-maze test, increased time spent in the light side and decreased latency to enter the light side of the light-dark box, and decreased latency to feed in the novelty suppressed feeding test. Blockade of JAK2/STAT3 signaling in the ventral tegmental area by AG490 attenuated the anxiolytic effect produced by systemic administration of leptin. Lepr(flox/flox) mice injected with AAV-Cre into the ventral tegmental area showed decreased leptin-induced STAT3 phosphorylation and enhanced anxiety-like behaviors in the elevated plus-maze test and the novelty suppressed feeding test. CONCLUSIONS: These findings suggest that leptin-LepRb signaling in the ventral tegmental area plays an important role in the regulation of anxiety-related behaviors. PMID- 26438802 TI - Realistic Consideration of Women and Violence is Critical. PMID- 26438803 TI - Mental Health and Immigrant Detainees in the United States: Competency and Self Representation. AB - Most immigrant detainees held in U.S. Immigration and Customs Enforcement (ICE) facilities do not have legal representation, because immigration proceedings are a matter of civil, not criminal, law. In 2005, Mr. Franco, an immigrant from Mexico with an IQ between 35 and 55, was found incompetent to stand trial, but was not appointed an attorney for his immigration proceedings. This failure led to a class action lawsuit, known as the Franco litigation, and in April 2013, a federal judge ordered the U. S. government to provide legal representation for immigrant detainees in California, Arizona, and Washington who are incompetent to represent themselves due to a mental disorder or defect. This development has implications for forensic evaluators, because there is likely to be an increase in the number of competency examinations requested by courts for immigrant detainees. Furthermore, forensic evaluators must understand that an evaluation for competency of an immigrant detainee includes both the Dusky criteria and capacity for self-representation. In this article, we explore the legal context and ethics concerns related to the Franco litigation. PMID- 26438804 TI - Commentary: Mental Health and Immigrant Detainees in the United States. AB - In this commentary, we reflect on Korngold and colleagues' comprehensive review of the legal challenges encountered by mentally ill immigrant detainees in the United States. Specifically, we further review the competency question as it relates to detainees, as well as recent developments in the legal system. We expand the discussion to general treatment and care of mentally ill detainees in United States Immigration and Customs Enforcement (ICE) facilities. In addition, we provide an allegory to the juvenile justice system and discuss cultural considerations. We conclude by highlighting the significant implications changes in the immigration justice system may have for forensic examiners and competency evaluations. PMID- 26438805 TI - Cognitive Fluctuations and the Lucid Interval in Dementia: Implications for Testamentary Capacity. AB - The lucid interval is a long-held legal concept widely accepted in case law as a possible means of countering a challenge to testamentary and related capacities. In parallel, the clinical phenomenon of cognitive fluctuations has been considered a common element of several neurodegenerative disorders (dementias), including Alzheimer Disease, but is especially prevalent in vascular dementia and dementia with Lewy bodies. In this article, we review the objective evidence for cognitive fluctuations in dementia and the implications for the validity of the legal notion of the lucid interval cited in recent case law. The literature on cognitive fluctuations in dementia shows that such fluctuations largely affect attention and alertness, rather than memory or the higher level executive functions that are essential components of testamentary capacity. Moreover, these fluctuations are small in magnitude and very short in duration. These findings cast doubt on the validity of the lucid interval and invite a critical rethinking of this legal concept as applied to will challenges involving testators with dementia. PMID- 26438806 TI - Commentary: Contested Wills and Will Contests. AB - When disinherited heirs challenge a will drafted by a person suspected of having dementia, a legal battle may ensue. The "lucid interval," a brief return to competence from a state of dementia, has been invoked in years past to establish the validity of contested wills. Shulman et al., having reviewed the medical and legal literature, make a convincing argument that no such period of competence occurs in the course of dementia. A neuropsychiatric autopsy is outlined in this commentary to provide a method of determining the validity of a last will and testament, by applying the clinical method described when witness statements do not provide accurate guidance. PMID- 26438807 TI - Commentary: The Lucid Interval-Coping with Unscientific Terminology. AB - The authors agree with Shulman et al. in their assertion that the term "lucid interval" does not describe what is now known to occur in the fluctuating mental status of some demented individuals. Therefore, its use by the courts to determine competency in such persons can result in an unjust outcome. However, we believe such criticism as Shulman and his coauthors levied at the legal profession should be broadened to consider antiquated and nonscientific terminology in our own field of psychiatry. PMID- 26438808 TI - Male Perpetrators of Intimate Partner Homicide: A Review and Proposed Typology. AB - Nearly one in seven homicides worldwide involve killing of an intimate partner, and men are four times more likely to be the perpetrators of these offenses. This article is a review of the literature on male perpetrators of intimate partner homicide (IPH) with an emphasis on the demographic, psychiatric, situational, and motivational characteristics consistently identified across diverse posthomicide samples. The existing literature supports the heterogeneity among male perpetrators of IPH. Based on patterns that emerge in the literature, a preliminary typology is described that includes four generally distinct subtypes of male IPH perpetrators: the mentally ill, the undercontrolled/dysregulated, chronic batterer, and overcontrolled/catathymic subtypes. Forensic implications related to risk assessment, risk management, and criminal intent are considered, and suggestions for future targeted research aimed at validating the proposed typology are offered. PMID- 26438809 TI - Nature and Utilization of Civil Commitment for Substance Abuse in the United States. AB - Substance abuse is a leading cause of morbidity and mortality in the United States. Although civil commitment has been used to address substance abuse for more than a century, little is known today about the nature and use of substance related commitment laws in the United States. We examined statutes between July 2010 and October 2012 from all 50 states and the District of Columbia for provisions authorizing civil commitment of adults for substance abuse and recorded the criteria and evidentiary standard for commitment and the location and the maximum duration of commitment orders. High-level state representatives evaluated these data and provided information on the use of commitment. Thirty three states have statutory provisions for the civil commitment of persons because of substance abuse. The application of these statutes ranged from a few commitment cases to thousands annually. Although dangerousness was the most common basis for commitment, many states permitted it in other contexts. The maximum duration of treatment ranged from less than 1 month to more than 1 year for both initial and subsequent civil commitment orders. These findings show wide variability in the nature and application of civil commitment statutes for substance abuse in the United States. Such diversity reflects a lack of consensus on the role that civil commitment should play in managing substance abuse and the problems associated with it. PMID- 26438810 TI - The Defense of Involuntary Intoxication by Prescribed Medications: An Appellate Case Review. AB - The defense of involuntary intoxication has long been an exception to the general notion that intoxication is not a defense to criminal liability. The consumption of medications prescribed by a physician can form the basis of an involuntary intoxication defense. In this article, I review cases where defendants relied on the use of prescribed medications for an involuntary-intoxication defense. The medications most frequently implicated by defendants are listed by name and by class. From the case law, I provide a summary of the defense and a review of the pitfalls of the defense to serve as practice pointers for forensic evaluators. PMID- 26438811 TI - Correlates of Competency to Stand Trial Among Youths Admitted to a Juvenile Mental Health Court. AB - Competency to stand trial (CST) assessment of juvenile offenders is a relatively recent phenomenon, as are juvenile mental health courts. Factors associated with youths' ability to participate in legal proceedings are not well understood, regardless of the court venue. Using a sample of 324 juveniles participating in the Los Angeles County Juvenile Mental Health Court (LAJMHC), we sought to explore the relationships of age, mental health diagnosis, and history of mental health treatment to CST status. Results suggest youths under the age of 15 were significantly more likely to have been found incompetent to stand trial (IST) when compared with older youths (p = .007). Youths with a diagnosis of a pervasive developmental disorder or intellectual disability were also more likely to be found IST than those without these diagnoses (p = .02 and p = .0001, respectively). Conversely, participants aged 16 or 17 years and diagnosed with a mood, substance abuse, or psychotic disorder were more likely to be found CST than those without these diagnoses (p < .0001, p = .035, and p = .0064, respectively). Participants with a history of psychotherapy or psychotropic medication were more likely to be found CST than were those without any treatment history (p < .0001). Further research on factors that affect CST status in juveniles who participate in mental health courts may be particularly salient to improve understanding of specific treatment and rehabilitative needs of youthful offenders, and to inform approaches to competency attainment and recidivism prevention services, both within these specialty courts and in juvenile proceedings in general. PMID- 26438812 TI - Treatment of Mentally Ill Offenders in Nine Developing Latin American Countries. AB - The prevalence of psychiatric conditions among prisoners in Latin America is greatly underestimated, and because of the lack of awareness about mental illness among service providers in Latin American prisons, oftentimes these conditions go unrecognized or are not treated properly. In the worst-case scenarios, human rights violations occur. Despite the high levels of need, many prisoners have not received adequate or timely treatment. The sparse existing literature documents prison conditions throughout Latin American countries, ranging from poor to extremely harsh, overcrowded, and life threatening. Most prison systems do not meet international prison standards. The information on forensic mental health services and the treatment of offenders with mental illness have been less extensively studied and compared with forensic practices in developed American nations. This study analyzes the existing literature on forensic psychiatry, focusing on nine socioeconomically developing nations in Latin America, to improve understanding of treatment approaches for offenders with mental illness and identify emerging themes. A review was conducted and data were included in regression analyses to investigate information relative to the treatment of offenders with mental illness and its interaction with the mental health system. PMID- 26438813 TI - Implications of the 2014 Senate Select Committee on Intelligence Report for Forensic Mental Health in the War on Terror. AB - In December 2014, the Senate Select Committee on Intelligence released a declassified executive summary on the use by the Central Intelligence Agency (CIA) of enhanced interrogation techniques against suspected terrorist detainees in the War on Terror. The report relies on 6 million pages of documents that describe the CIA's Detention and Interrogation Program, providing a systematic and comprehensive investigation into covert military and intelligence practices after the attacks on September 11, 2001. This article presents an analysis of key findings related to forensic mental health. I explore their implications for the ethics of mental health professionals who work with military and intelligence agencies and for facts disputed within the Guantanamo military commission system. Opportunities for further study and theoretical development are outlined. PMID- 26438814 TI - Pregnant Women and the Use of Corrections Restraints and Substance Use Commitment. AB - Recent evolving trends in the United States legal system regarding how policies and laws are applied to pregnant women include concerns over the use of restraints or shackles in pregnant inmates and forced treatment or commitment of pregnant women for substance abuse. These topics raise many questions, such as: how violent are women, particularly pregnant women; what are the informed consent and treatment implications; and who is at risk of harm? In addition, questions have been raised regarding maternal versus fetal rights, especially when the mother uses substances during a pregnancy. We review legal decisions and organizational position statements and highlight ethics-related concerns. PMID- 26438815 TI - Expanding Slayer Statutes to Elder Abuse. AB - Common law has a dictum that people must not benefit from their crimes. In years past, states have enacted slayer rules to prevent killers from inheriting from their victims. The specific criteria and applicability of slayer rules vary by jurisdiction. Recently, several states, including Washington, have expanded their slayer rules to disqualify persons from inheriting if they have been involved in abuse or financial exploitation of the deceased. Reviewed herein are the abuse disinheritance laws, the relationship of the laws to concepts of testamentary capacity and undue influence, and the relevance to forensic psychiatric evaluations. PMID- 26438816 TI - A lambda Cro-Like Repressor Is Essential for the Induction of Conjugative Transfer of SXT/R391 Elements in Response to DNA Damage. AB - Integrative and conjugative elements (ICEs) of the SXT/R391 family are the main contributors to acquired multidrug resistance in the seventh pandemic lineage of Vibrio cholerae, the etiological agent of the diarrheal disease cholera. Conjugative transfer of SXT/R391 ICEs is triggered by antibiotics and agents promoting DNA damage through RecA-dependent autoproteolysis of SetR, an ICE encoded lambda CI-like repressor. Here, we describe the role of CroS, a distant lambda Cro homolog, as a key component contributing to the regulation of expression of the activator SetCD that orchestrates the expression of the conjugative transfer genes. We show that deletion of croS abolishes the SOS response-dependent induction of SXT despite the presence of a functional setR gene. Using quantitative reverse transcription-PCR and lacZ reporter assays, we also show that CroS represses setR and setCD expression by binding to operator sites shared with SetR. Furthermore, we provide evidence of an additional operator site bound by SetR and CroS. Finally, we show that SetCD expression generates a positive feedback loop due to SXT excision and replication in a fraction of the cell population. Together, these results refine our understanding of the genetic regulation governing the propagation of major vectors of multidrug resistance. IMPORTANCE: Healthcare systems worldwide are challenged by an alarming drug resistance crisis caused by the massive and rapid propagation of antibiotic resistance genes and the associated emergence of multidrug-resistant pathogenic bacteria. SXT/R391 ICEs contribute to this phenomenon not only in clinical and environmental vibrios but also in several members of the family Enterobacteriaceae. We have identified and characterized here the regulator CroS as a key factor in the stimulation of conjugative transfer of these ICEs in response to DNA-damaging agents. We have also untangled conflicting evidence regarding autoactivation of transfer by the master activator of SXT/R391 ICEs, SetCD. Discovery of CroS provides a clearer and more complete understanding of the regulatory network that governs the dissemination of SXT/R391 ICEs in bacterial populations. PMID- 26438817 TI - Airpnp: Auto- and Integrated Regulation of Polynucleotide Phosphorylase. AB - The properties and expression of polynucleotide phosphorylase (PNPase), capable of both RNA degradation and polymerization, have been studied for 60 years. In this issue of the Journal of Bacteriology, Park et al. (H. Park, H. Yakhnin, M. Connolly, T. Romeo, and P. Babitzke, J Bacteriol 197:3751-3759, 2015, http://dx.doi.org/10.1128/JB.00721-15) write the latest chapter on the complex regulation of pnp gene expression involving CsrA. I describe how this new piece of the puzzle fits into the global scheme of PNPase autoregulation and how this is influenced by central carbon metabolism at both the posttranscriptional level and that of enzyme activity. PMID- 26438818 TI - CsrA Participates in a PNPase Autoregulatory Mechanism by Selectively Repressing Translation of pnp Transcripts That Have Been Previously Processed by RNase III and PNPase. AB - Csr is a conserved global regulatory system that represses or activates gene expression posttranscriptionally. CsrA of Escherichia coli is a homodimeric RNA binding protein that regulates transcription elongation, translation initiation, and mRNA stability by binding to the 5' untranslated leader or initial coding sequence of target transcripts. pnp mRNA, encoding the 3' to 5' exoribonuclease polynucleotide phosphorylase (PNPase), was previously identified as a CsrA target by transcriptome sequencing (RNA-seq). Previous studies also showed that RNase III and PNPase participate in a pnp autoregulatory mechanism in which RNase III cleavage of the untranslated leader, followed by PNPase degradation of the resulting 5' fragment, leads to pnp repression by an undefined translational repression mechanism. Here we demonstrate that CsrA binds to two sites in pnp leader RNA but only after the transcript is fully processed by RNase III and PNPase. In the absence of processing, both of the binding sites are sequestered in an RNA secondary structure, which prevents CsrA binding. The CsrA dimer bridges the upstream high-affinity site to the downstream site that overlaps the pnp Shine-Dalgarno sequence such that bound CsrA causes strong repression of pnp translation. CsrA-mediated translational repression also leads to a small increase in the pnp mRNA decay rate. Although CsrA has been shown to regulate translation and mRNA stability of numerous genes in a variety of organisms, this is the first example in which prior mRNA processing is required for CsrA-mediated regulation. IMPORTANCE: CsrA protein represses translation of numerous mRNA targets, typically by binding to multiple sites in the untranslated leader region preceding the coding sequence. We found that CsrA represses translation of pnp by binding to two sites in the pnp leader transcript but only after it is processed by RNase III and PNPase. Processing by these two ribonucleases alters the mRNA secondary structure such that it becomes accessible to the ribosome for translation as well as to CsrA. As one of the CsrA binding sites overlaps the pnp ribosome binding site, bound CsrA prevents ribosome binding. This is the first example in which regulation by CsrA requires prior mRNA processing and should link pnp expression to conditions affecting CsrA activity. PMID- 26438819 TI - p21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase. AB - Phosphatidylinositol 3,4,5-trisphosphate (PIP3)-dependent Rac exchanger 2 (PREX2) is a guanine nucleotide exchange factor (GEF) for the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase, facilitating the exchange of GDP for GTP on Rac1. GTP-bound Rac1 then activates its downstream effectors, including p21 activated kinases (PAKs). PREX2 and Rac1 are frequently mutated in cancer and have key roles within the insulin-signaling pathway. Rac1 can be inactivated by multiple mechanisms; however, negative regulation by insulin is not well understood. Here, we show that in response to being activated after insulin stimulation, Rac1 initiates its own inactivation by decreasing PREX2 GEF activity. Following PREX2-mediated activation of Rac1 by the second messengers PIP3 or Gbetagamma, we found that PREX2 was phosphorylated through a PAK dependent mechanism. PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gbetagamma. Cell fractionation experiments also revealed that phosphorylation prevented PREX2 from localizing to the cellular membrane. Furthermore, the onset of insulin-induced phosphorylation of PREX2 was delayed compared with AKT. Altogether, we propose that second messengers activate the Rac1 signal, which sets in motion a cascade whereby PAKs phosphorylate and negatively regulate PREX2 to decrease Rac1 activation. This type of regulation would allow for transient activation of the PREX2-Rac1 signal and may be relevant in multiple physiological processes, including diseases such as diabetes and cancer when insulin signaling is chronically activated. PMID- 26438820 TI - Structural Insights into the High-efficiency Catalytic Mechanism of the Sterile alpha-Motif/Histidine-Aspartate Domain-containing Protein. AB - Sterile alpha-motif/histidine-aspartate domain-containing protein (SAMHD1), a homo-tetrameric GTP/dGTP-dependent dNTP triphosphohydrolase, catalyzes the conversion of dNTP into deoxynucleoside and triphosphate. As the only characterized dNTP triphosphohydrolase in human cells, SAMHD1 plays an important role in human innate immunity, autoimmunity, and cell cycle control. Previous biochemical studies and crystal structures have revealed that SAMHD1 interconverts between an inactive monomeric or dimeric form and a dGTP/GTP induced active tetrameric form. Here, we describe a novel state of SAMHD1 (109 626 amino acids, SAMHD1C) that is characterized by a rapid initial hydrolysis rate. Interestingly, the crystal structure showed that this novel SAMHD1 tetramer contains only GTP and has structural features distinct from the GTP/dNTP-bound SAMHD1 tetramer. Our work thus reveals structural features of SAMHD1 that may represent one of its biological assembly states in cells. The biochemical and structural information generated by the present study not only provides an ordered pathway for the assembly and activation of SAMHD1 but also provides insights into the potential mechanisms of the high-efficiency catalytic activity of this enzyme family in vivo. PMID- 26438821 TI - Macrophage-specific de Novo Synthesis of Ceramide Is Dispensable for Inflammasome driven Inflammation and Insulin Resistance in Obesity. AB - Dietary lipid overload and calorie excess during obesity is a low grade chronic inflammatory state with diminished ability to appropriately metabolize glucose or lipids. Macrophages are critical in maintaining adipose tissue homeostasis, in part by regulating lipid metabolism, energy homeostasis, and tissue remodeling. During high fat diet-induced obesity, macrophages are activated by lipid derived "danger signals" such as ceramides and palmitate and promote the adipose tissue inflammation in an Nlrp3 inflammasome-dependent manner. Given that the metabolic fate of fatty acids in macrophages is not entirely elucidated, we have hypothesized that de novo synthesis of ceramide, through the rate-limiting enzyme serine palmitoyltransferase long chain (Sptlc)-2, is required for saturated fatty acid-driven Nlrp3 inflammasome activation in macrophages. Here we report that mitochondrial targeted overexpression of catalase, which is established to mitigate oxidative stress, controls ceramide-induced Nlrp3 inflammasome activation but does not affect the ATP-mediated caspase-1 cleavage. Surprisingly, myeloid cell-specific deletion of Sptlc2 is not required for palmitate-driven Nlrp3 inflammasome activation. Furthermore, the ablation of Sptlc2 in macrophages did not impact macrophage polarization or obesity-induced adipose tissue leukocytosis. Consistent with these data, investigation of insulin resistance using hyperinsulinemic-euglycemic clamps revealed no significant differences in obese mice lacking ceramide de novo synthesis machinery in macrophages. These data suggest that alternate metabolic pathways control fatty acid-derived ceramide synthesis in macrophage and the Nlrp3 inflammasome activation in obesity. PMID- 26438822 TI - An Integrated Approach for Analysis of the DNA Damage Response in Mammalian Cells: NUCLEOTIDE EXCISION REPAIR, DNA DAMAGE CHECKPOINT, AND APOPTOSIS. AB - DNA damage by UV and UV-mimetic agents elicits a set of inter-related responses in mammalian cells, including DNA repair, DNA damage checkpoints, and apoptosis. Conventionally, these responses are analyzed separately using different methodologies. Here we describe a unified approach that is capable of quantifying all three responses in parallel using lysates from the same population of cells. We show that a highly sensitive in vivo excision repair assay is capable of detecting nucleotide excision repair of a wide spectrum of DNA lesions (UV damage, chemical carcinogens, and chemotherapeutic drugs) within minutes of damage induction. This method therefore allows for a real-time measure of nucleotide excision repair activity that can be monitored in conjunction with other components of the DNA damage response, including DNA damage checkpoint and apoptotic signaling. This approach therefore provides a convenient and reliable platform for simultaneously examining multiple aspects of the DNA damage response in a single population of cells that can be applied for a diverse array of carcinogenic and chemotherapeutic agents. PMID- 26438823 TI - Proton Matrix ENDOR Studies on Ca2+-depleted and Sr2+-substituted Manganese Cluster in Photosystem II. AB - Proton matrix ENDOR spectra were measured for Ca(2+)-depleted and Sr(2+) substituted photosystem II (PSII) membrane samples from spinach and core complexes from Thermosynechococcus vulcanus in the S2 state. The ENDOR spectra obtained were similar for untreated PSII from T. vulcanus and spinach, as well as for Ca(2+)-containing and Sr(2+)-substituted PSII, indicating that the proton arrangements around the manganese cluster in cyanobacterial and higher plant PSII and Ca(2+)-containing and Sr(2+)-substituted PSII are similar in the S2 state, in agreement with the similarity of the crystal structure of both Ca(2+)-containing and Sr(2+)-substituted PSII in the S1 state. Nevertheless, slightly different hyperfine separations were found between Ca(2+)-containing and Sr(2+)-substituted PSII because of modifications of the water protons ligating to the Sr(2+) ion. Importantly, Ca(2+) depletion caused the loss of ENDOR signals with a 1.36-MHz separation because of the loss of the water proton W4 connecting Ca(2+) and YZ directly. With respect to the crystal structure and the functions of Ca(2+) in oxygen evolution, it was concluded that the roles of Ca(2+) and Sr(2+) involve the maintenance of the hydrogen bond network near the Ca(2+) site and electron transfer pathway to the manganese cluster. PMID- 26438824 TI - Multipart Chaperone-Effector Recognition in the Type III Secretion System of Chlamydia trachomatis. AB - Secretion of effector proteins into the eukaryotic host cell is required for Chlamydia trachomatis virulence. In the infection process, Scc1 and Scc4, two chaperones of the type III secretion (T3S) system, facilitate secretion of the important effector and plug protein, CopN, but little is known about the details of this event. Here we use biochemistry, mass spectrometry, nuclear magnetic resonance spectroscopy, and genetic analyses to characterize this trimolecular event. We find that Scc4 complexes with Scc1 and CopN in situ at the late developmental cycle of C. trachomatis. We show that Scc4 and Scc1 undergo dynamic interactions as part of the unique bacterial developmental cycle. Using alanine substitutions, we identify several amino acid residues in Scc4 that are critical for the Scc4-Scc1 interaction, which is required for forming the Scc4.Scc1.CopN ternary complex. These results, combined with our previous findings that Scc4 plays a role in transcription (Rao, X., Deighan, P., Hua, Z., Hu, X., Wang, J., Luo, M., Wang, J., Liang, Y., Zhong, G., Hochschild, A., and Shen, L. (2009) Genes Dev. 23, 1818-1829), reveal that the T3S process is linked to bacterial transcriptional events, all of which are mediated by Scc4 and its interacting proteins. A model describing how the T3S process may affect gene expression is proposed. PMID- 26438825 TI - Two-pore Channels (TPC2s) and Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) at Lysosomal-Sarcoplasmic Reticular Junctions Contribute to Acute and Chronic beta-Adrenoceptor Signaling in the Heart. AB - Ca(2+)-permeable type 2 two-pore channels (TPC2) are lysosomal proteins required for nicotinic acid adenine dinucleotide phosphate (NAADP)-evoked Ca(2+) release in many diverse cell types. Here, we investigate the importance of TPC2 proteins for the physiology and pathophysiology of the heart. NAADP-AM failed to enhance Ca(2+) responses in cardiac myocytes from Tpcn2(-/-) mice, unlike myocytes from wild-type (WT) mice. Ca(2+)/calmodulin-dependent protein kinase II inhibitors suppressed actions of NAADP in myocytes. Ca(2+) transients and contractions accompanying action potentials were increased by isoproterenol in myocytes from WT mice, but these effects of beta-adrenoreceptor stimulation were reduced in myocytes from Tpcn2(-/-) mice. Increases in amplitude of L-type Ca(2+) currents evoked by isoproterenol remained unchanged in myocytes from Tpcn2(-/-) mice showing no loss of beta-adrenoceptors or coupling mechanisms. Whole hearts from Tpcn2(-/-) mice also showed reduced inotropic effects of isoproterenol and a reduced tendency for arrhythmias following acute beta-adrenoreceptor stimulation. Hearts from Tpcn2(-/-) mice chronically exposed to isoproterenol showed less cardiac hypertrophy and increased threshold for arrhythmogenesis compared with WT controls. Electron microscopy showed that lysosomes form close contacts with the sarcoplasmic reticulum (separation ~ 25 nm). We propose that Ca(2+)-signaling nanodomains between lysosomes and sarcoplasmic reticulum dependent on NAADP and TPC2 comprise an important element in beta-adrenoreceptor signal transduction in cardiac myocytes. In summary, our observations define a role for NAADP and TPC2 at lysosomal/sarcoplasmic reticulum junctions as unexpected but major contributors in the acute actions of beta-adrenergic signaling in the heart and also in stress pathways linking chronic stimulation of beta-adrenoceptors to hypertrophy and associated arrhythmias. PMID- 26438826 TI - High Glucose-induced Retinal Pericyte Apoptosis Depends on Association of GAPDH and Siah1. AB - Diabetic retinopathy (DR) is a leading cause of blindness worldwide, and its prevalence is growing. Current therapies for DR address only the later stages of the disease, are invasive, and have limited effectiveness. Retinal pericyte death is an early pathologic feature of DR. Although it has been observed in diabetic patients and in animal models of DR, the cause of pericyte death remains unknown. A novel pro-apoptotic pathway initiated by the interaction between glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and the E3 ubiquitin ligase, seven in absentia homolog 1 (Siah1), was recently identified in ocular tissues. In this article we examined the involvement of the GAPDH/Siah1 interaction in human retinal pericyte (hRP) apoptosis. HRP were cultured in 5 mm normal glucose, 25 mm l- or d-glucose for 48 h (osmotic control and high glucose treatments, respectively). Siah1 siRNA was used to down-regulate Siah1 expression. TAT-FLAG GAPDH and/or Siah1-directed peptides were used to block GAPDH and Siah1 interaction. Co-immunoprecipitation assays were conducted to analyze the effect of high glucose on the association of GAPDH and Siah1. Apoptosis was measured by Annexin V staining and caspase-3 enzymatic activity assay. High glucose increased Siah1 total protein levels, induced the association between GAPDH and Siah1, and led to GAPDH nuclear translocation. Our findings demonstrate that dissociation of the GAPDH/Siah1 pro apoptotic complex can block high glucose-induced pericyte apoptosis, widely considered a hallmark feature of DR. Thus, the work presented in this article can provide a foundation to identify novel targets for early treatment of DR. PMID- 26438827 TI - Prion aggregate structure in yeast cells is determined by the Hsp104-Hsp110 disaggregase machinery. AB - Prions consist of misfolded proteins that have adopted an infectious amyloid conformation. In vivo, prion biogenesis is intimately associated with the protein quality control machinery. Using electron tomography, we probed the effects of the heat shock protein Hsp70 chaperone system on the structure of a model yeast [PSI+] prion in situ. Individual Hsp70 deletions shift the balance between fibril assembly and disassembly, resulting in a variable shell of nonfibrillar, but still immobile, aggregates at the surface of the [PSI+] prion deposits. Both Hsp104 (an Hsp100 disaggregase) and Sse1 (the major yeast form of Hsp110) were localized to this surface shell of [PSI+] deposits in the deletion mutants. Elevation of Hsp104 expression promoted the appearance of this novel, nonfibrillar form of the prion aggregate. Moreover, Sse1 was found to regulate prion fibril length. Our studies reveal a key role for Sse1 (Hsp110), in cooperation with Hsp104, in regulating the length and assembly state of [PSI+] prion fibrils in vivo. PMID- 26438828 TI - SAM68 is a physiological regulator of SMN2 splicing in spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by loss of motor neurons in patients with null mutations in the SMN1 gene. The almost identical SMN2 gene is unable to compensate for this deficiency because of the skipping of exon 7 during pre-messenger RNA (mRNA) processing. Although several splicing factors can modulate SMN2 splicing in vitro, the physiological regulators of this disease-causing event are unknown. We found that knockout of the splicing factor SAM68 partially rescued body weight and viability of SMADelta7 mice. Ablation of SAM68 function promoted SMN2 splicing and expression in SMADelta7 mice, correlating with amelioration of SMA-related defects in motor neurons and skeletal muscles. Mechanistically, SAM68 binds to SMN2 pre-mRNA, favoring recruitment of the splicing repressor hnRNP A1 and interfering with that of U2AF65 at the 3' splice site of exon 7. These findings identify SAM68 as the first physiological regulator of SMN2 splicing in an SMA mouse model. PMID- 26438829 TI - RanGTP aids anaphase entry through Ubr5-mediated protein turnover. AB - RanGTP is known to regulate the spindle assembly checkpoint (SAC), but the underlying molecular mechanism is unclear. BuGZ stabilizes SAC protein Bub3 through direct interaction and facilitates its mitotic function. Here we show that RanGTP promotes the turnover of BuGZ and Bub3 in metaphase, which in turn facilitates metaphase-to-anaphase transition. BuGZ and Bub3 interact with either importin-beta or an E3 ubiquitin ligase, Ubr5. RanGTP promotes the dissociation of importin-beta from BuGZ and Bub3 in metaphase. This results in increased binding of BuGZ and Bub3 to Ubr5, leading to ubiquitination and subsequent turnover of both proteins. We propose that elevated metaphase RanGTP levels use Ubr5 to couple overall chromosome congression to SAC silencing. PMID- 26438830 TI - Growth factor signaling to mTORC1 by amino acid-laden macropinosomes. AB - The rapid activation of the mechanistic target of rapamycin complex-1 (mTORC1) by growth factors is increased by extracellular amino acids through yet-undefined mechanisms of amino acid transfer into endolysosomes. Because the endocytic process of macropinocytosis concentrates extracellular solutes into endolysosomes and is increased in cells stimulated by growth factors or tumor-promoting phorbol esters, we analyzed its role in amino acid-dependent activation of mTORC1. Here, we show that growth factor-dependent activation of mTORC1 by amino acids, but not glucose, requires macropinocytosis. In murine bone marrow-derived macrophages and murine embryonic fibroblasts stimulated with their cognate growth factors or with phorbol myristate acetate, activation of mTORC1 required an Akt-independent vesicular pathway of amino acid delivery into endolysosomes, mediated by the actin cytoskeleton. Macropinocytosis delivered small, fluorescent fluid-phase solutes into endolysosomes sufficiently fast to explain growth factor-mediated signaling by amino acids. Therefore, the amino acid-laden macropinosome is an essential and discrete unit of growth factor receptor signaling to mTORC1. PMID- 26438831 TI - Resistance to ketolide antibiotics by coordinated expression of rRNA methyltransferases in a bacterial producer of natural ketolides. AB - Ketolides are promising new antimicrobials effective against a broad range of Gram-positive pathogens, in part because of the low propensity of these drugs to trigger the expression of resistance genes. A natural ketolide pikromycin and a related compound methymycin are produced by Streptomyces venezuelae strain ATCC 15439. The producer avoids the inhibitory effects of its own antibiotics by expressing two paralogous rRNA methylase genes pikR1 and pikR2 with seemingly redundant functions. We show here that the PikR1 and PikR2 enzymes mono- and dimethylate, respectively, the N6 amino group in 23S rRNA nucleotide A2058. PikR1 monomethylase is constitutively expressed; it confers low resistance at low fitness cost and is required for ketolide-induced activation of pikR2 to attain high-level resistance. The regulatory mechanism controlling pikR2 expression has been evolutionary optimized for preferential activation by ketolide antibiotics. The resistance genes and the induction mechanism remain fully functional when transferred to heterologous bacterial hosts. The anticipated wide use of ketolide antibiotics could promote horizontal transfer of these highly efficient resistance genes to pathogens. Taken together, these findings emphasized the need for surveillance of pikR1/pikR2-based bacterial resistance and the preemptive development of drugs that can remain effective against the ketolide-specific resistance mechanism. PMID- 26438832 TI - Discovery of progenitor cell signatures by time-series synexpression analysis during Drosophila embryonic cell immortalization. AB - The use of time series profiling to identify groups of functionally related genes (synexpression groups) is a powerful approach for the discovery of gene function. Here we apply this strategy during Ras(V12) immortalization of Drosophila embryonic cells, a phenomenon not well characterized. Using high-resolution transcriptional time-series datasets, we generated a gene network based on temporal expression profile similarities. This analysis revealed that common immortalized cells are related to adult muscle precursors (AMPs), a stem cell like population contributing to adult muscles and sharing properties with vertebrate satellite cells. Remarkably, the immortalized cells retained the capacity for myogenic differentiation when treated with the steroid hormone ecdysone. Further, we validated in vivo the transcription factor CG9650, the ortholog of mammalian Bcl11a/b, as a regulator of AMP proliferation predicted by our analysis. Our study demonstrates the power of time series synexpression analysis to characterize Drosophila embryonic progenitor lines and identify stem/progenitor cell regulators. PMID- 26438833 TI - pH homeostasis during coral calcification in a free ocean CO2 enrichment (FOCE) experiment, Heron Island reef flat, Great Barrier Reef. AB - Geochemical analyses (delta(11)B and Sr/Ca) are reported for the coral Porites cylindrica grown within a free ocean carbon enrichment (FOCE) experiment, conducted on the Heron Island reef flat (Great Barrier Reef) for a 6-mo period from June to early December 2010. The FOCE experiment was designed to simulate the effects of CO2-driven acidification predicted to occur by the end of this century (scenario RCP4.5) while simultaneously maintaining the exposure of corals to natural variations in their environment under in situ conditions. Analyses of skeletal growth (measured from extension rates and skeletal density) showed no systematic differences between low-pH FOCE treatments (DeltapH = ~-0.05 to -0.25 units below ambient) and present day controls (DeltapH = 0) for calcification rates or the pH of the calcifying fluid (pHcf); the latter was derived from boron isotopic compositions (delta(11)B) of the coral skeleton. Furthermore, individual nubbins exhibited near constant delta(11)B compositions along their primary apical growth axes (+/-0.02 pHcf units) regardless of the season or treatment. Thus, under the highly dynamic conditions of the Heron Island reef flat, P. cylindrica up-regulated the pH of its calcifying fluid (pHcf ~8.4-8.6), with each nubbin having near-constant pHcf values independent of the large natural seasonal fluctuations of the reef flat waters (pH ~7.7 to ~8.3) or the superimposed FOCE treatments. This newly discovered phenomenon of pH homeostasis during calcification indicates that coral living in highly dynamic environments exert strong physiological controls on the carbonate chemistry of their calcifying fluid, implying a high degree of resilience to ocean acidification within the investigated ranges. PMID- 26438834 TI - Medieval warming initiated exceptionally large wildfire outbreaks in the Rocky Mountains. AB - Many of the largest wildfires in US history burned in recent decades, and climate change explains much of the increase in area burned. The frequency of extreme wildfire weather will increase with continued warming, but many uncertainties still exist about future fire regimes, including how the risk of large fires will persist as vegetation changes. Past fire-climate relationships provide an opportunity to constrain the related uncertainties, and reveal widespread burning across large regions of western North America during past warm intervals. Whether such episodes also burned large portions of individual landscapes has been difficult to determine, however, because uncertainties with the ages of past fires and limited spatial resolution often prohibit specific estimates of past area burned. Accounting for these challenges in a subalpine landscape in Colorado, we estimated century-scale fire synchroneity across 12 lake-sediment charcoal records spanning the past 2,000 y. The percentage of sites burned only deviated from the historic range of variability during the Medieval Climate Anomaly (MCA) between 1,200 and 850 y B.P., when temperatures were similar to recent decades. Between 1,130 and 1,030 y B.P., 83% (median estimate) of our sites burned when temperatures increased ~0.5 degrees C relative to the preceding centuries. Lake-based fire rotation during the MCA decreased to an estimated 120 y, representing a 260% higher rate of burning than during the period of dendroecological sampling (360 to -60 y B.P.). Increased burning, however, did not persist throughout the MCA. Burning declined abruptly before temperatures cooled, indicating possible fuel limitations to continued burning. PMID- 26438835 TI - Photon gating in four-dimensional ultrafast electron microscopy. AB - Ultrafast electron microscopy (UEM) is a pivotal tool for imaging of nanoscale structural dynamics with subparticle resolution on the time scale of atomic motion. Photon-induced near-field electron microscopy (PINEM), a key UEM technique, involves the detection of electrons that have gained energy from a femtosecond optical pulse via photon-electron coupling on nanostructures. PINEM has been applied in various fields of study, from materials science to biological imaging, exploiting the unique spatial, energy, and temporal characteristics of the PINEM electrons gained by interaction with a "single" light pulse. The further potential of photon-gated PINEM electrons in probing ultrafast dynamics of matter and the optical gating of electrons by invoking a "second" optical pulse has previously been proposed and examined theoretically in our group. Here, we experimentally demonstrate this photon-gating technique, and, through diffraction, visualize the phase transition dynamics in vanadium dioxide nanoparticles. With optical gating of PINEM electrons, imaging temporal resolution was improved by a factor of 3 or better, being limited only by the optical pulse widths. This work enables the combination of the high spatial resolution of electron microscopy and the ultrafast temporal response of the optical pulses, which provides a promising approach to attain the resolution of few femtoseconds and attoseconds in UEM. PMID- 26438836 TI - Mutation of the ER retention receptor KDELR1 leads to cell-intrinsic lymphopenia and a failure to control chronic viral infection. AB - Endoplasmic reticulum (ER)-resident proteins are continually retrieved from the Golgi and returned to the ER by Lys-Asp-Glu-Leu (KDEL) receptors, which bind to an eponymous tetrapeptide motif at their substrate's C terminus. Mice and humans possess three paralogous KDEL receptors, but little is known about their functional redundancy, or if their mutation can be physiologically tolerated. Here, we present a recessive mouse missense allele of the prototypical mammalian KDEL receptor, KDEL ER protein retention receptor 1 (KDELR1). Kdelr1 homozygous mutants were mildly lymphopenic, as were mice with a CRISPR/Cas9-engineered frameshift allele. Lymphopenia was cell intrinsic and, in the case of T cells, was associated with reduced expression of the T-cell receptor (TCR) and increased expression of CD44, and could be partially corrected by an MHC class I-restricted TCR transgene. Antiviral immunity was also compromised, with Kdelr1 mutant mice unable to clear an otherwise self-limiting viral infection. These data reveal a nonredundant cellular function for KDELR1, upon which lymphocytes distinctly depend. PMID- 26438837 TI - Indoleamine 2,3-dioxygenase-1 is protective in atherosclerosis and its metabolites provide new opportunities for drug development. AB - Atherosclerosis is the major cause of cardiovascular disease (CVD), the leading cause of death worldwide. Despite much focus on lipid abnormalities in atherosclerosis, it is clear that the immune system also has important pro- and antiatherogenic functions. The enzyme indoleamine-2,3-dioxygenase (IDO) catalyses degradation of the essential amino acid tryptophan into immunomodulatory metabolites. How IDO deficiency affects immune responses during atherogenesis is unknown and we explored potential mechanisms in models of murine and human atherosclerosis. IDO deficiency in hypercholesterolemic ApoE(-/-) mice caused a significant increase in lesion size and surrogate markers of plaque vulnerability. No significant changes in cholesterol levels were observed but decreases in IL-10 production were found in the peripheral blood, spleen and lymph node B cells of IDO-deficient compared with IDO-competent ApoE(-/-) mice. 3,4,-Dimethoxycinnamoyl anthranilic acid (3,4-DAA), an orally active synthetic derivative of the tryptophan metabolite anthranilic acid, but not l-kynurenine, enhanced production of IL-10 in cultured splenic B cells. Finally, 3,4-DAA treatment reduced lesion formation and inflammation after collar-induced arterial injury in ApoE(-/-) mice, and reduced cytokine and chemokine production in ex vivo human atheroma cell cultures. Our data demonstrate that endogenous production of tryptophan metabolites via IDO is an essential feedback loop that controls atherogenesis and athero-inflammation. We show that the IDO pathway induces production of IL-10 in B cells in vivo and in vitro, suggesting that IDO may induce immunoregulatory functions of B cells in atherosclerosis. The favorable effects of anthranilic acid derivatives in atherosclerosis indicate a novel approach toward therapy of CVD. PMID- 26438838 TI - Epithelial estrogen receptor 1 intrinsically mediates squamous differentiation in the mouse vagina. AB - Estrogen-mediated actions in female reproductive organs are tightly regulated, mainly through estrogen receptor 1 (ESR1). The mouse vaginal epithelium cyclically exhibits cell proliferation and differentiation in response to estrogen and provides a unique model for analyzing the homeostasis of stratified squamous epithelia. To address the role of ESR1-mediated tissue events during homeostasis, we analyzed mice with a vaginal epithelium-specific knockout of Esr1 driven by keratin 5-Cre (K5-Esr1KO). We show here that loss of epithelial ESR1 in the vagina resulted in aberrant epithelial cell proliferation in the suprabasal cell layers and led to failure of keratinized differentiation. Gene expression analysis showed that several known estrogen target genes, including erbB growth factor ligands, were not induced by estrogen in the K5-Esr1KO mouse vagina. Organ culture experiments revealed that the addition of erbB growth factor ligands, such as amphiregulin, could activate keratinized differentiation in the absence of epithelial ESR1. Thus, epithelial ESR1 integrates estrogen and growth factor signaling to mediate regulation of cell proliferation in squamous differentiation, and our results provide new insights into estrogen-mediated homeostasis in female reproductive organs. PMID- 26438839 TI - Coexistence of both gyroid chiralities in individual butterfly wing scales of Callophrys rubi. AB - The wing scales of the Green Hairstreak butterfly Callophrys rubi consist of crystalline domains with sizes of a few micrometers, which exhibit a congenitally handed porous chitin microstructure identified as the chiral triply periodic single-gyroid structure. Here, the chirality and crystallographic texture of these domains are investigated by means of electron tomography. The tomograms unambiguously reveal the coexistence of the two enantiomeric forms of opposite handedness: the left- and right-handed gyroids. These two enantiomers appear with nonequal probabilities, implying that molecularly chiral constituents of the biological formation process presumably invoke a chiral symmetry break, resulting in a preferred enantiomeric form of the gyroid structure. Assuming validity of the formation model proposed by Ghiradella H (1989) J Morphol 202(1):69-88 and Saranathan V, et al. (2010) Proc Natl Acad Sci USA 107(26):11676-11681, where the two enantiomeric labyrinthine domains of the gyroid are connected to the extracellular and intra-SER spaces, our findings imply that the structural chirality of the single gyroid is, however, not caused by the molecular chirality of chitin. Furthermore, the wing scales are found to be highly textured, with a substantial fraction of domains exhibiting the <001> directions of the gyroid crystal aligned parallel to the scale surface normal. Both findings are needed to completely understand the photonic purpose of the single gyroid in gyroid-forming butterflies. More importantly, they show the level of control that morphogenesis exerts over secondary features of biological nanostructures, such as chirality or crystallographic texture, providing inspiration for biomimetic replication strategies for synthetic self-assembly mechanisms. PMID- 26438840 TI - Optofluidic wavelength division multiplexing for single-virus detection. AB - Optical waveguides simultaneously transport light at different colors, forming the basis of fiber-optic telecommunication networks that shuttle data in dozens of spectrally separated channels. Here, we reimagine this wavelength division multiplexing (WDM) paradigm in a novel context--the differentiated detection and identification of single influenza viruses on a chip. We use a single multimode interference (MMI) waveguide to create wavelength-dependent spot patterns across the entire visible spectrum and enable multiplexed single biomolecule detection on an optofluidic chip. Each target is identified by its time-dependent fluorescence signal without the need for spectral demultiplexing upon detection. We demonstrate detection of individual fluorescently labeled virus particles of three influenza A subtypes in two implementations: labeling of each virus using three different colors and two-color combinatorial labeling. By extending combinatorial multiplexing to three or more colors, MMI-based WDM provides the multiplexing power required for differentiated clinical tests and the growing field of personalized medicine. PMID- 26438841 TI - Mapping of histone modifications in episomal HBV cccDNA uncovers an unusual chromatin organization amenable to epigenetic manipulation. AB - Chronic hepatitis B virus (HBV) infection affects 240 million people worldwide and is a major risk factor for liver failure and hepatocellular carcinoma. Current antiviral therapy inhibits cytoplasmic HBV genomic replication, but is not curative because it does not directly affect nuclear HBV closed circular DNA (cccDNA), the genomic form that templates viral transcription and sustains viral persistence. Novel approaches that directly target cccDNA regulation would therefore be highly desirable. cccDNA is assembled with cellular histone proteins into chromatin, but little is known about the regulation of HBV chromatin by histone posttranslational modifications (PTMs). Here, using a new cccDNA ChIP-Seq approach, we report, to our knowledge, the first genome-wide maps of PTMs in cccDNA-containing chromatin from de novo infected HepG2 cells, primary human hepatocytes, and from HBV-infected liver tissue. We find high levels of PTMs associated with active transcription enriched at specific sites within the HBV genome and, surprisingly, very low levels of PTMs linked to transcriptional repression even at silent HBV promoters. We show that transcription and active PTMs in HBV chromatin are reduced by the activation of an innate immunity pathway, and that this effect can be recapitulated with a small molecule epigenetic modifying agent, opening the possibility that chromatin-based regulation of cccDNA transcription could be a new therapeutic approach to chronic HBV infection. PMID- 26438842 TI - NO binding kinetics in myoglobin investigated by picosecond Fe K-edge absorption spectroscopy. AB - Diatomic ligands in hemoproteins and the way they bind to the active center are central to the protein's function. Using picosecond Fe K-edge X-ray absorption spectroscopy, we probe the NO-heme recombination kinetics with direct sensitivity to the Fe-NO binding after 532-nm photoexcitation of nitrosylmyoglobin (MbNO) in physiological solutions. The transients at 70 and 300 ps are identical, but they deviate from the difference between the static spectra of deoxymyoglobin and MbNO, showing the formation of an intermediate species. We propose the latter to be a six-coordinated domed species that is populated on a timescale of ~ 200 ps by recombination with NO ligands. This work shows the feasibility of ultrafast pump-probe X-ray spectroscopic studies of proteins in physiological media, delivering insight into the electronic and geometric structure of the active center. PMID- 26438843 TI - cKit+ cardiac progenitors of neural crest origin. AB - The degree to which cKit-expressing progenitors generate cardiomyocytes in the heart is controversial. Genetic fate-mapping studies suggest minimal contribution; however, whether or not minimal contribution reflects minimal cardiomyogenic capacity is unclear because the embryonic origin and role in cardiogenesis of these progenitors remain elusive. Using high-resolution genetic fate-mapping approaches with cKit(CreERT2/+) and Wnt1::Flpe mouse lines, we show that cKit delineates cardiac neural crest progenitors (CNC(kit)). CNC(kit) possess full cardiomyogenic capacity and contribute to all CNC derivatives, including cardiac conduction system cells. Furthermore, by modeling cardiogenesis in cKit(CreERT2)-induced pluripotent stem cells, we show that, paradoxically, the cardiogenic fate of CNC(kit) is regulated by bone morphogenetic protein antagonism, a signaling pathway activated transiently during establishment of the cardiac crescent, and extinguished from the heart before CNC invasion. Together, these findings elucidate the origin of cKit(+) cardiac progenitors and suggest that a nonpermissive cardiac milieu, rather than minimal cardiomyogenic capacity, controls the degree of CNC(kit) contribution to myocardium. PMID- 26438844 TI - Genome-wide modeling of transcription kinetics reveals patterns of RNA production delays. AB - Genes with similar transcriptional activation kinetics can display very different temporal mRNA profiles because of differences in transcription time, degradation rate, and RNA-processing kinetics. Recent studies have shown that a splicing associated RNA production delay can be significant. To investigate this issue more generally, it is useful to develop methods applicable to genome-wide datasets. We introduce a joint model of transcriptional activation and mRNA accumulation that can be used for inference of transcription rate, RNA production delay, and degradation rate given data from high-throughput sequencing time course experiments. We combine a mechanistic differential equation model with a nonparametric statistical modeling approach allowing us to capture a broad range of activation kinetics, and we use Bayesian parameter estimation to quantify the uncertainty in estimates of the kinetic parameters. We apply the model to data from estrogen receptor alpha activation in the MCF-7 breast cancer cell line. We use RNA polymerase II ChIP-Seq time course data to characterize transcriptional activation and mRNA-Seq time course data to quantify mature transcripts. We find that 11% of genes with a good signal in the data display a delay of more than 20 min between completing transcription and mature mRNA production. The genes displaying these long delays are significantly more likely to be short. We also find a statistical association between high delay and late intron retention in pre-mRNA data, indicating significant splicing-associated production delays in many genes. PMID- 26438845 TI - Psychological and neural correlates of the emergence of morality in toddlers. PMID- 26438846 TI - Targeting glutamine metabolism rescues mice from late-stage cerebral malaria. AB - The most deadly complication of Plasmodium falciparum infection is cerebral malaria (CM) with a case fatality rate of 15-25% in African children despite effective antimalarial chemotherapy. There are no adjunctive treatments for CM, so there is an urgent need to identify new targets for therapy. Here we show that the glutamine analog 6-diazo-5-oxo-L-norleucine (DON) rescues mice from CM when administered late in the infection a time at which mice already are suffering blood-brain barrier dysfunction, brain swelling, and hemorrhaging accompanied by accumulation of parasite-specific CD8(+) effector T cells and infected red blood cells in the brain. Remarkably, within hours of DON treatment mice showed blood brain barrier integrity, reduced brain swelling, decreased function of activated effector CD8(+) T cells in the brain, and levels of brain metabolites that resembled those in uninfected mice. These results suggest DON as a strong candidate for an effective adjunctive therapy for CM in African children. PMID- 26438847 TI - Relation between rainfall intensity and savanna tree abundance explained by water use strategies. AB - Tree abundance in tropical savannas exhibits large and unexplained spatial variability. Here, we propose that differentiated tree and grass water use strategies can explain the observed negative relation between maximum tree abundance and rainfall intensity (defined as the characteristic rainfall depth on rainy days), and we present a biophysical tree-grass competition model to test this idea. The model is founded on a premise that has been well established in empirical studies, namely, that the relative growth rate of grasses is much higher compared with trees in wet conditions but that grasses are more susceptible to water stress and lose biomass more quickly in dry conditions. The model is coupled with a stochastic rainfall generator and then calibrated and tested using field observations from several African savanna sites. We show that the observed negative relation between maximum tree abundance and rainfall intensity can be explained only when differentiated water use strategies are accounted for. Numerical experiments reveal that this effect is more significant than the effect of root niche separation. Our results emphasize the importance of vegetation physiology in determining the responses of tree abundance to climate variations in tropical savannas and suggest that projected increases in rainfall intensity may lead to an increase in grass in this biome. PMID- 26438849 TI - Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration. AB - Sphingolipids typically have an 18-carbon (C18) sphingoid long chain base (LCB) backbone. Although sphingolipids with LCBs of other chain lengths have been identified, the functional significance of these low-abundance sphingolipids is unknown. The LCB chain length is determined by serine palmitoyltransferase (SPT) isoenzymes, which are trimeric proteins composed of two large subunits (SPTLC1 and SPTLC2 or SPTLC3) and a small subunit (SPTssa or SPTssb). Here we report the identification of an Sptssb mutation, Stellar (Stl), which increased the SPT affinity toward the C18 fatty acyl-CoA substrate by twofold and significantly elevated 20-carbon (C20) LCB production in the mutant mouse brain and eye, resulting in surprising neurodegenerative effects including aberrant membrane structures, accumulation of ubiquitinated proteins on membranes, and axon degeneration. Our work demonstrates that SPT small subunits play a major role in controlling SPT activity and substrate affinity, and in specifying sphingolipid LCB chain length in vivo. Moreover, our studies also suggest that excessive C20 LCBs or C20 LCB-containing sphingolipids impair protein homeostasis and neural functions. PMID- 26438848 TI - A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling. AB - Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) govern cellular homeostasis by inducing signaling. H2O2 modulates the activity of phosphatases and many other signaling molecules through oxidation of critical cysteine residues, which led to the notion that initiation of ROS signaling is broad and nonspecific, and thus fundamentally distinct from other signaling pathways. Here, we report that H2O2 signaling bears hallmarks of a regular signal transduction cascade. It is controlled by hierarchical signaling events resulting in a focused response as the results place the mitochondrial respiratory chain upstream of tyrosine-protein kinase Lyn, Lyn upstream of tyrosine-protein kinase SYK (Syk), and Syk upstream of numerous targets involved in signaling, transcription, translation, metabolism, and cell cycle regulation. The active mediators of H2O2 signaling colocalize as H2O2 induces mitochondria-associated Lyn and Syk phosphorylation, and a pool of Lyn and Syk reside in the mitochondrial intermembrane space. Finally, the same intermediaries control the signaling response in tissues and species responsive to H2O2 as the respiratory chain, Lyn, and Syk were similarly required for H2O2 signaling in mouse B cells, fibroblasts, and chicken DT40 B cells. Consistent with a broad role, the Syk pathway is coexpressed across tissues, is of early metazoan origin, and displays evidence of evolutionary constraint in the human. These results suggest that H2O2 signaling is under control of a signal transduction pathway that links the respiratory chain to the mitochondrial intermembrane space-localized, ubiquitous, and ancient Syk pathway in hematopoietic and nonhematopoietic cells. PMID- 26438850 TI - Dissecting pigment architecture of individual photosynthetic antenna complexes in solution. AB - Oligomerization plays a critical role in shaping the light-harvesting properties of many photosynthetic pigment-protein complexes, but a detailed understanding of this process at the level of individual pigments is still lacking. To study the effects of oligomerization, we designed a single-molecule approach to probe the photophysical properties of individual pigment sites as a function of protein assembly state. Our method, based on the principles of anti-Brownian electrokinetic trapping of single fluorescent proteins, step-wise photobleaching, and multiparameter spectroscopy, allows pigment-specific spectroscopic information on single multipigment antennae to be recorded in a nonperturbative aqueous environment with unprecedented detail. We focus on the monomer-to-trimer transformation of allophycocyanin (APC), an important antenna protein in cyanobacteria. Our data reveal that the two chemically identical pigments in APC have different roles. One (alpha) is the functional pigment that red-shifts its spectral properties upon trimer formation, whereas the other (beta) is a "protective" pigment that persistently quenches the excited state of alpha in the prefunctional, monomer state of the protein. These results show how subtleties in pigment organization give rise to functionally important aspects of energy transfer and photoprotection in antenna complexes. The method developed here should find immediate application in understanding the emergent properties of other natural and artificial light-harvesting systems. PMID- 26438851 TI - Region-wide synchrony and traveling waves of dengue across eight countries in Southeast Asia. AB - Dengue is a mosquito-transmitted virus infection that causes epidemics of febrile illness and hemorrhagic fever across the tropics and subtropics worldwide. Annual epidemics are commonly observed, but there is substantial spatiotemporal heterogeneity in intensity. A better understanding of this heterogeneity in dengue transmission could lead to improved epidemic prediction and disease control. Time series decomposition methods enable the isolation and study of temporal epidemic dynamics with a specific periodicity (e.g., annual cycles related to climatic drivers and multiannual cycles caused by dynamics in population immunity). We collected and analyzed up to 18 y of monthly dengue surveillance reports on a total of 3.5 million reported dengue cases from 273 provinces in eight countries in Southeast Asia, covering ~ 10(7) km(2). We detected strong patterns of synchronous dengue transmission across the entire region, most markedly during a period of high incidence in 1997-1998, which was followed by a period of extremely low incidence in 2001-2002. This synchrony in dengue incidence coincided with elevated temperatures throughout the region in 1997-1998 and the strongest El Nino episode of the century. Multiannual dengue cycles (2-5 y) were highly coherent with the Oceanic Nino Index, and synchrony of these cycles increased with temperature. We also detected localized traveling waves of multiannual dengue epidemic cycles in Thailand, Laos, and the Philippines that were dependent on temperature. This study reveals forcing mechanisms that drive synchronization of dengue epidemics on a continental scale across Southeast Asia. PMID- 26438852 TI - Remodeling nuclear architecture allows efficient transport of herpesvirus capsids by diffusion. AB - The nuclear chromatin structure confines the movement of large macromolecular complexes to interchromatin corrals. Herpesvirus capsids of approximately 125 nm assemble in the nucleoplasm and must reach the nuclear membranes for egress. Previous studies concluded that nuclear herpesvirus capsid motility is active, directed, and based on nuclear filamentous actin, suggesting that large nuclear complexes need metabolic energy to escape nuclear entrapment. However, this hypothesis has recently been challenged. Commonly used microscopy techniques do not allow the imaging of rapid nuclear particle motility with sufficient spatiotemporal resolution. Here, we use a rotating, oblique light sheet, which we dubbed a ring-sheet, to image and track viral capsids with high temporal and spatial resolution. We do not find any evidence for directed transport. Instead, infection with different herpesviruses induced an enlargement of interchromatin domains and allowed particles to diffuse unrestricted over longer distances, thereby facilitating nuclear egress for a larger fraction of capsids. PMID- 26438853 TI - A holistic picture of Austronesian migrations revealed by phylogeography of Pacific paper mulberry. AB - The peopling of Remote Oceanic islands by Austronesian speakers is a fascinating and yet contentious part of human prehistory. Linguistic, archaeological, and genetic studies have shown the complex nature of the process in which different components that helped to shape Lapita culture in Near Oceania each have their own unique history. Important evidence points to Taiwan as an Austronesian ancestral homeland with a more distant origin in South China, whereas alternative models favor South China to North Vietnam or a Southeast Asian origin. We test these propositions by studying phylogeography of paper mulberry, a common East Asian tree species introduced and clonally propagated since prehistoric times across the Pacific for making barkcloth, a practical and symbolic component of Austronesian cultures. Using the hypervariable chloroplast ndhF-rpl32 sequences of 604 samples collected from East Asia, Southeast Asia, and Oceanic islands (including 19 historical herbarium specimens from Near and Remote Oceania), 48 haplotypes are detected and haplotype cp-17 is predominant in both Near and Remote Oceania. Because cp-17 has an unambiguous Taiwanese origin and cp-17 carrying Oceanic paper mulberries are clonally propagated, our data concur with expectations of Taiwan as the Austronesian homeland, providing circumstantial support for the "out of Taiwan" hypothesis. Our data also provide insights into the dispersal of paper mulberry from South China "into North Taiwan," the "out of South China-Indochina" expansion to New Guinea, and the geographic origins of post-European introductions of paper mulberry into Oceania. PMID- 26438854 TI - Contribution of cyanobacterial alkane production to the ocean hydrocarbon cycle. AB - Hydrocarbons are ubiquitous in the ocean, where alkanes such as pentadecane and heptadecane can be found even in waters minimally polluted with crude oil. Populations of hydrocarbon-degrading bacteria, which are responsible for the turnover of these compounds, are also found throughout marine systems, including in unpolluted waters. These observations suggest the existence of an unknown and widespread source of hydrocarbons in the oceans. Here, we report that strains of the two most abundant marine cyanobacteria, Prochlorococcus and Synechococcus, produce and accumulate hydrocarbons, predominantly C15 and C17 alkanes, between 0.022 and 0.368% of dry cell weight. Based on global population sizes and turnover rates, we estimate that these species have the capacity to produce 2-540 pg alkanes per mL per day, which translates into a global ocean yield of ~ 308 771 million tons of hydrocarbons annually. We also demonstrate that both obligate and facultative marine hydrocarbon-degrading bacteria can consume cyanobacterial alkanes, which likely prevents these hydrocarbons from accumulating in the environment. Our findings implicate cyanobacteria and hydrocarbon degraders as key players in a notable internal hydrocarbon cycle within the upper ocean, where alkanes are continually produced and subsequently consumed within days. Furthermore we show that cyanobacterial alkane production is likely sufficient to sustain populations of hydrocarbon-degrading bacteria, whose abundances can rapidly expand upon localized release of crude oil from natural seepage and human activities. PMID- 26438855 TI - Current extinction rates of reptiles and amphibians. AB - There is broad concern that a mass extinction of amphibians and reptiles is now underway. Here I apply an extremely conservative Bayesian method to estimate the number of recent amphibian and squamate extinctions in nine important tropical and subtropical regions. The data stem from a combination of museum collection databases and published site surveys. The method computes an extinction probability for each species by considering its sighting frequency and last sighting date. It infers hardly any extinction when collection dates are randomized and it provides underestimates when artificial extinction events are imposed. The method also appears to be insensitive to trends in sampling; therefore, the counts it provides are absolute minimums. Extinctions or severe population crashes have accumulated steadily since the 1970s and 1980s, and at least 3.1% of frog species have already disappeared. Based on these data and this conservative method, the best estimate of the global grand total is roughly 200 extinctions. Consistent with previous results, frog losses are heavy in Latin America, which has been greatly affected by the pathogenic chytrid fungus Batrachochytrium dendrobatidis. Extinction rates are now four orders-of-magnitude higher than background, and at least another 6.9% of all frog species may be lost within the next century, even if there is no acceleration in the growth of environmental threats. PMID- 26438856 TI - Resource colimitation governs plant community responses to altered precipitation. AB - Ecological theory and evidence suggest that plant community biomass and composition may often be jointly controlled by climatic water availability and soil nutrient supply. To the extent that such colimitation operates, alterations in water availability caused by climatic change may have relatively little effect on plant communities on nutrient-poor soils. We tested this prediction with a 5-y rainfall and nutrient manipulation in a semiarid annual grassland system with highly heterogeneous soil nutrient supplies. On nutrient-poor soils, rainfall addition alone had little impact, but rainfall and nutrient addition synergized to cause large increases in biomass, declines in diversity, and near-complete species turnover. Plant species with resource-conservative functional traits (low specific leaf area, short stature) were replaced by species with resource acquisitive functional traits (high specific leaf area, tall stature). On nutrient-rich soils, in contrast, rainfall addition alone caused substantial increases in biomass, whereas fertilization had little effect. Our results highlight that multiple resource limitation is a critical aspect when predicting the relative vulnerability of natural communities to climatically induced compositional change and diversity loss. PMID- 26438857 TI - Allowing variance may enlarge the safe operating space for exploited ecosystems. AB - Variable flows of food, water, or other ecosystem services complicate planning. Management strategies that decrease variability and increase predictability may therefore be preferred. However, actions to decrease variance over short timescales (2-4 y), when applied continuously, may lead to long-term ecosystem changes with adverse consequences. We investigated the effects of managing short term variance in three well-understood models of ecosystem services: lake eutrophication, harvest of a wild population, and yield of domestic herbivores on a rangeland. In all cases, actions to decrease variance can increase the risk of crossing critical ecosystem thresholds, resulting in less desirable ecosystem states. Managing to decrease short-term variance creates ecosystem fragility by changing the boundaries of safe operating spaces, suppressing information needed for adaptive management, cancelling signals of declining resilience, and removing pressures that may build tolerance of stress. Thus, the management of variance interacts strongly and inseparably with the management of resilience. By allowing for variation, learning, and flexibility while observing change, managers can detect opportunities and problems as they develop while sustaining the capacity to deal with them. PMID- 26438858 TI - Kin discrimination between sympatric Bacillus subtilis isolates. AB - Kin discrimination, broadly defined as differential treatment of conspecifics according to their relatedness, could help biological systems direct cooperative behavior toward their relatives. Here we investigated the ability of the soil bacterium Bacillus subtilis to discriminate kin from nonkin in the context of swarming, a cooperative multicellular behavior. We tested a collection of sympatric conspecifics from soil in pairwise combinations and found that despite their history of coexistence, the vast majority formed distinct boundaries when the swarms met. Some swarms did merge, and most interestingly, this behavior was only seen in the most highly related strain pairs. Overall the swarm interaction phenotype strongly correlated with phylogenetic relatedness, indicative of kin discrimination. Using a subset of strains, we examined cocolonization patterns on plant roots. Pairs of kin strains were able to cocolonize roots and formed a mixed-strain biofilm. In contrast, inoculating roots with pairs of nonkin strains resulted in biofilms consisting primarily of one strain, suggestive of an antagonistic interaction among nonkin strains. This study firmly establishes kin discrimination in a bacterial multicellular setting and suggests its potential effect on ecological interactions. PMID- 26438859 TI - Consequences of zygote injection and germline transfer of mutant human mitochondrial DNA in mice. AB - Considerable evidence supports mutations in mitochondrial genes as the cause of maternally inherited diseases affecting tissues that rely primarily on oxidative energy metabolism, usually the nervous system, the heart, and skeletal muscles. Mitochondrial diseases are diverse, and animal models currently are limited. Here we introduced a mutant human mitochondrial gene responsible for Leber hereditary optic neuropathy (LHON) into the mouse germ line using fluorescence imaging for tissue-specific enrichment in the target retinal ganglion cells. A mitochondria targeted adeno-associated virus (MTS-AAV) containing the mutant human NADH ubiquinone oxidoreductase subunit 4 (ND4) gene followed by mitochondrial-encoded mCherry was microinjected into zygotes. Female founders with mCherry fluorescence on ophthalmoscopy were backcrossed with normal males for eight generations. Mutant human ND4 DNA was 20% of mouse ND4 and did not integrate into the host genome. Translated human ND4 protein assembled into host respiratory complexes, decreasing respiratory chain function and increasing oxidative stress. Swelling of the optic nerve head was followed by progressive demise of ganglion cells and their axons, the hallmarks of human LHON. Early visual loss that began at 3 mo and progressed to blindness 8 mo after birth was reversed by intraocular injection of MTS-AAV expressing wild-type human ND4. The technology of introducing human mitochondrial genes into the mouse germ line has never been described, to our knowledge, and has implications not only for creating animal models recapitulating the counterpart human disorder but more importantly for reversing the adverse effects of the mutant gene using gene therapy to deliver the wild-type allele. PMID- 26438860 TI - Variable genetic architectures produce virtually identical molecules in bacterial symbionts of fungus-growing ants. AB - Small molecules produced by Actinobacteria have played a prominent role in both drug discovery and organic chemistry. As part of a larger study of the actinobacterial symbionts of fungus-growing ants, we discovered a small family of three previously unreported piperazic acid-containing cyclic depsipeptides, gerumycins A-C. The gerumycins are slightly smaller versions of dentigerumycin, a cyclic depsipeptide that selectively inhibits a common fungal pathogen, Escovopsis. We had previously identified this molecule from a Pseudonocardia associated with Apterostigma dentigerum, and now we report the molecule from an associate of the more highly derived ant Trachymyrmex cornetzi. The three previously unidentified compounds, gerumycins A-C, have essentially identical structures and were produced by two different symbiotic Pseudonocardia spp. from ants in the genus Apterostigma found in both Panama and Costa Rica. To understand the similarities and differences in the biosynthetic pathways that produced these closely related molecules, the genomes of the three producing Pseudonocardia were sequenced and the biosynthetic gene clusters identified. This analysis revealed that dramatically different biosynthetic architectures, including genomic islands, a plasmid, and the use of spatially separated genetic loci, can lead to molecules with virtually identical core structures. A plausible evolutionary model that unifies these disparate architectures is presented. PMID- 26438861 TI - Longitudinal spread of mechanical excitation through tectorial membrane traveling waves. AB - The mammalian inner ear separates sounds by their frequency content, and this separation underlies important properties of human hearing, including our ability to understand speech in noisy environments. Studies of genetic disorders of hearing have demonstrated a link between frequency selectivity and wave properties of the tectorial membrane (TM). To understand these wave properties better, we developed chemical manipulations that systematically and reversibly alter TM stiffness and viscosity. Using microfabricated shear probes, we show that (i) reducing pH reduces TM stiffness with little change in TM viscosity and (ii) adding PEG increases TM viscosity with little change in TM stiffness. By applying these manipulations in measurements of TM waves, we show that TM wave speed is determined primarily by stiffness at low frequencies and by viscosity at high frequencies. Both TM viscosity and stiffness affect the longitudinal spread of mechanical excitation through the TM over a broad range of frequencies. Increasing TM viscosity or decreasing stiffness reduces longitudinal spread of mechanical excitation, thereby coupling a smaller range of best frequencies and sharpening tuning. In contrast, increasing viscous loss or decreasing stiffness would tend to broaden tuning in resonance-based TM models. Thus, TM wave and resonance mechanisms are fundamentally different in the way they control frequency selectivity. PMID- 26438862 TI - Effects of lymphocyte profile on development of EBV-induced lymphoma subtypes in humanized mice. AB - Epstein-Barr virus (EBV) infection causes both Hodgkin's lymphoma (HL) and non Hodgkin's lymphoma (NHL). The present study reveals that EBV-induced HL and NHL are intriguingly associated with a repopulated immune cell profile in humanized mice. Newborn immunodeficient NSG mice were engrafted with human cord blood CD34(+) hematopoietic stem cells (HSCs) for a 8- or 15-wk reconstitution period (denoted (8w)hN and (15w)hN, respectively), resulting in human B-cell and T-cell predominance in peripheral blood cells, respectively. Further, novel humanized mice were established via engraftment of hCD34(+) HSCs together with nonautologous fetal liver-derived mesenchymal stem cells (MSCs) or MSCs expressing an active notch ligand DLK1, resulting in mice skewed with human B or T cells, respectively. After EBV infection, whereas NHL developed more frequently in B-cell-predominant humanized mice, HL was seen in T-cell-predominant mice (P = 0.0013). Whereas human splenocytes from NHL-bearing mice were positive for EBV associated NHL markers (hBCL2(+), hCD20(+), hKi67(+), hCD20(+)/EBNA1(+), and EBER(+)) but negative for HL markers (LMP1(-), EBNA2(-), and hCD30(-)), most HL like tumors were characterized by the presence of malignant Hodgkin's Reed Sternberg (HRS)-like cells, lacunar RS (hCD30(+), hCD15(+), IgJ(-), EBER(+)/hCD30(+), EBNA1(+)/hCD30(+), LMP(+)/EBNA2(-), hCD68(+), hBCL2(-), hCD20( /weak,) Phospho STAT6(+)), and mummified RS cells. This study reveals that immune cell composition plays an important role in the development of EBV-induced B-cell lymphoma. PMID- 26438863 TI - Disulphide-reduced psoriasin is a human apoptosis-inducing broad-spectrum fungicide. AB - The unexpected resistance of psoriasis lesions to fungal infections suggests local production of an antifungal factor. We purified Trichophyton rubrum inhibiting activity from lesional psoriasis scale extracts and identified the Cys reduced form of S100A7/psoriasin (redS100A7) as a principal antifungal factor. redS100A7 inhibits various filamentous fungi, including the mold Aspergillus fumigatus, but not Candida albicans. Antifungal activity was inhibited by Zn(2+), suggesting that redS100A7 interferes with fungal zinc homeostasis. Because S100A7 mutants lacking a single cysteine are no longer antifungals, we hypothesized that redS100A7 is acting as a Zn(2+)-chelator. Immunogold electron microscopy studies revealed that it penetrates fungal cells, implicating possible intracellular actions. In support with our hypothesis, the cell-penetrating Zn(2+)-chelator TPEN was found to function as a broad-spectrum antifungal. Ultrastructural analyses of redS100A7-treated T. rubrum revealed marked signs of apoptosis, suggesting that its mode of action is induction of programmed cell death. TUNEL, SYTOX-green analyses, and caspase-inhibition studies supported this for both T. rubrum and A. fumigatus. Whereas redS100A7 can be generated from oxidized S100A7 by action of thioredoxin or glutathione, elevated redS100A7 levels in fungal skin infection indicate induction of both S100A7 and its reducing agent in vivo. To investigate whether redS100A7 and TPEN are antifungals in vivo, we used a guinea pig tinea pedes model for fungal skin infections and a lethal mouse Aspergillus infection model for lung infection and found antifungal activity in both in vivo animal systems. Thus, selective fungal cell-penetrating Zn(2+)-chelators could be useful as an urgently needed novel antifungal therapeutic, which induces programmed cell death in numerous fungi. PMID- 26438864 TI - Bubble nucleation and migration in a lead-iron hydr(oxide) core-shell nanoparticle. AB - Iron hydroxide is found in a wide range of contexts ranging from biominerals to steel corrosion, and it can transform to anhydrous oxide via releasing O2 gas and H2O. However, it is not well understood how gases transport through a crystal lattice. Here, we present in situ observation of the nucleation and migration of gas bubbles in iron (hydr)oxide using transmission electron microscopy. We create Pb-FeOOH model core-shell nanoparticles in a liquid cell. Under electron irradiation, iron hydroxide transforms to iron oxide, during which bubbles are generated, and they migrate through the shell to the nanoparticle surface. Geometric phase analysis of the shell lattice shows an inhomogeneous stain field at the bubbles. Our modeling suggests that the elastic interaction between the core and the bubble provides a driving force for bubble migration. PMID- 26438865 TI - Melanopsin-driven increases in maintained activity enhance thalamic visual response reliability across a simulated dawn. AB - Twice a day, at dawn and dusk, we experience gradual but very high amplitude changes in background light intensity (irradiance). Although we perceive the associated change in environmental brightness, the representation of such very slow alterations in irradiance by the early visual system has been little studied. Here, we addressed this deficit by recording electrophysiological activity in the mouse dorsal lateral geniculate nucleus under exposure to a simulated dawn. As irradiance increased we found a widespread enhancement in baseline firing that extended to units with ON as well as OFF responses to fast luminance increments. This change in baseline firing was equally apparent when the slow irradiance ramp appeared alone or when a variety of higher-frequency artificial or natural visual stimuli were superimposed upon it. Using a combination of conventional knockout, chemogenetic, and receptor-silent substitution manipulations, we continued to show that, over higher irradiances, this increase in firing originates with inner-retinal melanopsin photoreception. At the single-unit level, irradiance-dependent increases in baseline firing were strongly correlated with improvements in the amplitude of responses to higher frequency visual stimuli. This in turn results in an up to threefold increase in single-trial reliability of fast visual responses. In this way, our data indicate that melanopsin drives a generalized increase in dorsal lateral geniculate nucleus excitability as dawn progresses that both conveys information about changing background light intensity and increases the signal:noise for fast visual responses. PMID- 26438866 TI - 90Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin's lymphoma. AB - Despite significant advances in the treatment of Hodgkin's lymphoma (HL), a significant proportion of patients will not respond or will subsequently relapse. We identified CD25, the IL-2 receptor alpha subunit, as a favorable target for systemic radioimmunotherapy of HL. The scientific basis for the clinical trial was that, although most normal cells with exception of Treg cells do not express CD25, it is expressed by a minority of Reed-Sternberg cells and by most polyclonal T cells rosetting around Reed-Sternberg cells. Forty-six patients with refractory and relapsed HL were evaluated with up to seven i.v. infusions of the radiolabeled anti-CD25 antibody (90)Y-daclizumab. (90)Y provides strong beta emissions that kill tumor cells at a distance by a crossfire effect. In 46 evaluable HL patients treated with (90)Y-daclizumab there were 14 complete responses and nine partial responses; 14 patients had stable disease, and nine progressed. Responses were observed both in patients whose Reed-Sternberg cells expressed CD25 and in those whose neoplastic cells were CD25(-) provided that associated rosetting T cells expressed CD25. As assessed using phosphorylated H2AX (gamma-H2AX) as a bioindicator of the effects of radiation exposure, predominantly nonmalignant cells in the tumor microenvironment manifested DNA damage, as reflected by increased expression of gamma-H2AX. Toxicities were transient bone-marrow suppression and myelodysplastic syndrome in six patients who had not been evaluated with bone-marrow karyotype analyses before therapy. In conclusion, repeated (90)Y-daclizumab infusions directed predominantly toward nonmalignant T cells rosetting around Reed-Sternberg cells provided meaningful therapy for select HL patients. PMID- 26438867 TI - Peptidoglycan synthesis in Mycobacterium tuberculosis is organized into networks with varying drug susceptibility. AB - Peptidoglycan (PG), a complex polymer composed of saccharide chains cross-linked by short peptides, is a critical component of the bacterial cell wall. PG synthesis has been extensively studied in model organisms but remains poorly understood in mycobacteria, a genus that includes the important human pathogen Mycobacterium tuberculosis (Mtb). The principle PG synthetic enzymes have similar and, at times, overlapping functions. To determine how these are functionally organized, we carried out whole-genome transposon mutagenesis screens in Mtb strains deleted for ponA1, ponA2, and ldtB, major PG synthetic enzymes. We identified distinct factors required to sustain bacterial growth in the absence of each of these enzymes. We find that even the homologs PonA1 and PonA2 have unique sets of genetic interactions, suggesting there are distinct PG synthesis pathways in Mtb. Either PonA1 or PonA2 is required for growth of Mtb, but both genetically interact with LdtB, which has its own distinct genetic network. We further provide evidence that each interaction network is differentially susceptible to antibiotics. Thus, Mtb uses alternative pathways to produce PG, each with its own biochemical characteristics and vulnerabilities. PMID- 26438868 TI - Glycoprotein B7-H3 overexpression and aberrant glycosylation in oral cancer and immune response. AB - The incidence and mortality rate of oral cancer continue to rise, partly due to the lack of effective early diagnosis and increasing environmental exposure to cancer-causing agents. To identify new markers for oral cancer, we used a sialylation probe to investigate the glycoproteins differentially expressed on oral cancer cells. Of the glycoproteins identified, B7 Homolog 3 (B7-H3) was significantly overexpressed in oral squamous cell carcinoma (OSCC), and its overexpression correlated with larger tumor size, advanced clinical stage, and low survival rate in OSCC patients. In addition, knockdown of B7-H3 suppressed tumor cell proliferation, and restoration of B7-H3 expression enhanced tumor growth. It was also found that the N-glycans of B7-H3 from Ca9-22 oral cancer cells contain the terminal alpha-galactose and are more diverse with higher fucosylation and better interaction with DC-SIGN [DC-specific intercellular adhesion molecule-3 (ICAM-3)-grabbing nonintegrin] and Langerin on immune cells than that from normal cells, suggesting that the glycans on B7-H3 may also play an important role in the disease. PMID- 26438869 TI - Power decreases trust in social exchange. AB - How does lacking vs. possessing power in a social exchange affect people's trust in their exchange partner? An answer to this question has broad implications for a number of exchange settings in which dependence plays an important role. Here, we report on a series of experiments in which we manipulated participants' power position in terms of structural dependence and observed their trust perceptions and behaviors. Over a variety of different experimental paradigms and measures, we find that more powerful actors place less trust in others than less powerful actors do. Our results contradict predictions by rational actor models, which assume that low-power individuals are able to anticipate that a more powerful exchange partner will place little value on the relationship with them, thus tends to behave opportunistically, and consequently cannot be trusted. Conversely, our results support predictions by motivated cognition theory, which posits that low-power individuals want their exchange partner to be trustworthy and then act according to that desire. Mediation analyses show that, consistent with the motivated cognition account, having low power increases individuals' hope and, in turn, their perceptions of their exchange partners' benevolence, which ultimately leads them to trust. PMID- 26438870 TI - Algal ancestor of land plants was preadapted for symbiosis. AB - Colonization of land by plants was a major transition on Earth, but the developmental and genetic innovations required for this transition remain unknown. Physiological studies and the fossil record strongly suggest that the ability of the first land plants to form symbiotic associations with beneficial fungi was one of these critical innovations. In angiosperms, genes required for the perception and transduction of diffusible fungal signals for root colonization and for nutrient exchange have been characterized. However, the origin of these genes and their potential correlation with land colonization remain elusive. A comprehensive phylogenetic analysis of 259 transcriptomes and 10 green algal and basal land plant genomes, coupled with the characterization of the evolutionary path leading to the appearance of a key regulator, a calcium- and calmodulin-dependent protein kinase, showed that the symbiotic signaling pathway predated the first land plants. In contrast, downstream genes required for root colonization and their specific expression pattern probably appeared subsequent to the colonization of land. We conclude that the most recent common ancestor of extant land plants and green algae was preadapted for symbiotic associations. Subsequent improvement of this precursor stage in early land plants through rounds of gene duplication led to the acquisition of additional pathways and the ability to form a fully functional arbuscular mycorrhizal symbiosis. PMID- 26438871 TI - Population genomic structure and adaptation in the zoonotic malaria parasite Plasmodium knowlesi. AB - Malaria cases caused by the zoonotic parasite Plasmodium knowlesi are being increasingly reported throughout Southeast Asia and in travelers returning from the region. To test for evidence of signatures of selection or unusual population structure in this parasite, we surveyed genome sequence diversity in 48 clinical isolates recently sampled from Malaysian Borneo and in five lines maintained in laboratory rhesus macaques after isolation in the 1960s from Peninsular Malaysia and the Philippines. Overall genomewide nucleotide diversity (pi = 6.03 * 10(-3)) was much higher than has been seen in worldwide samples of either of the major endemic malaria parasite species Plasmodium falciparum and Plasmodium vivax. A remarkable substructure is revealed within P. knowlesi, consisting of two major sympatric clusters of the clinical isolates and a third cluster comprising the laboratory isolates. There was deep differentiation between the two clusters of clinical isolates [mean genomewide fixation index (FST) = 0.21, with 9,293 SNPs having fixed differences of FST = 1.0]. This differentiation showed marked heterogeneity across the genome, with mean FST values of different chromosomes ranging from 0.08 to 0.34 and with further significant variation across regions within several chromosomes. Analysis of the largest cluster (cluster 1, 38 isolates) indicated long-term population growth, with negatively skewed allele frequency distributions (genomewide average Tajima's D = -1.35). Against this background there was evidence of balancing selection on particular genes, including the circumsporozoite protein (csp) gene, which had the top Tajima's D value (1.57), and scans of haplotype homozygosity implicate several genomic regions as being under recent positive selection. PMID- 26438872 TI - Rapid Y degeneration and dosage compensation in plant sex chromosomes. AB - The nonrecombining regions of animal Y chromosomes are known to undergo genetic degeneration, but previous work has failed to reveal large-scale gene degeneration on plant Y chromosomes. Here, we uncover rapid and extensive degeneration of Y-linked genes in a plant species, Silene latifolia, that evolved sex chromosomes de novo in the last 10 million years. Previous transcriptome based studies of this species missed unexpressed, degenerate Y-linked genes. To identify sex-linked genes, regardless of their expression, we sequenced male and female genomes of S. latifolia and integrated the genomic contigs with a high density genetic map. This revealed that 45% of Y-linked genes are not expressed, and 23% are interrupted by premature stop codons. This contrasts with X-linked genes, in which only 1.3% of genes contained stop codons and 4.3% of genes were not expressed in males. Loss of functional Y-linked genes is partly compensated for by gene-specific up-regulation of X-linked genes. Our results demonstrate that the rate of genetic degeneration of Y-linked genes in S. latifolia is as fast as in animals, and that the evolutionary trajectories of sex chromosomes are similar in the two kingdoms. PMID- 26438873 TI - Expected time-invariant effects of biological traits on mammal species duration. AB - Determining which biological traits influence differences in extinction risk is vital for understanding the differential diversification of life and for making predictions about species' vulnerability to anthropogenic impacts. Here I present a hierarchical Bayesian survival model of North American Cenozoic mammal species durations in relation to species-level ecological factors, time of origination, and phylogenetic relationships. I find support for the survival of the unspecialized as a time-invariant generalization of trait-based extinction risk. Furthermore, I find that phylogenetic and temporal effects are both substantial factors associated with differences in species durations. Finally, I find that the estimated effects of these factors are partially incongruous with how these factors are correlated with extinction risk of the extant species. These findings parallel previous observations that background extinction is a poor predictor of mass extinction events and suggest that attention should be focused on mass extinctions to gain insight into modern species loss. PMID- 26438874 TI - Mechanism for rapid passive-dynamic prey capture in a pitcher plant. AB - Plants use rapid movements to disperse seed, spores, or pollen and catch animal prey. Most rapid-release mechanisms only work once and, if repeatable, regaining the prerelease state is a slow and costly process. We present an encompassing mechanism for a rapid, repeatable, passive-dynamic motion used by a carnivorous pitcher plant to catch prey. Nepenthes gracilis uses the impact of rain drops to catapult insects from the underside of the canopy-like pitcher lid into the fluid filled trap below. High-speed video and laser vibrometry revealed that the lid acts as a torsional spring system, driven by rain drops. During the initial downstroke, the tip of the lid reached peak velocities similar to fast animal motions and an order of magnitude faster than the snap traps of Venus flytraps and catapulting tentacles of the sundew Drosera glanduligera. In contrast to these active movements, the N. gracilis lid oscillation requires neither mechanical preloading nor metabolic energy, and its repeatability is only limited by the intensity and duration of rainfall. The underside of the lid is coated with friction-reducing wax crystals, making insects more vulnerable to perturbations. We show that the trapping success of N. gracilis relies on the combination of material stiffness adapted for momentum transfer and the antiadhesive properties of the wax crystal surface. The impact-driven oscillation of the N. gracilis lid represents a new kind of rapid plant movement with adaptive function. Our findings establish the existence of a continuum between active and passive trapping mechanisms in carnivorous plants. PMID- 26438875 TI - A runner's high depends on cannabinoid receptors in mice. AB - Exercise is rewarding, and long-distance runners have described a runner's high as a sudden pleasant feeling of euphoria, anxiolysis, sedation, and analgesia. A popular belief has been that endogenous endorphins mediate these beneficial effects. However, running exercise increases blood levels of both beta-endorphin (an opioid) and anandamide (an endocannabinoid). Using a combination of pharmacologic, molecular genetic, and behavioral studies in mice, we demonstrate that cannabinoid receptors mediate acute anxiolysis and analgesia after running. We show that anxiolysis depends on intact cannabinoid receptor 1 (CB1) receptors on forebrain GABAergic neurons and pain reduction on activation of peripheral CB1 and CB2 receptors. We thus demonstrate that the endocannabinoid system is crucial for two main aspects of a runner's high. Sedation, in contrast, was not influenced by cannabinoid or opioid receptor blockage, and euphoria cannot be studied in mouse models. PMID- 26438876 TI - Direct link between metabolic regulation and the heat-shock response through the transcriptional regulator PGC-1alpha. AB - In recent years an extensive effort has been made to elucidate the molecular pathways involved in metabolic signaling in health and disease. Here we show, surprisingly, that metabolic regulation and the heat-shock/stress response are directly linked. Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), a critical transcriptional coactivator of metabolic genes, acts as a direct transcriptional repressor of heat-shock factor 1 (HSF1), a key regulator of the heat-shock/stress response. Our findings reveal that heat-shock protein (HSP) gene expression is suppressed during fasting in mouse liver and in primary hepatocytes dependent on PGC-1alpha. HSF1 and PGC-1alpha associate physically and are colocalized on several HSP promoters. These observations are extended to several cancer cell lines in which PGC-1alpha is shown to repress the ability of HSF1 to activate gene-expression programs necessary for cancer survival. Our study reveals a surprising direct link between two major cellular transcriptional networks, highlighting a previously unrecognized facet of the activity of the central metabolic regulator PGC-1alpha beyond its well established ability to boost metabolic genes via its interactions with nuclear hormone receptors and nuclear respiratory factors. Our data point to PGC-1alpha as a critical repressor of HSF1-mediated transcriptional programs, a finding with possible implications both for our understanding of the full scope of metabolically regulated target genes in vivo and, conceivably, for therapeutics. PMID- 26438877 TI - Brain palpation from physiological vibrations using MRI. AB - We present a magnetic resonance elastography approach for tissue characterization that is inspired by seismic noise correlation and time reversal. The idea consists of extracting the elasticity from the natural shear waves in living tissues that are caused by cardiac motion, blood pulsatility, and any muscle activity. In contrast to other magnetic resonance elastography techniques, this noise-based approach is, thus, passive and broadband and does not need any synchronization with sources. The experimental demonstration is conducted in a calibrated phantom and in vivo in the brain of two healthy volunteers. Potential applications of this "brain palpation" approach for characterizing brain anomalies and diseases are foreseen. PMID- 26438878 TI - Structure and function of Caulobacter crescentus aldose-aldose oxidoreductase. AB - Aldose-aldose oxidoreductase (Cc AAOR) is a recently characterized enzyme from the bacterial strain Caulobacter crescentus CB15 belonging to the glucose fructose oxidoreductase/inositol dehydrogenase/rhizopine catabolism protein (Gfo/Idh/MocA) family. Cc AAOR catalyses the oxidation and reduction of a panel of aldose monosaccharides using a tightly bound NADP(H) cofactor that is regenerated in the catalytic cycle. Furthermore, Cc AAOR can also oxidize 1,4 linked oligosaccharides. In the present study, we present novel crystal structures of the dimeric Cc AAOR in complex with the cofactor and glycerol, D xylose, D-glucose, maltotriose and D-sorbitol determined to resolutions of 2.0, 1.8, 1.7, 1.9 and 1.8 A (1 A=0.1 nm), respectively. These complex structures allowed for a detailed analysis of the ligand-binding interactions. The structures showed that the C1 carbon of a substrate, which is either reduced or oxidized, is close to the reactive C4 carbon of the nicotinamide ring of NADP(H). In addition, the O1 hydroxy group of the substrate, which is either protonated or deprotonated, is unexpectedly close to both Lys(104) and Tyr(189), which may both act as a proton donor or acceptor. This led us to hypothesize that this intriguing feature could be beneficial for Cc AAOR to catalyse the reduction of a linear form of a monosaccharide substrate and the oxidation of a pyranose form of the same substrate in a reaction cycle, during which the bound cofactor is regenerated. PMID- 26438879 TI - Biophysical and physiological characterization of ZraP from Escherichia coli, the periplasmic accessory protein of the atypical ZraSR two-component system. AB - The ZraSR system belongs to the family of TCSs (two-component signal transduction systems). In Escherichia coli, it was proposed to participate in zinc balance and to protect cytoplasmic zinc overload by sequestering this metal ion into the periplasm. This system controls the expression of the accessory protein ZraP that would be a periplasmic zinc scavenger. ZraPSR is functionally homologous with CpxPAR that integrates signals of envelope perturbation, including misfolded periplasmic proteins. The auxiliary periplasmic regulator CpxP inhibits the Cpx pathway by interacting with CpxA. Upon envelope stress sensing, the inhibitory function of CpxP is relieved, resulting in CpxR activation. Similarly to CpxPAR, ZraPSR probably plays a role in envelope stress response as a zinc-dependent chaperone activity was demonstrated for ZraP in Salmonella. We have purified ZraP from E. coli and shown that it is an octamer containing four interfacial metal binding sites contributing to dimer stability. These sites are located close to the N-terminus, whereas the C-terminus is involved in polymerization of the protein to form a tetramer of dimers. In vitro, ZraP binds copper with a higher affinity than zinc and displays chaperone properties partially dependent on zinc binding. In vivo, zinc-bound ZraP is a repressor of the expression of the zraPSR operon. However, we have demonstrated that none of the Zra proteins are involved in zinc or copper resistance. We propose an integrated mechanism in which zinc is a marker of envelope stress perturbation and ZraPSR TCS is a sentinel sensing and responding to zinc entry into the periplasm. PMID- 26438882 TI - Holocord syrinx associated with haemangioblastoma. PMID- 26438880 TI - Adipocyte-derived PAMM suppresses macrophage inflammation by inhibiting MAPK signalling. AB - Macrophages within adipose tissue play a key role in mediating inflammatory responses in adipose tissue that are associated with obesity-related metabolic complications. In an effort to identify novel proteins secreted from adipocytes that may negatively regulate macrophage inflammation, we found that peroxiredoxin (PRX)-like 2 activated in M-CSF stimulated monocytes (PAMM), a CXXC-type PRX-like 2 domain-containing redox regulatory protein, is a novel secreted protein with potent anti-inflammatory properties. PAMM is secreted from mature human adipocytes but not preadipocytes. Overexpression of PAMM significantly attenuated lipopolysaccharide (LPS)-induced macrophage inflammation. Incubation of macrophages with adipocyte-conditional medium treated with anti-PAMM antibody significantly enhanced LPS-induced interleukin-12 (IL-12) expression in Raw264.7 cells. In addition, incubation of Raw264.7 cells with purified PAMM protein had a similar anti-inflammatory effect. Moreover, forced expression of PAMM in Raw264.7 cells resulted in decreased LPS-induced ERK1/2, p38 and c-Jun N-terminal kinase (JNK) phosphorylation, suggesting that PAMM exerted the anti-inflammatory function probably by suppressing the mitogen-activated protein kinase (MAPK) signalling pathway. Mutations in the CXXC motif of PAMM that suppressed its anti redox activity were still able to suppress production of inflammatory cytokines in LPS-stimulated macrophages, suggesting that PAMM's anti-inflammatory properties may be independent of its antioxidant properties. Finally, PAMM was highly expressed in both white (WAT) and brown adipose tissues (BAT) and further increased in obesity status. Our results suggest that adipocyte-derived PAMM may suppress macrophage activation by inhibiting MAPK signalling pathway. PMID- 26438881 TI - Consequences of postnatal vascular smooth muscle EGFR deletion on acute angiotensin II action. AB - Epi dermal growth factor (EGF) receptor (EGFR) is activated by its canonical ligands and transactivated by various vasoactive substances, e.g. angiotensin II (Ang II). Vascular EGFR has been proposed to be involved in vascular tissue homoeostasis and remodelling. Thus, most studies have focused on its role during long-term vascular changes whereas the relevance for acute regulation of vascular function in vivo and ex vivo is insufficiently understood. To investigate the postnatal role of VSMCs (vascular smooth muscle cells) EGFR in vivo and ex vivo, we generated a mouse model with cell-specific and inducible deletion of VSMC EGFR and studied the effect on basal blood pressure, acute pressure response to, among others, Ang II in vivo as well as ex vivo, cardiovascular tissue homoeostasis and vessel morphometry in male mice. In knockout (KO) animals, systolic, diastolic and mean blood pressures were reduced compared with wild-type (WT). Furthermore, Ang II-induced pressure load was lower in KO animals, as was Ang II-induced force development and extracellular-signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation in aortic rings from KO animals. By contrast, we observed no difference in force development during application of serotonin, KCl, endothelin 1 or endothelin-1-induced pressure load in KO animals. In addition, nitric oxide (NO)-mediated vasodilation was not affected. Heart weight (HW) increase and up regulation of aortic and cardiac expression of Ccl2 (chemoattractant protein-2) and serpinE1 (plasminogen activator inhibitor 1) during the transition from 4- to 10-months of age were prevented by VSMC EGFR KO. We conclude that VSMC EGFR is involved in basal blood pressure homoeostasis and acute pressure response to Ang II, and thereby contributes to maturation-related remodelling. PMID- 26438883 TI - Neurological letter from Italy. PMID- 26438884 TI - Role of emotional competence in residents' simulated emergency care performance: a mixed-methods study. AB - OBJECTIVE: Emergency situations can generate negative affect in medical personnel, which can negatively impact on the quality of care. Several studies have demonstrated a positive influence of emotional competence (EC) on negative affect. The goal of this study was to test the effect of EC level on simulated emergency care situation in medical residents. METHODS: The sample included 21 medical residents caring for a simulated seriously wounded person whose condition suddenly deteriorated. Medical performance was scored by expert medical doctors (MDs). EC level and affective states were evaluated with self-assessment questionnaires. Finally, the origin of the negative affect experienced by the residents was identified through individual interviews. RESULTS: Higher EC levels were found to be associated with better medical performance and a lower intensity of negative affect. The latter two variables were found to correlate negatively. The main source of negative affect for residents was the inability to establish a diagnosis, regardless of their EC level and their medical performance. CONCLUSIONS: The results suggest that residents who have a high EC level are better able to manage negative affect, so that they are better able to put their medical knowledge to work and explore alternative diagnoses. Emotional-management training for residents who, as new MDs, have limited experience may be beneficial to complement simulation exercises. Additional studies should be considered to better define the links between the affect experienced by MDs and their thought processes during establishment of a diagnosis. PMID- 26438890 TI - Gold nanodome-patterned microchips for intracellular surface-enhanced Raman spectroscopy. AB - While top-down substrates for surface-enhanced Raman spectroscopy (SERS) offer outstanding control and reproducibility of the gold nanopatterns and their related localized surface plasmon resonance, intracellular SERS experiments heavily rely on gold nanoparticles. These nanoparticles often result in varying and uncontrollable enhancement factors. Here we demonstrate the use of top-down gold-nanostructured microchips for intracellular sensing. We develop a tunable and reproducible fabrication scheme for these microchips. Furthermore we observe the intracellular uptake of these structures, and find no immediate influence on cell viability. Finally, we perform a proof-of-concept intracellular SERS experiment by the label-free detection of extraneous molecules. By bringing top down SERS substrates to the intracellular world, we set an important step towards time-dependent and quantitative intracellular SERS. PMID- 26438891 TI - Dual acid-responsive supramolecular nanoparticles as new anticancer drug delivery systems. AB - Considering the specific pH gradients of tumour microenvironments, a dual acid responsive drug delivery system, which can respond to the tumor extracellular and intercellular pH stimuli, has been fabricated via simple host-guest recognition. Firstly, we synthesise 2,4,6-trimethoxybenzaldehyde modified dextran (Dex-TMBA) and mPEG-imine-beta-cyclodextrin (PIC), respectively. And then, through the host guest recognition between the cyclodextrin (CD) of PIC and the benzene ring of Dex-TMBA, a kind of dual acid-responsive supramolecular drug delivery system can be fabricated. Under neutral pH conditions, anticancer drugs can be loaded by forming supramolecular nanoparticles via the host-guest recognition. While, at tumor extracellular pH (~6.8), the acid-labile benzoic-imine of PIC cleaves and the nanoparticles are amino positively charged to facilitate cell internalization. Subsequently, due to the hydrolysis of acetal bonds in Dex-TMBA under significantly increased acidity in subcellular compartments such as the endosomes (~5.3), the loaded doxorubicin releases from the endocytosed drug delivery. This dual acid-responsive nanoparticles can efficiently load and release drugs, acting as drug delivery systems for enhancing anticancer efficiency. PMID- 26438893 TI - Mark Gorney, M.D., 1924 to 2014. PMID- 26438894 TI - The Seventh Annual Meeting of the European Plastic Surgery Research Council. PMID- 26438892 TI - Single-molecule observations of RNA-RNA kissing interactions in a DNA nanostructure. AB - RNA molecules uniquely form a complex through specific hairpin loops, called a kissing complex. The kissing complex is widely investigated and used for the construction of RNA nanostructures. Molecular switches have also been created by combining a kissing loop and a ligand-binding aptamer to control the interactions of RNA molecules. In this study, we incorporated two kinds of RNA molecules into a DNA origami structure and used atomic force microscopy to observe their ligand responsive interactions at the single-molecule level. We used a designed RNA aptamer called GTPswitch, which has a guanosine triphosphate (GTP) responsive domain and can bind to the target RNA hairpin named Aptakiss in the presence of GTP. We observed shape changes of the DNA/RNA strands in the DNA origami, which are induced by the GTPswitch, into two different shapes in the absence and presence of GTP, respectively. We also found that the switching function in the nanospace could be improved by using a cover strand over the kissing loop of the GTPswitch or by deleting one base from this kissing loop. These newly designed ligand-responsive aptamers can be used for the controlled assembly of the various DNA and RNA nanostructures. PMID- 26438895 TI - Welcome from the Captain. PMID- 26438896 TI - Obituary: Dr. Yoshihito Otsuji. PMID- 26438897 TI - [Cognitive impairments in psychoactive drug addicts]. AB - This short literature review addresses common features of the pathogenesis and treatment of cognitive impairment in people with drug addiction (cocaine, opioids, hashish, amphetamine, benzodiazepines). A role of cholinergic deficit in the development of cognitive impairment and possibilities of its treatment with acetylcholineesterase inhibitions are analyzed. PMID- 26438898 TI - [Molecular aspects of the pathogenesis and current approaches to pharmacological correction of Alzheimer's disease]. AB - This review addresses the current hypotheses of the pathogenesis of Alzheimer's disease (AD) and methods of its pharmacological corrections. The following topics are reviewed: a role of beta-amyloid in the pathogenesis of AD, a role of tau protein in the pathogenesis of AD, main hypotheses of the pathogenesis, the relationship between beta-amyloid and tau-protein, the dysfunction of synapses in AD, a neuroimmune hypothesis, treatment approaches. PMID- 26438902 TI - Redefining acute care surgery: Surgical rescue. PMID- 26438903 TI - [Molecular-genetic and electroencephalographic markers of neurocognitive processes in depressive disorders]. AB - Perspectives of molecular-genetic approaches to the establishment of mechanisms of development and causes of heterogeneity of neurocognitive impairment are discussed. The current results indicate that candidate genes for depression can contribute to the variance of memory and regulatory functions in patients. At the same time, these genes are closely related to affective information processing and .cortisol level. By that fact, it can't be excluded that affective processes moderate the association between cognition and genes. EEG parameters could be useful phenotypes in the search for and understanding of genetic mechanisms of cognitive deficit in depression. Parameters of resting EEG and its reactive changes are known to reflect the certain cognitive processes. They are influenced by genetic factors and are sensitive indicators of mechanisms that might underlie cognitive impairment in depressive patients. Accumulating data on molecular genetic correlates of normal electric brain activity may be a source of choosing new candidate genes for cognitive impairment in depression. PMID- 26438904 TI - [Central and peripheral vestibular vertigo in neurological practice]. AB - This literature review is devoted to the differential diagnosis of central and peripheral vestibular vertigo from the point of view of modern otoneurology. In addition, an own case is given. PMID- 26438905 TI - [New possibilities of monotherapy of symptomatic and cryptogenic partial epilepsy]. AB - This literature review is devoted to the use of the antiepileptic drug zonisamide in the initial monotherapy of symptomatic and cryptogenic partial epilepsy. The review is based on the results of the trials, level of evidence A, that demonstrate the efficacy and tolerability of zonisamide comparable to those of carbamazepine. The possible advantages of zonisamide in different clinical situations and characteristics of its use related to molecule structure, pharmacokinetics, mechanisms of drug action are discussed. PMID- 26438906 TI - [By 120-th anniversary of Orel regional psychiatric hospital]. PMID- 26438908 TI - Retraction notice to "Identifying halophilic proteins based on random forests with preprocessing of the pseudo-amino acid composition" [J. Theor. Biol. 361 (2014) 175-181]. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the authors. When using the resampling method to preprocess the raw data of the paper used, some of the types of the proteins (i.e., the HI, HO and NP) were changed; thus, the predicting accuracy cannot reflect the real results. This means the effectiveness of resampling methods in this article gives false results. The Publisher apologizes for any inconvenience this may cause. PMID- 26438907 TI - [Stenosis of the vertebral canal in the lower spine]. AB - The article reviews modern literature on the pathophysiology and clinical signs of degenerative stenosis of the lower spine. Possibilities of modern instrumental diagnosis and the differential clinical diagnosis of lumbar stenosis are presented. A modern treatment tactics and indications for surgical treatment are described. A brief and schematic description of the methods of surgical treatment of tenosis is presented. The efficacy of surgical treatment, including remote and results in early patients, is discussed. PMID- 26438909 TI - Reply from the Author. PMID- 26438910 TI - Tough choices: the challenge of being a vet in an earthquake-stricken country. PMID- 26438912 TI - NEW REPORT SHOWS THAT 400 MILLION DO NOT HAVE ACCESS TO ESSENTIAL HEALTH SERVICES. PMID- 26438911 TI - WHO VALIDATES ELIMINATION OF MOTHER-TO-CHILD TRANSMISSION OF HIV AND SYPHILIS IN CUBA. PMID- 26438913 TI - Breaking down barriers in India. PMID- 26438915 TI - Practical management of strangles outbreaks in horses. PMID- 26438914 TI - Happy 90th birthday AVJ. PMID- 26438916 TI - Re: The Animal Protection Index. PMID- 26438917 TI - Announcement of 2016 Special Issue: The behavioural pharmacology of oxytocin. PMID- 26438918 TI - A morphology-based phylogeny of the Liolaemus alticolor-bibronii group (Iguania: Liolaemidae). AB - The genus Liolaemus was split in two subgenera, Liolaenus sensu stricto and Eulaemus. Inside the Liolaemus sensu stricto subgenus, many groups have been proposed. One of them is the L. alticolor-bibronii group. Here, I studied 184 morpho- logical characters of more than one thousand specimens that of the L. alticolor-bibronii group. Many of these characters are original from this study, especially the characters related to color pattern. Also, I include eight population without tax- onomic status. Using those characters and terminal taxa, I performed phylogenetic analyses using parsimony as optimality criterion, under implied weight. Two different topologies were found. The results show that the L. alticolor-bibronii group is monophyletic, and that it is sister to the L. gravenhorsti group. This finding is congruent with previous morphological and molecular phylogenies. Also, nested within the L. alticolor-bibronii group the L. lemniscatus and the L. robertmen- tensi groups are found. In contrast to previous hypotheses, Liolaemus tacnae is never recovered as a member of the L. alticolor bibronii group. PMID- 26438919 TI - A new species of Leptolalax (Anura: Megophryidae) from Gunung Mulu National Park, Sarawak, East Malaysia (Borneo). AB - We describe a new species of Leptolalax from Gunung Mulu National Park in eastern Sarawak, Malaysian Borneo. The new species had been assigned to Leptolalax dringi and Leptolalax gracilis in the past. It is shown to differ from both these species and from all other species of the genus by a unique combination of morphological characters including large body size, rounded snout, interorbital distance being smaller than width of upper eyelid, bipartite subgular vocal sac in males, basal toe webbing, shagreened skin with tiny tubercles on dorsum and dorsal side of head, angled supratympanic fold, small pectoral glands, absence of supraaxillary glands and ventrolateral glandular ridges, spotted venter, advertisement call consisting of long series of 8-289 notes, each composed of three or four pulses, and dominant frequency at 7225-9190 Hz, with prominent frequency modulation. PMID- 26438920 TI - New occurrences of lithodid crabs (Crustacea: Decapoda: Lithodidae) from the coasts of Africa, with the description of a new species of Paralomis White, 1856. AB - The Collection of Decapod and Stomatopod Crustaceans from the Cadiz Oceanographic Centre (CCDE-IEOCD) comprises a number of lithodid crabs from Spanish surveys carried out in African waters. The revision of this material allowed the confirmation of new records of Lithodesferox Filhol, 1885 in Guinea-Bissau and Mauritania, Lithodes mamillifer Macpherson, 1988 in Mozambique, Neolithodes asperrimus Barnard, 1947, Neolithodes grimaldii (A. Milne Edwards & Bouvier, 1894) and Paralomis erinacea Macpherson, 1988 in Mauritania, Paralomis africana Macpherson, 1982 in Namibia and Paralomis cristulata Macpherson, 1988 in Guinea Bissau. Some of these records contribute to extent the geographical and/or bathymetrical range of the species. One new species of the genus Paralomis from Namibia is described and illustrated. This species shows close affinity with its congener Paralomis pectinata Macpherson, 1988, from Venezuela. The morphological differences between the two species are included. PMID- 26438921 TI - A long-lost relic from the Eastern Ghats: Morphology, distribution and habitat of Sepsophis punctatus Beddome, 1870 (Squamata: Scincidae). AB - Sepsophis punctatus Beddome 1870, the only species of a monotypic genus, was described based on a single specimen from the Eastern Ghats of India. We rediscovered the species based on specimens from Odisha and Andhra Pradesh state, India, after a gap of 137 years, including four specimens from close to the type locality. The holotype was studied in detail, and we present additional morphological characters of the species with details on natural history, habitat and diet. The morphological characters of the holotype along with two additional specimens collected by Beddome are compared with the specimens collected by us. We also briefly discuss the distribution of other members of the subfamily Scincinae and their evolutionary affinities. PMID- 26438922 TI - Two new species of Psephenops Grouvelle from Belize (Coleoptera: Byrrhoidea: Psephenidae), with a key to the known species from Mexico and Central America. AB - Two new species, Psephenops spiniparameri sp. nov. and P. shepardi sp. nov. are described, based on specimens collected from Cayo and Toledo Districts in Belize, bringing the total number of described species assigned to the genus to ten. PMID- 26438923 TI - Sarcophaga (Hoa)flexuosa Ho (Diptera: Sarcophagidae): association of sexes using morphological and molecular approaches, and a redefinition of Hoa Rohdendorf. AB - Sarcophaga flexuosa Ho, 1934 is the type species of the currently monotypic genus group taxon Hoa Rohdendorf, 1937, which here is considered a subgenus of Sarcophaga Meigen, 1826. Using DNA sequences of mitochondrial genes (cytochrome oxidase I and cytochrome b), we positively identify, for the first time, the female of S. (H.)flexuosa. The female is described, the male is redescribed, and both sexes are illustrated using a combination of line drawings, photographs and scanning electron microscopy images. It is argued from the morphology of the male terminalia that Sarcophagaflexuosa is the sister taxon of Sarcophaga basiseta Baranov, 1931, and the subgenus Hoa is redefined to include both of these species. PMID- 26438924 TI - Five new species of Baeus Haliday, 1833 (Hymenoptera: Platygastroidea: Scelioninae) from Brazil with an updated key to Neotropical species. AB - The species of the genus Baeus are small endoparasitoids wasps that attack spiders' egg sacs. Although there are data of occurrence in several biogeographical regions, their distribution records are scarce, especially due to their small size, mak- ing difficult to collect them in natural environments. In this paper, five new species of Baeus are described as results of collections made in southeastern Brazil: Baeus fluminensis new species, B. itatiaiaensis new species, B. leucophthalmus new species, B. melanocephalus new species and B. morenus new species. An updated key to the known Neotropical spe- cies of the genus is also provided. PMID- 26438925 TI - Prodasineura yulan (Odonata: Zygoptera: Platycnemididae), a new species from Sarawak. AB - Prodasineura yulan is described from a male from Maludam National Park, Betong Division, Sarawak, Malaysian Borneo. It is allied to Prodasineura interrupta. PMID- 26438926 TI - Ctenus monaghani spec. nov., a nocturnal hunter from the forest floor in Laos (Araneae: Ctenidae). PMID- 26438927 TI - A new species of Margotrema (Digenea, Allocreadiidae) from the leopard splitfin Xenotaenia resolanae (Cyprinodontiformes, Goodeidae) from west-central Mexico. PMID- 26438928 TI - Ptilopachinae: a new subfamily of the Odontophoridae (Aves: Galliformes). PMID- 26438929 TI - A nomenclatorial confusion in Tanymastigidae (Crustacea: Branchiopoda: Anostraca). PMID- 26438930 TI - Casey's conundrum, a review of the genus Semanotus Mulsant (Coleoptera: Cerambycidae: Cerambycinae: Callidiini) in North America. AB - The North American species of Semanotus Mulsant, 1839 are reviewed. Semanotus ligneus (Fabricius, 1787), Semanotus amplus amplus (Casey, 1912) new status, S. amplus basalis (Casey, 1924) new status, Semanotus amplus sequoiae Van Dyke, 1923 new status, Semanotus conformis Casey, 1924 new status, Semanotus terminatus Casey, 1912 new status, Semanotus amethystinus (LeConte, 1853), Semanotus juniperi (Fisher, 1915), and Semanotus litigiosus (Casey, 1891) are recognized as valid. A key to the North American fauna, as well as to Semanotus japonicus Lacordaire, 1869 and Semanotus australis Giesbert, 1993 is included. A morphometric study was conducted using 37 measured characters from adults of S. litigiosus. Data were examined using stepwise discriminant analysis to determine which characters aid in the diagnosis of taxa, and their amounts of resolving power using canonical variates analysis. Morphometrics revealed significant sexual dimorphism among taxa and suggested that three taxa were present, however, only two taxa could be reasonably separated using observable characters. Phylogenetic analysis using a hypothetical ancestor as out-group returned a single most parsimonious tree for North American Semanotus. PMID- 26438931 TI - Description and Ecology of A New Cavernicolous, Arachnophilous Thread- legged Bug (Hemiptera: Reduviidae: Emesini) from Kartchner Caverns, Cochise County, Arizona. AB - A new cavernicolous, arachnophilous thread-legged bug (Phasmatocoris labyrinthicus sp. nov.; Reduviidae: Emesini) is described from Kartchner Caverns, a limestone cavern in Kartchner Caverns State Park near Benson, Arizona, USA. Cavernicolous emesines are recorded from caves in many parts of the world and are distributed across several genera, but are generally uncommon. P. labyrinthicus shows no obvious troglomorphy but ecological evidence suggests it is, at minimum, a cave-limited troglophile. The species seems to be low-humidity intolerant, due to its occurrence in a cave within a desert region, effectively confines the population to the cave, and the species may thus actually be troglobitic by default. Arachnophily in emesines is more common, including in Phasmatocoris Breddin, but has been previously documented in only a single cavernicolous species, Bagauda cavernicola Paiva, reported from India, Malaysia and Sri Lanka. However, unlike P. labyrinthicus, B. cavernicola is apparently not morphologically adapted for its arachnophilous association. P. labyrinthicus is the only known troglophilic emesine that is also a morphologically adapted and behaviorally functional arachnophile. The only other known cavernicolous Phasmatocoris (P. xavieri Gil-Santana, Alves, Barrett and Costa) is recorded from a sandstone cave in Brazil. P. xavieri exhibits morphological features indicative of a potentially arachnophilous habit, but its ecology has not been studied. Adults of P. labyrinthicus share characteristics with the species Phasmatocoris praecellens Bergroth, P. minor McAtee and Malloch, P. xavieri, P. spectrum Breddin, and P. rapax McAtee and Malloch. Phasmatocoris is primarily a Neotropical genus and the discovery of P. labyrinthicus represents a significant range extension for the genus, being the first Nearctic species identified, with its geographically nearest relative an undescribed species from Mazatlan, Mexico, over 1,000 km to the south. PMID- 26438932 TI - The type specimens of Tachinidae (Diptera) housed in the Museo Argentino de Ciencias Naturales "Bernardino Rivadavia", Buenos Aires. AB - The type material of species of Tachinidae (Diptera) housed in the collection of the Entomology Division of the Museo Argentino de Ciencias Naturales "Bernardino Rivadavia" were examined and are herein documented. The collection contains 202 type specimens consisting of 54 species described by E.E. Blanchard and 12 described by J. Brethes. Comparison of their original descriptions with the label information reveals the existence of 24 holotypes, 1 lectotype, 141 syntypes and 36 paratypes. Complete information is given for each type, including reference to the original description, label data, and preservation condition. PMID- 26438933 TI - A new barbeled goby from south China (Teleostei: Gobiidae). AB - A new goby species Tridentiger radiatus sp. nov. is described from Zhuhai, Guangdong Province of China. The new species, found in sympatry with a widely distributed barbeled congener Tridentiger barbatus (Gunther, 1861), is one of the only two Tridentiger species known to possess mandibular and cheek barbels. Tridentiger radiatus is diagnosed by having higher longitudinal and transverse scale counts, less developed barbels, unmottled colouration compared to T barbatus, and 3 dusky radiating infraorbital bands. Partial 12s rDNA sequence data obtained from 5 individuals of T radiatus and 2 individuals of T. barbatus, together with published sequence data of other congeners confirmed validity of the new species. The divergence between T. radiatus and T. barbatus well exceeds the divergence of other sister taxa in the same genus. Monophyly of the two barbeled species is supported. PMID- 26438934 TI - Anserobilharzia gen. n. (Digenea, Schistosomatidae) and redescription of A. brantae (Farr & Blankemeyer, 1956) comb. n. (syn. Trichobilharzia brantae), a parasite of geese (Anseriformes). AB - A new genus, Anserobilharzia, is proposed to accommodate Anserobilharzia brantae n. comb. (syn. Trichobilharzia bran- tae Farr & Blankemeyer, 1956), a species of avian schistosome thus far found exclusively in anserini geese (Anser, Branta, Chen) from Europe and North America, and Gyraulus snails. Recent collections and subsequent molecular analyses showed that A. brantae was distinct from Allobilharzia and Trichobilharzia and grouped basal to Trichobilharzia. Using nuclear 28S, ITS and mitochondrial cox1 as genetic yardsticks, samples of A. brantae from North America and Europe were each other's closest relative and distinct from Allobilharzia and Trichobilharzia. Anserobilharzia brantae was also distinct when compared morphologically with other species of closely related avian schistosomes. The following descrip- tion is based on males, females, eggs, and cercariae. The new genus is characterized by a) ovoid egg (72-145um x 44- 89 um) with spine, b) male with > 500 testes and caecal reunion anteriad to seminal vesicle, c) cercariae with 5+1 flame cells, and d) intermediate hosts are planorbid snails. The only confirmed species of snail host is Gyraulus parvus in North America. Based on presented data, we propose a new genus and new combination for A. brantae justified by morpholog- ical, host use, and molecular characteristics. PMID- 26438935 TI - Putative type specimens of Satyrichthys (Scorpaeniformes: Peristediidae) in the Bleeker collection of the Naturalis Biodiversity Center, Leiden, The Netherlands. AB - The presumed type status of the two remaining specimens of Peristedion moluccense Bleeker 1850 in the collection the Naturalis Biodiversity Center was examined by comparing them to descriptions in two Bleeker papers and an unpublished manuscript by Bleeker written for the Atlas Ichthyologique. Latin, French and Dutch parts of these papers were translated into English. The Dutch description of P. laticeps Schlegel 1852 was also translated. In the course of this study it became clear why Bleeker considered P. laticeps, a as a synonym of P. moluccense. PMID- 26438936 TI - A review of Neotropical species in Thienemanniella Kieffer (Diptera, Chironomidae). AB - Three species previously described from the neotropical region are revised and four new species are described: Thienemanniella biobio sp. n. and T. manihuales sp. n. as males and pupae from Chile, T. sancticaroli sp. n. and T ubatuba sp. n. as males, females and immature stages from Brazil. The new Thienemanniella spreta species group is delimited consisting of T. spreta (Roback) sensu Sublette & Sasa, T. sanctivincenta Saether, T. liae Paggi, T. sancticaroli sp. n. and T. ubatuba sp. n. Keys to the known Neotropical males, pupae and larvae are presented. PMID- 26438937 TI - Complex phylogeography in Rhinoclemmys melanosterna: conflicting mitochondrial and nuclear evidence suggests past hybridization (Testudines: Geoemydidae). AB - We examined differentiation within the Colombian wood turtle Rhinoclemmys melanosterna, and among R. melanosterna and the closely allied species R. diademata, R.funerea and R. punctularia, based on 1060 base pairs of the mitochondrial cyt b gene. We also assessed the phylogenetic relationships among these species using 2050 bp of mtDNA (partial cyt b, 12S and 16S genes) and 3620 bp of nuclear DNA (partial Rag 1, Rag 2, C-mos, R35 and ODC genes). There is considerable phylogeographic structuring within R. melanosterna, with seven distinct clades distributed across the species' range. These clades correlate to some extent with previously described differences in the dorsal pattern of head coloration. Individual and combined analyses of mitochondrial and nuclear DNA indicated contradictory relationships among R. melanosterna, R. diademata, R. funerea and R. punctularia. Mitochondrial DNA sequences revealed R. melanosterna to be non-monophyletic with respect to R. diademata, R. funerea and R. punctularia. In contrast, R. melanosterna constituted a well-supported monophyletic clade using nuclear DNA. This conflict between mitochondrial and nuclear data suggests past gene flow among the allopatrically and parapatrically distributed species R. melanosterna, R. diademata, R. funerea and R. punctularia. Compared to the other Rhinoclemmys species, the taxa under study are weakly differentiated. To assess their taxonomic status, further research is warranted using additional nuclear markers and additional samples of R. diademata, R. funerea and R. punctularia. For the time being, a continued classification of R. melanosterna, R. diademata, R. funerea and R. punctularia as distinct species is justified owing to their allopatric and parapatric distributions, and to conserve the established usage of names that is based on morphological and karyotypic differentiation. PMID- 26438938 TI - Redescription of Anomala eucoma Bates, 1888 and a description of three new species from Costa Rica (Coleoptera: Scarabaeidae: Rutelinae). AB - Anomala eucoma Bates, 1888 is redescribed and a lectotype from Guatemala is designated. Three new species from Costa Rica, A. flavacoma new species, A. megaparamera new species, and A. pseudoeucoma new species, are described, and a distribution map is given. The internal sac (endophallus) of the species covered is illustrated, and its use in separating closely related species in this region is discussed. An identification key for morphologically similar species from the Neotropical region is provided. PMID- 26438939 TI - Additional records of the pagurid hermit crab genus Trichopagurus de Saint Laurent, 1968 (Crustacea: Decapoda: Anomura), with description of a new species from the Philippines. AB - The pagurid hermit crab genus Trichopagurus de Saint Laurent, 1968 is currently represented by three shallow water spe- cies from the tropical Indo-West Pacific region. In this paper, three species of the genus, including one new species, are reported. Trichopagurus tenuidactylus n. sp. is described on the basis of a single ovigerous female from the Bohol Sea, the Philippines, and compared with two close relatives, T. asper Komai & Poupin, 2012 and T. macrochela Komai & Os- awa, 2005. New locality records are provided for T. macrochela (the Philippines) and T. trichophthalinus (Forest, 1954) (Taiwan and Marianas). An identification key to the four species of the genus is presented. PMID- 26438940 TI - On hypogean Roncocreagris (Arachnida: Pseudoscorpiones: Neobisiidae) from Portugal, with descriptions of three new species. AB - Three new hypogean species of the Iberian genus Roncocreagris Mahnert, 1974 are described from mainland Portugal: R. borgesi sp. nov. and R. gepesi sp. nov. from caves in the Sico massif, and R. occidentalis sp. nov. from caves in the Montejunto and Cesaredas karst plateau. This brings to nine the number of known hypogean species of the mostly Iberian genus Roncocreagris: five from Portugal and four from Spain. Ecological comments and new localities for some of the previously known species are also included. PMID- 26438941 TI - First records of the genus Hishimonus Ishihara from Thailand (Hemiptera: Cicadellidae: Deltocephalinae: Opsiini) including description of three new species. AB - Seven species of Hishimonus Ishihara are recorded in Thailand, four of which were previously recorded from neighbouring countries and three new species described herein: Hishimonus pallidus sp. nov., H. diffractus sp. nov. and H. gillespiei sp. nov. The other four species are H. concavus Knight, previously known from the Philippines, H. subtilis Knight recorded from Singapore, H. aberrans Knight recorded from Taiwan and H. phycitis (Distant), which is widespread in Asia from the Middle East to China. These species are all newly recorded from Thailand and represent the first records of the genus Hishimonus in that country. PMID- 26438942 TI - A new species of the putatively myrmecophilous genus Plaumanniola Costa Lima, with notes on the systematic position of Plaumanniolini (Coleoptera: Staphylinidae: Scydmaeninae). AB - The enigmatic Neotropical genus Plaumanniola Costa Lima is revised. Plaumanniola sanctaecatharinae is redescribed and P. regina sp. n. is described (both from Brazil). Morphological structures of Plaumanniola are illustrated and the systematic position of the tribe Plaumanniolini is discussed. A previously postulated myrmecophily of this morphologically highly unusual genus is found to be weakly supported by biological observations and should be treated as a supposition that needs further study. PMID- 26438943 TI - A new subtidal species of the genus Petrolisthes Stimpson, 1858 (Crustacea: Decapoda: Porcellanidae) from Okinawa, with an account of species of the genus known from the Ryukyu Islands, southwestern Japan. AB - A new porcellanid crab, Petrolisthes uruma sp. nov., is described based on a single specimen collected from Okinawajima Island in the Ryukyus, southwestern Japan. The unique holotype was collected from a subtidal depth of 10 m, though vast majority of the genus occur in intertidal to shallow subtidal zone. The new species is morphologically closest to P. noluccensis (De Man, 1888), but is distinguished by the weaker striation on the carapace, the proportionally longer carpus of the cheliped, the number of the anterior marginal teeth of the carpus of the cheliped, and the meri of the second and third pereopods each with a much stronger spine at the lateroventral distal angle. A brief note on species of Petrolisthes presently known from the Ryukyu Islands is given. PMID- 26438944 TI - Fissarcturus walteri sp. nov. from the Ross Sea of the Southern Ocean (Isopoda, Antarcturidae). AB - During the Victoria-Land Transect project two specimens of a new species, Fissarcturus walteri sp. nov., were found in the Ross Sea along the Victoria Land Coast, Antarctica, during the 19th Italica expedition in February 2004. This is the second species of Fissarcturus from the Ross Sea after F. rossi Brandt, 2007. F. walteri sp. nov. is most similar to Fissarcturus granulosus (Nordenstam, 1933) from South Georgia but can be distinguished by the blunt short, anteriorly directed supraocular spines and elevations and some other characters as described herewith. PMID- 26438945 TI - A new fairy shrimp Phallocryptus tserensodnomi (Branchiopoda: Anostraca) from Mongolia. AB - A new species of Phallocryptus Biraben 1951 (Branchiopoda, Anostraca) from Mongolia is described. Phallocryptus tserensodnomi sp. nov. is close to P. spinosa (Milne-Edwards 1840), but both morphological and molecular analyses (Cytochrome Oxidase I, COI) indicate that they represent separate species. Most relevant differential features of the new species include: (1) frontal appendage provided with small ventral conical outgrowths; (2) second antennamere evenly curved, sickle-shaped; (3) distal fleshy process on labrum evenly curved forwards and tapering; (4) short stout acute spine-like projections present at each side of basal portion of gonopods; (5) female second antennae shorter and wider than in P. spinosa, tapering. Based on morphological comparisons the new species appears to be a Mongolian endemic, although some genotypes of presumed P spinosa from Africa are similar to the new species, suggesting P. tserensodnomi might have a wider distribution. PMID- 26438947 TI - Taxonomic notes and description of the male of Xenochlora nigrofemorata (Smith, 1879) (Hymenoptera: Apidae: Halictinae). AB - The present work describes for the first time the male of the bee genus Xenochlora Engel, Brooks & Yanega, 1997. The male of X. nigrofemorata (Smith, 1879) is described and illustrated. Additionally, Megalopta opacicollis Friese, 1926 is placed as a junior synonym of X. nigrofemorata (Smith, 1879). PMID- 26438946 TI - A new leafhopper genus and two new species of the tribe Scaphytopiini (Hemiptera: Cicadellidae: Deltocephalinae) from China. AB - New leafhopper taxa in the deltocephaline tribe Scaphytopiini Oman are described: Xenovarta lui sp. n., and a new genus and species Aparaphysis lushuiiensis, gen. n., sp. n. from China. Detailed morphological descriptions and illustrations of the new genus and species are given. A checklist to genera of Scaphytopiini is provided. PMID- 26438948 TI - New Phlugidia species (Orthoptera: Tettigoniidae: Meconematinae, Phlugidini) from the Eastern Arc Mountains of Tanzania, Africa. AB - Two new species of Phlugidia (Orthoptera: Tettigoniidae: Meconematinae) are described from the Eastern Arc Mountains of Tanzania. P. planicercus Hemp n. sp. occurs in lowland forest at the foothills of the Uluguru Mountains, while P. ob- tusicercus Hemp n. sp. was collected in the Nguru Mountains. A key to Phlugidia species is provided. PMID- 26438949 TI - Two new quill mite species (Prostigmata: Syringophilidae) parasitizing Australian birds. AB - Two new quill mite species (Prostigmata: Cheyletoidea: Syringophilidae), Syringophilopsis philemonis sp. nov. from Philemon citreogularis (Gould) (Passeriformes: Meliphagidae) and Megasyringophilus cacatua sp. nov. from Cacatua galerita (Latham) (Psittaciformes: Psittacidae) are described from Australia. PMID- 26438950 TI - First Report of Sabella spallanzanii (Gmelin, 1791) (Annelida: Polychaeta) from Botany Bay, New South Wales, a northern range extension for the invasive species within Australia. PMID- 26438951 TI - The tadpole of the Melville Range Treefrog Litoria andiirrmalin (Anura: Hylidae). PMID- 26438952 TI - Nomenclatural changes for the genus name Perinetia, with a new replacement name for Perinetia Barnard, 1959 (Crustacea: Isopoda: Oniscidea: Philosciidae). PMID- 26438953 TI - Taxonomy and redescription of the Atherton Antechinus, Antechinus godmani (Thomas) (Marsupialia: Dasyuridae). AB - We provide a taxonomic redescription of the dasyurid marsupial Atherton Antechinus, Antechinus godmani (Thomas). A. godmani is only rarely encountered and limited to wet tropical rainforests of north-east Queensland, Australia, between the towns of Cardwell and Cairns (a distribution spanning 135 kilometres from north to south). The distinctive species occurs at altitudes of over 600 meters asl, in all major rainforest types, and can be found with both the northern subspecies of the Yellow-footed Antechinus, A. flavipes rubeculus Van Dyck and the Rusty Antechinus, A. adustus (Thomas). A. godmani is clearly separated from all congeners on the basis of both morphometrics and genetics. A. godmani can be distinguished from all extant congeners based on external morphology by a combination of large size, naked-looking tail and reddish fur on the face and head. A. godmani skulls are characteristically large, with a suite of long features: basicranium, palate, upper premolar tooth row, inter-palatal vacuity distance and dentary. Phylogenies generated from mt- and nDNA data position Antechinus godmani as monophyletic with respect to other members of the genus; A. godmani is strongly supported as the sister-group to a clade containing all other antechinus, but excluding the south-east Australian Dusky Antechinus, A. swainsonii (Waterhouse) and Swamp Antechinus, A. minimus (Geoffroy). Antechinus godmani are genetically very divergent compared to all congeners (mtDNA: range 12.9-16.3%). PMID- 26438954 TI - Review of the earthworm fauna of Iran with emphasis on Kohgiluyeh & Boyer-Ahmad Province. AB - Earthworms were collected in forests, damp habitats, springs, orchards and agricultural fields of the Kohgiluyeh & Boyer Ahmad Province, Iran, from April 2009 to April 2010. Specimens were collected at 20 established stations by digging and by diluted formalin methods. Ten species belonging to family Lumbricidae were identified based on morphology: Aporrectodea caliginosa (Savigny, 1826), Ap. rosea (Savigny, 1826), Ap. jassyensis (Michaelsen, 1891), Dendrobaena veneta (Rosa, 1886), D. byblica (Rosa, 1893) complex, D. orientalis orientalis Cernosvitov 1940, Eisenia fetida (Savigny, 1826), Eiseniella tetraedra (Savigny, 1826), Octolasion lacteum (Orley, 1881), Perelia kaznakovi (Michaelsen, 1910). Ap. caliginosa was the dominant species in this province and D. orientalis orientalis is a new record for Iran. A checklist of all earthworms species form Iran is presented, containing 19 species. Then, in order to show earthworm geographical affinities, hierarchical analysis were applied to available data on earthworm of Iran. PMID- 26438955 TI - Five new minute orb-weaving spiders of the family Mysmenidae from China (Araneae). AB - Five new mysmenid species are described from Southwest China including Mosu dayan n. sp. (male and female), Mosu tanjia n. sp. (male and female), Mysmena baoxingensis n. sp. (male and female), Mysimenella yinae n. sp. (male and female), Trogloneta uncata n. sp. (male). Males of the genus Mosu are described for the first time. All new species are from caves or leaf litter. Morphological illustrations and photos of all new species are given. PMID- 26438956 TI - Three new species of Oppioidea (Acari: Oribatida) from India. AB - Three new oribatid mite species of the superfamily Oppioidea--Cycloppia asetosa sp. nov., C. spindleformis sp. nov. and Hammerella (Hammerella) excisa sp. nov.- are described from India. The genus Cycloppia and subgenus Hammerella (Hammerella) are for the first time recorded in India. Cycloppia asetosa sp. nov. differs from all species of Cycloppia by the rostrum with indentation and the absence of interlamellar setae and their alveoli. Cycloppia spindleformis sp. nov. dif- fers from all species of Cycloppia by the presence of interlamellar alveoli only. Hammerella (H.) excisa sp. nov. differs from all species of Hammerella (Hammerella) by the rostrum with indentation and the presence of notogastral setae c. The identification keys to all known species of Cycloppia and Hammerella (Hammerella) are provided. PMID- 26438957 TI - Revision of the species of the bee genus Caenohalictus (Hymenoptera: Halictidae) occurring in Argentinean Patagonia. AB - The species of the halictid bee genus Caenohalictus Cameron occurring in Argentinean Patagonia are revised. Eight species are recognized, one of them here described as new: Caenohalictus flammeus n. sp. The female of C. turquesa Rojas & Toro 2000 is described for the first time. Pseudagapostemon babuarus Jorgensen 1912, based on the male holotype, is synonymized under Augochlora (Pseudaugochloropsis) thamyris Jorgensen 1912, based on the female lectotype. Lectotypes are designated for Augochlora (Pseudaugochloropsis) thamyris Jorgensen 1912 and Halictomorpha autumnalis Jorgensen 1912. Caenohalictus cyanopygus Rojas & Toro 2000, C. galletue Rojas & Toro 2000, C. iodurus (Vachal 1903), C. opaciceps (Friese 1916), and C. turquesa Rojas & Toro 2000, all known from Chile, are cited for Argentina for the first time. Notes on the variation observed within species, images of diagnostic structures, a key to the species and distributional data are provided. In addition, DNA barcoding results for four species are briefly discussed. PMID- 26438958 TI - Aphyosemion pamaense, a new killifish species (Cyprinodontiformes: Nothobranchiidae) from Cameroon. AB - Aphyosemion panaense sp. nov. is described from the Pama River, a small tributary of the Nyong, in the surroundings of Pama, Cameroon. It belongs to the subgenus Chromaphyosenion Radda, 1971 and is distinguished from its relatives by a unique/diagnostic combination of characters: orange unpaired fins, an anal fin without spots, an orange throat and purple to blue-grey flanks. The new species is also genetically differentiated from all the other Chromaphyosemion species as revealed by mtDNA (cytochrome b) analysis and characterised by a unique karyotype showing tentative sex chromosomes with 2n=35 chromosomes in males versus 2n=36 in females. PMID- 26438959 TI - New species of Aleurodamaeus Grandjean, 1954 (Oribatida: Aleurodamaeidae) from South Africa. AB - Seven new species of Aleurodamaeus (Oribatida: Aleurodamaeidae) from South Africa are described: A. salvadordalii sp. nov., A. vicinus sp. nov., A. angelae sp. nov., A. niedbalai sp. nov., A. minutus sp. nov., A. woasi sp. nov. and A. prominens sp. nov. Their distribution in South Africa is discussed. Aleurodamaeus deswardti (Hugo, 2010) comb. nov. is proposed. A key to all South African species of Aleurodamaeus is provided. PMID- 26438960 TI - Oribatid mite fossils from pre-Quaternary sediments in Slovenian caves II. Amiracarus pliocennatus n.gen., n.sp. (Microzetidae) from Pliocene, with comments on the other species of the genus. AB - Amiracarus pliocennatus n. gen., n. sp. is described based on fossils found in Pliocene and Pleistocene clastic sediments in caves of the Slovenian Classical Karst (Kras). Diagnosis and relationships of the new genus are given and relationships within the extant species of the genus are discussed as well as variability and reliability of some characters, used for species differentiation. Amiracarus senensis (Bernini 1975) n. comb. is proposed as a type species of the new genus, and other four extant species are newly placed in Amiracarus n. gen.: A. abeloosi (Lions 1978) n. comb., A. discrepans (Mahunka 1966) n. comb., A. grootaerti (Wauthy &Ducarme 2011) n. comb. and A. similis (Subias & Iturrondobeitia 1978) n. comb. Finding of a fossil individual of M. senensis Bernini 1975 in Ponicova Cave of South-West Carpathians in Romania is reported and a description of this individual is given. Relationships with the genus Miracarus Kunst 1959 are discussed and a new diagnosis of this genus is also given, along with the redescription of its type species, M. hurkai Kunst 1959. PMID- 26438961 TI - Description of a new species of Microhyla from Bali, Indonesia (Amphibia, Anura). AB - We describe a microhylid frog from Bali, Indonesia as a new species, Microhyla orientalis sp. nov. It belongs to the M. achatina group and is close to M. mantheyi, M. malang, and M. borneensis. It is distinguished from its congeners by a combination of the following characters: small size (adult males about 16-17 mm in SVL); a faint vertebral stripe present; a black lateral stripe from behind eye to half length of trunk; snout rounded in profile; eyelid without supraciliary spines; first finger less than one-fifth of third; tips of three outer fingers weakly dilated, forming weak disks, dorsally with median longitudinal groove; outer palmar tubercle single; tibiotarsal articulation reaching up to center of eye; tips of toes distinctly dilated into disks, dorsally with median longitudinal groove; inner and outer metatarsal tubercles present; four or more phalanges on inner and outer sides of fourth toe, and three phalanges on inner side of fifth toe free of web; and tail of larva with a black marking at middle. The male advertisement call of the new species consists of a series of notes each lasts for 0.01-0.08 s and composed of 3-5 pulses with a dominant frequency of 3.2 3.6 kHz. Uncorrected sequence divergences between M. orientalis and all homologous 16S rRNA sequences available were > 6.6%. At present, the new species is known from rice fields between 435-815 m elevation in Wongaya Gede and Batukaru. PMID- 26438962 TI - Two new species of Halacarus (Acari, Prostigmata) from Brazil. AB - The genus Halacarus is recorded from the Brazilian littoral for the first time. Two new species are described. Halacarus omului sp. nov., obtained from algae on the intertidal or immediate subtidal, is a member of the actenos species group and can be distinguished from most congeners by having fifth and sixth pairs of dorsal setae immediately adjacent to fourth and fifth pairs of gland pores, on same minute sclerite. Halacarus todaroi sp. nov. was obtained from sublittoral coarse sand and shell debris and can be distinguished from most congeners by lacking sexually dimorphic dorsal plates, the presence of the posterior dorsal plate, although it does not bear the fourth pair of gland pores, and the presence of ocular plates as a small platelet bearing the pore canaliculi. Further diagnoses are provided along with the species descriptions. PMID- 26438963 TI - Metabolomics-Driven Discovery of a Prenylated Isatin Antibiotic Produced by Streptomyces Species MBT28. AB - Actinomycetes are a major source of antimicrobials, anticancer compounds, and other medically important products, and their genomes harbor extensive biosynthetic potential. Major challenges in the screening of these microorganisms are to activate the expression of cryptic biosynthetic gene clusters and the development of technologies for efficient dereplication of known molecules. Here we report the identification of a previously unidentified isatin-type antibiotic produced by Streptomyces sp. MBT28, following a strategy based on NMR-based metabolomics combined with the introduction of streptomycin resistance in the producer strain. NMR-guided isolation by tracking the target proton signal resulted in the characterization of 7-prenylisatin (1) with antimicrobial activity against Bacillus subtilis. The metabolite-guided genome mining of Streptomyces sp. MBT28 combined with proteomics identified a gene cluster with an indole prenyltransferase that catalyzes the conversion of tryptophan into 7 prenylisatin. This study underlines the applicability of NMR-based metabolomics in facilitating the discovery of novel antibiotics. PMID- 26438964 TI - Fast, Ultrasensitive Detection of Reactive Oxygen Species Using a Carbon Nanotube Based-Electrocatalytic Intracellular Sensor. AB - Herein, we report a highly sensitive electrocatalytic sensor-cell construct that can electrochemically communicate with the internal environment of immune cells (e.g., macrophages) via the selective monitoring of a particular reactive oxygen species (ROS), hydrogen peroxide. The sensor, which is based on vertically aligned single-walled carbon nanotubes functionalized with an osmium electrocatalyst, enabled the unprecedented detection of a local intracellular "pulse" of ROS on a short second time scale in response to bacterial endotoxin (lipopolysaccharide-LPS) stimulation. Our studies have shown that this initial pulse of ROS is dependent on NADPH oxidase (NOX) and toll like receptor 4 (TLR4). The results suggest that bacteria can induce a rapid intracellular pulse of ROS in macrophages that initiates the classical innate immune response of these cells to infection. PMID- 26438968 TI - Predictors of health of pre-registration nursing and midwifery students: Findings from a cross-sectional survey. AB - BACKGROUND: Student nurses/midwives evidence less than exemplary lifestyle habits and poor emotional health, despite exposure to health education/promotion during their educational preparation. Knowledge of the factors that predict nursing/midwifery students' health could inform strategies to enhance their health and increase their credibility as future health promoters/educators. OBJECTIVE: To establish the predictors of nursing/midwifery student emotional health. DESIGN: Cross-sectional survey. SETTING: The research took place at a university in Ireland. PARTICIPANTS: We involved a total sample (n=473) student nurses/midwives. METHODS: Participants completed the General Health Questionnaire, Lifestyle Behaviour Questionnaire and Ways of Coping Questionnaire to determine their self-reported emotional health, lifestyle behaviour and coping processes. Multivariate regression was performed to identify the predictors of student emotional health (dependent variable). The independent variables were demographics, coping, lifestyle behaviour and students' perceptions of determinants of their health. RESULTS: Many respondents reported significant emotional distress (48.71%) and unhealthy lifestyle behaviours including smoking (27.94%), physical inactivity (34.29%), alcohol consumption (91.7%) and unhealthy diet (28.05%). Multivariate regressions indicated that the predictors of emotional distress included gender, year of study, smoking, passive coping and beliefs that their student life was stressful or/and that worry stress and boredom adversely impacted their diet. CONCLUSIONS: Targeting student's beliefs regarding influences upon their health, promotion of positive lifestyles and adaptive coping is necessary to facilitate health gain of future health professionals. PMID- 26438970 TI - Letter from the President of the Argentinian Society of Pharmacology. PMID- 26438969 TI - Assessing the efficacy of melatonin to curtail benzodiazepine/Z drug abuse. AB - The abuse of benzodiazepine (BZP) and Z drugs has become, due to the tolerance and dependence they produce, a serious public health problem. Thirty years ago, we demonstrated in experimental animals the interaction of melatonin with central BZD receptors, and in 1997 we published the first series of elderly patients who reduced BZP consumption after melatonin treatment. Almost every single neuron in the hypothalamic suprachiasmatic nuclei (SCN), the central pacemaker of the circadian system, contains gamma-aminobutyric acid (GABA) and many results in animals point out to a melatonin interaction with GABA-containing neurons. In addition, central-type BZD antagonism, that obliterates GABAA receptor function, blunted most behavioral effects of melatonin including sleep. Melatonin is involved in the regulation of human sleep. This is supported by the temporal relationship between the rise of plasma melatonin levels and sleep propensity as well as by the sleep-promoting effects of exogenously administered melatonin. Both meta-analyses and consensus agreements give support to the therapeutic use of melatonin in sleep disorders. This action is attributed to MT1 and MT2 melatoninergic receptors localized in the SCN, as well as in other brain areas. This review discusses available data on the efficacy of melatonin to curtail chronic BZD/Z drug use in insomnia patients. A major advantage is that melatonin has a very safe profile, it is usually remarkably well tolerated and, in some studies, it has been administered to patients at very large doses and for long periods of time, without any potentiality of abuse. Further studies on this application of melatonin are warranted. PMID- 26438971 TI - Co-targeting cancer drug escape pathways confers clinical advantage for multi target anticancer drugs. AB - Recent investigations have suggested that anticancer therapeutics may be enhanced by co-targeting the primary anticancer target and the corresponding drug escape pathways. Whether this strategy confers statistically significant clinical advantage has not been systematically investigated. This question was probed by the evaluation of the clinical status and the multiple targets of 23 approved and 136 clinical trial multi-target anticancer drugs with particular focus on those co-targeting EGFR, HER2, Abl, VEGFR2, mTOR, PI3K, Alk, MEK, KIT, and DNA topoisomerase, and some of the 14, 7, 13, 20, 6, 5, 7, 2, 4 and 10 cancer drug escape pathways respectively. Most of the approved (73.9%) and phase III (75.0%), the majority of the Phase II (62.8%) and I (53.6%), and the minority of the discontinued (35.3%) multi-target drugs were found to co-target cancer drug escape pathways. This suggests that co-targeting anticancer targets and drug escape pathways confer significant clinical advantage and such strategy can be more extensively explored. PMID- 26438972 TI - MRI-guided single fraction ablative radiotherapy for early-stage breast cancer: a brachytherapy versus volumetric modulated arc therapy dosimetry study. AB - BACKGROUND AND PURPOSE: A radiosurgical treatment approach for early-stage breast cancer has the potential to minimize the patient's treatment burden. The dosimetric feasibility for single fraction ablative radiotherapy was evaluated by comparing volumetric modulated arc therapy (VMAT) with an interstitial multicatheter brachytherapy (IMB) approach. METHODS AND MATERIALS: The tumors of 20 patients with early-stage breast cancer were delineated on a preoperative contrast-enhanced planning CT-scan, co-registered with a contrast-enhanced magnetic resonance imaging (MRI), both in radiotherapy supine position. A dose of 15 Gy was prescribed to the planned target volume of the clinical target volume (PTVCTV), and 20 Gy integrated boost to the PTV of the gross tumor volume (PTVGTV). Treatment plans for IMB and VMAT were optimized for adequate target volume coverage and minimal organs at risk (OAR) dose. RESULTS: The median PTVGTV/CTV receiving at least 95% of the prescribed dose was ?99% with both techniques. The median PTVCTV unintentionally receiving 95% of the prescribed PTVGTV dose was 65.4% and 4.3% with IMB and VMAT, respectively. OAR doses were comparable with both techniques. CONCLUSION: MRI-guided single fraction radiotherapy with an integrated ablative boost to the GTV is dosimetrically feasible with both techniques. We perceive IMB less suitable for clinical implementation due to PTVCTV overdosage. Future studies have to confirm the clinical feasibility of the single fraction ablative approach. PMID- 26438973 TI - Growth and development after oesophageal atresia surgery: Need for long-term multidisciplinary follow-up. AB - Survival rates in oesophageal atresia patients have reached over 90%. In long term follow-up studies the focus has shifted from purely surgical or gastrointestinal evaluation to a multidisciplinary approach. We reviewed the literature on the long-term morbidity of these patients and discuss mainly issues of physical growth and neurodevelopment. We conclude that growth problems - both stunting and wasting - are frequently seen, but that sufficient longitudinal data are lacking. Therefore, it is unclear whether catch-up growth into adolescence and adulthood occurs. Data on determinants of growth retardation are also lacking in current literature. Studies on neurodevelopment beyond preschool age are scarce but oesophageal atresia patients seem at risk for academic problems and motor function delay. Many factors contribute to the susceptibility to growth and development problems and we propose a multidisciplinary follow-up schedule into adulthood future care which may help improve quality of life. PMID- 26438974 TI - Predictors of Survival in Hepatocellular Carcinoma Patients. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common tumor worldwide, with an incidence equal to the death rate. MATERIAL AND METHODS: We aimed to detect the prognostic factors for HCC patients. We retrospectively analyzed 12 years data of 115 patients who have biopsy-proven HCC. Clinical and demographic characteristics of patients with treatment modalities, survival rates, and prognostic factors were analyzed. RESULTS: There were 93 male patients, and the mean age was 63.5+/-11.8 years. Most patients had cirrhosis due to hepatitis virus infection. Median follow-up time was 17 months (1 month-9.5 years) after the diagnosis of HCC. The nodule was single in 43 (37.4%) patients, there were 2-3 nodules in 30 (26.1%), and >3 or diffuse nodules in 42 (36.5%) patients. Distribution of treatment modalities was as follows: 23 (20%) patients had liver transplantation, 15 (13%) had HCC resection, 12 patients (10.4%) had radiofrequency ablation (RFA), 26 patients (22.6%) had transarterial chemoembolization (TACE), 2 (1.7%) had alcohol ablation, and 37 patients (32.2%) had no treatment. Tumor sizes of 9 patients (39.1%) in the transplanted group exceeded the Milan criteria. Mean survival was 72+/-6.9, 78.8 +/-12.5, 19.5+/ 2.8, 20.6+/-4.2, 16.0+/-5.9 months in those that received transplantation, resection, RFA, TACE, and no treatment, respectively (p<0.001). Survival was significantly poorer in patients >63 years old (p=0.001), with serum albumin level <=3.4 g/dL (p=0.01), and with diffuse HCC (p<0.001). CONCLUSIONS: Survival was significantly better in patients who underwent liver transplantation or surgical resection. Tumor number, age, and serum albumin level were the most important prognostic factors related to overall survival. PMID- 26438975 TI - Persistence and variation in microstructural design during the evolution of spider silk. AB - The extraordinary mechanical performance of spider dragline silk is explained by its highly ordered microstructure and results from the sequences of its constituent proteins. This optimized microstructural organization simultaneously achieves high tensile strength and strain at breaking by taking advantage of weak molecular interactions. However, elucidating how the original design evolved over the 400 million year history of spider silk, and identifying the basic relationships between microstructural details and performance have proven difficult tasks. Here we show that the analysis of maximum supercontracted single spider silk fibers using X ray diffraction shows a complex picture of silk evolution where some key microstructural features are conserved phylogenetically while others show substantial variation even among closely related species. This new understanding helps elucidate which microstructural features need to be copied in order to produce the next generation of biomimetic silk fibers. PMID- 26438976 TI - Vertical eruption patterns of impacted mandibular third molars after the mesialization of second molars using miniscrews. AB - OBJECTIVE: To investigate (1) whether vertical eruption of impacted third molars improves after mesialization of second molars and (2) what factors affect the vertical eruption of impacted third molars when space caused by missing molars is successfully closed by mesialization of the second molar using miniscrews. MATERIALS AND METHODS: The treatment group (Group 1) included 52 patients who had (1) missing mandibular first molars (ML-6) or missing deciduous mandibular second molars (ML-E), (2) initially impacted mandibular third molars, and (3) successful space closure of the edentulous area with orthodontics. Panoramic radiographs at start of treatment (T1) and at time of space closure (T2) were collected. The control group (Group 2) included 46 nonedentulous patients with impacted mandibular third molars without molar protraction treatment. Panoramic radiographs with similar T1/T2 treatment times were selected. Nine measurements were obtained regarding horizontal available space, vertical eruption, and third molar angulation. RESULTS: Third molars erupted vertically an average of 2.54 mm in Group 1 compared with 0.41 mm in Group 2. Age, gender, Nolla stage, and angle of the third molars did not show significant correlations with the vertical change of the impacted third molars, whereas the depth of third molar impaction and available space showed significant correlations. CONCLUSIONS: Impacted mandibular third molars vertically erupt as a result of uprighting with mesialization of the second molar, and vertical eruption is affected by the initial vertical location of impacted third molars and available space. PMID- 26438977 TI - Conformation-Dependent Photostability among and within Single Conjugated Polymers. AB - The relationship between photostability and conformation of 2-methoxy-5-(2' ethylhexyloxy)-1,4-phenylenevinylene (MEH-PPV) conjugated polymers was studied via excitation polarization modulation depth (M) measurements. Upon partial photobleaching, M distributions of collapsed, highly ordered MEH-PPV molecules shifted toward lower values. Conversely, M distributions of MEH-PPV molecules with random coil conformations moved toward higher values after partial photobleaching. Monte Carlo simulations of randomly distributed dipole moments along polymer chains subjected to partial photobleaching revealed that a statistical effect leads to an increase in peak M value. Decreases in M values seen experimentally in the population of MEH-PPV molecules with high M values, however, are due to conformation-dependent photostability within single MEH-PPV polymers. We show that, while folded MEH-PPV molecules are relatively more photostable than extended MEH-PPV molecules in an ensemble, extended portions of particular molecules are more photostable than folded domains within single MEH PPV molecules. PMID- 26438978 TI - ACC/AHA/STS Statement on the Future of Registries and the Performance Measurement Enterprise: A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures and The Society of Thoracic Surgeons. PMID- 26438979 TI - Reference range for the pulsatility index ductus venosus Doppler measurement between 11 and 13 + 6 weeks of gestation in a Brazilian population. AB - OBJECTIVE: To establish reference range for the pulsatility index (PI) ductus venosus (DV) Doppler measurement between 11 and 13 + 6 weeks of gestation in a Brazilian population. METHODS: A retrospective cross-sectional study was performed with 430 singleton pregnancies. The PI DV Doppler measurement was performed as routine during the first trimester screening. DV was identified by color Doppler and the pulsed Doppler gate was placed in the distal portion of the umbilical sinus. When at least three typical DV waveforms were obtained, PI DV was measured manually in one waveform. Polynomial regression was used to obtain the best fit using PI DV Doppler measurement and crown-rump length (CRL) with adjustments by the determination coefficient (R(2)). 5th, 50th and 95th percentiles for the PI DV Doppler measurements at each gestational were determined. RESULTS: The mean of PI DV Doppler measurement was 1.1 +/- 0.2 (range 0.8-3.7). The linear regression was the best fit: PI DV measurement = 1.288 0.0034*CRL (R(2 )= 0.03). CONCLUSIONS: Reference range for the PI DV Doppler measurement between 11 and 13 + 6 weeks of gestation in a Brazilian population was established. PMID- 26438980 TI - Bioactive-glass in periodontal surgery and implant dentistry. AB - Bioactive-glass (B-G) is a material known for its favorable biological response when in contact with surrounding fibro-osseous tissues, due not only to an osteoconductive property, but also to an osteostimulatory capacity, and superior biocompatibility for use in human body. The objectives of this paper are to review recent studies on B-G in periodontal and implant therapy, describing its basic properties and mechanism of activity as well as discoursing about state of art and future perspective of utilization. From a demonstrated clinical benefit as bone graft for the elimination of osseous defects due to periodontal disease (intrabony/furcation defects) and surgeries (alveolar ridge preservation, maxillary sinus augmentation), to a potential use for manufacturing bioactive dental implants, possibly allowing wider case selection criteria together with improved integration rates even in the more challenging osteoporotic and medically compromised patients, this biomaterial represents an important field of study with high academic, clinical and industrial importance. PMID- 26438981 TI - The influence of surface roughness and surface dynamics on the attachment of Methicillin-Resistant Staphylococcus aureus onto orthodontic retainer materials. AB - Staphylococci species have been isolated from removable orthodontic retainers. The aims of this study were to determine the most suitable device to analyze surface roughness of autopolymerized acrylic and thermoplastic materials and whether the surface dynamics of these materials influences the attachment of Methicillin-Resistant Staphylococcus aureus (MRSA). Clinically simulated samples of autopolymerized acrylic and thermoplastic material were first evaluated using laser non-contact, stylus mechanical profilometries and atomic force microscopy (AFM) followed by contact angle measurement to characterize their surface dynamics. Finally, an in vitro biofilm assay was carried out using a constant depth film fermentor to assess biofilm attachment. The results showed a significant difference between the roughness values obtained from the tested profilometers with the AFM exhibiting the most consistent roughness values. MRSA tended to accumulate initially within the microscopic irregularities of autopolymerized acrylic samples whereas acid-base and electron donor interactions influenced the bacterial attachment onto the thermoplastic samples. PMID- 26438983 TI - The effect of staining and vacuum sintering on optical and mechanical properties of partially and fully stabilized monolithic zirconia. AB - The effect of staining and vacuum sintering on optical properties and the bi axial flexural strength of partially and fully stabilized monolithic zirconia (PSZ, FSZ) were evaluated. Disc-shaped specimens divided into three subgroups (n=15): non-stained, stained and non-stained with vacuum sintering. After staining and sintering, optical properties were evaluated using a reflection spectrophotometer and bi-axial flexural strength was tested using the piston-on three balls technique. Statistical analysis was performed using multivariate analysis of variance (MANOVA) followed by post-hoc Tukey's tests (p<0.05). Staining decreased translucency parameter (TP) values of FSZ (p<0.05). Sintering under vacuum enhanced TP values for PSZ (p<0.05). Staining enhanced surface gloss for both types of zirconia (p<0.05). Staining increased bi-axial flexural strength of FSZ (p<0.05), while it decreased the strength of PSZ (p<0.05). Sintering under vacuum provided minimal benefits with either type of zirconia. PMID- 26438982 TI - Impact of surface treatment of different reinforced glass-ceramic anterior crowns on load bearing capacity. AB - This study investigated the influence of different surface treatments on fracture load (FL) of canine crowns fabricated from two different pressable lithium disilicate ceramics: A (HS10PC, estetic ceram, n=180) and B (IPS e.max Press, IvoclarVivadent, n=120). The standardized specimens were divided into groups of six different surface treatments and two glazing temperatures. A-group specimens were additionally assigned two glazing pastes with various thermal expansion coefficients (TEC). FL was measured and TECs were determined. Data were analyzed using three/one-way ANOVA followed by post-hoc Scheffe's test. B showed comparable or higher FL than A (B: 503-876 N; A: 375-734 N). Lithium-disilicate crowns show higher FL when not grinded but only polished or glazed. Glazing pastes affected FL depending on their TECs, firing temperature and crown treatment. TEC of A and B was 10 ppm/K, glazing pastes for A presented TECs of 7.5 ppm/K and 10 ppm/K and for B of 9 ppm/K. PMID- 26438984 TI - Influence of light intensity on surface-free energy and dentin bond strength of single-step self-etch adhesives. AB - In this study, we investigated the influence of light intensity on the surface free energy and dentin bond strength of single-step selfetch adhesives. The adhesives were applied to the dentin surfaces of bovine mandibular incisors and cured with light intensities of 0 (no irradiation), 200, 400, and 600 mW/cm(2). Surface-free energies were determined by measuring the contact angles of three test liquids placed on the cured adhesives. Dentin bond strengths of the specimens were also measured. Polymerization with a higher light intensity resulted in a lower surface-free energy of the cured adhesives. The greatest bond strength was achieved when a light intensity of 400 mW/cm(2) or greater was used. Our data suggest that the surface-free energy and dentin bond strength of single step self-etch adhesives are affected by light intensity of the curing unit. PMID- 26438985 TI - Effect of novel restoration techniques on the fracture resistance of teeth treated endodontically: An in vitro study. AB - The aim was to evaluate the effects of fiber-reinforced composite restorations and a bulk-fill resin composite on the fracture strength of mandibular premolars treated endodontically. Standard mesio-occluso-distal (MOD) cavities were prepared in 48 mandibular premolars. Following root canal treatment, teeth were assigned to four groups: Group 1, nano-hybrid resin composite; Group 2, polyethylene woven fiber plus nano-hybrid resin composite; Group 3, short fiber reinforced resin composite plus nano-hybrid resin composite; and Group 4, bulk fill resin composite plus nano-hybrid resin composite. Then, the teeth were subjected to the fracture toughness test. The data were analyzed statistically using one-way ANOVA, followed by Tukey's post-hoc test. The fiber-reinforced groups had better results than the nano-hybrid and bulk-fill composites (p<0.05), while the bulk-fill and nano-hybrid composite restorations gave similar results (p>0.05). Fiber-reinforcement improved the fracture strength of teeth with large MOD cavities treated endodontically. Bulk-fill composites can be used reliably as well as nano-hybrid composites. PMID- 26438987 TI - The effect of zirconia thickness on the biaxial flexural strength of zirconiaceramic bilayered discs. AB - The aim of this study was to assess the effect of zirconia core thickness on the biaxial flexural strength values of zirconia-porcelain bilayered discs. A total of 60 discs with 0.3, 0.4, and 0.5 mm thickness were obtained from a fully sintered zirconia block. A 1.5-mm thick layer of veneer porcelain was fired on the zirconia specimens and biaxial flexural strength tests were performed on the bilayered discs. In each group, the loading surface was the veneer porcelain in half of the specimens (core in tension) and the zirconia core surface in the other half (core in compression). The zirconia core thickness had no effect on the biaxial flexural strength of zirconiaporcelain bilayered discs when the core was in tension (p>0.05). Whereas, when the core was in compression, an increase in the zirconia core thickness resulted in an increase in the biaxial flexural strength (p<0.05). PMID- 26438986 TI - Effect of conventional water-bath and experimental microwave polymerization cycles on the flexural properties of denture base acrylic resins. AB - The effect of polymerization cycles on flexural properties of conventional (Vipi Cril((r))-VC) or microwave-processed (Vipi Wave((r))-VW) denture base acrylic resins was evaluated. Specimens (n=10) were submitted to the cycles: WB=65oC for 1 h+1 h boiling water (VC cycle); M630/25=10 min at 270 W+5 min at 0 W+10 min at 360 W (VW cycle); M650/5=5 min at 650 W; M700/4=4 min at 700 W; and M550/3=3 min at 550 W. Specimens were submitted to a three-point bending test at 5 mm/min until fracture. Flexural strength (MPa) and elastic modulus (GPa) data were analyzed by 2-way ANOVA/Tukey HSD (alpha=0.05). Overall, VC showed higher values than VW. The results obtained with microwave polymerization did not differ from those obtained with water-bath for both acrylic resins. The results observed when polymerization cycles using medium power and shorter time were used did not differ from those when manufacturer's recommended microwave cycle was applied. Conventional VC might be microwave-processed without compromising its flexural properties. PMID- 26438988 TI - Static and kinetic friction force and surface roughness of different archwire bracket sliding contacts. AB - The aim of this study was to determine the static and kinetic friction forces of the contact bracket-archwire with different dental material compositions in order to select those materials with lower resistance to sliding. We carried out sliding friction tests by means of a universal testing machine following an experimental procedure as described in ASTM D1894 standard. We determined the static and kinetic friction forces under dry and lubricating conditions using an artificial saliva solution at 36.5oC. The bracket-archwire pairs studied were: stainless steel-stainless steel; stainless steel-glass fiber composite; stainless steel-Nitinol 60; sapphire-stainless steel; sapphire-glass fiber composite; and sapphire-Nitinol 60. The best performance is obtained for Nitinol 60 archwire sliding against a stainless steel bracket, both under dry and lubricated conditions. These results are in agreement with the low surface roughness of Nitinol 60 with respect to the glass fiber composite archwire. The results described here contribute to establishing selection criteria for materials for dental archwire-brackets. PMID- 26438989 TI - Nanoleakage evaluation at adhesive-dentin interfaces by different observation methods. AB - The purpose of this study was to evaluate the capability and characteristics of different nanoleakage observation methods, including light microscope (LM), field emission scanning electron microscope (FESEM), transmission electron microscope (TEM), and confocal laser scanning microscope (CLSM). Dentin specimens were bonded with either an etch-and-rinse adhesive (SBMP) or a self-etch adhesive (GB), and prepared for nanoleakge evaluation according to different observation methods. LM, FESEM and CLSM results demonstrated that the SBMP group showed more interfacial nanoleakage than the GB group (p<0.05); by contrast, no significant difference was found in TEM results (p>0.05), however, TEM illustrated concrete nanoleakage forms or patterns. The results suggested that different observation methods might exhibit distinct images and a certain degree of variations in nanoleakage statistical results. Researchers should carefully design and calculate the optimum assembly in combination with qualitative and quantitative approaches to obtain objective and accurate nanoleakage evaluation. PMID- 26438990 TI - Initial and long-term bond strengths of one-step self-etch adhesives with silane coupling agent to enamel-dentin-composite in combined situation. AB - This study evaluated the effect of adding silane coupling agent on initial and long-term bond strengths of one-step self-etch adhesives to enamel-dentin composite in combined situation. Cervical cavities were prepared on extracted molars and filled with Clearfil AP-X. After water-storage for one-week, the filled teeth were sectioned in halves to expose enamel, dentin and composite surfaces and then enamel-dentin-composite surface was totally applied with one of adhesive treatments (Clearfil SE One, Clearfil SE One with Clearfil Porcelain Bond Activator, Beautibond Multi, Beautibond Multi with Beautibond Multi PR Plus and Scotchbond Universal). After designed period, micro-shear bond strengths (uSBSs) to each substrate were determined. For each period of water-storage, additive silane treatments significantly increased uSBS to composite (p<0.001). On the other hand, they significantly decreased uSBS to dentin (p<0.001), although did not have adverse effect on uSBS to enamel (p>0.05). Moreover, the stability of uSBS was depended on materials and substrates used. PMID- 26438991 TI - Suppression effects of dental glass-ceramics with polarization-induced highly dense surface charges against bacterial adhesion. AB - This study investigated the surface characteristics and antibacterial ability capacity of surface-improved dental glass-ceramics by an electrical polarization process. Commercially available dental glass-ceramic materials were electrically polarized to induce surface charges in a direct current field by heating. The surface morphology, chemical composition, crystal structure, and surface free energy (SFE) were evaluated using scanning electron microscopy, energy dispersive X-ray spectrometry, X-ray diffraction, and water droplet methods, respectively. The antibacterial capacity was assessed by a bacterial adhesion test using Streptococcus mutans. Although the surface morphology, chemical composition, and crystal structure were not affected by electrical polarization, the polar component and total SFE were enhanced. After 24 h incubation at 37oC, bacterial adhesion to the polarized samples was inhibited. The electrical polarization method may confer antibacterial properties on prosthetic devices, such as porcelain fused to metal crowns or all ceramic restorations, without any additional bactericidal agents. PMID- 26438992 TI - Machinability of an experimental Ti-Ag alloy in terms of tool life in a dental CAD/CAM system. AB - Titanium is difficult to machine because of its intrinsic properties. In a previous study, the machinability of titanium was improved by alloying with silver. This study aimed to evaluate the durability of tungsten carbide burs after the fabrication of frameworks using a Ti-20%Ag alloy and titanium with a computer-aided design and computer-aided manufacturing system. There was a significant difference in attrition area ratio between the two metals. Compared with titanium, the ratio of the area of attrition of machining burs was significantly lower for the experimental Ti-20%Ag alloy. The difference in the area of attrition for titanium and Ti-20%Ag became remarkable with increasing number of machining operations. The results show that the same burs can be used for a longer time with Ti-20%Ag than with pure titanium. Therefore, in terms of tool life, the machinability of the Ti-20%Ag alloy is superior to that of titanium. PMID- 26438993 TI - Three-dimensional evaluation of the repeatability of scans of stone models and impressions using a blue LED scanner. AB - In this study, we evaluated the repeatability of scans of stone models and impressions of abutment teeth using a blue LED scanner and compared the findings between different abutment teeth types. For the stone models as well as impression of the canines, premolars, and molars, we generated 10 color difference-maps and reports for each tooth type (n=10 per tooth type). One-way analysis of variance (ANOVA) and independent t-tests were performed to evaluate the repeatability of scans of the stone models and impressions obtained from a blue LED scanner. Our results indicate a high repeatability of scans of stone models and impressions of abutment teeth using the blue LED scanner and suggest a possible clinical advantage for scanning impressions of different abutment teeth types. PMID- 26438994 TI - Hard and soft tissue responses to three different implant materials in a dog model. AB - The aim of this study was to assess hard and soft tissue responses using three dental implants made of different materials. Implants made of titanium (Ti), yttria-stabilized tetragonal zirconia polycrystals (Y-TZP) and ceria partially stabilized zirconia/alumina nanocomposite (Ce-TZP/Al2O3) were used in a dog model. Five male beagles were sacrificed at three months after implantation, and harvested mandible were observed and analyzed. Histological observations were similar in all groups. There were no significant differences in any histomorphometric parameters. Our results suggested the possibility of Ce TZP/Al2O3 as a dental implant material, similar to Ti and Y-TZP. PMID- 26438995 TI - Effect of preheating on the viscoelastic properties of dental composite under different deformation conditions. AB - Preheating of dental composites improves their flowability, facilitating successful restorations. However, the flowability of dental composites is affected not only by temperature but also by the deformation conditions. In the present work, the effects of various deformation conditions upon the viscoelastic properties of a preheated dental composite were studied. The rheological properties of Z350 dental composites at 25, 45, and 60 degrees C were measured by a strain-controlled rheometer. When a low strain (0.03%) was applied, the preheated composite exhibited greater shear storage modulus (G') and complex viscosity (eta*) than a room-temperature composite. Oppositely, when a high strain (50%) was applied, G' and eta* of a preheated composite were lower than those of a room-temperature composite. Preheating of dental composites might be helpful in clinical practice both to increase the slumping resistance when minimal manipulation is used (e.g., during the build-up of a missing cusp tip) and to increase flowability when manipulation entailing high shear strain is applied (e.g., when uncured composite resin is spread on a dentin surface). PMID- 26438996 TI - Bioactive Co-Cr alloy for biomedical applications prepared by surface modification using self-assembled monolayers and poly-gamma-glutamic acid. AB - Cobalt-chromium (Co-Cr) alloys are used in clinical practice for the hard tissue reconstruction because of their favorable biocompatibility and mechanical properties. However, their applications have been limited because of their poor bioactivity, making them poor at bone-bonding. In this study, the bioactivity of a Co-Cr alloy was evaluated following the immobilization of cross-linked poly gamma-glutamic acid (gamma-PGA) onto its surface via the formation of 11 aminoundecylphosphonic acid self-assembled monolayers (SAMs). Results of X-ray photoelectron spectroscopy revealed the presence of a new P2p peak, which confirms SAMs formation. Furthermore, the surface became highly hydrophobic following the immobilization with gamma-PGA. Subsequent treatment with CaCl2 at 0.5 M or more and soaking in a simulated body fluid led to the formation of a low crystalline apatite. The present results show that chemical modification can be used to induce the formation of an apatite layer on the surface of a Co-Cr alloy in simulated body fluid. PMID- 26438997 TI - Calcification of MC3T3-E1 cells on titanium and zirconium. AB - To confirm similarity of hard tissue compatibility between titanium and zirconium, calcification of MC3T3-E1 cells on titanium and zirconium was evaluated in this study. Mirror-polished titanium (Ti) and zirconium (Zr) disks and zirconium-sputter deposited titanium (Zr/Ti) were employed in this study. The surface of specimens were characterized using scanning electron microscopy and X ray diffraction. Then, the cellular proliferation, differentiation and calcification of MC3T3-E1 cells on specimens were investigated. The surface of Zr/Ti was much smoother and cleaner than those of Ti and Zr. The proliferation of the cell was the same among three specimens, while the differentiation and calcification on Zr/Ti were faster than those on Ti and Zr. Therefore, Ti and Zr showed the identical hard tissue compatibility according to the evaluation with MC3T3-E1 cells. Sputter deposition may improve cytocompatibility. PMID- 26438998 TI - Halloysite Clay Nanotubes for Loading and Sustained Release of Functional Compounds. AB - Halloysite is an alumosilicate tubular clay with a diameter of 50 nm, an inner lumen of 15 nm and a length of 600-900 nm. It is a natural biocompatible nanomaterial available in thousands of tons at low price, which makes it a good candidate for nanoarchitectural composites. The inner lumen of halloysite may be adjusted by etching to 20-30% of the tube volume and loading with functional agents (antioxidants, anticorrosion agents, flame-retardant agents, drugs, or proteins) allowing for formulations with sustained release tuned by the tube end stoppers for hours and days. Clogging the tube ends in polymeric composites allows further extension of the release time. Thus, antioxidant-loaded halloysite doped into rubber enhances anti-aging properties for at least 12 months. The addition of 3-5 wt% of halloysite increases the strength of polymeric materials, and the possibility of the tube's orientation promises a gradient of properties. Halloysite nanotubes are a promising mesoporous media for catalytic nanoparticles that may be seeded on the tube surface or synthesized exclusively in the lumens, providing enhanced catalytic properties, especially at high temperatures. In vitro and in vivo studies on biological cells and worms indicate the safety of halloysite, and tests for efficient adsorption of mycotoxins in animals' stomachs are also carried out. PMID- 26438999 TI - Process Analytical Utility of Raman Microspectroscopy in the Directed Differentiation of Human Pancreatic Insulin-Positive Cells. AB - Continued advances toward cell-based therapies for human disease generate a growing need for unbiased and label-free monitoring of cellular characteristics. We used Raman microspectroscopy to characterize four important stages in the 26 day directed differentiation of human embryonic stem cells (hESCs) to insulin positive cells. The extent to which the cells retained spectroscopic features of pluripotent cells or developed spectroscopic features suggestive of pancreatic endocrine cells, as well as assessing the homogeneity of the cell populations at these developmental stages, were of particular interest. Such information could have implications for the utility of Raman microspectroscopy process analysis for the generation of insulin-positive cells from hESCs. Because hESC seeding density influences the subsequent pancreatic development, three different seeding density cultures were analyzed. Transcription factor and other marker analyses assessed the progress of the cells through the relevant developmental stages. Increases in the Raman protein-to-nucleic acid band ratios were observed at the final endocrine stage analyzed, but this increase was less than expected. Also, high glycogen band intensities, somewhat unexpected in pancreatic endocrine cells, suggested the presence of a substantial number of glycogen containing cells. We discuss the potential process analytical technology application of these findings and their importance for cell manufacturing. PMID- 26439000 TI - Novel microsatellite marker development from the unassembled genome sequence data of the marbled flounder Pseudopleuronectes yokohamae. AB - Various genome-scale data have been increasingly published in diverged species, but they can be reused for other purposes by re-analyzing in other ways. As a case study to utilize the published genome data, we developed microsatellite markers from the genome sequence data (assembled contigs and unassembled reads) of the marbled flounder Pseudopleuronectes yokohamae. No microsatellites were identified in the contig sequences, whereas the computer software found 781,773 sequences containing microsatellites with di- to hexa-nucleotide motif in the unassembled reads. For 86,732 unique sequences among them, a total of 331,368 primer pairs were designed. Screening based on PCR amplification, polymorphisms and accurate genotyping resulted in sixteen primer sets, which were later characterized using 45 samples collected in Onagawa Bay, Miyagi, Japan. The presence of null alleles was suggested at four loci in the studied population but no evidence of allelic dropout was found. The observed number of alleles and heterozygosity was 2-20 and 0-0.88889, respectively, indicating polymorphisms and usefulness for population genetic analyses of this species. In addition, a large number of the microsatellite primers developed in this study are potentially applicable also for kinship estimation, individual fingerprint and linkage map construction. PMID- 26439001 TI - MIFEPRISTONE AND CUSHING SYNDROME: A COMMENTARY. PMID- 26439002 TI - DRIVING UP THE DOSE: IMPLICATIONS FOR HIGH-DOSE VITAMIN D THERAPY. PMID- 26439003 TI - PANCREATIC KETOACIDOSIS (KABADI SYNDROME) MIMICKING DIABETIC KETOACIDOSIS. PMID- 26439004 TI - A PHYSICAL EXAMINATION MANEUVER THAT FACILITATES PALPATION OF CERVICAL LYMPHADENOPATHY. PMID- 26439005 TI - Correction. PMID- 26439006 TI - Delivery of human mesenchymal adipose-derived stem cells restores multiple urological dysfunctions in a rat model mimicking radical prostatectomy damages through tissue-specific paracrine mechanisms. AB - Urinary incontinence (UI) and erectile dysfunction (ED) are the most common functional urological disorders and the main sequels of radical prostatectomy (RP) for prostate cancer. Mesenchymal stem cell (MSC) therapy holds promise for repairing tissue damage due to RP. Because animal studies accurately replicating post-RP clinical UI and ED are lacking, little is known about the mechanisms underlying the urological benefits of MSC in this setting. To determine whether and by which mechanisms MSC can repair damages to both striated urethral sphincter (SUS) and penis in the same animal, we delivered human multipotent adipose stem cells, used as MSC model, in an immunocompetent rat model replicating post-RP UI and ED. In this model, we demonstrated by using noninvasive methods in the same animal from day 7 to day 90 post-RP injury that MSC administration into both the SUS and the penis significantly improved urinary continence and erectile function. The regenerative effects of MSC therapy were not due to transdifferentiation and robust engraftment at injection sites. Rather, our results suggest that MSC benefits in both target organs may involve a paracrine process with not only soluble factor release by the MSC but also activation of the recipient's secretome. These two effects of MSC varied across target tissues and damaged-cell types. In conclusion, our work provides new insights into the regenerative properties of MSC and supports the ability of MSC from a single source to repair multiple types of damage, such as those seen after RP, in the same individual. PMID- 26439007 TI - Impact of a decade of successful antiretroviral therapy initiated at HIV-1 seroconversion on blood and rectal reservoirs. AB - Persistent reservoirs remain the major obstacles to achieve an HIV-1 cure. Prolonged early antiretroviral therapy (ART) may reduce the extent of reservoirs and allow for virological control after ART discontinuation. We compared HIV-1 reservoirs in a cross-sectional study using polymerase chain reaction-based techniques in blood and tissue of early-treated seroconverters, late-treated patients, ART-naive seroconverters, and long-term non-progressors (LTNPs) who have spontaneous virological control without treatment. A decade of early ART reduced the total and integrated HIV-1 DNA levels compared with later treatment initiation, but not reaching the low levels found in LTNPs. Total HIV-1 DNA in rectal biopsies did not differ between cohorts. Importantly, lower viral transcription (HIV-1 unspliced RNA) and enhanced immune preservation (CD4/CD8), reminiscent of LTNPs, were found in early compared to late-treated patients. This suggests that early treatment is associated with some immunovirological features of LTNPs that may improve the outcome of future interventions aimed at a functional cure. PMID- 26439008 TI - Structure and conformational states of the bovine mitochondrial ATP synthase by cryo-EM. AB - Adenosine triphosphate (ATP), the chemical energy currency of biology, is synthesized in eukaryotic cells primarily by the mitochondrial ATP synthase. ATP synthases operate by a rotary catalytic mechanism where proton translocation through the membrane-inserted FO region is coupled to ATP synthesis in the catalytic F1 region via rotation of a central rotor subcomplex. We report here single particle electron cryomicroscopy (cryo-EM) analysis of the bovine mitochondrial ATP synthase. Combining cryo-EM data with bioinformatic analysis allowed us to determine the fold of the a subunit, suggesting a proton translocation path through the FO region that involves both the a and b subunits. 3D classification of images revealed seven distinct states of the enzyme that show different modes of bending and twisting in the intact ATP synthase. Rotational fluctuations of the c8-ring within the FO region support a Brownian ratchet mechanism for proton-translocation-driven rotation in ATP synthases. PMID- 26439009 TI - A mutation uncouples the tubulin conformational and GTPase cycles, revealing allosteric control of microtubule dynamics. AB - Microtubule dynamic instability depends on the GTPase activity of the polymerizing alphabeta-tubulin subunits, which cycle through at least three distinct conformations as they move into and out of microtubules. How this conformational cycle contributes to microtubule growing, shrinking, and switching remains unknown. Here, we report that a buried mutation in alphabeta-tubulin yields microtubules with dramatically reduced shrinking rate and catastrophe frequency. The mutation causes these effects by suppressing a conformational change that normally occurs in response to GTP hydrolysis in the lattice, without detectably changing the conformation of unpolymerized alphabeta-tubulin. Thus, the mutation weakens the coupling between the conformational and GTPase cycles of alphabeta-tubulin. By showing that the mutation predominantly affects post-GTPase conformational and dynamic properties of microtubules, our data reveal that the strength of the allosteric response to GDP in the lattice dictates the frequency of catastrophe and the severity of rapid shrinking. PMID- 26439010 TI - TAPBPR alters MHC class I peptide presentation by functioning as a peptide exchange catalyst. AB - Our understanding of the antigen presentation pathway has recently been enhanced with the identification that the tapasin-related protein TAPBPR is a second major histocompatibility complex (MHC) class I-specific chaperone. We sought to determine whether, like tapasin, TAPBPR can also influence MHC class I peptide selection by functioning as a peptide exchange catalyst. We show that TAPBPR can catalyse the dissociation of peptides from peptide-MHC I complexes, enhance the loading of peptide-receptive MHC I molecules, and discriminate between peptides based on affinity in vitro. In cells, the depletion of TAPBPR increased the diversity of peptides presented on MHC I molecules, suggesting that TAPBPR is involved in restricting peptide presentation. Our results suggest TAPBPR binds to MHC I in a peptide-receptive state and, like tapasin, works to enhance peptide optimisation. It is now clear there are two MHC class I specific peptide editors, tapasin and TAPBPR, intimately involved in controlling peptide presentation to the immune system. PMID- 26439011 TI - Odor-identity dependent motor programs underlie behavioral responses to odors. AB - All animals use olfactory information to perform tasks essential to their survival. Odors typically activate multiple olfactory receptor neuron (ORN) classes and are therefore represented by the patterns of active ORNs. How the patterns of active ORN classes are decoded to drive behavior is under intense investigation. In this study, using Drosophila as a model system, we investigate the logic by which odors modulate locomotion. We designed a novel behavioral arena in which we could examine a fly's locomotion under precisely controlled stimulus condition. In this arena, in response to similarly attractive odors, flies modulate their locomotion differently implying that odors have a more diverse effect on locomotion than was anticipated. Three features underlie odor guided locomotion: First, in response to odors, flies modulate a surprisingly large number of motor parameters. Second, similarly attractive odors elicit changes in different motor programs. Third, different ORN classes modulate different subset of motor parameters. PMID- 26439012 TI - Snf1/AMPK promotes the formation of Kog1/Raptor-bodies to increase the activation threshold of TORC1 in budding yeast. AB - The target of rapamycin complex I (TORC1) regulates cell growth and metabolism in eukaryotes. Previous studies have shown that nitrogen and amino acid signals activate TORC1 via the small GTPases, Gtr1/2. However, little is known about the way that other nutrient signals are transmitted to TORC1. Here we report that glucose starvation triggers disassembly of TORC1, and movement of the key TORC1 component Kog1/Raptor to a single body near the edge of the vacuole. These events are driven by Snf1/AMPK-dependent phosphorylation of Kog1 at Ser 491/494 and two nearby prion-like motifs. Kog1-bodies then serve to increase the threshold for TORC1 activation in cells that have been starved for a significant period of time. Together, our data show that Kog1-bodies create hysteresis (memory) in the TORC1 pathway and help ensure that cells remain committed to a quiescent state under suboptimal conditions. We suggest that other protein bodies formed in starvation conditions have a similar function. PMID- 26439013 TI - It takes two. AB - Two forms of an unconventional myosin motor protein have separate functions in the growth and maintenance of hair bundles in auditory hair cells. PMID- 26439014 TI - Fistula of the Stump: A Novel Approach With a "Stapled" Stent. AB - Postoperative bronchopleural fistulas are serious and uncommon complications after pneumonectomy. Available therapeutic approaches are medical, endoscopic, and/or surgical. A 42-year-old man underwent left pneumonectomy. Three years later he was admitted to an intensive care unit with pneumonia of the remaining lung, severe respiratory insufficiency, and a bronchopleural fistula with an air fluid level filling in the pneumonectomy cavity. A left chest drain was placed, and broad-spectrum antibiotics and mechanical ventilation were administered. Because of the unstable clinical condition, a blind end endobronchial stent closed by a stapler was placed in the left bronchial stump. He improved in a couple of months and underwent definitive surgical sealing of the fistula.Endoscopic interventions are usually safe and free from associated complications. They are an excellent option, when patient's clinical condition is contraindication to immediate surgery. PMID- 26439015 TI - Pulmonary Varices in an Adult. PMID- 26439016 TI - Safety and Clinical Utility of Flexible Bronchoscopic Cryoextraction in Patients With Non-neoplasm Tracheobronchial Obstruction: A Retrospective Chart Review. AB - BACKGROUND: Airway obstruction from blood clots, airway secretions, and foreign bodies is a potentially life-threatening condition. Optimal management of this problem, whether by rigid or flexible bronchoscopy, has not been well studied. We report our single-center experience on the safety and clinical utility of cryoprobe extraction for this indication. METHODS: We performed a retrospective chart review from January 2006 to November 2014 of all subjects aged 18 and older who underwent flexible bronchoscopic cryoprobe extraction. Subjects with obstruction due to benign or malignant neoplasm or airway stenosis were excluded. RESULTS: A total of 38 cryotherapy sessions performed on 30 subjects were identified for inclusion. Cryoprobe extraction was successful in reestablishing airway patency in 32/38 (84%) sessions overall and in 24/26 (92%) for blood clots, 4/6 (67%) for mucous plugging, 2/4 (50%) for foreign bodies, and 2/2 (100%) for plastic bronchitis. Twenty-one of 31 (68%) sessions resulted in improvement in oxygenation or ventilation. There was 1 complication related to sedation. CONCLUSIONS: We conclude that flexible bronchoscopic cryoprobe extraction of blood clots, mucous secretions, plastic bronchitis, and foreign bodies is a safe and effective option. It can be safely performed at the bedside and in many cases eliminates the need for rigid bronchoscopy. PMID- 26439017 TI - Coupling hybridization chain reaction with catalytic hairpin assembly enables non enzymatic and sensitive fluorescent detection of microRNA cancer biomarkers. AB - The identification and quantification of sequence-specific microRNAs (miRNAs) plays an important role in early diagnosis of different diseases. In this work, by integrating two independent signal amplification approaches, hybridization chain reaction and catalytic hairpin assembly, we report an enzyme-free and dual amplified approach for highly sensitive detection of a human prostate cancer biomarker, miR-141. The presence of miR-141 triggers the self-assembly of two hairpin DNAs into dsDNA polymers, which co-localize two split segments of ssDNA into proximity. Subsequently, these co-localized ssDNA sequences further act as triggers to initiate catalytic assembly of two fluorescently quenched hairpin DNAs to form numerous dsDNA strands, resulting in the recovery of the fluorescent emissions and remarkably amplified signals for highly sensitive detection of miR 141 down to 0.3 fM. In addition, this method is also selective for the target miRNA against other control sequences. With the advantages of high sensitivity and nanomaterial/enzyme-free detection format, the developed method can be a general sensing platform for the detection of trace amounts of sequence-specific nucleic acid targets. PMID- 26439018 TI - Mitochondrial enzyme dysfunction in autism spectrum disorders; a novel biomarker revealed from buccal swab analysis. AB - AIM: Mitochondrial function studies in autism spectrum disorders (ASD) have detected skeletal muscle mitochondrial enzyme deficiencies in respiratory complex (RC) activities. As a muscle biopsy is expensive and invasive, we assessed RC-I and RC-IV activities in buccal swabs. METHODS: 92 children with ASD and 68 controls were studied with immunocapture for RC-I and microspectrophotometry for RC-IV. RESULTS: Significant RC activity deficiencies were found in 39 (42%) ASD patients (p < 0.01) and more prevalent in more severe cases. Aberrant RC overactivity was seen in 9 children. RC-I/RC-IV activity ratio was significantly increased in 64% of the entire ASD cohort including 76% of those more severely affected (p < 0.05). CONCLUSION: Buccal swab analysis revealed extensive RC abnormalities in ASD providing a noninvasive biomarker to assess mitochondrial function in ASD patients. PMID- 26439019 TI - The pursuit of excellence in a climate of cost containment. PMID- 26439020 TI - Evaluation of cytotoxicity of some common ophthalmic drugs. AB - The article "Evaluation of cytotoxicity of some common ophthalmic drugs" by M. Li, X.-M. Chen, J.-J. Liu, D.-M. Wang, L. Gan, X. Lv, Y. Qiao, published in Eur Rev Med Pharmacol Sci 2015; 19 (11): 1945-1950 has been withdrawn. PMID- 26439021 TI - Respiratory cancers and pollution. PMID- 26439022 TI - Plasma rich in growth factors (PRGF) technology: simple facts that turn on the lights. PMID- 26439023 TI - What is the actual prevalence and clinical characteristics of mitral valve prolapse? PMID- 26439024 TI - Low prevalence of mitral valve prolapse in a population-based epidemiologic study. PMID- 26439025 TI - Bioinformatic analysis of the microarray gene expression profile in degenerative intervertebral disc cells exposed to TNF-alpha. AB - OBJECTIVE: We performed a bioinformatic analysis of the microarray data on the gene expression profiles of degenerative intervertebral disc cells after exposure to tumor necrosis factor-alpha (TNF-alpha) to uncover the key genes that were differentially expressed between cells with and without exposure, and to explore the related signaling pathways and interaction networks, providing clues for future investigations on the molecular mechanisms of disc degeneration. MATERIALS AND METHODS: The microarray data for degenerative intervertebral disc cells after stimulation with TNF-alpha were downloaded from a public database, the GEO (Gene Expression Omnibus), in order to identify the genes that were differentially expressed between untreated degenerative disc cells and those stimulated with TNF alpha, and then analyses of the gene ontology, signaling pathways and interaction networks for the differentially expressed genes were conducted using the DAVID, STRING and other online tools. RESULTS: A total of 753 differentially expressed genes were found in the degenerative annulus fibrosus disci intervertebralis cells after stimulation with TNF-alpha, including 458 upregulated genes and 295 downregulated genes. The Gene Ontology annotation analysis showed that these differentially expressed genes were mainly associated with the extracellular matrix, damage reactions, inflammatory reactions, and the regulation of apoptosis. A signaling pathway analysis showed that these differentially expressed genes were mainly involved in the interactions of cytokines, apoptosis, NOD-like receptors, chemokines, and other signal transduction pathways. The interaction network analysis indicated that JUN, CCL3, ANHK and other genes may play key roles in intervertebral disc degeneration. CONCLUSIONS: The bioinformatic analysis of the gene expression profiles of degenerative intervertebral disc cells stimulated with TNF-alpha showed that CCL3 and other genes may play a role in the development of the disc degeneration induced by inflammatory reactions. This suggests that bioinformatics methods can be used to identify potential therapeutic target genes, and to provide new insight into intervertebral disc degeneration. PMID- 26439026 TI - Current trends in spinal cord injury repair. AB - One of the rapidly prevailing neurological disorders affecting thousands of people per year is spinal cord injury (SCI). Though, great research has been made in recent past to understand thoroughly the molecular bases of the diseases, no fully restorative treatments for SCI are available. However, various rehabilitative, cellular and molecular therapies are being tested in animal models. Some of them have shown promising results. So, the present review shall enlighten all these latest developments in the field of spinal cord injury repair. The review shall discuss latest upcoming areas being focused for the management of SCI patients like stem cell therapy approach, cell-based approaches, combination therapeutic approaches, neuronal plasticity and possible use of omega-3 fatty acids in SCI repair. PMID- 26439027 TI - Preliminary study of IVIM-DWI and DCE-MRI in early diagnosis of esophageal cancer. AB - OBJECTIVE: To investigate the application value of double exponential model diffusion weighted imaging (IVIM-DWI) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in the diagnosis of early esophageal cancer. PATIENTS AND METHODS: 30 cases of patients with early esophageal cancer confirmed by pathology were collected. They were performed MRI plain scan, IVIM-DWI and DCE MRI scan. The normal esophageal tissue, SlowADC value in tumor focus, FastADC value, F value, Ktrans, Kep and Ve values were measured. The difference between cancer tissue and normal tissue was compared using two independent sample t test. The prediction parameters and diagnostic threshold were compared by drawing receiver operating characteristic curve (ROC). RESULTS: The average F, Ktrans and Kep values in esophageal cancer and normal esophageal tissue were: (0.48 +/- 0.19), (0.64 +/- 0.08); (0.45 +/- 0.19)/min, (0.14 +/- 0.04)/min and (1.14 +/- 0.42)/min, (0.56 +/- 0.25)/min respectively. Compared with normal esophageal tissue, esophageal cancer F value decreased, Ktrans value increased, Kep value increased, and the difference was statistically significant (p < 0.05); There was no difference in SlowADC, FastADC, Ve values of esophageal cancer and those in normal esophageal tissues (p > 0.05). The areas under ROC curve F, Ktrans and Kep values were 0.90, 0.98 and 0.92 respectively. They had the higher diagnostic efficiency. CONCLUSIONS: IVIM-DWI and DCE-MRI can be used as the imaging method to diagnose esophageal malignant tumor, which has the higher diagnostic value. PMID- 26439028 TI - Effect of personalized dietary intervention on nutritional, metabolic and vascular indices in patients with chronic kidney disease. AB - OBJECTIVE: Patients with chronic kidney disease (CKD) present a markedly increased cardiovascular (CV) morbidity and mortality since the early stages of the disease and a high prevalence of malnutrition, inflammation, and accelerated atherosclerosis. Personalized nutritional intervention, with of a low-protein diet (LPD), since the early stages of CKD should be able to achieve significant metabolic improvements. In our study we have verified the effects of a personalized dietary intervention in patients in the CKD stages 3/4 KDOQI on nutritional, metabolic and vascular indices. PATIENTS AND METHODS: We have evaluated renal function, lipid profile, mineral metabolism, inflammatory indices, and acid-base balance of 16 patients with CKD (stages 3/4 KDOQI). Assessment of nutritional status, body composition, bone mineral density and muscle mass, using body mass index (BMI), handgrip strength, bioelectrical impedance analysis (BIA), and dual energy X-ray absorptiometry (DEXA) was performed. Vascular indices and endothelial dysfunction such as carotid intima media thickness (cIMT) and the brachial artery flow-mediated dilation (baFMD) were also analyzed. RESULTS: After dietary interventions, we observed a significant increase in plasma bicarbonate (p = 0.004) and vitamin D levels (p = 0.03) and a concomitant significant reduction of phosphorus concentration (p = 0.001) and C-reactive protein (CRP) (p = 0.01). CONCLUSIONS: Nutritional intervention potentially plays a major role in reducing the progression of CKD and systemic complications of predialysis patients. A low-protein diet (LPD) ensuring vegetable protein intake and a reduced amount of specific micronutrients should be recommended to stage 3/4 CKD patients in order to ameliorate metabolic profile, renal outcome, and reduce cardiovascular risk factors. PMID- 26439029 TI - Prognostic significance of flow cytometry findings in Turkish adult acute leukemia patients. AB - OBJECTIVE: Several factors are known to affect prognosis of acute leukemia such as age, high leukocyte count, cytogenetic abnormality, performance status and recurrent leukemia. We aimed to investigate the association between cell surface markers and prognostic determinants such as recurrence at 6 and 12 months and survival at 6, 12 and 18 months in acute leukemia patients. PATIENTS AND METHODS: A total of 142 patients, 101 with acute myeloid leukemia (AML) and 41 with B-cell acute lymphoblastic leukemia (B-ALL) were included. The effects of surface markers on survival and recurrence rates were evaluated retrospectively. RESULTS: In AML patients, CD5+ and CD34+ immunophenotypes and in ALL patients cCD22+, CD34+ and CD49f + CD19+ immunophenotypes were positive prognostic indicators. In AML patients CD7 expression, and in ALL patients CD5+, CD7+ and CD117+ immunophenotypes and >90% CD45 expression were negative prognostic indicators. CONCLUSIONS: This study demonstrates that flow cytometry, a common diagnostic tool in acute leukemia, may also have prognostic value in acute leukemia in the future. PMID- 26439030 TI - Microarray based analysis of gene expression patterns in pancreatic neuroendocrine tumors. AB - OBJECTIVE: Pancreatic neuroendocrine tumors (PanNETs) are a small subgroup of tumors with a variety of biological behaviors. MATERIALS AND METHODS: We sought to identify the specially expressed genes and characterize significant pathways in PanNETs compared with non-neoplastic samples. Gene expression profile GSE43795 was obtained from Gene Expression Omnibus database, which included 6 PanNETs and 5 non-neoplastic samples. The differentially expressed genes (DEGs) were identified using Limma package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to enrich the functions and pathways of DEGs. Transcription factors (TFs) and tumor-associated genes (TAGs) were also identified. Finally, a protein-protein interaction (PPI) network was constructed, and hub proteins and functional module were screened out. RESULTS: Total of 821 DEGs (421 down-regulated, 400 up-regulated) were selected. GO and KEGG enrichment analyses showed that up-regulated DEGs were related to several pathways, including type 2 diabetes mellitus, Ca2+ signaling pathway, long-term potentiation, and long-term depression pathways. Down-regulated DEGs were enriched in several pathways, such as pancreatic secretion, protein digestion and absorption, and metabolic pathway. Interferon-stimulated gene protein 15 (ISG15), somatostatin (SST), and synaptosomal-associated protein 25 kDa (SNAP25) were identified as hub proteins. CONCLUSIONS: The genes involved in type 2 diabetes mellitus pathway may play important roles in the development of PanNETs. SNAP25, SST, and ISG15 may be used as potential targets for treatment of PanNETs. PMID- 26439031 TI - Identification of potential therapeutic target genes and mechanisms in non-small cell lung carcinoma in non-smoking women based on bioinformatics analysis. AB - OBJECTIVE: The study was aimed to explore the underlying mechanisms and identify the potential target genes by bioinformatics analysis for non-small-cell lung carcinoma (NSCLC) treatment in non-smoking women. MATERIALS AND METHODS: The microarray data of GSE19804 was downloaded from Gene Expression Omnibus (GEO) database. Paired samples (from the same patient) of tumor and normal lung tissues from 60 non-smoking female NSCLC patients were used to identify differentially expressed genes (DEGs). The functional enrichment analysis was performed. Furthermore, the protein-protein interaction (PPI) network of the DEGs was constructed by Cytoscape software. The module analysis was performed. RESULTS: Totally, 817 DEGs including 273 up- and 544 down-regulated genes were identified. The up-regulated genes were mainly enriched in extracellular matrix (ECM) receptor interaction, focal adhesion and cell cycle functions, while down regulated genes were mainly enriched in the cytokine-cytokine receptor interaction pathway. DEGs including hyaluronan-mediated motility receptor (HMMR), collagen, type I alpha 2 (COL1A2), cyclin A2 (CCNA2), MAD2 mitotic arrest deficient-like 1 (MAD2L1), interleukin 6 (IL6) and interleukin 1, beta (IL1B) were identified in these functions. These genes were hub nodes in PPI networks. Besides, there were 3 up-regulated modules and 1 down-regulated module. The significant pathways were ECM-receptor interaction and focal adhesion in up regulated modules, while in down-regulated module, the significant pathway was mitogen-activated protein kinase (MAPK) signaling pathway. CONCLUSIONS: The ECM receptor interaction, focal adhesion, cell cycle and cytokine-cytokine receptor interaction functions may be associated with NSCLC development. Genes such as HMMR, COL1A2, CCNA2, MAD2L1, IL6 and IL1B may be potential therapeutic target genes for NSCLC. PMID- 26439032 TI - Serum nerve growth factor level indicates therapeutic efficacy of 125I seed implantation in advanced pancreatic adenocarcinoma. AB - OBJECTIVE: To evaluate serum nerve growth factor (NGF) as a marker in predicting effectiveness of 125I seed implantation in advanced pancreatic carcinoma. PATIENTS AND METHODS: A total of 45 patients (30 males/15 females with mean age of 52.07+/-8.43 years) diagnosed with advanced pancreatic adenocarcinoma (PCa) between January 2011 to May 2014 were enrolled as PCa group in this study. Tumors were categorized as at least stage III with unresectionable condition by the TNM standard. The average tumour shortest diameter was 37.54+/-13.84 mm (18.50-71.20 mm). NGF level in serum before 125I seed implantation and in tumor tissue resected during surgery was measured by ELISA. After treatment, CT Scan was used to serially monitor the diameters of the tumour monthly for 6-month follow-up. RECIST was applied to evaluate the efficacy. Predictive value of serum and tumour derived NGF was evaluated based on ROC curve chart. RESULTS: We found that the serum NGF level was significantly increased in PCa patients (775.60 +/- 250.97 pg/ml) compared to the healthy control group (35.03 +/- 25.36 pg/ml), after age and gender adjustment. In the PCa group, the serum NGF level positively correlated with that from loci tumor tissue (r=0.487). The serum NGF level was compared between the effective group (537.42 +/- 122.61 pg/ml) and noneffective group (883.17 +/- 217.79 pg/ml), and significant difference was detected (p<0.0001). Patients with lower serum NGF level had good response to the 125I seeds implantation. Taking cut-off at 649.59 pg/ml, 85.70% specificity and 90.30% sensitivity were achieved by ROC. Area under the Curve of serum NGF was 0.945, standard deviation was 0.032, 95% confidence interval was 0.882-1.000. CONCLUSIONS: The level of serum NGF could be a referential index to predict the therapeutic efficacy of 125I seed implantation treatments in advanced pancreatic adenocarcinoma. PMID- 26439033 TI - Tegafur gimeracil oter combined with oxaliplatin for advanced colorectal cancer. AB - OBJECTIVE: To analyze the therapeutic actions of tegafur gimeracil oteracil combined with oxaliplatin for treating patients with advanced colorectal cancer, and its effects on the K-ras gene mutation and the CK20 mRNA. PATIENTS AND METHODS: Forty-one patients with advanced colorectal cancer from our hospital, from October 2013 to October 2014, were enrolled in this study. After obtaining consent from the hospital Ethics Committee and the patients as well as their relatives, all 41 patients were divided into two groups. The control group, which consisted of 20 cases, were treated with capecitabine combined with oxaliplatin. The study group, which comprised of 21 cases, were treated with tegafur gimeracil oteracil combined with oxaliplatin. Both groups were followed-up after six months to evaluate the treatment outcomes. RESULTS: The survival rate in the observation group was higher than that in the control group. The progression-free survival time (PFS) in the observation group was longer than that in the control group. The objective response rate (ORR) and disease control rate (DCR) were higher for the observation group. The differences had statistical significance (p < 0.05). The proportion of K-ras gene mutation in the observation group was substantially superior to that in the control group. The positive expression rate of CK 20 mRNA in the observation group was significantly lower than that in the control group. The differences had statistical significance (p < 0.05). The incidence of adverse reaction in the observation group was lower than that of the control group, and the differences had statistical significance (p < 0.05). CONCLUSIONS: Tegafur/gimeracil/oteracil combined with oxaliplatin therapy had better treatment outcomes than capecitabine combined oxaliplatin for advanced colorectal cancer. This maybe related to K-ras gene mutation and the reduction of CK20 mRNA expression. PMID- 26439034 TI - Overexpression of microRNA-21 in peripheral blood mononuclear cells of patients with B-cell non-Hodgkin's lymphoma is associated with disease stage and treatment outcome. AB - OBJECTIVE: We wished to assess the association between microRNA-21 (miR-21) and disease stage and treatment outcome in patients with B-cell non-Hodgkin's Lymphoma (B-NHL). PATIENTS AND METHODS: A total of consecutive 128 patients with B-NHL were enrolled; 30 healthy individuals served as controls. qPCR assay was utilized to quantify expression levels of miR-21 in peripheral blood mononuclear cells (PBMC; Ficoll isolation protocol). Expression of the miR-21 target, phosphatase and tensin homolog (PTEN), was assessed by Western blot analysis. RESULTS: miR-21 was overexpressed in PBMC of patients with B-NHL (p < 0.05 vs. healthy individuals). Furthermore, miR-21 expression levels were significantly higher in patients with the stage III/IV B-NHL (p < 0.05 vs. stage I/II B-NHL). After chemotherapy, miR-21 expression levels were significantly decreased in patients in complete remission and became comparable to those of healthy individuals. Also, miR-21 expression levels were lower in patients treated with chemotherapy combined with rituximab. There was a negative association between miR-21 overexpression and post-chemotherapy survival rates of the patients. Expression of PTEN was significantly lower in patients with B-NHL (p < 0.05 vs. healthy individuals). CONCLUSIONS: Overexpression of miR-21 is associated with disease stage and treatment outcome of B-NHL. This potentially involves negative modulation of PTEN. PMID- 26439035 TI - Long noncoding RNA UCA1 modulates breast cancer cell growth and apoptosis through decreasing tumor suppressive miR-143. AB - OBJECTIVE: Long non coding RNA (LncRNA) urothelial carcinoma-associated 1 (UCA1) is an oncogene in breast cancer. However, the detailed mechanism has not been fully revealed. This study explored whether UCA1 can directly interact with miR 143, a tumor suppressor in breast cancer and whether the UCA1-miR-143 axis is involved in regulation of cancer cell growth and apoptosis. PATIENTS AND METHODS: miRNA microarray was performed to identify the most dysregulated miRNAs between tumor and adjacent normal tissues of breast cancer. QRT-PCR analysis was performed to assess the expression of UCA1 and miR-143. The binding between UCA1 and miR-143 was verified using dual luciferase and RNA binding protein immunoprecipitation (RIP) assay. MTT assay and flow cytometry analysis were performed to study the role of UCA1-miR-143 axis in cell proliferation, cell cycle and apoptosis. RESULTS: UC1 was significantly upregulated, while miR-143 was significantly downregulated in the tumor tissues than in the adjacent normal tissues. There are direct interactions between miR-143 and the miRNA recognition sites of UCA1. UCA1 is present in Ago2-containing RNA-induced silencing complex (RISC), through association with miR-143. Through downregulating miR-143, UCA1 can modulate breast cancer cell growth and apoptosis. CONCLUSIONS: UCA1 can directly interact with miR-143, lower its expression and affect its downstream regulation. Therefore, the UCA1-miR-143 axis constitutes a part of the oncogenic role of UCA1 in breast cancer. PMID- 26439036 TI - microRNA-106a induces the proliferation and apoptosis of glioma cells through regulating JNK/MAPK pathway. AB - OBJECTIVE: To investigate the expression of microRNA-106a (miRNA-106a) in the brain tissue and the plasma of glioma patients, and explore the mechanism underlying the effect of miRNA-106a on the proliferation and apoptosis of glioma cells. PATIENTS AND METHODS: Brain tissues from 42 glioma patients admitted in our institution were included in study group, whereas normal brain tissues collected from 10 patients undergoing brain tissue resection due to decompression or exposure during cerebral surgery. Quantitative fluorescent RT-PCR (QF RT-PCR) was performed to measure miRNA-106a mRNA levels in the brain tissue and peripheral blood of patients in two groups. Human M059K glioma cells were transfected with miRNA-106a mimic and inhibitor, and the proliferation and apoptosis of glioma cells were analyzed. In addition, JNK/MAPK in glioma cells was examined at mRNA and protein levels. RESULTS: Compared with the normal population, miRNA-106a expression was significantly increased in the brain tissue of glioma patients (p < 0.05). Besides, miRNA-106a expression level was significantly elevated in the plasma of peripheral blood of glioma patients (p < 0.05). After the interference of miRNA-106a in M059K glioma cells, the proliferation of glioma cells was significantly reduced. However, the apoptotic regulatory factor, Bcl-2, was significantly increased, and JNK/MAPK protein level was significantly decreased. Overexpression of miRNA-106a in glioma cells resulted in significant increase in the proliferation of glioma cells and JNK/MAPK protein level, but obvious suppression in Bcl-2 protein level. CONCLUSIONS: Elevated expression of miRNA-106a plays a crucial role in the development and progression of glioma, probably by promoting the proliferation and suppressing the apoptosis of glioma cells through the JNK/MAPK signaling pathway. PMID- 26439037 TI - Ovarian transposition in young women and fertility sparing. AB - OBJECTIVE: Ovarian transposition is a highly effective surgical procedure used to preserve ovarian function in premenopausal patients with cancers requiring postoperative or primary pelvic radiotherapy. Pelvic irradiation determines severe damage of ovarian DNA and iatrogenic ovarian failure with premature menopause, necessity of long-term hormone replacement therapy and infertility. MATERIALS AND METHODS: We conducted an extensive research of the literature in Medline between January 2000 and April 2015 using the key-words "ovarian transposition radiotherapy", "radiotherapy gonadal function", radiotherapy fertility sparing". The population included young women with normal ovarian function affected by cancers that required pelvic radiotherapy. We have examined 32 articles reporting on 1189 women undergoing ovarian transposition. Median age was 32.5 years, follow up was median 48 months. The procedure has been performed in patients less than 40 years of age. Surgery has been achieved by laparotomy or laparoscoy. We have analyzed effects of radiotherapy on ovarian function. RESULTS: The proportion of women treated by ovarian transposition preserved ovarian function was 70%. About 86% of patients did not develop ovarian cysts and in 98-99% of cases did not occur any metastatic disease. CONCLUSIONS: Ovarian transposition is associated with significant preservation of ovarian function and a low frequency of complications as cysts and metastasis. In 31% of cases the procedure can fail. Further studies are needed to evaluate the efficacy of ovarian transposition and the follow up. Ovarian transposition should be discussed at the time of cancer diagnosis in every premenopausal woman requiring pelvic radiotherapy. PMID- 26439038 TI - Alpha Lipoic Acid (ALA) effects on subchorionic hematoma: preliminary clinical results. AB - OBJECTIVE: The clinic use of alpha Lipoic Acid (ALA) is linked to its capability to exert antioxidant effects and, more interestingly, to counteract the pathologic changes of complex networks of cytokines, chemokines and growth factors, restoring their physiological state. The aim of this randomized controlled clinical trial was to test the contribution of oral supplementation of ALA to the standard treatment with Progesterone vaginal suppositories, in healing subchorionic hematomas in patients with threatened miscarriage. Controls were administered only Progesterone suppositories. PATIENTS AND METHODS: Nineteen pregnant women in the first trimester of gestation, with threatened miscarriage and ultrasound evidence of subchorionic hematoma, were included in the trial and randomly divided in two groups: controls, treated with 400 mg Progesterone (200 mg 2 times per day), given by vaginal suppositories, and case study treated with the same Progesterone dosage, plus ALA, given orally at the dose of 600 mg (300 mg 2 times per day, DAV(r), Lo.Li. Pharma srl, Italy). Sixteen patients completed the trial. Treatment was performed until complete resolution of the clinical picture. RESULTS: In both groups, the subjects improved significantly but, in general, a better and faster evolution in the major signs of threatened miscarriage was observed in the subjects treated with ALA and Progesterone. In these patients, the speed of resorption of subchorionic hematoma was significantly (p <= 0.05) superior compared to controls. The ALA and Progesterone group showed a faster decrease or disappearance of all symptoms than that observed in the control group, however the difference was not significant. CONCLUSIONS: These preliminary results suggest that ALA supplementation significantly contributes to speed up the process of restoration of physiological conditions in threatened miscarriage and ameliorates the medical conditions of both the mothers and the foetus, probably modulating the networks of cytokines, growth factors and other molecules. PMID- 26439039 TI - Serum chitotriosidase levels in cancer patients undergoing high dose chemotherapy and stem cell transplantation. AB - OBJECTIVE: Human chitotriosidase (ChT) is an active chitinase expressed by activated phagocytes. Increased ChT activity has been reported in systemic Candida albicans infections and in Gram-negative and Gram-positive bacterial infections, indicating that an increase in ChT activity reflects phagocyte activation. The aim of this study was to determine the changes in serum ChT activity in patients who underwent high dose chemotherapy (HDC) and stem cell transplantation (SCT), who are at an increased risk for fungal and bacterial infections due to depression of the immune system during the neutropenic period. PATIENTS AND METHODS: A total of 55 SCT patients were included in the study. Serum ChT activity was determined before the initiation of HDC and during the neutropenic period after hematopoietic stem cell reinfusion on post-transplant first, fifth and tenth days. RESULTS: Chitotriosidase levels before transplantation were significantly lower than the results at first, fifth and tenth days post-hematopoietic stem cell reinfusion. CONCLUSIONS: Although the number of neutrophils was low, ChT enzyme activity was high in newly produced granules of neutrophils. Chitotriosidase may be supplemented as a drug for preventing and treating infections in the near future. PMID- 26439040 TI - Effects of oleic acid on SP-B expression and release in A549 cells. AB - OBJECTIVE: Pulmonary surfactant-associated protein B (SP-B), which is synthesized and secreted by alveolar epithelial type II cells, is crucial for normal functioning of pulmonary surfactant. Degeneration of pulmonary surfactant is the essential cause of acute lung injury (ALI). ALI is often studied in animal models using oleic acid, and the effects of oleic acid on pulmonary surfactant and SP-B are not clear. In this study, we examined the effects of oleic acid on the A549 cell line which resembles the alveolar epithelial type II cells. MATERIALS AND METHODS: A549 cells were exposed for 24 hours to 300, 400, 500 or 600 uM of oleic acid. Cell morphological changes were observed using an inverted microscope, and cell proliferation was quantified with the Cell Counting Kit-8. Extracellular SP B levels were assessed by ELISA, whereas intracellular SP-B expression by Western blot. RESULTS: Oleic acid caused dose-dependent changes in cell morphology of A549 cells and decreased their proliferation. This was accompanied by release of SP-B into extracellular supernatants and corresponding decrease of intracellular levels of this protein. CONCLUSIONS: Oleic acid causes a dose-dependent injury to A549 cells, release of SP-B into extracellular compartment, and decrease of intracellular SP-B expression. Our findings provide mechanistic insights into animal modeling of ALI with oleic acid. PMID- 26439041 TI - The study of prevalence rate, and clinical characteristics of high altitude deterioration. AB - OBJECTIVE: This study was aimed to investigate the prevalence rate and clinical characteristics of high altitude deterioration (HADT), which would provide a scientific basis for the diagnosis and prevention of HADT. SUBJECTS AND METHODS: A total of 175 subjects, who had migrated to a high altitude (4516 m) for more than 1 year, were investigated. A questionnaire survey based on the symptoms of HADT was conducted, and 117 subjects were determined to have HADT according to the diagnostic criteria of HADT. To explore the clinical characteristics of HADT, 117 HADT patients and 31 healthy individuals were assigned to HADT patient group and healthy control group, respectively. Their body mass indexes (BMIs), blood rheology, full blood count (including hemoglobin concentration, leukocyte count, neutrophil count, lymphocyte count and platelet count), blood pressure, heart rate, oxygen saturation as well as left ventricular ejection fraction (LVEF) and fraction shortening (LVFS) were assessed. RESULTS: The prevalence rate of HADT was 66.9% at a high altitude of 4516 m. Compared with those in healthy people at high altitude, some health indicators such as BMI, leukocyte count, neutrophil count, lymphocyte count, platelet count, systolic blood pressure, oxygen saturation, LVEF value and LVFS value were lower but other indicators including the blood viscosity, hematocrit, hemoglobin concentration and heart rate were higher in patients with HADT. CONCLUSIONS: The prevalence rate of HADT (66.9%) was high among people moving to a high altitude of 4516 m. Clinical characteristics of HADT were: (1) Impairment of left ventricular systolic function; (2) Immune depression; (3) Microcirculation disturbance; and (4) Decline of hemostasis and coagulation function. PMID- 26439042 TI - Insulin sensitivity indices: fasting versus glucose-stimulated indices in pediatric non-alcoholic fatty liver disease. AB - OBJECTIVE: We aimed to compare insulin sensitivity indices, fasting vs glucose stimulated, in children and adolescents with non-alcoholic fatty liver disease. PATIENTS AND METHODS: Two hundred-eleven obese children with median age of 11.24 +/- 2.65 years were evaluated. After initial clinical and anthropometric examination, B-mode ultrasonography (USG) was performed and all subjects underwent Oral Glucose Tolerance Test (OGTT). Quantitative insulin sensitivity check index (QUICKI), homeostatic model assessment for insulin resistance (Homa IR), the insulinogenic index (IGI), the Matsuda index, and the oral glucose insulin sensitivity (OGIS) model were used to determine peripheral insulin sensitivity. RESULTS: 59.24% (68 boys, 57 girls) of obese children had NALFD. The prevalence of FLD in obese adolescents was significantly higher than in prepubertal children (65.8% vs. 51.5%). Fasting glucose, insulin, Homa-IR, QUICKI, and OGIS and Matsuda were significantly different between subjects with and without NALFD. Insulin and glucose indices were not found to be significantly different in the prepubertal group, whereas Homa-IR, QUICKI, Matsuda, and OGIS were significantly different in the pubertal group. Age, waist circumference, and OUICKI were found to be risk factors associated with the presence of NALFD in the logistic-regression analysis. CONCLUSIONS: Age, waist circumference, and OUICKI were found to be risk factors associated with NALFD. As the value of QUICKI decreases, the probability of having steatosis increases. Although OGTT results gave the information about the glucose tolerance of a subject, indices derived from OGTT were not found to be superior to the traditional surrogates such as Homa-IR or QUICKI. PMID- 26439043 TI - Correlation research on the protein expression (p75NTR, bax, bcl-2, and caspase 3) and cortical neuron apoptosis following mechanical injury in rat. AB - OBJECTIVE: In this study, we aimed to survey the role of p75NTR, bax, bcl-2, and caspase-3 in the progress of traumatic brain injury (TBI). MATERIALS AND METHODS: A mechanical trauma model of vital neurons was established by putting external pressure, contusion and centrifugal acceleration on neurons. Morphological change, survival rate, assay of LDH activity, and apoptosis rate were evaluated for mild, medium and severe injury models. The expression of bax, bcl-2, caspase 3, p75NTR, p75NTR mRNA was determined by immunohistochemistry, immunofluorescence, Western blotting and RT-PCR. RESULTS: There was a transient high level Bcl-2 protein within 2 h after injury to increase neuronal tolerance and avoid apoptosis. Subsequently p75NTR, Bax/Bcl-2, and Caspase-3 reached their peaks from 48 to 72 h accompanied with the maximum apoptosis rate. CONCLUSIONS: Our results suggest that apoptosis ratio in varying degree injury groups are correlated with the expression level of p75NTRmRNA, p75NTR, Caspase-3, Bax/Bcl-2 ratio. PMID- 26439044 TI - A study on the protective role of doxycycline upon dopaminergic neuron of LPS-PD rat model rat. AB - OBJECTIVE: To investigate the protective role of doxycycline upon the dopaminergic neuron of the lipopolysaccharide-Parkinson disease (LPS-PD) model rat and its mechanism. MATERIALS AND METHODS: Animals were randomly divided into three groups: normal control group, LPS group and doxycycline intervention. Group; establishing The PD model was created by injecting LPS stereo-tactically into the substantia nigra; observing the changes in the dopaminergic neurons and the major histocompatibility complex II (MHC II) positive microglia before and after the intervention of doxycycline with immunohistochemical staining. Using the HPLC-ED (high performance liquid chromatography-electrochemical detector) to test the changes in the striatal dopamine (DA), and DOPAC (dihydroxy phenyl acetic acid) content; adopting Western blotting was adopted to test the expression of the substantia nigra microglia MHC II (major histocompatibility complex II) protein. RESULTS: After the intervention of doxycycline, in the LPS group, the surviving dopamine neurons in the substantia nigra rose from 38% +/- 5% to 79% +/- 4% (p < 0.01); striatal DA and DOPAC content of the LPS group increased from 4.89 +/- 0.27 and 0.70 +/- 0.07 to 7.00 +/- 0.34 and 1.10 +/- o. 10 respectively (p < 0.01). The average number of rotation induced intraperitoneal injection of apomorphine of the animals in the LPS group reduced from (208 +/- 14); time/30 min to (80 +/- 12) times/30 min (p < 0.01); while the number of the MHC II positive cells in the substantia nigra pars compacta in the LPS group reduced from 835 +/- 82 to 354 +/- 59 (p < 0.01); Western blotting of the MHC II protein expression showed a significant reduction. CONCLUSIONS: Doxycycline can inhibit degeneration of LPS-induced dopaminergic neurons. Its neuroprotective function is achieved by downregulating the microglia MHC II expression. PMID- 26439045 TI - Evaluation of aqueductal CSF flow dynamics with phase contrast cine MR imaging in idiopathic intracranial hypertension patients: preliminary results. AB - OBJECTIVE: We aimed to evaluate dynamic cerebrospinal fluid (CSF) flow in idiopathic intracranial hypertension (IIH) patients with new MRI technology phase contrast cine (PCC) MRI. PATIENTS AND METHODS: Nineteen patients diagnosed with idiopathic intracranial hypertension and 11 healthy volunteers were included in this study. Nine of the IIH cases had been previously diagnosed and had been on drug treatment and 10 cases were diagnosed with IIH recently and had not been put on drug treatment yet. All CSF flow datas were evaluated by phase contrast-MRI using a 1,5 T MRI. The CSF flow was calculated in the equidistant MRI sequence which was taken through a cardiac cycle. RESULTS: Mean aqueduct area in the IIH group was 3.04 +/- 1.14 mm2, mean peak rate was 3.29 +/- 1.77 cm/sec, mean average rate was 0.35 +/- 0.33 cm/sec and mean flow was 0.67 +/- 0.95 ml/min. In the control group mean aqueduct area was 2.87 +/- 1.01 mm2, mean peak rate was 4.20 +/- 1.40 cm/sec, mean average rate was 0.37 +/- 0.18 cm/sec and mean flow was 0.64 +/- 0.40 ml/min. A statistically significant difference was found for the PCC MRI parameter of mean rate value (p: 0.007) between the control group and IIH patients. A statistically insignificant (p: 0.058) but marked difference was found for mean flow value. CONCLUSIONS: To our knowledge this study is the first CSF flow study in the idiopathic intracranial hypertension patients. We found a difference between the IIH groups and controls in mean rate and flow parameters. It was interesting that the mean rate and flow values of the untreated group that were higher than the controls. CSF flow analysis may be a marker to follow up IIH patients. PMID- 26439046 TI - Study on the carotid atherosclerotic plaque of patients suffering from ischemic cerebrovascular disease by 64 slices CT. AB - OBJECTIVE: To explore the correlation between the features of a carotid plaque of patients suffering from carotid atherosclerosis and ischemic cerebrovascular disease by 64 slices computed tomography (CT). PATIENTS AND METHODS: One hundred patients with carotid atherosclerosis were divided into the ischemic event group (n=48) and non-ischemic event group (n=52). The features of the carotid plaque were detected by 64 slices CT. RESULTS: One hundred and thirteen plaques were found in the ischemic event group. The proportions of fatty, calcified, and mixed plaque were 35.4%, 30.1%, and 34.5%. There are 78 plaques found in the non ischemic event group. The proportions of fatty, calcified, and mixed plaque were 21.8%, 51.3%, and 26.9%. The distribution difference between the three types of plaques was statistically significant (p<0.05). The proportions of mixed plaque composed mainly of fatty plaque were 64.1% and 23.8%. These two constituent ratios are significantly different from those of statistical processing (p<0.01). There are 10 cases of plaque ulceration out of the 100 cases, among which eight are from the ischemic event group and two cases from the other group. After statistical processing, the incidence rates of plaque ulceration from these two groups are significantly different (p<0.05). CONCLUSIONS: The 64 slices CT can accurately present the morphological features of the carotid plaque. It indicates that the fatty plaque, mixed plaque composed mainly of fatty plaque and ulcerative plaque can cause ischemic cerebrovascular events. PMID- 26439047 TI - A study on the susceptibility of allogeneic human hepatocytes to porcine endogenous retrovirus. AB - OBJECTIVE: Porcine endogenous retrovirus (PERV) is a virus that can be integrated into porcine genome. It has been proved that PERV can infect the cells of a variety of species. However, little is known about the infectivity of PERV to human hepatocytes. The present study focused on the susceptibility of primary human hepatocytes to PERV. MATERIALS AND METHODS: Cell culture supernatant containing PERV was used to infect primary allogeneic hepatocytes and human embryonic kidney cell line HEK-293. The integration of PERV into the genome and PERV expression were detected by using PCR and RT-PCR. RESULTS: Gene and mRNA sequences of PERV were detected in HEK-293 cells; however, viral gene expression was not detected in 3 groups of primary allogeneic hepatocytes. CONCLUSIONS: HEK 293 cells can be infected by PERV, but 3 groups of primary allogeneic hepatocytes were not sensitive to PERV, indicating PERV had no infectivity to primary human hepatocytes. PMID- 26439048 TI - Key factors of therapeutic effects for surgery in patients with cirrhotic portal hypertension. AB - OBJECTIVE: In the clinical management of cirrhotic portal hypertension, surgery is often necessary; however, the operative mortality rate is high. PATIENTS AND METHODS: Data from 161 patients, who underwent surgery for cirrhotic portal hypertension, were analyzed, and 24 potential predictors of surgical outcome were assessed. A Kruskal-Wallis rank sum test was used for single-factor comparisons, and multivariate logistic regression for multifactor comparisons to identify key factors for poor surgical outcomes and calculate their scores. RESULTS: Six predictors of poor surgical outcomes were identified: postoperative bleeding within 30 h of > 2 L, with a score of 3; severe liver atrophy (an anteroposterior diameter of the left lobe of <= 55 mm and an oblique diameter of the right lobe <= 110 mm), with a score of 3; a base excess of <-3 mmol/L, with a score of 3; a platelet count of <3 T/L, with a score of 2; an amount of intraoperative bleeding of > 2 L, with a score of 2; and a red blood cell count of < 3 G/L, with a score of 1. For patients with good outcome (n = 147), all patients had a score of <= 3, except one patient who had a score of 4. With respect to patients who died (n = 14), all had a score of >= 5, except one patient who had a score of 4. A significant difference was observed between the two groups (p < 0.05). The mortality was 100% in patients with a score of >= 7. CONCLUSIONS: Six key factors for poor surgical outcomes were identified in this study. Operative mortality appears to be significantly increased in patients with a score of 5-6. Surgery should be contraindicated in patients with a score of >= 7. To reduce mortality, close attention should be paid to preoperative and intraoperative treatment and prevention to achieve a score of < 4. PMID- 26439049 TI - A role of pre-mir-10a coding region variant in host susceptibility to coxsackie virus-induced myocarditis. AB - OBJECTIVE: Acute viral myocarditis (VM) is an important cause of sudden cardiac death and heart failure in healthy young person. Direct virus-mediated injury and secondary immune reactions, including inflammatory and autoimmune responses, have been reported both in animal models and in humans. Recently, genetic variation has been confirmed related to myocarditis process and susceptibility to VM. In this study, we scanned 339bp of pri-miR-10a coding region in CVB3 VM patients, want to found genetic relations between miR-10a and VM susceptibility. PATIENTS AND METHODS: The secondary structure of two genotype 220 bp pri-miR-10a sequences was predicted using RNAfold web server. In vitro biological functional study concluded dual luciferase assay and Western blotting. RESULTS: We found the rare allele T of rs3809783 was accumulated in VM patients and related to VM significantly. Subsequently, we confirmed that ITCH, a NK-kappaB signaling suppressor, is a direct target of miR-10a. In vitro biological functional study indicated that this site variation reduced mature miR-10a expression and induced a down-regulated cytokine secretion in the cell culture supernatant. CONCLUSIONS: The results suggest that the rare allele T in pri-miR-10a coding region should be involved in the CVB3 caused VM pathogenesis through weakening host anti-virus immune response. This site may be used for clinical genetic evaluation for VM susceptibility. PMID- 26439050 TI - Two markers in predicting the cardiovascular events in patients with polycystic ovary syndrome: increased P-wave and QT dispersion. AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) is a prevalent disease with many potential long-term cardiovascular risks. P-wave dispersion (Pdis) and QT dispersion (QTdis) have been shown to be noninvasive electrocardiographic predictors for development of cardiac arrhythmias. In this study we aimed to search Pdis and QTdis parameters in patients with PCOS. PATIENTS AND METHODS: The study included 82 patients with PCOS and 74 age- and sex-matched healthy controls. Baseline 12-lead electrocardiographic and transthoracic echocardiographic measurements were evaluated. P-wave maximum duration (Pmax), P wave minimum duration (Pmin), Pdis, QT interval, heart rate-corrected QT dispersion and QTdis were calculated by two cardiologists. RESULTS: Patients wirh PCOS had significantly higher QT dispersion (49.5 +/- 14.1 vs. 37.9 +/- 12.6 ms, p < 0.001), and P wave dispersion (54.2 +/- 11.4 vs. 45.9 +/- 10.1 ms, p < 0.001) than the controls. Serum testosterone and estradiol levels was correlated with the Pdis (r = 0.677, p < 0.001 and r = 0.415, p < 0.001 respectively) and QTdis (r = 0.326, p < 0.001 and r = 0.321, p < 0.001 respectively). CONCLUSIONS: Pdis and QTdis are simple and useful electrocardiographic markers which may be used in the prediction of the risk of adverse cardiovascular events in PCOS patients. PMID- 26439051 TI - TRAM-34 attenuates hypoxia induced pulmonary artery smooth muscle cell proliferation. AB - OBJECTIVE: Hypoxia is an important risk factor for pulmonary arterial remodeling in pulmonary arterial hypertension (PAH). Pulmonary artery smooth muscle cell (PASMC) proliferation is a major contributor to pulmonary vascular remodeling. The intermediate-conductance Ca2+-activated K+ channel (Kca3.1) has been implicated in disease states characterized by excessive cell proliferation, but its role in hypoxia-induced PASMC proliferation is unknown. In the present study, we sought to investigate the effect of TRAM-34 (triarylmethane-34), a selective blocker of Kca3.1, on hypoxia-induced PASMC proliferation and underlying mechanisms. METHODS: PASMC was exposed to hypoxia (2% O2) for 24 hours, cell proliferation and cell cycle analysis were measured by cell counting kit (CCK-8) and flow cytometry. Cell signaling were examined using Quantitative real-time PCR and Western blotting. RESULTS: CCK8 results showed that TRAM-34 reduced PASMC proliferation under hypoxia. Flow cytometry revealed that TRAM-34 inhibited PASMC proliferation by G0/G1 arrest. Quantitative real-time PCR and western blotting results showed that Kca3.1 mRNA and protein levels were greater in PASMC after hypoxia exposure for 24 hours. Elevated BMP2 (bone morphogenetic protein 2) levels and decreased BMPR2/Smad1 signaling activation were also observed under hypoxia, which were significantly attenuated by TRAM-34 intervention. CONCLUSIONS: These results suggest that Kca3.1 inhibition with TRAM-34 inhibited hypoxia-induced PASMC proliferation in the G0/G1 phase. The capability of TRAM-34 to increase BMPR2/p-Smad1 signaling may be part of the mechanisms for hypoxia induced cell proliferation. Thus, our study implies that blockade of kca3.1 might provide benefits to attenuating PAH vascular remodeling. PMID- 26439052 TI - Comparison of propofol-remifentanil and propofol-ketamine combination for dilatation and currettage: a randomized double blind prospective trial. AB - OBJECTIVE: The purpose of this study was to compare the propofol-remifentanil combination and propofol-ketamine combination for Dilatation and Curettage (DC) procedure. PATIENTS AND METHODS: This prospective, double blind, and randomized study comprised 81 female patients undergoing diagnostic DC. Patients were randomly allocated to one of two groups; propofol-remifentanil (Group PR, n= 44) or propofol-ketamine (Group PK, n= 37). The level of sedation was assessed with the Ramsay Sedation Score (RSS). The patients' RSS scores were maintained at 4-5 with an additional 0.5 mg/kg bolus dose of propofol. Heart rate (HR), mean blood pressure (MBP), peripheral oxygen saturation (SpO2), and RSS were recorded. The Modify Aldrete Score (MAS) was used for postoperative recovery evaluation, and the time to reach MAS score of 10 was recorded. Total dose of propofol, procedure time, side effects, and satisfaction scores of patient and surgeon were also recorded. RESULTS: The mean HR and MBP values of Group PR were lower than those of Group PK, at all recording times. Sedation levels were significantly higher in Group PK. The total dose of propofol consumed was significantly higher in Group PR. The recovery time of Group PK was significantly longer than that of Group PF (p<0.05). Nausea-vomiting and bradycardia were more frequent in the Group PR. There was no difference in patient and surgeon satisfaction between the two groups. CONCLUSIONS: Ketamine-propofol combination provides better hemodynamic stability and better quality of sedation than propofol-remifentanil combination. Ketamine still seems as an advantageous and safe drug for such procedure. PMID- 26439053 TI - Oral misoprostol does not protect the kidneys from diclofenac induced toxicity: data from an unilateral ureteral obstructive rat model. AB - OBJECTIVE: Ureteral obstruction leads to permanent changes in the structure of the kidney by several mechanisms. In this study, it was hypothesized that there would be a protective effect of misoprostol against diclofenac in rats with unilateral ureteral obstruction (UUO). MATERIALS AND METHODS: Twenty-two female rats were randomized into 5 groups of 4 and 2 rats for the control group. The right ureter was sutured. The rats were grouped as control, contrast agent, contrast agent +N-acetylcysteine (NAC), diclofenac and diclofenac + misoprostol groups.Radiographic contrast agent was given iv on the 3rd day and other agents were administered orally for 1 week. The rats were sacrified after 1 week and histopathological and biochemical oxidative stress markers were evaluated. RESULTS: The contrast agent and NAC group had lower rates of hemorrhage, inflammation, obstructive dilatation and fatty degeneration compared to the contrast agent only group (p < 0.05). No differences were seen in the normal kidneys. Between all the groups, there was no difference for tubule epithelium damage (p > 0.05). The contrast agent and NAC group had higher rates of antioxidant SH level compared to the contrast agent only group (p < 0.05) and lower rates of oxidative end product carbonyl groups (p < 0.05). For normal kidneys no difference was seen. No statistical difference was seen in MDA levels (p > 0.05). Statistically no difference was seen between the diclofenac group and the diclofenac and misoprostol group neither pathologically nor chemically (p > 0.05). CONCLUSIONS: These results showed that NAC is protective against radiographic contrast agent toxicity when given before and after administration in obstructed kidneys as in previous data. Misoprostol was not observed to have any protective effect against diclofenac in obstructed kidneys. PMID- 26439054 TI - Three patients treated with daclatasvir and asunaprevir for recurrent hepatitis C after liver transplantation: Case report. AB - We previously reported our data on telaprevir or simeprevir used in combination with pegylated interferon (PEG IFN) and ribavirin (RBV) for the treatment of recurrent hepatitis C virus (HCV) genotype 1 infection after liver transplantation (LT). Here, we report three patients who achieved viral responses with no effect on the blood concentrations of immunosuppressive agents following daclatasvir and asunaprevir treatment. The first patient was a 57-year-old man with HCV-related liver cirrhosis who failed to respond to PEG IFN/RBV after living donor LT. He had been treated with 1 mg/day of tacrolimus. The second was a 63-year-old man with HCV-related liver cirrhosis and hepatocellular carcinoma who failed to respond to PEG IFN/RBV after living donor LT. He had been treated with 1 mg/day of tacrolimus. The third was a 61-year-old man with HCV-related liver cirrhosis. He had been treated with mycophenolate mofetil (MMF). Serum HCV RNA became undetectable by TaqMan polymerase chain reaction test after 4 weeks of daclatasvir and asunaprevir treatment in all patients, and no remarkable fluctuations in blood concentration were observed either in tacrolimus or in MMF during 24 weeks of therapy. No adverse events were observed, and all patients received the full dose of daclatasvir and asunaprevir over 24 weeks. Serum HCV RNA remained negative at 12 weeks after the end of treatment in all patients. The daclatasvir and asunaprevir treatment showed a remarkable viral response with little effect on blood levels of immunosuppressive agents for recurrent HCV genotype 1 infection after LT. PMID- 26439055 TI - The influential child: How children affect their environment and influence their own risk and resilience. AB - Views regarding children's influence on their environment and their own development have undergone considerable changes over the years. Following Bell's (1968) seminal paper, the notion of children's influence and the view of socialization as a bidirectional process have gradually gained wide acceptance. However, empirical research implementing this theoretical advancement has lagged behind. This Special Section compiles a collection of new empirical works addressing multiple forms of influential child processes, with special attention to their consequences for children's and others' positive functioning, risk and resilience. By addressing a wide variety of child influences, this Special Section seeks to advance integration of influential child processes into myriad future studies on development and psychopathology and to promote the translation of such work into preventive interventions. PMID- 26439056 TI - Externalizing symptoms, effortful control, and intrusive parenting: A test of bidirectional longitudinal relations during early childhood. AB - At approximately 30, 42, and 54 months of age (N = 231), the relations among children's externalizing symptoms, intrusive maternal parenting, and children's effortful control (EC) were examined. Both intrusive parenting and low EC have been related to psychopathology, but children's externalizing problems and low EC might affect the quality of parenting and one another. Mothers' intrusive behavior with their children was assessed with observations, children's EC was measured with mothers' and caregivers' reports, and children's externalizing symptoms were assessed with mothers', fathers', and caregivers' reports. In a structural equation panel model, bidirectional relations between intrusive parenting and EC were found: EC at 30 and 42 months predicted low levels of intrusive parenting a year later, controlling for prior levels of parenting and vice versa. Moreover, high levels of children's externalizing problems at both 30 and 42 months negatively predicted EC a year later, controlling for prior levels of EC. Although externalizing problems positively predicted high EC over time, this appeared to be a suppression effect because these variables had a strong negative pattern in the zero-order correlations. Moreover, when controlling for the stability of intrusive parenting, EC, and externalizing (all exhibited significant stability across time) and the aforementioned cross-lagged predictive paths, EC and externalizing problems were still negatively related within the 54 month assessment. The findings are consistent with the view that children's externalizing behavior undermines their EC and contributes to intrusive mothering and that relations between intrusive parenting and EC are bidirectional across time. Thus, interventions that focus on modifying children's externalizing problems (as well as the quality of parenting) might affect the quality of parenting they receive and, hence, subsequent problems with adjustment. PMID- 26439057 TI - The impact of children's internalizing and externalizing problems on parenting: Transactional processes and reciprocal change over time. AB - Most theoretical models of developmental psychopathology involve a transactional, bidirectional relation between parenting and children's behavior problems. The present study utilized a cross-lagged panel, multiple interval design to model change in bidirectional relations between child and parent behavior across successive developmental periods. Two major categories of child behavior problems, internalizing and externalizing, and two aspects of parenting, positive (use of support and structure) and harsh discipline (use of physical punishment), were modeled across three time points spaced 3 years apart. Two successive developmental intervals, from approximately age 7.5 to 10.5 and from 10.5 to 13.5, were included. Mother-child dyads (N = 138; 65 boys) from a lower income longitudinal sample of families participated, with standardized measures of mothers rating their own parenting behavior and teachers reporting on child's behavior. Results revealed different types of reciprocal relations between specific aspects of child and parent behavior, with internalizing problems predicting an increase in positive parenting over time, which subsequently led to a reduction in internalizing problems across the successive 3-year interval. In contrast, externalizing predicted reduced levels of positive parenting in a reciprocal sequence that extended across two successive intervals and predicted increased levels of externalizing over time. Implications for prevention and early intervention are discussed. PMID- 26439059 TI - Mutual influences between child emotion regulation and parent-child reciprocity support development across the first 10 years of life: Implications for developmental psychopathology. AB - Elucidating the mechanisms by which infant birth conditions shape development across lengthy periods is critical for understanding typical and pathological development and for targeted early interventions. This study examined how newborns' regulatory capacities impact 10-year outcomes via the bidirectional influences of child emotion regulation (ER) and reciprocal parenting across early development. Guided by dynamic systems theory, 125 infants were tested at seven time points: birth, 3, 6, 12, and 24 months and 5 and 10 years. Initial regulatory conditions were measured by respiratory sinus arrhythmia (RSA; vagal tone) and neurobehavioral regulation (Brazelton, 1973) at birth. At each assessment between 3 months and 5 years, infant ER was microcoded from age appropriate paradigms and mother-child reciprocity observed during social interactions. Four regulation-related outcomes were measured at 10 years: child RSA, empathy measured by mother-child conflict discussion and a lab paradigm, accident proneness, and behavior problems. An autoregressive cross-lagged structural model indicated that infant birth conditions impacted 10-year outcomes via three mechanisms. First, child ER and reciprocal parenting were individually stable across development and were each predicted by regulatory birth conditions, describing gradual maturation of ER and reciprocity over time. Second, better ER skills at one time point were related to greater reciprocity at the next time point and vice versa, and these cross-time effects defined a field of individual context mutual influences that mediated the links between neonatal RSA and 10 year outcomes. Third, direct associations emerged between neonatal regulation and outcome, suggesting that birth conditions may establish a neurobiological milieu that promotes a more mature and resilient system. These mechanisms describe distinct "attractor" states that constrain the system's future options, emphasize the importance of defining behavior-based phenotypes of heterotypic continuity, and suggest that infants may shape their development by initiating unique cascades of individual-context bidirectional effects. PMID- 26439058 TI - (Positive) power to the child: The role of children's willing stance toward parents in developmental cascades from toddler age to early preadolescence. AB - In a change from the once-dominant view of children as passive in the parent-led process of socialization, children are now seen as active agents who can considerably influence that process. However, these newer perspectives typically focus on the child's antagonistic influence, due either to a difficult temperament or aversive, resistant, negative behaviors that elicit adversarial responses from the parent and lead to future coercive cascades in the relationship. Children's capacity to act as receptive, willing, even enthusiastic, active socialization agents is largely overlooked. Informed by attachment theory and other relational perspectives, we depict children as able to adopt an active willing stance and to exert robust positive influence in the mutually cooperative socialization enterprise. A longitudinal study of 100 community families (mothers, fathers, and children) demonstrates that willing stance (a) is a latent construct, observable in diverse parent-child contexts, parallel at 38, 52, and 67 months and longitudinally stable; (b) originates within an early secure parent-child relationship at 25 months; and (c) promotes a positive future cascade toward adaptive outcomes at age 10. The outcomes include the parent's observed and child-reported positive, responsive behavior, as well as child-reported internal obligation to obey the parent and parent-reported low level of child behavior problems. The construct of willing stance has implications for basic research in typical socialization and in developmental psychopathology as well as for prevention and intervention. PMID- 26439061 TI - Stability and change in resolution of diagnosis among parents of children with autism spectrum disorder: Child and parental contributions. AB - The contribution of change over time in parent and child characteristics to parents' resolution of child's diagnosis was examined among 78 mothers and fathers of children with autism spectrum disorder. Children's characteristics (e.g., mental age and severity of symptoms), parental characteristics (e.g., attachment-related anxiety and stress level), and parents' resolution of their child's diagnosis (resolved vs. unresolved) were examined at Time 1, and reassessed 3 years later at Time 2. Results indicated a deferential contribution of change in parent and child characteristics among mothers and fathers. An increase in child symptom severity and in maternal attachment-related anxiety, as well as longer durations of time since receiving the diagnosis, significantly predicted maternal resolved status at Time 2. Conversely, none of the changes in children's or paternal characteristics predicted paternal resolved status at Time 2. Results are discussed in relation to child and parental contributions to resolution, the differences in the adjustment and well-being of mothers and fathers of children with autism spectrum disorder, parental growth following receiving the diagnosis, and the need for intervention components specific to parental resolution and attachment-related anxiety. PMID- 26439062 TI - Child effects and child care: Implications for risk and adjustment. AB - Evocative effects of child characteristics on the quality and quantity of child care were assessed in two studies using longitudinal data from the NICHD Study of Early Child Care. We focus on the influence of child characteristics on two important aspects of the child care experience: language stimulation provided by caregivers and quantity of care. In Study 1, associations between the developmental status of children aged 15 to 54 months and the language stimulation provided by their caregivers were examined using path models, and longitudinal child effects were detected across the earliest time points of the study. In Study 2, the associations among child behavior, temperament, development, and time in care were examined. Little evidence was found for such child effects on time in care. The results are discussed in terms of the effects of child care on child development and implications for developmental processes, particularly for children at greatest risk for developmental delay or psychopathology. PMID- 26439063 TI - Violent peer influence: The roles of self-esteem and psychopathic traits. AB - Evidence for the risks of psychopathic personality traits for adolescent antisocial behavior are well documented in the literature. Little is known, however, about who the peers of adolescents with these traits are and to what extent they influence one another. In the current study, three dimensions of psychopathic traits were distinguished: grandiose-manipulative traits, callous unemotional traits, and impulsive-irresponsible traits. A dynamic social network approach was used with three waves of longitudinal data from 1,772 adolescents (51.1% girls, M age = 13.03 at first measurement). Results showed that adolescents with grandiose-manipulative and callous-unemotional traits formed peer relationships with adolescents who had low self-esteem. Furthermore, peers' violence predicted stronger increases in violence for adolescents with low self esteem than for other adolescents, and peers' violence predicted stronger increases in adolescent violence for peers with high psychopathic traits than for other peers. Thus, findings indicate that adolescents with low self-esteem are vulnerable to deviant peer influence from peers with psychopathic traits. PMID- 26439060 TI - Adolescents', mothers', and fathers' gendered coping strategies during conflict: Youth and parent influences on conflict resolution and psychopathology. AB - We observed gendered coping strategies and conflict resolution outcomes used by adolescents and parents during a conflict discussion task to evaluate associations with current and later adolescent psychopathology. We studied 137 middle- to upper-middle-class, predominantly Caucasian families of adolescents (aged 11-16 years, 65 males) who represented a range of psychological functioning, including normative, subclinical, and clinical levels of problems. Adolescent coping strategies played key roles both in the extent to which parent adolescent dyads resolved conflict and in the trajectory of psychopathology symptom severity over a 2-year period. Gender-prototypic adaptive coping strategies were observed in parents but not youth, (i.e., more problem solving by fathers than mothers and more regulated emotion-focused coping by mothers than fathers). Youth-mother dyads more often achieved full resolution of conflict than youth-father dyads. There were generally not bidirectional effects among youth and parents' coping across the discussion except boys' initial use of angry/hostile coping predicted fathers' angry/hostile coping. The child was more influential than the parent on conflict resolution. This extended to exacerbation/alleviation of psychopathology over 2 years: higher conflict resolution mediated the association of adolescents' use of problem-focused coping with decreases in symptom severity over time. Lower conflict resolution mediated the association of adolescents' use of angry/hostile emotion coping with increases in symptom severity over time. Implications of findings are considered within a broadened context of the nature of coping and conflict resolution in youth-parent interactions, as well as on how these processes impact youth well being and dysfunction over time. PMID- 26439064 TI - Temperament and peer problems from early to middle childhood: Gene-environment correlations with negative emotionality and sociability. AB - Based in a transactional framework in which children's own characteristics and the social environment influence each other to produce individual differences in social adjustment, we investigated relationships between children's peer problems and their temperamental characteristics, using a longitudinal and genetically informed study of 939 pairs of Israeli twins followed from early to middle childhood (ages 3, 5, and 6.5). Peer problems were moderately stable within children over time, such that children who appeared to have more peer problems at age 3 tended to have also more peer problems at age 6.5. Children's temperament accounted for 10%-22% of the variance in their peer problems measured at the same age and for 2%-7% of the variance longitudinally. It is important that genetic factors accounted for the association between temperament and peer problems and were in line with a gene-environment correlation process, providing support for the proposal that biologically predisposed characteristics, particularly negative emotionality and sociability, have an influence on children's early experiences of peer problems. The results highlight the need for early and continuous interventions that are specifically tailored to address the interpersonal difficulties of children with particular temperamental profiles. PMID- 26439065 TI - Social and economic antecedents and consequences of adolescent aggressive personality: Predictions from the interactionist model. AB - The present study examined the development of a cohort of 279 early adolescents (52% female) from 1990 to 2005. Guided by the interactionist model of socioeconomic status and human development, we proposed that parent aggressive personality, economic circumstances, interparental conflict, and parenting characteristics would affect the development of adolescent aggressive personality traits. In turn, we hypothesized that adolescent aggressiveness would have a negative influence on adolescent functioning as an adult in terms of economic success, personality development, and close relationships 11 years later. Findings were generally supportive of the interactionist model proposition that social and economic difficulties in the family of origin intensify risk for adolescent aggressive personality (the social causation hypothesis) and that this personality trait impairs successful transition to adult roles (the social selection hypothesis) in a transactional process over time and generations. These results underscore how early development leads to child influences that appear to directly hamper the successful transition to adult roles (statistical main effects) and also amplify the negative impact of dysfunctional family systems on the transition to adulthood (statistical interaction effects). The findings suggest several possible points of intervention that might help to disrupt this negative developmental sequence of events. PMID- 26439066 TI - Take your mind off it: Coping style, serotonin transporter linked polymorphic region genotype (5-HTTLPR), and children's internalizing and externalizing problems. AB - Individuals with the short variant of the serotonin transporter linked polymorphic region gene are more susceptible than individuals homozygous for the long allele to the effects of stressful life events on risk for internalizing and externalizing problems. We tested whether individual differences in coping style explained this increased risk for problem behavior among youth who were at both genetic and environmental risk. Participants included 279 children, ages 8-11, from the Children's Experiences and Development Study. Caregivers and teachers reported on children's internalizing and externalizing symptoms, and caregivers and children on children's exposure to harsh parenting and parental warmth in middle childhood, and traumatic events. Children reported how frequently they used various coping strategies. Results revealed that short/short homozygotes had higher levels of internalizing problems compared with long allele carriers and that short allele carriers had higher levels of externalizing problems compared with long/long homozygotes under conditions of high cumulative risk. Moreover, among children who were homozygous for the short allele, those who had more cumulative risk indicators less frequently used distraction coping strategies, which partly explained why they had higher levels of internalizing problems. Coping strategies did not significantly mediate Gene * Environment effects on externalizing symptoms. PMID- 26439068 TI - Emergent patterns of risk for psychopathology: The influence of infant avoidance and maternal caregiving on trajectories of social reticence. AB - The current study investigated the influential role of infant avoidance on links between maternal caregiving behavior and trajectories at risk for psychopathology. A sample of 153 children, selected for temperamental reactivity to novelty, was followed from infancy through early childhood. At 9 months, infant avoidance of fear-eliciting stimuli in the laboratory and maternal sensitivity at home were assessed. At 36 months, maternal gentle discipline was assessed at home. Children were repeatedly observed in the lab with an unfamiliar peer across early childhood. A latent class growth analysis yielded three longitudinal risk trajectories of social reticence behavior: a high-stable trajectory, a high-decreasing trajectory, and a low-increasing trajectory. For infants displaying greater avoidance, 9-month maternal sensitivity and 36-month maternal gentle discipline were both positively associated with membership in the high-stable social reticence trajectory, compared to the high-decreasing social reticence trajectory. For infants displaying lower avoidance, maternal sensitivity was positively associated with membership in the high-decreasing social reticence trajectory, compared to the low-increasing trajectory. Maternal sensitivity was positively associated with the high-stable social reticence trajectory when maternal gentle discipline was lower. These results illustrate the complex interplay of infant and maternal behavior in early childhood trajectories at risk for emerging psychopathology. PMID- 26439069 TI - Child fear reactivity and sex as moderators of links between parenting and preschool behavior problems. AB - Reduced supportive parenting and elevated negative parenting behaviors increase risks for maladaptive social adjustment during early childhood (e.g., Campbell, Shaw, & Gilliom, 2000). However, the magnitude of these risks may vary according to children's individual characteristics, such as sex and temperament. The current study examines whether children's sex and fear reactivity moderate the associations between mothers' observed parenting and children's behavior problems 1 year later. The sample consists of 151 predominantly African American, low income families with one sibling who is approximately 2 years old and the closest aged older sibling who is approximately 4 years old. Results from fixed-effects within-family models indicate that fear distress (i.e., fearfulness) moderated associations between mothers' observed negative parenting and children's increased behavior problems, such that only those children with mean or higher observed fear distress scores showed increased behavior problems when exposed to mother's negative parenting. Child sex moderated associations between fear approach reactivity (i.e., fearlessness) and mothers' observed supportive parenting. Specifically, low fear approach combined with supportive parenting was associated with fewer behavior problems for boys only. Implications of these findings for preventive intervention are discussed. PMID- 26439070 TI - Infant negative reactivity defines the effects of parent-child synchrony on physiological and behavioral regulation of social stress. AB - How infants shape their own development has puzzled developmentalists for decades. Recent models suggest that infant dispositions, particularly negative reactivity and regulation, affect outcome by determining the extent of parental effects. Here, we used a microanalytic experimental approach and proposed that infants with varying levels of negative reactivity will be differentially impacted by parent-infant synchrony in predicting physiological and behavioral regulation of increasing social stress during an experimental paradigm. One hundred and twenty-two mother-infant dyads (4-6 months) were observed in the face to-face still face (SF) paradigm and randomly assigned to three experimental conditions: SF with touch, standard SF, and SF with arms' restraint. Mother infant synchrony and infant negative reactivity were observed at baseline, and three mechanisms of behavior regulation were microcoded; distress, disengagement, and social regulation. Respiratory sinus arrhythmia baseline, reactivity, and recovery were quantified. Structural equation modeling provided support for our hypothesis. For physiological regulation, infants high in negative reactivity receiving high mother-infant synchrony showed greater vagal withdrawal, which in turn predicted comparable levels of vagal recovery to that of nonreactive infants. In behavioral regulation, only infants low in negative reactivity who received high synchrony were able to regulate stress by employing social engagement cues during the SF phase. Distress was reduced only among calm infants to highly synchronous mothers, and disengagement was lowest among highly reactive infants experiencing high mother-infant synchrony. Findings chart two pathways by which synchrony may bolster regulation in infants of high and low reactivity. Among low reactive infants, synchrony builds a social repertoire for handling interpersonal stress, whereas in highly reactive infants, it constructs a platform for repeated reparation of momentary interactive "failures" and reduces the natural tendency of stressed infants to disengage from source of distress. Implications for the construction of synchrony-focused interventions targeting infants of varying dispositions are discussed. PMID- 26439067 TI - The interplay of birth weight, dopamine receptor D4 gene (DRD4), and early maternal care in the prediction of disorganized attachment at 36 months of age. AB - Disorganized attachment is an important early risk factor for socioemotional problems throughout childhood and into adulthood. Prevailing models of the etiology of disorganized attachment emphasize the role of highly dysfunctional parenting, to the exclusion of complex models examining the interplay of child and parental factors. Decades of research have established that extreme child birth weight may have long-term effects on developmental processes. These effects are typically negative, but this is not always the case. Recent studies have also identified the dopamine D4 receptor (DRD4) as a moderator of childrearing effects on the development of disorganized attachment. However, there are inconsistent findings concerning which variant of the polymorphism (seven-repeat long-form allele or non-seven-repeat short-form allele) is most likely to interact with caregiving in predicting disorganized versus organized attachment. In this study, we examined possible two- and three-way interactions and child DRD4 polymorphisms and birth weight and maternal caregiving at age 6 months in longitudinally predicting attachment disorganization at 36 months. Our sample is from the Maternal Adversity, Vulnerability and Neurodevelopment project, a sample of 650 mother-child dyads. Birth weight was cross-referenced with normative data to calculate birth weight percentile. Infant DRD4 was obtained with buccal swabs and categorized according to the presence of the putative allele seven repeat. Macroanalytic and microanalytic measures of maternal behavior were extracted from a videotaped session of 20 min of nonfeeding interaction followed by a 10-min divided attention maternal task at 6 months. Attachment was assessed at 36 months using the Strange Situation procedure, and categorized into disorganized attachment and others. The results indicated that a main effect for DRD4 and a two-way interaction of birth weight and 6-month maternal attention (frequency of maternal looking away behavior) and sensitivity predicted disorganized attachment in robust logistic regression models adjusted for social demographic covariates. Specifically, children in the midrange of birth weight were more likely to develop a disorganized attachment when exposed to less attentive maternal care. However, the association reversed with extreme birth weight (low and high). The DRD4 seven-repeat allele was associated with less disorganized attachment (protective), while non-seven-repeat children were more likely to be classified as disorganized attachment. The implications for understanding inconsistencies in the literature about which DRD4 genotype is the risk direction are also considered. Suggestions for intervention with families with infants at different levels of biological risk and caregiving risk are also discussed. PMID- 26439071 TI - The association of temperament and maternal empathy with individual differences in infants' neural responses to emotional body expressions. AB - We examined the role of infant temperament and maternal dispositional empathy in the neural processing of happy and fearful emotional body expressions in 8-month old infants by measuring event-related brain potentials. Our results revealed that infants' tendency to approach novel objects and people was positively correlated with the neural sensitivity (attention allocation) to fearful expressions, while infant fearfulness was negatively correlated to the neural sensitivity to fearful expressions. Maternal empathic concern was associated with infants' neural discrimination between happy and fearful expression, with infants of more empathetically concerned mothers showing greater neural sensitivity (attention allocation) to fearful compared to happy expressions. It is critical that our results also revealed that individual differences in the sensitivity to emotional information are explained by an interaction between infant temperament and maternal empathic concern. Specifically, maternal empathy appears to impact infants' neural responses to emotional body expressions, depending on infant fearfulness. These findings support the notion that the way in which infants respond to emotional signals in the environment is fundamentally linked to their temperament and maternal empathic traits. This adds an early developmental neuroscience dimension to existing accounts of social-emotional functioning, suggesting a complex and integrative picture of why and how infants' emotional sensitivity varies. PMID- 26439072 TI - Emerging psychopathology moderates upward social mobility: The intergenerational (dis)continuity of socioeconomic status. AB - Socioeconomic status (SES) is relatively stable across generations, but social policies may create opportunities for upward social mobility among disadvantaged populations during periods of economic growth. With respect to expanded educational opportunities that occurred in Quebec (Canada) during the 1960s, we hypothesized that children's social and academic competence would promote upward mobility, whereas aggression and social withdrawal would have the opposite effect. Out of 4,109 children attending low-SES schools in 1976-1978, a representative subsample of 503 participants were followed until midadulthood. Path analyses revealed that parents' SES predicted offspring's SES through associations with offspring's likeability, academic competence, and educational attainment. Interaction effects revealed individual risk factors that moderated children's ability to take advantage of intrafamilial or extrafamilial opportunities that could enhance their educational attainment. Highly aggressive participants and those presenting low academic achievement were unable to gain advantage from having highly educated parents. They reached lower educational attainment than their less aggressive or higher achieving peers who came from a similarly advantaged family background. Growing up with parents occupying low prestige jobs put withdrawn boys and outgoing girls at risk for low educational attainment. In conclusion, social policies can raise SES across generations, with great benefits for the most disadvantaged segments of the population. However, children presenting with emerging psychopathology or academic weaknesses do not benefit from these policies as much as others, and should receive additional, targeted services. PMID- 26439073 TI - The effects of violence exposure on the development of impulse control and future orientation across adolescence and early adulthood: Time-specific and generalized effects in a sample of juvenile offenders. AB - Impulse control and future orientation increase across adolescence, but little is known about how contextual factors shape the development of these capacities. The present study investigates how stress exposure, operationalized as exposure to violence, alters the developmental pattern of impulse control and future orientation across adolescence and early adulthood. In a sample of 1,354 serious juvenile offenders, higher exposure to violence was associated with lower levels of future orientation at age 15 and suppressed development of future orientation from ages 15 to 25. Increases in witnessing violence or victimization were linked to declines in impulse control 1 year later, but only during adolescence. Thus, beyond previous experiences of exposure to violence, witnessing violence and victimization during adolescence conveys unique risk for suppressed development of self-regulation. PMID- 26439074 TI - The stability of the feedback negativity and its relationship with depression during childhood and adolescence. AB - Feedback negativity (FN) is an event-related potential elicited by monetary reward and loss; it is thought to relate to reward-related neural activity and has been linked to depression in children and adults. In the current study, we examined the stability of FN, and its relationship with depression in adolescents, over 2 years in 45 8- to 13-year-old children. From Time 1 to Time 2, FN in response to monetary loss and in response to monetary gain showed moderate to strong reliability (rs = .64 and .67, respectively); these relationships remained significant even when accounting for related variables. FN also demonstrated high within-session reliability. Moreover, the relationship between a blunted FN and greater depression observed at Time 1 was reproduced at Time 2, and the magnitude of FN at Time 1 predicted depressive symptomatology at Time 2. These findings are consistent with the hypothesis that FN and its relationship with depression remain consistent over the course of development, and that FN may prospectively predict later depressive symptomatology. The current results suggest that FN may be suitable as a biomarker of depressive symptoms during adolescence. PMID- 26439075 TI - Identifying early pathways of risk and resilience: The codevelopment of internalizing and externalizing symptoms and the role of harsh parenting. AB - Psychological disorders co-occur often in children, but little has been done to document the types of conjoint pathways internalizing and externalizing symptoms may take from the crucial early period of toddlerhood or how harsh parenting may overlap with early symptom codevelopment. To examine symptom codevelopment trajectories, we identified latent classes of individuals based on internalizing and externalizing symptoms across ages 3-9 and found three symptom codevelopment classes: normative symptoms (low), severe-decreasing symptoms (initially high but rapidly declining), and severe symptoms (high) trajectories. Next, joint models examined how parenting trajectories overlapped with internalizing and externalizing symptom trajectories. These trajectory classes demonstrated that, normatively, harsh parenting increased after toddlerhood, but the severe symptoms class was characterized by a higher level and a steeper increase in harsh parenting and the severe-decreasing class by high, stable harsh parenting. In addition, a transactional model examined the bidirectional relationships among internalizing and externalizing symptoms and harsh parenting because they may cascade over time in this early period. Harsh parenting uniquely contributed to externalizing symptoms, controlling for internalizing symptoms, but not vice versa. In addition, internalizing symptoms appeared to be a mechanism by which externalizing symptoms increase. Results highlight the importance of accounting for both internalizing and externalizing symptoms from an early age to understand risk for developing psychopathology and the role harsh parenting plays in influencing these trajectories. PMID- 26439076 TI - Genetic covariance between psychopathic traits and anticipatory skin conductance responses to threat: Evidence for a potential endophenotype. AB - The genetic architecture of the association between psychopathic traits and reduced skin conductance responses (SCRs) is poorly understood. By using 752 twins aged 9-10 years, this study investigated the heritability of two SCR measures (anticipatory SCRs to impending aversive stimuli and unconditioned SCRs to the aversive stimuli themselves) in a countdown task. The study also investigated the genetic and environmental sources of the covariance between these SCR measures and two psychopathic personality traits: impulsive/disinhibited (reflecting impulsive-antisocial tendencies) and manipulative/deceitful (reflecting the affective-interpersonal features). For anticipatory SCRs, 27%, 14%, and 59% of the variation was due to genetic, shared environmental, and nonshared environmental effects, respectively, while the percentages for unconditioned SCRs were 44%, 2%, and 54%. The manipulative/deceitful (not impulsive/disinhibited) traits were negatively associated with both anticipatory SCRs (r = -.14, p < .05) and unconditioned SCRs (r = -.17, p < .05) in males only, with the former association significantly accounted for by genetic influences (r g = -.72). Reduced anticipatory SCRs represent a candidate endophenotype for the affective-interpersonal facets of psychopathic traits in males. PMID- 26439078 TI - Pubertal maturation and affective symptoms in adolescence and adulthood: Evidence from a prospective birth cohort. AB - The higher prevalence of affective symptoms among women compared to men emerges in adolescence, and it has been associated with pubertal maturation. However, it remains unclear whether pubertal timing has long-term influences on affective symptoms. Using data from the British 1946 birth cohort, we investigated whether pubertal timing was associated with affective symptoms over the life course, distinguishing those with symptoms in adolescence only, symptoms in adulthood only, and symptoms in both adolescence and adulthood. In females, there was no evidence that early pubertal maturation was a risk factor for affective symptoms. However, those with particularly late menarche (>=15 years) showed a lower risk of adult-onset affective symptoms (odds ratio = 0.54, 95% confidence interval = 0.31, 0.95). This effect of late pubertal timing was not explained by a range of sociobehavioral factors. In contrast, in males, late pubertal timing was associated with increased risk of adolescent-onset affective symptoms that tracked into adulthood (odds ratio = 2.10, 95% confidence interval = 1.44, 3.06). This effect was partly explained by low prepubertal body mass index. Sex-specific effects of pubertal timing on the long-term risk of affective symptoms might be due to different effects of gonadal hormonal on the central nervous system, as well as different social experiences during puberty. PMID- 26439077 TI - Childhood dyspraxia predicts adult-onset nonaffective-psychosis-spectrum disorder. AB - Several neurological variables have been investigated as premorbid biomarkers of vulnerability for schizophrenia and other related disorders. The current study examined whether childhood dyspraxia predicted later adult nonaffective-psychosis spectrum disorders. From a standardized neurological examination performed with children (aged 10-13) at genetic high risk of schizophrenia and controls, several measures of dyspraxia were used to create a scale composed of face/head dyspraxia, oral articulation, ideomotor dyspraxia (clumsiness), and dressing dyspraxia (n = 244). Multinomial logistic regression showed higher scores on the dyspraxia scale predict nonaffective-psychosis-spectrum disorders relative to other psychiatric disorders and no mental illness outcomes, even after controlling for genetic risk, chi2 (4, 244) = 18.61, p < .001. Findings that symptoms of dyspraxia in childhood (reflecting abnormalities spanning functionally distinct brain networks) specifically predict adult nonaffective psychosis-spectrum disorders are consistent with a theory of abnormal connectivity, and they highlight a marked early-stage vulnerability in the pathophysiology of nonaffective-psychosis-spectrum disorders. PMID- 26439079 TI - Variability in diurnal testosterone, exposure to violence, and antisocial behavior in young adolescents. AB - The purpose of this report is to provide evidence of an association between within-person variability in diurnal testosterone over 1 year, lifetime exposure to violence, and the manifestation of antisocial behavior in 135 pubertal-aged adolescents across 1 year. Adolescents' sex and lifetime history of violence exposure moderated the association between within-person variability in diurnal testosterone and antisocial behavior. Furthermore, sex-stratified analyses revealed that lifetime history of exposure to violence moderated the association between within-person variability in diurnal testosterone and antisocial behavior in females only. This report is unique in that it illuminates sex differences in within-person associations among exposure to violence, individual variability in diurnal testosterone, and antisocial behavior. PMID- 26439081 TI - The emergence of co-occurring adolescent polysubstance use and depressive symptoms: A latent growth modeling approach. AB - This study tests competing models of the relation between depression and polysubstance use over the course of adolescence. Participants included a nationwide sample of adolescents (N = 3,604), ages 12 to 17 at study Wave 1, assessed annually for 3 years. Models were tested using cohort-sequential latent growth curve modeling to determine whether depressive symptoms at baseline predicted concurrent and age-related changes in drug use, whether drug use at baseline predicted concurrent and age-related changes in depressive symptoms, and whether initial levels of depression predicted changes in substance use significantly better than vice versa. The results suggest a transactional model such that early polysubstance use promotes early depressive symptoms, which in turn convey elevated risk for increasing polysubstance use over time, which in turn conveys additional risk for future depressive symptoms, even after accounting for gender, ethnicity, and household income. In contrast, early drug use did not portend risk for future depressive symptoms. These findings suggest a complicated pattern of interrelations over time and indicate that many current models of co-occurring polysubstance use and depressive symptoms may not fully account for these associations. Instead, the results suggest a developmental cascade, in which symptoms of one disorder promote symptoms of the other across intrapersonal domains. PMID- 26439082 TI - Synthesis and O2 Reactivity of a Titanium(III) Metal-Organic Framework. AB - Metal-organic frameworks featuring pores lined with exposed metal cations have received attention for a wide range of adsorption-related applications. While many frameworks with coordinatively unsaturated M(II) centers have been reported, there are relatively few examples of porous materials with coordinatively unsaturated M(III) centers. Here, we report the synthesis and characterization of Ti3O(OEt)(bdc)3(solv)2 (Ti-MIL-101; bdc(2-) = 1,4-benzenedicarboxylate; solv = N,N-dimethylformamide, tetrahydrofuran), the first metal-organic framework containing exclusively Ti(III) centers. Through a combination of gas adsorption, X-ray diffraction, magnetic susceptibility, and electronic and vibrational spectroscopy measurements, this high-surface-area framework is shown to contain five-coordinate Ti(III) centers upon desolvation, which irreversibly bind O2 to form titanium(IV) superoxo and peroxo species. Electronic absorption spectra suggest that the five-coordinate Ti(III) sites adopt a distorted trigonal bipyramidal geometry that effectively shields nuclear charge and inhibits strong adsorption of nonredox-active gases. PMID- 26439080 TI - Emotion-based preventive intervention: Effectively promoting emotion knowledge and adaptive behavior among at-risk preschoolers. AB - Effectiveness studies of preschool social-emotional programs are needed in low income, diverse populations to help promote the well-being of at-risk children. Following an initial program efficacy study 2 years prior, 248 culturally diverse Head Start preschool children participated in the current effectiveness trial and received either the Emotion-Based Prevention Program (EBP) or the I Can Problem Solve (ICPS) intervention. Pre- and postdata collection included direct child assessment, teacher report, parent interview, and independent observations. Teachers implementing the EBP intervention demonstrated good and consistent fidelity to the program. Overall, children in EBP classrooms gained more emotion knowledge and displayed greater decreases in negative emotion expressions and internalizing behaviors across the implementation period as compared to children in ICPS classrooms. In addition, cumulative risk, parental depressive symptoms, and classroom climate significantly moderated treatment effects. For children experiencing more stress or less support, EBP produced more successful outcomes than did ICPS. These results provide evidence of EBP sustainability and program effectiveness, as did previous findings that demonstrated EBP improvements in emotion knowledge, regulation skills, and behavior problems replicated under unsupervised program conditions. PMID- 26439083 TI - Multiple glacial refugia for cool-temperate deciduous trees in northern East Asia: the Mongolian oak as a case study. AB - In East Asia, temperate forests are predicted to have retracted southward to c. 30 degrees N during the last glacial maximum (LGM) based on fossil pollen data, whereas phylogeographic studies have often suggested glacial in situ survival of cool-temperate deciduous trees in their modern northern ranges. Here we report a study of the genetic diversity and structure of 29 natural Mongolian oak (Quercus mongolica) populations using 19 nuclear simple sequence repeat (nSSR) loci and four chloroplast DNA fragments. Bayesian clustering analysis with nSSRs revealed five groups, which were inferred by approximate Bayesian computation (ABC) to have diverged in multiple refugia through multiple glacial-interglacial cycles. Analysis of chloroplast DNA variation revealed four lineages that were largely but incompletely geographically disjunct. Ecological niche modelling (ENMs) indicated a southward range shift of the oak's distribution at the LGM, although high suitability scores were also evident in the Changbai Mts. (Northeast China), the Korean Peninsula, areas surrounding the Bohai Sea, and along the coast of the Russian Far East. In addition, endemic chloroplast DNA haplotypes and nuclear lineages occurred in high-latitude northern areas where the ENM predicted no suitable habitat. The combined evidence from nuclear and chloroplast DNA, and the results of the ENM clearly demonstrate that multiple northern refugia, including cryptic ones, were maintained across the current distributional range of the Mongolian oak during the LGM or earlier glacial periods. Though spatially limited, postglacial expansions from these refugia have led to a pattern of decreased genetic diversity with increasing latitude. PMID- 26439084 TI - Drug-induced liver injury associated with Stevens-Johnson syndrome/toxic epidermal necrolysis: Patient characteristics, causes, and outcome in 36 cases. AB - The liver and skin are the organs most commonly involved in serious adverse drug reactions. Rarely a drug reaction can affect both organs concurrently. The association of drug-induced liver injury (DILI) and Stevens-Johnson syndrome (SJS) or toxic epidermal necrosis (TEN) is even rarer and not well studied. We describe our experience of DILI occurring in association with SJS/TEN including the etiologic agents, clinical and biochemical characteristics, and outcome. We identified patients who developed DILI in association with SJS/TEN from a registry of DILI patients from a single center. Causality assessment for DILI and SJS/TEN was carried out with the Roussel Uclaf Causality Assessment Method and the Algorithm for Drug Causality for Epidermal Necrolysis, respectively. Among 748 consecutive patients with DILI from 1997 to March 2015, 36 (4.8%) had associated features of SJS/TEN. The mean age was 32 years (females 19). Children and patients with human immunodeficiency virus constituted 25% (n = 9) and 22% (n = 8), respectively. Only a small number of "high-risk" drugs such as antiepileptic agents, sulfonamides, and antiretroviral drugs accounted for the majority of cases. Overall mortality was 36% (n = 13), which rose to 45.5% in the presence of jaundice. Mortality was less in children 11% (n = 1) and human immunodeficiency virus patients 12.5% (n = 1). CONCLUSIONS: DILI associated with SJS/TEN is rare and associated with a high death rate, particularly in those with jaundice; however, children and human immunodeficiency virus-infected individuals have a favorable outcome; a small group of drugs contributed to a disproportionate number of cases, and causality with Roussel Uclaf Causality Assessment Method and the Algorithm for Drug Causality for Epidermal Necrolysis was highly probable or probable in all cases. PMID- 26439086 TI - True Blood: dengue virus evolution. AB - This month's Genome Watch highlights insights into different selection pressures in dengue virus evolution. PMID- 26439087 TI - Possible Role of Phthalate in the Pathogenesis of Endometriosis: In Vitro, Animal, and Human Data. AB - CONTEXT: Although phthalates were shown to have several negative effects on reproductive function in animals, its role in the pathogenesis of endometriosis remains to be elucidated. OBJECTIVE: We aimed to investigate the in vitro and in vivo effects of di-(2-ethylhexyl)-phthalate (DEHP) and to compare the urinary levels of several phthalate metabolites between women with and without endometriosis. DESIGN: For experimental studies, we used endometrial cell culture and nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse models. We also performed a prospective case-control study for human sample analyses. SETTING: The study was conducted at an academic center. MAIN OUTCOME MEASURES: The activities of matrix metalloproteinase (MMP)-2 and 9, cellular invasiveness, phosphorylation of extracellular signal-regulated kinase (Erk), and expression of p21-activated kinase 4 were analyzed in endometrial cells treated with DEHP. The implant size was compared between NOD/SCID mice fed with and without DEHP. Urinary concentrations of several phthalate metabolites were compared between women with and without endometriosis. RESULTS: In vitro treatment of endometrial cells with DEHP led to significant increases of MMP-2 and 9 activities, cellular invasiveness, Erk phosphorylation, and p21-activated kinase 4 expression. The size of the endometrial implant was significantly larger in the NOD/SCID mice fed with DEHP compared with those fed with vehicle. The urinary concentration of mono (2-ethyl-5-hydroxyhexyl) phthalate, mono (2-ethyl-5-oxohexyl) phthalate, and mono (2-ethyl-5-carboxyphentyl) phthalate were significantly higher in women with endometriosis compared with controls. CONCLUSION: These findings strongly suggest that exposure to phthalate may lead to establishment of endometriosis by enhancing invasive and proliferative activities of endometrial cells. PMID- 26439089 TI - Strong quantum confinement effect and reduced Frohlich exciton-phonon coupling in ZnO quantum dots embedded inside a SiO2 matrix. AB - ZnO quantum dots (QDs) embedded in an amorphous SiO2 matrix were examined in depth by using variable-temperature photoluminescence (PL) and optical reflectance spectroscopies. Compared with ZnO bulk crystals, ZnO quantum dots with an average size of 4 nm exhibit a strong quantum confinement effect, evidenced by a large blue shift in both PL and reflectance peaks of excitons. More interestingly, a remarkably reduced long-range Frohlich interaction was revealed in ZnO QDs. These fascinating effects may make ZnO QDs a very appealing system in the fields of optoelectronics and others. PMID- 26439088 TI - The Genetic Variant I148M in PNPLA3 Is Associated With Increased Hepatic Retinyl Palmitate Storage in Humans. AB - CONTEXT: Previous studies revealed that the common sequence variant I148M in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is associated with liver fat content and liver diseases, but not with insulin resistance. Recent data suggest that the PNPLA3 I148M variant has reduced retinyl-palmitate lipase activity in hepatic stellate cells. OBJECTIVE: We hypothesized that the PNPLA3 I148M variant is associated with elevated retinyl-palmitate storage in human liver as a potential link to the clinical pathology. Design/Setting and Participants: Using HPLC, we quantified the retinoid metabolites in liver tissue extracts obtained from 42 human subjects, including 13 heterozygous and six homozygous carriers of the minor PNPLA3 I148M variant. MAIN OUTCOME MEASURE: Retinyl-palmitate is elevated in human livers of homozygous PNPLA3 I148M allele carriers Results: The PNPLA3 I148M variant was associated with a significant increase (1.4-fold) in liver fat. The content of retinyl-palmitate was elevated and the ratio of retinol/retinyl-palmitate was reduced in liver extracts obtained from homozygous PNPLA3 I148M minor allele carriers. In a multivariate model including liver fat content, these differences remained significant independent of liver fat content. The content of the minor retinyl-fatty acid esters was similarly increased in homozygous PNPLA3 I148M carriers. CONCLUSIONS: The increased content of hepatic retinyl-palmitate and the reduced ratio of retinol/retinyl-palmitate in PNPLA3 I148M minor allele carriers support in vitro findings of an altered retinyl-palmitate lipase activity. Our results indicate that the PNPLA3 I148M variant is relevant for the retinyl-palmitate content in human liver, providing a possible link to chronic liver disease. PMID- 26439085 TI - Filovirus pathogenesis and immune evasion: insights from Ebola virus and Marburg virus. AB - Ebola viruses and Marburg viruses, members of the filovirus family, are zoonotic pathogens that cause severe disease in people, as highlighted by the latest Ebola virus epidemic in West Africa. Filovirus disease is characterized by uncontrolled virus replication and the activation of host responses that contribute to pathogenesis. Underlying these phenomena is the potent suppression of host innate antiviral responses, particularly the type I interferon response, by viral proteins, which allows high levels of viral replication. In this Review, we describe the mechanisms used by filoviruses to block host innate immunity and discuss the links between immune evasion and filovirus pathogenesis. PMID- 26439090 TI - Late-onset arterial hemorrhage mimicking pseudoaneurysm after living donor liver transplantation. PMID- 26439091 TI - Helical Polybissilsesquioxane Bundles Prepared Using a Self-Templating Approach. AB - Polybissilsesquioxanes with single-handed helical morphologies attracted much attention during the last decade, which could be applied as asymmetric catalysts and chiral stationary phases. Herein, a pair of chiral biphenylene-bridged bissilsesquioxanes were synthesized. They self-assembled into helical bundles in ethanol, behavior that was confirmed in field emission scanning electron microscopy images. Circular dichroism analysis indicated that the biphenylene groups twisted in a single-handed fashion. Single-handed helical polybissilsesquioxane bundles were prepared via polycondensation of the bissilsesquioxanes, using a self-templating approach. Because of the shrinkage that occurred during polycondensation, the helical pitches of the bundles were shorter than those of their corresponding organic self-assemblies. The wide-angle X-ray diffraction pattern indicated that there were no pi-pi interactions among the diphenylene groups. The circular dichroism spectra indicated that the chirality was successfully transferred from the bissilsesquioxane self-assemblies to the polybissilsesquioxane. The polybissilsesquioxanes displayed a capacity for the adsorption of nitrobenzene and had potential application for enantioseparation. PMID- 26439092 TI - Myocyte-specific enhancer binding factor 2A expression is downregulated during temporal lobe epilepsy. AB - Myocyte-specific enhancer binding factor 2A (MEF2A) is a multifunctional nuclear protein that regulates synaptogenesis, dendritic morphogenesis, and neuronal survival. This study aimed to investigate the expression pattern of MEF2A in epileptogenic processes. MEF2A expression was detected in 20 temporal neocortex tissue samples from patients with temporal lobe epilepsy (TLE) and 20 samples from trauma patients without epilepsy by real-time quantitative polymerase chain reaction, immunohistochemistry, double-label immunofluorescent staining, and western blot analysis. In addition, the expression patterns of MEF2A in the hippocampus and adjacent cortex of a lithium-pilocarpine-induced TLE rat model and control rats were examined. MEF2A was found to be expressed in the nuclei of neurons but not in the dendrites of neurons and astrocytes. MEF2A expression was significantly downregulated in temporal neocortex of humans and rats with TLE compared to the control groups. In addition, in the lithium-pilocarpine-induced TLE model, MEF2A expression dynamically decreased within 2 months. Taken together, these data suggest that MEF2A is involved in the pathogenesis of TLE. PMID- 26439093 TI - Superior mesenteric artery thrombosis after abrupt discontinuation of rivaroxaban. AB - We report a case of superior mesenteric artery thrombosis after the abrupt discontinuation of rivaroxaban in a 59-year-old male patient. The initial presentation was of sudden onset abdominal pain, nausea, vomiting, diarrhea, and hematochezia in the setting of recently holding rivaroxaban anticoagulation for an atrial flutter ablative procedure. Imaging revealed thrombosis of the superior mesenteric artery and acute mesenteric ischemia requiring emergent surgical intervention for embolectomy. Upon exploratory laparotomy, the bowel was found to be viable, and an embolectomy with patch angioplasty was successful without complication. This case illustrates the need for emergency medicine clinician familiarity with this possible medication adverse event with rivaroxaban. PMID- 26439094 TI - What do we miss without contrast in patients with flank pain? AB - Flank pain is a common complaint in the emergency department, and the most frequent cause of flank pain is urolithiasis. Spontaneous renal artery dissection and renal artery thrombosis are rare causes of abdominal pain which can result in renal parenchymal injury. They are mostly difficult to diagnose and treat in the emergency setting. The present report describes 2 patients admitted to the emergency department because of acute flank pain who were diagnosed with renal infarction. PMID- 26439095 TI - Impact of the emergency department streaming decision on patients' outcomes. AB - BACKGROUND: Streaming occurs in emergency department (ED) to reduce crowding, but misallocation of patients may impact patients' outcome. AIM: The study aims to determine the outcomes of patients misallocated by the ED process of streaming into likely admission or discharge. METHODS: This is a retrospective cohort study, at an Australian, urban, tertiary referral hospital's ED between January 2010 and March 2012, using propensity score matching for comparison. Total and partitioned ED lengths of stay, inpatient length of stay, in-hospital mortality and 7- and 28-day unplanned readmission rate were compared between patients who were streamed to be admitted against those streamed to be discharged. RESULTS: Total ED length of stay did not differ significantly for admitted patients if allocated to the wrong stream (median 7.6 h, interquartile range 5.7-10.6, cf. 7.5 h, 5.3-11.2; P = 0.34). The median inpatient length of stay was shorter for those initially misallocated to the discharge stream (1.8 days, 1.1-3.0, cf. 2.4 days, 1.4-3.9; P < 0.001). In-hospital mortality and 7- and 28-day readmission rates were not adversely affected by misallocation. When considering patients eventually discharged from the ED, those allocated to the wrong stream stayed in the ED longer than those appropriately allocated (5.2 h, 3.7-7.3, cf. 4.6 h, 3.3 6.4; P < 0.001). CONCLUSION: There were no significant adverse consequences for an admitted patient initially misallocated by an ED admission/discharge streaming process. Patients' discharge from the ED was slower if they had been allocated to the admission stream. Streaming carries few risks for patients misallocated by such a process. PMID- 26439096 TI - Skin Lamellar Bodies are not Discrete Vesicles but Part of a Tubuloreticular Network. AB - Improved knowledge of the topology of lamellar bodies is a prerequisite for a molecular-level understanding of skin barrier formation, which in turn may provide clues as to the underlying causes of barrier-deficient skin disease. The aim of this study was to examine the key question of continuity vs. discreteness of the lamellar body system using 3 highly specialized and complementary 3 dimensional (3D) electron microscopy methodologies; tomography of vitreous sections (TOVIS), freeze-substitution serial section electron tomography (FS SET), and focused ion beam scanning electron microscopy (FIB-SEM) tomography. We present here direct evidence that lamellar bodies are not discrete vesicles, but are part of a tubuloreticular membrane network filling out the cytoplasm and being continuous with the plasma membrane of stratum granulosum cells. This implies that skin barrier formation could be regarded as a membrane folding/unfolding process, but not as a lamellar body fusion process. PMID- 26439097 TI - Hydrogen adsorption on nitrogen and boron doped graphene. AB - Hydrogen adsorption on boron and nitrogen doped graphene is investigated in detail by means of first-principles calculations. A comprehensive study is performed of the structural, electronic, and magnetic properties of chemisorbed hydrogen atoms and atom pairs near the dopant sites. The main effect of the substitutional atoms is charge doping which is found to greatly affect the adsorption process by increasing the binding energy at the sites closest to the substitutional species. It is also found that doping does not induce magnetism despite the odd number of electrons per atom introduced by the foreign species, and that it quenches the paramagnetic response of chemisorbed H atoms on graphene. Overall, the effects are similar for B and N doping, with only minor differences in the adsorption energetics due to different sizes of the dopant atoms and the accompanying lattice distortions. PMID- 26439098 TI - Investigation of Humidity Dependent Surface Morphology and Proton Conduction in Multi-Acid Side Chain Membranes by Conductive Probe Atomic Force Microscopy. AB - In this report, we employ phase-contrast tapping mode and conductive probe atomic force microscopy (cp-AFM) as tools to investigate the nanoscale morphology and proton conductance of a 3M perfluoro-imide acid (PFIA) membrane (625 EW) over a large range of relative humidity (3-95% RH). As a point of comparison, we also investigate 3M perfluorosulfonic acid (PFSA) (825 EW) and Nafion 212. With AFM, we assess the membrane's water retention and mechanical stability at low RH and high RH, respectively. Cp-AFM allows us to spatially resolve the hydrophilic and electrochemically active domains under a similar set of conditions and observe directly the ties between membrane morphology and proton conductance. From our data, we are able to correlate the improved water retention indicated by the size of the hydrophilic domains with the proton conductance in the PFIA membrane at elevated temperature and compare the result with that observed for the PFSA and Nafion. At high RH conditions, we see evidence of a nearly continuous hydrophilic phase, which indicates a high degree of swelling. PMID- 26439100 TI - Microneedles for Transdermal Biosensing: Current Picture and Future Direction. AB - A novel trend is rapidly emerging in the use of microneedles, which are a miniaturized replica of hypodermic needles with length-scales of hundreds of micrometers, aimed at the transdermal biosensing of analytes of clinical interest, e.g., glucose, biomarkers, and others. Transdermal biosensing via microneedles offers remarkable opportunities for moving biosensing technologies and biochips from research laboratories to real-field applications, and envisages easy-to-use point-of-care microdevices with pain-free, minimally invasive, and minimal-training features that are very attractive for both developed and emerging countries. In addition to this, microneedles for transdermal biosensing offer a unique possibility for the development of biochips provided with end effectors for their interaction with the biological system under investigation. Direct and efficient collection of the biological sample to be analyzed will then become feasible in situ at the same length-scale of the other biochip components by minimally trained personnel and in a minimally invasive fashion. This would eliminate the need for blood extraction using hypodermic needles and reduce, in turn, related problems, such as patient infections, sample contaminations, analysis artifacts, etc. The aim here is to provide a thorough and critical analysis of state-of-the-art developments in this novel research trend, and to bridge the gap between microneedles and biosensors. PMID- 26439099 TI - Persistent behavioral effects following early life exposure to retinoic acid or valproic acid in zebrafish. AB - BACKGROUND: Moderate to severe dysregulation in retinoid signaling during early development is associated with a constellation of physical malformations and/or neural tube defects, including spina bifida. It is thought that more subtle dysregulation of this system, which might be achievable via dietary (i.e. hypervitaminosis A) or pharmacological (i.e. valproic acid) exposure in humans, will manifest on behavioral domains including sociability, without overt physical abnormalities. METHODS: During early life, zebrafish were exposed to low doses of two chemicals that disrupt retinoid signaling. From 0 to 5dpf, larvae were reared in aqueous solutions containing retinoic acid (0, 0.02, 0.2 or 2nM) or valproic acid (0, 0.5, 5.0 or 50MUM). One cohort of zebrafish was assessed using a locomotor activity screen at 6-dpf; another was reared to adulthood and assessed using a neurobehavioral test battery (startle habituation, novel tank exploration, shoaling, and predator escape/avoidance). RESULTS: There was no significant increase in the incidence of physical malformation among exposed fish compared to controls. Both retinoic acid and valproic acid exposures during development disrupted larval activity with persisting behavioral alterations later in life, primarily manifesting as decreased social affiliation. CONCLUSIONS: Social behavior and some aspects of motor function were altered in exposed fish; the importance of examining emotional or psychological consequences of early life exposure to retinoid acting chemicals is discussed. PMID- 26439101 TI - The foot of Homo naledi. AB - Modern humans are characterized by a highly specialized foot that reflects our obligate bipedalism. Our understanding of hominin foot evolution is, although, hindered by a paucity of well-associated remains. Here we describe the foot of Homo naledi from Dinaledi Chamber, South Africa, using 107 pedal elements, including one nearly-complete adult foot. The H. naledi foot is predominantly modern human-like in morphology and inferred function, with an adducted hallux, an elongated tarsus, and derived ankle and calcaneocuboid joints. In combination, these features indicate a foot well adapted for striding bipedalism. However, the H. naledi foot differs from modern humans in having more curved proximal pedal phalanges, and features suggestive of a reduced medial longitudinal arch. Within the context of primitive features found elsewhere in the skeleton, these findings suggest a unique locomotor repertoire for H. naledi, thus providing further evidence of locomotor diversity within both the hominin clade and the genus Homo. PMID- 26439102 TI - Three-Dimensional (3D) Bicontinuous Hierarchically Porous Mn2O3 Single Crystals for High Performance Lithium-Ion Batteries. AB - Bicontinuous hierarchically porous Mn2O3 single crystals (BHP-Mn2O3-SCs) with uniform parallelepiped geometry and tunable sizes have been synthesized and used as anode materials for lithium-ion batteries (LIBs). The monodispersed BHP-Mn2O3 SCs exhibit high specific surface area and three dimensional interconnected bimodal mesoporosity throughout the entire crystal. Such hierarchical interpenetrating porous framework can not only provide a large number of active sites for Li ion insertion, but also good conductivity and short diffusion length for Li ions, leading to a high lithium storage capacity and enhanced rate capability. Furthermore, owing to their specific porosity, these BHP-Mn2O3-SCs as anode materials can accommodate the volume expansion/contraction that occurs with lithium insertion/extraction during discharge/charge processes, resulting in their good cycling performance. Our synthesized BHP-Mn2O3-SCs with a size of ~700 nm display the best electrochemical performance, with a large reversible capacity (845 mA h g(-1) at 100 mA g(-1) after 50 cycles), high coulombic efficiency (>95%), excellent cycling stability and superior rate capability (410 mA h g(-1) at 1 Ag(-1)). These values are among the highest reported for Mn2O3-based bulk solids and nanostructures. Also, electrochemical impedance spectroscopy study demonstrates that the BHP-Mn2O3-SCs are suitable for charge transfer at the electrode/electrolyte interface. PMID- 26439103 TI - Hand function assessment in the first years of life in unilateral cerebral palsy: Correlation with neuroimaging and cortico-spinal reorganization. AB - AIM: The purpose of the present study was to correlate early hand function assessment during the first years of life with neuroimaging findings and the different patterns of cortico-motor reorganization in children with unilateral cerebral palsy (UCP). METHODS: We conducted a long prospective observational study, in which 17 children with UCP (8 left-sided hemiplegia; Manual Ability Classification System level 1-3) were first assessed at a mean age of 24 months (range 18-28), and followed up by means of the Besta Scale, a new standardized protocol assessing both unimanual and bimanual hand function. They also underwent Melbourne Assessment of Unilateral Upper Limb Function (MUUL) and single-pulse Transcranial Magnetic Stimulation (TMS) at a mean age of 10 years 5 months (range 9 y 1 m-12 y 8 m). Brain MRIs of all the 17 children were independently assessed and scored by two blinded observers, according to a defined protocol. Possible correlations between hand function at first assessment, neuroimaging and TMS data were analyzed. RESULTS: Early hand function impairment significantly correlated with the extension of brain damage (rho = -0.531, p = 0.028), number of involved areas (rho = -0.608, p = 0.010), presence of radiological signs of cortico-spinal degeneration (rho = -0.628, p = 0.007), and basal ganglia involvement (rho = 0.485, p = 0.049). Additionally, higher hand function scores (i.e. better hand function) at first assessment significantly correlated with contralateral cortico spinal projections, while lower scores significantly correlated with either mixed or ipsilateral cortico-spinal projections to the affected hand (chi(2)(2) = 11.418, p = 0.003; post-hoc tests: contralateral TMS group versus ipsilateral: Z = -2.943, p = 0.002 and contralateral TMS group versus mixed: Z = -2.775, p = 0.006). CONCLUSIONS: To our knowledge, this is the first study correlating hand function assessment in the first years of life, and its evolution over time, with neuroimaging and cortico-spinal projection patterns in children with UCP. These findings could contribute to an improved prediction of prognosis and a better delineation of therapeutic interventions in young children with UCP. PMID- 26439104 TI - Analysis of T2 signal intensity helps in the differentiation between high and low grade brain tumours in paediatric patients. AB - PURPOSE: Previous studies hypothesized that the analysis of magnetic resonance intensity of the solid portion in paediatric tumours can provide pre-surgical information about the histopathology. Classically, high signal-intensity in T2weighted (T2w) images identifies low-grade tumours, while anaplasia is characterized by T2 hypointensity. We aimed to investigate if T2w signal intensities can pre-operatively distinguish between low-grade and high-grade brain tumours in paediatric patients. METHODS: Two raters, blinded to the histological diagnosis, rated the signal intensity of MR images (T2w) from 36 children with newly diagnosed brain tumours, 17 children with low-grade brain tumours and 19 children with high-grade brain tumours were included in this study. Relative T2 values were obtained by dividing the T2w values of the solid portion of the tumour by the T2w values of the vitreous humour. RESULTS: The best cut-off point to distinguish low and high-grade paediatric brain tumours was 0.8. If the signal intensity was less than or equal to 0.8 the tumour was expected to be a high-grade tumour with a sensitivity of 100%. Prediction of a low-grade tumour was more uncertain with a sensitivity of 70.5%. Overall, 86% of the tumours would have been predicted correctly. CONCLUSION: Our data suggest that T2w signal intensities of the solid portion of brain tumours in paediatrics can pre-operatively differentiate between low-grade and high-grade tumours. In addition, T2 hypointensity may be helpful in targeting stereotactic biopsy. PMID- 26439105 TI - Continuous intra-arterial nimodipine infusion in patients with severe refractory cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a feasibility study and outcome results. AB - BACKGROUND: Severe cerebral vasospasm is a major cause of death and disability in patients with aneurysmal subarachnoid hemorrhage. No causative treatment is yet available and hypertensive hypervolemic therapy (HHT) is often insufficient to avoid delayed cerebral ischemia and neurological deficits. We compared patients receiving continuous intra-arterial infusion of the calcium-antagonist nimodipine with a historical group treated with HHT and oral nimodipine alone. METHODS: Between 0.5 and 1.2 mg/h of nimodipine were continuously administered by intra arterial infusion via microcatheters either into the internal carotid or vertebral artery or both, depending on the areas of vasospasm. The effect was controlled via multimodal neuromonitoring and transcranial Doppler sonography. Outcome was determined by means of the Glasgow Outcome Scale at discharge and 6 months after the hemorrhage and compared to a historical control group. RESULTS: Twenty-one patients received 28 intra-arterial nimodipine infusions. Six months after discharge, the occurrence of cerebral infarctions was significantly lower (42.6 %) in the nimodipine group than in the control group (75.0 %). This result was reflected by a significantly higher proportion (76.0 %) of patients with good outcome in the nimodipine-treated group, when compared to 10.0 % good outcome in the control group. Median GOS was 4 in the nimodipine group and 2 in the control group (p = 0.001). CONCLUSIONS: Continuous intra-arterial nimodipine infusion is an effective treatment for patients with severe cerebral vasospasm who fail to respond to HHT and oral nimodipine alone. Key to the effective administration of continuous intra-arterial nimodipine is multimodal neuromonitoring and the individual adaptation of dosage and time of infusion for each patient. PMID- 26439106 TI - Photosensitized degradation kinetics of trace halogenated contaminants in natural waters using membrane introduction mass spectrometry as an in situ reaction monitor. AB - The photochemically mediated dechlorination of polyhalogenated compounds represents a potential decontamination strategy and a relevant environmental process in chemically reducing media. We report the UV irradiation of natural and artificial waters containing natural dissolved organic matter to effect the photo sensitized degradation of chlorinated organic compounds, including tetrachloromethane, 1,1,1-tricloroethane, perchloroethene, 1,2-dibromo-3 chloropropane and chlorobenzene at trace (ppb) levels in aqueous solution. The degradation kinetics are followed in situ using membrane introduction mass spectrometry. By re-circulating the reaction mixture in a closed loop configuration over a semi-permeable hollow fiber polydimethylsiloxane membrane in a flow cell interface, volatile and semi-volatile compounds are continuously monitored using a quadrupole ion trap mass spectrometer. The time resolved quantitative information provides useful mechanistic insights, including kinetic data. Pseudo first-order rate constants for the degradation of contaminant mixtures in natural waters are reported. PMID- 26439107 TI - Asymptotically robust variance estimation for person-time incidence rates. AB - Person-time incidence rates are frequently used in medical research. However, standard estimation theory for this measure of event occurrence is based on the assumption of independent and identically distributed (iid) exponential event times, which implies that the hazard function remains constant over time. Under this assumption and assuming independent censoring, observed person-time incidence rate is the maximum-likelihood estimator of the constant hazard, and asymptotic variance of the log rate can be estimated consistently by the inverse of the number of events. However, in many practical applications, the assumption of constant hazard is not very plausible. In the present paper, an average rate parameter is defined as the ratio of expected event count to the expected total time at risk. This rate parameter is equal to the hazard function under constant hazard. For inference about the average rate parameter, an asymptotically robust variance estimator of the log rate is proposed. Given some very general conditions, the robust variance estimator is consistent under arbitrary iid event times, and is also consistent or asymptotically conservative when event times are independent but nonidentically distributed. In contrast, the standard maximum likelihood estimator may become anticonservative under nonconstant hazard, producing confidence intervals with less-than-nominal asymptotic coverage. These results are derived analytically and illustrated with simulations. The two estimators are also compared in five datasets from oncology studies. PMID- 26439108 TI - A review of the changes to the licensing of influenza vaccines in Europe. AB - In 2014, the European Committee for Medicinal Products for Human Use (CHMP) published a draft regulatory guideline for the evaluation of influenza vaccines. Following a public consultation round, the final guidance will be published in the near future. Here, we highlight the main changes in the clinical section in this guideline and discuss the background to these changes and whether the new consolidated guidance document can be expected to achieve a better understanding of the performance of seasonal, zoonotic and pandemic influenza vaccines during the regulatory licensing process. The new influenza guideline reflects a changed approach to the regulatory assessment of influenza vaccines, resulting in the abolition of serological criteria, known as the CHMP criteria, which have been the mainstay for evaluating the influenza vaccine immunogenicity for several decades. The new guideline adopts a more diversified approach to the measurement and reporting of the immune response to influenza vaccines and sets a requirement to conduct clinical outcome trials in young children. Importantly, more emphasis is placed on the post-licensure monitoring of the benefit risk of influenza vaccines, including a request for continuous monitoring of efficacy and enhanced safety surveillance. Despite the improvements these new requirements will expectedly bring to the regulatory assessment of influenza vaccines, major challenges remain which cannot be overcome by new guidance alone. Ongoing initiatives in which academia, manufacturers, public health institutes and regulators work together to address these challenges are central to the development of robust tools to evaluate and monitor performance of influenza vaccines in the future. PMID- 26439109 TI - Preparation, characterisation and use for antioxidant oligosaccharides of a cellulase from abalone (Haliotis discus hannai) viscera. AB - BACKGROUND: In China, abalone (Haliotis discus hannai) production is growing annually. During industrial processing, the viscera, which are abundant of cellulase, are usually discarded or processed into low-value feedstuff. Thus, it is of interest to obtain cellulase from abalone viscera and investigate its application for preparation of functional oligosaccharides. RESULTS: A cellulase was purified from the hepatopancreas of abalone by ammonium sulfate precipitation and two-steps column chromatography. The molecular weight of the cellulase was 45 kDa on SDS-PAGE. Peptide mass fingerprinting analysis yielded 103 amino acid residues, which were identical to cellulases from other species of abalone. Substrate specificity analysis indicated that the cellulase is an endo-1,4-beta glucanase. Hydrolysis of seaweed Porphyra haitanensis polysaccharides by the enzyme produced oligosaccharides with degree of polymerisation of two to four, whose monosaccharide composition was 58% galactose, 4% glucose and 38% xylose. The oligosaccharides revealed 2,2'-diphenyl-1-picrylhydrazyl free radical as well as hydrogen peroxide scavenging activity. CONCLUSION: It is feasible and meaningful to utilise cellulase from the viscera of abalone for preparation of functional oligosaccharides. (c) 2015 Society of Chemical Industry. PMID- 26439110 TI - Language bias and self-rated health status among the Latino population: evidence of the influence of translation in a wording experiment. AB - PURPOSE: This research uses a translation experiment to assess the Spanish translation of the "fair" response in the self-rated health measure among a representative study of the Latino population in the USA. METHODS: Using a unique Latino-specific survey (n = 1200), researchers built in a split sample approach in the self-rated health status measure where half of the Spanish-speaking respondents (n = 600) were randomly given "regular" and the other half were given "Mas o Menos" in translating the English "fair" response. We first estimate a logistic regression model to estimate differences across language categories on the probability of reporting poor and fair health and then estimate a multinomial logistic regression to test whether respondents who took the survey in Spanish and given "regular" are more likely to rate their health as fair compared to English speakers and Spanish-speaking respondents who are given the "Mas o Menos" version. RESULTS: From our logistic regression model, we find that Spanish speaking respondents given the "regular" response are more likely to report poor health relative to English-speaking respondents and Spanish-speaking respondents who were randomly given "Mas o Menos." The results from our multinomial logistic models suggest that Spanish respondents provided with "Mas o Menos" are more likely to rate their health as good relative to the base category of fair and relative to both English and Spanish speakers given "regular." CONCLUSION: This research informs the study of racial and ethnic disparities by providing a detailed explanation for mixed findings in the Latino health disparities literature. Researchers interested in self-rated health should translate the general self-rated health option "fair" to "Mas o Menos" as our wording experiment suggests that the current wording "regular" overinflates the reporting of poor health. PMID- 26439111 TI - Erratum to: An EQ-5D-5L value set based on Uruguayan population preferences. PMID- 26439112 TI - Effects of Auditory Attention Training with the Dichotic Listening Task: Behavioural and Neurophysiological Evidence. AB - Facilitation of general cognitive capacities such as executive functions through training has stirred considerable research interest during the last decade. Recently we demonstrated that training of auditory attention with forced attention dichotic listening not only facilitated that performance but also generalized to an untrained attentional task. In the present study, 13 participants underwent a 4-week dichotic listening training programme with instructions to report syllables presented to the left ear (FL training group). Another group (n = 13) was trained using the non-forced instruction, asked to report whichever syllable they heard the best (NF training group). The study aimed to replicate our previous behavioural results, and to explore the neurophysiological correlates of training through event-related brain potentials (ERPs). We partially replicated our previous behavioural training effects, as the FL training group tended to show more allocation of auditory spatial attention to the left ear in a standard dichotic listening task. ERP measures showed diminished N1 and enhanced P2 responses to dichotic stimuli after training in both groups, interpreted as improvement in early perceptual processing of the stimuli. Additionally, enhanced anterior N2 amplitudes were found after training, with relatively larger changes in the FL training group in the forced-left condition, suggesting improved top-down control on the trained task. These results show that top-down cognitive training can modulate the left-right allocation of auditory spatial attention, accompanied by a change in an evoked brain potential related to cognitive control. PMID- 26439113 TI - Early-Phase 11C-PiB PET in Amyloid Angiopathy-Related Symptomatic Cerebral Hemorrhage: Potential Diagnostic Value? AB - Although late-phase (>35min post-administration) 11C-PiB-PET has good sensitivity in cerebral amyloid angiopathy (CAA), its specificity is poor due to frequently high uptake in healthy aged subjects. By detecting perfusion-like abnormalities, early-phase 11C-PiB-PET might add diagnostic value. Early-frame (1-6min) 11C-PiB PET was obtained in 11 non-demented patients with probable CAA-related symptomatic lobar intracerebral haemorrhage (70+/-7yrs), 9 age-matched healthy controls (HCs) and 10 HCs <55yrs. There was a significant decrease in early-phase atrophy-corrected whole-cortex SUV relative to cerebellar vermis (SUVR) in the CAA vs age-matched HC group. None of the age-matched controls fell below the lower 95% confidence limit derived from the young HCs, while 6/11 CAA patients did (sensitivity = 55%, specificity = 100%). Combining both early- and late-phase 11C-PiB data did not change the sensitivity and specificity of late-phase PiB, but combined early- and late-phase positivity entails a very high suspicion of underlying Abeta-related clinical disorder, i.e., CAA or Alzheimer disease (AD). In order to clarify this ambiguity, we then show that the occipital/posterior cingulate ratio is markedly lower in CAA than in AD (N = 7). These pilot data suggest that early-phase 11C-PiB-PET may not only add to late-phase PiB-PET with respect to the unclear situation of late-phase positivity, but also help differentiate CAA from AD. PMID- 26439116 TI - Asymmetric bromine-lithium exchange: on the importance of both the diamine ligand and the organolithium reagent. AB - The asymmetric bromine-lithium exchange on a series of prochiral biphenyls was investigated. As in many asymmetric organolithium reactions, the chiral ligand (here a diamine) was considered to be the enantiocontrolling element. We show here that the organolithium reagent also plays an important role. PMID- 26439114 TI - Lifestyle advice with or without pelvic floor muscle training for pelvic organ prolapse: a randomized controlled trial. AB - INTRODUCTION AND HYPOTHESIS: We evaluated the effect of adding pelvic floor muscle training (PFMT) to a structured lifestyle advice program. METHODS: This was a single-blinded randomized trial of women with symptomatic pelvic organ prolapse (POP) stage >= II. Participants were randomized to a structured lifestyle advice program with or without PFMT. Both groups received similar lifestyle advice in six separate group sessions. The combined group performed group PFMT after an individual assessment. Primary outcome was a global improvement scale at six-month follow-up. Secondary outcomes were the global scale and objective POP at three-month follow-up, symptoms and quality of life including sexuality, at three and six-month follow-up. A clinically relevant change of symptoms was defined as >= 15 %. RESULTS: We included 109 women. Eighty nine women (82 %) completed three months follow-up; 85 (78 %) completed six-month follow-up. At both follow-ups, significantly more women in the combined group reported improvement in the global scale. At the three-month follow-up, the combined group only had significant improvement of POP symptoms while only the lifestyle advice group had significant improvement of quality of life. Change in objective POP and sexuality was nonsignificant. The symptom score improved 17 % in the combined group and 14 % in the lifestyle advice group (P = 0.57). Significantly more women in the lifestyle advice group had sought further treatment at the six-month follow-up. CONCLUSION: Adding PFMT to a structured lifestyle advice program gave superior results in a global scale and for POP symptoms. Overall effect of either intervention barely reached clinical relevance. PMID- 26439115 TI - Detecting Horizontal Gene Transfer between Closely Related Taxa. AB - Horizontal gene transfer (HGT), the transfer of genetic material between organisms, is crucial for genetic innovation and the evolution of genome architecture. Existing HGT detection algorithms rely on a strong phylogenetic signal distinguishing the transferred sequence from ancestral (vertically derived) genes in its recipient genome. Detecting HGT between closely related species or strains is challenging, as the phylogenetic signal is usually weak and the nucleotide composition is normally nearly identical. Nevertheless, there is a great importance in detecting HGT between congeneric species or strains, especially in clinical microbiology, where understanding the emergence of new virulent and drug-resistant strains is crucial, and often time-sensitive. We developed a novel, self-contained technique named Near HGT, based on the synteny index, to measure the divergence of a gene from its native genomic environment and used it to identify candidate HGT events between closely related strains. The method confirms candidate transferred genes based on the constant relative mutability (CRM). Using CRM, the algorithm assigns a confidence score based on "unusual" sequence divergence. A gene exhibiting exceptional deviations according to both synteny and mutability criteria, is considered a validated HGT product. We first employed the technique to a set of three E. coli strains and detected several highly probable horizontally acquired genes. We then compared the method to existing HGT detection tools using a larger strain data set. When combined with additional approaches our new algorithm provides richer picture and brings us closer to the goal of detecting all newly acquired genes in a particular strain. PMID- 26439118 TI - Study of the activated macrophage transcriptome. AB - Transcriptome analysis is a powerful modern tool to study possible alterations of gene expression associated with human diseases. It turns out to be especially promising for evaluation of gene expression changes in immunopathology, as immune cells have flexible gene expression patterns that can be switched in response to infection, inflammatory stimuli and exposure to various cytokines. In particular, macrophage polarization towards pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes can be successfully studied using the modern transcriptome analysis approaches. The two mostly used techniques for transcriptome analysis are microarray and next generation sequencing. In this review we will provide an overview of known gene expression changes associated with immunopathology and discuss the advantage and limitations of different methods of transcriptome analysis. PMID- 26439117 TI - Dorsal Anterior Cingulate Thickness Is Related to Alexithymia in Childhood Trauma Related PTSD. AB - Alexithymia, or "no words for feelings", is highly prevalent in samples with childhood maltreatment and posttraumatic stress disorder (PTSD). The dorsal anterior cingulate cortex (dACC) has been identified as a key region involved in alexithymia, early life trauma, and PTSD. Functional alterations in the dACC also have been associated with alexithymia in PTSD. This study examined whether dACC morphology is a neural correlate of alexithymia in child maltreatment-related PTSD. Sixteen adults with PTSD and a history of childhood sexual abuse, physical abuse, or exposure to domestic violence, and 24 healthy controls (HC) completed the Toronto Alexithymia Scale 20 (TAS-20) and underwent magnetic resonance imaging. Cortical thickness of the dACC was measured using FreeSurfer, and values were correlated with TAS-20 scores, controlling for sex and age, in both groups. Average TAS-20 score was significantly higher in the PTSD than the HC group. TAS 20 scores were significantly positively associated with dACC thickness only in the PTSD group. This association was strongest in the left hemisphere and for TAS 20 subscales that assess difficulty identifying and describing feelings. We found that increasing dACC gray matter thickness is a neural correlate of greater alexithymia in the context of PTSD with childhood maltreatment. While findings are correlational, they motivate further inquiry into the relationships between childhood adversity, emotional awareness and expression, and dACC morphologic development in trauma-related psychopathology. PMID- 26439119 TI - Recurrence of endometriosis: risk factors, mechanisms and biomarkers. AB - While the incidence of endometriosis is up to 40-60% in women with severe dysmenorrhea/chronic pelvic pain, patients with subfertility carries a risk up to 20-30%. In symptomatic patients, although medical therapy is preferred in women with endometriosis, surgery might be needed in nonresponders or patients with an endometrioma. Following the surgery, recurrence of the disease and/or symptoms might be still noticed which will progressively increase as times goes by. Nevertheless, some risk factors have been identified for the risk of recurrence that decreases the success of the procedure. Those risk factors might be classified as patient-disease related and surgery-associated variables. Herein, we will address about the management of endometriosis regarding the risk factors for relapse, mechanisms of recurrence and potential biomarkers to predict the event. PMID- 26439120 TI - Perceptions of credibility of sexual abuse victims across generations. AB - The success of prosecutions of perpetrators of sexual abuse often depends substantially upon the perceived credibility of the victim witness. However, perceptions of credibility may vary by generation of the observer, and the constitution of juries may therefore lead to bias. In this study we examined whether perceptions of credibility of female victims of sexual abuse varied across generation Y, generation X, "baby boomers", and "builders". One hundred and twenty-eight jury-eligible members of the community from each generation (N=512) responded to ten questions assessing the perceived believability, competence, trustworthiness, demeanour and sexual naivete of females providing testimony related to alleged sexual abuse. Although consistent between-generation differences were not found for all questions, or all four groups of generational cohorts, in instances where significant differences were found, it was consistently the older generation groups (builders and baby boomers) that attributed less credibility to the victim than the younger generation groups (generation Y and generation X). The implications of these findings are discussed. PMID- 26439121 TI - Cyanotoxin bioaccumulation in freshwater fish, Washington State, USA. AB - Until recently, exposure pathways of concern for cyanotoxins have focused on recreational exposure, drinking water, and dermal contact. Exposure to cyanotoxins through fish consumption is a relatively new area of investigation. To address this concern, microcystins and other cyanotoxins were analyzed in fish collected from nine Washington lakes with recurrent toxic blooms using two types of enzyme-linked immunosorbent assays (ELISAs) and liquid chromatography/mass spectrometry/mass spectrometry (LC-MS/MS). Microcystins or microcystin-like compounds were elevated in fish liver relative to muscle and other tissues (liver>gut>muscle). Microcystin concentrations in fish fillet samples using anti Adda ELISA (range 6.3-11 MUg/kg wet weight) were consistently higher in all fish species than concentrations using anti-microcystin (MC)-leucine-arginine (LR) ELISA (range 0.25-2.4 MUg/kg wet weight). MC-leucine-alanine (LA) was the only variant detected in fish (2.5-12 MUg/kg in four livers) among the nine variants analyzed by LC-MS/MS. Fish fillets showed no accumulation of the MCs targeted by LC-MS/MS. Other cyanotoxins analyzed (anatoxin-a, saxitoxin, domoic acid, and okadaic acid) were not detected in fish. Based on this and evidence from other studies, we believe that people can safely consume two 8-oz fish fillet meals per week from lakes with blooms producing MCs (clean the fish and discard viscera). PMID- 26439122 TI - Occurrence and seasonal loads of pesticides in surface water and suspended particulate matter from a wetland of worldwide interest--the Ria Formosa Lagoon, Portugal. AB - Two novel methods were developed to extract and quantify 56 pesticides in surface waters, considering their content in both dissolved aqueous phase (DAP) and suspended particulate matter (SPM) fractions. These procedures were applied to coastal samples taken seasonally during 2012-2013, from three strategic sampling sites along the Ria Formosa Lagoon (south of Portugal). Briefly, 500 mL of water samples were filtrated, separating both fractions. The DAP fraction was extracted and pre-concentrated by solid-phase extraction (SPE), while the SPM was extracted using ultrasonic extraction technique (USE). Both fractions were then analyzed, and the pesticides were quantified and identified, within 35 min, by gas chromatography (GC) coupled to mass spectrometry (GC-MS and GC-MS/MS), respectively. The extraction of pesticides from the SPM fraction showed average recoveries of 102%, detection limits below 2.2 ng/L, and quantification limits ranging from 0.3 to 6.6 ng/L. Considering the real water samples, 73% of the selected pesticides were quantified in both DAP and SPM fractions (SigmaDAP+SPM 2.3 MUg/L) and their maximum levels were measured in autumn and winter. By category, the global loads of fungicides, herbicides, and insecticides were ~407, ~323, and ~1.6 MUg/L, respectively. Thirty-one percent of the quantified pesticides exceeded the European directives levels (2008/105/EC and 98/83/EC). From the total loads, the SPM fraction contribution was 32%, showing the importance of measuring pesticides in that fraction. The water physicochemical parameters revealed that the total nitrogen amounts were very high relatively to the legal required values, mainly close to the city of Faro (2.6 mg/L). In light of the above, measures are in need to meet European directives and protect both fauna and humans that use this area for leisure. PMID- 26439123 TI - Comparative study of humic acid removal and floc characteristics by electrocoagulation and chemical coagulation. AB - The current study aims at investigating the efficiency of electrocoagulation for the removal of humic acid from contaminated waters. In parallel, conventional chemical coagulation was conducted to asses humic acid removal patterns. The effect of varying contributing parameters (matrix pH, humic acid concentration, type of electrode (aluminum vs. iron), current density, solution conductivity, and distance between electrodes) was considered to optimize the electrocoagulation process for the best attainable humic acid removal efficiencies. Optimum removals were recorded at pH of 5.0-5.5, an electrical conductivity of 3000 MUS/cm at 25 degrees C, and an electrode distance of 1 cm for both electrode types. With aluminum electrodes, a current density of 0.05 mA/cm2 outperformed 0.1 mA/cm2 yet not higher densities, whereas a current density of 0.8 mA/cm2 was needed for iron electrodes to exhibit comparable performance. With both electrode types, higher initial humic acid concentrations were removed at a slower rate but ultimately attained almost complete removals. On the other hand, the best humic acid removals (~90%) by chemical coagulation were achieved at 4 mg/L for both coagulants. Also, higher removals were attained at elevated initial humic acid concentrations. Humic acid removals of 90% or higher at an initial HA concentration of 40 mg/L were exhibited, yet alum performed better at the highest experimented concentration. It was evident that iron flocs were larger, denser, and more geometrical in shape compared to aluminum flocs. PMID- 26439124 TI - A review of the ecohydrology of the Sakumo wetland in Ghana. AB - The Sakumo wetland is an internationally recognized Ramsar site located in a largely urban area and provides essential ecological and social services to wetland community dwellers. Despite its importance, the wetland has over the years been subjected to human interference resulting in considerable risks of deteriorating water quality, biodiversity loss, and drying up of most parts of the wetland. The conversion of land for residential and agricultural uses has significantly altered the hydrological characteristics of the land surface and modified pathways and flow of water into the wetland. Other drivers identified included drainage (mainly as runoff from agricultural farms), anthropogenic pressure (waste discharge) due to infrastructure development associated with urbanization, chemical contamination as a result of industrial and household pollution, and unsustainable fishing practices (overfishing). The purpose of the study was to review some of the physical and chemical properties of the Sakumo wetland on the changing wetland resources with emphasis on water quality. Rapid urbanization, industrialization, and overexploitation of wetland resources were identified as key causative factors affecting the wetland functions. Their effects on the wetland among others include increased nutrient and toxic chemical load which has resulted in reduced wetland surface water quality and decrease in species diversity. pH of the wetland waters was generally alkaline which is characteristic of water bodies influenced by seawater under oxygenated conditions. The increasing trends of electrical conductivity, phosphates, ammonia, nitrate, and nitrite, though small, point to deteriorating water quality in the wetland. The lagoon water was observed to be heavily polluted with nutrients particularly phosphate. The sequence of nutrient in the wetland was found to be in the order of PO4-P>NH3-N>NO3-N>NO2-N. These, if not checked, will result in further deterioration of the wetland function. In order to protect the wetland structure and function, it is recommended that a determination for both surface water and groundwater (quality and quantity) components of the ecological reserve (aquatic ecosystem) as well as the basic human need should be undertaken. In addition, a complete hydrological study of the wetland must be done. This will enable a well-balanced water allocation scheme to all users while still ensuring long-term survival and sustainability of the wetland. PMID- 26439125 TI - Holding-time and method comparisons for the analysis of fecal-indicator bacteria in groundwater. AB - As part of the US Geological Survey National Water-Quality Assessment Program, groundwater samples from domestic- and public-supply wells were collected and analyzed for fecal-indicator bacteria. A holding time comparison for total coliforms, Escherichia coli, and enterococci was done by analyzing samples within 8 h using presence/absence methods and within 18-30 h using quantitative methods. The data indicate that results obtained within 18-30 h were not significantly different from those obtained within 8 h for total coliforms and enterococci, by Colilert(r) and Enterolert(r) methods (IDEXX Laboratories Inc., Westbrook, ME), respectively. Quantitative laboratory methods for samples analyzed within 18-30 h showed a statistically significant higher detection frequency when compared to presence/absence methods done within 8 h for the following methods, E. coli by Colilert and enterococci by membrane filtration on mEI agar. Additionally, a comparison of methods for the enumeration of enterococci was done. Using non parametric statistical analyses, results from the two methods were statistically different. In this study, the membrane filtration method on mEI agar was more sensitive, resulted in more detections of enterococci, and results were easier to interpret than with the quantitative Enterolert method. The quantitative Enterolert method produced varying levels of fluorescence, which required additional verification steps to eliminate false-positive results. It may be more advantageous to analyze untreated groundwater for enterococci using the membrane filtration method on mEI agar. PMID- 26439126 TI - Microbiological quality of water from the rivers of Curitiba, Parana State, Brazil, and the susceptibility to antimicrobial drugs and pathogenicity of Escherichia coli. AB - Water safety is determined by several markers, and Escherichia coli is one of the most important indicators of water quality. The objective of this study was to evaluate the microbiological parameters in environmental samples of fresh water from rivers of Curitiba and its metropolitan area in Parana State, Brazil. In addition, we evaluated the pathogenicity and susceptibility to antimicrobial drugs in E. coli. These evaluations were performed by quantitative and qualitative methods employing selective media for isolating thermotolerant coliforms and biochemical tests for identifying E. coli. Pathogenic strains of E. coli were detected by PCR multiplex using specific primers. From the water samples, 494 thermotolerant coliforms were obtained, of which 96 (19.43%) isolates were characterized as E. coli. Three isolates were identified as enteroaggregative E. coli, one as enterotoxigenic E. coli, one as enteropathogenic E. coli, and two carried the Eae virulence gene. E. coli susceptibility to commonly employed antimicrobial drugs was analyzed by the disc diffusion method. The results showed 49 (51.04%) isolates resistant to all the drugs assayed, 16 (16.67%) with an intermediate resistance to all drugs, and 31 (32.29%) intermediately or fully resistant to one or more drugs tested. The highest rate of resistance was observed for tetracycline 30 MUg, streptomycin 10 MUg, and ceftazidime 30 MUg. Detection of E. coli is associated with water contamination by fecal material from humans and warm-blooded animals. The occurrence of resistant strains can be the result of the indiscriminate use of antimicrobial drugs and poor sanitation in the areas assayed. PMID- 26439127 TI - Temperature-dependence of L-type Ca(2+) current in ventricular cardiomyocytes of the Alaska blackfish (Dallia pectoralis). AB - To lend insight into the overwintering strategy of the Alaska blackfish (Dallia pectoralis), we acclimated fish to 15 or 5 degrees C and then utilized whole cell patch clamp to characterize the effects of thermal acclimation and acute temperature change on the density and kinetics of ventricular L-type Ca(2+) current (I Ca). Peak I Ca density at 5 degrees C (-1.1 +/- 0.1 pA pF(-1)) was 1/8th that at 15 degrees C (-8.8 +/- 0.6 pA pF(-1)). However, alterations of the Ca(2+)- and voltage-dependent inactivation properties of L-type Ca(2+) channels partially compensated against the decrease. The time constant tau (tau) for the kinetics of inactivation of I Ca was ~4.5 times greater at 5 degrees C than at 15 degrees C, and the voltage for half-maximal inactivation was shifted from 23.3 +/- 1.0 mV at 15 degrees C to -19.8 +/- 1.2 mV at 5 degrees C. These modifications increase the open probability of the channel and culminate in an approximate doubling of the L-type Ca(2+) window current, which contributes to approximately 15% of the maximal Ca(2+) conductance at 5 degrees C. Consequently, the charge density of I Ca (Q Ca) and the total Ca(2+) transferred through the L-type Ca(2+) channels (Delta[Ca(2+)]) were not as severely reduced at 5 degrees C as compared to peak I Ca density. In combination, the results suggest that while the Alaska blackfish substantially down-regulates I Ca with acclimation to low temperature, there is sufficient compensation in the kinetics of the L-type Ca(2+) channel to support the level of cardiac performance required for the fish to remain active throughout the winter. PMID- 26439128 TI - Circadian Clock Genes Are Essential for Normal Adult Neurogenesis, Differentiation, and Fate Determination. AB - Adult neurogenesis creates new neurons and glia from stem cells in the human brain throughout life. It is best understood in the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ). Circadian rhythms have been identified in the hippocampus, but the role of any endogenous circadian oscillator cells in hippocampal neurogenesis and their importance in learning or memory remains unclear. Any study of stem cell regulation by intrinsic circadian timing within the DG is complicated by modulation from circadian clocks elsewhere in the brain. To examine circadian oscillators in greater isolation, neurosphere cultures were prepared from the DG of two knockout mouse lines that lack a functional circadian clock and from mPer1::luc mice to identify circadian oscillations in gene expression. Circadian mPer1 gene activity rhythms were recorded in neurospheres maintained in a culture medium that induces neurogenesis but not in one that maintains the stem cell state. Although the differentiating neural stem progenitor cells of spheres were rhythmic, evidence of any mature neurons was extremely sparse. The circadian timing signal originated in undifferentiated cells within the neurosphere. This conclusion was supported by immunocytochemistry for mPER1 protein that was localized to the inner, more stem cell-like neurosphere core. To test for effects of the circadian clock on neurogenesis, media conditions were altered to induce neurospheres from BMAL1 knockout mice to differentiate. These cultures displayed unusually high differentiation into glia rather than neurons according to GFAP and NeuN expression, respectively, and very few BetaIII tubulin-positive, immature neurons were observed. The knockout neurospheres also displayed areas visibly devoid of cells and had overall higher cell death. Neurospheres from arrhythmic mice lacking two other core clock genes, Cry1 and Cry2, showed significantly reduced growth and increased astrocyte proliferation during differentiation, but they generated normal percentages of neuronal cells. Neuronal fate commitment therefore appears to be controlled through a non-clock function of BMAL1. This study provides insight into how cell autonomous circadian clocks and clock genes regulate adult neural stem cells with implications for treating neurodegenerative disorders and impaired brain functions by manipulating neurogenesis. PMID- 26439130 TI - Phytochemical Indicaxanthin Inhibits Colon Cancer Cell Growth and Affects the DNA Methylation Status by Influencing Epigenetically Modifying Enzyme Expression and Activity. AB - BACKGROUND: Recently, we have shown anti-proliferative and pro-apoptotic effects of indicaxanthin associated with epigenetic modulation of the onco-suppressor p16INK4a in the human colon cancer cell line CACO2. In the present study, the epigenetic activity of indicaxanthin and the mechanisms involved were further investigated in other colorectal cancer cell lines. METHODS: LOVO1, CACO2, HT29, HCT116, and DLD1 cells were used to evaluate the potential influence of consistent dietary concentrations of indicaxanthin on DNA methylation, and the epigenetic mechanisms involved were researched. RESULTS: Indicaxanthin exhibited anti-proliferative activity in all cell lines but HT29, induced demethylation in the promoters of some methylation-silenced onco-suppressor genes involved in colorectal carcinogenesis (p16INK4a, GATA4, and ESR1), and left unchanged others which were basally hypermethylated (SFRP1 and HPP1). In apparent contrast, cell exposure to indicaxanthin increased DNMT gene expression, although indicaxanthin appeared to be an inhibitor of DNMT activity. Indicaxanthin also increased the expression of genes involved in DNA demethylation. Finally, an in silico molecular modelling approach suggested stable binding of indicaxanthin at the DNMT1 catalytic site. CONCLUSIONS: Our findings contribute to new knowledge in the field of phytochemicals and specifically suggest dietary indicaxanthin as a potential epigenetic agent to protect colon cells against tumoral alterations. PMID- 26439129 TI - A Multicenter, Open-Label, Controlled Phase II Study to Evaluate Safety and Immunogenicity of MVA Smallpox Vaccine (IMVAMUNE) in 18-40 Year Old Subjects with Diagnosed Atopic Dermatitis. AB - BACKGROUND: Replicating smallpox vaccines can cause severe complications in individuals with atopic dermatitis (AD). Prior studies evaluating Modified Vaccinia Ankara virus (MVA), a non-replicating vaccine in humans, showed a favorable safety and immunogenicity profile in healthy volunteers. OBJECTIVE: This Phase II study compared the safety and immunogenicity of MVA enrolling groups of 350 subjects with AD (SCORAD <= 30) and 282 healthy subjects. METHODS: Subjects were vaccinated twice with MVA, each dose given subcutaneously 4 weeks apart. Adverse events, cardiac parameters, and the development of vaccinia virus humoral immune responses were monitored. RESULTS: The overall safety of the vaccine was similar in both groups. Adverse events affecting skin were experienced significantly more often in subjects with AD, but the majority of these events were mild to moderate in intensity. Seroconversion rates and geometric mean titers for total and neutralizing vaccinia-specific antibodies in the AD group were non-inferior compared to the healthy subjects. LIMITATIONS: The size of the study population limited the detection of serious adverse events occurring at a frequency less than 1%. CONCLUSION: MVA has a favorable safety profile and the ability to elicit vaccinia-specific immune responses in subjects with AD. TRIAL REGISTRATION: ClinicalTrials.gov NCT00316602. PMID- 26439131 TI - Triple Antithrombotic Therapy after Percutaneous Coronary Intervention (PCI) in Patients with Indication for Oral Anticoagulation: Data from a Single Center Registry. AB - Antithrombotic therapy consisting of a dual anti-platelet therapy (DAPT) and oral anti-coagulation (OAC) with a vitamin k antagonist is often referred to as triple therapy. This combined anticoagulation is applied in patients undergoing coronary artery stent implantation while also having an indication for OAC. Triple therapy increases the risk for bleeding events compared to either DAPT or OAC alone and thereby might be associated with adverse outcomes. Clinical data on the frequency of bleeding events in patients on triple therapy from clinical trials derives from pre-selected patients and may differ from the real world patients. We report data on patient characteristics and bleeding incidence of patients dismissed on triple therapy from a single university hospital. Within the time span from January 2000 to December 2012, we identified a total of 213 patients undergoing PCI who were prescribed a triple therapy for at least 4 weeks (representing 0.86% of all patients treated). The usage of triple therapy significantly increased over the observed time period. The average CHA2DS2-VASc Score was 3.1 +/- 1.1 with an average HAS-BLED score of 2.5 +/- 0.86 representing a high-risk group for thromboembolic events as well as considerable risk for bleeding events. An on treatment bleeding incidence of 9.4% was detected, with gastrointestinal and airway bleeding being the most frequent (5.1% and 1.4%, respectively). This is consistent with data from clinical trials and confirms the high risk of bleeding in patients on DAPT plus OAC. 29.0% of all patients receiving triple therapy had an indication for OAC other than non-valvular atrial fibrillation. This substantial patient group is underrepresented by clinical trials and needs further attention. PMID- 26439132 TI - BRCA1 and BRCA2 mutations in Japanese patients with ovarian, fallopian tube, and primary peritoneal cancer. AB - BACKGROUND: The contribution of BRCA1 and BRCA2 to ovarian cancer in Japanese patients is still unclear. This study investigated the frequency of germline mutations in BRCA1/2 in Japanese patients with ovarian, peritoneal, or fallopian tube cancer, regardless of their family histories, which were suggestive of hereditary breast and ovarian cancer. METHODS: Ninety-five unselected women with ovarian cancer who were seen from 2013 to 2015 at Yamanashi Prefectural Central Hospital were enrolled. Analyses of BRCA1/2 gene mutations were performed with next-generation sequencing. RESULTS: Twelve of the 95 patients (12.6%), including 5 in the BRCA1 (5.3%) and 7 in the BRCA2 (7.4%), had deleterious mutations. Among the 36 cases with a family history, 6 (16.7%) were found to carry mutations in BRCA1 and BRCA2. Notably, 6 of the 59 cases (10.2%) without a family history also had BRCA1/2 germline mutations. There was no statistical difference between the 2 groups (P = .36). The presence of mutations and their clinical relevance were studied. Mutation carriers were diagnosed at advanced stages (100% of positive cases among stage III or IV cases) and had poor prognostic histological subtypes (100% of positive cases had high-grade serous adenocarcinomas). CONCLUSIONS: In this unselected Japanese population, approximately 13% of the cases with ovarian cancer appeared to be associated with an inherited risk, regardless of a family history. This finding indicates that BRCA1/2 genetic testing should be performed for all patients with ovarian cancers. PMID- 26439133 TI - Fecal Fistula Communicating with a Femur Shaft Fracture Secondary to a Malpositioned Suprapubic Catheter: A Case Report. AB - BACKGROUND: Suprapubic catheter (SPC) insertion is a common urological procedure. Though considered a simple and safe procedure, complications are bound to occur if proper precautions are not taken during the procedure. The reported complications include gross hematuria, post-obstruction diuresis, insertion site skin-related complications, and intra-abdominal visceral injuries. Iatrogenic bowel injuries have been reported to occur as a complication in around 2.5% of cases. CASE REPORT: We report a very rare case of a bowel injury due to improper insertion of a SPC leading to fecal matter tracking along the muscle planes to reach the fracture site of the femur shaft and formation of an external fecal fistula along the lateral aspect of thigh, which according to us is the first reported case in the literature. CONCLUSIONS: This case report shows the devastating complication of a technically simple procedure done in an improper manner and successful management of a rare case of femur fracture with communicating fecal fistula. The purpose of this case report is to highlight the importance of taking proper precautions before the procedure. PMID- 26439134 TI - Molecular and Thermodynamic Factors Explain the Passivation Properties of Poly(ethylene glycol)-Coated Substrate Surfaces against Fluorophore-Labeled DNA Oligonucleotides. AB - Poly(ethylene glycol) (PEG) nanofilms are used to avert the nonspecific binding of biomolecules on substrate surfaces in biomedicine and bioanalysis including modern fluorescence-based DNA sensing and sequencing chips. A fundamental and coherent understanding of the interactions between fluorophore-tagged DNA, PEG films, and substrates in terms of molecular and energetic factors is, however, missing. Here we explore a large parameter space to elucidate how PEG layers passivate metal oxide surfaces against Cy3-labeled DNA probes. The driving force for probe adsorption is found to be the affinity of the fluorophore to the substrate, while the high-quality PEG films prevent adsorption to bare ITO surfaces. The amount of nonrepelled, surface-bound DNA strongly depends on oligonucleotide size, PEG chain length, and incubation temperature. To explain these observations, we develop an experimentally validated theory to provide a microscopic picture of the PEG layer and show that adsorbed DNA molecules reside within the film by end-tethering the fluorophore to the ITO surface. To compensate for the local accumulation of negatively charged DNA, counterions condense on the adsorbed probes within the layer. The model furthermore explains that surface passivation is governed by the interdependence of molecular size, conformation, charge, ion condensation, and environmental conditions. We finally report for the first time on the detailed thermodynamic values that show how adsorption results from a balance between large opposing energetic factors. The insight of our study can be applied to rationally engineer PEG nanolayers for improved functional performance in DNA analysis schemes and may be expanded to other polymeric thin films. PMID- 26439135 TI - High-Speed Intrinsic Dissolution Rate in One Minute Using the Single-Particle Intrinsic Dissolution Rate Method. AB - Intrinsic dissolution rate (IDR) has traditionally been determined from a constant surface area of a substance. Here we present an optofluidic single particle intrinsic dissolution rate (SIDR) method, by means of which real-time determination of IDR from continuously changing effective surface areas of dissolving individual microparticles, is possible. The changing surface area of the individual microparticles is characterized through continuous random orientation 3D particle morphology characterization during the dissolution process. Using noninvasive optical monitoring and nonspecific image analysis, we determined IDRs of a diverse set of substances from individual pure-substance microparticles (14-747 MUg) with an average relative standard deviation of 9.4%. A linear fit between SIDR and literature equilibrium solubility values (R(2) = 0.999) was achieved and kinetic solubility equivalent SIDRs were obtained, for all substances, in as little as 1 min. Such miniaturized methods could become valuable tools in drug discovery, by providing resource sparing higher quality data acquisition means to replace current high-throughput solubility methods. PMID- 26439137 TI - Looking for blood. AB - In vivo imaging has revealed new details about how the malaria parasite enters the bloodstream. PMID- 26439136 TI - Outcome of VATS Lobectomy for Elderly Non-Small Cell Lung Cancer: A Propensity Score-Matched Study. AB - PURPOSE: To analyze the short-term and long-term outcome of video-assisted thoracic surgery (VATS) lobectomy for elderly patients with non-small cell lung cancer. METHODS: 105 patients aged >=75 years with resected non-small cell lung cancer were matched with 105 younger patients by propensity score. Survival rates were calculated by the Kaplan-Meier method. The cumulative incidence functions of conditional survival rate according to the age of the patients were calculated by competing risk analysis. RESULTS: patients >=75 years was associated with higher postoperative complication rate (p <0.001), but similar perioperative death rate (p = 0.006). Patients >=75 years were less likely to receive adjuvant chemotherapy (p <0.001). The 5-year overall survival rates were 54.6% for patients >=75 years and 74.1% for patients <75 years (p = 0.001). No difference was seen in disease-free survival rate (59.5% vs. 71.9% respectively = 0.117). The cumulative incidence functions of 5-year cancer-specific death were similar between the two groups (28.7% vs. 24.6% respectively, p = 0.106). The cumulative incidence functions of 5-year non-cancer-specific death was significantly higher in the elderly group (18.7% vs. 1.0%, p <0.001). CONCLUSIONS: VATS lobectomy for non-small-cell lung cancer in patients >=75 years were feasible with increased morbidity but similar mortality. The resected elderly patients were more frequently associated with non-cancer-specific death. PMID- 26439138 TI - Maximal, Not Habitual, Walking Velocity is More Highly Correlated to Functional Fitness of Community-Dwelling Older Adults. AB - The aim of this investigation was to determine the relationship between usual and maximal walking velocities with measures of functional fitness (FF). Fifty-seven older adults (78.2 +/- 6.6 years) were recruited from a local retirement community. All participants completed the following assessments: 10-m usual and maximal walk, Short Physical Performance Battery (SPPB), 6-min walk (6MW), 8-foot up-and-go (UPGO), and 30-s chair stand. Based on their SPPB performance, low (<= 9) and high (>= 10) FF groups were formed. Among all participants, maximal walking velocity, not usual walking velocity, was significantly correlated with SPPB (r = .35; p < .05 and r = .19; p > .05, respectively). In the high functioning group, both maximal and usual walking velocities were correlated, but correlation coefficients were stronger for all variables for maximal walking velocity. These results suggest different walking conditions may be necessary to use for high and low functioning older adults; specifically, maximal walking velocity may be a preferred measure among high functioning older adults. PMID- 26439139 TI - Abstracts of the 2015 CSEP General Meeting / Resumes de la 2015 Congres annuelle de la SCPE. PMID- 26439144 TI - Thickness and Microdomain Orientation of Asymmetric PS-b-PMMA Block Copolymer Films Inside Periodic Gratings. AB - The ordering process of asymmetric PS-b-PMMA block copolymers (BCPs) is investigated on flat SiO2 surfaces and on topographically patterned substrates. The topographic patterns consist of periodic gratings of 10 trenches defined by conventional top-down approaches and subsequently neutralized using a P(S-r-MMA) random copolymer (RCP). When the ordering process is accomplished on a flat surface at a temperature ranging between 180 and 230 degrees C, cylindrical microdomains perpendicularly oriented with respect to the substrate are observed irrespective of annealing temperature. In contrast, when the ordering process occurs on topographically patterned substrates, different phenomena have to be considered. The simultaneous effect of the flow around the gratings and the BCP flux from the zone located between adjacent trenches (mesa) into the inner part of the trenches results in significant thickness variations of the confined BCP film. Therefore, the amount of BCP inside the trenches depends on the width of the mesa region, which acts as a BCP reservoir. Moreover, within each trench group, the BCP thickness progressively decreases from the external to the central trenches composing the periodic grating. The thickness variation of the BCP film within the trenches strongly affects the ordering process, ultimately leading to different orientations of the microdomains within the trenches. In particular, when the annealing temperature is 190 degrees C a precise confinement of the BCP within the trenches featuring a perpendicular cylinder morphology is observed. At higher temperatures, mixed or parallel orientations of the microdomains are obtained depending on the width of the trenches in the periodic grating. PMID- 26439145 TI - Induced Production of Halogenated Epidithiodiketopiperazines by a Marine-Derived Trichoderma cf. brevicompactum with Sodium Halides. AB - Marine-derived Trichoderma sp. TPU199 (cf. T. brevicompactum) produced gliovirin (1), pretrichodermamide A (2), and trichodermamide A (3) in a freshwater medium. Compounds 1 and 2 are rare epidithiodiketopiperazines possessing an unusual disulfide linkage. In the seawater medium, the strain biosynthesized the 5-chloro 5-deoxy derivatives (4 and 5) of 3 and 2. The production of 5 was proportional to the concentration of seawater (NaCl). Therefore, 5-bromo-5-deoxy (6) and 5-deoxy 5-iodo (7) derivatives were biosynthesized in the freshwater media supplemented with NaBr and NaI, respectively. The structure of a new iodo derivative (7) was elucidated on the basis of its spectroscopic data. PMID- 26439146 TI - Modeling C-reactive protein kinetic profiles for use as a clinical prediction tool in patients with Staphylococcus aureus bacteremia. AB - AIM: We hypothesized that C-reactive protein (CRP) kinetics can be accurately modeled and might have clinical utility in a cohort of patients with Staphylococcus aureus bacteremia. MATERIALS & METHODS: We constructed and validated a nonlinear mixed effects model using CRP values obtained during the first week of illness. RESULTS: Hematological malignancy, prosthetic heart valves and metastatic seeding were identified as major covariates that influenced CRP kinetics. When considering the presence of metastatic infection as an 'unknown', the model could predict its presence through analysis of the observed CRP profile with an Area-under-the-Receiver-Operator-Characteristic curve of 0.81, indicating some diagnostic accuracy. CONCLUSION: We conclude that early CRP kinetics can be accurately modeled and can help identify patients with metastatic seeding in S. aureus bacteremia. Further validation is required. PMID- 26439148 TI - Umbilical artery blood flows among pregnancies with single umbilical artery. PMID- 26439147 TI - Colloidal Quantum Dot Photovoltaics Enhanced by Perovskite Shelling. AB - Solution-processed quantum dots are a promising material for large-scale, low cost solar cell applications. New device architectures and improved passivation have been instrumental in increasing the performance of quantum dot photovoltaic devices. Here we report photovoltaic devices based on inks of quantum dot on which we grow thin perovskite shells in solid-state films. Passivation using the perovskite was achieved using a facile solution ligand exchange followed by postannealing. The resulting hybrid nanostructure created a more intrinsic CQD film, which, when incorporated into a photovoltaic device with graded bandstructure, achieved a record solar cell performance for single-step-deposited CQD films, exhibiting an AM1.5 solar power conversion efficiency of 8.95%. PMID- 26439149 TI - Stereotactic body radiotherapy of bone metastases in oligometastatic disease: prognostic factors of oncologic outcomes. AB - BACKGROUND: To evaluate the safety of stereotactic body radiotherapy (SBRT) of bone metastases in oligometastatic disease and to investigate prognostic factors of local control (LC), progression/disease-free survival (PDFS), and overall survival (OS). METHODS: Eligibility criteria were number of metastates <=5, controlled primary tumor without evidence of progression under systemic therapy, exclusion of surgery, and no previous radiotherapy of the lesion of interest. Oligometastatic status was classified into only bone (BOD) and outside bone disease (OBOD), whereas SBRT was delivered to bone lesions using 2 different schedules: 24 Gy/1 fraction or 27 Gy/3 fractions. A positron emission tomography study of the lesion of interest was performed at baseline and at 3 months after SBRT to evaluate metabolic response according to European Organization for Research and Treatment of Cancer (EORTC) criteria. A Cox regression model was used for univariate and multivariate analysis. RESULTS: Between January 2010 and December 2013, 40 patients were enrolled. Only 1 patient experienced severe late toxicity (radiation-related fracture). Local control was longer among responders' than nonresponders' lesions (94.2% and 91.2% versus 63% and 35% at 1 and 2 years, respectively) (p = 0.004; hazard ratio = 9.958). The multivariate analysis of PDFS showed a significant correlation with planning target volume (PTV) size (p = 0.003) and oligometastatic status (p = 0.002). The multivariate analysis of OS confirmed a statistically significant value of the oligometastatic status (p = 0.002) and a significant trend for PTV size (p = 0.065). CONCLUSIONS: Stereotactic body radiotherapy is safe with a low incidence of severe toxicity. Positron emission tomography response was a strong prognostic factor of LC whereas BOD status and small PTV size could identify a subset of oligometastatic patients at better prognosis. PMID- 26439150 TI - Psychological screening of onco-hematologic inpatients: Distress Thermometer administration. AB - PURPOSE: The screening of psychological distress is a milestone in psycho oncology. The National Comprehensive Cancer Network has established clinical guidelines for detecting and managing it and the Distress Thermometer (DT) was the recommended tool for the screening. Although its utility for oncologic patients has been reported frequently in the literature, less is known about hematologic patients. The present study involves a sample of onco-hematologic adult patients. METHODS: In the current study, we proposed the Distress Thermometer and the Problem List in a sample of hematologic inpatients at Ca' Foncello Hospital, Treviso, Italy. We evaluated 102 patients, 61% male and 39% female, median age 59 years (range 18-78). Enrolled patients had acute leukemia (31%), multiple myeloma (31%), or lymphoma (31%). RESULTS: A total of 41.6% of the patients presented psychological distress, and the DT score was associated with neither sex nor diagnosis. The psychological distress was mild in 21.8%, moderate in 13.8%, and severe in 12.9% of the patients. CONCLUSIONS: Our results were consistent with previous results regarding the validation process of DT in a large sample of Italian cancer patients. PMID- 26439151 TI - Conventional Therapy in Adults With XLH Improves Dental Manifestations, But Not Enthesopathy. PMID- 26439154 TI - Letter to the Editor: Comments on Hormone Changes in Peripubertal Girls. PMID- 26439155 TI - Letter to the Editor: Comment on "FGF21 Response to Critical Illness: Effect of Blood Glucose Control and Relation With Cellular Stress and Survival" by Thiessen S.E., et al. PMID- 26439156 TI - Letter to the Editor: Possible Mechanisms of Hyponatremia-Induced Osteoporosis. PMID- 26439157 TI - Response to the Letter to the Editor. PMID- 26439158 TI - Letter to the Editor: "GLP-1 Receptor Agonist Treatment Increases Bone Formation and Prevents Bone Loss in Weight-Reduced Obese Women" by Iepsen E.W., et al. PMID- 26439159 TI - Response to the Letter by Napoli N., et al. PMID- 26439160 TI - Letter to the Editor: Comment on Therapeutic Effectiveness of Screening for Multiple Endocrine Neoplasia Type 2A by Machens A. and Dralle H. PMID- 26439161 TI - Response to the Letter by Linane H.E. and Egan A.O. PMID- 26439162 TI - Letter to the Editor: Parathyroidectomy Halts the Deterioration of Renal Function in Primary Hyperparathyroidism. PMID- 26439163 TI - Response to the Letter by Molitch M.E. PMID- 26439164 TI - Microfluidic White Organic Light-Emitting Diode Based on Integrated Patterns of Greenish-Blue and Yellow Solvent-Free Liquid Emitters. AB - We demonstrated a novel microfluidic white organic light-emitting diode (microfluidic WOLED) based on integrated sub-100-MUm-wide microchannels. Single MUm-thick SU-8-based microchannels, which were sandwiched between indium tin oxide (ITO) anode and cathode pairs, were fabricated by photolithography and heterogeneous bonding technologies. 1-Pyrenebutyric acid 2-ethylhexyl ester (PLQ) was used as a solvent-free greenish-blue liquid emitter, while 2,8-di-tert-butyl 5,11-bis(4-tert-butylphenyl)-6,12-diphenyltetracene (TBRb)-doped PLQ was applied as a yellow liquid emitter. In order to form the liquid white light-emitting layer, the greenish-blue and yellow liquid emitters were alternately injected into the integrated microchannels. The fabricated electro-microfluidic device successfully exhibited white electroluminescence (EL) emission via simultaneous greenish-blue and yellow emissions under an applied voltage of 100 V. A white emission with Commission Internationale de l'Declairage (CIE) color coordinates of (0.40, 0.42) was also obtained; the emission corresponds to warm-white light. The proposed device has potential applications in subpixels of liquid-based microdisplays and for lighting. PMID- 26439165 TI - DNA Structural Correlation in Short and Long Ranges. AB - Recent single-molecule measurements have revealed the DNA allostery in protein/DNA binding. MD simulations showed that this allosteric effect is associated with the deformation properties of DNA. In this study, we used MD simulations to further investigate the mechanism of DNA structural correlation, its dependence on DNA sequence, and the chemical modification of the bases. Besides a random sequence, poly d(AT) and poly d(GC) are also used as simpler model systems, which show the different bending and twisting flexibilities. The base-stacking interactions and the methyl group on the 5-carbon site of thymine causes local structures and flexibility to be very different for the two model systems, which further lead to obviously different tendencies of the conformational deformations, including the long-range allosteric effects. PMID- 26439166 TI - Ab initio molecular dynamics investigations of low-energy recoil events in Ni and NiCo. AB - Low-energy recoil events in pure Ni and the equiatomic NiCo alloy are studied using ab initio molecular dynamics simulations. We found that the threshold displacement energies are strongly dependent on orientation and weakly dependent on composition. The minimum threshold displacement energies are along the [1 1 0] direction in both pure Ni and the NiCo alloy. Compared to pure Ni, the threshold displacement energies increase slightly in the NiCo alloy due to the stronger bonds in the alloy, irrespective of the element type of the PKA. A single Ni interstitial occupying the center of a tetrahedron formed by four Ni atoms and a <1 0 0> split interstitial is produced in pure Ni by the recoils, while only the <1 0 0> split interstitial is formed in the NiCo alloy. Compared to the replacement sequences in pure Ni, anti-site defect sequences are observed in the alloy, which have high efficiency for both producing defects and transporting energy outside of the cascade core. These results provide insights into energy transfer processes occurring in equiatomic alloys under irradiation. PMID- 26439167 TI - Cryoglobulinaemia (IgG-kappa-type and IgM-gamma-type) with Occluding Leukocytoclastic Vasculitis in a Patient with Vitiligo and Demyelinating Polyneuropathy. PMID- 26439169 TI - Direct Growth and Controlled Coalescence of Thick AlN Template on Micro-circle Patterned Si Substrate. AB - High-density micro-circle patterned Si substrates were successfully fabricated for the direct overgrowth of thick AlN templates by using NH3 pulsed-flow multilayer AlN growth and epitaxial lateral overgrowth techniques. The experimental results show that an 8-MUm-thick AlN template was grown at a very high growth rate on the substrates. The AlN template had full widths at half maximum of 0.23 degrees and 0.37 degrees for the (002) and (102) reflection planes in X-ray diffraction rocking curves. Atomic force microscopy and transmission electron microscopy confirmed that the roughness of the surface was low (3.5 nm) and the dislocation density was very low (1.5 * 10(8) cm(-2) (screw), 3.7 * 10(8) (edge) cm(-2)). PMID- 26439171 TI - Probing dispersion and re-agglomeration phenomena upon melt-mixing of polymer functionalized graphite nanoplates. AB - A one-step melt-mixing method is proposed to study dispersion and re agglomeration phenomena of the as-received and functionalized graphite nanoplates in polypropylene melts. Graphite nanoplates were chemically modified via 1,3 dipolar cycloaddition of an azomethine ylide and then grafted with polypropylene graft-maleic anhydride. The effect of surface functionalization on the dispersion kinetics, nanoparticle re-agglomeration and interface bonding with the polymer is investigated. Nanocomposites with 2 or 10 wt% of as-received and functionalized graphite nanoplates were prepared in a small-scale prototype mixer coupled to a capillary rheometer. Samples were collected along the flow axis and characterized by optical microscopy, scanning electron microscopy and electrical conductivity measurements. The as-received graphite nanoplates tend to re-agglomerate upon stress relaxation of the polymer melt. The covalent attachment of a polymer to the nanoparticle surface enhances the stability of dispersion, delaying the re agglomeration. Surface modification also improves interfacial interactions and the resulting composites presented improved electrical conductivity. PMID- 26439168 TI - Loss of KLF14 triggers centrosome amplification and tumorigenesis. AB - Centrosome amplification is frequent in cancer, but the underlying mechanisms remain unclear. Here we report that disruption of the Kruppel-like factor 14 (KLF14) gene in mice causes centrosome amplification, aneuploidy and spontaneous tumorigenesis. Molecularly, KLF14 functions as a transcriptional repressor of Plk4, a polo-like kinase whose overexpression induces centrosome overduplication. Transient knockdown of KLF14 is sufficient to induce Plk4-directed centrosome amplification. Clinically, KLF14 transcription is significantly downregulated, whereas Plk4 transcription is upregulated in multiple types of cancers, and there exists an inverse correlation between KLF14 and Plk4 protein expression in human breast and colon cancers. Moreover, KLF14 depletion promotes AOM/DSS-induced colon tumorigenesis. Our findings reveal that KLF14 reduction serves as a mechanism leading to centrosome amplification and tumorigenesis. On the other hand, forced expression of KLF14 leads to mitotic catastrophe. Collectively, our findings identify KLF14 as a tumour suppressor and highlight its potential as biomarker and therapeutic target for cancer. PMID- 26439172 TI - Comparison of the Ramirez technique for the closure of large open myelomeningocele defects with alternative methods. AB - BACKGROUND: To compare the Ramirez technique for the operative closure of large open myelomeningocele defects with conventional closure techniques in newborns. We hypothesized that the immediate surgical treatment with the Ramirez technique is superior to prior used operative techniques. METHODS: From 2003 to 2010, 23 children (8 female, 15 male) underwent closure of large open myelomeningocele defects using the Ramirez technique (group A), while from 1993 to 2002, 23 children (6 female, 17 male) underwent conventional closure techniques (group B). All children were included in the retrospective analysis with a mean follow-up period of 3.4 years. RESULTS: Perioperative variables were similar in both groups (P = ns). There were no hospital deaths in both groups. The operation time was significantly higher in group A (228.7 +/- 76.8 versus 157.8 +/- 70.3 min, P = 0.003). Mean length of hospital stay was significantly lower in group A (30.7 +/- 16.4 days versus 52.0 +/- 38.5; P = 0.02). Postoperative complication rate was significantly lower in group A (P = 0.01). Beyond postoperative day 10, liquor fluid leakage was significantly lower in group A (P = 0.05). During follow-up, there were no complications in group A. In group B, 2 children developed liquor fistulas. CONCLUSIONS: The Ramirez technique allows efficient and safe closure of large open myelomeningocele defects and reduces incidence of postoperative liquor fistulae. The increased operation time and surgical efforts seem to be justified. Treatment of large myelomeningocele defects requires an interdisciplinary team including paediatrician-neonatologists, neurosurgeons and plastic surgeons. PMID- 26439173 TI - Pectoralis major tear at its sternal origin after a seat-belt trauma. PMID- 26439174 TI - Directed differentiation of definitive hemogenic endothelium and hematopoietic progenitors from human pluripotent stem cells. AB - The generation of hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) remains a major goal for regenerative medicine and disease modeling. However, hPSC differentiation cultures produce mostly hematopoietic progenitors belonging to the embryonic HSC-independent hematopoietic program, which may not be relevant or accurate for modeling normal and disease-state adult hematopoietic processes. Through a stage-specific directed differentiation approach, it is now possible to generate exclusively definitive hematopoietic progenitors from hPSCs showing characteristics of the more developmentally advanced fetal hematopoiesis. Here, we summarize recent efforts at generating hPSC-derived definitive hematopoiesis through embryoid body differentiation under defined conditions. Embryoid bodies are generated through enzymatic dissociation of hPSCs from matrigel-coated plasticware, followed by recombinant BMP4, driving mesoderm specification. Definitive hematopoiesis is specified by a GSK3beta inhibitor, followed by recombinant VEGF and supportive hematopoietic cytokines. The CD34+ cells obtained using this method are then suitable for hematopoietic assays for definitive hematopoietic potential. PMID- 26439175 TI - Generating and characterizing the mechanical properties of cell-derived matrices using atomic force microscopy. AB - Mechanical interaction between cells and their surrounding extracellular matrix (ECM) controls key processes such as proliferation, differentiation and motility. For many years, two-dimensional (2D) models were used to better understand the interactions between cells and their surrounding ECM. More recently, variation of the mechanical properties of tissues has been reported to play a major role in physiological and pathological scenarios such as cancer progression. The 3D architecture of the ECM finely tunes cellular behavior to perform physiologically relevant tasks. Technical limitations prevented scientists from obtaining accurate assessment of the mechanical properties of physiologically realistic matrices. There is therefore a need for combining the production of high-quality cell-derived 3D matrices (CDMs) and the characterization of their topographical and mechanical properties. Here, we describe methods that allow to accurately measure the young modulus of matrices produced by various cellular types. In the first part, we will describe and review several protocols for generating CDMs matrices from endothelial, epithelial, fibroblastic, muscle and mesenchymal stem cells. We will discuss tools allowing the characterization of the topographical details as well as of the protein content of such CDMs. In a second part, we will report the methodologies that can be used, based on atomic force microscopy, to accurately evaluate the stiffness properties of the CDMs through the quantification of their young modulus. Altogether, such methodologies allow characterizing the stiffness and topography of matrices deposited by the cells, which is key for the understanding of cellular behavior in physiological conditions. PMID- 26439177 TI - New developments in inhaler devices within pharmaceutical companies: A systematic review of the impact on clinical outcomes and patient preferences. AB - BACKGROUND: Pharmaceutical companies offer an increasing number of inhaler devices, whether or not together with new substances, for maintenance treatment of patients with COPD or asthma. However, well-designed studies to support these developments are scarce. OBJECTIVES: The aim of this research was to evaluate how far new developments of inhaler devices are scientifically supported and translate into improvements of patient preferences and/or clinical outcomes. METHODS: A systematic literature review was performed to retrieve randomised controlled trials in patients with COPD or asthma that studied the in-company evolution of inhaler devices. Results were tabulated and discussed. RESULTS: A total of 30 studies were found comparing Respimat((r)) vs. HandiHaler((r)), Diskus((r))(Accuhaler((r))) vs. Diskhaler((r))(Rotadisk((r))) or pMDI, Ellipta((r)) vs. Diskus((r))(Accuhaler((r))), Nexthaler((r)) vs. pMDI, or Breezhaler((r)) vs. Aerolizer((r)). These studies show that developments of inhaler devices may improve patient satisfaction but do not lead to demonstrable improvements in clinical efficacy. Current changes of devices are most commonly parallelled by changes in administration frequency towards once daily treatment. The only well-documented effect was found for the Respimat((r)) Soft MistTM Inhaler, which realises a more than 3-fold lowering of the once-daily tiotropium dose through increased performance of the inhaler device. There are however, no data on clinical efficacy or safety comparing the two devices at the same dosage. CONCLUSIONS: Future developments of inhaler devices should all require well designed studies to demonstrate patient benefit. PMID- 26439176 TI - Efficient cleavage of single and clustered AP site lesions within mono-nucleosome templates by CHO-K1 nuclear extract contrasts with retardation of incision by purified APE1. AB - Clustered DNA damage is a unique characteristic of radiation-induced DNA damage and the formation of these sites poses a serious challenge to the cell's repair machinery. Within a cell DNA is compacted, with nucleosomes being the first order of higher level structure. However, few data are reported on the efficiency of clustered-lesion processing within nucleosomal DNA templates. Here, we show retardation of cleavage of a single AP site by purified APE1 when contained in nucleosomal DNA, compared to cleavage of an AP site in non-nucleosomal DNA. This retardation seen in nucleosomal DNA was alleviated by incubation with CHO-K1 nuclear extract. When clustered DNA damage sites containing bistranded AP sites were present in nucleosomal DNA, efficient cleavage of the AP sites was observed after treatment with nuclear extract. The resultant DSB formation led to DNA dissociating from the histone core and nucleosomal dispersion. Clustered damaged sites containing bistranded AP site/8-oxoG residues showed no retardation of cleavage of the AP site but retardation of 8-oxoG excision, compared to isolated lesions, thus DSB formation was not seen. An increased understanding of processing of clustered DNA damage in a nucleosomal environment may lead to new strategies to enhance the cytotoxic effects of radiotherapeutics. PMID- 26439179 TI - How Should We Follow-Up Asymptomatic Metal-on-Metal Hip Resurfacing Patients? A Prospective Longitudinal Cohort Study. AB - Current surveillance for metal-on-metal hip resurfacing (MoMHR) patients is not evidence based. This study established changes that occurred in 152 asymptomatic MoMHRs using repeat ultrasound and patient-reported outcomes. Factors associated with (1) ultrasound progression and (2) developing new pseudotumors were analyzed. Patients underwent repeat assessments 4.3 years later. Ultrasound progression was observed in 19% (n = 29), with 10% (n = 15) developing new pseudotumors. Key predictors of ultrasound progression included high blood cobalt (P = .00013) and chromium (P = .00065), and high initial ultrasound grade (P = .003) and volume (P = .036). No asymptomatic MoMHRs with initially normal metal ions (<2 MUg/L) and normal ultrasounds (33% of cohort) developed new pseudotumors. This patient subgroup does not require repeat follow-up within 5 years. PMID- 26439178 TI - Combined effects of mild-to-moderate obesity and asthma on physiological and sensory responses to exercise. AB - Despite the close link between asthma and obesity, there are no studies that have evaluated the sensory and physiological responses to exercise in obese asthmatics. We recently demonstrated that normal weight asthmatics with well controlled disease have preserved cardiorespiratory and sensory responses to exercise relative to non-asthmatic controls. However, these similarities may not hold true in patients with combined obesity and asthma. Accordingly, we sought to determine if combined asthma and obesity was associated with deleterious effects on cardiorespiratory fitness, exercise performance, dyspnoea, and physiological responses to exercise. Fourteen well-controlled obese asthmatics and fourteen age matched normal weight asthmatics performed routine spirometry and underwent an incremental cardiopulmonary cycle test to assess the ventilatory, pulmonary gas exchange, cardiovascular, and sensory responses to exercise. Groups were well matched for age, height, spirometry, and asthma control. Obese asthmatics had a significantly greater body mass index (33 +/- 3 vs. 23 +/- 1 kg/m(2), p < 0.001) and lower self-reported activity levels by 47 % relative to normal weight asthmatics (p < 0.05). Obese asthmatics had a significantly lower maximal oxygen uptake (VO(2)) (82 +/- 14 vs. 92 +/- 10 %predicted) and work rate (75 +/- 8 vs. 89 +/- 13 %predicted) relative to normal weight asthmatics (p < 0.05). The anaerobic threshold occurred at a lower VO(2) in obese asthmatics vs. normal weight asthmatics (54 +/- 15 vs. 66 +/- 16 %predicted, p < 0.05). Ventilatory responses were superimposed throughout exercise with no evidence of a ventilatory limitation in either group. Cardiovascular responses were normal in both groups. Dyspnoea responses were similar but the obese asthmatics experienced greater leg fatigue ratings at submaximal work rates. In conclusion, obese individuals with well controlled asthma have reduced cardiorespiratory fitness and greater leg fatigue ratings relative to normal weight asthmatics. The relatively reduced cardiorespiratory fitness and exercise performance in obese compared to normal weight asthmatics is most likely driven by their more sedentary lifestyle and resultant deconditioning rather than due to respiratory factors. PMID- 26439180 TI - Comments on "Meta-analysis of randomised controlled trials of oral mandibular advancement devices and continuous positive airway pressure for obstructive sleep apnoea-hypopnoea" by Sharples et al. PMID- 26439181 TI - Assessment of two multilocus sequence typing (MLST) schemes available for Streptococcus mutans. AB - OBJECTIVE: Two multilocus sequencing typing (MLST) schemes are currently available for Streptococcus mutans. The first, introduced by Nakano et al. in 2007, consists of 8 conserved housekeeping genes. The second, introduced in 2010 by Do et al., includes 6 housekeeping genes and 2 putative virulence genes. The purpose of the current study was to compare the two MLST schemes for use in validating repetitive extragenic palindromic polymerase chain reaction (rep-PCR) genotypes. DESIGN: Thirty-three S. mutans isolates, representing the 11 most commonly occurring rep-PCR genotype groups, were selected for MLST. MLST was performed with SYBR GreenTM PCR with published primers for both MLST schemes. Amplicons were purified, sequenced, and data checked against the www.PubMLST.org database for allelic and sequence type (ST) assignment. Discriminatory power, congruence, and convenience criteria were evaluated. Concatenated sequences for each scheme were analyzed using MEGA to generate phylogenetic trees using minimum evolution with bootstrap. RESULTS: No significant difference in discriminatory power was observed between the two MLST schemes for S. mutans. Clonal clusters were consistent for both schemes. Overall, MLST demonstrated marginally greater discriminatory power than rep-PCR; however all methods were found to be congruent. New alleles and ST are reported for each scheme and added to the PubMLST database. CONCLUSIONS: Clonality, supported by both methods and rep-PCR, indicates S. mutans genotypes are shared between unrelated subjects. Both Nakano and Do schemes demonstrates similar genotype discrimination for S. mutans isolates suggesting each are well designed and may be used to verify rep-PCR genotypes. PMID- 26439182 TI - Utilization and Costs of Severe Uncontrolled Asthma in a Managed-Care Setting. AB - BACKGROUND: Clinical and economic burden of patients with severe uncontrolled asthma (SUA) in a real-world managed-care setting required further documentation. OBJECTIVE: The objective of this study was to determine the characteristics, clinical, and economic burden of SUA in a managed-care setting. METHODS: This observational study identified patients with persistent asthma aged 12 years or more (N = 25,935) using the International Classification of Diseases, 9th Revision asthma codes and Healthcare Effectiveness Data and Information Set administrative criteria. An SUA subgroup was identified when all of the following 3 criteria were met in 2012: (1) 2 or more asthma exacerbations; (2) 6 or more medium- or high-dose dispensed canisters of inhaled corticosteroid (ICS) as monotherapy or with long-acting beta2-agonist; and (3) 3 or more dispensed non ICS controllers. Health care utilization and direct costs (all-cause and asthma related) in 2013 were compared between SUA and non-SUA subgroups using multivariable regression. RESULTS: Compared with the non-SUA subgroup (N = 25,350, 97.7%), the SUA subgroup (N = 585, 2.3%) at baseline was significantly older and had more comorbidities, asthma specialist care, controller medication dispensed, and asthma exacerbations. During follow-up, patients with SUA exhibited significantly more asthma exacerbations and short-acting beta2-agonist use, and higher all-cause and asthma-related costs than patients with non-SUA. The adjusted asthma-related average direct cost per patient at follow-up was significantly higher for SUA (mean +/- SE) ($2325 +/- $75) than non-SUA ($1261 +/ $9) with an incremental cost of $1056 (95% CI, $907-$1205). Asthma drugs accounted for the major difference (incremental cost of $848/patient; 95% CI, $737-$959). CONCLUSION: Increases and disparities in health care utilization and direct cost by SUA status suggest that patients with SUA require more intensive therapy, greater attention to adherence and comorbidities, more specialist care, and, possibly, personalized treatment approaches including novel biologic treatments. PMID- 26439184 TI - Prospective multicentre study of the U-SENS test method for skin sensitization testing. AB - The U-SENSTM is a test method based on the human myeloid U937 cell line to assess the skin sensitisation potential of substances. To demonstrate its robustness, a multicentre validation study with four laboratories testing 24 coded substances has been conducted according to internationally agreed principles. The primary objective of the study was to enlarge the U-SENSTM's reproducibility database. Secondary objectives were to provide additional evidence on its transferability and its predictive capability. Reproducibility within laboratories was approximately 92%, while the reproducibility between laboratories was 87.5%. Predictivity for the 24 validation substances was high, with sensitivity, specificity and accuracy being on average at least 93.8%. Similar performances are obtained for 38 substances when combining the study results with those of an earlier multicentre study, as well as with an automated version of the U-SENSTM. With reliability and relevance similar to comparable non-animal skin sensitisation test methods, which have achieved regulatory acceptance, it is concluded that the U-SENSTM is a well reproducible and predictive test method. This profiles the U-SENSTM as a valuable addition to the suite of non-animal testing methods for skin sensitisation with the potential to significantly contribute to the development of integrated testing strategies. PMID- 26439183 TI - Gait parameters associated with balance in healthy 2- to 4-year-old children. AB - The use of validated measurements of gait and balance are crucial to establish baseline function and assess effectiveness of therapeutic interventions. Gait in children changes with motor development requiring frequent observations to effectively track progress. Standardized baseline spatiotemporal measurements and a greater understanding of the relationship between gait and balance would provide important feedback to clinicians regarding the effectiveness of rehabilitation and guide treatment modifications. 84 subjects (2.0-4.9 years) walked along the GAITRite((r)), a walkway that records spatiotemporal parameters. The Pediatric Balance Scale (PBS) was administered to assess balance. Comparison of spatiotemporal parameter means between age groups showed trends associated with motor development similar to the ones described in the literature such as decreased cadence and increased step/stride length with increasing age. However, no significant differences in normalized spatiotemporal parameters were found between age groups. Age, leg length, cadence, step/stride length, step/stance time, and single/double support time showed significant correlation with balance scores. When the parameters were grouped into spatial, temporal, and age-related components using principal components analysis and included in a multiple regression model, they significantly predicted 51% of the balance score variance. Age-related components most strongly predicted balance outcomes. We suggest that balance can potentially be evaluated by assessment of spatial, temporal, and age related characteristics of gait such as step length, cadence, and leg length. This suggests the possibility of developing new gait measurement technology that could provide functional assessment and track improvements during rehabilitation regimens. If the same model can be applied to monitor treatment efficacy in children with gait abnormalities remains to be addressed. PMID- 26439185 TI - Conditioned place preferences in humans using secondary reinforcers. AB - The goal of this experiment was to examine whether a conditioned place preference could be established in humans using a secondary reinforcer that provided little obvious reward to the participants. Two experiments were conducted to answer this question. In Experiment 1, 244 undergraduates were placed into a VR environment consisting of two visually distinct rooms connected by a door. Throughout the experiment, one room was randomly paired with occasional point rewards while the other unique room was never paired with rewards. Participants received thee pairings in each room. After a short break, a test session was administered, and participants were given free access to the entire VR environment and no point rewards were administered. On the test day, we observe that participants displayed a significant CPP for the room paired with points, as evidenced by significant differences in rating each of the rooms in terms of enjoyment. In Experiment 2, 77 undergraduates were tested using a biased conditioning approach in which an initial test session was conducted to obtain the participant's preferred room bias, and then the least-preferred room was designated as the points reward room for each participant. Using this biased conditioning approach, participants spent a significantly greater amount of time in the points-paired room. In this case, participants showed preferences based on explicit and implicit measures. These results suggest new approaches to examine the role of secondary reinforcers in nontraditional addictions such as internet, gaming, and gambling dependencies. PMID- 26439186 TI - Clinical Management of Vertebral Compression Fractures. AB - Vertebral compression fractures (VCF's) are the most common form of osteoporotic fractures. Whether symptomatic or asymptomatic, they both represent a high risk for not only vertebral but also nonvertebral fractures in untreated populations. This high risk of future fracture after a VCF is independent of the T-score because bone strength is a combination of bone mineral density and bone quality. VCFs are the single greatest risk for future fractures at all other skeletal sites in untreated populations, including hip fractures. They are often unrecognized despite their exceptionally high prevalence in all genders and most ethnic groups as age increases. This article highlights some of the key messages about VCF's, and how assessment for their presence and then management will reduce the risk of all osteoporotic fractures. PMID- 26439187 TI - Palladium Nanoribbon Array for Fast Hydrogen Gas Sensing with Ultrahigh Sensitivity. AB - A lithographically aligned palladium nano-ribbon (Pd-NRB) array with gaps of less than 40 nm is fabricated on a poly(ethylene terephthalate) substrate using the direct metal transfer method. The 200 MUm Pd-NRB hydrogen gas sensor exhibits an unprecedented sensitivity of 10(9) % after bending treatment, along with fast sensing behavior (80% response time of 3.6 s and 80% recovery time of 8.7 s) at room temperature. PMID- 26439188 TI - Brief Report: Immune Microenvironment Determines the Immunogenicity of Induced Pluripotent Stem Cell Derivatives. AB - The breakthrough of induced pluripotent stem cells (iPSCs) has raised the possibility that patient-specific iPSCs can provide autologous cells for cell therapy without the concern for immune rejection. However, the immunogenicity of iPSC-derived cells remains controversial. Using syngeneic C57BL/6 (B6) mouse transplantation model, several studies indicate that B6 iPSC-derived cells exhibit some levels of immunogenicity when transplanted into B6 mice subcutaneously. In contrast, one recent study has concluded that various lineages of B6 iPSC-derived cells exhibit no immunogenicity when transplanted under the kidney capsule of B6 mice. To resolve the controversy concerning this critical issue of iPSC biology, we used the same B6 transplantation model to demonstrate that the immune response toward antigens is dependent on the immune environment of the transplantation site. Immunogenic antigen-expressing B6 embryonic stem cells (ESCs) as well as B6 iPSCs and their terminally differentiated cells survived under the kidney capsule but are immune rejected when transplanted subcutaneously or intramuscularly. The cotransplantation of mature B6 dendritic cells under the kidney capsule leads to immune rejection of B6 iPSC-derived grafts but not B6 ESC-derived grafts, indicating that the lack of detectable immune response to iPSC-derived grafts under the kidney capsule is due to the lack of functional antigen presenting cells. PMID- 26439189 TI - Citrus and melanoma risk: better to consume with dinner? PMID- 26439190 TI - Novel strategy to decrease reperfusion injuries and improve function of cold preserved livers using normothermic ex vivo liver perfusion machine. AB - Normothermic extracorporeal liver perfusion (NELP) can decrease ischemia/reperfusion injury to the greatest degree when cold ischemia time is minimized. Warm perfusion of cold-stored livers results in hepatocellular damage, sinusoidal endothelial cell (SEC) dysfunction, and Kupffer cell activation. However, the logistics of organ procurement mandates a period of cold preservation before NELP. The aim of this study was to determine the beneficial effects of gradual rewarming of cold-stored livers by placement on NELP. Three female porcine livers were used for each group. In the immediate NELP group, procured livers were immediately placed on NELP for 8 hours. In the cold NELP group, livers were cold-stored for 4 hours followed by NELP for 4 hours. In rewarming groups, livers were cold-stored for 4 hours, then gradually rewarmed in different durations to 38 degrees C and kept on NELP for an additional 4 hours. For comparison purposes, the last 4 hours of NELP runs were considered to be the evaluation phase. Immediate NELP livers had significantly lower concentrations of liver transaminases, hyaluronic acid, and beta-galactosidase and had higher bile production compared to the other groups. Rewarming livers had significantly lower concentrations of hyaluronic acid and beta-galactosidase compared to the cold NELP livers. In addition, there was a significant decline in international normalized ratio values, improved bile production, reduced biliary epithelial cell damage, and improved cholangiocyte function. Thus, if a NELP machine is not available at the procurement site and livers will need to undergo a period of cold preservation, a gradual rewarming protocol before NELP may greatly reduce damages that are associated with reperfusion. In conclusion, gradual rewarming of cold-preserved livers upon NELP can minimize the hepatocellular damage, Kupffer cell activation, and SEC dysfunction. PMID- 26439192 TI - Mapping the potential beverage quality of coffee produced in the Zona da Mata, Minas Gerais, Brazil. AB - BACKGROUND: Detailed knowledge of coffee production systems enables optimization of crop management, harvesting and post-harvest techniques. In this study, coffee quality is mapped as a function of coffee variety, altitude and terrain aspect attributes. The work was performed in the Zona da Mata, Minas Gerais, Brazil. RESULTS: A large range of coffee quality grades was observed for the Red Catuai variety. For the Yellow Catuai variety, no quality grades lower than 70 were observed. Regarding the terrain aspect, samples from the southeast-facing slope (SEFS) and the northwest-facing slope (NWFS) exhibited distinct behaviors. The SEFS samples had a greater range of quality grades than did the NWFS samples. The highest grade was obtained from an NWFS point. The lowest quality values and the largest range of grades were observed at lower altitudes. The extracts from the highest-altitude samples did not produce any low-quality coffee. CONCLUSIONS: The production site's position and altitude are the primary variables that influenced the coffee quality. The study area has micro-regions with grades ranging from 80 to 94. These areas have the potential for producing specialty coffees. (c) 2015 Society of Chemical Industry. PMID- 26439191 TI - Microbiota and host immune responses: a love-hate relationship. AB - A complex relationship between the microbiota and the host emerges early at birth and continues throughout life. The microbiota includes the prokaryotes, viruses and eukaryotes living among us, all of which interact to different extents with various organs and tissues in the body, including the immune system. Although the microbiota is most dense in the lower intestine, its influence on host immunity extends beyond the gastrointestinal tract. These interactions with the immune system operate through the actions of various microbial structures and metabolites, with outcomes ranging from beneficial to deleterious for the host. These differential outcomes are dictated by host factors, environment, and the type of microbes or products present in a specific ecosystem. It is also becoming clear that the microbes are in turn affected and respond to the host immune system. Disruption of this complex dialogue between host and microbiota can lead to immune pathologies such as inflammatory bowel diseases, diabetes and obesity. This review will discuss recent advances regarding the ways in which the host immune system and microbiota interact and communicate with one another. PMID- 26439193 TI - Improving discharge planning communication between hospitals and patients. AB - BACKGROUND: A potential barrier to patient discharge from hospital is communication problems between the treating team and the patient or family regarding discharge planning. AIM: To determine if a bedside 'Leaving Hospital Information Sheet' increases patient and family's knowledge of discharge date and destination and the name of the key clinician primarily responsible for team patient communication. METHODS: This article is a 'before-after' study of patients, their families and the interdisciplinary ward-based clinical team. Outcomes assessed pre-implementation and post-implementation of a bedside 'Leaving Hospital Information Sheet' containing discharge information for patients and families. Patients and families were asked if they knew the key clinician for team-patient communication and the proposed discharge date and discharge destination. Responses were compared with those set by the team. Staff were surveyed regarding their perceptions of patient awareness of discharge plans and the benefit of the 'Leaving Hospital Information Sheet'. RESULTS: Significant improvement occurred regarding patients' knowledge of their key clinician for team-patient communication (31% vs 75%; P = 0.0001), correctly identifying who they were (47% vs 79%; P = 0.02), and correctly reporting their anticipated discharge date (54% vs 86%; P = 0.004). There was significant improvement in the family's knowledge of the anticipated discharge date (78% vs 96%; P = 0.04). Staff reported the 'Leaving Hospital Information Sheet' assisted with communication regarding anticipated discharge date and destination (very helpful n = 11, 39%; a little bit helpful n = 11, 39%). CONCLUSIONS: A bedside 'Leaving Hospital Information Sheet' can potentially improve communication between patients, families and their treating team. PMID- 26439194 TI - Megakaryocytic differentiation of mouse embryonic stem cells via coculture with immortalized OP9 stromal cells. AB - Established from the calvaria of newborn macrophage colony-stimulating factor (M CSF)-deficient mice, OP9 is a stromal cell line that used as a feeder layer to support the in vitro differentiation of pluripotent stem cells into various hematopoietic lineage cells, including granulocytes, erythrocytes, lymphocytes, and megakaryocytes. However, as a primary culture cell line, OP9 can be used as stromal cells for only 1 month. Therefore, to obtain functional OP9 cells, numerous M-CSF-deficient newborn mice must be sacrificed. These limitations in some ways restrict the application of OP9 cells in longterm and largescale experiments. In this study, we used human papillomavirus 16 E6 and E7 genes to generate immortalized OP9 stromal cells, designated I-OP9 cells, and then tested their ability to support the megakaryocytic differentiation of pluripotent stem cells in vitro. I-OP9 cells have similar morphology and properties as do parental OP9 cells, and, as expected, have an extended lifespan and can support megakaryocytic differentiation. Our data suggest that the method used in this study, including establishing I-OP9 cells, enables the possibility to enlarge and lengthen the scale of the experiment and, more critically, provides a humanistic approach for preparing stromal cells that support the hematopoietic differentiation of pluripotent stem cells in vitro. PMID- 26439196 TI - A Meta-Analysis of Association Between Pesticides Exposure and Glioma Risk in Adults. PMID- 26439195 TI - Ectopic AP4 expression induces cellular senescence via activation of p53 in long term confluent retinal pigment epithelial cells. AB - When cells are grown to confluence, cell-cell contact inhibition occurs and drives the cells to enter reversible quiescence rather than senescence. Confluent retinal pigment epithelial (RPE) cells exhibiting contact inhibition was used as a model in this study to examine the role of overexpression of transcription factor AP4, a highly expressed transcription factor in many types of cancer, in these cells during long-term culture. We generated stable inducible RPE cell clones expressing AP4 or AP4 without the DNA binding domain (DN-AP4) and observed that, when cultured for 24 days, RPE cells with a high level of AP4 exhibit a large, flattened morphology and even cease proliferating; these changes were not observed in DN-AP4-expressing cells or non-induced cells. In addition, AP4 expressing cells exhibited senescence-associated beta-galactosidase activity and the senescence-associated secretory phenotype. We demonstrated that the induced cellular senescence was mediated by enhanced p53 expression and that AP4 regulates the p53 gene by binding directly to two of the three E-boxes present on the promoter of the p53 gene. Moreover, we showed that serum is essential for AP4 in inducing p53-associated cellular senescence. Collectively, we showed that overexpression of AP4 mediates cellular senescence involving in activation of p53 in long-term post-confluent RPE cells. PMID- 26439197 TI - Choroid Plexus Carcinoma in the External Ventricle of an Adult. PMID- 26439198 TI - An Unusual Deadly Craniofacial Trauma Case Due To Hot Liquid Plastic Infusion. PMID- 26439199 TI - Molluscum Contagiosum on the Lip. PMID- 26439200 TI - Conventional Panoramic Radiograph Cannot Identify the Bifid Mandibular Canal. PMID- 26439201 TI - Antibacterial Effects of Platelet-Rich Plasma in Promoting Facial Scars Healing in Combination With Adipose-Derived Stromal Vascular Fraction Cells. PMID- 26439202 TI - Pediatric Nevus Sebaceous of the Scalp: A Reconstructive Challenge. PMID- 26439203 TI - Intradiploic Epidermoid Cyst in the Skull. PMID- 26439204 TI - Fish Bone Induced Sialolith in Warthon Duct. PMID- 26439205 TI - Surgical Treatment and Immediate Reconstruction of Keratocystic Odontogenic Tumor. PMID- 26439206 TI - Malignant Transformation of Facial Epidermoid Cyst With Distant Metastasis. PMID- 26439207 TI - Age as a Risk Factor for Flap Failure in Free Tissue Transfer. PMID- 26439208 TI - The Prolonged Double Vision Is not Only Caused by Adhesion of Orbital Contents After Blowout Fractures: Important Role of the Orbital Proprioception. PMID- 26439209 TI - Impure Blow-in Orbital Fracture With Severe Proptosis. PMID- 26439210 TI - Hede: Postoperative Low-Flow Cerebrospinal Fluid Leak of Endoscopic Endonasal Transsphenoidal Surgery for Pituitary Adenoma: Wait and See, or Lumbar Drain? PMID- 26439211 TI - Clinical relevance of corrosion patterns attributed to inflammatory cell-induced corrosion: A retrieval study. AB - In vitro studies have shown that human osteoclasts can corrode stainless steel and titanium leading to the production of metal ions responsible for inflammatory reactions. Moreover, traces of cellular activities on metal orthopaedic explants have recently been reported as inflammatory cell-induced (ICI) corrosion being the result of the cells sealing on the metal surfaces and releasing reactive oxygen species (ROS) through Fenton-like reactions. The extent and clinical relevance of this phenomenon has yet to be understood. We analysed a cohort of 100 CoCr alloy hips collected at our retrieval centre; we performed macroscopic and microscopic screening and used statistical analysis to correlate our findings with implant and clinical variables. We found that 59% of our implants had evidence of surface damage consistent with what has previously been described as cell-induced corrosion. There was a significant association between the patterns and aseptic loosening for the ASR modular (r = -0.488, p = 0.016) and the Durom modular (r = 0.454, p = 0.026). This is the largest implant retrieval study to examine the phenomena of so-called ICI corrosion and is the first to investigate its clinical relevance. We recommend further work to determine the role of cells in the damage patterns observed. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 155-164, 2017. PMID- 26439212 TI - Osteomyelitis in adult patients on long-term parenteral nutrition: 2745 patient years of experience in a national referral centre. AB - BACKGROUND & AIMS: Osteomyelitis (OM) is a rare complication of catheter related sepsis after central venous catheter (CVC) use. The prevalence, characteristics and diagnosis of OM in patients with intestinal failure (IF) receiving long term parenteral nutrition (PN) through CVCs have not previously been described. METHODS: This was a retrospective study from a prospectively maintained database of patients referred to a National IF centre. Age, IF aetiology, past medical history, time on PN, OM site and organism(s) cultured were recorded. Patients were divided into 2 groups: OM occurring in the setting of acute (Type 2) IF (AIF) or chronic (Type 3) IF (CIF). Diagnosis of OM was made clinically and supported by radiological and/or microbial evidence. RESULTS: 21 cases of OM occurred in 17 patients (7 male (41%)) between 1994 and 2014. 0 cases were observed between 1994 and 1999, 1 case between 2000 and 2004, 6 cases between 2005 and 2009 and 14 cases between 2010 and 2014. There were 11 cases in 7 patients with CIF managed at the IFU between 1994 and 2014; the latter yielded a period prevalence for OM of 0.9% when compared to the 794 HPN patients managed by the IFU over this period. There were 10 cases of OM in 10 patients with AIF; patients with AIF had spent less time on PN before developing OM, compared to patients with CIF; despite this, the rate of preceding CVC infections was higher in the AIF (5.6/1000 catheter days) than in the CIF (0.3/1000 catheter days) group, as a result of patients with AIF contracting CVC infections prior to specialist referral. Patients with AIF had more severe OM compared to those with CIF, according to the Cierny Mader classification. All patients received at least 6 weeks antimicrobial chemotherapy. 4/10 (40%) AIF cases and 2/11 (18%) CIF cases required surgical intervention. No patient died from OM or its treatment. CONCLUSION: OM is a rare complication of IF and its treatment, but is being diagnosed more frequently than before and should be noted as a potential focus of sepsis in patients with IF, because it may lead to considerable morbidity. PMID- 26439213 TI - Combining mechanistic and data-driven approaches to gain process knowledge on the control of the metabolic shift to lactate uptake in a fed-batch CHO process. AB - A growing body of knowledge is available on the cellular regulation of overflow metabolism in mammalian hosts of recombinant protein production. However, to develop strategies to control the regulation of overflow metabolism in cell culture processes, the effect of process parameters on metabolism has to be well understood. In this study, we investigated the effect of pH and temperature shift timing on lactate metabolism in a fed-batch Chinese hamster ovary (CHO) process by using a Design of Experiments (DoE) approach. The metabolic switch to lactate consumption was controlled in a broad range by the proper timing of pH and temperature shifts. To extract process knowledge from the large experimental dataset, we proposed a novel methodological concept and demonstrated its usefulness with the analysis of lactate metabolism. Time-resolved metabolic flux analysis and PLS-R VIP were combined to assess the correlation of lactate metabolism and the activity of the major intracellular pathways. Whereas the switch to lactate uptake was mainly triggered by the decrease in the glycolytic flux, lactate uptake was correlated to TCA activity in the last days of the cultivation. These metabolic interactions were visualized on simple mechanistic plots to facilitate the interpretation of the results. Taken together, the combination of knowledge-based mechanistic modeling and data-driven multivariate analysis delivered valuable insights into the metabolic control of lactate production and has proven to be a powerful tool for the analysis of large metabolic datasets. PMID- 26439214 TI - Home Invasion Homicide Offenders: An Analysis of Subsequent Prison Rule Violations. AB - This study adds to the small body of research on home invasion by describing the circumstances surrounding home invasions that resulted in the death of a resident. The 2 most common types of home invasion homicides (HIHs) involved "drug ripoffs" and robberies of older adults for money and property. The study also examined subsequent rule-violating behavior of 132 HIH inmates while incarcerated. The rate of rule violations among HIH inmates was similar to a broader cohort of incarcerated homicide offenders. A logistic regression model identified variation in assaultive prison behavior based on some routine predictors (age, education, race, and prior imprisonment) and 2 associated with the crime (method of killing and age by gender of victims). PMID- 26439215 TI - The S-stamp in Descemet Membrane Endothelial Keratoplasty Safely Eliminates Upside-down Graft Implantation. AB - PURPOSE: To present 6-month clinical outcomes from a series of 165 consecutive Descemet membrane endothelial keratoplasty (DMEK) procedures before and after the introduction of a novel stromal-sided S-stamp preparation technique that has decreased the incidence of iatrogenic primary graft failure by eliminating upside down grafts. DESIGN: Retrospective nonrandomized comparative case series. PARTICIPANTS: We included 165 consecutive eyes that had undergone DMEK surgery for Fuchs' or pseudophakic bullous keratopathy. These cases were divided into 2 cohorts: the first cohort comprised 31 cases that used unstamped tissue before the S-stamp was introduced, and the second cohort comprised 133 cases after the S stamp was incorporated into the standardized technique. A single unstamped DMEK case was performed after the introduction of the S-stamp for a total of 32 unstamped cases. METHODS: Donor materials were prepared at a single eye bank using a standardized technique, which subsequently incorporated the addition of a dry ink gentian violet S-stamp to the stromal side of Descemet membrane. All surgeries were performed at a single clinical site by 5 surgeons (2 attending surgeons and 3 fellows). Two of the 165 DMEK cases were performed for pseudophakic bullous keratopathy (2 cases, 1 in each cohort), and the remaining cases were for Fuchs' endothelial dystrophy. Primary outcome measures were assessed at 6 months and maintained in a prospective institutional review board approved study. MAIN OUTCOME MEASURES: We analyzed the 6-month endothelial cell density, incidence of iatrogenic primary graft failure, upside-down graft implantation, and rebubble events. RESULTS: The S-stamp eliminated upside-down graft implantations (0/133 S-stamped vs 3/32 unstamped) and did not significantly alter 6-month endothelial cell loss (31+/-17% S-stamped vs 29+/-14% unstamped; P = 0.62) or frequency of rebubble (17/133 S-stamped vs 1/32 unstamped; P = 0.20). CONCLUSION: The incorporation of a stromal-sided S-stamp eliminates iatrogenic primary graft failure owing to upside-down implantation of DMEK grafts, without adversely affecting early postoperative complications or 6-month endothelial cell loss. PMID- 26439216 TI - Julian Robert Frayne (1935-2015). PMID- 26439217 TI - Missed diagnosis of brilliance in a colleague. PMID- 26439218 TI - Using PET and CT imaging to define the radiotherapy target for tumours that move with respiration. PMID- 26439220 TI - Instantaneous Click Chemistry by a Copper-Containing Polymeric-Membrane-Installed Microflow Catalytic Reactor. AB - The copper(I)-catalyzed Huisgen cycloaddition (azide-alkyne cycloaddition) is an important reaction in click chemistry that ideally proceeds instantaneously. An instantaneous Huisgen cycloaddition has been developed that uses a novel catalytic dinuclear copper complex-containing polymeric membrane-installed microflow device. A polymeric membranous copper catalyst was prepared from poly(4 vinylpyridine), copper(II) sulfate, sodium chloride, and sodium ascorbate at the interface of two laminar flows inside microchannels. Elucidation of the structure by XANES, EXAFS, and elemental analysis, as well as second-order Moller-Plesset perturbation theory (MP2) calculations and density functional theory (DFT) calculations assigned the local structure near Cu as a MU-chloro dinuclear Cu(I) complex. The microflow device promotes the instantaneous click reaction of a variety of alkynes and organic azides to afford the corresponding triazoles in quantitative yield. PMID- 26439221 TI - Reply. PMID- 26439222 TI - The more you look, the more you will find. PMID- 26439223 TI - Possible influence of AMPD1 on cholinergic neurotransmission and sleep. AB - It is known that adenosine excess due to monophosphate deaminase deficiency (AMPD1) can be linked to muscle problems. Recently, Perumal et al., 2014 reported a first case of possible impact of AMPD1 on sleep, REM sleep and cholinergic neurotransmission. We report a second patient with similar sleep complaints: long sleep duration with residual daytime sleepiness and a need to sleep after exercise. On polysomnography we observed a long sleep duration, with high sleep efficiency and a SOREMP; on MSLT a shortened sleep latency and 4 SOREMPS were observed. Frequency power spectral heart rate analysis during slow wave sleep, REM sleep and wakefulness revealed an increased parasympathetic tone. In conclusion, AMPD1 could have a profound influence on cholinergic neurotransmission and sleep; further studies are mandatory. PMID- 26439224 TI - Expression of TP53, BCL-2, and VEGFA Genes in Esophagus Carcinoma and its Biological Significance. AB - BACKGROUND: The pathogenesis of esophagus carcinoma involves a cascade process consisting of multiple factors and accumulation of gene mutations. It is known that vascular endothelial growth factor (VEGF) mainly regulates de novo vascular formation while B-cell lymphoma-2 (BCL-2) gene exerts a tumor-suppressing effect. The prominent expression of VEGFA and BCL-2 genes, along with the most famous tumor-suppressor gene, TP53, raise the possibly of gene interaction. This study therefore investigated the effect and correlation of TP53, BCL-2, and VEGFA genes on cell proliferation and apoptosis of esophagus carcinoma. MATERIAL AND METHODS: A total of 30 male rats were prepared by subcutaneous injection of methyl-benzyl nitrosamine (MBNA) to induce esophagus cancer, along with 30 controlled rats which received saline instead. After 4, 10, 20, or 30 weeks, rats were sacrificed to observe the morphological changes of esophageal mucosa. Cell apoptosis was quantified by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Immunohistochemical (IHC) staining was employed to examine the expression of TP53, BCL-2 and VEGFA genes. RESULTS: With the progression of cancer, pathological damages of esophageal tissue aggravated while the cancer cell apoptosis gradually decreased compared to controlled animals. Protein levels of p53, Bcl-2, and VEGF in the model group were significantly elevated at each time point. Positive correlations existed between p53 and Bcl-2 or VEGF. CONCLUSIONS: Abnormally elevated expression of TP53, BCL-2, and VEGFA genes may participate in the proliferation of esophagus cancer cells in a synergistic manner. PMID- 26439225 TI - Fast Liquid Transfer between Surfaces: Breakup of Stretched Liquid Bridges. AB - In this work, a systematic experimental study was performed to understand the fast liquid transfer process between two surfaces. According to the value of the Reynolds number (Re), the fast transfer is divided into two different scenarios, one with negligible inertia effects (Re ? 1) and the other with significant inertia effects (Re > 1). For Re ? 1, the influences of the capillary number (Ca) and the dimensionless minimum separation (H(min)* = H(min)/V(1/3), where H(min) is the minimum separation between two surfaces and V is the volume of liquid) on the transfer ratio (alpha, the volume of liquid transferred to the acceptor surface over the total liquid volume) are discussed. On the basis of the roles of each physical parameter, an empirical equation is presented to predict the transfer ratio, alpha = f(Ca). This equation involves two coefficients which are affected only by the surface contact angles and H(min)* but not by the liquid viscosity or surface tension. When Re > 1, it is shown for the first time that the transfer ratio does not converge to 0.5 with the increase in the stretching speed. PMID- 26439226 TI - Capture and Direct Amplification of DNA on Chitosan Microparticles in a Single PCR-Optimal Solution. AB - While nucleic acid amplification tests have great potential as tools for rapid diagnostics, complicated sample preparation requirements inhibit their use in near-patient diagnostics and low-resource-setting applications. Recent advancements in nucleic acid purification have leveraged pH-modulated charge switching polymers to reduce the number of steps required for sample preparation. The polycation chitosan (pKa 6.4) has been used to efficiently purify DNA by binding nucleic acids in acidic buffers and then eluting them at a pH higher than 8.0. Though it is an improvement over conventional methods, this multistep procedure has not transformed the application of nucleic acid amplification assays. Here we describe a simpler approach using magnetic chitosan microparticles that interact with DNA in a manner that has not been reported before. The microparticles capture DNA at a pH optimal for PCR (8.5) just as efficiently as at low pH. Importantly, the captured DNA is still accessible by polymerase, enabling direct amplification from the microparticles. We demonstrate quantitative PCR from DNA captured on the microparticles, thus eliminating nearly all of the sample preparation steps. We anticipate that this new streamlined method for preparing DNA for amplification will greatly expand the diagnostic applications of nucleic acid amplification tests. PMID- 26439233 TI - Nutritional management of patients with diabetic peripheral neuropathy with L methylfolate-methylcobalamin-pyridoxal-5-phosphate: results of a real-world patient experience trial. AB - OBJECTIVE: Current therapies for diabetic peripheral neuropathy with pain mask the painful symptoms while the underlying pathology continues to progress. This study assessed changes in symptoms and quality of life in patients taking a novel prescription medical food, L-methylfolate-methylcobalamin-pyridoxal-5-phosphate (LMF-MC-PP, Metanx ), intended to address the underlying metabolic needs of patients with diabetic peripheral neuropathy. RESEARCH DESIGN AND METHODS: Between November 2010 and April 2012, patients rated their experiences before and after using LMF-MC-PP through an automated telephone system that included symptomatic items from the Neuropathy Total Symptom Score-6 (NTSS-6) questionnaire and questions related to quality of life and medication satisfaction. RESULTS: A total of 544 patients participated in the study. Patients reported a mean reduction of 35% in NTSS-6 scores from after 12 weeks on LMF-MC-PP. Mean (standard deviation) score was reduced by 1.5 (1.8) at 12 weeks from a baseline of 4.3 (1.5) (p < 0.05). Patients achieved significant reductions in self-reported disruptions in work/school activities, social life, and family life, respectively. Overall pain rating decreased by 32% (p < 0.05). Patients previously treated with medications reported a 52% improvement in medication satisfaction (p < 0.05). CONCLUSIONS: In a real-world clinical setting, patients with diabetic peripheral neuropathy treated with LMF-MC-PP achieved significant improvements in total symptom score (NTSS-6) and in quality of life and functioning, together with greater medication satisfaction. A limitation of this study was the use of a survey instrument to collect data on patient outcomes. PMID- 26439234 TI - A Pilot Study to Assess the Feasibility of Group Exercise and Animal-Assisted Therapy in Older Adults. AB - This pilot study assessed the feasibility of incorporating animal-assisted therapy teams (ATT) into a 6-week group exercise program for older adults (77 +/- 6 years). Fifteen participants were randomly assigned to an exercise with ATT (E+ATT; n = 8) or exercise only (E; n = 7) group. Groups exercised 3x/week for 45 min. Feasibility was assessed by three objectives: (1) ATT will not need extensive preparation beyond their original therapy training; (2) the study will require minimal cost; and (3) ATT must not impair the effectiveness of the exercise program. By the study conclusion, all objectives were met. Time and cost were minimal for ATT, and adherence was 93% and 90% for E+ATT and E, respectively. There were significant improvements in both groups (p <= .05) for arm curls, get-up and go, and 6-min walk. The results of this pilot study suggest that it is feasible to incorporate ATT into group exercise programming for older adults. PMID- 26439239 TI - Surface Decoration on Polymeric Gate Dielectrics for Flexible Organic Field Effect Transistors via Hydroxylation and Subsequent Monolayer Self-Assembly. AB - A simple photochemical reaction based on confined photocatalytic oxidation (CPO) treatment and hydrolysis was employed to efficiently convert C-H bonds into C-OH groups on polymeric material surfaces, followed by investigation of monolayer self-assembly decoration on polymeric dielectrics via chemical bonding for the organic field-effect transistors (OFETs) applications. This method is a low temperature process and has negligible etching effect on polymeric dielectric layers. Various types of self-assembled monolayers have been tested and successfully attached onto the hydroxylated polymeric dielectric surfaces through chemical bonding, ensuring the stability of decorated functional films during the subsequent device fabrication consisting of solution processing of the polymer active layer. With the surface decoration of functional groups, both n-type and p type polymers exhibit enhanced carrier mobilities in the unipolar OFETs. In addition, enhanced and balanced mobilities are obtained in the ambipolar OFETs with the blend of polymer semiconductors. The anchored self-assembled monolayers on the dielectric surfaces dramatically preclude the solvent effect, thus enabling an improvement of carrier mobility up to 2 orders of magnitude. Our study opens a way of targeted modifications of polymeric surfaces and related applications in organic electronics. PMID- 26439240 TI - Clonidine increases bone resorption in humans. AB - SUMMARY: Inhibition of sympathetic signaling to bone reduces bone resorption in rodents. In contrast, we show that pharmacological reduction of the sympathetic tone increases bone resorption in humans in vivo. This effect does not appear to be mediated via a direct pharmacological effect on the osteoclast. INTRODUCTION: Inhibition of sympathetic signaling to bone reduces bone resorption in rodents. It is uncertain whether a similar role for the sympathetic nervous system exists in humans. The sympathetic tone can be reduced by clonidine, which acts via alpha 2-adrenergic receptors in the brainstem. Our objective was to determine the effect of clonidine on bone turnover in humans. METHODS: The acute effect of a single oral dose of 0.3 mg clonidine on serum bone turnover markers (C-terminal cross-linking telopeptides of collagen type I (CTx), a marker for bone resorption, and procollagen type 1 N propeptide (P1NP), a marker for bone formation) was determined in a randomized crossover design in 12 healthy volunteers, aged 18-70 years. In addition, we assessed the effect of clonidine on the number of tartrate-resistant acid phosphatase-positive multinucleated cells (TRAcP(+) MNCs) and bone resorption. RESULTS: CTx concentrations increased after clonidine treatment compared to the control condition (p = 0.035). P1NP concentrations were not affected by clonidine (p = 0.520). In vitro, clonidine had no effect on the number of TRAcP(+) MNCs (p = 0.513) or on bone resorption (p = 0.996). CONCLUSIONS: We demonstrated that clonidine increases bone resorption in humans in vivo. This effect does not appear to be mediated via a direct effect on the osteoclast. PMID- 26439241 TI - Renin inhibitor aliskiren exerts beneficial effect on trabecular bone by regulating skeletal renin-angiotensin system and kallikrein-kinin system in ovariectomized mice. AB - SUMMARY: The skeletal renin-angiotensin system contributes to the development of osteoporosis. The renin inhibitor aliskiren exhibited beneficial effects on trabecular bone of osteoporotic mice, and this action might be mediated through angiotensin and bradykinin receptor pathways. This study implies the potential application of renin inhibitor in the management for postmenopausal osteoporosis. INTRODUCTION: The skeletal renin-angiotensin system plays key role in the pathological process of osteoporosis. The present study is designed to elucidate the effect of renin inhibitor aliskiren on trabecular bone and its potential action mechanism in ovariectomized (OVX) mice. METHODS: The OVX mice were treated with low dose (5 mg/kg) or high dose (25 mg/kg) of aliskiren or its vehicle for 8 weeks. The bone turnover markers were measured by ELISA. The structural parameters of trabecular bone at lumbar vertebra (LV) and distal femoral metaphysis were measured by micro-CT. The expression of messenger RNA (mRNA) and protein was studied by RT-PCR and immunoblotting, respectively. RESULTS: Aliskiren treatment reduced urinary excretion of calcium and serum level of tartrate-resistant acid phosphatase in OVX mice. The treatment with aliskiren significantly increased bone volume (BV/TV) and connectivity density (Conn.D) of trabecular bone at LV-2 and LV-5 as well as dramatically enhanced BV/TV, Conn.D, bone mineral density (BMD/BV) and decreased bone surface (BS/BV) at the distal femoral end. Aliskiren significantly down-regulated the expression of angiotensinogen, angiotensin II (Ang II), Ang II type 1 receptor, bradykinin receptor (BR)-1, and osteocytic-specific gene sclerostin as well as the osteoclast-specific genes, including carbonic anhydrase II, matrix metalloproteinase-9, and cathepsin K. CONCLUSIONS: This study revealed that renin inhibitor aliskiren exhibited the beneficial effects on trabecular bone of ovariectomy-induced osteoporotic mice, and the underlying mechanism for this action might be mediated through Ang II and BR signaling pathways in bone. PMID- 26439242 TI - Parity and osteoporotic fracture risk in postmenopausal women: a dose-response meta-analysis of prospective studies. AB - The present dose-response meta-analysis shows linearly decreased hip fracture (HF) risk and nonlinearly decreased osteoporotic fracture (OF) risk associated with increasing number of parity of up to five live births among postmenopausal women. INTRODUCTION: Epidemiological reports suggest that parity is associated with reduced OF risk among women. However, these findings are controversial. Here, we present a meta-analysis of prospective studies of parity in relation to OF risk. METHODS: We performed systematic searches using Medline and Embase from January 1, 1966, to December 31, 2014, with limits of language in English and prospective study design. Relative risks (RRs) and confidence intervals (CIs) were derived mainly using random-effects models. Categorical, dose-response, heterogeneity, publication bias, and subgroup analyses were conducted. RESULTS: We analyzed 10 articles of 19 independent reports from 1966 to 2014, comprising a total of 217,295 participants and 26,525 cases of OF. Compared to nulliparous women, the OF and HF risks of parous women with at least one live birth were reduced by 11 % (95 % confidence interval (CI) 3-19 %; I (2) = 77.1 %, p < 0.001) and 26 % (95 % CI 17-35 %; I (2) = 19.5 %, p = 0.287), respectively. Representative nonlinearly and linearly inverse dose-response associations were found between parity (range of 0-6) and OF risk (p nonlinearity = 0.0163; I (2) = 79.7 %, p < 0.001), and between parity (range of 0-5) and HF risk (p nonlinearity = 0.054; I (2) = 76.5 %, p < 0.001), respectively. The lowest risk reduction for OF of 25 % (95 % CI 16-33 %) was observed for five live births. And, the summary risk reduction for HF was 12 % (95 % CI 9-15 %) for each one increased live birth. CONCLUSIONS: We found that increasing number of parity is associated with linearly reduced HF risks among women. The association between parity of six or more live births and HF risks should be studied further in future. PMID- 26439243 TI - Effect of glycemic state on postprandial hyperlipidemia and hyperinsulinemia in patients with coronary artery disease. AB - Both postprandial hyperlipidemia and hyperinsulinemia have been thought to play an important role in the development of atherosclerosis, and to be a potent risk factor for cardiovascular event. To examine effects of glycemic state on postprandial hyperlipidemia and hyperinsulinemia in patients with coronary artery disease (CAD), a total of 112 consecutive male pati ents with angiographically confirmed CAD were loaded with a high-fat and high-glucose test meal. CAD patients were divided into three groups as "non-diabetic", "prediabetic", and "diabetic" CAD groups. The serum triglyceride (TG) and remnant-like particle cholesterol (RLP-C) levels at the 6th hour in diabetic CAD group showed significantly higher than non-diabetic CAD group, and the incremental area under the curves (iAUCs) of these levels in diabetic CAD group were significantly greater than non-diabetic CAD group (TG, P = 0.0194; RLP-C, P = 0.0219). There were no significant differences in the iAUCs of TG or RLP-C between prediabetic and non-diabetic CAD group. The AUCs of plasma insulin levels or insulin resistance index (IRI): (AUCs of insulin) * (AUCs of glucose) as the insulin resistance marker were greater in diabetic CAD group than non-diabetic CAD group (insulin, P = 0.0373; IRI, P = 0.0228). The AUCs of serum TG or RLP-C levels showed a correlation with the AUCs of plasma insulin (AUC-TG, r = 0.5437, P < 0.0001; AUC-RLP-C, r = 0.6847, P < 0.0001), and they correlated well with the insulin resistance index (AUC-TG, r = 0.7724, P < 0.0001; AUC-RLP-C, r = 0.7645, P < 0.0001). We found that the insulin resistance showed a close relationship with postprandial hyperlipidemia in CAD patients. Diabetic, but not prediabetic state, may be a risk for postprandial impaired lipid metabolism in CAD patients. PMID- 26439245 TI - Erratum to: Effect of Colchicine on Platelet-Platelet and Platelet-Leukocyte Interactions: a Pilot Study in Healthy Subjects. PMID- 26439244 TI - Estrus response and fertility of Menz and crossbred ewes to single prostaglandin injection protocol. AB - Natural lambing in sheep in Ethiopia occurs throughout the year in a scattered manner negatively affecting survival and growth rates of the lambs born during the unfavorable season of the year. Thus, controlling the time of mating artificially using exogenous source of hormones is considered as one of the ways to mitigated problems related to haphazard lambing. To this end, an experiment was conducted to evaluate efficacy of prostaglandin-based estrus synchronization protocol in local and crossbred ewes. A total of 160 ewes (80 local and 80 crossbreds) which lambed at least once and aged 3-5 years were used. Lutalyse(r) (dinoprost tromethamine sterile solution equivalent to 5 mg dinoprost per ml) and its analog, Synchromate(r) (cloprostenol sodium equivalent to 0.250 mg cloprostenol per ml), were tested at different doses. The treatments used were intramuscular injection of (1) 2.50 ml of Lutalyse(r) (12.5 mg dinoprost tromethamine), (2) 2 ml of Lutalyse(r) (10.0 mg dinoprost tromethamine), (3) 1 ml of Synchromate(r) (0.25 mg of cloprostenol Sodium), and (4) 0.8 ml of Synchromate(r) (0.20 mg of cloprostenol Sodium). Forty ewes (20 local and 20 crossbreds) were allocated per treatment. Following injection of the respective hormones, rams of known fertility were introduced into the flock for the duration of 96 h at the ratio of one ram to 10 ewes. All estrus synchronization protocols except treatment 4 (0.8 ml of Synchromate(r)) induced estrus (heat) in majority (55-65%) of local and crossbred ewes within 96 h post-hormone injection. The time interval from hormone administration to onset of estrus was also more or less similar for all treatment groups except for treatment group 4 which showed heat quicker. The highest lambing rate was recorded in local ewes (84.62% (11/13) treated with 2.5 ml of Lutalyse(r), whereas the least was obtained in crossbreds (33.33% (3/9) treated with 0.8 ml Synchromate(r). In conclusion, even though 2.5 ml and 2 ml of Lutalyse(r) or 1 ml of Synchromate(r) were able to induce heat in majority of local and crossbred ewes, the highest lambing percentage was obtained from ewes treated with 2.5 ml of Lutalyse(r). Therefore, the use of 2.5 ml Lutalyse(r) is recommended to synchronize estrus in local and crossbred ewes under Ethiopian smallholder sheep production system for the benefit of improved lambing rate. PMID- 26439246 TI - Raloxifene Inhibits NF-kB Pathway and Potentiates Anti-Tumour Activity of Cisplatin with Simultaneous Reduction in its Nephrotoxictiy. AB - Cisplatin induced nephrotoxicity is the chief obstacle in the use of cisplatin as chemotherapeutic agent. However, it remains as most widely employed anticancer agent to treat various solid tumours like head-neck, testicular, ovarian and mammary gland cancer. Raloxifene is claimed to be potent anti-inflammatory as well as anti-cancer agent. The present study was carried out to explore the effect of pre-treatment of raloxifene on cisplatin induced nephrotoxicity and its anti-tumour activity in 7, 12 dimethyl benz [a] anthracene induced mammary tumour in animal model. Renal damage was accessed by measuring serum level of creatinine, blood urea nitrogen and albumin whereas systemic inflammation was accessed by measuring level of pro-inflammatory cytokines like tumour necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), interleukin 10 (IL-10) and nuclear factor kappa B (NFkappaB). Moreover, assessment of tumour reduction was done by measuring tumour volume and percentage tumour reduction. A single dose of cisplatin (7.5 mg/kg) resulted in significant increase in serum creatinine, blood urea nitrogen, NF-kB, TNF-alpha and IL-6 levels along with decrease in albumin and IL-10 levels. However, there were no significant changes in raloxifene (8 mg/kg) treated group. Pre-treatment of raloxifene (8 mg/kg) caused marked decrease in serum creatinine, blood urea nitrogen, TNF-alpha and IL-6 levels whereas increase in albumin and IL-10 levels. However, pre-treatment of raloxifene showed maximum tumour reduction as compared to cisplatin and raloxifene treated groups. The present study demonstrates that raloxifene potentiates anti-tumour activity of cisplatin with simultaneous reduction in its nephrotoxicity, and this effect is attributed to its direct anti-inflammatory activity. PMID- 26439247 TI - Entransia and Hormidiella, sister lineages of Klebsormidium (Streptophyta), respond differently to light, temperature, and desiccation stress. AB - The green-algal class Klebsormidiophyceae (Streptophyta), which occurs worldwide, comprises the genera Klebsormidium, Interfilum, Entransia, and Hormidiella. Ecophysiological research has so far focused on the first two genera because they are abundant in biological soil crust communities. The present study investigated the photosynthetic performances of Hormidiella attenuata and two strains of Entransia fimbriata under light, temperature, and desiccation stress. Their ultrastructure was compared using transmission electron microscopy. The two Entransia strains showed similar physiological responses. They used light more efficiently than Hormidiella, as indicated by higher oxygen production and relative electron transport rate under low light conditions, lower light saturation and compensation points, and higher maximum oxygen production during light saturation. Their requirement for low light levels explains the restriction of Entransia to dim limnetic habitats. In contrast, Hormidiella, which prefers drier soil habitats, responded to light gradients similarly to other aero terrestrial green algae. Compared to Entransia, Hormidiella was less affected by short-term desiccation, and rehydration allowed full recovery of the photosynthetic performance. Nevertheless, both strains of Entransia coped with low water availability better than other freshwater algae. Photosynthetic oxygen production in relation to respiratory consumption was higher in low temperatures (Entransia: 5 degrees C, Hormidiella: 10 degrees C) and the ratio decreased with increasing temperatures. Hormidiella exhibited conspicuous triangular spaces in the cell wall corners, which were filled either with undulating cell wall material or with various inclusions. These structures are commonly seen in various members of Klebsormidiophyceae. The data revealed significant differences between Hormidiella and Entransia, but appropriate adaptations to their respective habitats. PMID- 26439248 TI - Monocyte/HDL-cholesterol ratio predicts the definite stent thrombosis after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. AB - AIM: We investigated the predictive value of monocyte count to HDL ratio (M/H ratio) for stent thrombosis (ST) in ST elevation myocardial infarction (STEMI). PATIENTS & METHODS: 1170 STEMI patients treated with primary PCI were followed-up for a median of 37.2 months. RESULTS: During follow-up, 112 patients were diagnosed as 'definite' ST. The rate of ST was significantly highest in the third M/H ratio tertile. In Cox regression analysis, adjusted for other factors, having an M/H ratio in third tertile had a 2.2-fold increased risk of ST. Kaplan-Meier analysis revealed the higher occurrence of ST in the third tertile compared with others (p <0.001). CONCLUSION: M/H ratio as a novel marker of inflammation seemed to be an independent predictor of ST in STEMI patients. PMID- 26439249 TI - Dynamic Kinetic Resolution of Phthalides via Asymmetric Transfer Hydrogenation: A Strategy Constructs 1,3-Distereocentered 3-(2-Hydroxy-2-arylethyl)isobenzofuran 1(3H)-one. AB - Dynamic kinetic resolution of phthalides through asymmetric transfer hydrogenation for the construction of 3-(2-hydroxy-2-arylethyl)isobenzofuran 1(3H)-one with 1,3-distereocenters has been developed. This procedure is carried out under a mild condition at 40 degrees C catalyzed with RuCl[(S,S) TsDPEN](mesitylene) using HCOOH/Et3N (5:2) as a hydrogen source. A variety of phthalides are smoothly transferred to provide optically pure phthalides with high yields, excellent enantioselectivities, and acceptable diastereomeric ratios. PMID- 26439250 TI - Adolescents' perception of the severity of binge eating disorder: a population based study. AB - BACKGROUND: Binge eating disorder (BED) is relatively common in young people and is associated with marked impairment in physical and mental health. AIMS: We examined perceptions of the severity of BED in a population-based sample of adolescents. METHODS: Male (n = 531) and female (n = 1135) adolescents recruited from 12 Australian schools completed a survey that featured a vignette of a fictional female school student suffering from BED followed by a series of questions addressing perceptions of severity. RESULTS: Approximately half of participants agreed or strongly agreed that BED is a serious problem (male: 52.0%; female: 63.2%) requiring professional treatment (male: 48.2%; female: 54.5%). Approximately one-third of boys (30.7%) believed that BED is primarily a problem of "lack of will power/self-control", whereas one in five girls (19.3%) held this view. Less than half of participants (male: 42.7%; female: 44.1%) believed that someone with BED would be deserving of sympathy. CONCLUSION: The findings suggest that many adolescents, boys in particular, do not consider BED to be a serious mental health problem and believe that individuals with BED lack will-power and/or are undeserving of sympathy. Awareness and understanding of BED may need to be addressed in school-based mental health promotion programs. PMID- 26439251 TI - Platinum-Catalyzed, Terminal-Selective C(sp(3))-H Oxidation of Aliphatic Amines. AB - This Communication describes the terminal-selective, Pt-catalyzed C(sp(3))-H oxidation of aliphatic amines without the requirement for directing groups. CuCl2 is employed as a stoichiometric oxidant, and the reactions proceed in high yield at Pt loadings as low as 1 mol%. These transformations are conducted in the presence of sulfuric acid, which reacts with the amine substrates in situ to form ammonium salts. We propose that protonation of the amine serves at least three important roles: (i) it renders the substrates soluble in the aqueous reaction medium; (ii) it limits binding of the amine nitrogen to Pt or Cu; and (iii) it electronically deactivates the C-H bonds proximal to the nitrogen center. We demonstrate that this strategy is effective for the terminal-selective C(sp(3))-H oxidation of a variety of primary, secondary, and tertiary amines. PMID- 26439258 TI - A Generative Statistical Algorithm for Automatic Detection of Complex Postures. AB - This paper presents a method for automated detection of complex (non-self avoiding) postures of the nematode Caenorhabditis elegans and its application to analyses of locomotion defects. Our approach is based on progressively detailed statistical models that enable detection of the head and the body even in cases of severe coilers, where data from traditional trackers is limited. We restrict the input available to the algorithm to a single digitized frame, such that manual initialization is not required and the detection problem becomes embarrassingly parallel. Consequently, the proposed algorithm does not propagate detection errors and naturally integrates in a "big data" workflow used for large scale analyses. Using this framework, we analyzed the dynamics of postures and locomotion of wild-type animals and mutants that exhibit severe coiling phenotypes. Our approach can readily be extended to additional automated tracking tasks such as tracking pairs of animals (e.g., for mating assays) or different species. PMID- 26439259 TI - Concurrent Visualization of Acoustic Radiation Force Displacement and Shear Wave Propagation with 7T MRI. AB - Manual palpation is a common and very informative diagnostic tool based on estimation of changes in the stiffness of tissues that result from pathology. In the case of a small lesion or a lesion that is located deep within the body, it is difficult for changes in mechanical properties of tissue to be detected or evaluated via palpation. Furthermore, palpation is non-quantitative and cannot be used to localize the lesion. Magnetic Resonance-guided Focused Ultrasound (MRgFUS) can also be used to evaluate the properties of biological tissues non invasively. In this study, an MRgFUS system combines high field (7T) MR and 3 MHz focused ultrasound to provide high resolution MR imaging and a small ultrasonic interrogation region (~0.5 x 0.5 x 2 mm), as compared with current clinical systems. MR-Acoustic Radiation Force Imaging (MR-ARFI) provides a reliable and efficient method for beam localization by detecting micron-scale displacements induced by ultrasound mechanical forces. The first aim of this study is to develop a sequence that can concurrently quantify acoustic radiation force displacements and image the resulting transient shear wave. Our motivation in combining these two measurements is to develop a technique that can rapidly provide both ARFI and shear wave velocity estimation data, making it suitable for use in interventional radiology. Secondly, we validate this sequence in vivo by estimating the displacement before and after high intensity focused ultrasound (HIFU) ablation, and we validate the shear wave velocity in vitro using tissue mimicking gelatin and tofu phantoms. Such rapid acquisitions are especially useful in interventional radiology applications where minimizing scan time is highly desirable. PMID- 26439260 TI - Analyses of Twelve New Whole Genome Sequences of Cassava Brown Streak Viruses and Ugandan Cassava Brown Streak Viruses from East Africa: Diversity, Supercomputing and Evidence for Further Speciation. AB - Cassava brown streak disease is caused by two devastating viruses, Cassava brown streak virus (CBSV) and Ugandan cassava brown streak virus (UCBSV) which are frequently found infecting cassava, one of sub-Saharan Africa's most important staple food crops. Each year these viruses cause losses of up to $100 million USD and can leave entire families without their primary food source, for an entire year. Twelve new whole genomes, including seven of CBSV and five of UCBSV were uncovered in this research, doubling the genomic sequences available in the public domain for these viruses. These new sequences disprove the assumption that the viruses are limited by agro-ecological zones, show that current diagnostic primers are insufficient to provide confident diagnosis of these viruses and give rise to the possibility that there may be as many as four distinct species of virus. Utilizing NGS sequencing technologies and proper phylogenetic practices will rapidly increase the solution to sustainable cassava production. PMID- 26439262 TI - New Insights into Polychaete Traces and Fecal Pellets: Another Complex Ichnotaxon? AB - Neoichnological observations help refine paleoichnological records. The present study reports extensive observations on the distribution, morphology, occurrence and association of burrows and fecal pellets of the polychaete Nereis diversicolor in the Kundalika Estuary on the west coast of India. Our holistic study of these modern-day traces suggests it to be a complex trace arising from domichnial, fodinichnial and possibly pascichnial behavior of polychaetes. The study for the first time reports extensive fecal pellet production, distribution and their preservation as thick stacks in modern estuarine environment. These observations testify the fossilization potential of pellets and provide an explanation to their origin in the geological record. Their occurrence as strings associated with mounds not only suggests pascichnial behaviour of polychaetes but also allows the assignment of post-Paleozoic Tomaculum to the activity of polychaete worms. The production of fecal pellets in such large quantities plays a major role in increasing the average grain size of the substrate of these estuarine tidal flats, thereby improving aeration within the substrate. PMID- 26439261 TI - The Magnitude of Peripheral Muscle Fatigue Induced by High and Low Intensity Single-Joint Exercise Does Not Lead to Central Motor Output Reductions in Resistance Trained Men. AB - PURPOSE: To examine quadriceps muscle fatigue and central motor output during fatiguing single joint exercise at 40% and 80% maximal torque output in resistance trained men. METHOD: Ten resistance trained men performed fatiguing isometric knee extensor exercise at 40% and 80% of maximal torque output. Maximal torque, rate of torque development, and measures of central motor output and peripheral muscle fatigue were recorded at two matched volumes of exercise, and after a final contraction performed to exhaustion. Central motor output was quantified from changes in voluntary activation, normalized surface electromyograms (EMG), and V-waves. Quadriceps muscle fatigue was assessed from changes in the size and shape of the resting potentiated twitch (Q.(pot.tw)). Central motor output during the exercise protocols was estimated from EMG and interpolated twitches applied during the task (VA(sub)). RESULTS: Greater reductions in maximal torque and rate of torque development were observed during the 40% protocol (p<0.05). Maximal central motor output did not change for either protocol. For the 40% protocol reductions from pre-exercise in rate and amplitude variables calculated from the Q.(pot.tw) between 66.2 to 70.8% (p<0.001) exceeded those observed during the 80% protocol (p<0.01). V-waves only declined during the 80% protocol between 56.8 +/- 35.8% to 53.6 +/- 37.4% (p<0.05). At the end of the final 80% contraction VA(sub) had increased from 91.2 +/- 6.2% to 94.9 +/- 4.7% (p = 0.005), but a greater increase was observed during the 40% contraction where VA(sub) had increased from 67.1 +/- 6.1% to 88.9 +/- 9.6% (p<0.001). CONCLUSION: Maximal central motor output in resistance trained men is well preserved despite varying levels of peripheral muscle fatigue. Upregulated central motor output during the 40% contraction protocol appeared to elicit greater peripheral fatigue. V-waves declines during the 80% protocol suggest intensity dependent modulation of the Ia afferent pathway. PMID- 26439263 TI - Seventy Years of Asthma in Italy: Age, Period and Cohort Effects on Incidence and Remission of Self-Reported Asthma from 1940 to 2010. AB - BACKGROUND: It is well known that asthma prevalence has been increasing all over the world in the last decades. However, few data are available on temporal trends of incidence and remission of asthma. OBJECTIVE: To evaluate the rates of asthma incidence and remission in Italy from 1940 to 2010. METHODS: The subjects were randomly sampled from the general Italian population between 1991 and 2010 in the three population-based multicentre studies: ECRHS, ISAYA, and GEIRD. Individual information on the history of asthma (age at onset, age at the last attack, use of drugs for asthma control, co-presence of hay-fever) was collected on 35,495 subjects aged 20-84 and born between 1925-1989. Temporal changes in rates of asthma incidence and remission in relation to age, birth cohort and calendar period (APC) were modelled using Poisson regression and APC models. RESULTS: The average yearly rate of asthma incidence was 2.6/1000 (3,297 new cases among 1,263,885 person-years). The incidence rates have been linearly increasing, with a percentage increase of +3.9% (95%CI: 3.1-4.5), from 1940 up to the year 1995, when the rates begun to level off. The stabilization of asthma incidence was mainly due to a decrease in the rates of atopic asthma after 1995, while non atopic asthma has continued to increase. The overall rate of remission was 43.2/1000person-years, and it did not vary significantly across generations, but was associated with atopy, age at asthma onset and duration of the disease. CONCLUSIONS: After 50 years of a continuous upward trend, the rates of asthma incidence underwent a substantial stabilization in the late 90s. Despite remarkable improvements in the treatment of asthma, the rate of remission did not change significantly in the last seventy years. Some caveats are required in interpreting our results, given that our estimates are based on self-reported events that could be affected by the recall bias. PMID- 26439265 TI - The Value of Being Wrong: Intermittent Feedback Delivery Alters the Striatal Response to Negative Feedback. AB - Whereas positive feedback is both rewarding and informative, negative feedback can be construed as either punishing (because it is indicative of poor performance) or informative (because it may lead to goal attainment). In this neuroimaging experiment, we highlighted the informational value of negative feedback by intermixing trials with and without feedback. When performance feedback is expected, positive feedback triggers an increase in striatal activity, whereas negative feedback elicits a decrease in striatal activity. We predicted that, in contrast, when feedback receipt is unpredictable, the striatal response to negative feedback would increase. Participants performed a paired associate learning task during fMRI scanning. In one condition ("blocked feedback"), the receipt of feedback was predictable--participants knew whether or not they would receive feedback for their responses. In another condition ("mixed feedback"), the receipt of feedback was unpredictable--on a random 50% of trials, participants received feedback, and they otherwise received no feedback. Negative feedback in the mixed feedback condition elicited more striatal activity than negative feedback in the blocked feedback condition. In contrast, feedback omission evoked more striatal activity when feedback delivery was expected, compared to when it was unpredictable. This pattern emerged from an increase in caudate activity in response to negative feedback in the mixed feedback condition and a decrease in ventral striatal activity in response to no feedback in this condition. These results suggest that, by emphasizing the informational value of negative feedback, an unpredictable feedback context alters the striatal response to negative feedback and to the omission of feedback. PMID- 26439264 TI - Contrasting Effects of the Cytotoxic Anticancer Drug Gemcitabine and the EGFR Tyrosine Kinase Inhibitor Gefitinib on NK Cell-Mediated Cytotoxicity via Regulation of NKG2D Ligand in Non-Small-Cell Lung Cancer Cells. AB - INTRODUCTION: Several cytotoxic anticancer drugs inhibit DNA replication and/or mitosis, while EGFR tyrosine kinase inhibitors inactivate EGFR signalling in cancer cell. Both types of anticancer drugs improve the overall survival of the patients with non-small-cell lung cancer (NSCLC), although tumors often become refractory to this treatment. Despite several mechanisms by which the tumors become resistant having been described the effect of these compounds on anti tumor immunity remains largely unknown. METHODS: This study examines the effect of the cytotoxic drug Gemcitabine and the EGFR tyrosine kinase inhibitor Gefitinib on the expression of NK group 2 member D (NKG2D) ligands as well as the sensitivity of NSCLC cells to the NK-mediated lysis. RESULTS: We demonstrate that Gemcitabine treatment leads to an enhanced expression, while Gefitinib downregulated the expression of molecules that act as key ligands for the activating receptor NKG2D and promote NK cell-mediated recognition and cytolysis. Gemcitabine activated ATM and ATM- and Rad-3-related protein kinase (ATR) pathways. The Gemcitabine-induced phosphorylation of ATM as well as the upregulation of the NKG2D ligand expression could be blocked by an ATM-ATR inhibitor. In contrast, Gefitinib attenuated NKG2D ligand expression. Silencing EGFR using siRNA or addition of the PI3K inhibitor resulted in downregulation of NKG2D ligands. The observations suggest that the EGFR/PI3K pathway also regulates the expression of NKG2D ligands. Additionally, we showed that both ATM-ATR and EGFR regulate MICA/B via miR20a. CONCLUSION: In keeping with the effect on NKG2D expression, Gemcitabine enhanced NK cell-mediated cytotoxicity while Gefitinib attenuated NK cell killing in NSCLC cells. PMID- 26439266 TI - The Processing of Attended and Predicted Sounds in Time. AB - Neural responses to an attended event are typically enhanced relative to those from an unattended one (attention enhancement). Conversely, neural responses to a predicted event are typically reduced relative to those from an unpredicted one (prediction suppression). What remains to be established is what happens with attended and predicted events. To examine the interaction between attention and prediction, we combined two robust paradigms developed for studying attention and prediction effects on ERPs into an orthogonal design. Participants were presented with sounds in attended or unattended intervals with onsets that were either predicted by a moving visual cue or unpredicted (no cue was provided). We demonstrated an N1 enhancement effect for attended sounds and an N1 suppression effect for predicted sounds; furthermore, an interaction between these effects was found that emerged early in the N1 (50-95 msec), indicating that attention enhancement only occurred when the sound was unpredicted. This pattern of results can be explained by the precision of the predictive cue that reduces the need for attention selection in the attended and predicted condition. PMID- 26439267 TI - Prefrontal Goal Codes Emerge as Latent States in Probabilistic Value Learning. AB - The prefrontal cortex (PFC) supports goal-directed actions and exerts cognitive control over behavior, but the underlying coding and mechanism are heavily debated. We present evidence for the role of goal coding in PFC from two converging perspectives: computational modeling and neuronal-level analysis of monkey data. We show that neural representations of prospective goals emerge by combining a categorization process that extracts relevant behavioral abstractions from the input data and a reward-driven process that selects candidate categories depending on their adaptive value; both forms of learning have a plausible neural implementation in PFC. Our analyses demonstrate a fundamental principle: goal coding represents an efficient solution to cognitive control problems, analogous to efficient coding principles in other (e.g., visual) brain areas. The novel analytical-computational approach is of general interest because it applies to a variety of neurophysiological studies. PMID- 26439268 TI - Asymmetric Processing of Numerical and Nonnumerical Magnitudes in the Brain: An fMRI Study. AB - It is well established that, when comparing nonsymbolic magnitudes (e.g., dot arrays), adults can use both numerical (i.e., the number of items) and nonnumerical (density, total surface areas, etc.) magnitudes. It is less clear which of these magnitudes is more salient or processed more automatically. In this fMRI study, we used a nonsymbolic comparison task to ask if different brain areas are responsible for the automatic processing of numerical and nonnumerical magnitudes, when participants were instructed to attend to either the numerical or the nonnumerical magnitudes of the same stimuli. An interaction of task (numerical vs. nonnumerical) and congruity (congruent vs. incongruent) was found in the right TPJ. Specifically, this brain region was more strongly activated during numerical processing when the nonnumerical magnitudes were negatively correlated with numerosity (incongruent trials). In contrast, such an interference effect was not evident during nonnumerical processing when the task irrelevant numerical magnitude was incongruent. In view of the role of the right TPJ in the control of stimulus-driven attention, we argue that these data demonstrate that the processing of nonnumerical magnitudes is more automatic than that of numerical magnitudes and that, therefore, the influence of numerical and nonnumerical variables on each other is asymmetrical. PMID- 26439269 TI - The Role of the Frontal and Parietal Cortex in Proactive and Reactive Inhibitory Control: A Transcranial Direct Current Stimulation Study. AB - Mounting evidence suggests that response inhibition involves both proactive and reactive inhibitory control, yet its underlying neural mechanisms remain elusive. In particular, the roles of the right inferior frontal gyrus (IFG) and inferior parietal lobe (IPL) in proactive and reactive inhibitory control are still under debate. This study aimed at examining the causal role of the right IFG and IPL in proactive and reactive inhibitory control, using transcranial direct current stimulation (tDCS) and the stop signal task. Twenty-two participants completed three sessions of the stop signal task, under anodal tDCS in the right IFG, the right IPL, or the primary visual cortex (VC; 1.5 mA for 15 min), respectively. The VC stimulation served as the active control condition. The tDCS effect for each condition was calculated as the difference between pre- and post-tDCS performance. Proactive control was indexed by the RT increase for go trials (or preparatory cost), and reactive control by the stop signal RT. Compared to the VC stimulation, anodal stimulation of the right IFG, but not that of the IPL, facilitated both proactive and reactive control. However, the facilitation of reactive control was not mediated by the facilitation of proactive control. Furthermore, tDCS did not affect the intraindividual variability in go RT. These results suggest a causal role of the right IFG, but not the right IPL, in both reactive and proactive inhibitory control. PMID- 26439271 TI - Timing Matters? Learning of Complex Spatiotemporal Sequences in Left-hemisphere Stroke Patients. AB - During rehabilitation after stroke motor sequence learning is of particular importance because considerable effort is devoted to (re)acquiring lost motor skills. Previous studies suggest that implicit motor sequence learning is preserved in stroke patients but were restricted to the spatial dimension, although the timing of single action components is as important as their spatial order. As the left parietal cortex is known to play a critical role in implicit timing and spatiotemporal integration, in this study we applied an adapted version of the SRT task designed to assess both spatial (different stimulus locations) and temporal (different response-stimulus intervals) aspects of motor learning to 24 right-handed patients with a single left-hemisphere (LH) stroke and 24 age-matched healthy controls. Implicit retrieval of sequence knowledge was tested both at Day 1 and after 24 hr (Day 2). Additionally, voxel-based lesion symptom mapping was used to investigate the neurobiological substrates of the behavioral effects. Although LH stroke patients showed a combined spatiotemporal learning effect that was comparable to that observed in controls, LH stroke patients did not show learning effects for the learning probes in which only one type of sequence information was maintained whereas the other one was randomized. Particularly on Day 2, patients showed significantly smaller learning scores for these two learning probes than controls. Voxel-based lesion symptom mapping analyses revealed for all learning probes that diminished learning scores on Day 2 were associated with lesions of the striatum. This might be attributed to its role in motor chunking and offline consolidation as group differences occurred on Day 2 only. The current results suggest that LH stroke patients rely on multimodal information (here: temporal and spatial information) when retrieving motor sequence knowledge and are very sensitive to any disruption of the learnt sequence information as they seem to build very rigid chunks preventing them from forming independent spatial and temporal sequence representations. PMID- 26439270 TI - Biased Competition during Long-term Memory Formation. AB - A key task for the brain is to determine which pieces of information are worth storing in memory. To build a more complete representation of the environment, memory systems may prioritize new information that has not already been stored. Here, we propose a mechanism that supports this preferential encoding of new information, whereby prior experience attenuates neural activity for old information that is competing for processing. We evaluated this hypothesis with fMRI by presenting a series of novel stimuli concurrently with repeated stimuli at different spatial locations in Experiment 1 and from different visual categories (i.e., faces and scenes) in Experiment 2. Subsequent memory for the novel stimuli could be predicted from the reduction in activity in ventral temporal cortex for the accompanying repeated stimuli. This relationship was eliminated in control conditions where the competition during encoding came from another novel stimulus. These findings reveal how prior experience adaptively guides learning toward new aspects of the environment. PMID- 26439272 TI - Cortical Thickness in Fusiform Face Area Predicts Face and Object Recognition Performance. AB - The fusiform face area (FFA) is defined by its selectivity for faces. Several studies have shown that the response of FFA to nonface objects can predict behavioral performance for these objects. However, one possible account is that experts pay more attention to objects in their domain of expertise, driving signals up. Here, we show an effect of expertise with nonface objects in FFA that cannot be explained by differential attention to objects of expertise. We explore the relationship between cortical thickness of FFA and face and object recognition using the Cambridge Face Memory Test and Vanderbilt Expertise Test, respectively. We measured cortical thickness in functionally defined regions in a group of men who evidenced functional expertise effects for cars in FFA. Performance with faces and objects together accounted for approximately 40% of the variance in cortical thickness of several FFA patches. Whereas participants with a thicker FFA cortex performed better with vehicles, those with a thinner FFA cortex performed better with faces and living objects. The results point to a domain-general role of FFA in object perception and reveal an interesting double dissociation that does not contrast faces and objects but rather living and nonliving objects. PMID- 26439274 TI - Restricted antibody response to Bordetella pertussis filamentous hemagglutinin induced by whole-cell and acellular pertussis vaccines. AB - BACKGROUND: Filamentous hemagglutinin (FHA) is a principal virulence factor, an important immunogenic antigen of Bordetella pertussis, and a major component of many acellular pertussis vaccines. In the present study, the human antibody response to different regions of FHA was determined in healthy children and adults vaccinated with either whole-cell or acellular pertussis vaccines. METHODS: To define the immunodominant regions of FHA, four overlapping recombinant fragments were expressed and produced in Escherichia coli and then purified by His-tagged based affinity chromatography. Two groups comprising healthy preschool children (n = 50) and adults (n = 26) were vaccinated with a single dose of commercial whole-cell and acellular DTaP vaccines, respectively. An antigen-based ELISA was applied to measure serum levels of anti-FHA antibody to both native and recombinant proteins in vaccinated volunteers. RESULTS: In both groups of vaccinated individuals, the anti-FHA antibody response was mainly directed against epitopes located within a fragment of FHA spanning amino acid residues 1877-2250 of the mature FHA molecule (p < 0.001). No or little antibody was detected against the other recombinant segments of FHA. CONCLUSION: Our results suggest that the human antibody response to FHA is directed to an immunodominant region located within residues 1877-2250 of the FHA molecule. Characterization and epitope mapping of the major components of acellular pertussis vaccine and future modifications in vaccine formulation may improve its efficacy and protectivity. PMID- 26439275 TI - Ultrasound-Guided Versus Wire-Guided Breast-Conserving Surgery for Nonpalpable Breast Cancer. AB - PURPOSE: To determine the efficacy of ultrasound (US)-guided excision of nonpalpable breast cancer and compare it to standard wire-guided breast conserving surgery (BCS). METHODS: One hundred fifty-eight women with nonpalpable breast cancer who underwent BCS were retrospectively studied. Positive surgical margins and reexcision rates were investigated. RESULTS: Of the total cohort, 68 patients were treated with wire-guided and 90 with US-guided tumor excision. The tumor and patient characteristics were similar in the 2 groups; 13.2% and 12.2% of patients in the wire-guided and US-guided groups, respectively, had positive margins. Patient age, menopausal status, tumor size, histologic type, and histologic grade were associated with increased risk of positive margins. The shave margins were reexcised at the time of original operation more often by wire guided localization (26.5%) than in the US-guided group (10.0%) (P = .010). The surgeon was able to identify correctly the problematic margin in 100% via intraoperative US and in only 27.8% when the wire-guided surgery was used (P < .001). The reexcision rate by a second operation was similar in 2 groups (P = .798). Eight (11.8%) of 68 patients in the wire-guided group and 9 (10.0%) of 90 patients in the US-guided underwent a second operation. CONCLUSION: US-guided BCS is as effective and safe as standard wire-guided excision of nonpalpable breast tumors. PMID- 26439276 TI - Ultra-high voltage electron microscopy of primitive algae illuminates 3D ultrastructures of the first photosynthetic eukaryote. AB - A heterotrophic organism 1-2 billion years ago enslaved a cyanobacterium to become the first photosynthetic eukaryote, and has diverged globally. The primary phototrophs, glaucophytes, are thought to retain ancestral features of the first photosynthetic eukaryote, but examining the protoplast ultrastructure has previously been problematic in the coccoid glaucophyte Glaucocystis due to its thick cell wall. Here, we examined the three-dimensional (3D) ultrastructure in two divergent species of Glaucocystis using ultra-high voltage electron microscopy. Three-dimensional modelling of Glaucocystis cells using electron tomography clearly showed that numerous, leaflet-like flattened vesicles are distributed throughout the protoplast periphery just underneath a single-layered plasma membrane. This 3D feature is essentially identical to that of another glaucophyte genus Cyanophora, as well as the secondary phototrophs in Alveolata. Thus, the common ancestor of glaucophytes and/or the first photosynthetic eukaryote may have shown similar 3D structures. PMID- 26439277 TI - Decade in review-dementia: a decade of discovery and disappointment in dementia research. PMID- 26439279 TI - Borderline Lepromatous Leprosy: Cutaneous Manifestation and Type 1 Reversal Reaction. PMID- 26439278 TI - Aberrant intra- and inter-network connectivity architectures in Alzheimer's disease and mild cognitive impairment. AB - Alzheimer's disease (AD) patients and those with high-risk mild cognitive impairment are increasingly considered to have dysfunction syndromes. Large-scale network studies based on neuroimaging techniques may provide additional insight into AD pathophysiology. The aim of the present study is to evaluate the impaired network functional connectivity with the disease progression. For this purpose, we explored altered functional connectivities based on previously well-defined brain areas that comprise the five key functional systems [the default mode network (DMN), dorsal attention network (DAN), control network (CON), salience network (SAL), sensorimotor network (SMN)] in 35 with AD and 27 with mild cognitive impairment (MCI) subjects, compared with 27 normal cognitive subjects. Based on three levels of analysis, we found that intra- and inter-network connectivity were impaired in AD. Importantly, the interaction between the sensorimotor and attention functions was first attacked at the MCI stage and then extended to the key functional systems in the AD individuals. Lower cognitive ability (lower MMSE scores) was significantly associated with greater reductions in intra- and inter-network connectivity across all patient groups. These profiles indicate that aberrant intra- and inter-network dysfunctions might be potential biomarkers or predictors of AD progression and provide new insight into AD pathophysiology. PMID- 26439280 TI - Mechanically activated switching of Si-based single-molecule junction as imaged with three-dimensional dynamic probe. AB - Understanding and extracting the full functions of single-molecule characteristics are key factors in the development of future device technologies, as well as in basic research on molecular electronics. Here we report a new methodology for realizing a three-dimensional (3D) dynamic probe of single molecule conductance, which enables the elaborate 3D analysis of the conformational effect on molecular electronics, by the formation of a Si/single molecule/Si structure using scanning tunnelling microscopy (STM). The formation of robust covalent bonds between a molecule and Si electrodes, together with STM related techniques, enables the stable and repeated control of the conformational modulation of the molecule. By 3D imaging of the conformational effect on a 1,4 diethynylbenzene molecule, a binary change in conductance with hysteresis is observed for the first time, which is considered to originate from a mechanically activated conformational change. PMID- 26439282 TI - Carbon nanotubes-gold nanohybrid as potent electrocatalyst for oxygen reduction in alkaline media. AB - A carbon nanotube-gold nanohybrid was used as catalyst for the reduction of molecular oxygen in acidic and alkaline media, the relevant cathode reaction in fuel cells. In alkaline medium, the nanohybrid exhibits excellent activity with a dominant 4e(-) reduction of O2 and low overpotential requirement compared to previously reported nano-gold materials. This property is linked to its capability to efficiently mediate HO2(-) dismutation. PMID- 26439281 TI - Mechanism of C-Terminal Fragments of Amyloid beta-Protein as Abeta Inhibitors: Do C-Terminal Interactions Play a Key Role in Their Inhibitory Activity? AB - Targeting the early oligomerization of amyloid beta protein (Abeta) is a promising therapeutic strategy for Alzheimer's disease (AD). Recently, certain C terminal fragments (CTFs) derived from Abeta42 were shown to be potent inhibitors of Abeta-induced toxicity. The shortest peptide studied, Abeta(39-42), has been shown to modulate Abeta oligomerization and inhibit Abeta toxicity. Understanding the mechanism of these CTFs, especially Abeta(39-42), is of significance for future therapeutic development of AD and peptidomimetic-based drug development. Here we used ion mobility spectrometry-mass spectrometry to investigate the interactions between two modified Abeta(39-42) derivatives, VVIA-NH2 and Ac-VVIA, and full-length Abeta42. VVIA-NH2 was previously shown to inhibit Abeta toxicity, whereas Ac-VVIA did not. Our mass spectrometry analysis revealed that VVIA-NH2 binds directly to Abeta42 monomer and small oligomers while Ac-VVIA binds only to Abeta42 monomer. Ion mobility studies showed that VVIA-NH2 modulates Abeta42 oligomerization by not only inhibiting the dodecamer formation but also disaggregating preformed Abeta42 dodecamer. Ac-VVIA also inhibits and removes preformed Abeta42 dodecamer. However, the Abeta42 sample with the addition of Ac VVIA clogged the nanospray tip easily, indicating that larger aggregates are formed in the solution in the presence of Ac-VVIA. Molecular dynamics simulations suggested that VVIA-NH2 binds specifically to the C-terminal region of Abeta42 while Ac-VVIA binds dispersedly to multiple regions of Abeta42. This work implies that C-terminal interactions and binding to Abeta oligomers are important for C terminal fragment inhibitors. PMID- 26439284 TI - Swimming in a crystal. AB - We study catalytic Janus particles and Escherichia coli bacteria swimming in a two-dimensional colloidal crystal. The Janus particles orbit individual colloids and hop between colloids stochastically, with a hopping rate that varies inversely with fuel (hydrogen peroxide) concentration. At high fuel concentration, these orbits are stable for 100s of revolutions, and the orbital speed oscillates periodically as a result of hydrodynamic, and possibly also phoretic, interactions between the swimmer and the six neighbouring colloids. Motile E. coli bacteria behave very differently in the same colloidal crystal: their circular orbits on plain glass are rectified into long, straight runs, because the bacteria are unable to turn corners inside the crystal. PMID- 26439286 TI - Characterization of miRNAs from hydrothermal vent shrimp Rimicaris exoculata. AB - Deep-sea hydrothermal vent shrimp Rimicaris exoculata is a dominant species aggregating in vent fields along the Mid-Atlantic Ocean Ridge. MicroRNAs play important roles in life cycles of eukaryotes. However, little is known about miRNAs of vent animals. In the present study, a small RNA cDNA library from the muscle of R. exoculata was constructed and the miRNA sequencing was performed. The results indicated that a total of 7,983,331 raw reads were obtained, representing 569,354 unique sequences. Based on sequence analysis, R. exoculata contained 159 conserved miRNAs and 34 novel miRNAs. The conserved miRNAs included 54 families belonging to three different taxonomic units (bilaterian, protostomes and arthropods). The results also showed that miR-2001, a lost miRNA in crustaceans, existed in R. exoculata. Among the conserved miRNAs, iso-miRs were detected. Therefore, this study presented the first insight into the miRNAs of deep-sea hydrothermal vent animals. PMID- 26439287 TI - St.Gallen-2015 in Vienna: News from a successful breast cancer conference transposition! PMID- 26439285 TI - Reassessment of MxiH subunit orientation and fold within native Shigella T3SS needles using surface labelling and solid-state NMR. AB - T3SSs are essential virulence determinants of many Gram-negative bacteria, used to inject bacterial effectors of virulence into eukaryotic host cells. Their major extracellular portion, a ~50 nm hollow, needle-like structure, is essential to host cell sensing and the conduit for effector secretion. It is formed of a small, conserved subunit arranged as a helical polymer. The structure of the subunit has been studied by electron cryomicroscopy within native polymers and by solid-state NMR in recombinant polymers, yielding two incompatible atomic models. To resolve this controversy, we re-examined the native polymer used for electron cryomicroscopy via surface labelling and solid-state NMR. Our data show the orientation and overall fold of the subunit within this polymer is as established by solid-state NMR for recombinant polymers. PMID- 26439288 TI - Brownian dynamics simulation of amphiphilic block copolymers with different tail lengths, comparison with theory and comicelles. AB - Study on the effect of amphiphilic copolymers structure on their self assembly is an interesting subject, with important applications in the area of drug delivery and biological system treatments. Brownian dynamics simulations were performed to study self-assembly of the linear amphiphilic block copolymers with the same hydrophilic head, but hydrophobic tails of different lengths. Critical micelle concentration (CMC), gyration radius distribution, micelle size distribution, density profiles of micelles, shape anisotropy, and dynamics of micellization were investigated as a function of tail length. Simulation results were compared with predictions from theory and simulation for mixed systems of block copolymers with long and short hydrophobic tail, reported in our previous work. Interestingly, the equilibrium structural and dynamic parameters of pure and mixed block copolymers were similarly dependant on the intrinsic/apparent hydrophobic block length. Log (CMC) was, however; proportional to the tail length and had a different behavior compared to the mixed system. The power law scaling relation of equilibrium structural parameters for amphiphilic block copolymers predicts the same dependence for similar hydrophobic tail lengths, but the power law prediction of CMC is different, which is due to its simplifying assumptions as discussed here. PMID- 26439289 TI - Comparative study on the interfacial electron transfer of zinc porphyrins with meso-pi-extension at a 2(n) pattern. AB - Three zinc-tetraarylporphyrins were prepared in order to investigate the effects of systematic meso-pi-extension on the redox behaviors and interfacial electron transfer kinetics. The meso-pi-extension increased at a 2(n) pattern, where 2(n) was the benzene ring number in an aryl group and the aryl group represented phenyl, naphthyl and pyrenyl group, respectively. The structures of zinc tetraarylporphyrins and hydroquinone were optimized by using density functional theory. The bimolecular reactions between zinc-tetraarylporphyrins and hydroquinone at the liquid-liquid interface were studied by using scanning electrochemical microscopy. There was an inverse electron transfer rate-overall driving force dependence by comparison of three bimolecular reactions. It was suggested that the formation of a precursor between zinc-tetraarylporphyrin cation and hydroquinone was deeply influenced by the increasing steric hindrance from phenyl group to pyrenyl group. The electron transfer rate constant depended strongly on the overall driving force for each bimolecular reaction, with transfer coefficients of 0.41, 0.37 and 0.39. PMID- 26439290 TI - Rapid sphere sizing using a Bayesian analysis of reciprocal space imaging data. AB - Dispersed systems are important in many applications in a wide range of industries such as the petroleum, pharmaceutical and food industries. Therefore the ability to control and non-invasively measure the physical properties of these systems, such as the dispersed phase size distribution, is of significant interest, in particular for concentrated systems, where microscopy or scattering techniques may not apply or with very limited output quality. In this paper we show how reciprocal space data acquired using both 1D magnetic resonance imaging (MRI) and 2D X-ray micro-tomographic (X-ray MUCT) data can be analysed, using a Bayesian statistical model, to extract the sphere size distribution (SSD) from model sphere systems and dispersed food foam samples. Glass spheres-in-xanthan gels were used as model samples with sphere diameters (D) in the range of 45MUm?D?850MUm. The results show that the SSD was successfully estimated from both the NMR and X-ray MUCT with a good degree of accuracy for the entire range of glass spheres in times as short as two seconds. After validating the technique using model samples, the Bayesian sphere sizing method was successfully applied to air/water foam samples generated using a microfluidics apparatus with 160MUm?D?400MUm. The effect of different experimental parameters such as the standard deviation of the bubble size distribution and the volume fraction of the dispersed phase is discussed. PMID- 26439291 TI - One of these is not like the others. AB - A Mycobacterium tuberculosis metA mutant that is auxotrophic for methionine is unlike other auxotrophic mutants of this important species as methionine starvation results in rapid death instead of cessation of growth. Evidence suggests that this phenotype results from starvation affecting essential pathways that utilize S-adenosylmethionine in addition to methionine. PMID- 26439292 TI - Biofilm recruitment of Vibrio cholerae by matrix proteolysis. AB - The appearance of bacterial biofilms involves secretion of polysaccharides and proteins that form an extracellular matrix embedding the bacteria. Proteases have also been observed, but their role has remained unclear. Smith and co-workers have now found that proteolysis can contribute to further recruitment of bacteria to Vibrio cholerae biofilms. PMID- 26439294 TI - Roles of indole as an interspecies and interkingdom signaling molecule. AB - A number of bacteria, and some plants, produce large quantities of indole, which is widespread in animal intestinal tracts and in the rhizosphere. Indole, as an interspecies and interkingdom signaling molecule, plays important roles in bacterial pathogenesis and eukaryotic immunity. Furthermore, indole and its derivatives are viewed as potential antivirulence compounds against antibiotic resistant pathogens because of their ability to inhibit quorum sensing and virulence factor production. Indole modulates oxidative stress, intestinal inflammation, and hormone secretion in animals, and it controls plant defense systems and growth. Insects and nematodes can recognize indole, which controls some of their behavior. This review presents current knowledge regarding indole and its derivatives, their biotechnological applications and their role in prokaryotic and eukaryotic systems. PMID- 26439295 TI - Microbial malaise: how can we classify the microbiome? AB - The names and lineages of microorganisms are critical to our understanding of the microbiome. However, microbial taxonomy and phylogeny are in perpetual flux, with emerging criteria being used to rename and reshape our views of the microbial world. Different candidate molecular and nonmolecular criteria are often broadly consistent with one another, which underpins the pluralistic approach to taxonomy. However, the taxonomic picture is clouded when underlying criteria are not in agreement, or when reference datasets contain erroneously named organisms. How does the shifting taxonomic landscape impact our interpretation of microbial communities, especially in the face of inconsistencies and errors? How can taxonomy be applied in a consistent way when different users have different requirements of the classifications that emerge? The key path forward involves finding ways to integrate conflicting taxonomic criteria, choosing the right units of analysis for microbiomic studies, and making molecular taxonomy transparent and accessible in a way that complements current genomic resources. PMID- 26439293 TI - Bacterial amyloid formation: structural insights into curli biogensis. AB - Curli are functional amyloid fibers assembled by many Gram-negative bacteria as part of an extracellular matrix that encapsulates the bacteria within a biofilm. A multicomponent secretion system ensures the safe transport of the aggregation prone curli subunits across the periplasm and outer membrane, and coordinates subunit self-assembly into surface-attached fibers. To avoid the build-up of potentially toxic intracellular protein aggregates, the timing and location of the interactions of the different curli proteins are of paramount importance. Here we review the structural and molecular biology of curli biogenesis, with a focus on the recent breakthroughs in our understanding of subunit chaperoning and secretion. The mechanistic insight into the curli assembly pathway will provide tools for new biotechnological applications and inform the design of targeted inhibitors of amyloid polymerization and biofilm formation. PMID- 26439296 TI - Microbial invasions: the process, patterns, and mechanisms. AB - There has recently been a surge of literature examining microbial invasions into a variety of environments. These studies often include a component of biological diversity as a major factor determining an invader's fate, yet common results are rarely cross-compared. Since many studies only present a snapshot of the entire invasion process, a bird's eye view is required to piece together the entire continuum, which we find consists of introduction, establishment, spread, and impact phases. We further examine the patterns and mechanisms associated with invasion resistance and create a mechanistic synthesis governed by the species richness, species evenness, and resource availability of resident communities. We conclude by exploring the advantages of using a theoretical invasion framework across different fields. PMID- 26439297 TI - SAMHD1: at the crossroads of cell proliferation, immune responses, and virus restriction. AB - SAMHD1 is a triphosphohydrolase enzyme that controls the intracellular level of deoxyribonucleoside triphosphates (dNTPs) and plays a role in innate immune sensing and autoimmune disease. SAMHD1 has also been identified as an intrinsic virus restriction factor, inactivated through degradation by HIV-2 Vpx or through a post-transcriptional regulatory mechanism. Phosphorylation of SAMHD1 by cyclin dependent kinases has been strongly associated with inactivation of the virus restriction mechanism, providing an association between virus replication and cell proliferation. Tight regulation of cell proliferation suggests that viruses, particularly HIV-1 replication, latency, and reactivation, may be similarly controlled by multiple checkpoint mechanisms that, in turn, regulate dNTP levels. In this review, we discuss how SAMHD1 is a viral restriction factor, the mechanism associated with viral restriction, the pathway leading to its inactivation in proliferating cells, and how strategies aimed at controlling virus restriction could lead to a functional cure for HIV. PMID- 26439299 TI - Ten years of maintaining and expanding a microbial genome and metagenome analysis system. AB - Launched in March 2005, the Integrated Microbial Genomes (IMG) system is a comprehensive data management system that supports multidimensional comparative analysis of genomic data. At the core of the IMG system is a data warehouse that contains genome and metagenome datasets sequenced at the Joint Genome Institute or provided by scientific users, as well as public genome datasets available at the National Center for Biotechnology Information Genbank sequence data archive. Genomes and metagenome datasets are processed using IMG's microbial genome and metagenome sequence data processing pipelines and are integrated into the data warehouse using IMG's data integration toolkits. Microbial genome and metagenome application specific data marts and user interfaces provide access to different subsets of IMG's data and analysis toolkits. This review article revisits IMG's original aims, highlights key milestones reached by the system during the past 10 years, and discusses the main challenges faced by a rapidly expanding system, in particular the complexity of maintaining such a system in an academic setting with limited budgets and computing and data management infrastructure. PMID- 26439298 TI - Stealing the Keys to the Kitchen: Viral Manipulation of the Host Cell Metabolic Network. AB - Host cells possess the metabolic assets required for viral infection. Recent studies indicate that control of the host's metabolic resources is a core host pathogen interaction. Viruses have evolved mechanisms to usurp the host's metabolic resources, funneling them towards the production of virion components as well as the organization of specialized compartments for replication, maturation, and dissemination. Consequently, hosts have developed a variety of metabolic countermeasures to sense and resist these viral changes. The complex interplay between virus and host over metabolic control has only just begun to be deconvoluted. However, it is clear that virally induced metabolic reprogramming can substantially impact infectious outcomes, highlighting the promise of targeting these processes for antiviral therapeutic development. PMID- 26439300 TI - Rtt107 Is a Multi-functional Scaffold Supporting Replication Progression with Partner SUMO and Ubiquitin Ligases. AB - Elucidating the individual and collaborative functions of genome maintenance factors is critical for understanding how genome duplication is achieved. Here, we investigate a conserved scaffold in budding yeast, Rtt107, and its three partners: a SUMO E3 complex, a ubiquitin E3 complex, and Slx4. Biochemical and genetic findings show that Rtt107 interacts separately with these partners and contributes to their individual functions, including a role in replisome sumoylation. We also provide evidence that Rtt107 associates with replisome components, and both itself and its associated E3s are important for replicating regions far from initiation sites. Corroborating these results, replication defects due to Rtt107 loss and genotoxic sensitivities in mutants of Rtt107 and its associated E3s are rescued by increasing replication initiation events through mutating two master repressors of late origins, Mrc1 and Mec1. These findings suggest that Rtt107 functions as a multi-functional platform to support replication progression with its partner E3 enzymes. PMID- 26439303 TI - Proteomic analysis of Eimeria acervulina sporozoite proteins interaction with duodenal epithelial cells by shotgun LC-MS/MS. AB - Although it has been known for many years that Eimeria acervulina (E. acervulina) initiates infection by invading the duodenal epithelial cells of chicken, the key protein molecules and the mechanisms of the parasite in invading are unknow. In this study, we found that 85 proteins of E. acervulina could bind with the chicken duodenal epithelial cells from Eimeria protein database. Among them, sixteen were identified only in Eimeria spp. correlation with invasion and evasion and 69 proteins were found in Eimeria spp. with more than 2 unique pep count. Nine out of the 16 proteins and 41 out of the 69 proteins were annotated according to Gene Ontology Annotation in terms of molecular function, biological process, and cellular localization. Most of the 9 annotated proteins occurred in binding, catalytic activity and cellular process whereas, 29 (70.73%) out of the 41 proteins had binding activity and 20 proteins (48.78%) had catalytic activity. The findings provided an insight into the interactive relationship between E. acervulina and host cells and will shed new lights on the understanding of molecular mechanisms of E. acervulina invasion and pathogenesis. PMID- 26439302 TI - The PZP Domain of AF10 Senses Unmodified H3K27 to Regulate DOT1L-Mediated Methylation of H3K79. AB - AF10, a DOT1L cofactor, is required for H3K79 methylation and cooperates with DOT1L in leukemogenesis. However, the molecular mechanism by which AF10 regulates DOT1L-mediated H3K79 methylation is not clear. Here we report that AF10 contains a "reader" domain that couples unmodified H3K27 recognition to H3K79 methylation. An AF10 region consisting of a PHD finger-Zn knuckle-PHD finger (PZP) folds into a single module that recognizes amino acids 22-27 of H3, and this interaction is abrogated by H3K27 modification. Structural studies reveal that H3 binding triggers rearrangement of the PZP module to form an H3(22-27)-accommodating channel and that the unmodified H3K27 side chain is encased in a compact hydrogen bond acceptor-lined cage. In cells, PZP recognition of H3 is required for H3K79 dimethylation, expression of DOT1L-target genes, and proliferation of DOT1L addicted leukemic cells. Together, our results uncover a pivotal role for H3K27 via readout by the AF10 PZP domain-in regulating the cancer-associated enzyme DOT1L. PMID- 26439304 TI - Independent amino acid residues in the S2 pocket of falcipain-3 determine its specificity for P2 residues in substrates. AB - Falcipain-3 (FP3) is an essential and drug target cysteine protease of the most lethal human malaria parasite Plasmodium falciparum. FP3 and its majority of homologs in malaria parasites prefer Leu at the P2 position in substrates and inhibitors, whereas its major host homolog cathepsin L prefers Phe. However, FP3 is much less active on peptide substrates and has negligible activity against a P2 Arg-containing substrate (Z-RR-AMC) compared to its paralog falcipain-2A (FP2A). To identify the specificity determinants, the S2/3 pocket residues of FP3 were substituted with the corresponding residues in FP2 or cathepsin L, and the wild type and mutant proteases were assessed for hydrolysis of peptide and protein substrates. Our results indicate that the S2 pocket residues I94 and P181 of FP3 are chiefly responsible for its P2 Leu preference and negligible activity for Z-RR-AMC, respectively. E243 in FP3 and the corresponding residue D234 in FP2 have a key role in Z-RR-AMC hydrolysing activity, possibly through stabilization of side chain interactions, as their substitution with Ala abolished the activity. Several FP3 mutants, which retained P2 Leu preference and showed similar or more activity than wild type FP3 on peptide substrates, degraded haemoglobin less efficiently than wild type FP3, suggesting that multiple residues contribute to haemoglobinase activity. Furthermore, P181 and E243 appear to contribute to the optimum activity of FP3 in the food vacuole milieu (~pH 5.5). The identification of residues determining specificity of FP3 could aid in developing specific inhibitors of FP3 and its homologs in malaria parasites. PMID- 26439301 TI - YAP Drives Growth by Controlling Transcriptional Pause Release from Dynamic Enhancers. AB - The Hippo/YAP signaling pathway is a crucial regulator of tissue growth, stem cell activity, and tumorigenesis. However, the mechanism by which YAP controls transcription remains to be fully elucidated. Here, we utilize global chromatin occupancy analyses to demonstrate that robust YAP binding is restricted to a relatively small number of distal regulatory elements in the genome. YAP occupancy defines a subset of enhancers and superenhancers with the highest transcriptional outputs. YAP modulates transcription from these elements predominantly by regulating promoter-proximal polymerase II (Pol II) pause release. Mechanistically, YAP interacts and recruits the Mediator complex to enhancers, allowing the recruitment of the CDK9 elongating kinase. Genetic and chemical perturbation experiments demonstrate the requirement for Mediator and CDK9 in YAP-driven phenotypes of overgrowth and tumorigenesis. Our results here uncover the molecular mechanisms employed by YAP to exert its growth and oncogenic functions, and suggest strategies for intervention. PMID- 26439306 TI - All-Printed, Foldable Organic Thin-Film Transistors on Glassine Paper. AB - All-printed, foldable organic thin-film transistors are demonstrated on glassine paper with a combination of advanced materials and processing techniques. Glassine paper provides a suitable surface for high-performance printing methods, while graphene electrodes and an ion-gel gate dielectric enable robust stability over 100 folding cycles. Altogether, this study features a practical platform for low-cost, large-area, and foldable electronics. PMID- 26439305 TI - P-Selectin Sustains Extramedullary Hematopoiesis in the Gata1 low Model of Myelofibrosis. AB - Splenomegaly is a major manifestation of primary myelofibrosis (PMF) contributing to clinical symptoms and hematologic abnormalities. The spleen from PMF patients contains increased numbers of hematopoietic stem cells (HSC) and megakaryocytes (MK). These MK express high levels of P-selectin (P-sel) that, by triggering neutrophil emperipolesis, may cause TGF-beta release and disease progression. This hypothesis was tested by deleting the P-sel gene in the myelofibrosis mouse model carrying the hypomorphic Gata1(low) mutation that induces megakaryocyte abnormalities that recapitulate those observed in PMF. P-sel(null) Gata1(low) mice survived splenectomy and lived 3 months longer than P-sel(WT) Gata1(low) littermates and expressed limited fibrosis and osteosclerosis in the marrow or splenomegaly. Furthermore, deletion of P-sel disrupted megakaryocyte/neutrophil interactions in spleen, reduced TGF-beta content, and corrected the HSC distribution that in Gata1(low) mice, as in PMF patients, is abnormally expanded in spleen. Conversely, pharmacological inhibition of TGF-beta reduced P-sel expression in MK and corrected HSC distribution. Spleens, but not marrow, of Gata1(low) mice contained numerous cKIT(pos) activated fibrocytes, probably of dendritic cell origin, whose membrane protrusions interacted with MK establishing niches hosting immature cKIT(pos) hematopoietic cells. These activated fibrocytes were not detected in spleens from P-sel(null) Gata1(low) or TGF-beta-inhibited Gata1(low) littermates and were observed in spleen, but not in marrow, from PMF patients. Therefore, in Gata1(low) mice, and possibly in PMF, abnormal P-sel expression in MK may mediate the pathological cell interactions that increase TGF beta content in MK and favor establishment of a microenvironment that supports myelofibrosis-related HSC in spleen. PMID- 26439307 TI - Lichenoid drug eruption induced by colchicine. PMID- 26439308 TI - Paritaprevir/ritonavir, ombitasvir, and dasabuvir for treatment of recurrent hepatitis C virus infection in the human immunodeficiency virus coinfected liver transplant recipient. PMID- 26439310 TI - Determining the arsenic, cadmium, lead, copper and chromium contents by atomic absorption spectrometry in Pangasius fillets from Vietnam. AB - BACKGROUND: Pangasius is a fish produced on a large scale in Vietnam and exported to many countries. Since river contamination from human activities can affect the safety of this food, fish consumption can cause exposure to potentially toxic elements for humans. The aim of this study, therefore, was to assess arsenic, cadmium, lead, copper and chromium contents by atomic absorption spectrometry in Pangasius fillet produced in the provinces of Dong Thap and Can Tho (Vietnam) and exported to Brazil. RESULTS: The limits of detection were: arsenic 0.5443 ug kg( 1) , cadmium 0.0040 mg kg(-1) , chromium 0.0004 mg kg(-1) , copper 0.0037 mg kg( 1) and lead 0.0284 mg kg(-1) . Analysis of 20 samples showed results below the limit of detection for arsenic, chromium and lead, while copper average concentration was 0.0234 mg kg(-1) . Cadmium average concentration was 0.0547 mg kg(-1) , with no significant difference between the two regions studied. CONCLUSION: The samples of Pangasius had no detectable concentrations of arsenic, chromium, copper and lead, and do not represent a hazard to public health. However, cadmium analysis revealed non-compliant samples, demonstrating the importance of monitoring the quality of imported Pangasius fish. (c) 2015 Society of Chemical Industry. PMID- 26439311 TI - From species distributions to meta-communities. AB - The extent that biotic interactions and dispersal influence species ranges and diversity patterns across scales remains an open question. Answering this question requires framing an analysis on the frontier between species distribution modelling (SDM), which ignores biotic interactions and dispersal limitation, and community ecology, which provides specific predictions on community and meta-community structure and resulting diversity patterns such as species richness and functional diversity. Using both empirical and simulated datasets, we tested whether predicted occurrences from fine-resolution SDMs provide good estimates of community structure and diversity patterns at resolutions ranging from a resolution typical of studies within reserves (250 m) to that typical of a regional biodiversity study (5 km). For both datasets, we show that the imprint of biotic interactions and dispersal limitation quickly vanishes when spatial resolution is reduced, which demonstrates the value of SDMs for tracking the imprint of community assembly processes across scales. PMID- 26439309 TI - Comparative analysis of mediastinal fat-associated lymphoid cluster development and lung cellular infiltration in murine autoimmune disease models and the corresponding normal control strains. AB - We previously discovered mediastinal fat-associated lymphoid clusters (MFALCs) as novel lymphoid clusters associated with mediastinal fat tissue in healthy mice. However, no data about their morphology in immune-associated disease conditions, and their relationship with lung infiltration, is available to date. In the present study, we compared the morphological features of MFALCs in 4-month-old male murine autoimmune disease models (MRL/MpJ-lpr mice and BXSB/MpJ-Yaa mice) with those of the corresponding control strains (MRL/MpJ and BXSB/MpJ, respectively). In addition, we analysed their correlation with lung infiltration. Furthermore, immunohistochemistry for CD3, B220, Iba1, Gr1 and BrdU was performed to detect T cells and B cells, macrophages, granulocytes and proliferating cells, respectively. The spleen weight to body weight ratios and anti-double-stranded DNA autoantibody titres were found to be significantly higher in the autoimmune models than in the control strains. Furthermore, the autoimmune model presented prominent MFALCs, with a significantly greater ratio of lymphoid cluster area to total mediastinal fat tissue area, and more apparent diffused cellular infiltration into the lung lobes than the other studied strains. Higher numbers of T and B cells, macrophages and proliferating cells, but fewer granulocytes, were observed in the autoimmune models than in the control strains. Interestingly, a significant positive Pearson's correlation between the size of the MFALCs and the density of CD3-, B220- and Iba1-positive cells in the lung was observed. Therefore, our data suggest a potentially important role for MFALCs in the progression of lung disease. However, further investigation is required to clarify the pathological role of MFALCs in lung disease, especially in inflammatory disorders. PMID- 26439312 TI - The transition from naive to primed nociceptive state: A novel wind-up protocol in mice. AB - Wind-up (WU) is a progressive, frequency-dependent facilitation of spinal cord neurons in response to repetitive nociceptive stimulation of constant intensity. We identified a new WU-associated phenomenon in naive mice (not exposed to noxious stimulation immediately prior to WU stimulation), which were subjected to a novel experimental protocol composed of three consecutive trains of WU stimulation. The 1st train produced a typical linear 'wind-up' curve as expected following a repeating series of stimuli; in addition, this 1st train sensitized ('primed') the nociceptive system so that the responses to two subsequent trains (inter-train interval of 10 min) were significantly amplified compared with the response to the 1st train. We named this augmented response potentiation-of windup, or "PoW". The PoW phenomenon appears to be centrally mediated, as the augmented response was suppressed by administration of an NMDA receptor antagonist (MK-801) and by cutting the spinal cord. Furthermore, the PoW protocol is accompanied by enhanced pain behavior. The 'priming' effect of the 1st train could be mimicked by exposure to natural noxious stimuli prior to the PoW protocol. Presumably, the PoW phenomenon has not been previously reported due to a procedural reason: typically, WU protocols have been executed in 'primed' rather than naive animals, i.e., animals exposed to nociceptive stimulation prior to the actual WU recording. Our findings indicate that the PoW paradigm can distinguish between 'naive' and 'primed' states, suggesting its use as a tool for the assessment of central sensitization. PMID- 26439314 TI - Accordion-like swelling of layered perovskite crystals via massive permeation of aqueous solutions into 2D oxide galleries. AB - Platelet crystals of a layered perovskite showed massive accordion-like swelling in a tetrabutylammonium hydroxide solution. The permeation of the solution induced the huge expansion of the interlayer spacing as well as the crystal thickness up to 50-fold, leading to a very high water content of >90 wt%. PMID- 26439315 TI - A Unique Case of JOAG With Lamellar Ichthyosis With Rickets: A Case Report and Review of the Literature. AB - PURPOSE: Ichthyosis is known to have ocular associations such as blepharitis, hypertrophic conjunctivitis, corneal vascularization, ectropion, lagophthalmos, etc. However, no reports of its association with glaucoma are there, to the best of our knowledge. We report a unique case of juvenile open-angle glaucoma (JOAG) with lamellar ichthyosis. METHOD: A 16-year-old male child presented with a gradual, painless progressive diminution of vision in both eyes over a period of 3 years. Systemic examination revealed stunted body growth with knock-knees, suggestive of late-onset rickets. Generalized dry scaly lesions with erythema, along with hyperkeratosis of the palms and the soles, suggestive of lamellar ichthyosis were present. On ocular examination, the intraocular pressure was 36 mm Hg; optic nerve head examination revealed a horizontally oval disc with near total cupping in the right eye and total cupping in the left eye, with extensive neuroretinal rim thinning and pallor. Gonioscopy showed wide open angles with prominent iris processes. Screening of JOAG-associated genes (MYOC, NTF4, WDR36, and CYP1B1) and ichthyosis-associated gene (TGM1) was performed by the direct PCR sequencing method. RESULTS: A diagnosis of JOAG with advanced glaucomatous optic neuropathy with lamellar ichthyosis and rickets was made. The patient underwent right followed by left eye trabeculectomy with 0.2 mg/dL MMC (for 1 min). Postoperatively, the intraocular pressure was 8 mm Hg at 1 week, and 12 to 14 mm Hg at the 6-week, the 3-month, and the 6-month follow-up, and the visual acuity was maintained in the right eye. No mutations in MYOC, NTF4, WDR36, CYP1B1, and TGM1 were observed in the patient and his family. CONCLUSIONS: An association of glaucoma with ichthyosis should be kept in mind. Therefore, a detailed baseline ocular examination in children with ichthyosis is required, as early detection of glaucoma could prevent irreversible blindness. PMID- 26439316 TI - Answer to the authors. PMID- 26439313 TI - Ziram, a pesticide associated with increased risk for Parkinson's disease, differentially affects the presynaptic function of aminergic and glutamatergic nerve terminals at the Drosophila neuromuscular junction. AB - Multiple populations of aminergic neurons are affected in Parkinson's disease (PD), with serotonergic and noradrenergic loci responsible for some non-motor symptoms. Environmental toxins, such as the dithiocarbamate fungicide ziram, significantly increase the risk of developing PD and the attendant spectrum of both motor and non-motor symptoms. The mechanisms by which ziram and other environmental toxins increase the risk of PD, and the potential effects of these toxins on aminergic neurons, remain unclear. To determine the relative effects of ziram on the synaptic function of aminergic versus non-aminergic neurons, we used live-imaging at the Drosophila melanogaster larval neuromuscular junction (NMJ). In contrast to nearly all other studies of this model synapse, we imaged presynaptic function at both glutamatergic Type Ib and aminergic Type II boutons, the latter responsible for storage and release of octopamine, the invertebrate equivalent of noradrenalin. To quantify the kinetics of exo- and endo-cytosis, we employed an acid-sensitive form of GFP fused to the Drosophila vesicular monoamine transporter (DVMAT-pHluorin). Additional genetic probes were used to visualize intracellular calcium flux (GCaMP) and voltage changes (ArcLight). We find that at glutamatergic Type Ib terminals, exposure to ziram increases exocytosis and inhibits endocytosis. By contrast, at octopaminergic Type II terminals, ziram has no detectable effect on exocytosis and dramatically inhibits endocytosis. In contrast to other reports on the neuronal effects of ziram, these effects do not appear to result from perturbation of the Ubiquitin Proteasome System (UPS) or calcium homeostasis. Unexpectedly, ziram also caused spontaneous and synchronized bursts of calcium influx (measured by GCaMP) and electrical activity (measured by ArcLight) at aminergic Type II, but not glutamatergic Type Ib, nerve terminals. These events are sensitive to both tetrodotoxin and cadmium chloride, and thus appear to represent spontaneous depolarizations followed by calcium influx into Type II terminals. We speculate that the differential effects of ziram on Type II versus Type Ib terminals may be relevant to the specific sensitivity of aminergic neurons in PD, and suggest that changes in neuronal excitability could contribute to the increased risk for PD caused by exposure to ziram. We also suggest that the fly NMJ will be useful to explore the synaptic effects of other pesticides associated with an increased risk of PD. PMID- 26439317 TI - To editor, orthodontics and craniofacial research. PMID- 26439318 TI - Metabolic engineering of a laboratory-evolved Thermobifida fusca muC strain for malic acid production on cellulose and minimal treated lignocellulosic biomass. AB - Malic acid is mainly used as an acidulant and taste enhancer in the beverage and food industry. Previously, a mutant strain Thermobifida fusca muC, obtained by adaptive evolution was found to accumulate malic acid on cellulose with low yield. In this study, the malic acid synthesis pathway in T. fusca muC was confirmed to be from phosphoenolpyruvate to oxaloacetate, followed by reduction of oxaloacetate to malate. To increase the yield of malic acid by the muC strain significantly, the carbon flux from pyruvate was redirected to oxaloacetate by expressing an exogenous pyruvate carboxylase (PCx) gene from Corynebacterium glutamicum ATCC 13032 in the chromosome of T. fusca muC-16. The yield of malic acid in the engineered strain muC-16 was increased by 47.9% compared to the parent strain muC. The muC-16 strain was then grown on ~100 g/L cellulose and the highest titer of malic acid was 62.76 g/L by batch fermentation. T. fusca muC-16 strain converted milled corn stover to malic acid with the highest titer of 21.47 g/L with minimal treatment. PMID- 26439320 TI - Anxiety and depression in long-term testicular germ cell tumor survivors. AB - OBJECTIVE: Despite a good prognosis, the typically young age at diagnosis and physical sequelae may cause psychological distress in germ cell tumor survivors. We aimed to determine the frequency of anxiety and depression and analyze the impact of demographic and disease-related factors. METHOD: We enrolled N=164 testicular germ cell tumor survivors receiving routine follow-up care at the University Cancer Center Hamburg and a specialized private practice (mean, 11.6 years after diagnosis). Patients completed the Generalized Anxiety Disorder Screener-7, the Patient Health Questionnaire-9 and the Memorial Symptom Assessment Scale-Short Form. RESULTS: We found clinically significant anxiety present in 6.1% and depression present in 7.9% of survivors. A higher number of physical symptoms and having children were significantly associated with higher levels of both anxiety and depression in multivariate regression analyses controlling for age at diagnosis, cohabitation, socioeconomic status, time since diagnosis, metastatic disease and relapse. Younger age at diagnosis and shorter time since diagnosis were significantly associated with higher anxiety. CONCLUSION: Although rates of clinically relevant anxiety and depression were comparably low, attention toward persisting physical symptoms and psychosocial needs related to a young age at diagnosis and having children will contribute to address potential long-term psychological distress in germ cell tumor survivors. PMID- 26439321 TI - Gouty arthropathy: Review of clinico-pathologic and imaging features. AB - Gout is a common inflammatory arthropathy in adults, with the prevalence increasing in males of older age. It occurs when monosodium urate (MSU) crystals are deposited in joints and connective tissue causing inflammation. The gold standard for the diagnosis of gout is the demonstration of negatively birefringent, needle-shaped MSU crystals through synovial fluid aspiration. However, this is an invasive technique and may not always be conclusive or feasible. Imaging techniques have been developed to aid in diagnosis of gout non invasively. Radiography has a low utility in the early diagnosis of gout and demonstrates erosions in late stages. Ultrasound (US) has a high overall sensitivity in diagnosing gout with the 'double contour' sign having a high specificity. Magnetic resonance imaging is good at detecting tophi, bone marrow oedema and erosions, but has a limited role in diagnosis because of its high cost and limited availability. Conventional computed tomography (CT) has no role in the routine diagnosis of gout before development of erosions and tophi. A newer technology, dual-energy CT (DECT) has been shown to be able to detect MSU crystals burden with high accuracy. It has a higher specificity and lower sensitivity that US in gout diagnosis. However, because of radiation exposure and cost, it has a better utility in diagnosing clinically suspected gout complicated by other concurrent rheumatologic conditions or if radiography, US and synovial aspiration are inconclusive or not feasible. This paper will review the clinico pathologic and imaging features of gouty arthropathy. PMID- 26439319 TI - Epidemiological, clinical, virological features of hepatitis B newly diagnosed in 2011 in Marseille University hospitals, southeastern France. AB - Hepatitis B virus (HBV) infection is a public health problem. In France, 0.68% of adults are chronically infected. We aimed to describe the epidemiological, virological and clinical characteristics of HBV infections newly diagnosed in 2011 in University hospitals of Marseille, the second largest French city. HBV serology was performed for 18,130 sera from 15,744 patients. A total of 167 patients were newly-diagnosed with HBV based upon the detection of hepatitis B surface antigen and anti-hepatitis B core antibodies. Clinico-epidemiological features were analyzed for 78 patients. Patients included a majority of men (59%), women being significantly younger with a mean age of 36 +/- 17 versus 43.5 +/- 16.2 years (P = 0.009). Country of birth was available for 52 patients and 35% of them originated from sub-Saharan Africa. Levels of the liver biological parameters were significantly lower in women compared to men, in whom mean alanine aminotransferase and gammaglutamyl transferase levels were 24 +/- 39 versus 37 +/- 36 IU/l (P = 0.0001) and 20 +/- 20 versus 51 +/- 53 IU/l (P = 0.0001), respectively. Co-infections with hepatitis C and human immunodeficiency viruses were found in 5% and 6% of the patients, respectively. HBV DNA was detectable in 90% of the HBeAg-negative patients. In addition, there was a positive correlation between the HBsAg titer and the HBV DNA level (P = 0.001). Genotype D was the most common HBV genotype and was found in 53% of the patients tested, followed by genotype E (21%). HBV remains a major concern with a slightly greater number of new diagnoses than in 2004. HBV genetic diversity was substantial in the present cohort. PMID- 26439322 TI - Catalytic Asymmetric Michael Reaction of 5H-Oxazol-4-Ones with alpha,beta Unsaturated Acyl Imidazoles. AB - The asymmetric Michael reaction between 5H-oxazol-4-ones and alpha,beta unsaturated acyl imidazoles is reported. A novel 2-benzo[b]thiophenyl-modified chiral ProPhenol species is synthesized and used as a ligand, leading to good enantioselectivities in this asymmetric conjugate addition reaction. Furthermore, the introduction of phenol additives as achiral co-ligands is found to improve the reaction's chemical yields, diastereoselectivities, and enantioselectivities. PMID- 26439323 TI - Measurement of Anti-Factor Xa Activity in Patients on Apixaban for Non-Valvular Atrial Fibrillation. AB - BACKGROUND: Chromogenic anti-factor Xa activity (AXA) assay is reported to be the most appropriate method to measure the pharmacodynamics of apixaban, but the distribution of AXA in non-valvular atrial fibrillation (NVAF) patients on apixaban therapy has not been fully elucidated. METHODS AND RESULTS: Steady-state trough and peak AXA were measured in 124 NVAF patients taking apixaban. In 25 patients, baseline, first peak, and trough AXA were also examined, and were 0.01+/-0.02 IU/ml, 0.83+/-0.43 IU/ml, and 0.34+/-0.17 IU/ml, respectively. First trough AXA was significantly lower than steady-state trough AXA, although it was significantly higher than baseline (P<0.0001). Similarly, first peak AXA was significantly lower than steady-state peak AXA (P<0.0001). In 124 patients, steady-state peak AXA was significantly higher in the 5-mg b.i.d. group than in the 2.5-mg b.i.d. group (2.05+/-0.73 IU/ml vs. 1.51+/-0.65 IU/ml, respectively; P<0.001), although there was no significant difference in trough AXA. Other than dose, age and serum creatinine were significantly related to both trough and peak AXA. CONCLUSIONS: The distribution of AXA in Japanese NVAF patients on apixaban therapy in daily clinical practice both in the acute and steady-state phase was measured. In patients taking apixaban, measurement of AXA clearly showed the pharmacodynamic profile of this drug. PMID- 26439324 TI - Carotid Intima-Media Thickness in Patients With a History of Kawasaki Disease. AB - BACKGROUND: Kawasaki disease (KD) is an acute pediatric vasculitis with coronary artery aneurysms (CAA) as its main complication. Concerns have been raised regarding the possibility of a predisposition of KD to premature cardiovascular disease (CVD) risk later in life. Our aim was to assess carotid intima-media thickness (cIMT), as a surrogate marker of CVD risk, in patients with a history of KD compared with unaffected controls. METHODS AND RESULTS: B-mode ultrasound cIMT measurements were performed in 168 patients with a history of KD, and 82 controls; 7 patients were excluded because of incomplete cIMT assessments. Mean cIMT (+/-SD) was increased in patients with KD compared with controls (0.378+/ 0.030 mm vs. 0.360+/-0.027 mm, respectively; P adjusted <0.0001). If the cIMTs of CAA-negative patients and controls were plotted against age, increased cIMT was only apparent at young age. In patients with CAA, increased cIMT was observed over the entire age range. CONCLUSIONS: Our findings show that arterial wall thickening is more apparent in patients with a history of KD as compared with controls. In CAA-negative patients, cIMT is indistinguishable from controls at older age, whereas an increased cIMT is observed at any age in patients with CAA, suggesting a more general and severe effect of KD on the arterial wall. PMID- 26439326 TI - A meta-analysis of adjusted observational studies and randomized controlled trials of endovascular versus open surgical repair for ruptured abdominal aortic aneurysm. AB - INTRODUCTION: The aim of the present meta-analysis was to determine whether endovascular aneurysm repair (EVAR) reduces perioperative mortality and improves overall survival compared with open surgical repair (OSR) in patients with ruptured abdominal aortic aneurysm (RAAA). EVIDENCE ACQUISITION: Eligible studies were observational studies with adjusted risk estimates or randomized controlled trials (RCTs) of EVAR versus OSR enrolling individuals with RAAA and reporting perioperative (30-day or in-hospital) or overall (>=3-month) all-cause mortality. EVIDENCE SYNTHESIS: Twenty-four adjusted observational studies and 4 RCTs enrolling a total of 56,826 patients with RAAA were identified and included. For perioperative all-cause mortality, pooled analyses of 22 adjusted observational studies and 4 RCTs respectively demonstrated a statistically significant 49% reduction with EVAR relative to OSR (odds ratio [OR]=0.51; 95% confidence interval [CI]: 0.44 to 0.59; P<0.00001) and no statistically significant difference between EVAR and OSR (OR=0.91; 95% CI: 0.68 to 1.22; P=0.53) (P for subgroup differences = 0.0006). For overall (3 months to 8 years) all-cause mortality, a pooled analysis of 7 adjusted observational studies (hazard ratio [HR]=0.92; 95% CI: 0.77 to 1.10; P=0.37) and 3 RCTs (HR=0.89; 95% CI: 0.69 to 1.14; P=0.34) demonstrated no statistically significant difference between EVAR and OSR (P for subgroup differences = 0.81). CONCLUSIONS: In patients with RAAA, EVAR is likely effective in prevention of perioperative overall (3 months to 8 years), not all-cause mortality. PMID- 26439327 TI - Hypomethylation and hypohydroxymethylation of DNA in hepatocellular carcinoma and cholangiocarcinoma. PMID- 26439325 TI - Patient-reported physical functioning predicts the success of hematopoietic cell transplantation (BMT CTN 0902). AB - BACKGROUND: In hematopoietic cell transplantation (HCT), current risk adjustment strategies are based on clinical and disease-related variables. Although patient reported outcomes (PROs) predict mortality in multiple cancers, they have been less well studied within HCT. Improvements in risk adjustment strategies in HCT would inform patient selection, patient counseling, and quality reporting. The objective of the current study was to determine whether pre-HCT PROs, in particular physical health, predict survival among patients undergoing autologous or allogeneic transplantation. METHODS: In this secondary analysis, the authors studied pre-HCT PROs that were reported by 336 allogeneic and 310 autologous HCT recipients enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0902 protocol, a study with broad representation of patients who underwent transplantation in the United States. RESULTS: Among allogeneic HCT recipients, the pre-HCT Medical Outcomes Study Short Form-36 Health Survey (SF 36) physical component summary (PCS) scale independently predicted overall mortality (hazards ratio, 1.40 per 10-point decrease; P<.001) and performed at least as well as currently used, non-PRO risk indices. Survival probability estimates at 1 year for the first, second, third, and fourth quartiles of the baseline PCS were 50%, 65%, 75%, and 83%, respectively. Early post-HCT decreases in PCS were associated with higher overall and treatment-related mortality. When adjusted for patient variables included in the US Stem Cell Therapeutic Outcomes Database model for transplant center-specific reporting, the SF-36 PCS retained independent prognostic value. CONCLUSIONS: PROs have the potential to improve prognostication in HCT. The authors recommend the routine collection of PROs before HCT, and consideration of the incorporation of PROs into risk adjustment for quality reporting. PMID- 26439328 TI - Combined Effects of Sedentary Behavior and Moderate-to-Vigorous Physical Activity on Cardiovascular Health in Older, Community-Dwelling Latinos. AB - This study examined the combined effects of sedentary behavior and moderate-to vigorous physical activity (MVPA) on cardiovascular health in older Latinos. In a cross-sectional sample of 147 older, community-dwelling Latinos, time spent in sedentary behavior and MVPA were obtained using accelerometers. Analyses examined the effects of a measure of physical activity that combined levels of sedentary behavior (+/- 10 daily hours) and MVPA (< 30, 30-150, or > 150 weekly minutes) on cardiovascular health outcomes (blood pressure, BMI, waist circumference, cardiorespiratory fitness). Results suggest that cardiovascular health benefits of MVPA on BMI (p = .005), waist circumference (p = .002), and cardiorespiratory fitness (p = .012) may depend on a participant's level of sedentary behavior. For all three, health benefits of 30-150 weekly minutes of MVPA were found only for those without excessive sedentary behavior (>= 10 hr). Sedentary behavior may negatively impact cardiovascular health despite moderate participation in MVPA. Health guidelines should suggest reducing sedentary behavior while increasing MVPA. PMID- 26439330 TI - Equilibrium Shape of Colloidal Crystals. AB - Assembling colloidal particles into highly ordered configurations, such as photonic crystals, has significant potential for enabling a broad range of new technologies. Facilitating the nucleation of colloidal crystals and developing successful crystal growth strategies require a fundamental understanding of the equilibrium structure and morphology of small colloidal assemblies. Here, we report the results of a novel computational approach to determine the equilibrium shape of assemblies of colloidal particles that interact via an experimentally validated pair potential. While the well-known Wulff construction can accurately capture the equilibrium shape of large colloidal assemblies, containing O(10(4)) or more particles, determining the equilibrium shape of small colloidal assemblies of O(10) particles requires a generalized Wulff construction technique which we have developed for a proper description of equilibrium structure and morphology of small crystals. We identify and characterize fully several "magic" clusters which are significantly more stable than other similarly sized clusters. PMID- 26439329 TI - The value of short- and long-acting glucagon-like peptide-1 agonists in the management of type 2 diabetes mellitus: experience with exenatide. AB - BACKGROUND: Only about half of patients with type 2 diabetes treated with antihyperglycemic drugs achieve glycemic control (HbA1c <7%), most commonly due to poor treatment adherence. Glucagon-like peptide-1 (GLP-1) receptor agonists act on multiple targets involved in glucose homeostasis and have a low risk of causing hypoglycemia. While GLP-1 receptor (GLP-1R) agonists share the same mechanism of action, clinical profiles of individual agents differ, particularly between short- and long-acting agents. In this article, recent findings regarding the pharmacology of GLP-1 agonists are reviewed, and the clinical effects of short- versus long-acting agents are compared. DATA SOURCES: Relevant articles were identified through a search of PubMed using the keywords glucagon-like peptide-1, GLP-1, glucagon-like peptide-1 receptor agonist, GLP-1R agonist, and exenatide for publications up to 22 May 2015. Supporting data were obtained from additional searches for albiglutide, dulaglutide, liraglutide and lixisenatide as well as from the bibliographies of key articles. FINDINGS: Short-acting GLP-1R agonists produce greater reductions in postprandial glucose levels by slowing gastric emptying, whereas long-acting GLP-1R agonists produce greater reductions in fasting blood glucose by stimulating insulin secretion from the pancreas. These characteristics can be exploited to provide individualized treatment to patients. A large body of evidence supports the benefits of short- and long acting exenatide as add-on therapy in patients with inadequate glycemic control despite maximum tolerated doses of metformin and/or sulfonylurea. Exenatide is generally well tolerated and no new safety concerns were identified during long term follow-up of up to 5 years. A limitation of this review of short-and long acting GLP-1 receptor agonists is that it focuses on exenatide rather than all the drugs in this class. However, the focus on a single molecule helps to avoid any confusion that may be introduced as a result of differences in molecular structure and size. CONCLUSIONS: Short-acting GLP-1R agonists including exenatide are well suited to patients with type 2 diabetes with exaggerated postprandial glucose excursions and for co-administration with basal insulin therapy. Long acting GLP-1R agonists including once weekly exenatide offer greater convenience and are well suited to patients who require specific control of fasting hyperglycemia. PMID- 26439331 TI - Zoomusicology. PMID- 26439332 TI - Vectored antibody gene delivery mediates long-term contraception. AB - Development of non-surgical methods of long-term or permanent contraception remains a challenge. Towards this objective, we show that intramuscular injection of a replication-incompetent, recombinant adeno-associated virus (rAAV) designed to express an antibody that binds gonadotropin-releasing hormone (GnRH), a master regulator of reproduction in vertebrates, results in long-term infertility in male and female mice. Female mice are also rendered infertile through rAAV dependent expression of an antibody that binds to the zona pellucida (ZP), a glycoprotein matrix that surrounds the egg and functions as a sperm-binding site. Many proteins known or suspected to be important for reproduction can be targeted, potentially reversibly, using this approach, which we refer to as vectored contraception (VC). PMID- 26439333 TI - Eurasian reed warblers compensate for virtual magnetic displacement. PMID- 26439334 TI - Long-term census data reveal abundant wildlife populations at Chernobyl. PMID- 26439335 TI - Spatial Cognition: Grid Cell Firing Depends on Self-Motion Cues. AB - A recent study has found that the periodic spatial activity of grid cells is completely degraded when animals are moved passively around an enclosure, strengthening the view that grid-firing is generated on the basis of self-motion information. PMID- 26439336 TI - Animal Memory: Chimpanzees Anticipate What Comes Next in Short Movies. AB - A recent study shows that chimpanzees remember a movie they viewed one day earlier, and their eye movements show that they anticipate certain actions in that movie before those actions occur by looking to parts of the scene that are about to become relevant to the storyline. PMID- 26439337 TI - Visual Neuroscience: Dissociating Perceptual and Occulomotor Localization of Moving Objects. AB - A new experiment shows that the perceived motion path of a textured object is affected both by the path of the object and by the motion of texture within it, but that eye movements attempting to intercept the object are unaffected by the texture movement. PMID- 26439339 TI - Animal Navigation: Birds Have Magnetic Maps. AB - New 'virtual displacement' experiments demonstrate that migrating reed warblers know the magnetic coordinates of their destination, and can set a novel course to their goal with only magnetic-field parameters as a guide. PMID- 26439338 TI - Sensory Biology: Novel Peripheral Organization for Better Smell. AB - Sensory systems have adopted various ways to enhance detection and discrimination. A recent study shows a novel spatial organization of sensory cells in the peripheral olfactory system in mice for better odor detection. PMID- 26439340 TI - Stomatal Patterning: SERKs Put the Mouths in Their Right Place. AB - Plants have stomata, mouth-like pores on their surface, to adjust to environmental changes such as temperature and humidity to ensure optimum physiology and metabolism. A new study adds a key player, SERK, to the signal sensing apparatus to inform where stomata are to be formed on the leaf. PMID- 26439341 TI - Neural Evolution: Costing the Benefits of Eye Loss. AB - What selective forces contribute to eye loss in cave animals? A new study shows the eye and optic tectum of a cave fish consumes ~5-17% of the total energy consumption, emphasising that selection to reduce energy consumption may drive eye loss. PMID- 26439342 TI - Circadian Clocks: Unexpected Biochemical Cogs. AB - A circadian oscillation can be reconstituted in vitro from three proteins that cycles with a period of ~ 24 h. Two recent studies provide surprising biochemical answers to why this remarkable oscillator has such a long time constant and how it can switch effortlessly between alternating enzymatic modes. PMID- 26439343 TI - The tree view of life. PMID- 26439344 TI - History of life on Earth. PMID- 26439345 TI - Archaea. AB - A headline on the front page of the New York Times for November 3, 1977, read "Scientists Discover a Way of Life That Predates Higher Organisms". The accompanying article described a spectacular claim by Carl Woese and George Fox to have discovered a third form of life, a new 'domain' that we now call Archaea. It's not that these microbes were unknown before, nor was it the case that their peculiarities had gone completely unnoticed. Indeed, Ralph Wolfe, in the same department at the University of Illinois as Woese, had already discovered how it was that methanogens (uniquely on the planet) make methane, and the bizarre adaptations that allow extremely halophilic archaea (then called halobacteria) and thermoacidophiles to live in the extreme environments where they do were already under investigation in many labs. But what Woese and Fox had found was that these organisms were related to each other not just in their 'extremophily' but also phylogenetically. And, most surprisingly, they were only remotely related to the rest of the prokaryotes, which we now call the domain Bacteria (Figure 1). PMID- 26439346 TI - Photosynthesis and early Earth. AB - Life has been built on the evolution and innovation of microbial metabolisms. Even with our scant understanding of the full diversity of microbial life, it is clear that microbes have become integral components of the biogeochemical cycles that drive our planet. The antiquity of life further suggests that various microbial metabolisms have been core and essential to global elemental cycling for a majority of Earth's history. PMID- 26439347 TI - The Neoproterozoic. AB - The Neoproterozoic era was arguably the most revolutionary in Earth history. Extending from 1000 to 541 million years ago, it stands at the intersection of the two great tracts of evolutionary time: on the one side, some three billion years of pervasively microbial 'Precambrian' life, and on the other the modern 'Phanerozoic' biosphere with its extraordinary diversity of large multicellular organisms. The disturbance doesn't stop here, however: over this same stretch of time the planet itself was in the throes of change. Tectonically, it saw major super-continental reconfigurations, climatically its deepest ever glacial freeze, and geochemically some of the most anomalous perturbations on record. What lies behind this dramatic convergence of biological and geological phenomena, and how exactly did it give rise to the curiously complex world that we now inhabit? PMID- 26439348 TI - The Cambrian explosion. AB - The sudden appearance of fossils that marks the so-called 'Cambrian explosion' has intrigued and exercised biologists since Darwin's time. In On the Origin of Species, Darwin made it clear that he believed that ancestral forms 'lived long before' their first fossil representatives. While he considered such an invisible record necessary to explain the level of complexity already seen in the fossils of early trilobites, Darwin was at a loss to explain why there were no corresponding fossils of these earlier forms. In chapter 9 of the Origin, entitled 'On the imperfection of the geological record', he emphasized the 'poorness of our palaeontological collections' and stated categorically that 'no organism wholly soft can be preserved'. Fortunately much has been discovered in the last 150 years, not least multiple examples of Cambrian and Precambrian soft bodied fossils. We now know that the sudden appearance of fossils in the Cambrian (541-485 million years ago) is real and not an artefact of an imperfect fossil record: rapid diversification of animals coincided with the evolution of biomineralized shells. And although fossils in earlier rocks are rare, they are not absent: their rarity reflects the low diversity of life at this time, as well as the low preservation potential of Precambrian organisms (see Primer by Butterfield, in this issue). PMID- 26439349 TI - Insect evolution. AB - It goes without saying that insects epitomize diversity, and with over a million documented species they stand out as one of the most remarkable lineages in the 3.5-billion-year history of life on earth (Figure 1). This reality is passe to even the layperson and is taken for granted in the same way none of us think much of our breathing as we go about our day, and yet insects are just as vital to our existence. Insects are simultaneously familiar and foreign to us, and while a small fraction are beloved or reviled, most are simply ignored. These inexorable evolutionary overachievers outnumber us all, their segmented body plan is remarkably labile, they combine a capacity for high rates of speciation with low levels of natural extinction, and their history of successes eclipses those of the more familiar ages of dinosaurs and mammals alike. It is their evolution - persisting over vast expanses of geological time and inextricably implicated in the diversification of other lineages - that stands as one of the most expansive subjects in biology. PMID- 26439350 TI - Lobopodians. PMID- 26439351 TI - Phylogenomic Insights into Animal Evolution. AB - Animals make up only a small fraction of the eukaryotic tree of life, yet, from our vantage point as members of the animal kingdom, the evolution of the bewildering diversity of animal forms is endlessly fascinating. In the century following the publication of Darwin's Origin of Species, hypotheses regarding the evolution of the major branches of the animal kingdom - their relationships to each other and the evolution of their body plans - was based on a consideration of the morphological and developmental characteristics of the different animal groups. This morphology-based approach had many successes but important aspects of the evolutionary tree remained disputed. In the past three decades, molecular data, most obviously primary sequences of DNA and proteins, have provided an estimate of animal phylogeny largely independent of the morphological evolution we would ultimately like to understand. The molecular tree that has evolved over the past three decades has drastically altered our view of animal phylogeny and many aspects of the tree are no longer contentious. The focus of molecular studies on relationships between animal groups means, however, that the discipline has become somewhat divorced from the underlying biology and from the morphological characteristics whose evolution we aim to understand. Here, we consider what we currently know of animal phylogeny; what aspects we are still uncertain about and what our improved understanding of animal phylogeny can tell us about the evolution of the great diversity of animal life. PMID- 26439352 TI - The Origin and Diversification of Birds. AB - Birds are one of the most recognizable and diverse groups of modern vertebrates. Over the past two decades, a wealth of new fossil discoveries and phylogenetic and macroevolutionary studies has transformed our understanding of how birds originated and became so successful. Birds evolved from theropod dinosaurs during the Jurassic (around 165-150 million years ago) and their classic small, lightweight, feathered, and winged body plan was pieced together gradually over tens of millions of years of evolution rather than in one burst of innovation. Early birds diversified throughout the Jurassic and Cretaceous, becoming capable fliers with supercharged growth rates, but were decimated at the end-Cretaceous extinction alongside their close dinosaurian relatives. After the mass extinction, modern birds (members of the avian crown group) explosively diversified, culminating in more than 10,000 species distributed worldwide today. PMID- 26439353 TI - The Evolutionary Origin of a Terrestrial Flora. AB - Life on Earth as we know it would not be possible without the evolution of plants, and without the transition of plants to live on land. Land plants (also known as embryophytes) are a monophyletic lineage embedded within the green algae. Green algae as a whole are among the oldest eukaryotic lineages documented in the fossil record, and are well over a billion years old, while land plants are about 450-500 million years old. Much of green algal diversification took place before the origin of land plants, and the land plants are unambiguously members of a strictly freshwater lineage, the charophyte green algae. Contrary to single-gene and morphological analyses, genome-scale phylogenetic analyses indicate the sister taxon of land plants to be the Zygnematophyceae, a group of mostly unbranched filamentous or single-celled organisms. Indeed, several charophyte green algae have historically been used as model systems for certain problems, but often without a recognition of the specific phylogenetic relationships among land plants and (other) charophyte green algae. Insight into the phylogenetic and genomic properties of charophyte green algae opens up new opportunities to study key properties of land plants in closely related model. This review will outline the transition from single-celled algae to modern-day land plants, and will highlight the bright promise studying the charophyte green algae holds for better understanding plant evolution. PMID- 26439354 TI - Endosymbiosis and Eukaryotic Cell Evolution. AB - Understanding the evolution of eukaryotic cellular complexity is one of the grand challenges of modern biology. It has now been firmly established that mitochondria and plastids, the classical membrane-bound organelles of eukaryotic cells, evolved from bacteria by endosymbiosis. In the case of mitochondria, evidence points very clearly to an endosymbiont of alpha-proteobacterial ancestry. The precise nature of the host cell that partnered with this endosymbiont is, however, very much an open question. And while the host for the cyanobacterial progenitor of the plastid was undoubtedly a fully-fledged eukaryote, how - and how often - plastids moved from one eukaryote to another during algal diversification is vigorously debated. In this article I frame modern views on endosymbiotic theory in a historical context, highlighting the transformative role DNA sequencing played in solving early problems in eukaryotic cell evolution, and posing key unanswered questions emerging from the age of comparative genomics. PMID- 26439355 TI - Morphological Phylogenetics in the Genomic Age. AB - Evolutionary trees underpin virtually all of biology, and the wealth of new genomic data has enabled us to reconstruct them with increasing detail and confidence. While phenotypic (typically morphological) traits are becoming less important in reconstructing evolutionary trees, they still serve vital and unique roles in phylogenetics, even for living taxa for which vast amounts of genetic information are available. Morphology remains a powerful independent source of evidence for testing molecular clades, and - through fossil phenotypes - the primary means for time-scaling phylogenies. Morphological phylogenetics is therefore vital for transforming undated molecular topologies into dated evolutionary trees. However, if morphology is to be employed to its full potential, biologists need to start scrutinising phenotypes in a more objective fashion, models of phenotypic evolution need to be improved, and approaches for analysing phenotypic traits and fossils together with genomic data need to be refined. PMID- 26439356 TI - Novelty and Innovation in the History of Life. AB - The history of life as documented by the fossil record encompasses evolutionary diversifications at scales ranging from the Ediacaran-Cambrian explosion of animal life and the invasion of land by vascular plants, insects and vertebrates to the diversification of flowering plants over the past 100 million years and the radiation of horses. Morphological novelty and innovation has been a recurrent theme. The architects of the modern synthesis of evolutionary theory made three claims about evolutionary novelty and innovation: first, that all diversifications in the history of life represent adaptive radiations; second, that adaptive radiations are driven principally by ecological opportunity rather than by the supply of new morphological novelties, thus the primary questions about novelty and innovation focus on their ecological and evolutionary success; and third, that the rate of morphological divergence between taxa was more rapid early in the history of a clade but slowed over time as ecological opportunities declined. These claims have strongly influenced subsequent generations of evolutionary biologists, yet over the past two decades each has been challenged by data from the fossil record, by the results of comparative phylogenetic analyses and through insights from evolutionary developmental biology. Consequently a broader view of novelty and innovation is required. An outstanding issue for future work is identifying the circumstances associated with different styles of diversification and whether their frequency has changed through the history of life. PMID- 26439357 TI - Life in the Aftermath of Mass Extinctions. AB - The vast majority of species that have ever lived went extinct sometime other than during one of the great mass extinction events. In spite of this, mass extinctions are thought to have outsized effects on the evolutionary history of life. While part of this effect is certainly due to the extinction itself, I here consider how the aftermaths of mass extinctions might contribute to the evolutionary importance of such events. Following the mass loss of taxa from the fossil record are prolonged intervals of ecological upheaval that create a selective regime unique to those times. The pacing and duration of ecosystem change during extinction aftermaths suggests strong ties between the biosphere and geosphere, and a previously undescribed macroevolutionary driver - earth system succession. Earth system succession occurs when global environmental or biotic change, as occurs across extinction boundaries, pushes the biosphere and geosphere out of equilibrium. As species and ecosystems re-evolve in the aftermath, they change global biogeochemical cycles - and in turn, species and ecosystems - over timescales typical of the geosphere, often many thousands to millions of years. Earth system succession provides a general explanation for the pattern and timing of ecological and evolutionary change in the fossil record. Importantly, it also suggests that a speed limit might exist for the pace of global biotic change after massive disturbance - a limit set by geosphere biosphere interactions. For mass extinctions, earth system succession may drive the ever-changing ecological stage on which species evolve, restructuring ecosystems and setting long-term evolutionary trajectories as they do. PMID- 26439358 TI - The RNA World as a Model System to Study the Origin of Life. AB - Understanding how life arose is a fundamental problem of biology. Much progress has been made by adopting a synthetic and mechanistic perspective on originating life. We present a current view of the biochemistry of the origin of life, focusing on issues surrounding the emergence of an RNA World in which RNA dominated informational and functional roles. There is cause for optimism on this difficult problem: the prebiotic chemical inventory may not have been as nightmarishly complex as previously thought; the catalytic repertoire of ribozymes continues to expand, approaching the goal of self-replicating RNA; encapsulation in protocells provides evolutionary and biophysical advantages. Nevertheless, major issues remain unsolved, such as the origin of a genetic code. Attention to this field is particularly timely given the accelerating discovery and characterization of exoplanets. PMID- 26439364 TI - Hierarchical CdS Nanowires Based Rigid and Flexible Photodetectors with Ultrahigh Sensitivity. AB - Hierarchical CdS nanowires were synthesized via a facile vapor transport method, which were used to fabricate both rigid and flexible visible-light photodetectors. Studies found that the rigid photodetectors on SiO2/Si substrate showed ultrahigh photo-dark current ratio up to 1.96 * 10(4), several orders of magnitude higher than previously reported CdS nanostructures, as well as high specific detectivity (4.27 * 10(12) Jones), fast response speed and excellent environmental stability. Highly flexible photodetectors were also fabricated on polyimide substrate, which exhibited comparable photoresponse performance as the rigid one. In addition, the as-prepared flexible devices displayed excellent mechanical flexibility, electrical stability and folding endurance. The results indicate that the hierarchical CdS nanowires may be good candidates for nanoscale optoelectronic devices such as high-efficiency photoswitches and highly photosensitive detectors. PMID- 26439359 TI - Pineal hypoplasia, reduced melatonin and sleep disturbance in patients with PAX6 haploinsufficiency. AB - In rodent studies, paired box 6 (PAX6) appears to play an important role in the development of the pineal, the primary source of the circadian regulating hormone, melatonin. Pineal hypoplasia has been previously reported in patients with PAX6 haploinsufficiency (+/-); however, pineal measurement, melatonin concentrations and sleep quality have not been reported. This cross-sectional descriptive study examined pineal volume, melatonin secretion and sleep disturbance in 37 patients with PAX6+/- (age 15.3 +/- 9.9 years) and 17 healthy controls (16.0 +/- 7.2 years), within an inpatient setting at the Clinical Research Center of the National Institutes of Health, Bethesda, Maryland, USA. Pineal volume was evaluated by magnetic resonance imaging. Diurnal serum cortisol, serum melatonin and urine 6-sulphatoxymelatonin concentrations were measured by enzyme-linked immunosorbent assay. The Child Sleep Habits Questionnaire was administered for patients <13 years old. Pineal volume was fivefold lower in PAX6+/- versus controls (mean +/- SD: 25 +/- 15 versus 129 +/- 50 MUL, P < 0.001). Midnight serum cortisol was similar in PAX6+/- versus controls (P = 0.14). Midnight serum melatonin was > twofold lower in PAX6+/- versus controls [median (25th-75 th): 28 (22-42) versus 71 (46-88) pg mL-(1), P < 0.001]. First morning void urinary 6-sulphatoxymelatonin was fourfold lower in PAX6+/- versus controls [11 (6-26) versus 45 (34-61) ng mg(-1) Cr, P = 0.001]. Child Sleep Habits Questionnaire score was higher in PAX6+/- versus controls (48 +/- 6 versus 41 +/- 5, P = 0.03). The current findings suggest that PAX6+/- is associated with smaller pineal size, lower melatonin secretion and greater parental report of sleep disturbances in children. Further studies are needed to explore the potential use of melatonin replacement for improving sleep quality in patients with PAX6+/-. PMID- 26439365 TI - Exploration of Excited State Deactivation Pathways of Adenine Monohydrates. AB - Binding of a single water molecule has a dramatic effect on the excited state lifetime of adenine. Here we report a joint nonadiabatic dynamics and reaction paths study aimed at understanding the sub-100 fs lifetime of adenine in the monohydrates. Our nonadiabatic dynamics simulations, performed using the ADC(2) electronic structure method, show a shortening of the excited state lifetime in the monohydrates with respect to bare adenine. However, the computed lifetimes were found to be significantly longer that the observed one. By comparing the reaction pathways of several excited state deactivation processes in adenine and adenine monohydrates, we show that electron-driven proton transfer from water to nitrogen atom N3 of the adenine ring may be the process responsible for the observed ultrafast decay. The inaccessibility of the electron-driven proton transfer pathway to trajectory-based nonadiabatic dynamics simulation is discussed. PMID- 26439366 TI - Pseudomonas aeruginosa: arsenal of resistance mechanisms, decades of changing resistance profiles, and future antimicrobial therapies. AB - Antimicrobial resistance is one of the most serious public health issues facing humans since the discovery of antimicrobial agents. The frequent, prolonged, and uncontrolled use of antimicrobial agents are major factors in the emergence of antimicrobial-resistant bacterial strains, including multidrug-resistant variants. Pseudomonas aeruginosa is a leading cause of nosocomial infections. The abundant data on the increased resistance to antipseudomonal agents support the need for global action. There is a paucity of new classes of antibiotics active against P. aeruginosa. Here, we discuss recent antibacterial resistance profiles and mechanisms of resistance by P. aeruginosa. We also review future potential methods for controlling antibiotic-resistant bacteria, such as phage therapy, nanotechnology and antipseudomonal vaccines. PMID- 26439367 TI - Neuromotor tolerability and behavioural characterisation of cannabidiolic acid, a phytocannabinoid with therapeutic potential for anticipatory nausea. AB - RATIONALE: Anticipatory nausea (AN) is a poorly controlled side effect experienced by chemotherapy patients. Currently, pharmacotherapy is restricted to benzodiazepine anxiolytics, which have limited efficacy, have significant sedative effects and induce dependency. The non-psychoactive phytocannabinoid, cannabidiolic acid (CBDA), has shown considerable efficacy in pre-clinical AN models, however determination of its neuromotor tolerability profile is crucial to justify clinical investigation. Provisional evidence for appetite-stimulating properties also requires detailed investigation. OBJECTIVES: This study aims to assess the tolerability of CBDA in locomotor activity, motor coordination and muscular strength tests, and additionally for ability to modulate feeding behaviours. METHODS: Male Lister Hooded rats administered CBDA (0.05-5 mg/kg; p.o.) were assessed in habituated open field (for locomotor activity), static beam and grip strength tests. A further study investigated whether these CBDA doses modulated normal feeding behaviour. Finally, evidence of anxiolytic-like effects in the habituated open field prompted testing of 5 mg/kg CBDA for anxiolytic-like activity in unhabituated open field, light/dark box and novelty suppressed feeding (NSF) tests. RESULTS: CBDA had no adverse effects upon performance in any neuromotor tolerability test, however anxiolytic-like behaviour was observed in the habituated open field. Normal feeding behaviours were unaffected by any dose. CBDA (5 mg/kg) abolished the increased feeding latency in the NSF test induced by the 5-HT1AR antagonist, WAY-100,635, indicative of anxiolytic-like effects, but had no effect on anxiety-like behaviour in the novel open field or light/dark box. CONCLUSIONS: CBDA is very well tolerated and devoid of the sedative side effect profile of benzodiazepines, justifying its clinical investigation as a novel AN treatment. PMID- 26439368 TI - New development in a blood-based diagnostic test for early-stage arthritis. PMID- 26439369 TI - Silver(I)-Ferrophox Catalyzed Enantioselective Desymmetrization of Cyclopentenedione: Synthesis of Highly Substituted Bicyclic Pyrrolidines. AB - A highly enantioselective desymmetrization of prochiral cyclopentene-1,3-dione via [3 + 2] cycloaddition of azomethine ylide using a silver(I)-ferrophox complex has been demonstrated. The method has been utilized in the synthesis of highly functionalized enantioenriched 5,5-fused bicyclic pyrrolidine derivatives under mild reaction conditions. PMID- 26439370 TI - Near-infrared fluorescence cholangiography with indocyanine green for biliary atresia. Real-time imaging during the Kasai procedure: a pilot study. AB - INTRODUCTION: Hepatoportoenterostomy (HPE) with the Kasai procedure is the treatment of choice for biliary atresia (BA) as the initial surgery. However, the appropriate level of dissection level of the fibrous cone (FC) of the porta hepatis (PH) is frequently unclear, and the procedure sometimes results in unsuccessful outcomes. Recently, indocyanine green near-infrared fluorescence imaging (ICG-FCG) has been developed as a form of real-time cholangiography. METHODS: We applied this technique in five patients with BA to visualize the biliary flow at the PH intraoperatively. ICG was injected intravenously the day before surgery as the liver function test, and the liver was observed with a near infrared camera system during the operation while the patient's feces was also observed. RESULTS: In all patients, the whole liver fluoresced diffusely with ICG containing stagnant bile, whereas no extrahepatic structures fluoresced. The findings of the ICG fluorescence pattern of the PH after dissection of the FC were classified into three types: spotty fluorescence, one patient; diffuse weak fluorescence, three patients; and diffuse strong fluorescence, one patient. In all five patients, the feces evacuated after HPE showed distinct fluorescent spots, although that obtained before surgery showed no fluorescence. One patient with diffuse strong fluorescence who did not achieve JF underwent living related liver transplantation six months after the initial HPE procedure. Four patients, including three cases involving diffuse weak fluorescence and one case involving spotty fluorescence showed weak fluorescence compared to that of the surrounding liver surface. CONCLUSION: We were able to detect the presence of bile excretion at the time of HPE intraoperatively and successfully evaluated the extent of bile excretion using this new technique. Furthermore, the ICG-FCG findings may provide information leading to a new classification and potentially function as an indicator predicting the clinical outcomes after HPE. PMID- 26439371 TI - Laparoscopic modified bypass pyeloplasty: a simple procedure for straightforward ureteral spatulation and intracorporeal suturing. AB - PURPOSE: Bypass pyeloplasty (BP) is a simple, non-dismembered procedure that is a side-to-side anastomosis without dividing the ureteropelvic junction (UPJ). BP has been considered more suitable especially for novice surgeons than dismembered pyeloplasty via the laparoscopic approach, but not reported. However, the disadvantage of laparoscopic BP is that it is difficult to suture the side of the anastomosis that is far from the camera. To overcome this disadvantage, a modified technique was developed. This procedure and its initial results are reported. METHODS: Twenty-six consecutive patients underwent laparoscopic modified BP. The patients' median age at surgery was 10.5 years. Ten patients were adults and 16 were children. The key step of modified BP involves dividing the UPJ after ureteral spatulation and suture of the dependent portion. This provides both better visualization of the anastomosis portion and easy anastomosis. RESULTS: All procedures were completed by laparoscopic modified BP. The median operative time was 246 (range 170-357) min. The median time for ureteropelvic anastomosis was 205 (range 145-311) min. There were no significant differences in mean operative time and ureteropelvic anastomotic time between adults and children (adults/children = 243 +/- 49 min:252 +/- 58 min, p = 0.66, 192 +/- 33 min:214 +/- 48 min, p = 0.21, respectively). Successful resolution of UPJO was observed in 96 % of cases. CONCLUSIONS: Laparoscopic modified BP combines the advantages of non-dismembered and dismembered pyeloplasty. Because there were no differences in mean operative and anastomotic times between adults and children, laparoscopic modified BP might be an efficient procedure for all ages, especially children. PMID- 26439372 TI - A safe method of ciliary sulcus fixation of foldable intraocular lens using a ciliary sulcus guide. AB - To describe a novel technique for implantation of intraocular lens in the absence of capsular support using a ciliary sulcus guide. Based on the anatomic knowledge of the ciliary sulcus and the sclera, a new instrument was developed to pierce the needle safely through the ciliary sulcus and sclera. While the foldable lens is stored inside the cartridge, the leading haptic is sutured with a cow-hitch knot. The needle is then inserted into the ciliary sulcus guide. The tip of the guide is inserted from the corneal incision and proceeded under the iris to touch and fit the ciliary sulcus. The needle is pushed from back side. The needle comes out at precise point at the sclera. Implantation of the lens was performed through a 2.8 mm clear cornea incision using the injector. The trailing haptic is tied after implantation, and then the same procedure is performed at the opposite side. We performed this technique to 15 aphakic eyes without sufficient capsular support. There was no bleeding or other intraoperative complication. All the points coming out the sclera were between 2 and 2.5 mm from the limbus. The ab interno technique for scleral fixation of IOL is quicker, easier and less traumatic then ab externo techniques. A new ciliary sulcus guide which is usable with both straight and curved needles eliminates the blind maneuvers of ab interno technique and makes this technique more safe and precise. PMID- 26439374 TI - Non-pharmacological interventions for sleep promotion in the intensive care unit. AB - BACKGROUND: Adults in intensive care units (ICUs) often suffer from a lack of sleep or frequent sleep disruptions. Non-pharmacological interventions can improve the duration and quality of sleep and decrease the risk of sleep disturbance, delirium, post-traumatic stress disorder (PTSD), and the length of stay in the ICU. However, there is no clear evidence of the effectiveness and harms of different non-pharmacological interventions for sleep promotion in adults admitted to the ICU. OBJECTIVES: To assess the efficacy of non pharmacological interventions for sleep promotion in critically ill adults in the ICU.To establish whether non-pharmacological interventions are safe and clinically effective in improving sleep quality and reducing length of ICU stay in critically ill adults.To establish whether non-pharmacological interventions are cost effective. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2014, Issue 6), MEDLINE (OVID, 1950 to June 2014), EMBASE (1966 to June 2014), CINAHL (Cumulative Index to Nursing and Allied Health Literature, 1982 to June 2014), Institute for Scientific Information (ISI) Web of Science (1956 to June 2014), CAM on PubMed (1966 to June 2014), Alt HealthWatch (1997 to June 2014), PsycINFO (1967 to June 2014), the China Biological Medicine Database (CBM-disc, 1979 to June 2014), and China National Knowledge Infrastructure (CNKI Database, 1999 to June 2014). We also searched the following repositories and registries to June 2014: ProQuest Dissertations & Theses Global, the US National Institutes of Health Ongoing Trials Register (www.clinicaltrials.gov), the metaRegister of Controlled Trials (ISRCTN Register) (www.controlled-trials.com), the Chinese Clinical Trial Registry (www.chictr.org.cn), the Clinical Trials Registry-India (www.ctri.nic.in), the Grey Literature Report from the New York Academy of Medicine Library (www.greylit.org), OpenGrey (www.opengrey.eu), and the World Health Organization International Clinical Trials Registry platform (www.who.int/trialsearch). We handsearched critical care journals and reference lists and contacted relevant experts to identify relevant unpublished data. SELECTION CRITERIA: We included all randomized controlled trials (RCT) and quasi-RCTs that evaluated the effects of non-pharmacological interventions for sleep promotion in critically ill adults (aged 18 years and older) during admission to critical care units or ICUs. DATA COLLECTION AND ANALYSIS: Two authors independently screened the search results and assessed the risk of bias in selected trials. One author extracted the data and a second checked the data for accuracy and completeness. Where possible, we combined results in meta-analyses using mean differences and standardized mean differences for continuous outcomes and risk ratios for dichotomous outcomes. We used post-test scores in this review. MAIN RESULTS: We included 30 trials, with a total of 1569 participants, in this review. We included trials of ventilator mode or type, earplugs or eye masks or both, massage, relaxation interventions, foot baths, music interventions, nursing interventions, valerian acupressure, aromatherapy, and sound masking. Outcomes included objective sleep outcomes, subjective sleep quality and quantity, risk of delirium, participant satisfaction, length of ICU stay, and adverse events. Clinical heterogeneity (e.g., participant population, outcomes measured) and research design limited quantitative synthesis, and only a small number of studies were available for most interventions. The quality of the evidence for an effect of non pharmacological interventions on any of the outcomes examined was generally low or very low. Only three trials, all of earplugs or eye masks or both, provided data suitable for two separate meta-analyses. These meta-analyses, each of two studies, showed a lower incidence of delirium during ICU stay (risk ratio 0.55, 95% confidence interval (CI) 0.38 to 0.80, P value = 0.002, two studies, 177 participants) and a positive effect of earplugs or eye masks or both on total sleep time (mean difference 2.19 hours, 95% CI 0.41 to 3.96, P value = 0.02, two studies, 116 participants); we rated the quality of the evidence for both of these results as low.There was also some low quality evidence that music (350 participants; four studies) may improve subjective sleep quality and quantity, but we could not pool the data. Similarly, there was some evidence that relaxation techniques, foot massage, acupressure, nursing or social intervention, and sound masking can provide small improvements in various subjective measures of sleep quality and quantity, but the quality of the evidence was low. The effects of non-pharmacological interventions on objective sleep outcomes were inconsistent across 16 studies (we rated the quality of the evidence as very low): the majority of studies relating to the use of earplugs and eye masks found no benefit; results from six trials of ventilator modes suggested that certain ventilator settings might offer benefits over others, although the results of the individual trials did not always agree with each other. Only one study measured length of stay in the ICU and found no significant effect of earplugs plus eye masks. No studies examined the effect of any non-pharmacological intervention on mortality, risk of post-traumatic stress disorder, or cost-effectiveness; the included studies did not clearly report adverse effects, although there was very low quality evidence that ventilator mode influenced the incidence of central apnoeas and patient-ventilator asynchronies. AUTHORS' CONCLUSIONS: The quality of existing evidence relating to the use of non-pharmacological interventions for promoting sleep in adults in the ICU was low or very low. We found some evidence that the use of earplugs or eye masks or both may have beneficial effects on sleep and the incidence of delirium in this population, although the quality of the evidence was low. Further high-quality research is needed to strengthen the evidence base. PMID- 26439376 TI - Disability and Violent Victimization in a National Sample of Adolescents: A Longitudinal Study. AB - In the victimization literature, a significant association has been consistently observed between disability and the victimization of children and adolescents. It is largely unknown, however, whether individuals with disabilities continue to suffer from a heightened risk of violent victimization when they reach young adulthood and adulthood. In addition, despite the close nexus between victimization and perpetration, prior studies have generally failed to control for violent acts perpetrated by individuals with disabilities. This study addresses these issues by drawing on the panel design nature of the National Longitudinal Study of Adolescent Health. The results show that although physical disability is not linked to victimization risk, learning disability is significantly associated with an elevated risk of violent victimization. PMID- 26439377 TI - In vitro and in vivo insulinotropic properties of the multifunctional frog skin peptide hymenochirin-1B: a structure-activity study. AB - Hymenochirin-1b (Hym-1B; IKLSPETKDNLKKVLKGAIKGAIAVAKMV.NH2) is a cationic, alpha helical amphibian host-defense peptide with antimicrobial, anticancer, and immunomodulatory properties. This study investigates the abilities of the peptide and nine analogues containing substitutions of Pro(5), Glu(6), and Asp(9) by either L-lysine or D-lysine to stimulate insulin release in vitro using BRIN-BD11 clonal beta cells or isolated mouse islets and in vivo using mice fed a high-fat diet to produce obesity and insulin resistance. Hym-1B produced a significant and concentration-dependent increase in the rate of insulin release from BRIN-BD11 cells without cytotoxicity at concentrations up to 1 uM with a threshold concentration of 1 nM. The threshold concentrations for the analogues were: [P5K], [E6K], [D9K], [P5K, E6K] and [E6K, D9k] 0.003 nM, [E6K, D9K] and [D9k] 0.01 nM, [P5K, D9K] 0.1 nM and [E6k] 0.3 nM. All peptides displayed cytotoxicity at concentrations >=1 uM except the [P5K] and [D9k] analogues which were non toxic at 3 uM. The potency and maximum rate of insulin release from mouse islets produced by the [P5K] peptide were significantly greater than produced by Hym-1B. Neither Hym-1B nor the [P5K] analogue at 1 uM concentration had an effect on membrane depolarization or intracellular Ca(2+). The [P5K] analogue (1 uM) produced a significant increase in cAMP concentration in BRIN-BD11 cells and stimulated GLP-1 secretion from GLUTag cells. Down-regulation of the protein kinase A pathway by overnight incubation with forskolin completely abolished the insulin-releasing effects of [P5K]hym-1B. Intraperitoneal administration of the [P5K] and [D9k] analogues (75 nmol/kg body weight) to high-fat-fed mice with insulin resistance significantly enhanced glucose tolerance with a concomitant increase in insulin secretion. We conclude that [P5K]hym-1B and [D9k]hym-1B show potential for development into anti-diabetic agents. PMID- 26439378 TI - Drug response to HER2 gatekeeper T798M mutation in HER2-positive breast cancer. AB - The gatekeeper T798M mutation in HER2 kinase domain has been observed to considerably shift drug sensitivity to HER2 in breast cancer therapy. Here, drug response of clinical tyrosine kinase inhibitors (TKIs) to the mutation was profiled using a synthetic biology protocol. It was found that TKIs can be grouped into three classes in terms of their response behavior to T798M mutation: class I inhibitors exhibit drug resistance upon the mutation, such as lapatinib, TAK-285 and AEE788; class II inhibitors are insensitive to the mutation, such as erlotinib and gefitinib; and class III inhibitors can be sensitized by the mutation, such as staurosporine. However, kinetic study indicated that the mutation has only a modest effect on the binding of substrate ATP to HER2. Binding free energy analysis revealed that the drug response is primarily determined by direct interaction between the kinase and inhibitors, but not by indirect kinase interaction with competitive ATP. This is different to the molecular mechanism of "generic" drug resistance conferring from EGFR gatekeeper T790M mutation, which is caused by increased ATP affinity upon the mutation. Structural analysis of kinase-inhibitor complexes unraveled that HER2 T798M mutation induces significant steric hindrance to class I inhibitors, but can establish additional nonbonded interactions for class III inhibitors. PMID- 26439380 TI - Breast cancer prevention with anti-estrogens: review of the current evidence and future directions. AB - There is a potential for reducing the incidence of breast cancer by modifying or changing the reversible risk factors like dietary modifications, modifications in the sedentary life habits, etc. One of such methods which has gained popularity now is chemoprevention. Many agents have been evaluated in the chemoprevention setting in females with increased risk of breast cancers. Metformin, NSAIDS, Bisphosphonates, and statins were evaluated by various investigators with variable results. One of the agents that have been proven to be beneficial in this setting is the anti-estrogens. A major disadvantage of chemoprevention is that unlike prophylactic mastectomy it can never reduce the risk to near zero although it reduces the risk significantly. Another issue is the compliance as chemoprevention with anti-estrogens will need to be continued for 5 years while surgery is a one-time procedure. Another disadvantage is the possible side effects peculiar to each drug used which may not be a significant concern in prophylactic mastectomy group. All these factors must also be kept in mind and properly explained to the patient before starting chemoprevention using anti estrogens. Here in this review we intend to look into the large randomized controlled trials to quantify the present status of chemoprevention with anti estrogens. PMID- 26439379 TI - The influence of familial factors on the choice of the place of death for terminally ill breast cancer patients: a retrospective single-center study. AB - BACKGROUND: The social or familial factors influencing the location chosen for end-of-life (EOL) care for terminally ill breast cancer patients are unknown. METHODS: We retrospectively analyzed 195 patients with recurrent or progressive breast cancer who received anticancer treatment at the National Cancer Center Hospital between January 2008 and May 2012. Detailed data concerning the patients' demographic, familial, and clinical characteristics were collected, and multivariate and Cox logistic regression analyses were performed to evaluate the impact of these characteristics on the place of EOL care and on survival, respectively. RESULTS: Sixty-eight patients (34.9 %) died in a hospital, 26 patients (13.3 %) at home, and 101 patients (51.8 %) in hospice. Most of the patients having caregivers received EOL care at palliative care facilities (hospice or home) [odds ratio (OR) 2.57; 95 % confidence interval (CI) 1-6.6; p = 0.05]. In contrast, patients with factors suggesting a clinically severe status (performance status >=2, use of opioids, delirium, and ascites) more often received EOL care in a hospital. Among patients who received EOL care at hospice or home, patients with minor children received EOL care at home (OR 0.08; 95 % CI 0.02-0.38; p = 0.001). Patients with brain metastases chose hospice (OR 12.37; 95 % CI 2.25-68.13; p = 0.004). Furthermore, having a caregiver was associated with prolonged survival (hazard ratio 0.62; 95 % CI 0.39-0.97; p = 0.035). CONCLUSION: Familial factors such as having children and caregivers significantly influenced the place of EOL care for terminally ill breast cancer patients. PMID- 26439381 TI - National Trend and Characteristics of Acute Hepatitis C among HIV-Infected Individuals: A Matched Case-Control Study-Taiwan, 2001-2014. AB - BACKGROUND: Hepatitis C virus (HCV) infection has been increasingly recognized among HIV-infected men who have sex with men (MSM) worldwide. We investigated the trend of and factors associated with acute hepatitis C (AHC) among HIV-infected individuals in Taiwan. METHODS: The National Disease Surveillance System collects characteristics of AHC, HIV, syphilis, and gonorrhea cases through mandatory reports and patient interviews. Reported AHC patients in 2014 were interviewed additionally on sexual and parenteral exposures. Information on HCV genotypes were collected from the largest medical center serving HIV-infected Taiwanese. We defined an HIV/AHC case as a documented negative HCV antibody test result followed within 12 months by a positive test in a previously reported HIV infected individual. Each case was matched to two HIV-infected, non-AHC controls for age, age of HIV diagnosis, sex, transmission route, HIV diagnosis date, and county/city. Conditional logistic regression was used to identify associated characteristics. RESULTS: During 2001-2014, 93 of 6,624 AHC reports were HIV/AHC cases; the annual case count increased from one in 2009 to 34 in 2014. All were males (81 [87%] MSM) aged 21-49 years with AHC diagnosed 2-5,923 days after HIV diagnoses. Sixty-eight (73%) lived in the Taipei metropolitan area. Detected HCV genotypes were 2a (n = 6), 1b (n = 5), 1b + 2a (n = 1) and 2b (n = 1). Among 28 HIV/AHC patients interviewed in 2014, 13 (46%) reported engaging in unprotected sex <=3 months before AHC diagnosis. Seventy-nine HIV/AHC cases were matched to 158 controls. HIV/AHC was associated with recent syphilis (adjusted odds ratio [aOR], 10.9; 95% confidence interval [CI], 4.2-28.6) and last syphilis >6 months (aOR, 2.9; 95% CI, 1.2-6.9). CONCLUSIONS: HIV/AHC cases continued to increase particularly among sexually active HIV-infected MSM with a syphilis diagnosis in northern Taiwan. We recommend surveillance of associated behavioral and virologic characteristics and HCV counseling and testing for HIV-infected men in Taiwan. PMID- 26439382 TI - Analyzing and Quantifying the Gain-of-Function Enhancement of IP3 Receptor Gating by Familial Alzheimer's Disease-Causing Mutants in Presenilins. AB - Familial Alzheimer's disease (FAD)-causing mutant presenilins (PS) interact with inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) Ca(2+) release channels resulting in enhanced IP3R channel gating in an amyloid beta (Abeta) production independent manner. This gain-of-function enhancement of IP3R activity is considered to be the main reason behind the upregulation of intracellular Ca(2+) signaling in the presence of optimal and suboptimal stimuli and spontaneous Ca(2+) signals observed in cells expressing mutant PS. In this paper, we employed computational modeling of single IP3R channel activity records obtained under optimal Ca(2+) and multiple IP3 concentrations to gain deeper insights into the enhancement of IP3R function. We found that in addition to the high occupancy of the high-activity (H) mode and the low occupancy of the low-activity (L) mode, IP3R in FAD-causing mutant PS-expressing cells exhibits significantly longer mean life-time for the H mode and shorter life-time for the L mode, leading to shorter mean close-time and hence high open probability of the channel in comparison to IP3R in cells expressing wild-type PS. The model is then used to extrapolate the behavior of the channel to a wide range of IP3 and Ca(2+) concentrations and quantify the sensitivity of IP3R to its two ligands. We show that the gain-of function enhancement is sensitive to both IP3 and Ca(2+) and that very small amount of IP3 is required to stimulate IP3R channels in the presence of FAD causing mutant PS to the same level of activity as channels in control cells stimulated by significantly higher IP3 concentrations. We further demonstrate with simulations that the relatively longer time spent by IP3R in the H mode leads to the observed higher frequency of local Ca(2+) signals, which can account for the more frequent global Ca(2+) signals observed, while the enhanced activity of the channel at extremely low ligand concentrations will lead to spontaneous Ca(2+) signals in cells expressing FAD-causing mutant PS. PMID- 26439383 TI - Intracerebroventricular Injection of Alarin Increased Glucose Uptake in Skeletal Muscle of Diabetic Rats. AB - In order to investigate the central effect of alarin on glucose uptake, we administered alarin and/ or its inhibitor, ala6-25Cys into the cerebral ventricles of the type 2 diabetic rats. Then the relative parameters about glucose uptake in skeletal muscles were measured. We found that central treatment with alarin significantly increased the food intake, body weight and glucose infusion rates in hyperinsulinemic euglycemic clamp tests of the animals. Besides, the treatment also enhanced 2-deoxy-[3H]-D-glucose uptake, vesicle associated membrane protein 2 contents, glucose transporter 4 protein and mRNA expression, as well as pAktThr308, pAktSer473 and total Akt levels in muscle cells, but reduced plasma glucose and insulin levels of the rats. All of the alarin-inducing events may be antagonised by central injection of ala6-25Cys. These results suggest that central administration of alarin stimulates glucose uptake mediated by activation of Akt signal pathway in type 2 diabetic animals. PMID- 26439384 TI - Use of oral combination therapy for type 2 diabetes in primary care: Meeting individualized patient goals. AB - The management of type 2 diabetes mellitus (T2DM) by primary care physicians (PCPs) has become increasingly complex due to limitations on consultation time, an increasing array of drug treatment options, and issues of comorbidities and polypharmacy. Diabetes is a progressive condition and treatment with a single glucose-lowering agent can only address limited pathophysiologic targets and does not provide adequate glycemic control in many cases. Consequently, most patients with T2DM will eventually require treatment with multiple glucose-lowering medications. Oral combination therapy in T2DM may be given as multiple-pills, or as single-pill, fixed-dose combinations (FDCs), the latter of which offer convenience, ease of administration, and a reduction in the medication burden. Therefore, FDCs can potentially improve patients' treatment adherence and optimize achievement and maintenance of glycemic targets. However, cost factors also need to be considered. An understanding of the issues associated with the use of combination therapy in T2DM will help PCPs to guide patient-centered decision making and promote the effective management of T2DM. PMID- 26439385 TI - Precritical State Transition Dynamics in the Attractor Landscape of a Molecular Interaction Network Underlying Colorectal Tumorigenesis. AB - From the perspective of systems science, tumorigenesis can be hypothesized as a critical transition (an abrupt shift from one state to another) between proliferative and apoptotic attractors on the state space of a molecular interaction network, for which an attractor is defined as a stable state to which all initial states ultimately converge, and the region of convergence is called the basin of attraction. Before the critical transition, a cellular state might transit between the basin of attraction for an apoptotic attractor and that for a proliferative attractor due to the noise induced by the inherent stochasticity in molecular interactions. Such a flickering state transition (state transition between the basins of attraction for alternative attractors from the impact of noise) would become more frequent as the cellular state approaches near the boundary of the basin of attraction, which can increase the variation in the estimate of the respective basin size. To investigate this for colorectal tumorigenesis, we have constructed a stochastic Boolean network model of the molecular interaction network that contains an important set of proteins known to be involved in cancer. In particular, we considered 100 representative sequences of 20 gene mutations that drive colorectal tumorigenesis. We investigated the appearance of cancerous cells by examining the basin size of apoptotic, quiescent, and proliferative attractors along with the sequential accumulation of gene mutations during colorectal tumorigenesis. We introduced a measure to detect the flickering state transition as the variation in the estimate of the basin sizes for three-phenotype attractors from the impact of noise. Interestingly, we found that this measure abruptly increases before a cell becomes cancerous during colorectal tumorigenesis in most of the gene mutation sequences under a certain level of stochastic noise. This suggests that a frequent flickering state transition can be a precritical phenomenon of colorectal tumorigenesis. PMID- 26439386 TI - Rosuvastatin 1.2 mg In Situ Gel Combined With 1:1 Mixture of Autologous Platelet Rich Fibrin and Porous Hydroxyapatite Bone Graft in Surgical Treatment of Mandibular Class II Furcation Defects: A Randomized Clinical Control Trial. AB - BACKGROUND: A wide range of regenerative materials have been tried and tested in the treatment of furcation defects. Rosuvastatin (RSV) is a new synthetic, second generation, sulfur-containing, hydrophilic statin with potent anti-inflammatory and osseodifferentiation mechanisms of action. Platelet-rich fibrin (PRF) is a platelet concentrate having sustained release of various growth factors with regenerative potential to treat periodontal defects. Porous hydroxyapatite (HA) bone grafting material has a clinically satisfactory response when used to fill periodontal intrabony defects. This double-masked randomized study is designed to evaluate the potency of a combination of 1.2 mg RSV in situ gel with a 1:1 mixture of autologous PRF and HA bone graft in the surgical treatment of mandibular Class II furcation defects compared with autologous PRF and HA bone graft placed after open-flap debridement (OFD). METHODS: One hundred five mandibular furcation defects were treated with OFD + placebo gel (group 1), PRF + HA with OFD (group 2), or 1.2 mg RSV gel + PRF + HA with OFD (group 3). Clinical and radiologic parameters (i.e., probing depth [PD], relative vertical and relative horizontal clinical attachment level [rvCAL and rhCAL], intrabony defect depth, and percentage of defect fill) were recorded at baseline and 9 months postoperatively. RESULTS: Mean PD reduction was greater in group 2 (3.68 +/- 1.07 mm) and group 3 (4.62 +/- 1.03 mm) than group 1 (2.11 +/- 1.25 mm), and mean rvCAL and rhCAL gain were greater in group 2 (3.31 +/- 0.52 and 2.97 +/- 0.56 mm, respectively) and group 3 (4.17 +/- 0.70 and 4.05 +/- 0.76 mm) compared with group 1 (1.82 +/- 0.78 and 1.62 +/- 0.64 mm). A significantly greater percentage of mean bone fill was found in group 2 (54.69% +/- 1.93%) and group 3 (61.94% +/- 3.54%) compared with group 1 (10.09% +/- 4.28%). CONCLUSIONS: Treatment of furcation defects with 1.2 mg RSV in situ gel combined with autologous PRF and porous HA bone graft results in significant improvements of clinical and radiographic parameters compared with OFD alone. These results imply that the combination of RSV, PRF, and HA has synergistic effects, explaining their role as a regenerative material in the treatment of furcation defects. PMID- 26439388 TI - Colonization of C57BL/6 Mice by a Potential Probiotic Bifidobacterium bifidum Strain under Germ-Free and Specific Pathogen-Free Conditions and during Experimental Colitis. AB - The effects of at least some probiotics are restricted to live, metabolically active bacteria at their site of action. Colonization of and persistence in the gastrointestinal tract is thus contributing to the beneficial effects of these strains. In the present study, colonization of an anti-inflammatory Bifidobacterium bifidum strain was studied in C57BL/6J mice under germ-free (GF) and specific pathogen-free (SPF) conditions as well as during dextran sulfate sodium (DSS)-induced colitis. B. bifidum S17/pMGC was unable to stably colonize C57BL/6J mice under SPF conditions. Mono-association of GF mice by three doses on consecutive days led to long-term, stable detection of up to 109 colony forming units (CFU) of B. bifidum S17/pMGC per g feces. This stable population was rapidly outcompeted upon transfer of mono-associated animals to SPF conditions. A B. animalis strain was isolated from the microbiota of these re-conventionalized mice. This B. animalis strain displayed significantly higher adhesion to murine CMT-93 intestinal epithelial cells (IECs) than to human Caco-2 IECs (p = 0.018). Conversely, B. bifidum S17/pMGC, i.e., a strain of human origin, adhered at significantly higher levels to human compared to murine IECs (p < 0.001). Disturbance of the gut ecology and induction of colitis by DSS-treatment did not promote colonization of the murine gastrointestinal tract (GIT) by B. bifidum S17/pMGC. Despite its poor colonization of the mouse GIT, B. bifidum S17/pMGC displayed a protective effect on DSS-induced colitis when administered as viable bacteria but not as UV-inactivated preparation. Collectively, these results suggest a selective disadvantage of B. bifidum S17/pMGC in the competition with the normal murine microbiota and an anti-inflammatory effect that requires live, metabolically active bacteria. PMID- 26439389 TI - Muscle Carnosine Is Associated with Cardiometabolic Risk Factors in Humans. AB - BACKGROUND: Carnosine is a naturally present dipeptide abundant in skeletal muscle and an over-the counter food additive. Animal data suggest a role of carnosine supplementation in the prevention and treatment of obesity, insulin resistance, type 2 diabetes and cardiovascular disease but only limited human data exists. METHODS AND RESULTS: Samples of vastus lateralis muscle were obtained by needle biopsy. We measured muscle carnosine levels (high-performance liquid chromatography), % body fat (bioimpedance), abdominal subcutaneous and visceral adiposity (magnetic resonance imaging), insulin sensitivity (euglycaemic hyperinsulinemic clamp), resting energy expenditure (REE, indirect calorimetry), free-living ambulatory physical activity (accelerometers) and lipid profile in 36 sedentary non-vegetarian middle aged men (45+/-7 years) with varying degrees of adiposity and glucose tolerance. Muscle carnosine content was positively related to % body fat (r = 0.35, p = 0.04) and subcutaneous (r = 0.38, p = 0.02) but not visceral fat (r = 0.17, p = 0.33). Muscle carnosine content was inversely associated with insulin sensitivity (r = -0.44, p = 0.008), REE (r = -0.58, p<0.001) and HDL-cholesterol levels (r = -0.34, p = 0.048). Insulin sensitivity and physical activity were the best predictors of muscle carnosine content after adjustment for adiposity. CONCLUSION: Our data shows that higher carnosine content in human skeletal muscle is positively associated with insulin resistance and fasting metabolic preference for glucose. Moreover, it is negatively associated with HDL-cholesterol and basal energy expenditure. Intervention studies targeting insulin resistance, metabolic and cardiovascular disease risk factors are necessary to evaluate its putative role in the prevention and management of type 2 diabetes and cardiovascular disease. PMID- 26439390 TI - Evaluation of nonuniform field exposures with coupling factors. AB - In this study, the safety compliance for nonuniform field exposures is discussed using coupling factor concepts. The coupling factor, which is defined in the International Electrotechnical Commission 62311 standard, is extended to consider the effects of harmonics and also to apply to the specific absorption rate (for frequencies up to 30 MHz). The proposed compliance procedure is applied to and demonstrated for a prototype wireless power transfer (WPT) system with induction coupling operating at the fundamental frequency in 140 kHz band. First, measurements confirm that the perturbation of the external magnetic field strength and S11 parameter of a one-loop antenna by a human-equivalent phantom are sufficiently small, suggesting the applicability of the magneto-quasi-static approximation to frequencies up to 30 MHz. Then, the frequency characteristics of the coupling factor are derived for the WPT system. For the prototype system that is not optimized for commercial usage, the maximum allowable transmitting power is relaxed by a factor of 23 with the proposed procedure. The contribution of the harmonics decreased the allowable transmitting power by 39%, indicating their importance for safety compliance. PMID- 26439392 TI - Acute Coronary Syndrome: Foreword. PMID- 26439393 TI - Acute Coronary Syndrome: Out-of-Hospital Evaluation and Management. AB - Identifying acute coronary syndrome (ACS) in family medicine settings can be challenging, partly because it is uncommon in office practice and partly because symptoms can be atypical. Initial evaluation includes review of the patient's symptoms, an assessment of risk factors, and an electrocardiogram (ECG). When symptoms are typical, such as chest pain and diaphoresis, patients should be transported rapidly by emergency medical services (EMS) to the nearest emergency department. If not contraindicated, aspirin and nitroglycerin should be administered before transport. Oxygen should be administered if hypoxemia is present. Patients with atypical symptoms and ECG results consistent with ACS also should be transported by EMS. When patients have atypical symptoms and nondiagnostic ECG results, consider risk factors for ACS. These include older age; female sex; nonwhite race; and history of heart failure, stroke, diabetes, or hypertension. If any of these risk factors is present and there is concern about ACS, the patient should be transported to an emergency department. Family practices in remote or rural areas are not always able to easily transport patients to emergency departments. These remote or rural practices should have ECG capabilities and consider acquiring the ability to obtain point-of-care troponin assays. PMID- 26439391 TI - Antioxidant Capacity of Melatonin on Preimplantation Development of Fresh and Vitrified Rabbit Embryos: Morphological and Molecular Aspects. AB - Embryo cryopreservation remains an important technique to enhance the reconstitution and distribution of animal populations with high genetic merit. One of the major detrimental factors to this technique is the damage caused by oxidative stress. Melatonin is widely known as an antioxidant with multi-faceted ways to counteract the oxidative stress. In this paper, we investigated the role of melatonin in protecting rabbit embryos during preimplantation development from the potential harmful effects of oxidative stress induced by in vitro culture or vitrification. Rabbit embryos at morula stages were cultured for 2 hr with 0 or 10-3 M melatonin (C or M groups). Embryos of each group were either transferred to fresh culture media (CF and MF groups) or vitrified/devitrified (CV and MV groups), then cultured in vitro for 48 hr until the blastocyst stage. The culture media were used to measure the activity of antioxidant enzymes: glutathione-s transferase (GST) and superoxide dismutase (SOD), as well as the levels of two oxidative substrates: lipid peroxidation (LPO) and nitric oxide (NO). The blastocysts from each group were used to measure the expression of developmental related genes (GJA1, POU5F1 and Nanog) and oxidative-stress-response-related genes (NFE2L2, SOD1 and GPX1). The data showed that melatonin promoted significantly (P<0.05) the blastocyst rate by 17% and 12% in MF and MV groups compared to their controls (CF and CV groups). The GST and SOD activity significantly increased by the treatment of melatonin in fresh or vitrified embryos, while the levels of LPO and NO decreased (P<0.05). Additionally, melatonin considerably stimulated the relative expression of GJA1, NFE2L2 and SOD1 genes in MF and MV embryos compared to CF group. Furthermore, melatonin significantly ameliorated the reduction of POU5F1 and GPX1 expression induced by vitrification. The results obtained from the current investigation provide new and clear molecular aspects regarding the mechanisms by which melatonin promotes development of both fresh and vitrified rabbit embryos. PMID- 26439394 TI - Acute Coronary Syndrome: Emergency Department Evaluation and Management. AB - Patients with chest pain who present to emergency departments have a significantly higher incidence of acute coronary syndrome (ACS) than patients with chest pain presenting to outpatient settings, so emergency department clinicians should have a lower threshold for considering ACS as an etiology. Evaluating patients with suspected ACS in the emergency department involves obtaining a history, physical examination, electrocardiograms (ECGs), and cardiac troponin measurements in conjunction with risk calculators. These parameters cannot be used individually because, for example, a normal ECG result does not exclude ACS and troponin levels can be elevated in many conditions. All patients with suspected ACS should receive aspirin, if not contraindicated, as soon as possible. Those with an ST-segment elevation myocardial infarction (STEMI) or those without STEMI who are in unstable condition should be triaged to undergo reperfusion therapy, typically via percutaneous coronary intervention (PCI), within 120 minutes of first medical contact. If that time limit cannot be met because the patient must be transferred to a PCI-capable facility, fibrinolytic therapy should be initiated within 30 minutes of presentation if STEMI is present. (Fibrinolytic therapy is contraindicated for myocardial infarction without STEMI.) Patients also should receive nitroglycerin to relieve angina and beta blockers if not contraindicated. PMID- 26439395 TI - Acute Coronary Syndrome: Inpatient Management. AB - The first step in inpatient management of acute coronary syndrome (ACS) is determining whether the patient has ST-segment elevation myocardial infarction (STEMI). For STEMI, the initial approach to management is cardiac catheterization with percutaneous coronary intervention (PCI) to reperfuse the blocked artery; PCI should take place within 120 minutes of first medical contact. However, if no contraindications are present, fibrinolytic therapy is preferred if PCI will take more than 120 minutes. In ACS without STEMI, cardiac catheterization with PCI is the recommended approach for patients who are unstable, and for stable patients with high risk assessment scores, diabetes or renal insufficiency, stent placement within the past 6 months, or prior bypass surgery. Treatment of patients with ACS who do not meet the previously discussed criteria can be noninvasive when troponin levels are not elevated, no ST-segment elevations or depressions are present on electrocardiogram, and risk assessment scores are low. Assuming no contraindications exist, all patients with or without STEMI should receive medical therapy that includes nitroglycerin, antiplatelet agents, anticoagulants, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, aldosterone blockade if left ventricular function is impaired, beta blockers, and statins. PMID- 26439396 TI - Acute Coronary Syndrome: Posthospital Outpatient Management. AB - When providing care for patients who are discharged from the hospital after experiencing acute coronary syndrome (ACS), several issues should be addressed. Drug regimens should be reviewed to ensure that patients are taking appropriate drugs, including antiplatelet agents, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, aldosterone antagonists, beta blockers/calcium channel blockers, cholesterol-lowering drugs, and nitroglycerin. The review also should confirm that patients understand when and how to take their drugs, and that there are no obstacles (eg, cost) that might result in nonadherence to drug regimens. Lifestyle modifications, including improvements in diet and exercise regimens, along with participation in a cardiac rehabilitation program, should be encouraged. Risk factor reduction measures include smoking cessation for smokers, weight management for patients who are overweight, and optimal control of blood pressure and blood glucose levels. Appropriate vaccinations should be administered; influenza and pneumococcal vaccines are indicated for all patients with ACS in the absence of contraindications. Patients requiring pain control should avoid use of nonsteroidal anti-inflammatory drugs because they increase the risk of cardiovascular events; acetaminophen or other drugs should be used. Finally, depression is common among patients with ACS. Screening for and management of depression are significant components of care. PMID- 26439397 TI - Diacylglycerol Guides the Hopping of Clathrin-Coated Pits along Microtubules for Exo-Endocytosis Coupling. AB - Many receptor-mediated endocytic processes are mediated by constitutive budding of clathrin-coated pits (CCPs) at spatially randomized sites before slowly pinching off from the plasma membrane (60-100 s). In contrast, clathrin-mediated endocytosis (CME) coupled with regulated exocytosis in excitable cells occurs at peri-exocytic sites shortly after vesicle fusion (~10 s). The molecular mechanism underlying this spatiotemporal coupling remains elusive. We show that coupled endocytosis makes use of pre-formed CCPs, which hop to nascent fusion sites nearby following vesicle exocytosis. A dynamic cortical microtubular network, anchored at the cell surface by the cytoplasmic linker-associated protein on microtubules and the LL5beta/ELKS complex on the plasma membrane, provides the track for CCP hopping. Local diacylglycerol gradients generated upon exocytosis guide the direction of hopping. Overall, the CCP-cytoskeleton-lipid interaction demonstrated here mediates exocytosis-coupled fast recycling of both plasma membrane and vesicular proteins, and it is required for the sustained exocytosis during repetitive stimulations. PMID- 26439398 TI - LRP2 Acts as SHH Clearance Receptor to Protect the Retinal Margin from Mitogenic Stimuli. AB - During forebrain development, LRP2 promotes morphogen signaling as an auxiliary SHH receptor. However, in the developing retina, LRP2 assumes the opposing function, mediating endocytic clearance of SHH and antagonizing morphogen action. LRP2-mediated clearance prevents spread of SHH activity from the central retina into the retinal margin to protect quiescent progenitor cells in this niche from mitogenic stimuli. Loss of LRP2 in mice increases the sensitivity of the retinal margin for SHH, causing expansion of the retinal progenitor cell pool and hyperproliferation of this tissue. Our findings document the ability of LRP2 to act, in a context-dependent manner, as activator or inhibitor of the SHH pathway. Our current findings uncovered LRP2 activity as the molecular mechanism imposing quiescence of the retinal margin in the mammalian eye and suggest SHH-induced proliferation of the retinal margin as cause of the large eye phenotype observed in mouse models and patients with LRP2 defects. PMID- 26439400 TI - SrGAP2-Dependent Integration of Membrane Geometry and Slit-Robo-Repulsive Cues Regulates Fibroblast Contact Inhibition of Locomotion. AB - Migrating fibroblasts undergo contact inhibition of locomotion (CIL), a process that was discovered five decades ago and still is not fully understood at the molecular level. We identify the Slit2-Robo4-srGAP2 signaling network as a key regulator of CIL in fibroblasts. CIL involves highly dynamic contact protrusions with a specialized actin cytoskeleton that stochastically explore cell-cell overlaps between colliding fibroblasts. A membrane curvature-sensing F-BAR domain pre-localizes srGAP2 to protruding edges and terminates their extension phase in response to cell collision. A FRET-based biosensor reveals that Rac1 activity is focused in a band at the tip of contact protrusions, in contrast to the broad activation gradient in contact-free protrusions. SrGAP2 specifically controls the duration of Rac1 activity in contact protrusions, but not in contact-free protrusions. We propose that srGAP2 integrates cell edge curvature and Slit-Robo mediated repulsive cues to fine-tune Rac1 activation dynamics in contact protrusions to spatiotemporally coordinate CIL. PMID- 26439401 TI - Investigation of field effects in a solid-state nanopore transistor. AB - In order to calculate ion currents through solid-state nanopore transistors realistically, we propose a computational model based on the Poisson-Nernst-Plank equation. In the present model, we determine the surface charge density locally on the nanopore by imposing consistency between the ion distribution and the chemical reaction at the surface. The model can consider a non-uniform influence by the gate voltage on the inner surface of the nanopore membrane, which enables us to investigate ion currents depending on the gate geometry such as the thickness and vertical position within the nanopore. We verify the validity of the model by comparing the pH dependence of simulation results with the extant experimental results. We also investigate the transistor behaviour depending on the surface material, pore geometry and gate position. In particular, we propose an optimized system to enhance the on/off ratio of the nanopore transistor. PMID- 26439399 TI - Shared Enhancer Activity in the Limbs and Phallus and Functional Divergence of a Limb-Genital cis-Regulatory Element in Snakes. AB - The amniote phallus and limbs differ dramatically in their morphologies but share patterns of signaling and gene expression in early development. Thus far, the extent to which genital and limb transcriptional networks also share cis regulatory elements has remained unexplored. We show that many limb enhancers are retained in snake genomes, suggesting that these elements may function in non limb tissues. Consistent with this, our analysis of cis-regulatory activity in mice and Anolis lizards reveals that patterns of enhancer activity in embryonic limbs and genitalia overlap heavily. In mice, deletion of HLEB, an enhancer of Tbx4, produces defects in hindlimbs and genitalia, establishing the importance of this limb-genital enhancer for development of these different appendages. Further analyses demonstrate that the HLEB of snakes has lost hindlimb enhancer function while retaining genital activity. Our findings identify roles for Tbx4 in genital development and highlight deep similarities in cis-regulatory activity between limbs and genitalia. PMID- 26439402 TI - Facile Carbon Fixation to Performic Acids by Water-Sealed Dielectric Barrier Discharge. AB - Carbon fixation refers to the conversion of carbon dioxide (CO2) to organic materials, as commonly performed in nature through photosynthesis by plants and other autotrophic organisms. The creation of artificial carbon fixation processes is one of the greatest challenges for chemistry to solve the critical environmental issue concerning the reduction of CO2 emissions. We have developed an electricity-driven facile CO2 fixation process that yields performic acid, HCO2OH, from CO2 and water at neutral pH by dielectric barrier discharge with an input electric power conversion efficiency of currently 0.2-0.4%. This method offers a promising future technology for artificial carbon fixation on its own, and may also be scaled up in combination with e.g., the post-combustion CO2 capture and storage technology. PMID- 26439404 TI - Decade in review-technology: Technological advances transforming rheumatology. PMID- 26439403 TI - Molecular investigation of coexistent chronic myeloid leukaemia and peripheral T cell lymphoma - a case report. AB - Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm underlain by the formation of BCR-ABL1 - an aberrant tyrosine kinase - in the leukaemic blasts. Long-term survival rates in CML prior to the advent of tyrosine kinase inhibitors (TKIs) were dismal, albeit the incidence of secondary malignancies was higher than that of age-matched population. Current figures confirm the safety of TKIs with conflicting data concerning the increased risk of secondary tumours. We postulate that care has to be taken when distinguishing between coexisting, secondary-to-treatment and second in sequence, but independent tumourigenic events, in order to achieve an unbiased picture of the adverse effects of novel treatments. To illustrate this point, we present a case of a patient in which CML and peripheral T-cell lymphoma (PTCL) coexisted, although the clinical presentation of the latter followed the achievement of major molecular response of CML to TKIs. PMID- 26439407 TI - Rheumatoid arthritis: C5orf30 regulates severity of tissue destruction in RA. PMID- 26439405 TI - Genetics of ankylosing spondylitis--insights into pathogenesis. AB - Ankylosing spondylitis (AS), an immune-mediated arthritis, is the prototypic member of a group of conditions known as spondyloarthropathies that also includes reactive arthritis, psoriatic arthritis and enteropathic arthritis. Patients with these conditions share a clinical predisposition for spinal and pelvic joint dysfunction, as well as genetic associations, notably with HLA-B(*)27. Spondyloarthropathies are characterized by histopathological inflammation in entheses (regions of high mechanical stress where tendons and ligaments insert into bone) and in the subchondral bone marrow, and by abnormal osteoproliferation at involved sites. The association of AS with HLA-B(*)27, first described >40 years ago, led to hope that the cause of the disease would be rapidly established. However, even though many theories have been advanced to explain how HLA-B(*)27 is involved in AS, no consensus about the answers to this question has been reached, and no successful treatments have yet been developed that target HLA-B27 or its functional pathways. Over the past decade, rapid progress has been made in discovering further genetic associations with AS that have shed new light on the aetiopathogenesis of the disease. Some of these discoveries have driven translational ideas, such as the repurposing of therapeutics targeting the cytokines IL-12 and IL-23 and other factors downstream of this pathway. AS provides an excellent example of how hypothesis-free research can lead to major advances in understanding pathogenesis and to the development of innovative therapeutic strategies. PMID- 26439406 TI - Strategies for the prevention of knee osteoarthritis. AB - Osteoarthritis (OA) has been thought of as a disease of cartilage that can be effectively treated surgically at severe stages with joint arthroplasty. Today, OA is considered a whole-organ disease that is amenable to prevention and treatment at early stages. OA develops slowly over 10-15 years, interfering with activities of daily living and the ability to work. Many patients tolerate pain, and many health-care providers accept pain and disability as inevitable corollaries of OA and ageing. Too often, health-care providers passively await final 'joint death', necessitating knee and hip replacements. Instead, OA should be viewed as a chronic condition, where prevention and early comprehensive-care models are the accepted norm, as is the case with other chronic diseases. Joint injury, obesity and impaired muscle function are modifiable risk factors amenable to primary and secondary prevention strategies. The strategies that are most appropriate for each patient should be identified, by selecting interventions to correct--or at least attenuate--OA risk factors. We must also choose the interventions that are most likely to be acceptable to patients, to maximize adherence to--and persistence with--the regimes. Now is the time to begin the era of personalized prevention for knee OA. PMID- 26439408 TI - Acute Edema Blisters on a Skin Swelling: An Unusual Manifestation of Hereditary Angioedema. PMID- 26439409 TI - Combination of MD Simulations with Two-State Kinetic Rate Modeling Elucidates the Chain Melting Transition of Phospholipid Bilayers for Different Hydration Levels. AB - The phase behavior of membrane lipids plays an important role in the formation of functional domains in biological membranes and crucially affects molecular transport through lipid layers, for instance, in the skin. We investigate the thermotropic chain melting transition from the ordered Lbeta phase to the disordered Lalpha phase in membranes composed of dipalmitoylphosphatidylcholine (DPPC) by atomistic molecular dynamics simulations in which the membranes are subject to variable heating rates. We find that the transition is initiated by a localized nucleus and followed by the propagation of the phase boundary. A two state kinetic rate model allows characterizing the transition state in terms of thermodynamic quantities such as transition state enthalpy and entropy. The extrapolated equilibrium melting temperature increases with reduced membrane hydration and thus in tendency reproduces the experimentally observed dependence on dehydrating osmotic stress. PMID- 26439411 TI - Porous mixed metal oxides: design, formation mechanism, and application in lithium-ion batteries. AB - The relentless pursuit of new electrode materials for lithium ion batteries (LIBs) has been conducted for decades. Structures with either porous or nanostructure configurations have been confirmed as advantageous candidates for energy storage/conversion applications. The integration of the two features into one structure can provide another chance to improve the electroactivities. Recently, single-phased mixed metal oxides (MMOs) containing different metal cations, in particular, have confirmed high electrochemical activities because of their complex chemical composition, interfacial effects, and the synergic effects of the multiple metal species. In this review, we will focus on recent research advances of MMOs with porous architectures as anode materials in the matter of structural arrangement and compositional manipulation. Moreover, the application of self-supported MMO-based porous structures as LIB anodes is also explained herein. More importantly, investigations on the synthetic system and formation mechanism of porous MMOs will be highlighted. Some future trends for the innovative design of new electrode materials are also discussed in this review. The challenges and prospects will draw many researchers' attention. PMID- 26439410 TI - Terahertz-driven linear electron acceleration. AB - The cost, size and availability of electron accelerators are dominated by the achievable accelerating gradient. Conventional high-brightness radio-frequency accelerating structures operate with 30-50 MeV m(-1) gradients. Electron accelerators driven with optical or infrared sources have demonstrated accelerating gradients orders of magnitude above that achievable with conventional radio-frequency structures. However, laser-driven wakefield accelerators require intense femtosecond sources and direct laser-driven accelerators suffer from low bunch charge, sub-micron tolerances and sub femtosecond timing requirements due to the short wavelength of operation. Here we demonstrate linear acceleration of electrons with keV energy gain using optically generated terahertz pulses. Terahertz-driven accelerating structures enable high gradient electron/proton accelerators with simple accelerating structures, high repetition rates and significant charge per bunch. These ultra-compact terahertz accelerators with extremely short electron bunches hold great potential to have a transformative impact for free electron lasers, linear colliders, ultrafast electron diffraction, X-ray science and medical therapy with X-rays and electron beams. PMID- 26439413 TI - Identification and expression analysis of a novel stylicin antimicrobial peptide from Kuruma shrimp (Marsupenaeus japonicus). AB - Antimicrobial peptides (AMPs) are important components of the innate immune system and function as the first line of defense against invading pathogens. In current study we identified, cloned and characterized a novel stylicin AMP from Kuruma shrimp Marsupenaeus japonicus (Mj-sty). The full-length cDNA of Mj-sty was 428 bp with an open reading frame of 315 bp that encoded 104 amino acids. The theoretical molecular mass of mature Mj-sty was 8.693 kDa with an isoelectric point (pI) of 4.79. A proline-rich N-terminal region and a C-terminal region contained 13 cysteine residues were identified. Genomic sequence analysis with respect to its cDNA showed that Mj-sty was organized into two exons interrupted by one intron. Tissue-specific expression revealed that Mj-sty was mainly transcribed in gills and hemocytes. Expression of Mj-sty in early developmental stages demonstrated that Mj-sty mRNA were present from fertilized eggs to post larvae of 17 days (PL17), and the expression levels showed a significant variation in different developmental stages. After challenge of white spot syndrome virus (WSSV), the time-dependent expression pattern of Mj-sty in both gills and hepatopancrease showed down-regulation at the early hours of infection, subsequently up-regulation and down-regulation, and then up-regulation at the end hours to almost the half of the controls. The results indicate that Mj-sty is potentially involved in the ontogenesis and immune responses against WSSV. PMID- 26439414 TI - Identification and characterization of the TLR18 gene in grass carp (Ctenopharyngodon idella). AB - Toll-like receptors (TLRs) play a critical role in the innate immune system. Although TLR18 is an important member of this family of receptors in fish, the role of the tlr18 gene in responses to pathogen infection is still unclear. In this study, we identified and characterized the grass carp tlr18 gene (gctlr18) to further clarify the function of TLR18 in teleost fish. Gctlr18 spans over 3600 bp and encodes a polypeptide of 852 amino acids. Analysis of the deduced amino acid sequence showed that gctlr18 encodes structures typical of the TLR family, including a signal peptide, seven leucine-rich repeats (LRRs), a transmembrane region, and a (Toll-interleukin-1 receptor) TIR domain. Quantitative RT-PCR analysis showed that gctlr18 was constitutively expressed in all investigated tissues, with abundant expression in spleen, gill, heart, intestine, kidney and fin and low expression in skin, liver and brain. Following grass carp reovirus challenge and Aeromonas hydrophila inoculation, gctlr18 transcripts were upregulated significantly in immune-relevant tissues. Stimulation of Ctenopharyngodon idella kidney (CIK) cells with purified flagellin from Salmo typhimurium, lipopolysaccharide and polyinosinic-polycytidylic acid stimulation in vitro resulted in significantly increased gctlr18 expression, reaching a peak followed by restoration of normal levels. Overexpression of gctlr18 reduced A. hydrophila invasion by 83.4%. In CIK cells, gctlr18 induced the expression of proinflammatory cytokines, including il-8, inf-1 and tnf-alpha. Our results indicate that gctlr18 plays a key role in innate immune responses in teleost fish. PMID- 26439415 TI - The effects of feeding beta-glucan to Pangasianodon hypophthalmus on immune gene expression and resistance to Edwardsiella ictaluri. AB - Pangasianodon hypophthalmus (striped catfish) is an important aquaculture species and intensification of farming has increased disease problems, particularly Edwardsiella ictaluri. The effects of feeding beta-glucans on immune gene expression and resistance to E. ictaluri in P. hypophthalmus were explored. Fish were fed 0.1% fungal-derived beta-glucan or 0.1% commercial yeast-derived beta glucan or a basal control diet without glucan. After 14 days of feeding, the mRNA expression of immune genes (transferrin, C-reactive protein, precerebellin-like protein, Complement C3 and factor B, 2a MHC class II and interleukin-1 beta) in liver, kidney and spleen were determined. Following this fish from each of the three diet treatment groups were infected with E. ictaluri and further gene expression measured 24 h post-infection (h.p.i.), while the remaining fish were monitored over 2 weeks for mortalities. Cumulative percentage mortality at 14 days post-infection (d.p.i.) was less in beta-glucan fed fish compared to controls. There was no difference in gene expression between dietary groups after feeding for 14 days, but there was a clear difference between infected and uninfected fish at 24 h.p.i., and based on principal component analysis beta glucans stimulated the overall expression of immune genes in the liver, kidney and spleen at 24 h.p.i. PMID- 26439416 TI - Carbohydrate-binding motifs in a novel type lectin from the sea mussel Crenomytilus grayanus: Homology modeling study and site-specific mutagenesis. AB - The GalNAc/Gal-specific lectin from the sea mussel Crenomytilus grayanus (CGL) was shown to represent a novel family of lectins and to be characterized by three amino acid tandem repeats with high (up to 73%) sequence similarities to each other. We have used homology modeling approach to predict CGL sugar-binding sites. In silico analysis of CGL-GalNAc complexes showed that CGL contained three binding sites, each of which included conserved HPY(K)G motif. In silico substitutions of histidine, proline and glycine residues by alanine in the HPY(K)G motifs of the Sites 1-3 was shown to lead to loss of hydrogen bonds between His and GalNAc and to the increasing the calculated CGL-GalNAc binding energies. We have obtained recombinant CGL and used site-specific mutagenesis to experimentally examine the role of HPK(Y)G motifs in hemagglutinating and carbohydrate binding activities of CGL. Substitutions of histidine, proline and glycine residues by alanine in the HPYG motif of Site 1 and Site 2 was found to led to complete loss of CGL hemagglutinating and mucin-binding activities. The same mutations in HPKG motif of the Site 3 resulted in decreasing the mucin binding activity in 6-folds in comparison with the wild type lectin. The mutagenesis and in silico analysis indicates the importance of the all three HPY(K)G motifs in the carbohydrate-binding and hemagglutinating activities of CGL. PMID- 26439418 TI - The open retrograde approach as an alternative for failed percutaneous access for difficult below the knee chronic total occlusions-A case series. AB - Retrograde puncture via patent pedal vessels can be attempted in failed antegrade approach for infrapopliteal long chronic total occlusion. However in cases where the pedal vessels are unable to be visualized via duplex ultrasonography or fluoroscopy an open approach offers an additional option to a vascular surgeon for successful recanalization. Our case report highlights 3 cases where successful hybrid open retrograde approach was able to achieve recanalization of long chronic total occlusion. PRESENTATION OF CASES: The three cases in our series presented with critical limb ischaemia. All three cases had undergone duplex imaging of the affected arterial system. As the antegrade approach to cross the lesion failed a retrograde approach was attempted in all 3 cases. However when the usual modality of retrograde puncture via the use of ultrasound or fluoroscopy failed we proceeded with an open approach. DISCUSSION: Retrograde approach usually offers a better chance of successfully crossing a chronic total occlusion lesion. However puncturing a distal vessel successfully and traversing a catheter or guidewire across proves to be a challenge. An open approach offers an additional pathway for puncturing the target vessel when duplex imaging or fluoroscopic guidance fails. CONCLUSION: Open approach is usually attempted as a last resort by many endovascular surgeons. However procedural time, contrast and radiation usage could have been cut short in cases where the distal target vessels pose a technical challenge for approach via a percutaneous method. PMID- 26439417 TI - Effects of date palm fruit extracts on skin mucosal immunity, immune related genes expression and growth performance of common carp (Cyprinus carpio) fry. AB - The aim of this study was to investigate the effects of date palm fruit extracts (DPFE) on skin mucosal immunity, immune related genes expression and growth performance of fry common carp (Cyprinus carpio). One hundred and twenty specimens (4.06 +/- 0.13 g) were supplied and allocated into six aquaria; specimens in three aquaria were fed non-supplemented diet (control) while the fish in the other 3 aquaria were fed with DPFE at 200 ml kg(-1). At the end of feeding trial (8 weeks) skin mucus immune parameters (total immunoglobulins, lysozyme, protease and alkaline phosphatase activity) and immune related gene expression (tumor necrosis factor alpha [tnfa], lysozyme [ly] and interleukin-1 beta, [il1b]) in the head-kidney were studied. The results revealed that feeding carp fry with 200 ml kg(-1) DPFE remarkably elevated the three skin mucus immune parameters tested (P < 0.05). However, evaluation of immune related gene expression demonstrated that the expression of tnfa and il1b was considerably decreased (P < 0.05) in fish fed DPFE diet, while the expression of ly remained similar (P > 0.05) compared to control fish (fed control diet). Furthermore, growth performance parameters were significantly improved in fry fed DPFE (P < 0.05). More studies are needed to understand different aspects of DPFE administration in fry mucosal immunity. PMID- 26439419 TI - Scalp actinomycosis presenting as soft tissue tumour: A case report with literature review. AB - INTRODUCTION: Actinomycosis is a rare subacute or chronic bacterial infection caused by Gram positive, anaerobic or microaerophilic bacilli. It is characterized by suppuration, abscess formation, tissue fibrosis, draining sinuses & rarely as a soft tissue mass mimicking a tumor. CASE REPORT: A 16 year old boy sustained a trauma over right forehead & wound after which patient presented with swelling over right forehead which was excised and was histopathologically reported as angiomatous lesion. Patient presented with recurrent swelling with ulceration over the same site. CT scan showed soft tissue mass with periosteal reaction of right frontal bone. Wide local excision with removal of periosteum was carried out. Raw area was covered with rotational scalp flap. Histopathology of the excised specimen showed features of actinomycosis. DISCUSSION: Cutaneous actinomycosis presenting as pseudocarcinomatous or sarcomatous mass is rare. Trauma is a common preceding event which was observed in present case. Histopathological confirmation is mandatory with visualization of sulfur granules. It is managed by high dose IV antibiotics. Surgical resection is a useful adjuvant therapy specially in large, disfiguring masses not responding to medical treatment and where excisional biopsy is helpful in establishing the diagnosis surgical excision alone is not curative, post operative long term antibiotics are adjuvant therapy to avoid recurrence. CONCLUSION: Actinomycosis of scalp skin is a rare entity and tumor like presentation is still uncommon. Lesions not resolving with routine antibiotics therapy should be suspected clinically as actinomycosis and treated with high dose antibiotics as histopathology from small biopsy is unreliable. PMID- 26439420 TI - Cation Exchange Resins and colonic perforation. What surgeons need to know. AB - INTRODUCTION: Since 1961 the use of Cation Exchange Resins has been the mainstream treatment for chronic hyperkalemia. For the past 25 years different kind of complications derived from its clinical use have been recognized, being the colonic necrosis the most feared and lethal of all. PRESENTATION OF CASE: We report a case of a 72-year-old patient with chronic kidney disease, treated with calcium polystyrene sulfonate for hyperkalemia treatment who presented in the emergency department with constipation treated with hypertonic cathartics. With clinical deterioration 48h later progressed with colonic necrosis requiring urgent laparotomy, sigmoidectomy and open abdomen management with subsequent rectal stump perforation and dead. The histopathology finding: calcium polystyrene sulfonate embedded in the mucosa, consistent with the cause of perforation. DISCUSSION: Lillemoe reported the first case series of five uremic patients with colonic perforation associated with the use of SPS in sorbitol in 1987 and in 2009 the FDA removed from the market the SPS containing 70% of sorbitol. The pathophysiologic change of CER goes from mucosal edema, ulcers, pseudomembranes, and the most severe case transmural necrosis. Up to present day, some authors have questioned the use of CER in the setting of lowering serum potassium. Despite its worldwide use in hyperkalemia settings, multiple studies have not demonstrated a significant potassium excretion by CER. CONCLUSION: Despite the low incidence of colonic complication and lethal colonic necrosis associated with the CER clinical use, the general surgeon needs a high index of suspicion when dealing with patients treated with CER and abdominal pain. PMID- 26439422 TI - Lactic acid bacterium and yeast microbiotas of sixteen French traditional sourdoughs. AB - Sixteen sourdoughs (FS1-FS16) used for the manufacture of traditional French breads were characterized by strongly acid conditions (median value of pH 3.5). The concentration of free amino acids (FAA) was highly variable, due to different proteolytic activity of flour used for back slopping and of dominant microorganisms. Median value of cell density of lactic acid bacteria (LAB) was 9.2 log CFU/g. The ratio between LAB and yeasts ranged from 10,000:1 to 10:1. According to the culture-dependent method and 16S metagenetics, Lactobacillus sanfranciscensis was the dominant species in French sourdoughs. FS5 and FS15, propagated according to protocols including one back slopping step at 14 degrees C, were the only exceptions. High positive correlations were found between L. sanfranciscensis, temperature of back slopping and FAA. The results of this study highlighted the broad adaptability of L. sanfranciscensis to very acid sourdough. Besides species frequently encountered (e.g., Lactobacillus parabrevis/Lactobacillus hammesii, Lactobacillus plantarum and Leuconostoc mesenteroides), first Lactobacillus xiangfangensis (FS5) and Lactobacillus diolivorans (FS15) were found in sourdough. As determined by RAPD-PCR analyses, the sourdough samples showed a different number of strains, ranging from 5 (FS9, FS11 and FS15) to 12 (FS1 and FS13), meaning a highly variable bacterial diversity. Cluster analysis showed that different sourdoughs, especially when propagated in the same bakery, may harbor similar strains. Except for L. plantarum (FS5) and Ln. mesenteroides (FS3), all the dominant species were detected by both 16S metagenetics and culture-dependent method. Yeast diversity was lower than LAB. Except for FS4 (solely dominated by Kazachstania servazzii), yeast microbiota of French sourdoughs was dominated by Saccharomyces cerevisiae. Strains isolated in this study could be a useful base for developing new basic researches on physiology, metabolism, and intraspecific diversity of L. sanfranciscensis, as well as for standardizing the quality of traditional French breads. PMID- 26439421 TI - Meniscectomy versus meniscal repair: 10 years radiological and clinical results in vertical lesions in stable knee. AB - INTRODUCTION: Surgical management of meniscal lesion consists of either a meniscectomy or meniscal repair. Although repair offers immediate recovery after surgery, it is also associated with higher rates of revision. A meniscectomy, on the other hand is known to be associated with an early onset of osteoarthritis. The present study compared clinical and radiological results at 10 years between meniscectomy and meniscal repair in isolated vertical lesion in an otherwise stable knee. The hypothesis was that repair shows functional and radiological benefit over meniscectomy. PATIENTS AND METHOD: A multi-centric retrospective comparative study of 32 patients (24 male, 8 female). Mean follow-up was 10.6 years (range, 10-13 years). There were 10 meniscal repairs (group R) and 22 meniscectomies (group M), in 17 right and 15 left knees. Mean age at surgery was 33.45+/-12.3 years (range, 9-47 years). There were 28 medial and 4 lateral meniscal lesions; 26 were in the red-red zone and 6 in red-white zone. RESULTS: Functional score: KOOS score was significantly higher in group R than M on almost all parameters: 98+/-4.69 versus 77.38+/-21.97 for symptoms (P=0.0043), 96.89+/ 7.20 versus 78.57+/-18.9 for pain (P=0.0052), 99.89+/-0.33 versus 80.88+/-19.6 for daily life activities (P=0.0002), 96.11+/-9.83 versus 54.05+/-32.85 for sport and leisure (P=0.0005), but 91+/-16.87 versus 68.15+/-37.7 for quality of life (P=0.1048). Radiology score: in group R, 7 patients had no features of osteoarthritis, and 2 had grade 1 osteoarthritis. In group M, 5 patients had grade 1 osteoarthritis, 10 grade 2, 3 grade 3 and 3 grade 4. Mean quantitative score was 0 (mean, 0.22+/-0.44) in-group R and 2 (mean, 2.19+/-0.98) in group M (P<0.0001). DISCUSSION: At more than 10year's follow-up, functional scores were significantly better with meniscal repair than meniscectomy on all parameters of the KOOS scale except quality of life. Functional and radiological scores correlated closely. These results show that meniscal repair for vertical lesions in stable knees protects against osteoarthritis and is therefore strongly recommended. LEVEL OF EVIDENCE: IV; retrospective study. PMID- 26439423 TI - Modelling the effect of essential oil of betel leaf (Piper betle L.) on germination, growth, and apparent lag time of Penicillium expansum on semi synthetic media. AB - The current study aimed at characterizing the chemical components of betel leaf (Piper betle L. var. Tamluk Mitha) essential oil (BLEO) and modelling its effect on growth of Penicillium expansum on semi-synthetic medium. Gas chromatography mass spectrophotometry (GC-MS) analysis of BLEO revealed the presence of different bioactive phenolic compounds in significant amounts. Among 46 different components identified, chavibetol (22.0%), estragole (15.8%), beta-cubebene (13.6%), chavicol (11.8%), and caryophyllene (11.3%) were found to be the major compounds of BLEO. A disc diffusion and disc volatilization method were used to evaluate antifungal activity of the oil against a selected food spoilage mould. The logistic model was used to study the kinetics of spore germination. Prediction and validation of antifungal effect of BLEO was performed on semi synthetic medium (apple juice agar) using predictive microbiological tools. The Baranyi and Roberts model was used to estimate maximum growth rate (MUmax in mm/day) and apparent lag time (lambda in days) of the mould. Secondary modelling was performed using a re-parameterized Monod-type equation based on cardinal values to study the effect of different BLEO concentration on estimated growth parameters. Emax (minimum concentration of oil at which mould growth was inhibited) and MIC (minimum inhibitory concentration of BLEO at which lag time is infinite) value of BLEO against P. expansum was estimated to be 0.56 and 0.74 MUl/ml, respectively, which was found to be similar on potato dextrose agar (PDA) as well as apple juice agar (AJA) medium. The correlation between estimated growth parameters of the mould on both the media was obtained with satisfactory statistical indices (R(2) and RMSE). This study revealed inhibitory efficacy of BLEO on spore germination, mycelial growth and apparent lag time of P. expansum in a dose-dependent manner. Hence, BLEO has potential to be used as a natural food preservative. PMID- 26439424 TI - The association between aerobic fitness and cognitive function in older men mediated by frontal lateralization. AB - Previous studies have shown that higher aerobic fitness is related to higher cognitive function and higher task-related prefrontal activation in older adults. However, a holistic picture of these factors has yet to be presented. As a typical age-related change of brain activation, less lateralized activity in the prefrontal cortex during cognitive tasks has been observed in various neuroimaging studies. Thus, this study aimed to reveal the relationship between aerobic fitness, cognitive function, and frontal lateralization. Sixty male older adults each performed a submaximal incremental exercise test to determine their oxygen intake (V.O2) at ventilatory threshold (VT) in order to index their aerobic fitness. They performed a color-word Stroop task while prefrontal activation was monitored using functional near infrared spectroscopy. As an index of cognitive function, Stroop interference time was analyzed. Partial correlation analyses revealed significant correlations among higher VT, shorter Stroop interference time and greater left-lateralized dorsolateral prefrontal cortex (DLPFC) activation when adjusting for education. Moreover, mediation analyses showed that left-lateralized DLPFC activation significantly mediated the association between VT and Stroop interference time. These results suggest that higher aerobic fitness is associated with cognitive function via lateralized frontal activation in older adults. PMID- 26439426 TI - [First report of invasive fungal disease by Candida fabianii in a non-neonatal paediatric patient]. AB - BACKGROUND: Invasive fungal diseases have increased in recent years. Candida species are the most common aetiology. Candida albicans, Candida parapsilosis, Candida tropicalis, Candida glabrata and Candida krusei are the cause of most of them. The aim of this work is to describe the first isolation of Candida fabianii in the blood of a non-neonatal paediatric patient. CASE REPORT: A 2 year-old male with short bowel syndrome, severe malnutrition, and hypophosphataemic rickets deficiency was admitted to paediatric intensive care due to a respiratory tract infection and suspicion of an intestinal pseudo-obstruction. He received several cycles of broad-spectrum antibiotics for several infections due to Pseudomonas aeruginosa and Escherichia coli. After the surgical correction of the intestinal disorder he suffered a new episode of sepsis where yeasts were isolated by culture. The species identification was performed by means of mass spectrometry (MALDI-TOF system, Bruker Daltonic). The identity of the isolate was C.fabianii (anamorph)/Pichia fabianii (teleomorph) with a score of 2.149. Antifungal treatment with caspofungin was prescribed, with good progress of the patient. CONCLUSIONS: Molecular techniques are important for the identification of these species, although mass spectrometry offered a reliable and rapid diagnosis. Treatment with caspofungin was effective. PMID- 26439425 TI - Fragile X-associated tremor/ataxia syndrome: An under-recognised cause of tremor and ataxia. AB - Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive degenerative movement disorder resulting from a fragile X "premutation", defined as 55-200 CGG repeats in the 5'-untranslated region of the FMR1 gene. The FMR1 premutation occurs in 1/800 males and 1/250 females, with FXTAS affecting 40-45% of male and 8-16% of female premutation carriers over the age of 50. FXTAS typically presents with kinetic tremor and cerebellar ataxia. FXTAS has a classical imaging profile which, in concert with clinical manifestations and genetic testing, participates vitally in its diagnosis. The revised FXTAS diagnostic criteria include two major radiological features. The "MCP sign", referring to T2 hyperintensity in the middle cerebellar peduncle, has long been considered the radiological hallmark of FXTAS. Recently included as a major radiological criterion in the diagnosis of FXTAS is T2 hyperintensity in the splenium of the corpus callosum. Other imaging features of FXTAS include T2 hyperintensities in the pons, insula and periventricular white matter as well as generalised brain and cerebellar atrophy. FXTAS is an under-recognised and misdiagnosed entity. In patients with unexplained tremor, ataxia and cognitive decline, the presence of middle cerebellar peduncle and/or corpus callosum splenium hyperintensity should raise suspicion of FXTAS. Diagnosis of FXTAS has important implications not only for the patient but also, through genetic counselling and testing, for future generations. PMID- 26439427 TI - Complete genome sequence of Bifidobacterium longum KCTC 12200BP, a probiotic strain promoting the intestinal health. AB - Bifidobacteria constitute a major group of beneficial intestinal bacteria, and are therefore often used to formulate probiotic products in combination with lactic acid bacteria. The availability of bifidobacterial genome sequences has broadened our knowledge on health-promoting factors as well as their safety assessments. Here, we present the complete genome sequence of Bifidobacterium longum CBT BG7 that consists of a 2.45-Mb chromosome and a plasmid. PMID- 26439428 TI - Complete genome sequence of Lactobacillus plantarum ZS2058, a probiotic strain with high conjugated linoleic acid production ability. AB - Lactobacillus plantarum ZS2058 was isolated from sauerkraut and identified to synthesize the beneficial metabolite conjugated linoleic acid. The genome contains a 319,7363-bp chromosome and three plasmids. The sequence will facilitate identification and characterization of the genetic determinants for its putative biological benefits. PMID- 26439429 TI - Complete genome sequence of the probiotic bacterium Bifidobacterium breve KCTC 12201BP isolated from a healthy infant. AB - We present the completely sequenced genome of Bifidobacterium breve CBT BR3, which was isolated from the feces of a healthy infant. The 2.43-Mb genome contains several kinds of genetic factors associated with health promotion of the human host such as oligosaccharide-degrading genes and vitamin-biosynthetic genes. PMID- 26439431 TI - Treatment of dystrophic epidermolysis bullosa with bone marrow non-hematopoeitic stem cells: a randomized controlled trial. AB - Patients with dystrophic epidermolysis bullosa (DEB) have mutations in type VII collagen gene. Type VII collagen is synthesized by keratinocytes and fibroblasts. Based on the ability of bone marrow non-hematopoeitic stem cells (NHBMSC) to develop into fibroblasts, we decided to investigate the use of NHBMSC in the treatment of recessive DEB (RDEB). This study included fourteen patients with RDEB; the first seven of them were given cyclosporine after the infusion of NHBMSC. As cyclosporine has been used for the treatment of RDEB we decided not to use cyclosporine for the second group of seven patients. Skin biopsies from the lesions were studied by electron microscopy before and after treatment. The number of new blisters decreased significantly after treatment in both groups (p = 0.003 and 0.004 respectively) and the rate of healing of new blisters became significantly faster after treatment in both groups (p < 0.001) with no significant difference between the two groups. Electron microscopic examination revealed increased number of anchoring fibrils after treatment in both groups. No major side effects were reported during the 1-year follow-up period. Our findings highlight the efficacy as well as the safety of NHBMSC in the treatment of RDEB. PMID- 26439430 TI - EXPLORING PERSONALITY DIAGNOSIS STABILITY FOLLOWING ACUTE PSYCHOTHERAPY FOR CHRONIC POSTTRAUMATIC STRESS DISORDER. AB - BACKGROUND: Axis I comorbidity complicates diagnosing axis II personality disorders (PDs). PDs might influence Axis I outcome. No research has examined psychotherapy effects on PDs of treating Axis I comorbidity. Secondary analysis of a randomized controlled trial examined PD diagnostic stability after brief psychotherapy of chronic posttraumatic stress disorder (PTSD). METHODS: Patients with chronic PTSD were randomly assigned to 14 weeks of prolonged exposure, interpersonal psychotherapy, or relaxation therapy. Assessments included the Structured Clinical Interview for DSM-IV, Patient Version (SCID-P) and Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II) at baseline, week 14, and for treatment responders (>=30% clinician-administered PTSD scale improvement, defined a priori) at week 26 follow-up. We hypothesized patients whose PTSD improved would retain fewer baseline PD diagnoses posttreatment, particularly with personality traits PTSD mimics, e.g. paranoid and avoidant. RESULTS: Forty-seven (47%) of 99 SCID-II patients evaluated at baseline received a SCID-II diagnosis: paranoid (28%), obsessive-compulsive (27%), and avoidant (23%) PDs were most prevalent. Among 78 patients who repeated SCID-II evaluations posttreatment, 45% (N = 35) had baseline PD diagnoses, of which 43% (N = 15/35) lost at week 14. Three (7%) patients without baseline PDs acquired diagnoses at week 14; 10 others shifted diagnoses. Treatment modality and PTSD response were unrelated to PD improvement. Of treatment responders reevaluated at follow-up (N = 44), 56% with any baseline Axis II diagnosis had none at week 26. CONCLUSION: This first evaluation of Axis I psychotherapy effects on personality disorder stability found that acutely treating a chronic state decreased apparent trait across most PDs observed. These exploratory findings suggest personality diagnoses may have limited prognostic meaning in treating chronic PTSD. PMID- 26439432 TI - Reply. PMID- 26439433 TI - Shame, hatred, and pornography: Variations on an aspect of current times. AB - Drawing on a number of clinical vignettes, the author seeks to highlight the relations between shame, hatred and pornography in contemporary clinical practice, and to explore certain metapsychological avenues that can help us understand how these relations are established. PMID- 26439434 TI - Photorespiration participates in the assimilation of acetate in Chlorella sorokiniana under high light. AB - The development of microalgae on an industrial scale largely depends on the economic feasibility of mass production. High light induces productive suspensions during cultivation in a tubular photobioreactor. Herein, we report that high light, which inhibited the growth of Chlorella sorokiniana under autotrophic conditions, enhanced the growth of this alga in the presence of acetate. We compared pigments, proteomics and the metabolic flux ratio in C. sorokiniana cultivated under high light (HL) and under low light (LL) in the presence of acetate. Our results showed that high light induced the synthesis of xanthophyll and suppressed the synthesis of chlorophylls. Acetate in the medium was exhausted much more rapidly in HL than in LL. The data obtained from LC-MS/MS indicated that high light enhanced photorespiration, the Calvin cycle and the glyoxylate cycle of mixotrophic C. sorokiniana. The results of metabolic flux ratio analysis showed that the majority of the assimilated carbon derived from supplemented acetate, and photorespiratory glyoxylate could enter the glyoxylate cycle. Based on these data, we conclude that photorespiration provides glyoxylate to speed up the glyoxylate cycle, and releases acetate-derived CO2 for the Calvin cycle. Thus, photorespiration connects the glyoxylate cycle and the Calvin cycle, and participates in the assimilation of supplemented acetate in C. sorokiniana under high light. PMID- 26439435 TI - Functional trait diversity across trophic levels determines herbivore impact on plant community biomass. AB - Understanding the consequences of trophic interactions for ecosystem functioning is challenging, as contrasting effects of species and functional diversity can be expected across trophic levels. We experimentally manipulated functional identity and diversity of grassland insect herbivores and tested their impact on plant community biomass. Herbivore resource acquisition traits, i.e. mandible strength and the diversity of mandibular traits, had more important effects on plant biomass than body size. Higher herbivore functional diversity increased overall impact on plant biomass due to feeding niche complementarity. Higher plant functional diversity limited biomass pre-emption by herbivores. The functional diversity within and across trophic levels therefore regulates the impact of functionally contrasting consumers on primary producers. By experimentally manipulating the functional diversity across trophic levels, our study illustrates how trait-based approaches constitute a promising way to tackle existing links between trophic interactions and ecosystem functioning. PMID- 26439437 TI - Butyrylcholinesterase Atypical Mutation in a Patient Undergoing Electroconvulsive Therapy. PMID- 26439436 TI - Quantification of Adequate Bowel Preparation for Screening or Surveillance Colonoscopy in Men. AB - BACKGROUND & AIMS: Bowel preparation is defined as adequate if it is sufficient for identification of polyps greater than 5 mm. However, adequate preparation has not been quantified. We performed a prospective observational study to provide an objective definition of adequate preparation, based on the Boston Bowel Prep Scale (BBPS, which consists of 0-3 points for each of 3 colon segments). METHODS: We collected data from 438 men who underwent screening or surveillance colonoscopies and then repeat colonoscopy examinations within 60 days by a different blinded endoscopist (1161 colon segments total) at the West Haven Veterans Affairs Medical Center from January 2014 to February 2015. Missed polyps were defined as those detected on the second examination of patients with the best possible bowel preparation (colon segment BBPS score of 3) on the second examination. The primary outcome was the proportion of colon segments with adenomas larger than 5 mm that were missed in the first examination. We postulated that the miss rate was noninferior for segments with BBPS scores of 2 vs those with BBPS scores of 3 (noninferiority margin, <5%). Our secondary hypotheses were that miss rates were higher in segments with BBPS scores of 1 vs those with scores of 3 or of 2. RESULTS: The adjusted proportion with missed adenomas greater than 5 mm was noninferior for segments with BBPS scores of 2 (5.2%) vs those with BBPS scores of 3 (5.6%) (a difference of -0.4%; 95% confidence interval [CI], -2.9% to 2.2%). Of study subjects, 347 (79.2%) had BBPS scores of 2 or greater in all segments on the initial examination. A higher proportion of segments with BBPS scores of 1 had missed adenomas larger than 5 mm (15.9%) than segments with BBPS scores of 3 (5.6%) (a difference of 10.3%; 95% CI, 2.7%-17.9%) or 2 (5.2%) (a difference of 10.7%; 95% CI, 3.2%-18.1%). Screening and surveillance intervals based solely on the findings at the first examination would have been incorrect for 16.3% of patients with BBPS scores of 3 in all segments, for 15.3% with BBPS scores of 2 or 3 in all segments, and for 43.5% of patients with a BBPS score of 1 in 1 or more segments. CONCLUSIONS: Patients with BBPS scores of 2 or 3 for all colon segments have adequate bowel preparation for the detection of adenomas larger than 5 mm and should return for screening or surveillance colonoscopy at standard guideline-recommended intervals. Colon segments with a BBPS score of 1 have a significantly higher rate of missed adenomas larger than 5 mm than segments with scores of 2 or 3. This finding supports a recommendation for early repeat colonoscopic evaluation in patients with a BBPS score of 0 or 1 in any colon segment. PMID- 26439438 TI - Inhaled Loxapine for ECT Pretreatment for Agitation. PMID- 26439439 TI - A Tool for Assuring Continuity of Care During a Series of ECT Treatments. PMID- 26439441 TI - Arbitrary and Parallel Nanofabrication of 3D Metal Structures with Polymer Brush Resists. AB - 3D polymer brushes are reported for the first time as ideal resists for the alignment-free nanofabrication of complex 3D metal structures with sub-100 nm lateral resolution and sub-10 nm vertical resolution. Since 3D polymer brushes can be serially fabricated in parallel, this method is effective to generate arbitrary 3D metal structures over a large area at a high throughput. PMID- 26439440 TI - Genetic and epigenetic transgenerational implications related to omega-3 fatty acids. Part I: maternal FADS2 genotype and DNA methylation correlate with polyunsaturated fatty acid status in toddlers: an exploratory analysis. AB - Polyunsaturated fatty acid metabolism in toddlers is regulated by a complex network of interacting factors. The contribution of maternal genetic and epigenetic makeup to this milieu is not well understood. In a cohort of mothers and toddlers 16 months of age (n = 65 mother-child pairs), we investigated the association between maternal genetic and epigenetic fatty acid desaturase 2 (FADS2) profiles and toddlers' n-6 and n-3 fatty acid metabolism. FADS2 rs174575 variation and DNA methylation status were interrogated in mothers and toddlers, as well as food intake and plasma fatty acid concentrations in toddlers. A multivariate fit model indicated that maternal rs174575 genotype, combined with DNA methylation, can predict alpha-linolenic acid plasma concentration in all toddlers and arachidonic acid concentrations in boys. Arachidonic acid intake was predictive for its plasma concentration in girls, whereas intake of 3 major n-3 species (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids) were predictive for their plasma concentrations in boys. FADS2 genotype and DNA methylation in toddlers were not related to plasma concentrations or food intakes, except for CpG8 methylation. Maternal FADS2 methylation was a predictor for the boys' alpha-linolenic acid intakes. This exploratory study suggests that maternal FADS2 genetic and epigenetic status could be related to toddlers' polyunsaturated fatty acid metabolism. PMID- 26439442 TI - An approach for the improved immobilization of penicillin G acylase onto macroporous poly(glycidyl methacrylate-co-ethylene glycol dimethacrylate) as a potential industrial biocatalyst. AB - The use of penicillin G acylase (PGA) covalently linked to insoluble carrier is expected to produce major advances in pharmaceutical processing industry and the enzyme stability enhancement is still a significant challenge. The objective of this study was to improve catalytic performance of the covalently immobilized PGA on a potential industrial carrier, macroporous poly(glycidyl methacrylate-co ethylene glycol dimethacrylate) [poly(GMA-co-EGDMA)], by optimizing the copolymerization process and the enzyme attachment procedure. This synthetic copolymer could be a very promising alternative for the development of low-cost, easy-to-prepare, and stable biocatalyst compared to expensive commercially available epoxy carriers such as Eupergit or Sepabeads. The PGA immobilized on poly(GMA-co-EGDMA) in the shape of microbeads obtained by suspension copolymerization appeared to have higher activity yield compared to copolymerization in a cast. Optimal conditions for the immobilization of PGA on poly(GMA-co-EGDMA) microbeads were 1 mg/mL of PGA in 0.75 mol/L phosphate buffer pH 6.0 at 25 degrees C for 24 h, leading to the active biocatalyst with the specific activity of 252.7 U/g dry beads. Chemical amination of the immobilized PGA could contribute to the enhanced stability of the biocatalyst by inducing secondary interactions between the enzyme and the carrier, ensuring multipoint attachment. The best balance between the activity yield (51.5%), enzyme loading (25.6 mg/g), and stability (stabilization factor 22.2) was achieved for the partially modified PGA. PMID- 26439443 TI - Exercise Pills: At the Starting Line. AB - Sedentary lifestyles, limited physical exercise, and prolonged inactivity undoubtedly increase chronic diseases, including obesity, type 2 diabetes, and cardiovascular diseases. It is widely acknowledged that exercise induces a number of physiological adaptations that have beneficial effects in the prevention and treatment of these chronic metabolic diseases. Unfortunately, exercise compliance is extremely low and often not possible. The development of exercise science and molecular techniques has increased our understanding of the molecular pathways responsive to exercise. Knowledge of these molecular targets has led to the development of chemical interventions that can mimic the beneficial effects of exercise without requiring actual muscle activity. This review focuses on the concept of 'exercise pills' and how they mimic the effects produced by physical exercise including oxidative fiber-type transformation, mitochondrial biogenesis, increased fat oxidation, angiogenesis, and improvement of exercise capacity. We also review candidate exercise pills, and contrast the beneficial effects and molecular mechanisms between physical exercise and exercise pills. PMID- 26439449 TI - Role of radiation in the treatment of non-metastatic osseous Ewing sarcoma. AB - INTRODUCTION: Local control, either with surgery, radiation (RT) or both, is essential in the management of localised Ewing sarcoma; however, the relative role of RT remains controversial. METHODS: Using the Surveillance, Epidemiology, and End Results database, 612 patients treated for non-metastatic skeletal Ewing sarcoma between the years 1988 and 2010 were identified. RESULTS: Median age and follow-up were 13 years (range: 0-21) and 56 months (range: 0-287), respectively. Five-year overall survival (OS) for the cohort was 74.4 +/- 2.0%. Patients received surgery alone (51.3%), RT alone (21.6%) or both (27.1%). Patients with skeletal Ewing sarcoma had improved OS with surgery alone compared with other treatments. However, in subset analyses, RT was not inferior to surgery alone for appendicular (5-year OS: 80.0% vs. 79.3%), non-pelvic (84.3% vs. 79.9%) or localised disease (confined to cortex or periosteum; 79.7% vs. 80.6%). After controlling for stage and site, no increase in mortality was observed with RT versus surgery alone (hazard ratio = 0.77 (95% confidence interval: 0.49-1.19)). CONCLUSIONS: In regard to survival, RT did not appear to be inferior to surgery alone for most patients, particularly those with disease at favourable sites (localised, appendicular, non-pelvic). In select patients with Ewing sarcoma, RT may be an appropriate strategy for local control that does not necessarily compromise survival outcomes. PMID- 26439450 TI - Nonstoichiometric, Protic Azolium Azolate Ionic Liquids Provide Unique Environments for N-Donor Coordination Chemistry. AB - Here we demonstrate that neat reactions of amphoteric azoles with more basic azoles give a family of finely tunable, nonstoichiometric liquids which are useful for N-donor coordination chemistry. Reacting 4,5-dicyanoimidazole (4,5 DCNIm) with 1-methylimidazole (1-mim) gives new compounds with composition dependent speciation. Two crystalline compounds, a 1:1 protic salt, [H(1 mim)][4,5-DCNIm], and a 1:2 salt co-crystal, [H(1-mim)][4,5-DCNIm]?4,5-DCNIm, were isolated and structurally characterized, while differential scanning calorimetry revealed both suppression of crystallization and the presence of neutral and anionic species in the melt. Reactions of Cu(NO3 )2 ?2.5 H2 O, CuO, and ZnO with the neat 2:1 1-mim/4,5-DCNIm melt resulted in the isolation of entirely N-donor ligated complexes of the formula M(4,5-DCNIm)2 (1-mim)4 (M=Cu, Zn). PMID- 26439451 TI - Cardiovascular toxicity after antiangiogenic therapy in persons older than 65 years with advanced renal cell carcinoma. AB - BACKGROUND: Sorafenib and sunitinib are oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) approved in 2005 and 2006, respectively, for the treatment of patients with renal cell carcinoma (RCC). A population-based, observational cohort study of the cardiovascular risk of VEGFR TKI therapy in elderly RCC patients was conducted. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare database, this study analyzed patients who were 66 years old or older and were diagnosed with RCC from 2000 to 2009. The incidence of cardiovascular adverse events, including congestive heart failure and cardiomyopathy (CHF/CM), acute myocardial infarction (AMI), stroke, and cardiovascular deaths, was examined through December 2010. A Cox proportional hazards model was created to calculate the hazard ratio (HR), and adjustments were made for age, sex, comorbidity, and the use of other systemic therapy. RESULTS: A total of 171 of 670 patients who received sunitinib or sorafenib had cardiovascular events. The incidence rates for CHF/CM, AMI, and stroke were 0.87, 0.14, and 0.14 per 1000 person-days, respectively. Sunitinib or sorafenib use was associated with an increased risk of cardiovascular events (HR, 1.38; 95% confidence interval [CI], 1.02-1.87) and especially stroke (HR, 2.84; 95% CI, 1.52-5.31) in comparison with 788 patients diagnosed with advanced RCC from 2007 to 2009 who were eligible for Part D but did not receive either agent. In subgroup analyses, patients who were 66 to 74 years old at diagnosis had the highest increased risk of stroke associated with the use of either or both drugs. CONCLUSIONS: Sunitinib and sorafenib might be associated with an increased risk of cardiovascular events and particularly stroke. PMID- 26439452 TI - Long-segment percutaneous screw fixation for thoraco-lumbar spine metastases: a single center's experience. AB - BACKGROUND: The management of spine metastases is an increasing concern for spine surgeons. Their treatment is mainly palliative with the goal to preserve or restore the patients' quality of life. Many minimally invasive techniques have been introduced with the aim to reduce the morbidity associated with more traditional open approaches. We aimed to evaluate the efficiency of long segment percutaneous pedicle screw stabilization for the treatment of instability associated with symptomatic thoracolumbar spine metastases. METHODS: In this prospective study, we included all patients who underwent the percutaneous placement of pedicle screws in our institution between January 2008 and June 2014, for the palliative treatment of a symptomatic thoracolumbar spine metastasis. All patients had a normal examination. Postoperative radiation therapy was planned within 2 weeks following the stabilization. A clinical and radiological follow-up were planned at 3 months, 6 months and 1 year. Pain was measured using VAS and functional status was assessed using the Frankel Grading system. CT scan was performed before discharge and at each office evaluation. RESULTS: Forty-four patients have been included. There were 26 men and 18 women, with a mean age of 57.3 years (range 36-79 years). The mean operative time was 85 minutes (range 47-124 min), and the estimated blood loss was inferior to 100 mL in all cases. The mean length of hospital stay was 5.2 days (range 3-18 days). All patients underwent postoperative radiation therapy within 2 weeks. Pain was significantly improved from the early postoperative period (P<0.001). Visual Analogic Scale scores decreased from 6.3 (2-10) to 3.0 (0-6) at discharge. No patient worsened his neurological condition postoperatively. One patient required a revision surgery at 3 months due to an important tumor progression at the treated level. Radiological follow-up demonstrated no case of misplacement, hardware breakage or loosening. CONCLUSIONS: As the treatment of spine metastases is largely palliative, minimally invasive techniques should be discussed first to limit the impact of surgery in critical patients. Long-segment percutaneous screw fixation followed by early radiation therapy, appears to be a safe and effective treatment option to ensure solid and durable stability, as well as a good local tumor control. PMID- 26439453 TI - Neuroprotective effects of hemicraniectomy in malign middle cerebral artery infarctions: experimental study. AB - INTRODUCTION: Despite optimal medical therapy the mortality rate approaches 50% in MCA infarctions. Although recent studies have been showed life-saving effect of hemicraniectomy; there are a few data available in regard to neuroprotection effect of decompressive craniectomy (DC). We induced a malign cerebral ischemia model by intraluminal permanent middle cerebral artery occlusion (MCAo) in male rats for defining the neuroprotective effects of early DC on brain-blood barrier (BBB) molecular changes, infarct size and cerebral edema. MATERIAL-METHOD: 48 male Spraque Dawley rats were allocated to 4 groups; sham (n = 9), control (n = 9), experiment 1 (n = 15), experiment 2 (n = 15). DC was performed by creating a bone flap, after MCAo at 4th and 24th hours. After 28 hours of survival, all animals were sacrificed. Infarction volumes were calculated from TTC (2,3,5,triphenyltetrozolium chloride)- stained brain sections. In all groups, cerebral edema was quantified as a change in the percentage (%) of brain water content. Western Blot was used to analyze the expression of tight junction protein claudin-5 and occludin. RESULTS: Brain water content was calculated 75,18+/-0,75 % in the early DC group and 77,76 +/- 0,71 % in the late DC group. No significant difference was found between experiment groups (p= .178). In the early DC group; occludin and claudin-5 were significantly expressed at higher levels compared to late DC group (for occludin p = .013; for claudin-5 p = .034). At early DC group (73,38+/-23,11 mm3) the final infarct volumes (in terms of cubic millimeters; mm3) were significantly smaller than in the late DC group (377,18+/-39,23 mm3) (p = .013). CONCLUSION: The study results supported the neuroprotective effects of early DC in malign MCA infarcts. PMID- 26439454 TI - Developmental venous anomaly as a rare cause of obstructive hydrocephalus: literature review and a case report. AB - OBJECT: Developmental venous anomalies (DVA), previously known as cerebral venous malformations or Venous Angiomas, are common benign entities often incidentally discovered at MRI examinations. They are non-pathologic variants of normal deep parenchymal veins that are usually asymptomatic, but they can rarely cause some complications. In this paper we described a rare case of obstructive hydrocephalus caused by a DVA located within the cerebral aqueduct and we also reviewed the previous literature on this topic. CASE REPORT AND METHODS FOR LITERATURE REVIEW: A 37-year-old man was diagnosed with symptomatic tri ventricular hydrocephalus that during the last year caused episodes of ictal headaches accompanied by vertigo, diaphoresis and lipothimic events. The MRI and the angiography showed the presence of a large collector vein coursing within the aqueduct, which was part of a complex DVA in the posterior fossa, responsible for the aqueductal stenosis and obstructive hydrocephalus. The patient was submitted to endoscopic third ventriculostomy (ETV) and then he had a complete resolution of symptoms. A literature review was performed through Medline Pubmed (http://www.ncbi.nlm.nih.gov/pubmed) on papers published in English from 1937 to 2015 with the following key words: DVA, obstructive hydrocephalus, acqueductal stenosis, venous angioma, venous malformation, medullary malformation. RESULTS: Including our case, the literature research identified 16 reports in the Medline database for 18 patients presenting with obstructive hydrocephalus caused by a DVA including our case. In approximately 60% (10/17) of cases, the stenosis causing obstructive hydrocephalus was present in the cerebral aqueduct .. The floor of the IV ventricle and the third ventricle were the second most common locations and DVAs were identified in 20% of cases (3/17) for each of these regions. In the remaining case the venous malformation was found in the Foramen of Monro. Clinical presentation before diagnosis lasted on average 23 months ranging from 1 month to 7 years. The mean age at diagnosis was 27 (range 3 days- 58 years). The most common presenting symptom was persistent headache, representing a major complaint in 80% of cases (12/15). In 78% (14/18) of cases MRI was crucial in the diagnosis. ETV was performed in 47% (8/17) of patients, whereas no treatment or clinical follow-up was required in 18% (3/17) and VP Shunt in 12% (2/17) of cases. Instead, VA Shunt, Transcallosal approach and acqueductal stenting were performed in one patient each, corresponding singularly to 6% (1/17) of all cases. CONCLUSION: Despite the fact that DVAs are asymptomatic, they may rarely cause obstructive hydrocephalus because of impairment in the CSF flow. They should be considered in the differential diagnosis of any patient presenting with obstructive hydrocephalus. ETV has been demonstrated as an effective treatment option in the management of obstructive hydrocephalus due to a DVA. PMID- 26439455 TI - A Cross-Sectional Study of the Relationship of Physical Activity with Depression and Cognitive Deficit in Older Adults. AB - The aim of this study was to examine the association of physical activity with depression and cognition deficit, separately and combined, in Brazilian older adults. We analyzed data from 622 older adults. Physical activity was assessed using the International Physical Activity Questionnaire. Depressive symptoms were assessed using the Geriatric Depression Scale, while cognitive deficit was assessed using the Mini-Mental State Examination. Multinomial logistic regressions were used to assess associations of depression and cognitive deficit with sociodemographic, health, and behavioral variables. Prevalence of physical inactivity (< 150 min of moderate-to-vigorous physical activity/ week), depression, and cognitive deficit were 35.7%, 37.4%, and 16.7%. Physical inactivity was associated with depression (OR: 1.83, 95% CI: 1.14-2.94) and with depression and cognitive deficit combined (OR: 4.23, 95% CI: 2.01-8.91). Physically inactive participants were also more likely to present limitations in orientation and language functions. Physical inactivity was associated with depression and also with depression and cognitive deficit combined in older adults. PMID- 26439456 TI - Modeling the Assembly of Polymer-Grafted Nanoparticles at Oil-Water Interfaces. AB - Using dissipative particle dynamics (DPD), I model the interfacial adsorption and self-assembly of polymer-grafted nanoparticles at a planar oil-water interface. The amphiphilic core-shell nanoparticles irreversibly adsorb to the interface and create a monolayer covering the interface. The polymer chains of the adsorbed nanoparticles are significantly deformed by surface tension to conform to the interface. I quantitatively characterize the properties of the particle-laden interface and the structure of the monolayer in detail at different surface coverages. I observe that the monolayer of particles grafted with long polymer chains undergoes an intriguing liquid-crystalline-amorphous phase transition in which the relationship between the monolayer structure and the surface tension/pressure of the interface is elucidated. Moreover, my results indicate that the amorphous state at high surface coverage is induced by the anisotropic distribution of the randomly grafted chains on each particle core, which leads to noncircular in-plane morphology formed under excluded volume effects. These studies provide a fundamental understanding of the interfacial behavior of polymer-grafted nanoparticles for achieving complete control of the adsorption and subsequent self-assembly. PMID- 26439458 TI - The tumor microenvironment: the connective tissue/tumor cell/host organ system that modulates tumor progression. PMID- 26439457 TI - Cysteine as a Monothiol Reducing Agent to Prevent Copper-Mediated Oxidation of Interferon Beta During PEGylation by CuAAC. AB - Bioconjugation by copper-catalyzed azide-alkyne cycloaddition (CuAAC) provides a powerful means to produce site-specifically modified proteins. However, the use of a copper catalyst brings about the possible generation of reactive oxygen species that could cause degradation of vulnerable amino acid residues. We investigated whether PEGylation by CuAAC caused any modifications to the therapeutic protein interferon beta-1b, which was produced via global amino acid substitution with azidohomo-alanine at the N-terminus and contains no methionine residues. Using previously reported reaction conditions, LC-MS peptide mapping detected +32 Da and +48 Da oxidation modifications of tryptic peptides 28-33 (LEYCLK) and 137-147 (EYSHCAWTIVR) in the protein post-PEGylation. The oxidative degradation increased with reaction time, whereas reducing the copper concentration slowed the PEGylation rate as well as the oxidation rate. Replacing dithiothreitol (DTT) with any of five different monothiol reducing agents in anaerobic conditions allowed efficient PEGylation in 2-4 h and abrogated oxidative degradation. Free cysteine provided reproducible reaction results as a reducing agent in this system and has been successfully applied to other protein conjugations. Monothiol reducing agents, such as cysteine, may be useful tools as protective reducing agents for CuAAC in some bioconjugation systems. PMID- 26439459 TI - Developing hospital accreditation standards in Uganda. AB - BACKGROUND: Whereas accreditation is widely used as a tool to improve quality of healthcare in the developed world, it is a concept not well adapted in most developing countries for a host of reasons, including insufficient incentives, insufficient training and a shortage of human and material resources. The purpose of this paper is to describe refining use and outcomes of a self-assessment hospital accreditation tool developed for a resource-limited context. METHODS: We invited 60 stakeholders to review a set of standards (from which a self assessment tool was developed), and subsequently refined them to include 485 standards in 7 domains. We then invited 60 hospitals to test them. A study team traveled to each of the 40 hospitals that agreed to participate providing training and debrief the self-assessment. The study was completed in 8 weeks. RESULTS: Hospital self-assessments revealed hospitals were remarkably open to frank rating of their performance and willing to rank all 485 measures. Good performance was measured in outreach programs, availability of some types of equipment and running water, 24-h staff calls systems, clinical guidelines and waste segregation. Poor performance was measured in care for the vulnerable, staff living quarters, physician performance reviews, patient satisfaction surveys and sterilizing equipment. CONCLUSION: We have demonstrated the feasibility of a self-assessment approach to hospital standards in low-income country setting. This low-cost approach may be used as a good precursor to establishing a national accreditation body, as indicated by the Ministry's efforts to take the next steps. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26439467 TI - Anisotropic Effective Mass, Optical Property, and Enhanced Band Gap in BN/Phosphorene/BN Heterostructures. AB - Phosphorene is receiving great research interests because of its peculiar physical properties. Nonetheless, the phosphorus has a trouble of degradation due to oxidation. Hereby, we propose that the electrical and optical anisotropic properties can be preserved by encapsulating into hexagonal boron nitride (h-BN). We found that the h-BN contributed to enhancing the band gap of the phosphorene layer. Comparing the band gap of the pristine phosphorene layer, the band gap of the phosphorene/BN(1ML) system was enhanced by 0.15 eV. It was further enhanced by 0.31 eV in the BN(1ML)/phosphorene/BN(1ML) trilayer structure. However, the band gap was not further enhanced when we increased the thickness of the h-BN layers even up to 4 MLs. Interestingly, the anisotropic effective mass and optical property were still preserved in BN/phosphorene/BN heterostructures. Overall, we predict that the capping of phosphorene by the h-BN layers can be an excellent solution to protect the intrinsic properties of the phosphorene. PMID- 26439460 TI - Room for one more? A review of the literature on 'inappropriate' admissions to hospital for older people in the English NHS. AB - This paper reports the findings of a review of the literature on emergency admissions to hospital for older people in the UK, undertaken between May and June 2014 at the Health Services Management Centre, University of Birmingham. This review sought to explore: the rate of in/appropriate emergency admissions of older people in the UK; the way this is defined in the literature; solutions proposed to reduce the rate of inappropriate admissions; and the methodological issues which particular definitions of 'inappropriateness' raise. The extent to which a patient perspective is included in these definitions of inappropriateness was also noted, given patient involvement is such a key policy priority in other areas of health policy. Despite long-standing policy debates, relatively little research has been published on formal rates of 'inappropriate' emergency hospital admissions for older people in the UK NHS in recent years. What has been produced indicates varying rates of in/appropriateness, inconsistent ways of defining appropriateness and a lack of focus on the possible solutions to address the problem. Significantly, patient perspectives are lacking, and we would suggest that this is a key factor in fully understanding how to prevent avoidable admissions. With an ageing population, significant financial challenges and a potentially fragmented health and social care system, the issue of the appropriateness of emergency admission is a pressing one which requires further research, greater focus on the experiences of older people and their families, and more nuanced contextual and evidence-based responses. PMID- 26439468 TI - Approach to Modeling, Therapy Evaluation, Drug Selection, and Biomarker Assessments for a Multicenter Pre-Clinical Drug Screening Consortium for Acute Therapies in Severe Traumatic Brain Injury: Operation Brain Trauma Therapy. AB - Traumatic brain injury (TBI) was the signature injury in both the Iraq and Afghan wars and the magnitude of its importance in the civilian setting is finally being recognized. Given the scope of the problem, new therapies are needed across the continuum of care. Few therapies have been shown to be successful. In severe TBI, current guidelines-based acute therapies are focused on the reduction of intracranial hypertension and optimization of cerebral perfusion. One factor considered important to the failure of drug development and translation in TBI relates to the recognition that TBI is extremely heterogeneous and presents with multiple phenotypes even within the category of severe injury. To address this possibility and attempt to bring the most promising therapies to clinical trials, we developed Operation Brain Trauma Therapy (OBTT), a multicenter, pre-clinical drug screening consortium for acute therapies in severe TBI. OBTT was developed to include a spectrum of established TBI models at experienced centers and assess the effect of promising therapies on both conventional outcomes and serum biomarker levels. In this review, we outline the approach to TBI modeling, evaluation of therapies, drug selection, and biomarker assessments for OBTT, and provide a framework for reports in this issue on the first five therapies evaluated by the consortium. PMID- 26439469 TI - Atmospheric Chemistry of (CF3)2CHOCH3, (CF3)2CHOCHO, and CF3C(O)OCH3. AB - Smog chambers with in situ FTIR detection were used to measure rate coefficients in 700 Torr of air and 296 +/- 2 K of: k(Cl+(CF3)2CHOCH3) = (5.41 +/- 1.63) * 10( 12), k(Cl+(CF3)2CHOCHO) = (9.44 +/- 1.81) * 10(-15), k(Cl+CF3C(O)OCH3) = (6.28 +/ 0.98) * 10(-14), k(OH+(CF3)2CHOCH3) = (1.86 +/- 0.41) * 10(-13), and k(OH+(CF3)2CHOCHO) = (2.08 +/- 0.63) * 10(-14) cm(3) molecule(-1) s(-1). The Cl atom initiated oxidation of (CF3)2CHOCH3 gives (CF3)2CHOCHO in a yield indistinguishable from 100%. The OH radical initiated oxidation of (CF3)2CHOCH3 gives the following products (molar yields): (CF3)2CHOCHO (76 +/- 8)%, CF3C(O)OCH3 (16 +/- 2)%, CF3C(O)CF3 (4 +/- 1)%, and C(O)F2 (45 +/- 5)%. The primary oxidation product (CF3)2CHOCHO reacts with Cl atoms to give secondary products (molar yields): CF3C(O)CF3 (67 +/- 7)%, CF3C(O)OCHO (28 +/- 3)%, and C(O)F2 (118 +/- 12)%. CF3C(O)OCH3 reacts with Cl atoms to give: CF3C(O)OCHO (80 +/- 8)% and C(O)F2 (6 +/- 1)%. Atmospheric lifetimes of (CF3)2CHOCH3, (CF3)2CHOCHO, and CF3C(O)OCH3 were estimated to be 62 days, 1.5 years, and 220 days, respectively. The 100-year global warming potentials (GWPs) for (CF3)2CHOCH3, (CF3)2CHOCHO, and CF3C(O)OCH3 are estimated to be 6, 121, and 46, respectively. A comprehensive description of the atmospheric fate of (CF3)2CHOCH3 is presented. PMID- 26439470 TI - Direct and indirect effects of the 13-valent pneumococcal conjugate vaccine administered to infants and young children. AB - This paper analyzes the most recent reports regarding the direct and indirect effects of the 13-valent pneumococcal conjugate vaccine (PCV13) when administered to infants and young children. PCV13 extends the protective effects reported for the 7-valent pneumococcal conjugate vaccine (PCV7). A further reduction in the incidence of invasive pneumococcal disease, community-acquired pneumonia, acute otitis media, rhinosinusitis and carriage of PCV13 serotypes in vaccinated and unvaccinated subjects was found with PCV13 compared with PCV7. However, further studies are required to establish the effectiveness of PCV13 against serotypes 1, 5 and 3, the role of cross-protective antibodies evoked by serotype 6A on serotype 6C and the importance of the serotype replacement phenomenon following the extension of PCV13 use. PMID- 26439471 TI - Genetic polymorphisms of matrix metalloproteinases and protein levels in chronic obstructive pulmonary disease in a Mexican population. AB - AIM: To evaluate association of single nucleotide polymorphisms (SNPs) in the MMP1, MMP2, MMP9 and MMP12 genes and serum MMP-2 and MMP-9 levels in smoking chronic obstructive pulmonary disease (COPD) patients. MATERIALS & METHODS: Genotyping using real-time PCR in 330 smokers with COPD (COPD), 658 smokers without COPD (SNC) and 150 nonsmokers (NCNS), the analysis of samples used was chi(2) test. Using ELISA, the proteins were evaluated. Multiple comparisons were made by ANOVA. RESULTS: rs243864 (OR: 7.44; 95% CI: 3.62-15.26) and rs11646643 (OR: 1.58; 95% CI: 1.07-2.34) of the MMP-2 gene and rs3918253 (OR: 1.72; 95% CI: 1.08-2.71) of the MMP-9 gene, were associated with the risk of COPD. Serum MMP-2 level in the COPD group was lower compared with SNC (p < 0.05). Serum MMP-9 level was elevated in the COPD group compared with SNC (p < 0.05). CONCLUSION: Polymorphisms in MMP2 and MMP9 but not in MMP1 and MMP12 are associated with the risk of COPD in the Mexican mestizo population. PMID- 26439472 TI - Synthesis of Polyheteroaromatic Compounds via Rhodium-Catalyzed Multiple C-H Bond Activation and Oxidative Annulation. AB - Polyheteroaromatic compounds are potential optoelectronic conjugated materials due to their electro- and photochemical properties. Transition-metal-catalyzed multiple C-H activation and sequential oxidative annulation allows rapidly assembling of those compounds from readily available starting materials. A rhodium-catalyzed cascade oxidative annulation of beta-enamino esters or 4 aminocoumarins with internal alkynes is described to access those compounds, featuring multiple C-H/N-H bond cleavages and sequential C-C/C-N bond formations in one pot. PMID- 26439473 TI - Comparative effects of group metacognitive therapy versus behavioural activation in moderately depressed students. AB - BACKGROUND: The high incidence and prevalence rates of depression among students identify them as a vulnerable population and make the case for the development of cost-effective treatments. AIMS: We aimed to examine the comparative effects of brief group metacognitive therapy (MCT) versus behavioural activation (BA) treatments for depression, anxiety, and emotion regulation in university students. METHOD: All participants (25 women, 16 men; age range: 18-30 years) fulfilled criteria for major depression and were randomly assigned to MCT (n = 15), BA (n = 15), or a wait-list control group (n = 15). The treatment groups received 8 weekly MCT or BA sessions. Scores on the Beck Depression Inventory, Beck Anxiety Inventory, and Cognitive Emotion Regulation Questionnaire were used as outcome measures. RESULTS: This pilot study showed that both treatments were equally effective for depressive and anxiety symptoms. However, therapeutic techniques differed with regards to their effects on specific facets of emotion regulation, such as Positive Reappraisal and Catastrophizing, with MCT being more effective compared to BA. BA also showed a stronger relapse at follow-up with regards to Acceptance and Refocus on Planning. CONCLUSIONS: Results suggest that groups MCT and BA may be implemented as cost-effective treatments for students with moderate depression. PMID- 26439474 TI - Rapid analysis of diclofenac in freshwater and wastewater by a monoclonal antibody-based highly sensitive ELISA. AB - The non-steroidal anti-inflammatory drug (NSAID) diclofenac (DCF) is found worldwide in the aqueous environment. Therefore, it has raised increased public concern on potential long-term impact on human health and wildlife. The importance of DCF has been emphasized by the European Union recently by including this pharmaceutical in the first watch list of priority hazardous substances in order to gather Union-wide monitoring data. Rapid and cheap methods of analysis are therefore required for fresh and wastewater monitoring with high sample load. Here, for the first time, well-characterized monoclonal antibodies (mAbs) against DCF were generated and a highly sensitive ELISA developed. The best antibody (mAb 12G5) is highly affine (KD = 1.5 * 10(-10) M), stable to potential matrix interferences such as pH value (pH range 5.2-9.2), calcium ion concentration (up to 75 mg/L), and humic acid content (up to 20 mg/L). The limit of detection (LOD, S/N = 3) and IC50 of the ELISA calibration curve were 7.8 and 44 ng/L, respectively. The working range was defined between 11 and 180 ng/L. On average, about 10 % cross-reactivity (CR) was found for DCF metabolites 5-OH-DCF, 4'-OH DCF, and DCF-acyl glucuronide, but other structurally related NSAIDs showed binding <1 % compared to the parent compound. While DCF concentrations at the low ppt range were measured in river and lake water, higher values of 2.9 and 2.1 MUg/L were found in wastewater influents and effluents, respectively. These results could be confirmed by solid phase extraction combined with LC-MS. PMID- 26439476 TI - Correction to "Oxidatively Initiated NHC-Catalyzed Enantioselective Synthesis of 3,4-Disubstituted Cyclopentanones from Enals". PMID- 26439475 TI - Citrate salts for preventing and treating calcium containing kidney stones in adults. AB - BACKGROUND: Kidney stones affect people worldwide and have a high rate of recurrence even with treatment. Recurrences are particularly prevalent in people with low urinary citrate levels. These people have a higher incidence of calcium phosphate and calcium oxalate stones. Oral citrate therapy increases the urinary citrate levels, which in turn binds with calcium and inhibits the crystallisation thus reduces stone formation. Despite the widespread use of oral citrate therapy for prevention and treatment of calcium oxalate stones, the evidence to support its clinical efficacy remains uncertain. OBJECTIVES: The objective of this review was to determine the efficacy and adverse events associated with citrate salts for the treatment and prevention of calcium containing kidney stones. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register to 29 July 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that assessed the efficacy and adverse events associated with citrate salts for the treatment and prevention of calcium containing kidney stones in adults treated for a minimum of six months. DATA COLLECTION AND ANALYSIS: Two authors assessed studies for inclusion in this review. Data were extracted according to predetermined criteria. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. MAIN RESULTS: We included seven studies that included a total of 477 participants, most of whom had oxalate stones. Of these, three studies (247 participants) compared potassium citrate with placebo or no intervention; three (166 participants) compared potassium sodium citrate with no intervention; and one (64 participants) compared potassium magnesium citrate with placebo. Overall, quality of the reporting of the included studies was considered moderate to poor, and there was a high risk of attrition bias in two studies.Compared with placebo or no intervention, citrate therapy significantly reduced the stone size (4 studies, 160 participants: RR 2.35, 95% CI 1.36 to 4.05). New stone formation was significantly lower with citrate therapy compared to control (7 studies, 324 participants: RR 0.26, 95% CI 0.10 to 0.68). The beneficial effect on stone size stability was also evident (4 studies, 160 participants: RR 1.97, 95% CI 1.19 to 3.26). Adverse events were reported in four studies, with the main side effects being upper gastrointestinal disturbance and one patient reported a rash. There were more gastrointestinal adverse events in the citrate group; however this was not significant (4 studies, 271 participants: RR 2.55, 95% CI 0.71 to 9.16). There were significantly more dropouts due to adverse events with citrate therapy compared to control (4 studies, 271 participants: RR 4.45, 95% CI 1.28 to 15.50). The need for retreatment was significantly less with citrate therapy compared to control (2 studies, 157 participants: RR 0.22, 95% CI 0.06 to 0.89). AUTHORS' CONCLUSIONS: Citrate salts prevent new stone formation and reduce further stone growth in patients with residual stones that predominantly contain oxalate. The quality of reported literature remains moderate to poor; hence a well-designed statistically powered multi-centre RCT is needed in order to answer relevant questions concerning the efficacy of citrate salts. PMID- 26439477 TI - Protective activity of crocin against indomethacin-induced gastric lesions in rats. AB - The present study was designed to elucidate the mechanism(s) of the gastro protective effect of crocin against indomethacin-induced gastric lesions. Crocin or pantoprazole was administered to rats 30 min before indomethacin. Five hours later, the animals were killed and their stomachs were removed and examined macroscopically. Samples of gastric mucosa were collected for microscopic evaluation, mRNA expression of caspase-3, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 was quantified by RT-PCR, and protein levels of COX-1, COX-2, iNOS and caspase-3 were assessed by Western blotting. The pH, volume of gastric effluent and antioxidant activity were measured in 5 separate groups of rats following pylorus ligation. Indomethacin induced significant increases in mRNA and protein expression of iNOS and caspase-3 and increased MDA levels, and reduced the pH of the gastric effluent and protein and mRNA expression of COX-2 and protein expression of COX-1 and mucus content associated with gastric ulceration. Crocin and pantoprazole significantly inhibited mRNA and protein expression of iNOS, caspase-3 and MDA, and reduced mucus content induced by indomethacin. However, unlike pantoprazole, crocin failed to increase COX-1 and pH, but had variable increasing effects on mRNA and protein expression of COX-2. Macroscopic and microscopic observations showed that mucosal erosions induced by indomethacin were significantly inhibited by pantoprazole and crocin. These findings suggest that crocin exerts its gastro-protective effects mainly by inhibition of MDA, reduction in iNOS and caspase-3, and inhibition of the reduction in mucus content induced by indomethacin. Crocin is a novel agent that has potential in the prevention of ulceration induced by NSAIDs. PMID- 26439478 TI - LC-MS-based quantification method for Achyranthes root saponins. AB - A liquid chromatography mass spectrometry (LC-MS) method was developed for simultaneous quantitative analysis of Achyranthes root saponins: chikusetsusaponins IVa (1) and V (2), achyranthosides B (3), C (4), D (5), E (6), and G (7), sulfachyranthosides B (8) and D (9), and betavulgarosides II (10) and IV (11). Satisfactory separation of the saponins was achieved with the use of a volatile ion-pair reagent (dihexyl ammonium acetate) on a phenyl-hexylated silica gel column, and the amounts of saponins extracted under three different conditions were determined. When Achyranthes root was extracted with water at room temperature, achyranthosides B (3) and D (5) were the major saponins, and smaller amounts of other saponins (4, 6-11) were present. However, the amounts of chikusetsusaponins (1 and 2) were negligible. Under the condition to make a standard decoction of a Kampo formula, the major saponins were achyranthosides B (3), C (4), and D (5), and small amounts of chikusetsusaponins IVa (1) and V (2) appeared, whereas prolonged heating largely increased the amounts of chikusetsusaponins. This method can be used for quality control of Achyranthes root. PMID- 26439480 TI - Emotion Perception or Social Cognitive Complexity: What Drives Face Processing Deficits in Autism Spectrum Disorder? AB - Some, but not all, relevant studies have revealed face processing deficits among those with autism spectrum disorder (ASD). In particular, deficits are revealed in face processing tasks that involve emotion perception. The current study examined whether either deficits in processing emotional expression or deficits in processing social cognitive complexity drive face processing deficits in ASD. We tested adults with and without ASD on a battery of face processing tasks that varied with respect to emotional expression processing and social cognitive complexity. Results revealed significant group differences on tasks involving emotional expression processing, but typical performance on a non-emotional but socially complex task. These results support an emotion processing rather than a social complexity explanation for face processing deficits in ASD. PMID- 26439479 TI - Antiviral effects of Yinhuapinggan granule against influenza virus infection in the ICR mice model. AB - Yinhuapinggan granule (YHPG), a Chinese medicine granule based on Ma-Huang-Tang (Ephedra Decoction) and the clinical experience of Professor Wan Haitong, is used in traditional Chinese medicine (TCM) for the treatment of colds, influenza, fever, inflammation and cough. This study investigated the antiviral effects of YHPG on the production of inflammatory cytokines in influenza virus (IFV) infected mice and evaluated the effect of YHPG on the expression of NF-kappaB p65 and the level of key signaling molecules in the TLR4 signaling pathway. ICR mice were orally administrated YHPG at doses of 7.5, 15 and 30 g kg(-1) day(-1) for 2 or 6 days after IFV infection. On days 3 and 7 after infection, YHPG (15 g/kg and 30 g/kg) significantly increased levels of interleukin (IL)-2 and interferon gamma and decreased levels of IL-4, IL-5 and tumor necrosis factor (TNF) in serum compared with the IFV control group. Furthermore, the expression of TLR4, MyD88, TRAF6 and NF-kappaB p65 at the mRNA and protein level was significantly lower in the YHPG (15 and 30 g/kg) treatment groups than in the IFV control group. These results suggest that YHPG has antiviral effects in IFV-infected mice, which is associated with the inhibition of the TLR4-MyD88-TRAF6 signaling pathway and the expression of NF-kappaB p65. PMID- 26439482 TI - Celiac disease and dental enamel defects: what is the link? PMID- 26439481 TI - Are Non-intellectually Disabled Black Youth with ASD Less Impaired on Parent Report than Their White Peers? AB - There is a lack of research examining differences in functioning in autism spectrum disorder (ASD) across ethnicity, particularly among those without intellectual disability (ID). This study investigated ethnic differences in parent-reported impairment in executive function, adaptive behavior, and social emotional functioning. White and Black youth (n = 64; ages 6-17) with ASD without ID were compared on each of these domains. Black youth had significantly lower levels of impairment on all three domains. Findings may reflect better daily functioning among Black youth with ASD and/or cultural differences in parent response to questionnaires. Regardless, these findings raise concern about the sensitivity of commonly used measures for Black children with ASD and the impact of culture on daily functioning and symptom manifestation. PMID- 26439483 TI - A case of a strangulated umbilical hernia causing gangrenous appendicitis. PMID- 26439484 TI - A 10-year history of perinatal care at the Brockington Mother and Baby Unit Stafford. AB - Perinatal mother and baby units are an essential service for women suffering from perinatal mental illness by allowing the baby to stay with the mother whilst receiving inpatient mental health care. Such units enable the mother to develop a relationship with her baby in a safe and supportive environment whilst caring for her mental health needs and allow her to gain confidence in her role as a mother. This article presents the development of the Brockington Mother and Baby unit and its progressive advancement towards an exemplary service for women suffering from perinatal mental illness. The Brockington Mother and Baby unit (MBU) at South Staffordshire and Shropshire Healthcare Foundation Trust (SSSFT) is celebrating its 10th anniversary and is one of six MBUs accredited as excellent by the Royal College of Psychiatry (RCPsych). The unit is a member of the Royal College of Psychiatrists' Quality Care Network and thereby adheres to their national standard of care. This article describes the journey from a single lone worker in perinatal mental health to an exemplary service caring for women with perinatal mental illness during the first 12 months following the birth of their child. PMID- 26439485 TI - Cerebellar Contribution to Pattern Separation of Human Hippocampal Memory Circuits. AB - The cerebellum is a crucial structure for cognitive function as well as motor control. Benign brain tumors such as schwannomas, meningiomas, and epidermoids tend to occur in the cerebellopontine angle cisterns and may cause compression of the posterior lateral cerebellum near the superior posterior fissure, where the eloquent area for cognitive function was recently identified. The present study examined cognitive impairment in patients with benign cerebellar tumors before and after surgical intervention in order to clarify the functional implications of this region in humans. Patients with cerebellar tumors showed deficits in psychomotor speed and working memory compared with healthy controls. Moreover, these impairments were more pronounced in patients with right cerebellar tumors. Functional magnetic resonance imaging during performance of a lure task also demonstrated that cerebellar tumors affected pattern separation or the ability to distinguish similar experiences of episodic memory or events with discrete, non overlapping representations, which is one of the important cognitive functions related to the hippocampus. The present findings indicate that compression of the human posterior lateral cerebellum affects hippocampal memory function. PMID- 26439487 TI - Cytotoxicity of alkaloids isolated from Argemone mexicana on SW480 human colon cancer cell line. AB - CONTEXT: Argemone mexicana Linn. (Papaveraceae) has been used as traditional medicine in India and Taiwan for the treatment of skin diseases, inflammations, bilious, fever, etc. Some alkaloids of A. mexicana have been screened for their cytotoxicity on different cancer cell lines. OBJECTIVE: The study investigates potential cytotoxic effects of alkaloids isolated from aerial part of A. mexicana on SW480 human colon cancer cell line. MATERIALS AND METHODS: Six alkaloids, 13 oxoprotopine, protomexicine, 8-methoxydihydrosanguinarine, dehydrocorydalmine, jatrorrhizine, and 8-oxyberberine were isolated from the methanol extract of A. mexicana. Cytotoxicity of these alkaloids was studied on SW480 human colon cancer cell line at 1, 25, 50, 75, 100, 125, 150, and 200 ug/mL for 24 and 48 h. Cells were seeded in a 96-well micro-plate at a concentration of 2 * 10(4) cells per well and MTS assay was performed to assess cytotoxicity in terms of cell viability. RESULTS: At 200 ug/mL, protomexicine and 13-oxoprotopine showed mild cytotoxicity (~24-28%) whereas dehydrocorydalmine exhibited moderate cytotoxicity (~48%). 8-Oxyberberine was mildly cytotoxic (~27%) at 24 h but was more potent (~76%) at 48 h. Jatrorrhizine and 8-methoxydihydrosanguinarine were most potent (~95-100%) in inhibiting the human colon cancer cell proliferation showing complete reduction in cell viability. DISCUSSION AND CONCLUSION: This is the first study on the effect of these alkaloids on SW480 human colon cancer cell line. This study indicates that some alkaloids of A. mexicana strongly inhibit the cell proliferation in human colon cancer cells, and it might be a basis for future development of a potent chemotherapeutic drug. PMID- 26439488 TI - Child-to-Parent Violence: An Exploratory Study of the Roles of Family Violence and Parental Discipline Through the Stories Told by Spanish Children and Their Parents. AB - The aim of this study was to identify the role of exposure to family violence and parental discipline in the development of child-to-parent violence (CPV). A qualitative in-depth interview design was used. Fifteen adolescents (10 boys) who have perpetrated CPV (Mage=16 years; SDage=1.33 years) and their parents or foster parents took part in the study. Individually, they answered questions about exposure to violence and parenting practices. Results suggest that adolescents were frequently direct victims and also witnesses of violence. Furthermore, emotional neglect in the parent-child relationship was frequent and families were characterized by rules that are not consistently implemented. Different forms of violence seem to coexist in these families, and CPV should also be a target in the interventions. PMID- 26439491 TI - Combined Use of GPS and Accelerometry Reveals Fine Scale Three-Dimensional Foraging Behaviour in the Short-Tailed Shearwater. AB - Determining the foraging behaviour of free-ranging marine animals is fundamental for assessing their habitat use and how they may respond to changes in the environment. However, despite recent advances in bio-logging technology, collecting information on both at-sea movement patterns and activity budgets still remains difficult in small pelagic seabird species due to the constraints of instrument size. The short-tailed shearwater, the most abundant seabird species in Australia (ca 23 million individuals), is a highly pelagic procellariiform. Despite its ecological importance to the region, almost nothing is known about its at-sea behaviour, in particular, its foraging activity. Using a combination of GPS and tri-axial accelerometer data-loggers, the fine scale three-dimensional foraging behaviour of 10 breeding individuals from two colonies was investigated. Five at-sea behaviours were identified: (1) resting on water, (2) flapping flight, (3) gliding flight, (4) foraging (i.e., surface foraging and diving events), and (5) taking-off. There were substantial intra- and inter- individual variations in activity patterns, with individuals spending on average 45.8% (range: 17.1-70.0%) of time at sea resting on water and 18.2% (range: 2.3 49.6%) foraging. Individuals made 76.4 +/- 65.3 dives (range: 8-237) per foraging trip (mean duration 9.0 +/- 1.9 s), with dives also recorded during night-time. With the continued miniaturisation of recording devices, the use of combined data loggers could provide us with further insights into the foraging behaviour of small procellariiforms, helping to better understand interactions with their prey. PMID- 26439493 TI - Improving 4D plan quality for PBS-based liver tumour treatments by combining online image guided beam gating with rescanning. AB - Pencil beam scanned (PBS) proton therapy has many advantages over conventional radiotherapy, but its effectiveness for treating mobile tumours remains questionable. Gating dose delivery to the breathing pattern is a well-developed method in conventional radiotherapy for mitigating tumour-motion, but its clinical efficiency for PBS proton therapy is not yet well documented. In this study, the dosimetric benefits and the treatment efficiency of beam gating for PBS proton therapy has been comprehensively evaluated. A series of dedicated 4D dose calculations (4DDC) have been performed on 9 different 4DCT(MRI) liver data sets, which give realistic 4DCT extracting motion information from 4DMRI. The value of 4DCT(MRI) is its capability of providing not only patient geometries and deformable breathing characteristics, but also includes variations in the breathing patterns between breathing cycles. In order to monitor target motion and derive a gating signal, we simulate time-resolved beams' eye view (BEV) x-ray images as an online motion surrogate. 4DDCs have been performed using three amplitude-based gating window sizes (10/5/3 mm) with motion surrogates derived from either pre-implanted fiducial markers or the diaphragm. In addition, gating has also been simulated in combination with up to 19 times rescanning using either volumetric or layered approaches. The quality of the resulting 4DDC plans has been quantified in terms of the plan homogeneity index (HI), total treatment time and duty cycle. Results show that neither beam gating nor rescanning alone can fully retrieve the plan homogeneity of the static reference plan. Especially for variable breathing patterns, reductions of the effective duty cycle to as low as 10% have been observed with the smallest gating rescanning window (3 mm), implying that gating on its own for such cases would result in much longer treatment times. In addition, when rescanning is applied on its own, large differences between volumetric and layered rescanning have been observed as a function of increasing number of re-scans. However, once gating and rescanning is combined, HI to within 2% of the static plan could be achieved in the clinical target volume, with only moderately prolonged treatment times, irrespective of the rescanning strategy used. Moreover, these results are independent of the motion surrogate used. In conclusion, our results suggest image guided beam gating, combined with rescanning, is a feasible, effective and efficient motion mitigation approach for PBS-based liver tumour treatments. PMID- 26439489 TI - The Progressive BSSG Rat Model of Parkinson's: Recapitulating Multiple Key Features of the Human Disease. AB - The development of effective neuroprotective therapies for Parkinson's disease (PD) has been severely hindered by the notable lack of an appropriate animal model for preclinical screening. Indeed, most models currently available are either acute in nature or fail to recapitulate all characteristic features of the disease. Here, we present a novel progressive model of PD, with behavioural and cellular features that closely approximate those observed in patients. Chronic exposure to dietary phytosterol glucosides has been found to be neurotoxic. When fed to rats, beta-sitosterol beta-d-glucoside (BSSG) triggers the progressive development of parkinsonism, with clinical signs and histopathology beginning to appear following cessation of exposure to the neurotoxic insult and continuing to develop over several months. Here, we characterize the progressive nature of this model, its non-motor features, the anatomical spread of synucleinopathy, and response to levodopa administration. In Sprague Dawley rats, chronic BSSG feeding for 4 months triggered the progressive development of a parkinsonian phenotype and pathological events that evolved slowly over time, with neuronal loss beginning only after toxin exposure was terminated. At approximately 3 months following initiation of BSSG exposure, animals displayed the early emergence of an olfactory deficit, in the absence of significant dopaminergic nigral cell loss or locomotor deficits. Locomotor deficits developed gradually over time, initially appearing as locomotor asymmetry and developing into akinesia/bradykinesia, which was reversed by levodopa treatment. Late-stage cognitive impairment was observed in the form of spatial working memory deficits, as assessed by the radial arm maze. In addition to the progressive loss of TH+ cells in the substantia nigra, the appearance of proteinase K-resistant intracellular alpha-synuclein aggregates was also observed to develop progressively, appearing first in the olfactory bulb, then the striatum, the substantia nigra and, finally, hippocampal and cortical regions. The slowly progressive nature of this model, together with its construct, face and predictive validity, make it ideal for the screening of potential neuroprotective therapies for the treatment of PD. PMID- 26439490 TI - The Dynamic Genome and Transcriptome of the Human Fungal Pathogen Blastomyces and Close Relative Emmonsia. AB - Three closely related thermally dimorphic pathogens are causal agents of major fungal diseases affecting humans in the Americas: blastomycosis, histoplasmosis and paracoccidioidomycosis. Here we report the genome sequence and analysis of four strains of the etiological agent of blastomycosis, Blastomyces, and two species of the related genus Emmonsia, typically pathogens of small mammals. Compared to related species, Blastomyces genomes are highly expanded, with long, often sharply demarcated tracts of low GC-content sequence. These GC-poor isochore-like regions are enriched for gypsy elements, are variable in total size between isolates, and are least expanded in the avirulent B. dermatitidis strain ER-3 as compared with the virulent B. gilchristii strain SLH14081. The lack of similar regions in related species suggests these isochore-like regions originated recently in the ancestor of the Blastomyces lineage. While gene content is highly conserved between Blastomyces and related fungi, we identified changes in copy number of genes potentially involved in host interaction, including proteases and characterized antigens. In addition, we studied gene expression changes of B. dermatitidis during the interaction of the infectious yeast form with macrophages and in a mouse model. Both experiments highlight a strong antioxidant defense response in Blastomyces, and upregulation of dioxygenases in vivo suggests that dioxide produced by antioxidants may be further utilized for amino acid metabolism. We identify a number of functional categories upregulated exclusively in vivo, such as secreted proteins, zinc acquisition proteins, and cysteine and tryptophan metabolism, which may include critical virulence factors missed before in in vitro studies. Across the dimorphic fungi, loss of certain zinc acquisition genes and differences in amino acid metabolism suggest unique adaptations of Blastomyces to its host environment. These results reveal the dynamics of genome evolution and of factors contributing to virulence in Blastomyces. PMID- 26439494 TI - What's in the Gift? Towards a Molecular Dissection of Nuptial Feeding in a Cricket. AB - Nuptial gifts produced by males and transferred to females during copulation are common in insects. Yet, their precise composition and subsequent physiological effects on the female recipient remain unresolved. Male decorated crickets Gryllodes sigillatus transfer a spermatophore to the female during copulation that is composed of an edible gift, the spermatophylax, and the ampulla that contains the ejaculate. After transfer of the spermatophore, the female detaches the spermatophylax and starts to eat it while sperm from the ampulla are evacuated into the female reproductive tract. When the female has finished consuming the spermatophylax, she detaches the ampulla and terminates sperm transfer. Hence, one simple function of the spermatophylax is to ensure complete sperm transfer by distracting the female from prematurely removing the ampulla. However, the majority of orally active components of the spermatophylax itself and their subsequent effects on female behavior have not been identified. Here, we report the first analysis of the proteome of the G. sigillatus spermatophylax and the transcriptome of the male accessory glands that make these proteins. The accessory gland transcriptome was assembled into 17,691 transcripts whilst about 30 proteins were detected within the mature spermatophylax itself. Of these 30 proteins, 18 were encoded by accessory gland encoded messages. Most spermatophylax proteins show no similarity to proteins with known biological functions and are therefore largely novel. A spermatophylax protein shows similarity to protease inhibitors suggesting that it may protect the biologically active components from digestion within the gut of the female recipient. Another protein shares similarity with previously characterized insect polypeptide growth factors suggesting that it may play a role in altering female reproductive physiology concurrent with fertilization. Characterization of the spermatophylax proteome provides the first step in identifying the genes encoding these proteins in males and in understanding their biological functions in the female recipient. PMID- 26439486 TI - Consensus Paper: Cerebellar Development. AB - The development of the mammalian cerebellum is orchestrated by both cell autonomous programs and inductive environmental influences. Here, we describe the main processes of cerebellar ontogenesis, highlighting the neurogenic strategies used by developing progenitors, the genetic programs involved in cell fate specification, the progressive changes of structural organization, and some of the better-known abnormalities associated with developmental disorders of the cerebellum. PMID- 26439495 TI - Transcriptomic Analysis of Trout Gill Ionocytes in Fresh Water and Sea Water Using Laser Capture Microdissection Combined with Microarray Analysis. AB - Fish gills represent a complex organ composed of several cell types that perform multiple physiological functions. Among these cells, ionocytes are implicated in the maintenance of ion homeostasis. However, because the ionocyte represents only a small percent of whole gill tissue, its specific transcriptome can be overlooked among the numerous cell types included in the gill. The objective of this study is to better understand ionocyte functions by comparing the RNA expression of this cell type in freshwater and seawater acclimated rainbow trout. To realize this objective, ionocytes were captured from gill cryosections using laser capture microdissection after immunohistochemistry. Then, transcriptome analyses were performed on an Agilent trout oligonucleotide microarray. Gene expression analysis identified 108 unique annotated genes differentially expressed between freshwater and seawater ionocytes, with a fold change higher than 3. Most of these genes were up-regulated in freshwater cells. Interestingly, several genes implicated in ion transport, extracellular matrix and structural cellular proteins appeared up-regulated in freshwater ionocytes. Among them, several ion transporters, such as CIC2, SLC26A6, and NBC, were validated by qPCR and/or in situ hybridization. The latter technique allowed us to localize the transcripts of these ion transporters in only ionocytes and more particularly in the freshwater cells. Genes involved in metabolism and also several genes implicated in transcriptional regulation, cell signaling and the cell cycle were also enhanced in freshwater ionocytes. In conclusion, laser capture microdissection combined with microarray analysis allowed for the determination of the transcriptional signature of scarce cells in fish gills, such as ionocytes, and aided characterization of the transcriptome of these cells in freshwater and seawater acclimated trout. PMID- 26439497 TI - Molecular dynamics simulation study of distribution and dynamics of aqueous solutions of uranyl ions: the effect of varying temperature and concentration. AB - Investigating the characteristics of actinyl ions has been of great interest due to their direct relevance in the nuclear fuel cycle. All-atom molecular dynamics simulations have been employed to study the orientational structure and dynamics of aqueous solutions of uranyl ions of various concentrations. The orientational structure of water around a uranyl ion has been thoroughly investigated by calculating different orientational probability distributions corresponding to different molecular axes of water. The orientational distribution of water molecules in the first coordination shell of a uranyl ion is found to be markedly different from that in bulk water. Analysis of counterion distribution around the uranyl ion reveals the presence of nitrate ions along with water molecules in the first solvation shell. From the comparison of the number of coordinated water and nitrate ions at various uranyl nitrate concentrations, it is evident that these two species compete for occupying the first solvation shell of the uranyl ion. Orientational dynamics of water molecules about different molecular axes of water in the vicinity of uranyl ions have also been investigated and decreasing orientational mobility of water with increasing uranyl concentration has been found. However, it is observed that the orientational dynamics remains more or less the same whether we consider all the water molecules in the aqueous solution or only the solvation shell water molecules. The effect of temperature on the translational and orientational characteristics of the aqueous uranyl solutions has also been studied in detail. PMID- 26439496 TI - The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers. AB - Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional mechanism, but its genomic landscape and clinical relevance in cancer have not been investigated systematically. We characterized the global A-to-I RNA editing profiles of 6,236 patient samples of 17 cancer types from The Cancer Genome Atlas and revealed a striking diversity of altered RNA-editing patterns in tumors relative to normal tissues. We identified an appreciable number of clinically relevant editing events, many of which are in noncoding regions. We experimentally demonstrated the effects of several cross-tumor nonsynonymous RNA editing events on cell viability and provide the evidence that RNA editing could selectively affect drug sensitivity. These results highlight RNA editing as an exciting theme for investigating cancer mechanisms, biomarkers, and treatments. PMID- 26439498 TI - Host Transcriptional Profiles and Immunopathologic Response following Mycobacterium avium subsp. paratuberculosis Infection in Mice. AB - Paratuberculosis or Johne's disease is a chronic granulomatous enteropathy in ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP) infection. In the present study, we examined the host response to MAP infection in spleens of mice in order to investigate the host immunopathology accompanying host pathogen interaction. Transcriptional profiles of the MAP-infected mice at 3 and 6 weeks p.i. showed severe histopathological changes, whereas those at 12 weeks p.i. displayed reduced lesion severity in the spleen and liver. MAP-infected mice at 3 and 6 weeks p.i. showed up-regulation of interferon-related genes, scavenger receptor, and complement components, suggesting an initial innate immune reaction, such as macrophage activation, bactericidal activity, and macrophage invasion of MAP. Concurrently, MAP-infected mice at 3 and 6 weeks p.i. were also suggested to express M2 macrophage phenotype with up-regulation of Mrc1, and Marco and down-regulation of MHC class II, Ccr7, and Irf5, and canonical pathways related to the T cell response including ICOS-ICOSL signaling in T helper cells, calcium-induced T lymphocyte apoptosis, and CD28 signaling in T helper cell. These results provide information which furthers the understanding of the immunopathologic response to MAP infection in mice, thereby providing insights valuable for research into the pathogenesis for MAP infection. PMID- 26439499 TI - Comparison of intra-ocular pressure changes with liquid or flat applanation interfaces in a femtosecond laser platform. AB - Cataract surgery is the most common surgical procedure and femtosecond laser assisted cataract surgery (FLACS) has gained increased popularity. FLACS requires the application of a suction device to stabilize the laser head and focus the laser beam accurately. This may cause a significant escalation in intra-ocular pressure (IOP), which poses potential risks for patients undergoing cataract surgery. In this study we aimed to assess the effect of the Ziemer LDV Z8 femtosecond cataract machine on IOP. We demonstrated through a porcine model that IOP was significantly higher with a flat interface but could be abrogated by reducing surgical compression and vacuum. Pressure was lower with a liquid interface, and further altering angulation of the laser arm could reduce the IOP to 36 mmHg. A pilot series in patients showed comparable pressure rises with the porcine model (30 mmHg). These strategies may improve the safety profile in patients vulnerable to high pressure when employing FLACS with the Ziemer LDV Z8. PMID- 26439501 TI - Genetic Tailors: CTCF and Cohesin Shape the Genome During Evolution. AB - Research into chromosome structure and organization is an old field that has seen some fascinating progress in recent years. Modern molecular methods that can describe the shape of chromosomes have begun to revolutionize our understanding of genome organization and the mechanisms that regulate gene activity. A picture is beginning to emerge of chromatin loops representing a widespread organizing principle of the chromatin fiber and the proteins cohesin and CCCTC-binding factor (CTCF) as key players anchoring such chromatin loops. Here we review our current understanding of the features of CTCF- and cohesin-mediated genome organization and how their evolution may have helped to shape genome structure. PMID- 26439502 TI - Dating Tips for Divergence-Time Estimation. AB - The molecular clock is the only viable means of establishing an accurate timescale for Life on Earth, but it remains reliant on a capricious fossil record for calibration. 'Tip-dating' promises a conceptual advance, integrating fossil species among their living relatives using molecular/morphological datasets and evolutionary models. Fossil species of known age establish calibration directly, and their phylogenetic uncertainty is accommodated through the co-estimation of time and topology. However, challenges remain, including a dearth of effective models of morphological evolution, rate correlation, the non-random nature of missing characters in fossil data, and, most importantly, accommodating uncertainty in fossil age. We show uncertainty in fossil-dating propagates to divergence-time estimates, yielding estimates that are older and less precise than those based on traditional node calibration. Ultimately, node and tip calibrations are not mutually incompatible and may be integrated to achieve more accurate and precise evolutionary timescales. PMID- 26439500 TI - The Brain Activity in Brodmann Area 17: A Potential Bio-Marker to Predict Patient Responses to Antiepileptic Drugs. AB - In this study, we aimed to predict newly diagnosed patient responses to antiepileptic drugs (AEDs) using resting-state functional magnetic resonance imaging tools to explore changes in spontaneous brain activity. We recruited 21 newly diagnosed epileptic patients, 8 drug-resistant (DR) patients, 11 well healed (WH) patients, and 13 healthy controls. After a 12-month follow-up, 11 newly diagnosed epileptic patients who showed a poor response to AEDs were placed into the seizures uncontrolled (SUC) group, while 10 patients were enrolled in the seizure-controlled (SC) group. By calculating the amplitude of fractional low frequency fluctuations (fALFF) of blood oxygen level-dependent signals to measure brain activity during rest, we found that the SUC patients showed increased activity in the bilateral occipital lobe, particularly in the cuneus and lingual gyrus compared with the SC group and healthy controls. Interestingly, DR patients also showed increased activity in the identical cuneus and lingual gyrus regions, which comprise Brodmann's area 17 (BA17), compared with the SUC patients; however, these abnormalities were not observed in SC and WH patients. The receiver operating characteristic (ROC) curves indicated that the fALFF value of BA17 could differentiate SUC patients from SC patients and healthy controls with sufficient sensitivity and specificity prior to the administration of medication. Functional connectivity analysis was subsequently performed to evaluate the difference in connectivity between BA17 and other brain regions in the SUC, SC and control groups. Regions nearby the cuneus and lingual gyrus were found positive connectivity increased changes or positive connectivity changes with BA17 in the SUC patients, while remarkably negative connectivity increased changes or positive connectivity decreased changes were found in the SC patients. Additionally, default mode network (DMN) regions showed negative connectivity increased changes or negative changes with BA17 in the SUC patients. The abnormal increased in BA17 activity may be a key point that plays a substantial role in facilitating seizure onset. PMID- 26439503 TI - Reaching Consensus by Allowing Moments of Indecision. AB - Group decision-making processes often turn into a drawn out and costly battle between two opposing subgroups. Using analytical arguments based on a master equation description of the opinion dynamics occurring in a three-state model of cooperatively interacting units, we show how the capability of a social group to reach consensus can be enhanced when there is an intermediate state for indecisive individuals to pass through. The time spent in the intermediate state must be relatively short compared to that of the two polar states in order to create the beneficial effect. Furthermore, the cooperation between individuals must not be too low, as the benefit to consensus is possible only when the cooperation level exceeds a specific threshold. We also discuss how zealots, agents that remain in one state forever, can affect the consensus among the rest of the population by counteracting the benefit of the intermediate state or making it virtually impossible for an opposition to form. PMID- 26439504 TI - Clinical Implication of Serine Metabolism-Associated Enzymes in Colon Cancer. AB - PURPOSE: Recently, enzymes of the serine synthetic pathway (SSP) have been suggested as key player in the metabolic adaptation of oncogenesis. We assessed the expression of enzymes of the SSP in colonic tumor tissue (TT) and paired normal tissue (pNT) and the prognostic implications. METHODS: From 2006 to 2010, we included 486 patients with colon cancer who underwent curative surgery at Kyungpook National University Hospital. Phosphoglycerate dehydrogenase (PHGDH), pyruvate dehydrogenase kinase (PDK) 1, PDK2, pyruvate kinase M2 (PKM2), and phosphoserine aminotransferase (PSAT) expression were investigated by immunohistochemical staining (IHC) in TT and pNT. The IHC values were calculated by multiplying intensity by proportion. The final score was classified as follows: 0-2 as negative and 3-12 as positive. RESULTS: During the median follow up duration of 55.5 months (37.4-90.6), 78 patients experienced recurrence. The expression of PHGDH, PDK1, and PSAT was significantly higher in TT than pNT (p < 0.001 for each). The univariate analysis for relapse-free survival revealed that TT PDK2 positivity was the only positive prognostic factor (p = 0.023). However, the expression of TT PDK2 did not represent a prognostic value in multivariate analysis. CONCLUSIONS: In conclusion, PHGDH, PDK1, and PSAT were significantly increased in colonic TT compared with pNT. The prognostic implication of these enzymes needs to be further investigated. PMID- 26439505 TI - Prostate cancer: Wnt signalling induces resistance. PMID- 26439506 TI - Infection: PrEParation to be PROUD of. PMID- 26439507 TI - Prostate cancer: How to differenti-8 Gleason scores? PMID- 26439508 TI - Self-reported Occupational Skin Exposure and Risk of Physician-certified Long term Sick Leave: A Prospective Study of the General Working Population of Norway. AB - Little is known about the contribution of occupational skin exposure as a risk factor for physician-certified long-term sick leave in the general working population of Norway. This study drew a cohort (n = 12,255; response at baseline 69.9%) randomly from the general population of Norway. Occupational skin exposure (in 2009) was measured based on 5 items. The outcome of interest was physician certified long-term sick leave >= 16 days during 2010. Statistical adjustment for psychosocial and mechanical occupational exposures was performed. Long-term sick leave was predicted by occupational skin exposure to cleaning products (odds ratio (OR) 1.7; 95% confidence interval (95% CI) 1.1-2.5) and waste (OR 2.1; 95% CI 1.1-3.7) among men, and occupational skin exposure to water (OR 1.3; 95% CI 1.0-1.6) among women. The estimated population attributable risk for occupational skin exposure was 14.5%, which emphasizes its contribution as an important risk factor for long-term sick leave. PMID- 26439509 TI - Hydrodynamic schooling of flapping swimmers. AB - Fish schools and bird flocks are fascinating examples of collective behaviours in which many individuals generate and interact with complex flows. Motivated by animal groups on the move, here we explore how the locomotion of many bodies emerges from their flow-mediated interactions. Through experiments and simulations of arrays of flapping wings that propel within a collective wake, we discover distinct modes characterized by the group swimming speed and the spatial phase shift between trajectories of neighbouring wings. For identical flapping motions, slow and fast modes coexist and correspond to constructive and destructive wing-wake interactions. Simulations show that swimming in a group can enhance speed and save power, and we capture the key phenomena in a mathematical model based on memory or the storage and recollection of information in the flow field. These results also show that fluid dynamic interactions alone are sufficient to generate coherent collective locomotion, and thus might suggest new ways to characterize the role of flows in animal groups. PMID- 26439510 TI - Optical antennas with multiple plasmonic nanoparticles for tip-enhanced Raman microscopy. AB - Tip-enhanced Raman spectroscopy (TERS) has recently become one of the most important tools for analyzing advanced nano-devices and nano-materials, because it allows strong enhancement of weak Raman signal from the nanometric volume of a sample. However, consistent enhancement in TERS is still an issue and scientists have been struggling to fabricate good tips for reliable, strong and reproducible enhancement. There is a strong need to study the morphology and the arrangement of metal nanostructures near the tip apex for efficient plasmonic enhancement in TERS. Here, we present a study on the metal grains attached to the tip surface for producing higher and much consistent enhancement in TERS. Our study shows that the plasmonic enhancement strongly depends on the number of grains and on the their separations. We found through simulations that multiple grains arranged closely but discretely on a dielectric probe act as an efficient plasmonic antenna and that enhancement in TERS is maximum for an optimized number of grains. The number of grains and the nano-gap between them are crucial for reproducible enhancement. This promising result, which we also demonstrate and prove by experiments, will bring TERS to a new level, where it can be utilized with more confidence of large reproducible enhancement for those nano-sized samples that have extremely weak Raman scattering. PMID- 26439511 TI - Carbon dioxide capture and utilization: using dinuclear catalysts to prepare polycarbonates. AB - The copolymerization of epoxides, including cyclohexene oxide and vinyl cyclohexene oxide with carbon dioxide are presented. These processes are catalyzed using a homogeneous di-zinc complex that shows good activity and very high selectivities for polycarbonate polyol formation. The polymerizations are investigated in the presence of different amounts of exogenous reagents, including water, diols and diamines, as models for common contaminants in any carbon dioxide capture and utilization scenario. PMID- 26439512 TI - Coalescence of drops in a 2D microchannel: critical transitions to autocatalytic behaviour. AB - A single coalescence event in a 2D concentrated emulsion in a microchannel can trigger an avalanche of similar events that can destabilize the entire assembly of drops. The sensitive dependence of the process on numerous parameters makes the propagation dynamics appear probabilistic. In this article, a stochastic simulation framework is proposed to understand this collective behavior in a system employing a large number of drops. We discover that the coalescence propagation dynamics exhibit a critical behavior where two outcomes are favored: no avalanche and large avalanches. Our analysis reveals that this behavior is a result of the inherent autocatalytic nature of the process. The effect of the aspect ratio of the drop assembly on the propagation dynamics is studied. We generate a parametric plot that shows the region of the parameter space where the propagation, averaged over the ensemble, is autocatalytic: where the possibility of near destabilization of the drop assembly appears. PMID- 26439514 TI - The Washington University Central Neuroimaging Data Archive. AB - Since the early 2000's, much of the neuroimaging work at Washington University (WU) has been facilitated by the Central Neuroimaging Data Archive (CNDA), an XNAT-based imaging informatics system. The CNDA is uniquely related to XNAT, as it served as the original codebase for the XNAT open source platform. The CNDA hosts data acquired in over 1000 research studies, encompassing 36,000 subjects and more than 60,000 imaging sessions. Most imaging modalities used in modern human research are represented in the CNDA, including magnetic resonance (MR), positron emission tomography (PET), computed tomography (CT), nuclear medicine (NM), computed radiography (CR), digital radiography (DX), and ultrasound (US). However, the majority of the imaging data in the CNDA are MR and PET of the human brain. Currently, about 20% of the total imaging data in the CNDA is available by request to external researchers. CNDA's available data includes large sets of imaging sessions and in some cases clinical, psychometric, tissue, or genetic data acquired in the study of Alzheimer's disease, brain metabolism, cancer, HIV, sickle cell anemia, and Tourette syndrome. PMID- 26439515 TI - Mechanisms of hemispheric lateralization: Asymmetric interhemispheric recruitment in the face perception network. AB - Perceiving human faces constitutes a fundamental ability of the human mind, integrating a wealth of information essential for social interactions in everyday life. Neuroimaging studies have unveiled a distributed neural network consisting of multiple brain regions in both hemispheres. Whereas the individual regions in the face perception network and the right-hemispheric dominance for face processing have been subject to intensive research, the functional integration among these regions and hemispheres has received considerably less attention. Using dynamic causal modeling (DCM) for fMRI, we analyzed the effective connectivity between the core regions in the face perception network of healthy humans to unveil the mechanisms underlying both intra- and interhemispheric integration. Our results suggest that the right-hemispheric lateralization of the network is due to an asymmetric face-specific interhemispheric recruitment at an early processing stage - that is, at the level of the occipital face area (OFA) but not the fusiform face area (FFA). As a structural correlate, we found that OFA gray matter volume was correlated with this asymmetric interhemispheric recruitment. Furthermore, exploratory analyses revealed that interhemispheric connection asymmetries were correlated with the strength of pupil constriction in response to faces, a measure with potential sensitivity to holistic (as opposed to feature-based) processing of faces. Overall, our findings thus provide a mechanistic description for lateralized processes in the core face perception network, point to a decisive role of interhemispheric integration at an early stage of face processing among bilateral OFA, and tentatively indicate a relation to individual variability in processing strategies for faces. These findings provide a promising avenue for systematic investigations of the potential role of interhemispheric integration in future studies. PMID- 26439513 TI - White matter microstructure mediates the relationship between cardiorespiratory fitness and spatial working memory in older adults. AB - White matter structure declines with advancing age and has been associated with a decline in memory and executive processes in older adulthood. Yet, recent research suggests that higher physical activity and fitness levels may be associated with less white matter degeneration in late life, although the tract specificity of this relationship is not well understood. In addition, these prior studies infrequently associate measures of white matter microstructure to cognitive outcomes, so the behavioral importance of higher levels of white matter microstructural organization with greater fitness levels remains a matter of speculation. Here we tested whether cardiorespiratory fitness (VO2max) levels were associated with white matter microstructure and whether this relationship constituted an indirect pathway between cardiorespiratory fitness and spatial working memory in two large, cognitively and neurologically healthy older adult samples. Diffusion tensor imaging was used to determine white matter microstructure in two separate groups: Experiment 1, N=113 (mean age=66.61) and Experiment 2, N=154 (mean age=65.66). Using a voxel-based regression approach, we found that higher VO2max was associated with higher fractional anisotropy (FA), a measure of white matter microstructure, in a diverse network of white matter tracts, including the anterior corona radiata, anterior internal capsule, fornix, cingulum, and corpus callosum (PFDR-corrected<.05). This effect was consistent across both samples even after controlling for age, gender, and education. Further, a statistical mediation analysis revealed that white matter microstructure within these regions, among others, constituted a significant indirect path between VO2max and spatial working memory performance. These results suggest that greater aerobic fitness levels are associated with higher levels of white matter microstructural organization, which may, in turn, preserve spatial memory performance in older adulthood. PMID- 26439516 TI - QSAR model for predicting cell viability of human embryonic kidney cells exposed to SiO2 nanoparticles. AB - A predictive model for the viability (%) of cultured human embryonic kidney cells (HEK293) exposed to 20 and 50 nm silica nanoparticles was built using 'optimal descriptors' as mathematical functions of size, concentration and exposure time. The calculation was carried out with CORAL software (http://www.insilico.eu/coral/) on five random splits of combined systems (particle size-particle concentration-cell exposure time) into training, calibration, and validation sets. The R(2) values of the best models were above 0.68. The average statistical quality of the model for the viability (%) of HEK293 exposed to different concentrations of silica nanoparticles measured by MTT assay is satisfactory. PMID- 26439517 TI - Source apportionment and health risk assessment of trace metals in surface soils of Beijing metropolitan, China. AB - Understanding the exposure risks of trace metals in contamination soils and apportioning their sources are the basic preconditions for soil pollution prevention and control. In this study, a detailed investigation was conducted to assess the health risks of trace metals in surface soils of Beijing which is one of the most populated cities in the world and to apportion their potential sources. The data set of metals for 12 elements in 240 soil samples was collected. Pollution index and enrichment factor were used to identify the general contamination characteristic of soil metals. The probabilistic risk model was employed for health risk assessment, and a chemometrics technique, multivariate curve resolution-weighted alternating least squares (MCR-WALS), was applied to apportion sources. Results suggested that the soils in Beijing metropolitan region were contaminated by Hg, Cd, Cu, As, and Pb in varying degree, lying in the moderate pollution level. As a whole, the health risks posed by soil metals were acceptable or close to tolerable. Comparatively speaking, children and adult females were the relatively vulnerable populations for the non carcinogenic and carcinogenic risks, respectively. Atmospheric deposition, fertilizers and agrochemicals, and natural source were apportioned as the potential sources determining the contents of trace metals in soils of Beijing area with contributions of 15.5%-16.4%, 5.9%-7.7% and 76.0%-78.6%, respectively. PMID- 26439518 TI - Fluoride decreased the sperm ATP of mice through inhabiting mitochondrial respiration. AB - Fluoride-induced low sperm motility was observed in accumulated investigations. However, the effect of fluoride exposure on ATP generation which is essential to sperm motility remains to be elucidated. In this study, 120 healthy male mice were orally administrated with 0, 25, 50, and 100 mg L(-1) NaF for 90 d. Results showed that compared with controls, fluoride ingestion significantly reduced sperm count, survival, as well as mobility and total ATP level in sperm untreated with carbonyl cyanide m-chlorophenylhydrazone (CCCP) or pyruvate, which was used to establish glycolysis or mitochondrial respiration model, respectively. Data further revealed that sperm mobility and ATP level under mitochondrial respiration condition were significantly suppressed, while no statistical difference occurred in the model of glycolysis, indicating ATP derived from mitochondria was affected. Moreover, mRNA expressions of mitochondrial cytochrome b (mt-Cytb) and cytochrome c oxidase subunit 2 (mt-COX2), two important molecules in mitochondrial electron transport chain (ETC), were down-regulated in all fluoride treatment groups. Mitochondria in sperm of mice exposed to 100 mg L(-1) NaF appeared to be irregular and vacuolated. These findings suggested that decreased sperm motility induced by fluoride may result from low ATP generation due to the disturbed ETC in sperm mitochondrial. PMID- 26439519 TI - Influence of nitrite accumulation on "Candidatus Accumulibacter" population structure and enhanced biological phosphorus removal from municipal wastewater. AB - A modified University of Cape Town (MUCT) process was used to treat real municipal wastewater with low carbon to nitrogen ratio (C/N). To our knowledge, this is the first study where the influence of nitrite accumulation on "Candidatus Accumulibacter" clade-level population structure was investigated during nitritation establishment and destruction. Real time quantitative PCR assays were conducted using the polyphosphate kinase 1 gene (ppk1) as a genetic marker. Abundances of total "Candidatus Accumulibacter", the relative distributions and population structure of the five "Candidatus Accumulibacter" clades were characterized. Under complete nitrification, clade I using nitrate as electron acceptor was below 5% of total "Candidatus Accumulibacter". When the reactor was transformed into nitritation, clade I gradually disappeared. Clade IID using nitrite as electron acceptor for denitrifying phosphorus (P) removal was always the dominant "Candidatus Accumulibacter" throughout the operational period. This clade was above 90% on average in total "Candidatus Accumulibacter", even up to nearly 100%, which was associated with good performance of denitrifying P removal via nitrite pathway. The nitrite concentrations affected the abundance of clade IID. The P removal was mainly completed by anoxic P uptake of about 88%. The P removal efficiency clearly had a positive correlation with the nitrite accumulation ratio. Under nitritation, the P removal efficiency was 30% higher than that under complete nitrification, suggesting that nitrite was appropriate as electron acceptor for denitrifying P removal when treating carbon limited wastewater. PMID- 26439520 TI - The key to accuracy of zygoma repositioning: Suitability of the SynpliciTi customized guide-plates. AB - This study aimed at assessing the suitability and accuracy for secondary zygoma repositioning of custom-made drilling guides and plates designed from a computer assisted reversed planning. Mini-plates and pre-drilling guides were designed starting from the virtual planning of the repositioned zygoma. The pilot holes were drilled first during surgery. The zygoma was repositioned by inserting the screws in the pilot holes using the custom-made plates. Surgical planning and postoperative CT-scan were superimposed. The distances between each point of the planned and final zygoma positions indicated the accuracy of repositioning. We included 11 zygoma repositioning procedures in 10 consecutive patients. The medians of the distances between the planned and final zygoma positions in this cohort ranged from 0.05 mm to 0.38 mm (0.20 mm on average). 93%, 81%, and 57% of the points of the planned and final zygoma were less than 2 mm, 1 mm, and 0.5 mm away, respectively. The SynpliciTi customized guide-plate system allowed achieving highly accurate zygoma repositioning in short operative times in this series, without the need for expensive equipment with difficult implementation. Larger cohorts are needed to assess the overall benefit and cost-effectiveness of the SynpliciTi. PMID- 26439521 TI - Changes in anteroposterior position and inclination of the maxillary incisors after surgical-orthodontic treatment of skeletal class III malocclusions. AB - PURPOSE: The purpose of this study was to evaluate and compare the anteroposterior (AP) position and inclination of the maxillary incisors in subjects with class I normal occlusion and a harmonious profile with patients with skeletal class III malocclusions, and to investigate the changes in maxillary incisor inclination and AP position after surgical-orthodontic treatment in class III patients. MATERIAL AND METHODS: Sixty-five subjects (35 female and 30 male; mean age: 21.8 +/- 3.89 years) with normal profiles and class I skeletal and dental patterns were selected as a control sample. Sixty-seven patients (38 female and 29 male; mean age: 21.3 +/- 3.31 years) with skeletal and dental class III malocclusions who sought surgical-orthodontic treatment were used as the study sample. Subjects were asked to smile and profile photographs were taken with the head in a natural position and the maxillary central incisors and the forehead in full view; cephalograms were taken and superimposed on the profile pictures according to the outline of the forehead and nose. Forehead inclination, maxillary incisor facial inclination and the AP position of the maxillary central incisor relative to the forehead (FAFFA) were measured on the integrated images and statistical analyses were performed. RESULTS: In both groups, there were no significant male/female differences in either the maxillary central incisor inclination or AP position. Female subjects had a significantly steeper forehead inclination compared with males (P < 0.001) in both groups. After combined surgical-orthodontic treatment, the significant labial inclination (P < 0.001) and posterior positioning (P < 0.001) of the maxillary central incisors had been corrected to close to normal range (P > 0.05). In the control group, 84.6% had the facial axial point (FA) of their maxillary central incisors positioned between lines through the forehead facial axis (FFA) point and the glabella. In the study group, however, 79.1% had the maxillary central incisors positioned posterior to the line through the FFA point and the difference with the control group was statistically significant (P < 0.001). The position of the maxillary central incisors was strongly correlated with forehead inclination in the control sample (r(2) = 0.456; P < 0.01), but only a poor correlation was detected in the class III group (r(2) = 0.177; P > 0.05). CONCLUSIONS: With the integrated radiograph-photograph method, the lateral cephalogram was reoriented, which makes it possible to accurately measure the variables on profile photographs. The AP position and inclination of the maxillary central incisors relative to the forehead plays an important role in the esthetics of the profile during smiling and could be an important variable to be considered during diagnosis and treatment planning. PMID- 26439522 TI - Walking with eyes closed is easier than walking with eyes open without visual cues: The Romberg task versus the goggle task. AB - BACKGROUND: The Romberg test, with the subject standing and with eyes closed, gives diagnostic arguments for a proprioceptive disorder. Closing the eyes is also used in balance rehabilitation as a main way to stimulate neural plasticity with proprioceptive, vestibular and even cerebellar disorders. Nevertheless, standing and walking with eyes closed or with eyes open in the dark are certainly 2 different tasks. We aimed to compare walking with eyes open, closed and wearing black or white goggles in healthy subjects. METHODS: A total of 50 healthy participants were randomly divided into 2 protocols and asked to walk on a 5-m pressure-sensitive mat, under 3 conditions: (1) eyes open (EO), eyes closed (EC) and eyes open with black goggles (BG) and (2) EO, EO with BG and with white goggles (WG). Gait was described by velocity (m.s(-1)), double support (% gait cycle), gait variability index (GVI/100) and exit from the mat (%). Analysis involved repeated measures Anova, Holm-Sidak's multiple comparisons test for parametric parameters (GVI) and Dunn's multiple comparisons test for non parametric parameters. RESULTS: As compared with walking with EC, walking with BG produced lower median velocity, by 6% (EO 1.26; BG 1.01 vs EC 1.07 m.s(-1), P=0.0328), and lower mean GVI, by 8% (EO 91.8; BG 66.8 vs EC 72.24, P=0.009). Parameters did not differ between walking under the BG and WG conditions. CONCLUSION: The goggle task increases the difficulty in walking with visual deprivation compared to the Romberg task, so the goggle task can be proposed to gradually increase the difficulty in walking with visual deprivation (from eyes closed to eyes open in black goggles). PMID- 26439523 TI - Analysis of Chuanxiong Rhizoma and its active components by Fourier transform infrared spectroscopy combined with two-dimensional correlation infrared spectroscopy. AB - As complicated mixture systems, active components of Chuanxiong Rhizoma are very difficult to identify and discriminate. In this paper, the macroscopic IR fingerprint method including Fourier transform infrared spectroscopy (FT-IR), the second derivative infrared spectroscopy (SD-IR) and two-dimensional correlation infrared spectroscopy (2DCOS-IR), was applied to study and identify Chuanxiong raw materials and its different segmented production of HPD-100 macroporous resin. Chuanxiong Rhizoma is rich in sucrose. In the FT-IR spectra, water eluate is more similar to sucrose than the powder and the decoction. Their second derivative spectra amplified the differences and revealed the potentially characteristic IR absorption bands and combined with the correlation coefficient, concluding that 50% ethanol eluate had more ligustilide than other eluates. Finally, it can be found from 2DCOS-IR spectra that proteins were extracted by ethanol from Chuanxiong decoction by HPD-100 macroporous resin. It was demonstrated that the above three-step infrared spectroscopy could be applicable for quick, non-destructive and effective analysis and identification of very complicated and similar mixture systems of traditional Chinese medicines. PMID- 26439524 TI - SERS substrates fabricated using ceramic filters for the detection of bacteria. AB - SERS substrates were fabricated by filtering either Ag or Au colloidal particles onto rigid, ceramic filters - onto which suspensions of bacteria were then filtered. SERS spectra of the bacteria were obtained using a Raman spectrometer that has an 'orbital raster scan' capability. It was shown that bacteria samples prepared in this manner were uniformly distributed onto the surface of the SERS substrate. The effect of common buffer systems on the SERS spectra was investigated and the utility of using the SERS technique for speciation of bacteria was explored. PMID- 26439525 TI - Mixed hemimicelles solid-phase extraction based on sodium dodecyl sulfate (SDS) coated nano-magnets for the spectrophotometric determination of Fingolomid in biological fluids. AB - In this study, mixed hemimicelles solid-phase extraction (SPE) based on sodium dodecyl sulfate (SDS)-coated nano-magnets Fe3O4 was investigated as a novel method for the separation and determination of Fingolimod (FLM) in water, urine and plasma samples prior to spectrophotometeric determination. Due to the high surface area of these new sorbents and the excellent adsorption capacity after surface modification by SDS, satisfactory extraction recoveries can be produced. The main factors affecting the adsolubilization of analysts, such as pH, surfactant and adsorbent amounts, ionic strength, extraction time and desorption conditions were studied and optimized. Under the selected conditions, FLM has been quantitatively extracted. The accuracy of the method was evaluated by recovery measurements on spiked samples, and good recoveries of 96%, 95% and 88% were observed for water, urine and plasma respectively. Proper linear behaviors over the investigated concentration ranges of 2-26, 2-17 and 2-13 mg/L with good coefficients of determination, 0.998, 0.997 and 0.995 were achieved for water, urine and plasma samples, respectively. To the best of our knowledge, this is the first time that a mixed hemimicelles SPE method based on magnetic separation and nanoparticles has been used as a simple and sensitive method for monitoring of FLM in water and biological samples. PMID- 26439526 TI - Validated derivative and ratio derivative spectrophotometric methods for the simultaneous determination of levocetirizine dihydrochloride and ambroxol hydrochloride in pharmaceutical dosage form. AB - Three simple, precise, accurate and validated derivative spectrophotometric methods have been developed for the simultaneous determination of levocetirizine dihydrochloride (LCD) and ambroxol hydrochloride (ABH) in bulk powder and in pharmaceutical formulations. The first method is a first derivative spectrophotometric method ((1)D) using a zero-crossing technique of measurement at 210.4 nm for LCD and at 220.0 nm for ABH. The second method employs a second derivative spectrophotometry ((2)D) where the measurements were carried out at 242.0 and 224.4 nm for LCD and ABH, respectively. In the third method, the first derivative of the ratio spectra was calculated and the first derivative of the ratio amplitudes at 222.8 and 247.2 nm was selected for the determination of LCD and ABH, respectively. Calibration graphs were established in the ranges of 1.0 20.0 MUg mL(-1) for LCD and 4.0-20.0 MUg mL(-1) for ABH using derivative and ratio first derivative spectrophotometric methods with good correlation coefficients. The developed methods have been successfully applied to the simultaneous determination of both drugs in commercial tablet dosage form. PMID- 26439527 TI - Cell-Type-Specific Sensorimotor Processing in Striatal Projection Neurons during Goal-Directed Behavior. AB - Goal-directed sensorimotor transformation drives important aspects of mammalian behavior. The striatum is thought to play a key role in reward-based learning and action selection, receiving glutamatergic sensorimotor signals and dopaminergic reward signals. Here, we obtain whole-cell membrane potential recordings from the dorsolateral striatum of mice trained to lick a reward spout after a whisker deflection. Striatal projection neurons showed strong task-related modulation, with more depolarization and action potential firing on hit trials compared to misses. Direct pathway striatonigral neurons, but not indirect pathway striatopallidal neurons, exhibited a prominent early sensory response. Optogenetic stimulation of direct pathway striatonigral neurons, but not indirect pathway striatopallidal neurons, readily substituted for whisker stimulation evoking a licking response. Our data are consistent with direct pathway striatonigral neurons contributing a "go" signal for goal-directed sensorimotor transformation leading to action initiation. VIDEO ABSTRACT. PMID- 26439528 TI - Even-Skipped(+) Interneurons Are Core Components of a Sensorimotor Circuit that Maintains Left-Right Symmetric Muscle Contraction Amplitude. AB - Bilaterally symmetric motor patterns--those in which left-right pairs of muscles contract synchronously and with equal amplitude (such as breathing, smiling, whisking, and locomotion)--are widespread throughout the animal kingdom. Yet, surprisingly little is known about the underlying neural circuits. We performed a thermogenetic screen to identify neurons required for bilaterally symmetric locomotion in Drosophila larvae and identified the evolutionarily conserved Even skipped(+) interneurons (Eve/Evx). Activation or ablation of Eve(+) interneurons disrupted bilaterally symmetric muscle contraction amplitude, without affecting the timing of motor output. Eve(+) interneurons are not rhythmically active and thus function independently of the locomotor CPG. GCaMP6 calcium imaging of Eve(+) interneurons in freely moving larvae showed left-right asymmetric activation that correlated with larval behavior. TEM reconstruction of Eve(+) interneuron inputs and outputs showed that the Eve(+) interneurons are at the core of a sensorimotor circuit capable of detecting and modifying body wall muscle contraction. PMID- 26439529 TI - Cortical and Subcortical Contributions to Short-Term Memory for Orienting Movements. AB - Neural activity in frontal cortical areas has been causally linked to short-term memory (STM), but whether this activity is necessary for forming, maintaining, or reading out STM remains unclear. In rats performing a memory-guided orienting task, the frontal orienting fields in cortex (FOF) are considered critical for STM maintenance, and during each trial display a monotonically increasing neural encoding for STM. Here, we transiently inactivated either the FOF or the superior colliculus and found that the resulting impairments in memory-guided orienting performance followed a monotonically decreasing time course, surprisingly opposite to the neural encoding. A dynamical attractor model in which STM relies equally on cortical and subcortical regions reconciled the encoding and inactivation data. We confirmed key predictions of the model, including a time dependent relationship between trial difficulty and perturbability, and substantial, supralinear, impairment following simultaneous inactivation of the FOF and superior colliculus during memory maintenance. PMID- 26439530 TI - A Large-Scale Circuit Mechanism for Hierarchical Dynamical Processing in the Primate Cortex. AB - We developed a large-scale dynamical model of the macaque neocortex, which is based on recently acquired directed- and weighted-connectivity data from tract tracing experiments, and which incorporates heterogeneity across areas. A hierarchy of timescales naturally emerges from this system: sensory areas show brief, transient responses to input (appropriate for sensory processing), whereas association areas integrate inputs over time and exhibit persistent activity (suitable for decision-making and working memory). The model displays multiple temporal hierarchies, as evidenced by contrasting responses to visual versus somatosensory stimulation. Moreover, slower prefrontal and temporal areas have a disproportionate impact on global brain dynamics. These findings establish a circuit mechanism for "temporal receptive windows" that are progressively enlarged along the cortical hierarchy, suggest an extension of time integration in decision making from local to large circuits, and should prompt a re evaluation of the analysis of functional connectivity (measured by fMRI or electroencephalography/magnetoencephalography) by taking into account inter-areal heterogeneity. PMID- 26439532 TI - Many Light Touches Convey the Message. AB - Our attraction to precision and symmetry in everyday life must be put aside to appreciate how natural selection favors networks governed by weak interactions, multivalency, and proteins described as low complexity (LC) and/or intrinsically disordered (ID). Phosphorylation, ubiquitination, and glycosylation of proteins often act as weak docking sites for multivalent adaptor proteins in the formation of membrane-associated and soluble complexes that mediate information flow in cells. Multiple post-translational modification (PTM) sites together with LC and ID regions in proteins can mediate phase transition from soluble complexes to liquid droplets in the cytoplasm or tethering to the membrane. Although compositionally complex and highly dynamic, these systems display remarkable control of specificity, timing, and switch-like behavior in signaling pathways. PMID- 26439531 TI - Microhomology-Mediated End Joining: A Back-up Survival Mechanism or Dedicated Pathway? AB - DNA double-strand breaks (DSBs) disrupt the continuity of chromosomes and their repair by error-free mechanisms is essential to preserve genome integrity. Microhomology-mediated end joining (MMEJ) is an error-prone repair mechanism that involves alignment of microhomologous sequences internal to the broken ends before joining, and is associated with deletions and insertions that mark the original break site, as well as chromosome translocations. Whether MMEJ has a physiological role or is simply a back-up repair mechanism is a matter of debate. Here we review recent findings pertaining to the mechanism of MMEJ and discuss its role in normal and cancer cells. PMID- 26439533 TI - Alexander Rich: In Memoriam. PMID- 26439535 TI - Molecular epidemiological analyses of Cryptosporidium parvum virus 1 (CSpV1), a symbiotic virus of Cryptosporidium parvum, in Japan. AB - We show that Cryptosporidium parvum virus 1 (CSpV1), a member of the family Partitiviridae, genus Cryspovirus that can infect Cryptosporidium parvum, is a new candidate for high-resolution tool for tracing C. parvum. CSpV1 was detected in all C. parvum-positive samples tested. Phylogenetic analysis of dsRNA1 sequence from CSpV1 can distinguish infected areas of C. parvum on the national level. Sequences detected in samples from Iwate prefecture and other islands (Tanegashima, and Okinawa) belonged to a single clade. This system can differentiate the samples from Hokkaido and south part of Japan as well as from other countries. Samples from Iwate, Tanegashima, and Okinawa belonged to a single subclade, respectively. Therefore, the CSpV1 dsRNA sequences reflect the regional distribution of their host and have potential as a high-resolution tool to trace C. parvum IIaA15G2R1 subtype. PMID- 26439536 TI - Sequential solvent induced phase transition extraction for profiling of endogenous phytohormones in plants by liquid chromatography-mass spectrometry. AB - In the current study, a novel method for high-throughput and sensitive determination of 12 phytohormones in plants was developed by using sequential solvent induced phase transition extraction (SIPTE) coupled with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). In sequential SIPTE, 0.1% formic acid (v/v) and 50mM NaHCO3 aqueous solution were used for enrichment and purification of alkaline and acidic phytohormones from the acetonitrile extract of plant tissues in sequence, in which hydrophobic solvent (toluene) was added to the acetonitrile aqueous mixture for driving the phase separation. Under optimized sequential SIPTE conditions, the phytohormones in acetonitrile extract of plant tissues could be effectively enriched and purified, which was in favor of the following UPLC-MS/MS analysis with less matrix effect. The phytohormones could be detected using the developed sequential SIPTE-UPLC-MS/MS method with the limits of the detection (LODs) ranging from 0.56 to 438.60pgmL(-1) and linear range over 2 orders of magnitude with correlation coefficients (r)>0.9970. The relative recoveries of the detected phytohormones were in the range of 85.1-114.6%. Finally, the proposed method was applied to simultaneous determination of endogenous phytohormones in different tissues of model plants (Oryza sativa and Arabidopsis thaliana) with small amount of sample size (5mg, fresh weight). The proposed method may be suitable for studying the distribution of phytohormones in model plants. PMID- 26439537 TI - Impact of anaemia treatment for left ventricular remodelling prior to initiation of dialysis in chronic kidney disease patients: Efficacy and stability of long acting erythropoietin stimulating agents. AB - AIM: Anaemia is a common complication in patients with chronic kidney disease (CKD), which may initiate or accelerate left ventricular (LV) hypertrophy (LVH). The present study is a retrospective analysis to assess whether anaemia treatment is independently associated with LV remodelling prior to initiation of dialysis in CKD patients. METHODS: Biochemical and physical values were collected over a period of more than 120 days prior to the initiation of dialysis in 27 patients with CKD. The left ventricular mass index (LVMI) was evaluated by echocardiography twice (at the baseline and the follow-up at the initiation of the dialysis period). RESULTS: Patients using long-acting erythropoietin stimulating agents (L-ESA) had the tendency of maintaining higher levels of haemoglobin (Hb) than those using short-acting ESA (S-ESA). Patients using L-ESA showed a more significant improvement in the erythropoietin resistance index (ERI) than those of using S-ESA. In a multivariate regression analysis, the average Hb level for the observational period, the level of Hb at the initiation of dialysis and the use of L-ESA were independently associated factors for the LVMI at the initiation of dialysis. A lower LVMI at the initiation of dialysis and an improvement of the LVMI during the observational period were detected in the highest tertile of average Hb (10.4 g/dL). CONCLUSION: Long-acting ESA was effective and stable when treating anaemia until the start of dialysis. It is important to treat anaemia for the prevention of LV remodelling in CKD patients. These findings have some therapeutic implications for treatment strategies for pre-dialysis patients. PMID- 26439534 TI - H2S: A Novel Gasotransmitter that Signals by Sulfhydration. AB - Hydrogen sulfide (H2S) is a member of the growing family of gasotransmitters. Once regarded as a noxious molecule predominantly present in the atmosphere, H2S is now known to be synthesized endogenously in mammals. H2S participates in a myriad of physiological processes ranging from regulation of blood pressure to neuroprotection. Its chemical nature precludes H2S from being stored in vesicles and acting on receptor proteins in the fashion of other chemical messengers. Thus, novel cellular mechanisms have evolved to mediate its effects. This review focuses on sulfhydration (or persulfidation), which appears to be the principal post-translational modification elicited by H2S. PMID- 26439538 TI - Luminescent (N^C^C) Gold(III) Complexes: Stabilized Gold(III) Fluorides. AB - We report the design, synthesis, and application of a (N^C^C)-ligand framework able to stabilize highly electron-deprived gold(III) species. This novel platform enabled the preparation of C(sp(2))-gold(III) fluorides for the first time in monomeric, easy-to-handle, bench-stable form by a Cl/F ligand-exchange reaction. Devoid of oxidative conditions or stoichiometric use of toxic Hg salts, this method was applied to the preparation of multiple [C(sp(2))-Au(III)-F] complexes, which were used as mechanistic probes for the study of the unique properties and intrinsic reactivity of Au-F bonds. The improved photophysical properties of [(N^C^C)Au(III)] complexes compared to classical pincer (C^N^C)-Au systems paves the way for the design of new late-transition-metal-based OLEDs. PMID- 26439539 TI - Introduction: The role of shame in psychoanalytic theory and practice. AB - Introducing three papers by Leon Wurmser, Claude Janin and John Steiner the author gives an overview of the development of the concept of shame in psychoanalytic theory and practice. Different aspects of the phenomenon of shame are being discussed including its relation to guilt, object relations and identity as well as the role of gaze when emerging from a psychic retreat. PMID- 26439540 TI - Silencing Nicotiana attenuata LHY and ZTL alters circadian rhythms in flowers. AB - The rhythmic opening/closing and volatile emissions of flowers are known to attract pollinators at specific times. That these rhythms are maintained under constant light or dark conditions suggests a circadian clock involvement. Although a forward and reverse genetic approach has led to the identification of core circadian clock components in Arabidopsis thaliana, the involvement of these clock components in floral rhythms has remained untested, probably because of the weak diurnal rhythms in A. thaliana flowers. Here, we addressed the role of these core clock components in the flowers of the wild tobacco Nicotiana attenuata, whose flowers open at night, emit benzyl acetone (BA) scents and move vertically through a 140 degrees arc. We first measured N. attenuata floral rhythms under constant light conditions. The results suggest that the circadian clock controls flower opening, BA emission and pedicel movement, but not flower closing. We generated transgenic N. attenuata lines silenced in the homologous genes of Arabidopsis LATE ELONGATED HYPOCOTYL (LHY) and ZEITLUPE (ZTL), which are known to be core clock components. Silencing NaLHY and NaZTL strongly altered floral rhythms in different ways, indicating that conserved clock components in N. attenuata coordinate these floral rhythms. PMID- 26439584 TI - Graphene-oxide-supported ultrathin Au nanowires: efficient electrocatalysts for borohydride oxidation. AB - We report stable ultrathin Au nanowires supported on reduced graphene oxide with outstanding electrocatalytic activity for borohydride oxidation. Electrochemical impedance spectroscopy measurements showed abnormal inductive behavior, indicative of surface reactivation. DFT calculations indicate that the origin of the high activity stems from the position of the Au d-band center. PMID- 26439541 TI - Algorithm for the management of ERCP-related perforations. AB - BACKGROUND AND AIMS: Perforation is a rare but serious adverse event of ERCP. There is no consensus to guide the clinician on the management of ERCP-related perforations, with particular controversy surrounding the immediate surgical management of postprocedurally detected duodenal perforation because of overextension of a sphincterotomy. Our aim was to assess patient outcomes using a predetermined algorithm based on managing ERCP-related duodenal perforations according to the mechanism of injury. METHODS: A retrospective single-center study of all consecutive patients with Stapfer type I and II perforations between 2000 and 2014 were included. Our institutional algorithm since 2000 dictated that Stapfer type I perforations (duodenal wall perforation, endoscope related) should be managed surgically unless prohibited by underlying comorbidities and Stapfer type II perforations (periampullary, sphincterotomy related) managed nonsurgically unless a deterioration in clinical status necessitated surgery. RESULTS: Sixty-one patients (mean age, 51 years; 80% women) were analyzed with Stapfer type I perforations diagnosed in 7 (11%) and type II in 54 (89%). A postprocedural diagnosis of perforation was made in 55 patients (90%). Four patients (7%) had Stapfer type II perforations that failed medical management and required surgery. The mean length of stay (LOS) in the entire cohort was 9.6 days with a low mortality rate of 3%. Systemic inflammatory response syndrome was observed in 18 patients (33%) with Stapfer type II perforations and was not associated with the need for surgery. Concurrent post-ERCP pancreatitis was diagnosed in 26 patients (43%) and was associated with an increased LOS. CONCLUSIONS: Stapfer type II perforations have excellent outcomes when managed medically. We validate an algorithm for the management of ERCP-related perforations and propose that it should function as a guide. PMID- 26439585 TI - Blood Volume Monitoring to Assist Fluid Management in Hemodialysis Patients. PMID- 26439586 TI - Fabrication of 2D Heterojunction in Graphene via Low Energy N2(+) Irradiation. AB - Substitutional doping in graphene is locally induced with very low energy nitrogen ions. Irradiated and nonirradiated areas exhibit different charge carrier densities and are separated by a sharp boundary, stable up to 750 degrees C. The way towards lithographic control of the electronic properties of graphene by ion irradiation is paved, providing a proof of principle for the fabrication of 2D graphene-based heterojunctions. PMID- 26439587 TI - Endoneurial edema in sural nerve may indicate recent onset inflammatory neuropathy. AB - INTRODUCTION: Sural nerve biopsy is an important means of establishing the diagnosis of inflammatory neuropathies. We investigated the diagnostic value of endoneurial edema. METHODS: Diagnostic sural nerve biopsies from 42 patients with inflammatory and 28 patients with noninflammatory neuropathies were re-evaluated for the presence of endoneurial edema. Edema was assessed on hematoxylin-eosin stained paraffin and frozen sections and on azure II-methylene blue stained semithin sections. We determined the area of endoneurial edema on digitized images in relation to the entire endoneurial area of each fascicle. RESULTS: Edema was more extensive in neuropathies with short disease duration (<=12 months) as compared to long duration (>12 months; P < 0.01). Edema in inflammatory neuropathies of <=12 months duration covered a larger area than in noninflammatory neuropathies (P < 0.01), and the extent of edema correlated negatively with disease duration (P < 0.05). CONCLUSIONS: Endoneurial edema may be a useful additional disease marker in inflammatory neuropathies of recent onset. PMID- 26439588 TI - Testing the Assessment of New Radiation Oncology Technology and Treatments framework using the evaluation of post-prostatectomy radiotherapy techniques. AB - INTRODUCTION: We tested the ability of the Assessment of New Radiation Oncology Technology and Treatments framework to determine the clinical efficacy and safety of intensity-modulated radiation therapy (IMRT) compared with 3-dimensional radiation therapy (3DCRT) for post-prostatectomy radiation therapy (PPRT) to support its timely health economic evaluation. METHODS: Treatment plans produced using FROGG guidelines provided dosimetry parameters for both techniques at 64 Gy and 70 Gy and were also used to model early and late outcome probabilities. Clinical parameters were derived from early toxicity and quality of life patient data, systematic literature review and expert opinion. Dosimetry parameters were correlated with the measures of clinical efficacy and safety. RESULTS: Data from two patient cohorts (29 and 27 respectively) were collected within the project timeframe, providing evidence for acute toxicity and quality of life, and dosimetric comparisons. Relative rates of tumour control probability (TCP) and normal tissue control probability (NTCP) modelling were readily derived from the planning exercise and demonstrated advantages in uncomplicated TCP for IMRT over 3DCRT, predominantly due to normal tissue sparing. The safety of IMRT delivery was demonstrated with TCP uncompromised by IMRT protocol violations, which achieved rectal sparing only by reducing minimum target dose and coverage. CONCLUSION: Sources of desk-top and patient-based evidence were successfully used to demonstrate potential improved clinical efficacy and safety of applying dose escalation using IMRT instead of 3DCRT in PPRT. PMID- 26439589 TI - Direct Catalytic Asymmetric Mannich-Type Reaction of alpha-N3 Amide. AB - An alpha-N3 7-azaindoline amide serves as a latent enolate to directly engage in an asymmetric Mannich-type reaction with N-thiophosphinoyl imines by the action of a cooperative catalyst. The thus-obtained highly enantioenriched anti-adduct was transformed into beta-amino-alpha-azido acid in high yield by simple acidic treatment. PMID- 26439590 TI - Temperature and time variations during osteotomies performed with different piezosurgical devices: an in vitro study. AB - AIM: The aim of this experimental in vitro study was to evaluate the effects of the piezoelectric device in temperature and time variations in standardized osteotomies performed with similar tip inserts in bovine bone blocks. METHODS: Two different piezosurgical devices were used the OE-F15((r)) (Osada Inc., Los Angeles, California, USA) and the Surgybone((r)) (Silfradent Inc., Sofia, Forli Cesena, Italy). Serrated inserts with similar geometry were coupled with each device (ST94 insert/test A and P0700 insert/test B). Osteotomies 10 mm long and 3 mm deep were performed in bone blocks resembling type II (dense) and type IV (soft) bone densities with and without irrigation. Thermal changes and time variations were recorded. The effects of bone density, irrigation, and device on temperature changes and time necessary to accomplish the osteotomies were analyzed. RESULTS: Thermal analysis showed significant higher temperatures during piezosurgery osteotomies in hard bone without irrigation (P < 0.05). The type of piezosurgical device did not influence thermal variations (P > 0.05). Time analysis showed that the mean time values necessary to perform osteotomies were shorter in soft bone than in dense bone (P < 0.05). CONCLUSIONS: Within the limitations of this in vitro study, it may be concluded that the temperature increases more in piezosurgery osteotomies in dense bone without irrigation; the time to perform the osteotomy with piezosurgery is shorter in soft bone compared to hard bone; and the piezosurgical device have a minimal influence in the temperature and time variations when a similar tip design is used during piezosurgery osteotomies. PMID- 26439591 TI - Clinical experience of imiquimod 3.75% for actinic keratosis: results from a case series. AB - BACKGROUND: In clinical studies, imiquimod 3.75% was shown to detect and treat actinic keratosis (AK) lesions across an entire sun-exposed field such as the full face or balding scalp. The aim of this study was to evaluate imiquimod 3.75% in a real-life clinical setting. METHODS: Ten AK patients applied imiquimod 3.75% to the full face or scalp once-daily in two 2-week treatment cycles separated by a two-week treatment-free interval and were followed-up eight weeks later. Seven patients rated imiquimod 3.75% versus prior treatments (cryotherapy, photodynamic therapy, diclofenac sodium 3%, imiquimod 5%, ingenol mebutate). RESULTS: The median clinical lesion count at baseline was 12.5. This increased to a median Lmax (maximum lesion count during treatment) of 22.5 as imiquimod 3.75% unmasked previously invisible subclinical lesions. At final follow-up, the median lesion count was 0. Local skin reactions such as erythema, scabbing and erosion occurred during each treatment cycle and were easy to manage. All patients considered imiquimod 3.75% easier to apply than prior treatments and 5 reported fewer or similar side effects. CONCLUSIONS: In this cohort, imiquimod 3.75% effectively cleared clinical and subclinical lesions across the entire affected field and was well tolerated. PMID- 26439592 TI - Paraneoplastic skin disorders: a review. AB - Paraneoplastic disorders are manifestations of internal malignancies without the direct action of the tumor. Its pathogenesis involves production of substances that interfere with cellular activity of distant tissues. Paraneoplasias may be the first sign of cancer, and clinicians should be familiarized with its manifestations in order to perform an early diagnosis of the underlying neoplasm. The aim of this review was to describe most common paraneoplastic skin diseases. PMID- 26439593 TI - A new test and graphical tool to assess the goodness of fit of logistic regression models. AB - A prognostic model is well calibrated when it accurately predicts event rates. This is first determined by testing for goodness of fit with the development dataset. All existing tests and graphic tools designed for the purpose suffer several drawbacks, related mainly to the subgrouping of observations or to heavy dependence on arbitrary parameters. We propose a statistical test and a graphical method to assess the goodness of fit of logistic regression models, obtained through an extension of similar techniques developed for external validation. We analytically computed and numerically verified the distribution of the underlying statistic. Simulations on a set of realistic scenarios show that this test and the well-known Hosmer-Lemeshow approach have similar type I error rates. The main advantage of this new approach is that the relationship between model predictions and outcome rates across the range of probabilities can be represented in the calibration belt plot, together with its statistical confidence. By readily spotting any deviations from the perfect fit, this new graphical tool is designed to identify, during the process of model development, poorly modeled variables that call for further investigation. This is illustrated through an example based on real data. PMID- 26439594 TI - Biomedical applications of high gradient magnetic separation: progress towards therapeutic haeomofiltration. AB - High gradient magnetic separation is a well-established technology in the mineral processing industry, and has been used for decades in the bioprocessing industry. Less well known is the increasing role that high gradient magnetic separation is playing in biomedical applications, for both diagnostic and therapeutic purposes. We review here the state of the art in this emerging field, with a focus on therapeutic haemofiltration, the key enabling technologies relating to the functionalisation of magnetic nanoparticles with target-specific binding agents, and the development of extra-corporeal circuits to enable the in situ filtering of human blood. PMID- 26439595 TI - Magnetorelaxometry procedures for quantitative imaging and characterization of magnetic nanoparticles in biomedical applications. AB - BACKGROUND: Quantitative knowledge about the spatial distribution and local environment of magnetic nanoparticles (MNPs) inside an organism is essential for guidance and improvement of biomedical applications such as magnetic hyperthermia and magnetic drug targeting. Magnetorelaxometry (MRX) provides such quantitative information by detecting the magnetic response of MNPs following a fast change in the applied magnetic field. METHODS: In this article, we review our MRX based procedures that enable both the characterization and the quantitative imaging of MNPs in a biomedical environment. RESULTS: MRX characterization supported the selection of an MNP system with colloidal stability and suitable cellular MNP uptake. Spatially resolved MRX, a procedure employing multi-channel MRX measurements allowed for in-vivo monitoring of the MNP distribution in a pre clinical carcinoma animal model. Extending spatially resolved MRX by consecutive magnetization of distinct parts of the sample led to a demonstration of MRX tomography. With this tomography, we reconstructed the three dimensional MNP distribution inside animal sized phantoms with a sensitivity of milligrams of MNPs per cm3. In addition, the targeting efficiency of MNPs in whole blood was assessed using a flow phantom and MRX quantification. CONCLUSION: These MRX based measurement and analysis procedures have substantially supported the development of MNP based biomedical applications. PMID- 26439596 TI - Protective effect of telmisartan treatment against arsenic-induced testicular toxicity in rats. AB - Oxidative/nitrosative stress, inflammation, and apoptosis play a crucial role in the pathogenesis of arsenic-induced testicular injury. Telmisartan, the angiotensin II-receptor antagonist, possesses antioxidant and anti-inflammatory activities. The protective effect of telmisartan against arsenic-induced testicular damage was investigated in rats. Testicular damage was induced by sodium arsenite (10 mg kg-1/day, p.o., for 2 consecutive days). Telmisartan (10 mg kg-1/day, i.p.) was given for 3 consecutive days, starting 1 day before sodium arsenite administration. Telmisartan significantly attenuated the arsenic-induced decrease in the levels of serum testosterone and testicular reduced glutathione, and significantly decreased the elevation of the levels of testicular malondialdehyde, nitric oxide, and arsenic levels, as well as myeloperoxidase activity resulting from sodium arsenite administration. Histopathological and immunohistochemical examination revealed that telmisartan markedly attenuated testicular tissue changes, and decreased the arsenic-induced expression of vascular endothelial growth factor, inducible nitric oxide synthase, tumor necrosis factor-alpha, cyclooxygenase-2, nuclear factor-kappaB, and caspase-3. Telmisartan, via its antioxidant and/or anti-inflammatory effects, may represent a potential candidate to protect against the deleterious effects of arsenic on testicular tissue. PMID- 26439597 TI - Inhibition of AKT signaling by supercritical CO2 extract of mango ginger (Curcuma amada Roxb.) in human glioblastoma cells. AB - BACKGROUND: Mango ginger (Curcuma amada Roxb.) is a less-investigated herb for anticancer properties than other related Curcuma species. AKT (a serine/threonine protein kinase B, originally identified as an oncogene in the transforming retrovirus AKT8) plays a central role in the development and promotion of cancer. In this investigation, we have analyzed the effect of supercritical CO2 extract of mango ginger (CA) on the genetic pathways associated with AKT signaling in human glioblastoma cells. METHODS: The inhibitory effect of supercritical CO2 extract of mango ginger (Curcuma amada) on AKT signaling was investigated in U 87MG glioblastoma cells. RESULTS: CA was highly cytotoxic to glioblastoma cell line (IC50=4.92+/-0.81 ug/mL) compared to mHypoE-N1 normal mouse hypothalamus cell line (IC50=40.57+/-0.06 ug/mL). CA inhibits AKT (protein Kinase B) and adenosine monophophate -activated protein kinase alpha (AMPKalpha) phosphorylation significantly in a dose-dependent manner. The cell migration which is necessary for invasion and metastasis was also inhibited by CA treatment, with about 43% reduction at 20 ug/mL concentration. Analysis of mRNA and protein expression of genes associated with apoptosis, cell proliferation and angiogenesis showed that CA modulates expression of genes associated with apoptosis (Bax, Bcl-2, Bcl-X, BNIP3, caspase-3, mutant p53 and p21), cell proliferation (Ki67) and angiogenesis vascular endothelial growth factor (VEGF). Additionally, heat shock protein 90 (HSP90) and AMPKalpha genes interacting with the AKT signaling pathway were also downregulated by CA treatment. CONCLUSIONS: These results indicate the molecular targets and mechanisms underlying the anticancer effect of CA in human glioblastoma cells. PMID- 26439598 TI - Investigation of Mixed Surfactant Films at Water Surface Using Molecular Dynamics Simulations. AB - Multicomponent Langmuir monolayers are important models of organic coatings of naturally occurring water-vapor interfaces such as the surfaces of oceans or aerosol particles. We investigated mixed monolayers comprised of palmitic acid, C15H31COOH (PA) and 1-bromoalkanes of different chain length (C5, C10, and C16) at the air-water interface employing classical molecular dynamics simulations. Different composition ratios and lateral compression of the monolayers were considered. The structural parameters, such as density profiles, and deuterium order parameter, evaluated as functions of composition and the lateral film packing, provide microscopic information about organization and dynamics of the mixed monolayers. Simulations demonstrate that stable and well mixed monolayers are formed by the mixtures of PA and BrC16H33 (BrCl6), whereas the two considered shorter bromoalkanes, BrC5H11 (BrC5) and BrC10H21 (BrC10), do not form stable films. This is in accord with earlier experimental studies. Under high lateral pressures, in PA/BrC10 mixed systems molecules of the bromoalkane readily flip in the monolayer and subsequently leave the film, while the molecules of the longer BrC16 are expelled from the PA film but no flipping occurs. These results suggest that the film collapse under pressure is preceded by squeezing-out of bromoalkanes from the PA monolayer. PMID- 26439599 TI - Pharmacotherapeutic options for treating brain metastases in non-small cell lung cancer. AB - INTRODUCTION: Central nervous system (CNS) metastases represent an important cause of morbidity and mortality in non-small cell lung cancer (NSCLC) patients. Local approaches of neurosurgery (usually for single brain lesions), whole brain radiotherapy, and stereotactic radiosurgery are often withheld for the treatment of NSCLC-derived brain metastases (BMs). However, systemic treatment is consistently emerging as an option for patients with asymptomatic BMs, which could allow for delaying cranial radiotherapy at symptomatic/radiological progression. AREAS COVERED: Chemotherapy, monoclonal antibodies, tyrosine-kinase inhibitors (TKIs) for molecularly selected NSCLCs, such as epidermal growth factor receptor (EGFR)-mutant and anaplastic lymphoma kinase (ALK)-rearranged diseases, and immune checkpoint inhibitors are all systemic treatments that have shown activity against NSCLC-derived CNS metastases. Among these, EGFR- and ALK TKIs will be discussed more in detail owing to their superior efficacy in this context. EXPERT OPINION: Up-front systemic treatment should be considered for patients with asymptomatic, multiple BMs, as recently acknowledged by the European Society of Medical Oncology guidelines. Nevertheless, it must be emphasized that the best treatment strategy for NSCLC-derived BMs has to be defined within a multidisciplinary team. PMID- 26439600 TI - Novel POSS-PCU Nanocomposite Material as a Biocompatible Coating for Quantum Dots. AB - Quantum dots (QDs) are fluorescent nanoparticles with unique photophysical properties that enable them to potentially replace traditional organic dyes and fluorescent proteins in various bioimaging applications. However, the inherent toxicity of their cores based on cadmium salts limits their widespread biomedical use. We have developed a novel nanocomposite polymer emulsion based on polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSS-PCU) that can be used to coat quantum dots to nullify their toxicity and enhance photostability. Here we report the synthesis and characterization of a novel POSS-PCU nanocomposite polymer emulsion and describe its application for coating QDs for biological application. The polymer was synthesized by a process of emulsion polymerization and formed stable micelles of ~33 nm in diameter. CdTe/CdS/ZnS QDs were efficiently stabilized by the polymer emulsion through encapsulation within the polymer micelles. Characterization studies showed no significant change in the unique photophysical properties of QDs after coating. The polymer was biocompatible to HepG2, HUVECs, and mouse skeletal muscle cells at 2.5% after 24 h exposure on in vitro testing. Polymer encapsulated QDs showed enhanced photostability on exposure to high degrees of UV irradiation and air as well as significantly reduced cytotoxicity on exposure to HepG2 cells at 30 MUg/mL for 24 h. We have therefore concluded that the POSS-PCU polymer emulsion has the potential to make a biocompatible and photostable coating for QDs enabling a host of biomedical applications to take this technology to the next level. PMID- 26439601 TI - Engaging communities to improve mental health in African and African Caribbean groups: a qualitative study evaluating the role of community well-being champions. AB - Over the last decade, Britain has undergone reforms to promote engagement in local structures of governance. These reforms have encouraged the promotion of active citizenship and have been central to the government's public service modernisation agenda. This article presents the findings from a study evaluating a pilot outreach intervention which adopted a community engagement model to address the mental health needs of African and African Caribbean groups, which entailed a partnership between faith-based organisations, local public services and community organisations to co-produce the pilot project. Lay people were trained to raise awareness about mental health among these communities in South London. Between 2012 and 2013, a qualitative participatory approach was used to evaluate the pilot project, which enabled a researcher to take part in the engagement phase of the pilot project, and the project co-ordinators to be involved in the research process. Semi-structured, one-to-one interviews were carried out with 13 community and well-being champions (CWBCs) recruited from African and African Caribbean communities (seven male and six female). This study examines the impact of the relationship between the intervention and community through the participants' engagement in the pilot outreach project and the action undertaken as champions. We found that although CWBCs used circles of influence to share ideas about mental health and well-being and to encourage change, they encountered resistance on the part of the people they engaged with, which resulted from a lack of knowledge about mental health, taboos and ascribed stigma. We argue that CWBCs acted as healthy examples to communicate mental health knowledge to those approached, but that they needed to be equipped with bespoke communication skills to be able to talk about such sensitive issues as mental health. PMID- 26439602 TI - "When we are together I feel at home." Types and sources of social support among youth newly diagnosed with HIV in Kenya: implications for intervention. AB - Social support helps youth manage psychosocial stress. Though many studies have investigated the role of social support in helping youth in developed countries cope with their HIV status, such research is lacking among youth living in sub Saharan African countries, including Kenya. The importance of research on youth living with HIV in Kenya is enhanced given young people's unique developmental stages and the HIV prevalence rate of 8.8% among Kenyans aged 25 to 29 years. To gain further insight, qualitative focus group interviews were conducted with 53 youth aged 18 to 27 years who lived in the informal urban settlement of Kibera in Nairobi, Kenya. A phenomenological approach was used to analyse the data from which four major types of social support were identified: 1) emotional; 2) informational; 3) appraisal; and 4) instrumental. Within each of these overarching themes more specific sub-themes were identified. The youth also reported receiving social support from eight main sources: 1) family; 2) friends; 3) clinicians and clinical services; 4) counsellors; 5) support groups; 6) religious sources; 7) partners; and 8) other. These findings suggest that various forms of social support, provided by diverse sources, which may fall outside of those commonly involved in interventions, can help youth living with HIV cope with their diagnosis and promote healthy lifestyles. Future research should investigate the roles and interactions of different types and sources of support, specifically as they relate to interventions aiming to ameliorate the experiences of youth newly diagnosed with HIV. PMID- 26439603 TI - HIV-related disabilities: an extra burden to HIV and AIDS healthcare workers? AB - BACKGROUND: Healthcare workers have been at the forefront of dealing with the impact of HIV and AIDS at all stages of the pandemic. This brings new challenges to include disability into HIV care. However, the implications for healthcare workers in an already fragile health system along with HIV-related disabilities in persons living with HIV are little understood. This study examined the healthcare workers' perspective on disability in HIV care. METHOD: This article describes a qualitative study using in-depth interviews with 10 healthcare workers in a semi-urban hospital setting in KwaZulu-Natal, South Africa. The study aimed to understand healthcare workers' experiences with disability in the context of HIV. The International Classification of Functioning Disability and Health (ICF) was used as a guiding framework to understand disability. RESULTS: Healthcare workers described HIV-related disabilities on all three levels of disability, namely impairments/ body function, activity limitations and participation restrictions, as affecting the livelihood of their patients and household members. Issues also arose from disability and stigma that were perceived as affecting adherence to antiretroviral treatment. In addition, healthcare workers encounter challenges in dealing with the increased needs of care and support for those people living with HIV who experience HIV-related disabilities. They indicated a limited ability to cope and respond to these needs. Primarily they arrange additional referrals to manage complex or episodic disabilities. Participants also identified issues such as excessive work load, lack of resources and training and emotional challenges in dealing with disability. CONCLUSION: Healthcare workers need support to respond to the increased needs of people living with HIV who have HIV-related disabilities. Responses need to reflect: 1) increase in rehabilitative staff including in community outreach programmes; 2) skills training in HIV-related disability; and 3) psychosocial support for healthcare workers. PMID- 26439604 TI - Vanadium Nitride Nanowire Supported SnS2 Nanosheets with High Reversible Capacity as Anode Material for Lithium Ion Batteries. AB - The vulnerable restacking problem of tin disulfide (SnS2) usually leads to poor initial reversible capacity and poor cyclic stability, which hinders its practical application as lithium ion battery anode (LIB). In this work, we demonstrated an effective strategy to improve the first reversible capacity and lithium storage properties of SnS2 by growing SnS2 nanosheets on porous flexible vanadium nitride (VN) substrates. When evaluating lithium-storage properties, the three-dimensional (3D) porous VN coated SnS2 nanosheets (denoted as CC-VN@SnS2) yield a high reversible capacity of 75% with high specific capacity of about 819 mAh g(-1) at a current density of 0.65 A g(-1). Remarkable cyclic stability capacity of 791 mAh g(-1) after 100 cycles with excellent capacity retention of 97% was also achieved. Furthermore, discharge capacity as high as 349 mAh g(-1) is still retained after 70 cycles even at a elevated current density of 13 A g( 1). The excellent performance was due to the conductive flexible VN substrate support, which provides short Li-ion and electron pathways, accommodates large volume variation, contributes to the capacity, and provides mechanical stability, which allows the electrode to maintain its structural stability. PMID- 26439605 TI - Extending the reservoir of bla IMP-5: the emerging pathogen Acinetobacter bereziniae. AB - AIM: Acinetobacter bereziniae clinical relevance is starting to be recognized; however, very few descriptions of its carbapenem resistance currently exist. Here we characterize two carbapenem-resistant A. bereziniae isolates. MATERIALS & METHODS: Isolates were obtained from environmental and clinical samples. Carbapenemases were searched by phenotypic, biochemical and PCR assays. Clonality was studied by ApaI-PFGE and genetic location for carbapenemase genes were assessed by I-CeuI and S1 hybridizations. RESULTS: Isolates were not clonally related but both produced the 'exclusively Portuguese' IMP-5, with the clinical isolate also producing an OXA-58. The carbapenemase genes were plasmid located. CONCLUSION: Our results emphasize the role of non-baumannii Acinetobacter species as important reservoirs of clinically relevant resistance genes that could also contribute to their emergence as nosocomial pathogens. PMID- 26439606 TI - Interplay between Open-Shell Character, Aromaticity, and Second Hyperpolarizabilities in Indenofluorenes. AB - Focusing on the original and extended indenofluorene frameworks, we theoretically investigate the interplay between the open-shell character, the aromaticity, and the second hyperpolarizabilities gamma. Interestingly, the odd-electron density distribution, which illustrates the spatial contribution of the open-shell character, is found to well correlate with the magnetic shielding tensor distribution, which indicates the magnetic criteria of the aromaticity. This can be explained with the partial destruction of the pi-delocalization due to the emergence of odd (unpaired) electrons. Further investigation on the gamma values, which are third-order nonlinear optical (NLO) properties at the molecular scale, reveals the correlation of strong enhancement of gamma and its density distribution to the intermediate open-shell character and its odd-electron density distribution. These results will contribute not only to the detailed understanding of the structure-NLO property relationships in the indenofluorene frameworks but also to building new design guidelines for highly efficient NLO molecules based on the open-shell character-aromaticity correlation. PMID- 26439607 TI - Utility of checklist to describe experimental methods for investigating molecular biomarkers. AB - INTRODUCTION: In research articles, detailed description of experimental methods and reagents is fundamental for correct reproducibility of the published data. This becomes even more important when such data contribute to identify molecular targets and toxicity biomarkers whose role is crucial in the physiology and pathology of human health. Methods & Objectives: To achieve good reproducibility of data we took advantage of others' experiences and analyzed molecular biology and immunodetection techniques in 32 journal articles investigating the human NRF2 and Keap1 genes involved in the cell response to oxidative stress. RESULTS & CONCLUSIONS: In conclusion of the analysis, we assessed deficiency of information in the published methods, making it difficult to select appropriate protocols. Underlining the importance of assay reproducibility, this paper proposes the utility of a minimum information checklist of methods for biomarker detection. PMID- 26439608 TI - N-Heterocyclic Carbene-Catalyzed Activation of Esters of N-Hydroxyphthalimide: A Highly Enantioselective Route to Chiral Dihydropyridinones Bearing an All Carbon Quaternary Stereogenic Center. AB - An N-heterocyclic carbene-catalyzed highly enantioselective [3 + 3] annulation reaction of N-hydroxyphthalimide (NHPI) 3,3-disubstituted acrylates and N-Ts ketimines was developed. In most cases, the desired chiral dihydropyridinone products bearing an all carbon quaternary stereogenic center could be obtained in good yields with excellent enantioselectivities (>99% ee's), which demonstrated the NHPI acrylates as a kind of excellent substrate in NHC-catalysis. PMID- 26439609 TI - A systematic examination of the nature and content of vignettes in schizophrenia research. AB - BACKGROUND: Vignettes are often used in psychiatric research, yet there are few systematic studies on their content, creation, and use. AIMS: This article describes a study of: (a) how researchers create vignettes in research on schizophrenia and (b) how these vignettes portray individuals with schizophrenia. METHOD: We conducted a systematic search of the PubMed database for articles between 2008 and 2012 that used vignettes to measure attitudes about schizophrenia. We analyzed the identified vignettes using a tool developed in reference to DSM criteria. RESULTS: Within the vignettes, 98% of individuals portrayed demonstrated delusions, 91% demonstrated hallucinations and 29% demonstrated disorganized speech. The majority of vignettes portrayed individuals under 25 years and when both genders were not depicted, researchers chose to depict men much more frequently than women (41% vs. 8%). A majority of articles did not use original vignettes (55%), and many of the articles (53%) contained vignettes created by one team of researchers. Most vignettes did not include positive language or recovery-oriented information. CONCLUSIONS: This study highlights a need for critical thought on vignette development and utilization, especially as psychiatry is now moving towards a recovery-based understanding of mental illness. PMID- 26439610 TI - Percutaneous central venous catheters versus peripheral cannulae for delivery of parenteral nutrition in neonates. AB - BACKGROUND: Neonatal parenteral nutrition may be delivered via peripheral cannulas or central venous catheters (umbilical or percutaneous). As the result of complications associated with umbilical catheters, many neonatal units prefer to use percutaneous catheters after initial stabilisation. Although they can be difficult to place, these catheters may be more stable than peripheral cannulae and require less frequent replacement. These delivery methods may be associated with different risks of adverse events, including acquired invasive infection and extravasation injury. OBJECTIVES: To determine the effects of infusion of parenteral nutrition via percutaneous central venous catheters versus peripheral cannulae on nutrient input, growth and development and complications among hospitalised neonates receiving parenteral nutrition in terms of adverse consequences such as bacteraemia or invasive fungal infection, cardiac tamponade or other extravasation injuries. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 5), MEDLINE (1966 to June 2015) and EMBASE (1980 to June 2015), as well as conference proceedings and previous reviews. SELECTION CRITERIA: Randomised controlled trials that compared delivery of intravenous fluids (primarily parenteral nutrition) via percutaneous central venous catheters versus peripheral cannulae in hospitalised neonates. DATA COLLECTION AND ANALYSIS: We extracted data using standard methods of the Cochrane Neonatal Group, with separate evaluation of trial quality and data extraction by two review authors. MAIN RESULTS: We found six trials recruiting a total of 549 infants. One trial showed that use of a percutaneous central venous catheter was associated with a smaller deficit between prescribed and actual nutrient intake during the trial period (mean difference (MD) -7.1%, 95% confidence interval (CI) -11.02 to -3.2). Infants in the percutaneous central venous catheter group needed significantly fewer catheters/cannulae (MD -4.3, 95% CI -5.24, -3.43). Meta-analysis of data from all trials revealed no evidence of an effect on the incidence of invasive infection (typical risk ratio (RR) 0.95, 95% CI 0.72 to 1.25; typical risk difference (RD) -0.01, 95% CI -0.08 to 0.06). AUTHORS' CONCLUSIONS: Data from one small trial suggest that use of percutaneous central venous catheters to deliver parenteral nutrition increases nutrient input. The significance of this in relation to long-term growth and developmental outcomes is unclear. Three trials suggest that use of percutaneous central venous catheters decreases the number of catheters/cannulae needed to deliver nutrition. No evidence suggests that percutaneous central venous catheter use increases risks of adverse events, particularly invasive infection, although none of the included trials was large enough to rule out an effect on uncommon severe adverse events such as pericardial effusion. PMID- 26439611 TI - Preclinical antitoxic properties of Spirulina (Arthrospira). AB - CONTEXT: Spirulina (Arthrospira) exerts a wide spectrum of pharmacological activities which are mainly attributed to its antioxidant effect. However, Spirulina has also been reported (both in preclinical and in clinical scenarios) to exhibit other bioactive effects, including an antitoxic potential. OBJECTIVE: We performed a systematic review of the literature, conducted in TOXNET, PubMed/MEDLINE, and Science Direct-Scopus; all available years were included. Searching criteria included the effects of Spirulina on experimental poisonings from arsenic, cadmium, carbon tetrachloride, deltamethrin, fluoride, hexachlorocyclohexane, iron, lead, lindane, and mercury. RESULTS: In all cases, it was established that the blue-green alga, and its isolated compounds, effectively counteracted these pollutants toxic effects on the exposed organisms. Some molecular mechanisms are proposed, although they have not been fully elucidated yet. CONCLUSION: Spirulina could be a useful coadjuvant agent within clinical practice for treatment of these or other pollutants poisonings. PMID- 26439612 TI - Sexual Assault Experienced by Deaf Female Undergraduates: Prevalence and Characteristics. AB - Approximately 25% of hearing women in the United States experience rape in their life-time, whereas deaf women have been found to experience increased rates of assault consistent with other marginalized populations. This study explored sexual assault prevalence and characteristics of assault in deaf female undergraduate students. Results revealed that more than two-thirds of the participants (69%) endorsed experiencing at least one assault and more than half (56%) experienced multiple types of assault. Most assaults were committed by a man known to the survivor. Characteristics (e.g., hearing status, primary language, and ethnicity) of the survivors and the assailants are explored. The implications of this data are discussed as well as the development of culturally and linguistically sensitive outreach and educational programs. PMID- 26439613 TI - Paternal history of diabetes mellitus and hypertension affects the prevalence and phenotype of PCOS. AB - PURPOSE: The purpose of the present study is to determine if paternal or maternal history of diabetes mellitus (DM) and hypertension (HT) contributes to the prevalence and phenotype of polycystic ovary syndrome (PCOS). METHODS: We performed an epidemiologic study about PCOS from four districts in Beijing, China, between 2008 and 2009. Parental histories of DM and HT were collected, and the basic characteristics and serum indices of 123 PCOS patients and 718 non-PCOS controls were tested. RESULTS: The prevalence of a parental history of DM and HT was significantly higher in PCOS patients than non-PCOS women (17.1 % vs. 9.2 % and 42.3 % vs. 26.0 %, P < 0.05, respectively). When paternal history was separated from maternal history, only a paternal history of DM and HT reached statistical significance between PCOS and non-PCOS patients (odds ratio (OR) = 3.42, 95 % confidence interval (CI) = 1.69-6.91; OR = 2.50, 95 % CI = 1.58-3.93, respectively). A paternal history of both DM and HT was significantly associated with sex hormone-binding globulin, fasting plasma glucose, and fasting insulin levels, the free androgen index, and the homeostatic model assessment-insulin resistance in PCOS patients (P < 0.05 for all). There was no independent association between maternal history and the clinical or biochemical phenotype of PCOS. CONCLUSIONS: PCOS patients with a positive paternal history of both DM and HT have an adverse endocrine and metabolic profile. A paternal history of DM and HT poses a risk to PCOS. PMID- 26439616 TI - Generation of remote adaptive torsional shear waves with an octagonal phased array to enhance displacements and reduce variability of shear wave speeds: comparison with quasi-plane shear wavefronts. AB - A method based on adaptive torsional shear waves (ATSW) is proposed to overcome the strong attenuation of shear waves generated by a radiation force in dynamic elastography. During the inward propagation of ATSW, the magnitude of displacements is enhanced due to the convergence of shear waves and constructive interferences. The proposed method consists in generating ATSW fields from the combination of quasi-plane shear wavefronts by considering a linear superposition of displacement maps. Adaptive torsional shear waves were experimentally generated in homogeneous and heterogeneous tissue mimicking phantoms, and compared to quasi-plane shear wave propagations. Results demonstrated that displacement magnitudes by ATSW could be up to 3 times higher than those obtained with quasi-plane shear waves, that the variability of shear wave speeds was reduced, and that the signal-to-noise ratio of displacements was improved. It was also observed that ATSW could cause mechanical inclusions to resonate in heterogeneous phantoms, which further increased the displacement contrast between the inclusion and the surrounding medium. This method opens a way for the development of new noninvasive tissue characterization strategies based on ATSW in the framework of our previously reported shear wave induced resonance elastography (SWIRE) method proposed for breast cancer diagnosis. PMID- 26439615 TI - Structural characterization of amphiphilic siderophores produced by a soda lake isolate, Halomonas sp. SL01, reveals cysteine-, phenylalanine- and proline containing head groups. AB - Soap Lake, located in Washington State, is a naturally occurring saline and alkaline lake. Several organisms inhabiting this lake have been identified as producers of siderophores that are unique in structure. Bacterial isolates, enriched from Soap Lake sediment and water samples, were screened for siderophore production using both the chrome azurol S (CAS) agar plate and liquid methods. Bacterial isolate Halomonas sp. SL01 was found to produce relatively high concentrations of siderophores in liquid medium (up to 40 uM). Siderophores from the isolate were separated from the culture supernatant using solid phase extraction and purified by high-performance liquid chromatography (HPLC). Siderophore structure was determined using LC/MS/MS (liquid chromatography/mass spectrometry/mass spectrometry) and fatty acid methyl ester (FAME) GC. Two distinct new families of amphiphilic siderophores were produced by isolate SL01. All siderophores ranged in size from 989 to 1096 atomic mass units and consisted of a conserved peptidic head group (per family), which coordinates iron, coupled to fatty acid moieties. The fatty acyl moieties were C10-C14 in length and some with hydroxyl substitutions at the third alpha position. These siderophores resembled amphiphilic aquachelin siderophores produced by Halomonas aquamarina strain DS40M3, a marine bacterium as well as siderophores from isolate Halomonas sp. SL28 that was found to produce amphiphilic siderophores. Bacteria thriving under saline and alkaline conditions are capable of producing unique siderophores resembling those produced by microbes inhabiting marine environments. PMID- 26439617 TI - Large-Area Growth of Uniform Single-Layer MoS2 Thin Films by Chemical Vapor Deposition. AB - We report the largest-size thin films of uniform single-layer MoS2 on sapphire substrates grown by chemical vapor deposition based on the reaction of gaseous MoO3 and S evaporated from solid sources. The as-grown thin films of single-layer MoS2 were continuous and uniform in thickness for more than 4 cm without the existence of triangular-shaped MoS2 clusters. Compared to mechanically exfoliated crystals, the as-grown single-layer MoS2 thin films possessed consistent chemical valence states and crystal structure along with strong photoluminescence emission and optical absorbance at high energy. These results demonstrate that it is possible to scale up the growth of uniform single-layer MoS2 thin films, providing potentially important implications on realizing high-performance MoS2 devices. PMID- 26439618 TI - Analysis of Critical Dimensions for Nanowire Core-Multishell Heterostructures. AB - Critical dimensions for nanowire core-multishell heterostructures are analyzed by using finite-element method based on the energy equilibrium criteria. Results show that the nanowire core-shell heterostructure can sufficiently reduce the strain in the shell and increase the critical shell thickness. The critical dimensions for the nanowire core-multishell heterostructure are determined by the stress fields generated at two heterointerfaces. For thin barrier, the critical dimensions decrease as the core radius increases, while when the barrier is thick enough, the critical dimensions show an increase with the increase of core radius conversely. This can be attributed to a competition between the lattice mismatch and strain distribution, which dominate the critical dimensions alternatively. Two critical quantum well thicknesses are obtained in the nanowire core multishell heterostructure. Below the dislocation-free critical thickness, the structure will be coherent regardless of the barrier thickness. While above the dislocation-unavoidable thickness, dislocations are always energetically favored. In the dislocation-controllable region between the two critical thicknesses, coherent structure can be obtained via controlling the well and barrier thicknesses. The results are in good agreement with the experimental data and may serve as guidance for the design of coherent nanowire core-multishell quantum well structures and devices. PMID- 26439619 TI - Electromagnetic Enhancement of Graphene Raman Spectroscopy by Ordered and Size Tunable Au Nanostructures. AB - The size-controllable and ordered Au nanostructures were achieved by applying the self-assembled monolayer of polystyrene microspheres. Few-layer graphene was transferred directly on top of Au nanostructures, and the coupling between graphene and the localized surface plasmons (LSPs) of Au was investigated. We found that the LSP resonance spectra of ordered Au exhibited a redshift of ~20 nm and broadening simultaneously by the presence of graphene. Meanwhile, the surface enhanced Raman spectroscopy (SERS) of graphene was distinctly observed; both the graphene G and 2D peaks increased induced by local electric fields of plasmonic Au nanostructures, and the enhancement factor of graphene increased with the particle size, which can be ascribed to the plasmonic coupling between the ordered Au LSPs and graphene. PMID- 26439620 TI - Neuroendocrine tumor G3: a pancreatic well-differentiated neuroendocrine tumor with a high proliferative rate. AB - A 68-year-old man was referred to our hospital because of left upper quadrant pain. Contrast enhanced computed tomography showed a low density mass with delayed contrast effects as well as para-aortic node swelling with homogenous contrast effects. Histological examination of specimens obtained by endoscopic ultrasound fine needle aspiration revealed a pancreatic neuroendocrine tumor (NET) G2, according to the World Health Organization 2010 classification, and lymph node metastasis. Distal pancreatectomy and lymph node dissection were performed. On histological examination, the tumor showed well-differentiated morphology with an organoid pattern. The Ki67 labeling index was 21.6 %, and the mitotic count was 25/10 high power fields. As mentioned above, we made a final diagnosis of the lesion as "NET G3," because the tumor presented with well differentiated morphology. Chemotherapy with Everolimus was administered. Liver metastasis occurred 11 months after the first operation, and a partial hepatectomy was performed. Histological findings were similar to those of the first operation. Herein we present a case of pancreatic well-differentiated neuroendocrine tumor with a high proliferative rate referred to as "NET G3," and review the relevant literature. PMID- 26439621 TI - FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores. AB - Mechanisms of adaptation to environmental changes in osmolarity are fundamental for cellular and organismal survival. Here we identify a novel osmotic stress resistance pathway in Caenorhabditis elegans (C. elegans), which is dependent on the metabolic master regulator 5'-AMP-activated protein kinase (AMPK) and its negative regulator Folliculin (FLCN). FLCN-1 is the nematode ortholog of the tumor suppressor FLCN, responsible for the Birt-Hogg-Dube (BHD) tumor syndrome. We show that flcn-1 mutants exhibit increased resistance to hyperosmotic stress via constitutive AMPK-dependent accumulation of glycogen reserves. Upon hyperosmotic stress exposure, glycogen stores are rapidly degraded, leading to a significant accumulation of the organic osmolyte glycerol through transcriptional upregulation of glycerol-3-phosphate dehydrogenase enzymes (gpdh-1 and gpdh-2). Importantly, the hyperosmotic stress resistance in flcn-1 mutant and wild-type animals is strongly suppressed by loss of AMPK, glycogen synthase, glycogen phosphorylase, or simultaneous loss of gpdh-1 and gpdh-2 enzymes. Our studies show for the first time that animals normally exhibit AMPK-dependent glycogen stores, which can be utilized for rapid adaptation to either energy stress or hyperosmotic stress. Importantly, we show that glycogen accumulates in kidneys from mice lacking FLCN and in renal tumors from a BHD patient. Our findings suggest a dual role for glycogen, acting as a reservoir for energy supply and osmolyte production, and both processes might be supporting tumorigenesis. PMID- 26439622 TI - Combined Treatment with Exendin-4 and Metformin Attenuates Prostate Cancer Growth. AB - INTRODUCTION: Recently, the pleiotropic benefits of incretin-based therapy have been reported. We have previously reported that Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, attenuates prostate cancer growth. Metformin is known for its anti-cancer effect. Here, we examined the anti-cancer effect of Exendin-4 and metformin using a prostate cancer model. METHODS: Prostate cancer cells were treated with Exendin-4 and/or metformin. Cell proliferation was quantified by growth curves and 5-bromo-2'-deoxyuridine (BrdU) assay. TUNEL assay and AMP-activated protein kinase (AMPK) phosphorylation were examined in LNCaP cells. For in vivo experiments, LNCaP cells were transplanted subcutaneously into the flank region of athymic mice, which were then treated with Exendin-4 and/or metformin. TUNEL assay and immunohistochemistry were performed on tumors. RESULTS: Exendin-4 and metformin additively decreased the growth curve, but not the migration, of prostate cancer cells. The BrdU assay revealed that both Exendin-4 and metformin significantly decreased prostate cancer cell proliferation. Furthermore, metformin, but not Exendin-4, activated AMPK and induced apoptosis in LNCaP cells. The anti-proliferative effect of metformin was abolished by inhibition or knock down of AMPK. In vivo, Exendin-4 and metformin significantly decreased tumor size, and further significant tumor size reduction was observed after combined treatment. Immunohistochemistry on tumors revealed that the P504S and Ki67 expression decreased by Exendin-4 and/or metformin, and that metformin increased phospho-AMPK expression and the apoptotic cell number. CONCLUSION: These data suggest that Exendin-4 and metformin attenuated prostate cancer growth by inhibiting proliferation, and that metformin inhibited proliferation by inducing apoptosis. Combined treatment with Exendin-4 and metformin attenuated prostate cancer growth more than separate treatments. PMID- 26439623 TI - Development of a brachytherapy audit checklist tool. AB - PURPOSE: To develop a brachytherapy audit checklist that could be used to prepare for Nuclear Regulatory Commission or agreement state inspections, to aid in readiness for a practice accreditation visit, or to be used as an annual internal audit tool. METHODS AND MATERIALS: Six board-certified medical physicists and one radiation oncologist conducted a thorough review of brachytherapy-related literature and practice guidelines published by professional organizations and federal regulations. The team members worked at two facilities that are part of a large, academic health care center. Checklist items were given a score based on their judged importance. Four clinical sites performed an audit of their program using the checklist. The sites were asked to score each item based on a defined severity scale for their noncompliance, and final audit scores were tallied by summing the products of importance score and severity score for each item. RESULTS: The final audit checklist, which is available online, contains 83 items. The audit scores from the beta sites ranged from 17 to 71 (out of 690) and identified a total of 7-16 noncompliance items. The total time to conduct the audit ranged from 1.5 to 5 hours. CONCLUSIONS: A comprehensive audit checklist was developed which can be implemented by any facility that wishes to perform a program audit in support of their own brachytherapy program. The checklist is designed to allow users to identify areas of noncompliance and to prioritize how these items are addressed to minimize deviations from nationally-recognized standards. PMID- 26439624 TI - Structure study of a microemulsion system with an ionic liquid. AB - We found that an ionic liquid (IL) with a long alkyl chain moiety, 1-tetradecyl-3 methylimidazolium chloride (C14MIM.Cl), forms a single crystal after the addition of octanol in an alkane solvent. But the solution exhibits a structural change after adding a small amount of water. An optically clear solution is found within limits, and it is stable for several months. Since the IL molecule has an amphiphilic property, it behaves as a surfactant in the microemulsion system. But the IL formed a single crystal rather than a lyotropic liquid crystalline structure, unlike a typical surfactant. Therefore, it is important to understand the structure of the microemulsion system. We used the small angle neutron scattering (SANS) technique to investigate the structure. The scattering intensity was analyzed using a spherical core-shell model with the Schultz size distribution, and a contrast matching method was used to study the internal structure. The structure of the solution is confirmed to be a water-in-oil microemulsion system, and the swelling law is obeyed in the microemulsion system. PMID- 26439625 TI - Whole Blood Gene Expression Profiles of Patients with a Past Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: The pathogenesis of development and rupture of intracranial aneurysms (IA) is largely unknown. Also, screening for IA to prevent aneurysmal subarachnoid hemorrhage (aSAH) is inefficient, as disease markers are lacking. We investigated gene expression profiles in blood of previous aSAH patients, who are still at risk for future IA, aiming to gain insight into the pathogenesis of IA and aSAH, and to make a first step towards improvement of aSAH risk prediction. METHODS AND RESULTS: We collected peripheral blood of 119 patients with aSAH at least two years prior, and 118 controls. We determined gene expression profiles using Illumina HumanHT-12v4 BeadChips. After quality control, we divided the dataset in a discovery (2/3) and replication set (1/3), identified differentially expressed genes, and applied (co-)differential co-expression to identify disease related gene networks. No genes with a significant (false-discovery rate <5%) differential expression were observed. We detected one gene network with significant differential co-expression, but did not find biologically meaningful gene networks related to a history of aSAH. Next, we applied prediction analysis of microarrays to find a gene set that optimally predicts absence or presence of a history of aSAH. We found no gene sets with a correct disease state prediction higher than 40%. CONCLUSIONS: No gene expression differences were present in blood of previous aSAH patients compared to controls, besides one differentially co-expressed gene network without a clear relevant biological function. Our findings suggest that gene expression profiles, as detected in blood of previous aSAH patients, do not reveal the pathogenesis of IA and aSAH, and cannot be used for aSAH risk prediction. PMID- 26439626 TI - Size effects in the magnetic anisotropy of embedded cobalt nanoparticles: from shape to surface. AB - Strong size-dependent variations of the magnetic anisotropy of embedded cobalt clusters are evidenced quantitatively by combining magnetic experiments and advanced data treatment. The obtained values are discussed in the frame of two theoretical models that demonstrate the decisive role of the shape in larger nanoparticles and the predominant role of the surface anisotropy in clusters below 3 nm diameter. PMID- 26439627 TI - Comparison of the Five Danish Regions Regarding Demographic Characteristics, Healthcare Utilization, and Medication Use--A Descriptive Cross-Sectional Study. AB - BACKGROUND: While Denmark is well known for its plethora of registers. Many studies are conducted on research databases that only cover parts of Denmark, and regional differences could potentially threaten these studies' external validity. The aim of this study was to assess sociodemographic and health related homogeneity of the five Danish regions. METHODS: We obtained descriptive data for the five Danish regions, using publicly available data sources: Statbank Denmark, the Danish Ministry of Economic Affairs, and Medstat.dk. These data sources comprise aggregate data from four different nationwide registers: The Danish National Patient Register, The Danish Civil Registration System, The Danish Register of Medicinal Product Statistics, and The Danish National Health Service Register for Primary Care. We compared the Danish regions regarding demographic and socioeconomic characteristics, health care utilization, and use of medication. For each characteristic, one-year prevalence was obtained and analyses were performed for 2013 and 2008 to account for possible change over time. RESULTS: In 2013, 5,602,628 persons were living in Denmark. The mean age was 40.7 years in the entire Danish population and ranged between 39.6 to 42.4 years in the five regions (coefficient of variation between regions [CV] = 0.028). The proportion of women in Denmark was 50.4% (CV = 0.009). The proportion of residents with low education level was 28.7% (CV = 0.051). The annual number of GP contacts was 7.1 (range: 6.7-7.4, CV = 0.040), and 114 per 1,000 residents were admitted to the hospital (range: 101-131, CV = 0.107). The annual number of persons redeeming a prescription of any medication was 723 per 1,000 residents (range: 718-743, CV = 0.016). Analyses for 2008 showed comparable levels of homogeneity as for 2013. CONCLUSIONS: We found substantial homogeneity between all of the five Danish regions with regard to sociodemographic and health related characteristics. Epidemiologic studies conducted on regional subsets of Danish citizens have a high degree of generalizability. PMID- 26439628 TI - Non-Eosinophilic Nasal Polyps Shows Increased Epithelial Proliferation and Localized Disease Pattern in the Early Stage. AB - BACKGROUND: Non-eosinophilic nasal polyps (NPs) show less inflammatory changes and are less commonly associated with lower airway inflammatory disorders such as asthma, compared with eosinophilic NPs. However, the development of non eosinophilic NPs which is a predominant subtype in Asian population still remains unclear. METHODS: A total of 81 patients (45 with non-eosinophilic NPs and 36 with eosinophilic NPs) were enrolled. Clinical information and computed tomography (CT), endoscopic, and histological findings were investigated. Tissue samples were analyzed for total IgE levels and for mRNA expression levels of interleukin (IL)-4, IL-5, IL-13, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, IL-17A, IL-22, IL-23p19, transforming growth factor (TGF)-beta1, TGF beta2, TGF-beta3, and periostin. Immunostaining assessment of Ki-67 as a proliferation marker was performed. RESULTS: We found that epithelial in-growing patterns such as pseudocysts were more frequently observed in histological and endoscopic evaluations of non-eosinophilic NPs, which was linked to increase epithelial staining of Ki-67, a proliferating marker. Eosinophilic NPs were characterized by high infiltration of inflammatory cells, compared with non eosinophilic NPs. To investigate the developmental course of each subtype, CT was analyzed according to CT scores and subtypes. Non-eosinophilic NPs showed more localized pattern and maxillary sinus involvement, but lesser olfactory involvement in early stage whereas eosinophilic NPs were characterized by diffuse ethmoidal and olfactory involvement. In addition, high ethmoidal/maxillary (E/M) CT scores, indicating ethmoidal dominant involvement, were one of surrogate markers for eosinophilic NP. E/M CT scores was positively correlated with levels of TH2 inflammatory markers, including IL-4, IL-5, periostin mRNA expression and total IgE levels in NPs, whereas levels of the TH1 cytokine, IFN- gamma were inversely correlated. Moreover, if the combinatorial algorithm meet the three of the four markers, including IL-5 (<2.379), periostin (<3.889), IFN-gamma (>0.316), and E/M ratio (<2.167), non-eosinophilic CRSwNP are diagnosed with a sensitivity of 84.4% and a specificity of 84.8%. CONCLUSION: Histologic, immunologic and clinical data suggest that non-eosinophilic NPs showed enhanced epithelial alteration and more localized maxillary involvement. Combination of cutoff value on IL-5, periostin, IFN-gamma, and E/M scores may be one of surrogate markers for non-eosinophil NP subtype. PMID- 26439629 TI - Unusual spin dynamics in topological insulators. AB - The dynamic spin susceptibility (DSS) has a ubiquitous Lorentzian form around the Zeeman energy in conventional materials with weak spin orbit coupling, whose spectral width characterizes the spin relaxation rate. We show that DSS has an unusual non-Lorentzian form in topological insulators, which are characterized by strong SOC, and the anisotropy of the DSS reveals the orientation of the underlying spin texture of topological states. At zero temperature, the high frequency part of DSS is universal and increases in certain directions as omega(d 1) with d = 2 and 3 for surface states and Weyl semimetals, respectively, while for helical edge states, the interactions renormalize the exponent as d = 2K - 1 with K the Luttinger-liquid parameter. As a result, spin relaxation rate cannot be deduced from the DSS in contrast to the case of usual metals, which follows from the strongly entangled spin and charge degrees of freedom in these systems. PMID- 26439631 TI - Decomposition characteristics of humic-like matters with the hollow ellipsoid structure sludge inoculated from decayed soil in mature landfill leachate. AB - The organics in mature leachate are mainly humic-like matters, which account for over 80% weight of the total organics. In this work, the microorganisms in decayed soil were found to be capable of decomposing the humic-like matters evidently using an anaerobic-aerobic/anoxic bioprocess in two sequencing bio reactors. The 3D excitation-emission matrix and Fourier transform infrared (FT IR) were applied to characterize the variation of dissolved organic matters in mature leachate while sludge morphology was characterized by scanning electron microscopy. The intensities of fluorescence peaks A and C of leachate effluents were 71.66% and 48.75% lower than those of influents, respectively, which indicated the extraordinary degradation ability of microorganisms inoculated from the decayed soil. Meanwhile a kind of distinctive hollow ellipsoid structure sludge organized by tiny soil particles was observed, which might favour the humic-like matters' decomposition and has never been reported before as we know. The formation mechanisms of hollow ellipsoid structure sludge will need further study. PMID- 26439630 TI - Lactobacillus rhamnosus CNCMI-4317 Modulates Fiaf/Angptl4 in Intestinal Epithelial Cells and Circulating Level in Mice. AB - BACKGROUND AND OBJECTIVES: Identification of new targets for metabolic diseases treatment or prevention is required. In this context, FIAF/ANGPTL4 appears as a crucial regulator of energy homeostasis. Lactobacilli are often considered to display beneficial effect for their hosts, acting on different regulatory pathways. The aim of the present work was to study the effect of several lactobacilli strains on Fiaf gene expression in human intestinal epithelial cells (IECs) and on mice tissues to decipher the underlying mechanisms. SUBJECTS AND METHODS: Nineteen lactobacilli strains have been tested on HT-29 human intestinal epithelial cells for their ability to regulate Fiaf gene expression by RT-qPCR. In order to determine regulated pathways, we analysed the whole genome transcriptome of IECs. We then validated in vivo bacterial effects using C57BL/6 mono-colonized mice fed with normal chow. RESULTS: We identified one strain (Lactobacillus rhamnosus CNCMI-4317) that modulated Fiaf expression in IECs. This regulation relied potentially on bacterial surface-exposed molecules and seemed to be PPAR-gamma independent but PPAR-alpha dependent. Transcriptome functional analysis revealed that multiple pathways including cellular function and maintenance, lymphoid tissue structure and development, as well as lipid metabolism were regulated by this strain. The regulation of immune system and lipid and carbohydrate metabolism was also confirmed by overrepresentation of Gene Ontology terms analysis. In vivo, circulating FIAF protein was increased by the strain but this phenomenon was not correlated with modulation Fiaf expression in tissues (except a trend in distal small intestine). CONCLUSION: We showed that Lactobacillus rhamnosus CNCMI-4317 induced Fiaf expression in human IECs, and increased circulating FIAF protein level in mice. Moreover, this effect was accompanied by transcriptome modulation of several pathways including immune response and metabolism in vitro. PMID- 26439633 TI - Erythematous Variety of Bullous Pemphigoid: Case Report and Literature Review. PMID- 26439632 TI - Endovascular Management of Post-Irradiated Carotid Blowout Syndrome. AB - PURPOSE: To retrospectively evaluate the clinical and technical factors related to the outcomes of endovascular management in patients with head-and-neck cancers associated with post-irradiated carotid blowout syndrome (PCBS). MATERIALS AND METHODS: Between 2000 and 2013, 96 patients with PCBS underwent endovascular management. The 40 patients with the pathological lesions located in the external carotid artery were classified as group 1 and were treated with embolization. The other 56 patients with the pathological lesions located in the trunk of the carotid artery were divided into 2 groups as follows: group 2A comprised the 38 patients treated with embolization, and group 2B comprised the 18 patients treated with stent-graft placement. Fisher's exact test was used to examine endovascular methods, clinical severities, and postprocedural clinical diseases as predictors of outcomes. RESULTS: Technical success and immediate hemostasis were achieved in all patients. The results according to endovascular methods (group 1 vs 2A vs 2B) were as follows: technical complication (1/40[2.5%] vs 9/38[23.7%] vs 9/18[50.0%], P = 0.0001); rebleeding (14/40[35.0%] vs 5/38[13.2%] vs 7/18[38.9%]), P = 0.0435). The results according to clinical severity (acute vs ongoing PCBS) were as follows: technical complication (15/47[31.9%] vs 4/49[8.2%], P = 0.0035); rebleeding (18/47[38.3%] vs 8/49[16.3%], P = 0.0155). The results according to post-procedural clinical disease (regressive vs progressive change) were as follows: alive (14/21[66.7%] vs 8/75[10.7%], P<0.0001); survival time (34.1+/-30.6[0.3-110] vs 3.6+/-4.0[0.07-22] months, P<0.0001). CONCLUSION: The outcomes of endovascular management of PCBS can be improved by taking embolization as a prior way of treatment, performing endovascular intervention in slight clinical severity and aggressive management of the post-procedural clinical disease. PMID- 26439634 TI - Source-ful science. PMID- 26439635 TI - Solute carriers keep on rockin'. PMID- 26439636 TI - Molecular prejudice: RNA discrimination against purines allows response to a cellular alarm. PMID- 26439637 TI - SEC-uring membrane fusion: a sneak peek at SNARE-complex assembly driven by Sec1 Munc18 proteins. PMID- 26439638 TI - Reversible aggregation after heat shock. PMID- 26439640 TI - DNA nano-carrier for repeatable capture and release of biomolecules. AB - DNA can be manipulated to design nano-machines through specific sequence recognition. We report a switchable DNA carrier for repeatable capture and release of a single stranded DNA. The activity of the carrier was regulated by the interactions among a double-stranded actuator, single stranded target, fuel, and anti-fuel DNA strands. Inosine was used to maintain a stable triple-stranded complex when the actuator's conformation was switched between open (capture) and closed (release) configurations. Time lapse fluorescence measurements show repeatable capture and release of target strands. TEM images also show visible capture of target DNA strands when gold nanoparticles were attached to the DNA carrier and the target DNA strand. The carrier activity was controlled by length of toeholds, number of mismatches, and inosine substitutions. Significantly, unlike in previously published work that reported the devices functioned only when there is a perfect match between the interacting DNA strands, the present device works only when there are mismatches in the fuel strand and the best performance is achieved for 1-3 mismatches. The device was used to successfully capture and release gold nanoparticles when linked to the target single-stranded DNA. In general, this type of devices can be used for transport and delivery of theranostic molecules. PMID- 26439639 TI - Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors. AB - Myelin regeneration can occur spontaneously in demyelinating diseases such as multiple sclerosis (MS). However, the underlying mechanisms and causes of its frequent failure remain incompletely understood. Here we show, using an in-vivo remyelination model, that demyelinated axons are electrically active and generate de novo synapses with recruited oligodendrocyte progenitor cells (OPCs), which, early after lesion induction, sense neuronal activity by expressing AMPA (alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainate receptors. Blocking neuronal activity, axonal vesicular release or AMPA receptors in demyelinated lesions results in reduced remyelination. In the absence of neuronal activity there is a ~6-fold increase in OPC number within the lesions and a reduced proportion of differentiated oligodendrocytes. These findings reveal that neuronal activity and release of glutamate instruct OPCs to differentiate into new myelinating oligodendrocytes that recover lost function. Co-localization of OPCs with the presynaptic protein VGluT2 in MS lesions implies that this mechanism may provide novel targets to therapeutically enhance remyelination. PMID- 26439641 TI - Pharmacogenetic Effect of Complement Factor H Gene Polymorphism in Response to the Initial Intravitreal Injection of Bevacizumab for Wet Age-Related Macular Degeneration. AB - PURPOSE: To compare the functional and morphological response to the initial intravitreal (IVT) injection of bevacizumab in exudative age-related macular degeneration (AMD) patients with the complement factor H (CFH) gene polymorphism T1277C in the Brazilian population. METHODS: Twenty-five unrelated patients with treatment-naive exudative AMD underwent an IVT injection of 1.25 mg bevacizumab at the initial presentation (D0) and were reexamined 7 days (D7) and 28 days (D28) later. The time and extent of visual acuity (VA) and central retinal thickness (CRT) changes were evaluated according to the presence of the T1277C polymorphism. RESULTS: In the homozygous risk group (CC), VA improvement was detected mostly from D7 to D28, while in the heterozygous (CT) and homozygous for the wild-type allele (TT) groups, functional response occurred earlier, from D0 to D7. Morphological response to the first IVT injection of bevacizumab was significant in the CT and TT groups, while the CC group presented no significant change in CRT up to D28. CONCLUSION: The CC variant of the CFH gene polymorphism T1277C is related to delayed functional and limited morphological response to the initial IVT injection of bevacizumab in exudative AMD patients in a sample of the Brazilian population. PMID- 26439642 TI - Bile sequestration potential of an edible mineral (clinoptilolite) under simulated digestion of a high-fat meal: an in vitro investigation. AB - Bile, important for cholesterol homeostasis, is a potential target of hypercholesterolemia management. Bile sequestration by orally administered resins, while mostly effective in reducing blood cholesterol, presents several side effects and disadvantages. Thus, widely available natural edible minerals such as clinoptilolite with adsorptive properties offer an alternative for bile sequestration. In an experimental setting mimicking the physiological conditions of digestion/absorption (pH, temperature, and retention times) with a series of assessment methods, scanning electron microscopy-energy dispersion X-ray analysis (SEM-EDX), X-ray diffraction (XRD), Fourier transform infrared analysis (FT-IR), thermogravimetric differential thermal analysis (TG-DTA), and molecular docking modeling, the ability of natural unmodified clinoptilolite to retain bile, while mixed with a simulated high-fat meal, was investigated. Our results demonstrate that clinoptilolite sequesters bile via adsorption of macromicelles at 75.4% efficiency, when the former is administered at a reasonable dose of 4% (w/w) of a meal's weight. This work provides the possibility of clinoptilolite utilization as a bile-sequestering/cholesterol-reducing agent. PMID- 26439643 TI - Measurement of molecular mixing at a conjugated polymer interface by specular and off-specular neutron scattering. AB - Measurements have been performed on thermally equilibrated conjugated polymer/insulating-polymer bilayers, using specular and off-specular neutron reflectivity. While specular reflectivity is only sensitive to the structure normal to the sample, off-specular measurements can probe the structure of the buried polymer/polymer interface in the plane of the sample. Systematic analysis of the scattering from a set of samples with varying insulating-polymer thickness, using the distorted-wave Born approximation (DWBA), has allowed a robust determination of the intrinsic width at the buried polymer/polymer interface. The quantification of this width (12 A +/- 4 A) allows us to examine aspects of the conjugated polymer conformation at the interface, by appealing to self-consistent field theory (SCFT) predictions for equilibrium polymer/polymer interfaces in the cases of flexible and semi-flexible chains. This analysis enables us to infer that mixing at this particular interface cannot be described in terms of polymer chain segments that adopt conformations similar to a random walk. Instead, a more plausible explanation is that the conjugated polymer chain segments become significantly oriented in the plane of the interface. It is important to point out that we are only able to reach this conclusion following the extensive analysis of reflectivity data, followed by comparison with SCFT predictions. It is not simply the case that conjugated polymers would be expected to adopt this kind of oriented conformation at the interface, because of their relatively high chain stiffness. It is the combination of a high stiffness and a relatively narrow intrinsic interfacial width that results in a deviation from flexible chain behaviour. PMID- 26439644 TI - Improvement of the butanol production selectivity and butanol to acetone ratio (B:A) by addition of electron carriers in the batch culture of a new local isolate of Clostridium acetobutylicum YM1. AB - Improvement in the butanol production selectivity or enhanced butanol:acetone ratio (B:A) is desirable in acetone-butanol-ethanol (ABE) fermentation by Clostridium strains. In this study, artificial electron carriers were added to the fermentation medium of a new isolate of Clostridium acetobutylicum YM1 in order to improve the butanol yield and B:A ratio. The results revealed that medium supplementation with electron carriers changed the metabolism flux of electron and carbon in ABE fermentation by YM1. A decrease in acetone production, which subsequently improved the B:A ratio, was observed. Further improvement in the butanol production and B:A ratios were obtained when the fermentation medium was supplemented with butyric acid. The maximum butanol production (18.20 +/- 1.38 g/L) was gained when a combination of methyl red and butyric acid was added. Although the addition of benzyl viologen (0.1 mM) and butyric acid resulted in high a B:A ratio of 16:1 (800% increment compared with the conventional 2:1 ratio), the addition of benzyl viologen to the culture after 4 h resulted in the production of 18.05 g/L butanol. Manipulating the metabolic flux to butanol through the addition of electron carriers could become an alternative strategy to achieve higher butanol productivity and improve the B:A ratio. PMID- 26439645 TI - Effect of application rate on fumigant degradation in five agricultural soils. AB - Soil fumigation is an important pest management tool for many high value crops. To address the knowledge gap of how fumigant concentration in soil impacts dissipation, and thereby efficacy, this research determined the degradation characteristics of four fumigants as affected by application rate. Laboratory incubation experiments were conducted to determine degradation rates of 1,3 dichloropropene (both cis- and trans isomers), chloropicrin (CP), dimethyl disulfide (DMDS), and methyl iodide (MeI) in five agricultural soils. Fitted to pseudo first-order kinetics, the degradation rate constant (k) of CP, DMDS, and MeI decreased significantly as application rate increased while the 1,3-D isomers were the least affected by rate. Half-lives increased 12, 17, and 6-fold for CP, DMDS, and MeI, respectively, from the lowest to the highest application rate. At low application rates, the degradation rate of all fumigants in the Hueneme sandy loam soil was reduced by 50-95% in sterilized soil compared to the biologically active controls. However, this difference became much smaller or disappeared at high application rates indicating that biodegradation dominates at low concentrations but chemical degradation is more important at high concentrations. When co-applied, CP degradation was enhanced with biodegradation remained above 50%, while 1,3-D degradation was either reduced or not changed. Among the fumigants tested, the relative importance of biodegradation was DMDS>CP>MeI>1,3 D. These results are useful for determining effective fumigation rates and for informing regulatory decisions on emission controls under different fumigation scenarios. PMID- 26439646 TI - Commuter exposure to inhalable, thoracic and alveolic particles in various transportation modes in Delhi. AB - A public health concern is to understand the linkages between specific pollution sources and adverse health impacts. Commuting can be viewed as one of the significant-exposure activity in high-vehicle density areas. This paper investigates the commuter exposure to inhalable, thoracic and alveolic particles in various transportation modes in Delhi, India. Air pollution levels are significantly contributed by automobile exhaust and also in-vehicle exposure can be higher sometime than ambient levels. Motorcycle, auto rickshaw, car and bus were selected to study particles concentration along two routes in Delhi between Kashmere Gate and Dwarka. The bus and auto rickshaw were running on compressed natural gas (CNG) while the car and motorcycle were operated on gasoline fuel. Aerosol spectrometer was employed to measure inhalable, thoracic and alveolic particles during morning and evening rush hours for five weekdays. From the study, we observed that the concentration levels of these particles were greatly influenced by transportation modes. Concentrations of inhalable particles were found higher during morning in auto rickshaw (332.81 +/- 90.97 MUg/m(3)) while the commuter of bus exhibited higher exposure of thoracic particles (292.23 +/- 110.45 MUg/m(3)) and car commuters were exposed to maximum concentrations of alveolic particles (222.37 +/- 26.56 MUg/m(3)). We observed that in evening car commuters experienced maximum concentrations of all sizes of particles among the four commuting modes. Interestingly, motorcycle commuters were exposed to lower levels of inhalable and thoracic particles during morning and evening hours as compared to other modes of transport. The mean values were found greater than the median values for all the modes of transport suggesting that positive skewed distributions are characteristics of naturally occurring phenomenon. PMID- 26439647 TI - Environmental fate of the insecticide cypermethrin applied as microgranular and emulsifiable concentrate formulations in sunflower cultivated field plots. AB - A field dissipation and transport study of the insecticide cypermethrin applied as microgranular (MG) and emulsifiable concentrate (EC) formulations has been conducted in field sunflower cultivations and bare soil plots with two different slopes (1% and 5%). The dissipation of insecticide in soil (on planting rows) was monitored for a period of 193 days. Cypermethrin residual concentrations in the upper soil layer (0-10 cm), 2 days after soil application (DASA), ranged from 0.53 to 0.73 MUg g(- 1) when the maximum values were observed 7 DASA, ranged from 1.06 to 1.23 MUg g(-1). The dissipation rate was better described by first-order kinetics. The average half-life in cultivated (tilled and planted) plots was 23.07 and 24.24 days for soil slopes 5% and 1%, respectively. In uncultivated (tilled but not planted) plots the respective values were 22.01 and 22.37 days. The insecticide was found below the 10 cm soil layer occasionally in few samples at low concentrations (< 0.02 MUg g(- 1)). In runoff water it was detected once (7 days after foliar application, at levels below LOQ), when in sediment it was detectable for seven samplings. The maximum values were observed 7 days after foliar application, when they reached 0.097 and 0.143 MUg g(-1) in cultivated plots with soil slopes 1% and 5%; and 0.394 and 0.500 MUg g(-1) in uncultivated plots, respectively. The amount of cypermethrin which was transferred by the sediment remained at low levels (less than 0.01% of the totally applied active ingredient), even in plots with 5% inclination. The insecticide was detected in leaves and stems of the sunflower plants after the foliar application up to the day of harvest. On the contrary, in roots it was detectable during the whole cultivation period. No residues were detected in flowers or seeds. PMID- 26439648 TI - Temporal-spatial loss of diffuse pesticide and potential risks for water quality in China. AB - Increasing amount of pesticide has been used in Chinese agricultural system with effects on environmental quality and human health. The comprehensive inventory of pesticide use in six main crop categories over the period from 1990 to 2011 in China was conducted. The national average pesticide use intensity was estimated 1.74k g . ha(-1) for grain crops in paddy land, 1.31 kg . ha(-1) for grain crops in dry land, 1.38 kg . ha(-1) for economic crops, 3.82 kg . ha(-1) for vegetables, 1.54 kg . ha(-1) for tea plantations, and 3.49 kg . ha(-1) for orchards. The pesticide use was estimated to be approximately 5.24 * 10(4)t for grain crops in paddy land, 1.05 * 10(5)t for grain crops in dry land, 3.08 * 10(4)t for economic crops, 7.51 * 10(4)t for vegetables, 3.26 * 10(3)t for tea plantations, and 4.13 * 10(4)t for orchards. Based on the pesticide use and loss coefficients for each category, the distribution of pesticide loss in China was calculated. Total pesticide loss in China was estimated about 4.39 * 10(3)t in 2011. The pesticide loss from six main crop categories was about 14.84% for grain crops in paddy land of total pesticide loss, 33.31% for grain crops in dry land, 10.47% for economic crops, 26.37% for vegetables, 1.08% for tea plantations and 13.93% for orchards. The results indicated that the highest pesticide use intensity and highest pesticide loss rate occurred in China's eastern and central provinces. The Monte Carlo simulation was used to quantify the uncertainties associated with estimation of pesticide use and loss rate for the six types of crops. The potential risk to national water quality was assessed and the water in the provinces of Henan, Shandong, Hebei, Beijing and Shanghai was at high risk for pesticide pollution. The implication for the future agricultural and environmental policies on reducing the risk to environmental quality was also summarized. PMID- 26439649 TI - A methodological framework to assess the socio-economic impact of underground quarries: A case study from Belgian Limburg. AB - This study developed a methodology to assess the socio-economic impact of the presence and collapse of underground limestone quarries. For this we rely on case study evidence from Riemst, a village located in Eastern Belgium and use both secondary and primary data sources. A sinkhole inventory as well as data about the prevention costs provided by the municipality was used. To estimate the recreational values of the quarries, visitor data was obtained from the tourist office of Riemst. Next, two surveys were conducted among inhabitants and four real estate agents and one notary. The direct and indirect damages were assessed using respectively the repair cost and production and real estate value losses. The total yearly direct and indirect damage equals ?415000 (+/-?85000) and more than half of it can be attributed to the depreciation of real estate (?230000). The quarries have recreational, cultural-historical and ecological values and thus generate societal benefits. The yearly recreational value was at least ?613000 in 2012 values. The ecological and cultural-historical values augment to ?180000 per year (in 2012 values). Further, our study indicates that the gains from filling up the quarries below the houses located above an underground limestone quarry outweigh the costs in the case study area. The net gain from filling up the underground quarry ranges ?38700 to ?101700 per house. This is only the lower bound of the net gain from filling up these underground quarries since preventive filling makes future collapses less likely so that future direct repair costs will be most likely smaller. PMID- 26439650 TI - Stability of nTiO2 particles and their attachment to sand: Effects of humic acid at different pH. AB - The fate and transport of nano-scale or micro-scale titanium dioxide particles (nTiO2) in subsurface environments are strongly influenced by the stability of nTiO2 and their attachment to sediment grains. nTiO2 may carry either positive or negative charges in natural water, therefore, environmental factors such as pH, humic substances, and Fe oxyhydroxide coatings on sediment grains, which are known to control the stability and transport of negatively-charged colloids, may influence nTiO2 in different manners. The objective of this study is to investigate the effects of pH and humic acid (HA) on the stability and attachment of nTiO2 to sand at HA concentrations that are relevant to typical groundwater conditions, so that mechanisms that control nTiO2 immobilization and transport in natural systems can be elucidated. Stability and attachment of nTiO2 to quartz sand and Fe oxyhydroxide coated quartz sand are experimentally measured under a range of HA concentrations at pH5 and 9. Results show that at pH5, negatively charged HA strongly adsorbs to positively-charged nTiO2 and Fe oxyhydroxide, which, at low HA concentrations, partially neutralizes the positive charges on nTiO2 and Fe oxyhydroxide, and therefore decreases the repulsive electrostatic forces between the surfaces, resulting in nTiO2 aggregation and attachment. At high HA concentrations, adsorbed HA reverses the surface charges of nTiO2 and Fe oxyhydroxide, and makes nTiO2 and Fe oxyhydroxide strongly negatively charged, resulting in stable nTiO2 suspension and low nTiO2 attachment. At pH9, HA, nTiO2, and Fe oxyhydroxide are all negatively charged, and HA adsorption is low and does not have a strong impact on the stability and attachment of nTiO2. Overall, this study shows that changes in surface charges of nTiO2 and Fe oxyhydroxide coating caused by HA adsorption is a key factor that influences the stability and attachment of nTiO2. PMID- 26439651 TI - Lipophilicity of PCBs and fatty acids determines their mobilisation from blubber of weaned northern elephant seal pups. AB - Polychlorinated biphenyls (PCBs) exhibit lipophilic properties that lead to their bioaccumulation in adipose tissue. Following PCB exposition, northern elephant seals (Mirounga angustirostris) concentrate high amounts of these pollutants in their large adipose tissue stores. During lipolytic periods such as the post weaning fast, fatty acids (FAs), which form triglycerides, and PCBs are both mobilised from adipose tissue. Our results showed that the degree of lipophilicity of FAs and PCBs impacted their release: the more lipophilic FAs and PCBs tended to be more conserved in blubber over the fast than the less lipophilic ones. This led to an enrichment of more lipophilic compounds within adipocytes with the progression of the fast. Life history patterns that include fasting may thus influence the profile of blubber lipids and contaminants. PMID- 26439652 TI - Estimation of alcohol consumption during "Fallas" festivity in the wastewater of Valencia city (Spain) using ethyl sulfate as a biomarker. AB - Alcohol consumption has been increasing in the last years and it has become a sociological problem due its derived health and safety problems. Ethyl sulfate is a secondary metabolite of the alcohol degradation that is excreted through the urine (0.010-0.016%) after alcohol ingestion and it is quite stable in water. In this study, a new methodology to determine ethyl sulfate by ion-pair liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. Different ion pairs and additives were tested directly in the sample extracts or in the mobile phase. The best ion-pair was set up adding 0.5M of tributylamine and 0.1% of formic acid to the sample. The limit of quantification was 0.3 MUg L(-1) and the intra-day and inter-day precision of the method were <= 2.8 and <= 3.0%, respectively. Good linearity (r(2)<0.999) and low matrix effect (<30% corrected by using internal isotopically labelled internal standard) were achieved. The sampling campaign was from 4th to 20th March of 2014 covering the festivity of Fallas (15th to 19th March). Ethyl sulfate was determined in all influents of the 3 wastewater treatment plants (Pinedo I, Pinedo II and Quart-Benager) belonging to Valencia and surrounding area. Ethyl sulfate concentrations ranged from 1.46 to 19.85 MUg L(-1) and alcohol consumption ranged from 1.07 to 56.11 mL day(-1) inhab(-1), being the highest value of alcohol consumption determined during Fallas. This study presents a reliable and alternative method to traditional ones to determine alcohol consumption by population that provides real-time information of alcohol consumption. PMID- 26439653 TI - Effects of legume species introduction on vegetation and soil nutrient development on abandoned croplands in a semi-arid environment on the Loess Plateau, China. AB - Revegetation facilitated by legume species introduction has been used for soil erosion control on the Loess Plateau, China. However, it is still unclear how vegetation and soil resources develop during this restoration process, especially over the longer term. In this study, we investigated the changes of plant aboveground biomass, vegetation cover, species richness and density of all individuals, and soil total nitrogen, mineral nitrogen, total phosphorus and available phosphorus over 11 years from 2003 to 2013 in three treatments (natural revegetation, Medicago sativa L. introduction and Melilotus suaveolens L. introduction) on the semi-arid Loess Plateau. Medicago significantly increased aboveground biomass and vegetation cover, and soil total nitrogen and mineral nitrogen contents. The Medicago treatment had lower species richness and density of all individuals, lower soil moisture in the deep soil (i.e., 1.4-5m), and lower soil available phosphorus. Melilotus introduction significantly increased aboveground biomass in only the first two years, and it was not an effective approach to improve vegetation biomass and cover, and soil nutrients, especially in later stages of revegetation. Overall, our study suggests that M. sativa can be the preferred plant species for revegetation of degraded ecosystems on the Loess Plateau, although phosphorus fertilizer should be applied for the sustainability of the revegetation. PMID- 26439654 TI - European Code against Cancer 4th Edition: Process of reviewing the scientific evidence and revising the recommendations. AB - The European Code Against Cancer is a set of recommendations to give advice on cancer prevention. Its 4th edition is an update of the 3rd edition, from 2003. Working Groups of independent experts from different fields of cancer prevention were appointed to review the recommendations, supported by a Literature Group to provide scientific and technical support in the assessment of the scientific evidence, through systematic reviews of the literature. Common procedures were developed to guide the experts in identifying, retrieving, assessing, interpreting and summarizing the scientific evidence in order to revise the recommendations. The Code strictly followed the concept of providing advice to European Union citizens based on the current best available science. The advice, if followed, would be expected to reduce cancer risk, referring both to avoiding or reducing exposure to carcinogenic agents or changing behaviour related to cancer risk and to participating in medical interventions able to avert specific cancers or their consequences. The information sources and procedures for the review of the scientific evidence are described here in detail. The 12 recommendations of the 4th edition of the European Code Against Cancer were ultimately approved by a Scientific Committee of leading European cancer and public health experts. PMID- 26439655 TI - Benzodiazepines induce sequelae in immature mice with inflammation-induced status epilepticus. AB - OBJECTIVE: Since benzodiazepines (BZPs) became clinically available for the treatment of status epilepticus (SE) in children, the incidence of neurological sequelae has increased. However, the cause-effect relationship is poorly understood. In this paper, we examined the effect of BZPs on an inflammation induced SE (iSE) animal model. METHOD: Inflammation was induced by injecting poly(I:C) (pIC 10 mg/kg, postnatal day 12-14), seizure was induced by injecting pilocarpine hydrochloride (PILO 200 mg/kg, postnatal day 15) into C57BL/6J mice, and the pIC+PILO mice were used as the iSE model (miSE). The GABA-A receptor agonist midazolam (MDL 0.5 mg/kg) was used to inhibit seizures. Sequelae were evaluated by performing behavior and immunohistochemical analyses in the chronic phase. RESULT: The exploratory activity of mice in the miSE plus MDL group increased significantly, indicating that hyperactivity was newly induced by MDL in miSE mice. The contextual fear memory of the miSE mice was also significantly increased and that of miSE treated with MDL returned to the normal level. The parvalbumin-positive GABA neurons were decreased in number by pIC+PILO which was rescued by MDL. Apoptosis marker ssDNA-positive cells were increased by pIC+PILO which could not be rescued by MDL. Therefore, we propose that BZP-dependent therapy for SE needs to be rethought from the perspective of using other treatment approaches. PMID- 26439656 TI - Seizure detection approach using S-transform and singular value decomposition. AB - Automatic seizure detection plays a significant role in the diagnosis of epilepsy. This paper presents a novel method based on S-transform and singular value decomposition (SVD) for seizure detection. Primarily, S-transform is performed on EEG signals, and the obtained time-frequency matrix is divided into submatrices. Then, the singular values of each submatrix are extracted using singular value decomposition (SVD). Effective features are constructed by adding the largest singular values in the same frequency band together and fed into Bayesian linear discriminant analysis (BLDA) classifier for decision. Finally, postprocessing is applied to obtain higher sensitivity and lower false detection rate. A total of 183.07 hours of intracranial EEG recordings containing 82 seizure events from 20 patients were used to evaluate the system. The proposed method had a sensitivity of 96.40% and a specificity of 99.01%, with a false detection rate of 0.16/h. PMID- 26439657 TI - Evaluate the efficacy of minimum attenuation value in differentiation of adrenal adenomas from nonadenomas on unenhanced CT. AB - Most adrenal masses are adenomas which contain a large amount of intracytoplasmic lipid and have lower attenuation values on unenhanced computed tomography (CT) examinations. Mean atrioventricular and CT histogram analysis is commonly used for the diagnosis of adenomas; however, the former disregards tissue heterogeneities of the mass and diagnostic efficiency is decreased, and the latter demands specific post-processing workstation for analyzing the data. The purpose of our study is to develop a simple and sensitive method for the diagnosis of adenomas on unenhanced CT. PMID- 26439659 TI - Priming of pathogenesis related-proteins and enzymes related to oxidative stress by plant growth promoting rhizobacteria on rice plants upon abiotic and biotic stress challenge. AB - Two plant growth promoting rhizobacteria (PGPR) were tested to evaluate their capacity to prime rice seedlings against stress challenge (salt and Xanthomonas campestris infection). As is accepted that plants respond to biotic and abiotic stresses by generation of reactive oxygen species (ROS), enzyme activities related to oxidative stress (ascorbate peroxidase (APX, EC 1.11.1.11), guaiacol peroxidase (GPX, EC 1.11.1.7), glutathione reductase (GR, EC 1.6.4.2) and superoxide dismutase (SOD, EC 1.15.1.1)) as well as the pathogenesis-related proteins (PRs) beta-1,3-glucanase (PR2, EC 3.2.1.6) and chitinase (PR3, EC 3.2.1.14) were measured at 3 time points after stress challenge. In addition, photosynthetic parameters related with fluorescence emission of photosystem II (F0, Fv/Fm, PhiPSII and NPQ) were also measured although they were barely affected. Both strains were able to protect rice seedlings against salt stress. AMG272 reduced the salt symptoms over 47% with regard to control, and L81 over 90%. Upon pathogen challenge, 90% protection was achieved by both strains. All enzyme activities related to oxidative stress were modified by the two PGPR, especially APX and SOD upon salinity stress challenge, and APX and GR upon pathogen presence. Both bacteria induced chitinase activity 24 and 48 h after pathogen inoculation, and L81 induced beta-1,3-Glucanase activity 48 h after pathogen inoculation, evidencing the priming effect. These results indicate that these strains could be used as bio-fortifying agents in biotechnological inoculants in order to reduce the effects of different stresses, and indirectly reduce the use of agrochemicals. PMID- 26439658 TI - The effect of gender on outcomes of aortoiliac artery interventions for claudication. AB - OBJECTIVE: To explore the relationship between gender, native artery diameters, and outcomes of stent revascularization (ST) in the "Claudication: Exercise versus Endoluminal Revascularization" trial. METHODS: A comparative analysis was performed of the impact of gender, age, weight, height, body mass index, and body surface area on revascularization outcomes at baseline and 6months in 55 arterial segments of aorta, common iliac artery, and external iliac artery (EIA). RESULTS: Women demonstrated smaller diameter of the EIA. However, the clinical outcomes of revascularization were not negatively affected by the gender-based differences. CONCLUSION: Gender-based differences are unlikely to significantly impact outcome of ST. PMID- 26439660 TI - Exogenous administration of chronic corticosterone affects hepatic cholesterol metabolism in broiler chickens showing long or short tonic immobility. AB - Tonic immobility (TI) is an innate characteristic of animals related to fear or stress response. Animals can be classified into long TI (LTI) and short TI (STI) phenotypes based on TI test duration. In this study, effect of TI phenotype, chronic corticosterone administration (CORT), and their interaction on cholesterol metabolism in liver was evaluated in broilers. LTI broilers showed higher level of cholesterol in liver compared to STI chickens (p<0.05), and CORT significantly increased hepatic cholesterol content (p<0.01). Real-time PCR results showed that both TI and CORT potentially altered ABCA1 and CYP7A1 gene expressions (0.0527 years, of the Tehran Lipid and Glucose Study with complete data on serum creatinine, cardio-metabolic risk factors, and diet were included for cross-sectional analysis. After 3 years, 1690 subjects, free of baseline CKD and with complete follow-up data, were included for longitudinal analysis. Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease Study equation and CKD was defined as eGFR < 60 mL/min per 1.73 m(2) . Dietary intake was collected using a food-frequency questionnaire and SSSDs and all kinds of fruit juice drinks were combined to estimate the intake of SSBs. To assess the association of SSBs and CKD, logistic regression adjusted for age, sex, energy intake, smoking, physical activity, body mass index, sodium, diabetes, and hypertension were used. RESULTS: The mean age of participants and serving of SSBs/week were 45.0 years and 2.3, respectively. Compared to participants taking <0.5 serving/week, consumption of more than four servings of SSBs and SSSDs per week was associated with increased odds ratio (OR) of prevalent CKD (1.77 and 2.14, respectively). In longitudinal analyses, the risk of incident CKD increased by consumption of four servings/week, compared to less than 0.5 serving/week of SSBs (OR: 1.96; 95% confidence interval (CI):1.23-3.15) and SSSDs (OR: 2.45; 95% CI:1.55-3.89). CONCLUSION: Consumption of over four servings per week of SSBs and SSSDs was associated with higher prevalence and incidence of CKD. PMID- 26439669 TI - Stable Encapsulated Air Nanobubbles in Water. AB - The dispersion into water of nanocapsules bearing a highly hydrophobic fluorinated internal lining yielded encapsulated air nanobubbles. These bubbles, like their micrometer-sized counterparts (microbubbles), effectively reflected ultrasound. More importantly, the nanobubbles survived under ultrasonication 100 times longer than a commercial microbubble sample that is currently in clinical use. We justify this unprecedented stability theoretically. These nanobubbles, owing to their small size and potential ability to permeate the capillary networks of tissues, may expand the applications of microbubbles in diagnostic ultrasonography and find new applications in ultrasound-regulated drug delivery. PMID- 26439670 TI - International Society on Thrombosis and Haemostasis core curriculum project: core competencies in clinical thrombosis and hemostasis. AB - Essentials The priority of ISTH was to establish a global core curriculum in thrombosis and hemostasis. International survey to determine competencies required for clinical specialists was carried out in the field. Competency framework provides a reference point for mapping and developing regional curricula. Core curriculum informs and links to a variety of ISTH educational materials. SUMMARY: Background The International Society on Thrombosis and Haemostasis (ISTH) identified the need for an international core curriculum on thrombosis and hemostasis for its society members and the larger thrombosis and hemostasis community. Aims The current research sought consensus on the core competencies required by medical doctors who are ready to practise as independent clinical specialists in thrombosis and hemostasis with the aim of developing a core clinical curriculum for specialists in the field. Method A draft list of competencies was developed by the Working Group and formed the basis of an online survey. ISTH members and the larger thrombosis and hemostasis community were asked to rate the importance of each competency, on a Likert scale, for clinical specialists in thrombosis and hemostasis. Results There were a total of 644 responses to the online survey with broad geographical representation. There was general agreement on what level of competency would be required for clinical specialists in thrombosis and hemostasis at the specified level of training. Conclusions Using the survey to gain consensus on the level of competency required by clinical specialists in the field of thrombosis and hemostasis enabled the development of a core clinical curriculum that has been endorsed by the ISTH Council. The curriculum will offer a framework and international reference that will be used by the society, by national and regional organizations, and for further research. PMID- 26439671 TI - Assessing the structure and temporal dynamics of seabird communities: the challenge of capturing marine ecosystem complexity. AB - Understanding interspecific interactions, and the influences of anthropogenic disturbance and environmental change on communities, are key challenges in ecology. Despite the pressing need to understand these fundamental drivers of community structure and dynamics, only 17% of ecological studies conducted over the past three decades have been at the community level. Here, we assess the trophic structure of the procellariiform community breeding at South Georgia, to identify the factors that determine foraging niches and possible temporal changes. We collected conventional diet data from 13 sympatric species between 1974 and 2002, and quantified intra- and inter-guild, and annual variation in diet between and within foraging habits. In addition, we tested the reliability of stable isotope analysis (SIA) of seabird feathers collected over a 13-year period, in relation to those of their potential prey, as a tool to assess community structure when diets are diverse and there is high spatial heterogeneity in environmental baselines. Our results using conventional diet data identified a four-guild community structure, distinguishing species that mainly feed on crustaceans; large fish and squid; a mixture of crustaceans, small fish and squid; or carrion. In total, Antarctic krill Euphausia superba represented 32%, and 14 other species a further 46% of the combined diet of all 13 predators, underlining the reliance of this community on relatively few types of prey. Annual variation in trophic segregation depended on relative prey availability; however, our data did not provide evidence of changes in guild structure associated with a suggested decline in Antarctic krill abundance over the past 40 years. Reflecting the differences in delta(15) N of potential prey (crustaceans vs. squid vs. fish and carrion), analysis of delta(15) N in chick feathers identified a three-guild community structure that was constant over a 13 year period, but lacked the trophic cluster representing giant petrels which was identified using conventional diet data. Our study is the first in recent decades to examine dietary changes in seabird communities over time. Conventional dietary analysis provided better resolution of community structure than SIA. However, delta(15) N in chick feathers, which reflected trophic (level) specialization, was nevertheless an effective and less time-consuming means of monitoring temporal changes. PMID- 26439665 TI - Non-viral therapeutic approaches to ocular diseases: An overview and future directions. AB - Currently there are no viable treatment options for patients with debilitating inherited retinal degeneration. The vast variability in disease-inducing mutations and resulting phenotypes has hampered the development of therapeutic interventions. Gene therapy is a logical approach, and recent work has focused on ways to optimize vector design and packaging to promote optimized expression and phenotypic rescue after intraocular delivery. In this review, we discuss ongoing ocular clinical trials, which currently use viral gene delivery, but focus primarily on new advancements in optimizing the efficacy of non-viral gene delivery for ocular diseases. Non-viral delivery systems are highly customizable, allowing functionalization to improve cellular and nuclear uptake, bypassing cellular degradative machinery, and improving gene expression in the nucleus. Non viral vectors often yield transgene expression levels lower than viral counterparts, however their favorable safety/immune profiles and large DNA capacity (critical for the delivery of large ocular disease genes) make their further development a research priority. Recent work on particle coating and vector engineering presents exciting ways to overcome limitations of transient/low gene expression levels, but also highlights the fact that further refinements are needed before use in the clinic. PMID- 26439672 TI - Chondral fracture of the lateral femoral condyle in children with different treatment methods. AB - Adolescents are predisposed to chondral injuries of the knee; however, the incidence of traumatic chondral and osteochondral fractures and their role in the development of joint degeneration are not fully elucidated. Several methods are described for the treatment of chondral or osteochondral fractures of the knee. In our literature review, we could not find any report on the management of chondral fractures with autologous bone pegs or headless screws. We report three cases of traumatic cartilage fractures of the lateral femoral condyle in adolescents who were treated with three different methods. We also present their follow-up outcomes. PMID- 26439673 TI - Two follistatin-like 1 homologs are differentially expressed in adult tissues and during embryogenesis in grass carp (Ctenopharyngodon idellus). AB - Follistatin-like 1 (Fstl1) peptides play important roles in inhibiting myoblast proliferation and differentiation. Here, we characterized and examined the expression patterns of fstl1a and -b in grass carp (Ctenopharyngodon idellus). These genes encode 314 aa and 310 aa peptides, respectively, sharing a sequence identity of 83%. Except for the existence of the follistatin-N-terminal (FOLN) and Kazal-type 2 serine protease inhibitor (Kazal 2) domains, grass carp Fstl1a and -b do not share amino acid sequence similarity with Fst1 and -b. Both fstl1a and -b mRNAs were widely expressed in adult tissues. During embryogenesis, grass carp fstl1a and -b mRNA was detected in the presomitic mesoderm and somites at 12h post fertilization (hpf). At 24hpf, fstl1a mRNA was expressed in the hindbrain, somites, notochord and tailbud, while fstl1b mRNA was only detected in the tailbud. At 36hpf, fstl1a mRNA was detected in the hindbrain and notochord, and fstl1b was also expressed in the notochord. Furthermore, fstl1a and -b were downregulated in brain and liver tissue following injection with 10 or 50MUg hGH, while fstl1b was significantly up-regulated in muscle tissue after 10MUg hGH treatment. Both fstl1a and -b were significantly up-regulated at 2, 4 or 6days of nutrient restriction, and fstl1a was still highly expressed in the liver and muscle after 3days of refeeding, as was fstl1b in the brain and muscle. The expression of these genes returned to near control levels following 6days of refeeding. Our findings suggest that the two fstls play important but divergent roles in embryonic development and tissue growth regulation in grass carp. PMID- 26439674 TI - Cognitive-behavioral therapy for sleep disturbances in treating posttraumatic stress disorder symptoms: A meta-analysis of randomized controlled trials. AB - Sleep disturbances are frequently reported in patients with posttraumatic stress disorder (PTSD). There is evidence that sleep disturbance is not only a secondary symptom but also a risk factor for PTSD. Sleep-specific psychological treatments provide an alternative to conventional trauma-focused psychological treatments. The current meta-analysis evaluated the efficacy of sleep-specific cognitive behavioral therapy (CBT) in mitigating PTSD, sleep, and depressive symptoms. A total of 11 randomized controlled trials were included in the meta-analytic comparisons between sleep-specific CBT and waiting-list control groups at posttreatment. Random effects models showed significant reduction in self-report PTSD and depressive symptoms and insomnia severity in the sleep-specific CBT group. The corresponding effect sizes, measured in Hedges' g, were 0.58, 0.44, and 1.15, respectively. The effect sizes for sleep diary-derived sleep onset latency, wake after sleep onset, and sleep efficiency were 0.83, 1.02 and 1.15, respectively. The average study attrition rate of sleep-specific CBT was relatively low (12.8%), with no significant difference from the control group (9.4%). In conclusion, sleep-specific CBT appears to be efficacious and feasible in treating PTSD symptoms. Due to the relatively small number of randomized controlled trials available, further research is warranted to confirm its efficacy and acceptability, especially in comparison to trauma-specific psychological treatments. PMID- 26439675 TI - Temperate phages promote colicin-dependent fitness of Salmonella enterica serovar Typhimurium. AB - Bacteria employ bacteriocins for interference competition in microbial ecosystems. Colicin Ib (ColIb), a pore-forming bacteriocin, confers a significant fitness benefit to Salmonella enterica serovar Typhimurium (S. Tm) in competition against commensal Escherichia coli in the gut. ColIb is released from S. Tm into the environment, where it kills susceptible competitors. However, colicin specific release proteins, as they are known for other colicins, have not been identified in case of ColIb. Thus, its release mechanism has remained unclear. In the current study, we have established a new link between ColIb release and lysis activity of temperate, lambdoid phages. By the use of phage-cured S. Tm mutant strains, we show that the presence of temperate phages and their lysis genes is necessary and sufficient for release of active ColIb into the culture supernatant. Furthermore, phage-mediated lysis significantly enhanced S. Tm fitness in competition against a ColIb-susceptible competitor. Finally, transduction with the lambdoid phage 933W rescued the defect of E. coli strain MG1655 with respect to ColIb release. In conclusion, ColIb is released from bacteria in the course of phage lysis. Our data reveal a new mechanism for colicin release and point out a novel function of temperate phages in enhancing colicin-dependent bacterial fitness. PMID- 26439676 TI - A Survey of the Impact of Deyolking on Biological Processes Covered by Shotgun Proteomic Analyses of Zebrafish Embryos. AB - Deyolking, the removal of the most abundant protein from the zebrafish (Danio rerio) embryo, is a common technique for in-depth exploration of proteome-level changes in vivo due to various environmental stressors or pharmacological impacts during embryonic stage of development. However, the effect of this procedure on the remaining proteome has not been fully studied. Here, we report a label-free shotgun proteomics survey on proteome coverage and biological processes that are enriched and depleted as a result of deyolking. Enriched proteins are involved in cellular energetics and development pathways, specifically implicating enrichment related to mitochondrial function. Although few proteins were removed completely by deyolking, depleted molecular pathways were associated with calcium signaling and signaling events implicating immune system response. PMID- 26439677 TI - Hexagonal Boron Nitride-Graphene Heterostructures: Synthesis and Interfacial Properties. AB - Research on in-plane and vertically-stacked heterostructures of graphene and hexagonal boron nitride (h-BN) have attracted intense attentions for energy band engineering and device performance optimization of graphene. In this review article, recent advances in the controlled syntheses, interfacial structures, and electronic properties, as well as novel device constructions of h-BN and graphene heterostructures are highlighted. Firstly, diverse synthesis approaches for in plane h-BN and graphene (h-BN-G) heterostructures are reviewed, and their applications in nanoelectronics are briefly introduced. Moreover, the interfacial structures and electronic properties of h-BN-G heterojunctions are discussed, and a zigzag type interface is found to preferentially evolve at the linking edge of the two structural analogues. Secondly, several synthetic routes for the vertically-stacked graphene/h-BN (G/h-BN) heterostructures are also reviewed. The role of h-BN as perfect dielectric layers in promoting the device performance of graphene is presented. Finally, future research directions in the synthesis and application of such heterostructures are discussed. PMID- 26439678 TI - How will the semi-natural vegetation of the UK have changed by 2030 given likely changes in nitrogen deposition? AB - Nitrogen deposition is known to have major impacts on contemporary ecosystems but few studies have addressed how these impacts will develop over coming decades. We consider likely changes to British semi-natural vegetation up to the year 2030 both qualitatively, based on knowledge of species responses from experimental and gradient studies, and quantitatively, based on modelling of species relationships in national monitoring data. We used historical N deposition trends and national predictions of changing deposition to calculate cumulative deposition from 1900 to 2030. Data from the Countryside Survey (1978, 1990 and 1998) was used to parameterise models relating cumulative N deposition to Ellenberg N which were then applied to expected future deposition trends. Changes to habitat suitability for key species of grassland, heathland and bog, and broadleaved woodland to 2030 were predicted using the MultiMOVE model. In UK woodlands by 2030 there is likely to be reduced occurrence of lichens, increased grass cover and a shift towards more nitrophilic vascular plant species. In grasslands we expect changing species composition with reduced occurrence of terricolous lichens and, at least in acid grasslands, reduced species richness. In heaths and bogs we project overall reductions in species richness with decreased occurrence of terricolous lichens and some bryophytes, reduced cover of dwarf shrubs and small increases in grasses. Our study clearly suggests that changes in vegetation due to nitrogen deposition are likely to continue through coming decades. PMID- 26439679 TI - Correlation between electromyography and quantitative ultrasonography of facial muscles in patients with facial palsy. AB - INTRODUCTION: In this study we correlated results of ultrasonographic muscle thickness and contractility with facial electromyography (EMG) in patients with unilateral peripheral acute or chronic facial palsy. METHODS: Two hundred twenty measurements of 4 facial muscles (frontalis, orbicularis oculi, zygomaticus, and orbicularis oris) were performed in 44 patients. RESULTS: Facial muscle thickness at rest and during muscle contraction correlated best with EMG insertional activity, and facial muscle contractility correlated with EMG voluntary activity. The correlation was much higher at >14 days after onset of facial palsy. The orbicularis oris, followed by the frontalis muscle, showed the best correlation between ultrasound and EMG. CONCLUSIONS: Quantitative ultrasound of facial muscles helps confirm the results of facial EMG and is of particular additional value in the first 14 days after onset when the reliability of EMG is low. PMID- 26439680 TI - Development and preliminary evaluation of a genomewide single nucleotide polymorphisms resource generated by RAD-seq for the small yellow croaker (Larimichthys polyactis). AB - Recent advances in high-throughput sequencing technologies have offered the possibility to generate genomewide sequence data to delineate previously unidentified genetic structure, obtain more accurate estimates of demographic parameters and to evaluate potential adaptive divergence. Here, we identified 27 556 single nucleotide polymorphisms for the small yellow croaker (Larimichthys polyactis) using restriction-site-associated DNA (RAD) sequencing of 24 individuals from two populations. Significant sources of genetic variation were identified, with an average nucleotide diversity (pi) of 0.00105 +/- 0.000425 across individuals, and long-term effective population size was thus estimated to range between 26 172 and 261 716. According to the results, no differentiation between the two populations was detected based on the SNP data set of top quality score per contig or neutral loci. However, the two analysed populations were highly differentiated based on SNP data set of both top FST value per contig and the outlier SNPs. Moreover, local adaptation was highlighted by an FST -based outlier tests implemented in LOSITAN and a total of 538 potentially locally selected SNPs were identified. blast2go annotation of contigs containing the outlier SNPs yielded hits for 37 (66%) of 56 significant blastx matches. Candidate genes for local adaptation constituted a wide array of biological functions, including cellular response to oxidative stress, actin filament binding, ion transmembrane transport and synapse assembly. The generated SNP resources in this study provided a valuable tool for future population genetics and genomics studies of L. polyactis. PMID- 26439681 TI - Flavonoids of Korean Citrus aurantium L. Induce Apoptosis via Intrinsic Pathway in Human Hepatoblastoma HepG2 Cells. AB - Korean Citrus aurantium L. has long been used as a medicinal herb for its anti inflammatory, antioxidant, and anticancer properties. The present study investigates the anticancer role of flavonoids extracted from C. aurantium on human hepatoblastoma cell, HepG2. The Citrus flavonoids inhibit the proliferation of HepG2 cells in a dose-dependent manner. This result was consistent with the in vivo xenograft results. Apoptosis was detected by cell morphology, cell cycle analysis, and immunoblot. Flavonoids decreased the level of pAkt and other downstream targets of phosphoinositide-3-kinase/Akt pathway - P-4EBP1 and P p70S6K. The expressions of cleaved caspase 3, Bax, and Bak were increased, while those of Bcl-2 and Bcl-xL were decreased with an increase in the expression of Bax/Bcl-xL ratio in treated cells. Loss of mitochondrial membrane potential was also observed in flavonoid-treated HepG2 cells. It was also observed that the P p38 protein level was increased both dose and time dependently in flavonoid treated cells. Collectively, these results suggest that flavonoid extracted from Citrus inhibits HepG2 cell proliferation by inducing apoptosis via an intrinsic pathway. These findings suggest that flavonoids extracted from C. aurantium L. are potential chemotherapeutic agents against liver cancer. PMID- 26439682 TI - p21 upregulation in hair follicle stem cells is associated with telogen retention in aged mice. PMID- 26439683 TI - Automated prognostic pattern detection shows favourable diffuse pattern of FOXP3(+) Tregs in follicular lymphoma. AB - BACKGROUND: Histopathological prognostication relies on morphological pattern recognition, but as numbers of biomarkers increase, human prognostic pattern recognition ability decreases. Follicular lymphoma (FL) has a variable outcome, partly determined by FOXP3 Tregs. We have developed an automated method, hypothesised interaction distribution (HID) analysis, to analyse spatial patterns of multiple biomarkers which we have applied to tumour-infiltrating lymphocytes in FL. METHODS: A tissue microarray of 40 patient samples was used in triplex immunohistochemistry for FOXP3, CD3 and CD69, and multispectral imaging used to determine the numbers and locations of CD3(+), FOXP3/CD3(+) and CD69/CD3(+) T cells. HID analysis was used to identify associations between cellular pattern and outcome. RESULTS: Higher numbers of CD3(+) (P=0.0001), FOXP3/CD3(+) (P=0.0031) and CD69/CD3(+) (P=0.0006) cells were favourable. Cross-validated HID analysis of cell pattern identified patient subgroups with statistically significantly different survival (35.5 vs 142 months, P=0.00255), a more diffuse pattern associated with favourable outcome and an aggregated pattern with unfavourable outcome. CONCLUSIONS: A diffuse pattern of FOXP3 and CD69 positivity was favourable, demonstrating ability of HID analysis to automatically identify prognostic cellular patterns. It is applicable to large numbers of biomarkers, representing an unsupervised, automated method for identification of undiscovered prognostic cellular patterns in cancer tissue samples. PMID- 26439684 TI - HIF2alpha is involved in the expansion of CXCR4-positive cancer stem-like cells in renal cell carcinoma. AB - BACKGROUND: Hypoxia and the subsequent activation of hypoxia-inducible factor 2alpha (HIF2alpha) contribute to the progression of a variety of cancers. However, their role in the generation of renal cell carcinoma-derived stem cells has not been fully addressed. METHODS: A sphere formation assay, cell proliferation, RT-PCR, western blot, FACS, immunohistochemistry and tumour xenograft were used to study the role of HIF2alpha. RESULTS: Propagation of four renal cell carcinoma (RCC) cell lines (Caki-1, Caki-2, 786-O, 769-P) in anchorage independent floating spheres led to the expansion of cells bearing the CXCR4 (CD184) surface marker. Inhibition of the CXCR4 pathway reduced sphere expansion. The enhanced self-renewal activity of the CXCR4-positive spheres was preceded by the upregulation of HIF2alpha. Knockdown of HIF2alpha abrogated CXCR4 expression and sphere formation. Finally, RCC-derived spheres showed an undifferentiated phenotype in vivo and formed subcutaneous tumours that highly expressed HIF2alpha and CXCR4. Inhibition of HIF2alpha abolished tumour growth in animal models. CONCLUSIONS: These results suggest that the generation of RCC-derived CSCs involves the activation of HIF2alpha and may provide a foundation for the development of new strategies to prevent the induction of CSCs in RCC. PMID- 26439685 TI - Prediction of coronary artery disease risk based on multiple longitudinal biomarkers. AB - In the last decade, few topics in the area of cardiovascular disease (CVD) research have received as much attention as risk prediction. One of the well documented risk factors for CVD is high blood pressure (BP). Traditional CVD risk prediction models consider BP levels measured at a single time and such models form the basis for current clinical guidelines for CVD prevention. However, in clinical practice, BP levels are often observed and recorded in a longitudinal fashion. Information on BP trajectories can be powerful predictors for CVD events. We consider joint modeling of time to coronary artery disease and individual longitudinal measures of systolic and diastolic BPs in a primary care cohort with up to 20 years of follow-up. We applied novel prediction metrics to assess the predictive performance of joint models. Predictive performances of proposed joint models and other models were assessed via simulations and illustrated using the primary care cohort. PMID- 26439686 TI - Characterization of adipose-derived stem cells from subcutaneous and visceral adipose tissues and their function in breast cancer cells. AB - Adipose-derived stem cells are capable of differentiating into multiple cell types and thus considered useful for regenerative medicine. However, this differentiation feature seems to be associated with tumor initiation and metastasis raising safety concerns, which requires further investigation. In this study, we isolated adipose-derived stem cells from subcutaneous as well as from visceral adipose tissues of the same donor and systematically compared their features. Although being characteristic of mesenchymal stem cells, subcutaneous adipose-derived stem cells tend to be spindle form-like and are more able to home to cancer cells, whereas visceral adipose-derived stem cells incline to be "epithelial"-like and more competent to differentiate. Moreover, compared to subcutaneous adipose-derived stem cells, visceral adipose-derived stem cells are more capable of promoting proliferation, inducing the epithelial-to-mesenchymal transition, enhancing migration and invasion of breast cancer cells by cell-cell contact and by secreting interleukins such as IL-6 and IL-8. Importantly, ASCs affect the low malignant breast cancer cells MCF-7 more than the highly metastatic MDA-MB-231 cells. Induction of the epithelial-to-mesenchymal transition is mediated by the activation of multiple pathways especially the PI3K/AKT signaling in breast cancer cells. BCL6, an important player in B-cell lymphoma and breast cancer progression, is crucial for this transition. Finally, this transition fuels malignant properties of breast cancer cells and render them resistant to ATP competitive Polo-like kinase 1 inhibitors BI 2535 and BI 6727. PMID- 26439687 TI - RASSF8 downregulation promotes lymphangiogenesis and metastasis in esophageal squamous cell carcinoma. AB - Lymphatic vessels are the major routes of human esophageal squamous cell carcinoma (ESCC) metastasis. Tumor cells secrete pro-lymphangiogenic factors to induce new lymphatic vessels, promoting lymph node metastasis. In this study, we show that RAS association domain family 8 (RASSF8) expression in ESCC clinical samples was inversely correlated with lymph node metastasis and patients survival. Tumor cells with low RASSF8 expression had higher apparent migratory ability, and promoted and lymphangiogenesis both in vitro and in vivo. RASSF8 downregulation enhanced VEGF-C expression and caused subcellular redistribution of p65 in ESCC. Our results show that RASSF8 acts as a tumor suppressor in ESCC and is a potential therapeutic target for preventing lymph node metastasis. PMID- 26439688 TI - miRNA interventions serve as 'magic bullets' in the reversal of glioblastoma hallmarks. AB - microRNAs (miRNAs) are no longer deemed small pieces of RNA "trash" in the human transcriptome but are considered to be master regulators of gene expression that are critical in maintaining cellular homeostasis post-transcriptionally. The concept triggers great interest in studying miRNA dysregulations in human diseases, especially in cancers. Glioblastoma (GBM) has long been the leading cause of the high mortality and morbidity of CNS tumors in adults, which is a consequence of the lack of strategies to reverse the hallmark features of GBM (e.g., borderless expansion and diffuse infiltration). In the past decade, dissecting the molecular architecture of GBM has led to a better understanding of the molecular basis of the hallmarks, generating many promising pharmacological protein targets. However, few clinical responses have been highlighted, suggesting the demand for new therapeutic strategies and targets. In this review, we systemically summarize the context-dependently validated miRNAs with one or more functional targets in the development of GBM hallmarks and review the current miRNA-targeting strategies. We note that only a few miRNA-based therapeutics are trialed for clinical significance, and none of them is tailored to GBM, thereby urging us to bring miRNA therapeutics to the front line either alone or in combination. PMID- 26439689 TI - Vascular heterogeneity and targeting: the role of YKL-40 in glioblastoma vascularization. AB - Malignant glioblastomas (GBM) are highly malignant brain tumors that have extensive and aberrant tumor vasculature, including multiple types of vessels. This review focuses on recent discoveries that the angiogenic factor YKL-40 (CHI3L1) acts on glioblastoma-stem like cells (GSCs) to drive the formation of two major forms of tumor vascularization: angiogenesis and vasculogenic mimicry (VM). GSCs possess multipotent cells able to transdifferentiate into vascular pericytes or smooth muscle cells (PC/SMCs) that either coordinate with endothelial cells (ECs) to facilitate angiogenesis or assemble in the absence of ECs to form blood-perfused channels via VM. GBMs express high levels of YKL-40 that drives the divergent signaling cascades to mediate the formation of these distinct microvascular circulations. Although a variety of anti-tumor agents that target angiogenesis have demonstrated transient benefits for patients, they often fail to restrict tumor growth, which underscores the need for additional therapeutic tools. We propose that targeting YKL-40 may compliment conventional anti-angiogenic therapies to provide a substantial clinical benefit to patients with GBM and several other types of solid tumors. PMID- 26439690 TI - Genetic variations of body weight and GCRV resistance in a random mating population of grass carp. AB - The grass carp (Ctenopharyngodon idellus) is an important species in freshwater aquaculture both in China and on a global scale. Variety degeneration and frequent diseases have limited the further development of grass carp aquaculture. Thus, new and improved varieties are required. Here, we identified and assessed the body weight and disease resistance in a random mating population of 19 a?? * 22 a?? grass carp, which were derived from different water systems. In both the growth experimental group of 10,245 fish and grass carp reovirus (GCRV)-infected group with 10,000 fish, 78 full-sib families were statistically analyzed for body weight and GCRV resistance. The findings showed that body weight traits had low heritability (0.11 +/- 0.04, 0.10 +/- 0.03 and 0.12 +/- 0.05), GCRV resistance traits had high heritability (0.63 +/- 0.11); body weight was higher in 3 families, whereas GCRV resistance was significantly greater in 11 families. Our results confirmed that the natural germplasm resources of wild grass carp were genetically diverse. Breeding of GCRV resistant varieties of grass carp have better genetic basis. This study provides the basis for constructing basal populations for grass carp selective breeding, quantitative trait loci (QTL) and genome-wide association studies (GWAS) analysis. PMID- 26439691 TI - Aging with ING: a comparative study of different forms of stress induced premature senescence. AB - Cell senescence contributes to organismal aging and is induced by telomere erosion and an ensuing DNA damage signal as cells reach the end of their replicative lifespan in vitro or in vivo. Stresses induced by oncogene or tumor suppressor hyperactivation, oxidative stress, ionizing radiation and other DNA damaging agents result in forms of stress induced premature senescence (SIPS) that show similarities to replicative senescence. Since replicative senescence and SIPS occur over many days and many population doublings of the mass cultures of primary cells used to study senescence, the sequence of events that occur downstream of senescence signaling can be challenging to define. Here we compare a new model of ING1a-induced senescence with several other forms of senescence. The ING1a epigenetic regulator synchronously induces senescence in mass cultures several-fold faster than all other agents, taking 24 and 36 hours to activate the Rb/ p16INK4a, but not the p53 tumor suppressor axis to efficiently induce senescence. ING1a induces expression of intersectin 2, a scaffold protein necessary for endocytosis, altering the stoichiometry of endocytosis proteins, subsequently blocking growth factor uptake leading to activation of Rb signaling to block cell growth. ING1a acts as a novel link in the activation of the Rb pathway that can impose senescence in the absence of activating p53-mediated DNA damage signaling, and should prove useful in defining the molecular events contributing to Rb-induced senescence. PMID- 26439692 TI - Characterisation of inflammatory processes in Helicobacter pylori-induced gastric lymphomagenesis in a mouse model. AB - Gastric MALT lymphoma (GML) can be induced by Helicobacter pylori infection in BALB/c mice thymectomised at day 3 post-birth (d3Tx). This represented a unique opportunity to investigate the inflammatory process involved in the recruitment, proliferation and structuration of lymphoid infiltrates in the gastric mucosa of mice developing GML. Complementary molecular and proteomic approaches demonstrated that Th1 and Th2 cytokines were upregulated, along with activators/regulators of the lymphoid response and numerous chemokines. Interleukin-4, interferon gamma, lymphotoxin-alpha and -beta were significantly upregulated and correlated with the inflammatory scores for all the d3Tx mice. GML lesions in d3Tx mice infected with H. pylori were associated with the presence of the inflammatory response. The dysregulation of numerous members of the tumour necrosis factor superfamily was also evident and suggests that they could play an important role in GML pathology, especially in light of their ability to promote and control lymphocyte proliferation. PMID- 26439693 TI - Antitumor activity of a potent MEK inhibitor, TAK-733, against colorectal cancer cell lines and patient derived xenografts. AB - BACKGROUND: CRC is a significant cause of cancer mortality, and new therapies are needed for patients with advanced disease. TAK-733 is a highly potent and selective investigational novel MEK allosteric site inhibitor. MATERIALS AND METHODS: In a preclinical study of TAK-733, a panel of CRC cell lines were exposed to varying concentrations of the agent for 72 hours followed by a sulforhodamine B assay. Twenty patient-derived colorectal cancer xenografts were then treated with TAK-733 in vivo. Tumor growth inhibition index (TGII) was assessed to evaluate the sensitivity of the CRC explants to TAK-733 while linear regression was utilized to investigate the predictive effects of genotype on the TGII of explants. RESULTS: Fifty-four CRC cell lines were exposed to TAK-733, while 42 cell lines were deemed sensitive across a broad range of mutations. Eighty-two percent of the cell lines within the sensitive subset were BRAF or KRAS/NRAS mutant, whereas 80% of the cell lines within the sensitive subset were PIK3CA WT. Twenty patient-derived human tumor CRC explants were then treated with TAK-733. In total, 15 primary human tumor explants were found to be sensitive to TAK-733 (TGII <= 20%), including 9 primary human tumor explants that exhibited tumor regression (TGII > 100%). Explants with a BRAF/KRAS/NRAS mutant and PIK3CA wild-type genotype demonstrated increased sensitivity to TAK-733 with a median TGII of -6%. MEK-response gene signatures also correlated with responsiveness to TAK-733 in KRAS-mutant CRC. CONCLUSIONS: The MEK inhibitor TAK-733 demonstrated robust antitumor activity against CRC cell lines and patient-derived tumor explants. While the preclinical activity observed in this study was considerable, single-agent efficacy in the clinic has been limited in CRC, supporting the use of these models in an iterative manner to elucidate resistance mechanisms that can guide rational combination strategies. PMID- 26439694 TI - Comprehensive cancer-gene panels can be used to estimate mutational load and predict clinical benefit to PD-1 blockade in clinical practice. AB - Cancer gene panels (CGPs) are already used in clinical practice to match tumor's genetic profile with available targeted therapies. We aimed to determine if CGPs could also be applied to estimate tumor mutational load and predict clinical benefit to PD-1 and CTLA-4 checkpoint blockade therapy. Whole-exome sequencing (WES) mutation data obtained from melanoma and non-small cell lung cancer (NSCLC) patients published by Snyder et al. 2014 and Rizvi et al. 2015, respectively, were used to select nonsynonymous somatic mutations occurring in genes included in the Foundation Medicine Panel (FM-CGP) and in our own Institutional Panel (HSL CGP). CGP-mutational load was calculated for each patient using both panels and was associated with clinical outcomes as defined and reported in the original articles. Higher CGP-mutational load was observed in NSCLC patients presenting durable clinical benefit (DCB) to PD-1 blockade (FM-CGP P=0.03, HSL-CGP P=0.01). We also observed that 69% of patients with high CGP-mutational load experienced DCB to PD-1 blockade, as compared to 20% of patients with low CGP-mutational load (FM-CGP and HSL-CGP P=0.01). Noteworthy, predictive accuracy of CGP-mutational load for DCB was not statistically different from that estimated by WES sequencing (P=0.73). Moreover, a high CGP-mutational load was significantly associated with progression-free survival (PFS) in patients treated with PD-1 blockade (FM-CGP P=0.005, HR 0.27, 95% IC 0.105 to 0.669; HSL-CGP P=0.008, HR 0.29, 95% IC 0.116 to 0.719). Similar associations between CGP-mutational load and clinical benefit to CTLA-4 blockade were not observed. In summary, our data reveals that CGPs can be used to estimate mutational load and to predict clinical benefit to PD-1 blockade, with similar accuracy to that reported using WES. PMID- 26439695 TI - Remarkable similarities of chromosomal rearrangements between primary human breast cancers and matched distant metastases as revealed by whole-genome sequencing. AB - To better understand and characterize chromosomal structural variation during breast cancer progression, we enumerated chromosomal rearrangements for 11 patients by performing low-coverage whole-genome sequencing of 11 primary breast tumors and their 13 matched distant metastases. The tumor genomes harbored a median of 85 (range 18-404) rearrangements per tumor, with a median of 82 (26 310) in primaries compared to 87 (18-404) in distant metastases. Concordance between paired tumors from the same patient was high with a median of 89% of rearrangements shared (range 61-100%), whereas little overlap was found when comparing all possible pairings of tumors from different patients (median 3%). The tumors exhibited diverse genomic patterns of rearrangements: some carried events distributed throughout the genome while others had events mostly within densely clustered chromothripsis-like foci at a few chromosomal locations. Irrespectively, the patterns were highly conserved between the primary tumor and metastases from the same patient. Rearrangements occurred more frequently in genic areas than expected by chance and among the genes affected there was significant enrichment for cancer-associated genes including disruption of TP53, RB1, PTEN, and ESR1, likely contributing to tumor development. Our findings are most consistent with chromosomal rearrangements being early events in breast cancer progression that remain stable during the development from primary tumor to distant metastasis. PMID- 26439696 TI - Cx26 knockout predisposes the mammary gland to primary mammary tumors in a DMBA induced mouse model of breast cancer. AB - Down-regulation of the gap junction protein connexin26 (Cx26) is an early event following breast cancer onset and has led to Cx26 being classically described as a tumor suppressor. Interestingly, mutations in theCx26 gene (GJB2) reduce or ablate Cx26 gap junction channel function and are the most common cause of genetic deafness. It is unknown if patients with loss-of-function GJB2 mutations have a greater susceptibility to breast tumorigenesis or aggressive breast cancer progression. To investigate these possibilities, 7, 12 dimethylbenz[alpha]anthracene (DMBA)-induced tumor development was evaluated in BLG-Cre; Cx26fl/fl mice expressing Cre under the beta-Lactoglobulin promoter (Cre+) compared to Cx26fl/fl controlmice (Cre-) following pituitary isograft driven Cx26 knockout. A significantly increased number of DMBA-treated Cre+ mice developed primary mammary tumors, as well as developed multiple tumors, compared to Cre- mice. Primary tumors of Cre+ mice were of multiple histological subtypes and had similar palpable tumour onset and growth rate compared to tumors from Cre mice. Lungs were evaluated for evidence of metastases revealing a similar percentage of lung metastases in Cre+ and Cre- mice. Together, our results suggest that loss of Cx26 predisposes the mammary gland to chemically induced mammary tumour formation which may have important implications to patients with GJB2 mutations. PMID- 26439697 TI - Characterization of a mantle cell lymphoma cell line resistant to the Chk1 inhibitor PF-00477736. AB - Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by the chromosomal translocation t(11;14) that leads to constitutive expression of cyclin D1, a master regulator of the G1-S phase. Chk1 inhibitors have been recently shown to be strongly effective as single agents in MCL. To investigate molecular mechanisms at the basis of Chk1 inhibitor activity, a MCL cell line resistant to the Chk1 inhibitor PF-00477736 (JEKO-1 R) was obtained and characterized. The JEKO-1 R cell line was cross resistant to another Chk1 inhibitor (AZD-7762) and to the Wee1 inhibitor MK-1775. It displayed a shorter doubling time than parental cell line, likely due to a faster S phase. Cyclin D1 expression levels were decreased in resistant cell line and its re-overexpression partially re-established PF-00477736 sensitivity. Gene expression profiling showed an enrichment in gene sets involved in pro-survival pathways in JEKO-1 R. Dasatinib treatment partly restored PF-00477736 sensitivity in resistant cells suggesting that the pharmacological interference of pro-survival pathways can overcome the resistance to Chk1 inhibitors. These data further corroborate the involvement of the t(11;14) in cellular sensitivity to Chk1 inhibitors, fostering the clinical testing of Chk1 inhibitors as single agents in MCL. PMID- 26439698 TI - PPE26 induces TLR2-dependent activation of macrophages and drives Th1-type T-cell immunity by triggering the cross-talk of multiple pathways involved in the host response. AB - The pathophysiological functions and the underlying molecular basis of PE /PPE proteins of M. tuberculosis remain largely unknown. In this study, we focused on the link between PPE26 and host response. We demonstrated that PPE26 can induce extensive inflammatory responses in macrophages through triggering the cross-talk of multiple pathways involved in the host response, as revealed by iTRAQ-based subcellular quantitative proteomics. We observed that PPE26 is able to specifically bind to TLR2 leading to the subsequent activation of MAPKs and NF kappaB signaling. PPE26 functionally stimulates macrophage activation by augmenting pro-inflammatory cytokine production (TNF-alpha, IL-6 and IL-12 p40) and the expression of cell surface markers (CD80, CD86, MHC class I and II). We observed that PPE26-treated macrophages effectively polarizes naive CD4(+) T cells to up-regulate CXCR3 expression, and to secrete IFN-gamma and IL-2, indicating PPE26 contributes to the Th1 polarization during the immune response. Importantly, rBCG::PPE26 induces stronger antigen-specific TNF-alpha and IFN gamma activity, and higher levels of the Th1 cytokines TNF-alpha and IFN-gamma comparable to BCG. Moreover, PPE26 effectively induces the reciprocal expansion of effector/memory CD4(+)/CD8(+) CD44(high)CD62L(low) T cells in the spleens of mice immunized with this strain. These results suggest that PPE26 may be a TLR2 agonist that stimulates innate immunity and adaptive immunity, indicating that PPE26 is a potential antigen for the rational design of an efficient vaccine against M. tuberculosis. PMID- 26439701 TI - Switchable Opening and Closing of a Liquid Marble via Ultrasonic Levitation. AB - Liquid marbles have promising applications in the field of microreactors, where the opening and closing of their surfaces plays a central role. We have levitated liquid water marbles using an acoustic levitator and, thereby, achieved the manipulation of the particle shell in a controlled manner. Upon increasing the sound intensity, the stable levitated liquid marble changes from a quasi-sphere to a flattened ellipsoid. Interestingly, a cavity on the particle shell can be produced on the polar areas, which can be completely healed when decreasing the sound intensity, allowing it to serve as a microreactor. The integral of the acoustic radiation pressure on the part of the particle surface protruding into air is responsible for particle migration from the center of the liquid marble to the edge. Our results demonstrate that the opening and closing of the liquid marble particle shell can be conveniently achieved via acoustic levitation, opening up a new possibility to manipulate liquid marbles coated with non ferromagnetic particles. PMID- 26439699 TI - Piperine metabolically regulates peritoneal resident macrophages to potentiate their functions against bacterial infection. AB - Pepper, a daily-used seasoning for promoting appetite, is widely used in folk medicine for treating gastrointestinal diseases. Piperine is the major alkaloid in pepper and possesses a wide range of pharmacological activities. However, the mechanism for linking metabolic and medicinal activities of piperine remains unknown. Here we report that piperine robustly boosts mTORC1 activity by recruiting more system L1 amino acid transporter (SLC7A5/SLC3A2) to the cell membrane, thus promoting amino acid metabolism. Piperine-induced increase of mTORC1 activity in resident peritoneal macrophages (pMPhis) is correlated with enhanced production of IL-6 and TNF-alpha upon LPS stimulation. Such an enhancement of cytokine production could be abrogated by inhibitors of the mTOR signaling pathway, indicating mTOR's action in this process. Moreover, piperine treatment protected resident pMPhis from bacterium-induced apoptosis and disappearance, and increased their bacterial phagocytic ability. Consequently, piperine administration conferred mice resistance against bacterial infection and even sepsis. Our data highlight that piperine has the capacity to metabolically reprogram peritoneal resident macrophages to fortify their innate functions against bacterial infection. PMID- 26439700 TI - S-1 plus cisplatin versus fluorouracil plus cisplatin in advanced gastric or gastro-esophageal junction adenocarcinoma patients: a pilot study. AB - The safety and efficacy of S-1 plus cisplatin in Chinese advanced gastric cancer patients in first line setting is unknown. In this pilot study, patients with advanced gastric or gastro-esophageal junction adenocarcinoma were enrolled and randomly assigned in a 1:1 ratio to receive S-1 plus cisplatin (CS group) or 5-FU plus cisplatin (CF group). The primary endpoint was time to progression (TTP). Secondary end points included overall survival (OS) and safety. This study was registered on ClinicalTrials. Gov, number NCT01198392. A total of 236 patients were enrolled. Median TTP was 5.51 months in CS group compared with 4.62 months in CF group [hazard ratio (HR) 1.028, 95% confidential interval (CI) 0.758-1.394, p = 0.859]. Median OS was 10.00 months and 10.46 months in CS and CF groups (HR 1.046, 95%CI 0.709-1.543, p = 0.820), respectively. The most common adverse events in both groups were anemia, leukopenia, neutropenia, nausea, thrombocytopenia, vomiting, anorexia and diarrhea. We find that S-1 plus cisplatin is an effective and tolerable option for advanced gastric or gastro esophageal junction adenocarcinoma patients in China. PMID- 26439703 TI - Visible-Light-Induced Activity Control of Peroxidase Bound to Fe-Doped Titanate Nanosheets with Nanometric Lateral Dimensions. AB - Catalytic performance of horseradish peroxidase (HRP) electrostatically adsorbed on nanometric and semiconducting Fe-doped titanate (FT) nanosheets was successfully manipulated by visible light illumination. A colloidal solution of FT with a narrow band gap corresponding to a visible light region was fabricated through a hydrolysis reaction of metals sources. HRP could be easily bound to the FT at pH = 4 through an electrostatic interaction between them, and the formed HRP-FT was utilized for the visible-light-driven enzymatic reaction. Under exposure to visible light with enough energy for band gap excitation of the FT, catalytic activity of HRP-FT was dramatically enhanced as compared with free (unbound) HRP and was simply adjusted by light intensity. In addition, wavelength dependence of an enzymatic reaction rate was analogous to an optical absorption spectrum of the FT. These results substantiated an expected reaction mechanism in which the photoenzymatic reaction was initiated by band gap excitation of FT followed by transferring holes generated in the valence band of irradiated FT to HRP. The excited HRP oxidized substrates (amplex ultrared: AUR) accompanied by two-electron reduction to regenerate the resting state. In addition, the catalytic activity was clearly switched by turning on and off the light source. PMID- 26439704 TI - The Relationship Between Development of Neuronal and Astrocytic Tau Pathologies in Subcortical Nuclei and Progression of Argyrophilic Grain Disease. AB - Progressive supranuclear palsy (PSP) cases frequently have argyrophilic grain disease (AGD). However, the PSP-like tau pathology in AGD cases has not been fully clarified. To address this, we examined tau pathologies in the subcortical nuclei and frontal cortex in 19 AGD cases that did not meet the pathological criteria of PSP or corticobasal degeneration, nine PSP cases and 20 Braak NFT stage-matched controls. Of the 19 AGD cases, five (26.3%) had a few Gallyas positive tau-positive tufted astrocytes (TAs) and Gallyas-negative tau-positive TA-like astrocytic inclusions (TAIs), and six (31.6%) had only TAIs in the striatum and/or frontal cortex. Subcortical tau pathology was sequentially and significantly greater in AGD cases lacking these tau-positive astrocytic lesions, AGD cases having them, and PSP cases than in controls. There was a significant correlation between three histologic factors, including the AGD stage and the quantities of subcortical neuronal and astrocytic tau pathologies. Tau immunoblotting demonstrated 68- and 64-kDa bands and 33-kDa low-molecular mass tau fragments in PSP cases, and although with lesser intensity, in AGD cases with and without TAs and TAIs also. Given these findings, the progression of AGD may be associated with development of the neuronal and astrocytic tau pathologies characteristic of PSP. PMID- 26439706 TI - Amorphous and Crystalline Sodium Tantalate Composites for Photocatalytic Water Splitting. AB - A facile hydrothermal synthesis protocol for the fabrication of sodium tantalates for photocatalytic water splitting is presented. Mixtures of tantalum and sodium ethoxide precursors were dispersed in ethanol, and ammonium hydroxide solution was used as mineralizer. By adjusting the amount of mineralizer, a variety of sodium tantalates with various morphologies, textural parameters, band gaps, crystal phases, and degrees of crystallinity were fabricated. The reaction was carefully monitored with a pressure sensor inside the autoclave reactor, and the obtained samples were characterized using X-ray diffraction, transmission electron microscopy, N2-physisorption, and ultraviolet-visible light spectroscopy. Among the series, the amorphous sample and the composite sample that consists of amorphous and crystalline phases showed superior activity toward photocatalytic hydrogen production than highly crystalline samples. Particularly, an amorphous sodium tantalate with a small fraction of crystalline nanoparticles with perovskite structure was found to be the most active sample, reaching a hydrogen rate of 3.6 mmol h(-1) from water/methanol without the use of any cocatalyst. Despite its amorphous nature, this photocatalyst gave an apparent photocatalyst activity of 1200 MUmol g(-1) L(-1) h(-1) W(1-), which is 4.5-fold higher than highly crystalline NaTaO3. In addition, the most active sample gave promising activity for overall water splitting with a hydrogen production rate of 94 MUmol h(-1), which is superior to highly crystalline NaTaO3 prepared by conventional solid-solid state route. PMID- 26439705 TI - Effect of Age on Working Memory Performance and Cerebral Activation after Mild Traumatic Brain Injury: A Functional MR Imaging Study. AB - PURPOSE: To evaluate the age effect on working memory (WM) performance and functional activation after mild traumatic brain injury (MTBI). MATERIALS AND METHODS: This study was approved by the local research ethics committee. All participants provided written informed consent. N-back WM cerebral activation was assessed with functional magnetic resonance (MR) imaging in 13 younger (mean age, 26.2 years +/- 2.9; range, 21-30 years) and 13 older (mean age, 57.8 years +/- 6.6; range, 51-68 years) patients with MTBI and 26 age- and sex-matched control subjects. Two functional MR images were obtained within 1 month after injury and 6 weeks after the initial study. Group comparison and regression analysis were performed among postconcussion symptoms, neuropsychologic tests, and WM activity in both groups. RESULTS: In younger patients, initial hyperactivation was seen in the right precuneus and right inferior parietal gyrus (P = .047 and P = .025, respectively) in two-back greater than one-back conditions compared with younger control subjects, whereas in older patients, hypoactivation was seen in the right precuneus and right inferior frontal gyrus (P = .013 and P =.019, respectively) compared with older control subjects. Increased WM activity was associated with increased postconcussion symptoms in the right precuneus (r = 0.57; P = .026) and right inferior frontal gyrus (r = 0.60; P = .019) and poor WM performance in the right precuneus (r = -0.55; P = .027) in younger patients at initial studies but not in older patients. At follow-up examinations, partial recovery of activation pattern and decreased postconcussion symptoms (P = .04) were observed in younger patients but not in older patients. CONCLUSION: The different manifestations of postconcussion symptoms at functional MR imaging between younger and older patients confirmed the important role of age in the activation, modulation, and allocation of WM processing resources after MTBI. These findings also supported that younger patients have better neural plasticity and clinical recovery than do older patients. PMID- 26439702 TI - Molecular signature of pancreatic adenocarcinoma: an insight from genotype to phenotype and challenges for targeted therapy. AB - INTRODUCTION: Pancreatic adenocarcinoma remains one of the most clinically challenging cancers despite an in-depth characterization of the molecular underpinnings and biology of this disease. Recent whole-genome-wide studies have elucidated the diverse and complex genetic alterations which generate a unique oncogenic signature for an individual pancreatic cancer patient and which may explain diverse disease behavior in a clinical setting. AREAS COVERED: In this review article, we discuss the key oncogenic pathways of pancreatic cancer including RAS-MAPK, PI3KCA and TGF-beta signaling, as well as the impact of these pathways on the disease behavior and their potential targetability. The role of tumor suppressors particularly BRCA1 and BRCA2 genes and their role in pancreatic cancer treatment are elaborated upon. We further review recent genomic studies and their impact on future pancreatic cancer treatment. EXPERT OPINION: Targeted therapies inhibiting pro-survival pathways have limited impact on pancreatic cancer outcomes. Activation of pro-apoptotic pathways along with suppression of cancer-stem-related pathways may reverse treatment resistance in pancreatic cancer. While targeted therapy or a 'precision medicine' approach in pancreatic adenocarcinoma remains an elusive challenge for the majority of patients, there is a real sense of optimism that the strides made in understanding the molecular underpinnings of this disease will translate into improved outcomes. PMID- 26439707 TI - Host Phenology and Leaf Effects on Susceptibility of California Bay Laurel to Phytophthora ramorum. AB - Spread of the plant pathogen Phytophthora ramorum, causal agent of the forest disease sudden oak death, is driven by a few competent hosts that support spore production from foliar lesions. The relationship between traits of a principal foliar host, California bay laurel (Umbellularia californica), and susceptibility to P. ramorum infection were investigated with multiple P. ramorum isolates and leaves collected from multiple trees in leaf-droplet assays. We examined whether susceptibility varies with season, leaf age, or inoculum position. Bay laurel susceptibility was highest during spring and summer and lowest in winter. Older leaves (>1 year) were more susceptible than younger ones (8 to 11 months). Susceptibility was greater at leaf tips and edges than the middle of the leaf. Leaf surfaces wiped with 70% ethanol were more susceptible to P. ramorum infection than untreated leaf surfaces. Our results indicate that seasonal changes in susceptibility of U. californica significantly influence P. ramorum infection levels. Thus, in addition to environmental variables such as temperature and moisture, variability in host plant susceptibility contributes to disease establishment of P. ramorum. PMID- 26439709 TI - A Hybrid Program for Fitting Rotationally Resolved Spectra of Floppy Molecules with One Large-Amplitude Rotatory Motion and One Large-Amplitude Oscillatory Motion. AB - A new hybrid-model fitting program for methylamine-like molecules has been developed, on the basis of an effective Hamiltonian in which the ammonia-like inversion motion is treated using a tunneling formalism, whereas the internal rotation motion is treated using an explicit kinetic energy operator and potential energy function. The Hamiltonian in the computer program is set up as a 2 * 2 partitioned matrix, where each diagonal block contains a traditional torsion-rotation Hamiltonian (as in the earlier program BELGI), and the two off diagonal blocks contain tunneling terms. This hybrid formulation permits the use of the permutation-inversion group G6 (isomorphic to C(3v)) for terms in the two diagonal blocks but requires G12 for terms in the off-diagonal blocks. The first application of the new program is to 2-methylmalonaldehyde. Microwave data for this molecule were previously fit using an all-tunneling Hamiltonian formalism to treat both large-amplitude motions. For 2-methylmalonaldehyde, the hybrid program achieves the same quality of fit as was obtained with the all-tunneling program, but fits with the hybrid program eliminate a large discrepancy between internal rotation barriers in the OH and OD isotopologs of 2-methylmalonaldehyde that arose in fits with the all-tunneling program. This large isotopic shift in internal rotation barrier is thus almost certainly an artifact of the all tunneling model. Other molecules for application of the hybrid program are mentioned. PMID- 26439710 TI - Versatile Multicomponent Reaction Macrocycle Synthesis Using alpha-Isocyano-omega carboxylic Acids. AB - The direct macrocycle synthesis of alpha-isocyano-omega-carboxylic acids via an Ugi multicomponent reaction is introduced. This multicomponent reaction (MCR) protocol differs by being especially short, convergent, and versatile, giving access to 12-22 membered rings. PMID- 26439708 TI - Contaminated water delivery as a simple and effective method of experimental Salmonella infection. AB - AIM: In most infectious disease models, it is assumed that gavage needle infection is the most reliable means of pathogen delivery to the GI tract. However, this methodology can cause esophageal tearing and induces stress in experimental animals, both of which have the potential to impact early infection and the subsequent immune response. MATERIALS & METHODS: C57BL/6 mice were orally infected with virulent Salmonella Typhimurium SL1344 either by intragastric gavage preceded by sodium bicarbonate, or by contamination of drinking water. RESULTS: We demonstrate that water contamination delivery of Salmonella is equivalent to gavage inoculation in providing a consistent model of infection. Furthermore, exposure of mice to contaminated drinking water for as little as 4 h allowed maximal mucosal and systemic infection, suggesting an abbreviated window exists for natural intestinal entry. CONCLUSION: Together, these data question the need for gavage delivery for infection with oral pathogens. PMID- 26439712 TI - Trends in Anemia Management in Hemodialysis Patients with Cancer. AB - BACKGROUND: Erythropoiesis-stimulating agents (ESAs), intravenous iron, and blood transfusion are used to treat anemia in both end-stage renal disease (ESRD) and cancer. However, anemia treatment patterns have not been described among ESRD patients undergoing hemodialysis with concurrent cancer, especially in the recent era of ESA-related safety concerns. METHODS: We analyzed Medicare data from a cohort of hemodialysis patients diagnosed with incident cancer. We used multivariable generalized linear models to estimate trends and patterns in ESA use, iron use, transfusion use, epoetin alfa (EPO) dose, iron dose, and resulting hemoglobin levels (2000-2011). RESULTS: Of 43,760 eligible patients, quarterly ESA use declined slightly from a peak of 94.1 to 90.0%. Quarterly EPO dose increased from 2000 to 2004, then declined; quarterly hemoglobin levels followed a similar pattern. Iron use increased rapidly from 46.9 to 79.3%. Iron dose increased until 2010 and then declined. There was an increase in the quarterly transfusion use (6.3-11.7%) and in the mean number of transfusion days per year (1.4-1.8). Anemia treatment patterns varied by demographic/clinical subgroups, especially among patients receiving chemotherapy, who required higher ESA use, EPO dose, and frequency of transfusions. CONCLUSIONS: Despite safety concerns about ESAs in both the ESRD and cancer populations, the proportion of hemodialysis patients with cancer who used ESAs between 2000 and 2011 remained extremely high. EPO dose and hemoglobin levels increased and then decreased. Iron use, iron dose, and transfusions increased substantially. Future research examining the risk-benefit profile of different anemia management strategies in the dialysis population with cancer is needed. PMID- 26439713 TI - Alternative Splicing Signatures in RNA-seq Data: Percent Spliced in (PSI). AB - Thousands of alternative exons are spliced out of messenger RNA to increase protein diversity. High-throughput sequencing of short cDNA fragments (RNA-seq) generates a genome-wide snapshot of these post-transcriptional processes. RNA-seq reads yield insights into the regulation of alternative splicing by revealing the usage of known or unknown splice sites as well as the expression level of exons. Constitutive exons are never covered by split alignments, whereas alternative exonic parts are located within highly expressed splicing junctions. The ratio between reads including or excluding exons, also known as percent spliced in index (PSI), indicates how efficiently sequences of interest are spliced into transcripts. This protocol describes a method to calculate the PSI without prior knowledge of splicing patterns. It provides a quantitative, global assessment of exon usage that can be integrated with other tools that identify differential isoform processing. Novel, complex splicing events along a genetic locus can be visualized in an exon-centric manner and compared across conditions. PMID- 26439714 TI - Practical Integration-Free Episomal Methods for Generating Human Induced Pluripotent Stem Cells. AB - The advent of induced pluripotent stem (iPS) cell technology has revolutionized biomedicine and basic research by yielding cells with embryonic stem (ES) cell like properties. The use of iPS-derived cells for cell-based therapies and modeling of human disease holds great potential. While the initial description of iPS cells involved overexpression of four transcription factors via viral vectors that integrated within genomic DNA, advances in recent years by our group and others have led to safer and higher quality iPS cells with greater efficiency. Here, we describe commonly practiced methods for non-integrating induced pluripotent stem cell generation using nucleofection of episomal reprogramming plasmids. These methods are adapted from recent studies that demonstrate increased hiPS cell reprogramming efficacy with the application of three powerful episomal hiPS cell reprogramming factor vectors and the inclusion of an accessory vector expressing EBNA1. PMID- 26439715 TI - Chemically Defined Culture and Cardiomyocyte Differentiation of Human Pluripotent Stem Cells. AB - Since the first discovery that human pluripotent stem cells (hPS cells) can differentiate to cardiomyocytes, efforts have been made to optimize the conditions under which this process occurs. One of the most effective methodologies to optimize this process is reductionist simplification of the medium formula, which eliminates complex animal-derived components to help reveal the precise underlying mechanisms. Here we describe our latest, cost-effective and efficient methodology for the culture of hPS cells in the pluripotent state using a modified variant of chemically defined E8 medium. We provide exact guidelines for cell handling under these conditions, including non-enzymatic EDTA passaging, which have been optimized for subsequent cardiomyocyte differentiation. We describe in depth the latest version of our monolayer chemically defined small molecule differentiation protocol, including metabolic selection-based cardiomyocyte purification and the addition of triiodothyronine to enhance cardiomyocyte maturation. Finally, we describe a method for the dissociation of hPS cell-derived cardiomyocytes, cryopreservation, and thawing. PMID- 26439716 TI - Interpreting de novo Variation in Human Disease Using denovolyzeR. AB - Spontaneously arising (de novo) genetic variants are important in human disease, yet every individual carries many such variants, with a median of 1 de novo variant affecting the protein-coding portion of the genome. A recently described mutational model provides a powerful framework for the robust statistical evaluation of such coding variants, enabling the interpretation of de novo variation in human disease. Here we describe a new open-source software package, denovolyzeR, that implements this model and provides tools for the analysis of de novo coding sequence variants. PMID- 26439717 TI - Management of Incidental Findings in Clinical Genomic Sequencing. AB - Genomic sequencing is becoming accurate, fast, and increasingly inexpensive, and is rapidly being incorporated into clinical practice. Incidental or secondary findings, which can occur in large numbers from genomic sequencing, are a potential barrier to the utility of this new technology due to their relatively high prevalence and the lack of evidence or guidelines available to guide their clinical interpretation. This unit reviews the definition, classification, and management of incidental findings from genomic sequencing. The unit focuses on the clinical aspects of handling incidental findings, with an emphasis on the key role of clinical context in defining incidental findings and determining their clinical relevance and utility. PMID- 26439718 TI - Huntington Disease: Molecular Diagnostics Approach. AB - Huntington disease (HD) is caused by expansion of a CAG trinucleotide repeat in the first exon of the Huntingtin (HTT) gene. Molecular testing of Huntington disease for diagnostic confirmation and disease prediction requires detection of the CAG repeat expansion. There are three main types of HD genetic testing: (1) diagnostic testing to confirm or rule out disease, (2) presymptomatic testing to determine whether an at-risk individual inherited the expanded allele, and (3) prenatal testing to determine whether the fetus has inherited the expanded allele. This unit includes protocols that describe the complementary use of polymerase chain reactions (PCR) and Southern blot hybridization to accurately measure the CAG trinucleotide repeat size and interpret the test results. In addition, an indirect linkage analysis that does not reveal the unwanted parental HD status in a prenatal testing will also be discussed. PMID- 26439719 TI - Essential oil of Zygophyllum album inhibits key-digestive enzymes related to diabetes and hypertension and attenuates symptoms of diarrhea in alloxan-induced diabetic rats. AB - CONTEXT: Zygophyllum album L. (Zygophyllaceae), commonly known as Bougriba, is widely used to treat diabetes, digestive tract spasm, and hypertension in folk medicine, in Tunisia. OBJECTIVE: This study investigates the antidiabetic, antidiarrheal, and antihypertensive activities of the leaves of the essential oil from Zygophyllum album (OZA) in alloxan-induced diabetic rats. MATERIALS AND METHODS: The oil was obtained by hydrodistillation and analyzed by GC-MS. Males rats were divided into four groups: control, diabetic-untreated group, diabetic treated group with acarbose (10 mg/kg), and diabetic-treated rats with OZA (200 mg/kg) for 30 d. RESULTS: At the end of the experimental period, the OZA significantly decreased the activity of alpha-amylase in pancreas and serum of the diabetic rats by 43% and 38%, respectively, which led to reduce the serum glucose level by 60% and lower of glycated hemoglobin (HbA1c) rate by 17% as compared with untreated diabetic animals. Moreover, the OZA treatment attenuated symptoms of diarrhea, improved lipid disorders, and hypertension through inhibiting the pancreatic lipase and angiotensin-converting enzyme (ACE) activities by 47% and 25%, respectively, in serum of diabetic rats. CONCLUSION: OZA showed a good effect in the management of diabetes mellitus and exerted preventive action from related hypertension. PMID- 26439720 TI - Exploring Risk and Protective Factors for Recent and Past Intimate Partner Violence Against New Zealand Women. AB - The purpose of this investigation was to identify risk and protective factors associated with intimate partner violence (IPV) in a high-income country (New Zealand) and to identify those factors that distinguish between current versus previous exposure to IPV. Data were drawn from the New Zealand replication of the World Health Organization's Multi-Country Study on Women's Health and Domestic Violence. Logistic regression was conducted to identify those variables associated with experience of IPV. Problem drinking, a partner who has concurrent sexual relationships, and a partner who is violent outside the home were associated with increased likelihood of current as opposed to previous experience of IPV. Increased household income and both the respondent and her partner being employed were associated with reduced likelihood that women would experience current as opposed to prior IPV. The findings point toward the need for comprehensive approaches to reduce all forms of violence and to contribute to the primary prevention of IPV. Strategies that address early exposure to violence, problematic alcohol consumption, gender transformative approaches to working with boys and men, and economic empowerment for women may all hold promise. PMID- 26439721 TI - Impact of Growth Hormone on Adult Bone Quality in Turner Syndrome: A HR-pQCT Study. AB - Women with Turner syndrome (TS) are known to be at risk of osteoporosis. While childhood growth hormone (GH) treatment is common in TS, the impact of this therapy on bone health has been poorly understood. The objective of this study was to determine the influence of childhood GH treatment on adult bone quality in women with TS. 28 women aged 17-45 with confirmed TS (12 GH-treated) agreed to participate in this cross-sectional study. Dual X-ray absorptiometry (DXA) of lumbar spine, hip, and radius and high-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the radius and tibia were used to determine standard morphological and micro-architectural parameters of bone health. Finite element (FE) analysis and polar moment of inertia (pMOI) were used to estimate bone strength. GH-treated subjects were +7.4 cm taller (95% CI 2.5 12.3 cm, p = 0.005). DXA-determined areal BMD of hip, spine, and radius was similar between treatment groups. Both tibial and radial total bone areas were greater among GH-treated subjects (+20.4 and +21.2% respectively, p < 0.05), while other micro-architectural results were not different between groups. pMOI was significantly greater among GH-treated subjects (radius +35.0%, tibia +34.0%, p < 0.05). Childhood GH treatment compared to no treatment in TS was associated with an increased height, larger bones, and greater pMOI, while no significant difference in DXA-derived BMD, HR-pQCT micro-architectural parameters, or FE estimated bone strength was detected. The higher pMOI and greater bone size may confer benefit for fracture reduction in these GH-treated patients. PMID- 26439722 TI - Impact of preloading either dairy or soy milk on postprandial glycemia, insulinemia and gastric emptying in healthy adults. AB - PURPOSE: Milk protein ingestion reduces post-meal glycemia when consumed either before or together with carbohydrate foods. The aim of this study was to compare the effects of dairy and soy milk consumed either before (preload) or together with (co-ingestion) a carbohydrate (bread), on postprandial blood glucose, insulin and gastric emptying in healthy participants. METHODS: Twelve healthy Chinese male participants were studied on five separate occasions using a randomized crossover design. White wheat bread consumed with water was used as a reference meal. Capillary and venous bloods were sampled pretest and 3.5 h post test meal for glucose and insulin measurement. Gastric emptying was measured using real-time ultrasonography. RESULTS: Co-ingestion of dairy milk or soy milk with bread lowered postprandial blood glucose response and glycemic index. Co ingesting soy milk with bread increased insulin response and insulinemic index significantly compared to co-ingestion of dairy milk and preload treatments. Preloads (30 min prior to bread) significantly lowered postprandial glycemia and insulinemia compared to co-ingestion. Gastric emptying was slower after co ingesting dairy milk with bread than after reference meal. CONCLUSIONS: Preloading either soy milk or dairy milk results in greater reduction in glycemic response compared to co-ingestion alone. This dietary practice may have therapeutic advantage in communities consuming high GI diets. Optimal glucose control may have the potential for increasing the time of transition from prediabetes to type 2 diabetes in Asian communities. CLINICAL TRIAL REGISTRATION: This trial was registered at clinicaltrials.gov as NCT 02151188. PMID- 26439724 TI - Breakdown of Bragg-Gray behaviour for low-density detectors under electronic disequilibrium conditions in small megavoltage photon fields. AB - In small photon fields ionisation chambers can exhibit large deviations from Bragg-Gray behaviour; the EGSnrc Monte Carlo (MC) code system has been employed to investigate this 'Bragg-Gray breakdown'. The total electron (+positron) fluence in small water and air cavities in a water phantom has been computed for a full linac beam model as well as for a point source spectrum for 6 MV and 15 MV qualities for field sizes from 0.25 * 0.25 cm(2) to 10 * 10 cm(2). A water-to air perturbation factor has been derived as the ratio of total electron (+positron) fluence, integrated over all energies, in a tiny water volume to that in a 'PinPoint 3D-chamber-like' air cavity; for the 0.25 * 0.25 cm(2) field size the perturbation factors are 1.323 and 2.139 for 6 MV and 15 MV full linac geometries respectively. For the 15 MV full linac geometry for field sizes of 1 * 1 cm(2) and smaller not only the absolute magnitude but also the 'shape' of the total electron fluence spectrum in the air cavity is significantly different to that in the water 'cavity'. The physics of this 'Bragg-Gray breakdown' is fully explained, making reference to the Fano theorem. For the 15 MV full linac geometry in the 0.25 * 0.25 cm(2) field the directly computed MC dose ratio, water-to-air, differs by 5% from the product of the Spencer-Attix stopping-power ratio (SPR) and the perturbation factor; this 'difference' is explained by the difference in the shapes of the fluence spectra and is also formulated theoretically. We show that the dimensions of an air-cavity with a perturbation factor within 5% of unity would have to be impractically small in these highly non-equilibrium photon fields. In contrast the dose to water in a 0.25 * 0.25 cm(2) field derived by multiplying the dose in the single-crystal diamond dosimeter (SCDDo) by the Spencer-Attix ratio is within 2.9% of the dose computed directly in the water voxel for full linac geometry at both 6 and 15 MV, thereby demonstrating that this detector exhibits quasi Bragg-Gray behaviour over a wide range of field sizes and beam qualities. PMID- 26439723 TI - Gastrointestinal stability of urolithins: an in vitro approach. AB - PURPOSE: Urolithins are bioactive ellagitannin-derived metabolites showing a wide phenotypic variation in their production by the gut microbiota. This work represents a first in vitro step toward the development of new strategies focused on the oral supplementation of urolithins with the aim of overcoming their selective production and making their putative health benefits available for the whole population. METHODS: In order to study their gastrointestinal stability, urolithin A, urolithin B, and urolithin B-glucuronide, as well as ellagic acid, were subjected to a simulated gastrointestinal digestion model consisting of oral, gastric, and pancreatic steps followed by a 24-h fecal fermentation. The effect of the entero-hepatic recirculation on urolithin B-glucuronide, a phase II metabolite, was also investigated. RESULTS: Urolithin B was the molecule able to resist to a greater extent the conditions of the gastrointestinal tract, while urolithin A and ellagic acid were drastically unstable during the colonic step. Conjugation with glucuronic acid, ideally occurring in the liver, conferred to urolithin B an increased stability, which may be interesting in the framework of entero-hepatic recirculation. CONCLUSION: This set of experiments lets hypothesize that orally supplemented urolithins may come into contact with the colonic epithelium and become accessible for uptake or exert local anti inflammatory activity, overcoming the limitations of enterotypes unable to convert ellagitannins into these putatively beneficial metabolites. PMID- 26439727 TI - VA Palliative Care: The Filling and Relaxing of Diastole. PMID- 26439725 TI - Quantitative analysis of nuclear shape in oral squamous cell carcinoma is useful for predicting the chemotherapeutic response. AB - The number of people afflicted with oral carcinoma in Japan has increased in recent years. Although preoperative neoadjuvant therapy with cisplatin and 5 fluorouracil are performed, chemotherapeutic response varies widely among the patients. With the aim of establishing novel indices to predict the therapeutic response to chemotherapy, we investigated the relationship between morphological features of pre-treatment oral carcinoma nuclei and the chemotherapeutic response using quantifying morphology of cell nuclei in pathological specimen images. We measured 4 morphological features of the nucleus of oral squamous cell carcinoma cases classified by the response to chemotherapy: No Change (NC) group, Partial Response (PR) group and Complete Response (CR) group. Furthermore, we performed immunohistochemical staining for p53 and Ki67 and calculated their positive rates in cancer tissues. Compactness and symmetry of the nucleus were significantly higher and nuclear edge response was significantly lower in cancer cells with lower chemotherapeutic responses compared high chemotherapeutic responders. As for positive rates of p53 and Ki67, there were no significant differences between any of the response groups. Morphological features of cancer cell nuclei in pathological specimens are sensitive predictive factors for the chemotherapeutic response to oral squamous cell carcinoma. PMID- 26439728 TI - Opioid-Induced Constipation Part 2: Newer Therapies #295. PMID- 26439729 TI - Camera-based single-molecule FRET detection with improved time resolution. AB - The achievable time resolution of camera-based single-molecule detection is often limited by the frame rate of the camera. Especially in experiments utilizing single-molecule Forster resonance energy transfer (smFRET) to probe conformational dynamics of biomolecules, increasing the frame rate by either pixel-binning or cropping the field of view decreases the number of molecules that can be monitored simultaneously. Here, we present a generalised excitation scheme termed stroboscopic alternating-laser excitation (sALEX) that significantly improves the time resolution without sacrificing highly parallelised detection in total internal reflection fluorescence (TIRF) microscopy. In addition, we adapt a technique known from diffusion-based confocal microscopy to analyse the complex shape of FRET efficiency histograms. We apply both sALEX and dynamic probability distribution analysis (dPDA) to resolve conformational dynamics of interconverting DNA hairpins in the millisecond time range. PMID- 26439730 TI - A multitude of variations in the configuration of the circle of Willis: an autopsy study. AB - The circle of Willis (CW) is an anastomotic system of arteries located at the base of the brain. The aim of the study was to evaluate the anatomic configuration of the CW in the Polish population and to compare results with previously conducted research. Brains were obtained from 100 recently deceased human adults, and the diameters of cerebral vessels were measured using a slide caliper. Cerebral vessels were observed, paying attention to their origin, diameter, typical configuration and variations. Twenty-seven percent of cases presented the typical literature pattern. The remaining 73 % of all cases were atypical; in 16 % the CW was incomplete and in 57 % complete. Atypical findings involved the posterior communicating artery (PcomA), 62 %; anterior communicating artery (AcomA), 22 %; anterior cerebral artery (ACA), 14 %; posterior cerebral artery (PCA), 8 %. The most common variations were bilateral hypoplastic PcomAs (27 % of cases) and unilateral hypoplastic PcomAs (19 % of cases). Only 9 of the 22 types of CW variations classified previously in the literature were observed, and 26 variations (36 cases) in our study were labeled as 'other' type. Mean diameter values for typical CW patterns were internal carotid artery = 3.6 mm, ACA = 2.3 mm, AcomA = 1.9 mm, PCA = 2.2 mm and PcomA = 1.4 mm. Circle of Willis variations have a large impact on clinical practice. This study shows many rare variations that should be taken into consideration to avoid any unexpected complications during surgical procedures involving cerebral vessels. PMID- 26439731 TI - Molecular and anatomical evidence for the input pathway- and target cell type dependent regulation of glutamatergic synapses. AB - Glutamate mediates most fast excitatory transmission in the central nervous system by activating primarily two types of ionotropic glutamate receptors: alpha amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D aspartate (NMDA) receptors. Differential subunit combinations generate great functional diversity in both categories of receptors, making them highly suitable for meeting complex functional requirements. Converging evidence has indicated that distinct AMPA and NMDA receptor subtypes are selectively targeted to functionally different synapses according to different factors, including presynaptic inputs, postsynaptic cell types, and synaptic configurations. This article provides an overview of recent progress in understanding the basic principles governing the synaptic allocation of AMPA and NMDA receptors, and discusses the underlying mechanisms and functional implications. PMID- 26439732 TI - Anomalous course of the external carotid artery. AB - The course and the branching patterns of the external carotid artery were investigated macroscopically in a total of 550 bodies or 1100 head sides of Japanese subjects, donated for student dissection at Kumamoto University from 1994 to 2014. With the exception of 14 head sides, the external carotid arteries running between the posterior belly of the digastric and stylohyoid muscles were found in 42 (3.87 %) out of 1086 head sides. Strictly speaking, they passed between the stylohyoid muscle and the stylohyoid branch of the facial nerve in 23 out of these 42 head sides. In the remaining 19 instances, the stylohyoid branch of the facial nerve was cut and its relationship to the external carotid artery was not clear. The external carotid artery running lateral to the intact stylohyoid branch of the facial nerve, medial to the digastric muscle was not found. The external carotid arteries running lateral to the digastric muscle were found in 4 (0.37 %) out of 1086 head sides. As a result, it is proposed that plural, potential courses of the external carotid artery originally exist and that some parts of such potential courses remain as branches of the external carotid artery in the usual instance, while the anomalous courses of the external carotid artery are induced mainly by anastomosis between the muscular branches supplying the wall of the head and neck in contrast to the usual external carotid artery induced mainly by the branches originally supplying the pharynx. PMID- 26439733 TI - Sleeve Gastrectomy Decreases Body Weight, Whole-Body Adiposity, and Blood Pressure Even in Aged Diet-Induced Obese Rats. AB - BACKGROUND: Aging and obesity are two conditions associated with increased risk of cardiovascular disease. Our aim was to analyze whether an advanced age affects the beneficial effects of sleeve gastrectomy on weight loss and blood pressure in an experimental model of diet-induced obesity (DIO). METHODS: Young (6-month-old) and old (18-month-old) male Wistar DIO rats (n = 101) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary interventions (pair-fed to the amount of food eaten by sleeve gastrectomized animals). Systolic (SBP), diastolic (DBP), and mean (MBP) blood pressure values and heart rate (HR) were recorded in conscious, resting animals by non-invasive tail-cuff plethysmography before and 4 weeks after surgical or dietary interventions. RESULTS: Aging was associated with higher (P < 0.05) body weight and subcutaneous and perirenal fat mass as well as mild cardiac hypertrophy. Sleeve gastrectomy induced a reduction in body weight, whole-body adiposity, and serum total ghrelin in both young and old DIO rats. The younger group achieved a higher excess weight loss than the older group (164 +/- 60 vs. 82 +/- 17 %, P < 0.05). A significant (P < 0.05) decrease in insulin resistance, SBP, DBP, MBP, and HR without changes in heart weight was observed after sleeve gastrectomy independently of age. CONCLUSION: Our results provide evidence for the effectiveness of sleeve gastrectomy without increased operative risk in body weight and blood pressure reduction even in aged animals via endocrine changes that go beyond the mere caloric restriction. PMID- 26439736 TI - Racial and geographic disparities in the patterns of care and costs at the end of life for patients with lung cancer in 2007-2010 after the 2006 introduction of bevacizumab. AB - OBJECTIVES: To examine racial/ethnic and geographical disparities in cancer care and costs during the last 6 months of life for lung cancer decedents after the Food and Drug Administration's approval of expensive bevacizumab in October 2006. METHODS: We identified 37,393 cases from the Surveillance, Epidemiology and End Results (SEER) cancer registries and Medicare linked databases who were diagnosed with non-small cell lung cancer of all stages in 1991-2009 and died between July 2007 and December 2010. RESULTS: Overall, the proportion of patients receiving chemotherapy/targeted therapy (31.0%), bevacizumab (4.6%), growth factors (16.0%), surgery (2.8%), and hospice care (60.9) in the last 6 months of life was higher in whites than in other ethnic populations. Hospitalization rate was higher in blacks (83.2%) than in whites (76.0%) and others (78.0%). Those from metro areas had slightly higher percentages of receiving chemotherapy/targeted therapy, bevacizumab, growth factors, and hospice care, but had a higher hospitalization rate and lower emergency care visit. Mean total health care cost was $42,749 for the last 6 months of life in patients with lung cancer. Adjusted mean health care cost in the last 6 months of life was significantly higher in blacks or other ethnic population as compared to whites. CONCLUSION: There were substantial racial/ethnic and geographic disparities in the types of cancer care and costs in the last 6 months of life among lung cancer decedents, regardless of the length of survival times and hospice care status. A clinical guideline may help the appropriate use of costly treatment modalities and minimize racial/geographic disparities. PMID- 26439737 TI - Use of a Referring Physician Survey to Direct and Evaluate Department-Wide Radiology Quality Improvement Efforts. PMID- 26439734 TI - Kinetic characterization of trans-proteolytic activity of Chikungunya virus capsid protease and development of a FRET-based HTS assay. AB - Chikungunya virus (CHIKV) capsid protein (CVCP) is a serine protease that possesses cis-proteolytic activity essential for the structural polyprotein processing and plays a key role in the virus life cycle. CHIKV being an emerging arthropod-borne pathogenic virus, is a public health concern worldwide. No vaccines or specific antiviral treatment is currently available for chikungunya disease. Thus, it is important to develop inhibitors against CHIKV enzymes to block key steps in viral reproduction. In view of this, CVCP was produced recombinantly and purified to homogeneity. A fluorescence resonance energy transfer (FRET)-based proteolytic assay was developed for high throughput screening (HTS). A FRET peptide substrate (DABCYL-GAEEWSLAIE-EDANS) derived from the cleavage site present in the structural polyprotein of CVCP was used. The assay with a Z' factor of 0.64 and coefficient of variation (CV) is 8.68% can be adapted to high throughput format for automated screening of chemical libraries to identify CVCP specific protease inhibitors. Kinetic parameters Km and kcat/Km estimated using FRET assay were 1.26 +/- 0.34 MUM and 1.11 * 10(3) M(-1) sec(-1) respectively. The availability of active recombinant CVCP and cost effective fluorogenic peptide based in vitro FRET assay may serve as the basis for therapeutics development against CHIKV. PMID- 26439735 TI - KIF7 Controls the Proliferation of Cells of the Respiratory Airway through Distinct Microtubule Dependent Mechanisms. AB - The cell cycle must be tightly coordinated for proper control of embryonic development and for the long-term maintenance of organs such as the lung. There is emerging evidence that Kinesin family member 7 (Kif7) promotes Hedgehog (Hh) signaling during embryonic development, and its misregulation contributes to diseases such as ciliopathies and cancer. Kif7 encodes a microtubule interacting protein that controls Hh signaling through regulation of microtubule dynamics within the primary cilium. However, whether Kif7 has a function in nonciliated cells remains largely unknown. The role Kif7 plays in basic cell biological processes like cell proliferation or cell cycle progression also remains to be elucidated. Here, we show that Kif7 is required for coordination of the cell cycle, and inactivation of this gene leads to increased cell proliferation in vivo and in vitro. Immunostaining and transmission electron microscopy experiments show that Kif7dda/dda mutant lungs are hyperproliferative and exhibit reduced alveolar epithelial cell differentiation. KIF7 depleted C3H10T1/2 fibroblasts and Kif7dda/dda mutant mouse embryonic fibroblasts have increased growth rates at high cellular densities, suggesting that Kif7 may function as a general regulator of cellular proliferation. We ascertained that in G1, Kif7 and microtubule dynamics regulate the expression and activity of several components of the cell cycle machinery known to control entry into S phase. Our data suggest that Kif7 may function to regulate the maintenance of the respiratory airway architecture by controlling cellular density, cell proliferation, and cycle exit through its role as a microtubule associated protein. PMID- 26439738 TI - Radiology Residency Spots Should Be Drastically and Immediately Reduced. PMID- 26439739 TI - Rapid Proliferation and Differentiation of a Subset of Circulating IgM Memory B Cells to a CpG/Cytokine Stimulus In Vitro. AB - Circulating human IgM expressing memory B cells have been incompletely characterized. Here, we compared the phenotype and in vitro functional response (capacity to proliferate and differentiate to antibody secreting cells) in response to CpG and a cytokine cocktail (IL-2, IL-6, and IL-10) of sorted naive B cells, IgM memory B cells and isotype-switched circulating memory B cells. Compared to naive B cells, IgM memory B cells had lower integrated mean fluorescence intensity (iMFI) of BAFF-R, CD38, CD73, and IL-21R, but higher iMFI of CD95, CD11c, TLR9, PD-1, and CD122. Compared to switched memory B cells, IgM memory B cells had higher iMFI of BAFF-R, PD-1, IL-21R, TLR9, and CD122, but lower iMFI of CD38, CD95, and CD73. Four days after receiving the CpG/cytokine cocktail, higher frequencies of IgM than switched memory B cells-and these in turn greater than naive cells-proliferated and differentiated to antibody secreting cells. At this time point, a small percentage (median of 7.6%) of stimulated IgM memory B cells changed isotype to IgG. Thus, among the heterogeneous population of human circulating IgM memory B cells a subset is capable of a rapid functional response to a CpG/cytokine stimulus in vitro. PMID- 26439741 TI - Nickel Allergy Is a Risk Factor for Endometriosis: An 11-Year Population-Based Nested Case-Control Study. AB - BACKGROUND: A cross-sectional study has reported that nickel allergy is associated with endometriosis. However, causal studies of this association are limited. OBJECTIVE: The objective of this study was to compare the prevalence of nickel allergy in women with and without endometriosis. METHODS: We used a National Health Insurance Service (NHIS) sample cohort dataset that included approximately 1 million individuals from South Korea; the data were obtained between January 01, 2002, and December 31, 2013. We selected the endometriosis group according to diagnosis code (N80.X), surgery codes, and drug codes during the years 2009~2013. The controls were randomly matched to the endometriosis patients at a ratio of 4:1 by age and socioeconomic status. Patients with nickel allergy were defined in the cohort dataset as those with a simultaneous diagnosis code (L23.0) and patch test code during 2002~2008. RESULTS: In total, 4,985 women were selected from the NHIS cohort database and divided into an endometriosis group (997 women) and a control group (3,988 women). The number of patients with nickel allergy in the endometriosis group was eight (0.8%), and that in the control group was thirteen (0.3%). After adjustment for age and socioeconomic status, the rate of nickel allergy in was higher in the endometriosis group than in the control group [odds ratio: 2.474; 95% confidence interval: 1.023~5.988; p = 0.044]. CONCLUSIONS: We found that nickel allergy is a risk factor for endometriosis. PMID- 26439740 TI - Construction of a High-Density Genetic Map and Quantitative Trait Locus Mapping in the Sea Cucumber Apostichopus japonicus. AB - Genetic linkage maps are critical and indispensable tools in a wide range of genetic and genomic research. With the advancement of genotyping-by-sequencing (GBS) methods, the construction of a high-density and high-resolution linkage maps has become achievable in marine organisms lacking sufficient genomic resources, such as echinoderms. In this study, high-density, high-resolution genetic map was constructed for a sea cucumber species, Apostichopus japonicus, utilizing the 2b-restriction site-associated DNA (2b-RAD) method. A total of 7839 markers were anchored to the linkage map with the map coverage of 99.57%, to our knowledge, this is the highest marker density among echinoderm species. QTL mapping and association analysis consistently captured one growth-related QTL located in a 5 cM region of linkage group (LG) 5. An annotated candidate gene, retinoblastoma-binding protein 5 (RbBP5), which has been reported to be an important regulator of cell proliferation, was recognized in the QTL region. This linkage map represents a powerful tool for research involving both fine-scale QTL mapping and marker assisted selection (MAS), and will facilitate chromosome assignment and improve the whole-genome assembly of sea cucumber in the future. PMID- 26439742 TI - Correction: Pirfenidone for Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis. PMID- 26439743 TI - Bile Acid Alters Male Mouse Fertility in Metabolic Syndrome Context. AB - Bile acids have recently been demonstrated as molecules with endocrine activities controlling several physiological functions such as immunity and glucose homeostases. They act mainly through two receptors, the nuclear receptor Farnesol X-Receptor alpha (FXRalpha) and the G-protein coupled receptor (TGR5). These recent studies have led to the idea that molecules derived from bile acids (BAs) and targeting their receptors must be good targets for treatment of metabolic diseases such as obesity or diabetes. Thus it might be important to decipher the potential long term impact of such treatment on different physiological functions. Indeed, BAs have recently been demonstrated to alter male fertility. Here we demonstrate that in mice with overweight induced by high fat diet, BA exposure leads to increased rate of male infertility. This is associated with the altered germ cell proliferation, default of testicular endocrine function and abnormalities in cell-cell interaction within the seminiferous epithelium. Even if the identification of the exact molecular mechanisms will need more studies, the present results suggest that both FXRalpha and TGR5 might be involved. We believed that this work is of particular interest regarding the potential consequences on future approaches for the treatment of metabolic diseases. PMID- 26439745 TI - Up-regulation of Activation Markers on Basophils in Patients with Papuloerythroderma. PMID- 26439744 TI - Adipose Tissue Dysfunction and Altered Systemic Amino Acid Metabolism Are Associated with Non-Alcoholic Fatty Liver Disease. AB - BACKGROUND: Fatty liver is a major cause of obesity-related morbidity and mortality. The aim of this study was to identify early metabolic alterations associated with liver fat accumulation in 50- to 55-year-old men (n = 49) and women (n = 52) with and without NAFLD. METHODS: Hepatic fat content was measured using proton magnetic resonance spectroscopy (1H MRS). Serum samples were analyzed using a nuclear magnetic resonance (NMR) metabolomics platform. Global gene expression profiles of adipose tissues and skeletal muscle were analyzed using Affymetrix microarrays and quantitative PCR. Muscle protein expression was analyzed by Western blot. RESULTS: Increased branched-chain amino acid (BCAA), aromatic amino acid (AAA) and orosomucoid were associated with liver fat accumulation already in its early stage, independent of sex, obesity or insulin resistance (p<0.05 for all). Significant down-regulation of BCAA catabolism and fatty acid and energy metabolism was observed in the adipose tissue of the NAFLD group (p<0.001for all), whereas no aberrant gene expression in the skeletal muscle was found. Reduced BCAA catabolic activity was inversely associated with serum BCAA and liver fat content (p<0.05 for all). CONCLUSIONS: Liver fat accumulation, already in its early stage, is associated with increased serum branched-chain and aromatic amino acids. The observed associations of decreased BCAA catabolism activity, mitochondrial energy metabolism and serum BCAA concentration with liver fat content suggest that adipose tissue dysfunction may have a key role in the systemic nature of NAFLD pathogenesis. PMID- 26439746 TI - Metabolic abnormalities linked to an increased cardiovascular risk are associated with high-grade prostate cancer: a single biopsy cohort analysis. AB - BACKGROUND: Smoking, hypertension, abdominal obesity and metabolic abnormalities have been considered individual factors involved in prostate cancer (PCa) pathogenesis. All of these factors are used to define the individual cardiovascular risk (CVR). The aim of our study was to evaluate the association between CVR and PCa diagnosis and grade among a consecutive series of men undergoing prostate biopsy. METHODS: From 2010 onwards, consecutive patients undergoing 12-core prostate biopsy were enrolled. Body mass index was measured before the biopsy. Blood samples were collected and tested for: PSA, fasting glucose, triglycerides and high-density lipoproteins. Blood pressure was also recorded. Metabolic syndrome was defined according to the Adult Treatment Panel III and CVR according to the European Association of Cardiologist Guidelines. We evaluated the association between CVR and PCa biopsy Gleason score using logistic regression analyses. RESULTS: Five hundred and eighty-four patients were enrolled. Four hundred and six patients (70%) presented a moderate/high CVR. Two hundred and thirty-seven (40.6%) patients had cancer on biopsy; 157 with moderate/high CVR and 80 with low/no CVR (P=0.11). Out of the 237 patients with PCa, 113 had a Gleason score 6 and 124 a Gleason score ?7. Out of them, 92/124 (75%) presented a moderate/high CVR (P=0.004). Moderate/high CVR was not associated with an increased risk of PCa (odds ratio (OR): 0.741, confidence interval (CI): 0.474-1.156; P=0.186) but with an increased risk of Gleason score ?7 (OR: 2.154, CI: 1.076-4.314; P=0.030). CONCLUSIONS: In our study, a moderate/high CVR is associated with an increased risk of a high-grade Gleason score when PCa is diagnosed on biopsy. Although these results should be confirmed in multicentre studies, patients with moderate/high CVR should be carefully evaluated for PCa diagnosis. PMID- 26439747 TI - Preoperative low serum testosterone is associated with high-grade prostate cancer and an increased Gleason score upgrading. AB - BACKGROUND: To compare histological feature of prostate cancer (PCa) according androgenic status in patients who underwent radical prostatectomy (RP). METHODS: Between March 2007 and September 2013, we prospectively analysed 937 patients who were referred to our centre for RP. Clinical, pathological and biological data have been prospectively collected. Preoperative total testosterone (TT) and bioavailable testosterone (BT) serum determinations were carried out. The threshold for low serum testosterone was set at TT<3 ng/ml. Preoperative PSA value was registered. Gleason score (GS) and predominant Gleason pattern were determined in prostate biopsies and in prostate tissue specimens, crosschecked by two uro-pathologists. RESULTS: Nine hundred and thirty-seven consecutive patients were included. In all, 14.9% patients had low TT in the population. An exact match between biopsy and prostate specimens in GS grading was observed for 50.6% patients (n=474). Also, 40.9% of all patients were upgraded (n=383): 45.3% (n=63) in low serum testosterone patients and 40.1% (n=320) in normal serum testosterone patients. For prostate specimens, the proportion of patients with predominant Gleason pattern 4 was higher in patients with low TT compared with normal TT (41.7% vs 29.1%, P=0.0029). In all, 20.1% were upgraded from predominant Gleason pattern 3 on biopsies specimen to predominant Gleason 4 pattern on the prostate specimen in patients with low TT, whereas 11.6% were upgraded for normal TT patients (P=0.002). CONCLUSIONS: Low serum testosterone is an independent risk factor for predominant Gleason pattern 4 on prostate specimen after RP and for upgrading from low- to high-grade cancer between prostate needle biopsies and RP specimen. This observation should be taken into account in localised PCa management, especially for active surveillance or when a nerve-sparing approach is considered. PMID- 26439748 TI - A higher order visual neuron tuned to the spatial amplitude spectra of natural scenes. AB - Animal sensory systems are optimally adapted to those features typically encountered in natural surrounds, thus allowing neurons with limited bandwidth to encode challengingly large input ranges. Natural scenes are not random, and peripheral visual systems in vertebrates and insects have evolved to respond efficiently to their typical spatial statistics. The mammalian visual cortex is also tuned to natural spatial statistics, but less is known about coding in higher order neurons in insects. To redress this we here record intracellularly from a higher order visual neuron in the hoverfly. We show that the cSIFE neuron, which is inhibited by stationary images, is maximally inhibited when the slope constant of the amplitude spectrum is close to the mean in natural scenes. The behavioural optomotor response is also strongest to images with naturalistic image statistics. Our results thus reveal a close coupling between the inherent statistics of natural scenes and higher order visual processing in insects. PMID- 26439750 TI - Structure, viscoelasticity, and interfacial dynamics of a model polymeric bicontinuous microemulsion. AB - We have systematically studied the equilibrium structure and dynamics of a polymeric bicontinuous microemulsion (BMUE) composed of poly(cyclohexylethylene) (PCHE), poly(ethylene) (PE), and a volumetrically symmetric PCHE-PE diblock copolymer, using dynamic mechanical spectroscopy, small angle X-ray and neutron scattering, and transmission electron microscopy. The BMUE was investigated over an 80 degrees C temperature range, revealing a structural evolution and a rheological response not previously recognized in such systems. As the temperature is reduced below the point associated with the lamellar-disorder transition at compositions adjacent to the microemulsion channel, the interfacial area per chain of the BMUE approaches that of the neat (undiluted) lamellar diblock copolymer. With increasing temperature, the diblock-rich interface swells through homopolymer infiltration. Time-temperature-superposed linear dynamic data obtained as a function of frequency show that the viscoelastic response of the BMUE is strikingly similar to that of the fluctuating pure diblock copolymer in the disordered state, which we associate with membrane undulations and the breaking and reforming of interfaces. This work provides new insights into the structure and dynamics that characterize thermodynamically stable BMUEs in the limits of relatively weak and strong segregation. PMID- 26439749 TI - A Group of ent-Kaurane Diterpenoids Inhibit Hedgehog Signaling and Induce Cilia Elongation. AB - The Hedgehog (Hh) signaling pathway plays important roles in the tumorigenesis of multiple cancers and is a key target for drug discovery. In a screen of natural products extracted from Chinese herbs, we identified eight ent-Kaurane diterpenoids and two triterpene dilactones as novel Hh pathway antagonists. Epistatic analyses suggest that these compounds likely act at the level or downstream of Smoothened (Smo) and upstream of Suppressor of Fused (Sufu). The ent-Kauranoid-treated cells showed elongated cilia, suppressed Smo trafficking to cilia, and mitotic defects, while the triterpene dilactones had no effect on the cilia and ciliary Smo. These ent-Kaurane diterpenoids provide new prototypes of Hh inhibitors, and are valuable probes for deciphering the mechanisms of Smo ciliary transport and ciliogenesis. PMID- 26439751 TI - Promising wet chemical strategies to synthesize Cu nanowires for emerging electronic applications. AB - Copper nanowires (Cu NWs) are of particular interest for application as transparent and flexible conducting electrodes in 'see-through' and/or 'deformable' future electronics due to their excellent electrical, optical, and mechanical properties. It is necessary to develop reliable and facile methods to produce well-defined Cu NWs prior to their full exploitation. Among the wide variety of methods available to generate Cu NWs, solution-based synthesis routes are considered to be a promising strategy because of several advantages including fewer constraints on the selection of precursors, the solvent and reaction conditions, and the feasibility of large-scale low-cost production. Here, we provide a thorough review of various recently developed synthetic methodologies to obtain Cu NWs, with particular emphasis on wet chemical synthesis approaches including a hydrothermal route, reduction of metal precursors, and catalytic synthesis. The emerging applications of Cu NWs including transparent electrodes and flexible/stretchable electronics are also discussed, followed by brief comments on the remaining challenges and future research perspectives. PMID- 26439752 TI - The composition and function of the striatin-interacting phosphatases and kinases (STRIPAK) complex in fungi. AB - The striatin-interacting phosphatases and kinases (STRIPAK) complex is a highly conserved eukaryotic protein complex that was recently described for diverse animal and fungal species. Here, we summarize our current knowledge about the composition and function of the STRIPAK complex from the ascomycete Sordaria macrospora, which we discovered by investigating sexually sterile mutants (pro), having a defect in fruiting body development. Mass spectrometry and yeast two hybrid analysis defined core subunits of the STRIPAK complex, which have structural homologs in animal and other fungal organisms. These subunits (and their mammalian homologs) are PRO11 (striatin), PRO22 (STRIP1/2), SmMOB3 (Mob3), PRO45 (SLMAP), and PP2AA, the structural, and PP2Ac, the catalytic subunits of protein phosphatase 2A (PP2A). Beside fruiting body formation, the STRIPAK complex controls vegetative growth and hyphal fusion in S. macrospora. Although the contribution of single subunits to diverse cellular and developmental processes is not yet fully understood, functional analysis has already shown that mammalian homologs are able to substitute the function of distinct fungal STRIPAK subunits. This underscores the view that fungal model organisms serve as useful tools to get a molecular insight into cellular and developmental processes of eukaryotes in general. Future work will unravel the precise localization of single subunits within the cell and decipher their STRIPAK-related and STRIPAK independent functions. Finally, evidence is accumulating that there is a crosstalk between STRIPAK and various signaling pathways, suggesting that eukaryotic development is dependent on STRIPAK signaling. PMID- 26439753 TI - Quantifying the Ototoxicity of Mitomycin: Before versus after Myringotomy. AB - OBJECTIVES: Recent research has focused on mitomycin C (MMC) application as a means to circumvent complications that arise when using ventilation tubes during myringotomy. This study has two aims: (1) to synergize the current literature to create a standardized clinical approach for using MMC, and (2) to determine at which point during the myringotomy the application of MMC proves the safest (i.e., before or after incision). METHODS: We measured the auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) in 9 female chinchillas to determine whether applying MMC before or after incision was also the safest. The tests were then repeated on days 3, 10 and 17. RESULTS: The change in the ABR thresholds from baseline was greater in the experimental than in the control group; however, after stratification, the 'after' group experienced a statistically significant change (19.38 +/- 8.26) on day 17, whereas the 'before' group did not (2.00 +/- 3.26; p = 0.003). No such changes were seen with DPOAE testing. CONCLUSIONS: Mitomycin is less ototoxic to the middle ear when applied before myringotomy is done. We recommend future studies to apply the clinical approach we have designed to standardize its use in selected cases. PMID- 26439754 TI - Fear of hypoglycemia in adults with type 1 diabetes: impact of therapeutic advances and strategies for prevention - a review. AB - PURPOSE: This review summarizes the current state of the science related to fear of hypoglycemia (FOH) in adults with type 1 diabetes. Fear of hypoglycemia is a critical deterrent to diabetes self-management, psychological well-being, and quality of life. We examine the influence of contemporary treatment regimens, technology, and interventions to identify gaps in knowledge and opportunities for research and practice. BASIC PROCEDURES: A literature search was conducted of MEDLINE, PsycINFO, and EMBASE. Fifty-three studies that examined fear of hypoglycemia were included. MAIN FINDINGS: Fear of hypoglycemia influences diabetes management and quality of life. Gender and age differences exist in experiences and responses. Responses vary from increased vigilance to potentially immobilizing distress. Fear of hypoglycemia is greater at night and may contribute to poor sleep quality. Strategies to reduce fear of hypoglycemia have had varying success. Newer technologies hold promise but require further examination. CONCLUSIONS: Fear of hypoglycemia remains a problem, despite advances in technology, insulin analogs, and evidence-based diabetes management. Clinical care should consistently include assessment for its influence on diabetes self-management and psychological health. Further research is needed regarding the influence of newer technologies and individualized strategies to reduce fear of hypoglycemia while maintaining optimal glucose control. PMID- 26439755 TI - Applicability of modified Glasgow Prognostic Score in the assessment of elderly patients with cancer: A pilot study. AB - OBJECTIVES: To evaluate the relationship between inflammatory parameters through the modified Glasgow Prognostic Score (mGPS) and other clinical characteristics of elderly patients with cancer, including frailty evaluated by the Edmonton Frailty Scale (EFS). MATERIALS AND METHODS: We included patients from the oncology service at Faculdade de Medicina do ABC with a confirmed diagnosis of solid tumor aged 65 years or more at diagnosis. Patients were assessed by applying the translated and validated to Portuguese version of the EFS and also had blood sample collection for the evaluation of C-reactive protein (CRP) and albumin for calculation of the mGPS. RESULTS: We included 52 patients of both sexes, with median age of 72.5 years, of these 67.3% had localized disease and 32.7% metastatic disease. The mGPS presented 17.3% of high-risk patients. The frailty evaluated by EFS occurred in 57.6% of patients. Patients with both abnormal parameters (CRP and albumin) in the mGPS had significantly higher scores on EFS when compared to those with no change (6 vs. 9.56 points, p=0.021). The mGPS correlated also with clinical staging (p=0.019) and performance status (p=0.039). CONCLUSIONS: Inflammatory parameters correlate significantly with frailty, more advanced clinical stage and poor functional status. PMID- 26439756 TI - Early intervention and child physical health: Evidence from a Dublin-based randomized controlled trial. AB - This article investigates the impact of an early intervention program, which experimentally modifies the parenting and home environment of disadvantaged families, on child physical health in the first 3 years of life. We recruited and randomized 233 (115 intervention, 118 control) pregnant women from a socioeconomically disadvantaged community in Dublin, Ireland into an intervention or control group. The treatment includes regular home visits commencing antenatally and an additional parenting course commencing at 2 years. Maternal reports of child health are assessed at 6, 12, 18, 24, and 36 months. Treatment effects are estimated using permutation testing to account for small sample size, inverse probability weighting to account for differential attrition, and both the stepdown procedure and an indices approach to account for multiple hypothesis testing. Following adjustment for multiple testing and attrition, we observe a positive and statistically significant main treatment effect for wheezing/asthma. The intervention group are 15.5 percentage points (pp) less likely to require medical attention for wheezing/asthma compared to the control group. Subgroup analysis reveals more statistically significant adjusted treatment effects for boys than girls regarding fewer health problems (d=0.63), accidents (23.9pp), and chest infections (22.8-37.9pp). Our results suggest that a community-based home visiting program may have favorable impacts on early health conditions. PMID- 26439757 TI - Overweight trends among Polish schoolchildren before and after the transition from communism to capitalism. AB - This study aims to reveal the secular trends in body mass index (BMI) and the prevalence of overweight and obesity among Polish schoolchildren between the years 1966-2012, during which intense socio-political changes took place. Four surveys were conducted in several districts of Poland looking at 69,746 schoolchildren aged 7-18. Significant increase in mean BMI as well as in the prevalence of overweight and obesity was observed. During this time the highest increase in both mean BMI and excess weight was observed between 1988 and 2012, i.e. after the political transformation, resulting in the improvement of living conditions. However, with respect to girls in late adolescence, between these years, the mean BMI as well as the prevalence of overweight were leveling off, while the percentage of boys with excess body fat in the same developmental category significantly increased in 2012. In the years 1966-1978 and 1978-1988 the pattern of changes in the prevalence of overweight and obesity reflected the social and economic circumstances, i.e. temporary economic improvements, or deepening political crises and food shortage. In conclusion, the weight status of schoolchildren strongly reflects socio-political changes that took place in Poland, as well as in most of the Central European countries in the last half century. PMID- 26439758 TI - Paraumbilical fat graft for the correction of contour deformity following parotidectomy and prevention of Frey syndrome. AB - Following parotidectomy, patients develop retromandibular hollowing. A case series of patients for whom a free paraumbilical graft was used to reconstruct the parotid bed defect is presented here. This graft is harvested through a supra/sub-umbilical or suprapubic incision. Over-correction of approximately 50% is required due to atrophy and resorption with time. The graft is harvested with the overlying dermis and the graft should not be filleted, as this can cause necrosis. An antibiotic membrane is placed between the graft and the underlying bed and the graft is secured with Vicryl sutures. Since 1997, 130 patients have been treated successfully with this method. Regarding complications, nine patients developed a seroma, four developed a haematoma, two suffered graft liquefaction, and one suffered an infection with frank suppuration and loss of the graft. However, no complications have been noted in the most recent 70 patients. The incidence of Frey syndrome also appeared to be reduced. The paraumbilical fat graft appears to be a successful and reliable method of correcting facial defects after a superficial or total parotidectomy. The graft can also be used to correct temporal defects and has the added advantage of reducing Frey syndrome. PMID- 26439759 TI - Evaluation of the level of progression of extracapsular spread for cervical lymph node metastasis in oral squamous cell carcinoma. AB - Only a few reports on the level of progression of extracapsular spread (ECS) have been published. The aim of this study was to evaluate the efficacy of the level of progression of ECS in identifying those patients with oral squamous cell carcinoma (OSCC) at a high risk of recurrence who would benefit most from the intensification of adjuvant therapy. The level of progression of ECS for cervical lymph node metastasis in OSCC was divided into three types (A-C), and their relationships with patient prognosis were examined. ECS was observed in 87 of 441 patients with OSCC. The recurrence rate in patients with type C, which was defined as macroscopic tumour invasion into perinodal fat or muscle tissue, was high (69.8%), with 13 cases of death due to distant metastasis. The 3-year disease-specific survival rate for patients with type C was 49.0% and these patients also had a significantly poorer prognosis (P<0.01). The results of the multivariate analysis suggested that the prognosis of ECS in OSCC patients was associated with the level of progression of ECS, especially type C (P<0.01). Overall, the results of this study suggest that the level of progression of ECS is a useful prognostic factor in OSCC patients. PMID- 26439760 TI - Ultramicro-trauma in the endometrial-myometrial junctional zone and pale cell migration in adenomyosis. AB - OBJECTIVE: To determine if ultrastructural tissue trauma occurs in the junctional zone in uteri in adenomyosis. DESIGN: A case-control experimental study. SETTING: Endometriosis research center. PATIENT(S): Twelve uteri with adenomyosis, and 9 uteri without adenomyosis, were gained during laparoscopy-assisted vaginal hysterectomy. INTERVENTION(S): Transmission electron microscopic study of the junctional zone, as well as immunohistochemical staining for epithelial cadherin, and van Gieson staining and immunofluorescence for CD45 and CD68. MAIN OUTCOME MEASURE(S): Analysis of the electron microscopy photos and the immunoreactive scores of the staining. RESULT(S): The inner myometrial muscle fibers were diversely arranged in adenomyosis; they were parallel to the basal endometrial glands in nonadenomyosis. Nuclear membrane infolding of the basal glandular epithelium and the disruption of the interface between basal endometrium and inner myometrium in adenomyosis (but not in nonadenomyosis) were evident. Intraepithelial pale cells were seen in the basal endometrial glands in both groups, but they lacked CD45 and CD68 expression. They were seen actively migrating into the stroma in adenomyosis only. CONCLUSION(S): The myofiber disarray in the inner myometrium, and the nuclear membrane irregularities in adenomyosis, are evidence for ultramicro-trauma in adenomyosis. The migrating nonleukocytic pale cells may be involved in pathogenesis of adenomyosis. PMID- 26439761 TI - The conversation. PMID- 26439762 TI - Delayed orgasm and anorgasmia. AB - Delayed orgasm/anorgasmia defined as the persistent or recurrent difficulty, delay in, or absence of attaining orgasm after sufficient sexual stimulation, which causes personal distress. Delayed orgasm and anorgasmia are associated with significant sexual dissatisfaction. A focused medical history can shed light on the potential etiologies, which include medications, penile sensation loss, endocrinopathies, penile hyperstimulation, and psychological etiologies. Unfortunately, there are no excellent pharmacotherapies for delayed orgasm/anorgasmia, and treatment revolves largely around addressing potential causative factors and psychotherapy. PMID- 26439763 TI - Longitudinal associations of neighborhood socioeconomic characteristics and alcohol availability on drinking: Results from the Multi-Ethnic Study of Atherosclerosis (MESA). AB - Neighborhood socioeconomic characteristics and alcohol availability may affect alcohol consumption, but adequate longitudinal research to support these hypotheses does not exist. We used data from the Multi-Ethnic Study of Atherosclerosis (MESA) (N = 6163) to examine associations of changes in neighborhood socioeconomic status (SES) and alcohol outlet density, with current, weekly, and heavy daily alcohol consumption in hybrid effects models. We also examined whether these associations were moderated by gender, race/ethnicity, and income. Increases in neighborhood SES were associated with decreases in the probability of current alcohol use after adjustment for age, gender, race/ethnicity, individual SES, marital status and time since baseline [probability ratio (PR) per SD increase in neighborhood SES = 0.96, 95% confidence interval (CI) (0.96.0.99)]. Increases in liquor store densities were associated with increases in weekly alcohol consumption [ratio of weekly drinks per SD increase in outlet density = 1.07, 95% CI (1.01.1.05) for men, PR = 1.11, 95% CI (1.01.1.21) for women]. Relationships between current alcohol use and neighborhood SES and between weekly beer consumption and neighborhood SES were generally stronger among those with higher incomes. Neighborhood socioeconomic context and the availability of alcohol may be important for understanding patterns of alcohol use over time, and for targeting interventions and policies to reduce harmful alcohol use. PMID- 26439764 TI - The downside of tobacco control? Smoking and self-stigma: A systematic review. AB - OBJECTIVE: Little is known about the consequences of tobacco smoking stigma on smokers and how smokers may internalize smoking-related stigma. This review summarizes existing literature on tobacco smoking self-stigma, investigating to what extent smokers are aware of negative stereotypes, agree with them and apply them to themselves. METHODS: We carried out a systematic search of Pubmed/Web of Science/PsycInfo databases for articles related to smoking self-stigma through June 2013. Reference lists and citations of included studies were also checked and experts were contacted. After screening articles for inclusion/exclusion criteria we performed a quality assessment and summarized findings according to the stages of self-stigma as conceptualized in Corrigan's progressive model of self-stigma (aware, agree, apply and harm). Initial searches yielded 570 articles. RESULTS: Thirty of these articles (18 qualitative and 12 quantitative studies) met criteria for our review. Awareness of smoking stigma was virtually universal across studies. Coping strategies for smoking stigma and the degree to which individuals who smoke internalized this stigma varied both within and across studies. There was considerable variation in positive, negative, and non significant consequences associated with smoking self-stigma. Limited evidence was found for subgroup differences in smoking-related stigma. CONCLUSION: While there is some evidence that smoking self-stigma leads to reductions in smoking, this review also identified significant negative consequences of smoking self stigma. Future research should assess the factors related to differences in how individuals respond to smoking stigma. Public health strategies which limit the stigmatization of smokers may be warranted. PMID- 26439765 TI - A Naturally Occurring Repeat Protein with High Internal Sequence Identity Defines a New Class of TPR-like Proteins. AB - Linear repeat proteins often have high structural similarity and low (~25%) pairwise sequence identities (PSI) among modules. We identified a unique P. anserina (Pa) sequence with tetratricopeptide repeat (TPR) homology, which contains longer (42 residue) repeats (42PRs) with an average PSI >91%. We determined the crystal structure of five tandem Pa 42PRs to 1.6 A, and examined the stability and solution properties of constructs containing three to six Pa 42PRs. Compared with 34-residue TPRs (34PRs), Pa 42PRs have a one-turn extension of each helix, and bury more surface area. Unfolding transitions shift to higher denaturant concentration and become sharper as repeats are added. Fitted Ising models show Pa 42PRs to be more cooperative than consensus 34PRs, with increased magnitudes of intrinsic and interfacial free energies. These results demonstrate the tolerance of the TPR motif to length variation, and provide a basis to understand the effects of helix length on intrinsic/interfacial stability. PMID- 26439766 TI - Active-State Structures of a Small Heat-Shock Protein Revealed a Molecular Switch for Chaperone Function. AB - Small heat-shock proteins (sHsps) maintain cellular homeostasis by binding to denatured client proteins to prevent aggregation. Numerous studies indicate that the N-terminal domain (NTD) of sHsps is responsible for binding to client proteins, but the binding mechanism and chaperone activity regulation remain elusive. Here, we report the crystal structures of the wild-type and mutants of an sHsp from Sulfolobus solfataricus representing the inactive and active state of this protein, respectively. All three structures reveal well-defined NTD, but their conformations are remarkably different. The mutant NTDs show disrupted helices presenting a reformed hydrophobic surface compatible with recognizing client proteins. Our functional data show that mutating key hydrophobic residues in this region drastically altered the chaperone activity of this sHsp. These data suggest a new model in which a molecular switch located in NTD facilitates conformational changes for client protein binding. PMID- 26439767 TI - Charge-Triggered Membrane Insertion of Matrix Metalloproteinase-7, Supporter of Innate Immunity and Tumors. AB - Matrix metalloproteinase-7 (MMP-7) sheds signaling proteins from cell surfaces to activate bacterial killing, wound healing, and tumorigenesis. The mechanism targeting soluble MMP-7 to membranes has been investigated. Nuclear magnetic resonance structures of the zymogen, free and bound to membrane mimics without and with anionic lipid, reveal peripheral binding to bilayers through paramagnetic relaxation enhancements. Addition of cholesterol sulfate partially embeds the protease in the bilayer, restricts its diffusion, and tips the active site away from the bilayer. Its insertion of hydrophobic residues organizes the lipids, pushing the head groups and sterol sulfate outward toward the enzyme's positive charge on the periphery of the enlarged interface. Fluorescence probing demonstrates a similar mode of binding to plasma membranes and internalized vesicles of colon cancer cells. Binding of bilayered micelles induces allosteric activation and conformational change in the auto-inhibitory peptide and the adjacent scissile site, illustrating a potential intermediate in the activation of the zymogen. PMID- 26439769 TI - A morphometric study on flexor carpi radialis muscle of the forearm: A cadaveric study. AB - BACKGROUND: Flexor carpi radialis (FCR) is frequently used in reconstruction procedures involving the hand and wrist regions. Despite having tremendous clinical significance, very few studies have been conducted on the heterogeneity of the FCR. Its surgical importance in grafting techniques and tendon transfers prompted us to study the morphometry of FCR. MATERIALS AND METHODS: In this study, we used 37 upper limbs (25 right and 12 left sides) of formalin embalmed cadavers. FCR was neatly dissected in all upper limbs to measure its total length, muscle belly length, tendon length, width of muscle belly at proximal and distal ends, width of tendon at proximal and distal ends. RESULTS: Average total length of the muscle, muscle belly length, tendon length, width of muscle belly at the proximal end, width of muscle belly at the distal end, width of tendon at the proximal end, width of tendon at the distal end were 27.1 +/- 2.13, 12.38 +/- 2.23, 14.99 +/- 2.36, 1.99 +/- 0.72, 1.59 +/- 0.48, 1.59 +/- 0.48 and 0.42 +/- 0.12 cm, respectively. Ratio of mean muscle length and tendon length, ratio of mean tendon length and total length were found to be 0.45 +/- 0.07 and 0.55 +/- 0.07, respectively. No noted variations were observed in the proximal and distal attachments of the FCR muscle. CONCLUSION: Morphometric data of FCR reported increases the existing knowledge on the heterogeneity of FCR morphology, and further forms an anatomic basis while designing/elevating the graft in certain surgical procedures in hand and wrist regions. PMID- 26439768 TI - Structure of AcrH-AopB Chaperone-Translocator Complex Reveals a Role for Membrane Hairpins in Type III Secretion System Translocon Assembly. AB - Type III secretion systems (T3SSs) are adopted by pathogenic bacteria for the transport of effector proteins into host cells through the translocon pore composed of major and minor translocator proteins. Both translocators require a dedicated chaperone for solubility. Despite tremendous efforts in the past, structural information regarding the chaperone-translocator complex and the topology of the translocon pore have remained elusive. Here, we report the crystal structure of the major translocator, AopB, from Aeromonas hydrophila AH-1 in complex with its chaperone, AcrH. Overall, the structure revealed unique interactions between the various interfaces of AopB and AcrH, with the N-terminal "molecular anchor" of AopB crossing into the "N-terminal arm" of AcrH. AopB adopts a novel fold, and its transmembrane regions form two pairs of helical hairpins. From these structural studies and associated cellular assays, we deduced the topology of the assembled T3SS translocon; both termini remain extracellular after membrane insertion. PMID- 26439770 TI - In vitro evaluation of gammadelta T cells regulatory function in Behcet's disease patients and healthy controls. AB - CD8-positive gammadelta T lymphocytes (GDCD8(+)) are specifically increased in peripheral blood of Behcet's disease (BD) patients. GDCD8(+) have shown a T regulatory (Treg) function in autoimmune experimental models, human tumor infiltrates and intestinal intraepithelial lymphocytes from celiac patients. The aim of this study was to evaluate the Treg function of GDCD8(+) and GDCD8(-), freshly isolated from peripheral blood, in comparison to CD4(+)CD25(high) naturally occurring Treg cells (nTreg) in BD and healthy controls (HC). We tested their suppressive activity on CD4(+)CD25(-) T effector cells (Teff) proliferation by a CFSE dilution protocol, after suboptimal activation with anti-CD3, in the absence or presence of IL-2. Furthermore, secreted cytokines and suppressive latency associated peptide (LAP)-TGFbeta surface upregulation were determined after GD activation. We found that Vdelta1 chains contribution to GDCD8(+) was higher in BD than in HC, but neither GDCD8(+) nor GDCD8(-); (i) suppressed Teff proliferation, (ii) expressed LAP-TGFbeta (iii) nor secreted IL-10, in either group. Moreover, GD presented a proinflammatory cytokine profile, mainly producing IFNgamma and TNFalpha, in contrast to nTregs. In conclusion, peripheral GD could contribute more to the dysregulation of TH1 type of cytokines than to exerting a Treg function in BD. PMID- 26439771 TI - Electrical Conductivity and Strong Luminescence in Copper Iodide Double Chains with Isonicotinato Derivatives. AB - Direct reactions between CuI and isonicotinic acid (HIN) or the corresponding esters, ethyl isonicotinate (EtIN) or methyl isonicotinate (MeIN), give rise to the formation of the coordination polymers [CuI(L)]n with L=EtIN (1), MeIN (2) and HIN (3). Polymers 1-3 show similar structures based on a CuI double chain in which ethyl-, methyl isonicotinate or isonicotinic acid are coordinated as terminal ligands. Albeit, their supramolecular architecture differs considerably, affecting the distances and angles of the central CuI double chains and thereby their physical properties. Hence, the photoluminescence shows remarkable differences; 1 and 2 show a strong yellow emission, whereas 3 displays a weak emission; and 1 and 2 are semiconductors with moderate room temperature conductivities, whereas 3 has increased electrical conductivity up to 3*10(-3) S cm(-1) . Additionally, 1 and 2 present an irreversible transition to a highly conducting phase with a conductivity almost 4 orders of magnitude higher and a quasi-metallic behaviour. Thermogravimetric analysis (TGA) coupled to a mass spectrometer and magnetic measurements point to a partial thermally induced oxidation of the carboxylate groups of the ligands with Cu(I) to Cu(0) reduction. DFT calculations have been carried out to rationalise these observations. PMID- 26439772 TI - Re: Dijkstra-Eshuis J, Van den Bos TW, Splinter R, Bevers RF, Zonneveld WC, Putter H, Pelger RC, Voorham-van der Zalm PJ. Effect of preoperative pelvic floor muscle therapy with biofeedback versus standard care on stress urinary incontinence and quality of life in men undergoing laparoscopic radical prostatectomy: A randomised control trial. Neurourol Urodyn. 2015 Feb;34(2):144 50. PMID- 26439773 TI - Retracted: A new contemporary prostate cancer grading system. PMID- 26439774 TI - Polymer Cages as Universal Tools for the Precise Bottom-Up Synthesis of Metal Nanoparticles. AB - A template synthesis allows the preparation of monodisperse nanoparticles with high reproducibility and independent from self-assembly requirements. Tailor-made polymer cages were used for the preparation of nanoparticles, which were made of cross-linked macromolecules with pendant thiol groups. Gold nanoparticles (AuNPs) were prepared in the polymer cages in situ, by using different amounts of cages versus gold. The polymer cages exhibited a certain capacity, below which the AuNPs could be grown with excellent control over the size and shape. Control experiments with a linear diblock copolymer showed a continuous increase in the AuNP size as the gold feed increased. This completely different behavior regarding the AuNP size evolution was attributed to the flexibility of the polymer chain depending on cross-linking. Moreover, the polymer cages were suitable for the encapsulation of AgNPs, PdNPs, and PtNPs by the in situ method. PMID- 26439776 TI - The Validity and Reliability of Global Positioning Systems in Team Sport: A Brief Review. AB - The use of global positioning systems (GPS) has increased dramatically over the last decade. Using signals from orbiting satellites, the GPS receiver calculates the exact position of the device and the speed at which the device is moving. Within team sports GPS devices are used to quantify the external load experienced by an athlete, allowing coaches to better manage trainings loads and potentially identify athletes who are overreaching or overtraining. This review aims to collate all studies that have tested either (or both) the validity or reliability of GPS devices in a team sport setting, with a particular focus on (a) measurements of distance, speed, velocities, and accelerations across all sampling rates and (b) accelerometers, player/body load and impacts in accelerometer-integrated GPS devices. A comprehensive search of the online libraries identified 22 articles that fit search criteria. The literature suggests that all GPS units, regardless of sampling rate, are capable of tracking athlete's distance during team sport movements with adequate intraunit reliability. One Hertz and 5Hz GPS units have limitations in their reporting of distance during high-intensity running, velocity measures, and short linear running (particularly those involving changes of direction), although these limitations seem to be overcome during measures recorded during team sport movements. Ten Hertz GPS devices seem the most valid and reliable to date across linear and team sport simulated running, overcoming many limitations of earlier models, whereas the increase to 15Hz GPS devices have had no additional benefit. PMID- 26439777 TI - Relative Intensity Influences the Degree of Correspondence of Jump Squats and Push Jerks to Countermovement Jumps. AB - The aim of this study was to determine the mechanical similarity between push jerk (PJ) and jump squat (JS) to countermovement jump (CMJ) and further understand the effect increasing external load may have on this relationship. Eight physically trained men (age 22 +/- 3; height 176 +/- 7 kg; weight 83 +/- 8 kg) performed an unloaded CMJ followed by JS under a range of loads (10, 25, 35, and 50% 1RM back squat) and PJ (30, 50, 65, and 75% 1RM push jerk). A portable force platform and high-speed camera both collecting at 250 Hz were used to establish joint moments and impulse during the propulsive phase of the movements. A standard inverse dynamics model was used to determine joint moment and impulse at the hip, knee, and ankle. Significant correlations (p <= 0.05) were shown between CMJ knee joint moment and JS knee joint moment at 25% load and PJ knee joint moment at 30 and 50% load. Significant correlations were also observed between CMJ knee joint impulse and JS knee joint impulse at 10% load and PJ knee joint moment at 30 and 65% load. Significant correlation was also observed between CMJ hip joint impulse and PJ hip joint impulse at 30% load. No significant joint * load interaction was shown as load increased for either PJ or JS. Results from the study suggest partial correspondence between PJ and JS to CMJ, where a greater mechanical similarity was observed between the PJ and CMJ. This interaction is load and joint dependent where lower relative loads showed greatest mechanical similarity. Therefore using lower relative loads when programming may provide a greater transfer of training effect. PMID- 26439775 TI - Effect of Age, Duration of Exposure, and Dose of Atrazine on Sexual Maturation and the Luteinizing Hormone Surge in the Female Sprague-Dawley Rat. AB - Atrazine (ATZ) was administered daily by gavage to pregnant female Sprague Dawley rats at doses of 0, 6.25, 25 or 50 mg/kg/day, either during gestation, lactation and post-weaning (G/L/PW cohort) to F1 generation female offspring or only from postnatal day (PND 21) until five days after sexual maturation (vaginal opening) when the estrogen-primed, luteinizing hormone (LH) surge was evaluated (PW cohort). Additional subgroups of F1 females received the vehicle or ATZ from PND 21-133 or from PND 120-133. Slight reductions in fertility and the percentage of F1 generation pups surviving to PND 21 in the gestationally exposed 50 mg/kg dose group were accompanied by decreased food intake and body weight of dams and F1 generation offspring. The onset of puberty was delayed in of the F1 generation G/L/PW females at doses of 25 and 50 mg/kg/day. F1 generation females in the PW high-dose ATZ group also experienced a delay in the onset of puberty. ATZ had no effect on peak LH or LH AUC in ovariectomized rats 5 days after sexual maturation, irrespective of whether the F1 generation females were treated from gestation onward or only peripubertally. There was no effect of ATZ treatment on the estrous cycle, peak LH or LH AUC of F1 generation females exposed from gestation through to PND 133 or only for two weeks from PND 120-133. These results indicate that developing females exposed to ATZ are not more sensitive compared to animals exposed to ATZ as young adults. PMID- 26439778 TI - Acute Physiological Responses to Strongman Training Compared to Traditional Strength Training. AB - Strongman training (ST) has become an increasingly popular modality, but data on physiological responses are limited. This study sought to determine physiological responses to an ST session compared to a traditional strength exercise training (RST) session. Ten healthy men (23.6 +/- 27.5 years, 85.8 +/- 10.3 kg) volunteered in a crossover design, where all participants performed an ST session, an RST session, and a resting session within 7 days apart. The ST consisted of sled drag, farmer's walk, 1 arm dumbbell clean and press, and tire flip at loads eliciting approximately 30 seconds of near maximal effort per set. The RST consisted of squat, deadlift, bench press, and power clean, progressing to 75% of 1 repetition maximum. Sessions were equated for approximate total set duration. Blood lactate and salivary testosterone were recorded immediately before and after training sessions. Heart rate, caloric expenditure, and substrate utilization were measured throughout the resting session, both training protocols and for 80 minutes after training sessions. Analyses were conducted to determine differences in physiological responses within and between protocols. No significant changes in testosterone occurred at any time point for either session. Lactate increased significantly immediately after both sessions. Heart rate, caloric expenditure, and substrate utilization were all elevated significantly during ST and RST. Heart rate and fat expenditure were significantly elevated compared to resting in both sessions' recovery periods; calorie and carbohydrate expenditures were not. Compared to RST, ST represents an equivalent physiological stimulus on key parameters indicative of potential training-induced adaptive responses. Such adaptations could conceivably include cardiovascular conditioning. PMID- 26439780 TI - Comparative Effects of Vigorous-Intensity and Low-Intensity Blood Flow Restricted Cycle Training and Detraining on Muscle Mass, Strength, and Aerobic Capacity. AB - Traditional high-intensity aerobic training has been shown to improve muscle protein synthesis and aerobic capacity; however, recent research indicates that low-intensity aerobic training with blood flow restriction (BFR) may have similar effects. The purpose of this study was to compare the effects of vigorous intensity (VI) cycling vs. low-intensity cycling with BFR (LI-BFR) on muscle mass, strength, and aerobic capacity after training and subsequent detraining. Thirty-one physically active subjects were assigned to one of 3 groups: VI (n = 10, 60-70% heart rate reserve [HRR]), LI-BFR (n = 11, 30% HRR with BFR at 160-180 mm Hg), and no exercise control (n = 10, no exercise). Subjects in VI and LI-BFR cycled 3 times per week for 6 weeks (total 18 sessions). Body composition, muscle mass, strength, and aerobic capacity were measured pre, post, and after 3 weeks of detraining. A group * time interaction (p = 0.019) effect for both knee flexion and leg lean mass was found. For both VI and LI-BFR groups, knee flexion strength was significantly increased between pre and post (p = 0.024, p = 0.01) and between pre and 3 week-post (p = 0.039, p = 0.003), respectively. For the LI BFR group, leg lean mass was significantly increased between pre and 3 week-post (p = 0.024) and between post and 3 week-post (p = 0.013). However, there were no significant differences between groups for any variables. The LI-BFR elicits an increase in the knee flexion muscle strength over time similar to the VI. An increase in the leg lean mass over time was seen in the LI-BFR, but not in VI and CON. PMID- 26439781 TI - Time Course of Improvements in Power Characteristics in Elite Development Netball Players Entering a Full-Time Training Program. AB - We describe the time course of adaptation to structured resistance training on entering a full-time high-performance sport program. Twelve international caliber female netballers (aged 19.9 +/- 0.4 years) were monitored for 18 weeks with countermovement (CMJ: performed with body weight and 15 kg) and drop jumps (0.35 m box at body weight) at the start of each training week. Performance did not improve linearly or concurrently with loaded CMJ power improving 11% by Week 5 (effect size [ES] 0.93 +/- 0.72) in contrast, substantial positive changes were observed for unloaded CMJ power (12%; ES 0.78 +/- 0.39), and CMJ velocity (unloaded: 7.1%; ES 0.66 +/- 0.34; loaded: 7.5%; ES 0.90 +/- 0.41) by week 7. Over the investigation duration, large improvements were observed in unloaded CMJ power (24%; ES 1.45 +/- 1.11) and velocity (12%; ES 1.13 +/- 0.76). Loaded CMJ power also showed a large improvement (19%; ES 1.49 +/- 0.97) but only moderate changes were observed for loaded CMJ velocity (8.4%; ES 1.01 +/- 0.67). Jump height changes in either unloaded or loaded CMJ were unclear over the 18-week period. Drop jump performance improved throughout the investigation period with moderate positive changes in reactive strength index observed (35%; ES 0.97 +/- 0.69). The adaptation response to a structured resistance training program does not occur linearly in young female athletes. Caution should be taken if assessing jump height only, as this will provide a biased observation to a training response. Frequently assessing CMJ performance can aid program design coaching decisions to ensure improvements are seen past the initial neuromuscular learning phase in performance training. PMID- 26439782 TI - The Impact of Back Squat and Leg-Press Exercises on Maximal Strength and Speed Strength Parameters. AB - Strength training-induced increases in speed strength seem indisputable. For trainers and athletes, the most efficient exercise selection in the phase of preparation is of interest. Therefore, this study determined how the selection of training exercise influences the development of speed strength and maximal strength during an 8-week training intervention. Seventy-eight students participated in this study (39 in the training group and 39 as controls). Both groups were divided into 2 subgroups. The first training group (squat training group [SQ]) completed an 8-week strength training protocol using the parallel squat. The second training group (leg-press training group [LP]) used the same training protocol using the leg press (45 degrees leg press). The control group was divided in 2 subgroups as controls for the SQ or the LP. Two-factorial analyses of variance were performed using a repeated measures model for all group comparisons and comparisons between pretest and posttest results. The SQ exhibited a statistically significant (p <= 0.05) increase in jump performance in squat jump (SJ, 12.4%) and countermovement jump (CMJ, 12.0%). Whereas, the changes in the LP did not reach statistical significance and amounted to improvements in SJ of 3.5% and CMJ 0.5%. The differences between groups were statistically significant (p <= 0.05). There are also indications that the squat exercise is more effective to increase drop jump performance. Therefore, the squat exercise increased the performance in SJ, CMJ, and reactive strength index more effectively compared with the leg-press in a short-term intervention. Consequently, if the strength training aims at improving jump performance, the squat should be preferred because of the better transfer effects. PMID- 26439783 TI - Basketball Performance Is Related to Maturity and Relative Age in Elite Adolescent Players. AB - During a national championship, the anthropometric, physiological, and maturation characteristics of 13- to 14-year-old players of elite basketball teams and their association with sport performance were analyzed. Body parameters (weight, height, skinfold thicknesses, and lengths) were measured and physiological capacities assessed by sprint (20 m) and jump tests (i.e., countermovement jump with arm swing). Chronological age (CA) and maturity offset (years from age at peak height velocity; YAPHV) were calculated, and then predicted age at peak height velocity, as the difference between CA and YAPHV. Game performance was assessed with point averages and the performance index rating (PIR). The birth date distribution of players was biased, those born early in the selection year outnumbering those born later. Anthropometric analysis indicated that players who performed better had longer body lengths. Physiological testing showed that semi finalists had better sprint performance than quarter-finalists and those players with greater jump capacity scored more points. Early maturation and advanced maturity status were also associated with better PIR and scored points per game. Multiple blockwise regression analysis showed that, among the factors analyzed, YAPHV was the best predictor of basketball performance. In conclusion, around puberty, physical and physiological parameters associated with maturity and CA are important in determining the success of elite basketball players. Consequently, boys who are born in the second half of the year and/or late maturing tend to be marginalized or totally excluded, and not given the chance to play under equal conditions; their careers may then be held back by the relative disadvantage associated with inexperience. PMID- 26439784 TI - Physical Qualities of International Female Rugby League Players by Playing Position. AB - The purpose of this study was to investigate the anthropometric, body composition, and fitness characteristics of female rugby league players by playing position. Data were collected on 27 players who were part of the English elite women's rugby league squad. Player assessments comprised anthropometric (stature and body mass), body composition (dual-energy X-ray absorptiometry) and fitness {lower-body power (countermovement jump [CMJ], 20 kg jump squat [JS], and 30 cm drop jump), 5, 10, 20, 30, and 40 m sprint, 505 agility, Yo-Yo intermittent recovery test level 1} measures. Players were classified into playing position (i.e., forwards and backs) before analysis. A multivariate analysis of variance demonstrated significant (p <= 0.05) differences for body mass, stature, total fat, lean mass, and percentage body fat between forwards and backs. Positional differences were also observed for speed, agility, and lower-body power. Significant relationships were observed between total body fat and all fitness variables, and total lean mass was related to CMJ and JS peak power. This study provides comparative data for female rugby league forwards and backs. Body fat was strongly associated with performance and should therefore be considered in developing fitness characteristics. The relationship to match performance and trainability of these characteristics warrants further investigation. PMID- 26439785 TI - Effects of Coffee and Caffeine Anhydrous Intake During Creatine Loading. AB - The purpose of this study was to determine the effect of 5 days of creatine (CRE) loading alone or in combination with caffeine anhydrous (CAF) or coffee (COF) on upper-body and lower-body strength and sprint performance. Physically active males (n = 54; mean +/- SD; age = 20.1 +/- 2.1 years; weight = 78.8 +/- 8.8 kg) completed baseline testing, consisting of 1 repetition maximum (1RM) and repetitions to fatigue with 80% 1RM for bench press and leg press, followed by a repeated sprint test of five, 10-second sprints separated by 60-second rest on a cycle ergometer to determine peak power (PP) and total power (TP). At least 72 hours later, subjects were randomly assigned to supplement with CRE (5 g of CRE monohydrate, 4 times per day; n = 14), CRE + CAF (CRE +300 mg.d of CAF; n = 13), CRE + COF (CRE +8.9 g of COF, yielding 303 mg of CAF; n = 13), or placebo (PLA; n = 14) for 5 days. Serum creatinine (CRN) was measured before and after supplementation, and on day 6, participants repeated pretesting procedures. Strength measures were improved in all groups (p <= 0.05), with no significant time * treatment interactions. No significant interaction or main effects were observed for PP. For TP, a time * sprint interaction was observed (p <= 0.05), with no significant interactions among treatment groups. A time * treatment interaction was observed for serum CRN values (p <= 0.05) that showed increases in all groups except PLA. Four subjects reported mild gastrointestinal discomfort with CRE + CAF, with no side effects reported in other groups. These findings suggest that neither CRE alone nor in combination with CAF or COF significantly affected performance compared with PLA. PMID- 26439786 TI - The Acute Potentiating Effects of Heavy Sled Pulls on Sprint Performance. AB - This study examined the acute potentiating effects of heavy sprint-style sled pulls on sprint performance. Twenty-two experienced resistance-trained rugby athletes performed 2 heavy sprint-style sled pull training protocols on separate occasions using a randomized, crossover, and counterbalanced design. The protocols consisted of 2-baseline 15 m sprints followed by 15 m sprints at 4, 8, and 12 minutes after completing 15 and 7.5 m heavy sled pulls with loads of 75 and 150% body mass (respectively). A significantly faster (p <= 0.05) 15 m sprint time was observed at 12 minutes for the 75% body mass load. Small nonsignificant improvements (effect size [ES] = 0.22-0.33) in 5, 10, and 15 m sprint times were observed at 8 and 12 minutes after the 75% body mass sled pull. No significant changes were observed for any sprint time after the 150% body mass sled pull. Significant differences in the percentage of change in sprint times between the 2 sled pull conditions were observed at 4 (ES = 0.44-0.52), 8 (ES = 0.59), and 12 minutes (ES = 0.64). It would seem that the 75% body mass sled pull can be an effective preload stimulus for improving subsequent sprint performance provided that adequate recovery (8-12 minutes) is allowed. Practitioners should be advised that prescription of training load based on decrement in sprint velocity may be the best approach to determine loading for athletes. PMID- 26439787 TI - Reactive Strength Index Modified Is a Valid Measure of Explosiveness in Collegiate Female Volleyball Players. AB - The purpose of this study was to investigate the validity of the reactive strength index modified (RSImod) as a measure of lower body explosiveness. Fifteen female, National Collegiate Athletic Association Division I volleyball players performed vertical countermovement jumps (CMJs) while standing on a force plate. Each player performed 3 CMJs. The vertical ground reaction forces collected during each jump were used to calculate jump height, time to take-off, time to peak force, peak force, peak rate of force development, and peak power; the latter 3 variables were all normalized to body mass. Reactive strength index modified was calculated as the ratio between jump height and time to take-off. All variables, except for jump height, were then entered a factor analysis, which reduced the input data into 2 factors: a force factor and a speed factor. Although RSImod loaded more strongly onto the force factor, further analysis showed that RSImod loaded positively onto both force and speed factors. Visual analysis of the Cartesian coordinates also showed that RSImod loaded into the quadrant of greater force and speed abilities. These results indicate that the construct of RSImod, as derived from CMJ force-time data, captures a combination of speed-force factors that can be interpreted as lower body explosiveness during the CMJ. Reactive strength index modified therefore seems to be a valid measure to study lower body explosiveness. PMID- 26439788 TI - Sport-Specific Conditioning Variables Predict Offensive and Defensive Performance in High-Level Youth Water Polo Athletes. AB - Specific-conditioning capacities (SCC) are known to be generally important in water polo (WP), yet the independent associations to offensive and defensive performance is unknown. This study aimed to determine whether offense and defense abilities in WP were independently associated with SCC and anthropometrics. The participants were 82 high-level male youth WP players (all 17-19 years of age; body height, 186.3 +/- 6.07 cm; body mass, 84.8 +/- 9.6 kg). The independent variables were body height and body mass, and 5 sport-specific fitness tests: sprint swimming over 15 meters; 4 * 50-meter anaerobic-endurance test; vertical in-water-jump; maximum intensity isometric force in upright swimming using an eggbeater kick; and test of throwing velocity. The 6 dependent variables comprised parameters of defensive and offensive performance, such as polyvalence, i.e., ability to play on different positions in defensive tasks (PD) and offensive tasks (PO), efficacy in primary playing position in defensive (ED) and offensive (EO) tasks, and agility in defensive (AD) and offensive (AO) tasks. Analyses showed appropriate reliability for independent (intraclass coefficient of 0.82-0.91) and dependent variables (Cronbach alpha of 0.81-0.95). Multiple regressions were significant for ED (R = 0.25; p < 0.01), EO (R = 0.21; p < 0.01), AD (R = 0.40; p < 0.01), and AO (R = 0.35; p < 0.01). Anaerobic-swimming performance was positively related to AD (beta = -0.26; p <= 0.05), whereas advanced sprint swimming was related to better AO (beta = -0.38; p <= 0.05). In water-jumping performance held the significant positive relationship to EO (beta = 0.31; p <= 0.05), ED (beta = 0.33; p <= 0.05), and AD (beta = 0.37; p <= 0.05). Strength and conditioning professionals working in WP should be aware of established importance of SCC in performing unique duties in WP. The SCC should be specifically developed to meet the needs of offensive and defensive performance in young WP athletes. PMID- 26439789 TI - The Effects of Breakdown Set Resistance Training on Muscular Performance and Body Composition in Young Men and Women. AB - Breakdown (BD) training has been advocated by multiple commercial and academic publications and authors, seemingly as a result of the acute hormonal and muscle activation responses it produces. However, there is a relative dearth of research that has empirically considered this advanced method of resistance training (RT) over a chronic intervention while appropriately controlling other RT variables. The present study considered 36 male and female participants divided into 3 groups: BD (n = 11), heavy-load breakdown (n = 14), and traditional (n = 11), performing full-body RT programs 2 times per week for 12 weeks. No significant between-group differences were identified for change in absolute muscular endurance for chest press, leg press, or pull-down exercises or for body composition changes. Effect sizes for absolute muscular endurance changes were large for all groups and exercises (0.86-2.74). The present study supports previous research that the use of advanced training techniques stimulates no greater muscular adaptations when compared with performing more simplified RT protocols to momentary muscular failure. PMID- 26439790 TI - A Comparison of the Effect of Kettlebell Swings and Isolated Lumbar Extension Training on Acute Torque Production of the Lumbar Extensors. AB - The aim of this study was to use a fatigue response test to measure the muscular fatigue (defined as a reduction in torque production) sustained by the lumbar extensors after a single set of kettlebell swings (KBS) in comparison with isolated lumbar extensions (ILEX) and a control condition (CON). The purpose of which is to measure the physiological response of KBS against an already established modality. Subsequent data provide insight of the efficacy of kettlebells swings in strengthening the lumbar muscles and lower back pain treatment. Eight physically active males participated in a repeated measures design where participants completed all conditions. There were statistically significant reductions in maximal torque, reported as strength index (SI), after both KBS and ILEX exercise. A statistically significant difference was found for reductions in maximal torque between CON and both KBS (p = 0.005) and ILEX (p = 0.001) and between KBS and ILEX (p = 0.039). Mean reduction and effect sizes were -1824 +/- 1127.12 (SI) and -1.62 for KBS and -4775.6 +/- 1593.41 (SI) and -3.00 for ILEX. In addition, a statistically significant difference was found between KBS and ILEX for rate of perceived exertion (p = 0.012). Data suggest that both KBS and ILEX were able to fatigue the lumbar extensors. Isolated lumbar extension was able to generate a greater level of fatigue. However, contrary to previous research, the KBS was able to elicit a physiological response, despite the lack of pelvic restraint supporting the potential to strengthen the lumbar extensors. PMID- 26439791 TI - Avirulence gene mapping in the Hessian fly (Mayetiola destructor) reveals a protein phosphatase 2C effector gene family. AB - The genetic tractability of the Hessian fly (HF, Mayetiola destructor) provides an opportunity to investigate the mechanisms insects use to induce plant gall formation. Here we demonstrate that capacity using the newly sequenced HF genome by identifying the gene (vH24) that elicits effector-triggered immunity in wheat (Triticum spp.) seedlings carrying HF resistance gene H24. vH24 was mapped within a 230-kb genomic fragment near the telomere of HF chromosome X1. That fragment contains only 21 putative genes. The best candidate vH24 gene in this region encodes a protein containing a secretion signal and a type-2 serine/threonine protein phosphatase (PP2C) domain. This gene has an H24-virulence associated insertion in its promoter that appears to silence transcription of the gene in H24-virulent larvae. Candidate vH24 is a member of a small family of genes that encode secretion signals and PP2C domains. It belongs to the fraction of genes in the HF genome previously predicted to encode effector proteins. Because PP2C proteins are not normally secreted, our results suggest that these are PP2C effectors that HF larvae inject into wheat cells to redirect, or interfere, with wheat signal transduction pathways. PMID- 26439793 TI - Association of food consumption with total volumes of visceral and subcutaneous abdominal adipose tissue in a Northern German population. AB - Excess accumulation of visceral adipose tissue (VAT) is a known risk factor for cardiometabolic diseases; further, subcutaneous abdominal adipose tissue (SAAT) and the ratio of both (VAT:SAAT ratio) have been discussed as potentially detrimental. Information about the association between diet and adipose tissue is scarce. This study aimed to identify food group intake associated with VAT and SAAT and the VAT:SAAT ratio in a Northern German population. A cross-sectional analysis was conducted in 344 men and 241 women who underwent an MRI to quantify total volumes of VAT and SAAT. Intake of fourteen food groups was assessed with a self-administered 112-item FFQ. Linear regression models adjusted for age, sex, energy intake, physical activity, intake of other food groups and mutual adjustment for VAT and SAAT were calculated to analyse the associations between standardised food group intake and VAT and SAAT, or the VAT:SAAT ratio. Intakes of potatoes (P=0.043) and cakes (P=0.003) were positively and inversely, respectively, associated with both VAT and SAAT. By contrast, intake of cereals was negatively associated with VAT (P=0.045) only, whereas intakes of eggs (P=0.006) and non-alcoholic beverages (P=0.042) were positively associated with SAAT only. The association between eggs and non-alcoholic beverages with SAAT remained significant after further consideration of VAT. Intake of non-alcoholic beverages was also inversely associated with the VAT:SAAT ratio (P=0.001). Our analysis adds to the evidence that intake of foods is independently associated with VAT or SAAT volumes. PMID- 26439794 TI - Membrane glycoproteomics of fetal lung fibroblasts using LC/MS. AB - Some aberrant N-glycosylations are being used as tumor markers, and glycoproteomics is expected to provide novel diagnosis markers and targets of drug developments. However, one has trouble in mass spectrometric glycoproteomics of membrane fraction because of lower intensity of glycopeptides in the existence of surfactants. Previously, we developed a glycopeptide enrichment method by acetone precipitation, and it was successfully applied to human serum glycoproteomics. In this study, we confirmed that this method is useful to remove the surfactants and applicable to membrane glycoproteomics. The glycoproteomic approach to the human fetal lung fibroblasts membrane fraction resulted in the identification of over 272 glycoforms on 63 sites of the 44 glycoproteins. According to the existing databases, the structural features on 41 sites are previously unreported. The most frequently occurring forms at N-glycosylation site were high-mannose type containing nine mannose residues (M9) and monosialo fucosylated biantennary oligosaccharides. Several unexpected N-glycans, such as fucosylated complex-type and fucosylated high-mannose and/or fucosylated pauci mannose types were found in ER and lysosome proteins. Our method provides new insights into transport, biosynthesis, and degradation of glycoproteins. PMID- 26439796 TI - RNA-based regulation of transposon expression. AB - Throughout the domains of life, transposon activity represents a serious threat to genome integrity and evolution has realized different molecular mechanisms that aim to inhibit the transposition of mobile DNA. Small noncoding RNAs that function as guides for Argonaute effector proteins represent a key feature of so called RNA interference (RNAi) pathways and specialized RNAi pathways exist to repress transposon activity on the transcriptional and posttranscriptional level. Transposon transcription can be diminished by targeted DNA methylation or chromatin remodeling via repressive Histone modifications. Posttranscriptional transposon silencing bases on degradation of transposon transcripts to prevent either reverse transcription followed by genomic reintegration or translation into proteins that mediate the transposition process. In plants, Argonaute-like proteins guided by short interfering RNAs (siRNAs) are essential for transposon repression on the epigenetic and posttranscriptional level. In the germline of animals, these tasks are often assumed by a second subclass of Argonaute proteins referred to as Piwi-like proteins, which bind a distinct class of small noncoding RNAs named piwi-interacting RNAs (piRNAs). Though the principals of RNAi pathways are essentially the same in all eukaryotic organisms, remarkable differences can be observed even in closely related species reflecting the astonishing plasticity and diversity of these pathways. PMID- 26439795 TI - Esculetin induces apoptosis in human colon cancer cells by inducing endoplasmic reticulum stress. AB - Colorectal cancer has become more common in many regions of the world. Recently, we showed that esculetin, a natural coumarin, induces apoptosis in HT-29 colon cancer cells via the reactive oxygen species-mediated mitochondrial pathway. The present study examined whether esculetin induces apoptosis in HT-29 colon cancer cells by inducing endoplasmic reticulum (ER) stress. We found that esculetin induced characteristic signs of ER stress, confirmed by ER staining, mitochondrial calcium overload and expression of ER stress-related proteins (i.e. glucose regulated protein 78, phosphorylated ribonucleic acid-dependent protein kinase-like ER kinase, phosphorylated inositol requiring enzyme 1, phosphorylated eukaryotic initiation factor-2alpha, spliced X-box binding protein 1 and cleaved activating transcription factor 6). Esculetin also induced the expression of the CCAAT/enhancer-binding protein-homologous protein (CHOP) and pro-apoptotic factors caspase-12. Moreover, transfection of colon cancer cells with a small interfering ribonucleic acid targeting CHOP attenuated esculetin-induced apoptosis. Taken together, these results suggest that the ER stress response plays an important role in esculetin-induced apoptosis in human colon cancer cells. PMID- 26439798 TI - Secukinumab distributes into dermal interstitial fluid of psoriasis patients as demonstrated by open flow microperfusion. PMID- 26439797 TI - Sequential therapy with cyclophosphamide and mycophenolic acid in patients with progressive immunoglobulin A nephropathy: a long-term follow-up. AB - In progressive immunoglobulin (Ig)A nephropathy (IgAN), cyclophosphamide pulse therapy (CyP), high-dose intravenous immunoglobulins (IVIg) and mycophenolic acid (MPA) have been used to stop progressive loss of renal function, but disease progression may occur after the end of the initial treatment. Here, we report the long-term follow-up of patients with progressive IgAN with MPA as maintenance therapy after CyP (CyP-MPA). In a median observation time of 6.2 years, we analysed the slopes of the loss of renal function of 47 patients with biopsy proven IgAN and treated with CyP. Thirty-one patients with further progression were treated with MPA maintenance for a median time of 5.2 years. Follow-up was compared with symptomatic therapy and IVIg as historically matched control groups. Median loss of renal function was reduced significantly from 0.9 ml/min to 0.1 ml/min per month with CyP (P < 0.05), and with MPA in patients with a relapse from -0.4 ml/min to -0.1 ml/min per month (P < 0.05) until the end of the study. Proteinuria decreased significantly from 1.6 g/l to 1.0 g/l after CyP, and during MPA treatment to 0.6 g/l (P = 0.001 Friedman test). Median renal survival time was in patients with CyP 10.5 years (range = 3.2-17.8), with CyP-MPA 10.7 years (range = 8.3-13.1), with IVIg 4.7 years (range = 2.6-6.6), and in untreated patients 1.2 years (range = 0.8-1.6; log-rank test P < 0.01). In patients with progressive IgAN, our long-term follow-up observation indicates that sequential CyP-MPA therapy maintains renal survival significantly. PMID- 26439799 TI - Role of mitochondrial calcium uptake homeostasis in resting state fMRI brain networks. AB - Mitochondrial Ca(2+) uptake influences both brain energy metabolism and neural signaling. Given that brain mitochondrial organelles are distributed in relation to vascular density, which varies considerably across brain regions, we hypothesized different physiological impacts of mitochondrial Ca(2+) uptake across brain regions. We tested the hypothesis by monitoring brain "intrinsic activity" derived from the resting state functional MRI (fMRI) blood oxygen level dependent (BOLD) fluctuations in different functional networks spanning the somatosensory cortex, caudate putamen, hippocampus and thalamus, in normal and perturbed mitochondrial Ca(2+) uptake states. In anesthetized rats at 11.7 T, mitochondrial Ca(2+) uptake was inhibited or enhanced respectively by treatments with Ru360 or kaempferol. Surprisingly, mitochondrial Ca(2+) uptake inhibition by Ru360 and enhancement by kaempferol led to similar dose-dependent decreases in brain-wide intrinsic activities in both the frequency domain (spectral amplitude) and temporal domain (resting state functional connectivity; RSFC). The fact that there were similar dose-dependent decreases in the frequency and temporal domains of the resting state fMRI-BOLD fluctuations during mitochondrial Ca(2+) uptake inhibition or enhancement indicated that mitochondrial Ca(2+) uptake and its homeostasis may strongly influence the brain's functional organization at rest. Interestingly, the resting state fMRI-derived intrinsic activities in the caudate putamen and thalamic regions saturated much faster with increasing dosage of either drug treatment than the drug-induced trends observed in cortical and hippocampal regions. Regional differences in how the spectral amplitude and RSFC changed with treatment indicate distinct mitochondrion-mediated spontaneous neuronal activity coupling within the various RSFC networks determined by resting state fMRI. PMID- 26439800 TI - Sustained Epigenetic Drug Delivery Depletes Cholesterol-Sphingomyelin Rafts from Resistant Breast Cancer Cells, Influencing Biophysical Characteristics of Membrane Lipids. AB - Cell-membrane lipid composition can greatly influence biophysical properties of cell membranes, affecting various cellular functions. We previously showed that lipid synthesis becomes altered in the membranes of resistant breast cancer cells (MCF-7/ADR); they form a more rigid, hydrophobic lipid monolayer than do sensitive cell membranes (MCF-7). These changes in membrane lipids of resistant cells, attributed to epigenetic aberration, significantly affected drug transport and endocytic function, thus impacting the efficacy of anticancer drugs. The present study's objective was to determine the effects of the epigenetic drug, 5 aza-2'-deoxycytidine (DAC), delivered in sustained-release nanogels (DAC-NGs), on the composition and biophysical properties of membrane lipids of resistant cells. Resistant and sensitive cells were treated with DAC in solution (DAC-sol) or DAC NGs, and cell-membrane lipids were isolated and analyzed for lipid composition and biophysical properties. In resistant cells, we found increased formation of cholesterol-sphingomyelin (CHOL-SM) rafts with culturing time, whereas DAC treatment reduced their formation. In general, the effect of DAC-NGs was greater in changing the lipid composition than with DAC-sol. DAC treatment also caused a rise in levels of certain phospholipids and neutral lipids known to increase membrane fluidity, while reducing the levels of certain lipids known to increase membrane rigidity. Isotherm data showed increased lipid membrane fluidity following DAC treatment, attributed to decrease levels of CHOL-SM rafts (lamellar beta [Lbeta] structures or ordered gel) and a corresponding increase in lipids that form lamellar alpha-structures (Lalpha, liquid crystalline phase). Sensitive cells showed marginal or insignificant changes in lipid profile following DAC treatment, suggesting that epigenetic changes affecting lipid biosynthesis are more specific to resistant cells. Since membrane fluidity plays a major role in drug transport and endocytic function, treatment of resistant cells with epigenetic drugs with altered lipid profile could facilitate anticancer drug transport to overcome acquired drug resistance in a combination therapy. PMID- 26439801 TI - Hydrogen peroxide mediates hyperglycemia-induced invasive activity via ERK and p38 MAPK in human pancreatic cancer. AB - Diabetes mellitus and pancreatic cancer are intimately related, as approximately 85% of pancreatic cancer patients suffer from glucose intolerance or even diabetes. In this study, we evaluate the underlying mechanism by which hyperglycemia modulates the invasive potential of cancer cells and contributes to their enhanced metastatic behavior. Here we show that hyperglycemia increases the hydrogen peroxide (H2O2) concentration through up-regulation of manganese superoxide dismutase (SOD2) expression, which further activates the ERK and p38 MAPK pathways, as well as the transcription factors NF-kappaB and AP-1, in a time dependent manner. The invasion of pancreatic cancer cells resulting from the activation of the H2O2/MAPK axis under high glucose conditions is effectively inhibited by PD 98059 (ERK inhibitor), SB 203580 (p38 MAPK inhibitor), polyethylene glycol-conjugated catalase (PEG-CAT), or the siRNA specific to SOD2. In addition, streptozotocin-treated diabetic nude mice exhibit a stronger tumor invasive ability in renal capsule xenografts which could be suppressed by PEG-CAT treatment. Furthermore, the integrated optical density (IOD) of SOD2 and uPA stainings is higher in the tumor tissues of pancreatic cancer patients with diabetes compared with pancreatic cancer patients with euglycemia. Taken together, our results demonstrate that hyperglycemia enhances cell invasive ability through the SOD2/H2O2/MAPK axis in human pancreatic cancer. Thus, SOD2/H2O2/MAPK axis may represent a promising therapeutic target for pancreatic cancer patients combined with diabetes mellitus. PMID- 26439802 TI - Down-regulation of the Lamin A/C in neuroblastoma triggers the expansion of tumor initiating cells. AB - Tumor-initiating cells constitute a population within a tumor mass that shares properties with normal stem cells and is considered responsible for therapy failure in many cancers. We have previously demonstrated that knockdown of the nuclear envelope component Lamin A/C in human neuroblastoma cells inhibits retinoic acid-mediated differentiation and results in a more aggressive phenotype. In addition, Lamin A/C is often lost in advanced tumors and changes in the nuclear envelope composition occur during tumor progression. Based on our previous data and considering that Lamin A/C is expressed in differentiated tissues, we hypothesize that the lack of Lamin A/C could predispose cells toward a stem-like phenotype, thus influencing the development of tumor-initiating cells in neuroblastoma. This paper demonstrates that knockdown of Lamin A/C triggers the development of a tumor-initiating cell population with self-renewing features in human neuroblastoma cells. We also demonstrates that the development of TICs is due to an increased expression of MYCN gene and that in neuroblastoma exists an inverse relationship between LMNA and MYCN expression. PMID- 26439803 TI - Low EGFR/MET ratio is associated with resistance to EGFR inhibitors in non-small cell lung cancer. AB - PURPOSE: Although activating mutations in the epidermal growth factor receptor (EGFR) gene are predictive markers for response to EGFR inhibitors, 30-40% of EGFR-mutant non-small cell lung cancer (NSCLC) patients are de novo non responders. Hence, we sought to explore additional biomarkers of response. METHODS: We conducted a prospective pilot study to characterize the expression and/or activation of key receptor tyrosine kinases (RTKs) in stage IIIB-IV NSCLC tumors. A total of 37 patients were enrolled and 34 underwent EGFR inhibitor treatment. RESULTS: As expected, patients bearing activating EGFR mutations showed increased progression free survival (PFS) compared to patients with wild type EGFR status (9.3 vs 1.4 months, p = 0.0629). Analysis of baseline tumor RTK profiles revealed that, regardless of EGFR mutation status, higher levels of EGFR relative to MET correlated with longer PFS. At multiple EGFR/MET ratio cut-offs, including 1, 2 and 3, median PFS according to below vs. above cut-offs were 0.4 vs. 6.1 (p = 0.0001), 0.5 vs. 9.3 (p = 0.0006) and 1.0 vs. 11.2 months (p = 0.0008), respectively. CONCLUSION: The EGFR/MET ratio measured in tumors at baseline may help identify NSCLC patients most likely to benefit from prolonged PFS when treated with EGFR inhibitors. PMID- 26439805 TI - Targeting the Wnt signaling pathway in colorectal cancer. AB - INTRODUCTION: The treatment of patients with advanced colorectal cancer still remains challenging, and identification of new target molecules and therapeutic avenues remains a priority. The great majority of colorectal cancers have mutations in one of two genes involved in the Wnt signaling pathway: the adenomatous polyposis coli (APC) and beta-catenin (CTNNB1) genes. Up to now, however, no therapeutics for targeting this pathway have been established. AREAS COVERED: This review article begins with a brief summary of Wnt signaling from the viewpoints of genetics, cancer stem cell biology, and drug development. We then overview current attempts to develop drugs directed at various components of the Wnt signaling pathway. EXPERT OPINION: APC is a tumor suppressor, and therefore only downstream signal transducers of the APC protein can be considered as targets for pharmaceutical intervention. TRAF2 and NCK-interacting protein kinase (TNIK) was identified as the most downstream regulator of Wnt signaling by two independent research groups, and several classes of small-molecule inhibitors targeting this protein kinase have been developed. TNIK is a multifunctional protein with actions that extend beyond Wnt signaling regulation. Such TNIK inhibitors are expected to have a large variety of clinical applications. PMID- 26439804 TI - Inhibition of glutamine metabolism counteracts pancreatic cancer stem cell features and sensitizes cells to radiotherapy. AB - Pancreatic ductal adenocarcinoma (PDAC) cells utilize a novel non-canonical pathway of glutamine metabolism that is essential for tumor growth and redox balance. Inhibition of this metabolic pathway in PDAC can potentially synergize with therapies that increase intracellular reactive oxygen species (ROS) such as radiation. Here, we evaluated the dependence of pancreatic cancer stem cells (PCSCs) on this non-canonical glutamine metabolism pathway and researched whether inhibiting this pathway can enhance radiosensitivity of PCSCs. We showed that glutamine deprivation significantly inhibited self-renewal, decreased expression of stemness-related genes, increased intracellular ROS, and induced apoptosis in PCSCs. These effects were countered by oxaloacetate, but not alpha-ketoglutarate. Knockdown of glutamic-oxaloacetic transaminase dramatically impaired PCSCs properties, while glutamate dehydrogenase knockdown had a limited effect, suggesting a dependence of PCSCs on non-canonical glutamine metabolism. Additionally, glutamine deprivation significantly increased radiation-induced ROS and sensitized PCSCs to fractionated radiation. Moreover, transaminase inhibitors effectively enhanced ROS generation, promoted radiation sensitivity, and attenuated tumor growth in nude mice following radiation exposure. Our findings reveal that inhibiting the non-canonical pathway of glutamine metabolism enhances the PCSC radiosensitivity and may be an effective adjunct in cancer radiotherapy. PMID- 26439806 TI - Peptide pi-Electron Conjugates: Organic Electronics for Biology? AB - Highly ordered arrays of pi-conjugated molecules are often viewed as a prerequisite for effective charge-transporting materials. Studies involving these materials have traditionally focused on organic electronic devices, with more recent emphasis on biological systems. In order to facilitate the transition to biological environments, biomolecules that can promote hierarchical ordering and water solubility are often covalently appended to the pi-electron unit. This review highlights recent work on pi-conjugated systems bound to peptide moieties that exhibit self-assembly and aims to provide an overview on the development and emerging applications of peptide-based supramolecular pi-electron systems. PMID- 26439807 TI - The development of lung biochemical monitoring can play a key role in the early prediction of bronchopulmonary dysplasia. AB - AIM: Despite advances in perinatal management, there is a flat trend in incidences of respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) in preterm infants. The main feature of BPD development in preterm infants is an imbalance between increased exposure to free radicals and inadequate antioxidant defences. We investigated the associations between BPD and lipid hydro-peroxide (LOOH) and glutathione (GSH) concentrations in bronchoalveolar lavage fluid (BALF). METHODS: In this prospective study, BALF samples were collected from 44 preterm infants with RDS and oxidative stress markers were measured in 11 with BPD and 33 controls without BPD. RESULTS: LOOH levels were significantly higher (p < 0.01) in the BPD group (median 16.35; 25th-75th centile 13.75-17.05 nmol/mL) than in the no BPD group (median 13.18; 25th-75th centile 12.92-13.63 nmol/mL). Conversely, GSH levels were significantly lower in the BPD group (p < 0.01) (median 11.52; 25th-75th centile 6.95-13.85 MUmol/mg) than the no BPD group (median: 18.69; 25th-75th centile: 13.89-23.64 MUmol/mg). Multiple regression analysis showed significant correlations between BPD and mechanical ventilation time (p < 0.01) and LOOH levels (p < 0.05). CONCLUSION: Early LOOH level increases in preterm infants developing BPD suggest that lung biochemical monitoring of sick infants might be possible and BPD could be predicted early by evaluating biomarkers. PMID- 26439808 TI - Photoactive Self-Shaping Hydrogels as Noncontact 3D Macro/Microscopic Photoprinting Platforms. AB - A photocleavable terpolymer hydrogel cross-linked with o-nitrobenzyl derivative cross-linker is shown to be capable of self-shaping without losing its physical integrity and robustness due to spontaneous asymmetric swelling of network caused by UV-light-induced gradient cleavage of chemical cross-linkages. The continuum model and finite element method are used to elucidate the curling mechanism underlying. Remarkably, based on the self-changing principle, the photosensitive hydrogels can be developed as photoprinting soft and wet platforms onto which specific 3D characters and images are faithfully duplicated in macro/microscale without contact by UV light irradiation under the cover of customized photomasks. Importantly, a quick response (QR) code is accurately printed on the photoactive hydrogel for the first time. Scanning QR code with a smartphone can quickly connect to a web page. This photoactive hydrogel is promising to be a new printing or recording material. PMID- 26439811 TI - Does Staphylococcus aureus have a role in the development of Type 2 diabetes mellitus? PMID- 26439810 TI - Studies on Bacterial Proteins Corona Interaction with Saponin Imprinted ZnO Nanohoneycombs and Their Toxic Responses. AB - Molecular imprinting generates robust, efficient, and highly mesoporous surfaces for biointeractions. Mechanistic interfacial interaction between the surface of core substrate and protein corona is crucial to understand the substantial microbial toxic responses at a nanoscale. In this study, we have focused on the mechanistic interactions between synthesized saponin imprinted zinc oxide nanohoneycombs (SIZnO NHs), average size 80-125 nm, surface area 20.27 m(2)/g, average pore density 0.23 pore/nm and number-average pore size 3.74 nm and proteins corona of bacteria. The produced SIZnO NHs as potential antifungal and antibacterial agents have been studied on Sclerotium rolfsii (S. rolfsii), Pythium debarynum (P. debarynum) and Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), respectively. SIZnO NHs exhibited the highest antibacterial (~50%) and antifungal (~40%) activity against Gram-negative bacteria (E. coli) and fungus (P. debarynum), respectively at concentration of 0.1 mol. Scanning electron spectroscopy (SEM) observation showed that the ZnO NHs ruptured the cell wall of bacteria and internalized into the cell. The molecular docking studies were carried out using binding proteins present in the gram negative bacteria (lipopolysaccharide and lipocalin Blc) and gram positive bacteria (Staphylococcal Protein A, SpA). It was envisaged that the proteins present in the bacterial cell wall were found to interact and adsorb on the surface of SIZnO NHs thereby blocking the active sites of the proteins used for cell wall synthesis. The binding affinity and interaction energies were higher in the case of binding proteins present in gram negative bacteria as compared to that of gram positive bacteria. In addition, a kinetic mathematical model (KMM) was developed in MATLAB to predict the internalization in the bacterial cellular uptake of the ZnO NHs for better understanding of their controlled toxicity. The results obtained from KMM exhibited a good agreement with the experimental data. Exploration of mechanistic interactions, as well as the formation of bioconjugate of proteins and ZnO NHs would play a key role to interpret more complex biological systems in nature. PMID- 26439809 TI - Induced pluripotent stem cells for cardiovascular disease: from product-focused disease modeling to process-focused disease discovery. AB - Induced pluripotent stem (iPS) cell technology offers an unprecedented opportunity to study patient-specific disease. This biotechnology platform enables recapitulation of individualized disease signatures in a dish through differentiation of patient-derived iPS cells. Beyond disease modeling, the in vitro process of differentiation toward genuine patient tissue offers a blueprint to inform disease etiology and molecular pathogenesis. Here, we highlight recent advances in patient-specific cardiac disease modeling and outline the future promise of iPS cell-based disease discovery applications. PMID- 26439812 TI - Comparison between Free and Immobilized Ion Effects on Hydrophobic Interactions: A Molecular Dynamics Study. AB - Fundamental studies of the effect of specific ions on hydrophobic interactions are driven by the need to understand phenomena such as hydrophobically driven self-assembly or protein folding. Using beta-peptide-inspired nanorods, we investigate the effects of both free ions (dissolved salts) and proximally immobilized ions on hydrophobic interactions. We find that the free ion effect is correlated with the water density fluctuation near a nonpolar molecular surface, showing that such fluctuation can be an indicator of hydrophobic interactions in the case of solution additives. In the case of immobilized ion, our results demonstrate that hydrophobic interactions can be switched on and off by choosing different spatial arrangements of proximal ions on a nanorod. For globally amphiphilic nanorods, we find that the magnitude of the interaction can be further tuned using proximal ions with varying ionic sizes. In general, univalent proximal anions are found to weaken hydrophobic interactions. This is in contrast to the effect of free ions, which according to our simulations strengthen hydrophobic interactions. In addition, immobilized anions of increasing ionic size do not follow the same ordering (Hofmeister-like ranking) as free ions when it comes to their impact on hydrophobic interactions. The immobilized ion effect is not simply correlated with the water density fluctuation near the nonpolar side of the amphiphilic nanorod. We propose a molecular picture that explains the contrasting effects of immobilized versus free ions. PMID- 26439813 TI - Crystal-Templated Colloidal Clusters Exhibit Directional DNA Interactions. AB - Spherical colloids covered with grafted DNA have been used in the directed self assembly of a number of distinct crystal and gel structures. Simulation suggests that the use of anisotropic building blocks greatly augments the variety of potential colloidal assemblies that can be formed. Here, we form five distinct symmetries of colloidal clusters from DNA-functionalized spheres using a single type of colloidal crystal as a template. The crystals are formed by simple sedimentation of a binary mixture containing a majority "host" species that forms close-packed crystals with the minority "impurity" species occupying substitutional or interstitial defect sites. After the DNA strands between the two species are hybridized and enzymatically ligated, the results are colloidal clusters, one for each impurity particle, with a symmetry determined by the nearest neighbors in the original crystal template. By adjusting the size ratio of the two spheres and the timing of the ligation, we are able to generate clusters having the symmetry of tetrahedra, octahedra, cuboctahedra, triangular orthobicupola, and icosahedra, which can be readily separated from defective clusters and leftover spheres by centrifugation. We further demonstrate that these clusters, which are uniformly covered in DNA strands, display directional binding with spheres bearing complementary DNA strands, acting in a manner similar to patchy particles or proteins having multiple binding sites. The scalable nature of the fabrication process, along with the reprogrammability and directional nature of their resulting DNA interactions, makes these clusters suitable building blocks for use in further rounds of directed self-assembly. PMID- 26439814 TI - Lewis Basic Sulfide Catalyzed Electrophilic Bromocyclization of Cyclopropylmethyl Amide. AB - A Lewis basic sulfide catalyzed electrophilic bromocyclization of cyclopropylmethyl amide has been developed. The catalytic protocol is applicable to both 1,1- and 1,2-substituted cyclopropylmethyl amides, giving oxazolines and oxazines in good yields and excellent diastereoselectivity. PMID- 26439815 TI - Factors influencing Chinese college students' preferences for mental health professionals. AB - BACKGROUND: Transition from high school to college can be particularly difficult and stressful for Chinese college students because of parent expectations. AIMS: The purpose of this study was to examine therapist variables influencing Chinese college students' preferences for mental health professionals using conjoint analysis. METHOD: Two hundred fifty-eight community college students in Hong Kong were asked to rate the profile of 55 mental health professionals representing a combination of therapist characteristics (i.e., gender, age, race/ethnicity, professional background, and training institutions) from the most to least preferred therapist from whom to seek psychological counselling. FINDINGS: Results indicated that students' preference formation was based largely on professional background and training institution of the mental health professionals. Clinical psychologists and clinical social workers were preferred over educational psychologists (school psychologists), counsellors, and psychiatrists. Mental health professionals who received training from more prestigious schools were preferred over those trained at less prestigious schools. CONCLUSIONS: Understanding clients' preference formation for choosing mental health professionals could be the first step to gain insights for developing effective educational and outreach strategies to promote help seeking behavior and mental health service utilization among Chinese college students. PMID- 26439816 TI - The effects of metformin treatment of gestational diabetes on maternal weight and glucose tolerance postpartum--a prospective follow-up study. AB - INTRODUCTION: Metformin seems to reduce gestational weight gain compared with insulin in women with gestational diabetes (GDM). Women with GDM requiring insulin are more likely to develop abnormal glucose tolerance postpartum than women treated with diet only. In this prospective follow-up study of a randomized clinical trial, we investigated the effect of metformin treatment in women with GDM on weight gain and glucose tolerance postpartum. MATERIALS AND METHODS: Women with GDM with two or more pathologic glucose values at 2-h 75-g oral glucose tolerance test (OGTT) were recruited. Those needing medication to achieve sufficient glycemic control were randomized at 22-34 weeks of gestation to either metformin (n = 110) or insulin (n = 107) treatment until delivery. A third GDM group (n = 128) requiring no medication had only diet treatment. Weight, OGTT and glycosylated hemoglobin (HbA1c) were determined at 6-8 weeks and 1 year postpartum. RESULTS: At least one postpartum visit was attended by 104, 101 and 120 women in the metformin, insulin and diet-only groups, respectively. No significant differences were found in the change of weight, HbA1c or OGTT glucose values between the groups during the study (p >= 0.121 in all comparisons). One year postpartum the diet-only group had less impaired glucose tolerance compared with the metformin and insulin groups (7.1%, 19.1% and 15.6%, respectively; overall p = 0.039) and a lower incidence of diabetes (p = 0.027). CONCLUSIONS: Short-term metformin therapy does not affect weight, HbA1c or OGTT glucose values postpartum compared with insulin or diet-only treatments. Women with GDM requiring no medication are least likely to develop impaired glucose tolerance or diabetes postpartum. PMID- 26439817 TI - Variability, toxicity, and antioxidant activity of Eupatorium cannabinum (hemp agrimony) essential oils. AB - CONTENT: Eupatorium cannabinum L. (Asteraceae) is as a potential source of biologically active compounds. The plant is used in traditional medicine for the treatment of diarrhea and livers diseases. OBJECTIVE: The present study provides investigation on pharmacological properties (antioxidant and toxic activities) of essential oils of E. cannabinum, collected from 11 wild populations in Lithuania. MATERIALS AND METHODS: Twenty-two hemp agrimony essential oil samples were prepared by hydrodistillation according to the European Pharmacopoeia, and their chemical composition was determined by GC-FID and GC-MS. Compositional data were subjected to principal components analysis (PCA). Instead of conventional spectrophotometric methods, cyclic voltammetry (CV) and square wave voltammetry (SWV) techniques were applied to determine antioxidant activity of hemp agrimony essential oils. Meanwhile, toxicity of the oils was determined using brine shrimp (Artemia sp.) assay. RESULTS: Chemical profiles of E. cannabinum oils were described according to the first predominant components: germacrene D (<=22.0%), neryl acetate (<=20.0%), spathulenol (<=27.2%), and alpha-terpinene (11.5%). For the first time, alpha-zingiberene (<=7.8%) was found to be among three major constituents (as the second one) for hemp agrimony oils. SWV measurements revealed that oxidation potentials of compounds present in the oils are lower (below 0.1 V) compared with that of well-known antioxidant quercetin (0.15 V). Toxicity tests evaluated that hemp agrimony oils containing predominant amounts of germacrene D and neryl acetate were notably toxic (LC50 value 16.3-22.0 MUg/mL). CONCLUSION: The study provided some new data concerning chemical composition and pharmaceutical properties of E. cannabinum essential oils. PMID- 26439820 TI - Married Women's Justification of Intimate Partner Violence in Bangladesh: Examining Community Norm and Individual-Level Risk Factors. AB - One-third of the women worldwide experience intimate partner violence (IPV) that increases their vulnerability to both short- and long-term physical, sexual, reproductive, and mental health problems. Surprisingly, IPV is justified by many women globally. Although the IPV literature to date is mostly focused on risk factors associated with actual occurrences, little is known on attitudinal acceptance of such violence. Also, despite the growing scholarship of community influence and health link, IPV research has relatively overlooked the effects of norms at the community level. Using a representative national sample of 13,611 married women in Bangladesh, this study examined the association of community attitudes and women's individual attitudes toward wife beating. The results revealed that women living in communities with permissive attitudes toward wife beating were more likely to justify husbands' beating (OR=4.5). Women married at a younger age, who had less than primary-level education, lived in households categorized as poor or middle class, and did not consume media appeared to be at higher risk for justifying wife beating. This research adds to a growing research body on community influences on health by examining IPV attitudes and community norms link. PMID- 26439818 TI - Catalytic Olefin Hydroamidation Enabled by Proton-Coupled Electron Transfer. AB - Here we report a ternary catalyst system for the intramolecular hydroamidation of unactivated olefins using simple N-aryl amide derivatives. Amide activation in these reactions occurs via concerted proton-coupled electron transfer (PCET) mediated by an excited state iridium complex and weak phosphate base to furnish a reactive amidyl radical that readily adds to pendant alkenes. A series of H-atom, electron, and proton transfer events with a thiophenol cocatalyst furnish the product and regenerate the active forms of the photocatalyst and base. Mechanistic studies indicate that the amide substrate can be selectively homolyzed via PCET in the presence of the thiophenol, despite a large difference in bond dissociation free energies between these functional groups. PMID- 26439821 TI - The Effect of Iron Deficiency on Osmotic Sensitivity of Red Blood Cells from Neonatal Rats and Their Mothers. AB - Iron deficiency during pregnancy has many effects on both the mother and her developing foetus. These can be both short and long term. One effect is an alteration in fatty acid metabolism and we hypothesised that these changes may result in alterations in membrane function and structure. In order to test this hypothesis, we measured osmotic sensitivity in red blood cells isolated from neonates and their mothers at different times following birth. We fed female rats control or iron-deficient diets for 4 weeks prior to mating and kept them on the same diet until term. At that time, we returned one group of deficient dams to the control diet. The others were kept on the same diet. We showed that iron deficiency results in a decrease in osmotic sensitivity in the mothers but not in their neonates. Returning the dams to the control diet resulted in a return of their red cell osmotic sensitivity to control levels. In the neonates, there was no recovery in haematocrit or in any other parameter, though they did not get any worse, in contrast to the pups being suckled by deficient mothers. The data show two things. The first is that following birth, the mother restores her own iron stores at the expense of the pups, and secondly, there are differences in properties and sensitivities between red cells from mothers and their neonates. This latter observation cannot be explained by differences in the membrane fatty acid profiles, which were not significantly different. PMID- 26439822 TI - An expected increase in the efficiency of antiproton cancer therapy with the use of gold nanoparticles. AB - The use of gold nanoparticles in antiproton cancer therapy is proposed. The energy transferred to gold by particles bombarding a tumor and arising in it is considered as one of the parameters determining the biological effect of gold in proton and antiproton cancer therapies. An example corresponding to the assumption about the importance of this parameter is analyzed. It is shown that the energy transferred to gold by products of annihilation of stopped antiprotons in soft biological tissues can exceed that transferred by antiprotons before their annihilation. PMID- 26439823 TI - On-site semi-automatic calibration and registration of a projector-camera system using arbitrary objects with known geometry. AB - In the Shader Lamps concept, a projector-camera system augments physical objects with projected virtual textures, provided that a precise intrinsic and extrinsic calibration of the system is available. Calibrating such systems has been an elaborate and lengthy task in the past and required a special calibration apparatus. Self-calibration methods in turn are able to estimate calibration parameters automatically with no effort. However they inherently lack global scale and are fairly sensitive to input data. We propose a new semi-automatic calibration approach for projector-camera systems that - unlike existing auto calibration approaches - additionally recovers the necessary global scale by projecting on an arbitrary object of known geometry. To this end our method combines surface registration with bundle adjustment optimization on points reconstructed from structured light projections to refine a solution that is computed from the decomposition of the fundamental matrix. In simulations on virtual data and experiments with real data we demonstrate that our approach estimates the global scale robustly and is furthermore able to improve incorrectly guessed intrinsic and extrinsic calibration parameters thus outperforming comparable metric rectification algorithms. PMID- 26439824 TI - Radiometric compensation for cooperative distributed multi-projection system through 2-DOF distributed control. AB - This paper proposes a novel radiometric compensation technique for cooperative projection system based-on distributed optimization. To achieve high scalability and robustness, we assume cooperative projection environments such that 1. each projector does not have information about other projectors as well as target images, 2. the camera does not have information about the projectors either, while having the target images, and 3. only a broadcast communication from the camera to the projectors is allowed to suppress the data transfer bandwidth. To this end, we first investigate a distributed optimization based feedback mechanism that is suitable for the required decentralized information processing environment. Next, we show that this mechanism works well for still image projection, however not necessary for moving images due to the lack of dynamic responsiveness. To overcome this issue, we propose to implement an additional feedforward mechanism. Such a 2 Degree Of Freedom (2-DOF) control structure is well-known in control engineering community as a typical method to enhance not only disturbance rejection but also reference tracking capability, simultaneously. We theoretically guarantee and experimentally demonstrate that this 2-DOF structure yields the moving image projection accuracy that is overwhelming the best achievable performance only by the distributed optimization mechanisms. PMID- 26439825 TI - Very high frame rate volumetric integration of depth images on mobile devices. AB - Volumetric methods provide efficient, flexible and simple ways of integrating multiple depth images into a full 3D model. They provide dense and photorealistic 3D reconstructions, and parallelised implementations on GPUs achieve real-time performance on modern graphics hardware. To run such methods on mobile devices, providing users with freedom of movement and instantaneous reconstruction feedback, remains challenging however. In this paper we present a range of modifications to existing volumetric integration methods based on voxel block hashing, considerably improving their performance and making them applicable to tablet computer applications. We present (i) optimisations for the basic data structure, and its allocation and integration; (ii) a highly optimised raycasting pipeline; and (iii) extensions to the camera tracker to incorporate IMU data. In total, our system thus achieves frame rates up 47 Hz on a Nvidia Shield Tablet and 910 Hz on a Nvidia GTX Titan XGPU, or even beyond 1.1 kHz without visualisation. PMID- 26439826 TI - MobileFusion: real-time volumetric surface reconstruction and dense tracking on mobile phones. AB - We present the first pipeline for real-time volumetric surface reconstruction and dense 6DoF camera tracking running purely on standard, off-the-shelf mobile phones. Using only the embedded RGB camera, our system allows users to scan objects of varying shape, size, and appearance in seconds, with real-time feedback during the capture process. Unlike existing state of the art methods, which produce only point-based 3D models on the phone, or require cloud-based processing, our hybrid GPU/CPU pipeline is unique in that it creates a connected 3D surface model directly on the device at 25Hz. In each frame, we perform dense 6DoF tracking, which continuously registers the RGB input to the incrementally built 3D model, minimizing a noise aware photoconsistency error metric. This is followed by efficient key-frame selection, and dense per-frame stereo matching. These depth maps are fused volumetrically using a method akin to KinectFusion, producing compelling surface models. For each frame, the implicit surface is extracted for live user feedback and pose estimation. We demonstrate scans of a variety of objects, and compare to a Kinect-based baseline, showing on average ~ 1.5cm error. We qualitatively compare to a state of the art point-based mobile phone method, demonstrating an order of magnitude faster scanning times, and fully connected surface models. PMID- 26439827 TI - ModulAR: eye-controlled vision augmentations for head mounted displays. AB - In the last few years, the advancement of head mounted display technology and optics has opened up many new possibilities for the field of Augmented Reality. However, many commercial and prototype systems often have a single display modality, fixed field of view, or inflexible form factor. In this paper, we introduce Modular Augmented Reality (ModulAR), a hardware and software framework designed to improve flexibility and hands-free control of video see-through augmented reality displays and augmentative functionality. To accomplish this goal, we introduce the use of integrated eye tracking for on-demand control of vision augmentations such as optical zoom or field of view expansion. Physical modification of the device's configuration can be accomplished on the fly using interchangeable camera-lens modules that provide different types of vision enhancements. We implement and test functionality for several primary configurations using telescopic and fisheye camera-lens systems, though many other customizations are possible. We also implement a number of eye-based interactions in order to engage and control the vision augmentations in real time, and explore different methods for merging streams of augmented vision into the user's normal field of view. In a series of experiments, we conduct an in depth analysis of visual acuity and head and eye movement during search and recognition tasks. Results show that methods with larger field of view that utilize binary on/off and gradual zoom mechanisms outperform snapshot and sub windowed methods and that type of eye engagement has little effect on performance. PMID- 26439828 TI - Semi-parametric color reproduction method for optical see-through head-mounted displays. AB - The fundamental issues in Augmented Reality (AR) are on how to naturally mediate the reality with virtual content as seen by users. In AR applications with Optical See-Through Head-Mounted Displays (OST-HMD), the issues often raise the problem of rendering color on the OST-HMD consistently to input colors. However, due to various display constraints and eye properties, it is still a challenging task to indistinguishably reproduce the colors on OST-HMDs. An approach to solve this problem is to pre-process the input color so that a user perceives the output color on the display to be the same as the input. We propose a color calibration method for OST-HMDs. We start from modeling the physical optics in the rendering and perception process between the HMD and the eye. We treat the color distortion as a semi-parametric model which separates the non-linear color distortion and the linear color shift. We demonstrate that calibrated images regain their original appearance on two OST-HMD setups with both synthetic and real datasets. Furthermore, we analyze the limitations of the proposed method and remaining problems of the color reproduction in OST-HMDs. We then discuss how to realize more practical color reproduction methods for future HMD-eye system. PMID- 26439829 TI - Changes in intraocular pressure during surgery in the lateral decubitus position under sevoflurane and propofol anesthesia. AB - Intraocular pressure (IOP) has been shown to change with body position. Several studies have shown that the lateral decubitus position (LDP) is associated with a significant increase in IOP in the dependent eye. However, whether anesthetic agents alter IOP in the LDP remains unclear. This study investigated the effect of sevoflurane and propofol anesthesia on IOP in the LDP. A total of 28 patients undergoing surgery in the LDP were included. Patients were randomly allocated to sevoflurane or propofol groups. IOP in both eyes was recorded and compared between groups at five time points: after anesthesia induction, after endotracheal intubation, at 5 min and 1 h after a positional change to the LDP, and 5 min after returning to the supine position. In the sevoflurane group, IOP was significantly increased in both dependent and non-dependent eyes 1 h after changing to the LDP. In the propofol group, IOP decreased in both dependent and non-dependent eyes after tracheal intubation, but did not increase after changing to the LDP. The number of patients in whom IOP increased to >=28 mmHg was greater in the sevoflurane group than in the propofol group. Propofol may be better than sevoflurane for the maintenance of anesthesia in the LDP. Monitoring of IOP in the LDP might help avoid ophthalmic complications. PMID- 26439830 TI - Multi-parameter vital sign database to assist in alarm optimization for general care units. AB - Continual vital sign assessment on the general care, medical-surgical floor is expected to provide early indication of patient deterioration and increase the effectiveness of rapid response teams. However, there is concern that continual, multi-parameter vital sign monitoring will produce alarm fatigue. The objective of this study was the development of a methodology to help care teams optimize alarm settings. An on-body wireless monitoring system was used to continually assess heart rate, respiratory rate, SpO2 and noninvasive blood pressure in the general ward of ten hospitals between April 1, 2014 and January 19, 2015. These data, 94,575 h for 3430 patients are contained in a large database, accessible with cloud computing tools. Simulation scenarios assessed the total alarm rate as a function of threshold and annunciation delay (s). The total alarm rate of ten alarms/patient/day predicted from the cloud-hosted database was the same as the total alarm rate for a 10 day evaluation (1550 h for 36 patients) in an independent hospital. Plots of vital sign distributions in the cloud-hosted database were similar to other large databases published by different authors. The cloud-hosted database can be used to run simulations for various alarm thresholds and annunciation delays to predict the total alarm burden experienced by nursing staff. This methodology might, in the future, be used to help reduce alarm fatigue without sacrificing the ability to continually monitor all vital signs. PMID- 26439831 TI - Sensor fusion methods for reducing false alarms in heart rate monitoring. AB - Automatic patient monitoring is an essential resource in hospitals for good health care management. While alarms caused by abnormal physiological conditions are important for the delivery of fast treatment, they can be also a source of unnecessary noise because of false alarms caused by electromagnetic interference or motion artifacts. One significant source of false alarms is related to heart rate, which is triggered when the heart rhythm of the patient is too fast or too slow. In this work, the fusion of different physiological sensors is explored in order to create a robust heart rate estimation. A set of algorithms using heart rate variability index, Bayesian inference, neural networks, fuzzy logic and majority voting is proposed to fuse the information from the electrocardiogram, arterial blood pressure and photoplethysmogram. Three kinds of information are extracted from each source, namely, heart rate variability, the heart rate difference between sensors and the spectral analysis of low and high noise of each sensor. This information is used as input to the algorithms. Twenty recordings selected from the MIMIC database were used to validate the system. The results showed that neural networks fusion had the best false alarm reduction of 92.5 %, while the Bayesian technique had a reduction of 84.3 %, fuzzy logic 80.6 %, majority voter 72.5 % and the heart rate variability index 67.5 %. Therefore, the proposed algorithms showed good performance and could be useful in bedside monitors. PMID- 26439819 TI - Protective Effect of Salvia Przewalskii Extract on Puromycin-Induced Podocyte Injury. AB - BACKGROUND: To determine the effect of Salvia przewalskii extract (SPE) from total phenolic acids on puromycin aminonucleoside (PAN)-induced rat podocyte injury. METHODS: The rats were divided into groups that were treated with either PAN only or PAN followed by tacrolimus or SPE. We evaluated the effects of SPE on podocyte injury 5, 10, 15 and 21 days following treatment. RESULTS: (1) Proteinuria was observed starting on day 5 in all groups. The peak levels of proteinuria differed among the groups with tacrolimus and high-dose SPE, which significantly decreased proteinuria relative to the PAN and low- and medium-dose SPE groups. The proteinuria in each group decreased by day 15 and returned to a normal level by day 21. (2) H&E and PAS staining revealed no abnormality in glomerular morphology. With electron microscopy, we observed foot process effacement in the rats of all groups starting on day 5, but rats in the tacrolimus and high-dose SPE groups exhibited a lower degree. (3) IHC staining of nephrin and podocin revealed unaffected expression and better linear distributions in the high-dose SPE and tacrolimus groups. Western blot analysis confirmed that SPE could improve the expression of proteins. (4) The mRNA levels of nephrin and podocin in the tacrolimus and high-dose SPE groups were significantly higher than that in the others. CONCLUSION: In our study, we first demonstrated the ability of SPE to reduce proteinuria, preserve the morphology and structure of podocytes and retain the levels of slit diaphragm proteins on PAN-induced rat podocytes injury. PMID- 26439833 TI - Increase in the photoreactivity of uracil derivatives by doubling thionation. AB - The ability of 4-thiouracil to strongly absorb UVA radiation and to populate a reactive triplet state in high yield has enabled its use as a versatile photocrosslinker for nearly 50 years. In this contribution, we present a detailed spectroscopic and photochemical investigation of the 2-thiouracil, 4-thiouracil, and 2,4-dithiouracil series in an effort to further advance this chemistry and to scrutinize the photoreactivity of 2,4-dithiouracil. Our results reveal that excitation of 2,4-dithiouracil leads to intersystem crossing to the triplet manifold in 220 +/- 40 fs, which enables the population of the reactive triplet state with near unity yield (PhiT = 0.90 +/- 0.15) and ultimately leads to a ca. 50% singlet oxygen generation (PhiDelta = 0.49 +/- 0.02)-one of the highest singlet oxygen yields reported to date for a photoexcited thiobase. In addition, the long-lived triplet state of 2,4-dithiouracil reacts efficiently with the nucleic acid base adenine 5'-monophosphate through a direct, oxygen-independent photocycloaddition mechanism and at a rate that is at least 3-fold faster than that of 4-thiouracil under equal conditions. The new physico-chemical insights reported for these RNA-thiobase derivatives are compared to those of the DNA and RNA bases and the DNA-thiobase derivatives. Furthermore, the strong near-visible absorption and increased photoreactivity measured for 2,4-dithiouracil lays a solid foundation for developing RNA-targeted photocrosslinking and phototherapeutic agents that are more effective than those currently available. PMID- 26439834 TI - Association between the functional MHC2TA -168 A/G polymorphism and susceptibility to rheumatoid arthritis: a meta-analysis. AB - The aim of this study was to determine whether the functional major histocompatibility complex II transactivator (MHC2TA) -168 A/G polymorphism is associated with susceptibility to rheumatoid arthritis (RA). A meta-analysis was conducted to estimate the association between the MHC2TA-168 A/G polymorphism and RA. A total of 15 comparative studies, which included 14,158 patients and 13,642 controls, were included in the meta-analysis. Based on the meta-analysis, there was no association between RA and the MHC2TA -168 G allele in the study subjects (OR = 1.046, 95 % CI = 0.987-1.108, p = 0.130) or Caucasians (OR = 1.027, 95 % CI = 0.986-1.070, p = 0.193). However, the country-specific meta-analysis revealed an association between the MHC2TA -168 G allele and RA in the Swedish population (OR = 1.131, 95 % CI = 1.023-1.250, p = 0.016). A direct comparison between rheumatoid factor (RF)-positive and RF-negative patients revealed that the frequency of the G allele was significantly lower in RF-positive patients (OR = 0.783, 95 % CI = 0.628-0.975, p = 0.029) than in RF-negative patients. This meta analysis demonstrated that the MHC2TA -168 A/G polymorphism is not associated with susceptibility to RA in Caucasians. PMID- 26439835 TI - Dynamics of murine B lymphocytes is modulated by in vivo treatment with steroid ouabain. AB - Ouabain (OUA) is a steroid hormone capable of inhibiting the protein Na+K+ATPase present in the plasma membrane of cells. Ouabain was initially extracted from the roots of African trees such as Acocanthera ouabaio and Strophantus gratus seeds and later described as an endogenous component found in higher mammals. The adrenal gland is the main site of synthesis of ouabain and it is released in stressful situations, conditions similar to those where there is secretion of corticosteroids. Immunological functions have been shown to be regulated by ouabain. In order to understand the effects of ouabain on B lymphocyte populations in different lymphoid organs, mice received intraperitoneal injections of ouabain for 3 consecutive days. Twenty-four hours after the last injection, cells were analyzed by flow cytometry. In the spleen, ouabain modulated especially follicular B cells, inducing a significant decrease in the percentage and absolute numbers of those cells. Ouabain also reduced the absolute number of marginal zone B lymphocytes. No difference in the percentage or absolute number of B lymphocytes in the spleen forty-eight hours after the last injection was observed. An increase in the number of B cells was seen in mesenteric lymph nodes and this retention appears to be directly related to increased expression of CXCR5 chemokine receptor and reduction of CD62L, which also explains the observed reduction of B cells in the spleen. Our results indicate that ouabain regulates the dynamics of B lymphocytes in peripheral organs but production of total IgM and IgG in the serum of animals treated in vivo with ouabain was not affected. PMID- 26439832 TI - Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies. AB - Pathological tau aggregation leads to filamentous tau inclusions and characterizes neurodegenerative tauopathies such as Alzheimer's disease and frontotemporal dementia and parkinsonism linked to chromosome 17. Tau aggregation coincides with clinical symptoms and is thought to mediate neurodegeneration. Transgenic mice overexpressing mutant human P301S tau exhibit many neuropathological features of human tauopathies including behavioral deficits and increased mortality. Here, we show that the di-phenyl-pyrazole anle138b binds to aggregated tau and inhibits tau aggregation in vitro and in vivo. Furthermore, anle138b treatment effectively ameliorates disease symptoms, increases survival time and improves cognition of tau transgenic PS19 mice. In addition, we found decreased synapse and neuron loss accompanied by a decreased gliosis in the hippocampus. Our results suggest that reducing tau aggregates with anle138b may represent an effective and promising approach for the treatment of human tauopathies. PMID- 26439836 TI - Accurate and Efficient Resolution of Overlapping Isotopic Envelopes in Protein Tandem Mass Spectra. AB - It has long been an analytical challenge to accurately and efficiently resolve extremely dense overlapping isotopic envelopes (OIEs) in protein tandem mass spectra to confidently identify proteins. Here, we report a computationally efficient method, called OIE_CARE, to resolve OIEs by calculating the relative deviation between the ideal and observed experimental abundance. In the OIE_CARE method, the ideal experimental abundance of a particular overlapping isotopic peak (OIP) is first calculated for all the OIEs sharing this OIP. The relative deviation (RD) of the overall observed experimental abundance of this OIP relative to the summed ideal value is then calculated. The final individual abundance of the OIP for each OIE is the individual ideal experimental abundance multiplied by 1 + RD. Initial studies were performed using higher-energy collisional dissociation tandem mass spectra on myoglobin (with direct infusion) and the intact E. coli proteome (with liquid chromatographic separation). Comprehensive data at the protein and proteome levels, high confidence and good reproducibility were achieved. The resolving method reported here can, in principle, be extended to resolve any envelope-type overlapping data for which the corresponding theoretical reference values are available. PMID- 26439837 TI - Generation of Bioactive Oxylipins from Exogenously Added Arachidonic, Eicosapentaenoic and Docosahexaenoic Acid in Primary Human Brain Microvessel Endothelial Cells. AB - The human blood-brain barrier (BBB) is the restrictive barrier between the brain parenchyma and the circulating blood and is formed in part by microvessel endothelial cells. The brain contains significant amounts of arachidonic acid (ARA), and docosahexaenoic acid (DHA), which potentially give rise to the generation of bioactive oxylipins. Oxylipins are oxygenated fatty acid metabolites that are involved in an assortment of biological functions regulating neurological health and disease. Since it is not known which oxylipins are generated by human brain microvessel endothelial cells (HBMECs), they were incubated for up to 30 min in the absence or presence of 0.1-mM ARA, eicosapentaenoic acid (EPA) or DHA bound to albumin (1:1 molar ratio), and the oxylipins generated were examined using high performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS). Of 135 oxylipins screened in the media, 63 were present at >0.1 ng/mL at baseline, and 95 were present after incubation with fatty acid. Oxylipins were rapidly generated and reached maximum levels by 2-5 min. While ARA, EPA and DHA each stimulated the production of oxylipins derived from these fatty acids themselves, ARA also stimulated the production of oxylipins from endogenous 18- and 20-carbon fatty acids, including alpha linolenic acid. Oxylipins generated by the lipoxygenase pathway predominated both in resting and stimulated states. Oxylipins formed via the cytochrome P450 pathway were formed primarily from DHA and EPA, but not ARA. These data indicate that HBMECs are capable of generating a plethora of bioactive lipids that have the potential to modulate BBB endothelial cell function. PMID- 26439839 TI - Nanowire CdS-CdTe Solar Cells with Molybdenum Oxide as Contact. AB - Using a 10 nm thick molybdenum oxide (MoO3-x) layer as a transparent and low barrier contact to p-CdTe, we demonstrate nanowire CdS-CdTe solar cells with a power conversion efficiency of 11% under front side illumination. Annealing the as-deposited MoO3 film in N2 resulted in a reduction of the cell's series resistance, from 9.97 Omega/cm(2) to 7.69 Omega/cm(2), and increase in efficiency from 9.9% to 11%. Under illumination from the back, the MoO3-x/Au side, the nanowire solar cells yielded Jsc of 21 mA/cm(2) and efficiency of 8.67%. Our results demonstrate use of a thin layer transition metal oxide as a potential way for a transparent back contact to nanowire CdS-CdTe solar cells. This work has implications toward enabling a novel superstrate structure nanowire CdS-CdTe solar cell on Al foil substrate by a low cost roll-to roll fabrication process. PMID- 26439838 TI - Dietary Linseed Oil Reduces Growth While Differentially Impacting LC-PUFA Synthesis and Accretion into Tissues in Eurasian Perch (Perca fluviatilis). AB - The aim of this study was to evaluate the impact of replacing dietary fish oil (FO) with linseed oil (LO) on growth, fatty acid composition and regulation of lipid metabolism in Eurasian perch (Perca fluviatilis) juveniles. Fish (17.5 g initial body weight) were fed isoproteic and isoenergetic diets containing 116 g/kg of lipid for 10 weeks. Fish fed the LO diet displayed lower growth rates and lower levels of DHA in the liver and muscle than fish fed the FO diet, while mortality was not affected by dietary treatment. However, DHA content recorded in the liver and muscle of fish fed the LO diet remained relatively high, despite a weight gain of 134 % and a reduced dietary level of long-chain polyunsaturated fatty acids (LC-PUFA), suggesting endogenous LC-PUFA biosynthesis. This was supported by the higher amounts of pathway intermediates, including 18:4n-3, 20:3n-3, 20:4n-3, 18:3n-6 and 20:3n-6, recorded in the liver of fish fed the LO diet in comparison with those fed the FO diet. However, fads2 and elovl5 gene expression and FADS2 enzyme activity were comparable between the two groups. Similarly, the expression of genes involved in eicosanoid synthesis was not modulated by dietary LO. Thus, the present study demonstrated that in fish fed LO for 10 weeks, growth was reduced but DHA levels in tissues were largely maintained compared to fish fed FO, suggesting a physiologically relevant rate of endogenous LC-PUFA biosynthesis capacity. PMID- 26439840 TI - Assessment of pouch and stoma size in weight loss failure after Roux-en-Y gastric bypass. PMID- 26439841 TI - EP4 Receptor-Associated Protein in Macrophages Ameliorates Colitis and Colitis Associated Tumorigenesis. AB - Prostaglandin E2 plays important roles in the maintenance of colonic homeostasis. The recently identified prostaglandin E receptor (EP) 4-associated protein (EPRAP) is essential for an anti-inflammatory function of EP4 signaling in macrophages in vitro. To investigate the in vivo roles of EPRAP, we examined the effects of EPRAP on colitis and colitis-associated tumorigenesis. In mice, EPRAP deficiency exacerbated colitis induced by dextran sodium sulfate (DSS) treatment. Wild-type (WT) or EPRAP-deficient recipients transplanted with EPRAP-deficient bone marrow developed more severe DSS-induced colitis than WT or EPRAP-deficient recipients of WT bone marrow. In the context of colitis-associated tumorigenesis, both systemic EPRAP null mutation and EPRAP-deficiency in the bone marrow enhanced intestinal polyp formation induced by azoxymethane (AOM)/DSS treatment. Administration of an EP4-selective agonist, ONO-AE1-329, ameliorated DSS-induced colitis in WT, but not in EPRAP-deficient mice. EPRAP deficiency increased the levels of the phosphorylated forms of p105, MEK, and ERK, resulting in activation of stromal macrophages in DSS-induced colitis. Macrophages of DSS-treated EPRAP deficient mice exhibited a marked increase in the expression of pro-inflammatory genes, relative to WT mice. By contrast, forced expression of EPRAP in macrophages ameliorated DSS-induced colitis and AOM/DSS-induced intestinal polyp formation. These data suggest that EPRAP in macrophages functions crucially in suppressing colonic inflammation. Consistently, EPRAP-positive macrophages were also accumulated in the colonic stroma of ulcerative colitis patients. Thus, EPRAP may be a potential therapeutic target for inflammatory bowel disease and associated intestinal tumorigenesis. PMID- 26439844 TI - The association between chronological age, age at injury and employment: Is there a mediating effect of secondary health conditions? AB - STUDY DESIGN: Cross-sectional observational study with data from the 2012 community-based survey of the Swiss Spinal Cord Injury Cohort Study. OBJECTIVES: To examine the relationships between chronological age, age at injury, secondary health conditions (SHCs) and paid employment. SETTING: Community setting in Switzerland. METHODS: A total of 1159 individuals of working age (16-63 years for women and 64 years for men) with traumatic or non-traumatic spinal cord injury (SCI) were included in the study. Direct and indirect (via SHCs) effects of chronological age and age at injury on paid employment were tested using a decomposition method for logistic regression models. RESULTS: Both chronological age groups (age 35-49 and 50-63/64 years) and the group with age at injury beyond 40 years showed negative direct effects on employment status. A partial indirect effect (mediation) via chronic pain was found in the group with the highest chronological age (>50 years). Furthermore, pressure ulcer, pain and urinary tract infection were negatively related with employment in both models, that is, chronological age and employment and age at injury and employment. CONCLUSION: Being older and having a higher age at injury directly affects whether an individual is employed. Pain is mediating the relation between chronological age and employment. Furthermore, pressure ulcer, chronic pain and urinary tract infection directly reduce the likelihood to be employed and, therefore, represent important intervention targets in efforts to maintain or engage in employment of individuals with SCI. PMID- 26439842 TI - Functional Advantages of Conserved Intrinsic Disorder in RNA-Binding Proteins. AB - Proteins form large macromolecular assemblies with RNA that govern essential molecular processes. RNA-binding proteins have often been associated with conformational flexibility, yet the extent and functional implications of their intrinsic disorder have never been fully assessed. Here, through large-scale analysis of comprehensive protein sequence and structure datasets we demonstrate the prevalence of intrinsic structural disorder in RNA-binding proteins and domains. We addressed their functionality through a quantitative description of the evolutionary conservation of disordered segments involved in binding, and investigated the structural implications of flexibility in terms of conformational stability and interface formation. We conclude that the functional role of intrinsically disordered protein segments in RNA-binding is two-fold: first, these regions establish extended, conserved electrostatic interfaces with RNAs via induced fit. Second, conformational flexibility enables them to target different RNA partners, providing multi-functionality, while also ensuring specificity. These findings emphasize the functional importance of intrinsically disordered regions in RNA-binding proteins. PMID- 26439846 TI - Crystallization-driven one-dimensional self-assembly of polyethylene-b-poly(tert butylacrylate) diblock copolymers in DMF: effects of crystallization temperature and the corona-forming block. AB - Crystallization-driven self-assembly of polyethylene-b-poly(tert-butylacrylate) (PE-b-PtBA) block copolymers (BCPs) in N,N-dimethyl formamide (DMF) was studied. It is found that all three PE-b-PtBA BCPs used in this work can self-assemble into one-dimensional crystalline cylindrical micelles. When the BCP solution is cooled to crystallization temperature (Tc) from 130 degrees C, the seed micelles may be produced via two competitive processes in the initial period: stepwise micellization/crystallization and simultaneous crystallization/micellization. Subsequently, the seed micelles can undergo growth driven by the epitaxial crystallization of the unimers. The lengths of both the seed micelles and the grown micelles are longer for the BCP with a longer PtBA block at a higher Tc. Quasi-living growth of the PE-b-PtBA crystalline cylindrical micelles is achieved at a higher Tc. A longer PtBA block evidently retards the attachment of unimers to the crystalline micelles, leading to a slower growth rate. PMID- 26439849 TI - Correction: Comparative Incidence of Conformational, Neurodegenerative Disorders. PMID- 26439847 TI - Prehypertension Tsunami: A Decade Follow-Up of an Iranian Adult Population. AB - OBJECTIVE: Prehypertension is associated with cardiovascular disease (CVD). There is no study to examine the incidence and risk factors of prehypertension in a sex stratified setting. The aim of this study was to examine the effect modification of sex for different risk factors which predicts the progression from normotension to prehypertension in a Middle East population-based cohort, during a median follow-up of 9.2 years. METHODS: A multivariate Cox analysis was performed among 1466 and 2131 Iranian men and women, respectively, who were free of prehypertension, hypertension, CVD and diabetes at baseline and free of incident hypertension without preceding prehypertension at follow-up. Incident prehypertension at follow-up was defined as systolic blood pressure (SBP) of 120 139 mmHg and/or diastolic blood pressure (DBP) of 80-89 mmHg. RESULTS: Overall, 1440 new cases of prehypertension were identified resulting in an incidence rate of 593/10000 person-years; the corresponding values for women and men were 489/10000 and 764/10000person-years, respectively. There were significant interactions between gender with age, DBP, waist-to-hip-ratio (WHpR) and estimated glomerular filtration rate (eGFR) (all P-values <0.05) in multivariate analysis. Strong associations were found between age, body mass index (BMI) and SBP with incident prehypertension in both genders. However, the effect of DBP and WHpR was significant among women and 2-hour post challenge plasma glucose (2h PCPG)was an independent risk factor for men. In the sex-adjusted analysis, glomerular hyperfiltration [Hazard ratio (HR) and 95%CI: 1.01 (1.00-1.01), P value = 0.02], age, BMI, WHpR, SBP and DBP had higher risks while being female [HR (95%CI): 0.81(0.69-0.94), P-value = 0.01] had a lower risk for incident prehypertension. CONCLUSION: According to this study results, among Iranian population with high incidence of prehypertension, general adiposity and glomerular hyperfiltration in total, 2h-PCPG in men and central adiposity in women should be emphasized as risk factors for prehypertension. PMID- 26439850 TI - Extremely Low-Frequency Electromagnetic Fields Affect the miRNA-Mediated Regulation of Signaling Pathways in the GC-2 Cell Line. AB - Extremely low-frequency electromagnetic fields (ELF-EMFs) can affect male reproductive function, but the underlying mechanism of this effect remains unknown. miRNA-mediated regulation has been implicated as an important epigenetic mechanism for regulatory pathways. Herein, we profiled miRNA expression in response to ELF-EMFs in vitro. Mouse spermatocyte-derived GC-2 cells were intermittently exposed to a 50 Hz ELF-EMF for 72 h (5 min on/10 min off) at magnetic field intensities of 1 mT, 2 mT and 3 mT. Cell viability was assessed using the CCK-8 assay. Apoptosis and the cell cycle were analyzed with flow cytometry. miRNA expression was profiled using Affymetrix Mouse Genechip miRNA 3.0 arrays. Our data showed that the growth, apoptosis or cell cycle arrest of GC 2 cells exposed to the 50 Hz ELF-EMF did not significantly change. However, we identified a total of 55 miRNAs whose expression significantly changed compared with the sham group, including 19 differentially expressed miRNAs (7 miRNAs were upregulated, and 12 were downregulated) in the 1 mT exposure group and 36 (9 miRNAs were upregulated, and 27 were downregulated) in the 3 mT exposure group. The changes in the expression of 15 selected miRNAs measured by real-time PCR were consistent with the microarray results. A network analysis was used to predict core miRNAs and target genes, including miR-30e-5p, miR-210-5p, miR-196b 5p, miR-504-3p, miR-669c-5p and miR-455-3p. We found that these miRNAs were differentially expressed in response to different magnetic field intensities of ELF-EMFs. GO term and KEGG pathway annotation based on the miRNA expression profiling results showed that miRNAs may regulate circadian rhythms, cytokine cytokine receptor interactions and the p53 signaling pathway. These results suggested that miRNAs could serve as potential biomarkers, and the miRNA-mediated regulation of signaling pathways might play significant roles in the biological effects of ELF-EMFs. PMID- 26439843 TI - Construction of recombinant adenovirus containing picorna-viral 2A-peptide sequence for the co-expression of neuro-protective growth factors in human umbilical cord blood cells. AB - STUDY DESIGN: Experimental study. OBJECTIVE: Several neuro-degenerative disorders such as Alzheimer's dementia, Parkinson's disease and amyotrophic lateral sclerosis (ALS) are associated with genetic mutations, and replacing or disrupting defective sequences might offer therapeutic benefits. Single gene delivery has so far failed to achieve significant clinical improvements in humans, leading to the advent of co-expression of multiple therapeutic genes. Co transfection using two or more individual constructs might inadvertently result in disproportionate delivery of the products into the cells. To prevent this, and in order to rule out interference among the many promoters with varying strength, expressing multiple proteins in equimolar amounts can be achieved by linking open reading frames under the control of only one promoter. SETTING: Kazan, Russian Federation. METHODS: Here we describe a strategy for adeno-viral co-expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) interconnected through picorna-viral 2A-amino-acid sequence in transfected human umbilical cord blood mono-nuclear cells (hUCB-MCs). RESULTS: Presence of both growth factors, as well as absence of immune response to 2A-antigen, was demonstrated after 28-52 days. Following injection of hUCB-MCs into ALS transgenic mice, co-expression of VEGF and FGF2, as well as viable xeno transplanted cells, were observed in the spinal cord after 1 month. CONCLUSION: These results suggest that recombinant adeno-virus containing 2A-sequences could serve as a promising alternative in regenerative medicine for the delivery of therapeutic molecules to treat neurodegenerative diseases, such as ALS. PMID- 26439845 TI - Two-photon fluorescence lifetime imaging of primed SNARE complexes in presynaptic terminals and beta cells. AB - It remains unclear how readiness for Ca(2+)-dependent exocytosis depends on varying degrees of SNARE complex assembly. Here we directly investigate the SNARE assembly using two-photon fluorescence lifetime imaging (FLIM) of Forster resonance energy transfer (FRET) between three pairs of neuronal SNAREs in presynaptic boutons and pancreatic beta cells in the islets of Langerhans. These FRET probes functionally rescue their endogenous counterparts, supporting ultrafast exocytosis. We show that trans-SNARE complexes accumulated in the active zone, and estimate the number of complexes associated with each docked vesicle. In contrast, SNAREs were unassembled in resting state, and assembled only shortly prior to insulin exocytosis, which proceeds slowly. We thus demonstrate that distinct states of fusion readiness are associated with SNARE complex formation. Our FRET/FLIM approaches enable optical imaging of fusion readiness in both live and chemically fixed tissues. PMID- 26439848 TI - Studies on Immunogenicity and Antigenicity of Baculovirus-Expressed Binding Region of Plasmodium falciparum EBA-140 Merozoite Ligand. AB - The erythrocyte binding ligand 140 (EBA-140) is a member of the Plasmodium falciparum erythrocyte binding antigens (EBA) family, which are considered as prospective candidates for malaria vaccine development. EBA proteins were identified as important targets for naturally acquired inhibitory antibodies. Natural antibody response against EBA-140 ligand was found in individuals living in malaria-endemic areas. The EBA-140 ligand is a paralogue of the well characterized P. falciparum EBA-175 protein. They both share homology of domain structure, including the binding region (Region II), which consists of two homologous F1 and F2 domains and is responsible for ligand-erythrocyte receptor interaction during merozoite invasion. It was shown that the erythrocyte receptor for EBA-140 ligand is glycophorin C-a minor human erythrocyte sialoglycoprotein. In studies on the immunogenicity of P. falciparum EBA ligands, the recombinant proteins are of great importance. In this report, we have demonstrated that the recombinant baculovirus-obtained EBA-140 Region II is immunogenic and antigenic. It can raise specific antibodies in rabbits, and it is recognized by natural antibodies present in sera of patients with malaria, and thus, it may be considered for inclusion in multicomponent blood-stage vaccines. PMID- 26439851 TI - Variable-Selection Emerges on Top in Empirical Comparison of Whole-Genome Complex Trait Prediction Methods. AB - Accurate prediction of complex traits based on whole-genome data is a computational problem of paramount importance, particularly to plant and animal breeders. However, the number of genetic markers is typically orders of magnitude larger than the number of samples (p >> n), amongst other challenges. We assessed the effectiveness of a diverse set of state-of-the-art methods on publicly accessible real data. The most surprising finding was that approaches with feature selection performed better than others on average, in contrast to the expectation in the community that variable selection is mostly ineffective, i.e. that it does not improve accuracy of prediction, in spite of p >> n. We observed superior performance despite a somewhat simplistic approach to variable selection, possibly suggesting an inherent robustness. This bodes well in general since the variable selection methods usually improve interpretability without loss of prediction power. Apart from identifying a set of benchmark data sets (including one simulated data), we also discuss the performance analysis for each data set in terms of the input characteristics. PMID- 26439853 TI - Monolayer-by-monolayer stacked pyramid-like MoS2 nanodots on monolayered MoS2 flakes with enhanced photoluminescence. AB - The precise control of the morphology and crystal shape of MoS2 nanostructures is of particular importance for their application in nanoelectronic and optoelectronic devices. Here, we describe a single step route for the synthesis of monolayer-by-monolayer stacked pyramid-like MoS2 nanodots on monolayered MoS2 flakes using a chemical vapor deposition method. First-principles calculations demonstrated that the bandgap of the pyramid-like MoS2 nanodot is a direct bandgap. Enhanced local photoluminescence emission was observed in the pyramid like MoS2 nanodot, in comparison with monolayered MoS2 flakes. The findings presented here provide new opportunities to tailor the physical properties of MoS2via morphology-controlled synthesis. PMID- 26439855 TI - Pneumatically-actuated artificial cilia array for biomimetic fluid propulsion. AB - Arrays of beating cilia emerged in nature as one of the most efficient propulsion mechanisms at a small scale, and are omnipresent in microorganisms. Previous attempts at mimicking these systems have foundered against the complexity of fabricating small-scale cilia exhibiting complex beating motions. In this paper, we propose for the first time arrays of pneumatically-actuated artificial cilia that are able to address some of these issues. These artificial cilia arrays consist of six highly flexible silicone rubber actuators with a diameter of 1 mm and a length of 8 mm that can be actuated independently from each other. In an experimental setup, the effects of the driving frequency, phase difference and duty cycle on the net flow in a closed-loop channel have been studied. Net fluid speeds of up to 19 mm s(-1) have been measured. Further, it is possible to invert the flow direction by simply changing the driving frequency or by changing the duty cycle of the driving block pulse pressure wave without changing the bending direction of the cilia. Using PIV measurements, we corroborate for the first time existing mathematical models of cilia arrays to measurements on prototypes. PMID- 26439852 TI - Anti-CD20 Immunoglobulin G Radiolabeling with a 99mTc-Tricarbonyl Core: In Vitro and In Vivo Evaluations. AB - In recent years, the diagnostic and therapeutic uses of radioisotopes have shown significant progress. Immunoglobulin (Ig) appears to be a promising tracer, particularly due to its ability to target selected antigens. The main objective of this study is to optimize and assess an Ig radiolabeling method with Technetium 99m (99mTc), an attractive radioelement used widely for diagnostic imaging. Monoclonal anti-CD20 IgG was retained to study in vitro and in vivo radiolabeling impact. After IgG derivatization with 2-iminothiolane, IgG-SH was radiolabeled by an indirect method, using a 99mTc-tricarbonyl core. Radiolabeling stability was evaluated over 24h by thin-layer chromatography. IgG integrity was checked by sodium dodecyl sulfate-polyacrylamide gel electrophoresis coupled with Western blot and autoradiography. The radiolabeled Ig's immunoaffinity was assessed in vitro by a radioimmunoassay method and binding experiments with cells (EL4-hCD20 and EL4-WT). Biodistribution studies were performed in normal BALB/c mice. Tumor uptake was assessed in mice bearing EL4-hCD20 and EL4-WT subcutaneous xenografts. With optimized method, high radiolabeling yields were obtained (95.9 +/- 3.5%). 99mTc-IgG-SH was stable in phosphate-buffered saline (4 degrees C and 25 degrees C) and in serum (37 degrees C), even if important sensitivity to transchelation was observed. IgG was not degraded by derivatization and radiolabeling, as shown by Western blot and autoradiography results. 99mTc-anti CD20 IgG-SH immunoaffinity was estimated with Kd = 35 nM by both methods. In vivo biodistribution studies for 48h showed significant accumulation of radioactivity in plasma, liver, spleen, lungs and kidneys. Planar scintigraphy of mice bearing tumors showed a significant uptake of 99mTc-anti-CD20 IgG-SH in CD20+ tumor versus CD20- tumor. Radiolabeling of derivatized IgG with 99mTc-tricarbonyl was effective, stable and required few antibody amounts. This attractive radiolabeling method is "antibody safe" and preserves Ig affinity for antigen, as shown by both in vitro and in vivo experiments. This method could easily be used with noncommercial IgG or other antibody isotypes. PMID- 26439854 TI - Maternal Telomere Length and Risk of Down Syndrome: Epidemiological Impact of Smokeless Chewing Tobacco and Oral Contraceptive on Segregation of Chromosome 21. AB - BACKGROUND: We have previously demonstrated a relationship between children born with Down syndrome and maternal telomere length. Similarly, exposure to tobacco and oral contraceptives has been explored in one of our earlier studies as a risk factor for Down syndrome. OBJECTIVE: In the present study, we consider the interactions among these risk factors associated with Down syndrome in a population from Kolkata, India, using analyses stratified by maternal age. METHODS: We estimated the telomere length of women with children with Down syndrome by restriction enzyme/Southern blot methods. Linear regression was employed to estimate telomere shortening as an indicator of the maternal age of conception. Interactions among the various factors were analyzed by logistic regression. RESULT: We found an association between the use of smokeless chewing tobacco and shorter telomere length among women who experienced meiosis I nondisjunction at gametogenesis; the effect is seen across all maternal age groups. In contrast, oral contraceptive use alone did not exhibit a statistically significant association with maternal telomere length, but there was an interaction with the use of smokeless chewing tobacco in the older mothers who experienced meiotic II nondisjunction. CONCLUSION: Environmental/habitual factors interact with molecular components of the oocyte, which ultimately increases the risk of chromosome 21 nondisjunction and subsequently of giving birth to a child with Down syndrome. PMID- 26439856 TI - Barriers to early prenatal care in South Africa. AB - OBJECTIVE: To understand the barriers delaying early prenatal care for women in South Africa. METHODS: A mixed-methods study was conducted at a center in Pretoria. RESULTS: Following interviews with 21 women at a prenatal clinic in Pretoria, a quantitative survey was completed by 204 postpartum women. During interviews, women described presenting late owing to contemplating induced abortion, fear of HIV testing, and fear of jealousy and bewitching. The survey results demonstrated that a majority of women (133 [65.2%]) reported knowledge of recommendations to present before 12weeks; however, the average gestational age at initial presentation was 19.1+/-7.7weeks. Women were more likely to present earlier if the pregnancy was planned (P=0.013) and were less likely to if they had at any point contemplated induced abortion (P=0.021). Fears of bewitching and harmful psychological stress owing to a positive HIV test result prevailed in both the interviews and the surveys. CONCLUSION: Significant efforts should be devoted to improving access to contraception and prepregnancy counseling in order to improve early prenatal care attendance. Similarly, addressing cultural concerns and fears regarding pregnancy is imperative in promoting early attendance. PMID- 26439857 TI - Glucosensing in liver and Brockmann bodies of rainbow trout through glucokinase independent mechanisms. AB - We hypothesize that glucosensor mechanisms other than that mediated by glucokinase (GK) are present in the liver and Brockmann bodies (BB) of rainbow trout, and are affected by stress. We evaluated in these tissues changes in parameters related to putative glucosensor mechanisms based on liver X receptor (LXR), mitochondrial activity, sweet taste receptor, and SGLT-1 6h after intraperitoneal injection of saline solution alone (normoglycaemic treatment) or containing insulin (hypoglycaemic treatment), or d-glucose (hyperglycaemic treatment). Half of tanks were kept at normal stocking density (NSD; 10kgfishmass.m(-3)) whereas the remaining tanks were kept at high stocking density (HSD; 70kgfishmass.m(-3)). The results provide for the first time in fish evidence for the presence of putative glucosensor systems based on mitochondrial activity and sweet taste receptor in liver whereas in BB systems based on LXR, mitochondrial activity, sweet taste receptor, and SGLT-1 could be operative. We also obtained for the first time in fish evidence for the functioning of integrative metabolic sensors in response to changes in nutrient levels since changes in the mRNA abundance of sirtuin 1 (SIRT-1) were observed in response to increased glucose levels. The stress conditions elicited by HSD altered the response of the glucosensor systems based on mitochondrial activity, sweet taste receptor, and SGLT-1 in the liver, and LXR and SGLT-1 in the BB. PMID- 26439859 TI - A Monte Carlo simulation for the estimation of patient dose in rest and stress cardiac computed tomography with a 320-detector row CT scanner. AB - PURPOSE: To estimate organ dose and effective dose for patients for cardiac CT as applied in an international multicenter study (CORE320) with a 320-Detector row CT scanner using Monte Carlo (MC) simulations and voxelized phantoms. The effect of positioning of the arms, off-centering the patient and heart rate on patient dose was analyzed. METHODS: A MC code was tailored to simulate the geometry and characteristics of the CT scanner. The phantoms representing the adult reference male and female were implemented according to ICRP 110. Effective dose and organ doses were obtained for CT acquisition protocols for calcium scoring, coronary angiography and myocardial perfusion. RESULTS: For low heart rate, the normalized effective dose (E) for cardiac CT was higher for female (5.6 mSv/100 mAs) compared to male (2.2 mSv/100 mAs) due to the contribution of female breast tissue. Averaged E for female and male was 11.3 mSv for the comprehensive cardiac protocol consisting of calcium scoring (1.9 mSv); coronary angiography including rest cardiac perfusion (5.1 mSv) and stress cardiac perfusion (4.3 mSv). These values almost doubled at higher heart rates (20.1 mSv). Excluding the arms increased effective dose by 6-8%, centering the patient showed no significant effect. The k-factor (0.028 mSv/mGy.cm) derived from this study leads to effective doses up to 2-3 times higher than the values obtained using now outdated methodologies. CONCLUSION: MC modeling of cardiac CT examinations on realistic voxelized phantoms allowed us to assess patient doses accurately and we derived k-factors that are well above those published previously. PMID- 26439862 TI - Impacts of management and climate change on nitrate leaching in a forested karst area. AB - Forest management and climate change, directly or indirectly, affect drinking water resources, both in terms of quality and quantity. In this study in the Northern Limestone Alps in Austria we have chosen model calculations (LandscapeDNDC) in order to resolve the complex long-term interactions of management and climate change and their effect on nitrogen dynamics, and the consequences for nitrate leaching from forest soils into the karst groundwater. Our study highlights the dominant role of forest management in controlling nitrate leaching. Both clear-cut and shelterwood-cut disrupt the nitrogen cycle to an extent that causes peak concentrations and high fluxes into the seepage water. While this effect is well known, our modelling approach has revealed additional positive as well as negative impacts of the expected climatic changes on nitrate leaching. First, we show that peak nitrate concentrations during post cutting periods were elevated under all climate scenarios. The maximal effects of climatic changes on nitrate concentration peaks were 20-24 mg L(-1) in 2090 with shelterwood or clear-cut management. Second, climate change significantly decreased the cumulative nitrate losses over full forest rotation periods (by 10 20%). The stronger the expected temperature increase and precipitation decrease (in summer), the lesser were the observed nitrate losses. However, mean annual seepage water nitrate concentrations and cumulative nitrate leaching were higher under continuous forest cover management than with shelterwood-cut and clear-cut systems. Watershed management can thus be adapted to climate change by either reducing peak concentrations or long-term loads of nitrate in the karst groundwater. PMID- 26439861 TI - Simulation and optimization of a coking wastewater biological treatment process by activated sludge models (ASM). AB - Applications of activated sludge models (ASM) in simulating industrial biological wastewater treatment plants (WWTPs) are still difficult due to refractory and complex components in influents as well as diversity in activated sludges. In this study, an ASM3 modeling study was conducted to simulate and optimize a practical coking wastewater treatment plant (CWTP). First, respirometric characterizations of the coking wastewater and CWTP biomasses were conducted to determine the specific kinetic and stoichiometric model parameters for the consecutive aeration-anoxic-aeration (O-A/O) biological process. All ASM3 parameters have been further estimated and calibrated, through cross validation by the model dynamic simulation procedure. Consequently, an ASM3 model was successfully established to accurately simulate the CWTP performances in removing COD and NH4-N. An optimized CWTP operation condition could be proposed reducing the operation cost from 6.2 to 5.5 ?/m(3) wastewater. This study is expected to provide a useful reference for mathematic simulations of practical industrial WWTPs. PMID- 26439858 TI - Characterisation of grids of point detectors in maximum skin dose measurement in fluoroscopically-guided interventional procedures. AB - PURPOSE: Point detectors are frequently used to measure patient's maximum skin dose (MSD) in fluoroscopically-guided interventional procedures (IP). However, their performance and ability to detect the actual MSD are rarely evaluated. The present study investigates the sampling uncertainty associated with the use of grids of point detectors to measure MSD in IP. METHOD: Chemoembolisation of the liver (CE), percutaneous coronary intervention (PCI) and neuroembolisation (NE) procedures were studied. Spatial dose distributions were measured with XR-RV3 Gafchromic((r)) films for 176 procedures. These distributions were used to simulate measurements performed using grids of detectors such as thermoluminescence detectors, with detector spacing from 1.4 up to 10 cm. RESULTS: The sampling uncertainty was the highest in PCI and NE procedures. With 40 detectors covering the film area (36 cm * 44 cm), the maximum dose would be on average 86% and 63% of the MSD measured with Gafchromic((r)) films in CE and PCI procedures, respectively. In NE procedures, with 27 detectors covering the film area (14 cm * 35 cm), the maximum dose measured would be on average 82% of the MSD obtained with the Gafchromic((r)) films. CONCLUSION: Thermoluminescence detectors show good energy and dose response in clinical beam qualities. However the poor spatial resolution of such point-like dosimeters may far outweigh their good dosimetric properties. The uncertainty from the sampling procedure should be estimated when point detectors are used in IP because it may lead to strong underestimation of the MSD. PMID- 26439860 TI - Rapid enhanced photocatalytic degradation of dyes using novel N-doped ZrO2. AB - A novel N-doped ZrO2 (N-ZrO2) photocatalyst is synthesized through thermal decomposition of zirconium hydroxide-urea complex and is characterized using various techniques, including XRD, FTIR, TGA, SEM, TEM, UV-DRS, XPS, XANES, and BET. The N-ZrO2 possesses pure monoclinic structure with high crystallinity. By using the proposed facile route of synthesis, both interstitial and substitutional N doping with high dopant stability can be realized. The optical properties of the catalyst are significantly altered after N doping, giving an optical response in the visible and near infrared regions and an additional strong absorption peak in the UVA region. The N-ZrO2 showed a higher photocatalytic activity than pristine ZrO2 for the degradation of amaranth (AM) and methylene blue (MB) under visible or UV light irradiation, which could be attributed to the band gap narrowing, higher specific area, smaller crystalline size, and higher availability of surface hydroxyl groups. Due to its molecular structure and light absorption characteristics, MB is easier to degrade than AM. Overall removal efficiencies, including adsorption and photolysis, for AM and MB by N-ZrO2 at pH 7 with initial dye concentration of 10 mg/L, catalyst concentration of 1 g/L, and visible light irradiation of 144.7 W/m(2) are 67.2 and 96%, respectively. Using UVA light of only 3.5 W/m(2) under identical experimental conditions, complete removal of MB and AM is obtained. The photocatalytically treated solution of either AM or MB is nontoxic against Bacillus cereus, an agriculturally important soil microorganism. PMID- 26439864 TI - Quantitative Imaging of Gut Microbiota Spatial Organization. AB - Genomic technologies have significantly advanced our understanding of the composition and diversity of host-associated microbial populations. However, their spatial organization and functional interactions relative to the host have been more challenging to study. Here we present a pipeline for the assessment of intestinal microbiota localization within immunofluorescence images of fixed gut cross-sections that includes a flexible software package, BacSpace, for high throughput quantification of microbial organization. Applying this pipeline to gnotobiotic and human microbiota-colonized mice, we demonstrate that elimination of microbiota-accessible carbohydrates (MACs) from the diet results in thinner mucus in the distal colon, increased proximity of microbes to the epithelium, and heightened expression of the inflammatory marker REG3beta. Measurements of microbe-microbe proximity reveal that a MAC-deficient diet alters monophyletic spatial clustering. Furthermore, we quantify the invasion of Helicobacter pylori into the glands of the mouse stomach relative to host mitotic progenitor cells, illustrating the generalizability of this approach. PMID- 26439865 TI - Pathogen Virulence Impedes Mutualist-Mediated Enhancement of Host Juvenile Growth via Inhibition of Protein Digestion. AB - The microbial environment impacts many aspects of metazoan physiology through largely undefined molecular mechanisms. The commensal strain Lactobacillus plantarum(WJL) (Lp(WJL)) sustains Drosophila hormonal signals that coordinate systemic growth and maturation of the fly. Here we examine the underlying mechanisms driving these processes and show that Lp(WJL) promotes intestinal peptidase expression, leading to increased intestinal proteolytic activity, enhanced dietary protein digestion, and increased host amino acid levels. Lp(WJL) mediated peptidase upregulation is partly driven by the peptidoglycan recognition and signaling cascade PGRP-LE/Imd/Relish. Additionally, this mutualist-mediated physiological benefit is antagonized upon pathogen infection. Pathogen virulence selectively impedes Lp(WJL)-mediated intestinal peptidase activity enhancement and juvenile growth promotion but does not alter growth of germ-free animals. Our study reveals the adaptability of host physiology to the microbial environment, whereby upon acute infection the host switches to pathogen-mediated host immune defense at the expense of mutualist-mediated growth promotion. PMID- 26439863 TI - Cell Surface Proteomic Map of HIV Infection Reveals Antagonism of Amino Acid Metabolism by Vpu and Nef. AB - Critical cell surface immunoreceptors downregulated during HIV infection have previously been identified using non-systematic, candidate approaches. To gain a comprehensive, unbiased overview of how HIV infection remodels the T cell surface, we took a distinct, systems-level, quantitative proteomic approach. >100 plasma membrane proteins, many without characterized immune functions, were downregulated during HIV infection. Host factors targeted by the viral accessory proteins Vpu or Nef included the amino acid transporter SNAT1 and the serine carriers SERINC3/5. We focused on SNAT1, a beta-TrCP-dependent Vpu substrate. SNAT1 antagonism was acquired by Vpu variants from the lineage of SIVcpz/HIV-1 viruses responsible for pandemic AIDS. We found marked SNAT1 induction in activated primary human CD4+ T cells, and used Consumption and Release (CoRe) metabolomics to identify alanine as an endogenous SNAT1 substrate required for T cell mitogenesis. Downregulation of SNAT1 therefore defines a unique paradigm of HIV interference with immunometabolism. PMID- 26439867 TI - Adolescent vulnerability and the distress of rejection: Associations of adjustment problems and gender with control, emotions, and coping. AB - We examined adjustment problems as risks for patterns of emotions, appraisals, and coping with rejection, and explored whether these processes could account for sex (boy/girl) differences in coping. Young adolescents (N = 669, grades 6-8) completed questionnaires, which assessed responses to peer rejection threat with two short scenarios. Using structural equation modeling to test a multivariate process model, adolescents with heightened social anxiety had the most maladaptive responses to rejection threat, including elevated emotional reactions, more self-blame, and coping using more social isolation, rumination and opposition. Adolescents reporting more depressive symptoms felt less control and anticipated using less adaptive coping (less support seeking, distraction, and negotiation), whereas aggressive adolescents responded with more anger and coped via opposition. Moreover, as anticipated, sex differences in coping, symptoms, emotions, and appraisals were found. However, coping differences between boys and girls were mostly nonsignificant after accounting for symptoms, aggression, emotional reactions, and appraisals. PMID- 26439868 TI - The effects of pubertal timing on externalizing behaviors in adolescence and early adulthood: A meta-analytic review. AB - Using a meta-analytic approach, this investigation examines the association between early pubertal timing and externalizing behaviors in adolescence and early adulthood. The findings showed that the effect size of early pubertal maturation on externalizing behaviors was r = 0.180. This small, yet significant effect size is consistent with the models of early pubertal maturation in that early maturation is associated with higher levels of externalizing behaviors. Using contrast analyses, we examined three potential moderators of this association: sex, the concurrent versus long-term effect of early puberty, and types of puberty assessments. Neither sex nor type of pubertal timing assessment moderated the effect significantly. However, results indicated that the effect was stronger for studies that measured pubertal timing and externalizing behaviors concurrently rather than longitudinally (i.e., examining prospective effect of pubertal timing on later externalizing behaviors). The findings are discussed in terms of implications for future research. PMID- 26439866 TI - School-related social support and subjective well-being in school among adolescents: The role of self-system factors. AB - This 6-week longitudinal study aimed to examine a moderated mediation model that may explain the link between school-related social support (i.e., teacher support and classmate support) and optimal subjective well-being in school among adolescents (n = 1316). Analyses confirmed the hypothesized model that scholastic competence partially mediated the relations between school-related social support and subjective well-being in school, and social acceptance moderated the mediation process in the school-related social support--> subjective well-being in school path and in the scholastic competence--> subjective well-being in school path. The findings suggested that both social contextual factors (e.g., school-related social support) and self-system factors (e.g., scholastic competence and social acceptance) are crucial for adolescents' optimal subjective well-being in school. Limitations and practical applications of the study were discussed. PMID- 26439869 TI - Age estimation of decomposed bodies based on a combined arteriosclerotic index. AB - Several methods exist for the estimation of the age at the time of death, ranging from mere visual inspection to costly laboratory examinations. The "combined arteriosclerotic index (CAI)" is considered to be a suitable low-budget tool for undecayed corpses. It defines the ratio between diameter and longitudinal pre strain of the abdominal aorta. Its applicability in cases of decomposed corpses has not been studied yet. We examined whether it is a valid parameter in putrefied bodies as well and whether there is a correlation between CAI and the stage of decomposition. In conclusion the CAI becomes less accurate with increasing putrefaction. Nonetheless, even in case of high-grade putrefaction it remains a useful tool for instant age estimation which should be followed by the application of methods with higher accuracy. PMID- 26439870 TI - Characteristics of methadone-related fatalities in Norway. AB - There are currently over 7000 patients enrolled in opioid maintenance treatment (OMT) programs in Norway. A rise in methadone-related deaths proportional to increasing methadone sales over the period 2000-2006 has been observed, but the causative factors for these fatalities have been elusive. In the present study, individual characteristics, methadone concentrations and additional toxicological findings were analyzed. Methadone intoxication deaths (n = 264) were divided into 3 groups according to toxicological findings in whole blood: group 1 - methadone detected alone, or together with one additional drug at low or therapeutic levels, or a low concentration of ethanol (<1 g/L) (n = 21); group 2 - multiple additional drugs/substances detected below lethal levels (n = 175); group 3 - one or more additional drugs/substances detected at lethal levels, or ethanol >3 g/L (n = 55). Methadone blood concentrations in decedents who had been enrolled in OMT were higher than for decedents not in treatment, in all groups. Blood methadone concentrations around 1 mg/L were present in fatal multi-drug intoxications in OMT patients. Results suggest that some patients may be at risk of dying when combining therapeutic concentrations of methadone with other psychoactive substances. Somatic disease was a common finding among deceased OMT patients. Concentrations in methadone users not enrolled in OMT were predominantly between 0.3 and 0.4 mg/L and were not related to the presence of other drugs. However, methadone concentrations below 0.1 mg/L may be associated with intoxication following methadone use, both alone and in combination with other drugs. Younger male users (mean age 34 years) seemed to have a higher susceptibility to methadone intoxication. PMID- 26439871 TI - [An update on adenomyosis and implantation]. AB - Adenomyosis is an enigmatic disease whose impact on implantation and fertility outcome is still controversial. A negative effect on IVF outcome was already observed, but it is mainly explained by an increase in early spontaneous miscarriages. We reviewed scientific data in order to bring relevant information about adenomyosis and endometrial receptivity for patient counselling and to precise if screening of adenomyosis is indicated before IVF treatment. PMID- 26439872 TI - [Assessment of a multidisciplinary care for 169 excised women with an initial reconstructive surgery project]. AB - OBJECTIVE: To assess the benefits of a multidisciplinary care among excised women with an initial surgery project and identify the reasons for discarding surgery. METHODS: Descriptive and retrospective study performed between the 1st of January 2006 and the 31st of December 2011 at the Armand Trousseau Hospital, Paris. All excised patients went through consultations with a mid-wife, a sexologist, a psychologist, a gynaecologist-obstetrician and, for some of them, underwent a clitoral reconstructive surgery. RESULTS: One hundred and sixty-nine patients were included: among them, 61 patients (36%) were operated and 108 patients (64%) have given spontaneously to surgery, 32% being reinforced by consultation. Ninety one on 111 patients (82%) respondents were satisfied with their care pathway. The main motivation was to support identity for 39 patients operated (64%) while improving sex prevailed for 56 non-operated patients (52%). The study evidenced an improvement of the functional and sexual life quality after surgery: 17% experienced an orgasm versus 2% before surgery, 56% reported an increase in their libido and 41% a decrease in dyspareunia. CONCLUSION: Clitoral reconstructive surgery with multidisciplinary care tends to improve the functional and sexual life quality of excised patients, though it is not always necessary. Some of the patients discard their initial project of reconstructive surgery as in some of the cases, a multidisciplinary care only seems sufficient. PMID- 26439873 TI - Transcranial direct current stimulation in treatment-resistant obsessive compulsive disorder: An open-label pilot study. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is a severe mental illness. OCD symptoms are often resistant to available treatments. Abnormalities within the orbitofronto-striato-pallido-thalamic circuitry, especially orbitofrontal cortex (OFC) hyperactivity and cerebellar hypoactivity have been observed in patients. Non-invasive brain stimulation studies have indicated that transcranial direct current stimulation (tDCS) may be a useful alternative to alleviate treatment resistant symptoms in various neuropsychiatric conditions. METHODS: In an open label pilot study, 8 patients with treatment-resistant OCD received 10 sessions (twice a day) of 2mA tDCS applied with the cathode over the left OFC and the anode over the right cerebellum. OCD (Y-BOCS and OCD-VAS) as well as depressive (MADRS) symptoms were measured 4 times: one time before tDCS and 3 times after (immediately after, 1 and 3months after the 10th tDCS session). RESULTS: We reported a significant 26.4% (+/-15.8) decrease of Y-BOCS score (p=0.002). The beneficial effect lasted during the 3month follow-up. No effect of tDCS was observed on depressive symptoms. At end point, 5 out of 8 patients had a decrease of >=25%; and 3 out of 8 patients had a decrease of >=35% in Y-BOCS score. tDCS was well tolerated. CONCLUSION: tDCS with the cathode placed over the left OFC combined with the anode placed over the right cerebellum is a suitable and safe approach to decrease OCD symptoms in patients with treatment-resistant OCD. Large scale randomized controlled studies are needed to confirm this promising result. PMID- 26439874 TI - Synthesis and Analysis of the Structure, Diffusion and Cytotoxicity of Heterocyclic Platinum(IV) Complexes. AB - We have developed six dihydroxidoplatinum(IV) compounds with cytotoxic potential. Each derived from active platinum(II) species, these complexes consist of a heterocyclic ligand (HL) and ancillary ligand (AL) in the form [Pt(HL)(AL)(OH)2](2+), where HL is a methyl-functionalised variant of 1,10 phenanthroline and AL is the S,S or R,R isomer of 1,2-diaminocyclohexane. NMR characterisation and X-ray diffraction studies clearly confirmed the coordination geometry of the octahedral platinum(IV) complexes. The self-stacking of these complexes was determined using pulsed gradient stimulated echo nuclear magnetic resonance. The self-association behaviour of square planar platinum(II) complexes is largely dependent on concentration, whereas platinum(IV) complexes do not aggregate under the same conditions, possibly due to the presence of axial ligands. The cytotoxicity of the most active complex, exhibited in several cell lines, has been retained in the platinum(IV) form. PMID- 26439875 TI - Catalytic C-H bond functionalisation chemistry: the case for quasi-heterogeneous catalysis. AB - This feature article examines the potential of heterogeneous Pd species to mediate catalytic C-H bond functionalisation processes employing suitable substrates (e.g. aromatic/heteroaromatic compounds). A focus is placed on the reactivity of supported and non-supported Pd nanoparticle (PdNPs) catalysts, in addition to the re-appropriation of well-established heterogeneous Pd catalysts such as Pd/C. Where possible, reasonable comparisons are made between PdNPs and traditional 'homogeneous' Pd precatalyst sources (which form PdNPs). The involvement of higher order Pd species in traditional cross-coupling processes, such as Mizoroki-Heck, Sonogashira and Suzuki-Miyaura reactions, allows the exemplification of potential future topics for study in the area of catalytic C-H bond functionalisation processes. PMID- 26439877 TI - The favourable effects of long-term selenium supplementation on regression of cervical tissues and metabolic profiles of patients with cervical intraepithelial neoplasia: a randomised, double-blind, placebo-controlled trial. AB - This study was conducted to assess the effects of long-term Se administration on the regression and metabolic status of patients with cervical intraepithelial neoplasia grade 1 (CIN1). This randomised, double-blind, placebo-controlled trial was carried out among fifty-eight women diagnosed with CIN1. To diagnose CIN1, we used specific diagnostic procedures of biopsy, pathological diagnosis and colposcopy. Patients were randomly assigned to two groups to receive 200 MUg Se supplements as Se yeast (n 28) or placebo (n 28) daily for 6 months. After 6 months of taking Se supplements, a greater percentage of women in the Se group had regressed CIN1 (88.0 v. 56.0 %; P=0.01) compared with those in the placebo group. Long-term Se supplementation, compared with the placebo, resulted in significant decreases in fasting plasma glucose levels (-0.37 (sd 0.32) v. +0.07 (sd 0.63) mmol/l; P=0.002), serum insulin levels (-28.8 (sd 31.2) v. +13.2 (sd 40.2) pmol/l; P<0.001), homeostatic model assessment of insulin resistance values (-1.3 (se 1.3) v. +0.5 (se 1.4); P<0.001) and a significant elevation in quantitative insulin sensitivity check index (+0.03 (sd 0.03) v. -0.01 (sd 0.01); P<0.001). In addition, patients who received Se supplements had significantly decreased serum TAG (-0.14 (sd 0.55) v. +0.15 (sd 0.38) mmol/l; P=0.02) and increased HDL-cholesterol levels (+0.13 (sd 0.21) v. -0.01 (sd 0.15) mmol/l; P=0.003). In addition, compared with the placebo group, there were significant rises in plasma total antioxidant capacity (+186.1 (sd 274.6) v. +42.8 (sd 180.4) mmol/l; P=0.02) and GSH levels (+65.0 (sd 359.8) v. -294.2 (sd 581.8) MUmol/l; P=0.007) and a significant decrease in malondialdehyde levels (-1.5 (sd 2.1) v. +0.1 (sd 1.4) MUmol/l; P=0.001) among those who took Se supplements. Overall, taking Se supplements among patients with CIN1 led to its regression and had beneficial effects on their metabolic profiles. PMID- 26439876 TI - The IP3 R Binding Protein Released With Inositol 1,4,5-Trisphosphate Is Expressed in Rodent Reproductive Tissue and Spermatozoa. AB - Besides its capacity to inhibit the 1,4,5-trisphosphate (IP3) receptor, the regulatory protein IRBIT (IP3 receptor binding protein released with IP3) is also able to control the activity of numerous ion channels and electrolyte transporters and thereby creates an optimal electrolyte composition of various biological fluids. Since a reliable execution of spermatogenesis and sperm maturation critically depends on the establishment of an adequate microenvironment, the expression of IRBIT in male reproductive tissue was examined using immunohistochemical approaches combined with biochemical fractionation methods. The present study documents that IRBIT is expressed in Leydig and Sertoli cells. In addition, pronounced IRBIT expression was detected in sperm precursors during early stages of spermatogenesis as well as in spermatozoa. Analyzing tissue sections of rodent epididymides, IRBIT was found to co-localize with the proton pumping V-ATPase and the cystic fibrosis transmembrane conductance regulator (CFTR) at the apical surface of narrow and clear cells. A similar co-localization of IRBIT with CFTR was also observed for Sertoli cells and developing germ cells. Remarkably, assaying caudal sperm in immunogold electron microscopy, IRBIT was found to localize to the acrosomal cap and the flagellum as well as to the sperm nucleus; moreover, a prominent oligomerization was observed for spermatozoa. The pronounced occurrence of IRBIT in the male reproductive system and mature spermatozoa indicates a potential role for IRBIT in establishing the essential luminal environment for a faithful execution of spermatogenesis and epididymal sperm maturation, and suggest a participation of IRBIT during maturation steps after ejaculation and/or the final fertilization process. PMID- 26439878 TI - Tumor-derived microvesicles in the tumor microenvironment: How vesicle heterogeneity can shape the future of a rapidly expanding field. AB - Information transmission from tumor cells to non-tumor cells in the surrounding microenvironment via microvesicles is a more recently studied form of intercellular signaling that can have a marked impact on the tumor microenvironment. Tumor-derived microvesicles (TMVs) are packed with information including signaling proteins and nucleic acids, and can be taken up by target cells, enabling paracrine signaling. While previous research has focused on how vesicles released from pathologic cells differ from normal cells, the heterogeneity that exists within the TMV population itself is not fully characterized, and only beginning to be appreciated. In this review, we summarize current understanding of the biogenesis and roles of shed TMVs in the tumor microenvironment, and speculate on the consequences for tumor cell signaling in light of the hypothesis that there exists variance within the TMV population. The analysis of differential signaling upon cell-TMV interactions provides insights into potential mechanisms of intercellular communication. PMID- 26439879 TI - On the relative abundance of autopolyploids and allopolyploids. PMID- 26439880 TI - Serum club cell protein 16 is associated with asymptomatic airway responsiveness in adults: Findings from the French epidemiological study on the genetics and environment of asthma. AB - BACKGROUND AND OBJECTIVE: Club cell secretory protein (CC-16) is a sensitive biomarker of airways epithelium integrity. It has gained interest as a biological marker in chronic lung diseases because of its presumed relationship to inflammation. Little is known about the association between CC-16 serum level and asthma, lung function and airway responsiveness (AR). METHODS: Serum CC-16 level was determined by latex immunoassay in 1298 participants from the French Epidemiological case-control and family-based study on Genetics and Environment of Asthma (EGEA) (mean age 43 years; 49% men, 38% with asthma). Pre bronchodilator lung function (forced expiratory volume in 1 s (FEV1 ), forced vital capacity (FVC) and FEV1 /FVC) and degree of AR, expressed as a function of the dose-response slope to methacholine test were measured. Standardized residuals CC-16 z-scores were obtained by regressing CC-16 level on the glomerular filtration rate. CC-16 z-scores were correlated with asthma, lung function and AR in participants with and without asthma. RESULTS: CC-16 geometric mean level was 12.4 MUg/L (range: 2.2-70.6 MUg/L). In participants without asthma, lower CC-16 z-scores was associated with impaired FEV1 /FVC% (beta = 0.50 (95% CI: 0.06, 0.95) and with higher degree of AR (beta = 0.24 (95% CI: 0.09, 0.39)). CC-16 was not associated with impaired lung function or AR in participants with asthma. CONCLUSIONS: Lower CC-16 serum level was associated with impaired lung function and AR, suggesting that serum CC-16 level may reflect early damages to the lung epithelium in adults without asthma. PMID- 26439881 TI - Novel viral genomes identified from six metagenomes reveal wide distribution of archaeal viruses and high viral diversity in terrestrial hot springs. AB - Limited by culture-dependent methods the number of viruses identified from thermophilic Archaea and Bacteria is still very small. In this study we retrieved viral sequences from six hot spring metagenomes isolated worldwide, revealing a wide distribution of four archaeal viral families, Ampullaviridae, Bicaudaviridae, Lipothrixviridae and Rudiviridae. Importantly, we identified 10 complete or near complete viral genomes allowing, for the first time, an assessment of genome conservation and evolution of the Ampullaviridae family as well as Sulfolobus Monocaudavirus 1 (SMV1)-related viruses. Among the novel genomes, one belongs to a putative thermophilic virus infecting the bacterium Hydrogenobaculum, for which no virus has been reported in the literature. Moreover, a high viral diversity was observed in the metagenomes, especially among the Lipothrixviridae, as indicated by the large number of unique contigs and the lack of a completely assembled genome for this family. This is further supported by the large number of novel genes in the complete and partial genomes showing no sequence similarities to public databases. CRISPR analysis revealed hundreds of novel CRISPR loci and thousands of novel CRISPR spacers from each metagenome, reinforcing the notion of high viral diversity in the thermal environment. PMID- 26439882 TI - Tailored Fringed Platforms Produced by Laser Interference for Aligned Neural Cell Growth. AB - Ordering neural cells is of interest for the development of neural interfaces. The aim of this work is to demonstrate an easy-to-use, versatile, and cost/time effective laser-based approach for producing platforms that promote oriented neural growth. We use laser interferometry to generate fringed channels with topography on partially reduced graphene oxide layers as a proof-of-concept substrate. We study cell adhesion, morphology, viability, and differentiation in cultures of embryonic neural progenitor cells on platforms with a 9.4 MUm period. Results evidence that fringed platforms significantly promote neurite alignment (~50% at 6 d), while preserving viability and neural differentiation. PMID- 26439883 TI - Effect of Co-solutes on Template-Directed Nonenzymatic Replication of Nucleic Acids. AB - The widely acknowledged 'RNA world' theory pertains to how life might have chemically originated on early Earth. It presumes the existence of catalytic RNAs, which were also capable of storing and propagating genetic information. Substantial research has gone into understanding how enzyme-free reactions of nucleic acids might have led to the formation of such catalytic RNA polymers. However, most of these studies involved reactions that were performed in aqueous systems devoid of any "background" molecules. This scenario is not a true representation of the complex chemical environment that might have been prevalent on prebiotic Earth. In the present study, we analyzed the effect of co-solutes ("background" molecules) on the rate and accuracy of template-directed nonenzymatic replication of RNA, in a putative RNA world. Our results suggest that presence of co-solutes in the reaction affects the addition of purine monomers across their cognate template base. Reduction in the rate of these 'fast' cognate addition reactions resulted in an apparent increase in the frequency of mismatches in the presence of co-solutes. However, reactions that involved the addition of a mismatched base were not notably affected. Such a scenario could have led to an accrual of mutations during the propagation of functional sequences on early Earth, unless the relevant sequences were separated from the bulk reaction milieu by some limiting boundary structure (e.g., a membrane). In general, our results suggest that the presence of co-solutes could have affected certain prebiotic reaction rates to a larger extent than others. Even modest changes in nonenzymatic replication reaction rates could have eventually resulted in the accumulation of greater variation in RNA sequences over prolonged time periods. It, therefore, is pertinent to account for the chemical complexity intrinsic to prebiotic environments while studying relevant nonenzymatic reactions. PMID- 26439888 TI - Calcium-Catalyzed Dynamic Multicomponent Reaction. AB - The reversible formation of covalent bonds enabled by the remarkably high Lewis acidity of our calcium-based catalyst system was used for the development of a new type of multicomponent reaction. Accordingly, a pharmacologically interesting bicyclic amine was amplified from a highly efficient dynamic equilibrium. The product is formed with full diastereoselectivity, and as typical for our calcium catalyzed reactions, precautions for the exclusion of air and moisture are unnecessary. PMID- 26439887 TI - Antibiotic Stewardship: What's Not To Like? PMID- 26439884 TI - Unusual Aggregation-Induced Emission of a Coumarin Derivative as a Result of the Restriction of an Intramolecular Twisting Motion. AB - Aggregation-induced emission (AIE) is commonly observed for propeller-like luminogens with aromatic rotors and stators. Herein, we report that a coumarin derivative containing a seven-membered aliphatic ring (CD-7) but no rotors showed typical AIE characteristics, whereas its analogue with a five-membered aliphatic ring (CD-5) exhibited an opposite aggregation-caused quenching (ACQ) effect. Experimental and theoretical results revealed that a large aliphatic ring in CD-7 weakens structural rigidity and promotes out-of-plane twisting of the molecular backbone to drastically accelerate nonradiative excited-state decay, thus resulting in poor emission in solution. The restriction of twisting motion in aggregates blocks the nonradiative decay channels and enables CD-7 to fluoresce strongly. The results also show that AIE is a general phenomenon and not peculiar to propeller-like molecules. The AIE and ACQ effects can be switched readily by the modulation of molecular rigidity. PMID- 26439885 TI - Role of atmospheric pressure plasma (APP) in wound healing: APP-induced antifibrotic process in human dermal fibroblasts. PMID- 26439886 TI - Safety of Intracavernous Bone Marrow-Mononuclear Cells for Postradical Prostatectomy Erectile Dysfunction: An Open Dose-Escalation Pilot Study. AB - Evidence from animal models replicating postradical prostatectomy erectile dysfunction (pRP-ED) suggests intracavernous injection of bone marrow-mononuclear cells (BM-MNCs) as a promising treatment approach for pRP-ED. We conducted a phase 1/2 pilot clinical trial of intracavernous autologous BM-MNC injection to treat pRP-ED (NCT01089387). Twelve patients with localized prostate cancer and vasculogenic pRP-ED refractory to maximal medical treatment were divided into four equal groups treated with escalating BM-MNC doses (2*10(7), 2*10(8), 1*10(9), 2*10(9)). Tolerance was the primary endpoint. Secondary endpoints were the effects on erectile function and penile vascularization at 6 mo, as assessed using the International Index of Erectile Function-15 and Erection Hardness Scale questionnaires, and color duplex Doppler ultrasound. We measured the peak systolic velocity in cavernous arteries and assessed endothelial function using the penile nitric oxide release test. No serious side effects occurred. At 6 mo versus baseline, significant improvements of intercourse satisfaction (6.8+/-3.6, 3.9+/-2.5, p=0.044) and erectile function (17.4+/-8.9, 7.3+/-4.5, p=0.006) domains of the International Index of Erectile Function-15 and Erection Hardness Scale (2.6+/-1.1, 1.3+/-0.8, p=0.008) were observed in the total population. Spontaneous erections showed significantly greater improvement with the higher doses. Clinical benefits were associated with improvement of peak systolic velocity and of % penile nitric oxide release test and sustained after 1 yr. Our results need to be confirmed by phase 2 clinical trials. PATIENT SUMMARY: We report a phase 1/2 pilot clinical trial investigating cell therapy with injection of bone marrow mononucleated cells to treat postradical prostatectomy erectile dysfunction. No serious side effects occurred. Improvements of erectile function and penile vascularization were noted. Further studies are required to confirm these preliminary results. PMID- 26439889 TI - Selective remote C-H sulfonylation of aminoquinolines with arylsulfonyl chlorides via copper catalysis. AB - Copper-catalysed direct C-H bond sulfonylation of aminoquinolines using commercially available and inexpensive arylsulfonyl chlorides as the sulfonylation reagents is described. The reactions took place exclusively at the C5-H position of the quinoline rings and tolerated a wide spectrum of functional groups. Moreover, synthetic transformations of the sulfonylated products led to useful compounds. PMID- 26439890 TI - ACR Appropriateness Criteria(r) Intensive Care Unit Patients. AB - Portable chest radiography is a fundamental and frequently utilized examination in the critically ill patient population. The chest radiograph often represents a timely investigation of new or rapidly evolving clinical findings and an evaluation of proper positioning of support tubes and catheters. Thoughtful consideration of the use of this simple yet valuable resource is crucial as medical cost containment becomes even more mandatory. This review addresses the role of chest radiography in the intensive care unit on the basis of the existing literature and as formed by a consensus of an expert panel on thoracic imaging through the American College of Radiology. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 26439891 TI - Treatment Failure of Active Vitamin D Therapy in Chronic Kidney Disease: Predictive Factors. AB - BACKGROUND: In patients with chronic kidney disease (CKD), impaired renal function leads to decreased vitamin D levels, which causes an increase in parathyroid hormone (PTH) production and contributes to the development of secondary hyperparathyroidism (SHPT). This may result in adverse clinical effects such as bone disorders, vascular calcification, cardiovascular disease, and increased mortality. Current treatment practices and associated outcomes with active vitamin D treatment in patients with CKD were reviewed with the objective to assess parameters (such as PTH and serum calcium levels) that may be used to define the failure of vitamin D treatment. SUMMARY: Reports based on observational data have noted improved outcomes with active vitamin D treatment (calcitriol, paricalcitol, alfacalcidol, or doxercalciferol) in patients with CKD. Criteria for the identification of active vitamin D treatment failure are unclear from current guidelines, although up to 50% of patients may experience treatment failure eventually because of development of hypercalcemia or resistant SHPT, characterized by an elevated intact PTH (iPTH) level despite treatment. We propose a definition of vitamin D treatment failure as iPTH >600 pg/ml after 6 months of intravenous active vitamin D treatment and corrected total calcium serum levels >10.2 mg/dl, and review factors that may predict the response to vitamin D treatment. Key Message: Active vitamin D treatment failure is an important challenge in clinical practice. The aim of the proposed definition is to suggest a possible framework for hypothesis generation and to encourage further research into this common problem. PMID- 26439892 TI - An Electrochromic Tristable Molecular Switch. AB - A tristable [2]catenane, composed of a macrocyclic polyether incorporating 1,5 dioxynaphthalene (DNP) and tetrathiafulvalene (TTF) units along with a 4,4' bipyridinium (BIPY(*+)) radical cation as three very different potential recognition sites, interlocked mechanically with the tetracationic cyclophane, cyclobis(paraquat-p-phenylene) (CBPQT(4+)), was synthesized by donor-acceptor templation, employing a "threading-followed-by-cyclization" approach. In this catenane, movement of the CBPQT(4+) ring in its different redox states among these three potential recognition sites, with corresponding color changes, is achieved by tuning external redox potentials. In the starting state, where no external potential is applied, the ring encircles the TTF unit and displays a green color. Upon oxidation of the TTF unit, the CBPQT(4+) ring moves to the DNP unit, producing a red color. Finally, if all the BIPY(2+) units are reduced to BIPY(*+) radical cations, the resulting CBPQT(2(*+)) diradical dication will migrate to the BIPY(*+) unit, resulting in a purple color. These readily switchable electrochromic properties render the [2]catenane attractive for use in electro-optical devices. PMID- 26439894 TI - Nanoprecipitation and Spectroscopic Characterization of Curcumin-Encapsulated Polyester Nanoparticles. AB - Curcumin-encapsulated polyester nanoparticles (Cur-polyester NPs) of approximately 100 nm diameter with a negatively charged surface were prepared using a one-step nanoprecipitation method. The Cur-polyester NPs were prepared using polylactic acid, poly(D,L-lactic-co-glycolic acid) and poly(epsilon caprolactone) without any emulsifier or surfactant. The encapsulation of curcumin in these polyester NPs greatly suppresses curcumin degradation in the aqueous environment due to its segregation from water. In addition, the fluorescence of curcumin in polyester NPs has a quantum yield of 4 to 5%, which is higher than that of curcumin in micellar systems and comparable to those in organic solvents, further supporting the idea that the polyester NPs are capable of excluding water from curcumin. Furthermore, the results from femtosecond fluorescence upconversion spectroscopy reveal that there is a decrease in the signal amplitude corresponding to solvent reorganization of excited state curcumin in the polyester NPs compared with curcumin in micellar systems. The Cur-polyester NPs also show a lack of deuterium isotope effect in the fluorescence lifetime. These results indicate that the interaction between curcumin and water in the polyester NPs is significantly weaker than that in micelles. Therefore, the aqueous stability of curcumin is greatly improved due to highly effective segregation from water. The overall outcome suggests that the polyester NPs prepared using the method reported herein are an attractive system for encapsulating and stabilizing curcumin in the aqueous environment. PMID- 26439895 TI - Toward a Molecular Lego Approach for the Diversity-Oriented Synthesis of Cyclodextrin Analogues Designed as Scaffolds for Multivalent Systems. AB - A modular strategy has been developed to access a diversity of cyclic and acyclic oligosaccharide analogues designed as prefunctionalized scaffolds for the synthesis of multivalent ligands. This convergent approach is based on bifunctional sugar building blocks with two temporarily masked functionalities that can be orthogonally activated to perform Cu(I)-catalyzed azide-alkyne cycloaddition reactions (CuAAC). The reducing end is activated as a glycosyl azide and masked as a 1,6-anhydro sugar, while the nonreducing end is activated as a free alkyne and masked as a triethylsilyl-alkyne. Following a cyclooligomerization approach, the first examples of close analogues of cyclodextrins composed of d-glucose residues and triazole units bound together through alpha-(1,4) linkages were obtained. The cycloglucopyranoside analogue containing four sugar units was used as a template to prepare multivalent systems displaying a protected d-mannose derivative or an iminosugar by way of CuAAC. On the other hand, the modular approach led to acyclic alkyne-functionalized scaffolds of a controlled size that were used to synthesize multivalent iminosugars. PMID- 26439893 TI - Micronutrient status and neurodevelopment in internationally adopted children. AB - AIM: To assess the status of nutrients relevant for brain development in internationally adoptees from disparate global regions and determine whether identified deficiencies are associated with neurodevelopment. METHODS: Participants included children adopted from Post-Soviet States (n = 15), Ethiopia (n = 26) or China (n = 17), ages 8-18 months. A comprehensive nutritional battery and a neurodevelopmental assessment were completed at baseline (within one month of arrival) and follow-up (six months later). RESULTS: At baseline, 35% were stunted, and 68% had at least one abnormal nutritional biochemical marker. The most common were low retinol-binding protein (33%), zinc deficiency (29%), vitamin D insufficiency/deficiency (21%), and iron deficiency (15%). There was significant catch-up growth in height and weight at follow-up, but little improvement in micronutrient deficiencies. Iron deficiency was associated with lower cognitive scores on the Bayley Scales of Infant Development-III, p = 0.027, and slower speed of processing, p = 0.012. Zinc deficiency was associated with compromised memory functioning, p = 0.001. CONCLUSION: Nutrient deficiencies were common during the early adoption period in internationally adoptees from three global regions, and iron and zinc deficiencies were associated with poorer neurodevelopmental outcomes. Results emphasise the importance of monitoring micronutrient status at arrival and during the early adoption period, irrespective of country of origin. PMID- 26439896 TI - Reduction of Foxp3+ T cell subsets involved in incidence of chronic graft-versus host disease after allogeneic hematopoietic stem cell transplantation. AB - Foxp3+ T cells (CD4+ Tregs and CD8+ Treg) have been demonstrated to play roles in the maintenance of tolerance after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). We have found that Foxp3+ gammadeltaTCR+ Treg cells (gammadeltaTregs) exerted regulatory functions. In the current study, patients were recruited and divided as non-cGVHD, limited cGVHD and extensive cGVHD groups. Healthy volunteers were recruited as healthy group. Treg cells were evaluated by flow cytometry. Serum cytokine levels of IL-2, tumour necrosis factor-alpha, interferon-gamma and transforming growth factor-beta1 (TGF-beta1) were evaluated by ELISA. The results showed that percentages of CD4+ Tregs, CD8+ Tregs and gammadeltaTregs were all significantly increased in non-cGVHD group compared with those in healthy group, limited cGVHD group and extensive cGVHD group. Moreover, compared with extensive cGVHD group, percentages of these three types of Tregs were significantly increased in limited cGVHD group. The levels of TGF-beta1 increased dramatically in non-cGVHD group compared with other groups. Spearman's correlation analysis revealed that the increased levels of TGF-beta1 and IL-2 were positively associated with increased Treg subsets, indicating that TGF-beta1 and IL-2 participated in the expansion process of Foxp3+ Tregs in vivo. Our findings support that increasing the number of Tregs following allo-HSCT would be a preferential strategy for controlling cGVHD. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26439897 TI - Multifunctional Fluorescent-Magnetic Polymeric Colloidal Particles: Preparations and Bioanalytical Applications. AB - Fluorescent-magnetic particles (FMPs) play important roles in modern materials, especially as nanoscale devices in the biomedical field. The interesting features of FMPs are attributed to their dual detection ability, i.e., fluorescent and magnetic modes. Functionalization of FMPs can be performed using several types of polymers, allowing their use in various applications. The synergistic potentials for unique multifunctional, multilevel targeting nanoscale devices as well as combination therapies make them particularly attractive for biomedical applications. However, the synthesis of FMPs is challenging and must be further developed. In this review article, we summarized the most recent representative works on polymer-based FMP systems that have been applied particularly in the bioanalytical field. PMID- 26439900 TI - An automated, fast and accurate registration method to link stranded seeds in permanent prostate implants. AB - The geometry of a permanent prostate implant varies over time. Seeds can migrate and edema of the prostate affects the position of seeds. Seed movements directly influence dosimetry which relates to treatment quality. We present a method that tracks all individual seeds over time allowing quantification of seed movements. This linking procedure was tested on transrectal ultrasound (TRUS) and cone-beam CT (CBCT) datasets of 699 patients. These datasets were acquired intraoperatively during a dynamic implantation procedure, that combines both imaging modalities. The procedure was subdivided in four automatic linking steps. (I) The Hungarian Algorithm was applied to initially link seeds in CBCT and the corresponding TRUS datasets. (II) Strands were identified and optimized based on curvature and linefits: non optimal links were removed. (III) The positions of unlinked seeds were reviewed and were linked to incomplete strands if within curvature- and distance-thresholds. (IV) Finally, seeds close to strands were linked, also if the curvature-threshold was violated. After linking the seeds an affine transformation was applied. The procedure was repeated until the results were stable or the 6th iteration ended. All results were visually reviewed for mismatches and uncertainties. Eleven implants showed a mismatch and in 12 cases an uncertainty was identified. On average the linking procedure took 42 ms per case. This accurate and fast method has the potential to be used for other time spans, like Day 30, and other imaging modalities. It can potentially be used during a dynamic implantation procedure to faster and better evaluate the quality of the permanent prostate implant. PMID- 26439899 TI - Performance of interferon-gamma release assay for tuberculosis screening in inflammatory bowel disease patients: Disease activity as an influencing factor. PMID- 26439898 TI - Supramolecular Guest-Host Interactions for the Preparation of Biomedical Materials. AB - Supramolecular chemistry has emerged as an important technique for the formation of biomaterials, including nano- and microparticles and hydrogels. One specific class of supramolecular chemistry is the direct association of guest-host pairs, which involves host macrocycles such as cyclodextrins and cucurbit[n]urils and a wide range of guest molecules, where association is typically driven by molecule size and hydrophobicity. These systems are of particular interest in the biomedical field due to their dynamic nature, chemical diversity, relative ease of synthesis, and ability to interact with biological or synthetic molecules. In this review, we discuss aspects of polymeric material assembly mediated by guest host interactions, including the fundamentals of assembly into functional biomedical materials. Additionally, applications of biomaterials that utilize guest-host interactions are discussed with a focus on injectable material formulations, the sequestration and delivery of encapsulated cargo (i.e., drugs, biomolecules), and the investigation of cell-material interactions (i.e., adhesion, differentiation, and delivery). While methodologies for guest-host mediated assembly and biological interaction have rapidly evolved in recent years, they remain far from realizing their full potential in the biomaterials field. PMID- 26439901 TI - Untreated maternal hyperthyroidism responsible of early neonatal demise. PMID- 26439903 TI - Laterality, sex, and everyday spatial behaviours: an exploratory analysis. AB - Exploratory analyses of a 126-item self-report assessment of difficulty of spatial behaviours (revision of the Everyday Spatial Behavioral Questionnaire, ESBQ) were used to examine principal components and the underlying root structure of perceived spatial competencies. We also examined laterality measures (handedness, footedness, and earedness), sex, and age as predictors of spatial behaviour component scores. 12 principal components were identified that represented facets of spatial behaviour and perception. Canonical analysis revealed 2 underlying dimensions of perceived difficulty in performing spatial behaviours: difficulty with spatial relations in the context of movement and difficulty with judging how things relate to each other or to a larger surround. Sex was more closely related to the former dimension; laterality measures and age were more closely related to the latter. With respect to specific components, women tended to report more difficulty with making judgements in relation to earth-fixed axes but less difficulty in judging relations to nearby objects and how objects fit together or within a surround. Right-handedness was associated with more perceived difficulty in judging spatial relations while driving, overlaying surfaces, and moving in relation to other objects in nearby space. Future confirmatory analyses will be needed to establish subscales of the ESBQ and their usefulness for practical applications. PMID- 26439904 TI - Rebuilding the infarcted heart with noncellular material. PMID- 26439902 TI - IL-1alpha is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity. AB - Environmental signals can be translated into chromatin changes, which alter gene expression. Here we report a novel concept that cells can signal chromatin damage from the nucleus back to the surrounding tissue through the cytokine interleukin 1alpha (IL-1alpha). Thus, in addition to its role as a danger signal, which occurs when the cytokine is passively released by cell necrosis, IL-1alpha could directly sense DNA damage and act as signal for genotoxic stress without loss of cell integrity. Here we demonstrate localization of the cytokine to DNA-damage sites and its subsequent secretion. Interestingly, its nucleo-cytosolic shuttling after DNA damage sensing is regulated by histone deacetylases (HDAC) and IL 1alpha acetylation. To demonstrate the physiological significance of this newly discovered mechanism, we used IL-1alpha knockout mice and show that IL-1alpha signaling after UV skin irradiation and DNA damage is important for triggering a sterile inflammatory cascade in vivo that contributes to efficient tissue repair and wound healing. PMID- 26439905 TI - Antitussive, expectorant, and anti-inflammatory activities of four caffeoylquinic acids isolated from Tussilago farfara. AB - CONTEXT: The flower bud of Tussilago farfara L. (Compositae) (FTF) is one of the traditional Chinese medicinal herbs used to treat cough, phlegm, bronchitic, and asthmatic conditions. OBJECTIVE: The objective of this study is to isolate four caffeoylquinic acids from the ethyl acetate extract (EtE) of FTF and to evaluate their antitussive, expectorant, and anti-inflammatory activities. MATERIALS AND METHODS: The structures of compounds 1-4 isolated from EtE were determined by spectral analysis. Mice were orally treated with these compounds and their mixture (in a ratio of 5:28:41:26 as in EtE) at doses of 10 and 20 mg/kg once daily for 3 d. The antitussive and expectorant activities were evaluated separately with the ammonia liquor-induced model and the phenol red secretion model. The anti-inflammation activity was evaluated using leukocyte count in the bronchoalveolar lavage fluid after ammonia liquor-induced acute airway inflammation. RESULTS: The four compounds were identified as chlorogenic acid (1), 3,5-dicaffeoylquinic acid (2), 3,4-dicaffeoylquinic acid (3), and 4,5 dicaffeoylquinic acid (4). All compounds, especially compound 4 (58.0% inhibition in cough frequency), showed a significant antitussive effect. However, the mixture was the most effective to inhibit the cough frequency by 61.7%. All compounds also showed a significant expectorant effect, while compound 2 was the most potent to enhance the phenol red secretion by 35.7%. All compounds significantly alleviated inflammation, but compound 4 showed the strongest effect to inhibit the leukocytosis by 49.7%. DISCUSSION AND CONCLUSION: The caffeoylquinic acids and their mixture, exhibiting significant antitussive, expectorant, and anti-inflammatory effects, could be considered as the main effective ingredients of FTF, and they may act in a collective and synergistic way. PMID- 26439906 TI - Self-Assembly of Silver Metal Clusters of Small Atomicity on Cyclic Peptide Nanotubes. AB - Subnanometric noble metal clusters, composed by only a few atoms, behave like molecular entities and display magnetic, luminescent and catalytic activities. However, noncovalent interactions of molecular metal clusters, lacking of any ligand or surfactant, have not been seen at work. Theoretically attractive and experimentally discernible, van der Waals forces and noncovalent interactions at the metal/organic interfaces will be crucial to understand and develop the next generation of hybrid nanomaterials. Here, we present experimental and theoretical evidence of noncovalent interactions between subnanometric metal (0) silver clusters and aromatic rings and their application in the preparation of 1D self assembled hybrid architectures with ditopic peptide nanotubes. Atomic force microscopy, fluorescence experiments, circular dichroism and computational simulations verified the occurrence of these interactions in the clean and mild formation of a novel peptide nanotube and metal cluster hybrid material. The findings reported here confirmed the sensitivity of silver metal clusters of small atomicity toward noncovalent interactions, a concept that could find multiple applications in nanotechnology. We conclude that induced supramolecular forces are optimal candidates for the precise spatial positioning and properties modulation of molecular metal clusters. The reported results herein outline and generalize the possibilities that noncovalent interactions will have in this emerging field. PMID- 26439908 TI - Association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with preterm delivery and placental abruption: a systematic review and meta analysis. AB - INTRODUCTION: The aim of this study was to summarize evidence on the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and odds of preterm delivery and placental abruption. MATERIAL AND METHODS: PubMed, EMBASE, CBM (Chinese Biomedical Database) and CNKI (Chinese National Knowledge Infrastructure) were searched to identify eligible studies published in English or Chinese before 12 August 2014. The pooled odds ratios (ORs) with 95% confidence intervals were estimated for the association of MTHFR C677T polymorphism with preterm delivery and placental abruption using random effects models. RESULTS: A total of 22 studies that met inclusion and exclusion criteria were included in this meta-analysis. Regardless of the genetic model tested we found no statistically significant association of MTHFR C677T polymorphism with preterm delivery or placental abruption. Funnel plots inspections, Begg's test and Egger's test did not show evidence of publication bias. CONCLUSIONS: This meta-analysis demonstrated that overall there was no association of MTHFR C677T polymorphism with preterm delivery or placental abruption. PMID- 26439907 TI - Clostridium difficile recurrent infection: possible implication of TA systems. AB - Clostridium difficile is an important nosocomial pathogen associated with antibiotic treatments. C. difficile's ability to survive antimicrobial therapy and transition from inert colonization to active infection is one of the most perplexing aspects of C. difficile infections and suggests that additional mechanisms are involved in persistence. In this regard, novel mechanisms linked with pathogenesis and persistence of C. difficile such as toxin-antitoxin systems might significantly contribute to biofilm formation and persistent infection. This review will focus on advances of toxin-antitoxin systems in C. difficile and their putative roles will be discussed. PMID- 26439911 TI - A brief review of the application and pharmacology of ethnomedicines of Indigenous Australians. AB - OBJECTIVE: Indigenous Australians suffer higher mortality and have statistically worse outcomes for many chronic disease states than the non-Indigenous population. Although many of these people are prescribed pharmaceutical drugs for their illnesses, some still use medicines that were traditional to their culture. This report reviews some of the traditional medicines used for ailments seen in Indigenous Australian communities. DESIGN: A literature search was conducted, with the period between the publication of an 'Aboriginal Pharmacopoeia' in 1988 and 'current' our target interval for searching. The ethics of publishing knowledge belonging to Aboriginal people is briefly discussed in this context. RESULTS: Ailments were grouped into communicable diseases, pain and inflammation, skin disorders and gastrointestinal disorders. Although cancer is regarded as a disease of the 'white man', it is briefly discussed in the context that several traditional medicines and foods may have provided some protective effects. Where known, the ethnopharmacology of these medicines is discussed, as well as a brief description of their preparation and application. CONCLUSION: Some Indigenous Australians continue to use traditional medicines. We have tabulated these according to ailment, and have listed pharmacological actions where known. What is not known, however, is their potential to interact with pharmaceutical drugs. Further study in this area is needed to optimise health outcomes for Indigenous Australians, especially those in remote communities. PMID- 26439910 TI - [Quality of life as a function of treatment in black patients with primary open angle glaucoma]. PMID- 26439912 TI - Corrigendum. PMID- 26439913 TI - Mechanism for the stabilization of protein clusters above the solubility curve. AB - Pan, Vekilov and Lubchenko [J. Phys. Chem. B, 2010, 114, 7620] have proposed that dense stable protein clusters appearing in weak protein solutions above the solubility curve are composed of protein oligomers. The hypothesis is that a weak solution of oligomer species is unstable with respect to condensation causing the formation of dense, oligomer-rich droplets which are stabilized against growth by the monomer-oligomer reaction. Here, we show that such a combination of processes can be understood using a simple capillary model yielding analytic expressions for the cluster properties which can be used to interpret experimental data. We also construct a microscopic Dynamic Density Functional Theory model and show that it is consistent with the predictions of the capillary model. The viability of the mechanism is thus confirmed and it is shown how the radius of the stable clusters is related to physically interesting quantities such as the monomer oligomer rate constants. PMID- 26439916 TI - Thermal surface free energy and stress of iron. AB - Absolute values of surface energy and surface stress of solids are hardly accessible by experiment. Here, we investigate the temperature dependence of both parameters for the (001) and (110) surface facets of body-centered cubic Fe from first-principles modeling taking into account vibrational, electronic, and magnetic degrees of freedom. The monotonic decrease of the surface energies of both facets with increasing temperature is mostly due to lattice vibrations and magnetic disorder. The surface stresses exhibit nonmonotonic behaviors resulting in a strongly temperature dependent excess surface stress and surface stress anisotropy. PMID- 26439909 TI - Interaction of a dengue virus NS1-derived peptide with the inhibitory receptor KIR3DL1 on natural killer cells. AB - Killer immunoglobulin-like receptors (KIRs) interact with human leucocyte antigen (HLA) class I ligands and play a key role in the regulation and activation of NK cells. The functional importance of KIR-HLA interactions has been demonstrated for a number of chronic viral infections, but to date only a few studies have been performed in the context of acute self-limited viral infections. During our investigation of CD8(+) T cell responses to a conserved HLA-B57-restricted epitope derived from dengue virus (DENV) non-structural protein-1 (NS1), we observed substantial binding of the tetrameric complex to non-T/non-B lymphocytes in peripheral blood mononuclear cells (PBMC) from a long-standing clinical cohort in Thailand. We confirmed binding of the NS1 tetramer to CD56(dim) NK cells, which are known to express KIRs. Using depletion studies and KIR-transfected cell lines, we demonstrated further that the NS1 tetramer bound the inhibitory receptor KIR3DL1. Phenotypical analysis of PBMC from HLA-B57(+) subjects with acute DENV infection revealed marked activation of NS1 tetramer-binding natural killer (NK) cells around the time of defervescence in subjects with severe dengue disease. Collectively, our findings indicate that subsets of NK cells are activated relatively late in the course of acute DENV illness and reveal a possible role for specific KIR-HLA interactions in the modulation of disease outcomes. PMID- 26439914 TI - Nanometer-size hard magnetic ferrite exhibiting high optical-transparency and nonlinear optical-magnetoelectric effect. AB - Development of nanometer-sized magnetic particles exhibiting a large coercive field (Hc) is in high demand for densification of magnetic recording. Herein, we report a single-nanosize (i.e., less than ten nanometers across) hard magnetic ferrite. This magnetic ferrite is composed of epsilon-Fe2O3, with a sufficiently high Hc value for magnetic recording systems and a remarkably high magnetic anisotropy constant of 7.7 * 10(6) erg cm(-3). For example, 8.2-nm nanoparticles have an Hc value of 5.2 kOe at room temperature. A colloidal solution of these nanoparticles possesses a light orange color due to a wide band gap of 2.9 eV (430 nm), indicating a possibility of transparent magnetic pigments. Additionally, we have observed magnetization-induced second harmonic generation (MSHG). The nonlinear optical-magnetoelectric effect of the present polar magnetic nanocrystal was quite strong. These findings have been demonstrated in a simple iron oxide, which is highly significant from the viewpoints of economic cost and mass production. PMID- 26439918 TI - Prevalence of peripheral nervous system complications after major heart surgery. AB - We evaluated 374 consecutive patients from May 2013 to April 2014 who underwent major cardiac surgery. Each patient had an interview and a neurological clinical examination during the rehabilitation period. Patients with possible peripheral nervous system (PNS) complications underwent further electrodiagnostic tests. Among 374 patients undergoing major heart surgery (coronary artery bypass grafting, valvular heart surgery, ascending aortic aneurysm repair) 23 (6.1 %) developed 34 new PNS complications. We found four brachial plexopathies; four carpal tunnel syndromes; five critical illness neuropathies; three worsening of pre-existing neuropathies; two involvement of X, one of IX and one of XII cranial nerves; three peroneal (at knee), one saphenous, two median (at Struthers ligament), six ulnar (at elbow) mononeuropathies; two meralgia parestheticas. Diabetes is a strong risk factor for PNS complications (p = 0.002); we could not find any other relationship of PNS complications with clinical conditions, demographic data (gender, age) or type of surgical intervention. The mononeuropathies of right arms can be related to ipsilateral vein cannulation; position of body and stretching from chest wall retraction may be the cause of mononeuropathies of left arms (more frequent); the use of saphenous vein and position of the limbs may be the cause of mononeuropathies of the legs; surgical and anesthetical procedures can injure cranial nerves; respiratory failure and infection during the first days after surgery can cause critical illness neuropathies. Careful preoperative assessment and intraoperative management may reduce the risk of long-term PNS complications after cardiac surgery. PMID- 26439919 TI - The management of multiple sclerosis by reference centers in south of Italy: a 2011 survey on health demands and needs in Campania region. AB - This cross-sectional study has investigated the diagnostic and therapeutic management of patients suffering from multiple sclerosis (MS) in the Campania Region (Italy). A survey involving all the reference centers for MS in Campania Region was conducted from March to August 2011. Centers responded to a web administered questionnaire on management and clinical characteristics of MS patients. In the study period, 3263 patients (mean age 37 years, 66 % females) accessed the centers. Patients received a first diagnosis of MS in 161 cases (4.9 %). About 37 % of the subjects without a previous diagnosis came to the centers on their own initiative. All patients underwent a complete neurological examination and expanded disability status scale. The other most common investigations were magnetic resonance imaging (44.0 %) and evoked potentials (22.1 %). The number of treated patients was 2797 (87.1 %). The most used drugs were interferon beta and glatiramer acetate. The time between diagnosis and initiation of therapy exceeded 6 months in 32 % of cases. Second-line drugs were under-used: 16 % of patients who might benefit from them show high clinical and radiological disease activity despite treatment with immunomodulant drugs. The MS care management of the surveyed centers showed consistent margins for improvement in 2011. Even though these data do not represent the current situation, they can be used to monitor improvements in MS care. PMID- 26439917 TI - Cell Phone-Based and Adherence Device Technologies for HIV Care and Treatment in Resource-Limited Settings: Recent Advances. AB - Numerous cell phone-based and adherence monitoring technologies have been developed to address barriers to effective HIV prevention, testing, and treatment. Because most people living with HIV and AIDS reside in resource limited settings (RLS), it is important to understand the development and use of these technologies in RLS. Recent research on cell phone-based technologies has focused on HIV education, linkage to and retention in care, disease tracking, and antiretroviral therapy adherence reminders. Advances in adherence devices have focused on real-time adherence monitors, which have been used for both antiretroviral therapy and pre-exposure prophylaxis. Real-time monitoring has recently been combined with cell phone-based technologies to create real-time adherence interventions using short message service (SMS). New developments in adherence technologies are exploring ingestion monitoring and metabolite detection to confirm adherence. This article provides an overview of recent advances in these two families of technologies and includes research on their acceptability and cost-effectiveness when available. It additionally outlines key challenges and needed research as use of these technologies continues to expand and evolve. PMID- 26439915 TI - Neonicotinoid Residues in Wildflowers, a Potential Route of Chronic Exposure for Bees. AB - In recent years, an intense debate about the environmental risks posed by neonicotinoids, a group of widely used, neurotoxic insecticides, has been joined. When these systemic compounds are applied to seeds, low concentrations are subsequently found in the nectar and pollen of the crop, which are then collected and consumed by bees. Here we demonstrate that the current focus on exposure to pesticides via the crop overlooks an important factor: throughout spring and summer, mixtures of neonicotinoids are also found in the pollen and nectar of wildflowers growing in arable field margins, at concentrations that are sometimes even higher than those found in the crop. Indeed, the large majority (97%) of neonicotinoids brought back in pollen to honey bee hives in arable landscapes was from wildflowers, not crops. Both previous and ongoing field studies have been based on the premise that exposure to neonicotinoids would occur only during the blooming period of flowering crops and that it may be diluted by bees also foraging on untreated wildflowers. Here, we show that exposure is likely to be higher and more prolonged than currently recognized because of widespread contamination of wild plants growing near treated crops. PMID- 26439920 TI - The Mini Report: a Practical Tool to Address Lung Cancer Disparities in Rural Communities. AB - Community-based participatory research (CBPR) is an effective way to address cancer disparities in medically underserved populations. Our research demonstrates how CBPR principles were used to develop lung cancer and risk factor mini reports for a network of community coalitions in the Illinois Delta Region, a predominately rural region with high lung cancer disparities in southern Illinois. An academic-community partnership, including a community-based medical school, state public health department, and a healthcare system, used CBPR principles to translate epidemiological, behavioral, and demographic data into understandable, comprehensive, yet concise mini reports for each coalition. A cyclical and iterative process was used to draft, revise, and optimize these mini reports to raise awareness about lung cancer disparities in the community and to provide information to help guide the development of interventions that address these disparities. The use of CBPR principles was a successful way to create mini reports about local lung cancer disparities and risk factors that were usable in individual communities. Local coalitions used the mini reports to educate community members at local meetings, to guide strategic planning, and to disseminate information through their respective websites. Additionally, the process of creating these reports built trust among academic-community partners and provided additional avenues of engagement, such as the involvement of an academic partner in the strategic planning process of a local coalition. Using CBPR processes is an effective way to translate epidemiological data into a community-friendly format to address cancer disparities. PMID- 26439922 TI - Effects of Physical and Emotional Child Abuse and Its Chronicity on Crime Into Adulthood. AB - Analyses tested hypotheses that pertain to direct and indirect effects of parent reported physical and emotional abuse on later self-reported criminal behavior in a sample of 356 adults of a longitudinal study of more than 30 years. Childhood antisocial behavior was included in analyses as a potential mediator. Physical abuse only predicted adult crime indirectly through childhood antisocial behavior, whereas emotional abuse predicted adult outcome both directly and indirectly. Chronicity of physical abuse was indirectly related to later crime in a subsample test for those who had been physically abused (n=318), whereas chronicity of emotional abuse was neither directly nor indirectly related to adult crime in a test of those who had been emotionally abused (n=225). Implications for future research and practice are discussed. PMID- 26439924 TI - Correction: Derivation of Soil Ecological Criteria for Copper in Chinese Soils. PMID- 26439923 TI - Targeted Next-Generation Sequencing Revealed Novel Mutations in Chinese Ataxia Telangiectasia Patients: A Precision Medicine Perspective. AB - Ataxia telangiectasia (AT) is an autosomal recessive disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia and immunodeficiency due to mutations in the ATM gene. We performed targeted next-generation sequencing (NGS) on three unrelated patients and identified five disease-causing variants in three probands, including two pairs of heterozygous variants (FAT 1:c.4396C>T/p.R1466X, c.1608-2A>G; FAT-2:c.4412_4413insT/p.L1472Ffs*19, c.8824C>T/p.Q2942X) and one pair of homozygous variants (FAT-3: c.8110T>G/p.C2704G, Hom). With regard to precision medicine for rare genetic diseases, targeted NGS currently enables the rapid and cost-effective identification of causative mutations and is an updated molecular diagnostic tool that merits further optimization. This high-throughput data-based strategy would propel the development of precision diagnostic methods and establish a foundation for precision medicine. PMID- 26439921 TI - Uncovering Hidden Layers of Cell Cycle Regulation through Integrative Multi-omic Analysis. AB - Studying the complex relationship between transcription, translation and protein degradation is essential to our understanding of biological processes in health and disease. The limited correlations observed between mRNA and protein abundance suggest pervasive regulation of post-transcriptional steps and support the importance of profiling mRNA levels in parallel to protein synthesis and degradation rates. In this work, we applied an integrative multi-omic approach to study gene expression along the mammalian cell cycle through side-by-side analysis of mRNA, translation and protein levels. Our analysis sheds new light on the significant contribution of both protein synthesis and degradation to the variance in protein expression. Furthermore, we find that translation regulation plays an important role at S-phase, while progression through mitosis is predominantly controlled by changes in either mRNA levels or protein stability. Specific molecular functions are found to be co-regulated and share similar patterns of mRNA, translation and protein expression along the cell cycle. Notably, these include genes and entire pathways not previously implicated in cell cycle progression, demonstrating the potential of this approach to identify novel regulatory mechanisms beyond those revealed by traditional expression profiling. Through this three-level analysis, we characterize different mechanisms of gene expression, discover new cycling gene products and highlight the importance and utility of combining datasets generated using different techniques that monitor distinct steps of gene expression. PMID- 26439927 TI - Probing local pH-based precipitation processes in self-assembled silica-carbonate hybrid materials. AB - Crystallisation of barium carbonate in the presence of silica can lead to the spontaneous assembly of highly complex superstructures, consisting of uniform and largely co-oriented BaCO3 nanocrystals that are interspersed by a matrix of amorphous silica. The formation of these biomimetic architectures (so-called silica biomorphs) is thought to be driven by a dynamic interplay between the components, in which subtle changes of conditions trigger ordered mineralisation at the nanoscale. In particular, it has been proposed that local pH gradients at growing fronts play a crucial role in the process of morphogenesis. In the present work, we have used a special pH-sensitive fluorescent dye to directly trace these presumed local fluctuations by means of confocal laser scanning microscopy. Our data demonstrate the existence of an active region near the growth front, where the pH is locally decreased with respect to the alkaline bulk solution on a length scale of few microns. This observation provides fundamental and, for the first time, direct experimental support for the current picture of the mechanism underlying the formation of these peculiar materials. On the other hand, the absence of any temporal oscillations in the local pH - another key feature of the envisaged mechanism - challenges the notion of autocatalytic phenomena in such systems and raises new questions about the actual role of silica as an additive in the crystallisation process. PMID- 26439925 TI - Retracted article: In vitro derivation of mammalian germ cells from stem cells and their potential therapeutic application. AB - Pluripotent stem cells (PSCs) are a unique type of cells because they exhibit the characteristics of self-renewal and pluripotency. PSCs may be induced to differentiate into any cell type, even male and female germ cells, suggesting their potential as novel cell-based therapeutic treatment for infertility problems. Spermatogenesis is an intricate biological process that starts from self-renewal of spermatogonial stem cells (SSCs) and leads to differentiated haploid spermatozoa. Errors at any stage in spermatogenesis may result in male infertility. During the past decade, much progress has been made in the derivation of male germ cells from various types of progenitor stem cells. Currently, there are two main approaches for the derivation of functional germ cells from PSCs, either the induction of in vitro differentiation to produce haploid cell products, or combination of in vitro differentiation and in vivo transplantation. The production of mature and fertile spermatozoa from stem cells might provide an unlimited source of autologous gametes for treatment of male infertility. Here, we discuss the current state of the art regarding the differentiation potential of SSCs, embryonic stem cells, and induced pluripotent stem cells to produce functional male germ cells. We also discuss the possible use of livestock-derived PSCs as a novel option for animal reproduction and infertility treatment. PMID- 26439926 TI - Anchors as Semantic Primes in Value Construction: An EEG Study of the Anchoring Effect. AB - Previous research regarding anchoring effects has demonstrated that human judgments are often assimilated to irrelevant information. Studies have demonstrated that anchors influence the economic valuation of various products and experiences; however, the cognitive explanations of this effect remain controversial, and its neural mechanisms have rarely been explored. In the current study, we conducted an electroencephalography (EEG) experiment to investigate the anchoring effect on willingness to accept (WTA) for an aversive hedonic experience and the role of anchors in this judgment heuristic. The behavioral results demonstrated that random numbers affect participants' WTA for listening to pieces of noise. The participants asked for higher pay after comparing their WTA with higher numbers. The EEG results indicated that anchors also influenced the neural underpinnings of the valuation process. Specifically, when a higher anchor number was drawn, larger P2 and late positive potential amplitudes were elicited, reflecting the anticipation of more intensive pain from the subsequent noise. Moreover, higher anchors induced a stronger theta band power increase compared with lower anchors when subjects listened to the noises, indicating that the participants felt more unpleasant during the actual experience of the noise. The levels of unpleasantness during both anticipation and experience were consistent with the semantic information implied by the anchors. Therefore, these data suggest that a semantic priming process underlies the anchoring effect in WTA. This study provides proof for the robustness of the anchoring effect and neural evidence of the semantic priming model. Our findings indicate that activated contextual information, even seemingly irrelevant, can be embedded in the construction of economic value in the brain. PMID- 26439928 TI - Simulating Crop Evapotranspiration Response under Different Planting Scenarios by Modified SWAT Model in an Irrigation District, Northwest China. AB - Modelling crop evapotranspiration (ET) response to different planting scenarios in an irrigation district plays a significant role in optimizing crop planting patterns, resolving agricultural water scarcity and facilitating the sustainable use of water resources. In this study, the SWAT model was improved by transforming the evapotranspiration module. Then, the improved model was applied in Qingyuan Irrigation District of northwest China as a case study. Land use, soil, meteorology, irrigation scheduling and crop coefficient were considered as input data, and the irrigation district was divided into subdivisions based on the DEM and local canal systems. On the basis of model calibration and verification, the improved model showed better simulation efficiency than did the original model. Therefore, the improved model was used to simulate the crop evapotranspiration response under different planting scenarios in the irrigation district. Results indicated that crop evapotranspiration decreased by 2.94% and 6.01% under the scenarios of reducing the planting proportion of spring wheat (scenario 1) and summer maize (scenario 2) by keeping the total cultivated area unchanged. However, the total net output values presented an opposite trend under different scenarios. The values decreased by 3.28% under scenario 1, while it increased by 7.79% under scenario 2, compared with the current situation. This study presents a novel method to estimate crop evapotranspiration response under different planting scenarios using the SWAT model, and makes recommendations for strategic agricultural water management planning for the rational utilization of water resources and development of local economy by studying the impact of planting scenario changes on crop evapotranspiration and output values in the irrigation district of northwest China. PMID- 26439929 TI - PSMB4 expression associates with epithelial ovarian cancer growth and poor prognosis. AB - PURPOSE: In this study, we investigated the expression and role of PSMB4 in human epithelial ovarian cancer(EOC). METHODS: Western blot was used to evaluate the expression of PSMB4 in EOC tissues, and immunohistochemical analysis was performed on 115 cases of ovarian cancers. Then, we used Fisher exact test to analyze the correlation between PSMB4 and clinicopathological parameters. Starvation and re-feeding assay was used to assess cell cycle. CCK-8 assay and plate colony formation assay showed the influence of PSMB4 on proliferation of EOC cells. RESULTS: The expression of PSMB4 in EOC tissues was higher than normal ovary tissues and was significantly associated with clinical pathologic variables. Kaplan-Meier curve showed that high expression of PSMB4 was related to poor prognosis of EOC patients. Starvation and re-feeding assay suggested that PSMB4 played a critical role in EOC cell proliferation. CCK-8 assay and plate colony formation assay showed that EOC cells treated with PSMB4-siRNA reduced cell proliferation of EOC cells. Additionally, PSMB4 knockdown decreased NF kappaB activity. PSMB4 also regulated the expression of NF-kappaB mediated proteins, including cyclin D1, and cyclin E which involved in cell proliferation. CONCLUSIONS: Our findings implied that PSMB4 is involved in the progression of EOC and could serve as potential therapeutical target of EOC. These data suggested that PSMB4 may promote cell proliferation via the NF-kappaB-target gene in EOC. PMID- 26439931 TI - Influence of Solvation and Structural Contributions on Fluorescence of Dipyrrine Dyes. AB - The results of quantum-chemical and spectral researches of zinc((II)) complexes with alkylated dipyrrine and 3,3'-, 2,3'- and 2,2'-bis(dipyrrine)s in non-polar and polar solvents and their binary mixtures are presented. It was investigated the efficiency of the fluorescence quenching of fluorophores depending on of the solvation and structural contributions. Found that 3,3' bis(dipyrrinato)zinc((II)) demonstrates the highest sensitivity of the fluorescence to the presence of the electron-donor component compared with the studied complexes. The obtained results allow to offer dipyrrine and bis(dipyrrine) zinc((II)) complexes as new, highly sensitive and selective fluorescent sensors of the N- and O-containing toxicants. Graphical Abstract Influence of solvation and structural contributions on fluorescence of dipyrrine dyes. PMID- 26439930 TI - Determination of Some Non-sedating Antihistamines via Their Native Fluorescence and Derivation of Some Quantitative Fluorescence Intensity - Structure Relationships. AB - A validated simple, novel, and rapid spectrofluorimetric method was developed for the determination of some non-sedating antihistamines (NSAs); namely cetirizine (CTZ), ebastine (EBS), fexofenadine (FXD), and loratadine (LOR). The method is based on measuring the native fluorescence of the cited drugs after protonation in acidic media and studying their quantitative fluorescence intensity - structure relationships. There was a linear relationship between the relative fluorescence intensity and the concentration of the investigated drug. Under the optimal conditions, the linear ranges of calibration curves for the determination of the studied NSAs were 0.10-2.0, 0.20-6.0, and 0.02-1.0 [Formula: see text] for (CTZ, FXD), (EBS), and (LOR); respectively. The factors affecting the protonation of the studied drugs were carefully studied and optimized. The method was validated according to ICH guidelines. The suggested method is applicable for the determination of the four investigated drugs in bulk and pharmaceutical dosage forms with excellent recoveries (97.67-103.80%). Quantitative relationships were found between the relative fluorescence intensities of the protonated drugs and their physicochemical parameters namely: the pKa, log P, connectivity indexes (chi(v)) and their squares. Regression equations (76) were obtained and not previously reported. Six of these equations were highly significant and used for the prediction of RFI of the studied NSAs. PMID- 26439932 TI - The Chiropractic Care of Infants with Breastfeeding Difficulties. AB - OBJECTIVE: Chiropractors have long advocated on the benefits of breastfeeding and given the realized and potential role of chiropractors in the care of infants with breastfeeding difficulties, we performed this review of the literature on the subject to inform clinical practice. METHODS: For this article, we searched Pubmed [1966-2013], Manual, Alternative and Natural Therapy Index System (MANTIS) [1964-2013] and Index to Chiropractic Literature [1984-2013] for the relevant literature. The search terms utilized "breastfeeding", "breast feeding", "breastfeeding difficulties", "breastfeeding difficulty", "TMJ dysfunction", "temporomandibular joint", "birth trauma" and "infants", in the appropriate Boolean combinations. We also examined non-peer-reviewed articles as revealed by Index to Chiropractic Literature and secondary analysis of references. Inclusion criteria for review included breastfeeding difficulties regardless of peer-review and written in the English language. RESULTS: A total of 24 articles met our inclusion criteria. These consisted of 8 case reports, 2 case series, and 3 cohort studies. We were also able to identify 6 manuscripts (5 case reports and a case series) that involved breastfeeding difficulties as a secondary complaint. Our findings reveal a theoretical and clinical framework based on the detection of spinal and extraspinal subluxations involving the cervico-cranio-mandibular complex and assessment of the infant while breastfeeding. CONCLUSIONS: Chiropractors care of infants with breastfeeding difficulties by addressing spinal and extraspinal subluxations involving the cervico-cranio-mandibular complex. PMID- 26439933 TI - Spin-dependent recombination probed through the dielectric polarizability. AB - Despite residing in an energetically and structurally disordered landscape, the spin degree of freedom remains a robust quantity in organic semiconductor materials due to the weak coupling of spin and orbital states. This enforces spin selectivity in recombination processes which plays a crucial role in optoelectronic devices, for example, in the spin-dependent recombination of weakly bound electron-hole pairs, or charge-transfer states, which form in a photovoltaic blend. Here, we implement a detection scheme to probe the spin selective recombination of these states through changes in their dielectric polarizability under magnetic resonance. Using this technique, we access a regime in which the usual mixing of spin-singlet and spin-triplet states due to hyperfine fields is suppressed by microwave driving. We present a quantitative model for this behaviour which allows us to estimate the spin-dependent recombination rate, and draw parallels with the Majorana-Brossel resonances observed in atomic physics experiments. PMID- 26439934 TI - Association of a Human FABP1 Gene Promoter Region Polymorphism with Altered Serum Triglyceride Levels. AB - Liver fatty acid-binding protein (L-FABP), also known as fatty acid-binding protein 1 (FABP1), is a key regulator of hepatic lipid metabolism. Elevated FABP1 levels are associated with an increased risk of cardiovascular disease (CVD) and metabolic syndromes. In this study, we examine the association of FABP1 gene promoter variants with serum FABP1 and lipid levels in a Chinese population. Four promoter single-nucleotide polymorphisms (SNPs) of FABP1 gene were genotyped in a cross-sectional survey of healthy volunteers (n = 1,182) from Fuzhou city of China. Results showed that only the rs2919872 G>A variant was significantly associated with serum TG concentration(P = 0.032).Compared with the rs2919872 G allele, rs2919872 A allele contributed significantly to reduced serum TG concentration, and this allele dramatically decreased the FABP1 promoter activity(P < 0.05). The rs2919872 A allele carriers had considerably lower serum FABP1 levels than G allele carriers (P < 0.01). In the multivariable linear regression analysis, the rs2919872 A allele was negatively associated with serum FABP1 levels (beta = -0.320, P = 0.003), while serum TG levels were positively associated with serum FABP1 levels (beta = 0.487, P = 0.014). Our data suggest that compared with the rs2919872 G allele, the rs2919872 A allele reduces the transcriptional activity of FABP1 promoter, and thereby may link FABP1 gene variation to TG level in humans. PMID- 26439937 TI - Recasting the Callaway and von Baeyer thermal conductivity model on defective oxide materials: the ZnO-In2O3 system as an example. AB - Point defects and nanoscale interfaces effectively scatter short and mid-to-long wavelength phonons, respectively, thereby considerably reducing the thermal conductivity. In this paper, a classical physical model of phonon transport and scattering, the Callaway and von Bayer method, is recast with the introduction of the phonon mean free path cut-off, or equivalently, the minimum phonon relaxation time. To illustrate the method, we compute the thermal conductivity for the ZnO In2O3 binary system in which the compositionally dependent structure is available, including solid solutions consisting of point defects and natural superlattices. The calculated thermal conductivity is in good agreement with the experimental measurements, and suggests a threshold value of about 50 nm for the interface spacing, above which the thermal conductivity becomes less sensitive to the interfaces with increasing temperature. A useful design clue is implied for the nanostructural engineering of high temperature thermoelectrics and thermal barrier coatings. PMID- 26439935 TI - Accuracy of QuantiFERON-TB Gold Test for Tuberculosis Diagnosis in Children. AB - OBJECTIVES: To evaluate the accuracy of the QuantiFERON-TB Gold assay (QFT-IT) in children with suspected active or latent TB infection (LTBI). METHODS: A retrospective study was conducted on 621 children (0-14 years old) evaluated for TB infection or disease. Following clinical assessment, children were tested with the QFT-IT assay. RESULTS: Among the 140 active TB suspects, we identified 19 cases of active disease. The overall sensitivity for active TB was 87.5%, ranging from 62.5% in children 25-36 months old to 100% in children older than 49 months. The overall specificity for active TB was 93.6%. Among the 481 children tested for LTBI screening, 38 scored positive and all but 2 had at least one risk factor for TB infection. Among the 26 children with indeterminate results, bacterial, viral or fungal pneumonia were later diagnosed in 11 (42.3%) cases and non-TB related extra-pulmonary infections in 12 (46.1%). CONCLUSIONS: Our results indicate that the children's response to QFT-IT associates to active TB and risk factors for LTBI. Moreover, we show that mitogen response is also found in children of 1 year of age, providing support for QFT-IT use also in young children. PMID- 26439936 TI - Safety Profile of the Use of Iodopovidone for Pleurodesis in Patients with Malignant Pleural Effusion. AB - BACKGROUND: Iodopovidone is an alternative agent used to promote pleurodesis in patients with malignant pleural effusion (MPE). However, safety is a concern, and many authors still reject its use. OBJECTIVES: Our main objective is to describe the occurrence of common and severe adverse events after pleurodesis with two different doses of iodopovidone in patients with MPE. Our secondary objective is to evaluate dose dependency, efficacy, quality of life, and systemic inflammation. METHODS: We conducted a double-blind, randomized clinical trial including patients with recurrent MPE. Patients underwent chest tube insertion and were randomized into two groups according to the doses of iodopovidone: group 1 received 1% iodopovidone, and group 2 received 2% iodopovidone. During follow up, adverse events, inflammatory markers, quality of life, and imaging exams were systematically evaluated and registered. RESULTS: Sixty patients were analyzed (55 females, 5 males, median age 55.9 years). Overall, 227 adverse events possibly related to pleurodesis were registered, including 47 serious adverse events (in 34 patients). Pleuritic pain and hypertensive peaks were the most frequently observed serious adverse events (11 and 10 episodes, respectively). Grade 3/4 metabolic events such as hyponatremia and an increase in alkaline phosphatase, AST and ALT levels were also common. C-reactive protein (CRP) levels increased substantially and peaked 48 h after pleurodesis. No difference was observed between groups with regard to adverse events, CRP levels, efficacy, or quality of life. CONCLUSIONS: Adverse events after iodopovidone pleurodesis in patients with MPE are common and similar in the two doses studied. PMID- 26439938 TI - Locally-constrained boundary regression for segmentation of prostate and rectum in the planning CT images. AB - Automatic and accurate segmentation of the prostate and rectum in planning CT images is a challenging task due to low image contrast, unpredictable organ (relative) position, and uncertain existence of bowel gas across different patients. Recently, regression forest was adopted for organ deformable segmentation on 2D medical images by training one landmark detector for each point on the shape model. However, it seems impractical for regression forest to guide 3D deformable segmentation as a landmark detector, due to large number of vertices in the 3D shape model as well as the difficulty in building accurate 3D vertex correspondence for each landmark detector. In this paper, we propose a novel boundary detection method by exploiting the power of regression forest for prostate and rectum segmentation. The contributions of this paper are as follows: (1) we introduce regression forest as a local boundary regressor to vote the entire boundary of a target organ, which avoids training a large number of landmark detectors and building an accurate 3D vertex correspondence for each landmark detector; (2) an auto-context model is integrated with regression forest to improve the accuracy of the boundary regression; (3) we further combine a deformable segmentation method with the proposed local boundary regressor for the final organ segmentation by integrating organ shape priors. Our method is evaluated on a planning CT image dataset with 70 images from 70 different patients. The experimental results show that our proposed boundary regression method outperforms the conventional boundary classification method in guiding the deformable model for prostate and rectum segmentations. Compared with other state of-the-art methods, our method also shows a competitive performance. PMID- 26439939 TI - Tamarind seed coat ameliorates fluoride induced cytotoxicity, oxidative stress, mitochondrial dysfunction and apoptosis in A549 cells. AB - Fluoride (F) is an environmental contaminant and industrial pollutant. Molecular mechanisms remain unclear in F induced pulmonary toxicity even after numerous studies. Tamarind fruits act as defluoridating agents, but no study was conducted in in vitro systems. Hence, we aimed to assess the ameliorative impact of the tamarind seed coat extract (TSCE) against F toxicity utilizing lung epithelial cells, A549. Cells were exposed to sodium fluoride (NaF-5 mM) alone and in combination with TSCE (750 ng/ml) or Vitamin C (positive control) for 24 h and analyzed for F content, intracellular calcium ([Ca(2+)]i) level, oxidative stress, mitochondrial integrity and apoptotic markers. TSCE treatment prevented the F induced alterations in [Ca(2+)]i overload, F content, oxidant (reactive oxygen species generation, lipid peroxidation, protein carbonyl content and nitric oxide) and antioxidant (superoxide dismutase, catalase, glutathione peroxidase and glutathione) parameters. Further, TSCE modulates F activated changes in mitochondrial membrane potential, permeability transition pore opening, cytochrome-C release, Bax/Bcl-2 ratio, caspase-3 and PARP-1 expressions. In conclusion, our study demonstrated that TSCE as a potential protective agent against F toxicity, which can be utilized as a neutraceutical. PMID- 26439940 TI - Highly efficient single cell arraying by integrating acoustophoretic cell pre concentration and dielectrophoretic cell trapping. AB - To array rare cells at the single-cell level, the volumetric throughput may become a bottleneck in the cell trapping and the subsequent single-cell analysis, since the target cells per definition commonly exist in a large sample volume after purification from the original sample. Here, we present a novel approach for high throughput single cell arraying by integrating two original microfluidic devices: an acoustofluidic chip and an electroactive microwell array. The velocity of the cells is geared down in the acoustofluidic chip while maintaining a high volume flow rate at the inlet of the microsystem, and the cells are subsequently trapped one by one into the microwell array using dielectrophoresis. The integrated system exhibited a 10 times improved sample throughput compared to trapping with the electroactive microwell array chip alone, while maintaining a highly efficient cell recovery above 90%. The results indicate that the serial integration of the acoustophoretic pre-concentration with the dielectrophoretic cell trapping drastically improves the performance of the electroactive microwell array for highly efficient single cell analysis. This simple and effective system for high throughput single cell arraying with further possible integration of additional functions, including cell sorting and downstream analysis after cell trapping, has potential for development to a highly integrated and automated platform for single-cell analysis of rare cells. PMID- 26439941 TI - Lower Hydrogen Sulfide Is Associated with Cardiovascular Mortality, Which Involves cPKCbetaII/Akt Pathway in Chronic Hemodialysis Patients. AB - BACKGROUND/AIMS: To evaluate the relationship between plasma hydrogen sulfide (H2S) and cardiovascular risk markers, including pulse pressure (PP), left ventricular mass index (LVMI) and intima-media thickness (IMT), and mortality in chronic hemodialysis (CHD) patients and further investigate the underlying cardiovascular protection mechanism of H2S. METHODS: CHD patients, 113 of them, were studied. Plasma H2S was measured through zinc acetate reaction. cPKCbetaII membrane translocation and phosphorylation of Akt were detected by western blot. RESULTS: Lower plasma H2S level in CHD patients was predictor of an increased PP, LVMI and IMT. Patients with lower H2S had a lower survival at the end of the study. H2S was an independent predictor of all-cause and cardiovascular mortality when adjusted for other risk factors. CHD patients with lower H2S showed an increase of cPKCbetaII activation, but phosphorylation of Akt decreased. The level of VCAM-1 and ICAM-1 increased significantly. CONCLUSIONS: Lower plasma H2S in CHD patients is associated with cardiovascular risk factors and mortality, which may be mediated by the cPKCbetaII/Akt pathway and further VCAM-1/ICAM-1 upregulation. PMID- 26439942 TI - Longitudinal Assessment of Blood Pressure in School-Aged Children: A 3-Year Follow-Up Study. AB - The purpose of this study was to assess the prevalence of abnormal blood pressure in a population of school children during a 3-year follow-up period and its relationship with obesity. Anthropometric and blood pressure data were collected from a population of Italian school children during three consecutive years. During each year blood pressure measurements were repeated three times, at intervals of 1 week. A total of 564 school-children [311 boys; mean (SD) age 8.8 +/- 1.4 years] were recruited. During each year, systolic and diastolic blood pressure decreased from visit 1 to visit 3 (p < 0.001). This was associated with a decline in the percentage of prehypertension/hypertension from visit 1 to visit 3. An abnormal blood pressure value in at least one study visit was found in 8.8 17 % of children, whereas the prevalence of hypertension at all three study visits was between 5.2 and 7.8 %, and that of prehypertension at all three visits was between 2.8 and 3.8 %. High blood pressure was more frequent in obese children. In this population of school children the percentage of prehypertension/hypertension remarkably varied when based on one versus three annual assessments, thus emphasizing the importance of repeated measurement before making a diagnosis of abnormal blood pressure. Adiposity was confirmed to be a determinant of high blood pressure. PMID- 26439943 TI - Exercise Performance in Patients with D-Loop Transposition of the Great Arteries After Arterial Switch Operation: Long-Term Outcomes and Longitudinal Assessment. AB - The first patients to undergo a successful arterial switch operation (ASO) for d transposition of the great arteries (D-TGA) are now entering their fourth decade of life. Past studies of ASO survivors' exercise function have yielded conflicting results. We therefore undertook this study to describe the current function of ASO survivors, to identify factors related to inferior exercise performance and to determine whether their exercise function tends to deteriorate over time. A retrospective cohort study was designed examining all patients with D-TGA after the ASO who underwent comprehensive cardiopulmonary exercise testing (CPET). Patients with palliative surgery prior to ASO, ventricular hypoplasia or severe valvar dysfunction were excluded from the study. Data from CPETs in which the peak respiratory exchange ratio was <1.09 were also excluded. We identified 113 patients who met entry criteria and had 186 CPX at our institution between 1/2002 and 1/2013; 41 patients had at least 2 qualifying CPX. Mean age at the time of the initial test was 17 +/- 1 year. Peak oxygen consumption (VO2) averaged 84 +/- 2 % predicted. Peak VO2 was lower among patients with repaired ventricular septal defects (82 +/- 4 vs. 86 +/- 3 % predicted; p < 0.05) and among patients with >= moderate right-sided obstructive lesions (77 +/- 5 vs. 87 +/- 3 % predicted; p < 0.05). Surgery prior to 1991 was also associated with a lower peak VO2 (81 +/- 3 vs. 87 +/- 3 % predicted; p < 0.01). The mean % predicted peak heart rate was 92 +/- 1 %, with no significant difference between any of the subgroups. Non-diagnostic exercise-induced STT changes developed in 10 patients (12 studies). In the subgroup with at least 2 exercise tests, the annual decline in % predicted peak VO2 was quite slow (-0.3 % points/year; p < 0.01 vs. expected normal age-related decline). The exercise capacity of ASO survivors is well preserved and is only mildly reduced compared to normal subjects. Moreover, there is only a slight deterioration in exercise capacity over time. VSD repair, residual right-sided obstructive lesions, and earlier surgical era are associated with worse exercise performance. Peak heart rate was preserved with no significant change in follow up testing. PMID- 26439944 TI - What is a clinically important change in the Unified Dyskinesia Rating Scale in Parkinson's disease? AB - INTRODUCTION: Dyskinesia remain a significant problem in Parkinson Disease (PD). The translation process of novel drug targets for dyskinesia has proven difficult with several failures at phase III level. Determining the 'clinically important change' (CIC) for dyskinesia rating scales in phase II clinical trials may assist in optimizing drug development of new anti-dyskinetic treatments. We used a standard phase IIa acute levodopa infusion paradigm to determine for the first time the CIC for dyskinesia using the new UDysRS. METHODS: We performed a randomized, double-blind, placebo-controlled crossover study with eleven PD patients with stable bothersome dyskinesia. We used the following patient reported clinically important events as CIC anchors: onset, maximum intensity, remission of dyskinesia. Objective dyskinesia scores using the UDysRS part III Impairment were determined at these same events by blinded video-rating. The CIC was determined using the 'within-patient' score change and a sensitivity- and specificity-based approach. RESULTS: Patients were most aware of 'onset of dyskinesia', followed by 'remission of dyskinesia'. An 11.1-point median change (UDysRS Part III Impairment, p < 0.0001) was the CIC for patient-reported remission of dyskinesia from a practically defined-OFF state. A 2.32-point change (UDysRS Part III Impairment) had the best specificity and sensitivity to distinguish between patient-reported remission and perception of dyskinesia. CONCLUSIONS: In this study, we provide the first report of a CIC for the UDysRS Part III Impairment. Early knowledge of a CIC may help inform the decision to advance into phase III trials and contribute for a higher yield of success in finding new anti-dyskinetic treatments. PMID- 26439945 TI - Exercise-induced neuroplasticity in human Parkinson's disease: What is the evidence telling us? AB - INTRODUCTION: While animal models of exercise and PD have pushed the field forward, few studies have addressed exercise-induced neuroplasticity in human PD. METHOD: As a first step toward promoting greater international collaboration on exercise-induced neuroplasticity in human PD, we present data on 8 human PD studies (published between 2008 and 2015) with 144 adults with PD of varying disease severity (Hoehn and Yahr stage 1 to stage 3), using various experimental (e.g., randomized controlled trial) and quasi-experimental designs on the effects of cognitive and physical activity on brain structure or function in PD. We focus on plasticity mechanisms of intervention-induced increases in maximal corticomotor excitability, exercise-induced changes in voxel-based gray matter volume changes and increases in exercise-induced serum levels of brain derived neurotrophic factor (BDNF). Finally, we provide a future perspective for promoting international, collaborative research on exercise-induced neuroplasticity in human PD. CONCLUSION: An emerging body of evidence suggests exercise triggers several plasticity related events in the human PD brain including corticomotor excitation, increases and decreases in gray matter volume and changes in BDNF levels. PMID- 26439947 TI - Optimizing diagnosis in Parkinson's disease: Radionuclide imaging. AB - Parkinson's disease (PD) and other disorders characterized by basal ganglia dysfunction are often associated with limited structural imaging changes that might assist in the clinical or research setting. Radionuclide imaging has been used to assess characteristic functional changes. Presynaptic dopaminergic dysfunction in PD can be revealed through the imaging of different steps in the process of dopamine synthesis and storage: L-aromatic amino acid decarboxylase (AADC) activity, Vesicular Monoamine Transporter type 2 (VMAT2) binding or its reuptake via the dopamine transporter (DAT). Postsynaptic dopamine dysfunction can also be studied with a variety of different tracers that primarily assess D2 like dopamine receptor availability. The function of other neurotransmitters such as norepinephrine, serotonin and acetylcholine can be imaged as well, giving important information about the underlying pathophysiologic process of PD and its complications. The imaging of metabolic activity and pathologic changes has also provided great advances in the field. Together, these techniques have allowed for a better understanding of PD, may be of aid for differentiating PD from other forms of parkinsonism and will undoubtedly be useful for the establishment of new therapeutic targets. PMID- 26439946 TI - Biomarkers in Parkinson's disease: Advances and strategies. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive motor disturbances and affects more than 1% of the worldwide population. Despite considerable progress in understanding PD pathophysiology, including genetic and biochemical causes, diagnostic approaches lack accuracy and interventions are restricted to symptomatic treatments. PD is a complex syndrome with different clinical subtypes and a wide variability in disorder course. In order to deliver better clinical management of PD patients and discovery of novel therapies, there is an urgent need to find sensitive, specific, and reliable biomarkers. The development of biomarkers will not only help the scientific community to identify populations at risk, but also facilitate clinical diagnosis. Furthermore, these tools could monitor progression, which could ultimately deliver personalized therapeutic strategies. The field of biomarker discovery in PD has attracted significant attention and there have been numerous contributions in recent years. Although none of the parameters have been validated for clinical practice, some candidates hold promise. This review summarizes recent advances in the development of PD biomarkers and discusses new strategies for their utilization. PMID- 26439948 TI - Stiffness of Hydrogels Regulates Cellular Reprogramming Efficiency Through Mesenchymal-to-Epithelial Transition and Stemness Markers. AB - The stiffness of hydrogels has been reported to direct cell fate. Here, we found that the stiffness of hydrogels promotes the reprogramming of mouse embryonic fibroblasts into induced pluripotent stem cells (iPSCs). We prepared cell culture substrates of various stiffnesses (0.1, 1, 4, 10, and 20 kPa) using a polyacrylamide hydrogel. We found that culture on a soft hydrogel plays an important role in inducing cellular reprogramming into iPSCs via activation of mesenchymal-to-epithelial transition and enhancement of stemness marker expression. These results suggest that physical signals at the interface between cell and substrate can be used as a potent regulator to promote cell fate changes associated with reprogramming into iPSCs, which may lead to effective and reproducible iPSC-production. PMID- 26439950 TI - The functional organization of motor nerve terminals. AB - Neuromuscular junctions (NMJs) have long been studied as particularly accessible examples of chemical synapses. Nonetheless, some important features of neuromuscular transmission are still poorly understood. One of these is the low statistical variability of the number of transmitter quanta released from motor nerve terminals by successive nerve impulses. This variability is well-described by a binomial distribution, suggesting that the quanta released are drawn, at high probability, from a small subset of those in the terminals. However, the nature of that subset remains unclear. In an effort to clarify what is understood, and what is not, about quantal release at NMJs, this review addresses the relationship between NMJ structure and function. After setting the biological context in which NMJs operate, key aspects of the variability of release and the structure of the motor nerve terminals are described. These descriptions are then used to explore the functional logic of motor nerve terminal organization and the structural basis of the low variability of release. This analysis supports the suggestion that the probability of release differs significantly at the different 'active zones' from which quanta are released. Finally, after a brief consideration of how release is maintained in the long term, a comparison is made of the features of NMJs with those of some well-studied neuronal synapses. An important conclusion is that NMJs share some important features with neuronal synapses, so continuing efforts to understand how motor nerve terminals work are likely to have much more general implications. PMID- 26439949 TI - Tumor-induced solid stress activates beta-catenin signaling to drive malignant behavior in normal, tumor-adjacent cells. AB - Recent work by Fernandez-Sanchez and coworkers examining the impact of applied pressure on the malignant phenotype of murine colon tissue in vivo revealed that mechanical perturbations can drive malignant behavior in genetically normal cells. Their findings build upon an existing understanding of how the mechanical cues experienced by cells within a tissue become progressively modified as the tissue transforms. Using magnetically stimulated ultra-magnetic liposomes to mimic tumor growth -induced solid stress, Fernandez-Sanchez and coworkers were able to stimulate beta-catenin to promote the cancerous behavior of both a normal and genetically modified colon epithelium. In this perspective, we discuss their findings in the context of what is currently known regarding the role of the mechanical landscape in cancer progression and beta-catenin as a mechanotransducer. We review data that suggest that mechanically regulated activation of beta-catenin fosters development of a malignant phenotype in tissue and predict that mechanical cues may contribute to tumor heterogeneity. PMID- 26439951 TI - Serum insulin-like growth factor-I and amyloid beta protein in Alzheimer's disease: relationship with cognitive function. AB - AIMS: Previous studies have suggested that insulin-like growth factor-I (IGF-I) deficiency may lead to cognitive deficits in neurodegenerative diseases such as Alzheimer's disease. The present study aimed to investigate the possible relationship between cognitive function and concentration of IGF-I or amyloid beta protein (Abeta) in serum in Alzheimer's patients. METHODS: A total of 81 Japanese patients were enrolled in this study. Concentrations of IGF-I, Abeta42, and Abeta40 in serum were measured. Two neuropsychological tests, Mini-Mental State Examination and Hasegawa's Dementia Scale-Revised (HDS-R), were also performed. Linear correlations among the age, serum IGF-I, serum Abeta42 or Abeta40, Abeta42/Abeta40 ratio, Mini-Mental State Examination or HDS-R total score, and the scores for six HDS-R subscales were analyzed by regression analysis. RESULTS: IGF-I showed a significant negative correlation with age (beta = -0.357, P = 0.002) and a positive correlation with Abeta42/Abeta40 ratio (beta = 0.318, P = 0.007). Serum IGF-I and both the Mini-Mental State Examination and the HDS-R total score also correlated (beta = 0.505, beta = 0.524, P < 0.01). Among the HDS-R subscales, 'Recall' (rho = 0.379, P < 0.01), 'Verbal fluency' (rho = 0.360, P < 0.01), and 'Attention and calculation' (rho = 0.389, P < 0.01) showed significant positive correlations with serum IGF-I. CONCLUSION: The results, specifically that lower serum IGF-I was associated with cognitive impairment, suggest that metabolism of IGF-I may be involved in the pathogenesis of cognitive deficits in Alzheimer's disease. PMID- 26439952 TI - Trajectories of subcortical volume change in schizophrenia: A 5-year follow-up. PMID- 26439953 TI - Catalytic autoantibodies against myelin basic protein (MBP) isolated from serum of autistic children impair in vitro models of synaptic plasticity in rat hippocampus. AB - Autoantibodies from autistic spectrum disorder (ASD) patients react with multiple proteins expressed in the brain. One such autoantibody targets myelin basic protein (MBP). ASD patients have autoantibodies to MBP of both the IgG and IgA classes in high titers, but no autoantibodies of the IgM class. IgA autoantibodies act as serine proteinases and degrade MBP in vitro. They also induce a decrease in long-term potentiation in the hippocampi of rats either perfused with or previously inoculated with this IgA. Because this class of autoantibody causes myelin sheath destruction in multiple sclerosis (MS), we hypothesized a similar pathological role for them in ASD. PMID- 26439954 TI - Autoantibodies against vinculin in patients with chronic inflammatory demyelinating polyneuropathy. AB - To identify the target molecules of chronic inflammatory demyelinating polyneuropathy (CIDP), we used proteomic-based approach in the extracted proteins from porcine cauda equina. Two of 31 CIDP patients had markedly elevated serum autoantibodies against vinculin, a cell adhesion protein. Both of the patients with anti-vinculin antibodies had similar clinical manifestation, which are compatible with those of "typical" CIDP. Immunocytochemistry showed that vinculin was stained at the myelin sheath of the sciatic nerves by serum samples. Our results suggest that vinculin is a possible immunological target molecule in a subpopulation of typical CIDP patients. PMID- 26439955 TI - Increased serum peroxiredoxin 5 levels in myasthenia gravis. AB - Extracellular peroxiredoxin 5 (PRX5) is known to be an inflammatory mediator. The serum PRX5 levels of 40 patients with anti-acetylcholine receptor antibody positive MG and those of 40 controls were measured. PRX5 levels in patients with MG were higher than those in the controls (P=0.045). Thymoma-associated MG patients showed higher PRX5 levels than late-onset MG patients and controls (P<0.05). There were significant associations between the serum PRX5 levels and high mobility group box 1 levels. PRX5 elevation in MG could be related to the neuromuscular junction breakdown and plays a pivotal role in the pathogenic inflammation of MG. PMID- 26439956 TI - Heat shock protein 70 (Hsp70) interacts with the Notch1 intracellular domain and contributes to the activity of Notch signaling in myelin-reactive CD4 T cells. AB - Notch receptors (Notch1-4) are involved in the differentiation of CD4 T cells and the development of autoimmunity. Mechanisms regulating Notch signaling in CD4 T cells are not fully elucidated. In this study we investigated potential crosstalk between Notch pathway molecules and heat shock protein 70 (Hsp70), the major intracellular chaperone involved in the protein transport during immune responses and other stress conditions. Using Hsp70(-/-) mice we found that Hsp70 is critical for up-regulation of NICD1 and induction of Notch target genes in Jagged1- and Delta-like1-stimulated CD4 T cells. Co-immunoprecipitation analysis of wild-type CD4 T cells stimulated with either Jagged1 or Delta-like1 showed a direct interaction between NICD1 and Hsp70. Both molecules co-localized within the nucleus of CD4 T cells stimulated with Notch ligands. Molecular interaction and nuclear colocalization of NICD1 and Hsp70 were also detected in CD4 T cells reactive against myelin oligodendrocyte glycoprotein (MOG)35-55, which showed Hsp70-dependent up-regulation of both NICD1 and Notch target genes. In conclusion, we demonstrate for the first time that Hsp70 interacts with NICD1 and contributes to the activity of Notch signaling in CD4 T cells. Interaction between Hsp70 and NICD1 may represent a novel mechanism regulating Notch signaling in activated CD4 T cells. PMID- 26439957 TI - Hypertrophic pachymeningitis accompanying neuromyelitis optica spectrum disorder: A case report. AB - We report a case of idiopathic cerebral hypertrophic pachymeningitis accompanying neuromyelitis optica spectrum disorder. No other identifiable cause of pachymeningitis was detected. Corticosteroid therapy was effective for both diseases. Hypertrophic pachymeningitis is closely related to autoimmune inflammatory disease of the central nervous system. This case supports the hypothesis that hypertrophic pachymeningitis can be a rare comorbidity of neuromyelitis optica spectrum disorder. PMID- 26439958 TI - Favorable outcome of granulocyte colony-stimulating factor use in neuromyelitis optica patients presenting with agranulocytosis in the setting of rituximab. AB - Neuromyelitis optica is a severe autoimmune condition affecting the central nervous system characterized by a relapsing disease course. Rituximab is a chimeric monoclonal antibody against the protein CD20, and is one of the most utilized medications for management of this disease. A known complication of rituximab use is neutropenia. We report on two patients who developed symptomatic early-onset rituximab-induced agranulocytosis who safely received granulocyte colony-stimulating factor. Neutrophil counts recovered quickly and both patients continue to receive rituximab without further incident. PMID- 26439959 TI - Clinico-pathological correlation in adenylate kinase 5 autoimmune limbic encephalitis. AB - Autoantibodies associated with autoimmune limbic encephalitis (ALE) have been well-characterized, with intracellular neuronal antibodies being less responsive to immunotherapy than antibodies to cell surface antigens. Adenylate kinase 5 (AK5) is a nucleoside monophosphate kinase vital for neuronal-specific metabolism and is located intracellularly in the cytosol and expressed exclusively in the brain. Antibodies to AK5 had been previously identified but were not known to be associated with human disease prior to the report of two patients with AK5 related ALE (Tuzun et al., 2007). We present the complete clinical picture for one of these patients and the first reported neuropathology for AK5 ALE. PMID- 26439961 TI - Experimental autoimmune encephalomyelitis and age-related correlations of NADPH oxidase, MMP-9, and cell adhesion molecules: The increased disease severity and blood-brain barrier permeability in middle-aged mice. AB - The aim of the present study was to investigate effect of two different ages (6 weeks [6 W] vs. 6 months [6 M]) on blood-brain barrier (BBB) disruption in EAE and evaluate the expression and correlations of NADPH oxidase, MMP-9, ICAM-1, and VCAM-1 following increased age and EAE induction. Higher disease severity was observed in 6 M-EAE than 6 W-EAE. The four factors were significantly elevated and correlated in 6 M-EAE. BBB permeability increased with statistically significant interaction between age and EAE effects. We suggest strong correlations between NADPH oxidase and the other factors play important roles in increased BBB disruption and EAE susceptibility in middle-aged mice. PMID- 26439962 TI - Alzheimer's disease vaccine development: A new strategy focusing on immune modulation. AB - Despite significant advances in the development of Alzheimer's disease (AD) vaccines effective in animal models, these prototypes have been clinically unsuccessful; apparently the result of using immunogens modified to prevent inflammation. Hence, a new paradigm is needed that uses entire AD-associated immunogens, a notion supported by recent successful passive immunotherapy results, with adjuvants that induce Th2-only while inhibiting without abrogating Th1 immunity. Here, we discuss the obstacles to AD vaccine development and Th2 adjuvants that by acting on dendritic and T cells, would elicit regardless of the antigen a safe and effective antibody response, while preventing damaging neuroinflammation and ameliorating immunosenescence. PMID- 26439960 TI - Gelsolin decreases actin toxicity and inflammation in murine multiple sclerosis. AB - Gelsolin is the fourth most abundant protein in the body and its depletion in the blood has been found in multiple sclerosis (MS) patients. How gelsolin affects the MS brain has not been studied. We found that while the secreted form of gelsolin (pGSN) decreased in the blood of experimental autoimmune encephalomyelitis (EAE) mice, pGSN concentration increased in the EAE brain. Recombinant human pGSN (rhp-GSN) decreased extracellular actin and myeloperoxidase activity in the brain, resulting in reduced disease activity and less severe clinical disease, suggesting that gelsolin could be a potential therapeutic target for MS. PMID- 26439963 TI - Higher expression of IL-12Rbeta2 is associated with lower risk of relapse in relapsing-remitting multiple sclerosis patients on interferon-beta1b therapy during 3-year follow-up. AB - Cytokines produced by helper T (Th)1 cells, Th17 and regulatory T cells (Treg) are involved in multiple sclerosis (MS) immunopathogenesis. Interferon (IFN)-beta alters the numerous genes' expression, but how this alteration affects the treatment response is still elusive. We assessed relative gene expression of nineteen Th1/Th17/Treg-associated mediators in peripheral blood mononuclear cells and plasma levels of GM-CSF, IL-17A and IL-17F, in relapsing-remitting MS (RRMS) patients before IFN-beta1b treatment initiation and at 6, 12, 24 and 36 months of therapy. All mRNA levels changed significantly during the IFN-beta1b therapy. Higher IL-12Rbeta2 mRNA levels were associated with lower risk of relapse. Despite recent reports regarding role of GM-CSF in MS, our study failed to demonstrate its significance as therapy response biomarker, both on the mRNA and protein level. PMID- 26439964 TI - Recombinant adenovirus encoding NLRP3 RNAi attenuate inflammation and brain injury after intracerebral hemorrhage. AB - Numerous evidence have shown that microglia mediated inflammation plays a pivotal role in the development of brain injury after intracerebral hemorrhage (ICH). Therefore anti-inflammation therapy represents a potentially promising approach to ICH. Recently, NLRP3 inflammasome was discovered to facilitate the inflammatory response. However, the effect of NLRP3 inflammasome after ICH has not been fully studied. To explore the potential of NLRP3 inflammasome, we detected NLRP3 expression, inflammation, brain edema and neurological functions in vitro and in vivo. We found that ICH activated the NLRP3 inflammasome and inflammation. However, NLRP3 RNAi could attenuate inflammation and brain injury after ICH. Therefore, the findings suggested that recombinant adenovirus encoding NLRP3 RNAi might be valuable as a potential strategy for anti-inflammation therapy in ICH. PMID- 26439965 TI - Upregulation of integrin expression on monocytes in multiple sclerosis patients treated with natalizumab. AB - Natalizumab is a humanized monoclonal antibody against the alpha4 subunit of VLA 4 integrin that is used to treat conditions such as multiple sclerosis (MS). Although its effects on lymphocytes have been widely described, little is known about its effects on monocytes. Here we described the effects of natalizumab treatment on peripheral blood monocytes from a small cohort of MS patients in terms of relative frequencies and surface integrin (CD49d and CD18) expression. We showed that natalizumab treatment altered the surface integrin expression on monocyte subsets in the peripheral compartment, suggesting a role for them as mediators of natalizumab effects. PMID- 26439966 TI - Role of inflammation and apoptosis in multiple sclerosis: Comparative analysis between the periphery and the central nervous system. AB - Multiple sclerosis (MS) is a complex, multifactorial disease associated with damage to the axonal myelin sheaths and neuronal degeneration. The pathognomonic event in MS is oligodendrocyte loss accompanied by axonal damage, blood-brain barrier leakage, inflammation and infiltration of immune cells. The etiopathogenesis of MS is far from being elucidated. However, increasing evidence suggests that the inflammatory and apoptotic responses, occurring in patients either at the peripheral level or the central nervous system (CNS), can play a role. In this review, we give a comprehensive picture of general aspects of inflammation and apoptosis in MS, with special emphasis on the until now not well highlighted possible links between phenomena relevant to these aspects occurring in either the periphery or in the CNS during MS. PMID- 26439967 TI - Neurocognitive function, brain-derived neurotrophic factor (BDNF) and IL-6 levels in cancer patients with depression. AB - BACKGROUND: Increased IL-6 and decreased brain-derived neurotrophic factor (BDNF) levels have been implicated in the pathophysiology of depression. The objective was to assess the influence of BDNF and IL-6 on cognitive function and depression in patients with cancer. METHODS: Serum BDNF and plasma IL-6 were measured in patients with metastatic cancer. Diagnosis of depression was established according to DSM-IV criteria. Cognitive function was assessed by the Verbal Learning and Memory Test (VLMT). RESULTS: A total of 59 patients were recruited in this study. Only IL-6 levels were significantly elevated in patients with clinical depression (35.7 vs. 6.9 pg/ml; p<0.001). There were no differences in hemoglobin levels (p=0.3) or BDNF levels (p=0.16). Patients with clinical depression showed significant impairment of short-term memory (STM) (24.4 vs. 37.5; p=0.01), but not of long-term memory (LTM) (3.9 vs. 2.8; p=0.3). STM was dependent on the level of BDNF and younger age (b=0.60; p=0.001; b= -0.63; p=0.003, respectively). IL-6 was not only strongly associated with depression, but was an independent predictor of BDNF level as well (b= -0.50; p=0.01). LTM was associated only with a good KPS (b=0.47; p=0.037). Hemoglobin levels and the prior number of chemotherapy lines were not predictive of memory performance. CONCLUSIONS: Low BDNF is associated with cognitive impairment, STM, in patients with cancer, however no influence on depression could be found. IL-6 is strongly associated with depression and an independent predictor of BDNF levels. PMID- 26439968 TI - The spectrum of autoimmune encephalopathies. AB - Despite being a potentially reversible neurological condition, no clear guidelines for diagnosis or management of autoimmune encephalitis exist. In this study we analyzed clinical presentation, laboratory and imaging characteristics, and outcome of autoimmune encephalitis from three teaching hospitals. Non paraneoplastic autoimmune encephalitis associated with antibodies against membrane antigens was the most common syndrome, especially in the pediatric population. Clinical outcome was better for patients with shorter latency from symptom onset to diagnosis and initiation of immunomodulation. Patients with underlying malignancy were less likely to respond well to immunomodulatory therapy. The clinical spectrum of autoimmune encephalitis is fairly broad, but prompt recognition and treatment often leads to excellent outcome. PMID- 26439969 TI - Impact of glatiramer acetate on paraclinical markers of neuroprotection in multiple sclerosis: A prospective observational clinical trial. AB - Data from in vitro and animal studies support a neuroprotective role of glatiramer acetate (GA) in multiple sclerosis (MS). We investigated prospectively whether treatment with GA leads to clinical and paraclinical changes associated with neuroprotection in patients with relapsing-remitting (RR) MS. Primary aim of this clinical study was to determine serum BDNF levels in RR-MS patients who were started on GA as compared to patients who remained therapy-naive throughout 24 months. Secondary outcomes included relapses and EDSS, cognition, quality of life, fatigue and depression, BDNF expression levels on peripheral immune cells (FACS, RT-PCR), serum anti-myelin basic peptide (MBP) antibody status, evoked potential and cerebral MRI studies. While GA treatment did not alter serum levels or expression levels on peripheral immune cells of BDNF over time it resulted in a transient increase of serum IgG antibody response to MBP, mainly due to subtype IgG1 (p<0.05), after 3 months. However, no significant differences were found between GA treated and therapy-naive patients with regard to serum BDNF and intracellular BDNF expression levels, nerve conduction (including median and tibial nerve somatosensory, pattern-shift visual and upper and lower limb motor evoked potentials) or MRI (including volume of hyperintense lesions, volume of hypointense lesions after CE, mean diffusivity and fractional anisotropy) outcome parameters. In conclusion, our findings do not support a major impact of GA treatment on paraclinical markers of neuroprotection in human RR-MS. PMID- 26439970 TI - Early culture conversion and cure for extensively drug-resistant tuberculosis is possible with appropriate treatment: lessons learnt from a case study in South Africa. AB - Despite the relevance of extensively drug-resistant tuberculosis (XDR-TB) to global TB control efforts, case reports on patients achieving cure are scarce. The case of a patient who was treated for more than 3 years as a multidrug resistant TB (MDR-TB) case, and who was diagnosed retrospectively with XDR-TB, is presented herein. Soon after the initiation of a capreomycin and para aminosalicylic acid-based regimen, the patient converted and treatment was completed successfully. PMID- 26439971 TI - Dynamics of immune parameters during the treatment of active tuberculosis showing negative interferon gamma response at the time of diagnosis. AB - OBJECTIVES: In the performance of interferon gamma release assays (IGRA) for the diagnosis of tuberculosis (TB) infection, false-negative results are a major obstacle. In active TB patients, treatment-dependent changes of the negative test results remain unknown. METHODS: The treatment course of 19 smear positive/culture-confirmed TB patients who had IGRA-negative results by QuantiFERON-TB in-tube (QFT-IT) method at the time of diagnosis (month 0) in a previous study, were monitored in the present study. Blood was further collected at months 2 and 7, and the concentrations of 27 immune molecules were measured in the plasma supernatants remaining after performing the IGRA, using a suspension array system. RESULTS: After initiating treatment, eight of the 19 QFT-IT negative patients showed positive conversion, whereas the remaining 11 (58%) did not; the interferon gamma (IFN-gamma) response was restored to levels higher than 1 IU/ml in only three of the eight patients with positive conversion. Plasma concentrations of interleukin 1 receptor antagonist, interleukin 2, and interferon gamma-induced protein 10 remained low after Mycobacterium tuberculosis specific antigen stimulation at months 2 and 7 in the continuously QFT-IT negative group, whereas the parameters were elevated only in the transiently QFT IT-negative group. CONCLUSIONS: It was demonstrated that a majority of active TB patients showing negative IGRA results did not regain sufficient levels of immune responsiveness despite successful treatment. PMID- 26439972 TI - The role of a scientific journal in psychiatric research. PMID- 26439973 TI - Authors' response re: Valentini P, Nelson P. Letter to the Editor Re: Awada HK, Fletter PC, Zaszczurynski PJ, Cooper MA, Damaser MS. Conversion of urodynamic pressures measured simultaneously by air-charged and water-filled catheter systems. Neurourol Urodyn. 2015;34:507-12. PMID- 26439974 TI - Enantiodivergent Synthesis of Bis-Spiropyrrolidines via Sequential Interrupted and Completed (3 + 2) Cycloadditions. AB - Both (5R)- and (5S)-1,7-diazaspiro[4.4]nonan-6-ones are obtained via a sequence of interrupted and completed stepwise (3 + 2) cycloadditions between azomethine ylides and pi-deficient alkenes. The only source of chirality along the whole process is an enantiopure ferrocenyl pyrrolidine catalytic ligand. When the starting imine incorporates two aryl groups or one aryl group with one electron releasing substituent, the reaction between the azomethine ylide and the alkene stops at the first step, leading to the corresponding Michael adduct. When imines derived from p-methoxybenzaldehyde are used, the corresponding syn-alpha-amino gamma-nitro ester is obtained with almost complete enantiocontrol. In contrast, imines derived from benzophenone lead to the corresponding anti analogue. From this interrupted (3 + 2) cycloaddition, cis- and trans-alpha-amino-gamma-lactams can be obtained via hydrogenation of the nitro group followed by in situ cyclization. Imines derived from these latter compounds are the precursors of N metalated azomethine ylides from which up to four new chiral centers can be generated via completed (3 + 2) cycloaddition reactions with full regio- and diastereocontrol. Cis- and trans-gamma-lactams lead to opposite bis spiropyrrolidine enantiomers. Therefore, both enantiomeric series of spiro compounds can be obtained by means of the same catalytic system. The potential of these rigid, densely substituted homochiral compounds in medicinal chemistry is briefly described. PMID- 26439975 TI - Impact of nutritional labelling on 10-d energy intake, appetite perceptions and attitudes towards food. AB - The purpose of this study was to investigate the impact of nutritional labelling on energy intake, appetite perceptions and attitudes towards food. During a 10-d period, seventy normal-weight (BMI<25 kg/m2) and seventy-one obese women (BMI>=30 kg/m2) were given three meals per d under ad libitum conditions. Participants were randomly assigned to one of three experimental labelling groups in which the only difference was the label posted on lunch meal entree: (1) low-fat label, (2) energy label (energy content of the entree and average daily needs) and (3) no label (control). Average energy intake was calculated by weighing all foods before v. after daily consumption. Hunger and fullness perceptions were rated on visual analogue scales immediately before and after each meal. Satiety efficiency was assessed through the calculation of the satiety quotient (SQ). The appreciation and perceived healthiness of the lunch entrees were rated on eight point Likert scales. There was no difference in energy intake, SQ and attitudes towards food between the three labelling groups. Fasting hunger perception was higher in the low-fat label group compared with the two others groups (P=0.0037). No interactions between labelling groups and BMI categories were observed. In conclusion, although labelling does not seem to influence energy intake, a low fat label may increase women's fasting hunger perceptions compared with an energy label or no label. PMID- 26439976 TI - Lipid Profiles and Signals for Long Life. AB - Historically, fat was considered detrimental to health and lifespan. However, lipidomics, the quantification of all lipid molecules in a biological sample, and genetic studies in model organisms are revealing specific fats that may promote longevity. These emerging findings provide insight into the complex relationship between lipids and longevity. PMID- 26439978 TI - Analytical Lipidomics in Metabolic and Clinical Research. AB - Lipidomic analysis, which enables comprehensive characterization of molecular lipids in biological systems, is rapidly becoming an essential tool in biomedical research. While lipidomics already have contributed to several conceptual advances in metabolic research and led to new, validated disease biomarkers, its translation into the clinic remains a challenge. PMID- 26439977 TI - The Genetics of Pediatric Obesity. AB - Obesity among children and adults has notably escalated over recent decades and represents a global major health problem. We now know that both genetic and environmental factors contribute to its complex etiology. Genome-wide association studies (GWAS) have revealed compelling genetic signals influencing obesity risk in adults. Recent reports for childhood obesity revealed that many adult loci also play a role in the pediatric setting. Childhood GWAS have uncovered novel loci below the detection range in adult studies, suggesting that obesity genes may be more easily uncovered in the pediatric setting. Shedding light on the genetic architecture of childhood obesity will facilitate the prevention and treatment of pediatric cases, and will have fundamental implications for diseases that present later in life. PMID- 26439979 TI - Emerging Hubs in Plant Light and Temperature Signaling. AB - Due to their nature as sessile organisms, plants must accurately sense their surroundings and then translate this information into efficient acclimation responses to maximize development. Light and temperature are two major stimuli that provide immediate cues regarding energy availability, daylength, proximity of other species and seasonal changes. Both cues are sensed by complex systems and the integration of these signals is of very high value to properly respond to environmental changes without being disguised by random changes. For instance a cold day has a different significance if it occurs during the illuminated phase of the day or during the night, or when days are shortening during the fall instead of a long-day in spring. Here, we summarize recent advances in the nature of signaling components that operate as connectors of light and temperature signaling, with emphasis on the emerging hubs. Despite the nature of the thermosensors is still in its infancy compared to an important body of knowledge about plant sensory photoreceptors, the interaction of both types of signaling will not only bring clues of how plants integrate environmental information, but also will help in leading research in the nature of the thermosensors themselves. PMID- 26439980 TI - Preparation, Structural Determination, and Characterization of Electronic Properties of Bis-silylated and Bis-germylated Lu3 N@Ih -C80. AB - Bis-silylated and bis-germylated derivatives of Lu3 N@Ih -C80 (3, 4, 5) were successfully synthesized by the photochemical addition of disiliranes 1 a, 1 b or digermirane 2, and fully characterized by spectroscopic, electrochemical, and theoretical studies. Interestingly, digermirane 2 reacts more efficiently than disiliranes 1 a and 1 b because of its good electron-donor properties and lower steric hindrance around the Ge-Ge bond. The 1,4-adduct structures of 3, 4, 5 were unequivocally established by single-crystal X-ray crystallographic analyses. The electrochemical and theoretical studies reveal that the energy gaps between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of the 1,4-adducts are remarkably smaller than those of Lu3 N@Ih C80 , because the electron-donating groups effectively raise the HOMO levels. It is also observed that germyl groups are slightly more electron-donating than the silyl groups on the basis of the redox properties and the HOMO-LUMO energies of 4 and 5. Bis-silylation and bis-germylation are effective and versatile methods for tuning the electronic characteristics of endohedral metallofullerenes. PMID- 26439981 TI - Submolecular Plasticization Induced by Photons in Azobenzene Materials. AB - We demonstrate experimentally for the first time that the illumination of azobenzene derivatives leads to changes in molecular environment similar to those observed on heating but that are highly heterogeneous at the submolecular scale. This localized photoplasticization, which can be associated with a free volume gradient, helps to understand the puzzling phenomenon of photoinduced macroscopic material flow and photoexpansion upon illumination far below the glass transition temperature (T(g)). The findings stem from the correlation of infrared (IR) spectral band shifts measured upon illumination with those measured at controlled temperatures for two amorphous DR1-functionalized azo derivatives, a polymer, pDR1A, and a molecular glass, gDR1. This new approach reveals that IR spectroscopy can be used as an efficient label-free molecular-scale thermometer that allows the assignment of an effective temperature (T(eff)) to each moiety in these compounds when irradiated. While no band shift is observed upon illumination for the vibrational modes assigned to backbone moieties of pDR1A and gDR1 and a small band shift is found for the spacer moiety, dramatic band shifts are recorded for the azo moiety, corresponding to an increase in T(eff) of up to nearly 200 degrees C and a molecular environment that is equivalent to thermal heating well above the bulk T(g) of the material. An irradiated azo-containing material thus combines characteristic properties of amorphous materials both below and above its bulk T(g). The direct measurement of T(eff) is a powerful probe of the local environment at the submolecular scale, paving the way toward better rationalization of photoexpansion and the athermal malleability of azo containing materials upon illumination below their T(g). PMID- 26439982 TI - Cortical evolution 2015: Discussion of neural progenitor cell nomenclature. PMID- 26439983 TI - Childhood trauma and suicide risk in the population living in Zonguldak Province. AB - INTRODUCTION: No previous study has investigated the association between early trauma and suicidal behavior in Zonguldak. The aim of this study was to investigate the incidence of childhood abuse and neglect in the general population living in Zonguldak province and the relationship between childhood trauma and suicidal ideations and attempts. METHODS: The present study was carried out with 897 people in the general population, as assessed in a representative sample from Zonguldak province. The cluster sampling method was used. After obtaining written consent from the people who agreed to participate in the study, the Socio-demographic Information Form, Suicide Probability Scale, Childhood Trauma Questionnaire, Beck Depression Inventory, and Beck Anxiety Inventory were administered. RESULTS: The lifetime prevalence of suicidal ideations was 18.3% among those who experienced at least one type of early trauma, and it was 9.6% among those without a history of childhood trauma (P < 0.001). Only emotional abuse exhibited a significantly high odds ratio for lifetime suicidal ideations (odds ratio [OR] = 3.168, 95% confidence interval [CI] = 1.731-5.798) and attempts (OR = 3.467, 95% CI = 1.343-8.952). Emotional neglect showed a high odds ratio only for lifetime suicidal attempts (OR = 3.282, 95% CI = 1.287-8.371). There were significant correlations among the Beck Depression Inventory, Beck Anxiety Inventory, and Suicidal Probability Scale sub scores and all six Childhood Trauma Questionnaire scores. DISCUSSION: Emotional abuse and neglect in childhood are significantly associated with lifetime suicidal ideations and attempts in the general population living in Zonguldak province. Therefore, clinicians should be aware of the importance of the childhood trauma in the patients with suicidal ideations and attempts. PMID- 26439984 TI - Accelerating SNARE-Mediated Membrane Fusion by DNA-Lipid Tethers. AB - SNARE proteins are the core machinery to drive fusion of a vesicle with its target membrane. Inspired by the tethering proteins that bridge the membranes and thus prepare SNAREs for docking and fusion, we developed a lipid-conjugated ssDNA mimic that is capable of regulating SNARE function, in situ. The DNA-lipid tethers consist of a 21 base pairs binding segment at the membrane distal end that can bridge two liposomes via specific base-pair hybridization. A linker at the membrane proximal end is used to control the separation distance between the liposomes. In the presence of these artificial tethers, SNARE-mediated lipid mixing is significantly accelerated, and the maximum fusion rate is obtained with the linker shorter than 40 nucleotides. As a programmable tool orthogonal to any native proteins, the DNA-lipid tethers can be further applied to regulate other biological processes where capturing and bridging of two membranes are the prerequisites for the subsequent protein function. PMID- 26439986 TI - Estradiol induces apoptosis via activation of miRNA-23a and p53: implication for gender difference in liver cancer development. AB - Estrogen (E2) has been suggested to have a protective role in attenuating hepatocellular carcinoma (HCC) development. miRNAs have great potential as biomarkers and therapeutic agents owing to their ability to control gene expression. However, little is known about the mechanism underlying the protective role of E2 in hepatocarcinogenesis and the effects of E2 on apoptotic miRNAs expression. Using miRNA PCR array, we found more than 2-fold alteration was observed in 25 upregulated and 10 downregulated apoptotic miRNAs in E2 treated cells. Among these miRNAs, we found expression of miR-23a was related to p53 functional status in the male-derived liver cell-lines. We demonstrated that E2 via ERalpha transcriptionally activated miR-23a and p53 expression, and thus enhanced p53 activation of miR-23a expression. Moreover, miR-23a expression correlated inversely with the expression of target gene X-linked inhibitor of apoptosis protein (XIAP), but positively with the caspase-3/7 activity. Decreasing of XIAP might contribute to caspase-3 activity and cell apoptosis. Taken together, our findings reveal a novel E2-signaling mechanism in regulating miRNAs expression for controlling apoptosis in liver cells. Delineating the role of E2 in regulating the activation of p53 and miR-23a, expression in HCC is crucial to the understanding of the sex difference observed in HCC. PMID- 26439985 TI - B5, a thioredoxin reductase inhibitor, induces apoptosis in human cervical cancer cells by suppressing the thioredoxin system, disrupting mitochondrion-dependent pathways and triggering autophagy. AB - The synthetic curcumin analog B5 is a potent inhibitor of thioredoxin reductase (TrxR) that has potential anticancer effects. The molecular mechanism underlying B5 as an anticancer agent is not yet fully understood. In this study, we report that B5 induces apoptosis in two human cervical cancer cell lines, CaSki and SiHa, as evidenced by the downregulation of XIAP, activation of caspases and cleavage of PARP. The involvement of the mitochondrial pathway in B5-induced apoptosis was suggested by the dissipation of mitochondrial membrane potential and increased expression of pro-apoptotic Bcl-2 family proteins. In B5-treated cells, TrxR activity was markedly inhibited with concomitant accumulation of oxidized thioredoxin, increased formation of reactive oxygen species (ROS), and activation of ASK1 and its downstream regulatory target p38/JNK. B5-induced apoptosis was significantly inhibited in the presence of N-acetyl-l-cysteine. Microscopic examination of B5-treated cells revealed increased presence of cytoplasmic vacuoles. The ability of B5 to activate autophagy in cells was subsequently confirmed by cell staining with acridine orange, accumulation of LC3 II, and measurement of autophagic flux. Unlike B5-induced apoptosis, autophagy induced by B5 is not ROS-mediated but a role for the AKT and AMPK signaling pathways is implied. In SiHa cells but not CaSki cells, B5-induced apoptosis was promoted by autophagy. These data suggest that the anticarcinogenic effects of B5 is mediated by complex interplay between cellular mechanisms governing redox homeostasis, apoptosis and autophagy. PMID- 26439987 TI - MicroRNA-212 negatively regulates starvation induced autophagy in prostate cancer cells by inhibiting SIRT1 and is a modulator of angiogenesis and cellular senescence. AB - Among a number of non-coding RNAs, role of microRNAs (miRNAs) in cancer cell proliferation, cancer initiation, development and metastasis have been extensively studied and miRNA based therapeutic approaches are being pursued. Prostate cancer (PCa) is a major health concern and several deregulated miRNAs have been described in PCa. miR-212 is differentially modulated in multiple cancers however its function remains elusive. In this study, we found that miR 212 is downregulated in PCa tissues when compared with benign adjacent regions (n = 40). Also, we observed reduced levels of circulatory miR-212 in serum from PCa patients (n = 40) when compared with healthy controls (n = 32). Elucidating the functional role of miR-212, we demonstrate that miR-212 negatively modulates starvation induced autophagy in PCa cells by targeting sirtuin 1 (SIRT1). Overexpression of miR-212 also leads to inhibition of angiogenesis and cellular senescence. In conclusion, our study indicates a functional role of miR-212 in PCa and suggests the development of miR-212 based therapies. PMID- 26439990 TI - Unilateral ventral strabismus in an aquarium Silver Arowana (Osteoglossum bicirrhosum). AB - An adult silver arowana (Osteoglossum bicirrhosum) presented with a 2-month history of acute onset ventral strabismus of the right eye associated with a cystic structure overlying the dorsal aspect of the globe. Aspiration of the cyst, removal of redundant conjunctival tissue, and apposition of the surgical edges of the conjunctiva did not correct the strabismus. Magnetic resonance imaging of the head and histopathology of the eye did not reveal significant differences between affected and unaffected eyes except for a more posterior dorsal rectus muscle insertion site in the affected eye. This case report documents and describes a syndrome well known among arowana hobbyists as 'drop eye'. PMID- 26439988 TI - OX40 expression enhances the prognostic significance of CD8 positive lymphocyte infiltration in colorectal cancer. AB - BACKGROUND: OX40 is a TNF receptor family member expressed by activated T cells. Its triggering by OX40 ligand promotes lymphocyte survival and memory generation. Anti-OX40 agonistic monoclonal antibodies (mAb) are currently being tested in cancer immunotherapy. We explored the prognostic significance of tumor infiltration by OX40+ cells in a large colorectal cancer (CRC) collective. METHODS: OX40 gene expression was analyzed in 50 freshly excised CRC and corresponding healthy mucosa by qRT-PCR. A tissue microarray including 657 clinically annotated CRC specimens was stained with anti-OX40, -CD8 and -FOXP3 mAbs by standard immunohistochemistry. The CRC cohort was randomly split into training and validation sets. Correlations between CRC infiltration by OX40+ cells alone, or in combination with CD8+ or FOXP3+ cells, and clinical pathological data and overall survival were comparatively evaluated. RESULTS: OX40 gene expression in CRC significantly correlated with FOXP3 and CD8 gene expression. High CRC infiltration by OX40+ cells was significantly associated with favorable prognosis in training and validation sets in univariate, but not multivariate, Cox regression analysis. CRC with OX40(high)/CD8(high) infiltration were characterized by significantly prolonged overall survival, as compared to tumors with OX40(low)/CD8(high), OX40(high)/CD8(low) or OX40(low)/CD8(low) infiltration in both uni- and multivariate analysis. In contrast, prognostic significance of OX40+ and FOXP3+ cell infiltration was not enhanced by a combined evaluation. Irrespective of TNM stage, CRC with OX40(high)/CD8(high) density infiltrates showed an overall survival similar to that of all stage I CRC included in the study. CONCLUSIONS: OX40(high)/CD8(high) density tumor infiltration represents an independent, favorable, prognostic marker in CRC with an overall survival similar to stage I cancers. PMID- 26439989 TI - Antitumoral activity of the mithralog EC-8042 in triple negative breast cancer linked to cell cycle arrest in G2. AB - Triple negative breast cancer (TNBC) is an aggressive form of breast cancer. Despite response to chemotherapy, relapses are frequent and resistance to available treatments is often observed in the metastatic setting. Therefore, identification of new therapeutic strategies is required. Here we have investigated the effect of the mithramycin analog EC-8042 (demycarosil-3D-beta-D digitoxosyl mithramycin SK) on TNBC. The drug caused a dose-dependent inhibition of proliferation of a set of TNBC cell lines in vitro, and decreased tumor growth in mice xenografted with TNBC cells. Mechanistically, EC-8042 caused an arrest in the G2 phase of the cell cycle, coincident with an increase in pCDK1 and Wee1 levels in cells treated with the drug. In addition, prolonged treatment with the drug also causes apoptosis, mainly through caspase-independent routes. Importantly, EC-8042 synergized with drugs commonly used in the therapy of TNBC in vitro, and potentiated the antitumoral effect of docetaxel in vivo. Together, these data suggest that the mithralog EC-8042 exerts an antitumoral action on TNBC cells and reinforces the action of standard of care drugs used in the therapy of this disease. These characteristics, together with a better toxicology profile of EC-8042 with respect to mithramycin, open the possibility of its clinical evaluation. PMID- 26439992 TI - HORSE SPECIES SYMPOSIUM: Developmental programming: Applications in the horse. PMID- 26439991 TI - Chemopreventive effect of leflunomide against Ehrlich's solid tumor grown in mice: Effect on EGF and EGFR expression and tumor proliferation. AB - i) AIMS: The current study aimed to examine the effect of leflunomide on tumoral expression of epidermal growth factor and its receptor (EGFR) in Ehrlich's ascites carcinoma (EAC) grown in mice. ii) MATERIALS AND METHODS: Mice were injected subcutaneously with EAC cells and allocated into four groups; Group i: EAC control group. Groups ii-iv: mice treated with leflunomide (3, 10 or 30mg/kg/day, p.o.), respectively. Pharmacologic treatments were initiated at day 8 and continued for 14days. iii) KEY FINDINGS: Treatment with leflunomide evoked antitumor properties as indicated by reduction in tumor mass, histopathological score, number of intratumoral PCNA immunopositive nuclei. Leflunomide (3, 10 or 30mg/kg) exerted an anti-inflammatory effect as indicated by the reduction in serum tumor necrosis factor-alpha. Furthermore, leflunomide demonstrated anti angiogenic activity which was expressed as a decline in serum vascular endothelial growth factor and down-regulation of intratumoral EGF protein and mRNA expression as well as EGFR expression in addition to suppression of immunostaining for the endothelial marker, CD31. iv) SIGNIFICANCE: Taken together, the present results demonstrated that leflunomide possessed anti angiogenic and anti-proliferative activity against EAC solid tumors that might be correlated to down regulation of EGF and EGFR. Further, the current data indicated that leflunomide may have utility in the management of human cancer. PMID- 26439993 TI - HORSE SPECIES SYMPOSIUM: Glucocorticoid programming of hypothalamic-pituitary adrenal axis and metabolic function: Animal studies from mouse to horse. AB - Adrenal glucocorticoids, such as cortisol, are essential for normal fetal development and for maintaining homeostasis in adults. Developmental studies in humans and other animals have shown that exposure to excess glucocorticoids during critical windows of perinatal development can program permanent changes in hypothalamic-pituitary-adrenal (HPA) axis function and metabolic function, with adverse implications for the long-term health of the exposed offspring. The current review compares the programming of postnatal HPA axis function and glucose homeostasis among different species overexposed perinatally to glucocorticoids, with emphasis on the horse. The potential role of epigenetic modification of genes involved in the regulation of HPA axis and metabolic function at cellular and molecular levels is also discussed. PMID- 26439994 TI - HORSE SPECIES SYMPOSIUM: Nutritional programming and the impact on mare and foal performance. AB - Many environmental factors can alter the phenotype of offspring when applied during critical periods of early development. In most domestic species, maternal nutrition influences fetal development and the fetus is sensitive to the nutrition of the dam during pregnancy. Many experimental models have been explored including both under- and overnutrition of the dam. Both nutritional strategies have yielded potential consequences including altered glucose tolerance, pancreatic endocrine function, insulin sensitivity, body composition, and colostrum quality. Although the impact of maternal nutrition on fetal development in the equine has not been thoroughly investigated, overnutrition is a common occurrence in the industry. Work in our laboratory has focused on effects of maternal overnutrition on mare and foal performance, mare DMI, foaling parameters, colostrum quality and passive transfer of immunity, and glucose and insulin dynamics. Over several trials, mares were fed either 100 or 140% of NRC requirements for DE, and supplemental Se and arginine were added to diets in an attempt to mitigate potential intrauterine growth retardation resulting from dams overfed during the last third of pregnancy. As expected, when mares were overfed, BW, BCS, and rump fat values increased. Foal growth over 150 d was also not influenced. Maternal nutrition did not alter colostrum volume but influenced colostrum quality. Maternal overnutrition resulted in lower colostrum IgG concentrations but did not cause failure of passive transfer in foals. Supplemental Se and arginine were unable to mitigate this reduction in colostrum IgG. Additionally, mare and foal glucose and insulin dynamics were influenced by maternal nutrition. Mare glucose and insulin area under the curve (AUC) increased with increased concentrate supplementation. Foal insulin AUC and peak insulin concentrations were increased when mares were fed concentrate and, in a later trial, foal peak glucose values were reduced with arginine supplementation of the mare. This influence of maternal nutrition on glucose and insulin dynamics warrants further investigation because it may be related to athletic performance and metabolic disease in the adult. Further studies will be necessary to fully elucidate the influence of mare nutrition during pregnancy on development of the fetus as well as long-term consequences of developmental programming. PMID- 26439995 TI - Genetic analysis and genomic selection of stayability and productive life in New Zealand ewes. AB - Genetic parameters for ewes were estimated for stayability (STAY) and productive life (Prodlife). Records from 658,871 animals from 241 seed stock or ram breeder flocks and one research flock were used to estimate parameters for ram breeder flock STAY and Prodlife. These flocks would have a culling policy based on criteria typical of a commercial enterprise, but including culls based on knowledge such as estimated breeding values. A subset of 35,688 of these animals from 4 ram breeder and one research flock was used to infer the animals that might be culled based on the perspective of a commercial flock as these flocks recorded reasons for culling. These data were used to estimate parameters for commercial flock STAY and Prodlife. Heritability for ram breeder flock STAY until age 3 to 6 yr ranged from 0.07 to 0.09. The heritability of commercial flock STAY was similar in yr 5 and 6, but lower at 0.05 (age 3) and 0.07 (age 4). Heritability of Prodlife for ram breeder flock and commercial flock was respectively 0.10 and 0.13. The genetic correlations between ram breeder flock STAY and commercial flock STAY ranged from 0.20 to 0.99. Both STAY and Prodlife were most correlated genetically with the trait number of lambs born, at about 0.4, and to a lesser degree, live weight up to the age of 12 mo for the traits analyzed with lower genetic correlations estimated for the commercial flocks. Live weight at 18 mo and fleece weight had little or no correlation with STAY and Prodlife. From the data set used to estimate genetic parameters from a ram breeder flock, 4,330 animals were genotyped with the Illumina OvineSNP50 BeadChip and the genotypes used to develop genomic predictions via genomic best linear unbiased prediction. The animals used in the training data set were multibreed, but were heavily Romney breed based. The genomic prediction accuracy for ram breeder flock STAY, according to breed, was dependent on sample size and ranged from 0.4 to 0.44 for Romney and 0.26 to 0.4 for Coopworth. Accuracies for Perendale and Composites, for which sample sizes were less, were more variable. This study has derived genetic parameters for STAY and Prodlife and investigated genomic predictions for these traits. As these traits are of low heritability, sex limited and expressed late in life genomic selection will be useful. PMID- 26439996 TI - Comparison of serum biochemical parameters between two broiler chicken lines divergently selected for abdominal fat content. AB - In humans, obesity is associated with increased or decreased levels of serum biochemical indicators. However, the relationship is not as well understood in chickens. Due to long-term intense selection for fast growth rate, modern broilers have the problem of excessive fat deposition, exhibiting biochemical or metabolic changes. In the current study, the Northeast Agricultural University broiler lines divergently selected for abdominal fat content (NEAUHLF) were used to identify differences in serum biochemical parameters between the 2 lines. A total of 18 serum biochemical indicators were investigated in the 16th, 17th, and 18th generation populations of NEAUHLF, and the genetic parameters of these serum biochemical indicators were estimated. After analyzing the data from these 3 generations together, the results showed that the levels of 16 of the tested serum biochemical parameters were significantly different between the lean and fat birds. In the fat birds, serum concentrations of high-density lipoprotein cholesterol (HDL-C), HDL-C:low-density lipoprotein cholesterol (LDL-C), total bile acid, total protein, albumin, globulin, aspartate transaminase (AST):alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), uric acid, and creatinine were very significantly higher (P < 0.01), whereas LDL-C, albumin:globulin, glucose, AST, ALT, and free fatty acids concentrations in serum were very significantly lower than those in the lean birds (P < 0.01). Of these 16 serum biochemical parameters, 5 (LDL-C, HDL-C:LDL-C, total bile acid, albumin, and albumin:globulin) had high heritabilities (0.58 <= h2 <= 0.89), 6 (HDL-C, total protein, globulin, AST:ALT, GGT, and creatinine) had moderate heritabilities (0.29 <= h2 <= 0.48), and the remaining 5 had low heritabilities (h2 < 0.20). Serum HDL-C, HDL-C:LDL-C, and glucose had higher positive genetic correlation coefficients (rg) with abdominal fat traits (0.30 <= rg <= 0.80), whereas serum globulin, AST, and uric acid showed higher negative genetic correlations with abdominal fat traits (-0.62 <= rg <= -0.30). The remaining 10 serum biochemical parameters had lower genetic correlations with abdominal fat traits (-0.30 < rg < 0.30). In conclusion, we identified serum HDL-C and HDL C:LDL-C levels as potential biomarkers for selection of lean birds. These findings will also be useful in future studies for investigating obesity and lipid metabolism in humans as well as in other animal species. PMID- 26439997 TI - Estimates of genetic parameters for reproductive traits in Brahman cattle breed. AB - This study was designed to estimate genetic parameters for the following traits of Brahman cattle in Brazil: age at first calving (AFC), calving interval (CI), rebreeding (REB), and stayability (STAY). For REB, the value 1 was assigned to heifers that rebred and calved after first calving and the value 0 was assigned to heifers that failed to rebreed after first calving. Likewise, for STAY, the value 1 was assigned to cows that calved at least 3 times by the time they reach 6 yr of age; otherwise, the value 0 was assigned. A bivariate analysis was used to estimate covariances components by using linear animal model for CI and AFC and threshold animal model for REB and STAY. The mean h(2) were 0.10, 0.02, 0.22, and 0.10 for AFC, CI, REB, and STAY, respectively. The genetic correlations were 0.13 between AFC and CI, -0.35 between AFC and REB, -0.57 between AFC and STAY, and 0.32 between REB and STAY, which reveal that cows that remain productive for longer periods in the herd also start breeding younger and present greater chances to REB. The selection of Brahman cattle for reproductive traits, such as AFC, CI, REB, and STAY, will render low magnitude and long-term responses. PMID- 26439998 TI - Identification of signatures of selection for intramuscular fat and backfat thickness in two Duroc populations. AB - Intramuscular fat (IMF) content is an important trait affecting the quality of pork. Two Duroc populations, one under positive selection for IMF and the other selected for decreased backfat but under stabilizing selection for IMF, were used to identify signatures of selection associated with IMF using 60,000 single nucleotide polymorphism data. The effects of selection were analyzed between 2 lines or groups representing selected and control animals within each population using a discriminant analysis of principal components and Wright's fixation index (FST). Moreover, extended haplotype homozygosity-based approaches were used to examine the changes in haplotype frequency due to recent selection. Each statistical method identified 10-20 selection signatures. A few haplotype-based signatures of selection agreed with results from a genome-wide association study (GWAS), while FST measures showed a better agreement with GWAS results. Agreement of marker-trait associations and signatures of selection was limited, and further examination will be necessary to understand the effect of selection on IMF and why some regions identified by GWAS did not appear to respond to the selection practiced. The genes in 21 consensus selection signatures were examined. Several genes with an effect on overall fatness were identified, but further research is needed to assess whether or not some of them could have a specific effect on IMF. PMID- 26439999 TI - Genetic associations of short- and long-term aggressiveness identified by skin lesion with growth, feed efficiency, and carcass characteristics in growing pigs. AB - The objective of this study was to investigate the genetic relationships between skin lesion traits in group housed growing pigs as a measure of short- (in a newly mixed group) and long- (in a socially stable group) term aggression and commonly used commercial performance measures: growth, feed intake, feed efficiency, and carcass traits. Data on 2,413 growing pigs (138 groups) were available. Pigs were mixed into new social groups of 18 animals, and skin lesions were counted 24 h (SL24h) and 5 wk (SL5wk) postmixing. The animal model was used to estimate genetic parameters for skin lesion traits, test daily gain, lifetime daily gain, daily feed intake, feed efficiency (calculated as test daily gain divided by daily feed intake), loin depth, back fat, and HCW. Skin lesions had a heritable component, ranging from 0.08 for anterior SL24h to 0.22 for central SL5wk and would, therefore, be suitable as a method of phenotyping aggression for selection purposes. Significant positive genetic correlations were found between SL24h and SL5wk (0.46 to 0.81). Positive genetic correlations were also found between SL24h (central and posterior body regions) or SL5wk (all body regions) and the production traits lifetime daily gain, test daily gain, and HCW (0.29 to 0.54). Central SL24h, anterior SL5wk, and posterior SL5wk were found to correlate positively with feed efficiency (0.39 to 0.50), suggesting that pigs with more lesions convert feed more efficiently. Where significant, the magnitude of phenotypic correlations was low but positive (0.07 to 0.10). These results suggest that, genetically, animals that receive many lesions show improved performance compared to those with few lesions, except for anterior SL24h, which had previously been shown to be genetically positively correlated with the initiation of nonreciprocal attacks. It may, therefore, be possible, via selection against anterior skin lesions at mixing, to reduce this form of 1-sided aggression without adversely affecting production traits. PMID- 26440000 TI - Accuracy of genomic prediction using deregressed breeding values estimated from purebred and crossbred offspring phenotypes in pigs. AB - Genomic selection is applied to dairy cattle breeding to improve the genetic progress of purebred (PB) animals, whereas in pigs and poultry the target is a crossbred (CB) animal for which a different strategy appears to be needed. The source of information used to estimate the breeding values, i.e., using phenotypes of CB or PB animals, may affect the accuracy of prediction. The objective of our study was to assess the direct genomic value (DGV) accuracy of CB and PB pigs using different sources of phenotypic information. Data used were from 3 populations: 2,078 Dutch Landrace-based, 2,301 Large White-based, and 497 crossbreds from an F1 cross between the 2 lines. Two female reproduction traits were analyzed: gestation length (GLE) and total number of piglets born (TNB). Phenotypes used in the analyses originated from offspring of genotyped individuals. Phenotypes collected on CB and PB animals were analyzed as separate traits using a single-trait model. Breeding values were estimated separately for each trait in a pedigree BLUP analysis and subsequently deregressed. Deregressed EBV for each trait originating from different sources (CB or PB offspring) were used to study the accuracy of genomic prediction. Accuracy of prediction was computed as the correlation between DGV and the DEBV of the validation population. Accuracy of prediction within PB populations ranged from 0.43 to 0.62 across GLE and TNB. Accuracies to predict genetic merit of CB animals with one PB population in the training set ranged from 0.12 to 0.28, with the exception of using the CB offspring phenotype of the Dutch Landrace that resulted in an accuracy estimate around 0 for both traits. Accuracies to predict genetic merit of CB animals with both parental PB populations in the training set ranged from 0.17 to 0.30. We conclude that prediction within population and trait had good predictive ability regardless of the trait being the PB or CB performance, whereas using PB population(s) to predict genetic merit of CB animals had zero to moderate predictive ability. We observed that the DGV accuracy of CB animals when training on PB data was greater than or equal to training on CB data. However, when results are corrected for the different levels of reliabilities in the PB and CB training data, we showed that training on CB data does outperform PB data for the prediction of CB genetic merit, indicating that more CB animals should be phenotyped to increase the reliability and, consequently, accuracy of DGV for CB genetic merit. PMID- 26440001 TI - Strong connectedness within Norwegian Cheviot and Fur Sheep ram circles allows reliable estimation of breeding values. AB - Breeding programs for sheep in Norway are based on cooperatives of ram circles (RC). The key features of RC are selection of rams across member flocks and their rotation among RC flocks during the mating season. Genetic gains are disseminated to flocks outside RC (ORC). In both groups, natural service and AI are practiced. The objectives were to investigate 1) connectedness within and across RC and across RC and ORC, which impacts bias in genetic comparisons across flocks, and 2) opportunities to improve accuracy by including data from ORC flocks in genetic evaluation of RC flocks. Weaning weights in Cheviot and Fur Sheep from 1990 to 2010 were used. In Cheviot, in the last year of data (2010), there were 4 RC with 49 flocks and 1,824 ewes. Seventy-seven ORC flocks, with 1,246 ewes, also were recorded that year. In total, 214,391 pedigree and 131,012 performance records in Cheviot were available. For Fur Sheep, there was 1 RC with 8 flocks and 468 ewes in 2010 and 134 ORC flocks with 1,932 ewes. In total, 198,339 pedigree and 110,955 performance records in Fur Sheep were available. Unbiased comparison of EBV requires that genetic means of flock founders are similar or that flocks are genetically connected. The latter requires that rams sire enough progeny across flocks. In RC in both breeds and in 28.6% of Cheviot and 20% of Fur Sheep ORC flocks, the average prediction error correlation of flock mean EBV (flock rij) exceeded a threshold (0.10) for strong connectedness. These flocks also had similar genetic means: the variance between means of flock founders (genetic groups) was 1.05 (Cheviot) and 0.51 (Fur Sheep) times that of the additive variance for weaning weight. With less connected flocks included (flock rij <= 0.10), the between genetic group variance increased to 1.6 times the additive variance. When weaning weights from connected ORC flocks were included in the genetic evaluation of RC flocks, the size of the data increased by 1.07 times in Cheviot and by 3.6 times in Fur Sheep. However, the increase in accuracy of EBV of animals in RC flocks was trivial. Because founder animals of RC flocks had similar genetic means and were strongly connected, flock owners can comfortably focus on other aspects of their breeding program. Opportunities for closer cooperation between RC and connected ORC flocks exist and could be explored to accelerate genetic improvement within the Norwegian Cheviot and Fur Sheep breeds. PMID- 26440002 TI - Transcriptomic analysis by RNA sequencing reveals that hepatic interferon-induced genes may be associated with feed efficiency in beef heifers. AB - In beef cattle, production feedstuffs are the largest variable input cost. Beef cattle also have a large carbon footprint, raising concern about their environmental impact. Unfortunately, only a small proportion of dietary energy is directed toward protein deposition and muscle growth whereas the majority supports body maintenance. Improving feed efficiency would, therefore, have important consequences on productivity, profitability, and sustainability of the beef industry. Various measures of feed efficiency have been proposed to improve feed utilization, and currently, residual feed intake (RFI) is gaining popularity. However, the cost associated with measuring RFI and the limited knowledge of the biology underlying improved feed efficiency make its adoption prohibitive. Identifying molecular mechanisms explaining divergence in RFI in beef cattle would lead to the development of early detection methods for the selection of more efficient breeding stock. The objective of this study was to identify hepatic markers of metabolic feed efficiency in replacement beef heifers. A group of 87 heifers were tested for RFI adjusted for off-test backfat thickness (RFIfat). Preprandial liver biopsies were collected from 10 high- and 10 low-RFIfat heifers (7 Hereford-Aberdeen Angus and 3 Charolais-Red Angus-Main Anjou per group) and gene expression analysis was performed using RNA sequencing and quantitative real-time PCR. The heifers used in this study differed in RFIfat averaging 0.438 vs. -0.584 kg DM/d in high- and low-RFIfat groups, respectively. As expected, DMI was correlated with RFIfat and ADG did not differ between high- and low-RFIfat heifers. Through a combination of whole transcriptome and candidate gene analyses, we identified differentially expressed genes involved in inflammatory processes including hemoglobin beta (HBB), myxovirus resistance 1 interferon-inducible protein p78 (MX1), ISG15 ubiquitin-like modifier (ISG15), hect domain and RLD 6 (HERC6), and interferon-induced protein 44 (IFI44) whose mRNA abundance was lower (HBB) or higher (MX1, ISG15, HERC6, and IFI44) in low RFIfat heifers. These genes have been shown to be directly or indirectly modulated by interferon signaling and involved with innate immunity. Our results suggest that more efficient heifers respond differently to hepatic proinflammatory stimulus, potentially expending less energy toward combating systemic inflammation and redirecting nutrients toward growth and protein accretion. PMID- 26440003 TI - High dietary selenium and vitamin E supplementation ameliorates the impacts of heat load on oxidative status and acid-base balance in sheep. AB - The objective of this study was to determine the efficacy of supranutritional dietary selenium and vitamin E (Vit E) to ameliorate the effect of heat stress (HS) on oxidative status and acid-base balance in sheep. Thirty-two Merino * Poll Dorset ewes were acclimated to indoor individual pen feeding of a pelleted control diet (0.24 g Se and 10 IU of Vit E/kg DM) for 1 wk. Sheep were then moved to metabolism cages in climatic chambers and randomly allocated to a 2 * 2 * 2 factorial design with the respective factors being dietary Se (0.24 and 1.20 mg/kg DM as Sel-Plex; Alltech, Australia), Vit E (10 and 100 IU/kg DM), and temperature for 2 wk. After 1 wk of acclimation in metabolic cages, 1 climatic chamber continued on thermoneutral (TN) conditions (18 degrees C to 21 degrees C and 40% to 50% relative humidity [RH]), and the other one was set to HS conditions (28 degrees C to 40 degrees C and 30% to 40% RH) for 1 wk. The sheep were then returned to individual pens and fed the control diet for 1 wk before being returned to the same diet as in the first period but a reversed thermal treatment for a further 2 wk. Physiological parameters were recorded 3 times daily, and blood samples were collected on d 1 and 7 of thermal treatment. Average respiration rate and rectal temperature of sheep were increased (P < 0.001) during HS; however, combined supranutritional supplementation of Se and Vit E reversed the effects of HS. Sheep given the high Se and high Vit E diet had a lower respiration rate (191 vs. 232 breaths/min; P = 0.012) and rectal temperature (40.33 degrees C vs. 40.58 degrees C; P = 0.039) under peak HS (1700 h) compared with those fed the low Se and low Vit E diet. Plasma reactive oxygen metabolites concentrations were reduced (P = 0.048) by 20%, whereas biological antioxidant potential was increased (P = 0.17) by 10% in sheep fed the high Se and high Vit E diet compared with those fed the low Se and low Vit E diet. Blood pH was elevated (P = 0.007) and bicarbonate was reduced (P = 0.049) under HS, and again, these effects were ameliorated by the high Se and high Vit E diet. Both white blood cell glutathione peroxidase gene expression and red blood cell lysate glutathione peroxidase activity were increased in sheep fed the high Se and high Vit E diet. These data suggest that supranutritional dietary Se or Vit E can reduce some of the negative effects of HS. However, the synergism between the 2 antioxidants improves their potential to ameliorate the impacts of HS in sheep. PMID- 26440004 TI - Dietary chromium methionine supplementation could alleviate immunosuppressive effects of heat stress in broiler chicks. AB - The present study was conducted to investigate the effects of dietary supplementation of chromium methionine (CrMet) on performance, immune responses, and stress status of broiler chicks subjected to heat-stress conditions. A total of 450 day-old Ross 308 broiler chicks were randomly distributed between 5 replicate pens (15 birds each) of 6 experimental treatments according to a 2 * 3 factorial arrangement of treatments including 2 temperature conditions (thermoneutral and heat stress) and 3 supplemental Cr levels (0, 500, and 1,000 MUg/kg as CrMet). For induction of heat stress, the house temperature was set at 35 +/- 2 degrees C from 15 to 42 d of age. Results showed that the chicks subjected to heat-stress condition had lower (P < 0.01) feed intake, BW gain, and deteriorated (P < 0.05) feed conversion values compared with those kept in the thermoneutral house. Dietary supplementation with CrMet increased (P < 0.01) feed intake and improved (P < 0.01) weight gain and feed efficiency. There were significant Cr level * temperature interactions, so that inclusion of CrMet into the diets was more effective in heat-stressed chicks. Exposure to heat stress suppressed (P < 0.01) cutaneous hypersensivity response to phytohemagglutinin-P injection at 30 d of age, and dietary supplementation of 500 MUg Cr/kg induced (P < 0.05) this response, with the greater impacts in heat-stressed chicks, resulting in a significant (P < 0.01) Cr * temperature interaction. Antibody responses against Newcastle and infectious bronchitis disease viruses were diminished (P < 0.01) in heat-stressed chicks. Dietary inclusion of CrMet improved (P < 0.05) antibody responses to different immunostimulants, and this effect was more pronounced in heat-stressed chicks. Exposure to heat stress caused a significant (P < 0.05) decrease in the proportion of helper (CD4+) T lymphocytes and increased cytotoxic (CD8+) T lymphocytes, resulting in a decreased (P < 0.01) CD4+ to CD8+ ratio in peripheral blood circulation. Supplementation of CrMet to heat-stressed chicks modulated (P < 0.01) plasma corticosterone level. The present findings indicate that dietary CrMet supplementation could alleviate heat-stress-induced growth retardation in broiler chicks. Moreover, supplemental CrMet modulated suppressive effects of heat stress on cellular and humoral immune responses. PMID- 26440005 TI - Equine endometrial gene expression changes during and after maternal recognition of pregnancy. AB - The mechanism for maternal recognition of pregnancy (MRP) in horses is unknown. To maintain a pregnancy, a mobile conceptus must be recognized by the uterus before d 14 postovulation (PO). This recognition prevents endometrial secretion of PGF2alpha on d14 through 16, which would otherwise initiate luteolysis. The objective of this study was to evaluate gene expression in the endometrium of pregnant and nonpregnant mares during and after MRP to identify possible genes involved during this time. Twelve normally cycling mares were used in a crossover design and randomly assigned to a specific collection day. Endometrial samples were collected from a pregnant and nonpregnant (nonmated) mare on cycle d 12, 14, 16, and 18 (n = 3/d) PO. Microarray analysis comparing the endometrial gene expression in pregnant and nonpregnant mares revealed no differences at d 12. Ten genes were identified to have consistently higher or lower expression levels in the endometrium from pregnant versus nonpregnant mares on d 14, 16, and 18 (P < 0.001). The expression of these 10 genes was further analyzed with real-time PCR. d 14, 16, and 18 gene expression patterns were consistent with the microarray analysis, but on d 12, 4 of the 10 were identified as differentially expressed. Endometrial samples were then collected on d 13 PO (n = 3) and processed for western blot and immunohistochemical analysis of 2 proteins due to their reproductive significance. SPLA2 and DKK1 antibody specificity were confirmed via western blot analysis but were not different in samples from pregnant and nonpregnant mares (P = 0.114 and P = 0.514, respectively) and cellular localization was examined by immunohistochemical analysis. This is the first study to describe gene expression and cellular localization in the endometrium at the time of MRP for these genes and suggests that the uterus does not prepare to support a pregnancy until d 14. The function of these genes may be critical in the process of MRP. PMID- 26440006 TI - Postprandial glucose, insulin, and glucagon-like peptide-1 responses of different equine breeds adapted to meals containing micronized maize. AB - The enteroinsular axis is a complex system that includes the release of incretin hormones from the gut to promote the absorption and utilization of glucose after a meal. The insulinogenic effect of incretin hormones such as glucagon-like peptide-1 (GLP-1) remains poorly characterized in the horse. The aim of this study was to compare postprandial glucose, insulin, and GLP-1 responses of different equine breeds adapted to twice-daily meals containing micronized maize. Four Standardbred horses, 4 mixed-breed ponies, and 4 Andalusian cross horses in moderate BCS (5.5 +/- 0.2 out of 9) were fed meals at 0800 and 1600 h each day. The meals contained micronized maize (mixed with soaked soybean hulls and lucerne chaff), with the amount of maize gradually increased over 12 wk to reach a final quantity of 1.7 g/kg BW (1.1 g/kg BW starch) in each meal. Animals had ad libitum access to the same hay throughout. After 12 wk of acclimation, serial blood samples were collected from all animals over a 14-h period to measure concentrations of glucose, insulin, and GLP-1, with meals fed immediately after the 0 and 8 h samples. Glucose area under the curve (AUC) values were similar between breed groups (P = 0.41); however, ponies and Andalusian horses exhibited significantly higher insulin AUC values after both meals compared with Standardbred horses (both P < 0.005). Postprandial GLP-1 AUC values were also significantly higher in ponies and Andalusian horses compared with Standardbred horses (breed * time interaction; P < 0.001). Correlation analysis demonstrated a strong positive association between concentrations of insulin and GLP-1 over time (rs = 0.752; P < 0.001). The increased insulin concentrations in ponies and Andalusian horses may partly reflect lower insulin sensitivity but could also be attributed to increased GLP-1 release. Given that hyperinsulinemia is a recognized risk factor for the development of laminitis in domestic equids, this study provides evidence that the enteroinsular axis warrants further investigation. PMID- 26440007 TI - The effect of Bacillus coagulans-fermented and nonfermented Ginkgo biloba on the immunity status of broiler chickens. AB - To evaluate and compare the effects of Bacillus coagulans-fermented Ginkgo biloba (FG) and nonfermented Ginkgo biloba (NFG) on the immunity status of broiler chickens, 180 1-d-old female Arbor Acres chicks were divided into 3 groups and fed either a basal diet, a basal diet supplemented with 0.3% NFG, or a basal diet supplemented with 0.3% FG. Blood samples were taken on the seventh (before vaccination), 14th, 21st, 28th and 35th day for the assessment of serum IL-18 and interferon gamma (IFN-gamma) levels by ELISA. In addition, Newcastle disease antibody titer analysis was made via hemagglutination and hemagglutination inhibition test methods. On d 35, 6 chickens from each group were sacrificed and the thymus, liver, spleen, small intestine (jejunum segment), cecum, and bursa of Fabricius from each chicken were removed for analysis. RNA was isolated for defensin expression detection by real-time PCR (q-PCR). The results showed that serum IL-18 and IFN-gamma levels decreased after treatment with NFG and FG compared with untreated control chickens. The ND antibody titers did not differ significantly between the 3 groups on the seventh, 14th, 21st and 28th day; however, on the 35th day, the ND antibody titers of the NFG and FG chickens were both significantly higher than those of control group chickens. Defensin RNA expression levels were inhibited by NFG; however, they were induced by FG. In conclusion, fermentation of Ginkgo biloba with Bacillus coagulans can promote the beneficial effect of Gingko biloba on the immunity status of broiler chickens. PMID- 26440008 TI - Cortisol secretion in response to metabolic and inflammatory challenges in dairy cows. AB - Cortisol in dairy cows is released in an episodic manner underlying a circadian rhythm. The involvement of cortisol in numerous adaptive processes to cope with adverse conditions such as pain and inflammation is well characterized. Recent studies described contradictory effects of nutrition and metabolism on the secretory pattern of cortisol. However, up to now, the direct effects of single metabolites during various metabolic conditions without the profound endocrine changes around parturition on the glucocorticoid secretion in dairy cows have not been described. The objective of this study was to investigate the effects of long-term (56-h) manipulated metabolic states, that is, manipulated plasma concentrations of glucose and beta-hydroxybutyrate (BHBA), on the release of cortisol in midlactation dairy cows. Besides the concentration of cortisol at defined time points, its pulsatile secretory pattern was studied in combination with an acute immune challenge through an intramammary lipopolysaccharide (LPS) challenge. Twenty-five midlactation dairy cows were randomly assigned to 1 of 4 treatments (hyperinsulinemic hypoglycemic clamp [HypoG], hyperinsulinemic euglycemic clamp [EuG], continuous infusion of BHBA [HyperB], or infusion of saline solution for the control group [Control). Different metabolic states induced by infusion treatments affected the characteristics of cortisol secretion (elevation of baseline [the HypoG and HyperB treatments] and decreased peak length [the HypoG treatment]; P < 0.05), whereas amplitude, peak interval, height, peak area, area under the curve (AUC) above the baseline cortisol concentration (AUCb), and the total AUC (AUCt) were not different between infusion treatments. The induced inflammatory response due to the intramammary LPS challenge at simultaneously maintained infusion treatments diminished the pulsatile nature of cortisol release, whereas AUCb (and AUCt, respectively) was lowest for the HypoG treatment compared with the HyperB and Control treatments (P < 0.05). This study indicates that single metabolites (glucose and BHBA) and their availability or turnover (in case of glucose) have a different impact on the regulation of cortisol secretion resulting in changes of its pulsatile release. Furthermore, cortisol release during intramammary inflammation was found to be greater in the HyperB, EuG, and Control treatments compared with the HypoG treatment (P < 0.05). This finding emphasizes the regulatory role of the current metabolic status on the cortisol release during inflammation. PMID- 26440009 TI - Net energy content of dry extruded-expelled soybean meal fed with or without enzyme supplementation to growing pigs as determined by indirect calorimetry. AB - Two experiments were conducted to determine the NE content of dry extruded expelled soybean (DESBM) and the effect of a multienzyme carbohydrase (MC) mixture on the NE content of DESBM and to determine the effect of diet design on NE values in growing pigs using indirect calorimetry (IC). In Exp. 1, 24 barrows (19.6 +/- 0.51 kg BW) were allotted in a completely randomized design to 4 dietary treatments: a corn-soybean meal basal diet (Diet A), a diet containing Diet A and DESBM in an 80:20 ratio with a constant CP (Diet B), a diet with an 80:20 ratio of Diet A and DESBM with a constant corn:soybean meal ratio (Diet C), and a diet with simple substitution of Diet A with DESBM in an 80:20 ratio (Diet D). Pigs were fed in metabolism crates for a period of 16 d to determine the DE and ME and thereafter were moved into an indirect calorimeter where O2 consumption and CO2 production were measured to determine heat production and fasting heat production. The NE content of DESBM was calculated (difference method) to be 2,632, 2,548 and 2,540 kcal/kg DM in diets B, C, and D, respectively. Respective values obtained with published prediction equations were 2,624, 2,530 and 2,436 kcal/kg. In Exp. 2, 24 barrows (16.9 +/- 0.76 kg BW) were randomly allotted to 1 of 4 treatments. The diets were a corn-soybean meal basal diet and a diet containing the basal diet and DESBM in an 80:20 ratio with a constant corn:soybean meal ratio with or without 2 levels (0.05% and 0.1%) of MC. The experimental procedures were similar to those described in Exp. 1. Enzyme supplementation improved (P < 0.0001) the DE, ME, and NE content of the DESBM. Multienzyme carbohydrase at 0.05% and 0.1% of the diet improved NE values of DESBM by 4.9% and 3.7%, respectively. In conclusion, the NE values of DESBM obtained with the IC method were higher than the values obtained with prediction equations; the disparity was least when diets were formulated with a constant CP level. However, as the difference method was used to determine the NE of ingredient, it is more appropriate to maintain a constant ratio between the ingredients. Also, the NE value of DESBM obtained for diets C and D were not different. Hence, the average NE value of DESBM evaluated was 2,544 kcal/kg DM. Enzyme supplementation improved the NE content of DESBM fed to growing pigs. PMID- 26440010 TI - Effects of feed additives on ileal mucosa-associated microbiota composition of broiler chickens. AB - The effects of dietary supplementation with 2 recently developed feed additives on the composition of the mucosa-associated microbiota of the ileum were studied in growing broiler chickens. A total of 48 male 1-d-old broiler chickens of the Cobb 500 strain were distributed in 4 treatments with 2 replicates of 6 birds each. The 2 additives tested were a di-d-fructose dianhydride-enriched caramel (FC) and the garlic derivative propyl propane thiosulfonate (PTS-O). Dietary treatments were a control (commercial diet with no additive), INU (20 g inulin/kg diet), CAR (20 g FC/kg diet), and GAR (90 mgPTS-O/kg diet). As a result of this study, inulin supplementation resulted in lower (P < 0.05) and FC feeding resulted in higher (P < 0.05) Blautia coccoides/Eubacterium rectale log10 number of copies respect to controls. Higher (P < 0.05) bifidobacteria log10 number of copies with respect to the controls was determined in the ileal mucosa of birds fed the PTS-O-supplemented diet. Denaturing gradient gel electrophoresis and PCR analysis on Bifidobacterium spp. revealed the presence of Bifidobacterium longum, Bifidobacterium pseudolongum, and Bifidobacterium pseudocatenulatum in samples from chickens fed the control and the PTS-O-supplemented diet. Bifidobacterium longum was exclusively found in poultry fed the control diet, whereas B. pseudocatenulatum was found only in poultry fed the PTS-O-supplemented diet. This study showed that both PTS-O and FC were able to modulate the composition of the ileal mucosa-associated microbiota of growing broiler chickens. Finally, in addition to B. pseudolongum, the presence of B. longum and B. pseudocatenulatum, species not previously described in intestinal samples of broilers, was also demonstrated. PMID- 26440011 TI - Effects of zinc sulfate pretreatment on heat tolerance of Bama miniature pig under high ambient temperature. AB - The aim of this study was to evaluate the heat tolerance of Bama miniature pigs under high ambient temperature (40 degrees C) and Zn interactive functions during heat treatment (HT). Bama miniature pigs (male; n = 24; 6-mo old; BW = 10.79 +/- 0.06 kg) were randomly allotted to 4 groups and were fed a basal diet or the basal diet supplemented with 1,500 mg of Zn (ZnSO4.H2O)/kg diet for 38 d. At 7 mo of age (d 30), the thermal neutral (TN) groups remained at 25 degrees C, whereas the HT groups were exposed to ambient temperature at 40 degrees C for 5 h daily for 8 consecutive days. Pigs in 4 groups were sacrificed on d 38. Individual rectal temperatures, skin temperatures, and breathing rates were recorded at 3 h after the onset of HT and the blood samples were collected immediately after HT on d 30, 34, and 38. Pigs fed diets with or without Zn doubled their breathing rates (P < 0.05) and increased body surface, scrotal, and rectal temperatures during HT on d 30, 34, and 38, respectively. Zinc supplementation increased BW gain (BWG; P < 0.05) during 38-d experiment period, and HT decreased BWG only from d 30 to 34 (P < 0.05). Heat treatment increased serum testosterone on d 30 (P < 0.05). Zinc supplementation decreased the heat-induced increase of testosterone in HT on d 30 and 34 (P < 0.05). The relative weight of liver increased in HT groups (P < 0.05). Zinc supplementation decreased the relative weights of spleen (P < 0.05) and testis (P < 0.01). The values of abnormal lymphocyte count and large unstained cell count declined approximately 5 times in groups of Zn supplementation, whereas Zn supplementation increased the values of red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, and mean corpuscular hemoglobin. Zinc concentrations increased in serum, liver, kidney, epididymis, longissimus, hair, and feces in groups fed with Zn (P < 0.01). However, additional Zn decreased Zn concentrations in lung, spleen, and testis (P < 0.01). Moreover, HT decreased serum Zn concentrations (P < 0.01). In conclusion, Zn supplementation could be used to alleviate the decline of serum Zn during periods of high ambient temperatures. However, pretreated supplementation with pharmacological Zn did not promote heat tolerance but impacted the erythropoiesis, immunity, and reproductive organ development in Bama miniature pigs. PMID- 26440013 TI - Effects of microbial phytase on the apparent and standardized total tract digestibility of phosphorus in rice coproducts fed to growing pigs. AB - The objectives of this experiment were to determine the apparent total tract digestibility (ATTD) and the standardized total tract digestibility (STTD) of P and the effect of microbial phytase on ATTD and STTD of P in full-fat rice bran (FFRB), defatted rice bran (DFRB), brown rice, broken rice, and rice mill feed when fed to pigs. Ninety-six barrows (initial BW of 19.4 +/- 1.4 kg) were allotted to 12 diets with 8 replicate pigs per diet in a randomized complete block design. A basal diet based on corn and soybean meal was formulated. Five additional diets containing corn, soybean meal, and each rice coproduct were also formulated, and the ratio between corn and soybean meal in these diets was similar to that in the basal diet. Six additional diets that were similar to the initial 6 diets with the exception that 1,000 units of microbial phytase were added to the diets were also formulated. The ATTD and STTD of P were calculated for each diet using the direct procedure, and the ATTD and STTD of P in each rice coproduct were calculated using the difference procedure. Results of the experiment indicated that the concentration of P in feces was reduced (P < 0.05) from pigs fed diets with microbial phytase compared with pigs fed diets without phytase. No differences were observed between the basal diet and the broken rice diet, but the ATTD and the STTD of P in those diets was greater (P < 0.05) than in all other diets both without and with phytase. Among the rice coproducts, the greatest (P < 0.05) ATTD and STTD of P were observed for broken rice regardless of inclusion of phytase. If no microbial phytase was used, the values for STTD of P in brown rice, FFRB, DFRB, and rice mill feed were not different, but if microbial phytase was included in the diet, ATTD and STTD of P in brown rice was greater (P < 0.05) than in FFRB, DFRB, and rice mill feed. The STTD of P in brown rice, FFRB, and rice mill feed was greater (P < 0.05) if microbial phytase was used than if no microbial phytase was used. Addition of microbial phytase to the diets also increased (P < 0.05) the ATTD of Ca regardless of the rice coproducts used. In conclusion, the STTD of P is greater in broken rice than in all other rice coproducts. The STTD of P in brown rice, FFRB, DFRB, and rice mill feed is relatively low due to the high concentration of phytate in these ingredients, but addition of microbial phytase will increase the STTD of P in most rice coproducts. PMID- 26440012 TI - Effects of environmental temperature and dietary manganese on egg production performance, egg quality, and some plasma biochemical traits of broiler breeders. AB - An experiment was conducted to investigate the effects of environmental temperature and dietary Mn on egg production performance, egg quality, and some plasma biochemical traits of broiler breeders. A completely randomized factorial design involved 2 environmental temperatures (a normal temperature, 21 +/- 1 degrees C, and a high temperature, 32 +/- 1 degrees C) * 3 dietary Mn treatments (a Mn-unsupplemented corn-soybean meal basal diet or the basal diet supplemented with 120 mg of Mn/kg of diet as either MnSO4.H2O or manganese proteinate). There were 6 treatments with 6 replicates (4 birds per replicate). High temperature decreased egg weight (P < 0.0001), laying rate (P < 0.0001), egg yield (P < 0.0001), feed intake (P < 0.0001), egg:feed ratio (P < 0.0001), eggshell strength (P < 0.05) and thickness (P < 0.0001), plasma triiodothyronine level (P < 0.05), and alkaline phosphatase activity (P < 0.04) whereas it increased rectal temperature (P < 0.0001); plasma malondialdehyde level (P < 0.02); and activities (P < 0.002) of lactic dehydrogenase, aspartate aminotransferase, and creatine kinase. Broiler breeders fed the diets supplemented with Mn regardless of source had greater (P < 0.05) eggshell strength and lower (P <= 0.05) plasma triiodothyronine level and protein carbonyl content than those fed the control diet. The broiler breeders fed the diet supplemented with the organic Mn had greater (P < 0.01) eggshell thickness than those fed the control diet. There were interactions (P < 0.05) between environmental temperature and dietary Mn in laying rate, egg yield, feed intake, and egg:feed ratio. Under normal temperature, dietary Mn did not affect the above 4 parameters; however, under high temperature, broiler breeders fed the diet supplemented with the organic Mn showed greater (P < 0.03) improvements in these 4 parameters than those fed the control diet. The results from this study indicated that high temperature significantly impaired egg production performance and eggshell quality and induced lipid peroxidation and tissue damage whereas dietary supplementation of either organic or inorganic Mn improved eggshell strength and thermotolerance and reduced protein oxidation and that the organic Mn could alleviate the negative effect of high temperature on egg production performance of broiler breeders at the period of 32 to 45 wk of age. PMID- 26440014 TI - Effects of dietary supplementation with lysine-yielding Bacillus subtilis on gut morphology, cecal microflora, and intestinal immune response of Linwu ducks. AB - The effects of dietary supplementation with lysine-yielding Bacillus subtilis on gut morphology, cecal microflora, and expression of intestinal cytokine mRNA of Linwu ducks (a Chinese local domesticated duck) were investigated after a 63-d feeding trial. Two hundred forty 1-d-old female ducklings were randomly assigned to 1 of 4 dietary treatments, and there were 60 birds per treatment replicated 6 times with 10 birds each. The experimental diets consisted of a basal diet containing no antibiotic or growth promoters, the basal diet supplemented with 150 mg Aureomycin per kg feed, and 2 others supplemented with 5.0 * 108 and 5.0 * 1010 cfu B. subtilis/kg feed, respectively. Birds fed the diets supplemented with B. subtilis had increased (P < 0.001) villi height in the jejunum and ileum and reduced (P < 0.001) crypt depth in the jejunum compared with birds fed the control diet. Greatest (P < 0.01) villus height:crypt depth ratio was obtained with the jejunum and ileum of birds fed the diet supplemented with 5.0 * 1010 cfu B. subtilis/kg feed. Dietary supplementation with B. subtilis resulted in increased (P < 0.05) cecal counts of Megasphaera elsdenii. Greater cecal Lactobacillus counts were obtained in ducks fed the diets supplemented with Aureomycin and B. subtilis. Ducks fed the diets supplemented with B. subtilis showed suppressed (P < 0.001) expression of interleukin (IL)-1beta, IL-2, and IL 10 in their jejunum. When compared with the control, the expression of interferon (IFN)-gamma in the jejunum of ducks fed the diet supplemented with 5.0 * 108 cfu B. subtilis/kg feed was significantly increased (P < 0.05). Dietary supplementation with B. subtilis or Aureomycin reduced (P < 0.001) ileal expression of IL-10. When compared with the control, the expression of IL-2 and IL-8 in the ileum of ducks fed the diet supplemented with 5.0 * 1010 cfu B. subtilis/kg feed showed a significant decrease (P < 0.05). In conclusion, dietary supplementation with lysine-yielding B. subtilis improved gut morphology, increased the population of beneficial gut microflora, and stimulated increased intestinal immune response of Linwu ducks. PMID- 26440015 TI - Determination and prediction of energy values in corn distillers dried grains with solubles sources with varying oil content for growing pigs. AB - This study was conducted to determine the DE and ME content of 25 samples of corn distillers dried grains with solubles (DDGS) fed to growing pigs and to generate prediction equations for DE and ME based on chemical analysis. The 25 samples included 15 full-oil (no oil extracted; ether extract [EE] > 8%) DDGS and 10 reduced-oil (oil extracted; EE < 8%) DDGS collected from 17 ethanol plants in China. A corn-soybean meal diet constituted the basal diet and the other 25 diets replaced a portion of the corn, soybean meal, and lysine of the basal diet with 28.8% of 1 of the 25 corn DDGS sources. Seventy-eight barrows (initial BW = 42.6 +/- 6.2 kg) were used in the experiment conducted over 2 consecutive periods (n = 6 per treatment) using a completely randomized design. For each period, pigs were placed in metabolism cages for a 5-d total collection of feces and urine following a 7-d adaptation to the diets. Among the 25 corn DDGS samples, EE, NDF, DE, and ME content (DM basis) ranged from 2.8 to 14.2%, 31.0 to 46.6%, 3,255 to 4,103 kcal/kg, and 2,955 to 3,899 kcal/kg, respectively. Using a stepwise regression analysis, a series of DE and ME prediction equations were developed not only among all 25 DDGS but also only within 15 full-oil DDGS and 10 reduced oil DDGS samples. The best fit equations of DE (kcal/kg DM) for the complete set of 25 DDGS, 15 full-oil DDGS, and 10 reduced-oil DDGS were 2,064 - (38.51 * % NDF) + (0.64 * % GE) - (39.70 * % ash), -(87.53 * % ADF) + (1.02 * % GE) - (22.99 * % hemicellulose), and 3,491 - (40.25 * % NDF) + (46.95 * % CP), respectively. The best fit equations for ME (kcal/kg DM) for the complete set of 25 DDGS, 15 full-oil DDGS, and 10 reduced-oil DDGS were 1,554 - (44.11 * % NDF) + (0.77 * % GE) - (68.51 * % ash), 7,898 - (42.08 * % NDF) - (136.17 * % ash) + (101.19 * % EE) (103.83 * % CP), and 4,066 - (46.30 * % NDF) + (45.80 * % CP) - (106.19 * % ash), respectively. Using the sum of squared residuals to compare the accuracy of the 3 groups of prediction equations revealed that separate equations for full oil DDGS and reduced-oil DDGS each provided a better fit than a single equation for the entire set of DDGS sources. These results indicated that the DE and ME values in corn DDGS are related to the chemical composition, primarily the EE and fiber concentrations. Specific prediction equations derived from full-oil and reduced-oil DDGS are better than equations derived from the entire set of DDGS. PMID- 26440016 TI - Effects of protein intake on rate of growth, protein deposition, and carcass traits of heavy Iberian pigs. AB - A feeding, digestibility, and balance trial was performed to determine the effect of the incorporation of increasing amounts of soybean protein concentrate (SPC) to a basal acorn diet at a fixed energy intake on the rate of growth, protein deposition (PD), and carcass traits of heavy Iberian (IB) pigs. Sixteen purebred IB barrows (103.9 +/- 0.9 kg initial BW) were used. The pigs were individually confined and allocated to 4 groups of 4 pigs each. Whole acorns were provided with slight restriction to minimize acorn kernel (AK) remains. Water was freely available. The incorporation of SPC raised the available CP from 49.1 g/kg DM (1.91 g total Lys/kg DM) in AK up to 135 g/kg DM (7.24 g total Lys/kg DM). After 72 d of trial, the pigs achieved 134.4 +/- 1.3 kg BW and were then slaughtered. Average daily BW gain increased with increasing dietary CP (linear, P < 0.001; quadratic, P < 0.01), with a plateau at dietary CP concentrations (provided by AK and SPC) beyond 72.2 and 100 g/kg DM, respectively, for which an ADG of 449 g was achieved. There was a linear and quadratic effect of dietary CP and Lys level on the apparent digestibility of CP (linear, P < 0.001; quadratic, P < 0.05) and on the efficiencies of utilization of total N (retained N/N intake; linear, P < 0.001; quadratic, P < 0.001) and N apparently absorbed (retained N/apparent digestible N; linear, P < 0.05; quadratic, P = 0.067). Protein deposition ranged between -4.59 g/d in pigs not provided with SPC to 61.4 g/d in pigs fed the greatest level of SPC inclusion. The lowest daily intake of total Lys resulting in maximum PD (69.5 g/d) at the fixed level of energy intake observed (2.36 * ME maintenance requirements) was 21.0 g. Hot carcass and cold carcass weights, but not carcass yield, increased when feeding the daily ration containing 100 g SPC and leveled off thereafter (linear, P < 0.01; quadratic, P < 0.01). An average increase of 8.3% and 8.7% was obtained, respectively. The provision of SPC had no effect on back fat thickness. Primal cuts, but not yield (except for loin), increased (sirloin: linear, P < 0.05; loin: linear, P < 0.001; quadratic, P < 0.05; ham: linear, P < 0.05) or showed a tendency to increase (butt lean: linear, P = 0.068; quadratic, P = 0.077; ribs: quadratic, P = 0.067; shoulder: quadratic, P = 0.064) with the provision of dietary protein. No effect of the level of incorporation of SPC to the diet was observed on CP, total fat, total ash, and energy contents or on relative fatty acid profile of loin and sirloin. PMID- 26440017 TI - Effect of supplementing a fibrous diet with a xylanase and beta-glucanase blend on growth performance, intestinal glucose uptake, and transport-associated gene expression in growing pigs. AB - The present study evaluated supplemental carbohydrase effect on performance, intestinal nutrient uptake, and transporter mRNA expressions in growing pigs offered a high-fiber diet manufactured with distillers dried grains with solubles (DDGS). Twenty-four pigs (22.4 +/- 0.7 kg BW) were randomly assigned to 1of 3 nutritionally adequate diets (8 pigs per diet) based on corn and soybean meal (SBM) with either 0 (control) or 30% DDGS (high fiber [HF]). The third diet was supplemented with a xylanase and beta-glucanase blend (XB) in addition to the 30% DDGS (HF+XB). Parameters determined were ADFI, ADG, G:F, plasma glucose and plasma urea nitrogen (PUN) concentrations, jejunal tissue electrophysiological properties, and mRNA expressions of the sodium-dependent glucose transport 1 (SGLT1) and cationic AA transporter, bo,+AT, in the jejunal and ileal tissues. In addition, mRNA expressions of the short-chain fatty acid transporters, monocarboxylate transporter 1 (MCT1) and sodium-coupled monocarboxylate transporter, and mucin genes were quantified in the ileum. Feed intake, plasma glucose, and jejunal tissue electrophysiological properties were not affected (P > 0.05) by diet. However, control-fed pigs had superior growth rate and feed efficiency and higher PUN (P < 0.05) than HF- and HF+XB-fed pigs. The HF diet increased (P < 0.05) SGLT1 mRNA expression in the jejunum and decreased (P < 0.05) bo,+ mRNA expression in the ileum. The XB supplementation also increased bo,+ mRNA expression in the ileum relative to HF-fed pigs. Additionally, MCT1 mRNA expression was greater (P < 0.05) in the ileum of the HF- and HF+XB-fed pigs. In the present study, XB supplementation influenced nutrient transporter mRNA expression, although it was not accompanied by improved pig performance. PMID- 26440018 TI - Apparent and standardized total tract digestibility by growing pigs of phosphorus in canola meal from North America and 00-rapeseed meal and 00-rapeseed expellers from Europe without and with microbial phytase. AB - An experiment was conducted to determine apparent total tract digestibility (ATTD) and standardized total tract digestibility (STTD) by growing pigs of P in canola meal, 00-rapeseed meal, and 00-rapeseed expellers. Canola meal and 00 rapeseed meal are the coproducts produced after the residual oil has been solvent extracted from the prepressed canola seeds and 00-rapeseeds, respectively, whereas 00-rapeseeed expellers is the coproduct from 00-rapeseeds that have been only expeller pressed. Two hundred sixteen barrows (18.0 +/- 1.5 kg initial BW) were allotted to 36 diets and 6 replicate pigs per diet. Five samples of canola meal from solvent-extraction crushing plants in North America, 8 samples of 00 rapeseed meal from solvent-extraction crushing plants in Europe, and 5 samples of 00-rapeseed expellers from mechanical-press crushing plants in Europe were used in the experiment. Eighteen diets were prepared by including 40% of each source of canola meal, 00-rapeseed meal, or 00-rapeseed expellers in 1 diet. Eighteen additional diets were formulated by adding 1,500 units of microbial phytase to the diets. The only source of P in the diets was canola meal, 00-rapeseed meal, or 00-rapeseed expellers. Pigs were placed in metabolism crates that allowed for total fecal collection. Pigs were fed at 2.5 times their estimated energy requirement for maintenance. Ingredients, diets, and feces were analyzed for P, and the ATTD and STTD of each source of canola meal, 00-rapeseed meal, and 00 rapeseed expellers were calculated. A value for endogenous P loss of 190 mg/kg DMI was used to calculate the STTD of P. Results indicated that the ATTD and STTD of P for canola meal were not different from values obtained in 00-rapeseed meal, and the ATTD and STTD of P in 00-rapeseed meal were not different from values for 00-rapeseed expellers. The ATTD and STTD of P increased (P < 0.001) from 44.99 and 48.82% to 64.08 and 67.97% for canola meal, from 46.77 and 50.36% to 63.53 and 67.29% for 00-rapeseed meal, and from 44.83 and 48.60% to 69.18 and 72.99%, respectively, for 00-rapeseed expellers by adding microbial phytase to the diets. In conclusion, although the concentration of ether extract is much greater in 00 rapeseed expellers than in 00-rapeseed meal and canola meal, the ATTD and STTD of P for these ingredients are not different, and addition of microbial phytase results in improved digestibility of P in canola meal, 00-rapeseed meal, and 00 rapeseed expellers. PMID- 26440019 TI - Developmental changes in polyamines and autophagic marker levels in normal and growth-restricted fetal pigs. AB - Polyamines are essential for embryonic and fetal survival, growth, and development. Additionally, polyamines may induce autophagy in mammalian cells. However, little is known about the availability of polyamines or autophagy in the porcine conceptus with intrauterine growth restriction (IUGR). The present study was performed to evaluate the developmental changes of polyamine concentrations in IUGR and normal porcine fetuses as well as autophagic marker levels in the fetal intestinal mucosa during the second half of gestation when most fetal growth occurs. Allantoic fluid (ALF), amniotic fluid (AMF), umbilical vein, and the small-intestinal mucosa were obtained from both IUGR and normal fetal pigs at d 60, 90, and 110 of gestation. Concentrations of polyamines in fetal fluids as well as protein abundances of microtubule-associated protein light chain 3B (LC3B), an autophagic marker, in the fetal small-intestinal mucosa were determined. Concentrations of polyamines varied greatly in different fetal compartments and changed substantially with advancing gestation. Concentrations of polyamines in IUGR fetal fluids and the small-intestinal mucosa were markedly different from those in their normal counterparts at d 60 and 90 of gestation, whereas most of the differences were not detected by late (d 110) gestation. Specifically, polyamine levels were lower in the umbilical vein plasma but higher in ALF and AMF from IUGR fetuses. Furthermore, enhanced levels of an autophagic marker were observed in the small-intestinal mucosa of IUGR fetuses throughout mid and late gestation in association with abnormal spermidine levels in fetal plasma. These findings support the notion that enhanced autophagy may be an important survival mechanism in IUGR fetuses. Collectively, our findings provide a new framework for future studies to define the roles for polyamines in the prevention and treatment of IUGR in both human medicine and animal production. PMID- 26440020 TI - In vitro and in vivo digestibility of corn starch for weaned pigs: Effects of amylose:amylopectin ratio, extrusion, storage duration, and enzyme supplementation. AB - The objective of this study was to investigate the effects of amylose (AM):amylopectin (AP) ratio, extrusion, storage duration, and enzyme supplementation on starch digestibility of corn. Three corn varieties with high (0.60; HA), medium (0.44; MA), and low (0.39; LA) AM:AP ratios, respectively, were selected from 74 corn samples to evaluate the in vitro and in vivo digestibility of starch. In Exp. 1, during wk 4 after extrusion, resistant starch (RS) content of the 3 selected corn varieties (LA, MA, and HA) increased (P < 0.05) each week and starch digestibility in vitro decreased as storage time increased (P < 0.05). The AM:AP ratio affected the formation of RS (P < 0.01). The RS content of the 3 corn varieties was ranked as LA < MA < HA in each week (P < 0.05). Correlation analysis showed that AM:AP ratio and storage duration were both positively correlated with RS content (P < 0.01). Furthermore, a significant quadratic relation was found between storage duration and RS content in each corn variety as well as storage duration and digestibility. Starch digestibility was negatively correlated with RS content (P < 0.001). In Exp. 2, digestion trials were performed on cannulated pigs with BW of 13.20 +/- 0.94 kg. Extrusion increased ileal digestibility of GE and starch of either HA or LA compared with the enzyme-supplemented diets (P < 0.001). Enzyme supplementation did not improve ileal energy and starch digestibility. The ileal digestibility of starch and GE of LA varieties was greater than HA samples (P < 0.05). The results implied that AM:AP ratio and storage duration after extrusion may be important determinants of RS formation and digestibility of starch for corn. In addition, RS content could be an important indicator of digestibility of starch in extruded corn. Using a lower AM:AP ratio corn or reducing the storage duration of extruded corn would help to reduce the formation of RS and improve the starch bioavailability of corn for piglets. PMID- 26440021 TI - Age at puberty, ovulation rate, and uterine length of developing gilts fed two lysine and three metabolizable energy concentrations from 100 to 260 d of age. AB - The objective of this study was to determine the effect of ad libitum feeding diets differing in standard ileal digestible (SID) lysine and ME concentrations that bracket those fed to developing gilts in U.S. commercial settings. Average SID lysine and ME concentrations in diets currently fed to developing gilts were obtained from a poll of the U.S. commercial swine industry. Crossbred Large White * Landrace gilts (n = 1,221), housed in groups, were randomly allotted to 6 corn soybean diets in a 2 * 3 factorial arrangement formulated to provided 2 SID lysine and 3 ME concentrations. Gilts received grower diets formulated to provide 1.02% (control = survey average) or 0.86% (control minus 15%) SID lysine and 2.94, 3.25, or 3.57 (survey average ME +/- 10%) Mcal of ME/kg from 100 d of age until approximately 90 kg BW. Then, gilts were fed finisher diet containing 0.85% (control = survey average) or 0.73% (control minus 15%) SID lysine and 2.94, 3.26, or 3.59 (control +/- 10%) Mcal of ME/kg until 260 d of age. Gilts were weighed, and backfat thickness and loin muscle area were recorded at the beginning of the trial and then every 28 d. Starting at 160 d of age, gilts were exposed daily to vasectomized boars and observed for behavioral estrus. At approximately 260 d of age, gilts were slaughtered and their reproductive tract was collected. Each reproductive tract was examined to determine whether the gilt was cyclic, the stage of estrus cycle, ovulation rate, and uterine length. Data were evaluated for normality and analyzed using mixed model methods. Average age at puberty was 193 d of age with a range from 160 to 265 d. When all gilts on trial at 160 d of age were included in the analysis, 91.0% reached puberty as determine by observation of standing estrus. Differences between dietary treatments on age at puberty or measurements of the reproductive tract were not detected. Growth rates to 160 d were not limiting for attainment of puberty in response to daily boar stimulation from 160 d. PMID- 26440022 TI - Postnatal bacterial succession and functional establishment of hindgut in supplemental feeding and grazing goats. AB - The objectives of this study were 1) to investigate the age-related changes in functional achievement (establishment of fermentation capacity and enzyme activities) and bacterial succession (selected functional bacterial species) in the cecum and colon and 2) to assess the effect of feeding system (supplemental vs. grazing, Sup vs. G) on hindgut development in small ruminants. A total of 44 Liuyang black goat kids were randomly slaughtered at 0, 7, and 14 d of age (nonrumination period), 28 and 42 d of age (transition period), and 56 and 70 d of age (rumination period). Intestinal contents were sampled to determine VFA, activities of amylase, carboxymethylcellulase (CMCase), and xylanase, as well as abundances of total bacteria and selected functional bacterial species (genus Prevotella, cellulolytic and amylolytic bacteria) with quantitative PCR targeting the 16S rRNA subunit genes. Total VFA concentration (P < 0.01) and enzyme activities (P < 0.05) in hindgut contents were greater and total bacterial 16S rRNA gene copy numbers (P = 0.003) in the cecum were lower for Sup vs. G. Furthermore, irrespective of feeding system, hindgut total VFA concentrations and total bacterial 16S rRNA gene copy numbers increased with age (P < 0.01), with the greatest increase rate observed from 14 to 28 d. Amylase fluctuated with age, whereas CMCase and xylanase activities in Sup kids increased (P < 0.05) as age increased. The proportions of 16S rRNA copy numbers associated with the genus Prevotella and P. ruminicola increased (P < 0.05) with age, but those of cellulolytic bacteria and Ruminobacter amylophilus were detected only after 28 d of birth. The bacterial succession, fermentation capacity, and starch-degrading capacity in the hindgut of both groups were achieved at 1 mo, whereas fiber degrading capacity in Sup kids was established at 2 mo of age; and supplemental feeding surpassed the grazing system in shaping hindgut development. PMID- 26440023 TI - Effects of chitosan on nutrient digestibility, methane emissions, and in vitro fermentation in beef cattle. AB - Chitosan was evaluated as a feed additive to mitigate in vivo CH4 emissions in beef cattle. Twenty-four crossbred heifers (BW = 318 +/- 35 kg) were used in a randomized block design replicated in 2 periods. The design included a 2 * 3 factorial arrangement of treatments, which included diet (high concentrate [HC] or low concentrate [LC]) and 0.0, 0.5, or 1.0% of chitosan inclusion (DM basis). Diets were offered ad libitum and individual intake was recorded. An in vitro experiment to analyze chitosan's effect on fermentation parameters and gas production kinetics was performed. A diet effect (P < 0.01) was observed for CH4 emissions expressed as grams/day, grams/kilogram of BW0.75, and grams/kilogram of DMI. Heifers consuming the LC diet produced 130 g of CH4/d vs. 45 g of CH4/d in those consuming the HC diet. Incubation fluid pH increased linearly (P < 0.05) when chitosan was included in HC substrates. In vitro CH4 production was not affected (P > 0.10) by chitosan in HC substrate; however, when incubated with the LC substrate, CH4 production increased quadratically (P < 0.01) as chitosan inclusion increased. A digestibility marker * diet interaction occurred (P < 0.05) for DM, OM, CP, NDF, and ADF digestibility. Diet * chitosan interactions (P < 0.05) occurred for DM, OM, NDF, and ADF digestibility when Cr2O3 was used. When TiO2 was used, diet * chitosan interactions (P < 0.05) were observed for NDF and ADF. However, using indigestible NDF as an internal marker, DM and OM digestibility were improved (P < 0.05) by 21 and 19%, respectively, when chitosan was included in LC diets. In conclusion, feeding up to 1% of chitosan (DM basis) to heifers consuming a LC diet increased apparent total tract digestibility of nutrients. Enteric CH4 emissions were not affected by chitosan feeding, regardless of type of diet, and heifers consuming a 36% concentrate diet produced 2.6 times more methane per day than those consuming an 85% concentrate diet. PMID- 26440024 TI - A modified version of the Molly rumen model to quantify methane emissions from sheep. AB - We modified the rumen submodel of the Molly dairy cow model to simulate the rumen of a sheep and predict its methane emissions. We introduced a rumen hydrogen (H2) pool as a dynamic variable, which (together with the microbial pool in Molly) was used to predict methane production, to facilitate future consideration of thermodynamic control of methanogenesis. The new model corrected a misspecification of the equation of microbial H2 utilization in Molly95, which could potentially give rise to unrealistic predictions under conditions of low intake rates. The new model included a function to correct biases in the estimation of net H2 production based on the default stoichiometric relationships in Molly95, with this function specified in terms of level of intake. Model parameters for H2 and methane production were fitted to experimental data that included fresh temperate forages offered to sheep at a wide range of intake levels and then tested against independent data. The new model provided reasonable estimates relative to the calibration data set, but a different parameterization was needed to improve its predicted ability relative to the validation data set. Our results indicate that, although feedback inhibition on H2 production and methanogen activity increased with feeding level, other feedback effects that vary with diet composition need to be considered in future work on modeling rumen digestion in Molly. PMID- 26440025 TI - Additive methane-mitigating effect between linseed oil and nitrate fed to cattle. AB - The objective of this study was to test the effect of linseed oil and nitrate fed alone or in combination on methane (CH4) emissions and diet digestibility in cows. The experiment was conducted as a 2 * 2 factorial design using 4 multiparous nonlactating Holstein cows (initial BW 656 +/- 31 kg). Each experimental period lasted 5 wk, with measures performed in the final 3 wk (wk 3 to 5). Diets given on a DM basis were 1) control (CON; 50% natural grassland hay and 50% concentrate), 2) CON with 4% linseed oil (LIN), 3) CON with 3% calcium nitrate (NIT), and 4) CON with 4% linseed oil plus 3% calcium nitrate (LIN+NIT). Diets were offered twice daily and were formulated to deliver similar amounts (DM basis) of CP (12.2%), starch (25.5%), and NDF (39.5%). Feed offer was restricted to 90% of voluntary intake (12.4 kg DMI/d). Total tract digestibility and N balance were determined from total feces and urine collected separately for 6 d during wk 4. Daily CH4 emissions were quantified using open chambers for 4 d during wk 5. Rumen fermentation and microbial parameters were analyzed from samples taken before and 3 h after the morning feeding. Rumen concentrations of dissolved hydrogen (H2) were measured continuously up to 6 h after feeding using a H2 sensor. Compared with the CON diet linseed oil and nitrate decreased (P < 0.01) CH4 emissions (g/kg DMI) by 17 and 22%, respectively, when fed alone and by 32% when combined. The LIN diet reduced CH4 production throughout the day, increased (P = 0.02) propionate proportion, and decreased (P = 0.03) ruminal protozoa concentration compared with CON diet. The NIT diet strongly reduced CH4 production 3 h after feeding, with a simultaneous increase in rumen dissolved H2 concentration, suggesting that nitrate does not act only as an electron acceptor. As a combined effect, linseed plus nitrate also increased H2 concentrations in the rumen. Diets had no effect (P > 0.05) on total tract digestibility of nutrients, except linseed oil, which tended to reduce (P < 0.10) fiber digestibility. Nitrogen balance (% of N intake) was positive for all diets but retention was less (P = 0.03) with linseed oil. This study demonstrates an additive effect between nitrate and linseed oil for reducing methanogenesis in cows without altering diet digestibility. PMID- 26440026 TI - Feed restriction and subsequent realimentation in Holstein Friesian bulls: I. Effect on animal performance; muscle, fat, and linear body measurements; and slaughter characteristics. AB - Holstein Friesian bulls (n = 75) were used to evaluate the effect of restricted and subsequent compensatory growth on muscular and skeletal growth as well as the recovery of carcass and noncarcass components. Fifteen bulls were slaughtered on Day 0 to provide baseline parameters for carcass and noncarcass measurements. Of the remaining 60 bulls, 30 were fed ad libitum (ADLIB) and 30 were fed a restricted (RES) diet to grow at 0.6 kg/d for 125 d, denoted as Period 1. After 125 d of differential feeding, 15 bulls from each group were slaughtered. The remaining bulls in both treatment groups were then offered ad libitum access to feed for a further 55 d (realimentation), denoted as Period 2, after which they were also slaughtered. All animals received the same diet composed of 70% concentrate and 30% grass silage throughout the experimental trial. As planned, feed intake was greater for ADLIB bulls in Period 1 (P < 0.001); however, there was no difference in feed intake during realimentation (P > 0.05). During Period 1, RES bulls gained 0.6 kg/d whereas ADLIB bulls grew at 1.9 kg/d. During realimentation in Period 2, RES bulls displayed accelerated growth, gaining 2.5 kg/d compared with 1.4 kg/d for ADLIB bulls (P < 0.001). This amounted to a live weight difference between treatment groups of 161 kg at the end of Period 1 after restricted feeding, which was then reduced to 84 kg at the end of Period 2 (P < 0.001). Restricted animals achieved a compensatory growth (or recovery) index of 48% within 55 d of realimentation. During Period 2, RES bulls displayed a better feed conversion ratio (P < 0.001) than ADLIB bulls, indicating better feed efficiency. Ultrasonically measured longissmus dorsi growth was greater for ADLIB bulls compared with RES bulls during Period 1; however, this was reversed during Period 2 (P < 0.001). Metabolically active organs such as the liver and components of the gastrointestinal tract were lighter in RES bulls at the end of Period 1, with no difference in the weights of these components after realimentation (P < 0.01). The improved feed efficiency and muscle growth observed during feed restriction induced compensatory growth may be as a consequence of latent effects of reduced requirements of energetically demanding tissues into realimentation. PMID- 26440027 TI - Feed restriction and realimentation in Holstein-Friesian bulls: II. Effect on blood pressure and systemic concentrations of metabolites and metabolic hormones. AB - The objective of this study was to evaluate the endocrine response and metabolic rate in Holstein-Friesian bulls during restricted feeding and realimentation. Sixty bulls were allocated to 1 of 2 feeding regimes: 1) restricted feed allowance (RES; n = 30) or 2) ad libitum feeding (ADLIB; n = 30) for 125 d (Period 1). The bulls in both treatment groups were then offered ad libitum access to feed for a further 55 d (Period 2). Five and 4 blood samples were collected during periods 1 (n = 60) and 2 (n = 30), respectively. Plasma samples were assayed for hormones and metabolites including insulin, IGF-1, leptin, thyroid hormones, albumin, beta-hydroxy butyrate (BHB), creatinine, glucose, NEFA, total protein, triglycerides, and urea. Blood pressure measurements were determined on all animals at the beginning and end of each period as an indicator of metabolic rate. During Period 1, RES bulls gained 0.6 kg/d whereas ADLIB bulls grew at 1.9 kg/d. Following realimentation in Period 2, RES bulls displayed accelerated growth, gaining 2.5 kg/d compared with 1.4 kg/d for ADLIB bulls (P < 0.001). Treatment * period interactions (P < 0.05) were evident for all plasma analytes assayed. During Period 1, RES bulls had lower concentrations of glucose and insulin, reflecting their lower feed intake. Adipose and protein tissue mobilization was evident through greater concentrations of triglycerides, NEFA, BHB, creatinine, albumin, and total protein in RES animals in Period 1. Additionally, the effect of restricted feeding on growth was apparent through lower concentrations of IGF-1. A lower metabolic rate was also apparent through lower concentrations of thyroid hormones and fewer beats per minute in RES bulls during Period 1. During the initial stage of realimentation in Period 2, IGF-1, insulin, thyroid hormones, creatinine, glucose, total protein, and triglycerides followed the same pattern as per Period 1 with divergence maintained between RES and ADLIB bulls (P < 0.05), whereas concentrations of all of these hormones and metabolites had converged between the treatment groups by the end of Period 2. During realimentation, the number of heart beats per minute was greater in RES bulls, indicating greater metabolic rate in these animals (P < 0.001). Results from the current study clearly show that feed restriction followed by realimentation affects key indices of metabolic status as well as tissue catabolism and provides an insight into the metabolic control of compensatory growth in cattle. PMID- 26440028 TI - Effects of residual feed intake and dam body weight on replacement heifer intake, efficiency, performance, and metabolic response. AB - Thirty-eight Angus-based, crossbred, nulliparous beef heifers (BW = 280 +/- 26.3 kg) sired by 2 Angus sires were used to determine if dam BW affected heifer performance, DMI, residual feed intake (RFI), and endocrine markers. Heifers were housed in individual pens (2.2 by 9.1 m) equipped with 2.2 m of bunk space and fed a diet (90.4% DM, 13.7% CP, 67.2% NDF, and 56.2% TDN) consisting of 87.2% bermudagrass hay and 12.8% liquid protein supplement for a 14-d adaption period and a 70-d feeding period. Individual daily feed intake was used to calculate RFI for each heifer, and heifer was the experimental unit. Two-day beginning and end BW were recorded and hip height was used to calculate frame score (FS). Heifer dams were assigned to a light (LIT; 544 +/- 21.3 kg) or heavy (HEV; 621 +/- 34.8 kg) BW group on the basis of mean BW at the beginning of their lactation period the previous year to determine differences in heifer offspring DMI and RFI. Based on heifer RFI ranking, heifers were classified as positive (POS; 0.34) or negative (NEG; -0.31) RFI and low (LOW; -0.45), medium (MED; 0.00), or high (HI; 0.49) RFI for analysis of BW, FS, BW gain, and DMI. There were no dam BW group * sire interactions (P > 0.10) for all independent variables. Beginning and end BW was greater (P < 0.05) for heifers out of HEV compared with LIT BW dams. Body weight gain, ADG, FS, DMI, and RFI were not significant (P > 0.10) for heifers out of HEV compared with LIT BW dams; however, a sire effect existed (P < 0.01) for BW gain, ADG, FS, and DMI. Among RFI classifications, beginning and end BW, BW gain, ADG, and FS were not different (P > 0.10) whereas DMI was greater (P = 0.03) among heifers in the POS compared with the NEG RFI group and greater (P = 0.01) among heifers in the MED and HI compared with LOW RFI group, respectively. Plasma insulin levels were greater (P = 0.03) in the NEG compared with the POS RFI heifers, and thyroxine (T4) levels were greater (P = 0.02) in the POS compared with the NEG RFI heifers. A positive relationship existed (P <= 0.05) between dam BW and heifer DMI (r = 0.42), beginning and end BW (r = 0.45 and 54), and FS (r = 0.58) and between RFI and d 70 triiodothyronine (r = 0.34), d 70 T4 (r = 0.35), and d 0 and 70 combined T4 (r = 0.32), respectively. Heifers out of dams from the HEV BW group were heavier and a positive correlation existed between dam BW and heifer BW, gain, DMI, and FS, which can impact selection goals for replacement heifers. PMID- 26440029 TI - Effects of grind size when alkaline treating corn residue and impact of ratio of alkaline-treated residue and distillers grains on performance of finishing cattle. AB - Two studies were conducted to optimize use of alkaline-treated corn stover and wheat straw and distillers grains as partial corn replacements. In Exp. 1, a finishing experiment used 30 pens (12 steers/pen) of calf-fed steers (initial BW = 374 +/- 23.9 kg) with a 2 * 2 + 1 factorial arrangement of treatments with 6 replications per treatment. Factors were grind size, where corn stover was processed through a 2.54- or 7.62-cm screen, and chemical treatment (corn stover either fed in native, non-treated form [NT; 93.4% DM] or alkaline treated [AT; 5% CaO hydrated to 50% DM]). No interactions (P >= 0.38) were noted between grind size and chemical treatment. Feeding AT compared with NT improved (P <= 0.02) final BW, ADG, and G:F. Reducing grind size improved (P <= 0.01) ADG and G:F, and no interaction with chemical treatment was observed. Steers fed AT had similar DMI, ADG, G:F, and carcass characteristics compared with a 5% roughage control that contained 15 percentage units (DM basis) more corn. In Exp. 2, 60 individually fed steers (initial BW = 402 +/- 61.4 kg) were randomly assigned to 10 diets. Six treatments evaluated 10, 25, or 40% dry-rolled corn (DRC), which was replaced with either a 2:1 or 3:1 ratio (DM basis) of modified distillers grains plus solubles (MDGS) and treated corn stover analyzed as a 2 * 3 factorial. An additional 3 treatments were added where a 3:1 ratio of MDGS:straw were compared with a 3:1 ratio of MDGS:stover. As DRC increased, G:F (P = 0.06) quadratically increased for 3:1 MDGS:stover diets. Increasing DRC increased (P = 0.07) G:F in treated stover diets, regardless of ratio. Increasing DRC increased (P = 0.10) ADG for 3:1 ratios for both straw and stover. Reducing grind size, feeding a maximum of 20% treated crop residue, and maintaining at least 25% corn in the diet are strategies for optimizing cattle performance when replacing dry rolled and high-moisture corn with treated crop residues and distillers grains. PMID- 26440030 TI - Trailer temperature and humidity during winter transport of cattle in Canada and evaluation of indicators used to assess the welfare of cull beef cows before and after transport. AB - The current study evaluated 17 loads of cull beef cows transported in Canadian winter conditions to assess in-transit temperature and humidity, evaluation of events during loading and unloading, and animal condition and bruising. Regardless of the use of boards to block ventilation holes in trailers, temperatures were higher within trailers than at ambient locations during both travel and stationary periods (P < 0.01). Boarding was associated with smaller differences in trailer temperature, compared with ambient conditions, while the trailer was traveling at highway speeds versus when trailers were stationary (P < 0.01). Moisture levels within trailers were not different from ambient conditions when loads using boarding were traveling (P < 0.01), whereas loads without boarding had a larger difference (P < 0.01). The moisture within trailers relative to ambient conditions increased when trailers were stationary compared with traveling when boarding was used (P < 0.01). The majority of cattle transported were in good body condition (97.4% within BCS of 2 to 3.5) and had calm temperaments (96.7%). Although all comparisons were made, only the doghouse compartment had an increased risk of severe bruising compared with all other compartments (odds ratio [95% confidence interval]: 3.0 [1.6-5.5], 3.7 [2.1-6.4], 2.2 [1.3-3.7] and 3.8 [1.5-9.6] in comparison with the back, belly, deck, and nose compartments, respectively; P < 0.05). Increasing the duration of waiting to unload 30 min relative to a 1 h duration increased the odds of severe bruising by 1.18 times (95% confidence interval: 1.09-1.29; P < 0.01). Scoring systems that have been developed for auditing unloading of cattle had limited variation across loads at both loading and unloading. Pretransport assessment of animal condition using the American Meat Institute's compromised animal score was the only scoring system that was consistent with posttransport scores. We inferred from the temperature and humidity data in the current study that under commercial conditions, boarding may increase ventilation within trailers during travel and decrease ventilation during stationary periods. The current study provides the first indication that issues in Canadian cull cow transport may be related to pretransport animal condition and management of unloading. PMID- 26440031 TI - Technical note: Digital quantification of eye pigmentation of cattle with white faces. AB - Cancer of the eye in cattle with white faces occurs less frequently in cattle with pigmented eyelids. Corneoscleral pigmentation is related to eyelid pigmentation and occurrence of lesions that may precede cancer. Objectives of this study were to assess 1) variation in the proportion of eyelid and corneoscleral pigmentation in Hereford, Bos taurus, and Bos indicus crossbreds and 2) the occurrence of lesions with the presence of pigmentation in those areas. Hereford and Bos indicus crosses (Brahman or Nellore with Angus and Hereford and straightbred Brafords) and Bos taurus crosses (Angus-Hereford) were included in the study (n = 1,083). Eyelid pigmentation proportions were estimated by pixel quantification and were evaluated as total proportions and for upper and lower eyelids distinctly for each eye. Fixed effects included breed type, age categories, and sex of the animal. Lesion presence (1) or absence (0) was obtained by visual appraisal of image and was assumed to be binomially distributed. Eyelid pigmentation proportions (overall, upper, and lower eyelids) for Hereford ranged from 0.65 +/- 0.03 to 0.68 +/- 0.03 and were significantly lower than Bos indicus (range from 0.93 +/- 0.02 to 0.95 +/- 0.02) or Bos taurus (ranged from 0.88 +/- 0.02 to 0.92 +/- 0.02) crosses. Corneoscleral pigmentation in Hereford cows (0.17 +/- 0.06) did not differ (P = 0.91) from Hereford calves and yearlings (0.16 +/- 0.07). Bos indicus and Bos taurus crossbred cows had larger corneoscleral pigmentation (0.38 +/- 0.05 and 0.48 +/- 0.04 for left eyes and 0.37 +/- 0.05 and 0.53 +/- 0.04 for right eyes, respectively) than all calves (P < 0.001), and their corneoscleral pigmentations were greater than that of Hereford cows (P < 0.003). Bos indicus and Bos taurus cows had greater proportions of left eye corneoscleral pigmentation (0.38 +/- 0.05 and 0.48 +/- 0.04, respectively) than Hereford cows (0.17 +/- 0.06) and all young animal breed types (P < 0.05). Right eye proportions differed for all cow groups (P < 0.05; 0.53 +/- 0.04, 0.37 +/- 0.05, and 0.17 +/- 0.06). Among calves and yearlings, Hereford had a lower right eye corneoscleral pigmentation proportion (0.16 +/- 0.07) than Bos taurus (P = 0.02). The lesion proportion for Hereford (0.08 +/- 0.03) was significantly greater than that of either Bos indicus (0.01 +/- 0.005) or Bos taurus (0.01 +/- 0.003). Crossbreeding with Bos taurus or Bos indicus animals appears to increase eye pigmentation, which may help reduce the occurrence of cancer in eyes of cattle with white faces. PMID- 26440032 TI - Evaluation of multiple ancillary therapies used in combination with an antimicrobial in newly received high-risk calves treated for bovine respiratory disease. AB - Ancillary therapy (ANC) is commonly provided in conjunction with an antimicrobial when treating calves for suspected bovine respiratory disease (BRD) in an attempt to improve the response to a suspected BRD challenge. The first experiment evaluated the effects of 3 ANC in combination with an antimicrobial in high-risk calves treated for BRD during a 56-d receiving period. Newly received crossbred steers (n = 516; initial BW = 217 +/- 20 kg) were monitored by trained personnel for clinical signs of BRD. Calves that met antimicrobial treatment criteria (n = 320) were then randomly assigned to experimental ANC treatment (80 steers/experimental ANC treatment): intravenous flunixin meglumine injection (NSAID), intranasal viral vaccination (VACC), intramuscular vitamin C injection (VITC), or no ANC (NOAC). Animal served as the experimental unit for all variables except DMI and G:F (pen served as the experimental unit for DMI and G:F). Within calves treated 3 times for BRD, those receiving NOAC had lower (P < 0.01) clinical severity scores (severity scores ranged from 0 to 4 on the basis of observed clinical signs and severity) and heavier (P = 0.01) BW than those receiving NSAID, VACC, or VITC at the time of third treatment. Between the second and third BRD treatments, calves receiving NOAC had decreased (P < 0.01) daily BW loss (-0.13 kg ADG) compared with those receiving NSAID, VACC, or VITC (-1.30, 1.90, and -1.41 kg ADG, respectively). There were no differences in rectal temperature, combined mortalities and removals, or overall performance among the experimental ANC treatments. Overall, morbidity and mortality attributed to BRD across treatments were 66.5% and 13.2%, respectively. After the receiving period, a subset of calves (n = 126) were allocated to finishing pens to evaluate the effects ANC administration on finishing performance, carcass characteristics, and lung scores at harvest. Ultrasound estimates, BW, and visual appraisal were used to target a common physiological end point for each pen of calves. There were no differences among the experimental ANC observed during the finishing period (P >= 0.11). In summary, the use of NSAID, VACC, and VITC do not appear to positively impact clinical health and could potentially be detrimental to performance during the receiving period in high-risk calves receiving antimicrobial treatment for suspected BRD. PMID- 26440033 TI - Evaluation of the effect of alternative measurements of body weight gain and dry matter intake for the calculation of residual feed intake in growing purebred Charolais and Red Angus cattle. AB - The objective of this study was to determine the effects of alternative measurements of body weight and DMI used to evaluate residual feed intake (RFI). Weaning weight (WW), ADG, and DMI were recorded on 970 growing purebred Charolais bulls (n = 519) and heifers (n = 451) and 153 Red Angus growing steers (n = 69) and heifers (n = 84) using a GrowSafe (GrowSafe, Airdrie, Alberta, Canada) system. Averages of individual DMI were calculated in 10-d increments and compared to the overall DMI to identify the magnitude of the errors associated with measuring DMI. These incremental measurements were also used in calculation of RFI, computed from the linear regression of DMI on ADG and midtest body weight0.75 (MMWT). RFI_Regress was calculated using ADG_Regress (ADG calculated as the response of BW gain and DOF) and MMWT_PWG (metabolic midweight calculated throughout the postweaning gain test), considered the control in Red Angus. A similar calculation served as control for Charolais; RFI was calculated using 2-d consecutive start and finish weights (RFI_Calc). The RFI weaning weight (RFI_WW) was calculated using ADG_WW (ADG from weaning till the final out weight of the postweaning gain test) and MMWT_WW, calculated similarly. Overall average estimated DMI was highly correlated to the measurements derived over shorter periods, with 10 d being the least correlated and 60 d being the most correlated. The ADG_Calc (calculated using 2-d consecutive start and finish weight/DOF) and ADG_WW were highly correlated in Charolais. The ADG_Regress and ADG_Calc were highly correlated, and ADG_Regress and ADG_WW were moderately correlated in Red Angus. The control measures of RFI were highly correlated with the RFI_WW in Charolais and Red Angus. The outcomes of including abbreviated period DMI in the model with the weaning weight gain measurements showed that the model using 10 d of intake (RFI WW_10) was the least correlated with the control measures. The model with 60 d of intake had the largest correlation with the control measures. The fewest measured intake days coupled with the weaning weight values providing acceptable predictive value was RFI_WW_40, being highly correlated with the control measures. As established in the literature, at least 70 d is required to accurately measure ADG. However, we conclude that a shorter period, possibly as few as 40 d is needed to accurately estimate DMI for a reliable calculation of RFI. PMID- 26440034 TI - Stocking rate and monensin supplemental level effects on growth performance of beef cattle consuming warm-season grasses. AB - The objective of this study was to evaluate the effects of monensin supplementation on animals receiving warm-season grass with limited supplementation. In Exp. 1, treatments were a factorial combination of 2 stocking rates (1.2 and 1.7 animal unit [AU] [500 kg BW]/ha) and supplementation with monensin (200 mg/d) or control (no monensin) distributed in a complete randomized design with 3 replicates. Thirty Angus * Brahman crossbred heifers (Bos taurus * Bos indicus) with initial BW of 343 +/- 8 kg were randomly allocated into 12 bahiagrass (Paspalum notatum) pastures and supplemented with 0.4 kg DM of concentrate (14% CP and 78% TDN) daily for 86 d. Herbage mass (HM) and nutritive value evaluations were conducted every 14 d, and heifers were weighed every 28 d. There was no effect (P >= 0.97) of monensin on HM, herbage allowance (HA), and ADG; however, animals receiving monensin had greater (P = 0.03) plasma urea nitrogen (PUN) concentrations. The stocking rate treatments had similar HM in June (P = 0.20) and July (P = 0.18), but the higher stocking rate decreased (P < 0.01) HM and HA during August and September. Average daily gain was greater (P < 0.01) for the pastures with the lower stocking rate in August but not different in July and September (P >= 0.15). Gain per hectare tended to be greater on pastures with the higher stocking rate (P <= 0.06). In Exp. 2, treatments were 3 levels of monensin (125, 250, and 375 mg/animal per day) and control (no monensin) tested in a 4 * 4 Latin square with a 10-d adaptation period followed by 5 d of rumen fluid collection and total DMI evaluation. Blood samples were collected on d 4 and 5 of the collection period. Ground stargrass (Cynodon nlemfuensis) hay (11.0% CP and 52% in vitro digestible organic matter) was offered daily. The steers received the same supplementation regimen as in Exp. 1. Total DMI was not different among treatments (P = 0.64). There was a linear increase (P <= 0.01) in propionate and a tendency for decreased acetate (P <= 0.09) concentrations in the rumen with increasing levels of monensin; however, there was no effect (P >= 0.19) of monensin levels on ruminal pH and ruminal concentrations of butyrate and ammonia. In addition, there was no effect (P >= 0.73) of monensin levels on plasma concentrations of glucose, insulin, IGF-1, and PUN. In summary, monensin supplementation effects were not detected at either stocking rate and may not be effective in increasing performance of beef cattle grazing low-quality warm-season grasses with limited supplementation. PMID- 26440035 TI - Elk (Cervus Canadensis) preference for feeds varying in selenium concentration. AB - Selenium-accumulator plants are reputed to be unpalatable to large ungulates. Elk (Cervus canadensis) populations in southeastern Idaho overlap with populations of Se-rich plants, but there is no information on the influence of plant Se concentration on elk dietary preferences. The objective of this study was to determine, under controlled conditions, the preference of elk for feeds varying in Se concentrations. Seven yearling female elk (128 +/- 5 kg) were purchased from a commercial elk farm in southeastern Idaho and adapted to low-Se alfalfa pellets. Three feeding trials using pellets with predetermined Se concentrations were conducted. Alfalfa pellets were commercially made with the addition of Symphyotrichum ascendens (western aster) so that the pellets contained 0.4, 5, 20, 50, or 100 mg/kg (DM basis) Se. In trial 1, 5 Se-containing alfalfa pellets (0.4, 5, 20, 50, and 100 mg/kg Se) were offered for 10 d; trial 2 used 4 Se containing alfalfa pellet choices (0.4, 20, 50, and 100 mg/kg), and trial 3 used 3 pellet choices (0.4, 50, and 100 mg/kg) for 6 d. In trial 1, consumption of the control pellets by elk was greater than each of the other pellet choices (P < 0.001). Similarly, consumption of the 5-mg/kg Se pellet differed from control pellet and all other Se-containing pellets (P < 0.0001). There were no differences (P > 0.50) in consumption of the 20-, 50-, or 100-mg/kg Se pellets. In trial 2, elk consumed more (P < 0.0001) of the control pellet than the 20-, 50 , and 100-mg/kg Se pellets. Similarly, elk consumed more (P < 0.0001) of the 20 mg/kg Se pellet than the 50- and 100-mg/kg Se pellets. There were no differences (P > 0.99) in elk consumption of the 50- and 100-mg/kg Se pellets. In trial 3, elk consumption of the control and 50- and 100-mg/kg Se pellets differed (P <= 0.03) from one another each day except that on d 1 and 2, where elk consumption of the 50- and 100-mg/kg Se pellets did not differ (P >= 0.32). Elk clearly discriminated against pellets with the highest Se concentrations when they were given pellets with differing Se concentrations. These results suggest that elk are not likely to select forages with high Se concentrations, particularly when high-Se plants are present in a rangeland situation with numerous other forage choices. PMID- 26440036 TI - Effects of glycerin concentration in steam-flaked corn-based diets with supplemental yellow grease on performance and carcass characteristics of finishing beef steers. AB - Forty-eight individually fed crossbred steers (initial BW = 381 +/- 7.61 kg) were used to determine the effects of glycerin (GLY) concentration in steam-flaked corn (SFC)-based diets with added yellow grease on animal performance and carcass characteristics. Glycerin was included at 0, 2.5, 5, and 10% dietary DM replacing SFC. A completely randomized design was used with steers as the experimental unit, and the model included the fixed effects of diet. Contrast statements were used to determine linear and quadratic effects of GLY inclusion. Final BW and DMI were not affected (P > 0.27) by GLY concentration. Average daily gain and G:F based on live BW did not differ as GLY level increased in the diet from 0 to 10% of DM (P > 0.33). Carcass-adjusted final BW and carcass-adjusted G:F were also not affected by GLY concentration (P > 0.22); however, carcass-adjusted ADG tended to respond quadratically by decreasing from 2.5 to 5% GLY inclusion and increasing thereafter (P = 0.10). Calculated dietary NEm and NEg did not differ as GLY increased in the diet (P > 0.37). Hot carcass weight tended to respond quadratically, decreasing from 2.5 to 5% GLY and increasing thereafter (P = 0.10). Likewise, dressing percentage tended to respond quadratically by decreasing from 2.5 to 5% GLY inclusion and increasing to 10% GLY inclusion (P = 0.09). Fat thickness decreased linearly as GLY inclusion increased in the diet (P < 0.01); however, no differences were detected in marbling score and LM area (P > 0.21). Calculated yield grade (YG) decreased linearly as GLY increased in the diet from 0 to 10% of DM (P = 0.04). Based on our results, there was no animal performance benefit for replacing SFC with GLY in diets containing yellow grease, and the only change in carcass merit was a slight improvement in YG. PMID- 26440037 TI - Assessing adaptive immune response phenotypes in Australian Holstein-Friesian heifers in a pasture-based production system. AB - The objective of this study was to determine the repeatability of ranking Holstein-Friesian heifers reared in an Australian pasture-based production system for immune responses (IR) when ranking was based on secondary versus tertiary IR. Further objectives were to investigate associations between IR and stress responsiveness, ADG and resistance to internal parasites. A total of 100 heifers were IR phenotyped at 5 to 6 mo of age and again at 12 to 13 mo of age using commercial vaccine antigens to induce measurable IR. Antibody production to tetanus toxoid (TT) was used to assess antibody-mediated IR (AMIR), and delayed type hypersensitivity reactions to vaccine antigens were used to assess cell mediated IR (CMIR). Changes in serum cortisol and haptoglobin were used to assess stress responsiveness and fecal egg counts used as a measure of resistance to internal parasites. Based on testing, animals were categorized as either average to above-average (High) or low responders for IR. Secondary and tertiary AMIR were well correlated (r = 0.651, adjusted R(2) = 0.418, P < 0.0001), whereas correlations between secondary and tertiary CMIR were poor (r = 0.078, R(2) = 0.004, P = 0.450). A Cohen kappa (kappa) test of agreement was used to test the consistency of ranking of individual animal for IR and, therefore, the ability to consistently identify low immune responder animals within the herd across test periods. The consistency of ranking (High versus low) was moderately high for AMIR (kappa = 0.445), poor for CMIR (kappa = -0.055), and fair to moderate for combined IR (kappa = 0.395). High AMIR phenotype animals had significantly higher serum cortisol concentrations than their low immune responder counterparts (P = 0.045). A similar relationship was observed in heifers categorized for CMIR, with High CMIR responders having higher serum cortisol concentrations than their low responder counterparts (P = 0.008). High AMIR calves had a higher ADG compared with low AMIR calves (0.72 +/- 0.02 versus 0.66 +/- 0.06 kg/d; P = 0.009). Serum haptoglobin concentrations and worm egg counts were very low and could not be used to investigate associations with immune responsiveness. It is concluded that secondary and tertiary antibody responses to TT were well correlated in the Holstein-Friesian heifers in this study and that by using the testing procedure described here, low antibody responders were able to be consistently identified in the herd. PMID- 26440038 TI - The flipped classroom stimulates greater learning and is a modern 21st century approach to teaching today's undergraduates. AB - Many classrooms in higher education still rely on a transformative approach to teaching where students attend lectures and earn course grades through examination. In the modern age, traditional lectures are argued by some as obsolete and do not address the learning needs of today's students. An emerging pedagogical approach is the concept of the flipped classroom. The flipped classroom can simply be described as students viewing asynchronous video lectures on their own and then engaging in active learning during scheduled class times. In this study, we examined the flipped classroom teaching environment on student learning gains in an Introduction to Equine Science course. Students (n = 130) were asked to view 7.5 h of recorded lectures divided into 8 learning modules, take online quizzes to enforce lecture viewing, take 3 in-class exams, and prepare to participate in active learning during scheduled class times. Active learning approaches included individual activities, paired activities, informal small groups, and large group activities. When compared to students in the traditional lecture format in earlier years, students in the flipped format scored higher on all 3 exams (P < 0.05), with both formats taught by the same instructor. Analysis of ACT scores demonstrated no intellectual capacity differences between the student populations. To evaluate any gains in critical thinking, flipped format students were asked to take the Cornell Critical Thinking Exam (version X). Scores improved from the pretest (50.8 +/- 0.57) to the posttest (54.4 +/- 0.58; P < 0.01). In the flipped course, no correlations were found with student performance and interactions with online content. Students were asked in class to evaluate their experiences based on a 5-point Likert scale: 1 (strongly disagree) to 5 (strongly agree). The flipped classroom was ranked as an enjoyable learning experience with a mean of 4.4 +/- 0.10, while students responded positively to other pointed questions. In formal course evaluations, flipped format students ranked the following higher (P < 0.05): instructor availability to assist students; encouragement of independent, creative, and critical thinking; and amount learned. Overall, the flipped classroom proved to be a positive learning experience for students. As the classroom continues to modernize, pedagogical approaches such as the flipped classroom should be considered for many lecture-style courses taught in the animal sciences. PMID- 26440039 TI - Low efficacy of tobramycin in experimental Staphylococcus aureus endocarditis. AB - The empiric treatment of infective endocarditis (IE) varies widely and, in some places, a regimen of penicillin in combination with an aminoglycoside is administered. The increasing incidence of Staphylococcus aureus IE, poor tissue penetration by aminoglycosides and low frequency of penicillin-susceptible S. aureus may potentially lead to functional tobramycin monotherapy. Therefore, this study aimed to evaluate tobramycin monotherapy in an experimental S. aureus IE rat model. Catheter-induced IE at the aortic valves were established with S. aureus (NCTC 8325-4) and rats were randomised into untreated (n = 22) or tobramycin-treated (n = 13) groups. The treatment group received tobramycin once daily. Animals were evaluated at 1 day post infection (DPI), 2 DPI or 3 DPI. Quantitative bacteriology and cytokine expression were measured for valves, myocardium and serum. A decrease of bacterial load was observed in valves and the spleens of the treated (n = 6) compared to the untreated group at 2 DPI (n = 8) (p <= 0.02 and p <= 0.01, respectively), but not at 3 DPI (n = 7). Quantitative bacteriology in the myocardium was not different between the groups. Keratinocyte derived chemokine (KC) in the aortic valves was significantly reduced at 2 DPI in the tobramycin-treated group (p <= 0.03). However, the expression of interleukin (IL)-1b, IL-6 and granulocyte-colony stimulating factor (G-CSF) in the valves was not different between the two groups. In the myocardium, a significant reduction in IL-1b was observed at 2 DPI (p <= 0.001) but not at 3 DPI. Tobramycin as functional monotherapy only reduced bacterial load and inflammation transiently, and was insufficient in most cases of S. aureus IE. PMID- 26440040 TI - Molecular seasonal, age and gender distributions of Cryptosporidium in diarrhoeic Egyptians: distinct endemicity. AB - Cryptosporidiosis is a worldwide gastrointestinal disease caused by the protozoan Cryptosporidium parasite. It has a broad range of seasonal and age-related prevalence. We aimed to study the molecular prevalence and seasonality of Cryptosporidium over a period of 1 year in a cohort of Egyptian diarrhoeic patients. Stool samples were collected from 865 diarrhoeic patients attending outpatient clinics of Cairo University hospitals, from all age groups over a 12 month period, examined microscopically for faecal Cryptosporidium oocysts by the acid-fast staining method and for copro-DNA detection using nested polymerase chain reaction (nPCR) assays. PCR-positive samples were characterised molecularly by nPCR-restriction fragment length polymorphism (RFLP) to determine Cryptosporidium genotypes. Cryptosporidium copro-DNA was detected in 19.5% of the collected samples throughout the year, with a major peak in summer (August) and a small rise in spring (April). Infection was mainly C. hominis (95.8%) followed by C. parvum (3.0%), affecting all age groups, with predominance in the pre-school age group, and decrease with age. There were statistically significant associations between the detection of Cryptosporidium and season, diarrhoea, patient age and drinking water, while gender, contact with animals and presence of mucus in stool showed no association. Cryptosporidium in diarrhoeic Egyptians was of distinct endemicity, with the bi-model mostly influenced by population dynamics, with a clear high prevalence in pre-school children and predominating anthroponotic (C. hominis) transmission throughout the year. The obtained results highlight Cryptosporidium as a water contaminant and an important cause of health problems in Egypt, necessitating further studies of the risk factors. PMID- 26440042 TI - Insulin-like growth factor I and risk of incident cancer in elderly men - results from MrOS (Osteoporotic Fractures in Men) in Sweden. AB - OBJECTIVE: Studies of the association between circulating IGF-I and cancer risk have shown conflicting results. We have previously observed a U-shaped association between IGF-I and cancer mortality. This study test the hypotheses of a U-shaped association between IGF-I and incident cancer. DESIGN: Elderly men (2368), randomly recruited from the general community. METHODS: IGF-I was measured in a cohort of elderly men. Complete data for incident cancer were obtained from the Swedish Cancer Registry. Statistical analyses included Cox proportional hazards regressions with or without a spline approach. RESULTS: Three hundred and sixty-nine participants had incident cancer after baseline. Prostate cancer was most frequent (n = 140). There was no association between serum IGF-I and all cancer or prostate cancer incidence. However, there was a nonlinear association between IGF-I and nonprostate cancer incidence (P = <0.05). Exploratory analyses were performed for low and high serum IGF-I (quintiles 1 and 5) vs intermediate (quintiles 2-4, referent). There was a tendency of increased nonprostate cancer risk in men with high IGF-I (HR = 1.26, 95% confidence interval (CI): 0.92-1.71, P = 0.15). After excluding participants with follow-up of less than 2.6 years (half median follow-up time), to control for potential diagnostic delay, the association was statistically significant (HR = 1.55, CI: 1.03-2.35). CONCLUSION: There was a significant nonlinear association between IGF I and nonprostate cancer. No association between IGF-I and prostate cancer was observed. Future studies are warranted to further investigate this nonlinear association, including whether IGF-I concentration is a reproducible, and useful, risk marker of nonprostate cancer. PMID- 26440041 TI - Clostridium difficile infection in patients with liver disease: a review. AB - Over the past two decades, there has been a dramatic worldwide increase in both the incidence and severity of Clostridium difficile infection (CDI). Paralleling the increased incidence of CDI in the general population, there has been increased interest in CDI among patients with liver disease, particularly in those with liver cirrhosis and post liver transplantation. MEDLINE and several other electronic databases from January 1995 to December 2014 were searched in order to identify potentially relevant literature. Patients with cirrhosis and liver transplant recipients are at high risk for the development CDI because of antibiotics and proton pump inhibitors use, frequent and prolonged hospitalization, immunosuppressant therapy, and multiple comorbidities. Enzyme immunoassay to detect C. difficile toxins A and B in stool remains the most widely used test for CDI diagnosis, although, more recently, polymerase chain reaction (PCR)-based assays have become the preferred diagnostic test in many laboratories. Metronidazole and vancomycin, given orally, have proved to be effective in the treatment of CDI. Both cirrhotic patients and liver transplant recipients with CDI have longer length of hospital stay, increased mortality, and higher healthcare costs than those without CDI. A rapid diagnosis and adequate therapy of CDI are of paramount importance to improve liver disease patients' outcome. The aim of this review is to provide up-to-date information on the epidemiology, risk factors, pathogenesis, treatment, and outcomes in liver disease patients with CDI. PMID- 26440043 TI - Poly(ADP-ribosyl)ation is involved in pro-survival autophagy in porcine blastocysts. AB - Poly(ADP-ribosyl)ation (PARylation) prevents apoptosis through its involvement in pro-survival autophagy in cultured cells; whether or not the same is true for pre implantation embryos has not yet been documented. In this study, we investigated the participation of PARylation and autophagy in in vitro porcine pre implantation embryo development. The transcript levels of autophagy-related genes and poly(ADP-ribose) polymerase 1 (PARP1), an enzyme required for PARylation, were transiently up-regulated by fertilization, decreased at the late 1-cell stage, and maintained until the blastocyst stage. LC3, a marker of autophagosomes, and poly(ADP-ribose) (PAR) polymer were present in all stages of pre-implantation development. Exposure of embryos to 3-methyladenine, an autophagy inhibitor, or 3-aminobenzamide, a PARP inhibitor, suppressed the development of blastocysts. Pharmacological inhibition of PARylation further suppressed pro-survival autophagy by decreasing the expression of autophagy related genes (ATG5, BECLIN1, and LC3) and decreasing LC3 protein abundance while increasing the rate of apoptosis in blastocysts. Deficiency in autophagy also induced abnormal accumulation of SQSTM1/p62 aggregates in porcine blastocysts. Collectively, these data suggest that PARylation is involved in selective autophagic degradation of ubiquitinated proteins, functioning in a pro-survival role, in porcine in vitro-produced embryos. These pro-survival regulatory mechanisms may be important for the control of embryo quality. PMID- 26440044 TI - Predictors of successful weight reduction and maintenance in obese children and adolescents. PMID- 26440046 TI - Chondroitin Sulfate Glycosaminoglycan Hydrogels Create Endogenous Niches for Neural Stem Cells. AB - Neural stem cells (NSCs) possess great potential for neural tissue repair after traumatic injuries to the central nervous system (CNS). However, poor survival and self-renewal of NSCs after injury severely limits its therapeutic potential. Sulfated chondroitin sulfate glycosaminoglycans (CS-GAGs) linked to CS proteoglycans (CSPGs) in the brain extracellular matrix (ECM) have the ability to bind and potentiate trophic factor efficacy, and promote NSC self-renewal in vivo. In this study, we investigated the potential of CS-GAG hydrogels composed of monosulfated CS-4 (CS-A), CS-6 (CS-C), and disulfated CS-4,6 (CS-E) CS-GAGs as NSC carriers, and their ability to create endogenous niches by enriching specific trophic factors to support NSC self-renewal. We demonstrate that CS-GAG hydrogel scaffolds showed minimal swelling and degradation over a period of 15 days in vitro, absorbing only 6.5 +/- 0.019% of their initial weight, and showing no significant loss of mass during this period. Trophic factors FGF-2, BDNF, and IL10 bound with high affinity to CS-GAGs, and were significantly (p < 0.05) enriched in CS-GAG hydrogels when compared to unsulfated hyaluronic acid (HA) hydrogels. Dissociated rat subventricular zone (SVZ) NSCs when encapsulated in CS GAG hydrogels demonstrated ~88.5 +/- 6.1% cell viability in vitro. Finally, rat neurospheres in CS-GAG hydrogels conditioned with the mitogen FGF-2 demonstrated significantly (p < 0.05) higher self-renewal when compared to neurospheres cultured in unconditioned hydrogels. Taken together, these findings demonstrate the ability of CS-GAG based hydrogels to regulate NSC self-renewal, and facilitate growth factor enrichment locally. PMID- 26440045 TI - Self-Assembled DNA Immunonanoflowers as Multivalent CpG Nanoagents. AB - Synthetic unmethylated cytosine-guanine (CpG) oligodeoxynucleotides are immunostimulatory motifs that have shown promise as vaccines or adjuvants for diseases such as cancers and infectious diseases. In the present work, novel immuno-nanoflowers (NFs), self-assembled from long DNA integrated with tandem CpG through rolling circle replication, were developed for efficient CpG delivery and protection from nuclease degradation. In a model of macrophage-like cells, the CpG NFs proved to be potent immunostimulators by triggering the proliferation of these immune cells, which, in turn, secreted immunostimulatory cytokines, including tumor necrosis factor alpha, interleukin-6, and interleukin-10. These results demonstrate the ability of CpG NFs to induce cancer cell apoptosis and necrosis. PMID- 26440047 TI - Engineered Adhesion Peptides for Improved Silicon Adsorption. AB - Engineering peptides that present selective recognition and high affinity for a material is a major challenge for assembly-driven elaboration of complex systems with wide applications in the field of biomaterials, hard-tissue regeneration, and functional materials for therapeutics. Peptide-material interactions are of vital importance in natural processes but less exploited for the design of novel systems for practical applications because of our poor understanding of mechanisms underlying these interactions. Here, we present an approach based on the synthesis of several truncated peptides issued from a silicon-specific peptide recovered via phage display technology. We use the photonic response provided by porous silicon microcavities to evaluate the binding efficiency of 14 different peptide derivatives. We identify and engineer a short peptide sequence (SLVSHMQT), revealing the highest affinity for p(+)-Si. The molecular recognition behavior of the obtained peptide fragment can be revealed through mutations allowing identification of the preferential affinity of certain amino acids toward silicon. These results constitute an advance in both the engineering of peptides that reveal recognition properties for silicon and the understanding of biomolecule-material interactions. PMID- 26440048 TI - Chromatin-Remodelling Complex NURF Is Essential for Differentiation of Adult Melanocyte Stem Cells. AB - MIcrophthalmia-associated Transcription Factor (MITF) regulates melanocyte and melanoma physiology. We show that MITF associates the NURF chromatin-remodelling factor in melanoma cells. ShRNA-mediated silencing of the NURF subunit BPTF revealed its essential role in several melanoma cell lines and in untransformed melanocytes in vitro. Comparative RNA-seq shows that MITF and BPTF co-regulate overlapping gene expression programs in cell lines in vitro. Somatic and specific inactivation of Bptf in developing murine melanoblasts in vivo shows that Bptf regulates their proliferation, migration and morphology. Once born, Bptf-mutant mice display premature greying where the second post-natal coat is white. This second coat is normally pigmented by differentiated melanocytes derived from the adult melanocyte stem cell (MSC) population that is stimulated to proliferate and differentiate at anagen. An MSC population is established and maintained throughout the life of the Bptf-mutant mice, but these MSCs are abnormal and at anagen, give rise to reduced numbers of transient amplifying cells (TACs) that do not express melanocyte markers and fail to differentiate into mature melanin producing melanocytes. MSCs display a transcriptionally repressed chromatin state and Bptf is essential for reactivation of the melanocyte gene expression program at anagen, the subsequent normal proliferation of TACs and their differentiation into mature melanocytes. PMID- 26440049 TI - Alpha-linolenic acid regulates Cox2/VEGF/MAP kinase pathway and decreases the expression of HPV oncoproteins E6/E7 through restoration of p53 and Rb expression in human cervical cancer cell lines. AB - Cervical cancer represents the largest cause of mortality in women worldwide. In our previous report, we have shown how alpha-linolenic acid (ALA), an omega-3 fatty acid, regulated the growth of cervical cancer cells. The present study aimed to explore mechanistic details for the anticancer activity of ALA in cervical cancer cell lines, SiHa and HeLa. ALA significantly modulated the growth kinetics of the cells and reduced cell migration with concomitant decrease in the expression of VEGF, MMP-2, and MMP-9 proteins. Besides this, ALA significantly decreased the expression of phosphorylated p38, pERK1/2, c-JUN, NFkappaB, and COX2, proteins. Most importantly, ALA reduced the expression of HPV onco-proteins E6 and E7, resulting into restoration of expression of tumor suppressor proteins, p53 and Rb. These results suggested that ALA could be explored for its therapeutic potential in cervical cancer. PMID- 26440050 TI - Differential function and regulation of orphan nuclear receptor TR3 isoforms in endothelial cells. AB - TR3 has been reported to be an excellent target for angiogenesis therapies. We reported three TR3 transcript variant messenger RNAs (mRNAs) are expressed in human umbilical vein endothelial cell (HUVEC) and are differentially regulated by vascular endothelial growth factor (VEGF). TR3 transcript variant 1 (TR3-TV1) and variant 2 (TR3-TV2) encoding the same TR3 isoform 1 protein (TR3-iso1) that was named TR3 has been extensively studied. However, the function of TR3 isoform 2 protein (TR3-iso2) encoded by TR3 transcript variant 3 (TR3-TV3) is still not known. Here, we clone and express the novel TR3-iso2 protein and find that expression of TR3-iso2, in contrast to TR3-iso1, inhibits endothelial cell proliferation induced by VEGF-A, histamine, and phorbol-12-myristate-13-acetate (PMA). The differential function of TR3-iso2 correlates with the down-regulation of cyclin D1. However, TR3-iso2 plays similar roles in endothelial cell migration and monolayer permeability as TR3-iso1. We further demonstrate that several intracellular signaling pathways are involved in histamine-induced TR3 transcript variants, including histamine receptor H1-mediated phospholipase C (PLC)/calcium /calcineurin/protein kinase C (PKC)/protein kinase D (PKD) pathway and ERK pathway, as well as histamine receptor H3-mediated PKC-ERK pathway. Further, expressions of TR3-TV1, TR3-TV2, and TR3-TV3 by VEGF and histamine are regulated by different promoters, but not by their mRNA stability. PMID- 26440051 TI - HMGB1 enhances the protumoral activities of M2 macrophages by a RAGE-dependent mechanism. AB - The monocyte-macrophage lineage shows a high degree of diversity and plasticity. Once they infiltrate tissues, they may acquire two main functional phenotypes, being known as the classically activated type 1 macrophages (M1) and the alternative activated type 2 macrophages (M2). The M1 phenotype can be induced by bacterial products and interferon-gamma and exerts a cytotoxic effect on cancer cells. Conversely, the alternatively activated M2 phenotype is induced by Il 4/IL13 and promotes tumor cell growth and vascularization. Although receptor for advanced glycation end-products (RAGE) engagement in M1 macrophages has been reported by several groups to promote inflammation, nothing is known about the functionality of RAGE in M2 macrophages. In the current study, we demonstrate that RAGE is equally expressed in both macrophage phenotypes and that RAGE activation by high-mobility group protein box1 (HMGB1) promotes protumoral activities of M2 macrophages. MKN45 cells co-cultured with M2 macrophages treated with HMGB1 at different times displayed higher invasive abilities. Additionally, conditioned medium from HMGB1-treated M2 macrophages promotes angiogenesis in vitro. RAGE-targeting knockdown abrogates these activities. Overall, the present findings suggest that HMGB1 may contribute, by a RAGE-dependent mechanism, to the protumoral activities of the M2 phenotype. PMID- 26440053 TI - Thermodynamic Analysis of Allosteric and Chelate Cooperativity in Di- and Trivalent Ammonium/Crown-Ether Pseudorotaxanes. AB - A detailed thermodynamic analysis of the axle-wheel binding in di- and trivalent secondary ammonium/[24]crown-8 pseudorotaxanes is presented. Isothermal titration calorimetry (ITC) data and double mutant cycle analyses reveal an interesting interplay of positive as well as negative allosteric and positive chelate cooperativity thus providing profound insight into the effects governing multivalent binding in these pseudorotaxanes. PMID- 26440054 TI - Polymorphism of MDM2 promoter 309 (rs 2279744) and the risk of PCOS. AB - This study aimed at evaluating possible association between MDM2 SNP309 polymorphism (rs 2279744) and polycystic ovary syndrome (PCOS). One hundred and twenty-five women with PCOS and two hundred and fifty women without PCOS were collected from the department of reproductive medicine of college hospital in this case-control study. Peripheral blood samples were collected from all participants and DNA was extracted, MDM2 SNP309 polymorphism (rs 2279744) was determined from the 125 cases and 250 controls. Women were grouped into PCOS (n = 125) group and control group (n = 250). Odds ratios (OR) and 95% confidence intervals (CI) were used to evaluate the association between MDM2 SNP309 polymorphism (rs 2279744) and PCOS. The distribution of T allele was significant higher in PCOS cases than controls. MDM2 SNP 309 T allele is associated with PCOS. PMID- 26440052 TI - miR-137 acts as a tumor suppressor in astrocytoma by targeting RASGRF1. AB - Astrocytoma is one of the most common primary central nervous system tumors and has both high mortality and a poor 5-year survival rate. MicroRNAs (miRNAs) play important roles in carcinogenesis by acting on multiple signaling pathways. Although we have demonstrated that miR-137 is downregulated in astrocytoma tissues, the role of miR-137 in astrocytoma still remains unknown. In the present study, we aimed to investigate the function of miR-137 and its possible target genes in astrocytoma. miR-137 was significantly downregulated in astrocytoma tissues, and its expression level was inversely correlated with the clinical stage. Restoring miR-137 was able to dramatically inhibit cell proliferation, migration, and invasion and enhance apoptosis in vitro, whereas silencing its expression inhibited these processes. By overexpressing or inhibiting miR-137 in cancer cells, we experimentally confirmed that miR-137 directly recognized the 3' UTR (3'-untranslated region) of the RASGRF1 (Ras protein-specific guanine nucleotide-releasing factor 1) transcript and regulated RASGRF1 expression. Furthermore, an inverse correlation was observed between miR-137 levels and RASGRF1 protein levels, but not mRNA levels, in astrocytoma samples. The silencing of RASGRF1 resulted in similar effects to miR-137 restoration in cancer cells. Finally, overexpression of RASGRF1 rescued the inhibitory effects of miR 137. Taken together, our results indicate that miR-137 acts as a tumor suppressor in astrocytoma by targeting RASGRF1. These findings suggest that miR-137 may serve as a novel therapeutic target in astrocytoma treatment. PMID- 26440055 TI - Durability of direct immunofluorescence (DIF) slides stored at room temperature. AB - BACKGROUND: Prior studies suggested that direct immunofluorescence (DIF) slides can be stored at room temperature. OBJECTIVES: We sought to determine the durability of DIF slides stored at room temperature for 5 years. METHODS: This was a retrospective study of 83 DIF slides archived at room temperature during 2010. The pattern of immunoreactants was compared with those noted in the original report. RESULTS: Loss of reactivity was limited to cases with weak fluorescence at original diagnosis. Loss of IgG was noted in 12.5% of cases, IgA in 12%, C3 in 10%, and IgM in 9.75%. Fibrin showed no loss of reactivity. Preservation of immunofluorescence was not related to site of deposition. Overall, a reliable diagnosis could be made in 75 of 79 archived cases (94.9%). LIMITATIONS: Cases had been archived for periods varying from 4.5 to 5 years. Variations in processing and fluorochromes could affect durability. We have no way of knowing how long slides had been exposed to ultraviolet light at the time of initial examination. CONCLUSION: DIF showed excellent durability in slides kept at room temperature for 5 years. PMID- 26440057 TI - Docking-based classification models for exploratory toxicology studies on high quality estrogenic experimental data. AB - BACKGROUND: The ethical and practical limitation of animal testing has recently promoted computational methods for the fast screening of huge collections of chemicals. RESULTS: The authors derived 24 reliable docking-based classification models able to predict the estrogenic potential of a large collection of chemicals provided by the US Environmental Protection Agency. Model performances were challenged by considering AUC, EF1% (EFmax = 7.1), -LR (at sensitivity = 0.75); +LR (at sensitivity = 0.25) and 37 reference compounds comprised within the training set. Moreover, external predictions were made successfully on ten representative known estrogenic chemicals and on a set consisting of >32,000 chemicals. CONCLUSION: The authors demonstrate that structure-based methods, widely applied to drug discovery programs, can be fairly adapted to exploratory toxicology studies. PMID- 26440056 TI - Local and systemic responses following intravitreous injection of AAV2-encoded modified Volvox channelrhodopsin-1 in a genetically blind rat model. AB - We previously designed a modified channelrhodopsin-1 (mVChR1) protein chimera with a broader action than that of Chlamydomonas channelrhodopsin-2 and reported that its transduction into retinal ganglion cells can restore visual function in genetically blind, dystrophic Royal College of Surgeons (RCS) rats, with photostimuli ranging from 486 to 640 nm. In the current study, we sought to investigate the safety and influence of mVChR1 transgene expression. Adeno associated virus type 2 encoding mVChR1 was administered by intravitreous injection into dystrophic RCS rats. Reverse-transcription PCR was used to monitor virus and transgene dissemination and the results demonstrated that their expression was restricted specifically within the eye tissues, and not in non target organs. Moreover, examination of the blood, plasma and serum revealed that no excess immunoreactivity was present, as determined using standard clinical hematological parameters. Serum antibodies targeting the recombinant adeno associated virus (rAAV) capsid increased after the injection; however, no increase in mVChR1 antibody was detected during the observation period. In addition, retinal histological examination showed no signs of inflammation in rAAV-injected rats. In conclusion, our results demonstrate that mVChR1 can be exogenously expressed without harmful immunological reactions in vivo. These findings will aid in studies of AAV gene transfer to restore vision in late-stage retinitis pigmentosa. PMID- 26440058 TI - A three-dimensional skin equivalent reflecting some aspects of in vivo aged skin. AB - Human skin undergoes morphological, biochemical and functional modifications during the ageing process. This study was designed to produce a 3-dimensional (3D) skin equivalent in vitro reflecting some aspects of in vivo aged skin. Reconstructed skin was generated by co-culturing skin fibroblasts and keratinocytes on a collagen-glycosaminoglycan-chitosan scaffold, and ageing was induced by the exposition of fibroblasts to Mitomycin-C (MMC). Recently published data showed that MMC treatment resulted in a drug-induced accelerated senescence (DIAS) in human dermal fibroblast cultures. Next to established ageing markers, histological changes were analysed in comparison with in vivo aged skin. In aged epidermis, the filaggrin expression is reduced in vivo and in vitro. Furthermore, in dermal tissue, the amount of elastin and collagen is lowered in aged skin in vivo as well as after the treatment of 3D skin equivalents with MMC in vitro. Our results show histological signs and some aspects of ageing in a 3D skin equivalent in vitro, which mimics aged skin in vivo. PMID- 26440059 TI - Molecular Magnetic Resonance Imaging of Tumor Response to Therapy. AB - Personalized cancer medicine requires measurement of therapeutic efficacy as early as possible, which is optimally achieved by three-dimensional imaging given the heterogeneity of cancer. Magnetic resonance imaging (MRI) can obtain images of both anatomy and cellular responses, if acquired with a molecular imaging contrast agent. The poor sensitivity of MRI has limited the development of activatable molecular MR contrast agents. To overcome this limitation of molecular MRI, a novel implementation of our caspase-3-sensitive nanoaggregation MRI (C-SNAM) contrast agent is reported. C-SNAM is triggered to self-assemble into nanoparticles in apoptotic tumor cells, and effectively amplifies molecular level changes through nanoaggregation, enhancing tissue retention and spin lattice relaxivity. At one-tenth the current clinical dose of contrast agent, and following a single imaging session, C-SNAM MRI accurately measured the response of tumors to either metronomic chemotherapy or radiation therapy, where the degree of signal enhancement is prognostic of long-term therapeutic efficacy. Importantly, C-SNAM is inert to immune activation, permitting radiation therapy monitoring. PMID- 26440060 TI - DC-SIGN expression on podocytes and its role in inflammatory immune response of lupus nephritis. AB - Podocytes, the main target of immune complex, participate actively in the development of glomerular injury as immune cells. Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) is an innate immune molecular that has an immune recognition function, and is involved in mediation of cell adhesion and immunoregulation. Here we explored the expression of DC-SIGN on podocytes and its role in immune and inflammatory responses in lupus nephritis (LN). Expression of DC-SIGN and immunoglobulin (Ig)G1 was observed in glomeruli of LN patients. DC-SIGN was co-expressed with nephrin on podocytes. Accompanied by increased proteinuria of LN mice, DC-SIGN and IgG1 expressions were observed in the glomeruli from 20 weeks, and the renal function deteriorated up to 24 weeks. Mice with anti-DC-SIGN antibody showed reduced proteinuria and remission of renal function. After the podocytes were stimulated by serum of LN mice in vitro, the expression of DC-SIGN, major histocompatibility complex (MHC) class II and CD80 was up-regulated, stimulation of T cell proliferation was enhanced and the interferon (IFN)-gamma/interleukin (IL)-4 ratio increased. However, anti-DC-SIGN antibody treatment reversed these events. These results suggested that podocytes in LN can exert DC-like function through their expression of DC-SIGN, which may be involved in immune and inflammatory responses of renal tissues. However, blockage of DC-SIGN can inhibit immune functions of podocytes, which may have preventive and therapeutic effects. PMID- 26440061 TI - Micronized cellular adipose matrix as a therapeutic injectable for diabetic ulcer. AB - BACKGROUND: Despite the clinical potential of adipose-derived stem/stromal cells (ASCs), there are some clinical difficulties due to the regulation of cell therapies. MATERIALS & METHODS: Micronized cellular adipose matrix (MCAM) injectable was prepared through selective extraction of connective tissue fractions in fat tissue only through mechanical minimal manipulation procedures. RESULTS: It retained some capillaries and ASCs, but most adipocytes were removed. The presence of viable ASCs, vascular endothelial cells was confirmed and ASCs of MCAM kept intact mesenchymal differentiation capacity. In diabetic mice, skin wounds treated with MCAM showed significantly accelerated healing compared with phosphate-buffered saline-treated ones. CONCLUSION: The proven potential of MCAM to accelerate healing in ischemic diabetic ulcers may offer a simple, safe and minimally invasive means for tissue repair and revitalization. PMID- 26440062 TI - Development and Implementation of Team-Based Panel Management Tools: Filling the Gap between Patient and Population Information Systems. AB - Effective team-based models of care, such as the Patient-Centered Medical Home, require electronic tools to support proactive population management strategies that emphasize care coordination and quality improvement. Despite the spread of electronic health records (EHRs) and vendors marketing population health tools, clinical practices still may lack the ability to have: (1) local control over types of data collected/reports generated, (2) timely data (eg, up-to-date data, not several months old), and accordingly (3) the ability to efficiently monitor and improve patient outcomes. This article describes a quality improvement project at the hospital system level to develop and implement a flexible panel management (PM) tool to improve care of subpopulations of patients (eg, panels of patients with diabetes) by clinical teams. An in-depth case analysis approach is used to explore barriers and facilitators in building a PM registry tool for team based management needs using standard data elements (eg, laboratory values, pharmacy records) found in EHRs. Also described are factors that may contribute to sustainability; to date the tool has been adapted to 6 disease-focused subpopulations encompassing more than 200,000 patients. Two key lessons emerged from this initiative: (1) though challenging, team-based clinical end users and information technology needed to work together consistently to refine the product, and (2) locally developed population management tools can provide efficient data tracking for frontline clinical teams and leadership. The preliminary work identified critical gaps that were successfully addressed by building local PM registry tools from EHR-derived data and offers lessons learned for others engaged in similar work. (Population Health Management 2016;19:232 239). PMID- 26440063 TI - Phosphorylation Alters Oestrogen Receptor beta-Mediated Transcription in Neurones. AB - Nuclear steroid hormone receptors are ubiquitously expressed transcription factors whose activity can be altered by post-translational modifications, such as phosphorylation. The consequences of post-translational modifications have been described for several members of the nuclear steroid hormone receptor superfamily; however, little is known about the effects of oestrogen receptor (ER)beta phosphorylation in the brain. Moreover, to our knowledge, the presence of phosphorylated ERbeta has not been detected in the brain of any species to date. Oestrogen receptor beta is highly expressed in several regions of the brain and in vitro studies have demonstrated that it can be phosphorylated at two serine residues (S87 and S105) in the N-terminal AF-1 region. The present study aimed to determine whether phosphorylated ERbeta is detectable in the hippocampus of aged female rats, as well as the functional consequences of ERbeta S87 and S105 phosphorylation on transcriptional activity in neuronal cells. First, we used a novel PhosTag(TM) approach to detect phosphorylated forms of ERbeta in the dorsal hippocampus of aged female rats. The data obtained demonstrated abundant forms of phosphorylated ERbeta in the dorsal hippocampus, suggesting that this post-translational modification might be an important regulator of ERbeta function. To assess the functional consequences of ERbeta phosphorylation in neuronal cells, we created phospho-mimetic (S87E, S105E) and phospho-null (S87A, S105A) ERbeta receptors that were transiently transfected in a hippocampal derived cell line. Collectively, our results showed that phosphorylation of S87 and S105 altered both ligand-independent and ligand-dependent ERbeta transcriptional regulation. Overall, these data demonstrate that phosphorylated forms of ERbeta are present in the brain of aged female rats and that phosphorylation of ERbeta could differentially alter ERbeta-mediated gene expression. PMID- 26440064 TI - Identification of functional networks associated with cell death in the retina of OXYS rats during the development of retinopathy. AB - Age-related macular degeneration (AMD) is a major cause of blindness in developed countries, and the molecular pathogenesis of early events in AMD is poorly understood. Senescence-accelerated OXYS rats develop AMD-like retinopathy. The aim of this study was to explore the differences in retinal gene expression between OXYS and Wistar (control) rats at age 20 d and to identify the pathways of retinal cell death involved in the OXYS retinopathy initiation and progression. Retinal mRNA profiles of 20-day-old OXYS and Wistar rats were generated at the sequencing read depth 40 mln, in triplicate, using Illumina GAIIx. A terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay was performed to measure the apoptosis level. GeneMANIA was used to construct interaction networks for differentially expressed (DE) apoptosis-related genes at ages 20 d and 3 and 18 months. Functional analysis was suggestive of a developmental process, signal transduction, and cell differentiation as the most enriched biological processes among 245 DE genes at age 20 d An increased level of apoptosis was observed in OXYS rats at age 20 d but not at advanced stages. We identified functional clusters in the constructed interaction networks and possible hub genes (Rasa1, cFLAR, Birc3, Cdk1, Hspa1b, Erbb3, and Ntf3). We also demonstrated the significance of the extrinsic apoptotic pathway at preclinical, early, and advanced stages of retinopathy development. Besides the cell death signaling pathways, immune system-related processes and lipid-metabolic processes showed overrepresentation in the clusters of all networks. These characteristics of the expression profile of the genes functionally associated with apoptosis may contribute to the pathogenesis of AMD like retinopathy in senescence-accelerated OXYS rats. PMID- 26440065 TI - Biobanking of patient and patient-derived xenograft ovarian tumour tissue: efficient preservation with low and high fetal calf serum based methods. AB - Using patient-derived xenografts (PDXs) for preclinical cancer research demands proper storage of tumour material to facilitate logistics and to reduce the number of animals needed. We successfully established 45 subcutaneous ovarian cancer PDXs, reflecting all histological subtypes, with an overall take rate of 68%. Corresponding cells from mouse replaced human tumour stromal and endothelial cells in second generation PDXs as demonstrated with mouse-specific vimentin and CD31 immunohistochemical staining. For biobanking purposes two cryopreservation methods, a fetal calf serum (FCS)-based (95%v/v) "FCS/DMSO" protocol and a low serum-based (10%v/v) "vitrification" protocol were tested. After primary cryopreservation, tumour take rates were 38% and 67% using either the vitrification or FCS/DMSO-based cryopreservation protocol, respectively. Cryopreserved tumour tissue of established PDXs achieved take rates of 67% and 94%, respectively compared to 91% using fresh PDX tumour tissue. Genotyping analysis showed that no changes in copy number alterations were introduced by any of the biobanking methods. Our results indicate that both protocols can be used for biobanking of ovarian tumour and PDX tissues. However, FCS/DMSO-based cryopreservation is more successful. Moreover, primary engraftment of fresh patient-derived tumours in mice followed by freezing tissue of successfully established PDXs is the preferred way of efficient ovarian cancer PDX biobanking. PMID- 26440066 TI - RNA-seq is a valuable complement of conventional diagnostic tools in newly diagnosed AML patients. PMID- 26440067 TI - Genetic changes correlate with histopathology in a benign, borderline and malignant mucinous ovarian tumour. PMID- 26440068 TI - Effects of Exposure to WwTW Effluents over Two Generations on Sexual Development and Breeding in Roach Rutilus rutilus. AB - Exposure to environmental estrogens in wastewater treatment works (WwTW) effluents induces feminized responses in male fish, including the development of eggs in male testes. However, the impacts on the offspring of exposed fish are not well understood. In this study, we examined whether roach (Rutilus rutilus) from mothers that had been exposed to an undiluted WwTW effluent from early life to sexual maturity had altered susceptibility to gonadal feminization and an impaired capacity to reproduce. For males from both WwTW effluent exposed mothers and dilution water exposed mothers, effluent exposure for up to 3 years and 9 months induced feminized male gonads, although the intersex condition was relatively mild. There was no difference in the severity of gonadal feminization in roach derived from either WwTW effluent exposed or dilution water exposed mothers. Furthermore, a breeding study revealed that roach with effluent-exposed mothers reproduced with an equal success as roach with mothers exposed to clean water. Roach exposed to the effluent for 3 years in this study were able to reproduce successfully. Our findings provide no evidence for impacts of WwTW effluent exposure on reproduction or gonadal disruption in roach down the female germ line and add to existing evidence that male roach with a mild intersex condition are able to breed competitively. PMID- 26440069 TI - Efficient mass transport by optical advection. AB - Advection is critical for efficient mass transport. For instance, bare diffusion cannot explain the spatial and temporal scales of some of the cellular processes. The regulation of intracellular functions is strongly influenced by the transport of mass at low Reynolds numbers where viscous drag dominates inertia. Mimicking the efficacy and specificity of the cellular machinery has been a long time pursuit and, due to inherent flexibility, optical manipulation is of particular interest. However, optical forces are relatively small and cannot significantly modify diffusion properties. Here we show that the effectiveness of microparticle transport can be dramatically enhanced by recycling the optical energy through an effective optical advection process. We demonstrate theoretically and experimentally that this new advection mechanism permits an efficient control of collective and directional mass transport in colloidal systems. The cooperative long-range interaction between large numbers of particles can be optically manipulated to create complex flow patterns, enabling efficient and tunable transport in microfluidic lab-on-chip platforms. PMID- 26440070 TI - Biosignatures across Space and Time-Special Collection. PMID- 26440072 TI - Strain-tuned optoelectronic properties of hollow gallium sulphide microspheres. AB - Sulfide semiconductors have attracted considerable attention. The main challenge is to prepare materials with a designable morphology, a controllable band structure and optoelectronic properties. Herein, we report a facile chemical transportation reaction for the synthesis of Ga2S3 microspheres with novel hollow morphologies and partially filled volumes. Even without any extrinsic dopant, photoluminescence (PL) emission wavelength could be facilely tuned from 635 to 665 nm, depending on its intrinsic inhomogeneous strain distribution. Geometric phase analysis (GPA) based on high-resolution transmission electron microscopy (HRTEM) imaging reveals that the strain distribution and the associated PL properties can be accurately controlled by changing the growth temperature gradient, which depends on the distance between the boats used for raw material evaporation and microsphere deposition. The stacking-fault density, lattice distortion degree and strain distribution at the shell interfacial region of the Ga2S3 microspheres could be readily adjusted. Ab initio first-principles calculations confirm that the lowest conductive band (LCB) is dominated by S-3s and Ga-4p states, which shift to the low-energy band as a result of the introduction of tensile strain, well in accordance with the observed PL evolution. Therefore, based on our strain driving strategy, novel guidelines toward the reasonable design of sulfide semiconductors with tunable photoluminescence properties are proposed. PMID- 26440071 TI - Community centrality and social science research. AB - Community centrality is a growing requirement of social science. The field's research practices are increasingly expected to conform to prescribed relationships with the people studied. Expectations about community centrality influence scholarly activities. These expectations can pressure social scientists to adhere to models of community involvement that are immediate and that include community-based co-investigators, advisory boards, and liaisons. In this context, disregarding community centrality can be interpreted as failure. This paper considers evolving norms about the centrality of community in social science. It problematises community inclusion and discusses concerns about the impact of community centrality on incremental theory development, academic integrity, freedom of speech, and the value of liberal versus communitarian knowledge. Through the application of a constructivist approach, this paper argues that social science in which community is omitted or on the periphery is not failed science, because not all social science requires a community base to make a genuine and valuable contribution. The utility of community centrality is not necessarily universal across all social science pursuits. The practices of knowing within social science disciplines may be difficult to transfer to a community. These practices of knowing require degrees of specialisation and interest that not all communities may want or have. PMID- 26440073 TI - GM1-Modified Lipoprotein-like Nanoparticle: Multifunctional Nanoplatform for the Combination Therapy of Alzheimer's Disease. AB - Alzheimer's disease (AD) exerts a heavy health burden for modern society and has a complicated pathological background. The accumulation of extracellular beta amyloid (Abeta) is crucial in AD pathogenesis, and Abeta-initiated secondary pathological processes could independently lead to neuronal degeneration and pathogenesis in AD. Thus, the development of combination therapeutics that can not only accelerate Abeta clearance but also simultaneously protect neurons or inhibit other subsequent pathological cascade represents a promising strategy for AD intervention. Here, we designed a nanostructure, monosialotetrahexosylganglioside (GM1)-modified reconstituted high density lipoprotein (GM1-rHDL), that possesses antibody-like high binding affinity to Abeta, facilitates Abeta degradation by microglia, and Abeta efflux across the blood-brain barrier (BBB), displays high brain biodistribution efficiency following intranasal administration, and simultaneously allows the efficient loading of a neuroprotective peptide, NAP, as a nanoparticulate drug delivery system for the combination therapy of AD. The resulting multifunctional nanostructure, alphaNAP-GM1-rHDL, was found to be able to protect neurons from Abeta(1-42) oligomer/glutamic acid-induced cell toxicity better than GM1-rHDL in vitro and reduced Abeta deposition, ameliorated neurologic changes, and rescued memory loss more efficiently than both alphaNAP solution and GM1-rHDL in AD model mice following intranasal administration with no observable cytotoxicity noted. Taken together, this work presents direct experimental evidence of the rational design of a biomimetic nanostructure to serve as a safe and efficient multifunctional nanoplatform for the combination therapy of AD. PMID- 26440074 TI - Evaluation of Pistacia lentiscus seed oil and phenolic compounds for in vitro antiproliferative effects against BHK21 cells. AB - CONTEXT: Within the global context of increasing cancer diseases, natural products are important in devising new drugs and providing unique ideas in cancer therapy. In Tunisian folk medicine, Pistacia lentiscus L. (Anacardiaceae) fixed oil is used for cancer treatment. OBJECTIVE: This investigation studied, for the first time, the antiproliferative effect of Pistacia lentiscus fixed oil and its phenolic extract on BHK21 cancer cells. MATERIALS AND METHODS: Oil was extracted from fruits harvested in northwest Tunisia and the phenolic fraction was obtained by mixing with methanol. The anti-proliferative activity of the two tested substances on BHK 21 cells were investigated in vitro using trypan blue assays. Cells were treated with different concentrations of P. lentiscus oil (0.009, 0.018, 0.036, and 0.09 g/mL) and the phenolic extract (0.007, 0.014, 0.03, and 0.07 g/mL) for 24, 48, and 72 h. RESULTS: The inhibitory effect of Pistacia lentiscus fixed oil increases with the increase in dose. The IC50 value was estimated at 0.029 g/mL. The percentage of cell viability was 42.46 +/- 3.4% at a dose of 0.09 g/mL and was significantly lower than that of the untreated control (96.24 +/- 2.5%, p<0.01). The phenolic extract demonstrated a dose- and time dependent inhibitory effect on BHK21 cell growth. After 48 h of incubation, the IC50 value was estimated at 0.15 g/mL. DISCUSSION AND CONCLUSION: The results demonstrated the potential of Pistacia lentiscus fixed oil in treating cancer, as it is used in traditional medicine. PMID- 26440075 TI - Rethinking inheritance, yet again: inheritomes, contextomes and dynamic phenotypes. AB - In recent years, there have been many calls for an extended evolutionary synthesis, based in part upon growing evidence for nongenetic mechanisms of inheritance, i.e., similarities in phenotype between parents and offspring that are not due to shared genes. While there has been an impressive marshalling of evidence for diverse forms of nongenetic inheritance (epigenetic, ecological, behavioural and symbolic), there have been relatively few studies trying to integrate the different forms of inheritance into a common conceptual structure, a development that would be important to formalize elements of the extended evolutionary synthesis. Here, we propose a framework for an extended view of inheritance and introduce some conceptual distinctions that we believe, are important to this issue. In this framework, the phenotype is conceived of as a dynamic entity, its state, at any point in time resulting from intertwined effects of previous phenotypic state, and of hereditary materials (DNA and otherwise) and environment. We contrast our framework with the standard gene based view of inheritance, and also discuss our framework in the specific context of recent attempts to accommodate nongenetic inheritance within the framework of classical quantitative genetics and the Price equation. In particular, we believe that the extended view of inheritance and effects on the phenotype developed here is particularly well-suited to individual-based simulation studies of evolutionary dynamics. The results of such simulations, in turn, could be useful for assessing, how well extended models based on quantitative genetics or the Price equation perform at capturing complex evolutionary dynamics. PMID- 26440076 TI - Genomewide identification, classification and analysis of NAC type gene family in maize. AB - NAC transcription factors comprise a large plant-specific gene family. Increasing evidence suggests that members of this family have diverse functions in plant growth and development. In this study, we performed a genomewide survey of NAC type genes in maize (Zea mays L.). A complete set of 148 nonredundant NAC genes (ZmNAC1-ZmNAC148) were identifiedin the maize genome using Blast search tools, and divided into 12 groups (a-l) based on phylogeny. Chromosomal location of these genes revealed that they are distributed unevenly across all 10 chromosomes. Segmental and tandem duplication contributed largely to the expansion of the maize NAC gene family. The Ka/Ks ratio suggested that the duplicated genes of maize NAC family mainly experienced purifying selection, with limited functional divergence after duplication events.Microarray analysis indicated most of the maize NAC genes were expressed across different developmental stages. Moreover,19 maize NAC genes grouped with published stress responsive genes from other plants were found to contain putative stress responsive cis-elements in their promoter regions. All these stress-responsive genes belonged to the group d (stress-related).Further, these genes showed differential expression patterns over time in response to drought treatments by quantitative real-time PCR analysis. Our results reveal a comprehensive overview of the maize NAC, and form the foundation for future functional research to uncover their roles in maize growth and development. PMID- 26440077 TI - Biallelic expression of Tssc4, Nap1l4, Phlda2 and Osbpl5 in adult cattle. AB - Genomic imprinting of the Cdkn1c/Kcnq1ot1 region shows lack of conservation between human and mouse. This region has been reported to be associated with Beckwith-Wiedemann syndrome (BWS) and cancer. To increase our understanding of imprinted genes in bovine Cdkn1c/Kcnq1ot1 imprinting cluster, we assessed the imprinting status of four cattle genes (Tssc4,Nap1l4, Phlda2 and Osbpl5) in seven types of tissues: heart, liver, spleen, lung, kidney, skeletal muscle and subcutaneous fat using polymorphism-based sequencing approach. It was found that all the four genes showed biallelic expression in tissues in which transcripts were detected. Nap1l4 and Tssc4 were detected in all examined tissues, while the expression of Phlda2 and Osbpl5 was tissue-specific. Phlda2 was not detected in heart and subcutaneous fat, and Osbpl5 was not detected in spleen and skeletal muscle. In addition, identification of species-specific imprinted genes is necessary to understand the evolution of genomic imprinting and to elucidate mechanisms leading to allele-specific expression. PMID- 26440078 TI - Transcriptome analysis reveals dynamic changes in the gene expression of tobacco seedlings under low potassium stress. AB - Potassium plays a key role in plant development and reproduction. In agricultural practice, potassium deficiency is common worldwide, and leads to crop growth inhibition and output reduction. In this study, we analysed the transcriptome of tobacco seedlings under low potassium stress. Tobacco seedlings with or without decreased potassium treatment were harvested after 0 (control), 6, 12, or 24 h and were submitted for microarray analysis. The results showed that up to 3790 genes were upregulated or downregulated more than 2-fold as a result of the decreased potassium treatment. Gene ontology analysis revealed significantly differentially expressed genes that were categorized as cation binding, transcription regulation, metabolic processes, transporter activity and enzyme regulation. Some potassium, nitrogen and phosphorus transporters; transcription factors; and plant signal molecules, such as CPKs were also significantly differentially expressed under potassium deficiency. Our results indicate that the expression profiles of a large number of genes involved in various plant physiological processes are significantly altered in response to potassium deficiency, which can result in physiological and morphological changes in tobacco plants. PMID- 26440079 TI - The commonly used eye-specific sev-GAL4 and GMR-GAL4 drivers in Drosophila melanogaster are expressed in tissues other than eyes also. AB - The binary GAL4-UAS system of conditional gene expression is widely used by Drosophila geneticists to target expression of the desired transgene in tissue of interest. In many studies, a preferred target tissue is the Drosophila eye, for which the sev-GAL4 and GMR-GAL4 drivers are most widely used since they are believed to be expressed exclusively in the developing eye cells. However, several reports have noted lethality following expression of certain transgenes under these GAL4 drivers notwithstanding the fact that eye is not essential for survival of the fly. Therefore, to explore the possibility that these drivers may also be active in tissues other than eye, we examined the expression of UAS-GFP reporter driven by the sev-GAL4 or GMR-GAL4 drivers. We found that both these drivers are indeed expressed in additional tissues, including a common set of specific neuronal cells in larval and pupal ventral and cerebral ganglia. Neither sev nor glass gene has so far been reported to be expressed in these neuronal cells. Expression pattern of sev-GAL4 driver parallels that of the endogenous Sevenless protein. In addition to cells in which sev-GAL4 is expressed, the GMR GAL4 is expressed in several other larval cell types also. Further, two different GMR-GAL4 lines also show some specific differences in their expression domains outside the eye discs. These findings emphasize the need for a careful confirmation of the expression domains of a GAL4 driver being used in a given study, rather than relying only on the empirically claimed expression domains. PMID- 26440080 TI - Molecular characterization of zeta class glutathione S-transferases from Pinus brutia Ten. AB - Glutathione transferases (GSTs; EC 2.5.1.18) play important roles in stress tolerance and metabolic detoxification in plants.In higher plants, studies on GSTs have focussed largely on agricultural plants. There is restricted information about molecular characterization of GSTs in gymnosperms. To date, only tau class GST enzymes have been characterized from some pinus species. For the first time, the present study reports cloning and molecular characterization of two zeta class GST genes, namely PbGSTZ1 and PbGSTZ2 from Pinus brutia Ten., which is an economically important pine native to the eastern Mediterranean region and have to cope with several environmental stress conditions. The PbGSTZ1 gene was isolated from cDNA, whereas PbGSTZ2 was isolated from genomic DNA. Sequence analysis of PbGSTZ1 and PbGSTZ2 revealed the presence of an open reading frame of 226 amino acids with typical consensus sequences of the zeta class plant GSTs. Protein and secondary structure prediction analysis of two zeta class PbGSTZs have shared common features of other plant zeta class GSTs. Genomic clone, PbGSTZ2 gene, is unexpectedly intronless. Extensive sequence analysis of PbGSTZ2, with cDNA clone, PbGSTZ1, revealed 87% identity at nucleotide and 81% identity at amino acid levels with 41 amino acids differences suggesting that genomic PbGSTZ2 gene might be an allelic or a paralogue version of PbGSTZ1. PMID- 26440082 TI - Generation and characterization of Brassica rapa ssp. pekinensis - B. oleracea var. capitata monosomic and disomic alien addition lines. AB - Five monosomic alien addition lines (MAALs) of Brassica rapa ssp. pekinensis - B. oleracea var. capitata were obtained by hybridization and backcrossing between B. rapa ssp. pekinensis (female parent) and B. oleracea var. capitata. The alien linkage groups were identified using 42 B. oleracea var. capitata linkage group specific markers as B. oleracea linkage groups C2, C3, C6, C7 and C8. Based on the chromosomal karyotype of root tip cells, these five MAALs added individual chromosomes from B. oleracea var. capitata: chr 1 (the longest), chr 2 or 3, chr 5 (small locus of 25S rDNA), chr 7 (satellite-carrying) and chr 9 (the shortest). Five disomic alien addition lines were then generated by selfing their corresponding MAALs. PMID- 26440081 TI - In planta transformation of sorghum (Sorghum bicolor (L.) Moench) using TPS1 gene for enhancing tolerance to abiotic stresses. AB - An in planta transformation protocol for sorghum (Sorghum bicolor (L.) Moench) using shoot apical meristem of germinating seedlings is reported in this study. Agrobacterium tumefaciens strain, LBA4404 with pCAMBIA1303 vector and construct pCAMBIA1303TPS1 were individually used for transformation. Since, the transgene is integrated into the cells of already differentiated tissues, the T 0 plants were chimeric and stable integration was observed in T1 generation. beta Glucuronidase (GUS) expression in the seedlings and spikelets of emerging cob was the first indication of transformability in T0 generation which was further confirmed by PCR analysis using hpt and TPS1 gene-specific primers. Screening on 25 mg/L hygromycin combined with PCR analysis was used for selection of transformants in the T1 generation. Transformation efficiencies ranged between 34 38% and 26-34% using pCAMBIA1303 vector and construct pCAMBIA1303TPS1, respectively. Molecular characterization of the T2 transgenics using PCR, RT-PCR and Southern blot analyses further revealed the integration, expression and inheritance of the transgene. These results indicate the feasibility of the method to generate transgenics with pCAM-BIA1303 vector and construct pCAMBIA1303TPS1. The abiotic stress tolerance of TPS1 transgenics developed in the present study was evident by the ability of the transformants to tolerate 200 mM NaCl as well as higher root growth and biomass. PMID- 26440083 TI - Map-based cloning and expression analysis of BMR-6 in sorghum. AB - Brown midrib mutants in sorghum are associated with reduced lignin content and increased cell wall digestibility. In this study, we characterized a bmr-6 sorghum mutant, which shows reddish pigment in the midrib and stem after the fifth-leaf stage. Compared to wild type, Kalson lignin content of bmr-6 is decreased significantly. We used histological analysis to determine that the mutant exhibited a modified pattern of lignin staining and found an increased polysaccharide content. We cloned BMR-6 gene, a gene encoded a cinnamyl alcohol dehydrogenase (CAD), using a map-based cloning approach. Genetic complementation confirmed that CAD is responsible for the BMR-6 phenotype. BMR-6 gene was expressed in all tested sorghum tissues, with the highest being in midrib and stem. Transient expression assays in Nicotiana benthamiana leaves demonstrated cytomplasmic localization of BMR-6. We found that the expression level of bmr-6 was significantly decreased in the mutant but expression of SbCAD3 and SbCAD5 were significantly increased. Our results indicate that BMR-6 not only affects the distribution of lignin but also the biosynthesis of lignin in sorghum. PMID- 26440084 TI - Molecular survey of Tamyb10-1 genes and their association with grain colour and germinability in Chinese wheat and Aegilops tauschii. AB - To investigate allelic variation of Myb10-1 genes in Chinese wheat and to examine its association with germination level in wheat, a total of 582 Chinese bread wheat cultivars and 110 Aegilops tauschii accessions were used to identify allelic variations of three Myb10-1 genes. Identification results indicated that there is a novel Tamyb10-B1 allele, designated Tamyb10-B1c, in the five Chinese landraces. The Tamyb10-B1c possibly has a large deletion including Tamyb10-B1 gene. There are three novel Tamyb10-D1 alleles (Aetmyb10-D1c, Aetmyb10-D1d and Aetmyb10-D1e) that were discovered in Aegilops tauschii. Of them, Aetmyb10-D1c allele possessed a 104-bp deletion and this resulted in a frame shift in the open reading frame of the Aetmyb10-D1 gene. AETMYB10-D1d and AETMYB10-D1e proteins possessed three and two different amino acids when compared with TAMYB10-D1b protein, respectively. Association of Tamyb10-1 allelic variation with grain germination level indicated that all five allelic combinations with red grains showed a significantly higher GP (germination percentage) and GI (germination index) values than those of white-grained Tamyb10-A1a/Tamyb10-B1a/Tamyb10-D1a genotype after storing it for one year. Moreover, the Tamyb10-A1b/Tamyb10 B1c/Tamyb10-D1b genotype possesses the significantly highest GP and GI among the six different Tamyb10-1 combinations. This study could provide useful information for wheat breeding programme in terms of grain colour and germination level. PMID- 26440086 TI - Association between vitamin D receptor gene polymorphism (TaqI) and obesity in Chinese population. PMID- 26440087 TI - A simple route to maximum-likelihood estimates of two-locus recombination fractions under inequality restrictions. PMID- 26440085 TI - Gene structure, phylogeny and expression profile of the sucrose synthase gene family in cacao (Theobroma cacao L.). AB - In higher plants, sucrose synthase (Sus, EC 2.4.1.13) is widely considered as a key enzyme involved in sucrose metabolism. Although, several paralogous genes encoding different isozymes of Sus have been identified and characterized in multiple plant genomes, to date detailed information about the Sus genes is lacking for cacao. This study reports the identification of six novel Sus genes from economically important cacao tree. Analyses of the gene structure and phylogeny of the Sus genes demonstrated evolutionary conservation in the Sus family across cacao and other plant species. The expression of cacao Sus genes was investigated via real-time PCR in various tissues, different developmental phases of leaf, flower bud and pod. The Sus genes exhibited distinct but partially redundant expression profiles in cacao, with TcSus1, TcSus5 and TcSus6, being the predominant genes in the bark with phloem, TcSus2 predominantly expressing in the seed during the stereotype stage. TcSus3 and TcSus4 were significantly detected more in the pod husk and seed coat along the pod development, and showed development dependent expression profiles in the cacao pod. These results provide new insights into the evolution, and basic information that will assist in elucidating the functions of cacao Sus gene family. PMID- 26440088 TI - Two novel mutations in ILDR1 gene cause autosomal recessive nonsyndromic hearing loss in consanguineous Iranian families. PMID- 26440089 TI - Novel compound heterozygous frameshift mutations of C2orf37 in a familial Indian case of Woodhouse-Sakati syndrome. PMID- 26440090 TI - Sex-specific asymmetry in eye development in interspecific hybrids in the Drosophila bipectinata species complex. PMID- 26440091 TI - Characterization of low-molecular-weight glutenin subunit genes of Aegilops section Sitopsis and comparative analysis with those of wheat (Triticum aestivum L.) and some Aegilops species. PMID- 26440092 TI - Genetic variants of retinol-binding protein 4 in adolescents are associated with liver function and inflammatory markers but not with obesity and insulin resistance. PMID- 26440093 TI - Genetic portrait of Lisboa immigrant population from Cabo Verde with mitochondrial DNA analysis. PMID- 26440094 TI - Characterization and fine mapping of NGP4c(t), a novel gene controlling the number of grains per panicle in rice. PMID- 26440095 TI - Upgrade of Castanea sativa (Mill.) genetic resources by sequencing of barcode markers. PMID- 26440096 TI - Plant transcriptomics and responses to environmental stress: an overview. AB - Different stresses include nutrient deficiency, pathogen attack, exposure to toxic chemicals etc. Transcriptomic studies have been mainly applied to only a few plant species including the model plant, Arabidopsis thaliana. These studies have provided valuable insights into the genetic networks of plant stress responses. Transcriptomics applied to cash crops including barley, rice, sugarcane, wheat and maize have further helped in understanding physiological and molecular responses in terms of genome sequence, gene regulation, gene differentiation, posttranscriptional modifications and gene splicing. On the other hand, comparative transcriptomics has provided more information about plant's response to diverse stresses. Thus, transcriptomics, together with other biotechnological approaches helps in development of stress tolerance in crops against the climate change. PMID- 26440098 TI - Expansion of polyalanine tracts in the QA domain may play a critical role in the clavicular development of cleidocranial dysplasia. PMID- 26440097 TI - Genetic epidemiology of coronary artery disease: an Asian Indian perspective. AB - Coronary artery disease (CAD) has emerged as a major cause of morbidity and mortality worldwide. Recent findings on the role of genetic factors in the aetiopathology of CAD have implicated novel genes and variants in addition to those involved in lipid and lipoprotein metabolism. However, our present knowledge is limited due to lack of clarity on their exact identity and the quantum of impact on disease susceptibility, and incident risk. It is a matter of great interest to understand the role of genetic factors in ethnic populations that have a strong underlying predisposition to CAD such as the South Asian populations, particularly among Asian Indians living in India and abroad. Although, a number of isolated studies do implicate certain gene polymorphisms towards enhanced disease susceptibility, the available data remains scanty and inconclusive as they have not been validated in large, prospective cohorts. The present review aims to consolidate the available literature on the genetics of CAD in Asian Indians and seeks to provide insights on the concerns that need to be addressed in future studies to generate information having clinical value. PMID- 26440100 TI - [Acute dyspnea 8 days after Cesarean section]. PMID- 26440099 TI - [Cardiogenic shock after drug therapy for atrial fibrillation with tachycardia : Case report of an 89-year-old woman]. AB - beta-Blockers and calcium channel blockers are commonly used drugs in the treatment of atrial fibrillation with tachycardia. However, in patients with high myocardial susceptibility and vulnerability, combination therapy with beta blockers and non-dihydropyridine calcium channel blockers (verapamil or diltiazem) but also individual administration can cause drug-induced cardiogenic shock. Thus, the simultaneous administration of beta-blockers and non dihydropyridine calcium channel blockers is absolutely contraindicated. In case of acute heart failure, isolated application is also contraindicated. In the treatment of a cardiogenic shock induced by beta-blockers and/or non dihydropyridine calcium channel blockers, administration of intravenous calcium, glucagon or high-dose insulin is recommended. PMID- 26440101 TI - Correction: Multilevel Approach of a 1-Year Program of Dietary and Exercise Interventions on Bone Mineral Content and Density in Metabolic Syndrome - the RESOLVE Randomized Controlled Trial. PMID- 26440102 TI - A Comparison of Free-Standing versus Co-Located Long-Term Acute Care Hospitals. AB - BACKGROUND: Long-term acute care hospitals (LTACs) provide specialized treatment for patients with chronic critical illness. Increasingly LTACs are co-located within traditional short-stay hospitals rather than operated as free-standing facilities, which may affect LTAC utilization patterns and outcomes. METHODS: We compared free-standing and co-located LTACs using 2005 data from the United States Centers for Medicare & Medicaid Services. We used bivariate analyses to examine patient characteristics and timing of LTAC transfer, and used propensity matching and multivariable regression to examine mortality, readmissions, and costs after transfer. RESULTS: Of 379 LTACs in our sample, 192 (50.7%) were free standing and 187 (49.3%) were co-located in a short-stay hospital. Co-located LTACs were smaller (median bed size: 34 vs. 66, p <0.001) and more likely to be for-profit (72.2% v. 68.8%, p = 0.001) than freestanding LTACs. Co-located LTACs admitted patients later in their hospital course (average time prior to transfer: 15.5 days vs. 14.0 days) and were more likely to admit patients for ventilator weaning (15.9% vs. 12.4%). In the multivariate propensity-matched analysis, patients in co-located LTACs experienced higher 180-day mortality (adjusted relative risk: 1.05, 95% CI: 1.00-1.11, p = 0.04) but lower readmission rates (adjusted relative risk: 0.86, 95% CI: 0.75-0.98, p = 0.02). Costs were similar between the two hospital types (mean difference in costs within 180 days of transfer: -$3,580, 95% CI: -$8,720 -$1,550, p = 0.17). CONCLUSIONS: Compared to patients in free-standing LTACs, patients in co-located LTACs experience slightly higher mortality but lower readmission rates, with no change in overall resource use as measured by 180 day costs. PMID- 26440103 TI - Assessing Antigenic Drift of Seasonal Influenza A(H3N2) and A(H1N1)pdm09 Viruses. AB - Under selective pressure from the host immune system, antigenic epitopes of influenza virus hemagglutinin (HA) have continually evolved to escape antibody recognition, termed antigenic drift. We analyzed the genomes of influenza A(H3N2) and A(H1N1)pdm09 virus strains circulating in Thailand between 2010 and 2014 and assessed how well the yearly vaccine strains recommended for the southern hemisphere matched them. We amplified and sequenced the HA gene of 120 A(H3N2) and 81 A(H1N1)pdm09 influenza virus samples obtained from respiratory specimens and calculated the perfect-match vaccine efficacy using the pepitope model, which quantitated the antigenic drift in the dominant epitope of HA. Phylogenetic analysis of the A(H3N2) HA1 genes classified most strains into genetic clades 1, 3A, 3B, and 3C. The A(H3N2) strains from the 2013 and 2014 seasons showed very low to moderate vaccine efficacy and demonstrated antigenic drift from epitopes C and A to epitope B. Meanwhile, most A(H1N1)pdm09 strains from the 2012-2014 seasons belonged to genetic clades 6A, 6B, and 6C and displayed the dominant epitope mutations at epitopes B and E. Finally, the vaccine efficacy for A(H1N1)pdm09 (79.6-93.4%) was generally higher than that of A(H3N2). These findings further confirmed the accelerating antigenic drift of the circulating influenza A(H3N2) in recent years. PMID- 26440104 TI - Systematic Characteristic Exploration of the Chimeras Generated in Multiple Displacement Amplification through Next Generation Sequencing Data Reanalysis. AB - BACKGROUND: The chimeric sequences produced by phi29 DNA polymerase, which are named as chimeras, influence the performance of the multiple displacement amplification (MDA) and also increase the difficulty of sequence data process. Despite several articles have reported the existence of chimeric sequence, there was only one research focusing on the structure and generation mechanism of chimeras, and it was merely based on hundreds of chimeras found in the sequence data of E. coli genome. METHOD: We finished data mining towards a series of Next Generation Sequencing (NGS) reads which were used for whole genome haplotype assembling in a primary study. We established a bioinformatics pipeline based on subsection alignment strategy to discover all the chimeras inside and achieve their structural visualization. Then, we artificially defined two statistical indexes (the chimeric distance and the overlap length), and their regular abundance distribution helped illustrate of the structural characteristics of the chimeras. Finally we analyzed the relationship between the chimera type and the average insertion size, so that illustrate a method to decrease the proportion of wasted data in the procedure of DNA library construction. RESULTS/CONCLUSION: 131.4 Gb pair-end (PE) sequence data was reanalyzed for the chimeras. Totally, 40,259,438 read pairs (6.19%) with chimerism were discovered among 650,430,811 read pairs. The chimeric sequences are consisted of two or more parts which locate inconsecutively but adjacently on the chromosome. The chimeric distance between the locations of adjacent parts on the chromosome followed an approximate bimodal distribution ranging from 0 to over 5,000 nt, whose peak was at about 250 to 300 nt. The overlap length of adjacent parts followed an approximate Poisson distribution and revealed a peak at 6 nt. Moreover, unmapped chimeras, which were classified as the wasted data, could be reduced by properly increasing the length of the insertion segment size through a linear correlation analysis. SIGNIFICANCE: This study exhibited the profile of the phi29MDA chimeras by tens of millions of chimeric sequences, and helped understand the amplification mechanism of the phi29 DNA polymerase. Our work also illustrated the importance of NGS data reanalysis, not only for the improvement of data utilization efficiency, but also for more potential genomic information. PMID- 26440106 TI - Quantifying the stabilizing effects of protein-ligand interactions in the gas phase. AB - The effects of protein-ligand interactions on protein stability are typically monitored by a number of established solution-phase assays. Few translate readily to membrane proteins. We have developed an ion-mobility mass spectrometry approach, which discerns ligand binding to both soluble and membrane proteins directly via both changes in mass and ion mobility, and assesses the effects of these interactions on protein stability through measuring resistance to unfolding. Protein unfolding is induced through collisional activation, which causes changes in protein structure and consequently gas-phase mobility. This enables detailed characterization of the ligand-binding effects on the protein with unprecedented sensitivity. Here we describe the method and software required to extract from ion mobility data the parameters that enable a quantitative analysis of individual binding events. This methodology holds great promise for investigating biologically significant interactions between membrane proteins and both drugs and lipids that are recalcitrant to characterization by other means. PMID- 26440105 TI - Using the HISQUI29 to assess the sound quality levels of Spanish adults with unilateral cochlear implants and no contralateral hearing. AB - To evaluate cochlear implant (CI) users' self-reported level of sound quality and quality of life (QoL). Sound quality was self-evaluated using the hearing implant sound quality index (HISQUI29). HISQUI29 scores were further examined in three subsets. QoL was self-evaluated using the glasgow benefit inventory (GBI). GBI scores were further examined in three subsets. Possible correlations between the HISQUI29 and GBI were explored. Additional possible correlations between these scores and subjects' pure tone averages, speech perception scores, age at implantation, duration of hearing loss, duration of CI use, gender, and implant type were explored. Subjects derived a "moderate" sound quality level from their CI. Television, radio, and telephone tasks were easier in quiet than in background noise. 89 % of subjects reported their QoL benefited from having a CI. Mean total HISQUI29 score significantly correlated with all subcategories of the GBI. Age at implantation inversely correlated with the total HISQUI29 score and with television and radio understanding. Sentence in noise scores significantly correlated with all sound perception scores. Women had a better mean score in music perception and in telephone use than did men. CI users' self-reported levels of sound quality significantly correlated with their QoL. Cochlear implantation had a beneficial impact on subjects' QoL. Understanding speech is easier in quiet than in noise. Music perception remains a challenge for many CI users. The HISQUI29 and the GBI can provide useful information about the everyday effects of future treatment modalities, rehabilitation strategies, and technical developments. PMID- 26440107 TI - Violent Death Rates and Risk for Released Prisoners in North Carolina. AB - Released prisoners face high risk of early mortality. The risk of violent death, specifically homicide and suicide, are addressed in this study. Data on inmates released from the North Carolina Division of Adult Corrections (N = 476) matched to the Violent Death Reporting System are analyzed to estimate rates and demographic and criminal justice-related predictors. Violent death rates for persons released from prison were more than 7 times higher than for the general adult population. Results from multinomial logistic regression indicate decreased homicide risk for every year of age, whereas male gender and minority race increased risk. For suicide, minority race, release without supervision, and substance abuse treatment in prison decreased fatality risk. By contrast, a history of mental illness increased suicide risk. Implications for practice and research are discussed. PMID- 26440108 TI - Consumer Perspectives on Gambling Harm Minimisation Measures in an Australian Jurisdiction. AB - This paper investigates consumer perspectives of implemented and proposed gambling harm minimisation measures taken from a geographically stratified survey of adult residents in Tasmania, Australia. Electronic gaming machine (EGM) gamblers were asked whether current and proposed EGM harm minimisation measures impacted on their actual or anticipated gambling expenditure and enjoyment. Participants were analysed based on their endorsement of Problem Gambling Severity Index criteria (scores 0-27), and categorised as non-problem gamblers (score 0), low-risk gamblers (scores 1-2), and moderate/problem gamblers (scores 3+). Specifically, we wanted to identify harm minimisation policies that resulted in the lowest decreases in enjoyment for non-problem gamblers and the highest decreases in expenditure for moderate/problem gamblers. Regarding current policies, the lowest decrease in enjoyment for non-problem gamblers was the ban on Automatic Teller Machines (ATMs) in EGM venues (0.2 %) while the highest decrease in expenditure for moderate/problem gamblers was the reduction in maximum lines (46.9 %). For the proposed measures, the lowest decrease in enjoyment for non-problem gamblers was visible clocks (1.2 %) while the highest decrease in expenditure for moderate/problem gamblers was reducing cash withdrawals (36.3 %). These results suggest universal EGM harm minimisation measures can differentially target non-problem and moderate/problem gamblers. PMID- 26440110 TI - Correction: Temperature-dependent energy levels and size-independent thermodynamics. AB - Correction for 'Temperature-dependent energy levels and size-independent thermodynamics' by Rodrigo de Miguel, Phys. Chem. Chem. Phys., 2015, 17, 15691 15693. PMID- 26440109 TI - Divergent Evolution of the Transcriptional Network Controlled by Snf1-Interacting Protein Sip4 in Budding Yeasts. AB - Cellular responses to starvation are of ancient origin since nutrient limitation has always been a common challenge to the stability of living systems. Hence, signaling molecules involved in sensing or transducing information about limiting metabolites are highly conserved, whereas transcription factors and the genes they regulate have diverged. In eukaryotes the AMP-activated protein kinase (AMPK) functions as a central regulator of cellular energy homeostasis. The yeast AMPK ortholog SNF1 controls the transcriptional network that counteracts carbon starvation conditions by regulating a set of transcription factors. Among those Cat8 and Sip4 have overlapping DNA-binding specificity for so-called carbon source responsive elements and induce target genes upon SNF1 activation. To analyze the evolution of the Cat8-Sip4 controlled transcriptional network we have compared the response to carbon limitation of Saccharomyces cerevisiae to that of Kluyveromyces lactis. In high glucose, S. cerevisiae displays tumor cell-like aerobic fermentation and repression of respiration (Crabtree-positive) while K. lactis has a respiratory-fermentative life-style, respiration being regulated by oxygen availability (Crabtree-negative), which is typical for many yeasts and for differentiated higher cells. We demonstrate divergent evolution of the Cat8-Sip4 network and present evidence that a role of Sip4 in controlling anabolic metabolism has been lost in the Saccharomyces lineage. We find that in K. lactis, but not in S. cerevisiae, the Sip4 protein plays an essential role in C2 carbon assimilation including induction of the glyoxylate cycle and the carnitine shuttle genes. Induction of KlSIP4 gene expression by KlCat8 is essential under these growth conditions and a primary function of KlCat8. Both KlCat8 and KlSip4 are involved in the regulation of lactose metabolism in K. lactis. In chromatin immunoprecipitation experiments we demonstrate binding of both, KlSip4 and KlCat8, to selected CSREs and provide evidence that KlSip4 counteracts KlCat8 mediated transcription activation by competing for binding to some but not all CSREs. The finding that the hierarchical relationship of these transcription factors differs between K. lactis and S. cerevisiae and that the sets of target genes have diverged contributes to explaining the phenotypic differences in metabolic life-style. PMID- 26440111 TI - A Culture-Behavior-Brain Loop Model of Human Development. AB - Increasing evidence suggests that cultural influences on brain activity are associated with multiple cognitive and affective processes. These findings prompt an integrative framework to account for dynamic interactions between culture, behavior, and the brain. We put forward a culture-behavior-brain (CBB) loop model of human development that proposes that culture shapes the brain by contextualizing behavior, and the brain fits and modifies culture via behavioral influences. Genes provide a fundamental basis for, and interact with, the CBB loop at both individual and population levels. The CBB loop model advances our understanding of the dynamic relationships between culture, behavior, and the brain, which are crucial for human phylogeny and ontogeny. Future brain changes due to cultural influences are discussed based on the CBB loop model. PMID- 26440112 TI - Metabolomic Profiling of 13 Diatom Cultures and Their Adaptation to Nitrate Limited Growth Conditions. AB - Diatoms are very efficient in their use of available nutrients. Changes in nutrient availability influence the metabolism and the composition of the cell constituents. Since diatoms are valuable candidates to search for oil producing algae, measurements of diatom-produced compounds can be very useful for biotechnology. In order to explore the diversity of lipophilic compounds produced by diatoms, we describe the results from an analysis of 13 diatom strains. With the help of a lipidomics platform, which combines an UPLC separation with a high resolution/high mass accuracy mass spectrometer, we were able to measure and annotate 142 lipid species. Out of these, 32 were present in all 13 cultures. The annotated lipid features belong to six classes of glycerolipids. The data obtained from the measurements were used to create lipidomic profiles. The metabolomic overview of analysed cultures is amended by the measurement of 96 polar compounds. To further increase the lipid diversity and gain insight into metabolomic adaptation to nitrogen limitation, diatoms were cultured in media with high and low concentrations of nitrate. The growth in nitrogen-deplete or nitrogen-replete conditions affects metabolite accumulation but has no major influence on the species-specific metabolomic profile. Thus, the genetic component is stronger in determining metabolic patterns than nitrogen levels. Therefore, lipid profiling is powerful enough to be used as a molecular fingerprint for diatom cultures. Furthermore, an increase of triacylglycerol (TAG) accumulation was observed in low nitrogen samples, although this trend was not consistent across all 13 diatom strains. Overall, our results expand the current understanding of metabolomics diversity in diatoms and confirm their potential value for producing lipids for either bioenergy or as feed stock. PMID- 26440113 TI - Surgical Specialty Residents More Likely to Receive the Arnold P. Gold Humanism and Excellence in Teaching Award. AB - OBJECTIVE: The Arnold P. Gold Humanism and Excellence in Teaching Awards are given by medical students to residents. The aim of this study is to evaluate the distribution of this award based on residency specialty. The hypothesis is that surgical residents more commonly receive this award. METHODS: This was a retrospective study from 2004 to 2013. All award recipients were obtained from the Arnold P. Gold Foundation website. The specialties of award recipients were tabulated. The number of award winners per thousand specialty residents was estimated using the Accreditation Council for Graduate Medical Education Data Resource Book, adjusting for the number of awarding schools and resident specialties. All statistics used an alpha = 0.05. RESULTS: There were 2489 awards given during the study period, with 52.6% in medical specialties and 47.4% in surgical specialties (p = 0.45). The specialties most commonly awarded were General Surgery (22.3%), Internal Medicine (20.9%), and Obstetrics/Gynecology (20.4%). Adjusting for the number of eligible residents, there were 59.9 awards/1000 Obstetrics/Gynecology residents, 43.1 awards/1000 General Surgery residents, and 20.2 awards/1000 Internal Medicine residents (p < 0.001). CONCLUSION: Controlling for the number of eligible residents, the Arnold P. Gold Humanism and Excellence in Teaching Awards are more commonly given to surgical specialty residents. PMID- 26440114 TI - Interfacial ordering of thermotropic liquid crystals triggered by the secondary structures of oligopeptides. AB - We report that assemblies formed by eight oligopeptides at phospholipid-decorated interfaces of thermotropic liquid crystals (LCs) trigger changes in ordering of the LCs that are dependent on the secondary structures of the oligopeptides (as characterized in situ using infrared-visible sum-frequency spectroscopy). PMID- 26440116 TI - A Farewell to B-Lines: Ageing and Disappearance of Ultrasound Artifacts as a Diagnostic Tool. PMID- 26440117 TI - Production of Immunoabsorbent Nanoparticles by Displaying Single-Domain Protein A on Potato Virus X. AB - The combination of antibodies with nanoparticles provides wide-ranging applications in biosensing. While several covalent presentation strategies have been established, there is need for alternative, non-covalent methods to provide a routine for scalable nanomanufacturing. We report the multivalent presentation of the B domain of Staphylococcus aureus protein A (SpAB) on potato virus X (PVX) nanoparticles. Three different synthetic strategies were used to obtain chimeric PVX(SpAB) filaments. The protein A fragments displayed on the surface of all three PVX chimeras remained fully functional as an immunoabsorbent for antibody capture enabling biosensing. The new biomaterials presented could find applications as diagnostic tools for biomedical or environmental monitoring. PMID- 26440115 TI - Computational modeling of cytokine signaling in microglia. AB - Neuroinflammation due to glial activation has been linked to many CNS diseases. We developed a computational model of a microglial cytokine interaction network to study the regulatory mechanisms of microglia-mediated neuroinflammation. We established a literature-based cytokine network, including TNFalpha, TGFbeta, and IL-10, and fitted a mathematical model to published data from LPS-treated microglia. The addition of a previously unreported TGFbeta autoregulation loop to our model was required to account for experimental data. Global sensitivity analysis revealed that TGFbeta- and IL-10-mediated inhibition of TNFalpha was critical for regulating network behavior. We assessed the sensitivity of the LPS induced TNFalpha response profile to the initial TGFbeta and IL-10 levels. The analysis showed two relatively shifted TNFalpha response profiles within separate domains of initial condition space. Further analysis revealed that TNFalpha exhibited adaptation to sustained LPS stimulation. We simulated the effects of functionally inhibiting TGFbeta and IL-10 on TNFalpha adaptation. Our analysis showed that TGFbeta and IL-10 knockouts (TGFbeta KO and IL-10 KO) exert divergent effects on adaptation. TFGbeta KO attenuated TNFalpha adaptation whereas IL-10 KO enhanced TNFalpha adaptation. We experimentally tested the hypothesis that IL-10 KO enhances TNFalpha adaptation in murine macrophages and found supporting evidence. These opposing effects could be explained by differential kinetics of negative feedback. Inhibition of IL-10 reduced early negative feedback that results in enhanced TNFalpha-mediated TGFbeta expression. We propose that differential kinetics in parallel negative feedback loops constitute a novel mechanism underlying the complex and non-intuitive pro- versus anti-inflammatory effects of individual cytokine perturbations. PMID- 26440118 TI - Response to Majid: Neurocognitive and Cultural Approaches to Odor Naming are Complementary. PMID- 26440119 TI - Cultural Factors Shape Olfactory Language. PMID- 26440120 TI - Inhibition, Disinhibition, and the Control of Action in Tourette Syndrome. AB - Tourette syndrome (TS) is a neurological disorder characterized by vocal and motor tics. TS is associated with impairments in behavioral inhibition, dysfunctional signaling of the inhibitory neurotransmitter GABA, and alterations in the balance of excitatory and inhibitory influences within brain networks implicated in motor learning and the selection of actions. We review evidence that increased control over motor outputs, including the suppression of tics, may develop during adolescence in TS and be accompanied by compensatory, neuromodulatory, alterations in brain structure and function. In particular, we argue that increased control over motor outputs in TS is brought about by local increases in 'tonic' inhibition that lead to a reduction in the 'gain' of motor excitability. PMID- 26440121 TI - Imitation and Innovation: The Dual Engines of Cultural Learning. AB - Imitation and innovation work in tandem to support cultural learning in children and facilitate our capacity for cumulative culture. Here we propose an integrated theoretical account of how the unique demands of acquiring instrumental skills and cultural conventions provide insight into when children imitate, when they innovate, and to what degree. For instrumental learning, with an increase in experience, high fidelity imitation decreases and innovation increases. By contrast, for conventional learning, imitative fidelity stays high, regardless of experience, and innovation stays low. We synthesize cutting edge research on the development of imitative flexibility and innovation to provide insight into the social learning mechanisms underpinning the uniquely human mind. PMID- 26440122 TI - Decoding Rich Spatial Information with High Temporal Resolution. AB - New research suggests that magnetoencephalography (MEG) contains rich spatial information for decoding neural states. Even small differences in the angle of neighbouring dipoles generate subtle, but statistically separable field patterns. This implies MEG (and electroencephalography: EEG) is ideal for decoding neural states with high-temporal resolution in the human brain. PMID- 26440123 TI - Moral Perception. AB - Based on emerging research, we propose that human perception is preferentially attuned to moral content. We describe how moral concerns enhance detection of morally relevant stimuli, and both command and direct attention. These perceptual processes, in turn, have important consequences for moral judgment and behavior. PMID- 26440124 TI - Understanding What We See: How We Derive Meaning From Vision. AB - Recognising objects goes beyond vision, and requires models that incorporate different aspects of meaning. Most models focus on superordinate categories (e.g., animals, tools) which do not capture the richness of conceptual knowledge. We argue that object recognition must be seen as a dynamic process of transformation from low-level visual input through categorical organisation to specific conceptual representations. Cognitive models based on large normative datasets are well-suited to capture statistical regularities within and between concepts, providing both category structure and basic-level individuation. We highlight recent research showing how such models capture important properties of the ventral visual pathway. This research demonstrates that significant advances in understanding conceptual representations can be made by shifting the focus from studying superordinate categories to basic-level concepts. PMID- 26440125 TI - ER contact sites direct late endosome transport. AB - Endosomes shuttle select cargoes between cellular compartments and, in doing so, maintain intracellular homeostasis and enable interactions with the extracellular space. Directionality of endosomal transport critically impinges on cargo fate, as retrograde (microtubule minus-end directed) traffic delivers vesicle contents to the lysosome for proteolysis, while the opposing anterograde (plus-end directed) movement promotes recycling and secretion. Intriguingly, the endoplasmic reticulum (ER) is emerging as a key player in spatiotemporal control of late endosome and lysosome transport, through the establishment of physical contacts with these organelles. Earlier studies have described how minus-end directed motor proteins become discharged from vesicles engaged at such contact sites. Now, Raiborg et al. implicate ER-mediated interactions, induced by protrudin, in loading plus-end-directed motor kinesin-1 onto endosomes, thereby stimulating their transport toward the cell's periphery. In this review, we recast the prevailing concepts on bidirectional late endosome transport and discuss the emerging paradigm of inter-compartmental regulation from the ER endosome interface viewpoint. PMID- 26440126 TI - Sex commonalities and differences in the relationship between resilient personality and the intrinsic connectivity of the salience and default mode networks. AB - Increased resilience is associated with better health outcomes and reduced morbidity in response to injury and homeostatic perturbations. Proper functioning of the salience network (SN) and modulation of the default mode network (DMN) by SN may play a role in adaptively responding to stress. Here, we demonstrate that resilient personality in healthy subjects is associated with SN and DMN connectivity patterns and that these patterns are influenced by sex. While connectivity of SN with several brain regions including right anterior insula was significantly associated with resilient personality in both men and women, results suggest that increased functional integration of anterior DMN preferentially benefits women while increased functional integration of posterior DMN preferentially benefits men in terms of resilience. These findings may relate to previous demonstrations that men and women engage different information processing and behavioral strategies to achieve resilience and highlight the importance of considering sex in resilience research. PMID- 26440127 TI - Immune responses to human cancer stem-like cells/cancer-initiating cells. AB - Cancer stem-like cells (CSC)/cancer-initiating cells (CIC) are defined as minor subpopulations of cancer cells that are endowed with properties of higher tumor initiating ability, self-renewal ability and differentiation ability. Accumulating results of recent studies have revealed that CSC/CIC are resistant to standard cancer therapies, including chemotherapy, radiotherapy and molecular targeting therapy, and eradiation of CSC/CIC is, thus, critical to cure cancer. Cancer immunotherapy is expected to become the "fourth" cancer therapy. Cytotoxic T lymphocytes (CTL) play an essential role in immune responses to cancers, and CTL can recognize CSC/CIC in an antigen-specific manner. CSC/CIC express several tumor-associated antigens (TAA), and cancer testis (CT) antigens are reasonable sources for CSC/CIC-targeting immunotherapy. In this review article, we discuss CSC/CIC recognition by CTL, regulation of immune systems by CSC/CIC, TAA expression in CSC/CIC, and the advantages of CSC/CIC-targeting immunotherapy. PMID- 26440128 TI - Bowdler spur also found in camptomelic dysplasia. PMID- 26440130 TI - (14)N NQR, relaxation and molecular dynamics of the explosive TNT. AB - Multiple pulse sequences are widely used for signal enhancement in NQR detection applications. Since the various (14)N NQR relaxation times, signal decay times and frequency of each NQR line have a major influence on detection sequence performance, it is important to characterise these parameters and their temperature variation, as fully as possible. In this paper we discuss such measurements for a number of the nu+ and nu- NQR lines of monoclinic and orthorhombic TNT and relate the temperature variation results to molecular dynamics. The temperature variation of the (14)N spin-lattice relaxation times T1 is interpreted as due to hindered rotation of the NO2 group about the C-NO2 bond with an activation energy of 89 kJ mol(-1) for the ortho and para groups of monoclinic TNT and 70 kJ mol(-1) for the para group of orthorhombic TNT. PMID- 26440129 TI - Diagnostic accuracy of point-of-care ultrasound for catheter-related thrombosis in children. AB - BACKGROUND: Compared with consultative US performed by the radiology department, point-of-care US performed by non-radiology physicians can accurately diagnose deep venous thrombosis in adults. OBJECTIVE: In preparation for a multicenter randomized controlled trial, we determined the accuracy of point-of-care US in diagnosing central venous catheter-related thrombosis in critically ill children. MATERIALS AND METHODS: Children <18 years old with a central venous catheter who were admitted to the intensive care unit were enrolled. Consultative and point-of care compression ultrasounds with Doppler were done on the vein where the catheter was inserted within 24 h after insertion. Repeat US was obtained within 24 h of removal of the catheter. All images were centrally, blindly and independently adjudicated for thrombosis by a team of pediatric radiologists. Chance-corrected agreement between readings was calculated. RESULTS: From 84 children, 152 pairs of consultative and point-of-care ultrasounds were analyzed. A total of 38 (25.0%) consultative and 17 (11.2%) point-of-care ultrasounds were positive for thrombosis. The chance-corrected agreement between consultative and point-of-care ultrasounds was 0.17 (standard error: 0.07; P = 0.008). With consultative US as a reference, the sensitivity of point-of-care US was 28.1% (95% confidence interval: 13.7%-46.7%) with a specificity of 91.8% (95% confidence interval: 84.4%-96.4%). A catheter in the subclavian vein was associated with discordant readings (adjusted odds ratio: 4.00; 95% confidence interval: 1.45-13.94). CONCLUSION: Point-of-care US, when performed by non radiology physicians and centrally adjudicated by pediatric radiologists in the setting of a multicenter randomized controlled trial, may not accurately diagnose catheter-related thrombosis in critically ill children. PMID- 26440132 TI - Phenotypic screening: the future of antibody discovery. AB - Most antibody therapeutics have been isolated from high throughput target-based screening. However, as the number of validated targets diminishes and the target space becomes increasingly competitive, alternative strategies, such as phenotypic screening, are gaining momentum. Here, we review successful phenotypic screens, including those used to isolate antibodies against cancer and infectious agents. We also consider exciting advances in the expression and phenotypic screening of antibody repertoires in single cell autocrine systems. As technologies continue to develop, we believe that antibody phenotypic screening will increase further in popularity and has the potential to provide the next generation of therapeutic antibodies. PMID- 26440131 TI - Aromatic spectral editing techniques for magic-angle-spinning solid-state NMR spectroscopy of uniformly (13)C-labeled proteins. AB - The four aromatic amino acids in proteins, namely histidine, phenylalanine, tyrosine, and tryptophan, have strongly overlapping (13)C chemical shift ranges between 100 and 160ppm, and have so far been largely neglected in solid-state NMR determination of protein structures. Yet aromatic residues play important roles in biology through pi-pi and cation-pi interactions. To better resolve and assign aromatic residues' (13)C signals in magic-angle-spinning (MAS) solid-state NMR spectra, we introduce two spectral editing techniques. The first method uses gated (1)H decoupling in a proton-driven spin-diffusion (PDSD) experiment to remove all protonated (13)C signals and retain only non-protonated carbon signals in the aromatic region of the (13)C spectra. The second technique uses chemical shift filters and (1)H-(13)C dipolar dephasing to selectively detect the Calpha, Cbeta and CO cross peaks of aromatic residues while suppressing the signals of all aliphatic residues. We demonstrate these two techniques on amino acids, a model peptide, and the microcrystalline protein GB1, and show that they significantly simplify the 2D NMR spectra and both reveal and permit the ready assignment of the aromatic residues' signals. PMID- 26440133 TI - Do Basketball Players Have a High Risk of Pulmonary Embolism? A Scoping Review. AB - PURPOSE: Pulmonary embolism (PE) is a serious preventable disease that requires urgent care. In recent years, there have been several reports in the media about basketball players experiencing PE. The aim of the present study was to assess whether there is a need for in-depth studies to determine whether basketball players constitute a group particularly at risk of PE and to describe some hypotheses to be investigated. METHODS: We reviewed original articles about PE among professional and amateur basketball players in the scientific literature (PubMed) and the Internet (Google search) for the seasons 2010-2011 to 2014-2015, both of which were included. We used search strategies that included some combination of PE-related terms. Rates of PE were calculated and were compared with those obtained from other studies. RESULTS: Of the 15 cases detected, the majority were men (66.7%), mean ages being 28.8 yr among males and 20.4 yr among females. We focused on six cases which, were detected among National Basketball Association and Asociacion de Clubes de Baloncesto basketball players, resulting in an average incidence of 1.27 and 2.06 cases per 1000 players per year in the National Basketball Association and Asociacion de Clubes de Baloncesto, respectively. This incidence is much higher than that observed in general population studies for the same age group. CONCLUSIONS: Basketball players seem to have a higher risk of PE than their peers from the general population. More studies are needed to confirm these findings and identify factors predisposing them to PE to contribute to its prevention. PMID- 26440134 TI - Comparison of Three Popular Exercise Modalities on VO2max in Overweight and Obese. AB - INTRODUCTION: In this prospective randomized trial, we examined the effect of three popular exercise training modalities on maximal oxygen uptake (VO2max) in overweight and obese individuals. In addition, we examined possible concomitant adaptations in endurance exercise performance (time to exhaustion (TTE)), citrate synthase (CS) activity, venous and arterial function, blood volume, and calculated stroke volume (SV). METHODS: Thirty subjects were recruited (age, 41 +/- 9 yr; weight, 91 +/- 14 kg; height, 173 +/- 8 cm; body mass index, 30 +/- 4 kg.m(-2)) and randomized to either 6 wk of 4 * 4-min high-intensity interval training (4HIIT) at 85%-95% of HRmax, 10 * 1-min HIIT (1HIIT) at VO2max load, or 45-min moderate-intensity continuous training (MICT) at 70% of HRmax. VO2max, TTE, CS activity, venous and arterial function, as well as blood volume were measured before and after the training period. O2 pulse was calculated and used to estimate SV. Analysis was conducted per protocol. RESULTS: Only 4HIIT increased VO2max (P < 0.01) and significantly more compared with 1HIIT (P = 0.04) and MICT (P = 0.03) (4HIIT, 10%; 1HIIT, 3.3%; and MICT, 3.1%). All groups increased TTE (4HIIT, 198%; 1HIIT, 116%; MICT, 52%), with a higher increase after 4HIIT compared with that after MICT (P = 0.02). Calculated SV increased only after 4HIIT (14.4%). Plasma volume and hemoglobin mass increased after 1HIIT only (5.6% and 6.5%); however, no group differences were found. All groups increased CS activity (4HIIT, 35%; 1HIIT, 35%; MICT, 56%), with no group differences. Arterial inflow (15.7%) and venous outflow (22.7%) decreased after MICT, but there were no group differences. CONCLUSIONS: 4HIIT was superior to 1HIIT and MICT in improving VO2max likely because of an increased SV. PMID- 26440135 TI - 1,6-Conjugated Addition-Mediated [2+1] Annulation: Approach to Spiro[2.5]octa-4,7 dien-6-one. AB - A formal 1,6-conjugated addition-mediated [2+1] annulation to synthesize spiro[2.5]octa-4,7-dien-6-one with p-quinone methides and sulfur ylides has been described. This domino-type process was highly diastereoselective and exhibited good functional group tolerance and scalability without the use of metals and bases. PMID- 26440136 TI - Peroxidised dietary lipids impair intestinal function and morphology of the small intestine villi of nursery pigs in a dose-dependent manner. AB - The objective of this study was to investigate the effect of increasing degrees of lipid peroxidation on structure and function of the small intestine of nursery pigs. A total of 216 pigs (mean body weight was 6.5 kg) were randomly allotted within weight blocks and sex and fed one of five experimental diets for 35 d (eleven pens per treatment with three to four pigs per pen). Treatments included a control diet without added lipid, and diets supplemented with 6 % soyabean oil that was exposed to heat (80 degrees C) and constant oxygen flow (1 litre/min) for 0, 6, 9 and 12 d. Increasing lipid peroxidation linearly reduced feed intake (P<0.001) and weight gain (P=0.024). Apparent faecal digestibility of gross energy (P=0.001) and fat (P<0.001) decreased linearly as the degree of peroxidation increased. Absorption of mannitol (linear, P=0.097) and d-xylose (linear, P=0.089), measured in serum 2 h post gavage with a solution containing 0.2 g/ml of d-xylose and 0.3 g/ml of mannitol, tended to decrease progressively as the peroxidation level increased. Increasing peroxidation also resulted in increased villi height (linear, P<0.001) and crypt depth (quadratic, P=0.005) in the jejunum. Increasing peroxidation increased malondialdehyde concentrations (quadratic, P=0.035) and reduced the total antioxidant capacity (linear, P=0.044) in the jejunal mucosa. In conclusion, lipid peroxidation progressively diminished animal performance and modified the function and morphology of the small intestine of nursery pigs. Detrimental effects were related with the disruption of redox environment of the intestinal mucosa. PMID- 26440137 TI - Interleukin 4 inhibition as a potential therapeutic in pemphigus. AB - Pemphigus is an autoimmune bullous skin disease that results from desmosomal protein desmoglein 3 and 1 loss in pemphigus vulgaris and foliaceus, respectively. It can be considered as a Th2-dominant disease over-expressed by Th2 cell cytokines. Interleukin (IL)-4 is a key cytokine which can exacerbate Th2 over-expression in addition to isotype switching to immunoglobin (Ig)G1 and IgG4 that are responsible for desmoglein loss. Elevation of IL-4 level has also been reported in various studies. Considering the important role of IL-4 in severe phase of pemphigus and lack of effective and safeness therapy for this potentially fatal disease, anti-IL-4 therapy was introduced as a potential curative for pemphigus disease. This study reviewed all studies about any roles of IL-4 that can directly and indirectly be played in the development of pemphigus and IL-4 inhibition with interferons and dupilumab therapy were introduced as a novel pemphigus treatment for patients who are in relapse phase of the disease. Dupilumab was also introduced as a possible treatment for patients with severe pemphigus. It can directly inhibit IL-4 by targeting IL-4 alpha-chain receptor. IL-4 inhibition can lead to the creation of Th1:Th2 balance by various pathways, discussed in this study. PMID- 26440138 TI - Emerging roles of the Th17/IL-17-axis in glomerulonephritis. AB - Different T cell subsets have been implicated in the pathogenesis of glomerulonephritis. Several lines of evidence indicate the recently identified interleukin-17 (IL-17)-producing T cells (Th17 cells) to be involved in the renal inflammatory cascade associated with glomerulonephritis. In this review we outline different forms of glomerulonephritis and the contribution of the Th17/IL 17-axis in mediating the downstream effects and pathology associated with the disease. Learning more about the Th17/IL-17-axis can help to develop promising therapeutic strategy for the treatment of various forms of glomerulonephritis. PMID- 26440139 TI - Psychometric evaluation of the adolescent and parent versions of the Gaming Addiction Identification Test (GAIT). AB - The objective of the study is to evaluate the psychometric properties of the Gaming Addiction Identification Test (GAIT) and its parent version (GAIT-P), in a representative community sample of adolescents and parents in Vastmanland, Sweden. Self-rated and parent-rated gaming addictive symptoms identified by GAIT and GAIT-P were analyzed for frequency of endorsement, internal consistency, concordance, factor structure, prevalence of Internet gaming disorder (IGD), concurrence with the Gaming Addiction Scale for Adolescents, 7-item version (GAS) and the parent version of GAS (GAS-P), and for sex differences. The 12-month prevalence of IGD was found to be 1.3% with GAIT and 2.4% with GAIT-P. Results also indicate promising psychometric results within this population, with high internal consistency, and high concurrent validity with GAS and GAS-P. Concordance between adolescents and parents ratings was high, although moderate in girls. Although exploratory factor analysis indicated poor model fit, it also indicated unidimensionality and high factor loadings in all analyses. GAIT and GAIT-P are suitable for continued use in measuring gaming addiction in adolescents, and, with the additional two items, they now cover all nine IGD criteria. PMID- 26440140 TI - Synthesis of Upconverting Hydrogel Nanocomposites Using Thiol-Ene Click Chemistry: Template for the Formation of Dendrimer-Like Gold Nanoparticle Assemblies. AB - The synthesis of upconverting hydrogel nanocomposites by base-catalyzed thiol-ene click reaction between 10-undecenoic acid capped Yb(3+)/Er(3+)-doped NaYF4 nanoparticles and pentaerythritol tetrakis(3-mercaptopropionate) (PETMP) as tetrathiol monomer is reported. This synthetic strategy for nanocomposite gels is quite different from works where usually the preformed gels are mixed with the nanoparticles. Developing nanocomposites by surface modification of capping ligands would allow tuning and controlling of the separation of the nanoparticles inside the gel network. The hydrogel nanocomposites prepared by thiol-ene click reaction show strong enhancement in luminescence intensity compared to 10 undecenoic acid-capped Yb(3+)/Er(3+)-doped NaYF4 nanoparticles through the upconversion process (under 980 nm laser excitation). The hydrogel nanocomposites display strong swelling characteristics in water resulting in porous structures. Interestingly, the resulting nanocomposite gels act as templates for the synthesis of dendrimer-like Au nanostructures when HAuCl4 is reduced in the presence of the nanocomposite gels. PMID- 26440141 TI - Unique Electronic and Structural Effects in Vanadia/Ceria-Catalyzed Reactions. AB - Vanadia/ceria supported catalysts exhibit ultrahigh catalytic activities in oxidative dehydrogenation (ODH) reactions. Here, we performed systematic density functional theory calculations to illustrate the underlying mechanisms. It is found that unique electronic and structural effects are both crucial in the catalytic processes. Calculations of the catalytic performance of different oxygen species in oxidation of methanol to formaldehyde suggested that the oxygen of the interface V-O-Ce group is catalytically more active, especially when H adsorption energy is small, indicating the strong structural effect in the vanadia/ceria supported catalyst. In addition, new empty localized states of O 2p generated in a ceria-supported system through depositing VO3- and VO4-type monomeric vanadia species are determined to participate in the whole ODH reaction processes and help to reduce the barriers at various steps. PMID- 26440142 TI - The neuropeptide SIFamide in the brain of three cockroach species. AB - The sequence as well as the distribution pattern of SIFamide in the brain of different insects is highly conserved. As a general rule, at least four prominent SIFamide-immunoreactive somata occur in the pars intercerebralis. They arborize throughout the brain and the ventral nerve cord. Whereas SIFamide is implicated in mating and sleep regulation in Drosophila, other functions of this peptide remain largely unknown. To determine whether SIFamide plays a role in the circadian system of cockroaches, we studied SIFamide in Rhyparobia (= Leucophaea) maderae (Blaberidae), Periplaneta americana (Blattidae), and Therea petiveriana (Polyphagidae). Matrix-assisted laser desorption/ionization-time of flight (MALDI TOF) mass spectrometry revealed identical SIFamide sequences (TYRKPPFNGSIFamide) in the three species. In addition to four large immunoreactive cells in the pars intercerebralis (group 1), smaller SIFamide-immunoreactive somata were detected in the pars intercerebralis (group 2), in the superior median protocerebrum (group 3), and in the lateral protocerebrum (group 4). Additional cells in the optic lobe (group 5) and posterior protocerebrum (group 6) were stained only in P. americana. Almost the entire protocerebrum was filled with a beaded network of SIFamide-immunoreactive processes that especially strongly invaded the upper unit of the central body. Double-label experiments did not confirm colocalizations with gamma-aminobutyric acid (GABA) or the circadian coupling peptide pigment dispersing factor (PDF). In contrast to locusts, colocalization of SIFamide and histamine immunoreactivity occurred not in group 1, but in group 4 cells. Because the accessory medulla displayed SIFamide immunoreactivity and injections of SIFamide delayed locomotor activity rhythms circadian time-dependently, SIFamide plays a role in the circadian system of cockroaches. J. Comp. Neurol. 524:1337 1360, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26440143 TI - Editorial Comment. PMID- 26440145 TI - Chinese version of the Schizotypal Personality Questionnaire: Factor structure replication and invariance across sex. AB - INTRODUCTION: The Schizotypal Personality Questionnaire (SPQ) is a self-report measure assessing symptoms of schizotypy. The SPQ has been used in both normative and clinical samples and has much theoretical and empirical support. A three factor structure of the SPQ, derived on the basis of work in schizophrenia, consisting of Cognitive-Perceptual, Interpersonal, and Disorganized factors, has been well replicated. The present study aimed to (i) validate this three-factor structure in the Chinese version of the SPQ in a sample of individuals of Chinese ethnicity, and (ii) test for invariance across sex. METHODS: A total of 209 (99 males) undergraduate university students (Mage = 19.5, SD = 1.6) were administered the SPQ. RESULTS: Confirmatory factor analysis indicated a better fit between the data and the three-factor model compared with a one-factor model. Multigroup confirmatory factor analysis also found strong measurement invariance across sex. DISCUSSION: The current results add to a growing body of literature evidencing cross-cultural validity of the SPQ and its invariance across sex. Research and clinical implications of the current results are discussed. PMID- 26440146 TI - Environmental chemicals active as human antiandrogens do not activate a stickleback androgen receptor but enhance a feminising effect of oestrogen in roach. AB - Sexual disruption is reported in wild fish populations living in freshwaters receiving discharges of wastewater treatment works (WwTW) effluents and is associated primarily with the feminisation of males by exposure to oestrogenic chemicals. Antiandrogens could also contribute to the feminisation of male fish, but there are far less data supporting this hypothesis and almost nothing is known for the effects of oestrogens in combination with antiandrogens in fish. We conducted a series of in vivo exposures in two fish species to investigate the potency on reproductive-relevant endpoints of the antiandrogenic antimicrobials triclosan (TCS), chlorophene (CP) and dichlorophene (DCP) and the resin, abietic acid (AbA), all found widely in WwTW effluents. We also undertook exposures with a mixture of antiandrogens and a mixture of antiandrogens in combination with the oestrogen 17alpha-ethinyloestradiol (EE2). In stickleback (Gasterosteus aculeatus), DCP showed a tendency to reduce spiggin induction in females androgenised by dihydrotestosterone (DHT), but these findings were not conclusive. In roach (Rutilus rutilus), exposures to DCP (178 days), or a mixture of TCS, CP and AbA (185 days), or to the model antiandrogen flutamide (FL, 178 days) had no effect on gonadal sex ratio or on the development of the reproductive ducts. Exposure to EE2 (1.5ng/L, 185 days) induced feminisation of the ducts in 17% of the males and in the mixture of antiandrogens (TCS, CP, AbA) in combination with EE2, almost all (96%) of the males had a feminised reproductive ducts. In stickleback androgen receptor (ARalpha and ARbeta) transactivation assays, the model antiandrogens, FL and procymidone inhibited 11 ketotestosterone (11-KT) induced receptor activation, but none of the human antiandrogens, TCS, CP, DCP and AbA had an effect. These data indicate that antimicrobial antiandrogens in combination can contribute to the feminisation process in exposed males, but they do not appear to act through the androgen receptor in fish. PMID- 26440147 TI - Epigenetic silencing of miR-145-5p contributes to brain metastasis. AB - Brain metastasis is a major cause of morbidity and mortality of lung cancer patients. We assessed whether aberrant expression of specific microRNAs could contribute to brain metastasis. Comparison of primary lung tumors and their matched metastatic brain disseminations identified shared patterns of several microRNAs, including common down-regulation of miR-145-5p. Down-regulation was attributed to methylation of miR-145's promoter and affiliated elevation of several protein targets, such as EGFR, OCT-4, MUC-1, c-MYC and, interestingly, tumor protein D52 (TPD52). In line with these observations, restored expression of miR-145-5p and selective depletion of individual targets markedly reduced in vitro and in vivo cancer cell migration. In aggregate, our results attribute to miR-145-5p and its direct targets pivotal roles in malignancy progression and in metastasis. PMID- 26440148 TI - The timing of surgery after neoadjuvant radiotherapy influences tumor dissemination in a preclinical model. AB - Neoadjuvant radiotherapy (neoRT) used in cancer treatments aims at improving local tumor control and patient overall survival. The neoRT schedule and the timing of the surgical treatment (ST) are empirically based and influenced by the clinician's experience. The current study examines how the sequencing of neoRT and ST affects metastatic dissemination. In a breast carcinoma model, tumors were exposed to different neoRT schedules (2x5Gy or 5x2Gy) followed by surgery at day 4 or 11 post-RT. The impact on the tumor microenvironment and lung metastases was evaluated through immunohistochemical and flow cytometry analyses. After 2x5Gy, early ST (at day 4 post-RT) led to increased size and number of lung metastases as compared to ST performed at day 11. Inversely, after 5x2Gy neoRT, early ST protected the mice against lung metastases. This intriguing relationship between tumor aggressiveness and ST timing could not be explained by differences in classical parameters studied such as hypoxia, vessel density and matrix remodeling. The study of tumor-related inflammation and immunity reveals an increased circulating NK cell percentage following neoRT as compared to non irradiated mice. Then, radiation treatment and surgery were applied to tumor bearing NOD/SCID mice. In the absence of NK cells, neoRT appears to increase lung metastatic dissemination as compared to non irradiated tumor-bearing mice. Altogether our data demonstrate that the neoRT schedule and the ST timing affect metastasis formation in a pre-clinical model and points out the potential role of NK cells. These findings highlight the importance to cautiously tailor the optimal window for ST following RT. PMID- 26440149 TI - Lack of intracellular replication of M. tuberculosis and M. bovis BCG caused by delivering bacilli to lysosomes in murine brain microvascular endothelial cells. AB - Invasion and traversal of the blood-brain barrier (BBB) by Mycobacterium tuberculosis cause meningeal tuberculosis (TB) in the central nervous system (CNS). Meningeal TB is a serious, often fatal disease that disproportionately affects young children. The mechanisms involved in CNS invasion by M. tuberculosis bacilli are poorly understood. In this study, we microscopically examined endosomal trafficking and measured survival of M. tuberculosis and M. bovis Bacille Calmette-Guerin (BCG) bacilli in murine brain microvascular endothelial cells (BMECs). The results show that both species internalize but do not replicate in BMECs in the absence of a cytotoxic response. Confocal microscopy indicates that bacilli-containing vacuoles are associated with the early endosomal marker, Rab5, late endosomal marker, Rab7, and lysosomal marker, LAMP2, suggesting that bacilli-containing endosomes mature into endolysosomes in BMECs. Our data also show that a subset of intracellular M. tuberculosis, but not BCG bacilli, escape into the cytoplasm to avoid rapid lysosomal killing. However, the intracellular mycobacteria examined cannot spread cell-to-cell in BMECs. Taken together, these data show that with the exception of the small terminal cytoplasmic population of bacilli, M. tuberculosis does not modulate intracellular trafficking in BMECs as occurs in macrophages and lung epithelial and endothelial cells. PMID- 26440150 TI - Fendiline inhibits proliferation and invasion of pancreatic cancer cells by interfering with ADAM10 activation and beta-catenin signaling. AB - ADAM10 (A Disintegrin and Metalloprotease Domain 10) affects the pathophysiology of various cancers, and we had shown that inhibition of ADAM10 sensitizes pancreatic cancer cells to gemcitabine. ADAM10 is activated in response to calcium influx, and here we examined if calcium channel blockers (CCB) would impede ADAM10 activation and affect biology of pancreatic cancer cells. We find that the CCB, fendiline, significantly reduces proliferation, migration, invasion, and anchorage independent growth of pancreatic cancer cells. This was associated with ADAM10 inhibition and its localization at the actin-rich membrane protrusions. Further, fendiline-treated cells formed cadherin-catenin positive tight adherens junctions and elicited defective protein trafficking and recycling. Furthermore, the expression of beta-catenin target genes, cyclinD1, c Myc and CD44, were significantly decreased, suggesting that fendiline might prevent cell proliferation and migration by inhibiting ADAM10 function, cadherin proteolysis and stabilization of cadherin-catenin interaction at the plasma membrane. This will subsequently diminish beta-catenin intracellular signaling and repress TCF/LEF target gene expression. Supporting this notion, RNAi-directed downregulation of ADAM10 in cancer cells decreased the expression of cyclinD1, c Myc and CD44. Furthermore, analysis of human pancreatic tumor tissue microarrays and lysates showed elevated levels of ADAM10, suggesting that aberrant activation of ADAM10 plays a fundamental role in growth and metastasis of PDACs and inhibiting this pathway might be a viable strategy to combat PDACs. PMID- 26440151 TI - Dietary NiCl2 causes G2/M cell cycle arrest in the broiler's kidney. AB - Here we showed that dietary NiCl2 in excess of 300 mg/kg caused the G2/M cell cycle arrest and the reduction of cell proportion at S phase. The G2/M cell cycle arrest was accompanied by up-regulation of phosphorylated ataxia telangiectasia mutated (p-ATM), p53, p-Chk1, p-Chk2, p21 protein expression and ATM, p53, p21, Chk1, Chk2 mRNA expression, and down-regulation of p-cdc25C, cdc2, cyclinB and proliferating cell nuclear antigen (PCNA) protein expression and the cdc25, cdc2, cyclinB, PCNA mRNA expression. PMID- 26440152 TI - Human anterior thalamic nuclei are involved in emotion-attention interaction. AB - Patients treated with deep brain stimulation (DBS) provide an opportunity to study affective processes in humans with "lesion on demand" at key nodes in the limbic circuitries, such as at the anterior thalamic nuclei (ANT). ANT has been suggested to play a role in emotional control with its connection to the orbitofrontal cortex and the anterior cingulate cortex. However, direct evidence for its role in emotional function in human subjects is lacking. Reported side effects of ANT-DBS in the treatment of refractory epilepsy include depression related symptoms. In line with these mood-related clinical side effects, we have previously reported that stimulating the anterior thalamus increased emotional interference in a visual attention task as indicated by prolonged reaction times due to threat-related emotional distractors. We used event-related potentials to investigate potential attentional mechanism behind this behavioural observation. We hypothesized that ANT-DBS leads to greater attention capture by threat-related distractors. We tested this hypothesis using centro-parietal N2-P3 peak-to-peak amplitude as a measure of allocated attentional resources. Six epileptic patients treated with deep brain stimulation at ANT participated in the study. Electroencephalography was recorded while the patients performed a computer based Executive-Reaction Time test with threat-related emotional distractors. During the task, either ANT or a thalamic control location was stimulated, or the stimulation was turned off. Stimulation of ANT was associated with increased centro-parietal N2-P3 amplitude and increased reaction time in the context of threat-related emotional distractors. We conclude that high frequency electric stimulation of ANT leads to greater attentional capture by emotional stimuli. This is the first study to provide direct evidence from human subjects with on line electric manipulation of ANT for its role in emotion-attention interaction. PMID- 26440154 TI - Technical note: Production of tetraploid sturgeons. AB - Studies and practical application of androgenesis and gynogenesis in sturgeon are significantly hindered by strong influence of ploidy restoration treatment on survivability of progeny; therefore, developed method of production of tetraploid broodstock and, consequently, use of their diploid gametes might help to avoid ploidy restoration treatment. In the present study, for the first time was developed a protocol for tetraploidy induction in 2 model sturgeon species, sterlet () and Siberian sturgeon (). A high efficiency of treatment was achieved by optimization of heat shock using a temperature of 37 degrees C for 2 min timed between the end of female pronuclei formation and the beginning of pronuclei migration, that is, 0.8 to 1.0 tau (duration of 1 mitotic cycle during the period of synchronous cleavage division). Fertilized eggs developed in tetraploid larvae, up to 31 (89.6% in control) and 34% (70.9% in control) in sterlet and Siberian sturgeon, respectively. Most of the tetraploid larvae exhibited body malformations; as a result, consequent large scale study revealed high larval mortality, which drastically decreased after 2 mo of age. Consequent comparison of BW, length, and malformation rate and mortality between diploid and tetraploid progeny of sterlet did not reveal significant differences in fitness of diploid and tetraploid juveniles at 9 and 11 mo of age. The present study can be considered the first step towards improving the androgenesis methods of conservation of endangered sturgeons as well as understanding the sturgeon sex determination system through induction of mitotic gynogenesis. PMID- 26440153 TI - Genetic relationships between measures of sexual development, boar taint, health, and aggressiveness in pigs. AB - Breeding intact boars is a promising alternative to surgical castration of piglets. Genetic selection should enable farmers to solve problems due to boar taint and aggressiveness while taking into account potential consequences on other traits of interest. The aim of the study was to estimate genetic relations between sexual development, boar taint, health, and aggressiveness. About 1,600 Pietrain (purebred) or Pietrain * Large White (crossbred) boars were raised in a testing station. Blood samples were collected at about 105 kg BW for measuring sex hormones (testosterone and estradiol) and indicators of the inflammatory status (C-reactive protein [CRP], pig major acute-phase protein [pigMAP], and blood formula). Animals were slaughtered 9 d later and measured for boar taint compounds present in fat (androstenone and skatole) and skin lesions on carcass, an indicator of aggressiveness. For both genetic types, heritability was moderate for sex hormones (from 0.17 to 0.29) and skatole (0.24 for purebred and 0.37 for crossbred) and high for androstenone (0.63 and 0.70 for purebred and crossbred, respectively). Genetic correlations between sex hormones and boar taint compounds were moderate to high (from 0.31 to 0.95). Heritability was moderate for CRP (0.24 and 0.46 for purebred and crossbred, respectively) and very low for pigMAP (0.06 and 0.05 for purebred and crossbred, respectively. Numbers of leukocytes had moderate to high heritabilities according to the genetic type (from 0.21 to 0.52). Heritability of skin lesions was moderate for both genetic types (0.31). Genetic correlations were negative between sex hormones and inflammatory measures (from -0.46 to -0.05), positive between testosterone and number of lesions (0.43 and 0.53 for purebred and crossbred, respectively), and low between androstenone and lesions (-0.06 and -0.17 for purebred and crossbred, respectively). Overall, both breeds of pigs had very similar estimations of heritabilities, but estimates of genetic correlations were different for some pairs of traits. It would be possible to select boars based on their plasma concentration of sex hormones to decrease boar taint and aggressiveness without important consequences on the immune response. However, because of the strong links between boar taint and reproductive function, the possible consequences on the reproductive performance should be evaluated. PMID- 26440155 TI - Derivation of a new lamb survival trait for the New Zealand sheep industry. AB - Previous research identified that a review of the current industry New Zealand lamb survival trait was necessary as its recording accuracy was reliant on farmers notifying their Sheep Improvement Limited bureau of lamb deaths. This paper reports the decision rules and genetic parameters for a new lamb survival trait for the New Zealand sheep industry. These rules define the new lamb survival trait (NEWSUR) using lamb birth fate (BFATE) codes and the presence/absence of lamb weight measurements. Six univariate animal models were tested and used to estimate variance or covariance components and the resulting direct and maternal heritabilities for NEWSUR. The models differed in the way they adjust for the effect of day of birth, the exclusion or inclusion of a litter (dam/year of birth) random effect, and the application or not of a logit transformation of the phenotypes. For both the linear and logistic methods, models including the random effect of litter provided the best fit for NEWSUR according to log-likelihood values. Log-likelihoods for the linear and logistic models cannot be compared; therefore, a cross-validation method was used to assess whether the logit transformation was appropriate by analyzing the predictive ability of the models. The mean square errors were slightly lower for the linear compared with the logistic model, and therefore, the linear model was recommended for industry use. The heritability attributed to direct effects ranged from 2 to 5.5%. A direct heritability of 5.5% resulted from a linear model without litter effect and omitting the effect of day of birth on survival, whereas a direct heritability of 2% resulted from the logistic model fitting a random litter effect. The heritability attributed to maternal genetic effects ranged from 1.9 to 7.7%. A maternal genetic heritability of 7.7% resulted from the logistic model omitting the litter effect, whereas a maternal genetic heritability of 1.9% resulted from the linear model fitting a random litter effect. The addition of the litter random effect substantially decreased the maternal heritabilities in all cases and was recommended for industry use to avoid overestimation of the maternal genetic variance. Sheep Improvement Limited has implemented NEWSUR and the associated genetic evaluation model based on information described in this paper. Industry-wide implementation will enable sheep breeders to produce more accurate genetic evaluations to their commercial clients. PMID- 26440156 TI - Population genetic structure in farm and feral American mink (Neovison vison) inferred from RAD sequencing-generated single nucleotide polymorphisms. AB - Feral American mink populations (), derived from mink farms, are widespread in Europe. In this study we investigated genetic diversity and genetic differentiation between feral and farm mink using a panel of genetic markers (194 SNP) generated from RAD sequencing data. Sampling included a total of 211 individuals from 14 populations, 4 feral and 10 from farms, the latter including a total of 7 color types (Brown, Black, Mahogany, Sapphire, White, Pearl, and Silver). Our study revealed similar low levels of genetic diversity in both farm and feral mink. Results are consistent with small effective population size as a consequence of line selection in the farms and founder effects of a few escapees from the farms in feral populations. Moderately high genetic differentiation was found between farm and feral animals, suggesting a scenario in which wild populations were founded from farm escapes a few decades ago. Currently, escapes and gene flow are probably limited. Genetic differentiation was higher among farm color types than among farms, consistent with line selection using few individuals to create the lines. Finally, no indications of inbreeding were found in either farm or feral samples, with significant negative values found in most farm samples, showing farms are successful in avoiding inbreeding. PMID- 26440157 TI - Social genetic effects influence reproductive performance of group-housed sows. AB - Group housing of gestating sows has implications for reproductive performance due to detrimental interactions between sows within groups. Reproductive records ( = 10,748) were obtained for 8,444 pedigreed nucleus sows housed in a single facility, formed into 1,827 static groups during gestation. Only data from complete groups were used to estimate genetic parameters for total born (TB), number born alive (NBA), and gestation length (GL) and to compare models extended to account for group effects. Censored data for sows which did not farrow (0.8% of records) were augmented with biologically meaningful values. Group sizes ranged from 2 to 10, in pens designed to hold 4, 8, or 10 sows per pen. Sows were grouped by parity, line, and mating date after d 35 of pregnancy. Heritability estimates were generally constant across all model alternatives at 0.11 +/- 0.02 for TB and NBA and 0.32 +/- 0.03 for GL. However, models for all traits were significantly ( < 0.05) improved through inclusion of terms for nongenetic group and social genetic effects (SGE). Group effects were no longer significant in models containing both terms. The proportional contributions of SGE () to phenotypic variances were very low (<=0.002 across traits), but their contributions to calculated total genetic variance (T) were significant. The differences between h and T ranged between 3 and 5% under simple models, increasing to 8 to 14% in models accounting for both covariances between additive direct (A) and SGE and the effects of varying group size on the magnitude of estimates for SGE. Estimates of covariance between A and SGE were sensitive to the modeling of dilution factors for group size. The models of best fit for litter size traits used a customized dilution based on sows/pen relative to the maximum sows/pen. The best model supported a reduction in SGE with increased space per sow, independent of maximum group size, and no significant correlation between A and SGE. The latter is expected if A and SGE reflect different trait complexes. It is suggested that the SGE estimated for reproductive traits represented the expression of an unobserved phenotype, such as sow aggression, of an individual on its pen mates. Further investigation into the use of competitive effects models for genetic evaluation of reproductive traits for group-housed sows could be considered a strategy to improve welfare and performance of group housed sows. PMID- 26440158 TI - Genetic variation in efficiency to deposit fat and lean meat in Norwegian Landrace and Duroc pigs. AB - Feed costs amount to approximately 70% of the total costs in pork production, and feed efficiency is, therefore, an important trait for improving pork production efficiency. Production efficiency is generally improved by selection for high lean growth rate, reduced backfat, and low feed intake. These traits have given an effective slaughter pig but may cause problems in piglet production due to sows with limited body reserves. The aim of the present study was to develop a measure for feed efficiency that expressed the feed requirements per 1 kg deposited lean meat and fat, which is not improved by depositing less fat. Norwegian Landrace ( = 8,161) and Duroc ( = 7,202) boars from Topigs Norsvin's testing station were computed tomography scanned to determine their deposition of lean meat and fat. The trait was analyzed in a univariate animal model, where total feed intake in the test period was the dependent variable and fat and lean meat were included as random regression cofactors. These cofactors were measures for fat and lean meat efficiencies of individual boars. Estimation of fraction of total genetic variance due to lean meat or fat efficiency was calculated by the ratio between the genetic variance of the random regression cofactor and the total genetic variance in total feed intake during the test period. Genetic variance components suggested there was significant genetic variance among Norwegian Landrace and Duroc boars in efficiency for deposition of lean meat (0.23 +/- 0.04 and 0.38 +/- 0.06) and fat (0.26 +/- 0.03 and 0.17 +/- 0.03) during the test period. The fraction of the total genetic variance in feed intake explained by lean meat deposition was 12% for Norwegian Landrace and 15% for Duroc. Genetic fractions explained by fat deposition were 20% for Norwegian Landrace and 10% for Duroc. The results suggested a significant part of the total genetic variance in feed intake in the test period was explained by fat and lean meat efficiency. These new efficiency measures may give the breeders opportunities to select for animals with a genetic potential to deposit lean meat efficiently and at low feed costs in slaughter pigs rather than selecting for reduced the feed intake and backfat. PMID- 26440159 TI - Genetic principal components for reproductive and productive traits in dual purpose buffaloes in Colombia. AB - A multitrait model (MC) and 5 reduced-rank models with principal component structure (components PC, PC, PC, PC, and PC) were compared. The objectives were to determine the most appropriate model for estimating genetic parameters and to evaluate the genetic progress of dual-purpose buffaloes in Colombia using that model. The traits evaluated were weaning weight (WW), yearling weight (W12), weight at 18 mo of age (W18), weight at 2 yr of age (W24), age at first calving (AFC), and milk yield at 270 d of first lactation (MY270). Genealogy and productive information from 34,326 buffaloes born in Colombia between 1997 and 2014 were used. Colombian Association of Buffalo Breeders (ACB) provided the data. Direct additive genetic and residual random effects were included for all the traits. In addition, the maternal additive genetic effect and permanent environmental random effect were included for WW, while a maternal additive genetic effect was included for W12. The fixed effects were contemporary group (farm, year, and calving season: January to April, May to August, or September to December; for all traits) and sex (for WW, W12, W18, and W24). Additionally, parity was included as a fixed effect for WW and W12. Age at weighing was used as a covariate for WW, W12, W18, and W24. Genetic progress of all traits was analyzed using a generalized smooth model (GAM). According to the Akaike information criteria (AIC), the best model was the one with reduced rank and first 3 principal components (PC). This model maintained 100% of the original variance. Genetic parameters estimated with this model were similar to those estimated by MC, but with smaller standard errors. Heritability for weight related traits ranged between 0.23 and 0.44. Heritabilities for AFC and MY270 were 0.14 and 0.24, respectively. The genetic correlations obtained between all weights (WW, W12, W18, and W24) were positive and high. Correlations between all weights with AFC were negative and moderate. Correlations between all weights with MY270 were positive and moderate, and between MY270 with AFC were negative and low. PMID- 26440160 TI - Relationships among and variation within rare breeds of swine. AB - Extinction of rare breeds of livestock threatens to reduce the total genetic variation available for selection in the face of the changing environment and new diseases. Swine breeds facing extinction typically share characteristics such as small size, slow growth rate, and high fat percentage, which limit them from contributing to commercial production. Compounding the risk of loss of variation is the lack of pedigree information for many rare breeds due to inadequate herd books, which increases the chance that producers are breeding closely related individuals. By making genetic data available, producers can make more educated breeding decisions to preserve genetic diversity in future generations, and conservation organizations can prioritize investments in breed preservation. The objective of this study was to characterize genetic variation within and among breeds of swine and prioritize heritage breeds for preservation. Genotypes from the Illumina PorcineSNP60 BeadChip (GeneSeek, Lincoln, NE) were obtained for Guinea, Ossabaw Island, Red Wattle, American Saddleback, Mulefoot, British Saddleback, Duroc, Landrace, Large White, Pietrain, and Tamworth pigs. A whole genome analysis toolset was used to construct a genomic relationship matrix and to calculate inbreeding coefficients for the animals within each breed. Relatedness and average inbreeding coefficient differed among breeds, and pigs from rare breeds were generally more closely related and more inbred ( < 0.05). A multidimensional scaling diagram was constructed based on the SNP genotypes. Animals within breeds clustered tightly together except for 2 Guinea pigs. Tamworth, Duroc, and Mulefoot tended to not cluster with the other 7 breeds. PMID- 26440161 TI - Estimates of genetic parameters for growth traits in Brahman cattle using random regression and multitrait models. AB - Random regression models (RRM) and multitrait models (MTM) were used to estimate genetic parameters for growth traits in Brazilian Brahman cattle and to compare the estimated breeding values obtained by these 2 methodologies. For RRM, 78,641 weight records taken between 60 and 550 d of age from 16,204 cattle were analyzed, and for MTM, the analysis consisted of 17,385 weight records taken at the same ages from 12,925 cattle. All models included the fixed effects of contemporary group and the additive genetic, maternal genetic, and animal permanent environmental effects and the quadratic effect of age at calving (AAC) as covariate. For RRM, the AAC was nested in the animal's age class. The best RRM considered cubic polynomials and the residual variance heterogeneity (5 levels). For MTM, the weights were adjusted for standard ages. For RRM, additive heritability estimates ranged from 0.42 to 0.75, and for MTM, the estimates ranged from 0.44 to 0.72 for both models at 60, 120, 205, 365, and 550 d of age. The maximum maternal heritability estimate (0.08) was at 140 d for RRM, but for MTM, it was highest at weaning (0.09). The magnitude of the genetic correlations was generally from moderate to high. The RRM adequately modeled changes in variance or covariance with age, and provided there was sufficient number of samples, increased accuracy in the estimation of the genetic parameters can be expected. Correlation of bull classifications were different in both methods and at all the ages evaluated, especially at high selection intensities, which could affect the response to selection. PMID- 26440162 TI - Effect of resveratrol and lipoic acid on sirtuin-regulated expression of metabolic genes in bovine liver and muscle slice cultures. AB - Sirtuins (Sirt) are NAD-dependent deacetylases that are activated by the antioxidants resveratrol (RSV) and lipoic acid (LA). The objective of this study was to determine in bovine liver and muscle slice cultures the effect of RSV and LA treatment on the expresssion of Sirt1, Sirt3, peroxisome proliferator activated receptor gamma coactivator 1alpha (PPARGC1A), and the forkhead box O transcription factors FoxO1 and FoxO3 as well as other factors involved in glucose and lipid metabolism and related to Sirt activity. Tissue slices from crossbred bulls were treated during 60 min with 40 or 80 MU RSV and 30, 100, 300, or 1,000 MU LA under restricted conditions (Krebs-Ringer buffer without nutrients) and fed conditions (2.5 m propionate in combination with 1 n glucagon) for liver slices or with 0.01 MU epinephrine for muscle slices. Quantitative real time PCR was used to analyze the expression of the mRNA for the genes studied and western blot analysis for the expression of the protein for Sirt1. Our results show that the expression of the mRNA for Sirt1 was enhanced by RSV in liver under restriction ( <= 0.0112) and by LA in muscle, more under restriction ( <= 0.0121) than after epinephrine administration ( < 0.0001). Sirt3 is affected in a dose dependent manner by both compounds in both tissues and under both metabolic conditions ( <= 0.0452). The expression of the protein for Sirt1 was increased by LA in both tissues under restricted conditions ( = 0.0026 and = 0.0201, respectively) but in liver also in fed conditions ( = 0.0016). Genes involved in the antioxidant response were upregulated in both tissues. These results indicate that bovine Sirt respond differently to RSV and LA stimulation than monogastric Sirt do and that gluconeogenesis in ruminants is not related to Sirt to the same degree as in monogastric species. However, these results provide information about the possible role of Sirt in ruminant metabolism. PMID- 26440163 TI - Heat stress enhances adipogenic differentiation of subcutaneous fat depot-derived porcine stromovascular cells. AB - Heat stress (HS) results from excessive heat load on animals such that all adaptive mechanisms used to dissipate the heat do not return the body to normal body temperature. In pigs, HS results in increased fat deposition compared with pair-fed animals in a thermoneutral environment. Although there is evidence that HS increases activity of lipoprotein lipase (LPL) in adipose tissue of heat stressed pigs, the fundamental causes of the increased adiposity are still unknown. It remains unclear whether HS directly alters metabolism in adipocytes. Therefore, to understand the mechanism of HS effects on porcine adipocytes, we used an in vitro adipocyte differentiation model to characterize cellular responses that occur during differentiation of pig adipocytes. Preadipocytes (stromovascular cells) were differentiated for 9 d at a normal (37 degrees C) or HS (41.5 degrees C) temperature under 5% CO. Expressions of HS genes such as heat shock proteins (HSP; HSP27, HSP60, HSP70, and HSP90), adipogenic markers peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer binding proteins alpha (C/EBPalpha), fatty acid synthase (FAS), adipocyte protein 2 (aP2), fatty acid translocase 36 (CD36), fatty acid transport protein 4 (FATP4), fatty acid transport protein 6 (FATP6), LPL, glucose transporter protein type 4 (GLUT4), phosphoenolpyruvate carboxykinase 1 (PCK1 or PEPCK-C), and glycerol kinase (GK) and adipokines (adiponectin and leptin) were determined by real-time-PCR and immunoblotting or ELISA. Cellular triglyceride (TAG) and ATP concentrations were also determined. As expected, HS increased ( < 0.05) the expressions of HSP genes. There was no HS treatment effect on the level of PPARgamma, although C/EBPalpha was induced ( < 0.05) in HS. So it remains unclear whether HS affects adipocyte differentiation. However, HS leads to increased expressions of genes involved in fatty acid uptake and TAG synthesis (FAS, aP2, CD36, FATP4, FATP6, LPL, GLUT4, PCK1, and GK). This is supported by increased cellular TAG under HS. Therefore, HS promotes increased adipocyte TAG storage, perhaps through upregulation of genes involved in fatty acid uptake and TAG synthesis. PMID- 26440164 TI - The effect of the inclusion of recycled poultry bedding and the physical form of diet on the performance, ruminal fermentation, and plasma metabolites of fattening lambs. AB - During a 125-d experimental period, 24 Afshari * Kurdish male lambs initially weighing 25.2 +/- 1.2 kg were grouped by BW and randomly assigned to treatments under a completely randomized design with a 2 * 2 factorial arrangement of treatments to evaluate the effects of feeding recycled poultry bedding (RPB; 0 and 200 g/kg DM) and the physical form of the diet (mash and block) on nutrient intake and digestibility, ruminal and plasma parameters, microbial N supply, N balance, feeding behavior, and growth performance of the lambs. Two diets with and without RPB in both mash and block form were prepared. Neither the inclusion of RPB nor the physical form of the diet affected the concentration of VFA or the total tract apparent digestibility of nutrients. Dietary RPB inclusion increased DMI ( < 0.01), tended ( = 0.10) to reduce ADG, and decreased G:F ( = 0.05). The physical form of the diet had no effect on DMI but decreased ADG ( = 0.01) and G:F ( = 0.02) in lambs fed on the block diet compared with those fed on the mash diet. Neither the inclusion of RPB nor the physical form of the diets had any effect on microbial N supply (g/d) and N retention. Rate of eating ( = 0.07), time spent eating ( = 0.87) and ruminating ( = 0.28), and total chewing activity ( = 0.65) were not affected by dietary RPB inclusion. Rate of eating decreased ( < 0.01) and time spent eating and total chewing activity increased ( = 0.01 and = 0.02, respectively) in lambs fed on the block diet compared with those fed on the mash diet. Results of the current study showed that inclusion of RPB up to 200 g/kg DM in diets for fattening was possible without any effect on performance and animal health. Processing of feed into the mash form gave higher livestock productivity in comparison to the block form. PMID- 26440165 TI - Mean pulmonary arterial pressures in Angus steers increase from cow-calf to feedlot-finishing phases. AB - Pulmonary arterial hypertension due to hypoxia-induced pulmonary vascular remodeling is the predominant cause of right-sided congestive heart failure (CHF) in cattle. Historically, heart failure was problematic only at altitudes over 2,134 m. However, anecdotal reports suggest that the incidence of heart failure is increasing in feedlot cattle at moderate altitude (800 to 1,600 m), with late fed, or fat, cattle at greatest risk. The goal of this study was to evaluate pulmonary arterial pressures (PAP) in a cohort of male Angus calves from suckling to finishing to better understand why heart failure is particularly problematic in fat cattle. It was hypothesized that mean PAP would increase through the feeding period and that the calves with the greatest pressures at high altitude would have the greatest pressures as fat cattle. A total of 362 PAP measurements were obtained from 153 calves. Calves were tested at altitudes of 2,170 (4 and 6 mo old), 1,560 (13 mo old), and 1,300 m (13 and 18 mo old). Mean PAP were greater in 18-mo-old steers than any other age group (mean = 50.3 mm Hg; 95% confidence interval 48.2 to 52.4; < 0.05). Calves that had the greatest mean pressure at 6 mo of age tended to have the greatest mean pressures at 18 mo of age ( = 0.45, < 0.001). The increase in mean PAP with increasing age and adiposity likely predisposed the steers to an increased risk of CHF during the finishing phase. PMID- 26440166 TI - A comparison of the physiological response to tolt and trot in the Icelandic horse. AB - This study compared the effect of ridden tolt and trot at 3 speeds on physiological responses in trained adult (15.3 +/- 1.6 yr) Icelandic horses. The experiment had a crossover design with 8 horses, 2 treatments (incremental exercise test in tolt and trot), and 2 riders. Each horse performed 2 tests per day (1 gait with 2 riders, minimum 4.5 h between) on 2 separate days, with 1 d of rest in between. The exercise test consisted of three 642-m phases at 3.0 m/s (Speed), 4.0 m/s (Speed), and 5.0 m/s (Speed) and was performed outdoors on a 300 m oval gravel riding track in northern Iceland in May 2012. Heart rate (HR) was measured during warm-up, the exercise test, and after 5, 15, and 30 min of recovery. Blood samples were taken at rest, after warm-up, after each phase of the exercise test, and after 5, 15, and 30 min of recovery. Respiratory rate was counted for at least 15 s at rest, at the end of the exercise test, and at the end of the 30-min recovery, and rectal temperature was measured on these occasions. There were no differences in HR between tolt and trot at any time point ( > 0.05). At Speed, hematocrit and plasma lactate concentration were greater ( < 0.05) in tolt (40% +/- 1%, 1.1 +/- 0.06 mmol/L) than in trot (39% +/- 1%; 0.9 +/- 0.06 mmol/L). There was a prolonged recovery of hematocrit and respiratory rate, a slower decrease in rectal temperature, and a tendency of a prolonged recovery of plasma lactate concentration ( = 0.0675) after tolt. In conclusion, there were only minor differences in physiological responses to tolt and trot in this selected group of experienced adult Icelandic horses and the biological and practical significance of the slightly elevated physiological responses to tolt and the slower recovery remains to be determined. PMID- 26440167 TI - Metabolic, endocrine, and reproductive responses of beef heifers submitted to different growth strategies during the lactation and rearing periods. AB - The effects of different feeding strategies (0.7 kg/d target ADG [LO] and 1.0 kg/d target ADG [HI] during the lactation period (LACT; 0-6 mo) and the rearing period (REAR; 6-15 mo; HI-HI, HI-LO, LO-HI, and LO-LO treatments) on the growth and reproductive parameters of beef heifers bred by fixed-time AI at 15 mo were analyzed. Animal weights were recorded weekly (from birth to 18 mo), and size measures were recorded at 6 and 15 mo. Heifers were bled to determine the onset of puberty and the metabolic and endocrine (IGF-I and leptin) status. During lactation, calves in the high lactation treatment (LactHI) had greater weight ( < 0.001), weight gain ( < 0.001), and body size ( < 0.001) than calves in the low lactation treatment (LactLO). The greater energy balance of LactHI heifers at weaning was reflected in greater concentrations of plasma glucose ( < 0.001), urea ( < 0.001), and IGF-I ( < 0.001); plasma levels of NEFA were lower ( < 0.001). During REAR, LactLO heifers had a greater growth rate than did LactHI heifers ( < 0.001), partially overcoming the lower gains during lactation. The differences in size measurements registered at weaning were also compensated, with the exception of LO-LO heifers. The IGF-I profile was highly correlated with animal performance traits and metabolic profiles, providing a useful indicator of growth, nutritional, and metabolic status at key points in development. By contrast, the function of leptin as an indicator of growth and reproductive development of heifers was less clear. All treatments had similar weights at puberty onset (55.9% mature BW), although LactLO ( < 0.01) and the low rearing treatment (RearLO; < 0.001) heifers were older than the others. The animals with greater glucose and IGF-I levels at weaning and greater cholesterol concentrations during REAR reached puberty earlier. The fertility rate (86%) was similar among treatments. The heifers in the high rearing treatment (RearHI) required more AI services to become pregnant and were older at conception ( < 0.05). The age of conception was positively correlated with glucose ( = 0.57, < 0.01) and cholesterol ( = 0.68, < 0.001) at 9 mo. Our results show that a 0.7 kg/d gain from birth allowed the first breeding at 15 mo, 6 mo earlier than usual for these conditions, without any negative effect on heifer reproductive performance. PMID- 26440168 TI - Impact of visual, olfactory, and auditory cues on circulating concentrations of ghrelin in wethers. AB - Ghrelin is a hormone that stimulates feed intake and regulates energy homeostasis. A link has been observed in sheep, in which simulated feedings at scheduled meal times resulted in an increase in ghrelin concentrations. The present study sought to characterize the effect of feeding cues outside of scheduled meal times on circulating ghrelin concentrations in sheep. Katahdin wethers (age 201 +/- 4.9 d; weight 35 +/- 1.2 kg) were not offered feed (CONT; = 5), offered 275 g of feed (FED; = 5), or fitted with a muzzle and offered 275 g of feed (SHAM; = 5) during the sampling period, which began 2.5 h after normally scheduled daily feeding time. Blood samples were collected via jugular catheter every 15 min for 2.5 h. Feed was offered for 15 min 0.5 h after the start of blood sampling. The CONT samples were collected on d 1, and FED and SHAM samples were collected on d 2. The active ghrelin present in the plasma was then analyzed by RIA. After the Shapiro-Wilk W goodness of fit test demonstrated that 1 SHAM wether was an outlier and it was removed, data were tested for effect of treatment (FED, SHAM, or CONT), time, and treatment * time interaction using procedures for repeated measures with JMP Software (SAS Inst. Inc., Cary, NC). There was no treatment or time effect ( > 0.05); however, there was a treatment * time interaction on plasma ghrelin concentrations ( = 0.0028) such that ghrelin concentrations in SHAM wethers were greater than in CONT wethers 15, 60, and 90 min after feeding, whereas ghrelin concentrations in SHAM wethers were greater than those in FED wethers 30, 60, 90, and 120 min after feeding ( < 0.05). Within the SHAM treatment, ghrelin concentrations were greater at 15 min than at -30 min. Moreover, ghrelin concentrations within the FED treatment were greater at 30 min than at 30, 45, 60, 90, 105, and 120 min and at -15 min than at 15 through 120 min. The area under the curve representing circulating concentrations of ghrelin in CONT, FED, and SHAM treatments, determined using the trapezoidal method, yielded a treatment effect with a tendency toward significance ( = 0.0866). These results indicate plasma ghrelin concentrations in scheduled meal fed wethers are elevated following visual, olfactory, and auditory feeding cues outside of scheduled feeding times. PMID- 26440169 TI - Pattern of gamma-glutamyl transferase activity in cow milk throughout lactation and relationships with metabolic conditions and milk composition. AB - The main objective of this experiment was to study the gamma-glutamyl transferase (GGT) activity in milk during lactation and its relationship with metabolic status of dairy cows, milk yield, milk composition, and cheesemaking properties. The study was performed in a tied stall barn and involved 20 lactations from 12 healthy multiparous Italian Friesian dairy cows. During lactation starting at d 10, milk samples were collected weekly and analyzed for composition, somatic cells count, titratable acidity, and milk coagulation properties. The GGT activity was measured in defatted samples. Blood samples were collected weekly to assess biochemical indicators related to energy, protein, and mineral metabolism, markers of inflammation and some enzyme activities. The lactations of each cow were retrospectively categorized into 2 groups according to their milk GGT activity value through lactation. A median value of GGT activity in the milk of all lactations was calculated (3,045 U/L), and 10 lactations with lower GGT activity were classified as low while 10 lactations with greater GGT activity were classified as high. The average value of milk GGT activity during lactation was 3,863 and 3,024 U/L for high and low, respectively. The GGT activity decreased in early lactation and reached minimum values in the second month (3,289 and 2,355 U/L for high and low, respectively). Thereafter GGT activity increased progressively, reaching values in late lactation of 4,511 and 3,540 U/L in high and low, respectively. On average, milk yield was 40.81 and 42.76 kg/d in high and low, respectively, and a negative partial correlation with milk GGT activity was observed. A greater milk protein concentration was observed in high (3.39%) compared with low (3.18%), and a positive partial correlation with milk GGT activity was observed. Greater titratable acidity in high than that in low (3.75 vs. 3.45 degrees Soxhlet-Henkel/50 mL, respectively) was also observed. Plasma glucose was greater in cows of high than in low group, while plasma urea was lower in the high than in the low group. No relationship between plasma GGT and milk GGT activity was observed. Our results show an important effect of lactation stage on milk GGT activity. The individual effect observed from consecutive lactations and the relationship between milk GGT activity and milk protein concentration in healthy cows could open prospects for GGT as a future tool in improving milk protein content. PMID- 26440170 TI - Blood parameters in fattening pigs fed whole-ear corn silage and housed in group pens or in metabolic cages. AB - The aim of this work was to evaluate the effects of the inclusion of whole-ear corn silage (WECS) in diets for advanced fattening heavy pigs (substitution for part of the dry corn and wheat bran) allocated or not in metabolic cages on the main blood parameters. The high-moisture shelled corn is largely used in pig feeding while WECS is less often used despite the fact that it increases the DM crop yield. Three experimental diets were fed to 27 barrows (Italian Large White * Italian Duroc), with an average BW of 98.2 (+/-5.6) kg at the start of the trial, and randomly allotted to 3 experimental groups including a control diet (CON) containing cereal meals (corn, barley, and wheat, 80.2% DM in total), soybean meal (9% DM), wheat bran (8% DM), minerals and supplements (2.8% DM), and 2 diets containing WECS (15 or 30% DM referred to as 15WECS and 30WECS, respectively) in partial or complete substitution for wheat bran and corn meal. The pigs were randomly housed in 9 pens with 3 animals per pen and 3 pens per dietary treatment. Six pigs per each of the 3 treatments were moved from the pens to individual metabolic cages for 3 consecutive periods (2 pigs per treatment per period). Each period lasted 14 d, and blood was collected at the start and at the end of the periods. Blood was drawn from the jugular vein before feed distribution in the morning, at 14 d intervals, and analyzed for hematological, metabolic, and serum protein profiles. The effect of the metabolic cage housing was included in the statistical model to compare the results obtained in the 2 different environments of restrained and group-housed barrows. The WECS affected the neutrophil to lymphocyte ratio and mean corpuscular hemoglobin concentration. The main diet effect on plasma metabolites was recorded for plasma NEFA, with higher values in WECS diets compared with the CON. The metabolic cage housing affected both hematological (red blood cell count, hemoglobin, hematocrit) and metabolic (protein and its fractions) items, which can be markers of hemodilution. These results indicate the possibility to use this feed in the diet of heavy pigs without negative effects on physiology. The absolute values from metabolic profile of pigs in metabolic cages must be considered with caution for possible comparisons with values obtained on-field in group pens, particularly because a different hemodilution may affect the results. PMID- 26440171 TI - Effects of standardized ileal digestible tryptophan: lysine ratio on growth performance of nursery pigs. AB - Two experiments were conducted to estimate the standardized ileal digestible (SID) Trp:Lys ratio requirement for growth performance of nursery pigs. Experimental diets were formulated to ensure that lysine was the second limiting AA throughout the experiments. In Exp. 1 (6 to 10 kg BW), 255 nursery pigs (PIC 327 * 1050, initially 6.3 +/- 0.15 kg, mean +/- SD) arranged in pens of 6 or 7 pigs were blocked by pen weight and assigned to experimental diets (7 pens/diet) consisting of SID Trp:Lys ratios of 14.7%, 16.5%, 18.4%, 20.3%, 22.1%, and 24.0% for 14 d with 1.30% SID Lys. In Exp. 2 (11 to 20 kg BW), 1,088 pigs (PIC 337 * 1050, initially 11.2 kg +/- 1.35 BW, mean +/- SD) arranged in pens of 24 to 27 pigs were blocked by average pig weight and assigned to experimental diets (6 pens/diet) consisting of SID Trp:Lys ratios of 14.5%, 16.5%, 18.0%, 19.5%, 21.0%, 22.5%, and 24.5% for 21 d with 30% dried distillers grains with solubles and 0.97% SID Lys. Each experiment was analyzed using general linear mixed models with heterogeneous residual variances. Competing heteroskedastic models included broken-line linear (BLL), broken-line quadratic (BLQ), and quadratic polynomial (QP). For each response, the best-fitting model was selected using Bayesian information criterion. In Exp. 1 (6 to 10 kg BW), increasing SID Trp:Lys ratio linearly increased ( 0.05) ADG and G:F. For ADG, the best-fitting model was a QP in which the maximum ADG was estimated at 23.9% (95% confidence interval [CI]: [<14.7%, >24.0%]) SID Trp:Lys ratio. For G:F, the best-fitting model was a BLL in which the maximum G:F was estimated at 20.4% (95% CI: [14.3%, 26.5%]) SID Trp:Lys. In Exp. 2 (11 to 20 kg BW), increasing SID Trp:Lys ratio increased ( 0.05) ADG and G:F in a quadratic manner. For ADG, the best-fitting model was a QP in which the maximum ADG was estimated at 21.2% (95% CI: [20.5%, 21.9%]) SID Trp:Lys. For G:F, BLL and BLQ models had comparable fit and estimated SID Trp:Lys requirements at 16.6% (95% CI: [16.0%, 17.3%]) and 17.1% (95% CI: [16.6%, 17.7%]), respectively. In conclusion, the estimated SID Trp:Lys requirement in Exp. 1 ranged from 20.4% for maximum G:F to 23.9% for maximum ADG, whereas in Exp. 2 it ranged from 16.6% for maximum G:F to 21.2% for maximum ADG. These results suggest that standard recommendations may underestimate the SID Trp:Lys requirement for nursery pigs from 11 to 20 kg BW. PMID- 26440172 TI - Effects of fiber inclusion on growth performance and nutrient digestibility of piglets reared under optimal or poor hygienic conditions. AB - Two experiments were conducted to study the effects of inclusion of additional fiber in the Phase I diet on growth performance and nutrient digestibility in piglets reared under "optimal" or "poor" hygienic conditions. In both experiments, the design was completely randomized with a control diet that contained 2.2% crude fiber and 8 additional isonutritive diets that included 2.5 or 5.0% of sugar beet pulp (SBP), straw, oat hulls (OH), or wheat middlings (WHM). Preplanned polynomial contrasts were used to study the effects of 1) fiber inclusion (control diet vs. average of the 8 fiber-containing diets), 2) source of fiber, 3) level of fiber, and 4) interaction between source and level of fiber. In Exp. 1 (clean barn), fiber inclusion increased ( < 0.01) the incidence of postweaning diarrhea (PWD) and reduced ( < 0.05) feed efficiency and apparent total tract digestibility (ATTD) of all nutrients except that of CP, which was not affected. Piglet performance was not affected by source or level of dietary fiber. The ATTD of all nutrients decreased ( < 0.05) as the level of fiber increased and was lower in pigs fed straw or OH than in pigs fed SBP or WHM. The apparent ileal digestibility of GE and DM decreased ( < 0.05) with fiber inclusion, a reduction that was more pronounced ( < 0.05) with straw or SBP than with OH inclusion, with WHM inclusion being intermediate. Fiber inclusion did not affect villous height to crypt depth ratio of the ileum mucosa. The inclusion of 5% of a fiber source increased and counts in the cecum ( < 0.001) but the to ratio was not affected. In Exp. 2 (dirty barn), fiber inclusion did not affect piglet performance but tended to increase PWD ( = 0.07). Also, fiber inclusion reduced ( < 0.05) the ATTD of all dietary components except that of CP, which was not affected. Source and level of fiber did not affect ATTD of nutrients except for DM, which was greater for pigs fed SBP than for pigs fed straw ( < 0.05). In conclusion, in the current research, pigs reared under optimal hygienic conditions had lower incidence of PWD, better growth performance, and greater DM and GE digestibility than pigs reared under poor hygienic conditions. An excess of dietary fiber was more detrimental for all these traits in piglets reared under optimal hygienic conditions. The effects of the source and level of fiber on piglet performance was limited in the 2 experiments. PMID- 26440173 TI - Energy requirements for growth in male and female Saanen goats. AB - The aim of this study was to investigate the energy requirements of female and intact and castrated male Saanen goats. Animals were randomly assigned to 1 of 2 experiments designed to investigate the energy requirements for maintenance and gain. To determine the maintenance requirements, 85 goats were used (26 intact males, 30 castrated males, and 29 females) with an initial BW of 30.3 +/- 0.87 kg. Thirty goats (8 intact males, 9 castrated males, and 13 females) were slaughtered to be used as the baseline group. The remaining goats were assigned in a split-plot design using a 3 * 3 factorial arrangement (3 sexes-intact males, castrated males, and females-and 3 DMI levels-ad libitum and restricted fed to 75 or 50% of the ad libitum intake). The NE was obtained using 65 goats (20 intact males, 22 castrated males, and 23 females) fed ad libitum in a completely randomized design. Eight intact males, 9 castrated males, and 13 females were slaughtered at 30.5 +/- 1.53 kg BW. Seventeen goats (6 intact males, 6 castrated males, and 5 females) were slaughtered at 38.1 +/- 0.49 kg BW. The remaining goats were slaughtered at 44.0 +/- 0.50 kg BW. The NE did not differ between the sexes ( = 0.59; 258.5 kJ/kg BW), resulting in a ME for maintenance of 412.4 kJ/kg BW. The estimated energy use efficiency for maintenance was 0.627. During the growth phase, NE differed between the sexes ( < 0.001); intact males, castrated males, and females showed an average NE equal to 15.2, 18.6, and 22.7 MJ/kg of empty weight gain, respectively. The energy requirements for growth differed between the sexes. The difference was found to be due to distinct NE and partial efficiency of ME utilization for growth in intact and castrated males and females during the late growth phase. This study may contribute to adjustments in feeding system energy recommendations regarding the NE and NE found for goats during the late growth phase. PMID- 26440174 TI - In vivo ruminal degradation characteristics and apparent digestibility of low quality prairie hay for steers consuming monensin and Optimase. AB - Seven ruminally cannulated crossbred steers (BW = 720 +/- 62 kg) were used in a randomized crossover design (4 periods, each 18 d) to evaluate in vivo rumen characteristics and apparent digestibility of steers consuming low-quality prairie hay and 1 of 4 isonitrogenous protein supplements. Treatments included 1) 40% CP (DM basis) cottonseed meal and wheat middlings-based supplement (Control), 2) a cottonseed meal and wheat middlings-based supplement with slow-release urea and a fibrolytic feed enzyme (Optimase; Alltech, Inc., Nicholasville, KY) designed to replace 30% of plant-based CP provided in the Control (OPT), 3) the Control plus 0.40 mg?kg BW?d monensin (Rumensin 90; Elanco Animal Health, Greenfield, IN; MON), and 4) the OPT plus 0.40 mg?kg BW?d monensin (COMBO). Steers were allowed ad libitum access to prairie hay (5.0% CP and 76% NDF) and were provided each respective supplement at 0800 h daily at a rate of 1.0 g/kg of BW. Steers were adapted to diets for 10 d before sample collection. Beginning on d 11, DMI was measured and samples were collected to determine apparent digestibility. On d 15 of the 18-d period, rumen fluid was collected 10 times over a 24-h period. Forage DMI was greater ( <= 0.02) for steers consuming the OPT compared with steers consuming the MON or COMBO, although forage DMI was not different ( = 0.10) among steers consuming the Control compared with steers consuming the OPT, MON, or COMBO. Steers fed the MON and COMBO had lower ( <= 0.05) passage rate compared with steers fed the Control and the OPT. The MON-fed steers had lower ( = 0.01) ruminal pH and increased ( = 0.03) propionate as a percentage of total VFA production. A time * treatment ( = 0.01) interaction was observed for ruminal NH-N due to a rapid (0 to 1 h after feeding) increase followed by a quick (1 to 4 h after feeding) decline in NH-N by steers consuming the OPT and COMBO that was not observed for steers consuming all other treatments. Apparent digestibility of DM ( = 0.01) and NDF ( = 0.03) were improved for steers fed the COMBO supplement compared with steers consuming all other experimental supplements. This work suggests that the OPT may be an effective replacement for a portion of supplemental degradable intake protein in low-quality forage. Further research is necessary to determine if the combination of monensin and the Optimase consistently improves low-quality forage utilization. PMID- 26440175 TI - Using organic acids to control subacute ruminal acidosis and fermentation in feedlot cattle fed a high-grain diet. AB - The objective of this study was to determine whether supplementing organic acids can prevent incidences of subacute ruminal acidosis (SARA) in beef heifers fed a diet consisting of 8% barley silage and 92% barley grain-based concentrate (DM basis). Ten ruminally cannulated Hereford crossbred heifers (484 +/- 25 kg BW) were used in a replicated 5 * 5 Latin square design with 14-d periods including 10 d for dietary adaptation and 4 d for measurements. Dietary treatments included no supplementation (Control), low fumaric acid (61 g/d), high fumaric acid (125 g/d), low malic acid (59 g/d), and high malic acid (134 g/d). Organic acid supplementation had no effect on DMI ( = 0.77). Similarly, no effects were observed on mean ( = 0.74), minimum ( = 0.64), and maximum ( = 0.27) ruminal pH measured continuously for 48 h. Moreover, area under the curve for pH thresholds 6.2 ( = 0.97), 5.8 ( = 0.66), 5.5 ( = 0.55), and 5.2 ( = 0.93) was similar for all treatments. However, malic acid supplementation lowered the amount of time that ruminal pH was <6.2 compared with the Control ( = 0.02) and fumaric acid treatments ( < 0.01). No effects were observed on total VFA concentrations with organic acid supplementation ( = 0.98) compared with the Control, but greater total VFA concentrations were observed with fumaric acid compared with the malic acid treatments ( = 0.02). The population of total culturable bacteria 3 h after feeding was reduced with supplemental malic acid compared with the Control ( = 0.03) and fumaric acid treatments ( = 0.03). However, no effects were observed with organic acid supplementation on lactic acid-utilizing bacteria ( = 0.59). In conclusion, under the conditions of the present study, organic acid supplementation did not have any significant effects on ruminal fermentation parameters compared with the Control and were not effective in preventing SARA in beef cattle fed high-grain diets. PMID- 26440176 TI - Effects of alternate day feeding of dried distiller's grains plus solubles in forage-fed steers on intake, ruminal fermentation and passage rates, and serum nonesterified fatty acid. AB - Four ruminally and duodenally cannulated Holstein steers (BW = 449 +/- 7.3 kg) were used to examine the effects of feeding either dried distiller's grains plus solubles (DG) or grass hay on alternate days (every other day) on intake, ruminal fermentation and passage rates, and serum NEFA in forage-fed steers. Steers were assigned to 1 of 4 dietary treatments in a 4 * 4 Latin square: 1) only hay (CON), 2) hay and 0.4% of BW as DG DM daily (DG7), 3) hay daily and 0.8% BW DG every other day (DG2), and 4) alternate day feeding of hay and 0.8% of BW as DG (DGA). Treatment periods consisted of 13 d of adaptation and 8 d of collecting digesta and blood. Over the entire collection period, DMI was decreased ( = 0.004) for DGA compared with other treatments (13.0 +/- 0.8, 12.7 +/- 0.8, 13.3 +/- 0.8, and 10.9 +/- 0.8 kg/d for CON, DG7, DG2, and DGA, respectively). Immediately after feeding on days supplement was fed to DG2 and DGA (supplemented days [SUP]), ruminal pH of DGA was less than other treatments but by the end of the day was greater than other treatments (treatment * time, < 0.001). At feeding time on nonsupplemented days (NSUP), ruminal pH of DGA steers was greater than other treatments but was similar (treatment * time, < 0.001) to DG2 and CON by 5 h after feeding. Total concentrations of VFA were similar ( = 0.09) among treatments on SUP; however, on NSUP, total VFA concentrations were least in DGA from feeding until 4 h after feeding (treatment * time, = 0.02). No differences ( >= 0.06) were observed among treatments for apparent ruminal, total intestinal, and total tract DM, OM, or CP digestibility. There were no differences ( = 0.36) in serum NEFA among treatments on SUP; however, on NSUP, steers fed DGA (209.5 +/ 12.7 m) had greater ( < 0.01) NEFA compared with other treatments (84.4 +/- 12.7, 88.0 +/- 12.7, and 77.7 +/- 12.7 m for CON, DG7, and DG2, respectively). The DGA feeding strategy influenced DMI and ruminal kinetics and circulating NEFA without impacting total tract digestibility. PMID- 26440177 TI - Retention time of digesta in the gastrointestinal tract of growing Saanen goats. AB - This study examined the effect of increased BW on mean retention time (MRT) of both particulate and solute marker, gastrointestinal tract (GIT) development, and fiber digestion in the whole tract of growing Saanen goats using the slaughter technique. A total of 58 Saanen goats with initial BW of 15.7 +/- 0.9 kg were allocated into 9 treatments with a 3 * 3 factorial arrangement consisting of 3 sexes (female, castrated males, and intact males) and 3 slaughter weights (initial, intermediate, and final; target BW of 16, 23, and 30 kg at slaughter, respectively). They were fed twice daily (0700 and 1600 h) with the identical diets for ad libitum intake. Mean retention time of particulate matter was estimated by in situ determination of indigestible NDF (iNDF), and the MRT of solute marker was determined by Cr-EDTA. Treatment effects were evaluated in a split-plot design, with sex as the main plot and slaughter weight as the subplot. Orthogonal polynomial contrasts were used to determine linear and quadratic effects of slaughter weight, whereas the effect of sex was compared using the Tukey test. The effects of sex and sex * slaughter weight were not significant for most of variables evaluated. The results showed that DMI (% BW) linearly decreased as slaughter weight increased ( < 0.01). Generally wet weight of the total GIT tissues (% BW) decreased and digesta pool sizes (g) linearly increased with increasing slaughter weight ( <= 0.05). The ratio of iNDF:NDF for both ingested diet and reticulorumen digesta linearly increased as slaughter weight increased ( <= 0.05). The MRT of particles did not change with increasing slaughter weight ( = 0.94). Mean retention time of particulate matter linearly increased in the omasum but linearly decreased in the abomasum with increasing slaughter weight ( < 0.01). Mean retention time of solute marker in the forestomachs linearly increased with increasing slaughter weight ( < 0.01). The results revealed a decreased selectivity with increasing BW, as supported by a greater ratio of iNDF:NDF for ingested diet. Increasing BW led to neither a longer particle MRT in the reticulorumen nor a digestive advantage. The results also indicated that, on average, 91% of fiber digestion occurred in the forestomachs of the goats. PMID- 26440178 TI - The effect of restricted milk feeding through conventional or step-down methods with or without forage provision in starter feed on performance of Holstein bull calves. AB - The objective of the current study was to examine whether step-down (STP) milk feeding method together with forage provision would improve performance, rumen fermentation, nutrient digestibility, blood metabolites, and structural growth of calves. Holstein bull calves ( = 40) were randomly assigned to 1 of 4 treatments in a completely randomized design with a 2 * 2 factorial arrangement. Treatments were 1) conventional (COV) milk feeding without forage provision (COV-NF), 2) COV milk feeding with forage provision, 3) STP milk feeding without forage provision, and 4) STP milk feeding with forage provision. Calves in the COV method ( = 20) received 5.5 L/d milk until d 56 of age followed by 2 L/d milk from d 56 to 59 of age. Calves in the STP method ( = 20) received 7 L/d milk until d 35, 4 L/d milk from d 35 to 48, and 2 L/d milk from d 50 to 59 of age. All the calves received the starter ration from d 3 of the study until d 74 of age. Forage-supplemented calves ( = 10/milk feeding method) received 15% alfalfa hay mixed with finely ground starter as a total mixed ration. All calves were weaned on d 60 of age and remained in the study until d 74. Regardless of the milk feeding method, the final BW (92.54 vs. 83.14 kg/d), starter intake (0.90 vs. 0.65 kg/d), total DMI (1.43 vs. 1.17 kg/d), and ADG (0.73 vs. 0.60 kg/d) were greater ( < 0.01) in forage-supplemented calves than those that received no forage during the preweaning, postweaning, and overall periods. Milk feeding method had no effect on ruminal pH, total VFA, acetate, or acetate:propionate ratio as well as body measurements. Ruminal pH and the molar proportions of acetate were greater ( < 0.05) in the forage-supplemented calves than those that received no forage during the pre- and postweaning periods. Regardless of forage provision, STP methods increased ( < 0.05) the postweaning numbers of monocytes and lymphocytes. Overall, there was no interaction between milk feeding methods and forage provision with respect to BW, DMI, G:F, apparent nutrient digestibility (DM, OM, and CP), and body measurements. The interaction of milk feeding method and forage provision was significant for the rumen concentration of butyrate ( < 0.05), with the highest concentration for the COV-NF treatment on d 35 of the study. In conclusion, independent of the milk feeding method, inclusion of 15% alfalfa hay in starter diets enhances the performance of dairy calves. PMID- 26440179 TI - Effect of dietary fat concentration from condensed corn distillers' solubles, during the growing phase, on beef cattle performance, carcass traits, digestibility, and ruminal metabolism. AB - The objectives of this study were to determine the effect of fat concentration from corn distillers' solubles (CDS), fed during the growing phase, on DMI, gain, carcass traits, digestibility, ruminal metabolism, and methane emissions of steers. In Exp. 1, 40 steers (age = 136 +/- 20 d; BW = 185 +/- 11 kg) were randomly allotted to 1 of 5 dietary treatments: 1) a cosrn-based gro?wing diet (CNT), 2) 0% CDS, 3) 10% CDS, 4) 19% CDS, or 5) 27% CDS. Diets 2 through 5 included coproducts (corn gluten feed and soybean hulls) and were formulated to achieve fat concentrations of 3, 5, 7, and 9%, respectively. Diets were fed once daily for 106 d (growing phase). All steers were fed a corn-based diet from d 107 to 196. Contrasts were used to examine 1) the difference between CNT and 10% CDS and 2) linear and quadratic effects of CDS inclusion. During the growing phase, steers fed CNT had increased ( < 0.01) ADG and G:F compared with steers fed 10% CDS. Increasing CDS inclusion increased (linear, <= 0.02) ADG and G:F. Overall, steers fed CNT had increased ( < 0.01) ADG compared with steers fed 10% CDS, but increasing CDS inclusion had no effect ( = 0.19) on overall ADG. Overall DMI and G:F were not different ( >= 0.16) in any contrast. There was a trend (Linear; = 0.08) for ultrasound marbling at d 196 to increase as CDS inclusion increased; however, there were no effects ( >= 0.20) of treatment on carcass marbling or quality grade. In Exp. 2, 5 steers (BW = 335 +/- 56 kg) were fed Exp. 1 diets for ad libitum intakes in a 5 * 5 Latin square design. Apparent DM digestibility increased (linear, = 0.02) with increasing dietary CDS inclusion. Steers fed CNT had greater ( = 0.01) DM digestibility than those fed 10% CDS. Fat digestibility increased (linear, < 0.01) in steers with increasing CDS, but NDF and ADF digestibility were not affected ( >= 0.17) by treatment. Similarly, ruminal pH and VFA concentrations were not affected ( >= 0.13). Also, there was no difference ( >= 0.37) in ruminal methane emissions (g/h). In conclusion, feeding corn during the growing phase increased overall ADG compared with 10% CDS coproduct-based diet but did not affect carcass traits or methane production. Increasing dietary fat inclusion from CDS in coproduct-based diets linearly increased DM and fat digestibility and predicted marbling scores via ultrasound but did not affect marbling at slaughter, NDF digestibility, propionate, or methane production. PMID- 26440180 TI - Effects of feeding processed corn stover and distillers grains on growth performance and metabolism of beef cattle. AB - Objectives were to evaluate the effects of replacing corn in feedlot finishing diets with processed corn stover (CS), processed by various combinations of chemical and physical methods, and modified wet distillers grain with solubles (MWDGS) on growth performance, carcass characteristics, digestibility, and ruminal metabolism of cattle. Corn stover was physically processed (ground or extruded) and chemically processed with alkaline agents (CaO and NaOH) to reduce the crystallinity of the lignocellulosic structure. In Exp. 1 steers ( = 18, initial BW = 385 +/- 32 kg) and heifers ( = 41, initial BW = 381 +/- 27 kg) were allotted to 1 of 5 dietary treatments: 1) 55% dry, cracked corn, 35% MWDGS, 5% vitamin-mineral supplement, and 5% untreated ground CS (), 2) CS treated with 5% CaO (DM basis) and stored in an Ag-Bag (BGCS), 3) CS treated with 5% CaO (DM basis) and extruded (5 EXCS), 4) CS treated with 4% CaO and 1% NaOH (DM basis) and extruded (4,1 EXCS), or 5) CS treated with 3% CaO and 2% NaOH (DM basis) and extruded (3,2 EXCS). Extruded CS was hydrated to 34% moisture, then an additional 16% water was added, as a solution carrying CaO or NaOH or both, via a calibrated pump during processing through a dual-shafted encased extruder (Readco Kurimoto Continuous Processor, York, PA) with the desired exiting temperature of 76.7 degrees C +/- 2.8 degrees C. All treated CS diets contained 20% CS and 40% MWDGS (DM basis) to replace 20% corn when compared to CON. There were no effects ( >= 0.20) of dietary treatment on ADG, G:F, 12th-rib back fat, marbling score, LM area, or yield grade. However, cattle fed CON had increased ( = 0.02) DMI compared to cattle fed the treated CS diets. In Exp. 2, using the same diets as fed in Exp. 1, ruminally cannulated steers ( = 5; initial BW = 417 +/- 21 kg) were fed for 90% of ad libitum intake in a 5 * 5 Latin square design. Apparent digestibility of NDF and ADF increased ( < 0.01) when cattle were fed treated CS diets compared with CON, regardless of the treatment applied. Ruminal pH was reduced ( = 0.02) in cattle fed BGCS from 0 to 6 h postfeeding compared with cattle fed all other diets. Cattle fed the treated CS diets had the greatest ( < 0.01) mean acetate concentrations, which increased ( = 0.01) total VFA concentrations. Replacing a portion of the corn with treated CS in feedlot diets containing MWDGS increased fiber digestibility without affecting feedlot cattle gain, efficiency, marbling score, or LM area. PMID- 26440181 TI - Changes in lipid metabolism and beta-adrenergic response of adipose tissues of periparturient dairy cows affected by an energy-dense diet and nicotinic acid supplementation. AB - Dairy cattle will mobilize large amounts of body fat during early lactation as an effect of decreased lipogenesis and increased lipolysis. Regulation of lipid metabolism involves fatty acid synthesis from acetate and beta-adrenergic stimulated phosphorylation of hormone-sensitive lipase (HSL) and perilipin in adipocytes. Although basic mechanisms of mobilizing fat storage in transition cows are understood, we lack a sufficiently detailed understanding to declare the exact regulatory network of these in a broad range of dairy cattle. The objective of the present study was to quantify 1) protein abundance of fatty acid synthase (FAS), 2) extent of phosphorylation of HSL and perilipin in vivo, and 3) beta adrenergic stimulated lipolytic response of adipose tissues in vitro at different stages of the periparturient period. We fed 20 German Holstein cows an energy dense or an energetically adequate diet prepartum and 0 or 24 g/d nicotinic acid (NA) supplementation. Biopsy samples of subcutaneous and retroperitoneal adipose tissue were obtained at d 42 prepartum (d -42) and at d 1, 21, and 100 postpartum (d +1, d +21, d +100, respectively). To assess beta-adrenergic response, tissue samples were incubated with 1 MU isoproterenol for 90 min at 37 degrees C. The NEFA and glycerol release, as well as HSL and perilipin phosphorylation, was measured as indicators of in vitro stimulated lipolysis. In addition, protein expression of FAS and extent of HSL and perilipin phosphorylation were measured in fresh, nonincubated samples. There was no effect of dietary energy density or NA on the observed variables. The extent of HSL and perilipin phosphorylation under isoproterenol stimulation was strongly correlated with the release of NEFA and glycerol, consistent with the functional link between beta-adrenergic stimulated protein phosphorylation and lipolysis. In the nonincubated samples, FAS protein expression was decreased at d +1 and d +21, whereas HSL and perilipin phosphorylation increased from d -42 to d +1 and remained at an increased level throughout the first 100 d of lactation. In vitro lipolytic response was significant in prepartum samples at times when in vivo lipolysis was only minimally activated by phosphorylation. These data extend our understanding of the complex nature of control of lipolysis and lipogenesis in dairy cows and could be useful to the ongoing development of systems biology models of metabolism to help improve our quantitative knowledge of the cow. PMID- 26440182 TI - Effect of flint corn processing method and roughage level on finishing performance of Nellore-based cattle. AB - This study was conducted to evaluate the effects of flint corn processing method (CPM) and level of NDF from roughage (rNDF) on performance, carcass characteristics, and starch utilization by finishing Nellore-based cattle fed high-concentrate, flint corn-based diets. In this study, 112 Nellore type bulls (initial BW 384.07 +/- 29.53 kg and 24-36 mo of age) were individually fed using Calan gates or individual pens. The animals were used in a randomized complete block design in a 2 * 4 factorial arrangement with 2 CPM, high-moisture flint corn (HMC) or finely ground dry flint corn (FGC), with 1 of 4 levels of rNDF, 3, 8, 13, and 18% (DM basis), using sugarcane silage (SS) as roughage. Bulls were adapted to the finishing diet over a 21-d period and fed for a total of 81 d. Fecal starch (FS) concentration was determined on d 46 and 74 of the feeding period. There was a quadratic effect of rNDF on final BW ( < 0.01) and ADG ( = 0.01). Optimal concentrations of rNDF were estimated using the first derivative of second order polynomials, indicating that final BW and ADG were maximized with 13.3 and 13.0% rNDF, respectively. An interaction was observed between CPM and rNDF ( = 0.05) for DMI, with peak DMI occurring at 11.3 and 13.7% rNDF with FGC and HMC, respectively. Cattle fed HMC had 13.9% greater G:F ( < 0.01) compared with those fed FGC (0.172 vs. 0.151, respectively). There were quadratic effects of rNDF on HCW ( = 0.04) and ME intake ( < 0.01); heaviest carcass weights were estimated, in both cases, to be achieved with 12.8% rNDF. A quadratic effect of rNDF for renal, pelvic, and inguinal fat weight ( = 0.04) was observed, with a peak estimated to occur at 12.6% rNDF. An interaction between CPM and rNDF also was observed for FS ( < 0.05). Bulls fed FGC with 3% rNDF had greater FS content, and FS linearly decreased as concentration of rNDF increased. For bulls fed HMC, FS was 3.0% of DM and was unaffected by rNDF in the diet. Lower FS from bulls fed HMC suggests that availability of starch from flint corn was greater than that of FGC. For Nellore-based cattle fed a flint corn-based diet containing SS and 8% whole lint cottonseed, performance was optimized with 12.8% rNDF. In the absence of cottonseed addition to diets, optimal performance would be expected with about 14.5% rNDF. PMID- 26440183 TI - Effects of Juniperus species and stage of maturity on nutritional, in vitro digestibility, and plant secondary compound characteristics. AB - Rising feed costs and recurring feed shortages necessitate the investigation into alternative and underutilized feed resources. Nutritional characteristics of species are either unknown or limited to leaves and ground material from small stems. Therefore, the objective was to quantify nutritional characteristics, 48-h true IVDMD (tIVDMD), microbial gas production, and secondary compound characteristics of entire woody plant material of 4 species-, , , and -at immature and mature stages of growth. Immature plants had greater CP concentrations and lower NDF concentrations ( < 0.001) than mature plants regardless of species. Mature plants also had greater ( < 0.001) concentrations of ADF compared with immature plants with the exception of . In general, immature , , and had greater ( < 0.02) tIVDMD and total 48-h and asymptotic gas production than mature plants. Immature and plants were more digested (tIVDMD; < 0.001) than immature and , but tIVDMD did not differ in mature plant material across species. Condensed tannins (CT) were greater ( < 0.001) in immature and than mature plants; differences in CT concentrations among immature species were also detected ( < 0.04). Volatile oil yields were similar across maturity and species with 1 exception: immature yielded more ( < 0.02) volatile oil than mature material. Volatile oil composition across species varied and contained a range of 65 to 70 terpene compounds. The dominant terpenes across species were generally greater ( < 0.05) in immature vs. mature plant material with the exception of . Labdane acids were negligible in , , and and greater in ( < 0.001). Ground material from mature juniper species, although inferior in nutritional quality compared with immature plants, is comparable to traditional low-quality roughage ingredients. Given that has been successfully fed in lamb feedlot diets, the similarities of , and suggest that all three species have potential to be effective roughage ingredients. PMID- 26440184 TI - Expression of alpha-tocopherol-associated genes and alpha-tocopherol accumulation in Japanese Black (Wagyu) calves with and without alpha-tocopherol supplementation. AB - The aim of the study was to clarify 1) the distribution of 6 alpha-tocopherol (alpha-Toc)-associated gene expressions in 20 major tissues, including metabolic, reproductive, endocrine, immune, and digestive and absorptive tissues, in relation to alpha-Toc status and 2) the change in expression patterns of the genes induced when alpha-Toc was orally administered to Japanese Black (JB) calves. This study examined weaned male JB calves ( = 10), of which 5 calves were orally administered alpha-Toc for 2 wk (30 IU.kg BW.d; TOC group). The others did not receive the alpha-Toc supplement and were the control (CONT) group. The 20 tissues and venous blood (serum) were sampled on the final day. In both groups, the mean mRNA expression levels for alpha-Toc transfer protein, afamin (AFM), ATP binding cassette transporter A1, and tocopherol-associated protein were greatest in the liver ( < 0.05), whereas scavenger receptor class B, Type I (SR-BI) mRNA was greatest in the adrenal gland ( < 0.05). The gene for cytochrome P450 family 4, subfamily F, polypeptide 2 was most highly expressed in the liver, testes, and adrenal gland. The alpha-Toc content was greatest ( < 0.05) in the testes of the 20 sampled tissues in the CONT group. However, the levels in the testes and jejunum were similar and greater ( < 0.05) than the levels in the other 18 tissues in the TOC group. The mean increase in alpha-Toc levels after oral alpha Toc administration (mean alpha-Toc content for the TOC group divided by the CONT group content) were greater ( < 0.05) in the jejunum (40.7-fold) and duodenum and liver (26.3- and 23.1-fold) than in the serum (7.8-fold). In the liver, alpha-Toc administration significantly increased ( < 0.05) the AFM and SR-BI mRNA expression levels. The results show that the liver may play an important role in the regulation of alpha-Toc disposition, but other peripheral tissues that accumulate large amounts of alpha-Toc could moderate the local alpha-Toc status and functions, as inferred from the high expressions of the alpha-Toc-associated genes in JB calves. PMID- 26440185 TI - Effect of slow-release urea inclusion in diets containing modified corn distillers grains on total tract digestibility and ruminal fermentation in feedlot cattle. AB - Ruminal degradable intake protein (DIP) deficit may result when cattle are fed diets containing a greater inclusion of processed corn grain and small to moderate inclusion of corn distillers grains (DG). This deficit may arise from greater proportions of rapidly fermentable carbohydrates and RUP in corn grain. Urea-derived N is 100% DIP; however, rates of degradation of carbohydrates and conventional urea (CU) may not match. Therefore, beneficial effects may result from the use of slow-release urea (SRU) sources over CU when added to DIP deficient diets. An experiment was conducted to evaluate the effect of increasing DIP concentration through inclusion of 1 of 2 SRU sources or CU in DG-containing feedlot diets on ruminal fermentation and total tract digestibility. In addition, an in situ experiment was conducted to characterize N disappearance of urea sources from polyester bags. Four ruminally cannulated steers (initial BW = 588 +/- 8 kg) were arranged in a 4 * 4 Latin square design and assigned randomly to 1 of 4 dietary treatments containing 0% (CON) or 0.6% urea in the form of CU (UREA) or SRU as Optigen II (polymer-encapsulated urea; OPTI) or NitroShure (lipid encapsulated urea; NITRO), and 30% corn earlage, 20% modified corn DG with solubles, 7.8% corn silage, 4.3% dry supplement, and dry-rolled corn (DM basis). Dietary DIP was estimated at 6.6% and 8.3% for CON and urea-containing dietary treatments, respectively. Steers were fed ad libitum once daily. Differences in purine derivatives-to-creatinine (PDC) index between treatments were used as indicators of differences in microbial CP synthesis. Intake of OM, digestibility of OM, NDF, CP, and starch, ruminal pH, total VFA ruminal concentration, and PDC index were not affected by treatment ( >= 0.21). Concentration of ammonia-N noticeably peaked at 4 h after feed delivery for cattle fed UREA (treatment * time, = 0.06) and measured at least 5.5 mg/dL for any treatment and at any hour after feed delivery. During the first 12 h after incubation, N disappearance was greater for CU and NitroShure than Optigen II (urea source * time, < 0.01). Supplementing DIP through inclusion of CU or SRU did not affect feed intake, digestibility, or most of the ruminal fermentation parameters evaluated, which may relate to the lack of need of urea supplementation in the present experiment. More research is warranted to evaluate the use of SRU in DIP-deficient diets. PMID- 26440186 TI - Impact of synthetic antioxidants on lipid peroxidation of distiller's dried grains with solubles and distiller's corn oil stored under high temperature and humidity conditions. AB - This experiment evaluated the effect of antioxidants, oil content in distiller's dried grains with solubles (DDGS), quality of distiller's corn oil, and storage time on lipid peroxidation. A source of low-oil DDGS (LO-DDGS; 5.0% ether extract [EE], as-fed basis), high-oil DDGS (HO-DDGS; 13.0% EE, as-fed basis), and 2 sources of distiller's corn oil (DCO; 1.20, 0.08, and 0.48% moisture, insoluble impurities, and unsaponifiables [MIU], respectively [DCO-1], and 1.20, 0.01, and 0.10% MIU, respectively [DCO-2]) were obtained. Each of the 4 ingredients was divided into 18 representative subsamples (approximately 908 g for DDGS or 2 kg of DCO). Six subsamples of each ingredient were mixed with either no supplemental antioxidants (CON), Rendox-CQ (REN; 1,000 mg/kg EE; Kemin, Industries, Des Moines, IA), or Santoquin-Q4T (SAN; 1,500 mg/kg EE; Novus International, St. Louis, MO). Each mixture ( = 72) was split into thirds, and 1 portion was immediately frozen at -20 degrees C (d 0). Two portions were stored under hot (38.6 +/- 0.1 degrees C) and humid conditions (94.0 +/- 0.3% relative humidity) for 14 or 28 d. The MIXED procedure of SAS was used to evaluate the effects of ingredient, antioxidant, storage time, and interactions, with d-0 values used as a covariate. From d 14 to 28, peroxide value (PV), -anisidine value (AnV), and thiobarbituric acid reactive substances (TBARS) of DCO and DDGS increased by 3- to 4-fold ( < 0.05). Over the entire storage period, PV of DCO-1 and HO-DDGS (12.3 +/- 0.3 and 12.6 +/- 0.3 mEq O/kg oil, respectively) exceeded ( < 0.05) that of DCO-2 and LO-DDGS (9.6 +/- 0.3 and 9.3 +/- 0.3 mEq O/kg oil, respectively). Adding REN or SAN ( < 0.05) reduced TBARS and AnV relative to CON (TBARS = 11.0 +/- 0.2 mg malondialdehyde Eq/kg oil and AnV = 6.5 +/- 0.2) over the entire period (mean of d 14 and 28), but TBARS and AnV did not differ ( > 0.05) between antioxidants (TBARS = 6.1 +/- 0.2 and 5.9 +/- 0.2 mg malondialdehyde Eq/kg oil, respectively, and AnV = 1.9 +/- 0.2 and 1.8 +/- 0.2 for REN and SAN, respectively). The PV on d 14 and 28 and overall was less ( < 0.05) when either antioxidant was added relative to CON (16.0 mEq O/kg) and was greater for ingredients treated with SAN ( < 0.05) compared with REN (8.8 +/- 0.2 and 8.0 +/- 0.2 mEq O/kg oil for SAN and REN, respectively). In summary, antioxidants reduced peroxidation of DDGS and DCO by approximately 50% during 28 d of storage at 38.6 degrees C and 94.0% relative humidity, but neither antioxidant completely stabilized the ingredients. PMID- 26440187 TI - Temporary confinement of loose-housed hyperprolific sows reduces piglet mortality. AB - The objective of this study was to investigate piglet mortality in a commercial setting where sows were accommodated in a loose-housed system with an option to confine the sow for a few days around farrowing and during early lactation. The study was conducted in a Danish piggery where records were obtained from 2,139 farrowings. Sows were randomly allocated to 1 of 3 treatments: loose-loose (LL), loose-confined (LC), and confined-confined (CC). In LL, sows were loose housed from the time they entered the farrowing pens to weaning. In LC, sows were loose housed until farrowing was finished and then confined to d 4 after farrowing. In CC, sows were confined at d 114 of gestation to d 4 after farrowing. All sows were loose housed from d 5 to weaning. Total piglet mortality was analyzed at batch level to include piglets fostered by nurse sows and at sow level to analyze the effects of confinement during different time periods. Total piglet mortality was greater in LL (26.0%) and LC (25.4%) compared with CC (22.1%; < 0.001). The proportion of stillborn piglets was not different between treatments ( = 0.21) but a larger proportion was crushed in LL (10.7%) compared with LC (9.7%; = 0.03), which again was greater than CC (7.8%; < 0.001). Piglet mortality before equalization was lower in CC (3.7%) than in LL (7.5%) and LC (7.0%; < 0.001). Confinement reduced mortality from litter equalization to d 4 (7.6% for LL vs. 6.7% for LC; = 0.01) but more so in CC (5.6%) than in LC ( < 0.001). From d 4 to weaning, LL had lower mortality (5.6%) than LC (6.9%) and CC (6.6%; = 0.01). A larger proportion of sows in CC were classified as "low mortality" compared with LL and LC both before ( < 0.001) and after ( = 0.002) litter equalization. The results in this study emphasize that the period of time from the birth of the first piglet to litter equalization is important in relation to piglet mortality. The results also suggest that confinement for 4 d after farrowing can reduce mortality in this specific period, but only confinement from d 114 of gestation to d 4 after farrowing reduced total piglet mortality. PMID- 26440188 TI - Effect of growth implant regimen on health, performance, and immunity of high risk, newly received stocker cattle. AB - Growth implant efficacy may be affected when administered to nutritionally stressed calves, whereas the procedure may alter health or the humoral immune response to respiratory vaccination. The study objective was to determine the effect of different administration times (d 0, 14, or 28) of a growth implant containing 200 mg progesterone and 20 mg estradiol benzoate on health, performance, and metabolic and immunologic variables in high-risk, newly received beef calves used in a 120-d receiving/grazing stocker system. Crossbred bull and steer calves ( = 203) were weighed (initial BW = 203 +/- 2.7 kg), stratified by castrate status on arrival, and randomly assigned to experimental treatments consisting of 1) negative control (no growth implant administered), 2) growth implant administered on d 0, 3) growth implant administered on d 14, and 4) growth implant administered on d 28. There were no differences ( >= 0.16) in BW or ADG during the 42-d receiving period. However, ADG during the subsequent grazing period and overall was greater ( <= 0.01) for implanted calves versus the negative control. Growth implant timing did not affect the rate of clinical bovine respiratory disease morbidity ( = 0.52; 94% morbidity overall) or bovine viral diarrhea virus type 1a antibody titer concentration ( = 0.61). Indicative of an overall negative energy balance on arrival, NEFA decreased sharply subsequent to d 0 (day effect, < 0.001), but was not affected ( = 0.47) by the timing of growth implantation. Blood urea N concentrations increased transiently (day effect, < 0.001); however, no treatment effect was observed ( = 0.72). Therefore, under conditions of this study, the timing of growth implant administration did not affect growth implant efficacy, health, or metabolic or immunologic variables in newly received, high-risk beef stocker calves. Overall, our observations suggest that there is not a clear benefit to delaying growth implantation and that a growth implant does not affect health or vaccine response in newly received beef calves. PMID- 26440189 TI - Toxicity of endophyte-infected ryegrass hay containing high ergovaline level in lactating ewes. AB - The symbiotic association of var. (formerly named ) with perennial ryegrass () leads to the production of ergovaline (EV) and lolitrem B (LB) that are toxic for livestock. The objectives of this study were to determine the effects of feeding endophyte-infected ryegrass (SE+) hay on 16 lactating ewes (BW 80 +/- 10 kg) in comparison with endophyte-free ryegrass (SE-) hay to investigate the putative mechanisms of action of EV and LB and to evaluate their persistence in milk and animal tissues. The mean EV and LB concentrations in SE+ hay were 851 and 884 MUg/kg DM, respectively, whereas these alkaloids were below the limit of detection in SE- hay. No effect of SE+ was observed on animal health and skin temperature whereas prolactin decreased and significant differences between hays were observed from d 7 to 28 of the study ( < 0.03) but had no effect on milk production. Hematocrit and biochemical analyses of plasma revealed no significant difference between SE+ and SE-, whereas cortisol concentration differed significantly on d 28 ( = 0.001). Measurement of oxidative damage and antioxidant enzyme activities in plasma, liver, and kidneys revealed a slight increase in some enzyme activities involved in defense against oxidative damage in the SE+ fed ewes. Slight variations in the activities of hepatic and kidney flavin monooxygenase enzymes were observed, whereas in the kidney, glutathione transferase activity decreased significantly ( = 0.002) in the SE+ fed ewes, whereas uridine diphosphate glucuronosyltransferase activity increased ( = 0.001). After 28 d of exposure of ewes to the SE+ hay, low EV and LB concentrations were measured in tissues. The highest concentration of EV was observed in the liver (0.68 MUg/kg) whereas fat contained the highest concentration of LB (2.39 MUg/kg). Both toxins were also identified at the trace level in milk. PMID- 26440190 TI - Technical note: Evaluation of a system for monitoring individual feeding behavior and activity in beef cattle. AB - Behavioral observations are important to detect illness in beef cattle. However, traditional observation techniques are time and labor intensive and may be subjective. The objective was to validate a system for monitoring individual feeding behavior and activity in beef cattle (Fedometer [FEDO]; ENGS, Rosh Pina, Israel). Sixteen steers (initial BW +/- SD = 326 +/- 46 kg) were fitted with data loggers (FEDO) on their left front leg and housed in a pen with a feedbunk equipped with an antenna emitting an electromagnetic field that reached 30 +/- 2 cm in front of the feedbunk. Feedbunk attendance (duration of visit and frequency of meals) measured by FEDO was compared with live observations (27 observational periods lasting between 72 and 240 min; mean 126 min). Lying time and frequency of lying bouts were compared with previously validated accelerometers fitted to the hind leg (10 steers equipped for 10 to 12 d; HOBO Pendant G Acceleration Data Logger [HOBO]; Onset Computer Corporation, Pocasset, MA). Step counts were compared with video recordings (15 observations for 6-min intervals in 6 steers). Concordance correlation coefficients (CCC), accounting for repeated measures, and limits of agreement were computed. Comparison between FEDO and observed time at the feedbunk yielded a CCC of 0.98 (95% confidence interval [CI] 0.97-0.99). All 68 meal events observed were recorded by FEDO. However, FEDO recorded 4 meal events during the 27 observational periods that were not observed. Lying time measured by HOBO and FEDO were highly correlated (CCC = 0.98; 95% CI 0.97-0.99). However, frequency of lying bouts measured by FEDO was only moderately correlated to HOBO (CCC = 0.71; 95% CI 0.63-0.77); FEDO underestimating the number of lying bouts (on average, 0.4 fewer bouts per 6 h). Step count by FEDO was moderately correlated to video observations (CCC = 0.75; 95% CI 0.49-0.89); FEDO overestimating the number of steps (on average, 5 more steps per 6 min). In conclusion, the FEDO system accurately measured duration of feedbunk attendance, frequency of meals, and lying time. However, it overestimated the number of steps and underestimated the frequency of lying bouts. PMID- 26440191 TI - Determination of value of bovine respiratory disease control using a remote early disease identification system compared with conventional methods of metaphylaxis and visual observations. AB - Mitigation of the deleterious effects of bovine respiratory disease (BRD) is an important issue in the cattle industry. Conventional management of calves at high risk for BRD often includes mass treatment with antimicrobials at arrival followed by visual observation for individual clinical cases. These methods have proven effective; however, control program efficacy is influenced by the accuracy of visual observation. A remote early disease identification (REDI) system has been described that monitors cattle behavior to identify potential BRD cases. The objective of this research was to compare health and performance outcomes using either traditional BRD control (visual observation and metaphylaxis) or REDI during a 60-d postarrival phase in high-risk beef calves. The randomized controlled clinical trial was performed in 8 replicates at 3 different facilities over a 19-mo period. In each replicate, a single load of calves was randomly allocated to receive either conventional management (CONV; total = 8) or REDI (total = 8) as the method for BRD control. Cattle were monitored with each diagnostic method for the first 30 d on feed and performance variables were collected until approximately 60 d after arrival. Statistical differences ( < 0.10) were not identified in common performance (ADG) or health (morbidity, first treatment success, and mortality risk) among the treatment groups. Calves in the REDI pens had a lower ( < 0.01) average number of days on feed at first treatment (9.1 +/- 1.2 d) compared with CONV pens (15.8 +/- 1.2 d). There were no statistical differences ( > 0.10) in risk of BRD treatment and REDI calves were not administered antimicrobials at arrival; therefore, REDI calves had a lower ( < 0.01) average number of doses of antimicrobials/calf (0.75 +/- 0.1 doses) compared with CONV calves (1.67 +/- 0.1 doses). In this trial, the REDI system was comparable to conventional management with the potential advantages of earlier BRD diagnosis and decreased use of antimicrobials. Further research should be performed to evaluate the longer-term impacts of the 2 systems. PMID- 26440192 TI - Effect of surgical castration with or without oral meloxicam on the acute inflammatory response in yearling beef bulls. AB - Pain management and welfare are increasingly prevalent concerns within animal agriculture. Analgesics may alleviate pain and inflammation associated with castration of beef cattle. This study was conducted to elucidate the effects of surgical castration on the acute inflammatory response and immunomodulation and whether concurrent oral administration of meloxicam (1 mg/kg BW) would alter these responses. On d -1, crossbred bull calves ( = 30; initial BW = 227.4 +/- 10.3 kg) were fitted with indwelling jugular catheters and rectal temperature (RT) recording devices, placed into individual stanchions, and randomly assigned to 1 of 3 treatments. Treatment application occurred at h 0 and consisted of 1) intact bull calves treated with sham castration (CON), 2) bulls surgically castrated without meloxicam administration (CAS), and 3) bulls surgically castrated with oral meloxicam (1 mg/kg BW) administration (MEL). Blood samples were collected at 0.5-h intervals from h -2 to 4, 1.0-h intervals from h 4 to 8, and 12-h intervals from h 12 to 72. Serum was analyzed for cortisol and haptoglobin (Hp) concentrations using ELISA. Whole blood was analyzed for complete blood counts at -2, 0, 2, 4, 6, 8, 12, 24, 36, 48, 60, and 72 h, and RT was recorded in 5-min intervals. Postcastration RT was greatest for MEL (39.04), intermediate for CAS (38.99), and least for CON (38.93 degrees C; <= 0.01). Serum cortisol was increased ( < 0.001) for CAS (12.3) and MEL (11.3) compared with CON (6.7 ng/mL) during the postcastration period. At 0.5 and 1.5 h, cortisol concentration was greater in CAS and MEL than CON, whereas at 2 and 2.5 h, cortisol concentration was greatest for CAS, intermediate for MEL, and least for CON (treatment * time, < 0.001). Total white blood cell ( <= 0.04), lymphocyte ( <= 0.02), and monocyte ( <= 0.002) counts were greatest for CAS, intermediate for MEL, and least for CON. Administration of MEL reduced ( <= 0.002) eosinophil counts during the postcastration period when compared with CON and CAS. The change in serum Hp, relative to baseline values, was reduced for MEL at 36 ( < 0.01) and 60 h ( <= 0.03), and the overall Hp concentration was least for MEL ( < 0.001). Oral administration of meloxicam at the time of castration reduced the acute inflammatory response in castrates, as evidenced by a reduction in Hp and certain leukocyte concentrations; it also caused a delayed increase in RT. Further research is needed to determine if this reduced acute inflammatory response would equate to improved health and/or performance after castration. PMID- 26440193 TI - Postweaning substitution of grazed forage with a high-energy concentrate has variable long-term effects on subcutaneous fat and marbling in Bos taurus genotypes. AB - The objective of this study was to quantify the effects and interactions of stage of growth and genotype on commercial carcass traits and intramuscular fat (IMF) content in 5 muscles of steers ( = 165) and to test the hypothesis that substituting pasture with a high-energy concentrate during the immediate postweaning period increases IMF. Cattle of 3 genotypes (Angus, Hereford, and Wagyu * Angus; = 55/genotype) were selected at weaning from commercial herds, targeting genotypic differences in marbling and subcutaneous fatness. Following weaning, steers were fed for 168 d within 2 different improved, temperate pasture based nutritional systems: a forage-only system (FS) and forage with high-energy supplemented system (SS), with 2 replicates per system. The supplement was fed at a level of 1% of average BW adjusted every 2 wk to provide an estimated 50% of energy requirements for 168 d from weaning. Pasture on offer in both systems was managed to match the BW of the FS and SS steers during the postweaning treatment period to avoid confounding due to differences in growth rate during this period. Steers were then regrouped into 2 replicates and backgrounded on improved, temperate pasture for 158 d and then grain fed within 1 group for 105 d (short fed) or 259 d (long fed). Groups were slaughtered at commencement (d 0) and end of postweaning nutritional treatments (d 168), end of backgrounding (d 326), and after short (d 431) or long feedlotting (d 585). Serial slaughter stage had an effect on all traits assessed ( < 0.01). The FS steers had more rib fat ( < 0.01) and higher Meat Standards Australia marbling score ( < 0.05) and a tendency ( < 0.10) to have greater eye muscle area than the SS steers throughout the study. Genotypic differences were evident ( < 0.05) for all traits assessed except HCW, dressing percentage, rib fat depth, ossification score, ultimate pH, and IMF in the semitendinosus muscle. The results for marbling and IMF do not support the use of a high-energy feed as a substitute for an equivalent amount of energy from pasture during the immediate postweaning period to enhance development of marbling. PMID- 26440194 TI - The effect of a limit-fed diet and slow-feed hay nets on morphometric measurements and postprandial metabolite and hormone patterns in adult horses. AB - Modern horse management systems tend to limit a horse's opportunity to forage, rely on meal feeding, and may contribute to the increase in equine obesity. The use of slow-feed hay nets represents an opportunity to extend foraging time while feeding a restricted diet. The objectives of this study were to determine if limit feeding combined with a slow-feed hay net would affect morphometric measurements and postprandial metabolite and hormone patterns in overweight adult horses. Eight adult Quarter horses (BW 563 kg +/- 4.6 kg; BCS 7.2 +/- 0.3) were used in a randomized complete block design, with 4 horses assigned to feeding hay off the stall floor (FLOOR) and 4 horses assigned to feeding from a slow-feed hay net (NET). Horses were fed in individual stalls at 1% BW each day, split evenly between 2 meals at 0700 and 1600 h. Body weight, BCS, neck and girth circumference, cresty neck score, and ultrasound measurements of average rump fat, longissimus dorsi (LD) depth, and LD thickness were taken on d 0, 14, and 28. Three 24-h blood samplings were conducted on d 0, 14, and 28 and were analyzed for glucose, insulin, cortisol, and leptin concentrations. Samplings occurred every 30 min for 3 h postfeeding, with hourly samples occurring between feedings. Horses feeding from the FLOOR took less time to consume their hay meal compared with horses feeding from the NET ( < 0.001). All horses lost weight over the 28-d period ( < 0.0001); however, no difference was observed between treatments. There was no difference in BCS, neck and girth circumference, cresty neck score, rump fat, or LD depth between days or treatments ( >= 0.25). There was an effect of day on LD thickness in horses feeding from the NET. Longissimus dorsi thickness was lower on d 28 compared with that on d 0 ( = 0.0257). Only time to peak insulin and peak cortisol were affected by treatment ( <= 0.037), with horses feeding from the NET having lower values than horses feeding from the FLOOR. Average glucose, insulin, cortisol, and leptin were affected by day ( <= 0.0102). Glucose and insulin values increased, whereas cortisol and leptin levels decreased throughout the 28-d study. The use of a slow-feed hay net coupled with a limit-fed diet appears to be an effective method for decreasing BW and maintaining more homeostatic levels of postprandial metabolites and hormones when feeding overweight adult horses. PMID- 26440195 TI - Effects of supplementation during late gestation on goat performance and behavior under rangeland conditions. AB - This study evaluated the effects of peripartum feed supplementation on doe and kid BW and BCS, milk yield and composition, serum metabolites, and maternal neonatal behavior under rangeland conditions in northern Mexico. Adult does ( = 23) were randomly assigned to 3 nutritional plane groups: 1) goats supplemented (500 g of concentrate [18% CP/kg DM, 2.7 Mcal/kg DM, and 2% salt]) from 15 d prepartum to 7 d postpartum (G15; = 8), 2) the same supplementation as G15 but from 35 d before until 7 d after kidding (G35; = 8), and 3) nonsupplemented does (GC; = 7). Supplemented goats differed from GC goats in BW (48 +/- 1.8, 46.1 +/- 2.5, and 44.9 +/- 2.3 kg; < 0.05), milk yield (1.8 +/- 0.1, 1.9 +/- 0.2, and 1.2 +/- 0.1 kg at d 15 postpartum; < 0.01), kid birth weights (3.8 +/- 0.2, 3.6 +/- 0.2, and 3.4 +/- 0.2 kg; < 0.05), and kid BW at 15 d after birth (6.9 +/- 0.2, 6.6 +/- 0.2, and 5.6 +/- 0.2 kg; < 0.05) for the G35, G15, and GC, respectively. Serum concentrations for total protein, glucose, and cholesterol were not affected ( > 0.05) by treatments. Milk of GC goats showed increased ( < 0.05) percentages for fat, protein, lactose, and nonfat milk solids, whereas total quantities of these variables where higher ( < 0.05) in the G15 and G35 groups. Furthermore, GC dams spent more time seeking their offspring and emitted more low pitched bleats 4 h postpartum ( < 0.05) in a 2-choice test compared with the G15 and G35 groups. In general, peripartum supplementation promoted a closer dam-kid relationship at 8 h postpartum. Goat performance may be improved in this semiarid region of Mexico with marginal production through supplementation in late gestation. PMID- 26440196 TI - The economic and environmental value of genetic improvements in fattening pigs: An integrated dynamic model approach. AB - The selection of animals for improved performance affects the profitability of pig fattening and has environmental consequences. The goal of this paper was to examine how changes in genetic and market parameters impact the biophysical (feeding patterns, timing of slaughter, nitrogen excretion) and economic (return per pig space unit) results describing pig fattening in a Finnish farm. The analysis can be viewed as focusing on terminal line breeding goals. An integrated model using recursive stochastic dynamic programming and a biological pig growth model was used to estimate biophysical results and economic values. Combining these models allowed us to provide more accurate estimates for the value of genetic improvement and, thus, provide better feedback to animal breeding programs than the traditional approach, which is based on fixed management patterns. Besides the benchmark scenario, the results were simulated for 5 other scenarios. In each scenario, genotype was improved regarding daily growth potential, carcass lean meat content, or the parameters of the Gompertz growth curve (maturing rate [], adult weight of protein [alpha], and adult weight of lipid mass []). The change in each parameter was equal to approximately 1 SD genetic improvement (ceteris paribus). Increasing , , daily growth potential, or carcass lean meat content increased the return on pig space unit by ?12.60, ?7.60, ?4.10, or ?2.90 per year, respectively, whereas an increase in decreased the return by ?3.10. The genetic improvement in and resulted in the highest decrease in nitrogen excretion calculated in total or per kilogram of carcass gain but only under the optimal feeding pattern. Simulated changes in the Gompertz growth function parameters imply greater changes in ADG and lean meat content than changes in scenarios focusing on improving ADG and lean meat content directly. The economic value of genetic improvements as well as the quantity of nitrogen excreted during the fattening period largely depends on feeding. Improved genotypes can require changes in pig management pattern. Estimating the influence of the genotype on the nitrogen excretion without considering changes in the management pattern can result in flawed conclusions. To improve overall economic performance and to decrease the environmental footprint of fattening pig production, the pig producer can adjust the herd management pattern according to the pigs' genetics. PMID- 26440197 TI - Effects of diet form and feeder adjustment on growth performance of nursery and finishing pigs. AB - Three experiments were conducted to determine the effects of feeder adjustment and diet form on growth performance of nursery (Exp. 1 and 2) and finishing (Exp. 3) pigs. Treatments were arranged as a 2 * 3 factorial with the main effects of feeder adjustment and diet form. The 2 feeder adjustments were a narrow and wide feeder adjustment (minimum gap opening of 1.27 and 2.54 cm, respectively). The 3 diet forms were meal, poor-quality pellets (70% pellets and 30% fines for Exp. 1 and 2 and 50% pellets and 50% fines for Exp. 3), and screened pellets with minimal fines (3 to 10%). In Exp. 1, 210 pigs (initially 11.9 kg BW) were used in a 21-d trial with 7 pigs per pen and 5 pens per treatment. No feeder adjustment * diet form interactions were observed. There were no differences in ADG, ADFI, or G:F due to feeder adjustment. Pigs fed the meal diet had increased ( < 0.05) ADG and ADFI compared with pigs fed the poor-quality or screened pellets. Pigs fed meal or poor-quality pellets had decreased ( < 0.05) G:F compared with pigs fed screened pellets. In Exp. 2, 1,005 nursery pigs (initially 14.1 kg BW) were used in a 28-d trial with 26 to 28 pigs per pen and 6 pens per treatment. Pigs fed from the narrow feeder adjustment had decreased ( < 0.05) ADG and ADFI compared with pigs fed from the wide adjustment with no differences in G:F. Pigs fed the meal diet had decreased ( < 0.05) ADG compared with pigs fed poor-quality or screened pellets. Pigs fed meal or poor-quality pellets had decreased ( < 0.05) G:F compared with pigs fed screened pellets. In Exp. 3, 246 pigs (initially 56.8 kg BW) were used in a 69-d trial with 5 pens per treatment and 6 or 7 pigs per pen. Overall, ADFI decreased ( < 0.05) and G:F increased ( < 0.05) for pigs fed from the narrow adjusted feeders compared with the wide adjustment with no differences in ADG. Overall, pigs fed meal diets tended to have decreased ( < 0.10) ADG and had decreased ( < 0.05) G:F compared with pigs fed screened pellets; ADG and G:F in those fed poor-quality pellets were intermediate. Feeding meal or poor-quality pellets increased ( < 0.05) ADFI compared with pigs fed screened pellets. In conclusion, feeding nursery pigs from a wide feeder gap may increase ADG and ADFI with no negative effects on G:F. For finishing pigs, reducing feeder gap reduced feed disappearance and improved G:F. In all experiments, the greatest G:F improvements from pelleting were observed when the percentage of fines was minimized. PMID- 26440198 TI - The effect of administering multiple doses of tall larkspur (Delphinium barbeyi) to cattle. AB - Larkspurs ( spp.) are one of the most serious toxic plant problems on foothill and mountain rangelands in the western United States. A considerable amount of research has been conducted over the years in both field and pen settings. The results of these research efforts have significantly increased our understanding of the poisoning of cattle by larkspurs. However, most of the pen studies conducted thus far have used a dosing regimen of a single bolus dose, which does not accurately mimic the manner by which cattle are poisoned by larkspur while grazing. Consequently, the objective of this study was to evaluate the acute toxicity of tall larkspur ( collected near Manti, UT) when administered in multiple doses, with the intent to identify a no observable adverse effect level (NOAEL). The adverse effect selected for this study was muscle weakness to the point the cattle could no longer remain ambulatory as would be required in a grazing environment, thus becoming sternally recumbent when exercised. Hereford steers were administered various doses of tall larkspur at 12-h intervals for 4 d or until they showed marked signs of muscle weakness. The results suggest that a dose of 2 mg kg?d -(methylsuccinimido) anthranoyllycoctonine (MSAL)-type alkaloids is the NOAEL for a tall larkspur population with a norditerpenoid alkaloid profile containing 4 mg MSAL-type alkaloids/g plant material and 12 mg non-MSAL-type alkaloids/g plant material. Additionally, a computer model was generated to simulate multiple-dosing regimens at the various doses as well as different dosing regimens. The results from this study suggest that a 500-kg steer can consume a daily dose of 1.25 kg of fresh tall larkspur (with a similar alkaloid profile) without becoming severely poisoned (suffering from muscle weakness to the point of recumbency). Additionally, these results indicate that a serum concentration of approximately 355 ng methyllycaconitine/mL may represent a toxic threshold. PMID- 26440199 TI - Carbon flux assessment in cow-calf grazing systems. AB - Greenhouse gas (GHG) fluxes and soil organic carbon (SOC) accumulation in grassland ecosystems are intimately linked to grazing management. This study assessed the carbon equivalent flux (Ceq) from 1) an irrigated, heavily stocked, low-density grazing system, 2) a nonirrigated, lightly stocked, high-density grazing system, and 3) a grazing-exclusion pasture site on the basis of the GHG emissions from pasture soils and enteric methane emissions from cows grazing different pasture treatments. Soil organic carbon and total soil nitrogen stocks were measured but not included in Ceq determination because of study duration and time needed to observe a change in soil composition. Light- and heavy-stocking systems had 36% and 43% greater Ceq than nongrazed pasture sites, respectively ( < 0.01). The largest contributor to increased Ceq from grazing systems was enteric CH emissions, which represented 15% and 32% of the overall emissions for lightly and heavily stocked grazing systems, respectively. Across years, grazing systems also had increased nitrous oxide (N2O; < 0.01) and CH emissions from pasture soils ( < 0.01) compared with nongrazed pasture sites but, overall, minimally contributed to total emissions. Results indicate no clear difference in Ceqflux between the grazing systems studied when SOC change is not incorporated ( = 0.11). A greater stocking rate potentially increased total SOC stock ( = 0.02), the addition of SOC deeper into the soil horizon ( = 0.01), and soil OM content to 30 cm ( < 0.01). The incorporation of long-term annual carbon sequestration into the determination of Ceq could change results and possibly differentiate the grazing systems studied. PMID- 26440200 TI - Effect of different dietary energy on collagen accumulation in skeletal muscle of ram lambs. AB - Tenderness is one of the most appreciated characteristics of meat quality. The objective of this trial was to investigate the effect of different energy diets on collagen deposition and meat tenderness. Twelve one-half Dorper * one-half small thin-tailed sheep crossed ram lambs (20 +/- 0.5 kg of BW) were randomly selected and divided into 2 groups in a completely randomized design. Animals were offered identical diets at 100 or 65% of ad libitum intake. Lambs were euthanized when BW in the ad libitum group reached 35 kg, and the semitendinosus (ST) muscle were sampled. The results showed that Warner-Bratzler shear force (WBSF) was significantly increased when lambs were fed an energy-restricted diet ( < 0.05). Masson trichrome stain and hydroxyproline assay demonstrated increased collagen content in ST muscle of feed restriction lambs. Both and mRNA contents were significantly increased when lambs were fed an energy-restricted diet ( < 0.05), whereas no difference for mRNA expression was observed ( > 0.05). Expression of alpha () was greater in the feed restriction group ( < 0.01), and no differences were observed for both () and () mRNA contents ( > 0.05). In addition, 1, 2, 9, and 13 (, , , and ) did not change with the feed restriction, whereas both 1 and 2 ( and ) were increased. Feed restriction did not alter TGF beta and SMAD protein contents, but phosphor-p38 protein content was elevated. In summary, feed restriction enhanced collagen accumulation in ST muscle, which may negatively affect the lamb tenderness, and was associated with the upregulated p38 signaling pathway. PMID- 26440201 TI - Titanium-zirconium narrow-diameter versus titanium regular-diameter implants for anterior and premolar single crowns: 3-year results of a randomized controlled clinical study. AB - AIM: To test whether titanium-zirconium (Ti-Zr) 3.3 mm diameter implants perform differently from titanium (Ti) 4.1 mm diameter implants with respect to marginal bone level (MBL) and clinical parameters. MATERIAL AND METHODS: Forty patients in need of a single-implant crown in the anterior or premolar regions were enrolled in two centres. Following random allocation, either a Ti-Zr or a Ti implant was inserted. Porcelain-fused-to-metal crowns were inserted 6 months after implantation. Implant survival, change in MBL, clinical parameters, change in mid facial mucosa and papilla levels, and the occurrence of biological and technical complications were assessed at the 3-year follow-up. RESULTS: At 3 years, 32 of the 40 included patients were examined (15 Ti and 17 Ti-Zr implants). There were no implant failures. From the implant placement to 3 years, the median change in mean MBL amounted to 0.21 mm (mean: -0.31) in the Ti group and 0.10 mm (mean: 0.40) in the Ti-Zr group. There were no significant differences between the groups with respect to the change in MBL, the change in mucosa levels, and the occurrence of complications. CONCLUSIONS: Ti-Zr implants with 3.3 mm diameter used for the support of single crowns in the anterior and the premolar regions did not differ from Ti implants with 4.1 mm diameter regarding the clinical performance over a 3-year period. PMID- 26440202 TI - Switchable Bioelectrocatalysis Controlled by Dual Stimuli-Responsive Polymeric Interface. AB - The engineering of bionanointerfaces using stimuli-responsive polymers offers a new dimension in the design of novel bioelectronic interfaces. The integration of electrode surfaces with stimuli-responsive molecular cues provides a direct control and ability to switch and tune physical and chemical properties of bioelectronic interfaces in various biodevices. Here, we report a dual-responsive biointerface employing a positively responding dual-switchable polymer, poly(NIPAAm-co-DEAEMA)-b-HEAAm, to control and regulate enzyme-based bioelectrocatalysis. The design interface exhibits reversible activation deactivation of bioelectrocatalytic reactions in response to change in temperature and in pH, which allows manipulation of biomolecular interactions to produce on/off switchable conditions. Using electrochemical measurements, we demonstrate that interfacial bioelectrochemical properties can be tuned over a modest range of temperature (i.e., 20-60 degrees C) and pH (i.e., pH 4-8) of the medium. The resulting dual-switchable interface may have important implications not only for the design of responsive biocatalysis and on-demand operation of biosensors, but also as an aid to elucidating electron-transport pathways and mechanisms in living organisms by mimicking the dynamic properties of complex biological environments and processes. PMID- 26440203 TI - Efficacy of metformin on pregnancy complications in women with polycystic ovary syndrome: a meta-analysis. AB - OBJECTIVE: To evaluate the efficacy of metformin administration throughout pregnancy on pregnancy-related complications in women with polycystic ovary syndrome (PCOS). STUDY DESIGN: MEDLINE and ScienceDirect were searched to retrieve relevant trials. The endpoint was the incidence of complications of pregnancy, gestational diabetes mellitus (GDM), pre-eclampsia (PE), miscarriage and premature birth included. RESULTS: Five studies with 502 PCOS patients with metformin administration throughout pregnancy and 427 controls who used metformin just to get conception were included in our meta-analysis. In study group, a significantly lower change of emerging miscarriage and premature birth was observed, the pooled relative risk (RR) was 0.32 (95% confidence interval (CI): 0.19-0.56) for miscarriage and 0.40 (95%CI: 0.18-0.91) for premature birth. No significant difference was demonstrated in emerging GDM and PE. CONCLUSIONS: Metformin therapy throughout pregnancy can reduce the RR of miscarriage and premature birth incidence in PCOS patients with no serious side effects. PMID- 26440204 TI - Aminoketyl Radicals in Organic Synthesis: Stereoselective Cyclization of Five- and Six-Membered Cyclic Imides to 2-Azabicycles Using SmI2-H2O. AB - Synthetic application of aminoketyl radicals [R-C(*)(O(-))NR'R"] formed by a direct electron capture into the amide bond is limited. Herein, we demonstrate addition of aminoketyl radicals to unactivated alkenes using SmI2-H2O as a crucial promoter based on the generic five- and six-membered imide template. Notably, this method enables direct access to aminoketyl radicals with wide ranging applications in synthesis for the formation of C-C bonds adjacent to nitrogen via polarity reversal. PMID- 26440205 TI - Advances in Urinary Tract Endoscopy. AB - The use of endoscopy in veterinary medicine has become the mainstay of diagnosis and treatment in the subspecialty of small animal urology over the past decade. This subspecialty is termed endourology. With the common incidence of urinary tract obstructions, stones disease, renal disease, and urothelial malignancies, combined with the recognized invasiveness and morbidity associated with traditional surgical techniques, the use of endoscopic-assisted alternatives using interventional endoscopic techniques has become appealing to both owners and clinicians. This article provides a brief overview of some of the most common urologic procedures being performed in veterinary medicine. PMID- 26440206 TI - Identification of a Single Strand Origin of Replication in the Integrative and Conjugative Element ICEBs1 of Bacillus subtilis. AB - We identified a functional single strand origin of replication (sso) in the integrative and conjugative element ICEBs1 of Bacillus subtilis. Integrative and conjugative elements (ICEs, also known as conjugative transposons) are DNA elements typically found integrated into a bacterial chromosome where they are transmitted to daughter cells by chromosomal replication and cell division. Under certain conditions, ICEs become activated and excise from the host chromosome and can transfer to neighboring cells via the element-encoded conjugation machinery. Activated ICEBs1 undergoes autonomous rolling circle replication that is needed for the maintenance of the excised element in growing and dividing cells. Rolling circle replication, used by many plasmids and phages, generates single-stranded DNA (ssDNA). In many cases, the presence of an sso enhances the conversion of the ssDNA to double-stranded DNA (dsDNA) by enabling priming of synthesis of the second DNA strand. We initially identified sso1 in ICEBs1 based on sequence similarity to the sso of an RCR plasmid. Several functional assays confirmed Sso activity. Genetic analyses indicated that ICEBs1 uses sso1 and at least one other region for second strand DNA synthesis. We found that Sso activity was important for two key aspects of the ICEBs1 lifecycle: 1) maintenance of the plasmid form of ICEBs1 in cells after excision from the chromosome, and 2) stable acquisition of ICEBs1 following transfer to a new host. We identified sequences similar to known plasmid sso's in several other ICEs. Together, our results indicate that many other ICEs contain at least one single strand origin of replication, that these ICEs likely undergo autonomous replication, and that replication contributes to the stability and spread of these elements. PMID- 26440207 TI - Isolation and characterization of Clostridium difficile in farm animals from slaughterhouse to retail stage in Isfahan, Iran. AB - To determine the prevalence of Clostridium difficile in farm animals from slaughterhouse through to retail stage, a total of 750 samples of feces, posteviscerated and washed carcass were collected from cattle, camels, goats, and sheep in Isfahan, Iran. The overall prevalence of C. difficile in feces, posteviscerated and washed carcass were 20 (13.3%), 23 (15.3%), and 11 (7.3%), respectively; while C. difficile was isolated from 79 (26.3%) retail samples. Twenty-nine (3.8%) isolates were toxigenic, with most toxigenic isolates (n = 17, 5.6%) identified from the retail stage. All toxigenic isolates harbored tcdA and tcdB; however, all were negative for cdtB. The 29 isolates were classified into 21 different ribotypes. This study revealed evidence of existence of toxigenic C. difficile in farm animal feces and meat in Iran. PMID- 26440208 TI - Dogs Can Be Successfully Trained to Alert to Hypoglycemia Samples from Patients with Type 1 Diabetes. AB - INTRODUCTION: Hypoglycemia (Hypo) is the most common side effect of insulin therapy in people with type 1 diabetes (T1D). Over time, patients with T1D become unaware of signs and symptoms of Hypo. Hypo unawareness leads to morbidity and mortality. Diabetes alert dogs (DADs) represent a unique way to help patients with Hypo unawareness. Our group has previously presented data in abstract form which demonstrates the sensitivity and specificity of DADS. The purpose of our current study is to expand evaluation of DAD sensitivity and specificity using a method that reduces the possibility of trainer bias. METHODS: We evaluated 6 dogs aging 1-10 years old who had received an average of 6 months of training for Hypo alert using positive training methods. Perspiration samples were collected from patients during Hypo (BG 46-65 mg/dL) and normoglycemia (BG 85-136 mg/dl) and were used in training. These samples were placed in glass vials which were then placed into 7 steel cans (1 Hypo, 2 normal, 4 blank) randomly placed by roll of a dice. The dogs alerted by either sitting in front of, or pushing, the can containing the Hypo sample. Dogs were rewarded for appropriate recognition of the Hypo samples using a food treat via a remote control dispenser. The results were videotaped and statistically evaluated for sensitivity (proportion of lows correctly alerted, "true positive rate") and specificity (proportion of blanks + normal samples not alerted, "true negative rate") calculated after pooling data across all trials for all dogs. RESULTS: All DADs displayed statistically significant (p value <0.05) greater sensitivity (min 50.0%-max 87.5%) to detect the Hypo sample than the expected random correct alert of 14%. Specificity ranged from a min of 89.6% to a max of 97.9% (expected rate is not defined in this scenario). CONCLUSIONS: Our results suggest that properly trained DADs can successfully recognize and alert to Hypo in an in vitro setting using smell alone. PMID- 26440209 TI - LC-MS/MS analysis reveals a broad functional spectrum of proteins in the secretome of sebocytes. PMID- 26440210 TI - Xenopus borealis as an alternative source of oocytes for biophysical and pharmacological studies of neuronal ion channels. AB - For the past 30 years, oocytes from Xenopus laevis have been extensively used to express and characterise ion channels in an easily controlled environment. Here we report the first use of oocytes from the closely related species Xenopus borealis as an alternative expression system for neuronal ion channels. Using the two-electrode voltage-clamp technique, we show that a wide variety of voltage- and ligand-gated ion channels have the same channel properties and pharmacological profiles when expressed in either X. laevis or X. borealis oocytes. Potential advantages of the X. borealis oocytes include a smaller endogenous chloride current and the ability to produce more intense fluorescence signals when studied with voltage-clamp fluorometry. Scanning electron microscopy revealed a difference in vitelline membrane structure between the two species, which may be related to the discrepancy in fluorescence signals observed. We demonstrate that X. borealis oocytes are a viable heterologous system for expression of neuronal ion channels with some potential advantages over X. laevis oocytes for certain applications. PMID- 26440211 TI - Bilayered vascular graft derived from human induced pluripotent stem cells with biomimetic structure and function. AB - BACKGROUND: We developed an aligned bi-layered vascular graft derived from human induced pluripotent stem cells (iPSCs) that recapitulates the cellular composition, orientation, and anti-inflammatory function of blood vessels. MATERIALS & METHODS: The luminal layer consisted of longitudinal-aligned nanofibrillar collagen containing primary endothelial cells (ECs) or iPSC-derived ECs (iPSC-ECs). The outer layer contained circumferentially oriented nanofibrillar collagen with primary smooth muscle cells (SMCs) or iPSC-derived SMCs(iPSC-SMCs). RESULTS: On the aligned scaffolds, cells organized F-actin assembly within 8o from the direction of nanofibrils. When compared to randomly oriented scaffolds, EC-seeded aligned scaffolds had significant reduced inflammatory response, based on adhesivity to monocytes. CONCLUSION: This study highlights the importance of anisotropic scaffolds in directing cell form and function, and has therapeutic significance as physiologically relevant blood vessels. PMID- 26440213 TI - Adaptations of skeletal muscle mitochondria to exercise training. AB - Mitochondrial volume density (Mito(VD)) is composed of two distinct mitochondrial subpopulations--intermyofibrillar mitochondria (Mito(IMF)) and subsarcolemmal mitochondria (Mito(SS)). With exercise training, Mito(VD) may increase by up to 40% and is, for the most part, related to an increase in Mito(IMF). Exercise induced adaptations in mitochondrial function depend on the intensity of training and appear to be explained predominately by an increased expression of mitochondrial enzymes that facilitate aerobic metabolism. Although mitochondrial content often increases with training, it seems that mitochondrial adaptations are not needed to facilitate maximal oxygen uptake, whereas such adaptations are of greater importance for endurance capacity. PMID- 26440212 TI - Serum antibodies to human leucocyte antigen (HLA)-E, HLA-F and HLA-G in patients with systemic lupus erythematosus (SLE) during disease flares: Clinical relevance of HLA-F autoantibodies. AB - T lymphocyte hyperactivity and progressive inflammation in systemic lupus erythematosus (SLE) patients results in over-expression of human leucocyte antigen (HLA)-Ib on the surface of lymphocytes. These are shed into the circulation upon inflammation, and may augment production of antibodies promoting pathogenicity of the disease. The objective was to evaluate the association of HLA-Ib (HLA-E, HLA-F and HLA-G) antibodies to the disease activity of SLE. The immunoglobulin (Ig)G/IgM reactivity to HLA-Ib and beta2m in the sera of 69 German, 29 Mexican female SLE patients and 17 German female controls was measured by multiplex Luminex((r))-based flow cytometry. The values were expressed as mean flourescence intensity (MFI). Only the German SLE cohort was analysed in relation to the clinical disease activity. In the controls, anti-HLA-G IgG predominated over other HLA-Ib antibodies, whereas SLE patients had a preponderance of anti HLA-F IgG over the other HLA-Ib antibodies. The disease activity index, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2000, was reflected only in the levels of anti-HLA-F IgG. Anti-HLA-F IgG with MFI level of 500-1999 was associated with active SLE, whereas inactive SLE revealed higher MFI (>2000). When anti-HLA-F IgG were cross-reactive with other HLA-Ib alleles, their reactivity was reflected in the levels of anti-HLA-E and -G IgG. The prevalence of HLA-F-monospecific antibodies in SLE patients was also associated with the clinical disease activity. Anti-HLA-F IgG is possibly involved in the clearance of HLA-F shed from lymphocytes and inflamed tissues to lessen the disease's severity, and thus emerges as a beneficial immune biomarker. Therefore, anti-HLA Ib IgG should be considered as a biomarker in standard SLE diagnostics. PMID- 26440214 TI - ACC/AHA/STS Statement on the Future of Registries and the Performance Measurement Enterprise: A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures and The Society of Thoracic Surgeons. PMID- 26440215 TI - Patient-Centered Medical Home Features and Health Care Expenditures of Medicare Beneficiaries with Chronic Disease Dyads. AB - Three out of 4 Medicare beneficiaries have multiple chronic conditions, and managing the care of this growing population can be complex and costly because of care coordination challenges. This study assesses how different elements of the patient-centered medical home (PCMH) model may impact the health care expenditures of Medicare beneficiaries with the most prevalent chronic disease dyads (ie, co-occurring high cholesterol and high blood pressure, high cholesterol and heart disease, high cholesterol and diabetes, high cholesterol and arthritis, heart disease and high blood pressure). Data from the 2007-2011 Medical Expenditure Panel Survey suggest that increased access to PCMH features may differentially impact the distribution of health care expenditures across health care service categories depending on the combination of chronic conditions experienced by each beneficiary. For example, having no difficulty contacting a provider after regular hours was associated with significantly lower outpatient expenditures for beneficiaries with high cholesterol and diabetes (n = 635; P = 0.038), but it was associated with significantly higher inpatient expenditures for beneficiaries with high blood pressure and high cholesterol (n = 1599; P = 0.015), and no significant differences in expenditures in any category for beneficiaries with high blood pressure and heart disease (n = 1018; P > 0.05 for all categories). However, average total health care expenditures are largely unaffected by implementing the PCMH features considered. Understanding how the needs of Medicare beneficiaries with multiple chronic conditions can be met through the adoption of the PCMH model is important not only to be able to provide high-quality care but also to control costs. (Population Health Management 2016;19:206-211). PMID- 26440216 TI - Minimal role of base excision repair in TET-induced global DNA demethylation in HEK293T cells. AB - Oxidation of 5-methylcytosine by TET family proteins can induce DNA replication dependent (passive) DNA demethylation and base excision repair (BER)-based (active) DNA demethylation. The balance of active vs. passive TET-induced demethylation remains incompletely determined. In the context of large scale DNA demethylation, active demethylation may require massive induction of the DNA repair machinery and thus compromise genome stability. To study this issue, we constructed a tetracycline-controlled TET-induced global DNA demethylation system in HEK293T cells. Upon TET overexpression, we observed induction of DNA damage and activation of a DNA damage response; however, BER genes are not upregulated to promote DNA repair. Depletion of TDG (thymine DNA glycosylase) or APEX1 (apurinic/apyrimidinic endonuclease 1), two key BER enzymes, enhances rather than impairs global DNA demethylation, which can be explained by stimulated proliferation. By contrast, growth arrest dramatically blocks TET-induced global DNA demethylation. Thus, in the context of TET-induction in HEK293T cells, the DNA replication-dependent passive mechanism functions as the predominant pathway for global DNA demethylation. In the same context, BER-based active demethylation is markedly restricted by limited BER upregulation, thus potentially preventing a disastrous DNA damage response to extensive active DNA demethylation. PMID- 26440217 TI - Characterization of aggregate/aggresome structures formed by polyhedrin of Bombyx mori nucleopolyhedrovirus. AB - Virus infections often lead to formation of aggregates and aggresomes in host cells. In this study, production of aggregates and aggresomes by the highly expressed protein polyhedrin of Bombyx mori nucleopolyhedrovirus (BmNPV) at 24 h postinfection (p.i.) was detected with a fluorescent molecular dye, and verified by colocalization of polyhedrin with aggresomal markers, GFP-250 and gamma tubulin. Polyhedrin aggregates showed hallmark characteristics of aggresomes: formation was microtubule-dependent; they colocalized with heat shock cognates/proteins of the 70-kDa family (HSC/HSP70s), ubiquitinated proteins and recruited the mitochondria. Aggregated polyhedrin protein gradually gained its active conformation accompanying progress of BmNPV infection. At 48 h p.i. recovered polyhedrin bound directly to Bombyx mori microtubule-associated protein 1-light chain 3 (BmLC3), an autophagosome marker, and was colocalized with BmLC3 to the isolation membrane of autophagosome, implying the involvement of polyhedrin in cellular autophagy. Inhibition of autophagy by 3-methyladenine (3 MA) dramatically resulted in decrease of polyhedrin expression and polyhedra particle production. These observations suggested that highly expressed polyhedrin forms aggregate to get involved in cellular autophagy then play an important role in polyhedra production. PMID- 26440218 TI - Inhibition of phagocytic recognition of anti-D opsonized Rh D+ RBC by polymer mediated immunocamouflage. AB - The Rh D antigen posed both a significant clinical risk and inventory supply issue in transfusion medicine. The successful development of the immunocamouflaged RBC has the potential to address both the risk of acute anti-D transfusion reactions and to improve D- blood inventory in geographic locations where D- blood is rare (e.g., China). The immunocamouflage of RBC was mediated by the covalent grafting of methoxy(polyethylene glycol) to the cell membrane thereby obscuring the D protein from the immune system. To determine the potential efficacy of mPEG-D+ RBC in D- recipients, anti-D alloantibodies from previously alloimmunized individuals were utilized. The effects of polymer chain size (2-30 kDa) and grafting concentration (0-4 mM) on antibody binding and erythrophagocytosis were determined using the clinically validated monocyte monolayer assay (MMA) and flow cytometry. The immunocamouflage of D was polymer size and grafting concentration dependent as determined using human anti-D alloantibodies (both pooled [RhoGAM] and single donors). Importantly, the 20 kDa polymer provided excellent immunocamouflage of D and reached a clinically significant level of protection, as measured by the MMA, at grafting concentrations of >=1.5 mM. These findings further support the potential use of immunocamouflaged RBC to reduce the risk of acute transfusion reactions following administration of D+ blood to D- recipients in situations where D- units are unavailable or supply is geographically constrained. PMID- 26440219 TI - The application of soy isoflavones for subjective symptoms and objective signs of vaginal atrophy in menopause: A systematic review of randomised controlled trials. AB - Vaginal atrophy is a common complaint among many women in their menopause, presenting with a cluster of symptoms including dryness, itching, burning/soreness, discharge, irritation and painful intercourse. We searched for existing pertinent data in three chief registries. Specified time brackets included 1996-2013 for Medline, 1990-2013 for Scopus and 2013 for Cochrane Central Register of Controlled Trials (issue 1). Of 110 potentially relevant publications, 17 and 9 trials (7 on maturation value and 2 on vaginal dryness) were selected for qualitative and quantitative analysis, respectively. In general, soy isoflavones seem to improve vaginal symptoms as opposed to control arms. Soy isoflavones were also shown to be more efficacious in quantitative analysis, though this was statistically non-significant. Standardised difference in means of maturation value change was 0.072 (95% confidence interval [CI]: - 0.42 to 0.57), p = 0.777; heterogeneity P = 0.00; I(2) = 85.15%. Difference in means of vaginal dryness was - 0.204 (95% CI: - 0.28 to - 0.126), p < 0.001; heterogeneity P = 0.423; I(2) = 0.00. Soy isoflavones may relieve vaginal symptoms during menopause; nevertheless beneficial effects still remain uncertain due to possible publication bias or vast heterogeneity of the selected studies. Further studies with consistency in design as well as statistics are warranted. PMID- 26440220 TI - Global Gray Water Footprint and Water Pollution Levels Related to Anthropogenic Nitrogen Loads to Fresh Water. AB - This is the first global assessment of nitrogen-related water pollution in river basins with a specification of the pollution by economic sector, and by crop for the agricultural sector. At a spatial resolution of 5 by 5 arc minute, we estimate anthropogenic nitrogen (N) loads to freshwater, calculate the resultant gray water footprints (GWFs), and relate the GWFs per river basin to runoff to calculate the N-related water pollution level (WPL) per catchment. The accumulated global GWF related to anthropogenic N loads in the period 2002-2010 was 13*10(12) m3/y. China contributed about 45% to the global total. Three quarters of the GWF related to N loads came from diffuse sources (agriculture), 23% from domestic point sources and 2% from industrial point sources. Among the crops, production of cereals had the largest contribution to the N-related GWF (18%), followed by vegetables (15%) and oil crops (11%). The river basins with WPL>1 (where the N load exceeds the basin's assimilation capacity), cover about 17% of the global land area, contribute about 9% of the global river discharge, and provide residence to 48% of the global population. PMID- 26440221 TI - Soft-tissue and dermal arrangement in the wing of an Early Cretaceous bird: Implications for the evolution of avian flight. AB - Despite a wealth of fossils of Mesozoic birds revealing evidence of plumage and other soft-tissue structures, the epidermal and dermal anatomy of their wing's patagia remain largely unknown. We describe a distal forelimb of an enantiornithine bird from the Lower Cretaceous limestones of Las Hoyas, Spain, which reveals the overall morphology of the integument of the wing and other connective structures associated with the insertion of flight feathers. The integumentary anatomy, and myological and arthrological organization of the new fossil is remarkably similar to that of modern birds, in which a system of small muscles, tendons and ligaments attaches to the follicles of the remigial feathers and maintains the functional integrity of the wing during flight. The new fossil documents the oldest known occurrence of connective tissues in association with the flight feathers of birds. Furthermore, the presence of an essentially modern connective arrangement in the wing of enantiornithines supports the interpretation of these primitive birds as competent fliers. PMID- 26440222 TI - Gallic Acid: Review of the Methods of Determination and Quantification. AB - Gallic acid (3,4,5 trihydroxybenzoic acid) is a secondary metabolite present in most plants. This metabolite is known to exhibit a range of bioactivities including antioxidant, antimicrobial, anti-inflammatory, and anticancer. There are various methods to analyze gallic acid including spectrometry, chromatography, and capillary electrophoresis, among others. They have been developed to identify and quantify this active ingredient in most biological matrices. The aim of this article is to review the available information on analytical methods for gallic acid, as well as presenting the advantages and limitations of each technique. PMID- 26440223 TI - 'HIV has a woman's face': vaginal microbicides and a case of ambiguous failure. AB - The case is a primary unit of knowledge production in the field of HIV research, yet the work that is done to construct cases often goes unremarked. In this paper, the case takes centre stage in an analysis of a set of apparent failures in HIV prevention research, namely a series of clinical trials to test vaginal microbicides. Returning to the genesis of the microbicide concept in the early 1990s, I examine how the discourse of women's empowerment was linked to HIV prevention in a way that mobilized a particular vision of the case, which was both politically and scientifically expedient. Drawing on an in-depth empirical study of one particular trial, I show the success of the case in mobilizing funds and interest in the research, as well its success in accounting for the failure of the pharmaceutical technology. Drawing in alternative scientific accounts of the failure of microbicides, however, a different version of events is indicated, in which what can ultimately be said to have failed is not the technology itself, but the act of casing upon which its testing was founded. PMID- 26440224 TI - Chemo-, regio-, and stereo-selective perfluoroalkylations by a Grignard complex with zirconocene. AB - The synthesis of highly reactive perfluoroalkyl Grignard reagents with early transition metal zirconocene complexes and their new types of highly chemo-, regio-, and stereo-selective perfluoroalkylation reactions are reported with epoxides in particular. The zirconocene complex is advantageous in activating the perfluoroalkyl Grignard species. The zirconocene.Grignard complexes were clarified by DOSY. Both (1)H and (19)F DOSY analyses show that the addition of MAO and dioxane to the mixture of RFMgCl and Cp2ZrCl2 connects Cp2Zr and RFMg to generate the zirconocene/perfluoroalkyl-Grignard/dioxane complex. PMID- 26440225 TI - Tunable multiband metasurfaces by moire nanosphere lithography. AB - Moire nanosphere lithography (MNSL), which features the relative in-plane rotation between two layers of self-assembled monodisperse nanospheres as masks, provides a cost-effective approach for creating moire patterns on generic substrates. In this work, we experimentally and numerically investigate a series of moire metasurfaces by MNSL. Due to the variety of gradient plasmonic nanostructures in arrays, single moire metasurfaces can support multiple localized surface plasmon (LSP) modes with a wide range of resonant wavelengths from ~600 nm to ~4200 nm. We analyze the origin of the LSP modes based on the optical spectra and near-field electromagnetic distributions. In addition, we fabricate and analyze the metasurfaces with high-density nanogap structures. These nanogap structures support plasmonic gap modes with significant field enhancements. With their tunable multiband optical responses from visible to near infrared to mid-infrared regimes, these moire metasurfaces are applicable for ultrabroadband absorbers, multiband surface-enhanced infrared and Raman spectroscopy, and broadband single-molecule spectroscopy. PMID- 26440226 TI - Saponin-enriched sea cucumber extracts exhibit an antiobesity effect through inhibition of pancreatic lipase activity and upregulation of LXR-beta signaling. AB - CONTEXT: Sea cucumbers have been consumed as tonic, food, and nutrition supplements for many years. OBJECTIVE: The objective of this study is to investigate the antiobesity and lipid-lowering effects of sea cucumber extracts in in vitro and in vivo models and elucidate the mechanism of action of the extracts on obesity and dyslipidemia. MATERIALS AND METHODS: The 60% ethanol extracts from the body walls of 10 different sea cucumbers were investigated for the inhibition of pancreatic lipase (PL) activity in vitro. The optimal active extract (SC-3) was further chemically analyzed by LC-MS and UV. And 0.1% and 0.2% of SC-3 was mixed with a high-fat diet to treat C57/BL6 mice for 6 weeks or 2 weeks as preventive and therapeutic study. The body weight, serum, and liver lipid profile in the mice were investigated. RESULTS: The crude extract of Pearsonothuria graeffei Semper (Holothuriidae) inhibited the PL activity by 36.44% of control at 0.5 MUg/mL. SC-3 and echinoside A inhibited PL with an IC50 value at 2.86 MUg/mL and 0.76 MUM. 0.1% of SC-3 reduced the body weight (23.0 +/- 0.62 versus 26.3 +/- 0.76 g), the serum TC (2.46 +/- 0.04 versus 2.83 +/- 0.12 mmol/L), TG (0.19 +/- 0.08 versus 0.40 +/- 0.03 mmo/L), and LDL-c (0.48 +/- 0.02 versus 0.51 +/- 0.02 mmol/L), and liver TC (1.19 +/- 0.17 versus 1.85 +/- 0.13 mmol/mg) and TG (6.18 +/- 0.92 versus 10.87 +/- 0.97 mmol/mg) contents of the obese C57BL/six mice on a high-fat diet. DISCUSSION AND CONCLUSION: Sea cucumber may be used for developing antiobesity and antihyperlipidemia drugs. PMID- 26440228 TI - Ardous journey from IACTA education and research cell to Indian College of Cardiac Anaesthesia. PMID- 26440227 TI - Platelet inhibition with ticagrelor versus clopidogrel in Hispanic patients with stable coronary artery disease with or without diabetes mellitus. AB - BACKGROUND/PURPOSE: Diabetes mellitus (DM) disproportionately affects Hispanic patients. DM patients have enhanced platelet reactivity and reduced sensitivity to clopidogrel. Ticagrelor demonstrated a more rapid onset and greater magnitude of platelet inhibition than clopidogrel in Hispanic patients with stable coronary artery disease (CAD). This subgroup analysis examined the onset and level of platelet inhibition of ticagrelor and clopidogrel in Hispanic patients with DM. METHODS/MATERIALS: This was a subgroup analysis of a randomized, open-label, crossover study in which 40 Hispanic patients with stable CAD received ticagrelor 180 mg loading dose (LD)/90 mg twice-daily maintenance dose (MD) then clopidogrel 600 mg LD/75 mg once-daily MD, or vice versa. The primary end point was on treatment platelet reactivity at 2 hours post-LD using the VerifyNowTM P2Y12 test. RESULTS: 21 patients had DM and 19 were non-diabetic. At 2 hours post-LD, mean platelet reactivity in the diabetic group was 34.5 PRU with ticagrelor versus 219.3 PRU with clopidogrel (P<0.001), and in the non-diabetic group was 33.7 PRU with ticagrelor versus 181.0 PRU with clopidogrel (P<0.001). In both diabetic and non-diabetic subgroups, mean platelet reactivity declined to a significantly greater extent with ticagrelor than clopidogrel at all time points evaluated (0.5, 2, and 8 hours post LD and after 7-9 days of MD). Patients were significantly more likely to have high on-treatment platelet reactivity (>=208 PRU) during treatment with clopidogrel compared with ticagrelor, regardless of diabetic status. CONCLUSIONS: Among Hispanic patients with stable CAD, ticagrelor achieves a faster onset and greater magnitude of platelet inhibition compared with clopidogrel, irrespective of diabetic status. PMID- 26440229 TI - Optimizing current blood utilization practices in perioperative patients using the lean team approach. PMID- 26440230 TI - The increasing importance of percutaneous mechanical circulatory assist device therapy in heart failure management. AB - INTRODUCTION: Advances in medical and surgical care have made it possible for an increasing number of patients with Congenital Heart disease (CHD) to live into adulthood. Transposition of the great vessels (TGV) is the most common cyanotic congenital cardiac disease where the right ventricle serves as systemic ventricle. It is not uncommon for these patients to have systemic ventricular failure requiring transplantation. STUDY DESIGN: Hemodynamic decompensation in these patients can be swift and difficult to manage. Increasingly percutaneous LVAD's such as the Impella (Abiomed, Mass, USA) are gaining popularity in these situations owing to their relative ease of placement, both in and outside of the operating room. CONCLUSION: In this paper we demonstrate that Impella (IMP) CP placement through the axillary artery approach shows to be suitable option for short term cardiac support and improvement of end organ perfusion in anticipation of cardiac transplantation. PMID- 26440231 TI - An analysis of the factors influencing pulmonary artery catheter placement in anesthetized patients. AB - BACKGROUND: Pulmonary artery catheters are usually placed by resident anesthesiologists with pressure wave monitoring from educational point of view. In some cases, the placement needs longer time or is difficult only by observing the pressure waves. AIMS: We sought to examine the time required for the catheter placement in adult patients and determine factors influencing the placement. SETTINGS AND DESIGNS: Prospective, observational, cohort study. METHODS: We examined the time required for the catheter placement. If the catheter is placed in longer than 5 min, this could be a difficult placement. We examined the effect of the patient's age, body mass index, cardiothoracic ratio (CTR) and tricuspid regurgitation, left ventricular ejection fraction (LVEF) and training duration of a resident on the difficult catheter placement. Next, we excluded the difficult cases from the analysis and examined the effect of these factors on the placement time. STATISTICAL ANALYSIS: The data were analyzed by logistic regression analysis to assess factors for the difficult catheter placement and multiple linear regression analysis to evaluate the factors to increase the placement time after univariate analyses. RESULTS: The difficult placement occurred in 6 patients (5.7%). The analysis showed that LVEF was a significant factor to hinder the catheter placement (P = 0.02) while CTR was a significant factor to increase the placement time (P = 0.002). CONCLUSION: LVEF and CTRs are significant factors to be associated with the difficult catheter placement and to increase the placement time, respectively. PMID- 26440232 TI - Exertional-induced bronchoconstriction: comparison between cardiopulmonary exercise test and methacholine challenging test. AB - INTRODUCTION: Exertional-induced bronchoconstriction is a condition in which the physical activity causes constriction of airways in patients with airway hyper- responsiveness. In this study, we tried to study and evaluate any relationship between the findings of cardiopulmonary exercise testing (CPET) and the response to methacholine challenge test (MCT) in patients with dyspnea after activity. MATERIALS AND METHODS: Thirty patients with complaints of dyspnea following activity referred to "Lung Clinic" of Baqiyatallah Hospital but not suffering from asthma were entered into the study. The subjects were excluded from the study if: Suffering from any other pulmonary diseases, smoking more than 1 cigarette a week in the last year, having a history of smoking more than 10 packets of cigarettes/year, having respiratory infection in the past 4 weeks, having abnormal chest X-ray or electrocardiogram, and cannot discontinue the use of medicines interfering with bronchial provocation. Baseline spirometry was performed for all the patients, and the values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV/FVC were recorded. The MCT and then the CPET were performed on all patients. RESULTS: The mean VO 2 (volume oxygen) in patients with positive methacholine test (20.45 mL/kg/min) was significantly lower than patients with negative MCT (28.69 mL/kg/min) (P = 0.000). Respiratory rates per minute (RR) and minute ventilation in the group with positive MCT (38.85 and 1.636 L) were significantly lower than the group with negative methacholine test (46.78 and 2.114 L) (P < 0.05). Also, the O 2 pulse rate in the group with negative methacholine test (116.27 mL/beat) was significantly higher than the group with positive methacholine test (84.26 mL/beat) (P < 0.001). CONCLUSION: Pulmonary response to exercise in patients with positive methacholine test is insufficient. The dead space ventilation in these patients has increased. Also, dynamic hyperinflation in patients with positive methacholine test causes the reduced stroke volume and O 2 pulse in these patients. PMID- 26440233 TI - Impact comparison of ketamine and sodium thiopental on anesthesia during electroconvulsive therapy in major depression patients with drug-resistant; a double-blind randomized clinical trial. AB - BACKGROUND: Electroconvulsive therapy (ECT) is one of the available and the most effective therapies for the treatment of resistant depression. Considering the crucial role of seizure duration on therapeutic response in patients treated with ECT, this study aimed to compare the effect of ketamine and sodium thiopental anesthesia during ECT for treatment of patients with drug-resistant major depression (DRMD). MATERIALS AND METHODS: In a double-blind randomized clinical trial, 160 patients with DRMD were selected consequently and were assigned randomly into two groups including ketamine 0.8 mg/kg and sodium thiopental 1.5 mg/kg. The seizure duration, recovery time, and the side effects of anesthesia were evaluated after 1-h after anesthesia. Data of recovery time and complication collected in 2 nd , 4 th , 6 th , and 8 th ECT. Depression was assessed by Hamilton depression scale. RESULTS: The results indicated that ketamine and sodium thiopental had a significant effect on the reduction of depression scores in patients with DRMD (P < 0.05). Complications such as a headache, nausea, pain at the injection site, short-term delirium, and long-term delirium were higher in ketamine group (P > 0.05). But ketamine was more effective in improvement of depression score and increasing systolic and diastolic blood pressure (P < 0.05). The mean of seizure duration showed a decreasing trend and was significant between two study groups (P < 0.05). CONCLUSION: Anesthesia induced by ketamine during ECT therapy increased blood pressure and seizure duration. Therefore, due to lower medical complication and attack rate of seizure, ketamine is an appropriate option for anesthesia with ECT in patients with DRMD. PMID- 26440234 TI - Where does the pulmonary artery catheter float: transesophageal echocardiography evaluation. AB - BACKGROUND: Pulmonary artery (PA) catheter provides a variety of cardiac and hemodynamic parameters. In majority of the patients, the catheter tends to float in the right pulmonary artery (RPA) than the left pulmonary artery (LPA). We evaluated the location of PA catheter with the help of transesophageal echocardiography (TEE) to know the incidence of its localization. Three views were utilized for this purpose; midesophageal ascending aorta (AA) short-axis view, modified mid esophageal aortic valve long-axis view, and modified bicaval view. METHODS: We enrolled 135 patients undergoing elective cardiac surgery where both the PA catheter and TEE were to be used; for this prospective observational study. PA catheter was visualized by TEE in the above mentioned views and the degree of clarity of visualization by three views was also noted. Position of the PA catheter was further confirmed by a postoperative chest radiograph. RESULTS: One patient was excluded from the data analysis. PA catheter was visualized in RPA in 129 patients (96%) and in LPA in 4 patients (3%). In 1 patient, the catheter was visualized in main PA in the chest radiograph. The midesophageal AA short-axis, modified aortic valve long-axis, and modified bicaval view provided good visualization in 51.45%, 57.4%, and 62.3% patients respectively. Taken together, PA catheter visualization was good in 128 (95.5%) patients. CONCLUSION: We conclude that the PA catheter has a high probability of entering the RPA as compared to LPA (96% vs. 3%) and TEE provides good visualization of the catheter in RPA. PMID- 26440235 TI - Anti-inflammatory effects of propofol during cardiopulmonary bypass: a pilot study. AB - INTRODUCTION: Propofol has been suggested as a useful adjunct to cardiopulmonary bypass (CPB) because of its potential protective effect on the heart mediated by a decrease in ischemia-reperfusion injury and inflammation at clinically relevant concentrations. In view of these potentially protective properties, which modulate many of the deleterious mechanism of inflammation attributable to reperfusion injury and CPB, we sought to determine whether starting a low dose of propofol infusion at the beginning of CPB would decrease inflammation as measured by pro-inflammatory markers. MATERIALS AND METHODS: We enrolled 24 patients undergoing elective coronary artery bypass graft (CABG). The study group received propofol at rate of 120 mcg/kg/min immediately after starting CPB and was maintained throughout the surgery and for the following 6 hours in the intensive care unit (ICU). The control group received propofol dose of 30-50 mcg/kg/min which was started at the time of chest closure with wires and continued for the next 6 hours in the ICU. Interleukins (IL) -6, -8 and -10 and tumor necrosis factor alpha (TNFalpha) were assayed. RESULT: The most significant difference was in the level of IL-6 which had a P value of less than 0.06. Starting a low dose propofol early during the CPB was not associated with significant hemodynamic instability in comparison with the control group. CONCLUSION: Our study shows that propofol may be suitable as an anti-inflammatory adjunct for patients undergoing CABG. PMID- 26440236 TI - Comparison of the effects of inhalational anesthesia with desflurane and total intravenous anesthesia on cardiac biomarkers after aortic valve replacement. AB - OBJECTIVE (S): The aim of this study was to compare the effects of using inhalational anesthesia with desflurane with that of a total intravenous (iv) anesthetic technique using midazolam-fentanyl-propofol on the release of cardiac biomarkers after aortic valve replacement (AVR) for aortic stenosis (AS). The specific objectives included (a) determination of the levels of ischemia-modified albumin (IMA) and cardiac troponin I (cTnI) as markers of myocardial injury, (b) effect on mortality, morbidity, duration of mechanical ventilation, length of Intensive Care Unit (ICU) and hospital stay, incidence of arrhythmias, pacing, cardioversion, urine output, and serum creatinine. Methodology and Design: Prospective randomized clinical study. SETTING: Operation room of a cardiac surgery center of a tertiary teaching hospital. PARTICIPANTS: Seventy-six patients in New York Heart Association classification II to III presenting electively for AVR for severe symptomatic AS. INTERVENTIONS: Patients included in the study were randomized into two groups and subjected to either a desflurane fentanyl based technique or total IV anesthesia (TIVA). Blood samples were drawn at preordained intervals to determine the levels of IMA, cTnI, and serum creatinine. MEASUREMENTS AND MAIN RESULTS: The IMA and cTnI levels were not found to be significantly different between both the study groups. Patients in the desflurane group were found to had significantly lower ICU and hospital stays and duration of postoperative mechanical ventilation as compared to those in the TIVA group. There was no difference found in mean heart rate, urine output, serum creatinine, incidence of arrhythmias, need for cardioversion, and 30-day mortality between both groups. The patients in the TIVA group had higher mean arterial pressures on weaning off cardiopulmonary bypass as well as postoperatively in the ICU and recorded lower inotrope usage. CONCLUSION: The result of our study remains ambiguous regarding the overall protective effect of desflurane in patients undergoing AVR although some benefit in terms of shorter duration of postoperative mechanical ventilation, ICU and hospital stays, as well as cTnI, were seen. However, no difference in overall outcome could be clearly established between patients who received desflurane and those that were managed solely with IV anesthetic technique using propofol. PMID- 26440237 TI - Does intravenous sildenafil clinically ameliorate pulmonary hypertension during perioperative management of congenital heart diseases in children? - a prospective randomized study. AB - BACKGROUND: Pulmonary hypertension (PHT), if present, can be a significant cause of increased morbidity and mortality in children undergoing surgery for congenital heart diseases (CHD). Various techniques and drugs have been used perioperatively to alleviate the effects of PHT. Intravenous (IV) sildenafil is one of them and not many studies validate its clinical use. AIMS AND OBJECTIVES: To compare perioperative PaO 2 - FiO 2 ratio peak filling rate (PFR), systolic pulmonary artery pressure (PAP) - systolic aortic pressure (AoP) ratio, extubation time, and Intensive Care Unit (ICU) stay between two groups of children when one of them is administered IV sildenafil perioperatively during surgery for CHDs. MATERIALS AND METHODS: Patients with ventricular septal defects and proven PHT, <14 years of age, all American Society of Anesthesiologists physical status III, undergoing cardiac surgery, were enrolled into two groups - Group S (IV sildenafil) and Group C (control) - over a period of 14 months, starting from October 2013. Independent t-test and Mann-Whitney U-test were used to compare the various parameters between two groups. RESULTS: PFR was higher throughout, perioperatively, in Group S. PAP/AoP was 0.3 and 0.4 in Group S and Group C, respectively. In Group S, mean group extubation time was 7 +/- 7.34 h, whereas in Group C it was 22.1 +/- 10.6. Postoperative ICU stay in Group S and Group C were 42.3 +/- 8.8 h and 64.4 +/- 15.9 h, respectively. CONCLUSION: IV sildenafil, when used perioperatively, in children with CHD having PHT undergoing corrective surgery, improves not only PaO 2 - FiO 2 ratio and PAP - AoP ratio but also reduces extubation time and postoperative ICU stay. PMID- 26440238 TI - Perioperative venous thromboembolic disease and the emerging role of the novel oral anticoagulants: an analysis of the implications for perioperative management. AB - Venous thromboembolism includes 2 inter-related conditions: Deep venous thrombosis and pulmonary embolism. Heparin and low-molecular-weight heparin followed by oral anticoagulation with vitamin K agonists is the first line and current accepted standard therapy with good efficacy. However, this therapeutic strategy has many limitations including the significant risk of bleeding and drug, food and disease interactions that require frequent monitoring. Dabigatran, rivaroxaban, apixaban, and edoxaban are the novel oral anticoagulants that are available for use in stroke prevention in atrial fibrillation and for the treatment and prevention of venous thromboembolism (HYPERLINK?l "1). Recent prospective randomized trials comparing the NOACs with warfarin have shown similar efficacy between the treatment strategies but fewer bleeding episodes with the NOACs. This paper presents an evidence-based review describing the efficacy and safety of the new anticoagulants compared to warfarin. PMID- 26440239 TI - Percutaneous and minimally invasive approaches to mitral valve repair for severe mitral regurgitation-new devices and emerging outcomes. AB - Mitral valve disease is common in the United States and around the world, and if left untreated, increases cardiovascular morbidity and mortality. Mitral valve repair is technically more demanding than mitral valve replacement. Mitral valve repair should be considered the first line of treatment for mitral regurgitation in younger patients, mitral valve prolapse, annular dilatation, and with structural damage to the valve. Several minimally invasive percutaneous treatment options for mitral valve repair are available that are not restricted to conventional surgical approaches, and may be better received by patients. A useful classification system of these approaches proposed by Chiam and Ruiz is based on anatomic targets and device action upon the leaflets, annulus, chordae, and left ventricle. Future directions of minimally invasive techniques will include improving the safety profile through patient selection and risk stratification, improvement of current imaging and techniques, and multidisciplinary education. PMID- 26440240 TI - Intraoperative aortic dissection. AB - Intraoperative aortic dissection is a rare but fatal complication of open heart surgery. By recognizing the population at risk and by using a gentle operative technique in such patients, the surgeon can usually avoid iatrogenic injury to the aorta. Intraoperative transesophageal echocardiography and epiaortic scanning are invaluable for prompt diagnosis and determination of the extent of the injury. Prevention lies in the strict control of blood pressure during cannulation/decannulation, construction of proximal anastomosis, or in avoiding manipulation of the aorta in high-risk patients. Immediate repair using interposition graft or Dacron patch graft is warranted to reduce the high mortality associated with this complication. PMID- 26440241 TI - Pharmacologic agents for acute hemodynamic instability: recent advances in the management of perioperative shock- a systematic review. AB - Despite the growing body of evidence evaluating the efficacy of vasoactive agents in the management of hemodynamic instability and circulatory shock, it appears no agent is superior. This is becoming increasingly accepted as current guidelines are moving away from detailed algorithms for the management of shock, and instead succinctly state that vasoactive agents should be individualized and guided by invasive hemodynamic monitoring. This extends to the perioperative period, where vasoactive agent selection and use may still be left to the discretion of the treating physician with a goal-directed approach, consisting of close hemodynamic monitoring and administration of the lowest effective dose to achieve the hemodynamic goals. Successful therapy depends on the ability to rapidly diagnose the etiology of circulatory shock and thoroughly understand its pathophysiology as well as the pharmacology of vasoactive agents. This review focuses on the physiology and resuscitation goals in perioperative shock, as well as the pharmacology and recent advances in vasoactive agent use in its management. PMID- 26440243 TI - Perioperative atrial fibrillation: a systematic review of evolving therapeutic options in pharmacologic and procedural management. AB - Given the high incidence of atrial fibrillation (AF) in the surgical population and the associated morbidity, physicians managing these complicated patients in the perioperative period need to be aware of the new and emerging trends in its therapy. The cornerstones of AF management have always been rate/rhythm control as well as anticoagulation. Restoration of sinus rhythm remains the fundamental philosophy as it maintains the atrial contribution to cardiac output and improves ventricular function. The recent years have seen a dramatic increase in the number of randomized AF trials that have made significant advances to our understanding of both pharmacologic and procedural management, from the introduction of the new generation of oral anticoagulants (NOAC's) to catheter approaches for AF ablation. This paper will summarize the newest data that will affect the perioperative management of these patients. PMID- 26440244 TI - Large left ventricular pseudoaneurysm and spontaneous recanalized coronaries. AB - 35 year old with ruptured lateral wall of Left ventricle (LV) resulting in large pseudo aneurysm contained within the pericardium [Figure 1]. There was free flow of blood between the LV and pseudoaneurysm .He underwent endoventricular patch plasty of the defect after opening the wall of aneurysm [Figure 2]. PMID- 26440245 TI - Capnothorax induced subclavian artery compression. PMID- 26440246 TI - Noninvasive removal of a knotted pulmonary artery catheter. PMID- 26440242 TI - Mechanisms of oxidative stress and myocardial protection during open-heart surgery. AB - Cold heart protection via cardioplegia administration, limits the amount of oxygen demand. Systemic normothermia with warm cardioplegia was introduced due to the abundance of detrimental effects of hypothermia. A temperature of 32-33 degrees C in combination with tepid blood cardioplegia of the same temperature appears to be protective enough for both; heart and brain. Reduction of nitric oxide (NO) concentration is in part responsible for myocardial injury after the cardioplegic cardiac arrest. Restoration of NO balance with exogenous NO supplementation has been shown useful to prevent inflammation and apoptosis. In this article, we discuss the "deleterious" effects of the oxidative stress of the extracorporeal circulation and the up-to-date theories of "ideal'' myocardial protection. PMID- 26440247 TI - Role of phenoxybenzamine in perioperative clinical practice. PMID- 26440248 TI - Echocardiographic detection of free-floating thrombus in left ventricle during coronary artery bypass grafting. AB - We report an incident of detection of a free-floating thrombus in the left ventricle (LV) using intraoperative two-dimensional (2D) and three-dimensional (3D) transesophageal echocardiography (TEE) during proximal coronary artery bypass graft anastomosis. A 58-year-old man presented to us with a 6-month history of chest pain without any history suggestive of myocardial infarction or transient ischemic attacks. His preoperative echocardiography revealed the systolic dysfunction of LV, mild hypokinesia of basal and mid-anterior wall, and the absence of an aneurysm. He was scheduled for on-pump coronary artery bypass surgery. On intraoperative TEE before establishing cardiopulmonary bypass (CPB), a small immobile mass was found attached to LV apical area. After completion of distal coronary artery grafting, when the aortic cross-clamp was removed, the heart was filled partially and beating spontaneously. TEE examination using 2D mode revealed a free-floating mass in the LV, which was suspected to be a thrombus. Additional navigation using biplane and 3D modes confirmed the presence of the thrombus and distinguished it from papillary muscles and artifact. The surgeon opened the left atrium after re-establishing electromechanical quiescence and removed a thrombus measuring 1.5 cm Chi 1 cm from the LV. The LV mass in the apical region was no longer seen after discontinuation of CPB. Accurate TEE detection and timely removal of the thrombus averted disastrous embolic complications. Intraoperative 2D and recent biplane and 3D echocardiography modes are useful monitoring tools during the conduct of CPB. PMID- 26440249 TI - Transvalvular mitral regurgitation following mitral valve replacement a diagnostic dilemma. AB - After mitral valve replacement with a prosthetic valve, the valve should be competent and there should not be any residual prosthetic valve regurgitation. Transvalvular residual prosthetic valve regurgitation are difficult to diagnose and quantify. we are reporting interesting TEE images as a diagnostic dilemma in a case of transvalvular mitral regurgitation following mitral valve replacement secondary to entrapment of sub-valvular apparatus in a Chitra mechanical heart valve. PMID- 26440250 TI - Which valve is which? AB - A 25-year-old man presented with a history of breathlessness for the past 2 years. He had a history of operation for Tetralogy of Fallot at the age of 5 years and history suggestive of Rheumatic fever at the age of 7 years. On echocardiographic examination, all his heart valves were severely regurgitating. Morphologically, all the valves were irreparable. The ejection fraction was 35%. He underwent quadruple valve replacement. The aortic and mitral valves were replaced by metallic valve and the tricuspid and pulmonary by tissue valve. PMID- 26440251 TI - Case report of fatal complication of superior vena cava tear from balloon dilatation of iatrogenic superior vena cava narrowing. AB - The treatment options for superior vena cava (SVC) obstruction depends on the cause and severity of SVC narrowing. It ranges from conservative medical management to more elaborate endovascular and surgical repair of obstruction. There has always been a concern regarding the possibility of rupture of SVC during balloon dilatation, if the obstruction is secondary to the surgical cause. Very few cases are reported in the literature. We report a case of fatal complication of SVC tear in a 2-month-old child who had iatrogenic SVC narrowing. PMID- 26440252 TI - Role of transesophageal echocardiography: a rare case of acute left atrial free wall dissection. AB - Transesophageal echocardiography (TEE) has been used routinely in the diagnosis and follow-up of cardiac cases. Left atrial dissection (LAd), an exceedingly rare complication of cardiac surgery, is most commonly associated with mitral valve surgery. A case of LAd is presented, and the pathology was accurately defined and immediately diagnosed using intraoperative TEE. This case highlights the importance of prompt diagnosis of LAd using intraoperative TEE, and a second cardiac surgery was avoided. PMID- 26440253 TI - Airway compromise during central venous cannulation in an undiagnosed tubercular retropharyngeal abscess: a case report. AB - Central venous cannulation is often associated with complications during insertion even by expert's hand and with the aid of ultrasound. We encountered a patient for central line insertion through the right internal jugular vein having a retropharyngeal abscess of tubercular origin. We accidentally punctured the abscess cavity leading to increased respiratory distress and subsequent need of intubation to the patient. This kind of complication during central line insertion has never been reported before. We intend to report such a case to alert everyone about the grave complications it can lead to and the methods to minimize them in the times ahead. PMID- 26440254 TI - Unusual cause of hypoxemia after automatic implantable cardioverter defibrillatorleads extraction. AB - The indication of pacemaker/AICD removal are numerous. Serious complication can occur during their removal, severe tricuspid regurgitation is one of the complication. The occurrence of PFO is not uncommon among adult population. Shunting across PFO in most circumstance is negligible, but in some necessitates closure due to hypoxemia. We report a case of 62 year old man, while undergoing AICD removal, had an emergency sternotomy for cardiac tamponade. Postoperatively, he experienced profound hypoxemia refractory to oxygen therapy. Transthoracic Echocardiogram was performed to rule out intracardiac shunts at an early stage, but it was difficult to obtain an good imaging windows poststernotomy. A small pulmonary emboli was noted on CTPA, but was not sufficient to account for the level of hypoxemia and did not resolve with anticoagulation. Transesophageal echocardiogram showed flail septal tricuspid valve with severe TR and bidirectional shunt through large PFO. Patient was posted for surgery, tricuspid valve was replaced and PFO surgically closed. Subsequently, patient recovered well ad was discharged to home. Cause of hypoxemia might be due to respiratory or cardiac dysfunction. But for hypoxemia refractory to oxygen therapy, transoesophageal echocardiogram should be always considered and performed early as an diagnostic tool in post cardiac surgical patients. PMID- 26440255 TI - Challenges of valve surgeries in post-renal transplant patients. AB - Renal transplantation remains a mainstay of therapy for the end-stage renal disease. Cardiac disease has a high prevalence in this patient population. Cardiovascular disease remains the leading cause of death among kidney transplantation patients. The cardiac disease accounts for 43% of all-cause mortality among dialysis patients and for ~38% of all-cause mortality after transplantation. In this article, we review the factors and outcomes associated with valve surgeries in renal transplant recipients and evaluate the strategy for open heart surgery after renal transplantation performed. PMID- 26440256 TI - Selective use of superficial temporal artery cannulation in infants undergoing cardiac surgery. AB - Arterial cannulation is routinely performed in children undergoing cardiac surgery to aid the intraoperative and intensive care management. Most commonly cannulated peripheral site in children is radial artery, and alternatives include posterior tibial, dorsalis pedis, and rarely superficial temporal artery (STA). Two specific situations in cardiac surgery where STA cannulation and monitoring was useful during the surgical procedure are reported. To our knowledge, such selective use of STA pressure monitoring has not been reported in the literature previously. Our experience suggests that STA monitoring can be useful and reliable during repair of coarctation of aorta or administration of anterograde cerebral perfusion in patients having associated aberrant origin of the right subclavian artery. PMID- 26440258 TI - An efficient algorithm for calculating the exact Hausdorff distance. AB - The Hausdorff distance (HD) between two point sets is a commonly used dissimilarity measure for comparing point sets and image segmentations. Especially when very large point sets are compared using the HD, for example when evaluating magnetic resonance volume segmentations, or when the underlying applications are based on time critical tasks, like motion detection, then the computational complexity of HD algorithms becomes an important issue. In this paper we propose a novel efficient algorithm for computing the exact Hausdorff distance. In a runtime analysis, the proposed algorithm is demonstrated to have nearly-linear complexity. Furthermore, it has efficient performance for large point set sizes as well as for large grid size; performs equally for sparse and dense point sets; and finally it is general without restrictions on the characteristics of the point set. The proposed algorithm is tested against the HD algorithm of the widely used national library of medicine insight segmentation and registration toolkit (ITK) using magnetic resonance volumes with extremely large size. The proposed algorithm outperforms the ITK HD algorithm both in speed and memory required. In an experiment using trajectories from a road network, the proposed algorithm significantly outperforms an HD algorithm based on R-Trees. PMID- 26440257 TI - Lipomatous hypertrophy of the interatrial septum and fibrosing mediastinal lymphadenopathy causing superior vena cava obstruction. AB - Lipomatous hypertrophy of the interatrial septum (LHIS) is an uncommon cause of superior vena cava syndrome (SVCS). Fibrosing mediastinal lymphadenopathy is another cause of SVCS. We present a 65-year-old female patient with a history of tuberculosis (TB) and the coexistence of LHIS and fibrosing mediastinitis due to TB of the lung. Fibrosing or sclerosing mediastinitis is a rare entity with few cases published in the western literature. She presented with mild symptomatology of SVCS and she underwent on transthoracic and transesophageal echocardiography, computed tomography scan, magnetic resonance imaging, and venography. Due to the development of an abundant collateral venous system seen on venography and her negation for any treatment, she did not undergo yet on any intervention. To our knowledge, this is the first case reported in the international bibliography in which LHIS and sclerosing lymphadenopathy are simultaneously diagnosed in the same patient. PMID- 26440259 TI - Difference subspace and its generalization for subspace-based methods. AB - Subspace-based methods are known to provide a practical solution for image set based object recognition. Based on the insight that local shape differences between objects offer a sensitive cue for recognition, this paper addresses the problem of extracting a subspace representing the difference components between class subspaces generated from each set of object images independently of each other. We first introduce the difference subspace (DS), a novel geometric concept between two subspaces as an extension of a difference vector between two vectors, and describe its effectiveness in analyzing shape differences. We then generalize it to the generalized difference subspace (GDS) for multi-class subspaces, and show the benefit of applying this to subspace and mutual subspace methods, in terms of recognition capability. Furthermore, we extend these methods to kernel DS (KDS) and kernel GDS (KGDS) by a nonlinear kernel mapping to deal with cases involving larger changes in viewing direction. In summary, the contributions of this paper are as follows: 1) a DS/KDS between two class subspaces characterizes shape differences between the two respectively corresponding objects, 2) the projection of an input vector onto a DS/KDS realizes selective visualization of shape differences between objects, and 3) the projection of an input vector or subspace onto a GDS/KGDS is extremely effective at extracting differences between multiple subspaces, and therefore improves object recognition performance. We demonstrate validity through shape analysis on synthetic and real images of 3D objects as well as extensive comparison of performance on classification tests with several related methods; we study the performance in face image classification on the Yale face database B+ and the CMU Multi-PIE database, and hand shape classification of multi-view images. PMID- 26440260 TI - Fusion of range and stereo data for high-resolution scene-modeling. AB - This paper addresses the problem of range-stereo fusion, for the construction of high-resolution depth maps. In particular, we combine low-resolution depth data with high-resolution stereo data, in a maximum a posteriori (MAP) formulation. Unlike existing schemes that build on MRF optimizers, we infer the disparity map from a series of local energy minimization problems that are solved hierarchically, by growing sparse initial disparities obtained from the depth data. The accuracy of the method is not compromised, owing to three properties of the data-term in the energy function. First, it incorporates a new correlation function that is capable of providing refined correlations and disparities, via subpixel correction. Second, the correlation scores rely on an adaptive cost aggregation step, based on the depth data. Third, the stereo and depth likelihoods are adaptively fused, based on the scene texture and camera geometry. These properties lead to a more selective growing process which, unlike previous seed-growing methods, avoids the tendency to propagate incorrect disparities. The proposed method gives rise to an intrinsically efficient algorithm, which runs at 3FPS on 2.0 MP images on a standard desktop computer. The strong performance of the new method is established both by quantitative comparisons with state-of-the art methods, and by qualitative comparisons using real depth-stereo data-sets. PMID- 26440261 TI - Geometric change detection in urban environments using images. AB - We propose a method to detect changes in the geometry of a city using panoramic images captured by a car driving around the city. The proposed method can be used to significantly optimize the process of updating the 3D model of an urban environment that is changing over time, by restricting this process to only those areas where changes are detected. With this application in mind, we designed our algorithm to specifically detect only structural changes in the environment, ignoring any changes in its appearance, and ignoring also all the changes which are not relevant for update purposes such as cars, people etc. The approach also accounts for the challenges involved in a large scale application of change detection, such as inaccuracies in the input geometry, errors in the geo-location data of the images as well as the limited amount of information due to sparse imagery. We evaluated our approach on a small scale setup using high resolution, densely captured images and a large scale setup covering an entire city using instead the more realistic scenario of low resolution, sparsely captured images. A quantitative evaluation was also conducted for the large scale setup consisting of 14,000 images. PMID- 26440262 TI - Laplacian scale-space behavior of planar curve corners. AB - Scale-space behavior of corners is important for developing an efficient corner detection algorithm. In this paper, we analyze the scale-space behavior with the Laplacian of Gaussian (LoG) operator on a planar curve which constructs Laplacian Scale Space (LSS). The analytical expression of a Laplacian Scale-Space map (LSS map) is obtained, demonstrating the Laplacian Scale-Space behavior of the planar curve corners, based on a newly defined unified corner model. With this formula, some Laplacian Scale-Space behavior is summarized. Although LSS demonstrates some similarities to Curvature Scale Space (CSS), there are still some differences. First, no new extreme points are generated in the LSS. Second, the behavior of different cases of a corner model is consistent and simple. This makes it easy to trace the corner in a scale space. At last, the behavior of LSS is verified in an experiment on a digital curve. PMID- 26440263 TI - Learning shared, discriminative, and compact representations for visual recognition. AB - Dictionary-based and part-based methods are among the most popular approaches to visual recognition. In both methods, a mid-level representation is built on top of low-level image descriptors and high-level classifiers are trained on top of the mid-level representation. While earlier methods built the mid-level representation without supervision, there is currently great interest in learning both representations jointly to make the mid-level representation more discriminative. In this work we propose a new approach to visual recognition that jointly learns a shared, discriminative, and compact mid-level representation and a compact high-level representation. By using a structured output learning framework, our approach directly handles the multiclass case at both levels of abstraction. Moreover, by using a group-sparse prior in the structured output learning framework, our approach encourages sharing of visual words and thus reduces the number of words used to represent each class. We test our proposed method on several popular benchmarks. Our results show that, by jointly learning mid- and high-level representations, and fostering the sharing of discriminative visual words among target classes, we are able to achieve state-of-the-art recognition performance using far less visual words than previous approaches. PMID- 26440264 TI - Multi-view and 3D deformable part models. AB - As objects are inherently 3D, they have been modeled in 3D in the early days of computer vision. Due to the ambiguities arising from mapping 2D features to 3D models, 3D object representations have been neglected and 2D feature-based models are the predominant paradigm in object detection nowadays. While such models have achieved outstanding bounding box detection performance, they come with limited expressiveness, as they are clearly limited in their capability of reasoning about 3D shape or viewpoints. In this work, we bring the worlds of 3D and 2D object representations closer, by building an object detector which leverages the expressive power of 3D object representations while at the same time can be robustly matched to image evidence. To that end, we gradually extend the successful deformable part model [1] to include viewpoint information and part level 3D geometry information, resulting in several different models with different level of expressiveness. We end up with a 3D object model, consisting of multiple object parts represented in 3D and a continuous appearance model. We experimentally verify that our models, while providing richer object hypotheses than the 2D object models, provide consistently better joint object localization and viewpoint estimation than the state-of-the-art multi-view and 3D object detectors on various benchmarks (KITTI [2] , 3D object classes [3] , Pascal3D+ [4] , Pascal VOC 2007 [5] , EPFL multi-view cars[6] ). PMID- 26440266 TI - Probabilistic ToF and stereo data fusion based on mixed pixels measurement models. AB - This paper proposes a method for fusing data acquired by a ToF camera and a stereo pair based on a model for depth measurement by ToF cameras which accounts also for depth discontinuity artifacts due to the mixed pixel effect. Such model is exploited within both a ML and a MAP-MRF frameworks for ToF and stereo data fusion. The proposed MAP-MRF framework is characterized by site-dependent range values, a rather important feature since it can be used both to improve the accuracy and to decrease the computational complexity of standard MAP-MRF approaches. This paper, in order to optimize the site dependent global cost function characteristic of the proposed MAP-MRF approach, also introduces an extension to Loopy Belief Propagation which can be used in other contexts. Experimental data validate the proposed ToF measurements model and the effectiveness of the proposed fusion techniques. PMID- 26440265 TI - Optimal mass transport for shape matching and comparison. AB - Surface based 3D shape analysis plays a fundamental role in computer vision and medical imaging. This work proposes to use optimal mass transport map for shape matching and comparison, focusing on two important applications including surface registration and shape space. The computation of the optimal mass transport map is based on Monge-Brenier theory, in comparison to the conventional method based on Monge-Kantorovich theory, this method significantly improves the efficiency by reducing computational complexity from O(n(2)) to O(n) . For surface registration problem, one commonly used approach is to use conformal map to convert the shapes into some canonical space. Although conformal mappings have small angle distortions, they may introduce large area distortions which are likely to cause numerical instability thus resulting failures of shape analysis. This work proposes to compose the conformal map with the optimal mass transport map to get the unique area-preserving map, which is intrinsic to the Riemannian metric, unique, and diffeomorphic. For shape space study, this work introduces a novel Riemannian framework, Conformal Wasserstein Shape Space, by combing conformal geometry and optimal mass transport theory. In our work, all metric surfaces with the disk topology are mapped to the unit planar disk by a conformal mapping, which pushes the area element on the surface to a probability measure on the disk. The optimal mass transport provides a map from the shape space of all topological disks with metrics to the Wasserstein space of the disk and the pullback Wasserstein metric equips the shape space with a Riemannian metric. We validate our work by numerous experiments and comparisons with prior approaches and the experimental results demonstrate the efficiency and efficacy of our proposed approach. PMID- 26440267 TI - Robust estimation of unbalanced mixture models on samples with outliers. AB - Mixture models are often used to compactly represent samples from heterogeneous sources. However, in real world, the samples generally contain an unknown fraction of outliers and the sources generate different or unbalanced numbers of observations. Such unbalanced and contaminated samples may, for instance, be obtained by high density data sensors such as imaging devices. Estimation of unbalanced mixture models from samples with outliers requires robust estimation methods. In this paper, we propose a novel robust mixture estimator incorporating trimming of the outliers based on component-wise confidence level ordering of observations. The proposed method is validated and compared to the state-of-the art FAST-TLE method on two data sets, one consisting of synthetic samples with a varying fraction of outliers and a varying balance between mixture weights, while the other data set contained structural magnetic resonance images of the brain with tumors of varying volumes. The results on both data sets clearly indicate that the proposed method is capable to robustly estimate unbalanced mixtures over a broad range of outlier fractions. As such, it is applicable to real-world samples, in which the outlier fraction cannot be estimated in advance. PMID- 26440268 TI - Semi-automatic segmentation of prostate in CT images via coupled feature representation and spatial-constrained transductive lasso. AB - Conventional learning-based methods for segmenting prostate in CT images ignore the relations among the low-level features by assuming all these features are independent. Also, their feature selection steps usually neglect the image appearance changes in different local regions of CT images. To this end, we present a novel semi-automatic learning-based prostate segmentation method in this article. For segmenting the prostate in a certain treatment image, the radiation oncologist will be first asked to take a few seconds to manually specify the first and last slices of the prostate. Then, prostate is segmented with the following two steps: (i) Estimation of 3D prostate-likelihood map to predict the likelihood of each voxel being prostate by employing the coupled feature representation, and the proposed Spatial-COnstrained Transductive LassO (SCOTO); (ii) Multi-atlases based label fusion to generate the final segmentation result by using the prostate shape information obtained from both planning and previous treatment images. The major contribution of the proposed method mainly includes: (i) incorporating radiation oncologist's manual specification to aid segmentation, (ii) adopting coupled features to relax previous assumption of feature independency for voxel representation, and (iii) developing SCOTO for joint feature selection across different local regions. The experimental result shows that the proposed method outperforms the state-of-the-art methods in a real world prostate CT dataset, consisting of 24 patients with totally 330 images, all of which were manually delineated by the radiation oncologist for performance evaluation. Moreover, our method is also clinically feasible, since the segmentation performance can be improved by just requiring the radiation oncologist to spend only a few seconds for manual specification of ending slices in the current treatment CT image. PMID- 26440269 TI - Spherical hashing: binary code embedding with hyperspheres. AB - Many binary code embedding schemes have been actively studied recently, since they can provide efficient similarity search, and compact data representations suitable for handling large scale image databases. Existing binary code embedding techniques encode high-dimensional data by using hyperplane-based hashing functions. In this paper we propose a novel hypersphere-based hashing function, spherical hashing, to map more spatially coherent data points into a binary code compared to hyperplane-based hashing functions. We also propose a new binary code distance function, spherical Hamming distance, tailored for our hypersphere-based binary coding scheme, and design an efficient iterative optimization process to achieve both balanced partitioning for each hash function and independence between hashing functions. Furthermore, we generalize spherical hashing to support various similarity measures defined by kernel functions. Our extensive experiments show that our spherical hashing technique significantly outperforms state-of-the-art techniques based on hyperplanes across various benchmarks with sizes ranging from one to 75 million of GIST, BoW and VLAD descriptors. The performance gains are consistent and large, up to 100 percent improvements over the second best method among tested methods. These results confirm the unique merits of using hyperspheres to encode proximity regions in high-dimensional spaces. Finally, our method is intuitive and easy to implement. PMID- 26440270 TI - Supervised hashing using graph cuts and boosted decision trees. AB - To build large-scale query-by-example image retrieval systems, embedding image features into a binary Hamming space provides great benefits. Supervised hashing aims to map the original features to compact binary codes that are able to preserve label based similarity in the binary Hamming space. Most existing approaches apply a single form of hash function, and an optimization process which is typically deeply coupled to this specific form. This tight coupling restricts the flexibility of those methods, and can result in complex optimization problems that are difficult to solve. In this work we proffer a flexible yet simple framework that is able to accommodate different types of loss functions and hash functions. The proposed framework allows a number of existing approaches to hashing to be placed in context, and simplifies the development of new problem-specific hashing methods. Our framework decomposes the hashing learning problem into two steps: binary code (hash bit) learning and hash function learning. The first step can typically be formulated as binary quadratic problems, and the second step can be accomplished by training a standard binary classifier. For solving large-scale binary code inference, we show how it is possible to ensure that the binary quadratic problems are submodular such that efficient graph cut methods may be used. To achieve efficiency as well as efficacy on large-scale high-dimensional data, we propose to use boosted decision trees as the hash functions, which are nonlinear, highly descriptive, and are very fast to train and evaluate. Experiments demonstrate that the proposed method significantly outperforms most state-of-the-art methods, especially on high dimensional data. PMID- 26440271 TI - Transductive multi-view zero-shot learning. AB - Most existing zero-shot learning approaches exploit transfer learning via an intermediate semantic representation shared between an annotated auxiliary dataset and a target dataset with different classes and no annotation. A projection from a low-level feature space to the semantic representation space is learned from the auxiliary dataset and applied without adaptation to the target dataset. In this paper we identify two inherent limitations with these approaches. First, due to having disjoint and potentially unrelated classes, the projection functions learned from the auxiliary dataset/domain are biased when applied directly to the target dataset/domain. We call this problem the projection domain shift problem and propose a novel framework, transductive multi view embedding, to solve it. The second limitation is the prototype sparsity problem which refers to the fact that for each target class, only a single prototype is available for zero-shot learning given a semantic representation. To overcome this problem, a novel heterogeneous multi-view hypergraph label propagation method is formulated for zero-shot learning in the transductive embedding space. It effectively exploits the complementary information offered by different semantic representations and takes advantage of the manifold structures of multiple representation spaces in a coherent manner. We demonstrate through extensive experiments that the proposed approach (1) rectifies the projection shift between the auxiliary and target domains, (2) exploits the complementarity of multiple semantic representations, (3) significantly outperforms existing methods for both zero-shot and N-shot recognition on three image and video benchmark datasets, and (4) enables novel cross-view annotation tasks. PMID- 26440272 TI - Visual place recognition with repetitive structures. AB - Repeated structures such as building facades, fences or road markings often represent a significant challenge for place recognition. Repeated structures are notoriously hard for establishing correspondences using multi-view geometry. They violate the feature independence assumed in the bag-of-visual-words representation which often leads to over-counting evidence and significant degradation of retrieval performance. In this work we show that repeated structures are not a nuisance but, when appropriately represented, they form an important distinguishing feature for many places. We describe a representation of repeated structures suitable for scalable retrieval and geometric verification. The retrieval is based on robust detection of repeated image structures and a suitable modification of weights in the bag-of-visual-word model. We also demonstrate that the explicit detection of repeated patterns is beneficial for robust visual word matching for geometric verification. Place recognition results are shown on datasets of street-level imagery from Pittsburgh and San Francisco demonstrating significant gains in recognition performance compared to the standard bag-of-visual-words baseline as well as the more recently proposed burstiness weighting and Fisher vector encoding. PMID- 26440273 TI - Acidic phospholipids govern the enhanced activation of IgG-B cell receptor. AB - B cells that express the isotype-switched IgG-B cell receptor (IgG-BCR) are one of the driving forces for antibody memory. To allow for a rapid memory IgG antibody response, IgG-BCR evolved into a highly effective signalling machine. Here, we report that the positively charged cytoplasmic domain of mIgG (mIgG tail) specifically interacts with negatively charged acidic phospholipids. The key immunoglobulin tail tyrosine (ITT) in mIgG-tail is thus sequestered in the membrane hydrophobic core in quiescent B cells. Pre-disruption of such interaction leads to excessive recruitment of BCRs and inflated BCR signalling upon antigen stimulation, resulting in hyperproliferation of primary B cells. Physiologically, membrane-sequestered mIgG-tail can be released by antigen engagement or Ca(2+) mobilization in the initiation of B cell activation. Our studies suggest a novel regulatory mechanism for how dynamic association of mIgG tail with acidic phospholipids governs the enhanced activation of IgG-BCR. PMID- 26440274 TI - [Glomerulonephritides]. AB - Many forms of glomerulonephritis, even the more common types belong to the so called rare diseases; however, they are very important, for example with respect to health economics as they often affect young people. An example is immunoglobulin A (IgA) nephropathy, which is the most common cause of end stage renal disease in young adults. This review summarizes the current knowledge on the pathogenesis, clinical presentation and therapy of the most common European types of glomerulonephritis with a special focus on the most recently acquired knowledge on IgA nephropathy, membranous glomerulonephritis, minimal change nephropathy and focal segmental glomerulosclerosis (FSGS). PMID- 26440275 TI - Correction: Observational study assessing demographic, economic and clinical factors associated with access and utilization of health care services of patients with multiple sclerosis under treatment with interferon beta-1b (EXTAVIA). PMID- 26440277 TI - Maintenance Therapy Improves Survival Outcomes in Patients with Advanced Non small Cell Lung Cancer. PMID- 26440276 TI - Brain Function and Upper Limb Outcome in Stroke: A Cross-Sectional fMRI Study. AB - OBJECTIVE: The nature of changes in brain activation related to good recovery of arm function after stroke is still unclear. While the notion that this is a reflection of neuronal plasticity has gained much support, confounding by compensatory strategies cannot be ruled out. We address this issue by comparing brain activity in recovered patients 6 months after stroke with healthy controls. METHODS: We included 20 patients with upper limb paresis due to ischemic stroke and 15 controls. We measured brain activation during a finger flexion-extension task with functional MRI, and the relationship between brain activation and hand function. Patients exhibited various levels of recovery, but all were able to perform the task. RESULTS: Comparison between patients and controls with voxel wise whole-brain analysis failed to reveal significant differences in brain activation. Equally, a region of interest analysis constrained to the motor network to optimize statistical power, failed to yield any differences. Finally, no significant relationship between brain activation and hand function was found in patients. Patients and controls performed scanner task equally well. CONCLUSION: Brain activation and behavioral performance during finger flexion extensions in (moderately) well recovered patients seems normal. The absence of significant differences in brain activity even in patients with a residual impairment may suggest that infarcts do not necessarily induce reorganization of motor function. While brain activity could be abnormal with higher task demands, this may also introduce performance confounds. It is thus still uncertain to what extent capacity for true neuronal repair after stroke exists. PMID- 26440278 TI - Regulation of Connective Tissue Growth Factor and Cardiac Fibrosis by an SRF/MicroRNA-133a Axis. AB - Myocardial fibrosis contributes to the remodeling of heart and the loss of cardiac function leading to heart failure. SRF is a transcription factor implicated in the regulation of a large variety of genes involved in cardiac structure and function. To investigate the impact of an SRF overexpression in heart, we developed a new cardiac-specific and tamoxifen-inducible SRF overexpression mouse model by the Cre/loxP strategy. Here, we report that a high level overexpression of SRF leads to severe modifications of cardiac cytoarchitecture affecting the balance between cardiomyocytes and cardiac fibroblasts and also a profound alteration of cardiac gene expression program. The drastic development of fibrosis was characterized by intense sirius red staining and associated with an increased expression of genes encoding extracellular matrix proteins such as fibronectin, procollagen type 1alpha1 and type 3alpha1 and especially connective tissue growth factor (CTGF). Furthermore miR-133a, one of the most predominant cardiac miRNAs, is strongly downregulated when SRF is overexpressed. By comparison a low level overexpression of SRF has minor impact on these different processes. Investigation with miR-133a, antimiR 133a and AdSRF-VP16 experiments in H9c2 cardiac cells demonstrated that: 1)-miR 133a acts as a repressor of SRF and CTGF expression; 2)-a simultaneous overexpression of SRF by AdSRF-VP16 and inhibition of miR-133a by a specific antimiR increase CTGF expression; 3)-miR-133a overexpression can block the upregulation of CTGF induced by AdSRF-VP16. Taken together, these findings reveal a key role of the SRF/CTGF/miR-133a axis in the regulation of cardiac fibrosis. PMID- 26440279 TI - Severe Sepsis in Severely Malnourished Young Bangladeshi Children with Pneumonia: A Retrospective Case Control Study. AB - BACKGROUND: In developing countries, there is no published report on predicting factors of severe sepsis in severely acute malnourished (SAM) children having pneumonia and impact of fluid resuscitation in such children. Thus, we aimed to identify predicting factors for severe sepsis and assess the outcome of fluid resuscitation of such children. METHODS: In this retrospective case-control study SAM children aged 0-59 months, admitted to the Intensive Care Unit (ICU) of the Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh from April 2011 through July 2012 with history of cough or difficult breathing and radiologic pneumonia, who were assessed for severe sepsis at admission constituted the study population. We compared the pneumonic SAM children with severe sepsis (cases = 50) with those without severe sepsis (controls = 354). Severe sepsis was defined with objective clinical criteria and managed with fluid resuscitation, in addition to antibiotic and other supportive therapy, following the standard hospital guideline, which is very similar to the WHO guideline. RESULTS: The case-fatality-rate was significantly higher among the cases than the controls (40% vs. 4%; p<0.001). In logistic regression analysis after adjusting for potential confounders, lack of BCG vaccination, drowsiness, abdominal distension, acute kidney injury, and metabolic acidosis at admission remained as independent predicting factors for severe sepsis in pneumonic SAM children (p<0.05 for all comparisons). CONCLUSION AND SIGNIFICANCE: We noted a much higher case fatality among under-five SAM children with pneumonia and severe sepsis who required fluid resuscitation in addition to standard antibiotic and other supportive therapy compared to those without severe sepsis. Independent risk factors and outcome of the management of severe sepsis in our study children highlight the importance for defining optimal fluid resuscitation therapy aiming at reducing the case fatality in such children. PMID- 26440280 TI - Wistar audiogenic rats display abnormal behavioral traits associated with artificial selection for seizure susceptibility. AB - Accumulating evidence from different animal models has contributed to the understanding of the bidirectional comorbidity associations between the epileptic condition and behavioral abnormalities. A strain of animals inbred to enhance seizure predisposition to high-intensity sound stimulation, the Wistar audiogenic rat (WAR), underwent several behavioral tests: forced swim test (FST), open-field test (OFT), sucrose preference test (SPT), elevated plus maze (EPM), social preference (SP), marble burying test (MBT), inhibitory avoidance (IAT), and two way active avoidance (TWAA). The choice of tests aimed to investigate the correlation between underlying circuits believed to be participating in both WAR's innate susceptibility to sound-triggered seizures and the neurobiological substrates associated with test performance. Comparing WAR with its Wistar counterpart (i.e., resistant to audiogenic seizures) showed that WARs present behavioral despair traits (e.g., increased FST immobility) but no evidence of anhedonic behavior (e.g., increased sucrose consumption in SPT) or social impairment (e.g., no difference regarding juvenile exploration in SP). In addition, tests suggested that WARs are unable to properly evaluate degrees of aversiveness (e.g., performance on OFT, EPM, MBT, IAT, and TWAA). The particularities of the WAR model opens new venues to further untangle the neurobiology underlying the co-morbidity of behavioral disorders and epilepsy. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic". PMID- 26440281 TI - A Novel Method of Automatic Plant Species Identification Using Sparse Representation of Leaf Tooth Features. AB - Automatic species identification has many advantages over traditional species identification. Currently, most plant automatic identification methods focus on the features of leaf shape, venation and texture, which are promising for the identification of some plant species. However, leaf tooth, a feature commonly used in traditional species identification, is ignored. In this paper, a novel automatic species identification method using sparse representation of leaf tooth features is proposed. In this method, image corners are detected first, and the abnormal image corner is removed by the PauTa criteria. Next, the top and bottom leaf tooth edges are discriminated to effectively correspond to the extracted image corners; then, four leaf tooth features (Leaf-num, Leaf-rate, Leaf sharpness and Leaf-obliqueness) are extracted and concatenated into a feature vector. Finally, a sparse representation-based classifier is used to identify a plant species sample. Tests on a real-world leaf image dataset show that our proposed method is feasible for species identification. PMID- 26440282 TI - AMPK Protects Leukemia-Initiating Cells in Myeloid Leukemias from Metabolic Stress in the Bone Marrow. AB - How cancer cells adapt to metabolically adverse conditions in patients and strive to proliferate is a fundamental question in cancer biology. Here we show that AMP activated protein kinase (AMPK), a metabolic checkpoint kinase, confers metabolic stress resistance to leukemia-initiating cells (LICs) and promotes leukemogenesis. Upon dietary restriction, MLL-AF9-induced murine acute myeloid leukemia (AML) activated AMPK and maintained leukemogenic potential. AMPK deletion significantly delayed leukemogenesis and depleted LICs by reducing the expression of glucose transporter 1 (Glut1), compromising glucose flux, and increasing oxidative stress and DNA damage. LICs were particularly dependent on AMPK to suppress oxidative stress in the hypoglycemic bone marrow environment. Strikingly, AMPK inhibition synergized with physiological metabolic stress caused by dietary restriction and profoundly suppressed leukemogenesis. Our results indicate that AMPK protects LICs from metabolic stress and that combining AMPK inhibition with physiological metabolic stress potently suppresses AML by inducing oxidative stress and DNA damage. PMID- 26440283 TI - Mycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds. AB - Tuberculosis (TB) remains a worldwide problem and the need for new drugs is increasingly more urgent with the emergence of multidrug- and extensively-drug resistant TB. Inosine 5'-monophosphate dehydrogenase 2 (IMPDH2) from Mycobacterium tuberculosis (Mtb) is an attractive drug target. The enzyme catalyzes the conversion of inosine 5'-monophosphate into xanthosine 5' monophosphate with the concomitant reduction of NAD+ to NADH. This reaction controls flux into the guanine nucleotide pool. We report seventeen selective IMPDH inhibitors with antitubercular activity. The crystal structures of a deletion mutant of MtbIMPDH2 in the apo form and in complex with the product XMP and substrate NAD+ are determined. We also report the structures of complexes with IMP and three structurally distinct inhibitors, including two with antitubercular activity. These structures will greatly facilitate the development of MtbIMPDH2-targeted antibiotics. PMID- 26440284 TI - Lipoteichoic acid modulates inflammatory response in macrophages after phagocytosis of titanium particles through Toll-like receptor 2 cascade and inflammasomes. AB - Toll-like receptor 2 (TLR2) and nucleotide-binding and oligomerization domain like receptors with a pyrin domain 3 (NLRP3) inflammasomes have been presumed to participate in the pathogenesis of aseptic implant loosening. The aim of this study is to analyze the cellular localization of TLR2 and NLRP3 inflammasomes in the periprosthetic tissue from aseptically loose hip implants as well as the expression of these molecules in macrophages stimulated in vitro with titanium particles (Ti) coated with lipoteichoic acid (LTA). Using immunohistochemistry, immunoreactivity of TLR2 and NLRP3 inflammasomes was found in macrophages within the foreign body granulomatosis. Using RAW264.7 cells, stimulation with Ti increased the messenger RNA (mRNA) levels of TLR2 and TNF-alpha. Stimulation with LTA-coated Ti enhanced mRNA levels of NLRP3 and IL-1beta, whereas reinforced secretion of IL-1beta was not detected in spite of marked release of TNF-alpha. Finally, the same cells with silenced Irak2, an adaptor protein in the TLR2 cascade, suppressed this NLRP3 upregulation. This study suggests that TLR2 and NLRP3 inflammasomes are factors involved in cross-talk mediating the foreign body type response to wear particles. In addition, discrepant behavior in the release between TNF-alpha and IL-1beta release may explain the variable pathomechanisms of aseptic implant loosening without acute inflammatory reactions. PMID- 26440285 TI - Rapid chiral separation of racemic cetirizine in human plasma using subcritical fluid chromatography-tandem mass spectrometry. AB - A method for fast chiral separation of cetirizine and quantitation of levocetirizine in human plasma using subcritical fluid chromatography with tandem mass spectrometry was developed and validated. The chromatographic separation was performed using a Chiralpak IE column (2.1 mm*150 mm, 5 MUm) with an isocratic elution of CO2/organic modifier (55/45, v/v) at a flow rate of 0.85 mL/min. The organic modifier was composed of water/methanol (5/95, v/v). The makeup flow was optimized at water/methanol (10/90, v/v) and 0.2 mL/min. The most influential parameters on the separation of cetirizine affecting resolution, retention time and sensitivity were selected by fractional factorial design. The 3 selected factors were optimized by response surface methodology. Tandem mass spectrometry was used at electrospray ionization, positive ion mode, and multiple-reaction monitoring mode. Isotope-labeled cetirizine-d4 was used as the internal standard. The sample preparation of human plasma was conducted by solid phase extraction of hydrophilic-lipophilic balance (HLB) type. The developed method was validated for selectivity, linearity, precision, accuracy, recovery, limit of quantitation (LOQ), and limit of detection (LOD). The real human plasma samples were analyzed and the pharmacokinetic results were compared with results of previous research. The developed method was found to be reliable based on the similarity between the results of the current and previous methods. The chiral separation for cetirizine and economic feasibility were compared with those of previous studies using normal phase-HPLC or reversed phase-HPLC. The established analytical method could be successfully applied to pharmacokinetic study with reduction in the analysis time and costs. PMID- 26440286 TI - A novel LC-MS/MS assay for the simultaneous determination of melatonin and its two major metabolites, 6-hydroxymelatonin and 6-sulfatoxymelatonin in dog plasma: Application to a pharmacokinetic study. AB - A convenient and specific liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of melatonin (MEL) and its major metabolites, 6-hydroxymelatonin (6-O-MEL) and 6 sulfatoxymelationin (S-O-MEL) in dog plasma. After plasma samples were deproteinized with acetonitrile, the post-treatment samples were analyzed on a Phenomenex Kinetex C18 column (50*2.1 mm, 1.7 MUm) interfaced with a triple quadrupole tandem mass spectrometer. Electrospray ionization mode (ESI) and multiple reaction monitoring were used to assay MEL and its metabolites. Acetonitrile and 5 mM ammonium acetate were used as the mobile phase with a gradient elution at a flow rate of 0.2 mL/min. The analytical run time of 6.5 min was divided into two periods according to ionization mode. S-O-MEL was monitored in negative ionization mode (period 1), while MEL and 6-O-MEL were detected in positive ionization mode (period 2). All calibration curves showed good linearity (r>0.991) over the concentration range with a lower limit of quantification (LLOQ) of 0.02 ng/mL for MEL, 0.04 ng/mL for 6-O-MEL and 0.50 ng/mL for S-O-MEL. The intra- and inter-day precision was within 13.5% in terms of relative standard deviation (RSD%) and the accuracy within 13.0% in terms of relative error. This convenient and specific LC-MS/MS method was successfully applied to the pharmacokinetic study of MEL and its metabolites in Beagle dogs after an oral dose of 2.0mg MEL. After ingestion of MEL, S-O-MEL was the predominant component circulating in blood. 6-O-MEL showed similar pharmacokinetic profile to that of MEL. PMID- 26440287 TI - Chiral separation of asenapine enantiomers by capillary electrophoresis and characterization of cyclodextrin complexes by NMR spectroscopy, mass spectrometry and molecular modeling. AB - The enantiomers of asenapine maleate (ASN), a novel antipsychotic against schizophrenia and mania with bipolar I disorder have been separated by cyclodextrin (CD) modified capillary zone electrophoresis for the first time. 15 different CDs were screened as complexing agents and chiral selectors, investigating the stability of the inclusion complexes and their enantiodiscriminating capacities. Although initially, none of the applied chiral selectors gave baseline separation, beta-CD proved to be the most effective chiral selector. In order to improve resolution, an orthogonal experimental design was employed, altering the concentration of background electrolyte, organic modifier, pH, capillary temperature and applied voltage in a multivariate manner. The developed method (160 mM TRIS-acetate buffer pH 3.5, 7 mM beta-CD, at 20 degrees C, applying 15 kV) was successful for baseline separation of ASN enantiomers (R(s)=2.40+/-0.04). Our method was validated according to ICH guidelines and proved to be sensitive, linear, accurate and precise for the chiral separation of ASN. Properties of the inclusion complexes, such as stoichiometry, atomic level intermolecular host-guest connections are proposed on the basis of ROESY NMR measurement, ESI-MS spectrometry and molecular modeling studies. It was found that the ASN-beta-CD complex is of 1:1 composition, and either of the aromatic rings can be accommodated in the beta-CD cavity. PMID- 26440289 TI - Police Officers' Attitudes and Challenges With Charging Stalking. AB - This study examined 2 groups of police officers on perceived barriers and attitudes related to charging stalking. Police officers who categorized into groups based on if they had (n=73) or had not (n=90) previously charged stalking. Results indicated that officers who had never charged stalking viewed stalking as less dangerous, believed that officers do not file reports when called for stalking, and perceived all barriers related to charging stalking as more challenging than officers who had previously charged stalking. Officers who charged stalking had greater comprehension of the stalking statute and identified specific problems within the statute. The results have implications related to improving specialized police training in an effort to better protect victims of stalking and increase stalking charges. PMID- 26440288 TI - Preclinical pharmacokinetic evaluation of praziquantel loaded in poly (methyl methacrylate) nanoparticle using a HPLC-MS/MS. AB - Praziquantel (PZQ) is the drug recommended by the World Health Organization for treatment of schistosomiasis. However, the treatment of children with PZQ tablets is complicated due to difficulties to adapt the dose and the extremely bitter taste of PZQ. For this reason, poly (methyl methacrylate) nanoparticles loaded with Praziquantel (PZQ-NP) were developed for preparation of a new formulation to be used in the suspension form. For this reason, the main aim of the present study was to evaluate the pharmacokinetic (PK) profile of PZQ-NP, through HPLC MS/MS assays. Analyses were performed with an Omnisphere C18 column (5.0 MUm*4.6 mm*150.0 mm), using a mixture of an aqueous solution containing 0.1 wt% of formic acid and methanol (15:85-v/v) as the mobile phase at a flow rate of 0.800mL/min. Detection was performed with a hybrid linear ion-trap triple quadrupole mass spectrometer with multiple reactions monitoring in positive ion mode via electrospray ionization. The monitored transitions were m/z 313.18>203.10 for PZQ and m/z 285.31>193.00 for the Internal Standard. The method was validated with the quantification limit of 1.00 ng/mL, requiring samples of 25 MUL for analyses. Analytic responses were calibrated with known concentration data, leading to correlation coefficients (r) higher than 0.99. Validation performed with rat plasma showed that PZQ was stable for at least 10 months when stored below -70 degrees C (long-term stability), for at least 17 h when stored at room temperature (RT, 22 degrees C) (short-term stability), for at least 47 h when stored at room temperature in auto-sampler vials (post-preparative stability) and for at least 8 successive freeze/thaw cycles at -70 degrees C. For PK assays, Wistar rats, weighing between 200 and 300 g were used. Blood samples were collected from 0 to 24 h after oral administration of single doses of 60 mg/kg of PZQ-NP or raw PZQ (for the control group). PZQ was extracted from plasma by liquid-liquid extraction with terc-butyl methyl ether. The values obtained for maximum concentration (C(max)) and area under curve (AUC) for the PZQ-NP group were about 3 times smaller than the respective values obtained for the control group. However, the time for achieving maximum concentration (T(max)), the elimination constant (Ke) and the half-life time of elimination (T(1/2beta)) were not statistically different. These results suggest that PZQ absorption is probably the rate-limiting step for obtainment of better PK parameters for PZQ NP. Thus, further studies are needed to understand both the PZQ-NP absorption mechanisms and the drug diffusion process through the polymer matrix in vivo, in order to improve the PZQ-NP release profile. PMID- 26440290 TI - Synchrotron radiation based X-ray fluorescence shows changes in the elemental composition of the human substantia nigra in aged brains. AB - Human brain aging is considered to be the leading risk factor for a variety of neurodegenerative alterations. In particular, it is thought that the human substantia nigra might play a pivotal role in age-associated dopamine depletion which could be responsible for neuronal demise and subsequent emergence of different neurological alterations. A plethora of neurochemical redox- and non redox-driven mechanisms is mainly associated with modifications in the elemental composition of both neuromelanin-pigmented neurons and extraneuronal spaces in the human substantia nigra pars compacta (SNpc). An age-associated variation in the content of Fe, Cu, Zn and Ca has recently received great interest in neurology, as these elements are implicated in different biochemical mechanisms underlying malicious neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. Interestingly, to the best our knowledge, there is lack of a comprehensive study on age-associated variation in the elemental composition of the human SNpc. In that respect, the aim of the present study was to make a preliminary attempt to unravel some of the age-associated mechanisms responsible for the metabolism of some redox-active and redox-inactive elements in the elderly. To do so, substantia nigra tissue specimens, drawn from 37 individuals who deceased without any signs of neurodegeneration, were subjected to spectroscopic studies using synchrotron radiation based X-ray fluorescence. Both neuromelanin-pigmented neurons and extraneuronal areas were studied. It appears that in the neurons, Fe tends to decrease, whilst Cu, Zn and Ca were found to accumulate as an individual gets older. PMID- 26440291 TI - Smartphone Assisted Slit Lamp Free Anterior Segment Imaging: A novel technique in teleophthalmology. PMID- 26440292 TI - Is the Post-Radical Prostatectomy Gleason Score a Valid Predictor of Mortality after Neoadjuvant Hormonal Treatment? AB - PURPOSE: To evaluate the validity of the Gleason score after neoadjuvant hormonal treatment as predictor of disease-specific mortality after radical prostatectomy. PATIENTS AND METHODS: A total of 2,880 patients with a complete data set and a mean follow-up of 10.3 years were studied; 425 of them (15%) had a history of hormonal treatment prior to surgery. The cumulative incidence of deaths from prostate cancer was determined by univariate and multivariate competing risk analysis. Cox proportional hazard models for competing risks were used to study combined effects of the variables on prostate cancer-specific mortality. RESULTS: A higher portion of specimens with a history of neoadjuvant hormonal treatment were assigned Gleason scores of 8-10 (28 vs. 17%, p < 0.0001). The mortality curves in the Gleason score strata <8 vs. 8-10 were at large congruent in patients with and without neoadjuvant hormonal treatment. In patients with neoadjuvant hormonal treatment, a Gleason score of 8-10 was an independent predictor of prostate cancer-specific mortality; the hazard ratio was, however, somewhat lower than in patients without neoadjuvant hormonal treatment. CONCLUSION: This study suggests that the prognostic value of the post-radical prostatectomy Gleason score is not meaningfully jeopardized by heterogeneous neoadjuvant hormonal treatment in a routine clinical setting. PMID- 26440293 TI - Making health care safer: What is the contribution of health psychology? AB - While health care brings great benefits, all treatments, and many investigations, carry some risk. As patients, we should be told of the risks of specific treatments but we are also at risk from failings in the health care system itself. We suggest that, while there are many examples of individual health psychologists who have made important contributions, this has not yet translated into a broader disciplinary engagement. Health psychologists have devoted much more attention to patients and devoted much less attention to the potentially huge impact of studying and intervening with staff, clinical practice, and organizations. We believe that there are considerable opportunities for health psychology to engage more closely with patient safety and, more importantly, that this would be of great benefit to both patients and staff. Statement of contribution What is already known on this subject? While health care brings great benefits, all treatments, and many investigations, carry some risk. Patients are also at risk from failings in the health care system itself. Studies using review of medical records in many countries have found that between 8% and 12% of patients in hospital suffer an unintended harm due to health care. What does this study add? There are many examples of individual psychologists who have made important contributions, but this has not yet translated into a broader disciplinary engagement. There are considerable opportunities for health psychology to engage more closely with patient safety. These include health behaviour change, teamwork, communication after medical error, diagnosis and decision making, organisational culture, and improving compliance with rules and standards. Psychologists providing a clinical service to specialist services in any area could expand their remit from supporting patients to a more general support and engagement with safety and quality initiatives. Health psychologists have models to understand the behaviour of people, and recent developments in changing behaviour should be applicable to health professionals in addition to their patients. PMID- 26440294 TI - Preoperative surgical simulation of laparoscopic adrenalectomy for neuroblastoma using a three-dimensional printed model based on preoperative CT images. AB - BACKGROUND: Three-dimensional (3D) printed models based on computed tomography (CT) images facilitate the visualization of complex structures and are useful for understanding the surgical anatomy preoperatively. We developed a preoperative surgical simulation method using a 3D printed model based on CT images obtained prior to laparoscopic adrenalectomy for adrenal neuroblastomas (NBs). MATERIALS AND METHODS: The multi-detector CT images were transferred to a 3D workstation, and 3D volume data were obtained by reconstructing the sections. A model was made with a 3D printer using acrylic ultraviolet curable resin. The adrenal tumor, kidney, renal vein and artery, inferior vena cava, aorta, and outer body were fabricated. The pneumoperitoneum, insertion of trocars, and laparoscopic view were all attainable in this model. We used this model for three cases with adrenal NB. RESULTS: We used this model to discuss the port layout before the operation and to simulate the laparoscopic view and range of forceps movement. All three cases with NB were completely resected without any surgical complications. CONCLUSIONS: The surgical simulation using 3D printed models based on preoperative CT images for adrenal NB was very useful for understanding the patient's surgical anatomy and for planning the surgical procedures, especially for determining the optimal port layout. PMID- 26440295 TI - A combined cumulative threshold spectra and digital reconstruction analysis reveal structural alterations of microglia within the prefrontal cortex following low-dose LPS administration. AB - Sickness behaviors have become the focus of great interest in recent years as they represent a clear case of how peripheral disturbances in immune signaling can disrupt quite complex behaviors. In the current study, we were interested in examining whether we could identify any significant morphological disturbances in microglia associated with these sickness-like behaviors in adult male Sprague Dawley rats. We chose lipopolysaccharide (LPS 100 MUg/kg/i.p.), to induce sickness-like behaviors as it is the most well-validated approach to do so in rodents and humans. We were particularly interested in examining changes in microglia within the prefrontal cortex (PFC) as several recent neuroimaging studies have highlighted significant functional changes in this region following peripheral LPS administration. Paraformaldehyde-fixed tissue was collected from animals 24h post LPS administration and labeled immunohistochemically with an antibody directed to bind to Iba-1, a protein known to be involved in the structural remodeling of microglia. To analyze changes, we have made use of two recently described image analysis procedures. The first is known as cumulative threshold spectra (CTS) analysis. The second involves the unsupervised digital reconstruction of microglia. We undertook these complementary analysis of microglial cells in the both the pre- and infralimbic divisions of the PFC. Our results indicated that microglial soma size was significantly enlarged, while cell processes had contracted slightly following LPS administration. To our knowledge this study is to first to definitely demonstrate substantial microglial disturbances within the PFC following LPS delivered at a dose that was sufficient to induce significant sickness-like behavior. PMID- 26440296 TI - Stereotaxic Magnetic Resonance Imaging Brain Atlases for Infants from 3 to 12 Months. AB - BACKGROUND: Accurate labeling of brain structures within an individual or group is a key issue in neuroimaging. Methods for labeling infant brains have depended on the labels done on adult brains or average magnetic resonance imaging (MRI) templates based on adult brains. However, the features of adult brains differ in several ways from infant brains, so the creation of a labeled stereotaxic atlas based on infants would be helpful. The current work builds on the recent creation of age-appropriate average MRI templates during the first year (3, 4.5, 6, 7.5, 9, and 12 months) by creating anatomical label sets for each template. METHODS: We created stereotaxic atlases for the age-specific average MRI templates. Manual delineation of cortical and subcortical areas was done on the average templates based on infants during the first year. We also applied a procedure for automatic computation of macroanatomical atlases for individual infant participants using two manually segmented adult atlases (Hammers, LONI Probabilistic Brain Atlas LPBA40). To evaluate our methods, we did manual delineation of several cortical areas on selected individuals from each age. Linear and nonlinear registration of the individual and average template was used to transform the average atlas into the individual participant's space, and the average-transformed atlas was compared to the individual manually delineated brain areas. We also applied these methods to an external data set - not used in the atlas creation - to test generalizability of the atlases. RESULTS: Age-appropriate manual atlases were the best fit to the individual manually delineated regions, with more error seen at greater age discrepancy. There was a close fit between the manually delineated and the automatically labeled regions for individual participants and for the age appropriate template-based atlas transformed into participant space. There was close correspondence between automatic labeling of individual brain regions and those from the age-appropriate template. These relationships held even when tested on an external set of images. CONCLUSION: We have created age-appropriate labeled templates for use in the study of infant development at 6 ages (3, 4.5, 6, 7.5, 9, and 12 months). Comparison with manual methods was quite good. We developed three stereotaxic atlases (one manual, two automatic) for each infant age, which should allow more fine-grained analysis of brain structure for these populations than was previously possible with existing tools. The template-based atlases constructed in the current study are available online (http://jerlab.psych.sc.edu/NeurodevelopmentalMRIDatabase). PMID- 26440297 TI - The impact of altering filling pressures in diagnostic outpatient hysteroscopy on the procedure completion rates and associated pain: a randomised double-blind controlled trial. AB - BACKGROUND: Several studies have compared different distension media and analgesics to optimise the efficiency of outpatient hysteroscopy. However, studies comparing different uterine filling pressures are scarce. AIM: The objective of this study was to evaluate and compare different uterine filling pressures during diagnostic outpatient hysteroscopy in an attempt to find the optimal pressure allowing adequate visualisation while minimising pain and increasing patient satisfaction. MATERIALS AND METHODS: This was a double-blind randomised controlled trial. A total of 240 women who had diagnostic outpatient hysteroscopy were randomly divided into three equal groups: the uterine filling pressure was 30 mm Hg in group 1, 50 mm Hg in group 2 and 80 mm Hg in group 3. The primary outcome was adequate visualisation, and secondary outcomes were the proportion of completed procedures, pain perceived during the procedure, immediately after the procedure and 30 min later. RESULTS: Adequate visualisation was lower in group 1 (88.7% vs 97.5% and 98.7%; P = 0.009), but was not different between groups 2 and 3 (P > 0.999). The proportion of completed procedures was not different among the groups. There was a progressive increase in pain scores from the lower to the higher pressure groups during the procedure, immediately after the procedure and 30 min after completing the procedure. CONCLUSION: Uterine filling pressure of 50 mm Hg was associated with better visualisation than 30 mm Hg and lower pain scores than that of 80 mmHg with no difference in the proportion of completed procedures. PMID- 26440298 TI - The Bacterial and Fungal Diversity of an Aged PAH- and Heavy Metal-Contaminated Soil is Affected by Plant Cover and Edaphic Parameters. AB - Industrial wasteland soils with aged PAH and heavy metal contaminations are environments where pollutant toxicity has been maintained for decades. Although the communities may be well adapted to the presence of stressors, knowledge about microbial diversity in such soils is scarce. Soil microbial community dynamics can be driven by the presence of plants, but the impact of plant development on selection or diversification of microorganisms in these soils has not been established yet. To test these hypotheses, aged-contaminated soil samples from a field trial were collected. Plots planted with alfalfa were compared to bare soil plots, and bacterial and fungal diversity and abundance were assessed after 2 and 6 years. Using pyrosequencing of 16S rRNA gene and ITS amplicons, we showed that the bacterial community was dominated by Proteobacteria, Actinobacteria, and Bacteroidetes and was characterized by low Acidobacteria abundance, while the fungal community was mainly represented by members of the Ascomycota. The short term toxic impact of pollutants usually reduces the microbial diversity, yet in our samples bacterial and fungal species richness and diversity was high suggesting that the community structure and diversity adapted to the contaminated soil over decades. The presence of plants induced higher bacterial and fungal diversity than in bare soil. It also increased the relative abundance of bacterial members of the Actinomycetales, Rhizobiales, and Xanthomonadales orders and of most fungal orders. Multivariate analysis showed correlations between microbial community structure and heavy metal and PAH concentrations over time, but also with edaphic parameters (C/N, pH, phosphorus, and nitrogen concentrations). PMID- 26440300 TI - Cis-Trans Conformational Analysis of delta-Azaproline in Peptides. AB - The cis-trans isomerization and conformer specificity of delta-azaproline and its carbamate-protected form in linear and cyclic peptides were investigated using NMR and alpha-chymotrypsin assay. Comparisons of the chemical shift value of the alpha-hydrogen in each case of delta-azaproline-containing peptides with conformer-specific locked diketopiperazines reveal the fact that an upfield chemical shift value corresponds to cis conformer and a downfield value corresponds to a trans conformer. delta-Azaproline adopts cis-conformation in simple amides, dipeptides, and tripeptides whereas its carbamate-protected form adopts trans-conformation. In the case of longer, linear or cyclic peptides, vice versa results are obtained. Interestingly, in all these peptides exclusively one conformer, either cis or trans, is stabilized. This cis-trans isomerization is independent of both temperature and solvents; only the delta-nitrogen protecting group plays key role in the isomerization. delta-Azaproline is conformer-specific in either of its protected or deprotected forms, which is a unique property of this proline. Unlike other covalently modified proline surrogates, this isomerization of delta-azaproline can be tuned easily by a protecting group. The mechanism of cis-trans isomerization of delta-azaproline during deprotection and reprotection is supported by theoretical calculations. PMID- 26440299 TI - Comparative cytotoxicity and genotoxicity of soluble and particulate hexavalent chromium in human and hawksbill sea turtle (Eretmochelys imbricata) skin cells. AB - Chromium is both a global marine pollutant and a known human health hazard. In this study, we compare the cytotoxicity and genotoxicity of both soluble and particulate chromate in human and hawksbill sea turtle (Eretmochelys imbricata) skin fibroblasts. Our data show that both soluble and particulate Cr(VI) induce concentration-dependent increases in cytotoxicity, genotoxicity, and intracellular Cr ion concentrations in both human and hawksbill sea turtle fibroblasts. Based on administered concentration, particulate and soluble Cr(VI) were more cytotoxic and clastogenic to human cells than sea turtle cells. When the analysis was based on the intracellular concentration of Cr, the data showed that the response of both species was similar. The one exception was the cytotoxicity of intracellular Cr ions from soluble Cr(VI), which caused more cytotoxicity in sea turtle cells (LC50=271MUM) than that of human cells (LC50=471MUM), but its clastogenicity was similar between the two species. Thus, adjusting for differences in uptake indicated that the explanation for the difference in potency was mostly due to uptake rather than differently affected mechanisms. Overall these data indicate that sea turtles may be a useful sentinel for human health responses to marine pollution. PMID- 26440301 TI - Biological parameters of interbreeding subspecies of Meccus phyllosomus (Hemiptera: Reduviidae: Triatominae) in western Mexico. AB - Understanding the biological parameters of some triatomine subspecies of Meccus phyllosomus (Burmeister) is a crucial first step in estimating the epidemiological importance of this group. Biological parameters related to egg eclosion, egg-to-adult development time, number of blood meals to moult, percentage of females at the end of the cycle, number of laid eggs, and the accumulative mortality for each instar of three M. phyllosomus subspecies [Meccus phyllosomus pallidipennis (Stal), Meccus phyllosomus longipennis (Usinger), and Meccus phyllosomus picturatus (Usinger)] as well as their laboratory hybrids were evaluated and compared. No significant differences (P > 0.05) were recorded among the experimental hybrids (M. p. longipennis * M. p. pallidipennis, M. p. longipennis * M. p. picturatus, M. p. pallidipennis * M. p. picturatus) and reciprocal cohorts. In five of the six studied parameters (egg eclosion, egg-to adult development time, number of blood meals to moult, number of laid eggs and accumulative mortality), with the exception of the non-significant percentage of females obtained among all the studied cohorts, at least one of the parental cohorts in each set of crosses exhibited better fitness results than by those of their hybrid descendants. The lack of hybrid fitness in our study indicates the maintenance of reproductive isolation of parental genotypes. Moreover, the results lead us to propose that an incipient speciation process by distance is currently developing among the three studied subspecies, increasing the differences between them that modify the transmission efficiency of Trypanosoma cruzi to human beings in Mexico. PMID- 26440302 TI - Pharmacokinetic Characteristics and Clinical Outcomes of Vancomycin in Young Children With Various Degrees of Renal Function. AB - Although vancomycin pharmacokinetics are affected by age and renal function in adults and older children, its pharmacokinetics in children aged 1 month to 2 years remained unclear. We investigated clinical outcome and nephrotoxicity in younger children with renal insufficiency who were treated with vancomycin. One hundred and ten children aged 1 month to 2 years were enrolled, and they were divided into 3 groups: normal renal function (group A), mild renal insufficiency (group B), and moderate renal insufficiency (group C). A population pharmacokinetic model was established. Significant differences were observed for trough concentration, AUC0-24 h , CL, and t1/2 in the 3 groups. When given at 40 mg/kg per day, 36.4%, 62.5%, and 85.0% of children achieved the target of AUC/MIC >= 400, and 47.0%, 70.8%, and 95% of children obtained early good clinical outcomes in groups A, B, and C (P < .05), respectively. One child in group A and 4 children in group C suffered from acute kidney injury. These results indicated that children with renal insufficiency readily achieved the target AUC/MIC but were at increased risk of nephrotoxicity. Vancomycin clearance and creatinine clearance were not correlated with each other in children with renal insufficiency, indicating that both renal function and serum concentration should be monitored during vancomycin therapy. PMID- 26440303 TI - A Straightforward Route to Potent Phenolic Chain-Breaking Antioxidants by Acid Promoted Transposition of 1,4-Benzo[b]oxathiines to Dihydrobenzo[b]thiophenes. AB - The transformation of simple phenols with limited antioxidant activity into potent chain-breaking antioxidants was achieved by a three-step protocol, consisting of the conversion of phenols into 1,4-benzo[b]oxathiines followed by an unprecedented acid-promoted transposition to o hydroxydihydrobenzo[b]thiophenes, or dihydrobenzo[de]thiochromenes, starting from phenols or naphthols, respectively. These derivatives, bearing a benzo-fused heterocycle with a sulfide sulfur ortho to the phenolic OH, have a rate constant of reaction with alkylperoxyl radicals (kinh ) comparable to that of alpha tocopherol. A solid rationale for the transposition mechanism as well as for the structure-antioxidant activity relationship is presented. PMID- 26440304 TI - Rational Design of Polynuclear Organometallic Assemblies from a Simple Heteromultifunctional Ligand. AB - In modern coordination chemistry, supramolecular coordination complexes take advantage of ligand design to control the shapes and sizes of such architectures. Here we describe how to utilize starting building blocks and a multifunctional ligand to rationally design and synthesize different types of discrete assemblies. Using a hydroxamate ligand featuring two pair of chelating sites together with half-sandwich iridium and rhodium fragments, we were able to construct a series multinuclear organometallic macrocycles and cages through stepwise coordination-driven self-assembly. Experimental observations, supported by computational work, show that selective coordination modes were ascribed to the significant electronic density differences of the two chelating sites, (O,O') and (N,N'). The results underline the advantages of the discrimination between soft and hard binding sites, and suggest that hydroxamic acids can be used as a versatile class of facile multifunctional scaffold for the construction of novel two-dimensional and three-dimensional architectures. PMID- 26440305 TI - Elevated serum uric acid after injury correlates with the early acute kidney in severe burns. AB - OBJECTIVE: Early acute kidney injury (AKI) is one of the most serious and common complications in the early stage of severe burns, but the pathological mechanisms still need to be elucidated. High uric acid (UA) has been found to be correlated with renal dysfunction in some experimental and clinical studies; however, the study of the dynamic correlation between AKI and UA in severe burns is still lacking. METHODS: The diagnosis and classification of AKI were performed according to RIFLE criteria, UA, serum creatinine (Scr), estimated glomerular filtration rate (eGFR), C-reactive protein (CRP) and lactic acid (LA) were dynamically monitored within 2 days after injury in 59 severely burned patients. RESULTS: Within 2 days after injury, AKI occurred in 23 of 59 patients (risk in 12 cases, injury in seven cases and failure in four cases), UA level in AKI patients was significantly higher than that in No-AKI patients, and referring to the cutoff level of UA (375.5 MUmol/l) from ROC curve for predicting AKI, the abnormal increase of UA levels was earlier than acute deterioration of renal function in most of the AKI patients after injury. Among AKI patients, the Scr/eGFR levels were closely related to UA levels for 2 days after injury. Moreover, UA level in cases with severe grade of AKI was significantly higher than that in those with less severe grade of AKI. Furthermore, there was a positive correlation between UA and CRP for 2 days after injury in AKI patients, and a significant correlation between CRP and Scr/eGFR was found 1 day after injury. The positive correlation was also found between LA and UA after injury in AKI patients. CONCLUSION: The results suggest that elevated serum UA after injury due to hypoxia is closely correlated with early AKI after severe burns, and UA related aberrant inflammation also appears to be one of the pathogenic factors, providing the useful information for potential therapy. PMID- 26440306 TI - Long term outcomes data for the Burns Registry of Australia and New Zealand: Is it feasible? AB - BACKGROUND: Incorporating routine and standardised collection of long term outcomes following burn into burn registries would improve the capacity to quantify burn burden and evaluate care. AIMS: To evaluate methods for collecting the long term functional and quality of life outcomes of burns patients and establish the feasibility of implementing these outcomes into a multi-centre burns registry. METHODS: Five Burns Registry of Australia and New Zealand (BRANZ) centres participated in this prospective, longitudinal study. Patients admitted to the centres between November 2009 and November 2010 were followed-up at 1, 6, 12 and 24-months after injury using measures of burn specific health, health status, fatigue, itch and return to work. Participants in the study were compared to BRANZ registered patients at the centres over the study timeframe to identify participation bias, predictors of successful follow-up were established using a Generalised Estimating Equation model, and the completion rates by mode of administration were assessed. RESULTS: 463 patients participated in the study, representing 24% of all BRANZ admissions in the same timeframe. Compared to all BRANZ patients in the same timeframe, the median %TBSA and hospital length of stay was greater in the study participants. The follow-up rates were 63% at 1 month, 47% at 6-months; 40% at 12-months, and 21% at 24-months after injury, and there was marked variation in follow-up rates between the centres. Increasing age, greater %TBSA and opt-in centres were associated with greater follow-up. Centres which predominantly used one mode of administration experienced better follow-up rates. CONCLUSIONS: The low participation rates, high loss to follow-up and responder bias observed indicate that greater consideration needs to be given to alternative models for follow-up, including tailoring the follow-up protocol to burn severity or type. PMID- 26440307 TI - Warming alters the body shape of European perch Perca fluviatilis. AB - The consequences of elevated temperature on body shape were investigated by comparing European perch Perca fluviatilis from the Forsmark area of the Baltic Sea to P. fluviatilis from a nearby Biotest enclosure. The Biotest is a man-made enclosure within the Baltic Sea that has received warm water from a nuclear power plant since 1980, resulting in temperatures that are elevated 5-10 degrees C relative to the surrounding Baltic Sea. Sampled fish ranged from young-of-the year to 14 years. Geometric morphometrics and multivariate statistical analysis revealed significant morphological differences between individuals of P. fluviatilis from these two habitats. Most importantly, relative shape changed with size, with small individuals of P. fluviatilis from Biotest being characterized by a deeper body shape and a larger caudal peduncle than the smaller Baltic individuals. In large specimens, smaller differences were found with Biotest individuals being more slender than Baltic individuals. These results show that, in order to have a full understanding of the biological effects of elevated temperatures, studies that cover the entire size range of organisms will be important. Apart from the direct influence of temperature on growth rate and body shape, other ecological factors affected by temperature are discussed as possible contributors to the observed differences between the two populations. PMID- 26440308 TI - Direct Air Capture of CO2 by Physisorbent Materials. AB - Sequestration of CO2, either from gas mixtures or directly from air (direct air capture, DAC), could mitigate carbon emissions. Here five materials are investigated for their ability to adsorb CO2 directly from air and other gas mixtures. The sorbents studied are benchmark materials that encompass four types of porous material, one chemisorbent, TEPA-SBA-15 (amine-modified mesoporous silica) and four physisorbents: Zeolite 13X (inorganic); HKUST-1 and Mg-MOF-74/Mg dobdc (metal-organic frameworks, MOFs); SIFSIX-3-Ni, (hybrid ultramicroporous material). Temperature-programmed desorption (TPD) experiments afforded information about the contents of each sorbent under equilibrium conditions and their ease of recycling. Accelerated stability tests addressed projected shelf life of the five sorbents. The four physisorbents were found to be capable of carbon capture from CO2-rich gas mixtures, but competition and reaction with atmospheric moisture significantly reduced their DAC performance. PMID- 26440309 TI - Active YAP promotes pancreatic cancer cell motility, invasion and tumorigenesis in a mitotic phosphorylation-dependent manner through LPAR3. AB - The transcriptional co-activator Yes-associated protein, YAP, is a main effector in the Hippo tumor suppressor pathway. We recently defined a mechanism for positive regulation of YAP through CDK1-mediated mitotic phosphorylation. Here, we show that active YAP promotes pancreatic cancer cell migration, invasion and anchorage-independent growth in a mitotic phosphorylation-dependent manner. Mitotic phosphorylation is essential for YAP-driven tumorigenesis in animals. YAP reduction significantly impairs cell migration and invasion. Immunohistochemistry shows significant upregulation and nuclear localization of YAP in metastases when compared with primary tumors and normal tissue in human. Mitotic phosphorylation of YAP controls a unique transcriptional program in pancreatic cells. Expression profiles reveal LPAR3 (lysophosphatidic acid receptor 3) as a mediator for mitotic phosphorylation-driven pancreatic cell motility and invasion. Together, this work identifies YAP as a novel regulator of pancreatic cancer cell motility, invasion and metastasis, and as a potential therapeutic target for invasive pancreatic cancer. PMID- 26440310 TI - Targeted massively parallel sequencing of angiosarcomas reveals frequent activation of the mitogen activated protein kinase pathway. AB - Angiosarcomas are rare malignant mesenchymal tumors of endothelial differentiation. The clinical behavior is usually aggressive and the prognosis for patients with advanced disease is poor with no effective therapies. The genetic bases of these tumors have been partially revealed in recent studies reporting genetic alterations such as amplifications of MYC (primarily in radiation-associated angiosarcomas), inactivating mutations in PTPRB and R707Q hotspot mutations of PLCG1. Here, we performed a comprehensive genomic analysis of 34 angiosarcomas using a clinically-approved, hybridization-based targeted next-generation sequencing assay for 341 well-established oncogenes and tumor suppressor genes. Over half of the angiosarcomas (n = 18, 53%) harbored genetic alterations affecting the MAPK pathway, involving mutations in KRAS, HRAS, NRAS, BRAF, MAPK1 and NF1, or amplifications in MAPK1/CRKL, CRAF or BRAF. The most frequently detected genetic aberrations were mutations in TP53 in 12 tumors(35%) and losses of CDKN2A in9 tumors (26%). MYC amplifications were generally mutually exclusive of TP53 alterations and CDKN2A loss and were identified in 8 tumors (24%), most of which (n = 7, 88%) arose post-irradiation. Previously reported mutations in PTPRB (n = 10, 29%) and one (3%) PLCG1 R707Q mutation were also identified. Our results demonstrate that angiosarcomas are a genetically heterogeneous group of tumors, harboring a wide range of genetic alterations. The high frequency of genetic events affecting the MAPK pathway suggests that targeted therapies inhibiting MAPK signaling may be promising therapeutic avenues in patients with advanced angiosarcomas. PMID- 26440311 TI - Molecular targeting of protein arginine deiminases to suppress colitis and prevent colon cancer. AB - Ulcerative colitis (UC) is a chronic disease, in which the lining of the colon becomes inflamed and develops ulcers leading to abdominal pain, diarrhea, and rectal bleeding. The extent of these symptoms depends on disease severity. The protein arginine deiminase (PAD) family of enzymes converts peptidyl-Arginine to peptidyl-Citrulline through citrullination. PADs are dysregulated, with abnormal citrullination in many diseases, including UC and colorectal cancer (CRC). We have developed the small molecule, pan-PAD inhibitor, Chlor-amidine (Cl-amidine), with multiple goals, including treating UC and preventing CRC. Building off our recent results showing that: 1) Cl-amidine suppresses colitis in vivo in a dextran sulfate sodium (DSS) mouse model; and 2) Cl-amidine induces microRNA (miR)-16 in vitro causing cell cycle arrest, we tested the hypothesis that Cl amidine can prevent tumorigenesis and that miR-16 induction, by Cl-amidine, may be involved in vivo. Consistent with our hypothesis, we present evidence that Cl amidine, delivered in the drinking water, prevents colon tumorigenesis in our mouse model of colitis-associated CRC where mice are given carcinogenic azoxymethane (AOM), followed by multiple cycles of 2% DSS to induce colitis. To begin identifying mechanisms, we examined the effects of Cl-amidine on miR-16. Results show miR-16 suppression during the colitis-to-cancer sequence in colon epithelial cells, which was rescued by drinking Cl-amidine. Likewise, Ki67 and cellular proliferation targets of miR-16 (Cyclins D1 and E1) were suppressed by Cl-amidine. The decrease in cell proliferation markers and increase in tumor suppressor miRNA expression potentially define a mechanism of how Cl-amidine is suppressing tumorigenesis in vivo. PMID- 26440313 TI - Identification of the HrpS binding site in the hrpL promoter and effect of the RpoN binding site of HrpS on the regulation of the type III secretion system in Erwinia amylovora. AB - The type III secretion system (T3SS) is a key pathogenicity factor in Erwinia amylovora. Previous studies have demonstrated that the T3SS in E. amylovora is transcriptionally regulated by an RpoN-HrpL sigma factor cascade, which is activated by the bacterial alarmone (p)ppGpp. In this study, the binding site of HrpS, an enhancer binding protein, was identified for the first time in plant pathogenic bacteria. Complementation of the hrpL mutant with promoter deletion constructs of the hrpL gene and promoter activity analyses using various lengths of the hrpL promoter fused to a promoter-less green fluorescent protein (gfp) reporter gene delineated the upstream region for HrpS binding. Sequence analysis revealed a dyad symmetry sequence between -138 and -125 nucleotides (TGCAA-N4 TTGCA) as the potential HrpS binding site, which is conserved in the promoter of the hrpL gene among plant enterobacterial pathogens. Results of quantitative real time reverse transcription-polymerase chain reaction (qRT-PCR) and electrophoresis mobility shift assay coupled with site-directed mutagenesis (SDM) analysis showed that the intact dyad symmetry sequence was essential for HrpS binding, full activation of T3SS gene expression and virulence. In addition, the role of the GAYTGA motif (RpoN binding site) of HrpS in the regulation of T3SS gene expression in E. amylovora was characterized by complementation of the hrpS mutant using mutant variants generated by SDM. Results showed that a Y100F substitution of HrpS complemented the hrpS mutant, whereas Y100A and Y101A substitutions did not. These results suggest that tyrosine (Y) and phenylalanine (F) function interchangeably in the conserved GAYTGA motif of HrpS in E. amylovora. PMID- 26440312 TI - Detection of cancer through exhaled breath: a systematic review. AB - BACKGROUND: Timely diagnosis of cancer represents a challenging task; in particular, there is a need for reliable non-invasive screening tools that could achieve high levels of adherence at virtually no risk in population-based screening. In this review, we summarize the current evidence of exhaled breath analysis for cancer detection using standard analysis techniques and electronic nose. METHODS: Relevant studies were identified searching Pubmed and Web of Science databases until April 30, 2015. Information on breath test performance, such as sensitivity and specificity, was extracted together with volatile compounds that were used to discriminate cancer patients from controls. Performance of different breath analysis techniques is provided for various cancers together with information on methodological issues, such as breath sampling protocol and validation of the results. RESULTS: Overall, 73 studies were included, where two-thirds of the studies were conducted on lung cancer. Good discrimination usually required a combination of multiple biomarkers, and area under the receiver operating characteristic curve or accuracy reached levels of 0.9 or higher in multiple studies. In 25% of the reported studies, classification models were built and validated on the same datasets. Huge variability was seen in different aspects among the studies. CONCLUSIONS: Analyses of exhaled breath yielded promising results, although standardization of breath collection, sample storage and data handling remain critical issues. In order to foster breath analysis implementation into practice, larger studies should be implemented in true screening settings, paying particular attention to standardization in breath collection, consideration of covariates, and validation in independent population samples. PMID- 26440315 TI - Achieving crop stress tolerance and improvement--an overview of genomic techniques. AB - The inexorable exposure of plants to the combinations of abiotic stresses has affected the worldwide food supply. The crop improvement against these abiotic stresses has been captivating approach to increase the yield and enhance the stress tolerance. By using traditional and modern breeding methods, the characters that confer tolerance to these stresses were accomplished. No doubt genetic engineering and molecular breeding have helped in comprehending the intricate nature of stress response. Understanding of abiotic stress-involved cellular pathways provides vital information on such responses. On the other hand, genomic research for crop improvement has raised new assessments in breeding new varieties against abiotic stresses. Interpretation of responses of the crop plants under stress is of great significance by studying the main role of crops in food and biofuel production. This review presents genomic-based approaches revealing the complex networks controlling the mechanisms of abiotic stress tolerance, and the possible modes of assimilating information attained by genomic-based approaches due to the advancement in isolation and functional analysis of genes controlling the yield and abiotic stress tolerance are discussed. PMID- 26440314 TI - Assessment of Antioxidant Enzyme Activity and Mineral Nutrients in Response to NaCl Stress and its Amelioration Through Glutathione in Chickpea. AB - Salinity stress has been reckoned as one of the major threat towards crop productivity as it causes significant decline in the yield. The impact of NaCl stress (0, 1, 10, 50, 100 and 200 mg L(-1)) as well as glutathione (10 mg L(-1)) either alone or in combination has been evaluated on the induction of multiple shoots, antioxidant enzymes' activity, lipid peroxidation, relative permeability, concentration of nutrients, photosynthetic pigments, protein and proline content of nodal segments of chickpea after 14 days of culture. The antioxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), guaiacol peroxidase (GPX) and glutathione reductase (GR) were found to be increased under salt stress as well as glutathione-supplemented medium. A significant decrease in the concentrations of chlorophylls a, b, total chlorophyll and carotenoid was observed under salt stress. Concentrations of nitrogen, phosphorus, potassium, calcium, carbon, magnesium and sulphur showed an initial increase up to 10 mg L(-1) NaCl, but a decline was seen at higher NaCl levels. Proline content and malondialdehyde concentration were found to be increased under salt stress. Three isoforms of SOD, one of CAT and four of GPX were expressed during native polyacrylamide gel electrophoresis (PAGE) analysis. However, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of the stressed nodal explants revealed the over-expression of several polypeptide bands related to NaCl stress. These findings for the first time suggest that glutathione (GSH) helps in ameliorating NaCl stress in nodal explants of chickpea by manipulating various biochemical and physiological responses of plants. PMID- 26440316 TI - Effect of predictability on the stress response to chasing in Atlantic salmon (Salmo salar L.) parr. AB - The possibility to prepare for and respond to challenges in a proper manner is essential to cope with a changing environment, and learning allows fish to up or downregulate the stress response based on experience. The regulation of the response to predicted needs should be easier in more predictable environments. We exposed salmon parr to chasing of either 15 s (weak stressor) or 5 min (strong stressor) twice daily for a 7-day learning period, with chasing either announced by a 30 s light signal (conditioned) or not announced (unconditioned). The behavioural response to the light signal was different between the conditioned and unconditioned groups, demonstrating that conditioned groups associated the signal with chasing. We could, however, not demonstrate any effect on the stress response of anticipation. The fish habituated to repeated stress exposures with a similar decrease in oxygen hyperconsumption in all groups. Due to habituation, possible effects of predictable announcement of a stressor on the physiological stress response may not have been expressed in this study. Plasma cortisol concentrations 1h after light signal and chasing the day after the training period was moderate in all groups although higher after 5 min chasing (13 ng ml( 1)) than 15 s chasing (7 ng ml(-1)). There was no physiological stress response after exposure to the light signal only after the learning period. We argue that the benefit of predictability of stressors is limited when the fish have no way to avoid the stressor. PMID- 26440317 TI - Temporal discounting rates and their relation to exercise behavior in older adults. AB - As our nation's population ages, the rates of chronic illness and disability are expected to increase significantly. Despite the knowledge that exercise may prevent chronic disease and promote health among older adults, many still are inactive. Factors related to exercise behaviors have been explored in recent years. However, temporal discounting is a motivational concept that has not been explored in regard to exercise in older adults. Temporal discounting is a decision making process by which an individual chooses a smaller more immediate reward over a larger delayed reward. The aim of this study was to determine if temporal discounting rates vary between exercising and non-exercising older adults. DESIGN: This study used cross-sectional survey of 137 older adults living in the community. Older adults were recruited from 11 rural Arkansas churches. The Kirby delay-discounting Monetary Choice Questionnaire was used to collect discounting rates and then bivariate analysis was performed to compare temporal discounting rate between the exercisers and non-exercisers. Finally, multivariate analysis was used to compare discounting rate controlling for other covariates. RESULTS: The results indicated that exercising older adults display lower temporal discounting rates than non-exercising older adults. After controlling for education, exercisers still have lower temporal discounting rates than non exercisers (p<0.001). CONCLUSIONS AND IMPLICATIONS: These findings are important as several chronic health conditions relate to lack of exercise especially in older adults. This research suggests that if we can find appropriate incentives for discounting individuals, some type of immediate reward, then potentially we can design programs to engage and retain older adults in exercise. PMID- 26440318 TI - Behavioral characterization of a model of differential susceptibility to obesity induced by standard and personalized cafeteria diet feeding. AB - Despite the increase in obesity prevalence over the last decades, humans show large inter-individual variability for susceptibility to diet-induced obesity. Understanding the biological basis of this susceptibility could identify new therapeutic alternatives against obesity. We characterized behavioral changes associated with propensity to obesity induced by cafeteria (CAF) diet consumption in mice. We show that Balb/c mice fed a CAF diet display a large inter-individual variability in susceptibility to diet-induced obesity, such that based on changes in adiposity we can classify mice as obesity prone (OP) or obesity resistant (OR). Both OP and OR were hyperphagic relative to control-fed mice but caloric intake was similar between OP and OR mice. In contrast, OR had a larger increase in locomotor activity following CAF diet compared to OP mice. Obesity resistant and prone mice showed similar intake of sweet snacks, but OR ate more savory snacks than OP mice. Two bottle sucrose preference tests showed that OP decreased their sucrose preference compared to OR mice after CAF diet feeding. Finally, to test the robustness of the OR phenotype in response to further increases in caloric intake, we fed OR mice with a personalized CAF (CAF-P) diet based on individual snack preferences. When fed a CAF-P diet, OR increased their calorie intake compared to OP mice fed the standard CAF diet, but did not reach adiposity levels observed in OP mice. Together, our data show the contribution of hedonic intake, individual snack preference and physical activity to individual susceptibility to obesity in Balb/c mice fed a standard and personalized cafeteria-style diet. PMID- 26440320 TI - BEEF SPECIES SYMPOSIUM: Making more but using less: The future of the U.S. beef industry with a reduced cow herd and the challenge to feed the United States and world. PMID- 26440319 TI - Changes in jaw muscle activity and the physical properties of foods with different textures during chewing behaviors. AB - This study aimed to investigate how the activity of the masseter (Mas) and suprahyoid (Hyoid) muscles is influenced by the physical properties of food, how changes in the rheological properties of food differ between different foods during the process of food reduction, and how different salivary flow rates affect bolus-making capability during masticatory behavior in healthy humans. Ten healthy adults participated in this study. Electromyographic (EMG) recordings were obtained from the Mas and Hyoid muscles, and 15 g of steamed rice and rice cake was prepared as test foods. In the ingestion test, the subjects were asked to eat each food in their usual manner. The chewing duration, number of chewing cycles before the first swallow, Mas and Hyoid EMG activity, and chewing cycle time were compared between the foods. Total chewing duration was divided into three substages: early, middle, and late; chewing cycle time and EMG activity per chewing cycle of each substage were compared between the foods and among the substages. In the spitting test, the rheological properties of the bolus at the end of each substage were compared between the foods and among the substages. Finally, stimulated salivary flow rates were measured and the relationships between salivary flow rate and chewing duration, EMG activity, and changes in physical food characteristics were investigated. There were significant differences in total chewing duration and the number of chewing cycles, but not in chewing cycle time, between the foods, which had similar hardness values. The EMG activity levels of the Mas and Hyoid per chewing cycle for the rice cake were significantly greater than for the steamed rice throughout the recording periods. While Mas activity did not change among the substages during chewing, Hyoid EMG activity decreased as chewing progressed. Chewing cycle time also gradually decreased as chewing progressed. The hardness of both foods initially increased, then gradually decreased back to baseline. The adhesiveness of the rice cake initially increased, and did not fall throughout the recording period; the adhesiveness of the steamed rice did not significantly change. Cohesiveness barely changed in either of the two foods during chewing, but was significantly greater for the rice cake than for the steamed rice. Finally, a correlation between the stimulated salivary flow rate and chewing performance was evident only in a change in Mas EMG activity. The current results demonstrate that the activities of the Mas and Hyoid muscles changed as chewing progressed, and were affected by hardness, adhesiveness, and cohesiveness. Salivary flow rate may affect the changes in Mas activity during the process of bolus formation. PMID- 26440321 TI - BEEF SPECIES SYMPOSIUM: Economic considerations related to U.S. beef herd expansion. AB - Significant attention perpetually surrounds possible changes in breeding herd inventories in the U.S. beef cattle industry. This article outlines economic considerations of U.S. herd expansion. Factors restricting expansion include land availability, increasing production efficiency, operator demographics, capital requirements, and commodity price volatility. Several offsetting factors support herd expansion including unprecedented cow-calf returns, ongoing global beef demand growth, and timing within the current cattle cycle. In addition to these industry-wide factors, several important variations in individual ranch considerations are outlined. The authors' expectations on future herd dynamics are provided, highlighting broader implications for individual operations, industry leaders, and the entire beef-cattle supply chain. The substantial economic impact and importance of the cow-calf sector warrants broader appreciation of these economic factors impacting herd expansion. The future size of the U.S. cattle industry is determined by the individual decisions of over 70,000 cattle owners, making this issue worthy of review by all industry stakeholders. PMID- 26440322 TI - BEEF SPECIES SYMPOSIUM: Can we build the cowherd by increasing longevity of females? AB - Increasing longevity of beef cows by decreasing the proportion culled due to reproductive failure provides an efficient process to rebuild a cow herd and can reduce number of replacements needed to sustain a constant herd size. Rate of reproductive failure varies due to cow age, where failure in cows 2 to 4 yr of age is often greater than in cows 5 to 7 yr of age. In addition, BW of cow and calf at weaning increase as cows advance from 2 to 5 yr of age. The cumulative effect of increasing retention of young cows is improved production efficiency through decreased replacement rate and changing age structure of the herd resulting in a greater proportion of cows at maximal production potential for calf BW at weaning and cow BW at time of culling. Calculations from cow age specific culling and BW data from commercial and research herds indicated that reducing replacement rate from 18% to 14% resulted in a 23% increase in calf BW weaned and a 2% increase in cull cow BW per pregnant replacement heifer going into the herd. Although improving longevity increases production efficiency, genetic advancement in sustained reproductive function is challenging, as it is the sequential culmination of the annual repetition of numerous discrete physiological processes, each ending in a qualitative response. Successful completion of one process is prerequisite to evaluating subsequent processes. These physiological processes are subject to nutritional threshold requirements that may vary due to genetic potential for other production traits such as milk, growth, and mature size resulting in genetic-by-nutrition interactions. This is in contrast to most traits for which EPD exist, where genetic-by-environment interactions are not considered to be significant. Extensive research concerning impact of limited nutrition on reproduction has led to recommendations that heifers and cows be fed to a threshold BW or BCS to ensure reproductive success; a process that masks nutritional interactions that might otherwise result in reproductive failure. This management approach minimizes selection for animals capable of sustained reproductive function under limited nutritional environments. Rearing and managing cows under nutritionally limited environments may lead to adaptations that result in relatively high levels of reproductive success under lower input levels. Such adaptation may improve chances for longer retention in their offspring in nutrient-limited environments. PMID- 26440323 TI - BEEF SPECIES SYMPOSIUM: Beef production without mature cows. AB - Nutrients in animal feed get partitioned to growth, lactation, pregnancy, fat accretion, and/or maintenance. For mature beef cows, >80% of nutrients consumed annually go to unproductive maintenance. Integrated over the entire U.S. beef cattle production system, nearly one-half of the nutrients consumed go to maintenance of cow herds. This accounts for much of the inefficiency of beef production and can be minimized by the single-calf heifer system, in which heifers are fattened and slaughtered after having their first calf. We propose a modification, use of sexed semen, so that most heifers replace themselves with a heifer calf. This greatly decreases the size of the inherently inefficient cow herd required for beef production and greatly increases efficiency of beef production in terms of nutrients consumed and waste produced, such as methane, by increasing the ratio of nutrients used for growth to those used for maintenance. Additional management is required including AI, early weaning, and the attention required when calving 2-yr-old heifers. Low conception rates with sexed semen and less efficient growth of females than males also must be considered. However, these issues seem greatly outweighed by the benefits of increased efficiency from decreasing cow herd size while eliminating the need for breeding back lactating first-calf heifers, the need for castration, and health problems inherent in older cows such as mastitis and lameness. Moreover, the decreased generation interval can greatly accelerate genetic progress. PMID- 26440324 TI - Sex impact on the quality of fatty liver and its genetic determinism in mule ducks. AB - Recent changes to French regulations now allow farmers to produce "foie gras" from both male and female mule ducks. The aim of this study was to assess the quality of female fatty liver and to compare, from a phenotypic and genetic point of view, liver quality in males and females. A total of 914 mule ducks (591 males and 323 females), hatched in a single pedigree batch, were reared until 86 d of age and then force-fed for 12 d, before being slaughtered. Carcasses and livers were weighed and liver quality was assessed by grading the extent of liver veining and measuring the liver melting rate, either after sterilization of 60 g of liver or pasteurization of 180 g of liver. Sexual dimorphism was observed in favor of males, with a difference of approximately 10% in carcass and liver weights and up to 54% for the liver melting rate. Moreover, one-third of female livers showed moderate to high veining, whereas this was not the case for male livers. The fatty livers of female mule ducks are, therefore, of poorer quality and could not be transformed into a product with the appellation "100% fatty liver." According to sex and parental line, heritability values ranged from 0.12 +/- 0.05 to 0.18 +/- 0.07 for fatty liver weight and from 0.09 +/- 0.05 to 0.18 +/- 0.05 for the 2 melting rate traits. The genetic correlations between the fatty liver weight and both melting rates were high (greater than +0.80) in the Muscovy population, whereas in the Pekin population, the liver weight and melting rates were less strongly correlated (estimates ranging from +0.36 +/- 0.30 to +0.45 +/- 0.28). Selection for lower liver melting rates without reducing the liver weight would, therefore, be easier to achieve in the Pekin population. Finally, as the 2 melting rate measurements are highly correlated (0.91 and over 0.95 for phenotypic and genetic correlations, respectively), we suggest using the easiest method, that is, sterilization of 60 g of liver. PMID- 26440325 TI - Characterization and functional analysis of porcine estrogen-related receptors and their alternative splicing variants. AB - Estrogen-related receptors (ESRR) are orphan nuclear hormone receptors with unidentified ligands; they play important roles in tissue regulation and development and maintenance of pluripotent cell identity. The splicer variant, genomic organization, and physiological roles of ESRR have been elucidated in the human and the mouse. However, in livestock, they remain elusive. In this study, we cloned porcine ESRR family members , , and . Two alternative splicing variants, and , and a novel were identified. To determine the domain function, we constructed vectors with sequential deletions of the ESRRB coding sequence. The functional analysis showed that the C domain of ESRR plays a core role in promoting the activation of estrogen response elements that are found in all kinds of ESRR-targeting genes, whereas the E domain is not essential for transcription regulation of ESRR unless a specific and identified ligand is applied. PMID- 26440326 TI - Estimates of genetic parameters for content of boar taint compounds in adipose tissue of intact males at 160 and 220 days of age. AB - The aims of this study were to investigate variation in content of androstenone (AND), skatole (SKA), and indole (IND), quantified in adipose tissue of intact male pigs at 160 d of age (105 kg BW) and 220 d of age (155 kg BW), to estimate genetic parameters and to investigate the genetic relationships for AND, SKA, IND, and growth traits. A sample of adipose tissue was collected in vivo, using a biopsy device, from the neck of 500 intact males at the 2 ages and at slaughter from the ham of 100 of the investigated animals. Backfat depth was measured at 220 d of age, whereas BW was recorded at each sampling. Quantification of AND, SKA, and IND was performed by HPLC with fluorescence detection. Estimates of genetic parameters were obtained through Bayesian analyses after logarithmic transformations of original measures. Contents of boar taint compounds (BTC) measured at 220 d were higher than those at 160 d of age. Correlations between contents of BTC in backfat and ham fat ranged from 0.7 (IND) to 0.88 (SKA). Medium-high h were estimated for BTC at both ages, but estimates at 220 d (0.58, 0.60, and 0.69 for AND, SKA, and IND, respectively) were greater than those at 160 d. The genetic correlation between contents at 160 and 220 d of each BTC was positive, but the probability that such estimates were greater than 0.8 was very low, indicating that contents at 160 and 220 d were traits controlled by different genetic backgrounds. Different rankings were observed when breeding values for the content at 160 and 220 d of age were used to rank animals. As a consequence, performance testing programs for BTC should be based preferably on phenotypes measured at 220 d of age. Weak genetic correlations were observed between content of BT compounds and growth traits (BW, backfat depth, and daily gain from 160 to 220 d of age), indicating that selective breeding to reduce the risk of tainted pork is expected to exert trivial effects on growth performance and fat deposition. Results indicate that prevalence of BTC is high in mature and heavy pigs relative to young and light pigs. High heritability; positive genetic correlations between AND, SKA, and IND; and trivial effects on growth traits suggest that reduction of BTC through selective breeding is feasible and exploitable as an alternative to surgical castration also for pigs slaughtered at heavy BW. PMID- 26440327 TI - Genetic parameters for large-scale behavior traits and type traits in Charolais beef cows. AB - In the last decades, beef cattle breeding mainly focused on improving production and reproduction traits. Nowadays, there is a growing interest to include behavior and type traits in the breeding goal. There is an interest in behavior as it is associated with human safety and workability and in type traits as they might be associated with longevity of cows. The objective of the current study was to estimate the heritability for behavior and type traits in Charolais and to estimate the genetic correlations among these traits. Behavior traits, including aggressiveness at parturition, aggressiveness during gestation period, and maternal care, were scored by farmers using an on-farm recording system to enable large-scale collection of phenotypes. Type traits, including udder traits ( = 3), teat traits (3), feet and leg traits (5), and locomotion (1), were scored by 10 trained classifiers. Data was available on 6,649 cows in parity 1 to 12 and located in 380 herds. Results showed that differences between herds explained up to 23% of the total phenotypic variance in behavior traits. This might be due to differences in management or to consistent differences in scoring between farmers. Aggressiveness at parturition had higher heritability (0.19) and higher genetic coefficient of variation (CV = 11%) than aggressiveness during gestation ( = 0.06 and CV = 4%) and maternal care ( = 0.02 and CV = 2%). Heritabilities for udder traits (0.14 to 0.20) and teat traits (0.17 to 0.35) were higher than for feet and leg traits (0.02 to 0.19). Genetic coefficients of variation for udder and teat traits were also higher (up to 21%) than for feet and leg traits (up to 11%). Strong genetic correlations were found between behavior traits (with absolute values from 0.71 to 0.98). The genetic correlations indicate that it is difficulty to simultaneously improve maternal care and reduce aggressiveness. We concluded that there are good opportunities to implement selection for improved udder and teat traits and against aggressiveness at parturition using a simple on farm recording system of behavior. PMID- 26440328 TI - Description of the growth curve for Angus pasture-fed cows under extensive systems. AB - Growth curves are useful for describing the sigmoid shape of an animal's weight pattern over time. The purpose of the present study was to describe, for the first time, a complete growth curve for pasture-fed Angus cows in Uruguay and to analyze the major fixed effects that affect the estimation of mature cow weight (CW). A total of 22,743 records from 5,284 cows belonging to 73 herds were used in the statistical analysis. Five nonlinear models (Brody, Gompertz, Von Bertalanffy, logistic, and Richards) and a 3-knot cubic spline function were fitted to model weight change across age. Body weights were recorded at birth, weaning, and 18 mo and as an adult (at 2.3-3.6, 3.6-4.6, 4.6 to 5.6, 5.6 to 6.6, and 6.6 to 8.1 yr). After preliminary analyses, the fixed effects included in the model to estimate CW were BCS, herd, year and month of measurement, and age of dam. The herd and BCS were the major significant sources of variation. The Richards model had the lowest values for Akaike information criterion, Bayesian information criterion, and -2 log likelihood, with the asymptotic weight being 542 kg. The spline function was the model that fitted the data most closely to the observed weights followed by the Richards function. The Richards model gave better predictions of weights from birth to maturity than the other 4 nonlinear models, because these functions were shown to over- or underestimate weights at different ages in this beef cattle data set. The predicted curve showed that cows reach mature CW after 5 yr of age, which is the age commonly assumed as adult weight in beef cattle. Results form this analysis allowed the estimation of CW and rate of maturing and to take knowledge of the shape of growth curve for Angus females in Uruguay under extensive conditions, helping breeders to take selection decisions. In this way, breeders can optimize the management and efficiency for each production system. PMID- 26440329 TI - Role of G protein-coupled receptors (GPCR), matrix metalloproteinases 2 and 9 (MMP2 and MMP9), heparin-binding epidermal growth factor-like growth factor (hbEGF), epidermal growth factor receptor (EGFR), erbB2, and insulin-like growth factor 1 receptor (IGF-1R) in trenbolone acetate-stimulated bovine satellite cell proliferation. AB - Implanting cattle with steroids significantly enhances feed efficiency, rate of gain, and muscle growth. However, the mechanisms responsible for these improvements in muscle growth have not been fully elucidated. Trenbolone acetate (TBA), a testosterone analog, has been shown to increase proliferation rate in bovine satellite cell (BSC) cultures. The classical genomic actions of testosterone have been well characterized; however, our results indicate that TBA may also initiate a quicker, nongenomic response that involves activation of G protein-coupled receptors (GPCR) resulting in activation of matrix metalloproteinases 2 and 9 (MMP2 and MMP9) that release membrane-bound heparin binding epidermal growth factor-like growth factor (hbEGF), which then binds to and activates the epidermal growth factor receptor (EGFR) and/or erbB2. Furthermore, the EGFR has been shown to regulate expression of the IGF-1 receptor (IGF-1R), which is well known for its role in modulating muscle growth. To determine whether this nongenomic pathway is potentially involved in TBA stimulated BSC proliferation, we analyzed the effects of treating BSC with guanosine 5'-O-2-thiodiphosphate (GDPbetaS), an inhibitor of all GPCR; a MMP2 and MMP9 inhibitor (MMPI); CRM19, a specific inhibitor of hbEGF; AG1478, a specific EGFR tyrosine kinase inhibitor; AG879, a specific erbB2 kinase inhibitor; and AG1024, an IGF-1R tyrosine kinase inhibitor on TBA-stimulated proliferation rate (H-thymidine incorporation). Assays were replicated at least 9 times for each inhibitor experiment using BSC cultures obtained from at least 3 different animals. Bovine satellite cell cultures were obtained from yearling steers that had no previous exposure to androgenic or estrogenic compounds. As expected, BSC cultures treated with 10 n TBA showed ( < 0.05) increased proliferation rate when compared with control cultures. Additionally, treatment with 5 ng hbEGF/mL stimulated proliferation in BSC cultures ( < 0.05). Treatment with GDPbetaS, MMPI, CRM197, AG1024, AG1478, and/or AG879 all suppressed ( < 0.05) TBA-induced increases in proliferation. These data indicate that TBA likely initiates a nongenomic response involving GPCR, MMP2 and MMP9, hbEGF, EGFR, erbB2, and IGF 1R, which may play a role in TBA-mediated increases in BSC proliferation. PMID- 26440330 TI - Coordinated gene expression between skeletal muscle and intramuscular adipose tissue in growing beef cattle. AB - Previous research indicates that metabolism and fiber type of skeletal muscle is related to intramuscular lipid content. It is hypothesized that changes in skeletal muscle gene expression influence adipose tissue development. The objective of this study was to determine differences in the metabolism and intercellular signaling of skeletal muscle fibers within the same muscle group that could be responsible for the initiation of intramuscular adipose tissue development and differentiation. Longissimus dorsi muscle samples were collected from steers ( = 12; 385 d of age; 378 kg BW) grazing wheat pasture. Longissimus muscle samples were dissected under magnification and sorted into 3 categories based on visual stage of adipose tissue development: immature intramuscular adipose tissue (MM), intermediate intramuscular adipose tissue (ME), and mature intramuscular adipose tissue (MA). Additionally, muscle fibers lying adjacent to each intramuscular adipose tissue (IM) category and those not associated with IM tissue were collected and stored separately. Quantitative real-time PCR was used to determine relative fold change in genes involved in metabolism, angiogenesis, formation of extracellular matrix, and intercellular signaling pathways in both LM and IM samples. Gene expression data were analyzed using a GLM that included the fixed effect of tissue. Pearson correlation coefficients were also computed between gene expression in LM and IM tissue samples that were at the same stage of development. and gamma mRNA expression were 3.56- and 1.97-fold greater ( < 0.05) in ME and MA IM compared with MM IM whereas mRNA expression was 1.43-fold less ( < 0.01) in MA IM compared with MM IM, indicating successful separation into different development categories. Genes associated with metabolism and angiogenesis in LM tissue showed no differences among stages of development. Myostatin expression did not change in LM tissue; however, expression of and mRNA decreased ( < 0.01) as IM matured. and mRNA expression were 2.5- and 1.32-fold greater in LM associated with MM IM than in LM associated with ME IM. Angiogenic growth factors in MM IM tissue had a strong positive correlation ( >= 0.69) with angiogenic growth factors in LM associated with MM IM; however, no correlation was observed in ME or MA IM. These data indicate a coordinated effort between LM and IM in early stages of IM development. PMID- 26440331 TI - In utero heat stress increases postnatal core body temperature in pigs. AB - In utero heat stress (IUHS) negatively impacts postnatal development, but how it alters future body temperature parameters and energetic metabolism is not well understood. Future body temperature indices and bioenergetic markers were characterized in pigs from differing in utero thermal environments during postnatal thermoneutral (TN) and cyclical heat stress (HS) exposure. First-parity pregnant gilts ( = 13) were exposed to 1 of 4 ambient temperature (T) treatments (HS [cyclic 28 degrees C to 34 degrees C] or TN [cyclic 18 degrees C to 22 degrees C]) applied for the entire gestation (HSHS, TNTN), HS for the first half of gestation (HSTN), or HS for the second half of gestation (TNHS). Twenty-four offspring (23.1 +/- 1.2 kg BW; = 6 HSHS, = 6 TNTN, = 6 HSTN, = 6 TNHS) were housed in TN (21.7 degrees C +/- 0.7 degrees C) conditions and then exposed to 2 separate but similar HS periods (HS1 = 6 d; HS2 = 6 d; cycling 28 degrees C to 36 degrees C). Core body temperature (T) was assessed every 15 min with implanted temperature recorders. Regardless of in utero treatment, T increased during both HS periods ( = 0.01; 0.58 degrees C). During TN, HS1, and HS2, all IUHS pigs combined had increased T ( = 0.01; 0.36 degrees C, 0.20 degrees C, and 0.16 degrees C, respectively) compared to TNTN controls. Although unaffected by in utero environment, the total plasma thyroxine to triiodothyronine ratio was reduced ( = 0.01) during HS1 and HS2 (39% and 29%, respectively) compared with TN. In summary, pigs from IUHS maintained an increased T compared with TNTN controls regardless of external T, and this thermal differential may have practical implications to developmental biology and animal bioenergetics. PMID- 26440332 TI - Effect of xylanases on ileal viscosity, intestinal fiber modification, and apparent ileal fiber and nutrient digestibility of rye and wheat in growing pigs. AB - Two experiments were performed to study the effect of xylanase on ileal extract viscosity, in vivo fiber solubilization and degradation, and apparent ileal digestibility (AID) of fiber constituents, OM, CP, starch, and crude fat in rye and wheat in ileal-cannulated pigs. In Exp. 1, coarse rye without (NX) or with addition of xylanase from Aspergillus niger (AN), (BS), or (TR) was fed to 8 ileal-cannulated barrows (initial BW 30.9 +/- 0.3 kg) for 1 wk each according to a double 4 * 4 Latin square design. In Exp. 2, fine rye, fine wheat, and coarse wheat with or without a combination of xylanase from and were fed to 6 ileal cannulated barrows (initial BW 33.6 +/- 0.5 kg) for 1 wk according to a 6 * 6 Latin square design with a 2 * 3 factorial arrangement of enzyme and cereal matrix. Chromic oxide (0.2%) was used as an inert marker. Ileal effluent was collected for 8 h on d 5 and 7 and pooled for analysis. In Exp. 1, TR reduced intestinal viscosity of pigs fed rye from 9.3 mPa.s in the control diet (NX) to 6.0 mPa.s ( < 0.001), whereas AN and BS had no effect. None of the enzymes changed the concentration of total arabinoxylan, high-molecular-weight arabinoxylan (HMW-AX), or arabinoxylan oligosaccharides (AXOS) in the liquid phase of digesta. In Exp. 2, the enzyme combination reduced intestinal viscosity for all 3 cereal matrices ( < 0.05), but the viscosity was much higher with fine rye (7.6 mPa.s) than with fine and coarse wheat (<1.7 mPa.s). Simultaneously, the total concentration of arabinoxylan in the liquid phase of digesta increased by 82.4% in fine wheat ( < 0.002) and by 45.9% in coarse wheat ( < 0.006), and AXOS increased 16-fold with enzyme addition. Similar effects of enzyme were not seen with rye. The concentration of xylooligosaccharides in the liquid phase of digesta increased with enzyme addition, but for xylose, it was only significant for wheat, for which it increased 3.9-fold ( < 0.001). None of the xylanases affected AID of arabinoxylan of rye in Exp. 1. In Exp. 2, the enzyme combination increased AID of arabinoxylan by 91% to 107% ( < 0.001) across cereal matrices. Enzyme addition did not affect AID of nutrients in any of the experiments except for a higher starch and crude fat digestibility of fine wheat with enzyme addition ( < 0.012) in Exp. 2. Collectively, the results suggest that xylanase is more efficient in degrading arabinoxylan from wheat than from rye. PMID- 26440333 TI - Effects of a multi-strain Bacillus species-based direct-fed microbial on growth performance, nutrient digestibility, blood profile, and gut health in nursery pigs fed corn-soybean meal-based diets. AB - This experiment was conducted to investigate the effect of a spp.-based direct fed microbial (DFM) on growth performance, apparent total tract digestibility (ATTD), blood profile, intestinal histomorphology, and fecal gas emission in piglets fed corn and soybean meal-based diets. The DFM product was based on 1 strain of and 2 strains of and formulated to supply 1.5 * 10 cfu/g of feed. A total of 128 piglets ([Yorkshire * Landrace] * Duroc; 6.8 +/- 0.6 kg BW; weaning age: 24 d) were housed in groups (4 pigs/pen, 2 barrows and 2 gilts) and fed diets ( = 16) without or with DFM in a 2-phase feeding program: d 0 to 14 (phase I) and 15 to 42 (phase II). Feed intake and BW were measured weekly. At the end of each phase, samples for blood urea nitrogen (BUN), blood creatinine, ATTD, and fecal noxious gas emission were taken. At termination, 12 piglets per treatment were killed to access intestinal tissues for histomorphology. Overall, pigs fed DFM had a greater ( < 0.05) G:F than pigs fed the control diet. In phase I, pigs fed DFM showed a greater ( < 0.05) ADG and lower ( < 0.05) concentration of BUN and fecal ammonia emission than the control group. In phase II, a greater ( < 0.05) ATTD of nitrogen and longer ( < 0.05) duodenum and jejunum villi were observed in pigs fed the DFM diet compared with the control group. In conclusion, inclusion of DFM improved growth performance and villi length of the duodenum and jejunum in nursery pigs. Furthermore, DFM enhanced protein utilization as demonstrated by increased nitrogen digestibility, lower BUN, and lower fecal ammonia release. PMID- 26440334 TI - Effects of stocking rate on forage nutrient composition of Nebraska Sandhills upland range when grazed in early summer. AB - Twelve 2-ha, Nebraska Sandhills upland range paddocks were used in a 2-yr study to determine effects of stocking rate on grazed forage nutrient value in early summer. Paddocks contain a mixture of native cool- and warm-season grasses with forbs as a minor component. Stocking rates were 0 (control), 0.57 (light), and 0.85 (heavy) animal unit months per ha, respectively. Three esophageally fistulated cows collected diet samples on May 14 (d 0), May 21 (d 7), May 28 (d 14), and June 4 (d 21) in 2013 and 2014. Ten quadrats per paddock were clipped and separated into current or previous year growth on each diet sampling date. All samples were analyzed for CP, NDF, and in vitro OM disappearance, which was adjusted to an in vivo OM basis (). For diet samples, treatment interacted ( < 0.001) with sampling date for CP, NDF, and IVOMD. However, treatment and date did not interact ( >= 0.32) for clipped samples. Diets collected in control paddocks had greater ( < 0.05) IVOMD and CP and lower NDF compared with light and heavy stocking rate paddocks on d 7, 14, and 21 but light stocking rate paddocks did not differ ( >= 0.26) from heavy stocking rate paddocks on any sampling day except d 21 NDF ( = 0.03). In general, previous year growth IVOMD, CP, and NDF were not affected ( >= 0.11) by treatment. Generally, current year growth IVOMD and CP were not affected ( >= 0.22) by treatment. Current year growth NDF did not differ ( = 0.23) among stocking rates on d 0, but control paddock had lower ( = 0.02) NDF than light and heavy on d 7, 14, and 21. In stocked paddocks, diet samples had greater ( < 0.01) IVOMD and CP and lower NDF than current and previous year growth except IVOMD on d 0 where diet and current year growth did not differ ( = 0.34). Generally, in control paddocks, current year growth and diet samples had greater ( < 0.01) IVOMD and CP than previous year growth. Control paddocks had greater ( < 0.01) forage accumulation than stocked paddocks on d 7, 14, and 21; however, light and heavy stocked paddocks did not differ ( >= 0.29). On d 0 it was estimated that 96% of the diet was current year growth and only 4% previous year growth, whereas on d 21, 70% of the diet was current year growth vs. 30% previous year growth. Stocking pastures decrease current year growth forage mass and therefore diet nutritive value by forcing cattle to consume diets containing previous year growth in early summer. PMID- 26440335 TI - Finishing performance of feedlot cattle fed condensed distillers solubles. AB - Two experiments evaluated the effects of condensed distillers solubles (CDS) on performance and carcass characteristics of finishing beef cattle. In Exp. 1, 250 crossbred steers (initial BW = 355 +/- 18 kg) were fed 0, 9, 18, 27, or 36% CDS (DM basis) which replaced a portion of urea and a 1:1 ratio of dry-rolled corn (DRC) and high-moisture corn (HMC). Steers were divided into 3 BW blocks and were assigned randomly to 25 pens. Dietary fat increased from 3.7 to 9.4% as CDS inclusion increased from 0 to 36%. Intake decreased linearly ( < 0.01) as CDS increased. A quadratic response was observed for ADG ( = 0.01) and G:F ( < 0.01) with maximum gain calculated at 20.8% CDS and maximum G:F at 32.5% CDS inclusion, which was 12% more efficient than those fed 0% CDS. Experiment 2 was designed as a 2 * 4 factorial using 400 crossbred steers (initial BW = 339 +/- 15 kg) evaluating 0, 7, 14, or 21% CDS (DM basis) in 2 base byproduct diets containing either 20% modified distillers grains plus solubles (MDGS) or 20% Synergy (a blend of wet corn gluten feed and MDGS). Steers were divided into 2 BW blocks and were assigned randomly to 40 pens. A tendency for a base diet * CDS inclusion interaction was observed for ADG, HCW, and final BW ( < 0.10). Gain increased linearly ( = 0.01) and tended to increase quadratically ( = 0.09) in MDGS diets, with maximum calculated ADG at 16% CDS inclusion. Inclusion of CDS had no effect on ADG in Synergy-based diets. Increasing CDS resulted in a linear increase in G:F ( < 0.01) regardless of basal diet. Condensed distillers solubles may be included in the diet at greater than 30% (DM basis) without other byproducts and improve animal performance. Likewise, CDS can be fed in combination with other byproduct feeds but with less improvement in performance. PMID- 26440336 TI - Effects of roughage source and inclusion in beef finishing diets containing corn wet distillers' grains plus solubles. AB - Two experiments were conducted to determine the effects of roughage source and inclusion in diets containing wet distillers' grains plus solubles (WDGS) on finishing cattle performance and ruminal metabolism. In Exp. 1, 385 crossbred steer calves (initial BW = 346 kg [SD 29]) were used in a finishing trial. A control diet with no roughage inclusion was compared with 6 diets containing either alfalfa hay (ALF), corn silage (CSIL), or corn stalks (CSTK) at 2 inclusions as a 3 * 2 factorial. Alfalfa hay was included at 4 (low) or 8% (standard) of diet DM. Diets containing CSIL or CSTK were formulated to provide total dietary NDF equal to the low and standard ALF inclusion diets. The final diets contained 6.13 and 12.26% CSIL or 3.04 and 6.08% CSTK (DM basis). All diets contained 30% WDGS and a 1:1 mixture of dry-rolled and high-moisture corn (DM basis). Cattle fed no roughage had reduced ( < 0.01) DMI and tended ( <= 0.10) to have the lowest final BW and ADG compared with cattle fed roughage. There were no differences ( >= 0.11) in DMI, ADG, or G:F due to roughage source. Cattle fed a standard inclusion of roughage had greater ( <= 0.04) DMI and ADG compared with cattle fed diets with low inclusion, regardless of roughage source. Feed efficiency tended to be different among treatments ( = 0.09), with cattle fed no roughage having greater G:F than all treatments ( <= 0.06) except cattle fed the low level of CSTK, which had a similar G:F ( = 0.48). Feed efficiency was not affected by source of roughage ( = 0.23) or inclusion of roughage ( = 0.49). In Exp. 2, 6 ruminally fistulated steers (347 kg BW [SD 25]) were used in a 6 * 6 Latin square design. Treatments were arranged as a 2 * 3 factorial with ALF or CSTK included at zero, low, or standard levels similar to Exp. 1. Apparent total tract digestibility (%) of DM, OM, and NDF decreased linearly ( <= 0.07) due to increasing roughage inclusion. Average, maximum, and minimum ruminal pH increased linearly ( <= 0.09) as roughage inclusion was increased. Based on the results of this study, low levels of CSTK improved cattle performance relative to low inclusions of ALF or CSIL. Diets with standard inclusions of ALF, CSIL, or CSTK had similar performance. Roughage sources can be exchanged to provide equal NDF in finishing diets containing 30% WDGS without negatively impacting finishing cattle. Based on ADG, eliminating roughages when 30% WDGS was included in finishing diets was not beneficial. PMID- 26440337 TI - Effects of flaxseed encapsulation on biohydrogenation of polyunsaturated fatty acids by ruminal microorganisms: feedlot performance, carcass quality, and tissue fatty acid composition. AB - The objective of this study was to evaluate the efficacy of protecting PUFA within ground flaxseed against ruminal biohydrogenation by encapsulating them in a matrix consisting of a 1:1 blend of ground flaxseed and dolomitic lime hydrate (L-Flaxseed). Crossbreed heifers ( = 462, 346 +/- 19 kg) were blocked by weight and randomly assigned to pens. Pens were assigned to 1 of 6 dietary treatments in a randomized complete block design. Treatment 1 consisted of a combination of 54.6% steam-flaked corn (SFC), 30.0% wet corn gluten feed, 8.0% roughage, and supplement (0% flaxseed). In treatments 2 and 3, a proportion of SFC was replaced with 3 and 6% flaxseed, respectively; in treatments 4, 5, and 6, SFC was replaced with 2, 4, or 6% L-Flaxseed, respectively. Cattle were fed for 140 or 168 d and then harvested in a commercial abattoir where carcass data were collected. Approximately 24 h after harvest, carcasses were evaluated for 12th-rib fat thickness, KPH, LM area, marbling score, and USDA yield and quality grades. Samples of LM were also obtained for determination of long-chain fatty acid profiles. Cattle that were fed diets with 4 and 6% L-Flaxseed consumed less feed than other treatments ( < 0.05), which adversely affected ADG. Compared with cattle fed 0% flaxseed, cattle in these treatments had lower final BW (18 and 45 kg less for the 4 and 6% L-Flaxseed treatments, respectively), less ADG (0.16 and 0.48 kg/day less for the 4 and 6% L-Flaxseed treatments, respectively), and lower carcass weights, dressing percentages, LM areas, backfat thicknesses, and marbling scores ( < 0.05). The addition of flaxseed or 2% L-Flaxseed did not affect performance or carcass traits ( > 0.05). Supplementation with flaxseed increased ( < 0.05) the concentration of alpha-linolenic acid (ALA) in meat (0.173, 0.482, 0.743 mg/g for 0, 3, and 6% flaxseed, respectively). Furthermore, proportionate increases in the ALA content of muscle tissue were 47% greater when flaxseed was encapsulated within the dolomitic lime hydrate matrix (0.288, 0.433, 0.592 mg/g for 2, 4, and 6% L-Flaxseed, respectively). Both products showed a linear response in ALA concentration ( > 99%; increases for Flaxseed and L Flaxseed of 0.095 and 0.140 mg of ALA/g of tissue for each percentage of flaxseed added). This study indicates that a matrix consisting of dolomitic lime hydrate is an effective barrier to ruminal biohydrogenation of PUFA; however, adverse effects on DMI limit the amounts that can be fed. PMID- 26440338 TI - Chemical composition, silage fermentation characteristics, and in vitro ruminal fermentation parameters of potato-wheat straw silage treated with molasses and lactic acid bacteria and corn silage. AB - The aim of this study was to determine the effect of molasses and lactic acid bacteria (LAB) on the chemical composition, silage fermentation characteristics, and in vitro ruminal fermentation parameters of an ensiled potato-wheat straw mixture in a completely randomized design with 4 replicates. Wheat straw was harvested at full maturity and potato tuber when the leaves turned yellowish. The potato-wheat straw (57:43 ratio, DM basis) mixture was treated with molasses, LAB, or a combination. Lalsil Fresh LB (Lallemand, France; containing NCIMB 40788) or Lalsil MS01 (Lallemand, France; containing MA18/5U and MA126/4U) were each applied at a rate of 3 * 10 cfu/g of fresh material. Treatments were mixed potato-wheat straw silage (PWSS) without additive, PWSS inoculated with Lalsil Fresh LB, PWSS inoculated with Lalsil MS01, PWSS + 5% molasses, PWSS inoculated with Lalsil Fresh LB + 5% molasses, PWSS inoculated with Lalsil MS01 + 5% molasses, and corn silage (CS). The compaction densities of PWSS treatments and CS were approximately 850 and 980 kg wet matter/m, respectively. After anaerobic storage for 90 d, chemical composition, silage fermentation characteristics, in vitro gas production (GP), estimated OM disappearance (OMD), ammonia-N, VFA, microbial CP (MCP) production, and cellulolytic bacteria count were determined. Compared to CS, PWSS had greater ( < 0.001) values of DM, ADL, water-soluble carbohydrates, pH, and ammonia-N but lower ( < 0.05) values of CP, ash free-NDF (NDFom), ash, nitrate, and lactic, acetic, propionic, and butyric acids concentrations. When PWSS was treated with molasses, LAB, or both, the contents of CP and lactic and acetic acids increased, whereas NDFom, ammonia-N, and butyric acid decreased ( < 0.05). Based on in vitro ruminal experiments, PWSS had greater ( < 0.05) values of GP, OMD, and MCP but lower ( < 0.05) VFA and acetic acid compared to CS. With adding molasses alone or in combination with LAB inoculants to PWSS, the values of GP, OMD, MCP, cellulolytic bacteria population, VFA, and propionic acid increased ( < 0.05), whereas the acetic acid to propionic acid ratio decreased ( < 0.05). Overall, ensiling potato with wheat straw at a 57:43 ratio DM basis was possible; nevertheless, the fermentation quality of PWSS was lesser than that of CS. However, addition of molasses and molasses + LAB improved fermentation quality of PWSS. PMID- 26440339 TI - Effects of feeding a spray-dried multivalent polyclonal antibody preparation on feedlot performance, feeding behavior, carcass characteristics, rumenitis, and blood gas profile of Brangus and Nellore yearling bulls. AB - The objective of this study was to evaluate the effects of replacing monensin (MON) with a spray-dried multivalent polyclonal antibody preparation (PAP) against several ruminal microorganisms on feedlot performance, carcass characteristics, feeding behavior, blood gas profile, and the rumenitis incidence of Brangus and Nellore yearling bulls. The study was designed as a completely randomized design with a 2 * 2 factorial arrangement, replicated 6 times (4 bulls per pen and a total of 24 pens), in which bulls ( = 48) of each biotype were fed diets containing either MON fed at 300 mg/d or PAP fed at 3 g/d. No significant feed additive main effects were observed for ADG ( = 0.27), G:F ( = 0.28), HCW ( = 0.99), or dressing percentage ( = 0.80). However, bulls receiving PAP had greater DMI ( = 0.02) and larger ( = 0.02) final LM area as well as greater ( < 0.01) blood concentrations of bicarbonate and base excess in the extracellular fluid than bulls receiving MON. Brangus bulls had greater ( < 0.01) ADG and DMI expressed in kilograms, final BW, heavier HCW, and larger initial and final LM area than Nellore bulls. However, Nellore bulls had greater daily DMI fluctuation ( < 0.01), expressed as a percentage, and greater incidence of rumenitis ( = 0.05) than Brangus bulls. In addition, Brangus bulls had greater ( < 0.01) DMI per meal and also presented lower ( < 0.01) DM and NDF rumination rates when compared with Nellore bulls. Significant interactions ( < 0.05) between biotype and feed additive were observed for SFA, unsaturated fatty acids (UFA), MUFA, and PUFA concentrations in adipose tissues. When Nellore bulls were fed PAP, fat had greater ( < 0.05) SFA and PUFA contents but less ( < 0.01) UFA and MUFA than Nellore bulls receiving MON. For Brangus bulls, MON led to greater ( < 0.05) SFA and PUFA and less ( < 0.05) UFA and MUFA than Brangus bulls fed PAP. Feeding a spray-dried PAP led to similar feedlot performance compared with that when feeding MON. Spray-dried PAP might provide a new technology alternative to ionophores. PMID- 26440340 TI - Relationship of leptin concentrations with feed intake, growth, and efficiency in finishing beef steers. AB - The objective of this experiment was to determine the association of serum leptin concentrations with production measures including DMI, ADG, and G:F as well as carcass characteristics in genetically diverse finishing beef steers. Three cohorts of steers ( = 473 total) were individually fed a finishing ration for 92, 64, and 84 d for cohort 1, 2, and 3, respectively. Serum was collected on d 42, 22, and 19 of the experiment for cohort 1, 2, and 3, respectively. Leptin concentrations were positively correlated to DMI ( = 0.21, < 0.01) but negatively correlated to grams DMI per kilogram initial BW ( = -0.21, < 0.01). Leptin concentrations were also negatively correlated to ADG and G:F ( < 0.01). Leptin concentrations were positively correlated to 12th-rib fat thickness, yield grade, and marbling score ( < 0.01) and negatively correlated to LM area ( < 0.01). Using a mixed model analysis (SAS 9.3; SAS Inst. Inc., Cary, NC) to account for breed effects, leptin concentrations were positively associated with DMI ( = 0.01) and accounted for 1.10% of the variance. However, if initial BW and yield grade were included as covariates to account for body size and fatness, leptin was negatively associated with DMI ( = 0.02) and accounted for 0.54% of the variance. Regardless of covariates included in the model, leptin was negatively associated with ADG ( < 0.01) and G:F ( < 0.01) and accounted for 2.62 and 7.87% of the variance for ADG and G:F, respectively. Leptin concentrations were also positively associated with 12th-rib fat thickness, yield grade, and marbling score ( < 0.01) and accounted for 14.74, 12.74, and 6.99% of the variance for 12th-rib fat, yield grade, and marbling score, respectively. Leptin concentrations could be a useful physiological marker for growth and feed efficiency of finishing beef cattle. Genetic influences on the biology of leptin also need to be considered when using leptin as physiological marker for production measures. PMID- 26440341 TI - Effects of plant species, stage of maturity, and level of formic acid addition on lipolysis, lipid content, and fatty acid composition during ensiling. AB - Forage type and management influences the nutritional quality and fatty acid composition of ruminant milk. Replacing grass silage with red clover (RC; L.) silage increases milk fat 18:3-3 concentration. Red clover has a higher polyphenol oxidase (PPO) activity compared with grasses, which has been suggested to decrease lipolysis and . The present study characterized the abundance and fatty acid composition of esterified lipid and NEFA before and after ensiling of grass and RC to investigate the influence of forage species, growth stage, and extent of fermentation on lipolysis. A randomized block design with a 2 * 3 * 4 factorial arrangement of treatments was used. Treatments comprised RC or a mixture of timothy ( L.) and meadow fescue ( Huds.) harvested at 3 growth stages and treated with 4 levels of formic acid (0, 2, 4, and 6 L/t). Lipid in silages treated with 0 or 6 L/t formic acid were extracted and separated into 4 fractions by TLC. Total PPO activity in fresh herbage and the content of soluble bound phenols in all silages were determined. Concentrations of 18:3-3 and total fatty acids (TFA) were higher ( < 0.001) for RC than for grass. For both forage species, 18:3-3 and TFA content decreased linearly ( < 0.001) with advancing growth stage, with the highest abundance at the vegetative stage. Most of lipid in fresh RC and grass herbage (97%) was esterified, whereas NEFA accounted for 71% of TFA in both silages. Ensiling resulted in marginal increases in TFA content and the amounts of individual fatty acids compared with fresh herbages. Herbage total PPO activity was higher ( < 0.001) for RC than grass (11 vs. 0.11 MUkatal/g leaf fresh weight). Net lipolysis during ensiling was extensive for both forage species (660 to 759 g/kg fatty acid for grass and 563 to 737 g/kg fatty acid for RC). Formic acid application (0 vs. 6 L/t) resulted in a marked decrease ( = 0.026) in net lipolysis during the ensiling of RC, whereas the opposite was true ( = 0.026) for grass. In conclusion, results suggest that formic acid addition during the ensilage of RC decreases lipolysis . For both plant species, total PPO activity was not associated with the extent of lipolysis . However, bound phenols formed via PPO activity appear to have a role in protecting lipid and protein against degradation in grass and lowering proteolysis of RC during ensiling. PMID- 26440343 TI - Differential impact of birth weight and early growth on neonatal mortality in puppies. AB - Breeding kennels face a high rate of neonatal mortality, on which the impact of nutrition remains to be determined. This study was designed to evaluate the impact of birth weight (reflecting intrauterine growth) and early growth rate (reflecting colostrum intake) on risk of neonatal mortality in puppies and to determine the critical thresholds of both parameters. Puppies from various breeds were weighed at birth ( = 514) and at 2 d of age, and the growth rate over that period (early growth rate) was calculated for all survivors ( = 477). Linear mixed models evaluated the effect of birth weight on mortality between birth and 2 d of age and the effect of both birth weight and early growth rate on mortality between 2 and 21 d of age. Birth weight was influenced by litter size ( = 0.003), with more low-birth-weight puppies (the lightest 25% within a breed size) in large litters compared with smaller litters. Mortality over the first 2 d after birth was associated with birth weight ( < 0.001), with 81.1% of dying puppies characterized by a low birth weight. Mortality between 2 and 21 d of age was not related to birth weight but was found to be associated with early growth rate ( < 0.001), with higher risk of death in puppies with growth rate at or below -4% after the first 2 d of life. This study demonstrates the differential effect of intrauterine nutrition impacting mortality during the first 2 d of life and that of colostrum intake impacting mortality until 21 d of life. Birth weight and early growth rate thresholds provided in this study allow identification of puppies at risk, whereby provision can be made for adequate nursing to increase their chances to survive. PMID- 26440342 TI - Effects of porcine reproductive and respiratory syndrome virus on pig growth, diet utilization efficiency, and gas release from stored manure. AB - The objectives of this study were to examine the effects of porcine reproductive and respiratory syndrome virus (PRRSV) infection and vaccination on pig growth, dietary nutrient efficiency of utilization, manure output, and emissions of CO, CH, HS, NO, and NH gases from stored manure. Forty-eight pigs, aged 21 d at the start of the study, were subjected to 1 of 4 treatment combinations arranged in a 2 * 2 factorial design with main factors of PRRSV vaccination and PRRSV infection. Body weight, ADFI, manure output, and nutrient efficiency of utilization were assessed and gas emissions from stored manure were determined daily from 50 to 78 d of age and for 24 d after completion of the animal phase. Infection with PRRSV markedly reduced final BW, ADG, and ADFI ( < 0.01) and reduced efficiencies of ADF and ether extract utilization ( = 0.05 and = 0.02, respectively) regardless of vaccination status. No significant treatment effects were found on manure output, manure pH, efficiencies of lignin utilization, and N retention. Infecting pigs with PRRSV increased daily manure CO emission per pig ( = 0.01). There was an interaction between immunization and infection for NO per pig with manure from uninfected, vaccinated pigs producing as much as the manure from infected, vaccinated pigs whereas there was a difference by PRRSV infection state for nonvaccinated pigs. There were also interactions between treatments for HS and NO emissions per kilogram of manure volatile solids excreted ( = 0.01 and = 0.0001, respectively) with the same pattern as for NO per pig; that is, the vaccinated pigs had similar rates of emission regardless of infection state. Pigs infected with PRRSV increased NO nitrogen per kilogram of total N excreted compared with noninfected groups ( = 0.03). Collectively, these results indicated that PRRSV infection caused decreased growth rates and nutrient utilization efficiency and increased gas emissions from stored manure. PMID- 26440344 TI - Effects of vaccination against respiratory pathogens on feed intake, metabolic, and inflammatory responses in beef heifers. AB - The objective of this study was to evaluate intake, metabolic, inflammatory, and acute-phase responses in beef heifers vaccinated against pathogens that cause bovine respiratory disease (BRD). Eighteen weaned Angus heifers (initial BW 257 +/- 3 kg; initial age 245 +/- 2 d) were ranked by BW and allocated to 2 groups, which were assigned to 2 experiments of 7 d and the following treatments on d 1 of each experiment: 1) revaccinated against infectious bovine rhinotracheitis virus, parainfluenza-3 virus, bovine respiratory syncytial virus, bovine viral diarrhea Types 1 and 2 viruses, and (VAC; 2 mL [s.c.]) and 2) receiving a 2-mL s.c. injection of 0.9% sterile saline (CON). The group receiving VAC in Exp. 1 was assigned to CON in Exp. 2 and vice versa. Heifers were weaned 21 d before Exp. 1, when they all received the first dose of the aforementioned vaccine. Heifers were maintained in individual pens and offered free-choice mixed alfalfa grass hay and 3.5 kg/d (DM basis) of a corn-based supplement throughout the study. During Exp. 1, hay and concentrate intake were evaluated daily. During Exp. 2, blood samples were collected before (-2 and 0 h) and at 2, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120, 144, and 168 h after treatment administration. In Exp. 1, treatment * day interactions were detected ( < 0.01) for forage intake and total DMI; these parameters were reduced ( <= 0.05) in VAC heifers compared with CON heifers on d 1 and 2 by an average of 1.7 and 0.8 kg (DM basis), respectively. In Exp. 2, mean serum tumor necrosis factor alpha (TNFalpha) concentration was greater ( = 0.05) in VAC heifers compared with CON heifers and treatment * hour interactions were detected for all plasma variables ( <= 0.02), whereas a similar tendency was detected ( = 0.09) for blood alpha mRNA expression. Haptoglobin concentrations were greater ( <= 0.05) in VAC heifers compared with CON heifers from 16 to 120 h. Blood alpha mRNA expression was greater ( = 0.05) in VAC heifers compared with CON heifers at 12 h. Cortisol concentrations were greater ( <= 0.05) in VAC heifers compared with CON heifers from 2 to 16 h. Insulin concentration was greater ( = 0.02) in VAC heifers compared with CON heifers at 2 h. Leptin concentrations were greater ( <= 0.05) in VAC heifers compared with CON heifers from 6 to 16 h. In conclusion, vaccinating beef heifers against BRD pathogens decreased forage intake and total DMI during the 2 d following vaccination in Exp. 1, which can be associated with transient metabolic, inflammatory, and acute-phase responses elicited by vaccination in Exp. 2. PMID- 26440345 TI - The association between immunoglobulin G in sow colostrum and piglet plasma. AB - Colostrum provides newborn piglets with energy and passive immunity and is essential for survival of the piglets. The plasma concentration of immunoglobulin G (IgG) in piglets is dependent on several factors, most importantly the concentration of IgG in sow colostrum (colostrum IgG). The main aims of this study were to investigate the variation in concentration of colostrum IgG between herds and the individual sows within herd and to investigate factors associated with plasma IgG concentrations in piglets (piglet IgG). From 4 herds (A to D), 876 piglets from 62 sows were included in the study. Colostrum was sampled from sows immediately after expulsion of the first piglet and before the first suckling (t1), midway through farrowing (just after the sixth piglet was born; t2), and after the last piglet was born (t3). At d 1, 0.5 mL blood from piglets was collected in tubes containing EDTA, and IgG concentrations were analyzed. Mean colostrum IgG concentration across all herds was 53.9 g/L. Herd A had mean colostrum IgG of 38.3 g/L, whereas the other 3 herds (B,C, and D) had mean colostrum IgG of 47.4, 60.4, and 67.8 g/L, respectively. Colostrum IgG at t1, t2, and t3 across all herds was 56.2, 53.7, and 42.5 g/L, respectively. Mean concentration of piglet IgG across all samplings was 21.7 g/L. Multilevel linear regression analysis was performed with piglet IgG (g/L) as outcome. In this model, the herd effect accounted for 9% of the total variance and 34% of the variance resided at sow level. Piglet IgG was associated with herd, birth order (), body mass index (BMI) > 17 (kg/m), and colostrum IgG at t1 (g/L) with an overall -value < 0.01. Herd D had the highest predicted mean level of piglet IgG. The main model predicted that piglet IgG decreased linearly by 0.4 g/L with each piglet born ( < 0.01). The model also predicted an increase by 0.1 g/L for each gram per liter extra colostrum IgG in colostrum ( = 0.03). Piglets with a BMI above 17 kg/m had a greater piglet IgG (+4.5 g/L) than those with a BMI at 17 kg/m or below ( < 0.01). Concentrations of colostrum IgG varied largely between herds and between sows. The largest variation of piglet IgG was mainly on the piglet level, supporting the complex nature of IgG production and uptake. However, the strong association between colostrum IgG and piglet IgG shows that increased IgG level in colostrum will improve the levels of IgG in piglets and potentially increase survival of the piglets. PMID- 26440346 TI - In vivo prediction of goat kids body composition from the deuterium oxide dilution space determined by isotope-ratio mass spectrometry. AB - Deuterium oxide dilution space (DOS) determination is one of the most accurate methods for in vivo estimation of ruminant body composition. However, the time consuming vacuum sublimation of blood preceding infrared spectroscopy analysis, which is traditionally used to determine deuterium oxide (DO) concentration, limits its current use. The use of isotope-ratio mass spectrometry (IRMS) to determine the deuterium enrichment and thus quantify DO in plasma could counteract this limitation by reducing the sample preparation for plasma deproteinisation through centrifugal filters. The aim of this study was to validate the DOS technique using IRMS in growing goat kids to establish in vivo prediction equations of body composition. Seventeen weaned male Alpine goat kids (8.6 wk old) received a hay-based diet supplemented with 2 types of concentrates providing medium ( = 9) or high ( = 8) energy levels. Kids were slaughtered at 14.0 ( = 1, medium-energy diet), 17.2 ( = 4, medium-energy diet, and = 4, high energy diet), or 21.2 wk of age ( = 4, medium-energy diet, and = 4, high-energy diet). Two days before slaughter, DOS was determined after an intravenous injection of 0.2 g DO/kg body mass (BM) and the resulting study of DO dilution kinetics from 4 plasma samples (+5, +7, +29, and +31 h after injection). The deuterium enrichment was analyzed by IRMS. After slaughter, the gut contents were discarded, the empty body (EB) was minced, and EB water, lipid, protein, ash, and energy contents were measured by chemical analyses. Prediction equations for body components measured postmortem were computed from in vivo BM and DOS. The lack of postmortem variation of fat-free EB composition was confirmed (mean of 75.3% [SD 0.6] of water), and the proportion of lipids in the EB tended ( = 0.06) to be greater for the high-energy diet (13.1%) than for the medium-energy diet (11.1%). There was a close negative relationship (residual CV [rCV] = 3.9%, = 0.957) between EB water and lipid content, whereas DOS was closely related to total body water (rCV = 2.9%, = 0.944) but DOS overestimated it by 5.8%. Adding DOS to BM improved the in vivo predictions of EB lipid and energy content (rCV = 13.1% and rCV = 7.9%, respectively) but not those of protein or ash. Accuracy of the obtained prediction equations was similar to those reported in studies determining DOS by infrared spectroscopy. Therefore, the use of IRMS to quantify DOS provides a highly accurate measure of the in vivo body composition in goat kids. PMID- 26440347 TI - Increasing the metabolizable protein supply enhanced growth performance and led to variable results on innate and humoral immune response of preconditioning beef steers. AB - We evaluated the effects of MP supply on growth performance before and after preconditioning and measurements of innate and humoral immune response of beef steers following vaccination. Angus steers ( = 36; BW = 231 +/- 21 kg; age = 184 +/- 18 d) were weaned on d -6, stratified by BW and age on d 0, and randomly assigned to 1 of 18 drylot pens (2 steers/pen). Treatments were assigned to pens (6 pens/treatment) and consisted of corn silage-based diets formulated to provide 85%, 100%, or 115% of the daily MP requirements of a beef steer gaining 1.1 kg/d from d 0 to 42. Steers were vaccinated against infectious bovine rhinotracheitis virus, bovine viral diarrhea (BVDV) types 1 and 2 viruses, and clostridium on d 14 and 28. Blood samples were collected on d 0, 14, 15, 17, 21, 28, 29, 30, 35, and 42. Body weight did not differ ( >= 0.17) among treatments from d 0 to 28. On d 42, 115% MP steers were heaviest, 100% MP steers were intermediate, and 85% MP steers were lightest ( = 0.05; 297, 290, and 278 +/- 7 kg, respectively). Overall, ADG and G:F did not differ ( >= 0.13) between 100% and 115% MP steers and were least ( < 0.01) for 85% MP steers (1.2, 1.4, and 0.8 +/- 0.07 kg/d and 0.23, 0.24, and 0.19 +/- 0.008, respectively). Plasma haptoglobin (Hp) concentrations did not differ among treatments ( >= 0.46), whereas plasma ceruloplasmin (Cp) concentrations were greatest ( <= 0.04) for 85% MP steers, intermediate for 100% MP steers, and least for 115% MP steers on d 30, 35, and 42. Plasma cortisol concentrations were greater ( <= 0.03) for 85% vs. 100% and 115% MP steers on d 14 and 28. Liver mRNA expression of Cp and Hp and muscle mRNA expression of m-calpain, mammalian target of rapamycin, and ubiquitin did not differ among treatments ( >= 0.17). Serum neutralization titers to BVDV-1b titers were greater ( <= 0.02) for 115% vs. 85% and 100% MP steers on d 42 (5.8, 3.0, and 3.7 +/- 0.60 log, respectively), whereas mean serum leukotoxin titers were greater for 85% vs. 100% and 115% MP steers (3.1, 2.4, and 2.5 +/- 0.21 log, respectively). Preconditioning MP supply did not affect ( >= 0.26) ubsequent finishing growth performance and carcass characteristics. Thus, increasing MP supply from 85% to 115% of daily requirement of preconditioning beef steers had variable results on innate and humoral immune response and enhanced growth performance during a 42-d preconditioning period without affecting carcass characteristics at slaughter. PMID- 26440348 TI - Effects of diet form and type on growth performance, carcass yield, and iodine value of finishing pigs. AB - Two experiments were conducted to determine the effects of pelleting, diet type (fat and fiber level), and withdrawal of dietary fiber and fat before marketing on growth performance, carcass yield, and carcass fat iodine value (IV) of finishing pigs. Each experiment used 288 pigs (initially 49.6 and 48.5 kg BW, respectively) with 6 dietary treatments arranged as 2 * 3 factorials. In Exp. 1, main effects were diet form (meal vs. pellet) and diet regimen. Diet regimens were 1) a low-fiber, low-fat (corn-soybean meal) diet from d 0 to 81, 2) a high fiber, high-fat (30% dried distillers grains with solubles [DDGS] and 19% wheat middlings [midds]) diet from d 0 to 64 followed by the low-fiber, low-fat diet from d 64 to 81 (fiber and fat withdrawal), and 3) the high-fiber, high-fat diet fed from d 0 to 81. Pigs fed pelleted diets had increased ( < 0.05) ADG and G:F compared with those fed meal diets. Pigs fed pelleted diets had increased belly fat IV (2.9 mg/g) compared with those fed meal diets, with a greater increase when fed high-fiber, high-fat diets throughout the entire study (interaction, < 0.05). Pigs fed the low-fiber, low-fat diet throughout had increased ( < 0.001) G:F compared with pigs fed the other 2 treatments. Pigs fed low-fiber, low-fat diets throughout the study or pigs withdrawn from high-fiber, high-fat diets had increased ( < 0.001) carcass yield compared with pigs fed high-fiber, high-fat diets throughout. In Exp. 2, treatment main effects were diet form (meal vs. pellet) and diet type (corn-soybean meal-based control, the control with 30% DDGS and 19% midds, or the control diet with 3% corn oil). The diet containing corn oil was calculated to produce carcass fat IV similar to diets containing DDGS and midds. Overall, pigs fed pelleted diets had increased ( < 0.05) ADG, G:F, and belly fat IV (1.3 mg/g) compared with those fed meal diets. Pigs fed the diets containing DDGS and midds had decreased ( < 0.05) ADG, carcass yield, and HCW compared with pigs fed the control or corn oil diets and decreased ( < 0.001) G:F compared with pigs fed added corn oil. Belly IV was greatest ( < 0.001) for pigs fed diets with DDGS and midds and lowest for pigs fed the control diet, with pigs fed the corn oil diets intermediate. In conclusion, pelleting diets improves pig ADG (approximately 3%) and G:F (approximately 6%); however, a novel finding of this study is that pelleting diets fed to finishing pigs also increases belly fat IV. PMID- 26440349 TI - Glutamine synthetase and alanine transaminase expression are decreased in livers of aged vs. young beef cows and GS can be upregulated by 17beta-estradiol implants. AB - Aged beef cows (>= 8 yr of age) produce calves with lower birth and weaning weights. In mammals, aging is associated with reduced hepatic expression of glutamine synthetase (GS) and alanine transaminase (ALT), thus impaired hepatic Gln-Glu cycle function. To determine if the relative protein content of GS, ALT, aspartate transaminase (AST), glutamate transporters (EAAC1, GLT-1), and their regulating protein (GTRAP3-18) differed in biopsied liver tissue of (a) aged vs. young (3 to 4 yr old) nonlactating, nongestating Angus cows (Exp. 1 and 2) and (b) aged mixed-breed cows with and without COMPUDOSE (17beta-estradiol) ear implants (Exp. 3), Western blot analyses were performed. In Exp. 1, 12 young (3.62 +/- 0.01 yr) and 13 aged (10.08 +/- 0.42 yr) cows grazed the same mixed forage for 42 d (August-October). In Exp. 2, 12 young (3.36 +/- 0.01 yr) and 12 aged (10.38 +/- 0.47 yr) cows were individually fed (1.03% of BW) a corn-silage based diet to maintain BW for 20 d. For both Exp. 1 and 2, the effect of cow age was assessed by ANOVA using the MIXED procedure of SAS. Cow BW did not change ( >= 0.17). Hepatic ALT (78% and 61%) and GS (52% and 71%) protein content (Exp. 1 and 2, respectively) was decreased ( <= 0.01), whereas GTRAP3-18 (an inhibitor of EAAC1 activity) increased ( <= 0.01; 170% and 136%) and AST, GLT-1, and EAAC1 contents did not differ ( >= 0.17) in aged vs. young cows. In Exp. 2, free concentrations (nmol/g) of Glu, Ala, Gln, Arg, and Orn in liver homogenates were determined. Aged cows tended to have less ( = 0.10) free Gln (15.0%) than young cows, whereas other AA concentrations did not differ ( 0.26). In Exp. 3, 14 aged (> 10 yr) cows were randomly allotted ( = 7) to sham or COMPUDOSE (25.7 mg of 17beta-estradiol) implant treatment (TRT), and had ad libitum access to alfalfa hay for 28 d. Blood and liver biopsies were collected 14 and 28 d after implant treatment. Treatment, time after implant (DAY), and TRT * DAY effects were assessed by ANOVA using the MIXED procedure of SAS. Cow BW was not affected ( >= 0.96). Implant increased ( <= 0.02) total plasma estradiol by 220% (5.07 vs. 1.58 pg/mL) and GS protein by 300%, whereas the relative content of other proteins was not altered ( >= 0.16). We conclude that hepatic expression of ALT and GS are reduced in aged vs. young cows, and administration of 17beta-estradiol to aged cows increases plasma estradiol and hepatic GS, but not that of other proteins that support hepatic Glu metabolism. PMID- 26440350 TI - Characterization of protected designation of origin Italian meat products obtained from heavy pigs fed barley-based diets. AB - A study was conducted to evaluate the quality and sensory properties of protected designation of origin (PDO) Parma ham and Piacentina neck obtained from heavy pigs (Italian Duroc * Italian Large White) fed barley-based diets. Four diets were tested: 1) a corn-based diet (control), 2) the control diet with 80% of a normal-amylose hulled barley variety (Cometa), 3) the control diet with 80% of a normal-amylose hulless barley variety (Astartis), and 4) the control diet with 80% of a low-amylose hulless barley variety (Alamo). All the meat products were analyzed for physicochemical and color parameters. The dry-cured hams and necks were also evaluated for sensory properties. The data of physicochemical, color, and sensory parameters were separately analyzed by multivariate factor analysis, and interpretation of each extracted factor was based on specific original variables loading on each one. The meat products obtained from pigs fed the barley-based diets differed from those obtained from the control pigs on the PUFA factors characterized by C18:2-6 and omega-3:omega-6 ratio. In particular, the meat products obtained from pigs fed the barley-based diets had a lower content of C18:2-6 and a higher omega-3:omega-6 ratio ( < 0.05) than the control. In fresh hams, iodine number and SFA (C16:0 and C18:0) in addition to PUFA and omega 3:omega-6 ratio loaded on the PUFA/SFA factor. The fresh hams produced from pigs fed the barley-based diets had subcutaneous fat (SC) with a lower iodine number and a higher SFA level compared with those produced from the control pigs ( < 0.05). A sex effect was measured for PUFA/SFA and oleic acid factors. In particular, the barrow SC had a lower SFA content, higher PUFA and C18:1-9 levels, and a higher iodine number ( < 0.05) than the gilt SC. There were no appreciable differences in the color and sensory properties of meat products obtained from pigs fed the different diets. The hams from barrows differed from those obtained from gilts on the lean properties factor describing properties related to aspect and odor of dry-cured hams. Indeed, the hams from barrows were depreciated compared with the hams from gilts for minor intensity, brightness, and uniformity of the lean, pinkish intermuscular fat and cured odor. In conclusion, barley could be used as a replacement for corn in heavy pig diets for the production of PDO Italian products without negative effects on the physicochemical, color, or sensory characteristics of meat products. PMID- 26440351 TI - Impact of divergent selection for ultimate pH of pectoralis major muscle on biochemical, histological, and sensorial attributes of broiler meat. AB - The impact of divergent selection based on the ultimate pH (pHu) of pectoralis major (P. major) muscle on the chemical, biochemical, and histological profiles of the muscle and sensorial quality of meat was investigated in broiler chickens. The protein, lipid, DM, glycogen and lactate content, glycolytic potential, proteolysis, lipid and protein oxidation index, muscle fiber cross-sectional area, capillary density, and collagen surface were determined on the breast P. major muscle of 6-wk-old broilers issued from the high-pHu (pHu+) and low-pHu (pHu-) lines. Sensory attributes were also evaluated on the breast (roasted or grilled) and thigh (roasted) meat of the 2 lines. Protein, lipid, and DM content of P. major muscle were not affected by selection ( > 0.05). However, the P. major muscle of the pHu+ line was characterized by lower residual glycogen (-16%; <= 0.001) and lactate (-14%; <= 0.001) content and lower glycolytic potential ( 14%; <= 0.001) compared with the pHu- line. Although the average cross-sectional area of muscle fibers and surface occupied by collagen were similar ( > 0.05) in both lines, fewer capillaries per fiber (-15%; <= 0.05) were observed in the pHu+ line. The pHu+ line was also characterized by lower lipid oxidation (thiobarbituric acid reactive substance index: -23%; <= 0.05) but protein oxidation and proteolysis index were not different ( > 0.05) between the 2 lines. At the sensory level, selection on breast muscle pHu mainly affected the texture of grilled and roast breast meat, which was judged significantly more tender ( <= 0.001) in the pHu+ line, and the acid taste, which was less pronounced in the roasted breast meat of the pHu+ line ( <= 0.002). This study highlighted that selection based on pHu does not affect the chemical composition and structure of breast meat. However, by modifying muscle blood supply and glycogen turnover, it affects meat acidity and oxidant status, both of which are likely to contribute to the large differences in texture observed between the 2 lines. PMID- 26440352 TI - Effects of supplemental lysine and methionine with zilpaterol hydrochloride on feedlot performance, carcass merit, and skeletal muscle fiber characteristics in finishing feedlot cattle. AB - Feeding zilpaterol hydrochloride (ZH) with ruminally protected AA was evaluated in a small-pen feeding trial. Crossbred steers ( = 180; initial BW = 366 kg) were blocked by weight and then randomly assigned to treatments (45 pens; 9 pens/treatment). Treatment groups consisted of no ZH and no AA (Cont-), ZH and no AA (Cont+), ZH and a ruminally protected lysine supplement (Lys), ZH and a ruminally protected methionine supplement (Met), and ZH and ruminally protected lysine and methionine (Lys+Met). Zilpaterol hydrochloride (8.3 mg/kg DM) was fed for the last 20 d of the finishing period with a 3-d withdrawal period. Lysine and Met were top dressed daily for the 134-d feeding trial to provide 12 or 4 g.hd.d, respectively, to the small intestine. Carcass characteristics, striploins, and prerigor muscle samples were collected following harvest at a commercial facility. Steaks from each steer were aged for 7, 14, 21, and 28 d, and Warner-Bratzler shear force (WBSF) was determined as an indicator of tenderness. Prerigor muscle samples were used for immunohistological analysis. Cattle treated with Met and Lys+Met had increased final BW ( < 0.3) and ADG ( < 0.05) compared to Cont- and Cont+. Supplementation of Lys, Met, and Lys+Met improved G:F ( < 0.05) compared to Cont- during the ZH feeding period (d 111 to 134) as well as the entire feeding period ( < 0.05). Zilpaterol hydrochloride increased carcass ADG ( < 0.05) when compared to non-ZH-fed steers. Methionine and Lys+Met treatments had heavier HCW ( < 0.02) than that of Cont-. Yield grade was decreased ( < 0.04) for Cont+ steers compared to steers treated with Lys, Lys+Met, and Cont-. Tenderness was reduced ( < 0.05) with ZH regardless of AA supplementation. Lysine, Met, Lys+Met, and Cont+ had less tender steaks ( < 0.05) throughout all aging groups compared to Cont-. Steaks from Lys-treated steers were less tender ( < 0.05) than those of Cont+ during the 7- and 14-d aging periods. Nuclei density was the greatest with Cont- cattle compared to all other treatments suggesting a dilution effect of the nuclei in the larger muscle fibers with ZH feeding. Supplementation of Met in conjunction with ZH feeding increased ADG and HCW although this may lead to decreased tenderness even after aging for 28 d. These findings indicated that steers fed ZH may require additional AA absorbed from the small intestine to maximize performance. PMID- 26440353 TI - Carcass traits and cutting yields of entire and immunocastrated pigs fed increasing protein levels with and without ractopamine hydrochloride supplementation. AB - The objective of this study was to determine the effects of increasing balanced protein, with and without ractopamine hydrochloride (RAC), in the finisher diets of immunocastrates on their carcass cutting yields and respective muscle, fat, and bone proportions. Carcass traits and yields of 120 individually housed entire male pigs and immunocastrates were evaluated following a 2 * 2 * 3 factorial design. Vaccination occurred at 16 and 20 wk of age and slaughtering at 24 wk. Up until 20 wk of age, all pigs received a commercial grower diet. Low-, medium-, and high-protein (7.50, 9.79, and 12.07 g standardized ileal digestible [SID] lysine/kg, respectively) diets were then fed for the last 28 d with RAC supplemented at 0 or 10 mg/kg. Immunocastration and RAC supplementation increased ( = 0.003 and = 0.017, respectively) the live weight at slaughter. The interaction between sex and protein ( = 0.039) for caliper backfat depths showed greater backfat depths in immunocastrates fed medium protein whereas RAC decreased ( = 0.027) the caliper backfat depth. Feeding RAC increased the trotters ( = 0.040), tenderloins (fillets; < 0.001), shoulder ( = 0.002), hindquarter ( = 0.026), loin ( = 0.028), and belly ( = 0.044) percentages. The shoulder ( < 0.001), hindquarter ( < 0.001), and loin ( = 0.005) muscle percentages were increased and the hindquarter fat percentages were decreased ( = 0.032) with RAC supplementation. Immunocastration increased the belly cut ( = 0.006), loin fat ( < 0.001), and belly fat ( < 0.001) percentages. Therefore, carcass cutting and lean yields can be improved by RAC supplementation while decreasing the backfat depth, and the increase in backfat due to immunocastration could be avoided with the correct dietary protein level. PMID- 26440354 TI - Assessment of nonpenetrating captive bolt stunning followed by electrical induction of cardiac arrest in veal calves. AB - The purpose of this study was to evaluate the impact of nonpenetrating captive bolt stunning followed by electrical induction of cardiac arrest on veal calf welfare, veal quality, and blood yield. Ninety calves from the same farm were randomly assigned to 1 of 2 treatment groups in a balanced unpaired comparison design. The first treatment group (the "head-only" method-application of the pneumatic nonpenetrating stun to the frontal plate of the skull at the intersection of 2 imaginary lines extending from the lateral canthus to the opposite poll [CONTROL]) was stunned with a nonpenetrating captive bolt gun ( = 45). The second group ( = 45) was stunned with a nonpenetrating captive bolt gun followed by secondary electrical induction of cardiac arrest (the "head/heart" method-initial application of the pneumatic nonpenetrating captive bolt stun followed by 1 s application of an electrical stun to the ventral region of the ribcage directly caudal to the junction of the humerus and scapula while the stunned calf was in lateral recumbence [HEAD/HEART]). Stunning efficacy was the indicator of animal welfare used in this study. All calves were instantly rendered insensible by the initial stun and did not display common indicators of return to consciousness. For meat quality evaluation, all samples were collected from the 12th rib region of the longissimus thoracis. Meat samples were evaluated for color, drip loss, ultimate pH, cook loss, and Warner-Bratzler shear force. The L* values (measure of meat color lightness) were darker ( < 0.05) in the HEAD/HEART group (45.08 +/- 0.72) than the CONTROL group (47.10 +/- 0.72). There were no differences ( > 0.05) observed in a* (redness) and b* (yellowness) values between treatments. No differences ( > 0.05) were observed in drip loss, ultimate pH, cook loss, and Warner-Bratzler shear force. The blood yield from the CONTROL group (7,217.9 +/- 143.5 g) was greater ( < 0.05) than that from the HEAD/HEART group (6,656.4 +/- 143.5 g). Overall, the data indicated no difference between the CONTROL and HEAD/HEART groups with regard to animal welfare because the initial stun was effective in all calves. However, longissimus thoracis L* and blood yield were negatively impacted by the HEAD/HEART method. The data in this study suggest that secondary induction of cardiac arrest is not necessary with effective nonpenetrating captive bolt stunning in veal calves. PMID- 26440355 TI - A Nordic survey of management practices and owners' attitudes towards keeping horses in groups. AB - Keeping horses in groups is widely recommended but limited information is available about how this is implemented in practice. The aim of this survey was to describe how horses are kept in the Nordic countries in relation to sex, age, breed, and equestrian discipline and to assess owners' attitudes toward keeping horses in groups. Horse owners in Denmark, Finland, Norway, and Sweden were approached using a web-based questionnaire, which was translated into 4 languages and distributed online via equestrian forums, organizations, and social media. The number of respondents was 3,229, taking care of 17,248 horses. Only 8% of horses were never kept in groups, 47% were permanently grouped for 24 h/d, and 45% were stabled singly but grouped during turnout. Yearlings were most often permanently kept in groups (75%), mares and geldings more commonly during parts of the day (50 and 51%, respectively), and stallions were often kept alone (38%). Icelandic horses were more likely to be permanently kept in groups (36%) than warmbloods (16%) and ponies (15%). Twice as many competition horses (51%) were never grouped compared with horses used for breeding (20%) or leisure purposes (15%). The majority of respondents (86%) strongly agreed that group housing benefits horse welfare and that it is important for horses to have the company of conspecifics (92%). Nevertheless, not all horses were kept in groups, showing that attitudes toward group housing may not necessarily reflect current management. The risk of injury was a concern of many respondents (45%), as was introducing unfamiliar horses into already established groups (40%) and challenges in relation to feeding in groups (44%). Safety of people (23%) and difficulties handling group-kept horses (19%) were regarded as less problematic. Results suggest that the majority of horses have the possibility to freely interact with other horses, either as fulltime members of a group during 24 h/d or during turnout. Future research should address the extent to which being a part-time member of a group affects horse welfare. For permanent group housing to become more widespread, such as it is the case for most farm animals, future research could focus on solving some of the reoccurring problems perceived with keeping horses in groups. The dissemination of evidence-based information on all aspects around keeping horses in groups can ultimately stimulate further positive changes in the management of group-kept horses. PMID- 26440356 TI - Technical note: A method for assigning animals to treatment groups with unequal count per group that equalizes mean animal weight among groups. AB - Pastures available for grazing studies may be of unequal size and may have heterogeneous carrying capacity necessitating the assignment of unequal numbers of animals per pasture. To reduce experimental error, it is often desirable that the initial mean BW be similar among experimental units. The objective of this note is to present and illustrate the use of a method for assignment of animals to experimental units of different sizes such that the initial mean weight of animals in each unit is approximately the same as the overall mean. Two alternative models were developed and solved to assign each of 231 weaned steers () to 1 of 12 pastures with carrying capacity ranging from 5 to 26 animals per pasture. A solution to Model 1 was obtained in which the mean weights among pastures were approximately the same but the variances among pastures were heteroskedastic, meaning that weight variances across pens were different (-value < 0.05). An alternative model was developed (Model 2) and used to derive assignments with nearly equal mean weights and homoskedastic variances among pastures. PMID- 26440357 TI - Erratum. PMID- 26440358 TI - Headache attributed to masticatory myofascial pain: impact on facial pain and pressure pain threshold. AB - There is no clear evidence on how a headache attributed to temporomandibular disorder (TMD) can hinder the improvement of facial pain and masticatory muscle pain. The aim of this study was to measure the impact of a TMD-attributed headache on masticatory myofascial (MMF) pain management. The sample was comprised of adults with MMF pain measured according to the revised research diagnostic criteria for temporomandibular disorders (RDC/TMD) and additionally diagnosed with (Group 1, n = 17) or without (Group 2, n = 20) a TMD-attributed headache. Both groups received instructions on how to implement behavioural changes and use a stabilisation appliance for 5 months. The reported facial pain intensity (visual analogue scale--VAS) and pressure pain threshold (PPT--kgf cm( 2)) of the anterior temporalis, masseter and right forearm were measured at three assessment time points. Two-way anova was applied to the data, considering a 5% significance level. All groups had a reduction in their reported facial pain intensity (P < 0.001). Mean and standard deviation (SD) PPT values, from 1.33 (0.54) to 1.96 (1.06) kgf cm(-2) for the anterior temporalis in Group 1 (P = 0.016), and from 1.27 (0.35) to 1.72 (0.60) kgf cm(-2) for the masseter in Group 2 (P = 0.013), had significant improvement considering baseline versus the 5th month assessment. However, no differences between the groups were found (P > 0.100). A TMD-attributed headache in patients with MMF pain does not negatively impact pain management, but does change the pattern for muscle pain improvement. PMID- 26440359 TI - Trafficking of Gold Nanoparticles Coated with the 8D3 Anti-Transferrin Receptor Antibody at the Mouse Blood-Brain Barrier. AB - Receptor-mediated transcytosis has been widely studied as a possible strategy to transport neurotherapeutics across the blood-brain barrier (BBB). Monoclonal antibodies directed against the transferrin receptor (TfR) have been proposed as potential carrier candidates. A better understanding of the mechanisms involved in their cellular uptake and intracellular trafficking is required and could critically contribute to the improvement of delivery methods. Accordingly, we studied here the trafficking of gold nanoparticles (AuNPs) coated with the 8D3 anti-transferrin receptor antibody at the mouse BBB. 8D3-AuNPs were intravenously administered to mice and allowed to recirculate for a range of times, from 10 min to 24 h, before brain extraction and analysis by transmission electron microscope techniques. Our results indicated a TfR-mediated and clathrin-dependent internalization process by which 8D3-AuNPs internalize individually in vesicles. These vesicles then follow at least two different routes. On one hand, most vesicles enter intracellular processes of vesicular fusion and rearrangement in which the AuNPs end up accumulating in late endosomes, multivesicular bodies or lysosomes, which present a high AuNP content. On the other hand, a small percentage of the vesicles follow a different route in which they fuse with the abluminal membrane and open to the basal membrane. In these cases, the 8D3-AuNPs remain attached to the abluminal membrane, which suggests an endosomal escape, but not dissociation from TfR. Altogether, although receptor-mediated transport continues to be one of the most promising strategies to overcome the BBB, different optimization approaches need to be developed for efficient drug delivery. PMID- 26440360 TI - Stable Self-Assembly of Bovine alpha-Lactalbumin Exhibits Target-Specific Antiproliferative Activity in Multiple Cancer Cells. AB - Self-assembly of a protein is a natural phenomenon; however, the process can be performed under a suitable condition in vitro. Since proteins are nontoxic, biodegradable, and biocompatible in nature, they are used in various industrial applications such as biocatalyst, therapeutic agent, and drug carriers. Moreover, their flexible structural state and specific activity are being used as sensors and immensely attract many new applications. However, the inherent potential of protein self-assembly for various applications is yet to be explored in detail. In this study, spherical self-assembly of bovine alpha-lactalbumin (nsBLA) was synthesized using an optimized ethanol-mediated desolvation process with an average diameter of approximately 300 nm. The self-assembly was found to be highly stable against thermal, pH, and proteases stress. When nsBLA was administered in various cancer cells, it demonstrated high cytotoxicity in three different cancer cells via reactive oxygen species (ROS) generation, whereas it exhibited negligible toxicity in normal human and murine cells. When nsBLA was conjugated with folic acid, it improved the cytotoxicity and perhaps mediated through enhanced cellular uptake in cancer cells through binding with folate receptors. Further, experimental results confirmed that the cancer cell death induced by nsBLA was not caused by apoptosis but a necrotic-like death mechanism. When compared with a well-known protein-based anticancer agent BAMLET (bovine alpha-lactalbumin made lethal against tumor cell), the self-assembled BLA clearly exhibited higher cytotoxicity to cancer cells than BAMLET. While BAMLET exhibits poor biocompatibility, our nsBLA demonstrated excellent biocompatibility to normal cells. Therefore, in this study, we prepared self-assembled alpha lactalbumin that exhibits strong inherent antiproliferative potential in multiple cancer cells which can be used for efficient therapeutic approach in cancer. PMID- 26440361 TI - Serum leptin concentration in women of reproductive age with euthyroid autoimmune thyroiditis. AB - INTRODUCTION: Autoimmune thyroid disease (AITD) with elevated anti-thyroid peroxidase antibody (aTPO) levels appears in 12-25% of all women, apart from thyroid dysfunction. High titers of aTPO are more common in women with polycystic ovary syndrome and endometriosis. Elevated aTPO has been associated with infertility and poorer quality of life among euthyroid women, and may be related to other factors. OBJECTIVES: The aim of the study was to measure differences in serum leptin concentration between AITD+ and AITD- patients. Setting, patients and main outcome measures: The sample was comprised of 74 women who were hospitalized in the Department of Gynecological Endocrinology, Medical University of Warsaw. Data collected included age, body mass index (BMI), and serum aTPO, serum thyroid stimulating hormone (TSH), serum fT4, serum follitropin (FSH), serum estradiol and serum leptin. AITD positive status was defined as serum aTPO greater than 5.6 mIU/ml. RESULTS: Serum leptin concentrations were significantly higher in AITD+ patients compared to AITD- patients (17.13 ng/ml [SD 7.66] versus 12.78 ng/ml [SD 7.28]; p < 0.05). No differences by AITD status were found in age, BMI, TSH, FSH, estradiol and fT4. CONCLUSIONS: Serum leptin concentrations were higher in patients with AITD than in patients without AITD. PMID- 26440362 TI - Polyoxomolybdate-Calix[4]arene Hybrid: A Catalyst for Sulfoxidation Reactions with Hydrogen Peroxide. AB - An easily accessible polyoxomolybdate-calix[4]arene hybrid 1 has been synthesized and applied as a heterogeneous catalyst in the sulfoxidation of thioethers to sulfoxides and to sulfones under strictly stoichiometric amounts of 30% H2O2 in CH3CN as the solvent. This study represents the first promising example of successful employment of calixarenes-polyoxometalate (POM) hybrid materials in the area of catalytic oxidations. PMID- 26440363 TI - DNA double-strand breaks induced intractable glomerular fibrosis in renal allografts. AB - BACKGROUNDS: The relationship between DNA damage and glomerular fibrosis in renal allografts remains unclear. METHODS: We examined renal allograft specimens from 35 patients in which DNA double-strand breaks (DSBs) and glomerular fibrosis were detected by phospho-histone H2A.X (gamma-H2AX) expression and collagen (COL) types III, IV, and VI accumulation. We also examined the in vitro relationship between DNA damage and COL accumulation by mitomycin C (MMc)-induced DNA damage in human glomerular endothelial cells (HRGEc). RESULTS: The gamma-H2AX and COL type VI, which mainly accumulated in the subendothelial and mesangial regions, were positively correlated with the duration of the post-renal transplant (RT) period. In multiple regression analysis, the duration of the post-RT period and cg in the Banff '07 classification were identified as a significant predictor of COL type VI accumulation and gamma-H2AX expression in the glomerular capillaries. In addition, the gamma-H2AX-positive area was also identified as a predictor of glomerular accumulation of COL type VI. COL type VI was detected in the cytoplasm of the HRGEc, which was secreted into the supernatant after MMc stimulation with gamma-H2AX expression. The number of gamma-H2AX (-)/COL type VI (+) cells was inversely associated with the number of gamma-H2AX (+)/COL type VI (-) cells during 24-h MMc treatment. CONCLUSIONS: Our findings suggest that the long-term RT induces DSBs and HRGEc-secreted COL type VI accumulation in the glomerular capillaries, which might progress to intractable glomerular fibrosis. PMID- 26440365 TI - Serum long non-coding RNA, snoRNA host gene 5 level as a new tumor marker of malignant melanoma. PMID- 26440364 TI - PPP2R5C Couples Hepatic Glucose and Lipid Homeostasis. AB - In mammals, the liver plays a central role in maintaining carbohydrate and lipid homeostasis by acting both as a major source and a major sink of glucose and lipids. In particular, when dietary carbohydrates are in excess, the liver converts them to lipids via de novo lipogenesis. The molecular checkpoints regulating the balance between carbohydrate and lipid homeostasis, however, are not fully understood. Here we identify PPP2R5C, a regulatory subunit of PP2A, as a novel modulator of liver metabolism in postprandial physiology. Inactivation of PPP2R5C in isolated hepatocytes leads to increased glucose uptake and increased de novo lipogenesis. These phenotypes are reiterated in vivo, where hepatocyte specific PPP2R5C knockdown yields mice with improved systemic glucose tolerance and insulin sensitivity, but elevated circulating triglyceride levels. We show that modulation of PPP2R5C levels leads to alterations in AMPK and SREBP-1 activity. We find that hepatic levels of PPP2R5C are elevated in human diabetic patients, and correlate with obesity and insulin resistance in these subjects. In sum, our data suggest that hepatic PPP2R5C represents an important factor in the functional wiring of energy metabolism and the maintenance of a metabolically healthy state. PMID- 26440366 TI - Follicular Thyroid Carcinoma: How Have Histologic Diagnoses Changed in the Last Half-Century and What Are the Prognostic Implications? AB - BACKGROUND: Follicular thyroid carcinoma (FTC) comprises 10% of differentiated thyroid cancers. Diagnostic controversy and interobserver variability render the practical diagnosis of FTC difficult. Overall survival rates vary (46-97%). The aims of this study were to review FTC histologically at the authors' tertiary care institution and to evaluate long-term survival and recurrence. METHODS: Diagnostic slides from 66 FTC cases (1965-2007) were reviewed by three pathologists from two institutions (blinded to clinical outcomes), and consensus was obtained. Patient demographics, tumor characteristics, and treatment, survival, and recurrence data were collected. Thyroid cancer-specific and recurrence-free survival were calculated by original and reclassified diagnoses. RESULTS: Forty-seven cases (71%) were reclassified: 24 (36%) to papillary thyroid carcinoma (PTC), 18 (27%) to follicular adenoma (FA), and five (8%) to poorly differentiated carcinoma (PDC). Nineteen (29%) maintained a diagnosis of FTC. The extent of surgical resection and rates of radioiodine treatment did not differ by reclassification diagnosis. Pre-review FTC-specific survival was 83.5% and 75.1% at 10 and 20 years, respectively. Following contemporary reclassification, FTC specific survival was 77% and 33.7% at 10 and 20 years, respectively. There were no cancer-specific deaths in the FA or PTC groups. CONCLUSIONS: Over the past 50 years, changes in our understanding of the pathogenesis, histology, and behavior of thyroid carcinoma may partially account for the changes in histologic diagnosis. Elimination of PTC and FA "contaminants" led to decrease in survival following reclassification. Variability in histologic interpretation contributes to diagnostic challenges in follicular lesions. Histologic review of thyroid tumors for research studies is crucial, especially given the ever-changing diagnostic criteria. PMID- 26440367 TI - Stem cell research in Latin America: update, challenges and opportunities in a priority research area. AB - Stem cell research is attracting wide attention as a promising and fast-growing field in Latin America, as it is worldwide. Many countries in the region have defined Regenerative Medicine as a research priority and a focus of investment. This field generates not only opportunities but also regulatory, technical and operative challenges. In this review, scientists from Uruguay, Mexico, Chile, Brazil and Argentina provide their view on stem cell research in each of their countries. Despite country-specific characteristics, all countries share several issues such as regulatory challenges. Key initiatives of each country to promote stem cell research are also discussed. As a conclusion, it is clear that regional integration should be more emphasized and international collaboration, promoted. PMID- 26440369 TI - Revisiting dysanapsis: sex-based differences in airways and the mechanics of breathing during exercise. AB - NEW FINDINGS: What is the topic of this review? This review focuses on sex-based differences in the anatomy of the respiratory system, which manifest in mechanical ventilatory constraints and potentially alter the integrative response to exercise. What advances does it highlight? Recent evidence indicates that women have smaller conducting airways than men, even when matched for lung size. Consequently, women are more likely to experience mechanical ventilatory constraints to exercise hyperpnoea. Furthermore, at a given ventilation, women have a higher work and oxygen cost of breathing, both of which may lead to differences in the whole-body integrative response to dynamic exercise. Our understanding of the human ventilatory response to exercise is largely based on a historical body of literature focused primarily on male rather than female research subjects. In recent years, important sex-based differences in the anatomy of the human respiratory system have been identified; for a given lung size, women appear to have smaller-diameter conducting airways than men. The presence of such inherent differences in the tracheobronchial tree greatly affects the mechanics of airflow generation, especially during conditions of high ventilation rates, such as exercise. Data from a growing number of studies suggest that women may be more susceptible to respiratory system limitations during exercise than their male counterparts. Specifically, women are more likely to experience expiratory flow limitation and exercise-induced arterial hypoxaemia and have a higher metabolic cost of breathing for a given ventilation. Collectively, the available evidence suggests that sex differences in the ventilatory response to exercise are present and may have important ramifications for the integrated response to exercise; however, several fundamental questions remain unanswered. PMID- 26440368 TI - Induction of microglial toll-like receptor 4 by prothrombin kringle-2: a potential pathogenic mechanism in Parkinson's disease. AB - Microglia-mediated neuroinflammation may play an important role in the initiation and progression of dopaminergic (DA) neurodegeneration in Parkinson's disease (PD), and toll-like receptor 4 (TLR4) is essential for the activation of microglia in the adult brain. However, it is still unclear whether patients with PD exhibit an increase in TLR4 expression in the brain, and whether there is a correlation between the levels of prothrombin kringle-2 (pKr-2) and microglial TLR4. In the present study, we first observed that the levels of pKr-2 and microglial TLR4 were increased in the substantia nigra (SN) of patients with PD. In rat and mouse brains, intranigral injection of pKr-2, which is not directly toxic to neurons, led to the disruption of nigrostriatal DA projections. Moreover, microglial TLR4 was upregulated in the rat SN and in cultures of the BV 2 microglial cell line after pKr-2 treatment. In TLR4-deficient mice, pKr-2 induced microglial activation was suppressed compared with wild-type mice, resulting in attenuated neurotoxicity. Therefore, our results suggest that pKr-2 may be a pathogenic factor in PD, and that the inhibition of pKr-2-induced microglial TLR4 may be protective against degeneration of the nigrostriatal DA system in vivo. PMID- 26440370 TI - Community Health Needs Assessment: Potential for Population Health Improvement. AB - Derived from various health care policies and initiatives, the concept of population health has been newly adopted by health care and medicine. In particular, it has been suggested that the Patient Protection and Affordable Care Act provision that requires nonprofit hospitals to conduct a community health needs assessment (CHNA) and implement strategies to address health priorities has the potential to improve population health. A mixed methods study design was used to examine the potential for population health improvements to occur through the Internal Revenue Service (IRS)-mandated nonprofit hospital CHNA and planning processes. Methods involved a 2-phased approach composed of (1) content analysis of 95 CHNA/implementation strategies reports and (2) interviews with key informants, consultants, and community stakeholders involved in CHNA and planning processes. Although this is a great opportunity for the nonprofit hospital assessment and planning processes to influence population health outcomes, the findings from the first 3-year assessment and planning cycle (2011-2013) suggest this is unlikely. As nonprofit hospitals begin the second 3-year assessment and planning cycle, this article offers recommendations to increase the potential for nonprofit hospitals to improve population health. These recommendations include clarifying the purpose of IRS CHNA regulations, engaging community stakeholders in collaborative assessment and planning, understanding disease etiology and identifying and addressing broader determinants of health, adopting a public health assessment and planning model, and emphasizing population health improvement. (Population Health Management 2016;19:178-186). PMID- 26440371 TI - Magnetic Resonance Imaging Currently Fails to Fully Evaluate the Biceps-Labrum Complex and Bicipital Tunnel. AB - PURPOSE: To determine the diagnostic accuracy of magnetic resonance imaging (MRI) for biceps-labrum complex (BLC) lesions, including the extra-articular bicipital tunnel. METHODS: A retrospective review of 277 shoulders with chronic refractory BLC symptoms that underwent arthroscopic subdeltoid transfer of the long head of the biceps tendon (LHBT) to the conjoint tendon was conducted. Intraoperative lesions were categorized as "inside" (labral tears and dynamic LHBT incarceration), "junctional" (LHBT partial tears, LHBT subluxation, and biceps chondromalacia), or "bicipital tunnel" (extra-articular bicipital tunnel scar/stenosis, loose bodies, LHBT instability, and LHBT partial tears) based on anatomic location. Attending radiologist-generated MRI reports were graded dichotomously as positive or negative for biceps and labral damage and then compared with intraoperative findings. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for MRI with respect to intraoperative findings. RESULTS: With regard to inside lesions, MRI had an overall sensitivity, specificity, PPV, and NPV for labrum lesions of 77.3%, 68.2%, 57.3%, and 84.5% respectively. The sensitivity, specificity, PPV, and NPV of MRI for junctional lesions were 43.3%, 55.6%, 73.1%, and 26.0%, respectively. For the bicipital tunnel, MRI had a sensitivity, specificity, PPV, and NPV of 50.4%, 61.4%, 48.7%, and 63.0%, respectively. CONCLUSIONS: MRI was unreliable for ruling out BLC lesions among chronically symptomatic patients, including when the bicipital tunnel was affected. PMID- 26440372 TI - A Systematic Review of Meta-analyses Published in Arthroscopy: The Journal of Arthroscopic and Related Surgery. AB - PURPOSE: To determine whether the number of meta-analyses published by Arthroscopy: The Journal of Arthroscopic and Related Surgery has increased from the inception of the Journal through 2014. METHODS: A literature search of the Journal's Web site and Medline was carried out. All studies described as a "meta analysis" as well as systematic reviews that pooled data were included. The number of published meta-analyses was calculated and summarized by year of publication, region, topic, and level of evidence. RESULTS: The Journal's Web site search resulted in 517 citations for review, and the Medline search resulted in 400. After the results of each search were combined and duplicates were removed, a total of 60 studies were included in this review. The first published meta-analysis appeared in 2001. Of the 60 meta-analyses, 36 (60%) were published between 2013 and 2014. In light of the increase in the number of publications, a review of the design and conduct of a meta-analysis is presented in a straightforward question-and-answer format. CONCLUSIONS: The number of meta analyses appearing in Arthroscopy has increased over the past 2 decades. This increase highlights the importance of developing an understanding of the premise and components of a meta-analysis to allow the reader to critically appraise these studies. LEVEL OF EVIDENCE: Level IV, systematic review of Level I through IV meta-analyses. PMID- 26440373 TI - The Relationship Between Tibial Tuberosity-Trochlear Groove Distance and Abnormal Patellar Tracking in Patients With Unilateral Patellar Instability. AB - PURPOSE: To evaluate the role of tibial tuberosity-trochlear groove (TT-TG) distance in patellofemoral kinematics by retrospectively reviewing the dynamic computed tomography scans of patients with unilateral patellofemoral instability and comparing unstable and contralateral asymptomatic knees. METHODS: We reviewed all dynamic computed tomography scans obtained at one tertiary care hospital from 2008 through 2013 and identified 25 patients with a history of recurrent unilateral patellofemoral instability. During the scans, subjects performed active knee extension against gravity. Both knees were imaged simultaneously. Lateral patellar tilt (LPT) and bisect offset (BO) were measured to assess tracking. TT-TG distance was measured to assess alignment. Measurements were made in full extension, maximum flexion, and approximately 10 degrees increments in between. The significance level was set at P < .05. RESULTS: LPT, BO, and TT-TG distance were highest in extension and decreased with flexion. Measurements were higher in symptomatic than in asymptomatic knees, with significant differences identified for LPT, BO, and TT-TG distance at 5 degrees and 15 degrees and for TT-TG distance at 25 degrees and 35 degrees (P < .05). TT-TG distance was associated with LPT and BO, with r(2) values in symptomatic knees of 0.55 for TT TG distance and LPT and of 0.45 for TT-TG distance and BO. CONCLUSIONS: In patients with unilateral patellar instability, LPT, BO, and TT-TG distance are higher on the unstable side. An association exists between TT-TG distance and the tracking parameters studied, suggesting that TT-TG distance relates to patellar tracking, and a laterally positioned tibial tuberosity may predispose to instability episodes. LEVEL OF EVIDENCE: Level IV, diagnostic study. PMID- 26440374 TI - Coevolution of yeast mannan digestion: Convergence of the civilized human diet, distal gut microbiome, and host immunity. AB - The complex carbohydrates accessible to the distal gut microbiota (DGM) are key drivers in determining the structure of this ecosystem. Typically, plant cell wall polysaccharides and recalcitrant starch (i.e. dietary fiber), in addition to host glycans are considered the primary nutrients for the DGM; however, we recently demonstrated that alpha-mannans, highly branched polysaccharides that decorate the surface of yeast, are also nutrients for several members of Bacteroides spp. This relationship suggests that the advent of yeast in contemporary food technologies and the colonization of the intestine by endogenous fungi have roles in microbiome structure and function. Here we discuss the process of yeast mannan metabolism, and the intersection between various sources of intestinal fungi and their roles in recognition by the host innate immune system. PMID- 26440375 TI - Preliminary mutagenicity and genotoxicity evaluation of selected arylsulfonamide derivatives of (aryloxy)alkylamines with potential psychotropic properties. AB - Determination of the mutagenic and genotoxic liability of biologically active compounds is of great concern for preliminary toxicity testing and drug development. In this study, we focused on the evaluation of the mutagenic and genotoxic effects of selected arylsulfonamide derivatives of aryloxyethyl piperidines and pyrrolidines (1-8), classified as 5-HT7 receptor antagonist with antidepressant and procognitive properties, using in silico and in vitro methods: the Vibrio harveyi assay and the SOS/umu-test (umuC Easy CS test). Finally, the antimutagenic potential of tested compounds was evaluated with the V. harveyi assay. It was demonstrated that none of the examined compounds produced a positive response in in vitro assays and these results were in line with in silico prediction. Additionally, all the tested compounds demonstrated various antimutagenic potential, with compound 1 (5-chloro-N-((1-(2 phenoxyethyl)piperidin-4-yl)methyl)thiophene-2-sulfonamide) being the most active against NQNO-induced mutagenicity. PMID- 26440376 TI - Time-scales of hydrological forcing on the geochemistry and bacterial community structure of temperate peat soils. AB - Peatlands are an important global carbon reservoir. The continued accumulation of carbon in peatlands depends on the persistence of anoxic conditions, in part induced by water saturation, which prevents oxidation of organic matter, and slows down decomposition. Here we investigate how and over what time scales the hydrological regime impacts the geochemistry and the bacterial community structure of temperate peat soils. Peat cores from two sites having contrasting groundwater budgets were subjected to four controlled drought-rewetting cycles. Pore water geochemistry and metagenomic profiling of bacterial communities showed that frequent water table drawdown induced lower concentrations of dissolved carbon, higher concentrations of sulfate and iron and reduced bacterial richness and diversity in the peat soil and water. Short-term drought cycles (3-9 day frequency) resulted in different communities from continuously saturated environments. Furthermore, the site that has more frequently experienced water table drawdown during the last two decades presented the most striking shifts in bacterial community structure, altering biogeochemical functioning of peat soils. Our results suggest that the increase in frequency and duration of drought conditions under changing climatic conditions or water resource use can induce profound changes in bacterial communities, with potentially severe consequences for carbon storage in temperate peatlands. PMID- 26440377 TI - Dehydrated hereditary stomatocytosis. PMID- 26440378 TI - Diagnostic utility of NLR or PLR in predicting moderate/severe ovarian hyperstimulation syndrome: A biochemical aspect. PMID- 26440380 TI - Chemical recognition of fruit ripeness in spider monkeys (Ateles geoffroyi). AB - Primates are now known to possess well-developed olfactory sensitivity and discrimination capacities that can play a substantial role in many aspects of their interaction with conspecifics and the environment. Several studies have demonstrated that olfactory cues may be useful in fruit selection. Here, using a conditioning paradigm, we show that captive spider monkeys (Ateles geoffroyi) display high olfactory discrimination performance between synthetic odor mixtures mimicking ripe and unripe fruits of two wild, primate-consumed, Neotropical plant species. Further, we show that spider monkeys are able to discriminate the odor of ripe fruits from odors that simulate unripe fruits that become increasingly similar to that of ripe ones. These results suggest that the ability of spider monkeys to identify ripe fruits may not depend on the presence of any individual compound that mark fruit ripeness. Further, the results demonstrate that spider monkeys are able to identify ripe fruits even when the odor signal is accompanied by a substantial degree of noise. PMID- 26440379 TI - Inventory of PCBs in Chicago and Opportunities for Reduction in Airborne Emissions and Human Exposure. AB - Urban areas are important regional sources of airborne polychlorinated biphenyls (PCBs) and population-scale airborne exposure, yet a comprehensive bottom-up source inventory of PCB emissions has never been quantified at urban scales in the United States. Here we report a comprehensive parcel level inventory of PCB stocks and emissions for Chicago, Illinois, developed with a transferable method from publicly available data. Chicago's legacy stocks hold 276 +/- 147 tonnes ?PCBs, with 0.2 tonnes added annually. Transformers and building sealants represent the largest legacy categories at 250 and 20 tonnes, respectively. From these stocks, annual emissions rates of 203 kg for ?PCBs and 3 kg for PCB 11 explain observed concentrations in Chicago air. Sewage sludge drying contributes 25% to emissions, soils 31%, and transformers 21%. Known contaminated sites account for <1% of stocks and 17% of emissions to air. Paint is responsible for 0.00001% of stocks but up to 7% of ?PCBs emissions. Stocks and emissions are highly concentrated and not correlated with population density or demographics at the neighborhood scale. Results suggest that strategies to further reduce exposure and ecosystem deposition must focus on the largest emissions sources rather than the most contaminated sites or the largest closed source legacy stocks. PMID- 26440381 TI - An ex vivo potency assay to assess active drug levels of a GLP-1 agonistic peptide during preclinical safety studies. AB - BACKGROUND: During development of biologics, safety and efficacy assessments are often hampered by immune responses to the treatment. To assess active exposure of a drug peptide in a toxicology study, we developed an ex vivo potency assay which complemented the total drug quantification assay. METHODOLOGY: Compound activity was assessed in samples of treated monkeys by cell-based cAMP measurements. For each animal, activity was compared with its predose sample to which the compound has been added at the postdose concentration as determined by a total LC-MS/MS assay. CONCLUSION: We were able to show that despite a high total test compound level, activity was reduced tremendously in antidrug-antibody-positive monkeys. Therefore, the applied ex vivo potency assay supplements drug quantification methods to determine active exposures. PMID- 26440382 TI - Inhibition profiles of mono- and polyvalent FimH antagonists against 10 different Escherichia coli strains. AB - Mono- and polyvalent ligands with strong affinities for the mannose-binding adhesin FimH were synthesised, and their anti-adhesive properties against ten E. coli strains were compared in two cell-based assays. The compounds were assessed against the non-pathogenic E. coli K12 and nine strains isolated by coproculture or from patients with osteoarticular infections (OIs), Crohn's disease (CD) and urinary tract infections (UTIs). The results showed that the compounds could inhibit the whole set of bacterial strains but with marked differences in terms of effective concentrations. The relative inhibitory potency of the monovalent compounds was also conserved for the ten strains and in the two assays. These results clearly suggest that a potent monovalent anti-adhesive assessed on a single E. coli strain will probably be effective on a broad range of strains and may treat diverse E. coli infections (OIs, CD and UTIs). In contrast, the polyvalent compounds showed a significant strain-dependancy in preventing E. coli attachment to intestinal cells. The multivalent antiadhesive effect may therefore vary depending on the E. coli strain tested. PMID- 26440383 TI - Early Care and Education Settings Are Vital for Childhood Obesity Prevention. PMID- 26440384 TI - Predictors of Weight Loss in Young Adults. AB - BACKGROUND: Increased understanding of weight loss among healthy young people in naturalistic settings could inform the development of effective weight control programs. The aim of this study was to describe loss in BMI over 7 years in a population-based sample of healthy young adolescents (mean age 17 years at beginning of follow-up) and identify determinants of BMI loss. DESIGN AND METHOD: Data were available for 681 participants in the Nicotine Dependence in Teens Study (1999-2012), a longitudinal investigation of adolescents in Montreal (Canada). Loss in BMI was assessed between age 17 and 24 years. Potential predictors of BMI loss including age, sex, mother's education, worry about weight, physical activity, screen time, and cigarette smoking were studied in multivariable logistic regression. RESULTS: Males and females gained 2.0 and 1.4 BMI units, respectively, on average, between age 17 and 24 years. However, 9% of males and 14% of females experienced a loss in BMI >=1.0 unit. Female sex and a higher BMI at age 17 were associated with a higher probability of BMI loss, but none of age, mother's education, physical activity, screen time, or cigarette smoking were associated with BMI loss between ages 17 and 24. CONCLUSIONS: Whereas BMI increased on average between age 17 and 24 years in a population based sample of healthy young people, 12% of participants experienced a loss in BMI >=1 unit. Weight loss was highest among the heaviest persons and did not affect the prevalence of underweight. No single behavior at age 17 stands out as associated with predicting BMI loss. PMID- 26440385 TI - Body Mass Index Mediates the Effects of Low Income on Preschool Children's Executive Control, with Implications for Behavior and Academics. AB - BACKGROUND: Children from low-income backgrounds are more likely to have cognitive impairments, academic problems, and obesity. Biological mechanisms for the relationship between adiposity and neurocognitive functioning have been suggested, but the direction of effects is unclear. METHODS: The relations among income, BMI, and cognitive-behavioral functioning were modeled longitudinally. Children (n = 306) were assessed at 36-39 months (Time 1; T1) and 63-67 months (Time 4; T4) through anthropometry, measures of executive control (EC), delay ability (DA), and questionnaires on academic readiness, social competence, and behavioral adjustment. RESULTS: Income was positively related to T1 EC and DA and negatively related to T1 BMI. T1 BMI was negatively related to T4 EC, after controlling for T1 EC, but was unrelated to changes in DA. Neither T1 EC nor DA was related to changes in BMI. T4 EC predicted greater academic readiness and social competence and lower adjustment problems at T4. T4 BMI was related to higher T4 adjustment problems. There was an indirect effect of income on T4 EC through T1 BMI. There were indirect effects of T1 BMI on academic readiness, social competence, and adjustment through T4 EC. Children who were obese at T1 had a 19% lower rate of growth of EC, compared to nonobese children. CONCLUSIONS: BMI mediates the effect of income on children's EC and has negative implications for academic readiness, social competence, and behavioral adjustment. The dual impact of obesity and cognitive-behavioral problems underscores the importance of early identification of and intervention for overweight children which could have neurocognitive and social-emotional benefits. What's New: BMI mediates the effect of income on preschoolers' executive control (EC) and has negative implications for academic readiness and behavioral adjustment. EC and delay ability did not predict changes in BMI. Early identification of, and intervention for, overweight children may have neurocognitive and social-emotional benefits. PMID- 26440387 TI - Characteristics of Youth Presenting for Weight Management: Retrospective National Data from the POWER Study Group. AB - BACKGROUND: There are no existing multisite national data on obese youth presenting for pediatric weight management. The primary aim was to describe BMI status and comorbidities among youth with obesity presenting for pediatric weight management (PWM) at programs within the Pediatric Obesity Weight Evaluation Registry (POWER). METHODS: Data were collected from 2009-2010 among 6737 obese patients ages 2-17. Patients were classified in three groups by BMI (kg/m(2)) cutoffs and percent of the 95th percentile for BMI: (1) obesity; (2) severe obesity class 2; and (3) severe obesity class 3. Weighted percentages are presented for baseline laboratory tests, blood pressure, and demographics. Generalized logistic regression with clustering was used to examine the relationships between BMI status and comorbidities. RESULTS: Study youth were 11.6 +/- 3.4 years of age, 56% female, 31% black, 17% Hispanic, and 53% publicly insured. Twenty-five percent of patients had obesity (n = 1674), 34% (2337) had severe obesity class 2, and 41% (2726) had severe obesity class 3. Logistic regression revealed that males (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.5-2.0), blacks (OR, 1.7; 95% CI, 1.5-2.0), age <6 years (OR, 2.0; 95% CI, 1.5-2.6), and public insurance (OR, 1.8; 95% CI, 1.5-2.0) had a higher odds of severe obesity class 3. Severe obesity class 3 was associated with higher odds of laboratory abnormalities for hemoglobin A1c (OR, 1.7; 95% CI, 1.3-2.2), alanine aminotransferase >=40 U/L (OR, 1.9; 95% CI, 1.3-2.6), and elevated systolic blood pressure (OR, 2.5; 95% CI, 2.0-3.0). CONCLUSIONS: Youth with obesity need earlier access to PWM given that they are presenting when they have severe obesity with significant comorbidities. PMID- 26440386 TI - Healthier School Environment Leads to Decreases in Childhood Obesity: The Kearney Nebraska Story. AB - BACKGROUND: Schools play a role in addressing childhood obesity by implementing healthy eating and physical activity strategies. The primary aim of this case study was to describe prevalence of overweight and obesity among elementary school students in a rural Mid-western community between 2006 and 2012. The secondary aim was to use a novel approach called "population dose" to retrospectively evaluate the impact dose of each strategy implemented and its estimated potential population level impact on changes in overweight and obesity. METHODS: Weight and height were directly measured annually beginning in January 2006 to assess weight status, using BMI (kg/m(2)), for all kindergarten to fifth grade students (N ~ 2400 per year). Multiple evidence-based strategies were implemented in nine schools to increase physical activity and healthy eating behaviors. BMI reporting and revised school meal programs were implemented districtwide. Comprehensive school physical activity programs, school food environment, and supportive/promotional strategies were implemented at individual schools. RESULTS: The absolute change in prevalence of obesity (BMI >=95th percentile) decreased from 16.4% to 13.9%, indicating a 15.2% relative change in prevalence of obesity in 6 years. There was an inverse relationship between the number of strategies implemented and prevalence of overweight and obesity over time. CONCLUSIONS: District and school-level approaches have the potential to impact childhood obesity. Schools can successfully implement strategies to address overweight and obesity, but the extent of implementation between schools may vary. Population dose analysis can be used to estimate impact of clusters of strategies to address overweight/obesity. PMID- 26440388 TI - Hepatoprotective effect of cold-pressed Syzygium aromaticum oil against carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. AB - Contexts: Exposure to environmental pollutants such as carbon tetrachloride (CCl4) causes liver injuries. There are claims that extracts from Syzygium aromaticum (Linn.) Merrill & L.M.Perry, (Myrtaceae) protects from such injuries. OBJECTIVE: This study investigates the protective effects of cold-pressed S. aromaticum oil (CO) against CCl4-induced liver toxicity in rats. MATERIALS AND METHODS: CO was orally administered to rats in two doses (100 and 200 mg/kg) along with CCl4 (1 mL/kg in olive oil) for 8 weeks. Indices of liver and kidney functions, lipid profile, and peroxidation were evaluated in rats' serum and tissues. Fatty acids and bioactive lipids of CO were analyzed. RESULTS: High levels of monounsaturated fatty acids (39.7%) and polyunsaturated fatty acids (42.1%) were detected in CO. The oil contained high amounts of tocols and phenolics. The LD50 value at 24 h was approximately 5950 mg/kg. Treatment with 200 mg/kg CO resulted in a decrease of creatinine, urea, and uric acid levels to 0.86, 32.6, and 2.99 mg/dL, respectively. Levels of TL, TC, TAG, LDL-C, and VLDL C were decreased to 167, 195.3, 584.5, 74.6, and 39.0 mg/L, respectively, after 8 weeks of treatment. Hepatic malondialdehyde levels were reduced and glutathione levels were elevated in CO-treated rats. CO reduced the activities of AST, ALT, and ALP as well as kidney function markers, protein, and lipid profiles, respectively. Histopathological examination of liver indicated that CO treatment reduced fatty degenerations, cytoplasmic vacuolization, and necrosis. CONCLUSION: CO possessed a protective effect against CCl4-induced hepatotoxicity in rats, mediated possibly by the antioxidant properties of the oil. PMID- 26440389 TI - As I approach the end of my life.... PMID- 26440390 TI - Improving quality of informed consent in clinical research. PMID- 26440391 TI - Utility of portable monitoring in the diagnosis of obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is a common but underdiagnosed sleep disorder, which is associated with systemic consequences such as hypertension, stroke, metabolic syndrome, and ischemic heart disease. Nocturnal laboratory-based polysomnography (PSG) is the gold standard test for diagnosis of OSA. PSG consists of a simultaneous recording of multiple physiologic parameters related to sleep and wakefulness including electroencephalography (EEG), electrooculography (EOG), surface electromyography (EMG), airflow measurement using thermistor and nasal pressure transducer, pulse oximetry and respiratory effort (thoracic and abdominal). Multiple alternative and simpler methods that record respiratory parameters alone for diagnosing OSA have been developed in the past two decades. These devices are called portable monitors (PMs) and enable performing sleep studies at a lower cost with shorter waiting times. It has been observed and reported that comprehensive sleep evaluation coupled with the use of PMs can fulfill the unmet need for diagnostic testing in various out-of-hospital settings in patients with suspected OSA. This article reviews the available medical literature on PMs in order to justify the utility of PMs in the diagnosis of OSA, especially in resource-poor, high-disease burden settings. The published practice parameters for the use of these devices have also been reviewed with respect to their relevance in the Indian setting. PMID- 26440392 TI - Prevalence of angiotensin converting enzyme (ACE) gene insertion/deletion polymorphism in South Indian population with hypertension and chronic kidney disease. AB - CONTEXT: Chronic Kidney Disease (CKD) is associated with a high risk of developing further severe complications such as, cardiovascular disease and eventually End Stage Renal Disease (ESRD) leading to death. Hypertension plays a key role in the progression of renal failure and is also a chief risk factor for the occurrence of End Stage Renal Disease (ESRD). AIM: This study investigates the possible association of insertion (I) and deletion (D) polymorphism of ACE gene in patients of Chronic Kidney Disease (CKD) with and without hypertension (HT). SETTINGS AND DESIGN: Total 120 participants with 30 members in each group (Control, HT, CKD and CKD-HT) were chosen followed by informed consent. MATERIALS AND METHODS: Blood samples were collected and subjected to biochemical analyses and nested PCR amplification was performed to genotype the DNA, for ACE I/D using specific primers. STATISTICAL ANALYSIS: Statistical analyses were performed using SPSS version 13. Allele and genotypic frequency was calculated by direct gene counting method. Comparison of the different genotypes was done by using Chi square test. Odd's ratios were calculated with a 95% confidence interval limit. RESULTS: The ACE genotype were distributed as II, 27 (90%); DD, 2 (6.67%) and ID, 1 (3.33%) in control, II, 1 (3.33%); DD, 5 (16.67%) and ID, 24 (80%) in HT, II, 4 (13.33%); DD, 24 (80%) and ID, 2 (6.67%) in CKD and II, 0 (0%); DD, 2 (6.67%) and ID, 28 (93.33%) in CKD-HT group. CONCLUSIONS: D allele of ACE gene confers a greater role in genetic variations underlying CKD and hypertension. This result suggest that CKD patients should be offered analysis for defects in ACE I/D polymorphisms, especially if they are hypertensive. PMID- 26440393 TI - PIRO concept: staging of sepsis. AB - INTRODUCTION: Sepsis is common presenting illness to the emergency services and one of the leading causes of hospital mortality. Researchers and clinicians have realized that the systemic inflammatory response syndrome concept for defining sepsis is less useful and lacks specificity. The predisposition, infection (or insult), response and organ dysfunction (PIRO) staging of sepsis similar to malignant diseases (TNM staging) might give better information. MATERIALS AND METHODS: A prospective observational study was conducted in emergency medical services attached to medicine department of a tertiary care hospital in Northern India. Patients with age 18 years or more with proven sepsis were included in the first 24 hours of the diagnosis. Two hundred patients were recruited. Multivariate logistic regression analysis was done to assess the factors that predicted in-hospital mortality. RESULTS: Two hundred patients with proven sepsis, admitted to the emergency medical services were analysed. Male preponderance was noted (M: F ratio = 1.6:1). Mean age of study cohort was 50.50 +/- 16.30 years. Out of 200 patients, 116 (58%) had in-hospital mortality. In multivariate logistic regression analysis, the factors independently associated with in-hospital mortality for predisposition component of PIRO staging were age >70 years, chronic obstructive pulmonary disease, chronic liver disease, cancer and presence of foley's catheter; for infection/ insult were pneumonia, urinary tract infection and meningitis/encephalitis; for response variable were tachypnea (respiratory rate >20/minute) and bandemia (band >5%). Organ dysfunction variables associated with hospital mortality were systolic blood pressure <90mm Hg, prolonged activated partial thromboplastin time, raised serum creatinine, partial pressure of oxygen in arterial blood/ fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio <300, decreased urine output in first two hours of emergency presentation and Glasgow coma scale <=9. Each of the components of PIRO had good predictive capability for in-hospital mortality but the total score was more accurate than the individual score and increasing PIRO score was associated with higher in-hospital mortality. The area under receiver operating characteristic curve for cumulative PIRO staging system as a predictor of in-hospital mortality was 0.94. CONCLUSION: This study finds PIRO staging as an important tool to stratify and prognosticate hospitalised patients with sepsis at a tertiary care center. The simplicity of score makes it more practical to be used in busy emergencies as it is based on four easily assessable components. PMID- 26440394 TI - Prevalence of autism spectrum disorders among children (1-10 years of age) - findings of a mid-term report from Northwest India. AB - BACKGROUND: India is the second most populous country of the world. A large portion of the population of this country is below 20 years of age but still there is a paucity of information about the prevalence and incidence of many developmental disorders. This study was planned to estimate the prevalence of autism spectrum disorders (ASDs) in the selected areas (tribal, rural, and urban) of a northern state of India, Himachal Pradesh. METHODS: A cross-sectional two phase study was conducted covering all the children in the range of 1-10 years of age. Phase one included screening of all the children in the age group of 1-10 years, with the help of an indigenous assessment tool for autism. The sociodemographic profile of the participants was also recorded during phase one. Phase two involved the clinical evaluation of individuals who were suspected of autism on screening. RESULTS: The results show a prevalence rate of 0.9/1000. The highest prevalence rate was observed in the rural area. CONCLUSIONS: Socioeconomic status (SES) may be one of the fundamental indicators for ASDs in India. PMID- 26440395 TI - Intersecting pentagons as surrogate for identifying the use of mini mental state examination in assessment of dementia in a largely illiterate population. AB - BACKGROUND AND RATIONALE: The mini-mental state evaluation (MMSE) is often used to identify patients with dementia. One component of the MMSE is the intersecting pentagon copying (IPC) test, which may be difficult to be used in an illiterate population. MATERIALS AND METHODS: A post hoc analysis on an elderly population (60 years and above) from Himachal Pradesh was carried out. The data of only 1,513 elderly individuals out of a total of 2,000 participants with a score of more than 26 (nondemented) out of a possible score of 30 on cognitive battery available were used. The scores on the IPC were evaluated and their association with some demographic variables was also assessed. RESULTS: Illiterate participants, female participants, those with greater age, and the rural/tribal population groups faced the most difficulty in drawing the intersecting pentagons and even greater difficulty in drawing them correctly. DISCUSSION: The IPC presents challenges for people who are illiterate and the scoring method needs to be addressed and changed particularly when the test is used in largely illiterate populations. PMID- 26440396 TI - Incidence and factors associated with medication nonadherence in patients with mental illness: a cross-sectional study. AB - BACKGROUND: In spite of the progress made in the treatment of psychiatric disorders during the last few decades, nonadherence continues to be a frequent phenomenon, often associated with potentially severe clinical consequences and increased health-care costs. There are numerous factors associated with medication nonadherence in patients with mental illness. The aim of the study was to determine the incidence and factors associated with medication nonadherence among psychiatric outpatients. MATERIALS AND METHODS: A cross-sectional study was carried out in the outpatient psychiatric department of an Indian tertiary care private hospital over a period of 1 year. Patients aged 18 years and above who presented with mental illness as diagnosed by the International Classification of Diseases (ICD)-10 and who were receiving at least one psychotropic medication for at least 1 month were included in the study. Medication adherence was assessed using the Medication Adherence Rating Scale (MARS). RESULTS: Of the 400 patients, 172 (43%) were nonadherent to their prescribed medications. There is a statistically significant association between the education (P = 0.001), number of drugs (P = 0.002), family income (P = 0.013), and nonadherence. Among the 172 patients, 33.5 % were nonadherent to their therapy due to patient-related factors followed by drug-related factors (32%) and disease-related factors (31%). CONCLUSION: The overall incidence of medication nonadherence in patients with mental illness was 43%. Numerous factors contributed to medication nonadherence. Strategies need to be developed and implemented to enhance medication adherence, and thereby achieve a better therapeutic outcome in patients with mental illness. PMID- 26440397 TI - An audit of consent refusals in clinical research at a tertiary care center in India. AB - BACKGROUND AND RATIONALE: Ensuring research participants' autonomy is one of the core ethical obligations of researchers. This fundamental principle confers on every participant the right to refuse to take part in clinical research, and the measure of the number of consent refusals could be an important metric to evaluate the quality of the informed consent process. This audit examined consent refusals among Indian participants in clinical studies done at our center. MATERIALS AND METHODS: The number of consent refusals and their reasons in 10 studies done at our center over a 5-year period were assessed. The studies were classified by the authors according to the type of participant (healthy vs patients), type of sponsor (investigator-initiated vs pharmaceutical industry), type of study (observational vs interventional), level of risk [based on the Indian Council of Medical Research (ICMR) "Ethical Guidelines for Biomedical Research on Human Participants"], available knowledge of the intervention being studied, and each patient's disease condition. RESULTS: The overall consent refusal rate was 21%. This rate was higher among patient participants [23.8% vs. healthy people (14.9%); P = 0.002], in interventional studies [33.6% vs observational studies (7.5%); P < 0.0001], in pharmaceutical industry-sponsored studies [34.7% vs investigator-initiated studies (7.2%); P < 0.0001], and in studies with greater risk (P < 0.0001). The most common reasons for consent refusals were multiple blood collections (28%), inability to comply with the study protocol (20%), and the risks involved (20%). CONCLUSION: Our audit suggests the adequacy and reasonable quality of the informed consent process using consent refusals as a metric. PMID- 26440398 TI - Fish gall bladder consumption presenting as acute renal failure. AB - A forty two year old male was admitted with history of anuria and breathlessness following consumption of raw rohu fish gall bladder. He had azotemia and required hemodialysis. His renal failure improved over a period of about four weeks. Incidences have been reported from South East Asian countries associating consumption of raw rohu fish gall bladder with acute renal failure. PMID- 26440399 TI - Conducting evaluation in gestational diabetes. PMID- 26440400 TI - A case of probable bemiparin-induced heparin-induced thrombocytopenia type II managed with low-dose fondaparinux. PMID- 26440401 TI - A novel coumarin derivative, 8-methoxy chromen-2-one alleviates collagen induced arthritis by down regulating nitric oxide, NFkappaB and proinflammatory cytokines. AB - Ruta graveolens (Rue) is a well-known medicinal plant having anti-inflammatory and other healing properties. This contains many active phytochemicals such as coumarins which possess anti-inflammatory and anti-cancer activities. The present study was carried out to evaluate the therapeutic potential of a newly isolated coumarin derivative from rue plant, 8-methoxy-chromen-2-one (MCO) in the collagen induced arthritic (CIA) rat model. MCO showed inhibition of cytokines and NF kappaB in LPS stimulated J774 cells which prompted its possible use in animal. In CIA, arthritic index and arthritic score reduced markedly within 15days of MCO treatment at doses of 2mg and 20mg per kg body weight. Alleviation of joint damage in CIA animals on treatment with MCO was evident from radiographic and histological data. Behavioral studies by open field tests also showed convalescence in the MCO treated CIA rats. Further, escalated plasma levels of pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6, and also nitric oxide reduced significantly with the treatment. All these results indicate the therapeutic efficacy of MCO and its possible use as an anti-arthritic drug. PMID- 26440402 TI - Estrogen upregulates inflammatory signals through NF-kappaB, IFN-gamma, and nitric oxide via Akt/mTOR pathway in the lymph node lymphocytes of middle-aged female rats. AB - The alterations in the secretion of sex steroids, especially estrogen, in females throughout reproductive life and its decline with age alters the functions of the neuroendocrine-immune network and renders them susceptible to age-related diseases and cancers. This study investigates the mechanisms of estrogen-induced alterations in cell-mediated immune and inflammatory responses in the lymphocytes from lymph nodes (axillary and inguinal) of ovariectomized (OVX) middle-aged female rats. Ovariectomized middle-aged (MA) Sprague-Dawley female rats (n=8) were implanted with 17beta-estradiol (E2) 30-day release pellets (0.6 and 300MUg). At the end of the treatment period, lymph nodes (axillary and inguinal) were isolated and examined for serum 17beta-estradiol, lymphoproliferation, cytokine production, expression of p-Akt, p-mTOR, p-IkappaB-alpha and p-NF-kappaB (p50 and p65), extent of lipid peroxidation, nitric oxide (NO) production, cytochrome c oxidase activity and reactive oxygen species (ROS) production. There was an OVX-related decline in serum 17beta-estradiol level, Con A-induced lymphoproliferation, p-Akt and p-mTOR expression, and cytochrome c oxidase (COX) activity. E2 supplementation increased serum 17beta-estradiol level, lymphoproliferation, expression of p-Akt, p-mTOR, p-IkappaB-alpha and p-NF-kappaB (p50 and p65), lipid peroxidation, IFN-gamma, TNF-alpha, ROS and NO production, while it decreased IL-6 production. E2 mediates inflammatory responses by increasing the levels of NO and TNF-alpha by up regulating IFN-gamma and simultaneously promotes aging through the generation of free radicals as reflected by increased lipid peroxidation and ROS production in lymph nodes. These findings may have wide implications to immunity and inflammatory disorders including autoimmune diseases predominantly prevalent in females. PMID- 26440403 TI - Charge-transfer crystallites as molecular electrical dopants. AB - Ground-state integer charge transfer is commonly regarded as the basic mechanism of molecular electrical doping in both, conjugated polymers and oligomers. Here, we demonstrate that fundamentally different processes can occur in the two types of organic semiconductors instead. Using complementary experimental techniques supported by theory, we contrast a polythiophene, where molecular p-doping leads to integer charge transfer reportedly localized to one quaterthiophene backbone segment, to the quaterthiophene oligomer itself. Despite a comparable relative increase in conductivity, we observe only partial charge transfer for the latter. In contrast to the parent polymer, pronounced intermolecular frontier-orbital hybridization of oligomer and dopant in 1:1 mixed-stack co-crystallites leads to the emergence of empty electronic states within the energy gap of the surrounding quaterthiophene matrix. It is their Fermi-Dirac occupation that yields mobile charge carriers and, therefore, the co-crystallites-rather than individual acceptor molecules-should be regarded as the dopants in such systems. PMID- 26440405 TI - [Acute compartment syndrome after a bowling game]. AB - A 28-year-old male patient was initially conservatively treated by a general physician for muscle strain of the right calf after a bowling game. Due to increasing pain and swelling of the lower leg 5 days later, the differential diagnosis of a deep vein thrombosis was considered. Furthermore, the onset of neurological deficits and problems with raising the foot prompted inclusion of compartment syndrome in the differential diagnosis for the first time. Admission to hospital for surgical intervention was scheduled for the following day. At this point in time the laboratory results showed a negative d-dimer value and greatly increased C-reactive protein level. On day 6 a dermatofasciotomy was performed which revealed extensive muscular necrosis with complete palsy of the peroneal nerve. In the following lawsuit the patient accused the surgeon of having misdiagnosed the slow-onset compartment syndrome and thus delaying correct and mandatory treatment. The arbitration board ruled that the surgeon should have performed fasciotomy immediately on day 5 at the patient's consultation. The clinical presentation of progressive pain, swelling of the lower leg in combination with peroneal palsy must lead to the differential diagnosis of compartment syndrome resulting in adequate therapy. The delay of immediate surgery, therefore, was assessed to be faulty as this knowledge is to be expected of a surgeon. PMID- 26440404 TI - Influenza Virus Reassortment Is Enhanced by Semi-infectious Particles but Can Be Suppressed by Defective Interfering Particles. AB - A high particle to infectivity ratio is a feature common to many RNA viruses, with ~90-99% of particles unable to initiate a productive infection under low multiplicity conditions. A recent publication by Brooke et al. revealed that, for influenza A virus (IAV), a proportion of these seemingly non-infectious particles are in fact semi-infectious. Semi-infectious (SI) particles deliver an incomplete set of viral genes to the cell, and therefore cannot support a full cycle of replication unless complemented through co-infection. In addition to SI particles, IAV populations often contain defective-interfering (DI) particles, which actively interfere with production of infectious progeny. With the aim of understanding the significance to viral evolution of these incomplete particles, we tested the hypothesis that SI and DI particles promote diversification through reassortment. Our approach combined computational simulations with experimental determination of infection, co-infection and reassortment levels following co inoculation of cultured cells with two distinct influenza A/Panama/2007/99 (H3N2) based viruses. Computational results predicted enhanced reassortment at a given % infection or multiplicity of infection with increasing semi-infectious particle content. Comparison of experimental data to the model indicated that the likelihood that a given segment is missing varies among the segments and that most particles fail to deliver >=1 segment. To verify the prediction that SI particles augment reassortment, we performed co-infections using viruses exposed to low dose UV. As expected, the introduction of semi-infectious particles with UV-induced lesions enhanced reassortment. In contrast to SI particles, inclusion of DI particles in modeled virus populations could not account for observed reassortment outcomes. DI particles were furthermore found experimentally to suppress detectable reassortment, relative to that seen with standard virus stocks, most likely by interfering with production of infectious progeny from co infected cells. These data indicate that semi-infectious particles increase the rate of reassortment and may therefore accelerate adaptive evolution of IAV. PMID- 26440406 TI - Modulation of Limbic and Prefrontal Connectivity by Electroconvulsive Therapy in Treatment-resistant Depression: A Preliminary Study. AB - BACKGROUND: Although current models of depression suggest that a sequential modulation of limbic and prefrontal connectivity is needed for illness recovery, neuroimaging studies of electroconvulsive therapy (ECT) have focused on assessing functional connectivity (FC) before and after an ECT course, without characterizing functional changes occurring at early treatment phases. OBJECTIVE: To assess sequential changes in limbic and prefrontal FC during the course of ECT and their impact on clinical response. METHODS: Longitudinal intralimbic and limbic-prefrontal networks connectivity study. We assessed 15 patients with treatment-resistant depression at four different time-points throughout the entire course of an ECT protocol and 10 healthy participants at two functional neuroimaging examinations. Furthermore, a path analysis to test direct and indirect predictive effects of limbic and prefrontal FC changes on clinical response measured with the Hamilton Rating Scale for Depression was also performed. RESULTS: An early significant intralimbic FC decrease significantly predicted a later increase in limbic-prefrontal FC, which in turn significantly predicted clinical improvement at the end of an ECT course. CONCLUSIONS: Our data support that treatment response involves sequential changes in FC within regions of the intralimbic and limbic-prefrontal networks. This approach may help in identifying potential early biomarkers of treatment response. PMID- 26440407 TI - Identification of Novel and Conserved microRNAs in Homalodisca vitripennis, the Glassy-Winged Sharpshooter by Expression Profiling. AB - The glassy-winged sharpshooter (GWSS) Homalodisca vitripennis (Hemiptera: Cicadellidae), is a xylem-feeding leafhopper and an important vector of the bacterium Xylella fastidiosa; the causal agent of Pierce's disease of grapevines. MicroRNAs are a class of small RNAs that play an important role in the functional development of various organisms including insects. In H. vitripennis, we identified microRNAs using high-throughput deep sequencing of adults followed by computational and manual annotation. A total of 14 novel microRNAs that are not found in the miRBase were identified from adult H. vitripennis. Conserved microRNAs were also found in our datasets. By comparison to our previously determined transcriptome sequence of H. vitripennis, we identified the potential targets of the microRNAs in the transcriptome. This microRNA profile information not only provides a more nuanced understanding of the biological and physiological mechanisms that govern gene expression in H. vitripennis, but may also lead to the identification of novel mechanisms for biorationally designed management strategies through the use of microRNAs. PMID- 26440408 TI - A biomechanical evaluation of CNT-grown bone. AB - Beside their biochemical properties, the exceptional mechanical characteristics of carbon nanotubes (CNTs) suggested growing a reinforced composite material very similar to natural bone in structure and chemical composition, but significantly stronger and stiffer. This is where biomechanical considerations portray themselves to justify the need for further investigations, in order to verify the applicability of CNTs as scaffolds that may ease bone regeneration and simultaneously raise its mechanical strength and durability. This research, using several modeling approaches, attempts to look at some of the mechanical changes likely to take place in the promised artificial tissue, while considering the relationships between mechanical and living functions of bone, particularly the remodeling process. Results suggest that notwithstanding the significant improvements induced to the mechanical behavior of the artificial tissue, applications of such stiff inclusions as CNTs in reinforcing the material of bone may detrimentally change the thresholds of mechanical stimuli that are essential for the initiation and resumption of the bone remodeling process. PMID- 26440409 TI - A surge of late-occurring meiotic double-strand breaks rescues synapsis abnormalities in spermatocytes of mice with hypomorphic expression of SPO11. AB - Meiosis is the biological process that, after a cycle of DNA replication, halves the cellular chromosome complement, leading to the formation of haploid gametes. Haploidization is achieved via two successive rounds of chromosome segregation, meiosis I and II. In mammals, during prophase of meiosis I, homologous chromosomes align and synapse through a recombination-mediated mechanism initiated by the introduction of DNA double-strand breaks (DSBs) by the SPO11 protein. In male mice, if SPO11 expression and DSB number are reduced below heterozygosity levels, chromosome synapsis is delayed, chromosome tangles form at pachynema, and defective cells are eliminated by apoptosis at epithelial stage IV at a spermatogenesis-specific endpoint. Whether DSB levels produced in Spo11 (+/ ) spermatocytes represent, or approximate, the threshold level required to guarantee successful homologous chromosome pairing is unknown. Using a mouse model that expresses Spo11 from a bacterial artificial chromosome, within a Spo11 (-/-) background, we demonstrate that when SPO11 expression is reduced and DSBs at zygonema are decreased (approximately 40 % below wild-type level), meiotic chromosome pairing is normal. Conversely, DMC1 foci number is increased at pachynema, suggesting that under these experimental conditions, DSBs are likely made with delayed kinetics at zygonema. In addition, we provide evidences that when zygotene-like cells receive enough DSBs before chromosome tangles develop, chromosome synapsis can be completed in most cells, preventing their apoptotic elimination. PMID- 26440410 TI - Sex chromosome recombination failure, apoptosis, and fertility in male mice. AB - Lack of crossing-over in meiosis can trigger an apoptotic response at metaphase I by the spindle assembly checkpoint (SAC). In contrast to females, segregation of sex chromosomes in males poses a particular challenge as recombination and chiasma formation is restricted to the pseudoautosomal region, the small region of homology between X and Y chromosomes. Existing data indicate that low levels of crossover failure in male meiosis can be tolerated without compromising fertility, while high levels of X-Y dissociation (in >=70 % of cells) result in widespread apoptosis and subsequent infertility, demonstrated earlier, e.g., in Spo11beta-only mice. Here, we explore the threshold of X-Y recombination failure frequency that is compatible with fertility. We show that in Spo11beta-only(mb) mice with a mixed genetic background, in contrast to Spo11beta-only mice with a C57BL/6 background, X-Y pairing fails in ~50 % of cells but this still allows for sperm production without any overt impact on fertility. We also review data on apoptosis and fertility from other achiasmate mouse models and propose that the incidence of homolog dissociation that can be tolerated in vivo without compromising male fertility lies between 50 and 70 %. PMID- 26440411 TI - Anti-IL-20 Monoclonal Antibody Suppresses Prostate Cancer Growth and Bone Osteolysis in Murine Models. AB - Interleukin (IL)-20 is a proinflammatory cytokine in the IL-10 family. IL-20 is associated with tumor promotion in the pathogenesis of oral, bladder, and breast cancer. However, little is known about the role of IL-20 in prostate cancer. We hypothesize that IL-20 promotes the growth of prostate cancer cells. Immunohistochemical staining showed that IL-20 and its receptors were expressed in human PC-3 and LNCaP prostate cancer cell lines and in prostate tumor tissue from 40 patients. In vitro, IL-20 upregulated N-cadherin, STAT3, vimentin, fibronectin, RANKL, cathepsin G, and cathepsin K, and increased the migration and colony formation of prostate cancer cells via activated p38, ERK1/2, AKT, and NF kappaB signals in PC-3 cells. We investigated the effects of anti-IL-20 monoclonal antibody 7E on prostate tumor growth in vivo using SCID mouse subcutaneous and intratibial xenograft tumor models. In vivo, 7E reduced tumor growth, suppressed tumor-mediated osteolysis, and protected bone mineral density after intratibial injection of prostate cancer cells. We conclude that IL-20 is involved in the cell migration, colony formation, and tumor-induced osteolysis of prostate cancer. Therefore, IL-20 might be a novel target for treating prostate cancer. PMID- 26440412 TI - Invasion and Colonisation of a Tropical Stream by an Exotic Loricariid Fish: Indices of Gradual Displacement of the Native Common Pleco (Hypostomus punctatus) by the Red Fin Dwarf Pleco (Parotocinclus maculicauda) over Fifteen Years. AB - The introduction of invasive species represents a major threat to the integrity of stream-dwelling fish populations worldwide, and this issue is receiving increasing attention from scientists, in particular because of potential impact on biodiversity. In this study, we analysed the dispersal of an exotic loricariid fish the red fin dwarf pleco (Parotocinclus maculicauda) in a stream of the Atlantic Forest biome in coastal south-eastern Brazil and evaluated the effects of this invasion on the native loricariid common pleco (Hypostomus punctatus). Specimens were collected at eight sites located along the course of the stream over a 15-year period. The distribution and density of the two species were determined by the Successive Removal Method. The introduction of P. maculicauda occurred in the medium sector of the stream, and during the course of the study, the species dispersed to new sites further upstream. By the end of the study, it was found at all points upstream from the original site. Hypostomus punctatus was registered at all sample sites both before and after the introduction of P. maculicauda, but its density decreased at all upstream sites after the arrival of the exotic species. Our analysis shows that colonisation by P. maculicauda seems to have a negative effect on H. punctatus densities. The maintenance of H. punctatus densities at the sites not colonised by P. maculicauda reinforces the conclusion that the colonisation of the stream by the exotic species had deleterious effects on the density of the resident H. punctatus populations, either by direct or indirect action. PMID- 26440414 TI - Fabrication of ultra-thin silicon nanowire arrays using ion beam assisted chemical etching. AB - Uniform dispersion of Au-Ag alloy nanoparticles underneath the surface of a Si wafer is realized via Au film pre-deposition and Ag ion implantation. The Au-Ag nanoparticles are used as catalysts in metal assisted chemical etching for fabricating Si nanowire arrays with average diameters of less than 10 nm. We find that the alloy catalysts introduced by ion implantation are the key to obtaining thin nanowire arrays and we also demonstrate that SiNWAs with various diameters could be simply produced by changing the thickness of the pre-deposited Au layer. Compared with the traditional process, ion beam assisted chemical etching is proven to be a convenient and efficient approach to fabricate ultra-thin SiNWAs on a large scale. PMID- 26440413 TI - Pollen Morphology and Boron Concentration in Floral Tissues as Factors Triggering Natural and GA-Induced Parthenocarpic Fruit Development in Grapevine. AB - Parthenocarpic fruit development (PFD) reduces fruit yield and quality in grapevine. Parthenocarpic seedless berries arise from fruit set without effective fertilization due to defective pollen germination. PFD has been associated to micronutrient deficiency but the relation of this phenomenon with pollen polymorphism has not been reported before. In this work, six grapevine cultivars with different tendency for PFD and grown under micronutrient-sufficient conditions were analyzed to determine pollen structure and germination capability as well as PFD rates. Wide variation in non-germinative abnormal pollen was detected either among cultivars as well as for the same cultivar in different growing seasons. A straight correlation with PFD rates was found (R2 = 0.9896), suggesting that natural parthenocarpy is related to defective pollen development. Such relation was not observed when PFD was analyzed in grapevine plants exposed to exogenous gibberellin (GA) or abscissic acid (ABA) applications at pre anthesis. Increase (GA treatment) or reduction (ABA treatment) in PFD rates without significative changes in abnormal pollen was determined. Although these plants were maintained at sufficient boron (B) condition, a down-regulation of the floral genes VvBOR3 and VvBOR4 together with a reduction of floral B content in GA-treated plants was established. These results suggest that impairment in B mobility to reproductive tissues and restriction of pollen tube growth could be involved in the GA-induced parthenocarpy. PMID- 26440415 TI - Efficiency of a New Mesh-Type Nebulizer (NE-SM1 NEPLUS) for Intrapulmonary Delivery of Ipratropium Bromide in Surgical Patients. AB - This study was aimed to evaluate the efficiency of a new mesh-type nebulizer for the intrapulmonary delivery of ipratropium bromide in surgical patients under mechanical ventilation. A total of 20 patients were randomly allocated to receive 0.5 mg ipratropium bromide using either a control (Pariboy SX, Pari, Co., Starnberg, Germany, n = 10) or test (NE-SM1 NEPLUS, KTMED INC., Seoul, Korea, n = 10) nebulizer during general anaesthesia. Ipratropium bromide was nebulized continuously for 20 min. in each group. Plasma concentrations of ipratropium bromide were obtained from blood samples at preset intervals. Non-compartmental analysis of ipratropium bromide was performed to compare the efficiency of pulmonary drug delivery in both nebulizers. Population pharmacokinetic analysis of ipratropium bromide was performed. Additionally, the noise level during the nebulizer operation and the aerosol particle size for each device were measured. The dose-normalized AUC(last) was 0.10 min/L for both nebulizers. The pharmacokinetics of nebulized ipratropium bromide can be described best by a one compartment model with first-order absorption. The apparent volume of distribution and metabolic clearance were 1340 L and 6.78 L/min, respectively. Type of nebulizer was a significant covariate for absorption rate constant. The equivalent sound level and median aerosol particle diameter were 35.0 dB and 4.52 MUm for the test nebulizer, and 60.2 dB and 3.85 MUm for the control nebulizer, respectively. From the standpoint of the dose-normalized AUC(last) , a new vibrating mesh-type nebulizer shows similar performance in the intrapulmonary delivery of ipratropium bromide to that of a jet-type nebulizer in surgical patients. PMID- 26440417 TI - Current Use of Pain Scores in Dutch Intensive Care Units: A Postal Survey in the Netherlands. AB - BACKGROUND: Pain is a common problem for critically ill patients treated in the intensive care unit (ICU) and can have serious consequences. For this reason, the appropriate recognition and treatment of pain is of extreme importance. However, pain assessment in critically ill patients can be challenging because these patients are often unable to self-report. To identify attitudes and practices regarding the assessment and management of pain in ICU patients unable to self report, we surveyed all adult ICUs in the Netherlands. METHODS: A multicenter, exploratory survey was sent by mail to all adult ICUs in the Netherlands. RESULTS: Eighty-four of 107 ICUs returned the questionnaire for a response rate of 79%. In patients able to self-report, 94% (n = 79; 95% confidence interval [CI], 86.7%-98%) of the ICUs used a standardized pain score. Visual Analog Scale and Numerical Rating Scale were used in 57% (n = 48; 99.3% CI, 41%-72%) and 48% (n = 40; 99.3% CI, 33%-64%), respectively. Nonteaching hospitals used pain assessment tools more often than teaching hospitals (P = 0.012). In patients not able to self-report, pain assessment tools were used in 19% (n = 16) of the ICUs. In the ICUs that used behaviorally based scoring systems, the Critical Care Pain Observation Tool and Behavioral Pain Scale (BPS) were used in 6% (n = 5; 99.5% CI, 1.1%-17%) and 5% (n = 4; 99.5% CI, 0.1%-15%), respectively. Among Dutch nurses, nursing opinion was considered the gold standard assessment in 36% (n = 30; 98.8% CI, 23%-50%) of the respondents, even when a patient was able to self report and pain scales were used. In patients unable to self-report, nurses judged themselves to be more accurate than a behavioral pain assessment tool in 98% (n = 82; 98.8% CI, 89.7%-99.9%) of the patients. CONCLUSIONS: In the Netherlands, most ICUs used a standardized pain score in patients able to self report. Nonteaching hospitals used pain assessment tools more often than teaching hospitals. In patients unable to self-report, pain is not routinely measured with a validated behavioral pain assessment tool. Almost all nurses in our survey felt that their assessment of patient pain was more accurate than behavioral pain assessment tools in patients unable to self-report. More research is needed to identify factors preventing more widespread acceptance of validated behavioral pain scores in patients unable to self-report. PMID- 26440419 TI - Regulation of the NR2B-CREB-CRTC1 Signaling Pathway Contributes to Circadian Pain in Murine Model of Chronic Constriction Injury. AB - BACKGROUND: Numerous clinical investigations have revealed the circadian rhythm changes in the perception of chronic pain, and most clinical chronic pain types peak in the night. However, it is still undiscovered whether circadian rhythm of pain exists in rodents and the specific mechanism that may underlie it. Our study was conducted to investigate the rhythmic changes of hyperalgesia behavior in a chronic constrictive injury (CCI) model of rodents and to explore the role of the N-methyl-d-aspartate receptor 2B (NR2B)-cAMP response element binding protein (CREB)-CREB-regulated transcription coactivator 1 (CRTC1) signaling pathway in this pain rhythm. METHODS: A CCI operation was performed to mimic clinical chronic pain. Paw mechanical withdrawal threshold and paw withdrawal thermal latency were used to test pain behavior in rats; a von Frey cilia test was used to test mechanical hyperalgesia in mice at Zeitgeber time (ZT) 4, ZT10, ZT16, and ZT22 for 14 contiguous days. The relative mRNA and protein expression of NR2B, CREB and CRTC1 in the suprachiasmatic nuclei and the dorsal horn were measured by real-time polymerase chain reaction and Western blot. CRTC1 and CREB interference adenovirus vectors were injected intrathecally at 2 time points, respectively (ZT12 and ZT0), to further explore the proper time point for pain treatment. RESULTS: During the period of chronic pain state, the pain behavior of CCI rodents showed a circadian rhythm with the peak at ZT4 or ZT10 daily. The pain thresholds were significantly different between the activity period and the rest period. The expressions of NR2B, CRTC1, and CREB at the spinal level were consistent with the pain rhythm. The intrathecal treatment with CRTC1 or CREB interference adenovirus from day 7 to day 9 after CCI surgery markedly improved pain behaviors. Nevertheless, when given at ZT0, they were both more effective at relieving peak pain than drugs given at ZT12. CONCLUSIONS: Pain behavior in the chronic pain of CCI displayed circadian rhythm and was associated with circadian secretion of pain-related receptors. The NR2B-CREB-CRTC1 signaling pathway may play a crucial role in this rhythm. Moreover, our results suggest that measures to relieve pain should be taken before pain reaches its peak. PMID- 26440418 TI - The Effects of Temperature on Clot Microstructure and Strength in Healthy Volunteers. AB - BACKGROUND: Anesthesia, critical illness, and trauma are known to alter thermoregulation, which can potentially affect coagulation and clinical outcome. This in vitro preclinical study explores the relationship between temperature change and hemostasis using a recently validated viscoelastic technique. We hypothesize that temperature change will cause significant alterations in the microstructural properties of clot. METHODS: We used a novel viscoelastic technique to identify the gel point of the blood. The gel point identifies the transition of the blood from a viscoelastic liquid to a viscoelastic solid state. Furthermore, identification of the gel point provides 3 related biomarkers: the elastic modulus at the gel point, which is a measure of clot elasticity; the time to the gel point (TGP), which is a measure of the time required to form the clot; and the fractal dimension of the clot at the gel point, df, which quantifies the microstructure of the clot. The gel point measurements were performed in vitro on whole blood samples from 136 healthy volunteers over a temperature range of 27 degrees C to 43 degrees C. RESULTS: There was a significant negative correlation between increases in temperature, from 27 degrees C to 43 degrees C, and TGP (r = -0.641, P < 0.0005). Conversely, significant positive correlations were observed for both the elastic modulus at the gel point (r = 0.513, P = 0.0008) and df (r = 0.777, P < 0.0005) across the range of 27 degrees C to 43 degrees C. When temperature was reduced below 37 degrees C, significant reductions in df and TGP occurred at <=32 degrees C (Bonferroni-corrected P = 0.0093) and <=29 degrees C (Bonferroni-corrected P = 0.0317), respectively. No significant changes were observed when temperature was increased to >37 degrees C. CONCLUSIONS: This study demonstrates that the gel point technique can identify alterations in clot microstructure because of changes in temperature. This was demonstrated in slower forming clots with less structural complexity as temperature is decreased. We also found that significant changes in clot microstructure occurred when the temperature was <=32 degrees C. PMID- 26440416 TI - GIMAP5 Deficiency Is Associated with Increased AKT Activity in T Lymphocytes. AB - Long-term survival of T lymphocytes in quiescent state is essential to maintain their cell numbers in secondary lymphoid organs. In mice and in rats, the loss of functional GTPase of the immune associated nucleotide binding protein 5 (GIMAP5) causes peripheral T lymphopenia due to spontaneous death of T cells. The underlying mechanism responsible for the disruption of quiescence in Gimap5 deficient T cells remains largely unknown. In this study, we show that loss of functional Gimap5 results in increased basal activation of mammalian target of rapamycin (mTOR), independent of protein phosphatase 2A (PP2A) or AMP-activated protein kinase (AMPK). Our results suggest that the constitutive activation of the phosphoinositide 3-kinase (PI3K) pathway may be one of the consequences of the absence of functional GIMAP5. PMID- 26440420 TI - The Code of the Street and Violent Versus Property Crime Victimization. AB - Previous research has shown that individuals who adopt values in line with the code of the street are more likely to experience violent victimization (e.g., Stewart, Schreck, & Simons, 2006). This study extends this literature by examining the relationship between the street code and multiple types of violent and property victimization. This research investigates the relationship between street code-related values and 4 types of victimization (assault, breaking and entering, theft, and vandalism) using Poisson-based multilevel regression models. Belief in the street code was associated with higher risk of experiencing assault, breaking and entering, and vandalism, whereas theft victimization was not related to the street code. The results suggest that the code of the street influences victimization broadly--beyond violence--by increasing behavior that provokes retaliation from others in various forms. PMID- 26440422 TI - Bilateral Striatopallidodentate Calcinosis associated with Systemic Lupus Erythematosus: Case report and review of literature. PMID- 26440423 TI - Neuromyelitis optica spectrum disorder and varicella-zoster infection. PMID- 26440424 TI - Intermittent ascending muscle spasms and paraparesis associated with diffuse extradural meningeal cysts. PMID- 26440426 TI - Fear and time: Fear speeds up the internal clock. AB - We tested time perception in a bisection task featuring a wide range of durations (from 0.2 to about 8.0s) and highly arousing stimuli (delivery of an electric shock). In addition, self-report questionnaire responses and skin conductance responses were assessed to measure emotional reactivity. Results clearly demonstrated emotion-related time distortion, as stimulus durations were judged to be longer in the trials with an electric shock than in those without one. In addition, this lengthening effect increased with the length of durations. These findings are consistent with the hypothesis of an arousal-induced speeding up of the internal clock system. PMID- 26440427 TI - Trends Form Follows Function: New Ways to Inform and Inspire. PMID- 26440425 TI - PERIOD3 polymorphism is associated with sleep quality recovery after a mild traumatic brain injury. AB - BACKGROUND AND AIM: Mild traumatic brain injury (mTBI) causes transient sleep disorders and circadian dysrhythmia. One of the clock genes, PERIOD3 (PER3), regulates the circadian rhythm and contains a genetic polymorphism, namely a variable-number tandem repeat in the coding area with either four or five repeats. PER3(5) carriers are inclined to have a morning preference and associated with higher risk of bipolar disorder and diabetes. This study investigated the effects of PER3 polymorphism on sleep quality changes after mTBI. MATERIALS AND METHODS: From May 2012 to May 2014, a total of 96 mTBI patients completed the baseline (1 week after mTBI) and follow-up (6 weeks after mTBI) assessments, including the Pittsburgh Sleep Quality Index (PSQI) and anxiety and depression questionnaires. Statistics were analyzed using the Mann Whitney U test, Wilcox signed-rank test or chi-squared test. RESULTS: Among the 96 patients, 24 were heterozygous PER3(5) carriers (PER3(4/5)), and the rest of 72 were PER3(5) noncarriers (PER3(4/4)). The subscale of PSQI questionnaire results indicated that the PER3(5) allele was associated with significant sleep duration shortening, but improvement in overall sleep quality. Furthermore, analyzing patients with sleep disturbance at the baseline (PSQI >5) revealed that only the PER3(5) noncarriers exhibited a significant improvement in overall PSQI scores. CONCLUSION: PER3(5) carriers exhibited sleep duration shortening and improved daytime function 6 weeks after mTBI compared with the baseline values. On the other hand, among poor sleepers, PER3(5) carriers did not embrace a significant improvement of overall PSQI scores as noncarriers. The underlying mechanisms and clinical significances must be investigated further. PMID- 26440421 TI - Emerging immunopharmacological targets in multiple sclerosis. AB - Inflammatory demyelination of the central nervous system (CNS) is the hallmark of multiple sclerosis (MS), a chronic debilitating disease that affects more than 2.5 million individuals worldwide. It has been widely accepted, although not proven, that the major pathogenic mechanism of MS involves myelin-reactive T cell activation in the periphery and migration into the CNS, which subsequently triggers an inflammatory cascade that leads to demyelination and axonal damage. Virtually all MS medications now in use target the immune system and prevent tissue damage by modulating neuroinflammatory processes. Although current therapies such as commonly prescribed disease-modifying medications decrease the relapse rate in relapsing-remitting MS (RRMS), the prevention of long-term accumulation of deficits remains a challenge. Medications used for progressive forms of MS also have limited efficacy. The need for therapies that are effective against disease progression continues to drive the search for novel pharmacological targets. In recent years, due to a better understanding of MS immunopathogenesis, new approaches have been introduced that more specifically target autoreactive immune cells and their products, thus increasing specificity and efficacy, while reducing potential side effects such as global immunosuppression. In this review we describe several immunopharmacological targets that are currently being explored for MS therapy. PMID- 26440428 TI - Urban Plantings: 'Living Laboratories' for Climate Change Response. AB - Urban plantings are not only valuable resources for understanding 'urban plant physiology' but are 'living laboratories' for understanding plant response to climate change. Therefore, we encourage researchers who currently work in natural ecosystems to consider how urban plantings could enhance their research into plant physiological responses to a changing climate. PMID- 26440429 TI - WOX5 is Shining in the Root Stem Cell Niche. AB - The WUS-RELATED HOMEOBOX 5 (WOX5) gene is expressed in the quiescent center (QC) to regulate the columella stem cell (CSC) identity. Three recent reports not only show how WOX5 is controlled but also highlight the key role of WOX5 in root stem cell niche maintenance. PMID- 26440430 TI - Diversity in Plant Breeding: A New Conceptual Framework. AB - Faced with an accelerating rate of environmental change and the associated need for a more sustainable, low-input agriculture, the urgent new challenge for crop science is to find ways to introduce greater diversity to cropping systems. However, there is a dearth of generic formalism in programs seeking to diversify crops. In this opinion, we propose a new framework, derived from ecological theory, that should enable diversity targets to be incorporated into plant breeding programs. While ecological theory provides criteria for maintaining diversity and optimizing the production of mixtures, such criteria are rarely fully realized in natural ecosystems. Conversely, crop breeding should optimize both agronomic value and the ability of plants to perform and live alongside one another. This framework represents an opportunity to develop more sustainable crops and also a radical new way to apply ecological theory to cropping systems. PMID- 26440431 TI - Histone Acetylation Enzymes Coordinate Metabolism and Gene Expression. AB - Histone lysine acetylation is well known for being important in the epigenetic regulation of gene expression in eukaryotic cells. Recent studies have uncovered a plethora of acetylated proteins involved in important metabolic pathways, such as photosynthesis and respiration in plants. Enzymes involved in histone acetylation and deacetylation are being identified as regulators of acetylation of metabolic enzymes. Importantly, key metabolites, such as acetyl-CoA and NAD(+), are involved in protein acetylation and deacetylation processes, and their cellular levels may regulate the activity of histone acetyltransferases (HAT) and deacetylases (HDAC). Further research is required to determine whether and how HATs and HDACs sense cellular metabolite signals to control gene expression and metabolic enzyme activity through lysine acetylation and deacetylation. PMID- 26440433 TI - Illuminating Progress in Phytochrome-Mediated Light Signaling Pathways. AB - Light signals regulate a plethora of plant responses throughout their life cycle, especially the red and far-red regions of the light spectrum perceived by the phytochrome family of photoreceptors. However, the mechanisms by which phytochromes regulate gene expression and downstream responses remain elusive. Several recent studies have unraveled the details on how phytochromes regulate photomorphogenesis. These include the identification of E3 ligases that degrade PHYTOCHROME INTERACTING FACTOR (PIF) proteins, key negative regulators, in response to light, a better view of how phytochromes inhibit another key negative regulator, CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1), and an understanding of why plants evolved multiple negative regulators to repress photomorphogenesis in darkness. These advances will surely fuel future research on many unanswered questions that have intrigued plant photobiologists for decades. PMID- 26440432 TI - The Engineered Chloroplast Genome Just Got Smarter. AB - Chloroplasts are known to sustain life on earth by providing food, fuel, and oxygen through the process of photosynthesis. However, the chloroplast genome has also been smartly engineered to confer valuable agronomic traits and/or serve as bioreactors for the production of industrial enzymes, biopharmaceuticals, bioproducts, or vaccines. The recent breakthrough in hyperexpression of biopharmaceuticals in edible leaves has facilitated progression to clinical studies by major pharmaceutical companies. This review critically evaluates progress in developing new tools to enhance or simplify expression of targeted genes in chloroplasts. These tools hold the promise to further the development of novel fuels and products, enhance the photosynthetic process, and increase our understanding of retrograde signaling and cellular processes. PMID- 26440434 TI - Host to a Stranger: Arabidopsis and Fusarium Ear Blight. AB - Fusarium ear blight (FEB) is a devastating fungal disease of cereal crops. Outbreaks are sporadic and current control strategies are severely limited. This review highlights the use of Arabidopsis to study plant-FEB interactions. Use of this pathosystem has identified natural variation in Fusarium susceptibility in Arabidopsis, and native plant genes and signalling processes modulating the interaction. Recent breakthroughs include the identification of plant- and insect derived small molecules which increase disease resistance, and the use of a host induced gene silencing (HIGS) construct to silence an important Fusarium gene to prevent infection. Arabidopsis has also been used to study other fungi that cause cereal diseases. These findings offer the potential for translational research in cereals which could yield much-needed novel control strategies. PMID- 26440435 TI - Gene Networks in Plant Biology: Approaches in Reconstruction and Analysis. AB - Even though vast amounts of genome-wide gene expression data have become available in plants, it remains a challenge to effectively mine this information for the discovery of genes and gene networks, for instance those that control agronomically important traits. These networks reflect potential interactions among genes and, therefore, can lead to a systematic understanding of the molecular mechanisms underlying targeted biological processes. We discuss methods to analyze gene networks using gene expression data, specifically focusing on four common statistical approaches used to reconstruct networks: correlation, feature selection in supervised learning, probabilistic graphical model, and meta prediction. In addition, we discuss the effective use of these methods for acquiring an in-depth understanding of biological systems in plants. PMID- 26440436 TI - Plant-PET Scans: In Vivo Mapping of Xylem and Phloem Functioning. AB - Medical imaging techniques are rapidly expanding in the field of plant sciences. Positron emission tomography (PET) is advancing as a powerful functional imaging technique to decipher in vivo the function of xylem water flow (with (15)O or (18)F), phloem sugar flow (with (11)C or (18)F), and the importance of their strong coupling. However, much remains to be learned about how water flow and sugar distribution are coordinated in intact plants, both under present and future climate regimes. We propose to use PET analysis of plants (plant-PET) to visualize and generate these missing data about integrated xylem and phloem transport. These insights are crucial to understanding how a given environment will affect plant physiological processes and growth. PMID- 26440437 TI - Tramadol wound infiltration is not different from intravenous tramadol in children: a randomized controlled trial. AB - STUDY OBJECTIVE: The purpose of this trial was to assess if tramadol wound infiltration is superior to intravenous (IV) tramadol after minor surgical procedures in children because tramadol seems to have local anesthetic-like effect. DESIGN: Randomized double-blind controlled trial. SETTING: Postanesthesia care unit. PATIENTS: Forty children, American Society of Anesthesiologists physical status I or II, scheduled to elective inguinal hernia repair. INTERVENTIONS: Children were randomly distributed in 1 of 2 groups: IV tramadol (group 1) or subcutaneous infiltration with tramadol (group 2). At the end of the surgery, group 1 received 2 mg/kg tramadol (3 mL) by IV route and 3-mL saline into the surgical wound; group 2 received 2 mg/kg tramadol (3 mL) into the surgical wound and 3-mL saline by IV route. MEASUREMENTS: In the postanesthesia care unit, patients were evaluated for pain intensity, nausea and vomiting, time to first rescue medication, and total rescue morphine and dipyrone consumption. MAIN RESULTS: Pain scores measured during the postanesthesia recovery time were similar between groups. Time to first rescue medication was shorter, but not statistically significant in the IV group. The total dose of rescue morphine and dipyrone was also similar between groups. CONCLUSIONS: We concluded that tramadol was effective in reducing postoperative pain in children, and there was no difference in pain intensity, nausea and vomiting, or somnolence regarding IV route or wound infiltration. PMID- 26440438 TI - Perioperative goal-directed hemodynamic therapy in noncardiac surgery: a systematic review and meta-analysis. AB - STUDY OBJECTIVE: Goal-directed fluid therapy (GDHT) has been proposed as a method to reduce complications and mortality. DESIGN: Meta-analysis of the effects of perioperative GDHT in adult noncardiac surgery on mortality and postoperative complications was performed using the PRISMA methodology. A systematic search was performed in MEDLINE, PubMed, EMBASE, and the Cochrane Library (last update, October 2014). Inclusion criteria were as follows: randomized clinical trials (RCTs) in which perioperative GDHT was compared with conventional fluid management in noncardiac surgery. Exclusion criteria were as follows: trauma and pediatric surgery studies. End points were mortality and number of patients with complications. SETTING: District general hospital. PATIENTS: Thirty-nine RCTs were initially identified, with 8 fulfilling the inclusion criteria. Two RCTs were added by manual search, resulting in 10 RCTs in the final analysis, including 1527 patients. MEASUREMENTS: Those studies that fulfilled the entry criteria were examined in full and subjected to quantifiable analysis, predefined subgroup analysis (stratified by supraphysiological or physiological hemodynamic goal and by time the intervention was carried out, perioperative or postoperative), and predefined sensitivity analysis. MAIN RESULTS: A significant reduction was observed in mortality associated with GDHT compared with conventional fluid therapy (risk ratio, 0.63; 95% confidence interval, 0.42-0.94; P = .02). However, no differences were found in the number of patients with complications (risk ratio, 0.75; 95% confidence interval, 0.50-1.17; P = .21), and the sensitivity analysis did not confirm the results. CONCLUSIONS: This meta analysis, with its limitations, shows that the use of perioperative GDHT may reduce postoperative mortality, but it is unable to show a reduction in the number of patients with complications. PMID- 26440439 TI - Automated pulse pressure variation display in the operating room and in the intensive care unit. PMID- 26440440 TI - Modified jaw-thrust maneuver to insert laryngeal tube suction. PMID- 26440441 TI - Analgesic effect and pharmacological mechanism of fentanyl and butorphanol in a rat model of incisional pain. AB - OBJECTIVES: To explore analgesic effects of fentanyl and butorphanol on incisional pain in rats and to investigate the pharmacological mechanism of combination. METHODS: Seventy rats were randomly divided into control group (group N, n = 10), fentanyl group (group F, n = 30), and butorphanol group (group B, n = 30), to determine median effective dose (ED50) in fentanyl and butorphanol. Another 50 rats were treated with both fentanyl and butorphanol (joint group) to quantitatively detect response rate of joint application. Ninety rats were randomly divided into 1/4 ED50 fentanyl (group 1, n = 30), 1/2 ED50 fentanyl (group 2, n = 30), and 3/4 ED50 fentanyl (group 3, n = 30), to detect the correlation between combined pharmacological effects of 2 drugs and their dose proportionality. Statistical analysis was performed using SPSS 17.0. RESULTS: Probit analysis revealed that ED50 of fentanyl was 4.1 MUg/kg, whereas ED50 of butorphanol was 295 MUg/kg. The qualitative response rate of combination (Po) was 0.84, and expected qualitative response rate (Pe) was 0.75, with no statistical significance (P = 0.3). Furthermore, probit analysis showed that 155 MUg/kg butorphanol with 1/4 ED50 fentanyl could reach experimental ED50 of combination of 2 drugs; 115 MUg/kg butorphanol with 1/2 ED50 fentanyl could reach experimental combination ED50; and 88 MUg/kg butorphanol with 3/4 ED50 fentanyl could reach experimental combination ED50. CONCLUSION: Both fentanyl and butorphanol showed good analgesic effect on incisional pain in rats, but fentanyl was superior to butorphanol. The pharmacological mechanism of combination with ED50 of fentanyl and butorphanol showed independent joint action, and the combination efficacy was related to the dosage. PMID- 26440442 TI - Successful LMA-ProSeal insertion using a tracheal tube introducer in a patient with severe rheumatoid arthritis. PMID- 26440443 TI - Hepatocyte growth factor/c-met promotes proliferation, suppresses apoptosis, and improves matrix metabolism in rabbit nucleus pulposus cells in vitro. AB - The etiology of intervertebral disc (IVD) degeneration is closely related to apoptosis and extracellular matrix degradation in nucleus pulposus (NP) cells. These defects in NP cells are induced by excessive external stressors such as reactive oxygen species (ROS) and inflammatory cytokines. Recently, hepatocyte growth factor (HGF) has been shown to repair damage in various diseases through anti-apoptotic and anti-inflammatory activity. In this study, we investigated the effects of HGF on NP cell abnormality caused by ROS and inflammatory cytokines by using primary NP cells isolated from rabbit IVD. HGF significantly enhanced the proliferation of NP cells. Apoptosis of NP cells induced by H2 O2 or TNF-alpha was significantly inhibited by HGF. Induction of mRNA expression of the inflammation mediators cyclooxygenase-2 and matrix metalloproteinase-3 and -9 by TNF-alpha was significantly suppressed by HGF treatment. Expression of c-Met, a specific receptor for HGF, was confirmed in NP cells and was increased by TNF alpha, suggesting that inflammatory cytokines increase sensitivity to HGF. These findings demonstrate that activation of HGF/c-Met signaling suppresses damage caused by ROS and inflammation in NP cells through multiple pathways. We further suggest the clinical potential of HGF for counteracting IVD degradation involved in NP cell abnormalities. PMID- 26440444 TI - Cefcapene Pivoxil Hydrochloride Is a Potentially New Treatment for Palmoplantar Pustulosis with Pustulotic Arthro-Osteitis. AB - Pustulosis palmaris et plantaris or palmoplantar pustulosis (PPP) is a refractory pustular eruption of the palms and soles with unknown etiology. In addition to skin lesions, PPP patients may present with severe joint pain and pustulotic arthro-osteitis (PAO), especially of the sternoclavicular joint. PAO is sometimes regarded as a variant of synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome. Hence, macrolide and tetracycline antibiotics are used for the treatment of PPP with PAO. We report 3 cases of PPP with PAO that did not improve upon administration of macrolide antibiotics with NSAIDs. After administration of cefcapene pivoxil hydrochloride (CFPN-PI), a third-generation cephalosporin, the swelling and sternoclavicular joint pain were promptly reduced and dramatically improved in all 3 cases. We review the conventional antibiotic treatments used currently and propose CFPN-PI as a potentially new therapy for PPP or PPP + PAO. PMID- 26440445 TI - Detecting glaucomatous change in visual fields: Analysis with an optimization framework. AB - Detecting glaucomatous progression is an important aspect of glaucoma management. The assessment of longitudinal series of visual fields, measured using Standard Automated Perimetry (SAP), is considered the reference standard for this effort. We seek efficient techniques for determining progression from longitudinal visual fields by formulating the problem as an optimization framework, learned from a population of glaucoma data. The longitudinal data from each patient's eye were used in a convex optimization framework to find a vector that is representative of the progression direction of the sample population, as a whole. Post-hoc analysis of longitudinal visual fields across the derived vector led to optimal progression (change) detection. The proposed method was compared to recently described progression detection methods and to linear regression of instrument defined global indices, and showed slightly higher sensitivities at the highest specificities than other methods (a clinically desirable result). The proposed approach is simpler, faster, and more efficient for detecting glaucomatous changes, compared to our previously proposed machine learning-based methods, although it provides somewhat less information. This approach has potential application in glaucoma clinics for patient monitoring and in research centers for classification of study participants. PMID- 26440446 TI - Synthesis, Theoretical Analysis, and Experimental pKa Determination of a Fluorescent, Nonsymmetric, In-Out Proton Sponge. AB - Herein, we report the synthesis and theoretical investigation of a nonsymmetric bis(diisopropylamino)cyclopropenimine (DAC)-functionalized proton sponge derivative, coined the "Janus" sponge. The reported sponge was isolated as a monoprotonated salt, though no intramolecular hydrogen bond was observed. Homodesmotic equations supported the absence of a N-HN intramolecular hydrogen bond and a relatively low freebase strain, while DFT calculations and X-ray crystallography revealed the presence of a hydrogen bond to the Cl(-) counterion. Associated with this fact was the rare in-out geometry of the basic nitrogens, which represents the first such instance in a proton sponge not having an ortho substituent and/or being in a protonated state. Furthermore, NLP donation into the cyclopropenium cation was found to stabilize this unprecedented in-out geometry. The measured pKa was determined to be 23.8, in good agreement with the computed value of 23.9. Lastly, the Janus sponge was found to have fluorescent properties both in the solid state and in solution, which notably represents the first example of a cyclopropenimine-based fluorescent organic compound. PMID- 26440447 TI - Timing of Adjuvant Radiotherapy in Glioblastoma Patients: A Single-Institution Experience With More Than 400 Patients. AB - BACKGROUND: The standard of care for patients with newly diagnosed glioblastoma (GBM) is maximal safe resection followed by adjuvant radiation therapy (RT) and temozolomide (TMZ). OBJECTIVE: To investigate whether the timing of adjuvant RT after surgery affected outcome in patients with GBM. METHODS: We retrospectively reviewed all patients with a diagnosis of GBM at our institution. A total of 447 patients were included in our analysis. Patients were divided into 3 equal groups based on the interval between surgery and RT. The primary outcome was overall survival (OS). RESULTS: Patients who began RT less than 21 days after surgery tended to be older, have a lower a Karnofsky Performance Status score, and higher recursive partitioning analysis class. These patients were more likely to have undergone biopsy only and received 3-dimensional conformal RT or 2-dimensional RT. The median OS for patients who started RT less than 21 days after surgery, between 21 and 32 days after surgery, and more than 32 days after surgery was 374, 465, and 478 days, respectively (P = .004). On multivariate Cox regression analysis, Karnofsky Performance Status score lower than 70, undergoing biopsy only, recursive partitioning analysis classes IV and V/VI, use of less than 36 Gy RT, and lack of TMZ chemotherapy were predictors of worse OS. The interval between surgery and RT was not significantly associated with OS on multivariate analysis. CONCLUSION: Patients who begin RT less than 21 days after surgery tend to have worse prognostic factors than those who begin RT later. When accounting for significant covariates, the effect of timing between surgery and RT is not significant. PMID- 26440448 TI - Effects of dietary quercetin on performance and cytochrome P450 expression of the cotton bollworm, Helicoverpa armigera. AB - Quercetin is ubiquitous in terrestrial plants. The cotton bollworm Helicoverpa armigera as a highly polyphagous insect has caused severe crop losses. Until now, interactions between this pest and quercetin are poorly understood at the biochemical and molecular levels. In this study, we investigated the in vivo effects of quercetin on performance of cotton bollworm and on cytochrome P450 (P450) expression. Deleterious effects of quercetin on the performance of the cotton bollworm, including growth, survival, pupation and adult emergence were observed after oral administration of 3 and 10 mg g(-1) quercetin to larvae since the third instar, whereas no significant toxic effect was found at 0.1 mg g(-1) quercetin treatment. Piperonyl butoxide treatment enhanced the toxicity of quercetin. In vitro metabolism studies showed that quercetin was rapidly transformed by gut enzymes of fifth instar larvae of the cotton bollworm. qRT-PCR results revealed that the effect of quercetin on P450 expression was tissue- and dose-specific. Quercetin regulated P450 expression in a mild manner, and it could serve as P450 inducer (CYP337B1, CYP6B6) or repressor (CYP337B1, CYP6B7, CYP6B27, CYP9A14, CYP6AE11, and CYP4M7). These findings are important for advancing our understanding of the biochemical and molecular response of insects to plant toxins and have implications for a smart pest control. PMID- 26440449 TI - An examination of the stability of interpersonal hostile-dominance and its relationship with psychiatric symptomatology and post-discharge aggression. AB - The relevance of interpersonal hostile-dominance (HD) to post-discharge aggression in mental health patients is unclear. This study assessed whether (1) HD is stable over time; (2) the relationship between HD and positive, negative, disorganized, and excited symptoms is consistent over time; and (3) HD is related to aggression post-discharge. Two hundred psychiatric inpatients were recruited on admission to hospital; 41 were available for follow-up at 6 months post discharge, including 29 men and 12 women, with an age range of 19-63 (M = 39.63 years, SD = 12.69 years). Psychiatric symptomatology and interpersonal style were assessed at recruitment and follow-up; aggression in the community post-discharge was measured at follow-up. Results showed that (1) HD was stable over time despite an overall reduction in psychiatric symptoms, (2) HD was positively correlated with symptom severity at both time points, and (3) higher HD, excited symptoms, and positive symptoms measured in the community, and more severe positive symptoms measured in hospital, were associated with aggressive behavior post-discharge. These results suggest that HD is a risk factor for more severe psychopathology. Furthermore, HD, positive symptoms, and excited symptoms measured in the community act as risk factors for aggressive behavior post discharge. As such, treatment planning and risk assessment should consider HD. Aggr. Behav. 42:324-332, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26440451 TI - Experimental and Theoretical Study of an Intramolecular CF3-Group Shift in the Reactions of alpha-Bromoenones with 1,2-Diamines. AB - The reactions of trifluoromethylated 2-bromoenones and N,N'-dialkyl-1,2-diamines have been studied. Depending on the structures of the starting compounds, the formation of 2-trifluoroacetylpiperazine or 3-trifluoromethylpiperazine-2-ones was observed. The mechanism of the reaction is discussed in terms of multistep processes involving sequential substitution of bromine in the starting alpha bromoenones and intramolecular cyclization of the captodative aminoenones as key intermediates to form the target heterocycles. The results of theoretical calculations are in perfect agreement with the experimental data. The unique role of the trifluoromethyl group in this reaction is demonstrated. PMID- 26440450 TI - Imaging beta-amyloid using [(18)F]flutemetamol positron emission tomography: from dosimetry to clinical diagnosis. AB - In Alzheimer's disease (AD), the deposition of beta-amyloid (Abeta) is hypothesized to result in a series of secondary neurodegenerative processes, leading ultimately to synaptic dysfunction and neuronal loss. Since the advent of the first Abeta-specific positron emission tomography (PET) ligand, (11)C Pittsburgh compound B ([(11)C]PIB), several (18)F ligands have been developed that circumvent the limitations of [(11)C]PIB tied to its short half-life. To date, three such compounds have been approved for clinical use by the US and European regulatory bodies, including [(18)F]AV-45 ([(18)F]florbetapir; AmyvidTM), [(18)F]-BAY94-9172 ([(18)F]florbetaben; NeuraceqTM) and [(18)F]3'-F PIB ([(18)F]flutemetamol; VizamylTM). The present review aims to summarize and discuss the currently available knowledge on [(18)F]flutemetamol PET. As the (18)F analogue of [(11)C]PIB, [(18)F]flutemetamol may be of use in the differentiation of AD from related neurodegenerative disorders and may help with subject selection and measurement of target engagement in the context of clinical trials testing anti-amyloid therapeutics. We will also discuss its potential use in non-AD amyloidopathies. PMID- 26440452 TI - Meta-Atom Behavior in Clusters Revealing Large Spin Ground States. AB - The field of single molecule magnetism remains predicated on super- and double exchange mechanisms to engender large spin ground states. An alternative approach to achieving high-spin architectures involves synthesizing weak-field clusters featuring close M-M interactions to produce a single valence orbital manifold. Population of this orbital manifold in accordance with Hund's rules could potentially yield thermally persistent high-spin ground states under which the valence electrons remain coupled. We now demonstrate this effect with a reduced hexanuclear iron cluster that achieves an S = 19/2 (chi(M)T ~ 53 cm(3) K/mol) ground state that persists to 300 K, representing the largest spin ground state persistent to room temperature reported to date. The reduced cluster displays single molecule magnet behavior manifest in both variable-temperature zero-field (57)Fe Mossbauer and magnetometry with a spin reversal barrier of 42.5(8) cm(-1) and a magnetic blocking temperature of 2.9 K (0.059 K/min). PMID- 26440453 TI - Microglial Janus kinase/signal transduction and activator of transcription 3 pathway activity directly impacts astrocyte and spinal neuron characteristics. AB - After peripheral nerve injury microglial reactivity change in the spinal cord is associated with an early activation of Janus kinase (JAK)/STAT3 transduction pathway whose blockade attenuates local inflammation and pain hypersensitivity. However, the consequences of microglial JAK/STAT3-mediated signaling on neighboring cells are unknown. Using an in vitro paradigm we assessed the impact of microglial JAK/STAT3 activity on functional characteristics of astrocytes and spinal cord neurons. Purified rat primary microglia was stimulated with JAK/STAT3 classical activator interleukin-6 in the presence or absence of a selective STAT3 inhibitor and rat primary astrocytes or spinal cord neurons were exposed to microglia conditioned media (CM). JAK/STAT3 activity-generated microglial CM modulated both astrocyte and neuron characteristics. Beyond inducing mRNA expression changes in various targets of interest in astrocytes and neurons, microglia CM activated c-Jun N-terminal kinase, STAT3 and NF-kappaB intracellular pathways in astrocytes and promoted their proliferation. Without modifying neuronal excitability or survival, CM affected the nerve processes morphology and distribution of the post-synaptic density protein 95, a marker of glutamatergic synaptic contacts. These findings show that JAK/STAT3 activity in microglia impacts the functional characteristics of astrocytes and neurons. This suggests its participation in spinal cord tissue plasticity and remodeling occurring after peripheral nerve injury. We show that the activity of JAK/STAT3 pathway in microglial cells confers them a specific signaling modality toward neighboring cells, promoting astrocyte proliferation and changes in neuronal morphology. These in vitro data suggest that the early JAK/STAT3 activation in spinal cord microglia, associated with peripheral nerve injury, participates in functional alteration of various cell populations and in spinal tissue remodeling. PMID- 26440454 TI - Wrinkled Graphene Monoliths as Superabsorbing Building Blocks for Superhydrophobic and Superhydrophilic Surfaces. AB - Superhydrophobic and superhydrophilic surfaces are of great interest because of a large range of applications, for example, as antifogging and self-cleaning coatings, as antibiofouling paints for boats, in metal refining, and for water oil separation. An aqueous ink based on three-dimensional graphene monoliths (Gr) can be used for constructing both superhydrophobic and superhydrophilic surfaces on arbitrary substrates with different surficial structures from the meso- to the macroscale. The surface wettability of a Gr-coated surface mainly depends on which additional layers (air for a superhydrophobic surface and water for a superhydrophilic surface) are adsorbed on the surface of the graphene sheets. Switching a Gr-coated surface between being superhydrophobic and superhydrophilic can thus be easily achieved by drying and prewetting with ethanol. The Gr-based superhydrophobic membranes or films should have great potential as efficient separators for fast and gravity-driven oil-water separation. PMID- 26440456 TI - A patient with suspected non-ST elevation acute myocardial infarction and remarkably high brain natriuretic peptide levels. PMID- 26440455 TI - Sustained effect of health insurance and facility quality improvement on blood pressure in adults with hypertension in Nigeria: A population-based study. AB - BACKGROUND: Hypertension is a leading risk factor for death in sub-Saharan Africa. Quality treatment is often not available nor affordable. We assessed the effect of a voluntary health insurance program, including quality improvement of healthcare facilities, on blood pressure (BP) in hypertensive adults in rural Nigeria. METHODS: We compared changes in outcomes from baseline (2009) to midline (2011) and endline (2013) between non-pregnant hypertensive adults in the insurance program area (PA) and a control area (CA), through household surveys. The primary outcome was the difference between the PA and CA in change in BP, using difference-in-differences analysis. RESULTS: Of 1500 eligible households, 1450 (96.7%) participated, including 559 (20.8%) hypertensive individuals, of which 332 (59.4%) had follow-up data. Insurance coverage increased from 0% at baseline to 41.8% at endline in the PA and remained under 1% in the CA. The PA showed a 4.97 mm Hg (95% CI: -0.76 to +10.71 mm Hg) greater decrease in systolic BP and a 1.81 mm Hg (-1.06 to +4.68 mm Hg) greater decrease in diastolic BP from baseline to endline compared to the CA. Respondents with stage 2 hypertension showed an 11.43 mm Hg (95% CI: 1.62 to 21.23 mm Hg) greater reduction in systolic BP and 3.15 mm Hg (-1.22 to +7.53 mm Hg) greater reduction in diastolic BP in the PA compared to the CA. Attrition did not affect the results. CONCLUSION: Access to improved quality healthcare through an insurance program in rural Nigeria was associated with a significant longer-term reduction in systolic BP in subjects with moderate or severe hypertension. PMID- 26440457 TI - Stent collapse after guide extension catheter collision. Signature procedural finding by optical coherence tomography. PMID- 26440460 TI - Prioritized outcomes to evaluate the effectiveness of atrial fibrillation disease management: A systematic review and Delphi study. PMID- 26440459 TI - LASSBio-1425, an analog of thalidomide, decreases triglyceride and increases HDL cholesterol levels by inhibition of TNF-alpha production. PMID- 26440458 TI - HbA1c and all-cause mortality risk among patients with type 2 diabetes. AB - BACKGROUND: Several prospective studies have evaluated the association between glycosylated hemoglobin (HbA1c) and death risk among diabetic patients. However, the results have been inconsistent. METHODS: We performed a prospective study which included 13,334 men and 21,927 women with type 2 diabetes. Cox proportional hazards regression models were used to estimate the association of different levels of HbA1c with all-cause mortality. RESULTS: During a mean follow up of 8.7 years, 4199 (2082 men and 2117 women) patients died. The multivariable-adjusted hazard ratios (HRs) of all-cause mortality associated with different levels of HbA1c at baseline (<6.0%, 6.0-6.9% [reference], 7.0-7.9, 8.0-8.9%, 9.0-9.9%, 10.0 10.9%, and >=11.0%) were 1.06, 1.00, 1.10, 0.93, 1.26, 1.18 and 1.31 (Pnon linear=0.008) for men, and 1.21, 1.00, 1.01, 1.08, 1.30, 1.30 and 1.74 (Pnon linear<0.001) for women, respectively. The J-shaped association of HbA1c with all cause mortality was confirmed among African American and white diabetic patients, patients who were more than 50 years old, never smoked or used insulin. When we used an updated mean value of HbA1c, the J-shaped association of HbA1c with the risk of all-cause mortality did not change. CONCLUSIONS: Our study demonstrated a J-shaped association between HbA1c and the risk of all-cause mortality among men and women with type 2 diabetes. Both high and low levels of HbA1c were associated with an increased risk of all-cause mortality. PMID- 26440461 TI - The impact of dual antiplatelet therapy duration on primary composite endpoint after drug-eluting stent implantation: A meta-analysis of 10 randomized trials. PMID- 26440462 TI - HMGB1: A promising therapeutic approach for atherosclerosis. PMID- 26440463 TI - Multisector-reconstruction in 1st generation 320-slice CT at high pulsation-rates achieved accurate-evaluation of coronary-lumen patency after insertion of a XIENCE stent. XIENCE Phantom Study Part 4. PMID- 26440464 TI - The relationship of body mass index to blood pressure levels among children and adolescents in 30 provinces in China. PMID- 26440465 TI - Defined daily dose (DDD) and its potential use in clinical trials of resistant hypertension. PMID- 26440466 TI - Levosimendan as an adjunctive therapy to MitraClip implantation in patients with severe mitral regurgitation and left ventricular dysfunction. PMID- 26440467 TI - Preadmission treatment with sulfonylureas and infarct size after ST-elevation myocardial infarction. PMID- 26440468 TI - Intra-aortic balloon pump therapy for acute myocardial infarction: Trial sequential analysis. PMID- 26440469 TI - Interleukin-18 disruption suppresses hypoxia-induced pulmonary artery hypertension in mice. PMID- 26440470 TI - Comparison of endothelium-dependent and -independent vasomotor response after abluminal biodegradable polymer biolimus-eluting stent and persistent polymer everolimus-eluting stent implantation (COMPARE-IT). AB - BACKGROUND: Drug-eluting stents (DES) have been associated with local endothelial dysfunction in the segments proximal and distal to the stent (peristent segments) and increased thrombotic risk in long term follow-up. Little data exists on endothelial function post-implantation of new DES with biodegradable polymer. The aim of our study was to compare the local endothelial function assessed by exercise induced coronary vasomotion after implantation of a biolimus A9-eluting stent with biodegradable polymer (BES) with an everolimus-eluting stent with durable polymer (EES). METHODS: Coronary vasomotion was evaluated with quantitative coronary angiography at rest and during supine bicycle exercise in nine patients with EES and thirteen patients with BES, 16 months after stent implantation. Mean luminal diameter of the stent, peristent segments, and of a control vessel were determined at rest, during exercise, and after the administration of nitroglycerine. RESULTS: The control vessel showed exercise induced vasodilatation in both groups (EES: +6.4+/-5.5%, p=0.07; BES: +7.8+/ 10.1%, p=0.07). Vasomotion in the stented vessel segment was abolished. There was exercise-induced vasoconstriction in both groups in the segments proximal (EES: 9.6+/-4.5%; p=0.03; BES: -4.3+/-5.4%, p=0.02) and distal to the stent (EES: 3.2+/-9.3%; p=0.41, BES -8.6+/-8.0%, p<0.01). Sublingual nitroglycerin was associated with maximal vasodilatation of the peristent segments in both groups. CONCLUSION: Alike DES with durable polymer, stents with a biodegradable polymer are associated with exercise-induced paradoxical coronary vasoconstriction of the peristent segments. This data suggests that endothelial dysfunction after DES implantation is not primarily caused by the durability of the polymer coating. PMID- 26440471 TI - The safety and efficacy of ledipasvir/sofosbuvir for the treatment of a nosocomial outbreak of HCV in patients with significant cardiovascular disease. AB - BACKGROUND: There is an unmet need for interferon- and ribavirin-free treatment for chronic HCV infection in patients with comorbidities including cardiovascular disease (CVD). The aim of this study was to evaluate the rates of sustained virological response (SVR) and adverse events in a cohort of patients with nosocomially acquired HCV genotype-1b following 12 weeks of therapy with fixed dose combination (FDC) ledipasvir/sofosbuvir (LDV/SOF). METHODS: This is a prospective, single-centre, open-label study of five non-cirrhotic patients with HCV genotype-1b and significant comorbid CVD, conducted at the Massachusetts General Hospital. All patients were prescribed an FDC tablet (LDV 90 mg/SOF 400 mg) once daily for 12 weeks. Serial measurements of safety parameters, virology, host immune correlates and adherence were performed. The primary outcome was the proportion of patients with SVR (plasma HCV RNA level <25 IU/ml), 12 weeks after treatment completion (SVR12). RESULTS: All five patients (100%) achieved SVR12, with no episodes of on- or post-treatment relapse. The most commonly reported adverse events were gastrointestinal illness and upper respiratory viral-type illness. There were no serious adverse events or discontinuations of medication attributable to the study drug. Deep sequencing analysis revealed no baseline NS3, NS5A or NS5B resistance-associated variants. CONCLUSIONS: In this open label, uncontrolled, pilot study enrolling patients with HCV genotype-1b and significant CVD, administration of a fixed-dose, oral combination of LDV and SOF for 12 weeks was associated with high rates of SVR and minimal adverse events. Larger prospective studies that also include patients with cirrhosis and prior treatment non-responders are necessary. PMID- 26440472 TI - Childhood obesity as a predictor of morbidity in adulthood: a systematic review and meta-analysis. AB - Obese children are at higher risk of being obese as adults, and adult obesity is associated with an increased risk of morbidity. This systematic review and meta analysis investigates the ability of childhood body mass index (BMI) to predict obesity-related morbidities in adulthood. Thirty-seven studies were included. High childhood BMI was associated with an increased incidence of adult diabetes (OR 1.70; 95% CI 1.30-2.22), coronary heart disease (CHD) (OR 1.20; 95% CI 1.10 1.31) and a range of cancers, but not stroke or breast cancer. The accuracy of childhood BMI when predicting any adult morbidity was low. Only 31% of future diabetes and 22% of future hypertension and CHD occurred in children aged 12 or over classified as being overweight or obese. Only 20% of all adult cancers occurred in children classified as being overweight or obese. Childhood obesity is associated with moderately increased risks of adult obesity-related morbidity, but the increase in risk is not large enough for childhood BMI to be a good predictor of the incidence of adult morbidities. This is because the majority of adult obesity-related morbidity occurs in adults who were of healthy weight in childhood. Therefore, targeting obesity reduction solely at obese or overweight children may not substantially reduce the overall burden of obesity-related disease in adulthood. PMID- 26440473 TI - Abeta-42 lowering agents from the marine-derived fungus Dichotomomyces cejpii. AB - The ascomycete Dichotomomyces cejpii was isolated from the marine sponge Callyspongia cf. C. flammea. Three new steroids (1-3), two of which are present as glycosides, with an untypical pattern of carbon-carbon double bounds, were obtained from fungal extracts, as well as the known xanthocillin X dimethyl ether (4). Compounds 2 and 4 were evaluated in an Alzheimer's disease cellular assay and found capable of preventing the enhanced production of amyloid beta-42 in Aftin-5 treated cells. Abeta-42 lowering agents are considered as candidates for the treatment of neurodegenerative Alzheimer's disease. PMID- 26440474 TI - A simple and affordable membrane-feeding method for Aedes aegpyti and Anopheles minimus (Diptera: Culicidae). AB - This study developed an artificial feeding (AF) method to replace direct host feeding (DHF) for the maintenance of Aedes aegypti and Anopheles minimus mosquito colonies. The procedure can be adopted by all laboratories due to its simple and affordable materials and design. The apparatus consists of heparinized cow blood contained in a 5cm diameter glass petri dish with 5cm(2) Parafilm M (Bemis((r))) stretched thinly over the top, with a pre-heated bag of vegetable oil placed underneath to keep the blood warm. Both parts are contained within an insulated StyrofoamTM box with a hole in the lid for mosquitoes to access the membrane. Mosquitoes are fed by AF for 15min at a time. Feeding rate and fecundity of Ae. aegypti mosquitoes feeding on the AF device were compared to those feeding on a live rat (DHF(r)), and of Anopheles minimus mosquitoes feeding on the AF device compared to those feeding on a human arm (DHF(h)). Aedes aegypti mosquitoes fed by AF or DHF(r) had similar feeding rates (38.2+/-21.5% and 35.7+/-18.2%, respectively) and overall egg production (1.5% difference). Anopheles minimus mosquitoes fed by the AF method had a lower feeding rate (52.0+/-1.0% for AF compared to 70.7+/-20.2% for DHF(h)) and overall egg production (40% reduction compared to DHF(h)). However, the number of eggs produced by AF-fed mosquitoes (1808 eggs per 100 mosquitoes) was still sufficient for colony maintenance, and with increased feeding time both parameters are expected to increase. Reduced feeding rate and overall egg production was observed when Ae. aegypti mosquitoes were fed on blood refrigerated for over two weeks. In conclusion, an AF device has been developed which can replace DHF for Ae. aegypti and An. minimus colony maintenance when using blood refrigerated for a maximum of two weeks. PMID- 26440475 TI - Factors Affecting Early Services for Children Who Are Hard of Hearing. AB - PURPOSE: To describe factors affecting early intervention (EI) for children who are hard of hearing, we analyzed (a) service setting(s) and the relationship of setting to families' frequency of participation, and (b) provider preparation, caseload composition, and experience in relation to comfort with skills that support spoken language for children who are deaf and hard of hearing (CDHH). METHOD: Participants included 122 EI professionals who completed an online questionnaire annually and 131 parents who participated in annual telephone interviews. RESULTS: Most families received EI in the home. Family participation in this setting was significantly higher than in services provided elsewhere. EI professionals were primarily teachers of CDHH or speech-language pathologists. Caseload composition was correlated moderately to strongly with most provider comfort levels. Level of preparation to support spoken language weakly to moderately correlated with provider comfort with 18 specific skills. CONCLUSIONS: Results suggest family involvement is highest when EI is home-based, which supports the need for EI in the home whenever possible. Access to hands-on experience with this population, reflected in a high percentage of CDHH on providers' current caseloads, contributed to professional comfort. Specialized preparation made a modest contribution to comfort level. PMID- 26440476 TI - Shortcomings of prosthodontic rehabilitation of patients living in long-term care facilities. AB - Removable dentures are a non-invasive, cost-effective prosthodontic solution for the reduced dentition. Their intended purpose is the rehabilitation of harmonious oral function and aesthetics on a long-term basis. The prevalence of removable dentures among patients of advanced age is high and the quality of the dentures is often poor. The aim of this study was to find the most important shortcomings of removable dentures and address the main targets for improving the quality of prosthodontic rehabilitation. The records from dental check-ups in Austrian residential homes were analysed retrospectively. Dental anamnesis questionnaires and data from the clinical examinations of 105 denture wearers were analysed. The functional condition and retention of 192 dentures had been assessed, as well as the impact of the dentures on the intra-oral tissues. Insufficient denture retention was very common, particularly in the lower jaw (56.0%). Problems with the masticatory function were reported by 26.7% of the denture wearers, 11.4% were dissatisfied with the denture aesthetics, and 4.8% had difficulties with phonetics. Traumatic ulcers were found in 18.1%. Cracks, broken pieces (6.3%) or missing denture teeth (2.1%) were rare. It may be assumed that the findings of the present study also apply to a great percentage of community-dwelling seniors. The most important issues in prosthodontic rehabilitation with removable dentures are denture retention and masticatory function. Regular dental check-ups, denture adjustment and, when necessary, relining can maintain the primary denture quality and prevent damages of the oral tissues caused by ill-fitting dentures. PMID- 26440477 TI - Effect of Selenium Deficiency on Nitric Oxide and Heat Shock Proteins in Chicken Erythrocytes. AB - Selenium (Se) deficiency induces various types of diseases, including hemolytic anemia, which is one of the basic pathologies of erythrocyte damage. To investigate the effect of Se deficiency on chicken erythrocytes, we detected the effects of Se deficiency on the nitric oxide (NO) content and the levels of heat shock proteins (Hsps) in chicken erythrocytes, including Hsp27, Hsp40, Hsp60, Hsp70, and Hsp90. One-day-old chickens (180) were randomly divided into two groups, a low-Se group (L group, fed with a 0.008 mg/kg Se diet) and a control group (C group, fed with a 0.2 mg/kg Se diet). Next, erythrocytes were collected at 35 days old, and the NO content, activity of inducible nitric oxide synthase (iNOS), and levels of Hsps (27, 40, 60, 70, and 90) were examined. Compared with the C group, the NO and iNOS levels were significantly higher (P < 0.05), and the Hsps in the mRNA and protein levels were generally higher (P < 0.05) in the L group. Meanwhile, the correlation analysis showed that there were positive correlations between Hsps and NO. Thus, as typical damage biomarkers, NO and Hsps may play special roles in chicken erythrocyte injury by Se deficiency. PMID- 26440478 TI - Nickel Chloride (NiCl2) Induces Histopathological Lesions via Oxidative Damage in the Broiler's Bursa of Fabricius. AB - The purpose of this study was to investigate the histopathological lesions, oxidative damage, changes of immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA) contents in the bursa of Fabricius and serum immunoglobulins (IgG, IgM, IgA) induced by dietary nickel chloride (NiCl2). Two hundred and eighty-one-day-old broilers were randomly divided into four groups and fed on a control diet and three experimental diets supplemented with 300, 600, and 900 mg/kg of NiCl2 for 42 days. Lesions were observed in the NiCl2 treated groups. Histopathologically, lymphocytes were decreased in lymphoid follicles with thinner cortices and wider medullae. Concurrently, the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and the ability to inhibit hydroxyl radical and glutathione (GSH) contents were significantly (p < 0.05 or p < 0.01) decreased, while malondialdehyde (MDA) contents were increased in the NiCl2-treated groups. The serum IgG, IgM, and bursa IgG and IgM contents were significantly (p < 0.05 or p < 0.01) lower in the NiCl2-treated groups than those in the control group. The above-mentioned results show that dietary NiCl2 in excess of 300 mg/kg can cause histopathological lesions via oxidative damage, which finally impairs the function of the bursa of Fabricius and reduces IgG and IgM contents of the serum and the bursa of Fabricius. The study is aimed to provide helpful materials for studies on Ni- or Ni compounds-induced B cell toxicity in both human and other animals in the future. PMID- 26440479 TI - Functionalized Carbon Quantum Dots with Dopamine for Tyrosinase Activity Monitoring and Inhibitor Screening: In Vitro and Intracellular Investigation. AB - Sensitive assay of tyrosinase (TYR) activity is in urgent demand for both fundamental research and practical application, but the exploration of functional materials with good biocompatibility for its activity evaluation at the intracellular level is still challenging until now. In this work, we develop a convenient and real-time assay with high sensitivity for TYR activity/level monitoring and its inhibitor screening based on biocompatible dopamine functionalized carbon quantum dots (Dopa-CQDs). Dopamine with redox property was functionalized on the surface of carbon quantum dots to construct a Dopa-CQDs conjugate with strong bluish green fluorescence. When the dopamine moiety in Dopa CQDs conjugate was oxidized to a dopaquinone derivative under specific catalysis of TYR, an intraparticle photoinduced electron transfer (PET) process between CQDs and dopaquinone moiety took place, and then the fluorescence of the conjugate could be quenched simultaneously. Quantitative evaluation of TYR activity was established in terms of the relationship between fluorescence quenching efficiency and TYR activity. The assay covered a broad linear range of up to 800 U/L with a low detection limit of 7.0 U/L. Arbutin, a typical inhibitor of TYR, was chosen as an example to assess its function of inhibitor screening, and positive results were observed that fluorescence quenching extent of the probe was reduced in the presence of arbutin. It is also demonstrated that Dopa CQD conjugate possesses excellent biocompatibility, and can sensitively monitor intracellular tyrosinase level in melanoma cells and intracellular pH changes in living cells, which provides great potential in application of TYR/pH-associated disease monitoring and medical diagnostics. PMID- 26440480 TI - LDA-Mediated Synthesis of Triarylmethanes by Arylation of Diarylmethanes with Fluoroarenes at Room Temperature. AB - A practical and convenient approach for the secondary C(sp(3))-H arylation of diarylmethanes with various fluoroarenes is described. The reaction proceeds smoothly in the presence of LDA (lithium diisopropylamide) at room temperature and affords triarylmethanes in moderate to high yields. PMID- 26440481 TI - Evaluating the impact of accreditation and external peer review. AB - PURPOSE: Accreditation and external peer review play important roles in assessing and improving healthcare quality worldwide. Evidence on the impact on the quality of care remains indecisive because of programme features and methodological research challenges. The purpose of this paper is to create a general methodological research framework to design future studies in this field. DESIGN/METHODOLOGY/APPROACH: A literature search on effects of external peer review and accreditation was conducted using PubMed/Medline, Embase and Web of Science. Three researchers independently screened the studies. Only original research papers that studied the impact on the quality of care were included. Studies were evaluated by their objectives and outcomes, study size and analysis entity (hospitals vs patients), theoretical framework, focus of the studied programme, heterogeneity of the study population and presence of a control group. FINDINGS: After careful selection 50 articles were included out of an initial 2,025 retrieved references. Analysis showed a wide variation in methodological characteristics. Most studies are performed cross-sectionally and results are not linked to the programme by a theoretical framework. ORIGINALITY/VALUE: Based on the methodological characteristics of previous studies the authors propose a general research framework. This framework is intended to support the design of future research to evaluate the effects of accreditation and external peer review on the quality of care. PMID- 26440482 TI - Service quality of hospital outpatient departments: patients' perspective. AB - PURPOSE: Assessment of patient perceptions of health service quality as an important element in quality assessments has attracted much attention in recent years. The purpose of this paper is to assess the service quality of hospital outpatient departments affiliated to Shahid Beheshti University of Medical Sciences from the patients' perspective. DESIGN/METHODOLOGY/APPROACH: This cross sectional study was conducted in 2014 in Tehran, Iran. The study samples included 500 patients who were selected by multi-stage random sampling from four hospitals. The data collection instrument was a questionnaire consisting of 50 items, and the validity and reliability of the questionnaire were confirmed. For data analysis, exploratory and confirmatory factor analysis, Friedman test, and descriptive statistics were used through LISREL 8.54 and SPSS 18 applications. FINDINGS: Eight significant factors were extracted for outpatient service quality, which explained about 67 per cent of the total variance. Physician consultation, information provided to the patient, and the physical environment of the clinic were the three determining factors of the quality of outpatient services. The highest and lowest perceptions were related to physician consultation and perceived waiting time dimension, respectively. The mean score of patients' perception of outpatient service quality was 3.89 (+/-0.60). About 59.5 per cent of patients assessed the quality of outpatient services as good, 38.2 per cent as moderate, and 2.3 per cent as poor. Practical implications - The instrument developed for this study is valid and reliable, and it can help hospital managers to identify the areas needing improvement and correction. ORIGINALITY/VALUE: According to the findings of this study, the majority of patients had a positive experience with outpatient departments of teaching hospitals, and the services provided in these centres were of adequate quality, based on patient assessments. PMID- 26440483 TI - Investigating the connections between health lean management and clinical risk management. AB - PURPOSE: The purpose of this paper is to investigate connections and overlaps between health lean management (HLM) and clinical risk management (CRM) understanding whether and how these two approaches can be combined together to pursue efficiency and patient safety improvements simultaneously. DESIGN/METHODOLOGY/APPROACH: A systematic literature review has been carried out. Searching in academic databases, papers that focus not only on HLM, but also on clinical errors and risk reduction, were included. The general characteristics of the selected papers were analysed and a content analysis was conducted. FINDINGS: In most of the papers, pursing objectives of HLM and CRM and adopting tools and practices of both approaches, results of quality and, particularly, of safety improvements were obtained. A two-way arrow between HLM and CRM emerged but so far, none of the studies has been focused on the relationship between HLM and CRM. ORIGINALITY/VALUE: Results highlight an emerging research stream, with many useful theoretical and practical implications and opportunities for further research. PMID- 26440484 TI - Comparing Choice and Partnership Approach assumptions to Child and Adolescent Mental Health Services in NHS Greater Glasgow and Clyde. AB - PURPOSE: The purpose of this paper is to compare NHS Greater Glasgow and Clyde (NHSGGC) Child and Adolescent Mental Health Service (CAMHS) activity data over a one-year period to the Choice and Partnership Approach (CAPA) demand and capacity model assumptions, providing an evaluation of CAPA model implementation and its effects on actual demand and capacity of the service. DESIGN/METHODOLOGY/APPROACH: Three assumptions within the CAPA model are tested against activity data extracted from the patient management system. Analysis by patient record assesses the number of appointments the patients received and the patients' journey from assessment to treatment. A combination of community CAMHS data are combined to compare actual activity against assumed capacity required to meet demand according to the CAPA model. FINDINGS: Tested against an audit of 2,896 patient records, CAMHS average 7.76 core appointments per patient compared to the CAPA assumption of 7.5 appointments at a 0 per cent DNA rate. The second CAPA assumption states that 66 per cent of assessments will result in treatment, compared to 73.55 per cent in NHSGGC CAMHS. Finally, the workforce model in CAMHS has clinical capacity to meet demand according to the CAPA assumption of weekly accepted referral rates not exceeding the number of clinical whole time equivalent. ORIGINALITY/VALUE: The data allow for identification of inefficiencies within CAMHS and highlights how capacity can be increased, without increasing budgets, to meet a rising clinical demand. The results allow managers and clinicians to improve job planning to ensure more children and young people have quick access to services. PMID- 26440485 TI - Applying importance-performance analysis to patient safety culture. AB - PURPOSE: The Sexton et al.'s (2006) safety attitudes questionnaire (SAQ) has been widely used to assess staff's attitudes towards patient safety in healthcare organizations. However, to date there have been few studies that discuss the perceptions of patient safety both from hospital staff and upper management. The purpose of this paper is to improve and to develop better strategies regarding patient safety in healthcare organizations. DESIGN/METHODOLOGY/APPROACH: The Chinese version of SAQ based on the Taiwan Joint Commission on Hospital Accreditation is used to evaluate the perceptions of hospital staff. The current study then lies in applying importance-performance analysis technique to identify the major strengths and weaknesses of the safety culture. FINDINGS: The results show that teamwork climate, safety climate, job satisfaction, stress recognition and working conditions are major strengths and should be maintained in order to provide a better patient safety culture. On the contrary, perceptions of management and hospital handoffs and transitions are important weaknesses and should be improved immediately. Research limitations/implications - The research is restricted in generalizability. The assessment of hospital staff in patient safety culture is physicians and registered nurses. It would be interesting to further evaluate other staff's (e.g. technicians, pharmacists and others) opinions regarding patient safety culture in the hospital. ORIGINALITY/VALUE: Few studies have clearly evaluated the perceptions of healthcare organization management regarding patient safety culture. Healthcare managers enable to take more effective actions to improve the level of patient safety by investigating key characteristics (either strengths or weaknesses) that healthcare organizations should focus on. PMID- 26440486 TI - Patient satisfaction constructs. AB - PURPOSE: The purpose of this paper is to examine the five-factor structure of patients' satisfaction constructs toward private healthcare service providers. DESIGN/METHODOLOGY/APPROACH: This research is a cross-sectional study. A questionnaire-based survey was conducted with previous and current Bangladeshi patients. Exploratory factor analysis was employed to extract the underlying constructs. FINDINGS: Five underlying dimensions that play a significant role in structuring the satisfaction perceived by Bangladeshi private healthcare patients are identified in this study. Practical implications - The main contribution of this study is identifying the dimensions of satisfaction perceived by Bangladeshi patients regarding private healthcare service providers. ORIGINALITY/VALUE: Healthcare managers adopt the five identified underlying construct items in their business practices to improve their respective healthcare efficiency while ensuring overall customer satisfaction. PMID- 26440487 TI - Lean Six Sigma implementation and organizational culture. AB - PURPOSE: The purpose of this paper is to examine the relationship between four organizational cultural types defined by the Competing Values Framework and three Lean Six Sigma implementation components - management involvement, use of Lean Six Sigma methods and Lean Six Sigma infrastructure. DESIGN/METHODOLOGY/APPROACH: The study involved surveying 446 human resource and quality managers from 223 hospitals located in Maine, New Hampshire, Vermont, Massachusetts and Rhode Island using the Organizational Culture Assessment Instrument. Findings - In total, 104 completed responses were received and analyzed using multivariate analysis of variance. Follow-up analysis of variances showed management support was significant, F(3, 100)=4.89, p < 0.01, eta2=1.28; infrastructure was not significant, F(3, 100)=1.55, p=0.21, eta2=0.05; and using Lean Six Sigma methods was also not significant, F(3, 100)=1.34, p=0.26, eta2=0.04. Post hoc analysis identified group and development cultures having significant interactions with management support. PRACTICAL IMPLICATIONS: The relationship between organizational culture and Lean Six Sigma in hospitals provides information on how specific cultural characteristics impact the Lean Six Sigma initiative key components. This information assists hospital staff who are considering implementing quality initiatives by providing an understanding of what cultural values correspond to effective Lean Six Sigma implementation. ORIGINALITY/VALUE: Managers understanding the quality initiative cultural underpinnings, are attentive to the culture-shared values and norm's influence can utilize strategies to better implement Lean Six Sigma. PMID- 26440488 TI - Do clinical incidents, complaints and medicolegal claims overlap? AB - PURPOSE: Error reporting by healthcare staff, patient-derived complaints and patient-derived medico-legal claims are three separate processes present in most healthcare systems. It is generally assumed that all relate to the same cases. Given the high costs associated with these processes and strong desire to maximise quality and standards, the purpose of this paper is to see whether it was indeed the case that most complaints and claims related to medical errors and the relative resource allocation to each group. DESIGN/METHODOLOGY/APPROACH: Electronic databases for clinical error recording, patient complaints and medico legal claims in a large NHS healthcare provider organisation were reviewed and case overlap analysed. FINDINGS: Most complaints and medico-legal claims do not associate with a prior clinical error. Disproportionate resource is required for a small number of complaints and the medico-legal claims process. Most complaints and claims are not upheld. RESEARCH LIMITATIONS/IMPLICATIONS: The authors have only looked at data from one healthcare provider and for one period. It would be useful to analyse other healthcare organisations over a longer time period. The authors were unable to access data on secondary staffing costs, which would have been informative. As the medico-legal process can go on for many years, the authors do not know the ultimate outcomes for all cases. The authors also do not know how many medico-legal cases were settled out of court pragmatically to minimise costs. Practical implications - Staff error reporting systems and patient advisory services seem to be efficient and working well. However, the broader complaints and claims process is costing considerable time and money, yet may not be useful in driving up standards. System changes to maximise helpful complaints and claims, from a quality and standards perspective, and minimise unhelpful ones are recommended. ORIGINALITY/VALUE: This study provides important data on the lack of overlap between errors, complaints and claims cases. PMID- 26440489 TI - Early warning scores: unravelling detection and escalation. AB - PURPOSE: The purpose of this paper is to increase understanding of how patient deterioration is detected and how clinical care escalates when early warning score (EWS) systems are used. DESIGN/METHODOLOGY/APPROACH: The authors critically review a recent National Early Warning Score paper published in IJHCQA using personal experience and EWS-related publications, and debate the difference between detection and escalation. FINDINGS: Incorrect EWS choice or poorly understood EWS escalation may result in unnecessary workloads forward and responding staff. PRACTICAL IMPLICATIONS: EWS system implementers may need to revisit their guidance materials; medical and nurse educators may need to expand the curriculum to improve EWS system understanding and use. ORIGINALITY/VALUE: The paper raises the EWS debate and alerts EWS users that scrutiny is required. PMID- 26440490 TI - External Validation of the STONE Score, a Clinical Prediction Rule for Ureteral Stone: An Observational Multi-institutional Study. AB - STUDY OBJECTIVE: The STONE score is a clinical decision rule that classifies patients with suspected nephrolithiasis into low-, moderate-, and high-score groups, with corresponding probabilities of ureteral stone. We evaluate the STONE score in a multi-institutional cohort compared with physician gestalt and hypothesize that it has a sufficiently high specificity to allow clinicians to defer computed tomography (CT) scan in patients with suspected nephrolithiasis. METHODS: We assessed the STONE score with data from a randomized trial for participants with suspected nephrolithiasis who enrolled at 9 emergency departments between October 2011 and February 2013. In accordance with STONE predictors, we categorized participants into low-, moderate-, or high-score groups. We determined the performance of the STONE score and physician gestalt for ureteral stone. RESULTS: Eight hundred forty-five participants were included for analysis; 331 (39%) had a ureteral stone. The global performance of the STONE score was superior to physician gestalt (area under the receiver operating characteristic curve=0.78 [95% confidence interval {CI} 0.74 to 0.81] versus 0.68 [95% CI 0.64 to 0.71]). The prevalence of ureteral stone on CT scan ranged from 14% (95% CI 9% to 19%) to 73% (95% CI 67% to 78%) in the low-, moderate-, and high-score groups. The sensitivity and specificity of a high score were 53% (95% CI 48% to 59%) and 87% (95% CI 84% to 90%), respectively. CONCLUSION: The STONE score can successfully aggregate patients into low-, medium-, and high-risk groups and predicts ureteral stone with a higher specificity than physician gestalt. However, in its present form, the STONE score lacks sufficient accuracy to allow clinicians to defer CT scan for suspected ureteral stone. PMID- 26440492 TI - Are New Oral Anticoagulants Safer Than Vitamin K Antagonists in the Treatment of Venous Thromboembolism? PMID- 26440491 TI - A Case of Acute Upper Airway Obstruction in a Pediatric Hemophilia A Patient Because of Spontaneous Retropharyngeal Hemorrhage. AB - We report a rare case of acute upper airway obstruction caused by spontaneous retropharyngeal hemorrhage as a result of hemophilia A in a 16-year-old pediatric patient who routinely received factor VIII replacement. Initial diagnosis was delayed because the patient presented with symptoms, such as throat pain and odynophagia, similar to those of common benign upper airway infections. Within 2 days of the initial presentation of symptoms, the patient went into respiratory failure as a result of retropharyngeal hemorrhage. The possibility of spontaneous retropharyngeal or epiglottic hemorrhage or hematoma should be considered as a cause of rapidly progressing odynophagia and dyspnea by hemophilia patients. PMID- 26440493 TI - A Universal Animal Welfare Framework for Zoos. AB - The Detroit Zoological Society's (DZS) Center for Zoo Animal Welfare (CZAW) was created to advance the science and policy of the welfare of exotic nonhuman animals in captivity. This important part of the DZS mission is achieved through assessments of, and research on, the welfare of animals in zoos; by recognizing extraordinary achievement in the advancement of animal welfare; by widely sharing knowledge through a bibliographic resource center; by conducting professional training for animal care staff; and by convening important discussions in the form of international symposia. This special issue of the Journal of Applied Animal Welfare Science features selected papers from the most recent international CZAW symposium held at the Detroit Zoo in November 2014, as well as a universal framework for zoo animal welfare developed by the DZS. PMID- 26440494 TI - Bird-Window Collisions: A Critical Animal Welfare and Conservation Issue. AB - Sheet glass and plastic in the form of clear and reflective windows are universally lethal to birds. Reasonable interpretation of available scientific evidence describes windows as a principal human-associated avian mortality factor that is an indiscriminant killer of common species as well as species of conservation concern. A conservative toll estimates 1 billion or more annual fatalities in the United States alone. The injury and death from birds striking windows are foreseeable and preventable, but the most promising legal measures and commercial products are not being applied or made available to protect defenseless victims. Avian window casualties are important for birds and people, and they have nonhuman animal welfare, biodiversity, sustainability, legal, and ethical and moral value justifying responsible human action. Preventing this unintended and unwanted lethal hazard for free-flying birds should be an obligation. Short-term solutions include retrofitting existing panes with a variety of proven measures that among others include applying various materials to cover the outside surface of windows. Long-term solutions include current and proposed bird-safe sheet glass and plastic for remodeling and new construction that have patterns that transform windows into barriers that birds see and avoid. PMID- 26440495 TI - A "How-To" Guide for Designing Judgment Bias Studies to Assess Captive Animal Welfare. AB - Robust methods to assess nonhuman animal emotion are essential for ensuring good welfare in captivity. Cognitive bias measures such as the judgment bias task have recently emerged as promising tools to assess animal emotion. The simple design and objective response measures make judgment bias tasks suitable for use across species and contexts. In reviewing 64 studies published to date, it emerged that (a) judgment biases have been measured in a number of mammals and birds and an invertebrate; (b) no study has tested judgment bias in any species of fish, amphibian, or reptile; and (c) no study has yet investigated judgment bias in a zoo or aquarium. This article proposes that judgment bias measures are highly suitable for use with these understudied taxa and can provide new insight into welfare in endangered species housed in zoos and aquariums, where poor welfare impacts breeding success and, ultimately, species survival. The article includes a "how-to" guide to designing judgment bias tests with recommendations for working with currently neglected "exotics" including fishes, amphibians, and reptiles. PMID- 26440496 TI - A Multi-Institutional Assessment of Factors Influencing Locomotion and Pacing in Captive Okapis (Okapia johnstoni). AB - The okapi (Okapia johnstoni), native to the Democratic Republic of Congo, is a large, solitary, and diurnal forest-dwelling ungulate highly sensitive to captive conditions. The captive population demonstrates persistent health problems, reproductive abnormalities, and several potentially abnormal repetitive behaviors. This study reports on locomotion and pacing in adult male and female okapis. Commonly, data on repetitive behavior have been derived from surveys. Although insightful, the results are often highly generalized and provide little information about the true preponderance and nature of such behavior in a population. In this study, direct observations determining how often and when a behavior of interest occurs are paired with information on factors (intrinsic and extrinsic) that can impact a nonhuman animal's propensity to perform repetitive behavior. More than half of the North American okapi population comprised the study population. Each animal was studied for 2 summer and winter seasons. Factors predictive of pacing in both males and females included 3 housing and habitat factors and 4 management factors. Patterns of locomotion and the rate and pattern of pacing in males when compared with females suggested different mechanisms may be driving these behaviors in the different sexes and that a sex specific management strategy would benefit this species. PMID- 26440498 TI - Resistance to water and abrasion of a broad-spectrum sunscreen: a prospective, open-label study. PMID- 26440500 TI - Advancing Pharmacogenomics as a Component of Precision Medicine: How, Where, and Who? AB - Pharmacogenomics is an important element of precision medicine. Advances in pharmacogenomics implementation have been made but significant barriers remain, including evidence, reimbursement, and clinician knowledge, among others. Widespread adoption of pharmacogenomics requires overcoming these barriers, a clinician champion group, which we propose will be pharmacists, and an easily accessible setting, which may be the community pharmacy. Whatever the path, it must be evidence-driven and pharmacogenomics must improve drug-related outcomes to become a standard of care. PMID- 26440501 TI - Applied research of an emerging condition: Theileria associated bovine anaemia. PMID- 26440502 TI - Karyotype characterization and evolution in South American species of Lathyrus (Notolathyrus, Leguminosae) evidenced by heterochromatin and rDNA mapping. AB - Notolathyrus is a section of South American endemic species of the genus Lathyrus. The origin, phylogenetic relationship and delimitation of some species are still controversial. The present study provides an exhaustive analysis of the karyotypes of approximately half (10) of the species recognized for section Notolathyrus and four outgroups (sections Lathyrus and Orobus) by cytogenetic mapping of heterochromatic bands and 45S and 5S rDNA loci. The bulk of the parameters analyzed here generated markers to identify most of the chromosomes in the complements of the analyzed species. Chromosome banding showed interspecific variation in the amount and distribution of heterochromatin, and together with the distribution of rDNA loci, allowed the characterization of all the species studied here. Additionally, some of the chromosome parameters described (st chromosomes and the 45S rDNA loci) constitute the first diagnostic characters for the Notolathyrus section. Evolutionary, chromosome data revealed that the South American species are a homogeneous group supporting the monophyly of the section. Variation in the amount of heterochromatin was not directly related to the variation in DNA content of the Notolathyrus species. However, the correlation observed between the amount of heterochromatin and some geographical and bioclimatic variables suggest that the variation in the heterochromatic fraction should have an adaptive value. PMID- 26440504 TI - A Nanoparticle-based Sensor Platform for Cell Tracking and Status/Function Assessment. AB - Nanoparticles are increasingly popular choices for labeling and tracking cells in biomedical applications such as cell therapy. However, all current types of nanoparticles fail to provide real-time, noninvasive monitoring of cell status and functions while often generating false positive signals. Herein, a nanosensor platform to track the real-time expression of specific biomarkers that correlate with cell status and functions is reported. Nanosensors are synthesized by encapsulating various sensor molecules within biodegradable polymeric nanoparticles. Upon intracellular entry, nanosensors reside within the cell cytoplasm, serving as a depot to continuously release sensor molecules for up to 30 days. In the absence of the target biomarkers, the released sensor molecules remain 'Off'. When the biomarker(s) is expressed, a detectable signal is generated (On). As a proof-of-concept, three nanosensor formulations were synthesized to monitor cell viability, secretion of nitric oxide, and beta-actin mRNA expression. PMID- 26440503 TI - The Gyc76C Receptor Guanylyl Cyclase and the Foraging cGMP-Dependent Kinase Regulate Extracellular Matrix Organization and BMP Signaling in the Developing Wing of Drosophila melanogaster. AB - The developing crossveins of the wing of Drosophila melanogaster are specified by long-range BMP signaling and are especially sensitive to loss of extracellular modulators of BMP signaling such as the Chordin homolog Short gastrulation (Sog). However, the role of the extracellular matrix in BMP signaling and Sog activity in the crossveins has been poorly explored. Using a genetic mosaic screen for mutations that disrupt BMP signaling and posterior crossvein development, we identify Gyc76C, a member of the receptor guanylyl cyclase family that includes mammalian natriuretic peptide receptors. We show that Gyc76C and the soluble cGMP dependent kinase Foraging, likely linked by cGMP, are necessary for normal refinement and maintenance of long-range BMP signaling in the posterior crossvein. This does not occur through cell-autonomous crosstalk between cGMP and BMP signal transduction, but likely through altered extracellular activity of Sog. We identify a novel pathway leading from Gyc76C to the organization of the wing extracellular matrix by matrix metalloproteinases, and show that both the extracellular matrix and BMP signaling effects are largely mediated by changes in the activity of matrix metalloproteinases. We discuss parallels and differences between this pathway and other examples of cGMP activity in both Drosophila melanogaster and mammalian cells and tissues. PMID- 26440505 TI - Sex differences in fatigability of dynamic contractions. AB - NEW FINDINGS: What is the topic of this review? Women are usually less fatigable than men for isometric fatiguing contractions of similar intensity, but whether this occurs for dynamic tasks is less clear. This review presents evidence that the sex difference in muscle fatigue of repeated dynamic contractions is specific to the task requirements, including the velocity of shortening and the muscle group involved. What advances does it highlight? Contractile mechanisms are responsible for the sex differences in muscle fatigue for slow-velocity and low load dynamic tasks. The variability of the sex difference in fatigability among dynamic tasks has implications for fatiguing contractions prescribed in training and rehabilitation to men and women. Women are usually less fatigable than men during single-limb isometric contractions, primarily because of sex-related differences in contractile mechanisms. It is less clear whether these sex differences in muscle fatigue occur for dynamic fatiguing tasks. This review highlights new findings that the sex difference in fatigability for dynamic shortening contractions with a single limb is dependent on the contraction velocity and the muscle group involved. Recent studies demonstrate that women are less fatigable than men for a dynamic task as follows: (i) the elbow-flexor muscles at slow- but not high-velocity contractions; and (ii) the knee-extensor muscles when muscle fatigue was quantified as a reduction in the maximal voluntary isometric contraction force after the dynamic fatiguing task. Contractile mechanisms are responsible for the sex difference in muscle fatigue of the dynamic contractions, with no evidence for a sex difference in the reduction in voluntary activation (i.e. central fatigue). Thus, these findings indicate that the sex difference in muscle fatigue of dynamic contractions is task specific. These data also challenge the assumption that men and women respond in a similar manner to training and rehabilitation that involve fatiguing contractions to overload the neuromuscular system. There is, however, a tremendous opportunity for conducting high-impact studies to gain insight into those factors that define the sex-based differences in muscle fatigue during dynamic tasks. Such studies can define the boundaries to human performance in both men and women during athletic endeavours, ergonomic tasks and rehabilitation. PMID- 26440506 TI - Big data are coming to psychiatry: a general introduction. AB - Big data are coming to the study of bipolar disorder and all of psychiatry. Data are coming from providers and payers (including EMR, imaging, insurance claims and pharmacy data), from omics (genomic, proteomic, and metabolomic data), and from patients and non-providers (data from smart phone and Internet activities, sensors and monitoring tools). Analysis of the big data will provide unprecedented opportunities for exploration, descriptive observation, hypothesis generation, and prediction, and the results of big data studies will be incorporated into clinical practice. Technical challenges remain in the quality, analysis and management of big data. This paper discusses some of the fundamental opportunities and challenges of big data for psychiatry. PMID- 26440508 TI - Takotsubo Syndrome in Patients With Spontaneous Coronary Artery Dissection: Misdiagnosis or a Reality? PMID- 26440507 TI - Low self-recognition and awareness of past hypomanic and manic episodes in the general population. AB - BACKGROUND: Bipolar disorder is often underdiagnosed and undertreated. Its detection and correct diagnosis highly relies on the report of past hypomanic or manic episodes. We investigated the recognition and awareness of past hypomanic and manic episodes in a sample of respondents with bipolar disorder selected from a general population study. METHODS: In a reappraisal study from the Netherlands Mental Health Survey and Incidence Study (NEMESIS), we further investigated 40 respondents with lifetime bipolar disorder confirmed by the structured clinical interview for DSM-IV (SCID). Respondents were asked about awareness of past depressive, manic and hypomanic episodes, illness characteristics and treatment history. RESULTS: Most respondents (82.5 %) recognized that they had experienced a depressive episode while 75 % had consulted a health professional for a depressive episode. Only a minority (22.5 %) recognized that they had experienced a (hypo)manic episode and only 17.5 % had consulted a health professional for a (hypo)manic episode. Only 12.5 % of the respondents reported having received a diagnosis of bipolar disorder. Recognition of previous (hypo)manic episodes was not related to severity of bipolar disorder. CONCLUSIONS: In routine clinical practice history-taking on a syndromal level, i.e., only inquiring whether a patient presenting with depression ever experienced a hypomanic or manic episode or received treatment for such an episode, is not sufficient to confirm or exclude a diagnosis of bipolar disorder. Other efforts, such as an interview with a significant other and the use of self report questionnaires or (semi )structured interviews may be needed to recognize previous manic symptoms in patients with depression. PMID- 26440509 TI - Formation and Malformation of Cardiac Trabeculae: Biological Basis, Clinical Significance, and Special Yield of Magnetic Resonance Imaging in Assessment. AB - Adult and pediatric cardiologists are familiar with variation in cardiac trabeculation. Abnormal trabeculation is a key feature of left ventricular noncompaction, but it is also common in congenital heart diseases and in cardiomyopathies (dilated and hypertrophied). Trabeculae might be a measurable phenotypic marker that will allow insights into how cardiomyopathy and congenital heart disease arise and develop. This will require the linking together of clinical and preclinical information (such as embryology and genetics), with new analysis methods for trabecular quantitation. In adult cardiology several promising quantitative methods have been developed for echocardiography, computed tomography, and cardiovascular magnetic resonance, and earlier cross-sectional caliper approaches have now been refined to permit more advanced assessment. Adaptation of these methods for use in developmental biology might inform on better ways to measure and track trabecular morphology in model organisms. PMID- 26440510 TI - Reply to Letters From Madias and Y-Hassan--With Regard to "Spontaneous Coronary Artery Dissection Misdiagnosed as Takotsubo Cardiomyopathy: A Case Series". PMID- 26440511 TI - Standing on the Shoulders of Giants: J.A.P. Pare and the Birth of Cardiovascular Genetics. AB - Sudden death and stroke afflicted a family from rural Quebec with such frequency as to be called the Coaticook curse by the local community. In Montreal in the late 1950s, a team of physicians led by J.A.P. Pare investigated this family for inherited cardiovascular disease. Their efforts resulted in an extensive and now classic description of familial hypertrophic cardiomyopathy. A quarter of a century later, the same family was the subject of linkage analysis and direct sequencing, culminating in the isolation of a mutation in the gene encoding the beta myosin heavy chain. MYH7 was the first gene implicated in a cardiovascular disease, which paved the way for identification of mutations in other heritable disorders, mechanistic studies, and clinical applications, such as predictive testing. The present era of cardiovascular genomics arguably had its inception in the clinical observations of Dr Pare and his colleagues more than 50 years ago. PMID- 26440512 TI - A Systematic Review of Phenotypic Features Associated With Cardiac Troponin I Mutations in Hereditary Cardiomyopathies. AB - BACKGROUND: Genetic investigations have established that mutations in proteins of the contractile unit of the myocardium, known as the sarcomere, may be associated with hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), and dilated cardiomyopathy (DCM). It has become clinical practice to offer genetic testing in affected individuals to identify causative mutations, which provides the basis for presymptomatic testing of relatives who are at risk of disease development. This ensures adequate clinical follow-up of mutation carriers, whereas noncarriers can be discharged. However, before genetic testing can be used for individual risk assessment and prediction of prognosis, it is important to investigate if there is a relation between the clinical disease expression (phenotype) of the condition and mutations in specific disease genes (genotype). METHODS: We reviewed the literature in relation to phenotypic features reported to be associated with mutations in cardiac troponin I (cTnI; TNNI3), which is a recognized sarcomeric disease gene in all 3 cardiomyopathies. RESULTS: The results of this review did not identify specific genotype-phenotype relations in HCM or DCM, and cTnI appeared to be the most frequent disease gene in RCM. CONCLUSIONS: To further explore if there is a genotype-phenotype relation, long term follow-up studies are needed. It is essential to investigate the natural history of the condition among affected individuals and to provide clinical follow-up on disease development among healthy mutation carriers. Such information is required to provide evidence-based counselling for affected families and to elucidate if knowledge about specific genotypes can be used in future risk prediction models. PMID- 26440513 TI - The Impact of Comprehensive Pre-visit Preparation on Patient Engagement and Quality of Care in a Population of Underserved Patients with Diabetes: Evidence from the Care Management Medical Home Center Model. AB - This study evaluated the impact of pre-visit preparation, a key component of Patient-Centered Medical Home guidelines, on compliance with recommended tests and screenings in a diabetic patient population receiving care in Federally Qualified Health Centers in Miami-Dade County. The pre-visit preparation consisted of a pre-visit phone call to review patient compliance with recommended tests and screenings, provide encouragement for self-care goal setting, answer patient questions, assure referrals and tests were scheduled, and notify an in center patient care team about which services are required at the upcoming visit. Aggregated data from 7 health centers and a cohort analysis of 7491 patients showed significantly higher compliance among those who were successfully contacted prior to the visit compared to those who were not successfully contacted at 24 months for all compliance measures included in the study. These results included a 28.8 percentage point difference in compliance with HbA1c testing, a 14.6 percentage point difference in influenza immunization, a 27.7 percentage point difference in diabetic foot exam compliance, and a 33.2 percentage point difference in compliance with annual low-density lipoprotein testing. After 24 months, the patient no-show rate decreased by 6.8 percentage points (from 20.7% to 14.0%) among contacted patients and by 5.5 percentage points (from 20.7% to 15.2%) among patients who were not contacted. Study results suggest that proactive pre-visit preparation may be a key strategy for primary care practices to improve areas critical for chronic disease management, such as patient engagement, appointments kept, and compliance with recommended screenings, tests, and services. (Population Health Management 2016;19:171-177). PMID- 26440514 TI - The importance of age and menopausal status in endometrial complex hyperplasia with atypia. AB - The effects of menopausal status and age on the intra-operative and post operative pathology results of patients operated on with a pre-operative diagnosis of complex hyperplasia with atypia (CHA) were assessed. A hundred and eleven patients diagnosed in our centre between January 1993 and March 2013 were included. Cancer was detected in the paraffin blocks (PBs) of 52 (46.8%) patients. Among these, 50 patients had stage-IA disease. In 31.1% of the pre menopausal patients and 66% of the post-menopausal patients, PB revealed cancer (p < 0.0001). The results of frozen section (FS) and PB were concordant in 51% and 70% in the pre-menopausal and post-menopausal patients, respectively (p = 0.041). In the patients operated on with a pre-operative diagnosis of CHA, the probability of detecting cancer in PB increases with increasing age and menopause. The reliability of FS is limited in younger and pre-menopausal patients. PMID- 26440515 TI - Low Potassium Dialysate as a Protective Factor of Sudden Cardiac Death in Hemodialysis Patients with Hyperkalemia. AB - AIM: Hyperkalemia increases the risk of sudden cardiac death (SCD) in hemodialysis patients. Our objective was to determine the association between administering low potassium dialysate to hyperkalemic hemodialysis patients and SCD. METHODS: We conducted a retrospective cohort study with patients undergoing maintenance hemodialysis from May 1, 2006, through December 31, 2013. The dialysate composition was adjusted over time according to monthly laboratory results. A 1.0 mEq/L potassium dialysate was applied in patients with predialysis hyperkalemia (>5.5 mEq/L) and was included as a time-dependent confounding factor. The clinical characteristics of enrolled patients, the incidence and timing of SCD and risk factors for all-cause mortality and SCD were analyzed. RESULTS: There were 312 patients on maintenance hemodialysis during the study period. One hundred and fifty-seven patients had been dialyzed against a 1.0 mEq/L potassium dialysate at least once. The rates of all-cause mortality and SCD were 48.17 and 20.74 per 1000 patient-years, respectively. A 1.12-fold increase in the risk of SCD in the 24-hour period starting with the hemodialysis procedure and a 1.36-fold increase in the 24 hours preceding a weekly cycle were found (p = 0.017). Multivariate Cox proportional hazards models showed that age, diabetes mellitus and predialysis hyperkalemia (>5.0 mEq/L) were significant predictors of all-cause mortality and SCD. Exposure to 1.0 mEq/L potassium dialysate, Kt/V, and serum albumin were independent protective factors against all-cause mortality. Only exposure to 1.0 mEq/L potassium dialysate significantly prevented SCD (hazard ratio = 0.33, 95% CI = 0.13-0.85). CONCLUSIONS: Using low potassium dialysate in hyperkalemic hemodialysis patients may prevent SCD. PMID- 26440516 TI - Concordance of Results from Randomized and Observational Analyses within the Same Study: A Re-Analysis of the Women's Health Initiative Limited-Access Dataset. AB - BACKGROUND: Observational studies (OS) and randomized controlled trials (RCTs) often report discordant results. In the Women's Health Initiative Calcium and Vitamin D (WHI CaD) RCT, women were randomly assigned to CaD or placebo, but were permitted to use personal calcium and vitamin D supplements, creating a unique opportunity to compare results from randomized and observational analyses within the same study. METHODS: WHI CaD was a 7-year RCT of 1g calcium/400IU vitamin D daily in 36,282 post-menopausal women. We assessed the effects of CaD on cardiovascular events, death, cancer and fracture in a randomized design- comparing CaD with placebo in 43% of women not using personal calcium or vitamin D supplements- and in a observational design- comparing women in the placebo group (44%) using personal calcium and vitamin D supplements with non-users. Incidence was assessed using Cox proportional hazards models, and results from the two study designs deemed concordant if the absolute difference in hazard ratios was <=0.15. We also compared results from WHI CaD to those from the WHI Observational Study(WHI OS), which used similar methodology for analyses and recruited from the same population. RESULTS: In WHI CaD, for myocardial infarction and stroke, results of unadjusted and 6/8 covariate-controlled observational analyses (age-adjusted, multivariate-adjusted, propensity-adjusted, propensity-matched) were not concordant with the randomized design results. For death, hip and total fracture, colorectal and total cancer, unadjusted and covariate-controlled observational results were concordant with randomized results. For breast cancer, unadjusted and age-adjusted observational results were concordant with randomized results, but only 1/3 other covariate-controlled observational results were concordant with randomized results. Multivariate adjusted results from WHI OS were concordant with randomized WHI CaD results for only 4/8 endpoints. CONCLUSIONS: Results of randomized analyses in WHI CaD were concordant with observational analyses for 5/8 endpoints in WHI CaD and 4/8 endpoints in WHI OS. PMID- 26440517 TI - Food Polyphenols Fail to Cause a Biologically Relevant Reduction of COX-2 Activity. AB - Epidemiologic studies show a correlation between the dietary intake of food polyphenols and beneficial health effects. Several in vitro studies indicate that the anti-inflammatory potential of polyphenols is, at least in part, mediated by a modulation of the enzymes of the arachidonic acid cascade, such as the prostaglandin forming cyclooxygenases (COXs). Evidence that this mode of action can be transferred to the situation in vivo is scarce. This study characterized effects of a subset of polyphenols on COX-2 expression and activity in vitro and compared the potency with known drugs. Next, the in vivo relevance of the observed in vitro effects was tested. Enzyme assays and incubations of polyphenols with the cancer cell line HCA-7 and lipopolysaccharide (LPS) stimulated primary monocytes support the hypothesis that polyphenols can effect COX-2 expression and activity in vitro. The effects were most pronounced in the monocyte assay for wogonin, apigenin, resveratrol and genistein with IC50 values of 1.5 MUM, 2.6 MUM, 2.8 MUM and 7.4 MUM. However, these values are 100- to 1000 fold higher in comparison to those of the known pharmaceuticals celecoxib, indomethacin and dexamethasone. In an animal model of LPS induced sepsis, pretreatment with polyphenols (i. p. 100 mg/kg bw) did not result in decreased plasma or tissue prostaglandin levels, whereas the positive control celecoxib effectively attenuated LPS induced prostaglandin formation. These data suggest that despite the moderate potency in vitro, an effect of polyphenols on COX-2 during acute inflammation is unlikely, even if a high dose of polyphenols is ingested. PMID- 26440519 TI - [Practice relevant research in biological psychiatry]. AB - The practice of psychiatry would be unthinkable without modern psychopharmacology. Drug treatment, especially of severe psychiatric disorders, is often a precondition of community participation, societal reintegration and recovery. Seen in this context it is understandable that biological psychiatry has long been primarily defined by its close interconnection with psychopharmacology and has been perceived this way by practicing physicians. In recent years, however, the concept of what is "biological" has markedly expanded and so has the outreach of this approach into the practice of psychiatry. This article discusses examples showing that biological research methods provide new impulses for individualized medicine, psychotherapy and understanding environmental risks and therefore provide the basis for a preemptive and preventive approach that will be the key to master the challenges posed by the severe burden of mental illness. PMID- 26440518 TI - BCG Skin Infection Triggers IL-1R-MyD88-Dependent Migration of EpCAMlow CD11bhigh Skin Dendritic cells to Draining Lymph Node During CD4+ T-Cell Priming. AB - The transport of antigen from the periphery to the draining lymph node (DLN) is critical for T-cell priming but remains poorly studied during infection with Mycobacterium bovis Bacille Calmette-Guerin (BCG). To address this we employed a mouse model to track the traffic of Dendritic cells (DCs) and mycobacteria from the BCG inoculation site in the skin to the DLN. Detection of BCG in the DLN was concomitant with the priming of antigen-specific CD4+ T cells at that site. We found EpCAMlow CD11bhigh migratory skin DCs to be mobilized during the transport of BCG to the DLN. Migratory skin DCs distributed to the T-cell area of the LN, co-localized with BCG and were found in close apposition to antigen-specific CD4+ T cells. Consequently, blockade of skin DC traffic into DLN dramatically reduced mycobacterial entry into DLN and muted T-cell priming. Interestingly, DC and mycobacterial entry into the DLN was dependent on IL-1R-I, MyD88, TNFR-I and IL 12p40. In addition, we found using DC adoptive transfers that the requirement for MyD88 in BCG-triggered migration was not restricted to the migrating DC itself and that hematopoietic expression of MyD88 was needed in part for full-fledged migration. Our observations thus identify a population of DCs that contribute towards the priming of CD4+ T cells to BCG infection by transporting bacilli into the DLN in an IL-1R-MyD88-dependent manner and reveal both DC-intrinsic and extrinsic requirements for MyD88 in DC migration. PMID- 26440521 TI - [Transcranial alternating current stimulation. Entrainment and function control of neuronal networks]. AB - Transcranial alternating current stimulation (tACS) is a new technique for the modulation of oscillatory brain activity as measured in the electroencephalogram (EEG). In contrast to well-established stimulation techniques, such as transcranial direct current stimulation and transcranial magnetic stimulation, tACS applies a sinusoidal alternating current at a specific frequency. This enables the modulation of the amplitude and frequency of endogenous brain oscillations as well as related cognitive processes. Therefore, the use of tACS has the possibility to evaluate well-known correlations between brain oscillations and cognitive processes in terms of causality. Such causal relationships have been documented in numerous neurocognitive studies on sensory, motor and perceptual processes; however, the clinical application of tACS is still in its infancy. In principle, any pathology that can reliably be connected with brain oscillations of a defined frequency is treatable. A current main focus of clinical research is on symptoms of Parkinson's disease and to a lesser degree, tinnitus. For an effective application of tACS it is important to choose the electrode positions as well as the frequency, intensity and duration of the stimulation in a theory-based and symptom-related manner. A successful therapeutic intervention requires the persistence of the tACS effect after stimulation has ceased. A mechanism that offers not only an explanation to the origin of persistent tACS effects but is also of high therapeutic benefit is neural plasticity. Therefore, one current focus of research aims at a better understanding of tACS after effects. PMID- 26440520 TI - [Innovative patient-centered care systems: International perspectives]. AB - BACKGROUND: The "Psychiatrie-Enquete" (German Report on the State of Psychiatry) is 40 years old this year. It has always been inspirational; also internationally. OBJECTIVE: Which innovative elements of community mental health services can be found in an international perspective? MATERIALS AND METHODS: Narrative review. RESULTS: Community mental health care is a lively field with much research and innovative practice. With assertive community treatment (ACT) and home treatment (HT), internationally well-evaluated forms of community mental health care are available. CONCLUSION: Recovery-based and peer-to-peer approaches hold promise for the future. In terms of mid- and long-term perspectives, an increase in patient-centering via individualization of mental health care and a better implementation of community mental health interventions would be desirable in Germany. PMID- 26440522 TI - High-Throughput Development of SSR Markers from Pea (Pisum sativum L.) Based on Next Generation Sequencing of a Purified Chinese Commercial Variety. AB - Pea (Pisum sativum L.) is an important food legume globally, and is the plant species that J.G. Mendel used to lay the foundation of modern genetics. However, genomics resources of pea are limited comparing to other crop species. Application of marker assisted selection (MAS) in pea breeding has lagged behind many other crops. Development of a large number of novel and reliable SSR (simple sequence repeat) or microsatellite markers will help both basic and applied genomics research of this crop. The Illumina HiSeq 2500 System was used to uncover 8,899 putative SSR containing sequences, and 3,275 non-redundant primers were designed to amplify these SSRs. Among the 1,644 SSRs that were randomly selected for primer validation, 841 yielded reliable amplifications of detectable polymorphisms among 24 genotypes of cultivated pea (Pisum sativum L.) and wild relatives (P. fulvum Sm.) originated from diverse geographical locations. The dataset indicated that the allele number per locus ranged from 2 to 10, and that the polymorphism information content (PIC) ranged from 0.08 to 0.82 with an average of 0.38. These 1,644 novel SSR markers were also tested for polymorphism between genotypes G0003973 and G0005527. Finally, 33 polymorphic SSR markers were anchored on the genetic linkage map of G0003973 * G0005527 F2 population. PMID- 26440523 TI - Cholesterol granuloma: a case series & review of literature. AB - BACKGROUND: Cholesterol granuloma (CG) is a foreign body reaction to crystallized cholesterol. Orbitofrontal CG is a rare entity with few cases reported in literature. It is usually seen in young to middle-aged males with a history of trauma. Computed tomography features include hypodense lesion-causing bone erosion. CG has typical histopathological features with cholesterol clefts, multinucleated giant cells, histiocytes, foamy macrophages, and altered blood pigments. Management is by total excision of the lesion with curettage of the underlying bone to prevent recurrence. MATERIAL & METHOD: We present an interventional case series of five patients of orbitofrontal CG, two of them females. RESULT: None of the patients gave a history of trauma. Management was by excision of the lesion and curettage confirmed with a 30 degrees rigid endoscope. CONCLUSION: Cholesterol granulomas can present as superior orbital mass lesions in the absence of trauma. PMID- 26440525 TI - Gonadotropin-releasing hormone is prerequisite for the constitutive expression of pituitary annexin A5. AB - Annexin A5 (ANXA5), a member of the structurally related family of annexin proteins, is expressed in pituitary gonadotropes. We previously reported that ANXA5 expression is stimulated by gonadotropin-releasing hormone (GnRH). In the present study, we investigated ANXA5 expression in the anterior pituitary gland of GnRH-deficient mutant hypogonadal (hpg) mice. RT-PCR demonstrated that luteinizing hormone beta subunit (LHbeta) and ANXA5 mRNA levels were both lower in the pituitary gland of hpg mice than in wild-type mice. Immunohistochemistry showed that ANXA5 expression throughout the pituitary gland was very low in hpg mice, suggesting that ANXA5 is diminished in gonadotropes and also in other cell types. Subcutaneous administration of a GnRH analogue, des-gly10 (Pro9)-GnRH ethylamide (1 MUg/day for 7 days), augmented the expression of LHbeta and ANXA5 in the pituitary gland in hpg mice. However, LHbeta- and ANXA5-positive cells did not show exactly matched spatial distributions. These findings suggest that GnRH is necessary for constitutive ANXA5 expression in the pituitary gland, not only in gonadotropes but also in other pituitary gland cell types. A close relationship between ANXA5 and LHbeta expression was confirmed. It is suggested that a significant role of ANXA5 in the physiologic secretion of LH. PMID- 26440524 TI - Scutellarin's Cardiovascular Endothelium Protective Mechanism: Important Role of PKG-Ialpha. AB - Scutellarin (SCU), a flavonoid glycoside compound, has been successfully used in clinic for treatment of ischemic diseases in China. In this report, we checked the effects of SCU on endothelium dysfunction (ED) of coronary artery (CA) against myocardial ischemia reperfusion (MIR) injury in vivo. The involvement of PKG-Ialpha was further studied using cultured endothelial cells subjected to hypoxia reoxygenation (HR) injury in vitro. In rat MIR model, SCU (45 and 90 mg/kg, iv) significantly reduced ischemic size and restored the endothelium dependent vasodilation of isolated CA rings. PKG inhibitor Rp-8-Br-cGMP (50 MUg/kg, iv) could ameliorate the protective effects of SCU. Increase in phosphorylation of vasodilator-stimulated phosphoprotein (VASP), a main substrate of PKG, at Ser 239 was observed in both heart tissue and serum of SCU-treated animals. In cultured human cardiac microvascular endothelial cells (HCMECs), SCU (1 and 10 MUM) dose-dependently protected cell viability and increased the mRNA and protein level of PKG-Ialpha against HR injury. The activity of PKG was also increased by SCU treatment. The activation of PKG-1alpha was then studied using targeted proteomic analysis (MRM-MS) checking the phosphorylation state of the autophosphorylation domain (aa42-94). Significant decrease in phosphorylation of PKG-Ialpha at Ser50, Ser72, Ser89 was induced by HR injury while SCU treatment significantly increased the phosphorylation of PKG-Ialpha, not only at Ser50, Ser72 and Ser89, but also at Ser44 and Thr58 (two novel phosphorylation domains). Our results demonstrate PKG-Ialpha might play an important role in the protective effects of SCU on ED against MIR injury. PMID- 26440526 TI - Exponential increase of glutamic acid decarboxylase (GAD) antibody titer after initiating and stopping insulin in a patient with slowly progressive type 1 diabetes. AB - Few articles have described fluctuations in glutamic acid decarboxylase antibody (GADAb) levels after a diagnosis of slowly progressive type 1 diabetes (SPIDDM). Here, we present a case in which GADAb levels exponentially increased after initiating and stopping insulin. A 64-year-old female patient newly diagnosed with SPIDDM was admitted and started multiple daily insulin injections. The patient's GADAb titer was 6.9 U/mL (normal: <1.4 U/mL) and the patient had a type 1 diabetes susceptible HLA class II haplotype known in the Japanese population as: DRB1*04:05-DQB1*04:01. When the patient's "honeymoon period" set in, hypoglycemia was observed and the dose of insulin was reduced. Two months after the diagnosis, 1 unit of insulin glargine/day was being injected and the patient demonstrated good glycemic control. Subsequently, the patient's home doctor recommended that insulin injections be stopped. Three months after the diagnosis, the patient's GADAb titer suddenly increased to 1600 U/mL. The patient's GADAb titer decreased but was still positive (40 U/mL) 36 months after diagnosis. HbA1c levels were maintained below 7%, and oral glucose tolerance tests at 10, 26, and 36 months after diagnosis suggested that the patient had preserved insulin secretion. To the best of our knowledge, this is the first report that describes exponential increases in GADAb after initiating and stopping insulin in a patient with SPIDDM. PMID- 26440527 TI - Endothelin ETA receptor antagonist reverses naloxone-precipitated opioid withdrawal in mice. AB - Long-term use of opioids for pain management results in rapid development of tolerance and dependence leading to severe withdrawal symptoms. We have previously demonstrated that endothelin-A (ETA) receptor antagonists potentiate opioid analgesia and eliminate analgesic tolerance. This study was designed to investigate the involvement of central ET mechanisms in opioid withdrawal. The effect of intracerebroventricular administration of ETA receptor antagonist BQ123 on morphine and oxycodone withdrawal was determined in male Swiss Webster mice. Opioid tolerance was induced and withdrawal was precipitated by the opioid antagonist naloxone. Expression of ETA and ETB receptors, nerve growth factor (NGF), and vascular endothelial growth factor was determined in the brain using Western blotting. BQ123 pretreatment reversed hypothermia and weight loss during withdrawal. BQ123 also reduced wet shakes, rearing behavior, and jumping behavior. No changes in expression of vascular endothelial growth factor, ETA receptors, and ETB receptors were observed during withdrawal. NGF expression was unaffected in morphine withdrawal but significantly decreased during oxycodone withdrawal. A decrease in NGF expression in oxycodone- but not in morphine treated mice could be due to mechanistic differences in oxycodone and morphine. It is concluded that ETA receptor antagonists attenuate opioid-induced withdrawal symptoms. PMID- 26440528 TI - Giant Dielectric Permittivity in Ferroelectric Thin Films: Domain Wall Ping Pong. AB - The dielectric permittivity in ferroelectric thin films is generally orders of magnitude smaller than in their bulk. Here, we discover a way of increasing dielectric constants in ferroelectric thin films by ca. 500% by synchronizing the pulsed switching fields with the intrinsic switching time (nucleation of domain plus forward growth from cathode to anode). In a 170-nm lead zirconate titanate thin film with an average grain size of 850 nm this produces a dielectric constant of 8200 with the maximum nucleus density of 3.8 MUm(-2), which is one to three orders of magnitude higher than in other dielectric thin films. This permits smaller capacitors in memory devices and is a step forward in making ferroelectric domain-engineered nano-electronics. PMID- 26440529 TI - Quantifying Semantic Linguistic Maturity in Children. AB - We propose a method to quantify semantic linguistic maturity (SELMA) based on a high dimensional semantic representation of words created from the co-occurrence of words in a large text corpus. The method was applied to oral narratives from 108 children aged 4;0-12;10. By comparing the SELMA measure with maturity ratings made by human raters we found that SELMA predicted the rating of semantic maturity made by human raters over and above the prediction made using a child's age and number of words produced. We conclude that the semantic content of narratives changes in a predictable pattern with children's age and argue that SELMA is a measure quantifying semantic linguistic maturity. The study opens up the possibility of using quantitative measures for studying the development of semantic representation in children's narratives, and emphasizes the importance of word co-occurrences for understanding the development of meaning. PMID- 26440531 TI - Aryl Hydrocarbon Receptor Activation in Acne Vulgaris Skin: A Case Series from the Region of Naples, Italy. AB - BACKGROUND: Dioxins are persistent organic pollutants present in the environment. They exert their biological effects by binding to an intracellular receptor, the aryl hydrocarbon receptor (AhR). Activation of AhR leads to the induction of cytochrome p450 1A1 (CYP1A1). Expression of CYP1A1 in human skin is a key marker for AhR activation, and it may induce comedogenesis resulting in acne-like lesions known as chloracne/metabolising acquired dioxin-induced skin hamartomas (MADISH). The contribution of this pathway in patients seen in a busy acne clinic is unknown. MATERIALS AND METHODS: We explored the expression of CYP1A1 by immunohistochemistry in the acne lesions of 16 patients living in the region of Naples, Italy, where epidemiological studies have suggested a possibly increased exposure to environmental dioxins. A composite score to outline potential components of the chloracne/MADISH histological pattern was used. RESULTS: CYP1A1 expression was observed in 11 lesions (69%) and was distributed in sebaceous glands, follicular epithelium, cystic wall and endothelial cells. The histological score for chloracne/MADISH was 'likely' in 3 cases and 'possible' in 11 cases. Compared to current data on CYP1A1 expression in the skin of 67 patients with proven exposure to AhR agonists, these data indicate a high incidence of AhR activation in this series. CONCLUSION: This is the first study analysing AhR activation in skin in a series of patients from a hospital-based acne clinic. It provides information for future controlled prospective studies. The significance of CYP1A1 expression in terms of AhR ligand exposure is discussed. PMID- 26440530 TI - A comparison of anti-HER2 IgA and IgG1 in vivo efficacy is facilitated by high N glycan sialylation of the IgA. AB - Monomeric IgA has been proposed as an alternative antibody format for cancer therapy. Here, we present our studies on the production, purification and functional evaluation of anti-HER2 IgA antibodies as anti-cancer agents in comparison to the anti-HER2 IgG1 trastuzumab. MALDI-TOF MS analysis showed profound differences in glycosylation traits across the IgA isotypes and cell lines used for production, including sialylation and linkage thereof, fucosylation (both core and antennary) and the abundance of high-mannose type species. Increases in sialylation proved to positively correlate with in vivo plasma half-lives. The polymerization propensity of anti-HER2 IgA2m2 could be suppressed by an 18-aa deletion of the heavy chain tailpiece - coinciding with the loss of high-mannose type N-glycan species - as well as by 2 cysteine to serine mutations at positions 320 and 480. The HER2 F(ab')2-mediated anti proliferative effect of the IgA2m1 and IgA2m2 subtypes was similar to IgG1, whereas the IgA1 isotype displayed considerably lower potency and efficacy. The Fc-mediated induction of antibody-dependent cell-mediated cytotoxicity (ADCC) using human whole blood ADCC assays did not demonstrate such clear differences between the IgA isotypes. However, the potency of the anti-HER2 IgA antibodies in these ADCC assays was found to be significantly lower than that of trastuzumab. In vivo anti-tumor activity of the anti-HER2 IgA antibodies was compared to that of trastuzumab in a BT-474 breast cancer xenograft model. Multiple dosing and sialylation of the IgA antibodies compensated for the short in vivo half-life of native IgA antibodies in mice compared to a single dose of IgG1. In the case of the IgA2m2 antibody, the resulting high plasma exposure levels were sufficient to cause clear tumor stasis comparable to that observed for trastuzumab at much lower plasma exposure levels. PMID- 26440532 TI - Cardioprotection mechanism of mangiferin on doxorubicin-induced rats: Focus on intracellular calcium regulation. AB - CONTEXT: The molecular mechanism of doxorubicin (DOX) cardiotoxicity involves overproduction of free radicals that leads to intracellular calcium dysregulation and apoptosis. Mangiferin (MGR), a naturally occurring glucosylxanthone, has antioxidant and cardioprotective properties. However, its cardioprotection mechanism has yet to be revealed. OBJECTIVE: This study determines whether the cardioprotective effect of MGR is caused by its effect on intracellular calcium regulation. MATERIALS AND METHODS: Male Sprague-Dawley rats were induced by DOX intraperitoneally with a total dose of 15 mg/kg bw. MGR was given orally at the doses of 30 and 60 mg/kg bw/d for seven consecutive weeks. The parameters examined were mRNA expression levels of proinflammatory cytokine gene (TNF alpha), calcium regulatory gene (SERCA2a) and proapoptotic genes (caspase-9 and caspase-12), as well as cytosolic and mitochondrial calcium levels. RESULTS: Treatment with MGR at 60 mg/kg bw/d significantly decreased the mRNA expression levels of TNF-alpha by 44.55% and caspase-9 by 52.79%, as well as the cytosolic calcium level by 24.15% (p < 0.05). SERCA2a and caspase-12 expressions were only slightly affected (27.27% increase and 24.85% decrease for SERCA2a and caspase 12, respectively, p > 0.05). Meanwhile, MGR 30 mg/kg bw/d gave insignificant results in all parameters. DISCUSSION AND CONCLUSION: MGR protected against DOX induced cardiac inflammation and apoptosis via down-regulation of proapoptotic and proinflammatory gene expressions, upregulation of SERCA2a gene expression, and normalization of cytosolic calcium level. Thus, the cardioprotective effect of MGR is at least in part due to the regulation of intracellular calcium homeostasis. PMID- 26440533 TI - Feasibility and significance of preclinical diagnosis in hypertrophic cardiomyopathy. AB - Preclinical diagnosis in hypertrophic cardiomyopathy (HCM) refers to the detection of functional or histopathological abnormalities in subjects who carry any HCM-causing gene mutation, before or even without the development of left ventricular hypertrophy [genotype(+)/phenotype(-)subjects]. The concept that HCM pathology may exist in the absence of left ventricular hypertrophy is quite old but the ability to recognize the presence of early myocardial changes is quite new. Lessons from animal models have shown that in experimental human HCM, myocardial cell mechanical dysfunction precedes histopathological changes, such as myocyte disarray, fibrosis, and hypertrophy. Several clinical reports have demonstrated that the majority of HCM genotype(+)/phenotype(-) subjects display myocardial functional or histopathological changes, such as reduced tissue Doppler imaging-derived systolic and diastolic velocities, abnormal electrocardiogram, cardiac magnetic resonance-visualized myocardial crypts, mitral leaflet elongation, and evidence of a fibrotic state, such as increased type I procollagen synthesis, cardiac magnetic resonance-increased myocardial extracellular volume, and late gadolinium myocardial enhancement. All these signs have been proposed as preclinical markers of HCM. At present the separation of such a group of subjects in the early phase of their disease provides the opportunity to test new therapies to prevent the development of fibrosis, hypertrophy, and dysfunction. PMID- 26440534 TI - The heartbreak of psoriasis: a review of cardiovascular risk in patients with psoriasis. AB - Psoriasis is a common, chronic, autoimmune condition characterized by excessive growth and differentiation of keratinocytes that affects approximately 1% to 3% of the general population in the United States. Mounting evidence has led to an increasing awareness that psoriasis as a disease is more than "skin deep" and that it shares systemic manifestations with other chronic inflammatory diseases such as Crohn's and diabetes mellitus. Recent studies have not only shown an increased prevalence of cardiovascular risk factors in psoriasis but have also identified psoriasis as an independent risk factor for developing cardiovascular disease. This calls for an approach beyond managing traditional risk factors, which remain the standard guidelines at present. PMID- 26440535 TI - Microscopic identification of novel cell types in the integument of larval lake sturgeon, Acipenser fulvescens. AB - Osmoregulation, respiration, nutrient/mineral transport, and defense mechanisms are all evident in the integument of fish. The role of the integument in these physiological processes is particularly important during early life history in larval fishes, as functional systems such as the gills and gastrointestinal tract are not fully developed. Using a variety of microscopy techniques, we describe the morphology of keratinocytes, mitochondria rich cells, ciliated cells and mucous cells of the skin, yolk sac, and gills. The cytology we observed was similar to previous studies describing the integument of larval fish, however, we have also identified two novel cell types on the integument of larval Lake Sturgeon, Acipenser fulvescens, between 9 and 34 days post fertilization. Our detailed analysis included a multifaceted microscopy approach using scanning electron, transmission electron, and light microscopy to elucidate the histology of the tissue and cellular morphology in addition to quantification and distribution of these novel cell types. The first cell type had a characteristic ampullary shape with a central cavity and a pore opening at the surface. The second, located on the free surface of the epidermis, had an uneven plasma membrane surface. Based on the abundance of secretory vesicles, organelles necessary for protein synthesis, and the lack of neural connection in both cell types, we propose these cells to be involved in the release of semiochemicals that may act as a pheromone, alarm substance, or chemical defense mechanism. PMID- 26440536 TI - 4pi electrocyclisation in domino processes: contemporary trends and synthetic applications towards natural products. AB - Recent most instructive and reliable literature reports which deal with domino processes involving conrotatory 4pi electrocyclic reactions, along with a precise mechanistic insight and latest synthetic applications towards biologically active natural products are concisely reviewed. To inspire further research in this domain, a real insight into the overarching emerging themes and potential imminent prospects is also provided. PMID- 26440537 TI - Advancing the 3Rs in regulatory ecotoxicology: A pragmatic cross-sector approach. AB - The ecotoxicity testing of chemicals for prospective environmental safety assessment is an area in which a high number of vertebrates are used across a variety of industry sectors. Refining, reducing, and replacing the use of animals such as fish, birds, and amphibians for this purpose addresses the ethical concerns and the increasing legislative requirements to consider alternative test methods. Members of the UK-based National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) Ecotoxicology Working Group, consisting of representatives from academia, government organizations, and industry, have worked together over the past 6 y to provide evidence bases to support and advance the application of the 3Rs in regulatory ecotoxicity testing. The group recently held a workshop to identify the areas of testing, demands, and drivers that will have an impact on the future of animal use in regulatory ecotoxicology. As a result of these discussions, we have developed a pragmatic approach to prioritize and realistically address key opportunity areas, to enable progress toward the vision of a reduced reliance on the use of animals in this area of testing. This paper summarizes the findings of this exercise and proposes a pragmatic strategy toward our key long-term goals-the incorporation of reliable alternatives to whole-organism testing into regulations and guidance, and a culture shift toward reduced reliance on vertebrate toxicity testing in routine environmental safety assessment. Integr Environ Assess Manag 2016;12:417-421. (c) 2015 SETAC. PMID- 26440538 TI - Differential levels of p75NTR ectodomain in CSF and blood in patients with Alzheimer's disease: a novel diagnostic marker. AB - Alzheimer's disease (AD) is the primary cause of dementia in the elderly. The ectodomain of p75 neurotrophin receptor (p75NTR-ECD) has been suggested to play important roles in regulating beta-amyloid (Abeta) deposition and in protecting neurons from the toxicity of soluble Abeta. However, whether and how the serum and cerebrospinal fluid (CSF) levels of p75NTR-ECD change in patients with AD are not well documented. In the present study, we determined the concentrations of serum p75NTR-ECD in an AD group, a Parkinson disease group and a stroke group, as well as in a group of elderly controls without neurological disorders (EC). We also determined the levels of CSF p75NTR-ECD in a subset of the AD and EC groups. Our data showed that a distinct p75NTR-ECD profile characterized by a decreased CSF level and an increased serum level was present concomitantly with AD patients but not with other diseases. p75NTR-ECD levels in both the serum and CSF were strongly correlated with Mini-Mental State Examination (MMSE) scores and showed sound differential diagnostic value for AD. Moreover, when combining CSF Abeta42, CSF Abeta42/40, CSF ptau181 or CSF ptau181/Abeta42 with CSF p75NTR-ECD, the area under the receiver operating characteristic curve (AUC) and diagnostic accuracies improved. These findings indicate that p75NTR-ECD can serve as a specific biomarker for AD and the determination of serum and CSF p75NTR-ECD levels is likely to be helpful in monitoring AD progression. PMID- 26440540 TI - Use of the second-generation antipsychotic, risperidone, and secondary weight gain are associated with an altered gut microbiota in children. AB - The atypical antipsychotic risperidone (RSP) is often associated with weight gain and cardiometabolic side effects. The mechanisms for these adverse events are poorly understood and, undoubtedly, multifactorial in etiology. In light of growing evidence implicating the gut microbiome in the host's energy regulation and in xenobiotic metabolism, we hypothesized that RSP treatment would be associated with changes in the gut microbiome in children and adolescents. Thus, the impact of chronic (>12 months) and short-term use of RSP on the gut microbiome of pediatric psychiatrically ill male participants was examined in a cross-sectional and prospective (up to 10 months) design, respectively. Chronic treatment with RSP was associated with an increase in body mass index (BMI) and a significantly lower ratio of Bacteroidetes:Firmicutes as compared with antipsychotic-naive psychiatric controls (ratio=0.15 vs 1.24, respectively; P<0.05). Furthermore, a longitudinal observation, beginning shortly after onset of RSP treatment, revealed a gradual decrease in the Bacteroidetes:Firmicutes ratio over the ensuing months of treatment, in association with BMI gain. Lastly, metagenomic analyses were performed based on extrapolation from 16S ribosomal RNA data using the software package, Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). Those data indicate that gut microbiota dominating the RSP-treated participants are enriched for pathways that have been implicated in weight gain, such as short-chain fatty acid production. PMID- 26440539 TI - Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence. AB - We conducted a 1000 Genomes-imputed genome-wide association study (GWAS) meta analysis for nicotine dependence, defined by the Fagerstrom Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European ancestry samples. We identified genome-wide significant association in the alpha 4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 * 10(-9) across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08-1.17 for severe vs mild dependence). rs2273500 C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 * 10(-4)). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28 998, odds ratio=1.06 and 95% confidence interval=1.00-1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single 'cigarettes per day' item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences. PMID- 26440542 TI - Reduced cortical expression of a newly identified splicing variant of the DLG1 gene in patients with early-onset schizophrenia. AB - The human discs, large homolog 1 gene (DLG1) is mapped to the schizophrenia susceptibility locus 3q29, and it encodes a scaffold protein that interacts with the N-methyl-D-aspartate receptor presumably dysregulated in schizophrenia. In the current study, we have newly identified a splicing variant of DLG1, which is transcribed from an unreported 95-base-pair exon (exon 3b) and is labeled 3b(+). We investigated the mRNA expression of 3b(+) in the post-mortem dorsolateral prefrontal cortices of patients with psychiatric disorders, obtained from The Stanley Medical Research Institute, and examined the potential association of the expression with the genotype of the single-nucleotide polymorphism (SNP) rs3915512 located within exon 3b. A real-time quantitative reverse transcriptase polymerase chain reaction revealed that the mRNA levels of 3b(+) were significantly reduced in patients with early-onset schizophrenia (onset at <18 years old, P=0.0003) but not in those with non-early-onset schizophrenia, early onset or non-early-onset bipolar disorder or in the controls. Furthermore, the genotype at the rs3915512 SNP was closely associated with the levels of 3b(+) mRNA expression. It is inferred that the T allele fails to meet the exonic splicing enhancer consensus, thus resulting in skipping of exon 3b, leading to the expression of 3b(-) (the previously known DLG1 variant) but not 3b(+). Because all the subjects with early-onset schizophrenia in the current study possess the T/T genotype, the reduced level of the DLG1 3b(+) transcript may be involved in the susceptibility and/or pathophysiology of early-onset schizophrenia. PMID- 26440541 TI - Right external globus pallidus changes are associated with altered causal awareness in youth with depression. AB - Cognitive impairment is a functionally disabling feature of depression contributing to maladaptive decision-making, a loss of behavioral control and an increased disease burden. The ability to calculate the causal efficacy of ones actions in achieving specific goals is critical to normal decision-making and, in this study, we combined voxel-based morphometry (VBM), shape analysis and diffusion tensor tractography to investigate the relationship between cortical basal ganglia structural integrity and such causal awareness in 43 young subjects with depression and 21 demographically similar healthy controls. Volumetric analysis determined a relationship between right pallidal size and sensitivity to the causal status of specific actions. More specifically, shape analysis identified dorsolateral surface vertices where an inward location was correlated with reduced levels of causal awareness. Probabilistic tractography revealed that affected parts of the pallidum were primarily connected with the striatum, dorsal thalamus and hippocampus. VBM did not reveal any whole-brain gray matter regions that correlated with causal awareness. We conclude that volumetric reduction within the indirect pathway involving the right dorsolateral pallidum is associated with reduced awareness of the causal efficacy of goal-directed actions in young depressed individuals. This causal awareness task allows for the identification of a functionally and biologically relevant subgroup to which more targeted cognitive interventions could be applied, potentially enhancing the long term outcomes for these individuals. PMID- 26440543 TI - Histamine H4 receptor knockout mice display reduced inflammation in a chronic model of atopic dermatitis. AB - BACKGROUND: The histamine H4 receptor (H4R) was brought into focus as a new therapeutic target for the treatment of allergic disorders such as atopic dermatitis (AD). H4R antagonists have already been tested in several animal models of AD, but these studies have yielded conflicting results. MATERIAL AND METHODS: The development of ovalbumin-induced AD-like skin lesions was analysed in H4R(-/-) mice and in H4R antagonist (JNJ28307474)-treated mice. RESULTS: H4R( /-) mice showed a clear amelioration of the skin lesions, with a diminished influx of inflammatory cells and a reduced epidermal hyperproliferation at lesional skin sites. H4R(-/-) mice had a reduced amount of ovalbumin-specific IgE, a reduced number of splenocytes and lymph node cells with a decreased number of CD4+ T cells. The H4R modulated the cytokine secretion of CD4+ T cells and splenocytes and altered the cellular profile in the lymph nodes. The anti inflammatory effect could only partially be mimicked by JNJ28307474 and only when the H4R antagonist was given during sensitization and challenge and not when JNJ28307474 was only given during the provocation phase of the allergic reaction. CONCLUSION: The H4R modulates inflammation in a chronic allergic dermatitis setting. However, results of this study indicate that it is necessary to block the H4R during ontogeny and development of the allergic inflammation. PMID- 26440544 TI - What is the mechanism effect that links social support to coping and psychological outcome within individuals affected by prostate cancer? Real time data collection using mobile technology. AB - PURPOSE: Unmet support needs are prevalent in men affected by prostate cancer. Moreover, little is known about the optimal type of social support, or its mechanism effect between coping and emotional outcome in men affected by this disease to identify areas for clinical intervention. This study aimed to empirically test the propositions of social support theory in "real time" within individual men living with and beyond prostate cancer. METHODS: Purposeful sub sample from a larger prospective longitudinal study of prostate cancer survivors, took part in real time data collection using mobile technology. Self-reports were collected for 31 days prompted by an audio alarm 3 times per day (a total of 93 data entries) for each of the 12 case studies. Electronic data were analysed using time series analysis. RESULTS: Majority of response rates were >90%. Men reported a lack of satisfaction with their support over time. Testing the propositions of social support theory "within individuals" over time demonstrated different results for main effect, moderation and mediation pathways that linked coping and social support to emotional outcome. For two men, negative effects of social support were identified. For six men the propositions of social support theory did not hold considering their within-person data. CONCLUSION: This innovative study is one of the first, to demonstrate the acceptability of e health technology in an ageing population of men affected by prostate cancer. Collectively, the case series provided mixed support for the propositions of social support theory, and demonstrates that "one size does not fit all". PMID- 26440545 TI - Variation in bioaccumulation of persistent organic pollutants based on octanol air partitioning: Influence of respiratory elimination in marine species. AB - Risk assessments of persistent organic pollutants (POPs) are often based on octanol-water (KOW) partitioning dynamics and may not adequately reflect bioaccumulation in air-breathing organisms. It has been suggested that compounds with low KOW and high octanol-air partitioning (KOA) coefficients have the potential to bioaccumulate in air-breathing organisms, including marine mammals. Here we evaluate differences in concentrations of POPs for two trophically matched Arctic species, spotted seal (Phoca largha) and sheefish (Stenodus leucichthys). We compared concentrations of 108 POPs in matched tissues (liver and muscle) across three ranges of KOW. We found a significant positive correlation between POP concentration and log KOA in spotted seal tissues for low log KOW compounds (log KOW <5.5, p<0.05). This provides further evidence for empirical models and observed bioaccumulation patterns in air-breathing organisms, and highlights the potential for bioaccumulation of these compounds in Arctic marine mammals. PMID- 26440546 TI - The combined transverse upper gracilis and profunda artery perforator (TUGPAP) flap for breast reconstruction. AB - BACKGROUND: Surgical options for breast reconstruction include alloplastic and autogenous reconstructions. In autologous cases where the abdomen is not a suitable primary donor site, secondary donor sites such as the thigh or buttock are considered. The aim of this report is to describe a novel approach, the combined transverse upper gracilis and profunda artery perforator (TUGPAP) flap, aimed at medium to large volume breast reconstruction, with a single donor site used per breast. METHODS: Between January 2011 and June 2013, 32 consecutive unilateral immediate breast reconstruction cases were performed using free flaps. In nine cases, patients had previously undergone abdominal surgery, therefore abdominal flaps were excluded and TUGPAP flaps were performed. The TUGPAP flap consisted of the combination of two well-described flaps: the transverse upper gracilis (TUG) and the profunda artery perforator (PAP) flap. All TUGPAP flaps were based on two pedicles: the ascending branch of the medial circumflex femoral artery (MCFA) for the TUG component, and the profunda artery perforator itself for the PAP component. RESULTS: The mean size of the harvested skin paddle was 28.6 * 8 cm2 (range, 27 * 7 cm2 to 30 * 9 cm2). The average length of the TUG flap pedicle was 7 cm (range, 6-8 cm) and the PAP flap pedicle was 9 cm (range, 8.5-10 cm). The flap survival rate was 100% with no re-exploration, and no partial flap loss. Post-operatively there was one case of persistent donor site seroma, which was managed conservatively. CONCLUSION: With appropriate patient selection and surgical technique the TUGPAP flap could be a valuable option as an alternative method for autologous breast reconstruction. (c) 2015 Wiley Periodicals, Inc. Microsurgery, 2015. PMID- 26440547 TI - A unique alpha dosimetry technique using Gafchromic EBT3((r)) film and feasibility study for an activity calibrator for alpha-emitting radiopharmaceuticals. AB - OBJECTIVE: To develop an alpha dosimetry technique for activity calibration of alpha-emitting radiopharmaceuticals using the Gafchromic((r)) EBT3 (Gaf-EBT3) radiochromic film (International Speciality product, Wayne, NJ). METHODS: The Gaf EBT3 has a tissue equivalent radiosensitive layer (approximately 28 MUm) sandwiched between two 100-MUm thick polyester sheaths, thereby making it insensitive to alpha particles. We have split a Gaf-EBT3 sheet using a surgical scalpel to remove one of the polyester protective layers and covered the radiosensitive layer with thin Mylar((r)) foil (Goodfellow Cambridge Limited, Huntingdon, UK) (2.5 MUm). Small pieces of modified film were exposed at contact with a 560-Bq thin (241)Am source for 5, 10, 24 and 94 h. The optical density of the films was evaluated using an optical densitometer. The alpha energy spectra of the (241)Am source were recorded using a Si(Li) surface barrier detector. RESULTS: Time-integrated specific alpha surface activity (kBq cm(-2) h) was represented as a function of optical density. CONCLUSION: By removing one of the 100 MUm thick polyester protective layers, the authors have modified the Gaf-EBT3 film to a sensitive alpha dosemeter. The calibration function relevant to a (241)Am reference source was evaluated from the optical densities of the dosemeter foils. Furthermore, calibration functions for important alpha emitters such as (223)Ra, (225)Ac or (210)Bi were parameterized from the (241)Am reference data. ADVANCES IN KNOWLEDGE: The authors have developed and tested the principle of a clinical alpha dosemeter using Gaf-EBT3 radiochromic films originally developed for photon dosimetry. This novel, user-friendly technique could be implemented in quality assurance and calibration procedures of important alpha emitting radiopharmaceuticals prior to their clinical applications. PMID- 26440548 TI - MRI and thallium features of pigmented villonodular synovitis and giant cell tumours of tendon sheaths: a retrospective single centre study of imaging and literature review. AB - OBJECTIVE: The purpose of this study was to characterize the MRI and thallium-201 ((201)TI) scintigraphy attributes of pigmented villonodular synovitis (PVNS) and giant cell tumours of tendon sheaths (GCTTS). The epidemiology of these uncommon lesions was also assessed and less commonly encountered pathology reported on including multifocality, necrosis and concurrent malignancy. METHODS: A retrospective single centre review of MRI and (201)TI scintigraphy findings for 83 surgically proven or biopsy-proven consecutive cases of PVNS was undertaken. Radiological findings including lesion size, (201)TI uptake (as a marker of metabolic activity), location, extent and patient demographics were correlated with biopsy and surgical specimen histology. Typical appearances are described, as well as less common imaging manifestations. The study period encompassed all patients presenting or referred to a tertiary bone and soft-tissue tumour referral centre with PVNS or GCTTS between 1 January 2007 and the 1 December 2013. RESULTS: Lesions occur most commonly around the knee joint in the fourth decade of life, with younger patients showing a tendency to occur in the hip. Features of PVNS and GTTS include bone erosion, ligamentous and cartilage replacement, muscle infiltration and multifocality. MR signal characteristics were variable but post-contrast enhancement was near-universal. 14 of 83 cases showed no uptake of (201)TI and revealed a statistically significant smaller average axial dimension of 19.8 mm than lesions displaying active (201)TI uptake of 36.4 mm, p = 0.016. Four lesions demonstrated central necrosis on gross histology, two of each from both the (201)TI-avid and (201)TI-non-avid groups. CONCLUSION: MR is the imaging modality of choice when considering the diagnosis of these uncommon tumours. (201)TI scintigraphy as a marker of metabolic activity further adds minimal value although small lesions can appear to lack (201)TI avidity. ADVANCES IN KNOWLEDGE: This article depicts typical imaging findings of PVNS/GCTTS and also a subset of lesions that demonstrate no uptake on metabolic functional imaging, namely smaller sized lesions irrespective of anatomical location. This represents an important departure from previously documented imaging manifestations, whereby an absence of isotope accumulation suggested exclusion of these lesions from the differential diagnosis. These findings have important implications when considering the diagnosis of these uncommon lesions and may be important when interpreting post-treatment response. We suggest that further investigation, for example, with MRI is valuable in order to clarify potential post-treatment response, as well as the use of alternate functional imaging modalities such as positron emission tomography (PET), to further corroborate these findings. PMID- 26440549 TI - Can PEP-3 Provide a Cognitive Profile in Children with ASD? A Comparison Between the Developmental Ages of PEP-3 and IQ of Leiter-R. AB - BACKGROUND: The assessment of the intelligence quotient (IQ) in children with autism spectrum disorder (ASD) is important to plan a detailed therapeutic educative programme. The aim of the study was to evaluate the usefulness of the Psychoeducational Profile-third edition (PEP-3) to estimate the general cognitive development of children with ASD. METHOD: We recruited 30 children with ASD assessed with the Leiter International Performance Scale-Revised (Leiter-R) and the PEP-3. We compared the IQ of the Leiter-R with the developmental level (DL) of PEP-3. RESULTS: The findings showed a significant positive correlation between IQ with DL of the cognitive verbal/pre-verbal (P = 0.0005), DL of the area of expressive language (P = 0.0004), DL of the area of receptive language (P = 0.0001), DL of fine motor (P = 0.0066), DL of gross motor (P = 0.0217), DL of visuo-motor imitation (P = 0.02), DL of communication (P = 0.0001) and DL of motor (P = 0.0063). CONCLUSIONS: These findings show that the DLs could be considered as indicators of cognitive functioning in ASD. PMID- 26440550 TI - Neuromodulation for cardiac arrhythmia. AB - The autonomic nervous system is known to play a significant role in the genesis and maintenance of arrhythmias. Neuromodulation, mostly designed to increase the parasympathetic tone and suppress the sympathetic tone, has become an emerging therapeutic strategy for the treatment of arrhythmias. Emerging therapeutic approaches include cervical vagal stimulation, transcutaneous auricular vagal stimulation, baroreceptor activation therapy spinal cord stimulation, ganglionated plexi ablation, renal sympathetic denervation, and left cardiac sympathetic denervation. PMID- 26440551 TI - Implantable devices in young patients: Hitting the reset button on risk versus benefit. PMID- 26440552 TI - Mechanical thrombectomy as an alternative to thrombolysis in embolic stroke. PMID- 26440553 TI - Detecting association of rare and common variants by adaptive combination of P values. AB - Genome-wide association studies (GWAS) can detect common variants associated with diseases. Next generation sequencing technology has made it possible to detect rare variants. Most of association tests, including burden tests and nonburden tests, mainly target rare variants by upweighting rare variant effects and downweighting common variant effects. But there is increasing evidence that complex diseases are caused by both common and rare variants. In this paper, we extend the ADA method (adaptive combination of P-values; Lin et al., 2014) for rare variants only and propose a RC-ADA method (common and rare variants by adaptive combination of P-values). Our proposed method combines the per-site P values with the weights based on minor allele frequencies (MAFs). The RC-ADA is robust to directions of effects of causal variants and inclusion of a high proportion of neutral variants. The performance of the RC-ADA method is compared with several other association methods. Extensive simulation studies show that the RC-ADA method is more powerful than other association methods over a wide range of models. PMID- 26440554 TI - Benzophenone 1 induced photogenotoxicity and apoptosis via release of cytochrome c and Smac/DIABLO at environmental UV radiation. AB - Solar UV radiation is main factor of photocarcinogenesis, photoageing, and phototoxicity; thus, protection from UV radiation is major concern. Sunscreens containing UV filters are suggested as sun safe practices, but safety of UV filters remains in controversies. Benzophenone-1 (BP1) is commonly used in sunscreens as UV blocker. We assessed the photogenotoxicity and apoptotic parameters in human keratinocytes (HaCaT cells) by western blot, immunocytochemistry, flowcytometry, comet assay and TEM imaging. Our results exposed that BP1 photosensitized and generated intracellular ROS (2.02 folds) under sunlight/UVR. Decrease in cell viability was recorded as 80.06%, 60.98% and 56.24% under sunlight, UVA and UVB, respectively. Genotoxic potential of BP1 was confirmed through photomicronuclei and CPDs formation. BP1 enhanced lipid peroxidation and leakage of LDH enzyme (61.7%). Apoptotic cells were detected by AnnexinV/PI staining and sub G1 population of cell cycle. BP1 induced up regulation of apoptotic proteins Bax/Bcl2 ratio, Apaf-1, cytochrome c, Smac/DIABLO and cleaved caspase 3 was noticed. Down regulation of pro caspase 3 was inhibited by Z-VAD-fmk (inhibitor of caspase). Thus, study established the involvement of BP1 in photogenotoxicity and apoptosis via release of cytochrome c and Smac/DIABLO. These findings suggest sunscreen user to avoid BP1 in cosmetics preparation for its topical application. PMID- 26440555 TI - Transition and duration in disability: New evidence from administrative data. AB - BACKGROUND: In recent decades demographic changes (low fertility rates, increased life expectancy...) in most OECD countries, have brought profound changes in the population pyramid, with several effects in the welfare of society. One of them is the increase in the number of people with disabilities, since age is a determining factor in the emergence of this dependency. OBJECTIVE/HYPOTHESIS: This paper studies the probability to enter and transit in and from a disability state, as well as its associated mortality, by attending to the distinction between the initial disability level and the process that leads on from it, and by addressing whether and how education, age and income affect this transition. METHODS: Applying a Markov model and a survival analysis to new Spanish administrative data set (Muestra Continua de Vida Laboral (MCVL)) we estimate the probability that a person changes the state of disability and the duration of her progression in each case. RESULTS: We find that people with an initial state of disability have a higher propensity to change status and take less time to transit amongst different stages than those who have no disability. Men do so more frequently than women and income have negative effects on the transition. CONCLUSIONS: These results may help to incorporate into welfare programs some protection mechanisms for delaying transitions and target the most fragile population groups. PMID- 26440557 TI - Anion-specific aggregation induced phosphorescence emission (AIPE) in an ionic iridium complex in aqueous media. AB - Efficient aggregation induced phosphorescence emission (AIPE) of an ionic Ir(iii) complex occurs when the counterion (PF6(-)) is exchanged specifically by ClO4(-) in aqueous media. As a result, a rapid, highly selective "turn-on" phosphorescent response to ClO4(-) is observed in aqueous media. These studies pave the way for a new efficient phosphorescence-based detection strategy for anions. PMID- 26440556 TI - Systematic overview of economic evaluations of health-related rehabilitation. AB - BACKGROUND: Health related rehabilitation is instrumental in improving functioning and promoting participation by people with disabilities. To make clinical and policy decisions about health-related rehabilitation, resource allocation and cost issues need to be considered. OBJECTIVES: To provide an overview of systematic reviews (SRs) on economic evaluations of health-related rehabilitation. METHODS: We searched multiple databases to identify relevant SRs of economic evaluations of health-related rehabilitation. Review quality was assessed by AMSTAR checklist. RESULTS: We included 64 SRs, most of which included economic evaluations alongside randomized controlled trials (RCTs). The review quality was low to moderate (AMSTAR score 5-8) in 35, and high (score 9-11) in 29 of the included SRs. The included SRs addressed various health conditions, including spinal or other pain conditions (n = 14), age-related problems (11), stroke (7), musculoskeletal disorders (6), heart diseases (4), pulmonary (3), mental health problems (3), and injury (3). Physiotherapy was the most commonly evaluated rehabilitation intervention in the included SRs (n = 24). Other commonly evaluated interventions included multidisciplinary programmes (14); behavioral, educational or psychological interventions (11); home-based interventions (11); complementary therapy (6); self-management (6); and occupational therapy (4). CONCLUSIONS: Although the available evidence is often described as limited, inconsistent or inconclusive, some rehabilitation interventions were cost-effective or showed cost-saving in a variety of disability conditions. Available evidence comes predominantly from high income countries, therefore economic evaluations of health-related rehabilitation are urgently required in less resourced settings. PMID- 26440558 TI - CARD9 mutation linked to Corynespora cassiicola infection in a Chinese patient. AB - Corynespora cassiicola is a plant pathogen associated with leaf-spotting disease. The fungus has been found on diverse substrates: leaves, stems and roots of plants; nematode cysts and human skin. It rarely causes human infections. Here we report one case of subcutaneous phaeohyphomycosis caused by C. cassiicola with prominent tissue necrosis in a woman. All of her clinical features pointed towards a genetic linkage. Hence, whole-exome sequencing and Sanger sequencing were performed on this patient. One mutation of CARD9 was detected. PMID- 26440559 TI - Editorial Comment on "The Effect of Vortioxetine vs. Escitalopram on Sexual Functioning in Adults with Well-Treated Major Depressive Disorder Experiencing SSRI-Induced Sexual Dysfunction". PMID- 26440560 TI - Rhodium-Catalyzed C-H Alkylation of Indolines with Allylic Alcohols: Direct Access to beta-Aryl Carbonyl Compounds. AB - The rhodium(III)-catalyzed site-selective C-H alkylation of various N heterocycles, such as indolines, carbazoles, and pyrroles with readily available allylic alcohols is described. This protocol allows the generation of a heterocyclic scaffold containing a beta-aryl carbonyl moiety, which is known to be a crucial structural unit of biologically active compounds. PMID- 26440561 TI - The use of PCR-DGGE to determine bacterial fingerprints for poultry and red meat abattoir effluent. AB - Strict legislation and chemical composition monitoring of effluent may be useful, but the data generated do not allow for source tracking, and enforcing legislation remains problematic in the South African setting. These difficulties emphasize the necessity for effluent source traceability. Denaturing gradient gel electrophoresis (DGGE) targeting the V3 region of the 16S rRNA gene was considered as fingerprinting technique for effluent originating from abattoirs slaughtering different animal species. The influence of treatment to remove excess fat from effluent prior to molecular analyses and different PCR approaches on the detection of bacterial diversity were considered. Use of a treatment option to remove fat and a nested PCR approach resulted in up to 51% difference in inter-sample diversity similarity. A robust approach with no pre-treatment to remove PCR inhibitors, such as fat, and direct amplification from genomic DNA yielded optimal/maximal bacterial diversity fingerprints. Repeatable fingerprints were obtained for poultry abattoir effluent over a 4-month period, but profiles for the red meat abattoir varied with maximum similarity detected only 33.2%. Genetic material from faecal indicators Aeromona spp and Clostridium spp were detected. Genera unique to each effluent were present; Anoxybacillus, Patulibacter and Oleispira in poultry abattoir effluent and Porphyromonas and Peptostreptococcus in red meat abattoir effluent. SIGNIFICANCE AND IMPACT OF THE STUDY: This study was the first to demonstrate the application of denaturing gradient gel electrophoresis (DGGE) to construct bacterial diversity fingerprints for high-throughput abattoir effluents. Proved redundancy of fat removal as PCR inhibitor and change in diversity similarity introduced by nested PCR approach. The importance of limiting excessive handling/processing which could lead to misrepresented diversity profiles was emphasized. PMID- 26440562 TI - Exploratory Study on the RNA-Binding Structural Motifs by Library Screening Targeting pre-miRNA-29 a. AB - The metabolic stream of microRNA (miRNA) production, the so-called maturation process of miRNAs, became one of important metabolic paths for drug-targeting to modulate the expression of genes related to a number of diseases. We carried out discovery studies on small molecules binding to the precursor of miR-29a (pre-miR 29a) from a chemical library containing 41,119 compounds (AQ library) by the fluorescent indicator displacement (FID) assay using the xanthone derivative X2SdiMe as a fluorescent indicator. The FID assay provided 1075 compounds, which showed an increase of fluorescence. These compounds were subsequently submitted to a binding analysis in a surface plasmon resonance (SPR) assay on a pre-miR-29a immobilized surface. 21 hit compounds were identified with a good reproducibility in the binding. These compounds have not been reported to bind to RNA until now and can be classified into two groups on the basis of the kinetics in the binding. To gain more information on the motif structures that could be necessary for the binding to pre-miR-29a, 19 substructures were selected from the hit compounds. The substructure library (SS library) which consisted of 362 compounds was prepared from the AQ library. An SPR assay of the SS library on pre-miR-29a immobilized surface suggested that five substructures could potentially be important structural motifs to bind to pre-miR-29a. These studies demonstrate that the combination of FID-based screening of chemical library and subsequent SPR assay would be one way for obtaining practical solutions for the discovery of molecules which bind to the target pre-miRNAs. PMID- 26440563 TI - Nonparallel Stacks of Donor and Acceptor Chromophores Evade Geminate Charge Recombination. AB - We report a nonparallel stacked arrangement of donor-acceptor (D-A) pairs for prolonging the lifetime of photoinduced charge-separated states. Hydrogen hydrogen steric repulsion in naphthalimide-naphthalene (NIN) dyad destabilizes the planar geometry between the constituent units in solution/ground state. Sterically imposed nonplanar geometry of the dyad allows the access of nonparallel arrangement of the donor and acceptor stacks having triclinic space group in the crystalline state. Antiparallel trajectory of excitons in nonparallel D-A stacks can result in lower probability of geminate charge recombination, upon photoexcitation, thereby resulting in a long-lived charge separated state. Upon photoexcitation of the NIN dyad, electron transfer from naphthalene to the singlet excited state of naphthalimide moiety results in radical ion pair intermediates that survive >10,000-fold longer in the aggregated state (taucra > 1.2 ns) as compared to that of monomeric dyad (taucrm < 110 fs), monitored using femtosecond transient absorption spectroscopy. PMID- 26440564 TI - Liver metabolic activity changes over time with neoadjuvant therapy in locally advanced rectal cancer. AB - OBJECTIVE: The aim of this study was to evaluate, using PET/computed tomography (CT), changes in liver metabolic activity in patients with locally advanced rectal cancer (LARC) after neoadjuvant chemoradiotherapy (CRT). PATIENTS AND METHODS: A total of 29 biopsy-proven LARC patients between 2009 and 2012 were studied. Liver standardized uptake values (SUVs) and SUVs adjusted for lean body mass (SULs) were obtained from PET/CT images obtained at 1 h (early) and 2 h (late) after (18)F-fluorodeoxyglucose ((18)F-FDG) administration both before and after neoadjuvant CRT. Age, sex, BMI, lean body mass, blood glucose level, and (18)F-FDG dose, which can influence liver SUVs and SULs, were also analyzed. RESULTS: Fourteen (48%) men and 15 (52%) women with a mean age of 62+/-11 years (range 34-80 years) were included in the study. The mean SUVs and SULs were significantly decreased in the late scans. Sex was significantly correlated with the mean liver SUV in early and late scans. The mean SUV differed significantly between male and female patients in early and late images (P<0.05). In a multivariate stepwise regression analysis, only liver SUVs (maximum and mean) were significantly associated with BMI before and after therapy. SUVs were significantly higher in the high (>=25) BMI group after but not before therapy. Mean SUL was not influenced by BMI. CONCLUSION: Liver (18)F-FDG uptake is consistent before and after neoadjuvant CRT therapy in patients with LARC. When assessing response to therapy and using liver metabolic activity to indicate background activity, BMI should be considered as it can influence liver metabolic activity. PMID- 26440565 TI - Evaluation of scatter limitation correction: a new method of correcting photopenic artifacts caused by patient motion during whole-body PET/CT imaging. AB - OBJECTIVE: Overcorrection of scatter caused by patient motion during whole-body PET/computed tomography (CT) imaging can induce the appearance of photopenic artifacts in the PET images. The present study aimed to quantify the accuracy of scatter limitation correction (SLC) for eliminating photopenic artifacts. METHODS: This study analyzed photopenic artifacts in (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT images acquired from 12 patients and from a National Electrical Manufacturers Association phantom with two peripheral plastic bottles that simulated the human body and arms, respectively. The phantom comprised a sphere (diameter, 10 or 37 mm) containing fluorine-18 solutions with target-to background ratios of 2, 4, and 8. The plastic bottles were moved 10 cm posteriorly between CT and PET acquisitions. All PET data were reconstructed using model-based scatter correction (SC), no scatter correction (NSC), and SLC, and the presence or absence of artifacts on the PET images was visually evaluated. The SC and SLC images were also semiquantitatively evaluated using standardized uptake values (SUVs). RESULTS: Photopenic artifacts were not recognizable in any NSC and SLC image from all 12 patients in the clinical study. The SUVmax of mismatched SLC PET/CT images were almost equal to those of matched SC and SLC PET/CT images. Applying NSC and SLC substantially eliminated the photopenic artifacts on SC PET images in the phantom study. SLC improved the activity concentration of the sphere for all target-to-background ratios. The highest %errors of the 10 and 37-mm spheres were 93.3 and 58.3%, respectively, for mismatched SC, and 73.2 and 22.0%, respectively, for mismatched SLC. CONCLUSION: Photopenic artifacts caused by SC error induced by CT and PET image misalignment were corrected using SLC, indicating that this method is useful and practical for clinical qualitative and quantitative PET/CT assessment. PMID- 26440566 TI - Characterization of 'cold' vertebrae on 18F-FDG PET/CT. AB - INTRODUCTION: A photon-deficient ('cold') vertebra on fluorine-18 fluorodeoxyglucose (F-FDG) PET is a known entity and can arise as a result of varying etiologies. A proper interpretation of this observation is required to make an accurate diagnosis for appropriate management. METHODS: Twelve cases with 'cold' vertebrae on F-FDG PET/computed tomography (CT) were selected and analyzed from a population of 600 patients with a known malignancy who had undergone whole body F-FDG PET/CT for staging, disease viability assessment, response to treatment, or suspected recurrence purposes. The patterns were studied and correlated with clinical history and the results of the low-dose CT performed with the PET scan for attenuation correction and anatomical localization. RESULTS: The most common cause for cold vertebrae was found to be postexternal radiotherapy, causing photopenia involving multiple vertebrae corresponding to the radiotherapy portals. Two other causes found in the study were the destruction of the vertebral marrow cavity by metastatic tumor cells and vertebral hemangioma. Characteristic features of 'cold' vertebrae have been described in the study with illustrations. CONCLUSION: Pattern recognition coupled with clinical history and CT correlation of 'cold' vertebrae on F-FDG PET/CT can help in diagnosing the correct underlying etiology, which can help in better management of the patients. PMID- 26440567 TI - Variety in bone marrow 18F-FDG uptake in Hodgkin lymphoma patients without lymphomatous bone marrow involvement: does it have an explanation? AB - OBJECTIVE: To directly correlate fluorine-18 fluoro-2-deoxy-D-glucose (F-FDG) uptake of the iliac crest, as determined with PET, with both spatially matched histological bone marrow parameters and laboratory markers in Hodgkin lymphoma patients without lymphomatous bone marrow involvement at bone marrow biopsy. MATERIALS AND METHODS: This retrospective study included 21 patients with newly diagnosed Hodgkin lymphoma who underwent F-FDG-PET and who had a lymphoma negative bone marrow biopsy of the right posterior iliac crest. F-FDG-PET maximum standardized uptake value (SUVmax) was measured in the right posterior iliac crest and correlated to histological bone marrow parameters (cellularity, myeloid/erythroid ratio, degree of fibrosis, and reactive T- and B-lymphocytes) and laboratory markers (hemoglobin, C-reactive protein lactate dehydrogenase, and leukocyte and thrombocyte counts) using Pearson's correlation coefficient (R) for Gaussian data or Kendall's tau (tau) for non-Gaussian data. RESULTS: There was a significant moderate correlation between F-FDG-PET SUVmax and cellularity of the iliac crest (R=0.519, P=0.016). Furthermore, there was a significant strong inverse correlation between F-FDG-PET SUVmax of the iliac crest and hemoglobin level (R=-0.661, P=0.001) and there was a significant moderate correlation between F-FDG-PET SUVmax of the iliac crest and C-reactive protein level (tau=0.441, P=0.007). All other correlations, including F-FDG-PET SUVmax of the right iliac crest versus reactive T- and B-lymphocytes in the bone marrow, were not significant. CONCLUSION: The observations suggest increased bone marrow F-FDG uptake to be caused by red marrow hyperplasia because of anemia in Hodgkin lymphoma. Increased bone marrow F-FDG uptake is unlikely to be caused by inflammatory bone marrow changes. PMID- 26440568 TI - Comparison of WHO, RECIST 1.1, EORTC, and PERCIST criteria in the evaluation of treatment response in malignant solid tumors. AB - AIM: To compare response assessment according to the WHO, RECIST 1.1, EORTC, and PERCIST criteria in patients diagnosed with malignant solid tumors and who had received cytotoxic chemotherapy to establish the strength of agreement between each criterion. MATERIALS AND METHODS: Sixty patients with malignant solid tumors were included in this retrospective study. The baseline and the sequential follow up fluorine-18-fluorodeoxyglucose PET/computed tomography (CT) of each patient were evaluated according to the WHO, RECIST 1.1, EORTC, and PERCIST criteria. PET/CT images were used for both metabolic and anatomic evaluation. The concurrent diagnostic CT and MRI images (performed within 1 week of PET/CT) were also utilized when needed. The results were compared using the kappa-statistics. RESULTS: The response and progression rates according to the WHO criteria were 37 and 38%, respectively. The same ratios were also found for RECIST 1.1 (kappa=1). The response and progression rates according to the EORTC criteria were 47 and 40%, respectively. When PERCIST criteria were used, one patient with progressive disease was upgraded to stable disease (kappa=0.976). As we found the same results with WHO and RECIST 1.1 criteria, we used WHO criteria to compare the anatomic and metabolic criteria. When we compared the WHO and EORTC criteria, there was an agreement in 80% of the patients (kappa=0.711). With WHO and PERCIST criteria, there was an agreement in 81.6% of the patients (kappa=0.736). CONCLUSION: Significant agreement was detected when the WHO, RECIST 1.1, EORTC, and PERCIST criteria were compared both within as well as between each other. PMID- 26440569 TI - Quantitative analysis of basal and interim PET/CT images for predicting tumor recurrence in patients with Hodgkin's lymphoma. AB - OBJECTIVES: The qualitative analysis of interim PET has been reported to be useful for predicting the outcome of Hodgkin's lymphoma (HL) after chemotherapy. As the next step, our study aims to present a quantitative analysis on the basis of both a basal (PET/CT0) and an interim (PET/CT2) scan to improve the prognostic value of imaging in HL patients. PATIENTS AND METHODS: A cohort of 68 patients undergoing a basal and an interim scan with F-fluorodeoxyglucose after two cycles of chemotherapy consisting of adriamycin, bleomycin, vinblastine, and dacarbazine were examined. Two subsets of patients with a positive and a negative interim scan were selected. RESULTS: In patients with a negative scan, a total of 108 lymph node lesions showing a good response to chemotherapy were contoured, whereas in the remaining patients with positive scans, six responder and 12 relapsing lymph node lesions were contoured. Standardized uptake value (SUV) and Hounsfield unit (HU) values were included in the volumes contoured on coregistered basal and interim scans and included in a database. A linear regression model was used to identify the predictor of relapse at the lesion level. The support vector machine analysis and bootstrap approach were used to determine the model capability. The predictive models were presented as nomograms on the basis of basal or both basal and interim studies. SUV at the basal/interim study and basal HU values were predictors of a poor prognosis. In particular, the higher points were associated with lower values of SUV and HU at baseline and the higher values of SUV at the interim study. Using the bootstrap and support vector machine approach, the cut-off of the model increased up to 89%. CONCLUSION: The novel tool enables estimation of the risk of tumor relapse after chemotherapy in HL patients on the basis of basal and interim PET/CT scans including SUV and densitometric information. PMID- 26440570 TI - Evaluating the use of optimally respiratory gated 18F-FDG-PET in target volume delineation and its influence on radiation doses to the organs at risk in non small-cell lung cancer patients. AB - OBJECTIVE: This radiotherapy planning study evaluated tumour delineation using both optimally respiratory gated and nongated fluorine-18 fluorodeoxyglucose-PET (F-FDG-PET). METHODS: For 22 non-small-cell lung tumours, both scans were used to create the nongated and gated (g) gross tumour volumes (GTVg) together with the accompanying clinical target volumes (CTV) and planning target volumes (PTV). The size of the target volumes (TV) was evaluated and the accompanying radiotherapy plans were created to study the radiation doses to the organs at risk (OAR). RESULTS: The median volumes of GTVg, CTVg and PTVg were statistically significantly smaller compared with the corresponding nongated volumes, resulting in a median TV reduction of 0.5 cm (interquartile range 0.1-1.2), 1.5 cm (-0.2 to 7.0) and 2.3 cm (-0.5 to 11.3) for the GTVg, CTVg and PTVg, respectively. For the OAR, only the percentage of lung (GTV included) receiving at least 35 Gy was significantly smaller after gating, with a median difference in lung volume receiving at least 35 Gy of 5.7 cm (interquartile range -0.8 to 30.50). CONCLUSION: Compared with nongated F-FDG-PET, the TVs obtained with optimally respiratory gated F-FDG-PET were significantly smaller, however, without a clinically relevant difference in radiation dose to the OAR. PMID- 26440572 TI - The potential value of volume-based quantitative PET parameters and increased bone marrow uptake for the prediction of survival in patients with malignant pleural mesothelioma. AB - PURPOSE: The aim of this study was to investigate the relationship between volume based quantitative PET parameters and survival in patients with malignant pleural mesothelioma (MPM) and to evaluate the potential value of bone marrow (BM) uptake in predicting prognosis. MATERIALS AND METHODS: We retrospectively reviewed the data of 51 patients with MPM who underwent initial staging by fluorine-18 fluorodeoxyglucose (F-FDG) PET/computerized tomography (PET/CT). F-FDG-PET images were visually and quantitatively re-evaluated and maximum standardized uptake values (SUVmax), mean standardized uptake values (SUVmean), metabolic tumor volume (MTV), total lesion glycolysis of primary tumors, and pleural thickening were calculated. In addition, BM and liver uptakes were measured; also, the degree of BM uptake was scored visually. BM/liver ratio and visual BM uptake score were noted. The correlations between quantitative PET parameters, BM uptake, and overall survival were analyzed. RESULTS: F-FDG-PET scans upstaged 6 (11.8%) of 51 patients because of detection of previously unknown distant metastasis. On univariate analysis, advanced disease stage, high leukocyte count (>=10*10/ml), pleural thickening greater than 13 mm, SUVmax, SUVmean, MTV, total lesion glycolysis, BM/liver greater than 1.01, and visual score 1 and 2 were negative prognostic factors (P<0.05). In multivariate analysis, SUVmax greater than 8.6 [P=0.027, hazard ratio (HR): 2.961], MTV greater than 112 (P=0.001, HR: 4.861), and visual score 2 (P=0.035, HR: 3.827) were associated independently with a poor prognosis. CONCLUSION: The presence of distant metastasis is more predictive of survival than PET nodal status in MPM patients. PET/CT has the potential to provide prognostic information in MPM patients and there was a good correlation between overall survival and volume-based PET parameters. Determination of BM uptake may contribute toward the prediction of patient outcome with other quantitative PET parameters. PMID- 26440571 TI - Correlation between early 18F-FDG PET/CT response to BRAF and MEK inhibition and survival in patients with BRAF-mutant metastatic melanoma. AB - PURPOSE: Metabolic response to treatment measured by fluorine-18 fluorodeoxyglucose ((18)F-FDG) PET has prognostic implications in many cancers. This study investigated the association between survival and early changes on (18)F-FDG PET/computed tomography (CT) for patients with BRAF-mutant melanoma receiving combined BRAF and MEK inhibition therapy. MATERIALS AND METHODS: Overall, 24 patients with advanced BRAF-mutant melanoma were included. Patients were treated with a BRAF inhibitor (vemurafenib or dabrafenib) and a MEK inhibitor (cobimetinib or trametinib), and were imaged at baseline and shortly thereafter with (18)F-FDG PET/CT. Each scan yielded two values of maximum standardized uptake value (SUVmax): one for the most metabolically active focus and one for the least responsive focus. Short-term treatment response was assessed by evaluating the target lesions using the EROTC criteria. A Cox proportional hazards model was used to examine associations between overall survival (OS) and progression-free survival (PFS) and changes in SUVmax. RESULTS: The mean time to follow-up (18)F-FDG PET/CT was 26 days. At follow-up, two patients achieved a complete response. For the most metabolically active focus, 22 patients showed a partial response. For the least responsive focus, 18 patients showed a partial response, two had stable disease, and two had progressive disease.A total of 16 patients were alive at the end of the study. For the most metabolically active tumor, no association was observed between changes in SUVmax and OS (P=0.73) or PFS (P=0.17). For the least responsive tumor, change in SUVmax was associated with PFS [hazard ratio (HR)=1.34, 95% confidence interval (CI): 1.06-1.71, P=0.01], but not OS (P=0.52). The ECOG score was associated with OS (HR=11.81, 95% CI: 1.42-97.60, P=0.02) and PFS (HR=24.72, 95% CI: 3.23-189.42, P=0.002). CONCLUSION: Change in SUVmax for the least responsive tumor and baseline functional performance may be useful prognostic indicators for PFS in patients with BRAF-mutant melanoma. PMID- 26440573 TI - Abdominal aortic aneurysms and diabetes mellitus. AB - There is accumulating evidence that risk profiles differ between coronary artery disease and abdominal aortic aneurysms (AAAs). However, diabetes mellitus (DM) appears to be negatively associated with AAA formation. The underlying mechanisms for this negative relationship are far from defined, but may include: increased arterial wall matrix formation via advanced glycation end products; suppression of plasmin and reduction of levels and activity of matrix metalloproteinases (MMP)-2 and 9; diminished aortic wall macrophage infiltration, elastolysis and neovascularization. In addition, the effect of pharmacological agents used for the treatment of patients with DM on AAA formation has been studied with rather controversial results. Statins, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, fenofibrate, antibiotics and some hypoglycemic agents are beginning to be appreciated for a potential modest protection from AAAs, but further studies are needed. PMID- 26440574 TI - Does Trauma Impair Self-Control? Differences in Delaying Gratification Between Former Indentured Child Laborers and Nontraumatized Controls. AB - Traumatic experiences may affect an individual's ability to exercise self control, which is an essential characteristic for successfully managing life. As a measure of self-control, we used the delay discounting paradigm, that is, the extent to which a person devalues delayed gratification. The aim of this study was to investigate the relationship between childhood trauma and delay discounting using a control group design with elderly participants with a mean age of 76.2 years. Swiss former indentured child laborers (n=103) who had been exposed to trauma during their childhood were compared with nontraumatized controls (n=50). The trauma exposure group showed a considerably higher preference for immediate smaller rewards than the controls, indicating their lower self-control. A hierarchical regression analysis revealed that a history of abuse, current self-efficacy, and education were significantly associated with delay discounting. Implications for future research are discussed. PMID- 26440575 TI - Delineating the Role of Helical Intermediates in Natively Unfolded Polypeptide Amyloid Assembly and Cytotoxicity. AB - Amyloid deposition is a hallmark of many diseases, such as the Alzheimer's disease. Numerous amyloidogenic proteins, including the islet amyloid polypeptide (IAPP) associated with type II diabetes, are natively unfolded and need to undergo conformational rearrangements allowing the formation of locally ordered structure(s) to initiate self-assembly. Recent studies have indicated that the formation of alpha-helical intermediates accelerates fibrillization, suggesting that these species are on-pathway to amyloid assembly. By identifying an IAPP derivative with a restricted conformational ensemble that co-assembles with IAPP, we observed that helical species were off-pathway in homogenous environment and in presence of lipid bilayers or glycosaminoglycans. Moreover, preventing helical folding potentiated membrane perturbation and IAPP cytotoxicity, indicating that stabilization of helical motif(s) is a promising strategy to prevent cell degeneration associated with amyloidogenesis. PMID- 26440576 TI - Progress in Synthesis of Highly Active and Stable Nickel-Based Catalysts for Carbon Dioxide Reforming of Methane. AB - In recent decades, rising anthropogenic greenhouse gas emissions (mainly CO2 and CH4 ) have increased alarm due to escalating effects of global warming. The dry carbon dioxide reforming of methane (DRM) reaction is a sustainable way to utilize these notorious greenhouse gases. This paper presents a review of recent progress in the development of nickel-based catalysts for the DRM reaction. The enviable low cost and wide availability of nickel compared with noble metals is the main reason for persistent research efforts in optimizing the synthesis of nickel-based catalysts. Important catalyst features for the rational design of a coke-resistant nickel-based nanocatalyst for the DRM reaction are also discussed. In addition, several innovative developments based on salient features for the stabilization of nickel nanocatalysts through various means (which include functionalization with precursors, synthesis by plasma treatment, stabilization/confinement on mesoporous/microporous/carbon supports, and the formation of metal oxides) are highlighted. The final part of this review covers major issues and proposed improvement strategies pertaining to the rational design of nickel-based catalysts with high activity and stability for the DRM reaction. PMID- 26440577 TI - Characteristics and exacerbating factors of chronic low back pain in Parkinson's disease. AB - BACKGROUND: The aim of this study was to determine the exacerbating factors of chronic low back pain (LBP) and strategic points against LBP in patients with Parkinson's disease (PD). METHODS: Forty-four consecutive PD patients complaining of LBP were included. Clinical characteristics of PD and LBP, spinal musculoskeletal condition, and clinical health status were evaluated. RESULTS: Patient age at PD and LBP onset was contiguous, and LBP time period was mainly described as constant or upon waking up. Exacerbating factors of LBP included modified Hoehn and Yahr stage and motor complications of PD, such as the wearing off phenomenon and dyskinesia. Bone quality demonstrated osteopenia due to elevated bone resorption, with vitamins K and D insufficiencies. Spinal alignment demonstrated an increased sagittal vertical axis (120.2 +/- 65.4 mm) with decreased lumbar lordosis (-24.0 +/- 20.6 degrees ) and lumbar range of motion (28.7 +/- 10.2 degrees ), which were significantly related to severity of LBP and quality of life assessments. CONCLUSIONS: This study demonstrated that exacerbating factors of LBP include stage of motor function, motor complications of PD and stooped posture with decreased lumbar lordosis and range of lumbar movement. Therefore, control of PD, including motor complications, active treatment for osteoporosis and therapeutic exercise, are important for treating chronic LBP in patients with PD. PMID- 26440578 TI - A minimum attention control law for ball catching. AB - Digital implementations of control laws typically involve discretization with respect to both time and space, and a control law that can achieve a task at coarser levels of discretization can be said to require less control attention, and also reduced implementation costs. One means of quantitatively capturing the attention of a control law is to measure the rate of change of the control with respect to changes in state and time. In this paper we present an attention minimizing control law for ball catching and other target tracking tasks based on Brockett's attention criterion. We first highlight the connections between this attention criterion and some well-known principles from human motor control. Under the assumption that the optimal control law is the sum of a linear time varying feedback term and a time-varying feedforward term, we derive an LQR-based minimum attention tracking control law that is stable, and obtained efficiently via a finite-dimensional optimization over the symmetric positive-definite matrices. Taking ball catching as our primary task, we perform numerical experiments comparing the performance of the various control strategies examined in the paper. Consistent with prevailing theories about human ball catching, our results exhibit several familiar features, e.g., the transition from open-loop to closed-loop control during the catching movement, and improved robustness to spatiotemporal discretization. The presented control laws are applicable to more general tracking problems that are subject to limited communication resources. PMID- 26440579 TI - Driving mechanism and sources of groundwater nitrate contamination in the rapidly urbanized region of south China. AB - Nitrate contamination of groundwater has become an environmental problem of widespread concern in China. We collected 899 groundwater samples from a rapidly urbanized area, in order to identify the main sources and driving mechanisms of groundwater nitrate contamination. The results showed that the land use has a significant effect on groundwater nitrate concentration (P<0.001). Landfill leakage was an important source of nitrate in groundwater in the PRD (Pearl River Delta) region, since landfill yielded the highest nitrate concentration (38.14 mg/L) and the highest ratio of exceeded standard (42.50%). In this study, the driving mechanism of groundwater nitrate contamination was determined to be urban construction and the secondary and tertiary industrial development, and population growth. This study revealed that domestic wastewater and industrial wastewater were the main sources of groundwater nitrate pollution. Therefore, the priority method for relieving groundwater nitrate contamination is to control the random discharge of domestic and industrial wastewater in regions undergoing rapid urbanization. Capsule abstract. The main driving mechanism of groundwater nitrate contamination was determined to be urban construction and the secondary and tertiary industrial development, and population growth. PMID- 26440580 TI - The effects of gestational and chronic atrazine exposure on motor behaviors and striatal dopamine in male Sprague-Dawley rats. AB - This study sought to investigate the effects of environmentally relevant gestational followed by continued chronic exposure to the herbicide, atrazine, on motor function, cognition, and neurochemical indices of nigrostriatal dopamine (DA) activity in male rats. Dams were treated with 100 MUg/kg atrazine, 10mg/kg atrazine, or vehicle on gestational day 1 through postnatal day 21. Upon weaning, male offspring continued daily vehicle or atrazine gavage treatments for an additional six months. Subjects were tested in a series of behavioral assays, and 24h after the last treatment, tissue samples from the striatum were analyzed for DA and 3,4-dihydroxyphenylacetic acid (DOPAC). At 10mg/kg, this herbicide was found to produce modest disruptions in motor functioning, and at both dose levels it significantly lowered striatal DA and DOPAC concentrations. These results suggest that exposures to atrazine have the potential to disrupt nigrostriatal DA neurons and behaviors associated with motor functioning. PMID- 26440581 TI - Totarol prevents neuronal injury in vitro and ameliorates brain ischemic stroke: Potential roles of Akt activation and HO-1 induction. AB - The natural product totarol, a phenolic diterpenoid and a major constituent isolated from the sap of Podocarpus totara, has been reported to have a potent antimicrobial activity. In this study, we determined whether totarol possessed an additional neuroprotective activity in vitro and in vivo. We found that totarol prevented glutamate- and oxygen and glucose deprivation-induced neuronal death in primary rat cerebellar granule neuronal cells and cerebral cortical neurons. Totarol increased Akt and GSK-3beta phosphorylation, Nrf2 and heme oxygenase-1 (HO-1) protein expressions and suppressed oxidative stress by increasing GSH and SOD activities. The PI3K/Akt inhibitor LY294002 prevented totarol neuroprotective effect by suppressing the totarol-induced changes in HO-1 expression and the activities of GSH and SOD. The HO-1 inhibitor ZnPPIX also prevented totarol increased GSH and SOD activities. In a model of acute cerebral ischemic injury in Sprague-Dawley rats, produced by occlusion of the middle cerebral artery for 2h followed by 22 h or 46 h of reperfusion, totarol significantly reduced infarct volume and improved the neurological deficit. In this model, totarol increased HO 1 expression and the activities of GSH and SOD. These observations suggest that totarol may be a novel activator of the Akt/HO-1 pathway protecting against ischemic stroke through reduction of oxidative stress. PMID- 26440582 TI - Ergonomics in hair restoration surgeons. AB - BACKGROUND: Musculoskeletal disorders (MSDs) are potential sources of morbidity in hair restoration surgeons (HRS). This is particularly true for those who perform follicular unit extraction (FUE). OBJECTIVE: To describe the nature, prevalence, and extent of ergonomic or work-related MSDs among HRS. METHODS & MATERIALS: A survey regarding MSDs was e-mailed to 100 HRS. RESULTS: Thirty-eight HRS completed the survey, the majority of which were male and between the ages of 50-69. Fifty percent of respondents reported musculoskeletal symptoms occurring during or after hair restoration procedures. Reports of pain during and after surgery were higher for FUE procedures than single strip excision procedures. Pain/fatigue/discomfort persisted for longer following FUE procedures compared to strip excision procedures. MSD symptoms also negatively impacted quality of life. Although the majority of respondents felt that ergonomics was important, only 30% use ergonomic support when performing FUE procedures. CONCLUSION: Hair restoration surgeons should be aware of MSD symptoms and particularly when performing FUE. Symptoms reported included pain, fatigue, and discomfort, sometimes lasting several hours following surgery. More attention needs to be paid to ergonomics during hair restoration procedures in order to improve the quality of life of surgeons and ultimately prevent the development of MSDs. PMID- 26440583 TI - Post-pacemaker T-wave Inversions: Cardiac Memory. PMID- 26440584 TI - Survival rates of anterior composites in managing tooth wear: systematic review. AB - The use of composite restorations for patients with tooth wear is considered as a more conservative treatment option. The aim of this study was to systematically review the literature investigating the survival rates of anterior composite restorations when used in managing tooth wear in patients. PubMed and MEDLINE (Ovid) databases were screened for studies from 1995 to 2015. Cross-referencing was used to further identify articles. Article selection and data extraction were performed in duplication. Languages were restricted to English. A quality appraisal of included studies was carried out using the Strength of Recommendation Taxonomy system. Six hundred and sixty-six articles were initially identified from which eight articles were full-text reviewed. Six articles involving five studies were selected for inclusion. Three studies were prospective and two retrospective. Included studies involved placement of 772 direct and indirect anterior composite restorations in 100 patients with follow up periods between 5 months and 10 years. The survival rates of anterior composites were >90% and 50% at 2.5 and 5 years, respectively. Posterior occlusion was re-established in 91% of patients within 18 months. Meta-analysis could not be performed due to the heterogeneity of included studies. The systematic review's overall strength of recommendation was graded B. There is evidence to support the use of anterior composite restorations at an increased vertical dimension of occlusion in the short/medium-term management of tooth wear. Long-term reporting of outcomes remains limited. Further research is needed with standardised study design, detailed reporting of outcomes and long-term review. PMID- 26440585 TI - Comparison of positron emission tomography diffusion-weighted imaging (PET/DWI) registration quality in a PET/MR scanner: Zoomed DWI vs. Conventional DWI. AB - PURPOSE: To compare zoomed diffusion-weighted imaging (z-DWI) with reduced field of view (FOV) by spatially selective radiofrequency pulses and conventional echo planar imaging (EPI) DWI (c-DWI) with regard to registration quality using positron emission tomography / magnetic resonance (PET/MR) in patients with malignant tumors. MATERIALS AND METHODS: Fludeoxyglucose (18(F) ) PET imaging, c DWI, and z-DWI were conducted simultaneously in 21 patients with known or suspected malignancy using a PET/MR system. A fusion image showing the largest tumor area was generated for analysis. Registration accuracy between PET and DWI was assessed based on the area of maximum overlap and central point displacement of the tumor. EPI factor, echo time (TE), matching area, and displacement were compared between c-DWI and z-DWI by paired t-test. Agreement of apparent diffusion coefficient (ADC) acquired by the two sequences were also assessed with linear regression s and Bland-Altman plot analysis. RESULTS: Thirty-two lesions were detected on both PET and DWI (mean size 536.3 +/- 471.8 mm(2) ). At least one lesion was found in all subjects. In all cases, EPI factor was smaller with z DWI than c-DWI (43.1 +/- 15.6 vs. 62.0 +/- 10.0, P < 0.0001), and TE was also shorter for z-DWI (53.6 +/- 3.6 msec vs. 65.2 +/- 3.6 msec, P < 0.0001). Registration accuracy was better with z-DWI in 30 of 32 lesions (93.8%), and both average matching area and central point displacement were significantly improved (79.8 +/- 18.1% vs. 61.8 +/- 22.9%, P < 0.0001 and 3.92 +/- 2.69 mm vs. 7.51 +/- 4.07 mm, P < 0.0001). ADC values calculated with c-DWI and z-DWI showed good agreement. CONCLUSION: Zoomed DWI reduces image distortion and provides better registration accuracy with PET images. PMID- 26440586 TI - Origin of Outstanding Stability in the Lithium Solid Electrolyte Materials: Insights from Thermodynamic Analyses Based on First-Principles Calculations. AB - First-principles calculations were performed to investigate the electrochemical stability of lithium solid electrolyte materials in all-solid-state Li-ion batteries. The common solid electrolytes were found to have a limited electrochemical window. Our results suggest that the outstanding stability of the solid electrolyte materials is not thermodynamically intrinsic but is originated from kinetic stabilizations. The sluggish kinetics of the decomposition reactions cause a high overpotential leading to a nominally wide electrochemical window observed in many experiments. The decomposition products, similar to the solid electrolyte-interphases, mitigate the extreme chemical potential from the electrodes and protect the solid electrolyte from further decompositions. With the aid of the first-principles calculations, we revealed the passivation mechanism of these decomposition interphases and quantified the extensions of the electrochemical window from the interphases. We also found that the artificial coating layers applied at the solid electrolyte and electrode interfaces have a similar effect of passivating the solid electrolyte. Our newly gained understanding provided general principles for developing solid electrolyte materials with enhanced stability and for engineering interfaces in all-solid state Li-ion batteries. PMID- 26440587 TI - Stereoretentive formylation of (S)-proline: new application of the self regeneration of stereo-centres (SRS) principle via chelation to cobalt(III). AB - In a Vilsmeier-Haack-type formylation reaction the alpha-(dihydroxymethyl)-(S) prolinato complex (+)578-p-[Co(tren){(RC,SN)-Pro[CH(OH)2]O}]Cl2.2H2O (22) was produced stereoselectively (85% ee) from the (S)-prolinato complex, (+)578-p [Co(tren){(SC,SN)-ProO}]2(H3O)2(HOEt2)(O3SCF3)7 (18). Similar reaction of the (S) alaninato complex, (-)578-p-[Co(tren)(S-AlaO)](H3O)(O3SCF3)3 (13), produced the racemate, rac-p-[Co(tren)(Ala{CH(OH)2}O)]SO4.2H2O (17). The contrasting stereochemical outcomes of the formylation reaction with 18versus13 were ascribed to the stereogenic character of the coordinated sec. amine of the (S)-prolinate chelate in 18, which serves to uphold a chiral environment during reaction, whereas reaction intermediates derived from 13 lack this stereochemical feature. The stereoselective formylation of (S)-proline, relying on coordination to an inert metal centre, as conducted here, constitutes a novel application of the concept of Self-Regeneration of Stereocentres (SRS). The alpha-(hydroxymethyl) (S)-prolinato complex, (+)578-p-[Co(tren){(RC,SN)-Pro(CH2OH)O}]Cl2.2H2O (23) resulted from borohydride reduction of 22. The molecular structures of (+)578-p [Co(tren){(RC,SN)-Pro[CH(OH)2]O}]Cl2.2H2O (22), rac-p-[Co(tren) (Ala{CH(OH)2}O)]I2.H2O (17) and (+)578-p-[Co(tren){(RC,SN)-Pro(CH2OH)O}]Cl2.2H2O (23) were established by X-ray crystallography. PMID- 26440588 TI - Lewis Acid Assisted Diels-Alder Reaction with Regio- and Stereoselectivity: Anti 1,4-Adducts with Rigid Scaffolds and Their Application in Explosives Sensing. AB - Unusual anti-1,4-adducts of anthracene derivatives and anti-adducts of inert arenes with rigid scaffolds have been obtained via AlCl3-assisted Diels-Alder reaction in good to excellent yields under mild conditions. Further derivation of 1,4-adducts gave pi-conjugated polymers which could act as sensors of explosive species. This highly efficient synthesis method provides versatile approaches to solid-state emissive pi-conjugated polymers. PMID- 26440589 TI - The brain at risk: the sepsis syndrome and lessons from preclinical experiments. AB - There is a growing awareness of the chronic brain injury that results from the sepsis syndrome. We review experiments in several animal models of sepsis and show in one model, cecal ligation and puncture (CLP), that permanent structural pathology matures after the initial event. Specifically, we observed after exposure to CLP significant decreased spine density on the apical tree, but not the basal tree, of dendrites in the CA1 region of the dorsal hippocampus that was accompanied by a significantly diminished arbor of the apical dendrites, by 8 weeks, but not after 2 weeks. These novel data from dendritic arborizations elaborate information about a cohort of mice that had behaved in spatial memory tasks. These results raise questions about the relationship between long-term behavioral consequences and intervention strategies. PMID- 26440590 TI - Upregulation of long noncoding RNA TMEVPG1 enhances T helper type 1 cell response in patients with Sjogren syndrome. AB - Long noncoding RNAs (lncRNA) play key roles in regulating autoimmunity and immunity balance. LncRNA TMEVPG1, which is encoded by a gene located near the Ifn gene, contributes to interferon gamma expression. We investigated the expression of TMEVPG1 in patients with Sjogren syndrome (SS) to determine its role in the pathogenesis of SS. In this study, we detected the relative expression of TMEVPG1 in CD4(+) T cells of 25 SS patients and 25 healthy donors. Moreover, the proportion of Th1 cells and T-bet levels was also analyzed. Furthermore, we explored the correlation between the expression of TMEVPG1 and the level of autoantibodies, erythrocyte sedimentation rate (ESR) and IgG in SS patients. Our results indicated that the proportion of Th1 cells and the levels of TMEVPG1 and T-bet were increased in SS patients. In addition, the level of expression of TMEVPG1 was correlated with the level of SSA, ESR and IgG. Our data suggest that upregulation of lncRNA TMEVPG1 may be involved in the pathogenesis of Sjogren syndrome. PMID- 26440591 TI - Circulating T cell subsets are altered in individuals with chronic spinal cord injury. AB - Traumatic spinal cord injury (SCI) induces changes in the immune system, both acutely and chronically. To better understand changes in the chronic phase of SCI, we performed a prospective, observational study in a research institute and Department of Physical Medicine and Rehabilitation of an academic medical center to examine immune system parameters, including peripheral immune cell populations, in individuals with chronic SCI as compared to uninjured individuals. Here, we describe the relative frequencies of T cell populations in individuals with chronic SCI as compared to uninjured individuals. We show that the frequency of CD3+ and CD3+ CD4+ T cells are decreased in individuals with chronic SCI, although activated (HLA-DR+) CD4+ T cells are elevated in chronic SCI. We also examined regulatory T cells (Tregs), defined as CD3+ CD4+ CD25+ CD127lo and CCR4+, HLA-DR+ or CCR4+ HLA-DR+. To our knowledge, we provide the first evidence that CCR4+, HLA-DR+ or CCR4+ HLA-DR+ Tregs are expanded in individuals with SCI. These data support additional functional studies of T cells isolated from individuals with chronic SCI, where alterations in T cell homeostasis may contribute to immune dysfunction, such as immunity against infections or the persistence of chronic inflammation. PMID- 26440594 TI - Pitfalls of cleaning controls in ultrasonic washers. PMID- 26440592 TI - Exploratory study for identifying systemic biomarkers that correlate with pain response in patients with intervertebral disc disorders. AB - Molecular events that drive disc damage and low back pain (LBP) may precede clinical manifestation of disease onset and can cause detrimental long-term effects such as disability. Biomarkers serve as objective molecular indicators of pathological processes. The goal of this study is to identify systemic biochemical factors as predictors of response to treatment of LBP with epidural steroid injection (ESI). Since inflammation plays a pivotal role in LBP, this pilot study investigates the effect of ESI on systemic levels of 48 inflammatory biochemical factors (cytokines, chemokines, and growth factors) and examines the relationship between biochemical factor levels and pain or disability in patients with disc herniation (DH), or other diagnoses (Other Dx) leading to low back pain, which included spinal stenosis (SS) and degenerative disc disease (DDD). Study participants (n = 16) were recruited from a back pain management practice. Pain numerical rating score (NRS), Oswestry Disability Index (ODI), and blood samples were collected pre- and at 7 to 10 days post-treatment. Blood samples were assayed for inflammatory mediators using commercial multiplex assays. Mediator levels were compared pre- and post-treatment to investigate the potential correlations between clinical and biochemical outcomes. Our results indicate that a single ESI significantly decreased systemic levels of SCGF-beta and IL-2. Improvement in pain in all subjects was correlated with changes in chemokines (MCP-1, MIG), hematopoietic progenitor factors (SCGF-beta), and factors that participate in angiogenesis/fibrosis (HGF), nociception (SCF, IFN alpha2), and inflammation (IL-6, IL-10, IL-18, TRAIL). Levels of biochemical mediators varied based on diagnosis of LBP, and changes in pain responses and systemic mediators from pre- to post-treatment were dependent on the diagnosis cohort. In the DH cohort, levels of IL-17 and VEGF significantly decreased post treatment. In the Other Dx cohort, levels of IL-2Ralpha, IL-3, and SCGF-beta significantly decreased post-treatment. In order to determine whether mediator changes were related to pain, correlations between change in pain scores and change in mediator levels were performed. Subjects with DH demonstrated a profile signature that implicated hematopoiesis factors (SCGF-beta, GM-CSF) in pain response, while subjects with Other Dx demonstrated a biomarker profile that implicated chemokines (MCP-1, MIG) and angiogenic factors (HGF, VEGF) in pain response. Our findings provide evidence that systemic biochemical factors in patients with LBP vary by diagnosis, and pain response to treatment is associated with a unique profile of biochemical responses in each diagnosis group. Future hypothesis-based studies with larger subject cohorts are warranted to confirm the findings of this pilot exploratory study. PMID- 26440593 TI - Impact of rapid screening for discontinuation of methicillin-resistant Staphylococcus aureus contact precautions. AB - BACKGROUND: A history of methicillin-resistant Staphylococcus aureus (MRSA) is a determinant of inpatient bed assignment. METHODS: We assessed outcomes associated with rapid testing and discontinuation of MRSA contact precautions (CP) in a prospective cohort study of polymerase chain reaction (PCR)-based screening in the Emergency Department (ED) of Massachusetts General Hospital. Eligible patients had a history of MRSA and were assessed and enrolled if documented off antibiotics with activity against MRSA and screened for nasal colonization (subject visit). PCR-negative subjects had CP discontinued; the primary outcome was CP discontinuation. We identified semiprivate rooms in which a bed was vacant owing to the CP status of the study subject, calculated the hours of vacancy, and compared idle bed-hours by PCR results. Program costs were compared with predicted revenue. RESULTS: There were 2864 eligible patients, and 648 (22.6%) subject visits were enrolled. Of these, 65.1% (422/648) were PCR-negative and had CP discontinued. PCR-negative subjects had fewer idle bed-hours compared with PCR positive subjects (28.6 +/- 25.2 vs 75.3 +/- 70.5; P < .001). The expected revenues from occupied idle beds and averted CP costs ranged from $214,160 to $268,340, and exceeded the program costs. CONCLUSION: A program of targeted PCR based screening for clearance of MRSA colonization resulted in expected revenues and decreased CP costs that outweighed programmatic costs. PMID- 26440595 TI - Physical function and activity among older adults in Jodhpur, India. AB - BACKGROUND: Physical activity impacts the ageing process; yet, few studies have examined relationships among physical activity, functional abilities and health among older adults in non-Western settings. AIM: This study tests for associations among measures of physical activity, function and self-report health conditions among 200 older adults (49--50 years old) in Jodhpur, Rajasthan, India. METHODS: Seven consecutive days of accelerometry data were used in measures of physical activity (Total Daily Energy Expenditure [TDEE], Physical Activity Level [PAL], Daily Average Activity Count [AC] and Activity Energy Expenditure [AEE]). Measures of physical function included grip strength, timed walk and daily average sit time. Participants reported if they had been diagnosed with diabetes, hypertension, arthritis and/or depression. RESULTS: All four measures of physical activity were positively associated with grip strength (p <= 0.05). AC was negatively associated with timed walk (p <= 0.05), and both AC and AEE were negatively associated with daily average sit time (p <= 0.05). Women who reported diagnosis of hypertension had lower PAL and AC (p <= 0.05). CONCLUSION: This study provides further evidence for a positive relationship between physical activity and functional ability among older adults and between physical activity and cardiovascular health among women in India. PMID- 26440596 TI - Histology-guided protein digestion/extraction from formalin-fixed and paraffin embedded pressure ulcer biopsies. AB - Herein we present a simple, reproducible and versatile approach for in situ protein digestion and identification on formalin-fixed and paraffin-embedded (FFPE) tissues. This adaptation is based on the use of an enzyme delivery platform (hydrogel discs) that can be positioned on the surface of a tissue section. By simultaneous deposition of multiple hydrogels over select regions of interest within the same tissue section, multiple peptide extracts can be obtained from discrete histological areas. After enzymatic digestion, the hydrogel extracts are submitted for LC-MS/MS analysis followed by database inquiry for protein identification. Further, imaging mass spectrometry (IMS) is used to reveal the spatial distribution of the identified peptides within a serial tissue section. Optimization was achieved using cutaneous tissue from surgically excised pressure ulcers that were subdivided into two prime regions of interest: the wound bed and the adjacent dermal area. The robust display of tryptic peptides within these spectral analyses of histologically defined tissue regions suggests that LC-MS/MS in combination with IMS can serve as useful exploratory tools. PMID- 26440597 TI - Use of a Human Artificial Chromosome for Delivering Trophic Factors in a Rodent Model of Amyotrophic Lateral Sclerosis. AB - A human artificial chromosome (HAC) is maintained as an episome within a cell and avoids random integration into the host genome. It can transfer multiple and/or large transgenes along with their regulatory elements thereby resembling native chromosomes. Using this HAC system, we established mesenchymal stem cells (MSCs) that simultaneously expressed hepatocyte growth factor, glial cell line-derived neurotrophic factor, and insulin-like growth factor 1, termed HAC-MSCs. This cell line provides an opportunity for stable transplantation and thorough analyses. We then introduced the cells for the treatment of a neurodegenerative disorder, amyotrophic lateral sclerosis. The HAC-MSCs were transplanted via the fourth cerebral ventricle (CV) or intravenous (i.v.) infusion at various ages of recipient mice. Littermate- and sex-matched mice underwent a sham procedure. Compared to the controls, there was an encouraging trend of increased life span via CV transplantation and delayed onset in i.v. infusion 60 days after transplantation. Further, we confirmed a statistically significant increase in life span via CV transplantation at 100 days. This effect was not seen in mice transplanted with MSCs lacking the HAC. We successfully enhanced the trophic potential of the MSCs using the HAC. This strategy could be a promising direction for the treatment of neurodegenerative disorders. PMID- 26440598 TI - Pharmacokinetics of a Cholesterol-conjugated Aptamer Against the Hepatitis C Virus (HCV) NS5B Protein. AB - Hepatitis C virus (HCV) is the major cause of progressive liver disease such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Previously, we reported that a 29 nucleotide-long 2'-F pyrimidine modified RNA aptamer against the HCV nonstructural protein 5B efficiently inhibited HCV replication and suppressed HCV infectious virus particle formation in a cell culture system. In this study, we modified this aptamer through conjugation of cholesterol for in vivo availability. This cholesterol-conjugated aptamer (chol-aptamer) efficiently entered the cell and inhibited HCV RNA replication, without any alteration in gene expression profiling including innate immune response-related genes. Moreover, systemic administration of the chol-aptamer was well tolerated without any abnormalities in mice. To evaluate the pharmacokinetics of the chol-aptamer in vivo, dose proportionality, bioavailability, and pharmacokinetic parameters were evaluated by noncompartmental analyses in normal BALB/c mice. Population analysis was performed using nonlinear mixed effects modeling. Moreover, the pharmacokinetics of two different routes (intravenous, IV, versus intraperitoneal, IP) were compared. Cholesterol conjugation showed dose proportionality, extended the time that the aptamer was in the plasma, and enhanced aptamer exposure to the body. Noticeably, the IV route was more suitable than the IP route due to the chol-aptamer remaining in the plasma for a longer period of time. PMID- 26440599 TI - Peptide Nucleic Acid Promotes Systemic Dystrophin Expression and Functional Rescue in Dystrophin-deficient mdx Mice. AB - Antisense oligonucleotide (AO)-mediated exon-skipping therapeutics shows great promise for Duchenne muscular dystrophy (DMD) patients. However, recent failure with drisapersen, an AO candidate drug in phase 3 trial, highlights the importance of exploring other effective AO chemistries for DMD. Previously, we demonstrated the appreciable biological activity of peptide nucleic acid (PNA) AOs in restoring dystrophin expression in dystrophin-deficient mdx mice intramuscularly. Here, we further explore the systemic potential and feasibility of PNA AOs in mediating exon skipping in mdx mice as a comprehensive systemic evaluation remains lacking. Systemic delivery of PNA AOs resulted in therapeutic level of dystrophin expression in body-wide peripheral muscles and improved dystrophic pathology in mdx mice without any detectable toxicity. Up to 40% of dystrophin restoration was achieved in gastrocnemius, to a less extent with other skeletal muscles, with no dystrophin in heart. Notably, comparable systemic activity was obtained between PNA AOs and phosphorodiamidate morpholino oligomer, a DMD AO chemistry in phase 3 clinical trial, under an identical dosing regimen. Overall, our data demonstrate that PNA is viable for DMD exon-skipping therapeutics with 20 mer showing the best combination of activity, solubility, and safety and further modifications to increase PNA aqueous solubility can enable longer, more effective therapeutics without the associated toxicity. PMID- 26440601 TI - Atom-economical synthesis of a high silica CHA zeolite using a solvent-free route. AB - A high silica CHA zeolite is successfully synthesized in the presence of a small amount of N,N,N-dimethylethylcyclohexylammonium bromide under solvent-free conditions. Catalytic tests for the selective catalytic reduction of NOx with NH3 (NH3-SCR) and methanol-to-olefins (MTO) show that the sample from the solvent free route exhibits comparable catalytic properties to that from the conventional route. PMID- 26440600 TI - Preclinical Evaluation of miR-15/107 Family Members as Multifactorial Drug Targets for Alzheimer's Disease. AB - Alzheimer's disease (AD) is a multifactorial, fatal neurodegenerative disorder characterized by the abnormal accumulation of Abeta and Tau deposits in the brain. There is no cure for AD, and failure at different clinical trials emphasizes the need for new treatments. In recent years, significant progress has been made toward the development of miRNA-based therapeutics for human disorders. This study was designed to evaluate the efficiency and potential safety of miRNA replacement therapy in AD, using miR-15/107 paralogues as candidate drug targets. We identified miR-16 as a potent inhibitor of amyloid precursor protein (APP) and BACE1 expression, Abeta peptide production, and Tau phosphorylation in cells. Brain delivery of miR-16 mimics in mice resulted in a reduction of AD-related genes APP, BACE1, and Tau in a region-dependent manner. We further identified Nicastrin, a gamma-secretase component involved in Abeta generation, as a target of miR-16. Proteomics analysis identified a number of additional putative miR-16 targets in vivo, including alpha-Synuclein and Transferrin receptor 1. Top ranking biological networks associated with miR-16 delivery included AD and oxidative stress. Collectively, our data suggest that miR-16 is a good candidate for future drug development by targeting simultaneously endogenous regulators of AD biomarkers (i.e., Abeta and Tau), inflammation, and oxidative stress. PMID- 26440602 TI - Guidelines for Conducting a Victim-Sensitive Interview. AB - Victim sensitive interviews allow the adult investigator to gather vital facts from a child. Within these interviews, the investigator is provided with an opportunity to elicit responses from the child regarding allegations that have taken place. These allegations often have many origins and may involve sexual impropriety, abuse, taunting, and torture of a physical nature, verbal nature, or both. The purpose of this article is to provide standardized guidelines that can assist individuals from various occupational fields in conducting victim sensitive interviews. The standardized guidelines provided offer an assemblage of general principles that have consistently appeared within literature as well as in manuals provided by various jurisdictions. These guidelines refer to a practice of conduct that is recommended; however, variance with implementation is allowed. It is assumed that the reader brings a level of clinical experience to the material provided in this article. PMID- 26440603 TI - Drug-Induced Diabetes Mellitus: Evidence for Statins and Other Drugs Affecting Glucose Metabolism. AB - Abnormalities of glucose metabolism and glucose tolerance, either because of a reduction in tissue sensitivity to insulin (e.g., in liver, skeletal muscle, and adipose tissues) and/or a reduction in pancreatic insulin secretion, are associated with a number of unwanted health outcomes. Even small increases in circulating glucose levels (often described as dysglycemia or prediabetes) may confer an increased risk of cardiovascular (CV) disease and progression to overt type 2 diabetes. A number of drug therapies, many of them used long term in chronic disease management, have adverse effects on glucose metabolism, diabetes risk, and glycemic control among patients with preexisting diabetes. In this study, we review the evidence, underlying mechanisms, and the clinical significance of drug-related adverse effects on glucose metabolism. PMID- 26440605 TI - Interactions Between the Prefrontal Cortex and Attentional Systems During Volitional Affective Regulation: An Effective Connectivity Reappraisal Study. AB - Reappraisal is an emotion regulation strategy used to change reactions to emotion related stimuli by reinterpreting their meaning. During down-regulation of negative emotions, wide areas of the prefrontal cortex (PFC) inhibit emotion related brain areas such as the amygdala. Little is known, however, about how this control activity influences the earliest stages of affective responses by modulating perceptual and attentional areas. The aim of this study is to identify the connectivity patterns between the PFC and the core regions of two well-known attentional networks: the dorsal attentional network (which controls attention volitionally) and the ventral attentional network (which controls attention spontaneously) during reappraisal. We used a novel method to study emotional control processes: the directed transfer function, an autoregressive effective connectivity method based on Granger causality. It was applied to EEG recordings to quantify the direction and intensity of information flow during passively watching (control condition) or reappraising (experimental condition) negative film clips. Reappraisal was mostly associated with increased top-down influences from the right dorsolateral PFC over attentional and perceptual areas, reaching areas including dorsal attentional regions. The left dorsolateral PFC was associated with the activation of the ventral attentional network. Passively watching clips (control condition) resulted in increased flow from attentional areas to the left dorsolateral PFC, what is interpreted as a monitoring process. Thus, reappraisal seems to be related to both volitional and automatic control of attention, triggered by the right and left dorsolateral PFC respectively. PMID- 26440604 TI - Transcranial magnetic stimulation facilitates neurorehabilitation after pediatric traumatic brain injury. AB - Traumatic brain injury (TBI) is the leading cause of death and disability among children in the United States. Affected children will often suffer from emotional, cognitive and neurological impairments throughout life. In the controlled cortical impact (CCI) animal model of pediatric TBI (postnatal day 16 17) it was demonstrated that injury results in abnormal neuronal hypoactivity in the non-injured primary somatosensory cortex (S1). It materializes that reshaping the abnormal post-injury neuronal activity may provide a suitable strategy to augment rehabilitation. We tested whether high-frequency, non-invasive transcranial magnetic stimulation (TMS) delivered twice a week over a four-week period can rescue the neuronal activity and improve the long-term functional neurophysiological and behavioral outcome in the pediatric CCI model. The results show that TBI rats subjected to TMS therapy showed significant increases in the evoked-fMRI cortical responses (189%), evoked synaptic activity (46%), evoked neuronal firing (200%) and increases expression of cellular markers of neuroplasticity in the non-injured S1 compared to TBI rats that did not receive therapy. Notably, these rats showed less hyperactivity in behavioral tests. These results implicate TMS as a promising approach for reversing the adverse neuronal mechanisms activated post-TBI. Importantly, this intervention could readily be translated to human studies. PMID- 26440606 TI - The Effect of Age Correction on Multivariate Classification in Alzheimer's Disease, with a Focus on the Characteristics of Incorrectly and Correctly Classified Subjects. AB - The similarity of atrophy patterns in Alzheimer's disease (AD) and in normal aging suggests age as a confounding factor in multivariate models that use structural magnetic resonance imaging (MRI) data. To study the effect and compare different age correction approaches on AD diagnosis and prediction of mild cognitive impairment (MCI) progression as well as investigate the characteristics of correctly and incorrectly classified subjects. Data from two multi-center cohorts were included in the study [AD = 297, MCI = 445, controls (CTL) = 340]. 34 cortical thickness and 21 subcortical volumetric measures were extracted from MRI. The age correction approaches involved: using age as a covariate to MRI derived measures and linear detrending of age-related changes based on CTL measures. Orthogonal projections to latent structures was used to discriminate between AD and CTL subjects, and to predict MCI progression to AD, up to 36 months follow-up. Both age correction approaches improved models' quality in terms of goodness of fit and goodness of prediction, as well as classification and prediction accuracies. The observed age associations in classification and prediction results were effectively eliminated after age correction. A detailed analysis of correctly and incorrectly classified subjects highlighted age associations in other factors: ApoE genotype, global cognitive impairment and gender. The two methods for age correction gave similar results and show that age can partially masks the influence of other aspects such as cognitive impairment, ApoE-e4 genotype and gender. Age-related brain atrophy may have a more important association with these factors than previously believed. PMID- 26440608 TI - Practice standards for emergency nursing: An international review. AB - BACKGROUND: Presentations to emergency departments (EDs) and patient acuity continue to increase. Whilst strategies to deliver safe patient care in the ED are evolving, emergency nurses need to be well educated through specialist qualifications to enable delivery of advanced patient care. This paper presents a comparative analysis of available international practice and competency standards for nurses graduating from emergency nursing courses in Australia, Canada, New Zealand, the United Kingdom, and the United States. METHODS: CINAHL, Scopus, Ovid MEDLINE, and Embase were searched for papers, published in English, using the terms: 'emergency', 'accident and emergency', 'nursing', 'competency', 'practice standards', 'scope of practice', 'regulation', and 'specialist standards'. Secondary sources from relevant reference lists and professional websites were also searched. RESULTS: The standards from the five countries were common across five domains: clinical expertise, communication, teamwork, resources and environment, and legal. None of the standards were specific to the emergency nursing graduate, and there was variability in the level of expertise required for which the standards apply. CONCLUSIONS: The available practice standards demonstrated some commonality. Consideration of the utility of a universal framework for informing the development of emergency nursing practice standards and emergency nursing curriculum for nurses wishing to specialise is needed. PMID- 26440607 TI - Derivation and validation of two decision instruments for selective chest CT in blunt trauma: a multicenter prospective observational study (NEXUS Chest CT). AB - BACKGROUND: Unnecessary diagnostic imaging leads to higher costs, longer emergency department stays, and increased patient exposure to ionizing radiation. We sought to prospectively derive and validate two decision instruments (DIs) for selective chest computed tomography (CT) in adult blunt trauma patients. METHODS AND FINDINGS: From September 2011 to May 2014, we prospectively enrolled blunt trauma patients over 14 y of age presenting to eight US, urban level 1 trauma centers in this observational study. During the derivation phase, physicians recorded the presence or absence of 14 clinical criteria before viewing chest imaging results. We determined injury outcomes by CT radiology readings and categorized injuries as major or minor according to an expert-panel-derived clinical classification scheme. We then employed recursive partitioning to derive two DIs: Chest CT-All maximized sensitivity for all injuries, and Chest CT-Major maximized sensitivity for only major thoracic injuries (while increasing specificity). In the validation phase, we employed similar methodology to prospectively test the performance of both DIs. We enrolled 11,477 patients-6,002 patients in the derivation phase and 5,475 patients in the validation phase. The derived Chest CT-All DI consisted of (1) abnormal chest X-ray, (2) rapid deceleration mechanism, (3) distracting injury, (4) chest wall tenderness, (5) sternal tenderness, (6) thoracic spine tenderness, and (7) scapular tenderness. The Chest CT-Major DI had the same criteria without rapid deceleration mechanism. In the validation phase, Chest CT-All had a sensitivity of 99.2% (95% CI 95.4% 100%), a specificity of 20.8% (95% CI 19.2%-22.4%), and a negative predictive value (NPV) of 99.8% (95% CI 98.9%-100%) for major injury, and a sensitivity of 95.4% (95% CI 93.6%-96.9%), a specificity of 25.5% (95% CI 23.5%-27.5%), and a NPV of 93.9% (95% CI 91.5%-95.8%) for either major or minor injury. Chest CT Major had a sensitivity of 99.2% (95% CI 95.4%-100%), a specificity of 31.7% (95% CI 29.9%-33.5%), and a NPV of 99.9% (95% CI 99.3%-100%) for major injury and a sensitivity of 90.7% (95% CI 88.3%-92.8%), a specificity of 37.9% (95% CI 35.8% 40.1%), and a NPV of 91.8% (95% CI 89.7%-93.6%) for either major or minor injury. Regarding the limitations of our work, some clinicians may disagree with our injury classification and sensitivity thresholds for injury detection. CONCLUSIONS: We prospectively derived and validated two DIs (Chest CT-All and Chest CT-Major) that identify blunt trauma patients with clinically significant thoracic injuries with high sensitivity, allowing for a safe reduction of approximately 25%-37% of unnecessary chest CTs. Trauma evaluation protocols that incorporate these DIs may decrease unnecessary costs and radiation exposure in the disproportionately young trauma population. PMID- 26440609 TI - No evidence of risk-taking or impulsive behaviour in a person with episodic amnesia: Implications for the role of the hippocampus in future-regarding decision-making. AB - Does advantageous decision-making require one to explicitly remember the outcome of a series of past decisions or to imagine future personal consequences of one's choices? Findings that amnesic people with hippocampal damage cannot form a clear preference for advantageous decks over many learning trials on the Iowa Gambling Task (IGT) have been taken to suggest that complex decision-making on the IGT depends on declarative (episodic) memory and hippocampal integrity. Alternatively, impaired IGT performance in amnesic individuals could be secondary to risk-taking and/or impulsive behaviour resulting from impaired episodic future thinking (i.e. prospection) known to accompany amnesia. We tested this possibility in the amnesic individual K.C. using the IGT and the Toronto Gambling Task (TGT), a novel task that dissociates impulsivity from risk-taking without placing demands on declarative memory. K.C. did not develop a preference for advantageous over disadvantageous decks on the IGT and, instead, showed a slight preference for short-term gains and an inability to acquire a more adaptive appreciation of longer-term losses. He also did not display impulsive or risk taking behaviour on the TGT, despite a profound inability to imagine personal future experiences. These findings suggest that impaired decision-making on the IGT in amnesia is unlikely to reflect a predilection to act in the moment or failure to take future consequences into account. Instead, some forms of future regarding decision-making may be dissociable, with performance on tasks relying on declarative learning or on episodic-constructive processes more likely to be impaired. PMID- 26440610 TI - Overt Social Support Behaviors: Associations With PTSD, Concurrent Depressive Symptoms and Gender. AB - Women are twice as likely as men to develop a posttraumatic stress disorder (PTSD). Gender differences in social support after a traumatic event might partially explain this disparity. However, the portrait of the links among PTSD, depression, social support, and gender is still unclear. This study examined behaviors of individuals with PTSD and their significant other in relation to PTSD and concurrent depressive symptoms, and tested gender as a moderator of these associations. Observed overt supportive and countersupportive behaviors of 68 dyads composed of an individual with PTSD and a significant other in a trauma oriented discussion were coded with a support coding system and analyzed according to gender. Gender was revealed to act as a moderator of the links between interactional behaviors of individuals with PTSD and their concurrent depressive symptoms. More specifically, women were less implicated and less likely to propose positive solutions compared with men. On the other hand, men were more implicated and less likely to criticize their significant other than were women. PTSD and concurrent depressive symptoms were related to poorer interpersonal communication in women. Hence, women and men with PTSD and concurrent depressive symptoms might benefit from gender-tailored interventions targeting symptoms and dyadic behaviors. PMID- 26440611 TI - Association between depressive symptoms, weight and treatment outcome in a very large anorexia nervosa sample. PMID- 26440612 TI - Evaluating Written Patient Information for Eczema in German: Comparing the Reliability of Two Instruments, DISCERN and EQIP. AB - Patients actively seek information about how to cope with their health problems, but the quality of the information available varies. A number of instruments have been developed to assess the quality of patient information, primarily though in English. Little is known about the reliability of these instruments when applied to patient information in German. The objective of our study was to investigate and compare the reliability of two validated instruments, DISCERN and EQIP, in order to determine which of these instruments is better suited for a further study pertaining to the quality of information available to German patients with eczema. Two independent raters evaluated a random sample of 20 informational brochures in German. All the brochures addressed eczema as a disorder and/or therapy options and care. Intra-rater and inter-rater reliability were assessed by calculating intra-class correlation coefficients, agreement was tested with weighted kappas, and the correlation of the raters' scores for each instrument was measured with Pearson's correlation coefficient. DISCERN demonstrated substantial intra- and inter-rater reliability. It also showed slightly better agreement than EQIP. There was a strong correlation of the raters' scores for both instruments. The findings of this study support the reliability of both DISCERN and EQIP. However, based on the results of the inter-rater reliability, agreement and correlation analyses, we consider DISCERN to be the more precise tool for our project on patient information concerning the treatment and care of eczema. PMID- 26440613 TI - The Adaptor Protein Myd88 Is a Key Signaling Molecule in the Pathogenesis of Irinotecan-Induced Intestinal Mucositis. AB - Intestinal mucositis is a common side effect of irinotecan-based anticancer regimens. Mucositis causes cell damage, bacterial/endotoxin translocation and production of cytokines including IL-1 and IL-18. These molecules and toll-like receptors (TLRs) activate a common signaling pathway that involves the Myeloid Differentiation adaptor protein, MyD88, whose role in intestinal mucositis is unknown. Then, we evaluated the involvement of TLRs and MyD88 in the pathogenesis of irinotecan-induced intestinal mucositis. MyD88-, TLR2- or TLR9-knockout mice and C57BL/6 (WT) mice were given either saline or irinotecan (75 mg/kg, i.p. for 4 days). On day 7, animal survival, diarrhea and bacteremia were assessed, and following euthanasia, samples of the ileum were obtained for morphometric analysis, myeloperoxidase (MPO) assay and measurement of pro-inflammatory markers. Irinotecan reduced the animal survival (50%) and induced a pronounced diarrhea, increased bacteremia, neutrophil accumulation in the intestinal tissue, intestinal damage and more than twofold increased expression of MyD88 (200%), TLR9 (400%), TRAF6 (236%), IL-1beta (405%), IL-18 (365%), COX-2 (2,777%) and NF kappaB (245%) in the WT animals when compared with saline-injected group (P<0.05). Genetic deletion of MyD88, TLR2 or TLR9 effectively controlled the signs of intestinal injury when compared with irinotecan-administered WT controls (P<0.05). In contrast to the MyD88-/- and TLR2-/- mice, the irinotecan-injected TLR9-/- mice showed a reduced survival, a marked diarrhea and an enhanced expression of IL-18 versus irinotecan-injected WT controls. Additionally, the expression of MyD88 was reduced in the TLR2-/- or TLR9-/- mice. This study shows a critical role of the MyD88-mediated TLR2 and TLR9 signaling in the pathogenesis of irinotecan-induced intestinal mucositis. PMID- 26440614 TI - High Endogenous Expression of Chitinase 3-Like 1 and Excessive Epithelial Proliferation with Colonic Tumor Formation in MOLF/EiJ Mice. AB - Colorectal cancer (CRC) development is mediated by uncontrolled survival and proliferation of tumor progenitor cells. Using animal models to identify and study host-derived factors that underlie this process can aid interventions in preventing tumor expansion and metastasis. In healthy steady states in humans and mice (e.g. C57BL/6 strain), colonic Chitinase 3-like 1 (CHI3L1) gene expression is undetectable. However, this expression can be induced during intestinal inflammation and tumorigenesis where CHI3L1 plays an important role in tissue restitution and cell proliferation. Here, we show that a wild-derived mouse strain MOLF/EiJ expresses high levels of colonic epithelial CHI3L1 at the steady state due to several nucleotide polymorphisms in the proximal promoter regions of the CHI3L1 gene. Interestingly, these mice spontaneously developed polypoid nodules in the colon with signs of immune cell infiltrations at steady state. The CHI3L1 positive colonic epithelial cells were highly proliferative and exhibited malignant transformation and expansion when exposed in vivo to azoxymethane, one of the well-known colonic carcinogens. PMID- 26440615 TI - Nonlinear approach to difference imaging in diffuse optical tomography. AB - Difference imaging aims at recovery of the change in the optical properties of a body based on measurements before and after the change. Conventionally, the image reconstruction is based on using difference of the measurements and a linear approximation of the observation model. One of the main benefits of the linearized difference reconstruction is that the approach has a good tolerance to modeling errors, which cancel out partially in the subtraction of the measurements. However, a drawback of the approach is that the difference images are usually only qualitative in nature and their spatial resolution can be weak because they rely on the global linearization of the nonlinear observation model. To overcome the limitations of the linear approach, we investigate a nonlinear approach for difference imaging where the images of the optical parameters before and after the change are reconstructed simultaneously based on the two datasets. We tested the feasibility of the method with simulations and experimental data from a phantom and studied how the approach tolerates modeling errors like domain truncation, optode coupling errors, and domain shape errors. PMID- 26440616 TI - Multispectral tissue characterization for intestinal anastomosis optimization. AB - Intestinal anastomosis is a surgical procedure that restores bowel continuity after surgical resection to treat intestinal malignancy, inflammation, or obstruction. Despite the routine nature of intestinal anastomosis procedures, the rate of complications is high. Standard visual inspection cannot distinguish the tissue subsurface and small changes in spectral characteristics of the tissue, so existing tissue anastomosis techniques that rely on human vision to guide suturing could lead to problems such as bleeding and leakage from suturing sites. We present a proof-of-concept study using a portable multispectral imaging (MSI) platform for tissue characterization and preoperative surgical planning in intestinal anastomosis. The platform is composed of a fiber ring light-guided MSI system coupled with polarizers and image analysis software. The system is tested on ex vivo porcine intestine tissue, and we demonstrate the feasibility of identifying optimal regions for suture placement. PMID- 26440617 TI - Nondestructive observation of teeth post core-space using optical coherence tomography: comparison with microcomputed tomography and live images. AB - No previous reports have observed inside the root canal using both optical coherence tomography (OCT) and x-ray microcomputed tomography (MUCT) for the same sample. The purpose of this study was to clarify both OCT and MUCT image properties from observations of the same root canal after resin core build-up treatment. As OCT allows real-time observation of samples, gap formation may be able to be shown in real time. A dual-cure, one-step, self-etch adhesive system bonding agent, and dual-cure resin composite core material were used in root canals in accordance with instructions from the manufacturer. The resulting OCT images were superior for identifying gap formation at the interface, while MUCT images were better to grasp the tooth form. Continuous tomographic images from real-time OCT observation allowed successful construction of a video of the resin core build-up procedure. After 10 to 12 s of light curing, a gap with a clear new signal occurred at the root-core material interface, proceeding from the coronal side (6 mm from the cemento-enamel junction) to the apical side of the root. PMID- 26440618 TI - Our empathic brain and suicidal individuals. PMID- 26440620 TI - Fruits of trauma? Posttraumatic growth among suicide-bereaved parents. AB - BACKGROUND: While there is evidence that suicide-bereaved individuals may be at higher risk for trauma-related outcomes, such as posttraumatic stress disorder or prolonged grief, positive psychology suggests that suicide bereavement may also promote personal growth within the confines of distress characterized as posttraumatic growth (PTG). AIMS: The aim of this study was to investigate PTG and what variables, such as reflective rumination, resilience, personality variables, and mood states, contribute to PTG among suicide-bereaved parents. METHOD: Online survey methods were employed using a convenience sample of 154 parents bereaved by the suicide death of their child within 2 years. RESULTS: Multiple regression analyses revealed that resilience inversely predicted PTG scores, but reflective rumination did not predict PTG. PTG scores were in the low moderate range and were lower than those of parents bereaved by other causes of death. Items endorsed most strongly corresponded to the PTG factors Relating to Others, Spiritual Change, and Appreciation of Life. CONCLUSION: In this study, PTG manifests among suicide-bereaved parents, but may be complicated by the proximity to the death and by concurrent brooding and reflective rumination unique to answering the question of "why" in this population. PMID- 26440621 TI - Moderating role of trait hope in the relation between painful and provocative events and acquired capability for suicide. AB - BACKGROUND: The interpersonal theory of suicide has gained empirical support as a conceptualization of suicide risk; however, little research has examined the role of individual traits, such as trait hope, within the interpersonal theory of suicide. AIMS: The purpose of this study was to further investigate the role of trait hope components (i.e., pathways and agency) in acquired capability for suicide. METHOD: Participants were 711 college students who completed measures of acquired capability for suicide, painful and provocative events, and trait hope (i.e., pathways and agency). Linear regression was used to test the hypotheses. RESULTS: As hypothesized, there was a positive relation between pathways and acquired capability. Contrary to our hypotheses, after controlling for gender there was a significant relation between agency and acquired capability. In addition, after controlling for gender, pathways did not moderate the relation between painful and provocative events and acquired capability, whereas agency did moderate this relation. CONCLUSION: Painful and provocative events should be assessed as a risk factor for acquired capability for suicide, and this may be more salient for individuals higher in the agency component of trait hope. Future research should consider examining the role of other traits within the interpersonal theory of suicide. PMID- 26440619 TI - Re-examination of classic risk factors for suicidal behavior in the psychiatric population. AB - BACKGROUND: For decades we have understood the risk factors for suicide in the general population but have fallen short in understanding what distinguishes the risk for suicide among patients with serious psychiatric conditions. AIMS: This prompted us to investigate risk factors for suicidal behavior among psychiatric inpatients. METHOD: We reviewed all psychiatric hospital admissions (2008-2011) to a centralized psychiatric hospital in Ontario, Canada. Using multivariable logistic regression we evaluated the association between potential risk factors and lifetime history of suicidal behavior, and constructed a model and clinical risk score to predict a history of this behavior. RESULTS: The final risk prediction model for suicidal behavior among psychiatric patients (n = 2,597) included age (in three categories: 60-69 [OR = 0.74, 95% CI = 0.73-0.76], 70-79 [OR = 0.45, 95% CI = 0.44-0.46], 80+ [OR = 0.31, 95% CI = 0.30-.31]), substance use disorder (OR = 1.30, 95% CI = 1.27-1.32), mood disorder (OR = 1.49, 95% CI = 1.47-1.52), personality disorder (OR = 2.30, 95% CI = 2.25-2.36), psychiatric disorders due to general medical condition (OR = 0.52, 95% CI = 0.50-0.55), and schizophrenia (OR = 0.42, 95% CI = 0.41-0.43). The risk score constructed from the risk prediction model ranges from -9 (lowest risk, 0% predicted probability of suicidal behavior) to +5 (highest risk, 97% predicted probability). CONCLUSION: Risk estimation may help guide intensive screening and treatment efforts of psychiatric patients with high risk of suicidal behavior. PMID- 26440622 TI - Ethnic differences in correlates of suicidal behavior among women seeking help for intimate partner violence. AB - BACKGROUND: Women abused by an intimate partner are at risk of engaging in nonfatal suicidal behavior and suicidal communication (NSBSC). No studies have examined ethnic differences in correlates of NSBSC among abused women. AIMS: This secondary data analytic study examined whether correlates of NSBSC previously reported among a mixed ethnic sample of women seeking help for abuse by a male intimate partner differed for those who self-identified as Latina (N = 340), African American (N = 184), or European American (N = 67). METHOD: Logistic regression was used to examine correlates of NSBSC separately among Latina, African American, and European American women. RESULTS: More severe violence by a male intimate partner, having a chronic or disabling illness, being younger, and being unemployed were positively associated with NSBSC in bivariate analyses among Latina women, but unemployment did not remain significantly associated with NSBSC in the multiple logistic regression. There were no significant correlates of NSBSC for African American women. Having a chronic illness was significantly associated with NSBSC among European American women. CONCLUSION: Findings suggest the need for culturally tailored suicide prevention interventions and studies that examine risk and protective factors for NSBSC among a diversity of women abused by male intimate partners. PMID- 26440623 TI - Suicide prevention through online gatekeeping using search advertising techniques: a feasibility study. AB - BACKGROUND: Nurturing gatekeepers is an effective suicide prevention strategy. Internet-based methods to screen those at high risk of suicide have been developed in recent years but have not been used for online gatekeeping. AIMS: A preliminary study was conducted to examine the feasibility and effects of online gatekeeping. METHOD: Advertisements to promote e-mail psychological consultation service use among Internet users were placed on web pages identified by searches using suicide-related keywords. We replied to all emails received between July and December 2013 and analyzed their contents. RESULTS: A total of 139 consultation service users were analyzed. The mean age was 23.8 years (SD = 9.7), and female users accounted for 80% of the sample. Suicidal ideation was present in 74.1%, and 12.2% had a history of suicide attempts. After consultation, positive changes in mood were observed in 10.8%, 16.5% showed intentions to seek help from new supporters, and 10.1% of all 139 users actually took help-seeking actions. CONCLUSION: Online gatekeeping to prevent suicide by placing advertisements on web search pages to promote consultation service use among Internet users with suicidal ideation may be feasible. PMID- 26440624 TI - Revisiting the concept of knowledge: how much is learned by students participating in suicide prevention gatekeeper training? AB - BACKGROUND: Although gatekeeper training is effective at increasing knowledge, some question the effectiveness of these programs due to high pretraining knowledge levels. However, knowledge scores may be artificially inflated when students guess answer options correctly but lack information needed to assist suicidal peers. AIMS: To use free-recall questions to evaluate suicide prevention knowledge and compare levels of knowledge using this methodology with established assessment methods in the literature. METHOD: Free-recall knowledge questions were examined before and after participation in a student gatekeeper training program. Focus groups with students enriched interpretation of quantitative results. RESULTS: Unlike in studies using forced-choice assessment, students' baseline knowledge was markedly low using free-recall questions and, despite making significant improvement from pretraining levels, posttraining knowledge barely approached passable levels. Focus group findings suggest that training sessions may need to be more engaging and interactive in order to improve knowledge transfer. CONCLUSION: Free-recall questions may provide a less inflated measure of accessible knowledge learned from school-based suicide prevention curricula. Evaluators and programmatic partners should be cognizant of this methodological issue and consider using a mix of assessment methodologies to determine students' actual levels of knowledge after participation in gatekeeper training. PMID- 26440625 TI - Association between adolescent suicide and sociodemographic factors in Chile: cross-sectional ecological study. AB - BACKGROUND: Adolescent suicide rates (ASR) are a matter of concern worldwide. Causes of this trend are not understood and could correspond to socioeconomic factors such as inequality. AIM: To investigate sociodemographic variables related to ASR, particularly the potential association with indicators of socioeconomic inequality. METHOD: Cross-sectional ecological study analyzing data from 29 health districts with univariate and multivariable multilevel Poisson models. RESULTS: ASR were higher in male adolescents and at increasing age. No association was found between ASR and inequality (Gini coefficient and 20/20 ratio). Analysis revealed that living in a single-parent family is associated with ASR. CONCLUSIONS: The usual demographic patterns of adolescent suicide apply in Chile. An emerging variable of interest is single-parent family. No cross sectional association between social inequality and ASR was found based on conflicting evidence. These results should be explored in future prospective population studies to further understand associated social factors. PMID- 26440626 TI - Trait gratitude and suicidal ideation and behavior: an exploratory study. AB - BACKGROUND: Despite the progress of positive psychology, current knowledge regarding suicide protective factors is limited. Trait gratitude (a tendency to experience gratitude in daily life) may protect against suicidal ideation and behavior. AIMS: The study tested a model of causal effects among gratitude, religiosity, reasons for living, coping, and social support as predictors of suicidal ideation, suicide threats, and suicide attempts after controlling for depression and stressful life events. METHOD: A sample of 165 college students were administered measures of gratitude, religiosity, reasons for living, social support, coping skills, stress, and depression. The study assessed lifetime and current suicidal ideation as well as lifetime suicide threat and attempt. RESULTS: Both gratitude and religiosity, along with social support, coping skills, and reasons for living, correlated negatively with prior suicidal ideation, but not with prior attempted suicide. After controlling for risk factor (depression and stress), the impact of gratitude and religiosity was no longer statistically significant. CONCLUSION: Further research could help understand the role of positive emotions and human strengths, such as gratitude, in preventing and alleviating suicidal ideation and behavior. PMID- 26440628 TI - Induction of Cytotoxicity through Photorelease of Aminoferrocene. AB - Reactive oxygen species (ROS)-activated aminoferrocene-based anticancer prodrug candidates successfully take advantage of intrinsically high amounts of ROS in tumor tissues. Interestingly, the ROS-initiated activation of these prodrug candidates leads to formation of unstable aminoferrocene (Fc-NH2) derivatives, which decay to iron ions. The latter catalytically increases ROS concentration to a lethal level. In this work, we prepared light-controlled aminoferrocene prodrug candidates by derivatizing Fc-NH2 with an o-nitrophenyl and an o-nitrobiphenyl photolabile protecting group (PLPG), respectively, and by further conjugation to a mitochondria localization signal (MLS) peptide (Cys-D-Arg-Phe-Lys-NH2). The resulting bioconjugates were found to be more stable and less cytotoxic, in the dark, toward human promyelocytic leukemia cells (HL-60) compared to Fc-NH2. Upon light irradiation at 355 nm, both conjugates released Fc-NH2, albeit with very different photolysis quantum yields. The o-nitrobiphenyl photocage was in fact several orders of magnitude more efficient than the o-nitrophenyl photocage in releasing Fc-NH2. This difference was reflected by the light irradiation experiments on the HL-60 cell line, in which aminoferrocene conjugated with the o nitrobiphenyl cage and the MLS displayed the highest phototoxicity index (2.5 +/- 0.4) of all the compounds tested. The iron release assays confirmed the rise in iron ion concentrations upon light irradiation of both caged aminoferrocene derivatives. Together with the absence of phototoxicity on the nonmalignant hTERT immortalized retinal pigment epithelial (hTERT RPE-1) cell line, these results indicate catalytic generation of ROS as possible mode of action. PMID- 26440629 TI - Genetic Variations in Pattern Recognition Receptor Loci Are Associated with Anti TNF Response in Patients with Rheumatoid Arthritis. AB - OBJECTIVES: To determine whether genetic variation within genes related to the Toll-like receptor, inflammasome and interferon-gamma pathways contributes to the differences in treatment response to tumour necrosis factor inhibitors (anti-TNF) in patients with rheumatoid arthritis (RA). METHODS: In a retrospective case-case study, we assessed 23 functional single nucleotide polymorphisms (SNPs) in 15 genes. We included 538 anti-TNF naive Danish RA patients from the nationwide DANBIO database. Multivariable logistic regression analyses were performed to detect associations (p-value<0.05) between genotypes and European League Against Rheumatism (EULAR) treatment responses. False Discovery Rate corrections for multiple testing (q-value) and stratified analyses were performed to investigate association with individual therapies and IgM-rheumatoid factor (RF) status. RESULTS: Six of twenty successfully genotyped polymorphisms were nominally associated with EULAR treatment response. Three of these were in weak to moderate linkage disequilibrium with polymorphisms previously reported associated with anti-TNF treatment response. TLR5(rs5744174) variant allele carriers (odds ratio(OR) = 1.7(1.1-2.5),p = 0.010,q = 0.46) and TLR1(rs4833095) homozygous variant carriers (OR = 2.8(1.1-7.4),p = 0.037,q = 0.46) had higher odds for a positive treatment response. NLRP3(rs10754558) variant allele carriers (odds ratio(OR) = 0.6(0.4-1.0),p = 0.045,q = 0.46) were more likely to have a negative treatment response. The association in TLR5(rs5744174) remained significant after correction for multiple comparisons among patients negative for RF (OR = 6.2(2.4 16.3),p = 0.0002,q = 0.024). No other association withstood correction for multiple testing. Post hoc analyses showed that change in Patient Global score on a visual analogue scale (VAS) and change in pain VAS were the main factors responsible for the association. CONCLUSIONS: We reproduced previously reported associations between genetic variation in the TLR10/1/6 gene cluster, TLR5, and NLRP3 loci and response to anti-TNF treatment in RA. Changes in VAS pain and patient global scores were the main contributors to the association found for TLR5. Furthermore, we identified other candidate genes that require replication in independent cohorts. PMID- 26440630 TI - [Mechanical thrombectomy for acute ischemic stroke : current evidence and open questions]. AB - OBJECTIVE: To determine the importance of mechanical thrombectomy (MT) in the treatment of ischemic stroke. MATERIAL AND METHODS: Analysis and comparison of randomized controlled trials (RCT) of MT versus i.v. thrombolysis (IVT) considering pathophysiological and logistic aspects. RESULTS: The use of MT is more effective than IVT for internal carotid artery terminus (ICAT), M1 segment and tandem occlusions, i.e. proximal internal carotid artery (ICA) occlusion or stenosis, even in patients older than 75-80 years of age. Due to the small sample sizes this question cannot be answered for patients with M2 occlusions. It is still uncertain whether MT is needed in patients with a low National Institutes of Health stroke scale (NIHSS) score, whether IVT is needed before MT and what type of imaging should be performed. Approximately one third of eligible patients currently undergo MT in Germany. Results from RCTs with stent retrievers for patients with vertebrobasilar artery occlusions are lacking. CONCLUSION: After becoming established as a first-line therapy for patients with ICAT, M1 segment and tandem occlusions, the effectiveness of MT with stent retrievers has to proven in patients with more distal occlusions, low NIHSS scores and even vertebrobasilar artery occlusions. PMID- 26440631 TI - [Diagnosis and treatment options in vertigo syndromes]. AB - The key to diagnosing vertigo and balance disorders is systematic analysis of case history with clinical examination of the vestibular, oculomotor, and cerebral systems in particular. Important criteria for differentiating between the various vertigo syndromes are 1) the time course of symptoms, 2) the type of symptoms, 3) modulating factors, and 4) associated symptoms. For clinical examination of the vestibular system, six important tests are available: assessment of spontaneous nystagmus, head impulse test, dynamic visual acuity, subjective visual verticality, positioning manoeuvre, and the Romberg test/gait analysis with eyes open and closed. On the basis of five clinical signs (vertical divergence, central fixation nystagmus, gaze-evoked nystagmus, saccades, normal head impulse test), the clinical examination is able to differentiate between acute central and peripheral vestibular syndromes with a sensitivity and specificity of over 90%. The most relevant laboratory examinations are caloric irrigation and the video head-impulse test for canal function and the vestibular evoked myogenic potentials for otolith function. Finally, treatment is based upon four therapeutic principles: physiotherapy, pharmacotherapy, psychotherapy, and in rare cases, surgery. PMID- 26440633 TI - [Not Available]. PMID- 26440634 TI - Carboxylic Derivatives of Vitamin K2 Inhibit Hepatocellular Carcinoma Cell Growth through Caspase/Transglutaminase-Related Signaling Pathways. AB - Chemoprevention of hepatocellular carcinoma (HCC) is one of the most challenging aspects of medical research. Vitamin K2 (VK2) has been suggested for its chemopreventive role in treatment of HCC, while inconsistent results in clinical trials have been reported. The present study was initiated to add to our insight into the anti-HCC cell proliferative effect of VK2 and its derivatives from a viewpoint of chemical structure. No significant effect was observed with original VK2, while VK2 derivatives bearing both isoprene units and a carboxyl-terminated side chain dose-dependently inhibited the growth of HCC cells without affecting normal liver cells. Loss-of-function analyses revealed that the anti-HCC cell activity by the VK2 derivatives was not mediated by a VK2 binding protein Bcl-2 homologous antagonist/killer (Bak) but rather associated with caspase/transglutaminase-related signaling pathways. Further studies on the carboxylic derivatives of VK2 bearing isoprene structural units introduced in this study might shed new light on the systemic treatment and prevention of HCC. PMID- 26440635 TI - Serum Fatty Acid Binding Protein 4 Concentrations Are Positively and Independently Associated with Blood Pressure and Abdominal Fat among Parameters in Health Check-Ups in Ordinary Middle-Aged Japanese Males. AB - We wished to examine potential associations among blood concentrations of fatty acid-binding protein (FABP) 4 and parameters in health check-ups such as abdominal fat area (AFA) and blood pressure (BP) in middle-aged Japanese males. We conducted a cross-sectional study of males who participated in health check ups in Japan. We excluded participants diagnosed with metabolic diseases by the time of their check-up. A total of 305 subjects (30-64 [mean+/-standard deviation, 47.3+/-8.5] y) were recruited. Areas of total-abdominal, visceral and subcutaneous fat were measured using computed tomography. We compared the association of serum concentrations of FABP4 with various clinical parameters by Pearson product-moment correlation coefficient (PPMCC) analyses, and by step-wise multivariate linear regression analyses (MLRA). PPMCC analyses showed that blood concentrations of FABP4 were positively associated with: body mass index; areas of fat (total abdominal, visceral, subcutaneous); systolic BP; diastolic BP; total cholesterol; low-density lipoprotein-cholesterol; triacylglycerol; activities of gamma-glutamyl transpeptidase, aspartate aminotransferase and alanine aminotransferase; white blood cell count; and levels of creatinine. Step wise MLRA showed that AFAs (visceral and subcutaneous) and diastolic BP were positively and independently associated with serum concentrations of FABP4 among the parameters tested. These data suggest that serum concentrations of FABP4 are independently and positively associated with BP and AFA among parameters measured in health check-ups in middle-aged Japanese males. PMID- 26440636 TI - Effects of Aerobic Exercise on Postprandial Carbohydrate and Lipoprotein Metabolism Following Cookie Ingestion in Healthy Young Women. AB - We examined the acute effects of postprandial aerobic exercise on glucose and lipid metabolism following cookie ingestion. Fifteen healthy young women with a sedentary lifestyle, normal weight and apolipoprotein E3/3 participated. After a 12-h overnight fast, each subject ingested a cookie (1.53 g/kg, Meal Test C) and then performed two trials, one with postprandial exercise (E trial) and one without exercise (C trial), in a randomized crossover design. A single 30-min bout of walking exercise was performed 20 min after the cookie intake. Venous blood samples were drawn before (0 h) and 20 min and 1, 2, 4, and 6 h after cookie ingestion. The Deltaglucose concentration was not significantly different between the two trials, but the Deltainsulin concentration at 1 h and the incremental area under the curve (IAUC) (0-2 h)-insulin in the E trial were significantly lower than in the C trial. The ratio of glucose/insulin at 1 h was significantly higher in the E trial than in the C trial. The DeltaTG, DeltaRLP TG, DeltaapoB48 and DeltaRemL-C concentrations at 1 h in the E trial were significantly higher than in the C trial. The IAUC (0-2 h)-apoB48 in the E trial was significantly larger than in the C trial. Postprandial exercise showed an insulin-sparing effect following the cookie ingestion by increasing insulin sensitivity. However, postprandial exercise transiently stimulated the secretion of exogenous apoB48-containing lipoprotein during the early period, and no further effects were observed. These results suggest that postprandial aerobic exercise is effective for the promotion of postprandial carbohydrate metabolism, but not lipidemia. PMID- 26440637 TI - Boysenberry Polyphenols Suppressed Elevation of Plasma Triglyceride Levels in Rats. AB - Boysenberry, a hybrid Rubus berry, is mainly cultivated in New Zealand. We previously reported that consumption of boysenberry juice (BBJ) exhibited anti obesity effects in high-fat feeding rats. In this study, we focused on the suppressive effect of BBJ and its fraction on triglyceride absorption from the gastrointestinal tract. BBJ effectively inhibited pancreatic lipase activity in vitro, and was separated into four fractions (Fr1, Fr2, Fr3 and Fr4) by HP-20 column chromatography. Among all the fractions, Fr3, the ellagic acid-rich fraction, showed the most potent inhibition against pancreatic lipase in vitro with Fr2, the anthocyanin-rich fraction, second. Authentic ellagic acid equivalent in Fr3 showed poor activity against pancreatic lipase. Then, each fraction was orally administered with corn oil to rats fitted with a jugular catheter to examine the effects of each fraction on plasma triglyceride levels. Both Fr2 and Fr3 effectively suppressed the plasma triglyceride level elevation at a dose of 1,000 mg/kg body weight. These findings demonstrated that BBJ contains chemical components which inhibit triglyceride absorption from the gastrointestinal tract. PMID- 26440638 TI - Treatment with DPP-4I Anagliptin or alpha-GI Miglitol Reduces IGT Development and the Expression of CVD Risk Factors in OLETF Rats. AB - It has been reported that postprandial hyperglycemia from the pre-diabetic stage, especially from the impaired glucose tolerance (IGT) stage, is positively associated with subsequent incidences of cardiovascular diseases (CVD) and type 2 diabetes. In this study, we aimed to investigate whether treatment with a dipeptidyl peptidase-4 inhibitor (DPP-4I) or an alpha-glucosidase inhibitor (alpha-GI), either of which suppresses postprandial hyperglycemia, reduces the expression of CVD risk factors in an IGT animal model. A DPP-4I, anagliptin (1,200 ppm), or an alpha-GI, miglitol (600 ppm), in the diet was administered for 47 wk to Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model for spontaneously-developed type 2 diabetes, at the IGT stage. We examined whether each treatment reduced the expression of CVD risk factors such as inflammatory cytokines/cytokine-like factors in peripheral leukocytes and adhesion molecules in the aortic tissues and circulation. Treatment with either drug reduced IGT development and repressed expression of the interleukin-1beta, tumor necrosis factor-alpha, S100a9, and S100a11 genes in peripheral leukocytes in the fasting state at weeks 25 and 39. The mRNA levels of E-selectin in aortic tissues and protein levels of the soluble forms of E-selectin and ICAM-1 in arterial blood were significantly lower in the anagliptin and miglitol groups than in the control group. Our results suggest that long-term treatment with anagliptin or miglitol in OLETF rats at the IGT stage suppresses the expression of inflammatory cytokines in peripheral leukocytes and adhesion molecules in aortic tissues. PMID- 26440640 TI - Efficacy and Safety of High Specific Volume Polysaccharide-A New Type of Dietary Fiber for Treatment of Functional Constipation and IBS-C. AB - We investigated the efficacy and safety of a new type of dietary fiber (high specific volume polysaccharide) for use in treating constipation of different etiologies. Functional constipation patients and irritable bowel syndrome constipation (IBS-C) patients were administrated high specific volume polysaccharide (HSVP) three times daily for a period of 2 wk to relieve their symptoms. Scores on a stool form scale, and patient reports of straining during a bowel movement, having sensations of an incomplete bowel movement or a blocked anorectum, and abnormal defecation intervals were recorded, graded, and scored by a functional constipation sample group. Similarly, a cohort of IBS-C patients reported their occurrence of abdominal discomfort or pain, abnormal stool formation, defecation frequency, and straining during a bowel movement. Additionally, both groups reported any adverse reactions associated with taking HSVP. All patients in both groups returned for follow-up visits, and no adverse reactions to treatment with HSVP were reported. In the functional constipation group, HSVP was effective for treating symptoms of constipation in 81.46% and 93.17% of patients after 7 and 14 d of dosing, respectively (both p<0.05). In the IBS-C group, symptoms of constipation were relieved in 71.67% and 88.34% of patients after 7 and 14 d of dosing, respectively (both p<0.05). High specific volume polysaccharide was shown be effective for treatment of functional constipation and IBS-C, without causing significant adverse events. PMID- 26440639 TI - Selenium Intake in Hypertensive and Normotensive Post-Menopausal Indonesian Women. AB - The Indonesian Ministry of Health has predicted that the national prevalence of hypertension in Indonesia may reach 26.5% in 2013. Increasing age, stress, lack of physical activity, obesity and passive smoking are known to be risk factors of hypertension. In women over 50 y, hormonal changes that occur post-menopause may also increase the risk of hypertension and other vascular diseases. Antioxidant precursors, such as selenium, however, are known to provide protection against the development of several oxidative stress-related diseases, including hypertension. To prove the hypothesis, we compared the levels of consumption of selenium in hypertensive and normotensive post-menopausal women. An observational comparative study with cross-sectional design was conducted in groups of post menopausal women with hypertension and those who are normotensive. Structured interviews and food recall of 2*24 h were used to determine the level of consumption, and the Depression, Anxiety and Stress Scale (DASS) questionnaire was used to measure the level of stress. The result suggests a significant difference in the levels of selenium intake between the normotensive and hypertensive groups (p=0.008). Furthermore, the passive smoking and stress levels of the hypertensive group were significantly higher than those of the normotensive group. These result support the hypothesis that selenium may play a protective role in vascular disease. PMID- 26440641 TI - Effect of Kiwifruit on Bone Resorption in Ovariectomized Mice. AB - Kiwifruit is a good source of dietary components and has beneficial effects for health. In this study, we investigated the effects of two types of kiwifruit, green kiwifruit (GRK) and gold kiwifruit (GOK), on bone metabolism in ovariectomized (OVX) mice. Seven-week-old female Balb/c-strain mice were divided into four groups: sham-operated (sham) group, OVX group, and OVX mice that were fed a GRK-supplemented diet or GOK-supplemented diet. Freeze-dried GRK and GOK were prepared and added in the diet at a concentration of 3 g/100 g. After 9 wk, the mice were sacrificed, and the serum, uterus, and femurs were obtained. Final body weight did not differ significantly among the four groups. Compared to the sham group, uterine weight was significantly lower and serum C-terminal telopeptide of type I collagen (CTx) levels and receptor activator of NF-kappaB ligand (RANKL) mRNA expression of the whole femur were significantly higher in the OVX group. Compared to the OVX group, GRK, but not GOK, reduced serum CTx concentrations and RANKL mRNA expression of the whole femur without changes in uterine weight. These results suggest that the GRK inhibited bone resorption, which might be due to a decrease in RANKL mRNA expression in OVX mice. PMID- 26440642 TI - Polyphenol Intake from Beverages in Japan over an 18-Year Period (1996-2013): Trends by Year, Age, Gender and Season. AB - An association between the dietary intake of polyphenols and human health has been shown in many epidemiological studies. Since beverages are rich sources of polyphenols, we aimed to evaluate the polyphenol intake from beverages in Japanese individuals with a focus on differences according to year, age, gender and season. More than 10,000 Japanese male and female subjects aged 1-99 y old participated in this survey every year from 1996 to 2013, and their beverage consumption and amount of polyphenol intake were calculated. Polyphenol intake from beverages in Japan showed no tendency to increase or decrease over the 18-y period, and the major sources of polyphenols in Japanese daily life were coffee and green tea. Polyphenol intake was larger in participants with higher age up to 59 y old in both male and female subjects. There was a slight difference in polyphenol intake by gender, with adult males consuming more polyphenols than adult females. Polyphenols were consumed slightly more in the winter than the summer, although the seasonal difference in polyphenol intake was not large. Our results suggest that polyphenol intake from beverages is influenced by age rather than gender or season in Japan, and may not have changed over time, at least over the 18-y period beginning in 1996 in Japan. PMID- 26440643 TI - Effect of Polydextrose Intake on Constipation in Japanese Dialysis Patients: A Triple-Blind, Randomized, Controlled Trial. AB - The objective of the present study was to evaluate bowel habits induced by ingestion of 10 g polydextrose (PDX) fed to Japanese hemodialysis (HD) patients. This was a randomized, placebo-controlled, triple-blind, parallel-group controlled, 8-wk study. A total of 50 HD outpatients capable of self-management (51-79 y of age) were recruited at H Clinic, Japan. Inclusion criteria for participation in the study were ingestion of one or more laxative tablets for more than 3 mo and having received HD for more than 6 mo. The participants were randomly assigned to 2 groups: A (0 g polydextrose/d; control), B (10 g polydextrose/d; PDX). The primary outcome measure was stool frequency. Secondary outcomes were stool consistency, abdominal pain, intestinal bloating and clinical biochemistry indexes. PDX had no significant effect on blood biochemistry indexes. The PDX group showed significant improvements in bowel function (stool frequency increased from 3.0 times per week to 7.5 times per week) and reported no laxation problems (abdominal distention, cramps, and diarrhea) (p<0.01). Regular consumption of the PDX products increased dietary fiber intake to recommended levels and improved bowel habits. PMID- 26440644 TI - Feasibility of long-distance heart rate monitoring using transmittance photoplethysmographic imaging (PPGI). AB - Photoplethysmography (PPG) devices are widely used for monitoring cardiovascular function. However, these devices require skin contact, which restricts their use to at-rest short-term monitoring. Photoplethysmographic imaging (PPGI) has been recently proposed as a non-contact monitoring alternative by measuring blood pulse signals across a spatial region of interest. Existing systems operate in reflectance mode, many of which are limited to short-distance monitoring and are prone to temporal changes in ambient illumination. This paper is the first study to investigate the feasibility of long-distance non-contact cardiovascular monitoring at the supermeter level using transmittance PPGI. For this purpose, a novel PPGI system was designed at the hardware and software level. Temporally coded illumination (TCI) is proposed for ambient correction, and a signal processing pipeline is proposed for PPGI signal extraction. Experimental results show that the processing steps yielded a substantially more pulsatile PPGI signal than the raw acquired signal, resulting in statistically significant increases in correlation to ground-truth PPG in both short- and long-distance monitoring. The results support the hypothesis that long-distance heart rate monitoring is feasible using transmittance PPGI, allowing for new possibilities of monitoring cardiovascular function in a non-contact manner. PMID- 26440646 TI - High performance of PbSe/PbS core/shell quantum dot heterojunction solar cells: short circuit current enhancement without the loss of open circuit voltage by shell thickness control. AB - We fabricated heterojunction solar cells with PbSe/PbS core shell quantum dots and studied the precisely controlled PbS shell thickness dependency in terms of optical properties, electronic structure, and solar cell performances. When the PbS shell thickness increases, the short circuit current density (JSC) increases from 6.4 to 11.8 mA cm(-2) and the fill factor (FF) enhances from 30 to 49% while the open circuit voltage (VOC) remains unchanged at 0.46 V even with the decreased effective band gap. We found that the Fermi level and the valence band maximum level remain unchanged in both the PbSe core and PbSe/PbS core/shell with a less than 1 nm thick PbS shell as probed via ultraviolet photoelectron spectroscopy (UPS). The PbS shell reduces their surface trap density as confirmed by relative quantum yield measurements. Consequently, PbS shell formation on the PbSe core mitigates the trade-off relationship between the open circuit voltage and the short circuit current density. Finally, under the optimized conditions, the PbSe core with a 0.9 nm thick shell yielded a power conversion efficiency of 6.5% under AM 1.5. PMID- 26440647 TI - A Systematic Review of Patients' Experiences in Communicating with Primary Care Physicians: Intercultural Encounters and a Balance between Vulnerability and Integrity. AB - Communication difficulties persist between patients and physicians. In order to improve care, patients' experiences of this communication must be understood. The main objective of this study is to synthesize qualitative studies exploring patients' experiences in communicating with a primary care physician. A secondary objective is to explore specific factors pertaining to ethnic minority or majority patients and their influence on patients' experiences of communication. Pertinent health and social sciences electronic databases were searched systematically (PubMed, Cinahl, PsychNet, and IBSS). Fifty-seven articles were included in the review on the basis of being qualitative studies targeting patients' experiences of communication with a primary care physician. The meta ethnography method for qualitative studies was used to interpret data and the COREQ checklist was used to evaluate the quality of included studies. Three concepts emerged from analyses: negative experiences, positive experiences, and outcomes of communication. Negative experiences related to being treated with disrespect, experiencing pressure due to time constraints, and feeling helpless due to the dominance of biomedical culture in the medical encounter. Positive experiences are attributed to certain relational skills, technical skills, as well as certain approaches to care privileged by the physician. Outcomes of communication depend on patients' evaluation of the consultation. Four categories of specific factors exerted mainly a negative influence on consultations for ethnic minorities: language barriers, discrimination, differing values, and acculturation. Ethnic majorities also raised specific factors influencing their experience: differing values and discrimination. Findings of this review are limited by the fact that more than half of the studies did not explore cultural aspects relating to this experience. Future research should address these aspects in more detail. In conclusion, all patients seemed to face additional cultural challenges. Findings provide a foundation for the development of tailored interventions to patients' preferences, thus ensuring more satisfactory experiences. Health care providers should be sensitive to specific factors (cultural and micro-cultural) during all medical encounters. PMID- 26440648 TI - Expression of a kinase-dead form of CPK33 involved in florigen complex formation causes delayed flowering. AB - Regulation of flowering time is crucial for reproductive success of plants. FLOWERING LOCUS T (FT) protein is a central component of florigen and forms a ternary complex with 14-3-3 and FD, a basic leucine zipper transcription factor, in the shoot apex and promotes flowering. This complex formation requires phosphorylation of threonine residue at position 282 of FD. A calcium-dependent protein kinase CPK33 is responsible for the phosphorylation. However, possibly due to functional redundancy among calcium-dependent protein kinases, impact of the loss of CPK33 reported in the previous study was rather limited. Here, we report that expression of a kinase-dead form of CPK33 caused a clear delayed flowering phenotype, supporting for an important role of CPK33 in florigen function through FD phosphorylation. PMID- 26440650 TI - Short QT Syndrome in Current Clinical Practice. AB - Short QT syndrome is a rare inherited autosomal dominant cardiac channelopathy associated with malignant ventricular and atrial arrhythmias. A shortened corrected QT interval is a marker for risk of malignant arrhythmias, which are secondary to increased transmural dispersion of repolarization. The underlying gain of function mutations in the potassium channels are most common but genetic testing remains low yield. This review discusses the cellular mechanisms, genetic involvement, clinical presentation, and current recommended management of patients with short QT syndrome relevant to current clinical practice. PMID- 26440649 TI - Association between the angiotensin-converting enzyme gene insertion/deletion polymorphism and susceptibility to systemic lupus erythematosus in an Indian population. PMID- 26440651 TI - Use of Extracorporeal Membrane Oxygenation in Refractory Cardiogenic Shock. AB - Cardiogenic shock is a condition marked by low cardiac output and end-organ hypoperfusion frequently requiring hemodynamic support, and it carries a high mortality. Extracorporeal membrane oxygenation (ECMO) is an effective tool in providing mechanical circulatory support in patients with cardiogenic shock refractory to conventional medical therapies. ECMO can be an essential bridge to recovery, ventricular assist device implantation or transplant. A multidisciplinary team approach is needed in managing such patients and intensive monitoring is required to avoid complications from ECMO. Nevertheless, randomized clinic trials are warranted to prove a survival benefit. PMID- 26440652 TI - The Relationship Between Trust-in-God, Positive and Negative Affect, and Hope. AB - We aimed to test the relationships between Trust-in-God, positive and negative affect, and feelings of hope. A sample of university students (N = 282, 50 % female) completed the Positive and Negative Affect Schedule, the Adult Dispositional Hope Scale, and a Persian measure of Trust-in-God for Muslims. The results of a series of hierarchical regression analyses indicated that Trust-in God was positively associated with participants' scores for hope and positive affect but was negatively associated with their scores for negative affect. The results support the relationship between Trust-in-God and indices of mental health. PMID- 26440653 TI - Muscle Strength, Function and Heart Autonomic Regulation System Recovery at the Sub-Acute Stage Post Stroke. AB - BACKGROUND: To compare the rate of recovery of motor and functional ability and heart rate variability (HRV) parameters during the inpatient rehabilitation period. SUMMARY: Twenty-three patients post first stroke at the sub-acute phase underwent motor and functional ability and HRV assessments 20 and 50 days after the event. A significant improvement was noted in motor and functional ability performance during the follow-up period, while no such change was noted in the HRV parameters. KEY MESSAGES: Patients post first-ever stroke exhibited a significant motor and functional improvement during the sub-acute phase post stroke, while no change was noted in their HRV parameters, which may imply that no significant changes in the sympatho-vagal balance took place during this period. PMID- 26440654 TI - Myelination Is Associated with Processing Speed in Early Childhood: Preliminary Insights. AB - Processing speed is an important contributor to working memory performance and fluid intelligence in young children. Myelinated white matter plays a central role in brain messaging, and likely mediates processing speed, but little is known about the relationship between myelination and processing speed in young children. In the present study, processing speed was measured through inspection times, and myelin volume fraction (VFM) was quantified using a multicomponent magnetic resonance imaging (MRI) approach in 2- to 5-years of age. Both inspection times and VFM were found to increase with age. Greater VFM in the right and left occipital lobes, the body of the corpus callosum, and the right cerebellum was significantly associated with shorter inspection times, after controlling for age. A hierarchical regression showed that VFM in the left occipital lobe predicted inspection times over and beyond the effects of age and the VFM in the other brain regions. These findings are consistent with the hypothesis that myelin supports processing speed in early childhood. PMID- 26440655 TI - Characteristics of Hospitalized Cases of Pertussis in Catalonia and Navarra, Two Regions in the North of Spain. AB - Pertussis causes a large number of cases and hospitalizations in Catalonia and Navarra. We made a study of household cases of pertussis during 2012 and 2013 in order to identify risk factors for hospitalization in pertussis cases. Each primary case reported triggered the study of their contacts. Close contacts at home and people who were in contact for >2 hours during the transmission period of cases were included. The adjusted OR and 95% confidence intervals (CI) was calculated using logistic regression. A total of 1124 pertussis cases were detected, of which 14.9% were hospitalized. Inspiratory whoop (aOR: 1.64; CI: 1.02-2.65), apnoea (aOR: 2.47; CI: 1.51-4.03) and cyanosis (aOR: 15.51; CI: 1.87 128.09) were more common in hospitalized than in outpatient cases. Hospitalization occurred in 8.7% of correctly-vaccinated cases, 41.1% of non vaccinated cases and 9.4% of partially-vaccinated cases. In conclusion, inspiratory whoop, apnoea and cyanosis were associated factors to hospitalization while vaccination reduced hospitalizations due to pertussis. PMID- 26440656 TI - Sustainable Remediation of Legacy Mine Drainage: A Case Study of the Flight 93 National Memorial. AB - Pollution from mining activities is a global environmental concern, not limited to areas of current resource extraction, but including a broader geographic area of historic (legacy) and abandoned mines. The pollution of surface waters from acid mine drainage is a persistent problem and requires a holistic and sustainable approach to addressing the spatial and temporal complexity of mining specific problems. In this paper, we focus on the environmental, socio-economic, and legal challenges associated with the concurrent activities to remediate a coal mine site and to develop a national memorial following a catastrophic event. We provide a conceptual construct of a socio-ecological system defined at several spatial, temporal, and organizational scales and a critical synthesis of the technical and social learning processes necessary to achieving sustainable environmental remediation. Our case study is an example of a multi-disciplinary management approach, whereby collaborative interaction of stakeholders, the emergence of functional linkages for information exchange, and mediation led to scientifically informed decision making, creative management solutions, and ultimately environmental policy change. PMID- 26440658 TI - [The silent revolution]. PMID- 26440657 TI - Intranasal Immunization with DOTAP Cationic Liposomes Combined with DC Cholesterol Induces Potent Antigen-Specific Mucosal and Systemic Immune Responses in Mice. AB - Despite the progress made by modern medicine, infectious diseases remain one of the most important threats to human health. Vaccination against pathogens is one of the primary methods used to prevent and treat infectious diseases that cause illness and death. Vaccines administered by the mucosal route are potentially a promising strategy to combat infectious diseases since mucosal surfaces are a major route of entry for most pathogens. However, this route of vaccination is not widely used in the clinic due to the lack of a safe and effective mucosal adjuvant. Therefore, the development of safe and effective mucosal adjuvants is key to preventing infectious diseases by enabling the use of mucosal vaccines in the clinic. In this study, we show that intranasal administration of a cationic liposome composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 3beta [N-(N',N'-dimethylaminoethane)-carbamoyl] (DC-chol) (DOTAP/DC-chol liposome) has a potent mucosal adjuvant effect in mice. Intranasal vaccination with ovalbumin (OVA) in combination with DOTAP/DC-chol liposomes induced the production of OVA specific IgA in nasal tissues and increased serum IgG1 levels, suggesting that the cationic DOTAP/DC-chol liposome leads to the induction of a Th2 immune response. Additionally, nasal-associated lymphoid tissue and splenocytes from mice treated with OVA plus DOTAP/DC-chol liposome showed high levels of IL-4 expression. DOTAP/DC-chol liposomes also enhanced OVA uptake by CD11c+ dendritic cells in nasal-associated lymphoid tissue. These data demonstrate that DOTAP/DC chol liposomes elicit immune responses via an antigen-specific Th2 reaction. These results suggest that cationic liposomes merit further development as a mucosal adjuvant for vaccination against infectious diseases. PMID- 26440659 TI - The significance of aortic valve calcification in patients with bicuspid aortic valve disease. AB - Bicuspid aortic valve (BAV) is a common congenital heart disease. Our study was to analyze clinical features of BAV and evaluate whether aortic valve calcium score (AVCS) was a reliable marker for aortic stenosis (AS) in patients with BAV. 101 patients with BAV who both underwent echocardiology and cardiac computed tomography (CT) scan in our institution were included. Basic clinical data, haemodynamic feature, aortic valve and coronary calcium score were collected and compared among patients with different valve function and different degree of AS. Risk factors related to severe AS were evaluated by logistic regression, and a receiver operative characteristic curve was used to determine the cutoff calcium score greater than which the diagnosis of severe AS was optimized. Patients with aortic regurgitation (AR) were younger and demonstrated larger aortic annulus and sinus compared with patients with other valve dysfunction. Aortic valve calcium score was higher in patients with AS than with AR. For patients with different degree of AS, there were statistical significances in the value of age, aortic valve calcium score and coronary calcium score. AVCS was positively related to severe AS with an odd ratio of 1.286 (95% CI 1.099-1.504) by every 300 points increase. AVCS was also a strong predictor for severe AS with area under the curve 0.855 with a cutoff value of 897 (sensitivity 86.7%, specificity 72.2%). Conclusively, aortic calcium score calculated by quantitative CT is a reliable marker in evaluating severity of AS. PMID- 26440660 TI - Validity of the size-specific dose estimate in adults undergoing coronary CT angiography: comparison with the volume CT dose index. AB - Size-specific dose estimate (SSDE) takes into account the patient size but remains to be fully validated for adult coronary computed tomography angiography (CCTA). We investigated the appropriateness of SSDE for accurate estimation of patient dose by comparing the SSDE and the volume CT dose index (CTDIvol) in adult CCTA. This prospective study received institutional review board approval, and informed consent was obtained from each patient. We enrolled 37 adults who underwent CCTA with a 320-row CT. High-sensitivity metal oxide semiconductor field effect transistor dosimeters were placed on the anterior chest. CTDIvol reported by the scanner based on a 32-cm phantom was recorded. We measured chest diameter to convert CTDIvol to SSDE. Using linear regression, we then correlated SSDE with the mean measured skin dose. We also performed linear regression analyses between the skin dose/CTDIvol and the body mass index (BMI), and the skin dose/SSDE and BMI. There was a strong linear correlation (r = 0.93, P < 0.001) between SSDE (mean 37 +/- 22 mGy) and mean skin dose (mean 17.7 +/- 10 mGy). There was a moderate negative correlation between the skin dose/CTDIvol and BMI (r = 0.45, P < 0.01). The skin dose/SSDE was not affected by BMI (r = 0.06, P > 0.76). SSDE yields a more accurate estimation of the radiation dose without estimation errors attributable to the body size of adult patients undergoing CCTA. PMID- 26440661 TI - A new caring by the ground for severe stage of dementia. AB - Patients with severe stage of dementia present several psycho-behavioral disorders, caused by an altered perception of their environment and a feeling of isolation. Most of them are bedridden because of the advanced stage of Alzheimer's disease which causes cognitive dysfunctions and physical disorders, including coordination movement problems. Consequently, their freedoms of movement are limited as well as the quality of their communication. In this study, a new care support using activities on the ground is proposed to compensate for the massive cognitive and psychological losses and enhance their communication skills. The results of this study show that ground activities seem to be a promising way to reduce psycho-behavioral disorders and recreate communication link of the patients presenting with a severe stage of dementia. PMID- 26440662 TI - Functional decline and herpes zoster in older people: an interplay of multiple factors. AB - Herpes zoster is a frequent painful infectious disease whose incidence and severity increase with age. In older people, there is a strong bidirectional link between herpes zoster and functional decline, which refers to a decrement in ability to perform activities of daily living due to ageing and disabilities. However, the exact nature of such link remains poorly established. Based on the opinion from a multidisciplinary group of experts, we here propose a new model to account for the interplay between infection, somatic/psychiatric comorbidity, coping skills, polypharmacy, and age, which may account for the functional decline related to herpes zoster in older patients. This model integrates the risk of decompensation of underlying disease; the risk of pain becoming chronic (e.g. postherpetic neuralgia); the risk of herpes zoster non-pain complications; the detrimental impact of herpes zoster on quality of life, functioning, and mood; the therapeutic difficulties due to multimorbidity, polypharmacy, and ageing; and the role of stressful life events in the infection itself and comorbid depression. This model underlines the importance of early treatment, strengthening coping, and vaccine prevention. PMID- 26440663 TI - The N-silylation of sulfoximines. AB - The copper-catalyzed N-silylation of sulfoximines was achieved in the presence of di-tert-butyl peroxide. Notably, alkyl, phenyl and alkoxyl silanes were all suitable reaction partners. Mechanistic studies revealed that N-silyl acetamide serves as the intermediate. PMID- 26440664 TI - A novel missense mutation in the gene EDARADD associated with an unusual phenotype of hypohidrotic ectodermal dysplasia. AB - Hypohidrotic ectodermal dysplasia (HED) is a rare disorder characterized by deficient development of structures derived from the ectoderm including hair, nails, eccrine glands, and teeth. HED forms that are caused by mutations in the genes EDA, EDAR, or EDARADD may show almost identical phenotypes, explained by a common signaling pathway. Proper interaction of the proteins encoded by these three genes is important for the activation of the NF-kappaB signaling pathway and subsequent transcription of the target genes. Mutations in the gene EDARADD are most rarely implicated in HED. Here we describe a novel missense mutation, c.367G>A (p.Asp123Asn), in this gene which did not appear to influence the interaction between EDAR and EDARADD proteins, but led to an impaired ability to activate NF-kappaB signaling. Female members of the affected family showed either unilateral or bilateral amazia. In addition, an affected girl developed bilateral ovarian teratomas, possibly associated with her genetic condition. PMID- 26440665 TI - Neutralizing Antibody Response after Intramuscular Purified Vero Cell Rabies Vaccination (PVRV) in Iranian Patients with Specific Medical Conditions. AB - OBJECTIVE: Post exposure prophylaxis using one of the WHO-approved vaccines is the method of choice for preventing rabies. Abnormal immune function in patients with some specific medical conditions, such as pregnancy, chronic hepatitis B virus infection, different types of cancers like lymphoma, diabetes I and II, corticosteroid consumption by patients with rheumatoid arthritis and lupus erythematosus, could impair the immunologic response to various vaccines. The immune response to rabies vaccination has never been examined in patients with any of these described medical conditions. This study purposed to evaluate the neutralyzing antibody response after vaccination with purified Vero cell rabies vaccine (PVRV) according to the WHO-recommended Post-Exposure Prophylaxis (PEP) "ESSEN" regimen. METHODS: Thirty healthy volunteers and 50 volunteers with different medical conditions who were exposed to a suspected rabid animal in the 2nd or 3rd category of exposure received 5 doses of PVRV under the ESSEN protocol. Three blood samples were collected on days 0 (before the first dose), 14, and 35. The anti-rabies antibody titer was measured using the Rapid Fluorescent Foci Inhibition Test (RFFIT) and an ELISA Bio-Rad, Platelia, Rabies II kit. RESULTS: All subjects reached NAb titers above 0.5 IU/ml by day 14 after vaccination. On day 35 (1 week after receiving the last rabies vaccine), anti rabies antibodies were in the protective level (>0.5 IU/ml) in both groups. There was no statistically significant difference in anti-rabies antibody response due to the type of exposure (category 2 or 3), and successful seroconversion was confirmed in both groups. CONCLUSION: In conclusion, the ESSEN protocol using the PVRV vaccine is sufficient for rabies prophylaxis in patients with specific medical conditions. PMID- 26440666 TI - Arctigenin Suppress Th17 Cells and Ameliorates Experimental Autoimmune Encephalomyelitis Through AMPK and PPAR-gamma/ROR-gammat Signaling. AB - Arctigenin is a herb compound extract from Arctium lappa and is reported to exhibit pharmacological properties, including neuronal protection and antidiabetic, antitumor, and antioxidant properties. However, the effects of arctigenin on autoimmune inflammatory diseases of the CNS, multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis (EAE) are still unclear. In this study, we demonstrated that arctigenin-treated mice are resistant to EAE; the clinical scores of arctigenin-treated mice are significantly reduced. Histochemical assays of spinal cord sections also showed that arctigenin reduces inflammation and demyelination in mice with EAE. Furthermore, the Th1 and Th17 cells in peripheral immune organs are inhibited by arctigenin in vivo. In addition, the Th1 cytokine IFN-gamma and transcription factor T-bet, as well as the Th17 cytokines IL-17A, IL-17F, and transcription factor ROR-gammat are significantly suppressed upon arctigenin treatment in vitro and in vivo. Interestedly, Th17 cells are obviously inhibited in CNS of mice with EAE, while Th1 cells do not significantly change. Besides, arctigenin significantly restrains the differentiation of Th17 cells. We further demonstrate that arctigenin activates AMPK and inhibits phosphorylated p38, in addition, upregulates PPAR-gamma, and finally suppresses ROR-gammat. These findings suggest that arctigenin may have anti-inflammatory and immunosuppressive properties via inhibiting Th17 cells, indicating that it could be a potential therapeutic drug for multiple sclerosis or other autoimmune inflammatory diseases. PMID- 26440667 TI - Treatment of SMB-S15 Cells with Resveratrol Efficiently Removes the PrP(Sc) Accumulation In Vitro and Prion Infectivity In Vivo. AB - Prion diseases are transmissible and invariably fatal neurodegenerative disorders, which still lack of efficacious prophylactic and therapeutic tools. Our previous study has proposed that the natural phytoalexin, resveratrol, can reduce the amounts of PrP(Sc) in a scrapie-infected cell line SMB-S15. To address its anti-prion efficacy, the inhibitive activity of resveratrol on prion accumulation in vitro and prion infectivity in vivo was analyzed in the present study. Exposure of SMB-S15 cells to various concentrations of resveratrol (0.25 to 200 MUM) reduced and even removed cellular PrP(Sc) in a dose-dependent manner, with EC50 0.61 MUM. Meanwhile, PrP(Sc) signals in SMB-S15 cells treated with 5 and 10 MUM resveratrol maintained undetectable after drug withdrawal, indicating that the removal of PrP(Sc) in SMB-S15 cells by resveratrol is irreversible. Furthermore, the lysates of SMB-S15 cells exposed to 10 MUM resveratrol for 2 and 7 days were intracerebrally inoculated into CD1 mice. All mice (n = 9) infected with SMB-S15 cells without treatment of resveratrol appeared typical experimental scrapie symptoms from 155 to 228 day post inoculation (dpi), while all mice (n = 9) inoculated with SMB-S15 cells treated with resveratrol for 7 days maintained healthy by the end of observations (284 dpi). PrP-specific Western blots and neuropathological tests did not identify PrP(Sc) or prion disease-associated pathological abnormality in the brains of mice inoculated with 7-day resveratrol treated SMB-S15 cells. It indicates that the prion infectivity of SMB-S15 onto CD1 mice is eradicated by 1-week resveratrol treatment. Sensitivity of PrP(Sc) to resveratrol highlights its potential role in prion therapeutics. PMID- 26440669 TI - New clinical decision instruments can and should reduce radiation exposure. AB - In this Perspective linked to Rodriguez and colleagues, Emmanuel Lagarde discusses the importance of decision instruments that can help physicians avoid subjecting patients to radiation exposure from unnecessary CT scans. PMID- 26440668 TI - Inositol Hexakisphosphate Kinase 2 Promotes Cell Death in Cells with Cytoplasmic TDP-43 Aggregation. AB - TAR DNA-binding protein 43 (TDP-43) has been identified as a major component of ubiquitin-positive inclusions in the brains and spinal cords of patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) or amyotrophic lateral sclerosis (ALS). The phosphorylated C-terminal fragment of TDP-43 forms aggregates in the neuronal cytoplasm, possibly resulting in neuronal cell death in patients with FTLD-U or ALS. The inositol pyrophosphate known as diphosphoinositol pentakisphosphate (InsP7) contains highly energetic pyrophosphate bonds. We previously reported that inositol hexakisphosphate kinase type 2 (InsP6K2), which converts inositol hexakisphosphate (InsP6) to InsP7, mediates cell death in mammalian cells. Moreover, InsP6K2 is translocated from the nucleus to the cytosol during apoptosis. In this study, we verified that phosphorylated TDP-43 co-localized and co-bound with InsP6K2 in the cytoplasm of anterior horn cells of the spinal cord. Furthermore, we verified that cell death was augmented in the presence of cytoplasmic TDP-43 aggregations and activated InsP6K2. However, cells with only cytoplasmic TDP-43 aggregation survived because Akt activity increased. In the presence of both TDP-43 aggregation and activated InsP6K2 in the cytoplasm of cells, the expression levels of HSP90 and casein kinase 2 decreased, as the activity of Akt decreased. These conditions may promote cell death. Thus, InsP6K2 could cause neuronal cell death in patients with FTLD-U or ALS. Moreover, InsP6K2 plays an important role in a novel cell death pathway present in FTLD-U and ALS. PMID- 26440670 TI - Sudden onset unexplained encephalopathy in infants: think of cannabis intoxication. AB - The use of cannabis as both a therapeutic agent and recreational drug is common, and its availability is increasing as a result of legalization in many countries. Among older children, the manifestations of cannabis intoxication are numerous and include both neurological and systemic manifestations that are frequently non specific. There have been only a few reports detailing cannabis intoxication in infants and toddlers. We describe three infants who presented to the emergency department with encephalopathic signs without prominent systemic manifestations. During the initial interview of caregivers, no history of exposure to neurotoxic agents was obtained. All three patients were subsequently diagnosed with cannabis intoxication based on urine toxic screens for delta-9-tetrahydrocannabinol (THC). The infants recovered with supportive care that included fluids and monitoring. The non-specific symptomatology of cannabis intoxication in infants together with the wide differential for unexplained acute onset encephalopathy may delay diagnosis and lead to inappropriate procedures and interventions such as antimicrobial treatments and imaging studies. CONCLUSION: Healthcare personnel of emergency rooms, urgent care centers, and general clinics should be aware of the potential risk of cannabis ingestion in young infants. A thorough medical history and toxic screen are warranted in all infants with unexplained decreased sensorium. PMID- 26440671 TI - Carbamoylphosphate synthetase 1 (CPS1) deficiency: clinical, biochemical, and molecular characterization in Malaysian patients. AB - Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a rare autosomal recessive disorder of ureagenesis presenting as life-threatening hyperammonemia. In this study, we present the main clinical features and biochemical and molecular data of six Malaysian patients with CPS1 deficiency. All the patients have neonatal onset symptoms, initially diagnosed as infections before hyperammonemia was recognized. They have typical biochemical findings of hyperglutaminemia, hypocitrullinemia, and low to normal urinary excretion of orotate. One neonate succumbed to the first hyperammonemic decompensation. Five neonatal survivors received long-term treatment consisting of dietary protein restriction and ammonia-scavenging drugs. They have delayed neurocognitive development of varying severity. Genetic analysis revealed eight mutations in CPS1 gene, five of which were not previously reported. Five mutations were missense changes while another three were predicted to create premature stop codons. In silico analyses showed that these new mutations affected different CPS1 enzyme domains and were predicted to interrupt interactions at enzyme active sites, disturb local enzyme conformation, and destabilize assembly of intact enzyme complex. CONCLUSION: All mutations are private except one mutation; p.Ile1254Phe was found in three unrelated families. Identification of a recurrent p.Ile1254Phe mutation suggests the presence of a common and unique mutation in our population. Our study also expands the mutational spectrum of the CPS1 gene. PMID- 26440672 TI - MUOrgano: A Lego(r)-Like Plug & Play System for Modular Multi-Organ-Chips. AB - Human organ-on-a-chip systems for drug screening have evolved as feasible alternatives to animal models, which are unreliable, expensive, and at times erroneous. While chips featuring single organs can be of great use for both pharmaceutical testing and basic organ-level studies, the huge potential of the organ-on-a-chip technology is revealed by connecting multiple organs on one chip to create a single integrated system for sophisticated fundamental biological studies and devising therapies for disease. Furthermore, since most organ-on-a chip systems require special protocols with organ-specific media for the differentiation and maturation of the tissues, multi-organ systems will need to be temporally customizable and flexible in terms of the time point of connection of the individual organ units. We present a customizable Lego(r)-like plug & play system, MUOrgano, which enables initial individual culture of single organ-on-a chip systems and subsequent connection to create integrated multi-organ microphysiological systems. As a proof of concept, the MUOrgano system was used to connect multiple heart chips in series with excellent cell viability and spontaneously physiological beat rates. PMID- 26440673 TI - Nanofibrous microspheres via emulsion gelation and carbonization. AB - Nanofibrous hydrogel microspheres are formed by pH gelation of perylene diimide derivatives in emulsion droplets. These microspheres are freeze-dried and subsequently carbonized to produce discrete N-doped nanofibrous carbon microspheres. The carbon microspheres show high performance as electrode materials for supercapacitors. PMID- 26440674 TI - Hyperisampsins H-M, Cytotoxic Polycyclic Polyprenylated Acylphloroglucinols from Hypericum sampsonii. AB - Six new polycyclic polyprenylated acylphloroglucinols (PPAPs), named hyperisampsins H-M (1-6), were isolated from the aerial parts of Hypericum sampsonii, together with five known analogs (7-11). The structures of 1-6 were established by extensive spectroscopic analyses, including HRESIMS and NMR. In addition, the absolute configurations of these new compounds were determined by electronic circular dichroism (ECD) calculations. Compounds 1 and 2 represent the first examples of PPAPs possessing a unique gamma-lactone ring at C-23, while 3-6 differed from normal PPAPs with an unprecedented 1,2-dioxane ring. Compounds 1-7 were evaluated for their cytotoxic activities against a panel of human cancer cell lines in vitro, of which 3, 4, and 6 exhibited significant cytotoxic activities with IC50 values ranging from 0.56 to 3.00 MUM. Moreover, compound 3 induces leukemia cell apoptotic death, evidenced by activation of caspase-3, degradation of PARP, up-regulation of Bax, and down-regulation of Bcl-2 and Bcl xl. PMID- 26440675 TI - Electronic nose analysis of exhaled breath to diagnose ventilator-associated pneumonia. AB - BACKGROUND: Exhaled breath analysis is an emerging technology in respiratory disease and infection. Electronic nose devices (e-nose) are small and portable with a potential for point of care application. Ventilator-associated pneumonia (VAP) is a common nosocomial infection occurring in the intensive care unit (ICU). The current best diagnostic approach is based on clinical criteria combined with bronchoalveolar lavage (BAL) and subsequent bacterial culture analysis. BAL is invasive, laborious and time consuming. Exhaled breath analysis by e-nose is non-invasive, easy to perform and could reduce diagnostic time. Aim of this study was to explore whether an e-nose can be used as a non-invasive in vivo diagnostic tool for VAP. METHODS: Seventy-two patients met the clinical diagnostic criteria of VAP and underwent BAL. In thirty-three patients BAL analysis confirmed the diagnosis of VAP [BAL+(VAP+)], in thirty-nine patients the diagnosis was rejected [BAL-]. Before BAL was performed, exhaled breath was sampled from the expiratory limb of the ventilator into sterile Tedlar bags and subsequently analysed by an e-nose with metal oxide sensors (DiagNose, C-it, Zutphen, The Netherlands). From further fifty-three patients without clinical suspicion of VAP or signs of respiratory disease exhaled breath was collected to serve as a control group [control(VAP-]). The e-nose data from exhaled breath were analysed using logistic regression. RESULTS: The ROC curve comparing [BAL+(VAP+)] and [control(VAP-)] patients had an area under the curve (AUC) of 0.82 (95% CI 0.73-0.9). The sensitivity was 88% with a specificity of 66%. The comparison of [BAL+(VAP+)] and [BAL-] patients revealed an AUC of 0.69; 95% CI 0.57-0.81) with a sensitivity of 76% with a specificity of 56%. CONCLUSION: E nose lacked sensitivity and specificity in the diagnosis of VAP in the present study for current clinical application. Further investigation into this field is warranted to explore the diagnostic possibilities of this promising new technique. PMID- 26440676 TI - Prevalence and risk factors of COPD among never-smokers in two areas of Sweden - Occupational exposure to gas, dust or fumes is an important risk factor. AB - BACKGROUND: Although active tobacco smoking is the main risk factor for COPD, COPD is not uncommon also among never-smokers. Different study locations along with different spirometric definitions of COPD have historically yielded different prevalence estimates of the disease. AIM: To study current prevalence and risk factors of COPD among never-smokers in two areas of Sweden. METHODS: Data collected in 2008-2012 within the West Sweden Asthma Study and Obstructive Lung Disease in Northern Sweden Studies was pooled. The study population consisted of 1839 subjects who participated in spirometry and interviews. COPD was defined as post-bronchodilator a) FEV(1)/(F)VC < 0.7, b) FEV(1)/FVC < 0.7 and c) FEV(1)/FVC < lower limit of normal. RESULTS: Of the 1839 subjects, 967 (52.6%) were never-smokers. Among the never-smoking subjects, the prevalence of COPD according to definitions a-c was 7.7%, 4.9% and 3.0%, respectively. The corresponding prevalence of GOLD grade >=2 was 2.0%, 1.4% and 1.3%. No significant difference in prevalence between the two study areas was observed. In never-smokers, occupational exposure to gas, dust or fumes (GDF) was significantly associated with both COPD (OR 1.85, 95% CI 1.03-3.33), and GOLD >=2 (OR 4.51, 1.72-11.9) according to definition a), after adjusting for age, educational level and exposure to passive smoking at work. CONCLUSION: Depending on definition, prevalence of COPD among never-smokers was 3.0-7.7%, whereas GOLD >=2 was present in 1.3-2.0%. Occupational exposure to GDF remained independently and significantly associated with COPD regardless of spirometric definition of the disease. PMID- 26440677 TI - Association of FTO and IRX3 genetic variants to obesity risk in north India. AB - BACKGROUND: Obesity is an increasingly important health problem worldwide as well as in developing countries like India. Recent genetic studies suggest that obesity associated FTO and IRX3 are functionally linked and many effects due to genetic variants in FTO gene act through IRX3. AIM: To evaluate the association of FTO and IRX3 genetic variants towards obesity risk. SUBJECTS AND METHODS: North Indian individuals categorised as non-obese (BMI < 30 kg/m(2)) and obese (BMI >= 30 kg/m(2)) were selected. FTO rs8050136, rs1421085, rs9939609, rs17817449 and IRX3 rs3751723 were genotyped by means of validated Taqman(r) allelic discrimination to evaluate their association with obesity by means of single locus logistic regression by SPSS ver. 19 and multi-locus linkage and haplotype analysis by SNPStats and gene-gene interaction with Generalised Multifactor Dimensionality Reduction (GMDR) ver.6. RESULTS: In single locus analysis, FTO rs8050136 CA (p = 0.0001; OR (95% CI) = 2.4 (1.7-3.4) and AA (p = 0.0001; OR (95% CI) = 3.1 (1.9-5.2); FTO rs1421085 TA (p = 0.0001; OR (95% CI) = 2.1 (1.4-3.0) and AA (p = 0.0001; OR (95% CI) = 3.0 (1.8-5.0); FTO rs9939609 TC (p = 0.0001; OR (95% CI) = 2.1 (1.5-3.1) and CC (p = 0.0001; OR (95% CI) = 4.2 (2.5-7.3) along with TG (p = 0.001; OR (95% CI) = 2.1 (1.3-3.2) and GG (p = 0.021; OR (95% CI) = 3.8 (1.2-11.8) genotypes of FTO rs17817449 with GT (p = 0.0001; OR (95% CI) = 2.1 (1.5-3.1) and TT (p = 0.012; OR (95% CI) = 3.3 (1.8 3.6) genotypes of IRX3 rs3751723 were significantly associated with obesity. In multi-locus analysis, SNPs of FTO and IRX3 were in strong linkage disequilibrium and in haplotype and GMDR analysis the SNPs were significantly associated with obesity risk (p < 0.05). CONCLUSION: This is the first study to reveal that genetic variants of both FTO and IRX3 genes are in high linkage disequilibrium (LD) and are associated with obesity risk in North Indians. PMID- 26440678 TI - Analysis of the Interobserver Variability in Penile Length Assessment. AB - INTRODUCTION: Many men seek penile augmentation treatments-a standard tool for their counseling is to inform them of what is "normal." Although some studies suggest good correlation between stretched and erect penile length, those that have measured stretched and erect length simultaneously have shown significant variability. AIM: To assess the accuracy of differing penile measurements with multiple observers. METHODS: We recruited 201 adult men (mean age 49.6 years) who achieved full erection using intracavernosal injection. MAIN OUTCOME MEASURES: Penile measurements were taken by one of seven andrology specialists in a private, temperature-controlled (21 degrees C, 72 degrees F) environment. Stretched flaccid and erect length and circumference were measured. We analyzed the accuracy of each flaccid measurement using the erect measurements as a reference, for the overall patient population and for each observer. RESULTS: The mean underestimate of length from stretched flaccid to erect was 2.64 cm (21.4%) and girth 2.27 cm (19.5%). Interobserver variability ranged from a mean underestimate of 16-27% (length) and 15-27% (girth). CONCLUSIONS: In this large, multicenter, multi-observer study of penis size, flaccid measurements underestimated erect size. It also seems likely that there is significant interobserver variability. We believe erect penis measurements should be used for men being considered for treatment of small penis anxiety. PMID- 26440679 TI - [Diagnosis and treatment of esophagogastric junction cancer]. PMID- 26440680 TI - [Endoscopic diagnosis and treatment for carcinoma of the esophagogastric junction]. PMID- 26440681 TI - [Surgery for esophagogastric junction tumor]. PMID- 26440683 TI - [Not Available]. PMID- 26440682 TI - [Multidisciplinary therapy for esophagogastric junction cancer]. PMID- 26440684 TI - [Adherence to oral 5-aminosalicylic acid by patients with quiescent ulcerative colitis: a questionnaire survey]. AB - For patients with ulcerative colitis, adherence to 5-aminosalicylic acid (5-ASA) is generally expected to ensure better maintenance of remission. Over the past 2 years, we have conducted a questionnaire survey in our hospital of 120 outpatients with quiescent ulcerative colitis to assess their adherence to oral 5 ASA. Of them, 112 patients responded. The overall adherence rate was 57%; however, the adherence rate for 5-ASA taken once a day was 95%, which was significantly higher than that for 5-ASA taken twice or three times a day (50%; P=0.00044). Univariate analysis revealed that the factors associated with high adherence included the following: type of 5-ASA derivative, intake of fewer drugs being at a time, and once-daily intake of 5-ASA. However, once-daily intake of 5 ASA was the only factor found to have a statistically significant effect using multivariate analysis. The adherence rate improved from 23% to 100% when the prescription for 5-ASA was changed from two or three times daily to once daily (P=0.000054). PMID- 26440685 TI - [Rupture of a gastroduodenal artery aneurysm caused by duodenal ulcer: a case report]. AB - A 73-year-old man with a history of tarry stools was admitted to our hospital. Gastroduodenoscopy on admission revealed an ulcer with an exposed vessel at the duodenal bulb. During endoscopic clipping for prevention of re-bleeding, a large amount of bleeding from the vessel was observed. Hemostasis was achieved after the procedure. However, 7 days later, the patient passed a large amount of tarry stools and experienced hypovolemic shock. Endoscopic re-examination revealed a pulsatile aneurysmal vessel at the base of the duodenal ulcer. Abdominal contrast enhanced computed tomography and abdominal angiography demonstrated an aneurysm of the gastroduodenal artery, which was successfully treated with transcatheter arterial embolization. Thus, here we report a rare case of an aneurysm of the gastroduodenal artery caused by a duodenal ulcer. PMID- 26440686 TI - [Endoscopic nasobiliary and nasopancreatic drainage contributing to healing of duodenal ulcer perforation: a case report]. AB - A 75-year-old man with vomiting and right abdominal pain was admitted to the Department of Surgery in our hospital. With a diagnosis of perforated duodenal ulcer, he was treated conservatively. On the day 8 of hospitalization, his general condition worsened and he underwent surgery. During operation, the perforated duodenal ulcer and paraduodenal fluid collection was observed, and percutaneous drainage was accordingly established. After this procedure, renal dysfunction was exacerbated and he was transferred to our department for endoscopic treatment. On day 28 of hospitalization, nasobiliary and nasopancreatic drainage was administered. Renal dysfunction gradually improved, and healing of the perforated duodenal ulcer was recognized on day 93. On day 112, the patient was discharged. PMID- 26440687 TI - [A case of acquired immunodeficiency syndrome with ileocecal ulcer]. AB - We report a case of a patient with acquired immunodeficiency syndrome (AIDS) and ileocecal ulcer. A 31-year-old man was admitted with chief complaints of decreased body weight and abdominal pain. Colonoscopy revealed a round punched out ulcer on the ileocecal valve. Initially, we suspected entero-Behcet's disease and simple ulcer as the cause of the ileocecal ulcer. However, after histologic examination of tissue biopsies obtained during colonoscopy, we diagnosed the patient as having cytomegalovirus (CMV) enteritis. Based on the patient's white blood cell depletion and CMV enteritis, we performed a human immunodeficiency virus (HIV) antibody test. The test was positive, and the diagnosis of AIDS was established. The number of patients with AIDS has been increasing in Japan; thus, we should consider the possibility of CMV enteritis and AIDS in young adult patients affected by ileocecal ulcer with no notable history. PMID- 26440688 TI - [IgA vasculitis associated with anti-TNF-alpha inhibitors in a patient with Crohn's disease]. AB - Anti-TNF-alpha inhibitors have been widely used in the treatment of inflammatory bowel disease. Although they have good clinical efficacy and tolerance, they remain a matter of concern because they cause drug-induced autoimmune disorders as side effects. Here, we report a case of a patient with Crohn's disease who developed IgA vasculitis after infliximab and adalimumab treatment. A 17-year-old male with Crohn's disease who had received scheduled infliximab treatment for the preceding 19 months complained of purpura on his lower limbs. He was diagnosed with infliximab-induced IgA vasculitis. Switching infliximab to adalimumab resulted in rapid improvement of the condition. However, 21 months after switching to adalimumab, his purpura recurred. Drug-induced IgA vasculitis is a rare complication caused by infliximab and adalimumab; however, diagnosis in the early phase and appropriate management of patients receiving anti-TNF-alpha inhibitors is critical to a successful patient outcome. PMID- 26440689 TI - [A case of epidermoid cyst in an intrapancreatic accessory spleen showing cyst-in cyst-like structure mimicking mucinous cystic neoplasm]. AB - In 2010, a 39-year-old woman presented with a cystic lesion, 16 mm in diameter, in the tail of the pancreas. Regular follow-ups were conducted to monitor this lesion; its diameter was found to increase to 45 mm in 2013. Thus, the patient was admitted to our hospital for further examination and treatment. Abdominal US, abdominal contrast-enhanced CT, and MRI showed a cystic lesion of 45 mm in diameter in the tail of the pancreas, which had internal septae and mural nodules inside. EUS revealed a cyst-in-cyst-like structure, with a thickened cystic wall along the entire circumference. Thus, distal pancreatectomy and splenectomy were performed on the basis of a diagnosis of mucinous cystic neoplasm. Histopathological examination of a resected specimen showed that the lesion comprised a substantial component of red-brown tone, with adjacent cystic components. The final diagnosis was an epidermoid cyst in an intrapancreatic accessory spleen. PMID- 26440690 TI - A barrier retractor to reduce surgical site infections and wound disruptions in obese patients undergoing cesarean delivery: a randomized controlled trial. AB - BACKGROUND: Surgical site infections (SSIs) are an important cause of morbidity following cesarean delivery, particularly in obese patients. Methods to reduce SSIs after cesarean delivery would have an important impact in obese obstetric patients. OBJECTIVE: The purpose of this study was to determine whether the Alexis O cesarean delivery retractor, a barrier self-retaining retractor, reduces SSIs and wound disruptions in obese patients undergoing cesarean delivery. STUDY DESIGN: This was a randomized controlled trial of obese women (body mass index >= 30 kg/m(2)) undergoing nonemergent cesarean delivery. Patients were randomized to the treatment group (using the Alexis O cesarean delivery retractor) or to the control group (using conventional handheld retractors). The primary outcome was SSI or wound disruption during the 30 day postoperative period. Secondary outcomes included operative time, estimated blood loss, change in hemoglobin, antiemetic use, length of postoperative hospital stay, hospital readmission, and other postoperative complications. RESULTS: A total of 301 patients were enrolled in the study. One hundred forty-four patients were randomized to the treatment group and 157 to the control group. Baseline characteristics and indications for cesarean delivery were similar between the 2 groups. Median body mass index was 40.1 kg/m(2). There were no significant differences between the treatment and the control group in the primary outcome of SSI or wound disruption rates at the 30 day assessment (20.6% vs 17.6%, P = .62), during the postoperative inpatient hospitalization or at the 1-2 week postoperative visit. There were also no differences in the primary outcome when adjusting for obesity class or thickness of the subcuticular layer. Patients in the treatment group had lower rates of uterine exteriorization (54.3% vs 87.3%, P < .001), but there were no differences in all other outcomes. CONCLUSION: Use of the Alexis retractor in cesarean delivery deliveries did not decrease SSI or wound disruption rates in an obese population. Its use as a retractor should be left to the discretion of the surgeon and clinical circumstances. PMID- 26440692 TI - Long-term neurofunctional outcome, executive functioning, and behavioral adaptive skills following fetal myelomeningocele surgery. AB - BACKGROUND: Myelomeningocele (MMC) represents the first nonlethal anomaly to be treated by prenatal intervention. Case series and a prospective, randomized study show that fetal surgery for MMC before 26 weeks' gestation may preserve neurological function. Long-term follow-up is a fundamental component to evaluate the overall efficacy of any new medical or surgical procedure. To further delineate the long-term impact of fMMC surgery, we continued to follow children treated in our institution before the Management of Myelomeningocele Study trial by the means of parental questionnaires to assess changes in functional, developmental, and cognitive status as these unique patients grow older. OBJECTIVE: The objective of the study was to evaluate the long-term neurological outcome, executive functioning (EF), and behavioral adaptive skills (BAS) following fetal myelomeningocele (fMMC) surgery. STUDY DESIGN: Prior to the Management of Myelomeningocele Study trial, 54 patients underwent fMMC surgery at our institution. Parents of 42 children (78%) participated in structured questionnaires focusing on neurofunctional outcome. EF and BAS were measured by the Behavior Rating Inventory of Executive Function (BRIEF) and the Adaptive Behavioral Assessment System II. The BRIEF is organized into 3 primary indices including the following: Global Executive Composite, Metacognition Index, and Behavioral Regulation Index. The Adaptive Behavioral Assessment System II results in a general adaptive composite score. Based on SD intervals, EF and BAS were categorized as being average, borderline, or impaired. RESULTS: At a median follow-up age of 10 years (range, 8-14 years), 33 (79%) are community ambulators, 3 (9%) are household ambulators, and 6 (14%) are wheelchair dependent. Preschool ambulation was predictive of long-term ambulation (P < .01), whereas the need for tethered cord surgery was associated with persistent deterioration of ambulatory status (P = .007). Normal bladder function was found in 26%. Although the majority scored within the average range for the Behavioral Regulation Index, Metacognition Index, and Global Executive Composite indices, significantly more children who had fMMC surgery had deficits in EF in all 3 BRIEF indices compared with the population norms. The general adaptive composite scores were also more likely to fall below average following fMMC surgery. Normal early neurodevelopmental outcomes were predictive of normal EF and BAS (P < .01). Need for shunting was associated with a significant impairment of BAS (P = .02). CONCLUSION: The present study suggests that fMMC surgery improves long-term functional outcome. The majority of fMMC children can successfully complete everyday tasks at home and at school. Abnormalities of BAS appear to be more common than impairments in EF and therefore offer an area for early screening and interventional therapy for these at-risk children. Non-shunted fMMC children with normal early neurodevelopmental outcome are less likely to experience problems with EF and BAS. fMMC surgery improves long-term ambulatory status. Symptomatic spinal cord tethering with or without intradural inclusion cyst is associated with functional loss. More than expected fMMC children are continent, but bowel and bladder control continue to be an ongoing challenge for the fMMC children. PMID- 26440691 TI - A risk of waiting: the weekly incidence of hypertensive disorders and associated maternal and neonatal morbidity in low-risk term pregnancies. AB - BACKGROUND: Elective induction of labor (eIOL) prior to 39 weeks' gestation is discouraged because of presumed fetal benefits. However, few data exist on the maternal risks of expectant management. To date, no study has evaluated the maternal risk of developing a hypertensive disorder of pregnancy with expectant management of a low-risk gravid at term. OBJECTIVE: We sought to evaluate the development of hypertensive disorders in term low-risk expectantly managed patients. STUDY DESIGN: This is a retrospective cross-sectional study from 19 US hospitals, from 2002 to 2008 (Safe Labor Consortium) including all nonanomalous, cephalic, singleton pregnancies at 37-41 weeks. Women with a history of hypertension, diabetes mellitus, cardiovascular disease, or planned cesarean delivery or from centers with incomplete hypertensive data were excluded. Women with eIOL in each week were compared with women managed expectantly until the next week of gestation or beyond. The primary outcome was the frequency of hypertensive complications. RESULTS: Of 114,651 low-risk deliveries, 12,772 (11.1%) had eIOL. The cohort was 49.2% nulliparous, 51.1% white, and obese (mean body mass index 30.2 kg/m(2)). The risk of developing any hypertension in expectantly managed women was 4.1% after 37 weeks, 3.5% after 38 weeks, 3.2% after 39 weeks, and 2.6% after 40 weeks. Compared with eIOL, women with hypertensive disorders had significantly higher rates of cesarean delivery and maternal morbidities (intensive care unit admission or death, third- or fourth degree lacerations, maternal infections, and bleeding complications) at each week of gestation and the composite neonatal morbidity at 38 and 39 weeks of gestation. CONCLUSION: For women at low risk expectantly managed at term, there is a risk of developing hypertensive complications for each additional week of pregnancy, with associated increases in maternal and neonatal morbidities. PMID- 26440693 TI - Genome-wide linkage and exome sequencing analyses identify an initiation codon mutation of KRT5 in a unique Chinese family with generalized Dowling-Degos disease. PMID- 26440694 TI - Nitrene Insertion into C-C and C-H Bonds of Diamide Diimine Ligands Ligated to Chromium and Iron. AB - The impact of redox non-innocence (RNI) on chemical reactivity is a forefront theme in coordination chemistry. A diamide diimine ligand, [{-CH=N(1,2 C6H4)NH(2,6-iPr2C6H3)}2](n) (n = 0 to -4), (dadi)(n), chelates Cr and Fe to give [(dadi)M] ([1Cr(thf)] and [1Fe]). Calculations show [1Cr(thf)] (and [1Cr]) to have a d(4) Cr configuration antiferromagnetically coupled to (dadi)(2-)*, and [1Fe] to be S = 2. Treatment with RN3 provides products where RN is formally inserted into the C-C bond of the diimine or into a C-H bond of the diimine. Calculations on the process support a mechanism in which a transient imide (imidyl) aziridinates the diimine, which subsequently ring opens. PMID- 26440695 TI - Proximal humerus fragility fractures: recent trends in nonoperative and operative treatment in the Medicare population. AB - BACKGROUND: With an aging population, fragility fractures including injuries to the proximal humerus continue to rise in the United States. The purpose of this study was to investigate recent trends in the incidence and treatment of proximal humerus fractures (PHFs) in a cross-sectional elderly population. METHODS: Medicare data from 2005 to 2012 were queried to identify patients treated for PHF. Associated patient demographics, hospitalization data, treatment, and revision status were obtained. Statistical analyses were performed to identify significant trends in treatment. RESULTS: There were 259,506 PHFs recorded, with 79% occurring in female patients. In all age groups, nonoperative treatment of PHF was the most common method (67%). Within the surgical group, open reduction with internal fixation was most frequently used, and total shoulder arthroplasty (TSA) or reverse total shoulder arthroplasty (RTSA) was the least common (11%). However, although the overall rate of surgical intervention remained constant, there was a significant increase in treatment with TSA from 3% in 2005 to 17% in 2012. In particular, RTSA represented 89% of all TSAs for PHF in 2011. All surgical treatment options demonstrated high 2-year survival rates without revision surgery (97%). CONCLUSION: Recent trends show that in the elderly population, nonoperative management remains the most common treatment for PHFs. Within the surgically treated cohort, there has been an increase in treatment with arthroplasty including RTSA, with a low rate of early revisions. There are excellent survival rates in all surgically treated PHFs, but long-term data will be required to fully evaluate the viability of these surgical options. PMID- 26440696 TI - Computer algorithms for three-dimensional measurement of humeral anatomy: analysis of 140 paired humeri. AB - BACKGROUND: In the presence of severe osteoarthritis, osteonecrosis, or proximal humeral fracture, the contralateral humerus may serve as a template for the 3 dimensional (3D) preoperative planning of reconstructive surgery. The purpose of this study was to develop algorithms for performing 3D measurements of the humeral anatomy and further to assess side-to-side (bilateral) differences in humeral head retrotorsion, humeral head inclination, humeral length, and humeral head radius and height. METHODS: The 3D models of 140 paired humeri (70 cadavers) were extracted from computed tomographic data. Geometric characteristics quantifying the humeral anatomy in 3D were determined in a semiautomatic fashion using the developed computer algorithms. The results between the sides were compared for evaluating bilateral differences. RESULTS: The mean bilateral difference of the humeral retrotorsion angle was 6.7 degrees (standard deviation [SD], 5.7 degrees ; range, -15.1 degrees to 24.0 degrees ; P = .063); the mean side difference of the humeral head inclination angle was 2.3 degrees (SD, 1.8 degrees ; range, -5.1 degrees to 8.4 degrees ; P = .12). The side difference in humeral length (mean, 2.9 mm; SD, 2.5 mm; range, -8.7 mm to 10.1 mm; P = .04) was significant. The mean side difference in the head sphere radius was 0.5 mm (SD, 0.6 mm; range, -3.2 mm to 2.2 mm; P = .76), and the mean side difference in humeral head height was 0.8 mm (SD, 0.6 mm; range, -2.4 mm to 2.4 mm; P = .44). CONCLUSIONS: The contralateral anatomy may serve as a reliable reconstruction template for humeral length, humeral head radius, and humeral head height if it is analyzed with 3D algorithms. In contrast, determining humeral head retrotorsion and humeral head inclination from the contralateral anatomy may be more prone to error. PMID- 26440697 TI - Application of neural network method to detect type of uranium contamination by estimation of activity ratio in environmental alpha spectra. AB - The discrimination of the composition of environmental and non-environmental materials by the estimation of the (234)U/(238)U activity ratio in alpha-particle spectrometry is important in many applications. If the interfering elements are not completely separated from the uranium, they can interfere with the determination of (234)U. Thickness as a result of the existence of iron in the source preparation phase and their alpha lines can broaden the alpha line of (234)U in alpha spectra. Therefore, the asymmetric broadening of the alpha line of (234)U and overlapping of peaks make the analysis of the alpha particle spectra and the interpretation of the results difficult. Applying Artificial Neural Network (ANN) to a spectrometry system is a good idea because it eliminates limitations of classical approaches by extracting the desired information from the input data. In this work, the average of a partial uranium raw spectrum, were considered. Each point that its slope was of the order of 0-1% per 10 channels, was used as input to the multi-layer feed forward error-back propagation network. The network was trained by an alpha spectrum library which has been developed in the present work. The training data in this study was actual spectral data with any reasonable thickness and interfering elements. According to the results, the method applied to estimate the activity ratio in this work, can examine the alpha spectrum for peaks which would not be expected for a source of given element and provide the clues about composition of uranium contamination in the environmental samples in a fast screening and classifying procedures. PMID- 26440698 TI - Radioiodine in the atmosphere after the Fukushima Dai-ichi nuclear accident. AB - About 160 PBq of (131)I was released into the atmosphere during the accident at the Fukushima Dai-ichi Nuclear Power Plant. The chemistry of radioiodine is complicated, and it can be released in several different forms. In addition, the different physical forms, like molecular iodine, aerosol-form iodine, or organic iodine, would have all behaved differently once in the atmosphere, and would have been removed at different rates. These releases were detected by monitoring stations throughout Japan, and from these measurements, key insights can be made about the different chemical forms that were released, as well as the persistence of each in the environment. PMID- 26440699 TI - Spatial trends on an ungrazed West Cumbrian saltmarsh of surface contamination by selected radionuclides over a 25 year period. AB - Long term spatial and temporal variations in radionuclide activity have been measured in a contaminated ungrazed saltmarsh near Ravenglass, Cumbria. Over a twenty-five year period there has been a decrease in activity concentration with (106)Ru and (137)Cs showing the highest rate of change followed by Pu alpha and (241)Am. A number of factors contribute to the reduction with time; including radiological half lives, discharge and remobilisation. For (241)Am the lower reduction rate is partially due to ingrowth from (241)Pu and partially as a result of transport of sediment from the offshore Irish Sea mud patch. Considerable spatial variation for the different radionuclides was observed, which with time became less defined. The highest activity concentrations of long lived radionuclides were in low energy areas, typically where higher rates of sedimentation and vegetation occurred. The trend was reversed for the shorter lived radionuclide, (106)Ru, with higher activity concentrations observed in high energy areas where there was frequent tidal inundation. Surface scrape samples provide a pragmatic, practical method of measuring sediment contamination over large areas and is a sampling approach adopted by most routine environmental monitoring programs, but it does not allow for interpretation of the effect of variation in sedimentation rates. This paper proposes a method for calculating indicative sedimentation rates across the saltmarsh using surface scrape data, which produces results consistent with values experimentally obtained. PMID- 26440700 TI - Topologically robust sound propagation in an angular-momentum-biased graphene like resonator lattice. AB - Topological insulators do not allow conduction in the bulk, yet they support edge modes that travel along the boundary only in one direction, determined by the carried electron spin, with inherent robustness to defects and disorder. Topological insulators have inspired analogues in photonics and optics, in which one-way edge propagation in topologically protected two-dimensional materials is achieved breaking time-reversal symmetry with a magnetic bias. Here, we introduce the concept of topological order in classical acoustics, realizing robust topological protection and one-way edge propagation of sound in a suitably designed resonator lattice biased with angular momentum, forming the acoustic analogue of a magnetically biased graphene layer. Extending the concept of an acoustic nonreciprocal circulator based on angular-momentum bias, time-reversal symmetry is broken here using moderate rotational motion of air within each element of the lattice, which takes the role of the electron spin in determining the direction of modal edge propagation. PMID- 26440701 TI - Beyond Genomics: Multidimensional Analysis of Cancer Therapy Resistance. AB - Cancer resistance to therapy occurs through a selection process generally thought to be driven by mutations. In a recent study, Hugo et al. use multidimensional analysis of the dynamic genetic, transcriptional, epigenetic, and immune landscape alterations in baseline and MAPK inhibitor-resistant melanoma tumors, demonstrating a role for 'non-genomic' drivers in cancer evolution. PMID- 26440702 TI - Efficient Gene Editing in Primary Human T Cells. AB - Recent advances in T-cell therapy for cancer, viral infections, and autoimmune diseases highlight the broad therapeutic potential of T-cell engineering. However, site-specific genetic manipulation in primary human T cells remains challenging. Two recent studies describe efficient genome editing in T cells using CRISPR and TALEN approaches. PMID- 26440703 TI - Gestational diabetes mellitus in women with multiple pregnancies: is the metabolic abnormality milder? AB - OBJECTIVE: We aimed to compare maternal characteristics and dysglycemia after delivery in women with gestational diabetes mellitus (GDM) according to pregnancy being multiple (MP) or singleton (SP). The hypothesis was that women with GDM and MP would have a milder glycemic abnormality before and after pregnancy than those with SP. METHODS: We performed a cohort study of 2908 women giving birth between 1986 and 2009. Logistic regression was performed to discriminate between MP and SP after anamnestic pre-pregnancy characteristics. Kaplan-Meier and Cox regression analyses were performed to assess if MP was independently associated with both impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) and diabetes after delivery. RESULTS: Family history of diabetes was the only independent anamnestic pre-pregnancy characteristic discriminating MP versus SP, OR 2.04 (95% CI 1.12, 3.70, p 0.019). The median time to progress to IFG/IGT was 7.52 years in SP (95% CI 6.92, 8.13) and 7.41 in MP (95% CI 3.84, 10.98), ns and the progression to DM did not differ. In addition, MP was not associated to IFG/IGT or to DM in the Cox regression analysis. CONCLUSIONS: In this cohort of women with GDM, those with MP did not demonstrate a lesser degree of dysglycemia after controlling for other pregnancy characteristics and pregnancy-independent factors. PMID- 26440704 TI - Comprehending and Rehabilitating Roman Catholic Clergy Offenders of Child Sexual Abuse. AB - Many have studied Roman Catholic clergy who have sexually abused children, but the range of investigations remains disconnected. This article brings together various disciplinary perspectives to form a comprehensive view. A review of the literature is first undertaken to comprehend how clergy offenders have been conceptualized in psychosocial, sociocultural, and moral-religious studies. These perspectives are then used as a foundation for examining how these clergy can be rehabilitated. Three rehabilitative modalities--psychological treatment, rehabilitation through restorative justice, and ritual healing--are explored. The article concludes with a discussion of the insights gained from the literature review and how the modalities can be advanced in an interdependent and considered approach. PMID- 26440705 TI - Gyroscopic sensing in the wings of the hawkmoth Manduca sexta: the role of sensor location and directional sensitivity. AB - The wings of the hawkmoth Manduca sexta are lined with mechanoreceptors called campaniform sensilla that encode wing deformations. During flight, the wings deform in response to a variety of stimuli, including inertial-elastic loads due to the wing flapping motion, aerodynamic loads, and exogenous inertial loads transmitted by disturbances. Because the wings are actuated, flexible structures, the strain-sensitive campaniform sensilla are capable of detecting inertial rotations and accelerations, allowing the wings to serve not only as a primary actuator, but also as a gyroscopic sensor for flight control. We study the gyroscopic sensing of the hawkmoth wings from a control theoretic perspective. Through the development of a low-order model of flexible wing flapping dynamics, and the use of nonlinear observability analysis, we show that the rotational acceleration inherent in wing flapping enables the wings to serve as gyroscopic sensors. We compute a measure of sensor fitness as a function of sensor location and directional sensitivity by using the simulation-based empirical observability Gramian. Our results indicate that gyroscopic information is encoded primarily through shear strain due to wing twisting, where inertial rotations cause detectable changes in pronation and supination timing and magnitude. We solve an observability-based optimal sensor placement problem to find the optimal configuration of strain sensor locations and directional sensitivities for detecting inertial rotations. The optimal sensor configuration shows parallels to the campaniform sensilla found on hawkmoth wings, with clusters of sensors near the wing root and wing tip. The optimal spatial distribution of strain directional sensitivity provides a hypothesis for how heterogeneity of campaniform sensilla may be distributed. PMID- 26440706 TI - p53-based strategy to reduce hematological toxicity of chemotherapy: A proof of principle study. AB - p53 activation is a primary mechanism underlying pathological responses to DNA damaging agents such as chemotherapy and radiotherapy. Our recent animal studies showed that low dose arsenic (LDA)-induced transient p53 inhibition selectively protected normal tissues from chemotherapy-induced toxicity. Study objectives were to: 1) define the lowest safe dose of arsenic trioxide that transiently blocks p53 activation in patients and 2) assess the potential of LDA to decrease hematological toxicity from chemotherapy. Patients scheduled to receive minimum 4 cycles of myelosuppressive chemotherapy were eligible. For objective 1, dose escalation of LDA started at 0.005 mg/kg/day for 3 days. This dose satisfied objective 1 and was administered before chemotherapy cycles 2, 4, and 6 for objective 2. p53 level in peripheral lymphocytes was measured on day 1 of each cycle by ELISA assay. Chemotherapy cycles 1, 3, and 5 served as the baseline for the subsequent cycles of 2, 4, and 6 respectively. If p53 level for the subsequent cycle was lower (or higher) than the baseline cycle, p53 was defined as "suppressed" (or "activated") for the pair of cycles. Repeated measures linear models of CBC in terms of day, cycle, p53 activity and interaction terms were used. Twenty-six patients treated with 3 week cycle regimens form the base of analyses. The mean white blood cell, hemoglobin and absolute neutrophil counts were significantly higher in the "suppressed" relative to the "activated" group. These data support the proof of principle that suppression of p53 could lead to protection of bone marrow in patients receiving chemotherapy. This trial is registered in ClinicalTrials.gov. Identifier: NCT01428128. PMID- 26440712 TI - Synthesis and characterization of barium silicide (BaSi2) nanowire arrays for potential solar applications. AB - In order to utilize nanostructured materials for potential solar and other energy harvesting applications, scalable synthetic techniques for these materials must be developed. Herein we use a vapor phase conversion approach to synthesize nanowire (NW) arrays of semiconducting barium silicide (BaSi2) in high yield for the first time for potential solar applications. Dense arrays of silicon NWs obtained by metal-assisted chemical etching were converted to single-crystalline BaSi2 NW arrays by reacting with Ba vapor at about 930 degrees C. Structural characterization by X-ray diffraction and high-resolution transmission electron microscopy confirm that the converted NWs are single-crystalline BaSi2. The optimal conversion reaction conditions allow the phase-pure synthesis of BaSi2 NWs that maintain the original NW morphology, and tuning the reaction parameters led to a controllable synthesis of BaSi2 films on silicon substrates. The optical bandgap and electrochemical measurements of these BaSi2 NWs reveal a bandgap and carrier concentrations comparable to previously reported values for BaSi2 thin films. PMID- 26440707 TI - Sensitivity of plasma BRAFmutant and NRASmutant cell-free DNA assays to detect metastatic melanoma in patients with low RECIST scores and non-RECIST disease progression. AB - Melanoma lacks a clinically useful blood-based biomarker of disease activity to help guide patient management. To determine whether measurements of circulating, cell-free, tumor-associated BRAF(mutant) and NRAS(mutant) DNA (ctDNA) have a higher sensitivity than LDH to detect metastatic disease prior to treatment initiation and upon disease progression we studied patients with unresectable stage IIIC/IV metastatic melanoma receiving treatment with BRAF inhibitor therapy or immune checkpoint blockade and at least 3 plasma samples obtained during their treatment course. Levels of BRAF(mutant) and NRAS(mutant) ctDNA were determined using droplet digital PCR (ddPCR) assays. Among patients with samples available prior to treatment initiation ctDNA and LDH levels were elevated in 12/15 (80%) and 6/20 (30%) (p = 0.006) patients respectively. In patients with RECIST scores <5 cm prior to treatment initiation, ctDNA levels were elevated in 5/7 (71%) patients compared to LDH which was elevated in 1/13 (8%) patients (p = 0.007). Among all disease progression events the modified bootstrapped sensitivities for ctDNA and LDH were 82% and 40% respectively, with a median difference in sensitivity of 42% (95% confidence interval, 27%-58%; P < 0.001). In addition, ctDNA levels were elevated in 13/16 (81%) instances of non-RECIST disease progression, including 10/12 (83%) instances of new brain metastases. In comparison LDH was elevated 8/16 (50%) instances of non-RECIST disease progression, including 6/12 (50%) instances of new brain metastases. Overall, ctDNA had a higher sensitivity than LDH to detect disease progression, including non-RECIST progression events. ctDNA has the potential to be a useful biomarker for monitoring melanoma disease activity. PMID- 26440713 TI - Common type 2 diabetes risk variant in MTNR1B worsens the deleterious effect of melatonin on glucose tolerance in humans. AB - AIMS: The common MTNR1B genetic variant rs10830963 is associated with an increased risk of type 2 diabetes (T2D). To date, no experimental study has tested the effect of the MTNR1B variant on glucose metabolism in humans during exposure of the melatonin receptors to their ligand. The aim of this study was to investigate whether this MTNR1B variant influenced the effect of melatonin (5mg) on glucose tolerance assessed by an oral glucose tolerance test (OGTT; 75 g) at different times of the day (morning and evening) as compared to a placebo. METHODS: Seventeen normoglycemic women (24 +/- 6 years; BMI 23.0 +/- 3.3 kg/m(2)) completed the study (11 carriers of the risk allele [CG] and 6 noncarriers [CC]). RESULTS: The effect of melatonin on glucose tolerance depended on the genotype. In the morning, the effect of melatonin (melatonin-placebo) on the glucose area under the curve (AUC) above baseline differed significantly (P=0.036) between the carriers and noncarriers. This effect of melatonin in the carriers was six times as large as that in the noncarriers. The MTNR1B SNP explained over one-quarter (26%) of the inter-individual differences in the effect of melatonin on glucose AUC. However, in the evening, the effect of melatonin on glucose AUC of the carriers and noncarriers did not differ significantly (P>0.05). CONCLUSIONS: MTNR1B rs10830963 risk variant worsens the effect of melatonin on glucose tolerance, suggesting the importance of genotyping and personalized recommendations, especially in people consuming food when melatonin levels are elevated. Large-scale studies in vulnerable populations are necessary to translate these results into real-world, clinically relevant recommendations. PMID- 26440715 TI - Involvement of sinoaortic afferents in renal sympathoinhibition and vasodilation induced by acute hypernatremia. AB - Despite the abundance of evidence that supports the important role of aortic and carotid afferents to short-term regulation of blood pressure and detection of variation in the arterial PO2 , PCO2 and pH, relatively little is known regarding the role of these afferents during changes in the volume and composition of extracellular compartments. The present study sought to determine the involvement of these afferents in the renal vasodilation and sympathoinhibition induced by hypertonic saline (HS) infusion. Sinoaortic-denervated and sham male Wistar rats were anaesthetised with intravenous (i.v.) urethane (1.2 g/kg body weight (bw)) prior to the measurement of the mean arterial pressure (MAP), renal vascular conductance (RVC) and renal sympathetic nerve activity (RSNA). In the sham group, the HS infusion (3 mol/L NaCl, 1.8 mL/kg bw, i.v.) induced transient hypertension (12 +/- 4 mmHg from baseline, peak at 10 min; P < 0.05), an increase in RVC (127 +/- 9% and 150 +/- 13% from baseline, at 20 and 60 min respectively; P < 0.05) and a decrease in RSNA (-34 +/- 10% and -29 +/- 5% from baseline, at 10 and 60 min respectively; P < 0.05). In sinoaortic-denervated rats, HS infusion promoted a sustained pressor response (30 +/- 5 and 17 +/- 6 mmHg of baseline values, at 10 and 30 min respectively; P < 0.05) and abolished the increase in RVC (85 +/- 8% from baseline, at 10 min) and decrease in RSNA (-4 +/- 3% from baseline, at 10 min). These results suggest that aortic and carotid afferents are involved in cardiovascular and renal sympathoinhibition responses induced by acute hypernatremia. PMID- 26440716 TI - Fifty years on. PMID- 26440714 TI - Synthesis, cholinesterase inhibition and molecular modelling studies of coumarin linked thiourea derivatives. AB - Alzheimer's disease is among the most widespread neurodegenerative disorder. Cholinesterases (ChEs) play an indispensable role in the control of cholinergic transmission and thus the acetylcholine level in the brain is enhanced by inhibition of ChEs. Coumarin linked thiourea derivatives were designed, synthesized and evaluated biologically in order to determine their inhibitory activity against acetylcholinesterases (AChE) and butyrylcholinesterases (BChE). The synthesized derivatives of coumarin linked thiourea compounds showed potential inhibitory activity against AChE and BChE. Among all the synthesized compounds, 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(3-chlorophenyl)thiourea (2e) was the most potent inhibitor against AChE with an IC50 value of 0.04+/-0.01MUM, while 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(2-methoxyphenyl)thiourea (2b) showed the most potent inhibitory activity with an IC50 value of 0.06+/-0.02MUM against BChE. Molecular docking simulations were performed using the homology models of both cholinesterases in order to explore the probable binding modes of inhibitors. Results showed that the novel synthesized coumarin linked thiourea derivatives are potential candidates to develop for potent and efficacious acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. PMID- 26440717 TI - Technologies and religions. PMID- 26440719 TI - DNA nanotechnology: Nanoscale cable tacking. PMID- 26440720 TI - Matter-wave interference: Nanomechanical answer to Einstein. PMID- 26440722 TI - No such thing as a bad result. PMID- 26440723 TI - Structure and Dynamics of Solvation Shells of Copper(II) Complexes with N,O Containing Ligands. AB - EPR, NMR relaxation methods, and DFT calculations were jointly used to investigate the structural and dynamical characteristics of solvation shells of copper(II) complexes with iminodiacetic acid, glycylglycine, and glycyglycylglycine in comparison with the copper(II) bis-glycinate studied previously. A strong trans influence of deprotonated peptide nitrogen was revealed in EPR spectra parameters of copper(II) complexes with oligopeptides. With models of the experimental NMRD data and literature X-ray structural information, it was suggested that only one water molecule coordinates in axial position of copper(II) complexes with glycine and di- and triglycine (Cu(Gly)2, Cu(GGH(-1)), and Cu(GGGH(-2))(-)), and the copper ion in these complexes is pentacoordinated, while in the iminodiacetate complex, Cu(IDA), both apical positions can be occupied by solute molecules. The obtained structural results were confirmed by DFT calculations of structures of studied compounds using different functionals and basis sets. It was shown that the donor ability of equatorial ligands and trans influence have an effect on the characteristics of the axial water bond. With increasing donor strength of equatorial ligands, pentacoordination of copper(II) complexes in water solutions becomes more preferable. PMID- 26440724 TI - Fracture of the Manubrium of the Malleus. PMID- 26440721 TI - Bridging the divide between human and environmental nanotoxicology. AB - The need to assess the human and environmental risks of nanoscale materials has prompted the development of new metrological tools for their detection, quantification and characterization. Some of these methods have tremendous potential for use in various scenarios of nanotoxicology. However, in some cases, the limited dialogue between environmental scientists and human toxicologists has hampered the full exploitation of these resources. Here we review recent progress in the development of methods for nanomaterial analysis and discuss the use of these methods in environmental and human toxicology. We highlight the opportunities for collaboration between these two research areas. PMID- 26440725 TI - Bilateral Vestibulopathy Documented by Video Head Impulse Tests in Superficial Siderosis. AB - OBJECTIVE: Superficial siderosis (SS) of the CNS is associated with cerebellar ataxia, sensorineural hearing loss, and pyramidal symptoms, which result from iron depositions on CNS surfaces. SS can produce bilateral vestibulopathy as the vestibulo-cochlear nerve is particularly vulnerable. To our knowledge, however, vestibular dysfunction in SS has not been reported thoroughly in the literature. Here, we describe a case of bilateral vestibulopathy, documented quantitatively by the video head impulse test (vHIT), in a patient with SS. PATIENT: A 60-year old man presented with slowly progressing bilateral hearing loss, oscillopsia, and a severe gait disturbance that worsened in the dark. INTERVENTION: After noticing deficits in the bedside head impulse test in all six semicircular canals, the patient underwent vHIT and brain MRI. MAIN OUTCOME MEASURE: MRI demonstrated a rim of hypointensities and signal losses in T2-weighted and gradient echo images around the cerebellum, brainstem, and vestibulo-cochlear nerve, which were compatible with an SS diagnosis. In addition, vHIT revealed reduced vestibule-ocular reflex (VOR) gains, and abnormal catch-up saccades (both covert and overt saccades) in all semicircular canals. RESULTS: The vHIT showed impaired VOR gains that were 0.55, 0.59, and 0.45 in the horizontal, anterior, and posterior canals, respectively. CONCLUSION: SS may result in chronic bilateral vestibulopathy with SNHL. Bilateral vestibulopathy originated peripherally in our participant, without cerebellar dysfunctions such as those reported in the literature. vHIT findings have not been previously reported in patients with SS, and our study suggests that vHIT is a useful tool to document vestibular dysfunction. PMID- 26440726 TI - Successful Hearing Preservation After Reimplantation of a Failed Hybrid Cochlear Implant. AB - Objective: The purpose of this case study was to demonstrate hearing preservation of a subject who was implanted with a 10-mm short electrode cochlear implant that was determined to be malfunctioning at 6 months postimplantation and was explanted and reimplanted with a 16-mm short electrode device.Study Design: Single-subject case study.Setting: Research hospital.Patient: A 60-year old female with a history of gradual progressive bilateral steeply sloping sensorineural hearing loss.Intervention: Rehabilitative.Main Outcome Measure(s): Audiometric data and speech perception in quiet and in noise were collected pre- and postoperatively at 3 and 6 months with the 10-mm short electrode device and pre-explantation and postoperatively at 3, 6, and 12 months with the 16-mm short electrode device.Results: Functional hearing preservation was accomplished following surgical implantation of both short electrode devices. Overall, the subject had a 22 dB HL total shift in pure-tone-average (0.125-1 kHz) after two cochlear implant surgeries. Speech perception growth was limited over the 6 months the subject was implanted with the 10-mm short electrode device. After 3 months of experience with the 16-mm short electrode device, the subject experienced significant improvements in both speech perception in quiet and in noise.Conclusions: The inner ear might be more robust than once thought, as was determined through preservation of residual hearing after implantation of two hearing preservation cochlear implants and one device explantation. Furthermore, it is important that hearing professionals remain cognizant of unusual speech perception patterns associated with the cochlear implant. Key Words: Hearing preservation-Residual hearing-Short electode. [Corrected] PMID- 26440727 TI - 5-N-Arylaminothiazoles as Highly Twisted Fluorescent Monocyclic Heterocycles: Synthesis and Characterization. AB - A series of 5-N-arylaminothiazoles was prepared by reacting thioamide dianions derived from secondary thioamides with thioformamides, followed by sequential oxidation with iodine. X-ray analyses demonstrated that they adopt structures that are highly twisted from planar conformations. Their orientations were tuned by the steric and/or electronic interactions of the substituents at their 2-, 4-, and 5-positions. The 5-aminothiazoles exhibited a range of fluorescent emissions, from blue to orange. Although the absorption spectra were independent of the polarity of the solvent, fluorescent emissions were influenced by the polarity of the solvent: in more polar solvents, the emissions were red-shifted. These phenomena were examined in terms of Lippert-Mataga plots and the change in the dipole moment between the ground and excited states. They also exhibited emissions in the solid state, again from blue to orange. Cyclic voltammetry of the 5-aminothiazoles showed reversible waves of one-electron oxidation. The half potential of the oxidation was reduced by the introduction of electron-donating groups to the phenyl groups on the nitrogen atom at the 5-position. DFT calculations were carried out to determine the energy levels of the HOMO and LUMO. Finally, the results of TG-DTA showed that they are thermally stable. PMID- 26440728 TI - Validation of an early childhood caries risk assessment tool in a low-income Hispanic population. AB - OBJECTIVES: There is a recognized need for valid risk assessment tools for use by both dental and nondental personnel to identify young children at risk for, or with, precavitated stages of early childhood caries (i.e., early stage decalcifications or white spot lesions).The aim of this study is to establish concurrent criterion validity of "MySmileBuddy" (MSB), a novel technology assisted ECC risk assessment and behavioral intervention tool against four measures of ECC activity: semi-quantitative assays of salivary mutans streptococci levels, visible quantity of dental plaque, visual evidence of enamel decalcifications, and cavitation status (none, ECC, severe ECC). METHODS: One hundred eight children 2-6 years of age presenting to a pediatric dental clinic were recruited from a predominantly Spanish-speaking, low-income, urban population. All children received a comprehensive oral examination and saliva culture for assessment of ECC indicators. Their caregivers completed the iPad based MSB assessment in its entirety (15-20 minutes). MSB calculated both diet and comprehensive ECC risk scores. Associations between all variables were determined using ordinal logistic regression. RESULTS: MSB diet risk scores were significantly positively associated with salivary mutans (P < 0.05), and approached significance with visible plaque levels (P < 0.1). MSB comprehensive risk scores were significantly associated with both oral mutans and visible plaque (P < 0.05). Neither was associated with visually evident decalcifications or cavitations. CONCLUSIONS: Findings suggest that MSB may have clinical utility as a valid risk assessment tool for identifying children with early precursors of cavitations but does not add value in identifying children with extant lesions. PMID- 26440729 TI - Antimicrobial susceptibility, virulence gene profiles and molecular subtypes of Salmonella Newport isolated from humans and other sources. AB - Salmonella Newport (S. Newport) is a major serotype associated with human salmonellosis. A total of 79 S. Newport recovered from humans and other sources in China were characterized for antimicrobial susceptibility, virulence gene profiles and molecular subtypes using pulsed field gel electrophoresis (PFGE). Approximately 63.3% of the isolates were susceptible to all of 16 antimicrobials tested. Nearly one third of the isolates (31.6%) were resistant to sulfisoxazole, 20.3% to tetracycline and 13.9% to nalidixic acid. Twelve isolates (15.2%) were resistant to three or more antimicrobials. Among 10 virulence genes detected, Salmonella pathogenicity island genes avrA, ssaQ, mgtC, siiD, and sopB and fimbrial gene bcfC were present in most of the isolates (93.7% to 100%). Overall, we observed nine distinct virulence gene profiles, three of which (VP1, VP2 and VP3) were most common (86.1%). A total of 56 PFGE patterns were identified and mainly grouped into seven clusters (A to G) with 80% pattern similarity. Isolates from aquatic product shared a high similarity with those from humans in several clusters, highlighting a potential risk of aquatic product as a source of S. Newport that infect humans. Furthermore, there was a strong association between certain PFGE clusters and virulence gene profiles, suggesting virulence subtyping can be a useful epidemiological tool to discriminate S. Newport isolates. PMID- 26440730 TI - Analysis of the effects of depression associated polymorphisms on the activity of the BICC1 promoter in amygdala neurones. AB - The Bicaudal C Homolog 1 (BICC1) gene, which encodes an RNA binding protein, has been identified by genome wide association studies (GWAS) as a candidate gene associated with major depressive disorder (MDD). We explored the hypothesis that MDD associated single-nucleotide polymorphisms (SNPs) affected the ability of cis regulatory elements within intron 3 of the BICC1 gene to modulate the activity of the BICC1 promoter region. We initially established that the BICC1 promoter drove BICC1 mRNA expression in amygdala, hippocampus and hypothalamus. Intriguingly, we provide evidence that MDD associated polymorphisms alter the ability of the BICC1 promoter to respond to PKA signalling within amygdala neurones. Considering the known role of amygdala PKA pathways in fear learning and mood these observations suggest a possible mechanism through which allelic changes in the regulation of the BICC1 gene in amygdala neurones may contribute to mood disorders. Our findings also suggest a novel direction for the identification of novel drug targets and the design of future personalised therapeutics.The Pharmacogenomics Journal advance online publication, 6 October 2015; doi:10.1038/tpj.2015.62. PMID- 26440731 TI - Clinical pharmacology of tenofovir clearance: a pharmacokinetic/pharmacogenetic study on plasma and urines. AB - The HIV virus and hepatitis B virus nucleotide reverse transcriptase inhibitor tenofovir has been associated with proximal tubular toxicity; the latter was found to be predicted by plasma concentrations and with single-nucleotide polymorphisms in transporters-encoding genes. A cross-sectional analysis in adult HIV-positive patients with estimated creatinine clearance >60 ml min-1 was performed. Twelve-hour plasma and urinary tenofovir concentrations and single nucleotide polymorphisms in several transporter-encoding genes were analysed. In 289 patients 12-h tenofovir plasma, urinary and urinary to plasma ratios were 69 ng ml-1 (interquartile range 51.5-95), 24.3 mg ml-1 (14.3-37.7) and 384 (209 560). At multivariate analysis estimated creatinine clearance, protease inhibitors co-administration and SLC28A2 CT/TT genotypes were independently associated with plasma tenofovir exposure; ABCC10 GA/AA genotypes and protease inhibitor co-administration were independently associated with the urinary to plasma tenofovir ratio. Tenofovir clearance was associated with genetic polymorphisms in host genes and with co-administered drugs: if confirmed by ongoing studies these data may inform treatment tailoring and/or dose reductions. PMID- 26440732 TI - A truncating mutation in Alzheimer's disease inactivates neuroligin-1 synaptic function. AB - Neuroligins (NLs) are cell-adhesion proteins that regulate synapse formation and function. Neuroligin 1 (NL1) promotes the formation of glutamatergic synapses and mediates long-term potentiation in mouse models. Thus, altered NL1 function could mediate the synaptic and memory deficits associated with Alzheimer's disease (AD). Here, we describe a frameshift mutation, c.875_876insTT, in the neuroligin 1 gene (NLGN1) in a patient with AD and familial history of AD. The insertion generates a premature stop codon in the extracellular domain of NL1 (p.Thr271fs). Expression of mutant NL1 shows accumulation of truncated NL1 proteins in the endoplasmic reticulum. In hippocampal neurons, the p.Thr271fs mutation abolishes the ability of NL1 to promote the formation of glutamatergic synapses. Our data support a role for inactivating mutations in NLGN1 in AD. Previous studies have reported rare mutations in X-linked NLGNL3 and NLGNL4 genes in patients with autism, which result in the inactivation of the mutant alleles. Therefore, together with a role in neurodevelopmental disorders, altered NL function could underlie the molecular mechanisms associated with brain diseases in the elderly. PMID- 26440733 TI - Altered transcription of inflammation-related genes in dental pulp of coeliac children. AB - BACKGROUND: Coeliac disease is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten, and possible relationships between coeliac disease and dental pathogenic conditions during childhood have been poorly investigated. AIM: The dental pulp plays a pivotal role in the immune defence against possible entry of pathogens from teeth, and the aim of this work was to investigate quantitative transcription levels of selected genes (IL-9, IL-11, IL-15, IL-18, IL-21, IL-27, MICA, IFN-gamma) coding for pro-inflammatory immune innate activities in the pulp of primary teeth from healthy children and children with coeliac disease. DESIGN: The pulp from primary teeth of 10 healthy children and 10 children with coeliac disease was used to extract RNA and prepare cDNA for quantitative PCR transcription analysis employing commercial nucleotide probes for selected genes. RESULTS: In children with coeliac disease, the genes coding for pro-inflammatory cytokines IFN-gamma, IL-11, IL-18, and IL-21 were significantly overexpressed, suggesting the possible importance of these cytokines in the relationships between coeliac disease and dental disorders. CONCLUSION: For the first time, we reported in dental pulp of children possible relationships between coeliac disease and modulation in transcription of cytokine-dependent inflammatory activities. PMID- 26440734 TI - Mucoadhesion and mucosa-mimetic materials--A mini-review. AB - Mucoadhesion describes an attractive interaction between dosage form and mucosal membrane. The evaluation of mucoadhesive excipients often requires the use of ex vivo mucosal tissues taken from laboratory animals. These can be difficult to source, highly heterogeneous, and require the use of animal products. Thus, from both a user-convenience and ethical point-of-view, it is desirable to produce a synthetic alternative to these tissues-a mucosa-mimetic material. In this mini review, the use of alternative materials to test the performance of mucoadhesives is reviewed and discussed. There is a surprising prevalence of the use of mucosa mimics in the literature, which hitherto has not been compiled and compared. PMID- 26440735 TI - Inactivation of Cronobacter sakazakii in reconstituted infant formula by combination of thymoquinone and mild heat. AB - AIMS: The objective of this study was to determine the combined effect of thymoquinone (TQ) and mild heat on Cronobacter sakazakii in reconstituted infant formula. METHODS AND RESULTS: Reconstituted infant formula samples inoculated with a mixture of four C. sakazakii strains (approx. 6.5 log CFU ml(-1) ) were prepared with various concentrations of TQ (0, 5, 10, 20 and 30 mmol l(-1) ) and were heated to 45, 50 and 55 degrees C for 0, 10, 20, 30, 60 and 120 min, and the surviving populations of C. sakazakii at each sampling time were enumerated. To elucidate the mode of action of TQ, membrane integrity and changes in cell morphology were examined by LIVE/DEAD((r)) BacLight(TM) bacterial viability kit and field emission scanning electron microscope respectively. TQ at 30 mmol l(-1) reduced the pathogen to undetectable level in between 60 and 120 min at 45 degrees C, 60 min at 50 degrees C and 10 min at 55 degrees C respectively. CONCLUSIONS: Our results demonstrated that the combined treatments significantly reduced (P < 0.05) the population of C. sakazakii, compared to the control. Cronobacter sakazakii numbers were reduced much more rapidly with higher temperatures and increased concentrations of TQ. And combined treatment inactivated pathogen partly by causing cell membrane disruption. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings suggested that TQ, together with mild heat, may have potential application in infant formula to control C. sakazakii before consumption and therefore is a possible way to prevent infections associated with C. sakazakii in infant formula. PMID- 26440736 TI - Added sugar in the nutrition facts label: Consumer needs and scientific uncertainty. PMID- 26440737 TI - Binding of Janus kinase inhibitor tofacitinib with human serum albumin: multi technique approach. AB - In this report, we have investigated the binding affinity of tofacitinib with human serum albumin (HSA) under simulated physiological conditions by using UV visible spectroscopy, fluorescence quenching measurements, dynamic light scattering (DLS), differential scanning calorimetry (DSC) and molecular docking methods. The obtained results demonstrate that fluorescence intensity of HSA gets quenched by tofacitinib and quenching occurs in static manner. Binding parameters calculated from modified Stern-Volmer equation shows that the drug binds to HSA with a binding constant in the order of 10(5). Synchronous fluorescence data deciphered the change in the microenvironment of tryptophan residue in HSA. UV spectroscopy and DLS measurements deciphered complex formation and reduction in hydrodynamic radii of the protein, respectively. Further DSC results show that tofacitinib increases the thermo stability of HSA. Hydrogen bonding and hydrophobic interaction are the main binding forces between HSA and tofacitinib as revealed by docking results. PMID- 26440738 TI - Is it time for flexibility in botulinum inter-injection intervals? AB - Based largely on old retrospective reports, the recommendation of injecting BoNT as infrequently as possible, with the lowest possible dose, was formed. While BoNT is inherently immunogenic, with improved production, most patients no longer develop immune resistance and poor response to BoNT is often due to other factors. In a randomized controlled trial (RCT) using abobotulinumtoxinA for cervical dystonia (CD) by the German Dystonia Study Group, half of the patients treated with 250 and 500 U, and 39% in the 1000 U group required retreatment after 8 weeks. In a RCT comparing onabotulinumtoxinA and incobotulinumtoxinA for CD by Benecke et al., waning of effect was noted in 70 days for both toxins. Finally, two long-term prospective trials employing flexible intervals, with reinjections based on patient's request, have been performed using incobotulinumtoxinA. In the CD study, 22.5% were re-injected in <10 weeks and 24.6% between 10 and 12 weeks. In the blepharospasm study, the median injection interval was 6-10 weeks for 23.7% and 10-12 weeks for 32.3%) While long-term studies utilizing flexible/shortened intervals, with vigilance over immunogenicity are needed, the majority of current evidence no longer support the very stringent adherence to strict 90-day BoNT injection intervals. PMID- 26440739 TI - Cyclodextrin-Modified Porous Silicon Nanoparticles for Efficient Sustained Drug Delivery and Proliferation Inhibition of Breast Cancer Cells. AB - Over the past decade, the potential of polymeric structures has been investigated to overcome many limitations related to nanosized drug carriers by modulating their toxicity, cellular interactions, stability, and drug-release kinetics. In this study, we have developed a successful nanocomposite consisting of undecylenic acid modified thermally hydrocarbonized porous silicon nanoparticles (UnTHCPSi NPs) loaded with an anticancer drug, sorafenib, and surface-conjugated with heptakis(6-amino-6-deoxy)-beta-cyclodextrin (HABCD) to show the impact of the surface polymeric functionalization on the physical and biological properties of the drug-loaded nanoparticles. Cytocompatibility studies showed that the UnTHCPSi-HABCD NPs were not toxic to breast cancer cells. HABCD also enhanced the suspensibility and both the colloidal and plasma stabilities of the UnTHCPSi NPs. UnTHCPSi-HABCD NPs showed a significantly increased interaction with breast cancer cells compared to bare NPs and also sustained the drug release. Furthermore, the sorafenib-loaded UnTHCPSi-HABCD NPs efficiently inhibited cell proliferation of the breast cancer cells. PMID- 26440740 TI - (4+1) vs (4+2): Catalytic Intramolecular Coupling between Cyclobutanones and Trisubstituted Allenes via C-C Activation. AB - Herein we describe a rhodium-catalyzed (4+1) cyclization between cyclobutanones and allenes, which provides a distinct [4.2.1]-bicyclic skeleton containing two quaternary carbon centers. The reaction involves C-C activation of cyclobutanones and employs allenes as a one-carbon unit. A variety of functional groups can be tolerated, and a diverse range of polycyclic scaffolds can be accessed. Excellent enantioselectivity can be obtained, which is enabled by a TADDOL-derived phosphoramidite ligand. The bridged bicyclic products can be further functionalized or derivatized though simple transformations. PMID- 26440741 TI - Preclinical combination of TP-0903, an AXL inhibitor and B-PAC-1, a procaspase activating compound with ibrutinib in chronic lymphocytic leukemia. PMID- 26440742 TI - Nonunion Following Trapeziometacarpal Arthrodesis With Plate and Screw Fixation. PMID- 26440743 TI - Terrible Triad Injuries of the Elbow. AB - The treatment of terrible triad injuries of the elbow continues to evolve. Radial head fixation and arthroplasty, coronoid process fixation, and repair of the lateral collateral ligament continue to be the mainstays of treatment. In the elbow with persistent instability after repair of these elements, application of a static external fixation, hinged external fixation, ulnohumeral joint pinning, or an internal hinge may be needed. In patients who undergo treatment after the acute injury period, the coronoid may require reconstruction using radial head autograft, iliac crest autograft, olecranon autograft, or allograft. PMID- 26440744 TI - Pediatric Trigger Digits. AB - Pediatric trigger thumb presents not at birth but early in childhood. Most evidence suggests that it is caused by a developmental size mismatch between the flexor pollicis longus tendon and its sheath. Patients generally present with the thumb interphalangeal joint locked in flexion. Surgical reviews report near universally excellent outcomes after open release of the A1 pulley. However, recent reports indicate that there may be a role for nonsurgical treatment for families that are willing to wait several years for possible spontaneous resolution of the deformity. Triggering in digits other than the thumb in children is generally associated with an underlying diagnosis including anatomic abnormalities of the tendons, and metabolic, inflammatory, and infectious etiologies. Although some have advocated nonsurgical treatment, surgery is often necessary to address the underlying anatomic etiology. More extensive surgery beyond simple A1 pulley release is often required, including release of the A3 pulley and resection of a slip of the flexor digitorum superficialis tendon. PMID- 26440745 TI - Exclusion of a Huge Left Ventricular Outflow Tract Pseudoaneurysm with Konno's Procedure. AB - We present the use of Konno's procedure for the reconstruction of a huge left ventricular outflow tract pseudoaneurysm formed after aortic valve replacement. PMID- 26440746 TI - From Arabidopsis to cereal crops: Conservation of chloroplast protein degradation by autophagy indicates its fundamental role in plant productivity. AB - Autophagy is an evolutionarily conserved process leading to the degradation of intracellular components in eukaryotes, which is important for nutrient recycling especially in response to starvation conditions. Nutrient recycling is an essential process that underpins productivity in crop plants, such that remobilized nitrogen derived from older organs supports the formation of new organs or grain-filling within a plant. We extended our understanding of autophagy in a model plant, Arabidopsis thaliana, to an important cereal, rice (Oryza sativa). Through analysis of transgenic rice plants stably expressing fluorescent marker proteins for autophagy or chloroplast stroma, we revealed that chloroplast proteins are partially degraded in the vacuole via Rubisco-containing bodies (RCBs), a type of autophagosomes containing stroma. We further reported evidence that the RCB pathway functions during natural leaf senescence to facilitate subsequent nitrogen remobilization into newly expanding leaves. Thus, our recent studies establish the importance of autophagy in biomass production of cereals. PMID- 26440747 TI - Different effects of five depigmentary compounds, rhododendrol, raspberry ketone, monobenzone, rucinol and AP736 on melanogenesis and viability of human epidermal melanocytes. AB - Numerous medications are used to treat hyperpigmentation. However, several reports have indicated that repeated application of some agents, such as rhododendrol (RD), raspberry ketone (RK) and monobenzone (MB), can be toxic to melanocytes. Although these agents had severe side effects in human trials, no current in vitro methods can predict the safety of such drugs. This study assessed the in vitro effects of five depigmentary compounds including leukoderma inducing agents. In particular, we determined the effects of different concentrations and exposure times of different depigmentary agents on cell viability and melanogenesis in the presence and absence of ultraviolet B (UVB) radiation. Concentrations of RD, RK and MB that inhibit melanogenesis are similar to concentrations that are cytotoxic; however, concentrations of rucinol (RC) and AP736 that inhibit melanogenesis are much lower than concentrations that are cytotoxic. Furthermore, the concentrations that cause toxic effects depend on exposure duration, and prolonged exposure to RD, RK and MB had more cytotoxic effects than prolonged exposure to RC and AP736. The cytotoxic effects of RD and RK appear to be mediated by apoptosis due to increased expression of caspase-3 and caspase-8; UVB radiation increased the cytotoxicity of these agents and also increased caspase activity. Our results indicate that different leukoderma inducing compounds have different effects on the viability of normal epidermal melanocytes and suggest that the in vitro assay used here can be used to predict whether an investigational compound that induces leukoderma may lead to adverse effects in human trials. PMID- 26440748 TI - Symmetry analysis for monitoring safety of newly marketed drugs. AB - INTRODUCTION: A postmarketing study without a comparator group has been recognized as a problem as it provides no measure of association. Nevertheless, the design is sometimes used in company postmarketing studies particularly when the study involves the primary data collection. In this report, the "Symmetry Analysis Cohort Design" without a comparator group but with a control period is proposed. METHODS AND RESULTS: In the proposed design, the rate ratio is estimated using the method of prescription sequence symmetry analysis with slight modification so that the rate ratio can be estimated using data on subjects who have started the drug during the study period but no data on other subjects. DISCUSSION: The proposed design has an advantage that it can provide the measure of association. Another advantage common to all self-controlled methods is that the effect of the measured and unmeasured confounders is automatically canceled out when the effect is stable over the study period. Compared with the standard design with a comparator group, the proposed design also has weaknesses. For example, adjustment of confounding by the indication may be difficult when the indication is an acute condition. In addition, the rate ratio is not valid when the probability of the prescription of the drug is dependent on the occurrence of the outcome in the unexposed (pre-dose) period. The design may be used to evaluate the need for further studies although its real usefulness is to be determined in the future. PMID- 26440749 TI - Lenalidomide Treatment for Lower Risk Nondeletion 5q Myelodysplastic Syndromes Patients Yields Higher Response Rates When Used Before Azacitidine. AB - BACKGROUND: Lenalidomide and azanucleosides are commonly used to treat anemic patients with lower-risk myelodysplastic syndromes (LR-MDS) without chromosome 5q deletion (non-del5q) after failure of treatment with erythropoiesis-stimulating agents (ESAs). Nonetheless, response rates to lenalidomide after azanucleosides treatment failure and their optimal sequencing after failure of treatment with ESAs is unknown. PATIENTS AND METHODS: We identified patients with LR-MDS in the Moffitt Cancer Center Clinical Database who received lenalidomide and azacitidine after ESA treatment failure. Rates of erythroid hematologic improvement (HI-E) in patients who received lenalidomide first followed by azacitidine (group 1) and those who received lenalidomide after azacitidine (group 2) were examined according to the International Working Group 2006 criteria. RESULTS: Sixty-three patients (37 in group 1 and 26 in group 2) were identified. The HI-E rate with lenalidomide as first-line therapy was 38% versus only 12% when lenalidomide was used as second-line therapy (P = .04). There were no significant differences in overall survival (OS; median OS, 104 vs. 87 months, respectively; P = .55), rates of leukemic progression, or in HI-E rates after azacitidine use (38% when azacitidine was used after lenalidomide vs. 35% when azacitidine was administered before lenalidomide, P = .69). CONCLUSION: Lenalidomide appears to yield a higher HI-E rate in non-del5q LR-MDS when used as first-line therapy after ESA treatments failure. If validated in larger cohorts, lenalidomide rather than azacitidine should be considered for first-line therapy after ESA treatment failure. PMID- 26440750 TI - Subtle Dynamic Changes Accompany Hck Activation by HIV-1 Nef and are Reversed by an Antiretroviral Kinase Inhibitor. AB - The HIV-1 virulence factor Nef interacts with the macrophage Src-family kinase Hck, resulting in constitutive kinase activation that contributes to viral replication and immune escape. Previous chemical library screens identified the diphenylfuranopyrimdine kinase inhibitor DFP-4AB, which selectively inhibits Nef dependent Hck activity in biochemical assays and potently blocks HIV replication in vitro. In the present study, hydrogen exchange mass spectrometry (HX MS) was used to study conformational changes in downregulated Hck that result from Nef binding, as well as the impact of DFP-4AB on these changes. Remarkably, interaction with Nef induced only subtle changes in deuterium uptake by Hck, with the most significant changes in the N-lobe of the kinase domain adjacent to the docking site for Nef on the SH3 domain. No changes in hydrogen exchange were observed in the Hck SH2 domain or C-terminal tail, indicating that this regulatory interaction is unaffected by Nef binding. When HX MS was performed in the presence of DFP-4AB, the effect of Nef on Hck N-lobe dynamics was completely reversed. These results show that constitutive activation of Hck by HIV-1 Nef requires only modest changes to the conformational dynamics of the overall kinase structure. DFP-4AB reverses these effects, consistent with its activity against this Nef-induced signaling event in HIV-infected cells. PMID- 26440752 TI - PROTEOMICS ANALYSIS OF OVEREXPRESSED PLASMA PROTEINS IN RESPONSE TO COLD ACCLIMATION IN Ostrinia furnacalis. AB - Many insects in temperate regions overwinter in diapause. In these insects, one of the metabolic adaptations to cold stress is the synthesis of responsive proteins. Using proteomic analysis, an investigation aimed to a better understanding of the molecular adaptation mechanisms to cold stress was carried out in Ostrinia furnacalis larva. Proteins were extracted from the larval hemolymph collected from both control and overwintering larva. By polyethylene glycol precipitation, approximately 560 protein spots were separated and visualized on two-dimensional (2D) gels after silver staining. Eighteen protein spots were found to be upregulated in overwinter larval plasma in different patterns. As an initial work, 13 of these proteins were identified using MALDI TOF/TOF MS. The differentially overexpressed proteins include heat shock 70 kDa cognate protein, small heat shock protein (sHSP), putative aliphatic nitrilase, arginine kinase, phosphoglyceromutase, triosephosphateisomerase, and glutathione transferase. Alterations in the levels of these proteins were further confirmed by qPCR. This study is the first analysis of differentially expressed plasma proteins in O. furnacalis diapause larvae under extremely low temperature conditions and gives new insights into the acclimation mechanisms responsive to cold stress. Our results also support the idea that energy metabolism, alanine and proline metabolism, and antioxidative reaction act in the cold acclimation of O. furnacalis diapause larvae. PMID- 26440751 TI - Rhodium-Catalyzed Stereoselective Intramolecular [5 + 2] Cycloaddition of 3 Acyloxy 1,4-Enyne and Alkene. AB - The first rhodium-catalyzed intramolecular [5 + 2] cycloaddition of 3-acyloxy 1,4 enyne and alkene was developed. The cycloaddition is highly diastereoselective in most cases. Various cis-fused bicyclo[5.3.0]decadienes were prepared stereoselectively. The chirality in the propargylic ester starting materials could be transferred to the bicyclic products with high efficiency. Electron deficient phosphine ligand greatly facilitated the cycloaddition. Up to three new stereogenic centers could be generated. The resulting diene in the products could be hydrolyzed to enones, which allowed the introduction of more functional groups to the seven-membered ring. PMID- 26440753 TI - INCIDENCE OF, AND RISK FACTORS FOR, MALNUTRITION AMONG CHILDREN AGED 5-7 YEARS IN SOUTH INDIA. AB - Protein-energy malnutrition is a major health problem contributing to the burden of disease in developing countries. The aim of this study was to assess the incidence of, and risk factors for, malnutrition among school-going children in south India. A total of 2496 children aged 5-7 years from rural and urban areas of south India were recruited in 1982 and followed up for malnutrition over a period of 9 years. Their body heights and weights were measured every six months and socio-demographic factors such as mother's education and father's education and relevant household characteristics and hygiene practices collected. Body mass index and height-for-age z-scores were used to determine children's levels of underweight and stunting, respectively, classified as normal, mild/moderate or severe. Risk factor analysis was done for pre-pubertal ages only using Generalized Estimating Equations with cumulative odds assumption. There was a significant difference between male and female children in the incidence of severe underweight and stunting (6.4% and 4.2% respectively). Children in households with no separate kitchen had 1.3 (1.0-1.6) times higher odds of being severely underweight (p=0.044) compared with those with a kitchen. Children without a toilet facility had significantly higher odds of severe underweight compared with those who did. Children with illiterate parents had higher odds of severe stunting than those with literate parents. In conclusion, the prevalence of malnutrition among these south Indian children has not changed over the years, and the incidence of severe malnutrition was highest in children when they were at pubertal age. The risk factors for stunting were mostly poverty-related, and those for underweight were mostly hygiene-related. Adolescent children in south India should be screened periodically at school for malnutrition and provided with nutritional intervention if necessary. PMID- 26440754 TI - Is Action Planning Helpful for Smoking Cessation? Assessing the Effects of Action Planning in a Web-Based Computer-Tailored Intervention. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to examine the efficacy of a web-assisted computer-tailored smoking cessation intervention, an action planning (AP) intervention in which potential quitters were encouraged to form action plans (e.g., plan a quit date) and execute them (e.g., remove ashtrays). We also investigated whether the AP intervention resulted in more AP and plan execution than a similar, control intervention without the supplementary AP component. METHODS: In a randomized controlled trial, the AP intervention (N = 977) was compared with the control intervention (N = 1,005) in terms of self-reported continued abstinence (CA) and point prevalence abstinence (PPA) six months after baseline. AP, plan execution, and opinion of the intervention were measured one month after baseline. RESULTS: Complete-case logistic regression analysis showed that the AP intervention had a significant effect on CA (OR = 2.01; CI 1.08-3.84, p = .02), whereas intention-to-treat analysis showed a borderline significant effect (OR = 1.68; CI .96-2.92, p = .07). Sixteen percent of the experimental group achieved CA compared to 10% of the control group. The AP intervention had no effect on PPA. The experimental group also showed significantly more AP and plan execution at one month. Execution of plans was associated with smoking cessation. CONCLUSIONS: The effects of the AP intervention on CA, AP, and execution of plans were encouraging. The potential for widespread use of web based interventions means that even small behavioral effects may have an impact on public health. We recommend that the intervention be intensified and improved. PMID- 26440755 TI - Epidemiology of tinea capitis in northeast Iran: a retrospective analysis from 1998 to 2012. AB - BACKGROUND: Tinea capitis is a common disease of the pediatric population. This disease typically follows one of several clinical patterns, i.e., scaling, hair loss, and/or inflammatory lesions, which are usually caused predominantly by two dermatophytic genera: Microsporum and Trichophyton. The aim of this study was to investigate tinea capitis and its etiological agents in Sari city of Mazandaran province, Iran. METHODS: We studied the spectrum of tinea capitis by means of a retrospective analysis involving 1745 patients referred to both the Reference Laboratory of Medical Mycology (RLMM) and Bo Ali Sina Hospital at Sari, Iran (1998-2012). Specimens were assessed by standard mycological techniques based on macroscopic and microscopic morphology. RESULTS: Among the patients, 480 (27.5%; 61 males and 39% females) were confirmed through a mycological examination. The peak incidence was in the 5-14 years age group. Endothrix (263 cases; 54.8%) was the most frequent clinical feature by direct exam. The predominant causative agents of tinea capitis were T. tonsurans (186 cases; 38.8%) and T. violaceum (119 cases; 24.8%), followed by T. mentagrophytes (46 cases; 9.6%), T. schoenleinii (28; 5.8%), T. rubrum (20 cases; 4.2%), M. gypseum (15 cases; 3.1%), T. verrucosum (14 cases; 2.9%), and Epidermophyton floccosum (1 cases; 0.2%). CONCLUSION: The present study showed that tinea capitis is mainly due to the anthropophilic species, and the most common species were T. tonsurans and T. violaceum. Owing to the high frequency of anthropophilic species, future studies may be useful in the development of preventive and educational strategies to reduce healthcare expenditure. PMID- 26440756 TI - Free DOX and chitosan-N-arginine conjugate stabilized indocyanine green nanoparticles for combined chemophotothermal therapy. AB - Indocyanine green (ICG) is a FDA-approved near-infrared (NIR) cyanine dye used in medical diagnostics. However, the utility of ICG remains limited by its unstable optical property, and concentration-dependent aggregation and precipitation. A chitosan-arginine conjugate (CS-N-Arg) was developed to increase the stability of ICG in physiological buffer saline via formation of strong electrostatic interactions between ICG and CS-N-Arg. The CS-N-Arg/ICG complex prevented ICG from aggregation and precipitation, thus it could serve as a theranostic nanomaterial for image-guided photothermal cancer therapy. The CS-N-Arg/ICG NPs showed excellent photostability, clear fluorescent images, and rapid temperature rise under laser irradiation. Cell viability assay indicated that CS-N-Arg/ICG NPs could efficiently suppress the growth of doxorubicin (DOX) resistant breast cancer cell (MCF-7/ADR cells) under NIR photothermal treatments. In combination of DOX with CS-N-Arg/ICG NPs, a combined effect was observed in MCF-7/ADR breast cancer cells due to dual hyperthermia and chemical therapeutic effects. The present observations suggest that CS-N-Arg/ICG NPs can effectively deliver ICG molecules to MCF-7/ADR breast cancer cells and overcome DOX resistance in the cells by hyperthermia. PMID- 26440757 TI - Hyaluronic acid-conjugated polyamidoamine dendrimers for targeted delivery of 3,4 difluorobenzylidene curcumin to CD44 overexpressing pancreatic cancer cells. AB - The current study was aimed to develop a targeted dendrimer formulation of 3, 4 difluorobenzylidene curcumin (CDF) and evaluate its potential in CD44 targeted therapy for pancreatic cancer. Using amine terminated fourth generation poly(amidoamine) (PAMAM) dendrimer nanocarrier and hyaluronic acid (HA) as a targeting ligand, we engineered a CD44-targeted PAMAM dendrimer (HA-PAMAM) formulation of CDF. The resulting dendrimer nanosystem (HA-PAMAM-CDF) had a particle size and surface charge of 9.3 +/- 1.5 nm and -7.02 +/- 9.53 mV, respectively. When CD44 receptor overexpressing MiaPaCa-2 and AsPC-1 human pancreatic cancer cells were treated with HA-PAMAM-CDF, a dose-dependent cytotoxicity was observed. Furthermore, blocking the CD44 receptors present on the MiaPaCa-2 cells using free excess soluble HA prior to treatment with HA-PAMAM CDF nano-formulation resulted in 1.71 fold increase in the IC50 value compared to non-targeted formulation (PAMAM-CDF), confirming target specificity of HA-PAMAM CDF. Additionally, HA-PAMAM-CDF formulation when compared to PAMAM-CDF, displayed higher cellular uptake in MiaPaCa-2 cancer cell lines as shown by fluorescence studies. In summary, the novel CD44 targeted dendrimer based nanocarriers appear to be proficient in mediating site-specific delivery of CDF via CD44 receptors, with an improved therapeutic margin and safety. PMID- 26440758 TI - Immobilization of enzymes using non-ionic colloidal liquid aphrons (CLAs): Surface and enzyme effects. AB - The use of non-ionic colloidal liquid aphrons (CLAs) as a support for enzyme immobilisation was investigated. Formulation required the mixing of an aqueous surfactant solution with a relatively non-polar solvent-surfactant solution, forming a solvent droplet surrounded by a thin stabilised aqueous film (soapy shell). Studies utilising anionic surfactants have showed increased retention, however, very little have been understood about the forces governing immobilisation. This study seeks to determine the effects of enzyme properties on CLA immobilisation by examining a non-ionic/non-polar solvent system comprised of two non-ionic surfactants, Tween 20 and 80, mineral oil and the enzymes lipase, aprotinin and alpha-chymotrypsin. From these results it was deduced that hydrophobic interactions strongly governed immobilisation. Confocal Scanning Laser Microscopy (CSLM) revealed that immobilisation was predominantly achieved by surface adsorption attributed to hydrophobic interactions between the enzyme and the CLA surface. Enzyme surface affinity was found to increase when added directly to the formulation (pre-manufacture addition), as opposed to the bulk continuous phase (post-manufacture addition), with alpha-chymotrypsin and aprotinin being the most perturbed, while lipase was relatively unaffected. The effect of zeta potential on immobilisation showed that enzymes adsorbed better closer to their pI, indicating that charge minimisation was necessary for immobilisation. Finally, the effect of increasing enzyme concentration in the aqueous phase resulted in an increase in adsorption for all enzymes due to cooperativity between protein molecules, with saturation occurring faster at higher adsorption rates. PMID- 26440759 TI - Effect of temperature on extracellular organic matter (EOM) of Chlorella pyrenoidosa and effect of EOM on irreversible membrane fouling. AB - Extracellular organic matter (EOM) can cause serious membrane fouling during the algae harvesting process. In this study, the secretion of EOM, including bound EOM (bEOM) and dissolved-EOM (dEOM), by Chlorella pyrenoidosa (C. pyrenoidosa) at different culturing temperatures, and their influences on membrane filtration, have been investigated. The secretion of EOM was markedly reduced at high temperatures. The specific EOM secretion rate (SEOM) reached 831.1 +/- 55.3mg/g at the lowest temperatures of 15 degrees C; in contrast, the SEOM decreased to only 370-442 and 356-406 mg/g with temperature rising above 20-25 and 30-35 degrees C, respectively. Based on membrane filtration experiments, the influence of EOM on irreversible membrane fouling was studied. In a critical flux experiment, low critical flux (24 L/m(2)h) was observed in a system with a high EOM concentration. The fouled membranes were rinsed by water and then used for continuous filtration, scanning electron microscope (SEM) analysis and fourier transform infrared spectroscopy (FTIR) analysis. The results revealed that there was irreversible membrane fouling caused by EOM, and irreversible membrane fouling can be more serious when an algae solution contains high EOM levels. PMID- 26440761 TI - Non-alignment stagnation-point flow of a nanofluid past a permeable stretching/shrinking sheet: Buongiorno's model. AB - The paper deals with a stagnation-point boundary layer flow towards a permeable stretching/shrinking sheet in a nanofluid where the flow and the sheet are not aligned. We used the Buongiorno model that is based on the Brownian diffusion and thermophoresis to describe the nanofluid in this problem. The main purpose of the present paper is to examine whether the non-alignment function has the effect on the problem considered when the fluid suction and injection are imposed. It is interesting to note that the non-alignment function can ruin the symmetry of the flows and prominent in the shrinking sheet. The fluid suction will reduce the impact of the non-alignment function of the stagnation flow and the stretching/shrinking sheet but at the same time increasing the velocity profiles and the shear stress at the surface. Furthermore, the effects of the pertinent parameters such as the Brownian motion, thermophoresis, Lewis number and the suction/injection on the flow and heat transfer characteristics are also taken into consideration. The numerical results are shown in the tables and the figures. It is worth mentioning that dual solutions are found to exist for the shrinking sheet. PMID- 26440760 TI - Augmented microscopy: real-time overlay of bright-field and near-infrared fluorescence images. AB - Intraoperative applications of near-infrared (NIR) fluorescent contrast agents can be aided by instrumentation capable of merging the view of surgical field with that of NIR fluorescence. We demonstrate augmented microscopy, an intraoperative imaging technique in which bright-field (real) and electronically processed NIR fluorescence (synthetic) images are merged within the optical path of a stereomicroscope. Under luminance of 100,000 lx, representing typical illumination of the surgical field, the augmented microscope detects 189 nM concentration of indocyanine green and produces a composite of the real and synthetic images within the eyepiece of the microscope at 20 fps. Augmentation described here can be implemented as an add-on module to visualize NIR contrast agents, laser beams, or various types of electronic data within the surgical microscopes commonly used in neurosurgical, cerebrovascular, otolaryngological, and ophthalmic procedures. PMID- 26440762 TI - Optimal Timing of Mesenchymal Stem Cell Therapy for Neonatal Intraventricular Hemorrhage. AB - We recently showed that intraventricular transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) significantly attenuated posthemorrhagic hydrocephalus (PHH) and brain injury after severe intraventricular hemorrhage (IVH) in newborn rat pups. The purpose of this study was to optimize the timing of MSC transplantation for severe IVH. Severe IVH was induced by injecting 100 ul of blood into each ventricle of Sprague-Dawley rats on postnatal day 4 (P4). Human UCB-derived MSCs (1 * 10(5) cells in 10 ul of normal saline) were transplanted intraventricularly under stereotaxic guidance either early at P6 or late at P11. Serial brain MRIs and behavioral function tests, such as negative geotaxis and rotarod tests, were performed. At P32, brain tissue samples were obtained for histological and biochemical analyses. Intracerebroventricular transplantation of MSCs significantly attenuated the development of PHH, behavioral impairment, increased apoptosis and astrogliosis, reduced corpus callosum thickness and brain myelination, and upregulated inflammatory cytokines including interleukin (IL)-1alpha, IL-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) at P6 but not at P11 after induction of severe IVH. Intracerebroventricular transplantation of human UCB-derived MSCs attenuated PHH and brain injury after severe IVH in newborn rats in a time dependent manner. Significant neuroprotection was only demonstrated when administered early at 2 days after induction but not late at 7 days after induction of severe IVH. PMID- 26440763 TI - An anatomical study of the dorsal and ventral nasal conchal bullae in normal horses: Computed tomographic anatomical and morphometric findings. AB - REASONS FOR PERFORMING STUDY: Infection of the dorsal nasal conchal bulla and ventral nasal conchal bulla has recently been shown to cause clinical disease in horses, but the anatomy of these 2 structures is poorly documented. OBJECTIVES: To describe the anatomical features, dimensions and relationships to adjacent structures of the dorsal conchal bulla and ventra conchal bulla in normal horses using computed tomography (CT). STUDY DESIGN: Descriptive imaging study using cadavers. METHODS: Computed tomographic images acquired from 60 equine cadaver heads that were shown to be free of sinonasal disease were categorised into 3 age groups (0-5; 6-15; >16 years old). Linear and volumetric measurements and descriptive anatomical assessments of the dorsal conchal bulla and ventral conchal bulla were produced from these CT images and the anatomical relationships between the dorsal conchal bulla and ventral conchal bulla and the adjacent structures, particularly the maxillary cheek teeth, were examined. The associations between bullae dimensions with horse ages and skull dimensions were assessed using linear regression. RESULTS: Mean (range) dorsal conchal bulla measurements were: length 7.5 cm (4.6-14), width 1.9 cm (1.3-2.5), height 2.8 cm (1.8-4), volume 24 cm3 (5.9-50.5). Mean ventral conchal bulla measurements were: length 5.7 cm (2.5-8.5), width 1.6 cm (0.7-2.9), height 2.4 cm (0.8-3.7), volume 15 cm3 (0.4-30). In both dorsal conchal bulla and ventral conchal bulla, there were significant differences in sizes between the different age groups (smaller in younger animals). In the ventral conchal bulla, this was probably related to protrusion of the large dental alveoli of younger horses into the lateral nasal cavity. Measures of bullae size and volume were significantly associated with head size. The anatomical positions (rostro-caudal boundaries) of the dorsal conchal bulla and ventral conchal bulla were closely associated with specific maxillary cheek teeth. CONCLUSIONS: Computed tomography was a useful technique to establish the linear and volumetric dimensions of the nasal conchal bullae in normal horses. Both dorsal conchal bulla and ventral conchal bulla sizes increased with animal age. Relatively consistent anatomical relationships were shown between the rostral and caudal limits of the bullae and certain maxillary cheek teeth, which would be of diagnostic value with conventional radiography and act as landmarks in the surgical treatment of nasal bulla disease. PMID- 26440764 TI - Dermochondrocorneal dystrophy (Francois syndrome) in a Mexican patient and literature review. AB - Dermochondrocorneal Dystrophy (OMIM 221800) is a very rare disease first described by Francois in 1949. It is characterized by the appearance of skin nodules, osteochondral deformities, and corneal opacities during childhood. Only a few cases have been reported. There is uncertainty about the inheritance pattern and no gene or genes have been associated to this disease. We report a patient from Mexican mestizo origin with the classic manifestations of Dermochondrocorneal Dystrophy. We perform a multidisciplinary assessment in order to contribute to the knowledge of the clinical presentation of this uncommon condition. Among the few documented patients, this is the third patient of Mexican ancestry reported with this syndrome. PMID- 26440765 TI - One-pot synthesis of benzoxaborole derivatives from the palladium-catalyzed cross coupling reaction of alkoxydiboron with unprotected o-bromobenzylalcohols. AB - Under very mild conditions, functionalized benzoxaborole derivatives were prepared in good to excellent yields via a palladium-catalyzed Miyaura borylation reaction of readily available unprotected o-bromobenzylalcohols, and bis(pinacolato)diboron (B2pin2) without the assistance of an acid. Blue-light emitting materials based on spiro benzoxaborole building blocks have been obtained with potential applications in organic electronics and biomedicine. PMID- 26440766 TI - Editorial Comment on "Adjuvant Maneuvers for Residual Curvature Correction during Penile Prosthesis Implantation in Men with Peyronie's Disease". PMID- 26440767 TI - Mid-term clinical outcomes of ABSORB bioresorbable vascular scaffold implantation in a real-world population: A single-center experience. AB - BACKGROUND: Available data on the use of the ABSORB bioresorbable vascular scaffold (BVS) (Abbott Vascular, Santa Clara, CA) in real-world patients is limited. The aim of this study was to assess the mid-term clinical outcomes in a real-world population treated with ABSORB BVS. METHODS AND MATERIALS: We retrospectively evaluated all patients treated with ABSORB at Papworth Hospital, Papworth Everard, UK between July 2012 and July 2014. A total of 108 patients (126 lesions) were identified. Clinical follow-up was performed on all subjects by clinic visit or telephone interview. RESULTS: Most patients were male (91.7%) with a relative high incidence of previous myocardial infarction (MI) (40.7%). Clinical presentation was equally divided between stable angina and acute coronary syndrome (ACS) (51.8% vs. 48.2%, p=0.59). Of the ACS patients, 26.9% presented with ST-elevation myocardial MI. Intravascular imaging was used in all cases. Predilatation (92.9%) and postdilatation (82.5%) were frequently performed. Major adverse cardiac event (MACE) rates defined as the composite of all-cause death, follow-up MI and target vessel revascularization were 2.5% at 6 month and 4.5% at 1-year. The 1-year target lesion failure rate, defined as the composite of cardiac death, target-vessel MI and target lesion revascularization was 1.9%. There was 1 case of subacute stent thrombosis. CONCLUSIONS: The use of ABSORB BVS in real-world patients appears to be associated with good mid-term clinical outcomes when guided by intravascular imaging. Larger studies are required to evaluate further the role of BVS in routine clinical practice and examine how this compares to metallic devices. SUMMARY: Available data on the use of the ABSORB BVS in real-world patients is limited. We retrospectively evaluated all patients treated with ABSORB BVS between July 2012 and July 2014. A total of 108 patients (126 lesions) were identified. Clinical presentation was equally divided between stable angina and acute coronary syndrome (51.8% vs. 48.2%, p=0.59). Predilatation (92.9%) and postdilatation (82.5%) were frequently performed. Estimated MACE rates at 6-month and 1-year were 2.5% and 4.5% respectively, with a 1-year TLF rate of 1.9%. These results suggest that the use of ABSORB BVS use in the real-world is associated with good mid-term clinical outcomes when guided by intravascular imaging. PMID- 26440768 TI - Cost-effectiveness of transcatheter versus surgical management of structural heart disease. AB - Transcatheter management of valvular and structural heart disease is the most growing aspect of interventional cardiology. While the early experience was limited to patients who were not candidate for surgery, the continuous improvement in the efficacy and safety expanded its use to different degree depending on the procedure and the disease involved. The cost of these procedures is a major concern for health care in developed world. Cost-effectiveness of these transcatheter structural procedures varies depending on the procedure itself, the burden of the underlying disease, the feasibility and cost of both the Transcatheter and surgical procedures. In this review, we turn now to a specific discussion of the medical economics of percutaneous valvular and structural interventions. PMID- 26440770 TI - Tuning the Ising-type anisotropy in trigonal bipyramidal Co(II) complexes. AB - This paper demonstrates the engineering and tuning of Ising-type magnetic anisotropy in trigonal bipyramidal Co(II) complexes. Here, we predict that employing a ligand that forces a trigonal bipyramidal arrangement and has weak equatorial sigma-donating atoms, increases (in absolute value) the negative zero field splitting parameter D. With these considerations in mind, we used a sulfur containing ligand (NS3(iPr)), which imposes a trigonal bipyramidal geometry to the central Co(II) ion with long equatorial Co-S bonds. The resulting complex exhibits a larger anisotropy barrier and a longer relaxation time in comparison to the complex prepared with a nitrogen containing ligand (Me6tren). PMID- 26440769 TI - The C-terminal amyloidogenic peptide contributes to self-assembly of Avibirnavirus viral protease. AB - Unlike other viral protease, Avibirnavirus infectious bursal disease virus (IBDV) encoded viral protease VP4 forms unusual intracellular tubule-like structures during viral infection. However, the formation mechanism and potential biological functions of intracellular VP4 tubules remain largely elusive. Here, we show that VP4 can assemble into tubules in diverse IBDV-infected cells. Dynamic analysis show that VP4 initiates the assembly at early stage of IBDV infection, and gradually assembles into larger size of fibrils within the cytoplasm and nucleus. Intracellular assembly of VP4 doesn't involve the host cytoskeleton, other IBDV encoded viral proteins or vital subcellular organelles. Interestingly, the last C terminal hydrophobic and amyloidogenic stretch (238)YHLAMA(243) with two "aggregation-prone" alanine residues was found to be essential for its intracellular self-assembly. The assembled VP4 fibrils show significantly low solubility, subsequently, the deposition of highly assembled VP4 structures ultimately deformed the host cytoskeleton and nucleus, which was potentially associated with IBDV lytic infection. Importantly, the assembly of VP4 significantly reduced the cytotoxicity of protease activity in host cells which potentially prevent the premature cell death and facilitate viral replication. This study provides novel insights into the formation mechanism and biological functions of the Avibirnavirus protease-related fibrils. PMID- 26440771 TI - Bosma arrhinia microphthalmia syndrome in a Mexican patient with a molecular analysis of PAX6. AB - The association of anophthalmia, arrhinia, and hypogonadism constitutes the major clinical features for Bosma arrhinia microphthalmia syndrome. However, there is variability in the presentation of this disease; arrhinia is the most constant clinical feature, which is then combined with a spectrum of anophthalmia/microphthalmia and/or hypogonadism. This rare entity is not associated with any specific genes, but the genes that are related to arrhinia and anophthalmia have been studied in an attempt to explain this phenomenon. We analyzed the PAX6 gene in a Bosma arrhinia microphthalmia syndrome patient but found no variation or mutation that could constitute or establish a causal association in our patient. PMID- 26440772 TI - Optimal blood pressure in patients with peripheral artery disease following endovascular therapy. AB - This study examined the associations between blood pressure (BP) and event incidence to define optimal BP after endovascular therapy (EVT) in patients who underwent EVT. BP was monitored every 6 months for 5 years, and the patients were divided into two groups by average BP: >= 140/90 mmHg and < 140/90 mmHg. The association of BP with several events was examined. Although no significant differences in total mortality were observed between the groups, restenosis rates were significantly higher among patients who did not achieve target BP (36.2%) than among those who did (18.2%) (p < 0.01). The percentage of patients with glycosylated haemoglobin > 7.0% was significantly higher among those who did not achieve target BP in the restenosis group (42.9%) than in the other group (10.8%) (p < 0.01). In the restenosis group, there was a significantly higher percentage of patients taking metformin (p < 0.01) than in the other group. Metformin seemed to be administered to patients with more severe diabetes mellitus. In conclusion, it is important to manage hypertension and diabetes to prevent restenosis after EVT. PMID- 26440773 TI - Learning to drink: How Chinese adolescents make decisions about the consumption (or not) of alcohol. AB - BACKGROUND: The aim of the study was to provide in-depth understanding of how Chinese adolescents learn to drink and how they make decisions about the consumption (or not) of alcohol. This study explored the ways in which social and cultural factors shape the drinking trajectories of Chinese underage young people. METHODS: The study used a qualitative design to collect and analyse the data. We recruited adolescents aged between 14 and 17 from a range of secondary schools in Hong Kong. Focus group interviews were undertaken with 22 groups encompassing 111 participants. A thematic analysis based upon grounded theory was performed using NVivo 10. RESULTS: The traditional Chinese drinking culture, characterised by the coming together of friends and relatives for celebrations, signifies the Chinese adolescents' first alcohol experiment. The adolescents' motivations for drinking essentially reflect the value placed upon alcohol within the Chinese culture - promoting conviviality, sociability and camaraderie. Whereas a sense of commonality encouraged alcohol use among them, there was little indication that drinkers and non-drinkers separately clustered around friendship networks. A high degree of self-regulation was exercised when drinking and this emerged as an acceptable social norm amongst young drinkers within social and cultural contexts. Most respondents saw underage drinking as an entirely normal and accepted part of social lives provided that it is kept under control. CONCLUSIONS: This study sheds light on the Chinese adolescents' own understandings and interpretations of their drinking. Our findings suggest that interventions aimed to curtail underage drinking need to reflect social and cultural contexts within which alcohol comes into play and importantly, consider social environments that are conducive to underage drinking. PMID- 26440774 TI - Overlap in attitudes to policy measures on alcohol, tobacco and illegal drugs. AB - BACKGROUND: Effective alcohol, tobacco and illegal drug policies reduce the harm to users and third parties. Knowledge about determinants and interrelations between attitudes held by the general public to different types of policy measures can benefit policy-makers who aim to increase acceptance for effective policy. The present study describes the level of support for various policy measures held by the general public, and investigates the association between attitudes to policy measures on alcohol, tobacco and illegal drug. METHODS: A sample of the Norwegian general population aged 16-64 (N=1803) was interviewed by telephone. Respondents reported demographic information, personal substance use and attitudes to various policy measures. Associations between attitudes were assessed with correlation and regression analysis. RESULTS: Associations between attitudes were strongest for similar policy measures across substance groups (e.g. tax increases on alcohol and tobacco). There was a weaker association between attitudes to different policy measures aimed at the same substance (e.g. tax increase on alcohol and campaigns on alcohol). CONCLUSION: The degree to which people approve or disapprove of the use of particular types of policy measures is irrespective of the targeted substance. PMID- 26440775 TI - Body Mass Index Underestimates Adiposity in Persons With Multiple Sclerosis. AB - OBJECTIVES: To examine the relation between body mass index (BMI) and adiposity assessed by dual-energy x-ray absorptiometry in persons with multiple sclerosis (MS) and non-MS controls as well as to determine the accuracy of standard and alternate BMI thresholds for obesity. DESIGN: Cross-sectional. SETTING: University research laboratory. PARTICIPANTS: The sample included persons with MS (n=235) and controls (n=53) (N=288). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Main outcome measures included BMI, whole body soft tissue composition (ie, percent body fat [%BF], fat mass, and lean soft tissue mass), bone mineral content, and bone mineral density. RESULTS: We observed significant strong associations between BMI and sex-specific %BF in persons with MS and non-MS controls, and BMI explained ~40% of the variance in %BF in both MS and control samples. Receiver operating characteristic curve analyses indicated that the standard BMI threshold for obesity (ie, 30kg/m(2)) had excellent specificity (93% 100%) but poor sensitivity (37%-44%) in persons with MS and non-MS controls. The BMI threshold that best identified %BF-defined obesity was 24.7kg/m(2) in the MS sample and 25.1kg/m(2) in the control sample. CONCLUSIONS: We determined a strong association between BMI and adiposity; however, the current BMI threshold for classifying obesity underestimates true adiposity in persons with MS. A similar relation was observed between BMI and obesity in non-MS controls. The non-MS sample included primarily middle-aged women, and similar BMI-%BF misclassifications have been reported in these samples. PMID- 26440776 TI - Clinical Course and Prognostic Factors in Conservatively Managed Carpal Tunnel Syndrome: A Systematic Review. AB - OBJECTIVE: To summarize the available evidence regarding the course of symptoms and prognostic factors in patients with diagnosed carpal tunnel syndrome (CTS) who are treated conservatively. DATA SOURCES: Computerized databases, reference checking, and experts in the field were used to identify studies for inclusion in the review. STUDY SELECTION: Multiple reviewers were used to identify studies which included adults (aged >=18y) diagnosed with CTS in either a clinical setting or population setting. The study must have observed the course of CTS over at least a 6-week period in patients receiving no treatment or usual care that included conservative (nonsurgical) treatments. The design was of a longitudinal cohort study with either prospective or retrospective data collection. There were no language restrictions, and none of the research identified was only reported in abstract form. DATA EXTRACTION: Methodological bias was assessed using the Quality in Prognosis Studies tool. A high risk of bias (predominantly relating to study attrition, confounding, and/or statistical analysis and reporting) was judged to be present in 8 studies. Designs showed wide variability with respect to characteristics of the included population, definition of CTS, assessment of prognostic factors, types of interventions provided, and types of outcome measures applied. This prevented pooled estimates from being produced. DATA SYNTHESIS: A negative outcome at 3 years' follow-up of conservatively treated participants ranged from 23% to 89%. Four included studies observed the rate of surgical intervention after initial conservative management and found this to be 57% to 66%. Evidence regarding factors predicting the negative outcome of no treatment or conservative treatment was graded, taking into account the number of studies evaluating the factor, the methodological quality of these studies, and the consistency of the available evidence. There was 100% agreement in at least 3 cohorts with a medium or high risk of bias that symptom duration, a positive Phalen's test, and thenar wasting were associated with a negative outcome of conservative management; however, not all results were statistically significant, and hence the overall judgment remained inconclusive. CONCLUSIONS: Results of this review should be treated with caution because of the heterogeneity of studies and the risks of bias identified. However, the course of CTS appears variable, and poor prognosis may be predicted by a longer symptom duration, a positive Phalen's test, and thenar wasting. PMID- 26440777 TI - Systematic Review and Meta-Analysis of the Effects of Exercise for Those With Cancer-Related Lymphedema. AB - OBJECTIVES: To evaluate the effects of exercise on cancer-related lymphedema and related symptoms, and to determine the need for those with lymphedema to wear compression during exercise. DATA SOURCES: CINAHL, Cochrane, EBSCOhost, MEDLINE, PubMed, ProQuest Health and Medical Complete, ProQuest Nursing and Allied Health Source, ScienceDirect, and SPORTDiscus databases were searched for trials published before January 1, 2015. STUDY SELECTION: Randomized and nonrandomized controlled trials and single-group pre-post studies published in English were included. Twenty-one (exercise) and 4 (compression and exercise) studies met inclusion criteria. DATA EXTRACTION: Data were extracted into tabular format using predefined data fields by 1 reviewer and assessed for accuracy by a second reviewer. Study quality was evaluated using the Effective Public Health Practice Project Quality Assessment Tool. DATA SYNTHESIS: Data were pooled using a random effects model to assess the effects of acute and long-term exercise on lymphedema and lymphedema-associated symptoms, with subgroup analyses for exercise mode and intervention length. There was no effect of exercise (acute or intervention) on lymphedema or associated symptoms, with standardized mean differences from all analyses ranging between -0.2 and 0.1 (P values >=.22). Findings from subgroup analyses for exercise mode (aerobic, resistance, mixed, other) and intervention duration (>12wk or <=12wk) were consistent with these findings-that is, no effect on lymphedema or associated symptoms. There were too few studies evaluating the effect of compression during regular exercise to conduct a meta-analysis. CONCLUSIONS: Individuals with secondary lymphedema can safely participate in progressive, regular exercise without experiencing a worsening of lymphedema or related symptoms. However, there is insufficient evidence to support or refute the current clinical recommendation to wear compression garments during regular exercise. PMID- 26440778 TI - Immunohistochemical analysis for G protein in the olfactory organs of soft shelled turtle, Pelodiscus sinensis. AB - In turtles, the epithelia lining the upper and lower chambers of the nasal cavity project axons to the ventral and dorsal parts of the olfactory bulbs, respectively. In a semi-aquatic soft-shelled turtle, Pelodiscus sinensis, more than 1,000 odorant receptor genes have been found, but it is not known where they are expressed. In this study, we aimed to clarify the distribution of cells expressing these genes in the olfactory organs of soft-shelled turtles. Immunoreactions for the Galphaolf, the alpha subunit of G protein coupled to the odorant receptors, were detected on the surface of epithelia lining both the upper and lower chambers of the nasal cavity. The receptor cells in the epithelium of both chambers possessed cilia on the tip of their dendrites, whereas microvillous, non-ciliated, receptor cells were not found. These data suggest that the odorant receptor genes are expressed by the ciliated receptor cells in the upper and lower chamber epithelia. Precise location of the vomeronasal epithelium is not known at present. PMID- 26440779 TI - Disappearing Enantiomorphs: Single Handedness in Racemate Crystals. AB - Although crystallization is the most important method for the separation of enantiomers of chiral molecules in the chemical industry, the chiral recognition involved in this process is poorly understood at the molecular level. We report on the initial steps in the formation of layered racemate crystals from a racemic mixture, as observed by STM at submolecular resolution. Grown on a copper single crystal surface, the chiral hydrocarbon heptahelicene formed chiral racemic lattice structures within the first layer. In the second layer, enantiomerically pure domains were observed, underneath which the first layer contained exclusively the other enantiomer. Hence, the system changed from a 2D racemate into a 3D racemate with enantiomerically pure layers after exceeding monolayer saturation coverage. A chiral bias in form of a small enantiomeric excess suppressed the crystallization of one double-layer enantiomorph so that the pure minor enantiomer crystallized only in the second layer. PMID- 26440780 TI - Seizures, Takotsubo syndrome, and sudden unexpected death in epilepsy: A still puzzling triangle. PMID- 26440781 TI - A glycemia-structured population model. AB - Structured models are population models in which the individuals are characterized with respect to the value of some variable of interest, called the structure variable. In the present paper, we propose a glycemia-structured population model, based on a linear partial differential equation with variable coefficients. The model is characterized by three rate functions: a new-adult population glycemic profile, a glycemia-dependent mortality rate and a glycemia dependent average worsening rate. First, we formally analyze some properties of the solution, the transient behavior and the equilibrium distribution. Then, we identify the key parameters and functions of the model from real-life data and we hypothesize some plausible modifications of the rate functions to obtain a more beneficial steady-state behavior. The interest of the model is that, while it summarizes the evolution of diabetes in the population in a completely different way with respect to previously published Monte Carlo aggregations of individual based models, it does appear to offer a good approximation of observed reality and of the features expected in the clinical setting. The model can offer insights in pharmaceutical research and be used to assess possible public health intervention strategies. PMID- 26440782 TI - Chromatographic fingerprint similarity analysis for pollutant source identification. AB - In the present study, a similarity analysis method was proposed to evaluate the source-sink relationships among environmental media for polybrominated diphenyl ethers (PBDEs), which were taken as the representative contaminants. Chromatographic fingerprint analysis has been widely used in the fields of natural products chemistry and forensic chemistry, but its application to environmental science has been limited. We established a library of various sources of media containing contaminants (e.g., plastics), recognizing that the establishment of a more comprehensive library allows for a better understanding of the sources of contamination. We then compared an environmental complex mixture (e.g., sediment, soil) with the profiles in the library. These comparisons could be used as the first step in source tracking. The cosine similarities between plastic and soil or sediment ranged from 0.53 to 0.68, suggesting that plastic in electronic waste is an important source of PBDEs in the environment, but it is not the only source. A similarity analysis between soil and sediment indicated that they have a source-sink relationship. Generally, the similarity analysis method can encompass more relevant information of complex mixtures in the environment than a profile-based approach that only focuses on target pollutants. There is an inherent advantage to creating a data matrix containing all peaks and their relative levels after matching the peaks based on retention times and peak areas. This data matrix can be used for source identification via a similarity analysis without quantitative or qualitative analysis of all chemicals in a sample. PMID- 26440783 TI - Shadows of anyons and the entanglement structure of topological phases. AB - The low-temperature dynamics of quantum systems are dominated by the low-energy eigenstates. For two-dimensional systems in particular, exotic phenomena such as topological order and anyon excitations can emerge. While a complete low-energy description of strongly correlated systems is hard to obtain, essential information about the elementary excitations is encoded in the eigenvalue structure of the quantum transfer matrix. Here we study the transfer matrix of topological quantum systems using the tensor network formalism and demonstrate that topological quantum order requires a particular type of 'symmetry breaking' for the fixed point subspace. We also relate physical anyon excitations to domain wall excitations at the level of the transfer matrix. This formalism enables us to determine the structure of the topological sectors in two-dimensional gapped phases very efficiently, therefore opening novel avenues for studying fundamental questions related to anyon condensation and confinement. PMID- 26440784 TI - Host Manipulation by Parasites: A Look Back Before Moving Forward. AB - The ability to manipulate host behaviour is among the most fascinating and best studied adaptations of parasites. In this opinion article, we highlight trends and biases in the study of this phenomenon that may cloud or limit our understanding of its evolution. For instance, reviews and theoretical studies have shown a disproportionately sharp increase in the past decade relative to empirical studies. We also discuss taxonomic biases in the host-parasite systems investigated, as well as recent declines in the use of experimental infections and in the proportion of these systems in which fitness benefits for the parasites have been confirmed. We finish this opinion article by offering recommendations for the continued success of research in this area. PMID- 26440785 TI - Parasite-Parasite Interactions in the Wild: How To Detect Them? AB - Inter-specific interactions between parasites impact on parasite intra-host dynamics, host health, and disease management. Identifying and understanding interaction mechanisms in the wild is crucial for wildlife disease management. It is however complex because several scales are interlaced. Parasite-parasite interactions are likely to occur via mechanisms at the within-host level, but also at upper levels (host population and community). Furthermore, interactions occurring at one level of organization spread to upper levels through cascade effects. Even if cascade effects are important confounding factors, we argue that we can also benefit from them because upper scales often provide a way to survey a wider range of parasites at lower cost. New protocols and theoretical studies (especially across scales) are necessary to take advantage of this opportunity. PMID- 26440786 TI - Induction, Propagation, and Activity of Host Nitric Oxide: Lessons from Leishmania Infection. AB - The production of nitric oxide (NO) by the inducible NO synthase (iNOS) is a key defense mechanism against intracellular pathogens such as Leishmania. Numerous studies have investigated the antimicrobial properties of this small molecule in vitro but its precise mode of action during Leishmania infection in vivo is still unclear. In this review, we discuss how iNOS is induced in infected tissues and how NO acts to control the expansion of Leishmania parasites and limit tissue damage resulting from the infection. We highlight recently described mechanisms that result in widespread iNOS expression in infected tissues. We also discuss how the collective production and subsequent diffusion of NO generates an antimicrobial milieu that promotes parasite control at the tissue level. PMID- 26440787 TI - Born to be Wild--Don't Forget the Invertebrates. PMID- 26440789 TI - Life without a Host Cell: What is Cryptosporidium? AB - Cryptosporidium is a parasite responsible for widespread disease in livestock and humans. Recent phylogenetic reclassification of Cryptosporidium from a coccidian to a gregarine dictates an urgent need to reconsider the biology and behavior of this parasite. Overwhelming data now confirm that, like its close relatives, Cryptosporidium is a facultatively epicellular apicomplexan that is able to multiply in a host cell-free environment. We complement the latest phylogenetic and taxonomic proposals with advances in our understanding of Cryptosporidium's biology, with particular focus on in vitro studies that have characterized the development of Cryptosporidium stages in the absence of host cells. Opportunities to revisit in vivo infections are discussed and questions about the Cryptosporidium host cell-free life cycle that remain unanswered highlighted. PMID- 26440788 TI - Methods for Quantification of Soil-Transmitted Helminths in Environmental Media: Current Techniques and Recent Advances. AB - Limiting the environmental transmission of soil-transmitted helminths (STHs), which infect 1.5 billion people worldwide, will require sensitive, reliable, and cost-effective methods to detect and quantify STHs in the environment. We review the state-of-the-art of STH quantification in soil, biosolids, water, produce, and vegetation with regard to four major methodological issues: environmental sampling; recovery of STHs from environmental matrices; quantification of recovered STHs; and viability assessment of STH ova. We conclude that methods for sampling and recovering STHs require substantial advances to provide reliable measurements for STH control. Recent innovations in the use of automated image identification and developments in molecular genetic assays offer considerable promise for improving quantification and viability assessment. PMID- 26440790 TI - Commit and Transmit: Molecular Players in Plasmodium Sexual Development and Zygote Differentiation. AB - During each cycle of asexual endomitotic division in erythrocytes, the malaria parasite makes a fundamental and crucial decision: to continue to invade and proliferate or to differentiate into gametocytes ready for continuation of sexual development. The proteins and regulatory pathways involved in Plasmodium sexual development have been of great interest in recent years as targets for blocking malaria transmission. However, the 'Holy Grail', the master switch orchestrating asexual-to-sexual commitment and further differentiation, has remained elusive - until now. Here we highlight the recent studies identifying the epigenetic and transcriptional master regulators of sexual commitment and discuss the key players in reversible phosphorylation pathways involved in sexual and zygote differentiation. PMID- 26440791 TI - A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis. AB - PURPOSE: To develop a Gamma Knife-based mouse model of late time-to-onset, cerebral radiation necrosis (RN) with serial evaluation by magnetic resonance imaging (MRI) and histology. METHODS AND MATERIALS: Mice were irradiated with the Leksell Gamma Knife(r) (GK) PerfexionTM (Elekta AB; Stockholm, Sweden) with total single-hemispheric radiation doses (TRD) of 45- to 60-Gy, delivered in one to three fractions. RN was measured using T2-weighted MR images, while confirmation of tissue damage was assessed histologically by hematoxylin & eosin, trichrome, and PTAH staining. RESULTS: MRI measurements demonstrate that TRD is a more important determinant of both time-to-onset and progression of RN than fractionation. The development of RN is significantly slower in mice irradiated with 45-Gy than 50- or 60-Gy, where RN development is similar. Irradiated mouse brains demonstrate all of the pathologic features observed clinically in patients with confirmed RN. A semi-quantitative (0 to 3) histologic grading system, capturing both the extent and severity of injury, is described and illustrated. Tissue damage, as assessed by a histologic score, correlates well with total necrotic volume measured by MRI (correlation coefficient = 0.948, with p<0.0001), and with post-irradiation time (correlation coefficient = 0.508, with p<0.0001). CONCLUSIONS: Following GK irradiation, mice develop late time-to-onset cerebral RN histology mirroring clinical observations. MR imaging provides reliable quantification of the necrotic volume that correlates well with histologic score. This mouse model of RN will provide a platform for mechanism of action studies, the identification of imaging biomarkers of RN, and the development of clinical studies for improved mitigation and neuroprotection. PMID- 26440793 TI - Tumor DNA Index and alpha-Fetoprotein Level Define Outcome following Liver Transplantation for Advanced Hepatocellular Carcinoma. AB - BACKGROUND: Patients with hepatocellular carcinoma (HCC) beyond the Milan criteria are expected to have inferior outcome after liver transplantation (LT) and are therefore currently not considered for LT in many countries. The purpose of this study was to identify predictive factors for overall survival following LT for HCC that may support the Milan criteria in the selection of appropriate transplant candidates. METHODS: Clinicopathological data on 364 patients with HCC who underwent LT between 1989 and 2010 were retrospectively evaluated. Predictors of overall survival in the entire cohort as well as in subsets of patients within (n = 214) and beyond (n = 150) the Milan criteria were analyzed. RESULTS: Multivariate analysis in the entire cohort identified DNA index >1.5 (p < 0.0001), alpha-fetoprotein level (AFP) >200 ng/ml (p = 0.005), and HCC beyond the Milan criteria (p = 0.002) to be associated with worse overall survival. In patients within the Milan criteria (median survival: 170 months), DNA index >1.5 (p < 0.0001) was the only predictor of worse overall survival in multivariate analysis. In patients beyond the Milan criteria (median survival: 44 months), DNA index >1.5, AFP >200 ng/ml, microvascular invasion, patient age >60 years, and DNA index >1.5 concomitant with AFP >200 ng/ml were associated with worse overall survival in univariate analysis. Multivariate analysis identified DNA index >1.5 concomitant with AFP >200 ng/ml (p < 0.0001) as the only independent predictor of worse overall survival. Consequently, patients beyond the Milan criteria with a combined favorable DNA index <=1.5 and AFP <=200 ng/ml had a median survival (147 months) comparable to that of patients within the Milan criteria. CONCLUSIONS: DNA index and AFP level predict overall survival following LT in patients with advanced HCC beyond the Milan criteria. A combined assessment of these markers during the evaluation of transplant candidates can contribute to the selection of patients with HCC who may benefit from LT independently of their tumor burden. PMID- 26440792 TI - Preterm infants' behaviors and skin conductance responses to nurse handling in the NICU. AB - Stress response patterns are indicative of the neonate's unique ability to cope with environmental demands and can be evaluated through autonomic and behavioral response parameters. OBJECTIVE: To characterize stress responses during tactile stimulation to standard nurse handling in the NICU, and their association with severity of illness in preterm infants. METHODS: Thirty preterm neonates were studied at postnatal day 4-5 during standard nurse caregiving. Heart rate (HR), respiratory rate (RR), skin conductance responses per second (SCR/s), and NIDCAP(r) stress behaviors were recorded before and during care. Non-parametric tests were used to assess differences from before to during care. Pearson's correlations were used to determine the association of biological and behavioral variables to the score for neonatal acute physiology (SNAP), a severity of illness index. RESULTS: HR, RR, SCR/s and NIDCAP(r) behaviors (motor and attentional cues, and ability to self-console) increased from before to during the care (p < 0.01). NIDCAP(r) behaviors showed a significant negative association to the SNAP score (R = -0.45, p < 0.05). CONCLUSIONS: HR, RR, SCR/s and NIDCAP(r) behaviors significantly increased during care. NIDCAP(r) stress behaviors were influenced by the severity of illness of the infant, while SCR/s was not influenced by severity of illness. PMID- 26440794 TI - Passage-Based Bibliographic Coupling: An Inter-Article Similarity Measure for Biomedical Articles. AB - Biomedical literature is an essential source of biomedical evidence. To translate the evidence for biomedicine study, researchers often need to carefully read multiple articles about specific biomedical issues. These articles thus need to be highly related to each other. They should share similar core contents, including research goals, methods, and findings. However, given an article r, it is challenging for search engines to retrieve highly related articles for r. In this paper, we present a technique PBC (Passage-based Bibliographic Coupling) that estimates inter-article similarity by seamlessly integrating bibliographic coupling with the information collected from context passages around important out-link citations (references) in each article. Empirical evaluation shows that PBC can significantly improve the retrieval of those articles that biomedical experts believe to be highly related to specific articles about gene-disease associations. PBC can thus be used to improve search engines in retrieving the highly related articles for any given article r, even when r is cited by very few (or even no) articles. The contribution is essential for those researchers and text mining systems that aim at cross-validating the evidence about specific gene disease associations. PMID- 26440795 TI - Delayed Wound Healing in Heat Stable Antigen (HSA/CD24)-Deficient Mice. AB - BACKGROUND: Healthy individuals rarely have problems with wound healing. Most skin lesions heal rapidly and efficiently within one to two weeks. However, many medical and surgical complications can be attributed to deficiencies in wound repair. Open wounds have lost the barrier that protects tissues from bacterial invasion and allows the escape of vital fluids. Without expeditious healing, infections become more frequent. The CD24 gene encodes a heavily-glycosylated cell surface protein anchored to the membrane by phosphatidylinositol. CD24 plays an important role in the adaptive immune response and controls an important genetic checkpoint for homeostasis and autoimmune diseases in both mice and humans. We have previously shown that overexpression of CD24 results in increased proliferation and migration rates. AIM: To examine the role of CD24 in the wound healing process. METHODS: An excisional model of wound healing was used and delayed wound healing was studied in genetically modified heat stable antigen (HSA/CD24)-deficient mice (HSA-/-) compared to wild-type (WT) mice. RESULTS: Large full-thickness skin wounds, excised on the back of mice, exhibited a significant delay in the formation of granulation tissue, and in wound closure when compared to their WTHSA+/+ littermates. Wounds were histologically analyzed and scored, based on the degree of cellular invasion, granulation tissue formation, vascularity, and re-epithelialization. Additionally, in stitched wounds, the HSA-/- mice failed to maintain their stitches; they did not hold and fell already 24 hours, revealing erythematous wound fields. Re-expression of HSA, delivered by lentivirus, restored the normal healing phenotype, within 24 hours post-injury, and even improved the healing in WT, and in BalbC mice. CONCLUSIONS: Delayed wound-healing in the absence of HSA/CD24 suggests that CD24 plays an important role in this process. Increased expression of CD24, even in the normal state, may be used to enhance wound repair. PMID- 26440797 TI - Quality of life among former Soviet Union and Israeli origin methadone users. AB - A common treatment intervention for heroin addiction is methadone maintenance. In recent years a wider perspective has been adapted to understand and evaluate addiction through quality of life. This article examines quality of life conditions of 170 male former Soviet Union and Israeli origin drug users in methadone maintenance and provides an understanding of conditions linked to the World Health Organization Quality of Life project's best available techniques reference document. Having a partner or spouse and less chronic illness are positive factors affecting quality of life regardless of country of origin. Israeli born drug users reported better quality of life based on their psychological health and environment domain responses; no difference was found for the physical health and social relationship domains of the Israeli and former Soviet Union origin males. Because heroin addiction is a chronic and relapsing illness, one of the goals of methadone maintenance is to address patients' health status from a broad perspective. Based on clinical observations, the treatment of special populations may be enhanced if their particular needs are considered and met. Quality of life factors are relevant for assessing high risk groups, including those from different ethnic origins, in poor physical and psychological health, their treatment and personal adjustment, and their service personnel training needs. PMID- 26440796 TI - Development of Human-Like scFv-Fc Neutralizing Botulinum Neurotoxin E. AB - BACKGROUND: Botulinum neurotoxins (BoNTs) are considered to be the most toxic substances known on earth and are responsible for human botulism, a life threatening disease characterized by flaccid muscle paralysis that occurs naturally by food-poisoning or colonization of the gastrointestinal tract by BoNT producing clostridia. BoNTs have been classified as category A agent by the Centers of Disease Control and Prevention (CDC) and are listed among the six agents with the highest risk to be used as bioweapons. Neutralizing antibodies are required for the development of effective anti-botulism therapies to deal with the potential risk of exposure. RESULTS: In this study, a macaque (Macaca fascicularis) was immunized with recombinant light chain of BoNT/E3 and an immune phage display library was constructed. After a multi-step panning, several antibody fragments (scFv, single chain fragment variable) with nanomolar affinities were isolated, that inhibited the endopeptidase activity of pure BoNT/E3 in vitro by targeting its light chain. Furthermore, three scFv were confirmed to neutralize BoNT/E3 induced paralysis in an ex vivo mouse phrenic nerve-hemidiaphragm assay. The most effective neutralization (20LD50/mL, BoNT/E3) was observed with scFv ELC18, with a minimum neutralizing concentration at 0.3 nM. Furthermore, ELC18 was highly effective in vivo when administered as an scFv Fc construct. Complete protection of 1LD50 BoNT/E3 was observed with 1.6 ng/dose in the mouse flaccid paralysis assay. CONCLUSION: These scFv-Fcs antibodies are the first recombinant antibodies neutralizing BoNT/E by targeting its light chain. The human-like nature of the isolated antibodies is predicting a good tolerance for further clinical development. PMID- 26440798 TI - Voluntary Exercise Prevents Oxidative Stress in the Brain of Phenylketonuria Mice. AB - BACKGROUND: High phenylalanine levels in phenylketonuria (PKU) have been associated with brain oxidative stress and amino acid imbalance. Exercise has been shown to improve brain function in hyperphenylalaninemia and neurodegenerative diseases. This study aimed to verify the effects of exercise on coordination and balance, plasma and brain amino acid levels, and brain oxidative stress markers in PKU mice. METHODS: Twenty wild-type (WT) and 20 PAH(enu2) (PKU) C57BL/6 mice were placed in cages with (exercise, Exe) or without (sedentary, Sed) running wheels during 53 days. At day 43, a balance beam test was performed. Plasma and brain were collected for analyses of amino acid levels and the oxidative stress parameters superoxide dismutase (SOD) activity, sulfhydryl and reduced glutathione (GSH) contents, total radical-trapping antioxidant potential (TRAP), and total antioxidant reactivity (TAR). RESULTS: SedPKU showed poor coordination (p < 0.001) and balance (p < 0.001), higher plasma and brain phenylalanine (p < 0.001), and increased brain oxidative stress (p < 0.05) in comparison to SedWT. ExePKU animals ran less than ExeWT (p = 0.018). Although no improvement was seen in motor coordination and balance, exercise in PKU restored SOD, sulfhydryl content, and TRAP levels to controls. TAR levels were increased in ExePKU in comparison to SedPKU (p = 0.012). Exercise decreased plasma and brain glucogenic amino acids in ExePKU, but did not change plasma and brain phenylalanine in both WT and PKU. CONCLUSIONS: Exercise prevents oxidative stress in the brain of PKU mice without modifying phenylalanine levels. Hence, exercise positively affects the brain, demonstrating its value as an intervention to improve brain quality in PKU. PMID- 26440799 TI - Fine mapping of qhir8 affecting in vivo haploid induction in maize. AB - KEY MESSAGE: The QTL qhir8 affecting in vivo haploid induction in maize was mapped to a 789 kb region, embryo abortion rate and segregation ratios were analyzed, linkage markers for MAS were developed. The doubled-haploid (DH) technology has become an important tool for line development in modern maize breeding. However, the genetic basis of haploid induction remains elusive. In previous QTL mapping research, qhir8 besides qhir1 significantly affected haploid induction rate (HIR). Our objective was to fine map qhir8 and assess its effect on HIR, segregation distortion (SD) and embryo abortion (EmA). A total of 3989 F2 plants from the cross of inducers CAUHOI and UH400 were screened for recombinants in the qhir8 region. F2 plants and F3 plants from selfing progenies of 34 recombinant F2 plants were evaluated for HIR, SD and EmA. In parallel, we developed 31 new markers providing good coverage of the qhir8 region. We confirmed that qhir8 has an increasing effect on HIR and EmA, but not on SD. Moreover, we successfully narrowed down the qhir8 locus to a 789 kb region flanked by markers 4292232 and umc1867. PMID- 26440800 TI - What do metabolic rates tell us about thermal niches? Mechanisms driving crayfish distributions along an altitudinal gradient. AB - Humans are rapidly altering thermal landscapes, so a central challenge to organismal ecologists is to better understand the thermal niches of ectotherms. However, there is much disagreement over how we should go about this. Some ecologists assume that a statistical model of abundance as a function of habitat temperature provides a sufficient approximation of the thermal niche, but ecophysiologists have shown that the relationship between fitness and temperature can be complicated, and have stressed the need to elucidate the causal mechanisms underlying the response of species to thermal change. Towards this end, we studied the distribution of two crayfishes, Euastacus woiwuru and Euastacus armatus, along an altitudinal gradient, and for both species conducted experiments to determine the temperature-dependence of: (1) aerobic scope (the difference between maximum and basal metabolic rate; purported to be a proxy of the thermal niche); and (2) burst locomotor performance (primarily fuelled using anaerobic pathways). E. woiwuru occupied cooler habitats than E. armatus, but we found no difference in aerobic scope between these species. In contrast, locomotor performance curves differed significantly and strongly between species, with peak locomotor performances of E. woiwuru and E. armatus occurring at ~10 and ~18 degrees C, respectively. Crayfish from different thermal landscapes may have similar aerobic thermal performance curves but different anaerobic thermal performance curves. Our results support a growing body of literature implying different components of ectotherm fitness have different thermal performance curves, and further challenge our understanding of the ecology and evolution of thermal niches. PMID- 26440801 TI - Local adaptation to parasite selective pressure: comparing three congeneric co occurring hosts. AB - Local adaptation may optimize an organism's investment in defenses in response to the risk of infection by spatially heterogeneous parasites and other natural enemies. However, local adaptation may be constrained if recruitment is decoupled from selective pressure experienced by the parent generation. We predicted that the ability of three intertidal littorinid snail species to defend against trematode parasites would depend on prior levels of population exposure to parasites and on larval dispersal mode, a proxy for population openness. In a common garden experiment, for two snail species with direct development and localized recruitment (Littorina obtusata and Littorina saxatilis), hosts from sites with high trematode infection risk were less susceptible to infection than hosts from low-risk sites. However, this relationship was not apparent for a third host species with broadcast larvae (Littorina littorea), suggesting that broad larval dispersal can impede local adaptation; alternatively, the lack of response in this species could owe to other factors that limited experimental infection in this host. Our findings support that locally recruiting hosts can adapt their defenses to scale with localized infection risk. PMID- 26440802 TI - Intrinsic surface dipole in topological insulators. AB - We calculate the local density of states of two prototypical topological insulators (Bi2Se3 and Bi2Te2Se) as a function of distance from the surface within density functional theory. We find that, in the absence of disorder or doping, there is a 2 nm thick surface dipole the origin of which is the occupation of the topological surface states above the Dirac point. As a consequence, the bottom of the conduction band is bent upward by about 75 meV near the surface, and there is a hump-like feature associated with the top of the valence band. We expect that band bending will occur in all pristine topological insulators as long as the Fermi level does not cross the Dirac point. Our results show that topological insulators are intrinsic Schottky barrier solar cells. PMID- 26440804 TI - Synchronous Ipsilateral Parotid Tumors with Cytologic-Histologic Correlation. AB - Synchronous ipsilateral tumor formation within a major salivary gland is a very rare event. In this case, a 54-year-old female tobacco smoker presented with a slowly enlarging left parotid gland. Computed tomography of the neck demonstrated a solid mass superficial to a cystic mass in the deep lobe of the gland. Ultrasound-guided fine needle aspiration yielded oncocytic cells, lymphoid cells, and granular debris along with rare cohesive groups of basaloid cells. Parotidectomy was performed, and the resected gland was found to contain two adjacent but distinct masses. One mass, a predominantly solid, well-circumscribed lesion composed of ribbons of double-layered oncocytic cells and a lymphoid stroma with germinal center formation, was a Warthin tumor. The other mass, a predominantly cystic lesion composed of cords and nests of basaloid cells with associated deposits of basement membrane-like material, was a basal cell adenoma of the membranous type. To our knowledge, this is the first reported case of synchronous Warthin tumor and basal cell adenoma of the parotid gland with cytologic-histologic correlation attributable to each tumor. PMID- 26440803 TI - The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement. AB - Routinely collected health data, obtained for administrative and clinical purposes without specific a priori research goals, are increasingly used for research. The rapid evolution and availability of these data have revealed issues not addressed by existing reporting guidelines, such as Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). The REporting of studies Conducted using Observational Routinely collected health Data (RECORD) statement was created to fill these gaps. RECORD was created as an extension to the STROBE statement to address reporting items specific to observational studies using routinely collected health data. RECORD consists of a checklist of 13 items related to the title, abstract, introduction, methods, results, and discussion section of articles, and other information required for inclusion in such research reports. This document contains the checklist and explanatory and elaboration information to enhance the use of the checklist. Examples of good reporting for each RECORD checklist item are also included herein. This document, as well as the accompanying website and message board (http://www.record statement.org), will enhance the implementation and understanding of RECORD. Through implementation of RECORD, authors, journals editors, and peer reviewers can encourage transparency of research reporting. PMID- 26440805 TI - Huperzine A Alleviates Oxidative Glutamate Toxicity in Hippocampal HT22 Cells via Activating BDNF/TrkB-Dependent PI3K/Akt/mTOR Signaling Pathway. AB - Oxidative glutamate toxicity is involved in diverse neurological disorders including epilepsy and ischemic stroke. Our present work aimed to assess protective effects of huperzine A (HupA) against oxidative glutamate toxicity in a mouse-derived hippocampal HT22 cells and explore its potential mechanisms. Cell survival and cell injury were analyzed by MTT method and LDH release assay, respectively. The production of ROS was measured by detection kits. Protein expressions of BDNF, phosphor-TrkB (p-TrkB), TrkB, phosphor-Akt (p-Akt), Akt, phosphor-mTOR (p-mTOR), mTOR, phosphor-p70s6 (p-p70s6) kinase, p70s6 kinase, Bcl 2, Bax, and beta-actin were assayed via Western blot analysis. Enzyme-linked immunosorbent assay was employed to measure the contents of nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin 4 (NT-4). Our findings illustrated 10 MUM HupA for 24 h significantly protected HT22 from cellular damage and suppressed the generation of ROS. Additionally, after treating with LY294002 or wortmannin [the selective inhibitors of phosphatidylinositol 3 kinase (PI3K)], HupA dramatically prevented the down regulations of p-Akt, p-mTOR, and p-p70s6 kinase in HT22 cells under oxidative toxicity. Furthermore, it was observed that the protein levels of BDNF and p-TrkB were evidently enhanced after co-treatment with HupA and glutamate in HT22 cells. The elevations of p-Akt and p-mTOR were abrogated under toxic conditions after blockade of TrkB by TrkB IgG. Cellular apoptosis was significantly suppressed (decreased caspase-3 activity and enhanced Bcl-2 protein level) after HupA treatment. It was concluded that HupA attenuated oxidative glutamate toxicity in murine hippocampal HT22 cells via activating BDNF/TrkB-dependent PI3K/Akt/mTOR signaling pathway. PMID- 26440806 TI - Role of the Outer Membrane Protein OprD2 in Carbapenem-Resistance Mechanisms of Pseudomonas aeruginosa. AB - We investigated the relationship between the outer membrane protein OprD2 and carbapenem-resistance in 141 clinical isolates of Pseudomonas aeruginosa collected between January and December 2013 from the First Affiliated Hospital of Anhui Medical University in China. Agar dilution methods were employed to determine the minimum inhibitory concentration of meropenem (MEM) and imipenem (IMP) for P. aeruginosa. The gene encoding OprD2 was amplified from141 P. aeruginosa isolates and analyzed by PCR and DNA sequencing. Differences between the effects of IMPR and IMPS groups on the resistance of the P. aeruginosa were observed by SDS-poly acrylamide gel electrophoresis (SDS-PAGE). Three resistance types were classified in the 141 carbapenem-resistant P. aeruginosa (CRPA) isolates tested, namely IMPRMEMR (66.7%), IMPRMEMS (32.6%), and IMPRMEMS (0.7%). DNA sequencing revealed significant diverse gene mutations in the OprD2-encoding gene in these strains. Thirty-four strains had large fragment deletions in the OprD2gene, in 6 strains the gene contained fragment inserts, and in 96 resistant strains, the gene featured small fragment deletions or multi-site mutations. Only 4 metallo-beta-lactamase strains and 1 imipenem-sensitive (meropenem-resistant) strain showed a normal OprD2 gene. Using SDS-PAGE to detect the outer membrane protein in 16 CRPA isolates, it was found that 10 IMPRMEMR strains and 5 IMPRMEMS strains had lost the OprD2 protein, while the IMPSMEMR strain contained a normal 46-kDa protein. In conclusion, mutation or loss of the OprD2-encoding gene caused the loss of OprD2, which further led to carbapenem-resistance of P. aeruginosa. Our findings provide insights into the mechanism of carbapenem resistance in P. aeruginosa. PMID- 26440810 TI - Evaluation of Blood Glucose Meter Efficacy in an Antenatal Diabetes Clinic. AB - BACKGROUND: The optimal treatment of diabetes in pregnancy requires accurate measurement of blood glucose levels, in order to minimize adverse outcomes for both mother and neonate. Self-monitoring of blood glucose is routinely used to measure glycemic control and to assess whether treatment targets are being met; however, the accuracy of blood glucose meters in pregnancy is unclear. MATERIALS AND METHODS: Pregnant women with gestational, type 1, or type 2 diabetes mellitus were eligible to participate. Nonfasting capillary blood glucose levels were measured in duplicate using the BGStar((r)) (Sanofi, Sydney, Australia) and FreeStyle Lite((r)) (Abbott, Sydney) blood glucose meters. Venous blood samples were collected and analyzed for plasma glucose, hematocrit, and glycated hemoglobin. Capillary blood glucose was compared with plasma glucose and further assessed according to International Organization for Standardization (ISO) 15197:2013 standards. RESULTS: One hundred ten women were recruited, providing 96 samples suitable for analysis. The mean +/- SD laboratory plasma glucose level was 4.6 +/- 1.4 mmol/L; the BGStar and FreeStyle Lite capillary blood glucose values were 5.3 +/- 1.4 mmol/L and 5.0 +/- 1.3 mmol/L, respectively. Both meters showed a positive bias (0.42 mmol/L for the FreeStyle Lite and 0.65 mmol/L for the BGStar). Furthermore, neither meter fulfilled the ISO 15197:2013 standards, and there was a nonsignificant improvement in meter performance at blood glucose levels of <=4.2 mmol/L. Hematocrit did not affect the results of either blood glucose meter. Clarke Error Grid analysis demonstrated that approximately 70% of the results of both meters would lead to appropriate clinical action. CONCLUSIONS: The BGStar and FreeStyle Lite blood glucose meters did not meet ISO 15197:2013 recommendations for blood glucose monitoring systems when assessed in a population of women with diabetes in pregnancy. Clinicians should consider this difference in blood glucose readings when making diabetes-related treatment decisions. PMID- 26440811 TI - Size- and shape-dependent phase diagram of In-Sb nano-alloys. AB - Nano-scale alloy systems with at least one dimension below 100 nm have different phase stabilities than those observed in the macro-scale systems due to a large surface to volume ratio. We have used the semi-empirical thermodynamic modelling, i.e. the CALPHAD method, to predict the phase equilibria of the In-Sb nano-scale systems as a function of size and shape. To calculate the size- and shape dependent phase diagram of the In-Sb system, we have added size-dependent surface energy terms to the Gibbs energy expressions in the In-Sb thermodynamic database. We estimated the surface energies of the solution phases and of the InSb intermetallic phase using the Butler equation and DFT calculations, respectively. A melting point and eutectic point depression were observed for both nanoparticle and nanowire systems. The eutectic composition on the In-rich and Sb-rich sides of the phase diagram shifted towards higher solubility. We believe that the phase diagram of In-Sb nano-alloys is useful for an increased understanding of the growth parameters and mechanisms of InSb nanostructures. PMID- 26440812 TI - Tipping the Balance between Concerted versus Sequential Proton-Coupled Electron Transfer. AB - We use quantized molecular dynamics simulations to investigate the competition between concerted and sequential proton-coupled electron-transfer (PCET) reaction mechanisms in inorganic catalysts. By analyzing reactive nonadiabatic PCET trajectories and computing both concerted and sequential rate constants, we characterize various molecular features that govern inorganic PCET reactions, including the solvent polarity, ligand-mediated electron-proton interactions, and intrinsic proton-transfer (PT) energy barrier. Using atomistic simulations with over 1200 atoms, we find that the symmetric iron biimidazoline system is extremely biased toward the concerted mechanism because of the strong ligand mediated electron-proton interaction and the short PT distance. However, by investigating system-bath models in which electron-proton interactions are shielded, which are representative of ruthenium terpyridylbenzoates and iron (tetraphenylporphyrin)benzoates, we predict that a crossover between the concerted and sequential PCET mechanisms may be possible either by increasing the polarity of the solvent or by increasing the intrinsic PT energy barrier. In addition, we predict the possibility of a crossover in the PCET mechanism by directly varying the strength of the ligand-mediated electron-proton interactions. The results presented here reveal new strategies for altering the competition between the competing PCET mechanisms and design principles for controlling PCET in catalytic systems. PMID- 26440814 TI - Invasive Group A Streptococcal Infections in Children: A Nationwide Survey in Finland. AB - BACKGROUND: The incidence of invasive group A streptococcus (iGAS) infections varies in time and geographically for unknown reasons. We performed a nationwide survey to assess the population-based incidence rates and outcomes of children with iGAS infections. METHODS: We collected data on patients from hospital discharge registries and the electronic databases of microbiological laboratories in Finland for the period 1996-2010. We then recorded the emm types or serotypes of the strains. The study physician visited all university clinics and collected the clinical data using the same data entry sheet. RESULTS: We identified 151 children with iGAS infection. Varicella preceded iGAS infection in 20% of cases and fasciitis infection in 83% of cases. The annual incidence rate of iGAS infection was 0.93 per 100,000 in 1996-2000, 1.80 in 2001-2005 and 2.50 in 2006 2010. The proportion of emm 1.0 or T1M1 strains peaked in 1996-2000 and again in 2006-2010, to 44% and 37% of all typed isolates. The main clinical diagnoses of the patients were severe soft-tissue infection (46%), sepsis (28%), empyema (10%), osteoarticular infection (9%) and primary peritonitis (5%). Severe pain was the most typical symptom for soft-tissue infections. More than half of the patients underwent surgery and received clindamycin. The readmission rate was 7%, and the case fatality rate was 2%. CONCLUSIONS: The incidence rate of pediatric iGAS infections tripled during our study. The increase was not, however, the result of a change in the strain types causing iGAS. Varicella immunization would likely have prevented a significant number of the cases. PMID- 26440813 TI - Reductions in Cortico-Striatal Hyperconnectivity Accompany Successful Treatment of Obsessive-Compulsive Disorder with Dorsomedial Prefrontal rTMS. AB - Obsessive-compulsive disorder (OCD) is a disabling illness with high rates of nonresponse to conventional treatments. OCD pathophysiology is believed to involve abnormalities in cortico-striatal-thalamic-cortical circuits through regions such as dorsomedial prefrontal cortex (dmPFC) and ventral striatum. These regions may constitute therapeutic targets for neuromodulation treatments, such as repetitive transcranial magnetic stimulation (rTMS). However, the neurobiological predictors and correlates of successful rTMS treatment for OCD are unclear. Here, we used resting-state functional magnetic resonance imaging (fMRI) to identify neural predictors and correlates of response to 20-30 sessions of bilateral 10 Hz dmPFC-rTMS in 20 treatment-resistant OCD patients, with 40 healthy controls as baseline comparators. A region of interest in the dmPFC was used to generate whole-brain functional connectivity maps pre-treatment and post treatment. Ten of 20 patients met the response criteria (?50% improvement on Yale Brown Obsessive-Compulsive Scale, YBOCS); response to dmPFC-rTMS was sharply bimodal. dmPFC-rTMS responders had higher dmPFC-ventral striatal connectivity at baseline. The degree of reduction in this connectivity, from pre- to post treatment, correlated to the degree of YBOCS symptomatic improvement. Baseline clinical and psychometric data did not predict treatment response. In summary, reductions in fronto-striatal hyperconnectivity were associated with treatment response to dmPFC-rTMS in OCD. This finding is consistent with previous fMRI studies of deep brain stimulation in OCD, but opposite to previous reports on mechanisms of dmPFC-rTMS in major depression. fMRI could prove useful in predicting the response to dmPFC-rTMS in OCD. PMID- 26440815 TI - The Whole School, Whole Community, Whole Child model: a new approach for improving educational attainment and healthy development for students. AB - BACKGROUND: The Whole Child approach and the coordinated school health (CSH) approach both address the physical and emotional needs of students. However, a unified approach acceptable to both the health and education communities is needed to assure that students are healthy and ready to learn. METHODS: During spring 2013, the ASCD (formerly known as the Association for Supervision and Curriculum Development) and the US Centers for Disease Control and Prevention (CDC) convened experts from the field of education and health to discuss lessons learned from implementation of the CSH and Whole Child approaches and to explore the development of a new model that would incorporate the knowledge gained through implementation to date. RESULTS: As a result of multiple discussions and review, the Whole School, Whole Community, Whole Child (WSCC) approach was developed. The WSCC approach builds upon the traditional CSH model and ASCD's Whole Child approach to learning and promotes greater alignment between health and educational outcomes. CONCLUSION: By focusing on children and youth as students, addressing critical education and health outcomes, organizing collaborative actions and initiatives that support students, and strongly engaging community resources, the WSCC approach offers important opportunities that will improve educational attainment and healthy development for students. PMID- 26440817 TI - Lessons learned from the whole child and coordinated school health approaches. AB - BACKGROUND: The new Whole School, Whole Community, Whole Child (WSCC) model, designed to depict links between health and learning, is founded on concepts of coordinated school health (CSH) and a whole child approach to education. METHODS: The existing literature, including scientific articles and key publications from national agencies and organizations, was reviewed and synthesized to describe (1) the historical context for CSH and a whole child approach, and (2) lessons learned from the implementation and evaluation of these approaches. RESULTS: The literature revealed that interventions conducted in the context of CSH can improve health-related and academic outcomes, as well as policies, programs, or partnerships. Several structural elements and processes have proved useful for implementing CSH and a whole child approach in schools, including use of school health coordinators, school-level and district-level councils or teams; systematic assessment and planning; strong leadership and administrative support, particularly from school principals; integration of health-related goals into school improvement plans; and strong community collaborations. CONCLUSIONS: Lessons learned from years of experience with CSH and the whole child approaches have applicability for developing a better understanding of the WSCC model as well as maximizing and documenting its potential for impacting both health and education outcomes. PMID- 26440816 TI - Critical connections: health and academics. AB - BACKGROUND: While it is a national priority to support the health and education of students, these sectors must better align, integrate, and collaborate to achieve this priority. This article summarizes the literature on the connection between health and academic achievement using the Whole School, Whole Community, and Whole Child (WSCC) framework as a way to address health-related barriers to learning. METHODS: A literature review was conducted on the association between student health and academic achievement. RESULTS: Most of the evidence examined the association between student health behaviors and academic achievement, with physical activity having the most published studies and consistent findings. The evidence supports the need for school health services by demonstrating the association between chronic conditions and decreased achievement. Safe and positive school environments were associated with improved health behaviors and achievement. Engaging families and community members in schools also had a positive effect on students' health and achievement. CONCLUSIONS: Schools can improve the health and learning of students by supporting opportunities to learn about and practice healthy behaviors, providing school health services, creating safe and positive school environments, and engaging families and community. This evidence supports WSCC as a potential framework for achieving national educational and health goals. PMID- 26440818 TI - What have we learned from collaborative partnerships to concomitantly improve both education and health? AB - BACKGROUND: Collaborative partnerships are an essential means to concomitantly improve both education outcomes and health outcomes among K-12 students. METHODS: We describe examples of contemporaneous, interactive, and evolving partnerships that have been implemented, respectively, by a national governmental health organization, national nongovernmental education and health organizations, a state governmental education organization, and a local nongovernmental health organization that serves partner schools. RESULTS: Each of these partnerships strategically built operational infrastructures that enabled partners to efficiently combine their resources to improve student education and health. CONCLUSIONS: To implement a Whole School, Whole Community, Whole Child Framework, we need to purposefully strengthen, expand, and interconnect national, state, and local collaborative partnerships and supporting infrastructures that concomitantly can improve both education and health. PMID- 26440819 TI - How the Whole School, Whole Community, Whole Child model works: creating greater alignment, integration, and collaboration between health and education. AB - BACKGROUND: The Whole School, Whole Community, Whole Child (WSCC) model calls for greater collaboration across the community, school, and health sectors to meet the needs and support the full potential of each child. This article reports on how 3 states and 2 local school districts have implemented aspects of the WSCC model through collaboration, leadership and policy creation, alignment, and implementation. METHODS: We searched state health and education department websites, local school district websites, state legislative databases, and sources of peer-reviewed and gray literature to identify materials demonstrating adoption and implementation of coordinated school health, the WSCC model, and associated policies and practices in identified states and districts. We conducted informal interviews in each state and district to reinforce the document review. RESULTS: States and local school districts have been able to strategically increase collaboration, integration, and alignment of health and education through the adoption and implementation of policy and practice supporting the WSCC model. Successful utilization of the WSCC model has led to substantial positive changes in school health environments, policies, and practices. CONCLUSIONS: Collaboration among health and education sectors to integrate and align services may lead to improved efficiencies and better health and education outcomes for students. PMID- 26440820 TI - Placing students at the center: the Whole School, Whole Community, Whole Child model. AB - BACKGROUND: Students are the heart of the Whole School, Whole Community, Whole Child (WSCC) model. Students are the recipients of programs and services to ensure that they are healthy, safe, engaged, supported, and challenged and also serve as partners in the implementation and dissemination of the WSCC model. METHODS: A review of the number of students nationwide enjoying the 5 Whole Child tenets reveals severe deficiencies while a review of student-centered approaches, including student engagement and student voice, appears to be one way to remedy these deficiencies. RESULTS: Research in both education and health reveals that giving students a voice and engaging students as partners benefits them by fostering development of skills, improvement in competence, and exertion of control over their lives while simultaneously improving outcomes for their peers and the entire school/organization. CONCLUSIONS: Creating meaningful roles for students as allies, decision makers, planners, and consumers shows a commitment to prepare them for the challenges of today and the possibilities of tomorrow. PMID- 26440821 TI - Supporting the whole child through coordinated policies, processes, and practices. AB - BACKGROUND: The Whole School, Whole Community, Whole Child (WSCC) model provides a framework for promoting greater alignment, integration, and collaboration between health and education across the school setting and improving students' cognitive, physical, social, and emotional development. By providing a learning environment that ensures each student is emotionally and physically healthy, safe, actively engaged, supported, and challenged, the WSCC model presents a framework for school systems to evaluate, streamline, implement, and sustain policies, processes, and practices. METHODS: This article examines the essential roles of the school district and of schools in aligning, developing, and implementing policy, processes, and practices to create optimal learning environments that support the whole child. RESULTS: Three key factors advance efforts to align policies, processes, and practices. These include hiring a coordinator at the district and school levels, having collaborative teams address health and learning at the district and school levels, and using data to make decisions and build health outcomes into school and district accountability systems. CONCLUSIONS: These key factors provide a road map for successfully implementing WSCC. More research is needed to determine the extent that coordinators, collaborative teams, and the inclusion of health indicators in accountability systems impact student health and learning. PMID- 26440822 TI - A whole school approach: collaborative development of school health policies, processes, and practices. AB - BACKGROUND: The Whole School, Whole Community, Whole Child (WSCC) model shows the interrelationship between health and learning and the potential for improving educational outcomes by improving health outcomes. However, current descriptions do not explain how to implement the model. METHODS: The existing literature, including scientific articles, programmatic guidance, and publications by national agencies and organizations, was reviewed and synthesized to describe an overview of interrelatedness of learning and health and the 10 components of the WSCC model. RESULTS: The literature suggests potential benefits of applying the WSCC model at the district and school level. But, the model lacks specific guidance as to how this might be made actionable. A collaborative approach to health and learning is suggested, including a 10-step systematic process to help schools and districts develop an action plan for improving health and education outcomes. Essential preliminary actions are suggested to minimize the impact of the challenges that commonly derail systematic planning processes and program implementation, such as lack of readiness, personnel shortages, insufficient resources, and competing priorities. CONCLUSIONS: All new models require testing and evidence to confirm their value. District and schools will need to test this model and put plans into action to show that significant, substantial, and sustainable health and academic outcomes can be achieved. PMID- 26440823 TI - Building sustainable health and education partnerships: stories from local communities. AB - BACKGROUND: Growing health disparities have a negative impact on young people's educational achievement. Community schools that involve deep relationships with partners across multiple domains address these disparities by providing opportunities and services that promote healthy development of young people, and enable them to graduate from high school ready for college, technical school, on the-job training, career, and citizenship. METHODS: Results from Milwaukie High School, North Clackamas, OR; Oakland Unified School District, Oakland, CA; and Cincinnati Community Learning Centers, Cincinnati, OH were based on a review of local site documents, web-based information, interviews, and e-mail communication with key local actors. RESULTS: The schools and districts with strong health partnerships reflecting community schools strategy have shown improvements in attendance, academic performance, and increased access to mental, dental, vision, and health supports for their students. CONCLUSIONS: To build deep health education partnerships and grow community schools, a working leadership and management infrastructure must be in place that uses quality data, focuses on results, and facilitates professional development across sectors. The leadership infrastructure of community school initiatives offers a prototype on which others can build. Moreover, as leaders build cross-sector relationships, a clear definition of what scaling up means is essential for subsequent long-term systemic change. PMID- 26440824 TI - Using the Whole School, Whole Community, Whole Child model: implications for practice. AB - BACKGROUND: Schools, school districts, and communities seeking to implement the Whole School, Whole Community, Whole Child (WSCC) model should carefully and deliberately select planning, implementation, and evaluation strategies. METHODS: In this article, we identify strategies, steps, and resources within each phase that can be integrated into existing processes that help improve health outcomes and academic achievement. Implementation practices may vary across districts depending upon available resources and time commitments. RESULTS: Obtaining and maintaining administrative support at the beginning of the planning phase is imperative for identifying and implementing strategies and sustaining efforts to improve student health and academic outcomes. Strategy selection hinges on priority needs, community assets, and resources identified through the planning process. Determining the results of implementing the WSCC is based upon a comprehensive evaluation that begins during the planning phase. Evaluation guides success in attaining goals and objectives, assesses strengths and weaknesses, provides direction for program adjustment, revision, and future planning, and informs stakeholders of the effect of WSCC, including the effect on academic indicators. CONCLUSIONS: With careful planning, implementation, and evaluation efforts, use of the WSCC model has the potential of focusing family, community, and school education and health resources to increase the likelihood of better health and academic success for students and improve school and community life in the present and in the future. PMID- 26440825 TI - Novel computer vision algorithm for the reliable analysis of organelle morphology in whole cell 3D images--A pilot study for the quantitative evaluation of mitochondrial fragmentation in amyotrophic lateral sclerosis. AB - The function of intact organelles, whether mitochondria, Golgi apparatus or endoplasmic reticulum (ER), relies on their proper morphological organization. It is recognized that disturbances of organelle morphology are early events in disease manifestation, but reliable and quantitative detection of organelle morphology is difficult and time-consuming. Here we present a novel computer vision algorithm for the assessment of organelle morphology in whole cell 3D images. The algorithm allows the numerical and quantitative description of organelle structures, including total number and length of segments, cell and nucleus area/volume as well as novel texture parameters like lacunarity and fractal dimension. Applying the algorithm we performed a pilot study in cultured motor neurons from transgenic G93A hSOD1 mice, a model of human familial amyotrophic lateral sclerosis. In the presence of the mutated SOD1 and upon excitotoxic treatment with kainate we demonstrate a clear fragmentation of the mitochondrial network, with an increase in the number of mitochondrial segments and a reduction in the length of mitochondria. Histogram analyses show a reduced number of tubular mitochondria and an increased number of small mitochondrial segments. The computer vision algorithm for the evaluation of organelle morphology allows an objective assessment of disease-related organelle phenotypes with greatly reduced examiner bias and will aid the evaluation of novel therapeutic strategies on a cellular level. PMID- 26440827 TI - Rehabilitation lessons from the 2005 Pakistan earthquake and others since - looking back and ahead? PMID- 26440826 TI - GSK-3beta controls autophagy by modulating LKB1-AMPK pathway in prostate cancer cells. AB - BACKGROUND: Glycogen synthase kinase 3beta (GSK3B, GSK-3beta) is a multi functional protein kinase involved in various cellular processes and its activity elevates after serum deprivation. We have shown that inhibition of GSK-3beta activity triggered a profound autophagic response and subsequent necrotic cell death after serum deprivation in prostate cancer cells. In this study, we dissected the mechanisms involved in GSK-3beta inhibition-triggered autophagy. METHODS: Prostate cancer PC-3 and DU145 cells were used in the study. Multiple GSK-3beta specific inhibitors were used including small chemicals TDZD8, Tideglusib, TWS119, and peptide L803-mts. Western blot assay coupled with phospho specific antibodies were used in detecting signal pathway activation. ATP levels were assessed with ATPLite kit and HPLC methods. Autophagy response was determined by evaluating Microtubule-associated proteins 1A/1B light chain 3B (LC3B) processing and p62 protein stability in Western blot assays. Immunofluorescent microscopy was used to detect LKB1 translocation. RESULTS: Inhibition of GSK-3beta activity resulted in a significant decline of cellular ATP production, leading to a significant increase of AMP/ATP ratio, a strong trigger of AMP-activated protein kinase (AMPK) activation in prostate cancer PC-3 cells. In parallel with increased LC-3B biosynthesis and p62 protein reduction, the classical sign of autophagy induction, AMPK was activated after inhibition of GSK-3beta activity. Further analysis revealed that Liver kinase B1 (LKB1) but not Calcium/calmodulin-dependent protein kinase kinase beta (CaMKKbeta) is involved in AMPK activation and autophagy induction triggered by GSK-3beta inhibition. Meanwhile, GSK-3beta inhibition promoted LKB1 translocation from nuclear to cytoplasmic compartment and enhanced LKB1 interaction with its regulatory partners Mouse protein-25 (MO25) and STE20-related adaptor (STRAD). CONCLUSIONS: In conclusion, our data suggest that GSK-3beta plays an important role in controlling autophagy induction by modulating the activation of LKB1-AMPK pathway after serum deprivation. PMID- 26440828 TI - Clinical practice guidelines and introduction of CME/CPD for all GPs and specialist: A science of continuing medical education, should it be considered mandatory? PMID- 26440829 TI - The effect of home-based pulmonary rehabilitation on self-efficacy in chronic obstructive pulmonary disease patients. AB - OBJECTIVE: To investigate the effect of pulmonary rehabilitation on the self efficacy of patients with chronic obstructive pulmonary disease. METHODS: The randomised case-control trial was conducted from December 2010 to February 2011 at Masih-Daneshvari Hospital, Tehran, Iran, in an outpatient clinic and comprised patients with mild to moderate chronic obstructive pulmonary disease. The patients were randomly divided into experimental and control groups. The pulmonary rehabilitation programme for the experimental group consisted of education about the disease, diet therapy, stress reduction methods, effective cough, breathing exercises, and muscle stretching exercises. The patients were encouraged to practise the programme at home three times per week for 7 weeks. They were followed up through weekly telephone contacts. The control group received only routine visits and weekly telephone follow-up. Data were gathered using the Persian version of chronic obstructive pulmonary disease self-efficacy scale, which was filled out at baseline and 7 weeks post-intervention. SPSS 16 was used for statistical analysis. RESULTS: Of the 66 patients in the study, 34(51.5%) were in cases and 32(48.5%) were controls. The overall mean age was 56.65+/-8.83 years and 47(71.2%) were males. There was a significant difference between the two groups in total score of self-efficacy (p<0.001) and so was the case with all subscales of self-efficacy (p<0.001). CONCLUSIONS: Pulmonary rehabilitation programme can be used by nurses during discharge planning for patients in order to improve all subscales of self-efficacy of those suffering from chronic obstructive pulmonary disease. PMID- 26440830 TI - Premarital genetic screening for beta thalassemia carrier status of indexed families using HbA2 electrophoresis. AB - OBJECTIVE: To devise a strategy for prevention of beta thalassemia in newborns through reliable screening of indexed families. METHODS: The cross-sectional study was conducted over six months in 2011 and comprised blood samples collected from subjects belonging to different ethnic groups from families of beta thalassemia major children registered with the Abbottonian Medical Association Blood Care Centre, Abbottabad, in Pakistan's Khyber Pakhtunkhwa province. Electrophoretic separation of human haemoglobin like A, F, S and C was done and then haemoglobin in the gel was immobilised in a fixative solution and the gel was dried to a film. Haemoglobin pattern was visualised by staining the film with a protein-specific stain. The pattern was quantified by densitometry. RESULTS: Of the 98 samples, 57(58.2%) had b-thalassemia trait with elevated haemoglobin alpha 2 level, and 41(41.8%) had normal level. Out of the 57 carriers, 33(57.89%) were males and 24(42.10%) were females. Mean age of carriers was 11.65+/-6.25 years compared to 10.93+/-7.75 in normal patients. Mean haemoglobin alpha 2 level of carriers was 5.2+/-0.56% compared to 2.34+/-0.57% in normal subjects. CONCLUSIONS: Carrying out mass screening programmes throughout Pakistan for the detection of thalassemia carriers and providing them the benefit of marriage counselling may decrease the incidence of thalassemia Major. PMID- 26440831 TI - Perceptions of undergraduate medical students regarding case based learning and tutorial format. AB - OBJECTIVE: To evaluate the perception of medical students regarding tutorial and case-based learning formats. METHODS: The within stage mixed model research was conducted at the Army Medical College, National University of Sciences and Technology, Islamabad, Pakistan, from April 2012 to March 2013, and comprised medical students of 4th year. Data-collection tool was a self-developed questionnaire, and it was statistically analysed using SPSS 16. RESULTS: Of the 144 students, 86(60%) were males. The overall age range was 21.5-23.4 years. Case based learning method had significantly higher scores compared to tutorial method for learning process (p<0.001), for behavioural influence of facilitators (p<0.001), for group dynamics (p<0.001), and for learning environment (p<0.001). For open-ended questions regarding like or dislike of the two methods, majority named some faculty members as their role models and appreciated their support in better and in-depth learning through case-based learning format. CONCLUSIONS: Case-based learning format was significantly more appreciated and favoured as a learning strategy by students. PMID- 26440832 TI - Frequency of corneal dystrophies on the basis of histopathology in surgically removed corneas. AB - OBJECTIVE: To assess the frequency of corneal dystrophies on the basis of histopathology in surgically-removed corneas. METHODS: The descriptive study was conducted at Foundation University Medical College, Islamabad, and Al Shifa Eye Hospital, Rawalpindi, Pakistan, from May to October 2011, and comprised post keratoplasty corneal specimen irrespective of age and gender. The surgically removed corneas were processed according to the standard guidelines of histopathological processing. The histopathological sections were examined for various corneal dystrophies. Data was recorded on a proforma and was analysed using SPSS 17. RESULTS: Of the 63 patients in the study, 12(19%) were diagnosed as having corneal dystrophies. In these 12 patients, 6(50%)were diagnosed as stromal corneal dystrophies and 5(42%)had posterior corneal dystrophies, and 1(8%)had anterior corneal dystrophy. CONCLUSIONS: Histopathological examination of corneas is a reliable method to diagnose and classify corneal dystrophies. PMID- 26440833 TI - Socio-demographic risk factors of mobility dysfunction and limitations in physical functioning disability among the elderly in Iran: A nationwide cross sectional survey. AB - OBJECTIVE: To examine self-reported mobility and limitation in physical functioning among the elderly and associated socio-demographic risk factors. METHODS: The population-based cross-sectional study was conducted from January 2012 to January 2013 and comprised subjects from five provinces of Iran. The variables were measured using a questionnaire. Self-reported mobility disability and physical functioning disability were defined as having no problems in daily activities and physical tasks. Logistic regression was used to calculate the odds ratio for association of socio-demographic risk factors and outcomes. RESULTS: Of the 1325 subjects, 636(48%) were men. The overall mean age was 69.14+/-7.37 years. Prevalence of mobility disability and limitation in physical functioning was 401(63%) and 553(87%) in men, and 524(76%) and 641(93%) in women. There was a significant association between mobility disability and family composition and satisfaction with financial situation and housing tenure in both genders (p<0.05 each). Physical functioning had a significant relationship with family composition, and satisfaction with financial situations and housing tenure in men and women and population density in men and marital status in women (p<0.05 each). CONCLUSIONS: The elderly had a high risk of disability. Social factors had more association with mobility disability and limitation in physical functioning and required specific social support. PMID- 26440834 TI - Short term outcome and predictors of response to neoadjuvant treatment in rectal cancer. AB - OBJECTIVE: To evaluate response to neoadjuvant chemoradiation in the treatment of rectal cancer and to see if it can be predicted whether a particular patient will benefit from such treatment. METHODS: The retrospective case series was done at the Aga Khan University Hospital, Karachi, and comprised data related to period from January 2005 to December 2014 of patients with rectal cancer who had received neoadjuvant treatment. They were divided into responders and non responders on the basis of imaging. Pre-treatment factors were compared to identify differences in the two groups. SPSS 19 was used for statistical analysis. RESULTS: The median age of 35 patients whose records were studied was 44 years (interquartile range: 33-54). Response to neoadjuvant treatment was seen in 13(37%) patients with complete pathological response in 8(22.9%). There was no statistically significant difference in age, gender, pre-treatment tumour stage, tumour biology and distance from anal verge among the responders and the non responders (p>0.05 each). CONCLUSIONS: Response to neoadjuvant treatment in rectal cancer was low. PMID- 26440835 TI - Challenges of providing timely feedback to residents: Faculty perspectives. AB - OBJECTIVE: To explore faculty's perceptions of challenges in providing verbal feedback to the Residents and suggest ways to overcome the barriers. METHODS: As part of a larger study on feedback assessment, five focus group discussions were conducted at the Department of Medicine, Aga Khan University Hospital, Karachi, during faculty development workshops held from January to June 2010. Qualitative grounded theory was used to explore faculty perceptions of challenges in providing verbal feedback to the Residents. RESULTS: Of the 54 faculty members, 49(91%) participated. Four themes that emerged were 'time constraint' indicating high patient load; 'faculty related issues' indicating faculty's apprehension about its own evaluation by Residents; 'educational issues' indicating that the importance of feedback was not emphasised; and 'system and logistic issues' indicating that the assessment form used for assessing Residents was ambiguous. CONCLUSIONS: Work load of the faculty and the expectations with respect to patient care responsibilities may have an impact on the quality, timing, content and delivery of the feedback provided to the Residents. PMID- 26440836 TI - Knowledge, attitude and practices amongst the Pakistani females towards breast cancer screening programme. AB - OBJECTIVE: To assess the knowledge, attitude and practices amongst Pakistani females towards breast screening programmes. METHODS: The descriptive cross sectional study was conducted from June 2013 to July2014 at Mayo Hospital, Lahore, and comprised attendants and patients who visited out-patients department and/or were treated as in-patients. The questionnaire contained 25 open and close ended questions regarding knowledge and attitude, along with 7 questions regarding practices. Data was analysed using SPSS 17. RESULTS: There were 1184 women with a mean age of 32.7+/-8.6 years. The mean score was 12.7+/-4.9. Positive family history of breast cancer was reported by 156(13.2%) women; 420(35.5%) believed advancing age was a risk factor; 1041(87.9%) never had breast self-examination; 1106(93.4%) never had a clinical breast examination; and 1171(98.9%) never had screening mammogram. CONCLUSIONS: The knowledge and practices regarding breast cancer screening, breast self-examination and mammogram among women were not good. The knowledge about breast cancer risk factors was very poor and showed an alarming attitude towards practices. PMID- 26440837 TI - The effects of healthy lifestyle behaviors of mothers on obesity in preschool children. AB - OBJECTIVE: To determine the relationship between healthy lifestyle behaviours of mothers and obesity in their pre-school children. METHODS: The cross-sectional study was performed in a district of Istanbul, Turkey, between April and June 2011, and comprised children aged 4-6 years attending public pre-schools and their mothers.. Data was obtained using a questionnaire and Healthy Lifestyle Behaviours Scale-II. Number Cruncher Statistical System 2007 was used for statistical analysis. RESULTS: Of the 531 children in the study, 246(46.3%) were girls. Overall prevalence of overweight was 136(25.6%), obesity 77(14.5%)Overweight mothers were 126(23.7%), and obese mothers were 31(5.8%). The mothers of obese children obtained lower scores in the physical activity (p<0.05) and nutrition (p=0.001) subscales, and their total score was also lower (p<0.05).. CONCLUSIONS: Lifestyle behaviours of mothers, especially with respect to nutrition and physical activity, may influence obesity among preschool children. Strategies should be developed to improve the physical activity and eating habits of mothers. PMID- 26440838 TI - Role of vitamin E in preventing arteriohyalinization in kidneys of streptozotocin induced diabetic mice. AB - OBJECTIVE: To evaluate the role of vitamin E on the arteriolar hyalinisation in kidneys of diabetic mice. METHODS: The laboratory-based randomised control trial was conducted at the Department of Anatomy, Army Medical College, Rawalpindi, in collaboration with National Institute of Health, Islamabad, from November 2009 to November 2010. Adult female BALB/C mice were randomly divided into three groups. Group A served as control group. Group B was made diabetic by the intraperitoneal injection of streptozotocin. Group C received streptozotocin injection and was fed with vitamin E (alphatocopherol) supplemented diet. After 12 weeks,the animals were sacrificed and their kidneys were removed for histomorphological study. SPSS 16 was used for statistical analysis. RESULTS: Diabetes caused significant histomorphological changes in arteriole of kidneys of Experimental Group B compared to Control Group A (p>0.05), but these changes were prevented in Group C. In experimental group B, 2(20%) animals had arteriolar hyalinisation of score 1, while score 2 was revealed in 8(80%) animals. Experimental group C showed no hyalinisation in any arteriole. CONCLUSIONS: Vitamin E prevents the arteriohyalinization in kidneys of mice with STZ induced diabetes. PMID- 26440839 TI - Root cause analysis of methicillin resistant Staphylococcus aureus bacteraemia. AB - OBJECTIVE: To find the important risk factors and sources of bacteraemia in patients suffering from methicillin-resistant staphylococcus aureus bacteraemia. METHODS: The descriptive study was carried out at Shaikh Zayed Hospital, Lahore, from October 2010 to August 2011. Blood cultures were processed to isolate methicillin-resistant staphylococcus aureus. A questionnaire was completed by the participating patients suffering from bacteraemia. Information about risk factors present at the time and risk factors that served as the source of bacteraemia were noted. RESULTS: Total 4058 blood cultures were processed and 669(16.5%) were positive. Of them, 194(29%) cultures were found to be positive for staphylococci. Out of these 194 blood cultures, coagulase-negative staphylococci were isolated from 117(60%), and 77(40%) were positive for S. aureus. Out of these 77 samples, 26(34%) were found to be methicillin-sensitive staphylococcus aureus and 51(66%) were methicillin-resistant staphylococcus aureus. The overall frequency of methicillin-resistant staphylococcus aureus was 1.25%; 7.62% out of positive blood culture; 26.28% out of total staphylococci; and 66% out of total S. aureus. As for the source of infection, central venous pressure line 11(21.6%), post influenza pneumonia 9(17.6%), peripheral intravenous line 8(15.7%) and dialysis line 7(13.7%) were major reasons. CONCLUSIONS: Taking care of aseptic measures while insertion, frequent change and early removal of the central venous and dialysis lines is of critical significance. PMID- 26440840 TI - Role of nicotine and camellia sinensis on the developing femur of chick. AB - OBJECTIVE: To study the harmful effects of nicotine on the developing femur of chick and to observe the role of antioxidant camellia sinensis in the prevention of these effects. METHODS: The experimental study was conducted at Army Medical College, Rawalpindi, from November 2, 2011, to November 1, 2012, and comprised fresh fertilised eggs of Fayoumi species at zero hour of incubation of Fayoumi species. The eggs were divided into four equal groups. Control group G1 was given normal saline; G2 was given green tea extract; G3 was given 0.0001% nicotine solution; and G4 was given both 0.0001% nicotine solution and green tea extract. First exposure was at 48 hours of incubation and second at 48 hours of hatching (post-natal dose).At the age of one month, the chicks were sacrifised. The length of the femurs was measured with the help of measuring scale by keeping the ruler between greater trochanter and the lateral condyle. SPSS 16 was used for statistical analysis. RESULTS: The four groups had 10 eggs each. G3 and G4 showed decreased growth compared to G1 and G2 (p<0.05). In G4, better growth was noticed compared to G3 (p<0.05), but its growth was less in comparison with G1 and G2(p>0.05). CONCLUSIONS: Camellia sinensis antioxidant property helped to neutralise the oxidative injury by the use of nicotine, but was unable to recover it fully. PMID- 26440842 TI - Fresh garlic amelioration of high-fat-diet induced fatty liver in albino rats. AB - OBJECTIVE: To observe the effect of fresh garlic on high-fat-diet-induced fatty liver changes. METHODS: The experimental study was conducted at the Jinnah Postgraduate Medical Centre, Karachi, from October to November 2008, and comprised adult albino rats weighing 200-240g each. The rats were divided into 5 groups according to dietary regimen for eight weeks each. Group A received control diet; Group B received high saturated fat diet; Group C received high unsaturated fat diet; Group D received high saturated fat diet with fresh garlic; and Group E received high unsaturated fat diet with garlic for 8 weeks. Liver tissue slides were stained with Oil red-O and haematoxylin and Periodic acid Schiff-haematoxylin. RESULTS: The 50 rats in the study were divided into five groups of 10(20%) each. There was marked deposition of fat in hepatocyte along with marked decrease in glycogen content in liver of rats in Groups B and C, with Group B showing more marked changes. The changes in fat and glycogen content were reversed and ameliorated close to Group A in rats belonging to Groups D and E. CONCLUSIONS: Fresh garlic minimised the high-fat-diet-induced fatty liver changes in rats. PMID- 26440841 TI - Pregnancy of unknown location: Outcome in a tertiary care hospital. AB - OBJECTIVE: To find out the outcome of a cohort of women with pregnancy of unknown location presenting to a tertiary care hospital. METHODS: The prospective study was conducted from January to December, 2011, at Early Pregnancy Assessment Unit, King Faisal Military Hospital, Khamis Mushait, Saudi Arabia. Data was collected for women with early pregnancy or with history of amenorrhoea, bleeding or pain. These women were investigated with serum beta-human chorionic gonadotrophin levels twice weekly and transvaginal ultrasonography weekly. Expectant management was done for failing pregnancy of unknown location while medical or surgical management was considered for persistent pregnancy of unknown location and ectopic pregnancy. RESULTS: During study period, 7215 patients were admitted, and, of them, 2212(30.6%) were patients with early pregnancy. Meeting the inclusion criteria were 183(2.53%) patients who formed the study sample. There were 131(71.6%) patients presenting with amenorrhoea, 90(49.2%) had bleeding and 93(50.8%) presented with pain. Outcome of 100(54.6%) patients was failing pregnancy of unknown location, 58(31.7%) had intrauterine pregnancy, 14(7.7%) converted to ectopic pregnancy, while 11(6%) had persistent pregnancy of unknown location. All patients with persistent pregnancy of unknown location and 5(36%) patients with ectopic pregnancy were medically treated. Five (36%) patients having ectopic pregnancy were managed surgically. CONCLUSIONS: Management of choice for asymptomatic patients having pregnancy of unknown location is expectant management. Most of the patients suspected to have Most of the patients with persistent pregnancy of unknown location and ectopic pregnancy can be managed medically. PMID- 26440843 TI - The awareness of experience innovation and an application in private hospitals. AB - OBJECTIVE: To evaluate the perspective of private hospitals regarding experience innovation. METHODS: The qualification-type study was conducted in Istanbul, Turkey, in February 2015, and comprised 17 hospitals where patients and employees were interviewed using a semi-structured consultation guide. The employees were examined regarding the meaning of innovation, awareness of experience innovation and its measurement. The patients were asked about the reason for choosing a hospital, the actual reason for arrival at the hospital and the impressions while leaving the hospital. Based on the obtained answers, experience innovation was examined. RESULTS: Of the 87 subjects interviewed, 51(59%) were patients and 36(41%) were hospital employees. Overall, there were 61(70%) women and 26(30%) men in the age range of 21-75 years. It was observed that the tendencies of hospitals for innovation activities were high, but they confused it with novelty. CONCLUSIONS: Investments made without taking experience innovation into account do not convert into targeted results. PMID- 26440844 TI - Saudi Arabia: A future regional hub for advanced education, research, science and technology. AB - Saudi Arabia is the largest country of the Arabian Peninsula, blessed with significant natural resources, including oil, gas and minerals. Saudi Arabia has recognised the importance of education in social and economic transformation, and has established a large number of universities, research and advanced technical institutes which have broken the metropolitan boundaries and have been extended to the far-flung areas of the country. There are 68 universities and degree awarding institutes. The educational budget reached its highest-ever level of $56.56 billion for the year 2014. About 124,000 Saudi students are pursuing higher education in about 500 universities around the world. Saudi Arabia produced 177826 research papers in Institute for Scientific Information (ISI) database and in the year 2014 alone, 26168 research papers were published in indexed science journals with a rising h-index of 144. The country is turning into a regional hub for advanced education, research, science and technology while swiftly shifting from an oil-based to a knowledge-based economy. PMID- 26440845 TI - Gender association of prayer for health - perspective from university students in Islamabad and Rawalpindi. AB - The role of religion and spirituality in coping with disease and promoting health has been reported from many parts of the World. However, no scientific studies on the use of prayers for health and wellbeing have been reported from Pakistan. A cross-sectional survey, using a self-administered questionnaire, was conducted among 1342 graduate and undergraduate students in the twin cities of Islamabad and Rawalpindi. A huge majority of students had prayed for their own as well as their family members' health in the preceding three months. There is a need to better understand the role in Pakistan of prayers related to health. PMID- 26440846 TI - A rare and unexpected case of retained foetal bone after an unsafe abortion. AB - Unsafe abortion is one of the most neglected healthcare problems in developing countries. One of the rare complications of unsafe abortion is retained foetal bone. Prevalence of disease is around 0.15% among patients undergoing diagnostic hysteroscopy. Patients have no specific symptoms. Case reports have focused on subfertility, abnormal uterine bleeding, lower abdominal pain, abnormal vaginal discharge, dyspareunia, dysmenorrhoea and spontaneous passage of bony fragments. Retained foetal bone fragments may cause acute pelvic inflammatory disease in rare cases regardless of the time interval after abortion. This condition can also present as recurrent vagitinis or endometritis refractory to ampirical antimicrobial treatment. In such cases, foreign body in uterine cavity should be kept in mind. Such patients should primarily be evaluated by ultrasonography which has substantial clinical importance in differential diagnosis of these cases. We present a case of misdiagnosed retained foetal bone complicated with recurrent vaginal discharge and acute pelvic inflammatory disease. PMID- 26440847 TI - Cryptococcus neoformans and Streptococcus pneumoniae co-infection in post traumatic meningitis in a patient with unknown HIV status. AB - Meningitis is a serious disease associated with considerable morbidity and mortality. Mixed meningeal infections due to bacteria and fungi are exceptionally rare. Here we report a case of meningeal co-infection with cryptococcus neoformans and streptococcus pneumoniae in a patient with unknown human immunodeficiency virus status. Because of the rarity of such cases, stringent screening of every cerebrospinal fluid specimen to exclude the presence of multiple pathogens is imperative. Assessment of patients for immunodeficiencies in case of isolation of an opportunistic organism like cryptococcus is also needed. PMID- 26440848 TI - Autoimmune pancreatitis with extraocular muscles involvement. AB - Autoimmune pancreatitis is characterised by diffuse enlargement of pancreas, narrowing of pancreatic duct, lymphoplasmacytic infiltrations and fibrosis. The disease is responsive to corticosteroid. We report the case of a 32-year-old male who presented with unilateral exophthalmos and obstructive jaundice secondary to pancreatic head mass and biliary tract stricture. Serum immunoglobulin G level was raised with a very high immunoglobulin G4 subclass. Ophthalmological imaging revealed unilateral thickening of extraocular muscles. The patient responded well to corticosteroid with resolution of biliary strictures, pancreatic head mass and exophthalmos. PMID- 26440849 TI - Hereditary Sensory Autonomic Neuropathy II, a rare disease in a large Pakistani family. AB - Hereditary Sensory Autonomic Neuropathy II (HSAN II) is a rare genetic disorder, characterized by severe loss of pain, temperature and touch sensation. Injuries in these patients can progress to necrosis and shedding of digits and limbs. Here we report two cases of HSAN II belonging to a Pakistani family. Individual 1, a forty five year old man, had complete loss of pain sensation since birth. Self mutilation and complication of injuries resulted in the shedding of all the digits and right foot and surgical amputation of left leg. Individual 2, a five year old girl,had delay in healing of wounds and self-mutilation. Examination showed a complete lack of pain sensation throughout her body and hyporeflexia. As the genetic cause of HSAN II is unknown, identification of more patients will allow further research on this disease and possibly develop a cure. PMID- 26440850 TI - Isoniazid induced motor-dominant neuropathy. AB - Isoniazid though a very effective treatment for tuberculosis can cause severe motor-dominant neuropathy which can be reversible with pyridoxine supplementation. A 45-year-old female diagnosed with psoas abscess, culture positive for mycobacterium tuberculosis, was started on anti- tuberculous treatment with four drugs, including isoniazid at a dose of 5 mg/kg/day. Three months later she developed severe motor weakness of lower limbs with loss of ankle and knee reflexes. She was treated with vitamin B6 injections and isoniazid treatment was continued. Her motor weakness gradually improved in a few months, but mild sensory impairment persisted even after two years. There is need for vigilance regarding neurological effects of isoniazid in seemingly low-risk individuals in whom development of symptoms should raise the suspicion about slow acetylator status. Timely therapeutic intervention with high-dose vitamin B6 can reduce the long-term morbidity associated with this easily reversible condition. PMID- 26440851 TI - Breast feeding: preventive therapy for type 2 diabetes. AB - Exclusive breastfeeding for six months, continued along with top feed up to the age of 2 years and beyond, is strongly recommended by the World Health Organization. Apart from the various benefits that it provides, breast feeding may also serve to prevent the development of type 2 diabetes and metabolic syndrome in mothers, and type 1 diabetes and overweight/ obesity in their offspring. This review discusses the evidence related to breastfeeding and type 2 diabetes. It highlights pertinent aspects of breast feeding management, which can help facilitate optimal use of this natural preventive intervention. PMID- 26440852 TI - Psychiatric disorders in diabetes. AB - Diabetes and psychiatric disorders share a bi-directional relationship, with both affecting each other adversely. Just as achieving glycaemic control is important, so is ensuring that the person enjoys a good quality of life. All individuals with diabetes must be screened regularly for co-morbidity, especially depressive and anxiety disorders. Multiple evidence based psychotropic pharmacological interventions are available for management of these psychiatric disorders. Additionally, non-pharmacological interventions play a key role in comprehensive management of such patients. PMID- 26440853 TI - Stepwise and simple guide to medical writing and research for beginners. PMID- 26440854 TI - Life of medical professionals in Pakistan. PMID- 26440855 TI - Effect of nutritional deficiency on the efficacy of the polio vaccines in Pakistan. PMID- 26440856 TI - Laparoscopic-assisted percutaneous endoscopic gastrostomy tube insertion in the immediate post-partum period for head and neck cancer. AB - Percutaneous endoscopic gastrostomy (PEG) tube placement serves as a well tolerated and efficacious technique for long-term enteral access in patients with medical conditions precluding oral food intake. The nutritional optimisation of patients with oral cancer is mostly achieved via PEG tube placement. However, certain special situations, such as pregnancy and the immediate post-partum period, may render the placement of PEG tubes to be a challenge. A 28-year-old pregnant female patient presented to us with the diagnosis of squamous cell carcinoma of the tongue during her third trimester. Definitive surgical resection was planned post-delivery along with simultaneous PEG tube placement. Immediately following delivery via an elective Caesarean section, she successfully underwent laparoscopic-assisted PEG tube placement. A gravid uterus or an immediately post partum distended uterus poses significant difficulties whilst attempting PEG insertion. However, laparoscopic-assisted PEG insertion in a controlled setting may make the process safer to perform. PMID- 26440857 TI - Ethnobotanical study of medicinal plants used by traditional healers in Mascara (North West of Algeria). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plants are considered as a rich source of bioactive compounds. The present study aimed to document the local knowledge of medicinal plants' use by traditional healers in Mascara, North-west Algeria. MATERIALS AND METHODS: The present study was carried out in Mascara (North West of Algeria). Ethnobotanical data were recorded from 43 traditional healers practicing in Mascara. Data collected was analysed using quantitative indices such as the use value (UV), fidelity level (FL) and Informant Consensus Factor (FIC). RESULTS: Traditional healers reported 141 medicinal plant species belonging to 54 families and 125 genera for the treatment of different ailments grouped into 14 ailments categories. Lamiaceae were the most represented family with 19 species (13.57%) followed by Asteracea, Apiaceae and Fabaceae. Thymus vulgaris L. was the most frequently used by local informants, with the highest UV of 0.883 (38 use reports). Our findings revealed that 39 species have not been previously reported as medicinal plants in the region. Furthermore, we report for the first time a total of 100 new therapeutic uses for 37 known plant species. FIC values ranged from 0.125 to 0.658. Gastro-intestinal diseases had the highest FIC (0.658) with 60 species and 261 use reports. CONCLUSION: The present study revealed the important local knowledge as showed by the variety of species used to treat several ailments. Recorded species with high UV should be subjects of further pharmacological studies to validate their popular use and to isolate the bioactive compounds. PMID- 26440858 TI - Development and comparison of a generic multiple-locus variable-number tandem repeat analysis with pulsed-field gel electrophoresis for typing of Salmonella enterica subsp. enterica. AB - AIMS: Salmonella enterica subsp. enterica causes salmonellosis in humans and animals. Serovar-specific multiple-locus variable-number tandem repeat analysis (MLVA) is widely used for Salmonella surveillance; however, isolates have to be serotyped prior to MLVA typing and only the most common serovars can be typed. We developed a MLVA scheme for high-discriminatory typing of Salmonella. METHODS AND RESULTS: Sixty-six unique VNTRs were investigated and the polymorphisms of seven promising VNTRs were evaluated with a panel 163 diverse isolates of 14 serotypes of significance for human health. Five VNTRs were selected for MLVA analysis. The discriminatory power was evaluated within serovars by 163 isolates and MLVA yielded 79 genotypes (DI of 0.9790) and pulsed-field gel electrophoresis (PFGE) revealed 87 genotypes (DI of 0.9989). MLVA divided each serotype into 2-8 different profiles and identified six pairs of outbreak-related strains. CONCLUSIONS: The technique showed a high-discriminatory power within most serotypes comparable with or better than that of PFGE. SIGNIFICANCE AND IMPACT OF THE STUDY: This MLVA assay makes it possible to use a single typing method for Salmonella surveillance and outbreak investigations. This allows inexpensive and fast surveillance for laboratories without resources for both serotyping and molecular typing, e.g. PFGE or sequence-based methods, and thereby improve the effectiveness of epidemiological investigations of Salmonella infections globally. PMID- 26440859 TI - Mesenchymal stromal SB623 cell implantation mitigates nigrostriatal dopaminergic damage in a mouse model of Parkinson's disease. AB - Regenerative medicine for the treatment of motor features in Parkinson's disease (PD) is a promising therapeutic option. Donor cells can simultaneously address multiple pathological mechanisms while responding to the needs of the host tissue. Previous studies have demonstrated that mesenchymal stromal cells (MSCs) promote recovery using various animal models of PD. SanBio Inc. has developed a novel cell type designated SB623, which are adult bone marrow-derived MSCs transfected with Notch intracellular domain. In this preclinical study, SB623 cells protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced nigrostriatal injury when transplanted unilaterally into C57BL/6 mouse striatum 3 days prior to toxin exposure. Specifically, mice with the SB623 cell transplants revealed significantly higher levels of striatal dopamine, tyrosine hydroxylase immunoreactivity and stereological nigral cell counts in the ipsilateral hemisphere vs vehicle-treated mice following MPTP administration. Interestingly, improvement in markers of striatal dopaminergic integrity was also noted in the contralateral hemisphere. These data indicate that MSCs transplantation, specifically SB623 cells, may represent a novel therapeutic option to ameliorate damage related to PD, not only at the level of striatal terminals (i.e. the site of implantation) but also at the level of the nigral cell body. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26440860 TI - Investigation of binding mechanism of novel 8-substituted coumarin derivatives with human serum albumin and alpha-1-glycoprotein. AB - Coumarin molecules have biological activities possessing lipid-controlling activity, anti-hepatitis C activity, anti-diabetic, anti-Parkinson activity, and anti-cancer activity. Here, we have presented an inclusive study on the interaction of 8-substituted-7-hydroxy coumarin derivatives (Umb-1/Umb-2) with alpha-1-glycoprotein (AGP) and human serum albumin (HSA) which are the major carrier proteins in the human blood plasma. Binding constants obtained from fluorescence emission data were found to be KUmb-1=3.1 +/- .01 * 10(4) M(-1), KUmb-2 = 7 +/- .01 * 10(4) M(-1), which corresponds to -6.1 and -6.5 kcal/mol of free energy for Umb-1 and Umb-2, respectively, suggesting that these derivatives bind strongly to HSA. Also these molecules bind to AGP with binding constants of KUmb-1-AGP=3.1 +/- .01 * 10(3) M(-1) and KUmb-2-AGP = 4.6 +/- .01 * 10(3) M(-1). Further, the distance, r between the donor (HSA) and acceptor (Umb-1/Umb-2) was calculated based on the Forster's theory of non-radiation energy transfer and the values were observed to be 1.14 and 1.29 nm in Umb-1-HSA and Umb-2-HSA system, respectively. The protein secondary structure of HSA was partially unfolded upon binding of Umb-1 and Umb-2. Furthermore, site displacement experiments with lidocaine, phenylbutazone (IIA), and ibuprofen (IIIA) proves that Umb derivatives significantly bind to subdomain IIIA of HSA which is further supported by docking studies. Furthermore, Umb-1 binds to LYS402 with one hydrogen bond distance of 2.8 A and Umb-2 binds to GLU354 with one hydrogen bond at a distance of 2.0 A. Moreover, these molecules are stabilized by hydrophobic interactions and hydrogen bond between the hydroxyl groups of carbon-3 of coumarin derivatives. PMID- 26440861 TI - Metabolically healthy obese individuals: Key protective factors. AB - OBJECTIVES: Obesity is a significant quality of life-impairing health problem affecting industrialized nations. However, despite carrying a large fat mass, some very obese individuals exhibit normal metabolic profiles (metabolically healthy obesity). The physiological factors underlying their protective and favorable metabolic profiles remain poorly defined. METHODS: A search of the National Library of Medicine PubMed database was performed using the following keywords: Metabolically healthy obese, metabolically normal obese, insulin resistance, metabolically unhealthy normal weight, and uncomplicated obesity. RESULTS: This article reviewed factors associated with severe obesity that lacks complications, and suggests putative activities by which these obese individuals avoid developing the clinical features of metabolic syndrome, or the metabolic complications associated with severe obesity. CONCLUSIONS: Despite the knowledge that visceral fat deposition is the seminal factor that ultimately causes insulin resistance (IR) and the detrimental inflammatory and hormonal profile that contributes to increase risk for cardiovascular disease, it remains unknown whether metabolically healthy obesity (MHO) has genetic predisposing factors, and whether MHO ultimately succumbs to IR and the metabolic syndrome, indicating a need for prophylatic bariatric surgery. PMID- 26440862 TI - An empirical method to determine inadequacy of dietary water. AB - OBJECTIVES: The physiological regulation of total body water and fluid concentrations is complex and dynamic. The human daily water requirement varies because of differences in body size, dietary solute load, exercise, and activities. Although chronically concentrated urine increases the risk of renal diseases, an empirical method to determine inadequate daily water consumption has not been described for any demographic group; instead, statistical analyses are applied to estimate nutritional guidelines (i.e., adequate intake). This investigation describes a novel empirical method to determine the 24-h total fluid intake (TFI; TFI = water + beverages + moisture in food) and 24-h urine volume, which correspond to inadequate 24-h water intake (defined as urine osmolality of 800 mOsm/kg; U800). METHODS: Healthy young women (mean +/- standard deviation; age, 20 +/- 2 y, mass, 60.8 +/- 11.7 kg; n = 28) were observed for 7 consecutive days. A 24-h urine sample was analyzed for volume and osmolality. Diet records were analyzed to determine 24-h TFI. RESULTS: For these 28 healthy young women, the U800 corresponded to a TFI >=2.4 L/d (>=39 mL/kg/d) and a urine volume >=1.3 L/d. CONCLUSIONS: The U800 method could be employed to empirically determine 24-h TFI and 24-h urine volumes that correspond to inadequate water intake in diverse demographic groups, residents of specific geographic regions, and individuals who consume specialized diets or experience large daily water turnover. Because laboratory expertise and instrumentation are required, this technique provides greatest value in research and clinical settings. PMID- 26440863 TI - Enzyme Substrate Specificity Conferred by Distinct Conformational Pathways. AB - Substrate recognition is one of the hallmarks of enzyme catalysis. Enzyme conformational changes have been linked to selectivity between substrates with little direct evidence. Aldolase, a glycolytic enzyme, must distinguish between two physiologically important substrates, fructose 1-phosphate and fructose 1,6 bisphosphate, and provides an excellent model system for the study of this question. Previous work has shown that isozyme specific residues (ISRs) distant from the active site are responsible for kinetic distinction between these substrates. Notably, most of the ISRs reside in a cluster of five surface alpha helices, and the carboxyl-terminal region (CTR), and cooperative interactions among these helices have been demonstrated. To test the hypothesis that conformational changes are at the root of these changes, single surface-cysteine variants were created with the cysteine located on helices of the cluster and CTR. This allowed for site-specific labeling with an environmentally sensitive fluorophore, and subsequent monitoring of conformational changes by fluorescence emission spectrophotometry. These labeled variants revealed different spectra in the presence of saturating amounts of each substrate, which suggested the occurrence of different conformations. Emission spectra collected at various substrate concentrations showed a concentration dependence of the fluorescence spectra, consistent with binding events. Lastly, stopped-flow fluorescence spectrophotometry showed that the rate of these fluorescence changes was on the same time-scale as catalysis, thus suggesting a link between the different fluorescence changes and events during catalysis. On the basis of these results, we propose that different conformational changes may be a common mechanism for dictating substrate specificity in other enzymes with multiple substrates. PMID- 26440864 TI - Comparing the fixational and functional preferred retinal location in a pointing task. AB - Patients with central vision loss (CVL) typically adopt eccentric viewing strategies using a preferred retinal locus (PRL) in peripheral retina. Clinically, the PRL is defined monocularly as the area of peripheral retina used to fixate small stimuli. It is not clear if this fixational PRL describes the same portion of peripheral retina used during dynamic binocular eye-hand coordination tasks. We studied this question with four participants each with a unique CVL history. Using a scanning laser ophthalmoscope, we measured participants' monocular visual fields and the location and stability of their fixational PRLs. Participants' monocular and binocular visual fields were also evaluated using a computer monitor and eye tracker. Lastly, eye-hand coordination was tested over several trials where participants pointed to and touched a small target on a touchscreen monitor. Trials were blocked and carried out monocularly and binocularly, with a target appearing at 5 degrees or 15 degrees from screen center, in one of 8 locations. During pointing, our participants often exhibited long movement durations, an increased number of eye movements and impaired accuracy, especially in monocular conditions. However, these compensatory changes in behavior did not consistently worsen when loci beyond the fixational PRL were used. While fixational PRL size, location and fixation stability provide a necessary description of behavior, they are not sufficient to capture the pointing PRL used in this task. Generally, patients use a larger portion of peripheral retina than one might expect from measures of the fixational PRL alone, when pointing to a salient target without time constraints. While the fixational and pointing PRLs often overlap, the fixational PRL does not predict the large area of peripheral retina that can be used. PMID- 26440866 TI - Improvement in All-Cause Mortality With Blood Pressure Control in a Group of US Veterans With Drug-Resistant Hypertension. AB - The current definition of drug-resistant hypertension includes patients with uncontrolled (URH) (taking >=3 antihypertensive medications) and controlled hypertension (CRH; blood pressure [BP] <=140/90 mm Hg) (taking >=4 medications). The authors hypothesized that all-cause mortality is reduced when URH is controlled. Qualified patients followed at the Washington DC VA Medical Center were included. BPs were averaged for each year of follow-up. In 2006, among 2906 patients who met the criteria for drug-resistant hypertension, 628 had URH. During follow-up, 234 patients were controlled (group 1) and 394 patients remained uncontrolled (group 2). The mortality rate among patients with URH was 28% (110 of 394) and among patients with CRH was 13% (30 of 234), a 54% reduction (P<.01). Multivariate analysis identified independent predictors of mortality as uncontrolled HTN (hazard ratio, 2.5; 95% confidence interval, 1.67-3.75; P<.01), age (hazard ratio, 1.03; 95% confidence interval, 1.01-1.04; P<.01), and diabetes (hazard ratio, 1.46; 95% confidence interval, 1.04-2.05; P<.027). The authors conclude that controlling drug-resistant hypertension markedly reduces all-cause mortality. PMID- 26440865 TI - Perceptual organization, visual attention, and objecthood. AB - We have previously demonstrated that the mere organization of some elements in the visual field into an object attracts attention automatically. Here, we explored three different aspects of this automatic attentional capture: (a) Does the attentional capture by an object involve a spatial component? (b) Which Gestalt organization factors suffice for an object to capture attention? (c) Does the strength of organization affect the object's ability to capture attention? Participants viewed multi-elements displays and either identified the color of one element or responded to a Vernier target. On some trials, a subset of the elements grouped by Gestalt factors into an object that was irrelevant to the task and not predictive of the target. An object effect - faster performance for targets within the object than for targets outside the object - was found even when the target appeared after the object offset, and was sensitive to target object distance, suggesting that the capture of attention by an object is accompanied by a deployment of attention to the object location. Object effects of similar magnitude were found for objects grouped by a combination of factors (collinearity, closure, and symmetry, or closure and symmetry) or by a single factor when it was collinearity, but not symmetry, suggesting that collinearity, or closure combined with symmetry, suffices for automatic capture of attention by an object, but symmetry does not. Finally, the strength of grouping in modal completion, manipulated by varying contrast polarity between and within elements, affected the effectiveness of the attentional capture by the induced object. PMID- 26440867 TI - Complexities emanating from legalization of marijuana. PMID- 26440868 TI - Moral decision-making among assertive community treatment (ACT) case managers: a focus group study. AB - The context of care in assertive community treatment (ACT) can be precarious and generate ethical issues involving the principles of autonomy and paternalism. This focus group study examined case managers' situated accounts of moral reasoning. Our findings show how they expressed strong moral obligation towards helping the clients. Their moral reasoning reflected a paternalistic position where, on different occasions, the potential benefits of their interventions would be prioritised at the expense of protecting the clients' personal autonomy. The case managers' reasoning emphasised situational awareness, but there was a risk of supporting paternalistic interventions and denying the clients' right to autonomy. PMID- 26440869 TI - Exploring sexual risks in a forensic mental health hospital: perspectives from patients and nurses. AB - Patients utilising forensic mental health inpatient services experience a range of sexual risks, including vulnerability to sexual exploitation and exposure to sexually transmissible infections. However, there is a paucity of research exploring the issue of sexual risks from the standpoint of patients and the nurses who work closely with them in inpatient secure settings. This article presents findings from a qualitative exploratory study, which investigated the views of patients and nurses about sexual relationships in forensic mental health settings. Risk was a major theme arising from the data and is the focus of this article. Subthemes from nurse participants included sexual safety, sexual vulnerability, unplanned pregnancies, and male sexuality issues. Subthemes from patients included risks associated with sexual activity, access to information and sexual health care, unplanned pregnancies, vulnerability, and male sexuality issues. Knowledge about these sexual risks by patients and nurses were well articulated, however information and assistance were considered by patients to be less than satisfactory in improving their knowledge or in providing the support they considered important to reduce sexual risks. The issue of risk needs to be addressed, and nurses would be well placed to contribute; however they require education to improve their ability to provide sexual health education to patients along with strategies to ensure patients receive the support and services they require to reduce their exposure to sexual risks. PMID- 26440870 TI - Medical emergency team response processes for behavioral health inpatient units: implications for nursing education. AB - Following a literature review of nurses' attitudes and perceived barriers regarding the utilization of medical emergency teams (METs) and completing key informant interviews with psychiatric nurses, a questionnaire developed by the researcher was administered to inpatient psychiatric nurses to further examine their attitudes and perceived barriers about MET utilization. Using a 23-item questionnaire, the psychiatric nurses were asked to rate each item using a 5 point Likert scale. Results indicated that nurses did not have a clear understanding of the criteria for calling a MET and also tended to seek out other staff personnel and/or a physician consultation prior to initiating a MET call. Results of this descriptive, quality improvement project were then used to revise and refine nursing education and practice regarding MET utilization. PMID- 26440871 TI - Unmet physical and mental healthcare needs among stimulant-using gay and bisexual homeless men. AB - The aim of this study was to gain a greater understanding of predictors of the unmet physical and mental healthcare needs of homeless, stimulant-using, gay and bisexual (G/B) men. This study correlated baseline self-reported unmet physical and mental healthcare needs among stimulant-using homeless G/B men (n = 422, 18 46 years of age). A structured questionnaire was administered at baseline and data were collected from October 2009 to January 2013. The study was approved by the University of California Human Subjects' Protection committee and the Friends Research Institute Human Research Protection Committee. Logistic regression revealed that those who self-reported ever being married, being in fair or poor health and in moderate-to-very severe pain, were more likely to experience unmet needs for physical health care. In terms of unmet mental health needs, those who self-reported moderate-to-very severe pain and/or those reporting having sex while high, were more likely to report unmet needs for mental health care. In contrast, those reporting receiving social support from others were less likely to have an unmet mental healthcare need. Research implications are discussed as they relate to access to healthcare needs among this vulnerable population. PMID- 26440872 TI - Apathy: who cares? A concept analysis. AB - Apathy has been identified as an independent clinical syndrome. As prevalent and problematic as it is in the field of neuropsychiatry, there is no fully accepted definition of apathy. In this study, a concept analysis utilizing Rodgers' evolutionary approach was performed. CINAHL Plus with Full Text was searched, and altogether 36 publications were identified for the concept analysis. Our study shows that psychometric scales may have resulted in an inappropriate diagnosis of depression instead of apathy. As a whole, the literature showed that apathy was defined in comparison to depression as well as altered motivation, emotionality, activity, interest, and initiative. We discuss the advances in the development of apathy as an evolutionary concept. Consistent with Rodgers' evolutionary method, these findings are not an endpoint. PMID- 26440873 TI - A synthesis of the literature on trauma-informed care. AB - Patients with a history of traumatic life events can become distressed or re traumatized as the result of healthcare experiences. These patients can benefit from trauma-informed care that is sensitive to their unique needs. However, despite the widespread prevalence of traumatic life experiences such as sexual assault and intimate partner violence, trauma-informed care has not been widely researched or implemented. The purpose of this synthesis of the literature is to examine existing research on trauma-informed care for survivors of physical and sexual abuse. The following themes are discussed: trauma screening and patient disclosure, provider-patient relationships, minimizing distress and maximizing autonomy, multidisciplinary collaboration and referrals, and trauma-informed care in diverse settings. This synthesis also explores implications for trauma informed care research, practice and policy. The themes identified here could be used as a framework for creating provider and survivor educational interventions and for implementing trauma-informed care across disciplines. The findings of this synthesis support further research on patient and provider experiences of trauma-informed care, and research to test the efficacy of trauma-informed care interventions across healthcare settings. Universal implementation of trauma informed care can ensure that the unique needs of trauma survivors as patients are met, and mitigate barriers to care and health disparities experienced by this vulnerable population. PMID- 26440875 TI - The leadership role of nurse educators in mental health nursing. AB - Leadership behaviors and actions influence others to act, and leadership in clinical practice is an important mediator influencing patient outcomes and staff satisfaction. Indeed, positive clinical leadership has been positioned as a crucial element for transformation of health care services and has led to the development of the Practice Doctorate Movement in the United States. Nurse educators in health care have a vital leadership role as clinical experts, role models, mentors, change agents, and supporters of quality projects. By enacting these leadership attributes, nurse educators ensure a skilled and confident workforce that is focused on optimizing opportunities for students and graduates to integrate theory and practice in the workplace as well as developing more holistic models of care for the consumer. Nurse educators need to be active in supporting staff and students in health care environments and be visible leaders who can drive policy and practice changes and engage in professional forums, research, and scholarship. Although nurse educators have always been a feature of the nursing workplace, there is a paucity of literature on the role of nurse educators as clinical leaders. This discursive article describes the role and attributes of nurse educators with a focus on their role as leaders in mental health nursing. We argue that embracing the leadership role is fundamental to nurse educators and to influencing consumer-focused care in mental health. We also make recommendations for developing the leadership role of nurse educators and provide considerations for further research such as examining the impact of clinical leaders on client, staff, and organizational outcomes. PMID- 26440874 TI - Whose stress is making me sick? Network-stress and emotional distress in African American women. AB - Research on stress-related health outcomes in African-American women often neglects "network-stress": stress related to events that occur to family, friends, or loved ones. Data from the African-American Women's Well-Being Study were analyzed to examine self-stress and network-stress for occurrence, perceived stressfulness, and association with symptoms of psychological distress. Women reported a higher number of network-stress events compared with self-stress events. Occurrences of network-stress were perceived as undesirable and bothersome as self-stress. Both types of stress were significantly associated with psychological distress symptoms. Including network-stress may provide a more complete picture of the stress experiences of African-American women. PMID- 26440876 TI - The factor structure of the internet addiction tool with university students in Jordan. AB - Internet addiction is a growing phenomenon affecting people in varying ways around the globe. This study examined the factor structure and internal reliability of the Internet Addiction Test (IAT) with a heterogeneous sample of university students in Jordan. The study used a cross-sectional design, and all the questionnaires were completed in classrooms. A sample of 587 students from seven universities in Jordan was obtained. The exploratory and confirmatory factor analyses of the 20-item IAT revealed that a four-factor solution offered the most parsimonious explanation of the data. The IAT reliably assesses distinct domains of Internet addiction. These domains are Excessive Use, Loss/Suffer, Attached To, and Impaired Social Relations. Thus, it is recommended to use the obtained four factors when assessing Internet addiction among a similar population. PMID- 26440877 TI - Expressions of happiness. PMID- 26440878 TI - "Keeping the peace": relevance of the concept for mental health nursing. PMID- 26440879 TI - Pharmacotherapy as prophylactic treatment of post-traumatic stress disorder: a review of the literature. AB - Post-traumatic stress disorder has a lifetime prevalence of almost 9% in the United States. The diagnosis is associated with increased rates of comorbid substance abuse and increased rates of depression. Providers are taught how to diagnose and treat PTSD, but little discussion is devoted to how to prevent the disorder. Behavioral research in animal studies has provided some evidence for the use of medications in decreasing the fear response and the reconsolidation of memories. A heightened fear response and the re-experience of traumatic memory are key components for diagnosis. The purpose of this literature review is to examine the evidence for pharmacotherapy as prophylactic treatment in acute stress/trauma in order to prevent the development of post-traumatic stress disorder. The body of the review includes discussions on medications, medications as adjunct to script-driven imagery, and special considerations for military, first responders, and women. This article concludes with implications for practice and recommendations for future research. The key words used for the literature search were "prophylactic treatment of PTSD," "pharmacotherapy and trauma," "pharmacological prevention of PTSD," "beta blockers and the prevention of PTSD," "acute stress and prevention of PTSD," "propranolol and PTSD," "secondary prevention of PTSD," and "medications used to prevent PTSD." Findings were categorized by medications and medications as adjunct to script-driven imagery. The literature suggests that hydrocortisone, propranolol, and morphine may decrease symptoms and diagnosis of post-traumatic stress disorder. PMID- 26440881 TI - Classical and non-classical metabolic transformation of vitamin D in dermal fibroblasts. PMID- 26440882 TI - Structural and Functional Evidence for Testosterone Activation of GPRC6A in Peripheral Tissues. AB - G protein-coupled receptor (GPCR) family C group 6 member A (GPRC6A) is a multiligand GPCR that is activated by cations, L-amino acids, and osteocalcin. GPRC6A plays an important role in the regulation of testosterone (T) production and energy metabolism in mice. T has rapid, transcription-independent (nongenomic) effects that are mediated by a putative GPCR. We previously found that T can activate GPRC6A in vitro, but the possibility that T is a ligand for GPRC6A remains controversial. Here, we demonstrate direct T binding to GPRC6A and construct computational structural models of GPRC6A that are used to identify potential binding poses of T. Mutations of the predicted binding site residues were experimentally found to block T activation of GPRC6A, in agreement with the modeling. Using Gpr6ca(-/-) mice, we confirmed that loss of GPRC6A resulted in loss of T rapid signaling responses and elucidated several biological functions regulated by GPRC6A-dependent T rapid signaling, including T stimulation of insulin secretion in pancreatic islets and enzyme expression involved in the biosynthesis of T in Leydig cells. Finally, we identified a stereo-specific effect of an R-isomer of a selective androgen receptor modulator that is predicted to bind to and shown to activate GPRC6A but not androgen receptor. Together, our data show that GPRC6A directly mediates the rapid signaling response to T and uncovers previously unrecognized endocrine networks. PMID- 26440883 TI - The Membrane Mimetic Affects the Spatial Structure and Mobility of EGFR Transmembrane and Juxtamembrane Domains. AB - The epidermal growth factor receptor (EGFR) is one of the most extensively studied receptor tyrosine kinases, as it is involved in a wide range of cellular processes and severe diseases. Recent works reveal that the single-helix transmembrane domains and cytoplasmic juxtamembrane regions play an important role in the receptor activation process. Here we present the results of our investigation of the spatial structure and mobility of the EGFR transmembrane domain and juxtamembrane regions in various membranelike environments, which shed light on the effects of the membrane physical properties and composition on the behavior of the juxtamembrane domain. PMID- 26440884 TI - PKA Phosphorylation of NCLX Reverses Mitochondrial Calcium Overload and Depolarization, Promoting Survival of PINK1-Deficient Dopaminergic Neurons. AB - Mitochondrial Ca(2+) overload is a critical, preceding event in neuronal damage encountered during neurodegenerative and ischemic insults. We found that loss of PTEN-induced putative kinase 1 (PINK1) function, implicated in Parkinson disease, inhibits the mitochondrial Na(+)/Ca(2+) exchanger (NCLX), leading to impaired mitochondrial Ca(2+) extrusion. NCLX activity was, however, fully rescued by activation of the protein kinase A (PKA) pathway. We further show that PKA rescues NCLX activity by phosphorylating serine 258, a putative regulatory NCLX site. Remarkably, a constitutively active phosphomimetic mutant of NCLX (NCLX(S258D)) prevents mitochondrial Ca(2+) overload and mitochondrial depolarization in PINK1 knockout neurons, thereby enhancing neuronal survival. Our results identify an mitochondrial Ca(2+) transport regulatory pathway that protects against mitochondrial Ca(2+) overload. Because mitochondrial Ca(2+) dyshomeostasis is a prominent feature of multiple disorders, the link between NCLX and PKA may offer a therapeutic target. PMID- 26440885 TI - Mondo-Mlx Mediates Organismal Sugar Sensing through the Gli-Similar Transcription Factor Sugarbabe. AB - The ChREBP/Mondo-Mlx transcription factors are activated by sugars and are essential for sugar tolerance. They promote the conversion of sugars to lipids, but beyond this, their physiological roles are insufficiently understood. Here, we demonstrate that in an organism-wide setting in Drosophila, Mondo-Mlx controls the majority of sugar-regulated genes involved in nutrient digestion and transport as well as carbohydrate, amino acid, and lipid metabolism. Furthermore, human orthologs of the Mondo-Mlx targets display enrichment among gene variants associated with high circulating triglycerides. In addition to direct regulation of metabolic genes, Mondo-Mlx maintains metabolic homeostasis through downstream effectors, including the Activin ligand Dawdle and the Gli-similar transcription factor Sugarbabe. Sugarbabe controls a subset of Mondo-Mlx-dependent processes, including de novo lipogenesis and fatty acid desaturation. In sum, Mondo-Mlx is a master regulator of other sugar-responsive pathways essential for adaptation to a high-sugar diet. PMID- 26440886 TI - An Aminopeptidase in the Drosophila Testicular Niche Acts in Germline Stem Cell Maintenance and Spermatogonial Dedifferentiation. AB - Extrinsic cues from the niche are known to regulate adult stem cell self-renewal versus differentiation. Here, we report that an aminopeptidase Slamdance (Sda) acts in the Drosophila testicular niche to maintain germline stem cells (GSCs) and regulate progenitor germ cell dedifferentiation. Mutations in sda lead to dramatic testicular niche deterioration and stem cell loss. Recombinant Sda has specific aminopeptidase activity in vitro, and the in vivo function of Sda requires an intact aminopeptidase domain. Sda is required for accumulation of mature DE-cadherin, and overexpression of DE-cadherin rescues most sda mutant phenotypes, suggesting that DE-cadherin is an important target of Sda. Finally, Sda is both necessary and sufficient to promote dedifferentiation during aging and recovery from genetically manipulated depletion of GSCs. Together, our results suggest that a niche factor promotes both stem cell maintenance and progenitor cell dedifferentiation. PMID- 26440887 TI - ASIC3 Mediates Itch Sensation in Response to Coincident Stimulation by Acid and Nonproton Ligand. AB - The regulation and mechanisms underlying itch sensation are complex. Here, we report a role for acid-sensing ion channel 3 (ASIC3) in mediating itch evoked by certain pruritogens during tissue acidosis. Co-administration of acid with Ser Leu-Ile-Gly-Arg-Leu-NH2 (SL-NH2) increased scratching behavior in wild-type, but not ASIC3-null, mice, implicating the channel in coincident detection of acidosis and pruritogens. Mechanistically, SL-NH2 slowed desensitization of proton-evoked currents by targeting the previously identified nonproton ligand-sensing domain located in the extracellular region of ASIC3 channels in primary sensory neurons. Ablation of the ASIC3 gene reduced dry-skin-induced scratching behavior and pathological changes under conditions with concomitant inflammation. Taken together, our data suggest that ASIC3 mediates itch sensation via coincident detection of acidosis and nonproton ligands that act at the nonproton ligand sensing domain of the channel. PMID- 26440888 TI - Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway. AB - Upon DNA stimulation, cyclic GMP-AMP synthase (cGAS) synthesizes the second messenger cyclic GMP-AMP (cGAMP) that binds to the STING, triggering antiviral interferon-beta (IFN-beta) production. However, it has remained undetermined how hosts regulate cGAS enzymatic activity after the resolution of DNA immunogen. Here, we show that Akt kinase plays a negative role in cGAS-mediated anti-viral immune response. Akt phosphorylated the S291 or S305 residue of the enzymatic domain of mouse or human cGAS, respectively, and this phosphorylation robustly suppressed its enzymatic activity. Consequently, expression of activated Akt led to the reduction of cGAMP and IFN-beta production and the increase of herpes simplex virus 1 replication, whereas treatment with Akt inhibitor augmented cGAS mediated IFN-beta production. Furthermore, expression of the phosphorylation resistant cGAS S291A mutant enhanced IFN-beta production upon DNA stimulation, HSV-1 infection, and vaccinia virus infection. Our study identifies an Akt kinase mediated checkpoint to fine-tune hosts' immune responses to DNA stimulation. PMID- 26440889 TI - Reversion of FMR1 Methylation and Silencing by Editing the Triplet Repeats in Fragile X iPSC-Derived Neurons. AB - Fragile X syndrome (FXS) is the most common form of inherited intellectual disability, resulting from a CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. Here, we report a strategy for CGG repeat correction using CRISPR/Cas9 for targeted deletion in both embryonic stem cells and induced pluripotent stem cells derived from FXS patients. Following gene correction in FXS induced pluripotent stem cells, FMR1 expression was restored and sustained in neural precursor cells and mature neurons. Strikingly, after removal of the CGG repeats, the upstream CpG island of the FMR1 promoter showed extensive demethylation, an open chromatin state, and transcription initiation. These results suggest a silencing maintenance mechanism for the FMR1 promoter that is dependent on the existence of the CGG repeat expansion. Our strategy for deletion of trinucleotide repeats provides further insights into the molecular mechanisms of FXS and future therapies of trinucleotide repeat disorders. PMID- 26440890 TI - A Single Let-7 MicroRNA Bypasses LIN28-Mediated Repression. AB - Let-7 microRNAs (miRNAs) are critical regulators of animal development, stem cell differentiation, glucose metabolism, and tumorigenesis. Mammalian genomes contain 12 let-7 isoforms that suppress expression of a common set of target mRNAs. LIN28 proteins selectively block let-7 biogenesis in undifferentiated cells and in cancer. The current model for coordinate let-7 repression involves the LIN28 cold shock domain (CSD) binding the terminal loop and the two CCHC-type zinc fingers recognizing a GGAG sequence motif in precursor let-7 (pre-let-7) RNAs. Here, we perform a systematic analysis of all let-7 miRNAs and find that a single let-7 family member, human let-7a-3 (and its murine ortholog let-7c-2), escapes LIN28 mediated regulation. Mechanistically, we find that the pre-let-7c-2 loop precludes LIN28A binding and regulation. These findings refine the current model of let-7 regulation by LIN28 proteins and have important implications for understanding the LIN28/let-7 axis in development and disease. PMID- 26440891 TI - Mammary Stem Cell Self-Renewal Is Regulated by Slit2/Robo1 Signaling through SNAI1 and mINSC. AB - Tissue homeostasis requires somatic stem cell maintenance; however, mechanisms regulating this process during organogenesis are not well understood. Here, we identify asymmetrically renewing basal and luminal stem cells in the mammary end bud. We demonstrate that SLIT2/ROBO1 signaling regulates the choice between self renewing asymmetric cell divisions (ACDs) and expansive symmetric cell divisions (SCDs) by governing Inscuteable (mInsc), a key member of the spindle orientation machinery, through the transcription factor Snail (SNAI1). Loss of SLIT2/ROBO1 signaling increases SNAI1 in the nucleus. Overexpression of SNAI1 increases mInsc expression, an effect that is inhibited by SLIT2 treatment. Increased mInsc does not change cell proliferation in the mammary gland (MG) but instead causes more basal cap cells to divide via SCD, at the expense of ACD, leading to more stem cells and larger outgrowths. Together, our studies provide insight into how the number of mammary stem cells is regulated by the extracellular cue SLIT2. PMID- 26440892 TI - Principles Governing A-to-I RNA Editing in the Breast Cancer Transcriptome. AB - Little is known about how RNA editing operates in cancer. Transcriptome analysis of 68 normal and cancerous breast tissues revealed that the editing enzyme ADAR acts uniformly, on the same loci, across tissues. In controlled ADAR expression experiments, the editing frequency increased at all loci with ADAR expression levels according to the logistic model. Loci-specific "editabilities," i.e., propensities to be edited by ADAR, were quantifiable by fitting the logistic function to dose-response data. The editing frequency was increased in tumor cells in comparison to normal controls. Type I interferon response and ADAR DNA copy number together explained 53% of ADAR expression variance in breast cancers. ADAR silencing using small hairpin RNA lentivirus transduction in breast cancer cell lines led to less cell proliferation and more apoptosis. A-to-I editing is a pervasive, yet reproducible, source of variation that is globally controlled by 1q amplification and inflammation, both of which are highly prevalent among human cancers. PMID- 26440893 TI - Calcitonin Receptor Signaling Inhibits Muscle Stem Cells from Escaping the Quiescent State and the Niche. AB - Calcitonin receptor (Calcr) is expressed in adult muscle stem cells (muscle satellite cells [MuSCs]). To elucidate the role of Calcr, we conditionally depleted Calcr from adult MuSCs and found that impaired regeneration after muscle injury correlated with the decreased number of MuSCs in Calcr-conditional knockout (cKO) mice. Calcr signaling maintained MuSC dormancy via the cAMP-PKA pathway but had no impact on myogenic differentiation of MuSCs in an undifferentiated state. The abnormal quiescent state in Calcr-cKO mice resulted in a reduction of the MuSC pool by apoptosis. Furthermore, MuSCs were found outside their niche in Calcr-cKO mice, demonstrating cell relocation. This emergence from the sublaminar niche was prevented by the Calcr-cAMP-PKA and Calcr cAMP-Epac pathways downstream of Calcr. Altogether, the findings demonstrated that Calcr exerts its effect specifically by keeping MuSCs in a quiescent state and in their location, maintaining the MuSC pool. PMID- 26440895 TI - Elevated RNA Editing Activity Is a Major Contributor to Transcriptomic Diversity in Tumors. AB - Genomic mutations in key genes are known to drive tumorigenesis and have been the focus of much attention in recent years. However, genetic content also may change farther downstream. RNA editing alters the mRNA sequence from its genomic blueprint in a dynamic and flexible way. A few isolated cases of editing alterations in cancer have been reported previously. Here, we provide a transcriptome-wide characterization of RNA editing across hundreds of cancer samples from multiple cancer tissues, and we show that A-to-I editing and the enzymes mediating this modification are significantly altered, usually elevated, in most cancer types. Increased editing activity is found to be associated with patient survival. As is the case with somatic mutations in DNA, most of these newly introduced RNA mutations are likely passengers, but a few may serve as drivers that may be novel candidates for therapeutic and diagnostic purposes. PMID- 26440896 TI - GDH-Dependent Glutamate Oxidation in the Brain Dictates Peripheral Energy Substrate Distribution. AB - Glucose, the main energy substrate used in the CNS, is continuously supplied by the periphery. Glutamate, the major excitatory neurotransmitter, is foreseen as a complementary energy contributor in the brain. In particular, astrocytes actively take up glutamate and may use it through oxidative glutamate dehydrogenase (GDH) activity. Here, we investigated the significance of glutamate as energy substrate for the brain. Upon glutamate exposure, astrocytes generated ATP in a GDH dependent way. The observed lack of glutamate oxidation in brain-specific GDH null CnsGlud1(-/-) mice resulted in a central energy-deprivation state with increased ADP/ATP ratios and phospho-AMPK in the hypothalamus. This induced changes in the autonomous nervous system balance, with increased sympathetic activity promoting hepatic glucose production and mobilization of substrates reshaping peripheral energy stores. Our data reveal the importance of glutamate as necessary energy substrate for the brain and the role of central GDH in the regulation of whole-body energy homeostasis. PMID- 26440894 TI - A Gene Regulatory Network Cooperatively Controlled by Pdx1 and Sox9 Governs Lineage Allocation of Foregut Progenitor Cells. AB - The generation of pancreas, liver, and intestine from a common pool of progenitors in the foregut endoderm requires the establishment of organ boundaries. How dorsal foregut progenitors activate pancreatic genes and evade the intestinal lineage choice remains unclear. Here, we identify Pdx1 and Sox9 as cooperative inducers of a gene regulatory network that distinguishes the pancreatic from the intestinal lineage. Genetic studies demonstrate dual and cooperative functions for Pdx1 and Sox9 in pancreatic lineage induction and repression of the intestinal lineage choice. Pdx1 and Sox9 bind to regulatory sequences near pancreatic and intestinal differentiation genes and jointly regulate their expression, revealing direct cooperative roles for Pdx1 and Sox9 in gene activation and repression. Our study identifies Pdx1 and Sox9 as important regulators of a transcription factor network that initiates pancreatic fate and sheds light on the gene regulatory circuitry that governs the development of distinct organs from multi-lineage-competent foregut progenitors. PMID- 26440897 TI - Circulating Th1-Cell-type Tfh Cells that Exhibit Impaired B Cell Help Are Preferentially Activated during Acute Malaria in Children. AB - Malaria-specific antibody responses are short lived in children, leaving them susceptible to repeated bouts of febrile malaria. The cellular and molecular mechanisms underlying this apparent immune deficiency are poorly understood. Recently, T follicular helper (Tfh) cells have been shown to play a critical role in generating long-lived antibody responses. We show that Malian children have resting PD-1(+)CXCR5(+)CD4(+) Tfh cells in circulation that resemble germinal center Tfh cells phenotypically and functionally. Within this population, PD 1(+)CXCR5(+)CXCR3(-) Tfh cells are superior to Th1-polarized PD 1(+)CXCR5(+)CXCR3(+) Tfh cells in helping B cells. Longitudinally, we observed that malaria drives Th1 cytokine responses, and accordingly, the less-functional Th1-polarized Tfh subset was preferentially activated and its activation did not correlate with antibody responses. These data provide insights into the Tfh cell biology underlying suboptimal antibody responses to malaria in children and suggest that vaccine strategies that promote CXCR3(-) Tfh cell responses may improve malaria vaccine efficacy. PMID- 26440898 TI - p62 Plays a Specific Role in Interferon-gamma-Induced Presentation of a Toxoplasma Vacuolar Antigen. AB - Also known as Sqstm1, p62 is a selective autophagy adaptor with a ubiquitin binding domain. However, the role of p62 in the host defense against Toxoplasma gondii infection is unclear. Here, we show that interferon gamma (IFN-gamma) stimulates ubiquitin and p62 recruitment to T. gondii parasitophorous vacuoles (PVs). Some essential autophagy-related proteins, but not all, are required for this recruitment. Regardless of normal IFN-gamma-induced T. gondii clearance activity and ubiquitination, p62 deficiency in antigen-presenting cells (APCs) and mice diminishes the robust IFN-gamma-primed activation of CD8(+) T cells that recognize the T. gondii-derived antigen secreted into PVs. Because the expression of Atg3 and Irgm1/m3 in APCs is essential for PV disruption, ubiquitin and p62 recruitment, and vacuolar-antigen-specific CD8(+) T cell activation, IFN-gamma mediated ubiquitination and the subsequent recruitment of p62 to T. gondii are specifically required for the acquired immune response after PV disruption by IFN gamma-inducible GTPases. PMID- 26440900 TI - Anatomical and physiological basis for the allometric scaling of cisplatin clearance in dogs. AB - Cisplatin is a platinum-containing cytotoxic drug indicated for the treatment of solid tumors in veterinary and human patients. Several of the algorithms used to standardize the doses of cytotoxic drugs utilize allometry, or the nonproportional relationships between anatomical and physiological variables, but the underlying basis for these relationships is poorly understood. The objective of this proof of concept study was to determine whether allometric equations explain the relationships between body weight, kidney weight, renal physiology, and clearance of a model, renally cleared anticancer agent in dogs. Postmortem body, kidney, and heart weights were collected from 364 dogs (127 juveniles and 237 adults, including 51 dogs >= 8 years of age). Renal physiological and cisplatin pharmacokinetic studies were conducted in ten intact male dogs including two juvenile and eight adult dogs (4-55 kg). Glomerular filtration rate (GFR), effective renal plasma flow, effective renal blood flow, renal cisplatin clearance, and total cisplatin clearance were allometrically related to body weight with powers of 0.75, 0.59, 0.61, 0.71, and 0.70, respectively. The similar values of these diverse mass exponents suggest a common underlying basis for the allometry of kidney size, renal physiology, and renal drug handling. PMID- 26440899 TI - ATM Dependent Silencing Links Nucleolar Chromatin Reorganization to DNA Damage Recognition. AB - Resolution of DNA double-strand breaks (DSBs) is essential for the suppression of genome instability. DSB repair in transcriptionally active genomic regions represents a unique challenge that is associated with ataxia telangiectasia mutated (ATM) kinase-mediated transcriptional silencing. Despite emerging insights into the underlying mechanisms, how DSB silencing connects to DNA repair remains undefined. We observe that silencing within the rDNA depends on persistent DSBs. Non-homologous end-joining was the predominant mode of DSB repair allowing transcription to resume. ATM-dependent rDNA silencing in the presence of persistent DSBs led to the large-scale reorganization of nucleolar architecture, with movement of damaged chromatin to nucleolar cap regions. These findings identify ATM-dependent temporal and spatial control of DNA repair and provide insights into how communication between DSB signaling and ongoing transcription promotes genome integrity. PMID- 26440901 TI - Transcatheter Treatment of Apicoaortic Conduit Dysfunction. AB - We report a 77-year-old male patient with a history of aortic valve bypass with an apicoaortic conduit 11 years ago for severe aortic stenosis, presenting with acute decompensated congestive heart failure. Severe conduit valve regurgitation and was successfully treated with transcatheter aortic valve replacement (TAVR) of the native aortic valve using a self-expanding bioprosthesis followed by transcatheter closure of the apicoaortic conduit. PMID- 26440904 TI - 4th European Congrses of Immunology--Servus from Vienna! PMID- 26440905 TI - Hobit and human effector T-cell differentiation: The beginning of a long journey. AB - Besides growing plants, eating a lot, and drinking beer, Tolkien's Hobbits enjoy maintaining a quiet state. Regarding the latter, the name chosen for a recently discovered transcription factor seems to be unintentionally appropriate. The zinc finger protein ZNF683 was originally named "Hobit" for Homolog of Blimp-1 in T cells. In this issue of the European Journal of Immunology, Braga et al. [Eur. J. Immunol. 2015. 45: 2945-2958] demonstrate that in humans, Hobit is almost exclusively expressed in effector T cells, in particular in quiescent and long lived effector-type CD8(+) T cells. Hobit may initially appear as another "player" in the quest for transcription factors guiding T-cell differentiation; the discoveries of T-bet, Eomes, Blimp-1, and others have significantly contributed to our understanding of how this process is tightly regulated. However, Hobit may be special--the currently available results suggest substantial differences in Hobit's regulatory functions between mice and humans, such as expression patterns and IFN-gamma regulation. And it may turn out that Hobit's function in human T cells is highly adapted to lifelong, periodic challenges with varying, physiological doses of pathogens. Thus, the new study about Hobit in human T cells may be the beginning of a long journey. PMID- 26440909 TI - Carbonylative Mizoroki-Heck Reaction of Alkyl Iodides with Arylalkenes Using a Pd/Photoirradiation System. AB - A carbonylative Mizoroki-Heck reaction using alkyl iodides was achieved with a Pd/photoirradiation system using DBU as a base. In this reaction, alkyl radicals were formed from alkyl iodides via single-electron transfer (SET) and then underwent a sequential addition to CO and alkenes to give beta-keto radicals. It is proposed that DBU would abstract a proton alpha to carbonyl to form radical anions, giving alpha,beta-unsaturated ketones via SET. PMID- 26440910 TI - CLONING AND EXPRESSING TRYPSIN MODULATING OOSTATIC FACTOR IN Chlorella desiccata TO CONTROL MOSQUITO LARVAE. AB - The insect peptide hormone trypsin modulating oostatic factor (TMOF), a decapeptide that is synthesized by the mosquito ovary and controls the translation of the gut's trypsin mRNA was cloned and expressed in the marine alga Chlorella desiccata. To express Aedes aegypti TMOF gene (tmfA) in C. desiccata cells, two plasmids (pYES2/TMOF and pYDB4-tmfA) were engineered with pKYLX71 DNA (5 Kb) carrying the cauliflower mosaic virus (CaMV) promoter 35S(2) and the kanamycin resistant gene (neo), as well as, a 8 Kb nitrate reductase gene (nit) from Chlorella vulgaris. Transforming C. desiccata with pYES2/TMOF and pYDB4-tmfA show that the engineered algal cells express TMOF (20 +/- 4 MUg +/- SEM and 17 +/ 3 MUg +/- SEM, respectively in 3 * 10(8) cells) and feeding the cells to mosquito larvae kill 75 and 60% of Ae. aegypti larvae in 4 days, respectively. Southern and Northern blots analyses show that tmfA integrated into the genome of C. desiccata by homologous recombination using the yeast 2 MU circle of replication and the nit in pYES2/TMOF and pYDB4-tmfA, respectively, and the transformed algal cells express tmfA transcript. Using these algal cells it will be possible in the future to control mosquito larvae in the marsh. PMID- 26440911 TI - Fasciola hepatica mucin-encoding gene: expression, variability and its potential relevance in host-parasite relationship. AB - Fasciola hepatica is the causative agent of fasciolosis, a zoonosis with significant impact both in human and animal health. Understanding the basic processes of parasite biology, especially those related to interactions with its host, will contribute to control F. hepatica infections and hence liver pathology. Mucins have been described as important mediators for parasite establishment within its host, due to their key roles in immune evasion. In F. hepatica, mucin expression is upregulated in the mammalian invasive newly excysted juvenile (NEJ) stage in comparison with the adult stage. Here, we performed sequencing of mucin cDNAs prepared from NEJ RNA, resulting in six different cDNAs clusters. The differences are due to the presence of a tandem repeated sequence of 66 bp encoded by different exons. Two groups of apomucins one with three and the other with four repeats, with 459 and 393 bp respectively, were identified. These cDNAs have open reading frames encoding Ser-Thr enriched proteins with an N-terminal signal peptide, characteristic of apomucin backbone. We cloned a 4470 bp gene comprising eight exons and seven introns that encodes all the cDNA variants identified in NEJs. By real time polymerase chain reaction and high-resolution melting approaches of individual flukes we infer that fhemuc 1 is a single-copy gene, with at least two different alleles. Our data suggest that both gene polymorphism and alternative splicing might account for apomucin variability in the fhemuc-1 gene that is upregulated in NEJ invasive stage. The relevance of this variation in host-parasite interplay is discussed. PMID- 26440912 TI - Significant Misuse of Sildenafil in London Nightclubs. AB - BACKGROUND: There is anecdotal evidence of misuse of erectile dysfunction medication, particularly to counteract some of the unwanted effects of recreational drugs on erectile function. However, there is little data from the United Kingdom (UK). AIM: To evaluate the prevalence of sildenafil misuse in a UK population that has previously been shown to have high recreational drug use. DESIGN: Questionnaire survey. METHODS: Individuals attending nightclubs catering for the men who have sex with men (MSM) community in South London were asked about lifetime and last year use of recreational drugs and sildenafil. RESULTS: 313 individuals were surveyed over four nights in 2013: 282 (90.1%) were males and 248 (79.2%) were MSM. Last year use of recreational drugs was high: mephedrone (74.1%), cocaine (61.3%), MDMA/Ecstasy (59.2%), GHB/GBL (52.8%), cannabis (51.8%), and ketamine (50%). 136 (49.1%) MSM versus 6 (18.8%) non-MSM clubbers had misused sildenafil in the last year (p < .001). Amongst the MSM clubbers, 232 (93.5%) had heard of sildenafil, 161 (64.9%) reported misuse of sildenafil in their lifetime and 133 (53.6%) had misused sildenafil in the last year. CONCLUSION: This study demonstrates a high prevalence of sildenafil misuse in a population who are heavy users of recreational drugs; it is not likely that this young population have underlying erectile dysfunction as a reason for legitimate sildenafil use. There is the potential for interaction with other recreational drugs used including cocaine and volatile nitrites. Further work is required in to determine the extent and reason for the misuse. PMID- 26440914 TI - Broadband quantitative phase microscopy with extended field of view using off axis interferometric multiplexing. AB - We propose a new portable imaging configuration that can double the field of view (FOV) of existing off-axis interferometric imaging setups, including broadband off-axis interferometers. This configuration is attached at the output port of the off-axis interferometer and optically creates a multiplexed interferogram on the digital camera, which is composed of two off-axis interferograms with straight fringes at orthogonal directions. Each of these interferograms contains a different FOV of the imaged sample. Due to the separation of these two FOVs in the spatial-frequency domain, they can be fully reconstructed separately, while obtaining two complex wavefronts from the sample at once. Since the optically multiplexed off-axis interferogram is recorded by the camera in a single exposure, fast dynamics can be recorded with a doubled imaging area. We used this technique for quantitative phase microscopy of biological samples with extended FOV. We demonstrate attaching the proposed module to a diffractive phase microscopy interferometer, illuminated by a broadband light source. The biological samples used for the experimental demonstrations include microscopic diatom shells, cancer cells, and flowing blood cells. PMID- 26440915 TI - Strong Coupling between the Hydrogen Bonding Environment and Redox Chemistry during the S2 to S3 Transition in the Oxygen-Evolving Complex of Photosystem II. AB - We have studied the early phase of the S2 -> S3 transition in the oxygen-evolving complex (OEC) of photosystem II using the hybrid density functional theory with a quantum mechanical model composed of 338-341 atoms. Special attention is given to the vital role of water molecules in the vicinity of the Mn4CaO5 core. Our results demonstrate how important the dynamic behavior of surrounding water molecules is in mediating critical chemical transformations such as binding and deprotonation of substrates and hydration of the catalytic site and identify a strong coupling of water-chain relocation near the redox-active tyrosine residue Tyr161 (TyrZ) with oxidation of the Mn4CaO5 cluster by TyrZ(*+). The oxidation reaction is further promoted when the catalytic site is more solvated by water. These results indicate the importance of surrounding water molecules in biological catalysts as they ultimately lead to effective catalytic function and/or favorable electron-transfer dynamics. PMID- 26440913 TI - Comparative analysis of pentavalent rotavirus vaccine strains and G8 rotaviruses identified during vaccine trial in Africa. AB - RotaTeqTM is a pentavalent rotavirus vaccine based on a bovine rotavirus genetic backbone in vitro reassorted with human outer capsid genes. During clinical trials of RotaTeqTM in Sub-Saharan Africa, the vaccine efficacy over a 2-year follow-up was lower against the genotypes contained in the vaccine than against the heterotypic G8P[6] and G8P[1] rotavirus strains of which the former is highly prevalent in Africa. Complete genome analyses of 43 complete rotavirus genomes collected during phase III clinical trials of RotaTeqTM in Sub-Saharan Africa, were conducted to gain insight into the high level of cross-protection afforded by RotaTeqTM against these G8 strains. Phylogenetic analysis revealed the presence of a high number of bovine rotavirus gene segments in these human G8 strains. In addition, we performed an in depth analysis on the individual amino acid level which showed that G8 rotaviruses were more similar to the RotaTeqTM vaccine than non-G8 strains. Because RotaTeqTM possesses a bovine genetic backbone, the high vaccine efficacy against G8 strains might be partially explained by the fact that all these strains contain a complete or partial bovine like backbone. Altogether, this study supports the hypothesis that gene segments other than VP7 and VP4 play a role in vaccine-induced immunity. PMID- 26440916 TI - Prevention of post operative complications following surgical treatment of equine colic: Current evidence. AB - Changes in management of the surgical colic patient over the last 30 years have resulted in considerable improvement in post operative survival rates. However, post operative complications remain common and these impact negatively on horse welfare, probability of survival, return to previous use and the costs of treatment. Multiple studies have investigated risk factors for post operative complications following surgical management of colic and interventions that might be effective in reducing the likelihood of these occurring. The findings from these studies are frequently contradictory and the evidence for many interventions is lacking or inconclusive. This review discusses the current available evidence and identifies areas where further studies are necessary and factors that should be taken into consideration in study design. PMID- 26440918 TI - Design Model Parameter Analysis for Nitrifying Trickling Filters. AB - Nitrifying trickling filters (NTFs) represent an effective technology for water resource recovery facilities (WRRFs) to achieve compliance with ammonia-N permits. However, while the potential benefits of NTFs are many, the design methods and associated parameter databases are underdeveloped. Research herein focused on analysis of pilot-scale NTF data to develop enhanced design guidance. rn(max,0) values ranged from 1.19-3.38 gN m-2*d-1, and correlated with influent ammonia-N concentration and loading. The transition concentration from rn(max,0) ranged from 0.9-22.2 mgN/L, and correlated with ammonia-N loading. Zero-order nitrification ranging from 0.24-1.58 gN m-2*d-1 was observed down-gradient of rn(max,0). First-order nitrification was not observed, nor was there a strong exponential correlation for decreasing nitrification rate. To translate results to NTF media different from that utilized, a relationship between the NTF media effectiveness parameter, E, and rn(max,0) was established. Collectively, the data presented enhances the engineer's ability to model and design NTFs. PMID- 26440917 TI - Genome-wide significant linkage of schizophrenia-related neuroanatomical trait to 12q24. AB - The insula and medial prefrontal cortex (mPFC) share functional, histological, transcriptional, and developmental characteristics, and they serve higher cognitive functions of theoretical relevance to schizophrenia and related disorders. Meta-analyses and multivariate analysis of structural magnetic resonance imaging (MRI) scans indicate that gray matter density and volume reductions in schizophrenia are the most consistent and pronounced in a network primarily composed of the insula and mPFC. We used source-based morphometry, a multivariate technique optimized for structural MRI, in a large sample of randomly ascertained pedigrees (N = 887) to derive an insula-mPFC component and to investigate its genetic determinants. Firstly, we replicated the insula-mPFC gray matter component as an independent source of gray matter variation in the general population, and verified its relevance to schizophrenia in an independent case-control sample. Secondly, we showed that the neuroanatomical variation defined by this component is largely determined by additive genetic variation (h(2) = 0.59), and genome-wide linkage analysis resulted in a significant linkage peak at 12q24 (LOD = 3.76). This region has been of significant interest to psychiatric genetics as it contains the Darier's disease locus and other proposed susceptibility genes (e.g., DAO, NOS1), and it has been linked to affective disorders and schizophrenia in multiple populations. Thus, in conjunction with previous clinical studies, our data imply that one or more psychiatric risk variants at 12q24 are co-inherited with reductions in mPFC and insula gray matter concentration. (c) 2015 Wiley Periodicals, Inc. PMID- 26440919 TI - Synthesis of virtually enantiopure aminodiols with three adjacent stereogenic centers by epoxidation and ring-opening. AB - A virtually complete enantioselective synthesis of 3-amino-1,2-diols with three consecutive stereocenters was accomplished by a sequential cascade of two kinetic resolutions, which features a Sharpless or Hafnium-catalyzed asymmetric epoxidation and a subsequent W-catalyzed aminolysis. Enantiopure products with up to >99.9% ee and >99.9 : 0.1 dr were obtained and could serve as potential building blocks for pharmaceutical or biological significant molecules. PMID- 26440921 TI - Editorial Comment on "Bias in Evaluating Erectile Function in Lifelong Premature Ejaculation Patients with the International Index of Erectile Function-5". PMID- 26440920 TI - Changing of bloodstream infections in a medical center neonatal intensive care unit. AB - BACKGROUND/PURPOSE: Bloodstream infections (BSIs) are associated with high mortality and morbidity in neonatal intensive care units (NICUs). The epidemiology of these infections may change after the application of new infection control policies. The aims of this study are to reveal the changing epidemiology of BSIs in our NICU and inspect the effects of infection control efforts. METHODS: We reviewed and analyzed the clinical characteristics of culture-proven BSIs in our NICU from 2008 to 2013 and compared them with our two previously reported data (1992-2001 and 2002-2007). RESULTS: The mortality rate decreased from 16.3% in 1992-2001 to 5.6% in 2008-2013. In the recent study period, Gram-positive infections became predominant (58.0%). Coagulase-negative staphylococci remained the most commonly isolated organisms (26.0%). Group B Streptococcus (GBS) BSIs had the highest mortality rate (30.0%). Most GBS infected infants' mother did not perform prenatal GBS screening. There was a decrease in the total fungal infection rate after fluconazole prophylaxis for very-low-birth-weight (VLBW) neonates, but the infections of fluconazole resistant Malassezia pachydermatis increased. The incidence of central line associated BSI increased to 10.6% in 2011. After restricting the catheter duration to <21 days, the incidence decreased to 4.2% in 2013. CONCLUSION: Through the years, the overall mortality rate of BSIs in our NICU decreased. Maternal GBS screening is an important issue for avoiding early onset GBS mortality. Fungal infection rate decreased after antifungal prophylaxis policy for VLBW infants, but we should be aware of resistant strains. Restriction of the catheter duration may decrease the incidence of catheter-related BSI. PMID- 26440922 TI - Mammalian Host-Versus-Phage immune response determines phage fate in vivo. AB - Emerging bacterial antibiotic resistance draws attention to bacteriophages as a therapeutic alternative to treat bacterial infection. Examples of phage that combat bacteria abound. However, despite careful testing of antibacterial activity in vitro, failures nevertheless commonly occur. We investigated immunological response of phage antibacterial potency in vivo. Anti-phage activity of phagocytes, antibodies, and serum complement were identified by direct testing and by high-resolution fluorescent microscopy. We accommodated the experimental data into a mathematical model. We propose a universal schema of innate and adaptive immunity impact on phage pharmacokinetics, based on the results of our numerical simulations. We found that the mammalian-host response to infecting bacteria causes the concomitant removal of phage from the system. We propose the notion that this effect as an indirect pathway of phage inhibition by bacteria with significant relevance for the clinical outcome of phage therapy. PMID- 26440923 TI - Effects of vitamin D supplementation as an adjuvant therapy in coronary artery disease patients. AB - OBJECTIVES: Low vitamin D status has been shown to be associated with coronary artery disease. We planned to research the effects of vitamin D3 supplementation on the severity of coronary artery disease. DESIGN: We investigated the effect of 0.5 MUg vitamin D3 per day in a randomized, placebo-controlled, double-blind study in 90 stable coronary artery disease patients residing in Beijing. Coronary angiography was performed before and after 6 months of treatment that took place between January and June. 25-Hydroxyvitamin D was measured by chemiluminescence assay. Coronary artery disease severity was assessed by using the SYNTAX scores. RESULTS: In vitamin D supplementation group, there was a significant increase in mean 25-hydroxyvitamin D levels from baseline (19.9 +/- 9.8 ng/ml) to 6 months (35.8 +/- 12.1 ng/ml; p < 0.001). At 6 months, the primary end point, a difference in the fall of SYNTAX score between the groups was -2.5 (95% CI -5.1 to -0.5; p < 0.001) under intention to treat analysis. Compared with the control group, patients treated with vitamin D3 also had greater decreases in high sensitivity C-reactive protein and renin-angiotensin system activity (p < 0.05). CONCLUSIONS: Vitamin D supplementation has beneficial effects on coronary artery disease; it can be an adjuvant therapy for patients with coronary artery disease. PMID- 26440924 TI - Carriage of Haemophilus influenzae in the oropharynx of young children and molecular epidemiology of the isolates after fifteen years of H. influenzae type b vaccination in Italy. AB - BACKGROUND: Haemophilus influenzae is an important pathogen able to cause a wide spectrum of diseases in children. Colonization of the upper respiratory tract is a risk factor for developing disease. This study aimed to investigate the oropharyngeal carriage rate of H. influenzae in young children in two Italian cities, 15 years after H. influenzae type b (Hib) vaccination was introduced. Antibiotic resistant traits and genotypes of the colonizing H. influenzae isolates were investigated. METHODS: Oropharyngeal swabs were obtained from 717 healthy children aged <6 years (June 2012-July 2013). Potential risk factors for H. influenzae colonization were investigated. H. influenzae isolates from carriage were characterized by PCR capsular typing, ampicillin susceptibility testing, resistance-associated gene sequencing and multilocus sequence typing (MLST). For comparison purposes, 38 non-typeable H. influenzae (NTHi) isolates from invasive disease were genotyped by MLST. RESULTS: The overall H. influenzae carriage rate was 14.1% (101/717). Age, study site, presence of young siblings, and complete Hib vaccination status were independently associated with colonization. Of 101 isolates, 98 were NTHi, 2 were type e and 1 was type f. The overall ampicillin resistance rate was 15.8% (16/101). Resistance was mediated by TEM-1 beta-lactamase production in half of isolates (n=8) or modifications in penicillin-binding protein (PBP) 3 in the other half (n=8). Several substitutions were discovered in PBP3 including the Asn526Lys change. Seventy-six different STs were identified among 98 NTHi isolates from carriage, with only 4 STs (ST12, ST57, ST238, ST1238) encompassing >= 3 isolates. Comparison of carriage and disease isolates found that several STs were shared between the two sources, although none of the major disease-associated STs were observed in carriage isolates. CONCLUSIONS: NTHi is the predominant serotype in carriage. The importance of monitoring both NTHi colonization rate and circulating genotypes should be emphasized in the era of the Hib conjugate vaccines. PMID- 26440925 TI - Unmasking in an observational vaccine safety study: Using type 2 diabetes mellitus as an example. AB - BACKGROUND: In observational vaccine safety studies, diagnosis codes assigned prior to or on the day of vaccination (Day 0) are often excluded from analysis of safety signals since they usually represent pre-existing conditions. The limitations of this approach have been described for autoimmune conditions but not for other chronic conditions. We draw on our experience in a post-licensure quadrivalent human papillomavirus vaccine (HPV4) safety study to examine the effectiveness of exclusion of pre-existing and Day 0 diagnoses of type 2 diabetes mellitus (T2DM) in excluding prevalent T2DM. METHODS: Subjects included all 117,402 females ages 9-26 years who received HPV4 August 2006-March 2008 in Kaiser Permanente Southern California. We identified potential incident T2DM cases using ICD9 code 250.xx associated with inpatient and emergency room visits during the 60 days following each HPV4 dose, excluding those with this code prior to their first HPV4 dose. Electronic medical records were reviewed to determine the dates of symptom onset, diagnostic labs, vaccine administration and T2DM diagnosis. RESULTS: Of 33 potential incident T2DM cases identified using automated data, 4 (12%) were confirmed to have new onset T2DM after medical record review. Nineteen cases were excluded that did not have T2DM or had T2DM diagnosed before Day 0; nine had an abnormal fasting blood sugar (FBS) ordered on Day 0, prompting subsequent evaluation and diagnosis of T2DM; and one had elevated FBS and glucosuria prior to the first dose of HPV4 but T2DM diagnosed at a visit following vaccination. CONCLUSION: These results suggest that among adolescents and young adults, the workup and subsequent diagnosis of pre-existing conditions may result from a visit at which a vaccination is administered. This "unmasking" phenomenon is not entirely eliminated by exclusion of pre-existing and Day 0 diagnoses. Medical record review should be considered in the evaluation of potential safety signals. PMID- 26440926 TI - Comparison of different methods to include recycling in LCAs of aluminium cans and disposable polystyrene cups. AB - Many methods have been reported and used to include recycling in life cycle assessments (LCAs). This paper evaluates six widely used methods: three substitution methods (i.e. substitution based on equal quality, a correction factor, and alternative material), allocation based on the number of recycling loops, the recycled-content method, and the equal-share method. These six methods were first compared, with an assumed hypothetical 100% recycling rate, for an aluminium can and a disposable polystyrene (PS) cup. The substitution and recycled-content method were next applied with actual rates for recycling, incineration and landfilling for both product systems in selected countries. The six methods differ in their approaches to credit recycling. The three substitution methods stimulate the recyclability of the product and assign credits for the obtained recycled material. The choice to either apply a correction factor, or to account for alternative substituted material has a considerable influence on the LCA results, and is debatable. Nevertheless, we prefer incorporating quality reduction of the recycled material by either a correction factor or an alternative substituted material over simply ignoring quality loss. The allocation-on-number-of-recycling-loops method focusses on the life expectancy of material itself, rather than on a specific separate product. The recycled-content method stimulates the use of recycled material, i.e. credits the use of recycled material in products and ignores the recyclability of the products. The equal-share method is a compromise between the substitution methods and the recycled-content method. The results for the aluminium can follow the underlying philosophies of the methods. The results for the PS cup are additionally influenced by the correction factor or credits for the alternative material accounting for the drop in PS quality, the waste treatment management (recycling rate, incineration rate, landfilling rate), and the source of avoided electricity in case of waste incineration. The results for the PS cup, which are less dominated by production of virgin material than aluminium can, furthermore depend on the environmental impact categories. This stresses the importance to consider other impact categories besides the most commonly used global warming impact. The multitude of available methods complicates the choice of an appropriate method for the LCA practitioner. New guidelines keep appearing and industries also suggest their own preferred method. Unambiguous ISO guidelines, particularly related to sensitivity analysis, would be a great step forward in making more robust LCAs. PMID- 26440927 TI - Erv14 cargo receptor participates in yeast salt tolerance via its interaction with the plasma-membrane Nha1 cation/proton antiporter. AB - The yeast Nha1p Na(+), K(+)/H(+) antiporter has a house-keeping role in pH and cation homeostasis. It is also needed to alleviate excess Na(+) or K(+) from the cytoplasm under high external concentrations of these cations. Erv14p, a putative cargo receptor for transmembrane proteins is required for trafficking of Nha1p from the endoplasmic reticulum to the plasma membrane. Sensitivity to high Na(+) concentrations of the erv14 mutant associated to the intracellular mislocalization of Nha1p-GFP, together with a lower Na(+) efflux, indicate the involvement of this mutual association to accomplish the survival of the yeast cell upon sodium stress. This observation is supported by the protein-protein interaction between Erv14p and Nha1p detected by the mating-based Split Ubiquitin System and co-immunoprecipitation assays. Our results indicate that even though Erv14p interacts with Nha1p through the TMD, the C-terminal is important not only for the efficient delivery of Nha1p to the plasma membrane but also for its dimerization to accomplish its role in yeast salt tolerance. PMID- 26440928 TI - Trace Element Content of Monovarietal and Commercial Portuguese Olive Oils. AB - Olive (Olea europaea L.) represents one of the most important and ancient crops in the Mediterranean countries, being widely known due to the optimal organoleptic characteristics of its oil, besides the important health benefits assigned to this product in the last few years. Since olive oil composition, respecting specific trace elements, has a direct impact on the quality and safety of this product, eleven monovarietal and twelve commercial olive oils were analysed spectrometrically concerning their metal composition. Regarding quality parameters, the monovarietal olive oils display larger quantities of Mg, Fe, Mn, while the commercial samples are characterized by greater amounts of Na, Ca, Cu and Zn. In which respects to safety parameters, the commercial samples present higher values for Al and Pb, and lower quantities of Cd, respecting the monovarietal ones. The assessment of the values observed for the trace elements, resorting to multivariate statistical methods, allowed to clearly distinguish the type of olive oil production-monovarietal or commercial blend. For this purpose, besides Cluster analysis, the data have been subjected to Principal Component Analysis-undertaken for either all the evaluated parameters simultaneously, or the quality/safety parameters separately, both data sets allowing the discrimination of the samples. PMID- 26440930 TI - Development of a Dinitrosyl Iron Complex Molecular Catalyst into a Hydrogen Evolution Cathode. AB - Despite extensive efforts, the electrocatalytic reduction of water using homogeneous/heterogeneous Fe, Co, Ni, Cu, W, and Mo complexes remains challenging because of issues involving the development of efficient, recyclable, stable, and aqueous-compatible catalysts. In this study, evolution of the de novo designed dinitrosyl iron complex DNIC-PMDTA from a molecular catalyst into a solid-state hydrogen evolution cathode, considering all the parameters to fulfill the electronic and structural requirements of each step of the catalytic cycle, is demonstrated. DNIC-PMDTA reveals electrocatalytic reduction of water at neutral and basic media, whereas its deposit on electrode preserves exceptional longevity, 139 h. This discovery will initiate a systematic study on the assembly of [Fe(NO)2] motif into current collector for mass production of H2, whereas the efficiency remains tailored by its molecular precursor [(L)Fe(NO)2]. PMID- 26440929 TI - Identification of germline genetic mutations in patients with pancreatic cancer. AB - BACKGROUND: Pancreatic adenocarcinoma (PAC) is part of several cancer predisposition syndromes; however, indications for genetic counseling/testing are not well-defined. In the current study, the authors sought to determine mutation prevalence and characteristics that are predictive of an inherited predisposition for PAC. METHODS: A total of 175 consecutive patients with PAC who underwent clinical genetics assessment at Memorial Sloan Kettering Cancer Center between 2011 and 2014 were identified. Clinical data, family history, and germline results were evaluated. RESULTS: Among 159 patients with PAC who pursued genetic testing, 24 pathogenic mutations were identified (15.1%; 95% confidence interval, 9.5%-20.7%), including BRCA2 (13 mutations), BRCA1 (4 mutations), p16 (2 mutations), PALB2 (1 mutation), and Lynch syndrome (4 mutations). BRCA1/BRCA2 prevalence was 13.7% in Ashkenazi Jewish (AJ) patients (95 patients) and 7.1% in non-AJ patients (56 patients). In AJ patients with a strong, weak, or absent family history of BRCA-associated cancers, the mutation prevalence was 16.7%, 15.8%, and 7.4%, respectively. The mean age at the time of diagnosis in all mutation carriers was 58.5 years (range, 45-75 years) compared with 64 years (range, 27-87 years) in those not carrying a mutation (P = .02). Although BRCA2 was the most common mutation identified, no patients with early-onset PAC (diagnosed at age <= 50 years) harbored a BRCA2 mutation and the mean age at diagnosis in BRCA2 carriers was equivalent to that of individuals who were not mutation carriers (P = .34). Mutation prevalence in patients with early-onset disease (21 patients) was 28.6%, including BRCA1 (2 mutations), p16 (2 mutations), MSH2 (1 mutation), and MLH1 (1 mutation). CONCLUSIONS: Mutations in BRCA2 account for > 50% of patients with PAC with an identified susceptibility syndrome. AJ patients were found to have high BRCA1/BRCA2 prevalence regardless of personal/family history, suggesting that ancestry alone indicates a need for genetic evaluation. With the exception of BRCA2-associated PAC, an inherited predisposition for PAC is associated with an earlier age at PAC diagnosis, suggesting that this subset of patients may also represent a population warranting further evaluation. PMID- 26440931 TI - A Rare Intermetatarsal Coalition With Rigid Fifth Metatarsal Deformity and Symptomatic Plantar Lesion. AB - Coalition or synostosis of the foot is a relatively uncommon abnormality. Some cases of synostosis of the foot, primarily involving the midfoot and hindfoot, have been reported. However, intermetatarsal coalition is extremely rare, with only a small number of cases reported. We report a case of a unilateral, congenital metatarsal coalition between the fourth and fifth metatarsal bones in a 27-year-old female. She had initially been referred because of a symptomatic plantar lesion under the fifth metatarsal head. Surgery consisted of separating the affected metatarsals, combined with a proximal osteotomy, which proved successful in establishing pain-free and more natural weightbearing. PMID- 26440932 TI - Surgical Treatment of Calcaneal Avulsion Fracture in Elderly Patients Using Cannulated Cancellous Screws and Titanium Wire. AB - Avulsion fractures of the calcaneus are relatively uncommon and are seen most frequently in elderly or osteoporotic patients. A surgical method that avoids displacement of the avulsed fragment after fixation has not been developed. We report the cases of 3 patients (a 73-year-old male, an 85-year-old male, and an 81-year-old female) treated by open reduction and internal fixation using titanium wire and cannulated cancellous screws. The posterior approach was used by way of a vertical midline incision. The fracture was fixed with 2 screws, and then a titanium wire was passed through the holes of the cannulated screws. A small incision on the lateral side of planter was added for the exit and return of the wire. The wire knot was bent inside the proximal Achilles tendon bursa in 2 patients and was directed to the plantar side in 1 to avoid irritation. Bony union was achieved without repeat displacement of the fragment in all 3 patients. Normal ankle function was restored, and the patients recovered the activities of daily living almost to the original level. Although an additional plantar incision is required, this surgical technique provides strong internal fixation. PMID- 26440933 TI - Pronounced polarization-induced energy level shifts at boundaries of organic semiconductor nanostructures. AB - Organic semiconductor devices rely on the movement of charge at and near interfaces, making an understanding of energy level alignment at these boundaries an essential element of optimizing materials for electronic and optoelectronic applications. Here we employ low temperature scanning tunneling microscopy and spectroscopy to investigate a model system: two-dimensional nanostructures of the prototypical organic semiconductor, PTCDA (3,4,9,10-perylenetetracarboxylic dianhydride) adsorbed on NaCl (2 ML)/Ag(111). Pixel-by-pixel scanning tunneling spectroscopy allows mapping of occupied and unoccupied electronic states across these nanoislands with sub-molecular spatial resolution, revealing strong electronic differences between molecules at the edges and those in the centre, with energy level shifts of up to 400 meV. We attribute this to the change in electrostatic environment at the boundaries of clusters, namely via polarization of neighbouring molecules. The observation of these strong shifts illustrates a crucial issue: interfacial energy level alignment can differ substantially from the bulk electronic structure in organic materials. PMID- 26440934 TI - Empathy levels in undergraduate paramedic students: A three-year longitudinal study. AB - Empathetic behaviour is regarded as a positive trait amongst healthcare professionals and has been attributed to increased patient compliance, greater patient satisfaction, and greater diagnostic accuracy and reduced rates of clinical errors. In particular, paramedic students have typically displayed lower rates of empathy when compared to their healthcare counterparts. The objective of this study is to assess both the level of empathy and changes in empathy in undergraduate paramedic students over a 3-year period at a single tertiary institution. A cross sectional study employing a convenience sample of first, second and third year undergraduate paramedic students at Monash University. Student empathy scores where measured with the Jefferson Scale of Empathy-Health Profession Student version (JSE-HPS); a validated, self-reporting questionnaire. 552 students were enrolled in the study. The mean overall JSE-HPS score for the cohort was 108.60 (SD = 12.50). Female students displayed significantly higher empathy scores of 110.27 (SD = 11.62) compared to males at 105.36 (SD = 13.57). There was also a significant difference (p = 0.03) noted between the 2008 JSE-HPS score 106.32 (SD = 14.02), when compared to the 2009 cohort, 110.18 (SD = 12.91). Results from this study suggest that paramedic students display lower empathy than those reported by fellow healthcare students within the literature. PMID- 26440935 TI - The prevalence of monosodium urate and calcium pyrophosphate crystals in synovial fluid from wrist and finger joints. AB - The aim of this study was to assess the frequency of monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals in synovial fluids (SFs) aspirated from wrist and finger joints of patients with previously diagnosed joint diseases. We reviewed the results of SF analysis of 1593 samples and identified 126 patients with effusions in the small joints of the hands and wrists. We reported from patients' medical files data about sex, age, diagnosis, disease duration and the microscopic SF results. The prevalence of CPP crystals in SF was 85.71% in CPP crystals arthritis (CPP-CA), 19.35% in rheumatoid arthritis (RA), 13.89% in osteoarthritis (OA) and 0% in psoriatic arthritis (PsA), spondyloarthritis (SpA), gout and miscellanea. The prevalence of MSU crystals in SF was 83.3% in gout, 10% in PsA, 2.8% in OA and 0% in RA, SpA, miscellanea and CPP-CA. Consistent with previously reported data concerning the big joints, microcrystals can be frequently found also in the small joints of patients with previous diagnosis. The finding underlines the importance of analyzing SF from the hand and wrist joints in the attempt to identify comorbidities associated with the presence of crystals and to develop targeted treatment strategies. PMID- 26440936 TI - Serum IL-10 Predicts Worse Outcome in Cancer Patients: A Meta-Analysis. AB - BACKGROUND: IL-10 is an important immunosuppressive cytokine which is frequently elevated in tumor microenvironment. Some studies have reported that overexpression of serous IL-10 is correlated with worse outcome in patients with malignant tumor. Here, we conducted a meta-analysis to assess the prognostic impact of serous IL-10 expression in cancer patients. METHODS: We searched PubMed and EBSCO for studies in evaluating the association of IL-10 expression-in serum and clinical outcome in cancer patients. Overall survival (OS) was the primary prognostic indicator and disease-free survival (DFS) was the secondary indicator. Extracted data were computed into odds ratios (ORs) and 95% confidence interval (CI) or a P value for survival at 1, 3 and 5 years. Pooled data were weighted using the Mantel-Haenszel Fixed-effect model. All statistical tests were two sided. RESULTS: A total of 1788 patients with cancer from 21 published studies were incorporated into this meta-analysis. High level of serum IL-10 was significantly associated with worse OS at 1-year (OR = 3.70, 95% CI = 2.81 to 4.87, P < 0.00001), 3-year (OR = 3.33, 95% CI = 2.53 to 4.39, P < 0.0001) and 5 year (OR = 2.80, 95% CI = 1.90 to 4.10, P < 0.0001) of cancer. Subgroup analysis showed that the correlation between serous IL-10 expression and outcome of patients with solid tumors and hematological malignancies are consistent. The association of IL-10 with worse DFS at 1-year (OR = 3.34, 95% CI = 1.40 to 7.94, P = 0.006) and 2-year (OR = 3.91, 95% CI = 1.79 to 8.53, P = 0.0006) was also identified. CONCLUSIONS: High expression of serous IL-10 leads to an adverse survival in most types of cancer. IL-10 is a valuable biomarker for prognostic prediction and targeting IL-10 treatment options for both solid tumors and hematological malignancies. PMID- 26440938 TI - Religiosity and youth substance use in a Muslim context. AB - The literature shows that young people are more vulnerable than adults to substance use. Religiosity is one of the factors that has been considered to protect youth from substance use and has also been interpreted as contributing to the substance abuse recovery process. Conceptualizing religiosity as a multidimensional construct, this study aimed to investigate the influence of religiosity on substance use among youth. Three dimensions of religiosity-belief about religion, religious self-practice, and religious social environment-were examined as predictors of substance use. The survey data collected in 2010 by the Governance of Istanbul, Istanbul Department of Education, and Istanbul Police Department were used. Participants were high school students (n = 31,272) between 14 and 18 years old. Structural equation modeling was used for statistical analysis and hypothesis testing. The study found a negative relationship between the three dimensions of religiosity and substance use. Religious social environment was found to be the strongest of the three dimensions. The findings suggest that religion has the potential to reduce the risk of substance use among youth. Implications for future research and policymakers were also discussed. PMID- 26440937 TI - Family Violence and Maltreatment of Women During the Perinatal Period: Associations with Infant Morbidity in Indian Slum Communities. AB - OBJECTIVES: To determine the prevalence of non-violent, gender-based forms of maltreatment of women by husbands and in-laws [i.e., gender-based household maltreatment (GBHM)] during pregnancy and postpartum; to clarify the role of GBHM in compromising infant health, and whether this role extends beyond that previously observed for intimate partner violence (IPV). METHODS: Cross sectional, quantitative data were collected from women (ages 15-35) seeking immunizations for their infants <6 months of age (N = 1061) in urban health centers in Mumbai, India. Logistic regression models were constructed to assess associations between maternal abuse (perinatal IPV, in-law violence and GBHM) and recent infant morbidity (diarrhea, respiratory distress, fever, colic and vomiting). RESULTS: More than one in four women (28.4%) reported IPV during their recent pregnancy and/or during the postpartum period, 2.6% reported perinatal violence from in-laws, and 49.0% reported one or more forms of perinatal GBHM. In adjusted regression models that included all forms of family violence and maltreatment, perinatal GBHM remained significantly associated with infant morbidity (AORs 1.4-1.9); perinatal IPV and in-law violence ceased to predict infant morbidity in models including GBHM. CONCLUSIONS: Findings indicate that non-violent expressions of gender inequity (e.g., nutritional deprivation, deprivation of sleep, blocking access to health care during pregnancy) are more strongly associated with poor infant health than physical or sexual violence from husbands or in-laws in urban India. These results strongly suggest the need to expand the conception of gender inequities beyond IPV to include non-violent forms of gendered mistreatment in considering their impact on infant health. PMID- 26440939 TI - Increased Steroid Excretion in Children with Extremely Low Birth Weight at a Median Age of 9.8 years. AB - BACKGROUND: Events during foetal or early extrauterine life may affect bodily structure and/or functions and even pave the way for adult diseases. AIMS: To find whether extremely low birth weight (ELBW) infants differ from healthy controls regarding the excretion of steroid metabolites. METHODS: The study compared 17 female and 10 male ELBW infants, all prepubertal, aged 8-11 years, birth weight <1,000 g, with 27 age- and sex-matched controls. All were healthy at the time of the study. Height, weight and BMI did not differ between the groups. Results were adjusted according to body surface area. 36 urinary steroid metabolites were quantified by gas chromatography-mass spectrometry. RESULTS: In the ELBW girls 33/36 steroid metabolites were higher (19 significantly) than in the controls. All 36 steroid metabolites were higher in the ELBW boys (9 significantly) than in the controls. Sums of mineralocorticoid precursors, metabolites descriptive for cortisol and parameters of adrenal androgen production were significantly higher in ELBW infants (both sexes). Only the sum of the metabolites known to be illustrative for adrenal 11beta-hydroxysteroid dehydrogenase activity was not different. CONCLUSION: Prepubertal ELBW children have an augmented urinary excretion of adrenal androgens, cortisol and mineralocorticoid precursors. These findings corroborate and help to explain the link between early-life adversity and subsequent adrenocortical function. PMID- 26440940 TI - Fermi points and topological quantum phase transitions in a multi-band superconductor. AB - The importance of models with an exact solution for the study of materials with non-trivial topological properties has been extensively demonstrated. The Kitaev model plays a guiding role in the search for Majorana modes in condensed matter systems. Also, the sp-chain with an anti-symmetric mixing among the s and p bands is a paradigmatic example of a topological insulator with well understood properties. Interestingly, these models share the same universality class for their topological quantum phase transitions. In this work we study a two-band model of spinless fermions with attractive inter-band interactions. We obtain its zero temperature phase diagram, which presents a rich variety of phases including a Weyl superconductor and a topological insulator. The transition from the topological to the trivial superconducting phase has critical exponents different from those of Kitaev's model. PMID- 26440942 TI - A Hierarchical Bayesian Model to Predict Self-Thinning Line for Chinese Fir in Southern China. AB - Self-thinning is a dynamic equilibrium between forest growth and mortality at full site occupancy. Parameters of the self-thinning lines are often confounded by differences across various stand and site conditions. For overcoming the problem of hierarchical and repeated measures, we used hierarchical Bayesian method to estimate the self-thinning line. The results showed that the self thinning line for Chinese fir (Cunninghamia lanceolata (Lamb.)Hook.) plantations was not sensitive to the initial planting density. The uncertainty of model predictions was mostly due to within-subject variability. The simulation precision of hierarchical Bayesian method was better than that of stochastic frontier function (SFF). Hierarchical Bayesian method provided a reasonable explanation of the impact of other variables (site quality, soil type, aspect, etc.) on self-thinning line, which gave us the posterior distribution of parameters of self-thinning line. The research of self-thinning relationship could be benefit from the use of hierarchical Bayesian method. PMID- 26440941 TI - MDM2 Inhibitor, Nutlin 3a, Induces p53 Dependent Autophagy in Acute Leukemia by AMP Kinase Activation. AB - MDM2 (mouse double minute 2) inhibitors that activate p53 and induce apoptosis in a non-genotoxic manner are in clinical development for treatment of leukemias. P53 can modulate other programmed cell death pathways including autophagy both transcriptionally and non-transcriptionally. We investigated autophagy induction in acute leukemia by Nutlin 3a, a first-in-class MDM2 inhibitor. Nutlin 3a induced autophagy in a p53 dependent manner and transcriptional activation of AMP kinase (AMPK) is critical, as this effect is abrogated in AMPK -/- mouse embryonic fibroblasts. Nutlin 3a induced autophagy appears to be pro-apoptotic as pharmacological (bafilomycin) or genetic inhibition (BECLIN1 knockdown) of autophagy impairs apoptosis induced by Nutlin 3a. PMID- 26440943 TI - The Health Effects of Passive Smoking: An Overview of Systematic Reviews Based on Observational Epidemiological Evidence. AB - PURPOSE: We aim to systematically summarize the available epidemiological evidence to identify the impact of environmental tobacco smoke on health. METHODS: A systematic literature search of PubMed, Embase, Web of Science, and Scopus for meta-analyses was conducted through January 2015. We included systematic reviews that investigated the association between passive smoking and certain diseases. Quantitative outcomes of association between passive smoking and the risk of certain diseases were summarized. RESULTS: Sixteen meta-analyses covering 130 cohort studies, 159 case-control studies, and 161 cross-sectional studies and involving 25 diseases or health problems were reviewed. Passive smoking appears not to be significantly associated with eight diseases or health problems, but significantly elevates the risk for eleven specific diseases or health problems, including invasive meningococcal disease in children (OR 2.18; 95% CI 1.63-2.92), cervical cancer (OR 1.73; 95% CI 1.35-2.21), Neisseria meningitidis carriage (OR 1.68; 95% CI 1.19-2.36), Streptococcus pneumoniae carriage (OR 1.66; 95% CI 1.33-2.07), lower respiratory infections in infancy (OR 1.42; 95% CI 1.33-1.51), food allergy (OR 1.43; 95% CI 1.12-1.83), and so on. CONCLUSIONS: Our overview of systematic reviews of observational epidemiological evidence suggests that passive smoking is significantly associated with an increasing risk of many diseases or health problems, especially diseases in children and cancers. PMID- 26440944 TI - [A study of men born in 1913 show the art of becoming 100 years. Nonsmoking, moderate coffee consumption and good income helps]. PMID- 26440945 TI - [Psychiatry and psychology integrated in somatics is a profit for the clinic. Consultation liaison psychiatry important for the future of healthcare]. AB - The mental health needs of patients receiving physical health care often remain undiagnosed and untreated, resulting in significant costs to the health care system. However, some countries have recently seen fast progress with the development of consultation liaison psychiatry. In Sweden, this service has developed quite slowly, but a breakthrough may be imminent. There is evidence that providing better support for co-morbid health problems may improve the psychological quality of care and reduce physical health care costs in acute hospitals. Consultation liaison psychiatry fits well with the current trends of value-based health care, personalized care, and an emphasis on networking in care. PMID- 26440947 TI - [A unique collection of fetuses in jars. Tornbladinstitutet--living history of medicine]. PMID- 26440946 TI - [Longer waiting time and higher mortality in older people with traumatic brain injuries. Mapping of emergency prehospital management and hospital management in Vasterbotten]. AB - The main purpose was to study the prehospital and early intrahospital treatment of patients with traumatic brain injury (TBI) in the county of Vasterbotten 2011 2012. In total, 162 patients were included. The main finding was that a large proportion of TBI patients were older men who fell in the same or from a different level. Older patients had higher mortality and had to wait longer for diagnostic imaging compared to younger patients. Furthermore, most patients were initially relatively unaffected by the injury and around 1/5 of the patients were transported to hospital by private transport. Finally, we observed that most patients were admitted to hospital and computer tomography scan of the head was performed within 4 hours. PMID- 26440948 TI - [E-prescriptions should not govern physicians and pharmacists]. PMID- 26440949 TI - [Recent study shows iodine deficiency among pregnant women in Sweden]. PMID- 26440950 TI - [Wake up SALAR, the wheel is already invented!]. PMID- 26440951 TI - [Medical research and man broken into pieces]. PMID- 26440952 TI - [Higher mortality related to cannabis than to alcohol among young people]. PMID- 26440954 TI - [In Process Citation]. PMID- 26440953 TI - [In Process Citation]. PMID- 26440955 TI - [Despite the traffic barrier]. PMID- 26440956 TI - [The project has a wider purpose]. PMID- 26440957 TI - [2015 Nobel Prize in Physiology or Medicine. Better health for millions of people thanks to drugs against parasites]. PMID- 26440958 TI - Balloon dilatation in patients with gastric outlet obstruction related to peptic ulcer disease. AB - BACKGROUND AND STUDY AIMS: Gastric outlet obstruction (GOO) is a rare complication of peptic ulcer disease (PUD). The endoscopic balloon dilatation (EBD) associated with medical treatment of Helicobacter pylori is a successful method in the management of pyloric stenosis. The aim of this study was to describe epidemiological, clinical, and endoscopic characteristics of GOO related to PUD and to evaluate the effectiveness, safety, and outcome of EBD. PATIENTS AND METHODS: In a retrospective study of patients seen between 1999 and 2009 with symptoms of GOO secondary to PUD, pyloro-bulbar stenosis was confirmed by endoscopic examination. Balloon dilatation was performed when obstruction persisted after treatment with double-dose proton-pump inhibitor (PPI) intravenously for 7-10days. The H. pylori status was assessed with histology, and eradication therapy was prescribed for infection. RESULTS: A total of 45 consecutive patients (38 males, 7 females median age, 51.9years; range, 20 58years) with symptoms of GOO secondary to PUD underwent EBD. Median follow-up time of the 45 patients was 32months (range, 4-126months). The immediate success rate of the procedure was 95.5%. Clinical remission was noted in 84.4% of the patients. Remission without relapse was observed in 55.8%, 30months after the dilatation. Pyloric stenosis relapsed in 15 patients (39.5%) after a median period of 22.9months. The dilatation was complicated in three patients (6.7%, two perforations and one bleeding). A total of 13 patients (29%) underwent surgery. H. pylori was found to be positive in 97.7% of the patients, and was eradicated in 78.4% of them. Smoking and failure of H. pylori eradication were associated with the relapse of the stenosis. CONCLUSION: EBD is a simple, effective, and safe therapy for the GOO related to PUD, producing short- and long-term remission. PMID- 26440963 TI - Impact of a Serious Videogame Designed for Flexible Insulin Therapy on the Knowledge and Behaviors of Children with Type 1 Diabetes: The LUDIDIAB Pilot Study. AB - BACKGROUND: Flexible (or functional) insulin therapy method is a self-management education approach for intensive insulin therapy in patients with type 1 diabetes. The serious game (or applied game) "L'Affaire Birman" ("Mr. Birman's File") (available at www.gluciweb.com ) was specifically designed as an educational tool for the flexible insulin therapy method. Its educational impact was evaluated in children with type 1 diabetes. MATERIALS AND METHODS: This prospective multicenter pilot study evaluated the effect of this videogame on the therapeutic knowledge and behavior of children with type 1 diabetes. PedCarbQuiz (PCQ) and Diabetes Self-Management Profile (DSMP) questionnaires were used before (T0), immediately after (T1), and 6 months after (T2) the unstructured use of the videogame. RESULTS: The 38 children enrolled in the study were 42% boys and 58% girls; they had a mean age of 13.7 +/- 2.1 years old, a diabetes duration of 6.0 +/- 3.8 years, and hemoglobin A1c (HbA1c) levels of 8.5 +/- 1.4% (69.4 +/- 9.4 mmol/mol). The children connected to the game 3.3 +/- 2.8 times during this 6 month study. Their PCQ score increased from 31.6 +/- 4.9 at T0 to 36.0 +/- 4.0 at T2 (P < 0.05). Two PCQ subscores also increased significantly: the insulin titration score at T1 and T2 and the carbohydrate quantification score at T2. Conversely, the DSMP score was not different at T0, T1, and T2 (59.1 +/- 9.9, 60.2 +/- 9.8, and 60.0 +/- 10.0, respectively), and HbA1c levels also remained stable throughout the study (8.4 +/- 1.3%, 8.4 +/- 1.2%, and 8.5 +/- 1.5% at T0, T1, and T2, respectively). Subgroup analysis found a greater impact of the game in children with poor glycemic control and low knowledge at baseline. Adherence to the game was rather low (half of the children played less than 2.5 bouts), but no criterion was found to be predictive of this low attractiveness. CONCLUSIONS: Nonsupervised usage of the serious game "L'Affaire Birman" was able to improve insulin titration and carbohydrate quantification in children with type 1 diabetes. PMID- 26440964 TI - Effects of Hypoxia on the Physiology of Zebrafish (Danio rerio): Initial Responses, Acclimation and Recovery. AB - Hypoxia often occurs in aquatic environments as dissolved oxygen (DO) concentration decrease to a level where it is detrimental to aquatic organisms. To investigate the effects of hypoxia on the physiology of zebrafishes (Danio rerio), the organisms were kept at normoxic conditions (DO: 8 +/- 0.3 mg L(-1): control group) or were subjected to mild (DO: 3 +/- 0.3 mg L(-1)) or severe hypoxia (DO: 1 +/- 0.2 mg L(-1)) for 48 h and a subsequent restoration of oxygen concentrations (DO: 8 +/- 0.3 mg L(-1)) for another 96 h at 25 degrees C. We found that the enzyme activities show different initial responses, acclimation and recovery to severe hypoxia relative to normoxic conditions, but no significant difference was observed between normoxic conditions and mild hypoxia. The results suggest that zebrafishes can acclimate to the mild hypoxia (3 mg L( 1)) quickly but oxidative damage would occur when DO decreased below 1 mg L(-1). Our findings could be useful for water resource managers to set protection limits of DO for aquatic organisms. PMID- 26440965 TI - High yield expression of novel glutaminase free L-asparaginase II of Pectobacterium carotovorum MTCC 1428 in Bacillus subtilis WB800N. AB - Gene encoding glutaminase-free L-asparaginase II (ans B2) from Pectobacterium carotovorum MTCC 1428 was cloned into pHT43, transformed in Bacillus subtilis WB800N and optimised the expression levels of recombinant enzyme. A three-fold higher enzyme production was observed with an efficient transformant as compared to native strain. Enzyme localization studies revealed that >90% of recombinant enzyme is secreted extracellularly, a little fraction is attached to the membrane (>6%) and localised intracellularly (3%). The expression of recombinant L asparaginase II was confirmed by SDS-PAGE, IMAC (Immobilised metal ion affinity chromatography) purification followed by Western blotting. Process parameter optimization with OFAT (one factor at a time) revealed that rpm (120), temperature (37 degrees C), Isopropyl beta-D-1-thiogalactopyranoside (IPTG) concentration (1 mM) and time of induction (0.8 OD600nm) plays a vital role where a maximum of 55 IU/ml was achieved. Further, consecutive induction by IPTG improved the enzyme production up to 105 IU/ml with a specific activity of 101 IU/mg of protein. Molecular modelling analysis depicted that amino acids, GLY60, GLY119 and ALA252 in the active site are responsible for the glutaminase free L asparaginase II activity. This is the first report on enhanced expression of recombinant glutaminase-free L-asparaginase II by intermediate addition of IPTG. PMID- 26440966 TI - Impact of apoptosis on the on-line measured dielectric properties of CHO cells. AB - Apoptosis is a common type of cell death in biopharmaceutical cell culture processes which causes decrease in viable cell density and product yield. The progression of apoptosis has been reported to influence the dielectric properties of mammalian cells; however, the on-line detection of these effects has been rarely described. This study provides a comprehensive analysis of the on-line detectability of dielectric changes upon apoptosis induction in an industrial fed batch process of CHO cells expressing a recombinant monoclonal antibody. Using capacitance signals, measured at 25 frequencies, the impact of apoptosis on the dielectric spectra was investigated in eight bioreactor cultivations in which various process conditions were combined with two different apoptosis induction strategies (camptothecin treatment and glucose starvation). To differentiate the apoptosis-related information from the cell concentration-associated variance in the multivariate capacitance datasets, principal component analysis (PCA) was used. A second principal component, explaining an explicit proportion (>20%) of the variance, was identified to be related to dielectric changes induced by apoptosis. Furthermore, the analysis of caspase-3 and -7 activation and DNA fragmentation showed that the detected dielectric change occurred in the early phase of apoptosis. The presented results verify that apoptosis has a considerable impact on the dielectric features of CHO cells and it can be monitored on-line with the introduced tool-set combining capacitance measurement with multivariate data analysis. PMID- 26440968 TI - Hydrophobic pocket targeting probes for enteroviruses. AB - Visualization and tracking of viruses without compromising their functionality is crucial in order to understand virus targeting to cells and tissues, and to understand the subsequent subcellular steps leading to virus uncoating and replication. Enteroviruses are important human pathogens causing a vast number of acute infections, and are also suggested to contribute to the development of chronic diseases like type I diabetes. Here, we demonstrate a novel method to target site-specifically the hydrophobic pocket of enteroviruses. A probe, a derivative of Pleconaril, was developed and conjugated to various labels that enabled the visualization of enteroviruses under light and electron microscopes. The probe mildly stabilized the virus particle by increasing the melting temperature by 1-3 degrees, and caused a delay in the uncoating of the virus in the cellular endosomes, but could not however inhibit the receptor binding, cellular entry or infectivity of the virus. The hydrophobic pocket binding moiety of the probe was shown to bind to echovirus 1 particle by STD and tr-NOESY NMR methods. Furthermore, binding to echovirus 1 and Coxsackievirus A9, and to a lesser extent to Coxsackie virus B3 was verified by using a gold nanocluster labeled probe by TEM analysis. Molecular modelling suggested that the probe fits the hydrophobic pockets of EV1 and CVA9, but not of CVB3 as expected, correlating well with the variations in the infectivity and stability of the virus particles. EV1 conjugated to the fluorescent dye labeled probe was efficiently internalized into the cells. The virus-fluorescent probe conjugate accumulated in the cytoplasmic endosomes and caused infection starting from 6 hours onwards. Remarkably, before and during the time of replication, the fluorescent probe was seen to leak from the virus-positive endosomes and thus separate from the capsid proteins that were left in the endosomes. These results suggest that, like the physiological hydrophobic content, the probe may be released upon virus uncoating. Our results collectively thus show that the gold and fluorescently labeled probes may be used to track and visualize the studied enteroviruses during the early phases of infection opening new avenues to follow virus uncoating in cells. PMID- 26440967 TI - Permethrin-Treated Clothing as Protection against the Dengue Vector, Aedes aegypti: Extent and Duration of Protection. AB - INTRODUCTION: Dengue transmission by the mosquito vector, Aedes aegypti, occurs indoors and outdoors during the day. Personal protection of individuals, particularly when outside, is challenging. Here we assess the efficacy and durability of different types of insecticide-treated clothing on laboratory reared Ae. aegypti. METHODS: Standardised World Health Organisation Pesticide Evaluation Scheme (WHOPES) cone tests and arm-in-cage assays were used to assess knockdown (KD) and mortality of Ae. aegypti tested against factory-treated fabric, home-dipped fabric and microencapsulated fabric. Based on the testing of these three different treatment types, the most protective was selected for further analysis using arm-in cage assays with the effect of washing, ultra violet light, and ironing investigated using high pressure liquid chromatography. RESULTS: Efficacy varied between the microencapsulated and factory dipped fabrics in cone testing. Factory-dipped clothing showed the greatest effect on KD (3 min 38.1%; 1 hour 96.5%) and mortality (97.1%) with no significant difference between this and the factory dipped school uniforms. Factory-dipped clothing was therefore selected for further testing. Factory dipped clothing provided 59% (95% CI = 49.2%- 66.9%) reduction in landing and a 100% reduction in biting in arm-in cage tests. Washing duration and technique had a significant effect, with insecticidal longevity shown to be greater with machine washing (LW50 = 33.4) compared to simulated hand washing (LW50 = 17.6). Ironing significantly reduced permethrin content after 1 week of simulated use, with a 96.7% decrease after 3 months although UV exposure did not reduce permethrin content within clothing significantly after 3 months simulated use. CONCLUSION: Permethrin-treated clothing may be a promising intervention in reducing dengue transmission. However, our findings also suggest that clothing may provide only short-term protection due to the effect of washing and ironing, highlighting the need for improved fabric treatment techniques. PMID- 26440969 TI - Serial investigation of PTPN11 mutation in nonhematopoietic tissues in a patient with juvenile myelomonocytic leukemia who was treated with unrelated cord blood transplantation. AB - After allogeneic stem-cell transplantation, nonhematopoietic tissues contain donor-derived cells; however, whether cells from malignant hematological disease can also be found in nonhematopoietic tissues is unclear. This report describes a juvenile myelomonocytic leukemia (JMML) case with a typical PTPN11 mutation (p.E76K) at different allele frequencies in the bone marrow mononuclear cells, buccal smear cells, and fingernails at diagnosis, which was suggestive of PTPN11 somatic mosaicism; however, the PTPN11 mutation in the buccal smear cells and fingernails was lost after unrelated cord blood transplantation. These results suggest that JMML-derived cells may migrate into and reside in nonhematopoietic tissues and furthermore that these cells can be eradicated by cord blood transplantation. PMID- 26440970 TI - Outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for multiple myeloma. AB - We retrospectively evaluated single-institute outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with a reduced-intensity conditioning regimen consisting of fludarabine (125 mg/m2) and melphalan (140 mg/m2) for multiple myeloma. Twenty-three patients (median age: 46 years) were evaluated. Stem cell sources were bone marrow or peripheral blood stem cells from siblings (n = 4) and bone marrow from unrelated donors (n = 19). For graft-versus host disease prophylaxis, cyclosporine A or tacrolimus with short-term methotrexate was given. Disease status at time of transplant was complete response in four patients, very good partial or partial response in 13, and stable or progressive disease in six. The median follow-up period of 7 survivors at analysis was 73.2 months (range 46.0-158.9 months). During the follow-up, disease recurrence or progression was observed in 21 patients, and was primary causes of death in 88% of the patients. The 5-year overall survival and progression-free survival rates were 38.6% (95% CI 19.3-57.7%) and 5.4% (95% CI 0.4-21.6%), respectively. Although allo-HSCT with this conditioning could be safely performed, further refinement of this approach aiming at more effective eradication of myeloma cells is clearly warranted. PMID- 26440971 TI - Absolute lymphocyte count at the end of induction therapy is a prognostic factor in childhood acute lymphoblastic leukemia. AB - Recent studies have reported that the absolute lymphocyte count (ALC) during induction therapy is predictive of treatment outcome in de novo acute lymphoblastic leukemia (ALL); however, the significance of ALC on outcomes remains controversial. In the present study, we assessed the significance of ALC at day 29 (ALC-29), the end of induction therapy, on outcomes in our Japanese cohort. The outcomes of 141 patients aged <=18 years with newly diagnosed ALL who were enrolled on the JACLS ALL-02 at our hospitals were analyzed in terms of ALC 29. Patients with ALC-29 >=750/MUL (n = 81) had a superior 5-year EFS (95.2 +/- 2.7 vs 84.3 +/- 4.8 %, P = 0.016) and OS (100 vs 87.0 +/- 4.7 %, P = 0.0062). A multivariate analysis identified ALC-29 >=750/MUL as a significant predictor of improved EFS and OS after controlling for confounding factors. A multiple linear regression model revealed a significant inverse relationship between the percentage of blasts in bone marrow on day 15 and ALC-29 (P = 0.005). These results indicate that ALC is a simple prognostic factor in childhood ALL, and, thus, has the potential to refine current risk algorithms. PMID- 26440972 TI - Aging, clonal hematopoiesis and preleukemia: not just bad luck? AB - Chronological human aging is associated with a number of changes in the hematopoietic system, occurring at many levels from stem to mature cells, and the marrow microenvironment as well. This review will focus mainly on the aging of hematopoietic stem and progenitor cells (HSPCs), and on the associated increases in the incidence of hematological malignancies. HSPCs manifest reduced function and acquire molecular changes with chronological aging. Furthermore, while for many years it has been known that the human hematopoietic system becomes increasingly clonal with chronological aging (clonal hematopoiesis), only in the last few years has it become clear that clonal hematopoiesis may result from the accumulation of preleukemic mutations in HSPCs. Such mutations confer a selective advantage that leads to clonal hematopoiesis, and that may occasionally result in the development of leukemia, and define the existence of both preleukemic stem cells, and of 'preleukemia' as a clinical entity. While it is well appreciated that clonal hematopoiesis is very common in the elderly, several questions remain unanswered: why and how does clonal hematopoiesis develop? How is clonal hematopoiesis related to the age-related changes observed in the hematopoietic system? And why do only some individuals with clonal hematopoiesis develop leukemia? PMID- 26440973 TI - Bleeding complications in BCR-ABL negative myeloproliferative neoplasms: prevalence, type, and risk factors in a single-center cohort. AB - The BCR-ABL1-negative myeloproliferative neoplasms (MPN) share an increased risk of thrombotic and hemorrhagic complications. Risk factors for hemorrhage are less well defined than those for thrombosis. Because patients with CALR mutations have higher platelet counts compared to JAK2 V617F-mutated patients, bleeding rates may be increased in this group. Our aim was to retrospectively evaluate whether acquired von Willebrand disease (AvWD), thrombocytosis, mutational status, or treatment history are associated with bleeding in a cohort of MPN patients. Using an electronic database, MPN patients seen between 2005 and 2013 were retrospectively identified using ICD-9 codes and billing records. A bleeding event was defined as one that was identified in the medical record and graded based on the Common Terminology Criteria for Adverse Event (CTCAE) version 4.0. Among 351 MPN patients, 15.6 % experienced 64 bleeding event types. There was no association of bleeding with mutational status, gender, MPN subtype, aspirin use, prior thrombosis, or platelet count at presentation. There was an association between bleeding and older age at diagnosis. aVWD was identified in six patients. In this single-center retrospective study, bleeding events were identified in 15 % of patients, and associated with older age at diagnosis. aVWD was rarely tested for in this cohort. PMID- 26440974 TI - Microarray CGH analysis of hematological patients with del(20q). AB - Deletion of the long arm of chromosome 20 is a common abnormality underlying hematological malignancy. We analyzed 21 patients with hematologic diseases confirmed to carry the del(20q) by conventional cytogenetics and fluorescence in situ hybridization using microarray comparative genomic hybridization (aCGH). Seventeen patients were positive for del(20q), but this deletion was not detected in four patients. All deletions detected were interstitial of which continuous deletions were seen in 12 patients and discrete deletions in five. Three commonly deleted regions (CDRs) and two commonly retained regions (CRRs) were defined: CDR1 spanning 3.05Mb (34560497-37608229) within 20q11.23, CDR2 spanning 1.76Mb (37851501-39615698) within 20q12, CDR3 spanning 116Kb (48120412-48236791) within 20q13.13, CRR1 spanning 1.1Mb (29374726-30428250) within 20q11.21, and CRR2 spanning 2.5Mb (60484668-62963548) within 20q13.33. Duplications of retained regions (20q11.21) were found in five cases with similar erythroid hyperplasia (2 M6, 3 MDS). Moreover, duplication of 20p13-p11.21 was also found in two cases with M6. Using the CDRs and CRRs, we identified the candidate genes we searched for using the UCSC Genome Browser. Our data suggest that aCGH analysis is useful for more precisely defining breakpoints on 20q. Further work is required to identify candidate pathogenic genes within these CDRs and CRRs. PMID- 26440975 TI - Impairment of hematopoietic stem cell niches in patients with aplastic anemia. AB - Aplastic anemia (AA) is a serious hematological disorder characterized by pancytopenia and defective bone marrow (BM) microenvironment. Previous investigations have demonstrated that there is a defect of angiogenesis in the BM of patients with AA. However, whether abnormalities of the BM microenvironment, particularly the overall specialization of niches, which have been classified into osteoblastic, vascular, and perivascular niches, are involved in the pathogenesis of AA is unknown. In the present study, 46 patients with AA and 15 controls were selected. The cellular elements of the BM microenvironment, including endosteal, vascular, and perivascular cells, were analyzed by immunohistochemical staining in situ. Patients with AA showed markedly fewer endosteal cells [0.33 vs 3.67 per high-power field (hpf); P < 0.05], vascular cells (8.00 vs 12.67 per hpf; P < 0.05), and perivascular cells (7.17 vs 10.67 per hpf; P < 0.05) compared with controls. These data indicate that AA is associated with impaired hematopoietic stem cell niches. PMID- 26440976 TI - Bilateral psoas muscle lymphoma: an unusual presentation of EBV-positive diffuse large B-cell lymphoma of the elderly. PMID- 26440977 TI - Integrin beta-3 genetic variants and risk of venous thromboembolism in colorectal cancer patients. AB - BACKGROUND: Integrin beta3 is involved in tumor and endothelial cell biology as well as in platelet aggregation. Herein, we evaluated the predictive potential of three germline single nucleotide polymorphisms (SNPs) in the integrin beta3 gene (rs3809865, rs5918 and rs4642) to predict the risk of venous thromboembolism (VTE) in colorectal cancer (CRC) patients, which is one of the leading causes of death among cancer patients. METHODS: 112 patients diagnosed with CRC enrolled in the prospective Vienna Cancer and Thrombosis Study (CATS) were assessed with a median follow-up of 46 months. DNA was isolated from venous blood samples and SNPs were analyzed by the PCR-RFLP method. RESULTS: VTE occurred in 12% (n=13) of all patients. The SNPs rs5918 and rs4642 were not associated with VTE risk. For rs3809565, 23% (n=11) of patients had the A/A genotype, 4% (n=2) had the A/T genotype, but none (0%) had the T/T genotype. In the univariate analysis, patients with the A/A genotype had a significantly higher risk to develop VTE compared to the other polymorphisms (P=0.0005 after Fine and Gray). In the multivariable analysis, the predictive value remained significant. CONCLUSIONS: This study identified the rs3809865 A/A genotype as an independent risk factor for VTE in CRC patients. Our findings would help identify high risk patients and would be essential for tailored anticoagulant prophylaxis. PMID- 26440978 TI - The Impact of Tic Severity, Comorbidity and Peer Attachment on Quality of Life Outcomes and Functioning in Tourette's Syndrome: Parental Perspectives. AB - The aim of this controlled, community-based study based on data from parents of youth (aged 7-16 years) with Tourette's syndrome (TS; n = 86) and parents of age and gender matched peers (n = 108) was to test several hypotheses involving a range of variables salient to the TS population, including peer attachment, quality of life, severity of tics, comorbidity, and psychological, behavioural and social dysfunction. Multivariate between-group analyses confirmed that TS group youth experienced lower quality of life, increased emotional, behavioural and social difficulties, and elevated rates of insecure peer attachment relative to controls, as reported by their primary caregiver. Results also confirmed the main hypothesis that security of peer attachment would be associated with individual variability in outcomes for youth with TS. As predicted, multivariate within-TS group analyses determined strong relationships among adverse quality of life outcomes and insecure attachment to peers, increased tic severity, and the presence of comorbid disorder. Findings suggest that youth with TS are at increased risk for insecure peer attachment and that this might be an important variable impacting the quality of life outcomes for those diagnosed. PMID- 26440979 TI - "Vision for Action" in Young Children Aligning Multi-Featured Objects: Development and Comparison with Nonhuman Primates. AB - Effective vision for action and effective management of concurrent spatial relations underlie skillful manipulation of objects, including hand tools, in humans. Children's performance in object insertion tasks (fitting tasks) provides one index of the striking changes in the development of vision for action in early life. Fitting tasks also tap children's ability to work with more than one feature of an object concurrently. We examine young children's performance on fitting tasks in two and three dimensions and compare their performance with the previously reported performance of adult individuals of two species of nonhuman primates on similar tasks. Two, three, and four year-old children routinely aligned a bar-shaped stick and a cross-shaped stick but had difficulty aligning a tomahawk-shaped stick to a matching cut-out. Two year-olds were especially challenged by the tomahawk. Three and four year-olds occasionally held the stick several inches above the surface, comparing the stick to the surface visually, while trying to align it. The findings suggest asynchronous development in the ability to use vision to achieve alignment and to work with two and three spatial features concurrently. Using vision to align objects precisely to other objects and managing more than one spatial relation between an object and a surface are already more elaborated in two year-old humans than in other primates. The human advantage in using hand tools derives in part from this fundamental difference in the relation between vision and action between humans and other primates. PMID- 26440980 TI - Oxidation of Ni-ECp* Complexes: Stable Open-Shell Ni(I) Cations [Ni(ECp*)n(PPh3)(4-n)](+) (n = 2, 4; E = Al, Ga). AB - Uncommon Ni(I) cationic complexes were synthesized by treating [Ni(ECp*)2(PPh3)2] (E = Al, Ga; Cp* = pentamethylcyclopentadienyl) with 1 equiv of [FeCp2][BAr4(F)]. All compounds have been prepared readily in high yield. The paramagnetic compounds were characterized by single-crystal X-ray crystallography, mass spectrometry, elemental analysis, magnetic susceptibility, and electron paramagnetic resonance spectroscopy. PMID- 26440982 TI - Hypertension: PATHWAY to improving the treatment of drug-resistant hypertension. PMID- 26440981 TI - Biomarkers: Troponin testing--risk stratification to stratified medicine. AB - Among patients with diabetes mellitus and ischaemic heart disease, high sensitivity testing effectively identified 39.3% of patients with elevated troponin levels who were at high 5-year risk of cardiovascular death, myocardial infarction, or stroke. Compared with optimal medical therapy, revascularization did not reduce ischaemic events among patients with elevated troponin levels. PMID- 26440983 TI - Constrictive pericarditis--a curable diastolic heart failure. PMID- 26440984 TI - Important role of myocardial tissue characterization by cardiac MRI in diagnosing Takotsubo syndrome. PMID- 26440985 TI - Valvular disease: Importance of balloon valvuloplasty before TAVI to prevent embolization. PMID- 26440986 TI - Use of cardiac MRI to diagnose Takotsubo syndrome. PMID- 26440987 TI - Risk factors: Alcohol intake, MI, and income level. PMID- 26440992 TI - Bronchoconstriction induced by inhaled methacholine delays desflurane uptake and elimination in a piglet model. AB - Bronchoconstriction is a hallmark of asthma and impairs gas exchange. We hypothesized that pharmacokinetics of volatile anesthetics would be affected by bronchoconstriction. Ventilation/perfusion (VA/Q) ratios and pharmacokinetics of desflurane in both healthy state and during inhalational administration of methacholine (MCh) to double peak airway pressure were studied in a piglet model. In piglets, MCh administration by inhalation (100 MUg/ml, n=6) increased respiratory resistance, impaired VA/Q distribution, increased shunt, and decreased paO2 in all animals. The uptake and elimination of desflurane in arterial blood was delayed by nebulization of MCh, as determined by Micropore Membrane Inlet Mass Spectrometry (wash-in time to P50, healthy vs. inhalation: 0.5 min vs. 1.1 min, to P90: 4.0 min vs. 14.8 min). Volatile elimination was accordingly delayed. Inhaled methacholine induced severe bronchoconstriction and marked inhomogeneous VA/Q distribution in pigs, which is similar to findings in human asthma exacerbation. Furthermore, MCh-induced bronchoconstriction delayed both uptake and elimination of desflurane. These findings might be considered when administering inhalational anesthesia to asthmatic patients. PMID- 26440993 TI - Epidemiology of severe trauma in Spain. Registry of trauma in the ICU (RETRAUCI). Pilot phase. AB - OBJECTIVE: To describe the characteristics and management of severe trauma disease in Spanish Intensive Care Units (ICUs). Registry of trauma in the ICU (RETRAUCI). Pilot phase. DESIGN: A prospective, multicenter registry. SETTING: Thirteen Spanish ICUs. PATIENTS: Patients with trauma disease admitted to the ICU. INTERVENTIONS: None. MAIN VARIABLES OF INTEREST: Epidemiology, out-of hospital attention, registry of injuries, resources utilization, complications and outcome were evaluated. RESULTS: Patients, n=2242. Mean age 47.1+/-19.02 years. Males 79%. Blunt trauma 93.9%. Injury Severity Score 22.2+/-12.1, Revised Trauma Score 6.7+/-1.6. Non-intentional in 84.4% of the cases. The most common causes of trauma were traffic accidents followed by pedestrian and high-energy falls. Up to 12.4% were taking antiplatelet medication or anticoagulants. Almost 28% had a suspected or confirmed toxic influence in trauma. Up to 31.5% required an out-of-hospital artificial airway. The time from trauma to ICU admission was 4.7+/-5.3hours. At ICU admission, 68.5% were hemodynamically stable. Brain and chest injuries predominated. A large number of complications were documented. Mechanical ventilation was used in 69.5% of the patients (mean 8.2+/-9.9 days), of which 24.9% finally required a tracheostomy. The median duration of stay in the ICU and in hospital was 5 (range 3-13) and 9 (5-19) days, respectively. The ICU mortality rate was 12.3%, while the in-hospital mortality rate was 16.0%. CONCLUSIONS: The pilot phase of the RETRAUCI offers a first impression of the epidemiology and management of trauma disease in Spanish ICUs. PMID- 26440994 TI - [Forty years since description of the Kirby index (PaO2/FiO2)]. PMID- 26440995 TI - Stereoselective [3+2] Carbocyclization of Indole-Derived Imines and Electron-Rich Alkenes: A Divergent Synthesis of Cyclopenta[b]indole or Tetrahydroquinoline Derivatives. AB - An unprecedented stereoselective [3+2] carbocyclization reaction of indole-2 carboxaldehydes, anilines, and electron-rich alkenes to obtain cyclopenta[b]indoles is disclosed. This pathway is different from the well established Povarov reaction: the formal [4+2] cycloaddition involving the same components, which affords tetrahydroquinolines. Moreover, by simply changing the Bronsted acid catalyst, this multicomponent coupling process could be divergently directed towards the conventional Povarov pathway to produce tetrahydroquinolines or to the new pathway (anti-Povarov) to generate cyclopenta[b]indoles. Supported by computational studies, a stepwise Mannich/Friedel-Crafts cascade is proposed for the new anti-Povarov reaction, whereas a concerted [4+2] cycloaddition mechanism is proposed for the Povarov reaction. PMID- 26440996 TI - Crystal structure of quinone-dependent alcohol dehydrogenase from Pseudogluconobacter saccharoketogenes. A versatile dehydrogenase oxidizing alcohols and carbohydrates. AB - The quinone-dependent alcohol dehydrogenase (PQQ-ADH, E.C. 1.1.5.2) from the Gram negative bacterium Pseudogluconobacter saccharoketogenes IFO 14464 oxidizes primary alcohols (e.g. ethanol, butanol), secondary alcohols (monosaccharides), as well as aldehydes, polysaccharides, and cyclodextrins. The recombinant protein, expressed in Pichia pastoris, was crystallized, and three-dimensional (3D) structures of the native form, with PQQ and a Ca(2+) ion, and of the enzyme in complex with a Zn(2+) ion and a bound substrate mimic were determined at 1.72 A and 1.84 A resolution, respectively. PQQ-ADH displays an eight-bladed beta propeller fold, characteristic of Type I quinone-dependent methanol dehydrogenases. However, three of the four ligands of the Ca(2+) ion differ from those of related dehydrogenases and they come from different parts of the polypeptide chain. These differences result in a more open, easily accessible active site, which explains why PQQ-ADH can oxidize a broad range of substrates. The bound substrate mimic suggests Asp333 as the catalytic base. Remarkably, no vicinal disulfide bridge is present near the PQQ, which in other PQQ-dependent alcohol dehydrogenases has been proposed to be necessary for electron transfer. Instead an associated cytochrome c can approach the PQQ for direct electron transfer. PMID- 26440997 TI - Postnatal nicotine effects on the expression of nicotinic acetylcholine receptors in the developing piglet hippocampus and brainstem. AB - Postnatal exposure to cigarette smoke during infancy is associated with increased number of respiratory illnesses, impaired pulmonary function, and the occurrence of Sudden Infant Death Syndrome (SIDS). It is also associated with reduced cognitive functioning and attention deficits in childhood. Nicotine, the major neurotoxic component of cigarette smoke, induces its actions by binding to nicotinic acetylcholine receptors (nAChR). Using a piglet model of postnatal nicotine exposure, we studied the immunohistochemical expression of nAChR subunits alpha2, alpha3, alpha4, alpha5, alpha7, alpha9, beta1 and beta2 in the brainstem medulla and the hippocampus, given the role of these structures in cardiorespiratory control and cognition, respectively. We compared piglets exposed postnatally to 2mg/kg/day nicotine for 14 days (n=14: 7 males: 7 females) to controls (n=14: 7 males: 7 females). In the hippocampus, decreased expression was seen for alpha3 in CA1 (p=0.017), alpha9 in CA1 (p<0.001) and CA2 (p<0.001), beta1 in CA1 (p=0.001) and CA2 (p=0.001) and beta2 in CA3 (p=0.036). In the medulla, the nucleus of the spinal trigeminal tract had increased alpha2 and alpha4; vestibular nucleus increased alpha2 and alpha3, and decreased alpha4; hypoglossal decreased alpha3 and beta1; dorsal motor nucleus of the vagus decreased alpha4 and beta1. This is the first demonstration that non-classical nAChR subunits are affected by postnatal nicotine in the developing brain, and the implications are discussed. PMID- 26440999 TI - Estimating the cost-effectiveness of daclatasvir plus asunaprevir in difficult to treat Japanese patients chronically infected with hepatitis C genotype 1b. AB - AIM: Standard of care for chronic hepatitis C in Japan is currently a pegylated interferon (IFN)-alpha + ribavirin (PR)-based regimen, notably associated with efficacy and tolerability issues. The advent of novel direct-acting antivirals (DAA) has provided more efficacious and better tolerated treatments. This study investigated the cost-effectiveness of the daclatasvir + asunaprevir (DCV + ASV) DAA regimen in patients infected with hepatitis C virus (HCV) genotype 1b who had previously not responded to or were ineligible for IFN-containing regimens. METHODS: A cost-utility analysis using an established Markov model compared DCV + ASV with simeprevir + PR (SMV + PR), telaprevir + PR (TVR + PR) and no treatment using Japanese-specific model inputs, with costs and utility values discounted at 2%. A cohort of patients was simulated until death and predicted quality-adjusted life-years (QALY) and costs were estimated. A subgroup analysis of patients with no DCV resistance was conducted. RESULTS: In all scenarios, DCV + ASV was predicted to be dominant over the comparator; namely, DCV + ASV was associated with increased QALY gains and decreased cost. In patients treated during the chronic hepatitis C stage, cost reductions were Y1 057 288-2 619 206, and in patients treated during the compensated cirrhosis (CC) stage, reductions were Y1 032 224-2 531 930. QALY gains were 0.749-2.609 and 0.874-3.043, respectively. Results improved when considering the subgroup of patients without DCV resistance. CONCLUSION: Cost-effectiveness conclusions are similar for patients treated in the chronic hepatitis C and CC disease stages, with DCV + ASV expected to be cost-saving versus standard of care in Japan for patients with HCV genotype 1b patients who have failed prior therapy or are IFN-ineligible/intolerant. PMID- 26440998 TI - Suppression of Dendritic Cell-Derived IL-12 by Endogenous Glucocorticoids Is Protective in LPS-Induced Sepsis. AB - Sepsis, an exaggerated systemic inflammatory response, remains a major medical challenge. Both hyperinflammation and immunosuppression are implicated as causes of morbidity and mortality. Dendritic cell (DC) loss has been observed in septic patients and in experimental sepsis models, but the role of DCs in sepsis, and the mechanisms and significance of DC loss, are poorly understood. Here, we report that mice with selective deletion of the glucocorticoid receptor (GR) in DCs (GR(CD11c-cre)) were highly susceptible to LPS-induced septic shock, evidenced by elevated inflammatory cytokine production, hypothermia, and mortality. Neutralizing anti-IL-12 antibodies prevented hypothermia and death, demonstrating that endogenous GC-mediated suppression of IL-12 is protective. In LPS-challenged GR(CD11c-cre) mice, CD8(+) DCs were identified as the major source of prolonged IL-12 production, which correlated with elevations of NK cell derived IFN-gamma. In addition, the loss of GR in CD11c(+) cells rescued LPS induced loss of CD8(+) DCs but not other DC subsets. Unlike wild-type animals, exposure of GR(CD11c-cre) mice to low-dose LPS did not induce CD8(+) DC loss or tolerance to subsequent challenge with high dose, but neutralization of IL-12 restored the ability of low-dose LPS to tolerize. Therefore, endogenous glucocorticoids blunt LPS-induced inflammation and promote tolerance by suppressing DC IL-12 production. PMID- 26441000 TI - Remote histology learning from static versus dynamic microscopic images. AB - Histology is the study of microscopic structures in normal tissue sections. Curriculum redesign in medicine has led to a decrease in the use of optical microscopes during practical classes. Other imaging solutions have been implemented to facilitate remote learning. With advancements in imaging technologies, learning material can now be digitized. Digitized microscopy images can be presented in either a static or dynamic format. This study of remote histology education identifies whether dynamic pictures are superior to static images for the acquisition of histological knowledge. Test results of two cohorts of second-year Bachelor in Medicine students at Ghent University were analyzed in two consecutive academic years: Cohort 1 (n = 190) and Cohort 2 (n = 174). Students in Cohort 1 worked with static images whereas students in Cohort 2 were presented with dynamic images. ANCOVA was applied to study differences in microscopy performance scores between the two cohorts, taking into account any possible initial differences in prior knowledge. The results show that practical histology scores are significantly higher with dynamic images as compared to static images (F (1,361) = 15.14, P < 0.01), regardless of student's gender and performance level. Several reasons for this finding can be explained in accordance with cognitivist learning theory. Since the findings suggest that knowledge construction with dynamic pictures is stronger as compared to static images, dynamic images should be introduced in a remote setting for microscopy education. Further implementation within a larger electronic learning management system needs to be explored in future research. Anat Sci Educ 9: 222-230. (c) 2015 American Association of Anatomists. PMID- 26441001 TI - Structural and dynamical correlations in PfHGXPRT oligomers: A molecular dynamics simulation study. AB - PfHGXPRT is a key enzyme involved in purine nucleotide salvage pathway of the malarial parasite, Plasmodium falciparum. Atomistic molecular dynamics simulations have been performed on two types of PfHGXPRT dimers (D1 and D3) and its tetramer in their apo and ligand-bound states. A significant event in the catalytic cycle is the dynamics of a gate that provides access for the ligand molecules to the reaction center. The gate is formed by loops II and IV, the former being the most flexible. Large amplitude conformational changes have been observed in active site loop II. Upon complete occupancy of the active site, loop II gets stabilized due to specific interactions between its residues and the ligand molecules. Remote loop, X, is seen to be less fluxional in the D3 dimer than in D1 which is rationalized as due to the greater number of inter-subunit contacts in the former. The presence of ligand molecules in subunits of the tetramer further reduces the flexibility of loop X epitomizing a communication between this region and the active sites in the tetramer. These observations are in accordance with the outcomes of several experimental investigations. Participation of loop X in the oligomerization process has also been discerned. Between the two types of dimers in solution, D1 tetramerizes readily and thus would not be present as free dimers. We conjecture an equilibrium to exist between D3 and the tetramer in solution; upon binding of the ligand molecules to the D3 dimer, this equilibrium shifts toward the tetramer. PMID- 26441003 TI - Integration of DNA sequence and DNA methylation changes in monozygotic twin pairs discordant for schizophrenia. AB - Schizophrenia is a complex mental disorder with high heritability (80%), extensive genetic heterogeneity, environmental contributions and only 50% concordance in discordant monozygotic (MZ) twins. Discordant MZ twins provide an exceptional opportunity to assess patient specific genome-wide genetic and epigenetic changes that may account for the disease phenotype. A combined analysis of genetic and epigenetic changes on the same twin pairs is expected to provide a more effective approach for two reasons. First, it is now possible to generate relatively reliable complete genome sequences as well as promoter methylation states on an individual level and second, the unaffected twin that originated from the same zygote provides a near perfect genetic match for contrast and comparison. This report deals with the combined analysis of DNA sequence data and methylation data on two pairs of discordant MZ twins that have been clinically followed for over 20 years. Results on Family 1 show that 58 genes differ in DNA sequence as well as promoter methylation in a schizophrenia affected twin as compared to her healthy co-twin. The corresponding number for family 2 was 13. The two lists are over represented by neuronal genes and include a number of known schizophrenia candidate genes and drug targets. The results argue that changes in multiple genes via co-localized genetic and epigenetic alteration contribute to a liability threshold that is necessary for development of schizophrenia. This novel hypothesis, although logical, remains to be validated. PMID- 26441002 TI - Iridium-Catalyzed Enantioselective Allylic Substitution of Enol Silanes from Vinylogous Esters and Amides. AB - The enol silanes of vinylogous esters and amides are classic dienes for Diels Alder reactions. Here, we report their reactivity as nucleophiles in Ir catalyzed, enantioselective allylic substitution reactions. A variety of allylic carbonates react with these nucleophiles to give allylated products in good yields with high enantioselectivities and excellent branched-to-linear ratios. These reactions occur with KF or alkoxide as the additive, but mechanistic studies suggest that these additives do not activate the enol silanes. Instead, they serve as bases to promote the cyclometalation to generate the active Ir catalyst. The carbonate anion, which was generated from the oxidative addition of the allylic carbonate, likely activates the enol silanes to trigger their activity as nucleophiles for reactions with the allyliridium electrophile. The synthetic utility of this method was illustrated by the synthesis of the anti muscarinic drug, fesoterodine. PMID- 26441004 TI - Severity of thought disorder predicts psychosis in persons at clinical high-risk. AB - BACKGROUND: Improving predictive accuracy is of paramount importance for early detection and prevention of psychosis. We sought a symptom severity classifier that would improve psychosis risk prediction. METHODS: Subjects were from two cohorts of the North American Prodrome Longitudinal Study. All subjects met Criteria of Psychosis-Risk States. In Cohort-1 (n=296) we developed a classifier that included those items of the Scale of Psychosis-Risk Symptoms that best distinguished subjects who converted to psychosis from nonconverters, with performance initially validated by randomization tests in Cohort-1. Cohort-2 (n=592) served as an independent test set. RESULTS: We derived 2-Item and 4-Item subscales. Both included unusual thought content and suspiciousness; the latter added reduced ideational richness and difficulties with focus/concentration. The Concordance Index (C-Index), a measure of discrimination, was similar for each subscale across cohorts (4-Item subscale Cohort-2: 0.71, 95% CI=[0.64, 0.77], Cohort-1: 0.74, 95% CI=[0.69, 0.80]; 2-Item subscale Cohort-2: 0.68, 95% CI=[0.3, 0.76], Cohort-1: 0.72, 95% CI=[0.66-0.79]). The 4-Item performed better than the 2-Item subscale in 742/1000 random selections of 80% subsets of Cohort-2 subjects (p-value=1.3E-55). Subscale calibration between cohorts was proportional (higher scores/lower survival), but absolute conversion risk predicted from Cohort-1 was higher than that observed in Cohort-2, reflecting the cohorts' differences in 2 year conversion rates (Cohort-2: 0.16, 95% CI=[0.13, 0.19]; Cohort-1: 0.30, 95% CI=[0.24, 0.36]). CONCLUSION: Severity of unusual thought content, suspiciousness, reduced ideational richness, and difficulty with focus/concentration informed psychosis risk prediction. Scales based on these symptoms may have utility in research and, assuming further validation, eventual clinical applications. PMID- 26441005 TI - The MATRICS Consensus Cognitive Battery (MCCB): Co-norming and standardization in China. AB - MATRICS Consensus Cognitive Battery (MCCB), packaging 10 tests selected from more than 90 nominated tests, is a method developed by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) group to evaluate the efficacy of treatments targeting cognitive impairments in schizophrenia. MCCB had been translated into a number of languages, but only the US and Spain had normative data reported. Inconsistency in translation and cultural differences make direct application of MCCB in China problematic. In this study, we administered the battery to a representative community sample based on Chinese population census in 2005 and obtained normative data. The effects of age, gender, education level, and scale of residence area on test performance were examined. The sample included 656 healthy volunteers from six sites in China. At each site, sample was stratified according to age, gender, and educational level, and scale of the area one was born in, grew up in and currently living in was recorded. We found age, gender, and education had significant effects on the normative data for MCCB in China, which are comparable to those found for the original standardized English version in the U.S. and the Spanish version in Spain. Remarkably, the residence scale effects on neuropsychological performance were significant, which should be taking into account when calculating the standardized T score for each subject. The practice effects were minor and test retest reliability of MCCB was good, which suggests MCCB as an appropriate measure for clinical and research usage in China. PMID- 26441006 TI - Dorsal striatal volumes in never-treated patients with first-episode schizophrenia before and during acute treatment. AB - BACKGROUND: Studies of pre-and post-treatment striatal volume in schizophrenia have reported conflicting results. MATERIALS AND METHODS: We assessed dorsal striatal (caudate and putamen) volumes bilaterally in 22 never-treated, non substance-abusing patients with first-episode schizophrenia or schizophreniform disorder and 23 healthy controls matched for age, sex and educational status. Patients received either risperidone or flupenthixol long acting injection and were compared by structural MRI with controls at weeks 0, 4 and 13. T1-weighted data on a 3T MRI scanner were obtained and images were reconstructed using FreeSurfer. Treatment outcome was assessed by changes in psychopathology, insight, functionality, cognitive performance and motor symptoms. RESULTS: Caudate, but not putamen volumes was significantly larger in patients bilaterally at baseline (P=0.01). Linear mixed effects repeated measures found no significant group * time interactions for any of the regions. Caudate volume was not significantly associated with improvements in psychotic symptoms. Also, the findings of a regression model were inconsistent insofar as larger caudate volume was associated with less improvement in depression scores, greater improvement in functionality and greater improvement in verbal learning but less improvement in reasoning and problem solving (left caudate) and composite cognitive score (right caudate). CONCLUSIONS: The increased caudate volumes prior to treatment are contrary to previous reports in never-treated patients with first-episode schizophrenia, and together with our failure to demonstrate volume changes related to acute treatment, call into question previous proposals that enlarged caudate volume is a consequence of antipsychotic treatment. PMID- 26441007 TI - Conceptual disorganization weakens links in cognitive pathways: Disentangling neurocognition, social cognition, and metacognition in schizophrenia. AB - Disentangling links between neurocognition, social cognition, and metacognition offers the potential to improve interventions for these cognitive processes. Disorganized symptoms have shown promise for explaining the limiting relationship that neurocognition holds with both social cognition and metacognition. In this study, primary aims included: 1) testing whether conceptual disorganization, a specific disorganized symptom, moderated relationships between cognitive processes, and 2) examining the level of conceptual disorganization necessary for links between cognitive processes to break down. To accomplish these aims, comprehensive assessments of conceptual disorganization, neurocognition, social cognition, and metacognition were administered to 67 people with schizophrenia spectrum disorders. We found that conceptual disorganization significantly moderated the relationship between neurocognition and metacognition, with links between cognitive processes weakening when conceptual disorganization is present even at minimal levels of severity. There was no evidence that conceptual disorganization-or any other specific disorganized symptom-drove the limiting relationship of neurocognition on social cognition. Based on our findings, conceptual disorganization appears to be a critical piece of the puzzle when disentangling the relationship between neurocognition and metacognition. Roles of specific disorganized symptoms in the neurocognition - social cognition relationship were less clear. Findings from this study suggest that disorganized symptoms are an important treatment consideration when aiming to improve cognitive impairments. PMID- 26441008 TI - The effect of lifestyle interventions on the quality of life of gynaecological cancer survivors: A systematic review and meta-analysis. AB - OBJECTIVE: We aimed to evaluate the effectiveness of lifestyle interventions in improving the quality of life (QoL) of endometrial and ovarian cancer survivors. METHODS: The review was performed according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, and the Cochrane Handbook for Systematic Reviews of Interventions. We performed a search of MEDLINE (1946-2015), EMBASE (1980-2015), CINAHL (1981-2015), PsycINFO (1806-2015) and the Cochrane Trial Register to identify studies evaluating the effect of lifestyle interventions on the QoL of endometrial and ovarian cancer survivors. RESULTS: Eight studies fulfilled the inclusion criteria and comprised a total of 413 patients. Three studies were randomised controlled trials (RCTs), which showed that lifestyle interventions may improve physical functioning and significantly reduce fatigue in endometrial cancer survivors. In addition, lifestyle interventions in endometrial cancer survivors resulted in significant weight loss and improved physical activity levels, but did not show improvements in global QoL in the meta-analysis (P=0.75, P=0.49). Non-randomised trials in ovarian cancer survivors support the feasibility of lifestyle interventions and suggest they may result in QoL improvements. CONCLUSIONS: Lifestyle interventions have the potential to improve the QoL of endometrial cancer and ovarian cancer survivors, and may significantly reduce fatigue. However, the current evidence is limited and there is a need for future studies to further evaluate lifestyle interventions and their effect on QoL outcomes. PMID- 26441010 TI - Cancer Recurrence and Regional Anesthesia: The Theories, the Data, and the Future in Outcomes. AB - OBJECTIVE: More than one million people each year in the United States are diagnosed with cancer. Surgery is considered curative, but the perioperative phase represents a vulnerable period for residual disease to spread. Regional anesthesia has been proposed to reduce the incidence of recurrence by attenuating the sympathetic nervous system's response during surgery, reducing opioid requirements thus diminishing their immunosuppressant effects, and providing antitumor and anti-inflammatory effects directly through systemic local anesthetic action. In this article, we present a description of the perioperative period, a summary of the proposed hypotheses and available literature on the effects of regional anesthesia on cancer recurrence, and put regional anesthesia in context in regard to its potential role in reducing cancer recurrence during the perioperative period. METHODS: A literature review was conducted through PubMed by examining the following topics: effects of surgery on tumor progression, roles of multiple perioperative variables (analgesics, hypothermia, blood transfusion, beta-blockade) in cancer recurrence, and available in vitro, animal, and human studies regarding the effects of regional anesthesia on cancer recurrence. RESULTS: in vitro, animal and human retrospective studies suppport the hypothesis that in certain types of cancer, regional anesthesia may be associated with lower recurrence rates. A few well-planned human randomized clinical trials are currently under way that may provide more solid evidence to substantiate or refute the benefits of regional anesthesia in reducing cancer recurrence. CONCLUSIONS: The benefits of regional anesthesia in reducing cancer recurrence have a sound theoretical basis and, in certain cancers, are supported by the existing body of literature. This article outlines the current state of our knowledge on the relationship between cancer progression and regional analgesia. PMID- 26441011 TI - Exogenous brain-derived neurotrophic factor relieves pain symptoms of diabetic rats by reducing excitability of dorsal root ganglion neurons. AB - Diabetic peripheral neuropathy (DPN) is a common complication of diabetes lacking of effective treatments. Enhanced excitability of dorsal root ganglion (DRG) neuron plays a crucial role in the progression of diabetic neuropathic hyperalgesia. Brain-derived neurotrophic factor (BDNF) is known as a neuromodulator of nociception, but whether and how BDNF modulates the excitability of DRG neurons in the development of DPN remain to be clarified. This study investigated the role of exogenous BDNF and its high-affinity tropomyosin receptor kinase B (TrkB) in rats with streptozotocin-induced diabetic neuropathic pain. The results showed that continued intrathecal administration of BDNF to diabetic rats dramatically alleviated mechanical and thermal hyperalgesia, as well as inhibited hyperexcitability of DRG neurons. These effects were blocked by pretreatment with TrkB Fc (a synthetic fusion protein consisting of the extracellular ligand-binding domain of the TrkB receptor). The expression of BDNF and TrkB was upregulated in the DRG of diabetic rats. Intrathecal administration of BDNF did not affect this upregulation. These data provide novel information that exogenous BDNF relieved pain symptoms of diabetic rats by reducing hyperexcitability of DRG neurons and might be the potential treatment of painful diabetic neuropathy. PMID- 26441009 TI - Disparate Mutations Confer Therapeutic Gain of Hsp104 Function. AB - Hsp104, a protein disaggregase from yeast, can be engineered and potentiated to counter TDP-43, FUS, or alpha-synuclein misfolding and toxicity implicated in neurodegenerative disease. Here, we reveal that extraordinarily disparate mutations potentiate Hsp104. Remarkably, diverse single missense mutations at 20 different positions interspersed throughout the middle domain (MD) and small domain of nucleotide-binding domain 1 (NBD1) confer a therapeutic gain of Hsp104 function. Moreover, potentiation emerges from deletion of MD helix 3 or 4 or via synergistic missense mutations in the MD distal loop and helix 4. We define the most critical aspect of Hsp104 potentiation as enhanced disaggregase activity in the absence of Hsp70 and Hsp40. We suggest that potentiation likely stems from a loss of a fragilely constrained autoinhibited state that enables precise spatiotemporal regulation of disaggregase activity. PMID- 26441012 TI - Pathogenicity and tissue tropism of currently circulating highly pathogenic avian influenza A virus (H5N1; clade 2.3.2) in tufted ducks (Aythya fuligula). AB - Reports describing the isolation of highly pathogenic avian influenza (HPAI) virus (H5N1) clade 2.3.2 in feces from apparently healthy wild birds and the seemingly lower pathogenicity of this clade compared to clade 2.2 in several experimentally infected species, caused concern that the new clade might be maintained in the wild bird population. To investigate whether the pathogenicity of a clade 2.3.2 virus was lower than that of clades previously occurring in free living wild birds in Europe, four tufted ducks were inoculated with influenza A/duck/HongKong/1091/2011 (H5N1) clade 2.3.2 virus. The ducks were monitored and sampled for virus excretion daily during 4 days, followed by pathologic, immunohistochemical, and virological investigations. The virus produced severe disease as evidenced by clinical signs, presence of marked lesions and abundant viral antigen in several tissues, especially the central nervous system. The study shows that HPAI-H5N1 virus clade 2.3.2 is highly pathogenic for tufted ducks and thus, they are unlikely to maintain this clade in the free-living population or serve as long-distance vectors. PMID- 26441013 TI - Schmallenberg disease in sheep or goats: Past, present and future. AB - Schmallenberg disease has emerged in North-Western Europe in 2011 and has since spread widely, even across the European borders. It has the potency to infect many, mainly ruminant, species, but seems to lack zoonotic potential. Horizontal transmission occurs through various Culicoides biting midges and subsequent trans placental transmission causes teratogenic effects. In some small ruminants, clinical signs, including fever, decreased milk production and diarrhea occur during the viraemic phase, but infection is mostly asymptomatic. However, fetal Schmallenberg virus infection in naive ewes and goats can result in stillborn offspring, showing a congenital arthrogryposis-hydranencephaly syndrome. The economic impact of infection depends on the number of malformed lambs, but is generally limited. There is debate on whether Schmallenberg virus has newly emerged or is re-emerging, since it is likely one of the ancestors of Shamonda virus, both Orthobunyaviruses belonging to the species Sathuperi virus within the Simbu serogroup viruses. Depending on the vector-borne transmission and the serologic status, future outbreaks of Schmallenberg disease induced congenital disease are expected. PMID- 26441014 TI - Regional volumes in brain stem and cerebellum are associated with postural impairments in young brain-injured patients. AB - Many patients with traumatic brain injury (TBI) suffer from postural control impairments that can profoundly affect daily life. The cerebellum and brain stem are crucial for the neural control of posture and have been shown to be vulnerable to primary and secondary structural consequences of TBI. The aim of this study was to investigate whether morphometric differences in the brain stem and cerebellum can account for impairments in static and dynamic postural control in TBI. TBI patients (n = 18) and healthy controls (n = 30) completed three challenging postural control tasks on the EquiTest(r) system (Neurocom). Infratentorial grey matter (GM) and white matter (WM) volumes were analyzed with cerebellum-optimized voxel-based morphometry using the spatially unbiased infratentorial toolbox. Volume loss in TBI patients was revealed in global cerebellar GM, global infratentorial WM, middle cerebellar peduncles, pons and midbrain. In the TBI group and across both groups, lower postural control performance was associated with reduced GM volume in the vermal/paravermal regions of lobules I-IV, V and VI. Moreover, across all participants, worse postural control performance was associated with lower WM volume in the pons, medulla, midbrain, superior and middle cerebellar peduncles and cerebellum. This is the first study in TBI patients to demonstrate an association between postural impairments and reduced volume in specific infratentorial brain areas. Volumetric measures of the brain stem and cerebellum may be valuable prognostic markers of the chronic neural pathology, which complicates rehabilitation of postural control in TBI. PMID- 26441015 TI - Cellular Signaling in Metabolic Syndrome. PMID- 26441016 TI - The possible interaction between periostin expressed by cancer stroma and tumor associated macrophages in developing mycosis fungoides. AB - Mycosis fungoides (MF) starts as an indolent disease, progresses from a patch stage to confluent plaques and ultimately develops skin tumors. Tumor-associated macrophages (TAMs) play roles in maintaining the tumor microenvironment in MF. The purpose of this study was to elucidate the involvement of TAMs in the lesional skin of different stages of MF. First, we immunohistologically examined the percentage of CD163+ macrophages and CD206+ cells, as well as the levels of periostin and IL-4 in cancer stroma. The percentage of CD206+ cells increased in parallel with tumor progression, while there was no significant difference in the percentage of CD163+ cells. Periostin was prominent in the stromal area at the patch and plaque stages but decreased at the tumor stage. In contrast, IL-4 was prominently stained at both plaque and tumor stages. To further elucidate the molecular mechanisms of the effects of these stromal factors on TAMs, we examined their effects on mRNA expression in monocyte-derived macrophages in vitro. Based on microarray analysis and gene ontology, we examined a series of chemokines and MMPs whose expression was strongly connected with periostin stimulation. The DNA microarray results were verified in M2 macrophages using real-time PCR. We further examined the mRNA expression of these chemokines and MMPs in the presence of periostin and IL-4 to simulate the advanced stages of MF and validated their protein expression by ELISA. Our present report suggests possible roles of periostin on TAMs in establishing the tumor microenvironment in MF. PMID- 26441018 TI - Tonsillolithiasis. PMID- 26441017 TI - Breast pain and imaging. AB - Breast pain is a common reason for consultation and a source of anxiety for patients. Cyclical breast pain can be distinguished from non-cyclical pain and breast pain with other symptoms. Many causes, usually benign are possible and the clinical enquiry and physical examination are essential to establish predisposing factors. Although imaging is not always needed for isolated breast pain, it is still useful for the diagnosis of specific causes such as tension cysts, giant adenofibromas or Mondor's thrombophlebitis. Ultrasound is the first line investigation before mammography, MRI or biopsy, which may be indicated for suspicious abnormalities. Some cancers may be associated with pain, which implies that radiologists and physicians should always take breast pain seriously. PMID- 26441019 TI - Acute pelvic pain in females in septic and aseptic contexts. AB - Acute pelvic pain in women is a common reason for emergency department admission. There is a broad range of possible aetiological diagnoses, with gynaecological and gastrointestinal causes being the most frequently encountered. Gynaecological causes include upper genital tract infection and three types of surgical emergency, namely ectopic pregnancy, adnexal torsion, and haemorrhagic ovarian cyst rupture. The main gastrointestinal cause is acute appendicitis, which is the primary differential diagnosis for acute pelvic pain of gynaecological origin. The process of diagnosis will be guided by the clinical examination, laboratory study results, and ultrasonography findings, with suprapubic transvaginal pelvic ultrasonography as the first-line examination in this young population, and potentially cross-sectional imaging findings (computed tomography and MR imaging) if diagnosis remains uncertain. PMID- 26441020 TI - Chronic pelvic pain: An imaging approach. AB - Chronic pelvic pain is defined as disabling pain of at least six months duration. Chronic pelvic pain has often multiple causative factors. Careful analysis of clinical history and detailed clinical examination must be carried out to guide further imaging investigations. Endometriosis is a common cause of chronic pelvic pain, although there is no correlation between the severity of lesions and pain intensity. Pelvic ultrasonography should be the first line imaging examination to search for causative conditions that include endometriosis, adenomyosis, pelvic varices and chronic infection. Magnetic resonance imaging (MRI) is useful for making the positive diagnosis and assessing the spread of endometriosis. MRI is more accurate than ultrasonography for the diagnosis of tubo-ovarian abscess when an adnexal mass is identified. Duplex and color Doppler ultrasonography as well as MR angiography are the best imaging technique for the diagnosis of pelvic congestion syndrome. In patients with pudendal neuralgia, cross-sectional imaging help exclude nerve compression. PMID- 26441021 TI - Pharmacokinetics and pharmacodynamics of gamithromycin in pulmonary epithelial lining fluid in naturally occurring bovine respiratory disease in multisource commingled feedlot cattle. AB - The objectives of this study were to determine (i) whether an association exists between individual pharmacokinetic parameters and treatment outcome when feeder cattle were diagnosed with bovine respiratory disease (BRD) and treated with gamithromycin (Zactran((r)) ) at the label dose and (ii) whether there was a stronger association between treatment outcome and gamithromycin concentration in plasma or in the pulmonary epithelial lining fluid (PELF) effect compartment. The study design was a prospective, blinded, randomized clinical trial utilizing three groups of 60 (362-592 lb) steers/bulls randomly allocated within origin to sham injection or gamithromycin mass medication. Cattle were evaluated daily for signs of BRD by a veterinarian blinded to treatment. Animals meeting the BRD case definition were enrolled and allocated to a sample collection scheme consisting of samples for bacterial isolation (bronchoalveolar lavage fluid and nasopharyngeal swabs) and gamithromycin concentration determination (PELF and plasma). Gamithromycin susceptibility of M. haemolytica (n = 287) and P. multocida (n = 257) were determined using broth microdilution with frozen panels containing gamithromycin at concentrations from 0.03 to 16 MUg/mL. A two compartment plasma pharmacokinetic model with an additional compartment for gamithromycin in PELF was developed using rich data sets from published and unpublished studies. The sparse data from our study were then fit to this model using nonlinear mixed effects modeling to estimate individual parameter values. The resulting parameter estimates were used to simulate full time-concentration profiles for each animal in this study. These profiles were analyzed using noncompartmental methods so that PK/PD indices (AUC24 /MIC, AUCinfinity /MIC, CMAX /MIC) could be calculated for plasma and PELF (also T>MIC) for each individual. The calculated PK/PD indices were indicative that for both M. haemolytica and P. multocida a higher drug exposure in terms of concentration, and duration of exposure relative to the MIC of the target pathogen, was favorable to a successful case outcome. A significant association was found between treatment success and PELF AUC0-24 /MIC for P. multocida. The calves in this study demonstrated an increased clearance and volume of distribution in plasma as compared to the healthy calves in two previously published reports. Ultimately, the findings from this study indicate that higher PK/PD indices were predictive of positive treatment outcomes. PMID- 26441022 TI - Synthesis of Azulen-1-yl Ketones via Oxidative Cleavage of C-C Multiple Bonds in N-Sulfonyl Enamides and 1-Alkynes under Air and Natural Sunlight. AB - A synthetic method to prepare azulen-1-yl ketones was developed via oxidative cleavage of the C-C double bond in the reaction of easily obtainable N-sulfonyl enamides with Cs2CO3 under air and natural sunlight and in the absence of a photosensitizer. Oxidative cleavage of C-C triple bonds was also demonstrated for the synthesis of azulen-1-yl ketones via a tandem Cu-catalyzed [3 + 2] cycloaddition, Rh-catalyzed arylation, photooxygenation, and ring-opening reaction in one pot under air and natural sunlight. PMID- 26441023 TI - Are Dimensions of Parenting Differentially Linked to Substance Use Across Caucasian and Asian American College Students? AB - BACKGROUND: Parental warmth and autonomy granting are commonly thought of as protective factors against substance use among Caucasians. However, limited research has examined whether associations between parenting dimensions and substance use outcomes are the same or different among Asian Americans. METHOD: A final analytic sample of 839 college students was used to test whether race (Caucasian vs. Asian American) moderated the relations between parenting dimensions and substance use outcomes across Caucasians and Asian Americans. We utilized the Parental Bonding Instrument (Parker, Tupling, & Brown, 1979) to measure maternal and paternal warmth, encouragement of behavioral freedom, and denial of psychological autonomy. RESULTS: Multivariate regression models controlling for covariates including age, gender, and paternal education indicated four significant parenting by race interactions on alcohol problems and/or marijuana use. Specifically, maternal warmth was inversely associated with both alcohol problems and marijuana use among Caucasians but not among Asian Americans. Both maternal and paternal denial of psychological autonomy were positively associated with alcohol problems among Caucasians but not among Asian Americans. CONCLUSIONS: Consistent with emerging cross-cultural research, the associations between parenting dimensions and substance use behaviors observed in Caucasian populations may not be readily generalized to Asian Americans. These findings highlight the importance of considering different parenting dimensions in understanding substance use etiology among Asian Americans. Future research should use longitudinal data to replicate these findings across development and seek to identify other parenting dimensions that may be more relevant for Asian American youth. PMID- 26441024 TI - Source investigation of two outbreaks of skin and soft tissue infection by Mycobacterium abscessus subsp. abscessus in Venezuela. AB - Outbreaks of soft tissue or skin infection due to non-tuberculous mycobacteria are reported frequently in scientific journals but in general the infection source in these outbreaks remains unknown. In Venezuela, in two distinct outbreaks, one after breast augmentation surgery and another after hydrolipoclasy therapy, 16 patients contracted a soft tissue infection due to Mycobacterium abscessus subsp. abscessus. Searching for the possible environmental infection sources in these outbreaks, initially the tap water (in the hydrolipoclasy therapy outbreak) and a surgical skin marker (in the breast implant surgery outbreak), were identified as the infection sources. Molecular typing of the strains with a variable number tandem repeat typing assay confirmed the tap water as the infection source but the molecular typing technique excluded the skin marker. We discuss the results and make a call for the implementation of stringent hygiene and disinfection guidelines for cosmetic procedures in Venezuela. PMID- 26441025 TI - Tunable Mechanics in Electrospun Composites via Hierarchical Organization. AB - Design strategies from nature provide vital clues for the development of synthetic materials with tunable mechanical properties. Employing the concept of hierarchy and controlled percolation, a new class of polymer nanocomposites containing a montmorillonite (MMT)-reinforced electrospun poly(vinyl alcohol) (PVA) filler embedded within a polymeric matrix of either poly(vinyl acetate) (PVAc) or ethylene oxide-epichlorohydrin copolymer (EO-EPI) were developed to achieve a tunable mechanical response upon exposure to specific stimuli. Mechanical response and switching times upon hydration were shown to be dependent on the weight-fraction of MMT in the PVA electrospun fibers and type of composite matrix. PVA/MMT.PVAc composite films retained excellent two-way switchability for all MMT fractions; however, the switching time upon hydration was decreased dramatically as the MMT content was increased due to the highly hydrophilic nature of MMT. Additionally, for the first time, significant two-way switchability of PVA/MMT.EO-EPI composites was achieved for higher weight fractions (12 wt %) of MMT. An extensive investigation into the effects of fiber diameter, crystallinity, and MMT content revealed that inherent rigidity of MMT platelets plays an important role in controlling the mechanical response of these hierarchical electrospun composites. PMID- 26441026 TI - Biocatalysis conversion of methanol to methane in an upflow anaerobic sludge blanket (UASB) reactor: Long-term performance and inherent deficiencies. AB - Long-term performance of methanol biocatalysis conversion in a lab-scale UASB reactor was evaluated. Properties of granules were traced to examine the impact of methanol on granulation. Methanolic wastewater could be stably treated during initial 240d with the highest biogas production rate of 18.6 +/- 5.7 L/Ld at OLR 48 g-COD/Ld. However, the reactor subsequently showed severe granule disintegration, inducing granule washout and process upsets. Some steps (e.g. increasing influent Ca(2+) concentration, etc.) were taken to prevent rising dispersion, but no clear improvement was observed. Further characterizations in granules revealed that several biotic/abiotic factors all caused the dispersion: (1) depletion of extracellular polymeric substances (EPS) and imbalance of protein/polysaccharide ratio in EPS; (2) restricted formation of hard core and weak Ca-EPS bridge effect due to insufficient calcium supply; and (3) simplification of species with the methanol acclimation. More efforts are required to solve the technical deficiencies observed in methanolic wastewater treatment. PMID- 26441027 TI - Production of biohydrogen from crude glycerol in an upflow column bioreactor. AB - A continuous attached growth process for the production of biohydrogen from crude glycerol was developed. The process consisted of an anaerobic up-flow column bioreactor (UFCB), packed with cylindrical ceramic beads, which constituted the support matrix for the attachment of bacterial cells. The effect of crude glycerol concentration, pH and hydraulic retention time on glycerol conversion, hydrogen yield and metabolite distribution was investigated. It was shown that the most critical parameter for the efficient bioconversion was the pH of the influent, whereas the hydrogen yield increased with an increase in feed glycerol concentration and a decrease in the hydraulic retention time. The main soluble metabolite detected was 1,3-propanediol in all cases, followed by butyric and hexanoic acids. The latter is reported to be produced from glycerol for the first time. Acidification of the waste reached 38.5%, and the maximum H2 productivity was 107.3 +/- 0.7 L/kg waste glycerol at optimal conditions. PMID- 26441028 TI - Simultaneous conversion of glucose and xylose to 3-hydroxypropionic acid in engineered Escherichia coli by modulation of sugar transport and glycerol synthesis. AB - Escherichia coli expressing the Lactobacillus brevis dhaB1B2B3 and dhaR1R2 clusters and Pseudomonas aeruginosa aldhH was engineered to produce 3-HP from glucose and xylose via the glycerol biosynthetic pathway. Glycerol, a key precursor for 3-HP biosynthesis was produced by overexpression of the GPD1 and GPP2 genes from Saccharomyces cerevisiae. For relief of carbon catabolite repression, deletion of the chromosomal ptsG gene and overexpression of the endogenous xylR gene rendered engineered E. coli JHS01300/pCPaGGRm to utilize glucose and xylose simultaneously and to produce glycerol at 0.48 g/g yield and 0.35 g/L-h productivity. Finally, engineered E. coli JHS01300/pELDRR+pCPaGGRm produced 29.4 g/L of 3-HP with 0.54 g/L-h productivity and 0.36 g/g yield in a sugar-limited fed-batch fermentation. It was concluded that dual modulation of sugar transport and glycerol biosynthesis is a promising strategy for efficient conversion of glucose and xylose to 3-HP. PMID- 26441029 TI - Nuclease stability of boron-modified nucleic acids: application to label-free mismatch detection. AB - 5'-End boronic acid-modified oligonucleotides were evaluated against various nucleases at single and double stranded levels. The results show that these modifications induce a high resistance to degradation by calf-spleen and snake venom phosphodiesterases. More importantly, this eventually led to the development of a new label-free enzyme-assisted fluorescence-based method for single mismatch detection. PMID- 26441030 TI - Competitive SWIFT cluster templates enhance detection of aging changes. AB - Clustering-based algorithms for automated analysis of flow cytometry datasets have achieved more efficient and objective analysis than manual processing. Clustering organizes flow cytometry data into subpopulations with substantially homogenous characteristics but does not directly address the important problem of identifying the salient differences in subpopulations between subjects and groups. Here, we address this problem by augmenting SWIFT--a mixture model based clustering algorithm reported previously. First, we show that SWIFT clustering using a "template" mixture model, in which all subpopulations are represented, identifies small differences in cell numbers per subpopulation between samples. Second, we demonstrate that resolution of inter-sample differences is increased by "competition" wherein a joint model is formed by combining the mixture model templates obtained from different groups. In the joint model, clusters from individual groups compete for the assignment of cells, sharpening differences between samples, particularly differences representing subpopulation shifts that are masked under clustering with a single template model. The benefit of competition was demonstrated first with a semisynthetic dataset obtained by deliberately shifting a known subpopulation within an actual flow cytometry sample. Single templates correctly identified changes in the number of cells in the subpopulation, but only the competition method detected small changes in median fluorescence. In further validation studies, competition identified a larger number of significantly altered subpopulations between young and elderly subjects. This enrichment was specific, because competition between templates from consensus male and female samples did not improve the detection of age related differences. Several changes between the young and elderly identified by SWIFT template competition were consistent with known alterations in the elderly, and additional altered subpopulations were also identified. Alternative algorithms detected far fewer significantly altered clusters. Thus SWIFT template competition is a powerful approach to sharpen comparisons between selected groups in flow cytometry datasets. PMID- 26441032 TI - When has enough evidence accumulated to change neonatal practice? AB - Randomized clinical trials are the best method to assess the safety and efficacy of therapeutic interventions. However, it is not always clear how much evidence from randomized trials is required to change clinical practice. Throughout the history of neonatal medicine, some therapies were subject to excessive and unnecessary testing through replication of clinical trials. Other therapies were adopted into clinical practice with insufficient evidence. In only a few cases was the right amount of evidence accumulated to drive a change in practice. Here we present a case history for each of these three scenarios. Arising from these, we suggest principles to identify when enough evidence exists for a therapy to become standard practice. PMID- 26441031 TI - Alleviation of skin inflammation after Lin(-) cell transplantation correlates with their differentiation into myeloid-derived suppressor cells. AB - To understand the cellular mechanism underlying the therapeutic effects exerted by hematopoietic stem cell transplantation in the repair of tissue damage, we investigated the in vivo dynamics of bone marrow (BM) lineage-negative (Lin(-)) cells transplanted into mice with hyper sensitivity dermatitis. Longitudinal in vivo imaging and flow cytometry analyses revealed that Lin(-) cells home directly to inflamed skin within 6 h, where they undergo extensive expansion with the peak on day 14 post-transplantation, and preferential differentiation into CD11b(+)Ly6G(int)Ly6C(+) cells by day 7. Cells with phenotypic profiles of neutrophils, macrophages, and DCs appeared in inflamed skin on day 14. Progenies of transplanted Lin(-) cells showed similar kinetics of expansion and myeloid differentiation in BM. However, differentiation into CD11b(+)Ly6G(int)Ly6C(+) cells in the inflamed skin on day 7 was more skewed toward CD115(+) cells (>=60%) with immune suppressive function and higher expression levels of iNOS, arginase, and IL-10, compared with those in the BM. Transplantation of Lin(-) cells reduced the levels of Cd3 transcript and CD4(+)/CD8(+) cells in inflamed skin. These results demonstrate differentiation of transplanted Lin(-) cells into myeloid derived suppressor cells in inflamed skin to be the basis of the alleviation of skin inflammation after Lin(-) cell transplantation. PMID- 26441033 TI - Molecular characterization of T-cell immunoglobulin mucin domain-3 and Galectin-9 genes of swamp- and riverine-type water buffaloes. AB - Molecular characterization of T-cell immunoglobulin mucin domain-3 (TIM-3) and Galectin-9 (GAL-9) genes of swamp- and riverine-type water buffaloes was conducted to compare these genes with other species; determine the unique characteristic specific in water buffalo; and provide baseline information for the assessment of disease progression in buffalo species. TIM-3 and GAL-9 genes were amplified, purified, sequenced and characterized. The sequence result of TIM 3 in both types of water buffaloes contained 843 nucleotides encoding to 280 amino acids while GAL-9 of swamp-type and riverine-type water buffaloes contained 1023 and 972 nucleotides encoding to 340 and 323 amino acids, respectively. Meanwhile, the nucleotide and amino sequence of TIM-3 in water buffalo were 83 98% and 94-97% identical with other artiodactyl species, respectively. On the other hand, GAL-9 nucleotide and amino acid sequence in water buffalo were 85-98% and 76-96% identical with other artiodactyl species. The tyrosine-kinase phosphorylation motif and potential glycosylation sites were conserved within the tribe Bovinae. It is imperative to have further studies in the assessment of the role of these genes in disease progression in water buffalo during chronic infection. The study is the first report that describes the genetic characteristic of TIM-3 and GAL-9 genes in water buffalo. PMID- 26441034 TI - Pulsed Near-IR Photoresponse in a Bi-metal Contacted Graphene Photodetector. AB - We use an ultra-fast near-infrared pulse coincidence technique to study the time, temperature, and power dependence of the photoresponse of a bi-metal contacted graphene photodetector. We observe two components of the photovoltage signal. One component is gate-voltage dependent, linear in power at room temperature and sub linear at low temperature-consistent with the hot-electron photothermoelectric effect due to absorption in the graphene. The power dependence is consistent with supercollision-dominated cooling in graphene. The other component is gate-voltage independent and linear in temperature and power, which we interpret as due to thermoelectricity of the metal electrodes due to differential light absorption. PMID- 26441035 TI - Stromal cell-derived factor 1alpha (SDF-1alpha): A marker of disease burden in patients with atrial fibrillation. AB - OBJECTIVES: Stromal cell-derived factor 1a (SDF-1alpha), is a chemokine and is able to home hematopoietic progenitor cells to injured areas of heart tissue for structural repair. Previous studies have found increased levels of SDF-1alpha in several cardiac diseases, but only few studies have investigated SDF-1alpha in patients with atrial fibrillation (AF). We aimed to test SDF-1alpha in a large cohort of patients with AF and its role as a prognostic marker. DESIGN: Between January 1st 2008 to December 1st 2012, 290 patients with ECG documented AF were enrolled from the in- and outpatient clinics at the Department of Cardiology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark. Plasma levels of SDF-1alpha were measured using ELISA technique. Clinical data were registered and patient follow-up was conducted. RESULTS: Patients with permanent AF had significantly higher SDF-1alpha levels (2199.5 pg/ml) than the patients with paroxysmal AF (1982.0 pg/ml) and persistent AF (1906.0 pg/ml), p < 0.0005. Higher SDF-1alpha level was associated with longer time spent in the hospital per readmission, p < 0.05. CONCLUSION: In AF patients, a higher SDF-1alpha level was found in patients with a more progressive state of arrhythmia and was associated with longer hospitalizations. These findings suggest that SDF-1alpha could prove valuable in risk stratification and evaluating the disease burden in AF patients. PMID- 26441036 TI - Letter to the Editor: Examination of Potential Sex Influences in . Auditory Function in Normal-Hearing, Noise-Exposed Human Ears, Ear Hear, 36, 172-184. PMID- 26441037 TI - The use of circulating biomarkers in early clinical trials in patients with cancer. AB - The development of targeted therapies has changed the approach to early oncological clinical trial design. Identification of patient populations most likely to derive benefit and the biologically effective dose are now as important as determination of the maximum tolerated dose. Completion of the 'pharmacological audit trail' highlights drugs most likely to progress through to license, so resources can be allocated appropriately. Key to the success of this changing model is the validation/qualification of circulating biomarkers. These might provide a readily accessible and dynamic picture of drug effect, tumor response and toxicity with minimum risk to patients. This review article examines circulating biomarkers currently used in early oncological clinical trials. It considers the evidence for their employment, limitations and challenges for future development. PMID- 26441038 TI - Giant cell tumour 2nd metatarsal-Result with en-bloc excision and autologous fibular grafting. AB - Giant cell tumour (GCT) of the small bones is relatively uncommon tumour. It occurs most commonly in the distal portions of femur and radius and proximal end of tibia. GCT of small bones presents at advanced stages with major bony destruction. These tumours represent more aggressive course; associated with increased local recurrence rates (40%) and metastasis. Various treatment modalities like en-bloc resection, cryosurgery, intralesional curettage with burring/phenolization or bone cement are available. In our case en-bloc resection with reconstruction using nonvascular autogenous fibular strut graft was used in patient of 2nd metatarsal GCT and a favourable functional outcome was observed. PMID- 26441039 TI - Vitamin D insufficiency and deficiency in patients with fractures of the fifth metatarsal. AB - INTRODUCTION: The fifth metatarsal is a common site for both acute and stress fractures in the foot. They are usually isolated low-energy or stress fractures. Vitamin D deficiency has been associated with fragility fractures in many parts of the body. We believe that low Vitamin D could be a significant aetiological factor in fractures of the fifth metatarsal. METHODOLOGY: A prospective study of patients with fractures of the fifth metatarsal was conducted. Patients presenting to fracture clinic with these fractures had their vitamin D and calcium levels measured. We also conducted a literature review of studies of vitamin D levels in the Northern Hemisphere between 1990 and 2014. RESULTS: Forty patients with fifth metatarsal fractures were studied (22 metatarsal base fractures, 6 shaft fractures, and 2 stress fractures). The average patient age was 49 (range 22-83). 12 patients (30%) had a Vitamin D level consistent with deficiency, and a further 14 (35%) had a level consistent with insufficiency. Average Vitamin D levels in winter fractures were significantly lower (52.23nmol/L) than for those sustained in summer (76.73nmol/L). CONCLUSIONS: Hypovitaminosis D was common in patients with fifth metatarsal fractures. Vitamin D supplementation has been shown in animal studies to improve fracture healing rates, and in humans to decrease the risk of fragility fracture. It should be part of regular practice to check Vitamin D levels in these patients, and supplement where necessary. PMID- 26441040 TI - Occupational safety and health in the service of people. PMID- 26441042 TI - RETRACTED: Targeting Mycobacterial Enzymes with Natural Products. AB - Tuberculosis (TB) is a recurring threat to contemporary civilization. It affects not only those within developing countries, but has also appeared again in places where it was once considered eradicated. TB co-infection in patients infected by HIV is, at the time of writing, the most common cause of death. In the field of searching for new antimycobacterial drug leads, compounds of natural origin still remain a promising source. The review is intended to gather information about natural products (metabolites of plants, fungi, bacteria, and marine sponges) that show activity against mycobacterial enzymes. Here, natural metabolites are presented as being inhibitors/activators of the mycobacterial enzymes involved in mycobacterial growth in vitro (ClpC1, ClpP, MurE ligase, mycothiol S-conjugate amidase, beta-ketoacyl-ACP synthase, InhA) and in vivo, as regards the host cell (PtpB). Each enzyme is briefly described so as to generate an understanding of its role in mycobacterial growth and engender a perception of the mechanism of action of the studied natural compounds. Furthermore, after the introduction of the enzyme, its inhibitors are listed and exactly characterized. PMID- 26441041 TI - Trends, predictors, and impact of systemic chemotherapy in small cell lung cancer patients between 1985 and 2005. AB - BACKGROUND: The last 3 decades have witnessed limited therapeutic advances in small cell lung cancer (SCLC) management. This study evaluated real-world trends in the use of systemic therapies and the impact on patient outcomes in the United States. METHODS: The Surveillance, Epidemiology, and End Results-Medicare database was used to find patients diagnosed with SCLC between 1985 and 2005. The 1985-1990 period served as the baseline for a temporal analysis conducted at 5 year intervals (1985-1990, 1991-1995, 1996-2000, and 2001-2005). Cox proportional models were used to estimate the effect of chemotherapy on survival. Results were validated with a propensity-matched analysis. RESULTS: There were 47,351 eligible patients: 52% were male; the median age was 71 years; and 87% were white, 7% were black, and 1.4% were Asian. The proportion of patients treated with chemotherapy was low but increased over time (38%, 55%, 50%, and 53%; P < .001). Race, diagnosis period, age, stage, and location of residence significantly predicted chemotherapy use. Females (51%), Asians (53%), and rural residents (60%) were more likely to receive chemotherapy. The median overall survival with and without chemotherapy was 9.6 and 3.6 months, respectively. Linear trend analyses showed a modest reduction in the impact of chemotherapy on survival for patients treated with chemotherapy versus untreated patients (hazard ratios [HRs], 0.59, 0.61, 0.64, and 0.62; P < .001) but an overall trend of improved survival for treated (HRs, 1.0, 1.03, 1.00, and 0.96; P = .005) and untreated patients (HRs, 1.0, 0.99, 0.94, and 0.92; P < .001). There was no survival difference between patients treated with carboplatin and patients treated with cisplatin (HR, 0.99; confidence interval [CI], 0.81-1.19; P = .875). Additional therapy beyond platinum-based chemotherapy was associated with a survival benefit (HR, 0.78; CI, 0.75-0.81; P < .001). CONCLUSIONS: Chemotherapy use was associated with a survival benefit in Medicare patients with SCLC treated in a real-world setting. PMID- 26441043 TI - In-Depth High-Throughput Screening of Protein Engineering Libraries by Split-GFP Direct Crude Cell Extract Data Normalization. AB - Here, we report a widely and generally applicable strategy to obtain reliable information in high-throughput protein screenings of enzyme mutant libraries. The method is based on the usage of the split-GFP technology for the normalization of the expression level of each individual protein variant combined with activity measurements, thus resolving the important problems associated with the different solubility of each mutant and allowing the detection of previously invisible variants. The small size of the employed protein tag (16 amino acids) required for the reconstitution of the GFP fluorescence reduces possible interferences such as enzyme activity variations or solubility disturbances to a minimum. Specific enzyme activity measurements without purification, in situ soluble protein expression monitoring, and data normalization are the powerful outputs of this methodology, thus enabling the accurate identification of improved protein variants during high-throughput screening by substantially reducing the occurrence of false negatives and false positives. PMID- 26441044 TI - The validity of the Substance Use Risk Profile Scale (SURPS) among Australian adolescents. AB - AIMS: This study investigated the validity of a brief personality screening measure for substance use in adolescents, the Substance Use Risk Profile Scale (SURPS), among Australian adolescents. DESIGN AND PARTICIPANTS: A total of 527 adolescents (mean age: 13.38years, SD=0.43) from seven Australian schools were assessed at two time points 24months apart. The concurrent and predictive validity of the SURPS was determined using a series of linear and logistic regressions, and was compared to the results in a United Kingdom (UK) sample. SURPS subscale scores for the Australian population were also reported and compared to those in the UK. FINDINGS: Overall, the SURPS subscale scores for Australian adolescents were similar to those for adolescents from the UK. Tests of concurrent and predictive validity in the Australian sample demonstrated that the all four personality profiles - Hopelessness (H), Anxiety Sensitivity (AS), Impulsivity (IMP), and Sensation Seeking (SS) - were related to measures of substance use and other behavioural and emotional characteristics. In addition, all the predicted specific prospective relationships between the personality profiles and particular substance use and other behavioural problems were confirmed except that H was not associated with illicit drug use. Overall, the results were similar between the Australian and UK samples. CONCLUSIONS: The SURPS is a valid and useful measure for identifying Australian adolescents at high-risk for substance use and other emotional and behavioural problems. Implications for prevention are discussed. PMID- 26441045 TI - Motivation to quit as a predictor of smoking cessation and abstinence maintenance among treated Spanish smokers. AB - INTRODUCTION: Although quitting motivation predicts smoking cessation, there have been inconsistent findings regarding motivation predicting long-term maintenance of abstinence. Moreover, most such research has been conducted in North America and the United Kingdom. The aim of this study was to examine motivation to quit as a predictor of smoking cessation and of abstinence maintenance in a Spanish sample. METHOD: The sample comprised 286 Spanish smokers undergoing psychological treatment for smoking cessation. Motivation to quit was assessed pre-treatment and post-treatment with the Readiness to Quit Ladder. Abstinence post-treatment and at 6month follow-up was biochemically verified. RESULTS: Participants with higher levels of pre-treatment and post-treatment motivation were more likely to be abstinent at the end of the treatment (OR=1.36) and at 6month follow-up (OR=4.88). Among abstainers at the end of the treatment (61.9%), higher levels of motivation to quit post-treatment predicted maintaining abstinence at 6months (OR=2.83). Furthermore, participants who failed to quit smoking reported higher levels of motivation to quit post-treatment than they had pretreatment (p<.001). CONCLUSIONS: Motivation to quit smoking predicted short and long-term cessation, and also predicted long-term maintenance of abstinence. These results have implications for understanding motivational processes of smoking cessation in general, while extending research to Spanish smokers. They may also help in the design of cessation and relapse-prevention interventions. Specifically, the results suggest that motivational enhancement is important throughout the cessation and maintenance periods. PMID- 26441046 TI - Surprising trunk rotational capabilities in chimpanzees and implications for bipedal walking proficiency in early hominins. AB - Human walking entails coordinated out-of-phase axial rotations of the thorax and pelvis. A long-held assumption is that this ability relies on adaptations for trunk flexibility present in humans, but not in chimpanzees, other great apes, or australopithecines. Here we use three-dimensional kinematic analyses to show that, contrary to current thinking, chimpanzees walking bipedally rotate their lumbar and thoracic regions in a manner similar to humans. This occurs despite differences in the magnitude of trunk motion, and despite morphological differences in truncal 'rigidity' between species. These results suggest that, like humans and chimpanzees, early hominins walked with upper body rotations that countered pelvic rotation. We demonstrate that even if early hominins walked with pelvic rotations 50% larger than humans, they may have accrued the energetic and mechanical benefits of out-of-phase thoracic rotations. This would have allowed early hominins to reduce work and locomotor cost, improving walking efficiency early in hominin evolution. PMID- 26441047 TI - Current applications of in utero intervention for lower urinary tract obstruction. AB - PURPOSE: Since the early 1980s with the inception of fetal intervention for obstructive uropathy, there have been creative attempts to improve both perinatal and long-term outcomes. Despite advances in technology and an improved understanding of lower urinary tract obstruction (LUTO) in the fetus, the results for these therapeutic interventions remain guarded and the long-term renal morbidity among survivors remains problematic. RECENT FINDINGS: Fetal LUTO represents a range of disorders but the most common of these is posterior urethral valves (PUVs). Selection criteria for candidates of possible intervention have improved with our understanding of fetal renal physiology. Serial urinalysis has marginally improved our ability to predict those that may ultimately respond to treatment [1,2], but the potential in the development of biomarkers for renal development or maldevelopment holds greater promise [3]. Advancements in fetal surgery may result in less fetal and maternal morbidity, but limited long-term improvement in outcomes highlights the controversial nature of the various interventions [4-10]. We must counsel families that fetal surgery offers hope but we cannot allow them to hold unrealistic expectations for cure. SUMMARY: In appropriately selected fetuses, intervention may improve perinatal survival but not without risk to mother and fetus. Long-term renal outcomes remain problematic amongst survivors. In the case of PUV, postnatal primary valve ablation remains the cornerstone of treatment for nephron preservation; however, our ability to mimic these results in the prenatal population remains poor [11]. Disease severity has likely predetermined those that will survive through the perinatal period with or without intervention. Nonetheless, our drive to assess and manage fetal obstructive uropathy perseveres so that we may ultimately relieve obstruction and preserve renal and lung function. We must maintain optimism that continued advances will ultimately improve outcomes, but also be realistic with our current expectations. This paper reviews the status of current in utero interventions and outcomes. PMID- 26441048 TI - Anatomy of the cutaneous surface of the male genitalia, with elaboration upon the inner preputial coronal-shaft junction. AB - INTRODUCTION: Descriptions of the penile prepuce in anatomical and clinical texts either omit details or contain a small, yet potentially serious, error with regard to the manner of its attachment to the penis. OBJECTIVE: This study sought to cast light on a ubiquitous but poorly understood and under-appreciated structure, while correcting a long-standing mistake in the medical literature. STUDY DESIGN: The foreskins of five male stillborn babies were dissected and carefully examined. Tissue from the apposing surfaces of the various regions of the inner and outer prepuce surfaces and the transition zone itself were collected, embedded in paraffin, sectioned, stained, examined and photographed under microscopy. RESULTS: Contradicting the prevailing descriptions in the literature that the inner prepuce is a single, uniform sheath, this study's observations and histological findings demonstrated that it actually splits into separate laminae that connect distally to the shaft at the base of the corona and proximally with the shaft fascia, respectively (Figure). DISCUSSION: The penile prepuce is a discrete and deceptively complex part of the male anatomy, yet key details of its interposing surfaces are inaccurately described or entirely omitted in the literature. Understanding the normal anatomy of the prepuce is critically relevant, particularly for urologists and others involved in the performance of circumcision. For example, avoiding potentially catastrophic avulsion of the inner preputial remnant beyond the coronal sulcus during circumcision and accurate assessment of tissue positioning prior to penile reconstruction in cases of hypospadias. CONCLUSION: The findings of this study correct a misunderstanding in the anatomy of the prepuce. PMID- 26441049 TI - Response to K.M. Szymanski re 'Further analysis of the glans-urethral meatus shaft (GMS) hypospadias score: Correlation with postoperative complications'. PMID- 26441050 TI - Cytokine modulation (IL-6, IL-8, IL-10) by human breast milk lipids on intestinal epithelial cells (Caco-2). AB - Human breast milk is the best form of nourishment for infants during the first year of life. It is composed by a complex mixture of carbohydrates, proteins and fats. Breast milk provides nutrients and bioactive factors that themselves modulate maturation and development of the gastrointestinal tract. Many studies have shown that it provides protection against gastrointestinal tract inflammation. In this sense, this study aimed to evaluate the effect of human breast milk lipids on epithelial intestinal cells (Caco-2) cytokine regulation and the fatty acid transporter protein (FATP) involved in this process. Caco-2 cells were cultivated and stimulated with different concentration of human milk lipids from healthy human mothers (18-30-year-olds) or single commercial lipids for 48 h. We measured the concentrations and mRNA levels of IL-6, IL-8 and IL-10 cytokines by immunoassay (ELISA) and quantitative-PCR (qRT-PCR) technique, respectively. We observed a two to three times decrease in pro-inflammatory cytokine levels (p < 0.01) as well as an increase in anti-inflammatory IL-10 levels in cells stimulated with increasing concentrations of breast milk lipids. These results suggest that human breast milk lipids could have an important role on the cytokine modulation in the newborn bowel. PMID- 26441051 TI - Genetics of endometriosis. AB - Endometriosis is a heritable complex disorder that is influenced by multiple genetic and environmental factors. Identification of these genetic factors will aid a better understanding of the underlying biology of the disease. In this article, we describe different methods of studying genetic variation of endometriosis, summarize results from genetic studies performed to date and provide recommendations for future studies to uncover additional factors contributing to the heritable component of endometriosis. PMID- 26441052 TI - Predicting complex mineral structures using genetic algorithms. AB - We show that symmetry-adapted genetic algorithms are capable of finding the ground state of a range of complex crystalline phases including layered- and incommensurate super-structures. This opens the way for the atomistic prediction of complex crystal structures of functional materials and mineral phases. PMID- 26441053 TI - Arabidopsis NAC016 promotes chlorophyll breakdown by directly upregulating STAYGREEN1 transcription. AB - KEY MESSAGE: The Arabidopsis transcriptional factor NAC016 directly activates chlorophyll degradation during leaf senescence by binding to the promoter of SGR1 and upregulating its transcription. During leaf senescence or abiotic stress in Arabidopsis thaliana, STAYGREEN1 (SGR1) promotes chlorophyll (Chl) degradation, acting with Chl catabolic enzymes, but the mechanism regulating SGR1 transcription remains largely unknown. Here, we show that the Arabidopsis senescence-associated NAC transcription factor NAC016 directly activates SGR1 transcription. Under senescence-promoting conditions, the expression of SGR1 was downregulated in nac016-1 mutants and upregulated in NAC016-overexpressing (NAC016-OX) plants. By yeast one-hybrid and chromatin immunoprecipitation assays, we found that NAC016 directly binds to the SGR1 promoter, which contains the NAC016-specific binding motif (termed the NAC016BM). Furthermore, nac016-1 SGR1 OX plants showed an early leaf yellowing phenotype, similar to SGR1-OX plants, confirming that NAC016 directly activates SGR1 expression in the leaf senescence regulatory cascade. Although we found that NAC016 activates SGR1 expression in senescing leaves, this transcriptional regulation is considerably weaker in maturing seeds; the seeds of sgr1-1 mutants (also known as nonyellowing1-1, nye1 1) stayed green, while the seeds of nac016-1 mutants turned from green to yellow normally. We also found that the abscisic acid (ABA) signaling-related transcription factor genes ABI5 and EEL and the ABA biosynthesis gene AAO3, which activate SGR1 expression directly or indirectly, were significantly downregulated in nac016-1 mutants and upregulated in NAC016-OX plants. However, the NAC016BM does not exist in their promoter regions, indicating that NAC016 may indirectly activate these ABA signaling and biosynthesis genes, probably by directly activating transcriptional cascades regulated by the NAC transcription factor NAP. The NAC016-mediated regulatory cascades of SGR1 and other Chl degradation related genes are discussed. PMID- 26441054 TI - Fine mapping of a palea defective 1 (pd1), a locus associated with palea and stamen development in rice. AB - KEY MESSAGE : pd1, a genetic factor in a 69 kb region between RM11239 and RM11245 on rice chromosome 1, controls stamen number and palea development. Spikelets are important organs that store photosynthetic products in rice. Spikelet development directly affects grain yield and rice quality. Here, we report a palea defective (pd1) mutant identified from selfing progenies of indica cv. 93-11 after (60)Co gamma ray treatment. pd1 mutant flowers only had four stamens (wild-type has six), but pollen fertility was not affected. Compared with 93-11 palea, pd1 mutant palea showed smaller and flatter leaf, which caused the lemma to bend excessively inward. pd1 mutants had only 46% seed setting rate and 21.6 g 1000 grain weight, which led to two-thirds loss of grain yield. Scanning electron microscope analysis revealed that pd1 mutants had reduced epidermal cell size and reduced numbers of fibrous sclerenchyma cells in both palea and lemma. To analyze the genetic factors involved, we crossed pd1 mutants with three japonica cultivars and generated F1 and F2 populations. The F1 phenotype and F2 segregation ratio indicated that a recessive gene controlled the mutant traits. Using the F2 population, we found that pd1 mapped between the simple sequence repeat markers RM11236 and RM11280 on rice chromosome 1. From a segregating population of 2836 plants, 77 recombinants were screened by RM11236 and RM11280. High-resolution linkage analysis narrowed the pd1 locus to a 69 kb region between RM11239 and RM11245 that contained 10 open reading frames (ORFs). Sequence alignment and quantitative real-time PCR expression analysis of these ORFs between 93-11 and pd1 mutant plants found no unequivocal evidence to identify the pd1 gene. PMID- 26441055 TI - The role of photorespiration during H2 photoproduction in Chlorella protothecoides under nitrogen limitation. AB - KEY MESSAGE: Photorespiration in Chlorella protothecoides plays an important role in photoprotection of photosystem (PS) II in the late phase of H(2) photoproduction, allowing PSII to supply more electrons to hydrogenase. PMID- 26441056 TI - Artemisinin production by plant hairy root cultures in gas- and liquid-phase bioreactors. AB - KEY MESSAGE: Alternative biotechnological protocol for large-scale artemisinin production was established. It featured enhanced growth and artemisinin production by cultivation of hairy roots in nutrient mist bioreactor (NMB) coupled with novel cultivation strategies. Artemisinin is used for the treatment of cerebral malaria. Presently, its main source is from seasonal plant Artemisia annua. This study featured investigation of growth and artemisinin production by A. annua hairy roots (induced by Agrobacterium rhizogenes-mediated genetic transformation of explants) in three bioreactor configurations-bubble column reactor, NMB and modified NMB particularly to establish their suitability for commercial production. It was observed that cultivation of hairy roots in a non stirred bubble column reactor exhibited a biomass accumulation of 5.68 g/l only while batch cultivation in a custom-made NMB exhibited a higher biomass concentration of 8.52 g/l but relatively lower artemisinin accumulation of 0.22 mg/g was observed in this reactor. A mixture of submerged liquid-phase growth (for 5 days) followed by gas-phase cultivation in nutrient mist reactor operation strategy (for next 15 days) was adopted for hairy root cultivation in this investigation. Reasonably, high (23.02 g/l) final dry weight along with the artemisinin accumulation (1.12 mg/g, equivalent to 25.78 mg/l artemisinin) was obtained in this bioreactor, which is the highest reported artemisinin yield in the gas-phase NMB cultivation. PMID- 26441057 TI - Investigation of the ASR family in foxtail millet and the role of ASR1 in drought/oxidative stress tolerance. AB - KEY MESSAGE: Six foxtail millet ASR genes were regulated by various stress related signals. Overexpression of ASR1 increased drought and oxidative tolerance by controlling ROS homeostasis and regulating oxidation-related genes in tobacco plants. Abscisic acid stress ripening (ASR) proteins with ABA/WDS domains constituted a class of plant-specific transcription factors, playing important roles in plant development, growth and abiotic stress responses. However, only a few ASRs genes have been characterized in crop plants and none was reported so far in foxtail millet (Setaria italic), an important drought-tolerant crop and model bioenergy grain crop. In the present study, we identified six foxtail millet ASR genes. Gene structure, protein alignments and phylogenetic relationships were analyzed. Transcript expression patterns of ASR genes revealed that ASRs might play important roles in stress-related signaling and abiotic stress responses in diverse tissues in foxtail millet. Subcellular localization assays showed that SiASR1 localized in the nucleus. Overexpression of SiASR1 in tobacco remarkably increased tolerance to drought and oxidative stresses, as determined through developmental and physiological analyses of germination rate, root growth, survival rate, relative water content, ion leakage, chlorophyll content and antioxidant enzyme activities. Furthermore, expression of SiASR1 modulated the transcript levels of oxidation-related genes, including NtSOD, NtAPX, NtCAT, NtRbohA and NtRbohB, under drought and oxidative stress conditions. These results provide a foundation for evolutionary and functional characterization of the ASR gene family in foxtail millet. PMID- 26441058 TI - Engineering low phorbol ester Jatropha curcas seed by intercepting casbene biosynthesis. AB - KEY MESSAGE: Casbene is a precursor to phorbol esters and down-regulating casbene synthase effectively reduces phorbol ester biosynthesis. Seed-specific reduction of phorbol ester (PE) helps develop Jatropha seed cake for animal nutrition. Phorbol esters (PEs) are diterpenoids present in some Euphorbiaceae family members like Jatropha curcas L. (Jatropha), a tropical shrub yielding high quality oil suitable as feedstock for biodiesel and bio jet fuel. Jatropha seed contains up to 40 % of oil and can produce oil together with cake containing high quality proteins. However, skin-irritating and cancer-promoting PEs make Jatropha cake meal unsuitable for animal nutrition and also raise some safety and environmental concerns on its planting and processing. Two casbene synthase gene (JcCASA163 and JcCASD168) homologues were cloned from Jatropha genome and both genes were highly expressed during seed development. In vitro functional analysis proved casbene synthase activity of JcCASA163 in converting geranylgeranyl diphosphate into casbene which has been speculated to be the precursor to PEs. A seed-specific promoter driving inverted repeats for RNAi interference targeting at either JcCASA163 or both genes could effectively down-regulate casbene synthase gene expression with concurrent marked reduction of PE level (by as much as 85 %) in seeds with no pleiotropic effects observed. Such engineered low PE in seed was heritable and co-segregated with the transgene. Our work implicated casbene synthase in Jatropha PE biosynthesis and provided evidence for casbene being the precursor for PEs. The success in reducing seed PE content through down regulation of casbene synthase demonstrates the feasibility of intercepting PE biosynthesis in Jatropha seed to help address safety concerns on Jatropha plantation and seed processing and facilitate use of its seed protein for animal nutrition. PMID- 26441059 TI - Interferon-beta Modulates the Innate Immune Response against Glioblastoma Initiating Cells. AB - Immunotherapy targeting glioblastoma initiating cells (GIC) is considered a promising strategy. However, GIC are prone to evade immune response and there is a need for potent adjuvants. IFN-beta might enhance the immune response and here we define its net effect on the innate immunogenicity of GIC. The transcriptomes of GIC treated with IFN-beta and controls were assessed by microarray-based expression profiling for altered expression of immune regulatory genes. Several genes involved in adaptive and innate immune responses were regulated by IFN beta. We validated these results using reverse transcription (RT)-PCR and flow cytometry for corresponding protein levels. The up-regulation of the NK cell inhibitory molecules HLA-E and MHC class I was balanced by immune stimulating effects including the up-regulation of nectin-2. In 3 out of 5 GIC lines tested we found a net immune stimulating effect of IFN-beta in cytotoxicity assays using NKL cells as effectors. IFN-beta therefore warrants further investigation as an adjuvant for immunotherapy targeting GIC. PMID- 26441060 TI - Experimental evidence for the therapeutic potential of tempol in the treatment of acute liver injury. AB - Oxidative stress is one of the mechanisms involved in the acute carbon tetrachloride (CCl4)-induced hepatotoxicity. Since 4-hydroxy-2,2,6,6 tetramethylpiperidin-1-oxyl, known as tempol, has powerful antioxidant properties, we investigated its potential hepatoprotective effects and the underlying mechanisms that may add further benefits for its clinical usefulness using an acute model of CCl4-induced hepatotoxicity. One hour after CCl4 induction of acute hepatotoxicity, mice were treated with a daily dose of 20 mg/kg/day tempol for 3 days. It was found that treatment of animals with tempol significantly negated the pathological changes in liver function parameters as well as histology induced by CCl4. In addition, tempol significantly ameliorated CCl4-induced lipid peroxidation and GSH depletion, and improved catalase activity. Furthermore, tempol alleviated the inflammation induced by CCl4 as indicated by reducing the liver expression level of nuclear factor-kappa B (NF kappaB) and tumor necrosis factor-alpha (TNF-alpha). Finally, tempol significantly reduced expression level of the B-cell lymphoma-2 protein (Bcl-2) and active caspase-3 which are known markers of apoptosis. In conclusion, the present study provides important evidences for the promising hepatoprotective effects of tempol that can be explained by amelioration of oxidative stress mainly through replenishment of GSH, restoration of antioxidant enzyme activities, and reduction of lipid peroxides alongside its anti-inflammatory properties. PMID- 26441061 TI - Dynamic analysis of phospholipid metabolism of mouse macrophages treated with common non-steroidal anti-inflammatory drugs. AB - Through studying the changes of the total phospholipid components in mouse macrophages under the inflammatory status and the drug intervention status, we found the targets of non-steroidal anti-inflammatory drugs on phospholipids, thus providing the basis for the targets of in vitro anti-inflammatory effects of non steroidal anti-inflammatory drugs. After RAW264.7 cells were pretreated with common non-steroidal anti-inflammatory drugs (aspirin and ibuprofen) and, respectively, stimulated with KLA for various periods (0.5, 4, 12, 16, and 24 h), the phospholipids were extracted. The dynamic changes of phospholipids in cells under various stimulations were analyzed with UPLC-Q-TOF-MS technique. Through the statistical analysis of Simca-P, we explored the potential targets of non steroidal anti-inflammatory drugs on phospholipids. Through the dynamic analysis of phospholipids, we found two biomarkers (PC(17:1/18:1), PA(18:0/18:4)) which might be in vitro intervention inflammatory response targets of non-steroidal anti-inflammatory drugs. The analysis results show that in anti-inflammatory effects, non-steroidal anti-inflammatory drugs can inhibit COX, induce the cellular fatty acid desaturation and the changes of phospholipid components, stimulate free fatty acids, activate calcium ion channels of endoplasmic reticulum, and promote cell endocytosis, thus controlling inflammation and activating cells. Non-steroidal anti-inflammatory drugs can promote endocytosis, alter cell inflammatory response, and activate the process cells, thus realizing the anti-inflammatory effects. PMID- 26441062 TI - Joint involvement secondary to Epstein-Barr virus. AB - We describe a group of patients with Epstein-Barr virus (EBV) infection and joint involvement. Between February 2011 and January 2012, there were six cases in our unit. Two presented with a pattern similar to rheumatoid arthritis, three had polyarthralgia with an inflammatory pattern and only one patient had asymmetrical oligoarthritis of large joints. They were all women aged between 25 and 75 (4 were of child-bearing potential). Diagnosis in all the cases was made by exclusion of other possible causes and negative IgM were obtained for the rest of the "Herpesviridae" family viruses. In our series, EBV joint involvement was more common in women of childbearing potential. Clinical presentation was heterogeneous but was predominantly in the form of inflammatory joint pain. When it presents in the form of symmetrical polyarthritis, it can become chronic and require the use of disease-modifying anti-rheumatic drugs. PMID- 26441063 TI - Lavandula angustifolia and Lavandula latifolia Essential Oils from Spain: Aromatic Profile and Bioactivities. AB - Compositions of true lavender (Lavandula angustifolia) and spike lavender (Lavandula latifolia) essential oils, cultivated and extracted in the Southeast of Spain, were determined by gas chromatography coupled with mass spectrometry detection, obtaining both relative (peak area) and absolute (using standard curves) concentrations. Linalool (37-54 %), linalyl acetate (21-36 %) and (E) beta-caryophyllene (1-3 %) were the most abundant components for L. angustifolia. Linalool (35-51 %), eucalyptol (26-32 %), camphor (10-18 %), alpha-pinene (1-2 %), alpha-terpineol (1-2 %) and alpha-bisabolene (1-2 %) were the most abundant components for L. latifolia. The characterization was completed with enantioselective gas chromatography, in which the determined main molecules were (-)-linalool, (-)-linalyl acetate and (+)-camphor. (S)-(-)-camphene, (R)-(+) limonene, (1R, 9S)-(-)-(E)-beta-caryophyllene and (1R, 4R, 6R, 10S)-(-) caryophyllene oxide were found in this study as the predominant enantiomers in Spanish L. angustifolia. The characterised essential oils were tested for their antioxidant activity against free radicals ABTS, DPPH, ORAC, chelating, and reducing power. Inhibitory activity on lipoxygenase was observed indicating a possible anti-inflammatory activity, mainly due to linalool, camphor, p-cymene and limonene. These results can be the starting point for a future study of the potential use of L. angustifolia and L. latifolia essential oils as natural cosmetic and natural pharmaceutical ingredients for several skin diseases. PMID- 26441064 TI - Sesquiterpene Lactones from Cynara cornigera: Acetyl Cholinesterase Inhibition and In Silico Ligand Docking. AB - Wild artichoke (Cynara cornigera), a thistle-like perennial belonging to the Asteraceae family, is native to the Mediterranean region, northwestern Africa, and the Canary Islands. While the pleasant, albeit bitter, taste of the leaves and flowers is attributed to the sesquiterpene lactones cynaropicrin and cynarin, a comprehensive phytochemical investigation still needs to be reported. In this study seven sesquiterpene lactones were isolated from an aqueous methanol plant extract, including a new halogenated metabolite (1), the naturally isolated compound sibthorpine (2), and five metabolites isolated for the first time from C. cornigera. Structures were established by spectroscopic methods, including HREIMS, (1 )H, (13 )C, DEPT, (1 )H-(1 )H COSY, HMQC, and HMBC-NMR experiments as well as by X-ray analysis. The isolated bioactive nutrients were analyzed for their antioxidant and metal chelating activity. Compound 1 exhibited a potent metal chelating activity as well as a high antioxidant capacity. Moreover, select compounds were effective as acetyl cholinesterase inhibitors presenting the possibility for such compounds to be examined for anti-neurodegenerative activity. A computational pharmacophore elucidation and docking study was performed to estimate the pharmacophoric features and binding conformation of isolated compounds in the acetyl cholinesterase active site. PMID- 26441065 TI - Review and Assessment of Medicinal Safety Data of Orally Used Echinacea Preparations. AB - Echinacea purpurea, Echinacea angustifoli and Echinacea pallida are frequently used as medicinal plants. Besides asking for evidence on their efficacy, there is an increasing interest for safety data. This review systematically presents the available literature on drug interactions, contraindications, adverse events, duration of use, and safety of use in pregnant and nursing women, and assesses the safety profile of corresponding Echinacea preparations. It is noteworthy that all safety data reported are as product specific as the pharmacological or efficacy data are. In pharmacokinetic herb-drug interaction studies performed in vivo, no significant inhibitions of human CYP2D6 and CYP3A4 isoforms have been found after the administration of standardized E. purpurea preparations. However, contradictory results exist in studies using liver microsomes. Adverse events reported during clinical trials following administration of Echinacea spp. mono preparations were generally mild and mostly without causality. Due to published long term studies with continuous ingestion of different Echinacea preparations up to 6 month with no reported toxicological concerns, Echinacea can be recommended also for long-term use. Moreover, the contraindications in cases of autoimmune diseases and immune-suppression are questionable, since lipophilic Echinacea preparations containing alkamides suppress cellular immune responses, and beneficial effects in autoimmunity were reported. The same applies for the use during pregnancy. Although there has been some impact reported on embryonic angiogenesis in mice, no association with an increased risk for major or minor malformations during organogenesis was found in a literature review. Altogether, the different evaluated Echinacea preparations are well-tolerated herbal medicines in the management in children and adults alike. PMID- 26441071 TI - Effect of Porcine Epidemic Diarrhea Virus Infectious Doses on Infection Outcomes in Naive Conventional Neonatal and Weaned Pigs. AB - Porcine epidemic diarrhea virus (PEDV) was identified in the United States (U.S.) swine population for the first time in April 2013 and rapidly spread nationwide. However, no information has been published regarding the minimum infectious dose (MID) of PEDV in different pig models. The main objective of this study was to determine the oral minimum infectious dose of PEDV in naive conventional neonatal piglets and weaned pigs. A U.S. virulent PEDV prototype isolate (USA/IN19338/2013) with known infectious titer was serially ten-fold diluted in virus-negative cell culture medium. Dilutions with theoretical infectious titers from 560 to 0.0056 TCID50/ml together with a medium control were orogastrically inoculated (10ml/pig) into 7 groups of 5-day-old neonatal pigs (n = 4 per group) and 7 groups of 21-day-old weaned pigs (n = 6 per group). In 5-day-old pigs, 10ml of inoculum having titers 560-0.056 TCID50/ml, corresponding to polymerase chain reaction (PCR) cycle threshold (Ct) values 24.2-37.6, resulted in 100% infection in each group; 10ml of inoculum with titer 0.0056 TCID50/ml (Ct>45) caused infection in 25% of the inoculated pigs. In 21-day-old pigs, 10ml of inoculum with titers 560-5.6 TCID50/ml (Ct 24.2-31.4) resulted in 100% infection in each group while 10ml of inoculum with titers 0.56-0.0056 TCID50/ml (Ct values 35.3 >45) did not establish infection in any pigs under study conditions as determined by clinical signs, PCR, histopathology, immunohistochemistry, and antibody response. These data reveal that PEDV infectious dose is age-dependent with a significantly lower MID for neonatal pigs compared to weaned pigs. This information should be taken into consideration when interpreting clinical relevance of PEDV PCR results and when designing a PEDV bioassay model. The observation of such a low MID in neonates also emphasizes the importance of strict biosecurity and thorough cleaning/disinfection on sow farms. PMID- 26441072 TI - Pricing a Protest: Forecasting the Dynamics of Civil Unrest Activity in Social Media. AB - Online social media activity can often be a precursor to disruptive events such as protests, strikes, and "occupy" movements. We have observed that such civil unrest can galvanize supporters through social networks and help recruit activists to their cause. Understanding the dynamics of social network cascades and extrapolating their future growth will enable an analyst to detect or forecast major societal events. Existing work has primarily used structural and temporal properties of cascades to predict their future behavior. But factors like societal pressure, alignment of individual interests with broader causes, and perception of expected benefits also affect protest participation in social media. Here we develop an analysis framework using a differential game theoretic approach to characterize the cost of participating in a cascade, and demonstrate how we can combine such cost features with classical properties to forecast the future behavior of cascades. Using data from Twitter, we illustrate the effectiveness of our models on the "Brazilian Spring" and Venezuelan protests that occurred in June 2013 and November 2013, respectively. We demonstrate how our framework captures both qualitative and quantitative aspects of how these uprisings manifest through the lens of tweet volume on Twitter social media. PMID- 26441074 TI - A visualized probe method for localization of surface oxygen vacancy on TiO2: Au in situ reduction. AB - Surface oxygen vacancy has been investigated extensively due to its great influence on photocatalysis in recent years. Among these investigations, the location of surface defects is found to be a key factor during the photocatalytic procedure. Especially when a crystal facet is involved, the synergistic action between these two factors may greatly increase the photocatalytic efficiency. Location of defects would greatly help in understanding the mechanism of this coupling action. Without an available technique, however, it is very difficult to gain the position information directly. In this paper, we provide a low-cost and visualized method to solve this problem via in situ reduction of Au. TiO2 with surface oxygen vacancy on a specific area is synthesized via a photochemical reaction. Then the Au ion was reduced at the place where oxygen vacancy exists on the TiO2 surface. Hence, the localization of surface vacancy will be determined by examining the location of Au particles. Moreover, application of this method can be extended to other surface defects such as oxygen vacancy on oxide semiconductors, Ti(3+) in TiO2, Zn vacancy on ZnO, etc. This technique is helpful for understanding how surface defects affect the properties of semiconductors. PMID- 26441073 TI - Intermittent Administration of Parathyroid Hormone [1-34] Prevents Particle Induced Periprosthetic Osteolysis in a Rat Model. AB - We examined whether intermittent administration of parathyroid hormone [1-34] (PTH[1-34]; 60 MUg/kg/day) can prevent the negative effects of titanium (Ti) particles on implant fixation and periprosthetic osteolysis in a rat model. Eighteen adult male rats (12 weeks old, bones still growing) received intramedullary Ti implants in their bilateral femurs; 6 rats from the blank group received vehicle injections, and 12 rats from the control group and PTH treatment group received Ti particle injections at the time of operation and intra articular injections 2 and 4 weeks postoperatively. Six of the rats that received Ti particles from the PTH group also received PTH[1-34] treatment. Six weeks postoperatively, all specimens were collected for assessment by X-ray, micro-CT, biomechanical, scanning electron microscopy (SEM), and dynamic histomorphometry. A lower BMD, BV/TV, Tb.N, maximal fixation strength, and mineral apposition rate were observed in the control group compared to the blank group, demonstrating that a periprosthetic osteolysis model had been successfully established. Administration of PTH[1-34] significantly increased the bone mineral density of the distal femur, BV/TV, Tb.N, Tb.Th, Tb.Sp, Con.D, SMI, and maximal fixation strength in the PTH group compared to that in the control group. SEM revealed higher bone-implant contact, thicker lamellar bone, and larger trabecular bone area in the PTH group than in the control group. A higher mineral apposition rate was observed in the PTH group compared to both the blank and control groups. These findings imply that intermittent administration of PTH[1-34] prevents periprosthetic osteolysis by promoting bone formation. The effects of PTH[1-34] were evaluated at a suprapharmacological dosage to the human equivalent in rats; therefore, additional studies are required to demonstrate its therapeutic potential in periprosthetic osteolysis. PMID- 26441075 TI - [Scoliosis update]. PMID- 26441076 TI - Do-not-resuscitate orders among advanced-stage Chinese lung cancer patients who died in hospital. AB - PURPOSE: Do-not-resuscitate (DNR) orders are an important part of end-of-life care (EOL) for patients with incurable advanced lung cancer. The aim of this study was to investigate the clinical factors related to the acceptance of DNR orders by Chinese patients. METHODS: This study was a retrospective analysis involving patients with advanced-stage (IIIB or IV) lung cancer who died in hospital at our center from August 2004 through August 2014. The patients' clinical characteristics and DNR forms were reviewed. RESULTS: Of the 348 patients enrolled, 260 (74.7 %) provided DNR orders signed only by surrogates. The signing rate of DNR orders increased annually. The median interval from signing a DNR order to death was 1 day (range, 0-72 days). Patients with poor performance status (PS) (>=2) 1 week prior to death (OR, 3.395; 95 % CI, 1.536 7.502, P = 0.003) and relatively longer overall survival (OS) (>3 months) (OR, 2.464; 95 % CI, 1.566-4.472, P < 0.001) were more likely to sign DNR orders. CPR was performed on 10.3 % (27/260) of patients with DNR orders, and was withheld in 22.7 % (20/88) of patients without DNR orders. CONCLUSIONS: The DNR order-signing rate has been increasing annually among terminal patients with lung cancer in China. DNR orders, all of which were signed by surrogates, were more likely to be accepted by patients with slowly deteriorating disease and longer OS. More effort should be taken to help patients and medical professionals establish a sensible understanding of EOL care, including DNR orders, at earlier points during the disease course. PMID- 26441078 TI - Cancer rehabilitation and palliative care--two important parts of comprehensive cancer care. PMID- 26441077 TI - Malignancy associated hypercalcaemia-responsiveness to IV bisphosphonates and prognosis in a palliative population. AB - BACKGROUND: Hypercalcaemia is a potentially fatal paraneoplastic complication of malignancy. It primarily manifests during the advanced phase of cancer, with the life expectancy of patients ranging from weeks to months. The mainstay of treatment is with bisphosphonates, but these are not frequently used in a palliative population due to potential conflict with goals of care. GOAL: The goals of this study was to determine the reversibility of hypercalcaemia amongst patients whose underlying malignancy is not being treated and assess whether correction results in improvement in symptoms attributable to hypercalcaemia, while identifying risk factors that can predict responsiveness. METHODS: We conducted a retrospective cohort study of 63 patients aged >18 years who were admitted to the St Joseph's Palliative Care Unit, Australia between 2007 and 2013, having evidence of malignancy-associated hypercalcaemia which was treated with bisphosphonates. We assessed the response to bisphosphonates based on improvement of symptoms attributable to hypercalcaemia, as well as a reduction in serum calcium. We used the Kaplan-Meier survival method and parametric survival analysis to estimate the effect of the independent variables on time till death. RESULTS: Thirty-six of sixty three patients achieved normocalcaemia following treatment with an intravenous bisphosphonate. Complete response was influenced by the number of instances of hypercalcaemia in the past and patient factors, such as age and albumin levels. We found that a reduction in calcium level was associated with a significantly prolonged survival, as well as symptomatic improvement, irrespective of whether normocalcaemia was achieved. CONCLUSION: Our study suggests that bisphosphonates can be recommended as a palliative measure for selected patients to improve symptoms and prolong survival. PMID- 26441079 TI - Tight junction defects are seen in the buccal mucosa of patients receiving standard dose chemotherapy for cancer. AB - PURPOSE: Oral mucositis is one of the most common and debilitating side effects of chemotherapy treatment. Patients are often unable to eat and drink, which can lead to poor clinical outcomes and extensive resource utilisation. The primary aim of this study was to determine the molecular integrity of oral epithelial tight junctions in patients undergoing chemotherapy. The secondary aim was to correlate these changes with proinflammatory cytokines and matrix metalloproteinase profiles. METHODS: Patients (n = 23) were recruited from the Royal Adelaide Hospital between 2000 and 2003. Reach patient underwent two oral buccal mucosa biopsies (4 mm): one prior to chemotherapy treatment and a second one after chemotherapy treatment. Oral buccal mucosa biopsies were also taken from seven healthy volunteers with no history of cancer, chemo- or radiotherapy treatment or inflammatory disorders. Routine haematoxylin and eosin staining was performed to determine epithelial thickness. Immunohistochemical staining was performed for claudin-1, zonular occludens-1, occludin, interleukin-1beta, tumour necrosis factor, interleukin-6, matrix metalloproteinase-2 and metalloproteinase 9. RESULTS: Patients receiving standard dose chemotherapy had significant epithelial atrophy. Elevations in all cytokines and matrix metalloproteinases were seen, with significant lamina propria staining for interleukin-6 and tumour necrosis factor. Matrix metalloproteinase-2 appeared most upregulated within the oral epithelium. These changes coincided with altered tight junction staining properties. Changes in the staining intensity and localisation were both noted, with clear cytoplasmic staining for zonular occludens-1 and claudin-1 in patients treated with chemotherapy. CONCLUSIONS: Chemotherapy causes defects in oral tight junctions, coupled with altered cytokine and matrix metalloproteinase profiles. Tight junction disruption in the epithelium may contribute to ulcer development or lead to poor tissue integrity, and the timing of these events may be a target for preventative treatment. PMID- 26441081 TI - Photophysics and Nonlinear Absorption of Gold(I) and Platinum(II) Donor-Acceptor Donor Chromophores. AB - A series of Au(I) and Pt(II) acetylide complexes of a pi-conjugated donor acceptor-donor (D-A-D) chromophore were studied to develop quantitative structure property relationships for their photophysical and nonlinear optical properties. The D-A-D chromophore consists of a "TBT" unit, where T = 3-hexyl-2,5-thienylene and BTD = 2,1,3-benzothiadiazole, capped with ethynylene groups. The D-A-D chromophore is functionalized with Au(I)PR3 (R = -Me and -Ph) and trans Pt(II)(PR3)2-CCPh (R = -Me and -Bu) "auxochromes". All of the metal complexes were characterized by ground-state absorption, photoluminescence, nanosecond transient absorption, and two-photon absorption (2PA) spectroscopy. The experiments provided quantitative values of the photophysical parameters, including rates for radiative decay and intersystem crossing (ISC), triplet yields, and two-photon absorption cross sections. Pronounced solvatochromism in the fluorescence spectra suggests an enhanced dipole moment in the excited state of the complexes compared to the unmetalated TBT chromophore. The gold complexes feature larger fluorescence quantum yields and longer emission lifetimes compared to platinum. The Pt(II) complexes exhibit enhanced triplet-triplet absorption, reduced triplet-state lifetimes, and larger singlet oxygen quantum yields, consistent with more efficient ISC compared to the Au(I) complexes. When excited by 100 fs pulses, all of the D-A-D chromophores exhibit moderate two-photon absorption in the near-infrared between 700 and 900 nm. The 2PA cross section for the Au(I) complexes is almost the same as the unmetalated D-A-D chromophore (~100 GM). The Pt(II) complexes exhibit significantly enhanced 2PA compared to the other chromophores, reaching 1000 GM at 750 nm. Taken together, the results indicate that the Pt(II) center is considerably more effective in inducing singlet-triplet ISC and in enhancing the 2PA cross section. This result reveals the greater promise for Pt(II) acetylides in chromophores for temporal and frequency agile nonlinear absorption. PMID- 26441082 TI - Clinical trials: Early phase clinical trials-are dose expansion cohorts needed? PMID- 26441080 TI - New Insights into the Geographic Distribution of Mycobacterium leprae SNP Genotypes Determined for Isolates from Leprosy Cases Diagnosed in Metropolitan France and French Territories. AB - BACKGROUND: Between 20 and 30 bacteriologically confirmed cases of leprosy are diagnosed each year at the French National Reference Center for mycobacteria. Patients are mainly immigrants from various endemic countries or living in French overseas territories. We aimed at expanding data regarding the geographical distribution of the SNP genotypes of the M. leprae isolates from these patients. METHODOLOGY/PRINCIPAL FINDINGS: Skin biopsies were obtained from 71 leprosy patients diagnosed between January 2009 and December 2013. Data regarding age, sex and place of birth and residence were also collected. Diagnosis of leprosy was confirmed by microscopic detection of acid-fast bacilli and/or amplification by PCR of the M. leprae-specific RLEP region. Single nucleotide polymorphisms (SNP), present in the M. leprae genome at positions 14 676, 1 642 875 and 2 935 685, were determined with an efficiency of 94% (67/71). Almost all patients were from countries other than France where leprosy is still prevalent (n = 31) or from French overseas territories (n = 36) where leprosy is not totally eradicated, while only a minority (n = 4) was born in metropolitan France but have lived in other countries. SNP type 1 was predominant (n = 33), followed by type 3 (n = 17), type 4 (n = 11) and type 2 (n = 6). SNP types were concordant with those previously reported as prevalent in the patients' countries of birth. SNP types found in patients born in countries other than France (Comoros, Haiti, Benin, Congo, Sri Lanka) and French overseas territories (French Polynesia, Mayotte and La Reunion) not covered by previous work correlated well with geographical location and history of human settlements. CONCLUSIONS/SIGNIFICANCE: The phylogenic analysis of M. leprae strains isolated in France strongly suggests that French leprosy cases are caused by SNP types that are (a) concordant with the geographic origin or residence of the patients (non-French countries, French overseas territories, metropolitan France) or (b) more likely random in regions where diverse migration flows occurred. PMID- 26441084 TI - Metabolic flux analysis of the halophilic archaeon Haladaptatus paucihalophilus. AB - This work reports the (13)C-assisted metabolic flux analysis of Haladaptatus paucihalophilus, a halophilic archaeon possessing an intriguing osmoadaption mechanism. We showed that the carbon flow is through the oxidative tricarboxylic acid (TCA) cycle whereas the reductive TCA cycle is not operative in H. paucihalophilus. In addition, both threonine and the citramalate pathways contribute to isoleucine biosynthesis, whereas lysine is synthesized through the diaminopimelate pathway and not through the alpha-aminoadipate pathway. Unexpected, the labeling patterns of glycine from the cells grown on [1 (13)C]pyruvate and [2-(13)C]pyruvate suggest that, unlike all the organisms investigated so far, in which glycine is produced exclusively from the serine hydroxymethyltransferase (SHMT) pathway, glycine biosynthesis in H. paucihalophilus involves different pathways including SHMT, threonine aldolase (TA) and the reverse reaction of glycine cleavage system (GCS), demonstrating for the first time that other pathways instead of SHMT can also make a significant contribution to the cellular glycine pool. Transcriptional analysis confirmed that both TA and GCS genes were transcribed in H. paucihalophilus, and the transcriptional level is independent of salt concentrations in the culture media. This study expands our understanding of amino acid biosynthesis and provides valuable insights into the metabolism of halophilic archaea. PMID- 26441083 TI - Omeprazole induces NAD(P)H quinone oxidoreductase 1 via aryl hydrocarbon receptor independent mechanisms: Role of the transcription factor nuclear factor erythroid 2-related factor 2. AB - Activation of the aryl hydrocarbon receptor (AhR) transcriptionally induces phase I (cytochrome P450 (CYP) 1A1) and phase II (NAD(P)H quinone oxidoreductase 1 (NQO1) detoxifying enzymes. The effects of the classical and nonclassical AhR ligands on phase I and II enzymes are well studied in human hepatocytes. Additionally, we observed that the proton pump inhibitor, omeprazole (OM), transcriptionally induces CYP1A1 in the human adenocarcinoma cell line, H441 cells via AhR. Whether OM activates AhR and induces the phase II enzyme, NAD(P)H quinone oxidoreductase 1 (NQO1), in fetal primary human pulmonary microvascular endothelial cells (HPMEC) is unknown. Therefore, we tested the hypothesis that OM will induce NQO1 in HPMEC via the AhR. The concentrations of OM used in our experiments did not result in cytotoxicity. OM activated AhR as evident by increased CYP1A1 mRNA expression. However, contrary to our hypothesis, OM increased NQO1 mRNA and protein via an AhR-independent mechanism as AhR knockdown failed to abrogate OM-mediated increase in NQO1 expression. Interestingly, OM activated Nrf2 as evident by increased phosphoNrf2 (S40) expression in OM-treated compared to vehicle-treated cells. Furthermore, Nrf2 knockdown abrogated OM mediated increase in NQO1 expression. In conclusion, we provide evidence that OM induces NQO1 via AhR-independent, but Nrf2-dependent mechanisms. PMID- 26441085 TI - AKT-independent Reelin signaling requires interactions of heterotrimeric Go and Src. AB - Reelin, a large secreted extracellular matrix glycoprotein, plays a key role in neuronal migration during cortical development and promotes neuronal maturation. The signaling pathway regulating neuronal maturation in the postnatal period are relatively less well understood. In this study, we demonstrated that a heterotrimeric G protein, Go, is a novel target of Reelin-induced signaling to promote neurite outgrowth. In primary hippocampal neurons of Reelin-deficient reeler mice, neurite outgrowth was significantly reduced and rescued upon addition of Reelin. Pertussis toxin (PTX) treatment or transfection with Galphao siRNA suppressed Reelin-mediated neurite outgrowth in wild-type neurons. Additionally, Reelin treatment led to increased phosphorylation of AKT, GSK3beta, and JNK, which were all effectively blocked by the PI3K inhibitor, LY294002. By comparison, PTX specifically blocked JNK activation, but not AKT and GSK3beta. Immunoprecipitation assays disclosed that Reelin increases the active forms of both Src and Galphao and promotes their direct association. Notably, Dab1, a cytoplasmic adaptor molecule that mediates Reelin signaling, did not interact with Galphao. Neurite outgrowth by Reelin was induced via activating Src kinase, which directly stimulated Galphao, activity, leading to JNK activation. Based on the collective findings, we suggest that Reelin-dependent signaling mechanisms may be split into Src-AKT-dependent and Src-Go-dependent pathways. Our results additionally provide evidence that Reelin receptors cross-communicate with heterologous G protein-coupled receptors (GPCR) independently of the cognate ligands of GPCR. PMID- 26441086 TI - Replication of partial double-stranded RNAs by Qbeta replicase. AB - Qbeta replicase, an RNA-dependent RNA polymerase of bacteriophage Qbeta, uses single-stranded RNA as a template to synthesize the complementary strand. A single-stranded RNA template may contain rigid secondary structures, such as long stems, intermolecular double-stranded RNA regions. Presently, the effect of the size of such double-stranded regions on the replication of RNA by Qbeta replicase is unknown. In this study, we prepared RNA templates hybridized with complementary RNA or DNA strands of various sizes and analyzed their replication by Qbeta replicase. We found that Qbeta replicase synthesizes the complementary strand as long as the template RNA is hybridized with no more than 200 nt fragments, although the replication amounts were decreased. This is important information to evaluate processivity of Qbeta replicase. PMID- 26441088 TI - Discussion: Microbotox of the Lower Face and Neck: Evolution of a Personal Technique and Its Clinical Effects. PMID- 26441087 TI - Radiesse: Advanced Techniques and Applications for a Unique and Versatile Implant. AB - BACKGROUND: Radiesse is a well-tolerated facial injectable with unique filling and lifting capabilities. Although initially approved for facial volumizing in HIV-related lipodystrophy patients, it quickly gained wide acceptance for aesthetic facial rejuvenation. In the USA, the Food and Drug Administration has approved several new indications for its use. This synopsis presents the experience and injection techniques currently favored by the primary author after many years of use in thousands of patients. METHODS: The anecdotal practice of an experienced injector is presented along with the current Food and Drug Administration-approved standards of Radiesse injection. RESULTS: Radiesse has many on- and off-label applications that can be thoughtfully incorporated into clinical practice. Its unique chemical composition allows for immediate lifting and filling with long-term collagen stimulation. The product can be reconstituted to increase its versatility and minimize adverse events. Injections can be performed in the supraperiosteal space and the subcutaneous layer and are best administered in small, calculated doses to prevent nodules or vascular occlusion. Various techniques for Radiesse injection in specific areas are discussed in detail. CONCLUSIONS: Radiesse is a versatile injectable implant and a valuable tool for short- and long-term cosmetic and reconstructive treatments. In addition to various off-label uses, this injectable is often used in conjunction with botox, other injectables, collagen stimulators and tightening devices. A customized reconstitution of product increases its versatility for natural appearing and long lasting results that are both economical and effective for full facial rejuvenation. PMID- 26441089 TI - Neurotoxins: Expanding Uses of Neuromodulators in Medicine--Headache. AB - Over the course of the past 17 years, since the initial discovery of the association between botulinum toxin-A (BT-A) and the reduction of headache symptoms, the use of this neurotoxin has greatly evolved. BT-A has emerged as an alternative to prophylactic pharmacological therapies in the prevention of chronic migraine headaches, with an excellent safety profile and proven efficacy, and is Food and Drug Administration-approved for on-label use since October 2010. The mechanism of BT-A involves its effect at the neuromuscular junction, inhibition of neuropeptide and neurotransmitter release in peripheral sensory neurons, and retrograde axonal transport allowing for its direct effect on inhibiting central sensitization. Through its diagnostic and therapeutic utility, BT-A has proven to be an integral part in the treatment of chronic headache disorders. PMID- 26441090 TI - Neurotoxins: Expanding Uses of Neuromodulators in Medicine--Major Depressive Disorder. AB - BACKGROUND: Botulinum toxin A (BTA) is one of the most diversely used medications of the 21st century and is now being researched as a treatment for major depressive disorder (MDD). METHODS: The authors performed a literature search of PubMed, Web of Science, and the Cochrane Register of Controlled Trials. The primary investigators of the studies were contacted for additional unpublished data. RESULTS: The authors identified 5 studies that met the criteria of using BTA in the treatment of MDD. All studies showed significant reduction in depressive symptoms with BTA injected into the glabellar muscles. In a pooled analysis, botulinum toxin (n=59) vs placebo (n=75) had a -47% vs -16% reduction in self-rated depression scores (P<0.0001) and a -46% vs -15% reduction in expert rated depression scores (P<0.0001), respectively. Adverse reactions were mild (temporary headaches and local irritation immediately after injection) and did not differ between active group (13.6%) and placebo group (9.3%) (P=0.44). CONCLUSIONS: Botulinum toxin injections in the glabellar frown muscles have been associated with a significant improvement in depressive symptoms. Given the prevalence of MDD, the promising results of preliminary trials, and the excellent tolerability of this treatment intervention, larger studies are warranted. PMID- 26441091 TI - Analysis of Facial Aesthetics as Applied to Injectables. AB - Understanding the role of volume loss in the aging face has resulted in a paradigm shift in facial rejuvenation techniques. Injectable materials for volume restoration are among the most widespread cosmetic procedures performed. A new approach to the aesthetics of facial aging is necessary to allow the greatest improvement from volumetric techniques while maintaining natural appearing results. Examining the face in terms of facial frames and facial shadows provides the fundamental basis for our injectable analysis. PMID- 26441092 TI - Introduction to Fillers. AB - BACKGROUND: Over the last few years, injectable soft-tissue fillers have become an integral part of cosmetic therapy, with a wide array of products designed to fill lines and folds and revolumize the face. METHODS: This review describes cosmetic fillers currently approved by the Food and Drug Administration and discusses new agents under investigation for use in the United States. RESULTS: Because of product refinements over the last few years-greater ease of use and longevity, the flexibility of multiple formulations within one line of products, and the ability to reverse poor clinical outcomes-practitioners have gravitated toward the use of biodegradable agents that stimulate neocollagenesis for sustained aesthetic improvements lasting up to a year or more with minimal side effects. Permanent implants provide long-lasting results but are associated with greater potential risk of complications and require the skilled hand of the experienced injector. CONCLUSIONS: A variety of biodegradable and nonbiodegradable filling agents are available or under investigation in the United States. Choice of product depends on injector preference and the area to be filled. Although permanent agents offer significant clinical benefits, modern biodegradable fillers are durable and often reversible in the event of adverse effects. PMID- 26441093 TI - Current Concepts in the Use of Small-Particle Hyaluronic Acid. AB - BACKGROUND: Soft-tissue augmentation with hyaluronic acid (HA) fillers has become one of the most popular cosmetic procedures performed. HA fillers represent safe and commonly used fillers. Several different HA fillers are available. The differences lie in the manufacturing process, allowing for tailored uses. A small particle HA with lidocaine (SP-HAL; Restylane Silk; Galderma, Uppsala, Sweden) was approved by the US Food and Drug Administration in June 2014 but has been available for many years in Canada as Restylane Fine Lines and in Europe as Restylane Vital. METHODS: Relevant articles were reviewed relating to the composition, effectiveness, and safety of SP-HAL. We also discuss the author's extensive clinical experience in the use of this product in Canada. RESULTS: SP HAL has demonstrated proven benefits for lip fullness, augmentation, and treatment of perioral rhytides. Although off-label in the United States, SP-HAL is also well suited for the treatment of superficial fine lines, including periorbital, forehead, marionette, and smile lines. In addition, it has also been used in the tear trough region. A novel application for SP-HAL includes use as a skinbooster with intradermal micropuncture. In this technique, small aliquots of product are injected so as to gradually rejuvenate the skin in areas such as the face and hands. Side effects of SP-HAL were generally transient and mild. The most common side effects were swelling, tenderness, bruising, pain, and redness. CONCLUSION: SP-HAL is an effective and safe HA filler with varied clinical uses. PMID- 26441094 TI - Current Concepts in the Use of Voluma, Volift, and Volbella. AB - BACKGROUND: Hyaluronic acids (HAs) are very popular temporary fillers with a very good safety record. Improvements and adaptations in clinical use are continuing. METHODS: We have assessed the available literature to investigate the relatively new Vycross technology that uses a mixture of high- and low-molecular-weight HAs with a relatively low but varying HA concentration with enhanced cross-linking to produce a number of products that have differing clinical indications. RESULTS: Voluma has the highest HA concentration at 20 mg/mL, a high G prime translating into lift capacity and cohesivity keeping the product capable to lift vertically adding structure, form, and volume, whereas Volbella has much lower concentration at 15 mg/mL, a lower G prime and cohesivity allowing it to be used in more a horizontal spreading fashion enabling a superficial approach to lips, lines, and more subtle depressions. Volift at 17.5 mg/mL HA is half way between the 2 other products, allowing more subtle lift capacity but retaining an element of spread making it a useful agent for the perioral region in general and in the treatment of fine lines. CONCLUSION: A range of products has been released that allows different components of facial structure, volume, and lines to be adequately addressed. PMID- 26441095 TI - Cohesive Polydensified Matrix Hyaluronic Acid for Fine Lines. AB - BACKGROUND: Fine lines and crepey skin are dermal manifestations of multilevel, age-related volume loss. It is, therefore, logical to combine intradermal volumetry for fine lines with subcutaneous volumetry for contours. This publication provides evidence- and experience-based rationales for application of cohesive polydensified matrix hyaluronic acid filler (Belotero Balance). METHODS: Evidence level II data demonstrate efficacy of this product and longevity for up to a year or more with intradermal, superficial blanch injection. Its softness, flow tendencies, and homogeneous tissue integration are informed by low elasticity (G') and viscosity, high cohesivity, and high tan delta. Ultrastructural analysis confirms variable-density cross-linking, intended to confer resilience, and absence of detectable particles, minimizing Tyndall effect. RESULTS: Scientific properties of Belotero Balance predict its 3 dimensional tissue expansion with prominent horizontal vectoring. We define this as superficial flow volumetry. High cohesivity and resilience can maintain structural integrity in typically mobile facial areas with strong muscular forces, uneven pressure, and significant hyaluronidase activity. This facilitates a natural appearance, both in repose and animation. CONCLUSIONS: Based on available evidence and experience, cohesive polydensified matrix hyaluronic acid is a notably efficacious fine line filler. The ideal fine line filler would restore dermis structurally and dynamicaly-moving as one with it, efficaciously expanding it, withstanding mechanical stress, swelling minimally, and potentially stimulating collagenesis. The relative contributions of space-filling, water binding, and collagenesis have implications for efficacy. A focus of current research is to determine the impact of filler cohesivity and tissue integration on these ideal qualities. PMID- 26441096 TI - Current Concepts in the Use of Bellafill. AB - As demonstrated by American Society of Plastic Surgeons statistics (2013), patients seeking nonsurgical facial rejuvenation are increasing. A variety of temporary and semipermanent soft-tissue fillers, such as hyaluronic acid, poly-L lactic acid, and calcium hydroxylapatite, are readily available; however, they have not been proven effective in treating facial acne scarring. Patient tolerance for the inconvenience and repeat cost of short-term, temporary fillers is waning as newer generation fillers with longer durations are coming on the market. Permanent injectable fillers, such a Bellafill (Suneva Medical Inc., San Diego, Calif.), represent a desirable solution for patients who want a long-term result. With the recent Food and Drug Administration approval for the treatment of moderate-to-severe, atrophic, distensible facial acne scars on the cheek(s) in patients over the age of 21 years, Bellafill (polymethylmethacrylate collagen) represents an effective solution for the treatment of facial acne scarring of the face while maintaining an excellent safety profile. PMID- 26441097 TI - Current Concepts in the Use of PLLA: Clinical Synergy Noted with Combined Use of Microfocused Ultrasound and Poly-L-Lactic Acid on the Face, Neck, and Decolletage. AB - BACKGROUND: Aging of the face, neck, and decolletage is a multifactorial process involving epidermal photodamage and loss of soft tissue and bony volume. Multilevel rejuvenation of these areas can be obtained by enhancing volume restoration, neocollagenesis, and tissue contraction with combined efficacy of poly-L-lactic acid (PLLA) and microfocused ultrasound (MFU, Ultherapy) treatments. METHODS: The authors reviewed the use of PLLA and MFUs as collaborative modalities to improve the appearance of the face, neck, and decolletage. RESULTS: Experienced cosmetic dermatology centers deliver PLLA and MFU in a single session to target multiple tissue planes. CONCLUSIONS: Concurrent treatment with PLLA and MFUs can be performed efficiently and safely; however, additional research is needed to explore the synergistic effects of these treatments. Patients may also benefit from decreased overall downtime and necessary office visits. PMID- 26441098 TI - Science of Hyaluronic Acid Beyond Filling: Fibroblasts and Their Response to the Extracellular Matrix. AB - Loss of viscoelasticity is one of the primarily signs of skin aging, followed by appearance of visible wrinkles. Hyaluronic acid (HA)-based fillers are widely used to fill wrinkles and compensate for volume loss. Recent clinical observations demonstrate persistence of the filling effect longer than the biological availability of the filler. Stimulation of new collagen by cross linked HA and up-regulation of elastin have been suggested as possible explanation to this observation and have been supported experimentally. Cross linked HA substitutes for fragmented collagen in restoring extracellular matrix required for normal activity of fibroblasts, such as collagen and elastin production. To restore extracellular matrix efficiently, serial monthly treatments are required. Boosting of facial and nonfacial skin through fibroblast activation is a new indication for HA-based products. Injectable HA has also been recently registered in Europe as agents specific for the improvement of skin quality (Restylane Skinboosters). Further explanation of the possible mechanisms supported by long-term clinical examples is presented herein. PMID- 26441099 TI - Understanding, Avoiding, and Managing Severe Filler Complications. AB - Any injectable filler may elicit moderate-to-severe adverse events, ranging from nodules to abscesses to vascular occlusion. Fortunately, severe adverse events are uncommon for the majority of fillers currently on the market. Because these are rare events, it is difficult to identify the relevant risk factors and to design the most efficacious treatment strategies. Poor aesthetic outcomes are far more common than severe adverse events. These in contrast should be easily avoidable by ensuring that colleagues receive proper training and follow best practices. PMID- 26441100 TI - The "Soft-Tissue Fillers and Neuromodulators: International and Multidisciplinary Perspectives" Supplement. PMID- 26441101 TI - Upper Face: Clinical Anatomy and Regional Approaches with Injectable Fillers. AB - BACKGROUND: The use of facial fillers has been rapidly increased as the range of injectable products and indications continues to expand. Complications may arise from improper placement or technique. This article highlights the importance of anatomic knowledge when using injectable fillers in the face. METHODS: A detailed review of the clinical anatomy of the upper face is performed. Regional approaches are described using the applied anatomy to efficiently and safely augment the different subunits of the upper face. RESULTS: Key aspects of safe and successful injection of fillers in the upper face include a thorough knowledge of the location of fat compartments and neurovascular structures. Awareness of these structures enables the practitioner to maximize injections, while avoiding damage to important nerves and vessels. CONCLUSION: A detailed knowledge of the anatomy and properties of the product is paramount to maximize the efficacy while minimizing the risk of complications. PMID- 26441103 TI - Ethnic and Gender Considerations in the Use of Facial Injectables: Asian Patients. AB - BACKGROUND: Asians have distinct facial characteristics due to underlying skeletal and morphological features that differ greatly with those of whites. This together with the higher sun protection factor and the differences in the quality of the skin and soft tissue create a profound effect on their aging process. Understanding of these differences and their effects in the aging process in Asians is crucial in determining effective utilization and placement of injectable products to ensure optimal aesthetic outcomes. METHODS: For younger Asian women, the main treatment goal is to address the inherent structural deficits through reshaping and the provision of facial support. Facial injectables are used to provide anterior projection, to reduce facial width, and to lengthen facial height. In the older group, the aim is for rejuvenation and also to address the underlying structural issues that has compounded due to age related volume loss. CONCLUSION: Asian women requesting cosmetic procedures do not want to be Westernized but rather seeking to enhance and optimize their Asian ethnic features. PMID- 26441102 TI - Midface: Clinical Anatomy and Regional Approaches with Injectable Fillers. AB - The clinical approach towards the midface is one of the most important interventions for practitioners when treating age-related changes of the face. Currently a plethora of procedures are used and presented. However, few of these approaches have been validated or passed review board assigned evaluations. Therefore, it is the aim of this work to establish a guideline manual for practitioners for a safe and effective mid-face treatment based on the most current concepts of facial anatomy. The latter is based on the 5-layered structural arrangement and its understanding is the key towards the favoured outcome and for minimizing complications. PMID- 26441104 TI - Lower Face: Clinical Anatomy and Regional Approaches with Injectable Fillers. AB - The use of injectable fillers enables facial sculpting through treatment of volume depletion and modeling of facial contours. Injectable fillers are among the most frequently performed minimally invasive cosmetic procedures.However, treatment of the lower third of the face can be challenging and requires expertise in facial anatomy. In this article, the authors provide a comprehensive review of the anatomy of the lower third of the face, highlighting danger zones. In addition, the authors describe their preferred approach and detailed technique used in the treatment of each specific area, namely the jawline, prejowl sulcus, melomental folds, and lips. PMID- 26441105 TI - Hand: Clinical Anatomy and Regional Approaches with Injectable Fillers. AB - BACKGROUND: Cosmetic physicians are more and more frequently asked for hand rejuvenation. They commonly propose the same techniques as for the face. The authors undertook an anatomical study of the hand dorsum to understand the optimal location for an injected filler and to design the safest technique of placement. METHODS: The first part of the study included dissections of 19 fresh cadaveric hands and duplex ultrasounds investigation of 28 healthy hands. A technique of injection specifically designed from anatomical findings was then tested on 8 fresh cadaveric hands using magnetic resonance imaging and dissection in comparison with 3 other commonly used techniques of rejuvenating injections. RESULTS: Between the dermis and the tendons, the thickness of the fascial plane was measured from 0.3 to 2.2 mm. Because of numerous fibrous septa, the entire plane was found as a 3-dimensional sponge-like framework. Veins could be located in all levels of this framework. There was no predefined free space. The optimal place for the deposition of a filler was found to be the undersurface of the dermis. The specific technique named Scrape Skin Threading Technique and using a cannula scraping the deep side of the dermis was checked as the only technique which could give a perfect placement of product restricted to the fascial layer. CONCLUSION: The Scrape Skin Threading Technique was designed to inject safely and accurately any kind of injectable in contact with the undersurface of the dermis, which appeared anatomically as the optimal location of a filler for enhancing the outer appearance of the dorsum of hands. PMID- 26441106 TI - Decolletage: Regional Approaches with Injectable Fillers. AB - BACKGROUND: Patients increasingly request rejuvenation of the aging and photodamaged decolletage. Rhytides in this area can be addressed with injectables such as poly-L-lactic acid and hyaluronic acid products and energy-based devices, such as fractionated ablative and nonablative lasers and microfocused ultrasound with visualization. METHODS: This article will review the anatomy of the chest wall as it pertains to injectables that can be utilized in this area and injection technique. A review of the literature and the authors' experience will be discussed. CONCLUSION: Cosmetic injectables can be utilized safely and effectively to improve the appearance of rhytides on the decolletage. PMID- 26441107 TI - Ethnic and Gender Considerations in the Use of Facial Injectables: African American Patients. AB - The United States is becoming increasingly more diverse as the nonwhite population continues to rise faster than ever. By 2044, the US Census Bureau projects that greater than 50% of the US population will be of nonwhite descent. Ethnic patients are the quickest growing portion of the cosmetic procedures market, with African-Americans comprising 7.1% of the 22% of ethnic minorities who received cosmetic procedures in the United States in 2014. The cosmetic concerns and natural features of this ethnic population are unique and guided by differing structural and aging processes than their white counterparts. As people of color increasingly seek nonsurgical cosmetic procedures, dermatologists and cosmetic surgeons must become aware that the Westernized look does not necessarily constitute beauty in these diverse people. The use of specialized aesthetic approaches and understanding of cultural and ethnic-specific features are warranted in the treatment of these patients. This article will review the key principles to consider when treating African-American patients, including the average facial structure of African-Americans, the impact of their ethnicity on aging and structure of face, and soft-tissue augmentation strategies specific to African-American skin. PMID- 26441108 TI - Ethnic and Gender Considerations in the Use of Facial Injectables: Latino Patients. AB - BACKGROUND: Globalization marks an important change in the world's perception of elective procedures: patients are becoming consumers and cosmetic procedures are being viewed as commodities. The quest to achieve and preserve a youthful appearance has no geographic boundaries or ethnic limitations. Cosmetic injectables have become an increasingly popular treatment option designed to improve and preserve facial appearance. Hispanic (Latino) patients are one of the rapidly increasing ethnic groups worldwide, seeking injectable treatments. METHODS: The author evaluated the trends in the use of injectables in his practice, mainly in Hispanic (Latino) patients, during one of the year's busiest seasons, specifically December 2014. RESULTS: The results reflect Latino patients' behavior toward injectables and how a high-volume injector addresses the needs of patients, taking into consideration ethnic characteristics and socioeconomic factors in balance with the provider plan for cosmetic improvement or facial restoration. CONCLUSIONS: The author's Latino-Hispanic patients have embraced the concept of "less invasive" facial rejuvenation, and in his experience, he has found that their goal is to achieve precise results in a natural manner. Ethnicity does not play a role in patients' behavior toward cosmetic procedures. This "behavior" tends to be related more to the socioeconomic status and/or the level of education, rather than ethnicity, which move the patient toward specific procedures. PMID- 26441109 TI - Ethnic and Gender Considerations in the Use of Facial Injectables: Male Patients. AB - The contemporary male look includes sharp contours of the face with strong nose, significant malar-midface structure, and a powerful chin with well-defined jawline. Neurotoxins in the upper facial lines should preserve a lower position of the brows and flatter arch in men. Excessive lifting of the eyebrows and full correction of forehead and periorbital lines are not desirable. The use of dermal fillers is fully accepted into the nasolabial. Male patients with sagginess and hollowness related or not related to acquired lipodystrophies are candidates for cheek correction with volumizers. Female attractiveness lies in the cheekbones, and for men, it lies in the chin. The use of volumizers in the chin is very much appreciated by male patients, especially when it is recessed. A strong and masculine appearance is obtained by creating a square chin. Men present slight thinner lips, especially the upper one. Lip reshape in male patients is very much rejected. It requires expertise both in communication and in technical skills to convince male patients to undergo lip treatments with fillers. The use of injectables in male patients is growing. Neurotoxins in the upper facial lines and the use of dermal fillers in the nasolabial folds are widely accepted. The use of volumizers in the chin is highly appreciated. There is clear need of volumizers in the cheek to correct sagginess and hollowness in men. However, proper communication and technique are required. The same applies for the lips. Cheek and lip reshape is still considered a taboo for most patients and injectors. PMID- 26441110 TI - Newer Understanding of Specific Anatomic Targets in the Aging Face as Applied to Injectables: Aging Changes in the Craniofacial Skeleton and Facial Ligaments. AB - Logical correction of aging contour changes of the face is based on understanding its structure and the processes involved in the aging appearance. Aging changes are seen at all tissue levels between the skin and bone although the relative contribution of each component to the overall change of facial appearance has yet to be satisfactorily determined. Significantly, the facial skeleton changes profoundly with aging as a consequence of significant resorption of the bones of dental origin in particular. The resultant loss of skeletal projection gives the visual impression of descent while the reduced ligamentous support leads to laxity of the overlying soft tissues. Understanding the specific changes of the face with aging is fundamental to achieving optimum correction and safe use of injectables for facial rejuvenation. PMID- 26441111 TI - Newer Understanding of Specific Anatomic Targets in the Aging Face as Applied to Injectables: Superficial and Deep Facial Fat Compartments--An Evolving Target for Site-Specific Facial Augmentation. AB - The identification of specific fat compartments of the face has greatly improved the plastic surgeon's approach to facial rejuvenation. These superficial and deep compartments are discretely partitioned into multiple independent units by fascial barriers and undergo age-dependant volumetric changes. This knowledge has created a topographical map allowing for the direct and precise augmentation of those compartments that are deflated preferentially. These include the deep medial cheek, nasolabial, superficial middle, and lateral cheek compartments. Once this volume loss has been addressed, the overlying superficial musculoaponeurotic system and skin envelope can be treated to address laxity and bridge the compartments, creating a smooth cheek contour. Facial augmentation can be performed alone in the correct patient; however, it most often complements face-lifting. It is, therefore, important to have a thorough understanding of this anatomy and the changes that occur during aging. PMID- 26441113 TI - Newer Understanding of Specific Anatomic Targets in the Aging Face as Applied to Injectables: Facial Muscles--Identifying Optimal Targets for Neuromodulators. AB - The muscular anatomy of the face is complex. Animation patterns of facial muscles vary significantly among individuals. Activity of facial muscles determines expression and emotion and affects the eyes aperture and the amount and extent of facial rhytids. Injection of botulin toxin for facial rejuvenation has become a very popular procedure and allows the practitioner the ability to modulate facial expression and to decrease the amount of facial rhytids. A thorough knowledge of the variant facial anatomy is necessary to maximize the efficiency of botulin toxin injection. This knowledge will also aid in minimizing complication an untoward side effect. PMID- 26441114 TI - Aesthetic Uses of Neuromodulators: Current Uses and Future Directions. AB - BACKGROUND: The introduction of neuromodulators for aesthetic facial improvements greatly expanded the limits of nonsurgical facial rejuvenation. Although many current uses are considered "off-label," the widespread acceptance and favorable safety profile of properly used botulinum toxins have made them one of the most common aesthetic treatments available. METHODS: A literature review of current facial aesthetic uses of various botulinum toxin preparations was done, and general concepts were identified. RESULTS: Currently, Food and Drug Administration-approved botulinum toxin preparations onabotulinumtoxinA (Botox), abobotulinumtoxinA (Dysport), and incobotulinumtoxinA (Xeomin) have similar off label indications and clinical uses. CONCLUSIONS: Although not considered interchangeable, administration and clinical outcomes are not much different between the 3 commonly used botulinum products. The impact of botulinum products currently in development has yet to be determined. PMID- 26441115 TI - Neurotoxins: Current Concepts in Cosmetic Use on the Face and Neck--Upper Face (Glabella, Forehead, and Crow's Feet). AB - There are 3 Food and Drug Administration-approved botulinum toxin formulations now being successfully used for treatment in the upper face. The most common areas for botulinum toxin treatment are the upper face, including the glabella, forehead, brows, and lateral canthal lines or crow's feet. The frozen look is no more desired in patients. Thus, physicians are more commonly individualizing dosage based on the patient's variation in anatomy, muscle mass, asymmetry, and, most importantly, desired outcome. PMID- 26441116 TI - Neurotoxins: Current Concepts in Cosmetic Use on the Face and Neck--Lower Face. AB - Botulinum toxin A was Food and Drug Administration approved in 2002 for the temporary correction of glabellar frown lines. Since that time, a variety of neuromodulators have established a convincing profile for both safety and efficacy in the treatment hyperdynamic rhytides of the upper face. With increasing clinical experience and expertise, these applications have been expanded to include targeted treatment of muscles in both the mid and lower face. This article details common techniques using botulinum toxin to treat orbicularis oris, depressor anguli oris, mentalis, and masseter muscles for the temporary correction of unwanted lower face hyperdynamic rhytides and facial contouring. Although we detail our suggested quantity of units per injection site based on onabotulinumtoxinA, all neuromodulators can be used in all of these suggested treatment areas with adjustment of the quantity of units based on the efficacy of the specific neuromodulator. A more compete discussion on the relative efficacy of all neuromodulators is beyond the scope of this article. PMID- 26441117 TI - Neurotoxins: Current Concepts in Cosmetic Use on the Face and Neck--Jawline Contouring/Platysma Bands/Necklace Lines. AB - The platysma muscle acts as a major depressor in the lower face with subsequent inaesthetic implications. Botulinum toxin-A can be very useful to reverse some of these and this chapter describes how to (1) sharpen the jawline with the Nefertiti Lift, (2) treat anterior neck bands, and (3) soften necklace lines. PMID- 26441118 TI - Anatomy of the Lower Face and Botulinum Toxin Injections. AB - The use of botulinum toxin in the lower face is more complex and less reliable than its use in the upper face. Use in the lower face is also fraught with more adverse events. The anatomy of the lower face is complex, as the muscles of this region are very close together and interface at different levels and depths to perform heterogeneous functions, such as talking, eating, drinking, and expressivity of the face. This article, based on the anatomical knowledge of each muscle of the lower face, provides recommendations and guidelines to perform botulinum toxin injection safely. The review of each muscle with its relevant anatomy and relationship of this three-dimensional anatomy with the cutaneous plane gives the exact position of injectable locations. For each muscle, the number of points related to the motor end plate location and the exact dose related to the muscular mass are indicated. Summary tables are provided. PMID- 26441119 TI - Microbotox of the Lower Face and Neck: Evolution of a Personal Technique and Its Clinical Effects. AB - Microbotox is the injection of multiple microdroplets of diluted onabotulinumtoxinA into the dermis or the interface between the dermis and the superficial layer of facial muscles. The intention is to decrease sweat and sebaceous gland activity to improve skin texture and sheen and to target the superficial layer of muscles that find attachment to the undersurface of the dermis causing visible rhytides. For treatment of the lower face and neck, hundreds of microdroplets of diluted Botox are injected into the dermis or immediate subdermal plane to improve skin texture, smoothen horizontal creases, and decrease vertical banding of the neck, as well as to achieve better apposition of the platysma to the jawline and neck, improving contouring of the cervicomental angle. The Microbotox solution is mixed in the syringe by adding a small volume of lidocaine to the calculated dose of onabotulinumtoxinA drawn from a standard bottle of Botox prepared with 2.5 mL saline. Each 1 mL syringe of Microbotox solution contains 20-28 units of onabotulinumtoxinA per mL of solution and is used to deliver 100-120 injections. The lower face and neck will usually require 1 mL per side. The injections are delivered intradermally using a 30- or 32-G needle raising a tiny blanched weal at each point. The author has over 1867 documented cases of Microbotox in various parts of the face (forehead, glabellar, crow's-feet, infraorbital, and cheeks) and neck, the majority of these patients being treated in forehead or the lower face and neck as described in this article. PMID- 26441120 TI - Introduction to "Soft-Tissue Fillers and Neuromodulators: International and Multidisciplinary Perspectives". PMID- 26441121 TI - In vitro screening of natural feed additives from crustaceans, diatoms, seaweeds and plant extracts to manipulate rumen fermentation. AB - BACKGROUND: Eight natural products from animal, unicellular algae, brown seaweed and plant origins were chosen according to their theoretical antimicrobial activity: Diatomaceous earths (DE), insoluble chitosan (ICHI), soluble chitosan (CHI), seaweed meal (SWM), Ascophyllum nodosum (ASC), Laminaria digitata (LAM), neem oil (NOIL) and an ivy fruit extract rich in saponins (IVY). Dose-response incubations were conducted to determine their effect on rumen fermentation pattern and gas production, while their anti-protozoal activity was tested using (14) C-labelled bacteria. RESULTS: DE, SWM, NOIL and ICHI had very small effects on rumen function when used at inclusion rate up to 2 g L(-1) . ASC had anti protozoal effects (up to -23%) promoting a decrease in gas production and methanogenesis (-15%). LAM increased VFA production (+7%) and shifted from butyrate to acetate. CHI also shifted fermentation towards propionate production and lower methane (-23%) and protozoal activity (-56%). IVY decreased protozoal activity (-39%) and ammonia concentration (-56%), as well as increased feed fermentation (+11% VFA concentration) and shifted from acetate to propionate production. CONCLUSIONS: ASC, LAM, CHI and IVY showed promising potential in vitro as feed additives to improve rumen function, thus more research is needed to investigate their mode of action in the rumen microbial ecosystem. (c) 2015 Society of Chemical Industry. PMID- 26441122 TI - Genotoxicity of commercial fungicide Cabrio Plus on human cell. AB - Cabrio Plus, a commercial fungicide, is used in agriculture as the control agent for a broad spectrum of diseases including black dot, early blight, late blight and powdery mildew. This study aimed to evaluate the genotoxicity of commercial formulation of Cabrio Plus which has been inadequately evaluated. The genotoxic potential of Cabrio Plus in isolated human peripheral blood lymphocytes was measured by means of an alkaline version of the comet assay (pH > 13) and in whole blood by use of the in vitro micronucleus test. Cabrio Plus induced a statistically significant increase in DNA damage assessed with the in vitro micronucleus assay and the comet assay. Cabrio Plus also induced cytotoxicity in a dose-dependent manner with the in vitro micronucleus assay. It can be concluded that a commercially available pesticide formulation, Cabrio Plus, has the ability to cause DNA damage and cytotoxicity. PMID- 26441123 TI - Guided bone regeneration using resorbable membrane and different bone substitutes: Early histological and molecular events. AB - Bone insufficiency remains a major challenge for bone-anchored implants. The combination of guided bone regeneration (GBR) and bone augmentation is an established procedure to restore the bone. However, a proper understanding of the interactions between the bone substitute and GBR membrane materials and the bone healing environment is lacking. This study aimed to investigate the early events of bone healing and the cellular activities in response to a combination of GBR membrane and different calcium phosphate (CaP) materials. Defects were created in the trabecular region of rat femurs, and filled with deproteinized bovine bone (DBB), hydroxyapatite (HA) or strontium-doped HA (SrHA) or left empty (sham). All the defects were covered with an extracellular matrix membrane. Defects were harvested after 12h, 3d and 6d for histology/histomorphometry, immunohistochemistry and gene expression analyses. Histology revealed new bone, at 6d, in all the defects. Larger amount of bone was observed in the SrHA-filled defect. This was in parallel with the reduced expression of osteoclastic genes (CR and CatK) and the osteoblast-osteoclast coupling gene (RANKL) in the SrHA defects. Immunohistochemistry indicated fewer osteoclasts in the SrHA defects. The observations of CD68 and periostin-expressing cells in the membrane per se indicated that the membrane may contribute to the healing process in the defect. It is concluded that the bone-promoting effects of Sr in vivo are mediated by a reduction in catabolic and osteoblast-osteoclast coupling processes. The combination of a bioactive membrane and CaP bone substitute material doped with Sr may produce early synergistic effects during GBR. STATEMENT OF SIGNIFICANCE: The study provides novel molecular, cellular and structural evidence on the promotion of early bone regeneration in response to synthetic strontium containing hydroxyapatite (SrHA) substitute, in combination with a resorbable, guided bone regeneration (GBR) membrane. The prevailing view, based mainly upon in vitro data, is that the beneficial effects of Sr are exerted by the stimulation of bone-forming cells (osteoblasts) and the inhibition of bone resorbing cells (osteoclasts). In contrast, the present study demonstrates that the local effect of Sr in vivo is predominantly via the inhibition of osteoclast number and activity and the reduction of osteoblast-osteoclast coupling. This experimental data will form the basis for clinical studies, using this material as an interesting bone substitute for guided bone regeneration. PMID- 26441124 TI - Surface nitridation improves bone cell response to melt-derived bioactive silicate/borosilicate glass composite scaffolds. AB - Novel bioactive amorphous glass-glass composite scaffolds (ICIE16/BSG) with interconnected porosity have been developed. Hierarchically interconnected porous glass scaffolds were prepared from a mixture of two melt-derived glasses: a ICIE16 bioactive glass that was previously developed by Wu et al. (2011) to prevent crystallization, and a borosilicate glass of composition 73.48 SiO2-11.35 B2O3-15.15 Na2O (wt%). The resulting melt derived glass-glass composite scaffolds (ICIE16/BSG) were subject to surface functionalization to further improve its interaction with biological systems. Surface functionalization was performed by a nitridation process with hot gas N2/ammonia at 550 degrees C for 2h, obtaining the ICIE16/BSG-NITRI. Evaluation of the degradation rate and the conversion to hydroxyapatite after immersion in simulated body fluid predicted a good biological activity of all the scaffolds, but particularly of the nitrided ones. In vitro evaluation of osteoblastic cells cultured onto the nitrided and non nitrided scaffolds showed cell attachment, proliferation and differentiation on all scaffolds, but both proliferation and differentiation were improved in the nitrided ICIE16/BSG-NITRI. STATEMENT OF SIGNIFICANCE: Biomaterials are often required in the clinic to stimulate bone repair. We have developed a novel bioglass (ICIE16/SBG-NITRI) that can be sintered into highly porous 3D scaffolds, and we have further improved its bioactivity by nitridation. ICIE16/SBG-NITRI was synthesized from a mixture of two melt-derived glasses through combined gel casting and foam replication techniques, followed by nitridation. To mimic bone, it presents high-interconnected porosity while being mechanically stable. Nitridation improved its reactivity and bioactivity facilitating its resorption and the deposition of apatite (bone-like mineral) on its surface and increasing its degradation rate. The nitrided surface also improved the bioglass' interaction with bone cells, which were found to attach better to ICIE16/SBG NITRI and to differentiate earlier on its surface. PMID- 26441125 TI - A materials perspective of Martyniaceae fruits: Exploring structural and micromechanical properties. AB - Several species of the plant family Martyniaceae are characterised by unique lignified capsules with hook-shaped extensions that interlock with hooves and ankles of large mammals to disperse the seeds. The arrangement of fruit endocarp fibre tissues is exceptional and intriguing among plants. Structure-function relationships of these slender, curved, but mechanically highly stressed fruit extensions are of particular interest that may inspire advanced biomimetic composite materials. In the present study, we analyse mechanical properties and fracture behaviour of the hook-shaped fruit extensions under different load conditions. The results are correlated with calculated stress distributions, the specific cell wall structure, and chemical composition, providing a detailed interpretation of the complex fruit tissue microstructure. At the cell wall level, both a large microfibril angle and greater strain rates resulted in Young's moduli of 4-9 GPa, leading to structural plasticity. Longitudinally arranged fibre bundles contribute to a great tensile strength. At the tissue level, transversely oriented fibres absorb radial stresses upon bending, whereas cells encompass and pervade longitudinal fibre bundles, thus, stabilise them against buckling. During bending and torsion, microcracks between axial fibre bundles are probably spanned analogous to a circular anchor. Our study fathoms a highly specialized plant structure, substantiating former assumptions about epizoochory as dispersal mode. While the increased flexibility allows for proper attachment of fruits during dynamical locomotion, the high strength and stability prevent a premature failure due to heavy loads exerted by the animal. PMID- 26441126 TI - The proangiogenic potential of a novel calcium releasing biomaterial: Impact on cell recruitment. AB - In current bone tissue engineering strategies the achievement of sufficient angiogenesis during tissue regeneration is still a major limitation in order to attain full functionality. Several strategies have been described to tackle this problem, mainly by the use of angiogenic factors or endothelial progenitor cells. However, when facing a clinical scenario these approaches are inherently complex and present a high cost. As such, more cost effective alternatives are awaited. Here, we demonstrate the potential of electrospun poly(lactic acid) (PLA) fiber based membranes, containing calcium phosphate ormoglass (CaP) particles, to elicit angiogenesis in vivo, in a subcutaneous model in mice. We show that the current approach elicited the local expression of angiogenic factors, associated to a chemotactic effect on macrophages, and sustained angiogenesis into the biomaterial. As both PLA and CaP are currently accepted for clinical application these off-the-shelf novel membranes have great potential for guided bone regeneration applications. STATEMENT OF SIGNIFICANCE: In current bone tissue engineering approaches the achievement of sufficient angiogenesis, during tissue regeneration, is a major limitation in order to attain full tissue functionality. Recently, our group has found that calcium ions released by the degradation of calcium phosphate ormoglasses (CaP) are effective angiogenic promoters. Based on this, in this work we successfully produced hybrid fibrous mats with different contents of CaP nanoparticles and thus with different calcium ion release rates, using an ormoglass - poly(lactic acid) blend approach. We show that these matrices, upon implantation in a subcutaneous site, could elicit the local expression of angiogenic factors, associated to a chemotactic effect on macrophages, and sustained angiogenesis into the biomaterial, in a CaP dose dependent manner. This off-the-shelf cost effective approach presents great potential to translate to the clinics. PMID- 26441127 TI - A glial cell line-derived neurotrophic factor delivery system enhances nerve regeneration across acellular nerve allografts. AB - Acellular nerve allografts (ANAs) are used clinically to bridge nerve gaps but these grafts, lacking Schwann cells and therapeutic levels of neurotrophic factors, do not support regeneration to the same extent as autografts. Here we investigated a local drug delivery system (DDS) for glial cell line-derived neurotrophic factor (GDNF) controlled release to implanted ANAs in rats using drug-loaded polymeric microspheres (MSs) embedded in a fibrin gel. In a rat hindlimb nerve gap model, a 10mm ANA was used to bridge a 5mm common peroneal (CP) nerve gap. Experimental groups received DDS treatment at both suture sites of the allografts releasing GDNF for either 2 weeks or 4 weeks. In negative control groups, rats received no DDS treatment or empty DDS. Rats receiving nerve isografts served as the positive control group. The numbers of motor and sensory neurons that regenerated their axons in all the groups with GDNF MS and isograft treatment were indistinguishable and significantly higher as compared to the negative control groups. Nerve histology distal to the nerve graft demonstrated increased axon counts and a shift to larger fiber diameters due to GDNF MS treatment. The sustained delivery of GDNF to the implanted ANA achieved in this study demonstrates the promise of this DDS for the management of severe nerve injuries in which allografts are placed. STATEMENT OF SIGNIFICANCE: This work addresses the common clinical situation in which a nerve gap is bridged using acellular nerve allografts. However, these allografts are not as effective in supporting nerve regeneration as the gold standard method of autografting. The novel local drug delivery system used in this study provides sustained and controlled release of glial cell line-derived neurotrophic factor (GDNF), one of the most potent neurotrophic factors, which significantly improves nerve regeneration following severe nerve injuries. Results from this research will provide a mean of improving nerve allografts with locally delivered GDNF. This strategy may lead to a novel "off the shelf" alternative to the current management of severe nerve injuries. PMID- 26441128 TI - Phage as versatile nanoink for printing 3-D cell-laden scaffolds. AB - Bioprinting is an emerging technology for producing tissue-mimetic 3-D structures using cell-containing hydrogels (bioink). Various synthetic and natural hydrogels with key characteristics, including biocompatibility, biodegradability, printability and crosslinkability, have been employed as ink materials in bioprinting. Choosing the right cell-containing "bioink" material is the most essential step for fabricating 3-D constructs with a controlled mechanical and biochemical microenvironment that can lead to successful tissue regeneration and repair. Here, we demonstrate that the genetically engineered M13 phage holds great potential for use as a versatile nanoink for printing 3-D cell-laden matrices. In particular, M13 phages displaying integrin-binding (GRGDS) and calcium-binding (DDYD) domains on their surface were blended with alginate to successfully form Ca(2+)-crosslinked hydrogels. Furthermore, 3-D cell-laden scaffolds with high cell viability were generated after optimizing the printing process. The MC3T3-E1 cells within these scaffolds showed enhanced proliferation and differentiation rates that increased proportionally with the concentration of phages in the 3-D matrices compared with the rates of cells in pure alginate scaffolds. STATEMENT OF SIGNIFICANCE: Bioprinting is an emerging technology for producing tissue-mimetic 3-D structures using cell-containing hydrogels called bioink. Choosing the right bioink is essential for fabricating 3-D structures with controlled mechanical and biochemical properties which lead to successful tissue regeneration. Therefore, there is a growing demand for a new bioink material that can be designed from molecular level. Here, we demonstrate that genetically engineered M13 phage holds great potential for use as versatile bioink. The phage-based bioink benefits from its replicability, self-assembling property, and tunable molecular design and enables bioprinted scaffolds to exhibit improved cell viability, proliferation and differentiation. This study opens the door for the development of genetically tunable nanofibrous bioink materials which closely mimic natural structural proteins in the extracellular matrix. PMID- 26441129 TI - Osteogenic differentiation and bone regeneration of iPSC-MSCs supported by a biomimetic nanofibrous scaffold. AB - Induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) are a new type of MSCs that come with attractive merits over the iPSCs per se. Aimed for regenerating bone tissues, this study was designed to investigate osteogenic differentiation and bone regeneration capacities of iPSC-MSCs by using biomimetic nanofibers of hydroxyapatite/collagen/chitosan (HAp/Col/CTS). Murine iPSCs were firstly induced to differentiate into iPSC-MSCs and thoroughly characterized. Effects of HAp/Col/CTS nanofibers prepared from electrospinning of Col-doped HAp/CTS nanocomposite, on osteogenic differentiation of the generated iPSC-MSCs were then evaluated in detail, including cell morphology, proliferation, migration, quantified specific osteogenic gene and protein expressions. Compared with different controls (TCP, CTS, and HAp/CTS), the HAp/Col/CTS scaffold was found to have more favorable effects on attachment and proliferation of iPSC-MSCs than others (P<0.01). Expressions of osteogenic genes, Runx2, Ocn, Alp, and Col, were significantly upregulated in iPSC-MSCs cultured on HAp/Col/CTS than CTS (P<0.01). Similarly, there appeared considerably higher secreting activities of osteogenesis protein markers, ALP and Col. Furthermore, mouse cranial defects were created to investigate efficacy of using iPSC-MSCs in combination with HAp/Col/CTS scaffold for regenerative bone repair in vivo. Examinations by computed tomography (CT) imaging, bone mineral density and hematoxylin eosin (HE) staining corroborated that cell-scaffold construct of iPSC-MSCs+HAp/Col/CTS could effectively promote bone regeneration. After 6 weeks of implantation, bone mineral density of the iPSC-MSCs+HAp/Col/CTS group was found to be nearly 2-fold higher than others. Our results demonstrated that biomimetic nanofibers of HAp/Col/CTS promoted the osteogenic differentiation and bone regeneration of iPSC MSCs. The iPSC-MSCs+HAp/Col/CTS complex could be used as a new 'stem cell scaffold' system for realizing personalized and efficacious bone regeneration in future. STATEMENT OF SIGNIFICANCE: In bone tissue engineering, stem cells have become the most important source of seed cells. iPSC-MSCs are a new type of MSCs that come with attractive merits over the iPSCs per se. However, how to obtain befitting iPSC-MSCs and regulate their osteogenic differentiation are the key issues to be addressed. Given the great biomimicking capacity to extracellular matrix, electrospun nanofibers may be explored to modulate osteogenic differentiation of the iPSC-MSCs. This study successfully demonstrated that biomimetic nanofibers of HAp/Col/CTS significantly promoted the osteogenic differentiation and bone regeneration of iPSC-MSCs, which thereby suggests that nanofibrous scaffold supported iPSC-MSCs complex may be a new 'stem cell scaffold' system for regulating the fate of osteogenic differentiation of iPSC MSCs towards patient-specific bone regeneration in future. PMID- 26441130 TI - Comparative study of impact of hemodialysis and renal transplantation on cognitive functions in ESRD patients. AB - Cognitive impairment is defined as a newly appeared deficit in at least two areas of cognitive functions, including disturbances in memory, executive functioning, attention or speed of information processing, perceptual motor abilities, or language. Cognitive impairment is highly prevalent in ESRD patients when compared with the general population. It has also been associated with a decreased quality of life. Cognitive functions in patients with ESRD showed improvement with dialysis and renal transplantation. These findings illustrate the potential importance of evaluating and comparing the effects of hemodialysis and transplantation regarding cognitive performance and thus quality of life in ESRD patients and normal subjects. This study was carried out in 100 patients (50 ESRD patients on regular hemodialysis for at least 6 months and 50 post-transplant patients who had maintained successful kidney graft for at least 3 months). All patients underwent laboratory and psychometric scoring tests, including trail making test part A, trail making test part B, digit span, and mini-mental state examination. Thirty healthy adults matched by age and sex served as a control group. The results showed significant differences in cognitive function tests results between transplant and hemodialysis patients (P<0.01), suggesting that transplant patients were superior in their cognitive performance, with the correction of anemia being the most important factor for improving cognitive performance in both groups. There were no significant differences between transplant patients and control subjects in psychometric measures (P>0.05). CONCLUSION: Renal transplantation as a modality of treatment, in ESRD patients, is superior to hemodialysis in terms of cognitive performance improvement. PMID- 26441131 TI - Low Levels of Dehydroepiandrosterone Sulfate in Younger Burnout Patients. AB - OBJECTIVE: Dehydroepiandrosterone sulphate (DHEA-s) is an anabolic protective hormone of importance for maintenance of health. DHEA-s levels peak in young adults and decline thereafter with age. DHEA-s has previously been shown to be lower in individuals reporting prolonged stress. This study investigates DHEA-s levels in patients with clinical burnout, a disorder caused by long-term psychosocial stress. METHODS: 122 patients (51% men) and 47 controls (51% men) in the age 25-54 years were included in the study. DHEA-s levels were compared between patients and controls in the whole sample and within each of the three 10 year-interval age groups. RESULTS: In the youngest age group (25-34 years), DHEA s levels were on average 25% lower in the patients (p = 0.006). The differences in DHEA-s levels between patients and controls were more pronounced among female than male participants (on average 32% and 13% lower, respectively). There were no differences in DHEA-s levels between patients and controls in the age group 35 44 years (p = 0.927) or 45-54 years (p = 0.897) or when analyzing all age groups together (p = 0.187). CONCLUSION: The study indicates that levels of the health promoting "youth" hormone DHEA-s are low in younger burnout patients. The fact that younger adults have much higher DHEA-s levels and more pronounced inter subject variability in DHEA-s levels than older individuals might explain why burnout status differentiates patients from controls only among the youngest patients included in this study. PMID- 26441132 TI - Efficient Chemical Modification of Carbon Nanotubes with Metallacarboranes. AB - As-produced single-walled carbon nanotubes (SWCNTs) tend to aggregate in bundles due to pi-pi interactions. Several approaches are nowadays available to debundle, at least partially, the nanotubes through surface modification by both covalent and noncovalent approaches. Herein, we explore different strategies to afford an efficient covalent functionalization of SWCNTs with cobaltabisdicarbollide anions. Aberration-corrected HRTEM analysis reveals the presence of metallacarboranes along the walls of the SWCNTs. This new family of materials presents an outstanding water dispersibility that facilitates its processability for potential applications. PMID- 26441133 TI - Successful application of the DBLOC method to the hydroxylation of camphor by cytochrome p450. AB - The activation barrier for the hydroxylation of camphor by cytochrome P450 was computed using a mixed quantum mechanics/molecular mechanics (QM/MM) model of the full protein-ligand system and a fully QM calculation using a cluster model of the active site at the B3LYP/LACVP*/LACV3P** level of theory, which consisted of B3LYP/LACV3P** single point energies computed at B3LYP/LACVP* optimized geometries. From the QM/MM calculation, a barrier height of 17.5 kcal/mol was obtained, while the experimental value was known to be less than or equal to 10 kcal/mol. This process was repeated using the D3 correction for hybrid DFT in order to investigate whether the inadequate treatment of dispersion interaction was responsible for the overestimation of the barrier. While the D3 correction does reduce the computed barrier to 13.3 kcal/mol, it was still in disagreement with experiment. After application of a series of transition metal optimized localized orbital corrections (DBLOC) and without any refitting of parameters, the barrier was further reduced to 10.0 kcal/mol, which was consistent with the experimental results. The DBLOC method to C?H bond activation in methane monooxygenase (MMO) was also applied, as a second, independent test. The barrier in MMO was known, by experiment, to be 15.4 kcal/mol. After application of the DBLOC corrections to the MMO barrier compute by B3LYP, in a previous study, and accounting for dispersion with Grimme's D3 method, the unsigned deviation from experiment was improved from 3.2 to 2.3 kcal/mol. These results suggested that the combination of dispersion plus localized orbital corrections could yield significant quantitative improvements in modeling the catalytic chemistry of transition-metal containing enzymes, within the limitations of the statistical errors of the model, which appear to be on the order of approximately 2 kcal/mole. PMID- 26441134 TI - Differential effects of stress on microglial cell activation in male and female medial prefrontal cortex. AB - Susceptibility to stress-linked psychological disorders, including post-traumatic stress disorder and depression, differs between men and women. Dysfunction of medial prefrontal cortex (mPFC) has been implicated in many of these disorders. Chronic stress affects mPFC in a sex-dependent manner, differentially remodeling dendritic morphology and disrupting prefrontally mediated behaviors in males and females. Chronic restraint stress induces microglial activation, reflected in altered microglial morphology and immune factor expression, in mPFC in male rats. Unstressed females exhibit increased microglial ramification in several brain regions compared to males, suggesting both heightened basal activation and a potential for sex-dependent effects of stress on microglial activation. Therefore, we assessed microglial density and ramification in the prelimbic region of mPFC, and immune-associated genes in dorsal mPFC in male and female rats following acute or chronic restraint stress. Control rats were left unstressed. On the final day of restraint, brains were collected for either qPCR or visualization of microglia using Iba-1 immunohistochemistry. Microglia in mPFC were classified as ramified, primed, reactive, or amoeboid, and counted stereologically. Expression of microglia-associated genes (MHCII, CD40, IL6, CX3CL1, and CX3CR1) was also assessed using qPCR. Unstressed females showed a greater proportion of primed to ramified microglia relative to males, alongside heightened CX3CL1-CX3CR1 expression. Acute and chronic restraint stress reduced the proportion of primed to ramified microglia and microglial CD40 expression in females, but did not significantly alter microglial activation in males. This sex difference in microglial activation could contribute to the differential effects of stress on mPFC structure and function in males versus females. PMID- 26441135 TI - Towards a blood-based diagnostic panel for bipolar disorder. AB - BACKGROUND: Bipolar disorder (BD) is a costly, devastating and life shortening mental disorder that is often misdiagnosed, especially on initial presentation. Misdiagnosis frequently results in ineffective treatment. We investigated the utility of a biomarker panel as a diagnostic test for BD. METHODS AND FINDINGS: We performed a meta-analysis of eight case-control studies to define a diagnostic biomarker panel for BD. After validating the panel on established BD patients, we applied it to undiagnosed BD patients. We analysed 249 BD, 122 pre-diagnostic BD, 75 pre-diagnostic schizophrenia and 90 first onset major depression disorder (MDD) patients and 371 controls. The biomarker panel was identified using ten fold cross-validation with lasso regression applied to the 87 analytes available across the meta-analysis studies. We identified 20 protein analytes with excellent predictive performance [area under the curve (AUC)?0.90]. Importantly, the panel had a good predictive performance (AUC 0.84) to differentiate 12 misdiagnosed BD patients from 90 first onset MDD patients, and a fair to good predictive performance (AUC 0.79) to differentiate between 110 pre-diagnostic BD patients and 184 controls. We also demonstrated the disease specificity of the panel. CONCLUSIONS: An early and accurate diagnosis has the potential to delay or even prevent the onset of BD. This study demonstrates the potential utility of a biomarker panel as a diagnostic test for BD. PMID- 26441137 TI - Proximity Driven Commensurate Pinning in YBa2Cu3O7 through All-Oxide Magnetic Nanostructures. AB - The design of artificial vortex pinning landscapes is a major goal toward large scale applications of cuprate superconductors. Although disordered nanometric inclusions have shown to modify their vortex phase diagram and to produce enhancements of the critical current ( MacManus-Driscoll , J. L. ; Foltyn , S. R. ; Jia , Q. X. ; Wang , H. ; Serquis , A. ; Civale , L. ; Maiorov , B. ; Hawley , M. E. ; Maley , M. P. ; Peterson , D. E. Nat. Mater. 2004 , 3 , 439 - 443 and Yamada , Y. ; Takahashi , K. ; Kobayashi , H. ; Konishi , M. ; Watanabe , T. ; Ibi , A. ; Muroga , T. ; Miyata , S. ; Kato , T. ; Hirayama , T. ; Shiohara , Y. Appl. Phys. Lett. 2005 , 87 , 1 - 3 ), the effect of ordered oxide nanostructures remains essentially unexplored. This is due to the very small nanostructure size imposed by the short coherence length, and to the technological difficulties in the nanofabrication process. Yet, the novel phenomena occurring at oxide interfaces open a wide spectrum of technological opportunities to interplay with the superconductivity in cuprates. Here, we show that the unusual long-range suppression of the superconductivity occurring at the interface between manganites and cuprates affects vortex nucleation and provides a novel vortex pinning mechanism. In particular, we show evidence of commensurate pinning in YBCO films with ordered arrays of LCMO ferromagnetic nanodots. Vortex pinning results from the proximity induced reduction of the condensation energy at the vicinity of the magnetic nanodots, and yields an enhanced friction between the nanodot array and the moving vortex lattice in the liquid phase. This result shows that all-oxide ordered nanostructures constitute a powerful, new route for the artificial manipulation of vortex matter in cuprates. PMID- 26441138 TI - Covalent functionalization of N-doped graphene by N-alkylation. AB - Nitrogen doped graphene was modified by N-alkylation using a combination of phase transfer catalysis and microwave irradiation. The resulting derivatives of N doped graphene were analysed showing that the bandgap of the material varied depending on the alkylation agent used. PMID- 26441136 TI - Assessing blood granulocyte colony-stimulating factor as a potential biomarker of acute traumatic brain injury in mice and humans. AB - Previous work has found that serum G-CSF was acutely elevated in mice 24h but not one week after controlled cortical impact (CCI). The purpose of this study was to investigate whether blood G-CSF correlates with the elevated brain cytokines in mice after CCI and also if it correlates with traumatic brain injury (TBI) in humans. Here, we found in mice undergoing CCI, a procedure that induces direct injury to the brain, that serum G-CSF correlated directly or indirectly with several brain cytokines, indicating it is a useful marker for the neuroinflammation of TBI. A pilot study in humans (phase I, n=19) confirmed that plasma G-CSF is acutely elevated on day 1 (p<0.001) of TBI and has returned to baseline by one week. In a second human sample (phase II) (n=80), we found plasma G-CSF peaks about 12h after arriving in the emergency department (41.6+/-5.4 pg/ml). Aging was weakly associated (p<0.05) with a less robust elevation in serum G-CSF, but there was no difference with gender. ISS, a measure of total severity of injury, correlated with the degree of elevation in serum G-CSF (r=.419; p<0.05), but severity of head injury (via AIS) did not. The latter may have been because of the statistically narrow range of head injuries among our cases and the high number of cases diagnosed with closed head injury (a non codable diagnosis). In conclusion, plasma G-CSF may be a useful biomarker of TBI, correlating with neuroinflammation in the animal model and in the human studies with time since injury and total severity of injury. As such, it may be useful in determining whether TBI has occurred within the last 24h. PMID- 26441139 TI - Monitoring the use of anatomical teaching material using a low-cost radio frequency identification system: A comprehensive assessment. AB - The correct tracking and monitoring of anatomical specimens is not only imperative in any modern body donation programs but also in any universities for which teaching the next generation of health care professionals is the primary mission. This has long been an arduous process for anatomy institutions across the world, and the recent focus of new curricula on self-directed learning adds new stress on specimens which are used by students. The radio frequency identification (RFID) technology has been proposed as a very effective tracking system in healthcare considering that it enables automatic identification and data capture of multiple items at once. In this study, the feasibility of a low cost RFID inventory system is assessed, from its design to the performance of commercially available RFID tags in a gross anatomy laboratory. The results show that ultrahigh frequency-based RFID tags successfully performed when attached to a collection of 112 plastinated and 280 wet dissected specimens. Comparison analysis of different tags reveals, however, that careful selection of RFID tags needs to be considered when wet specimens need to be tracked as preservation fluids can absorb radio waves energy. This study demonstrates that it is economically feasible to incorporate RFID technology to closely monitor the use of anatomical teaching specimens. The described RFID inventory system was not only able to preserve the integrity of the specimens being used by limiting handling and therefore human error but was also able to identify missing or misplaced specimens and to update their status. PMID- 26441140 TI - Bladder Regeneration Using a Smart Acellular Collagen Scaffold with Growth Factors VEGF, FGF2 and HB-EGF. AB - Tissue engineering may become an alternative to current bladder augmentation techniques. Large scaffolds are needed for clinically significant augmentation, but can result in fibrosis and graft shrinkage. The purpose of this study was to investigate whether smart acellular collagen-heparin scaffolds with growth factors (GFs) VEGF, FGF2, and HB-EGF enhance bladder tissue regeneration and bladder capacity in a large animal model of diseased bladder. Scaffolds of bovine type I collagen with heparin and VEGF, FGF2, and HB-EGF measuring 3.2 cm in diameter were prepared. In 23 fetal sheep, a bladder exstrophy was surgically created at 79 days of gestation. One week after birth (at full term), the bladder was reconstructed by primary closure (PC group) or using a collagen-heparin scaffold with GFs (COLGF group) and compared to a historical group reconstructed with a collagen scaffold without GFs (COL group). Functional (video urodynamics) and histological evaluation was performed 1 and 6 months after bladder repair. The overall survival rate was 57%. Cystograms were normal in all animals, except for low-grade reflux in all groups. Urodynamics showed no statistically significant differences in bladder capacity and compliance between groups. Histological evaluation at 1 month revealed increased urothelium formation, improved angiogenesis, and enhanced ingrowth of smooth muscle cells (SMCs) in the COLGF group compared to the COL group. At 6 months, improved SMC ingrowth was found in the COLGF group compared to the COL group; both scaffold groups showed normal urothelial lining and standard extracellular matrix development. Bladder regeneration using a collagen-heparin scaffold with VEGF, FGF2, and HB-EGF improved bladder tissue regeneration in a large animal model of diseased bladder. Larger GF-loaded constructs need to be tested to reach clinically significant augmentation. PMID- 26441141 TI - TREK1 channel blockade induces an antidepressant-like response synergizing with 5 HT1A receptor signaling. AB - Current antidepressants often remain the inadequate efficacy for many depressive patients, which warrant the necessary endeavor to develop the new molecules and targets for treating depression. Recently, the two-pore domain potassium channel TREK1 has been implicated in mood regulation and TREK-1 antagonists could be the promising antidepressant. This study has screened a TREK1 blocker (SID1900) with a satisfactory blood-brain barrier permeation and bioavailability. Electrophysiological research has shown that SID1900 and the previously reported TREK1 blocker (spadin) efficiently blocked TREK-1 current in HEK293 cells and specifically blocked two-pore domain potassium channels in primary-cultured rat hippocampal neurons. SID1900 and spadin induced a significant antidepressant-like response in the rat model of chronic unpredictable mild stress (CUMS). Both two TREK1 blockers substantially increased the firing rate of 5-HT-ergic neurons in the dorsal raphe nuclei (DRN) and PFC of CUMS rats. SID1900 and spadin significantly up-regulated the expression of PKA-pCREB-BDNF signaling in DRN, hippocampus and PFC of CUMS rats, which were enhanced and reversed by a 5-HTR1A agonist (8-OH-DPAT) and antagonist (WAY100635) respectively. The present findings suggested that TREK1 channel blockers posses the substantial antidepressant-like effect and have the potential synergistic effect with 5-HT1A receptor activation through the common CREB-BDNF signal transduction. PMID- 26441143 TI - Bacterial Genome Mining of Enzymatic Tools for Alkyne Biosynthesis. AB - The alkyne is an important functionality widely used in material science, pharmaceutical science, and chemical biology, but the importance of this functionality is contrasted by the very limited number of enzymes known to be involved in alkyne biosynthesis. We recently reported the first known carrier protein-dependent pathway for terminal alkyne formation, and in silico analysis suggested that this mechanism could be widespread in bacteria. In this paper, we screened additional homologous gene cassettes presumed to be involved in alkyne biosynthesis using both in vitro biochemical study and an E. coli-polyketide synthase (PKS) reporting system for in vivo analysis. We discovered and characterized a new terminal alkyne biosynthetic pathway comprised of TtuA, -B, and -C from Teredinibacter turnerae T7901. While the acyl-CoA ligase homologue (TtuA) demonstrated promiscuity in the activation and loading of medium-chain fatty acids onto the carrier protein (TtuC), the desaturase homologue (TtuB) showed stringent substrate specificity toward C10 fatty acyl moieties. In addition, TtuB was demonstrated to be a bifunctional desaturase/acetylenase that efficiently catalyzed two sequential O2-dependent dehydrogenation reactions. A novel terminal-alkyne bearing polyketide was further produced upon coexpression of ttuABC and a PKS gene in E. coli. The discovery and characterization of TtuA, B, and -C provides us with a new bifunctional desaturase/acetylenase for mechanistic and structural study and expands the scarce enzyme inventory for the biosynthesis of the alkyne functionality, which has important applications in synthetic and chemical biology. PMID- 26441144 TI - Glucocorticoids Reduce Sepsis by Diminishing Dendritic Cell Responses. AB - How does the body's immune system strike the delicate balance between under- and over-response? A new study shows that glucocorticoids limit the production of the proinflammatory cytokine interleukin-12 by dendritic cells in response to invading bacteria, thereby helping to avoid sepsis. Read the Research Article. PMID- 26441142 TI - CRF antagonism within the ventral tegmental area but not the extended amygdala attenuates the anxiogenic effects of cocaine in rats. AB - In addition to its initial rewarding effects, cocaine has been shown to produce profound negative/anxiogenic actions. Recent work on the anxiogenic effects of cocaine has examined the role of corticotropin releasing factor (CRF), with particular attention paid to the CRF cell bodies resident to the extended amygdala (i.e., the central nucleus of the amygdala [CeA] and the bed nucleus of the stria terminalis [BNST]) and the interconnections within and projections outside the region (e.g., to the ventral tegmental area [VTA]). In the current study, localized CRF receptor antagonism was produced by intra-BNST, intra-CeA or intra-VTA application of the CRF antagonists, D-Phe CRF(12-41) or astressin-B. The effect of these treatments were examined in a runway model of i.v. cocaine self-administration that has been shown to be sensitive to both the initial rewarding and delayed anxiogenic effects of the drug in the same animal on the same trial. These dual actions of cocaine are reflected in the development of an approach-avoidance conflict ("retreat behaviors") about goal box entry that stems from the mixed associations that subjects form about the goal. CRF antagonism within the VTA, but not the CeA or BNST, significantly reduced the frequency of approach-avoidance retreat behaviors while leaving start latencies (an index of the positive incentive properties of cocaine) unaffected. These results suggest that the critical CRF receptors contributing to the anxiogenic state associated with acute cocaine administration may lie outside the extended amygdala, and likely involve CRF projections to the VTA. PMID- 26441145 TI - Cognitive-Motivational Influences on Health Behavior Change in Adults with Chronic Pain. AB - OBJECTIVE: The primary aim was to assess the psychological factors that influence engagement in health behaviors in individuals with chronic pain using a new measure, the Behavioral Engagement Test for Chronic Pain (BET-CP). A secondary aim was to determine preliminary psychometric properties of the BET-CP. SUBJECTS: Participants were 86 adults with chronic musculoskeletal pain recruited from University of Florida pain clinics and the community. METHODS: Participants completed a battery of self-report instruments online, including the BET-CP and measures of related constructs. Items on the BET-CP assessed motivation, self efficacy, outcome expectations, and the symptom benefit required to engage across four health behaviors: exercise, diet, sleep, and pain self-management (e.g., relaxation and activity pacing). RESULTS: Participants reported modest expectations of pain-related symptom improvement if they practiced the health behaviors (22-26% improvement), but they required twice that (47-54% improvement) to make it worth their while to commit to practicing them. Participants expected to get the most symptom relief from relaxation and activity pacing, but they were most confident and motivated to eat a healthy diet. In a subsample of participants who provided data for psychometric analysis, the BET-CP demonstrated strong test-retest reliability across 7 days and adequate convergent validity. CONCLUSION: While patients with musculoskeletal pain have outcome expectancies that are nearly in line with research on behavioral pain treatments, their stringent requirements for symptom benefit may impede engagement in the health behaviors recommended for their pain-related symptoms. Additional psychometric study with larger sample sizes is needed to further validate the BET-CP. PMID- 26441146 TI - Abnormal functional integration of thalamic low frequency oscillation in the BOLD signal after acute heroin treatment. AB - Heroin addiction is a severe relapsing brain disorder associated with impaired cognitive control, including deficits in attention allocation. The thalamus has a high density of opiate receptors and is critically involved in orchestrating cortical activity during cognitive control. However, there have been no studies on how acute heroin treatment modulates thalamic activity. In a cross-over, double-blind, vehicle-controlled study, 29 heroin-maintained outpatients were studied after heroin and placebo administration, while 20 healthy controls were included for the placebo condition only. Resting-state functional magnetic resonance imaging was used to analyze functional integration of the thalamus by three different resting state analysis techniques. Thalamocortical functional connectivity (FC) was analyzed by seed-based correlation, while intrinsic thalamic oscillation was assessed by analysis of regional homogeneity (ReHo) and the fractional amplitude of low frequency fluctuations (fALFF). Relative to the placebo treatment and healthy controls, acute heroin administration reduced thalamocortical FC to cortical regions, including the frontal cortex, while the reductions in FC to the mediofrontal cortex, orbitofrontal cortex, and frontal pole were positively correlated with the plasma level of morphine, the main psychoactive metabolite of heroin. Furthermore, heroin treatment was associated with increased thalamic ReHo and fALFF values, whereas fALFF following heroin exposure correlated negatively with scores of attentional control. The heroin associated increase in fALFF was mainly dominated by slow-4 (0.027-0.073 Hz) oscillations. Our findings show that there are acute effects of heroin within the thalamocortical system and may shed new light on the role of the thalamus in cognitive control in heroin addiction. Future research is needed to determine the underlying physiological mechanisms and their role in heroin addiction. PMID- 26441147 TI - Phenotypic and functional changes in dermal primary fibroblasts isolated from intrinsically aged human skin. AB - Dermal fibroblasts play a key role in maintaining skin homoeostasis by synthesizing and degrading extracellular matrix components. During ageing, they are subjected to changes, such as the loss of type I collagen expression and an increased synthesis of metalloproteinase I, leading to fragmentation of collagen fibrils with consequent reduction of the mechanical tension and defects of skin wound healing. Most information about fibroblast ageing was obtained from experiments performed on replicative-senescent dermal fibroblasts in vitro. However, the senescence status of fibroblasts isolated from intrinsically aged skins and its consequences on functionality need to be deeper investigated. Herein, we studied age-related phenotypic and functional alteration of fibroblasts from 'young' (<35 years) and 'old' (>50 years) donors. Our results brought evidence of the senescent status of 'old' fibroblasts by senescence associated beta-galactosidase (SA-betagal) positive staining and p16 expression. A PCR array focusing on senescence highlighted a subset of downregulated genes including cell cycle progression and ECM genes in 'old' fibroblasts as well as a subset of upregulated genes involved in senescence features. In 'old' fibroblasts, we measured a downregulation of proliferative and contractile capacities of migratory potential under PDGF stimulation and activation into myofibroblasts under TGFbeta. Old fibroblasts were also more sensitive to oxidative stress than 'young' ones. Of interest, downregulation of p16 expression partially reversed the senescent phenotype of 'old' fibroblasts but failed to restore their functional properties. In conclusion, our data brought evidence of phenotypic and functional differences between fibroblasts from young and intrinsically aged skin that may contribute to the alterations observed with ageing. PMID- 26441148 TI - Oligonucleotide Immobilization and Hybridization on Aldehyde-Functionalized Poly(2-hydroxyethyl methacrylate) Brushes. AB - DNA biosensing requires high oligonucleotide binding capacity interface chemistries that can be tuned to maximize probe presentation as well as hybridization efficiency. This contribution investigates the feasibility of aldehyde-functionalized poly(2-hydroxyethyl methacrylate) (PHEMA) brush-based interfaces for oligonucleotide binding and hybridization. These polymer brushes, which allow covalent immobilization of oligonucleotides, are prepared by surface initiated atom transfer radical polymerization (SI-ATRP) of HEMA followed by a postpolymerization oxidation step to generate side chain aldehyde groups. A series of polymer brushes covering a range of film thicknesses and grafting densities was investigated with regard to their oligonucleotide binding capacity as well as their ability to support oligonucleotide hybridization. Densely grafted brushes were found to have probe oligonucleotide binding capacities of up to ~30 pmol/cm(2). Increasing the thickness of these densely grafted brush films, however, resulted in a decrease in the oligonucleotide binding capacity. Less densely grafted brushes possess binding capacities of ~10 pmol/cm(2), which did not significantly depend on film thickness. The oligonucleotide hybridization efficiencies, however, were highest (93%) on those brushes that present the lowest surface concentration of the probe oligonucleotide. These results highlight the importance of optimizing the probe oligonucleotide surface concentration and binding interface chemistry. The versatility and tunability of the PHEMA-based brushes presented herein makes these films a very attractive platform for the immobilization and hybridization of oligonucleotides. PMID- 26441149 TI - Mouse Sensitivity is an Independent Risk Factor for Rhinitis in Children with Asthma. AB - BACKGROUND: Although mouse and cockroach allergy is known to be important in urban children with asthma, the independent association of mouse and cockroach sensitization with rhinitis in these children is unknown. OBJECTIVE: To determine the association of mouse and cockroach sensitization with rhinitis in urban children with asthma. METHODS: As part of the Mouse Allergen and Asthma Intervention Trial, 499 urban children (5-17 years) with persistent asthma underwent spirometry, skin prick testing to 14 common environmental allergens, and serology for mouse-specific IgE. In 269 subjects, cockroach-specific IgE serology was also obtained. Patient/parent-reported rhinitis in the last 2 weeks and the last 1 year was the primary outcome measure. Mouse/cockroach exposure was measured by reported frequency of sightings. Mouse allergen-settled bedroom dust samples were also measured in mouse-sensitized children. RESULTS: Rhinitis was reported in 49.9% and 70.2% of the participants within the last 2 weeks and the last 1 year, respectively. Serum mouse IgE level of 0.35 IU/mL or more was associated with rhinitis in the past 2 weeks (adjusted odds ratio, 2.15; 95% CI, 1.02-4.54; P = .04) and the past 1 year (adjusted odds ratio, 2.40; 95% CI, 1.12 5.1; P = .02) after controlling for age, race, sex, the presence of any smokers at home, primary caregiver education level, number of allergen sensitivities, cockroach IgE level of 0.35 IU/mL or more, and study site (Boston or Baltimore). Measures of home mouse exposure were not associated with rhinitis, regardless of mouse sensitivity. Cockroach sensitivity was not associated with rhinitis regardless of sensitization to other allergens. CONCLUSIONS: In urban children with asthma, increased mouse IgE, but not cockroach IgE, in the sera (mouse IgE >= 0.35 IU/mL) may be associated independently with rhinitis. PMID- 26441151 TI - An Electronic Asthma Self-Management Intervention for Young African American Adults. AB - BACKGROUND: Health disparities are seen in many chronic conditions including asthma. Young African American adults represent a population at high risk for poor asthma outcomes due to both their minority status and the difficult transition from adolescence to adulthood. Recruitment and retention has been challenging in this demographic stratum, and traditional asthma education is often not feasible. OBJECTIVE: The objective of this study was to develop and assess the feasibility of an electronic asthma self-management program for young African American adults. METHODS: A total of 44 African American adults (age 18 30 years) with uncontrolled persistent asthma were enrolled in an asthma self management program. The 6-week Breathe Michigan program (predicated on the social cognitive theory) was tailored specifically to the concerns and preferences of young African American adults. The entire program was completed electronically, without any specialized human support. At 2 weeks and 3 months after program completion, participants were contacted for follow-up. RESULTS: A total of 89% of enrolled subjects completed the 6-week intervention, and 77% were available for evaluation at 3 months. All subjects completing the 2-week postprogram survey reported that the program was helpful, and 97% would recommend it to others. Asthma control as measured by the Asthma Control Test improved from 16.1 to 19.3 (P < .01), and asthma quality of life as measured by the Mini Asthma Quality of Life Questionnaire improved from 4.0 to 5.1 (P < .01). CONCLUSIONS: The Breathe Michigan program is feasible for recruitment and retention, and demonstrated an improvement in asthma control and quality of life for young African American adults. PMID- 26441150 TI - Persistent Food Allergy and Food Allergy Coexistent with Eczema Is Associated with Reduced Growth in the First 4 Years of Life. AB - BACKGROUND: Food allergy has been associated with lower weight and height in cross-sectional studies in children; however, this has not been investigated in longitudinal studies to explore growth over time, and previous studies have not accounted for coexisting eczema. OBJECTIVE: The objective of this study was to examine the association of IgE-mediated food allergy and eczema with anthropometric measures at 1 and 4 years of age. METHODS: In the HealthNuts population-based cohort, infants recruited at age 1 year underwent a skin prick test to egg, peanut, and sesame; those sensitized had oral food challenges. Food challenges repeated at 4 years determined food allergy persistence or resolution. Eczema was defined as parent report of eczema diagnosis. Parent-reported weight and height and child health record data were used to calculate age- and sex adjusted percentiles from World Health Organization charts. Multivariable linear regression models were fitted to examine the effect of food allergy and eczema on weight and height controlling for potential confounders. RESULTS: Children with both food allergy and eczema at age 1 had lower percentiles for mean weight (51.3 vs 58.3 percentile, P = .001) and height (48.4 vs 53.4, P = .028) at age 1 compared with those with neither condition. There was no difference for children with only food allergy or eczema at age 1. By age 4, children with persistent food allergy and persistent eczema, but not those with resolved food allergy, were still shorter and lighter. CONCLUSIONS: Children with both food allergy and eczema were shorter and lighter throughout early childhood, with more pronounced differences in those with persistent food allergy. PMID- 26441152 TI - A case of IgG4-related bronchial disease successfully treated with inhaled corticosteroids. PMID- 26441153 TI - Evidence for polymorphism in the cytochrome P450 2D50 gene in horses. AB - Metabolism is an essential factor in the clearance of many drugs and as such plays a major role in the establishment of dosage regimens and withdrawal times. CYP2D6, the human orthologue to equine CYP2D50, is a drug-metabolizing enzyme that is highly polymorphic in humans leading to widely differing levels of metabolic activity. As CYP2D6 is highly polymorphic, in this study it was hypothesized that the gene coding for the equine orthologue, CYP2D50, may also be prone to polymorphism. Blood samples were collected from 150 horses, the CYP2D50 gene was cloned and sequenced; and full-length sequences were analyzed for single nucleotide polymorphisms (SNPs), deletions, or insertions. Pharmacokinetic data were collected from a subset of horses following the administration of a single oral dose of tramadol and probit analysis used to calculate metabolic ratios. Prior to drug administration, the ability of recombinant CYP2D50 to metabolize tramadol to O-desmethyltramadol was confirmed. Sequencing of CYP2D50 identified 126 exonic SNPs, with 31 of those appearing in multiple horses. Oral administration of tramadol to a subset of these horses revealed variable metabolic ratios (tramadol: O-desmethyltramadol) in individual horses and separation into three metabolic groups. While a limited number of horses of primarily a single breed were studied, the variability in tramadol metabolism to O-desmethyltramadol between horses and preliminary evidence of what appears to be poor, extensive, and ultra-rapid metabolizers supports further study of the potential for genetic polymorphisms in the CYP2D50 gene in horses. PMID- 26441154 TI - Protein structure refinement with adaptively restrained homologous replicas. AB - A novel protein refinement protocol is presented which utilizes molecular dynamics (MD) simulations of an ensemble of adaptively restrained homologous replicas. This approach adds evolutionary information to the force field and reduces random conformational fluctuations by coupling of several replicas. It is shown that this protocol refines the majority of models from the CASP11 refinement category and that larger conformational changes of the starting structure are possible than with current state of the art methods. The performance of this protocol in the CASP11 experiment is discussed. We found that the quality of the refined model is correlated with the structural variance of the coupled replicas, which therefore provides a good estimator of model quality. Furthermore, some remarkable refinement results are discussed in detail. Proteins 2016; 84(Suppl 1):302-313. (c) 2015 Wiley Periodicals, Inc. PMID- 26441155 TI - Neural Correlates of the Propensity for Retaliatory Behavior in Youths With Disruptive Behavior Disorders. AB - OBJECTIVE: Youths with disruptive behavior disorders (DBD) (conduct disorder and oppositional defiant disorder) have an elevated risk for maladaptive reactive aggression. Theory suggests that this is due to an elevated sensitivity of basic threat circuitry implicated in retaliation (amygdala/periaqueductal gray) in youths with DBD and low levels of callous-unemotional traits and dysfunctional regulatory activity in the ventromedial prefrontal cortex in youths with DBD irrespective of callous-unemotional traits. METHOD: A total of 56 youths 10-18 years of age (23 of them female) participated in the study: 30 youths with DBD, divided by median split into groups with high and low levels of callous unemotional traits, and 26 healthy youths. All participants completed an ultimatum game task during functional MRI. RESULTS: Relative to the other groups, youths with DBD and low levels of callous-unemotional traits showed greater increases in activation of basic threat circuitry when punishing others and dysfunctional down-regulation of the ventromedial prefrontal cortex during retaliation. Relative to healthy youths, all youths with DBD showed reduced amygdala-ventromedial prefrontal cortex connectivity during high provocation. Ventromedial prefrontal cortex responsiveness and ventromedial prefrontal cortex amygdala connectivity were related to patients' retaliatory propensity (behavioral responses during the task) and parent-reported reactive aggression. CONCLUSIONS: These data suggest differences in the underlying neurobiology of maladaptive reactive aggression in youths with DBD who have relatively low levels of callous-unemotional traits. Youths with DBD and low callous-unemotional traits alone showed significantly greater threat responses during retaliation relative to comparison subjects. These data also suggest that ventromedial prefrontal cortex-amygdala connectivity is critical for regulating retaliation/reactive aggression and, when dysfunctional, contributes to reactive aggression, independent of level of callous-unemotional traits. PMID- 26441156 TI - Reproductive Safety of Second-Generation Antipsychotics: Current Data From the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics. AB - OBJECTIVE: Second-generation antipsychotics are used to treat a spectrum of psychiatric illnesses in reproductive-age women. The National Pregnancy Registry for Atypical Antipsychotics was established to determine the risk of major malformations among infants exposed to second-generation antipsychotics during pregnancy relative to a comparison group of unexposed infants of mothers with histories of psychiatric morbidity. METHOD: Women were prospectively followed during pregnancy and the postpartum period; obstetric, labor, delivery, and pediatric medical records were obtained. Eligible enrollees were pregnant women ages 18-45. The Registry is based at the Center for Women's Mental Health at Massachusetts General Hospital. Women were recruited through provider referral, self-referral, and the Center's web site. RESULTS: As of December 2014, 487 women were enrolled: 353 who used second-generation antipsychotics and 134 comparison women. Medical records were obtained for 82% of participants. A total of 303 women had completed the study and were eligible for inclusion in the analysis. Of 214 live births with first-trimester exposure to second-generation antipsychotics, three major malformations were confirmed. In the control group (N=89), one major malformation was confirmed. The absolute risk of major malformations was 1.4% for exposed infants and 1.1% for unexposed infants. The odds ratio for major malformations comparing exposed infants with unexposed infants was 1.25 (95% CI=0.13-12.19). CONCLUSIONS: The results suggest that it would be unlikely for second-generation antipsychotics to raise the risk of major malformations more than 10-fold beyond that observed in the general population or among control groups using other psychotropic medications. If the estimate stabilizes around the null with ongoing data collection, findings may be reassuring for both clinicians and women trying to make risk-benefit treatment decisions about using atypical antipsychotics during pregnancy. These findings are timely given the renewed focus of regulatory agencies on reproductive safety. PMID- 26441158 TI - Pattern of Drug Use and Associated Behaviors Among Female Injecting Drug Users From Northeast India: A Multi-Centric, Cross-Sectional, Comparative Study. AB - BACKGROUND: Studies from developed countries document the presence of injecting drug use among females and significantly higher vulnerabilities and risks as compared with male injecting drug users (IDUs). Studies comparing vulnerabilities and drug use patterns between female and male IDUs are not available for developing countries. OBJECTIVES: The aim of the study was to assess the drug use pattern and related HIV vulnerabilities among female IDUs and compare these findings with those from male IDUs from four states of Northeast India. METHOD: The study used data collected as part of a nationwide study of drug use pattern and related HIV vulnerabilities among IDUs. Ninety-eight female and 202 male IDUs accessing services from harm reduction sites across the four states of Northeast region of India were chosen through random sampling methodology. Drug use pattern, injecting practices, and knowledge of HIV were assessed using a structured questionnaire. RESULTS: Significantly higher proportion of female IDUs was uneducated, unemployed, reported their occupation as sex workers, and switched to injecting drug use faster as compared with male IDUs. Female IDUs practicing sex work differed significantly from those who did not with respect to frequency of daily injections, choice of drugs injected, and concomitant use of non-injecting drugs. More than half of female IDUs initiated sharing within the first month of injecting. CONCLUSIONS: The study demonstrates that female IDUs differ from male IDUs in their drug use pattern, initiation into injection as well as injecting behavior, which would be an important consideration during designing of female-specific interventions. PMID- 26441157 TI - Gating Deficit Heritability and Correlation With Increased Clinical Severity in Schizophrenia Patients With Positive Family History. AB - OBJECTIVE: The Consortium on the Genetics of Schizophrenia Family Study evaluated 12 primary and other supplementary neurocognitive and neurophysiological endophenotypes in schizophrenia probands and their families. Previous analyses of prepulse inhibition (PPI) and P50 gating measures in this sample revealed heritability estimates that were lower than expected based on earlier family studies. Here the authors investigated whether gating measures were more heritable in multiply affected families with a positive family history compared with families with only a single affected proband (singleton). METHOD: A total of 296 nuclear families consisting of a schizophrenia proband, at least one unaffected sibling, and both parents underwent a comprehensive endophenotype and clinical characterization. The Family Interview for Genetic Studies was administered to all participants and used to obtain convergent psychiatric symptom information for additional first-degree relatives. Among the families, 97 were multiply affected, and 96 were singletons. RESULTS: Both PPI and P50 gating displayed substantially increased heritability in the 97 multiply affected families (47% and 36%, respectively) compared with estimates derived from the entire sample of 296 families (29% and 20%, respectively). However, no evidence for heritability was observed for either measure in the 96 singleton families. Schizophrenia probands derived from the multiply affected families also displayed a significantly increased severity of clinical symptoms compared with those from singleton families. CONCLUSIONS: PPI and P50 gating measures demonstrate substantially increased heritability in schizophrenia families with a higher genetic vulnerability for illness, providing further support for the commonality of genes underlying both schizophrenia and gating measures. PMID- 26441159 TI - Food insecurity, overweight and obesity among low-income African-American families in Baltimore City: associations with food-related perceptions. AB - OBJECTIVE: To examine associations between food insecurity, excess body weight, psychosocial factors and food behaviours among low-income African-American families. DESIGN: Cross-sectional survey of participants in the baseline evaluation of the B'More Healthy Communities for Kids (BHCK) obesity prevention trial. We collected data on socio-economic factors, food source destinations, acquiring food, preparation methods, psychosocial factors, beliefs and attitudes, participation in food assistance programmes, anthropometry and food security. We used principal component analysis to identify patterns of food source destinations and logistic regression to examine associations. SETTING: Fourteen low-income, predominantly African-American neighbourhoods in Baltimore City, MD, USA. SUBJECTS: Two hundred and ninety-eight adult caregiver-child (10-14 years old) dyads. RESULTS: Of households, 41.6 % had some level of food insecurity and 12.4 % experienced some level of hunger. Food-insecure participants with hunger were significantly more likely to be unemployed and to have lower incomes. We found high rates of excess body weight (overweight and obesity) among adults and children (82.8 % and 37.9 % among food insecure without hunger, 89.2 % and 45.9 % among food insecure with hunger, respectively), although there were no significant differences by food security status. Food source usage patterns, food acquisition, preparation, knowledge, self-efficacy and intentions did not differ by food security. Food security was associated with perceptions that healthy foods are affordable and convenient. Greater caregiver body satisfaction was associated with food insecurity and excess body weight. CONCLUSIONS: In this setting, obesity and food insecurity are major problems. For many food-insecure families, perceptions of healthy foods may serve as additional barriers to their purchase and consumption. PMID- 26441161 TI - Feasibility of Ionization-Mediated Pathway for Ultraviolet-Induced Melanin Damage. AB - Melanin is the pigment found in human skin that is responsible for both photoprotection and photodamage. Recently there have been reports that greater photodamage of DNA occurs when cells containing melanin are irradiated with ultraviolet (UV) radiation, thus suggesting that the photoproducts of melanin cause DNA damage. Photoionization processes have also been implicated in the photodegradation of melanin. However, not much is known about the oxidation potential of melanin and its monomers. In this work we calculate the ionization energies of monomers, dimers, and few oligomers of eumelanin to estimate the threshold energy required for the ionization of eumelanin. We find that this threshold is within the UV-B region for eumelanin. We also look at the charge and spin distributions of the various ionized states of the monomers that are formed to understand which of the ionization channels might favor monomerization from a covalent dimer. PMID- 26441163 TI - Insurers Again at Odds With Hospitals and Physicians. PMID- 26441160 TI - Worldwide Prevalence of Human Papillomavirus and Relative Risk of Prostate Cancer: A Meta-analysis. AB - Despite the increasing number of studies conducted recently to evaluate the association between HPV infections and the risk of prostate cancer, the results remain inconclusive. Furthermore, the prevalence and distribution of overall and individual HPV types worldwide in prostate cancer has not been reported until now. Therefore, we estimated the prevalence of HPV in prostate cancer by pooling data of 46 studies with 4919 prostate cancer cases, taking into account the heterogeneity of major related parameters, including study region, specimen type, HPV DNA source, detection method, publication calendar period and Gleason score. Moreover, we tested the association of HPV infections with prostate cancer risks by a meta-analysis of 26 tissue-based case-control studies. We found that the prevalence of HPV infection was 18.93% (95% CI = 17.84-20.05%) in prostate cancer cases, and most of which were high-risk HPV types (17.73%, 95% CI = 16.52 18.99%). The prevalence varied by region, PCR primers used, publication calendar period and Gleason score. Our study also showed a significantly increased risk of prostate cancer with the positivity of overall HPV detected in prostate tissues (OR = 1.79, 95% CI = 1.29-2.49) and revealed the geographic variation of association strength (P < 0.001). In conclusion, HPV infections may contribute to the risk of prostate cancer. PMID- 26441166 TI - Landscape With Poplars: Paul Gauguin. PMID- 26441167 TI - Exploring the Promise of Mindfulness as Medicine. PMID- 26441175 TI - Facilitating Quality Improvement: Pushing the Pendulum Back Toward Process Measures. PMID- 26441162 TI - Detection of early stage changes associated with adipogenesis using Raman spectroscopy under aseptic conditions. AB - There is growing interest in the development of methods capable of non-invasive characterization of stem cells prior to their use in cell-based therapies. Raman spectroscopy has previously been used to detect biochemical changes commensurate with the osteogenic, cardiogenic, and neurogenic differentiation of stem cells. The aim of this study was to characterize the adipogenic differentiation of live adipose derived stem cells (ASCs) under aseptic conditions. ASCs were cultured in adipogenic or basal culture medium for 14 days in customized culture flasks containing quartz windows. Raman spectra were acquired every 3 days. Principal component analysis (PCA) was used to identify spectral changes in the cultures over time. Adipogenic differentiation was confirmed using quantitative reverse transcription polymerase chain reaction for the marker genes PPARgamma and ADIPOQ and Oil red O staining performed. PCA demonstrated that lipid associated spectral features varied throughout ASC differentiation with the earliest detection of the lipid associated peak at 1,438 cm(-1) after 3 days of induction. After 7 days of culture there were clear differences between the spectra acquired from ASCs in adipogenic or basal culture medium. No changes were observed in the spectra acquired from undifferentiated ASCs. Significant up-regulation in the expression of both PPARgamma and ADIPOQ genes (P < 0.001) was observed after 14 days of differentiation as was prominent Oil red O staining. However, the Raman sampling process resulted in weaker gene expression compared with ASCs that had not undergone Raman analysis. This study demonstrated that Raman spectroscopy can be used to detect biochemical changes associated with adipogenic differentiation in a non-invasive and aseptic manner and that this can be achieved as early as three days into the differentiation process. PMID- 26441176 TI - Hospital Networks and Value-Based Payment: Fertile Ground for Regionalizing High Risk Surgery. PMID- 26441177 TI - A PIECE OF MY MIND. All for One. PMID- 26441178 TI - Minimally Invasive Approaches to Rectal Cancer and Diverticulitis: Does Less Mean More? PMID- 26441179 TI - Effect of Laparoscopic-Assisted Resection vs Open Resection of Stage II or III Rectal Cancer on Pathologic Outcomes: The ACOSOG Z6051 Randomized Clinical Trial. AB - IMPORTANCE: Evidence about the efficacy of laparoscopic resection of rectal cancer is incomplete, particularly for patients with more advanced-stage disease. OBJECTIVE: To determine whether laparoscopic resection is noninferior to open resection, as determined by gross pathologic and histologic evaluation of the resected proctectomy specimen. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, balanced, noninferiority, randomized trial enrolled patients between October 2008 and September 2013. The trial was conducted by credentialed surgeons from 35 institutions in the United States and Canada. A total of 486 patients with clinical stage II or III rectal cancer within 12 cm of the anal verge were randomized after completion of neoadjuvant therapy to laparoscopic or open resection. INTERVENTIONS: Standard laparoscopic and open approaches were performed by the credentialed surgeons. MAIN OUTCOMES AND MEASURES: The primary outcome assessing efficacy was a composite of circumferential radial margin greater than 1 mm, distal margin without tumor, and completeness of total mesorectal excision. A 6% noninferiority margin was chosen according to clinical relevance estimation. RESULTS: Two hundred forty patients with laparoscopic resection and 222 with open resection were evaluable for analysis of the 486 enrolled. Successful resection occurred in 81.7% of laparoscopic resection cases (95% CI, 76.8%-86.6%) and 86.9% of open resection cases (95% CI, 82.5%-91.4%) and did not support noninferiority (difference, -5.3%; 1-sided 95% CI, -10.8% to infinity; P for noninferiority = .41). Patients underwent low anterior resection (76.7%) or abdominoperineal resection (23.3%). Conversion to open resection occurred in 11.3% of patients. Operative time was significantly longer for laparoscopic resection (mean, 266.2 vs 220.6 minutes; mean difference, 45.5 minutes; 95% CI, 27.7-63.4; P < .001). Length of stay (7.3 vs 7.0 days; mean difference, 0.3 days; 95% CI, -0.6 to 1.1), readmission within 30 days (3.3% vs 4.1%; difference, -0.7%; 95% CI, -4.2% to 2.7%), and severe complications (22.5% vs 22.1%; difference, 0.4%; 95% CI, -4.2% to 2.7%) did not differ significantly. Quality of the total mesorectal excision specimen in 462 operated and analyzed surgeries was complete (77%) and nearly complete (16.5%) in 93.5% of the cases. Negative circumferential radial margin was observed in 90% of the overall group (87.9% laparoscopic resection and 92.3% open resection; P = .11). Distal margin result was negative in more than 98% of patients irrespective of type of surgery (P = .91). CONCLUSIONS AND RELEVANCE: Among patients with stage II or III rectal cancer, the use of laparoscopic resection compared with open resection failed to meet the criterion for noninferiority for pathologic outcomes. Pending clinical oncologic outcomes, the findings do not support the use of laparoscopic resection in these patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00726622. PMID- 26441181 TI - Laparoscopic Lavage vs Primary Resection for Acute Perforated Diverticulitis: The SCANDIV Randomized Clinical Trial. AB - IMPORTANCE: Perforated colonic diverticulitis usually requires surgical resection, which is associated with significant morbidity. Cohort studies have suggested that laparoscopic lavage may treat perforated diverticulitis with less morbidity than resection procedures. OBJECTIVE: To compare the outcomes from laparoscopic lavage with those for colon resection for perforated diverticulitis. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized clinical superiority trial recruiting participants from 21 centers in Sweden and Norway from February 2010 to June 2014. The last patient follow-up was in December 2014 and final review and verification of the medical records was assessed in March 2015. Patients with suspected perforated diverticulitis, a clinical indication for emergency surgery, and free air on an abdominal computed tomography scan were eligible. Of 509 patients screened, 415 were eligible and 199 were enrolled. INTERVENTIONS: Patients were assigned to undergo laparoscopic peritoneal lavage (n = 101) or colon resection (n = 98) based on a computer-generated, center stratified block randomization. All patients with fecal peritonitis (15 patients in the laparoscopic peritoneal lavage group vs 13 in the colon resection group) underwent colon resection. Patients with a pathology requiring treatment beyond that necessary for perforated diverticulitis (12 in the laparoscopic lavage group vs 13 in the colon resection group) were also excluded from the protocol operations and treated as required for the pathology encountered. MAIN OUTCOMES AND MEASURES: The primary outcome was severe postoperative complications (Clavien Dindo score >IIIa) within 90 days. Secondary outcomes included other postoperative complications, reoperations, length of operating time, length of postoperative hospital stay, and quality of life. RESULTS: The primary outcome was observed in 31 of 101 patients (30.7%) in the laparoscopic lavage group and 25 of 96 patients (26.0%) in the colon resection group (difference, 4.7% [95% CI, -7.9% to 17.0%]; P = .53). Mortality at 90 days did not significantly differ between the laparoscopic lavage group (14 patients [13.9%]) and the colon resection group (11 patients [11.5%]; difference, 2.4% [95% CI, -7.2% to 11.9%]; P = .67). The reoperation rate was significantly higher in the laparoscopic lavage group (15 of 74 patients [20.3%]) than in the colon resection group (4 of 70 patients [5.7%]; difference, 14.6% [95% CI, 3.5% to 25.6%]; P = .01) for patients who did not have fecal peritonitis. The length of operating time was significantly shorter in the laparoscopic lavage group; whereas, length of postoperative hospital stay and quality of life did not differ significantly between groups. Four sigmoid carcinomas were missed with laparoscopic lavage. CONCLUSIONS AND RELEVANCE: Among patients with likely perforated diverticulitis and undergoing emergency surgery, the use of laparoscopic lavage vs primary resection did not reduce severe postoperative complications and led to worse outcomes in secondary end points. These findings do not support laparoscopic lavage for treatment of perforated diverticulitis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01047462. PMID- 26441183 TI - Challenges in Reducing Surgical "Never Events". PMID- 26441180 TI - Effect of Laparoscopic-Assisted Resection vs Open Resection on Pathological Outcomes in Rectal Cancer: The ALaCaRT Randomized Clinical Trial. AB - IMPORTANCE: Laparoscopic procedures are generally thought to have better outcomes than open procedures. Because of anatomical constraints, laparoscopic rectal resection may not be better because of limitations in performing an adequate cancer resection. OBJECTIVE: To determine whether laparoscopic resection is noninferior to open rectal cancer resection for adequacy of cancer clearance. DESIGN, SETTING, AND PARTICIPANTS: Randomized, noninferiority, phase 3 trial (Australasian Laparoscopic Cancer of the Rectum; ALaCaRT) conducted between March 2010 and November 2014. Twenty-six accredited surgeons from 24 sites in Australia and New Zealand randomized 475 patients with T1-T3 rectal adenocarcinoma less than 15 cm from the anal verge. INTERVENTIONS: Open laparotomy and rectal resection (n = 237) or laparoscopic rectal resection (n = 238). MAIN OUTCOMES AND MEASURES: The primary end point was a composite of oncological factors indicating an adequate surgical resection, with a noninferiority boundary of Delta = -8%. Successful resection was defined as meeting all the following criteria: (1) complete total mesorectal excision, (2) a clear circumferential margin (>=1 mm), and (3) a clear distal resection margin (>=1 mm). Pathologists used standardized reporting and were blinded to the method of surgery. RESULTS: A successful resection was achieved in 194 patients (82%) in the laparoscopic surgery group and 208 patients (89%) in the open surgery group (risk difference of -7.0% [95% CI, -12.4% to infinity]; P = .38 for noninferiority). The circumferential resection margin was clear in 222 patients (93%) in the laparoscopic surgery group and in 228 patients (97%) in the open surgery group (risk difference of 3.7% [95% CI, -7.6% to 0.1%]; P = .06), the distal margin was clear in 236 patients (99%) in the laparoscopic surgery group and in 234 patients (99%) in the open surgery group (risk difference of -0.4% [95% CI, -1.8% to 1.0%]; P = .67), and total mesorectal excision was complete in 206 patients (87%) in the laparoscopic surgery group and 216 patients (92%) in the open surgery group (risk difference of -5.4% [95% CI, -10.9% to 0.2%]; P = .06). The conversion rate from laparoscopic to open surgery was 9%. CONCLUSIONS AND RELEVANCE: Among patients with T1-T3 rectal tumors, noninferiority of laparoscopic surgery compared with open surgery for successful resection was not established. Although the overall quality of surgery was high, these findings do not provide sufficient evidence for the routine use of laparoscopic surgery. Longer follow-up of recurrence and survival is currently being acquired. TRIAL REGISTRATION: anzctr.org Identifier: ACTRN12609000663257. PMID- 26441182 TI - Rehabilitation After Immobilization for Ankle Fracture: The EXACT Randomized Clinical Trial. AB - IMPORTANCE: The benefits of rehabilitation after immobilization for ankle fracture are unclear. OBJECTIVES: To determine the effectiveness of a supervised exercise program and advice (rehabilitation) compared with advice alone and to determine if effects are moderated by fracture severity or age and sex. DESIGN, SETTING, AND PARTICIPANTS: The EXACT trial was a pragmatic, randomized clinical trial conducted from December 2010 to June 2014. Patients with isolated ankle fracture presenting to fracture clinics in 7 Australian hospitals were randomized on the day of removal of immobilization. Of 571 eligible patients, 357 chose not to participate and 214 were allocated to rehabilitation (n = 106) or advice alone (n = 108), with 194 (91%) followed up at 1 month, 173 (81%) at 3 months, and 170 (79%) at 6 months. There were no withdrawals attributed to adverse effects. Recruitment terminated early on December 31, 2013 (planned enrollment, 342; actual, 214), because funding was exhausted. INTERVENTIONS: Supervised exercise program and advice about self-management (rehabilitation) (individually tailored, prescribed, monitored, and progressed) or advice alone, both delivered by a physical therapist. MAIN OUTCOMES AND MEASURES: Primary outcomes were activity limitation assessed using the Lower Extremity Functional Scale (score range, 0 80; higher scores indicate better activity), and quality of life assessed using the Assessment of Quality of Life (score range, 0-1; higher scores indicate better quality of life), measured at baseline and at 1, 3 (primary time point), and 6 months. RESULTS: Mean activity limitation and quality of life at baseline were 30.1 (SD, 12.5) and 0.51 (SD, 0.24), respectively, for advice and 30.2 (SD, 13.2) and 0.54 (SD, 0.24) for rehabilitation, increasing to 64.3 (SD, 13.5) and 0.85 (SD, 0.17) for advice vs 64.3 (SD, 15.1) and 0.85 (SD, 0.20) for rehabilitation at 3 months. Rehabilitation was not more effective than advice for activity limitation (mean effect at 3 months, 0.4 [95% CI, -3.3 to 4.1]) or quality of life (-0.01 [95% CI, -0.06 to 0.04]). Treatment effects were not moderated by fracture severity or age and sex. CONCLUSIONS AND RELEVANCE: A supervised exercise program and advice did not confer additional benefits in activity limitation or quality of life compared with advice alone for patients with isolated and uncomplicated ankle fracture. These findings do not support the routine use of supervised exercise programs after removal of immobilization for patients with isolated and uncomplicated ankle fracture. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12610000979055. PMID- 26441184 TI - Eliminating the Confusion Surrounding Concussions in Sports. PMID- 26441185 TI - Recurrent Painful Abdominal Rash. PMID- 26441186 TI - Return to Acute Care Following Ambulatory Surgery. PMID- 26441187 TI - Extended Follow-up of a Randomized Clinical Trial of Open vs Endoscopic Release Surgery for Carpal Tunnel Syndrome. PMID- 26441188 TI - Treatment of Uncomplicated Acute Appendicitis. PMID- 26441189 TI - Treatment of Uncomplicated Acute Appendicitis. PMID- 26441190 TI - Treatment of Uncomplicated Acute Appendicitis. PMID- 26441192 TI - Incorrect Title for Table. PMID- 26441191 TI - Treatment of Uncomplicated Acute Appendicitis--Reply. PMID- 26441193 TI - Omitted Financial Disclosures. PMID- 26441194 TI - Failure to Report Financial Disclosure Information. PMID- 26441196 TI - Laparoscopic Cholecystectomy: A Remarkable Development. PMID- 26441198 TI - Correction with autologous fat grafting for contour changes of the breasts after implant removal in Asian women. AB - BACKGROUND: Patients who were diagnosed with symptomatic capsular contracture or with safety concerns for the implant would be often reluctant to accept the operation of implant exchange, choosing instead removal without exchange or taking other options to rebuild their breasts. These patients may benefit from augmenting the overlying soft tissue of the breasts with autologous fat grafting after removing the prosthesis. OBJECTIVES: A retrospective analysis of the patients receiving fat grafting for breast augmentation after implant removal was performed in this study. METHODS: Between March 2011 and November 2013, 27 patients receiving autologous fat grafting after breast implant removal. Objective evaluation was made by measuring the change in breast thickness with ultrasonography taken before and after the treatment. Aesthetic evaluation was performed using a 5-point Likert scale for patient satisfaction and comparing preoperative and postoperative digital photographs for physician satisfaction. RESULTS: The mean breast thickness change was 13.1 mm (SD = 3.3) which was an increment by 154% in comparison to the averaged breast thickness of 8.5 mm after implant removal. The results of patient satisfaction and physician satisfaction were 16.3 (SD = 1.2) and 16.7 (SD = 1.6). Complications included recipient site infection, fat necrosis, and small areas of induration. The overall complication rate was 22.2% (6 of 27). CONCLUSION: Autologous fat grafting is beneficial for the correction of deformed breasts after implant removal. With its preferential fill qualities, the wide cleavage and excessive upper pole fullness associated with existing implants can also be corrected. PMID- 26441197 TI - JAMA PATIENT PAGE. How to Use Online Clinician Rating Systems. PMID- 26441199 TI - Validation of a family-centred outcome questionnaire for pinnaplasty: a cross sectional pilot study. AB - OBJECTIVES: Comparison of pinnaplasty techniques is difficult due to variation in the reporting of outcomes. We aimed to develop a family-centred outcome questionnaire for use after pinnaplasty and assess it for reliability and validity. DESIGN: Cross-sectional study. SETTING: Tertiary referral paediatric otolaryngology centre. PARTICIPANTS: 20 prospective and 71 retrospective pinnaplasty patients and their parent(s). METHODS: The Post-Operative Pinnaplasty Questionnaire (POPQ) was developed after semi-structured interview with families of children undergoing pinnaplasty. Children aged 4-16 were recruited. Three different ear measurements (auriculocephalic angle, helix-mastoid distance and Walker's ratio) were performed pre-operatively. Children were reviewed 3 months post-operatively and asked to complete a POPQ and Glasgow Children's Benefit Inventory with their parent(s). Ear measurements were repeated and data collected on surgical technique and complications. 200 retrospective pinnaplasty patients were posted a POPQ and Glasgow Children's Benefit Inventory and data collected on surgical technique, complication rate and Walker's angle. MAIN OUTCOMES MEASURES: Validity and reliability of the POPQ. RESULTS: Age range was 4-16 (median 12). POPQ correlated well with Glasgow Children's Benefit Inventory (Spearman's rho = 0.776, P < 0.001). There was no correlation of POPQ scores with age, sex, complication or surgical technique. POPQ score was not associated with severe prominence pre-op nor change or degree of prominence post-op. POPQ displayed good internal consistency (Cronbach's alpha 0.850) and ease-of-use scores. CONCLUSIONS: We have developed a family-focused outcome tool for pinnaplasty that displays good face validity, internal consistency and correlation with health related quality of life and that is simple and easy to use. No correlation was seen with more traditional measures of outcome such as complications or ear measurements. Further refinement and testing of validity and reliability on a larger sample is planned. PMID- 26441200 TI - Highly Effective Conductance Modulation in Planar Silicene Field Effect Devices Due to Buckling. AB - Silicene is an exciting two-dimensional material that shares many of graphene's electronic properties, but differs in its structural buckling. This buckling allows opening a bandgap in silicene through the application of a perpendicular electric field. Here we show that this buckling also enables highly effective modulation of silicene's conductance by means of an in-plane electric field applied through silicene side gates, which can be realized concurrently within the same silicene monolayer. We illustrate this by using silicene to implement Self-Switching Diodes (SSDs), which are two-dimensional field effect nanorectifiers realized within a single silicene monolayer. Our quantum simulation results show that the atomically-thin silicene SSDs, with sub-10 nm dimensions, achieve a current rectification ratio that exceeds 200, without the need for doping, representing a 30 fold enhancement over graphene SSDs. We attribute this enhancement to a bandgap opening due to the in-plane electric field, as a consequence of silicene's buckling. Our results suggest that silicene is a promising material for the realization of planar field effect devices. PMID- 26441201 TI - Expression of Prostaglandin-Synthesizing Enzymes (Cyclooxygenase 1, Cyclooxygenase 2) in the Ovary of the Quail (Coturnix japonica). AB - Cyclooxygenase is known to be the ratelimiting enzyme in the production of prostaglandins. So far, in different bird species there have been found two isoforms of cyclooxygenases (COX), cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). These isoforms along with prostaglandins are regarded to possess a determining influence on the success in female reproduction. Only in a few bird species the expression sites of cyclooxygenases have been investigated. In this study we report on the expression of COX-1 and COX-2 in the ovary of the quail (Coturnix japonica) using PCR, immunohistochemistry and non-radioactive in situ hybridization techniques. Using real time-polymerase chain reaction (RT-PCR), a distinct signal for COX-1 and COX-2 could be shown in small and large follicles of quail ovary. Antibodies to COX-1 distinctly labelled smooth muscle cells of the stroma, whereas COX-2 showed marked immunostaining in the thecal glands and the ovarian surface epithelium. In the same location, a signal of the corresponding mRNAs of COX-1 and COX-2 was found using in situ hybridization. This expression pattern in the quail is therefore completely different from the localization of COX-1 and COX-2 in the hen and ostrich, which suggests different functions of the cyclooxygenases in this small galliform avian species. According to our results, in quails COX-2 is involved in the synthesis of prostaglandins in the ovary's interstitial glands, which until now have been considered mainly as steroid-secreting cells. COX-1, which is expressed in the smooth muscles of the stroma, possibly plays a role in ovulation. PMID- 26441202 TI - Aequorin as Intracellular Ca2+ Indicator Incorporated in Follicular Lymphoma Cells by Hypoosmotic Shock Treatment. AB - Natural proteins can be used in measuring intracellular Ca(2+) concentration. As one of the Ca(2+)- regulated photoproteins, aequorin has several advantages in comparison to widely used Ca(2+) fluorescence indicators (e.g., fura-2, indo-1 and fluo-3), including high dynamic range and resistance to motion artefacts. However, incorporation of aequorin into cells remains a challenge. Hypoosmotic shock treatment was optimized and used as a method for loading aequorin into the cytoplasm of follicular lymphoma cells. Measurement of aequorin luminescence in the cells was performed using a luminometer with a sensitive photomultiplier tube and the luminescence intensity was recalculated into intracellular [Ca(2+)]. The value of (0.85 +/- 0.52).10-6 M was found. We show that the optimized method of incorporation was effective for loading aequorin into follicular lymphoma cells in vitro. The cell viability remains high immediately after the procedure. This method can also be used for measuring intracellular Ca(2+) concentration in other types of non-adherent cells. PMID- 26441203 TI - Pericentric Inversion of Human Chromosome 9 Epidemiology Study in Czech Males and Females. AB - Pericentric inversion of human chromosome 9 [inv(9)] is a relatively common cytogenetic finding. It is largely considered a clinically insignificant variant of the normal human karyotype. However, numerous studies have suggested its possible association with certain pathologies, e.g., infertility, habitual abortions or schizophrenia. We analysed the incidence of inv(9) and the spectrum of clinical indications for karyotyping among inv(9) carriers in three medical genetics departments in Prague. In their cytogenetic databases, among 26,597 total records we identified 421 (1.6 %) cases of inv(9) without any concurrent cytogenetic pathology. This study represents the world's largest epidemiological study on inv(9) to date. The incidence of inv(9) calculated in this way from diagnostic laboratory data does not differ from the incidence of inv(9) in three specific populationbased samples of healthy individuals (N = 4,166) karyotyped for preventive (amniocentesis for advanced maternal age, gamete donation) or legal reasons (children awaiting adoption). The most frequent clinical indication in inv(9) carriers was "idiopathic reproductive failure" - 37.1 %. The spectra and percentages of indications in individuals with inv(9) were further statistically evaluated for one of the departments (N = 170) by comparing individuals with inv(9) to a control group of 661 individuals with normal karyotypes without this inversion. The proportion of clinical referrals for "idiopathic reproductive failure" among inv(9) cases remains higher than in controls, but the difference is not statistically significant for both genders combined. Analysis in separated genders showed that the incidence of "idiopathic reproductive failure" could differ among inv(9) female and male carriers. PMID- 26441204 TI - Benfluron Induces Cell Cycle Arrest, Apoptosis and Activation of p53 Pathway in MOLT-4 Leukemic Cells. AB - The aim of our study was to determine the effect of potential anti-tumour agent benfluron on human leukemic cells MOLT-4 and elucidate the molecular mechanisms of response of tumour cells to this chemotherapeutic agent. It has been shown that the mechanisms of action of benfluron are complex, but the molecular pathways of the cytostatic effect have remained unknown and the present study contributes to their elucidation. In this work, benfluron reduced viability of the treated cells and induced caspase-mediated apoptosis. The programmed cell death was associated with activation of caspases 8, 9 and 3/7. Moreover, exposure of cells to benfluron resulted in accumulation of the cells primarily in late S and G2/M phases. The changes in the levels of key proteins show that benfluron provoked activation of p53 and induced phosphorylation of p53 on serine 15 and serine 392. The application of benfluron led to phosphorylation of Chk1 on serine 345 and phosphorylation of Chk2 on threonine 68 in the treated cells. Higher doses of benfluron caused phosphorylation of ERK1/2 on threonine 202 and tyrosine 204, whereas JNK and p38 kinases were not activated. In conclusion, benfluron induces apoptosis, cell cycle arrest in late S and G2/M phases, and activates various signalling pathways of the DNA damage response. PMID- 26441205 TI - Nobody Is Perfect: Comparison of the Accuracy of PCR-RFLP and KASPTM Method for Genotyping. ADH1B and FTO Polymorphisms as Examples. AB - DNA genotyping is among the most common analyses currently performed in scientific research. Two high-throughput genotyping techniques are widely used - the "classic" PCR-RFLP and probe-based methods such as TaqMan(r) PCR assay or KASPTM genotyping. The probe-based techniques are claimed to be more accurate than PCR-RFLP; however, the evidence for this claim is sparse. We have directly compared results of genotyping of two SNPs (rs1229984 and rs17817449) obtained by the PCR-RFLP and KASPTM in 1,502 adult Caucasians. The results were identical in 97.3 % and 95.9 % cases, respectively. Discrepancies (either different results or result obtained with one but not with the other method) were addressed by confirmatory analysis using direct sequencing. The sequencing revealed that both methods can give incorrect results, but the frequency of incorrect genotyping of rs1229984 and rs17817449 was very low for both methods - 0.1 % and 0.5 %, respectively, for PCR-RFLP and 0.1 % and 0.3 %, respectively, for KASPTM. These results confirm that the KASPTM technique is slightly more accurate, but it achieves slightly lower call rates than PCR-RFLP. When carefully set up, both PCR RFLP and KASPTM could have accuracy of 99.5 % or higher. PMID- 26441206 TI - Validation of the Portuguese version of a questionnaire to measure Quality of Care Through the Eyes of Patients with Inflammatory Bowel Disease (QUOTE-IBD). AB - BACKGROUND/AIM: The patient's perspective on the healthcare that they receive has become increasingly important in the assessment of healthcare quality, especially in chronic diseases such as inflammatory bowel disease (IBD). In this context, the questionnaire QUOTE-IBD (Quality of Care Through the Patient's Eyes with Inflammatory Bowel Disease) was created to assess the healthcare quality from the point of view of a patient with IBD. This questionnaire does not yet have a validated Portuguese version (PT-QUOTE-IBD). We aimed to assess the acceptability, validity, and reliability of PT-QUOTE-IBD. PATIENTS AND METHODS: This was an observational longitudinal unicentric study with three sequential phases: (a) translation and cultural adaptation of QUOTE-IBD that explores the Importance, Performance and Quality Impact of several dimensions of healthcare; (b) assessment of validity by correlation of the results of PT-QUOTE-IBD and visual analogue scales (VAS); and (c) assessment of the reliability of PT-QUOTE IBD through a second administration of the questionnaire, with a minimum interval of 4 weeks. RESULTS: We included 114 patients with IBD (77 Crohn's disease and 37 ulcerative colitis). Fifty-nine percent of the patients completed all the questions of QUOTE-IBD and VAS. We obtained positive and significant Pearson's correlation coefficients between QUOTE-IBD scores and VAS for Performance and Quality Impact of Total Care and dimensions Accessibility and Information. Thirty four (30%) patients completed the second questionnaire adequately. We obtained positive and significant Pearson's correlation coefficients between the two questionnaires for Performance and Quality Impact of Total Care, Accessibility, Continuity of Care, Courtesy and Information, and for Performance of Cost. CONCLUSION: PT-QUOTE-IBD is acceptable, valid, and reliable in the assessment of Performance and Quality Impact of Total Care, but not of all dimensions of healthcare. PMID- 26441207 TI - Prognostic significance of the EGFR pathway in nasopharyngeal carcinoma: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the prognostic impact of the EGF receptor (EGFR) pathway molecules and assess their clinical usefulness. METHODS: We conducted a systematic review. Pubmed and EMBASE were searched January 2014. The prognostic relevance of EGFR, JAK, PI3K, PIK3CA, STAT3, STAT5, PTEN, AKT, mTOR, GRB2, SOS, RAF, RAS, MAPK, ERK, MEK and CCND1 in nasopharyngeal carcinoma was assessed. The outcomes considered were overall survival, disease-free survival and tumor-node metastasis stage. Twenty-two studies were included. Risk of bias was evaluated. Meta-analysis for which pooled hazard ratios and 95% CIs were calculated. CONCLUSION: EGFR overexpression predicts a worse overall survival and disease free survival in nasopharyngeal carcinoma, but no specific causal pathway molecule could be identified. PMID- 26441208 TI - Unprecedented transformation of [I(-).I3(-)] to [I4(2-)] polyiodides in the solid state: structures, phase transitions and characterization of dipyrazolium iodide triiodide. AB - Dipyrazolium iodide triiodide, [C3N2H5(+)]2[I(-).I3(-)], has been synthesized and studied by means of X-ray diffraction, differential scanning calorimetry, dielectric measurements, and UV-Vis spectroscopy. Two reversible, solid-solid phase transitions (Imma (I) <-> (II) <->Pbam (III)) at 254 K and 182/188 K respectively have been revealed. The anionic network experiences spectacular changes associated with a huge rebuilding of the inorganic network from [I(-).I3( )] to [I4(2-)]. The low frequency dielectric relaxation process occurs in phase II with the activation energy of ca. 34 kJ mol(-1). The molecular motion of the pyrazolium cations in [C3N2H5(+)]2[I(-).I3(-)] has been studied by means of proton magnetic resonance studies ((1)H NMR). The ferroelastic properties of all phases have been confirmed by polarizing microscopy observations. The molecular mechanism of the phase transitions in the compound is proposed. PMID- 26441209 TI - Risk Factors for Pancreatic Cancer in China: A Multicenter Case-Control Study. AB - BACKGROUND: Despite having one of the highest mortality rates of all cancers, the risk factors of pancreatic cancer remain unclear. We assessed risk factors of pancreatic cancer in China. METHODS: A case-control study design was conducted using data from four hospital-based cancer registries (Henan Provincial Cancer Hospital, Beijing Cancer Hospital, Hebei Provincial Cancer Hospital, and Cancer Hospital of Chinese Academy of Medical Sciences). Controls were equally matched and selected from family members of non-pancreatic cancer patients in the same hospitals. Face-to-face interviews were conducted by trained staff using questionnaires. Conditional logistic regression models were used to assess odd ratios (ORs) and 95% confident intervals (CIs). RESULTS: Among 646 recruited participants, 323 were pancreatic cancer patients and 323 were controls. Multivariate logistic analysis suggested that pancreatic cancer family history (adjusted OR 1.23; 95% CI, 1.11-3.70), obesity (adjusted OR 1.77; 95% CI, 1.22 2.57), diabetes (adjusted OR 2.96; 95% CI, 1.48-5.92) and smoking (adjusted OR 1.78; 95% CI, 1.02-3.10) were risk factors for pancreatic cancer, but that drinking tea (adjusted OR 0.49; 95% CI, 0.25-0.84) was associated with reduced risk of pancreatic cancer. CONCLUSIONS: Cigarette smoking, family history, obesity, and diabetes are risk factors of pancreatic cancer, which is important information for designing early intervention and preventive strategies for pancreatic cancer and may be beneficial to pancreatic cancer control in China. PMID- 26441210 TI - Association of Combined Tobacco Smoking and Oral Contraceptive Use With Cervical Intraepithelial Neoplasia 2 or 3 in Korean Women. AB - BACKGROUND: Cigarette smoking and oral contraceptive (OC) use have been associated with cervical neoplasia, and the combination of smoking and OC use could influence cervical carcinogenesis. We aimed to assess the joint effect of smoking and OC use on the risk of cervical intraepithelial neoplasia (CIN). METHODS: From a cohort of human papillomavirus-positive subjects recruited from 6 hospitals in Korea from March 2006 to November 2012, a total of 678 subjects (411 control, 133 CIN 1, and 134 CIN 2 or 3 cases) were selected for this study (mean age, 43 years). The risk of CIN associated with smoking and OC use on additive and multiplicative scales was estimated via multinomial logistic regression after adjustment for potential confounding factors. The relative excess risk due to interaction (RERI) and the synergy index (S) were used to evaluate the additive interaction. RESULTS: OC users (odds ratio [OR] 1.98; 95% confidence interval [CI], 1.07-3.69) and long-term OC use (>=20 months; OR 2.71; 95% CI, 1.11-6.59) had a higher risk of CIN 2/3, but had no association with CIN 1, compared to non OC users. Smokers and heavy smoking (>=8 cigarettes/day) were not associated with any CIN grade. Combined smoking and OC use (OR 4.91; 95% CI, 1.68-14.4; RERI/S, 3.77/27.4; P for multiplicative interaction = 0.003) and combined heavy smoking and long-term OC use (OR 11.5; 95% CI, 1.88-70.4; RERI/S, 9.93/18.8; P for multiplicative interaction = 0.009) had a higher risk of CIN 2/3 but had no association with CIN 1 compared to combined non-smoking and non-OC use. CONCLUSIONS: OC use and smoking acted synergistically to increase the risk of CIN 2 or 3 in Korean women. PMID- 26441211 TI - Effects of a Public Education Campaign on the Association Between Knowledge of Early Stroke Symptoms and Intention to Call an Ambulance at Stroke Onset: The Acquisition of Stroke Knowledge (ASK) Study. AB - BACKGROUND: An immediate ambulance call offers the greatest opportunity for acute stroke therapy. Effectively using ambulance services requires strengthening the association between knowledge of early stroke symptoms and intention to call an ambulance at stroke onset, and encouraging the public to use ambulance services. METHODS: The present study utilized data from the Acquisition of Stroke Knowledge (ASK) study, which administered multiple-choice, mail-in surveys regarding awareness of early stroke symptoms and response to a stroke attack before and after a 2-year stroke education campaign in two areas subject to intensive and moderate intervention, as well as in a control area, in Japan. In these three areas, 3833 individuals (1680, 1088 and 1065 participants in intensive intervention, moderate intervention, and control areas, respectively), aged 40 to 74 years, who responded appropriately to each survey were included in the present study. RESULTS: After the intervention, the number of correctly identified symptoms significantly associated with intention to call an ambulance (P < 0.05) increased (eg, from 4 to 5 correctly identified symptoms), without increasing choice of decoy symptoms in the intensive intervention area. Meanwhile, in other areas, rate of identification of not only correct symptoms but also decoy symptoms associated with intention to call an ambulance increased. Furthermore, the association between improvement in the knowledge of stroke symptoms and intention to call an ambulance was observed only in the intensive intervention area (P = 0.009). CONCLUSIONS: Our results indicate that intensive interventions are useful for strengthening the association between correct knowledge of early stroke symptoms and intention to call an ambulance, without strengthening the association between incorrect knowledge and intention to call an ambulance. PMID- 26441212 TI - Increased risk of second malignant neoplasms in adolescents and young adults with cancer. AB - BACKGROUND: The authors describe the incidence and characteristics of secondary malignant neoplasms (SMNs) in adolescent and young adult (AYA) cancer survivors compared with those in younger and older cancer survivors. METHODS: Children aged <= 14 years, AYAs aged 15 to 39, and older adults aged >= 40 years at the time of primary diagnosis who were reported as cancer survivors in the Surveillance, Epidemiology, and End Results (SEER) program between 1973 and 2011 were compared in this population-based analysis. The primary analysis was the risk that an SMN would occur >= 5 years after the original diagnosis for patients who had the more common AYA cancers (leukemia, lymphoma, testicular malignancy, ovarian malignancy, melanoma, and cancers of the thyroid, breast, soft tissue, or bone). The standardized incidence ratio (SIR), absolute excess risk (AER), and cumulative incidence of SMN for the selected cancers were assessed. The risk of SMN for the entire cohort also was analyzed. RESULTS: Of the 148,558 AYA survivors who were diagnosed with a selected cancer, 7384 developed an SMN 5 years after their original diagnosis. The SIRs (95% confidence intervals [CIs]) were 1.58 (95% CI, 1.55-1.62) for AYAs, 4.26 (95% CI, 3.77-4.80) for children, and 1.10 (95% CI, 1.09-1.11) for older adults, and the AERs were 22.9, 16.6, and 14.7, respectively. The cumulative incidence of SMN at 30 years was 13.9% for the AYA group. The most common SMNs in AYAs were breast cancer, gastrointestinal cancer, genital cancers, and melanoma. AYAs who had received radiation therapy had a higher cumulative incidence of SMN. CONCLUSIONS: AYAs who survive cancer for more than 5 years have a higher relative risk of SMN compared with the general population and have a higher absolute risk of SMN compared with younger or older cancer survivors. PMID- 26441213 TI - A Survey of Academic Radiology Department Chairs on Hiring Recent Graduates as New Attending Physicians. AB - RATIONALE AND OBJECTIVES: To determine hiring preferences among academic radiology department chairs with emphasis on recent residency and fellowship graduates. MATERIALS AND METHODS: With the assistance of the Society of Chairs of Academic Radiology Departments (SCARD), an anonymous survey was distributed to academic radiology department chairs during the time period December 2014-March 2015, with additional reminder emails during the study period. Varied multiple choice questions were designed to gather information regarding program details; qualities most valued in new attending hires; level of difficulty recruiting subspecialty fellowship-trained radiologists; and the effect of the new ABR certification process on hiring practices. Descriptive statistics and analyses are reported. RESULTS: Surveys were completed by 79 of 184 eligible academic radiology chairs, a response rate of 43%. The most important hiring criteria cited were expertise in subspecialty, fellowship training, and perceived ability to work well with referring physicians. The most popular recruitment tools cited were hiring candidates from a chair's own program, journal ads, and academic networks. A minority of chairs (16%), primarily those of smaller departments, will not hire new graduates before completing board certification under the new certification structure (P = .0143). CONCLUSIONS: Expertise in a candidate's subspecialty was consistently cited as the most important hiring criterion. Changes to the ABR certification process, however, will affect hiring decisions, particularly within smaller academic departments. PMID- 26441214 TI - Computational Insights into Excited-State Proton-Transfer Reactions in Azo and Azomethine Dyes. AB - State of the art density functional theory approaches are employed to provide an accurate description of the photophysical properties of azodyes and Schiff bases displaying intramolecular hydrogen-bonding features. These compounds exist as tautomeric mixtures at the ground state and, in the case of Schiff bases, an excited-state intramolecular proton transfer (ESIPT) occurs upon excitation. The experimentally observed photophysical properties are discussed here in light of the theoretical findings. To rationalize the different experimentally observed radiative behavior of the azo and azomethine structures, a nonradiative decay pathway that is possibly active in such systems is determined. The characterization of this deactivation path, tested for two related compounds exhibiting different fluorescence quantum yields, enables us to disentangle the different and contrasting effects governing the excited-state behavior of these molecular systems. PMID- 26441215 TI - Diabetes Management in Older Adults: Seeing the Forest for the Trees. PMID- 26441217 TI - Surgery for endometriosis-related pain. PMID- 26441218 TI - Ab initio phonon properties of half-Heusler NiTiSn, NiZrSn and NiHfSn. AB - A theoretical investigation of phonon properties from first-principles calculations is carried out for the half-Heusler compounds NiXSn, [Formula: see text], Zr and Hf. The crystal structures are optimised via ab initio calculations within the framework of density functional theory. The phonon properties are retrieved from harmonic and anharmonic interatomic force constants calculations using the finite size displacements method and many-body perturbation theory. A solution to the linearized phonon Boltzmann transport equation is then used to compute the ab initio thermal conductivities. For X = Ti, Zr and Hf, we found 15.4, 13.3 and 15.8 W m(-1) K(-1) at 300 K, respectively. Thanks to a spectral analysis of the velocities and lifetimes we were able appreciate the differences in the thermal conductivities between the three compounds under study. Our results provide insights to understand the behaviour of the thermal conductivity and therefore to improve the thermoelectric figure of merit for such materials. PMID- 26441220 TI - Clinical study of continuous micropump infusion of atropine and pralidoxime chloride for treatment of severe acute organophosphorus insecticide poisoning. AB - BACKGROUND: Our study sought to assess the effectiveness of a constant micropump infusion of atropine and pralidoxime chloride compared with repeated-bolus doses in patients with severe acute organophosphorus insecticide poisoning (AOPP). METHODS: A total of 60 patients with severe AOPP, defined as cholinergic crisis with respiratory failure or cerebral edema, were randomly divided into two groups of 30 patients each. In the experimental group, patients received a continuous micropump of atropine and pralidoxime chloride; in the control group, patients were given intermittent injections of atropine and pralidoxime chloride. Primary outcome measures were the dose of atropine required for atropinization, Acute Physiology and Chronic Health Evaluation II (APACHE II) score at atropinization, time to atropinization and acetylcholinesterase (AchE) recovery time. Additionally, the case fatality rate was measured as a secondary outcome. RESULTS: Compared to patients in the control group, the time to atropinization, AchE recovery time, dose of atropine when atropinization occurred, and APACHE II score in the experimental group showed a statistically significant therapeutic effect (p < 0.05), and the case fatality rate of the experimental group was lower than that of the control group (p < 0.05). CONCLUSION: Continuous micropump of atropine and pralidoxime chloride combined is more effective than the use of repeated-bolus injection in the treatment of severe acute organophosphorus insecticide poisoning. PMID- 26441219 TI - The hand of Homo naledi. AB - A nearly complete right hand of an adult hominin was recovered from the Rising Star cave system, South Africa. Based on associated hominin material, the bones of this hand are attributed to Homo naledi. This hand reveals a long, robust thumb and derived wrist morphology that is shared with Neandertals and modern humans, and considered adaptive for intensified manual manipulation. However, the finger bones are longer and more curved than in most australopiths, indicating frequent use of the hand during life for strong grasping during locomotor climbing and suspension. These markedly curved digits in combination with an otherwise human-like wrist and palm indicate a significant degree of climbing, despite the derived nature of many aspects of the hand and other regions of the postcranial skeleton in H. naledi. PMID- 26441216 TI - A new antibiotic regimen treats and prevents intra-amniotic inflammation/infection in patients with preterm PROM. AB - OBJECTIVES: To determine whether a new antibiotic regimen could reduce the frequency of intra-amniotic inflammation/infection in patients with preterm PROM. STUDY DESIGN: This retrospective cohort study was conducted to evaluate the effect of antibiotics on the frequency of intra-amniotic inflammation/infection based on the results of follow-up transabdominal amniocenteses from 89 patients diagnosed with preterm PROM who underwent serial amniocenteses. From 1993-2003, ampicillin and/or cephalosporins or a combination was used ("regimen 1"). A new regimen (ceftriaxone, clarithromycin and metronidazole) was used from 2003-2012 ("regimen 2"). Amniotic fluid was cultured and matrix metalloproteinase-8 (MMP-8) concentrations were measured. RESULTS: (1) The rates of intra-amniotic inflammation and intra-amniotic inflammation/infection in patients who received regimen 2 decreased during treatment from 68.8% to 52.1% and from 75% to 54.2%, respectively. In contrast, in patients who received regimen 1, the frequency of intra-amniotic inflammation and infection/inflammation increased during treatment (31.7% to 55% and 34.1% to 58.5%, respectively); and (2) intra-amniotic inflammation/infection was eradicated in 33.3% of patients who received regimen 2, but in none who received regimen 1. CONCLUSION: The administration of ceftriaxone, clarithromycin and metronidazole was associated with a more successful eradication of intra-amniotic inflammation/infection and prevented secondary intra-amniotic inflammation/infection more frequently than an antibiotic regimen which included ampicillin and/or cephalosporins in patients with preterm PROM. PMID- 26441221 TI - Do People "Pop Out"? AB - The human body is a highly familiar and socially very important object. Does this mean that the human body has a special status with respect to visual attention? In the current paper we tested whether people in natural scenes attract attention and "pop out" or, alternatively, are at least searched for more efficiently than targets of another category (machines). Observers in our study searched a visual array for dynamic or static scenes containing humans amidst scenes containing machines and vice versa. The arrays consisted of 2, 4, 6 or 8 scenes arranged in a circular array, with targets being present or absent. Search times increased with set size for dynamic and static human and machine targets, arguing against pop out. However, search for human targets was more efficient than for machine targets as indicated by shallower search slopes for human targets. Eye tracking further revealed that observers made more first fixations to human than to machine targets and that their on-target fixation durations were shorter for human compared to machine targets. In summary, our results suggest that searching for people in natural scenes is more efficient than searching for other categories even though people do not pop out. PMID- 26441222 TI - MicroRNA (miRNA)-Mediated Pathogenetic Signaling in Alzheimer's Disease (AD). AB - Alzheimer's disease (AD) is an expanding health and socioeconomic concern in industrialized societies, and the leading cause of intellectual impairment in our aging population. The cause of AD remains unknown, and there are currently no effective treatments to stop or reverse the progression of this uniquely human and age-related neurological disorder. Elucidation of the AD mechanism and factors that contribute to the initiation, progression, and spreading of this chronic and fatal neurodegeneration will ultimately result in improved and effective diagnostics and therapeutic strategies.microRNAs (miRNAs) comprise a relatively recently discovered category of 20-24 nucleotide non-coding RNAs that function post-transcriptionally in shaping the transcriptome of the cell, and in doing so, contribute to the molecular-genetics and phenotype of human CNS health and disease. To date about 2550 unique mature human miRNAs have been characterized, however only highly selected miRNA populations appear to be enriched in different anatomical compartments within the CNS.This general commentary for the 'Special Issue: 40th Year of Neurochemical Research' will bring into perspective (i) some very recent findings on the extraordinary biophysics and signaling properties of CNS miRNA in AD and aging human brain; (ii) how specific intrinsic biophysical attributes of miRNAs may play defining roles in the establishment, proliferation and spreading of the AD phenotype; and (iii) how miRNAs can serve as prospective therapeutic targets and biomarkers potentially useful in the clinical management of this terminal neurological disease whose incidence in our rapidly aging population is reaching epidemic proportions. PMID- 26441224 TI - Adsorbent 2D and 3D carbon matrices with protected magnetic iron nanoparticles. AB - We report on the synthesis of two and three dimensional carbonaceous sponges produced directly from graphene oxide (GO) into which functionalized iron nanoparticles can be introduced to render it magnetic. This simple, low cost procedure, wherein an iron polymeric resin precursor is introduced into the carbon framework, results in carbon-based materials with specific surface areas of the order of 93 and 66 m(2) g(-1), compared to approx. 4 m(2) g(-1) for graphite, decorated with ferromagnetic iron nanoparticles giving coercivity fields postulated to be 216 and 98 Oe, values typical for ferrite magnets, for 3.2 and 13.5 wt% Fe respectively. The strongly magnetic iron nanoparticles are robustly anchored to the GO sheets by a layer of residual graphite, on the order of 5 nm, formed during the pyrolysis of the precursor material. The applicability of the carbon sponges is demonstrated in their ability to absorb, store and subsequently elute an organic dye, Rhodamine B, from water as required. It is possible to regenerate the carbon-iron hybrid material after adsorption by eluting the dye with a solvent to which it has a high affinity, such as ethanol. The use of a carbon framework opens the hybrid materials to further chemical functionalization, for enhanced chemical uptake of contaminants, or co-decoration with, for example, silver nanoparticles for bactericidal properties. Such analytical properties, combined with the material's magnetic character, offer solutions for environmental decontamination at land and sea, wastewater purification, solvent extraction, and for the concentration of dilute species. PMID- 26441223 TI - Rhynchophylline Protects Against the Amyloid beta-Induced Increase of Spontaneous Discharges in the Hippocampal CA1 Region of Rats. AB - Accumulated soluble amyloid beta (Abeta)-induced aberrant neuronal network activity has been recognized as a key causative factor leading to cognitive deficits which are the most outstanding characteristic of Alzheimer's disease (AD). As an important structure associated with learning and memory, the hippocampus is one of the brain regions that are impaired very early in AD, and the hippocampal CA1 region is selectively vulnerable to soluble Abeta oligomers. Our recent study showed that soluble Abeta1-42 oligomers induced hyperactivity and perturbed the firing patterns in hippocampal neurons. Rhynchophylline (RIN) is an important active tetracyclic oxindole alkaloid isolated from Uncaria rhynchophylla which is a traditional Chinese medicine and often used to treat central nervous system illnesses such as hypertension, convulsions, tremor, stroke etc. Previous evidence showed that RIN possessed neuroprotective effects of improving the cognitive function of mice with Alzheimer-like symptoms. In the present study, we aimed to investigate the protective effect of RIN against soluble Abeta1-42 oligomers-induced hippocampal hyperactivity. The results showed that (1) the mean frequency of spontaneous discharge was increased by the local application of 3 MUM soluble Abeta1-42 oligomers; (2) 30 MUM RIN did not exert any obvious effects on basal physiological discharges; and (3) treatment with RIN effectively inhibited the soluble Abeta1-42 oligomers-induced enhancement of spontaneous discharge, in a concentration-dependent manner with an IC50 = 9.0 MUM. These in vivo electrophysiological results indicate that RIN can remold the spontaneous discharges disturbed by Abeta and counteract the deleterious effect of Abeta1-42 on neural circuit. The experimental findings provide further evidence to affirm the potential of RIN as a worthy candidate for further development into a therapeutic agent for AD. PMID- 26441225 TI - Altering Transplantation Time to Avoid Periods of High Temperature Can Efficiently Reduce Bacterial Wilt Disease Incidence with Tomato. AB - Tomato bacterial wilt caused by Ralstonia solanacearum bacterium is a severe problem in Southern China, where relatively high environmental temperatures commonly prevails during the crop seasons. Previous research has indicated that bacterial wilt disease incidence generally increases during the warm months of summer leading to reduced tomato yield. Moreover, the efficacy of bio-organic fertilizers (BOFs)-organic compost fortified with pathogen-suppressive bacteria is often lost during the periods of high environmental temperatures. Here we studied if the disease incidence could be reduced and the BOF performance enhanced by simply preponing and postponing the traditional seedling transplantation times to avoid tomato plant development during periods of high environmental temperature. To this end, a continuous, two-year field experiment was conducted to evaluate the performance of BOF in two traditional (late-spring [LS] and early-autumn [EA]) and two alternative (early-spring [ES] and late autumn [LA]) crop seasons. We found that changing the transplantation times reduced the mean disease incidence from 33.9% (LS) and 54.7% (EA) to 11.1% (ES) and 7.1% (LA), respectively. Reduction in disease incidence correlated with the reduction in R. Solanacearum pathogen density in the tomato plant rhizosphere and stem base. Applying BOF during alternative transplantation treatments improved biocontrol efficiency from 43.4% (LS) and 3.1% (EA) to 67.4% (ES) and 64.8% (LA). On average, the mean maximum air temperatures were positively correlated with the disease incidence, and negatively correlated with the BOF biocontrol efficacy over the crop seasons. Crucially, even though preponing the transplantation time reduced the tomato yield in general, it was still economically more profitable compared to LS season due to reduced crop losses and relatively higher market prices. Preponing and postponing traditional tomato transplantation times to cooler periods could thus offer simple but effective way to control R. solanacearum disease outbreaks. PMID- 26441227 TI - Expression of activation markers in circulating basophils and the relationship to allergen-induced bronchoconstriction in subjects with mild allergic asthma. PMID- 26441226 TI - Diverse activation and differentiation of multiple B-cell subsets in patients with atopic dermatitis but not in patients with psoriasis. AB - BACKGROUND: Atopic dermatitis (AD) and psoriasis pathogeneses involve skin barrier impairment and immune dysregulation; however, the contribution of B-cell imbalances to these diseases has not yet been determined. OBJECTIVE: We sought to quantify B-cell populations and antibody-secreting cells in the blood of patients with AD, patients with psoriasis, and control subjects. METHODS: We studied 34 adults with moderate-to-severe AD (mean SCORAD score, 65), 24 patients with psoriasis (mean Psoriasis Area and Severity Index score, 16), and 27 healthy subjects using an 11-color flow cytometric antibody panel. IgD/CD27 and CD24/CD38 core gating systems were used to determine frequencies of plasmablasts and naive, memory, transitional, and activated B cells. RESULTS: We measured increased CD19(+)CD20(+) B-cell counts in the skin and blood of patients with AD (P < .01). Significantly higher frequencies of chronically activated CD27(+) memory and nonswitched memory B cells were observed in patients with AD (P < .05), with lower values of double-negative populations (4% for patients with AD vs. 7% for patients with psoriasis [P = .001] and 6% for control subjects [P = .02]). CD23 expression was highest in patients with AD and correlated with IgE levels (P < .01) and disease severity (r = 0.6, P = .0002). Plasmablast frequencies and IgE expression were highest in all memory subsets of patients with AD (P < .01). Finally, CD19(+)CD24(++)CD38(++) transitional and CD19(+)CD24(-)CD38(-) new memory B-cell counts were higher in patients with AD versus those in patients with psoriasis (2.8% vs. 1.4% [P = .001] and 9.2% vs. 5.7% [P = .02], respectively). CONCLUSIONS: AD is accompanied by systemic expansion of transitional and chronically activated CD27(+) memory, plasmablast, and IgE expressing memory subsets. These data create a critical basis for the future understanding of this debilitating skin disease. PMID- 26441229 TI - Identification of checkpoints in human T-cell development using severe combined immunodeficiency stem cells. AB - BACKGROUND: Severe combined immunodeficiency (SCID) represents congenital disorders characterized by a deficiency of T cells caused by arrested development in the thymus. Yet the nature of these developmental blocks has remained elusive because of the difficulty of taking thymic biopsy specimens from affected children. OBJECTIVE: We sought to identify the stages of arrest in human T-cell development caused by various major types of SCID. METHODS: We performed transplantation of SCID CD34(+) bone marrow stem/progenitor cells into an optimized NSG xenograft mouse model, followed by detailed phenotypic and molecular characterization using flow cytometry, immunoglobulin and T-cell receptor spectratyping, and deep sequencing of immunoglobulin heavy chain (IGH) and T-cell receptor delta (TRD) loci. RESULTS: Arrests in T-cell development caused by mutations in IL-7 receptor alpha (IL7RA) and IL-2 receptor gamma (IL2RG) were observed at the most immature thymocytes much earlier than expected based on gene expression profiling of human thymocyte subsets and studies with corresponding mouse mutants. T-cell receptor rearrangements were functionally required at the CD4(-)CD8(-)CD7(+)CD5(+) stage given the developmental block and extent of rearrangements in mice transplanted with Artemis-SCID cells. The xenograft model used is not informative for adenosine deaminase-SCID, whereas hypomorphic mutations lead to less severe arrests in development. CONCLUSION: Transplanting CD34(+) stem cells from patients with SCID into a xenograft mouse model provides previously unattainable insight into human T-cell development and functionally identifies the arrest in thymic development caused by several SCID mutations. PMID- 26441228 TI - Association of eosinophilic esophagitis and hypertrophic cardiomyopathy. PMID- 26441230 TI - Stress responses to repeated exposure to a combined physical and social evaluative laboratory stressor in young healthy males. AB - Repeated exposure to homotypic laboratory psychosocial stressors typically instigates rapid habituation in hypothalamic-pituitary-adrenal (HPA) axis mediated stress responses in humans. However, emerging evidence suggests the combination of physical stress and social evaluative threat may be sufficient to attenuate this response habituation. Neuroendocrine, cardiovascular and subjective stress responses following repeated exposure to a combined physical and social evaluative stress protocol were assessed to examine the habituation response dynamic in this context. The speech task of the Trier social stress test (TSST; Kirschbaum et al., 1993) and the socially evaluated cold pressor task (SECPT; Schwabe et al., 2008) were administered in a combined stressor protocol. Salivary cortisol, cardiovascular and subjective stress responses to a non-stress control and repeat stressor exposure separated by six weeks were examined in males (N=24) in a crossover manner. Stressor exposure resulted in significant elevations in all stress parameters. In contrast to the commonly reported habituation in cortisol response, a comparable post-stress response was demonstrated. Cortisol, heart rate and subjective stress responses were also characterised by a heightened response in anticipation to repeated stress exposure. Blood pressure responses were comparatively uniform across repeated exposures. Findings suggest a combined physical and social evaluative stressor is a potentially useful method for study designs that require repeated presentation of a homotypic stressor. PMID- 26441231 TI - Determinants of cortisol awakening responses to naps and nighttime sleep. AB - The cortisol awakening response (CAR) is a phenomenon describing the sharp increase in basal cortisol levels shortly after waking from sleep. While extensively studied, little is known about the role of sleep architecture contributing to CAR. Furthermore, the potential for CAR after a shorter bout of sleep--a nap--has not been directly investigated. The current studies thus aimed at assessed sleep duration, time of day, and sleep architecture as potential determinants of the cortisol awakening response. Saliva samples were collected during the first hour (0, 30, 45, 60 min) following several EEG-monitored laboratory sleep conditions. Those included afternoon naps wherein 17 participants (4 men; ages 18-26) napped for 50 min and 24 participants (11 men; ages 18-24) napped for 90 min. Furthermore, 20 participants (10 men; ages 18-35) visited the lab twice and in addition to staying overnight, napped 90 min in the morning either under placebo conditions or pharmacologically-manipulated sleep conditions (5mg Zolpidem). Cortisol increases were observed in response to each sleep condition except to 50-min afternoon naps. Furthermore, CARs were predicted by Stage 2 sleep when following nighttime sleep (r=.46, p=.04) and by Stage 1 sleep when following placebo morning naps (r=.54, p=.01). The current study established cortisol awakening responses to naps and implicates sleep duration and architecture in the generation of CAR to both napping and nighttime sleep. Assessing CAR in conjunction with the specific type of sleep may thus contribute to our understanding of mechanisms underlying positive and negative health effects of napping. PMID- 26441236 TI - Dynamics of ADAM17-Mediated Shedding of ACE2 Applied to Pancreatic Islets of Male db/db Mice. AB - Angiotensin-converting enzyme 2 (ACE2) gene therapy aimed at counteracting pancreatic ACE2 depletion improves glucose regulation in two diabetic mouse models: db/db mice and angiotensin II-infused mice. A disintegrin and metalloproteinase 17 (ADAM17) can cause shedding of ACE2 from the cell membrane. The aim of our studies was to determine whether ADAM17 depletes ACE2 levels in pancreatic islets and beta-cells. Dynamics of ADAM17-mediated ACE2 shedding were investigated in 832/13 insulinoma cells. Within a wide range of ACE2 expression levels, including the level observed in mouse pancreatic islets, overexpression of ADAM17 increases shed ACE2 and decreases cellular ACE2 levels. We provide a mathematical description of shed and cellular ACE2 activities as a function of the ADAM17 activity. The effect of ADAM17 on the cellular ACE2 content was relatively modest with an absolute control strength value less than 0.25 and approaching 0 at low ADAM17 activities. Although we found that ADAM17 and ACE2 are both expressed in pancreatic islets, the beta-cell is not the major cell type expressing ACE2 in islets. During diabetes progression in 8-, 12-, and 15-week old db/db mice, ACE2 mRNA and ACE2 activity levels in pancreatic islets were not decreased over time nor significantly decreased compared with nondiabetic db/m mice. Levels of ADAM17 mRNA and ADAM17 activity were also not significantly changed. Inhibiting basal ADAM17 activity in mouse islets failed to affect ACE2 levels. We conclude that whereas ADAM17 has the ability to shed ACE2, ADAM17 does not deplete ACE2 from pancreatic islets in diabetic db/db mice. PMID- 26441237 TI - 17beta-Estradiol Enhances ASIC Activity in Primary Sensory Neurons to Produce Sex Difference in Acidosis-Induced Nociception. AB - Sex differences have been reported in a number of pain conditions. Women are more sensitive to most types of painful stimuli than men, and estrogen plays a key role in the sex differences in pain perception. However, it is unclear whether there is a sex difference in acidosis-evoked pain. We report here that both male and female rats exhibit nociceptive behaviors in response to acetic acid, with females being more sensitive than males. Local application of exogenous 17beta estradiol (E2) exacerbated acidosis-evoked nociceptive response in male rats. E2 and estrogen receptor (ER)-alpha agonist 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H pyrazole, but not ERbeta agonist 2,3-bis(4-hydroxyphenyl)-propionitrile, replacement also reversed attenuation of the acetic acid-induced nociceptive response in ovariectomized females. Moreover, E2 can exert a rapid potentiating effect on the functional activity of acid-sensing ion channels (ASICs), which mediated the acidosis-induced events. E2 dose dependently increased the amplitude of ASIC currents with a 42.8 +/- 1.6 nM of EC50. E2 shifted the concentration response curve for proton upward with a 50.1% +/- 6.2% increase of the maximal current response to proton. E2 potentiated ASIC currents via an ERalpha and ERK1/2 signaling pathway. E2 also altered acidosis-evoked membrane excitability of dorsal root ganglia neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acidic stimuli. E2 potentiation of the functional activity of ASICs revealed a peripheral mechanism underlying this sex difference in acetic acid-induced nociception. PMID- 26441238 TI - Ghrelin Is an Essential Factor for Motilin-Induced Gastric Contraction in Suncus murinus. AB - Motilin was discovered in the 1970s as the most important hormone for stimulating strong gastric contractions; however, the mechanisms by which motilin causes gastric contraction are not clearly understood. Here, we determined the coordinated action of motilin and ghrelin on gastric motility during fasted and postprandial contractions by using house musk shrew (Suncus murinus; order: Insectivora, suncus named as the laboratory strain). Motilin-induced gastric contractions at phases I and II of the migrating motor complex were inhibited by pretreatment with (D-Lys(3))-GHRP-6 (6 mg/kg/h), a ghrelin receptor antagonist. Administration of the motilin receptor antagonist MA-2029 (0.1 mg/kg) and/or (D Lys(3))-GHRP-6 (0.6 mg/kg) at the peak of phase III abolished the spontaneous gastric phase III contractions in vivo. Motilin did not stimulate gastric contractions in the postprandial state. However, in the presence of a low dose of ghrelin, motilin evoked phase III-like gastric contractions even in the postprandial state, and postprandial gastric emptying was accelerated. In addition, pretreatment with (D-Lys(3))-GHRP-6 blocked the motilin-induced gastric contraction in vitro and in vivo, and a gamma-aminobutyric acid (GABA) antagonist reversed this block in gastric contraction. These results indicate that blockade of the GABAergic pathway by ghrelin is essential for motilin-induced gastric contraction. PMID- 26441240 TI - Ablation of p38alpha MAPK Signaling in Osteoblast Lineage Cells Protects Mice From Bone Loss Induced by Estrogen Deficiency. AB - Estrogen deficiency causes bone loss by increasing the number of bone-resorbing osteoclasts. Selective p38alpha MAPK inhibitors prevent bone-wasting effects of estrogen withdrawal but implicated mechanisms remain to be identified. Here, we show that inactivation of the p38alpha-encoding gene in osteoblast lineage cells with the use of an osteocalcin-cre transgene protects mice from ovariectomy induced bone loss (a murine model of postmenopausal osteoporosis). Ovariectomy fails to induce bone loss, increase bone resorption, and stimulate receptor activator of nuclear factor kappaB ligand and IL-6 expression in mice lacking p38alpha in osteoblasts and osteocytes. Finally, TNFalpha or IL-1, which are osteoclastogenic cytokines overproduced in the bone marrow under estrogen deficiency, can activate p38alpha signaling in osteoblasts, but those cytokines cannot enhance Rankl and Il6 expressions or increase osteoclast formation in p38a deficient osteoblast cultures. These findings demonstrate that p38alpha MAPK signaling in osteoblast lineage cells mediates ovariectomy-induced bone loss by up-regulating receptor activator of nuclear factor kappaB ligand and IL-6 production. PMID- 26441239 TI - A High-Calcium and Phosphate Rescue Diet and VDR-Expressing Transgenes Normalize Serum Vitamin D Metabolite Profiles and Renal Cyp27b1 and Cyp24a1 Expression in VDR Null Mice. AB - Vitamin D receptor (VDR)-mediated 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) dependent gene expression is compromised in the VDR null mouse. The biological consequences include: hypocalcemia, hypophosphatemia, elevated parathyroid hormone (PTH) and 1,25(OH)2D3, and consequential skeletal abnormalities. CYP24A1 is a cytochrome P450 enzyme that is involved in the side chain oxidation and destruction of both 1,25(OH)2D3 and 25-hydroxyvitamin D3 (25-OH-D3). In the current studies, we used liquid chromatography-tandem mass spectrometry technology to compare the metabolic profiles of VDR null mice fed either a normal or a calcium and phosphate-enriched rescue diet and to assess the consequence of transgenic expression of either mouse or human VDR genes in the same background. Serum 1,25(OH)2D3 levels in VDR null mice on normal chow were highly elevated (>3000 pg/mL) coincident with undetectable levels of catabolites such as 24,25 (OH)2D3 and 25-OH-D3-26,23-lactone normally observed in wild-type mice. The rescue diet corrected serum Ca(++), PTH, and 1,25(OH)2D3 values and restored basal expression of Cyp24a1 as evidenced by both renal expression of Cyp24a1 and detection of 24,25-(OH)2D3 and the 25-OH-D3-26,23-lactone. Unexpectedly, this diet also resulted in supranormal levels of 3-epi-24,25-(OH)2D3 and 3-epi-25-OH D3-26,23-lactone. The reappearance of serum 24,25-(OH)2D3 and renal Cyp24a1 expression after rescue suggests that basal levels of Cyp24a1 may be repressed by high PTH. Introduction of transgenes for either mouse or human VDR also normalized vitamin D metabolism in VDR null mice, whereas this metabolic pattern was unaffected by a transgene encoding a ligand binding-deficient mutant (L233S) human VDR. We conclude that liquid chromatography-tandem mass spectrometry-based metabolic profiling is an ideal analytical method to study mouse models with alterations in calcium/phosphate homeostasis. PMID- 26441241 TI - SHBG-C57BL/ksJ-db/db: A New Mouse Model to Study SHBG Expression and Regulation During Obesity Development. AB - Low plasma sex hormone-binding globulin (SHBG) levels in overweight individuals are a biomarker for the metabolic syndrome and are predictive of type 2 diabetes and cardiovascular disease risk. There are no in vivo models to study SHBG expression and regulation during obesity development. The main reason for this is that the obesity-prone rodent models cannot be used to study this issue, because rodents, unlike humans, do not express the SHBG gene in their livers. We have developed a unique mouse model that expresses the human SHBG, and it develops obesity, by crossing the human SHBG transgenic mice with the C57BL/ksJ-db/db mice. The results obtained with the SHBG-C57BL/ksJ-db/db mouse model have allowed us to determine that the SHBG overexpression in the C57BL/ksJ-db/db reduced the body weight gain but did not change the metabolic profile of these mice. Moreover, we elucidated the molecular mechanisms and transcription factors causing the SHBG down-regulation during obesity development, which involved changes in liver hepatocyte nuclear factor 4alpha and peroxisome proliferator activated receptor-gamma mRNA and protein levels. Furthermore, these results were confirmed using human liver biopsies. Importantly, we also showed that this model resembles what occurs in human obese subjects, because plasma SHBG and total testosterone levels where reduced in obese mice when compared with lean mice. Future research using this unique mouse model will determine the role of SHBG in the development and progression of obesity, type 2 diabetes, or fatty liver disease. PMID- 26441242 TI - Periodontal Bacterial DNA and Their Link to Human Cardiac Tissue: Findings of a Pilot Study. AB - BACKGROUND: The aim of this pilot study was to detect correlations of microbiological DNA, inflammatory proteins, and infection parameters in patients with periodontal disease (PD) and valvular heart disease (VHD). METHODS: A perioperative comprehensive dental examination for the investigation of periodontal status, including sampling of specific subgingival bacteria, was performed in 10 patients with indication for surgery of aortic valve stenosis with or without concomitant myocardial revascularization. Standard protocol biopsies were taken from right atrium (A), left septal myocardium (M), and aortic valve (V). Eleven periodontal pathogens DNA in oral and cardiac tissue samples (A/M/V) were analyzed using polymerase chain reaction. For cardiac tissue samples, Western blot analysis of LPS-binding protein (LBP), immunohistochemical (IHC) detection of LBP-big42, LPS-binding protein receptor (CD14), and macrophages (CD68), as well as inflammation scoring measurement were performed. RESULTS: Periodontitis was present in all patients with severe intensity in 7, moderate in 2 and mild in one patient. Same bacterial DNA was detected in A, M, and V in different distribution, and detection was more often in atrium than in myocardium or valve tissue. Morphological investigation revealed increased extracellular inflammatory cell migration. In IHC markers of LBP, CD68 and CD14 showed positive findings for all patients in atrium and myocardium. CONCLUSION: Our results demonstrate the presence of oral bacterial DNA in human cardiac tissue, as well as inflammatory markers potentially indicating connection of PD and VHD. Further investigation is necessary to confirm these preliminary data. PMID- 26441243 TI - H-Ferritin Is Preferentially Incorporated by Human Erythroid Cells through Transferrin Receptor 1 in a Threshold-Dependent Manner. AB - Ferritin is an iron-storage protein composed of different ratios of 24 light (L) and heavy (H) subunits. The serum level of ferritin is a clinical marker of the body's iron level. Transferrin receptor (TFR)1 is the receptor not only for transferrin but also for H-ferritin, but how it binds two different ligands and the blood cell types that preferentially incorporate H-ferritin remain unknown. To address these questions, we investigated hematopoietic cell-specific ferritin uptake by flow cytometry. Alexa Fluor 488-labeled H-ferritin was preferentially incorporated by erythroid cells among various hematopoietic cell lines examined, and was almost exclusively incorporated by bone marrow erythroblasts among human primary hematopoietic cells of various lineages. H-ferritin uptake by erythroid cells was strongly inhibited by unlabeled H-ferritin but was only partially inhibited by a large excess of holo-transferrin. On the other hand, internalization of labeled holo-transferrin by these cells was not inhibited by H ferritin. Chinese hamster ovary cells lacking functional endogenous TFR1 but expressing human TFR1 with a mutated RGD sequence, which is required for transferrin binding, efficiently incorporated H-ferritin, indicating that TFR1 has distinct binding sites for H-ferritin and holo-transferrin. H-ferritin uptake by these cells required a threshold level of cell surface TFR1 expression, whereas there was no threshold for holo-transferrin uptake. The requirement for a threshold level of TFR1 expression can explain why among primary human hematopoietic cells, only erythroblasts efficiently take up H-ferritin. PMID- 26441244 TI - Hyperuricemia Inversely Correlates with Disease Severity in Taiwanese Nonalcoholic Steatohepatitis Patients. AB - BACKGROUND & AIMS: Asians are more susceptible to non-alcoholic steatohepatitis (NASH) as well as metabolic disorder than other ethnicities. We aimed to assess the interaction between metabolic factors and fibrosis in Taiwanese NASH patients. METHODS: A total of 130 biopsy-proven Taiwanese NASH patients (94 males, age = 43.0 +/- 13.0 years) were consecutively enrolled. Their demographic, metabolic profiles and histopathological manifestations were analyzed. RESULTS: Twenty-four (18.5%) NASH patients were non-obese. Thirty-three (25.4%) patients had significant fibrosis (F2) or more: 22 (16.9%) patients were of F2, whilst 11 (8.5%) patients were of advanced fibrosis (F3-4). The prevalence of metabolic syndrome, diabetes and hypertension were 60.8%, 39.4%, and 61.5%, respectively. There was a significant inverse correlation between hyperuricemia and fibrosis stages, ranging from 48.4% of F0-1, 33.3% of F2, and 9.1% of F3-4, respectively (P = 0.01, linear trend). Multivariate logistic regression analysis showed that a decreased serum albumin level (OR = 40.0, 95% CI = 4.5-300, P = 0.001) and normal uric acid level (OR = 5.6, 95% CI = 1.5-21.7, P = 0.01) were the significant factors associated with significant fibrosis. CONCLUSIONS: Hyperuricemia inversely predicts fibrosis stages. Females might carry a more disease severity than males in Taiwanese NASH patients. PMID- 26441245 TI - A novel approach for estimating ingested dose associated with paracetamol overdose. AB - AIM: In cases of paracetamol (acetaminophen, APAP) overdose, an accurate estimate of tissue-specific paracetamol pharmacokinetics (PK) and ingested dose can offer health care providers important information for the individualized treatment and follow-up of affected patients. Here a novel methodology is presented to make such estimates using a standard serum paracetamol measurement and a computational framework. METHODS: The core component of the computational framework was a physiologically-based pharmacokinetic (PBPK) model developed and evaluated using an extensive set of human PK data. Bayesian inference was used for parameter and dose estimation, allowing the incorporation of inter-study variability, and facilitating the calculation of uncertainty in model outputs. RESULTS: Simulations of paracetamol time course concentrations in the blood were in close agreement with experimental data under a wide range of dosing conditions. Also, predictions of administered dose showed good agreement with a large collection of clinical and emergency setting PK data over a broad dose range. In addition to dose estimation, the platform was applied for the determination of optimal blood sampling times for dose reconstruction and quantitation of the potential role of paracetamol conjugate measurement on dose estimation. CONCLUSIONS: Current therapies for paracetamol overdose rely on a generic methodology involving the use of a clinical nomogram. By using the computational framework developed in this study, serum sample data, and the individual patient's anthropometric and physiological information, personalized serum and liver pharmacokinetic profiles and dose estimate could be generated to help inform an individualized overdose treatment and follow-up plan. PMID- 26441246 TI - Noninnocently Behaving Bridging Anions of the Widely Distributed Antioxidant Ellagic Acid in Diruthenium Complexes. AB - Dinuclear compounds [L2Ru(MU-E)RuL2](n) where L is acetylacetonate (acac(-), 2,4 pentanedionate), 2,2'-bipyridine (bpy), or 2-phenylazopyridine (pap) and EH4 is ellagic acid, an antioxidative bis-catechol natural product, were studied by voltammetric and spectroelectrochemical techniques (UV-vis-NIR and electron paramagnetic resonance (EPR)). The electronic structures of the isolated forms (NBu4)2[(acac)2Ru(MU-E)Ru(acac)2] ((NBu4)2[1]), [(bpy)2Ru(MU-E)Ru(bpy)2]ClO4 ([2]ClO4), and [(pap)2Ru(MU-E)Ru(pap)2] ([3]) were characterized by density functional theory (DFT) in conjunction with EPR and UV-vis-NIR measurements. The crystal structure of (NBu4)2[1] revealed the meso form and a largely planar Ru(MU E)Ru center. Several additional charge states of the compounds were electrochemically accessible and were identified mostly as complexes with noninnocently behaving pap(0/*-) or bridging ellagate (E(n-)) anions (n = 2, 3, 4) but not as mixed-valence intermediates. The free anions E(n-), n = 1-4, were calculated by time-dependent DFT to reveal NIR transitions for the radical forms with n = 1 and 3 and a triplet ground state for the bis(o-semiquinone) dianion E(2-). PMID- 26441247 TI - Viral hepatitis: A new HCV cell culture model for the next clinical challenges. AB - Despite advances in hepatitis C treatment, substantial clinical hurdles remain to achieve universal cure and global control of infection. Saeed et al. identified SEC14L2 as a host factor permitting replication of clinical HCV isolates in cell culture, providing a novel system to model infection of patient-derived viruses. PMID- 26441248 TI - Regenerative medicine: Hepatic progenitor cells up their game in the therapeutic stakes. AB - Bipotential hepatic progenitor cells (HPCs) are recognized as making modest contributions to hepatocyte regeneration, though never credited with major liver repopulation. A new study in mice demonstrates HPCs can make a massive contribution to hepatocyte replacement, suggesting HPCs have the potential to be an effective cell therapy for liver failure. PMID- 26441249 TI - Therapy: Targeting chromatin remodelling proteins to treat pancreatic cancer. PMID- 26441250 TI - Autophagy exacerbates caspase-dependent apoptotic cell death after short times of starvation. AB - Autophagy is generally regarded as a mechanism to promote cell survival. However, autophagy can occasionally be the mechanism responsible of cell demise. We have found that a concomitant depletion of glucose, nutrients and growth factors provoked cell death in a variety of cell lines. This death process was contingent upon caspase activation and was mediated by BAX/BAK proteins, thus indicating its apoptotic nature and the engagement of an intrinsic pathway. In order to abrogate autophagy, 3-methyladenine (3-MA), BECLIN-1 siRNA and Atg5 knock-out (Tet-Off type) approaches were alternatively employed. Irrespective of the procedure, at short times of starvation, we found that the ongoing autophagy was sensitizing cells to the permeabilization of the mitochondrial outer membrane (MOMP), caspase activation and, therefore, apoptosis. On the contrary, at longer times of starvation, autophagy displayed its characteristic pro-survival effect on cells. As far as we know, we provide the first experimental paradigm where time is the only variable determining the final outcome of autophagy. In other words, we have circumscribed in time the shift transforming autophagy from a cell death to a protection mechanism. Moreover, at short times, starvation-driven autophagy exacerbated the apoptotic cell death caused by several antitumor agents. In agreement with this fact, their apoptotic effects were greatly diminished by autophagy inhibition. The implications of these facts in tumor biology will be discussed. PMID- 26441251 TI - Use of physiologically based kinetic (PBK) modeling to study interindividual human variation and species differences in plasma concentrations of quercetin and its metabolites. AB - Biological activities of flavonoids in vivo ultimately depend on the systemic bioavailability of the aglycones and their metabolites. We aimed to develop physiologically based kinetic (PBK) models to predict plasma concentrations of the flavonoid quercetin and its metabolites in individual human subjects and to define species differences compared with male rat. The human models were developed based on in vitro metabolic parameters derived from incubations with pooled and 20 individual human tissue fractions and by fitting kinetic parameters to available in vivo data. The outcomes obtained were compared to a previously developed model for quercetin and its metabolites formation in male rat. Quercetin-3'-O-glucuronide was predicted to be the major circulating metabolite in 19 out of 20 individuals, while in male rat di- and tri-conjugates of quercetin containing a glucuronic acid, sulfate and/or methyl moieties are the major metabolites. Significant species differences occur in major circulating metabolites of quercetin suggesting that rat is not an adequate model to study effects of quercetin in man. The defined PBK models can be used to guide the experimental design of in vitro experiments with flavonoids, especially to better take into account the relevance of metabolism and the contribution of metabolites to the biological activity in humans. PMID- 26441252 TI - Severe arthritis predicts greater improvements in function following total knee arthroplasty. AB - PURPOSE: Although excellent outcomes are routinely reported following total knee replacement, up to 20 % of patients remain dissatisfied. The aim of this study was to determine whether pre-operative radiographic classification was associated with functional outcomes following surgery. METHODS: A retrospective review of a prospective arthroplasty database identified 256 patients that fulfilled the inclusion criteria over an 18-month period. Baseline demographic data on all patients were collected prospectively. All pre-operative radiographs were assessed using the Kellgren and Lawrence (K&L) classification system. Patients were prospectively assessed using the American Knee Society Score pre-operatively and at 1, 3 and 5 years post-surgery. RESULTS: An association was found between the pre-operative radiographic severity of arthritis and the pre-operative American Knee Society Knee (AKSK) scores, with worsening radiographic grade corresponding to worsening AKSK scores (p = 0.020). There was an association between K&L classification and improvement in AKSK scores from pre-operative to 1 year (p = 0.003) and 3 years (p = 0.04), with K&L grades 3 and 4 demonstrating the most significant improvements. On multivariate regression analysis, K&L classification was the only significant predictor of improvement in AKSK at 1 year (p = 0.009). No correlation was found between K&L grade and the American Knee Society Functional Scores at any stage. CONCLUSIONS: The results of this study may help to improve satisfaction rates in total knee replacement by targeting treatment. Patients can be counselled that although radiographic severity of arthritic changes can predict knee-specific functional improvement, the extent of their global functional improvement cannot. LEVEL OF EVIDENCE: IV. PMID- 26441253 TI - The results of a consecutive series of dynamic posterior stabilizations using the PercuDyn device. AB - PURPOSE: To evaluate the results of a consecutive series of patients affected by lumbar discogenic pain associated with facet pain and canal stenosis surgically treated with the PercuDyn device. METHODS: From 2009, 129 consecutive patients (96 M, 33 F, mean age 62) were treated with posterior dynamic stabilization screws (PercuDyn). Inclusion criteria were minimum follow-up of 24 months; pain localized at the lumbar spine column alone or in association to lower limb radicular pain; magnetic resonance evidence of disc degeneration associated with facet degeneration and canal stenosis. Patients were clinically studied using VAS scale and Oswestry Disability Index (ODI); CT assessment of the neuroforamina and spinal canal areas was done at 1 month of follow-up. RESULTS: At 24 months of follow-up, 96 patients fulfilled the inclusion criteria. 96 intervertebral spaces were treated (85 levels L5-S1, 11 levels L4-L5). The VAS scale showed a statistically significant difference at 1 month, 6 months and 2 years with respect to the pre-operative value (p < 0.001). The ODI score registered a significant difference with the same fashion (p < 0.001 both at 1- and 6-month, and 2-year follow-up with respect to the pre-operatory). At 1-month follow-up, neuroforamina and spinal canal areas were considerably wider (p < 0.05). 70 (72.5 %) patients were satisfied of the procedure. CONCLUSIONS: In this wide cohort study, the PercuDyn ensured good clinical and radiological results, with more than 70 % of patients satisfied of the procedure. Very few complications were noted, with an immediate return to daily activities. At longer follow-ups, 10 % of patients received revision surgery. PMID- 26441254 TI - Does surgery for Scheuermann kyphosis influence sagittal spinopelvic parameters? AB - PURPOSE: To analyze changes in sagittal spinopelvic parameters (SSPs) after surgical treatment of Scheuermann's Kyphosis (SK). METHODS: We analyzed 20 patients affected by SK and subjected to posterior correction of the kyphosis by facetectomy, Ponte osteotomy, fusion and multilevel instrumentation with pedicle screw system. Four spinal and three pelvic parameters were measured: sagittal vertical axis (SVA), thoracic kyphosis (TK), thoracolumbar kyphosis, lumbar lordosis (LL), pelvic incidence (PI), sacral slope (SS) and pelvic tilt (PT). Analysis of changes in postprocedural SSPs compared to preoperative values was performed. RESULTS: TK passed from 78.6 degrees preoperatively to 45.8 degrees (p = 0.003). LL passed from 74.5 degrees preoperatively to 53.5 degrees (p = 0.01). No significant changes occurred in SVA, SS, PT and PI compared to preoperative values. CONCLUSION: We confirm the positive effect of surgery by Ponte osteotomy and posterior spinal fusion on TK and LL in patients with SK. In our experience, pelvic parameters did not change after surgery. PMID- 26441255 TI - Spinopelvic balance and body image perception in Parkinson's disease: analysis of correlation. AB - PURPOSE: The purpose of this study was to describe the association between body image perception and sagittal balance (SB) parameters in Parkinson's Disease (PD) patients. METHODS: 77 consecutive PD patients were included: 44 males, 33 females; 68.9 +/- 6.8 years; 5.3 +/- 3.8 years from diagnosis (YFD); Hoehn Yahr (HY) 2.0 +/- 0.8, Unified Parkinson's Disease rating Score-Motor section (UPDRS M) 11.8 +/- 9.3. Spinopelvic angles and SB were radiographically assessed. Body image perception was assessed through Trunk appearance scale (TAPS) and Stunkard Figure rating scale for BMI. Beck Depression Inventory (BDI) was used to evaluate depressive mood. RESULTS: We detected 32 (41.5 % of cohort) Parkinson Disease patients with scoliosis >=15 degrees Cobb. The mean calculated BMI was 27.1 +/- 3.9 kg/m(2). According to the Figure Rating Scale, the perceived BMI averaged 27.2 +/- 4.5 kg/m(2), while the mean desired BMI was 24.4 +/- 2.7 kg/m(2), TAPS scored 3.4 +/- 0.9 points, while BDI 12.3 +/- 7.9 points. TAPS had a weak negative correlation with the duration of disease (r = -0.25, p < 0.05) and a correlation with H&Y score (r = 0.28, p < 0.05). Sacral Slope was weakly correlated to the calculated BMI (r = -0.24, p < 0.05). SSA and SPA had a negative correlation with the TAPS mean score (respectively, r = -0.36 and -0.24, p < 0.05). BDI presented a weak correlation with TAPS (r = 0.27, p < 0.05) but not with self esteemed BMI values (p > 0.05). CONCLUSIONS: Spinopelvic parameters and depression had a specific and concurrent influence on trunk deformity perception but not on BMI self-esteem. PMID- 26441256 TI - Biomechanical and clinical study of single posterior oblique cage POLIF in the treatment of degenerative diseases of the lumbar spine. AB - INTRODUCTION: Aim of the study was to evaluate the biomechanical stability and the clinical efficacy of a lumbar interbody fusion obtained by single oblique cage implanted by a posterior approach. METHOD: Through the realization of three finite element models (FEMs), the biomechanics of POLIF was compared to PLIF and TLIF. Ninety-four patients underwent interbody fusion by POLIF with instrumented posterolateral fusion. Clinical and radiographic outcomes were evaluated at regular intervals for at least 6 months. RESULTS: The FEMs showed no statistically significant differences in stability in compression and flexion extension. Mean preoperative VAS score was 7.1, decreased to 2.1 at follow-up. Mean preoperative SF-12 value was 34.5 %, increased to 75.4 % at follow-up. All patients showed a good fusion rate and no hardware failure. DISCUSSION: POLIF associated to instrumented posterolateral fusion is a viable and safe surgical technique, which ensures a biomechanical stability similar to other surgical techniques. PMID- 26441257 TI - Long vs. short fusions for adult lumbar degenerative scoliosis: does balance matters? AB - PURPOSE: Surgery of adult scoliosis was based upon coronal plane radiographical analysis using Cobb angle measurements, but recently it has been demonstrated that sagittal spinopelvic alignment plays a critical role in determining the final outcome. The aim of this paper is to compare the clinical and radiological results of 81 patients affected by adult scoliosis, treated with short or long fusions, and followed for 2-5 year follow-up. MATERIALS AND METHODS: 81 patients affected by degenerative lumbar scoliosis managed by posterior-only surgery were retrospectively evaluated. Fifty-seven patients underwent to a short fusion procedure, while 24 had a long fusion. Clinical and radiographic coronal and sagittal spinopelvic parameters were compared between the two groups. RESULTS: Coronal Cobb angle was 24 degrees preoperatively and passed to 12 degrees in the short fusion group, while changed from 45 degrees to 10 degrees in the long fusion group. Lumbar lordosis was 45 degrees preoperatively and 60 degrees at final follow-up in the short fusion group passed from 24 degrees to 55 degrees in the long fusion group. Sacral slope passed from 25 degrees to 45 degrees in the short fusion group, while from 10 degrees to 40 degrees in the long fusion group. Pelvic tilt passed from 24 degrees to 13 degrees in the short fusion group, and from 28 degrees to 23 degrees in the long fusion group. CONCLUSION: Surgical treatment of degenerative lumbar scoliosis improved balance and alignment of the spine, and also the coronal plane in terms of Cobb angle. These results were associated to a consistent clinical improvement and an acceptable rate of complications. PMID- 26441259 TI - Surgical management of syringomyelia unrelated to Chiari malformation or spinal cord injury. AB - PURPOSE: Syringomyelia is a misleading disease since the problem always lies elsewhere. Arachnoiditis, because it is radiographically difficult to discern, is an especially insidious cause. To better guide selection from among surgical treatment options for syringomyelia, we reviewed our case series of patients without Chiari malformation or spinal injury. METHODS: Excluding syringomyelia due to Chiari malformation, spinal cord injury, and tumors, 32 patients (mean age 44 years) were operated on between 1995 and 2013 and followed up for a mean of 53.8 months. Presumed causes at diagnosis, clinical and radiological findings, type of operation, clinical and radiological outcome were reviewed. RESULTS: Duration of clinical history varied widely (range 6-164 months). Clinical assessment was based on the McCormick classification (15 independent, 17 dependent). Causes included birth trauma, pyogenic meningitis, tuberculous meningitis, postoperative scarring, dysraphism, and basilar impression. Treatment was local decompression with arachnoid lysis and shunts. Hindbrain-related syringomyelia was differentiated from non hindbrain-related syringomyelia. Hindbrain arachnoiditis was significantly associated with radiological findings at the foramen magnum (p = 0.01) and craniocervical decompression (p < 0.03), with good clinical and radiological outcome at 6 months and later follow-up controls (p = 0.02), whereas uneven results were observed in cases of non hindbrain arachnoiditis. CONCLUSIONS: To remove the cause of syringomyelia, surgical planning will rely on thorough clinical history and accurate imaging to determine the site of cerebrospinal fluid obstruction. Craniocervical decompression to dissect basal arachnoiditis in the posterior fossa can be recommended in hindbrain syringomyelia. Treatment of non-hindbrain arachnoiditis is more controversial, probably owing to uncertainties about the extent of adhesions. PMID- 26441258 TI - Cervical spine alignment in disc arthroplasty: should we change our perspective? AB - PURPOSE: The alignment at the cervical spine has been considered a determinant of degeneration at the adjacent disc, but this issue in cervical disc replacement surgery is poorly explored and discussed in this patient population. The aim of this systematic review is to compare anterior cervical fusion and total disc replacement (TDR) in terms of preservation of the overall cervical alignment and complications. METHODS: A systematic review of the current literature was performed, together with the evaluation of the methodological quality of all the retrieved studies. RESULTS: In most of the retrieved studies, a tendency towards a more postoperative kyphotic alignment in TDR was reported. The reported mean complication rate was of 12.5 % (0-66.2 %). Complications associated with cervical prosthesis included heterotopic ossification, device migration, mechanical instability, failure, implant removal, reoperations and revision. CONCLUSIONS: Even though cervical disc arthroplasty leads to similar outcomes compared to arthrodesis in the middle term follow-up, no evidence of superiority of cervical TDR is available up to date. We understand that the overall cervical alignment after TDR tends towards the loss of lordosis, but only longer follow-up can determine its influence on the clinical results. PMID- 26441261 TI - D-CHART: A Novel Method of Measuring Metamorphopsia in Epiretinal Membrane and Macular Hole. AB - BACKGROUND: Metamorphopsia is common in macular disease. Current techniques for measuring metamorphopsia require good vision or costly equipment. The authors report a method that uses printed cards. METHODS: The cards have a grid of squares arranged in a ring around fixation. There are four rings, at different distances from fixation, divided into eight sectors. The separation of the grid elements ranges from 0.4 degrees to 1.8 degrees . Subjects indicate in which sector lines of squares are distorted. The sum of the maximum separation perceived as distorted in each sector gives the total metamorphopsia score. Thirty-three eyes with epiretinal membrane and 29 eyes with macular hole were tested. Twenty-four eyes were tested again after surgery. In 18 subjects, the preoperative test was performed twice to assess repeatability. RESULTS: The median preoperative total metamorphopsia score was 10.2 for macular hole and 5.2 for epiretinal membrane. After surgery, the median total metamorphopsia score was 0.5 for macular hole and 0.45 for epiretinal membrane. Test-retest results showed good correlation. Improvement in metamorphopsia did not correlate with change in visual acuity. CONCLUSION: Measurement of metamorphopsia may be useful in the management of macular hole and epiretinal membrane. D-charts are a simple and inexpensive method of quantifying metamorphopsia that can be used in a clinical setting. PMID- 26441260 TI - Comprehensive Survey of Domiciliary Triatomine Species Capable of Transmitting Chagas Disease in Southern Ecuador. AB - BACKGROUND: Chagas disease is endemic to the southern Andean region of Ecuador, an area with one of the highest poverty rates in the country. However, few studies have looked into the epidemiology, vectors and transmission risks in this region. In this study we describe the triatomine household infestation in Loja province, determine the rate of Trypanosoma cruzi infection in triatomines and study the risk factors associated with infestation. METHODOLOGY/PRINCIPAL FINDINGS: An entomological survey found four triatomine species (Rhodnius ecuadoriensis, Triatoma carrioni, Panstrongylus chinai, and P. rufotuberculatus) infesting domiciles in 68% of the 92 rural communities examined. Nine percent of domiciles were infested, and nymphs were observed in 80% of the infested domiciles. Triatomines were found in all ecological regions below 2,200 masl. We found R. ecuadoriensis (275 to 1948 masl) and T. carrioni (831 to 2242 masl) mostly in bedrooms within the domicile, and they were abundant in chicken coops near the domicile. Established colonies of P. chinai (175 to 2003 masl) and P. rufotuberculatus (404 to 1613 masl) also were found in the domicile. Triatomine infestation was associated with surrogate poverty indicators, such as poor sanitary infrastructure (lack of latrine/toilet [w = 0.95], sewage to environment [w = 1.0]). Vegetation type was a determinant of infestation [w = 1.0] and vector control program insecticide spraying was a protective factor [w = 1.0]. Of the 754 triatomines analyzed, 11% were infected with Trypanosoma cruzi and 2% were infected with T. rangeli. CONCLUSIONS/SIGNIFICANCE: To date, only limited vector control efforts have been implemented. Together with recent reports of widespread sylvatic triatomine infestation and frequent post-intervention reinfestation, these results show that an estimated 100,000 people living in rural areas of southern Ecuador are at high risk for T. cruzi infection. Therefore, there is a need for a systematic, sustained, and monitored vector control intervention that is coupled with improvement of socio-economic conditions. PMID- 26441262 TI - Pseudofovea on Optical Coherence Tomography: An Unusual Appearance. PMID- 26441263 TI - Idiopathic Retinal Vasculitis, Aneurysms, and Neuroretinitis Syndrome. PMID- 26441264 TI - IMPACT OF INTERNAL LIMITING MEMBRANE PEELING ON MACULAR HOLE REOPENING: A Systematic Review and Meta-Analysis. AB - PURPOSE: To assess the literature regarding macular hole reopening rates stratified by whether the internal limiting membrane (ILM) was peeled during vitrectomy surgery. METHODS: Systematic review and meta-analysis of studies reporting on macular hole reopenings among previously surgically closed idiopathic macular holes. A comprehensive literature search using the National Library of Medicine PubMed interface was used to identify potentially eligible publications in English. The minimum mean follow-up period for reports to be included in this study was 12 months. Analysis was divided into eyes that underwent vitrectomy with and without ILM peeling. The primary outcome parameter was the proportion of macular hole reopenings among previously closed holes between the two groups. Secondary outcome parameters included duration from initial surgery to hole reopening and preoperative and postoperative best corrected correct visual acuities among the non-ILM peeling and ILM peeling groups. RESULTS: A total of 50 publications reporting on 5,480 eyes met inclusion criteria and were assessed in this meta-analysis. The reopening rate without ILM peeling was 7.12% (125 of 1,756 eyes), compared with 1.18% (44 of 3,724 eyes) with ILM peeling (odds ratio: 0.16; 95% confidence interval: 0.11-0.22; Fisher's exact test: P < 0.0001). There were no other identifiable associations or risk factors for reopening. CONCLUSION: The results of this meta-analysis support the concept that ILM peeling during macular hole surgery reduces the likelihood of macular hole reopening. PMID- 26441265 TI - HISTORY OF SUNLIGHT EXPOSURE IS A RISK FACTOR FOR AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To evaluate effects of current and past sunlight exposure and iris color on early and late age-related macular degeneration (AMD). METHODS: Of 3,701 individuals from the EUGENDA database, 752 (20.3%) showed early AMD, 1,179 (31.9%) late AMD, and 1,770 (47.8%) were controls. Information about current and past sunlight exposure, former occupation type, subdivided in indoor working and outdoor working, and iris color were obtained by standardized interviewer assisted questionnaires. Associations between environmental factors adjusted for age, gender, and smoking and early and late AMD were performed by multivariate regression analysis. RESULTS: Current sunlight exposure showed no association with early AMD or late AMD, but past sunlight exposure (>=8 hours outside daily) was significantly associated with early AMD (odds ratio: 5.54, 95% confidence interval 1.25-24.58, P = 0.02) and late AMD (odds ratio: 2.77, 95% confidence interval 1.25-6.16, P = 0.01). Outside working was found to be associated with late AMD (odds ratio: 2.57, 95% confidence interval 1.89-3.48, P = 1.58 * 10). No association was observed between iris color and early or late AMD. CONCLUSION: Sunlight exposure during working life is an important risk factor for AMD, whereas sunlight exposure after retirement seems to have less influence on the disease development. Therefore, preventive measures, for example, wearing sunglasses to minimize sunlight exposure, should start early to prevent development of AMD later in life. PMID- 26441266 TI - RISK OF RETINAL VEIN OCCLUSION WITH CENTRAL SEROUS CHORIORETINOPATHY. AB - PURPOSE: To investigate the risk of retinal vein occlusion (RVO) after central serous chorioretinopathy (CSCR). METHODS: The study included 2882 CSCR patients and 17,292 control patients matched by age, sex, number of visits to an ophthalmologist, diabetes mellitus, hypertension, and hyperlipidemia from January 2001 to December 2010 from the Taiwan Longitudinal Health Insurance Database 2000. Information for each patient was collected until December 2011. Cox proportional hazard regression analysis was used to obtain the adjusted hazard ratio for RVO. The RVO-free survival rate was calculated using Kaplan-Meier analysis. RESULTS: There was a significantly higher risk of RVO in CSCR patients than in controls (incidence rate ratio = 3.07, 95% confidence interval = 1.86 5.07). After adjustment for potential confounders, the adjusted hazard ratio for developing RVO in the CSCR patients was 3.15 times higher than that of the controls (adjusted hazard ratio = 3.15, 95% confidence interval = 1.91-5.21). CONCLUSION: Central serous chorioretinopathy increases the risk of RVO. For CSCR patients, the authors recommend thorough retinal vessel evaluation, regular follow-up, and education regarding RVO for patients with CSCR. PMID- 26441267 TI - Correspondence. PMID- 26441268 TI - Correspondence. PMID- 26441269 TI - TYPE 2 NEOVASCULARIZATION SECONDARY TO AGE-RELATED MACULAR DEGENERATION IMAGED BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. AB - PURPOSE: Optical coherence tomography angiography is a novel and noninvasive technique for imaging retinal microvasculature by detecting changes in reflectivity that is related to blood flow. The purpose of this study was to describe Type 2 neovascularization characteristics in age-related macular degeneration using optical coherence tomography angiography. METHODS: Fourteen eyes of 14 consecutive patients with Type 2 neovascularization were prospectively included. All patients underwent a complete ophthalmological examination, including color and infrared fundus photography, fluorescein and indocyanine green angiography, spectral domain optical coherence tomography angiography, and optical coherence tomography angiography. RESULTS: In all cases, Type 2 lesions could be detected by optical coherence tomography angiography, presenting as a hyperflow lesion in the outer retina, with a glomerulus (4/14) or medusa shape (10/14), surrounded by a dark halo. The superficial layer and the deep retina showed no abnormal flow. Surprisingly, the Type 2 lesions could also be observed in the presumed choriocapillaris layer. These glomerulus- or medusa-shaped lesions were connected, in 10/14 eyes, to a thicker main branch, which seemed to continue deep into the choroidal layers. CONCLUSION: Optical coherence tomography angiography may be a new imaging method for the diagnosis of Type 2 neovascularization in clinical routine. However, the specificity of the features needs to be investigated in further studies. PMID- 26441270 TI - OUTER RETINA CAPILLARY INVASION AND ELLIPSOID ZONE LOSS IN MACULAR TELANGIECTASIA TYPE 2 IMAGED BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. AB - PURPOSE: Macular telangiectasia Type 2 (MacTel2) is a neurodegenerative and vascular disease limited to the macular area, resulting ultimately in Muller cell and photoreceptor loss and intra or subretinal proliferation. Optical coherence tomography angiography was used to correlate the proliferation of capillaries in the outer retina with the topography of the ellipsoid zone (EZ) loss. METHODS: Thirty eyes of 15 patients with MacTel2 were examined using optical coherence tomography angiography. Images of the superficial and deep capillary plexus were analyzed and compared with en-face angio-flow images of the outer retina and en face image of the EZ. RESULTS: Twenty-one eyes were available for the study, including 12 with invasion of the outer retina capillary on optical coherence tomography angiography but without subretinal neovascularization. The outer retina capillary proliferation had a radial pattern in eight cases, formed loops in four, and was circumscribed to an area of EZ loss on en-face images. In nine cases, there was no outer capillary proliferation including two cases with foci of EZ loss. CONCLUSION: Optical coherence tomography angiography shows capillary proliferation in the outer retina corresponding to areas of EZ loss, which could be a useful marker to monitor the efficacy of possible treatments in MacTel2 disease. PMID- 26441271 TI - Bimanual Technique for Retinal Tacking of Epiretinal Prosthesis. PMID- 26441272 TI - Reply: To PMID 25105313. PMID- 26441273 TI - Reply: To PMID 25322466. PMID- 26441274 TI - Hospitalized dogs recovery from naturally occurring heatstroke; does serum heat shock protein 72 can provide prognostic biomarker? AB - Heatstroke is a serious illness in dogs characterized by core temperatures above 41 degrees C with central nervous system dysfunction. Experimental heatstroke models have tried to correlate biomarker levels with the severity of the syndrome. Serum heat shock protein (eHSP70) levels were recently evaluated as a biomarker of heat tolerance and acclimation, their role as a marker of heatstroke is inconclusive. Here, we monitored eHSP70 levels in correlation with systemic biomarkers in 30 naturally occurring canine heatstroke cases. Thirty dogs diagnosed with environmental (33%) or exertional (66%) heatstroke admitted to hospital (0-14 h post-injury) were tested for biomarkers of organ damage and coagulation parameters. eHSP70 levels were measured upon admission and 4, 12, and 24 h later (T1, T2, and T3, respectively). No differences were found between exertional and environmental heatstroke cases. The eHSP profile demonstrated an inverted bell shape, with the lowest levels at the 12 h time point. A positive correlation between eHSP70, lactate, and aPPT was also noted at T2 in all the dogs in the study. Twenty-four h after presentation, eHSP70 levels returned to those measured upon admission, this change was only significant in the survivors. The obtained results suggest that eHSP72 level profile may be predictive of survival. PMID- 26441275 TI - The Electronic Health Record Paradox: Observations of a GI Consultant. PMID- 26441276 TI - GRG Profiles: David A. Lieberman. PMID- 26441277 TI - Mean Platelet Volume in Crohn's Disease Patients Predicts Sustained Response to a 52-Week Infliximab Therapy: A Pilot Study. AB - BACKGROUND: The loss of response to infliximab in Crohn's disease (CD) patients is currently a major clinical problem. Recently, mean platelet volume (MPV) has been proposed as a new biomarker of CD activity. Here, we hypothesized that MPV may be used as cheap and efficient biomarker of subclinical inflammation during 52-week therapy in CD patients responding to infliximab induction treatment. AIMS: The aim of study was to establish whether MPV at baseline and pre-infusion at week 14 are good predictors of sustained response after week 14 in CD patients undergoing 52-week infliximab therapy. METHODS: A retrospective study of 30 adult CD patients who underwent a 52-week course of treatment with infliximab and achieved response at week 14 to induction treatment was performed. The association between MPV, baseline disease parameters and maintained clinical response or remission during infliximab therapy was assessed. RESULTS: Higher MPV at week 14 was observed in CD patients with sustained response to infliximab after week 14 than in patients with loss of response (p = 0.0019). In patients with loss of response to maintenance infliximab treatment, lower DeltaMPV between baseline and week 14 was calculated (p = 0.0003). MPV > 10.3 fl at week 14 predicts sustained response with 67 % sensitivity and 80 % specificity. DeltaMPV between baseline and week 14 >0.4 fl predicts sustained response with 87 % sensitivity and 93 % specificity. CONCLUSION: MPV at week 14 and DeltaMPV between baseline and week 14 are good predictors of sustained response to infliximab maintenance treatment in CD patients. PMID- 26441278 TI - Clinically Diagnosed Acute Diverticulitis in Outpatients: Misdiagnosis in Patients with Irritable Bowel Syndrome. AB - BACKGROUND: Physicians often diagnose diverticulitis and prescribe antibiotics in outpatients with abdominal pain and tenderness without other evidence. AIM: We investigated the misattribution of irritable bowel syndrome (IBS) symptoms to diverticulitis in outpatients. METHODS: In patients diagnosed with diverticulitis and dispensed antibiotics in an integrated healthcare system, we retrospectively compared 15,846 outpatients managed without computed tomography (CT) versus 3750 emergency department/inpatients who had CT. We assessed demographics and past history, including 17 symptom-based somatic and 11 mental disorders and three somatic-mental comorbidity pairs (dyads) coded over 3 years and seven drug classes dispensed over 1 year before diagnosis. RESULTS: Univariate analysis showed small intergroup demographic differences. Outpatients had increases in prior diverticulitis, including outpatient-managed episodes, total somatic diagnoses (p < .0001), eight somatic and three mental disorders (p <= .015), all three dyads (p <= .05), and dispensing of three drug classes (p <= .016). IBS had been diagnosed in 2399 (15.1 %) outpatients versus 361 (9.6 %) emergency department/inpatients (p < .0001), the greatest increase in any comorbidity. Emergency department/inpatients had no somatic comorbidity more often but more alcohol dependence, non-dependent drug abuse, and opioid dispensing (p <= .05). Regression analysis revealed outpatient care was independently positively associated with younger age, non-Hispanic white race/ethnicity, less Charlson comorbidity, diverticulitis history, IBS, chest pain, dyspepsia, fibromyalgia, low back pain, migraine, acute reaction to stress, and antispasmodic and anxiolytic dispensing and negatively associated with non-dependent drug abuse and opioid dispensing (p <= .0226). CONCLUSIONS: Multiple types of indirect and concordant evidence suggest misattribution of IBS pain to diverticulitis and unnecessary antibiotic therapy in outpatients. PMID- 26441279 TI - Noninvasive Prediction of Erosive Esophagitis Using a Controlled Attenuation Parameter (CAP)-Based Risk Estimation Model. AB - BACKGROUND: Erosive esophagitis and fatty liver share obesity and visceral fat as common critical pathogenesis. However, the relationship between the amount of hepatic fat and the severity of erosive esophagitis was not well investigated, and there is no risk estimation model for erosive esophagitis. AIM: To evaluate the relationship between the amount of hepatic fat and the severity of erosive esophagitis and then develop a risk estimation model for erosive esophagitis. METHODS: We enrolled 1045 consecutive participants (training cohort, n = 705; validation cohort, n = 340) who underwent esophagogastroduodenoscopy and CAP. The relationship between severity of fatty liver and erosive esophagitis was investigated, and independent predictors for erosive esophagitis that have been investigated through logistic regression analyses were used as components for establishing a risk estimation model. RESULTS: The prevalence of erosive gastritis was 10.7 %, and the severity of erosive esophagitis was positively correlated with the degree of hepatic fatty accumulation (P < 0.05). A CAP-based risk estimation model for erosive esophagitis using CAP, Body mass index, and significant alcohol Drinking as constituent variables was established and was dubbed the CBD score (AUROC = 0.819, range 0-11). The high-risk group (CBD score >=3) showed significantly higher risk of having erosive esophagitis than the low risk group (CBD score <3) (24.1 vs. 2.7 %, respectively; P < 0.001). The diagnostic accuracy of CBD score was maintained in the validation cohort (AUROC = 0.848). CONCLUSION: The severity of erosive esophagitis was positively correlated with the degree of hepatic fatty accumulation, and the CBD score might be a simple CAP-based risk model for predicting erosive esophagitis. PMID- 26441280 TI - Comparison of Risk Factors Between Small Intestinal Ulcerative and Vascular Lesions in Occult Versus Overt Obscure Gastrointestinal Bleeding. AB - BACKGROUND AND AIMS: The detailed risk factors such as bleeding pattern, comorbidities, and medication usage of patients with obscure gastrointestinal bleeding (OGIB) are largely unknown. We evaluated the risk factors related to ulcerative and vascular lesions of the small intestine diagnosed by capsule endoscopy or balloon-assisted endoscopy in OGIB cases. METHODS: We retrospectively evaluated 390 OGIB cases (occult, n = 101; overt, n = 289) in our hospital between January 2005 and March 2011 using univariate and multivariate logistic regression analyses to determine the related risk factors. RESULTS: In occult (n = 36) and overt (n = 120) OGIB cases, some lesions were detected in the small intestine. Ulcerative and vascular lesions were detected in both occult (n = 25, 69.4 %; n = 8, 22.2 %, respectively) and overt (n = 57, 47.5 %; n = 39, 32.5 %, respectively) cases. For ulcerative lesions, non-steroidal anti inflammatory drugs were identified as a risk factor in overt cases [odds ratio (OR) 2.974, 95 % confidence interval (CI) 1.522-5.809, P = 0.001]. For vascular lesions, lowest hemoglobin level (OR 0.634, 95 % CI 0.422-0.953, P = 0.028) and hematologic disease (OR 8.575, 95 % CI 1.076-68.309, P = 0.042) were identified as risk factors in occult cases, whereas hemodialysis (OR 3.71, 95 % CI 1.315 10.467, P = 0.013) was identified in overt cases. Additionally, liver cirrhosis was noted as a risk factor in both occult (OR 7.453, 95 % CI 1.213-45.773, P = 0.013) and overt (OR 4.900, 95 % CI 2.099-11.443, P < 0.001) OGIB cases. CONCLUSION: There are differences in risk factors related to ulcerative versus vascular lesions in the small intestine in occult and overt OGIB cases. Differences were seen in both medication usage and comorbidities. PMID- 26441281 TI - The Tolerability and Efficacy of Rapid Infliximab Infusions in Patients with Inflammatory Bowel Disease. AB - OBJECTIVE: Few studies have assessed the loss of efficacy or patient and caregiver satisfaction with rapid infliximab infusions. The aim of this study is to assess the tolerability, loss of efficacy and to describe the impact on resource utilization and patient satisfaction in rapid infliximab infusions. METHODS: Subjects with inflammatory bowel disease receiving rapid infliximab infusions were included in the study. Subjects received maintenance infusions from June 2011 to June 2013. Incidence of adverse reactions and the total number of rapid infliximab infusions were recorded. Efficacy was compared to published studies evaluating the long-term efficacy of infliximab infusions. Patient satisfaction was addressed through a survey following the implementation of the rapid infusion protocol. RESULTS: Seventy-five subjects with IBD were included in the study. Five hundred and twenty-two rapid infliximab infusions were provided to patients. There were no acute or delayed infusion reactions. Ten subjects (13 %) required either a dose escalation or interval adjustment between infliximab infusions. A majority of patients reported increased satisfaction with 1-h infliximab infusions, and 97 % of surveyed patients opted to continue rapid infusions. The rapid infliximab infusion protocol increased infusion unit efficiency by increasing capacity by 15 %. Cost savings in the elimination of nursing time translated to approximately $108,150 savings at our institution. CONCLUSIONS: Rapid infliximab infusions do not appear to increase the risk of loss of response compared to historical studies of long-term infliximab efficiency. A rapid infliximab infusion protocol improved efficiency in our infusion unit and increased patient and nursing satisfaction. PMID- 26441282 TI - Hepatic Arterial Buffer Response Maintains the Homeostasis of Graft Hemodynamics in Patient Receiving Living Donor Liver Transplantation. AB - BACKGROUND: In living donor liver transplantation (LDLT), the hepatic hemodynamics plays important roles in graft regeneration, and the hepatic blood inflows are associated with graft size. However, the data of interplay between the hepatic arterial buffer response (HABR) and graft-to-recipient weight ratio (GRWR) in clinical LDLT are lacking. AIMS: To identify the effect of the HABR on the hepatic hemodynamics and recovery of graft function and to evaluate the safe lower limit of the GRWR in carefully selected recipients. METHODS: Portal venous and hepatic arterial blood flow was measured in recipients with ultrasonography, and the graft functional recovery, various complications, and survive states after LDLT were compared. RESULTS: In total, 246 consecutive patients underwent LDLT with right lobe grafts. In total, 26 had a GRWR < 0.7 % (A), 29 had a GRWR between 0.7 and 0.8 % (B), and 181 had a GRWR > 0.8 % (C). For small-for-size syndrome, there was no significant difference (P = 0.176). Graft survival rates at 1, 3, and 5 year were not different (P = 0.710). The portal vein flow and portal vein flow per 100 g graft weight peaks were significantly higher in the A. Hepatic arterial velocity and hepatic arterial flow decreased in all the three groups on postoperative day 1; however, the hepatic arterial flow per 100 g graft weight was close to healthy controls. CONCLUSIONS: HABR played important roles not only in the homeostasis of hepatic afferent blood supply but also in maintaining enough hepatic perfusion to the graft. PMID- 26441283 TI - Eosinophilic Esophagitis in Children and Its Relationship with Parental Allergies: Texas Children's Hospital Experience. AB - BACKGROUND: Eosinophilic esophagitis (EoE) is an allergen-mediated, clinicopathological condition affecting all ages. The characteristics of children with EoE in the southwestern USA have not been fully described. Furthermore, very little is known about the relationship between parental allergies and risk of EoE in their offspring in this patient population. AIMS: To characterize children with EoE and to examine the relationship between prevalence of parental allergies and occurrence of EoE in their offspring at a single referral pediatric center in the southwestern USA. METHODS: Demographic and clinical information of 126 children (<=18 years of age) with EoE was abstracted in a pre-determined data extraction form and analyzed. The allergy history was collected from biological parents of 61 children (parent-child cluster) with EoE in a standardized questionnaire and analyzed. RESULTS: The median age at presentation was 8 years (interquartile range 4-13). The majority of our patients were male (71 %) and Caucasian (59 %). Overall, 84 % of children reported allergies. Prevalence of food allergy was significantly higher compared to environmental allergies (P = 0.001). At least 46 % of parents reported allergies. A significantly higher proportion of fathers had developed allergies during their childhood compared to adulthood (P = 0.03). CONCLUSIONS: The characteristics of EoE in our patients were similar to those reported from other parts of the country. Childhood onset of paternal allergies appears to be a risk factor for occurrence of EoE in their offspring. Additional research to elucidate the relationship between parental allergies and occurrence of EoE in their offspring is warranted. PMID- 26441284 TI - Sex-Based Differences in Asthma among Preschool and School-Aged Children in Korea. AB - The purpose of this study was to explore risk factors related to asthma prevalence among preschool and school-aged children using a representative national dataset from the Korea National Health and Nutrition Examination Survey (KNHANES) conducted from 2009-2011. We evaluated the demographic information, health status, household environment, socioeconomic status, and parents' health status of 3,542 children aged 4-12 years. A sex-stratified multivariate logistic regression was used to obtain adjusted prevalence odds ratios (ORs) and 95% confidence intervals after accounting for primary sample units, stratification, and sample weights. The sex-specific asthma prevalence in the 4- to 12-year-old children was 7.39% in boys and 6.27% in girls. Boys and girls with comorbid atopic dermatitis were more likely to have asthma than those without atopic dermatitis (boys: OR = 2.20, p = 0.0071; girls: OR = 2.33, p = 0.0031). Boys and girls with >=1 asthmatic parent were more likely to have asthma than those without asthmatic parents (boys: OR = 3.90, p = 0.0006; girls: OR = 3.65, p = 0.0138). As girls got older, the prevalence of asthma decreased (OR = 0.90, p = 0.0408). Girls residing in rural areas were 60% less likely to have asthma than those residing in urban areas (p = 0.0309). Boys with >=5 family members were more likely to have asthma than those with <=3 family members (OR = 2.45, p = 0.0323). The factors related to asthma prevalence may differ depending on sex in preschool and school-aged children. By understanding the characteristics of sex based differences in asthma, individualized asthma management plans may be established clinically. PMID- 26441285 TI - Modification of gelatin-DNA interaction for optimised DNA extraction from gelatin and gelatin capsule. AB - BACKGROUND: Poor quality and quantity of DNA extracted from gelatin and gelatin capsules often causes failure in the determination of animal species using PCR. Gelatin, which is mainly derived from porcine and bovine, has been a matter of concern among customers in order to fulfill religious obligation and safety precaution against several transmissible infectious diseases associated with bovine species. Thus, optimised DNA extraction from gelatin is very important for successful real-time PCR detection of gelatin species. In this work, the DNA extraction method was optimised in terms of lysis incubation period and inclusion of pre-treatment pH modification of samples. RESULTS: The yield of DNA extracted from porcine gelatin was significantly increased when the pH of the samples was adjusted to pH 8.5 prior to DNA precipitation with isopropanol. The optimal pH for DNA precipitation from bovine gelatin solution was then determined at the original pH range of solution: pH 7.6 to 8. A DNA fragment of approximately 300 base pairs was available for PCR amplification. CONCLUSION: DNA extracted from gelatin and commercially available capsules has been successfully utilised for species detection using real-time PCR assay. However, significant adulterations of porcine and bovine in pure gelatin and capsules have been detected, which require further analytical techniques for validation. (c) 2015 Society of Chemical Industry. PMID- 26441287 TI - Low charge overpotentials in lithium-oxygen batteries based on tetraglyme electrolytes with a limited amount of water. AB - High charge overpotentials are a great challenge for the realization of lithium oxygen batteries. Here, we construct a Li-O2 battery system by introducing a limited amount of water into tetraglyme based electrolytes and electrolytic MnO2 (EMD) and Ru supported on Super P as cathodes for Li-O2 batteries. This results in low charge potentials of around 3.2 V, corresponding to overpotentials of 0.24 V, and outstanding rate capability and cycling performance. PMID- 26441286 TI - Frontoparietal Structural Connectivity Mediates the Top-Down Control of Neuronal Synchronization Associated with Selective Attention. AB - Neuronal synchronization reflected by oscillatory brain activity has been strongly implicated in the mechanisms supporting selective gating. We here aimed at identifying the anatomical pathways in humans supporting the top-down control of neuronal synchronization. We first collected diffusion imaging data using magnetic resonance imaging to identify the medial branch of the superior longitudinal fasciculus (SLF), a white-matter tract connecting frontal control areas to parietal regions. We then quantified the modulations in oscillatory activity using magnetoencephalography in the same subjects performing a spatial attention task. We found that subjects with a stronger SLF volume in the right compared to the left hemisphere (or vice versa) also were the subjects who had a better ability to modulate right compared to left hemisphere alpha and gamma band synchronization, with the latter also predicting biases in reaction time. Our findings implicate the medial branch of the SLF in mediating top-down control of neuronal synchronization in sensory regions that support selective attention. PMID- 26441288 TI - [Prevalence of non-alcoholic fatty liver disease in a population with elevated transaminases and level of accuracy of the diagnosis in Primary Care]. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated transaminases in adults. AIM: Determine the prevalence of NASH in patients with sustained hypertransaminasemia, and Know the adequacy of the registered in Primary Care (AP) diagnosis. MATERIAL AND METHODS: 1) Cross-sectional study with a random sample of patients with elevated alanine aminotransferase (ALT) held (ALT> 32 for >=6 months), ruling out other causes of liver disease, according to clinical, laboratory and ultrasound scan criteria in AP and 2) cross-sectional description of all cases diagnosed with NASH recorded (K76 - ICD10) with diagnostic adequacy analysis according to standard criteria. RESULTS: 290 patients were analyzed: 76 were diagnosed as NASH (26.1%), 44 women (57.9%). Multivariate analysis adjusted for age and sex showed no association between NASH and male gender (OR: 0.5; CI95%: 0.3-0.9), diabetes mellitus (DM) (OR: 2.42; CI95%: 1.2-4.9) and hypertension blood pressure (HBP) (OR: 3.07; CI 95% 1.6-5.6). Of the 209 diagnosed with NASH record: 51 (24.4%) met the criteria for NASH. The rest had insufficient records. HIGHLIGHTS: 53.1% lacked sustained hypertransaminasemia; 48% of viral serology; 11% supported and 53.1% abdominal ultrasound registration of alcohol. CONCLUSIONS: Severe NASH is frequent among patients with sustained hypertransaminasemia. The DM and hypertension significantly increase the risk of NASH. The diagnosis of NASH is recorded without considering all criteria and mainly NASH made by ultrasonography. They should unify diagnostic criteria in the register of NASH. PMID- 26441290 TI - Upper airway resistance during growth: A longitudinal study of children from 8 to 17 years of age. AB - OBJECTIVE: To study upper airway breathing in 115 children annually from 8 to 17 years of age with the hypothesis that upper airway respiratory needs increase steadily during growth and show sexual dimorphism. MATERIAL AND METHODS: To calculate nasal resistance, airflow rate (mL/s) and oronasal pressures (cmH2O) were measured during rest breathing in a seated position using the pressure-flow technique. RESULTS: Median values of oronasal pressure ranged at different ages in girls from 0.88 to 1.13 and in boys from 0.92 to 1.44 cmH2O, being 0.95 and 0.93 cmH2O at the age of 17 years, respectively. The gender differences were statistically significant in four age groups (P < .05 by the Mann-Whitney test). Mean values of nasal resistance decreased from 8 to 17 years of age in girls from 4.0 (+/-3.27) to 2.4 (+/-2.30) and in boys from 3.3 (+/-2.48) to 1.5 (+/-0.81) cmH2O/L/s. However, there was an increase in resistance in 11-year-old girls and 12-year-old boys and at the age of 15 in both genders (P < .05 by paired t-test). CONCLUSIONS: Respiratory efforts stabilize oronasal pressure to maintain vital functions at optimal level. Nasal resistance decreased with age but increased temporarily at the prepubertal and pubertal phases, in accordance with other growth and possibly hormonal changes. When measuring upper airway function for clinical purposes, especially in patients with sleep apnea, asthma, allergies, cleft palate, or maxillary expansion, the measurements need to be compared with age- and gender-specific values obtained from healthy children. PMID- 26441289 TI - Million Veteran Program: A mega-biobank to study genetic influences on health and disease. AB - OBJECTIVE: To describe the design and ongoing conduct of the Million Veteran Program (MVP), as an observational cohort study and mega-biobank in the Department of Veterans Affairs (VA) health care system. STUDY DESIGN AND SETTING: Data are being collected from participants using questionnaires, the VA electronic health record, and a blood sample for genomic and other testing. Several ongoing projects are linked to MVP, both as peer-reviewed research studies and as activities to help develop an infrastructure for future, broad based research uses. RESULTS: Formal planning for MVP commenced in 2009; the protocol was approved in 2010, and enrollment began in 2011. As of August 3, 2015, and with a steady state of ~50 recruiting sites nationwide, N = 397,104 veterans have been enrolled. Among N = 199,348 with currently available genotyping data, most participants (as expected) are male (92.0%) between the ages of 50 and 69 years (55.0%). On the basis of self-reported race, white (77.2%) and African American (13.5%) populations are well represented. CONCLUSIONS: By helping to promote the future integration of genetic testing in health care delivery, including clinical decision making, the MVP is designed to contribute to the development of precision medicine. PMID- 26441292 TI - Electrochemically Exfoliated Graphene and Graphene Oxide for Energy Storage and Electrochemistry Applications. AB - Top-down methods are of key importance for large-scale graphene and graphene oxide preparation. Electrochemical exfoliation of graphite has lately gained much interest because of the simplicity of execution, the short process time, and the good quality of graphene that can be obtained. Here, we test three different electrolytes, that is, H2 SO4 , Na2 SO4 , and LiClO4 , with a common exfoliation procedure to evaluate the difference in structural and chemical properties that result for the graphene. The properties are analyzed by means of scanning transmission electron microscopy (STEM), Raman spectroscopy, and X-ray photoelectron spectroscopy. We then tested the graphene materials for electrochemical applications, measuring the heterogeneous electron transfer (HET) rates with a Fe(CN)6 (3-/4-) redox probe, and their capacitive behavior in alkaline solutions. We correlate the electrochemical features with the presence of structural defects and oxygen functionalities on the graphene materials. In particular, the use of LiClO4 during the electrochemical exfoliation of graphite allowed the formation of highly oxidized graphene with a C/O ratio close to 4.0 and represents a possible avenue for the mass production of graphene oxide as valid alternative to the current laborious and dangerous chemical procedures, which also have limited scalability. PMID- 26441293 TI - Elemental Anisotropic Growth and Atomic-Scale Structure of Shape-Controlled Octahedral Pt-Ni-Co Alloy Nanocatalysts. AB - Multimetallic shape-controlled nanoparticles offer great opportunities to tune the activity, selectivity, and stability of electrocatalytic surface reactions. However, in many cases, our synthetic control over particle size, composition, and shape is limited requiring trial and error. Deeper atomic-scale insight in the particle formation process would enable more rational syntheses. Here we exemplify this using a family of trimetallic PtNiCo nanooctahedra obtained via a low-temperature, surfactant-free solvothermal synthesis. We analyze the competition between Ni and Co precursors under coreduction "one-step" conditions when the Ni reduction rates prevailed. To tune the Co reduction rate and final content, we develop a "two-step" route and track the evolution of the composition and morphology of the particles at the atomic scale. To achieve this, scanning transmission electron microscopy and energy dispersive X-ray elemental mapping techniques are used. We provide evidence of a heterogeneous element distribution caused by element-specific anisotropic growth and create octahedral nanoparticles with tailored atomic composition like Pt1.5M, PtM, and PtM1.5 (M = Ni + Co). These trimetallic electrocatalysts have been tested toward the oxygen reduction reaction (ORR), showing a greatly enhanced mass activity related to commercial Pt/C and less activity loss than binary PtNi and PtCo after 4000 potential cycles. PMID- 26441294 TI - Self-Assembly of Perylene Imide Molecules into 1D Nanostructures: Methods, Morphologies, and Applications. PMID- 26441291 TI - Structure of RagB, a major immunodominant outer-membrane surface receptor antigen of Porphyromonas gingivalis. AB - Porphyromonas gingivalis is the main causative agent of periodontitis. It deregulates the inflammatory and innate host immune responses through virulence factors, which include the immunodominant outer-membrane surface receptor antigens A (PgRagA) and B (PgRagB), co-transcribed from the rag pathogenicity island. The former is predicted to be a Ton-dependent porin-type translocator but the targets of this translocation and the molecular function of PgRagB are unknown. Phenomenologically, PgRagB has been linked with epithelial cell invasion and virulence according to murine models. It also acts as a Toll-like receptor agonist and promotes multiple mediators of inflammation. Hence, PgRagB is a candidate for the development of a periodontitis vaccine, which would be facilitated by the knowledge of its atomic structure. Here, we crystallized and solved the structure of 54-kDa PgRagB, which revealed a single domain centered on a curved helical scaffold. It consists of four tetratrico peptide repeats (TPR1 4), each arranged as two helices connected by a linker, plus two extra downstream capping helices. The concave surface bears four large intertwined irregular inserts (A-D), which contribute to an overall compact moiety. Overall, PgRagB shows substantial structural similarity with Bacteroides thetaiotaomicron SusD and Tannerella forsythia NanU, which are, respectively, engaged in binding and uptake of malto-oligosaccharide/starch and sialic acid. This suggests a similar sugar-binding function for PgRagB for uptake by the cognate PgRagA translocator, and, consistently, three potential monosaccharide-binding sites were tentatively assigned on the molecular surface. PMID- 26441295 TI - High-Performance Electrochemical Catalysts Based on Three-Dimensional Porous Architecture with Conductive Interconnected Networks. AB - The electrochemical applications of traditional carbon nanomaterials such as carbon nanotubes (CNTs) and graphene (G) powders are significantly impeded by their poor three-dimensional (3D) conductivity and lack of hierarchical porous structure. Here, we have constructed a 3D highly conductive CNTs networks and further combined it with mesoporous carbon (mC) for the creation of a core-shell structured (CNT@mC) composite sponge that featured 3D conductivity and hierarchical porous structure. In the composite sponge, interconnected CNTs efficiently eliminates the contact resistance and the hierarchical pores significantly facilitate the mass transport. The electron transfer rates, electroactive surface area and catalytic activity of the CNT@mC composite sponge based catalysts were tested in the direct methanol fuel cells (DMFCs) and electrochemical sensors. In DMFCs, the Pd nanoparticles deposited CNT@mC showed significantly improved catalytic activity and methanol oxidization current. As for amperometric sensing of endocrine disrupting compounds (EDCs), CNT@mC-based catalyst gave a liner range from 10 nM to 1 mM for bisphenol A (BPA) detection and showed great promise for simultaneous detection of multiple EDCs. BPA recovery from environmental water further indicated the potential practical applications of the sensor for BPA detection. Finally, the electrochemical performance of CNT@mC were also investigated in impedimetric sensors. Good selectivity was obtained in impedimetric sensing of BPA and the detection limit was measured to be 0.3 nM. This study highlighted the exceptional electrochemical properties of the CNT@mC composite sponge enabled by its 3D conductivity and hierarchical porous structure. The strategy described may further pave a way for the creation of novel functional materials through integrating multiple superior properties into a single nanostructure for future clean energy technologies and environmental monitoring systems. PMID- 26441296 TI - Factors influencing quit attempts among male daily smokers in China. AB - BACKGROUND: China has the largest population of smokers in the world, yet the quit rate is low. We used data from the 2010 Global Adult Tobacco Survey China to identify factors influencing quit attempts among male Chinese daily smokers. METHODS: The study sample included 3303 male daily smokers. To determine the factors that were significantly associated with making a quit attempt, we conducted logistic regression analyses. In addition, mediation analyses were carried out to investigate how the intermediate association among demographics (age, education, urbanicity) and smoking-related variables affected making a quit attempt. RESULTS: An estimated 11.0% of male daily smokers tried to quit smoking in the 12 months prior to the survey. Logistic regression analysis indicated that younger age (15-24 years), being advised to quit by a health care provider (HCP) in the past 12 months, lower cigarette cost per pack, monthly or less frequent exposure to smoking at home, and awareness of the harms of tobacco use were significantly associated with making a quit attempt. Additional mediation analyses showed that having knowledge of the harm of tobacco, exposure to smoking at home, and having been advised to quit by an HCP were mediators of making a quit attempt for other independent variables. CONCLUSION: Evidence-based tobacco control measures such as conducting educational campaigns on the harms of tobacco use, establishing smoke-free policies at home, and integrating tobacco cessation advice into primary health care services can increase quit attempts and reduce smoking among male Chinese daily smokers. PMID- 26441297 TI - Quantifying the physical activity energy expenditure of commuters using a combination of global positioning system and combined heart rate and movement sensors. AB - BACKGROUND: Active commuting may help to increase adults' physical activity levels. However, estimates of its energy cost are derived from a small number of studies which are laboratory-based or use self-reported measures. METHODS: Adults working in Cambridge (UK) recruited through a predominantly workplace-based strategy wore combined heart rate and movement sensors and global positioning system (GPS) devices for one week, and completed synchronous day-by-day travel diaries in 2010 and 2011. Commuting journeys were delineated using GPS data, and metabolic intensity (standard metabolic equivalents; MET) was derived and compared between journey types using mixed-effects linear regression. RESULTS: 182 commuting journeys were included in the analysis. Median intensity was 1.28 MET for car journeys; 1.67 MET for bus journeys; 4.61 MET for walking journeys; 6.44 MET for cycling journeys; 1.78 MET for journeys made by car in combination with walking; and 2.21 MET for journeys made by car in combination with cycling. The value for journeys made solely by car was significantly lower than those for all other journey types (p<0.04). On average, 20% of the duration of journeys incorporating any active travel (equating to 8 min) was spent in moderate-to vigorous physical activity (MVPA). CONCLUSIONS: We have demonstrated how GPS and activity data from a free-living sample can be used simultaneously to provide objective estimates of commuting energy expenditure. On average, incorporating walking or cycling into longer journeys provided over half the weekly recommended activity levels from the commute alone. This may be an efficient way of achieving physical activity guidelines and improving population health. PMID- 26441298 TI - Back on track-Smoking cessation and weight changes over 9 years in a community based cohort study. AB - OBJECTIVE: To examine the impact of smoking cessation on body weight compared with normal long-term weight development. METHODS: Of 1970 adults (20-69 years) in a rural town in Denmark invited to take part in the study in 1998-2000, 1374 (70%) participated. After 9 years, 1121 participated in the follow-up study. Weight changes were compared using multivariable regression models. RESULTS: The mean baseline weight of never-smokers was 76.4 kg (SD 16.0). The adjusted weight of smokers and ex-smokers differed by -4.2 kg (95% CI: -5.9, -2.6), and -0.7 kg (95% CI: -2.5, 1.1), respectively. The adjusted weight gain rate (kg/year) of never-smokers, smokers, and ex-smokers was 0.213, 0.127, and 0.105, respectively. The absolute post cessation weight gain (PCWG) was 5.0 kg (SD 7.0), and the adjusted PCWG was 2.8 kg (95% CI: 1.7, 3.9) compared with never-smokers, and 3.5 kg (95% CI: 2.3, 4.8) compared with smokers. The follow-up weight did not differ between quitters and never-smokers (0.1 kg; 95% CI: -2.4, 2.6). CONCLUSION: Smokers weigh less than never-smokers. By quitting, they gain weight and end up weighing the same as comparable never-smokers. Weight gain rates differ by smoking status. Consequently, PCWG depends on the length of follow-up. Our graphical model indicates that smoking cessation results in a return to normal weight development. PMID- 26441299 TI - Smoking dependence in 18 European countries: Hard to maintain the hardening hypothesis. AB - OBJECTIVE: When the prevalence of smoking decreases in a population, there is a hypothesis-the so-called "hardening hypothesis"-that the remaining smokers form a subgroup of "hardcore smokers." Our aims were to test the hardening hypothesis and to analyze the determinants of high dependence taking into account both individual and country-level characteristics. METHOD: Within the Pricing Policies and Control of Tobacco in Europe (PPACTE) project, we conducted a face-to-face survey on smoking between January and July 2010 in 18 European countries, including 2882 male and 2254 female smokers with complete information on smoking dependence. The Heaviness of Smoking Index (HSI) was used as a measure of tobacco dependence. We correlated smoking prevalence and dependence using the country as unit of analysis. Moreover, we fitted multilevel logistic regression models. RESULTS: Country-specific prevalence of smoking was positively, although not significantly, correlated with the proportion of highly tobacco-dependent smokers (overall rsp=0.203, p=0.419), both in men (rsp=0.235, p=0.347) and women (rsp=0.455, p=0.058). Using individual-level analysis, high dependence was positively related to age, and, although not significantly, to smoking prevalence, and inversely related to level of education. The lack of a smoking ban at home was positively related to smoking dependence. CONCLUSIONS: Using both ecological and individual-level analyses, the relations between smoking prevalence and HSI were not significant, but in the opposite direction as compared to that assumed by the "hardening hypothesis." Therefore, our data provide empirical evidence against this theory, thus supporting the feasibility of an endgame strategy. PMID- 26441300 TI - Providers' knowledge, attitudes, and practices related to colorectal cancer control in Brazil. AB - In Brazil, colorectal cancer (CRC) is the fourth most common cause of cancer related death among men, and the third most common among women. We aimed to examine CRC screening-related knowledge, attitudes, and practices among physicians and nurses working in Brazil's network of health units, and to describe the capacity of these units for CRC screening. In 2011, 1600 health units were randomly selected from all 26 states and the Federal District. One coordinator and one health care provider were selected for the interview. Response rates were 78% for coordinators, 34% for physicians, and 65% for nurses. The Brazilian National Cancer Institute (INCA) recommendations for CRC screening were not often used in the health units, but screening outreach and use of CRC exams were more common in units that were using them. Physicians and nurses differed in most characteristics, and in their knowledge, attitudes, and practices of CRC screening. Forty-seven percent of physicians reported not conducting CRC screening compared to 65% of nurses. Fecal occult blood test was most often used by physicians and nurses, but fewer physicians than nurses perceived this exam as very effective in reducing CRC mortality. Physicians' gender, years since graduation, and geographical region of practice in Brazil were associated to CRC screening practice. The findings may reflect the low influence of INCA CRC screening recommendations, physicians receiving their medical education when CRC burden in Brazil was of low concern, and the lack of CRC screening capacity in some regions of Brazil. PMID- 26441301 TI - Targeting sexual health services in primary care: A systematic review of the psychosocial correlates of adverse sexual health outcomes reported in probability surveys of women of reproductive age. AB - BACKGROUND: Women using primary care vary in need for sexually transmitted infections (STIs) testing and contraception. Psychosocial correlates of these needs may be useful for targeting services. We undertook a systematic review to identify psychosocial correlates of STI acquisition, unplanned pregnancy (UP), abortion and risky sexual behaviours in general population samples of women of reproductive age. METHODS: We searched bibliographic databases for probability surveys of women aged 16-44 years in the European Union, USA, Canada, Australia, UK or New Zealand undertaken January 1994-January 2014. RESULTS: Eleven papers were included. Unplanned pregnancy was associated with smoking, depression, being single and sexual debut <16 years. Abortion was associated with lack of closeness to parents, leaving home at an early age, and relationship break-up. Multiple partnerships were associated with intensity of marijuana and alcohol use, and smoking. STI diagnosis was associated with relationship break-up and younger partners. Non-use of contraception was associated with smoking, obesity, relationship status, sedentary lifestyles, fatalistic pregnancy attitudes and lower alcohol use. Condom non-use was higher (at first sex) with partners 5+years older and lower (at last sex) in less stable partnerships. CONCLUSION: Psychosocial variables, particularly relationship status and smoking, may help identify women in primary care for STI testing and contraception advice and supply. PMID- 26441303 TI - Synthesis of Unsymmetrical Sulfides and Their Oxidation to Sulfones to Discover Potent Antileishmanial Agents. AB - Unsymmetrical sulfides were first synthesized using combinations of a 1,3 dicarbonyl, an aromatic aldehyde and a thiol in the presence of 10 mol % ethanolic piperidine. These sulfides derivatives were subsequently converted into corresponding sulfones via oxidation in the presence of m-chloroperoxybenzoic acid (m-CPBA) at ice-bath to room temperature. The former reaction was achieved at room temperature through one-pot three-component. The later was obtained in good yields using mild reaction conditions with flexibility in choice from a range of substrates. The antimicrobial properties of the newly synthesized sulfone derivatives were investigated against the protozoan parasite, Leishmania donovani, a causative agent of visceral leishmaniasis (VL). Nine sulfone derivatives were found to be efficacious and exhibited significant antimicrobial activity. Further, these compounds were nontoxic on murine peritoneal macrophages thus eliminating potential cytoxicity in the host cells. These compounds may be indicated as potential leads in the treatment of visceral leishmaniasis. PMID- 26441302 TI - The burden of behavioral risk factors for cardiovascular disease in Europe. A significant prevention deficit. AB - OBJECTIVE: The study objective was to assess the burden of major cardiovascular disease (CVD) behavioral risk factors (BRFs) (i.e., smoking, excess body weight, physical inactivity, risky alcohol consumption) among individuals in the community with and without CVD history. METHODS: For the current study, a subset of the data from the Survey of Health, Ageing and Retirement in Europe (SHARE) was analyzed, which were collected from 26,743 individuals aged 50+ years old, during the 1st wave of SHARE in 2004/05 in eleven European countries. RESULTS: Among those with CVD, there is a statistically significant higher percentage of inactive individuals (81.4% vs. 69.5 among those without CVD), and of individuals with excess body weight (64.3%) or obese (21.6%). Patients with CVD had a lower prevalence of smoking and risky alcohol consumption in most countries, whereas the prevalence of high body weight and physical inactivity was higher in CVD patients compared to individuals without CVD in almost all countries. More than half of the population has at least two BRFs, with a significantly higher prevalence of multiple BRFs among those diagnosed with CVD. CONCLUSION: Study findings suggest that a significant burden of behavioral risk factors for CVD remains in the population overall but also among patients diagnosed with CVD. Given the significant prevalence of BRFs, the prevention benefits would be immense for all stakeholders involved and negligence would be perilous. PMID- 26441304 TI - Are human faces unique? A metric approach to finding single individuals without duplicates in large samples. AB - In the forensic sciences it is inferred that human individuals are unique and thus can be reliably identified. The concept of individual uniqueness is claimed to be unprovable because another individual of same characteristics may exist if population size were infinite. It is proposed to replace "unique" with "singular" defined as a situation when only one individual in a specific population has a particular set of characteristics. The likelihood that in a population there will be no duplicate individual with exactly the same set of characteristics can be calculated from datasets of relevant characteristics. To explore singularity, the ANSUR database which contains anthropometric measurements of 3982 individuals was used. Eight facial metric traits were used to search for duplicates. With the addition of each trait, the chances of finding a duplicate were reduced until singularity was achieved. Singularity was consistently achieved at a combination of the maximum of seven traits. The larger the traits in dimension, the faster singularity was achieved. By exploring how singularity is achieved in subsamples of 200, 500, etc. it has been determined that about one trait needs to be added when the size of the target population increases by 1000 individuals. With the combination of four facial dimensions, it is possible to achieve a probability of finding a duplicate of the order of 10(-7), while, the combination of 8 traits reduces probability to the order of 10(-14), that is less than one in a trillion. PMID- 26441306 TI - Secreted Ephrin Receptor A7 Promotes Somatic Cell Reprogramming by Inducing ERK Activity Reduction. AB - The role of secreted molecules in cellular reprogramming has been poorly understood. Here we identify a truncated form of ephrin receptor A7 (EPHA7) as a key regulator of reprogramming. Truncated EPHA7 is prominently upregulated and secreted during reprogramming. EPHA7 expression is directly regulated by OCT3/4. EphA7 knockdown results in marked reduction of reprogramming efficiency, and the addition of truncated EPHA7 is able to restore it. ERK activity is markedly reduced during reprogramming, and the secreted, truncated EPHA7 is responsible for ERK activity reduction. Remarkably, treatment of EphA7-knockdown MEFs with the ERK pathway inhibitor restores reprogramming efficiency. Analyses show that truncated EPHA7-induced ERK activity reduction plays an important role in the middle phase of reprogramming. Thus, our findings uncover the importance of secreted EPHA7-induced ERK activity reduction in reprogramming. PMID- 26441305 TI - Crestospheres: Long-Term Maintenance of Multipotent, Premigratory Neural Crest Stem Cells. AB - Premigratory neural crest cells comprise a transient, embryonic population that arises within the CNS, but subsequently migrates away and differentiates into many derivatives. Previously, premigratory neural crest could not be maintained in a multipotent, adhesive state without spontaneous differentiation. Here, we report conditions that enable maintenance of neuroepithelial "crestospheres" that self-renew and retain multipotency for weeks. Moreover, under differentiation conditions, these cells can form multiple derivatives in vitro and in vivo after transplantation into chick embryos. Similarly, human embryonic stem cells directed to a neural crest fate can be maintained as crestospheres and subsequently differentiated into several derivatives. By devising conditions that maintain the premigratory state in vitro, these results demonstrate that neuroepithelial neural crest precursors are capable of long-term self-renewal. This approach will help uncover mechanisms underlying their developmental potential, differentiation and, together with the induced pluripotent stem cell techniques, the pathology of human neurocristopathies. PMID- 26441309 TI - Free Thiol of Transthyretin in Human Plasma Most Accessible to Modification/Oxidation. AB - Free-thiol(s) in proteins, especially, when located on the surface of the molecule, are susceptible to oxidation/modification, which may cause loss of function or an alteration in the ternary structure. This suggests that the status of thiol group(s) of cysteine residue(s) in a protein, i.e., free-thiol versus an oxidized/modified form, in vivo, could reflect the physiological state of the molecule with respect to susceptibility to oxidative stress. To address this issue, we established an efficient method for isolating proteins that contain free thiol groups from a complex mixture, which permits the amount of free-thiol form(s) to modified/oxidized forms to be estimated. Albumin, which accounts for 55% of the total plasma proteins and has such a free thiol and has been reported to scavenge various reactive oxygen species (ROS) in vivo. The developed method was used to isolate the free form of albumin from fresh plasma. However, contrary to our expectations, transthyretin (TTR), which also has a single free thiol, was found to be the major protein that was the most susceptible to modification/oxidation. In addition, the free-thiol form could be separated from oxidized or modified molecules, permitting the relative abundance of the free thiol form to be estimated. The findings show that the levels of the free-thiol form of TTR in plasma was significantly lowered after a hydrogen peroxide treatment, even at low concentrations (0.1 mM), suggesting that TTR could be a useful biomarker for monitoring a ROS imbalance in relation to various oxidative stress conditions. PMID- 26441307 TI - Vascular Platform to Define Hematopoietic Stem Cell Factors and Enhance Regenerative Hematopoiesis. AB - Hematopoietic stem cells (HSCs) inhabit distinct microenvironments within the adult bone marrow (BM), which govern the delicate balance between HSC quiescence, self-renewal, and differentiation. Previous reports have proposed that HSCs localize to the vascular niche, comprised of endothelium and tightly associated perivascular cells. Herein, we examine the capacity of BM endothelial cells (BMECs) to support ex vivo and in vivo hematopoiesis. We demonstrate that AKT1 activated BMECs (BMEC-Akt1) have a unique transcription factor/cytokine profile that supports functional HSCs in lieu of complex serum and cytokine supplementation. Additionally, transplantation of BMEC-Akt1 cells enhanced regenerative hematopoiesis following myeloablative irradiation. These data demonstrate that BMEC-Akt1 cultures can be used as a platform for the discovery of pro-HSC factors and justify the utility of BMECs as a cellular therapy. This technical advance may lead to the development of therapies designed to decrease pancytopenias associated with myeloablative regimens used to treat a wide array of disease states. PMID- 26441310 TI - Get Your Atoms in Order--An Open-Source Implementation of a Novel and Robust Molecular Canonicalization Algorithm. AB - Finding a canonical ordering of the atoms in a molecule is a prerequisite for generating a unique representation of the molecule. The canonicalization of a molecule is usually accomplished by applying some sort of graph relaxation algorithm, the most common of which is the Morgan algorithm. There are known issues with that algorithm that lead to noncanonical atom orderings as well as problems when it is applied to large molecules like proteins. Furthermore, each cheminformatics toolkit or software provides its own version of a canonical ordering, most based on unpublished algorithms, which also complicates the generation of a universal unique identifier for molecules. We present an alternative canonicalization approach that uses a standard stable-sorting algorithm instead of a Morgan-like index. Two new invariants that allow canonical ordering of molecules with dependent chirality as well as those with highly symmetrical cyclic graphs have been developed. The new approach proved to be robust and fast when tested on the 1.45 million compounds of the ChEMBL 20 data set in different scenarios like random renumbering of input atoms or SMILES round tripping. Our new algorithm is able to generate a canonical order of the atoms of protein molecules within a few milliseconds. The novel algorithm is implemented in the open-source cheminformatics toolkit RDKit. With this paper, we provide a reference Python implementation of the algorithm that could easily be integrated in any cheminformatics toolkit. This provides a first step toward a common standard for canonical atom ordering to generate a universal unique identifier for molecules other than InChI. PMID- 26441311 TI - Host-Parasite Interactions from the Inside: Plant Reproductive Ontogeny Drives Specialization in Parasitic Insects. AB - Host plant interactions are likely key drivers of evolutionary processes involved in the diversification of phytophagous insects. Granivory has received substantial attention for its crucial role in shaping the interaction between plants and their seed parasites, but fine-scale mechanisms explaining the role of host plant reproductive biology on specialization of seed parasites remain poorly described. In a comparative approach using plant histological techniques, we tested the hypotheses that different seed parasite species synchronize their life cycles to specific stages in seed development, and that the stage they target depends on major differences in seed development programs. In a pinaceous system, seed storage products are initiated before ovule fertilization and the wasps target the ovule's nucellus during megagametogenesis, a stage at which larvae may benefit from the by-products derived from both secreting cells and dying nucellar cells. In a cupressaceous system, oviposition activity peaks later, during embryogenesis, and the wasps target the ovule's megagametophyte where larvae may benefit from cell disintegration during embryogenesis. Our cytohistological approach shows for the first time how, despite divergent oviposition targets, different parasite species share a common strategy that consists of first competing for nutrients with developing plant structures, and then consuming these developed structures to complete their development. Our results support the prediction that seed developmental program is an axis for specialization in seed parasites, and that it could be an important parameter in models of their ecological and taxonomic divergence. This study provides the basis for further investigating the possibility of the link between plant ontogeny and pre dispersal seed parasitism. PMID- 26441312 TI - Work characteristics and health: how to analyze change. PMID- 26441313 TI - Concentration of antiepileptic drugs in persons with epilepsy: a comparative study in serum and saliva. AB - AIM OF THE STUDY: The monitoring of antiepileptic drugs (AEDs) in clinical setting is important for measuring the efficacy of drugs and their safety and in personalizing drug therapy. We investigated the levels of AED, carbamazepine (CBZ), phenytoin (PHT) and phenobarbital (PHB), to understand their association in saliva compared with those in serum during the therapy. MATERIALS AND METHODS: In this study, we performed a prospective study of 116 persons with epilepsy (PWE; mean age 26.90 +/- 11.83 years). Serum and saliva samples were collected at trough levels from the patients, who were under the treatment of CBZ, PHT and PHB either alone or in combination of these drugs for at least three months. The drug levels were assessed by high-performance liquid chromatography. RESULTS AND CONCLUSIONS: The number of males (n = 88; 75.86%) was higher than females (n = 28; 24.14%) among the recruited patients. The intake of CBZ, PHT and PHB was observed in 49.14%, 68.10% and 38.79% of PWE, respectively. The levels of these AEDs showed a significant correlation (p < 0.05) between serum and saliva. Interestingly, the levels of mono-therapy or bi-therapy showed a significant association (p < 0.05) between serum and saliva, however, there was no significant association in case of poly-therapy. This is the first report in the Indian population on simultaneous estimation of the three commonly used AEDs, such as CBZ, PHT and PHB in serum and saliva implicating their associations, either in mono-therapy or bi-therapy in PWE. PMID- 26441315 TI - Cyclic fatigue resistance of ProTaper Next nickel-titanium rotary files. PMID- 26441314 TI - Exploring autistic-like traits relating to empathic attitude and psychological distress in hospital pharmacists. AB - BACKGROUND: Pharmacists are expected to play a key role in modern cancer care. Research suggests that an empathic approach and attitude in medical staff improves the quality of patient care. An empathic attitude and psychological distress are thought to be associated with autistic-like traits, but little is known about such traits. OBJECTIVE: In this study, we aimed to clarify the associations among autistic-like traits, empathic attitude in a medical context, and psychological health in hospital pharmacists. SETTING: Eligibility criteria for inclusion were certified pharmacists working at hospitals for patient care who returned their questionnaires. METHOD: Eight hundred and twenty-three hospital pharmacists completed a number of self-administered questionnaires anonymously by mail. MAIN OUTCOME MEASURES: Scores were obtained on the Autism Spectrum Quotient, the Jefferson Scale of Empathy, the General Health Questionnaire-12, and subscales of the Interpersonal Reactivity Index (Perspective Taking, IRI-Empathic Concern, IRIPersonal Distress). We performed correlation and mediation analyses to confirm that the empathy and general health questionnaires were associated with autism-spectrum quotient scores, and with each IRI subscale. RESULTS: Complete responses were obtained from 379 pharmacists comprising 151 males (39.8 %) with a mean age of 37.7 +/- 10.8 years (missing data, n = 13) and a median of 11 years after qualification as a pharmacist. Autism-Spectrum Quotient scores were inversely correlated with empathy (r = 0.22, p < 0.001) and positively correlated with general health scores (r = 0.40, p < 0.001). In the models with mediation, the inverse correlation between autism spectrum quotient and empathy scores was mediated indirectly by IRI-Perspective Taking and IRI-Empathic Concern, and the positive correlation between autism spectrum quotient and general health was mediated indirectly by IRI-Personal Distress. There were also direct effects, with significant effects of autism spectrum quotient on empathy and general health scores. CONCLUSION: Our findings suggest that autistic-like traits affect both empathic attitude in a medical context and the psychological health of pharmacists. We recommend that to improve empathy in those with high levels of autistic-like traits, we may need to develop specialized interventions, such as improving communication skills training. PMID- 26441316 TI - Response: Cyclic fatigue resistance of ProTaper Next nickel-titanium rotary instruments. PMID- 26441317 TI - Corrigendum. PMID- 26441318 TI - Prospective case-controlled sound localisation study after cochlear implantation in adults with single-sided deafness and ipsilateral tinnitus. AB - OBJECTIVES: To analyse the sound localisation skills of subjects with profound single-sided deafness (SSD) and accompanied ipsilateral tinnitus who are using a cochlear implant (CI) for between 4 and 11 years. DESIGN: Sound localisation skills were tested using nine loudspeakers in a frontal semicircle ranging from 90 degrees to +90 degrees . Subjects were tested in the CION and the CIOFF conditions via 3 localisation stimuli: broadband noise (BB), low-pass noise (LP) and high-pass noise (HP). PARTICIPANTS: The test group consisted of 10 adult subjects with profound sensorineural SSD, ipsilateral tinnitus and a CI. Normative data of a control group of 30 normal hearing subjects were used for comparison. MAIN OUTCOME MEASURES: Sound location accuracy was analysed via the root-mean-square error (RMSE), the mean absolute error (MAE), the localisation bias ('b') and the bias-adjusted deviation ('db '). Subjective dynamic aspects of hearing were assessed via a reduced version of the Speech, Spatial and Qualities of Hearing Scale (SSQ5 ). RESULTS: For all 3 stimuli, the RMSE improved significantly in SSD subjects in the CION condition compared to the CIOFF condition. The localisation accuracy of subjects with SSD improved significantly for BB and HP stimuli. A significant bias-adjusted deviation 'db ' was found for the BB and HP stimuli. Subjects' mean SSQ5 scores were significantly higher in the CION condition at test date than in the CIOFF condition preoperatively. CONCLUSIONS: Subjects can better locate sound in the CION condition than in the CIOFF condition. PMID- 26441319 TI - [Erratum to: The German Acanthamoeba keratitis register : Initial results of a multicenter study]. PMID- 26441320 TI - Sobriety Treatment and Recovery Teams: Implementation Fidelity and Related Outcomes. AB - BACKGROUND: Although integrated programs between child welfare and substance abuse treatment are recommended for families with co-occurring child maltreatment and substance use disorders, implementing integrated service delivery strategies with fidelity is a challenging process. OBJECTIVE: This study of the first five years of the Sobriety Treatment and Recovery Team (START) program examines implementation fidelity using a model proposed by Carroll et al. (2007). The study describes the process of strengthening moderators of implementation fidelity, trends in adherence to START service delivery standards, and trends in parent and child outcomes. METHODS: Qualitative and quantitative measures were used to prospectively study three START sites serving 341 families with 550 parents and 717 children. RESULTS: To achieve implementation fidelity to service delivery standards required a pre-service year and two full years of operation, persistent leadership, and facilitative actions that challenged the existing paradigm. Over four years of service delivery, the time from the child protective services report to completion of five drug treatment sessions was reduced by an average of 75 days. This trend was associated with an increase in parent retention, parental sobriety, and parent retention of child custody. Conclusions/Importance: Understanding the implementation processes necessary to establish complex integrated programs may support realistic allocation of resources. Although implementation fidelity is a moderator of program outcome, complex inter-agency interventions may benefit from innovative measures of fidelity that promote improvement without extensive cost and data collection burden. The implementation framework applied in this study was useful in examining implementation processes, fidelity, and related outcomes. PMID- 26441322 TI - ZNF1 Encodes a Putative C2H2 Zinc-Finger Protein Essential for Appressorium Differentiation by the Rice Blast Fungus Magnaporthe oryzae. AB - The rice blast fungus Magnaporthe oryzae forms specialized infection structures called appressoria which are essential for gaining entry to plant tissue. Here, we report the identification of a novel nonpathogenic T-DNA-tagged mutant XF696 of M. oryzae with a single insertion in the promoter of ZNF1, which encodes a putative transcription factor (TF). Targeted gene deletion mutants of ZNF1 are nonpathogenic and unable to develop appressoria. However, Deltaznf1 mutants still respond to exogenous cyclic AMP on hydrophilic surfaces and can sense hydrophobic surfaces, initiating the differentiation of germ tubes. Interestingly, Deltaznf1 mutants also produce significantly more conidia compared with the isogenic wild type strain. Quantitative reverse-transcription polymerase chain reaction analysis and green fluorescent protein fusion experiments revealed that expression of ZNF1 was highly induced during germination and appressorium development in M. oryzae and potentially regulated by the Pmk1 mitogen-activated protein kinase pathway. We observed that Deltaznf1 mutants are affected in mitosis and impaired in mobilization and degradation of lipid droplets and glycogen reserves during appressorium differentiation. Site-directed mutagenesis confirmed that three of the four C2H2 zinc-finger domains are essential for the function of Znf1. Taken together, we conclude that a C2H2 zinc-finger TF encoded by ZNF1 is essential for appressorium development by the rice blast fungus. PMID- 26441321 TI - Spatial patterns of atrophy, hypometabolism, and amyloid deposition in Alzheimer's disease correspond to dissociable functional brain networks. AB - Recent neuroimaging studies of Alzheimer's disease (AD) have emphasized topographical similarities between AD-related brain changes and a prominent cortical association network called the default-mode network (DMN). However, the specificity of distinct imaging abnormalities for the DMN compared to other intrinsic connectivity networks (ICNs) of the limbic and heteromodal association cortex has not yet been examined systematically. We assessed regional amyloid load using AV45-PET, neuronal metabolism using FDG-PET, and gray matter volume using structural MRI in 473 participants from the Alzheimer's Disease Neuroimaging Initiative, including preclinical, predementia, and clinically manifest AD stages. Complementary region-of-interest and voxel-based analyses were used to assess disease stage- and modality-specific changes within seven principle ICNs of the human brain as defined by a standardized functional connectivity atlas. Amyloid deposition in AD dementia showed a preference for the DMN, but high effect sizes were also observed for other neocortical ICNs, most notably the frontoparietal-control network. Atrophic changes were most specific for an anterior limbic network, followed by the DMN, whereas other neocortical networks were relatively spared. Hypometabolism appeared to be a mixture of both amyloid- and atrophy-related profiles. Similar patterns of modality-dependent network specificity were also observed in the predementia and, for amyloid deposition, in the preclinical stage. These quantitative data confirm a high vulnerability of the DMN for multimodal imaging abnormalities in AD. However, rather than being selective for the DMN, imaging abnormalities more generally affect higher order cognitive networks and, importantly, the vulnerability profiles of these networks markedly differ for distinct aspects of AD pathology. PMID- 26441323 TI - Penetration Peg Formation and Invasive Hyphae Development Require Stage-Specific Activation of MoGTI1 in Magnaporthe oryzae. AB - The hemibiotrophic pathogen Magnaporthe oryzae causes one of the most destructive diseases in cultivated rice. Complex infection-related morphogenesis and production of various effectors are known to be important for successful colonization and disease development. In this study, we characterized the activation of the MoGTI1 transcription factor and its role in infection-related morphogenesis and effector gene expression. The Mogti1 mutant was nonpathogenic, although it was normal in appressorium formation and turgor generation. Close examination showed that Mogti1 was defective in penetration and growth of normal invasive hyphae. Deletion of MoGTI1 affected the expression of the majority of effector genes. The expression of MoGti1 appeared to be controlled by the Mps1 but not Pmk1 mitogen-activated protein kinase (MAPK), and the mps1 and Mogti1 mutants had similar phenotypes in plant infection and cell wall integrity defects. However, lack of MAPK phosphorylation sites and dispensability of the putative MAPK docking site suggested that MoGti1 is not a direct target of Mps1. Site-specific mutagenesis analyses showed that the putative protein kinase A phosphorylation site was not essential for localization of MoGti1 to the nucleus but important for its normal function. Although the cyclin-dependent kinase (CDK) phosphorylation site of MoGti1 is dispensable during vegetative growth and appressorium formation, the S77A mutation affected penetration and invasive growth. Localization of MoGti1(S77A)-green fluorescent protein to the nucleus in late stages of appressorium formation and during invasive growth was not observed, suggesting a stage-specific CDK phosphorylation of MoGti1. Overall, our data indicate that Mps1 may indirectly regulate the expression of MoGti1 in maintaining cell wall integrity, conidiation, and plant infection. MoGti1 is likely a stage-specific target of CDK and plays a crucial role in effector gene expression and morphogenesis related to the development of penetration pegs and invasive hyphae. PMID- 26441324 TI - Surface Model and Tomographic Archive of Fossil Primate and Other Mammal Holotype and Paratype Specimens of the Ditsong National Museum of Natural History, Pretoria, South Africa. AB - Nearly a century of paleontological excavation and analysis from the cave deposits of the Cradle of Humankind UNESCO World Heritage Site in northeastern South Africa underlies much of our understanding of the evolutionary history of hominins, other primates and other mammal lineages in the late Pliocene and early Pleistocene of Africa. As one of few designated fossil repositories, the Plio Pleistocene Palaeontology Section of the Ditsong National Museum of Natural History (DNMNH; the former Transvaal Museum) curates much of the mammalian faunas recovered from the fossil-rich deposits of major South African hominin-bearing localities, including the holotype and paratype specimens of many primate, carnivore, and other mammal species (Orders Primates, Carnivora, Artiodactyla, Eulipotyphla, Hyracoidea, Lagomorpha, Perissodactyla, and Proboscidea). Here we describe an open-access digital archive of high-resolution, full-color three dimensional (3D) surface meshes of all 89 non-hominin holotype, paratype and significant mammalian specimens curated in the Plio-Pleistocene Section vault. Surface meshes were generated using a commercial surface scanner (Artec Spider, Artec Group, Luxembourg), are provided in formats that can be opened in both open source and commercial software, and can be readily downloaded either via an online data repository (MorphoSource) or via direct request from the DNMNH. In addition to providing surface meshes for each specimen, we also provide tomographic data (both computerized tomography [CT] and microfocus [microCT]) for a subset of these fossil specimens. This archive of the DNMNH Plio-Pleistocene collections represents the first research-quality 3D datasets of African mammal fossils to be made openly available. This simultaneously provides the paleontological community with essential baseline information (e.g., updated listing and 3D record of specimens in their current state of preservation) and serves as a single resource of high-resolution digital data that improves collections accessibility, reduces unnecessary duplication of efforts by researchers, and encourages ongoing imaging-based paleobiological research across a range of South African non-hominin fossil faunas. Because the types, paratypes, and key specimens include globally-distributed mammal taxa, this digital archive not only provides 3D morphological data on taxa fundamental to Neogene and Quaternary South African palaeontology, but also lineages critical to research on African, other Old World, and New World paleocommunities. With such a broader impact of the DNMNH 3D data, we hope that establishing open access to this digital archive will encourage other researchers and institutions to provide similar resources that increase accessibility to paleontological collections and support advanced paleobiological analyses. PMID- 26441325 TI - ITPA Polymorphisms Are Associated with Hematological Side Effects during Antiviral Therapy for Chronic HCV Infection. AB - BACKGROUND/OBJECTIVE: Genetic polymorphisms in the inosine triphosphatase (ITPA) gene have been associated with the protection from early ribavirin(RBV)-induced hemolytic anemia among patients with chronic hepatitis C virus (HCV) infection. The aim of the present study was to investigate the association between the functional ITPA variants and hematological side effects during antiviral therapy with pegylated interferon (PegIFN) and RBV. PATIENTS AND METHODS: This cohort study included all consecutive Caucasian patients treated for chronic HCV infection with PegIFN and RBV between 2000 and 2009 for whom a serum sample was available for genetic testing. The predicted inosine triphosphate pyrophosphatase (ITPase) activity was based on the genotypes of the SNPs rs1127354 and rs7270101. Decline in hemoglobin (Hb) during antiviral therapy, as well as dose reductions, blood transfusions and use of erythropoietin were assessed. RESULTS: In total, 213 patients were included. The predicted ITPase activity was normal among 152 (71%) patients; 61 (29%) patients had ITPase deficiency. By multivariable linear regression, RBV dose in mg per kilogram (Beta 0.09, 95%CI 0.04-0.13, p<0.001) and normal ITPase activity (Beta 0.89, 95%CI 0.64-1.14, p<0.001) were associated with more Hb decline at week 4 of treatment. Patients with normal ITPase activity underwent more dose adjustments of RBV than patients with ITPase deficiency (19(13%) vs 1(2%),p = 0.014) and received erythropoietin more frequently (12 (8%) vs 0 (0%),p = 0.024). CONCLUSION: Genetic variants in the ITPA gene protected against RBV treatment-induced anemia among Caucasian patients with chronic HCV infection. Patients with normal ITPase activity underwent more dose reductions of RBV and received erythropoietin more frequently. PMID- 26441326 TI - A light-regulated bZIP module, photozipper, induces the binding of fused proteins to the target DNA sequence in a blue light-dependent manner. AB - Aureochrome-1 (AUREO1) has been identified as a blue light (BL) receptor responsible for the BL-induced blanching of a stramenopile alga, Vaucheria frigida. BL induces the dimerization of monomeric AUREO1, which subsequently increases its affinity for the target sequence. We made a synthetic gene encoding N-terminally truncated monomeric AUREO1 (Photozipper protein) containing a basic region/leucine zipper (bZIP) domain and a light-oxygen-voltage-sensing domain. In the present study, yellow fluorescent protein or mCherry protein was fused with the Photozipper (PZ) protein, and their oligomeric structures and DNA-binding were compared in the dark and light states. Dynamic light scattering and size exclusion chromatography demonstrated that the hydrodynamic radii and molecular masses of the fusion proteins increased upon BL illumination, suggesting that fusion PZs underwent BL-induced dimerization. Moreover, BL-induced dimerization enhanced their affinities for the target sequence. Taken together, PZ likely functions as a BL-regulated bZIP module in fusion proteins, and can possibly provide a new approach for controlling bZIP transcription factors. PMID- 26441328 TI - In Absentia: An Exploratory Study of How Patients Are Considered in Multidisciplinary Cancer Team Meetings. AB - BACKGROUND: Multidisciplinary team meetings and shared decision-making are potential means of delivering patient-centred care. Not much is known about how those two paradigms fit together in cancer care. This study aimed to investigate how decisions are made in multidisciplinary team meetings and whether patient perspectives are incorporated in these decisions. MATERIALS AND METHODS: A qualitative study was conducted using non-participant observation at multidisciplinary team meetings (also called tumor boards) at the University Cancer Center Hamburg-Eppendorf, Germany. Two researchers recorded structured field notes from a total of N = 15 multidisciplinary team meetings. Data were analyzed using content analysis and descriptive statistics. RESULTS: Physicians mainly exchanged medical information and based their decision-making on this information. Individual patient characteristics or their treatment preferences were rarely considered or discussed. In the few cases where patient preferences were raised as a topic, this information did not seem to be taken into account in decision-making processes about treatment recommendations. CONCLUSION: The processes in multidisciplinary team meetings we observed did not exhibit shared decision-making. Patient perspectives were absent. If multidisciplinary team meetings wish to become more patient-centred they will have to modify their processes and find a way to include patient preferences into the decision-making process. PMID- 26441327 TI - Neuropeptide Y: A stressful review. AB - Stress is defined as an adverse condition that disturbs the homeostasis of the body and activates adaptation responses. Among the many pathways and mediators involved, neuropeptide Y (NPY) stands out due to its unique stress-relieving, anxiolytic and neuroprotective properties. Stress exposure alters the biosynthesis of NPY in distinct brain regions, the magnitude and direction of this effect varying with the duration and type of stress. NPY is expressed in particular neurons of the brainstem, hypothalamus and limbic system, which explains why NPY has an impact on stress-related changes in emotional-affective behaviour and feeding as well as on stress coping. The biological actions of NPY in mammals are mediated by the Y1, Y2, Y4 and Y5 receptors, Y1 receptor stimulation being anxiolytic whereas Y2 receptor activation is anxiogenic. Emerging evidence attributes NPY a role in stress resilience, the ability to cope with stress. Thus there is a negative correlation between stress-induced behavioural disruption and cerebral NPY expression in animal models of post traumatic stress disorder. Exogenous NPY prevents the negative consequences of stress, and polymorphisms of the NPY gene are predictive of impaired stress processing and increased risk of neuropsychiatric diseases. Stress is also a factor contributing to, and resulting from, neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease, in which NPY appears to play an important neuroprotective role. This review summarizes the evidence for an implication of NPY in stress-related and neurodegenerative pathologies and addresses the cerebral NPY system as a therapeutic target. PMID- 26441329 TI - Tibial baseplate positioning in robotic-assisted and conventional unicompartmental knee arthroplasty. AB - This study compared tibial baseplate alignment (TBA) between robotic-arm-assisted (RAA) and conventional (CONV) unicompartmental knee arthroplasties (UKAs). We hypothesized that RAA would increase the percentage of implants within a predetermined safe zone (SZ). We identified 177 CONV and 87 RAA UKAs through our center's patient registry. Two individuals reviewed postoperative knee radiographs and determined TBA. Coronal baseplate positioning was more accurate (i.e., within the SZ) for RAA (2.6 degrees +/- 1.5 degrees vs. 3.9 degrees +/- 2.4 degrees , p < 0. 0001). Conversely, sagittal alignment was more accurate for CONV (4.9 degrees +/- 2.8 degrees vs. 2.4 degrees +/- 1.6 degrees , p < 0.0001). RAA was more precise in both planes (p < 0.0001). There was no difference in the percentage of implants within the SZ between the two groups (p = 1.0). PMID- 26441330 TI - Prospective multicentre study of the clinical and functional outcomes following quadriceps tendon repair with suture anchors. AB - INTRODUCTION: Quadriceps tendon avulsions are typically treated by reattaching the tendon through bone tunnels, with or without tendon or hardware augmentation. The operated knee joint can be moved right away; however, tendon grafting or tension banding will be required to protect the repair, and the hardware must be removed later on. The goal of this study was to evaluate the clinical and functional outcomes when suture anchors are used to reattached torn quadriceps tendon, and also to assess tendon healing using MRI. MATERIALS AND METHODS: Thirteen consecutive patients with avulsed quadriceps tendons were operated and then followed prospectively. The surgical technique consisted of tendon reattachment using at least three anchors, in addition to intratendinous weaving of the sutures. Weight bearing was allowed while using a splint. Rehabilitation was initiated immediately after surgery according to a set protocol. RESULTS: Eleven patients were followed for a mean of 14.7 months. Two retears occurred in patients who did not wear the splint. Eighty-two per cent of patients were satisfied or very satisfied with the outcome. The mean knee flexion was 124.5 degrees . All patients were able to return to their pre-injury activity levels. The mean time for clinical and functional recovery was 3 months. MRI performed 6 months after the surgical repair revealed good tendon healing. DISCUSSION: This was the first prospective study performed on quadriceps avulsion patients undergoing suture anchor repair. Prior clinical case reports have shown that this method leads to predictable clinical and functional results. Our results were comparable to those in published cases. CONCLUSION: The procedure is simpler when only suture anchors are used. Tendon healing was observed on MRI in all cases. This simple, reproducible technique is free of the drawbacks associated with the typical repair augmentation. PMID- 26441333 TI - miRNAs: early prognostic biomarkers for Type 2 diabetes mellitus? AB - Type 2 diabetes mellitus (T2DM) has reached epidemic proportions and is associated with peripheral insulin resistance. The currently used therapies aim to delay progression of T2DM. Their efficacy could drastically be improved if implemented at earlier stages. Classical diagnostic markers (blood glucose and HbA1C) are generally detected once metabolic imbalance has already set in. Therefore, development of biomarkers for early diagnosis would help identify individuals at risk for developing T2DM. Along with genetic predisposition, epigenetics also plays a major role in T2DM development. In this review, we discuss the potential role of early diagnostic markers such as circulating miRNAs, studies done so far and challenges to be considered while taking into account the novel role of miRNAs as prognostic biomarkers. PMID- 26441331 TI - TGF-beta1 Reduces miR-29a Expression to Promote Tumorigenicity and Metastasis of Cholangiocarcinoma by Targeting HDAC4. AB - Transforming growth factor beta1 (TGF-beta1) and miRNAs play important roles in cholangiocarcinoma progression. In this study, miR-29a level was found significantly decreased in both cholangiocarcinoma tissues and tumor cell lines. TGF-beta1 reduced miR-29a expression in tumor cell lines. Furthermore, anti-miR 29a reduced the proliferation and metastasis capacity of cholangiocarcinoma cell lines in vitro, overexpression of miR-29a counteracted TGF-beta1-mediated cell growth and metastasis. Subsequent investigation identified HDAC4 is a direct target of miR-29a. In addition, restoration of HDAC4 attenuated miR-29a-mediated inhibition of cell proliferation and metastasis. CONCLUSIONS: TGF-beta1/miR 29a/HDAC4 pathway contributes to the pathogenesis of cholangiocarcinoma and our data provide new therapeutic targets for cholangiocarcinoma. PMID- 26441332 TI - Reduced error signalling in medication-naive children with ADHD: associations with behavioural variability and post-error adaptations. AB - BACKGROUND: We examined the blood-oxygen level-dependent (BOLD) activation in brain regions that signal errors and their association with intraindividual behavioural variability and adaptation to errors in children with attention deficit/hyperactivity disorder (ADHD). METHODS: We acquired functional MRI data during a Flanker task in medication-naive children with ADHD and healthy controls aged 8-12 years and analyzed the data using independent component analysis. For components corresponding to performance monitoring networks, we compared activations across groups and conditions and correlated them with reaction times (RT). Additionally, we analyzed post-error adaptations in behaviour and motor component activations. RESULTS: We included 25 children with ADHD and 29 controls in our analysis. Children with ADHD displayed reduced activation to errors in cingulo-opercular regions and higher RT variability, but no differences of interference control. Larger BOLD amplitude to error trials significantly predicted reduced RT variability across all participants. Neither group showed evidence of post-error response slowing; however, post-error adaptation in motor networks was significantly reduced in children with ADHD. This adaptation was inversely related to activation of the right-lateralized ventral attention network (VAN) on error trials and to task-driven connectivity between the cingulo opercular system and the VAN. LIMITATIONS: Our study was limited by the modest sample size and imperfect matching across groups. CONCLUSION: Our findings show a deficit in cingulo-opercular activation in children with ADHD that could relate to reduced signalling for errors. Moreover, the reduced orienting of the VAN signal may mediate deficient post-error motor adaptions. Pinpointing general performance monitoring problems to specific brain regions and operations in error processing may help to guide the targets of future treatments for ADHD. PMID- 26441334 TI - Temperature Calibration for In Situ Environmental Transmission Electron Microscopy Experiments. AB - In situ environmental transmission electron microscopy (ETEM) experiments require specimen heating holders to study material behavior in gaseous environments at elevated temperatures. In order to extract meaningful kinetic parameters, such as activation energies, it is essential to have a direct and accurate measurement of local sample temperature. This is particularly important if the sample temperature might fluctuate, for example when room temperature gases are introduced to the sample area. Using selected-area diffraction (SAD) in an ETEM, the lattice parameter of Ag nanoparticles was measured as a function of the temperature and pressure of hydrogen gas to provide a calibration of the local sample temperature. SAD permits measurement of temperature to an accuracy of +/ 30 degrees C using Ag lattice expansion. Gas introduction can cause sample cooling of several hundred degrees celsius for gas pressures achievable in the ETEM. PMID- 26441335 TI - Evaluation of X-ray doses and their corresponding biological effects on experimental animals in cone-beam micro-CT scans (R-mCT2). AB - Studies show that the radiation dose received during a micro-CT examination may have adverse effects on living subjects. However, the correlations between the biological effects and the radiation doses have never been thoroughly evaluated in the majority of cases. In this study, we evaluated the biological radiation effects of measured radiation doses in ICR mice using cone-beam micro-CT scans. Long-term in vivo whole-body micro-CT scans of ICR mice were performed for a duration of 4 weeks. Although a scanning frequency of three scans per week is higher than that necessary for conventional studies, this study represents particular cases where the subjects may undergo an extreme number of examinations. The average X-ray dose of a CT scan measures 16.19 mGy at the center of a phantom and 16.24 mGy at an offset position of 7.5 mm from the center of the phantom. The total average dose at the center of the phantom during the 4 week scanning period was 194.3 mGy. No significant radiation effects were observed in the weight gain curves, organ weights, blood analyses, litter sizes, reared offspring sizes, and the histopathologic results. Therefore, it is unlikely that the measured doses for the CT scans caused any radiation damage in the mice. PMID- 26441337 TI - Molecular networks: Protein droplets in the spotlight. PMID- 26441336 TI - Increased basophil activation in adult patients with anaphylaxis. PMID- 26441338 TI - Development: Ubiquitylation determines cell fate. PMID- 26441339 TI - Assessing the potential for intrinsic recovery in a Collembola two-generation study: possible implementation in a tiered soil risk assessment approach for plant protection products. AB - Collembola are soil dwelling organisms that provide important ecosystem services within soils. To increase realism in evaluating potential effects of plant protection products a Collembola two-generation study was developed. This test assesses the potential for recovery of Collembola when exposed to plant protection products. Juvenile individuals of Folsomia candida (Willem, Ann Soc Entomol Belg 46:275-283, 1902) which hatched under conditions of exposure to a test substance in a modified OECD 232 bioassay were introduced into a second consecutive bioassay containing the same test substance aged in soil. This test system determines whether a population which was initially impacted by a substance in a 1st bioassay shows normal reproduction or survival in a 2nd bioassay after aging of the test substance in soil. An intermediate period for juvenile growth is included between the 1st and 2nd bioassay in order to reduce the control treatment variability in reproduction and mortality to fulfill the validity criteria according to the OECD 232 guideline. The Collembola two generation study is able to differentiate between substances showing either a potential long-term risk or comprising a low risk. Comparing the results of this two generation study with data from semi-field or field studies indicates a high degree of conservatism when this test is considered within a tiered risk assessment scheme. This approach represents a valuable tool which makes the risk assessment more efficient by providing an alternative refinement option for highly conservative tier 1 Collembola risk assessment. PMID- 26441340 TI - Diagnostic Value of the Combination of Golgi Protein 73 and Alpha-Fetoprotein in Hepatocellular Carcinoma: A Meta-Analysis. AB - Conflicting results have been widely reported on the use of Golgi protein 73 (GP73) as a serum biomarker for diagnosing hepatocellular carcinoma (HCC). This study evaluated the accuracy of GP73, alpha-fetoprotein (AFP), and GP73 + AFP for diagnosing HCC. The meta-analysis was performed on 11 studies that were selected by means of a comprehensive systematic literature review. Summary diagnostic accuracy, meta-regression analysis for heterogeneity and publication bias, and other statistical analyses were performed using Meta-Disc (version 1.4) and Stata (version 12.0). Pooled sensitivity, specificity, and diagnostic odds ratio were 0.77 (95% CI: 0.75-0.79), 0.91 (95% CI: 0.90-0.92), and 12.49 (95% CI: 4.91 31.79) for GP73; 0.62 (95% CI: 0.60-0.64), 0.84 (95% CI: 0.83-0.85), and 11.61 (95% CI: 8.02-16.81) for AFP; and 0.87 (95% CI: 0.85-0.89), 0.85 (95% CI: 0.84 0.86), and 30.63 (95% CI: 18.10-51.84) for GP73 + AFP. The area under the curve values were 0.86, 0.84, and 0.91 for GP73, AFP, and GP73 + AFP, respectively. These results indicate that for HCC diagnosis, the accuracy of GP73 was higher than that of AFP, and that GP73 + AFP exhibited significantly higher diagnostic accuracy than did GP73 or AFP alone. PMID- 26441342 TI - Combining 3D Hydraulic Tomography with Tracer Tests for Improved Transport Characterization. AB - Hydraulic tomography (HT) is a method for resolving the spatial distribution of hydraulic parameters to some extent, but many details important for solute transport usually remain unresolved. We present a methodology to improve solute transport predictions by combining data from HT with the breakthrough curve (BTC) of a single forced-gradient tracer test. We estimated the three dimensional (3D) hydraulic-conductivity field in an alluvial aquifer by inverting tomographic pumping tests performed at the Hydrogeological Research Site Lauswiesen close to Tubingen, Germany, using a regularized pilot-point method. We compared the estimated parameter field to available profiles of hydraulic-conductivity variations from direct-push injection logging (DPIL), and validated the hydraulic conductivity field with hydraulic-head measurements of tests not used in the inversion. After validation, spatially uniform parameters for dual-domain transport were estimated by fitting tracer data collected during a forced gradient tracer test. The dual-domain assumption was used to parameterize effects of the unresolved heterogeneity of the aquifer and deemed necessary to fit the shape of the BTC using reasonable parameter values. The estimated hydraulic conductivity field and transport parameters were subsequently used to successfully predict a second independent tracer test. Our work provides an efficient and practical approach to predict solute transport in heterogeneous aquifers without performing elaborate field tracer tests with a tomographic layout. PMID- 26441341 TI - Primary Visual Cortex as a Saliency Map: A Parameter-Free Prediction and Its Test by Behavioral Data. AB - It has been hypothesized that neural activities in the primary visual cortex (V1) represent a saliency map of the visual field to exogenously guide attention. This hypothesis has so far provided only qualitative predictions and their confirmations. We report this hypothesis' first quantitative prediction, derived without free parameters, and its confirmation by human behavioral data. The hypothesis provides a direct link between V1 neural responses to a visual location and the saliency of that location to guide attention exogenously. In a visual input containing many bars, one of them saliently different from all the other bars which are identical to each other, saliency at the singleton's location can be measured by the shortness of the reaction time in a visual search for singletons. The hypothesis predicts quantitatively the whole distribution of the reaction times to find a singleton unique in color, orientation, and motion direction from the reaction times to find other types of singletons. The prediction matches human reaction time data. A requirement for this successful prediction is a data-motivated assumption that V1 lacks neurons tuned simultaneously to color, orientation, and motion direction of visual inputs. Since evidence suggests that extrastriate cortices do have such neurons, we discuss the possibility that the extrastriate cortices play no role in guiding exogenous attention so that they can be devoted to other functions like visual decoding and endogenous attention. PMID- 26441343 TI - MiR-302/367 regulate neural progenitor proliferation, differentiation timing, and survival in neurulation. AB - How neural progenitor cell (NPC) behaviors are temporally controlled in early developing embryos remains undefined. The in vivo functions of microRNAs (miRNAs) in early mammalian development remain largely unknown. Mir-302/367 is a miRNA cluster that encodes miR-367 and four miR-302 members (miR302a-d). We show that miR-302b is highly expressed in early neuroepithelium and its expression decline as development progresses. We generated a mir-302/367 knockout mouse model and found that deletion of mir-302/367 results in an early embryonic lethality and open neural tube defect (NTD). NPCs exhibit enhanced proliferation, precocious differentiation, and decreased cell survival in mutant embryos. Furthermore, we identified Fgf15, Cyclin D1, and D2 as direct targets of miR-302 in NPCs in vivo, and their expression is enhanced in mutant NPCs. Ectopic expression of Cyclin D1 and D2 increases NPC proliferation, while FGF19 (human ortholog of Fgf15) overexpression leads to an increase of NPC differentiation. Thus, these findings reveal essential roles of miR-302/367 in orchestrating gene expression and NPC behaviors in neurulation; they also point to miRNAs as critical genetic components associated with neural tube formation. PMID- 26441345 TI - Thyroid Cancer Detection by Ultrasound Among Residents Ages 18 Years and Younger in Fukushima, Japan: 2011 to 2014. AB - BACKGROUND: After the Great East Japan Earthquake and Tsunami in March 2011, radioactive elements were released from the Fukushima Daiichi Nuclear Power Plant. Based on prior knowledge, concern emerged about whether an increased incidence of thyroid cancer among exposed residents would occur as a result. METHODS: After the release, Fukushima Prefecture performed ultrasound thyroid screening on all residents ages <=18 years. The first round of screening included 298,577 examinees, and a second round began in April 2014. We analyzed the prefecture results from the first and second round up to December 31, 2014, in comparison with the Japanese annual incidence and the incidence within a reference area in Fukushima Prefecture. RESULTS: The highest incidence rate ratio, using a latency period of 4 years, was observed in the central middle district of the prefecture compared with the Japanese annual incidence (incidence rate ratio = 50; 95% confidence interval [CI] = 25, 90). The prevalence of thyroid cancer was 605 per million examinees (95% CI = 302, 1,082) and the prevalence odds ratio compared with the reference district in Fukushima Prefecture was 2.6 (95% CI = 0.99, 7.0). In the second screening round, even under the assumption that the rest of examinees were disease free, an incidence rate ratio of 12 has already been observed (95% CI = 5.1, 23). CONCLUSIONS: An excess of thyroid cancer has been detected by ultrasound among children and adolescents in Fukushima Prefecture within 4 years of the release, and is unlikely to be explained by a screening surge. PMID- 26441346 TI - Efficient and Substantial DNA Lesions From Near 0 eV Electron-Induced Decay of the O4-Hydrogenated Thymine Nucleotides: A DFT Study. AB - Possible electron-induced ruptures of C3'-O3', C5'-O5', and N1-C1' bonds in O4 hydrogenated 2'-deoxythymidine-3'-monophosphate (3'-dT(O4H)MPH) and 2' deoxythymidine-5'-monophosphate (5'-dT(O4H)MPH) are investigated using density functional theory calculations, and efficient pathways are proposed. Electron attachment causes remarkable structural relaxation in the thymine C6 site. A concerted process of intramolecular proton transfer (IPT) from the C2' site of 2' deoxyribose to the C6 site and the C3'-O3' bond rupture is observed in [3' dT(O4H)MPH](-). A low activation barrier (9.32 kcal/mol) indicates that this pathway is the most efficient one as compared to other known pathways leading to backbone breaks of a single strand DNA at the non-3'-end thymine, which prevents the N1-C1' bond cleavage in [3'-dT(O4H)MPH](-). However, essentially spontaneous N1-C1' bond cleavage following similar IPT is predicted in [5'-dT(O4H)MPH](-). A moderate activation barrier (13.02 kcal/mol) for the rate-controlling IPT step suggests that base release from the N1-C1' cleavage arises readily at the 3'-end of single strand DNA with the strand ended by a thymine. The C5'-O5' bond has only an insignificant change in the IPT process. Solvent effects are found to increase slightly the energy requirements for either bond ruptures (11.23 kcal/mol (C3'-O3') vs 16.18 kcal/mol (N1-C1')), but not change their relative efficiencies. PMID- 26441347 TI - IL-1beta promotes Th17 differentiation by inducing alternative splicing of FOXP3. AB - CD4(+)FOXP3(+) regulatory T (Treg) cells are essential for maintaining immunological self-tolerance. Treg cell development and function depend on the transcription factor FOXP3, which is present in several distinct isoforms due to alternative splicing. Despite the importance of FOXP3 in the proper maintenance of Treg cells, the regulation and functional consequences of FOXP3 isoform expression remains poorly understood. Here, we show that in human Treg cells IL 1beta promotes excision of FOXP3 exon 7. FOXP3 is not only expressed by Treg cells but is also transiently expressed when naive T cells differentiate into Th17 cells. Forced splicing of FOXP3 into FOXP3Delta2Delta7 strongly favored Th17 differentiation in vitro. We also found that patients with Crohn's disease express increased levels of FOXP3 transcripts lacking exon 7, which correlate with disease severity and IL-17 production. Our results demonstrate that alternative splicing of FOXP3 modulates T cell differentiation. These results highlight the importance of characterizing FOXP3 expression on an isoform basis and suggest that immune responses may be manipulated by modulating the expression of FOXP3 isoforms, which has broad implications for the treatment of autoimmune diseases. PMID- 26441348 TI - Mechanical strain determines the axis of planar polarity in ciliated epithelia. AB - Epithelia containing multiciliated cells align beating cilia along a common planar axis specified by the conserved planar cell polarity (PCP) pathway. Specification of the planar axis is also thought to require a long-range cue to align the axis globally, but the nature of this cue in ciliated and other epithelia remains poorly understood. We examined this issue using the Xenopus larval skin, where ciliary flow aligns to the anterior-posterior (A-P) axis. We first show that a planar axis initially arises in the developing skin during gastrulation, based on the appearance of polarized apical microtubules and cell junctions with increased levels of stable PCP components. This axis also arises in severely ventralized embryos, despite their deficient embryonic patterning. Because ventralized embryos still gastrulate, producing a mechanical force that strains the developing skin along the A-P axis, we asked whether this strain alone drives global planar patterning. Isolated skin explanted before gastrulation lacks strain and fails to acquire a global planar axis but responds to exogenous strain by undergoing cell elongation, forming polarized apical microtubules, and aligning stable components of the PCP pathway orthogonal to the axis of strain. The planar axis in embryos can be redirected by applying exogenous strain during a critical period around gastrulation. Finally, we provide evidence that apical microtubules and the PCP pathway interact to align the planar axis. These results indicate that oriented tissue strain generated by the gastrulating mesoderm plays a major role in determining the global axis of planar polarity of the developing skin. PMID- 26441349 TI - All spiking, sustained ON displaced amacrine cells receive gap-junction input from melanopsin ganglion cells. AB - Retinal neurons exhibit sustained versus transient light responses, which are thought to encode low- and high-frequency stimuli, respectively. This dichotomy has been recognized since the earliest intracellular recordings from the 1960s, but the underlying mechanisms are not yet fully understood. We report that in the ganglion cell layer of rat retinas, all spiking amacrine interneurons with sustained ON photoresponses receive gap-junction input from intrinsically photosensitive retinal ganglion cells (ipRGCs), recently discovered photoreceptors that specialize in prolonged irradiance detection. This input presumably allows ipRGCs to regulate the secretion of neuromodulators from these interneurons. We have identified three morphological varieties of such ipRGC driven displaced amacrine cells: (1) monostratified cells with dendrites terminating exclusively in sublamina S5 of the inner plexiform layer, (2) bistratified cells with dendrites in both S1 and S5, and (3) polyaxonal cells with dendrites and axons stratifying in S5. Most of these amacrine cells are wide field, although some are medium field. The three classes respond to light differently, suggesting that they probably perform diverse functions. These results demonstrate that ipRGCs are a major source of tonic visual information within the retina and exert widespread intraretinal influence. They also add to recent evidence that ganglion cells signal not only to the brain. PMID- 26441350 TI - Drosophila Lgr3 Couples Organ Growth with Maturation and Ensures Developmental Stability. AB - Early transplantation and grafting experiments suggest that body organs follow autonomous growth programs [1-3], therefore pointing to a need for coordination mechanisms to produce fit individuals with proper proportions. We recently identified Drosophila insulin-like peptide 8 (Dilp8) as a relaxin and insulin like molecule secreted from growing tissues that plays a central role in coordinating growth between organs and coupling organ growth with animal maturation [4, 5]. Deciphering the function of Dilp8 in growth coordination relies on the identification of the receptor and tissues relaying Dilp8 signaling. We show here that the orphan receptor leucine-rich repeat-containing G protein-coupled receptor 3 (Lgr3), a member of the highly conserved family of relaxin family peptide receptors (RXFPs), mediates the checkpoint function of Dilp8 for entry into maturation. We functionally identify two Lgr3-positive neurons in each brain lobe that are required to induce a developmental delay upon overexpression of Dilp8. These neurons are located in the pars intercerebralis, an important neuroendocrine area in the brain, and make physical contacts with the PTTH neurons that ultimately control the production and release of the molting steroid ecdysone. Reducing Lgr3 levels in these neurons results in adult flies exhibiting increased fluctuating bilateral asymmetry, therefore recapitulating the phenotype of dilp8 mutants. Our work reveals a novel Dilp8/Lgr3 neuronal circuitry involved in a feedback mechanism that ensures coordination between organ growth and developmental transitions and prevents developmental variability. PMID- 26441351 TI - A Multisensory Network for Olfactory Processing. AB - Primary gustatory cortex (GC) is connected (both mono- and polysynaptically) to primary olfactory (piriform) cortex (PC)-connections that might be hypothesized to underlie the construction of a "flavor" percept when both gustatory and olfactory stimuli are present. Here we use multisite electrophysiology and optical inhibition of GC neurons (GCx, produced via infection with ArchT) to demonstrate that, indeed, during gustatory stimulation, taste-selective information is transmitted from GC to PC. We go on to show that these connections impact olfactory processing even in the absence of gustatory stimulation: GCx alters PC responses to olfactory stimuli presented alone, enhancing some and eliminating others, despite leaving the path from nasal epithelium to PC intact. Finally, we show the functional importance of this latter phenomenon, demonstrating that GCx renders rats unable to properly recognize odor stimuli. This sequence of findings suggests that sensory processing may be more intrinsically integrative than previously thought. PMID- 26441352 TI - Individual Aesthetic Preferences for Faces Are Shaped Mostly by Environments, Not Genes. AB - Although certain characteristics of human faces are broadly considered more attractive (e.g., symmetry, averageness), people also routinely disagree with each other on the relative attractiveness of faces. That is, to some significant degree, beauty is in the "eye of the beholder." Here, we investigate the origins of these individual differences in face preferences using a twin design, allowing us to estimate the relative contributions of genetic and environmental variation to individual face attractiveness judgments or face preferences. We first show that individual face preferences (IP) can be reliably measured and are readily dissociable from other types of attractiveness judgments (e.g., judgments of scenes, objects). Next, we show that individual face preferences result primarily from environments that are unique to each individual. This is in striking contrast to individual differences in face identity recognition, which result primarily from variations in genes [1]. We thus complete an etiological double dissociation between two core domains of social perception (judgments of identity versus attractiveness) within the same visual stimulus (the face). At the same time, we provide an example, rare in behavioral genetics, of a reliably and objectively measured behavioral characteristic where variations are shaped mostly by the environment. The large impact of experience on individual face preferences provides a novel window into the evolution and architecture of the social brain, while lending new empirical support to the long-standing claim that environments shape individual notions of what is attractive. PMID- 26441353 TI - Sensory Feedback Reduces Individuality by Increasing Variability within Subjects. AB - Behavioral variability is ubiquitous [1-6], yet variability is more than just noise. Indeed, humans exploit their individual motor variability to improve tracing and reaching tasks [7]. What controls motor variability? Increasing the variability of sensory input, or applying force perturbations during a task, increases task variability [8, 9]. Sensory feedback may also increase task irrelevant variability [9, 10]. In contrast, sensory feedback during locust flight or to multiple cortical areas just prior to task performance decreases variability during task-relevant motor behavior [11, 12]. Thus, how sensory feedback affects both task-relevant and task-irrelevant motor outputs must be understood. Furthermore, since motor control is studied in populations, the effects of sensory feedback on variability must also be understood within and across subjects. For example, during locomotion, each step may vary within and across individuals, even when behavior is normalized by step cycle duration [13]. Our previous work demonstrated that motor components that matter for effective behavior show less individuality [14]. Is sensory feedback the mechanism for reducing individuality? We analyzed durations and relative timings of motor pools within swallowing motor patterns in the presence and absence of sensory feedback and related these motor program components to behavior. Here, at the level of identified motor neurons, we show that sensory feedback to motor program components highly correlated with behavioral efficacy reduces variability across subjects but-surprisingly-increases variability within subjects. By controlling intrinsic, individual differences in motor neuronal activity, sensory feedback provides each subject access to a common solution space. PMID- 26441355 TI - Actin-Based Transport Adapts Polarity Domain Size to Local Cellular Curvature. AB - Intracellular structures and organelles such as the nucleus, the centrosome, or the mitotic spindle typically scale their size to cell size [1]. Similarly, cortical polarity domains built around the active form of conserved Rho-GTPases, such as Cdc42p, exhibit widths that may range over two orders of magnitudes in cells with different sizes and shapes [2-6]. The establishment of such domains typically involves positive feedback loops based on reaction-diffusion and/or actin-mediated vesicle transport [3, 7, 8]. How these elements may adapt polarity domain size to cellular geometry is not known. Here, by tracking the width of successive oscillating Cdc42-GTP domains in fission yeast spores [9], we find that domain width scales with local cell-surface radii of curvature over an 8 fold range, independently of absolute cell volume, surface, or Cdc42-GTP concentration. This local scaling requires formin-nucleated cortical actin cables and the fusion of secretory vesicles transported along these cables with the membrane. These data suggest that reaction-diffusion may set a minimal domain size and that secretory vesicle transport along actin cables may dilute and extend polarity domains to adapt their size to local cell-surface curvature. This work reveals that actin networks may act as micrometric curvature sensors and uncovers a generic morphogenetic principle for how polarity domains define their size according to cell morphologies. PMID- 26441354 TI - The Nuclear Proteome of a Vertebrate. AB - The composition of the nucleoplasm determines the behavior of key processes such as transcription, yet there is still no reliable and quantitative resource of nuclear proteins. Furthermore, it is still unclear how the distinct nuclear and cytoplasmic compositions are maintained. To describe the nuclear proteome quantitatively, we isolated the large nuclei of frog oocytes via microdissection and measured the nucleocytoplasmic partitioning of ~9,000 proteins by mass spectrometry. Most proteins localize entirely to either nucleus or cytoplasm; only ~17% partition equally. A protein's native size in a complex, but not polypeptide molecular weight, is predictive of localization: partitioned proteins exhibit native sizes larger than ~100 kDa, whereas natively smaller proteins are equidistributed. To evaluate the role of nuclear export in maintaining localization, we inhibited Exportin 1. This resulted in the expected re localization of proteins toward the nucleus, but only 3% of the proteome was affected. Thus, complex assembly and passive retention, rather than continuous active transport, is the dominant mechanism for the maintenance of nuclear and cytoplasmic proteomes. PMID- 26441356 TI - Contextual Feedback to Superficial Layers of V1. AB - Neuronal cortical circuitry comprises feedforward, lateral, and feedback projections, each of which terminates in distinct cortical layers [1-3]. In sensory systems, feedforward processing transmits signals from the external world into the cortex, whereas feedback pathways signal the brain's inference of the world [4-11]. However, the integration of feedforward, lateral, and feedback inputs within each cortical area impedes the investigation of feedback, and to date, no technique has isolated the feedback of visual scene information in distinct layers of healthy human cortex. We masked feedforward input to a region of V1 cortex and studied the remaining internal processing. Using high-resolution functional brain imaging (0.8 mm(3)) and multivoxel pattern information techniques, we demonstrate that during normal visual stimulation scene information peaks in mid-layers. Conversely, we found that contextual feedback information peaks in outer, superficial layers. Further, we found that shifting the position of the visual scene surrounding the mask parametrically modulates feedback in superficial layers of V1. Our results reveal the layered cortical organization of external versus internal visual processing streams during perception in healthy human subjects. We provide empirical support for theoretical feedback models such as predictive coding [10, 12] and coherent infomax [13] and reveal the potential of high-resolution fMRI to access internal processing in sub-millimeter human cortex. PMID- 26441357 TI - Oral azithromycin as the systemic treatment of choice in the treatment of meibomian gland disease. PMID- 26441358 TI - Sex in Nursing Homes: A Survey of Nursing Home Policies Governing Resident Sexual Activity. AB - OBJECTIVE: To identify nursing home (NH) standards related to sexual activity and sexual relationships for residents through a nationwide survey of directors of nursing (DONs). METHODS: A national survey was distributed online and was completed by 366 DONs of skilled nursing facilities. The DONs answered questions concerning policies and experiences related to sexual activities of their residents including types of resident sexual activity they have encountered, perceptions about residents with dementia engaging in sexual activity, and policies pertaining to sexual activity including masturbation. RESULTS: The results of the survey demonstrated that the vast majority (71.2%) indicated that there had been issues regarding residents' sexual activities in their facilities with over one-half (58%) of the DONs reporting situations of resident with resident sexual activity and 60% with situations of resident masturbation. More than one-half (56.6%) require a family or designated representative to approve sexual activity for a cognitively impaired resident. For a cognitively intact resident, 12.4% of facilities still require family or designated representative to approve sexual activity. However, despite the prevalence of sexual activity, the majority of NHs (63.4%) actually do not have policies dealing with resident sexual activity. Of the NHs with policies, 58.6% have written policies in place, with 11.2% requiring a physician order to allow sexual activity and 9.5% requiring a physician order to restrict sexual activity. CONCLUSIONS: Issues related to sexual activity in NH residents are quite prevalent, however, the rates of policies related to sexual activity are low and the policies and restrictions are not uniform. Our study suggests nursing homes should have a clear policy addressing resident sexual activity. It would be beneficial for such a policy to be communicated to residents and their families as part of an admission package instead of waiting for sexual interest to be noticed. This would enable residents to engage in sexual activity with understanding and support rather than hiding. PMID- 26441361 TI - Error in the Article by Kavanaugh et al (Arthritis Care Res (Hoboken), March 2015). PMID- 26441362 TI - N400-like responses to three-chord harmonic sequences with unexpected out of key endings: scalp topography, cortical sources, and perspectives for a clinical use. AB - A series of ERP components, each provided with both a precise timing with respect to stimulation and a specific cortical localization, reflects the temporal succession of processing stages of music information. This makes the musical stimulus potentially usable to probe residual brain functions in non communicating patients with disorders of consciousness. In an attempt to find a simple stimulation protocol that was suitable for use in a clinical setting, the purpose of this study was to verify whether a minimum-length musical stimulus, provided with a definite music-syntactic connotation, was still able to elicit musical ERPs in a group of eight healthy subjects. The stimulus was composed of the minimum number of chords necessary and sufficient to enable the subject to predict a plausible closure of the sequence (priming) and, at the same time, to provide him/her with the closing chord of the sequence (target), either congruous (probable closing) or not (improbable closing) to the tonal context. The subject's task was to discriminate and recognize the irregular targets. The components that were expected to be elicited, in this experimental situation, were ERAN, N5, P600/LPC. Conversely, in addition to these former components, we unexpectedly observed a N400-like component. To determine whether this component was a real N400, we submitted our data to a sLORETA analysis in order to identify its cortical generators. Irregular chords showed higher current densities with respect to regular ones on the right-sided medial and superior temporal gyri, superior and inferior parietal lobules, fusiform and parahippocampal gyri, and on the bilateral posterior cingulate cortex. In particular, the N400-like wave seems to share with the word-primed music-elicited N400 certain generators that are located in cortical areas BA 21/37 and BA 22. This suggests that even chord primed chord targets can convey extra-musical meanings and that, consequently, they might be useful in assessing residual higher-order information-processing capabilities in non-communicating patients with disorders of consciousness. PMID- 26441359 TI - Advanced Age and Medication Prescription: More Years, Less Medications? A Nationwide Report From the Italian Medicines Agency. AB - BACKGROUND: In older adults co-occurrence of multiple diseases often leads to use of multiple medications (polypharmacy). The aim of the present study is to describe how prescription of medications varies across age groups, with specific focus on the oldest old. METHODS: We performed a cross-sectional study using 2013 data from the OsMed Health-DB database (mean number of medicines and defined daily doses prescribed in 15,931,642 individuals). There were 3,378,725 individuals age 65 years or older (21.2% of the study sample). RESULTS: The mean number of prescribed medications progressively rose from 1.9 in the age group <65 years to 7.4 in the age group 80-84 years and then declined, with a more marked reduction in the age group 95 years or older with a mean number of 2.8 medications. A similar pattern was observed for the mean number of defined daily doses. Among participants age >=65 years, proton pump inhibitors were the most commonly prescribed medication (40.9% of individuals >=65 years), followed by platelet aggregation inhibitors (32.8%) and hydroxy-methylglutaryl-coenzyme A reductase inhibitors (26.1%). A decline in prescription was observed among individuals age 90 years or older, but this reduction was less consistent for medications used to treat acute conditions (ie, antibiotics and glucocorticoids) rather than preventive medicines commonly used to treat chronic diseases (ie, antihypertensive medications and hydroxy-methylglutaryl-coenzyme A reductase inhibitors). CONCLUSIONS: The burden of medication treatment progressively increases till age 85 and substantially declines after age of 90 years. Patterns of medication prescription widely vary across age groups. PMID- 26441363 TI - Cognitive processess and cognitive reserve in multiple sclerosis. AB - Multiple Sclerosis (MS) is characterized by motor, cognitive, and neuropsychiatric symptoms, which can occur independently. While MS is traditionally considered an inflammatory disease of the white matter, degeneration of gray matter is increasingly recognized as an important contributor to the progressive cognitive decline. A protective factor against the progression of cognitive dysfunction in MS could be the cognitive reserve, defined as resistance to brain dysfunction. Aim of the present study is to evaluate the role of cognitive reserve for different aspects of cognitive dysfunction of patients with MS. We found that patients with MS and lower cognitive reserve have poorer neuropsychological performance and slower information speed processing. These findings support the notion that intellectual reserve may protect some aspects of cognitive function in patients with MS. PMID- 26441364 TI - Failure in evoking the trigeminal cardiac reflex by mandibular stretching in healthy volunteers. AB - Stimulation of trigeminal sensory afferences has been reported to evoke hypotension and bradycardia, a phenomenon known as the trigeminal cardiac reflex. We attempted to evoke such a reflex through cycles of alternate mandibular stretching in healthy volunteers, as previously reported, for its possible therapeutic exploitation. In Phase 1 of the study, 10 healthy volunteers [5 male, 5 female, age (mean +/- SD) 27+/-2 years)] underwent 2 randomized sessions of automated monitoring, every 6 minutes, of systolic blood pressure (SBP), diastolic (D) BP, and heart rate (HR), with a one-week interval, either with mandibular stretching (12 minutes with a spring device fitted in the mouth), or nothing (control). Observation was prolonged for 180 minute after the end of the stretching. In Phase 2, 7 other volunteers (4 male and 3 female, age 24+/-1.3 years) repeated the protocol with a sampling interval of 2 minutes until the end of stretching. Baseline levels of SBP, DBP and HR were similar in the test and control sessions. There was a progressive fall of BP and HR as a function of time during the test session. With stretching: SBP changed from 119.2+/-10.1 to 118.1+/-10.1 to 115.8+/-10.5 mmHg, at baseline, end of stretching and 180 minutes after, respectively, p<0.001 at ANOVA for time effect). However, similar changes occurred in the control group: from 120.7+/-12.0 to 120.8+/-12.0 to 115.4+/-3.6 mmHg at the same times, P=0.822 for group effect). In Phase 2, again we observed no significant changes for any of the parameters investigated as a function of treatment. Despite attempts at maximum standardization of study condition and the use of operator-independent BP and HR measurements, we could not detect significant BP or HR effects of repeated mandibular stretching. PMID- 26441365 TI - Hypnotizability and the position sense: proprioceptive localization of the hand. AB - We investigated whether healthy subjects with high (highs) and low (lows) hypnotizability scores differ in the ability to report the position of their right hand in the horizontal plane at the end of passive and active arm movements directed to lateral, intermediate and medial targets of the right hemispace under correct or incorrect visual feedback. Results showed that incorrect visual feedback increased the error in both groups. In lows, the error was similar after active and passive movements; in highs, it was lower for active than passive movements toward the medial position, but lower for passive than for active movements for the lateral one. The highs' error was significantly lower than the lows' one only for the active movements directed toward the medial hand position. Hypnotizability-related differences may be due to different role of efferent copies in highs and lows. PMID- 26441366 TI - Effects of combined ferrous sulfate administration and exposure to static magnetic field on brain oxidative stress and emotional behavior. AB - The present study was done to investigate behavioral effects and oxidative stress in iron- treated and co-exposed static magnetic field (SMF)-iron rats. Anxiety in the elevated plus- maze test, and motor skills were also assessed in the stationary beam and suspended string tests. After behavioral tests, the rats were anesthetized and their brains were removed for biochemical analysis. The co exposure to iron and SMF induced a significant difference in elevated plus-maze test in rats. The frequency of entries and time spent in the open arms was significantly reduced (p<0.05) in the iron- and SMF-exposed group compared with the group treated with iron alone and in the control group. However, no significant difference was noticed for the motor skill test between the three groups. The biochemical investigation showed that malondialdehyde level increased (p<0.001) and that glutathione level and catalase enzyme activity decreased (p<0.001) in brain of iron- and SMF-exposed group. The dose of iron alone used in present study, was unable to induce any effect. However, the 128 mT SMF in the presence of iron ions in the body can induce disruption in the emotional behavior and can produce oxidative stress in brain tissue of rats. PMID- 26441367 TI - Cystadenocarcinoma of the salivary glands with potential lymph node metastasis. AB - Cystadenocarcinoma derived from the salivary gland in the head and neck region is an extremely rare malignancy. Therefore, the clinicopathological characteristics is not well understood. The purpose of this study was to clarify the clinicopathological characteristics, and present a total of four patients who were treated at the National Cancer Center Hospital East during the period between 1995 and 2012. The patients were all male, with ages ranging from 47 to 74 years old. The primary sites were the parotid glands, submandibular gland and minor salivary gland of the tongue. Within the follow-up period from 19 to 54 months, lymph node metastases were observed in three of the four patients. However, all the patients were salvaged by additional resection, including neck dissection, and remain alive to date without distant metastases. Cystadenocarcinoma is classified as a low-grade histological subtype of salivary gland tumors. Although the tumor has the potential to produce lymph node metastases, as shown in our patients, it is generally an indolent tumor with a good prognosis as compared with high-grade subtypes. This study suggests that a long-term follow up paying close attention to lymph node metastases is necessary for cystadenocarcinoma. PMID- 26441368 TI - Predictive factors and pattern of central lymph node metastasis in unilateral papillary thyroid carcinoma. AB - OBJECTIVE: Prophylactic central neck dissection (CND) for papillary thyroid carcinoma (PTC) remains controversial. The aim of this study was to evaluate the patterns and predictive factors of central lymph node metastasis in cases of PTC that were clinically determined to be node negative. METHODS: We studied 485 patients who have unilateral PTC without clinical lymph node metastasis and underwent total thyroidectomy and prophylactic bilateral CND from 2003 to 2012, retrospectively. The frequency, subsite and predictive factors of central lymph node metastasis were analyzed. RESULTS: In total, 166 (32.4%) patients had occult central lymph node metastases. The most common subsite of central node metastases was the ipsilateral paratracheal lymph node (26.0%), followed by pretracheal (12.5%), prelaryngeal (5.0%), and contralateral paratracheal (3.9%) lymph nodes. The tumor size larger than 0.5cm (p=0.003), age under 45 (p<0.001) and extrathyroidal extension (p=0.028) were associated with ipsilateral central compartment metastasis in multivariate analysis. Contralateral central node metastasis was associated with tumor size >3cm, age under 45, and multifocality and ipsilateral central node metastasis in univariate analysis, but it was associated with only ipsilateral central node metastasis in multivariate analysis (p=0.001). CONCLUSION: Prophylactic CND might be considered for PTC patients with large tumor size or extrathyroidal extension based on rates of lymph node metastasis. Unilateral CND might be appropriate as prophylactic CND due to the low metastatic rate to the contralateral paratracheal node. PMID- 26441369 TI - Posttraumatic olfactory dysfunction. AB - Impairment of smell may occur following injury to any portion of the olfactory tract, from nasal cavity to brain. A thorough understanding of the anatomy and pathophysiology combined with comprehensively obtained history, physical exam, olfactory testing, and neuroimaging may help to identify the mechanism of dysfunction and suggest possible treatments. Although most olfactory deficits are neuronal mediated and therefore currently unable to be corrected, promising technology may provide novel treatment options for those most affected. Until that day, patient counseling with compensatory strategies and reassurance is essential for the maintenance of safety and QoL in this unique and challenging patient population. PMID- 26441370 TI - Past, present and future of macrolide therapy for chronic rhinosinusitis in Japan. AB - In 1984, the effectiveness of low-dose, long-term erythromycin treatment (macrolide therapy) for diffuse panbronchiolitis (DPB) was first reported in Japan. The 5-year survival rate for DPB improved from 62.9 to 91.4% after implementation of macrolide therapy. The usefulness of this treatment has since been demonstrated in patients with other chronic airway diseases, such as chronic bronchitis, cystic fibrosis, bronchiectasis, bronchial asthma, and chronic rhinosinusitis (CRS). The new 14-membered macrolides clarithromycin and roxithromycin and the 15-membered macrolide azithromycin are also effective for treating these inflammatory diseases. The mechanism of action of the 14- and 15 membered macrolides may involve anti-inflammatory rather than anti-bacterial activities. Macrolide therapy is now widely used for the treatment of CRS in Japan; it is particularly effective for treating neutrophil-associated CRS and is useful for suppressing mucus hypersecretion. However, macrolide therapy is not effective for eosinophil-predominant CRS, which is characterized by serum and tissue eosinophilia, high serum IgE levels, multiple polyposis, and bronchial asthma. Recent reports have described the clinical efficacy of macrolides in treating other inflammatory diseases and new biological activities (e.g., anti viral). New macrolide derivatives exhibiting anti-inflammatory but not anti bacterial activity thus have therapeutic potential as immunomodulatory drugs. The history, current state, and future perspectives of macrolide therapy for treating CRS in Japan will be discussed in this review. PMID- 26441371 TI - Synthesis of Well-Defined Oligo(2,5-dialkoxy-1,4-phenylene vinylene)s with Chiral End Groups: Unique Helical Aggregations Induced by the Chiral Chain Ends. AB - Oligo(2,5-dialkoxy-1,4-phenylenevinylene)s containing three different chiral alkoxy substituents on the phenyl end groups with structurally regular (all trans) controlled repeat units have been prepared; these compounds showed highly enhanced aggregation-induced circular dichroism (AICD; formation of supramolecular polymers), and an inversion of the CD signal was observed even with the same end groups under certain conditions. PMID- 26441372 TI - Chiral Pool-Based Synthesis of Naphtho-Fused Isocoumarins. AB - A variety of chiral derivatives of benzo[d]naphtho[1,2-b]pyran-6-one were prepared in a single step by Et3 N-mediated condensation of homophthalic anhydride with different derivatives of (S)-amino acid chlorides at -5 degrees C by employing a chiral pool methodology. PMID- 26441373 TI - A systematic review of the neurophysiology of mindfulness on EEG oscillations. AB - Mindfulness meditation has been purported to be a beneficial practice for wellbeing. It would therefore be expected that the neurophysiology of mindfulness would reflect this impact on wellbeing. However, investigations of the effects of mindfulness have generated mixed reports of increases, decreases, as well as no differences in EEG oscillations in comparison with a resting state and a variety of tasks. We have performed a systematic review of EEG studies of mindfulness meditation in order to determine any common effects and to identify factors which may impact on the effects. Databases were reviewed from 1966 to August 2015. Eligibility criteria included empirical quantitative analyses of mindfulness meditation practice and EEG measurements acquired in relation to practice. A total of 56 papers met the eligibility criteria and were included in the systematic review, consisting of a total 1715 subjects: 1358 healthy individuals and 357 individuals with psychiatric diagnoses. Studies were principally examined for power outcomes in each bandwidth, in particular the power differentials between mindfulness and a control state, as well as outcomes relating to hemispheric asymmetry and event-related potentials. The systematic review revealed that mindfulness was most commonly associated with enhanced alpha and theta power as compared to an eyes closed resting state, although such outcomes were not uniformly reported. No consistent patterns were observed with respect to beta, delta and gamma bandwidths. In summary, mindfulness is associated with increased alpha and theta power in both healthy individuals and in patient groups. This co-presence of elevated alpha and theta may signify a state of relaxed alertness which is conducive to mental health. PMID- 26441374 TI - The anatomy of fear learning in the cerebellum: A systematic meta-analysis. AB - Recent neuro-imaging studies have implicated the cerebellum in several higher order functions. Its role in human fear conditioning has, however, received limited attention. The current meta-analysis examines the loci of cerebellar contributions to fear conditioning in healthy subjects, thus mapping, for the first time, the neural response to conditioned aversive stimuli onto the cerebellum. By using the activation likelihood estimation (ALE) technique for analyses, we identified several distinct regions in the cerebellum that activate in response to the presentation of the conditioned stimulus: the cerebellar tonsils, lobules HIV-VI, and the culmen. These regions have separately been implicated in fear acquisition, consolidation of fear memories and expression of conditioned fear responses. Their specific role in these processes may be attributed to the general contribution of cerebellar cortical networks to timing and prediction. Our meta-analysis highlights the potential role of the cerebellum in human cognition and emotion in general, and addresses the possibility how deficits in associative cerebellar learning may play a role in the pathogenesis of anxiety disorders. Future studies are needed to further clarify the mechanistic role of the cerebellum in higher order functions and neuropsychiatric disorders. PMID- 26441375 TI - Langerhans cells in a dermoid cyst epithelium lining. PMID- 26441376 TI - Long-term intake of white tea prevents oxidative damage caused by adriamycin in kidney of rats. AB - BACKGROUND: White tea infusion (Camelia sinensis) has antioxidants properties. The infusion contains polyphenols that have been proposed to induce antioxidant response element (ARE) response via nuclear factor E2-related factor 2 (NRF2). Adriamycin (ADR) has antitumour properties and oxidative effects. Oxidative stress is related to a variety of kidney diseases. Prevention of the oxidative stress through long-term intake of white tea and the study of the molecular mechanisms involved in protection could be of great interest. Rats were given distilled water, 0.015 or 0.045 g of solid white tea extract kg(-1) body weight for 12 months. Animals received an injection of ADR. In kidney, oxidative stress parameters were measured, the expressions of nuclear factor E2-related factor 2 gene (Nrf2), and detoxifying and antioxidants genes were analysed, and the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione reductase (GR) were measured. RESULTS: ADR administration increased oxidative parameters and decreased the antioxidant activity; significantly increased the expression of analysed genes and the activity of CAT and SOD and decreased GR activity. The highest white tea dose protected redox status and inhibited ARE response. CONCLUSION: Long-term intake of white tea protected kidney against the oxidative stress. ADR activated the ARE response but in animals treated with the highest dose of white tea, this response was inhibited, probably for antioxidant protection. (c) 2015 Society of Chemical Industry. PMID- 26441377 TI - Characterization of Disopyramide derivative ADD424042 as a non-cardiotoxic neuronal sodium channel blocker with broad-spectrum anticonvulsant activity in rodent seizure models. AB - It was reported that antiarrhythmic drugs (AADs) can be useful in controlling refractory seizures in humans or in enhancing the action of antiepileptic drugs (AEDs) in animal models. Disopyramide phosphate (DISO) is an AAD that blocks sodium channels in cardiac myocytes. We evaluated a DISO derivative, 2-(2 chlorophenyl)-2-(pyridin-2-yl)acetamide (ADD424042) for its anticonvulsant activity in a battery of rodent models of epileptic seizures. The compound displayed a broad spectrum of activity in the 'classical' models as well as in the models of pharmacoresistant seizures. Furthermore, ADD424042 showed good therapeutic indices between the anticonvulsant activity and the motor impairment. On the contrary, no anticonvulsant effects but severe lethality were observed in the primary anticonvulsant testing of the parent DISO. By performing the whole cell voltage-clamp experiments in dispersed cortical neurons we demonstrated that ADD424042 decreased the maximal amplitude of voltage-gated sodium channels with an IC50 value in nM range. Moreover, the compound enhanced use-dependent block and decreased excitability in pyramidal neurons in the current-clamp experiments in cortical slices. Importantly, we found that ADD424042 possessed either no, or very small cardiotoxic effect. In contrast to DISO, ADD424042 did not produce any apparent changes in electrocardiogram (ECG) and arterial blood pressure recordings. ADD424042 had no effect on QT and corrected QT intervals, at a dose which was 15 times higher than ED50 for the anticonvulsant effect in the MES model. Taken together, these data suggest that ADD424042 has the potential to become a lead structure for novel broadly acting AEDs with wide margin of cardiac safety. PMID- 26441378 TI - Post-progression survival and progression-free survival in patients with advanced hepatocellular carcinoma treated by sorafenib. AB - AIM: Although sorafenib is a standard drug for advanced hepatocellular carcinoma (HCC), little is known about a patient's clinical course after treatment. We investigated the effect of post-progression survival (PPS) and progression-free survival (PFS) on overall survival (OS) in patients whose advanced HCC was treated by sorafenib. METHODS: We searched in the PubMed database for reports with survival data of patients with HCC treated with sorafenib monotherapy, and selected reports with 20 or more patients each that provided data for both OS and PFS or time to progression (TTP). Median PPS (mPPS) was defined as the period obtained by subtracting median PFS or TTP (mPFS/TTP) from median OS (mOS). We identified 56 reports with 5803 patients. We investigated the correlation of mOS and either mPPS or mPFS/TTP using weighted linear regression. RESULTS: Median PPS correlated with mOS (r = 0.834) very strongly, whereas mPFS/TTP did not correlate with mOS as highly as PPS did (r = 0.546). When we stratified survival data by Child-Pugh classification, a significantly greater average percentage of mPPS to mOS was seen in Child-Pugh class A (54.4 +/- 17.6%) than in Child-Pugh class B (32.0 +/- 11.6%) (P = 0.015). CONCLUSION: PPS highly correlated with OS, and its importance should be more emphasized for advanced HCC patients treated after sorafenib therapy, whereas we need to take more care in interpreting the results of PFS to evaluate treatment efficacy in clinical trials of advanced HCC. PMID- 26441379 TI - Hydrophilic Molecularly Imprinted Resorcinol-Formaldehyde-Melamine Resin Prepared in Water with Excellent Molecular Recognition in Aqueous Matrices. AB - Hydrophilic molecularly imprinted resorcinol-formaldehyde-melamine resin (MIRFM) is synthesized in water and shows excellent molecular recognition in aqueous matrices. The double functional monomers resorcinol and melamine, and the cross linker formaldehyde, are all hydrophilic, and then the hydrophilic groups (such as hydroxyls, imino groups, and ether linkages) can be introduced into MIRFM, which make the material compatible with aqueous samples. The general principle is demonstrated by the synthesis of MIRFM using sulfanilamide as a dummy template for the selective recognition to sulfonamides (SAs) in milk samples. Resorcinol and melamine can interact with the template mainly by hydrogen bonding and pi-pi interaction, which makes MIRFM and the analytes have strong affinity. Besides, melamine can improve the rigidity of MIRFM and accelerate the polymerization process, so there is no need to add base or acid as a catalyst, which guarantees the success of molecular imprinting. MIRFM shows higher recovery and improved purification effect for SAs, in comparison to silica, HLB, C18, and SCX. Because of its excellent hydrophilicity and specificity, MIRFM is promising to be applied in biological, environmental, and clinical fields. PMID- 26441380 TI - Can Abdominal Hypopressive Technique Change Levator Hiatus Area?: A 3-Dimensional Ultrasound Study. AB - This study aimed to evaluate the levator hiatus area (LHA) at rest and during the performance of maximal pelvic floor muscle (PFM) contractions, during the abdominal hypopressive technique (AHT), and during the combination of PFM contractions (PFMCs) and the AHT. The study included 17 healthy nulliparous women who had no history of pelvic floor disorders. The LHA was evaluated with the patients in the lithotomy position. After a physiotherapist instructed the patients on the proper performance of the PFM and AHT exercises, 1 gynecologist performed the 3-dimensional translabial ultrasound examinations. The LHA was measured with the patients at rest. The PFMC alone, the AHT alone or the AHT in combination with a PFMC with 30 seconds of rest between the evaluations were performed. Each measurement was performed 2 times, and the mean value was used for statistical analysis. The Wilcoxon test was used to test the differences between the 2 maneuvers. Similar values were observed when comparing the LHA of the PFM at rest (12.2 +/- 2.4) cm and during the AHT (11.7 +/- 2.6) cm (P = 0.227). The AHT+ PFMC (10.2 +/- 1.9) cm demonstrated lower values compared with AHT alone (11.7 +/- 2.6) cm (P = 0.002). When comparing the PFMC (10.4 +/- 2.1) cm with the AHT + PFMC (10.2 +/- 1.9) cm, no significant difference (P = 0.551) was observed. During PFMC, the constriction was 1.8 cm; during the AHT, the constriction was 0.5 cm; and during the AHT + PFMC, it was 2 cm. The LHA assessed by 3-dimensional ultrasound did not significantly change with AHT. These results support the theory that AHT does not strengthen PFM. PMID- 26441381 TI - Thyroid Nodule Doubling Time is Not a Reliable Indicator of Benign or Malignant Nature. AB - Thyroid nodules are often followed up with serial ultrasound imaging. Doubling time is well established in the evaluation of lung nodules. We examined whether benign and malignant thyroid nodules exhibit differences in doubling time.This retrospective, IRB-approved study included patients with nodules aspirated between January and June 2012 (benign), and January 2012 to December 2014 (suspicious or malignant), no interval thyroidectomy, and two ultrasound examinations longer than 180 days apart. Diameters and morphology were assessed by a single observer, demographics recorded, and doubling time calculated. Area under the receiver operating characteristic curve was derived. Society of Radiologists in Ultrasound criteria were used to determine aspiration appropriateness initially and after follow-up.59 patients with 61 nodules were included. Statistically significant between-group differences exist for sex, solidity, echogenicity, and microcalcifications, with no significant differences in doubling time, age, days between studies, vascularity, or mean diameter. Benign nodules' doubling time was 340 to 7134 days (mean, 2196; median, 1593), with 9 nodules that decreased in size. Malignant nodules' doubling time was 451 to 17182 days (mean, 3940; median, 2137), with 7 nodules that decreased in size. Using a threshold of 1100 days, sensitivity and specificity of doubling time to predict malignancy are 19.0% and 86.7%, respectively. Area under the receiver operating characteristic curve is 0.39. Follow-up imaging resulted in 6 additional benign and 0 additional malignant nodules meeting criteria.There is no significant difference in benign or malignant nodules' doubling times, and a decrease in nodule size is nonspecific. These findings challenge the underlying rationale for routine imaging follow-up of thyroid nodules. PMID- 26441382 TI - Risks of Being Malignant or High Risk and Their Characteristics in Breast Lesions 20 mm or Larger After Benign Results on Ultrasonography-Guided 14-Gauge Core Needle Biopsy. AB - PURPOSE: The malignancy risk, risk of being high-risk lesions after benign results on ultrasonography-guided 14-gauge core needle biopsies (US-CNBs), and their characteristics in breast lesions of 20 mm or greater were investigated. METHODS: Eight hundred forty-seven breast lesions with benign results on US-CNB were classified as benign, high risk, and malignant through excision and clinical follow-up. The risks of being malignant or high risk were analyzed in all lesions, lesions 20 to 29 mm, and lesions 30 mm or greater. Their clinicopathological characteristics were evaluated. RESULTS: Of 847, 18 (2.1%) were malignant, 53 (6.3%) were high-risk lesions, and 776 (91.6%) were benign. Of 18 malignancies, 6 (33.3%) were malignant phyllodes tumors and 12 (66.7%) were carcinomas. In benign lesions 20 to 29 mm, risks of being malignant or high risk were 1.6% (9 of 566) and 4.4% (25 of 566). In 281 lesions 30 mm or greater, the risks of being malignant or high risk were 3.2% and 10%. The risk of being high risk in lesions 30 mm or greater was 10%, significantly higher than 4.4% of lesions 20 to 29 mm (P = 0.002). CONCLUSIONS: Excision can be considered in lesions measuring 20 mm or larger because of the 2.1% malignancy risk and the 6.3% risk of being high-risk lesions despite benign results on US-CNB. Excision should be considered in lesions measuring 30 mm or larger because of the 3.2% malignancy risk and the 10% risk of being high-risk lesions. PMID- 26441383 TI - Novel genetic capacitors and potentiators for the natural genetic variation of sensory bristles and their trait specificity in Drosophila melanogaster. AB - Cryptic genetic variation (CGV) is defined as the genetic variation that has little effect on phenotypic variation under a normal condition, but contributes to heritable variation under environmental or genetic perturbations. Genetic buffering systems that suppress the expression of CGV and store it in a population are called genetic capacitors, and the opposite systems are called genetic potentiators. One of the best-known candidates for a genetic capacitor and potentiator is the molecular chaperone protein, HSP90, and one of its characteristics is that it affects the genetic variation in various morphological traits. However, it remains unclear whether the wide-ranging effects of HSP90 on a broad range of traits are a general feature of genetic capacitors and potentiators. In the current study, I searched for novel genetic capacitors and potentiators for quantitative bristle traits of Drosophila melanogaster and then investigated the trait specificity of their genetic buffering effect. Three bristle traits of D. melanogaster were used as the target traits, and the genomic regions with genetic buffering effects were screened using the 61 genomic deficiencies examined previously for genetic buffering effects in wing shape. As a result, four and six deficiencies with significant effects on increasing and decreasing the broad-sense heritability of the bristle traits were identified, respectively. Of the 18 deficiencies with significant effects detected in the current study and/or by the previous study, 14 showed trait-specific effects, and four affected the genetic buffering of both bristle traits and wing shape. This suggests that most genetic capacitors and potentiators exert trait-specific effects, but that general capacitors and potentiators with effects on multiple traits also exist. PMID- 26441384 TI - Formulation and stabilization of nano-/microdispersion systems using naturally occurring edible polyelectrolytes by electrostatic deposition and complexation. AB - This review paper presents an overview of the formulation and functionalization of nano-/microdispersion systems composed of edible materials. We first summarized general aspects on the stability of colloidal systems and the roles of natural polyelectrolytes such as proteins and ionic polysaccharides for the formation and stabilization of colloidal systems. Then we introduced our research topics on (1) stabilization of emulsions by the electrostatic deposition using natural polyelectrolytes and (2) formulation of stable nanodispersion systems by complexation of natural polyelectrolytes. In both cases, the preparation procedures were relatively simple, without high energy input or harmful chemical addition. The properties of the nano-/microdispersion systems, such as particle size, surface charge and dispersion stability were significantly affected by the concerned materials and preparation conditions, including the type and concentration of used natural polyelectrolytes. These dispersion systems would be useful for developing novel foods having high functionality and good stability. PMID- 26441385 TI - Electrical Instability Induced by Electron Trapping in Low-Bandgap Donor-Acceptor Polymer Field-Effect Transistors. AB - The mechanism of electrical instability and the double slope of p-type organic field-effect transistors (OFETs) fabricated from low-bandgap donor-acceptor copolymers are resolved. Those polymers enable electron conduction in the device, which leads to electron trapping and consequent formation of -SiO(-). This causes a turn-on voltage shift, hole-mobility increase, and double-slope occurrence. These findings tremendously impact the molecular design and device engineering of OFETs. PMID- 26441386 TI - Human bocaviruses: Possible etiologic role in respiratory infection. AB - Four species of human bocaviruses (HBoV) are currently included in the Bocavirus genus. There is satisfactory evidence demonstrating an association between HBoV1 and respiratory disease in children, and there is evidence that HBoV2 (and possibly the HBoV3 and HBoV4 species) are associated with gastroenteritis. In particular, HBoV1 has been associated with a prolonged period of persistence in the mucosa of the respiratory tract. Virus persistence does play a role in the high frequency of co-infections with proper pathogens of the upper and lower respiratory tracts. The high detection rate of multiple respiratory viruses in up to 83% of respiratory specimens and the presence of asymptomatic HBoV1 infections complicate the elucidation of the pathogenic role of the agent. Overall, a large amount of data are available concerning HBoV1, whereas little information is available about other bocavirus species. High viral loads are often associated with symptoms, and viremia may be associated with systemic manifestations such as encephalopathy. The effects and mechanisms of latency, persistence, reactivation, and reinfection are poorly understood. Thus, particularly in co-infections, the pathogenic contribution of the detected bocavirus species cannot be accurately stated. This review summarizes the current knowledge of HBoV species and provides perspectives for future clinical studies. PMID- 26441387 TI - Nationwide shift from microscopic to endoscopic transsphenoidal pituitary surgery. AB - PURPOSE: Transsphenoidal pituitary surgery can be carried out with either an operating microscope or with an endoscope, but the relative frequency of both techniques is unknown. METHODS: All microscopic and endoscopic transsphenoidal pituitary surgeries were extracted from the Centers for Medicare and Medicaid Services Part B data files between the years 2003 and 2013. National and state level trends were compared over time. RESULTS: Endoscopic surgery significantly increased and microscopic surgery significantly decreased over the years 2003 2013. Thirty-eight of 48 states increased their use of endoscopic surgery, while 38 of 48 states decreased their use of microscopic surgery. CONCLUSIONS: Nationwide data show a clear trend for an increasing use of endoscopic transsphenoidal surgery at the expense of microscopic surgery. The underlying causes of these trends are unknown, but clearly deserve further investigation. PMID- 26441388 TI - Risk model for suspected acute coronary syndrome is of limited value in an emergency department. AB - INTRODUCTION: Among patients with acute chest pain, acute coronary syndrome (ACS) is seen only in a minority of the patients, which raises the question, whether it is possible to separate a group with a high risk of ACS for admission to a cardiac care unit (CCU) from those with a low risk who would be treated at an emergency department (ED). The aim of this study was to describe a risk stratification model for a Danish context. METHODS: This was a historic prospective cohort study of patients with suspicion of ACS. The patient was defined as a low-risk patient and admitted to the ED if: 1) electrocardiogram (ECG) was normal, 2) the patient did not have persisting chest pain and 3) there was no history of ischaemic heart disease, heart failure or cardioverter defibrillator. Otherwise, patients were admitted to the CCU. The primary outcome was whether the ACS diagnosis was confirmed or rejected. RESULTS: We included a total of 488 patients with suspicion of ACS, 50% of whom were low-risk patients. 17% had a verified ACS; 10% of those in the low-risk group and 24% of those in the high-risk group (p = 0.0001). Among the verified ACS cases, 71% went primarily to the CCU. The odds ratio for an ACS if assigned to the high-risk group was 3.0. Allocation to the high-risk group, male gender and age above 60 years was associated with a higher risk of ACS. For patients fulfilling the high risk definition, sensitivity was 71%, specificity 55%, negative predictive value 90% and positive predictive value 24% for an ACS. CONCLUSIONS: The model for stratification separated patients into two equal groups, allocated 71% of all ACS directly to the CCU and could not be improved by any of the additional factors examined. Further development of referral strategies for chest pain patients is required. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 26441389 TI - Exploring challenges and solutions in the preparation of surgical patients. AB - INTRODUCTION: Handover of surgical patients from ward to operating room is a sensible point for information and communication failures. Guidelines were developed for preparation of surgical patients. Our aim was to explore if patients are sufficiently prepared for surgery according to local guidelines and to identify challenges and solutions for correct preparation through interactive table simulation-based workshops involving the various professions and specialties. METHODS: Firstly, specific tasks in the hospital guidelines were monitored for all surgical procedures during one week. Secondly, workshops including table simulations involving the various professions and specialties were held. RESULTS: In total, 314 surgical procedures were performed of which 196 were eligible for analysis. Emergency procedures showed the poorest results with non-completed tasks comprising 58% of electronic patient management system tasks, 26% of anaesthesia record tasks, 24% of medication tasks, 14% of blood test tasks and 12% of patient record tasks. In two workshops held for each of four specialties, a total of 21 participants mapped the preoperative patient journey with related responsibilities, tasks and written documentation. Furthermore, challenges and suggestions for solutions were identified. CONCLUSIONS: Completion of mandatory tasks for surgical patient preparation was poor. Workshops with table simulations actively involved the stakeholders from various professions and specialties in describing the patient trajectory and mandatory tasks according to hospital guidelines in addition to identifying challenges and solutions for improvement. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 26441390 TI - Changing presentation of cutaneous malignant melanoma. AB - INTRODUCTION: The incidence of cutaneous malignant melanoma is rapidly increasing in Denmark like in other Northern and Western European countries. Our objective was to investigate the characteristics of current patients suffering from cutaneous malignant melanoma. METHODS: We evaluated patient and tumour characteristics in a cross-sectional study based on data from the Danish Melanoma Register. We included all patients diagnosed with cutaneous malignant melanoma in Healthcare Region Zealand in 2012 and 2013. RESULTS: We identified 520 patients with invasive cutaneous malignant melanoma. More females than males suffered from cutaneous malignant melanoma. Furthermore, females were younger than males, and the anatomical distribution of malignant melanoma varied between the genders. Outcome of sentinel lymph node biopsy was associated with tumour thickness. CONCLUSIONS: When comparing findings in our study with earlier Danish studies, we see a trend towards an increase in age at diagnosis. Furthermore, tumour thickness is decreasing and the topical distribution of cutaneous malignant melanoma in females changes towards a male pattern. FUNDING: none. TRIAL REGISTRATION: The study has been approved by the Danish National Data Protection Agency. PMID- 26441391 TI - Changes in antimicrobial susceptibility patterns of Klebsiella pneumoniae, Escherichia coli and Staphylococcus aureus over the past decade. AB - INTRODUCTION: Development of antimicrobial resistance is an ongoing and increasing problem. To provide the best possible treatment for patients it is crucial that clinicians are aware of the local antimicrobial susceptibility patterns. The aim of this study was to present an overview of the percentage of bacterial isolates that are covered by the most commonly used antibiotics in the area of Copenhagen and to provide clinicians with a practical tool to help chose the right antimicrobial treatment for their patients. METHODS: We conducted a study of all bacteria isolates tested for antimicrobial susceptibility at Hvidovre Hospital, Denmark, from 2004 to 2008. Due to a suspected rise in resistance in Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae after this period, updated data for these bacteria are shown for selected antibiotics until 2014. The department receives samples from hospitals as well as from primary healthcare. Only one isolate per species per patient per year was included. RESULTS: A total of 224,033 bacteria isolates were included in this study. The antimicrobial susceptibility of the various bacteria is presented in a table. No clinically relevant changes in resistance patterns were noted up to 2014. CONCLUSIONS: A comprehensive and manageable inventory of the resistance patterns of the major bacteria covering the 2004-2008 period is presented. Clinicians are encouraged to use the pocket-size table as guidance when choosing antibiotic treatment. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 26441392 TI - suPAR as a biomarker for risk of readmission and mortality in the acute medical setting. AB - INTRODUCTION: The urokinase-type plasminogen activator receptor (uPAR) and its ligand (suPAR) are involved in numerous physiological and pathological pathways. Previous studies have shown that an elevated plasma suPAR level is associated with disease severity and mortality. The aim of this prospective observational study was to determine if the suPAR level was associated with readmission and mortality in the acute medical setting. METHODS: Plasma suPAR levels were measured in 1,036 patients at admission. Follow-up ranged 3-10 months. Cox proportional hazards model was used to assess the relative contribution of different risk factors to mortality and readmission. The ANOVA test and Pearson's chi-squared test were used to compare suPAR tertile level with various variables. RESULTS: The highest suPAR tertile level was significantly associated with mortality within 30 days after discharge, with a 6.66 hazard ratio (HR). Similar associations were found with readmission within the maximum observation period (HR = 2.26) and within 30 days (HR = 2.08), although the latter became insignificant when covariates were included. CONCLUSIONS: This study confirms previous findings of increased mortality and adds the finding that increased long term readmission rates are associated with elevated suPAR levels. The present data do, however, not indicate that suPAR may serve as an independent biomarker for increased risk of short-term readmission in the acute medical setting. FUNDING: This study was funded by a grant from ViroGates A/S, the company that produces the suPARnostic assay. TRIAL REGISTRATION: No: H-B-2009-075. PMID- 26441393 TI - Factors affecting patients' ratings of health-care satisfaction. AB - INTRODUCTION: Surveys that include rating scales are commonly used to collect data about patients' experiences. We studied how patients associated their ratings with their experiences of care. METHODS: A survey and a qualitative study were conducted at a Danish hospital. Initially, 19 female patients completed a questionnaire using the response categories from very good to very bad; and subsequently they participated in a semi-structured interview held within two days after they completed the questionnaire. Additionally, 44 female patients participated in an interview within six weeks of completing a questionnaire. A phenomenological-hermeneutical approach was used in the analysis and interpretation. RESULTS: Two major themes emerged: experienced versus expected clinical quality and health-care professional attitude. Patients responded to each question by combining their experiences of both themes, e.g. a "very good" experience required that clinical service was provided at the expected level, at the very least, and that it was provided with recognition and respect. CONCLUSIONS: The female patients associated their experiences with their ratings, and two types of relation seemed to be at play: a care relation and a human relation. This finding can inform health-care practice, but department-specific examples may be needed to initiate improvements. FUNDING: The study received funding from the Centre for Patient Experience and Evaluation, Copenhagen, Denmark. The Danish Scientific Ethical Committees deemed it unnecessary to be involved in this project. TRIAL REGISTRATION: The Danish Data Protection Agency number of this study is 2008-58-0035. PMID- 26441394 TI - Fatal poisoning among patients with drug addiction. AB - INTRODUCTION: Fatal poisonings among drug addicts in Denmark in 2012 were examined. Cause of death, abuse pattern and geographic differences are discussed and data are compared with previous studies. METHODS: All fatal poisonings examined at the three institutes of forensic medicine in Denmark in 2012 were included in the study. RESULTS: A total of 188 fatal intoxications were recorded. The median age increased from 37.5 in 2007 to 41.5 in 2012. The majority were men (77%). Methadone (59%) was the main intoxicant. The decrease in the frequency of heroin/morphine deaths since 1997 (71%) continued, declining to 44% in 2002, 33% in 2007 and finally to 27% in 2012. Few deaths from central stimulants (amphetamine and cocaine) occurred. Multiple drug use was common and consisted mainly of opioids, cocaine, amphetamine, cannabis, benzodiazepines and alcohol. Heroin/morphine use was most frequent on Funen and in South Jutland. Cocaine was most frequently detected in East Denmark, while amphetamine was more frequent in West Denmark. CONCLUSIONS: The number of fatal poisonings among drug addicts has stabilised around 200. The increase in methadone deaths continued and, as in 2007, methadone was the main intoxicant. The increase in methadone deaths seems to be associated with use of methadone in substitution treatment. Nevertheless, methadone treatment also seems to save lives, as indicated by the increasing median age. Use of antidepressants and antipsychotics increased to a high level compared with 2007, indicating that a considerable number of drug addicts also have psychiatric illness. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 26441395 TI - Depression is associated with poor prognosis in patients with chronic obstructive pulmonary disease - a systematic review. AB - INTRODUCTION: Patients with depression have significantly increased mortality from somatic disease. The purpose of this article was to review studies that investigate if there is a prognostic association with depression as co-morbidity in patients with chronic obstructive pulmonary disease (COPD). We chose the following outcomes: mortality, suicide behaviour, risk of COPD exacerbation, use of primary care and prescription data. METHODS: A literature review was performed on 16 December 2014 in PubMed, Embase, OVID Medline and Cochrane for cohort studies. Only studies with mortality and exacerbation/hospital admissions were found. Studies failing to meet relevant criteria in terms of design or/and outcome, and studies with significant methodological faults were excluded. RESULTS: A total of 22 cohort studies were included. Of these studies, 20 were prospective, one retrospective and one was a combined retro- and prospective study. There was a tendency for studies with more patients and higher methodological quality to show a positive correlation. Sixteen of the studies showed that depression was associated with increased mortality (relative risk (RR): 1.02-3.6) and more COPD exacerbations (RR: 1.3-7.0). CONCLUSIONS: The results showed that not only is depression a debilitating disease on its own, it also predisposes to COPD exacerbations and increased mortality in patients with COPD. Depression in patients with COPD is under-diagnosed and undertreated, and a stronger focus on the clinical significance of depression as co-morbidity is warranted. PMID- 26441396 TI - Neuromuscular blockade for improvement of surgical conditions during laparotomy: protocol for a randomised study. AB - INTRODUCTION: During laparotomy, surgeons frequently experience difficult surgical conditions if the patient's abdominal wall or diaphragm is tense. This issue is particularly pertinent while closing the fascia and placing the intestines into the abdominal cavity. Establishment of a deep neuromuscular blockade (NMB), defined as a post-tetanic-count (PTC) of 0-1, paralyses the abdominal wall muscles and the diaphragm. We hypothesised that deep NMB (PTC 0-1) would improve surgical conditions during upper laparotomy as compared to standard NMB with bolus administration. METHODS: This is an investigator-initiated, assessor- and patient-blinded, randomised study. A total of 128 patients scheduled for elective upper laparotomy will be included and randomised to either continuous deep NMB or standard NMB defined as bolus administrations. Surgical conditions are evaluated using a five-point rating scale every 30 min. Primary outcome is the average score for a patient's surgical condition. Secondary outcomes are, among others, surgical rating score during fascial closure, wound dehiscence, wound infection requiring surgical drainage and incisional hernia at the six-month follow-up. CONCLUSIONS: This randomised, double-blinded study investigates potential effects of deep NMB on surgical conditions and patient outcomes during elective laparotomy. FUNDING: The study is funded in part by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp. TRIAL REGISTRATION: NCT02140593. PMID- 26441397 TI - The effect of generic switching on concerns about medicine and non-persistence among Danish adults in a general practice setting. AB - BACKGROUND: Generic substitution means that one medicinal product is replaced by another product containing the same active substance. Generic substitution has existed in Denmark since 1991, and pharmacies are obliged to substitute a generic version of a medication, unless the general practitioner (GP) has explicitly stated that it should not be done, or the patient insists on having the more expensive drug. Generic prescribing, that is prescribing the substance name, is not allowed in Denmark. Some specialists and patients cast doubt on the real interchange-ability of generics, although international studies have shown that most patients have positive attitudes towards generic substitution. The severity of disease is known to be associated with patients being more concerned about generic substitution. The generic substitution scheme implies changing from one drug to another that may vary in brand-name, form, size, colour and taste. Speculations have been raised as to whether these medication changes between generic brands or from brand-name drugs to generics or vice versa may cause patient concerns. Qualitative studies have shown problems in recognising the substituted medicine and lack of confidence in the identical effect of the substitutable medicines. Several studies have focused on one specific drug group such as antihypertensive drugs. However, the influence of generic switching may affect concerns about medicine differently, depending on drug categories. Research on generic substitution often focuses on incident drug users, whose prescription is substituted at their first redemption. Most of these studies did not identify significant associations between generic substitution and non adherence, but one study assessing the association between generic substitution and persistence showed reduced persistence. So far, studies of the effect of generic drug substitution on drug continuation have not focused on patients' overall experience of generic switches within one specific drug. AIMS: To analyse associations between generic substitution and patient characteristics as well as patients' views on generic medicines, confidence in the healthcare system, beliefs about medicine, and experience with earlier generic substitution. To investigate the possible association between a specific generic switch and patients' concerns about their medicine. To examine how generic switch influences persistence with long-term treatment with special focus on importance of patients' concerns and views on generic medicine. METHODS: The design was a combined cross-sectional questionnaire and register study and additionally a cohort study. The study was conducted among 6,000 medicine users, who had redeemed generically substitutable drugs with general reimbursement in September 2008 (2,000 users of antidepressants, 2,000 users of antiepileptics and 2,000 users of other substitutable drugs), who were aged 20 years or older and living in the Region of Southern Denmark. The medicine users were identified through Odense PharmacoEpidemiologic Database (OPED). The purpose of the questionnaire survey was to elucidate patients' experience with medicine, combined with information from OPED on a single well-defined generic switch of the index drug. The questionnaire was adapted to the individual subject with reference to their specific drug (index drug) in every question and index date printed on the questionnaire. The questionnaire comprises scales from the validated Beliefs about Medicine Questionnaire (BMQ) and ad hoc constructed scales. By means of OPED data it was possible to conduct a cohort study comprising information on all purchased medicine during the 12 months following the index date. The cohort comprised users of antidepressants and users of antiepileptics. RESULTS: A total of 2,476 patients (44.1%) were included in the analyses. Experience with earlier generic switches within the index ATC code was associated with experience of a generic switch on the index day (OR 5.93; 95% CI 4.70-7.49). However, experience with earlier generic switches was drug-specific, e.g. having had more than five earlier switches within other ATC codes reduced the odds of experiencing a generic switch on the index day. Having negative views on generic medicines also reduced the odds of experiencing a generic switch on the index day. The second study showed no statistically significant associations between experiencing a generic switch on the index day and having more or less concerns about the index medicine (-0.02 95% CI: -0.10-0.05). Patients experiencing their first-time switch of a specific drug were at higher risk of non-persistence, hazard ratio 2.98, 95% CI 1.81-4.89, versus those who have never switched, and 35.7% became non-persistent during the first year of follow-up. Generic switching did not influence persistence considerably in those having previous experience with generic switching of the specific drug. CONCLUSION: The overall results from the thesis showed that experience with earlier generic switches of a specific drug was associated with making a future generic switch and did not cause additional concerns about the index medicine. The effect of previous experience with generic substitution has been shown to be drug-specific. The third study showed that patients, who are first-time switchers of a specific drug, were at higher risk of becoming non-persistent compared to never switchers and those having experienced previous generic switching. PMID- 26441398 TI - Clinical epidemiological studies of women undergoing surgery for urogynaecological disorders. AB - This PhD thesis was performed during my employment at the Center for Clinical Epidemiology, Odense University Hospital and University of Southern Denmark, 2010 2013. It comprises an overview and four papers, two published in international peer-reviewed scientific journals, one under review, and one in draft. INTRODUCTION: Urinary incontinence (UI) and pelvic organ prolapse (POP) are prevalent disorders among women worldwide, affecting their psychological and social wellbeing, with reductions in quality of life. Treatment options are conservative (e.g. pelvic floor exercises, weight loss, and bladder training), pharmacological, and surgical. Surgery has especially for UI undergone an improvement during the last decades with development of minimally-invasive sub urethral sling procedures, and the number of surgeries has increased in Denmark and other countries. AIMS: In a population of Danish women undergoing surgery for UI or POP, we aimed: to describe the establishment of the Danish Urogynaecological Database (DugaBase), and to evaluate the completeness and the validity of surgery registration in the DugaBase; to study patient reported outcome measures in Danish women undergoing urogynaecological surgery; to study the use of symptom-relieving drugs before and after surgery for UI; to study the use of antibiotics for urinary tract infection (UTI) before and after surgery for UI METHODS: Study I The completeness of DugaBase was assessed by comparing procedure codes in the DugaBase to iodes registered in the National Patient Registry, 2006-2010. The study also included review of medical journals from 200 women (computed randomly from DugaBase), representing 22 departments in Denmark. Information on selected variables was compared to registered data in the DugaBase. DATA SOURCES: the National Patient Registry, the DugaBase, and medical records. Study II was based on a national cohort of women undergoing surgery for UI and POP registered in the DugaBase, 2006-2011. Clinical data and data from patient questionnaires were retrieved. DATA SOURCES: the DugaBase. Study III+IV were cohort studies based on national register data and prescription data. A total of 2,151 women with a first time surgical procedure for UI within 1996-2010 were included. The data were supplemented with registry information on redeemed prescriptions on symptom-relieving drugs/antibiotics for UTI/oestrogen, comorbidity, and educational level and income. DATA SOURCES: the Danish National Patient Registry, Odense University Pharmacoepidemiologic Database, and the Register for Education Statistics, and the Register of Family Income. RESULTS: Study I: A total of 16,509 procedures were registered in the DugaBase by 31 December 2010. The database completeness has increased from 38.2% to 93.2% during the years. According to the validation, all 200 medical records were retrieved. The overall percentage agreement between medical records and the DugaBase was at least 90% for selected key variables: procedure code, date, hospital department, use of antibiotics, prior surgery, height, weight, parity, and smoking. Study II: In the study period, 20,629 urogynaecological procedures were performed in Denmark and reported to the DugaBase. For approximately one third of these women, the patient questionnaires on severity of symptoms and quality of life were completed both pre- and postoperatively, and thus included. After both UI and POP surgery, more than 80% had improved symptoms and showed a significant improvement in quality of life. Study III: A total of 2,151 women with a primary UI procedure were included. Of these, 358 (16.6%) were exposed to symptom-relieving drugs preoperatively, and 1,793 (83.4%) were not. Preoperative usage of symptom relieving drugs was the strongest risk factor of postoperative use, both within 0 60 days OR (adjusted) = 33.0 (95% confidence interval (CI) 20.0-54.7)) and 61-365 days OR (adjusted) = 7.2 (95% CI 5.4-9.6)). Adjusted for age, procedure type, calendar year, comorbidity, preoperative use of oestrogen, educational level, and personal annual income. Only a minority of preoperative non-users started using symptom-relieving drugs postoperatively. Study IV: The same study population as in study III. Of the 2,151 women, 496 (23.1%) were antibiotic users prior to surgery, and 1,655 (76.9%) were non-users. Preoperative usages of antibiotics for UTI was a strong risk factor of postoperative use of the same antibiotics, both within 0-60 days OR (adjusted) = 2.6 (95% CI 2.9-3.5), and within 61-356 days OR (adjusted) = 4.5 (95% CI 3.5-5.7)). Adjusted for age, procedure type, calendar year, comorbidity, preoperative use of oestrogen, educational level, and personal annual income. Comorbidity and procedure types were found to be significant risk factors as well, although less important than preoperative antibiotic use. CONCLUSIONS: Due to a high completeness and data of high validity the DugaBase offers a unique possibility for continuing quality assessment of urogynaecological surgery in Denmark, as well as for future research. Surgeries for UI and POP performed in Danish women were effective in alleviating symptoms of UI and POP and improvement in quality of life based on patient reported outcome measures. Our pharmacoepidemiological studies showed that preoperative use of symptom-relieving drugs and antibiotics for UTI were strong risk factors of postoperative usage of the same drugs. PMID- 26441399 TI - Maternal pelvic size, fetal growth and risk of stroke in adult offspring in a large Swedish cohort. AB - Earlier research suggests that maternal pelvic size is associated with offspring's stroke risk in later life. We followed 6362 men and women from Uppsala, Sweden, born between 1915 and 1929 from 1964 to 2008 to assess whether maternal pelvic size was associated with incidence of thrombotic stroke (TS), haemorrhagic stroke (HS) and other stroke (OS). Offspring whose mothers had a flat pelvis had lower birth weight and birth-weight-for-gestational-age compared with those who did not. Inverse linear associations of birth-weight-for gestational-age were observed with TS and OS. Female offspring whose mothers had a flat pelvis had increased risk of TS, but flat pelvis was not associated with other types of stroke. A smaller difference between intercristal and interspinous diameters and a smaller external conjugate diameter were independently associated with HS, whereas no pelvic measurements were associated with OS. We conclude that a smaller pelvis in women may impact the health of their offspring in adulthood. PMID- 26441400 TI - Dextromethorphan Addiction Mediated Through the NMDA System: Common Pathways With Alcohol? AB - Dextromethorphan, an antitussive (cough suppressant) drug of the morphinan class with sedative and dissociative properties found in cough syrup and other over-the counter products, is also a substance of abuse, seen primarily in young adults all over the world. A case of dextromethorphan use disorder is presented in a 45 year-old women. Her repeated attempts at abstinence were unsuccessful secondary to continued intense cravings. Treatment with topiramate resulted in complete resolution of her cravings. Topiramate was chosen empirically because of a common action with dextromethorphan in the NMDA system. Genetic testing was obtained and the patient was found to be a carrier of the GRIK1 rs2832407(C:C) allele. The (C:C) allele has been associated with an increased risk of alcohol use disorder and a treatment response of patients with heavy drinking to topiramate. This case provides an opportunity to discuss personalized medicine (treatment options aided by the use of genetic testing) and the possible shared genetic susceptibility for dependence in 2 substances of abuse. PMID- 26441402 TI - Clinicians' Beliefs and Practices Regarding Drug Use Care of Their Community Health Center Patients. AB - OBJECTIVES: Integration of behavioral health including substance use problems into primary care is an essential benefit that federally qualified health centers (FQHCs) will offer as part of the Affordable Care Act. This study explores FQHC primary care clinicians' beliefs and practices regarding illicit drug use assessment and treatment. METHODS: We administered a 10-minute questionnaire to 68 primary care clinicians of 5 FQHCs in Los Angeles. RESULTS: Clinicians expressed limited confidence in their ability to address patients' illicit drug use, scoring on average 3.31 on a 5-point Likert scale. Two thirds reported that they assess for drug use routinely "at every visit" and/or "at annual visits." When asked how often they counsel regarding drug use (on a 5-point Likert scale from "never" to "always"), the median response was 4 ("usually"). Regarding their perspectives on the best practical resource for addressing drug use in their clinics, 45.6% named primary care clinicians. A minority (29.4%) of clinicians had completed a clinical rotation dealing with substance use, and 27.2% reported receiving more than 10 hours of training regarding substance use problems. Having a substance use rotation was associated with greater confidence in drug use assessment and treatment (P < 0.01). More hours of substance use training was associated with greater confidence (P = 0.01) and routinely addressing substance use in their patients (P = 0.04). CONCLUSIONS: Although two thirds of the surveyed clinicians assess for drug use routinely, and on average, report that they usually address drug use, clinicians' confidence in substance use care seems to be suboptimal, but both confidence and routinely addressing substance use are associated with increased substance use education. Improving clinicians' training and integrating drug use care in FQHCs may improve confidence in substance use care and facilitate the Affordable Care Act's mandate to integrate behavioral health into routine FQHC primary care. PMID- 26441401 TI - Longitudinal Modeling of the Association Between Transmissible Risk, Affect During Drug Use and Development of Substance Use Disorder. AB - OBJECTIVE: This longitudinal investigation examined the hypothesis that subjective experience during consumption of preferred drugs mediates the association of transmissible risk for substance use disorder (SUD) measured in childhood and adolescence, and SUD diagnosis in adulthood. Transmissible risk denotes the psychological characteristics having intergenerational continuity between parents and their biological children. METHODS: The transmissible liability index (TLI) was administered to four hundred eighty-three 10 to 12-year old boys (baseline). Follow-up evaluations were conducted when the boys attained 12-14, 16, 19, and 22 years of age, using age-specific versions of the TLI. Frequency of consumption of the participants' three most preferred drugs, affect on an ordinary day, affect while under influence of the preferred substances, and presence/absence of current SUD were assessed at 22 years of age. RESULTS: Consumption frequency of preferred drugs among boys mediates the association of transmissible risk during childhood, and adolescence and SUD diagnosis in adulthood. Severity of negative affect on a drug-free day predicts frequency of consumption of preferred drugs, which, in turn, predicts severity of negative affect during the drug use event. Neither affect on a drug-free day nor affect during the drug use event mediates the association of transmissible risk and SUD. CONCLUSIONS: Affect on drug-free days, and while under influence of preferred substances, covary with consumption frequency; however, affect is not related to transmissible SUD risk or SUD outcome. PMID- 26441403 TI - Patterns of call communication between group-housed zebra finches change during the breeding cycle. AB - Vocal signals such as calls play a crucial role for survival and successful reproduction, especially in group-living animals. However, call interactions and call dynamics within groups remain largely unexplored because their relation to relevant contexts or life-history stages could not be studied with individual level resolution. Using on-bird microphone transmitters, we recorded the vocalisations of individual zebra finches (Taeniopygia guttata) behaving freely in social groups, while females and males previously unknown to each other passed through different stages of the breeding cycle. As birds formed pairs and shifted their reproductive status, their call repertoire composition changed. The recordings revealed that calls occurred non-randomly in fine-tuned vocal interactions and decreased within groups while pair-specific patterns emerged. Call-type combinations of vocal interactions changed within pairs and were associated with successful egg-laying, highlighting a potential fitness relevance of calling dynamics in communication systems. PMID- 26441405 TI - Analysis of Moving-Coil Actuator Jet Injectors for Viscous Fluids. AB - OBJECTIVE: A jet injector is a device that can be used to deliver liquid drugs through the skin using a fluid jet, without the use of a needle. Most jet injectors are designed and used for the delivery of inviscid liquids, and are not optimized for the delivery of viscous drug compounds. To better understand the requirements for delivering viscous drugs, we have developed a mathematical model of the electromechanics of a moving-coil actuated jet injector as it delivers viscous fluids. METHODS: The model builds upon previous work by incorporating the nonlinear electrical properties of the motor, compliant elements of the mechanical piston and ampoule system, and the effect of viscosity on injector characteristics. The model has been validated by monitoring the movement of the piston tip and measurements of the jet force. RESULTS: The results of the model indicate that the jet speed is diminished with increasing fluid viscosity, but overshoot and ringing in the jet speed is unaffected. However, a stiffer ampoule and piston will allow for a better control of the jet speed profile during an injection, and reduce ringing. CONCLUSION: We identified that the piston friction coefficient, the compliance of the injector components, and the viscous properties of the fluid are important determinants of performance when jet injecting viscous fluids. SIGNIFICANCE: By expanding upon previous jet injector models, this study has provided informative simulations of jet injector characteristics and performance. The model can be used to guide the design of future jet injectors for viscous fluids. PMID- 26441404 TI - Cell-to-cell infection by HIV contributes over half of virus infection. AB - Cell-to-cell viral infection, in which viruses spread through contact of infected cell with surrounding uninfected cells, has been considered as a critical mode of virus infection. However, since it is technically difficult to experimentally discriminate the two modes of viral infection, namely cell-free infection and cell-to-cell infection, the quantitative information that underlies cell-to-cell infection has yet to be elucidated, and its impact on virus spread remains unclear. To address this fundamental question in virology, we quantitatively analyzed the dynamics of cell-to-cell and cell-free human immunodeficiency virus type 1 (HIV-1) infections through experimental-mathematical investigation. Our analyses demonstrated that the cell-to-cell infection mode accounts for approximately 60% of viral infection, and this infection mode shortens the generation time of viruses by 0.9 times and increases the viral fitness by 3.9 times. Our results suggest that even a complete block of the cell-free infection would provide only a limited impact on HIV-1 spread. PMID- 26441406 TI - Iterative Correction Scheme Based on Discrete Cosine Transform and L1 Regularization for Fluorescence Molecular Tomography With Background Fluorescence. AB - GOAL: High-intensity background fluorescence is generally encountered in fluorescence molecular tomography (FMT), because of the accumulation of fluorescent probes in nontarget tissues or the existence of autofluorescence in biological tissues. The reconstruction results are affected or even distorted by the background fluorescence, especially when the distribution of fluorescent targets is relatively sparse. The purpose of this paper is to reduce the negative effect of background fluorescence on FMT reconstruction. METHODS: After each iteration of the Tikhonov regularization algorithm, 3-D discrete cosine transform is adopted to filter the intermediate results. And then, a sparsity constraint step based on L1 regularization is applied to restrain the energy of the objective function. RESULTS: Phantom experiments with different fluorescence intensities of homogeneous and heterogeneous background are carried out to validate the performance of the proposed scheme. The results show that the reconstruction quality can be improved with the proposed iterative correction scheme. CONCLUSION AND SIGNIFICANCE: The influence of background fluorescence in FMT can be reduced effectively because of the filtering of the intermediate results, the detail preservation, and noise suppression of L1 regularization. PMID- 26441407 TI - Elastic Stability of Concentric Tube Robots Subject to External Loads. AB - Concentric tube robots, which are comprised of precurved elastic tubes that are concentrically arranged, are being developed for many medical interventions. The shape of the robot is determined by the rotation and translation of the tubes relative to each other, and also by any external forces applied by the environment. As the tubes rotate and translate relative to each other, elastic potential energy caused by tube bending and twisting can accumulate; if a configuration is not locally elastically stable, then a dangerous snapping motion may occur as energy is suddenly released. External loads on the robot also influence elastic stability. In this paper, we provide a second-order sufficient condition, and also a separate necessary condition, for elastic stability. Using methods of optimal control theory, we show that these conditions apply to general concentric tube robot designs subject to arbitrary conservative external loads. They can be used to assess the stability of candidate robot configurations. Our results are validated via comparison with other known stability criteria, and their utility is demonstrated by an application to stable path planning. PMID- 26441409 TI - Biomimetic Accommodating Intraocular Lens Using a Valved Deformable Liquid Balloon. AB - OBJECTIVE: Presbyopia is a common age-related condition that prevents people from focusing on near objects. The etiology of presbyopia continues to be debated, but the end effect of all postulated mechanisms is the lack of deformation of the human lens. Using our understanding of the biomechanical properties of the natural human lens, we created a unique accommodating intraocular lens. Although this lens can be used for lenticular disease such as myopia and hyperoperopia, this study addresses the needs of cataract patients with presbyopia. METHODS: The lens was implanted into presbyopic human cadaver eyes. Focal length of the lens was measured with simulated muscle contraction. Lens dimensions were measured using artificial tissue and a finite-element analysis (FEA) to simulate accommodation. Lens power was measured at various fill volumes. Accelerated soak testing for an equivalent of 7.4 years was performed and lens weight and optical transmittance were measured. RESULTS: Previously presbyopic human eyes were able to accommodate between 2.0 and 7.4 diopters after lens implantation. FEA and lens measurements demonstrated a change in curvature of the anterior and posterior portions of the lens during accommodation. After accelerated aging, lens weight remained unchanged and optical transmission was 96%. Lens power increased with fill volume. CONCLUSION: A deformable liquid lens reversed presbyopia, can be individualized by optically adjusting for each patient, is stable for long periods of time, and is compatible with minimally invasive surgical techniques. SIGNIFICANCE: A deformable liquid-filled lens can significantly improve accommodation over the presbyopic natural lens. PMID- 26441408 TI - Behavioral Informatics and Computational Modeling in Support of Proactive Health Management and Care. AB - Health-related behaviors are among the most significant determinants of health and quality of life. Improving health behavior is an effective way to enhance health outcomes and mitigate the escalating challenges arising from an increasingly aging population and the proliferation of chronic diseases. Although it has been difficult to obtain lasting improvements in health behaviors on a wide scale, advances at the intersection of technology and behavioral science may provide the tools to address this challenge. In this paper, we describe a vision and an approach to improve health behavior interventions using the tools of behavioral informatics, an emerging transdisciplinary research domain based on system-theoretic principles in combination with behavioral science and information technology. The field of behavioral informatics has the potential to optimize interventions through monitoring, assessing, and modeling behavior in support of providing tailored and timely interventions. We describe the components of a closed-loop system for health interventions. These components range from fine grain sensor characterizations to individual-based models of behavior change. We provide an example of a research health coaching platform that incorporates a closed-loop intervention based on these multiscale models. Using this early prototype, we illustrate how the optimized and personalized methodology and technology can support self-management and remote care. We note that despite the existing examples of research projects and our platform, significant future research is required to convert this vision to full-scale implementations. PMID- 26441410 TI - Real-Time Visual Tracking of Deformable Objects in Robot-Assisted Surgery. AB - One of the most challenging problems in robot-assisted surgical systems is to provide surgical realism at interactive simulation rates. The proposed visual tracking system can track and register object deformations in real time using a physically based formulation, despite the occlusions produced by the robotic system itself. The results obtained provide an accurate visual representation of the deformed solid and will thus enable new assistance approaches to help surgeons during surgical procedures. PMID- 26441411 TI - Electrophysiology Catheter Detection and Reconstruction From Two Views in Fluoroscopic Images. AB - Electrophysiology (EP) studies and catheter ablation have become important treatment options for several types of cardiac arrhythmias. We present a novel image-based approach for automatic detection and 3-D reconstruction of EP catheters where the physician marks the catheter to be reconstructed by a single click in each image. The result can be used to provide 3-D information for enhanced navigation throughout EP procedures. Our approach involves two X-ray projections acquired from different angles, and it is based on two steps: First, we detect the catheter in each view after manual initialization using a graph search method. Then, the detection results are used to reconstruct a full 3-D model of the catheter based on automatically determined point pairs for triangulation. An evaluation on 176 different clinical fluoroscopic images yielded a detection rate of 83.4%. For measuring the error, we used the coupling distance which is a more accurate quality measure than the average point-wise distance to a reference. For successful outcomes, the 2-D detection error was 1.7 mm +/-1.2 mm. Using successfully detected catheters for reconstruction, we obtained a reconstruction error of 1.8 mm +/-1.1 mm on phantom data. On clinical data, our method yielded a reconstruction error of 2.2 mm +/-2.2 mm. PMID- 26441412 TI - Improving Computer-Aided Detection Using Convolutional Neural Networks and Random View Aggregation. AB - Automated computer-aided detection (CADe) has been an important tool in clinical practice and research. State-of-the-art methods often show high sensitivities at the cost of high false-positives (FP) per patient rates. We design a two-tiered coarse-to-fine cascade framework that first operates a candidate generation system at sensitivities ~ 100% of but at high FP levels. By leveraging existing CADe systems, coordinates of regions or volumes of interest (ROI or VOI) are generated and function as input for a second tier, which is our focus in this study. In this second stage, we generate 2D (two-dimensional) or 2.5D views via sampling through scale transformations, random translations and rotations. These random views are used to train deep convolutional neural network (ConvNet) classifiers. In testing, the ConvNets assign class (e.g., lesion, pathology) probabilities for a new set of random views that are then averaged to compute a final per-candidate classification probability. This second tier behaves as a highly selective process to reject difficult false positives while preserving high sensitivities. The methods are evaluated on three data sets: 59 patients for sclerotic metastasis detection, 176 patients for lymph node detection, and 1,186 patients for colonic polyp detection. Experimental results show the ability of ConvNets to generalize well to different medical imaging CADe applications and scale elegantly to various data sets. Our proposed methods improve performance markedly in all cases. Sensitivities improved from 57% to 70%, 43% to 77%, and 58% to 75% at 3 FPs per patient for sclerotic metastases, lymph nodes and colonic polyps, respectively. PMID- 26441413 TI - Improving the Accuracy of Registration-Based Biomechanical Analysis: A Finite Element Approach to Lung Regional Strain Quantification. AB - Tissue deformation plays an important role in lung physiology, as lung parenchyma largely deforms during spontaneous ventilation. However, excessive regional deformation may lead to lung injury, as observed in patients undergoing mechanical ventilation. Thus, the accurate estimation of regional strain has recently received great attention in the intensive care community. In this work, we assess the accuracy of regional strain maps computed from direct differentiation of B-Spline (BS) interpolations, a popular technique employed in non-rigid registration of lung computed tomography (CT) images. We show that, while BS-based registration methods give excellent results for the deformation transformation, the strain field directly computed from BS derivatives results in predictions that largely oscillate, thus introducing important errors that can even revert the sign of strain. To alleviate such spurious behavior, we present a novel finite-element (FE) method for the regional strain analysis of lung CT images. The method follows from a variational strain recovery formulation, and delivers a continuous approximation to the strain field in arbitrary domains. From analytical benchmarks, we show that the FE method results in errors that are a fraction of those found for the BS method, both in an average and pointwise sense. The application of the proposed FE method to human lung CT images results in 3D strain maps are heterogeneous and smooth, showing high consistency with specific ventilation maps reported in the literature. We envision that the proposed FE method will considerably improve the accuracy of image-based biomechanical analysis, making it reliable enough for routine medical applications. PMID- 26441414 TI - Color Image Demosaicing Using Iterative Residual Interpolation. AB - A recently developed demosaicing methodology, called residual interpolation (RI), has demonstrated superior performance over the conventional color-component difference interpolation. However, it has been observed that the existing RI based methods fail to fully exploit the potential of RI strategy on the reconstruction of the most important G channel, as only the R and B channels are restored through the RI strategy. Since any reconstruction error introduced in the G channel will be carried over into the demosaicing process of the other two channels, this makes the restoration of the G channel highly instrumental to the quality of the final demosaiced image. In this paper, a novel iterative RI (IRI) process is developed for reconstructing a highly accurate G channel first; in essence, it can be viewed as an iterative refinement process for the estimation of those missing pixel values on the G channel. The key novelty of the proposed IRI process is that all the three channels will mutually guide each other until a stopping criterion is met. Based on the restored G channel, the mosaiced R and B channels will be, respectively, reconstructed by exploiting the existing RI method without iteration. Extensive simulations conducted on two commonly-used test datasets for demosaicing algorithms have demonstrated that our algorithm has achieved the best performance in most cases, compared with the existing state-of the-art demosaicing methods on both objective and subjective performance evaluations. PMID- 26441415 TI - Edge-Preserving Decomposition-Based Single Image Haze Removal. AB - Single image haze removal is under-constrained, because the number of freedoms is larger than the number of observations. In this paper, a novel edge-preserving decomposition-based method is introduced to estimate transmission map for a haze image so as to design a single image haze removal algorithm from the Koschmiedars law without using any prior. In particular, weighted guided image filter is adopted to decompose simplified dark channel of the haze image into a base layer and a detail layer. The transmission map is estimated from the base layer, and it is applied to restore the haze-free image. The experimental results on different types of images, including haze images, underwater images, and normal images without haze, show the performance of the proposed algorithm. PMID- 26441416 TI - A Boosted Multi-Task Model for Pedestrian Detection With Occlusion Handling. AB - Pedestrian detection is a challenging problem in computer vision, and has achieved impressive progress in recent years. However, the current state-of-the art methods suffer from significant performance decline with increasing occlusion level of pedestrians. A common approach for occlusion handling is to train a set of occlusion-specific detectors and merge their results directly, but these detectors are trained independently and the relationship among them is ignored. In this paper, we consider pedestrian detection in different occlusion levels as different but related problems, and propose a boosted multi-task model to jointly consider their relatedness and differences. The proposed model adopts multi-task learning algorithm to map pedestrians in different occlusion levels to a common space, where all models corresponding to different occlusion levels are constrained to share a common set of features, and a boosted detector is then constructed to distinguish pedestrians from background. The proposed approach is evaluated on three challenging pedestrian detection data sets, including Caltech, TUD-Brussels, and INRIA, and achieves superior performances against state of the art in the literature on different occlusion-specific test sets. PMID- 26441417 TI - Local inverse tone curve learning for high dynamic range image scalable compression. AB - This paper presents a scalable high dynamic range (HDR) image coding scheme in which the base layer is a low dynamic range version of the image that may have been generated by an arbitrary tone mapping operator (TMO). No restriction is imposed on the TMO, which can be either global or local, so as to fully respect the artistic intent of the producer. Our method successfully handles the case of complex local TMOs thanks to a block-wise and non-linear approach. A novel template-based interlayer prediction (ILP) is designed in order to perform the inverse tone mapping of a block without the need to transmit any additional parameter to the decoder. This method enables the use of a more accurate inverse tone mapping model than the simple linear regression commonly used for block-wise ILP. In addition, this paper shows that a linear adjustment of the initially predicted block can further improve the overall coding performance by using an efficient encoding scheme of the scaling parameters. Our experiments have shown an average bitrate saving of 47% on the HDR enhancement layer, compared with the previous local ILP methods. PMID- 26441418 TI - Interface Detection Using a Quenched-Noise Version of the Edwards-Wilkinson Equation. AB - We report here a multipurpose dynamic-interface-based segmentation tool, suitable for segmenting planar, cylindrical, and spherical surfaces in 3D. The method is fast enough to be used conveniently even for large images. Its implementation is straightforward and can be easily realized in many environments. Its memory consumption is low, and the set of parameters is small and easy to understand. The method is based on the Edwards-Wilkinson equation, which is traditionally used to model the equilibrium fluctuations of a propagating interface under the influence of temporally and spatially varying noise. We report here an adaptation of this equation into multidimensional image segmentation, and its efficient discretization. PMID- 26441419 TI - Single Object Tracking With Fuzzy Least Squares Support Vector Machine. AB - Single object tracking, in which a target is often initialized manually in the first frame and then is tracked and located automatically in the subsequent frames, is a hot topic in computer vision. The traditional tracking-by-detection framework, which often formulates tracking as a binary classification problem, has been widely applied and achieved great success in single object tracking. However, there are some potential issues in this formulation. For instance, the boundary between the positive and negative training samples is fuzzy, and the objectives of tracking and classification are inconsistent. In this paper, we attempt to address the above issues from the fuzzy system perspective and propose a novel tracking method by formulating tracking as a fuzzy classification problem. First, we introduce the fuzzy strategy into tracking and propose a novel fuzzy tracking framework, which can measure the importance of the training samples by assigning different memberships to them and offer more strict spatial constraints. Second, we develop a fuzzy least squares support vector machine (FLS SVM) approach and employ it to implement a concrete tracker. In particular, the primal form, dual form, and kernel form of FLS-SVM are analyzed and the corresponding closed-form solutions are derived for efficient realizations. Besides, a least squares regression model is built to control the update adaptively, retaining the robustness of the appearance model. The experimental results demonstrate that our method can achieve comparable or superior performance to many state-of-the-art methods. PMID- 26441420 TI - Bitplane Image Coding With Parallel Coefficient Processing. AB - Image coding systems have been traditionally tailored for multiple instruction, multiple data (MIMD) computing. In general, they partition the (transformed) image in codeblocks that can be coded in the cores of MIMD-based processors. Each core executes a sequential flow of instructions to process the coefficients in the codeblock, independently and asynchronously from the others cores. Bitplane coding is a common strategy to code such data. Most of its mechanisms require sequential processing of the coefficients. The last years have seen the upraising of processing accelerators with enhanced computational performance and power efficiency whose architecture is mainly based on the single instruction, multiple data (SIMD) principle. SIMD computing refers to the execution of the same instruction to multiple data in a lockstep synchronous way. Unfortunately, current bitplane coding strategies cannot fully profit from such processors due to inherently sequential coding task. This paper presents bitplane image coding with parallel coefficient (BPC-PaCo) processing, a coding method that can process many coefficients within a codeblock in parallel and synchronously. To this end, the scanning order, the context formation, the probability model, and the arithmetic coder of the coding engine have been re-formulated. The experimental results suggest that the penalization in coding performance of BPC-PaCo with respect to the traditional strategies is almost negligible. PMID- 26441421 TI - Effective Clipart Image Vectorization through Direct Optimization of Bezigons. AB - Bezigons, i.e., closed paths composed of Bezier curves, have been widely employed to describe shapes in image vectorization results. However, most existing vectorization techniques infer the bezigons by simply approximating an intermediate vector representation (such as polygons). Consequently, the resultant bezigons are sometimes imperfect due to accumulated errors, fitting ambiguities, and a lack of curve priors, especially for low-resolution images. In this paper, we describe a novel method for vectorizing clipart images. In contrast to previous methods, we directly optimize the bezigons rather than using other intermediate representations; therefore, the resultant bezigons are not only of higher fidelity compared with the original raster image but also more reasonable because they were traced by a proficient expert. To enable such optimization, we have overcome several challenges and have devised a differentiable data energy as well as several curve-based prior terms. To improve the efficiency of the optimization, we also take advantage of the local control property of bezigons and adopt an overlapped piecewise optimization strategy. The experimental results show that our method outperforms both the current state-of the-art method and commonly used commercial software in terms of bezigon quality. PMID- 26441422 TI - Event-Related Beta EEG Changes During Active, Passive Movement and Functional Electrical Stimulation of the Lower Limb. AB - A number of electroencephalographic (EEG) studies have reported on event-related desynchronization/synchronization (ERD/ERS) during active movements, passive movements, and the movements induced by functional electrical stimulation (FES). However, the quantitative differences in ERD values and affected frequency bands associated with the lower limb have not been discussed. The goal of this paper was to quantitatively compare the ERD patterns during active movement, passive movement and FES-induced movement of the lower limb. 64-channel EEG signals were recorded to investigate the brain oscillatory patterns during active movement, passive movement and FES-induced movement of the lower limb in twelve healthy subjects. And passive movement and FES-induced movement were also performed in a hemiplegic stroke patient. For healthy subjects, FES-induced movement presented significantly higher characteristic frequency of central beta ERD while there was no significant difference in ERD values compared with active or passive movement. Meanwhile, beta ERD values of FES-induced movement were significantly correlated with those of active movement, and spatial distribution of beta ERD pattern for FES-induced movement was more correlated with that for active movement. In addition, the stroke patient presented central ERD patterns during FES-induced movement, while no ERD with similar frequencies could be found during passive movement. This work implies that the EEG oscillatory pattern under FES-induced movement tends more towards active movement instead of passive movement. The quantification of ERD patterns could be expected as a potential technique to evaluate the brain response during FES-induced movement. PMID- 26441423 TI - Robustness and Reliability of Synergy-Based Myocontrol of a Multiple Degree of Freedom Robotic Arm. AB - In this study, we test the feasibility of the synergy- based approach for application in the realistic and clinically oriented framework of multi-degree of freedom (DOF) robotic control. We developed and tested online ten able-bodied subjects in a semi-supervised method to achieve simultaneous, continuous control of two DOFs of a robotic arm, using muscle synergies extracted from upper limb muscles while performing flexion-extension movements of the elbow and shoulder joints in the horizontal plane. To validate the efficacy of the synergy-based approach in extracting reliable control signals, compared to the simple muscle pair method typically used in commercial applications, we evaluated the repeatability of the algorithm over days, the effect of the arm dynamics on the control performance, and the robustness of the control scheme to the presence of co-contraction between pairs of antagonist muscles. Results showed that, without the need for a daily calibration, all subjects were able to intuitively and easily control the synergy-based myoelectric interface in different scenarios, using both dynamic and isometric muscle contractions. The proposed control scheme was shown to be robust to co-contraction between antagonist muscles, providing better performance compared to the traditional muscle-pair approach. The current study is a first step toward user-friendly application of synergy-based myocontrol of assistive robotic devices. PMID- 26441424 TI - Towards a Computer Aided Prognosis for Brain Glioblastomas Tumor Growth Estimation. AB - Bridging the gap between mathematical and biological models and clinical applications could be considered as one of the new challenges of medical image analysis over the ten last years. This paper presents an advanced and convivial algorithm for brain glioblastomas tumor growth modelization. The brain glioblastomas tumor region would be extracted using a fast distribution matching developed algorithm based on global pixel wise information. A new model to simulate the tumor growth based on two major elements: cellular automata and fast marching method (CFMM) has been developed and used to estimate the brain tumor evolution during the time. On the basis of this model, experiments were carried out on twenty pathological MRI selected cases that were carefully discussed with the clinical part. The obtained simulated results were validated with ground truth references (real tumor growth measure) using dice metric parameter. As carefully discussed with the clinical partner, experimental results showed that our proposed algorithm for brain glioblastomas tumor growth model proved a good agreement. Our main purpose behind this research was of course to make advances and progress during clinical explorations helping therefore radiologists in their diagnosis. Clinical decisions and guidelines would be hence so more focused with such an advanced tool that could help clinicians and ensuring more accuracy and objectivity. PMID- 26441425 TI - A High Sensitivity Impedimetric Biosensor Using the Tannin From Quercusmacrolepis as Biorecognition Element for Heavy Metals Detection. AB - A new poly(vinylchloride) (PVC) membrane electrode based on tannin from the bark of Quercusmacrolepis (acorn) as the ionophore was prepared and modified onto the surface of a gold electrode. The electrochemical impedance spectroscopy (EIS) technique was used to study the sensitivity of the electrode that was modified with a thin layer of polymeric biomembrane, in order to detect heavy metals ions in solution. The device shows a good sensitivity for Zn(2+), Ni(2+) ions and a little less for Cd(2+). The electrode indicates a good linear response for the three metals over a wide concentration range from 1.0*10(-9) to 1.0*10(-4) M, with a detection limit of 1.0*10(-9) M. PMID- 26441426 TI - Quantitative Verification of Dynamic Wedge Dose Distribution Using a 2D Ionization Chamber Array. AB - The accuracy of two calculation algorithms of the Eclipse 8.9 treatment planning system (TPS)--the anisotropic analytic algorithm (AAA) and pencil-beam convolution (PBC)--in modeling the enhanced dynamic wedge (EDW) was investigated. Measurements were carried out for 6 and 18 MV photon beams using a 2D ionization chamber array. Accuracy of the TPS was evaluated using a gamma index analysis with the following acceptance criteria for dose differences (DD) and distance to agreement (DTA): 3%/3 mm and 2%/2 mm. The TPS models the dose distribution accurately except for 20*20 cm(2) field size, 60 ( degrees ) and 45 ( degrees ) wedge angles using PBC at 6 MV photon energy. For these latter fields, the pass rate and the mean value of gamma were less than 90% and more than 0.5, respectively at the (3%/3 mm) acceptance criteria. In addition, an accuracy level of (2%/2 mm) was achieved using AAA with better agreement for 18 MV photon energy. PMID- 26441427 TI - A Cascade Random Forests Algorithm for Predicting Protein-Protein Interaction Sites. AB - Protein-protein interactions exist ubiquitously and play important roles in the life cycles of living cells. The interaction sites (residues) are essential to understanding the underlying mechanisms of protein-protein interactions. Previous research has demonstrated that the accurate identification of protein-protein interaction sites (PPIs) is helpful for developing new therapeutic drugs because many drugs will interact directly with those residues. Because of its significant potential in biological research and drug development, the prediction of PPIs has become an important topic in computational biology. However, a severe data imbalance exists in the PPIs prediction problem, where the number of the majority class samples (non-interacting residues) is far larger than that of the minority class samples (interacting residues). Thus, we developed a novel cascade random forests algorithm (CRF) to address the serious data imbalance that exists in the PPIs prediction problem. The proposed CRF resolves the negative effect of data imbalance by connecting multiple random forests in a cascade-like manner, each of which is trained with a balanced training subset that includes all minority samples and a subset of majority samples using an effective ensemble protocol. Based on the proposed CRF, we implemented a new sequence-based PPIs predictor, called CRF-PPI, which takes the combined features of position-specific scoring matrices, averaged cumulative hydropathy, and predicted relative solvent accessibility as model inputs. Benchmark experiments on both the cross validation and independent validation datasets demonstrated that the proposed CRF-PPI outperformed the state-of-the-art sequence-based PPIs predictors. The source code for CRF-PPI and the benchmark datasets are available online at http://csbio.njust.edu.cn/bioinf/CRF-PPI for free academic use. PMID- 26441428 TI - Spatial Resolution Improvement of EEG Source Reconstruction Using swLORETA. AB - Electroencephalography (EEG) and magnetic resonance imaging (MRI) are noninvasive neuro-imaging modalities largely used in neurology explorations. MRI is considered as a static modality and could be so important for anatomy by its high spatial resolution. EEG, on the other hand, is an important tool permitting to image temporal dynamic activities of the human brain. Fusion of these two essential modalities would be hence a so emerging research domain targeting to explore brain activities with the MRI static modality. Our present research investigates a sophisticated approach for localization of the cerebral activity that could be involved by the dynamic EEG modality and carefully illustrated within MRI static modality. Such careful cerebral activity localization would be first based on an advanced methodology yielding therefore a singular value decomposition-based lead field weighting to sLORETA method formalism, for solving in fact the inverse problem in the EEG. The conceived method for source localization, carried out on different cases of simulated dipoles experiments, showed satisfactory results. Different cases of simulated dipoles experiments and metrics were used to confirm the reliability of the proposed method. The experimental results confirm that our method presents a flexible and robust tool for EEG source imaging. PMID- 26441429 TI - Practical Guidelines for Incorporating Knowledge-Based and Data-Driven Strategies into the Inference of Gene Regulatory Networks. AB - Modeling gene regulatory networks (GRNs) is essential for conceptualizing how genes are expressed and how they influence each other. Typically, a reverse engineering approach is employed; this strategy is effective in reproducing possible fitting models of GRNs. To use this strategy, however, two daunting tasks must be undertaken: one task is to optimize the accuracy of inferred network behaviors; and the other task is to designate valid biological topologies for target networks. Although existing studies have addressed these two tasks for years, few of the studies can satisfy both of the requirements simultaneously. To address these difficulties, we propose an integrative modeling framework that combines knowledge-based and data-driven input sources to construct biological topologies with their corresponding network behaviors. To validate the proposed approach, a real dataset collected from the cell cycle of the yeast S. cerevisiae is used. The results show that the proposed framework can successfully infer solutions that meet the requirements of both the network behaviors and biological structures. Therefore, the outcomes are exploitable for future in vivo experimental design. PMID- 26441430 TI - Assessing Short-Term Voltage Stability of Electric Power Systems by a Hierarchical Intelligent System. AB - In the smart grid paradigm, growing integration of large-scale intermittent renewable energies has introduced significant uncertainties to the operations of an electric power system. This makes real-time dynamic security assessment (DSA) a necessity to enable enhanced situational-awareness against the risk of blackouts. Conventional DSA methods are mainly based on the time-domain simulation, which are insufficiently fast and knowledge-poor. In recent years, the intelligent system (IS) strategy has been identified as a promising approach to facilitate real-time DSA. While previous works mainly concentrate on the rotor angle stability, this paper focuses on another yet increasingly important dynamic insecurity phenomenon-the short-term voltage instability, which involves fast and complex load dynamics. The problem is modeled as a classification subproblem for transient voltage collapse and a prediction subproblem for unacceptable dynamic voltage deviation. A hierarchical IS is developed to address the two subproblems sequentially. The IS is based on ensemble learning of random-weights neural networks and is implemented in an offline training, a real-time application, and an online updating pattern. The simulation results on the New England 39-bus system verify its superiority in both learning speed and accuracy over some state of-the-art learning algorithms. PMID- 26441431 TI - Robust Kernel Low-Rank Representation. AB - Recently, low-rank representation (LRR) has shown promising performance in many real-world applications such as face clustering. However, LRR may not achieve satisfactory results when dealing with the data from nonlinear subspaces, since it is originally designed to handle the data from linear subspaces in the input space. Meanwhile, the kernel-based methods deal with the nonlinear data by mapping it from the original input space to a new feature space through a kernel induced mapping. To effectively cope with the nonlinear data, we first propose the kernelized version of LRR in the clean data case. We also present a closed form solution for the resultant optimization problem. Moreover, to handle corrupted data, we propose the robust kernel LRR (RKLRR) approach, and develop an efficient optimization algorithm to solve it based on the alternating direction method. In particular, we show that both the subproblems in our optimization algorithm can be efficiently and exactly solved, and it is guaranteed to obtain a globally optimal solution. Besides, our proposed algorithm can also solve the original LRR problem, which is a special case of our RKLRR when using the linear kernel. In addition, based on our new optimization technique, the kernelization of some variants of LRR can be similarly achieved. Comprehensive experiments on synthetic data sets and real-world data sets clearly demonstrate the efficiency of our algorithm, as well as the effectiveness of RKLRR and the kernelization of two variants of LRR. PMID- 26441432 TI - A Survey of Mobile Phone Sensing, Self-Reporting, and Social Sharing for Pervasive Healthcare. AB - The current institution-based model for healthcare service delivery faces enormous challenges posed by an aging population and the prevalence of chronic diseases. For this reason, pervasive healthcare, i.e., the provision of healthcare services to individuals anytime anywhere, has become a major focus for the research community. In this paper, we map out the current state of pervasive healthcare research by presenting an overview of three emerging areas in personalized health monitoring, namely: 1) mobile phone sensing via in-built or external sensors, 2) self-reporting for manually captured health information, such as symptoms and behaviors, and 3) social sharing of health information within the individual's community. Systems deployed in a real-life setting as well as proofs-of-concept for achieving pervasive health are presented, in order to identify shortcomings and increase our understanding of the requirements for the next generation of pervasive healthcare systems addressing these three areas. PMID- 26441433 TI - Nonsmooth Finite-Time Synchronization of Switched Coupled Neural Networks. AB - This paper is concerned with the finite-time synchronization (FTS) issue of switched coupled neural networks with discontinuous or continuous activations. Based on the framework of nonsmooth analysis, some discontinuous or continuous controllers are designed to force the coupled networks to synchronize to an isolated neural network. Some sufficient conditions are derived to ensure the FTS by utilizing the well-known finite-time stability theorem for nonlinear systems. Compared with the previous literatures, such synchronization objective will be realized when the activations and the controllers are both discontinuous. The obtained results in this paper include and extend the earlier works on the synchronization issue of coupled networks with Lipschitz continuous conditions. Moreover, an upper bound of the settling time for synchronization is estimated. Finally, numerical simulations are given to demonstrate the effectiveness of the theoretical results. PMID- 26441434 TI - A Hybrid Approach to Clustering in Big Data. AB - Clustering of big data has received much attention recently. In this paper, we present a new clusiVAT algorithm and compare it with four other popular data clustering algorithms. Three of the four comparison methods are based on the well known, classical batch k -means model. Specifically, we use k -means, single pass k -means, online k -means, and clustering using representatives (CURE) for numerical comparisons. clusiVAT is based on sampling the data, imaging the reordered distance matrix to estimate the number of clusters in the data visually, clustering the samples using a relative of single linkage (SL), and then noniteratively extending the labels to the rest of the data-set using the nearest prototype rule. Previous work has established that clusiVAT produces true SL clusters in compact-separated data. We have performed experiments to show that k -means and its modified algorithms suffer from initialization issues that cause many failures. On the other hand, clusiVAT needs no initialization, and almost always finds partitions that accurately match ground truth labels in labeled data. CURE also finds SL type partitions but is much slower than the other four algorithms. In our experiments, clusiVAT proves to be the fastest and most accurate of the five algorithms; e.g., it recovers 97% of the ground truth labels in the real world KDD-99 cup data (4 292 637 samples in 41 dimensions) in 76 s. PMID- 26441435 TI - Discriminative Tracking Using Tensor Pooling. AB - How to effectively organize local descriptors to build a global representation has a critical impact on the performance of vision tasks. Recently, local sparse representation has been successfully applied to visual tracking, owing to its discriminative nature and robustness against local noise and partial occlusions. Local sparse codes computed with a template actually form a three-order tensor according to their original layout, although most existing pooling operators convert the codes to a vector by concatenating or computing statistics on them. We argue that, compared to pooling vectors, the tensor form could deliver more intrinsic structural information for the target appearance, and can also avoid high dimensionality learning problems suffered in concatenation-based pooling methods. Therefore, in this paper, we propose to represent target templates and candidates directly with sparse coding tensors, and build the appearance model by incrementally learning on these tensors. We propose a discriminative framework to further improve robustness of our method against drifting and environmental noise. Experiments on a recent comprehensive benchmark indicate that our method performs better than state-of-the-art trackers. PMID- 26441436 TI - Detection-Free Multiobject Tracking by Reconfigurable Inference With Bundle Representations. AB - This paper presents a conceptually simple but effective approach to track multiobject in videos without requiring elaborate supervision (i.e., training object detectors or templates offline). Our framework performs a bi-layer inference of spatio-temporal grouping to exploit rich appearance and motion information in the observed sequence. First, we generate a robust middle-level video representation based on clustered point tracks, namely video bundles. Each bundle encapsulates a chunk of point tracks satisfying both spatial proximity and temporal coherency. Taking the video bundles as vertices, we build a spatio temporal graph that incorporates both competitive and compatible relations among vertices. The multiobject tracking can be then phrased as a graph partition problem under the Bayesian framework, and we solve it by developing a reconfigurable belief propagation (BP) algorithm. This algorithm improves the traditional BP method by allowing a converged solution to be reconfigured during optimization, so that the inference can be reactivated once it gets stuck in local minima and thus conduct more reliable results. In the experiments, we demonstrate the superior performances of our approach on the challenging benchmarks compared with other state-of-the-art methods. PMID- 26441437 TI - Adaptive and Energy Efficient Walking in a Hexapod Robot Under Neuromechanical Control and Sensorimotor Learning. AB - The control of multilegged animal walking is a neuromechanical process, and to achieve this in an adaptive and energy efficient way is a difficult and challenging problem. This is due to the fact that this process needs in real time: 1) to coordinate very many degrees of freedom of jointed legs; 2) to generate the proper leg stiffness (i.e., compliance); and 3) to determine joint angles that give rise to particular positions at the endpoints of the legs. To tackle this problem for a robotic application, here we present a neuromechanical controller coupled with sensorimotor learning. The controller consists of a modular neural network for coordinating 18 joints and several virtual agonist antagonist muscle mechanisms (VAAMs) for variable compliant joint motions. In addition, sensorimotor learning, including forward models and dual-rate learning processes, is introduced for predicting foot force feedback and for online tuning the VAAMs' stiffness parameters. The control and learning mechanisms enable the hexapod robot advanced mobility sensor driven-walking device (AMOS) to achieve variable compliant walking that accommodates different gaits and surfaces. As a consequence, AMOS can perform more energy efficient walking, compared to other small legged robots. In addition, this paper also shows that the tight combination of neural control with tunable muscle-like functions, guided by sensory feedback and coupled with sensorimotor learning, is a way forward to better understand and solve adaptive coordination problems in multilegged locomotion. PMID- 26441438 TI - Methods for Improving the Curvature of Steerable Needles in Biological Tissue. AB - OBJECTIVE: Robotic needle steering systems have the potential to improve percutaneous interventions such as radiofrequency ablation of liver tumors, but steering techniques described to date have not achieved sufficiently small radius of curvature in biological tissue to be relevant to this application. In this study, the impact of tip geometry on steerable needle curvature was examined. METHODS: Finite-element simulations and experiments with bent-tip needles in ex vivo liver tissue were performed. Motivated by the results of this analysis, a new articulated-tip steerable needle was designed, in which a distal section is actively switched by a robotic system between a straight tip (resulting in a straight path) and a bent tip (resulting in a curved path). RESULTS: Selection of tip length and angle can greatly improve curvature, with radius of curvature below 5 cm in liver tissue possible through judicious selection of these parameters. An articulated-tip mechanism allows the tip length and angle to be increased, while the straight configuration allows the needle tip to still pass through an introducer sheath and rotate inside the body. CONCLUSION: Validation testing in liver tissue shows that the new articulated-tip steerable needle achieves smaller radius of curvature compared to bent-tip needles described in previous work. SIGNIFICANCE: Steerable needles with optimized tip parameters, which can generate tight curves in liver tissue, increase the clinical relevance of needle steering to percutaneous interventions. PMID- 26441439 TI - A Motion Interference-Insensitive Flexible Dry Electrode. AB - OBJECTIVE: A novel dry electrode is developed to improve the comfortability and the capability of alleviating motion interference by combining microneedles array (MNA) with flexible substrate. METHODS: Silicon MNA with sharp tips and limited height is fabricated and transferred on a flexible Polydimethylsiloxane (PDMS) substrate through bonding. Poly (3, 4-ethylenedioxythiophene) doped with poly (styrenesulfonate) (PEDOT/PSS) is coated on the surface of flexible MNA to form a conductive layer. RESULTS: Flexible dry electrode with 1.2 cm diameter is successfully fabricated. The mean impedance magnitudes (measured on skin) at 10 Hz are 61.2 +/-31.3 kOmega.cm(2) for flexible dry electrode, while the values are 114.9 +/-36.1 kOmega.cm(2) for wet electrode and 335.7 +/-110.5 kOmega.cm(2) for flexible planar dry electrode, respectively. In the process of biopotential recording, the flexible dry electrode has the similar performance as that of wet electrode. It exhibits more stable recording stability than rigid dry electrode in the movement state. CONCLUSION: By integrating flexible PDMS substrate, sharp and hard MNA structure, as well as PEDOT/PSS coated surface together, a novel dry electrode is developed to meet the comfortable and antimotion interference requirement of wearable equipment. SIGNIFICANCE: The novel flexible dry electrode provides a simple and comfortable method to record biopotential signals in daily life. PMID- 26441440 TI - Comparison of Auditory Middle-Latency Responses From Two Deconvolution Methods at 40 Hz. AB - GOAL: Auditory middle-latency responses (MLRs) are reported to be particularly susceptible to stimulation rate. Deconvolution methods are necessary to unwrap the overlapping responses at a high rate under the linear superposition assumption. This study aims to investigate and compare the MLR characteristics at high and conventional stimulation rates. METHODS: The characteristics were examined in healthy adults by using two closely related deconvolution paradigms, namely continuous-loop averaging deconvolution and multirate steady-state averaging deconvolution at a mean rate of 40 Hz, and a conventional low rate of 5 Hz. RESULTS: The morphology and stability of the MLRs can benefit from a high rate stimulation. It appears that stimulation sequencing strategies of deconvolution methods exerted divergent rate effects on MLR characteristics, which might be associated with different adaptation mechanisms. CONCLUSION: MLRs obtained by two deconvolution methods and the conventional reference feature differently from one another. SIGNIFICANCE: These findings have critical implications in our current understanding of the rate effects on MLR characteristics which may inspire further studies to explore the characteristics of evoked responses at high rates and deconvolution paradigms. PMID- 26441441 TI - Spiking Neural Network With Distributed Plasticity Reproduces Cerebellar Learning in Eye Blink Conditioning Paradigms. AB - GOAL: In this study, we defined a realistic cerebellar model through the use of artificial spiking neural networks, testing it in computational simulations that reproduce associative motor tasks in multiple sessions of acquisition and extinction. METHODS: By evolutionary algorithms, we tuned the cerebellar microcircuit to find out the near-optimal plasticity mechanism parameters that better reproduced human-like behavior in eye blink classical conditioning, one of the most extensively studied paradigms related to the cerebellum. We used two models: one with only the cortical plasticity and another including two additional plasticity sites at nuclear level. RESULTS: First, both spiking cerebellar models were able to well reproduce the real human behaviors, in terms of both "timing" and "amplitude", expressing rapid acquisition, stable late acquisition, rapid extinction, and faster reacquisition of an associative motor task. Even though the model with only the cortical plasticity site showed good learning capabilities, the model with distributed plasticity produced faster and more stable acquisition of conditioned responses in the reacquisition phase. This behavior is explained by the effect of the nuclear plasticities, which have slow dynamics and can express memory consolidation and saving. CONCLUSIONS: We showed how the spiking dynamics of multiple interactive neural mechanisms implicitly drive multiple essential components of complex learning processes. SIGNIFICANCE: This study presents a very advanced computational model, developed together by biomedical engineers, computer scientists, and neuroscientists. Since its realistic features, the proposed model can provide confirmations and suggestions about neurophysiological and pathological hypotheses and can be used in challenging clinical applications. PMID- 26441442 TI - MAPS: A Quantitative Radiomics Approach for Prostate Cancer Detection. AB - This paper presents a quantitative radiomics feature model for performing prostate cancer detection using multiparametric MRI (mpMRI). It incorporates a novel tumor candidate identification algorithm to efficiently and thoroughly identify the regions of concern and constructs a comprehensive radiomics feature model to detect tumorous regions. In contrast to conventional automated classification schemes, this radiomics-based feature model aims to ground its decisions in a way that can be interpreted and understood by the diagnostician. This is done by grouping features into high-level feature categories which are already used by radiologists to diagnose prostate cancer: Morphology, Asymmetry, Physiology, and Size (MAPS), using biomarkers inspired by the PI-RADS guidelines for performing structured reporting on prostate MRI. Clinical mpMRI data were collected from 13 men with histology-confirmed prostate cancer and labeled by an experienced radiologist. These annotated data were used to train classifiers using the proposed radiomics-driven feature model in order to evaluate the classification performance. The preliminary experimental results indicated that the proposed model outperformed each of its constituent feature groups as well as a comparable conventional mpMRI feature model. A further validation of the proposed algorithm will be conducted using a larger dataset as future work. PMID- 26441443 TI - A New Feature-Enhanced Speckle Reduction Method Based on Multiscale Analysis for Ultrasound B-Mode Imaging. AB - GOAL: Effective speckle reduction in ultrasound B-mode imaging is important for enhancing the image quality and improving the accuracy in image analysis and interpretation. In this paper, a new feature-enhanced speckle reduction (FESR) method based on multiscale analysis and feature enhancement filtering is proposed for ultrasound B-mode imaging. In FESR, clinical features (e.g., boundaries and borders of lesions) are selectively emphasized by edge, coherence, and contrast enhancement filtering from fine to coarse scales while simultaneously suppressing speckle development via robust diffusion filtering. In the simulation study, the proposed FESR method showed statistically significant improvements in edge preservation, mean structure similarity, speckle signal-to-noise ratio, and contrast-to-noise ratio (CNR) compared with other speckle reduction methods, e.g., oriented speckle reducing anisotropic diffusion (OSRAD), nonlinear multiscale wavelet diffusion (NMWD), the Laplacian pyramid-based nonlinear diffusion and shock filter (LPNDSF), and the Bayesian nonlocal means filter (OBNLM). Similarly, the FESR method outperformed the OSRAD, NMWD, LPNDSF, and OBNLM methods in terms of CNR, i.e., 10.70 +/- 0.06 versus 9.00 +/- 0.06, 9.78 +/ 0.06, 8.67 +/- 0.04, and 9.22 +/- 0.06 in the phantom study, respectively. Reconstructed B-mode images that were developed using the five speckle reduction methods were reviewed by three radiologists for evaluation based on each radiologist's diagnostic preferences. All three radiologists showed a significant preference for the abdominal liver images obtained using the FESR methods in terms of conspicuity, margin sharpness, artificiality, and contrast, p<0.0001. For the kidney and thyroid images, the FESR method showed similar improvement over other methods. However, the FESR method did not show statistically significant improvement compared with the OBNLM method in margin sharpness for the kidney and thyroid images. These results demonstrate that the proposed FESR method can improve the image quality of ultrasound B-mode imaging by enhancing the visualization of lesion features while effectively suppressing speckle noise. PMID- 26441444 TI - Distributed Multi-Target Tracking and Data Association in Vision Networks. AB - Distributed algorithms have recently gained immense popularity. With regards to computer vision applications, distributed multi-target tracking in a camera network is a fundamental problem. The goal is for all cameras to have accurate state estimates for all targets. Distributed estimation algorithms work by exchanging information between sensors that are communication neighbors. Vision based distributed multi-target state estimation has at least two characteristics that distinguishes it from other applications. First, cameras are directional sensors and often neighboring sensors may not be sensing the same targets, i.e., they are naive with respect to that target. Second, in the presence of clutter and multiple targets, each camera must solve a data association problem. This paper presents an information-weighted, consensus-based, distributed multi-target tracking algorithm referred to as the Multi-target Information Consensus (MTIC) algorithm that is designed to address both the naivety and the data association problems. It converges to the centralized minimum mean square error estimate. The proposed MTIC algorithm and its extensions to non-linear camera models, termed as the Extended MTIC (EMTIC), are robust to false measurements and limited resources like power, bandwidth and the real-time operational requirements. Simulation and experimental analysis are provided to support the theoretical results. PMID- 26441445 TI - Approximate Fisher Kernels of Non-iid Image Models for Image Categorization. AB - The bag-of-words (BoW) model treats images as sets of local descriptors and represents them by visual word histograms. The Fisher vector (FV) representation extends BoW, by considering the first and second order statistics of local descriptors. In both representations local descriptors are assumed to be identically and independently distributed (iid), which is a poor assumption from a modeling perspective. It has been experimentally observed that the performance of BoW and FV representations can be improved by employing discounting transformations such as power normalization. In this paper, we introduce non-iid models by treating the model parameters as latent variables which are integrated out, rendering all local regions dependent. Using the Fisher kernel principle we encode an image by the gradient of the data log-likelihood w.r.t. the model hyper parameters. Our models naturally generate discounting effects in the representations; suggesting that such transformations have proven successful because they closely correspond to the representations obtained for non-iid models. To enable tractable computation, we rely on variational free-energy bounds to learn the hyper-parameters and to compute approximate Fisher kernels. Our experimental evaluation results validate that our models lead to performance improvements comparable to using power normalization, as employed in state-of-the art feature aggregation methods. PMID- 26441446 TI - Towards Personalized Statistical Deformable Model and Hybrid Point Matching for Robust MR-TRUS Registration. AB - Registration and fusion of magnetic resonance (MR) and 3D transrectal ultrasound (TRUS) images of the prostate gland can provide high-quality guidance for prostate interventions. However, accurate MR-TRUS registration remains a challenging task, due to the great intensity variation between two modalities, the lack of intrinsic fiducials within the prostate, the large gland deformation caused by the TRUS probe insertion, and distinctive biomechanical properties in patients and prostate zones. To address these challenges, a personalized model-to surface registration approach is proposed in this study. The main contributions of this paper can be threefold. First, a new personalized statistical deformable model (PSDM) is proposed with the finite element analysis and the patient specific tissue parameters measured from the ultrasound elastography. Second, a hybrid point matching method is developed by introducing the modality independent neighborhood descriptor (MIND) to weight the Euclidean distance between points to establish reliable surface point correspondence. Third, the hybrid point matching is further guided by the PSDM for more physically plausible deformation estimation. Eighteen sets of patient data are included to test the efficacy of the proposed method. The experimental results demonstrate that our approach provides more accurate and robust MR-TRUS registration than state-of-the-art methods do. The averaged target registration error is 1.44 mm, which meets the clinical requirement of 1.9 mm for the accurate tumor volume detection. It can be concluded that the presented method can effectively fuse the heterogeneous image information in the elastography, MR, and TRUS to attain satisfactory image alignment performance. PMID- 26441447 TI - Video Compression Artifact Reduction via Spatio-Temporal Multi-Hypothesis Prediction. AB - Annoying compression artifacts exist in most of lossy coded videos at low bit rates, which are caused by coarse quantization of transform coefficients or motion compensation from distorted frames. In this paper, we propose a compression artifact reduction approach that utilizes both the spatial and the temporal correlation to form multi-hypothesis predictions from spatio-temporal similar blocks. For each transform block, three predictions with their reliabilities are estimated, respectively. The first prediction is constructed by inversely quantizing transform coefficients directly, and its reliability is determined by the variance of quantization noise. The second prediction is derived by representing each transform block with a temporal auto-regressive (TAR) model along its motion trajectory, and its corresponding reliability is estimated from local prediction errors of the TAR model. The last prediction infers the original coefficients from similar blocks in non-local regions, and its reliability is estimated based on the distribution of coefficients in these similar blocks. Finally, all the predictions are adaptively fused according to their reliabilities to restore high-quality videos. The experimental results show that the proposed method can efficiently reduce most of the compression artifacts and improve both subjective and objective quality of block transform coded videos. PMID- 26441448 TI - Normalized cut-based saliency detection by adaptive multi-level region merging. AB - Existing salient object detection models favor over-segmented regions upon which saliency is computed. Such local regions are less effective on representing object holistically and degrade emphasis of entire salient objects. As a result, the existing methods often fail to highlight an entire object in complex background. Toward better grouping of objects and background, in this paper, we consider graph cut, more specifically, the normalized graph cut (Ncut) for saliency detection. Since the Ncut partitions a graph in a normalized energy minimization fashion, resulting eigenvectors of the Ncut contain good cluster information that may group visual contents. Motivated by this, we directly induce saliency maps via eigenvectors of the Ncut, contributing to accurate saliency estimation of visual clusters. We implement the Ncut on a graph derived from a moderate number of superpixels. This graph captures both intrinsic color and edge information of image data. Starting from the superpixels, an adaptive multi-level region merging scheme is employed to seek such cluster information from Ncut eigenvectors. With developed saliency measures for each merged region, encouraging performance is obtained after across-level integration. Experiments by comparing with 13 existing methods on four benchmark datasets, including MSRA 1000, SOD, SED, and CSSD show the proposed method, Ncut saliency, results in uniform object enhancement and achieves comparable/better performance to the state-of-the-art methods. PMID- 26441449 TI - Beyond Explicit Codebook Generation: Visual Representation Using Implicitly Transferred Codebooks. AB - The bag-of-visual-words model plays a very important role for visual applications. Local features are first extracted and then encoded to get the histogram-based image representation. To encode local features, a proper codebook is needed. Usually, the codebook has to be generated for each data set which means the codebook is data set dependent. Besides, the codebook may be biased when we only have a limited number of training images. Moreover, the codebook has to be pre-learned which cannot be updated quickly, especially when applied for online visual applications. To solve the problems mentioned above, in this paper, we propose a novel implicit codebook transfer method for visual representation. Instead of explicitly generating the codebook for the new data set, we try to make use of pre-learned codebooks using non-linear transfer. This is achieved by transferring the pre-learned codebooks with non-linear transformation and use them to reconstruct local features with sparsity constraints. The codebook does not need to be explicitly generated but can be implicitly transferred. In this way, we are able to make use of pre-learned codebooks for new visual applications by implicitly learning the codebook and the corresponding encoding parameters for image representation. We apply the proposed method for image classification and evaluate the performance on several public image data sets. Experimental results demonstrate the effectiveness and efficiency of the proposed method. PMID- 26441450 TI - Feature Surfaces in Symmetric Tensor Fields Based on Eigenvalue Manifold. AB - Three-dimensional symmetric tensor fields have a wide range of applications in solid and fluid mechanics. Recent advances in the (topological) analysis of 3D symmetric tensor fields focus on degenerate tensors which form curves. In this paper, we introduce a number of feature surfaces, such as neutral surfaces and traceless surfaces, into tensor field analysis, based on the notion of eigenvalue manifold. Neutral surfaces are the boundary between linear tensors and planar tensors, and the traceless surfaces are the boundary between tensors of positive traces and those of negative traces. Degenerate curves, neutral surfaces, and traceless surfaces together form a partition of the eigenvalue manifold, which provides a more complete tensor field analysis than degenerate curves alone. We also extract and visualize the isosurfaces of tensor modes, tensor isotropy, and tensor magnitude, which we have found useful for domain applications in fluid and solid mechanics. Extracting neutral and traceless surfaces using the Marching Tetrahedra method can cause the loss of geometric and topological details, which can lead to false physical interpretation. To robustly extract neutral surfaces and traceless surfaces, we develop a polynomial description of them which enables us to borrow techniques from algebraic surface extraction, a topic well researched by the computer-aided design (CAD) community as well as the algebraic geometry community. In addition, we adapt the surface extraction technique, called A-patches, to improve the speed of finding degenerate curves. Finally, we apply our analysis to data from solid and fluid mechanics as well as scalar field analysis. PMID- 26441451 TI - Detecting Multivariate Gene Interactions in RNA-Seq Data Using Optimal Bayesian Classification. AB - Differential gene expression testing is an analysis commonly applied to RNA-Seq data. These statistical tests identify genes that are significantly different across phenotypes. We extend this testing paradigm to multivariate gene interactions from a classification perspective with the goal to detect novel gene interactions for the phenotypes of interest. This is achieved through our novel computational framework comprised of a hierarchical statistical model of the RNA Seq processing pipeline and the corresponding optimal Bayesian classifier. Through Markov Chain Monte Carlo sampling and Monte Carlo integration, we compute quantities where no analytical formulation exists. The performance is then illustrated on an expression dataset from a dietary intervention study where we identify gene pairs that have low classification error yet were not identified as differentially expressed. Additionally, we have released the software package to perform OBC classification on RNA-Seq data under an open source license and is available at http://bit.ly/obc_package. PMID- 26441452 TI - Robust Multiobjective Controllability of Complex Neuronal Networks. AB - This paper addresses robust multiobjective identification of driver nodes in the neuronal network of a cat's brain, in which uncertainties in determination of driver nodes and control gains are considered. A framework for robust multiobjective controllability is proposed by introducing interval uncertainties and optimization algorithms. By appropriate definitions of robust multiobjective controllability, a robust nondominated sorting adaptive differential evolution (NSJaDE) is presented by means of the nondominated sorting mechanism and the adaptive differential evolution (JaDE). The simulation experimental results illustrate the satisfactory performance of NSJaDE for robust multiobjective controllability, in comparison with six statistical methods and two multiobjective evolutionary algorithms (MOEAs): nondominated sorting genetic algorithms II (NSGA-II) and nondominated sorting composite differential evolution. It is revealed that the existence of uncertainties in choosing driver nodes and designing control gains heavily affects the controllability of neuronal networks. We also unveil that driver nodes play a more drastic role than control gains in robust controllability. The developed NSJaDE and obtained results will shed light on the understanding of robustness in controlling realistic complex networks such as transportation networks, power grid networks, biological networks, etc. PMID- 26441453 TI - The Effects of Fluidic Loading on Underwater Contact Sensing with Robotic Fins and Beams. AB - As robots become more involved in underwater operations, understanding underwater contact sensing with compliant systems is fundamental to engineering useful haptic interfaces and vehicles. Despite knowledge of contact sensation in air, little is known about contact sensing underwater and the impact of fluid on both the robotic probe and the target object. The objective of this work is to understand the effects of fluidic loading, fin webbing, and target object geometry on strain sensation within compliant robotic fins and beams during obstacle contact. General descriptions of obstacle contact were sought for strain measurements in fins and beams. Multiple phases of contact were characterized where the robot, fluid, and object interact to affect sensory signals. Unlike in air, the underwater structure-fluid-structure interaction (SFSI) caused changes to strain in each phase of contact. The addition of webbing to beams created a mechanical coupling between adjacent beams, which changed contact strains. Complex obstacle geometries tended to make contact less apparent and caused stretch in fins. This work demonstrates several effects of fluidic loading on strain sensing with compliant robotic beams and fins as they contact obstacles in air and underwater, and provides guidance for future work in underwater active sensing with compliant manipulators. PMID- 26441455 TI - Space Structure and Clustering of Categorical Data. AB - Learning from categorical data plays a fundamental role in such areas as pattern recognition, machine learning, data mining, and knowledge discovery. To effectively discover the group structure inherent in a set of categorical objects, many categorical clustering algorithms have been developed in the literature, among which k -modes-type algorithms are very representative because of their good performance. Nevertheless, there is still much room for improving their clustering performance in comparison with the clustering algorithms for the numeric data. This may arise from the fact that the categorical data lack a clear space structure as that of the numeric data. To address this issue, we propose, in this paper, a novel data-representation scheme for the categorical data, which maps a set of categorical objects into a Euclidean space. Based on the data representation scheme, a general framework for space structure based categorical clustering algorithms (SBC) is designed. This framework together with the applications of two kinds of dissimilarities leads two versions of the SBC-type algorithms. To verify the performance of the SBC-type algorithms, we employ as references four representative algorithms of the k -modes-type algorithms. Experiments show that the proposed SBC-type algorithms significantly outperform the k -modes-type algorithms. PMID- 26441454 TI - Design and Evaluation of a Cable-Driven fMRI-Compatible Haptic Interface to Investigate Precision Grip Control. AB - Our hands and fingers are involved in almost all activities of daily living and, as such, have a disproportionately large neural representation. Functional magnetic resonance imaging investigations into the neural control of the hand have revealed great advances, but the harsh MRI environment has proven to be a challenge to devices capable of delivering a large variety of stimuli necessary for well-controlled studies. This paper presents a fMRI-compatible haptic interface to investigate the neural mechanisms underlying precision grasp control. The interface, located at the scanner bore, is controlled remotely through a shielded electromagnetic actuation system positioned at the end of the scanner bed and then through a high stiffness, low inertia cable transmission. We present the system design, taking into account requirements defined by the biomechanics and dynamics of the human hand, as well as the fMRI environment. Performance evaluation revealed a structural stiffness of 3.3 N/mm, renderable forces up to 94 N, and a position control bandwidth of at least 19 Hz. MRI compatibility tests showed no degradation in the operation of the haptic interface or the image quality. A preliminary fMRI experiment during a pilot study validated the usability of the haptic interface, illustrating the possibilities offered by this device. PMID- 26441456 TI - MSDLSR: Margin Scalable Discriminative Least Squares Regression for Multicategory Classification. AB - In this brief, we propose a new margin scalable discriminative least squares regression (MSDLSR) model for multicategory classification. The main motivation behind the MSDLSR is to explicitly control the margin of DLSR model. We first prove that the DLSR is a relaxation of the traditional L2 -support vector machine. Based on this fact, we further provide a theorem on the margin of DLSR. With this theorem, we add an explicit constraint on DLSR to restrict the number of zeros of dragging values, so as to control the margin of DLSR. The new model is called MSDLSR. Theoretically, we analyze the determination of the margin and support vectors of MSDLSR. Extensive experiments illustrate that our method outperforms the current state-of-the-art approaches on various machine leaning and real-world data sets. PMID- 26441457 TI - Robust Optimization-Based Coronary Artery Labeling From X-Ray Angiograms. AB - In this paper, we present an efficient robust labeling method for coronary arteries from X-ray angiograms based on energy optimization. The fundamental goal of this research is to facilitate the analysis and diagnosis of interventional surgery in the most efficient way, and such effort could also improve the performance during doctor training, and surgery simulation and planning. Compared to the prior state-of-the-art, our method is much more robust to resist noises and is tolerant to even incomplete data because of the "built-in" nature of global optimization. We start with a fully parallelized algorithm based on Hessian matrix to extract the tubular structure from the X-ray angiograms as vessel candidates. Then, instead of using the candidates directly, we use the grow cut (Vezhnevets and V. Konouchine, Growcut: Interactive multi-label N-D image segmentation by cellular automata, in Proc. of Graphicon, 2005, pp. 150 156.) method, which is similar to graph cut (Boykov et al. , Fast approximate energy minimization via graph cuts, IEEE Trans. Pattern Anal. Mach. Intell. , vol. 23, no. 11, pp. 1222-1239, Nov. 2001.)but with better performance to extract the precise vessel structure from the images. Next, we use the fast marching method with second derivatives and cross neighbors to extract the accurate skeleton segments. After that, we propose an efficient method based on iterative closest point (Z. Zhang, Iterative point matching for registration of free-form curves and surfaces, Int J. Comput. Vis., vol. 13, no. 2, pp. 119-152, 1994.) to organize the skeleton segments by treating the continuity and similarity as extra constraints. Finally, we formulate the vessel labeling problem as an energy optimization problem and solve it using belief propagation. We also demonstrate several typical applications including flow velocity estimation, heart beat estimation, and vessel diameter estimation to show its practical uses in clinical diagnosis and treatment. Our experiments exhibit the correctness and robustness, as well as the high performance of our algorithm. We envision that our system would be of high utility for diagnosis and therapy to treat vessel-related diseases in a clinical setting in the near future. PMID- 26441458 TI - Structure Sensitive Hashing With Adaptive Product Quantization. AB - Hashing has been proved as an attractive solution to approximate nearest neighbor search, owing to its theoretical guarantee and computational efficiency. Though most of prior hashing algorithms can achieve low memory and computation consumption by pursuing compact hash codes, however, they are still far beyond the capability of learning discriminative hash functions from the data with complex inherent structure among them. To address this issue, in this paper, we propose a structure sensitive hashing based on cluster prototypes, which explicitly exploits both global and local structures. An alternating optimization algorithm, respectively, minimizing the quantization loss and spectral embedding loss, is presented to simultaneously discover the cluster prototypes for each hash function, and optimally assign unique binary codes to them satisfying the affinity alignment between them. For hash codes of a desired length, an adaptive bit assignment is further appended to the product quantization of the subspaces, approximating the Hamming distances and meanwhile balancing the variance among hash functions. Experimental results on four large-scale benchmarks CIFAR-10, NUS WIDE, SIFT1M, and GIST1M demonstrate that our approach significantly outperforms state-of-the-art hashing methods in terms of semantic and metric neighbor search. PMID- 26441459 TI - Hierarchical Model Predictive Image-Based Visual Servoing of Underwater Vehicles With Adaptive Neural Network Dynamic Control. AB - This paper proposes a hierarchical image-based visual servoing (IBVS) strategy for dynamic positioning of a fully actuated underwater vehicle. In the kinematic loop, the desired velocity is generated by a nonlinear model predictive controller, which optimizes a cost function of the predicted image trajectories under the constraints of visibility and velocity. A velocity reference model, representing the desired closed-loop vehicle dynamics, is integrated with an IBVS kinematic model to predict the future trajectories. In the dynamic velocity tracking loop, a neural-network-based model reference adaptive controller is designed to ensure the convergence of the velocity tracking error in the presence of uncertainties associated with vehicle dynamic parameters, water velocity, and thrust forces. Comparative simulations with different control and system configurations are performed to verify the effectiveness of the proposed scheme and to illustrate the influences of the prediction horizon, cost function, closed loop vehicle dynamics, and predictive velocity reference model on the IBVS system performance. PMID- 26441460 TI - Formation Control With Size Scaling Via a Complex Laplacian-Based Approach. AB - We consider the control of formations of a leader-follower network, where the objective is to steer a team of multiple mobile agents into a formation of variable size. We assume that the shape description of the formation is known to all the agents, which is captured by a complex-valued Laplacian associated with the sensing graph, but the size scaling of the formation is not known or only known to two agents, called the leaders in the network. A distributed linear control strategy is developed in this paper such that the agents converge to the desired formation shape, for which the size of the formation is determined by the two leaders. Moreover, in order to make all agents in a formation move with a common velocity, the distributed control law also incorporates a velocity consensus component, which is implemented with the help of a communication network that may, in general, be of different topology from the sensing graph. Both the setup of single-integrator kinematics and the one of double-integrator dynamics are addressed in the same framework except that the acceleration control in the double-integrator setup has an extra damping term. PMID- 26441461 TI - Vision-Based Human Tracking Control of a Wheeled Inverted Pendulum Robot. AB - In this paper, a vision-based adaptive control is designed for a wheeled inverted pendulum (WIP) robot to track a moving human target by integration of multisensor data. A new algorithm is employed in the system to combine an OptiTrack camera and a Kinect camera, such that more robust and efficient performance can be achieved for human target detection and tracking. Robust adaptive control has been developed for the WIP robot to maintain its balance on two wheels and to follow the human target using visual feedback. Leader-follower control, dynamic balance control and visual tracking are efficiently combined together to achieved desired tracking and balancing performance. Extensive experiment studies have been performed to test the effectiveness of the proposed control strategies. PMID- 26441462 TI - Road Risk Modeling and Cloud-Aided Safety-Based Route Planning. AB - This paper presents a safety-based route planner that exploits vehicle-to-cloud to-vehicle (V2C2V) connectivity. Time and road risk index (RRI) are considered as metrics to be balanced based on user preference. To evaluate road segment risk, a road and accident database from the highway safety information system is mined with a hybrid neural network model to predict RRI. Real-time factors such as time of day, day of the week, and weather are included as correction factors to the static RRI prediction. With real-time RRI and expected travel time, route planning is formulated as a multiobjective network flow problem and further reduced to a mixed-integer programming problem. A V2C2V implementation of our safety-based route planning approach is proposed to facilitate access to real time information and computing resources. A real-world case study, route planning through the city of Columbus, Ohio, is presented. Several scenarios illustrate how the "best" route can be adjusted to favor time versus safety metrics. PMID- 26441463 TI - An Event-Triggered Approach to State Estimation for a Class of Complex Networks With Mixed Time Delays and Nonlinearities. AB - In this paper, the state estimation problem is investigated for a class of discrete-time complex networks subject to nonlinearities, mixed delays, and stochastic noises. A set of event-based state estimators is constructed so as to reduce unnecessary data transmissions in the communication channel. Compared with the traditional state estimator whose measurement signal is received under a periodic clock-driven rule, the event-based estimator only updates the measurement information from the sensors when the prespecified "event" is violated. Attention is focused on the analysis and design problem of the event based estimators for the addressed discrete-time complex networks such that the estimation error is exponentially bounded in mean square. A combination of the stochastic analysis approach and Lyapunov theory is employed to obtain sufficient conditions for ensuring the existence of the desired estimators and the upper bound of the estimation error is also derived. By using the convex optimization technique, the gain parameters of the desired estimators are provided in an explicit form. Finally, a simulation example is used to demonstrate the effectiveness of the proposed estimation strategy. PMID- 26441464 TI - Discontinuous Neural Networks for Finite-Time Solution of Time-Dependent Linear Equations. AB - This paper considers a class of nonsmooth neural networks with discontinuous hard limiter (signum) neuron activations for solving time-dependent (TD) systems of algebraic linear equations (ALEs). The networks are defined by the subdifferential with respect to the state variables of an energy function given by the L 1 norm of the error between the state and the TD-ALE solution. It is shown that when the penalty parameter exceeds a quantitatively estimated threshold the networks are able to reach in finite time, and exactly track thereafter, the target solution of the TD-ALE. Furthermore, this paper discusses the tightness of the estimated threshold and also points out key differences in the role played by this threshold with respect to networks for solving time invariant ALEs. It is also shown that these convergence results are robust with respect to small perturbations of the neuron interconnection matrices. The dynamics of the proposed networks are rigorously studied by using tools from nonsmooth analysis, the concept of subdifferential of convex functions, and that of solutions in the sense of Filippov of dynamical systems with discontinuous nonlinearities. PMID- 26441465 TI - EEG-Based Classification of Implicit Intention During Self-Relevant Sentence Reading. AB - From electroencephalography (EEG) data during self-relevant sentence reading, we were able to discriminate two implicit intentions: 1) "agreement" and 2) "disagreement" to the read sentence. To improve the classification accuracy, discriminant features were selected based on Fisher score among EEG frequency bands and electrodes. Especially, the time-frequency representation with Morlet wavelet transforms showed clear differences in gamma, beta, and alpha band powers at frontocentral area, and theta band power at centroparietal area. The best classification accuracy of 75.5% was obtained by a support vector machine classifier with the gamma band features at frontocentral area. This result may enable a new intelligent user-interface which understands users' implicit intention, i.e., unexpressed or hidden intention. PMID- 26441466 TI - Effects of Social Network Exposure on Nutritional Learning: Development of an Online Educational Platform. AB - BACKGROUND: Social networking sites (SNSs) such as Facebook have the potential to enhance online public health interventions, in part, as they provide social exposure and reinforcement. OBJECTIVE: The objective of the study was to evaluate whether social exposure provided by SNSs enhances the effects of online public health interventions. METHODS: As a sample intervention, we developed Food Hero, an online platform for nutritional education in which players feed a virtual character according to their own nutritional needs and complete a set of virtual sport challenges. The platform was developed in 2 versions: a "private version" in which a user can see only his or her own score, and a "social version" in which a user can see other players' scores, including preexisting Facebook friends. We assessed changes in participants' nutritional knowledge using 4 quiz scores and 3 menu-assembly scores. Monitoring feeding and exercising attempts assessed engagement with the platform. RESULTS: The 2 versions of the platform were randomly assigned between a study group (30 members receiving the social version) and a control group (33 members, private version). The study group's performance on the quizzes gradually increased over time, relative to that of the control group, becoming significantly higher by the fourth quiz (P=.02). Furthermore, the study group's menu-assembly scores improved over time compared to the first score, whereas the control group's performance deteriorated. Study group members spent an average of 3:40 minutes assembling each menu compared to 2:50 minutes in the control group, and performed an average of 1.58 daily sport challenges, compared to 1.21 in the control group (P=.03). CONCLUSIONS: This work focused on isolating the SNSs' social effects in order to help guide future online interventions. Our results indicate that the social exposure provided by SNSs is associated with increased engagement and learning in an online nutritional educational platform. PMID- 26441468 TI - Basal Temperature Measurement Using a Multi-Sensor Armband in Australian Young Women: A Comparative Observational Study. AB - BACKGROUND: The menstrual cycle is a key marker of health in women of reproductive age. Monitoring ovulation is useful in health studies involving young women. The upward shift in basal body temperature, which occurs shortly after ovulation and continues until the next menses, is a potentially useful marker of ovulation, which has been exploited in clinical and research settings. OBJECTIVE: We investigated the utility of BodyMedia SenseWear (BMSW) in monitoring ovulation in young women by analyzing the correlation and agreement of basal temperatures measured using BMSW and a digital oral thermometer. METHODS: Kappa statistics were used to determine the agreement in ovulation detection between the two devices, for each participant, under each form of analysis. Participants also completed an online questionnaire assessing the acceptability of both devices. RESULTS: We recruited 16 participants with 15 of them providing analyzable data (11 OCP non-users, 4 OCP users). Weak to moderate correlations were observed between thermometer and BMSW temperature measurements averaged over 5 different time intervals. However, no agreement between methods was observed using Bland-Altman plots. There was a significant difference in the range of temperatures that each device recorded (thermometer: 35.3-37.2 degrees C, BMSW: 29.7-36.7 degrees C) with BMSW temperatures significantly lower than thermometer temperatures: mean 34.6 degrees C (SD 1.2) versus 36.4 degrees C (SD 0.3) respectively, P<.001. Poor agreement was observed between devices under quantitative analysis of ovulation while fair agreement was observed under visual analysis. Under both quantitative and visual analysis, there was 0% agreement for evidence of ovulation. CONCLUSIONS: This study demonstrated the importance of evaluating biomeasures collected using mobile monitoring devices by comparison with standard methods. It revealed a relatively poor correlation between BMSW and oral thermometer temperature readings and suggested that BMSW is unlikely to detect an upward shift in basal body temperature. Participant behavior suggested poor compliance in the use of BMSW for basal temperature measurement and that the basal body temperature method may not be suitable for use in unselected samples of young women. There is a need for research tools for monitoring ovulation that are simple, self-administered, and inexpensive, yet appealing to young women. PMID- 26441467 TI - Health Coaching Reduces HbA1c in Type 2 Diabetic Patients From a Lower Socioeconomic Status Community: A Randomized Controlled Trial. AB - BACKGROUND: Adoptions of health behaviors are crucial for maintaining good health after type 2 diabetes mellitus (T2DM) diagnoses. However, adherence to glucoregulating behaviors like regular exercise and balanced diet can be challenging, especially for people living in lower-socioeconomic status (SES) communities. Providing cost-effective interventions that improve self-management is important for improving quality of life and the sustainability of health care systems. OBJECTIVE: To evaluate a health coach intervention with and without the use of mobile phones to support health behavior change in patients with type 2 diabetes. METHODS: In this noninferiority, pragmatic randomized controlled trial (RCT), patients from two primary care health centers in Toronto, Canada, with type 2 diabetes and a glycated hemoglobin/hemoglobin A1c (HbA1c) level of >=7.3% (56.3 mmol/mol) were randomized to receive 6 months of health coaching with or without mobile phone monitoring support. We hypothesized that both approaches would result in significant HbA1c reductions, although health coaching with mobile phone monitoring would result in significantly larger effects. Participants were evaluated at baseline, 3 months, and 6 months. The primary outcome was the change in HbA1c from baseline to 6 months (difference between and within groups). Other outcomes included weight, waist circumference, body mass index (BMI), satisfaction with life, depression and anxiety (Hospital Anxiety and Depression Scale [HADS]), positive and negative affect (Positive and Negative Affect Schedule [PANAS]), and quality of life (Short Form Health Survey-12 [SF 12]). RESULTS: A total of 138 patients were randomized and 7 were excluded for a substudy; of the remaining 131, 67 were allocated to the intervention group and 64 to the control group. Primary outcome data were available for 97 participants (74.0%). While both groups reduced their HbA1c levels, there were no significant between-group differences in change of HbA1c at 6 months using intention-to-treat (last observation carried forward [LOCF]) (P=.48) or per-protocol (P=.83) principles. However, the intervention group did achieve an accelerated HbA1c reduction, leading to a significant between-group difference at 3 months (P=.03). This difference was reduced at the 6-month follow-up as the control group continued to improve, achieving a reduction of 0.81% (8.9 mmol/mol) (P=.001) compared with a reduction of 0.84% (9.2 mmol/mol)(P=.001) in the intervention group. Intervention group participants also had significant decreases in weight (P=.006) and waist circumference (P=.01) while controls did not. Both groups reported improvements in mood, satisfaction with life, and quality of life. CONCLUSIONS: Health coaching with and without access to mobile technology appeared to improve glucoregulation and mental health in a lower-SES, T2DM population. The accelerated improvement in the mobile phone group suggests the connectivity provided may more quickly improve adoption and adherence to health behaviors within a clinical diabetes management program. Overall, health coaching in primary care appears to lead to significant benefits for patients from lower SES communities with poorly controlled type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02036892; http://clinicaltrials.gov/ct2/show/NCT02036892 (Archived by WebCite at http://www.webcitation.org/6b3cJYJOD). PMID- 26441469 TI - Current Theories on the Prevention of Severe Preeclampsia With Low-Molecular Weight Heparin. PMID- 26441471 TI - Modeling Localization of Amplitude-Panned Virtual Sources in Sagittal Planes. AB - Vector-base amplitude panning (VBAP) aims at creating virtual sound sources at arbitrary directions within multichannel sound reproduction systems. However, VBAP does not consistently produce listener-specific monaural spectral cues that are essential for localization of sound sources in sagittal planes, including the front-back and up-down dimensions. In order to better understand the limitations of VBAP, a functional model approximating human processing of spectro-spatial information was applied to assess accuracy in sagittal-plane localization of virtual sources created by means of VBAP. First, we evaluated VBAP applied on two loudspeakers in the median plane, and then we investigated the directional dependence of the localization accuracy in several three-dimensional loudspeaker arrangements designed in layers of constant elevation. The model predicted a strong dependence on listeners' individual head-related transfer functions, on virtual source directions, and on loudspeaker arrangements. In general, the simulations showed a systematic degradation with increasing polar-angle span between neighboring loudspeakers. For the design of VBAP systems, predictions suggest that spans up to 40 degrees polar angle yield a good trade-off between system complexity and localization accuracy. Special attention should be paid to the frontal region where listeners are most sensitive to deviating spectral cues. PMID- 26441472 TI - Attracting Views and Going Viral: How Message Features and News-Sharing Channels Affect Health News Diffusion. AB - This study examined how intrinsic as well as perceived message features affect the extent to which online health news stories prompt audience selections and social retransmissions, and how news-sharing channels (e-mail vs. social media) shape what goes viral. The study analyzed actual behavioral data on audience viewing and sharing of New York Times health news articles, and associated article content and context data. News articles with high informational utility and positive sentiment invited more frequent selections and retransmissions. Articles were also more frequently selected when they presented controversial, emotionally evocative, and familiar content. Informational utility and novelty had stronger positive associations with e-mail-specific virality, while emotional evocativeness, content familiarity, and exemplification played a larger role in triggering social media-based retransmissions. PMID- 26441470 TI - Endothelial Mineralocorticoid Receptor Deletion Prevents Diet-Induced Cardiac Diastolic Dysfunction in Females. AB - Overnutrition and insulin resistance are especially prominent risk factors for the development of cardiac diastolic dysfunction in females. We recently reported that consumption of a Western diet (WD) containing excess fat (46%), sucrose (17.5%), and high fructose corn syrup (17.5%) for 16 weeks resulted in cardiac diastolic dysfunction and aortic stiffening in young female mice and that these abnormalities were prevented by mineralocorticoid receptor blockade. Herein, we extend those studies by testing whether WD-induced diastolic dysfunction and factors contributing to diastolic impairment, such as cardiac fibrosis, hypertrophy, inflammation, and impaired insulin signaling, are modulated by excess endothelial cell mineralocorticoid receptor signaling. Four-week-old female endothelial cell mineralocorticoid receptor knockout and wild-type mice were fed mouse chow or WD for 4 months. WD feeding resulted in prolonged relaxation time, impaired diastolic septal wall motion, and increased left ventricular filling pressure indicative of diastolic dysfunction. This occurred in concert with myocardial interstitial fibrosis and cardiomyocyte hypertrophy that were associated with enhanced profibrotic (transforming growth factor beta1/Smad) and progrowth (S6 kinase-1) signaling, as well as myocardial oxidative stress and a proinflammatory immune response. WD also induced cardiomyocyte stiffening, assessed ex vivo using atomic force microscopy. Conversely, endothelial cell mineralocorticoid receptor deficiency prevented WD induced diastolic dysfunction, profibrotic, and progrowth signaling, in conjunction with reductions in macrophage proinflammatory polarization and improvements in insulin metabolic signaling. Therefore, our findings indicate that increased endothelial cell mineralocorticoid receptor signaling associated with consumption of a WD plays a key role in the activation of cardiac profibrotic, inflammatory, and growth pathways that lead to diastolic dysfunction in female mice. PMID- 26441473 TI - The Transition to Adulthood: Life Course Structures and Subjective Perceptions. AB - We examine the relationships between objective life course structures and the subjective sense of timing of adult roles and acquisition of adult identity. Hierarchical latent class analysis is applied to longitudinal data from the Youth Development Study, describing roles related to school, work, family formation, and living arrangements from age 17 to 30. The transition to adulthood in this cohort is well-represented by five pathways probabilistically mapping the timing and sequencing of these roles and their configurations. Three pathways are characterized by a school-to-work transition with on-time, delayed, or negligible family formation. The remaining pathways involve early parenthood with either a partner and stable full-time work or the lack of a partner and low labor force attachment. We then show that the subjective sense of timing with respect to certain adult roles and adult identity acquisition is empirically tied to these life course structures. PMID- 26441474 TI - Practical approaches for evaluating adrenal toxicity in nonclinical safety assessment. AB - The adrenal gland has characteristic morphological and biochemical features that render it particularly susceptible to the actions of xenobiotics. As is the case with other endocrine organs, the adrenal gland is under the control of upstream organs (hypothalamic-pituitary system) in vivo, often making it difficult to elucidate the mode of toxicity of a test article. It is very important, especially for pharmaceuticals, to determine whether a test article-related change is caused by a direct effect or other associated factors. In addition, antemortem data, including clinical signs, body weight, food consumption and clinical pathology, and postmortem data, including gross pathology, organ weight and histopathologic examination of the adrenal glands and other related organs, should be carefully monitored and evaluated. During evaluation, the following should also be taken into account: (1) species, sex and age of animals used, (2) metabolic activation by a cytochrome P450 enzyme(s) and (3) physicochemical properties and the metabolic pathway of the test article. In this review, we describe the following crucial points for toxicologic pathologists to consider when evaluating adrenal toxicity: functional anatomy, blood supply, hormone production in each compartment, steroid biosynthesis, potential medulla-cortex interaction, and species and gender differences in anatomical features and other features of the adrenal gland which could affect vulnerability to toxic effects. Finally practical approaches for evaluating adrenal toxicity in nonclinical safety studies are discussed. PMID- 26441475 TI - Therapeutic antibodies: their mechanisms of action and the pathological findings they induce in toxicity studies. AB - Antibodies can swiftly provide therapeutics to target disease-related molecules discovered in genomic research. Antibody engineering techniques have been actively developed and these technological innovations have intensified the development of therapeutic antibodies. From the mid-1990's, a series of therapeutic antibodies were launched that are now being used in clinic. The disease areas that therapeutic antibodies can target have subsequently expanded, and antibodies are currently utilized as pharmaceuticals for cancer, inflammatory disease, organ transplantation, cardiovascular disease, infection, respiratory disease, ophthalmologic disease, and so on. This paper briefly describes the modes of action of therapeutic antibodies. Several non-clinical study results of the pathological changes induced by therapeutic antibodies are also presented to aid the future assessment of the toxic potential of an antibody developed as a therapeutic. PMID- 26441476 TI - Evaluation of the teratogenic effects of three traditional Chinese medicines, Si Jun Zi Tang, Liu Jun Zi Tang and Shenling Baizhu San, during zebrafish pronephros development. AB - The aim of this study was to evaluate the teratogenic effects of three common Chinese medical prescriptions, Si Jun Zi Tang (SJZT), Liu Jun Zi Tang (LJZT) and Shenling Baizhu San (SLBS), during zebrafish pronephros development. We used the transgenic zebrafish line Tg(wt1b:EGFP) to assess the teratogenic effects using 12 different protocols, which comprised combinations of 4 doses (0, 25, 250, 1,250 ng/mL) and 3 exposure methods [methods I, 12-36 hours post fertilization (hpf), II, 24-48 hpf, and III, 24-36 hpf]. As a result, few defects in the kidneys were observed in the embryos exposed to 25 ng/mL of each medical prescription. The percentage of kidney malformation phenotypes increased as the exposure concentrations increased (25 ng/mL, 0-10%; 250 ng/mL, 0-60%; 1,250 ng/mL, 80-100%). Immunohistochemistry for alpha6F, which is a basolateral and renal tubular differentiation marker, revealed no obvious defective phenotypes in either SJZT- or LJZT-treated embryos, indicating that these Chinese medical prescriptions had minimal adverse effects on the pronephric duct. However, SLBS treated embryos displayed a defective phenotype in the pronephric duct. According to these findings, we suggest (1) that the Chinese medical prescriptions induced kidney malformation phenotypes that are dose dependent and (2) that the embryonic zebrafish kidney was more sensitive to SLBS than SJZT and LJZT. PMID- 26441477 TI - Comparison of changes in urinary and blood levels of biomarkers associated with proximal tubular injury in rat models. AB - To investigate useful biomarkers associated with proximal tubular injury, we assessed changes in levels of a focused set of biomarkers in urine and blood. Male rats administered a single dose or four doses of gentamicin (GM, 240 mg/kg/day) or a single dose of cisplatin (CDDP, 5 mg/kg) were euthanized on days 2 (the day after initial dosing) 5, or 12. At each time point, histopathological examination of the kidney and immunohistochemistry for biomarkers, kidney injury molecule-1 (Kim-1), lipocalin (NGAL), clusterin (CLU), cystatin C (CysC) and beta2-microglobulin (beta2M) were performed. Biomarker levels were measured in urine and blood. In both treatment groups, degenerated/necrotic proximal tubules and regenerated tubules were mainly observed on days 5 and 12, respectively. At the same time as these tubular injuries, urinary Kim-1, CysC and beta2M levels were increased. Moreover, urinary levels of CysC and beta2M in GM-treated animals and Kim-1 in CDDP-treated animals increased (on day 2) prior to tubular injury on day 5. This was considered to reflect the characteristics of drug toxicity. Although almost all of the biomarkers in blood were not sufficiently sensitive to detect proximal tubular injury, urinary and plasma beta2M levels simultaneously increased. Therefore, in addition to urinary Kim-1, CysC and beta2M levels, plasma beta2M levels were also considered useful for detecting proximal tubular injury. PMID- 26441478 TI - Histopathology and oxidative stress analysis of concomitant misoprostol and celecoxib administration. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs), non-selective or selective inhibitors of cyclooxygenase (COX-1 and -2), reduce pain and inflammation associated with arthritic diseases. Celecoxib, a COX-2-selective inhibitor providing decreased gastric injury relative to non-selective NSAIDs, is commonly prescribed. Misoprostol, a prostaglandin analog, supplements NSAID-inhibited prostaglandin levels. As concomitant celecoxib and misoprostol administration has been shown to intensify renal adverse effects, this article examined the influence of concomitant administration on hepatic histopathology, oxidative stress, and celecoxib concentration. On days 1 and 2, rat groups (n = 6) were gavaged twice daily (two groups with vehicle and two groups with 100 MUg/kg misoprostol). From day 3 to day 9, one celecoxib dose (40 mg/kg) replaced a vehicle dose of one group and one group received celecoxib in addition to misoprostol. Livers were harvested on day 10. No hepatic abnormalities were observed denoting a lack of influence by either drug. Also no change in mean biomarker levels was detected. The changes in hepatic celecoxib concentration in the misoprostol-receiving group compared to control were not significant. Thus misoprostol does not influence hepatic celecoxib effects in terms of histopathology, oxidative stress, or celecoxib concentration level at the dosage and duration examined. PMID- 26441479 TI - A spontaneously occurring malignant pituicytoma in a male sprague dawley rat. AB - Pituicytoma is an extremely rare neoplasm derived from pituicytes, which are glial cells in the posterior lobe of the pituitary gland. A malignant pituicytoma was found in the intracranial cavity of a 55-week-old male Sprague-Dawley rat. Macroscopically, the tumor was located on the sphenoid bone and involved the pituitary gland. The tumor was composed of sheets of fusiform cells with spindle- or pleomorphic-shaped nuclei and abundant eosinophilic cytoplasms. The cells were arranged in a whirling or irregular growth pattern. Some tumor cells were bizarre multinucleated giant cells with cytoplasmic eosinophilic hyaline droplets. Many tumor cells were strongly positive for vimentin and glial fibrillary acidic protein, and some cells were positive for ED-1 and S-100. These findings closely resembled those of a giant cell glioblastoma derived from the pituitary gland, suggesting anaplastic pituicytoma. From our review of the literature, we believe this is the first report of a spontaneous malignant pituicytoma in a rodent. PMID- 26441480 TI - Spontaneous necrotizing sialometaplasia of the submandibular salivary gland in a Beagle dog. AB - A single mass was found on the left submandibular salivary gland at necropsy of a 15-month-old male commercially bred laboratory Beagle dog from a control dose group from a repeat toxicity study. Microscopically, the mass was composed of a well-demarcated area of coagulative necrosis surrounded and separated from the normal salivary gland tissue by a thick fibrovascular capsule. Necrosis was admixed with areas of hemorrhage, fibrin, edema, fibrinoid necrosis of the vascular tunica media, and thrombosis of small and large vessels. Within the necrotic tissue, there was marked ductal hyperplasia, and squamous metaplasia of duct and acinar epithelium. The mass was diagnosed as necrotizing sialometaplasia of the submandibular gland. Hyperplastic ductal elements and squamous metaplasia can be mistaken microscopically with squamous cell carcinoma. Therefore, pathologists should be aware of this lesion as to avoid errors in the diagnosis of this benign pathologic condition. PMID- 26441481 TI - Stakeholder Perceptions of Risk in Construction. AB - Safety management in construction is an integral effort and its success requires inputs from all stakeholders across design and construction phases. Effective risk mitigation relies on the concordance of all stakeholders' risk perceptions. Many researchers have noticed the discordance of risk perceptions among critical stakeholders in safe construction work, however few have provided quantifiable evidence describing them. In an effort to fill this perception gap, this research performs an experiment that investigates stakeholder perceptions of risk in construction. Data analysis confirms the existence of such discordance, and indicates a trend in risk likelihood estimation. With risk perceptions from low to high, the stakeholders are architects, contractors/safety professionals, and engineers. Including prior studies, results also suggest that designers have improved their knowledge in building construction safety, but compared to builders they present more difficultly in reaching a consensus of perception. Findings of this research are intended to be used by risk management and decision makers to reassess stakeholders' varying judgments when considering injury prevention and hazard assessment. PMID- 26441482 TI - Spin-labeled small unilamellar vesicles with the T1-sensitive saturation-recovery EPR display as an oxygen sensitive analyte for measurement of cellular respiration. AB - This study validated the use of small unilamellar vesicles (SUVs) made of 1 palmitoyl-2-oleoylphosphatidylcholine with 1 mol% spin label of 1-palmitoyl-2-(16 doxylstearoyl)phosphatidylcholine (16-PC) as an oxygen sensitive analyte to study cellular respiration. In the analyte the hydrocarbon environment surrounds the nitroxide moiety of 16-PC. This ensures high oxygen concentration and oxygen diffusion at the location of the nitroxide as well as isolation of the nitroxide moiety from cellular reductants and paramagnetic ions that might interfere with spin-label oximetry measurements. The saturation-recovery EPR approach was applied in the analysis since this approach is the most direct method to carry out oximetric studies. It was shown that this display (spin-lattice relaxation rate) is linear in oxygen partial pressure up to 100% air (159 mmHg). Experiments using a neuronal cell line in suspension were carried out at X-band for closed chamber geometry. Oxygen consumption rates showed a linear dependence on the number of cells. Other significant benefits of the analyte are: the fast effective rotational diffusion and slow translational diffusion of the spin-probe is favorable for the measurements, and there is no cross reactivity between oxygen and paramagnetic ions in the lipid bilayer. PMID- 26441483 TI - Expression and Function of Hypoxia Inducible Factor-1alpha and Vascular Endothelial Growth Factor in Pulp Tissue of Teeth under Orthodontic Movement. AB - Orthodontic force may lead to cell damage, circulatory disturbances, and vascular changes of the dental pulp, which make a hypoxic environment in pulp. In order to maintain the homeostasis of dental pulp, hypoxia will inevitably induce the defensive reaction. However, this is a complex process and is regulated by numerous factors. In this study, we established an experimental animal model of orthodontic tooth movement to investigate the effects of mechanical force on the expression of VEGF and HIF-1alpha in dental pulp. Histological analysis of dental pulp and expressions of HIF-1alpha and VEGF proteins in dental pulp were examined. The results showed that inflammation and vascular changes happened in dental pulp tissue in different periods. Additionally, there were significant changes in the expression of HIF-1alpha and VEGF proteins under orthodontic force. After application of mechanical load, expression of HIF-1alpha and VEGF was markedly positive in 1, 3, 7 d, and 2 w groups, and then it weakened in 4 w group. These findings suggested that the expression of HIF-1alpha and VEGF was enhanced by mechanical force. HIF-1alpha and VEGF may play an important role in retaining the homeostasis of dental pulp during orthodontic tooth movement. PMID- 26441484 TI - Galactomannan Downregulates the Inflammation Responses in Human Macrophages via NFkappaB2/p100. AB - We show that galactomannan, a polysaccharide consisting of a mannose backbone with galactose side groups present on the cell wall of several fungi, induces a reprogramming of the inflammatory response in human macrophages through dectin-1 receptor. The nuclear factor kappa-light-chain-enhancer of activated B cells 2 (NFkappaB2)/p100 was overexpressed after galactomannan challenge. Knocking down NFkappaB2/p100 using small interfering RNA (siRNA) indicated that NFkappaB2/p100 expression is a crucial factor in the progression of the galactomannan-induced refractoriness. The data presented in this study could be used as a modulator of inflammatory response in clinical situations where refractory state is required. PMID- 26441485 TI - Effectiveness of Liraglutide in Type II Diabetes Mellitus Management: Experience in Emirati Patients. AB - OBJECTIVE: To measure effectiveness of liraglutide in reducing glycated hemoglobin (HbA1C), weight, and systolic blood pressure (SBP) in Emirati patients. DESIGN: A retrospective cohort study. SETTING: Endocrinology clinic in a 300-bed military hospital. PATIENTS: A total of 152 patients who qualified for liraglutide between September 21, 2012, (first patient visit) and May 5, 2014 (last patient visit). METHODS: Team collected demographic and clinical data using a standard form. Data keeper performed univariate analyses to measure the effect of liraglutide in reducing the three outcomes of interest; namely, HbA1C, weight, and SBP. RESULTS: One hundred patients had at least the first visit in the clinic and 98 patients came for a second follow-up visit while on the medication. Adherence of clinicians to the internal criteria for prescribing liraglutide was 92%. Patients' ages were 47.9 +/- 11.7 years. Male-to-female ratio was almost 1:1. Overall, in the paired analyses, HbA1C decreased from first to second visits (8.7 +/- 1.9 vs. 7.6 +/- 1.8, P > 0.0001) and remained unchanged in subsequent visits (eg, in visit 3, HbA1C was 7.4 +/- 1.8). Patients lost an average of 1.3 kg between the first and second visits (99.3 +/- 19.3 vs. 98.0 +/- 19.5, P = 0.0003). The reduction in SBP between visits 1 and 2 was less (130.9 +/- 15.8 vs. 129.9 +/- 16.5, P = 0.5896). ANOVA yielded a significant reduction in HbA1C at 4 months and 6 months (P values < 0.05). SBP dropped by about 3.6 mmHg and weight by about 2.3 kg (P values > 0.05). CONCLUSIONS: Liraglutide is effective in reducing HbA1C, weight, and to a lesser extent, SBP in Emirati patients. PMID- 26441486 TI - Analyzing the Factors Contributing to Withdrawal from Insulin Therapy Following Additional Administration of Alogliptin: Retrospective Study after Removing Glucotoxicity with Insulin. AB - We attempted to examine whether withdrawal from insulin therapy is or is not possible with administration of additional alogliptin and identify the contributing factors. The subjects were 43 adult patients with type 2 diabetes undergoing insulin therapy after admission. After glucotoxicity was removed, 25 mg alogliptin was additionally administered. Insulin was reduced by 15.6 +/- 13.0 units (mean +/- SD), and 17 patients (39.5%) completely withdrew from insulin therapy. Several factors were compared between the two groups of patients: those who could withdraw from insulin therapy and those who could not. The former group showed lower HbA1c levels on admission, a lower insulin dose before adding alogliptin, lower injection frequencies, and longer treatment histories prior to admission. Logistic regression analysis showed that lower insulin dose contributed significantly to withdrawal. These results suggest that a lower insulin dose is the best predictor for withdrawal from insulin therapy after adding alogliptin. PMID- 26441487 TI - Cox Regression Models with Functional Covariates for Survival Data. AB - We extend the Cox proportional hazards model to cases when the exposure is a densely sampled functional process, measured at baseline. The fundamental idea is to combine penalized signal regression with methods developed for mixed effects proportional hazards models. The model is fit by maximizing the penalized partial likelihood, with smoothing parameters estimated by a likelihood-based criterion such as AIC or EPIC. The model may be extended to allow for multiple functional predictors, time varying coefficients, and missing or unequally-spaced data. Methods were inspired by and applied to a study of the association between time to death after hospital discharge and daily measures of disease severity collected in the intensive care unit, among survivors of acute respiratory distress syndrome. PMID- 26441488 TI - Guidelines for the use and interpretation of diagnostic methods in adult food allergy. AB - Food allergy has an increasing prevalence in the general population and in Italy concerns 8 % of people with allergies. The spectrum of its clinical manifestations ranges from mild symptoms up to potentially fatal anaphylactic shock. A number of patients can be diagnosed easily by the use of first- and second-level procedures (history, skin tests and allergen specific IgE). Patients with complex presentation, such as multiple sensitizations and pollen-food syndromes, frequently require a third-level approach including molecular diagnostics, which enables the design of a component-resolved sensitization profile for each patient. The use of such techniques involves specialists' and experts' skills on the issue to appropriately meet the diagnostic and therapeutic needs of patients. Particularly, educational programs for allergists on the use and interpretation of molecular diagnostics are needed. PMID- 26441490 TI - Participant report of therapist-delivered active ingredients in a telephone delivered brief motivational intervention predicts taking steps towards change. AB - OBJECTIVE: Given the widespread potential for disseminating Motivational Interviewing (MI) through technology, the question of whether MI active ingredients are present when not delivered in person is critical to assure high treatment quality. The Participant Rating Form (PRF) was developed and used to evaluate therapist-delivered active ingredients in phone-delivered MI with hazardous drinking Emergency Department patients. METHOD: A factor analysis of all PRFs completed after receiving one call (n=256) was conducted. Multiple regression analysis was used to examine whether PRF factors predicted a measure of motivation to change -- taking steps-at the second call (n=214). RESULTS: The majority of participants were male (65%), with a mean age of 32 years and with an average alcohol ASSIST (Alcohol, Smoking, and Substance Involvement Screening Test) score of 20.5 (SD = 7.1). Results of the factor analysis for the PRF revealed Relational (working collaboration) and Technical (MI behaviors) factors. After controlling for demographics, alcohol severity, and baseline readiness, the technical factor predicted self-report of increased taking steps towards change while the relational factor did not explain any additional variance. CONCLUSIONS: Our study adds to the growing literature investigating patient perspectives of therapist skill as a source of information to better understand MI active ingredients. The PRF is a feasible instrument for measuring the patient's experience of phone-based MI. Results indicate that MI active ingredients of change (relational and technical components) were present in the telephone intervention as hypothesized. Clinical Trial Registration # 01326169. PMID- 26441491 TI - Modulation of autonomic activity in neurological conditions: Epilepsy and Tourette Syndrome. AB - This manuscript considers the central but neglected role of the autonomic nervous system in the expression and control of seizures in epilepsy (small) and tics in Tourette Syndrome (TS). In epilepsy, consideration of autonomic involvement is typically confined to differential diagnoses (e.g., syncope), or in relation to Sudden Unexpected Death in Epilepsy (SUDEP). Investigation is more limited in Tourette Syndrome. The role of the autonomic nervous system in the generation and prevention of epileptic seizures is largely overlooked. Emotional stimuli such as anxiety and stress are potent causes of seizures and tic activity in epilepsy and TS, respectively. This manuscript will describe a possible neural mechanism by which afferent autonomic projections linked to cognition and behavior influence central thalamo-cortical regulation, which appears to be an important means for controlling both seizure and tic activity. It also summarizes the link between the integrity of the default mode network and autonomic regulation in patients with epilepsy as well as the link between impaired motor control and autonomic regulation in patients with TS. Two neurological conditions; epilepsy and TS were chosen, as seizures and tics represent parameters that can be easily measured to investigate influences of autonomic functions. The EDA biofeedback approach is anticipated to gain a strong position within the next generation of treatment for epilepsy, as a non-invasive technique with minimal side effects. This approach also takes advantage of the current practical opportunity to utilize growing digital health technology. PMID- 26441489 TI - Immunotherapy of Metastatic Colorectal Cancer: Prevailing Challenges and New Perspectives. AB - Patients with recurring or metastatic colorectal cancer (mCRC) have strikingly low long-term survival, while conventional treatments such as chemotherapeutic intervention and radiation therapy marginally improve longevity. Although, many factors involving immunosurveillance and immunosuppression were recently validated as important for patient prognosis and care, a multitude of experimental immunotherapies designed to combat unresectable mCRC have, in few cases, successfully mobilized antitumor immune cells against malignancies, nor conclusively or consistently granted protection, complete remission, and/or stable disease from immunotherapy - of which benefit less than 10% of those receiving therapy. After decades of progress, however, new insights into the mechanisms of immunosuppression, tolerance, and mutation profiling established novel therapies that circumvent these immunological barriers. This review underlines the most exciting methods to date that manipulate immune cells to curb mCRC, including adoptive cell therapy, dendritic cell vaccines, and checkpoint inhibitor antibodies - of which hint at effective and enduring protection against disease progression and undetected micrometastases. PMID- 26441492 TI - The interaction of vision and audition in two-dimensional space. AB - Using a mouse-driven visual pointer, 10 participants made repeated open-loop egocentric localizations of memorized visual, auditory, and combined visual auditory targets projected randomly across the two-dimensional frontal field (2D). The results are reported in terms of variable error, constant error and local distortion. The results confirmed that auditory and visual maps of the egocentric space differ in their precision (variable error) and accuracy (constant error), both from one another and as a function of eccentricity and direction within a given modality. These differences were used, in turn, to make predictions about the precision and accuracy within which spatially and temporally congruent bimodal visual-auditory targets are localized. Overall, the improvement in precision for bimodal relative to the best unimodal target revealed the presence of optimal integration well-predicted by the Maximum Likelihood Estimation (MLE) model. Conversely, the hypothesis that accuracy in localizing the bimodal visual-auditory targets would represent a compromise between auditory and visual performance in favor of the most precise modality was rejected. Instead, the bimodal accuracy was found to be equivalent to or to exceed that of the best unimodal condition. Finally, we described how the different types of errors could be used to identify properties of the internal representations and coordinate transformations within the central nervous system (CNS). The results provide some insight into the structure of the underlying sensorimotor processes employed by the brain and confirm the usefulness of capitalizing on naturally occurring differences between vision and audition to better understand their interaction and their contribution to multimodal perception. PMID- 26441493 TI - An empirical Bayes normalization method for connectivity metrics in resting state fMRI. AB - Functional connectivity analysis using resting-state functional magnetic resonance imaging (rs-fMRI) has emerged as a powerful technique for investigating functional brain networks. The functional connectivity is often quantified by statistical metrics (e.g., Pearson correlation coefficient), which may be affected by many image acquisition and preprocessing steps such as the head motion correction and the global signal regression. The appropriate quantification of the connectivity metrics is essential for meaningful and reproducible scientific findings. We propose a novel empirical Bayes method to normalize the functional brain connectivity metrics on a posterior probability scale. Moreover, the normalization function maps the original connectivity metrics to values between zero and one, which is well-suited for the graph theory based network analysis and avoids the information loss due to the (negative value) hard thresholding step. We apply the normalization method to a simulation study and the simulation results show that our normalization method effectively improves the robustness and reliability of the quantification of brain functional connectivity and provides more powerful group difference (biomarkers) detection. We illustrate our method on an analysis of a rs-fMRI dataset from the Autism Brain Imaging Data Exchange (ABIDE) study. PMID- 26441494 TI - Impaired sense of smell and altered olfactory system in RAG-1(-/-) immunodeficient mice. AB - Immune deficiencies are often associated with a number of physical manifestations including loss of sense of smell and an increased level of anxiety. We have previously shown that T and B cell-deficient recombinase activating gene (RAG-1)( /-) knockout mice have an increased level of anxiety-like behavior and altered gene expression involved in olfaction. In this study, we expanded these findings by testing the structure and functional development of the olfactory system in RAG-1 (-/-) mice. Our results show that these mice have a reduced engagement in different types of odors and this phenotype is associated with disorganized architecture of glomerular tissue and atrophy of the main olfactory epithelium. Most intriguingly this defect manifests specifically in adult age and is not due to impairment in the patterning of the olfactory neuron staining at the embryo stage. Together these findings provide a formerly unreported biological evidence for an altered function of the olfactory system in RAG-1 (-/-) mice. PMID- 26441495 TI - HDAC I inhibition in the dorsal and ventral hippocampus differentially modulates predator-odor fear learning and generalization. AB - Although predator odors are ethologically relevant stimuli for rodents, the molecular pathways and contribution of some brain regions involved in predator odor conditioning remain elusive. Inhibition of histone deacetylases (HDACs) in the dorsal hippocampus has been shown to enhance shock-induced contextual fear learning, but it is unknown if HDACs have differential effects along the dorso ventral hippocampal axis during predator odor fear learning. We injected MS-275, a class I HDAC inhibitor, bilaterally in the dorsal or ventral hippocampus of mice and found that it had no effects on innate anxiety in either region. We then assessed the effects of MS-275 at different stages of fear learning along the longitudinal hippocampal axis. Animals were injected with MS-275 or vehicle after context pre-exposure (pre-conditioning injections), when a representation of the context is first formed, or after exposure to coyote urine (post-conditioning injections), when the context becomes associated with predator odor. When MS-275 was administered after context pre-exposure, dorsally injected animals showed enhanced fear in the training context but were able to discriminate it from a neutral environment. Conversely, ventrally injected animals did not display enhanced learning in the training context but generalized the fear response to a neutral context. However, when MS-275 was administered after conditioning, there were no differences between the MS-275 and vehicle control groups in either the dorsal or ventral hippocampus. Surprisingly, all groups displayed generalization to a neutral context, suggesting that predator odor exposure followed by a mild stressor such as restraint leads to fear generalization. These results may elucidate distinct functions of the dorsal and ventral hippocampus in predator odor-induced fear conditioning as well as some of the molecular mechanisms underlying fear generalization. PMID- 26441496 TI - Temporary inactivation of the anterior part of the bed nucleus of the stria terminalis blocks alarm pheromone-induced defensive behavior in rats. AB - Rats emit an alarm pheromone in threatening situations. Exposure of rats to this alarm pheromone induces defensive behaviors, such as head out behavior, and increases c-Fos expression in brain areas involved in the mediation of defensive behaviors. One of these brain areas is the anterior bed nucleus of the stria terminalis (aBNST). The goal of the present study was to investigate if pharmacological inactivation of the aBNST by local microinjections of the GABAA receptor-agonist muscimol modulates alarm pheromone-induced defensive behaviors. We first established the behavioral paradigm of alarm pheromone-induced defensive behaviors in Sprague-Dawley rats in our laboratory. In a second experiment, we inactivated the aBNST, then exposed rats to one of four different odors (neck odor, female urine, alarm pheromone, fox urine) and tested the effects of the aBNST inactivation on the behavior in response to these odors. Our data show that temporary inactivation of the aBNST blocked head out behavior in response to the alarm pheromone. This indicates that the aBNST plays an important role in the mediation of the alarm pheromone-induced defensive behavior in rats. PMID- 26441498 TI - A FreeSurfer view of the cortical transcriptome generated from the Allen Human Brain Atlas. PMID- 26441497 TI - From UBE3A to Angelman syndrome: a substrate perspective. AB - Angelman syndrome (AS) is a debilitating neurodevelopmental disorder that is characterized by motor dysfunction, intellectual disability, speech impairment, seizures and common features of autism spectrum disorders (ASDs). Some of these AS related phenotypes can be seen in other neurodevelopmental disorders (Williams, 2011; Tan et al., 2014). AS patients commonly carry mutations that render the maternally inherited UBE3A gene non-functional. Duplication of the chromosomal region containing the UBE3A gene is associated with ASDs. Although the causative role for UBE3A gene mutations in AS is well established, a long standing challenge in AS research has been to identify neural substrates of UBE3A, an E3 ubiquitin ligase. A prevailing hypothesis is that changes in UBE3A protein levels would alter the levels of a collection of protein substrates, giving rise to the unique phenotypic aspects of AS and possibly UBE3A associated ASDs. Interestingly, proteins altered in AS are linked to additional ASDs that are not previously associated with changes in UBE3A, indicating a possible molecular overlap underlying the broad-spectrum phenotypes of these neurogenetic disorders. This idea raises the possibility that there may exist a "one-size-fits all" approach to the treatment of neurogenetic disorders with phenotypes overlapping AS. Furthermore, while a comprehensive list of UBE3A substrates and downstream affected pathways should be developed, this is only part of the story. The timing of when UBE3A protein functions, through either changes in UBE3A or possibly substrate expression patterns, appears to be critical for AS phenotype development. These data call for further investigation of UBE3A substrates and their timing of action relevant to AS phenotypes. PMID- 26441499 TI - Methylenedioxypyrovalerone (MDPV) mimics cocaine in its physiological and behavioral effects but induces distinct changes in NAc glucose. AB - Methylenedioxypyrovalerone (MDPV) is generally considered to be a more potent cocaine-like psychostimulant, as it shares a similar pharmacological profile with cocaine and induces similar physiological and locomotor responses. Recently, we showed that intravenous cocaine induces rapid rise in nucleus accumbens (NAc) glucose and established its relation to neural activation triggered by the peripheral drug actions. This study was conducted to find out whether MDPV, at a behaviorally equivalent dose, shares a similar pattern of NAc glucose dynamics. Using enzyme-based glucose sensors coupled with amperometery in freely moving rats, we found that MDPV tonically decreases NAc glucose levels, a response that is opposite to what we previously observed with cocaine. By analyzing Skin-Muscle temperature differentials, a valid measure of skin vascular tone, we found that MDPV induces vasoconstriction; a similar effect at the level of cerebral vessels could be responsible for the MDPV-induced decrease in NAc glucose. While cocaine also induced comparable, if not slightly stronger peripheral vasoconstriction, this effect was overpowered by local neural activity-induced vasodilation, resulting in rapid surge in NAc glucose. These results imply that cocaine-users may be more susceptible to addiction than MDPV-users due to the presence of an interoceptive signal (i.e., sensory cue), which may result in earlier and more direct reward detection. Additionally, while health complications arising from acute cocaine use are typically cardiovascular related, MDPV may be more dangerous to the brain due to uncompensated cerebral vasoconstriction. PMID- 26441500 TI - DeID - a data sharing tool for neuroimaging studies. AB - Funding institutions and researchers increasingly expect that data will be shared to increase scientific integrity and provide other scientists with the opportunity to use the data with novel methods that may advance understanding in a particular field of study. In practice, sharing human subject data can be complicated because data must be de-identified prior to sharing. Moreover, integrating varied data types collected in a study can be challenging and time consuming. For example, sharing data from structural imaging studies of a complex disorder requires the integration of imaging, demographic and/or behavioral data in a way that no subject identifiers are included in the de-identified dataset and with new subject labels or identification values that cannot be tracked back to the original ones. We have developed a Java program that users can use to remove identifying information in neuroimaging datasets, while still maintaining the association among different data types from the same subject for further studies. This software provides a series of user interaction wizards to allow users to select data variables to be de-identified, implements functions for auditing and validation of de-identified data, and enables the user to share the de-identified data in a single compressed package through various communication protocols, such as FTPS and SFTP. DeID runs with Windows, Linux, and Mac operating systems and its open architecture allows it to be easily adapted to support a broader array of data types, with the goal of facilitating data sharing. DeID can be obtained at http://www.nitrc.org/projects/deid. PMID- 26441501 TI - Enhanced functional connectivity involving the ventromedial hypothalamus following methamphetamine exposure. AB - Methamphetamine (MA) consumption causes disruption of many biological rhythms including the sleep-wake cycle. This circadian effect is seen shortly following MA exposure and later in life following developmental MA exposure. MA phase shifts, entrains the circadian clock and can also alter the entraining effect of light by currently unknown mechanisms. We analyzed and compared immunoreactivity of the immediate early gene c-Fos, a marker of neuronal activity, to assess neuronal activation 2 h following MA exposure in the light and dark phases. We used network analyses of correlation patterns derived from global brain immunoreactivity patterns of c-Fos, to infer functional connectivity between brain regions. There were five distinct patterns of neuronal activation. In several brain areas, neuronal activation following exposure to MA was stronger in the light than the dark phase, highlighting the importance of considering circadian periods of increased effects of MA in defining experimental conditions and understanding the mechanisms underlying detrimental effects of MA exposure to brain function. Functional connectivity between the ventromedial hypothalamus (VMH) and other brain areas, including the paraventricular nucleus of the hypothalamus and basolateral and medial amygdala, was enhanced following MA exposure, suggesting a role for the VMH in the effects of MA on the brain. PMID- 26441503 TI - Identification of resilient individuals and those at risk for performance deficits under stress. AB - Human task performance is affected by exposure to physiological and psychological stress. The ability to measure the physiological response to stressors and correlate that to task performance could be used to identify resilient individuals or those at risk for stress-related performance decrements. Accomplishing this prior to performance under severe stress or the development of clinical stress disorders could facilitate focused preparation such as tailoring training to individual needs. Here we measure the effects of stress on physiological response and performance through behavior, physiological sensors, and subjective ratings, and identify which individuals are at risk for stress related performance decrements. Participants performed military-relevant training tasks under stress in a virtual environment, with autonomic and hypothalamic pituitary-adrenal axis (HPA) reactivity analyzed. Self-reported stress, as well as physiological indices of stress, increased in the group pre-exposed to socioevaluative stress. Stress response was effectively captured via electrodermal and cardiovascular measures of heart rate and skin conductance level. A resilience classification algorithm was developed based upon physiological reactivity, which correlated with baseline unstressed physiological and self-reported stress values. Outliers were identified in the experimental group that had a significant mismatch between self-reported stress and salivary cortisol. Baseline stress measurements were predictive of individual resilience to stress, including the impact stress had on physiological reactivity and performance. Such an approach may have utility in identifying individuals at risk for problems performing under severe stress. Continuing work has focused on adapting this method for military personnel, and assessing the utility of various coping and decision-making strategies on performance and physiological stress. PMID- 26441504 TI - Editorial: From sex differences in neuroscience to a neuroscience of sex differences: new directions and perspectives. PMID- 26441502 TI - An animal model of differential genetic risk for methamphetamine intake. AB - The question of whether genetic factors contribute to risk for methamphetamine (MA) use and dependence has not been intensively investigated. Compared to human populations, genetic animal models offer the advantages of control over genetic family history and drug exposure. Using selective breeding, we created lines of mice that differ in genetic risk for voluntary MA intake and identified the chromosomal addresses of contributory genes. A quantitative trait locus was identified on chromosome 10 that accounts for more than 50% of the genetic variance in MA intake in the selected mouse lines. In addition, behavioral and physiological screening identified differences corresponding with risk for MA intake that have generated hypotheses that are testable in humans. Heightened sensitivity to aversive and certain physiological effects of MA, such as MA induced reduction in body temperature, are hallmarks of mice bred for low MA intake. Furthermore, unlike MA-avoiding mice, MA-preferring mice are sensitive to rewarding and reinforcing MA effects, and to MA-induced increases in brain extracellular dopamine levels. Gene expression analyses implicate the importance of a network enriched in transcription factor genes, some of which regulate the mu opioid receptor gene, Oprm1, in risk for MA use. Neuroimmune factors appear to play a role in differential response to MA between the mice bred for high and low intake. In addition, chromosome 10 candidate gene studies provide strong support for a trace amine-associated receptor 1 gene, Taar1, polymorphism in risk for MA intake. MA is a trace amine-associated receptor 1 (TAAR1) agonist, and a non functional Taar1 allele segregates with high MA consumption. Thus, reduced TAAR1 function has the potential to increase risk for MA use. Overall, existing findings support the MA drinking lines as a powerful model for identifying genetic factors involved in determining risk for harmful MA use. Future directions include the development of a binge model of MA intake, examining the effect of withdrawal from chronic MA on MA intake, and studying potential Taar1 gene * gene and gene * environment interactions. These and other studies are intended to improve our genetic model with regard to its translational value to human addiction. PMID- 26441505 TI - An array of highly flexible electrodes with a tailored configuration locked by gelatin during implantation-initial evaluation in cortex cerebri of awake rats. AB - BACKGROUND: A major challenge in the field of neural interfaces is to overcome the problem of poor stability of neuronal recordings, which impedes long-term studies of individual neurons in the brain. Conceivably, unstable recordings reflect relative movements between electrode and tissue. To address this challenge, we have developed a new ultra-flexible electrode array and evaluated its performance in awake non-restrained animals. METHODS: An array of eight separated gold leads (4 * 10 MUm), individually flexible in 3D, were cut from a gold sheet using laser milling and insulated with Parylene C. To provide structural support during implantation into rat cortex, the electrode array was embedded in a hard gelatin based material, which dissolves after implantation. Recordings were made during 3 weeks. At termination, the animals were perfused with fixative and frozen to prevent dislocation of the implanted electrodes. A thick slice of brain tissue, with the electrode array still in situ, was made transparent using methyl salicylate to evaluate the conformation of the implanted electrode array. RESULTS: Median noise levels and signal/noise remained relatively stable during the 3 week observation period; 4.3-5.9 MUV and 2.8-4.2, respectively. The spike amplitudes were often quite stable within recording sessions and for 15% of recordings where single-units were identified, the highest-SNR unit had an amplitude higher than 150 MUV. In addition, high correlations (>0.96) between unit waveforms recorded at different time points were obtained for 58% of the electrode sites. The structure of the electrode array was well preserved 3 weeks after implantation. CONCLUSIONS: A new implantable multichannel neural interface, comprising electrodes individually flexible in 3D that retain its architecture and functionality after implantation has been developed. Since the new neural interface design is adaptable, it offers a versatile tool to explore the function of various brain structures. PMID- 26441506 TI - Emotion, rationality, and decision-making: how to link affective and social neuroscience with social theory. AB - In this paper, we argue for a stronger engagement between concepts in affective and social neuroscience on the one hand, and theories from the fields of anthropology, economics, political science, and sociology on the other. Affective and social neuroscience could provide an additional assessment of social theories. We argue that some of the most influential social theories of the last four decades-rational choice theory, behavioral economics, and post-structuralism contain assumptions that are inconsistent with key findings in affective and social neuroscience. We also show that another approach from the social sciences plural rationality theory-shows greater compatibility with these findings. We further claim that, in their turn, social theories can strengthen affective and social neuroscience. The former can provide more precise formulations of the social phenomena that neuroscientific models have targeted, can help neuroscientists who build these models become more aware of their social and cultural biases, and can even improve the models themselves. To illustrate, we show how plural rationality theory can be used to further specify and test the somatic marker hypothesis. Thus, we aim to accelerate the much-needed merger of social theories with affective and social neuroscience. PMID- 26441507 TI - Neuroimaging assessment of early and late neurobiological sequelae of traumatic brain injury: implications for CTE. AB - Traumatic brain injury (TBI) has been increasingly accepted as a major external risk factor for neurodegenerative morbidity and mortality. Recent evidence indicates that the resultant chronic neurobiological sequelae following head trauma may, at least in part, contribute to a pathologically distinct disease known as Chronic Traumatic Encephalopathy (CTE). The clinical manifestation of CTE is variable, but the symptoms of this progressive disease include impaired memory and cognition, affective disorders (i.e., impulsivity, aggression, depression, suicidality, etc.), and diminished motor control. Notably, mounting evidence suggests that the pathology contributing to CTE may be caused by repetitive exposure to subconcussive hits to the head, even in those with no history of a clinically evident head injury. Given the millions of athletes and military personnel with potential exposure to repetitive subconcussive insults and TBI, CTE represents an important public health issue. However, the incidence rates and pathological mechanisms are still largely unknown, primarily due to the fact that there is no in vivo diagnostic tool. The primary objective of this manuscript is to address this limitation and discuss potential neuroimaging modalities that may be capable of diagnosing CTE in vivo through the detection of tau and other known pathological features. Additionally, we will discuss the challenges of TBI research, outline the known pathology of CTE (with an emphasis on Tau), review current neuroimaging modalities to assess the potential routes for in vivo diagnosis, and discuss the future directions of CTE research. PMID- 26441509 TI - The neuroscience of social conformity: implications for fundamental and applied research. AB - The development of closer ties between researchers and practitioners in the domain of behavior and behavioral change offers useful opportunities for better informing public policy campaigns via a deeper understanding of the psychological processes that operate in real-world decision-making. Here, we focus on the domain of social conformity, and suggest that the recent emergence of laboratory work using neuroscientific techniques to probe the brain basis of social influence can prove a useful source of data to better inform models of conformity. In particular, we argue that this work can have an important role to play in better understanding the specific mechanisms at work in social conformity, in both validating and extending current psychological theories of this process, and in assessing how behavioral change can take place as a result of exposure to the judgments of others. We conclude by outlining some promising future directions in this domain, and indicating how this research could potentially be usefully applied to policy issues. PMID- 26441508 TI - Oxytocin and vasopressin: linking pituitary neuropeptides and their receptors to social neurocircuits. AB - Oxytocin and vasopressin are pituitary neuropeptides that have been shown to affect social processes in mammals. There is growing interest in these molecules and their receptors as potential precipitants of, and/or treatments for, social deficits in neurodevelopmental disorders, including autism spectrum disorder. Numerous behavioral-genetic studies suggest that there is an association between these peptides and individual social abilities; however, an explanatory model that links hormonal activity at the receptor level to complex human behavior remains elusive. The following review summarizes the known associations between the oxytocin and vasopressin neuropeptide systems and social neurocircuits in the brain. Following a micro- to macro- level trajectory, current literature on the synthesis and secretion of these peptides, and the structure, function and distribution of their respective receptors is first surveyed. Next, current models regarding the mechanism of action of these peptides on microcircuitry and other neurotransmitter systems are discussed. Functional neuroimaging evidence on the acute effects of exogenous administration of these peptides on brain activity is then reviewed. Overall, a model in which the local neuromodulatory effects of pituitary neuropeptides on brainstem and basal forebrain regions strengthen signaling within social neurocircuits proves appealing. However, these findings are derived from animal models; more research is needed to clarify the relevance of these mechanisms to human behavior and treatment of social deficits in neuropsychiatric disorders. PMID- 26441510 TI - Dopamine D4 receptor gene and religious affiliation correlate with dictator game altruism in males and not females: evidence for gender-sensitive gene * culture interaction. AB - On a large sample of 2288 Han Chinese undergraduates, we investigated how religion and DRD4 are related to human altruistic giving behavior as measured with the Andreoni-Miller Dictator Game. This game enables us to clearly specify (non-)selfishness, efficiency, and fairness motives for sharing. Participants were further classified into religious categories (Christian, Buddhist-Tao, and No Religion) based on self-reports, and genotyped for the dopamine D4 receptor (DRD4) gene exon III VNTR. Our analysis revealed a significant interaction between religion and DRD4 correlated with giving behavior solely among males: Whereas no significant association between religion and sharing decisions was observed in the majority 4R/4R genotype group, a significant difference in giving behavior between Christian and non-Christian males was seen in the non-4R/4R group, with Christian men being overall more altruistic (less selfish and fairer) than non-Christian men. These results support the vantage sensitivity hypothesis regarding DRD4 that the non-4R/4R "susceptibility" genotype is more responsive to a positive environment provided by some religions. PMID- 26441512 TI - Cross-domain processing of musical and vocal emotions in cochlear implant users. PMID- 26441511 TI - Golgi fragmentation in Alzheimer's disease. AB - The Golgi apparatus is an essential cellular organelle for post-translational modifications, sorting, and trafficking of membrane and secretory proteins. Proper functionality of the Golgi requires the formation of its unique cisternal stacking morphology. The Golgi structure is disrupted in a variety of neurodegenerative diseases, suggesting a common mechanism and contribution of Golgi defects in neurodegenerative disorders. A recent study on Alzheimer's disease (AD) revealed that phosphorylation of the Golgi stacking protein GRASP65 disrupts its function in Golgi structure formation, resulting in Golgi fragmentation. Inhibiting GRASP65 phosphorylation restores the Golgi morphology from Abeta-induced fragmentation and reduces Abeta production. Perturbing Golgi structure and function in neurons may directly impact trafficking, processing, and sorting of a variety of proteins essential for synaptic and dendritic integrity. Therefore, Golgi defects may ultimately promote the development of AD. In the current review, we focus on the cellular impact of impaired Golgi morphology and its potential relationship to AD disease development. PMID- 26441513 TI - NF-kappaB transcription factor role in consolidation and reconsolidation of persistent memories. AB - Transcriptional regulation is an important molecular process required for long term neural plasticity and long-term memory (LTM) formation. Thus, one main interest in molecular neuroscience in the last decades has been the identification of transcription factors that are involved in memory processes. Among them, the nuclear factor kappaB (NF-kappaB) family of transcription factors has gained interest due to a significant body of evidence that supports a key role of these proteins in synaptic plasticity and memory. In recent years, the interest was particularly reinforced because NF-kappaB was characterized as an important regulator of synaptogenesis. This function may be explained by its participation in synapse to nucleus communication, as well as a possible local role at the synapse. This review provides an overview of experimental work obtained in the last years, showing the essential role of this transcription factor in memory processes in different learning tasks in mammals. We focus the review on the consolidation and reconsolidation memory phases as well as on the regulation of immediate-early and late genes by epigenetic mechanisms that determine enduring forms of memories. PMID- 26441515 TI - Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, attenuates postoperative cognitive dysfunction in aging mice. AB - Postoperative cognitive dysfunction (POCD) is a recognized clinical entity characterized with cognitive deficits after anesthesia and surgery, especially in aged patients. Previous studies have shown that histone acetylation plays a key role in hippocampal synaptic plasticity and memory formation. However, its role in POCD remains to be determined. Here, we show that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, attenuates POCD in aging Mice. After exposed to the laparotomy, a surgical procedure involving an incision into abdominal walls to examine the abdominal organs, 16- but not 3-month old male C57BL/6 mice developed obvious cognitive impairments in the test of long-term contextual fear conditioning. Intracerebroventricular (i.c.v.) injection of SAHA at the dose of (20 MUg/2 MUl) 3 h before and daily after the laparotomy restored the laparotomy-induced reduction of hippocampal acetyl-H3 and acetyl-H4 levels and significantly attenuated the hippocampus-dependent long-term memory (LTM) impairments in 16-month old mice. SAHA also reduced the expression of cleaved caspase-3, inducible nitric oxide synthase (iNOS) and N-methyl-D-aspartate (NMDA) receptor-calcium/calmodulin dependent kinase II (CaMKII) pathway, and increased the expression of brain-derived neurotrophic factor (BDNF), synapsin 1, and postsynaptic density 95 (PSD95). Taken together, our data suggest that the decrease of histone acetylation contributes to POCD and may serve as a target to improve the neurological outcome of POCD. PMID- 26441514 TI - MAG, myelin and overcoming growth inhibition in the CNS. AB - While neurons in the central nervous system (CNS) have the capacity to regenerate their axons after injury, they fail to do so, in part because regeneration is limited by growth inhibitory proteins present in CNS myelin. Myelin-associated glycoprotein (MAG) was the first myelin-derived growth inhibitory protein identified, and its inhibitory activity was initially elucidated in 1994 independently by the Filbin lab and the McKerracher lab using cell-based and biochemical techniques, respectively. Since that time we have gained a wealth of knowledge concerning the numerous growth inhibitory proteins that are present in myelin, and we also have dissected many of the neuronal signaling pathways that act as stop signs for axon regeneration. Here we give an overview of the early research efforts that led to the identification of myelin-derived growth inhibitory proteins, and the importance of this family of proteins for understanding neurotrauma and CNS diseases. We further provide an update on how this knowledge has been translated towards current clinical studies in regenerative medicine. PMID- 26441516 TI - Habituation of glomerular responses in the olfactory bulb following prolonged odor stimulation reflects reduced peripheral input. AB - Following prolonged odor stimulation, output from olfactory bulb (OB) mitral/tufted (M/T) cells is decreased in response to subsequent olfactory stimulation. Currently, it is unclear if this decrease is a function of adaptation of peripheral olfactory sensory neuron (OSN) responses or reflects depression of bulb circuits. We used wide-field calcium imaging in anesthetized transgenic GCaMP2 mice to compare excitatory glomerular layer odor responses before and after a 30-s odor stimulation. Significant habituation of subsequent glomerular odor responses to both the same and structurally similar odorants was detected with our protocol. To test whether depression of OSN terminals contributed to this habituation, olfactory nerve layer (ON) stimulation was used to drive glomerular layer responses in the absence of peripheral odor activation of the OSNs. Following odor habituation, in contrast to odor-evoked glomerular responses, ON stimulation-evoked glomerular responses were not habituated. The difference in response between odor and electrical stimulation following odor habituation provides evidence that odor response reductions measured in the glomerular layer of the OB are most likely the result of OSN adaptation processes taking place in the periphery. PMID- 26441517 TI - NF-kappaB mediates Gadd45beta expression and DNA demethylation in the hippocampus during fear memory formation. AB - Gadd45-mediated DNA demethylation mechanisms have been implicated in the process of memory formation. However, the transcriptional mechanisms involved in the regulation of Gadd45 gene expression during memory formation remain unexplored. NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) controls transcription of genes in neurons and is a critical regulator of synaptic plasticity and memory formation. In silico analysis revealed several NF kappaB (p65/RelA and cRel) consensus sequences within the Gadd45beta gene promoter. Whether NF-kappaB activity regulates Gadd45 expression and associated DNA demethylation in neurons during memory formation is unknown. Here, we found that learning in a fear conditioning paradigm increased Gadd45beta gene expression and brain-derivedneurotrophic factor (BDNF) DNA demethylation in area CA1 of the hippocampus, both of which were prevented with pharmacological inhibition of NF-kappaB activity. Further experiments found that conditional mutations in p65/RelA impaired fear memory formation but did not alter changes in Gadd45beta expression. The learning-induced increases in Gadd45beta mRNA levels, Gadd45beta binding at the BDNF gene and BDNF DNA demethylation were blocked in area CA1 of the c-rel knockout mice. Additionally, local siRNA-mediated knockdown of c-rel in area CA1 prevented fear conditioning-induced increases in Gadd45beta expression and BDNF DNA demethylation, suggesting that c-Rel containing NF-kappaB transcription factor complex is responsible for Gadd45beta regulation during memory formation. Together, these results support a novel transcriptional role for NF-kappaB in regulation of Gadd45beta expression and DNA demethylation in hippocampal neurons during fear memory. PMID- 26441518 TI - Functional characterization of ivermectin binding sites in alpha1beta2gamma2L GABA(A) receptors. AB - GABAA receptors (GABAARs) are the major inhibitory neurotransmitter receptors in the brain and are therapeutic targets for many indications including sedation, anesthesia and anxiolysis. There is, however, considerable scope for the development of new therapeutics with improved beneficial effects and reduced side effect profiles. The anthelminthic drug, ivermectin, activates the GABAAR although its binding site is not known. The molecular site of action of ivermectin has, however, been defined by crystallography in the homologous glutamate-gated chloride channel. Resolving the molecular mechanisms of ivermectin binding to alpha1beta2gamma2L GABAARs may provide insights into the design of improved therapeutics. Given that ivermectin binds to subunit interfaces, we sought to define (1) which subunit interface sites it binds to, (2) whether these sites are equivalent in terms of ivermectin sensitivity or efficacy, and (3) how many must be occupied for maximal efficacy. Our approach involved precluding ivermectin from binding to particular interfaces by introducing bulky M3 domain 36'F sidechains to the "+" side of those interfaces. We thereby demonstrated that ivermectin produces irreversible channel activation only when it binds to the single gamma2L-beta2 interface site. When it binds to alpha1-beta2 sites it elicits potentiation of GABA-gated currents but has no irreversible activating effect. Ivermectin cannot bind to the beta2-alpha1 interface site due to its endogenous bulky 36' methionine. Replacing this with an alanine creates a functional site at this interface, but surprisingly it is inhibitory. Molecular docking simulations reveal that the gamma2L-beta2 interface forms more contacts with ivermectin than the other interfaces, possibly explaining why ivermectin appears to bind irreversibly at this interface. This study demonstrates unexpectedly stark pharmacological differences among GABAAR ivermectin binding sites. PMID- 26441519 TI - Hair cell-type dependent expression of basolateral ion channels shapes response dynamics in the frog utricle. AB - The dynamics of vestibular afferent responses are thought to be strongly influenced by presynaptic properties. In this paper, by performing whole-cell perforated-patch experiments in the frog utricle, we characterized voltage dependent currents and voltage responses to current steps and 0.3-100 Hz sinusoids. Current expression and voltage responses are strongly related to hair cell type. In particular, voltage responses of extrastriolar type eB (low pass, 3 dB corner at 52.5 +/- 12.8 Hz) and striolar type F cells (resonant, tuned at 60 +/- 46 Hz) agree with the dynamics (tonic and phasic, respectively) of the afferent fibers they contact. On the other hand, hair cell release (measured with single-sine membrane DeltaCm measurements) was linearly related to Ca in both cell types, and therefore did not appear to contribute to dynamics differences. As a tool for quantifying the relative contribution of basolateral currents and other presynaptic factors to afferent dynamics, the recorded current, voltage and release data were used to build a NEURON model of the average extrastriolar type eB and striolar type F hair cell. The model contained all recorded conductances, a basic mechanosensitive hair bundle and a ribbon synapse sustained by stochastic voltage-dependent Ca channels, and could reproduce the recorded hair cell voltage responses. Simulated release obtained from eB-type and F-type models display significant differences in dynamics, supporting the idea that basolateral currents are able to contribute to afferent dynamics; however, release in type eB and F cell models does not reproduce tonic and phasic dynamics, mainly because of an excessive phase lag present in both cell types. This suggests the presence in vestibular hair cells of an additional, phase-advancing mechanism, in cascade with voltage modulation. PMID- 26441520 TI - Mechanical stress activates neurites and somata of myenteric neurons. AB - The particular location of myenteric neurons, sandwiched between the 2 muscle layers of the gut, implies that their somata and neurites undergo mechanical stress during gastrointestinal motility. Existence of mechanosensitive enteric neurons (MEN) is undoubted but many of their basic features remain to be studied. In this study, we used ultra-fast neuroimaging to record activity of primary cultured myenteric neurons of guinea pig and human intestine after von Frey hair evoked deformation of neurites and somata. Independent component analysis was applied to reconstruct neuronal morphology and follow neuronal signals. Of the cultured neurons 45% (114 out of 256, 30 guinea pigs) responded to neurite probing with a burst spike frequency of 13.4 Hz. Action potentials generated at the stimulation site invaded the soma and other neurites. Mechanosensitive sites were expressed across large areas of neurites. Many mechanosensitive neurites appeared to have afferent and efferent functions as those that responded to deformation also conducted spikes coming from the soma. Mechanosensitive neurites were also activated by nicotine application. This supported the concept of multifunctional MEN. 14% of the neurons (13 out of 96, 18 guinea pigs) responded to soma deformation with burst spike discharge of 17.9 Hz. Firing of MEN adapted rapidly (RAMEN), slowly (SAMEN), or ultra-slowly (USAMEN). The majority of MEN showed SAMEN behavior although significantly more RAMEN occurred after neurite probing. Cultured myenteric neurons from human intestine had similar properties. Compared to MEN, dorsal root ganglion neurons were activated by neurite but not by soma deformation with slow adaptation of firing. We demonstrated that MEN exhibit specific features very likely reflecting adaptation to their specialized functions in the gut. PMID- 26441522 TI - Surgery plus anesthesia induces loss of attention in mice. AB - There is a need to develop animal models to study postoperative delirium. Inattention is one of the symptoms of delirium. Increases in the levels of alpha synuclein and S100beta have been reported to be associated with delirium. Therefore, we set out to determine the effects of surgery plus general anesthesia on the behavioral changes (including loss of attention) in mice and on the levels of alpha-synuclein and S100beta in the brain tissues of these mice. C57BL/6J mice (2- to 8-months-old) had a simple laparotomy plus isoflurane anesthesia. The behavioral changes, including attention level and the speed of movements, were determined 12, 24, and 48 h after the surgery plus anesthesia in the mice. The levels of alpha-synuclein and S100beta in the cortex of these mice following the surgery plus anesthesia were determined by Western blot analysis. We found that there was a loss of attention at 24, but not 12 or 48 h following the surgery plus anesthesia (49% +/- 5 vs. 33% +/- 2.9, P = 0.011, N = 12) in the mice without significantly affecting the speed of their movements. There were increases in the levels of total alpha-synuclein (139% +/- 33.5 vs. 100% +/- 13.7, P = 0.037, N = 6) and S100beta (142% +/- 7.7 vs. 100% +/- 6, P = 0.002, N = 6) in the cortex of the mice 12 h following the surgery plus anesthesia. These findings suggested that the surgery plus isoflurane anesthesia might induce behavioral and biochemical/cellular changes associated with delirium. We could use the surgery plus anesthesia in mice to develop an animal model to study postoperative delirium. PMID- 26441523 TI - Leptin-dependent neurotoxicity via induction of apoptosis in adult rat neurogenic cells. AB - Adipocyte-derived hormone leptin has been recently implicated in the control of neuronal plasticity. To explore whether modulation of adult neurogenesis may contribute to leptin control of neuronal plasticity, we used the neurosphere assay of neural stem cells derived from the adult rat subventricular zone (SVZ). Endogenous expression of specific leptin receptor (ObRb) transcripts, as revealed by RT-PCR, is associated with activation of both ERK and STAT-3 pathways via phosphorylation of the critical ERK/STAT-3 amino acid residues upon addition of leptin to neurospheres. Furthermore, leptin triggered withdrawal of neural stem cells from the cell cycle as monitored by Ki67 labeling. This effect was blocked by pharmacological inhibition of ERK activation thus demonstrating that ERK mediates leptin effects on neural stem cell expansion. Leptin-dependent withdrawal of neural stem cells from the cell cycle was associated with increased apoptosis, as detected by TUNEL, which was preceded by cyclin D1 induction. Cyclin D1 was indeed extensively colocalized with TUNEL-positive, apoptotic nuclei. Cyclin-D1 silencing by specific shRNA prevented leptin-induced decrease of the cell number per neurosphere thus pointing to the causal relationship between leptin actions on apoptosis and cyclin D1 induction. Leptin target cells in SVZ neurospheres were identified by double TUNEL/phenotypic marker immunocytofluorescence as differentiating neurons mostly. The inhibition of neural stem cell expansion via ERK/cyclin D1-triggered apoptosis defines novel biological action of leptin which may be involved in adiposity-dependent neurotoxicity. PMID- 26441524 TI - Clock and clock-controlled genes are differently expressed in the retina, lamina and in selected cells of the visual system of Drosophila melanogaster. AB - The retina and the first optic neuropil (lamina) of Drosophila show circadian rhythms in various processes. To learn about the regulation of circadian rhythms in the retina and lamina and in two cell types, glial and the lamina L2 interneurons, we examined expression of the following clock genes; per, tim, clk, and cry and clock-controlled genes (ccgs); Atpalpha, nrv2, brp, Pdfr. We found that the expression of gene studied is specific for the retina and lamina. The rhythms of per and tim expression in the retina and glial cells are similar to that observed in the whole head and in clock neurons, while they differ in the lamina and L2 cells. In both the retina and lamina, CRY seems to be a repressor of clk expression. In L2 interneurons per expression is not cyclic indicating the other function of PER in those cells than in the circadian molecular clock. In contrast to per and tim, the pattern of clk and cry expression is similar in both the retina and lamina. The retina holds the autonomous oscillators but the expression of cry and ccgs, Atpalpha and nrv2, is also regulated by inputs from the pacemaker transmitted by PDF and ITP neuropeptides. PMID- 26441521 TI - Neurodegeneration and microtubule dynamics: death by a thousand cuts. AB - Microtubules form important cytoskeletal structures that play a role in establishing and maintaining neuronal polarity, regulating neuronal morphology, transporting cargo, and scaffolding signaling molecules to form signaling hubs. Within a neuronal cell, microtubules are found to have variable lengths and can be both stable and dynamic. Microtubule associated proteins, post-translational modifications of tubulin subunits, microtubule severing enzymes, and signaling molecules are all known to influence both stable and dynamic pools of microtubules. Microtubule dynamics, the process of interconversion between stable and dynamic pools, and the proportions of these two pools have the potential to influence a wide variety of cellular processes. Reduced microtubule stability has been observed in several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and tauopathies like Progressive Supranuclear Palsy. Hyperstable microtubules, as seen in Hereditary Spastic Paraplegia (HSP), also lead to neurodegeneration. Therefore, the ratio of stable and dynamic microtubules is likely to be important for neuronal function and perturbation in microtubule dynamics might contribute to disease progression. PMID- 26441525 TI - Breaking boundaries-coagulation and fibrinolysis at the neurovascular interface. AB - Blood proteins at the neurovascular unit (NVU) are emerging as important molecular determinants of communication between the brain and the immune system. Over the past two decades, roles for the plasminogen activation (PA)/plasmin system in fibrinolysis have been extended from peripheral dissolution of blood clots to the regulation of central nervous system (CNS) functions in physiology and disease. In this review, we discuss how fibrin and its proteolytic degradation affect neuroinflammatory, degenerative and repair processes. In particular, we focus on novel functions of fibrin-the final product of the coagulation cascade and the main substrate of plasmin-in the activation of immune responses and trafficking of immune cells into the brain. We also comment on the suitability of the coagulation and fibrinolytic systems as potential biomarkers and drug targets in diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD) and stroke. Studying coagulation and fibrinolysis as major molecular pathways that regulate cellular functions at the NVU has the potential to lead to the development of novel strategies for the detection and treatment of neurologic diseases. PMID- 26441526 TI - Potentials and limits to enhance cognitive functions in healthy and pathological aging by tDCS. AB - Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that is increasingly used in research and clinical settings to enhance the effects of cognitive training. In our present review, we will first summarize studies using tDCS alone and in combination with cognitive training in older adults and patients with Alzheimer's dementia (AD). We will also review one study (Meinzer et al., 2014c) that showed an improvement in cognitive performance during anodal tDCS over the left inferior frontal cortex in patients with mild cognitive impairment (MCI) which is regarded as a prodromal stage of AD. Although promising short-term results have been reported, evidence from randomized controlled trials (RCTs) with sufficient sample sizes is scarce. In addition, stimulation protocols (in terms of intensity, duration, and repetition of stimulation) that lead to sustained improvements in outcome measures relevant for daily life still remain to be established. Following, we will discuss modulating factors such as technical parameters as well as the question whether there are specific cognitive functions (e.g., learning, memory consolidation, executive control) which are more amenable to tDCS enhancement than others. Finally, we will highlight future directions and limitations in this field and emphasize the need to conduct RCTs to establish efficacy of interventions for activities of daily life for a given patient population. PMID- 26441527 TI - Editorial: The role of glia in plasticity and behavior. PMID- 26441529 TI - Editorial: Progenitor diversity and neural cell specification in the central nervous system. PMID- 26441528 TI - Systematic Review of the Neurobiological Relevance of Chemokines to Psychiatric Disorders. AB - Psychiatric disorders are highly prevalent and disabling conditions of increasing public health relevance. Much recent research has focused on the role of cytokines in the pathophysiology of psychiatric disorders; however, the related family of immune proteins designated chemokines has been relatively neglected. Chemokines were originally identified as having chemotactic function on immune cells; however, recent evidence has begun to elucidate novel, brain-specific functions of these proteins of relevance to the mechanisms of psychiatric disorders. A systematic review of both human and animal literature in the PubMed and Google Scholar databases was undertaken. After application of all inclusion and exclusion criteria, 157 references were remained for the review. Some early mechanistic evidence does associate select chemokines with the neurobiological processes, including neurogenesis, modulation of the neuroinflammatory response, regulation of the hypothalamus-pituitary-adrenal axis, and modulation of neurotransmitter systems. This early evidence however does not clearly demonstrate any specificity for a certain psychiatric disorder, but is primarily relevant to mechanisms which are shared across disorders. Notable exceptions include CCL11 that has recently been shown to impair hippocampal function in aging - of distinct relevance to Alzheimer's disease and depression in the elderly, and pre-natal exposure to CXCL8 that may disrupt early neurodevelopmental periods predisposing to schizophrenia. Pro-inflammatory chemokines, such as CCL2, CCL7, CCL8, CCL12, and CCL13, have been shown to drive chemotaxis of pro-inflammatory cells to the inflamed or injured CNS. Likewise, CX3CL has been implicated in promoting glial cells activation, pro-inflammatory cytokines secretion, expression of ICAM-1, and recruitment of CD4+ T-cells into the CNS during neuroinflammatory processes. With further translational research, chemokines may present novel diagnostic and/or therapeutic targets in psychiatric disorders. PMID- 26441530 TI - Quantifying mechanical force in axonal growth and guidance. AB - Mechanical force plays a fundamental role in neuronal development, physiology, and regeneration. In particular, research has shown that force is involved in growth cone-mediated axonal growth and guidance as well as stretch-induced elongation when an organism increases in size after forming initial synaptic connections. However, much of the details about the exact role of force in these fundamental processes remain unknown. In this review, we highlight: (1) standing questions concerning the role of mechanical force in axonal growth and guidance; and (2) different experimental techniques used to quantify forces in axons and growth cones. We believe that satisfying answers to these questions will require quantitative information about the relationship between elongation, forces, cytoskeletal dynamics, axonal transport, signaling, substrate adhesion, and stiffness contributing to directional growth advance. Furthermore, we address why a wide range of force values have been reported in the literature, and what these values mean in the context of neuronal mechanics. We hope that this review will provide a guide for those interested in studying the role of force in development and regeneration of neuronal networks. PMID- 26441531 TI - Expression and function of Neuregulin 1 and its signaling system ERBB2/3 in the enteric nervous system. AB - Neuregulin 1 (NRG1) is suggested to promote the survival and maintenance of the enteric nervous system (ENS). As deficiency in its corresponding receptor signaling complex ERBB2/ERBB3 leads to postnatal colonic hypo/aganglionosis we assessed the distributional and expressional pattern of the NRG1-ERBB2/ERBB3 system in the human colon and explored the neurotrophic capacity of NRG1 on cultured enteric neurons. Site-specific mRNA expression of the NRG1-ERBB2/3 system was determined in microdissected samples harvested from enteric musculature and ganglia. Localization of NRG1, ERBB2 and ERBB3 was determined by dual-label-immunohistochemistry using pan-neuronal and pan-glial markers. Morphometric analysis was performed on NRG1-stimulated rat enteric nerve cultures to evaluate neurotrophic effects. mRNA expression of the NRG1-ERBB2/3 system was determined by qPCR. Co-localization of NRG1 with neuronal or synaptic markers was analyzed in enteric nerve cultures stimulated with glial cell line-derived neurotrophic factor (GDNF). The NRG1 system was expressed in both neurons and glial cells of enteric ganglia and in nerve fibers. NRG1 significantly enhanced growth parameters in enteric nerve cell cultures and ErB3 mRNA expression was down-regulated upon NRG1 stimulation. GDNF negatively regulates ErbB2 and ErbB3 mRNA expression. The NRG1-ERBB2/3 system is physiologically present in the human ENS and NRG1 acts as a neurotrophic factor for the ENS. The down-regulation of ErbB3/ErbB2 in GDNF stimulated nerve cell cultures points to an interaction of both neurotrophic factors. Thus, the data may provide a basis to assess disturbed signaling components of the NRG1 system in enteric neuropathies. PMID- 26441532 TI - Activated regulatory T cell regulates neural stem cell proliferation in the subventricular zone of normal and ischemic mouse brain through interleukin 10. AB - Recent studies have demonstrated that the depletion of Regulatory T cells (Tregs) inhibits neural progenitor cell migration after brain ischemia. However, whether Tregs affect neural stem/progenitor cell proliferation is unclear. We explored the effect of Tregs on neurogenesis in the subventricular zone (SVZ) after ischemia. Tregs were isolated and activated in vitro. Adult male C57BL/6 mice underwent 60 min transient middle cerebral artery occlusion (tMCAO). Then Tregs (1 * 10(5)) were injected into the left lateral ventricle (LV) of normal and ischemic mouse brain. Neurogenesis was determined by immunostaining. The mechanism was examined by inhibiting interleukin 10 (IL-10) and transforming growth factor (TGF-beta) signaling. We found that the number of BrdU(+) cells in the SVZ was significantly increased in the activated Tregs-treated mice. Double immunostaining showed that these BrdU(+) cells expressed Mash1. Blocking IL-10 reduced the number of Mash1(+)/BrdU(+) cells, but increased the amount of GFAP(+)/BrdU(+) cells. Here, we conclude that activated Tregs enhanced neural stem cell (NSC) proliferation in the SVZ of normal and ischemic mice; blockage of IL-10 abolished Tregs-mediated NSC proliferation in vivo and in vitro. Our results suggest that activated Tregs promoted NSC proliferation via IL-10, which provides a new therapeutic approach for ischemic stroke. PMID- 26441533 TI - Neonatal seizures alter NMDA glutamate receptor GluN2A and 3A subunit expression and function in hippocampal CA1 neurons. AB - Neonatal seizures are commonly caused by hypoxic and/or ischemic injury during birth and can lead to long-term epilepsy and cognitive deficits. In a rodent hypoxic seizure (HS) model, we have previously demonstrated a critical role for seizure-induced enhancement of the AMPA subtype of glutamate receptor (GluA) in epileptogenesis and cognitive consequences, in part due to GluA maturational upregulation of expression. Similarly, as the expression and function of the N Methyl-D-aspartate (NMDA) subtype of glutamate receptor (GluN) is also developmentally controlled, we examined how early life seizures during the critical period of synaptogenesis could modify GluN development and function. In a postnatal day (P)10 rat model of neonatal seizures, we found that seizures could alter GluN2/3 subunit composition of GluNs and physiological function of synaptic GluNs. In hippocampal slices removed from rats within 48-96 h following seizures, the amplitudes of synaptic GluN-mediated evoked excitatory postsynaptic currents (eEPSCs) were elevated in CA1 pyramidal neurons. Moreover, GluN eEPSCs showed a decreased sensitivity to GluN2B selective antagonists and decreased Mg(2+) sensitivity at negative holding potentials, indicating a higher proportion of GluN2A and GluN3A subunit function, respectively. These physiological findings were accompanied by a concurrent increase in GluN2A phosphorylation and GluN3A protein. These results suggest that altered GluN function and expression could potentially contribute to future epileptogenesis following neonatal seizures, and may represent potential therapeutic targets for the blockade of future epileptogenesis in the developing brain. PMID- 26441534 TI - Microglia mechanics: immune activation alters traction forces and durotaxis. AB - Microglial cells are key players in the primary immune response of the central nervous system. They are highly active and motile cells that chemically and mechanically interact with their environment. While the impact of chemical signaling on microglia function has been studied in much detail, the current understanding of mechanical signaling is very limited. When cultured on compliant substrates, primary microglial cells adapted their spread area, morphology, and actin cytoskeleton to the stiffness of their environment. Traction force microscopy revealed that forces exerted by microglia increase with substrate stiffness until reaching a plateau at a shear modulus of ~5 kPa. When cultured on substrates incorporating stiffness gradients, microglia preferentially migrated toward stiffer regions, a process termed durotaxis. Lipopolysaccharide-induced immune-activation of microglia led to changes in traction forces, increased migration velocities and an amplification of durotaxis. We finally developed a mathematical model connecting traction forces with the durotactic behavior of migrating microglial cells. Our results demonstrate that microglia are susceptible to mechanical signals, which could be important during central nervous system development and pathologies. Stiffness gradients in tissue surrounding neural implants such as electrodes, for example, could mechanically attract microglial cells, thus facilitating foreign body reactions detrimental to electrode functioning. PMID- 26441535 TI - ProNGF derived from rat sciatic nerves downregulates neurite elongation and axon specification in PC12 cells. AB - Several reports have shown that a sciatic nerve conditioned media (CM) causes neuronal-like differentiation in PC12 cells. This differentiation is featured by neurite outgrowth, which are exclusively dendrites, without axon or sodium current induction. In previous studies, our group reported that the CM supplemented with a generic inhibitor for tyrosine kinase receptors (k252a) enhanced the CM-induced morphological differentiation upregulating neurite outgrowth, axonal formation and sodium current elicitation. Sodium currents were also induced by depletion of endogenous precursor of nerve growth factorr (proNGF) from the CM (pNGFd-CM). Given that sodium currents, neurite outgrowth and axon specification are important features of neuronal differentiation, in the current manuscript, first we investigated if proNGF was hindering the full PC12 cell neuronal-like differentiation. Second, we studied the effects of exogenous wild type (pNGFwt) and mutated (pNGFmut) proNGF isoforms over sodium currents and whether or not their addition to the pNGFd-CM would prevent sodium current elicitation. Third, we investigated if proNGF was exerting its negative regulation through the sortilin receptor, and for this, the proNGF action was blocked with neurotensin (NT), a factor known to compete with proNGF for sortilin. Thereby, here we show that pNGFd-CM enhanced cell differentiation, cell proportion with long neurites, total neurite length, induced axonal formation and sodium current elicitation. Interestingly, treatment of PC12 cells with wild type or mutated proNGF isoforms elicited sodium currents. Supplementing pNGFd-CM with pNGFmut reduced 35% the sodium currents. On the other hand, pNGFd-CM+pNGFwt induced larger sodium currents than pNGFd-CM. Finally, treatments with CM supplemented with NT showed that sortilin was mediating proNGF negative regulation, since its blocking induced similar effects than the pNGFd-CM treatment. Altogether, our results suggest that proNGF within the CM, is one of the main inhibitors of full neuronal differentiation, acting through sortilin receptor. PMID- 26441538 TI - Tracking the activity-dependent diffusion of synaptic proteins using restricted photoconversion of Dendra2. AB - Spines are small protrusions on dendritic membranes receiving inputs from axonal termini. They consist in a head connected to the dendritic shaft by a narrow neck and contain multiple synaptic proteins that interact in a coordinated manner to allow for synaptic communication. This process involves many proteins that are moving in and out spines. However, comparing this synaptodendritic movement in basal and stimulated conditions is very challenging. Here we describe an elegant method to measure the activity-dependent diffusion of synaptic proteins using Dendra2 photoconversion. We provide a successful method to obtain Dendra2 photoconverted images and a step-by-step procedure to analyze the data. This live imaging approach may also apply to investigate the diffusion of proteins across other subcellular compartments or organelles including but not restricted to, nucleus, nucleolus, ER, or vesicular structures. Once the imaging system is set up, data can be acquired in 1-30 min and analyzed in approximately 1-4 h. PMID- 26441537 TI - CD36 is involved in oleic acid detection by the murine olfactory system. AB - Olfactory signals influence food intake in a variety of species. To maximize the chances of finding a source of calories, an animal's preference for fatty foods and triglycerides already becomes apparent during olfactory food search behavior. However, the molecular identity of both receptors and ligands mediating olfactory dependent fatty acid recognition are, so far, undescribed. We here describe that a subset of olfactory sensory neurons expresses the fatty acid receptor CD36 and demonstrate a receptor-like localization of CD36 in olfactory cilia by STED microscopy. CD36-positive olfactory neurons share olfaction-specific transduction elements and project to numerous glomeruli in the ventral olfactory bulb. In accordance with the described roles of CD36 as fatty acid receptor or co-receptor in other sensory systems, the number of olfactory neurons responding to oleic acid, a major milk component, in Ca(2+) imaging experiments is drastically reduced in young CD36 knock-out mice. Strikingly, we also observe marked age dependent changes in CD36 localization, which is prominently present in the ciliary compartment only during the suckling period. Our results support the involvement of CD36 in fatty acid detection by the mammalian olfactory system. PMID- 26441536 TI - The aged brain: genesis and fate of residual progenitor cells in the subventricular zone. AB - Neural stem cells (NSCs) persist in the adult mammalian brain through life. The subventricular zone (SVZ) is the largest source of stem cells in the nervous system, and continuously generates new neuronal and glial cells involved in brain regeneration. During aging, the germinal potential of the SVZ suffers a widespread decline, but the causes of this turn down are not fully understood. This review provides a compilation of the current knowledge about the age-related changes in the NSC population, as well as the fate of the newly generated cells in the aged brain. It is known that the neurogenic capacity is clearly disrupted during aging, while the production of oligodendroglial cells is not compromised. Interestingly, the human brain seems to primarily preserve the ability to produce new oligodendrocytes instead of neurons, which could be related to the development of neurological disorders. Further studies in this matter are required to improve our understanding and the current strategies for fighting neurological diseases associated with senescence. PMID- 26441539 TI - Neto2-null mice have impaired GABAergic inhibition and are susceptible to seizures. AB - Neto2 is a transmembrane protein that interacts with the neuron-specific K(+)-Cl( ) cotransporter (KCC2) in the central nervous system (CNS). Efficient KCC2 transport is essential for setting the neuronal Cl(-) gradient, which is required for fast GABAergic inhibition. Neto2 is required to maintain the normal abundance of KCC2 in neurons, and increases KCC2 function by binding to the active oligomeric form of this cotransporter. In the present study, we characterized GABAergic inhibition and KCC2-mediated neuronal chloride homeostasis in pyramidal neurons from adult hippocampal slices. Using gramicidin perforated patch clamp recordings we found that the reversal potential for GABA (EGABA) was significantly depolarized. We also observed that surface levels of KCC2 and phosphorylation of KCC2 serine 940 (Ser940) were reduced in Neto2(-/-) neurons compared to wild-type controls. To examine GABAergic inhibition we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) and found that Neto2(-/-) neurons had significant reductions in both their amplitude and frequency. Based on the critical role of Neto2 in regulating GABAergic inhibition we rationalized that Neto2-null mice would be prone to seizure activity. We found that Neto2-null mice demonstrated a decrease in the latency to pentylenetetrazole (PTZ)-induced seizures and an increase in seizure severity. PMID- 26441540 TI - Proteolytic regulation of synaptic plasticity in the mouse primary visual cortex: analysis of matrix metalloproteinase 9 deficient mice. AB - The extracellular matrix (ECM) is known to play important roles in regulating neuronal recovery from injury. The ECM can also impact physiological synaptic plasticity, although this process is less well understood. To understand the impact of the ECM on synaptic function and remodeling in vivo, we examined ECM composition and proteolysis in a well-established model of experience-dependent plasticity in the visual cortex. We describe a rapid change in ECM protein composition during Ocular Dominance Plasticity (ODP) in adolescent mice, and a loss of ECM remodeling in mice that lack the extracellular protease, matrix metalloproteinase-9 (MMP9). Loss of MMP9 also attenuated functional ODP following monocular deprivation (MD) and reduced excitatory synapse density and spine density in sensory cortex. While we observed no change in the morphology of existing dendritic spines, spine dynamics were altered, and MMP9 knock-out (KO) mice showed increased turnover of dendritic spines over a period of 2 days. We also analyzed the effects of MMP9 loss on microglia, as these cells are involved in extracellular remodeling and have been recently shown to be important for synaptic plasticity. MMP9 KO mice exhibited very limited changes in microglial morphology. Ultrastructural analysis, however, showed that the extracellular space surrounding microglia was increased, with concomitant increases in microglial inclusions, suggesting possible changes in microglial function in the absence of MMP9. Taken together, our results show that MMP9 contributes to ECM degradation, synaptic dynamics and sensory-evoked plasticity in the mouse visual cortex. PMID- 26441541 TI - Cell-type specific modulation of neocortical UP and DOWN states. PMID- 26441542 TI - Development and regulation of chloride homeostasis in the central nervous system. AB - gamma-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter of the mature central nervous system (CNS). The developmental switch of GABAergic transmission from excitation to inhibition is induced by changes in Cl(-) gradients, which are generated by cation-Cl(-) co-transporters. An accumulation of Cl(-) by the Na(+)-K(+)-2Cl(-) co-transporter (NKCC1) increases the intracellular Cl(-) concentration ([Cl(-)]i) such that GABA depolarizes neuronal precursors and immature neurons. The subsequent ontogenetic switch, i.e., upregulation of the Cl(-)-extruder KCC2, which is a neuron-specific K(+)-Cl(-) co transporter, with or without downregulation of NKCC1, results in low [Cl(-)]i levels and the hyperpolarizing action of GABA in mature neurons. Development of Cl(-) homeostasis depends on developmental changes in NKCC1 and KCC2 expression. Generally, developmental shifts (decreases) in [Cl(-)]i parallel the maturation of the nervous system, e.g., early in the spinal cord, hypothalamus and thalamus, followed by the limbic system, and last in the neocortex. There are several regulators of KCC2 and/or NKCC1 expression, including brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF), and cystic fibrosis transmembrane conductance regulator (CFTR). Therefore, regionally different expression of these regulators may also contribute to the regional developmental shifts of Cl(-) homeostasis. KCC2 and NKCC1 functions are also regulated by phosphorylation by enzymes such as PKC, Src-family tyrosine kinases, and WNK1-4 and their downstream effectors STE20/SPS1-related proline/alanine-rich kinase (SPAK)-oxidative stress responsive kinase-1 (OSR1). In addition, activation of these kinases is modulated by humoral factors such as estrogen and taurine. Because these transporters use the electrochemical driving force of Na(+) and K(+) ions, topographical interaction with the Na(+)-K(+) ATPase and its modulators such as creatine kinase (CK) should modulate functions of Cl(-) transporters. Therefore, regional developmental regulation of these regulators and modulators of Cl(-) transporters may also play a pivotal role in the development of Cl(-) homeostasis. PMID- 26441543 TI - Dual processing of sulfated steroids in the olfactory system of an anuran amphibian. AB - Chemical communication is widespread in amphibians, but if compared to later diverging tetrapods the available functional data is limited. The existing information on the vomeronasal system of anurans is particularly sparse. Amphibians represent a transitional stage in the evolution of the olfactory system. Most species have anatomically separated main and vomeronasal systems, but recent studies have shown that in anurans their molecular separation is still underway. Sulfated steroids function as migratory pheromones in lamprey and have recently been identified as natural vomeronasal stimuli in rodents. Here we identified sulfated steroids as the first known class of vomeronasal stimuli in the amphibian Xenopus laevis. We show that sulfated steroids are detected and concurrently processed by the two distinct olfactory subsystems of larval Xenopus laevis, the main olfactory system and the vomeronasal system. Our data revealed a similar but partially different processing of steroid-induced responses in the two systems. Differences of detection thresholds suggest that the two information channels are not just redundant, but rather signal different information. Furthermore, we found that larval and adult animals excrete multiple sulfated compounds with physical properties consistent with sulfated steroids. Breeding tadpole and frog water including these compounds activated a large subset of sensory neurons that also responded to synthetic steroids, showing that sulfated steroids are likely to convey intraspecific information. Our findings indicate that sulfated steroids are conserved vomeronasal stimuli functioning in phylogenetically distant classes of tetrapods living in aquatic and terrestrial habitats. PMID- 26441544 TI - Bi-frontal transcranial alternating current stimulation in the ripple range reduced overnight forgetting. AB - High frequency oscillations in the hippocampal structures recorded during sleep have been proved to be essential for long-term episodic memory consolidation in both animals and in humans. The aim of this study was to test if transcranial Alternating Current Stimulation (tACS) of the dorsolateral prefrontal cortex (DLPFC) in the hippocampal ripple range, applied bi-frontally during encoding, could modulate declarative memory performance, measured immediately after encoding, and after a night's sleep. An associative word-pair learning test was used. During an evening encoding phase, participants received 1 mA 140 Hz tACS or sham stimulation over both DLPFCs for 10 min while being presented twice with a list of word-pairs. Cued recall performance was investigated 10 min after training and the morning following the training session. Forgetting from evening to morning was observed in the sham condition, but not in the 140 Hz stimulation condition. 140 Hz tACS during encoding may have an effect on the consolidation of declarative material. PMID- 26441545 TI - Bypassing hazard of housekeeping genes: their evaluation in rat granule neurons treated with cerebrospinal fluid of multiple sclerosis subjects. AB - Gene expression studies employing real-time PCR has become an intrinsic part of biomedical research. Appropriate normalization of target gene transcript(s) based on stably expressed housekeeping genes is crucial in individual experimental conditions to obtain accurate results. In multiple sclerosis (MS), several gene expression studies have been undertaken, however, the suitability of housekeeping genes to express stably in this disease is not yet explored. Recent research suggests that their expression level may vary under different experimental conditions. Hence it is indispensible to evaluate their expression stability to accurately normalize target gene transcripts. The present study aims to evaluate the expression stability of seven housekeeping genes in rat granule neurons treated with cerebrospinal fluid of MS patients. The selected reference genes were quantified by real time PCR and their expression stability was assessed using GeNorm and NormFinder algorithms. GeNorm identified transferrin receptor (Tfrc) and microglobulin beta-2 (B2m) the most stable genes followed by ribosomal protein L19 (Rpl19) whereas beta-actin (ActB) and glyceraldehyde-3-phosphate dehydrogenase (Gapdh) the most fluctuated ones in these neurons. NormFinder identified Tfrc as the best invariable gene followed by B2m and Rpl19. ActB and Gapdh were the least stable genes as analyzed by NormFinder algorithm. Both methods reported Tfrc and B2m the most stably expressed genes and Gapdh the least stable one. Altogether our data demonstrate the significance of pre-validation of housekeeping genes for accurate normalization and indicates Tfrc and B2m as best endogenous controls in MS. ActB and Gapdh are not recommended in gene expression studies related to current one. PMID- 26441546 TI - A new measure for the strength of electrical synapses. AB - Electrical synapses, like chemical synapses, mediate intraneuronal communication. Electrical synapses are typically quantified by subthreshold measurements of coupling, which fall short in describing their impact on spiking activity in coupled neighbors. Here, we describe a novel measurement for electrical synapse strength that directly evaluates the effect of synaptically transmitted activity on spike timing. This method, also applicable to neurotransmitter-based synapses, communicates the considerable strength of electrical synapses. For electrical synapses measured in rodent slices of the thalamic reticular nucleus and in simple model neurons, spike timing is modulated by tens of ms by activity in a coupled neighbor. PMID- 26441548 TI - The olfactory thalamus: unanswered questions about the role of the mediodorsal thalamic nucleus in olfaction. AB - The mediodorsal thalamic nucleus (MDT) is a higher order thalamic nucleus and its role in cognition is increasingly well established. Interestingly, components of the MDT also have a somewhat unique sensory function as they link primary olfactory cortex to orbitofrontal associative cortex. In fact, anatomical evidence firmly demonstrates that the MDT receives direct input from primary olfactory areas including the piriform cortex and has dense reciprocal connections with the orbitofrontal cortex. The functions of this olfactory pathway have been poorly explored but lesion, imaging, and electrophysiological studies suggest that these connections may be involved in olfactory processing including odor perception, discrimination, learning, and attention. However, many important questions regarding the MDT and olfaction remain unanswered. Our goal here is not only to briefly review the existing literature but also to highlight some of the remaining questions that need to be answered to better define the role(s) of the MDT in olfactory processing. PMID- 26441547 TI - Spatial diversity of spontaneous activity in the cortex. AB - The neocortex is a layered sheet across which a basic organization is thought to widely apply. The variety of spontaneous activity patterns is similar throughout the cortex, consistent with the notion of a basic cortical organization. However, the basic organization is only an outline which needs adjustments and additions to account for the structural and functional diversity across cortical layers and areas. Such diversity suggests that spontaneous activity is spatially diverse in any particular behavioral state. Accordingly, this review summarizes the laminar and areal diversity in cortical activity during fixation and slow oscillations, and the effects of attention, anesthesia and plasticity on the cortical distribution of spontaneous activity. Among questions that remain open, characterizing the spatial diversity in spontaneous membrane potential may help elucidate how differences in circuitry among cortical regions supports their varied functions. More work is also needed to understand whether cortical spontaneous activity not only reflects cortical circuitry, but also contributes to determining the outcome of plasticity, so that it is itself a factor shaping the functional diversity of the cortex. PMID- 26441549 TI - Efficient population coding of naturalistic whisker motion in the ventro posterior medial thalamus based on precise spike timing. AB - The rodent whisker-associated thalamic nucleus (VPM) contains a somatotopic map where whisker representation is divided into distinct neuronal sub-populations, called "barreloids". Each barreloid projects to its associated cortical barrel column and so forms a gateway for incoming sensory stimuli to the barrel cortex. We aimed to determine how the population of neurons within one barreloid encodes naturalistic whisker motion. In rats, we recorded the extracellular activity of up to nine single neurons within a single barreloid, by implanting silicon probes parallel to the longitudinal axis of the barreloids. We found that play-back of texture-induced whisker motion evoked sparse responses, timed with millisecond precision. At the population level, there was synchronous activity: however, different subsets of neurons were synchronously active at different times. Mutual information between population responses and whisker motion increased near linearly with population size. When normalized to factor out firing rate differences, we found that texture was encoded with greater informational efficiency than white noise. These results indicate that, within each VPM barreloid, there is a rich and efficient population code for naturalistic whisker motion based on precisely timed, population spike patterns. PMID- 26441551 TI - Asymmetric projections of the arcuate fasciculus to the temporal cortex underlie lateralized language function in the human brain. AB - The arcuate fasciculus (AF) in the human brain has asymmetric structural properties. However, the topographic organization of the asymmetric AF projections to the cortex and its relevance to cortical function remain unclear. Here we mapped the posterior projections of the human AF in the inferior parietal and lateral temporal cortices using surface-based structural connectivity analysis based on diffusion MRI and investigated their hemispheric differences. We then performed the cross-modal comparison with functional connectivity based on resting-state functional MRI (fMRI) and task-related cortical activation based on fMRI using a semantic classification task of single words. Structural connectivity analysis showed that the left AF connecting to Broca's area predominantly projected in the lateral temporal cortex extending from the posterior superior temporal gyrus to the mid part of the superior temporal sulcus and the middle temporal gyrus, whereas the right AF connecting to the right homolog of Broca's area predominantly projected to the inferior parietal cortex extending from the mid part of the supramarginal gyrus to the anterior part of the angular gyrus. The left-lateralized projection regions of the AF in the left temporal cortex had asymmetric functional connectivity with Broca's area, indicating structure-function concordance through the AF. During the language task, left-lateralized cortical activation was observed. Among them, the brain responses in the temporal cortex and Broca's area that were connected through the left-lateralized AF pathway were specifically correlated across subjects. These results suggest that the human left AF, which structurally and functionally connects the mid temporal cortex and Broca's area in asymmetrical fashion, coordinates the cortical activity in these remote cortices during a semantic decision task. The unique feature of the left AF is discussed in the context of the human capacity for language. PMID- 26441552 TI - A clearer view of the insect brain-combining bleaching with standard whole-mount immunocytochemistry allows confocal imaging of pigment-covered brain areas for 3D reconstruction. AB - In the study of insect neuroanatomy, three-dimensional (3D) reconstructions of neurons and neuropils have become a standard technique. As images have to be obtained from whole-mount brain preparations, pigmentation on the brain surface poses a serious challenge to imaging. In insects, this is a major problematic in the first visual neuropil of the optic lobe, the lamina, which is obstructed by the pigment of the retina as well as by the pigmented fenestration layer. This has prevented inclusion of this major processing center of the insect visual system into most neuroanatomical brain atlases and hinders imaging of neurons within the lamina by confocal microscopy. It has recently been shown that hydrogen peroxide bleaching is compatible with immunohistochemical labeling in insect brains, and we therefore developed a simple technique for removal of pigments on the surface of insect brains by chemical bleaching. We show that our technique enables imaging of the pigment-obstructed regions of insect brains when combined with standard protocols for both anti-synapsin-labeled as well as neurobiotin-injected samples. This method can be combined with different fixation procedures, as well as different fluorophore excitation wavelengths without negative effects on staining quality. It can therefore serve as an effective addition to most standard histology protocols used in insect neuroanatomy. PMID- 26441553 TI - Heterogeneous generation of new cells in the adult echinoderm nervous system. AB - Adult neurogenesis, generation of new functional cells in the mature central nervous system (CNS), has been documented in a number of diverse organisms, ranging from humans to invertebrates. However, the origin and evolution of this phenomenon is still poorly understood for many of the key phylogenetic groups. Echinoderms are one such phylum, positioned as a sister group to chordates within the monophyletic clade Deuterostomia. They are well known for the ability of their adult organs, including the CNS, to completely regenerate after injury. Nothing is known, however, about production of new cells in the nervous tissue under normal physiological conditions in these animals. In this study, we show that new cells are continuously generated in the mature radial nerve cord (RNC) of the sea cucumber Holothuria glaberrima. Importantly, this neurogenic activity is not evenly distributed, but is significantly more extensive in the lateral regions of the RNC than along the midline. Some of the new cells generated in the apical region of the ectoneural neuroepithelium leave their place of origin and migrate basally to populate the neural parenchyma. Gene expression analysis showed that generation of new cells in the adult sea cucumber CNS is associated with transcriptional activity of genes known to be involved in regulation of various aspects of neurogenesis in other animals. Further analysis of one of those genes, the transcription factor Myc, showed that it is expressed, in some, but not all radial glial cells, suggesting heterogeneity of this CNS progenitor cell population in echinoderms. PMID- 26441550 TI - Morphological changes of glutamatergic synapses in animal models of Parkinson's disease. AB - The striatum and the subthalamic nucleus (STN) are the main entry doors for extrinsic inputs to reach the basal ganglia (BG) circuitry. The cerebral cortex, thalamus and brainstem are the key sources of glutamatergic inputs to these nuclei. There is anatomical, functional and neurochemical evidence that glutamatergic neurotransmission is altered in the striatum and STN of animal models of Parkinson's disease (PD) and that these changes may contribute to aberrant network neuronal activity in the BG-thalamocortical circuitry. Postmortem studies of animal models and PD patients have revealed significant pathology of glutamatergic synapses, dendritic spines and microcircuits in the striatum of parkinsonians. More recent findings have also demonstrated a significant breakdown of the glutamatergic corticosubthalamic system in parkinsonian monkeys. In this review, we will discuss evidence for synaptic glutamatergic dysfunction and pathology of cortical and thalamic inputs to the striatum and STN in models of PD. The potential functional implication of these alterations on synaptic integration, processing and transmission of extrinsic information through the BG circuits will be considered. Finally, the significance of these pathological changes in the pathophysiology of motor and non-motor symptoms in PD will be examined. PMID- 26441555 TI - Editorial: Parkinson's disease: cell vulnerability and disease progression. PMID- 26441554 TI - Comparative density of CCK- and PV-GABA cells within the cortex and hippocampus. AB - Cholecystokinin (CCK)- and parvalbumin (PV)-expressing neurons constitute the two major populations of perisomatic GABAergic neurons in the cortex and the hippocampus. As CCK- and PV-GABA neurons differ in an array of morphological, biochemical and electrophysiological features, it has been proposed that they form distinct inhibitory ensembles which differentially contribute to network oscillations and behavior. However, the relationship and balance between CCK- and PV-GABA neurons in the inhibitory networks of the brain is currently unclear as the distribution of these cells has never been compared on a large scale. Here, we systemically investigated the distribution of CCK- and PV-GABA cells across a wide number of discrete forebrain regions using an intersectional genetic approach. Our analysis revealed several novel trends in the distribution of these cells. While PV-GABA cells were more abundant overall, CCK-GABA cells outnumbered PV-GABA cells in several subregions of the hippocampus, medial prefrontal cortex and ventrolateral temporal cortex. Interestingly, CCK-GABA cells were relatively more abundant in secondary/association areas of the cortex (V2, S2, M2, and AudD/AudV) than they were in corresponding primary areas (V1, S1, M1, and Aud1). The reverse trend was observed for PV-GABA cells. Our findings suggest that the balance between CCK- and PV-GABA cells in a given cortical region is related to the type of processing that area performs; inhibitory networks in the secondary cortex tend to favor the inclusion of CCK-GABA cells more than networks in the primary cortex. The intersectional genetic labeling approach employed in the current study expands upon the ability to study molecularly defined subsets of GABAergic neurons. This technique can be applied to the investigation of neuropathologies which involve disruptions to the GABAergic system, including schizophrenia, stress, maternal immune activation and autism. PMID- 26441557 TI - Editorial: Individual differences: from neurobiological bases to new insight on approach and avoidance behavior. PMID- 26441556 TI - Neuropeptide S- and Neuropeptide S receptor-expressing neuron populations in the human pons. AB - Neuropeptide S (NPS) is a regulatory peptide with potent pharmacological effects. In rodents, NPS is expressed in a few pontine cell clusters. Its receptor (NPSR1) is, however, widely distributed in the brain. The anxiolytic and arousal promoting effects of NPS make the NPS-NPSR1 system an interesting potential drug target in mood-related disorders. However, so far possible disease-related mechanisms involving NPS have only been studied in rodents. To validate the relevance of these animal studies for i.a. drug development, we have explored the distribution of NPS-expressing neurons in the human pons using in situ hybridization and stereological methods and we compared the distribution of NPS mRNA expressing neurons in the human and rat brain. The calculation revealed a total number of 22,317 +/- 2411 NPS mRNA-positive neurons in human, bilaterally. The majority of cells (84%) were located in the parabrachial area in human: in the extension of the medial and lateral parabrachial nuclei, in the Kolliker-Fuse nucleus and around the adjacent lateral lemniscus. In human, in sharp contrast to the rodents, only very few NPS-positive cells (5%) were found close to the locus coeruleus. In addition, we identified a smaller cell cluster (11% of all NPS cells) in the pontine central gray matter both in human and rat, which has not been described previously even in rodents. We also examined the distribution of NPSR1 mRNA-expressing neurons in the human pons. These cells were mainly located in the rostral laterodorsal tegmental nucleus, the cuneiform nucleus, the microcellular tegmental nucleus region and in the periaqueductal gray. Our results show that both NPS and NPSR1 in the human pons are preferentially localized in regions of importance for integration of visceral autonomic information and emotional behavior. The reported interspecies differences must, however, be considered when looking for targets for new pharmacotherapeutical interventions. PMID- 26441558 TI - BASCO: a toolbox for task-related functional connectivity. AB - BASCO (BetA Series COrrelation) is a user-friendly MATLAB toolbox with a graphical user interface (GUI) which allows investigating functional connectivity in event-related functional magnetic resonance imaging (fMRI) data. Connectivity analyses extend and compliment univariate activation analyses since the actual interaction between brain regions involved in a task can be explored. BASCO supports seed-based functional connectivity as well as brain network analyses. Although there are a multitude of advanced toolboxes for investigating resting state functional connectivity, BASCO is the first toolbox for evaluating task related whole-brain functional connectivity employing a large number of network nodes. Thus, BASCO allows investigating task-specific rather than resting-state networks. Here, we summarize the main features of the toolbox and describe the methods and algorithms. PMID- 26441559 TI - Effect of saccade automaticity on perisaccadic space compression. AB - Briefly presented stimuli occurring just before or during a saccadic eye movement are mislocalized, leading to a compression of visual space toward the target of the saccade. In most cases this has been measured in subjects over-trained to perform a stereotyped and unnatural task where saccades are repeatedly driven to the same location, marked by a highly salient abrupt onset. Here, we asked to what extent the pattern of perisaccadic mislocalization depends on this specific context. We addressed this question by studying perisaccadic localization in a set of participants with no prior experience in eye-movement research, measuring localization performance as they practiced the saccade task. Localization was marginally affected by practice over the course of the experiment and it was indistinguishable from the performance of expert observers. The mislocalization also remained similar when the expert observers were tested in a condition leading to less stereotypical saccadic behavior-with no abrupt onset marking the saccade target location. These results indicate that perisaccadic compression is a robust behavior, insensitive to the specific paradigm used to drive saccades and to the level of practice with the saccade task. PMID- 26441560 TI - Superior memorizers employ different neural networks for encoding and recall. AB - Superior memorizers often employ the method of loci (MoL) to memorize large amounts of information. The MoL, known since ancient times, relies on a complex process where information to be memorized is bound to landmarks along mental routes in a previously memorized environment. However, functional magnetic resonance imaging data on groups of trained superior memorizer are rare. Based on the memorizing strategy reported by superior memorizers, we developed a scheme of the processes successively employed during memorizing and recalling digits and relate these to brain activation that is specific for the encoding and recall period. In the examined superior memorizers several regions, suggested to be involved in mental navigation and digit-to-word processing, were specifically activated during encoding: bilateral early visual cortex, retrosplenial cortex, left parahippocampus, left visual cortex, and left superior parietal cortex. Although the scheme suggests that some steps during encoding and recall seem to be analog, none of the encoding areas were specifically activated during the recall. Instead, we found strong activation in left anterior superior temporal gyrus, which we relate to recalling the sequential order of the digits, and right motor cortex that may be related to reciting the digits. PMID- 26441561 TI - Enhancing astronaut performance using sensorimotor adaptability training. AB - Astronauts experience disturbances in balance and gait function when they return to Earth. The highly plastic human brain enables individuals to modify their behavior to match the prevailing environment. Subjects participating in specially designed variable sensory challenge training programs can enhance their ability to rapidly adapt to novel sensory situations. This is useful in our application because we aim to train astronauts to rapidly formulate effective strategies to cope with the balance and locomotor challenges associated with new gravitational environments-enhancing their ability to "learn to learn." We do this by coupling various combinations of sensorimotor challenges with treadmill walking. A unique training system has been developed that is comprised of a treadmill mounted on a motion base to produce movement of the support surface during walking. This system provides challenges to gait stability. Additional sensory variation and challenge are imposed with a virtual visual scene that presents subjects with various combinations of discordant visual information during treadmill walking. This experience allows them to practice resolving challenging and conflicting novel sensory information to improve their ability to adapt rapidly. Information obtained from this work will inform the design of the next generation of sensorimotor countermeasures for astronauts. PMID- 26441562 TI - Distinguishing cognitive state with multifractal complexity of hippocampal interspike interval sequences. AB - Fractality, represented as self-similar repeating patterns, is ubiquitous in nature and the brain. Dynamic patterns of hippocampal spike trains are known to exhibit multifractal properties during working memory processing; however, it is unclear whether the multifractal properties inherent to hippocampal spike trains reflect active cognitive processing. To examine this possibility, hippocampal neuronal ensembles were recorded from rats before, during and after a spatial working memory task following administration of tetrahydrocannabinol (THC), a memory-impairing component of cannabis. Multifractal detrended fluctuation analysis was performed on hippocampal interspike interval sequences to determine characteristics of monofractal long-range temporal correlations (LRTCs), quantified by the Hurst exponent, and the degree/magnitude of multifractal complexity, quantified by the width of the singularity spectrum. Our results demonstrate that multifractal firing patterns of hippocampal spike trains are a marker of functional memory processing, as they are more complex during the working memory task and significantly reduced following administration of memory impairing THC doses. Conversely, LRTCs are largest during resting state recordings, therefore reflecting different information compared to multifractality. In order to deepen conceptual understanding of multifractal complexity and LRTCs, these measures were compared to classical methods using hippocampal frequency content and firing variability measures. These results showed that LRTCs, multifractality, and theta rhythm represent independent processes, while delta rhythm correlated with multifractality. Taken together, these results provide a novel perspective on memory function by demonstrating that the multifractal nature of spike trains reflects hippocampal microcircuit activity that can be used to detect and quantify cognitive, physiological, and pathological states. PMID- 26441563 TI - NeuroControl of movement: system identification approach for clinical benefit. AB - Progress in diagnosis and treatment of movement disorders after neurological diseases like stroke, cerebral palsy (CP), dystonia and at old age requires understanding of the altered capacity to adequately respond to physical obstacles in the environment. With posture and movement disorders, the control of muscles is hampered, resulting in aberrant force generation and improper impedance regulation. Understanding of this improper regulation not only requires the understanding of the role of the neural controller, but also attention for: (1) the interaction between the neural controller and the "plant", comprising the biomechanical properties of the musculaskeletal system including the viscoelastic properties of the contractile (muscle) and non-contractile (connective) tissues: neuromechanics; and (2) the closed loop nature of neural controller and biomechanical system in which cause and effect interact and are hence difficult to separate. Properties of the neural controller and the biomechanical system need to be addressed synchronously by the combination of haptic robotics, (closed loop) system identification (SI), and neuro-mechanical modeling. In this paper, we argue that assessment of neuromechanics in response to well defined environmental conditions and tasks may provide for key parameters to understand posture and movement disorders in neurological diseases and for biomarkers to increase accuracy of prediction models for functional outcome and effects of intervention. PMID- 26441565 TI - Spontaneous movement tempo can be influenced by combining action observation and somatosensory stimulation. AB - Spontaneous movement tempo (SMT) was a popular field of study of the Gestalt psychologists It can be determined from subjects freely tapping out a rhythm with their finger, and it has been found to average about 2 Hz. A previous study showed that SMT changed after the observation of rhythmical movements performed at frequency different from the SMT. This effect was long-lasting only when movement execution immediately followed action observation (AO). We recently demonstrated that only when AO was combined with peripheral nerve stimulation (AO PNS) was it possible to induce plastic changes in the excitability of the motor cortex, whereas AO and PNS alone did not evoke any changes. Here we investigated whether the observation of rhythmical actions at a frequency higher than the SMT combined with PNS induced lasting changes in SMT even in absence of immediate movement execution. Forty-eight participants were assigned to four groups. In AO PNS group they observed a video showing a right hand performing a finger opposition movement sequence at 3 Hz and contemporarily received an electrical stimulation at the median nerve; in AO group and PNS group participants either observed the same video or received the same electrical stimulation of the AO-PNS group, respectively; in LANDSCAPE group subjects observed a neutral video. Participants performed a finger opposition movement sequence at spontaneous movement rate before and 30 min after the conditioning protocols. Results showed that SMT significantly changed only after AO-PNS. This result suggested that the AO-PNS protocol was able to induce lasting changes in SMT due to neuroplasticity mechanisms, indicating possible application of AO-PNS in rehabilitative treatments. PMID- 26441564 TI - Motion perception: a review of developmental changes and the role of early visual experience. AB - Significant controversies have arisen over the developmental trajectory for the perception of global motion. Studies diverge on the age at which it becomes adult like, with estimates ranging from as young as 3 years to as old as 16. In this article, we review these apparently conflicting results and suggest a potentially unifying hypothesis that may also account for the contradictory literature in neurodevelopmental disorders, such as Autism Spectrum Disorder (ASD). We also discuss the extent to which patterned visual input during this period is necessary for the later development of motion perception. We conclude by addressing recent studies directly comparing different types of motion integration, both in typical and atypical development, and suggest areas ripe for future research. PMID- 26441566 TI - Building an adaptive brain across development: targets for neurorehabilitation must begin in infancy. AB - Much progress has been made toward behavioral and pharmacological intervention in intellectual disability, which was once thought too difficult to treat. Down syndrome (DS) research has shown rapid advances, and clinical trials are currently underway, with more on the horizon. Here, we review the literature on the emergent profile of cognitive development in DS, emphasizing that treatment approaches must consider how some "end state" impairments, such as language deficits, may develop from early alterations in neural systems beginning in infancy. Specifically, we highlight evidence suggesting that there are pre- and early postnatal alterations in brain structure and function in DS, resulting in disturbed network function across development. We stress that these early alterations are likely amplified by Alzheimer's disease (AD) progression and poor sleep. Focusing on three network hubs (prefrontal cortex, hippocampus, and cerebellum), we discuss how these regions may relate to evolving deficits in cognitive function in individuals with DS, and to their language profile in particular. PMID- 26441568 TI - Motor imagery reinforces brain compensation of reach-to-grasp movement after cervical spinal cord injury. AB - Individuals with cervical spinal cord injury (SCI) that causes tetraplegia are challenged with dramatic sensorimotor deficits. However, certain rehabilitation techniques may significantly enhance their autonomy by restoring reach-to-grasp movements. Among others, evidence of motor imagery (MI) benefits for neurological rehabilitation of upper limb movements is growing. This literature review addresses MI effectiveness during reach-to-grasp rehabilitation after tetraplegia. Among articles from MEDLINE published between 1966 and 2015, we selected ten studies including 34 participants with C4 to C7 tetraplegia and 22 healthy controls published during the last 15 years. We found that MI of possible non-paralyzed movements improved reach-to-grasp performance by: (i) increasing both tenodesis grasp capabilities and muscle strength; (ii) decreasing movement time (MT), and trajectory variability; and (iii) reducing the abnormally increased brain activity. MI can also strengthen motor commands by potentiating recruitment and synchronization of motoneurons, which leads to improved recovery. These improvements reflect brain adaptations induced by MI. Furthermore, MI can be used to control brain-computer interfaces (BCI) that successfully restore grasp capabilities. These results highlight the growing interest for MI and its potential to recover functional grasping in individuals with tetraplegia, and motivate the need for further studies to substantiate it. PMID- 26441569 TI - Physical attractiveness and sex as modulatory factors of empathic brain responses to pain. AB - Empathy is a process that comprises affective sharing, imagining, and understanding the emotions and mental states of others. The brain structures involved in empathy for physical pain include the anterior insula (AI), and the anterior cingulate cortex (ACC). High empathy may lead people to undertake pro social behavior. It is important to understand how this process can be changed, and what factors these empathic responses depend on. Physical attractiveness is a major social and evolutional cue, playing a role in the formation of interpersonal evaluation. The aim of the study was to determine how attractiveness affects the level of empathy both in relation to self-rated behavior and in terms of activation of specific empathy-related brain regions. Twenty-seven subjects (14 female and 13 male) were studied using functional magnetic resonance imaging (fMRI) method while they were watching short video scenes involving physically more and less attractive men and women who exhibited pain responses. In the absence of behavioral effects in compassion ratings, we observed stronger activation in empathic brain structures (ACC; AI) for less attractive men and for attractive women than for attractive men. Evolutionary psychology studies suggest that beauty is valued more highly in females than males, which might lead observers to empathize more strongly with the attractive woman than the men. Attractive mens' faces are typically associated with enhanced masculine facial characteristics and are considered to possess fewer desirable personality traits compared with feminized faces. This could explain why more empathy was shown to less attractive men. In conclusion, the study showed that the attractiveness and sex of a model are important modulators of empathy for pain. PMID- 26441567 TI - Non-mammalian models in behavioral neuroscience: consequences for biological psychiatry. AB - Current models in biological psychiatry focus on a handful of model species, and the majority of work relies on data generated in rodents. However, in the same sense that a comparative approach to neuroanatomy allows for the identification of patterns of brain organization, the inclusion of other species and an adoption of comparative viewpoints in behavioral neuroscience could also lead to increases in knowledge relevant to biological psychiatry. Specifically, this approach could help to identify conserved features of brain structure and behavior, as well as to understand how variation in gene expression or developmental trajectories relates to variation in brain and behavior pertinent to psychiatric disorders. To achieve this goal, the current focus on mammalian species must be expanded to include other species, including non-mammalian taxa. In this article, we review behavioral neuroscientific experiments in non-mammalian species, including traditional "model organisms" (zebrafish and Drosophila) as well as in other species which can be used as "reference." The application of these domains in biological psychiatry and their translational relevance is considered. PMID- 26441570 TI - The down syndrome biomarker initiative (DSBI) pilot: proof of concept for deep phenotyping of Alzheimer's disease biomarkers in down syndrome. AB - To gain further knowledge on the preclinical phase of Alzheimer's disease (AD), we sought to characterize cognitive performance, neuroimaging and plasma-based AD biomarkers in a cohort of non-demented adults with down syndrome (DS). The goal of the down syndrome biomarker Initiative (DSBI) pilot is to test feasibility of this approach for future multicenter studies. We enrolled 12 non-demented participants with DS between the ages of 30-60 years old. Participants underwent extensive cognitive testing, volumetric MRI, amyloid positron emission tomography (PET; 18F-florbetapir), fluorodeoxyglucose (FDG) PET (18F-fluorodeoxyglucose) and retinal amyloid imaging. In addition, plasma beta-amyloid (Abeta) species were measured and Apolipoprotein E (ApoE) genotyping was performed. Results from our multimodal analysis suggest greater hippocampal atrophy with amyloid load. Additionally, we identified an inverse relationship between amyloid load and regional glucose metabolism. Cognitive and functional measures did not correlate with amyloid load in DS but did correlate with regional FDG PET measures. Biomarkers of AD can be readily studied in adults with DS as in other preclinical AD populations. Importantly, all subjects in this feasibility study were able to complete all test procedures. The data indicate that a large, multicenter longitudinal study is feasible to better understand the trajectories of AD biomarkers in this enriched population. This trial is registered with ClinicalTrials.gov, number NCT02141971. PMID- 26441571 TI - The translational study of apathy-an ecological approach. AB - Apathy, a quantitative reduction in goal-directed behavior, is a prevalent symptom dimension with a negative impact on functional outcome in various neuropsychiatric disorders including schizophrenia and depression. The aim of this review is to show that interview-based assessment of apathy in humans and observation of spontaneous rodent behavior in an ecological setting can serve as an important complementary approach to already existing task-based assessment, to study and understand the neurobiological bases of apathy. We first discuss the paucity of current translational approaches regarding animal equivalents of psychopathological assessment of apathy. We then present the existing evaluation scales for the assessment of apathy in humans and propose five sub-domains of apathy, namely self-care, social interaction, exploration, work/education and recreation. Each of the items in apathy evaluation scales can be assigned to one of these sub-domains. We then show that corresponding, well-validated behavioral readouts exist for rodents and that, indeed, three of the five human apathy sub domains have a rodent equivalent. In conclusion, the translational ecological study of apathy in humans and rodents is possible and will constitute an important approach to increase the understanding of the neurobiological bases of apathy and the development of novel treatments. PMID- 26441572 TI - Normal Neurochemistry in the Prefrontal and Cerebellar Brain of Adults with Attention-Deficit Hyperactivity Disorder. AB - Attention-deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. In an attempt to extend earlier neurochemical findings, we organized a magnetic resonance spectroscopy (MRS) study as part of a large, government funded, prospective, randomized, multicenter clinical trial comparing the effectiveness of specific psychotherapy with counseling and stimulant treatment with placebo treatment (Comparison of Methylphenidate and Psychotherapy Study). We report the baseline neurochemical data for the anterior cingulate cortex (ACC) and the cerebellum in a case-control setting. For the trial, 1,480 adult patients were contacted for participation, 518 were assessed for eligibility, 433 were randomized, and 187 were potentially eligible for neuroimaging. The control group included 119 healthy volunteers. Single-voxel proton MRS was performed. In the patient group, 113 ACC and 104 cerebellar spectra fulfilled all quality criteria for inclusion in statistical calculations, as did 82 ACC and 78 cerebellar spectra in the control group. We did not find any significant neurometabolic differences between the ADHD and control group in the ACC (Wilks' lambda test: p = 0.97) or in the cerebellum (p = 0.62). Thus, we were unable to replicate earlier findings in this methodologically sophisticated study. We discuss our findings in the context of a comprehensive review of other MRS studies on ADHD and a somewhat skeptical neuropsychiatric research perspective. As in other neuropsychiatric disorders, the unclear nosological status of ADHD might be an explanation for false-negative findings. PMID- 26441573 TI - A shared neural network for emotional expression and perception: an anatomical study in the macaque monkey. AB - Over the past two decades, the insula has been described as the sensory "interoceptive cortex". As a consequence, human brain imaging studies have focused on its role in the sensory perception of emotions. However, evidence from neurophysiological studies in non-human primates have shown that the insula is also involved in generating emotional and communicative facial expressions. In particular, a recent study demonstrated that electrical stimulation of the mid ventral sector of the insula evoked affiliative facial expressions. The present study aimed to describe the cortical connections of this "affiliative field". To this aim, we identified the region with electrical stimulation and injected neural tracers to label incoming and outgoing projections. Our results show that the insular field underlying emotional expression is part of a network involving specific frontal, cingulate, temporal, and parietal areas, as well as the amygdala, the basal ganglia, and thalamus, indicating that this sector of the insula is a site of integration of motor, emotional, sensory and social information. Together with our previous functional studies, this result challenges the classic view of the insula as a multisensory area merely reflecting bodily and internal visceral states. In contrast, it supports an alternative perspective; that the emotional responses classically attributed to the insular cortex are endowed with an enactive component intrinsic to each social and emotional behavior. PMID- 26441575 TI - Neurochemical measurements in the zebrafish brain. AB - The zebrafish is an ideal model organism for behavioral genetics and neuroscience. The high conservation of genes and neurotransmitter pathways between zebrafish and other vertebrates permits the translation of research between species. Zebrafish behavior can be studied at both larval and adult stages and recent research has begun to establish zebrafish models for human disease. Fast scan cyclic voltammetry (FSCV) is an electrochemical technique that permits the detection of neurotransmitter release and reuptake. In this study we have used in vitro FSCV to measure the release of analytes in the adult zebrafish telencephalon. We compare different stimulation methods and present a characterization of neurochemical changes in the wild-type zebrafish brain. This study represents the first FSCV recordings in zebrafish, thus paving the way for neurochemical analysis of the fish brain. PMID- 26441574 TI - Distinct BOLD Activation Profiles Following Central and Peripheral Oxytocin Administration in Awake Rats. AB - A growing body of literature has suggested that intranasal oxytocin (OT) or other systemic routes of administration can alter prosocial behavior, presumably by directly activating OT sensitive neural circuits in the brain. Yet there is no clear evidence that OT given peripherally can cross the blood-brain barrier at levels sufficient to engage the OT receptor. To address this issue we examined changes in blood oxygen level-dependent (BOLD) signal intensity in response to peripheral OT injections (0.1, 0.5, or 2.5 mg/kg) during functional magnetic resonance imaging (fMRI) in awake rats imaged at 7.0 T. These data were compared to OT (1 MUg/5 MUl) given directly to the brain via the lateral cerebroventricle. Using a 3D annotated MRI atlas of the rat brain segmented into 171 brain areas and computational analysis, we reconstructed the distributed integrated neural circuits identified with BOLD fMRI following central and peripheral OT. Both routes of administration caused significant changes in BOLD signal within the first 10 min of administration. As expected, central OT activated a majority of brain areas known to express a high density of OT receptors, e.g., lateral septum, subiculum, shell of the accumbens, bed nucleus of the stria terminalis. This profile of activation was not matched by peripheral OT. The change in BOLD signal to peripheral OT did not show any discernible dose-response. Interestingly, peripheral OT affected all subdivisions of the olfactory bulb, in addition to the cerebellum and several brainstem areas relevant to the autonomic nervous system, including the solitary tract nucleus. The results from this imaging study do not support a direct central action of peripheral OT on the brain. Instead, the patterns of brain activity suggest that peripheral OT may interact at the level of the olfactory bulb and through sensory afferents from the autonomic nervous system to influence brain activity. PMID- 26441576 TI - Effects of social sustainability signaling on neural valuation signals and taste experience of food products. AB - Value-based decision making occurs when individuals choose between different alternatives and place a value on each alternative and its attributes. Marketing actions frequently manipulate product attributes, by adding, e.g., health claims on the packaging. A previous imaging study found that an emblem for organic products increased willingness to pay (WTP) and activity in the ventral striatum (VS). The current study investigated neural and behavioral processes underlying the influence of Fair Trade (FT) labeling on food valuation and choice. Sustainability is an important product attribute for many consumers, with FT signals being one way to highlight ethically sustainable production. Forty participants valuated products in combination with an FT emblem or no emblem and stated their WTP in a bidding task while in an MRI scanner. After that, participants tasted-objectively identical-chocolates, presented either as "FT" or as "conventionally produced". In the fMRI task, WTP was significantly higher for FT products. FT labeling increased activity in regions important for reward processing and salience, that is, in the VS, anterior and posterior cingulate, as well as superior frontal gyrus. Subjective value, that is, WTP was correlated with activity in the ventromedial prefrontal cortex (vmPFC). We find that the anterior cingulate, VS and superior frontal gyrus exhibit task-related increases in functional connectivity to the vmPFC when an FT product was evaluated. Effective connectivity analyses revealed a highly probable directed modulation of the vmPFC by those three regions, suggesting a network which alters valuation processes. We also found a significant taste-placebo effect, with higher experienced taste pleasantness and intensity for FT labeled chocolates. Our results reveal a possible neural mechanism underlying valuation processes of certified food products. The results are important in light of understanding current marketing trends as well as designing future interventions that aim at positively influencing food choice. PMID- 26441577 TI - The beneficial effect of testing: an event-related potential study. AB - The enhanced memory performance for items that are tested as compared to being restudied (the testing effect) is a frequently reported memory phenomenon. According to the episodic context account of the testing effect, this beneficial effect of testing is related to a process which reinstates the previously learnt episodic information. Few studies have explored the neural correlates of this effect at the time point when testing takes place, however. In this study, we utilized the ERP correlates of successful memory encoding to address this issue, hypothesizing that if the benefit of testing is due to retrieval-related processes at test then subsequent memory effects (SMEs) should resemble the ERP correlates of retrieval-based processing in their temporal and spatial characteristics. Participants were asked to learn Swahili-German word pairs before items were presented in either a testing or a restudy condition. Memory performance was assessed immediately and 1-day later with a cued recall task. Successfully recalling items at test increased the likelihood that items were remembered over time compared to items which were only restudied. An ERP subsequent memory contrast (later remembered vs. later forgotten tested items), which reflects the engagement of processes that ensure items are recallable the next day were topographically comparable with the ERP correlate of immediate recollection (immediately remembered vs. immediately forgotten tested items). This result shows that the processes which allow items to be more memorable over time share qualitatively similar neural correlates with the processes that relate to successful retrieval at test. This finding supports the notion that testing is more beneficial than restudying on memory performance over time because of its engagement of retrieval processes, such as the re-encoding of actively retrieved memory representations. PMID- 26441578 TI - Altered activity of the medial prefrontal cortex and amygdala during acquisition and extinction of an active avoidance task. AB - Altered medial prefrontal cortex (mPFC) and amygdala function is associated with anxiety-related disorders. While the mPFC-amygdala pathway has a clear role in fear conditioning, these structures are also involved in active avoidance. Given that avoidance perseveration represents a core symptom of anxiety disorders, the neural substrate of avoidance, especially its extinction, requires better understanding. The present study was designed to investigate the activity, particularly, inhibitory neuronal activity in mPFC and amygdala during acquisition and extinction of lever-press avoidance in rats. Neural activity was examined in the mPFC, intercalated cell clusters (ITCs) lateral (LA), basal (BA) and central (CeA) amygdala, at various time points during acquisition and extinction, using induction of the immediate early gene product, c-Fos. Neural activity was greater in the mPFC, LA, BA, and ITC during the extinction phase as compared to the acquisition phase. In contrast, the CeA was the only region that was more activated during acquisition than during extinction. Our results indicate inhibitory neurons are more activated during late phase of acquisition and extinction in the mPFC and LA, suggesting the dynamic involvement of inhibitory circuits in the development and extinction of avoidance response. Together, these data start to identify the key brain regions important in active avoidance behavior, areas that could be associated with avoidance perseveration in anxiety disorders. PMID- 26441579 TI - The longitudinal development of social and executive functions in late adolescence and early adulthood. AB - Our earlier work suggests that, executive functions and social cognition show protracted development into late adolescence and early adulthood (Taylor et al., 2013). However, it remains unknown whether these functions develop linearly or non-linearly corresponding to dynamic changes to white matter density at these age ranges. Executive functions are particularly in demand during the transition to independence and autonomy associated with this age range (Ahmed and Miller, 2011). Previous research examining executive function (Romine and Reynolds, 2005) and social cognition (Dumontheil et al., 2010a) in late adolescence has utilized a cross sectional design. The current study employed a longitudinal design with 58 participants aged 17, 18, and 19 years completing social cognition and executive function tasks, Wechsler Abbreviated Scale of Intelligence (Wechsler, 1999), Positive and Negative Affect Schedule (Watson et al., 1988), and Hospital Anxiety and Depression Scale (Zigmond and Snaith, 1983) at Time 1 with follow up testing 12-16 months later. Inhibition, rule detection, strategy generation and planning executive functions and emotion recognition with dynamic stimuli showed longitudinal development between time points. Self-report empathy and emotion recognition functions using visual static and auditory stimuli were stable by age 17 whereas concept formation declined between time points. The protracted development of some functions may reflect continued brain maturation into late adolescence and early adulthood including synaptic pruning (Sowell et al., 2001) and changes to functional connectivity (Stevens et al., 2007) and/or environmental change. Clinical implications, such as assessing the effectiveness of rehabilitation following Head Injury, are discussed. PMID- 26441580 TI - Brain-derived neurotrophic factor serum levels correlate with cognitive performance in Parkinson's disease patients with mild cognitive impairment. AB - Brain-derived neurotrophic factor (BDNF) is a trophic factor regulating cell survival and synaptic plasticity. Recent findings indicate that BDNF could be a potential regulatory factor for cognitive functioning in normal and/or neuropathological conditions. With regard to neurological disorders, recent data suggest that individuals with Parkinson's disease (PD) may be affected by cognitive deficits and that they have altered BDNF production. Therefore, the hypothesis can be advanced that BDNF levels are associated with the cognitive state of these patients. With this in mind, the present study was aimed at exploring the relationship between BDNF serum levels and cognitive functioning in PD patients with mild cognitive impairment (MCI). Thirteen PD patients with MCI were included in the study. They were administered an extensive neuropsychological test battery that investigated executive, episodic memory, attention, visual-spatial and language domains. A single score was obtained for each cognitive domain by averaging z-scores on tests belonging to that specific domain. BDNF serum levels were measured by enzyme-linked immunoassay (ELISA). Pearson's correlation analyses were performed between BDNF serum levels and cognitive performance. Results showed a significant positive correlation between BDNF serum levels and both attention (p < 0.05) and executive (p < 0.05) domains. Moreover, in the executive domain we found a significant correlation between BDNF levels and scores on tests assessing working memory and self monitoring/inhibition. These preliminary data suggest that BDNF serum levels are associated with cognitive state in PD patients with MCI. Given the role of BDNF in regulating synaptic plasticity, the present findings give further support to the hypothesis that this trophic factor may be a potential biomarker for evaluating cognitive changes in PD and other neurological syndromes associated with cognitive decline. PMID- 26441581 TI - Gradual extinction reduces reinstatement. AB - The current study investigated whether gradually reducing the frequency of aversive stimuli during extinction can prevent the return of fear. Thirty-one participants of a three-stage procedure (acquisition, extinction and a reinstatement test on day 2) were randomly assigned to a standard extinction (SE) and gradual extinction (GE) procedure. The two groups differed only in the extinction procedure. While the SE group ran through a regular extinction process without any negative events, the frequency of the aversive stimuli during the extinction phase was gradually reduced for the GE group. The unconditioned stimulus (US) was an air blast (5 bar, 10 ms). A spider and a scorpion were used as conditioned stimuli (CS). The outcome variables were contingency ratings and physiological measures (skin conductance response, SCR and startle response). There were no differences found between the two groups for the acquisition and extinction phases concerning contingency ratings, SCR, or startle response. GE compared to SE significantly reduced the return of fear in the reinstatement test for the startle response but not for SCR or contingency ratings. This study was successful in translating the findings in rodent to humans. The results suggest that the GE process is suitable for increasing the efficacy of fear extinction. PMID- 26441582 TI - Cathodal HD-tDCS on the right V5 improves motion perception in humans. AB - Brain lesions in the visual associative cortex are known to impair visual perception, i.e., the capacity to correctly perceive different aspects of the visual world, such as motion, color, or shapes. Visual perception can be influenced by non-invasive brain stimulation such as transcranial direct current stimulation (tDCS). In a recently developed technique called high definition (HD) tDCS, small HD-electrodes are used instead of the sponge electrodes in the conventional approach. This is believed to achieve high focality and precision over the target area. In this paper we tested the effects of cathodal and anodal HD-tDCS over the right V5 on motion and shape perception in a single blind, within-subject, sham controlled, cross-over trial. The purpose of the study was to prove the high focality of the stimulation only over the target area. Twenty one healthy volunteers received 20 min of 2 mA cathodal, anodal and sham stimulation over the right V5 and their performance on a visual test was recorded. The results showed significant improvement in motion perception in the left hemifield after cathodal HD-tDCS, but not in shape perception. Sham and anodal HD-tDCS did not affect performance. The specific effect of influencing performance of visual tasks by modulating the excitability of the neurons in the visual cortex might be explained by the complexity of perceptual information needed for the tasks. This provokes a "noisy" activation state of the encoding neuronal patterns. We speculate that in this case cathodal HD-tDCS may focus the correct perception by decreasing global excitation and thus diminishing the "noise" below threshold. PMID- 26441583 TI - Similarities and Differences in Decision-Making Impairments between Autism Spectrum Disorder and Schizophrenia. AB - Although individuals with autism spectrum disorders (ASD) and schizophrenia (SCH) share overlapping characteristics and may perform similarly on many cognitive tasks, cognitive dysfunctions common to both disorders do not necessarily share the same underlying mechanisms. Decision-making is currently a major research interest for both ASD and SCH. The aim of the present study was to make direct comparisons of decision-making and disorder-specific underlying neuropsychological mechanisms between the two disorders. Thirty-seven participants with ASD, 46 patients with SCH, and 80 healthy controls (HC) were assessed with the Iowa Gambling Task (IGT), which measures decision-making under ambiguity, and the Game of Dice Task (GDT), which measures decision-making under risk. The results revealed that both the ASD and SCH groups had deficits for both the IGT and the GDT compared with the HC. More importantly, in the IGT, participants with ASD displayed a preference for deck A, indicating that they had more sensitivity to the magnitude of loss than to the frequency of loss, whereas patients with SCH displayed a preference for deck B, indicating that they showed more sensitivity to the frequency of loss than to the magnitude of loss. In the GDT, the impaired performance might be due to the deficits in executive functions in patients with SCH, whereas the impaired performance might be due to the deficits in feedback processing in participants with ASD. These findings demonstrate that there are similar impairments in decision-making tasks between ASD and SCH; however, these two disorders may have different impairment mechanisms. PMID- 26441584 TI - Resting state functional connectivity differences between behavioral variant frontotemporal dementia and Alzheimer's disease. AB - INTRODUCTION: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are the most common types of early-onset dementia. Early differentiation between both types of dementia may be challenging due to heterogeneity and overlap of symptoms. Here, we apply resting state functional magnetic resonance imaging (fMRI) to study functional brain connectivity differences between AD and bvFTD. METHODS: We used resting state fMRI data of 31 AD patients, 25 bvFTD patients, and 29 controls from two centers specialized in dementia. We studied functional connectivity throughout the entire brain, applying two different analysis techniques, studying network-to-region and region to-region connectivity. A general linear model approach was used to study group differences, while controlling for physiological noise, age, gender, study center, and regional gray matter volume. RESULTS: Given gray matter differences, we observed decreased network-to-region connectivity in bvFTD between (a) lateral visual cortical network and lateral occipital and cuneal cortex, and (b) auditory system network and angular gyrus. In AD, we found decreased network-to-region connectivity between the dorsal visual stream network and lateral occipital and parietal opercular cortex. Region-to-region connectivity was decreased in bvFTD between superior temporal gyrus and cuneal, supracalcarine, intracalcarine cortex, and lingual gyrus. CONCLUSION: We showed that the pathophysiology of functional brain connectivity is different between AD and bvFTD. Our findings support the hypothesis that resting state fMRI shows disease-specific functional connectivity differences and is useful to elucidate the pathophysiology of AD and bvFTD. However, the group differences in functional connectivity are less abundant than has been shown in previous studies. PMID- 26441585 TI - Immunological findings in psychotic syndromes: a tertiary care hospital's CSF sample of 180 patients. AB - Immunological mechanisms and therapy approaches in psychotic syndromes were recently supported by the discovery of autoantibody-associated limbic and non limbic encephalitis. However, how clinical diagnostic procedures in psychiatry should be adapted to these new insights is still unclear. In this study, we analyzed the cerebrospinal fluid (CSF) and neuroimmunological alterations and their association with cerebral MRI (cMRI) and electroencephalographic (EEG) findings. From 2006 to 2013, we acquired 180 CSF samples from psychotic patients. Between 2006 and 2009, CSF examinations were only performed in cases in which organic brain disease was suspected. Since then, this procedure has been integrated into our routine diagnostic workup. CSF basic diagnostics were supplemented by measuring antineuronal antibodies against intracellular synaptic antigens, antibodies against intracellular onconeural antigens, antibodies against neuronal cell surface antigens and thyroid antibodies. In addition, cMRIs and EEGs were conducted. We found white cell counts elevated in 3.4% of the cases, albumin quotient elevated in 21.8%, and protein concentration elevated in 42.2%. Evidence of intrathecal immunoglobulin synthesis was found in 7.2% of the cases. Antibodies measured against neuronal cell surface antigens were positive in 3.2%. Reactivity on antibodies against intracellular onconeural antigens were detected in 3.5%. Serum thyroid antibodies were elevated in 24.7%. Abnormalities were found in 39.5% of cMRIs and in 34.3% of EEGs. The main finding of our study was the high prevalence of CSF and autoantibody abnormalities in 54.4% of psychotic patients. In combination with cMRIs and EEGs, 75.6% showed abnormal findings. Our results are discussed with regard to the concept of immunological encephalopathy. Future studies should analyze the efficacy of immunomodulatory therapies. PMID- 26441587 TI - Thinking in three dimensions: a different point of view for understanding autism. PMID- 26441586 TI - Home-based neurologic music therapy for upper limb rehabilitation with stroke patients at community rehabilitation stage-a feasibility study protocol. AB - BACKGROUND: Impairment of upper limb function following stroke is more common than lower limb impairment and is also more resistant to treatment. Several lab based studies with stroke patients have produced statistically significant gains in upper limb function when using musical instrument playing and techniques where rhythm acts as an external time-keeper for the priming and timing of upper limb movements. METHODS: For this feasibility study a small sample size of 14 participants (3-60 months post stroke) has been determined through clinical discussion between the researcher and study host in order to test for management, feasibility and effects, before planning a larger trial determined through power analysis. A cross-over design with five repeated measures will be used, whereby participants will be randomized into either a treatment (n = 7) or wait list control (n = 7) group. Intervention will take place twice weekly over 6 weeks. The ARAT and 9HPT will be used to measure for quantitative gains in arm function and finger dexterity, pre/post treatment interviews will serve to investigate treatment compliance and tolerance. A lab based EEG case comparison study will be undertaken to explore audio-motor coupling, brain connectivity and neural reorganization with this intervention, as evidenced in similar studies. DISCUSSION: Before evaluating the effectiveness of a home-based intervention in a larger scale study, it is important to assess whether implementation of the trial methodology is feasible. This study investigates the feasibility, efficacy and patient experience of a music therapy treatment protocol comprising a chart of 12 different instrumental exercises and variations, which aims at promoting measurable changes in upper limb function in hemiparetic stroke patients. The study proposes to examine several new aspects including home-based treatment and dosage, and will provide data on recruitment, adherence and variability of outcomes. PMID- 26441588 TI - Multi-modal representation of effector modality in frontal cortex during rule switching. AB - We report a functional magnetic resonance imaging (fMRI) study which investigated whether brain areas involved in updating task rules within the frontal lobe of the cerebral cortex show activity related to the modality of motor response used in the task. Participants performed a rule switching task using different effector modalities. In some blocks participants responded with left/right button presses, whilst in other blocks left/right saccades were required. The color of a Cue event instructed a left or right response based upon a rule, followed by a Feedback which indicated whether the rule was to stay the same or "Flip" on the next trial. The findings revealed variation in the locus of activity within the ventrolateral frontal cortex dependent upon effector modality. Other frontal areas showed no significant difference in activity between response epochs but changed their pattern of connectivity with posterior cortical areas dependent upon response. Multivariate analysis revealed that the pattern of activity evoked by Flip rule Feedbacks within an apparently supra modal frontal region (dorsolateral frontal cortex) discriminated between response epochs. The results are consistent with the existence of multi-modal representations of stimulus response (SR) rules within the frontal cerebral cortex. PMID- 26441589 TI - Research domain criteria: a final paradigm for psychiatry? PMID- 26441590 TI - Social anxiety disorder and the psychobiology of self-consciousness. AB - Individuals with social anxiety disorder (SAD) are characterized by fear or anxiety about social situations, but also by important alterations in self referential processing. Given advances in our understanding of the neurocircuitry and neurochemistry of SAD, the question arises of the relationship between this research and an emergent literature on the psychobiology of self and self consciousness. A number of investigations of SAD have highlighted altered activity in the medial prefrontal cortex (mPFC; involved in self-representation), insula (involved in interoceptive processing), and other structures that play a role in bodily self-consciousness, as well as the potential value of interventions such as selective serotonin reuptake inhibitors (SSRI) and self focused reappraisal in normalizing such changes. Future studies to more closely investigate associations between psychobiological alterations and changes in self related processing in SAD, may be useful in shedding additional light on both SAD and self-consciousness. PMID- 26441591 TI - Response: A commentary on: "Neural overlap in processing music and speech". PMID- 26441592 TI - Neural regions discriminating contextual information as conveyed through the learned preferences of others. AB - The human brain consists of a network of regions that are engaged when one observes the movements of others. Observing unexpected movements, as defined by the context, often elicits greater activity, particularly in the right posterior superior temporal sulcus (pSTS). This implies that observers use contextual information to form expectations about an agent's goal and subsequent movements. The current study sought to identify regions that support the formation of these context-dependent expectations, with the pSTS being one candidate, given the consistent contextual modulation of its activity. We presented participants with fictitious individuals who had emotion-dependent food preferences, and instructed participants to indicate which food they expected each individual to choose based on the individual's current emotional state. Each individual's preference and emotional state therefore created a context that informed the observer's expectation of the individual's choice. Multi-voxel pattern analysis (MVPA) was used to assess if these different contexts could be discriminated in the pSTS and elsewhere in the brain. No evidence for context discrimination was found in the pSTS. Context discrimination was found instead a network of other brain regions including the anterior medial prefrontal cortex (amPFC), bilateral parietal cortex, left middle temporal gyrus (L MTG) and left anterior temporal lobe (L ATL), which have been previously associated with context processing, and semantic and memory retrieval. All together, these regions possibly support the formation of context-dependent expectations of an agent's goal. PMID- 26441593 TI - The dissociation between command following and communication in disorders of consciousness: an fMRI study in healthy subjects. AB - Neuroimaging studies have identified a subgroup of patients with a Disorder of Consciousness (DOC) who, while being behaviorally non-responsive, are nevertheless able to follow commands by modulating their brain activity in motor imagery (MI) tasks. These techniques have even allowed for binary communication in a small number of DOC patients. However, the majority of patients who can follow commands are unable to use their responses to communicate. A similar dissociation between present command following (CF) and absent communication abilities has been reported in overt behavioral assessments. However, the neural correlates of this dissociation in both overt and covert modalities are unknown. Here, we used functional magnetic resonance imaging (fMRI) to explore the neural mechanisms underlying CF and selection of responses for binary communication using either executed or imagined movements. Fifteen healthy participants executed or imagined two different types of arm movements that were either pre determined by the experimenters (CF) or decided by them (action selection, AS). Action selection involved greater activity in high-level associative areas in frontal and parietal regions than CF. Additionally, motor execution (ME), as compared to MI, activated contralateral motor cortex, while the opposite contrast revealed activation in the ipsilateral sensorimotor cortex and the left inferior frontal gyrus. Importantly, there was no interaction between the task (CF/AS) and modality (MI/ME). Our results suggest that the neural processes involved in following a motor command or selecting between two motor actions are not dependent on how the response is expressed (via ME/MI). They also suggest a potential neural basis for the distinction in cognitive abilities seen in DOC patients. PMID- 26441594 TI - A closer look at cognitive control: differences in resource allocation during updating, inhibition and switching as revealed by pupillometry. AB - The present study investigated resource allocation, as measured by pupil dilation, in tasks measuring updating (2-Back task), inhibition (Stroop task) and switching (Number Switch task). Because each cognitive control component has unique characteristics, differences in patterns of resource allocation were expected. Pupil and behavioral data from 35 participants were analyzed. In the 2 Back task (requiring correct matching of current stimulus identity at trial p with the stimulus two trials back, p -2) we found that better performance (low total of errors made in the task) was positively correlated to the mean pupil dilation during correctly responding to targets. In the Stroop task, pupil dilation on incongruent trials was higher than those on congruent trials. Incongruent vs. congruent trial pupil dilation differences were positively related to reaction time differences between incongruent and congruent trials. Furthermore, on congruent Stroop trials, pupil dilation was negatively related to reaction times, presumably because more effort allocation paid off in terms of faster responses. In addition, pupil dilation on correctly-responded-to congruent trials predicted a weaker Stroop interference effect in terms of errors, probably because pupil dilation on congruent trials were diagnostic of task motivation, resulting in better performance. In the Number Switch task we found higher pupil dilation in switch as compared to non-switch trials. On the Number Switch task, pupil dilation was not related to performance. We also explored error-related pupil dilation in all tasks. The results provide new insights in the diversity of the cognitive control components in terms of resource allocation as a function of individual differences, task difficulty and error processing. PMID- 26441595 TI - Altered connectivity of the dorsal and ventral visual regions in dyslexic children: a resting-state fMRI study. AB - While there is emerging evidence from behavioral studies that visual attention skills are impaired in dyslexia, the corresponding neural mechanism (i.e., deficits in the dorsal visual region) needs further investigation. We used resting-state fMRI to explore the functional connectivity (FC) patterns of the left intraparietal sulcus (IPS) and the visual word form area (VWFA) in dyslexic children (N = 21, age mean = 12) and age-matched controls (N = 26, age mean = 12). The results showed that the left IPS and the VWFA were functionally connected to each other in both groups and that both were functionally connected to left middle frontal gyrus (MFG). Importantly, we observed significant group differences in FC between the left IPS and the left MFG and between the VWFA and the left MFG. In addition, the strengths of the identified FCs were significantly correlated with the score of fluent reading, which required obvious eye movement and visual attention processing, but not with the lexical decision score. We conclude that dyslexics have deficits in the network composed of the prefrontal, dorsal visual and ventral visual regions and may have a lack of modulation from the left MFG to the dorsal and ventral visual regions. PMID- 26441596 TI - Perceptual decision-making difficulty modulates feedforward effective connectivity to the dorsolateral prefrontal cortex. AB - Diverse cortical structures are known to coordinate activity as a network in relaying and processing of visual information to discriminate visual objects. However, how this discrimination is achieved is still largely unknown. To contribute to answering this question, we used face-house categorization tasks with three levels of noise in face and house images in functional magnetic resonance imaging (fMRI) experiments involving thirty-three participants. The behavioral performance error and response time (RT) were correlated with noise in face-house images. We then built dynamical causal models (DCM) of fMRI blood oxygenation level dependent (BOLD) signals from the face and house category specific regions in ventral temporal (VT) cortex, the fusiform face area (FFA) and parahippocampal place area (PPA), and the dorsolateral prefrontal cortex (dlPFC). We found a strong feed-forward intrinsic connectivity pattern from FFA and PPA to dlPFC. Importantly, the feed-forward connectivity to dlPFC was significantly modulated by the perception of both faces and houses. The dlPFC BOLD activity, the connectivity from FFA and PPA to the dlPFC all increased with noise level. These results suggest that the FFA-PPA-dlPFC network plays an important role for relaying and integrating competing sensory information to arrive at perceptual decisions. PMID- 26441597 TI - Gender differences in human single neuron responses to male emotional faces. AB - Well-documented differences in the psychology and behavior of men and women have spurred extensive exploration of gender's role within the brain, particularly regarding emotional processing. While neuroanatomical studies clearly show differences between the sexes, the functional effects of these differences are less understood. Neuroimaging studies have shown inconsistent locations and magnitudes of gender differences in brain hemodynamic responses to emotion. To better understand the neurophysiology of these gender differences, we analyzed recordings of single neuron activity in the human brain as subjects of both genders viewed emotional expressions. This study included recordings of single neuron activity of 14 (6 male) epileptic patients in four brain areas: amygdala (236 neurons), hippocampus (n = 270), anterior cingulate cortex (n = 256), and ventromedial prefrontal cortex (n = 174). Neural activity was recorded while participants viewed a series of avatar male faces portraying positive, negative or neutral expressions. Significant gender differences were found in the left amygdala, where 23% (n = 15/66) of neurons in men were significantly affected by facial emotion, vs. 8% (n = 6/76) of neurons in women. A Fisher's exact test comparing the two ratios found a highly significant difference between the two (p < 0.01). These results show specific differences between genders at the single neuron level in the human amygdala. These differences may reflect gender-based distinctions in evolved capacities for emotional processing and also demonstrate the importance of including subject gender as an independent factor in future studies of emotional processing by single neurons in the human amygdala. PMID- 26441598 TI - Editorial: What can we make of theories of embodiment and the role of the human mirror neuron system? PMID- 26441599 TI - Mu rhythm desynchronization by tongue thrust observation. AB - We aimed to investigate the mu rhythm in the sensorimotor area during tongue thrust observation and to obtain an answer to the question as to how subtle non verbal orofacial movement observation activates the sensorimotor area. Ten healthy volunteers performed finger tap execution, tongue thrust execution, and tongue thrust observation. The electroencephalogram (EEG) was recorded from 128 electrodes placed on the scalp, and regions of interest were set at sensorimotor areas. The event-related desynchronization (ERD) and event-related synchronization (ERS) for the mu rhythm (8-13 Hz) and beta (13-25 Hz) bands were measured. Tongue thrust observation induced mu rhythm ERD, and the ERD was detected at the left hemisphere regardless whether the observed tongue thrust was toward the left or right. Mu rhythm ERD was also recorded during tongue thrust execution. However, temporal analysis revealed that the ERD associated with tongue thrust observation preceded that associated with execution by approximately 2 s. Tongue thrust observation induces mu rhythm ERD in sensorimotor cortex with left hemispheric dominance. PMID- 26441600 TI - An engineered glove for investigating the neural correlates of finger movements using functional magnetic resonance imaging. AB - Objective measurement of concomitant finger motor performance is recommended for functional magnetic resonance imaging (fMRI) studies investigating brain activity during finger tapping tasks, because performance modality and ability can influence the selection of different neural networks. In this study, we present a novel glove system for quantitative evaluation of finger opposition movements during fMRI (called Glove Analyzer for fMRI, GAF). Several tests for magnetic resonance (MR) compatibility were performed concerning magnet forces, image artifacts and right functioning of the system. Then, pilot fMRI of finger opposition tasks were conducted at 1.5T and 3T to investigate the neural correlates of sequences of finger opposition movements with the right hand, with simultaneous behavioral recording by means of GAF. All the MR compatibility tests succeeded, and the fMRI analysis revealed mainly the activation of the left sensorimotor areas and right cerebellum, regions that are known to be involved in finger movements. No artifactual clusters were detected in the activation maps. At the same time, through the parameters calculated by GAF it was possible to describe the sensorimotor strategy adopted by the subjects during the required task. Thus, the proposed device resulted to be MR compatible and can be useful for future fMRI studies investigating the neural correlates of finger opposition movements, allowing follow-up studies and comparisons among different groups of patients. PMID- 26441601 TI - Neural correlates of reward processing in healthy siblings of patients with schizophrenia. AB - Deficits in motivational behavior and psychotic symptoms often observed in schizophrenia (SZ) may be driven by dysfunctional reward processing (RP). RP can be divided in two different stages; reward anticipation and reward consumption. Aberrant processing during reward anticipation seems to be related to SZ. Studies in patients with SZ have found less activation in the ventral striatum (VS) during anticipation of reward, but these findings do not provide information on effect of the genetic load on reward processing. Therefore, this study investigated RP in healthy first-degree relatives of SZ patients. The sample consisted of 94 healthy siblings of SZ patients and 57 healthy controls. Participants completed a classic RP task, the Monetary Incentive Delay task, during functional magnetic resonance imaging (fMRI). As expected, there were no behavioral differences between groups. In contrast to our expectations, we found no differences in any of the anticipatory reward related brain areas (region of interest analyses). Whole-brain analyses did reveal group differences during both reward anticipation and reward consumption; during reward anticipation siblings showed less deactivation in the insula, posterior cingulate cortex (PCC) and medial frontal gyrus (MFG) than controls. During reward consumption siblings showed less deactivation in the PCC and the right MFG compared to controls and activation in contrast to deactivation in controls in the precuneus and the left MFG. Exclusively in siblings, MFG activity correlated positively with subclinical negative symptoms. These regions are typically associated with the default mode network (DMN), which normally shows decreases in activation during task-related cognitive processes. Thus, in contrast to prior literature in patients with SZ, the results do not point to altered brain activity in classical RP brain areas, such as the VS. However, the weaker deactivation found outside the reward-related network in siblings could indicate reduced task-related suppression (i.e., hyperactivation) of the DMN. The presence of DMN hyperactivation during reward anticipation and reward consumption might indicate that siblings of patients with SZ have a higher baseline level of DMN activation and possible abnormal network functioning. PMID- 26441602 TI - Implicit learning of predictable sound sequences modulates human brain responses at different levels of the auditory hierarchy. AB - Deviant stimuli, violating regularities in a sensory environment, elicit the mismatch negativity (MMN), largely described in the Event-Related Potential literature. While it is widely accepted that the MMN reflects more than basic change detection, a comprehensive description of mental processes modulating this response is still lacking. Within the framework of predictive coding, deviance processing is part of an inference process where prediction errors (the mismatch between incoming sensations and predictions established through experience) are minimized. In this view, the MMN is a measure of prediction error, which yields specific expectations regarding its modulations by various experimental factors. In particular, it predicts that the MMN should decrease as the occurrence of a deviance becomes more predictable. We conducted a passive oddball EEG study and manipulated the predictability of sound sequences by means of different temporal structures. Importantly, our design allows comparing mismatch responses elicited by predictable and unpredictable violations of a simple repetition rule and therefore departs from previous studies that investigate violations of different time-scale regularities. We observed a decrease of the MMN with predictability and interestingly, a similar effect at earlier latencies, within 70 ms after deviance onset. Following these pre-attentive responses, a reduced P3a was measured in the case of predictable deviants. We conclude that early and late deviance responses reflect prediction errors, triggering belief updating within the auditory hierarchy. Beside, in this passive study, such perceptual inference appears to be modulated by higher-level implicit learning of sequence statistical structures. Our findings argue for a hierarchical model of auditory processing where predictive coding enables implicit extraction of environmental regularities. PMID- 26441603 TI - LTP-like plasticity in the visual system and in the motor system appear related in young and healthy subjects. AB - LTP-like plasticity measured by visual evoked potentials (VEP) can be induced in the intact human brain by presenting checkerboard reversals. Also associated with LTP-like plasticity, around two third of participants respond to transcranial magnetic stimulation (TMS) with a paired-associate stimulation (PAS) protocol with a potentiation of their motor evoked potentials. LTP-like processes are also required for verbal and motor learning tasks. We compared effect sizes, responder rates and intercorrelations as well as the potential influence of attention between these four assessments in a group of 37 young and healthy volunteers. We observed a potentiation effect of the N75 and P100 VEP component which positively correlated with plasticity induced by PAS. Subjects with a better subjective alertness were more likely to show PAS and VEP potentiation. No correlation was found between the other assessments. Effect sizes and responder rates of VEP potentiation were higher compared to PAS. Our results indicate a high variability of LTP-like effects and no evidence for a system-specific nature. As a consequence, studies wishing to assess individual levels of LTP-like plasticity should employ a combination of multiple assessments. PMID- 26441605 TI - Use the brain: complementary methods to analyse the effects of motivational music. PMID- 26441604 TI - Expert and crowd-sourced validation of an individualized sleep spindle detection method employing complex demodulation and individualized normalization. AB - A spindle detection method was developed that: (1) extracts the signal of interest (i.e., spindle-related phasic changes in sigma) relative to ongoing "background" sigma activity using complex demodulation, (2) accounts for variations of spindle characteristics across the night, scalp derivations and between individuals, and (3) employs a minimum number of sometimes arbitrary, user-defined parameters. Complex demodulation was used to extract instantaneous power in the spindle band. To account for intra- and inter-individual differences, the signal was z-score transformed using a 60 s sliding window, per channel, over the course of the recording. Spindle events were detected with a z score threshold corresponding to a low probability (e.g., 99th percentile). Spindle characteristics, such as amplitude, duration and oscillatory frequency, were derived for each individual spindle following detection, which permits spindles to be subsequently and flexibly categorized as slow or fast spindles from a single detection pass. Spindles were automatically detected in 15 young healthy subjects. Two experts manually identified spindles from C3 during Stage 2 sleep, from each recording; one employing conventional guidelines, and the other, identifying spindles with the aid of a sigma (11-16 Hz) filtered channel. These spindles were then compared between raters and to the automated detection to identify the presence of true positives, true negatives, false positives and false negatives. This method of automated spindle detection resolves or avoids many of the limitations that complicate automated spindle detection, and performs well compared to a group of non-experts, and importantly, has good external validity with respect to the extant literature in terms of the characteristics of automatically detected spindles. PMID- 26441606 TI - Commentary: "Neural signatures of intransitive preferences". PMID- 26441607 TI - Atypical delayed auditory feedback effect and Lombard effect on speech production in high-functioning adults with autism spectrum disorder. AB - Individuals with autism spectrum disorder (ASD) show impaired social interaction and communication, which may be related to their difficulties in speech production. To investigate the mechanisms of atypical speech production in this population, we examined feedback control by delaying the auditory feedback of their own speech, which degraded speech fluency. We also examined feedforward control by adding loud pink noise to the auditory feedback, which led to increased vocal effort in producing speech. The results of Japanese speakers show that, compared with neurotypical (NT) individuals, high-functioning adults with ASD (including Asperger's disorder, autistic disorder, and pervasive developmental disorder not otherwise specified) were more affected by delayed auditory feedback but less affected by external noise. These findings indicate that, in contrast to NT individuals, those with ASD relied more on feedback control than on feedforward control in speech production, which is consistent with the hypothesis that this population exhibits attenuated Bayesian priors. PMID- 26441608 TI - Depth discrimination of constant angular size stimuli in action space: role of accommodation and convergence cues. AB - In our daily life experience, the angular size of an object correlates with its distance from the observer, provided that the physical size of the object remains constant. In this work, we investigated depth perception in action space (i.e., beyond the arm reach), while keeping the angular size of the target object constant. This was achieved by increasing the physical size of the target object as its distance to the observer increased. To the best of our knowledge, this is the first time that a similar protocol has been tested in action space, for distances to the observer ranging from 1.4-2.4 m. We replicated the task in virtual and real environments and we found that the performance was significantly different between the two environments. In the real environment, all participants perceived the depth of the target object precisely. Whereas, in virtual reality (VR) the responses were significantly less precise, although, still above chance level in 16 of the 20 observers. The difference in the discriminability of the stimuli was likely due to different contributions of the convergence and the accommodation cues in the two environments. The values of Weber fractions estimated in our study were compared to those reported in previous studies in peripersonal and action space. PMID- 26441609 TI - Task-related activity in sensorimotor cortex in Parkinson's disease and essential tremor: changes in beta and gamma bands. AB - In Parkinson's disease patients in the OFF medication state, basal ganglia local field potentials exhibit changes in beta and gamma oscillations that correlate with reduced voluntary movement, manifested as rigidity and akinesia. However, magnetoencephalography and low-resolution electrocorticography (ECoG) studies in Parkinson's patients suggest that changes in sensorimotor cortical oscillations differ from those of the basal ganglia. To more clearly define the role of sensorimotor cortex oscillatory activity in Parkinson's, we performed intraoperative, high-resolution (4 mm spacing) ECoG recordings in 10 Parkinson's patients (2 females, ages 47-72) undergoing deep brain stimulation (DBS) lead placement in the awake, OFF medication state. We analyzed ECoG potentials during a computer-controlled reaching task designed to separate movement preparation from movement execution and compared findings to similar invasive recordings in eight patients with essential tremor (3 females, ages 59-78), a condition not associated with rigidity or akinesia. We show that (1) cortical beta spectral power at rest does not differ between Parkinson's and essential tremor patients (p = 0.85), (2) early motor preparation in Parkinson's patients in the OFF medication state is associated with a larger beta desynchronization compared to patients with essential tremor (p = 0.0061), and (3) cortical broadband gamma power is elevated in Parkinson's patients compared to essential tremor patients during both rest and task recordings (p = 0.004). Our findings suggest an oscillatory profile in sensorimotor cortex of Parkinson's patients that, in contrast to the basal ganglia, may act to promote movement to oppose the anti kinetic bias of the dopamine-depleted state. PMID- 26441611 TI - Beauty and the beholder: the role of visual sensitivity in visual preference. AB - For centuries, the essence of aesthetic experience has remained one of the most intriguing mysteries for philosophers, artists, art historians and scientists alike. Recently, views emphasizing the link between aesthetics, perception and brain function have become increasingly prevalent (Ramachandran and Hirstein, 1999; Zeki, 1999; Livingstone, 2002; Ishizu and Zeki, 2013). The link between art and the fractal-like structure of natural images has also been highlighted (Spehar et al., 2003; Graham and Field, 2007; Graham and Redies, 2010). Motivated by these claims and our previous findings that humans display a consistent preference across various images with fractal-like statistics, here we explore the possibility that observers' preference for visual patterns might be related to their sensitivity for such patterns. We measure sensitivity to simple visual patterns (sine-wave gratings varying in spatial frequency and random textures with varying scaling exponent) and find that they are highly correlated with visual preferences exhibited by the same observers. Although we do not attempt to offer a comprehensive neural model of aesthetic experience, we demonstrate a strong relationship between visual sensitivity and preference for simple visual patterns. Broadly speaking, our results support assertions that there is a close relationship between aesthetic experience and the sensory coding of natural stimuli. PMID- 26441610 TI - Recovery of resting brain connectivity ensuing mild traumatic brain injury. AB - Brains reveal amplified plasticity as they recover from an injury. We aimed to define time dependent plasticity changes in patients recovering from mild traumatic brain injury (mTBI). Twenty-five subjects with mild head injury were longitudinally evaluated within 36 h, 3 and 6 months using resting state functional connectivity (RSFC). Region of interest (ROI) based connectivity differences over time within the patient group and in comparison with a healthy control group were analyzed at p < 0.005. We found 33 distinct ROI pairs that revealed significant changes in their connectivity strength with time. Within 3 months, the majority of the ROI pairs had decreased connectivity in mTBI population, which increased and became comparable to healthy controls at 6 months. Within this diffuse decreased connectivity in the first 3 months, there were also few regions with increased connections. This hyper connectivity involved the salience network and default mode network within 36 h, and lingual, inferior frontal and fronto-parietal networks at 3 months. Our findings in a fairly homogenous group of patients with mTBI evaluated during the 6 month window of recovery defines time varying brain connectivity changes as the brain recovers from an injury. A majority of these changes were seen in the frontal and parietal lobes between 3 and 6 months after injury. Hyper connectivity of several networks supported normal recovery in the first 6 months and it remains to be seen in future studies whether this can predict an early and efficient recovery of brain function. PMID- 26441612 TI - Effects of broken affordance on visual extinction. AB - Previous studies have shown that visual extinction can be reduced if two objects are positioned to "afford" an action. Here we tested if this affordance effect was disrupted by "breaking" the affordance, i.e., if one of the objects actively used in the action had a broken handle. We assessed the effects of broken affordance on recovery from extinction in eight patients with right hemisphere lesions and left-sided extinction. Patients viewed object pairs that were or were not commonly used together and that were positioned for left- or right-hand actions. In the unrelated pair conditions, either two tools or two objects were presented. In line with previous research (e.g., Riddoch et al., 2006), extinction was reduced when action-related object pairs and when unrelated tool pairs were presented compared to unrelated object pairs. There was no significant difference in recovery rate between action-related (object-tool) and unrelated tool pairs. In addition, performance with action-related objects decreased when the tool appeared on the ipsilesional side compared to when it was on the contralesional side, but only when the tool handle was intact. There were minimal effects of breaking the handle of an object rather than a tool, and there was no effect of breaking the handle on either tools or objects on single item trials. The data suggest that breaking the handle of a tool lessens the degree to which it captures attention, with this attentional capture being strongest when the tool appears on the ipsilesional side. The capture of attention by the ipsilesional item then reduces the chance of detecting the contralesional stimulus. This attentional capture effect is mediated by the affordance to the intact tool. PMID- 26441613 TI - The neural representation of Arabic digits in visual cortex. AB - In this study, we investigated how Arabic digits are represented in the visual cortex, and how their representation changes throughout the ventral visual processing stream, compared to the representation of letters. We probed these questions with two functional magnetic resonance imaging (fMRI) experiments. In Experiment 1, we explored whether we could find brain regions that were more activated for digits than for number words in a subtraction task. One such region was detected in lateral occipital cortex. However, the activity in this region might have been confounded by string length-number words contain more characters than digits. We therefore conducted a second experiment in which string length was systematically controlled. Experiment 2 revealed that the findings of the first experiment were task dependent (as it was only observed in a task in which numerosity was relevant) or stimulus dependent (as it was only observed when the number of characters of a stimulus was not controlled). We further explored the characteristics of the activation patterns for digit and letter strings across the ventral visual processing stream through multi-voxel pattern analyses. We found an alteration in representations throughout the ventral processing stream from clustering based on amount of visual information in primary visual cortex (V1) towards clustering based on symbolic stimulus category higher in the visual hierarchy. The present findings converge to the conclusion that in the ventral visual system, as far as can be detected with fMRI, the distinction between Arabic digits and letter strings is represented in terms of distributed patterns rather than separate regions. PMID- 26441614 TI - The neurochemistry and social flow of singing: bonding and oxytocin. AB - Music is used in healthcare to promote physical and psychological well-being. As clinical applications of music continue to expand, there is a growing need to understand the biological mechanisms by which music influences health. Here we explore the neurochemistry and social flow of group singing. Four participants from a vocal jazz ensemble were conveniently sampled to sing together in two separate performances: pre-composed and improvised. Concentrations of plasma oxytocin and adrenocorticotropic hormone (ACTH) were measured before and after each singing condition to assess levels of social affiliation, engagement and arousal. A validated assessment of flow state was administered after each singing condition to assess participants' absorption in the task. The feasibility of the research methods were assessed and initial neurochemical data was generated on group singing. Mean scores of the flow state scale indicated that participants experienced flow in both the pre-composed (M = 37.06) and improvised singing conditions (M = 34.25), with no significant difference between conditions. ACTH concentrations decreased in both conditions, significantly so in the pre-composed singing condition, which may have contributed to the social flow experience. Mean plasma oxytocin levels increased only in response to improvised singing, with no significant difference between improvised and pre-composed singing conditions observed. The results indicate that group singing reduces stress and arousal, as measured by ACTH, and induces social flow in participants. The effects of pre composed and improvised group singing on oxytocin are less clear. Higher levels of plasma oxytocin in the improvised condition may perhaps be attributed to the social effects of improvising musically with others. Further research with a larger sample size is warranted. PMID- 26441616 TI - Corrigendum: Exploring associations between gaze patterns and putative human mirror neuron system activity. AB - [This corrects the article on p. 396 in vol. 9, PMID: 26236215.]. PMID- 26441615 TI - Rehabilitation of aphasia: application of melodic-rhythmic therapy to Italian language. AB - Aphasia is a complex disorder, frequent after stroke (with an incidence of 38%), with a detailed pathophysiological characterization. Effective approaches are crucial for devising an efficient rehabilitative strategy, in order to address the everyday life and professional disability. Several rehabilitative procedures are based on psycholinguistic, cognitive, psychosocial or pragmatic approaches, including amongst those with a neurobehavioral approach the Melodic Intonation Therapy (MIT). Van Eeckhout's adaptation of MIT to French language (Melodic Rhythmic Therapy: MRT) has implemented the training strategy by adding a rhythmic structure reproducing French prosody. The purpose of this study was to adapt MRT rehabilitation procedures to Italian language and to verify its efficacy in a group of six chronic patients (five males) with severe non-fluent aphasia and without specific aphasic treatments during the previous 9 months. The patients were treated 4 days a week for 16 weeks, with sessions of 30-40 min. They were assessed 6 months after the end of the treatment (follow-up). The patients showed a significant improvement at the Aachener Aphasie Test (AAT) in different fields of spontaneous speech, with superimposable results at the follow-up. Albeit preliminary, these findings support the use of MRT in the rehabilitation after stroke. Specifically, MRT seems to benefit from its stronger structure than the available stimulation-facilitation procedures and allows a better quantification of the rehabilitation efficacy. PMID- 26441617 TI - Response: Commentary: Viewing photos and reading nouns of natural graspable objects similarly modulate motor responses. PMID- 26441618 TI - Synchronization by the hand: the sight of gestures modulates low-frequency activity in brain responses to continuous speech. AB - During social interactions, speakers often produce spontaneous gestures to accompany their speech. These coordinated body movements convey communicative intentions, and modulate how listeners perceive the message in a subtle, but important way. In the present perspective, we put the focus on the role that congruent non-verbal information from beat gestures may play in the neural responses to speech. Whilst delta-theta oscillatory brain responses reflect the time-frequency structure of the speech signal, we argue that beat gestures promote phase resetting at relevant word onsets. This mechanism may facilitate the anticipation of associated acoustic cues relevant for prosodic/syllabic-based segmentation in speech perception. We report recently published data supporting this hypothesis, and discuss the potential of beats (and gestures in general) for further studies investigating continuous AV speech processing through low frequency oscillations. PMID- 26441619 TI - Neurovascular coupling: a parallel implementation. AB - A numerical model of neurovascular coupling (NVC) is presented based on neuronal activity coupled to vasodilation/contraction models via the astrocytic mediated perivascular K(+) and the smooth muscle cell (SMC) Ca(2+) pathway termed a neurovascular unit (NVU). Luminal agonists acting on P2Y receptors on the endothelial cell (EC) surface provide a flux of inositol trisphosphate (IP3) into the endothelial cytosol. This concentration of IP3 is transported via gap junctions between EC and SMC providing a source of sarcoplasmic derived Ca(2+) in the SMC. The model is able to relate a neuronal input signal to the corresponding vessel reaction (contraction or dilation). A tissue slice consisting of blocks, each of which contain an NVU is connected to a space filling H-tree, simulating a perfusing arterial tree (vasculature) The model couples the NVUs to the vascular tree via a stretch mediated Ca(2+) channel on both the EC and SMC. The SMC is induced to oscillate by increasing an agonist flux in the EC and hence increased IP3 induced Ca(2+) from the SMC stores with the resulting calcium-induced calcium release (CICR) oscillation inhibiting NVC thereby relating blood flow to vessel contraction and dilation following neuronal activation. The coupling between the vasculature and the set of NVUs is relatively weak for the case with agonist induced where only the Ca(2+) in cells inside the activated area becomes oscillatory however, the radii of vessels both inside and outside the activated area oscillate (albeit small for those outside). In addition the oscillation profile differs between coupled and decoupled states with the time required to refill the cytosol with decreasing Ca(2+) and increasing frequency with coupling. The solution algorithm is shown to have excellent weak and strong scaling. Results have been generated for tissue slices containing up to 4096 blocks. PMID- 26441620 TI - Modeling spontaneous activity across an excitable epithelium: Support for a coordination scenario of early neural evolution. AB - Internal coordination models hold that early nervous systems evolved in the first place to coordinate internal activity at a multicellular level, most notably the use of multicellular contractility as an effector for motility. A recent example of such a model, the skin brain thesis, suggests that excitable epithelia using chemical signaling are a potential candidate as a nervous system precursor. We developed a computational model and a measure for whole body coordination to investigate the coordinative properties of such excitable epithelia. Using this measure we show that excitable epithelia can spontaneously exhibit body-scale patterns of activation. Relevant factors determining the extent of patterning are the noise level for exocytosis, relative body dimensions, and body size. In smaller bodies whole-body coordination emerges from cellular excitability and bidirectional excitatory transmission alone. Our results show that basic internal coordination as proposed by the skin brain thesis could have arisen in this potential nervous system precursor, supporting that this configuration may have played a role as a proto-neural system and requires further investigation. PMID- 26441621 TI - Is predictive coding theory articulated enough to be testable? PMID- 26441622 TI - Volterra representation enables modeling of complex synaptic nonlinear dynamics in large-scale simulations. AB - Chemical synapses are comprised of a wide collection of intricate signaling pathways involving complex dynamics. These mechanisms are often reduced to simple spikes or exponential representations in order to enable computer simulations at higher spatial levels of complexity. However, these representations cannot capture important nonlinear dynamics found in synaptic transmission. Here, we propose an input-output (IO) synapse model capable of generating complex nonlinear dynamics while maintaining low computational complexity. This IO synapse model is an extension of a detailed mechanistic glutamatergic synapse model capable of capturing the input-output relationships of the mechanistic model using the Volterra functional power series. We demonstrate that the IO synapse model is able to successfully track the nonlinear dynamics of the synapse up to the third order with high accuracy. We also evaluate the accuracy of the IO synapse model at different input frequencies and compared its performance with that of kinetic models in compartmental neuron models. Our results demonstrate that the IO synapse model is capable of efficiently replicating complex nonlinear dynamics that were represented in the original mechanistic model and provide a method to replicate complex and diverse synaptic transmission within neuron network simulations. PMID- 26441623 TI - Thalamic neuron models encode stimulus information by burst-size modulation. AB - Thalamic neurons have been long assumed to fire in tonic mode during perceptive states, and in burst mode during sleep and unconsciousness. However, recent evidence suggests that bursts may also be relevant in the encoding of sensory information. Here, we explore the neural code of such thalamic bursts. In order to assess whether the burst code is generic or whether it depends on the detailed properties of each bursting neuron, we analyzed two neuron models incorporating different levels of biological detail. One of the models contained no information of the biophysical processes entailed in spike generation, and described neuron activity at a phenomenological level. The second model represented the evolution of the individual ionic conductances involved in spiking and bursting, and required a large number of parameters. We analyzed the models' input selectivity using reverse correlation methods and information theory. We found that n-spike bursts from both models transmit information by modulating their spike count in response to changes to instantaneous input features, such as slope, phase, amplitude, etc. The stimulus feature that is most efficiently encoded by bursts, however, need not coincide with one of such classical features. We therefore searched for the optimal feature among all those that could be expressed as a linear transformation of the time-dependent input current. We found that bursting neurons transmitted 6 times more information about such more general features. The relevant events in the stimulus were located in a time window spanning ~100 ms before and ~20 ms after burst onset. Most importantly, the neural code employed by the simple and the biologically realistic models was largely the same, implying that the simple thalamic neuron model contains the essential ingredients that account for the computational properties of the thalamic burst code. Thus, our results suggest the n-spike burst code is a general property of thalamic neurons. PMID- 26441624 TI - A predictive model of muscle excitations based on muscle modularity for a large repertoire of human locomotion conditions. AB - Humans can efficiently walk across a large variety of terrains and locomotion conditions with little or no mental effort. It has been hypothesized that the nervous system simplifies neuromuscular control by using muscle synergies, thus organizing multi-muscle activity into a small number of coordinative co activation modules. In the present study we investigated how muscle modularity is structured across a large repertoire of locomotion conditions including five different speeds and five different ground elevations. For this we have used the non-negative matrix factorization technique in order to explain EMG experimental data with a low-dimensional set of four motor components. In this context each motor components is composed of a non-negative factor and the associated muscle weightings. Furthermore, we have investigated if the proposed descriptive analysis of muscle modularity could be translated into a predictive model that could: (1) Estimate how motor components modulate across locomotion speeds and ground elevations. This implies not only estimating the non-negative factors temporal characteristics, but also the associated muscle weighting variations. (2) Estimate how the resulting muscle excitations modulate across novel locomotion conditions and subjects. The results showed three major distinctive features of muscle modularity: (1) the number of motor components was preserved across all locomotion conditions, (2) the non-negative factors were consistent in shape and timing across all locomotion conditions, and (3) the muscle weightings were modulated as distinctive functions of locomotion speed and ground elevation. Results also showed that the developed predictive model was able to reproduce well the muscle modularity of un-modeled data, i.e., novel subjects and conditions. Muscle weightings were reconstructed with a cross-correlation factor greater than 70% and a root mean square error less than 0.10. Furthermore, the generated muscle excitations matched well the experimental excitation with a cross-correlation factor greater than 85% and a root mean square error less than 0.09. The ability of synthetizing the neuromuscular mechanisms underlying human locomotion across a variety of locomotion conditions will enable solutions in the field of neurorehabilitation technologies and control of bipedal artificial systems. Open-access of the model implementation is provided for further analysis at https://simtk.org/home/p-mep/. PMID- 26441625 TI - Leg mechanics contribute to establishing swing phase trajectories during memory guided stepping movements in walking cats: a computational analysis. AB - When quadrupeds stop walking after stepping over a barrier with their forelegs, the memory of barrier height and location is retained for many minutes. This memory is subsequently used to guide hind leg movements over the barrier when walking is resumed. The upslope of the initial trajectory of hind leg paw movements is strongly dependent on the initial location of the paw relative to the barrier. In this study, we have attempted to determine whether mechanical factors contribute significantly in establishing the slope of the paw trajectories by creating a four-link biomechanical model of a cat hind leg and driving this model with a variety of joint-torque profiles, including average torques for a range of initial paw positions relative to the barrier. Torque profiles for individual steps were determined by an inverse dynamic analysis of leg movements in three normal cats. Our study demonstrates that limb mechanics can contribute to establishing the dependency of trajectory slope on the initial position of the paw relative to the barrier. However, an additional contribution of neuronal motor commands was indicated by the fact that the simulated slopes of paw trajectories were significantly less than the observed slopes. A neuronal contribution to the modification of paw trajectories was also revealed by our observations that both the magnitudes of knee flexor muscle EMG bursts and the initial knee flexion torques depended on initial paw position. Previous studies have shown that a shift in paw position prior to stepping over a barrier changes the paw trajectory to be appropriate for the new paw position. Our data indicate that both mechanical and neuronal factors contribute to this updating process, and that any shift in leg position during the delay period modifies the working memory of barrier location. PMID- 26441626 TI - Dynamic trajectory of multiple single-unit activity during working memory task in rats. AB - Working memory plays an important role in complex cognitive tasks. A popular theoretical view is that transient properties of neuronal dynamics underlie cognitive processing. The question raised here as to how the transient dynamics evolve in working memory. To address this issue, we investigated the multiple single-unit activity dynamics in rat medial prefrontal cortex (mPFC) during a Y maze working memory task. The approach worked by reconstructing state space from delays of the original single-unit firing rate variables, which were further analyzed using kernel principal component analysis (KPCA). Then the neural trajectories were obtained to visualize the multiple single-unit activity. Furthermore, the maximal Lyapunov exponent (MLE) was calculated to quantitatively evaluate the neural trajectories during the working memory task. The results showed that the neuronal activity produced stable and reproducible neural trajectories in the correct trials while showed irregular trajectories in the incorrect trials, which may establish a link between the neurocognitive process and behavioral performance in working memory. The MLEs significantly increased during working memory in the correctly performed trials, indicating an increased divergence of the neural trajectories. In the incorrect trials, the MLEs were nearly zero and remained unchanged during the task. Taken together, the trial specific neural trajectory provides an effective way to track the instantaneous state of the neuronal population during the working memory task and offers valuable insights into working memory function. The MLE describes the changes of neural dynamics in working memory and may reflect different neuronal population states in working memory. PMID- 26441628 TI - A unified framework for spiking and gap-junction interactions in distributed neuronal network simulations. AB - Contemporary simulators for networks of point and few-compartment model neurons come with a plethora of ready-to-use neuron and synapse models and support complex network topologies. Recent technological advancements have broadened the spectrum of application further to the efficient simulation of brain-scale networks on supercomputers. In distributed network simulations the amount of spike data that accrues per millisecond and process is typically low, such that a common optimization strategy is to communicate spikes at relatively long intervals, where the upper limit is given by the shortest synaptic transmission delay in the network. This approach is well-suited for simulations that employ only chemical synapses but it has so far impeded the incorporation of gap junction models, which require instantaneous neuronal interactions. Here, we present a numerical algorithm based on a waveform-relaxation technique which allows for network simulations with gap junctions in a way that is compatible with the delayed communication strategy. Using a reference implementation in the NEST simulator, we demonstrate that the algorithm and the required data structures can be smoothly integrated with existing code such that they complement the infrastructure for spiking connections. To show that the unified framework for gap-junction and spiking interactions achieves high performance and delivers high accuracy in the presence of gap junctions, we present benchmarks for workstations, clusters, and supercomputers. Finally, we discuss limitations of the novel technology. PMID- 26441627 TI - The basal ganglia select the expected sensory input used for predictive coding. AB - While considerable evidence supports the notion that lower-level interpretation of incoming sensory information is guided by top-down sensory expectations, less is known about the source of the sensory expectations or the mechanisms by which they are spread. Predictive coding theory proposes that sensory expectations flow down from higher-level association areas to lower-level sensory cortex. A separate theory of the role of prediction in cognition describes "emulations" as linked representations of potential actions and their associated expected sensation that are hypothesized to play an important role in many aspects of cognition. The expected sensations in active emulations are proposed to be the top-down expectation used in predictive coding. Representations of the potential action and expected sensation in emulations are claimed to be instantiated in distributed cortical networks. Combining predictive coding with emulations thus provides a theoretical link between the top-down expectations that guide sensory expectations and the cortical networks representing potential actions. Now moving to theories of action selection, the basal ganglia has long been proposed to select between potential actions by reducing inhibition to the cortical network instantiating the desired action plan. Integration of these isolated theories leads to the novel hypothesis that reduction in inhibition from the basal ganglia selects not just action plans, but entire emulations, including the sensory input expected to result from the action. Basal ganglia disinhibition is hypothesized to both initiate an action and also allow propagation of the action's associated sensory expectation down towards primary sensory cortex. This is a novel proposal for the role of the basal ganglia in biasing perception by selecting the expected sensation, and initiating the top-down transmission of those expectations in predictive coding. PMID- 26441629 TI - Distributed recurrent neural forward models with synaptic adaptation and CPG based control for complex behaviors of walking robots. AB - Walking animals, like stick insects, cockroaches or ants, demonstrate a fascinating range of locomotive abilities and complex behaviors. The locomotive behaviors can consist of a variety of walking patterns along with adaptation that allow the animals to deal with changes in environmental conditions, like uneven terrains, gaps, obstacles etc. Biological study has revealed that such complex behaviors are a result of a combination of biomechanics and neural mechanism thus representing the true nature of embodied interactions. While the biomechanics helps maintain flexibility and sustain a variety of movements, the neural mechanisms generate movements while making appropriate predictions crucial for achieving adaptation. Such predictions or planning ahead can be achieved by way of internal models that are grounded in the overall behavior of the animal. Inspired by these findings, we present here, an artificial bio-inspired walking system which effectively combines biomechanics (in terms of the body and leg structures) with the underlying neural mechanisms. The neural mechanisms consist of (1) central pattern generator based control for generating basic rhythmic patterns and coordinated movements, (2) distributed (at each leg) recurrent neural network based adaptive forward models with efference copies as internal models for sensory predictions and instantaneous state estimations, and (3) searching and elevation control for adapting the movement of an individual leg to deal with different environmental conditions. Using simulations we show that this bio-inspired approach with adaptive internal models allows the walking robot to perform complex locomotive behaviors as observed in insects, including walking on undulated terrains, crossing large gaps, leg damage adaptations, as well as climbing over high obstacles. Furthermore, we demonstrate that the newly developed recurrent network based approach to online forward models outperforms the adaptive neuron forward models, which have hitherto been the state of the art, to model a subset of similar walking behaviors in walking robots. PMID- 26441630 TI - Editorial: Brain cholinergic mechanisms. PMID- 26441631 TI - The evolutionary origin of the need to sleep: an inevitable consequence of synaptic neurotransmission? AB - It is proposed that the evolutionary origin of the need to sleep is the removal of neurotransmitters (NTs) that escape reuptake and accumulate in brain interstitial fluid (ISF). Recent work suggests that the activity of ionotropic postsynaptic receptors, rapidly initiated by binding of NTs to extracellular sites, is modulated over longer times by adsorption of these NTs to the lipid bilayers in which the receptors are embedded. This bilayer-mediated mechanism is far less molecularly specific than binding, so bilayer adsorption of NTs that have diffused into synapses for other receptors would modulate their activity as well. Although NTs are recycled by membrane protein reuptake, the process is less than 100% efficient; a fraction escapes the region in which these specific reuptake proteins are localized and eventually diffuses throughout the ISF. It is estimated that even if only 0.1% of NTs escape reuptake, they would accumulate and adsorb to bilayers in synapses of other receptors sufficiently to affect receptor activity, the harmful consequences of which are avoided by sleep: a period of efficient convective clearance of solutes together with greatly reduced synaptic activity. PMID- 26441632 TI - Co-release of glutamate and GABA from single vesicles in GABAergic neurons exogenously expressing VGLUT3. AB - The identity of the vesicle neurotransmitter transporter expressed by a neuron largely corresponds with the primary neurotransmitter that cell releases. However, the vesicular glutamate transporter subtype 3 (VGLUT3) is mainly expressed in non-glutamatergic neurons, including cholinergic, serotonergic, or GABAergic neurons. Though a functional role for glutamate release from these non glutamatergic neurons has been demonstrated, the interplay between VGLUT3 and the neuron's characteristic neurotransmitter transporter, particularly in the case of GABAergic neurons, at the synaptic and vesicular level is less clear. In this study, we explore how exogenous expression of VGLUT3 in striatal GABAergic neurons affects the packaging and release of glutamate and GABA in synaptic vesicles (SVs). We found that VGLUT3 expression in isolated, autaptic GABAergic neurons leads to action potential evoked release of glutamate. Under these conditions, glutamate and GABA could be packaged together in single vesicles release either spontaneously or asynchronously. However, the presence of glutamate in GABAergic vesicles did not affect uptake of GABA itself, suggesting a lack of synergy in vesicle filling for these transmitters. Finally, we found postsynaptic detection of glutamate released from GABAergic terminals difficult when bona fide glutamatergic synapses were present, suggesting that co-released glutamate cannot induce postsynaptic glutamate receptor clustering. PMID- 26441633 TI - Measuring sleep quality in older adults: a comparison using subjective and objective methods. AB - Sleep quality decreases with aging and thus sleep complaints are prevalent in older adults, particularly for those with cognitive impairment and dementia. For older adults, emerging evidence suggests poor sleep quality increases risk of developing cognitive impairment and dementia. Given the aging population-and the impending economic burden associated with increasing numbers of dementia patients there is pressing need to improve sleep quality among older adults. As such, research efforts have increased focus on investigating the association between age-related sleep changes and cognitive decline in older adults. Sleep quality is a complex construct to evaluate empirically, and yet the Pittsburg Sleep Quality Index (PSQI) is commonly used in studies as their only measure of sleep quality. Furthermore, the PSQI may not be the best sleep quality measure for older adults, due to its reliance on the cognitive capacity to reflect on the past month. Further study is needed to determine the PSQI's validity among older adults. Thus, the current study examined sleep quality for 78 community dwelling adults 55+ to determine the PSQI's predictive validity for objective sleep quality (as measured by actigraphy). We compared two subjective measures of sleep quality-the PSQI and Consensus Sleep Diary (CSD)-with actigraphy (MotionWatch 8(c); camntech). Our results suggest perceived sleep quality is quite different from objective reality, at least for adults 55+. Importantly, we show this difference is unrelated to age, gender, education, or cognitive status (assessed using standard screens). Previous studies have shown the PSQI to be a valuable tool for assessing subjective sleep quality; however, our findings indicate for older adults the PSQI should not be used as a substitute for actigraphy, or vice versa. Hence, we conclude best practice is to include both subjective and objective measures when examining sleep quality in older adults (i.e., the PSQI, CSD, and actigraphy). PMID- 26441634 TI - Exergaming as a Viable Therapeutic Tool to Improve Static and Dynamic Balance among Older Adults and People with Idiopathic Parkinson's Disease: A Systematic Review and Meta-Analysis. AB - The use of virtual reality games (known as "exergaming") as a neurorehabilitation tool is gaining interest. Therefore, we aim to collate evidence for the effects of exergaming on the balance and postural control of older adults and people with idiopathic Parkinson's disease (IPD). Six electronic databases were searched, from inception to April 2015, to identify relevant studies. Standardized mean differences (SMDs) and 95% confidence intervals (CI) were used to calculate effect sizes between experimental and control groups. I (2) statistics were used to determine levels of heterogeneity. 325 older adults and 56 people with IPD who were assessed across 11 -studies. The results showed that exergaming improved static balance (SMD 1.069, 95% CI 0.563-1.576), postural control (SMD 0.826, 95% CI 0.481-1.170), and dynamic balance (SMD -0.808, 95% CI -1.192 to -0.424) in healthy older adults. Two IPD studies showed an improvement in static balance (SMD 0.124, 95% CI -0.581 to 0.828) and postural control (SMD 2.576, 95% CI 1.534 3.599). Our findings suggest that exergaming might be an appropriate therapeutic tool for improving balance and postural control in older adults, but more -large scale trials are needed to determine if the same is true for people with IPD. PMID- 26441635 TI - Association of Pancreatic Polypeptide with Mild Cognitive Impairment Varies by APOE epsilon4 Allele. AB - We conducted a preliminary case-control investigation of the association of pancreatic polypeptide (PP) with mild cognitive impairment (MCI) in 202 MCI cases (mean age, 81.6 years) and 202 age- and sex-matched cognitively normal controls in the Mayo Clinic Study of Aging. Plasma PP was measured and examined as the natural logarithm (continuous) and dichotomized at the median. The OR (95% CI) of MCI increased with increasing PP [1.46 (1.04-2.05)]. There was a negative interaction of PP with apolipoprotein E (APOE) epsilon4 allele; compared to the reference group (no APOE epsilon4 allele and low PP), the OR (95% CI) for combinations of epsilon4 and PP were: 2.64 (1.39-5.04) for APOE epsilon4 plus low PP; 2.09 (1.27-3.45) for no APOE epsilon4 plus high PP; and 1.91 (1.04-3.53) for no APOE epsilon4 plus high PP (P for interaction = 0.017). There was also a trend toward a negative interaction with type 2 diabetes (P for interaction = 0.058). Compared to no diabetes and low PP, the OR (95% CI) was 3.02 (1.22-7.46) for low PP plus diabetes but 1.80 (1.01-3.22) for high PP plus diabetes. Participants with high PP had a greater mean (SD) weight loss (kilograms per decade) than persons with low PP [-2.27 (4.07) vs. -1.61 (5.24); P = 0.016]. MCI cases had a non-significantly greater weight loss per decade compared to controls. These findings suggest that high PP alone or jointly with APOE epsilon4 allele or type 2 diabetes is associated with MCI, and that high PP may mitigate some effects of APOE epsilon4 allele and type 2 diabetes on cognition. Potential mechanisms may involve PP-related weight loss and centrally mediated effects of PP on cognition. These findings remain to be validated in other studies. PMID- 26441636 TI - Sex Differences in Stroke Subtypes, Severity, Risk Factors, and Outcomes among Elderly Patients with Acute Ischemic Stroke. AB - BACKGROUND: Although the age-specific incidence and mortality of stroke is higher among men, stroke has a greater clinical effect on women. However, the sex differences in stroke among elderly patients are unknown. Therefore, we aimed to assess the sex differences in stroke among elderly stroke patients. METHODS: Between 2005 and 2013, we recruited 1484 consecutive acute ischemic stroke (AIS) patients (>=75 years old) from a specialized neurology hospital in Tianjin, China. Information regarding their stroke subtypes, severity, risk factors, and outcomes at 3 and 12 months after stroke were recorded. RESULTS: Comparing with men, women had a significantly higher prevalence of severe stroke (17.20 vs. 12.54%), hypertension (76.42 vs. 66.39%), dyslipidemias (30.35 vs. 22.76%), and obesity (18.40 vs. 9.32%), P < 0.05. Comparing with women, men had a significantly higher prevalence of intracranial artery stenosis (23.11 vs. 17.45%), current smoking (29.60 vs. 13.05%), and alcohol consumption (12.15 vs. 0.47%), P < 0.05. Moreover, dependency was more common among women at 3 and 12 months after stroke, although the sex difference disappeared after adjusting for stroke subtypes, severity, and risk factors. CONCLUSION: Elderly women with AIS had more severe stroke status and worse outcomes at 3 and 12 months after stroke. Thus, elderly female post-AIS patients are a crucial population that should be assisted with controlling their risk factors for stroke and changing their lifestyle. PMID- 26441637 TI - Oxytocin modulates meta-mood as a function of age and sex. AB - Attending to and understanding one's own feelings are components of meta-mood and constitute important socio-affective skills across the entire lifespan. Growing evidence suggests a modulatory role of the neuropeptide oxytocin on various socio affective processes. Going beyond previous work that almost exclusively examined young men and perceptions of emotions in others, the current study investigated effects of intranasal oxytocin on meta-mood in young and older men and women. In a double-blind between-group design, participants were randomly assigned to self administer either intranasal oxytocin or a placebo before responding to items from the Trait Meta-Mood Scale (TMMS) about attention to feelings and clarity of feelings. In contrast to older women, oxytocin relative to placebo increased attention to feelings in older men. Oxytocin relative to placebo enhanced meta mood in young female participants but reduced it in older female participants. This pattern of findings supports an age- and sex-differential modulatory function of the neuropeptide oxytocin on meta-mood, possibly associated with neurobiological differences with age and sex. PMID- 26441638 TI - Switching between hands in a serial reaction time task: a comparison between young and old adults. AB - Healthy aging is associated with a variety of functional and structural brain alterations. These age-related brain alterations have been assumed to negatively impact cognitive and motor performance. Especially important for the execution of everyday activities in older adults (OA) is the ability to perform movements that depend on both hands working together. However, bimanual coordination is typically deteriorated with increasing age. Hence, a deeper understanding of such age-related brain-behavior alterations might offer the opportunity to design future interventional studies in order to delay or even prevent the decline in cognitive and/or motor performance over the lifespan. Here, we examined to what extent the capability to acquire and maintain a novel bimanual motor skill is still preserved in healthy OA as compared to their younger peers (YA). For this purpose, we investigated performance of OA (n = 26) and YA (n = 26) in a bimanual serial reaction time task (B-SRTT), on two experimental sessions, separated by 1 week. We found that even though OA were generally slower in global response times, they showed preserved learning capabilities in the B-SRTT. However, sequence specific learning was more pronounced in YA as compared to OA. Furthermore, we found that switching between hands during B-SRTT learning trials resulted in increased response times (hand switch costs), a phenomenon that was more pronounced in OA. These hand switch costs were reduced in both groups over the time course of learning. More interestingly, there were no group differences in hand switch costs on the second training session. These results provide novel evidence that bimanual motor skill learning is capable of reducing age-related deficits in hand switch costs, a finding that might have important implications to prevent the age-related decline in sensorimotor function. PMID- 26441639 TI - Regional electroencephalogram (EEG) alpha power and asymmetry in older adults: a study of short-term test-retest reliability. AB - Although regional alpha power and asymmetry measures have been widely used as indices of individual differences in emotional processing and affective style in younger populations, there have been relatively few studies that have examined these measures in older adults. Here, we examined the short-term test-retest reliability of resting regional alpha power (7.5-12.5 Hz) and asymmetry in a sample of 38 active, community-dwelling older adults (M age = 71.2, SD = 6.5 years). Resting electroencephalogram recordings were made before and after a perceptual computer task. Pearson and intra-class correlations indicated acceptable test-retest reliability for alpha power and asymmetry measures in all regions. Interestingly, alpha asymmetry appeared to be less affected by the task than was alpha power. Findings suggest that alpha asymmetry may reflect more enduring, "trait-like" characteristics, while alpha power may reflect more "state like" processes in older adults. PMID- 26441640 TI - Environmental enrichment does not influence hypersynchronous network activity in the Tg2576 mouse model of Alzheimer's disease. AB - The cognitive reserve hypothesis claims that the brain can overcome pathology by reinforcing preexistent processes or by developing alternative cognitive strategies. Epidemiological studies have revealed that this reserve can be built throughout life experiences as education or leisure activities. We previously showed that an early transient environmental enrichment (EE) durably improves memory performances in the Tg2576 mouse model of Alzheimer's disease (AD). Recently, we evidenced a hypersynchronous brain network activity in young adult Tg2576 mice. As aberrant oscillatory activity can contribute to memory deficits, we wondered whether the long-lasting memory improvements observed after EE were associated with a reduction of neuronal network hypersynchrony. Thus, we exposed non-transgenic (NTg) and Tg2576 mice to standard or enriched housing conditions for 10 weeks, starting at 3 months of age. Two weeks after EE period, Tg2576 mice presented similar seizure susceptibility to a GABA receptor antagonist. Immediately after and 2 weeks after this enrichment period, standard and enriched housed Tg2576 mice did not differ with regards to the frequency of interictal spikes on their electroencephalographic (EEG) recordings. Thus, the long-lasting effect of this EE protocol on memory capacities in Tg2576 mice is not mediated by a reduction of their cerebral aberrant neuronal activity at early ages. PMID- 26441642 TI - Commentary: Duration-dependent effects of the BDNF Val66Met polymorphism on anodal tDCS induced motor cortex plasticity in older adults: a group and individual perspective. PMID- 26441641 TI - The impact of aging on the spatial accuracy of quick corrective arm movements in response to sudden target displacement during reaching. AB - Age-related declines in visuomotor processing speed can have a large impact on motor performance in elderly individuals. Contrary to previous findings, however, recent studies revealed that elderly individuals are able to quickly react to displacement of a visual target during reaching. Here, we investigated the influence of aging on quick, corrective responses to perturbations during reaching in the terms of their functional contribution to accuracy. Elderly and young adults performed reaching movements to a visual target that could be displaced during reaching, and they were requested to move their hand to reach the final target location as quickly as possible. Results showed that, for the younger group, the variance in the directional error of the corrective response correlated with the variance in the reaching trajectory at the halfway point of the reach, but the correlation decreased at the end of the reaching. On the other hand, such correlations were not significant in elderly participants, although the variance of the directional error did not show a significant difference between age groups. Thus, the quick, corrective response seems to play an important role in decreasing variability, especially before the end of reaching, and aging can impair this process. PMID- 26441643 TI - Basal Forebrain Atrophy Contributes to Allocentric Navigation Impairment in Alzheimer's Disease Patients. AB - The basal forebrain degenerates in Alzheimer's disease (AD) and this process is believed to contribute to the cognitive decline observed in AD patients. Impairment in spatial navigation is an early feature of the disease but whether basal forebrain dysfunction in AD is responsible for the impaired navigation skills of AD patients is not known. Our objective was to investigate the relationship between basal forebrain volume and performance in real space as well as computer-based navigation paradigms in an elderly cohort comprising cognitively normal controls, subjects with amnestic mild cognitive impairment and those with AD. We also tested whether basal forebrain volume could predict the participants' ability to perform allocentric- vs. egocentric-based navigation tasks. The basal forebrain volume was calculated from 1.5 T magnetic resonance imaging (MRI) scans, and navigation skills were assessed using the human analog of the Morris water maze employing allocentric, egocentric, and mixed allo/egocentric real space as well as computerized tests. When considering the entire sample, we found that basal forebrain volume correlated with spatial accuracy in allocentric (cued) and mixed allo/egocentric navigation tasks but not the egocentric (uncued) task, demonstrating an important role of the basal forebrain in mediating cue-based spatial navigation capacity. Regression analysis revealed that, although hippocampal volume reflected navigation performance across the entire sample, basal forebrain volume contributed to mixed allo/egocentric navigation performance in the AD group, whereas hippocampal volume did not. This suggests that atrophy of the basal forebrain contributes to aspects of navigation impairment in AD that are independent of hippocampal atrophy. PMID- 26441644 TI - Unexploited opportunities for phage therapy. PMID- 26441645 TI - The ever unfolding story of cAMP signaling in trypanosomatids: vive la difference! AB - Kinetoplastids are unicellular, eukaryotic, flagellated protozoans containing the eponymous kinetoplast. Within this order, the family of trypanosomatids are responsible for some of the most serious human diseases, including Chagas disease (Trypanosoma cruzi), sleeping sickness (Trypanosoma brucei spp.), and leishmaniasis (Leishmania spp). Although cAMP is produced during the life cycle stages of these parasites, its signaling pathways are very different from those of mammals. The absence of G-protein-coupled receptors, the presence of structurally different adenylyl cyclases, the paucity of known cAMP effector proteins and the stringent need for regulation of cAMP in the small kinetoplastid cells all suggest a significantly different biochemical pathway and likely cell biology. However, each of the main kinetoplastid parasites express four class 1 type cyclic nucleotide-specific phosphodiesterases (PDEA-D), which have highly similar catalytic domains to that of human PDEs. To date, only TbrPDEB, expressed as two slightly different isoforms TbrPDEB1 and B2, has been found to be essential when ablated. Although the genomes contain reasonably well conserved genes for catalytic and regulatory domains of protein kinase A, these have been shown to have varied structural and functional roles in the different species. Recent discovery of a role of cAMP/AMP metabolism in a quorum-sensing signaling pathway in T. brucei, and the identification of downstream cAMP Response Proteins (CARPs) whose expression levels correlate with sensitivity to PDE inhibitors, suggests a complex signaling cascade. The interplay between the roles of these novel CARPs and the quorum-sensing signaling pathway on cell division and differentiation makes for intriguing cell biology and a new paradigm in cAMP signal transduction, as well as potential targets for trypanosomatid-specific cAMP pathway-based therapeutics. PMID- 26441646 TI - Advances in optical imaging for pharmacological studies. AB - Imaging approaches are an essential tool for following up over time representative parameters of in vivo models, providing useful information in pharmacological studies. Main advantages of optical imaging approaches compared to other imaging methods are their safety, straight-forward use and cost effectiveness. A main drawback, however, is having to deal with the presence of high scattering and high absorption in living tissues. Depending on how these issues are addressed, three different modalities can be differentiated: planar imaging (including fluorescence and bioluminescence in vivo imaging), optical tomography, and optoacoustic approaches. In this review we describe the latest advances in optical in vivo imaging with pharmacological applications, with special focus on the development of new optical imaging probes in order to overcome the strong absorption introduced by different tissue components, especially hemoglobin, and the development of multimodal imaging systems in order to overcome the resolution limitations imposed by scattering. PMID- 26441647 TI - Salvinorin A, a kappa-opioid receptor agonist hallucinogen: pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders. AB - Salvinorin A is a potent hallucinogen, isolated from the ethnomedical plant Salvia divinorum. Salvinorin A is a selective high efficacy kappa-opioid receptor (KOPr) agonist, and thus implicates the KOPr system and its endogenous agonist ligands (the dynorphins) in higher functions, including cognition and perceptual effects. Salvinorin A is the only selective KOPr ligand to be widely available outside research or medical settings, and salvinorin A-containing products have undergone frequent non-medical use. KOPr/dynorphin systems in the brain are known to be powerful counter-modulatory mechanisms to dopaminergic function, which is important in mood and reward engendered by natural and chemical reinforcers (including drugs of abuse). KOPr activation (including by salvinorin A) can thus cause aversion and anhedonia in preclinical models. Salvinorin A is also a completely new scaffold for medicinal chemistry approaches, since it is a non nitrogenous neoclerodane, unlike other known opioid ligands. Ongoing efforts have the goal of discovering novel semi-synthetic salvinorin analogs with potential KOPr-mediated pharmacotherapeutic effects (including partial agonist or biased agonist effects), with a reduced burden of undesirable effects associated with salvinorin A. PMID- 26441648 TI - Cellular imaging: a key phenotypic screening strategy for predictive toxicology. AB - Incorporating phenotypic screening as a key strategy enhances predictivity and translatability of drug discovery efforts. Cellular imaging serves as a "phenotypic anchor" to identify important toxicologic pathology that encompasses an array of underlying mechanisms, thus provides an effective means to reduce drug development failures due to insufficient safety. This mini-review highlights the latest advances in hepatotoxicity, cardiotoxicity, and genetic toxicity tests that utilized cellular imaging as a screening strategy, and recommends path forward for further improvement. PMID- 26441650 TI - When cure becomes an illness-abuse of addictive prescription medicines. PMID- 26441651 TI - An update on the Pharmacovigilance Programme of India. PMID- 26441649 TI - Targeting protein-protein interactions in complexes organized by A kinase anchoring proteins. AB - Cyclic AMP is a ubiquitous intracellular second messenger involved in the regulation of a wide variety of cellular processes, a majority of which act through the cAMP - protein kinase A (PKA) signaling pathway and involve PKA phosphorylation of specific substrates. PKA phosphorylation events are typically spatially restricted and temporally well controlled. A-kinase anchoring proteins (AKAPs) directly bind PKA and recruit it to specific subcellular loci targeting the kinase activity toward particular substrates, and thereby provide discrete spatiotemporal control of downstream phosphorylation events. AKAPs also scaffold other signaling molecules into multi-protein complexes that function as crossroads between different signaling pathways. Targeting AKAP coordinated protein complexes with high-affinity peptidomimetics or small molecules to tease apart distinct protein-protein interactions (PPIs) therefore offers important means to disrupt binding of specific components of the complex to better understand the molecular mechanisms involved in the function of individual signalosomes and their pathophysiological role. Furthermore, development of novel classes of small molecules involved in displacement of AKAP-bound signal molecules is now emerging. Here, we will focus on mechanisms for targeting PPI, disruptors that modulate downstream cAMP signaling and their role, especially in the heart. PMID- 26441652 TI - Acylated flavonol glycosides from Tagetes minuta with antibacterial activity. AB - Wild marigold (Tagetes minuta), a flowering plant of the family Asteraceae contains compounds of pharmaceutical and nutritional importance especially essential oils and flavonols. Identification, characterization of flavonols and determination of their antibacterial activity were major objectives of the current study. The isolation and purification of flavonols was accomplished using chromatographic techniques while structural elucidation was completed by LC-MS and NMR spectroscopy. The extracts and purified compounds were tested against various bacterial strains for antibacterial activity. A total of 19 flavonols were isolated from this species. Of these, 17 were of butanol and two of ethyl acetate extracts. Based on the concentration and purity, eight potential flavonols were selected and structurally elucidated. Four flavonols, 6 hydroxyquercetin 7-O-beta-(6''-galloylglucopyranoside; 2), 6-hydroxykaempferol 7 O-beta-glucopyranoside (5), 6-hydroxykaempferol 7-O-beta-(6'' galloylglucopyranoside; 7), 6-hydroxyquercetin 7-O-beta-(6'' caffeoylglucopyranoside; 9), were identified for the first time from T. minuta. Butanol and ethyl acetate extracts of flowers and seeds showed significant antibacterial activity against Micrococcus leteus, Staphylococcus aureus, Bacillus subtilis, and Pseudomonas pikettii. Among the isolated flavonols only 1, 2, and 18 were found to possess significant antibacterial activity against M. luteus. The extracts and purified flavonols from T. minuta can be potential candidates for antibacterial drug discovery and support to ethnopharmacological use. PMID- 26441653 TI - Genetically-encoded tools for cAMP probing and modulation in living systems. AB - Intracellular 3'-5'-cyclic adenosine monophosphate (cAMP) is one of the principal second messengers downstream of a manifold of signal transduction pathways, including the ones triggered by G protein-coupled receptors. Not surprisingly, biochemical assays for cAMP have been instrumental for basic research and drug discovery for decades, providing insights into cellular physiology and guiding pharmaceutical industry. However, despite impressive track record, the majority of conventional biochemical tools for cAMP probing share the same fundamental shortcoming-all the measurements require sample disruption for cAMP liberation. This common bottleneck, together with inherently low spatial resolution of measurements (as cAMP is typically analyzed in lysates of thousands of cells), underpin the ensuing limitations of the conventional cAMP assays: (1) genuine kinetic measurements of cAMP levels over time in a single given sample are unfeasible; (2) inability to obtain precise information on cAMP spatial distribution and transfer at subcellular levels, let alone the attempts to pinpoint dynamic interactions of cAMP and its effectors. At the same time, tremendous progress in synthetic biology over the recent years culminated in drastic refinement of our toolbox, allowing us not only to bypass the limitations of conventional assays, but to put intracellular cAMP life-span under tight control-something, that seemed scarcely attainable before. In this review article we discuss the main classes of modern genetically-encoded tools tailored for cAMP probing and modulation in living systems. We examine the capabilities and weaknesses of these different tools in the context of their operational characteristics and applicability to various experimental set-ups involving living cells, providing the guidance for rational selection of the best tools for particular needs. PMID- 26441655 TI - Assessing the synergy between cholinomimetics and memantine as augmentation therapy in cognitive impairment in schizophrenia. A virtual human patient trial using quantitative systems pharmacology. AB - While many drug discovery research programs aim to develop highly selective clinical candidates, their clinical success is limited because of the complex non linear interactions of human brain neuronal circuits. Therefore, a rational approach for identifying appropriate synergistic multipharmacology and validating optimal target combinations is desperately needed. A mechanism-based Quantitative Systems Pharmacology (QSP) computer-based modeling platform that combines biophysically realistic preclinical neurophysiology and neuropharmacology with clinical information is a possible solution. This paper reports the application of such a model for Cognitive Impairment In Schizophrenia (CIAS), where the cholinomimetics galantamine and donepezil are combined with memantine and with different antipsychotics and smoking in a virtual human patient experiment. The results suggest that cholinomimetics added to antipsychotics have a modest effect on cognition in CIAS in non-smoking patients with haloperidol and risperidone and to a lesser extent with olanzapine and aripiprazole. Smoking reduces the effect of cholinomimetics with aripiprazole and olanzapine, but enhances the effect in haloperidol and risperidone. Adding memantine to antipsychotics improves cognition except with quetiapine, an effect enhanced with smoking. Combining cholinomimetics, antipsychotics and memantine in general shows an additive effect, except for a negative interaction with aripiprazole and quetiapine and a synergistic effect with olanzapine and haloperidol in non-smokers and haloperidol in smokers. The complex interaction of cholinomimetics with memantine, antipsychotics and smoking can be quantitatively studied using mechanism-based advanced computer modeling. QSP modeling of virtual human patients can possibly generate useful insights on the non-linear interactions of multipharmacology drugs and support complex CNS R&D projects in cognition in search of synergistic polypharmacy. PMID- 26441654 TI - Evolution of contrast agents for ultrasound imaging and ultrasound-mediated drug delivery. AB - Ultrasound (US) is one of the most frequently used diagnostic methods. It is a non-invasive, comparably inexpensive imaging method with a broad spectrum of applications, which can be increased even more by using bubbles as contrast agents (CAs). There are various different types of bubbles: filled with different gases, composed of soft- or hard-shell materials, and ranging in size from nano- to micrometers. These intravascular CAs enable functional analyses, e.g., to acquire organ perfusion in real-time. Molecular analyses are achieved by coupling specific ligands to the bubbles' shell, which bind to marker molecules in the area of interest. Bubbles can also be loaded with or attached to drugs, peptides or genes and can be destroyed by US pulses to locally release the entrapped agent. Recent studies show that US CAs are also valuable tools in hyperthermia induced ablation therapy of tumors, or can increase cellular uptake of locally released drugs by enhancing membrane permeability. This review summarizes important steps in the development of US CAs and introduces the current clinical applications of contrast-enhanced US. Additionally, an overview of the recent developments in US probe design for functional and molecular diagnosis as well as for drug delivery is given. PMID- 26441656 TI - Systems pharmacology of adiposity reveals inhibition of EP300 as a common therapeutic mechanism of caloric restriction and resveratrol for obesity. AB - Both caloric restriction (CR) and resveratrol (RSV) have beneficial effects on obesity. However, the biochemical pathways that mediate these beneficial effects might be complex and interconnected and have not been fully elucidated. To reveal the common therapeutic mechanism of CR and RSV, we performed a comparative transcriptome analysis of adipose tissues from diet-induced obese (DIO) zebrafish and obese humans. We identified nine genes in DIO zebrafish and seven genes in obese humans whose expressions were regulated by CR and RSV. Although the gene lists did not overlap except for one gene, the gene ontologies enriched in the gene lists were highly overlapped, and included genes involved in adipocyte differentiation, lipid storage and lipid metabolism. Bioinformatic analysis of cis-regulatory sequences of these genes revealed that their transcriptional regulators also overlapped, including EP300, HDAC2, CEBPB, CEBPD, FOXA1, and FOXA2. We also identified 15 and 46 genes that were dysregulated in the adipose tissue of DIO zebrafish and obese humans, respectively. Bioinformatics analysis identified EP300, HDAC2, and CEBPB as common transcriptional regulators for these genes. EP300 is a histone and lysyl acetyltransferase that modulates the function of histone and various proteins including CEBPB, CEBPD, FOXA1, and FOXA2. We demonstrated that adiposity in larval zebrafish was significantly reduced by C646, an inhibitor of EP300 that antagonizes acetyl-CoA. The reduction of adiposity by C646 was not significantly different from that induced by RSV or co treatment of C646 and RSV. These results indicate that the inhibition of EP300 might be a common therapeutic mechanism between CR and RSV in adipose tissues of obese individuals. PMID- 26441657 TI - 5-HT6 receptor agonism facilitates emotional learning. AB - Serotonin (5-HT) and its receptors play crucial roles in various aspects of mood and cognitive functions. However, the role of specific 5-HT receptors in these processes remains to be better understood. Here, we examined the effects of the selective and potent 5-HT6 agonist (WAY208466) on mood, anxiety and emotional learning in mice. Male C57Bl/6J mice were therefore tested in the forced swim test (FST), elevated plus-maze (EPM), and passive avoidance tests (PA), respectively. In a dose-response experiment, mice were treated intraperitoneally with WAY208466 at 3, 9, or 27 mg/kg and examined in an open field arena open field test (OFT) followed by the FST. 9 mg/kg of WAY208466 reduced immobility in the FST, without impairing the locomotion. Thus, the dose of 9 mg/kg was subsequently used for tests of anxiety and emotional learning. There was no significant effect of WAY208466 in the EPM. In the PA, mice were trained 30 min before the treatment with saline or WAY208466. Two separate sets of animals were used for short term memory (tested 1 h post-training) or long term memory (tested 24 h post-training). WAY208466 improved both short and long term memories, evaluated by the latency to enter the dark compartment, in the PA. The WAY208466 treated animals also showed more grooming and rearing in the light compartment. To better understand the molecular mechanisms and brain regions involved in the facilitation of emotional learning by WAY208466, we studied its effects on signal transduction and immediate early gene expression. WAY208466 increased the levels of phospho-Ser(845)-GluA1 and phospho-Ser(217/221)-MEK in the caudate-putamen. Levels of phospho-Thr(202/204)-Erk1/2 and the ratio mature BDNF/proBDNF were increased in the hippocampus. Moreover, WAY208466 increased c-fos in the hippocampus and Arc expression in both hippocampus and prefrontal cortex (PFC). The results indicate antidepressant efficacy and facilitation of emotional learning by 5-HT6 receptor agonism via mechanisms that promote neuronal plasticity in caudate putamen, hippocampus, and PFC. PMID- 26441658 TI - Agonist and antagonist effects of tobacco-related nitrosamines on human alpha4beta2 nicotinic acetylcholine receptors. AB - Regulation of the "neuronal" nicotinic acetylcholine receptors (nAChRs) is implicated in both tobacco addiction and smoking-dependent tumor promotion. Some of these effects are caused by the tobacco-derived N-nitrosamines, which are carcinogenic compounds that avidly bind to nAChRs. However, the functional effects of these drugs on specific nAChR subtypes are largely unknown. By using patch-clamp methods, we tested 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) on human alpha4beta2 nAChRs. These latter are widely distributed in the mammalian brain and are also frequently expressed outside the nervous system. NNK behaved as a partial agonist, with an apparent EC50 of 16.7 MUM. At 100 MUM, it activated 16% of the maximal current activated by nicotine. When NNK was co-applied with nicotine, it potentiated the currents elicited by nicotine concentrations <= 100 nM. At higher concentrations of nicotine, NNK always inhibited the alpha4beta2 nAChR. In contrast, NNN was a pure inhibitor of this nAChR subtype, with IC50 of approximately 1 nM in the presence of 10 MUM nicotine. The effects of both NNK and NNN were mainly competitive and largely independent of Vm. The different actions of NNN and NNK must be taken into account when interpreting their biological effects in vitro and in vivo. PMID- 26441659 TI - Spatiotemporal regulation of cAMP signaling controls the human trophoblast fusion. AB - During human placentation, mononuclear cytotrophoblasts fuse to form multinucleated syncytia ensuring hormonal production and nutrient exchanges between the maternal and fetal circulation. Syncytial formation is essential for the maintenance of pregnancy and for fetal growth. The cAMP signaling pathway is the major route to trigger trophoblast fusion and its activation results in phosphorylation of specific intracellular target proteins, in transcription of fusogenic genes and assembly of macromolecular protein complexes constituting the fusogenic machinery at the plasma membrane. Specificity in cAMP signaling is ensured by generation of localized pools of cAMP controlled by cAMP phosphodiesterases (PDEs) and by discrete spatial and temporal activation of protein kinase A (PKA) in supramolecular signaling clusters inside the cell organized by A-kinase-anchoring proteins (AKAPs) and by organization of signal termination by protein phosphatases (PPs). Here we present original observations on the available components of the cAMP signaling pathway in the human placenta including PKA, PDE, and PP isoforms as well as AKAPs. We continue to discuss the current knowledge of the spatiotemporal regulation of cAMP signaling triggering trophoblast fusion. PMID- 26441660 TI - Sensorimotor gating impairments induced by MK-801 treatment may be reduced by tolerance effect and by familiarization in monkeys. AB - Dizocilpine (MK-801) is a non-competitive NMDA antagonist that induces schizophreniclike effects. It is therefore widely used in experimental models of schizophrenia including prepulse inhibition (PPI) impairments in rodents. Nevertheless, MK-801 has never been tested in monkeys on a PPI paradigm. In order to evaluate MK-801 effects on monkeys' PPI, we tested eight capuchin monkeys (Sapajus spp.) using three different doses of MK-801 (0.01; 0.02; 0.03 mg/kg). Results show PPI impairment in acute administration of the highest dose (0.03 mg/kg). PPI impairment induced by MK-801 was reversed by re-exposure to the PPI test throughout treatment trials, in contrast with rodent studies. These results indicate that tolerance effect and familiarization with PPI test may reduce the sensorimotor gating deficits induced by MK-801 in monkeys, suggesting a drug training interaction. PMID- 26441661 TI - Multi-target pharmacology: possibilities and limitations of the "skeleton key approach" from a medicinal chemist perspective. AB - Multi-target drugs have raised considerable interest in the last decade owing to their advantages in the treatment of complex diseases and health conditions linked to drug resistance issues. Prospective drug repositioning to treat comorbid conditions is an additional, overlooked application of multi-target ligands. While medicinal chemists usually rely on some version of the lock and key paradigm to design novel therapeutics, modern pharmacology recognizes that the mid- and long-term effects of a given drug on a biological system may depend not only on the specific ligand-target recognition events but also on the influence of the repeated administration of a drug on the cell gene signature. The design of multi-target agents usually imposes challenging restrictions on the topology or flexibility of the candidate drugs, which are briefly discussed in the present article. Finally, computational strategies to approach the identification of novel multi-target agents are overviewed. PMID- 26441663 TI - Insights to ligand binding to the monoamine transporters-from homology modeling to LeuBAT and dDAT. AB - Understanding of drug binding to the human biogenic amine transporters (BATs) is essential to explain the mechanism of action of these pharmaceuticals but more importantly to be able to develop new and improved compounds to be used in the treatment of depression or drug addiction. Until recently no high resolution structure was available of the BATs and homology modeling was a necessity. Various studies have revealed experimentally validated binding modes of numerous ligands to the BATs using homology modeling. Here we examine and discuss the similarities between the binding models of substrates, antidepressants, psychostimulants, and mazindol in homology models of the human BATs and the recently published crystal structures of the Drosophila dopamine transporter and the engineered protein, LeuBAT. The comparison reveals that careful computational modeling combined with experimental data can be utilized to predict binding of molecules to proteins that agree very well with crystal structures. PMID- 26441662 TI - A review on mitochondrial restorative mechanism of antioxidants in Alzheimer's disease and other neurological conditions. AB - Neurodegenerative diseases are intricate in nature because of the involvement of the multiple pathophysiological events including mitochondrial dysfunction, neuroinflammation and oxidative stress. Alzheimer's disease (AD) is a neurodegenerative disease explained by extracellular amyloid beta deposits, intracellular neurofibrillary tangles and mitochondrial dysfunction. Increasing evidence has indicated that mitochondrial dysfunction displays significant role in the pathophysiological processes of AD. Mitochondrial dysfunction involves alterations in mitochondrial respiratory enzyme complex activities, oxidative stress, opening of permeability transition pore, and enhanced apoptosis. Various bioenergetics and antioxidants have been tried or under different investigational phase against AD and other neurodegenerative disorders (Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis) because of their complex and multiple site of action. These mitochondrial-targeting bioenergetics and antioxidant compounds such as coenzyme Q10, idebenone, creatine, mitoQ, mitovitE, MitoTEMPOL, latrepirdine, methylene blue, triterpenoids, SS peptides, curcumin, Ginkgo biloba, and omega-3 polyunsaturated fatty acids with potential efficacy in AD have been identified. Present review is intent to discuss mitochondrial restorative mechanisms of these bioenergetics and antioxidants as a potential alternative drug strategy for effective management of AD. PMID- 26441664 TI - Developing multi-target therapeutics to fine-tune the evolutionary dynamics of the cancer ecosystem. PMID- 26441665 TI - Different pH-sensitivity patterns of 30 sodium channel inhibitors suggest chemically different pools along the access pathway. AB - The major drug binding site of sodium channels is inaccessible from the extracellular side, drug molecules can only access it either from the membrane phase, or from the intracellular aqueous phase. For this reason, ligand-membrane interactions are as important determinants of inhibitor properties, as ligand protein interactions. One-way to probe this is to modify the pH of the extracellular fluid, which alters the ratio of charged vs. uncharged forms of some compounds, thereby changing their interaction with the membrane. In this electrophysiology study we used three different pH values: 6.0, 7.3, and 8.6 to test the significance of the protonation-deprotonation equilibrium in drug access and affinity. We investigated drugs of several different indications: carbamazepine, lamotrigine, phenytoin, lidocaine, bupivacaine, mexiletine, flecainide, ranolazine, riluzole, memantine, ritanserin, tolperisone, silperisone, ambroxol, haloperidol, chlorpromazine, clozapine, fluoxetine, sertraline, paroxetine, amitriptyline, imipramine, desipramine, maprotiline, nisoxetine, mianserin, mirtazapine, venlafaxine, nefazodone, and trazodone. We recorded the pH-dependence of potency, reversibility, as well as onset/offset kinetics. As expected, we observed a strong correlation between the acidic dissociation constant (pKa) of drugs and the pH-dependence of their potency. Unexpectedly, however, the pH-dependence of reversibility or kinetics showed diverse patterns, not simple correlation. Our data are best explained by a model where drug molecules can be trapped in at least two chemically different environments: A hydrophilic trap (which may be the aqueous cavity within the inner vestibule), which favors polar and less lipophilic compounds, and a lipophilic trap (which may be the membrane phase itself, and/or lipophilic binding sites on the channel). Rescue from the hydrophilic and lipophilic traps can be promoted by alkalic and acidic extracellular pH, respectively. PMID- 26441666 TI - Decreased expression of alpha-2-HS glycoprotein in the sera of rats treated with Eurycoma longifolia extract. AB - Eurycoma longifolia is a Malaysian native herb that has been widely used as an aphrodisiac and a remedy for andropause. Although the physiological effects of the plant extract were predicted as a result of the alterations in protein expression, the key protein(s) involved in these alterations are still unclear. In the present study, we have investigated the effect of standardized E. longifolia extract on serum protein expression up to 28 days following oral administration in rats. Serum protein profiles were analyzed by 2-dimensional electrophoresis, and altered proteins were identified via mass spectrometry. We observed that alpha-2-HS glycoprotein (AHS) was significantly decreased in the serum of experimentally treated rats compared to pre-treated animals. Moreover, reduction in AHS was confirmed using competitive enzyme-linked immunosorbent assay. AHS expression is known to be associated with insulin resistance and diabetes. Our data indicated that serum AHS was reduced in rats treated with standardized E. longifolia extract, and therefore form a prelude for further investigation into the effects of this natural extract in animal models involving infertility and diabetes. PMID- 26441667 TI - Corrigendum: Impact of kinase activating and inactivating patient mutations on binary PKA interactions. AB - [This corrects the article on p. 170 in vol. 6, PMID: 26347651.]. PMID- 26441668 TI - Revisiting the mitogenetic effect of ultra-weak photon emission. AB - This paper reviews the 90 years long controversial history of the so-called "mitogenetic radiation," the first case of non-chemical distant interactions, reported by Gurwitsch (1923). It was soon described as ultraweak UV, emitted by a number of biological systems, and stimulating mitosis in "competent" (in this sense) cells. In the following 20 years this phenomenon attracted enormous interest of the scientific community, and gave rise to more than 700 publications around the world. Yet, this wave of research vanished after several ostensibly disproving works in late 1930-s, and was not resumed later, regardless of quite serious grounds for that. The authors discuss separately two aspects of the problem: (1) do living organisms emit ultraweak radiation in the UV range (irrespective of whether it has any biological role), and (2) are there any real effects of this ultraweak photon emission (UPE) upon cell division and/or other biological functions? Analysis of the available data permits to conclude, that UV fraction of UPE should be regarded real, while its biological effects are difficult to reproduce. This causes a paradox. A number of presently known qualities of UPE were initially discovered (predicted?) by the "early workers" on the basis of biological effects. Yet the qualities they discovered were proved later (the UV component of UPE, the sources of UPE among biological systems, etc...), while the biological effect they used for UPE "detection" remains questionable. Importance of this area for basic biology and medicine, and potential usefulness of UPE as a non-invasive research method, invite scientists to attack this problem again, applying powerful research facilities of modern science. Yet, because of complexity and uncertainty of the problem, further progress in this area demands comprehensive examination of both positive and negative works, with particular attention to their methodical details. PMID- 26441669 TI - TRPA1 mediates amplified sympathetic responsiveness to activation of metabolically sensitive muscle afferents in rats with femoral artery occlusion. AB - Autonomic responses to activation of mechanically and metabolically sensitive muscle afferent nerves during static contraction are augmented in rats with femoral artery occlusion. Moreover, metabolically sensitive transient receptor potential cation channel subfamily A, member 1 (TRPA1) has been reported to contribute to sympathetic nerve activity (SNA) and arterial blood pressure (BP) responses evoked by static muscle contraction. Thus, in the present study, we examined the mechanisms by which afferent nerves' TRPA1 plays a role in regulating amplified sympathetic responsiveness due to a restriction of blood flow directed to the hindlimb muscles. Our data show that 24-72 h of femoral artery occlusion (1) upregulates the protein levels of TRPA1 in dorsal root ganglion (DRG) tissues; (2) selectively increases expression of TRPA1 in DRG neurons supplying metabolically sensitive afferent nerves of C-fiber (group IV); and (3) enhances renal SNA and BP responses to AITC (a TRPA1 agonist) injected into the hindlimb muscles. In addition, our data demonstrate that blocking TRPA1 attenuates SNA and BP responses during muscle contraction to a greater degree in ligated rats than those responses in control rats. In contrast, blocking TRPA1 fails to attenuate SNA and BP responses during passive tendon stretch in both groups. Overall, results of this study indicate that alternations in muscle afferent nerves' TRPA1 likely contribute to enhanced sympathetically mediated autonomic responses via the metabolic component of the muscle reflex under circumstances of chronic muscle ischemia. PMID- 26441671 TI - Databases for multilevel biophysiology research available at Physiome.jp. AB - Physiome.jp (http://physiome.jp) is a portal site inaugurated in 2007 to support model-based research in physiome and systems biology. At Physiome.jp, several tools and databases are available to support construction of physiological, multi hierarchical, large-scale models. There are three databases in Physiome.jp, housing mathematical models, morphological data, and time-series data. In late 2013, the site was fully renovated, and in May 2015, new functions were implemented to provide information infrastructure to support collaborative activities for developing models and performing simulations within the database framework. This article describes updates to the databases implemented since 2013, including cooperation among the three databases, interactive model browsing, user management, version management of models, management of parameter sets, and interoperability with applications. PMID- 26441670 TI - Bridging scales through multiscale modeling: a case study on protein kinase A. AB - The goal of multiscale modeling in biology is to use structurally based physico chemical models to integrate across temporal and spatial scales of biology and thereby improve mechanistic understanding of, for example, how a single mutation can alter organism-scale phenotypes. This approach may also inform therapeutic strategies or identify candidate drug targets that might otherwise have been overlooked. However, in many cases, it remains unclear how best to synthesize information obtained from various scales and analysis approaches, such as atomistic molecular models, Markov state models (MSM), subcellular network models, and whole cell models. In this paper, we use protein kinase A (PKA) activation as a case study to explore how computational methods that model different physical scales can complement each other and integrate into an improved multiscale representation of the biological mechanisms. Using measured crystal structures, we show how molecular dynamics (MD) simulations coupled with atomic-scale MSMs can provide conformations for Brownian dynamics (BD) simulations to feed transitional states and kinetic parameters into protein-scale MSMs. We discuss how milestoning can give reaction probabilities and forward-rate constants of cAMP association events by seamlessly integrating MD and BD simulation scales. These rate constants coupled with MSMs provide a robust representation of the free energy landscape, enabling access to kinetic, and thermodynamic parameters unavailable from current experimental data. These approaches have helped to illuminate the cooperative nature of PKA activation in response to distinct cAMP binding events. Collectively, this approach exemplifies a general strategy for multiscale model development that is applicable to a wide range of biological problems. PMID- 26441672 TI - Pre- and postsynaptic changes in the neuromuscular junction in dystrophic mice. AB - Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease in which weakness, increased susceptibility to muscle injury, and inadequate repair appear to underlie the pathology. While most attention has focused within the muscle fiber, we recently demonstrated in mdx mice (murine model for DMD) significant morphologic alterations at the motor endplate of the neuromuscular junction (NMJ) and corresponding NMJ transmission failure after injury. Here we extend these initial observations at the motor endplate to gain insight into the pre- vs. postsynaptic morphology, as well as the subsynaptic nuclei in healthy (WT) vs. mdx mice. We quantified the discontinuity and branching of the terminal nerve in adult mice. We report mdx- and age-dependent changes for discontinuity and an increase in branching when compared to WT. To examine mdx- and age-dependent changes in the relative localization of pre- and postsynaptic structures, we calculated NMJ occupancy, defined as the ratio of the footprint occupied by presynaptic vesicles vs. that of the underlying motor endplate. The normally congruent coupling between presynaptic and postsynaptic morphology was altered in mdx mice, independent of age. Finally we found an almost two-fold increase in the number of nuclei and an increase in density (nuclei/area) underlying the NMJ. These outcomes suggest substantial remodeling of the NMJ during dystrophic progression. This remodeling reflects plasticity in both pre- and postsynaptic contributors to NMJ structure, and thus perhaps also NM transmission and muscle function. PMID- 26441673 TI - Caloric restriction induces energy-sparing alterations in skeletal muscle contraction, fiber composition and local thyroid hormone metabolism that persist during catch-up fat upon refeeding. AB - Weight regain after caloric restriction results in accelerated fat storage in adipose tissue. This catch-up fat phenomenon is postulated to result partly from suppressed skeletal muscle thermogenesis, but the underlying mechanisms are elusive. We investigated whether the reduced rate of skeletal muscle contraction relaxation cycle that occurs after caloric restriction persists during weight recovery and could contribute to catch-up fat. Using a rat model of semistarvation-refeeding, in which fat recovery is driven by suppressed thermogenesis, we show that contraction and relaxation of leg muscles are slower after both semistarvation and refeeding. These effects are associated with (i) higher expression of muscle deiodinase type 3 (DIO3), which inactivates tri iodothyronine (T3), and lower expression of T3-activating enzyme, deiodinase type 2 (DIO2), (ii) slower net formation of T3 from its T4 precursor in muscles, and (iii) accumulation of slow fibers at the expense of fast fibers. These semistarvation-induced changes persisted during recovery and correlated with impaired expression of transcription factors involved in slow-twitch muscle development. We conclude that diminished muscle thermogenesis following caloric restriction results from reduced muscle T3 levels, alteration in muscle-specific transcription factors, and fast-to-slow fiber shift causing slower contractility. These energy-sparing effects persist during weight recovery and contribute to catch-up fat. PMID- 26441674 TI - A multiscale computational model of spatially resolved calcium cycling in cardiac myocytes: from detailed cleft dynamics to the whole cell concentration profiles. AB - Mathematical modeling of excitation-contraction coupling (ECC) in ventricular cardiac myocytes is a multiscale problem, and it is therefore difficult to develop spatially detailed simulation tools. ECC involves gradients on the length scale of 100 nm in dyadic spaces and concentration profiles along the 100 MUm of the whole cell, as well as the sub-millisecond time scale of local concentration changes and the change of lumenal Ca(2+) content within tens of seconds. Our concept for a multiscale mathematical model of Ca(2+) -induced Ca(2+) release (CICR) and whole cardiomyocyte electrophysiology incorporates stochastic simulation of individual LC- and RyR-channels, spatially detailed concentration dynamics in dyadic clefts, rabbit membrane potential dynamics, and a system of partial differential equations for myoplasmic and lumenal free Ca(2+) and Ca(2+) binding molecules in the bulk of the cell. We developed a novel computational approach to resolve the concentration gradients from dyadic space to cell level by using a quasistatic approximation within the dyad and finite element methods for integrating the partial differential equations. We show whole cell Ca(2+) concentration profiles using three previously published RyR-channel Markov schemes. PMID- 26441675 TI - Comparison of swimming capacity and energetics of migratory European eel (Anguilla anguilla) and New Zealand short-finned eel (A. australis). AB - The spawning migration of the European eel (Anguilla anguilla) can cover more than 6000 km, while that of the New Zealand short-finned eel (A. australis) is assumed to be approximately 3000 km. Since these species are expected to show adaptive traits to such an important lifetime event, we hypothesized differences in swimming capacity and energetics as a response to this adaptation. In an experimental swimming respirometer set-up, critical swimming speed (Ucrit), optimal swimming speed (Uopt), mass specific oxygen consumption rate (MO2), standard metabolic rate (SMR), active metabolic rate at Ucrit (AMRcrit) and at Uopt (AMRopt), the minimum cost of transport at Uopt (COTmin), and the scope for activity, were assessed and compared between the species. With a similar body length and mass, European eels showed ca. 25% higher values for both Ucrit and Uopt, and 23% lower values for COTmin, compared to New Zealand short-finned eels. However, SMR, AMRcrit, AMRopt, and scope for activity did not differ between the species, indicating very similar swimming physiology traits. This study discusses physiological aspects of long distance migration and provides recommendations for (a) swimming respirometry in anguilliform fish, and (b) telemetry research using externally attached pop-up tags. PMID- 26441676 TI - Designing and testing regenerative pulp treatment strategies: modeling the transdentinal transport mechanisms. AB - The need for simulation models to thoroughly test the inflammatory effects of dental materials and dentinogenic effects of specific signaling molecules has been well recognized in current dental research. The development of a model that simulates the transdentinal flow and the mass transfer mechanisms is of prime importance in terms of achieving the objectives of developing more effective treatment modalities in restorative dentistry. The present protocol study is part of an ongoing investigation on the development of a methodology that can calculate the transport rate of selected molecules inside a typical dentinal tubule. The transport rate of biological molecules has been investigated using a validated CFD code. In that framework we propose a simple algorithm that, given the type of molecules of the therapeutic agent and the maximum acceptable time for the drug concentration to attain a required value at the pulpal side of the tubules, can estimate the initial concentration to be imposed. PMID- 26441677 TI - Cardiac autonomic responses after resistance exercise in treated hypertensive subjects. AB - The aim of this study was to assess and to compare heart rate variability (HRV) after resistance exercise (RE) in treated hypertensive and normotensive subjects. Nine hypertensive men [HT: 58.0 +/- 7.7 years, systolic blood pressure (SBP) = 133.6 +/- 6.5 mmHg, diastolic blood pressure (DBP) = 87.3 +/- 8.1 mmHg; under antihypertensive treatment] and 11 normotensive men (NT: 57.1 +/- 6.0 years, SBP = 127 +/- 8.5 mmHg, DBP = 82.7 +/- 5.5 mmHg) performed a single session of RE (2 sets of 15-20 repetitions, 50% of 1 RM, 120 s interval between sets/exercise) for the following exercises: leg extension, leg press, leg curl, bench press, seated row, triceps push-down, seated calf flexion, seated arm curl. HRV was assessed at resting and during 10 min of recovery period by calculating time (SDNN, RMSSD, pNN50) and frequency domain (LF, HF, LF/HF) indices. Mean values of HRV indices were reduced in the post-exercise period compared to the resting period (HT: lnHF: 4.7 +/- 1.4 vs. 2.4 +/- 1.2 ms(2); NT: lnHF: 4.8 +/- 1.5 vs. 2.2 +/- 1.1 ms(2), p < 0.01). However, there was no group vs. time interaction in this response (p = 0.8). The results indicate that HRV is equally suppressed after RE in normotensive and hypertensive individuals. These findings suggest that a single session of RE does not bring additional cardiac autonomic stress to treated hypertensive subjects. PMID- 26441679 TI - Neuro-mechanical determinants of repeated treadmill sprints - Usefulness of an "hypoxic to normoxic recovery" approach. AB - To improve our understanding of the limiting factors during repeated sprinting, we manipulated hypoxia severity during an initial set and examined the effects on performance and associated neuro-mechanical alterations during a subsequent set performed in normoxia. On separate days, 13 active males performed eight 5-s sprints (recovery = 25 s) on an instrumented treadmill in either normoxia near sea-level (SL; FiO2 = 20.9%), moderate (MH; FiO2 = 16.8%) or severe normobaric hypoxia (SH; FiO2 = 13.3%) followed, 6 min later, by four 5-s sprints (recovery = 25 s) in normoxia. Throughout the first set, along with distance covered [larger sprint decrement score in SH (-8.2%) compared to SL (-5.3%) and MH (-7.2%); P < 0.05], changes in contact time, step frequency and root mean square activity (surface electromyography) of the quadriceps (Rectus femoris muscle) in SH exceeded those in SL and MH (P < 0.05). During first sprint of the subsequent normoxic set, the distance covered (99.6, 96.4, and 98.3% of sprint 1 in SL, MH, and SH, respectively), the main kinetic (mean vertical, horizontal, and resultant forces) and kinematic (contact time and step frequency) variables as well as surface electromyogram of quadriceps and plantar flexor muscles were fully recovered, with no significant difference between conditions. Despite differing hypoxic severity levels during sprints 1-8, performance and neuro-mechanical patterns did not differ during the four sprints of the second set performed in normoxia. In summary, under the circumstances of this study (participant background, exercise-to-rest ratio, hypoxia exposure), sprint mechanical performance and neural alterations were largely influenced by the hypoxia severity in an initial set of repeated sprints. However, hypoxia had no residual effect during a subsequent set performed in normoxia. Hence, the recovery of performance and associated neuro-mechanical alterations was complete after resting for 6 min near sea level, with a similar fatigue pattern across conditions during subsequent repeated sprints in normoxia. PMID- 26441680 TI - Analysis of the protein related receptor GPR92 in G-cells. AB - A continuous assessment of ingested food in the gastric lumen is essential for fine-tuning the digestive activities, including the secretion of the regulatory hormones such as gastrin. It has been proposed that G-cells may be able to sense the amount of ingested proteins and adjust the secretion of gastrin accordingly. Our previous studies have shown that G-cells express suitable receptor types, most notably the peptone-receptor GPR92 and the amino acid receptors GPRC6A and CaSR; however, their relative importance remained unclear. To determine the relative quantity of each receptor type, individual G-cells isolated from the transgenic mouse line mGas-EGFP were analyzed by means of a Liquid Chromatography Tandem-Mass Spectrometry (LC-MS/MS) procedure. The results indicate that the relative amount of receptor protein for GPR92 was much higher than for the receptor types GPRC6A and CaSR. These findings support the notion that the peptone-receptor GPR92 may be particularly relevant for sensing partially digested protein products. This view was supported by the finding that a high protein diet affected the expression level of the peptone-receptor GPR92 in the gastric antrum as well as in the circumvallate papillae. PMID- 26441681 TI - Dual effect of lithium on NFAT5 activity in kidney cells. AB - Lithium salts are used widely for treatment of bipolar and other mental disorders. Lithium therapy is accompanied frequently by renal side effects, such as nephrogenic diabetes insipidus or chronic kidney disease (CKD), but the molecular mechanisms underlying these effects are still poorly understood. In the present study we examined the effect of lithium on the activity of the osmosensitive transcriptional activator nuclear factor of activated T cells 5 (NFAT5, also known as TonEBP), which plays a key role in renal cellular osmoprotection and urinary concentrating ability. Interestingly, we found different effects of lithium on NFAT5 activity, depending on medium osmolality and incubation time. When cells were exposed to lithium for a relative short period (24 h), NFAT5 activity was significantly increased, especially under isosmotic conditions, resulting in an enhanced expression of the NFAT5 target gene heat shock protein 70 (HSP70). Further analysis revealed that the increase of NFAT5 activity depended primarily on an enhanced activity of the c-terminal transactivation domain (TAD), while NFAT5 protein abundance was largely unaffected. Enhanced activity of the TAD is probably mediated by lithium-induced inhibitory phosphorylation of glycogen synthase kinase 3beta (GSK-3beta), which is in accordance with previous studies. When cells were exposed to lithium for a longer period (96 h), cellular NFAT5 activity and subsequently expression of HSP70 significantly decreased under hyperosmotic conditions, due to diminished NFAT5 protein abundance, also resulting from GSK-3beta inhibition. Taken together, our results provide evidence that lithium has opposing effects on NFAT5 activity, depending on environmental osmolality and exposure duration. The potential impacts of these observations on the diverse effects of lithium on kidney function are discussed. PMID- 26441682 TI - Stem cell origin differently affects bone tissue engineering strategies. AB - Bone tissue engineering approaches are encouraging for the improvement of conventional bone grafting technique drawbacks. Thanks to their self-renewal and multi-lineage differentiation ability, stem cells are one of the major actors in tissue engineering approaches, and among these adult mesenchymal stem cells (MSCs) hold a great promise for regenerative medicine strategies. Bone marrow MSCs (BM-MSCs) are the first- identified and well-recognized stem cell population used in bone tissue engineering. Nevertheless, several factors hamper BM-MSC clinical application and subsequently, new stem cell sources have been investigated for these purposes. The fruitful selection and combination of tissue engineered scaffold, progenitor cells, and physiologic signaling molecules allowed the surgeon to reconstruct the missing natural tissue. On the basis of these considerations, we analyzed the capability of two different scaffolds, planned for osteochondral tissue regeneration, to modulate differentiation of adult stem cells of dissimilar local sources (i.e., periodontal ligament, maxillary periosteum) as well as adipose-derived stem cells (ASCs), in view of possible craniofacial tissue engineering strategies. We demonstrated that cells are differently committed toward the osteoblastic phenotype and therefore, taking into account their specific features, they could be intriguing cell sources in different stem cell-based bone/periodontal tissue regeneration approaches. PMID- 26441678 TI - The similarity between N-terminal targeting signals for protein import into different organelles and its evolutionary relevance. AB - The proper distribution of proteins between the cytosol and various membrane bound compartments is crucial for the functionality of eukaryotic cells. This requires the cooperation between protein transport machineries that translocate diverse proteins from the cytosol into these compartments and targeting signal(s) encoded within the primary sequence of these proteins that define their cellular destination. The mechanisms exerting protein translocation differ remarkably between the compartments, but the predominant targeting signals for mitochondria, chloroplasts and the ER share the N-terminal position, an alpha-helical structural element and the removal from the core protein by intraorganellar cleavage. Interestingly, similar properties have been described for the peroxisomal targeting signal type 2 mediating the import of a fraction of soluble peroxisomal proteins, whereas other peroxisomal matrix proteins encode the type 1 targeting signal residing at the extreme C-terminus. The structural similarity of N-terminal targeting signals poses a challenge to the specificity of protein transport, but allows the generation of ambiguous targeting signals that mediate dual targeting of proteins into different compartments. Dual targeting might represent an advantage for adaptation processes that involve a redistribution of proteins, because it circumvents the hierarchy of targeting signals. Thus, the co existence of two equally functional import pathways into peroxisomes might reflect a balance between evolutionary constant and flexible transport routes. PMID- 26441684 TI - Attentional Profiles and White Matter Correlates in Attention Deficit/Hyperactivity Disorder Predominantly Inattentive Type. AB - Attention-deficit/hyperactivity disorder (ADHD) is a widely studied neurodevelopmental disorder. It is a highly heterogeneous condition, encompassing different types of expression. The predominantly inattentive type is the most prevalent and the most stable over the lifetime, yet it is the least-studied presentation. To increase understanding of its cognitive profile, 29 children with attention-deficit/hyperactivity disorder of predominantly inattentive type (ADHD-I) and 29 matched controls, aged 7-15 years, had their attentional abilities assessed through the Conners' continuous performance test. Diffusion tensor imaging data were collected for all of the participants using a 3.0-T MRI system. Fractional anisotropy (FA) values were obtained for 20 fiber tracts, and brain-behavior correlations were calculated for 42 of the children. The ADHD-I children differed significantly from the typically developing (TD) children with respect to attentional measures, such as the ability to maintain response-time consistency throughout the task (Hit RT SE and Variability), vigilance (Hit RT ISI and Hit RT ISI SE), processing speed (Hit RT), selective attention (Omissions), sustained attention (Hit RT Block Change), error profile (Response Style), and inhibitory control (Perseverations). Evidence of significant differences between the ADHD-I and the TD participants was not found with respect to the mean FA values in the fiber tracts analyzed. Moderate and strong correlations between performance on the attention indicators and the tract average FA values were found for the ADHD-I group. Our results contribute to a better characterization of the attentional profile of ADHD-I individuals and suggest that in children and adolescents with ADHD-I, attentional performance is mainly associated with the white matter structure of the long associative fibers that connect anterior-posterior brain areas. PMID- 26441683 TI - The Impact of Neuroimmune Alterations in Autism Spectrum Disorder. AB - Autism spectrum disorder (ASD) involves a complex interplay of both genetic and environmental risk factors, with immune alterations and synaptic connection deficiency in early life. In the past decade, studies of ASD have substantially increased, in both humans and animal models. Immunological imbalance (including autoimmunity) has been proposed as a major etiological component in ASD, taking into account increased levels of pro-inflammatory cytokines observed in postmortem brain from patients, as well as autoantibody production. Also, epidemiological studies have established a correlation of ASD with family history of autoimmune diseases; associations with major histocompatibility complex haplotypes and abnormal levels of immunological markers in the blood. Moreover, the use of animal models to study ASD is providing increasing information on the relationship between the immune system and the pathophysiology of ASD. Herein, we will discuss the accumulating literature for ASD, giving special attention to the relevant aspects of factors that may be related to the neuroimmune interface in the development of ASD, including changes in neuroplasticity. PMID- 26441685 TI - Assessing and Stabilizing Aberrant Neuroplasticity in Autism Spectrum Disorder: The Potential Role of Transcranial Magnetic Stimulation. AB - Exciting developments have taken place in the neuroscience research in autism spectrum disorder (ASD), and results from these studies indicate that brain in ASD is associated with aberrant neuroplasticity. Transcranial magnetic stimulation (TMS) has rapidly evolved to become a widely used, safe, and non invasive neuroscientific tool to investigate a variety of neurophysiological processes, including neuroplasticity. The diagnostic and therapeutic potential of TMS in ASD is beginning to be realized. In this article, we briefly reviewed evidence of aberrant neuroplasticity in ASD, suggested future directions in assessing neuroplasticity using repetitive TMS (rTMS), and discussed the potential of rTMS in rectifying aberrant neuroplasticity in ASD. PMID- 26441687 TI - Attention Deficit Hyperactivity Disorder in the Light of the Epigenetic Paradigm. AB - Attention deficit hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder characterized by a definite behavioral pattern that might lead to performance problems in the social, educational, or work environments. In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, the symptoms of ADHD were restricted to those associated with cognitive (attention deficit) and behavioral (hyperactivity/impulsivity) deficits, while deficient emotional self-regulation, a relevant source of morbidity, was left out. The etiology of it is complex, as its exact causes have not yet been fully elucidated. ADHD seems to arise from a combination of various genetic and environmental factors that alter the developing brain, resulting in structural and functional abnormalities. The aim of this paper was to review epigenetics and ADHD focused on how multidimensional mechanisms influence the behavioral phenotype. PMID- 26441686 TI - Cigarette Cravings, Impulsivity, and the Brain. AB - Craving is a core feature of tobacco use disorder as well as a significant predictor of smoking relapse. Studies have shown that appetitive smoking-related stimuli (e.g., someone smoking) trigger significant cravings in smokers impede their self-control capacities and promote drug seeking behavior. In this review, we begin by an overview of functional magnetic resonance imaging (fMRI) studies investigating the neural correlates of smokers to appetitive smoking cues. The literature reveals a complex and vastly distributed neuronal network underlying smokers' craving response that recruits regions involved in self-referential processing, planning/regulatory processes, emotional responding, attentional biases, and automatic conducts. We then selectively review important factors contributing to the heterogeneity of results that significantly limit the implications of these findings, namely between- (abstinence, smoking expectancies, and self-regulation) and within-studies factors (severity of smoking dependence, sex-differences, motivation to quit, and genetic factors). Remarkably, we found that little to no attention has been devoted to examine the influence of personality traits on the neural correlates of cigarette cravings in fMRI studies. Impulsivity has been linked with craving and relapse in substance and tobacco use, which prompted our research team to examine the influence of impulsivity on cigarette cravings in an fMRI study. We found that the influence of impulsivity on cigarette cravings was mediated by fronto-cingulate mechanisms. Given the high prevalence of cigarette smoking in several psychiatric disorders that are characterized by significant levels of impulsivity, we conclude by identifying psychiatric patients as a target population whose tobacco-smoking habits deserve further behavioral and neuro-imaging investigation. PMID- 26441688 TI - Music and Sound in Time Processing of Children with ADHD. AB - ADHD involves cognitive and behavioral aspects with impairments in many environments of children and their families' lives. Music, with its playful, spontaneous, affective, motivational, temporal, and rhythmic dimensions can be of great help for studying the aspects of time processing in ADHD. In this article, we studied time processing with simple sounds and music in children with ADHD with the hypothesis that children with ADHD have a different performance when compared with children with normal development in tasks of time estimation and production. The main objective was to develop sound and musical tasks to evaluate and correlate the performance of children with ADHD, with and without methylphenidate, compared to a control group with typical development. The study involved 36 participants of age 6-14 years, recruited at NANI-UNIFESP/SP, subdivided into three groups with 12 children in each. Data was collected through a musical keyboard using Logic Audio Software 9.0 on the computer that recorded the participant's performance in the tasks. Tasks were divided into sections: spontaneous time production, time estimation with simple sounds, and time estimation with music. RESULTS: (1) performance of ADHD groups in temporal estimation of simple sounds in short time intervals (30 ms) were statistically lower than that of control group (p < 0.05); (2) in the task comparing musical excerpts of the same duration (7 s), ADHD groups considered the tracks longer when the musical notes had longer durations, while in the control group, the duration was related to the density of musical notes in the track. The positive average performance observed in the three groups in most tasks perhaps indicates the possibility that music can, in some way, positively modulate the symptoms of inattention in ADHD. PMID- 26441689 TI - Game Theory Paradigm: A New Tool for Investigating Social Dysfunction in Major Depressive Disorders. AB - Social dysfunction is a prominent source of distress and disability in patients with major depressive disorder (MDD) but is commonly omitted from current clinical studies, although some researchers propose an evolutionary strategy to understand these negative outcomes. Limited knowledge about the neural basis of social dysfunction in MDD results from traditional paradigms, which lack insights into social interactions. Game theoretical modeling offers a new tool for investigating social-interaction impairments in neuropsychiatric disorders. This review first introduces three widely used games from game theory and the major behavioral and neuroimaging findings obtained using these games in healthy populations. We also address the factors that modulate behaviors in games and their neural bases. We then summarize the current findings obtained by using these games in depressed patients and discuss the clinical implications of these abnormal game behaviors. Finally, we briefly discuss future prospects that may further elucidate the clinical use of a game theory paradigm in MDD. PMID- 26441690 TI - Very-Brief, Web-Based Interventions for Reducing Alcohol Use and Related Problems among College Students: A Review. AB - Very-brief, web-based alcohol interventions have great potential due to their convenience, ease of dissemination, and college students' stated preference for this intervention modality. To address the efficacy of these interventions, we conducted a review of the literature to identify randomized controlled trials (RCTs). Fifteen published reports were included. All RCTs meeting criteria for inclusion tested an intervention that featured personalized feedback on students' patterns of alcohol consumption. This review found some evidence to support the efficacy of very-brief, web-based interventions among college students for alcohol use reduction. Several trials, however, reported no evidence of efficacy and the methods of multiple trials raised concerns about potential bias that may have influenced study results. By contrast, this review did not yield evidence to support the efficacy of very-brief, web-based interventions for reduction of alcohol--related problems among college students. We found evidence to support the efficacy of two main types of intervention content: (a) focused solely on personalized normative feedback designed to correct misconceptions about peer alcohol consumption and (b) multi-component interventions. Future research is needed to test enhancements to very-brief, web-based interventions that feature personalized feedback on patterns of alcohol use and to determine for which types of college drinkers (e.g., heavier or lighter drinkers) these interventions are most efficacious. In addition, future studies are needed to test novel, very brief, web-based interventions featuring approaches other than personalized feedback. In summary, this review yielded some evidence supporting very-brief, web-based interventions in reducing alcohol use but not related problems in college students. Very-brief, web-based interventions are worth pursuing given their convenience, privacy, and potential public health benefit. PMID- 26441692 TI - The Impact on Family Functioning of Social Media Use by Depressed Adolescents: A Qualitative Analysis of the Family Options Study. AB - BACKGROUND: Adolescent depression is a prevalent mental health problem, which can have a major impact on family cohesion. In such circumstances, excessive use of the Internet by adolescents may exacerbate family conflict and lack of cohesion. The current study aims to explore these patterns within an intervention study for depressed adolescents. METHOD: The current study draws upon data collected from parents within the family options randomized controlled trial that examined family based interventions for adolescent depression (12-18 years old) in Melbourne, Australia (2012-2014). Inclusion in the trial required adolescents to meet diagnostic criteria for a major depressive disorder via the Structured Clinical Interview for DSM-IV Childhood Disorders. The transcripts of sessions were examined using qualitative thematic analysis. The transcribed sessions consisted of 56 h of recordings in total from 39 parents who took part in the interventions. RESULTS: The thematic analysis explored parental perceptions of their adolescent's use of social media (SM) and access to Internet content, focusing on the possible relationship between adolescent Internet use and the adolescent's depressive disorder. Two overarching themes emerged as follows: the sense of loss of parental control over the family environment and parents' perceived inability to protect their adolescent from material encountered on the Internet and social interactions via SM. CONCLUSION: Parents within the context of family based treatments felt that prolonged exposure to SM exposed their already vulnerable child to additional stressors and risks. The thematic analysis uncovered a sense of parental despair and lack of control, which is consistent with their perception of SM and the Internet as relentless and threatening to their parental authority and family cohesion. PMID- 26441691 TI - Examining the Role of Vasopressin in the Modulation of Parental and Sexual Behaviors. AB - Vasopressin (VP) and VP-like neuropeptides are evolutionarily stable peptides found in all vertebrate species. In non-mammalian vertebrates, vasotocin (VT) plays a role similar to mammalian VP, whereas mesotocin and isotocin are functionally similar to mammalian oxytocin (OT). Here, we review the involvement of VP in brain circuits, synaptic plasticity, evolution, and function, highlighting the role of VP in social behavior. In all studied species, VP is encoded on chromosome 20p13, and in mammals, VP is produced in specific hypothalamic nuclei and released by the posterior pituitary. The role of VP is mediated by the stimulation of the V1a, V1b, and V2 receptors as well as the oxytocinergic and purinergic receptors. VT and VP functions are usually related to osmotic and cardiovascular homeostasis when acting peripherally. However, these neuropeptides are also critically involved in the central modulation of social behavior displays, such as pairing recognition, pair-bonding, social memory, sexual behavior, parental care, and maternal and aggressive behavior. Evidence suggests that these effects are primarily mediated by V1a receptor in specific brain circuits that provide important information for the onset and control of social behaviors in normal and pathological conditions. PMID- 26441693 TI - Ethnicity and Smoking-Associated DNA Methylation Changes at HIV Co-Receptor GPR15. AB - Smoking is associated with poorer health outcomes for both African and European Americans. In order to better understand whether ethnic-specific genetic variation may underlie some of these differences, we compared the smoking associated genome-wide methylation signatures of African Americans with those of European Americans, and followed up this analysis with a focused examination of the most ethnically divergent locus, cg19859270, at the GPR15 gene. We examined the association of methylation at this locus to the rs2230344 SNP and GPR15 gene and protein expression. Consistent with prior analyses, AHRR residue cg05575921 was the most differentially methylated residue in both African Americans and European Americans. However, the second most differentially methylated locus in African Americans, cg19859270, was only modestly differentially methylated in European Americans. Interrogation of the methylation status of this CpG residue found in GPR15, a chemokine receptor involved in HIV pathogenesis, showed a significant interaction of ethnicity with smoking as well as a marginal effect of genotype at rs2230344, a neighboring non-synonymous SNP, but only among African Americans. Gene and protein expression analyses showed that demethylation at cg19859270 was associated with an increase in both mRNA and protein levels. Since GPR15 is involved in the early stages of viral replication for some HIV-1 and HIV 2 isolates, and the prevalence of HIV is increased in African Americans and smokers, these data support a possible role for GPR15 in the ethnically dependent differential prevalence of HIV. PMID- 26441694 TI - Regulatory Issues Surrounding Audit of Electronic Cigarette Charge Composition. PMID- 26441695 TI - Neurobiology of Sleep Disturbances in PTSD Patients and Traumatized Controls: MRI and SPECT Findings. AB - OBJECTIVE: Sleep disturbances such as insomnia and nightmares are core components of post-traumatic stress disorder (PTSD), yet their neurobiological relationship is still largely unknown. We investigated brain alterations related to sleep disturbances in PTSD patients and controls by using both structural and functional neuroimaging techniques. METHOD: Thirty-nine subjects either developing (n = 21) or not developing (n = 18) PTSD underwent magnetic resonance imaging and a symptom-provocation protocol followed by the injection of 99mTc hexamethylpropyleneamineoxime. Subjects were also tested with diagnostic and self rating scales on the basis of which a Sleep Disturbances Score (SDS; i.e., amount of insomnia/nightmares) was computed. RESULTS: Correlations between SDS and gray matter volume (GMV)/regional cerebral blood flow (rCBF) were computed in the whole sample and separately in the PTSD and control groups. In the whole sample, higher sleep disturbances were associated with significantly reduced GMV in amygdala, hippocampus, anterior cingulate, and insula; increased rCBF in midbrain, precuneus, and insula; and decreased rCBF in anterior cingulate. This pattern was substantially confirmed in the PTSD group, but not in controls. CONCLUSION: Sleep disturbances are associated with GMV loss in anterior limbic/paralimbic, PTSD-sensitive structures and with functional alterations in regions implicated in rapid eye movement-sleep control, supporting the existence of a link between PTSD and sleep disturbance. PMID- 26441696 TI - Psychosocial adjustment to ALS: a longitudinal study. AB - For the current study the Lazarian stress-coping theory and the appendant model of psychosocial adjustment to chronic illness and disabilities (Pakenham, 1999) has shaped the foundation for identifying determinants of adjustment to ALS. We aimed to investigate the evolution of psychosocial adjustment to ALS and to determine its long-term predictors. A longitudinal study design with four measurement time points was therefore, used to assess patients' quality of life, depression, and stress-coping model related aspects, such as illness characteristics, social support, cognitive appraisals, and coping strategies during a period of 2 years. Regression analyses revealed that 55% of the variance of severity of depressive symptoms and 47% of the variance in quality of life at T2 was accounted for by all the T1 predictor variables taken together. On the level of individual contributions, protective buffering, and appraisal of own coping potential accounted for a significant percentage in the variance in severity of depressive symptoms, whereas problem management coping strategies explained variance in quality of life scores. Illness characteristics at T2 did not explain any variance of both adjustment outcomes. Overall, the pattern of the longitudinal results indicated stable depressive symptoms and quality of life indices reflecting a successful adjustment to the disease across four measurement time points during a period of about two years. Empirical evidence is provided for the predictive value of social support, cognitive appraisals, and coping strategies, but not illness parameters such as severity and duration for adaptation to ALS. The current study contributes to a better conceptualization of adjustment, allowing us to provide evidence-based support beyond medical and physical intervention for people with ALS. PMID- 26441697 TI - Thematic orders and the comprehension of subject-extracted relative clauses in Mandarin Chinese. AB - This study investigates the comprehension of three kinds of subject-extracted relative clauses (SRs) in Mandarin Chinese: standard SRs, relative clauses involving the disposal ba construction ("disposal SRs"), and relative clauses involving the long passive bei constructions ("passive SRs"). In a self-paced reading experiment, the regions before the relativizer (where the sentential fragments are temporarily ambiguous) showed reading patterns consistent with expectation-based incremental processing: standard SRs, with the highest constructional frequency and the least complex syntactic structure, were processed faster than the other two variants. However, in the regions after the relativizer and the head noun where the existence of a relative clause is unambiguously indicated, a top-down global effect of thematic ordering was observed: passive SRs, whose thematic role order conforms to the canonical thematic order of Chinese, were read faster than both the standard SRs and the disposal SRs. Taken together, these results suggest that two expectation-based processing factors are involved in the comprehension of Chinese relative clauses, including both the structural probabilities of pre-relativizer constituents and the overall surface thematic orders in the relative clauses. PMID- 26441698 TI - Hallucinations as a trauma-based memory: implications for psychological interventions. AB - The relationship between hallucinations and life events is a topic of significant clinical importance. This review discusses the extent to which auditory and visual hallucinations may be directly related to traumatic events. Evidence suggests that intrusive images occur frequently within individuals who also report hallucinatory experiences. However, there has been limited research specifically investigating the extent to which hallucinations are the re experiencing of a traumatic event. Our current theoretical understanding of these relationships, along with methodological difficulties associated with research in this area, are considered. Recent clinical studies, which adopt interventions aimed at the symptoms of posttraumatic stress disorder in people diagnosed with a psychotic disorder, are reviewed. There is a need for the development of evidence based interventions in this area. PMID- 26441699 TI - Mental health literacy: a cross-cultural approach to knowledge and beliefs about depression, schizophrenia and generalized anxiety disorder. AB - Many families worldwide have at least one member with a behavioral or mental disorder, and yet the majority of the public fails to correctly recognize symptoms of mental illness. Previous research has found that Mental Health Literacy (MHL)-the knowledge and positive beliefs about mental disorders-tends to be higher in European and North American cultures, compared to Asian and African cultures. Nonetheless quantitative research examining the variables that explain this cultural difference remains limited. The purpose of our study was fourfold: (a) to validate measures of MHL cross-culturally, (b) to examine the MHL model quantitatively, (c) to investigate cultural differences in the MHL model, and (d) to examine collectivism as a predictor of MHL. We validated measures of MHL in European American and Indian samples. The results lend strong quantitative support to the MHL model. Recognition of symptoms of mental illness was a central variable: greater recognition predicted greater endorsement of social causes of mental illness and endorsement of professional help-seeking as well as lesser endorsement of lay help-seeking. The MHL model also showed an overwhelming cultural difference; namely, lay help-seeking beliefs played a central role in the Indian sample, and a negligible role in the European American sample. Further, collectivism was positively associated with causal beliefs of mental illness in the European American sample, and with lay help-seeking beliefs in the Indian sample. These findings demonstrate the importance of understanding cultural differences in beliefs about mental illness, particularly in relation to help-seeking beliefs. PMID- 26441700 TI - The sense of agency in autism spectrum disorders: a dissociation between prospective and retrospective mechanisms? AB - While a large number of studies have reported impairments in social and interpersonal abilities in individuals with autism spectrum disorder (ASD), relatively few studies have focused on self-related knowledge in this population. One of the processes implicated in the physical dimension of the Self is the sense of agency (SoA), i.e., the experience of initiating and controlling one's own actions and producing desired changes in the world via these actions. So far, the few studies investigating SoA in ASD have reported contrasting results, with some showing spared, others impaired SoA. Here, we review the existing literature and suggest that the distinction between prospective and retrospective mechanisms of the SoA might help reconcile the existing findings. In the light of a multi componential model of SoA, we propose the view that a specific impairment at the level of prospective mechanisms acting on internal agency signals (i.e., the intention, action selection, or command produced to achieve the goal) may be responsible for the reduced SoA in ASD, along with spared retrospective mechanisms. Future research should shed light on the impact of abnormal SoA on social and self-related dysfunctions in ASD. PMID- 26441702 TI - Prior knowledge in recalling arguments in bioethical dilemmas. AB - Prior knowledge is known to facilitate learning new information. Normally in studies confirming this outcome the relationship between prior knowledge and the topic to be learned is obvious: the information to be acquired is part of the domain or topic to which the prior knowledge belongs. This raises the question as to whether prior knowledge of various domains facilitates recalling information. In this study 79 eleventh-grade students completed a questionnaire on their prior knowledge of seven different domains related to the bioethical dilemma of prenatal diagnostics. The students read a text containing arguments for and arguments against prenatal diagnostics. After 1 week and again 12 weeks later they were asked to write down all the arguments they remembered. Prior knowledge helped them recall the arguments 1 week (r = 0.350) and 12 weeks (r = 0.316) later. Prior knowledge of three of the seven domains significantly helped them recall the arguments 1 week later (correlations between r = 0.194 and 0.394). Partial correlations with interest as a control item revealed that interest did not explain the relationship between prior knowledge and recall. Prior knowledge of different domains jointly supports the recall of arguments related to bioethical topics. PMID- 26441701 TI - Top-down modulation of visual processing and knowledge after 250 ms supports object constancy of category decisions. AB - People categorize objects more slowly when visual input is highly impoverished instead of optimal. While bottom-up models may explain a decision with optimal input, perceptual hypothesis testing (PHT) theories implicate top-down processes with impoverished input. Brain mechanisms and the time course of PHT are largely unknown. This event-related potential study used a neuroimaging paradigm that implicated prefrontal cortex in top-down modulation of occipitotemporal cortex. Subjects categorized more impoverished and less impoverished real and pseudo objects. PHT theories predict larger impoverishment effects for real than pseudo objects because top-down processes modulate knowledge only for real objects, but different PHT variants predict different timing. Consistent with parietal prefrontal PHT variants, around 250 ms, the earliest impoverished real object interaction started on an N3 complex, which reflects interactive cortical activity for object cognition. N3 impoverishment effects localized to both prefrontal and occipitotemporal cortex for real objects only. The N3 also showed knowledge effects by 230 ms that localized to occipitotemporal cortex. Later effects reflected (a) word meaning in temporal cortex during the N400, (b) internal evaluation of prior decision and memory processes and secondary higher order memory involving anterotemporal parts of a default mode network during posterior positivity (P600), and (c) response related activity in posterior cingulate during an anterior slow wave (SW) after 700 ms. Finally, response activity in supplementary motor area during a posterior SW after 900 ms showed impoverishment effects that correlated with RTs. Convergent evidence from studies of vision, memory, and mental imagery which reflects purely top-down inputs, indicates that the N3 reflects the critical top-down processes of PHT. A hybrid multiple-state interactive, PHT and decision theory best explains the visual constancy of object cognition. PMID- 26441704 TI - Children's and adolescents' snacking: interplay between the individual and the school class. AB - OBJECTIVE: In schools, perceived norms of classmates facilitate but can also inhibit unhealthy food intake in children and adolescents. However, the role of actual class behaviors and attitudes is less established. Thus, the present study examined classmates' actual eating behavior and food preferences in relation to actual food intake. In addition, it tested whether these normative effects are facilitated by corresponding individual and class food preferences or a positive social self-concept. METHODS: The food preferences, social self-concept, and unhealthy snacking frequency of 734 Finnish, 829 German, and 555 Romanian children and adolescents (aged 8-19) from 127 school-classes were assessed. RESULTS: Multilevel analysis at individual and class level showed that classmates shared similar snacking habits (14.7% variance). Moreover, the unhealthy food preference of a school-class was associated with its collective snacking [[Formula: see text], p < 0.001, PRV = 0.32). This effect was facilitated by individual, unhealthy food preferences [[Formula: see text], p < 0.001, PRV = 0.57] and a positive social self-concept [[Formula: see text], p = 0.015, PRV = 0.12]. CONCLUSIONS: Actual class norms are related to children's and adolescents' eating, but their impact depends on individual differences in preferences and social self-concept. PMID- 26441703 TI - The neuroscience of positive memory deficits in depression. AB - Adults with unipolar depression typically show poor episodic memory for positive material, but the neuroscientific mechanisms responsible for this deficit have not been characterized. I suggest a simple hypothesis: weak memory for positive material in depression reflects disrupted communication between the mesolimbic dopamine pathway and medial temporal lobe (MTL) memory systems during encoding. This proposal draws on basic research showing that dopamine release in the hippocampus is critical for the transition from early- to late-phase long-term potentiation (LTP) that marks the conversion of labile, short-term memories into stable, long-term memories. Neuroimaging and pharmacological data from healthy humans paint a similar picture: activation of the mesolimbic reward circuit enhances encoding and boosts retention. Unipolar depression is characterized by anhedonia-loss of pleasure-and reward circuit dysfunction, which is believed to reflect negative effects of stress on the mesolimbic dopamine pathway. Thus, I propose that the MTL is deprived of strengthening reward signals in depressed adults and memory for positive events suffers accordingly. Although other mechanisms are important, this hypothesis holds promise as an explanation for positive memory deficits in depression. PMID- 26441705 TI - The impact of threat of shock on the framing effect and temporal discounting: executive functions unperturbed by acute stress? AB - Anxiety and stress-related disorders constitute a large global health burden, but are still poorly understood. Prior work has demonstrated clear impacts of stress upon basic cognitive function: biasing attention toward unexpected and potentially threatening information and instantiating a negative affective bias. However, the impact that these changes have on higher-order, executive, decision making processes is unclear. In this study, we examined the impact of a translational within-subjects stress induction (threat of unpredictable shock) on two well-established executive decision-making biases: the framing effect (N = 83), and temporal discounting (N = 36). In both studies, we demonstrate (a) clear subjective effects of stress, and (b) clear executive decision-making biases but (c) no impact of stress on these decision-making biases. Indeed, Bayes factor analyses confirmed substantial preference for decision-making models that did not include stress. We posit that while stress may induce subjective mood change and alter low-level perceptual and action processes (Robinson et al., 2013c), some higher-level executive processes remain unperturbed by these impacts. As such, although stress can induce a transient affective biases and altered mood, these need not result in poor financial decision-making. PMID- 26441706 TI - Dubious decision evidence and criterion flexibility in recognition memory. AB - When old-new recognition judgments must be based on ambiguous memory evidence, a proper criterion for responding "old" can substantially improve accuracy, but participants are typically suboptimal in their placement of decision criteria. Various accounts of suboptimal criterion placement have been proposed. The most parsimonious, however, is that subjects simply over-rely on memory evidence - however faulty - as a basis for decisions. We tested this account with a novel recognition paradigm in which old-new discrimination was minimal and critical errors were avoided by adopting highly liberal or conservative biases. In Experiment 1, criterion shifts were necessary to adapt to changing target probabilities or, in a "security patrol" scenario, to avoid either letting dangerous people go free (misses) or harming innocent people (false alarms). Experiment 2 added a condition in which financial incentives drove criterion shifts. Critical errors were frequent, similar across sources of motivation, and only moderately reduced by feedback. In Experiment 3, critical errors were only modestly reduced in a version of the security patrol with no study phase. These findings indicate that participants use even transparently non-probative information as an alternative to heavy reliance on a decision rule, a strategy that precludes optimal criterion placement. PMID- 26441707 TI - Self-concept in fairness and rule establishment during a competitive game: a computational approach. AB - People consider fairness as well as their own interest when making decisions in economic games. The present study proposes a model that encompasses the self concept determined by one's own kindness as a factor of fairness. To observe behavioral patterns that reflect self-concept and fairness, a chicken game experiment was conducted. Behavioral data demonstrates four distinct patterns; "switching," "mutual rush," "mutual avoidance," and "unfair" patterns. Model estimation of chicken game data shows that a model with self-concept predicts those behaviors better than previous models of fairness, suggesting that self concept indeed affects human behavior in competitive economic games. Moreover, a non-stationary parameter analysis revealed the process of reaching consensus between the players in a game. When the models were fitted to a continuous time window, the parameters of the players in a pair with "switching" and "mutual avoidance" patterns became similar as the game proceeded, suggesting that the players gradually formed a shared rule during the game. In contrast, the difference of parameters between the players in the "unfair" and "mutual rush" patterns did not become stable. The outcomes of the present study showed that people are likely to change their strategy until they reach a mutually beneficial status. PMID- 26441708 TI - Hypothesis-driven research for G * E interactions: the relationship between oxytocin, parental divorce during adolescence, and depression in young adulthood. AB - Research in molecular genetics has generally focused on genome-wide association studies (GWAS) and exploratory candidate gene and candidate gene-environment (G * E) studies. In this article it is proposed that hypothesis-driven and biologically informed research provides a complementary approach to GWAS to advance pressing research questions about G * E relations that are of public health relevance. Prior research studies and developmental and evolutionary theory were used to guide hypothesis testing of G * E relationships in this study. The study investigated whether the oxytocin polymorphism, rs53576, moderated the relationship between parental divorce during adolescence and depression symptoms in young adulthood. Oxytocin is a neuropeptide that has been related to the regulation of complex social cognition and behaviors such as empathy, attachment, and nurturance. We hypothesized that the GG polymorphism would be associated with more depressive symptoms following parental divorce, and that this effect would be stronger in females than males. The sample consisted of 340 individuals who participated in a longitudinal study with data used both from adolescence and young adulthood. Findings using prospective follow-up and autoregressive change models supported the hypothesized relationships. Young adult females who had experienced parental divorce during adolescence and had the GG oxytocin genotype reported almost twice as many depressive symptoms relative to young adult females who also experienced parental divorce during adolescence but had the AA or AG genotype. This pattern was not indicated among males. Findings were discussed with regard to how molecular genetic factors in combination with environmental stressors, such parental divorce, framed within a developmental framework may facilitate the future study of G * E relationships in the parental divorce-child adjustment literature and contribute to a prevention science perspective. PMID- 26441710 TI - Suspending the next turn as a form of repair initiation: evidence from Argentine Sign Language. AB - Practices of other-initiated repair deal with problems of hearing or understanding what another person has said in the fast-moving turn-by-turn flow of conversation. As such, other-initiated repair plays a fundamental role in the maintenance of intersubjectivity in social interaction. This study finds and analyses a special type of other-initiated repair that is used in turn-by-turn conversation in a sign language: Argentine Sign Language (Lengua de Senas Argentina or LSA). We describe a type of response termed a "freeze-look," which occurs when a person has just been asked a direct question: instead of answering the question in the next turn position, the person holds still while looking directly at the questioner. In these cases it is clear that the person is aware of having just been addressed and is not otherwise accounting for their delay in responding (e.g., by displaying a "thinking" face or hesitation, etc.). We find that this behavior functions as a way for an addressee to initiate repair by the person who asked the question. The "freeze-look" results in the questioner "re doing" their action of asking a question, for example by repeating or rephrasing it. Thus, we argue that the "freeze-look" is a practice for other-initiation of repair. In addition, we argue that it is an "off-record" practice, thus contrasting with known on-record practices such as saying "Huh?" or equivalents. The findings aim to contribute to research on human understanding in everyday turn-by-turn conversation by looking at an understudied sign language, with possible implications for our understanding of visual bodily communication in spoken languages as well. PMID- 26441709 TI - Motivation for aggressive religious radicalization: goal regulation theory and a personality * threat * affordance hypothesis. AB - A new set of hypotheses is presented regarding the cause of aggressive religious radicalization (ARR). It is grounded in classic and contemporary theory of human motivation and goal regulation, together with recent empirical advances in personality, social, and neurophysiological psychology. We specify personality traits, threats, and group affordances that combine to divert normal motivational processes toward ARR. Conducive personality traits are oppositional, anxiety prone, and identity-weak (i.e., morally bewildered). Conducive threats are those that arise from seemingly insurmountable external forces and frustrate effective goal regulation. Conducive affordances include opportunity for immediate and concrete engagement in active groups that are powered by conspiracy narratives, infused with cosmic significance, encouraging of moral violence, and sealed with religious unfalsifiability. We propose that ARR is rewarding because it can spur approach motivated states that mask vulnerability for people whose dispositions and circumstances would otherwise leave them mired in anxious distress. PMID- 26441711 TI - Doctor, what does my positive test mean? From Bayesian textbook tasks to personalized risk communication. AB - Most of the research on Bayesian reasoning aims to answer theoretical questions about the extent to which people are able to update their beliefs according to Bayes' Theorem, about the evolutionary nature of Bayesian inference, or about the role of cognitive abilities in Bayesian inference. Few studies aim to answer practical, mainly health-related questions, such as, "What does it mean to have a positive test in a context of cancer screening?" or "What is the best way to communicate a medical test result so a patient will understand it?". This type of research aims to translate empirical findings into effective ways of providing risk information. In addition, the applied research often adopts the paradigms and methods of the theoretically-motivated research. But sometimes it works the other way around, and the theoretical research borrows the importance of the practical question in the medical context. The study of Bayesian reasoning is relevant to risk communication in that, to be as useful as possible, applied research should employ specifically tailored methods and contexts specific to the recipients of the risk information. In this paper, we concentrate on the communication of the result of medical tests and outline the epidemiological and test parameters that affect the predictive power of a test-whether it is correct or not. Building on this, we draw up recommendations for better practice to convey the results of medical tests that could inform health policy makers (What are the drawbacks of mass screenings?), be used by health practitioners and, in turn, help patients to make better and more informed decisions. PMID- 26441712 TI - Framing effects reveal discrete lexical-semantic and sublexical procedures in reading: an fMRI study. AB - According to the dual-route model, a printed string of letters can be processed by either a grapheme-to-phoneme conversion (GPC) route or a lexical-semantic route. Although meta-analyses of the imaging literature support the existence of distinct but interacting reading procedures, individual neuroimaging studies that explored neural correlates of reading yielded inconclusive results. We used a list-manipulation paradigm to provide a fresh empirical look at this issue and to isolate specific areas that underlie the two reading procedures. In a lexical condition, we embedded disyllabic Italian words (target stimuli) in lists of either loanwords or trisyllabic Italian words with unpredictable stress position. In a GPC condition, similar target stimuli were included within lists of pseudowords. The procedure was designed to induce participants to emphasize either the lexical-semantic or the GPC reading procedure, while controlling for possible linguistic confounds and keeping the reading task requirements stable across the two conditions. Thirty-three adults participated in the behavioral study, and 20 further adult participants were included in the fMRI study. At the behavioral level, we found sizeable effects of the framing manipulations that included slower voice onset times for stimuli in the pseudoword frames. At the functional anatomical level, the occipital and temporal regions, and the intraparietal sulcus were specifically activated when subjects were reading target words in a lexical frame. The inferior parietal and anterior fusiform cortex were specifically activated in the GPC condition. These patterns of activation represented a valid classifying model of fMRI images associated with target reading in both frames in the multi-voxel pattern analyses. Further activations were shared by the two procedures in the occipital and inferior parietal areas, in the premotor cortex, in the frontal regions and the left supplementary motor area. These regions are most likely involved in either early input or late output processes. PMID- 26441713 TI - Improving working memory abilities in individuals with Down syndrome: a treatment case study. AB - Working memory (WM) skills of individuals with Down's syndrome (DS) tend to be very poor compared to typically developing children of similar mental age. In particular, research has found that in individuals with DS visuo-spatial WM is better preserved than verbal WM. This study investigated whether it is possible to train short-term memory (STM) and WM abilities in individuals with DS. The cases of two teenage children are reported: EH, 17 years and 3 months, and AS, 15 years and 11 months. A school-based treatment targeting visuo-spatial WM was given to EH and AS for six weeks. Both prior to and after the treatment, they completed a set of assessments to measure WM abilities and their performance was compared with younger typically developing non-verbal mental age controls. The results showed that the trained participants improved their performance in some of the trained and non-trained WM tasks proposed, especially with regard to the tasks assessing visuo-spatial WM abilities. These findings are discussed on the basis of their theoretical, educational, and clinical implications. PMID- 26441714 TI - Multimethod latent class analysis. AB - Correct and, hence, valid classifications of individuals are of high importance in the social sciences as these classifications are the basis for diagnoses and/or the assignment to a treatment. The via regia to inspect the validity of psychological ratings is the multitrait-multimethod (MTMM) approach. First, a latent variable model for the analysis of rater agreement (latent rater agreement model) will be presented that allows for the analysis of convergent validity between different measurement approaches (e.g., raters). Models of rater agreement are transferred to the level of latent variables. Second, the latent rater agreement model will be extended to a more informative MTMM latent class model. This model allows for estimating (i) the convergence of ratings, (ii) method biases in terms of differential latent distributions of raters and differential associations of categorizations within raters (specific rater bias), and (iii) the distinguishability of categories indicating if categories are satisfyingly distinct from each other. Finally, an empirical application is presented to exemplify the interpretation of the MTMM latent class model. PMID- 26441715 TI - Erotic subset for the Nencki Affective Picture System (NAPS ERO): cross-sexual comparison study. AB - Research on the processing of sexual stimuli has proved that such material has high priority in human cognition. Yet, although sex differences in response to sexual stimuli were extensively discussed in the literature, sexual orientation was given relatively little consideration, and material suitable for relevant research is difficult to come by. With this in mind, we present a collection of 200 erotic images, accompanied by their self-report ratings of emotional valence and arousal by homo- and heterosexual males and females (n = 80, divided into four equal-sized subsamples). The collection complements the Nencki Affective Picture System (NAPS) and is intended to be used as stimulus material in experimental research. The erotic images are divided into five categories, depending on their content: opposite-sex couple (50), male couple (50), female couple (50), male (25) and female (25). Additional 100 control images from the NAPS depicting people in a non-erotic context were also used in the study. We showed that recipient sex and sexual orientation strongly influenced the evaluation of erotic content. Thus, comparisons of valence and arousal ratings in different subject groups will help researchers select stimuli set for the purpose of various experimental designs. To facilitate the use of the dataset, we provide an on-line tool, which allows the user to browse the images interactively and select proper stimuli on the basis of several parameters. The NAPS ERO image collection together with the data are available to the scientific community for non-commercial use at http://naps.nencki.gov.pl. PMID- 26441717 TI - A functional approach to movement analysis and error identification in sports and physical education. AB - In a hypothesis-and-theory paper, a functional approach to movement analysis in sports is introduced. In this approach, contrary to classical concepts, it is not anymore the "ideal" movement of elite athletes that is taken as a template for the movements produced by learners. Instead, movements are understood as the means to solve given tasks that in turn, are defined by to-be-achieved task goals. A functional analysis comprises the steps of (1) recognizing constraints that define the functional structure, (2) identifying sub-actions that subserve the achievement of structure-dependent goals, (3) explicating modalities as specifics of the movement execution, and (4) assigning functions to actions, sub actions and modalities. Regarding motor-control theory, a functional approach can be linked to a dynamical-system framework of behavioral shaping, to cognitive models of modular effect-related motor control as well as to explicit concepts of goal setting and goal achievement. Finally, it is shown that a functional approach is of particular help for sports practice in the context of structuring part practice, recognizing functionally equivalent task solutions, finding innovative technique alternatives, distinguishing errors from style, and identifying root causes of movement errors. PMID- 26441716 TI - Subjective memory complaints among patients on sick leave are associated with symptoms of fatigue and anxiety. AB - OBJECTIVE: The aim of this study was to identify symptoms associated with subjective memory complaints (SMCs) among subjects who are currently on sick leave due to symptoms of chronic pain, fatigue, depression, anxiety, and insomnia. METHODS: This was a cross-sectional study, subjects (n = 167) who were currently on sick leave were asked to complete an extensive survey consisting of the following: items addressing their sociodemographics, one item from the SF-8 health survey measuring pain, Chalder Fatigue Questionnaire, Hospital Anxiety and Depression Scale, Insomnia Severity Index, and Everyday Memory Questionnaire - Revised. General linear modeling was used to analyze variables associated with SMCs. RESULTS: Symptoms of fatigue (p-value < 0.001) and anxiety (p-value = 0.001) were uniquely and significantly associated with perceived memory failures. The associations with symptoms of pain, depression, and insomnia were not statistically significant. CONCLUSIONS: Subjective memory complaints should be recognized as part of the complex symptomatology among patients who report multiple symptoms, especially in cases of fatigue and anxiety. Self-report questionnaires measuring perceived memory failures may be a quick and easy way to incorporate and extend this knowledge into clinical practice. PMID- 26441718 TI - Sound frequency affects speech emotion perception: results from congenital amusia. AB - Congenital amusics, or "tone-deaf" individuals, show difficulty in perceiving and producing small pitch differences. While amusia has marked effects on music perception, its impact on speech perception is less clear. Here we test the hypothesis that individual differences in pitch perception affect judgment of emotion in speech, by applying low-pass filters to spoken statements of emotional speech. A norming study was first conducted on Mechanical Turk to ensure that the intended emotions from the Macquarie Battery for Evaluation of Prosody were reliably identifiable by US English speakers. The most reliably identified emotional speech samples were used in Experiment 1, in which subjects performed a psychophysical pitch discrimination task, and an emotion identification task under low-pass and unfiltered speech conditions. Results showed a significant correlation between pitch-discrimination threshold and emotion identification accuracy for low-pass filtered speech, with amusics (defined here as those with a pitch discrimination threshold >16 Hz) performing worse than controls. This relationship with pitch discrimination was not seen in unfiltered speech conditions. Given the dissociation between low-pass filtered and unfiltered speech conditions, we inferred that amusics may be compensating for poorer pitch perception by using speech cues that are filtered out in this manipulation. To assess this potential compensation, Experiment 2 was conducted using high-pass filtered speech samples intended to isolate non-pitch cues. No significant correlation was found between pitch discrimination and emotion identification accuracy for high-pass filtered speech. Results from these experiments suggest an influence of low frequency information in identifying emotional content of speech. PMID- 26441719 TI - Observed effects of "distributional learning" may not relate to the number of peaks. A test of "dispersion" as a confounding factor. AB - Distributional learning of speech sounds is learning from simply being exposed to frequency distributions of speech sounds in one's surroundings. In laboratory settings, the mechanism has been reported to be discernible already after a few minutes of exposure, in both infants and adults. These "effects of distributional training" have traditionally been attributed to the difference in the number of peaks between the experimental distribution (two peaks) and the control distribution (one or zero peaks). However, none of the earlier studies fully excluded a possibly confounding effect of the dispersion in the distributions. Additionally, some studies with a non-speech control condition did not control for a possible difference between processing speech and non-speech. The current study presents an experiment that corrects both imperfections. Spanish listeners were exposed to either a bimodal distribution encompassing the Dutch contrast /alpha/~/a/ or a unimodal distribution with the same dispersion. Before and after training, their accuracy of categorization of [alpha]- and [a]-tokens was measured. A traditionally calculated p-value showed no significant difference in categorization improvement between bimodally and unimodally trained participants. Because of this null result, a Bayesian method was used to assess the odds in favor of the null hypothesis. Four different Bayes factors, each calculated on a different belief in the truth value of previously found effect sizes, indicated the absence of a difference between bimodally and unimodally trained participants. The implication is that "effects of distributional training" observed in the lab are not induced by the number of peaks in the distributions. PMID- 26441720 TI - A normative inference approach for optimal sample sizes in decisions from experience. AB - "Decisions from experience" (DFE) refers to a body of work that emerged in research on behavioral decision making over the last decade. One of the major experimental paradigms employed to study experience-based choice is the "sampling paradigm," which serves as a model of decision making under limited knowledge about the statistical structure of the world. In this paradigm respondents are presented with two payoff distributions, which, in contrast to standard approaches in behavioral economics, are specified not in terms of explicit outcome-probability information, but by the opportunity to sample outcomes from each distribution without economic consequences. Participants are encouraged to explore the distributions until they feel confident enough to decide from which they would prefer to draw from in a final trial involving real monetary payoffs. One commonly employed measure to characterize the behavior of participants in the sampling paradigm is the sample size, that is, the number of outcome draws which participants choose to obtain from each distribution prior to terminating sampling. A natural question that arises in this context concerns the "optimal" sample size, which could be used as a normative benchmark to evaluate human sampling behavior in DFE. In this theoretical study, we relate the DFE sampling paradigm to the classical statistical decision theoretic literature and, under a probabilistic inference assumption, evaluate optimal sample sizes for DFE. In our treatment we go beyond analytically established results by showing how the classical statistical decision theoretic framework can be used to derive optimal sample sizes under arbitrary, but numerically evaluable, constraints. Finally, we critically evaluate the value of deriving optimal sample sizes under this framework as testable predictions for the experimental study of sampling behavior in DFE. PMID- 26441721 TI - The cognitive-behavioral system of leadership: cognitive antecedents of active and passive leadership behaviors. AB - In the present paper, we propose a cognitive-behavioral understanding of active and passive leadership. Building on core evaluations theory, we offer a model that explains the emergence of leaders' active and passive behaviors, thereby predicting stable, inter-individual, as well as variable, intra-individual differences in both types of leadership behavior. We explain leaders' stable behavioral tendencies by their fundamental beliefs about themselves, others, and the world (core evaluations), while their variable, momentary behaviors are explained by the leaders' momentary appraisals of themselves, others, and the world (specific evaluations). By introducing interactions between the situation the leader enters, the leader's beliefs, appraisals, and behavior, we propose a comprehensive system of cognitive mechanisms that underlie active and passive leadership behavior. PMID- 26441722 TI - Moral dilemmas in females: children are more utilitarian than adults. AB - Influential theories on moral judgments propose that they rely either on emotions or on innate moral principles. In contrast, the mental model theory postulates that moral judgments rely on reasoning, either intuition or deliberation. The theory allows for the possibility that intuitions lead to utilitarian judgments. This paper reports two experiments involving fifth-grade children, adolescents, and adults; the results revealed that children reason intuitively to resolve moral dilemmas in which action and inaction lead to different outcomes. In particular, the results showed female children to be more utilitarian than female adults in resolving classical moral dilemmas: they preferred an action that achieved a good outcome for a greater number of people. Within the mental model theory's framework there is no reason to expect that females and males differ in their ability to reason, but at the moment the results for females cannot be generalized to males who were not properly represented in the adults groups of the two experiments. The result revealing that (female) children are more utilitarian than (female) adults, which is hard to explain via many current theories, was predicted by the mental model theory. PMID- 26441723 TI - Interference in the processing of adjunct control. AB - Recent research on the memory operations used in language comprehension has revealed a selective profile of interference effects during memory retrieval. Dependencies such as subject-verb agreement show strong facilitatory interference effects from structurally inappropriate but feature-matching distractors, leading to illusions of grammaticality (Pearlmutter et al., 1999; Wagers et al., 2009; Dillon et al., 2013). In contrast, dependencies involving reflexive anaphors are generally immune to interference effects (Sturt, 2003; Xiang et al., 2009; Dillon et al., 2013). This contrast has led to the proposal that all anaphors that are subject to structural constraints are immune to facilitatory interference. Here we use an animacy manipulation to examine whether adjunct control dependencies, which involve an interpreted anaphoric relation between a null subject and its licensor, are also immune to facilitatory interference effects. Our results show reliable facilitatory interference in the processing of adjunct control dependencies, which challenges the generalization that anaphoric dependencies as a class are immune to such effects. To account for the contrast between adjunct control and reflexive dependencies, we suggest that variability within anaphora could reflect either an inherent primacy of animacy cues in retrieval processes, or differential degrees of match between potential licensors and the retrieval probe. PMID- 26441724 TI - Phonological similarity affects production of gestures, even in the absence of overt speech. AB - Highlights Does phonological similarity affect gesture production in the absence of speech?Participants produced gestures from pictures with no words presented or spoken.Same pictures and gestures but different training labels were used.Phonologically similar labels led to more errors in subsequent gestures.Thus, phonological similarity affects gesture production in the absence of speech. Are manual gestures affected by inner speech? This study tested the hypothesis that phonological form influences gesture by investigating whether phonological similarity between words that describe motion gestures creates interference for production of those gestures in the absence of overt speech. Participants learned to respond to a picture of a bottle by gesturing to open the bottle's cap, and to a picture of long hair by gesturing to twirl the hair. In one condition, the gestures were introduced with phonologically-similar labels "twist" and "twirl" (similar condition), while in the other condition, they were introduced with phonologically-dissimilar labels "unscrew" and "twirl" (dissimilar condition). During the actual experiment, labels were not produced and participants only gestured by looking at pictures. In both conditions, participants also gestured to a control pair that was used as a baseline. Participants made significantly more errors on gestures in the similar than dissimilar condition after correction for baseline differences. This finding shows the influence of phonology on gesture production in the absence of overt speech and poses new constraints on the locus of the interaction between language and gesture systems. PMID- 26441725 TI - The acquisition process of musical tonal schema: implications from connectionist modeling. AB - Using connectionist modeling, we address fundamental questions concerning the acquisition process of musical tonal schema of listeners. Compared to models of previous studies, our connectionist model (Learning Network for Tonal Schema, LeNTS) was better equipped to fulfill three basic requirements. Specifically, LeNTS was equipped with a learning mechanism, bound by culture-general properties, and trained by sufficient melody materials. When exposed to Western music, LeNTS acquired musical 'scale' sensitivity early and 'harmony' sensitivity later. The order of acquisition of scale and harmony sensitivities shown by LeNTS was consistent with the culture-specific acquisition order shown by musically westernized children. The implications of these results for the acquisition process of a tonal schema of listeners are as follows: (a) the acquisition process may entail small and incremental changes, rather than large and stage like changes, in corresponding neural circuits; (b) the speed of schema acquisition may mainly depend on musical experiences rather than maturation; and PMID- 26441726 TI - What is the right place for atypical exemplars? Commentary: The right hemisphere contribution to semantic categorization: a TMS study. PMID- 26441727 TI - The effect of gaze-contingent stimulus elimination on preference judgments. AB - This study examined how stimulus elimination (SE) in a preference judgment task affects observers' choices. Previous research suggests that biasing gaze toward one alternative can increase preference for it; this preference reciprocally promotes gaze bias. Shimojo et al. (2003) called this phenomenon the Gaze Cascade Effect. They showed that the likelihood that an observer's gaze was directed toward their chosen alternative increased steadily until the moment of choosing. Therefore, we tested whether observers would prefer an alternative at which they had been gazing last if both alternatives were removed prior to the start of this rising gaze likelihood. To test this, we used a preference judgment task and controlled stimulus presentation based on gaze using an eye-tracking system. A pair of non-sensical figures was presented on the computer screen and both stimuli were eliminated while participants were still making their preference decision. The timing of the elimination differed between two experiments. In Experiment 1, after gazing at both stimuli one or more times, stimuli were removed when the participant's gaze fell on one alternative, pre-selected as the target stimulus. There was no significant difference in the preference of the two alternatives. In Experiment 2, we did not predefine any target stimulus. After the participant gazed at both stimuli one or more times, both stimuli were eliminated when the participant next fixated on either. The likelihood of choosing the stimulus that was gazed at last (at the moment of elimination) was greater than chance. Results showed that controlling participants' choices using gaze-contingent SE was impossible, but the different results between these two experiments suggest that participants decided which stimulus to choose during their first period of gazing at each alternative. Thus, we could predict participants' choices by analyzing eye movement patterns at the moment of SE. PMID- 26441728 TI - Tolerating the "doubting Thomas": how centrality of religious beliefs vs. practices influences prejudice against atheists. AB - Past research has found a robust effect of prejudice against atheists in largely Christian-dominated (belief-oriented) samples. We propose that religious centrality of beliefs vs. practices influences attitudes toward atheists, such that religious groups emphasizing beliefs perceive non-believers more negatively than believers, while groups emphasizing practices perceive non-practicing individuals more negatively than practicing individuals. Studies 1-2, in surveys of 41 countries, found that Muslims and Protestants (belief-oriented) had more negative attitudes toward atheists than did Jews and Hindus (practice-oriented). Study 3 experimentally manipulated a target individual's beliefs and practices. Protestants had more negative attitudes toward a non-believer (vs. a believer), whereas Jews had more negative attitudes toward a non-practicing individual (vs. a practicing individual, particularly when they had a Jewish background). This research has implications for the psychology of religion, anti-atheist prejudice, and cross-cultural attitudes regarding where dissent in beliefs or practices may be tolerated or censured within religious groups. PMID- 26441729 TI - Dissociative states in dreams and brain chaos: implications for creative awareness. AB - This article reviews recent findings indicating some common brain processes during dissociative states and dreaming with the aim to outline a perspective that neural chaotic states during dreaming can be closely related to dissociative states that may manifest in dreams scenery. These data are in agreement with various clinical findings that dissociated states can be projected into the "dream scenery" in REM sleep periods and dreams may represent their specific interactions that may uncover unusual psychological potential of creativity in psychotherapy, art, and scientific discoveries. PMID- 26441730 TI - Labile sleep promotes awareness of abstract knowledge in a serial reaction time task. AB - Sleep has been identified as a critical brain state enhancing the probability of gaining insight into covert task regularities. Both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep have been implicated with offline re activation and reorganization of memories supporting explicit knowledge generation. According to two-stage models of sleep function, offline processing of information during sleep is sequential requiring multiple cycles of NREM and REM sleep stages. However, the role of overnight dynamic sleep macrostructure for insightfulness has not been studied so far. In the present study, we test the hypothesis that the frequency of interactions between NREM and REM sleep stages might be critical for awareness after sleep. For that aim, the rate of sleep stage transitions was evaluated in 53 participants who learned implicitly a serial reaction time task (SRTT) in which a determined sequence was inserted. The amount of explicit knowledge about the sequence was established by verbal recall after a night of sleep following SRTT learning. Polysomnography was recorded in this night and in a control night before and was analyzed to compare the rate of sleep-stage transitions between participants who did or did not gain awareness of task regularity after sleep. Indeed, individual ability of explicit knowledge generation was strongly associated with increased rate of transitions between NREM and REM sleep stages and between light sleep stages and slow wave sleep. However, the rate of NREM-REM transitions specifically predicted the amount of explicit knowledge after sleep in a trait-dependent way. These results demonstrate that enhanced lability of sleep goes along with individual ability of knowledge awareness. Observations suggest that facilitated dynamic interactions between sleep stages, particularly between NREM and REM sleep stages play a role for offline processing which promotes rule extraction and awareness. PMID- 26441732 TI - Cross-linguistic evidence for gender as a prominence feature. AB - This paper discusses recent findings in the online sentence processing research that suggest to consider gender information a prominence feature. Prominence features are hierarchically ordered information types that interact with formal features of arguments (e.g., grammatical functions, thematic roles) and thus determine the readers' ability to efficiently interpret linguistic ambiguities. While previous research addressed a number of prominence features (e.g., animacy, definiteness, person), there is now first empirical evidence indicating that gender information also influences the assignment of thematic roles across languages. Grammatically masculine role nouns are processed faster as agents than patients compared to feminine ones. Stereotypically male role nouns (e.g., electrician) are integrated with an agent role easier than neutral ones (e.g., musician), which in turn are integrated easier than female ones (e.g., beautician). Conceptualizing gender as a prominence feature will not only expand our knowledge about information types relevant for online comprehension but also uncover subtle gender biases present in language. The present work explores the possibility for a theoretical integration of social psychological and psycholinguistic research focusing on gender with research on prominence. Potential advantages an interdisciplinary approach to the study of gender as a prominence feature, open questions and future directions are discussed. PMID- 26441731 TI - Brain asymmetry in the white matter making and globularity. AB - Recent studies from the field of language genetics and evolutionary anthropology have put forward the hypothesis that the emergence of our species-specific brain is to be understood not in terms of size, but in light of developmental changes that gave rise to a more globular braincase configuration after the split from Neanderthals-Denisovans. On the grounds that (i) white matter myelination is delayed relative to other brain structures and, in humans, is protracted compared with other primates and that (ii) neural connectivity is linked genetically to our brain/skull morphology and language-ready brain, I argue that one significant evolutionary change in Homo sapiens' lineage is the interhemispheric connectivity mediated by the Corpus Callosum. The size, myelination and fiber caliber of the Corpus Callosum present an anterior-to-posterior increase, in a way that inter hemispheric connectivity is more prominent in the sensory motor areas, whereas "high- order" areas are more intra-hemispherically connected. Building on evidence from language-processing studies that account for this asymmetry ('lateralization') in terms of brain rhythms, I present an evo-devo hypothesis according to which the myelination of the Corpus Callosum, Brain Asymmetry, and Globularity are conjectured to make up the angles of a co-evolutionary triangle that gave rise to our language-ready brain. PMID- 26441733 TI - Encoding audio motion: spatial impairment in early blind individuals. AB - The consequence of blindness on auditory spatial localization has been an interesting issue of research in the last decade providing mixed results. Enhanced auditory spatial skills in individuals with visual impairment have been reported by multiple studies, while some aspects of spatial hearing seem to be impaired in the absence of vision. In this study, the ability to encode the trajectory of a 2-dimensional sound motion, reproducing the complete movement, and reaching the correct end-point sound position, is evaluated in 12 early blind (EB) individuals, 8 late blind (LB) individuals, and 20 age-matched sighted blindfolded controls. EB individuals correctly determine the direction of the sound motion on the horizontal axis, but show a clear deficit in encoding the sound motion in the lower side of the plane. On the contrary, LB individuals and blindfolded controls perform much better with no deficit in the lower side of the plane. In fact the mean localization error resulted 271 +/- 10 mm for EB individuals, 65 +/- 4 mm for LB individuals, and 68 +/- 2 mm for sighted blindfolded controls. These results support the hypothesis that (i) it exists a trade-off between the development of enhanced perceptual abilities and role of vision in the sound localization abilities of EB individuals, and (ii) the visual information is fundamental in calibrating some aspects of the representation of auditory space in the brain. PMID- 26441734 TI - Movement plans for posture selection do not transfer across hands. AB - In a sequential task, the grasp postures people select depend on their movement history. This motor hysteresis effect results from the reuse of former movement plans and reduces the cognitive cost of movement planning. Movement plans for hand trajectories not only transfer across successive trials, but also across hands. We therefore asked whether such a transfer would also be found in movement plans for hand postures. To this end, we designed a sequential, continuous posture selection task. Participants had to open a column of drawers with cylindrical knobs in ascending and descending sequences. A hand switch was required in each sequence. Hand pro/supination was analyzed directly before and after the hand switch. Results showed that hysteresis effects were present directly before, but absent directly after the hand switch. This indicates that, in the current study, movement plans for hand postures only transfer across trials, but not across hands. PMID- 26441735 TI - Commentary: Why sprint interval training is inappropriate for a largely sedentary population. PMID- 26441736 TI - Response: Commentary "The sexualized-body-inversion hypothesis revisited: Valid indicator of sexual objectification or methodological artifact?". PMID- 26441737 TI - "Put your Hands up in the Air"? The interpersonal effects of pride and shame expressions on opponents and teammates. AB - The aim of the present research was to investigate the interpersonal effects of pride and shame expressions amongst opponents and teammates in a soccer penalty scenario. Across a series of experiments using the point-light method, pride and shame expressions exerted strong effects upon observers' anticipated emotions, associated cognitions, and performance expectations. Using the Implicit Association Test (IAT) in two pilot studies we demonstrated that the created pride and shame point-light stimuli were implicitly associated with status and performance related attributes. In Experiment 1, observing pride expressions caused opponents to anticipate more negative emotions, cognitions, and lower performance expectancies toward their next performance in comparison with neutral expressions. In contrast, pride expressions led teammates to anticipate more positive emotions (i.e., pride and happiness), cognitions, and performance expectations toward their next performance than neutral expressions (Experiments 2-4). The results are discussed within the emotions as social information (EASI, Van Kleef, 2009) framework by arguing that the social context has to be taken into account when investigating the interpersonal effects of emotion expressions. In conclusion, the present research highlights the potential interpersonal influence of the nonverbal expressions of pride and shame in soccer penalty shootouts. PMID- 26441738 TI - Investigating the ability to read others' intentions using humanoid robots. AB - The ability to interact with other people hinges crucially on the possibility to anticipate how their actions would unfold. Recent evidence suggests that a similar skill may be grounded on the fact that we perform an action differently if different intentions lead it. Human observers can detect these differences and use them to predict the purpose leading the action. Although intention reading from movement observation is receiving a growing interest in research, the currently applied experimental paradigms have important limitations. Here, we describe a new approach to study intention understanding that takes advantage of robots, and especially of humanoid robots. We posit that this choice may overcome the drawbacks of previous methods, by guaranteeing the ideal trade-off between controllability and naturalness of the interactive scenario. Robots indeed can establish an interaction in a controlled manner, while sharing the same action space and exhibiting contingent behaviors. To conclude, we discuss the advantages of this research strategy and the aspects to be taken in consideration when attempting to define which human (and robot) motion features allow for intention reading during social interactive tasks. PMID- 26441739 TI - Explanatory model of emotional-cognitive variables in school mathematics performance: a longitudinal study in primary school. AB - This study tested a structural model of cognitive-emotional explanatory variables to explain performance in mathematics. The predictor variables assessed were related to students' level of development of early mathematical competencies (EMCs), specifically, relational and numerical competencies, predisposition toward mathematics, and the level of logical intelligence in a population of primary school Chilean students (n = 634). This longitudinal study also included the academic performance of the students during a period of 4 years as a variable. The sampled students were initially assessed by means of an Early Numeracy Test, and, subsequently, they were administered a Likert-type scale to measure their predisposition toward mathematics (EPMAT) and a basic test of logical intelligence. The results of these tests were used to analyse the interaction of all the aforementioned variables by means of a structural equations model. This combined interaction model was able to predict 64.3% of the variability of observed performance. Preschool students' performance in EMCs was a strong predictor for achievement in mathematics for students between 8 and 11 years of age. Therefore, this paper highlights the importance of EMCs and the modulating role of predisposition toward mathematics. Also, this paper discusses the educational role of these findings, as well as possible ways to improve negative predispositions toward mathematical tasks in the school domain. PMID- 26441740 TI - Visual perception can account for the close relation between numerosity processing and computational fluency. AB - Studies have shown that numerosity processing (e.g., comparison of numbers of dots in two dot arrays) is significantly correlated with arithmetic performance. Researchers have attributed this association to the fact that both tasks share magnitude processing. The current investigation tested an alternative hypothesis, which states that visual perceptual ability (as measured by a figure-matching task) can account for the close relation between numerosity processing and arithmetic performance (computational fluency). Four hundred and twenty four third- to fifth-grade children (220 boys and 204 girls, 8.0-11.0 years old; 120 third graders, 146 fourth graders, and 158 fifth graders) were recruited from two schools (one urban and one suburban) in Beijing, China. Six classes were randomly selected from each school, and all students in each selected class participated in the study. All children were given a series of cognitive and mathematical tests, including numerosity comparison, figure matching, forward verbal working memory, visual tracing, non-verbal matrices reasoning, mental rotation, choice reaction time, arithmetic tests and curriculum-based mathematical achievement test. Results showed that figure-matching ability had higher correlations with numerosity processing and computational fluency than did other cognitive factors (e.g., forward verbal working memory, visual tracing, non-verbal matrix reasoning, mental rotation, and choice reaction time). More important, hierarchical multiple regression showed that figure matching ability accounted for the well-established association between numerosity processing and computational fluency. In support of the visual perception hypothesis, the results suggest that visual perceptual ability, rather than magnitude processing, may be the shared component of numerosity processing and arithmetic performance. PMID- 26441741 TI - Meta-analyses are no substitute for registered replications: a skeptical perspective on religious priming. AB - According to a recent meta-analysis, religious priming has a positive effect on prosocial behavior (Shariff et al., 2015). We first argue that this meta-analysis suffers from a number of methodological shortcomings that limit the conclusions that can be drawn about the potential benefits of religious priming. Next we present a re-analysis of the religious priming data using two different meta analytic techniques. A Precision-Effect Testing-Precision-Effect-Estimate with Standard Error (PET-PEESE) meta-analysis suggests that the effect of religious priming is driven solely by publication bias. In contrast, an analysis using Bayesian bias correction suggests the presence of a religious priming effect, even after controlling for publication bias. These contradictory statistical results demonstrate that meta-analytic techniques alone may not be sufficiently robust to firmly establish the presence or absence of an effect. We argue that a conclusive resolution of the debate about the effect of religious priming on prosocial behavior - and about theoretically disputed effects more generally - requires a large-scale, preregistered replication project, which we consider to be the sole remedy for the adverse effects of experimenter bias and publication bias. PMID- 26441743 TI - Hedonic and eudaimonic well-being: the role of resilience beyond fluid intelligence and personality traits. AB - Resilience is a key factor in the well-being of individuals. The present study set out to analyze the role of fluid intelligence, personality traits, and resilience in hedonic and eudaimonic well-being (EWB) in order to determine the incremental validity of resilience with respect to fluid intelligence and personality traits in 168 Italian high school students. The Advanced Progressive Matrices, the Big Five Questionnaire, the Connor-Davidson Resilience Scale, the Satisfaction With Life Scale, the Positive and Negative Affect Schedule, the Meaningful Life Measure, the Authenticity Scale were administered to the participants in the study. The results showed that resilience added a significant percentage of incremental variance with respect to fluid intelligence and personality traits in relation to life satisfaction, positive affect, life meaning, and authenticity. These results underline the value of resilience in both hedonic and EWB, thus offering new perspectives for research and intervention. PMID- 26441742 TI - Efficient multitasking: parallel versus serial processing of multiple tasks. AB - In the context of performance optimizations in multitasking, a central debate has unfolded in multitasking research around whether cognitive processes related to different tasks proceed only sequentially (one at a time), or can operate in parallel (simultaneously). This review features a discussion of theoretical considerations and empirical evidence regarding parallel versus serial task processing in multitasking. In addition, we highlight how methodological differences and theoretical conceptions determine the extent to which parallel processing in multitasking can be detected, to guide their employment in future research. Parallel and serial processing of multiple tasks are not mutually exclusive. Therefore, questions focusing exclusively on either task-processing mode are too simplified. We review empirical evidence and demonstrate that shifting between more parallel and more serial task processing critically depends on the conditions under which multiple tasks are performed. We conclude that efficient multitasking is reflected by the ability of individuals to adjust multitasking performance to environmental demands by flexibly shifting between different processing strategies of multiple task-component scheduling. PMID- 26441744 TI - Changes in aspects of social functioning depend upon prior changes in neurodisability in people with acquired brain injury undergoing post-acute neurorehabilitation. AB - Post-acute community-based rehabilitation is effective in reducing disability. However, while social participation and quality of life are valued as distal outcomes of neurorehabilitation, it is often not possible to observe improvements on these outcomes within the limited time-frames used in most investigations of rehabilitation. The aim of the current study was to examine differences in the sequence of attainments for people with acquired brain injury (ABI) undergoing longer term post-acute neurorehabilitation. Participants with ABI who were referred to comprehensive home and community-based neurorehabilitation were assessed at induction to service, at 6 months and again at 1.5 years while still in service on the Mayo-Portland Adaptability Index (MPAI-4), Community Integration Questionnaire, Hospital Anxiety and Depression Scale, and World Health Organisation Quality of Life measure. At 6 months post-induction to service, significant differences were evident in MPAI abilities, adjustment, and total neurodisability; and in anxiety and depression. By contrast, there was no significant effect at 6 months on more socially oriented features of experience namely quality of life (QoL), Community Integration and Participation. Eighteen month follow-up showed continuation of the significant positive effects with the addition of QoL-related to physical health, Psychological health, Social aspects of QoL and Participation at this later time point. Regression analyses demonstrated that change in QoL and Participation were dependent upon prior changes in aspects of neurodisability. Age, severity or type of brain injury did not significantly affect outcome. Results suggest that different constructs may respond to neurorehabilitation at different time points in a dose effect manner, and that change in social aspects of experience may be dependent upon the specific nature of prior neurorehabilitation attainments. PMID- 26441745 TI - Absence of modulatory action on haptic height perception with musical pitch. AB - Although acoustic frequency is not a spatial property of physical objects, in common language, pitch, i.e., the psychological correlated of frequency, is often labeled spatially (i.e., "high in pitch" or "low in pitch"). Pitch-height is known to modulate (and interact with) the response of participants when they are asked to judge spatial properties of non-auditory stimuli (e.g., visual) in a variety of behavioral tasks. In the current study we investigated whether the modulatory action of pitch-height extended to the haptic estimation of height of a virtual step. We implemented a HW/SW setup which is able to render virtual 3D objects (stair-steps) haptically through a PHANTOM device, and to provide real time continuous auditory feedback depending on the user interaction with the object. The haptic exploration was associated with a sinusoidal tone whose pitch varied as a function of the interaction point's height within (i) a narrower and (ii) a wider pitch range, or (iii) a random pitch variation acting as a control audio condition. Explorations were also performed with no sound (haptic only). Participants were instructed to explore the virtual step freely, and to communicate height estimation by opening their thumb and index finger to mimic the step riser height, or verbally by reporting the height in centimeters of the step riser. We analyzed the role of musical expertise by dividing participants into non-musicians and musicians. Results showed no effects of musical pitch on high-realistic haptic feedback. Overall there is no difference between the two groups in the proposed multimodal conditions. Additionally, we observed a different haptic response distribution between musicians and non-musicians when estimations of the auditory conditions are matched with estimations in the no sound condition. PMID- 26441746 TI - Opinion: Paradigms, methods, and the (as yet) failed striving for methodological diversity in educational psychology published research. PMID- 26441747 TI - Gender differences in experiential and facial reactivity to approval and disapproval during emotional social interactions. AB - Negative social evaluations represent social threats and elicit negative emotions such as anger or fear. Positive social evaluations, by contrast, may increase self-esteem and generate positive emotions such as happiness and pride. Gender differences are likely to shape both the perception and expression of positive and negative social evaluations. Yet, current knowledge is limited by a reliance on studies that used static images of individual expressers with limited external validity. Furthermore, only few studies considered gender differences on both the expresser and perceiver side. The present study approached these limitations by utilizing a naturalistic stimulus set displaying nine males and nine females (expressers) delivering social evaluative sentences to 32 female and 26 male participants (perceivers). Perceivers watched 30 positive, 30 negative, and 30 neutral messages while facial electromyography (EMG) was continuously recorded and subjective ratings were obtained. Results indicated that men expressing positive evaluations elicited stronger EMG responses in both perceiver genders. Arousal was rated higher when positive evaluations were expressed by the opposite gender. Thus, gender differences need to be more explicitly considered in research of social cognition and affective science using naturalistic social stimuli. PMID- 26441748 TI - Wearing weighted backpack dilates subjective visual duration: the role of functional linkage between weight experience and visual timing. AB - Bodily state plays a critical role in our perception. In the present study, we asked the question whether and how bodily experience of weights influences time perception. Participants judged durations of a picture (a backpack or a trolley bag) presented on the screen, while wearing different weight backpacks or without backpack. The results showed that the subjective duration of the backpack picture was dilated when participants wore a medium weighted backpack relative to an empty backpack or without backpack, regardless of identity (e.g., color) of the visual backpack. However, the duration dilation was not manifested for the picture of trolley bag. These findings suggest that weight experience modulates visual duration estimation through the linkage between the wore backpack and to be-estimated visual target. The congruent action affordance between the wore backpack and visual inputs plays a critical role in the functional linkage between inner experience and time perception. We interpreted our findings within the framework of embodied time perception. PMID- 26441749 TI - The Bergen Shopping Addiction Scale: reliability and validity of a brief screening test. AB - Although excessive and compulsive shopping has been increasingly placed within the behavioral addiction paradigm in recent years, items in existing screens arguably do not assess the core criteria and components of addiction. To date, assessment screens for shopping disorders have primarily been rooted within the impulse-control or obsessive-compulsive disorder paradigms. Furthermore, existing screens use the terms 'shopping,' 'buying,' and 'spending' interchangeably, and do not necessarily reflect contemporary shopping habits. Consequently, a new screening tool for assessing shopping addiction was developed. Initially, 28 items, four for each of seven addiction criteria (salience, mood modification, conflict, tolerance, withdrawal, relapse, and problems), were constructed. These items and validated scales (i.e., Compulsive Buying Measurement Scale, Mini International Personality Item Pool, Hospital Anxiety and Depression Scale, Rosenberg Self-Esteem Scale) were then administered to 23,537 participants (M age = 35.8 years, SD age = 13.3). The highest loading item from each set of four pooled items reflecting the seven addiction criteria were retained in the final scale, The Bergen Shopping Addiction Scale (BSAS). The factor structure of the BSAS was good (RMSEA = 0.064, CFI = 0.983, TLI = 0.973) and coefficient alpha was 0.87. The scores on the BSAS converged with scores on the Compulsive Buying Measurement Scale (CBMS; 0.80), and were positively correlated with extroversion and neuroticism, and negatively with conscientiousness, agreeableness, and intellect/imagination. The scores of the BSAS were positively associated with anxiety, depression, and low self-esteem and inversely related to age. Females scored higher than males on the BSAS. The BSAS is the first scale to fully embed shopping addiction within an addiction paradigm. A recommended cutoff score for the new scale and future research directions are discussed. PMID- 26441750 TI - Cognitive synergy in groups and group-to-individual transfer of decision-making competencies. AB - In a field study (148 participants organized in 38 groups) we tested the effect of group synergy and one's position in relation to the collaborative zone of proximal development (CZPD) on the change of individual decision-making competencies. We used two parallel sets of decision tasks reported in previous research to test rationality and we evaluated individual decision-making competencies in the pre-group and post-group conditions as well as group rationality (as an emergent group level phenomenon). We used multilevel modeling to analyze the data and the results showed that members of synergetic groups had a higher cognitive gain as compared to members of non-synergetic groups, while highly rational members (members above the CZPD) had lower cognitive gains compared to less rational group members (members situated below the CZPD). These insights extend the literature on group-to-individual transfer of learning and have important practical implications as they show that group dynamics influence the development of individual decision-making competencies. PMID- 26441751 TI - Brain readiness and the nature of language. AB - To identify the neural components that make a brain ready for language, it is important to have well defined linguistic phenotypes, to know precisely what language is. There are two central features to language: the capacity to form signs (words), and the capacity to combine them into complex structures. We must determine how the human brain enables these capacities. A sign is a link between a perceptual form and a conceptual meaning. Acoustic elements and content elements, are already brain-internal in non-human animals, but as categorical systems linked with brain-external elements. Being indexically tied to objects of the world, they cannot freely link to form signs. A crucial property of a language-ready brain is the capacity to process perceptual forms and contents offline, detached from any brain-external phenomena, so their "representations" may be linked into signs. These brain systems appear to have pleiotropic effects on a variety of phenotypic traits and not to be specifically designed for language. Syntax combines signs, so the combination of two signs operates simultaneously on their meaning and form. The operation combining the meanings long antedates its function in language: the primitive mode of predication operative in representing some information about an object. The combination of the forms is enabled by the capacity of the brain to segment vocal and visual information into discrete elements. Discrete temporal units have order and juxtaposition, and vocal units have intonation, length, and stress. These are primitive combinatorial processes. So the prior properties of the physical and conceptual elements of the sign introduce combinatoriality into the linguistic system, and from these primitive combinatorial systems derive concatenation in phonology and combination in morphosyntax. Given the nature of language, a key feature to our understanding of the language-ready brain is to be found in the mechanisms in human brains that enable the unique means of representation that allow perceptual forms and contents to be linked into signs. PMID- 26441753 TI - Manipulating target size influences perceptions of success when learning a dart throwing skill but does not impact retention. AB - Positive feedback or experiences of success during skill acquisition have been shown to benefit motor skill learning. In this study, our aim was to manipulate learners' success perceptions through a minor adjustment to goal criterion (target size) in a dart-throwing task. Two groups of novice participants practiced throwing at a large (easy) or a small (difficult) target from the same distance. In reference to the origin/center of the target, the practice targets were alike in objective difficulty and indeed participants in both groups were not different in their objective practice performance (i.e., radial error from the center). Although the groups experienced markedly different success rates, with the large target group experiencing more hits and reporting greater confidence (or self-efficacy) than the small target group, these practice effects were not carried into longer-term retention, which was assessed after a 1-week delay. For success perceptions to moderate or benefit motor learning, we argue that unambiguous indicators of positive performance are necessary, especially for tasks where intrinsic feedback about objective error is salient. PMID- 26441754 TI - Answering research questions without calculating the mean. PMID- 26441752 TI - FRAS1-related extracellular matrix 3 (FREM3) single-nucleotide polymorphism effects on gene expression, amygdala reactivity and perceptual processing speed: An accelerated aging pathway of depression risk. AB - The A allele of the FRAS1-related extracellular matrix protein 3 (FREM3) rs7676614 single nucleotide polymorphism (SNP) was linked to major depressive disorder (MDD) in an early genome-wide association study (GWAS), and to symptoms of psychomotor retardation in a follow-up investigation. In line with significant overlap between age- and depression-related molecular pathways, parallel work has shown that FREM3 expression in postmortem human brain decreases with age. Here, we probe the effect of rs7676614 on amygdala reactivity and perceptual processing speed, both of which are altered in depression and aging. Amygdala reactivity was assessed using a face-matching BOLD fMRI paradigm in 365 Caucasian participants in the Duke Neurogenetics Study (DNS) (192 women, mean age 19.7 +/- 1.2). Perceptual processing speed was indexed by reaction times in the same task and the Trail Making Test (TMT). The effect of rs7676614 on FREM3 mRNA brain expression levels was probed in a postmortem cohort of 169 Caucasian individuals (44 women, mean age 50.8 +/- 14.9). The A allele of rs7676614 was associated with blunted amygdala reactivity to faces, slower reaction times in the face-matching condition (p < 0.04), as well as marginally slower performance on TMT Part B (p = 0.056). In the postmortem cohort, the T allele of rs6537170 (proxy for the rs7676614 A allele), was associated with trend-level reductions in gene expression in Brodmann areas 11 and 47 (p = 0.066), reminiscent of patterns characteristic of older age. The low-expressing allele of another FREM3 SNP (rs1391187) was similarly associated with reduced amygdala reactivity and slower TMT Part B speed, in addition to reduced BA47 activity and extraversion (p < 0.05). Together, these results suggest common genetic variation associated with reduced FREM3 expression may confer risk for a subtype of depression characterized by reduced reactivity to environmental stimuli and slower perceptual processing speed, possibly suggestive of accelerated aging. PMID- 26441755 TI - Moral asymmetries in judgments of agency withstand ludicrous causal deviance. AB - Americans have been shown to attribute greater intentionality to immoral than to amoral actions in cases of causal deviance, that is, cases where a goal is satisfied in a way that deviates from initially planned means (e.g., a gunman wants to hit a target and his hand slips, but the bullet ricochets off a rock into the target). However, past research has yet to assess whether this asymmetry persists in cases of extreme causal deviance. Here, we manipulated the level of mild to extreme causal deviance of an immoral versus amoral act. The asymmetry in attributions of intentionality was observed at all but the most extreme level of causal deviance, and, as we hypothesized, was mediated by attributions of blame/credit and judgments of action performance. These findings are discussed as they support a multiple-concepts interpretation of the asymmetry, wherein blame renders a naive concept of intentional action (the outcome matches the intention) more salient than a composite concept (the outcome matches the intention and was brought about by planned means), and in terms of their implications for cross cultural research on judgments of agency. PMID- 26441756 TI - There or not there? A multidisciplinary review and research agenda on the impact of transparent barriers on human perception, action, and social behavior. AB - Through advances in production and treatment technologies, transparent glass has become an increasingly versatile material and a global hallmark of modern architecture. In the shape of invisible barriers, it defines spaces while simultaneously shaping their lighting, noise, and climate conditions. Despite these unique architectural qualities, little is known regarding the human experience with glass barriers. Is a material that has been described as being simultaneously there and not there from an architectural perspective, actually there and/or not there from perceptual, behavioral, and social points of view? In this article, we review systematic observations and experimental studies that explore the impact of transparent barriers on human cognition and action. In doing so, the importance of empirical and multidisciplinary approaches to inform the use of glass in contemporary architecture is highlighted and key questions for future inquiry are identified. PMID- 26441757 TI - The sweetest thing: the influence of angularity, symmetry, and the number of elements on shape-valence and shape-taste matches. AB - A within-participants experiment was conducted in two countries (the UK and Colombia) in order to investigate the matching of shapes to taste words. Comparing the two countries allowed us to explore some of the cultural differences that have been reported thus far solely in terms of people's visual preferences. In particular, we addressed the question of whether properties other than angularity influence shape-valence and shape-taste matching (crossmodal correspondences). The participants in the present study repeatedly matched eight shapes, varying in terms of their angularity, symmetry, and number of elements to one of two words-pleasant or unpleasant and sweet or sour. Participants' choices, as well as the latency of their responses, and their hand movements, were evaluated. The participants were more likely to judge those shapes that were rounder, symmetrical, and those shapes that had fewer elements as both pleasant and sweet. Those shapes that were more angular, asymmetrical, and that had a greater number of elements, were more likely to be judged as both unpleasant and sour instead. The evidence presented here therefore suggests that aside from angularity and roundness, both symmetry/asymmetry and the number of elements present in a shape also influence valence and taste categorizations. PMID- 26441759 TI - Corrigendum: Tactile input and empathy modulate the perception of ambiguous biological motion. AB - [This corrects the article on p. 161 in vol. 6, PMID: 25750631.]. PMID- 26441758 TI - How do different components of Effortful Control contribute to children's mathematics achievement? AB - This work sought to investigate the specific contribution of two different components of Effortful Control (EC) -attentional focusing (AF) and inhibitory control- to children's mathematics achievement. The sample was composed of 142 children aged 9-12 year-old. EC components were measured through the Temperament in Middle Childhood Questionnaire (TMCQ; parent's report); math achievement was measured via teacher's report and through the standard Woodcock-Johnson test. Additionally, the contribution of other cognitive and socio-emotional processes was taken into account. Our results showed that only AF significantly contributed to the variance of children's mathematics achievement; interestingly, mediational models showed that the relationship between effortful attentional self-regulation and mathematics achievement was mediated by academic peer popularity, as well as by intelligence and study skills. Results are discussed in the light of the current theories on the role of children's self-regulation abilities in the context of school. PMID- 26441761 TI - Automated facial coding software outperforms people in recognizing neutral faces as neutral from standardized datasets. AB - Little is known about people's accuracy of recognizing neutral faces as neutral. In this paper, I demonstrate the importance of knowing how well people recognize neutral faces. I contrasted human recognition scores of 100 typical, neutral front-up facial images with scores of an arguably objective judge - automated facial coding (AFC) software. I hypothesized that the software would outperform humans in recognizing neutral faces because of the inherently objective nature of computer algorithms. Results confirmed this hypothesis. I provided the first-ever evidence that computer software (90%) was more accurate in recognizing neutral faces than people were (59%). I posited two theoretical mechanisms, i.e., smile as-a-baseline and false recognition of emotion, as possible explanations for my findings. PMID- 26441760 TI - Source unreliability decreases but does not cancel the impact of social information on metacognitive evaluations. AB - Through metacognitive evaluations, individuals assess their own cognitive operations with respect to their current goals. We have previously shown that non verbal social cues spontaneously influence these evaluations, even when the cues are unreliable. Here, we explore whether a belief about the reliability of the source can modulate this form of social impact. Participants performed a two alternative forced choice task that varied in difficulty. The task was followed by a video of a person who was presented as being either competent or incompetent at performing the task. That person provided random feedback to the participant through facial expressions indicating agreement, disagreement or uncertainty. Participants then provided a metacognitive evaluation by rating their confidence in their answer. Results revealed that participants' confidence was higher following agreements. Interestingly, this effect was merely reduced but not canceled for the incompetent individual, even though participants were able to perceive the individual's incompetence. Moreover, perceived agreement induced zygomaticus activity, but only when the feedback was provided for difficult trials by the competent individual. This last result strongly suggests that people implicitly appraise the relevance of social feedback with respect to their current goal. Together, our findings suggest that people always integrate social agreement into their metacognitive evaluations, even when epistemic vigilance mechanisms alert them to the risk of being misinformed. PMID- 26441762 TI - Looking at the evidence in visual world: eye-movements reveal how bilingual and monolingual Turkish speakers process grammatical evidentiality. AB - This study presents pioneering data on how adult early bilinguals (heritage speakers) and late bilingual speakers of Turkish and German process grammatical evidentiality in a visual world setting in comparison to monolingual speakers of Turkish. Turkish marks evidentiality, the linguistic reference to information source, through inflectional affixes signaling either direct (-DI) or indirect ( mIs) evidentiality. We conducted an eye-tracking-during-listening experiment where participants were given access to visual 'evidence' supporting the use of either a direct or indirect evidential form. The behavioral results indicate that the monolingual Turkish speakers comprehended direct and indirect evidential scenarios equally well. In contrast, both late and early bilinguals were less accurate and slower to respond to direct than to indirect evidentials. The behavioral results were also reflected in the proportions of looks data. That is, both late and early bilinguals fixated less frequently on the target picture in the direct than in the indirect evidential condition while the monolinguals showed no difference between these conditions. Taken together, our results indicate reduced sensitivity to the semantic and pragmatic function of direct evidential forms in both late and early bilingual speakers, suggesting a simplification of the Turkish evidentiality system in Turkish heritage grammars. We discuss our findings with regard to theories of incomplete acquisition and first language attrition. PMID- 26441763 TI - Gender stereotypes across the ages: On-line processing in school-age children, young and older adults. AB - Most research to date on implicit gender stereotyping has been conducted with one age group - young adults. The mechanisms that underlie the on-line processing of stereotypical information in other age groups have received very little attention. This is the first study to investigate real time processing of gender stereotypes at different age levels. We investigated the activation of gender stereotypes in Italian in four groups of participants: third- and fifth-graders, young and older adults. Participants heard a noun that was stereotypically associated with masculine (preside "headmaster") or feminine roles (badante "social care worker"), followed by a male (padre "father") or female kinship term (madre "mother"). The task was to decide if the two words - the role noun and the kinship term - could describe the same person. Across all age groups, participants were significantly faster to respond, and significantly more likely to press 'yes,' when the gender of the target was congruent with the stereotypical gender use of the preceding prime. These findings suggest that information about the stereotypical gender associated with a role noun is incorporated into the mental representation of this word and is activated as soon as the word is heard. In addition, our results show differences between male and female participants of the various age groups, and between male- and female oriented stereotypes, pointing to important gender asymmetries. PMID- 26441764 TI - A word on standardization in longitudinal studies: don't. PMID- 26441765 TI - Speech intelligibility and recall of first and second language words heard at different signal-to-noise ratios. AB - Free recall of spoken words in Swedish (native tongue) and English were assessed in two signal-to-noise ratio (SNR) conditions (+3 and +12 dB), with and without half of the heard words being repeated back orally directly after presentation [shadowing, speech intelligibility (SI)]. A total of 24 word lists with 12 words each were presented in English and in Swedish to Swedish speaking college students. Pre-experimental measures of working memory capacity (operation span, OSPAN) were taken. A basic hypothesis was that the recall of the words would be impaired when the encoding of the words required more processing resources, thereby depleting working memory resources. This would be the case when the SNR was low or when the language was English. A low SNR was also expected to impair SI, but we wanted to compare the sizes of the SNR-effects on SI and recall. A low score on working memory capacity was expected to further add to the negative effects of SNR and language on both SI and recall. The results indicated that SNR had strong effects on both SI and recall, but also that the effect size was larger for recall than for SI. Language had a main effect on recall, but not on SI. The shadowing procedure had different effects on recall of the early and late parts of the word lists. Working memory capacity was unimportant for the effect on SI and recall. Thus, recall appear to be a more sensitive indicator than SI for the acoustics of learning, which has implications for building codes and recommendations concerning classrooms and other workplaces, where both hearing and learning is important. PMID- 26441766 TI - The effect of a brief mindfulness induction on processing of emotional images: an ERP study. AB - The ability to effectively direct one's attention is an important aspect of regulating emotions and a component of mindfulness. Mindfulness practices have been established as effective interventions for mental and physical illness; however, the underlying neural mechanisms of mindfulness and how they relate to emotional processing have not been explored in depth. The current study used a within-subjects repeated measures design to examine if focused breathing, a brief mindfulness induction, could modulate event-related potentials (ERPs) during emotional image processing relative to a control condition. We related ERP measures of processing positive, negative, and neutral images (the P300 and late positive potential - LPP) to state and trait mindfulness measures. Overall, the brief mindfulness induction condition did not influence ERPs reflecting emotional processing; however, in the brief mindfulness induction condition, those participants who reported feeling more decentered (a subscale of the Toronto Mindfulness Scale) after viewing the images had reduced P300 responses to negative versus neutral images. PMID- 26441767 TI - The power of putting a label on it: green labels weigh heavier than contradicting product information for consumers' purchase decisions and post-purchase behavior. AB - Green products are appealing. Thus, labeling products as environmentally friendly is an effective strategy to increase sales. However, the labels often promise more than the products can actually deliver. In the present research, we examined the expectation that consumers with high ecological motivation have strong preferences for green-labeled products - even when presented product information contradicts the label's image. This unsettling hypothesis is grounded in the labels' potential to create a cognitive match between the labeled product and consumers' motives. For labels indicating environmental friendliness (green product labels), this link should be strongest when consumers' ecological motivation is high. Findings in a series of three experiments support our assumption, showing that consumers with high ecological motivation had strong preferences (i.e., product evaluations, purchase intentions, and simulated purchase decisions) for green-labeled products as compared to consumers with low ecological motivation (Studies 1-3). Crucially, these preferences were robust, despite contradicting environmental product information (Studies 1 and 2). We extended our findings by additionally examining the impact of product labels and motivation on moral self-regulation processes. This was established by assessing participants' pro-social behavior after the purchase task: participants with high ecological motivation acted, consistent with their motives, more pro-socially in post-decision occasions. In accordance with moral cleansing effects, pro-social behavior was intensified after purchasing conventional products (Studies 2 and 3). Green labels protected participants with high ecological motivation from moral threats due to the purchase, thus making pro-social behavior less likely. Findings suggest that highly ecologically motivated consumers are most susceptible to green labels, which may override detailed product information. PMID- 26441768 TI - Dream-reality confusion in borderline personality disorder: a theoretical analysis. AB - This paper presents an analysis of dream-reality confusion (DRC) in relation to the characteristics of borderline personality disorder (BPD), based on research findings and theoretical considerations. It is hypothesized that people with BPD are more likely to experience DRC compared to people in non-clinical population. Several variables related to this hypothesis were identified through a theoretical analysis of the scientific literature. Sleep disturbances: problems with sleep are found in 15-95.5% of people with BPD (Hafizi, 2013), and unstable sleep and wake cycles, which occur in BPD (Fleischer et al., 2012), are linked to DRC. Dissociation: nearly two-thirds of people with BPD experience dissociative symptoms (Korzekwa and Pain, 2009) and dissociative symptoms are correlated with a fantasy proneness; both dissociative symptoms and fantasy proneness are related to DRC (Giesbrecht and Merckelbach, 2006). Negative dream content: People with BPD have nightmares more often than other people (Semiz et al., 2008); dreams that are more likely to be confused with reality tend to be more realistic and unpleasant, and are reflected in waking behavior (Rassin et al., 2001). Cognitive disturbances: Many BPD patients experience various cognitive disturbances, including problems with reality testing (Fiqueierdo, 2006; Mosquera et al., 2011), which can foster DRC. Thin boundaries: People with thin boundaries are more prone to DRC than people with thick boundaries, and people with BPD tend to have thin boundaries (Hartmann, 2011). The theoretical analysis on the basis of these findings suggests that people who suffer from BPD may be more susceptible to confusing dream content with actual waking events. PMID- 26441770 TI - Polish pseudo-words list: dataset of 3023 stimuli with competent judges' ratings. AB - Pseudo-words are stimuli, which are useful in research concerning lexical processing. As in the case of existing words, they are language dependent; thus, they should be generated for each language separately. The Polish Pseudo-words List (PPwL) is a dataset presenting a set of 3023 stimuli (words of 4-13 letters long). They were generated using an algorithm substituting random letters in existing words with respect to the frequency of letters in certain positions. We put out the raw set for a competent judges' assessment and included the responses in the dataset. PPwL allows the choice of suitable control stimuli for experiments concerning lexical processing. PMID- 26441769 TI - Associations between speech understanding and auditory and visual tests of verbal working memory: effects of linguistic complexity, task, age, and hearing loss. AB - Listeners with hearing loss commonly report having difficulty understanding speech, particularly in noisy environments. Their difficulties could be due to auditory and cognitive processing problems. Performance on speech-in-noise tests has been correlated with reading working memory span (RWMS), a measure often chosen to avoid the effects of hearing loss. If the goal is to assess the cognitive consequences of listeners' auditory processing abilities, however, then listening working memory span (LWMS) could be a more informative measure. Some studies have examined the effects of different degrees and types of masking on working memory, but less is known about the demands placed on working memory depending on the linguistic complexity of the target speech or the task used to measure speech understanding in listeners with hearing loss. Compared to RWMS, LWMS measures using different speech targets and maskers may provide a more ecologically valid approach. To examine the contributions of RWMS and LWMS to speech understanding, we administered two working memory measures (a traditional RWMS measure and a new LWMS measure), and a battery of tests varying in the linguistic complexity of the speech materials, the presence of babble masking, and the task. Participants were a group of younger listeners with normal hearing and two groups of older listeners with hearing loss (n = 24 per group). There was a significant group difference and a wider range in performance on LWMS than on RWMS. There was a significant correlation between both working memory measures only for the oldest listeners with hearing loss. Notably, there were only few significant correlations among the working memory and speech understanding measures. These findings suggest that working memory measures reflect individual differences that are distinct from those tapped by these measures of speech understanding. PMID- 26441771 TI - Electrophysiology of subject-verb agreement mediated by speakers' gender. AB - An important property of speech is that it explicitly conveys features of a speaker's identity such as age or gender. This event-related potential (ERP) study examined the effects of social information provided by a speaker's gender, i.e., the conceptual representation of gender, on subject-verb agreement. Despite numerous studies on agreement, little is known about syntactic computations generated by speaker characteristics extracted from the acoustic signal. Slovak is well suited to investigate this issue because it is a morphologically rich language in which agreement involves features for number, case, and gender. Grammaticality of a sentence can be evaluated by checking a speaker's gender as conveyed by his/her voice. We examined how conceptual information about speaker gender, which is not syntactic but rather social and pragmatic in nature, is interpreted for the computation of agreement patterns. ERP responses to verbs disagreeing with the speaker's gender (e.g., a sentence including a masculine verbal inflection spoken by a female person 'the neighbors were upset because I (*)stoleMASC plums') elicited a larger early posterior negativity compared to correct sentences. When the agreement was purely syntactic and did not depend on the speaker's gender, a disagreement between a formally marked subject and the verb inflection (e.g., the womanFEM (*)stoleMASC plums) resulted in a larger P600 preceded by a larger anterior negativity compared to the control sentences. This result is in line with proposals according to which the recruitment of non syntactic information such as the gender of the speaker results in N400-like effects, while formally marked syntactic features lead to structural integration as reflected in a LAN/P600 complex. PMID- 26441772 TI - Infant discrimination of humanoid robots. AB - Recently, extremely humanlike robots called "androids" have been developed, some of which are already being used in the field of entertainment. In the context of psychological studies, androids are expected to be used in the future as fully controllable human stimuli to investigate human nature. In this study, we used an android to examine infant discrimination ability between human beings and non human agents. Participants (N = 42 infants) were assigned to three groups based on their age, i.e., 6- to 8-month-olds, 9- to 11-month-olds, and 12- to 14-month olds, and took part in a preferential looking paradigm. Of three types of agents involved in the paradigm-a human, an android modeled on the human, and a mechanical-looking robot made from the android-two at a time were presented side by-side as they performed a grasping action. Infants' looking behavior was measured using an eye tracking system, and the amount of time spent focusing on each of three areas of interest (face, goal, and body) was analyzed. Results showed that all age groups predominantly looked at the robot and at the face area, and that infants aged over 9 months watched the goal area for longer than the body area. There was no difference in looking times and areas focused on between the human and the android. These findings suggest that 6- to 14-month olds are unable to discriminate between the human and the android, although they can distinguish the mechanical robot from the human. PMID- 26441773 TI - Embodiment and enculturation: the future of architectural design. AB - A half-century ago the Dutch architect Aldo van Eyck encouraged designers to think about "space and time" not as abstractions in themselves but rather as cultural events better approached through the medium of "place and occasion." Van Eyck made this point on the basis of his own travels and through his extensive readings in cultural anthropology, and his prescience is only now acquiring the credibility that it deserves through the work of a multitude of interdisciplinary researchers. Phenomenologists argue that we are embodied organisms-acting-within environments, and these inhabiting abodes are constructed of both material and cultural dimensions. We are thus preeminently social in our range of self consciousness, and intensely ceremonial in every facet of our being. Evolutionary psychologists and anthropologists are currently locating the origin and development of our most basic social behaviors far in our pre-human past; neuroscientists are today modeling our social circuits in the deepest reaches of our brains. Architecture would gain much from an updated cultural theory grounded in these new models of human existence. PMID- 26441774 TI - Interpersonal trust: an event-based account. PMID- 26441775 TI - Gender inequalities in the workplace: the effects of organizational structures, processes, practices, and decision makers' sexism. AB - Gender inequality in organizations is a complex phenomenon that can be seen in organizational structures, processes, and practices. For women, some of the most harmful gender inequalities are enacted within human resources (HRs) practices. This is because HR practices (i.e., policies, decision-making, and their enactment) affect the hiring, training, pay, and promotion of women. We propose a model of gender discrimination in HR that emphasizes the reciprocal nature of gender inequalities within organizations. We suggest that gender discrimination in HR-related decision-making and in the enactment of HR practices stems from gender inequalities in broader organizational structures, processes, and practices. This includes leadership, structure, strategy, culture, organizational climate, as well as HR policies. In addition, organizational decision makers' levels of sexism can affect their likelihood of making gender biased HR-related decisions and/or behaving in a sexist manner while enacting HR practices. Importantly, institutional discrimination in organizational structures, processes, and practices play a pre-eminent role because not only do they affect HR practices, they also provide a socializing context for organizational decision makers' levels of hostile and benevolent sexism. Although we portray gender inequality as a self-reinforcing system that can perpetuate discrimination, important levers for reducing discrimination are identified. PMID- 26441776 TI - Children's spontaneous emotional expressions while receiving (un)wanted prizes in the presence of peers. AB - Although current emotion theories emphasize the importance of contextual factors for emotional expressive behavior, developmental studies that examine such factors are currently thin on the ground. In this research, we studied the course of emotional expressions of 8- and 11-year-old children after winning a (large) first prize or a (substantially smaller) consolation prize, while playing a game competing against the computer or a physically co-present peer. We analyzed their emotional reactions by conducting two perception tests in which participants rated children's level of happiness. Results showed that co-presence positively affected children's happiness only when receiving the first prize. Moreover, for children who were in the presence of a peer, we found that eye contact affected children's expressions of happiness, but that the effect was different for different age groups: 8-year-old children were negatively affected, and 11-year old children positively. Overall, we can conclude that as children grow older and their social awareness increases, the presence of a peer affects their non-verbal expressions, regardless of their appreciation of their prize. PMID- 26441778 TI - Gender stereotype endorsement differentially predicts girls' and boys' trait state discrepancy in math anxiety. AB - Mathematics is associated with anxiety for many students; an emotion linked to lower well-being and poorer learning outcomes. While findings typically show females to report higher trait math anxiety than males, no gender differences have to date been found in state (i.e., momentary) math anxiety. The present diary study aimed to replicate previous findings in investigating whether levels of academic self-concept was related to this discrepancy in trait vs. state anxiety measures. Additionally, mathematics-related gender stereotype endorsement (mathematics is a male domain) was investigated as an additional predictor of the trait-state discrepancy. The sample included 755 German 9th and 10th graders who completed self-report measures of trait math anxiety, math self-concept, and gender stereotype endorsement, in addition to state measures of anxiety after math classes by use of a standardized diary for 2-3 weeks (N within = 6207). As expected, females reported higher trait math anxiety but no gender differences were found for state math anxiety. Also in line with our assumptions, multilevel analyses showed the discrepancy between trait and state anxiety to be negatively related to students' self-concept (i.e., a lower discrepancy for students with higher self-concepts). Furthermore, gender stereotype endorsement differentially predicted the trait-state discrepancy: When controlling for self-concept in mathematics, females who endorsed the gender stereotype of math being a male domain more strongly overestimated their trait math anxiety as compared to their state anxiety whereas this effect was not significant for males. The present findings suggest that gender stereotype endorsement plays an important role in explaining gender differences in math anxiety above and beyond academic self concept. Implications for future research and educational practice are discussed. PMID- 26441779 TI - The use of personalized behavioral feedback for online gamblers: an empirical study. AB - Over the last few years, online gambling has become a more common leisure time activity. However, for a small minority, the activity can become problematic. Consequently, the gambling industry has started to acknowledge their role in player protection and harm minimization and some gambling companies have introduced responsible gambling tools as a way of helping players stay in control. The present study evaluated the effectiveness of mentor (a responsible gambling tool that provides personalized feedback to players) among 1,015 online gamblers at a European online gambling site, and compared their behavior with matched controls (n = 15,216) on the basis of age, gender, playing duration, and theoretical loss (i.e., the amount of money wagered multiplied by the payout percentage of a specific game played). The results showed that online gamblers receiving personalized feedback spent significantly less time and money gambling compared to controls that did not receive personalized feedback. The results suggest that responsible gambling tools providing personalized feedback may help the clientele of gambling companies gamble more responsibly, and may be of help those who gamble excessively to stay within their personal time and money spending limits. PMID- 26441780 TI - Interoception and the uneasiness of the mind: affect as perceptual style. AB - Autonomous system models of interoception describe perception of bodily sensations as an active process in which the brain generates and tests hypotheses about the body on the basis of proximal information. This view of perception as inference allows a new perspective on the role of affect in perception. Affect and interoception are closely linked, but processes underlying this link are poorly understood. We suggest that a predictive coding perspective allows acknowledging affect as integral part of information processing. We outline how affect may intrinsically modify processes of interoception by acting as threshold mechanism in stimulus grouping and information compression. We outline how well established methods, for example, from categorization research may allow quantifying this influence of affect on perception in empirical tests of predictive coding models. We discuss how this may enrich the study of the relationship between affect and interoception and may have important clinical relevance. PMID- 26441777 TI - The contributions of vision and haptics to reaching and grasping. AB - This review aims to provide a comprehensive outlook on the sensory (visual and haptic) contributions to reaching and grasping. The focus is on studies in developing children, normal, and neuropsychological populations, and in sensory deprived individuals. Studies have suggested a right-hand/left-hemisphere specialization for visually guided grasping and a left-hand/right-hemisphere specialization for haptically guided object recognition. This poses the interesting possibility that when vision is not available and grasping relies heavily on the haptic system, there is an advantage to use the left hand. We review the evidence for this possibility and dissect the unique contributions of the visual and haptic systems to grasping. We ultimately discuss how the integration of these two sensory modalities shape hand preference. PMID- 26441782 TI - Imitation by combination: preschool age children evidence summative imitation in a novel problem-solving task. AB - Children are exceptional, even 'super,' imitators but comparatively poor independent problem-solvers or innovators. Yet, imitation and innovation are both necessary components of cumulative cultural evolution. Here, we explored the relationship between imitation and innovation by assessing children's ability to generate a solution to a novel problem by imitating two different action sequences demonstrated by two different models, an example of imitation by combination, which we refer to as "summative imitation." Children (N = 181) from 3 to 5 years of age and across three experiments were tested in a baseline condition or in one of six demonstration conditions, varying in the number of models and opening techniques demonstrated. Across experiments, more than 75% of children evidenced summative imitation, opening both compartments of the problem box and retrieving the reward hidden in each. Generally, learning different actions from two different models was as good (and in some cases, better) than learning from 1 model, but the underlying representations appear to be the same in both demonstration conditions. These results show that summative imitation not only facilitates imitation learning but can also result in new solutions to problems, an essential feature of innovation and cumulative culture. PMID- 26441781 TI - Measuring anhedonia: impaired ability to pursue, experience, and learn about reward. AB - Ribot's (1896) long standing definition of anhedonia as "the inability to experience pleasure" has been challenged recently following progress in affective neuroscience. In particular, accumulating evidence suggests that reward consists of multiple subcomponents of wanting, liking and learning, as initially outlined by Berridge and Robinson (2003), and these processes have been proposed to relate to appetitive, consummatory and satiety phases of a pleasure cycle. Building on this work, we recently proposed to reconceptualize anhedonia as "impairments in the ability to pursue, experience, and/or learn about pleasure, which is often, but not always accessible to conscious awareness." (Romer Thomsen et al., 2015). This framework is in line with Treadway and Zald's (2011) proposal to differentiate between motivational and consummatory types of anhedonia, and stresses the need to combine traditional self-report measures with behavioral measures or procedures. In time, this approach may lead to improved clinical assessment and treatment. In line with our reconceptualization, increasing evidence suggests that reward processing deficits are not restricted to impaired hedonic impact in major psychiatric disorders. Successful translations of animal models have led to strong evidence of impairments in the ability to pursue and learn about reward in psychiatric disorders such as major depressive disorder, schizophrenia, and addiction. It is of high importance that we continue to systematically target impairments in all phases of reward processing across disorders using behavioral testing in combination with neuroimaging techniques. This in turn has implications for diagnosis and treatment, and is essential for the purposes of identifying the underlying neurobiological mechanisms. Here I review recent progress in the development and application of behavioral procedures that measure subcomponents of anhedonia across relevant patient groups, and discuss methodological caveats as well as implications for assessment and treatment. PMID- 26441783 TI - Can money heal all wounds? Social exchange norm modulates the preference for monetary versus social compensation. AB - Compensation is a kind of pro-social behavior that can restore a social relationship jeopardized by interpersonal transgression. The effectiveness of a certain compensation strategy (e.g., repaying money, sharing loss, etc.) may vary as a function of the social norm/relationship. Previous studies have shown that two types of norms (or relationships), monetary/exchange and social/communal, differentially characterize people's appraisal of and response to social exchanges. In this study, we investigated how individual differences in preference for these norms affect individuals' perception of others' as well as the selection of their own reciprocal behaviors. In a two-phase experiment with interpersonal transgression, we asked the participant to perform a dot-estimation task with two partners who occasionally and unintentionally inflicted noise stimulation upon the participant (first phase). As compensation one partner gave money to the participant 80% of the time (the monetary partner) and the other bore the noise for the participant 80% of the time (the social partner). Results showed that the individuals' preference for compensation (repaying money versus bearing noise) affected their relationship (exchange versus communal) with the partners adopting different compensation strategies: participants tended to form communal relationships and felt closer to the partner whose compensation strategy matched their own preference. The participants could be differentiated into a social group, who tended to form communal relationship with the social partner, and a monetary group, who tended to form communal relationship with the monetary partner. In the second phase of the experiment, when the participants became transgressors and were asked to compensate for their transgression with money, the social group offered more compensation to the social partners than to the monetary partners, while the monetary group compensated less than the social group in general and showed no difference in their offers to the monetary and social partners. These findings demonstrate that the effectiveness of compensation varies as a function of individuals' preference for communal versus monetary norm and that monetary compensation alone does not heal all wounds. PMID- 26441784 TI - Socioeconomic status and oppositional defiant disorder in preschoolers: parenting practices and executive functioning as mediating variables. AB - OBJECTIVES: To investigate the mediating mechanisms of oppositional defiant disorder (ODD) in preschoolers through pathways analysis, considering the family socioeconomic status (SES) as the independent variable and the parenting style and the children's executive functioning (EF) as the mediating factors. METHOD: The sample included 622 three-year-old children from the general population. Multi-informant reports from parents and teachers were analyzed. RESULTS: Structural Equation Modeling showed that the associations between SES, EF, parenting style and ODD levels differed by children's gender: (a) for girls, the association of low SES and high ODD scores was partially mediated by difficulties in EF inhibition, and parenting practices defined by corporal punishment and inconsistent discipline obtained a quasi-significant indirect effect into the association between SES and ODD; (b) for boys, SES and EF (inhibition and emotional control) had a direct effect on ODD with no mediation. CONCLUSION: SES seems a good indicator to identify children at high-risk for prevention and intervention programs for ODD. Girls with ODD in families of low SES may particularly benefit from parent training practices and training in inhibition control. PMID- 26441785 TI - Corrigendum: A comparative study of exceptional experiences of clients seeking advice and of subjects in an ordinary population. AB - [This corrects the article on p. 65 in vol. 4, PMID: 23423775.]. PMID- 26441786 TI - Predicting self-rated mental and physical health: the contributions of subjective socioeconomic status and personal relative deprivation. AB - Lower subjective socioeconomic status (SSS) and higher personal relative deprivation (PRD) relate to poorer health. Both constructs concern people's perceived relative social position, but they differ in their emphasis on the reference groups people use to determine their comparative disadvantage (national population vs. similar others) and the importance of resentment that may arise from such adverse comparisons. We investigated the relative utility of SSS and PRD as predictors of self-rated physical and mental health (e.g., self-rated health, stress, health complaints). Across six studies, self-rated physical and mental health were on the whole better predicted by measures of PRD than by SSS while controlling for objective socioeconomic status (SES), with SSS rarely contributing unique variance over and above PRD and SES. Studies 4-6 discount the possibility that the superiority of PRD over SSS in predicting health is due to psychometric differences (e.g., reliability) or response biases between the measures. PMID- 26441787 TI - Social coordination in animal vocal interactions. Is there any evidence of turn taking? The starling as an animal model. AB - Turn-taking in conversation appears to be a common feature in various human cultures and this universality raises questions about its biological basis and evolutionary trajectory. Functional convergence is a widespread phenomenon in evolution, revealing sometimes striking functional similarities between very distant species even though the mechanisms involved may be different. Studies on mammals (including non-human primates) and bird species with different levels of social coordination reveal that temporal and structural regularities in vocal interactions may depend on the species' social structure. Here we test the hypothesis that turn-taking and associated rules of conversations may be an adaptive response to the requirements of social life, by testing the applicability of turn-taking rules to an animal model, the European starling. Birdsong has for many decades been considered as one of the best models of human language and starling songs have been well described in terms of vocal production and perception. Starlings do have vocal interactions where alternating patterns predominate. Observational and experimental data on vocal interactions reveal that (1) there are indeed clear temporal and structural regularities, (2) the temporal and structural patterning is influenced by the immediate social context, the general social situation, the individual history, and the internal state of the emitter. Comparison of phylogenetically close species of Sturnids reveals that the alternating pattern of vocal interactions varies greatly according to the species' social structure, suggesting that interactional regularities may have evolved together with social systems. These findings lead to solid bases of discussion on the evolution of communication rules in relation to social evolution. They will be discussed also in terms of processes, at the light of recent neurobiological findings. PMID- 26441788 TI - Emotional processing in Parkinson's disease and schizophrenia: evidence for response bias deficits in PD. AB - Deficits in facial emotion recognition in Parkinson's disease (PD) patients has been well documented. Nevertheless, it is still not clear whether facial emotion recognition deficits are secondary to other cognitive impairments. The aim of this study was to answer the question of whether deficits in facial emotion recognition in PD result from impaired sensory processes, or from impaired decision processes. To address this question, we tested the ability to recognize a mixture of basic and complex emotions in 38 non-demented PD patients and 38 healthy controls matched on demographic characteristics. By using a task with an increased level of ambiguity, in conjunction with the signal detection theory, we were able to differentiate between sensitivity and response bias in facial emotion recognition. Sensitivity and response bias for facial emotion recognition were calculated using a d-prime value and a c index respectively. Our study is the first to employ the EIS-F scale for assessing facial emotion recognition among PD patients; to test its validity as an assessment tool, a group comprising schizophrenia patients and healthy controls were also tested. Patients with PD recognized emotions with less accuracy than healthy individuals (d-prime) and used a more liberal response criterion (c index). By contrast, patients with schizophrenia merely showed diminished sensitivity (d-prime). Our results suggest that an impaired ability to recognize facial emotions in PD patients may result from both decreased sensitivity and a significantly more liberal response criteria, whereas facial emotion recognition in schizophrenia may stem from a generalized sensory impairment only. PMID- 26441789 TI - Brain lateralization and self-reported symptoms of ADHD in a population sample of adults: a dimensional approach. AB - Many clinical studies reported a compromised brain lateralization in patients with Attention-Deficit/Hyperactivity Disorder (ADHD) without being conclusive about whether the deficit existed in the left or right hemisphere. It is well recognized that studying ADHD dimensionally is more controlled for comorbid problems and medication effects, and provides more accurate assessment of the symptoms. Therefore, the present study applied the dimensional approach to test the relationship between brain lateralization and self-reported ADHD symptoms in a population sample. Eighty-five right-handed university students filled in the Conners' Adult ADHD Rating Scales and performed a lateralization reaction time task. The task consists of two matching conditions: one condition requires nominal identification for letters tapping left hemisphere specialization (Letter Name-Identity condition) and the other one requires physical and visuospatial identification for shapes tapping right hemisphere specialization (Shape Physical Identity condition). The letters or shapes to be matched are presented in left or right visual field of a fixation cross. For both task conditions, brain lateralization was indexed as the difference in mean reaction time between left and right visual field. Linear regression analyses, controlled for mood symptoms reported by a depression, anxiety, and stress scale, showed no relationship between the variables. These findings from a population sample of adults do not support the dimensionality of lateralized information processing deficit in ADHD symptomatology. However, group comparison analyses showed that subjects with high level of inattention symptoms close to or above the clinical cut-off had a reduced right hemisphere processing in the Shape Physical-Identity condition. PMID- 26441790 TI - Neural correlates of cognitive aging during the perception of facial age: the role of relatively distant and local texture information. AB - Previous event-related potential (ERP) research revealed that older relative to younger adults show reduced inversion effects in the N170 (with more negative amplitudes for inverted than upright faces), suggestive of impairments in face perception. However, as these studies used young to middle-aged faces only, this finding may reflect preferential processing of own- relative to other-age faces rather than age-related decline. We conducted an ERP study in which young and older participants categorized young and old upright or inverted faces by age. Stimuli were presented either unfiltered or low-pass filtered at 30, 20, or 10 cycles per image (CPI). Response times revealed larger inversion effects, with slower responses for inverted faces, for young faces in young participants. Older participants did not show a corresponding effect. ERPs yielded a trend toward reduced N170 inversion effects in older relative to younger adults independent of face age. Moreover, larger inversion effects for young relative to old faces were detected, and filtering resulted in smaller N170 amplitudes. The reduced N170 inversion effect in older adults may reflect age-related changes in neural correlates of face perception. A smaller N170 inversion effect for old faces may indicate that facial changes with age hamper early face perception stages. PMID- 26441791 TI - Linguistic explanation and domain specialization: a case study in bound variable anaphora. AB - The core question behind this Frontiers research topic is whether explaining linguistic phenomena requires appeal to properties of human cognition that are specialized to language. We argue here that investigating this issue requires taking linguistic research results seriously, and evaluating these for domain specificity. We present a particular empirical phenomenon, bound variable interpretations of pronouns dependent on a quantifier phrase, and argue for a particular theory of this empirical domain that is couched at a level of theoretical depth which allows its principles to be evaluated for domain specialization. We argue that the relevant principles are specialized when they apply in the domain of language, even if analogs of them are plausibly at work elsewhere in cognition or the natural world more generally. So certain principles may be specialized to language, though not, ultimately, unique to it. Such specialization is underpinned by ultimately biological factors, hence part of UG. PMID- 26441792 TI - "A letter for Dr. Outgroup": on the effects of an indicator of competence and chances for altruism toward a member of a stigmatized out-group. AB - The lost letter technique is an unobtrusive method to investigate attitudes in a particular population. Ostensibly lost letters from senders who apparently belong to different groups or addressed to recipients from apparently different groups are dispersed in public places, and return rates represent a measure of altruistic or discriminatory behavior toward one group or another. In two field experiments using the lost letter technique, we investigated the influence of group membership and the presence or absence of a doctorate degree as an indicator of competence on the likelihood of receiving helping behavior. Experiment 1 showed that a generic member of a low-status ethnic out-group (Turks living in Germany) was the target of discrimination, while a generic member of a non-stigmatized out-group (French in Germany) was not. Moreover, when the name of the member from the stigmatized out-group was (vs. was not) preceded by a doctorate degree, more of the allegedly lost letters were returned. There were no such differential effects for recipients who were members of the in-group (Germans) or the non-stigmatized out-group (French). Experiment 2 showed that a recipient from the stigmatized out-group (Turk) with a doctorate degree received more letters when the sender was German versus Turkish (i.e., from the recipient's own group). Overall, the sender's ethnic group membership was an important factor for the likelihood of receiving an ostensibly lost letter, in that fewer letters arrived from a sender with a Turkish (vs. German) name. We conclude that the likelihood of altruistic behavior toward out-group members can increase when in-group members intend to communicate with competent out-group members. Therefore, under certain conditions, the presentation of a highly competent member of an otherwise stigmatized out-group may serve as a discrimination buffer. PMID- 26441793 TI - The duality of gaze: eyes extract and signal social information during sustained cooperative and competitive dyadic gaze. AB - In contrast to non-human primate eyes, which have a dark sclera surrounding a dark iris, human eyes have a white sclera that surrounds a dark iris. This high contrast morphology allows humans to determine quickly and easily where others are looking and infer what they are attending to. In recent years an enormous body of work has used photos and schematic images of faces to study these aspects of social attention, e.g., the selection of the eyes of others and the shift of attention to where those eyes are directed. However, evolutionary theory holds that humans did not develop a high contrast morphology simply to use the eyes of others as attentional cues; rather they sacrificed camouflage for communication, that is, to signal their thoughts and intentions to others. In the present study we demonstrate the importance of this by taking as our starting point the hypothesis that a cornerstone of non-verbal communication is the eye contact between individuals and the time that it is held. In a single simple study we show experimentally that the effect of eye contact can be quickly and profoundly altered merely by having participants, who had never met before, play a game in a cooperative or competitive manner. After the game participants were asked to make eye contact for a prolonged period of time (10 min). Those who had played the game cooperatively found this terribly difficult to do, repeatedly talking and breaking gaze. In contrast, those who had played the game competitively were able to stare quietly at each other for a sustained period. Collectively these data demonstrate that when looking at the eyes of a real person one both acquires and signals information to the other person. This duality of gaze is critical to non verbal communication, with the nature of that communication shaped by the relationship between individuals, e.g., cooperative or competitive. PMID- 26441794 TI - The linguistic roots of natural pedagogy. AB - Natural pedagogy is a human-specific capacity that allows us to acquire cultural information from communication even before the emergence of the first words, encompassing three core elements: (i) a sensitivity to ostensive signals like eye contact that indicate to infants that they are being addressed through communication, (ii) a subsequent referential expectation (satisfied by the use of declarative gestures) and (iii) a biased interpretation of ostensive-referential communication as conveying relevant information about the referent's kind (Csibra and Gergely, 2006, 2009, 2011). Remarkably, the link between natural pedagogy and another human-specific capacity, namely language, has rarely been investigated in detail. We here argue that children's production and comprehension of declarative gestures around 10 months of age are in fact expressions of an evolving faculty of language. Through both declarative gestures and ostensive signals, infants can assign the roles of third, second, and first person, building the 'deictic space' that grounds both natural pedagogy and language use. Secondly, we argue that the emergence of two kinds of linguistic structures (i.e., proto-determiner phrases and proto-sentences) in the one-word period sheds light on the different kinds of information that children can acquire or convey at different stages of development (namely, generic knowledge about kinds and knowledge about particular events/actions/state of affairs, respectively). Furthermore, the development of nominal and temporal reference in speech allows children to cognize information in terms of spatial and temporal relations. In this way, natural pedagogy transpires as an inherent aspect of our faculty of language, rather than as an independent adaptation that pre-dates language in evolution or development (Csibra and Gergely, 2006). This hypothesis is further testable through predictions it makes on the different linguistic profiles of toddlers with developmental disorders. PMID- 26441795 TI - Neuroenhancement and the strength model of self-control. AB - Neuroenhancement (NE), the use of substances as a means to enhance performance, has garnered considerable scientific attention of late. While ethical and epidemiological publications on the topic accumulate, there is a lack of theory driven psychological research that aims at understanding psychological drivers of NE. In this perspective article we argue that self-control strength offers a promising theory-based approach to further understand and investigate NE behavior. Using the strength model of self-control, we derive two theory-driven perspectives on NE-self-control research. First, we propose that individual differences in state/trait self-control strength differentially affect NE behavior based on one's individual experience of NE use. Building upon this, we outline promising research questions that (will) further elucidate our understanding of NE based on the strength model's propositions. Second, we discuss evidence indicating that popular NE substances (like Methylphenidate) may counteract imminent losses of self-control strength. We outline how further research on NE's effects on the ego-depletion effect may further broaden our understanding of the strength model of self-control. PMID- 26441797 TI - Perceptual influence of elementary three-dimensional geometry: (2) fundamental object parts. AB - Objects usually consist of parts and the question arises whether there are perceptual features which allow breaking down an object into its fundamental parts without any additional (e.g., functional) information. As in the first paper of this sequence, we focus on the division of our world along convex to concave surface transitions. Here we are using machine vision to produce convex segments from 3D-scenes. We assume that a fundamental part is one, which we can easily name while at the same time there is no natural subdivision possible into smaller parts. Hence in this experiment we presented the computer vision generated segments to our participants and asked whether they can identify and name them. Additionally we control against segmentation reliability and we find a clear trend that reliable convex segments have a high degree of name-ability. In addition, we observed that using other image-segmentation methods will not yield nameable entities. This indicates that convex-concave surface transition may indeed form the basis for dividing objects into meaningful entities. It appears that other or further subdivisions do not carry such a strong semantical link to our everyday language as there are no names for them. PMID- 26441796 TI - Theory-of-mind in individuals with Alstrom syndrome is related to executive functions, and verbal ability. AB - OBJECTIVE: This study focuses on cognitive prerequisites for the development of theory-of-mind (ToM), the ability to impute mental states to self and others in young adults with Alstrom syndrome (AS). AS is a rare and quite recently described recessively inherited ciliopathic disorder which causes progressive sensorineural hearing loss and juvenile blindness, as well as many other organ dysfunctions. Two cognitive abilities were considered; Phonological working memory (WM) and executive functions (EF), both of importance in speech development. METHODS: Ten individuals (18-37 years) diagnosed with AS, and 20 individuals with no known impairment matched for age, gender, and educational level participated. Sensory functions were measured. Information about motor functions and communicative skills was obtained from responses to a questionnaire. ToM was assessed using Happes strange stories, verbal ability by a vocabulary test, phonological WM by means of an auditory presented non-word serial recall task and EF by tests of updating and inhibition. RESULTS: The AS group performed at a significantly lower level than the control group in both the ToM task and the EF tasks. A significant correlation was observed between recall of non-words and EF in the AS group. Updating, but not inhibition, correlated significantly with verbal ability, whereas both updating and inhibition were significantly related to the ability to initiate and sustain communication. Poorer performance in the ToM and EF tasks were related to language perseverance and motor mannerisms. CONCLUSION: The AS group displayed a delayed ToM as well as reduced phonological WM, EF, and verbal ability. A significant association between ToM and EF, suggests a compensatory role of EF. This association may reflect the importance of EF to perceive and process input from the social environment when the social interaction is challenged by dual sensory loss. We argue that limitations in EF capacity in individuals with AS, to some extent, may be related to early blindness and progressive hearing loss, but maybe also to gene specific abnormalities. PMID- 26441798 TI - Commentary: Unlearning implicit social biases during sleep. PMID- 26441799 TI - The simultaneous perception of auditory-tactile stimuli in voluntary movement. AB - The simultaneous perception of multimodal information in the environment during voluntary movement is very important for effective reactions to the environment. Previous studies have found that voluntary movement affects the simultaneous perception of auditory and tactile stimuli. However, the results of these experiments are not completely consistent, and the differences may be attributable to methodological differences in the previous studies. In this study, we investigated the effect of voluntary movement on the simultaneous perception of auditory and tactile stimuli using a temporal order judgment task with voluntary movement, involuntary movement, and no movement. To eliminate the potential effect of stimulus predictability and the effect of spatial information associated with large-scale movement in the previous studies, we randomized the interval between the start of movement and the first stimulus, and used small scale movement. As a result, the point of subjective simultaneity (PSS) during voluntary movement shifted from the tactile stimulus being first during involuntary movement or no movement to the auditory stimulus being first. The just noticeable difference (JND), an indicator of temporal resolution, did not differ across the three conditions. These results indicate that voluntary movement itself affects the PSS in auditory-tactile simultaneous perception, but it does not influence the JND. In the discussion of these results, we suggest that simultaneous perception may be affected by the efference copy. PMID- 26441800 TI - The eye-voice span during reading aloud. AB - Although eye movements during reading are modulated by cognitive processing demands, they also reflect visual sampling of the input, and possibly preparation of output for speech or the inner voice. By simultaneously recording eye movements and the voice during reading aloud, we obtained an output measure that constrains the length of time spent on cognitive processing. Here we investigate the dynamics of the eye-voice span (EVS), the distance between eye and voice. We show that the EVS is regulated immediately during fixation of a word by either increasing fixation duration or programming a regressive eye movement against the reading direction. EVS size at the beginning of a fixation was positively correlated with the likelihood of regressions and refixations. Regression probability was further increased if the EVS was still large at the end of a fixation: if adjustment of fixation duration did not sufficiently reduce the EVS during a fixation, then a regression rather than a refixation followed with high probability. We further show that the EVS can help understand cognitive influences on fixation duration during reading: in mixed model analyses, the EVS was a stronger predictor of fixation durations than either word frequency or word length. The EVS modulated the influence of several other predictors on single fixation durations (SFDs). For example, word-N frequency effects were larger with a large EVS, especially when word N-1 frequency was low. Finally, a comparison of SFDs during oral and silent reading showed that reading is governed by similar principles in both reading modes, although EVS maintenance and articulatory processing also cause some differences. In summary, the EVS is regulated by adjusting fixation duration and/or by programming a regressive eye movement when the EVS gets too large. Overall, the EVS appears to be directly related to updating of the working memory buffer during reading. PMID- 26441801 TI - Adoptive parenting and attachment: association of the internal working models between adoptive mothers and their late-adopted children during adolescence. AB - INTRODUCTION: Recent literature has shown that the good outcome of adoption would mostly depend on the quality of adoptive parenting, which is strongly associated with the security of parental internal working models (IWMs) of attachment. Specifically, attachment states-of-mind of adoptive mothers classified as free and autonomous and without lack of resolution of loss or trauma could represent a good protective factor for adopted children, previously maltreated and neglected. While most research on adoptive families focused on pre-school and school-aged children, the aim of this study was to assess the concordance of IWMs of attachment in adoptive dyads during adolescence. METHOD: Our pilot-study involved 76 participants: 30 adoptive mothers (mean age = 51.5 +/- 4.3), and their 46 late adopted adolescents (mean age = 13.9 +/- 1.6), who were all aged 4-9 years old at time of adoption (mean age = 6.3 +/- 1.5). Attachment representations of adopted adolescents were assessed by the Friend and Family Interview (FFI), while adoptive mothers' state-of-mind with respect to attachment was classified by the Adult Attachment Interview (AAI). Adolescents' verbal intelligence was controlled for. RESULTS: Late-adopted adolescents were classified as follows: 67% secure, 26% dismissing, and 7% preoccupied in the FFI, while their adoptive mothers' AAI classifications were 70% free-autonomous, 7% dismissing, and 23% unresolved. We found a significant concordance of 70% (32 dyads) between the secure-insecure FFI and AAI classifications. Specifically adoptive mothers with high coherence of transcript and low unresolved loss tend to have late-adopted children with high secure attachment, even if the adolescents' verbal intelligence made a significant contribution to this prediction. DISCUSSION: Our results provides an empirical contribution to the literature concerning the concordance of attachment in adoptive dyads, highlighting the beneficial impact of highly coherent states of-mind of adoptive mothers on the attachment representations of their late adopted adolescent children. PMID- 26441802 TI - Why language really is not a communication system: a cognitive view of language evolution. AB - While most evolutionary scenarios for language see it as a communication system with consequences on the language-ready brain, there are major difficulties for such a view. First, language has a core combination of features-semanticity, discrete infinity, and decoupling-that makes it unique among communication systems and that raise deep problems for the view that it evolved for communication. Second, extant models of communication systems-the code model of communication (Millikan, 2005) and the ostensive model of communication (Scott Phillips, 2015) cannot account for language evolution. I propose an alternative view, according to which language first evolved as a cognitive tool, following Fodor's (1975, 2008) Language of Thought Hypothesis, and was then exapted (externalized) for communication. On this view, a language-ready brain is a brain profoundly reorganized in terms of connectivity, allowing the human conceptual system to emerge, triggering the emergence of syntax. Language as used in communication inherited its core combination of features from the Language of Thought. PMID- 26441803 TI - Learning from history: the need for a synthetic approach to human cognition. PMID- 26441804 TI - Happiness in texting times. AB - Assessing national levels of happiness has become an important research and policy issue in recent years. We examined happiness and satisfaction in Ireland using phone text messaging to collect large-scale longitudinal data from 3,093 members of the general Irish population. For six consecutive weeks, participants' happiness and satisfaction levels were assessed. For four consecutive weeks (weeks 2-5) a different random third of the sample got feedback on the previous week's mean happiness and satisfaction ratings. Text messaging proved a feasible means of assessing happiness and satisfaction, with almost three quarters (73%) of participants completing all assessments. Those who received feedback on the previous week's mean ratings were eight times more likely to complete the subsequent assessments than those not receiving feedback. Providing such feedback data on mean levels of happiness and satisfaction did not systematically bias subsequent ratings either toward or away from these normative anchors. Texting is a simple and effective means to collect population level happiness and satisfaction data. PMID- 26441805 TI - Warm-hearted businessmen, competitive housewives? Effects of gender-fair language on adolescents' perceptions of occupations. AB - Recent studies from countries with grammatical gender languages (e.g., French) found both children and adults to more frequently think of female jobholders and to consider women's success in male dominated occupations more likely when the jobs were described in pair forms (i.e., by explicit reference to male and female jobholders, e.g., inventeuses et inventeurs; French feminine and masculine plural forms for inventors), rather than masculine only forms (e.g., inventors). To gain a better understanding of this phenomenon, we systematically varied the gender connotation of occupations (males overrepresented, females overrepresented, equal share of males and females) and measured additional dependent variables, predicting that gender fair language would reduce the impact of the gender connotation on participants' perceptions. In a sample of 222 adolescents (aged 12 17) from French speaking Switzerland, we found that pair forms attenuated the difference in the ascription of success to male and female jobholders in gendered occupations and attenuated the differential ascription of warmth to prototypical jobholders in male vs. female dominated jobs. However, no effect of language form on the ascription of competence was found. These findings suggest that language policies are an effective tool to impact gendered perceptions, however, they also hint at competence-related gender stereotypes being in decline. PMID- 26441806 TI - Using item response theory to investigate the structure of anticipated affect: do self-reports about future affective reactions conform to typical or maximal models? AB - In the present research, we used item response theory (IRT) to examine whether effective predictions (anticipated affect) conforms to a typical (i.e., what people usually do) or a maximal behavior process (i.e., what people can do). The former, correspond to non-monotonic ideal point IRT models, whereas the latter correspond to monotonic dominance IRT models. A convenience, cross-sectional student sample (N = 1624) was used. Participants were asked to report on anticipated positive and negative affect around a hypothetical event (emotions surrounding the start of a new business). We carried out analysis comparing graded response model (GRM), a dominance IRT model, against generalized graded unfolding model, an unfolding IRT model. We found that the GRM provided a better fit to the data. Findings suggest that the self-report responses to anticipated affect conform to dominance response process (i.e., maximal behavior). The paper also discusses implications for a growing literature on anticipated affect. PMID- 26441807 TI - Watch the target! Effects in the affective misattribution procedure become weaker (but not eliminated) when participants are motivated to provide accurate responses to the target. AB - Previous research showed that priming effects in the affective misattribution procedure (AMP) are unaffected by direct warnings to avoid an influence of the primes. The present research examined whether a priming influence is diminished by task procedures that encourage accurate judgments of the targets. Participants were motivated to categorize the affective meaning of nonsense targets accurately by being made to believe that a true word was presented in each trial and by providing feedback on (allegedly) incorrect responses. This condition produced robust priming effects. Priming was however reduced and less reliable relative to more typical AMP conditions in which participants guessed the meaning of openly presented nonsense targets. Affective judgments of nonsense targets were not affected by advance knowledge of the response mapping during the priming phase, which argues against a response-priming explanation of AMP effects. These findings show that affective primes influence evaluative judgments even in conditions in which the motivation to provide accurate responses is high and a priming of motor responses is not possible. Priming effects were however weaker with high accuracy motivation, suggesting that a focus on accurate judgments is an effective strategy to control for an unwanted priming influence in the AMP. PMID- 26441808 TI - Antecedents of maternal parenting stress: the role of attachment style, prenatal attachment, and dyadic adjustment in first-time mothers. AB - The transition to parenthood is widely considered a period of increased vulnerability often accompanied by stress. Abidin conceived parenting stress as referring to specific difficulties in adjusting to the parenting role. Most studies of psychological distress arising from the demands of parenting have investigated the impact of stress on the development of dysfunctional parent child relationships and on adult and child psychopathology. Studies have largely focused on mothers' postnatal experience; less attention has been devoted to maternal prenatal characteristics associated with subsequent parental stress and studies of maternal prenatal predictors are few. Furthermore, no studies have examined that association exclusively with samples of first-time mothers. With an observational prospective study design with two time periods, the aim of this study was to investigate the role of mothers' attachment style, maternal prenatal attachment to the fetus and dyadic adjustment during pregnancy (7th months of gestation) and their potential unique contribution to parenting stress 3 months after childbirth in a sample of nulliparous women. Results showed significant correlations between antenatal measures. Maternal attachment style (especially relationship anxiety) was negatively correlated with prenatal attachment and with dyadic adjustment; positive correlations resulted between prenatal attachment and dyadic adjustment. Each of the investigated variables was also good predictor of parenting stress 3 months after childbirth. Findings suggested how these dimensions could be considered as risk factors in the transition to motherhood and in the very beginning of the emergence of the caregiving system, especially with first-time mothers. PMID- 26441809 TI - Measuring strategic control in implicit learning: how and why? AB - Several methods have been developed for measuring the extent to which implicitly learned knowledge can be applied in a strategic, flexible manner. Examples include generation exclusion tasks in Serial Reaction Time (SRT) learning (Goschke, 1998; Destrebecqz and Cleeremans, 2001) and 2-grammar classification tasks in Artificial Grammar Learning (AGL; Dienes et al., 1995; Norman et al., 2011). Strategic control has traditionally been used as a criterion for determining whether acquired knowledge is conscious or unconscious, or which properties of knowledge are consciously available. In this paper I first summarize existing methods that have been developed for measuring strategic control in the SRT and AGL tasks. I then address some methodological and theoretical questions. Methodological questions concern choice of task, whether the measurement reflects inhibitory control or task switching, and whether or not strategic control should be measured on a trial-by-trial basis. Theoretical questions concern the rationale for including measurement of strategic control, what form of knowledge is strategically controlled, and how strategic control can be combined with subjective awareness measures. PMID- 26441810 TI - How should we measure chunks? a continuing issue in chunking research and a way forward. PMID- 26441811 TI - Influence of adult attachment insecurities on parenting self-esteem: the mediating role of dyadic adjustment. AB - BACKGROUND: Parenting self-esteem includes two global components, parents' self efficacy and satisfaction with their parental role, and has a crucial role in parent-child interactions. The purpose of this study was to develop an integrative model linking adult attachment insecurities, dyadic adjustment, and parenting self-esteem. METHODS: The study involved 118 pairs (236 subjects) of heterosexual parents of a firstborn child aged 0-6 years. They were administered the Experiences in Close Relationships-Revised (ECR-R) questionnaire, the Dyadic Adjustment Scale, and the Parenting Sense of Competence Scale. RESULTS: Path analysis was used to design and test a theoretical integrative model, achieving a good fit with the data. Findings showed that dyadic adjustment mediates the negative influence on parenting self-efficacy of both attachment anxiety and attachment avoidance. Parenting satisfaction is positively influenced by parenting self-efficacy and negatively affected by child's age. Attachment anxiety negatively influences parenting satisfaction. CONCLUSION: Our findings are in line with the theoretical expectations and have promising implications for future research and intervention programs designed to improve parenting self esteem. PMID- 26441812 TI - Historical roots of histrionic personality disorder. AB - Histrionic Personality Disorder is one of the most ambiguous diagnostic categories in psychiatry. Hysteria is a classical term that includes a wide variety of psychopathological states. Ancient Egyptians and Greeks blamed a displaced womb, for many women's afflictions. Several researchers from the 18th and 19th centuries studied this theme, namely, Charcot who defined hysteria as a "neurosis" with an organic basis and Sigmund Freud who redefined "neurosis" as a re-experience of past psychological trauma. Histrionic personality disorder (HPD) made its first official appearance in the Diagnostic and Statistical Manual of Mental Disorders II (DSM-II) and since the DSM-III, HPD is the only disorder that kept the term derived from the old concept of hysteria. The subject of hysteria has reflected positions about health, religion and relationships between the sexes in the last 4000 years, and the discussion is likely to continue. PMID- 26441813 TI - Skin to skin interactions. Does the infant massage improve the couple functioning? AB - Transition to parenthood is a critical stage of life due to several changes the couple has to handle. A large body of studies described how transition to parenthood can be linked to the onset of depressive symptoms, as well as the perception of a low social support, and an increased stress, representing a risk for the early mother-baby relationship. Infant massage (IM) emerged as a helpful tool to improve maternal skills in interacting with the baby, and leading toward a decreasing of post-partum symptoms. However, a growing body of literature highlights that men also may experience post-partum diseases, representing an additional risk for the development of the baby. To date, no study observed the impact of the IM on both partners. The aim of the current qualitative research is to observe the impact of the IM on a single couple of parents at childbirth. Pre (Time 1) and post-intervention (Time 3) procedure has been established to observe the changes occurring over the time in the couple. In particular, each member of the couple filled out the EPDS, the BDI-II, the MSPSS, and the PSI-SF both at Time 1 and at Time 3. The treatment (Time 2) was represented by the IM training, and lasted 4 weeks. Findings revealed a decrease in depressive symptoms in both partners, as well as an improvement of their perception of stress related to parental role. No changes has been detected with respect to the perception of social support. The IM seems to be a helpful approach to prevent the establishment of pathological conditions in new parents. Although no direct measures on the child were used, the current qualitative data seem to suggest that the IM may represent a valuable tool to prevent the onset of early negative outcomes of the baby. Further investigations and empirical data are needed to improve the knowledge in this field. PMID- 26441814 TI - Attentional bias in competitive situations: winner does not take all. AB - Compared to previous studies of competition with participants' direct involvement, the current study for the first time investigated the influence of competitive outcomes on attentional bias from a perspective of an onlooker. Two simple games were employed: the Rock-Paper-Scissors game (Experiment 1) in which the outcome is based on luck, and Arm-wrestling (Experiment 2), in which the outcome is based on the competitors' strength. After observing one of these games, participants were asked to judge a stimulus presented on either the winner's or loser's side of a screen. Both experiments yielded the same results, indicating that the onlookers made much quicker judgments on stimuli presented on the loser's side than the winner's side. This suggests the existence of an attention bias for loser-related information once a competition has ended. Our findings provide a new lens through which the influence of competition results on human cognitive processing can be understood. PMID- 26441815 TI - Frequency-dependent changes in the amplitude of low-frequency fluctuations in internet gaming disorder. AB - Neuroimaging studies have revealed that the task-related functional brain activities are impaired in internet gaming disorder (IGD) subjects. However, little is known about the alternations in spontaneous brain activities about them. Recent studies have proposed that the brain activities of different frequency ranges are generated by different nervous activities and have different physiological and psychological functions. Thus, in this study, we set to explore the spontaneous brain activities in IGD subjects by measuring the fractional amplitude of low-frequency fluctuation (fALFF), to investigate band-specific changes of resting-state fALFF. We subdivided the frequency range into five bands based on literatures. Comparing to healthy controls, the IGD group showed decreased fALFF values in the cerebellum posterior lobe and increased fALFF values in superior temporal gyrus. Significant interactions between frequency bands and groups were found in the cerebellum, the anterior cingulate, the lingual gyrus, the middle temporal gyrus, and the middle frontal gyrus. Those brain regions are proved related to the executive function and decision-making. These results revealed the changed spontaneous brain activity of IGD, which contributed to understanding the underlying pathophysiology of IGD. PMID- 26441816 TI - Functional MRI Preprocessing in Lesioned Brains: Manual Versus Automated Region of Interest Analysis. AB - Functional magnetic resonance imaging (fMRI) has significant potential in the study and treatment of neurological disorders and stroke. Region of interest (ROI) analysis in such studies allows for testing of strong a priori clinical hypotheses with improved statistical power. A commonly used automated approach to ROI analysis is to spatially normalize each participant's structural brain image to a template brain image and define ROIs using an atlas. However, in studies of individuals with structural brain lesions, such as stroke, the gold standard approach may be to manually hand-draw ROIs on each participant's non-normalized structural brain image. Automated approaches to ROI analysis are faster and more standardized, yet are susceptible to preprocessing error (e.g., normalization error) that can be greater in lesioned brains. The manual approach to ROI analysis has high demand for time and expertise, but may provide a more accurate estimate of brain response. In this study, commonly used automated and manual approaches to ROI analysis were directly compared by reanalyzing data from a previously published hypothesis-driven cognitive fMRI study, involving individuals with stroke. The ROI evaluated is the pars opercularis of the inferior frontal gyrus. Significant differences were identified in task-related effect size and percent-activated voxels in this ROI between the automated and manual approaches to ROI analysis. Task interactions, however, were consistent across ROI analysis approaches. These findings support the use of automated approaches to ROI analysis in studies of lesioned brains, provided they employ a task interaction design. PMID- 26441817 TI - A Role for Fragment-Based Drug Design in Developing Novel Lead Compounds for Central Nervous System Targets. AB - Hundreds of millions of U.S. dollars are invested in the research and development of a single drug. Lead compound development is an area ripe for new design strategies. Therapeutic lead candidates have been traditionally found using high throughput in vitro pharmacological screening, a costly method for assaying thousands of compounds. This approach has recently been augmented by virtual screening (VS), which employs computer models of the target protein to narrow the search for possible leads. A variant of VS is fragment-based drug design (FBDD), an emerging in silico lead discovery method that introduces low-molecular weight fragments, rather than intact compounds, into the binding pocket of the receptor model. These fragments serve as starting points for "growing" the lead candidate. Current efforts in virtual FBDD within central nervous system (CNS) targets are reviewed, as is a recent rule-based optimization strategy in which new molecules are generated within a 3D receptor-binding pocket using the fragment as a scaffold. This process not only places special emphasis on creating synthesizable molecules but also exposes computational questions worth addressing. Fragment based methods provide a viable, relatively low-cost alternative for therapeutic lead discovery and optimization that can be applied to CNS targets to augment current design strategies. PMID- 26441818 TI - Therapeutic Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy - Where to from Here? AB - Hypoxia-ischemia before or around the time of birth occurs in approximately 2/1000 live births and is associated with a high risk of death or lifelong disability. Therapeutic hypothermia is now well established as standard treatment for infants with moderate to severe hypoxic-ischemic encephalopathy but is only partially effective. There is compelling preclinical and clinical evidence that hypothermia is most protective when it is started as early as possible after hypoxia-ischemia. Further improvements in outcome from therapeutic hypothermia are very likely to arise from strategies to reduce the delay before starting treatment of affected infants. In this review, we examine evidence that current protocols are reasonably close to the optimal depth and duration of cooling, but that the optimal rate of rewarming after hypothermia is unclear. The potential for combination treatments to augment hypothermic neuroprotection has considerable promise, particularly with endogenous targets such as melatonin and erythropoietin, and noble gases such as xenon. We dissect the critical importance of preclinical studies using realistic delays in treatment and clinically relevant cooling protocols when examining combination treatment, and that for many strategies overlapping mechanisms of action can substantially attenuate any effects. PMID- 26441820 TI - End of OSLER Test Sessions in Parkinson's Disease do not Correspond to True Sleep Onset: Results from an Exploratory Study. AB - The aim of the present study was to evaluate the correlation between the end of an Oxford sleep resistance (OSLER) test session and a neurophysiological marker of sleep onset in Parkinson's disease (PD) patients. Single center study was conducted in PD patients with excessive daytime sleepiness [Epworth sleepiness scale (ESS) >9]. The OSLER test was conducted with a concomitant electroencephalography (EEG), electromyography (mentalis), right and left electroculogram, and video monitoring. Neurophysiological (NP) sleep onset was defined according to AASM criteria (2005). Five PD patients with mean ESS of 14 (10-16) were included. OSLER test duration was shorter than 40 min in all patients (mean duration 20 min and 39 s). No patient fulfilled neurophysiological criteria to sleep onset at the time of OSLER test termination. In 13 OSLER sessions that ended before 40 min, eight had microsleeps in the last 30 s before the end of the test. NP monitoring showed signs of sleepiness in all patients. In PD patients, the early termination of an OSLER test session may not correspond to NP criteria of sleep onset. However, in all PD patients with abnormal OSLER results, there were EEG signs of sleepiness, which do not exclude the potential utility of OSLER test to evaluate the risk of falling asleep. PMID- 26441819 TI - Pushing the Limits: Chronotype and Time of Day Modulate Working Memory-Dependent Cerebral Activity. AB - Morning-type individuals experience more difficulties to maintain optimal attentional performance throughout a normal waking day than evening types. However, time-of-day modulations may differ across cognitive domains. Using functional magnetic resonance imaging (fMRI), we investigated how chronotype and time of day interact with working memory at different levels of cognitive load/complexity in a N-back paradigm (N0-, N2-, and N3-back levels). Extreme morning- and evening-type individuals underwent two fMRI sessions during N-back performance, one 1.5 h (morning) and one 10.5 h (evening) after wake-up time scheduled according to their habitual sleep-wake preference. At the behavioral level, increasing working memory load resulted in lower accuracy while chronotype and time of day only exerted a marginal impact on performance. Analyses of neuroimaging data disclosed an interaction between chronotype, time of day, and the modulation of cerebral activity by working memory load in the thalamus and in the middle frontal cortex. In the subjective evening hours, evening types exhibited higher thalamic activity than morning types at the highest working memory load condition only (N3-back). Conversely, morning-type individuals exhibited higher activity than evening-type participants in the middle frontal gyrus during the morning session in the N3-back condition. Our data emphasize interindividual differences in time-of-day preferences and underlying cerebral activity, which should be taken into account when investigating vigilance state effects in task-related brain activity. These results support the hypothesis that higher task complexity leads to a chronotype-dependent increase in thalamic and frontal brain activity, permitting stabilization of working memory performance across the day. PMID- 26441821 TI - Reconciling Magnetically Induced Vertigo and Nystagmus. PMID- 26441822 TI - New Cerebral Microbleeds and Mechanism of Post-Thrombolysis Remote Intracerebral Hemorrhage: "Red Meets White" Revisited. PMID- 26441823 TI - Protein Citrullination: A Proposed Mechanism for Pathology in Traumatic Brain Injury. AB - Protein citrullination is a calcium-driven post-translational modification proposed to play a causative role in the neurodegenerative disorders of Alzheimer's disease, multiple sclerosis (MS), and prion disease. Citrullination can result in the formation of antigenic epitopes that underlie pathogenic autoimmune responses. This phenomenon, which is best understood in rheumatoid arthritis, may play a role in the chronic dysfunction following traumatic brain injury (TBI). Despite substantial evidence of aberrations in calcium signaling following TBI, there is little understanding of how TBI alters citrullination in the brain. The present investigation addressed this gap by examining the effects of TBI on the distribution of protein citrullination and on the specific cell types involved. Immunofluorescence revealed that controlled cortical impact in rats profoundly up--regulated protein citrullination in the cerebral cortex, external capsule, and hippocampus. This response was exclusively seen in astrocytes; no such effects were observed on the status of protein citrullination in neurons, oligodendrocytes or microglia. Further, proteomic analyses demonstrated that the effects of TBI on citrullination were confined to a relatively small subset of neural proteins. Proteins most notably affected were those also reported to be citrullinated in other disorders, including prion disease and MS. In vivo findings were extended in an in vitro model of simulated TBI employing normal human astrocytes. Pharmacologically induced calcium excitotoxicity was shown to activate the citrullination and breakdown of glial fibrillary acidic protein, producing a novel candidate TBI biomarker and potential target for autoimmune recognition. In summary, these findings demonstrate that the effects of TBI on protein citrullination are selective with respect to brain region, cell type, and proteins modified, and may contribute to a role for autoimmune dysfunction in chronic pathology following TBI. PMID- 26441824 TI - The Effects of Aging on Clinical Vestibular Evaluations. AB - Balance disorders are common issues for aging populations due to the effects of normal aging on peripheral vestibular structures. These changes affect the results of vestibular function evaluations and make the interpretation of these results more difficult. The objective of this article is to review the current state of knowledge of clinically relevant vestibular measures. We will first focus on otolith function assessment methods cervical-VEMP (cVEMP) and ocular VEMP (oVEMP), then the caloric and video-head impulse test (vHIT) methods for semicircular canals assessment. cVEMP and oVEMP are useful methods, though research on the effects of age for some parameters are still inconclusive. vHIT results are largely independent of age as compared to caloric stimulation and should therefore be preferred for the evaluation of the semicircular canals function. PMID- 26441825 TI - Anti-Abeta Autoantibodies in Amyloid Related Imaging Abnormalities (ARIA): Candidate Biomarker for Immunotherapy in Alzheimer's Disease and Cerebral Amyloid Angiopathy. AB - Amyloid-related imaging abnormalities (ARIA) represent the major severe side effect of amyloid-beta (Abeta) immunotherapy for Alzheimer's disease (AD). Early biomarkers of ARIA represent an important challenge to ensure safe and beneficial effects of immunotherapies, given that different promising clinical trials in prodromal and subjects at risk for AD are underway. The recent demonstration that cerebrospinal fluid (CSF) anti-Abeta autoantibodies play a key role in the development of the ARIA-like events characterizing cerebral amyloid angiopathy related inflammation generated great interest in the field of immunotherapy. Herein, we critically review the growing body of evidence supporting the monitoring of CSF anti-Abeta autoantibody as a promising candidate biomarker for ARIA in clinical trials. PMID- 26441827 TI - In a Class of Their Own - RXFP1 and RXFP2 are Unique Members of the LGR Family. AB - The leucine-rich repeat-containing G protein-coupled receptors (LGRs) family consists of three groups: types A, B, and C and all contain a large extracellular domain (ECD) made up of the structural motif - the leucine-rich repeat (LRR). In the LGRs, the ECD binds the hormone or ligand, usually through the LRRs, that ultimately results in activation and signaling. Structures are available for the ECD of type A and B LGRs, but not the type C LGRs. This review discusses the structural features of LRR proteins, and describes the known structures of the type A and B LGRs and predictions that can be made for the type C LGRs. The mechanism of activation of the LGRs is discussed with a focus on the role of the low-density lipoprotein class A (LDLa) module, a unique feature of the type C LGRs. While the LDLa module is essential for activation of the type C LGRs, the molecular mechanism for this process is unknown. Experimental data for the potential interactions of the type C LGR ligands with the LRR domain, the transmembrane domain, and the LDLa module are summarized. PMID- 26441828 TI - Early Life Stress Induced by Limited Nesting Material Produces Metabolic Resilience in Response to a High-Fat and High-Sugar Diet in Male Rats. AB - Environmental conditions experienced in early life can profoundly influence long term metabolic health, but the additive impact of poor nutrition is poorly understood. Here, we tested the hypothesis that early life stress (ELS) induced by limited nesting material (LN) combined with high-fat and high-sugar diet (HFHS) post-weaning would worsen diet-related metabolic risk. Sprague-Dawley male rats were exposed to LN, postnatal days 2-9, and at weaning (3 weeks), siblings were given unlimited access to chow or HFHS resulting in (Con-Chow, Con-HFHS, LN Chow, and LN-HFHS, n = 11-15/group). Glucose and insulin tolerance were tested and rats were killed at 13 weeks. LN rats weighed less at weaning but were not different to control at 13 weeks; HFHS diet led to similar increases in body weight. LN-chow rats had improved glucose and insulin tolerance relative to Con Chow, whereas LN-HFHS improved insulin sensitivity versus Con-HFHS, associated with increased peroxisome proliferator-activated receptor gamma co-activator-1 alpha (Pgc-1alpha) mRNA in muscle. No effect of LN on plasma or liver triglycerides was observed, and hepatic gluconeogenic regulatory genes were unaltered. In summary, this study demonstrates that ELS induced by LN conferred some metabolic protection against insulin and/or glucose intolerance in a diet dependent manner during adulthood. PMID- 26441829 TI - Effects of a Macro-Nutrient Preload on Type 2 Diabetic Patients. AB - AIMS: Macro-nutrient preloads given 30 min before regular meals may improve metabolism. The aim was to investigate how type 2 diabetic patients react to a preload consisting of a blend of macro-nutrients with a low-glycemic index (Inzone Preload((r))). METHODS: In a before-after study design, 30 subjects with type 2 diabetes mellitus (T2DM) were enrolled in a 12-week program. All subjects were given Inzone Preload (43% proteins, 29% carbohydrates, 10% lipids, and 9% fibers, 71 kcal), 30 min before each meal during 12 weeks. Fasting glucose and postprandial 2 h glucose were monitored every second week. Body weight (BW) and waist circumference were measured each month. Fasting plasma glucose, glycosylated hemoglobin, serum lipids, fasting insulin, C-reactive protein, and homeostasis model assessment were evaluated before and after the intervention. Subjective appetite was monitored using visual analogue scales after the Inzone Preload. RESULTS: The dietary intervention significantly influenced several metabolic parameters compared to base line. Inzone Preload treatment reduced mean postprandial plasma glucose levels (12.2 +/- 1.2 vs. 10.5 +/- 2.0 mmol/L), HbA1c (7.4 +/- 0.3 vs. 7.1 +/- 0.2%), mean total cholesterol (4.8 +/- 0.9 vs. 4.3 +/- 0.8 mmol/L), low-density lipoprotein cholesterol (2.8 +/- 0.6 vs. 2.5 +/- 0.4 mmol/L), and CRP (1.5 +/- 1.4 vs. 0.7 +/- 0.7 mg/L). BW loss of more than 3% was seen in 13 participants (43%). Feelings of satiety were significantly higher after Inzone Preload than after habitual breakfast (p < 0.05). No significant changes in fasting blood glucose, high-density lipoprotein and total triacylglycerol, HOMA-IR, and HOMA-beta were observed. CONCLUSION: A macro nutrient preload treatment reduces postprandial glucose, inflammatory markers, and serum lipids in patients with T2DM. Approximately half of the study group also displayed reduced BW. PMID- 26441826 TI - Diabetes and Hepatitis C: A Two-Way Association. AB - Diabetes and hepatitis C infection are both prevalent diseases worldwide, and are associated with increased morbidity and mortality. Most studies, but not all, have shown that patients with chronic hepatitis C are more prone to develop type 2 diabetes (T2D) compared to healthy controls, as well as when compared to patients with other liver diseases, including hepatitis B. Furthermore, epidemiological studies have revealed that patients with T2D may also be at higher risk for worse outcomes of their hepatitis C infection, including reduced rate of sustained virological response, progression to fibrosis and cirrhosis, and higher risk for development of hepatocellular carcinoma. Moreover, hepatitis C infection and mainly its treatment, interferon alpha, can trigger the development of type 1 diabetes. In this review, we discuss the existing data on this two-way association between diabetes and hepatitis C infection with emphasis on possible mechanisms. It remains to be determined whether the new curative therapies for chronic hepatitis C will improve outcomes in diabetic hepatitis C patients, and conversely whether treatment with Metformin will reduce complications from hepatitis C virus infection. We propose an algorithm for diabetes screening and follow-up in hepatitis C patients. PMID- 26441830 TI - Differences in Signal Activation by LH and hCG are Mediated by the LH/CG Receptor's Extracellular Hinge Region. AB - The human lutropin (hLH)/choriogonadotropin (hCG) receptor (LHCGR) can be activated by binding two slightly different gonadotropic glycoprotein hormones, choriogonadotropin (CG) - secreted by the placenta, and lutropin (LH) - produced by the pituitary. They induce different signaling profiles at the LHCGR. This cannot be explained by binding to the receptor's leucine-rich-repeat domain (LRRD), as this binding is similar for the two hormones. We therefore speculate that there are previously unknown differences in the hormone/receptor interaction at the extracellular hinge region, which might help to understand functional differences between the two hormones. We have therefore performed a detailed study of the binding and action of LH and CG at the LHCGR hinge region. We focused on a primate-specific additional exon in the hinge region, which is located between LRRD and the serpentine domain. The segment of the hinge region encoded by exon10 was previously reported to be only relevant to hLH signaling, as the exon10-deletion receptor exhibits decreased hLH signaling, but unchanged hCG signaling. We designed an advanced homology model of the hormone/LHCGR complex, followed by experimental characterization of relevant fragments in the hinge region. In addition, we examined predictions of a helical exon10-encoded conformation by block-wise polyalanine (helix supporting) mutations. These helix preserving modifications showed no effect on hormone-induced signaling. However, introduction of a structure-disturbing double-proline mutant LHCGR-Q303P/E305P within the exon10-helix has, in contrast to exon10-deletion, no impact on hLH, but only on hCG signaling. This opposite effect on signaling by hLH and hCG can be explained by distinct sites of hormone interaction in the hinge region. In conclusion, our analysis provides details of the differences between hLH- and hCG induced signaling that are mainly determined in the L2-beta loop of the hormones and in the hinge region of the receptor. PMID- 26441831 TI - Pituitary Adenoma and the Chemokine Network: A Systemic View. PMID- 26441832 TI - Discovery and Development of Small Molecule Allosteric Modulators of Glycoprotein Hormone Receptors. AB - Glycoprotein hormones, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH) are heterodimeric proteins with a common alpha-subunit and hormone-specific beta-subunit. These hormones are dominant regulators of reproduction and metabolic processes. Receptors for the glycoprotein hormones belong to the family of G protein-coupled receptors. FSH receptor (FSHR) and LH receptor are primarily expressed in somatic cells in ovary and testis to promote egg and sperm production in women and men, respectively. TSH receptor is expressed in thyroid cells and regulates the secretion of T3 and T4. Glycoprotein hormones bind to the large extracellular domain of the receptor and cause a conformational change in the receptor that leads to activation of more than one intracellular signaling pathway. Several small molecules have been described to activate/inhibit glycoprotein hormone receptors through allosteric sites of the receptor. Small molecule allosteric modulators have the potential to be administered orally to patients, thus improving the convenience of treatment. It has been a challenge to develop a small molecule allosteric agonist for glycoprotein hormones that can mimic the agonistic effects of the large natural ligand to activate similar signaling pathways. However, in the past few years, there have been several promising reports describing distinct chemical series with improved potency in preclinical models. In parallel, proposal of new structural model for FSHR and in silico docking studies of small molecule ligands to glycoprotein hormone receptors provide a giant leap on the understanding of the mechanism of action of the natural ligands and new chemical entities on the receptors. This review will focus on the current status of small molecule allosteric modulators of glycoprotein hormone receptors, their effects on common signaling pathways in cells, their utility for clinical application as demonstrated in preclinical models, and use of these molecules as novel tools to dissect the molecular signaling pathways of these receptors. PMID- 26441835 TI - Editorial: Podocyte Pathology and Nephropathy. PMID- 26441834 TI - Novel Regulator of Acylated Ghrelin, CF801, Reduces Weight Gain, Rebound Feeding after a Fast, and Adiposity in Mice. AB - Ghrelin is a 28 amino acid hormonal peptide that is intimately related to the regulation of food intake and body weight. Once secreted, ghrelin binds to the growth hormone secretagogue receptor-1a, the only known receptor for ghrelin and is capable of activating a number of signaling cascades, ultimately resulting in an increase in food intake and adiposity. Because ghrelin has been linked to overeating and the development of obesity, a number of pharmacological interventions have been generated in order to interfere with either the activation of ghrelin or interrupting ghrelin signaling as a means to reducing appetite and decrease weight gain. Here, we present a novel peptide, CF801, capable of reducing circulating acylated ghrelin levels and subsequent body weight gain and adiposity. To this end, we show that IP administration of CF801 is sufficient to reduce circulating plasma acylated ghrelin levels. Acutely, intraperitoneal injections of CF801 resulted in decreased rebound feeding after an overnight fast. When delivered chronically, they decreased weight gain and adiposity without affecting caloric intake. CF801, however, did cause a change in diet preference, decreasing preference for a high-fat diet and increasing preference for regular chow diet. Given the complexity of ghrelin receptor function, we propose that CF801, along with other compounds that regulate ghrelin secretion, may prove to be a beneficial tool in the study of the ghrelin system, and potential targets for ghrelin-based obesity treatments without altering the function of ghrelin receptors. PMID- 26441833 TI - Plasticity of the Melanocortin System: Determinants and Possible Consequences on Food Intake. AB - The melanocortin system is one of the most important neuronal pathways involved in the regulation of food intake and is probably the best characterized. Agouti related peptide (AgRP) and proopiomelanocortin (POMC) expressing neurons located in the arcuate nucleus of the hypothalamus are the key elements of this system. These two neuronal populations are sensitive to circulating molecules and receive many excitatory and inhibitory inputs from various brain areas. According to sensory and metabolic information they integrate, these neurons control different aspects of feeding behavior and orchestrate autonomic responses aimed at maintaining energy homeostasis. Interestingly, composition and abundance of pre synaptic inputs onto arcuate AgRP and POMC neurons vary in the adult hypothalamus in response to changes in the metabolic state, a phenomenon that can be recapitulated by treatment with hormones, such as leptin or ghrelin. As described in other neuroendrocrine systems, glia might be determinant to shift the synaptic configuration of AgRP and POMC neurons. Here, we discuss the physiological outcome of the synaptic plasticity of the melanocortin system, and more particularly its contribution to the control of energy balance. The discovery of this attribute has changed how we view obesity and related disorders, and opens new perspectives for their management. PMID- 26441836 TI - Editorial: Cell-Based Therapies for Diabetic Microvascular Complications. PMID- 26441837 TI - Research Perspectives on the Regulation and Physiological Functions of FGF21 and its Association with NAFLD. AB - Fibroblast growth factor 21 (FGF21) is a metabolic hormone primarily secreted from the liver and functions in multiple tissues. Various transcription factors induce FGF21 expression in the liver, which indicates that FGF21 is a mediator of multiple environmental cues. FGF21 alters metabolism under starvation conditions, protects the body from energy depletion, and extends life span. Pharmacological administration of FGF21 alleviates dyslipidemia and induces weight loss in obese animals. In addition to the well-studied functions of FG21, several lines of recent evidence indicate a possible link between FGF21 and non-alcoholic fatty liver disease (NAFLD). High serum levels of FGF21 are associated with NAFLD and its risk factors, such as endoplasmic reticulum stress and chronic inflammation. In addition, FGF21 alleviates the major risk factors of NAFLD, including obesity, dyslipidemia, and insulin insensitivity. Thus, FGF21 is a potential drug candidate for diseases, such as NAFLD, dyslipidemia, and type 2 diabetes. In this review, the research perspectives of FGF21 and therapeutic potencies of FGF21 as a modulator of NAFLD are summarized. PMID- 26441838 TI - Metabolic Effects of FGF-21: Thermoregulation and Beyond. AB - Fibroblast growth factor (FGF)-21, a member of the FGF family, is a novel hormone involved in the control of metabolism by modulating glucose homeostasis, insulin sensitivity, ketogenesis, and promoting adipose tissue "browning." Recent studies demonstrated that brown adipose tissue is not only a target for FGF-21, but is also a potentially important source of systemic FGF-21. These findings support the hypothesis that FGF-21 plays a physiologic role in thermogenesis and thermogenic recruitment of white adipose tissue by an autocrine-paracrine axis. This review examines the role of FGF-21 in thermogenesis from the perspective of cell-based, animal model, and human studies. We also present recent advances in the characterization of FGF-21's regulation of metabolism. PMID- 26441840 TI - Regulation and Function of RFRP-3 (GnIH) Neurons during Postnatal Development. AB - RFamide-related peptide-3 (RFRP-3) [mammalian ortholog to gonadotropin-inhibiting hormone (GnIH)] potently inhibits gonadotropin secretion in mammals. Studies of RFRP-3 immunoreactivity and Rfrp expression (the gene encoding RFRP-3) in mammalian brains have uncovered several possible pathways regulating RFRP-3 neurons, shedding light on their potential role in reproduction and other processes, and pharmacological studies have probed the target sites of RFRP-3 action. Despite this, there is currently no major consensus on RFRP-3's specific endogenous role(s) in reproductive physiology. Here, we discuss the latest evidence relating to RFRP-3 neuron regulation and function during development and sexual maturation, focusing on rodents. We highlight significant changes in RFRP 3 and Rfrp expression, as well as RFRP-3 neuronal activation, during key stages of postnatal and pubertal development and also discuss recent evidence testing the requisite role of RFRP-3 receptors for normal pubertal timing and developmental LH secretion. Interestingly, some findings suggest that endogenous RFRP-3 signaling may not be necessary for the puberty timing, at least in some species, forcing new hypotheses to be generated regarding this peptide's functional significance to sexual maturation and development. PMID- 26441839 TI - Neuronal Control of Adaptive Thermogenesis. AB - The obesity epidemic continues rising as a global health challenge, despite the increasing public awareness and the use of lifestyle and medical interventions. The biomedical community is urged to develop new treatments to obesity. Excess energy is stored as fat in white adipose tissue (WAT), dysfunction of which lies at the core of obesity and associated metabolic disorders. By contrast, brown adipose tissue (BAT) burns fat and dissipates chemical energy as heat. The development and activation of "brown-like" adipocytes, also known as beige cells, result in WAT browning and thermogenesis. The recent discovery of brown and beige adipocytes in adult humans has sparked the exploration of the development, regulation, and function of these thermogenic adipocytes. The central nervous system drives the sympathetic nerve activity in BAT and WAT to control heat production and energy homeostasis. This review provides an overview of the integration of thermal, hormonal, and nutritional information on hypothalamic circuits in thermoregulation. PMID- 26441841 TI - Fgf8-Deficient Mice Compensate for Reduced GnRH Neuronal Population and Exhibit Normal Testicular Function. AB - Gonadotropin-releasing hormone (GnRH) is critical for the onset and maintenance of reproduction in vertebrates. The development of GnRH neurons is highly dependent on fibroblast growth factor (Fgf) signaling. Mice with a hypomorphic Fgf8 allele (Fgf8 Het) exhibited a ~50% reduction in GnRH neuron number at birth. Female Fgf8 Het mice were fertile but showed significantly delayed puberty. However, it was unclear if these mice suffered additional loss of GnRH neurons after birth, and if male Fgf8 Het mice had normal pubertal transition and testicular function. In this study, we examined postnatal GnRH neuron number and hypothalamic GnRH content in Fgf8 Het mice from birth to 120 days of age. Further, we examined seminal vesicle and testicular growth, testicular histology, and circulating luteinizing hormone (LH) around and after pubertal transition. Our results showed that GnRH neuron numbers were significantly and consistently reduced in Fgf8 Het mice of both sexes in all ages examined, suggesting these animals were born with an inherently defective GnRH system, and no further postnatal loss of GnRH neurons had occurred. Despite an innately compromised GnRH system, male and female Fgf8 mice exhibited normal levels of immunoassayable hypothalamic GnRH peptide at all ages examined except on 60 days of age, suggesting increased GnRH synthesis or reduced turnover as a compensatory mechanism. Fgf8 Het males also had normal seminal vesicle and testicular mass/body mass ratios, testicular histology, and circulating LH. Overall, our data speak to the extraordinary ability of a GnRH system permanently compromised by developmental defect to overcome pre-existing deficiencies to ensure pubertal progression and reproduction. PMID- 26441842 TI - Mineralocorticoid Receptors in the Pathophysiology of Vascular Inflammation and Atherosclerosis. AB - Atherosclerosis is a chronic inflammatory disease of the vasculature that causes significant morbidity and mortality from myocardial infarction, stroke, and peripheral vascular disease. Landmark clinical trials revealed that mineralocorticoid receptor (MR) antagonists improve outcomes in cardiovascular patients. Conversely, enhanced MR activation by the hormone aldosterone is associated with increased risk of MI, stroke, and cardiovascular death. This review summarizes recent advances in our understanding of the role of aldosterone and the MR in the pathogenesis of vascular inflammation and atherosclerosis as it proceeds from risk factor-induced endothelial dysfunction and inflammation to plaque formation, progression, and ultimately rupture with thrombosis, the cause of acute ischemia. The role of the MR in converting cardiac risk factors into endothelial dysfunction, in enhancing leukocyte adhesion and infiltration into the vasculature, in promoting systemic inflammation and vascular oxidative stress, and in plaque destabilization and thrombosis are discussed. A greater understanding of the mechanisms by which the MR promotes atherosclerosis has substantial potential to identify novel treatment targets to improve cardiovascular health and decrease mortality. PMID- 26441843 TI - Paracoccidioides spp. ferrous and ferric iron assimilation pathways. AB - Iron is an essential micronutrient for almost all organisms, including fungi. Usually, fungi can uptake iron through receptor-mediated internalization of a siderophore or heme, and/or reductive iron assimilation (RIA). Traditionally, the RIA pathway consists of ferric reductases (Fres), ferroxidase (Fet3) and a high affinity iron permease (Ftr1). Paracoccidioides spp. genomes do not present an Ftr1 homolog. However, this fungus expresses zinc regulated transporter homologs (Zrts), members of the ZIP family of membrane transporters that are able in some organisms to transport zinc and iron. A 2,3,5-triphenyltetrazolium chloride (TTC) overlay assay indicates that both Pb01 and Pb18 express a ferric reductase activity; however, (59)Fe uptake assays indicate that only in Pb18 is this activity coupled to a reductase-dependent iron uptake pathway. In addition, Zrts are up-regulated in iron deprivation, as indicated by RNAseq and qRT-PCR using Pb01 transcripts. RNAseq strategy also demonstrated that transcripts related to siderophore uptake and biosynthesis are up-regulated in iron-deprived condition. The data suggest that the fungus could use both a non-classical RIA, comprising ferric reductases and Fe/Zn permeases (Zrts), and siderophore uptake pathways under iron-limited conditions. The study of iron metabolism reveals novel surface molecules that could function as accessible targets for drugs to block iron uptake and, consequently, inhibit pathogen's proliferation. PMID- 26441844 TI - Deep subsurface mine stalactites trap endemic fissure fluid Archaea, Bacteria, and Nematoda possibly originating from ancient seas. AB - Stalactites (CaCO3 and salt) from water seeps are frequently encountered in ceilings of mine tunnels whenever they intersect water-bearing faults or fractures. To determine whether stalactites could be mineralized traps for indigenous fracture water microorganisms, we analyzed stalactites collected from three different mines ranging in depth from 1.3 to 3.1 km. During sampling in Beatrix gold mine (1.4 km beneath the surface), central South Africa, CaCO3 stalactites growing on the mine tunnel ceiling were collected and observed, in two cases, to contain a living obligate brackish water/marine nematode species, Monhystrella parvella. After sterilization of the outer surface, mineral layers were physically removed from the outside to the interior, and DNA extracted. Based upon 16S and 18S rRNA gene sequencing, Archaea, Bacteria, and Eukarya in different combinations were detected for each layer. Using CT scan and electron microscopy the inner structure of CaCO3 and salt stalactites were analyzed. CaCO3 stalactites show a complex pattern of lamellae carrying bacterially precipitated mineral structures. Nematoda were clearly identified between these layers confirming that bacteria and nematodes live inside the stalactites and not only in the central straw. Salt stalactites exhibit a more uniform internal structure. Surprisingly, several Bacteria showing highest sequence identities to marine species were identified. This, together with the observation that the nematode M. parvella recovered from Beatrix gold mine stalactite can only survive in a salty environment makes the origin of the deep subsurface colonization enigmatic. The possibility of a Permian origin of fracture fluids is discussed. Our results indicate stalactites are suitable for biodiversity recovery and act as natural traps for microorganisms in the fissure water long after the water that formed the stalactite stopped flowing. PMID- 26441845 TI - Biopolymers from lactic acid bacteria. Novel applications in foods and beverages. AB - Lactic acid bacteria (LAB) are microorganisms widely used in the fermented food industry worldwide. Certain LAB are able to produce exopolysaccharides (EPS) either attached to the cell wall (capsular EPS) or released to the extracellular environment (EPS). According to their composition, LAB may synthesize heteropolysaccharides or homopolysaccharides. A wide diversity of EPS are produced by LAB concerning their monomer composition, molecular mass, and structure. Although EPS-producing LAB strains have been traditionally applied in the manufacture of dairy products such as fermented milks and yogurts, their use in the elaboration of low-fat cheeses, diverse type of sourdough breads, and certain beverages are some of the novel applications of these polymers. This work aims to collect the most relevant issues of the former reviews concerning the monomer composition, structure, and yields and biosynthetic enzymes of EPS from LAB; to describe the recently characterized EPS and to present the application of both EPS-producing strains and their polymers in the fermented (specifically beverages and cereal-based) food industry. PMID- 26441847 TI - Fe biomineralization mirrors individual metabolic activity in a nitrate-dependent Fe(II)-oxidizer. AB - Microbial biomineralization sometimes leads to periplasmic encrustation, which is predicted to enhance microorganism preservation in the fossil record. Mineral precipitation within the periplasm is, however, thought to induce death, as a result of permeability loss preventing nutrient and waste transit across the cell wall. This hypothesis had, however, never been investigated down to the single cell level. Here, we cultured the nitrate reducing Fe(II) oxidizing bacteria Acidovorax sp. strain BoFeN1 that have been previously shown to promote the precipitation of a diversity of Fe minerals (lepidocrocite, goethite, Fe phosphate) encrusting the periplasm. We investigated the connection of Fe biomineralization with carbon assimilation at the single cell level, using a combination of electron microscopy and Nano-Secondary Ion Mass Spectrometry. Our analyses revealed strong individual heterogeneities of Fe biomineralization. Noteworthy, a small proportion of cells remaining free of any precipitate persisted even at advanced stages of biomineralization. Using pulse chase experiments with (13)C-acetate, we provide evidence of individual phenotypic heterogeneities of carbon assimilation, correlated with the level of Fe biomineralization. Whereas non- and moderately encrusted cells were able to assimilate acetate, higher levels of periplasmic encrustation prevented any carbon incorporation. Carbon assimilation only depended on the level of Fe encrustation and not on the nature of Fe minerals precipitated in the cell wall. Carbon assimilation decreased exponentially with increasing cell-associated Fe content. Persistence of a small proportion of non-mineralized and metabolically active cells might constitute a survival strategy in highly ferruginous environments. Eventually, our results suggest that periplasmic Fe biomineralization may provide a signature of individual metabolic status, which could be looked for in the fossil record and in modern environmental samples. PMID- 26441846 TI - Microbiomes: unifying animal and plant systems through the lens of community ecology theory. AB - The field of microbiome research is arguably one of the fastest growing in biology. Bacteria feature prominently in studies on animal health, but fungi appear to be the more prominent functional symbionts for plants. Despite the similarities in the ecological organization and evolutionary importance of animal bacterial and plant-fungal microbiomes, there is a general failure across disciplines to integrate the advances made in each system. Researchers studying bacterial symbionts in animals benefit from greater access to efficient sequencing pipelines and taxonomic reference databases, perhaps due to high medical and veterinary interest. However, researchers studying plant-fungal symbionts benefit from the relative tractability of fungi under laboratory conditions and ease of cultivation. Thus each system has strengths to offer, but both suffer from the lack of a common conceptual framework. We argue that community ecology best illuminates complex species interactions across space and time. In this synthesis we compare and contrast the animal-bacterial and plant fungal microbiomes using six core theories in community ecology (i.e., succession, community assembly, metacommunities, multi-trophic interactions, disturbance, restoration). The examples and questions raised are meant to spark discussion amongst biologists and lead to the integration of these two systems, as well as more informative, manipulatory experiments on microbiomes research. PMID- 26441848 TI - Versatile transformations of hydrocarbons in anaerobic bacteria: substrate ranges and regio- and stereo-chemistry of activation reactions. AB - Anaerobic metabolism of hydrocarbons proceeds either via addition to fumarate or by hydroxylation in various microorganisms, e.g., sulfate-reducing or denitrifying bacteria, which are specialized in utilizing n-alkanes or alkylbenzenes as growth substrates. General pathways for carbon assimilation and energy gain have been elucidated for a limited number of possible substrates. In this work the metabolic activity of 11 bacterial strains during anaerobic growth with crude oil was investigated and compared with the metabolite patterns appearing during anaerobic growth with more than 40 different hydrocarbons supplied as binary mixtures. We show that the range of co-metabolically formed alkyl- and arylalkyl-succinates is much broader in n-alkane than in alkylbenzene utilizers. The structures and stereochemistry of these products are resolved. Furthermore, we demonstrate that anaerobic hydroxylation of alkylbenzenes does not only occur in denitrifiers but also in sulfate reducers. We propose that these processes play a role in detoxification under conditions of solvent stress. The thermophilic sulfate-reducing strain TD3 is shown to produce n alkylsuccinates, which are suggested not to derive from terminal activation of n alkanes, but rather to represent intermediates of a metabolic pathway short cutting fumarate regeneration by reverse action of succinate synthase. The outcomes of this study provide a basis for geochemically tracing such processes in natural habitats and contribute to an improved understanding of microbial activity in hydrocarbon-rich anoxic environments. PMID- 26441849 TI - Staphylococcus aureus strains associated with food poisoning outbreaks in France: comparison of different molecular typing methods, including MLVA. AB - Staphylococcal food poisoning outbreaks (SFPOs) are frequently reported in France. However, most of them remain unconfirmed, highlighting a need for a better characterization of isolated strains. Here we analyzed the genetic diversity of 112 Staphylococcus aureus strains isolated from 76 distinct SFPOs that occurred in France over the last 30 years. We used a recently developed multiple-locus variable-number tandem-repeat analysis (MLVA) protocol and compared this method with pulsed field gel electrophoresis (PFGE), spa-typing and carriage of genes (se genes) coding for 11 staphylococcal enterotoxins (i.e., SEA, SEB, SEC, SED, SEE, SEG, SEH, SEI, SEJ, SEP, SER). The strains known to have an epidemiological association with one another had identical MLVA types, PFGE profiles, spa-types or se gene carriage. MLVA, PFGE and spa-typing divided 103 epidemiologically unrelated strains into 84, 80, and 50 types respectively demonstrating the high genetic diversity of S. aureus strains involved in SFPOs. Each MLVA type shared by more than one strain corresponded to a single spa-type except for one MLVA type represented by four strains that showed two different but closely related-spa-types. The 87 enterotoxigenic strains were distributed across 68 distinct MLVA types that correlated all with se gene carriage except for four MLVA types. The most frequent se gene detected was sea, followed by seg and sei and the most frequently associated se genes were sea-seh and sea-sed-sej ser. The discriminatory ability of MLVA was similar to that of PFGE and higher than that of spa-typing. This MLVA protocol was found to be compatible with high throughput analysis, and was also faster and less labor-intensive than PFGE. MLVA holds promise as a suitable method for investigating SFPOs and tracking the source of contamination in food processing facilities in real time. PMID- 26441850 TI - HIV-1 Tat and cocaine mediated synaptopathy in cortical and midbrain neurons is prevented by the isoflavone Equol. AB - Illicit drugs, such as cocaine, are known to increase the likelihood and severity of HIV-1 associated neurocognitive disorders (HAND). In the current studies synaptic integrity was assessed following exposure to low concentrations of the HIV-1 viral protein Tat 1-86B, with or without cocaine, by quantifying filamentous actin (F-actin) rich structures (i.e., puncta and dendritic spines) on neuronal dendrites in vitro. In addition, the synapse-protective effects of either R-Equol (RE) or S-Equol (SE; derivatives of the soy isoflavone, daidzein) were determined. Individually, neither low concentrations of HIV-1 Tat (10 nM) nor low concentrations of cocaine (1.6 MUM) had any significant effect on F-actin puncta number; however, the same low concentrations of HIV-1 Tat + cocaine in combination significantly reduced dendritic synapses. This synaptic reduction was prevented by pre-treatment with either RE or SE, in an estrogen receptor beta dependent manner. In sum, targeted therapeutic intervention with SE may prevent HIV-1 + drug abuse synaptopathy, and thereby potentially influence the development of HAND. PMID- 26441851 TI - Phenotypic changes in the brain of SIV-infected macaques exposed to methamphetamine parallel macrophage activation patterns induced by the common gamma-chain cytokine system. AB - One factor in the development of neuroAIDS is the increase in the migration of pro-inflammatory CD8 T cells across the blood-brain barrier. Typically these cells are involved with keeping the viral load down. However, the persistence of above average numbers of CD8 T cells in the brain, not necessarily specific to viral peptides, is facilitated by the upregulation of IL15 from astrocytes, in the absence of IL2, in the brain environment. Both IL15 and IL2 are common gamma chain (gammac) cytokines. Here, using the non-human primate model of neuroAIDS, we have demonstrated that exposure to methamphetamine, a powerful illicit drug that has been associated with HIV exposure and neuroAIDS severity, can cause an increase in molecules of the gammac system. Among these molecules, IL15, which is upregulated in astrocytes by methamphetamine, and that induces the proliferation of T cells, may also be involved in driving an inflammatory phenotype in innate immune cells of the brain. Therefore, methamphetamine and IL15 may be critical in the development and aggravation of central nervous system immune-mediated inflammatory pathology in HIV-infected drug abusers. PMID- 26441853 TI - Filamentous fungi from extreme environments as a promising source of novel bioactive secondary metabolites. AB - Natural product search is undergoing resurgence upon the discovery of a huge previously unknown potential for secondary metabolite (SM) production hidden in microbial genomes. This is also the case for filamentous fungi, since their genomes contain a high number of "orphan" SM gene clusters. Recent estimates indicate that only 5% of existing fungal species have been described, thus the potential for the discovery of novel metabolites in fungi is huge. In this context, fungi thriving in harsh environments are of particular interest since they are outstanding producers of unusual chemical structures. At present, there are around 16 genomes from extreme environment-isolated fungi in databases. In a preliminary analysis of three of these genomes we found that several of the predicted SM gene clusters are probably involved in the biosynthesis of compounds not yet described. Genome mining strategies allow the exploitation of the information in genome sequences for the discovery of new natural compounds. The synergy between genome mining strategies and the expected abundance of SMs in fungi from extreme environments is a promising path to discover new natural compounds as a source of medically useful drugs. PMID- 26441852 TI - Bacterial diversity and successional patterns during biofilm formation on freshly exposed basalt surfaces at diffuse-flow deep-sea vents. AB - Many deep-sea hydrothermal vent systems are regularly impacted by volcanic eruptions, leaving fresh basalt where abundant animal and microbial communities once thrived. After an eruption, microbial biofilms are often the first visible evidence of biotic re-colonization. The present study is the first to investigate microbial colonization of newly exposed basalt surfaces in the context of vent fluid chemistry over an extended period of time (4-293 days) by deploying basalt blocks within an established diffuse-flow vent at the 9 degrees 50' N vent field on the East Pacific Rise. Additionally, samples obtained after a recent eruption at the same vent field allowed for comparison between experimental results and those from natural microbial re-colonization. Over 9 months, the community changed from being composed almost exclusively of Epsilonproteobacteria to a more diverse assemblage, corresponding with a potential expansion of metabolic capabilities. The process of biofilm formation appears to generate similar surface-associated communities within and across sites by selecting for a subset of fluid-associated microbes, via species sorting. Furthermore, the high incidence of shared operational taxonomic units over time and across different vent sites suggests that the microbial communities colonizing new surfaces at diffuse-flow vent sites might follow a predictable successional pattern. PMID- 26441854 TI - Carbon fixation by basalt-hosted microbial communities. AB - Oceanic crust is a massive potential habitat for microbial life on Earth, yet our understanding of this ecosystem is limited due to difficulty in access. In particular, measurements of rates of microbial activity are sparse. We used stable carbon isotope incubations of crustal samples, coupled with functional gene analyses, to examine the potential for carbon fixation on oceanic crust. Both seafloor-exposed and subseafloor basalts were recovered from different mid ocean ridge and hot spot environments (i.e., the Juan de Fuca Ridge, the Mid Atlantic Ridge, and the Loihi Seamount) and incubated with (13)C-labeled bicarbonate. Seafloor-exposed basalts revealed incorporation of (13)C-label into organic matter over time, though the degree of incorporation was heterogeneous. The incorporation of (13)C into biomass was inconclusive in subseafloor basalts. Translating these measurements into potential rates of carbon fixation indicated that 0.1-10 nmol C g(-1) rock d(-1) could be fixed by seafloor-exposed rocks. When scaled to the global production of oceanic crust, this suggests carbon fixation rates of 10(9)-10(12) g C year(-1), which matches earlier predictions based on thermodynamic calculations. Functional gene analyses indicate that the Calvin cycle is likely the dominant biochemical mechanism for carbon fixation in basalt-hosted biofilms, although the reductive acetyl-CoA pathway and reverse TCA cycle likely play some role in net carbon fixation. These results provide empirical evidence for autotrophy in oceanic crust, suggesting that basalt-hosted autotrophy could be a significant contributor of organic matter in this remote and vast environment. PMID- 26441856 TI - Magnesium ions mitigate biofilm formation of Bacillus species via downregulation of matrix genes expression. AB - The objective of this study was to investigate the effect of Mg(2+) ions on biofilm formation by Bacillus species, which are considered as problematic microorganisms in the food industry. We found that magnesium ions are capable to inhibit significantly biofilm formation of Bacillus species at 50 mM concentration and higher. We further report that Mg(2+) ions don't inhibit bacterial growth at elevated concentrations; hence, the mode of action of Mg(2+) ions is apparently specific to inhibition of biofilm formation. Biofilm formation depends on the synthesis of extracellular matrix, whose production in Bacillus subtilis is specified by two major operons: the epsA-O and tapA operons. We analyzed the effect of Mg(2+) ions on matrix gene expression using transcriptional fusions of the promoters for eps and tapA to the gene encoding beta galactosidase. The expression of the two matrix operons was reduced drastically in response to Mg(2+) ions suggesting about their inhibitory effect on expression of the matrix genes in B. subtilis. Since the matrix gene expression is tightly controlled by Spo0A dependent pathway, we conclude that Mg(2+) ions could affect the signal transduction for biofilm formation through this pathway. PMID- 26441855 TI - Chassis optimization as a cornerstone for the application of synthetic biology based strategies in microbial secondary metabolism. AB - The increased number of bacterial genome sequencing projects has generated over the last years a large reservoir of genomic information. In silico analysis of this genomic data has renewed the interest in bacterial bioprospecting for bioactive compounds by unveiling novel biosynthetic gene clusters of unknown or uncharacterized metabolites. However, only a small fraction of those metabolites is produced under laboratory-controlled conditions; the remaining clusters represent a pool of novel metabolites that are waiting to be "awaken". Activation of the biosynthetic gene clusters that present reduced or no expression (known as cryptic or silent clusters) by heterologous expression has emerged as a strategy for the identification and production of novel bioactive molecules. Synthetic biology, with engineering principles at its core, provides an excellent framework for the development of efficient heterologous systems for the expression of biosynthetic gene clusters. However, a common problem in its application is the host-interference problem, i.e., the unpredictable interactions between the device and the host that can hamper the desired output. Although an effort has been made to develop orthogonal devices, the most proficient way to overcome the host-interference problem is through genome simplification. In this review we present an overview on the strategies and tools used in the development of hosts/chassis for the heterologous expression of specialized metabolites biosynthetic gene clusters. Finally, we introduce the concept of specialized host as the next step of development of expression hosts. PMID- 26441857 TI - Functional analysis of the sporulation-specific diadenylate cyclase CdaS in Bacillus thuringiensis. AB - Cyclic di-AMP (c-di-AMP) is a recently discovered bacterial secondary messenger molecule, which is associated with various physiological functions. In the genus Bacillus, the intracellular level and turnover of c-di-AMP are mainly regulated by three diadenylate cyclases (DACs), including DisA, CdaA and CdaS, and two c-di AMP-specific phosphodiesterases (GdpP and PgpH). In this study, we demonstrated that CdaS protein from B. thuringiensis is a hexameric DAC protein that can convert ATP or ADP to c-di-AMP in vitro and the N-terminal YojJ domain is essential for the DAC activity. Based on the markerless gene knock-out method, we demonstrated that the transcription of cdaS was initiated by the sporulation specific sigma factor sigma(H) and the deletion of cdaS significantly delayed sporulation and parasporal crystal formation. These findings contrast with similar experiments conducted using B. subtilis, wherein transcription of its cdaS was initiated by the sigma factor sigma(G). Deletion of all the three DAC genes from a single strain was unsuccessful, suggesting that c-di-AMP is an indispensable molecule in B. thuringiensis. Phylogenetic analysis indicated increased diversity of CdaS in the B. cereus and B. subtilis Bacillus subgroups. In summary, this study identifies important aspects in the regulation of c-di-AMP in the genus Bacillus. PMID- 26441858 TI - Manipulation of oil synthesis in Nannochloropsis strain NIES-2145 with a phosphorus starvation-inducible promoter from Chlamydomonas reinhardtii. AB - Microalgae accumulate triacylglycerols (TAGs) under conditions of nutrient stress. Phosphorus (P) starvation induces the accumulation of TAGs, and the cells under P starvation maintain growth through photosynthesis. We recently reported that P starvation-dependent overexpression of type-2 diacylglycerol acyl-CoA acyltransferase (CrDGTT4) from Chlamydomonas reinhardtii using a sulfoquinovosyldiacylglycerol synthase 2 (SQD2) promoter, which has increased activity during P starvation, enhances TAG accumulation in C. reinhardtii cells. As a result, the content of C18:1 fatty acid, a preferred substrate of CrDGTT4, is increased in TAGs. Here we isolated genes encoding SQD2 from strain NIES-2145 of the eustigmatophyte Nannochloropsis and showed that their expression, like that in C. reinhardtii, was up-regulated during P starvation. To enhance oil accumulation under P starvation, we transformed pCrSQD2-CrDGTT4 into Nannochloropsis strain NIES-2145. The transformants had a fatty acid composition that was more similar to that of C. reinhardtii, which resulted in enhanced TAG accumulation and higher 18:1(9) content. The results indicated that the P starvation-inducible promoter of C. reinhardtii was able to drive expression of the CrDGTT4 gene in Nannochloropsis strain NIES-2145 under P starvation. We conclude that the heterologous CrSQD2 promoter is effective in manipulating TAG synthesis in Nannochloropsis during P starvation. PMID- 26441859 TI - Characterization of antibiotic resistance in commensal bacteria from an aquaculture ecosystem. AB - The objective of the study was to improve the understanding of antibiotic resistance (AR) ecology through characterization of antibiotic-resistant commensal isolates associated with an aquaculture production system. A total of 4767 isolates non-susceptible to sulfamethoxazole/trimethoprim (Sul/Tri), tetracycline (Tet), erythromycin (Erm), or cefotaxime (Ctx), originated from fish, feed, and environmental samples of an aquaculture farm with no known history of antibiotic applications were examined. Close to 80% of the isolates exhibited multi-drug resistance in media containing the corresponding antibiotics, and representative AR genes were detected in various isolates by PCR, with feed isolates had the highest positive rate detected. Identified AR gene carriers involved 18 bacterial genera. Selected AR genes led to acquired resistance in other bacteria by transformation. The AR traits in many isolates were stable in the absence of selective pressure. AR-rich feed and possibly environmental factors may contribute to AR in the aquaculture ecosystem. For minimum inhibitory concentration test, brain heart infusion medium was found more suitable for majority of the bacteria examined than cation-adjusted Mueller Hinton broth, with latter being the recommended medium for clinical isolates by standard protocol. The data indicated a need to update the methodology due to genetic diversity of microbiota for better understanding of the AR ecology. PMID- 26441860 TI - Prevalence and distribution of soil-borne zoonotic pathogens in Lahore district of Pakistan. AB - A multidisciplinary, collaborative project was conducted to determine the prevalence and distribution of soil-borne zoonotic pathogens in Lahore district of Pakistan and ascertain its Public Health Significance. Using a grid-based sampling strategy, soil samples (n = 145) were collected from villages (n = 29, 5 samples/village) and examined for Bacillus anthracis, Burkholderia mallei/pseudomallei, Coxiella burnetii, Francisella tularensis, and Yersinia pestis using real time PCR assays. Chemical analysis of soil samples was also performed on these samples. The relationship between soil composition and absence or presence of the pathogen, and seven risk factors was evaluated. DNA of B. anthracis (CapB), B. mallei/pseudomallei (chromosomal gene), C. burnetii (IS1111, transposase gene), and F. tularensis (lipoprotein/outer membrane protein) was detected in 9.6, 1.4, 4.8, and 13.1% of soil samples, respectively. None of the samples were positive for protective antigen plasmid (PA) of B. anthracis and Y. pestis (plasminogen activating factor, pPla gene). The prevalence of B. anthracis (CapB) was found to be associated with organic matter, magnesium (Mg), copper (Cu), chromium (Cr), manganese (Mn), cobalt (Co), cadmium (Cd), sodium (Na), ferrous (Fe), calcium (Ca), and potassium (K). Phosphorous (P) was found to be associated with prevalence of F. tularensis while it were Mg, Co, Na, Fe, Ca, and K for C. burnetii. The odds of detecting DNA of F. tularensis were 2.7, 4.1, and 2.7 higher when soil sample sites were >1 km from animal markets, >500 m from vehicular traffic roads and animal density of < 1000 animals, respectively. While the odds of detecting DNA of C. burnetii was 32, 11.8, and 5.9 higher when soil sample sites were >500 m from vehicular traffic roads, presence of ground cover and animal density of < 1000 animals, respectively. In conclusion, the distribution pattern of the soil-borne pathogens in and around the areas of Lahore district puts both human and animal populations at a high risk of exposure. Further studies are needed to explore the genetic nature and molecular diversity of prevailing pathogens together with their seroconversion in animals and humans. PMID- 26441861 TI - The human gut virome: a multifaceted majority. AB - Here, we outline our current understanding of the human gut virome, in particular the phage component of this ecosystem, highlighting progress, and challenges in viral discovery in this arena. We reveal how developments in high-throughput sequencing technologies and associated data analysis methodologies are helping to illuminate this abundant 'biological dark matter.' Current evidence suggests that the human gut virome is a highly individual but temporally stable collective, dominated by phages exhibiting a temperate lifestyle. This viral community also appears to encode a surprisingly rich functional repertoire that confers a range of attributes to their bacterial hosts, ranging from bacterial virulence and pathogenesis to maintaining host-microbiome stability and community resilience. Despite the significant advances in our understanding of the gut virome in recent years, it is clear that we remain in a period of discovery and revelation, as new methods and technologies begin to provide deeper understanding of the inherent ecological characteristics of this viral ecosystem. As our understanding increases, the nature of the multi-partite interactions occurring between host and microbiome will become clearer, helping us to more rationally define the concepts and principles that will underpin approaches to using human gut virome components for medical or biotechnological applications. PMID- 26441862 TI - Serological response and diagnostic value of recombinant candida cell wall protein enolase, phosphoglycerate kinase, and beta-glucosidase. AB - There are no specific signs and symtoms for invasive candidiasis (IC), which makes its diagnosis a challenge. Efforts have been made for decades to establish serological assays for rapid diagnosis of IC, but none of them have found widespread clinical use. Using a systemic candiasis murine model, serological response to recombinant proteins of enolase (rEno1), phosphoglycerate kinase (rPgk1), and beta-glucosidase (rBgl2) were evaluated and rEno1 was found to possess the strongest immunoreactivity, followed by rPgk1 and rBgl2. Likewise, IgG antibody titers to rEno1, rPgk1, and rBgl2 in the positive sera of proven IC patients were determined by ELISA. Results show anti-rEno1 antibody possesses the highest titer, followed by rPgk1 and rBgl2. Antibodies against rEno1, rPgk1, and rBgl2 were detected by ELISA tests in a group of 52 proven IC patients or 50 healthy subjects, The sensitivity, specificity, positive and negative predictive values were 88.5, 90.0, 90.2, and 88.2% for anti-rEno1 detection, 86.5, 92.0, 91.8, and 86.8% for anti-rPgk1 detection, and 80.8, 90.0, 89.4, and 81.8% for anti-rBgl2 detection, respectively. The data clearly demonstrate that the recombinant proteins of Eno1, Pgk1, and Bgl2 are promising candidates for IC serodiagnosis. There's great possibility that the recombinant Eno1 will be more applicable in serodiagnosis and vaccine research on account of its strong serological response. PMID- 26441863 TI - Regulation of arsenite oxidation by the phosphate two-component system PhoBR in Halomonas sp. HAL1. AB - Previously, the expression of arsenite [As(III)] oxidase genes aioBA was reported to be regulated by a three-component regulatory system, AioXSR, in a number of As(III)-oxidizing bacterial strains. However, the regulation mechanism is still unknown when aioXSR genes are absent in some As(III)-oxidizing bacterial genomes, such as in Halomonas sp. HAL1. In this study, transposon mutagenesis and gene knock-out mutation were performed, and two mutants, HAL1-phoR 931 and HAL1-?phoB, were obtained in strain HAL1. The phoR and phoB constitute a two-component system which is responsible for phosphate (Pi) acquisition and assimilation. Both of the mutants showed negative As(III)-oxidation phenotypes in low Pi condition (0.1 mM) but not under normal Pi condition (1 mM). The phoBR complementation strain HAL1 ?phoB-C reversed the mutants' null phenotypes back to wild type status. Meanwhile, lacZ reporter fusions using pCM-lacZ showed that the expression of phoBR and aioBA were both induced by As(III) but were not induced in HAL1-phoR 931 and HAL1-?phoB. Using 15 consensus Pho box sequences, a putative Pho box was found in the aioBA regulation region. PhoB was able to bind to the putative Pho box in vivo (bacterial one-hybrid detection) and in vitro (electrophoretic mobility gel shift assay), and an 18-bp binding sequence containing nine conserved bases were determined. This study provided the evidence that PhoBR regulates the expression of aioBA in Halomonas sp. HAL1 under low Pi condition. The new regulation model further implies the close metabolic connection between As and Pi. PMID- 26441865 TI - Systemic responses in a tolerant olive (Olea europaea L.) cultivar upon root colonization by the vascular pathogen Verticillium dahliae. AB - Verticillium wilt of olive (VWO) is caused by the vascular pathogen Verticillium dahliae. One of the best VWO management measures is the use of tolerant cultivars; however, our knowledge on VWO tolerance/resistance genetics is very limited. A transcriptomic analysis was conducted to (i) identify systemic defense responses induced/repressed in aerial tissues of the tolerant cultivar Frantoio upon root colonization by V. dahliae, and (ii) determine the expression pattern of selected defense genes in olive cultivars showing differential susceptibility to VWO. Two suppression subtractive hybridization cDNA libraries, enriched in up regulated (FU) and down-regulated (FD) genes respectively, were generated from "Frantoio" aerial tissues. Results showed that broad systemic transcriptomic changes are taking place during V. dahliae-"Frantoio" interaction. A total of 585 FU and 381 FD unigenes were identified, many of them involved in defense response to (a)biotic stresses. Selected genes were then used to validate libraries and evaluate their temporal expression pattern in "Frantoio." Four defense genes were analyzed in cultivars Changlot Real (tolerant) and Picual (susceptible). An association between GRAS1 and DRR2 gene expression patterns and susceptibility to VWO was observed, suggesting that these transcripts could be further evaluated as markers of the tolerance level of olive cultivars to V. dahliae. PMID- 26441864 TI - Interplay between the alpharetroviral Gag protein and SR proteins SF2 and SC35 in the nucleus. AB - Retroviruses are positive-sense, single-stranded RNA viruses that reverse transcribe their RNA genomes into double-stranded DNA for integration into the host cell chromosome. The integrated provirus is used as a template for the transcription of viral RNA. The full-length viral RNA can be used for the translation of the Gag and Gag-Pol structural proteins or as the genomic RNA (gRNA) for encapsidation into new virions by the Gag protein. The mechanism by which Gag selectively incorporates unspliced gRNA into virus particles is poorly understood. Although Gag was previously thought to localize exclusively to the cytoplasm and plasma membrane where particles are released, we found that the Gag protein of Rous sarcoma virus, an alpharetrovirus, undergoes transient nuclear trafficking. When the nuclear export signal of RSV Gag is mutated (Gag.L219A), the protein accumulates in discrete subnuclear foci reminiscent of nuclear bodies such as splicing speckles, paraspeckles, and PML bodies. In this report, we observed that RSV Gag.L219A foci appeared to be tethered in the nucleus, partially co-localizing with the splicing speckle components SC35 and SF2. Overexpression of SC35 increased the number of Gag.L219A nucleoplasmic foci, suggesting that SC35 may facilitate the formation of Gag foci. We previously reported that RSV Gag nuclear trafficking is required for efficient gRNA packaging. Together with the data presented herein, our findings raise the intriguing hypothesis that RSV Gag may co-opt splicing factors to localize near transcription sites. Because splicing occurs co-transcriptionally, we speculate that this mechanism could allow Gag to associate with unspliced viral RNA shortly after its transcription initiation in the nucleus, before the viral RNA can be spliced or exported from the nucleus as an mRNA template. PMID- 26441866 TI - Extensive in silico analysis of Mimivirus coded Rab GTPase homolog suggests a possible role in virion membrane biogenesis. AB - Rab GTPases are the key regulators of intracellular membrane trafficking in eukaryotes. Many viruses and intracellular bacterial pathogens have evolved to hijack the host Rab GTPase functions, mainly through activators and effector proteins, for their benefit. Acanthamoeba polyphaga mimivirus (APMV) is one of the largest viruses and belongs to the monophyletic clade of nucleo-cytoplasmic large DNA viruses (NCLDV). The inner membrane lining is integral to the APMV virion structure. APMV assembly involves extensive host membrane modifications, like vesicle budding and fusion, leading to the formation of a membrane sheet that is incorporated into the virion. Intriguingly, APMV and all group I members of the Mimiviridae family code for a putative Rab GTPase protein. APMV is the first reported virus to code for a Rab GTPase (encoded by R214 gene). Our thorough in silico analysis of the subfamily specific (SF) region of Mimiviridae Rab GTPase sequences suggests that they are related to Rab5, a member of the group II Rab GTPases, of lower eukaryotes. Because of their high divergence from the existing three isoforms, A, B, and C of the Rab5-family, we suggest that Mimiviridae Rabs constitute a new isoform, Rab5D. Phylogenetic analysis indicated probable horizontal acquisition from a lower eukaryotic ancestor followed by selection and divergence. Furthermore, interaction network analysis suggests that vps34 (a Class III PI3K homolog, coded by APMV L615), Atg-8 and dynamin (host proteins) are recruited by APMV Rab GTPase during capsid assembly. Based on these observations, we hypothesize that APMV Rab plays a role in the acquisition of inner membrane during virion assembly. PMID- 26441867 TI - Seeking sunlight: rapid phototactic motility of filamentous mat-forming cyanobacteria optimize photosynthesis and enhance carbon burial in Lake Huron's submerged sinkholes. AB - We studied the motility of filamentous mat-forming cyanobacteria consisting primarily of Oscillatoria-like cells growing under low-light, low-oxygen, and high-sulfur conditions in Lake Huron's submerged sinkholes using in situ observations, in vitro measurements and time-lapse microscopy. Gliding movement of the cyanobacterial trichomes (100-10,000 MUm long filaments, composed of cells ~10 MUm wide and ~3 MUm tall) revealed individual as well as group-coordinated motility. When placed in a petri dish and dispersed in ground water from the sinkhole, filaments re-aggregated into defined colonies within minutes, then dispersed again. Speed of individual filaments increased with temperature from ~50 MUm min(-1) or ~15 body lengths min(-1) at 10 degrees C to ~215 MUm min(-1) or ~70 body lengths min(-1) at 35 degrees C - rates that are rapid relative to non-flagellated/ciliated microbes. Filaments exhibited precise and coordinated positive phototaxis toward pinpoints of light and congregated under the light of foil cutouts. Such light-responsive clusters showed an increase in photosynthetic yield - suggesting phototactic motility aids in light acquisition as well as photosynthesis. Once light source was removed, filaments slowly spread out evenly and re-aggregated, demonstrating coordinated movement through inter-filament communication regardless of light. Pebbles and pieces of broken shells placed upon intact mat were quickly covered by vertically motile filaments within hours and became fully buried in the anoxic sediments over 3-4 diurnal cycles - likely facilitating the preservation of falling debris. Coordinated horizontal and vertical filament motility optimize mat cohesion and dynamics, photosynthetic efficiency and sedimentary carbon burial in modern-day sinkhole habitats that resemble the shallow seas in Earth's early history. Analogous cyanobacterial motility may have played a key role in the oxygenation of the planet by optimizing photosynthesis while favoring carbon burial. PMID- 26441868 TI - Interactive effects of cocaine on HIV infection: implication in HIV-associated neurocognitive disorder and neuroAIDS. AB - Substantial epidemiological studies suggest that not only, being one of the reasons for the transmission of the human immunodeficiency virus (HIV), but drug abuse also serves its role in determining the disease progression and severity among the HIV infected population. This article focuses on the drug cocaine, and its role in facilitating entry of HIV into the CNS and mechanisms of development of neurologic complications in infected individuals. Cocaine is a powerfully addictive central nervous system stimulating drug, which increases the level of neurotransmitter dopamine (DA) in the brain, by blocking the dopamine transporters (DAT) which is critical for DA homeostasis and neurocognitive function. Tat protein of HIV acts as an allosteric modulator of DAT, where as cocaine acts as reuptake inhibitor. When macrophages in the CNS are exposed to DA, their number increases. These macrophages release inflammatory mediators and neurotoxins, causing chronic neuroinflammation. Cocaine abuse during HIV infection enhances the production of platelet monocyte complexes (PMCs), which may cross transendothelial barrier, and result in HIV-associated neurocognitive disorder (HAND). HAND is characterized by neuroinflammation, including astrogliosis, multinucleated giant cells, and neuronal apoptosis that is linked to progressive virus infection and immune deterioration. Cocaine and viral proteins are capable of eliciting signaling transduction pathways in neurons, involving in mitochondrial membrane potential loss, oxidative stress, activation of JNK, p38, and ERK/MAPK pathways, and results in downstream activation of NF kappaB that leads to HAND. Tat-induced inflammation provokes permeability of the blood brain barrier (BBB) in the platelet dependent manner, which can potentially be the reason for progression to HAND during HIV infection. A better understanding on the role of cocaine in HIV infection can give a clue in developing novel therapeutic strategies against HIV-1 infection in cocaine using HIV infected population. PMID- 26441869 TI - Genetic determinants of heat resistance in Escherichia coli. AB - Escherichia coli AW1.7 is a heat resistant food isolate and the occurrence of pathogenic strains with comparable heat resistance may pose a risk to food safety. To identify the genetic determinants of heat resistance, 29 strains of E. coli that differed in their of heat resistance were analyzed by comparative genomics. Strains were classified as highly heat resistant strains, exhibiting a D60-value of more than 6 min; moderately heat resistant strains, exhibiting a D60 value of more than 1 min; or as heat sensitive. A ~14 kb genomic island containing 16 predicted open reading frames encoding putative heat shock proteins and proteases was identified only in highly heat resistant strains. The genomic island was termed the locus of heat resistance (LHR). This putative operon is flanked by mobile elements and possesses >99% sequence identity to genomic islands contributing to heat resistance in Cronobacter sakazakii and Klebsiella pneumoniae. An additional 41 LHR sequences with >87% sequence identity were identified in 11 different species of beta- and gamma-proteobacteria. Cloning of the full length LHR conferred high heat resistance to the heat sensitive E. coli AW1.7DeltapHR1 and DH5alpha. The presence of the LHR correlates perfectly to heat resistance in several species of Enterobacteriaceae and occurs at a frequency of 2% of all E. coli genomes, including pathogenic strains. This study suggests the LHR has been laterally exchanged among the beta- and gamma-proteobacteria and is a reliable indicator of high heat resistance in E. coli. PMID- 26441870 TI - Diversity of laccase-coding genes in Fusarium oxysporum genomes. AB - Multiple studies confirm laccase role in fungal pathogenicity and lignocellulose degradation. In spite of broad genomic research, laccases from plant wilt pathogen Fusarium oxysporum are still not characterized. The study aimed to identify F. oxysporum genes that may encode laccases sensu stricto and to characterize the proteins in silico in order to facilitate further research on their impact on the mentioned processes. Twelve sequenced F. oxysporum genomes available on Broad Institute of Harvard and MIT (2015) website were analyzed and three genes that may encode laccases sensu stricto were found. Their amino acid sequences possess all features essential for their catalytic activity, moreover, the homology models proved the characteristic 3D laccase structures. The study shades light on F. oxysporum as a new source of multicopper oxidases, enzymes with possible high redox potential and broad perspective in biotechnological applications. PMID- 26441871 TI - Adaptation strategies of endolithic chlorophototrophs to survive the hyperarid and extreme solar radiation environment of the Atacama Desert. AB - The Atacama Desert, northern Chile, is one of the driest deserts on Earth and, as such, a natural laboratory to explore the limits of life and the strategies evolved by microorganisms to adapt to extreme environments. Here we report the exceptional adaptation strategies of chlorophototrophic and eukaryotic algae, and chlorophototrophic and prokaryotic cyanobacteria to the hyperarid and extremely high solar radiation conditions occurring in this desert. Our approach combined several microscopy techniques, spectroscopic analytical methods, and molecular analyses. We found that the major adaptation strategy was to avoid the extreme environmental conditions by colonizing cryptoendolithic, as well as, hypoendolithic habitats within gypsum deposits. The cryptoendolithic colonization occurred a few millimeters beneath the gypsum surface and showed a succession of organized horizons of algae and cyanobacteria, which has never been reported for endolithic microbial communities. The presence of cyanobacteria beneath the algal layer, in close contact with sepiolite inclusions, and their hypoendolithic colonization suggest that occasional liquid water might persist within these sub microhabitats. We also identified the presence of abundant carotenoids in the upper cryptoendolithic algal habitat and scytonemin in the cyanobacteria hypoendolithic habitat. This study illustrates that successful lithobiontic microbial colonization at the limit for microbial life is the result of a combination of adaptive strategies to avoid excess solar irradiance and extreme evapotranspiration rates, taking advantage of the complex structural and mineralogical characteristics of gypsum deposits-conceptually called "rock's habitable architecture." Additionally, self-protection by synthesis and accumulation of secondary metabolites likely produces a shielding effect that prevents photoinhibition and lethal photooxidative damage to the chlorophototrophs, representing another level of adaptation. PMID- 26441872 TI - Impact of CO2 leakage from sub-seabed carbon dioxide capture and storage (CCS) reservoirs on benthic virus-prokaryote interactions and functions. AB - Atmospheric CO2 emissions are a global concern due to their predicted impact on biodiversity, ecosystems functioning, and human life. Among the proposed mitigation strategies, CO2 capture and storage, primarily the injection of CO2 into marine deep geological formations has been suggested as a technically practical option for reducing emissions. However, concerns have been raised that possible leakage from such storage sites, and the associated elevated levels of pCO2 could locally impact the biodiversity and biogeochemical processes in the sediments above these reservoirs. Whilst a number of impact assessment studies have been conducted, no information is available on the specific responses of viruses and virus-host interactions. In the present study, we tested the impact of a simulated CO2 leakage on the benthic microbial assemblages, with specific focus on microbial activity and virus-induced prokaryotic mortality (VIPM). We found that exposure to levels of CO2 in the overlying seawater from 1,000 to 20,000 ppm for a period up to 140 days, resulted in a marked decrease in heterotrophic carbon production and organic matter degradation rates in the sediments, associated with lower rates of VIPM, and a progressive accumulation of sedimentary organic matter with increasing CO2 concentrations. These results suggest that the increase in seawater pCO2 levels that may result from CO2 leakage, can severely reduce the rates of microbial-mediated recycling of the sedimentary organic matter and viral infections, with major consequences on C cycling and nutrient regeneration, and hence on the functioning of benthic ecosystems. PMID- 26441873 TI - Biochemistry and genetics of ACC deaminase: a weapon to "stress ethylene" produced in plants. AB - 1-aminocyclopropane-1-carboxylate deaminase (ACCD), a pyridoxal phosphate dependent enzyme, is widespread in diverse bacterial and fungal species. Owing to ACCD activity, certain plant associated bacteria help plant to grow under biotic and abiotic stresses by decreasing the level of "stress ethylene" which is inhibitory to plant growth. ACCD breaks down ACC, an immediate precursor of ethylene, to ammonia and alpha-ketobutyrate, which can be further metabolized by bacteria for their growth. ACC deaminase is an inducible enzyme whose synthesis is induced in the presence of its substrate ACC. This enzyme encoded by gene AcdS is under tight regulation and regulated differentially under different environmental conditions. Regulatory elements of gene AcdS are comprised of the regulatory gene encoding LRP protein and other regulatory elements which are activated differentially under aerobic and anaerobic conditions. The role of some additional regulatory genes such as AcdB or LysR may also be required for expression of AcdS. Phylogenetic analysis of AcdS has revealed that distribution of this gene among different bacteria might have resulted from vertical gene transfer with occasional horizontal gene transfer (HGT). Application of bacterial AcdS gene has been extended by developing transgenic plants with ACCD gene which showed increased tolerance to biotic and abiotic stresses in plants. Moreover, distribution of ACCD gene or its homolog's in a wide range of species belonging to all three domains indicate an alternative role of ACCD in the physiology of an organism. Therefore, this review is an attempt to explore current knowledge of bacterial ACC deaminase mediated physiological effects in plants, mode of enzyme action, genetics, distribution among different species, ecological role of ACCD and, future research avenues to develop transgenic plants expressing foreign AcdS gene to cope with biotic and abiotic stressors. Systemic identification of regulatory circuits would be highly valuable to express the gene under diverse environmental conditions. PMID- 26441874 TI - Flow cytometric evaluation of physico-chemical impact on Gram-positive and Gram negative bacteria. AB - Since heat sensitivity of fruits and vegetables limits the application of thermal inactivation processes, new emerging inactivation technologies have to be established to fulfill the requirements of food safety without affecting the produce quality. The efficiency of inactivation treatments has to be ensured and monitored. Monitoring of inactivation effects is commonly performed using traditional cultivation methods which have the disadvantage of the time span needed to obtain results. The aim of this study was to compare the inactivation effects of peracetic acid (PAA), ozonated water (O3), and cold atmospheric pressure plasma (CAPP) on Gram-positive and Gram-negative bacteria using flow cytometric methods. E. coli cells were completely depolarized after treatment (15 s) with 0.25% PAA at 10 degrees C, and after treatment (10 s) with 3.8 mg l(-1) O3 at 12 degrees C. The membrane potential of CAPP treated cells remained almost constant at an operating power of 20 W over a time period of 3 min, and subsequently decreased within 30 s of further treatment. Complete membrane permeabilization was observed after 10 s O3 treatment, but treatment with PAA and CAPP did not completely permeabilize the cells within 2 and 4 min, respectively. Similar results were obtained for esterase activity. O3 inactivates cellular esterase but esterase activity was detected after 4 min CAPP treatment and 2 min PAA treatment. L. innocua cells and P. carotovorum cells were also permeabilized instantaneously by O3 treatment at concentrations of 3.8 +/- 1 mg l(-1). However, higher membrane permeabilization of L. innocua and P. carotovorum than of E. coli was observed at CAPP treatment of 20 W. The degree of bacterial damage due to the inactivation processes is highly dependent on treatment parameters as well as on treated bacteria. Important information regarding the inactivation mechanisms can be obtained by flow cytometric measurements and this enables the definition of critical process parameters. PMID- 26441875 TI - Nonlinear electrical impedance spectroscopy of viruses using very high electric fields created by nanogap electrodes. AB - Our living sphere is constantly exposed to a wide range of pathogenic viruses, which can be either known, or of novel origin. Currently, there is no methodology for continuously monitoring the environment for viruses in general, much less a methodology that allows the rapid and sensitive identification of a wide variety of viruses responsible for communicable diseases. Traditional approaches, based on PCR and immunodetection systems, only detect known or specifically targeted viruses. We here describe a simple device that can potentially detect any virus between nanogap electrodes using nonlinear impedance spectroscopy. Three test viruses, differing in shape and size, were used to demonstrate the general applicability of this approach: baculovirus, tobacco mosaic virus (TMV), and influenza virus. We show that each of the virus types responded differently in the nanogap to changes in the electric field strength, and the impedance of the virus solutions differed depending both on virus type and virus concentration. These preliminary results show that the three virus types can be distinguished and their approximate concentrations determined. Although further studies are required, the proposed nonlinear impedance spectroscopy method may achieve a sensitivity comparable to that of more traditional, but less versatile, virus detection systems. PMID- 26441876 TI - Co-occurrence of Methanosarcina mazei and Geobacteraceae in an iron (III) reducing enrichment culture. AB - Methanosaeta harundinacea and Methanosarcina barkeri, known as classic acetoclastic methanogens, are capable of directly accepting electrons from Geobacter metallireducens for the reduction of carbon dioxide to methane, having been revealed as direct interspecies electron transfer (DIET) in the laboratory co-cultures. However, whether their co-occurrences are ubiquitous in the iron (III)-reducing environments and the other species of acetoclastic methanogens such as Methanosarcina mazei are capable of DIET are still unknown. Instead of initiating the co-cultures with pure cultures, two-step cultivation was employed to selectively enrich iron (III)-reducing microorganisms in a coastal gold mining river, Jiehe River, with rich iron content in the sediments. First, iron (III) reducers including Geobacteraceae were successfully enriched by 3-months successive culture on amorphous Fe(III) oxides as electron acceptor and acetate as electron donor. High-throughput Illumina sequencing, terminal restriction fragment length polymorphism (T-RFLP) and clone library analysis based on 16S rRNA genes revealed that the enrichment cultures actively contained the bacteria belong to Geobacteraceae and Bacilli, exclusively dominated by the archaea belong to Methanosarcinaceae. Second, the enrichment cultures including methanogens and Geobacteraceae were transferred with ethanol as alternative electron donor. Remarkably, aggregates were successively formed in the enrichments after three transfers. The results revealed by RNA-based analysis demonstrate that the co occurrence of Methanosarcina mazei and Geobacteraceae in an iron (III)-reducing enrichment culture. Furthermore, the aggregates, as close physical contact, formed in the enrichment culture, indicate that DIET could be a possible option for interspecies electron transfer in the aggregates. PMID- 26441877 TI - Halo(natrono)archaea isolated from hypersaline lakes utilize cellulose and chitin as growth substrates. AB - Until recently, extremely halophilic euryarchaeota were considered mostly as aerobic heterotrophs utilizing simple organic compounds as growth substrates. Almost nothing is known on the ability of these prokaryotes to utilize complex polysaccharides, such as cellulose, xylan, and chitin. Although few haloarchaeal cellulases and chitinases were recently characterized, the analysis of currently available haloarchaeal genomes deciphered numerous genes-encoding glycosidases of various families including endoglucanases and chitinases. However, all these haloarchaea were isolated and cultivated on simple substrates and their ability to grow on polysaccharides in situ or in vitro is unknown. This study examines several halo(natrono)archaeal strains from geographically distant hypersaline lakes for the ability to grow on insoluble polymers as a sole growth substrate in salt-saturated mineral media. Some of them belonged to known taxa, while other represented novel phylogenetic lineages within the class Halobacteria. All isolates produced extracellular extremely salt-tolerant cellulases or chitinases, either cell-free or cell-bound. Obtained results demonstrate a presence of diverse populations of haloarchaeal cellulo/chitinotrophs in hypersaline habitats indicating that euryarchaea participate in aerobic mineralization of recalcitrant organic polymers in salt-saturated environments. PMID- 26441878 TI - Recombinant expression library of Pyrococcus furiosus constructed by high throughput cloning: a useful tool for functional and structural genomics. AB - Hyperthermophile Pyrococcus furiosus grows optimally near 100 degrees C and is an important resource of many industrial and molecular biological enzymes. To study the structure and function of P. furiosus proteins at whole genome level, we constructed expression plasmids of each P. furiosus gene using a ligase independent cloning method, which was based on amplifying target gene and vector by PCR using phosphorothioate-modified primers and digesting PCR products by lambda exonuclease. Our cloning method had a positive clone percentage of >= 80% in 96-well plate cloning format. Small-scale expression experiment showed that 55 out of 80 genes were efficiently expressed in Escherichia coli Strain Rosetta 2(DE3)pLysS. In summary, this recombinant expression library of P. furiosus provides a platform for functional and structural studies, as well as developing novel industrial enzymes. Our cloning scheme is adaptable to constructing recombinant expression library of other sequenced organisms. PMID- 26441879 TI - Geriatric Respondents and Non-Respondents to Probiotic Intervention Can be Differentiated by Inherent Gut Microbiome Composition. AB - SCOPE: Probiotic interventions are known to have been shown to influence the composition of the intestinal microbiota in geriatrics. The growing concern is the apparent variation in response to identical strain dosage among human volunteers. One factor that governs this variation is the host gut microbiome. In this study, we attempted to define a core gut metagenome, which could act as a predisposition signature marker of inherent bacterial community that can help predict the success of a probiotic intervention. METHODS AND RESULTS: To characterize the geriatric gut microbiome, we designed primers targeting the 16S rRNA hypervariable region V2-V3 followed by semiconductor sequencing using Ion Torrent PGM. Among respondents and non-respondents, the chief genera of phylum Firmicutes that showed significant differences are Lactobacillus, Clostridium, Eubacterium, and Blautia (q < 0.002), while in the genera of phylum Proteobacteria included Shigella, Escherichia, Burkholderia and Camphylobacter (q < 0.002). CONCLUSION: We have identified potential microbial biomarkers and taxonomic patterns that correlate with a positive response to probiotic intervention in geriatric volunteers. Future work with larger cohorts of geriatrics with diverse dietary influences could reveal the potential of the signature patterns of microbiota for personalized nutrition. PMID- 26441881 TI - Antibiotic resistance and mecA characterization of coagulase-negative staphylococci isolated from three hotels in London, UK. AB - Antibiotic resistance in bacteria isolated from non-healthcare environments, is a potential problem to public health. In our survey a total of 71 coagulase negative staphylococci (CNS) belonging to 11 different species were isolated from three large hotels in London, UK. The most prevalent species was Staphylococcus haemolyticus, with S. hominis, S. warneri, S. cohnii, and Staphylococcus epidermidis commonly detected. Antimicrobial susceptibilities and carriage of the mecA gene were determined for all of these isolates. Most (85.9%) staphylococci were resistant to multiple antibiotics with all displaying increased susceptibility toward penicillin, fusidic acid, erythromycin, and cefepime. Twenty-one (29.5%) of the isolates were mecA positive, however MIC values to oxacillin, normally associated with the carriage of mecA, varied widely in this group (from 0.06 to 256 mg/L). Fifteen of the twenty-one mecA positive isolates carried SCCmec of these seven were type V, one type I, one type II, and one type IV. Additionally, five of these 15 isolates carried a previously unreported type, 1A, which involves an association between class A mec complex and ccr type 1. The remaining six of the 21 isolates were non-typeable and carried a combination of class A mec complex and ccrC. In addition to this, we also report on new MLST types which were assigned for five S. epidermidis isolates. Four out of these five isolates had MICs between 0.06 and 256 mg/L to oxacillin and would be regarded as clinically susceptible but one isolate had a high oxacillin MIC of 256 mg/L. We demonstrated widespread multiple drug resistance among different staphylococcal species isolated from non-healthcare environments highlighting the potential for these species to act as a reservoir for methicillin and other forms of drug resistance. PMID- 26441880 TI - Legume-rhizobia signal exchange: promiscuity and environmental effects. AB - Although signal exchange between legumes and their rhizobia is among the best known examples of this biological process, most of the more characterized data comes from just a few legume species and environmental stresses. Although a relative wealth of information is available for some model legumes and some of the major pulses such as soybean, little is known about tropical legumes. This relative disparity in current knowledge is also apparent in the research on the effects of environmental stress on signal exchange; cool-climate stresses, such as low-soil temperature, comprise a relatively large body of research, whereas high-temperature stresses and drought are not nearly as well understood. Both tropical legumes and their environmental stress-induced effects are increasingly important due to global population growth (the demand for protein), climate change (increasing temperatures and more extreme climate behavior), and urbanization (and thus heavy metals). This knowledge gap for both legumes and their environmental stresses is compounded because whereas most temperate legume rhizobia symbioses are relatively specific and cultivated under relatively stable environments, the converse is true for tropical legumes, which tend to be promiscuous, and grow in highly variable conditions. This review will clarify some of this missing information and highlight fields in which further research would benefit our current knowledge. PMID- 26441884 TI - Spontaneous large-scale autolysis in Clostridium acetobutylicum contributes to generation of more spores. AB - Autolysis is a widespread phenomenon in bacteria. In batch fermentation of Clostridium acetobutylicum ATCC 824, there is a spontaneous large-scale autolysis phenomenon with significant decrease of cell density immediately after exponential phase. To unravel the role of autolysis, an autolysin-coding gene, CA_C0554, was disrupted by using ClosTron system to obtain the mutant C. acetobutylicum lyc::int(72). The lower final cell density and faster cell density decrease rate of C. acetobutylicum ATCC 824 than those of C. acetobutylicum lyc::int(72) indicates that CA_C0554 was an important but not the sole autolysin coding gene responding for the large-scale autolysis. Similar glucose utilization and solvents production but obvious lower cell density of C. acetobutylicum ATCC 824 comparing to C. acetobutylicum lyc::int(72) suggests that lysed C. acetobutylicum ATCC 824 cells were metabolic inactive. On the contrary, the spore density of C. acetobutylicum ATCC 824 is 26.1% higher than that of C. acetobutylicum lyc::int(72) in the final culture broth of batch fermentation. We speculated that spontaneous autolysis of metabolic-inactive cells provided nutrients for the sporulating cells. The present study suggests that one important biological role of spontaneous large-scale autolysis in C. acetobutylicum ATCC 824 batch fermentation is contributing to generation of more spores during sporulation. PMID- 26441882 TI - Role of MRP transporters in regulating antimicrobial drug inefficacy and oxidative stress-induced pathogenesis during HIV-1 and TB infections. AB - Multi-Drug Resistance Proteins (MRPs) are members of the ATP binding cassette (ABC) drug-efflux transporter superfamily. MRPs are known to regulate the efficacy of a broad range of anti-retroviral drugs (ARV) used in highly active antiretroviral therapy (HAART) and antibacterial agents used in Tuberculus Bacilli (TB) therapy. Due to their role in efflux of glutathione (GSH) conjugated drugs, MRPs can also regulate cellular oxidative stress, which may contribute to both HIV and/or TB pathogenesis. This review focuses on the characteristics, functional expression, and modulation of known members of the MRP family in HIV infected cells exposed to ARV drugs and discusses their known role in drug inefficacy in HIV/TB-induced dysfunctions. Currently, nine members of the MRP family (MRP1-MRP9) have been identified, with MRP1 and MRP2 being the most extensively studied. Details of the other members of this family have not been known until recently, but differential expression has been documented in inflammatory tissues. Researchers have found that the distribution, function, and reactivity of members of MRP family vary in different types of lymphocytes and macrophages, and are differentially expressed at the basal and apical surfaces of both endothelial and epithelial cells. Therefore, the prime objective of this review is to delineate the role of MRP transporters in HAART and TB therapy and their potential in precipitating cellular dysfunctions manifested in these chronic infectious diseases. We also provide an overview of different available options and novel experimental strategies that are being utilized to overcome the drug resistance and disease pathogenesis mediated by these membrane transporters. PMID- 26441885 TI - Cooperative pathogenicity in cystic fibrosis: Stenotrophomonas maltophilia modulates Pseudomonas aeruginosa virulence in mixed biofilm. AB - The present study was undertaken in order to understand more about the interaction occurring between S. maltophilia and P. aeruginosa, which are frequently co-isolated from CF airways. For this purpose, S. maltophilia RR7 and P. aeruginosa RR8 strains, co-isolated from the lung of a chronically infected CF patient during a pulmonary exacerbation episode, were evaluated for reciprocal effect during planktonic growth, adhesion and biofilm formation onto both polystyrene and CF bronchial cell monolayer, motility, as well as for gene expression in mixed biofilms. P. aeruginosa significantly affected S. maltophilia growth in both planktonic and biofilm cultures, due to an inhibitory activity probably requiring direct contact. Conversely, no effect was observed on P. aeruginosa by S. maltophilia. Compared with monocultures, the adhesiveness of P. aeruginosa on CFBE41o- cells was significantly reduced by S. maltophilia, which probably acts by reducing P. aeruginosa's swimming motility. An opposite trend was observed for biofilm formation, confirming the findings obtained using polystyrene. When grown in mixed biofilm with S. maltophilia, P. aeruginosa significantly over-expressed aprA, and algD-codifying for protease and alginate, respectively-while the quorum sensing related rhlR and lasI genes were down regulated. The induced alginate expression by P. aeruginosa might be responsible for the protection of S. maltophilia against tobramycin activity we observed in mixed biofilms. Taken together, our results suggest that the existence of reciprocal interference of S. maltophilia and P. aeruginosa in CF lung is plausible. In particular, S. maltophilia might confer some selective "fitness advantage" to P. aeruginosa under the specific conditions of chronic infection or, alternatively, increase the virulence of P. aeruginosa thus leading to pulmonary exacerbation. PMID- 26441883 TI - Regulatory principles governing Salmonella and Yersinia virulence. AB - Enteric pathogens such as Salmonella and Yersinia evolved numerous strategies to survive and proliferate in different environmental reservoirs and mammalian hosts. Deciphering common and pathogen-specific principles for how these bacteria adjust and coordinate spatiotemporal expression of virulence determinants, stress adaptation, and metabolic functions is fundamental to understand microbial pathogenesis. In order to manage sudden environmental changes, attacks by the host immune systems and microbial competition, the pathogens employ a plethora of transcriptional and post-transcriptional control elements, including transcription factors, sensory and regulatory RNAs, RNAses, and proteases, to fine-tune and control complex gene regulatory networks. Many of the contributing global regulators and the molecular mechanisms of regulation are frequently conserved between Yersinia and Salmonella. However, the interplay, arrangement, and composition of the control elements vary between these closely related enteric pathogens, which generate phenotypic differences leading to distinct pathogenic properties. In this overview we present common and different regulatory networks used by Salmonella and Yersinia to coordinate the expression of crucial motility, cell adhesion and invasion determinants, immune defense strategies, and metabolic adaptation processes. We highlight evolutionary changes of the gene regulatory circuits that result in different properties of the regulatory elements and how this influences the overall outcome of the infection process. PMID- 26441886 TI - The vaginal isolate Lactobacillus paracasei LPC-S01 (DSM 26760) is suitable for oral administration. AB - Bacterial vaginosis is one of the most common urogenital diseases affecting women in reproductive age. The administration of probiotics as vaginal suppository has been proposed as a strategy to cure this condition and reduce its recurrence. Nonetheless, also oral consumption of probiotics, which is a more practical route of administration, proved to be an efficient strategy. In this perspective, we studied Lactobacillus paracasei LPC-S01 (DSM 26760), a human vaginal isolate included in commercial probiotic preparations for topical use, in order to assess if this bacterium can also perform as gastrointestinal probiotic. Comparative genomics revealed the presence of several accessory genes suggesting that LPC-S01 is a niche-generalist member of its species. According to a procedure conventionally used to predict the probiotic potential, we demonstrated that the probiotic properties of strain LPC-S01, with respect to those of the well-known probiotic references L. paracasei Shirota and DG, are equal for the bile tolerance and the reduction of NF-kappaB activation in Caco-2 cells, or superior for the tolerance to gastric juice and the adhesion to Caco-2 epithelial cells. We then demonstrated that LPC-S01 is susceptible to antibiotics indicated by EFSA and does not produce biogenic amines. Finally, a double-blind cross-over pilot intervention trial on healthy human volunteers showed that, after a 7-days oral consumption of capsules containing about 24 billion live cells, the fecal cell concentrations of strains LPC-S01 and DG (evaluated by qPCR) were not dissimilar. Specifically, both probiotics' cell concentrations were above the detection limit for an average of 5 days from the end of the treatment, corresponding to a mean number of evacuations of 7 +/- 2. Taken together, these data demonstrate that the vaginal isolate L. paracasei LPC-S01 possesses safety and functional properties that may support its use as probiotic to be administered per os for potential intestinal as well as vaginal applications. PMID- 26441887 TI - Effect of carbon on whole-biofilm metabolic response to high doses of streptomycin. AB - Biofilms typically exist as complex communities comprising multiple species with the ability to adapt to a variety of harsh conditions. In clinical settings, antibiotic treatments based on planktonic susceptibility tests are often ineffective against biofilm infections. Using a CO2 evolution measurement system we delineated the real-time metabolic response in continuous flow biofilms to streptomycin doses much greater than their planktonic susceptibilities. Stable biofilms from a multispecies culture (containing mainly Pseudomonas aeruginosa and Stenotrophomonas maltophilia), Gram-negative environmental isolates, and biofilms formed by pure culture P. aeruginosa strains PAO1 and PAO1 DeltaMexXY (minimum planktonic inhibitory concentrations between 1.5 and 3.5 mg/l), were exposed in separate experiments to 4000 mg/l streptomycin for 4 h after which growth medium resumed. In complex medium, early steady state multispecies biofilms were susceptible to streptomycin exposure, inferred by a cessation of CO2 production. However, multispecies biofilms survived high dose exposures when there was extra carbon in the antibiotic medium, or when they were grown in defined citrate medium. The environmental isolates and PAO1 biofilms showed similar metabolic profiles in response to streptomycin; ceasing CO2 production after initial exposure, with CO2 levels dropping toward baseline levels prior to recovery back to steady state levels, while subsequent antibiotic exposure elicited increased CO2 output. Monitoring biofilm metabolic response in real-time allowed exploration of conditions resulting in vulnerability after antibiotic exposure compared to the resistance displayed following subsequent exposures. PMID- 26441888 TI - Diversity and antibiotic susceptibility of autochthonous dairy enterococci isolates: are they safe candidates for autochthonous starter cultures? AB - Enterococci represent the most controversial group of dairy bacteria. They are found to be the main constituent of many traditional Mediterranean dairy products and contribute to their characteristic taste and flavor. On the other hand, during the last 50 years antibiotic-resistant enterococci have emerged as leading causes of nosocomial infections worldwide. The aim of this study was to determine the diversity, technological properties, antibiotic susceptibility and virulence traits of 636 enterococci previously isolated from 55 artisan dairy products from 12 locations in the Western Balkan countries (WBC) of Serbia, Croatia and Bosnia and Herzegovina. All strains were identified both by microbiological and molecular methods. The predominant species was Enterococcus durans, followed by Enterococcus faecalis and Enterococcus faecium. Over 44% of the isolates were resistant to ciprofloxacin and erythromycin, while 26.2% of the isolates were multi-resistant to three or more antibiotics belonging to different families. 185 isolates (29.1%) were susceptible to all 13 of the antibiotics tested. The antibiotic-susceptible isolates were further tested for possible virulence genes and the production of biogenic amines. Finally, five enterococci isolates were found to be antibiotic susceptible with good technological characteristics and without virulence traits or the ability to produce biogenic amines, making them possible candidates for biotechnological application as starter cultures in the dairy industry. PMID- 26441889 TI - Direct sequencing of human gut virome fractions obtained by flow cytometry. AB - The sequence assembly of the human gut virome encounters several difficulties. A high proportion of human and bacterial matches is detected in purified viral samples. Viral DNA extraction results in a low DNA concentration, which does not reach the minimal limit required for sequencing library preparation. Therefore, the viromes are usually enriched by whole genome amplification (WGA), which is, however, prone to the development of chimeras and amplification bias. In addition, as there is a very wide diversity of gut viral species, very extensive sequencing efforts must be made for the assembling of whole viral genomes. We present an approach to improve human gut virome assembly by employing a more precise preparation of a viral sample before sequencing. Particles present in a virome previously filtered through 0.2 MUm pores were further divided into groups in accordance with their size and DNA content by fluorescence activated cell sorting (FACS). One selected viral fraction was sequenced excluding the WGA step, so that unbiased sequences with high reliability were obtained. The DNA extracted from the 314 viral particles of the selected fraction was assembled into 34 contigs longer than 1,000 bp. This represents an increase to the number of assembled long contigs per sequenced Gb in comparison with other studies where non-fractioned viromes are sequenced. Seven of these contigs contained open reading frames (ORFs) with explicit matches to proteins related to bacteriophages. The remaining contigs also possessed uncharacterized ORFs with bacteriophage-related domains. When the particles that are present in the filtered viromes are sorted into smaller groups by FACS, large pieces of viral genomes can be recovered easily. This approach has several advantages over the conventional sequencing of non-fractioned viromes: non-viral contamination is reduced and the sequencing efforts required for viral assembly are minimized. PMID- 26441891 TI - A water-forming NADH oxidase from Lactobacillus pentosus suitable for the regeneration of synthetic biomimetic cofactors. AB - The cell-free biocatalytic production of fine chemicals by oxidoreductases has continuously grown over the past years. Since especially dehydrogenases depend on the stoichiometric use of nicotinamide pyridine cofactors, an integrated efficient recycling system is crucial to allow process operation under economic conditions. Lately, the variety of cofactors for biocatalysis was broadened by the utilization of totally synthetic and cheap biomimetics. Though, to date the regeneration has been limited to chemical or electrochemical methods. Here, we report an enzymatic recycling by the flavoprotein NADH-oxidase from Lactobacillus pentosus (LpNox). Since this enzyme has not been described before, we first characterized it in regard to its optimal reaction parameters. We found that the heterologously overexpressed enzyme only contained 13% FAD. In vitro loading of the enzyme with FAD, resulted in a higher specific activity towards its natural cofactor NADH as well as different nicotinamide derived biomimetics. Apart from the enzymatic recycling, which gives water as a by-product by transferring four electrons onto oxygen, unbound FAD can also catalyze the oxidation of biomimetic cofactors. Here a two electron process takes place yielding H2O2 instead. The enzymatic and chemical recycling was compared in regard to reaction kinetics for the natural and biomimetic cofactors. With LpNox and FAD, two recycling strategies for biomimetic cofactors are described with either water or hydrogen peroxide as by-product. PMID- 26441890 TI - Yersinia pestis and Yersinia pseudotuberculosis infection: a regulatory RNA perspective. AB - Yersinia pestis, responsible for causing fulminant plague, has evolved clonally from the enteric pathogen, Y. pseudotuberculosis, which in contrast, causes a relatively benign enteric illness. An ~97% nucleotide identity over 75% of their shared protein coding genes is maintained between these two pathogens, leaving much conjecture regarding the molecular determinants responsible for producing these vastly different disease etiologies, host preferences and transmission routes. One idea is that coordinated production of distinct factors required for host adaptation and virulence in response to specific environmental cues could contribute to the distinct pathogenicity distinguishing these two species. Small non-coding RNAs that direct posttranscriptional regulation have recently been identified as key molecules that may provide such timeous expression of appropriate disease enabling factors. Here the burgeoning field of small non coding regulatory RNAs in Yersinia pathogenesis is reviewed from the viewpoint of adaptive colonization, virulence and divergent evolution of these pathogens. PMID- 26441892 TI - Model-driven discovery of synergistic inhibitors against E. coli and S. enterica serovar Typhimurium targeting a novel synthetic lethal pair, aldA and prpC. AB - Mathematical models of biochemical networks form a cornerstone of bacterial systems biology. Inconsistencies between simulation output and experimental data point to gaps in knowledge about the fundamental biology of the organism. One such inconsistency centers on the gene aldA in Escherichia coli: it is essential in a computational model of E. coli metabolism, but experimentally it is not. Here, we reconcile this disparity by providing evidence that aldA and prpC form a synthetic lethal pair, as the double knockout could only be created through complementation with a plasmid-borne copy of aldA. Moreover, virtual and biological screening against the two proteins led to a set of compounds that inhibited the growth of E. coli and Salmonella enterica serovar Typhimurium synergistically at 100-200 MUM individual concentrations. These results highlight the power of metabolic models to drive basic biological discovery and their potential use to discover new combination antibiotics. PMID- 26441893 TI - Isolation, characterization, and complete genome analysis of P1312, a thermostable bacteriophage that infects Thermobifida fusca. AB - Thermobifida fusca is a moderately thermophilic and cellulolytic actinobacterium. It is of particular interest due to its ability to not only produce a variety of biotechnologically relevant enzymes but also serve as an alternative host for metabolic engineering for the production of valuable chemicals from lignocellulosic agricultural wastes. No bacteriophage that infects T. fusca has been reported, despite its potential impacts on the utilization of T. fusca. In this study, an extremely thermostable bacteriophage P1312 that infects T. fusca was isolated from manure compost. Electron microscopy showed that P1312 has an icosahedral head and a long flexible non-contractile tail, a characteristic of the family Siphoviridae. P1312 has a double-stranded DNA genome of 60,284 bp with 93 potential ORFs. Thirty-one ORFs encode proteins having putative biological functions. The genes involved in phage particle formation cluster together in a region of approximately 16 kb, followed by a segment containing genes presumably for DNA degradation/modification and cell wall disruption. The genes required for DNA replication and transcriptional control are dispersed within the rest of the genome. Phylogenetic analysis of large terminase subunit suggests that P1312 is a headful packaging phage containing a chromosome with circularly permuted direct terminal repeats. PMID- 26441894 TI - Spatial and temporal dynamics of virus occurrence in two freshwater lakes captured through metagenomic analysis. AB - Viruses are the most abundant microorganisms in the aquatic environment, yet the identification of viruses and assessing their diversity still remains a challenge. Here, we present a robust, routinely usable approach to identify viruses from two freshwater lakes of the lower Great Lakes region, Lake Ontario, and Lake Erie. We collected water samples from six different beaches of these two lakes during the summer period of 2012 and 2013, and separated into three distinct fractions, namely a bacterial fraction, a virus like particle (VLP) fraction, and a fraction of eDNA (environmental DNA). DNA extracted from all three fractions was sequenced and bioinformatic analyses of sequences revealed the presence of viruses from major viral families. The analyzed viral sequences were dominated by bacteriophage sequences, but also contained many plant and animal viruses. Within the context of this study, geographic location does not appear to have a major impact on viral abundance and diversity, since virome composition of both lakes were similar. Comparative analyses between eDNA and viral fractions showed that eDNA can be used in combination with VLP fractions to identify viruses from the environment. PMID- 26441895 TI - pH-driven shifts in overall and transcriptionally active denitrifiers control gaseous product stoichiometry in growth experiments with extracted bacteria from soil. AB - Soil pH is a strong regulator for activity as well as for size and composition of denitrifier communities. Low pH not only lowers overall denitrification rates but also influences denitrification kinetics and gaseous product stoichiometry. N2O reductase is particularly sensitive to low pH which seems to impair its activity post-transcriptionally, leading to higher net N2O production. Little is known about how complex soil denitrifier communities respond to pH change and whether their ability to maintain denitrification over a wider pH range relies on phenotypic redundancy. In the present study, we followed the abundance and composition of an overall and transcriptionally active denitrifier community extracted from a farmed organic soil in Sweden (pH H2O = 7.1) when exposed to pH 5.4 and drifting back to pH 6.6. The soil was previously shown to retain much of its functioning (low N2O/N2 ratios) over a wide pH range, suggesting a high functional versatility of the underlying community. We found that denitrifier community composition, abundance and transcription changed throughout incubation concomitant with pH change in the medium, allowing for complete reduction of nitrate to N2 with little accumulation of intermediates. When exposed to pH 5.4, the denitrifier community was able to grow but reduced N2O to N2 only when near neutral pH was reestablished by the alkalizing metabolic activity of an acid tolerant part of the community. The genotypes proliferating under these conditions differed from those dominant in the control experiment run at neutral pH. Denitrifiers of the nirS-type appeared to be severely suppressed by low pH and nirK-type and nosZ-containing denitrifiers showed strongly reduced transcriptional activity and growth, even after restoration of neutral pH. Our study suggests that low pH episodes alter transcriptionally active populations which shape denitrifier communities and determine their gas kinetics. PMID- 26441896 TI - Identification of natural inhibitors of Entamoeba histolytica cysteine synthase from microbial secondary metabolites. AB - Amebiasis is a common worldwide diarrheal disease, caused by the protozoan parasite, Entamoeba histolytica. Metronidazole has been a drug of choice against amebiasis for decades despite its known side effects and low efficacy against asymptomatic cyst carriers. E. histolytica is also capable of surviving sub therapeutic levels of metronidazole in vitro. Novel drugs with different mode of action are therefore urgently needed. The sulfur assimilatory de novo L-cysteine biosynthetic pathway is essential for various cellular activities, including the proliferation and anti-oxidative defense of E. histolytica. Since the pathway, consisting of two reactions catalyzed by serine acetyltransferase (SAT) and cysteine synthase (CS, O-acetylserine sulfhydrylase), does not exist in humans, it is a rational drug target against amebiasis. To discover inhibitors against the CS of E. histolytica (EhCS), the compounds of Kitasato Natural Products Library were screened against two recombinant CS isozymes: EhCS1 and EhCS3. Nine compounds inhibited EhCS1 and EhCS3 with IC50 values of 0.31-490 MUM. Of those, seven compounds share a naphthoquinone moiety, indicating the structural importance of the moiety for binding to the active site of EhCS1 and EhCS3. We further screened >9,000 microbial broths for CS inhibition and purified two compounds, xanthofulvin and exophillic acid from fungal broths. Xanthofulvin inhibited EhCS1 and EhCS3. Exophillic acid showed high selectivity against EhCS1, but exhibited no inhibition against EhCS3. In vitro anti-amebic activity of the 11 EhCS inhibitors was also examined. Deacetylkinamycin C and nanaomycin A showed more potent amebicidal activity with IC50 values of 18 and 0.8 MUM, respectively, in the cysteine deprived conditions. The differential sensitivity of trophozoites against deacetylkinamycin C in the presence or absence of L-cysteine in the medium and the IC50 values against EhCS suggest the amebicidal effect of deacetylkinamycin C is due to CS inhibition. PMID- 26441897 TI - Pseudomonas Exotoxin A: optimized by evolution for effective killing. AB - Pseudomonas Exotoxin A (PE) is the most toxic virulence factor of the pathogenic bacterium Pseudomonas aeruginosa. This review describes current knowledge about the intoxication pathways of PE. Moreover, PE represents a remarkable example for pathoadaptive evolution, how bacterial molecules have been structurally and functionally optimized under evolutionary pressure to effectively impair and kill their host cells. PMID- 26441898 TI - IncF plasmid diversity in multi-drug resistant Escherichia coli strains from animals in China. AB - The purpose of this study was to characterize a collection of 103 multidrug resistance IncF plasmids recovered from Escherichia coli of food producing and companion animals between 2003 and 2012. A total of 103 incF plasmids were characterized using an established PCR-based IncF replicon sequence typing (RST) system to identify FII, FIA, and FIB (FAB) groups. Plasmids were also analyzed using-restriction fragment length polymorphism (RFLP). Antibiotic Resistance determinants bla CTX-M , plasmid-mediated quinolone resistance (PMQR) genes and rmtB and plasmid addiction systems (PAS) were identified by PCR screening. A total of 20 different RSTs from 103 IncF plasmids were identified. The groups F2 and F33 with the RST formulae A-: B- were the most frequently encountered types (63.1%). The antibiotic resistance genes (ARGs) bla CTX-M , rmtB, and oqxB were carried by 82, 37, and 34 IncF plasmids, respectively. Most of these plasmids carried more than one resistance gene (59.2%, 61/103). The IncF plasmids also had a high frequency of addiction systems (mean 2.54) and two antisense RNA-regulated systems (hok-sok and srnBC) and a protein antitoxin-regulated system (pemKI) were the most prevalent. Not surprisingly, RFLP profiles among the IncF plasmids were diverse even though some shared identical IncF-RSTs. This is the first extensive study of IncF plasmid-positive E. coli isolates from animals in China. Our results demonstrate that IncF is the most prevalent plasmid family in E. coli plasmids and they commonly carry multiple resistance determinants that render them resistant to different antibiotic classes simultaneously. IncF plasmids also harbor addiction systems, promoting their stability and maintenance in the bacterial host, under changing environmental conditions. PMID- 26441899 TI - Malaria vaccines: identifying Plasmodium falciparum liver-stage targets. AB - The development of a highly efficacious and durable vaccine for malaria remains a top priority for global health researchers. Despite the huge rise in recognition of malaria as a global health problem and the concurrent rise in funding over the past 10-15 years, malaria continues to remain a widespread burden. The evidence of increasing resistance to anti-malarial drugs and insecticides is a growing concern. Hence, an efficacious and durable preventative vaccine for malaria is urgently needed. Vaccines are one of the most cost-effective tools and have successfully been used in the prevention and control of many diseases, however, the development of a vaccine for the Plasmodium parasite has proved difficult. Given the early success of whole sporozoite mosquito-bite delivered vaccination strategies, we know that a vaccine for malaria is an achievable goal, with sub unit vaccines holding great promise as they are simple and cheap to both manufacture and deploy. However a major difficulty in development of sub-unit vaccines lies within choosing the appropriate antigenic target from the 5000 or so genes expressed by the parasite. Given the liver-stage of malaria represents a bottle-neck in the parasite's life cycle, there is widespread agreement that a multi-component sub-unit malaria vaccine should preferably contain a liver-stage target. In this article we review progress in identifying and screening Plasmodium falciparum liver-stage targets for use in a malaria vaccine. PMID- 26441900 TI - Metagenomic analysis reveals that modern microbialites and polar microbial mats have similar taxonomic and functional potential. AB - Within the subarctic climate of Clinton Creek, Yukon, Canada, lies an abandoned and flooded open-pit asbestos mine that harbors rapidly growing microbialites. To understand their formation we completed a metagenomic community profile of the microbialites and their surrounding sediments. Assembled metagenomic data revealed that bacteria within the phylum Proteobacteria numerically dominated this system, although the relative abundances of taxa within the phylum varied among environments. Bacteria belonging to Alphaproteobacteria and Gammaproteobacteria were dominant in the microbialites and sediments, respectively. The microbialites were also home to many other groups associated with microbialite formation including filamentous cyanobacteria and dissimilatory sulfate-reducing Deltaproteobacteria, consistent with the idea of a shared global microbialite microbiome. Other members were present that are typically not associated with microbialites including Gemmatimonadetes and iron-oxidizing Betaproteobacteria, which participate in carbon metabolism and iron cycling. Compared to the sediments, the microbialite microbiome has significantly more genes associated with photosynthetic processes (e.g., photosystem II reaction centers, carotenoid, and chlorophyll biosynthesis) and carbon fixation (e.g., CO dehydrogenase). The Clinton Creek microbialite communities had strikingly similar functional potentials to non-lithifying microbial mats from the Canadian High Arctic and Antarctica, but are functionally distinct, from non-lithifying mats or biofilms from Yellowstone. Clinton Creek microbialites also share metabolic genes (R (2) < 0.750) with freshwater microbial mats from Cuatro Cienegas, Mexico, but are more similar to polar Arctic mats (R (2) > 0.900). These metagenomic profiles from an anthropogenic microbialite-forming ecosystem provide context to microbialite formation on a human-relevant timescale. PMID- 26441901 TI - Biogeography and evolution of Thermococcus isolates from hydrothermal vent systems of the Pacific. AB - Thermococcus is a genus of hyperthermophilic archaea that is ubiquitous in marine hydrothermal environments growing in anaerobic subsurface habitats but able to survive in cold oxygenated seawater. DNA analyses of Thermococcus isolates were applied to determine the relationship between geographic distribution and relatedness focusing primarily on isolates from the Juan de Fuca Ridge and South East Pacific Rise. Amplified fragment length polymorphism (AFLP) analysis and multilocus sequence typing (MLST) were used to resolve genomic differences in 90 isolates of Thermococcus, making biogeographic patterns and evolutionary relationships apparent. Isolates were differentiated into regionally endemic populations however there was also evidence in some lineages of cosmopolitan distribution. The biodiversity identified in Thermococcus isolates and presence of distinct lineages within the same vent site suggests the utilization of varying ecological niches in this genus. In addition to resolving biogeographic patterns in Thermococcus, this study has raised new questions about the closely related Pyrococcus genus. The phylogenetic placement of Pyrococcus type strains shows the close relationship between Thermococcus and Pyrococcus and the unresolved divergence of these two genera. PMID- 26441902 TI - Attributes of carbapenemase encoding conjugative plasmid pNDM-SAL from an extensively drug-resistant Salmonella enterica Serovar Senftenberg. AB - A carbapenem resistant Salmonella enterica serovar Senftenberg isolate BCH 2406 was isolated from a diarrheal child attending an outpatient unit of B.C. Roy Hospital in Kolkata, India. This isolate was positive for the bla NDM-1 in the PCR assay, which was confirmed by amplicon sequencing. Except for tetracycline, this isolate was resistant to all the tested antimicrobials. The bla NDM-1 was found to be located on a 146.13-kb mega plasmid pNDM-SAL, which could be conjugally transferred into Escherichia coli and other enteric pathogens such as Vibrio cholerae O1 Ogawa and Shigella flexneri 2a. However, the expression of beta-lactam resistance is not the same in different bacteria. The whole genome sequence of pNDM-SAL was determined and compared with other pNDM plasmids available in public domain. This plasmid is an IncA/C incompatibility type composed of 155 predicted coding sequences and shares homology with plasmids of E. coli pNDM-1_Dok01, Klebsiella pNDM-KN, and Citrobacter pNDM-CIT. In pNDM-SAL, gene cluster containing bla NDM-1 was located between IS26 and IS4321 elements. Between the IS26 element and the bla NDM-1, a truncated ISAba125 insertion sequence was identified. Downstream of the bla NDM-1, other genes, such as ble MBL, trpF, tat, and an ISCR1 element with class 1 integron containing aac(6')-Ib were detected. Another beta-lactacamase gene, bla CMY -4 was found to be inserted in IS1 element within the type IV conjugative transfer loci of the plasmid. This gene cluster had blc and sugE downstream of the bla CMY -4. From our findings, it appears that the strain S. Senftenberg could have acquired the NDM plasmid from the other members of Enterobacteriaceae. Transfer of NDM plasmids poses a danger in the management of infectious diseases. PMID- 26441903 TI - French invasive Asian tiger mosquito populations harbor reduced bacterial microbiota and genetic diversity compared to Vietnamese autochthonous relatives. AB - The Asian tiger mosquito Aedes albopictus is one of the most significant pathogen vectors of the twenty-first century. Originating from Asia, it has invaded a wide range of eco-climatic regions worldwide. The insect-associated microbiota is now recognized to play a significant role in host biology. While genetic diversity bottlenecks are known to result from biological invasions, the resulting shifts in host-associated microbiota diversity has not been thoroughly investigated. To address this subject, we compared four autochthonous Ae. albopictus populations in Vietnam, the native area of Ae. albopictus, and three populations recently introduced to Metropolitan France, with the aim of documenting whether these populations display differences in host genotype and bacterial microbiota. Population-level genetic diversity (microsatellite markers and COI haplotype) and bacterial diversity (16S rDNA metabarcoding) were compared between field-caught mosquitoes. Bacterial microbiota from the whole insect bodies were largely dominated by Wolbachia pipientis. Targeted analysis of the gut microbiota revealed a greater bacterial diversity in which a fraction was common between French and Vietnamese populations. The genus Dysgonomonas was the most prevalent and abundant across all studied populations. Overall genetic diversities of both hosts and bacterial microbiota were significantly reduced in recently established populations of France compared to the autochthonous populations of Vietnam. These results open up many important avenues of investigation in order to link the process of geographical invasion to shifts in commensal and symbiotic microbiome communities, as such shifts may have dramatic impacts on the biology and/or vector competence of invading hematophagous insects. PMID- 26441904 TI - The diversity of the N2O reducers matters for the N2O:N2 denitrification end product ratio across an annual and a perennial cropping system. AB - Agriculture is the main source of terrestrial emissions of N2O, a potent greenhouse gas and the main cause of ozone layer depletion. The reduction of N2O into N2 by microorganisms carrying the nitrous oxide reductase gene (nosZ) is the only biological process known to eliminate this greenhouse gas. Recent studies showed that a previously unknown clade of N2O-reducers was related to the capacity of the soil to act as an N2O sink, opening the way for new strategies to mitigate emissions. Here, we investigated whether the agricultural practices could differently influence the two N2O reducer clades with consequences for denitrification end-products. The abundance of N2O-reducers and producers was quantified by real-time PCR, and the diversity of both nosZ clades was determined by 454 pyrosequencing. Potential N2O production and potential denitrification activity were used to calculate the denitrification gaseous end-product ratio. Overall, the results showed limited differences between management practices but there were significant differences between cropping systems in both the abundance and structure of the nosZII community, as well as in the [rN2O/r(N2O+N2)] ratio. More limited differences were observed in the nosZI community, suggesting that the newly identified nosZII clade is more sensitive than nosZI to environmental changes. Potential denitrification activity and potential N2O production were explained mainly by the soil properties while the diversity of the nosZII clade on its own explained 26% of the denitrification end-product ratio, which highlights the importance of understanding the ecology of this newly identified clade of N2O reducers for mitigation strategies. PMID- 26441905 TI - Efficient recombinant production of prodigiosin in Pseudomonas putida. AB - Serratia marcescens and several other bacteria produce the red-colored pigment prodigiosin which possesses bioactivities as an antimicrobial, anticancer, and immunosuppressive agent. Therefore, there is a great interest to produce this natural compound. Efforts aiming at its biotechnological production have so far largely focused on the original producer and opportunistic human pathogen S. marcescens. Here, we demonstrate efficient prodigiosin production in the heterologous host Pseudomonas putida. Random chromosomal integration of the 21 kb prodigiosin biosynthesis gene cluster of S. marcescens in P. putida KT2440 was employed to construct constitutive prodigiosin production strains. Standard cultivation parameters were optimized such that titers of 94 mg/L culture were obtained upon growth of P. putida at 20 degrees C using rich medium under high aeration conditions. Subsequently, a novel, fast and effective protocol for prodigiosin extraction and purification was established enabling the straightforward isolation of prodigiosin from P. putida growth medium. In summary, we describe here a highly efficient method for the heterologous biosynthetic production of prodigiosin which may serve as a basis to produce large amounts of this bioactive natural compound and may provide a platform for further in-depth studies of prodiginine biosynthesis. PMID- 26441906 TI - Oleylphosphocholine (OlPC) arrests Cryptosporidium parvum growth in vitro and prevents lethal infection in interferon gamma receptor knock-out mice. AB - Cryptosporidium parvum is a species of protozoa that causes cryptosporidiosis, an intestinal disease affecting many mammals including humans. Typically, in healthy individuals, cryptosporidiosis is a self-limiting disease. However, C. parvum can cause a severe and persistent infection that can be life-threatening for immunocompromised individuals, such as AIDS patients. As there are no available treatments for these patients that can cure the disease, there is an urgent need to identify treatment options. We tested the anti-parasitic activity of the alkylphosphocholine oleylphosphocholine (OlPC), an analog of miltefosine, against C. parvum in in vitro and in vivo studies. In vitro experiments using C. parvum infected human ileocecal adenocarcinoma cells (HCT-8 cells) showed that OlPC has an EC50 of 18.84 nM. Moreover, no cell toxicity has been seen at concentrations <=50 MUM. C57BL/6 interferon gamma receptor knock-out mice, were infected by gavage with 4000 C. parvum oocysts on Day 0. Oral treatments, with OlPC, miltefosine, paromomycin or PBS, began on Day 3 post-infection for 10 days. Treatment with OlPC, at 40 mg/kg/day resulted in 100% survival, complete clearance of parasite in stools and a 99.9% parasite burden reduction in the intestines at Day 30. Doses of 30 and 20 mg/kg/day also demonstrated an increased survival rate and a dose-dependent parasite burden reduction. Mice treated with 10 mg/kg/day of miltefosine resulted in 50% survival at Day 30. In contrast, control mice, treated with PBS or 100 mg/kg/day of paromomycin, died or had to be euthanized between Days 6 and 13 due to severe illness. Results of parasite burden were obtained by qPCR and cross-validated by both flow cytometry of stool oocysts and histological sections of the ileum. Together, our results strongly support that OlPC represents a potential candidate for the treatment of C. parvum infections in immunocompromised patients. PMID- 26441907 TI - Corrigendum: Vesicles-mediated resistance to antibiotics in bacteria. AB - [This corrects the article on p. 758 in vol. 6, PMID: 26257725.]. PMID- 26441908 TI - Optimization and characterization of biosurfactant production from marine Vibrio sp. strain 3B-2. AB - A biosurfactant-producing bacterium, designated 3B-2, was isolated from marine sediment and identified as Vibrio sp. by 16S rRNA gene sequencing. The culture medium composition was optimized to increase the capability of 3B-2 for producing biosurfactant. The produced biosurfactant was characterized in terms of protein concentration, surface tension, and oil-displacement efficiency. The optimal medium for biosurfactant production contained: 0.5% lactose, 1.1% yeast extract, 2% sodium chloride, and 0.1% disodium hydrogen phosphate. Under optimal conditions (28 degrees C), the surface tension of crude biosurfactant could be reduced to 41 from 71.5 mN/m (water), while its protein concentration was increased to up to 6.5 g/L and the oil displacement efficiency was improved dramatically at 6.5 cm. Two glycoprotein fractions with the molecular masses of 22 and 40 kDa were purified from the biosurfactant, which held great potential for applications in microbial enhanced oil recovery and bioremediation. PMID- 26441909 TI - Genome sequence of the plant growth promoting endophytic yeast Rhodotorula graminis WP1. PMID- 26441910 TI - Insights on virulence from the complete genome of Staphylococcus capitis. AB - Staphylococcus capitis is an opportunistic pathogen of the coagulase negative staphylococci (CoNS). Functional genomic studies of S. capitis have thus far been limited by a lack of available complete genome sequences. Here, we determined the closed S. capitis genome and methylome using Single Molecule Real Time (SMRT) sequencing. The strain, AYP1020, harbors a single circular chromosome of 2.44 Mb encoding 2304 predicted proteins, which is the smallest of all complete staphylococcal genomes sequenced to date. AYP1020 harbors two large mobile genetic elements; a plasmid designated pAYP1020 (59.6 Kb) and a prophage, PhiAYP1020 (48.5 Kb). Methylome analysis identified significant adenine methylation across the genome involving two distinct methylation motifs (1972 putative 6-methyladenine (m6A) residues identified). Putative adenine methyltransferases were also identified. Comparative analysis of AYP1020 and the closely related CoNS, S. epidermidis RP62a, revealed a host of virulence factors that likely contribute to S. capitis pathogenicity, most notably genes important for biofilm formation and a suite of phenol soluble modulins (PSMs); the expression/production of these factors were corroborated by functional assays. The complete S. capitis genome will aid future studies on the evolution and pathogenesis of the coagulase negative staphylococci. PMID- 26441911 TI - Application of tea polyphenols in combination with 6-gingerol on shrimp paste of during storage: biogenic amines formation and quality determination. AB - Tea polyphenols (TP) have shown antioxidant activity and antimicrobial properties in the food industry. Assessment of anti-oxidation potential of 6-gingerol (GR) has also been verified. As little is known about the use of tea polyphenols either individually or in combination with 6-gingerol in shrimp paste, we aimed to investigate the effect of tea polyphenols combined with 6-gingerol on the biogenic amines inhibition and quality of shrimp paste stored at 25 degrees C for 160 days. The shrimp paste samples were assigned into four groups: (1) control; (2) tea polyphenols treatment (0.3%); (3) 6-gingerol treatment (0.3%); (4) tea polyphenols (0.15%) + 6-gingerol (0.15%). Samples with no addition were used as control. The results indicate that treatment with tea polyphenols + 6-gingerol (TPGR) maintained paste appearance, inhibited oxidation of protein and lipids, and reduced microorganism counts compared to control treatment. The efficiency was superior to that of tea polyphenols or 6-gingerol treatment. Furthermore, shrimp paste treated with TPGR also exhibited significantly higher inhibition of biogenic amines. Total amino acids determination proved the efficacy of TPGR by maintaining the more amino acids of shrimp paste during ambient temperature storage. Our study suggests that TPGR might be a promising candidate for fermented foods due to its synergistic effect to maintain products quality and extending their shelf-life. PMID- 26441912 TI - Fungal endophyte Phomopsis liquidambari affects nitrogen transformation processes and related microorganisms in the rice rhizosphere. AB - The endophytic fungus Phomopsis liquidambari performs an important ecosystem service by assisting its host with acquiring soil nitrogen (N), but little is known regarding how this fungus influences soil N nutrient properties and microbial communities. In this study, we investigated the impact of P. liquidambari on N dynamics, the abundance and composition of N cycling genes in rhizosphere soil treated with three levels of N (urea). Ammonia-oxidizing archaea (AOA), ammonia-oxidizing bacteria (AOB) and diazotrophs were assayed using quantitative real-time polymerase chain reaction and denaturing gradient gel electrophoresis at four rice growing stages (S0: before planting, S1: tillering stage, S2: grain filling stage, and S3: ripening stage). A significant increase in the available nitrate and ammonium contents was found in the rhizosphere soil of endophyte-infected rice under low N conditions. Moreover, P. liquidambari significantly increased the potential nitrification rates, affected the abundance and community structure of AOA, AOB, and diazotrophs under low N conditions in the S1 and S2 stages. The root exudates were determined due to their important role in rhizosphere interactions. P. liquidambari colonization altered the exudation of organic compounds by rice roots and P. liquidambari increased the concentration of soluble saccharides, total free amino acids and organic acids in root exudates. Plant-soil feedback mechanisms may be mediated by the rice endophyte interaction, especially in nutrient-limited soil. PMID- 26441913 TI - A new wine Torulaspora delbrueckii killer strain with broad antifungal activity and its toxin-encoding double-stranded RNA virus. AB - Wine Torulaspora delbrueckii strains producing a new killer toxin (Kbarr-1) were isolated and selected for wine making. They killed all the previously known Saccharomyces cerevisiae killer strains, in addition to other non-Saccharomyces yeasts. The Kbarr-1 phenotype is encoded by a medium-size 1.7 kb dsRNA, TdV-Mbarr 1, which seems to depend on a large-size 4.6 kb dsRNA virus (TdV-LAbarr) for stable maintenance and replication. The TdV-Mbarr-1 dsRNA was sequenced by new generation sequencing techniques. Its genome structure is similar to those of S. cerevisiae killer M dsRNAs, with a 5'-end coding region followed by an internal A rich sequence and a 3'-end non-coding region. Mbarr-1 RNA positive strand carries cis acting signals at its 5' and 3' termini for transcription and replication respectively, similar to those RNAs of yeast killer viruses. The ORF at the 5' region codes for a putative preprotoxin with an N-terminal secretion signal, potential Kex2p/Kexlp processing sites, and N-glycosylation sites. No relevant sequence identity was found either between the full sequence of Mbarr-1 dsRNA and other yeast M dsRNAs, or between their respective toxin-encoded proteins. However, a relevant identity of TdV-Mbarr-1 RNA regions to the putative replication and packaging signals of most of the M-virus RNAs suggests that they are all evolutionarily related. PMID- 26441914 TI - Salmonella Typhimurium exploits inflammation to its own advantage in piglets. AB - Salmonella Typhimurium (S. Typhimurium) is responsible for foodborne zoonotic infections that, in humans, induce self-limiting gastroenteritis. The aim of this study was to evaluate whether the wild-type strain S. Typhimurium (STM14028) is able to exploit inflammation fostering an active infection. Due to the similarity between human and porcine diseases induced by S. Typhimurium, we used piglets as a model for salmonellosis and gastrointestinal research. This study showed that STM14028 is able to efficiently colonize in vitro porcine mono-macrophages and intestinal columnar epithelial (IPEC-J2) cells, and that the colonization significantly increases with LPS pre-treatment. This increase was then reversed by inhibiting the LPS stimulation through LPS antagonist, confirming an active role of LPS stimulation in STM14028-intracellular colonization. Moreover, LPS in vivo treatment increased cytokines blood level and body temperature at 4 h post infection, which is consistent with an acute inflammatory stimulus, capable to influence the colonization of STM14028 in different organs and tissues. The present study proves for the first time that in acute enteric salmonellosis, S. Typhimurium exploits inflammation for its benefit in piglets. PMID- 26441915 TI - Insights into arsenic multi-operons expression and resistance mechanisms in Rhodopseudomonas palustris CGA009. AB - Arsenic (As) is widespread in the environment and causes numerous health problems. Rhodopseudomonas palustris has been regarded as a good model organism for studying arsenic detoxification since it was first demonstrated to methylate environmental arsenic by conversion to soluble or gaseous methylated species. However, the detailed arsenic resistance mechanisms remain unknown though there are at least three arsenic-resistance operons (ars1, ars2, and ars3) in R. palustris. In this study, we investigated how arsenic multi-operons contributed to arsenic detoxification in R. palustris. The expression of ars2 or ars3 operons increased with increasing environmental arsenite (As(III)) concentrations (up to 1.0 mM) while transcript of ars1 operon was not detected in the middle log-phase (55 h). ars2 operon was actively expressed even at the low concentration of As(III) (0.01 MUM), whereas the ars3 operon was expressed at 1.0 MUM of As(III), indicating that there was a differential regulation mechanism for the three arsenic operons. Furthermore, ars2 and ars3 operons were maximally transcribed in the early log-phase where ars2 operon was 5.4-fold higher than that of ars3 operon. A low level of ars1 transcript was only detected at 43 h (early log phase). Arsenic speciation analysis demonstrated that R. palustris could reduce As(V) to As(III). Collectively, strain CGA009 detoxified arsenic by using arsenic reduction and methylating arsenic mechanism, while the latter might occur with the presence of higher concentrations of arsenic. PMID- 26441916 TI - Physiological and genomic characterization of Arcobacter anaerophilus IR-1 reveals new metabolic features in Epsilonproteobacteria. AB - In this study we characterized and sequenced the genome of Arcobacter anaerophilus strain IR-1 isolated from enrichment cultures used in nitrate amended corrosion experiments. A. anaerophilus IR-1 could grow lithoautotrophically on hydrogen and hydrogen sulfide and lithoheterothrophically on thiosulfate and elemental sulfur. In addition, the strain grew organoheterotrophically on yeast extract, peptone, and various organic acids. We show for the first time that Arcobacter could grow on the complex organic substrate tryptone and oxidize acetate with elemental sulfur as electron acceptor. Electron acceptors utilized by most Epsilonproteobacteria, such as oxygen, nitrate, and sulfur, were also used by A. anaerophilus IR-1. Strain IR-1 was also uniquely able to use iron citrate as electron acceptor. Comparative genomics of the Arcobacter strains A. butzleri RM4018, A. nitrofigilis CI and A. anaerophilus IR-1 revealed that the free-living strains had a wider metabolic range and more genes in common compared to the pathogen strain. The presence of genes for NAD(+)-reducing hydrogenase (hox) and dissimilatory iron reduction (fre) were unique for A. anaerophilus IR-1 among Epsilonproteobacteria. Finally, the new strain had an incomplete denitrification pathway where the end product was nitrite, which is different from other Arcobacter strains where the end product is ammonia. Altogether, our study shows that traditional characterization in combination with a modern genomics approach can expand our knowledge on free living Arcobacter, and that this complementary approach could also provide invaluable knowledge about the physiology and metabolic pathways in other Epsilonproteobacteria from various environments. PMID- 26441917 TI - Growth and activity of ANME clades with different sulfate and sulfide concentrations in the presence of methane. AB - Extensive geochemical data showed that significant methane oxidation activity exists in marine sediments. The organisms responsible for this activity are anaerobic methane-oxidizing archaea (ANME) that occur in consortia with sulfate reducing bacteria. A distinct zonation of different clades of ANME (ANME-1, ANME 2a/b, and ANME-2c) exists in marine sediments, which could be related to the localized concentrations of methane, sulfate, and sulfide. In order to test this hypothesis we performed long-term incubation of marine sediments under defined conditions with methane as a headspace gas: low or high sulfate (+/-4 and +/-21 mM, respectively) in combination with low or high sulfide (+/-0.1 and +/-4 mM, respectively) concentrations. Control incubations were also performed, with only methane, high sulfate, or high sulfide. Methane oxidation was monitored and growth of subtypes ANME-1, ANME-2a/b, and ANME-2c assessed using qPCR analysis. A preliminary archaeal community analysis was performed to gain insight into the ecological and taxonomic diversity. Almost all of the incubations with methane had methane oxidation activity, with the exception of the incubations with combined low sulfate and high sulfide concentrations. Sulfide inhibition occurred only with low sulfate concentrations, which could be due to the lower Gibbs free energy available as well as sulfide toxicity. ANME-2a/b appears to mainly grow in incubations which had high sulfate levels and methane oxidation activity, whereas ANME-1 did not show this distinction. ANME-2c only grew in incubations with only sulfate addition. These findings are consistent with previously published in situ profiling analysis of ANME subclusters in different marine sediments. Interestingly, since all ANME subtypes also grew in incubations with only methane or sulfate addition, ANME may also be able to perform anaerobic methane oxidation under substrate limited conditions or alternatively perform additional metabolic processes. PMID- 26441918 TI - The globally widespread genus Sulfurimonas: versatile energy metabolisms and adaptations to redox clines. AB - Sulfurimonas species are commonly isolated from sulfidic habitats and numerous 16S rRNA sequences related to Sulfurimonas species have been identified in chemically distinct environments, such as hydrothermal deep-sea vents, marine sediments, the ocean's water column, and terrestrial habitats. In some of these habitats, Sulfurimonas have been demonstrated to play an important role in chemoautotrophic processes. Sulfurimonas species can grow with a variety of electron donors and acceptors, which may contribute to their widespread distribution. Multiple copies of one type of enzyme (e.g., sulfide:quinone reductases and hydrogenases) may play a pivotal role in Sulfurimonas' flexibility to colonize disparate environments. Many of these genes appear to have been acquired through horizontal gene transfer which has promoted adaptations to the distinct habitats. Here we summarize Sulfurimonas' versatile energy metabolisms and link their physiological properties to their global distribution. PMID- 26441919 TI - The novel cis-encoded antisense RNA AsrC positively regulates the expression of rpoE-rseABC operon and thus enhances the motility of Salmonella enterica serovar typhi. AB - Bacterial non-coding RNAs are essential in many cellular processes, including response to environmental stress, and virulence. Deep sequencing analysis of the Salmonella enterica serovar typhi (S. typhi) transcriptome revealed a novel antisense RNA transcribed in cis on the strand complementary to rseC, an activator gene of sigma factor RpoE. In this study, expression of this antisense RNA was confirmed in S. typhi by Northern hybridization. Rapid amplification of cDNA ends and sequence analysis identified an 893 bp sequence from the antisense RNA coding region that covered all of the rseC coding region in the reverse direction of transcription. This sequence of RNA was named as AsrC. After overexpression of AsrC with recombinantant plasmid in S. typhi, the bacterial motility was increased obviously. To explore the mechanism of AsrC function, regulation of rseC and rpoE expression by AsrC was investigated. We found that AsrC increased the levels of rseC mRNA and protein. The expression of rpoE was also increased in S. typhi after overexpression of AsrC, which was dependent on rseC. Thus, we propose that AsrC increased RseC level and indirectly activating RpoE which can initiate fliA expression and promote the motility of S. typhi. PMID- 26441920 TI - Quantitative RT-PCR assay for high-throughput screening (HTS) of drugs against the growth of Cryptosporidium parvum in vitro. AB - Our laboratory has previously developed a qRT-PCR assay to assess drug efficacy on the growth of Cryptosporidium parvum in vitro by detecting the levels of parasite 18S rRNA. This approach displayed up to four orders of magnitude of linear dynamic range and was much less labor-intensive than the traditional microscopic methods. However, conventional qRT-PCR protocol is not very amendable to high-throughput analysis when total RNA needs to be purified by lengthy, multi step procedures. Recently, several commercial reagents are available for preparing cell lysates that could be directly used in downstream qRT-PCR analysis (e.g., Ambion Cell-to-cDNA kit and Bio-Rad iScript sample preparation reagent). Using these reagents, we are able to adapt the qRT-PCR assay into high-throughput screening of drugs in vitro (i.e., 96-well and 384-well formats for the cultivation of parasites and qRT-PCR detection, respectively). This qRT-PCR protocol is able to give a >150-fold linear dynamic range using samples isolated from cells infected with various numbers of parasites. The new assay is also validated by the NIH-recommended intra-plate, inter-plate, and inter-day uniformity tests. The robustness and effectiveness of the assay are also confirmed by evaluating the anti-cryptosporidial efficacy of paromomycin and by a small scale screening of compounds. PMID- 26441921 TI - The death mechanism of the harmful algal bloom species Alexandrium tamarense induced by algicidal bacterium Deinococcus sp. Y35. AB - Harmful algal blooms (HABs) cause a variety of deleterious effects on aquatic ecosystems, especially the toxic dinoflagellate Alexandrium tamarense, which poses a serious threat to marine economic and human health based on releasing paralytic shellfish poison into the environment. The algicidal bacterium Deinococcus sp. Y35 which can induce growth inhibition on A. tamarense was used to investigate the functional mechanism. The growth status, reactive oxygen species (ROS) content, photosynthetic system and the nuclear system of algal cells were determined under algicidal activity. A culture of strain Y35 not only induced overproduction of ROS in algal cells within only 0.5 h of treatment, also decrease the total protein content as well as the response of the antioxidant enzyme. Meanwhile, lipid peroxidation was induced and cell membrane integrity was lost. Photosynthetic pigments including chlorophyll a and carotenoid decreased along with the photosynthetic efficiency being significantly inhibited. At the same time, photosynthesis-related gene expression showed down-regulation. More than, the destruction of cell nuclear structure and inhibition of proliferating cell nuclear antigen (PCNA) related gene expression were confirmed. The potential functional mechanism of the algicidal bacterium on A. tamarense was investigated and provided a novel viewpoint which could be used in HABs control. PMID- 26441922 TI - Thiomonas sp. CB2 is able to degrade urea and promote toxic metal precipitation in acid mine drainage waters supplemented with urea. AB - The acid mine drainage (AMD) in Carnoules (France) is characterized by the presence of toxic metals such as arsenic. Several bacterial strains belonging to the Thiomonas genus, which were isolated from this AMD, are able to withstand these conditions. Their genomes carry several genomic islands (GEIs), which are known to be potentially advantageous in some particular ecological niches. This study focused on the role of the "urea island" present in the Thiomonas CB2 strain, which carry the genes involved in urea degradation processes. First, genomic comparisons showed that the genome of Thiomonas sp. CB2, which is able to degrade urea, contains a urea genomic island which is incomplete in the genome of other strains showing no urease activity. The urease activity of Thiomonas sp. CB2 enabled this bacterium to maintain a neutral pH in cell cultures in vitro and prevented the occurrence of cell death during the growth of the bacterium in a chemically defined medium. In AMD water supplemented with urea, the degradation of urea promotes iron, aluminum and arsenic precipitation. Our data show that ureC was expressed in situ, which suggests that the ability to degrade urea may be expressed in some Thiomonas strains in AMD, and that this urease activity may contribute to their survival in contaminated environments. PMID- 26441923 TI - Whole genome resequencing of Botrytis cinerea isolates identifies high levels of standing diversity. AB - How standing genetic variation within a pathogen contributes to diversity in host/pathogen interactions is poorly understood, partly because most studied pathogens are host-specific, clonally reproducing organisms which complicates genetic analysis. In contrast, Botrytis cinerea is a sexually reproducing, true haploid ascomycete that can infect a wide range of diverse plant hosts. While previous work had shown significant genomic variation between two isolates, we proceeded to assess the level and frequency of standing variation in a population of B. cinerea. To begin measuring standing genetic variation in B. cinerea, we re sequenced the genomes of 13 different isolates and aligned them to the previously sequenced T4 reference genome. In addition one of these isolates was resequenced from four independently repeated cultures. A high level of genetic diversity was found within the 13 isolates. Within this variation, we could identify clusters of genes with major effect polymorphisms, i.e., polymorphisms that lead to a predicted functional knockout, that surrounded genes involved in controlling vegetative incompatibility. The genotype at these loci was able to partially predict the interaction of these isolates in vegetative fusion assays showing that these loci control vegetative incompatibility. This suggests that the vegetative incompatibility loci within B. cinerea are associated with regions of increased genetic diversity. The genome re-sequencing of four clones from the one isolate (Grape) that had been independently propagated over 10 years showed no detectable spontaneous mutation. This suggests that B. cinerea does not display an elevated spontaneous mutation rate. Future work will allow us to test if, and how, this diversity may be contributing to the pathogen's broad host range. PMID- 26441924 TI - Rapid detection of Acinetobacter baumannii and molecular epidemiology of carbapenem-resistant A. baumannii in two comprehensive hospitals of Beijing, China. AB - Acinetobacter baumannii is an important opportunistic pathogen associated with a variety of nosocomial infections. A rapid and sensitive molecular detection in clinical isolates is quite needed for the appropriate therapy and outbreak control of A. baumannii. Group 2 carbapenems have been considered the agents of choice for the treatment of multiple drug-resistant A. baumannii. But the prevalence of carbapenem-resistant A. baumannii (CRAB) has been steadily increasing in recent years. Here, we developed a loop-mediated isothermal amplification (LAMP) assay for the rapid detection of A. baumannii in clinical samples by using high-specificity primers of the bla OXA-51 gene. Then we investigated the OXA-carbapenemases molecular epidemiology of A. baumannii isolates in two comprehensive hospitals in Beijing. The results showed that the LAMP assay could detect target DNA within 60 min at 65 degrees C. The detection limit was 50 pg/MUl, which was about 10-fold greater than that of PCR. Furthermore, this method could distinguish A. baumannii from the homologous A. nosocomialis and A. pittii. A total of 228 positive isolates were identified by this LAMP-based method for A. baumannii from 335 intensive care unit patients with clinically suspected multi-resistant infections in two hospitals in Beijing. The rates of CRAB are on the rise and are slowly becoming a routine phenotype for A. baumannii. Among the CRABs, 92.3% harbored both the bla OXA-23 and bla OXA-51 genes. Thirty-three pulsotypes were identified by pulsed-field gel electrophoresis, and the majority belonged to clone C. In conclusion, the LAMP method developed for detecting A. baumannii was faster and simpler than conventional PCR and has great potential for both point-of-care testing and basic research. We further demonstrated a high distribution of class D carbapenemase encoding genes, mainly OXA-23, which presents an emerging threat in hospitals in China. PMID- 26441925 TI - Meta-omic signatures of microbial metal and nitrogen cycling in marine oxygen minimum zones. AB - Iron (Fe) and copper (Cu) are essential cofactors for microbial metalloenzymes, but little is known about the metalloenyzme inventory of anaerobic marine microbial communities despite their importance to the nitrogen cycle. We compared dissolved O2, NO[Formula: see text], NO[Formula: see text], Fe and Cu concentrations with nucleic acid sequences encoding Fe and Cu-binding proteins in 21 metagenomes and 9 metatranscriptomes from Eastern Tropical North and South Pacific oxygen minimum zones and 7 metagenomes from the Bermuda Atlantic Time series Station. Dissolved Fe concentrations increased sharply at upper oxic anoxic transition zones, with the highest Fe:Cu molar ratio (1.8) occurring at the anoxic core of the Eastern Tropical North Pacific oxygen minimum zone and matching the predicted maximum ratio based on data from diverse ocean sites. The relative abundance of genes encoding Fe-binding proteins was negatively correlated with O2, driven by significant increases in genes encoding Fe-proteins involved in dissimilatory nitrogen metabolisms under anoxia. Transcripts encoding cytochrome c oxidase, the Fe- and Cu-containing terminal reductase in aerobic respiration, were positively correlated with O2 content. A comparison of the taxonomy of genes encoding Fe- and Cu-binding vs. bulk proteins in OMZs revealed that Planctomycetes represented a higher percentage of Fe genes while Thaumarchaeota represented a higher percentage of Cu genes, particularly at oxyclines. These results are broadly consistent with higher relative abundance of genes encoding Fe-proteins in the genome of a marine planctomycete vs. higher relative abundance of genes encoding Cu-proteins in the genome of a marine thaumarchaeote. These findings highlight the importance of metalloenzymes for microbial processes in oxygen minimum zones and suggest preferential Cu use in oxic habitats with Cu > Fe vs. preferential Fe use in anoxic niches with Fe > Cu. PMID- 26441926 TI - Assessment of combination therapy in BALB/c mice injected with carbapenem resistant Enterobacteriaceae strains. AB - Monotherapeutic options for carbapenem resistant infections are limited. Studies suggest that combination therapy may be associated with better outcomes than monotherapies. However, this is still controversial. This study assessed, the efficacy of combination therapy against carbapenem resistant Enterobacteriaceae harboring singly various extended spectrum beta lactamase or carbapenemase encoding genes. Thus, four isolates harboring either bla CTXM-15, bla CTXM-15 and bla OXA-48, bla NDM-1, or bla KPC-2 genes were selected for testing. Minimal inhibitory concentration was determined by broth dilution method. Gene transcript levels on single and combined treatments were done in vitro and in vivo by qRT PCR. Assessment of treatments was done in BALB/c mice according to a specific protocol. As such, the qRT-PCR revealed a significant decrease of transcript levels in all isolates upon using rifampicin or tigecycline, singly or in combination with colistin. However, variable levels were obtained using colistin singly or in combination with meropenem or fosfomycin. In vivo assessment showed that all combinations used were effective against isolates harboring bla CTXM-15, bla OXA-48, and bla NDM-1. Conversely, the most significant combination against the isolate harboring bla KPC-2 gene was colistin with either carbapenem, fosfomycin, or kanamycin. As a conclusion, combination therapy selected based on the type of carbapenemase produced, appeared to be non-toxic and might be effective in BALB/c mice. Therefore, the use of a rationally optimized combination therapy might lead to better results than monotherapy, however, clinical trials are needed for human consumption. PMID- 26441927 TI - Assessment of the rabbit as a wildlife reservoir of bovine viral diarrhea virus: serological analysis and generation of trans-placentally infected offspring. AB - Eradication of bovine viral diarrhea virus (BVDV) is ongoing in many European countries and is based on removal of persistently infected (PI) cattle. In this context, low-level risks, including alternative reservoirs of infection, may become more important as the number of BVDV-free herds increases. Alternative reservoirs include livestock, such as sheep and goats, as well as wildlife, including deer and rabbits. Due to the extensive nature of the beef industry in Scotland, where an eradication program started in 2010, contact between cattle and alternative reservoir hosts is common. Seroprevalence to BVDV in rabbit populations can be high. In addition, rabbits can be infected with BVDV by natural routes, indicating that they could be a wildlife reservoir of infection. We analyzed the potential risk to livestock from rabbit populations in the UK by two approaches. First, ~260 serum samples from free-ranging wild rabbits in Scotland and northern England were tested for BVDV-specific antibodies by ELISA. Only three samples exhibited low level BVDV-specific reactivity, suggesting that BVDV infection of rabbits was not frequent. Second, rabbits were challenged with BVDV at day 7 or 12 of pregnancy. This did not lead to any clinical signs in the infected animals or obvious increases in abortion or stillbirth in the infected dams. Samples from the dams, placental material and ~130 offspring were tested by BVDV-specific RT-PCR and antibody ELISA. Positive PCR results in the placentas and in the tissues and body fluids of rabbits up to 10 days old showed that trans placental infection of rabbits with BVDV had occurred. Many of the offspring had BVDV-specific antibodies. These data support the view that a wildlife reservoir of BVDV in rabbit poses a small but non-zero risk of re-infection for BVDV-free cattle herds. Rabbits are susceptible to infection with BVDV but only a small proportion of free-living rabbits in the UK appear to have been infected. PMID- 26441928 TI - Interaction of fibrinogen and muramidase-released protein promotes the development of Streptococcus suis meningitis. AB - Muramidase-released protein (MRP) is as an important virulence marker of Streptococcus suis (S. suis) serotype 2. Our previous works have shown that MRP can bind human fibrinogen (hFg); however, the function of this interaction in S. suis meningitis is not known. In this study, we found that the deletion of mrp significantly impairs the hFg-mediated adherence and traversal ability of S. suis across human cerebral microvascular endothelial cells (hCMEC/D3). Measurement of the permeability to Lucifer yellow in vitro and Evans blue extravasation in vivo show that the MRP-hFg interaction significantly increases the permeability of the blood-brain barrier (BBB). In the mouse meningitis model, wild type S. suis caused higher bacterial loads in the brain and more severe histopathological signs of meningitis than the mrp mutant at day 3 post-infection. Western blot analysis and immunofluorescence observations reveal that the MRP-hFg interaction can destroy the cell adherens junction protein p120-catenin of hCMEC/D3. These results indicate that the MRP-hFg interaction is important in the development of S. suis meningitis. PMID- 26441929 TI - Recombinant protein production facility for fungal biomass-degrading enzymes using the yeast Pichia pastoris. AB - Filamentous fungi are the predominant source of lignocellulolytic enzymes used in industry for the transformation of plant biomass into high-value molecules and biofuels. The rapidity with which new fungal genomic and post-genomic data are being produced is vastly outpacing functional studies. This underscores the critical need for developing platforms dedicated to the recombinant expression of enzymes lacking confident functional annotation, a prerequisite to their functional and structural study. In the last decade, the yeast Pichia pastoris has become increasingly popular as a host for the production of fungal biomass degrading enzymes, and particularly carbohydrate-active enzymes (CAZymes). This study aimed at setting-up a platform to easily and quickly screen the extracellular expression of biomass-degrading enzymes in P. pastoris. We first used three fungal glycoside hydrolases (GHs) that we previously expressed using the protocol devised by Invitrogen to try different modifications of the original protocol. Considering the gain in time and convenience provided by the new protocol, we used it as basis to set-up the facility and produce a suite of fungal CAZymes (GHs, carbohydrate esterases and auxiliary activity enzyme families) out of which more than 70% were successfully expressed. The platform tasks range from gene cloning to automated protein purifications and activity tests, and is open to the CAZyme users' community. PMID- 26441930 TI - Pichia pastoris-expressed dengue 3 envelope-based virus-like particles elicit predominantly domain III-focused high titer neutralizing antibodies. AB - Dengue poses a serious public health risk to nearly half the global population. It causes ~400 million infections annually and is considered to be one of the fastest spreading vector-borne diseases. Four distinct serotypes of dengue viruses (DENV-1, -2, -3, and -4) cause dengue disease, which may be either mild or extremely severe. Antibody-dependent enhancement (ADE), by pre-existing cross reactive antibodies, is considered to be the major mechanism underlying severe disease. This mandates that a preventive vaccine must confer simultaneous and durable immunity to each of the four prevalent DENV serotypes. Recently, we used Pichia pastoris, to express recombinant DENV-2 E ectodomain, and found that it assembled into virus-like particles (VLPs), in the absence of prM, implicated in the elicitation of ADE-mediating antibodies. These VLPs elicited predominantly type-specific neutralizing antibodies that conferred significant protection against lethal DENV-2 challenge, in a mouse model. The current work is an extension of this approach to develop prM-lacking DENV-3 E VLPs. Our data reveal that P. pastoris-produced DENV-3 E VLPs not only preserve the antigenic integrity of the major neutralizing epitopes, but also elicit potent DENV-3 virus neutralizing antibodies. Further, these neutralizing antibodies appear to be exclusively directed toward domain III of the DENV-3 E VLPs. Significantly, they also lack discernible ADE potential toward heterotypic DENVs. Taken together with the high productivity of the P. pastoris expression system, this approach could potentially pave the way toward developing a DENV E-based, inexpensive, safe, and efficacious tetravalent sub-unit vaccine, for use in resource-poor dengue endemic countries. PMID- 26441931 TI - Effects of sub-lethal high-pressure homogenization treatment on the outermost cellular structures and the volatile-molecule profiles of two strains of probiotic lactobacilli. AB - Applying sub-lethal levels of high-pressure homogenization (HPH) to lactic acid bacteria has been proposed as a method of enhancing some of their functional properties. Because the principal targets of HPH are the cell-surface structures, the aim of this study was to examine the effect of sub-lethal HPH treatment on the outermost cellular structures and the proteomic profiles of two known probiotic bacterial strains. Moreover, the effect of HPH treatment on the metabolism of probiotic cells within a dairy product during its refrigerated storage was investigated using SPME-GC-MS. Transmission electron microscopy was used to examine the microstructural changes in the outermost cellular structures due to HPH treatment. These alterations may be involved in the changes in some of the technological and functional properties of the strains that were observed after pressure treatment. Moreover, the proteomic profiles of the probiotic strains treated with HPH and incubated at 37 degrees C for various periods showed different peptide patterns compared with those of the untreated cells. In addition, there were differences in the peaks that were observed in the low-mass spectral region (2000-3000 Da) of the spectral profiles of the control and treated samples. Due to pressure treatment, the volatile-molecule profiles of buttermilk inoculated with treated or control cells and stored at 4 degrees C for 30 days exhibited overall changes in the aroma profile and in the production of molecules that improved its sensory profile, although the two different species imparted specific fingerprints to the product. The results of this study will contribute to understanding the changes that occur in the outermost cellular structures and the metabolism of LAB in response to HPH treatment. The findings of this investigation may contribute to elucidating the relationships between these changes and the alterations of the technological and functional properties of LAB induced by pressure treatment. PMID- 26441932 TI - New process for production of fermented black table olives using selected autochthonous microbial resources. AB - Table olives represent one important fermented product in Europe and, in the world, their demand is constantly increasing. At the present time, no systems are available to control black table olives spontaneous fermentation by the Greek method. During this study, a new protocol for the production of black table olives belonging to two Italian (Cellina di Nardo and Leccino) and two Greek (Kalamata and Conservolea) cultivars has been developed: for each table olive cultivar, starter-driven fermentations were performed inoculating, firstly, one selected autochthonous yeast starter and, subsequently, one selected autochthonous LAB starter. All starters formulation were able to dominate fermentation process. The olive fermentation was monitored using specific chemical descriptors able to identify a first stage (30 days) mainly characterized by aldehydes; a second period (60 days) mainly characterized by higher alcohols, styrene and terpenes; a third fermentation stage represented by acetate esters, esters and acids. A significant decrease of fermentation time (from 8 to 12 months to a maximum of 3 months) and an significant improvement in organoleptic characteristics of the final product were obtained. This study, for the first time, describes the employment of selected autochthonous microbial resources optimized to mimic the microbial evolution already recorded during spontaneous fermentations. PMID- 26441933 TI - Bacterial endophyte communities in the foliage of coast redwood and giant sequoia. AB - The endophytic bacterial microbiome, with an emerging role in plant nutrient acquisition and stress tolerance, is much less studied in natural plant populations than in agricultural crops. In a previous study, we found consistent associations between trees in the pine family and acetic acid bacteria (AAB) occurring at high relative abundance inside their needles. Our objective here was to determine if that pattern may be general to conifers, or alternatively, is more likely restricted to pines or conifers growing in nutrient limited and exposed environments. We used 16S rRNA pyrosequencing to characterize the foliar endophyte communities of two conifers in the Cupressaceae family: Two coast redwood (CR; Sequoia sempervirens) populations and one giant sequoia (GS; Sequoiadendron giganteum) population were sampled. Similar to the pines, the endophyte communities of the giant trees were dominated by Proteobacteria, Firmicutes, Acidobacteria, and Actinobacteria. However, although some major operational taxonomic units (OTUs) occurred at a high relative abundance of 10 40% in multiple samples, no specific group of bacteria dominated the endophyte community to the extent previously observed in high-elevation pines. Several of the dominating bacterial groups in the CR and GS foliage (e.g., Bacillus, Burkholderia, Actinomycetes) are known for disease- and pest suppression, raising the possibility that the endophytic microbiome protects the giant trees against biotic stress. Many of the most common and abundant OTUs in our dataset were most similar to 16S rRNA sequences from bacteria found in lichens or arctic plants. For example, an OTU belonging to the uncultured Rhizobiales LAR1 lineage, which is commonly associated with lichens, was observed at high relative abundance in many of the CR samples. The taxa shared between the giant trees, arctic plants, and lichens may be part of a broadly defined endophyte microbiome common to temperate, boreal, and tundra ecosystems. PMID- 26441934 TI - Anthrax prophylaxis: recent advances and future directions. AB - Anthrax is a serious, potentially fatal disease that can present in four distinct clinical patterns depending on the route of infection (cutaneous, gastrointestinal, pneumonic, or injectional); effective strategies for prophylaxis and therapy are therefore required. This review addresses the complex mechanisms of pathogenesis employed by the bacterium and describes how, as understanding of these has developed over many years, so too have current strategies for vaccination and therapy. It covers the clinical and veterinary use of live attenuated strains of anthrax and the subsequent identification of protein sub-units for incorporation into vaccines, as well as combinations of protein sub-units with spore or other components. It also addresses the application of these vaccines for conventional prophylactic use, as well as post exposure use in conjunction with antibiotics. It describes the licensed acellular vaccines AVA and AVP and discusses the prospects for a next generation of recombinant sub-unit vaccines for anthrax, balancing the regulatory requirement and current drive for highly defined vaccines, against the risk of losing the "danger" signals required to induce protective immunity in the vaccinee. It considers novel approaches to reduce time to immunity by means of combining, for example, dendritic cell vaccination with conventional approaches and considers current opportunities for the immunotherapy of anthrax. PMID- 26441935 TI - Organogel-nanoemulsion containing nisin and D-limonene and its antimicrobial activity. AB - The aim of this study was to investigate a novel delivery system containing D limonene and nisin by food organogel-nanoemulsion and study its effect on the antimicrobial activity. Organogel-nanoemulsion containing with D-limonene and nisin or without nisin was prepared by a homogenization method. Factors that may affect the droplet size and stability of organogel-nanoemulsion such as pressure and surfactant to oil ratio (SOR) were studied. The average droplet size decreased with pressure, and the organogel-nanoemulsion could achieve good stability at low SOR. Positive effects and outstanding antimicrobial activities of organogel-nanoemulsion containing with D-limonene and nisin were confirmed by minimal inhibitory concentrations comparison, growth curves of bacteria, scanning electron microscopy and determination of cell constituents' release. Furthermore, the organogel-nanoemulsion applied as food preservative in milk also shown excellent antimicrobial performance. Overall, the research described in the current article show that organogel-nanoemulsion containing with D-limonene and nisin may be an effective antimicrobial system for the production and preservation of food. PMID- 26441936 TI - Control regions for chromosome replication are conserved with respect to sequence and location among Escherichia coli strains. AB - In Escherichia coli, chromosome replication is initiated from oriC by the DnaA initiator protein associated with ATP. Three non-coding regions contribute to the activity of DnaA. The datA locus is instrumental in conversion of DnaA(ATP) to DnaA(ADP) (datA dependent DnaA(ATP) hydrolysis) whereas DnaA rejuvenation sequences 1 and 2 (DARS1 and DARS2) reactivate DnaA(ADP) to DnaA(ATP). The structural organization of oriC, datA, DARS1, and DARS2 were found conserved among 59 fully sequenced E. coli genomes, with differences primarily in the non functional spacer regions between key protein binding sites. The relative distances from oriC to datA, DARS1, and DARS2, respectively, was also conserved despite of large variations in genome size, suggesting that the gene dosage of either region is important for bacterial growth. Yet all three regions could be deleted alone or in combination without loss of viability. Competition experiments during balanced growth in rich medium and during mouse colonization indicated roles of datA, DARS1, and DARS2 for bacterial fitness although the relative contribution of each region differed between growth conditions. We suggest that this fitness advantage has contributed to conservation of both sequence and chromosomal location for datA, DARS1, and DARS2. PMID- 26441938 TI - Corrigendum: Leishmanicidal activities of Artemisia annua leaf essential oil against Visceral Leishmaniasis. AB - [This corrects the article on p. 626 in vol. 5, PMID: 25505453.]. PMID- 26441939 TI - Ongoing burden of disease and mortality from HIV/CMV coinfection in Africa in the antiretroviral therapy era. AB - Human Cytomegalovirus (CMV) is a well-recognized pathogen in the context of HIV infection, but since the roll out of ART, clinical and scientific interest in the problem of HIV/CMV coinfection has diminished. However, CMV remains a significant cofactor in HIV disease, with an influence on HIV acquisition, disease progression, morbidity, and mortality. Disease manifestations may be a result of direct interplay between the two viruses, or may arise as a secondary consequence of immune dysregulation and systemic inflammation. The problem is most relevant when the rates of coinfection are high, most notably in sub-Saharan Africa, and in children at risk of acquiring both infections early in life. Understanding the interplay between these viruses and developing strategies to diagnose, treat and prevent CMV should be a priority. PMID- 26441937 TI - Thermophilic and alkaliphilic Actinobacteria: biology and potential applications. AB - Microbes belonging to the phylum Actinobacteria are prolific sources of antibiotics, clinically useful bioactive compounds and industrially important enzymes. The focus of the current review is on the diversity and potential applications of thermophilic and alkaliphilic actinobacteria, which are highly diverse in their taxonomy and morphology with a variety of adaptations for surviving and thriving in hostile environments. The specific metabolic pathways in these actinobacteria are activated for elaborating pharmaceutically, agriculturally, and biotechnologically relevant biomolecules/bioactive compounds, which find multifarious applications. PMID- 26441940 TI - Targeted metagenomics unveils the molecular basis for adaptive evolution of enzymes to their environment. AB - Microorganisms have a wonderful ability to adapt rapidly to new or altered environmental conditions. Enzymes are the basis of metabolism in all living organisms and, therefore, enzyme adaptation plays a crucial role in the adaptation of microorganisms. Comparisons of homology and parallel beneficial mutations in an enzyme family provide valuable hints of how an enzyme adapted to an ecological system; consequently, a series of enzyme collections is required to investigate enzyme evolution. Targeted metagenomics is a promising tool for the construction of enzyme pools and for studying the adaptive evolution of enzymes. This perspective article presents a summary of targeted metagenomic approaches useful for this purpose. PMID- 26441941 TI - Mannitol metabolism during pathogenic fungal-host interactions under stressed conditions. AB - Numerous plants and fungi produce mannitol, which may serve as an osmolyte or metabolic store; furthermore, mannitol also acts as a powerful quencher of reactive oxygen species (ROS). Some phytopathogenic fungi use mannitol to stifle ROS-mediated plant resistance. Mannitol is essential in pathogenesis to balance cell reinforcements produced by both plants and animals. Mannitol likewise serves as a source of reducing power, managing coenzymes, and controlling cytoplasmic pH by going about as a sink or hotspot for protons. The metabolic pathways for mannitol biosynthesis and catabolism have been characterized in filamentous fungi by direct diminishment of fructose-6-phosphate into mannitol-1-phosphate including a mannitol-1-phosphate phosphatase catalyst. In plants mannitol is integrated from mannose-6-phosphate to mannitol-1-phosphate, which then dephosphorylates to mannitol. The enzyme mannitol dehydrogenase plays a key role in host-pathogen interactions and must be co-localized with pathogen-secreted mannitol to resist the infection. PMID- 26441942 TI - On Lactococcus lactis UL719 competitivity and nisin (Nisaplin((r))) capacity to inhibit Clostridium difficile in a model of human colon. AB - Clostridium difficile is the most frequently identified enteric pathogen in patients with nosocomially acquired, antibiotic-associated diarrhea and pseudomembranous colitis. Although metronidazole and vancomycin were effective, an increasing number of treatment failures and recurrence of C. difficile infection are being reported. Use of probiotics, particularly metabolically active lactic acid bacteria, was recently proposed as an alternative for the medical community. The aim of this study was to assess a probiotic candidate, nisin Z-producer Lactococcus lactis UL719, competitivity and nisin (Nisaplin((r))) capacity to inhibit C. difficile in a model of human colon. Bacterial populations was enumerated by qPCR coupled to PMA treatment. L. lactis UL719 was able to survive and proliferate under simulated human colon, did not alter microbiota composition, but failed to inhibit C. difficile. While a single dose of 19 MUmol/L (5* the MIC) was not sufficient to inhibit C. difficile, nisin at 76 MUmol/L (20*the MIC) was effective at killing the pathogen. Nisin (at 76 MUmol/L) caused some temporary changes in the microbiota with Gram-positive bacteria being the mostly affected. These results highlight the capacity of L. lactis UL719 to survive under simulated human colon and the efficacy of nisin as an alternative in the treatment of C. difficile infections. PMID- 26441943 TI - Diversity of cultivable protease-producing bacteria in sediments of Jiaozhou Bay, China. AB - Although protease-producing bacteria are key players in the degradation of organic nitrogen and essential for the nitrogen recycling in marine sediments, diversity of both these bacteria and their extracellular proteases is still largely unknown. This study investigated the diversity of the cultivable protease producing bacteria and their extracellular proteases in the sediments of the eutrophied Jiaozhou Bay, China through phylogenetic analysis and protease inhibitor tests. The abundance of the cultivable protease-producing bacteria was up to 10(4) cells/g in all six sediment samples. The cultivated protease producing bacteria mostly belonged to the phyla Proteobacteria and Firmicutes with the predominant genera being Photobacterium (39.4%), Bacillus (25.8%), and Vibrio (19.7%). Protease inhibitor tests revealed that extracellular proteases secreted by the bacteria were mainly serine proteases and/or metalloproteases with relatively low proportions of cysteine proteases. This study represents the first comprehensive analysis on the diversity of protease-producing bacteria and their extracellular proteases in sediments of a eutrophic bay. PMID- 26441944 TI - Temporal stability of bacterial symbionts in a temperate ascidian. AB - In temperate seas, both bacterioplankton communities and invertebrate lifecycles follow a seasonal pattern. To investigate whether the bacterial community associated with the Mediterranean ascidian Didemnum fulgens exhibited similar variations, we monitored its bacterial community structure monthly for over a year using terminal restriction fragment length polymorphism and clone library analyses based on a nearly full length fragment of the 16S rRNA gene. D. fulgens harbored a bacterial consortium typical of ascidians, including numerous members of the phylum Proteobacteria, and a few members of the phyla Cyanobacteria and Acidobacteria. The overall bacterial community in D. fulgens had a distinct signature from the surrounding seawater and was stable over time and across seasonal fluctuations in temperature. Bacterial symbionts were also observed around animal cells in the tunic of adult individuals and in the inner tunic of D. fulgens larvae by transmission electron microscopy. Our results suggest that, as seen for sponges and corals, some species of ascidians host stable and unique bacterial communities that are at least partially inherited by their progeny by vertical transmission. PMID- 26441946 TI - Nucleation of Fe-rich phosphates and carbonates on microbial cells and exopolymeric substances. AB - Although phosphate and carbonate are important constituents in ancient and modern environments, it is not yet clear their biogeochemical relationships and their mechanisms of formation. Microbially mediated carbonate formation has been widely studied whereas little is known about the formation of phosphate minerals. Here we report that a new bacterial strain, Tessarococcus lapidicaptus, isolated from the subsurface of Rio Tinto basin (Huelva, SW Spain), is capable of precipitating Fe-rich phosphate and carbonate minerals. We observed morphological differences between phosphate and carbonate, which may help us to recognize these minerals in terrestrial and extraterrestrial environments. Finally, considering the scarcity and the unequal distribution and preservation patterns of phosphate and carbonates, respectively, in the geological record and the biomineralization process that produces those minerals, we propose a hypothesis for the lack of Fe phosphates in natural environments and ancient rocks. PMID- 26441945 TI - Expression of the translocator protein (TSPO) from Pseudomonas fluorescens Pf0-1 requires the stress regulatory sigma factors AlgU and RpoH. AB - The translocator protein (TSPO), previously designated as peripheral-type benzodiazepine receptor, is an evolutionary conserved protein that is found in many Eukarya, Archae, and Bacteria, in which it plays several important functions including for example membrane biogenesis, signaling, and stress response. A tspo homolog gene has been identified in several members of the Pseudomonas genus, among which the soil bacterium P. fluorescens Pf0-1. In this bacterium, the tspo gene is located in the vicinity of a putative hybrid histidine kinase-encoding gene. Since tspo has been involved in water stress related response in plants, we explored the effects of hyperosmolarity and temperature on P. fluorescens Pf0-1 tspo expression using a strategy based on lux-reporter fusions. We show that the two genes Pfl01_2810 and tspo are co-transcribed forming a transcription unit. The expression of this operon is growth phase-dependent and is increased in response to high concentrations of NaCl, sucrose and to a D-cycloserine treatment, which are conditions leading to activity of the major cell wall stress responsive extracytoplasmic sigma factor AlgU. Interestingly, the promoter region activity is strongly lowered in a P. aeruginosa algU mutant, suggesting that AlgU may be involved at least partly in the molecular mechanism leading to Pfl01_2810 tspo expression. In silico analysis of this promoter region failed to detect an AlgU consensus binding site; however, a putative binding site for the heat shock response RpoH sigma factor was detected. Accordingly, the promoter activity of the region containing this sequence is increased in response to high growth temperature and slightly lowered in a P. aeruginosa rpoH mutant strain. Taken together, our data suggest that P. fluorescens tspo gene may belong at least partly to the cell wall stress response. PMID- 26441947 TI - Exploring antibiotic resistance genes and metal resistance genes in plasmid metagenomes from wastewater treatment plants. AB - Plasmids operate as independent genetic elements in microorganism communities. Through horizontal gene transfer (HGT), they can provide their host microorganisms with important functions such as antibiotic resistance and heavy metal resistance. In this study, six metagenomic libraries were constructed with plasmid DNA extracted from influent, activated sludge (AS) and digested sludge (DS) of two wastewater treatment plants (WWTPs). Compared with the metagenomes of the total DNA extracted from the same sectors of the wastewater treatment plant, the plasmid metagenomes had significantly higher annotation rates, indicating that the functional genes on plasmids are commonly shared by those studied microorganisms. Meanwhile, the plasmid metagenomes also encoded many more genes related to defense mechanisms, including ARGs. Searching against an antibiotic resistance genes (ARGs) database and a metal resistance genes (MRGs) database revealed a broad-spectrum of antibiotic (323 out of a total 618 subtypes) and MRGs (23 out of a total 23 types) on these plasmid metagenomes. The influent plasmid metagenomes contained many more resistance genes (both ARGs and MRGs) than the AS and the DS metagenomes. Sixteen novel plasmids with a complete circular structure that carried these resistance genes were assembled from the plasmid metagenomes. The results of this study demonstrated that the plasmids in WWTPs could be important reservoirs for resistance genes, and may play a significant role in the horizontal transfer of these genes. PMID- 26441949 TI - Commentary: With a little help from my enteric microbial friends. PMID- 26441950 TI - Glycan cross-feeding activities between bifidobacteria under in vitro conditions. AB - Bifidobacteria colonize the gut of various mammals, including humans, where they may metabolize complex, diet-, and host-derived carbohydrates. The glycan associated metabolic features encoded by bifidobacteria are believed to be strongly influenced by cross-feeding activities due to the co-existence of strains with different glycan-degrading properties. In this study, we observed an enhanced growth yield of Bifidobacterium bifidum PRL2010 when co-cultivated with Bifidobacterium breve 12L, Bifidobacterium adolescentis 22L, or Bifidobacterium thermophilum JCM1207. This enhanced growth phenomenon was confirmed by whole genome transcriptome analyses, which revealed co-cultivation-associated transcriptional induction of PRL2010 genes involved in carbohydrate metabolism, such as those encoding for carbohydrate transporters and associated energy production, and genes required for translation, ribosomal structure, and biogenesis, thus supporting the idea that co-cultivation of certain bifidobacterial strains with B. bifidum PRL2010 causes enhanced metabolic activity, and consequently increased lactate and/or acetate production. Overall, these data suggest that PRL2010 cells benefit from the presence of other bifidobacterial strains. PMID- 26441948 TI - Next-generation sequencing (NGS) for assessment of microbial water quality: current progress, challenges, and future opportunities. AB - Water quality is an emergent property of a complex system comprised of interacting microbial populations and introduced microbial and chemical contaminants. Studies leveraging next-generation sequencing (NGS) technologies are providing new insights into the ecology of microbially mediated processes that influence fresh water quality such as algal blooms, contaminant biodegradation, and pathogen dissemination. In addition, sequencing methods targeting small subunit (SSU) rRNA hypervariable regions have allowed identification of signature microbial species that serve as bioindicators for sewage contamination in these environments. Beyond amplicon sequencing, metagenomic and metatranscriptomic analyses of microbial communities in fresh water environments reveal the genetic capabilities and interplay of waterborne microorganisms, shedding light on the mechanisms for production and biodegradation of toxins and other contaminants. This review discusses the challenges and benefits of applying NGS-based methods to water quality research and assessment. We will consider the suitability and biases inherent in the application of NGS as a screening tool for assessment of biological risks and discuss the potential and limitations for direct quantitative interpretation of NGS data. Secondly, we will examine case studies from recent literature where NGS based methods have been applied to topics in water quality assessment, including development of bioindicators for sewage pollution and microbial source tracking, characterizing the distribution of toxin and antibiotic resistance genes in water samples, and investigating mechanisms of biodegradation of harmful pollutants that threaten water quality. Finally, we provide a short review of emerging NGS platforms and their potential applications to the next generation of water quality assessment tools. PMID- 26441951 TI - Phenotype MicroArrays as a complementary tool to next generation sequencing for characterization of tree endophytes. AB - There is an increasing need to calibrate microbial community profiles obtained through next generation sequencing (NGS) with relevant taxonomic identities of the microbes, and to further associate these identities with phenotypic attributes. Phenotype MicroArray (PM) techniques provide a semi-high throughput assay for characterization and monitoring the microbial cellular phenotypes. Here, we present detailed descriptions of two different PM protocols used in our recent studies on fungal endophytes of forest trees, and highlight the benefits and limitations of this technique. We found that the PM approach enables effective screening of substrate utilization by endophytes. However, the technical limitations are multifaceted and the interpretation of the PM data challenging. For the best result, we recommend that the growth conditions for the fungi are carefully standardized. In addition, rigorous replication and control strategies should be employed whether using pre-configured, commercial microwell plates or in-house designed PM plates for targeted substrate analyses. With these precautions, the PM technique is a valuable tool to characterize the metabolic capabilities of individual endophyte isolates, or successional endophyte communities identified by NGS, allowing a functional interpretation of the taxonomic data. Thus, PM approaches can provide valuable complementary information for NGS studies of fungal endophytes in forest trees. PMID- 26441952 TI - Assessing the antimicrobial activities of Ocins. AB - The generation of a zone of inhibition on a solid substrate indicates the bioactivity of antimicrobial peptides such as bacteriocin and enterocin. The indicator strain plays a significant role in bacteriocin assays. Other characteristics of bacteriocins, such as their dispersal ability and the different zymogram components, also affect bacteriocin assays. However, universal well diffusion assays for antimicrobials, irrespective of their ability to diffuse (bacteriocin and enterocin), do not exist. The ability of different zymography components to generate non-specific activities have rarely been explored in the literature. The purpose of the present work was to evaluate the impact of major factors (diffusion and rate of diffusion) in a solid substrate bioassay, and to document the adverse effects of sodium dodecyl sulfate in zymograms used to estimate the approximate molecular weight of bacteriocins. PMID- 26441953 TI - Epicatechin gallate, a naturally occurring polyphenol, alters the course of infection with beta-lactam-resistant Staphylococcus aureus in the zebrafish embryo. AB - (-)-epicatechin gallate (ECg) substantially modifies the properties of Staphylococcus aureus and reversibly abrogates beta-lactam resistance in methicillin/oxacillin resistant (MRSA) isolates. We have determined the capacity of ECg to alter the course of infection in zebrafish embryos challenged with epidemic clinical isolate EMRSA-16. At 30 h post fertilization (hpf), embryos were infected by injection of 1-5 * 10(3) colony forming units (CFU) of EMRSA-16 into the circulation valley or yolk sac. Infection by yolk sac injection was lethal with a challenge dose above 3 * 10(3) CFU, with no survivors at 70 hpf. In contrast, survival at 70 hpf after injection into the circulation was 83 and 44% following challenge with 3 * 10(3) and 1-5 * 10(3) CFU, respectively. No significant increases in survival were noted when infected embryos were maintained in medium containing 12.5-100 MUg/mL ECg with or without 4 or 16 MUg/mL oxacillin. However, when EMRSA-16 was grown in medium containing 12.5 MUg/mL ECg and the bacteria used to infect embryos by either the circulation valley or yolk sac, there were significant increases in embryo survival in both the presence and absence of oxacillin. ECg-modified and unmodified, GFP transformed EMRSA-16 bacteria were visualized within phagocytic cells in the circulation and yolk sac; pre-treatment with ECg also significantly increased induction of the respiratory burst and suppressed increases in IL-1beta expression typical of infection with untreated EMRSA-16. We conclude that exposure to ECg prior to infection reduces the lethality of EMRSA-16, renders cells more susceptible to elimination by immune processes and compromises their capacity to establish an inflammatory response in comparison to non-exposed bacteria. PMID- 26441954 TI - Epigenetic Codes Programing Class Switch Recombination. AB - Class switch recombination imparts B cells with a fitness-associated adaptive advantage during a humoral immune response by using a precision-tailored DNA excision and ligation process to swap the default constant region gene of the antibody with a new one that has unique effector functions. This secondary diversification of the antibody repertoire is a hallmark of the adaptability of B cells when confronted with environmental and pathogenic challenges. Given that the nucleotide sequence of genes during class switching remains unchanged (genetic constraints), it is logical and necessary therefore, to integrate the adaptability of B cells to an epigenetic state, which is dynamic and can be heritably modulated before, after, or even during an antibody-dependent immune response. Epigenetic regulation encompasses heritable changes that affect function (phenotype) without altering the sequence information embedded in a gene, and include histone, DNA and RNA modifications. Here, we review current literature on how B cells use an epigenetic code language as a means to ensure antibody plasticity in light of pathogenic insults. PMID- 26441955 TI - MF59- and Al(OH)3-Adjuvanted Staphylococcus aureus (4C-Staph) Vaccines Induce Sustained Protective Humoral and Cellular Immune Responses, with a Critical Role for Effector CD4 T Cells at Low Antibody Titers. AB - Staphylococcus aureus (S. aureus) is an important opportunistic pathogen that may cause invasive life-threatening infections, like sepsis and pneumonia. Due to the increasing antibiotic resistance, the development of an effective vaccine against S. aureus is needed. Although a correlate of protection against staphylococcal diseases is not yet established, several findings suggest that both antibodies and CD4 T cells might contribute to optimal immunity. In this study, we show that adjuvanting a multivalent vaccine (4C-Staph) with MF59, an oil-in-water emulsion licensed in human vaccines, further potentiated antigen-specific IgG titers and CD4 T-cell responses compared to alum and conferred protection in the peritonitis model of S. aureus infection. Moreover, we showed that MF59- and alum-adjuvanted 4C-Staph vaccines induced persistent antigen-specific humoral and T-cell responses, and protected mice from infection up to 4 months after immunization. Furthermore, 4C-Staph formulated with MF59 was used to investigate which immune compartment is involved in vaccine-induced protection. Using CD4 T cell-depleted mice or B cell-deficient mice, we demonstrated that both T and B-cell responses contributed to 4C-Staph vaccine-mediated protective immunity. However, the role of CD4 T cells seemed more evident in the presence of low-antibody responses. This study provides preclinical data further supporting the use of the adjuvanted 4C-Staph vaccines against S. aureus diseases, and provides critical insights on the correlates of protective immunity necessary to combat this pathogen. PMID- 26441959 TI - Whole Genome Expression Microarray Analysis of Highly Versus Poorly Tumorigenic Murine Melanoma Cell Lines Provides Insights into Factors That Regulate Tumor Growth, Metastasis, and Immunogenicity. PMID- 26441956 TI - A Tale from TGF-beta Superfamily for Thymus Ontogeny and Function. AB - Multiple signaling pathways control every aspect of cell behavior, organ formation, and tissue homeostasis throughout the lifespan of any individual. This review takes an ontogenetic view focused on the large superfamily of TGF beta/bone morphogenetic protein ligands to address thymus morphogenesis and function in T cell differentiation. Recent findings on a role of GDF11 for reversing aging-related phenotypes are also discussed. PMID- 26441958 TI - Subversion of Cell-Autonomous Immunity and Cell Migration by Legionella pneumophila Effectors. AB - Bacteria trigger host defense and inflammatory processes, such as cytokine production, pyroptosis, and the chemotactic migration of immune cells toward the source of infection. However, a number of pathogens interfere with these immune functions by producing specific so-called "effector" proteins, which are delivered to host cells via dedicated secretion systems. Air-borne Legionella pneumophila bacteria trigger an acute and potential fatal inflammation in the lung termed Legionnaires' disease. The opportunistic pathogen L. pneumophila is a natural parasite of free-living amoebae, but also replicates in alveolar macrophages and accidentally infects humans. The bacteria employ the intracellular multiplication/defective for organelle trafficking (Icm/Dot) type IV secretion system and as many as 300 different effector proteins to govern host cell interactions and establish in phagocytes an intracellular replication niche, the Legionella-containing vacuole. Some Icm/Dot-translocated effector proteins target cell-autonomous immunity or cell migration, i.e., they interfere with (i) endocytic, secretory, or retrograde vesicle trafficking pathways, (ii) organelle or cell motility, (iii) the inflammasome and programed cell death, or (iv) the transcription factor NF-kappaB. Here, we review recent mechanistic insights into the subversion of cellular immune functions by L. pneumophila. PMID- 26441957 TI - Modes of Antigen Presentation by Lymph Node Stromal Cells and Their Immunological Implications. AB - Antigen presentation is no longer the exclusive domain of cells of hematopoietic origin. Recent works have demonstrated that lymph node stromal cell (LNSC) populations, such as fibroblastic reticular cells, lymphatic and blood endothelial cells, not only provide a scaffold for lymphocyte interactions but also exhibit active immunomodulatory roles that are critical to mounting and resolving effective immune responses. Importantly, LNSCs possess the ability to present antigens and establish antigen-specific interactions with T cells. One example is the expression of peripheral tissue antigens, which are presented on major histocompatibility complex (MHC)-I molecules with tolerogenic consequences on T cells. Additionally, exogenous antigens, including self and tumor antigens, can be processed and presented on MHC-I complexes, which result in dysfunctional activation of antigen-specific CD8(+) T cells. While MHC-I is widely expressed on cells of both hematopoietic and non-hematopoietic origins, antigen presentation via MHC-II is more precisely regulated. Nevertheless, LNSCs are capable of endogenously expressing, or alternatively, acquiring MHC-II molecules. Transfer of antigen between LNSC and dendritic cells in both directions has been recently suggested to promote tolerogenic roles of LNSCs on the CD4(+) T cell compartment. Thus, antigen presentation by LNSCs is thought to be a mechanism that promotes the maintenance of peripheral tolerance as well as generates a pool of diverse antigen-experienced T cells for protective immunity. This review aims to integrate the current and emerging literature to highlight the importance of LNSCs in immune responses, and emphasize their role in antigen trafficking, retention, and presentation. PMID- 26441960 TI - gammadelta T Cells and NK Cells - Distinct Pathogenic Roles as Innate-Like Immune Cells in CNS Autoimmunity. PMID- 26441963 TI - Computational Models for Transplant Biomarker Discovery. AB - Translational medicine offers a rich promise for improved diagnostics and drug discovery for biomedical research in the field of transplantation, where continued unmet diagnostic and therapeutic needs persist. Current advent of genomics and proteomics profiling called "omics" provides new resources to develop novel biomarkers for clinical routine. Establishing such a marker system heavily depends on appropriate applications of computational algorithms and software, which are basically based on mathematical theories and models. Understanding these theories would help to apply appropriate algorithms to ensure biomarker systems successful. Here, we review the key advances in theories and mathematical models relevant to transplant biomarker developments. Advantages and limitations inherent inside these models are discussed. The principles of key computational approaches for selecting efficiently the best subset of biomarkers from high--dimensional omics data are highlighted. Prediction models are also introduced, and the integration of multi-microarray data is also discussed. Appreciating these key advances would help to accelerate the development of clinically reliable biomarker systems. PMID- 26441962 TI - Female Bias in Systemic Lupus Erythematosus is Associated with the Differential Expression of X-Linked Toll-Like Receptor 8. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of anti-nuclear antibodies. SLE is one of many autoimmune disorders that have a strong gender bias, with 70-90% of SLE patients being female. Several explanations have been postulated to account for the severity of autoimmune diseases in females, including hormonal, microbiota, and gene dosage differences. X-linked toll-like receptors (TLRs) have recently been implicated in disease progression in females. Our previous studies using the 564Igi mouse model of SLE on a Tlr7 and Tlr9 double knockout background showed that the presence of Tlr8 on both X chromosomes was required for the production of IgG autoantibodies, Ifn-I expression and granulopoiesis in females. Here, we show the results of our investigation into the role of Tlr8 expression in SLE pathogenesis in 564Igi females. Female mice have an increase in serum pathogenic anti-RNA IgG2a and IgG2b autoantibodies. 564Igi mice have also been shown to have an increase in neutrophils in vivo, which are major contributors to Ifn-alpha expression. Here, we show that neutrophils from C57BL/6 mice express Ifn-alpha in response to 564 immune complexes and TLR8 activation. Bone marrow-derived macrophages from 564Igi females have a significant increase in Tlr8 expression compared to male-derived cells, and RNA fluorescence in situ hybridization data suggest that Tlr8 may escape X-inactivation in female-derived macrophages. These results propose a model by which females may be more susceptible to SLE pathogenesis due to inefficient inactivation of Tlr8. PMID- 26441961 TI - Development and Function of Protective and Pathologic Memory CD4 T Cells. AB - Immunological memory is one of the defining features of the adaptive immune system. As key orchestrators and mediators of immunity, CD4 T cells are central to the vast majority of adaptive immune responses. Generated following an immune response, memory CD4 T cells retain pertinent information about their activation environment enabling them to make rapid effector responses upon reactivation. These responses can either benefit the host by hastening the control of pathogens or cause damaging immunopathology. Here, we will discuss the diversity of the memory CD4 T cell pool, the signals that influence the transition of activated T cells into that pool, and highlight how activation requirements differ between naive and memory CD4 T cells. A greater understanding of these factors has the potential to aid the design of more effective vaccines and to improve regulation of pathologic CD4 T cells, such as in the context of autoimmunity and allergy. PMID- 26441965 TI - Synergy between CD40 and MyD88 Does Not Influence Host Survival to Salmonella Infection. AB - Previous studies using purified toll-like receptor (TLR) ligands plus agonistic anti-CD40 antibodies showed that TLRs and CD40 can act synergistically on dendritic cells (DCs) to optimize T cell activation and Th1 differentiation. However, a synergistic effect of TLRs and CD40 during bacterial infection is not known. Here, we show that mice lacking the TLR adaptor MyD88 alone, or lacking both MyD88 and CD40 [double knockout (DKO) mice], are compromised in survival to Salmonella infection but have intact recruitment of neutrophils and inflammatory monocytes as well as unaltered abundance of DC subsets and DC activation in infected tissues. In contrast to infected wildtype and CD40(-/-) mice, both MyD88(-/-) mice and DKO mice lack detectable serum IFN-gamma and have elevated IL 10. A synergistic effect of TLRs and CD40 was revealed in co-culture experiments where OT-II T cell proliferation was compromised when DKO DCs were pulsed with OVA protein and OVA323-339 peptide, but not with heat-killed Salmonella expressing OVA (HKSOVA), relative to MyD88(-/-) DCs. By contrast, MyD88(-/-) or DKO DCs pulsed with any of the antigens had a similar ability to induce IFN-gamma that was lower than WT or CD40(-/-) DCs. DKO DCs pulsed with HKSOVA, but not with OVA or OVA323-339, had increased IL-10 relative to MyD88(-/-) DCs. Finally, HKSOVA-pulsed MyD88(-/-) and DKO DCs had similar and low induction of NFkappaB dependent and -independent genes upon co-culture with OT-II cells. Overall, our data revealed that synergistic effects of CD40 and MyD88 do not influence host survival to Salmonella infection or serum levels of IFN-gamma or IL-10. However, synergistic effects of MyD88 and CD40 may be apparent on some (IL-10 production) but not all (OT-II proliferation and IFN-gamma production) DC functions and depend on the complexity of the antigen. Indeed, synergistic effects observed using purified ligands and well-defined antigens may not necessarily apply when complex antigens, such as live bacteria, challenge the immune system. PMID- 26441964 TI - Macroautophagy in Endogenous Processing of Self- and Pathogen-Derived Antigens for MHC Class II Presentation. AB - Although autophagy is a process that has been studied for several years its link with antigen presentation and T cell immunity has only recently emerged. Autophagy, which means "self-eating," is important to maintain cell homeostasis and refers to a collection of mechanisms that delivers intracellular material for degradation into lysosomes. Among them, macroautophagy pathway has many implications in different biological processes, including innate and adaptive immunity. In particular, macroautophagy can provide a substantial source of intracellular antigens for loading onto MHC class II molecules using the alternative MHC class II pathway. Through autophagosomes, endogenous self antigens as well as antigens derived from intracellular pathogens can be delivered to MHC class II compartment and presented to CD4(+) T cells. The pathway will, therefore, impact both peripheral T cell tolerance and the pathogen specific immune response. This review will describe the contribution of autophagy to intracellular presentation of endogenous self- or pathogen-derived antigens via MHC class II and its consequences on CD4(+) T cell responses. PMID- 26441966 TI - Positive and Negative Regulatory Mechanisms for Fine-Tuning Cellularity and Functions of Medullary Thymic Epithelial Cells. AB - Self-tolerant T cells and regulatory T cells develop in the thymus. A wide variety of cell-cell interactions in the thymus is required for the differentiation, proliferation, and repertoire selection of T cells. Various secreted and cell surface molecules expressed in thymic epithelial cells (TECs) mediate these processes. Moreover, cytokines expressed by cells of hematopoietic origin regulate the cellularity of TECs. Tumor necrosis factor (TNF) family RANK ligand, lymphotoxin, and CD40 ligand, expressed in T cells and innate lymphoid cells (ILCs), promote the differentiation and proliferation of medullary TECs (mTECs) that play critical roles in the induction of immune tolerance. A recent study suggests that interleukin-22 (IL-22) produced by ILCs promotes regeneration of TECs after irradiation. Intriguingly, tumor growth factor-beta and osteoprotegerin limit cellularity of mTECs, thereby attenuating regulatory T cell generation. We will review recent insights into the molecular basis for cell-cell interactions regulating differentiation and proliferation of mTECs and also discuss about a perspective on use of mathematical models for understanding this complicated system. PMID- 26441967 TI - Transcriptional Enhancers in the Regulation of T Cell Differentiation. AB - The changes in phenotype and function that characterize the differentiation of naive T cells to effector and memory states are underscored by large-scale, coordinated, and stable changes in gene expression. In turn, these changes are choreographed by the interplay between transcription factors and epigenetic regulators that act to restructure the genome, ultimately ensuring lineage appropriate gene expression. Here, we focus on the mechanisms that control T cell differentiation, with a particular focus on the role of regulatory elements encoded within the genome, known as transcriptional enhancers (TEs). We discuss the central role of TEs in regulating T cell differentiation, both in health and disease. PMID- 26441968 TI - Pathologic and Protective Roles for Microglial Subsets and Bone Marrow- and Blood Derived Myeloid Cells in Central Nervous System Inflammation. AB - Inflammation is a series of processes designed for eventual clearance of pathogens and repair of damaged tissue. In the context of autoimmune recognition, inflammatory processes are usually considered to be pathological. This is also true for inflammatory responses in the central nervous system (CNS). However, as in other tissues, neuroinflammation can have beneficial as well as pathological outcomes. The complex role of encephalitogenic T cells in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) may derive from heterogeneity of the myeloid cells with which these T cells interact within the CNS. Myeloid cells, including resident microglia and infiltrating bone marrow derived cells, such as dendritic cells (DC) and monocytes/macrophages [bone marrow-derived macrophages (BMDM)], are highly heterogeneous populations that may be involved in neurotoxicity and also immunoregulation and regenerative processes. Better understanding and characterization of myeloid cell heterogeneity is essential for future development of treatments controlling inflammation and inducing neuroprotection and neuroregeneration in diseased CNS. Here, we describe and compare three populations of myeloid cells: CD11c(+) microglia, CD11c(-) microglia, and CD11c(+) blood-derived cells in terms of their pathological versus protective functions in the CNS of mice with EAE. Our data show that CNS-resident microglia include functionally distinct subsets that can be distinguished by their expression of CD11c. These subsets differ in their expression of Arg-1, YM1, iNOS, IL-10, and IGF-1. Moreover, in contrast to BMDM/DC, both subsets of microglia express protective interferon-beta (IFNbeta), high levels of colony-stimulating factor-1 receptor, and do not express the Th1 associated transcription factor T-bet. Taken together, our data suggest that CD11c(+) microglia, CD11c(-) microglia, and infiltrating BMDM/DC represent separate and distinct populations and illustrate the heterogeneity of the CNS inflammatory environment. PMID- 26441969 TI - Endogenous Antigen Presentation of MHC Class II Epitopes through Non-Autophagic Pathways. AB - Antigenic peptides presented by major histocompatibility complex (MHC) class II molecules are generally derived from exogenous proteins acquired by antigen presenting cells. However, in some circumstances, MHC class II molecules can present intracellular proteins expressed within the antigen-presenting cells. There are several described pathways by which endogenous antigens are degraded and gain access to MHC class II molecules. These include autophagy and other non autophagic pathways; the latter category includes the MHC class I-like pathways, heat shock protein 90-mediated pathways, and internalization from the plasma membrane. This review will summarize and discuss the non-autophagic pathways. PMID- 26441970 TI - Animal Models to Study Links between Cardiovascular Disease and Renal Failure and Their Relevance to Human Pathology. AB - The close association between cardiovascular pathology and renal dysfunction is well documented and significant. Patients with conventional risk factors for cardiovascular disease like diabetes and hypertension also suffer renal dysfunction. This is unsurprising if the kidney is simply regarded as a "modified blood vessel" and thus, traditional risk factors will affect both systems. Consistent with this, it is relatively easy to comprehend how patients with either sudden or gradual cardiac and or vascular compromise have changes in both renal hemodynamic and regulatory systems. However, patients with pure or primary renal dysfunction also have metabolic changes (e.g., oxidant stress, inflammation, nitric oxide, or endocrine changes) that affect the cardiovascular system. Thus, cardiovascular and renal systems are intimately, bidirectionally and inextricably linked. Whilst we understand several of these links, some of the mechanisms for these connections remain incompletely explained. Animal models of cardiovascular and renal disease allow us to explore such mechanisms, and more importantly, potential therapeutic strategies. In this article, we review various experimental models used, and examine critically how representative they are of the human condition. PMID- 26441971 TI - Mucosal-Associated Invariant T Cells in the Human Gastric Mucosa and Blood: Role in Helicobacter pylori Infection. AB - Mucosal-associated invariant T (MAIT) cells represent a class of antimicrobial innate-like T cells that have been characterized in human blood, liver, lungs, and intestine. Here, we investigated, for the first time, the presence of MAIT cells in the stomach of children, adults, and the elderly undergoing routine endoscopy and assessed their reactivity to Helicobacter pylori (H. pylori - Hp), a major gastric pathogen. We observed that MAIT cells are present in the lamina propria compartment of the stomach and display a similar memory phenotype to blood MAIT cells. We then demonstrated that gastric and blood MAIT cells are able to recognize H. pylori. We found that CD8(+) and CD4(-)CD8(-) (double negative) MAIT cell subsets respond to H. pylori-infected macrophages stimulation in a MR-1 restrictive manner by producing cytokines (IFN-gamma, TNF-alpha, IL-17A) and exhibiting cytotoxic activity. Interestingly, we observed that blood MAIT cell frequency in Hp(+ve) individuals was significantly lower than in Hp(-ve) individuals. However, gastric MAIT cell frequency was not significantly different between Hp(+ve) and Hp(-ve) individuals, demonstrating a dichotomy between blood and gastric tissues. Further, we observed that the majority of gastric MAIT cells (>80%) expressed tissue-resident markers (CD69(+) CD103(+)), which were only marginally present on PBMC MAIT cells (<3%), suggesting that gastric MAIT cells are readily available to respond quickly to pathogens. These results contribute important new information to the understanding of MAIT cells function on peripheral and mucosal tissues and its possible implications in the host response to H. pylori. PMID- 26441972 TI - Nutritional Modulation of Gene Expression: Might This be of Benefit to Individuals with Crohn's Disease? AB - The incidence of inflammatory bowel diseases (IBD), including Crohn's disease (CD), is increasing worldwide, especially in young children and adolescents. Although hospitalized patients are usually provided with enteral or parenteral support, continuing care typically requires a trial-and-error approach to suppressing symptoms and maintaining disease remission. Current nutritional advice does not differ from general population guidelines. International collaborative studies have revealed 163 distinct genetic loci affecting susceptibility to IBD, in some of which host-microbe interactions can be seen to play an important role. The nature of these loci enables a rationale for predicting nutritional requirements that may not be evident through standard therapeutic approaches. Certain recognized nutrients, such as vitamin D and long chain omega-3 polyunsaturated fatty acids, may be required at higher than anticipated levels. Various phytochemicals, not usually considered in the same class as classic nutrients, could play an important role. Prebiotics and probiotics may also be beneficial. Genomic approaches enable proof of principle of nutrient optimization rather than waiting for disease symptoms to appear and/or progress. We suggest a paradigm shift in diagnostic tools and nutritional therapy for CD, involving a systems biology approach for implementation. PMID- 26441973 TI - Lower Affinity T Cells are Critical Components and Active Participants of the Immune Response. AB - Kinetic and biophysical parameters of T cell receptor (TCR) and peptide:MHC (pMHC) interaction define intrinsic factors required for T cell activation and differentiation. Although receptor ligand kinetics are somewhat cumbersome to assess experimentally, TCR:pMHC affinity has been shown to predict peripheral T cell functionality and potential for forming memory. Multimeric forms of pMHC monomers have often been used to provide an indirect readout of higher affinity T cells due to their availability and ease of use while allowing simultaneous definition of other functional and phenotypic characteristics. However, multimeric pMHC reagents have introduced a bias that underestimates the lower affinity components contained in the highly diverse TCR repertoires of all polyclonal T cell responses. Advances in the identification of lower affinity cells have led to the examination of these cells and their contribution to the immune response. In this review, we discuss the identification of high- vs. low affinity T cells as well as their attributed signaling and functional differences. Lastly, mechanisms are discussed that maintain a diverse range of low- and high-affinity T cells. PMID- 26441974 TI - Induction of Regulatory T Cells by Intravenous Immunoglobulin: A Bridge between Adaptive and Innate Immunity. AB - Intravenous immunoglobulin (IVIg) is a polyclonal immunoglobulin G preparation with potent immunomodulatory properties. The mode of action of IVIg has been investigated in multiple disease states, with various mechanisms described to account for its benefits. Recent data indicate that IVIg increases both the number and the suppressive capacity of regulatory T cells, a subpopulation of T cells that are essential for immune homeostasis. IVIg alters dendritic cell function, cytokine and chemokine networks, and T lymphocytes, leading to development of regulatory T cells. The ability of IVIg to influence Treg induction has been shown both in animal models and in human diseases. In this review, we discuss data on the potential mechanisms contributing to the interaction between IVIg and the regulatory T-cell compartment. PMID- 26441975 TI - Meningeal Infiltration of the Spinal Cord by Non-Classically Activated B Cells is Associated with Chronic Disease Course in a Spontaneous B Cell-Dependent Model of CNS Autoimmune Disease. AB - We characterized B cell infiltration of the spinal cord in a B cell-dependent spontaneous model of central nervous system (CNS) autoimmunity that develops in a proportion of mice with mutant T and B cell receptors specific for myelin oligodendrocyte glycoprotein. We found that, while males are more likely to develop disease, females are more likely to have a chronic rather than monophasic disease course. B cell infiltration of the spinal cord was investigated by histology and FACs. CD4(+) T cell infiltration was pervasive throughout the white and in some cases gray matter. B cells were almost exclusively restricted to the meninges, often in clusters reminiscent of those described in human multiple sclerosis. These clusters were typically found adjacent to white matter lesions and their presence was associated with a chronic disease course. Extensive investigation of these clusters by histology did not identify features of lymphoid follicles, including organization of T and B cells into separate zones, CD35(+) follicular dendritic cells, or germinal centers. The majority of cluster B cells were IgD(+) with little evidence of class switch. Consistent with this, B cells isolated from the spinal cord were of the naive/memory CD38(hi) CD95(lo) phenotype. Nevertheless, they were CD62L(lo) and CD80(hi) compared to lymph node B cells suggesting that they were at least partly activated and primed to present antigen. Therefore, if meningeal B cells contribute to CNS pathology in autoimmunity, follicular differentiation is not necessary for the pathogenic mechanism. PMID- 26441976 TI - How Neutrophils Shape Adaptive Immune Responses. AB - Neutrophils are classically considered as cells pivotal for the first line of defense against invading pathogens. In recent years, evidence has accumulated that they are also important in the orchestration of adaptive immunity. Neutrophils rapidly migrate in high numbers to sites of inflammation (e.g., infection, tissue damage, and cancer) and are subsequently able to migrate to draining lymph nodes (LNs). Both at the site of inflammation as well as in the LNs, neutrophils can engage with lymphocytes and antigen-presenting cells. This crosstalk occurs either directly via cell-cell contact or via mediators, such as proteases, cytokines, and radical oxygen species. In this review, we will discuss the current knowledge regarding locations and mechanisms of interaction between neutrophils and lymphocytes in the context of homeostasis and various pathological conditions. In addition, we will highlight the complexity of the microenvironment that is involved in the generation of suppressive or stimulatory neutrophil phenotypes. PMID- 26441977 TI - The Fyn-ADAP Axis: Cytotoxicity Versus Cytokine Production in Killer Cells. AB - Lymphocyte signaling cascades responsible for anti-tumor cytotoxicity and inflammatory cytokine production must be tightly regulated in order to control an immune response. Disruption of these cascades can cause immune suppression as seen in a tumor microenvironment, and loss of signaling integrity can lead to autoimmunity and other forms of host-tissue damage. Therefore, understanding the distinct signaling events that exclusively control specific effector functions of "killer" lymphocytes (T and NK cells) is critical for understanding disease progression and formulating successful immunotherapy. Elucidation of divergent signaling pathways involved in receptor-mediated activation has provided insights into the independent regulation of cytotoxicity and cytokine production in lymphocytes. Specifically, the Fyn signaling axis represents a branch point for killer cell effector functions and provides a model for how cytotoxicity and cytokine production are differentially regulated. While the Fyn-PI(3)K pathway controls multiple functions, including cytotoxicity, cell development, and cytokine production, the Fyn-ADAP pathway preferentially regulates cytokine production in NK and T cells. In this review, we discuss how the structure of Fyn controls its function in lymphocytes and the role this plays in mediating two facets of lymphocyte effector function, cytotoxicity and production of inflammatory cytokines. This offers a model for using mechanistic and structural approaches to understand clinically relevant lymphocyte signaling. PMID- 26441978 TI - Role of Memory T Cells and Perspectives for Intervention in Organ Transplantation. AB - Memory T cells are necessary for protective immunity against invading pathogens, especially under conditions of immunosuppression. However, their presence also threatens transplant survival, making transplantation a great challenge. Significant progress has been achieved in recent years in advancing our understanding of the role that memory T cells play in transplantation. This review focuses on the latest advances in our understanding of the involvement of memory T cells in graft rejection and transplant tolerance and discusses potential strategies for targeting memory T cells in order to minimize allograft rejection and optimize clinical outcomes. PMID- 26441979 TI - Controlling HIV-1: Non-Coding RNA Gene Therapy Approaches to a Functional Cure. AB - The current treatment strategy for HIV-1 involves prolonged and intensive combined antiretroviral therapy (cART), which successfully suppresses plasma viremia. It has transformed HIV-1 infection into a chronic disease. However, despite the success of cART, a latent form of HIV-1 infection persists as integrated provirus in resting memory CD4(+) T cells. Virus can reactivate from this reservoir upon cessation of treatment, and hence HIV requires lifelong therapy. The reservoir represents a major barrier to eradication. Understanding molecular mechanisms regulating HIV-1 transcription and latency are crucial to develop alternate treatment strategies, which impact upon the reservoir and provide a path toward a "functional cure" in which there is no detectable viremia in the absence of cART. Numerous reports have suggested ncRNAs are involved in regulating viral transcription and latency. This review will discuss the latest developments in ncRNAs, specifically short interfering (si)RNA and short hairpin (sh)RNA, targeting molecular mechanisms of HIV-1 transcription, which may represent potential future therapeutics. It will also briefly address animal models for testing potential therapeutics and current gene therapy clinical trials. PMID- 26441980 TI - Mechanisms of Kidney Injury in Lupus Nephritis - the Role of Anti-dsDNA Antibodies. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a breakdown of self-tolerance, production of auto-antibodies and immune-mediated injury, resulting in damage accrual in multiple organs. Kidney involvement, termed lupus nephritis, is a major cause of morbidity and mortality that affects over half of the SLE population during the course of disease. The etiology of lupus nephritis is multifactorial and remains to be fully elucidated. Accumulating evidence suggests that in addition to forming immune complexes and triggering complement activation, anti-dsDNA antibodies contribute to the pathogenesis of lupus nephritis through binding, either directly or indirectly, to cross-reactive antigens or chromatin materials, respectively, to resident renal cells and/or extracellular matrix components, thereby triggering downstream cellular activation and proliferation as well as inflammatory and fibrotic processes. Several cross-reactive antigens that mediate anti-dsDNA antibody binding have been identified, such as annexin II and alpha-actinin. This review discusses the mechanisms through which anti-dsDNA antibodies contribute to immunopathogenesis in lupus nephritis. Corticosteroids combined with either mycophenolic acid (MPA) or cyclophosphamide is the current standard of care immunosuppressive therapy for severe lupus nephritis. This review also discusses recent data showing distinct effects of MPA and cyclophosphamide on inflammatory and fibrotic processes in resident renal cells. PMID- 26441981 TI - A Dataset of 26 Candidate Gene and Pro-Inflammatory Cytokine Variants for Association Studies in Idiopathic Pulmonary Fibrosis: Frequency Distribution in Normal Czech Population. PMID- 26441983 TI - S100A9 Tetramers, Which are Ligands of CD85j, Increase the Ability of MVAHIV Primed NK Cells to Control HIV Infection. AB - Natural killer (NK) cells are the major antiviral effector population of the innate immune system. We previously found that S100A9 is a novel ligand of the receptor CD85j and that S100A9 tetramers enhance the anti-HIV activity of NK cells. Also, we found that dendritic cells (DCs) infected by the HIV vaccine candidate, MVAHIV, prime NK cells to specifically control HIV infection in autologous CD4(+) T cells. In this study, we analyzed whether stimulation of NK cells by S100A9 tetramers prior to the priming by MVAHIV-infected DCs modulates the subsequent anti-HIV activity of NK cells. We found that S100A9 tetramers activate NK cells and that DCs enhance the anti-HIV activity of NK cells. Interestingly, we observed that stimulation of NK cells by S100A9 tetramers, prior to the priming, significantly increased the subsequent anti-HIV activity of NK cells and that the enhanced anti-HIV activity was observed following different conditions of priming, including the MVAHIV-priming. As S100A9 tetramers alone directly increase the anti-HIV activity of NK cells and as this increased anti HIV activity is also observed following the interaction of NK cells with MVAHIV infected DCs, we propose S100A9 tetramers as potential adjuvants to stimulate the anti-HIV activity of NK cells. PMID- 26441982 TI - Dipeptidyl Peptidase-4 Regulation of SDF-1/CXCR4 Axis: Implications for Cardiovascular Disease. AB - Dipeptidyl peptidase-4 (DPP4) is a ubiquitously expressed protease that regulates diverse number of physiological functions. As a dipeptidase, it exerts its catalytic effects on proteins/peptides with proline, alanine, or serine in the penultimate (P1) amino acid residue from the amino terminus. The evidence to date supports an important effect of DPP4 in catalytic cleavage of incretin peptides and this perhaps represents the main mechanism by which DPP4 inhibition improves glycemic control. DPP4 also plays an important role in the degradation of multiple chemokines of which stromal cell-derived factor-1 (SDF-1, also known as CXCL12) is perhaps an increasingly recognized target, given its importance in processes, such as hematopoiesis, angiogenesis, and stem cell homing. In the current review, we will summarize the importance of DPP4-mediated enzymatic processing of cytokines/chemokines with an emphasis on SDF-1 and resultant implications for cardiovascular physiology and disease. PMID- 26441984 TI - Splenic Macrophage Subsets and Their Function during Blood-Borne Infections. AB - The spleen is one of the major immunological sites for maintaining blood homeostasis. Previous studies showed that heterogeneous splenic macrophage populations contribute in complimentary ways to control blood-borne infections and induce effective immune responses. Marginal metallophilic macrophages (MMMPhis) and marginal zone macrophages (MZMPhis) are cells with great ability to internalize blood-borne pathogens such as virus or bacteria. Their localization adjacent to T- and B-cell-rich splenic areas favors the rapid contact between these macrophages and cells from adaptive immunity. Indeed, MMMPhis and MZMPhis are considered important bridges between innate and adaptive immunity. Although red pulp macrophages (RpMPhis) are mainly considered scavengers for senescent erythrocytes, several data indicate a role for RpMPhis in control of infections such as blood-stage malaria as well as in the induction of innate and adaptive immunity. Here, we review current data on how different macrophage subsets recognize and help eliminate blood-borne pathogens, and, in turn, how the inflammatory microenvironment in different phases of infection (acute, chronic, and after pathogen clearance) influences macrophage function and survival. PMID- 26441985 TI - Editorial: Pattern Recognition Receptors and Cancer. PMID- 26441986 TI - Critical Role of Tumor Microenvironment in Shaping NK Cell Functions: Implication of Hypoxic Stress. AB - Blurring the boundary between innate and adaptive immune system, natural killer (NK) cells, a key component of the innate immunity, are recognized as potent anticancer mediators. Extensive studies have been detailed on how NK cells get activated and recognize cancer cells. In contrast, few studies have been focused on how tumor microenvironment-mediated immunosubversion and immunoselection of tumor-resistant variants may impair NK cell function. Accumulating evidences indicate that several cell subsets (macrophages, myeloid-derived suppressive cells, T regulatory cells, dendritic cells, cancer-associated fibroblasts, and tumor cells), their secreted factors, as well as metabolic components (i.e., hypoxia) have immunosuppressive roles in the tumor microenvironment and are able to condition NK cells to become anergic. In this review, we will describe how NK cells react with different stromal cells in the tumor microenvironment. This will be followed by a discussion on the role of hypoxic stress in the regulation of NK cell functions. The aim of this review is to provide a better understanding of how the tumor microenvironment impairs NK cell functions, thereby limiting the use of NK cell-based therapy, and we will attempt to suggest more efficient tools to establish a more favorable tumor microenvironment to boost NK cell cytotoxicity and control tumor progression. PMID- 26441987 TI - CD74 in Kidney Disease. AB - CD74 (invariant MHC class II) regulates protein trafficking and is a receptor for macrophage migration inhibitory factor (MIF) and d-dopachrome tautomerase (d DT/MIF-2). CD74 expression is increased in tubular cells and/or glomerular podocytes and parietal cells in human metabolic nephropathies, polycystic kidney disease, graft rejection and kidney cancer and in experimental diabetic nephropathy and glomerulonephritis. Stressors like abnormal metabolite (glucose, lyso-Gb3) levels and inflammatory cytokines increase kidney cell CD74. MIF activates CD74 to increase inflammatory cytokines in podocytes and tubular cells and proliferation in glomerular parietal epithelial cells and cyst cells. MIF overexpression promotes while MIF targeting protects from experimental glomerular injury and kidney cysts, and interference with MIF/CD74 signaling or CD74 deficiency protected from crescentic glomerulonephritis. However, CD74 may protect from interstitial kidney fibrosis. Furthermore, CD74 expression by stressed kidney cells raises questions about the kidney safety of cancer therapy strategies delivering lethal immunoconjugates to CD74-expressing cells. Thus, understanding CD74 biology in kidney cells is relevant for kidney therapeutics. PMID- 26441988 TI - Mathematical Modeling of Early Cellular Innate and Adaptive Immune Responses to Ischemia/Reperfusion Injury and Solid Organ Allotransplantation. AB - A mathematical model of the early inflammatory response in transplantation is formulated with ordinary differential equations. We first consider the inflammatory events associated only with the initial surgical procedure and the subsequent ischemia/reperfusion (I/R) events that cause tissue damage to the host as well as the donor graft. These events release damage-associated molecular pattern molecules (DAMPs), thereby initiating an acute inflammatory response. In simulations of this model, resolution of inflammation depends on the severity of the tissue damage caused by these events and the patient's (co)-morbidities. We augment a portion of a previously published mathematical model of acute inflammation with the inflammatory effects of T cells in the absence of antigenic allograft mismatch (but with DAMP release proportional to the degree of graft damage prior to transplant). Finally, we include the antigenic mismatch of the graft, which leads to the stimulation of potent memory T cell responses, leading to further DAMP release from the graft and concomitant increase in allograft damage. Regulatory mechanisms are also included at the final stage. Our simulations suggest that surgical injury and I/R-induced graft damage can be well tolerated by the recipient when each is present alone, but that their combination (along with antigenic mismatch) may lead to acute rejection, as seen clinically in a subset of patients. An emergent phenomenon from our simulations is that low level DAMP release can tolerize the recipient to a mismatched allograft, whereas different restimulation regimens resulted in an exaggerated rejection response, in agreement with published studies. We suggest that mechanistic mathematical models might serve as an adjunct for patient- or sub-group-specific predictions, simulated clinical studies, and rational design of immunosuppression. PMID- 26441989 TI - Gut-Associated Plasmacytoid Dendritic Cells Display an Immature Phenotype and Upregulated Granzyme B in Subjects with HIV/AIDS. AB - Plasmacytoid dendritic cells (pDCs) in the periphery of subjects with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) decrease over time, and the fate of these cells has been the subject of ongoing investigation. Previous studies using animal models as well as studies with humans suggest that these cells may redistribute to the gut. Other studies using animal models propose that the periphery pDCs are depleted and gut is repopulated with naive pDCs from the bone marrow. In the present study, we utilized immunohistochemistry to survey duodenum biopsies of subjects with HIV/AIDS and controls. We observed that subjects with HIV/AIDS had increased infiltration of Ki-67(+)/CD303(+) pDCs, a phenotype consistent with bone marrow-derived pre-pDCs. In contrast, Ki-67(+)/CD303(+) pDCs were not observed in control biopsies. We additionally observed that gut-associated pDCs in HIV/AIDS cases upregulate the proapoptotic enzyme granzyme B; however, no granzyme B was observed in the pDCs of control biopsies. Our data are consistent with reports in animal models that suggest periphery pDCs are depleted by exhaustion and that naive pDCs egress from the bone marrow and ultimately infiltrate the gut mucosa. Additionally, our observation of granzyme B upregulation in naive pDCs may identify a contributing factor to the gut pathology associated with HIV infection. PMID- 26441990 TI - Ontogeny of Tissue-Resident Macrophages. AB - The origin of tissue-resident macrophages, crucial for homeostasis and immunity, has remained controversial until recently. Originally described as part of the mononuclear phagocyte system, macrophages were long thought to derive solely from adult blood circulating monocytes. However, accumulating evidence now shows that certain macrophage populations are in fact independent from monocyte and even from adult bone marrow hematopoiesis. These tissue-resident macrophages derive from sequential seeding of tissues by two precursors during embryonic development. Primitive macrophages generated in the yolk sac (YS) from early erythro-myeloid progenitors (EMPs), independently of the transcription factor c Myb and bypassing monocytic intermediates, first give rise to microglia. Later, fetal monocytes, generated from c-Myb(+) EMPs that initially seed the fetal liver (FL), then give rise to the majority of other adult macrophages. Thus, hematopoietic stem cell-independent embryonic precursors transiently present in the YS and the FL give rise to long-lasting self-renewing macrophage populations. PMID- 26441991 TI - Functional Role of G9a Histone Methyltransferase in Cancer. AB - Post-translational modifications of DNA and histones are epigenetic mechanisms, which affect the chromatin structure, ultimately leading to gene expression changes. A number of different epigenetic enzymes are actively involved in the addition or the removal of various covalent modifications, which include acetylation, methylation, phosphorylation, ubiquitination, and sumoylation. Deregulation of these processes is a hallmark of cancer. For instance, G9a, a histone methyltransferase responsible for histone H3 lysine 9 (H3K9) mono- and dimethylation, has been observed to be upregulated in different types of cancer and its overexpression has been associated with poor prognosis. Key roles played by these enzymes in various diseases have led to the hypothesis that these molecules represent valuable targets for future therapies. Several small molecule inhibitors have been developed to specifically block the epigenetic activity of these enzymes, representing promising therapeutic tools in the treatment of human malignancies, such as cancer. In this review, the role of one of these epigenetic enzymes, G9a, is discussed, focusing on its functional role in regulating gene expression as well as its implications in cancer initiation and progression. We also discuss important findings from recent studies using epigenetic inhibitors in cell systems in vitro as well as experimental tumor growth and metastasis assays in vivo. PMID- 26441992 TI - Therapeutic Potential of Hyporesponsive CD4(+) T Cells in Autoimmunity. AB - The interaction between dendritic cells (DCs) and T cells is crucial on immunity or tolerance induction. In an immature or semi-mature state, DCs induce tolerance through T-cell deletion, generation of regulatory T cells, and/or induction of T cell anergy. Anergy is defined as an unresponsive state that retains T cells in an "off" mode under conditions in which immune activation is undesirable. This mechanism is crucial for the control of T-cell responses against self-antigens, thereby preventing autoimmunity. Tolerogenic DCs (tDCs), generated in vitro from peripheral blood monocytes of healthy donors or patients with autoimmune pathologies, were shown to modulate immune responses by inducing T-cell hyporesponsiveness. Animal models of autoimmune diseases confirmed the impact of T-cell anergy on disease development and progression in vivo. Thus, the induction of T-cell hyporesponsiveness by tDCs has become a promising immunotherapeutic strategy for the treatment of T-cell-mediated autoimmune disorders. Here, we review recent findings in the area and discuss the potential of anergy induction for clinical purposes. PMID- 26441993 TI - Intestinal Microbiota and the Innate Immune System - A Crosstalk in Crohn's Disease Pathogenesis. AB - Crohn's disease (CD) is a chronic, relapsing inflammatory disorder that can occur anywhere along the gastrointestinal tract. The precise etiology of CD is still unclear but it is widely accepted that a complex series of interactions between susceptibility genes, the immune system and environmental factors are implicated in the onset and perpetuation of the disease. Increasing evidence from experimental and clinical studies implies the intestinal microbiota in disease pathogenesis, thereby supporting the hypothesis that chronic intestinal inflammation arises from an abnormal immune response against the microorganisms of the intestinal flora in genetically susceptible individuals. Given that CD patients display changes in their gut microbiota composition, collectively termed "dysbiosis," the question raises whether the altered microbiota composition is a cause of disease or rather a consequence of the inflammatory state of the intestinal environment. This review will focus on the crosstalk between the gut microbiota and the innate immune system during intestinal inflammation, thereby unraveling the role of the microbiota in CD pathogenesis. PMID- 26441994 TI - Inulin-Type beta2-1 Fructans have Some Effect on the Antibody Response to Seasonal Influenza Vaccination in Healthy Middle-Aged Humans. AB - beta2-1 fructans are prebiotics and, as such, may modulate some aspects of immune function. Improved immune function could enhance the host's ability to respond to infections. There is limited information on the effects of beta2-1 fructans on immune responses in humans. The objective of the study was to determine the effect of a specific combination of long-chain inulin and oligofructose (Orafti((r)) Synergy1) on immune function in middle-aged humans, with the primary outcome being response to seasonal influenza vaccination. Healthy middle-aged humans (45-63 years of age) were randomly allocated to consume beta2-1 fructans in the form of Orafti((r)) Synergy1 (8 g/day; n = 22) or maltodextrin as control (8 g/day; n = 21) for 8 weeks. After 4 weeks, participants received the 2008/2009 seasonal influenza vaccine. Blood and saliva samples were collected prior to vaccination and 2 and 4 weeks after vaccination. They were used to measure various immune parameters. The primary outcome was the serum concentration of anti-vaccine antibodies. Serum antibody titers against the vaccine and vaccine specific immunoglobulin concentrations increased post-vaccination. Antibodies to the H3N2-like hemagglutinin type 3, neuraminidase type 2-like strain were higher in the Synergy1 group (P = 0.020 for overall effect of treatment group), as was serum vaccine-specific IgG1 2 weeks post-vaccination (P = 0.028 versus control). There were no other differences between groups in antibody titers or anti-vaccine immunoglobulin concentrations, in blood immune cell phenotypes, or in a range of immune parameters. It is concluded that Orafti((r)) Synergy1, a combination of beta2-1 fructans, can enhance some aspects of the immune response in healthy middle-aged adults, but that this is not a global effect. PMID- 26441995 TI - Editorial: Antimicrobial Peptides and Complement - Maximising the Inflammatory Response. PMID- 26441998 TI - An improved high-throughput screening assay for tunicamycin sensitivity in Arabidopsis seedlings. AB - Tunicamycin (Tm) sensitivity assays are a useful method for studies of endoplasmic reticulum stress and the unfolded protein response in eukaryotic cells. While Tm sensitivity and Tm recovery assays have been previously described, these existing methods are time-consuming, labor intensive, and subjected to mechanical wounding. This study shows an improved method of testing Tm sensitivity in Arabidopsis using liquid Murashige and Skoog medium versus the traditional solid agar plates. Liquid medium bypasses the physical manipulation of seedlings, thereby eliminating the risk of potential mechanical damage and additional unwanted stress to seedlings. Seedlings were subjected to comparative treatments with various concentrations of Tm on both solid and liquid media and allowed to recover. Determination of fresh weight, chlorophyll contents analysis and qRT-PCR results confirm the efficacy of using liquid medium to perform quantitative Tm stress assays. PMID- 26441997 TI - NKp46 Clusters at the Immune Synapse and Regulates NK Cell Polarization. AB - Natural killer (NK) cells play an important role in first-line defense against tumor and virus-infected cells. The activity of NK cells is tightly regulated by a repertoire of cell surface expressed inhibitory and activating receptors. NKp46 is a major NK cell-activating receptor that is involved in the elimination of target cells. NK cells form different types of synapses that result in distinct functional outcomes: cytotoxic, inhibitory, and regulatory. Recent studies revealed that complex integration of NK receptor signaling controls cytoskeletal rearrangement and other immune synapse-related events. However, the distinct nature by which NKp46 participates in NK immunological synapse formation and function remains unknown. In this study, we determined that NKp46 forms microclusters structures at the immune synapse between NK cells and target cells. Over-expression of human NKp46 is correlated with increased accumulation of F actin mesh at the immune synapse. Concordantly, knock-down of NKp46 in primary human NK cells decreased recruitment of F-actin to the synapse. Live cell imaging experiments showed a linear correlation between NKp46 expression and lytic granules polarization to the immune synapse. Taken together, our data suggest that NKp46 signaling directly regulates the NK lytic immune synapse from early formation to late function. PMID- 26441996 TI - FOXP3(+) Treg Cells and Gender Bias in Autoimmune Diseases. AB - CD4(+)CD25(+) regulatory T (Treg) cells play a pivotal role in the maintenance of immune homeostasis, where the X-linked master transcription factor forkhead box P3 (FOXP3) determines Treg cell development and function. Genetic deficiency of foxp3 induces dysfunction of Treg cells and immuno-dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome in humans. Functionally deficient Treg cells or the development of exTreg cells positively correlate with autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and ankylosing spondylitis (AS). In general, females are more susceptible to SLE and MS but less susceptible to AS, where the expression of FOXP3 and its protein complex are perturbed by multiple factors, including hormonal fluctuations, inflammatory cytokines, and danger signals. Therefore, it is critical to explore the potential molecular mechanisms involved and these differences linked to gender. Here, we review recent findings on the regulation of FOXP3 activity in Treg cells and also discuss gender difference in the determination of Treg cell function in autoimmune diseases. PMID- 26441999 TI - Colonization of root cells and plant growth promotion by Piriformospora indica occurs independently of plant common symbiosis genes. AB - Arbuscular mycorrhiza (AM) fungi (Glomeromycota) form symbiosis with and deliver nutrients via the roots of most angiosperms. AM fungal hyphae are taken up by living root epidermal cells, a program which relies on a set of plant common symbiosis genes (CSGs). Plant root epidermal cells are also infected by the plant growth-promoting fungus Piriformospora indica (Basidiomycota), raising the question whether this interaction relies on the AM-related CSGs. Here we show that intracellular colonization of root cells and intracellular sporulation by P. indica occurred in CSG mutants of the legume Lotus japonicus and in Arabidopsis thaliana, which belongs to the Brassicaceae, a family that has lost the ability to form AM as well as a core set of CSGs. A. thaliana mutants of homologs of CSGs (HCSGs) interacted with P. indica similar to the wild-type. Moreover, increased biomass of A. thaliana evoked by P. indica was unaltered in HCSG mutants. We conclude that colonization and growth promotion by P. indica are independent of the CSGs and that AM fungi and P. indica exploit different host pathways for infection. PMID- 26442000 TI - NAC transcription factor family genes are differentially expressed in rice during infections with Rice dwarf virus, Rice black-streaked dwarf virus, Rice grassy stunt virus, Rice ragged stunt virus, and Rice transitory yellowing virus. AB - Expression levels of the NAC gene family were studied in rice infected with Rice dwarf virus (RDV), Rice black-streaked dwarf virus (RBSDV), Rice grassy stunt virus (RGSV), Rice ragged stunt virus (RRSV), and Rice transitory yellowing virus (RTYV). Microarray analysis showed that 75 (68%) OsNAC genes were differentially regulated during infection with RDV, RBSDV, RGSV, and RRSV compared with the control. The number of OsNAC genes up-regulated was highest during RGSV infection, while the lowest number was found during RTYV infection. These phenomena correlate with the severity of the syndromes induced by the virus infections. Most of the genes in the NAC subgroups NAC22, SND, ONAC2, ANAC34, and ONAC3 were down-regulated for all virus infections. These OsNAC genes might be related to the health stage maintenance of the host plants. Interestingly, most of the genes in the subgroups TIP and SNAC were more highly expressed during RBSDV and RGSV infections. These results suggested that OsNAC genes might be related to the responses induced by the virus infection. All of the genes assigned to the TIP subgroups were highly expressed during RGSV infection when compared with the control. For RDV infection, the number of activated genes was greatest during infection with the S-strain, followed by the D84-strain and the O strain, with seven OsNAC genes up-regulated during infection by all three strains. The Os12g03050 and Os11g05614 genes showed higher expression during infection with four of the five viruses, and Os11g03310, Os11g03370, and Os07g37920 genes showed high expression during at least three viral infections. We identified some duplicate genes that are classified as neofunctional and subfunctional according to their expression levels in different viral infections. A number of putative cis-elements were identified, which may help to clarify the function of these key genes in network pathways. PMID- 26442001 TI - Expression profiling and functional analysis reveals that TOR is a key player in regulating photosynthesis and phytohormone signaling pathways in Arabidopsis. AB - Target of rapamycin (TOR) acts as a master regulator to control cell growth by integrating nutrient, energy, and growth factors in all eukaryotic species. TOR plays an evolutionarily conserved role in regulating the transcription of genes associated with anabolic and catabolic processes in Arabidopsis, but little is known about the functions of TOR in photosynthesis and phytohormone signaling, which are unique features of plants. In this study, AZD8055 (AZD) was screened as the strongest active-site TOR inhibitor (asTORi) in Arabidopsis compared with TORIN1 and KU63794 (KU). Gene expression profiles were evaluated using RNA-seq after treating Arabidopsis seedlings with AZD. More than three-fold differentially expressed genes (DEGs) were identified in AZD-treated plants relative to rapamycin-treated plants in previous studies. Most of the DEGs and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in cell wall elongation, ribosome biogenesis, and cell autophagy were common to both AZD- and rapamycin-treated samples, but AZD displayed much broader and more efficient inhibition of TOR compared with rapamycin. Importantly, the suppression of TOR by AZD resulted in remodeling of the expression profile of the genes associated with photosynthesis and various phytohormones, indicating that TOR plays a crucial role in modulating photosynthesis and phytohormone signaling in Arabidopsis. These newly identified DEGs expand the understanding of TOR signaling in plants. This study elucidates the novel functions of TOR in photosynthesis and phytohormone signaling and provides a platform to study the downstream targets of TOR in Arabidopsis. PMID- 26442003 TI - Effects of different carbohydrate sources on fructan metabolism in plants of Chrysolaena obovata grown in vitro. AB - Chrysolaena obovata (Less.) Dematt., previously named Vernonia herbacea, is an Asteraceae native to the Cerrado which accumulates about 80% of the rhizophore dry mass as inulin-type fructans. Considering its high inulin production and the wide application of fructans, a protocol for C. obovata in vitro culture was recently established. Carbohydrates are essential for in vitro growth and development of plants and can also act as signaling molecules involved in cellular adjustments and metabolic regulation. This work aimed to evaluate the effect of different sources of carbohydrate on fructan metabolism in plants grown in vitro. For this purpose, C. obovata plants cultivated in vitro were submitted to carbon deprivation and transferred to MS medium supplemented with sucrose, glucose or fructose. Following, their fructan composition and activity and expression of genes encoding enzymes for fructan synthesis (1-SST and 1-FFT) and degradation (1-FEH) were evaluated. For qRT-PCR analysis partial cDNA sequences corresponding to two different C. obovata genes, 1-SST and 1-FFT, were isolated. As expected, C. obovata sequences showed highest sequence identity to other Asteraceae 1-SST and 1-FFT, than to Poaceae related proteins. A carbon deficit treatment stimulated the transcription of the gene 1-FEH and inhibited 1-SST and 1-FFT and carbohydrate supplementation promoted reversal of the expression profile of these genes. With the exception of 1-FFT, a positive correlation between enzyme activity and gene expression was observed. The overall results indicate that sucrose, fructose and glucose act similarly on fructan metabolism and that 1-FEH and 1-SST are transcriptionally regulated by sugar in this species. Cultivation of plants in increasing sucrose concentrations stimulated synthesis and inhibited fructan mobilization, and induced a distinct pattern of enzyme activity for 1-SST and 1-FFT, indicating the existence of a mechanism for differential regulation between them. PMID- 26442002 TI - Transcriptomic analysis reveals importance of ROS and phytohormones in response to short-term salinity stress in Populus tomentosa. AB - Populus tomentosa (Chinese white poplar) is well adapted to various extreme environments, and is considered an important species to study the effects of salinity stress on poplar trees. To decipher the mechanism of poplar's rapid response to short-term salinity stress, we firstly detected the changes in H2O2 and hormone, and then profiled the gene expression pattern of 10-week-old seedling roots treated with 200 mM NaCl for 0, 6, 12, and 24 h (h) by RNA-seq on the Illumina-Solexa platform. Physiological determination showed that the significant increase in H2O2 began at 6 h, while that in hormone ABA was at 24 h, under salt stress. Compared with controls (0 h), 3991, 4603, and 4903 genes were up regulated, and 1408, 2206, and 3461 genes were down regulated (adjusted P <= 0.05 and |log2Ratio|>=1) at 6, 12, and 24 h time points, respectively. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation revealed that the differentially expressed genes (DEGs) were highly enriched in hormone- and reactive oxygen species-related biological processes, including "response to oxidative stress or abiotic stimulus," "peroxidase activity," "regulation of transcription," "hormone synthetic and metabolic process," "hormone signal transduction," "antioxidant activity," and "transcription factor activity." Moreover, K-means clustering demonstrated that DEGs (total RPKM value>12 from four time points) could be categorized into four kinds of expression trends: quick up/down over 6 or 12 h, and slow up/down over 24 h. Of these, DEGs involved in H2O2- and hormone- producing and signal-related genes were further enriched in this analysis, which indicated that the two kinds of small molecules, hormones and H2O2, play pivotal roles in the short-term salt stress response in poplar. This study provides a basis for future studies of the molecular adaptation of poplar and other tree species to salinity stress. PMID- 26442004 TI - Expression of chickpea CIPK25 enhances root growth and tolerance to dehydration and salt stress in transgenic tobacco. AB - Calcium signaling plays an important role in adaptation and developmental processes in plants and animals. A class of calcium sensors, known as Calcineurin B-like (CBL) proteins sense specific temporal changes in cytosolic Ca(2+) concentration and regulate activities of a group of ser/thr protein kinases called CBL-interacting protein kinases (CIPKs). Although a number of CIPKs have been shown to play crucial roles in the regulation of stress signaling, no study on the function of CIPK25 or its orthologs has been reported so far. In the present study, an ortholog of Arabidopsis CIPK25 was cloned from chickpea (Cicer arietinum). CaCIPK25 gene expression in chickpea increased upon salt, dehydration, and different hormonal treatments. CaCIPK25 gene showed differential tissue-specific expression. 5'-upstream activation sequence (5'-UAS) of the gene and its different truncated versions were fused to a reporter gene and studied in Arabidopsis to identify promoter regions directing its tissue-specific expression. Replacement of a conserved threonine residue with an aspartic acid at its catalytic site increased the kinase activity of CaCIPK25 by 2.5-fold. Transgenic tobacco plants overexpressing full-length and the high active versions of CaCIPK25 displayed a differential germination period and longer root length in comparison to the control plants. Expression of CaCIPK25 and its high active form differentially increased salt and water-deficit tolerance demonstrated by improved growth and reduced leaf chlorosis suggesting that the kinase activity of CaCIPK25 was required for these functions. Expressions of the abiotic stress marker genes were enhanced in the CaCIPK25-expressing tobacco plants. Our results suggested that CaCIPK25 functions in root development and abiotic stress tolerance. PMID- 26442005 TI - Agave as a model CAM crop system for a warming and drying world. AB - As climate change leads to drier and warmer conditions in semi-arid regions, growing resource-intensive C3 and C4 crops will become more challenging. Such crops will be subjected to increased frequency and intensity of drought and heat stress. However, agaves, even more than pineapple (Ananas comosus) and prickly pear (Opuntia ficus-indica and related species), typify highly productive plants that will respond favorably to global warming, both in natural and cultivated settings. With nearly 200 species spread throughout the U.S., Mexico, and Central America, agaves have evolved traits, including crassulacean acid metabolism (CAM), that allow them to survive extreme heat and drought. Agaves have been used as sources of food, beverage, and fiber by societies for hundreds of years. The varied uses of Agave, combined with its unique adaptations to environmental stress, warrant its consideration as a model CAM crop. Besides the damaging cycles of surplus and shortage that have long beset the tequila industry, the relatively long maturation cycle of Agave, its monocarpic flowering habit, and unique morphology comprise the biggest barriers to its widespread use as a crop suitable for mechanized production. Despite these challenges, agaves exhibit potential as crops since they can be grown on marginal lands, but with more resource input than is widely assumed. If these constraints can be reconciled, Agave shows considerable promise as an alternative source for food, alternative sweeteners, and even bioenergy. And despite the many unknowns regarding agaves, they provide a means to resolve disparities in resource availability and needs between natural and human systems in semi-arid regions. PMID- 26442006 TI - Influence of Rhizoctonia solani and Trichoderma spp. in growth of bean (Phaseolus vulgaris L.) and in the induction of plant defense-related genes. AB - Many Trichoderma species are well-known for their ability to promote plant growth and defense. We study how the interaction of bean plants with R. solani and/or Trichoderma affect the plants growth and the level of expression of defense related genes. Trichoderma isolates were evaluated in vitro for their potential to antagonize R. solani. Bioassays were performed in climatic chambers and development of the plants was evaluated. The effect of Trichoderma treatment and/or R. solani infection on the expression of bean defense-related genes was analyzed by real-time PCR and the production of ergosterol and squalene was quantified. In vitro growth inhibition of R. solani was between 86 and 58%. In in vivo assays, the bean plants treated with Trichoderma harzianum T019 always had an increased size respect to control and the plants treated with this isolate did not decrease their size in presence of R. solani. The interaction of plants with R. solani and/or Trichoderma affects the level of expression of seven defense related genes. Squalene and ergosterol production differences were found among the Trichoderma isolates, T019 showing the highest values for both compounds. T. harzianum T019 shows a positive effect on the level of resistance of bean plants to R. solani. This strain induces the expression of plant defense-related genes and produces a higher level of ergosterol, indicating its ability to grow at a higher rate in the soil, which would explain its positive effects on plant growth and defense in the presence of the pathogen. PMID- 26442007 TI - The polyamine spermine induces the unfolded protein response via the MAPK cascade in Arabidopsis. AB - In Arabidopsis three basic region leucine zipper (bZIP) transcription factor genes, bZIP17, bZIP28, and bZIP60, play crucial roles in the unfolded protein response (UPR). Previously we found that bZIP60 is one of the spermine-induced genes. Consequently we further investigated the response of all the three bZIP genes to spermine. Expression of bZIP17, bZIP28, and bZIP60, and also their target genes was activated by spermine application as well as in plants with elevated endogenous spermine levels. Furthermore, spermine activated the splicing of the bZIP60 transcript mediated by the ribonuclease activity of inositol requiring enzyme 1 and also recruited bZIP17 and bZIP60 proteins from endoplasmic reticulum to nucleus. We therefore propose that spermine is a novel UPR inducer. Moreover, induction of UPR by spermine required calcium-influx to the cytoplasm and the genes for mitogen-activated protein kinase kinase 9 (MKK9), mitogen activated protein kinase 3 (MPK3) and MPK6. The result indicates that spermine induced UPR is mediated by the MKK9-MPK3/MPK6 cascade in Arabidopsis. PMID- 26442008 TI - A case study on the genetic origin of the high oleic acid trait through FAD2-1 DNA sequence variation in safflower (Carthamus tinctorius L.). AB - The safflower (Carthamus tinctorius L.) is considered a strongly domesticated species with a long history of cultivation. The hybridization of safflower with its wild relatives has played an important role in the evolution of cultivars and is of particular interest with regards to their production of high quality edible oils. Original safflower varieties were all rich in linoleic acid, while varieties rich in oleic acid have risen to prominence in recent decades. The high oleic acid trait is controlled by a partially recessive allele ol at a single locus OL. The ol allele was found to be a defective microsomal oleate desaturase FAD2-1. Here we present DNA sequence data and Southern blot analysis suggesting that there has been an ancient hybridization and introgression of the FAD2-1 gene into C. tinctorius from its wild relative C. palaestinus. It is from this gene that FAD2-1Delta was derived more recently. Identification and characterization of the genetic origin and diversity of FAD2-1 could aid safflower breeders in reducing population size and generations required for the development of new high oleic acid varieties by using perfect molecular marker-assisted selection. PMID- 26442009 TI - Biogeography of photoautotrophs in the high polar biome. AB - The global latitudinal gradient in biodiversity weakens in the high polar biome and so an alternative explanation for distribution of Arctic and Antarctic photoautotrophs is required. Here we identify how temporal, microclimate and evolutionary drivers of biogeography are important, rather than the macroclimate features that drive plant diversity patterns elsewhere. High polar ecosystems are biologically unique, with a more central role for bryophytes, lichens and microbial photoautotrophs over that of vascular plants. Constraints on vascular plants arise mainly due to stature and ontogenetic barriers. Conversely non vascular plant and microbial photoautotroph distribution is correlated with favorable microclimates and the capacity for poikilohydric dormancy. Contemporary distribution also depends on evolutionary history, with adaptive and dispersal traits as well as legacy influencing biogeography. We highlight the relevance of these findings to predicting future impacts on diversity of polar photoautotrophs and to the current status of plants in Arctic and Antarctic conservation policy frameworks. PMID- 26442010 TI - Epigenetic silencing in transgenic plants. AB - Epigenetic silencing is a natural phenomenon in which the expression of genes is regulated through modifications of DNA, RNA, or histone proteins. It is a mechanism for defending host genomes against the effects of transposable elements and viral infection, and acts as a modulator of expression of duplicated gene family members and as a silencer of transgenes. A major breakthrough in understanding the mechanism of epigenetic silencing was the discovery of silencing in transgenic tobacco plants due to the interaction between two homologous promoters. The molecular mechanism of epigenetic mechanism is highly complicated and it is not completely understood yet. Two different molecular routes have been proposed for this, that is, transcriptional gene silencing, which is associated with heavy methylation of promoter regions and blocks the transcription of transgenes, and post-transcriptional gene silencing (PTGS), the basic mechanism is degradation of the cytosolic mRNA of transgenes or endogenous genes. Undesired transgene silencing is of major concern in the transgenic technologies used in crop improvement. A complete understanding of this phenomenon will be very useful for transgenic applications, where silencing of specific genes is required. The current status of epigenetic silencing in transgenic technology is discussed and summarized in this mini-review. PMID- 26442012 TI - Cryotolerance of apple tree bud is independent of endodormancy. AB - Increasing interest in cryopreservation of dormant buds reveals the need for better understanding of the role of dormancy in cryotolerance. Dormancy stage and low-temperature survival of vegetative apple buds (Malus domestica Borkh.), cultivars 'Sampion' and 'Spartan', collected from orchard were evaluated during three seasons contrasting in temperature and precipitation throughout the arrested plant growth period. During each season, the cultivars differed either in the onset of the endodormancy or in the length of the endodormant period. A simple relation between endodormancy of the buds and their water content was not detected. The cryosurvival of vegetative apple buds of both cultivars correlated with their cold hardening without direct regard to their particular phase of dormancy. The period of the highest bud cryotolerance after low-temperature exposure overlapped with the endodormant period in some evaluated seasons. Both cultivars had the highest cryosurvival in December and January. The presented data were compared with our previous results from a dormancy study of in vitro apple culture. Endodormancy coincided with the period of successful cryosurvival of apple buds after liquid nitrogen exposure, but as such, it was not decisive for their survival and did not limit their successful cryopreservation. PMID- 26442011 TI - Impacts of strigolactone on shoot branching under phosphate starvation in chrysanthemum (Dendranthema grandiflorum cv. Jinba). AB - Chrysanthemum (Dendranthema grandiflorum cv. Jinba) shoot branching is determined by bud outgrowth during the vegetative growth stage. The degree of axillary bud outgrowth is highly influenced by environmental conditions, such as nutrient availability. Here, we demonstrated that phosphorus (Pi) starvation significantly reduces axillary bud outgrowth in chrysanthemum. A strigolactone (SL) biosynthesis gene, DgCCD7, was isolated and characterized as an ortholog of MAX3/DAD3/RMS5/D17. By using ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS), three putative SLs were identified and levels of all three SLs showed strong increase under Pi starvation conditions. Determinations of the distribution of SLs and regulation of DgCCD7/8 in response to Pi changes in root indicate that SL acts systemically. However, temporal expression patterns of biosynthesis and signaling genes in nodes revealed that Pi starvation causes a local response of SL pathway. Treatment of node segments with or without auxin and Pi revealed that in the absence of exogenous auxin, Pi delayed axillary buds outgrowth and up-regulated local SL pathway genes. These data indicated that an auxin-SL regulatory loop responded to Pi starvation for delaying bud outgrowth locally, root biosynthesized SLs were transported acropetally and functioned in shoot branching inhibition under Pi starvation. We proposed that SLs contributed to chrysanthemum shoot branching control in response to Pi-limiting conditions in a systemic way. PMID- 26442013 TI - Species delimitation, genetic diversity and population historical dynamics of Cycas diannanensis (Cycadaceae) occurring sympatrically in the Red River region of China. AB - Delimitating species boundaries could be of critical importance when evaluating the species' evolving process and providing guidelines for conservation genetics. Here, species delimitation was carried out on three endemic and endangered Cycas species with resembling morphology and overlapped distribution range along the Red River (Yuanjiang) in China: Cycas diananensis Z. T. Guan et G. D. Tao, Cycas parvula S. L. Yang and Cycas multiovula D. Y. Wang. A total of 137 individuals from 15 populations were genotyped by using three chloroplastic (psbA-trnH, atpI atpH, and trnL-rps4) and two single copy nuclear (RPB1 and SmHP) DNA sequences. Basing on the carefully morphological comparison and cladistic haplotype aggregation (CHA) analysis, we propose all the populations as one species, with the rest two incorporated into C. diannanensis. Genetic diversity and structure analysis of the conflated C. diannanensis revealed this species possessed a relative lower genetic diversity than estimates of other Cycas species. The higher genetic diversity among populations and relative lower genetic diversity within populations, as well as obvious genetic differentiation among populations inferred from chloroplastic DNA (cpDNA) suggested a recent genetic loss within this protected species. Additionally, a clear genetic structure of C. diannanensis corresponding with geography was detected based on cpDNA, dividing its population ranges into "Yuanjiang-Nanhun" basin and "Ejia-Jiepai" basin groups. Demographical history analyses based on combined cpDNA and one nuclear DNA (nDNA) SmHP both showed the population size of C. diannanensis began to decrease in Quaternary glaciation with no subsequent expansion, while another nDNA RPB1 revealed a more recent sudden expansion after long-term population size contraction, suggesting its probable bottleneck events in history. Our findings offer grounded views for clarifying species boundaries of C. diannanensis when determining the conservation objectives. For operational guidelines, the downstream populations which occupy high and peculiar haplotypes should be given prior in-situ conservation. In addition, ex-situ conservation and reintroduction measures for decades of generations are supplemented for improving the population size and genetic diversity of the endemic and endangered species. PMID- 26442014 TI - Natural variation in cross-talk between glucosinolates and onset of flowering in Arabidopsis. AB - Naturally variable regulatory networks control different biological processes including reproduction and defense. This variation within regulatory networks enables plants to optimize defense and reproduction in different environments. In this study we investigate the ability of two enzyme-encoding genes in the glucosinolate pathway, AOP2 and AOP3, to affect glucosinolate accumulation and flowering time. We have introduced the two highly similar enzymes into two different AOP (null) accessions, Col-0 and Cph-0, and found that the genes differ in their ability to affect glucosinolate levels and flowering time across the accessions. This indicated that the different glucosinolates produced by AOP2 and AOP3 serve specific regulatory roles in controlling these phenotypes. While the changes in glucosinolate levels were similar in both accessions, the effect on flowering time was dependent on the genetic background pointing to natural variation in cross-talk between defense chemistry and onset of flowering. This variation likely reflects an adaptation to survival in different environments. PMID- 26442015 TI - Transgenerational inheritance or resetting of stress-induced epigenetic modifications: two sides of the same coin. AB - The transgenerational inheritance of stress-induced epigenetic modifications is still controversial. Despite several examples of defense "priming" and induced genetic rearrangements, the involvement and persistence of transgenerational epigenetic modifications is not known to be general. Here I argue that non transmission of epigenetic marks through meiosis may be regarded as an epigenetic modification in itself, and that we should understand the implications for plant evolution in the context of both selection for and selection against transgenerational epigenetic memory. Recent data suggest that both epigenetic inheritance and resetting are mechanistically directed and targeted. Stress induced epigenetic modifications may buffer against DNA sequence-based evolution to maintain plasticity, or may form part of plasticity's adaptive potential. To date we have tended to concentrate on the question of whether and for how long epigenetic memory persists. I argue that we should now re-direct our question to investigate the differences between where it persists and where it does not, to understand the higher order evolutionary methods in play and their contribution. PMID- 26442016 TI - Rhizosphere ecology of lumichrome and riboflavin, two bacterial signal molecules eliciting developmental changes in plants. AB - Lumichrome and riboflavin are novel molecules from rhizobial exudates that stimulate plant growth. Reported studies have revealed major developmental changes elicited by lumichrome at very low nanomolar concentrations (5 nM) in plants, which include early initiation of trifoliate leaves, expansion of unifoliate and trifoliate leaves, increased stem elongation and leaf area, and consequently greater biomass accumulation in monocots and dicots. But higher lumichrome concentration (50 nM) depressed root development and reduced growth of unifoliate and second trifoliate leaves. While the mechanisms remain unknown, it is possible that lumichrome released by rhizobia induced the biosynthesis of classical phytohormones that caused the observed developmental changes in plants. We also showed in earlier studies that applying either 10 nM lumichrome, 10 nM ABA, or 10 ml of infective rhizobial cells (0.2 OD600) to roots of monocots and dicots for 44 h produced identical effects, which included decreased stomatal conductance and leaf transpiration in Bambara groundnut, soybean, and maize, increased stomatal conductance and transpiration in cowpea and lupin, and elevated root respiration in maize (19% by rhizobia and 20% by lumichrome). Greater extracellular exudation of lumichrome, riboflavin and indole acetic acid by N2-fixing rhizobia over non-fixing bacteria is perceived to be an indication of their role as symbiotic signals. This is evidenced by the increased concentration of lumichrome and riboflavin in the xylem sap of cowpea and soybean plants inoculated with infective rhizobia. In fact, greater xylem concentration of lumichrome in soybean and its correspondingly increased accumulation in leaves was found to result in dramatic developmental changes than in cowpea. Furthermore, lumichrome and riboflavin secreted by soil rhizobia are also known to function as (i) ecological cues for sensing environmental stress, (ii) growth factors for microbes, plants, and humans, (iii) signals for stomatal functioning in land plants, and (iv) protectants/elicitors of plant defense. The fact that exogenous application of ABA to plant roots caused the same effect as lumichrome on leaf stomatal functioning suggests molecular cross-talk in plant response to environmental stimuli. PMID- 26442018 TI - Nuclear localization of the dehydrin OpsDHN1 is determined by histidine-rich motif. AB - The cactus OpsDHN1 dehydrin belongs to a large family of disordered and highly hydrophilic proteins known as Late Embryogenesis Abundant (LEA) proteins, which accumulate during the late stages of embryogenesis and in response to abiotic stresses. Herein, we present the in vivo OpsDHN1 subcellular localization by N terminal GFP translational fusion; our results revealed a cytoplasmic and nuclear localization of the GFP::OpsDHN1 protein in Nicotiana benthamiana epidermal cells. In addition, dimer assembly of OpsDHN1 in planta using a Bimolecular Fluorescence Complementation (BiFC) approach was demonstrated. In order to understand the in vivo role of the histidine-rich motif, the OpsDHN1-DeltaHis version was produced and assayed for its subcellular localization and dimer capability by GFP fusion and BiFC assays, respectively. We found that deletion of the OpsDHN1 histidine-rich motif restricted its localization to cytoplasm, but did not affect dimer formation. In addition, the deletion of the S-segment in the OpsDHN1 protein affected its nuclear localization. Our data suggest that the deletion of histidine-rich motif and S-segment show similar effects, preventing OpsDHN1 from getting into the nucleus. Based on these results, the histidine-rich motif is proposed as a targeting element for OpsDHN1 nuclear localization. PMID- 26442017 TI - Response and adaptation of photosynthesis, respiration, and antioxidant systems to elevated CO2 with environmental stress in plants. AB - It is well known that plant photosynthesis and respiration are two fundamental and crucial physiological processes, while the critical role of the antioxidant system in response to abiotic factors is still a focus point for investigating physiological stress. Although one key metabolic process and its response to climatic change have already been reported and reviewed, an integrative review, including several biological processes at multiple scales, has not been well reported. The current review will present a synthesis focusing on the underlying mechanisms in the responses to elevated CO2 at multiple scales, including molecular, cellular, biochemical, physiological, and individual aspects, particularly, for these biological processes under elevated CO2 with other key abiotic stresses, such as heat, drought, and ozone pollution, as well as nitrogen limitation. The present comprehensive review may add timely and substantial information about the topic in recent studies, while it presents what has been well established in previous reviews. First, an outline of the critical biological processes, and an overview of their roles in environmental regulation, is presented. Second, the research advances with regard to the individual subtopics are reviewed, including the response and adaptation of the photosynthetic capacity, respiration, and antioxidant system to CO2 enrichment alone, and its combination with other climatic change factors. Finally, the potential applications for plant responses at various levels to climate change are discussed. The above issue is currently of crucial concern worldwide, and this review may help in a better understanding of how plants deal with elevated CO2 using other mainstream abiotic factors, including molecular, cellular, biochemical, physiological, and whole individual processes, and the better management of the ecological environment, climate change, and sustainable development. PMID- 26442019 TI - Tree water status and growth of saplings and mature Norway spruce (Picea abies) at a dry distribution limit. AB - We evaluated the size effect on stem water status and growth in Norway spruce (Picea abies (L.) Karst.) occurring at the edge of its natural range in a dry inner Alpine environment (750 m asl, Tyrol, Austria). Intra-annual dynamics of stem water deficit (DeltaW), maximum daily shrinkage (MDS), and radial growth (RG) were compared among saplings (stem diameter/height: 2.2 cm/93 cm; n = 7) and mature adult trees (25 cm/12.7 m; n = 6) during 2014. DeltaW, MDS, and RG were extracted from stem diameter variations, which were continuously recorded by automatic dendrometers and the influence of environmental drivers was evaluated by applying moving correlation analysis (MCA). Additionally, we used Morlet wavelet analysis to assess the differences in cyclic radial stem variations between saplings and mature trees. Results indicate that saplings and mature trees were experiencing water limitation throughout the growing season. However, saplings exhibited a more strained stem water status and higher sensitivity to environmental conditions than mature trees. Hence, the significantly lower radial increments in saplings (0.16 +/- 0.03 mm) compared to mature trees (0.54 +/- 0.14 mm) is related to more constrained water status in the former, affecting the rate and duration of RG. The wavelet analysis consistently revealed more distinct diurnal stem variations in saplings compared to mature trees. Intra-annual RG was most closely related to climate variables that influence transpiration, i.e., vapor pressure deficit, relative air humidity, and air temperature. MCA, however, showed pronounced instability of climate-growth relationships, which masked missing temporal or significant correlations when the entire study period (April October) was considered. We conclude that an increase in evaporative demand will impair regeneration and long-term stability of drought-prone inner Alpine Norway spruce forests. PMID- 26442020 TI - The future of lupin as a protein crop in Europe. AB - Europe has become heavily dependent on soya bean imports, entailing trade agreements and quality standards that do not satisfy the European citizen's expectations. White, yellow, and narrow-leafed lupins are native European legumes that can become true alternatives to soya bean, given their elevated and high quality protein content, potential health benefits, suitability for sustainable production, and acceptability to consumers. Nevertheless, lupin cultivation in Europe remains largely insufficient to guarantee a steady supply to the food industry, which in turn must innovate to produce attractive lupin-based protein rich foods. Here, we address different aspects of the food supply chain that should be considered for lupin exploitation as a high-value protein source. Advanced breeding techniques are needed to provide new lupin varieties for socio economically and environmentally sustainable cultivation. Novel processes should be optimized to obtain high-quality, safe lupin protein ingredients, and marketable foods need to be developed and offered to consumers. With such an integrated strategy, lupins can be established as an alternative protein crop, capable of promoting socio-economic growth and environmental benefits in Europe. PMID- 26442021 TI - Ethephon induced abscission in mango: physiological fruitlet responses. AB - Fruitlet abscission of mango is typically very severe, causing considerable production losses worldwide. Consequently, a detailed physiological and molecular characterization of fruitlet abscission in mango is required to describe the onset and time-dependent course of this process. To identify the underlying key mechanisms of abscission, ethephon, an ethylene releasing substance, was applied at two concentrations (600 and 7200 ppm) during the midseason drop stage of mango. The abscission process is triggered by ethylene diffusing to the abscission zone where it binds to specific receptors and thereby activating several key physiological responses at the cellular level. The treatments reduced significantly the capacity of polar auxin transport through the pedicel at 1 day after treatment and thereafter when compared to untreated pedicels. The transcript levels of the ethylene receptor genes MiETR1 and MiERS1 were significantly upregulated in the pedicel and pericarp at 1, 2, and 3 days after the ethephon application with 7200 ppm, except for MiETR1 in the pedicel, when compared to untreated fruitlet. In contrast, ethephon applications with 600 ppm did not affect expression levels of MiETR1 in the pedicel and of MiERS1 in the pericarp; however, MiETR1 in the pericarp at day 2 and MiERS1 in the pedicel at days 2 and 3 were significantly upregulated over the controls. Moreover, two novel short versions of the MiERS1 were identified and detected more often in the pedicel of treated than untreated fruitlets at all sampling times. Sucrose concentration in the fruitlet pericarp was significantly reduced to the control at 2 days after both ethephon treatments. In conclusion, it is postulated that the ethephon-induced abscission process commences with a reduction of the polar auxin transport capacity in the pedicel, followed by an upregulation of ethylene receptors and finally a decrease of the sucrose concentration in the fruitlets. PMID- 26442022 TI - A meta-analysis approach for assessing the diversity and specificity of belowground root and microbial volatiles. AB - Volatile organic compounds are secondary metabolites emitted by all organisms, especially by plants and microbes. Their role as aboveground signals has been established for decades. Recent evidence suggests that they might have a non negligible role belowground and might be involved in root-root and root microbial/pest interactions. Our aim here was to make a comprehensive review of belowground volatile diversity using a meta-analysis approach. At first we synthesized current literature knowledge on plant root volatiles and classified them in terms of chemical diversity. In a second step, relying on the mVOC database of microbial volatiles, we classified volatiles based on their emitters (bacteria vs. fungi) and their specific ecological niche (i.e., rhizosphere, soil). Our results highlight similarities and differences among root and microbial volatiles and also suggest that some might be niche specific. We further explored the possibility that volatiles might be involved in intra- and inter-specific root-root communication and discuss the ecological implications of such scenario. Overall this work synthesizes current knowledge on the belowground volatilome and the potential signaling role of its constituents. It also highlights that the total diversity of belowground volatiles might be orders of magnitude larger that the few hundreds of compounds described to date. PMID- 26442023 TI - Signaling in the phytomicrobiome: breadth and potential. AB - Higher plants have evolved intimate, complex, subtle, and relatively constant relationships with a suite of microbes, the phytomicrobiome. Over the last few decades we have learned that plants and microbes can use molecular signals to communicate. This is well-established for the legume-rhizobia nitrogen-fixing symbiosis, and reasonably elucidated for mycorrhizal associations. Bacteria within the phytomircobiome communicate among themselves through quorum sensing and other mechanisms. Plants also detect materials produced by potential pathogens and activate pathogen-response systems. This intercommunication dictates aspects of plant development, architecture, and productivity. Understanding this signaling via biochemical, genomics, proteomics, and metabolomic studies has added valuable knowledge regarding development of effective, low-cost, eco-friendly crop inputs that reduce fossil fuel intense inputs. This knowledge underpins phytomicrobiome engineering: manipulating the beneficial consortia that manufacture signals/products that improve the ability of the plant-phytomicrobiome community to deal with various soil and climatic conditions, leading to enhanced overall crop plant productivity. PMID- 26442024 TI - Using targeted enrichment of nuclear genes to increase phylogenetic resolution in the neotropical rain forest genus Inga (Leguminosae: Mimosoideae). AB - Evolutionary radiations are prominent and pervasive across many plant lineages in diverse geographical and ecological settings; in neotropical rainforests there is growing evidence suggesting that a significant fraction of species richness is the result of recent radiations. Understanding the evolutionary trajectories and mechanisms underlying these radiations demands much greater phylogenetic resolution than is currently available for these groups. The neotropical tree genus Inga (Leguminosae) is a good example, with ~300 extant species and a crown age of 2-10 MY, yet over 6 kb of plastid and nuclear DNA sequence data gives only poor phylogenetic resolution among species. Here we explore the use of larger scale nuclear gene data obtained though targeted enrichment to increase phylogenetic resolution within Inga. Transcriptome data from three Inga species were used to select 264 nuclear loci for targeted enrichment and sequencing. Following quality control to remove probable paralogs from these sequence data, the final dataset comprised 259,313 bases from 194 loci for 24 accessions representing 22 Inga species and an outgroup (Zygia). Bayesian phylogenies reconstructed using either all loci concatenated or a gene-tree/species-tree approach yielded highly resolved phylogenies. We used coalescent approaches to show that the same targeted enrichment data also have significant power to discriminate among alternative within-species population histories within the widespread species I. umbellifera. In either application, targeted enrichment simplifies the informatics challenge of identifying orthologous loci associated with de novo genome sequencing. We conclude that targeted enrichment provides the large volumes of phylogenetically-informative sequence data required to resolve relationships within recent plant species radiations, both at the species level and for within-species phylogeographic studies. PMID- 26442025 TI - Tissue specific and abiotic stress regulated transcription of histidine kinases in plants is also influenced by diurnal rhythm. AB - Two-component system (TCS) is one of the key signal sensing machinery which enables species to sense environmental stimuli. It essentially comprises of three major components, sensory histidine kinase proteins (HKs), histidine phosphotransfer proteins (Hpts), and response regulator proteins (RRs). The members of the TCS family have already been identified in Arabidopsis and rice but the knowledge about their functional indulgence during various abiotic stress conditions remains meager. Current study is an attempt to carry out comprehensive analysis of the expression of TCS members in response to various abiotic stress conditions and in various plant tissues in Arabidopsis and rice using MPSS and publicly available microarray data. The analysis suggests that despite having almost similar number of genes, rice expresses higher number of TCS members during various abiotic stress conditions than Arabidopsis. We found that the TCS machinery is regulated by not only various abiotic stresses, but also by the tissue specificity. Analysis of expression of some representative members of TCS gene family showed their regulation by the diurnal cycle in rice seedlings, thus bringing-in another level of their transcriptional control. Thus, we report a highly complex and tight regulatory network of TCS members, as influenced by the tissue, abiotic stress signal, and diurnal rhythm. The insights on the comparative expression analysis presented in this study may provide crucial leads toward dissection of diverse role(s) of the various TCS family members in Arabidopsis and rice. PMID- 26442026 TI - Understanding salinity responses and adopting 'omics-based' approaches to generate salinity tolerant cultivars of rice. AB - Soil salinity is one of the main constraints affecting production of rice worldwide, by reducing growth, pollen viability as well as yield of the plant. Therefore, detailed understanding of the response of rice towards soil salinity at the physiological and molecular level is a prerequisite for its effective management. Various approaches have been adopted by molecular biologists or breeders to understand the mechanism for salinity tolerance in plants and to develop salt tolerant rice cultivars. Genome wide analysis using 'omics-based' tools followed by identification and functional validation of individual genes is becoming one of the popular approaches to tackle this task. On the other hand, mutation breeding and insertional mutagenesis has also been exploited to obtain salinity tolerant crop plants. This review looks into various responses at cellular and whole plant level generated in rice plants toward salinity stress thus, evaluating the suitability of intervention of functional genomics to raise stress tolerant plants. We have tried to highlight the usefulness of the contemporary 'omics-based' approaches such as genomics, proteomics, transcriptomics and phenomics towards dissecting out the salinity tolerance trait in rice. In addition, we have highlighted the importance of integration of various 'omics' approaches to develop an understanding of the machinery involved in salinity response in rice and to move forward to develop salt tolerant cultivars of rice. PMID- 26442027 TI - Differentially expressed seed aging responsive heat shock protein OsHSP18.2 implicates in seed vigor, longevity and improves germination and seedling establishment under abiotic stress. AB - Small heat shock proteins (sHSPs) are a diverse group of proteins and are highly abundant in plant species. Although majority of these sHSPs were shown to express specifically in seed, their potential function in seed physiology remains to be fully explored. Our proteomic analysis revealed that OsHSP18.2, a class II cytosolic HSP is an aging responsive protein as its abundance significantly increased after artificial aging in rice seeds. OsHSP18.2 transcript was found to markedly increase at the late maturation stage being highly abundant in dry seeds and sharply decreased after germination. Our biochemical study clearly demonstrated that OsHSP18.2 forms homooligomeric complex and is dodecameric in nature and functions as a molecular chaperone. OsHSP18.2 displayed chaperone activity as it was effective in preventing thermal inactivation of Citrate Synthase. Further, to analyze the function of this protein in seed physiology, seed specific Arabidopsis overexpression lines for OsHSP18.2 were generated. Our subsequent functional analysis clearly demonstrated that OsHSP18.2 has ability to improve seed vigor and longevity by reducing deleterious ROS accumulation in seeds. In addition, transformed Arabidopsis seeds also displayed better performance in germination and cotyledon emergence under adverse conditions. Collectively, our work demonstrates that OsHSP18.2 is an aging responsive protein which functions as a molecular chaperone and possibly protect and stabilize the cellular proteins from irreversible damage particularly during maturation drying, desiccation and aging in seeds by restricting ROS accumulation and thereby improves seed vigor, longevity and seedling establishment. PMID- 26442028 TI - Comparative analysis of endogenous hormones level in two soybean (Glycine max L.) lines differing in waterlogging tolerance. AB - Waterlogged condition due to flooding is one of the major abiotic stresses that drastically affect the soybean growth and yield around the world. As a result, many breeders have focused on the development of waterlogging tolerance in soybean varieties, and thus, several tolerant varieties were developed. However, the physiological mechanism of waterlogging tolerance is not yet fully understood. We particularly studied the endogenous hormones regulation during waterlogging in two contrasting soybean genotypes. According to our results, adventitious roots were better developed in the waterlogging tolerant line (WTL) than in the waterlogging susceptible line (WSL). Endogenous hormones also showed significant differences between WTL and WSL. The ethylene production ratio was higher in WTL than in WSL, and methionine was higher in WTL than in WSL. Other endogenous abscisic acid (ABA) contents were lower in WTL than in WSL. Conversely, gibberellic acid (GA) showed a tendency to be high in WTL, especially the levels of the bioactive GA4. The ratio of total GA and ABA was significantly higher in WTL than in WSL. Anatomical study of the root revealed that aerenchyma cells in the stele were better developed in WTL than in WSL. PMID- 26442029 TI - A complex protein derivative acts as biogenic elicitor of grapevine resistance against powdery mildew under field conditions. AB - Powdery mildew caused by Erysiphe necator is one of the most important grapevine diseases in several viticulture areas, and high fungicide input is required to control it. However, numerous synthetic chemical pesticides are under scrutiny due to concerns about their impact on human health and the environment. Biopesticides, such as biogenic elicitors, are a promising alternative to chemical fungicides. Although several studies have reported on effective elicitors against grapevine diseases, their efficacy under field conditions has not been investigated extensively or has occurred at rather limited levels. Our goal was to examine the efficacy of a protein-based composition, namely nutrient broth (NB), against powdery mildew under field conditions and to characterize its mechanism of action. Weekly treatments with NB was highly effective in controlling powdery mildew on grapevine across seasons with different disease pressures. The level of disease control achieved with NB was comparable to standard fungicide treatments both on leaves and bunches across three different years. NB has no direct toxic effect on the germination of E. necator conidia, and it activates plant resistance with both systemic and translaminar effect in experiments with artificial inoculation under controlled conditions. NB induced the expression of defense-related genes in grapevine, demonstrating stimulation of plant defense mechanisms, prior to and in the early stages of pathogen infection. NB is a natural derivative from meat and yeast, substances that tend not to raise concerns about toxicological and ecotoxicological properties. NB represents a valid control tool for integrated plant protection programs against powdery mildew, to reduce the use of synthetic pesticides on grapevine. PMID- 26442031 TI - Co-silencing of tomato S-adenosylhomocysteine hydrolase genes confers increased immunity against Pseudomonas syringae pv. tomato DC3000 and enhanced tolerance to drought stress. AB - S-adenosylhomocysteine hydrolase (SAHH), catalyzing the reversible hydrolysis of S-adenosylhomocysteine (SAH) to adenosine and homocysteine, is a key enzyme that maintain the cellular methylation potential in all organisms. We report here the biological functions of tomato SlSAHHs in stress response. The tomato genome contains three SlSAHH genes that encode SlSAHH proteins with high level of sequence identity. qRT-PCR analysis revealed that SlSAHHs responded with distinct expression induction patterns to Pseudomonas syringae pv. tomato (Pst) DC3000 and Botrytis cinerea as well as to defense signaling hormones such as salicylic acid, jasmonic acid and a precursor of ethylene. Virus-induced gene silencing-based knockdown of individual SlSAHH gene did not affect the growth performance and the response to Pst DC3000. However, co-silencing of three SlSAHH genes using a conserved sequence led to significant inhibition of vegetable growth. The SlSAHH co-silenced plants displayed increased resistance to Pst DC3000 but did not alter the resistance to B. cinerea. Co-silencing of SlSAHHs resulted in constitutively activated defense responses including elevated SA level, upregulated expression of defense-related and PAMP-triggered immunity marker genes and increased callose deposition and H2O2 accumulation. Furthermore, the SlSAHH-co-silenced plants also exhibited enhanced drought stress tolerance although they had relatively small roots. These data demonstrate that, in addition to the functions in growth and development, SAHHs also play important roles in regulating biotic and abiotic stress responses in plants. PMID- 26442030 TI - Local and systemic signaling of iron status and its interactions with homeostasis of other essential elements. AB - Iron (Fe) is essential for plant growth and development. However, alkaline soils, which occupy approximately 30% of the world's arable lands, are considered Fe limiting for plant growth because insoluble Fe (III) chelates prevail under these conditions. In contrast, high bioavailability of Fe in acidic soils can be toxic to plants due to the ability of Fe ions to promote oxidative stress. Therefore, plants have evolved sophisticated mechanisms to sense and respond to the fluctuation of Fe availability in the immediate environment and to the needs of developing shoot tissues to preclude deficiency while avoiding toxicity. In this review, we focus on recent advances in our understanding of local and systemic signaling of Fe status with emphasis on the contribution of Fe, its interaction with other metals and metal ligands in triggering molecular responses that regulate Fe uptake and partitioning in the plant body. PMID- 26442032 TI - A novel workflow correlating RNA-seq data to Phythophthora infestans resistance levels in wild Solanum species and potato clones. AB - Comparative transcriptomics between species can provide valuable understanding of plant-pathogen interactions. Here, we focus on wild Solanum species and potato clones with varying degree of resistance against Phytophthora infestans, which causes the devastating late blight disease in potato. The transcriptomes of three wild Solanum species native to Southern Sweden, Solanum dulcamara, Solanum nigrum, and Solanum physalifolium were compared to three potato clones, Desiree (cv.), SW93-1015 and Sarpo Mira. Desiree and S. physalifolium are susceptible to P. infestans whereas the other four have different degrees of resistance. By building transcript families based on de novo assembled RNA-seq across species and clones and correlating these to resistance phenotypes, we created a novel workflow to identify families with expanded or depleted number of transcripts in relation to the P. infestans resistance level. Analysis was facilitated by inferring functional annotations based on the family structure and semantic clustering. More transcript families were expanded in the resistant clones and species and the enriched functions of these were associated to expected gene ontology (GO) terms for resistance mechanisms such as hypersensitive response, host programmed cell death and endopeptidase activity. However, a number of unexpected functions and transcripts were also identified, for example transmembrane transport and protein acylation expanded in the susceptible group and a cluster of Zinc knuckle family proteins expanded in the resistant group. Over 400 expressed putative resistance (R-)genes were identified and resistant clones Sarpo Mira and SW93-1015 had ca 25% more expressed putative R-genes than susceptible cultivar Desiree. However, no differences in numbers of susceptibility (S-)gene homologs were seen between species and clones. In addition, we identified P. infestans transcripts including effectors in the early stages of P. infestans-Solanum interactions. PMID- 26442033 TI - A Populus TIR1 gene family survey reveals differential expression patterns and responses to 1-naphthaleneacetic acid and stress treatments. AB - The plant hormone auxin is a central regulator of plant growth. TRANSPORT INHIBITOR RESPONSE 1/AUXIN SIGNALING F-BOX (TIR1/AFB) is a component of the E3 ubiquitin ligase complex SCF(TIR1/AFB) and acts as an auxin co-receptor for nuclear auxin signaling. The SCF(TIR1/AFB)-proteasome machinery plays a central regulatory role in development-related gene transcription. Populus trichocarpa, as a model tree, has a unique fast-growth trait to which auxin signaling may contribute. However, no systematic analyses of the genome organization, gene structure, and expression of TIR1-like genes have been undertaken in this woody model plant. In this study, we identified a total of eight TIR1 genes in the Populus genome that are phylogenetically clustered into four subgroups, PtrFBL1/PtrFBL2, PtrFBL3/PtrFBL4, PtrFBL5/PtrFBL6, and PtrFBL7/PtrFBL8, representing four paralogous pairs. In addition, the gene structure and motif composition were relatively conserved in each paralogous pair and all of the PtrFBL members were localized in the nucleus. Different sets of PtrFBLs were strongly expressed in the leaves, stems, roots, cambial zones, and immature xylem of Populus. Interestingly, PtrFBL1 and 7 were expressed mainly in vascular and cambial tissues, respectively, indicating their potential but different roles in wood formation. Furthermore, Populus FBLs responded differentially upon exposure to various stresses. Finally, over-expression studies indicated a role of FBL1 in poplar stem growth and response to drought stress. Collectively, these observations lay the foundation for further investigations into the potential roles of PtrFBL genes in tree growth and development. PMID- 26442034 TI - Genetic variation of temperature-regulated curd induction in cauliflower: elucidation of floral transition by genome-wide association mapping and gene expression analysis. AB - Cauliflower (Brassica oleracea var. botrytis) is a vernalization-responsive crop. High ambient temperatures delay harvest time. The elucidation of the genetic regulation of floral transition is highly interesting for a precise harvest scheduling and to ensure stable market supply. This study aims at genetic dissection of temperature-dependent curd induction in cauliflower by genome-wide association studies and gene expression analysis. To assess temperature-dependent curd induction, two greenhouse trials under distinct temperature regimes were conducted on a diversity panel consisting of 111 cauliflower commercial parent lines, genotyped with 14,385 SNPs. Broad phenotypic variation and high heritability (0.93) were observed for temperature-related curd induction within the cauliflower population. GWA mapping identified a total of 18 QTL localized on chromosomes O1, O2, O3, O4, O6, O8, and O9 for curding time under two distinct temperature regimes. Among those, several QTL are localized within regions of promising candidate flowering genes. Inferring population structure and genetic relatedness among the diversity set assigned three main genetic clusters. Linkage disequilibrium (LD) patterns estimated global LD extent of r(2) = 0.06 and a maximum physical distance of 400 kb for genetic linkage. Transcriptional profiling of flowering genes FLOWERING LOCUS C (BoFLC) and VERNALIZATION 2 (BoVRN2) was performed, showing increased expression levels of BoVRN2 in genotypes with faster curding. However, functional relevance of BoVRN2 and BoFLC2 could not consistently be supported, which probably suggests to act facultative and/or might evidence for BoVRN2/BoFLC-independent mechanisms in temperature regulated floral transition in cauliflower. Genetic insights in temperature regulated curd induction can underpin genetically informed phenology models and benefit molecular breeding strategies toward the development of thermo-tolerant cultivars. PMID- 26442035 TI - Structural and metabolic changes in rhizophores of the Cerrado species Chrysolaena obovata (Less.) Dematt. as influenced by drought and re-watering. AB - The high fructan contents in underground organs of Cerrado species, high water solubility, and fast metabolism of these compounds highlight their role as carbon storage and as an adaptive feature in plants under drought. In this study, we showed that anatomical structure, in association with soluble compounds and metabolism of inulin-type fructans were modified in rhizophores of Crysolaena obovata submitted to water suppression and recovery after re-watering. Plants were subjected to daily watering (control), suppression of watering for 22 days (water suppression) and suppression of watering followed by re-watering after 10 days (re-watered). Plants were collected at time 0 and after 3, 7, 10, 12, 17, and 22 days of treatment. In addition to changes in fructan metabolism, high proline content was detected in drought stressed plants, contributing to osmoregulation and recovery after water status reestablishment. Under water suppression, total inulin was reduced from approx. 60 to 40%, mainly due to exohydrolase activity. Concurrently, the activity of fructosyltransferases promoted the production of short chain inulin, which could contribute to the increase in osmotic potential. After re-watering, most parameters analyzed were similar to those of control plants, indicating the resumption of regular metabolism, after water absorption. Inulin sphero-crystals accumulated in parenchymatic cells of the cortex, vascular tissues and pith were reduced under drought and accompanied anatomical changes, starting from day 10. At 22 days of drought, the cortical and vascular tissues were collapsed, and inulin sphero crystals and inulin content were reduced. The localization of inulin sphero crystals in vascular tissues of C. obovata, as well as the decrease of total inulin and the increase in oligo:polysaccharide ratio in water stressed plants is consistent with the role of fructans in protecting plants against drought. PMID- 26442036 TI - Inter-organismal signaling and management of the phytomicrobiome. AB - The organisms of the phytomicrobiome use signal compounds to regulate aspects of each other's behavior. Legumes use signals (flavonoids) to regulate rhizobial nod gene expression during establishment of the legume-rhizobia N2-fixation symbiosis. Lipochitooligosaccharides (LCOs) produced by rhizobia act as return signals to the host plant and are recognized by specific lysine motif receptor like kinases, which triggers a signal cascade leading to nodulation of legume roots. LCOs also enhance plant growth, particularly when plants are stressed. Chitooligosaccharides activate plant immune responses, providing enhanced resistance against diseases. Co-inoculation of rhizobia with other plant growth promoting rhizobacteria (PGPR) can improve nodulation and crop growth. PGPR also alleviate plant stress by secreting signal compounds including phytohormones and antibiotics. Thuricin 17, a small bacteriocin produced by a phytomicrobiome member promotes plant growth. Lumichrome synthesized by soil rhizobacteria function as stress-sensing cues. Inter-organismal signaling can be used to manage/engineer the phytomicrobiome to enhance crop productivity, particularly in the face of stress. Stressful conditions are likely to become more frequent and more severe because of climate change. PMID- 26442037 TI - Shared and unique responses of plants to multiple individual stresses and stress combinations: physiological and molecular mechanisms. AB - In field conditions, plants are often simultaneously exposed to multiple biotic and abiotic stresses resulting in substantial yield loss. Plants have evolved various physiological and molecular adaptations to protect themselves under stress combinations. Emerging evidences suggest that plant responses to a combination of stresses are unique from individual stress responses. In addition, plants exhibit shared responses which are common to individual stresses and stress combination. In this review, we provide an update on the current understanding of both unique and shared responses. Specific focus of this review is on heat-drought stress as a major abiotic stress combination and, drought pathogen and heat-pathogen as examples of abiotic-biotic stress combinations. We also comprehend the current understanding of molecular mechanisms of cross talk in relation to shared and unique molecular responses for plant survival under stress combinations. Thus, the knowledge of shared responses of plants from individual stress studies and stress combinations can be utilized to develop varieties with broad spectrum stress tolerance. PMID- 26442038 TI - Quantifying floral shape variation in 3D using microcomputed tomography: a case study of a hybrid line between actinomorphic and zygomorphic flowers. AB - The quantification of floral shape variations is difficult because flower structures are both diverse and complex. Traditionally, floral shape variations are quantified using the qualitative and linear measurements of two-dimensional (2D) images. The 2D images cannot adequately describe flower structures, and thus lead to unsatisfactory discrimination of the flower shape. This study aimed to acquire three-dimensional (3D) images by using microcomputed tomography (MUCT) and to examine the floral shape variations by using geometric morphometrics (GM). To demonstrate the advantages of the 3D-MUCT-GM approach, we applied the approach to a second-generation population of florist's gloxinia (Sinningia speciosa) crossed from parents of zygomorphic and actinomorphic flowers. The flowers in the population considerably vary in size and shape, thereby served as good materials to test the applicability of the proposed phenotyping approach. Procedures were developed to acquire 3D volumetric flower images using a MUCT scanner, to segment the flower regions from the background, and to select homologous characteristic points (i.e., landmarks) from the flower images for the subsequent GM analysis. The procedures identified 95 landmarks for each flower and thus improved the capability of describing and illustrating the flower shapes, compared with typically lower number of landmarks in 2D analyses. The GM analysis demonstrated that flower opening and dorsoventral symmetry were the principal shape variations of the flowers. The degrees of flower opening and corolla asymmetry were then subsequently quantified directly from the 3D flower images. The 3D-MUCT-GM approach revealed shape variations that could not be identified using typical 2D approaches and accurately quantified the flower traits that presented a challenge in 2D images. The approach opens new avenues to investigate floral shape variations. PMID- 26442039 TI - Metabolic engineering of the chloroplast genome reveals that the yeast ArDH gene confers enhanced tolerance to salinity and drought in plants. AB - Osmoprotectants stabilize proteins and membranes against the denaturing effect of high concentrations of salts and other harmful solutes. In yeast, arabitol dehydrogenase (ArDH) reduces D-ribulose to D-arabitol where D-ribulose is derived by dephosphorylating D-ribulose-5-PO4 in the oxidized pentose pathway. Osmotolerance in plants could be developed through metabolic engineering of chloroplast genome by introducing genes encoding polyols since chloroplasts offer high level transgene expression and containment. Here, we report that ArDH expression in tobacco chloroplasts confers tolerance to NaCl (up to 400 mM). Transgenic plants compared to wild type (WT) survived for only 4-5 weeks on 400 mM NaCl whereas plants remained green and grew normal on concentrations up to 350 mM NaCl. Further, a-week-old seedlings were also challenged with poly ethylene glycol (PEG, up to 6%) in the liquid medium, considering that membranes and proteins are protected under stress conditions due to accumulation of arabitol in chloroplasts. Seedlings were tolerant to 6% PEG, suggesting that ARDH enzyme maintains integrity of membranes in chloroplasts under drought conditions via metabolic engineering. Hence, the gene could be expressed in agronomic plants to withstand abiotic stresses. PMID- 26442040 TI - Companion cropping with potato onion enhances the disease resistance of tomato against Verticillium dahliae. AB - Intercropping could alleviate soil-borne diseases, however, few studies focused on the immunity of the host plant induced by the interspecific interactions. To test whether or not intercropping could enhance the disease resistance of host plant, we investigated the effect of companion cropping with potato onion on tomato Verticillium wilt caused by Verticillium dahliae (V. dahliae). To investigate the mechanisms, the root exudates were collected from tomato and potato onion which were grown together or separately, and were used to examine the antifungal activities against V. dahliae in vitro, respectively. Furthermore, RNA-seq was used to examine the expression pattern of genes related to disease resistance in tomato companied with potato onion compared to that in tomato grown alone, under the condition of infection with V. dahliae. The results showed that companion cropping with potato onion could alleviate the incidence and severity of tomato Verticillium wilt. The further studies revealed that the root exudates from tomato companied with potato onion significantly inhibited the mycelia growth and spore germination of V. dahliae. However, there were no significant effects on these two measurements for the root exudates from potato onion grown alone or from potato onion grown with tomato. RNA-seq data analysis showed the disease defense genes associated with pathogenesis-related proteins, biosynthesis of lignin, hormone metabolism and signal transduction were expressed much higher in the tomato companied with potato onion than those in the tomato grown alone, which indicated that these defense genes play important roles in tomato against V. dahliae infection, and meant that the disease resistance of tomato against V. dahliae was enhanced in the companion copping with potato onion. We proposed that companion cropping with potato onion could enhance the disease resistance of tomato against V. dahliae by regulating the expression of genes related to disease resistance response. This may be a potential mechanism for the management of soil-borne plant diseases in the intercropping system. PMID- 26442041 TI - Evaluation on the effectiveness of 2-deoxyglucose-6-phosphate phosphatase (DOG(R)1) gene as a selectable marker for oil palm (Elaeis guineensis Jacq.) embryogenic calli transformation mediated by Agrobacterium tumefaciens. AB - DOG(R)1, which encodes 2-deoxyglucose-6-phosphate phosphatase, has been used as a selectable marker gene to produce transgenic plants. In this study, a transformation vector, pBIDOG, which contains the DOG(R)1 gene, was transformed into oil palm embryogenic calli (EC) mediated by Agrobacterium tumefaciens strain LBA4404. Transformed EC were exposed to 400 mg l(-1) 2-deoxyglucose (2-DOG) as the selection agent. 2-DOG resistant tissues were regenerated into whole plantlets on various regeneration media containing the same concentration of 2 DOG. The plantlets were later transferred into soil and grown in a biosafety screenhouse. PCR and subsequently Southern blot analyses were carried out to confirm the integration of the transgene in the plantlets. A transformation efficiency of about 1.0% was obtained using DOG(R)1 gene into the genome of oil palm. This result demonstrates the potential of using combination of DOG(R)1 gene and 2-DOG for regenerating transgenic oil palm. PMID- 26442043 TI - The plant detectives: innovative undergraduate teaching to inspire the next generation of plant biologists. AB - Encouraging more students to embrace plant science research is a global priority. We have evolved a second year undergraduate course from a standard lecture/practical format into an innovative research-led learning design that gives students hands-on experience of cutting-edge plant science research and specialist instrumentation. By making tangible the links between plant genetics, biochemistry, physiology and function, the active learning curriculum extends students to their limits, and gives them insights into the multi-faceted nature of plant science research. Using genetically-mapped mutants of Arabidopsis thaliana, we challenge our students to apply their conceptual learning immediately to identify "unknown" genetic mutations affecting plant form and function. By exposing students early in their student careers to the challenges, rigors and excitement of plant science research, we have helped them grow quickly into astute researchers who truly deserve the title "Plant Detectives." Many have become motivated to continue their studies as plant biologists in research focused honors (pre-doctoral) and doctoral programs. PMID- 26442042 TI - Metabolite profiling and transcript analysis reveal specificities in the response of a berry derived cell culture to abiotic stresses. AB - As climate changes, there is a need to understand the expected effects on viticulture. In nature, stresses exist in a combined manner, hampering the elucidation of the effect of individual cues on grape berry metabolism. Cell suspension culture originated from pea-size Gamy Red grape berry was used to harness metabolic response to high light (HL; 2500 MUmol m(-2)s(-1)), high temperature (HT; 40 degrees C) and their combination in comparison to 25 degrees C and 100 MUmol m(-2)s(-1) under controlled condition. When LC-MS and GC-MS based metabolite profiling was implemented and integrated with targeted RT-qPCR transcript analysis specific responses were observed to the different cues. HL enhanced polyphenol metabolism while HT and its combination with HL induced amino acid and organic acid metabolism with additional effect on polyphenols. The trend of increment in TCA cycle genes like ATCs, ACo1, and IDH in the combined treatment might support the observed increment in organic acids, GABA shunt, and their derivatives. The apparent phenylalanine reduction with polyphenol increment under HL suggests enhanced fueling of the precursor toward the downstream phenylpropanoid pathway. In the polyphenol metabolism, a differential pattern of expression of flavonoid 3',5' hydroxylase and flavonoid 3' hydroxylase was observed under high light (HL) and combined cues which were accompanied by characteristic metabolite profiles. HT decreased glycosylated cyanidin and peonidin forms while the combined cues increased acetylated and coumarylated peonidin forms. Transcription factors regulating anthocyanin metabolism and their methylation, MYB, OMT, UFGT, and DFR, were expressed differentially among the treatments, overall in agreement with the metabolite profiles. Taken together these data provide insights into the coordination of central and secondary metabolism in relation to multiple abiotic stresses. PMID- 26442044 TI - Plasticity in variation of xylem and phloem cell characteristics of Norway spruce under different local conditions. AB - There is limited information on intra-annual plasticity of secondary tissues of tree species growing under different environmental conditions. To increase the knowledge about the plasticity of secondary growth, which allows trees to adapt to specific local climatic regimes, we examined climate-radial growth relationships of Norway spruce [Picea abies (L.) H. Karst.] from three contrasting locations in the temperate climatic zone by analyzing tree-ring widths for the period 1932-2010, and cell characteristics in xylem and phloem increments formed in the years 2009-2011. Variation in the structure of xylem and phloem increments clearly shows that plasticity in seasonal dynamics of cambial cell production and cell differentiation exists on xylem and phloem sides. Anatomical characteristics of xylem and phloem cells are predominantly site specific characteristics, because they varied among sites but were fairly uniform among years in trees from the same site. Xylem and phloem tissues formed in the first part of the growing season seemed to be more stable in structure, indicating their priority over latewood and late phloem for tree performance. Long-term climate and radial growth analyses revealed that growth was in general less dependent on precipitation than on temperature; however, growth sensitivity to local conditions differed among the sites. Only partial dependence of radial growth of spruce on climatic factors on the selected sites confirms its strategy to adapt the structure of wood and phloem increments to function optimally in local conditions. PMID- 26442045 TI - Identification of early salt stress responsive proteins in seedling roots of upland cotton (Gossypium hirsutum L.) employing iTRAQ-based proteomic technique. AB - Soil salinity is a major abiotic stress that limits plant growth and agricultural productivity. Upland cotton (Gossypium hirsutum L.) is highly tolerant to salinity; however, large-scale proteomic data of cotton in response to salt stress are still scant. Here, an isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic technique was employed to identify the early differentially expressed proteins (DEPs) from salt-treated cotton roots. One hundred and twenty-eight DEPs were identified, 76 of which displayed increased abundance and 52 decreased under salt stress conditions. The majority of the proteins have functions related to carbohydrate and energy metabolism, transcription, protein metabolism, cell wall and cytoskeleton metabolism, membrane and transport, signal transduction, in addition to stress and defense. It is worth emphasizing that some novel salt-responsive proteins were identified, which are involved in cell cytoskeleton metabolism (actin-related protein2, ARP2, and fasciclin-like arabinogalactan proteins, FLAs), membrane transport (tonoplast intrinsic proteins, TIPs, and plasma membrane intrinsic proteins, PIPs), signal transduction (leucine-rich repeat receptor-like kinase encoding genes, LRR-RLKs) and stress responses (thaumatin-like protein, TLP, universal stress protein, USP, dirigent-like protein, DIR, desiccation-related protein PCC13-62). High positive correlation between the abundance of some altered proteins (superoxide dismutase, SOD, peroxidase, POD, glutathione S-transferase, GST, monodehydroascorbate reductase, MDAR, and malate dehydrogenase, MDH) and their enzyme activity was evaluated. The results demonstrate that the iTRAQ-based proteomic technique is reliable for identifying and quantifying a large number of cotton root proteins. qRT-PCR was used to study the gene expression levels of the five above-mentioned proteins; four patterns are consistent with those of induced protein. These results showed that the proteome of cotton roots under NaCl stress is complex. The comparative protein profiles of roots under salinity vs control improves the understanding of the molecular mechanisms involved in the tolerance of plants to salt stress. This work provides a good basis for further functional elucidation of these DEPs using genetic and/or other approaches, and, consequently, candidate genes for genetic engineering to improve crop salt tolerance. PMID- 26442046 TI - Potential of soil amendments (Biochar and Gypsum) in increasing water use efficiency of Abelmoschus esculentus L. Moench. AB - Water being an essential component for plant growth and development, its scarcity poses serious threat to crops around the world. Climate changes and global warming are increasing the temperature of earth hence becoming an ultimate cause of water scarcity. It is need of the day to use potential soil amendments that could increase the plants' resistance under such situations. Biochar and gypsum were used in the present study to improve the water use efficiency (WUE) and growth of Abelmoschus esculentus L. Moench (Lady's Finger). A 6 weeks experiment was conducted under greenhouse conditions. Stress treatments were applied after 30 days of sowing. Plant height, leaf area, photosynthesis, transpiration rate (Tr), stomatal conductance and WUE were determined weekly under stressed [60% field capacity (F.C.)] and non-stressed (100% F.C.) conditions. Stomatal conductance and Tr decreased and reached near to zero in stressed plants. Stressed plants also showed resistance to water stress upto 5 weeks and gradually perished at sixth week. On the other hand, WUE improved in stressed plants containing biochar and gypsum as compared to untreated plants. Biochar alone is a better strategy to promote plant growth and WUE specifically of A. esculentus, compared to its application in combination with gypsum. PMID- 26442047 TI - A stranger in a strange land: the utility and interpretation of heterologous expression. AB - One of the major goals of the modern study of evodevo is to understand the evolution of gene function across a range of contexts, including sub/neofunctionalization, co-option of genetic modules, and the evolution of morphological novelty. To these ends, comparative studies of gene expression can be useful for constructing hypotheses, but cannot provide direct evidence of functional evolution. Unfortunately, determining endogenous gene function in non model species is often not an option. Faced with this dilemma, a common approach is to use heterologous expression (HE) in genetically tractable model species as a proxy for functional analyses. Such experiments have important limitations, however, and require caution in the interpretation of their results. How do we dissociate biochemical function from its original genomic context? In the end, what does HE actually tell us? Here, I argue that HE only sheds light on specific types of biochemical conservation, but can be useful when experiments are carefully interpreted. PMID- 26442048 TI - Proteomic analysis of middle and late stages of bread wheat (Triticum aestivum L.) grain development. AB - Proteomic approaches were applied in four grain developmental stages of the Chinese bread wheat Yunong 201 and its ethyl methanesulfonate (EMS) mutant line Yunong 3114. 2-DE and tandem MALDI-TOF/TOF-MS analyzed proteome characteristics during middle and late grain development of the Chinese bread wheat Yunong 201 and its EMS mutant line Yunong 3114 with larger grain sizes. We identified 130 differentially accumulated protein spots representing 88 unique proteins, and four main expression patterns displayed a dynamic description of middle and late grain formation. Those identified protein species participated in eight biochemical processes: stress/defense, carbohydrate metabolism, protein synthesis/assembly/degradation, storage proteins, energy production and transportation, photosynthesis, transcription/translation, signal transduction. Comparative proteomic characterization demonstrated 12 protein spots that co accumulated in the two wheat cultivars with different expression patterns, and six cultivar-specific protein spots including serpin, small heat shock protein, beta-amylase, alpha-amylase inhibitor, dimeric alpha-amylase inhibitor precursor, and cold regulated protein. These cultivar-specific protein spots possibly resulted in differential yield-related traits of the two wheat cultivars. Our results provide valuable information for dissection of molecular and genetics basis of yield-related traits in bread wheat and the proteomic characterization in this study could also provide insights in the biology of middle and late grain development. PMID- 26442049 TI - Identification, isolation, and expression analysis of heat shock transcription factors in the diploid woodland strawberry Fragaria vesca. AB - Heat shock transcription factors (Hsfs) are known to play dominant roles in plant responses to heat, as well as other abiotic or biotic stress stimuli. While the strawberry is an economically important fruit plant, little is known about the Hsf family in the strawberry. To explore the functions of strawberry Hsfs in abiotic and biotic stress responses, this study identified 17 Hsf genes (FvHsfs) in a wild diploid woodland strawberry (Fragaria vesca, 2n = 2x = 14) and isolated 14 of these genes. Phylogenetic analysis divided the strawberry FvHsfs genes into three main groups. The evolutionary and structural analyses revealed that the FvHsf family is conserved. The promoter sequences of the FvHsf genes contain upstream regulatory elements corresponding to different stress stimuli. In addition, 14 FvHsf-GFP fusion proteins showed differential subcellular localization in Arabidopsis mesophyll protoplasts. Furthermore, we examined the expression of the 17 FvHsf genes in wild diploid woodland strawberries under various conditions, including abiotic stresses (heat, cold, drought, and salt), biotic stress (powdery mildew infection), and hormone treatments (abscisic acid, ethephon, methyl jasmonate, and salicylic acid). Fifteen of the seventeen FvHsf genes exhibited distinct changes on the transcriptional level during heat treatment. Of these 15 FvHsfs, 8 FvHsfs also exhibited distinct responses to other stimuli on the transcriptional level, indicating versatile roles in the response to abiotic and biotic stresses. Taken together, the present work may provide the basis for further studies to dissect FvHsf function in response to stress stimuli. PMID- 26442050 TI - Genome-wide identification and expression analysis of calcium-dependent protein kinase and its closely related kinase genes in Capsicum annuum. AB - As Ca2+ sensors and effectors, calcium-dependent protein kinases (CDPKs) play important roles in plant growth, development, and response to environmental cues. However, no CDPKs have been characterized in Capsicum annuum thus far. Herein, a genome wide comprehensive analysis of genes encoding CDPKs and CDPK-related protein kinases (CRKs) was performed in pepper, a total of 31 CDPK genes and five closely related kinase genes were identified, which were phylogenetically divided into four distinct subfamilies and unevenly distributed across nine chromosomes. Conserved sequence and exon-intron structures were found to be shared by pepper CDPKs within the same subfamily, and the expansion of the CDPK family in pepper was found to be due to segmental duplication events. Five CDPKs in the C. annuum variety CM334 were found to be mutated in the Chiltepin variety, and one CDPK present in CM334 was lost in Chiltepin. The majority of CDPK and CRK genes were expressed in different pepper tissues and developmental stages, and 10, 12, and 8 CDPK genes were transcriptionally modified by salt, heat, and Ralstonia solanacearum stresses, respectively. Furthermore, these genes were found to respond specifically to one stress as well as respond synergistically to two stresses or three stresses, suggesting that these CDPK genes might be involved in the specific or synergistic response of pepper to salt, heat, and R. solanacearum. Our results lay the foundation for future functional characterization of pepper CDPK and its closely related gene families. PMID- 26442051 TI - Hierarchical additive effects on heterosis in rice (Oryza sativa L.). AB - Exploitation of heterosis in crops has contributed greatly to improvement in global food and energy production. In spite of the pervasive importance of heterosis, a complete understanding of its mechanisms has remained elusive. In this study, a small test-crossed rice population was constructed to investigate the formation mechanism of heterosis for 13 traits. The results of the relative mid-parent heterosis and modes of inheritance of all investigated traits demonstrated that additive effects were the foundation of heterosis for complex traits in a hierarchical structure, and multiplicative interactions among the component traits were the framework of heterosis in complex traits. Furthermore, new balances between unit traits and related component traits provided hybrids with the opportunity to achieve an optimal degree of heterosis for complex traits. This study dissected heterosis of both reproductive and vegetative traits from the perspective of hierarchical structure for the first time. Additive multiplicative interactions of component traits were proven to be the origin of heterosis in complex traits. Meanwhile, more attention should be paid to component traits, rather than complex traits, in the process of revealing the mechanism of heterosis. PMID- 26442052 TI - Global analysis of lysine acetylation in strawberry leaves. AB - Protein lysine acetylation is a reversible and dynamic post-translational modification. It plays an important role in regulating diverse cellular processes including chromatin dynamic, metabolic pathways, and transcription in both prokaryotes and eukaryotes. Although studies of lysine acetylome in plants have been reported, the throughput was not high enough, hindering the deep understanding of lysine acetylation in plant physiology and pathology. In this study, taking advantages of anti-acetyllysine-based enrichment and high-sensitive mass spectrometer, we applied an integrated proteomic approach to comprehensively investigate lysine acetylome in strawberry. In total, we identified 1392 acetylation sites in 684 proteins, representing the largest dataset of acetylome in plants to date. To reveal the functional impacts of lysine acetylation in strawberry, intensive bioinformatic analysis was performed. The results significantly expanded our current understanding of plant acetylome and demonstrated that lysine acetylation is involved in multiple cellular metabolism and cellular processes. More interestingly, nearly 50% of all acetylated proteins identified in this work were localized in chloroplast and the vital role of lysine acetylation in photosynthesis was also revealed. Taken together, this study not only established the most extensive lysine acetylome in plants to date, but also systematically suggests the significant and unique roles of lysine acetylation in plants. PMID- 26442053 TI - Crop improvement using life cycle datasets acquired under field conditions. AB - Crops are exposed to various environmental stresses in the field throughout their life cycle. Modern plant science has provided remarkable insights into the molecular networks of plant stress responses in laboratory conditions, but the responses of different crops to environmental stresses in the field need to be elucidated. Recent advances in omics analytical techniques and information technology have enabled us to integrate data from a spectrum of physiological metrics of field crops. The interdisciplinary efforts of plant science and data science enable us to explore factors that affect crop productivity and identify stress tolerance-related genes and alleles. Here, we describe recent advances in technologies that are key components for data driven crop design, such as population genomics, chronological omics analyses, and computer-aided molecular network prediction. Integration of the outcomes from these technologies will accelerate our understanding of crop phenology under practical field situations and identify key characteristics to represent crop stress status. These elements would help us to genetically engineer "designed crops" to prevent yield shortfalls because of environmental fluctuations due to future climate change. PMID- 26442054 TI - Differential expression of seven conserved microRNAs in response to abiotic stress and their regulatory network in Helianthus annuus. AB - Biotic and abiotic stresses affect plant development and production through alternation of the gene expression pattern. Gene expression itself is under the control of different regulators such as miRNAs and transcription factors (TFs). MiRNAs are known to play important roles in regulation of stress responses via interacting with their target mRNAs. Here, for the first time, seven conserved miRNAs, associated with drought, heat, salt and cadmium stresses were characterized in sunflower. The expression profiles of miRNAs and their targets were comparatively analyzed between leaves and roots of plants grown under the mentioned stress conditions. Gene ontology analysis of target genes revealed that they are involved in several important pathways such as auxin and ethylene signaling, RNA mediated silencing and DNA methylation processes. Gene regulatory network highlighted the existence of cross-talks between these stress-responsive miRNAs and the other stress responsive genes in sunflower. Based on network analysis, we suggest that some of these miRNAs in sunflower such as miR172 and miR403 may play critical roles in epigenetic responses to stress. It seems that depending on the stress type, theses miRNAs target several pathways and cellular processes to help sunflower to cope with drought, heat, salt and cadmium stress conditions in a tissue-associated manner. PMID- 26442055 TI - The auxin response factor gene family in banana: genome-wide identification and expression analyses during development, ripening, and abiotic stress. AB - Auxin signaling regulates various auxin-responsive genes via two types of transcriptional regulators, Auxin Response Factors (ARF) and Aux/IAA. ARF transcription factors act as critical components of auxin signaling that play important roles in modulating various biological processes. However, limited information about this gene family in fruit crops is currently available. Herein, 47 ARF genes were identified in banana based on its genome sequence. Phylogenetic analysis of the ARFs from banana, rice, and Arabidopsis suggested that the ARFs could be divided into four subgroups, among which most ARFs from the banana showed a closer relationship with those from rice than those from Arabidopsis. Conserved motif analysis showed that all identified MaARFs had typical DNA binding and ARF domains, but 12 members lacked the dimerization domain. Gene structure analysis showed that the number of exons in MaARF genes ranged from 5 to 21, suggesting large variation amongst banana ARF genes. The comprehensive expression profiles of MaARF genes yielded useful information about their involvement in diverse tissues, different stages of fruit development and ripening, and responses to abiotic stresses in different varieties. Interaction networks and co-expression assays indicated the strong transcriptional response of banana ARFs and ARF-mediated networks in early fruit development for different varieties. Our systematic analysis of MaARFs revealed robust tissue-specific, development-dependent, and abiotic stress-responsive candidate MaARF genes for further functional assays in planta. These findings could lead to potential applications in the genetic improvement of banana cultivars, and yield new insights into the complexity of the control of MaARF gene expression at the transcriptional level. Finally, they support the hypothesis that ARFs are a crucial component of the auxin signaling pathway, which regulates a wide range of physiological processes. PMID- 26442056 TI - Genome-wide association for grain yield under rainfed conditions in historical wheat cultivars from Pakistan. AB - Genome-wide association studies (GWAS) were undertaken to identify SNP markers associated with yield and yield-related traits in 123 Pakistani historical wheat cultivars evaluated during 2011-2014 seasons under rainfed field conditions. The population was genotyped by using high-density Illumina iSelect 90K single nucleotide polymorphism (SNP) assay, and finally 14,960 high quality SNPs were used in GWAS. Population structure examined using 1000 unlinked markers identified seven subpopulations (K = 7) that were representative of different breeding programs in Pakistan, in addition to local landraces. Forty four stable marker-trait associations (MTAs) with -log p > 4 were identified for nine yield related traits. Nine multi-trait MTAs were found on chromosomes 1AL, 1BS, 2AL, 2BS, 2BL, 4BL, 5BL, 6AL, and 6BL, and those on 5BL and 6AL were stable across two seasons. Gene annotation and syntey identified that 14 trait-associated SNPs were linked to genes having significant importance in plant development. Favorable alleles for days to heading (DH), plant height (PH), thousand grain weight (TGW), and grain yield (GY) showed minor additive effects and their frequencies were slightly higher in cultivars released after 2000. However, no selection pressure on any favorable allele was identified. These genomic regions identified have historically contributed to achieve yield gains from 2.63 million tons in 1947 to 25.7 million tons in 2015. Future breeding strategies can be devised to initiate marker assisted breeding to accumulate these favorable alleles of SNPs associated with yield-related traits to increase grain yield. Additionally, in silico identification of 454-contigs corresponding to MTAs will facilitate fine mapping and subsequent cloning of candidate genes and functional marker development. PMID- 26442057 TI - Temporal small RNA transcriptome profiling unraveled partitioned miRNA expression in developing maize endosperms between reciprocal crosses. AB - In angiosperms, the endosperm nurtures the embryo and provides nutrients for seed germination. To identify the expression pattern of small interfering RNA in the developing maize endosperm, we have performed high-throughput small RNA transcriptome sequencing of kernels at 0, 3, and 5 days after pollination (DAP) and endosperms at 7, 10, and 15 DAP using B73 and Mo17 reciprocal crosses in previous study. Here, we further explored these small RNA-seq data to investigate the potential roles of miRNAs in regulating the gene expression process. In total, 57 conserved miRNAs and 18 novel miRNAs were observed highly expressed in maize endosperm. Temporal expression profiling indicated that these miRNAs exhibited dynamic and partitioned expression patterns at different developmental stages between maize reciprocal crosses, and quantitative RT-PCR results further confirmed our observation. In addition, we found a subset of distinct tandem miRNAs are generated from a single stem-loop structure in maize that might be conserved in monocots. Furthermore, a SNP variation of Zma-miR408-5p at 11th base position was characterized between B73 and Mo17 which might lead to completely different functions in repressing targets. More interestingly, Zma-miR408-5p exhibited B73-biased expression pattern in the B73 and Mo17 reciprocal hybrid endosperms at 7, 10, and 15 DAP according to the reads abundance with SNPs and CAPS experiment. Together, this study suggests that miRNA plays a crucial role in regulating endosperm development, and exhibited distinct expression patterns in developing endosperm between maize reciprocal crosses. PMID- 26442058 TI - Analysis of the transgenerational iron deficiency stress memory in Arabidopsis thaliana plants. AB - We investigated the existence of the transgenerational memory of iron (Fe) deficiency stress, in Arabidopsis thaliana. Plants were grown under Fe deficiency/sufficiency, and so were their offspring. The frequency of somatic homologous recombination (SHR) events, of DNA strand breaks as well as the expression of the transcription elongation factor TFIIS-like gene increase when plants are grown under Fe deficiency. However, SHR frequency, DNA strand break events, and TFIIS-like gene expression do not increase further when plants are grown for more than one generation under the same stress, and furthermore, they decrease back to control values within two succeeding generations grown under control conditions, regardless of the Fe deficiency stress history of the mother plants. Seedlings produced from plants grown under Fe deficiency evolve more oxygen than control seedlings, when grown under Fe sufficiency: however, this trait is not associated with any change in the protein profile of the photosynthetic apparatus and is not transmitted to more than one generation. Lastly, plants grown for multiple generations under Fe deficiency produce seeds with greater longevity: however, this trait is not inherited in offspring generations unexposed to stress. These findings suggest the existence of multiple step control of mechanisms to prevent a genuine and stable transgenerational transmission of Fe deficiency stress memory, with the tightest control on DNA integrity. PMID- 26442059 TI - Expression of Arabidopsis FCS-Like Zinc finger genes is differentially regulated by sugars, cellular energy level, and abiotic stress. AB - Cellular energy status is an important regulator of plant growth, development, and stress mitigation. Environmental stresses ultimately lead to energy deficit in the cell which activates the SNF1-RELATED KINASE 1 (SnRK1) signaling cascade which eventually triggering a massive reprogramming of transcription to enable the plant to survive under low-energy conditions. The role of Arabidopsis thaliana FCS-Like Zinc finger (FLZ) gene family in energy and stress signaling is recently come to highlight after their interaction with kinase subunits of SnRK1 were identified. In a detailed expression analysis in different sugars, energy starvation, and replenishment series, we identified that the expression of most of the FLZ genes is differentially modulated by cellular energy level. It was found that FLZ gene family contains genes which are both positively and negatively regulated by energy deficit as well as energy-rich conditions. Genetic and pharmacological studies identified the role of HEXOKINASE 1- dependent and energy signaling pathways in the sugar-induced expression of FLZ genes. Further, these genes were also found to be highly responsive to different stresses as well as abscisic acid. In over-expression of kinase subunit of SnRK1, FLZ genes were found to be differentially regulated in accordance with their response toward energy fluctuation suggesting that these genes may work downstream to the established SnRK1 signaling under low-energy stress. Taken together, the present study provides a conceptual framework for further studies related to SnRK1-FLZ interaction in relation to sugar and energy signaling and stress response. PMID- 26442060 TI - Photosynthetic characteristics of the subtending leaf of cotton boll at different fruiting branch nodes and their relationships with lint yield and fiber quality. AB - To investigate photosynthetic characteristics of the subtending leaf at the 2-3rd and 10-11th fruiting branch (FBN, FB2-3, and FB10-11), and their relationship with cotton yield and quality, field experiments were conducted using two cotton cultivars, Kemian 1 and Sumian 15. The results showed that with FBN increasing, chlorophyll (Chl) components, Pn and non-photochemical quenching (NPQ) in the subtending leaf significantly declined, while soluble sugar, amino acid and their ratio (C SS/C AA) as well as F v/F m increased. These results indicated that (1) non-radiative dissipation of excess light energy at FB2-3 was reduced to improve solar energy utilization efficiency to compensate for lower Pn, (2) higher NPQ at FB10-11 played a role in leaf photo-damage avoidance, (3) boll weight was related to the C SS/C AA ratio rather than carbohydrates content alone, (4) with FBN increasing, lint biomass and lint/seed ratio increased significantly, but lint yield decreased due to lower relative amount of bolls, and (5) the decreases in Pn, sucrose content and C SS /C AA in the subtending leaf at FB2-3 resulted in lower boll weight and fiber strength. PMID- 26442061 TI - The heat shock factor gene family in Salix suchowensis: a genome-wide survey and expression profiling during development and abiotic stresses. AB - Heat shock transcription factors (Hsfs), which act as important transcriptional regulatory proteins, play crucial roles in plant developmental processes, and stress responses. Recently, the genome of the shrub willow Salix suchowensis was fully sequenced. In this study, a total of 27 non-redundant Hsf genes were identified from the S. suchowensis genome. Phylogenetic analysis revealed that the members of the SsuHsf family can be divided into three groups (class A, B, and C) based on their structural characteristics. Promoter analysis indicated that the SsuHsfs promoters included various cis-acting elements related to hormone and/or stress responses. Furthermore, the expression profiles of 27 SsuHsfs were analyzed in different tissues and under various stresses (heat, drought, salt, and ABA treatment) using RT-PCR. The results demonstrated that the SsuHsfs were involved in abiotic stress responses. Our results contribute to a better understanding of the complexity of the SsuHsf gene family, and will facilitate functional characterization in future studies. PMID- 26442062 TI - De novo assembly and transcriptome analysis of two contrary tillering mutants to learn the mechanisms of tillers outgrowth in switchgrass (Panicum virgatum L.). AB - Tillering is an important trait in monocotyledon plants. The switchgrass (Panicum virgatum), studied usually as a source of biomass for energy production, can produce hundreds of tillers in its lifetime. Studying the tillering of switchgrass also provides information for other monocot crops. High-tillering and low-tillering mutants were produced by ethyl methanesulfonate mutagenesis. Alteration of tillering ability resulted from different tiller buds outgrowth in the two mutants. We sequenced the tiller buds transcriptomes of high-tillering and low-tillering plants using next-generation sequencing technology, and generated 34 G data in total. In the de novo assembly results, 133,828 unigenes were detected with an average length of 1,238 bp, and 5,290 unigenes were differentially expressed between the two mutants, including 3,225 up-regulated genes and 2,065 down-regulated genes. Differentially expressed gene analysis with functional annotations was performed to identify candidate genes involved in tiller bud outgrowth processes using Gene Ontology classification, Cluster of Orthologous Groups of proteins, and Kyoto Encyclopedia of Genes and Genomes pathway analysis. This is the first study to explore the tillering transcriptome in two types of tillering mutants by de novo sequencing. PMID- 26442064 TI - In silico study for diversing the molecular pathway of pigment formation: an alternative to manual coloring in cotton fibers. AB - Diversity of colors in flowers and fruits is largely due to anthocyanin pigments. The flavonoid/anthocyanin pathway has been most extensively studied. Dihydroflavonol 4-reductase (DFR) is a vital enzyme of the flavonoid pathway which displays major impact on the formation of anthocyanins, flavan 3-ols and flavonols. The substrate specificity of the DFR was found to play a crucial role in determination of type of anthocyanidins. Altering the flavonoid/anthocyanin pathway through genetic engineering to develop color of our own choice is an exciting subject of future research. In the present study, comparison among four DFR genes (Gossypium hirsutum, Iris * hollandica, Ang. DFRI and DFRII), sequence alignment for homology as well as protein modeling and docking is demonstrated. Estimation of catalytic sites, prediction of substrate preference and protein docking were the key features of this article. For specific substrate uptake, a proline rich region and positions 12 plus 26 along with other positions emphasizing the 26-amino acid residue region (132-157) was tested. Results showed that proline rich region position 12, 26, and 132-157 plays an important role in selective attachment of DFRs with respective substrates. Further, "Expasy ProtParam tool" results showed that Iris * hollandica DFR amino acids (Asn 9: Asp 23) are favorable for reducing DHQ and DHM thus accumulating delphinidin, while Gossypium hirsutum DFR has (Asn 13: Asp 21) hypothesized to consume DHK. Protein docking data showed that amino acid residues in above mentioned positions were just involved in attachment of DFR with substrate and had no role in specific substrate uptake. Advanced bioinformatics analysis has revealed that all above mentioned positions have role in substrate attachment. For substrate specificity, other residues region is involved. It will help in color manipulations in different plant species. PMID- 26442063 TI - Plant and pathogen nutrient acquisition strategies. AB - Nutrients are indispensable elements required for the growth of all living organisms including plants and pathogens. Phyllosphere, rhizosphere, apoplast, phloem, xylem, and cell organelles are the nutrient niches in plants that are the target of bacterial pathogens. Depending upon nutrients availability, the pathogen adapts various acquisition strategies and inhabits the specific niche. In this review, we discuss the nutrient composition of different niches in plants, the mechanisms involved in the recognition of nutrient niche and the sophisticated strategies used by the bacterial pathogens for acquiring nutrients. We provide insight into various nutrient acquisition strategies used by necrotrophic, biotrophic, and hemibiotrophic bacteria. Specifically we discuss both modulation of bacterial machinery and manipulation of host machinery. In addition, we highlight the current status of our understanding about the nutrient acquisition strategies used by bacterial pathogens, namely targeting the sugar transporters that are dedicated for the plant's growth and development. Bacterial strategies for altering the plant cell membrane permeability to enhance the release of nutrients are also enumerated along with in-depth analysis of molecular mechanisms behind these strategies. The information presented in this review will be useful to understand the plant-pathogen interaction in nutrient perspective. PMID- 26442065 TI - Reactivity and effectiveness of traditional and novel ligands for multi micronutrient fertilization in a calcareous soil. AB - This study compares the effectiveness of multi-micronutrient formulations containing iron (Fe), manganese (Mn), and zinc (Zn) with traditional (EDTA, DTPA, HEEDTA, and EDDHAm) or novel chelates (o,p-EDDHA, S,S-EDDS, and IDHA) and natural complexing agents (gluconate and lignosulfonate). The stability and reactivity of the formulations were studied on batch experiments with calcareous soil and by speciation modeling. Formulations containing traditional ligands maintained higher Mn but lower Zn concentration in soil solution than the novel ligands. The gluconate and lignosulfonate maintained low concentrations of both Mn and Zn in soil solution. Selected formulations were applied into calcareous soil and their efficacy was evaluated in a pot experiment with soybean. The formulation containing DTPA led to the highest Zn concentration in plants, as well as the formulation containing S,S-EDDS in the short-term, which correlated with its biodegradability. The application of traditional or novel ligands in formulations did not result in sufficient plant Mn concentrations, which was related to the low Mn stability observed for all formulations under moderate oxidation conditions. The results highlight the need to consider the effect of metals and ligands interactions in multi-nutrient fertilization and the potential of S,S EDDS to be used for Zn fertilization. Furthermore, it is necessary to explore new sources of Mn fertilization for calcareous soils that have greater stability and efficiency, or instead to use foliar fertilization. PMID- 26442066 TI - Plant growth conditions alter phytolith carbon. AB - Many plants, including grasses and some important human food sources, accumulate, and precipitate silica in their cells to form opaline phytoliths. These phytoliths contain small amounts of organic matter (OM) that are trapped during the process of silicification. Previous work has suggested that plant silica is associated with compounds such as proteins, lipids, lignin, and carbohydrate complexes. It is not known whether these compounds are cellular components passively encapsulated as the cell silicifies, polymers actively involved in the precipitation process or random compounds assimilated by the plant and discarded into a "glass wastebasket." Here, we used Raman spectroscopy to map the distribution of OM in phytoliths, and to analyze individual phytoliths isolated from Sorghum bicolor plants grown under different laboratory treatments. Using mapping, we showed that OM in phytoliths is distributed throughout the silica and is not related to dark spots visible in light microscopy, previously assumed to be the repository for phytolith OM. The Raman spectra exhibited common bands indicative of C-H stretching modes of general OM, and further more diagnostic bands consistent with carbohydrates, lignins, and other OM. These Raman spectra exhibited variability of spectral signatures and of relative intensities between sample treatments indicating that differing growth conditions altered the phytolith carbon. This may have strong implications for understanding the mechanism of phytolith formation, and for use of phytolith carbon isotope values in dating or paleoclimate reconstruction. PMID- 26442067 TI - Essentiality of nickel in plants: a role in plant stresses. AB - The element Ni is considered an essential plant micronutrient because it acts as an activator of the enzyme urease. Recent studies have shown that Ni may activate an isoform of glyoxalase I, which performs an important step in the degradation of methylglyoxal (MG), a potent cytotoxic compound naturally produced by cellular metabolism. Reduced glutathione (GSH) is consumed and regenerated in the process of detoxification of MG, which is produced during stress (stress-induced production). We examine the role of Ni in the relationship between the MG cycle and GSH homeostasis and suggest that Ni may have a key participation in plant antioxidant metabolism, especially in stressful situations. PMID- 26442068 TI - Characterization and expression profile of CaNAC2 pepper gene. AB - The plant-specific NAC (NAM, ATAF, and CUC) transcription factors have diverse role in development and stress regulation. A new transcript encoding NAC protein, homologous to nam-like protein 4 from Petunia was identified from an ABA regulated subtractive cDNA library of Capsicum annuum seedling. Here, this homolog (named CaNAC2) from C. annuum was characterized and investigated its role in abiotic stress tolerance. Our results indicated that a plant-specific and conserved NAC domain was located in the N-terminus domain of CaNAC2 which was predicted to encode a polypeptide of 410 amino acids. Phylogenetic analysis showed that CaNAC2 belonged to the NAC2 subgroup of the orthologous group 4d. The protein CaNAC2 was subcellularly localized in the nucleus and it had transcriptional activity in yeast cell. CaNAC2 was expressed mainly in seed and root. The transcription expression of CaNAC2 was strongly induced by cold, salt and ABA treatment and inhibited by osmotic stress and SA treatment. Silence of CaNAC2 in virus-induced gene silenced pepper seedlings resulted in the increased susceptibility to cold stress and delayed the salt-induced leaf chlorophyll degradation. These results indicated that this novel CaNAC2 gene might be involved in pepper response to abiotic stress tolerance. PMID- 26442069 TI - The impact of fire on the Late Paleozoic Earth system. AB - Analyses of bulk petrographic data indicate that during the Late Paleozoic wildfires were more prevalent than at present. We propose that the development of fire systems through this interval was controlled predominantly by the elevated atmospheric oxygen concentration (p(O2)) that mass balance models predict prevailed. At higher levels of p(O2), increased fire activity would have rendered vegetation with high-moisture contents more susceptible to ignition and would have facilitated continued combustion. We argue that coal petrographic data indicate that p(O2) rather than global temperatures or climate, resulted in the increased levels of wildfire activity observed during the Late Paleozoic and can, therefore, be used to predict it. These findings are based upon analyses of charcoal volumes in multiple coals distributed across the globe and deposited during this time period, and that were then compared with similarly diverse modern peats and Cenozoic lignites and coals. Herein, we examine the environmental and ecological factors that would have impacted fire activity and we conclude that of these factors p(O2) played the largest role in promoting fires in Late Paleozoic peat-forming environments and, by inference, ecosystems generally, when compared with their prevalence in the modern world. PMID- 26442071 TI - Partially dissecting the steady-state electron fluxes in Photosystem I in wild type and pgr5 and ndh mutants of Arabidopsis. AB - Cyclic electron flux (CEF) around Photosystem I (PS I) is difficult to quantify. We obtained the linear electron flux (LEFO2) through both photosystems and the total electron flux through PS I (ETR1) in Arabidopsis in CO2-enriched air. DeltaFlux = ETR1 - LEFO2 is an upper estimate of CEF, which consists of two components, an antimycin A-sensitive, PGR5 (proton gradient regulation 5 protein) dependent component and an insensitive component facilitated by a chloroplastic nicotinamide adenine dinucleotide dehydrogenase-like complex (NDH). Using wild type as well as pgr5 and ndh mutants, we observed that (1) 40% of the absorbed light was partitioned to PS I; (2) at high irradiance a substantial antimycin A sensitive CEF occurred in the wild type and the ndh mutant; (3) at low irradiance a sizable antimycin A-sensitive CEF occurred in the wild type but not in the ndh mutant, suggesting an enhancing effect of NDH in low light; and (4) in the pgr5 mutant, and the wild type and ndh mutant treated with antimycin A, a residual DeltaFlux existed at high irradiance, attributable to charge recombination and/or pseudo-cyclic electron flow. Therefore, in low-light-acclimated plants exposed to high light, DeltaFlux has contributions from various paths of electron flow through PS I. PMID- 26442070 TI - Importance of Mediator complex in the regulation and integration of diverse signaling pathways in plants. AB - Basic transcriptional machinery in eukaryotes is assisted by a number of cofactors, which either increase or decrease the rate of transcription. Mediator complex is one such cofactor, and recently has drawn a lot of interest because of its integrative power to converge different signaling pathways before channeling the transcription instructions to the RNA polymerase II machinery. Like yeast and metazoans, plants do possess the Mediator complex across the kingdom, and its isolation and subunit analyses have been reported from the model plant, Arabidopsis. Genetic, and molecular analyses have unraveled important regulatory roles of Mediator subunits at every stage of plant life cycle starting from flowering to embryo and organ development, to even size determination. It also contributes immensely to the survival of plants against different environmental vagaries by the timely activation of its resistance mechanisms. Here, we have provided an overview of plant Mediator complex starting from its discovery to regulation of stoichiometry of its subunits. We have also reviewed involvement of different Mediator subunits in different processes and pathways including defense response pathways evoked by diverse biotic cues. Wherever possible, attempts have been made to provide mechanistic insight of Mediator's involvement in these processes. PMID- 26442072 TI - Silicon enhanced salt tolerance by improving the root water uptake and decreasing the ion toxicity in cucumber. AB - Although the effects of silicon application on enhancing plant salt tolerance have been widely investigated, the underlying mechanism has remained unclear. In this study, seedlings of cucumber, a medium silicon accumulator plant, grown in 0.83 mM silicon solution for 2 weeks were exposed to 65 mM NaCl solution for another 1 week. The dry weight and shoot/root ratio were reduced by salt stress, but silicon application significantly alleviated these decreases. The chlorophyll concentration, net photosynthetic rate, transpiration rate and leaf water content were higher in plants treated with silicon than in untreated plants under salt stress conditions. Further investigation showed that salt stress decreased root hydraulic conductance (Lp), but that silicon application moderated this salt induced decrease in Lp. The higher Lp in silicon-treated plants may account for the superior plant water balance. Moreover, silicon application significantly decreased Na(+) concentration in the leaves while increasing K(+) concentration. Simultaneously, both free and conjugated types of polyamines were maintained at high levels in silicon-treated plants, suggesting that polyamines may be involved in the ion toxicity. Our results indicate that silicon enhances the salt tolerance of cucumber through improving plant water balance by increasing the Lp and reducing Na(+) content by increasing polyamine accumulation. PMID- 26442073 TI - Modulation of phenolic metabolism under stress conditions in a Lotus japonicus mutant lacking plastidic glutamine synthetase. AB - This paper was aimed to investigate the possible implications of the lack of plastidic glutamine synthetase (GS2) in phenolic metabolism during stress responses in the model legume Lotus japonicus. Important changes in the transcriptome were detected in a GS2 mutant called Ljgln2-2, compared to the wild type, in response to two separate stress conditions, such as drought or the result of the impairment of the photorespiratory cycle. Detailed transcriptomic analysis showed that the biosynthesis of phenolic compounds was affected in the mutant plants in these two different types of stress situations. For this reason, the genes and metabolites related to this metabolic route were further investigated using a combined approach of gene expression analysis and metabolite profiling. A high induction of the expression of several genes for the biosynthesis of different branches of the phenolic biosynthetic pathway was detected by qRT-PCR. The extent of induction was always higher in Ljgln2-2, probably reflecting the higher stress levels present in this genotype. This was paralleled by accumulation of several kaempferol and quercetine glycosides, some of them described for the first time in L. japonicus, and of high levels of the isoflavonoid vestitol. The results obtained indicate that the absence of GS2 affects different aspects of phenolic metabolism in L. japonicus plants in response to stress. PMID- 26442074 TI - Specialization for resistance in wild host-pathogen interaction networks. AB - Properties encompassed by host-pathogen interaction networks have potential to give valuable insight into the evolution of specialization and coevolutionary dynamics in host-pathogen interactions. However, network approaches have been rarely utilized in previous studies of host and pathogen phenotypic variation. Here we applied quantitative analyses to eight networks derived from spatially and temporally segregated host (Linum marginale) and pathogen (Melampsora lini) populations. First, we found that resistance strategies are highly variable within and among networks, corresponding to a spectrum of specialist and generalist resistance types being maintained within all networks. At the individual level, specialization was strongly linked to partial resistance, such that partial resistance was effective against a greater number of pathogens compared to full resistance. Second, we found that all networks were significantly nested. There was little support for the hypothesis that temporal evolutionary dynamics may lead to the development of nestedness in host-pathogen infection networks. Rather, the common patterns observed in terms of nestedness suggests a universal driver (or multiple drivers) that may be independent of spatial and temporal structure. Third, we found that resistance networks were significantly modular in two spatial networks, clearly reflecting spatial and ecological structure within one of the networks. We conclude that (1) overall patterns of specialization in the networks we studied mirror evolutionary trade offs with the strength of resistance; (2) that specific network architecture can emerge under different evolutionary scenarios; and (3) network approaches offer great utility as a tool for probing the evolutionary and ecological genetics of host-pathogen interactions. PMID- 26442075 TI - Investigation of the multifunctional gene AOP3 expands the regulatory network fine-tuning glucosinolate production in Arabidopsis. AB - Quantitative trait loci (QTL) mapping studies enable identification of loci that are part of regulatory networks controlling various phenotypes. Detailed investigations of genes within these loci are required to ultimately understand the function of individual genes and how they interact with other players in the network. In this study, we use transgenic plants in combination with natural variation to investigate the regulatory role of the AOP3 gene found in GS-AOP locus previously suggested to contribute to the regulation of glucosinolate defense compounds. Phenotypic analysis and QTL mapping in F2 populations with different AOP3 transgenes support that the enzymatic function and the AOP3 RNA both play a significant role in controlling glucosinolate accumulation. Furthermore, we find different loci interacting with either the enzymatic activity or the RNA of AOP3 and thereby extend the regulatory network controlling glucosinolate accumulation. PMID- 26442077 TI - Design of an F1 hybrid breeding strategy for ryegrasses based on selection of self-incompatibility locus-specific alleles. AB - Relatively modest levels of genetic gain have been achieved in conventional ryegrass breeding when compared to cereal crops such as maize, current estimates indicating an annual improvement of 0.25-0.6% in dry matter production. This property is partially due to an inability to effectively exploit heterosis through the formation of F1 hybrids. Controlled crossing of ryegrass lines from geographically distant origins has demonstrated the occurrence of heterosis, which can result in increases of dry matter production in the order of 25%. Although capture of hybrid vigor offers obvious advantages for ryegrass cultivar production, to date there have been no effective and commercially suitable methods for obtaining high proportions of F1 hybrid seed. Continued advances in fine-scale genetic and physical mapping of the gametophytic self-incompatibility (SI) loci (S and Z) of ryegrasses are likely in the near future to permit the identification of closely linked genetic markers that define locus-specific haplotypes, allowing prediction of allelic variants and hence compatibility between different plant genotypes. Given the availability of such information, a strategy for efficient generation of ryegrass cultivars with a high proportion of F1 hybrid individuals has been simulated, which is suitable for commercial implementation. Through development of two parental pools with restricted diversity at the SI loci, relative crossing compatibility between pools is increased. Based on simulation of various levels of SI allele diversity restriction, the most effective scheme will generate 83.33% F1 hybrids. Results from the study, including the impact of varying flowering time, are discussed along with a proposed breeding design for commercial application. PMID- 26442076 TI - Genome-wide gene expression perturbation induced by loss of C2 chromosome in allotetraploid Brassica napus L. AB - Aneuploidy with loss of entire chromosomes from normal complement disrupts the balanced genome and is tolerable only by polyploidy plants. In this study, the monosomic and nullisomic plants losing one or two copies of C2 chromosome from allotetraploid Brassica napus L. (2n = 38, AACC) were produced and compared for their phenotype and transcriptome. The monosomics gave a plant phenotype very similar to the original donor, but the nullisomics had much smaller stature and also shorter growth period. By the comparative analyses on the global transcript profiles with the euploid donor, genome-wide alterations in gene expression were revealed in two aneuploids, and their majority of differentially expressed genes (DEGs) resulted from the trans-acting effects of the zero and one copy of C2 chromosome. The higher number of up-regulated genes than down-regulated genes on other chromosomes suggested that the genome responded to the C2 loss via enhancing the expression of certain genes. Particularly, more DEGs were detected in the monosomics than nullisomics, contrasting with their phenotypes. The gene expression of the other chromosomes was differently affected, and several dysregulated domains in which up- or downregulated genes obviously clustered were identifiable. But the mean gene expression (MGE) for homoeologous chromosome A2 reduced with the C2 loss. Some genes and their expressions on C2 were correlated with the phenotype deviations in the aneuploids. These results provided new insights into the transcriptomic perturbation of the allopolyploid genome elicited by the loss of individual chromosome. PMID- 26442078 TI - Extracellular vesicles including exosomes in cross kingdom regulation: a viewpoint from plant-fungal interactions. PMID- 26442079 TI - ROS mediated MAPK signaling in abiotic and biotic stress- striking similarities and differences. AB - Plants encounter a number of environmental stresses throughout their life cycles, most of which activate mitogen activated protein kinase (MAPK) pathway. The MAPKs show crosstalks at several points but the activation and the final response is known to be specific for particular stimuli that in-turn activates specific set of downstream targets. Interestingly, reactive oxygen species (ROS) is an important and common messenger produced in various environmental stresses and is known to activate many of the MAPKs. ROS activates a similar MAPK in different environmental stimuli, showing different downstream targets with different and specific responses. In animals and yeast, the mechanism behind the specific activation of MAPK by different concentration and species of ROS is elaborated, but in plants this aspect is still unclear. This review mainly focuses on the aspect of specificity of ROS mediated MAPK activation. Attempts have been made to review the involvement of ROS in abiotic stress mediated MAPK signaling and how it differentiates with that of biotic stress. PMID- 26442080 TI - Computational analyses of ancient pathogen DNA from herbarium samples: challenges and prospects. AB - The application of DNA sequencing technology to the study of ancient DNA has enabled the reconstruction of past epidemics from genomes of historically important plant-associated microbes. Recently, the genome sequences of the potato late blight pathogen Phytophthora infestans were analyzed from 19th century herbarium specimens. These herbarium samples originated from infected potatoes collected during and after the Irish potato famine. Herbaria have therefore great potential to help elucidate past epidemics of crops, date the emergence of pathogens, and inform about past pathogen population dynamics. DNA preservation in herbarium samples was unexpectedly good, raising the possibility of a whole new research area in plant and microbial genomics. However, the recovered DNA can be extremely fragmented resulting in specific challenges in reconstructing genome sequences. Here we review some of the challenges in computational analyses of ancient DNA from herbarium samples. We also applied the recently developed linkage method to haplotype reconstruction of diploid or polyploid genomes from fragmented ancient DNA. PMID- 26442081 TI - Comparative genomic analysis of duplicated homoeologous regions involved in the resistance of Brassica napus to stem canker. AB - All crop species are current or ancient polyploids. Following whole genome duplication, structural and functional modifications result in differential gene content or regulation in the duplicated regions, which can play a fundamental role in the diversification of genes underlying complex traits. We have investigated this issue in Brassica napus, a species with a highly duplicated genome, with the aim of studying the structural and functional organization of duplicated regions involved in quantitative resistance to stem canker, a disease caused by the fungal pathogen Leptosphaeria maculans. Genome-wide association analysis on two oilseed rape panels confirmed that duplicated regions of ancestral blocks E, J, R, U, and W were involved in resistance to stem canker. The structural analysis of the duplicated genomic regions showed a higher gene density on the A genome than on the C genome and a better collinearity between homoeologous regions than paralogous regions, as overall in the whole B. napus genome. The three ancestral sub-genomes were involved in the resistance to stem canker and the fractionation profile of the duplicated regions corresponded to what was expected from results on the B. napus progenitors. About 60% of the genes identified in these duplicated regions were single-copy genes while less than 5% were retained in all the duplicated copies of a given ancestral block. Genes retained in several copies were mainly involved in response to stress, signaling, or transcription regulation. Genes with resistance-associated markers were mainly retained in more than two copies. These results suggested that some genes underlying quantitative resistance to stem canker might be duplicated genes. Genes with a hydrolase activity that were retained in one copy or R-like genes might also account for resistance in some regions. Further analyses need to be conducted to indicate to what extent duplicated genes contribute to the expression of the resistance phenotype. PMID- 26442082 TI - Genome-wide analysis and expression profiling under heat and drought treatments of HSP70 gene family in soybean (Glycine max L.). AB - Heat shock proteins (HSPs) perform a fundamental role in protecting plants against abiotic stresses. Previous studies have made great efforts in the functional analysis of individual family members, but there has not yet been an overall analysis or expression profiling of the HSP70 gene family in soybeans (Glycine max L.). In this study, an investigation of the soybean genome revealed 61 putative HSP70 genes, which were evaluated. These genes were classified into eight sub-families, denoted I-VIII, based on a phylogenetic analysis. In each sub family, the constituent parts of the gene structure and motif were relatively conserved. These GmHSP70 genes were distributed unequally on 17 of the 20 chromosomes. The analysis of the expression profiles showed that 53 of the 61 GmHSP70 genes were differentially expressed across the 14 tissues. However, most of the GmHSP70s were differentially expressed in a tissue-specific expression pattern. Furthermore, the expression of some of the duplicate genes was partially redundant, while others showed functional diversity. The quantitative real-time PCR (qRT-PCR) analysis of the 61 soybean HSP70 genes confirmed their stress inducible expression patterns under both drought and heat stress. These findings provide a thorough overview of the evolution and modification of the GmHSP70 gene family, which will help to determine the functional characteristics of the HSP70 genes in soybean growth and development. PMID- 26442083 TI - The effects of bacterial volatile emissions on plant abiotic stress tolerance. AB - Plant growth-promoting rhizobacteria (PGPR) are beneficial plant symbionts that have been successfully used in agriculture to increase seedling emergence, plant weight, crop yield, and disease resistance. Some PGPR strains release volatile organic compounds (VOCs) that can directly and/or indirectly mediate increases in plant biomass, disease resistance, and abiotic stress tolerance. This mini-review focuses on the enhancement of plant abiotic stress tolerance by bacterial VOCs. The review considers how PGPR VOCs induce tolerance to salinity and drought stress and also how they improve sulfur and iron nutrition in plants. The potential complexities in evaluating the effects of PGPR VOCs are also discussed. PMID- 26442084 TI - How and why do root apices sense light under the soil surface? AB - Light can penetrate several centimeters below the soil surface. Growth, development and behavior of plant roots are markedly affected by light despite their underground lifestyle. Early studies provided contrasting information on the spatial and temporal distribution of light-sensing cells in the apical region of root apex and discussed the physiological roles of plant hormones in root responses to light. Recent biological and microscopic advances have improved our understanding of the processes involved in the sensing and transduction of light signals, resulting in subsequent physiological and behavioral responses in growing root apices. Here, we review current knowledge of cellular distributions of photoreceptors and their signal transduction pathways in diverse root tissues and root apex zones. We are discussing also the roles of auxin transporters in roots exposed to light, as well as interactions of light signal perceptions with sensing of other environmental factors relevant to plant roots. PMID- 26442085 TI - Common protein sequence signatures associate with Sclerotinia borealis lifestyle and secretion in fungal pathogens of the Sclerotiniaceae. AB - Fungal plant pathogens produce secreted proteins adapted to function outside fungal cells to facilitate colonization of their hosts. In many cases such as for fungi from the Sclerotiniaceae family the repertoire and function of secreted proteins remains elusive. In the Sclerotiniaceae, whereas Sclerotinia sclerotiorum and Botrytis cinerea are cosmopolitan broad host-range plant pathogens, Sclerotinia borealis has a psychrophilic lifestyle with a low optimal growth temperature, a narrow host range and geographic distribution. To spread successfully, S. borealis must synthesize proteins adapted to function in its specific environment. The search for signatures of adaptation to S. borealis lifestyle may therefore help revealing proteins critical for colonization of the environment by Sclerotiniaceae fungi. Here, we analyzed amino acids usage and intrinsic protein disorder in alignments of groups of orthologous proteins from the three Sclerotiniaceae species. We found that enrichment in Thr, depletion in Glu and Lys, and low disorder frequency in hot loops are significantly associated with S. borealis proteins. We designed an index to report bias in these properties and found that high index proteins were enriched among secreted proteins in the three Sclerotiniaceae fungi. High index proteins were also enriched in function associated with plant colonization in S. borealis, and in in planta-induced genes in S. sclerotiorum. We highlight a novel putative antifreeze protein and a novel putative lytic polysaccharide monooxygenase identified through our pipeline as candidate proteins involved in colonization of the environment. Our findings suggest that similar protein signatures associate with S. borealis lifestyle and with secretion in the Sclerotiniaceae. These signatures may be useful for identifying proteins of interest as targets for the management of plant diseases. PMID- 26442086 TI - Identification and characterization of miRNAs in ripening fruit of Lycium barbarum L. using high-throughput sequencing. AB - MicroRNAs (miRNAs) are master regulators of gene activity documented to play central roles in fruit ripening in model plant species, yet little is known of their roles in Lycium barbarum L. fruits. In this study, miRNA levels in L. barbarum fruit samples at four developmental stages, were assayed using Illumina HiSeqTM2000. This revealed the presence of 50 novel miRNAs and 38 known miRNAs in L. barbarum fruits. Of the novel miRNAs, 36 were specific to L. barbarum fruits compared with L. chinense. A number of stage-specific miRNAs were identified and GO terms were assigned to 194 unigenes targeted by miRNAs. The majority of GO terms of unigenes targeted by differentially expressed miRNAs are "intracellular organelle," "binding," "metabolic process," "pigmentation," and "biological regulation." Enriched KEGG analysis indicated that nucleotide excision repair and ubiquitin mediated proteolysis were over-represented during the initial stage of ripening, with ABC transporters and sulfur metabolism pathways active during the middle stages and ABC transporters and spliceosome enriched in the final stages of ripening. Several miRNAs and their targets serving as potential regulators in L. barbarum fruit ripening were identified using quantitative reverse transcription polymerase chain reaction. The miRNA-target interactions were predicted for L. barbarum ripening regulators including miR156/157 with LbCNR and LbWRKY8, and miR171 with LbGRAS. Additionally, regulatory interactions potentially controlling fruit quality and nutritional value via sugar and secondary metabolite accumulation were identified. These include miR156 targeting of fructokinase and 1-deoxy-D-xylulose-5-phosphate synthase and miR164 targeting of beta-fructofuranosidase. In sum, valuable information revealed by small RNA sequencing in this study will provide a solid foundation for uncovering the miRNA mediated mechanism of fruit ripening and quality in this nutritional food. PMID- 26442087 TI - Influence of stripe rust infection on the photosynthetic characteristics and antioxidant system of susceptible and resistant wheat cultivars at the adult plant stage. AB - Wheat stripe rust (Puccinia striiformis f. sp. tritici, Pst), is one of the most serious diseases of wheat (Triticum aestivum L.) worldwide. To gain a better understanding of the protective mechanism against stripe rust at the adult plant stage, the differences in photosystem II and antioxidant enzymatic systems between susceptible and resistant wheat in response to stripe rust disease (P. striiformis) were investigated. We found that chlorophyll fluorescence and the activities of the antioxidant enzymes were higher in resistant wheat than in susceptible wheat after stripe rust infection. Compared with the susceptible wheat, the resistant wheat accumulated a higher level of D1 protein and a lower level of reactive oxygen species after infection. Furthermore, our results demonstrate that D1 and light-harvesting complex II (LHCII) phosphorylation are involved in the resistance to stripe rust in wheat. The CP29 protein was phosphorylated under stripe rust infection, like its phosphorylation in other monocots under environmental stresses. More extensive damages occur on the thylakoid membranes in the susceptible wheat compared with the resistant wheat. The findings provide evidence that thylakoid protein phosphorylation and antioxidant enzyme systems play important roles in plant responses and defense to biotic stress. PMID- 26442088 TI - Genome-wide identification and transcriptional expression analysis of mitogen activated protein kinase and mitogen-activated protein kinase kinase genes in Capsicum annuum. AB - The tripartite mitogen-activated protein kinase (MAPK) signaling cascades have been implicated in plant growth, development, and environment adaptation, but a comprehensive understanding of MAPK signaling at genome-wide level is limited in Capsicum annuum. Herein, genome-wide identification and transcriptional expression analysis of MAPK and MAPK kinase (MAPKK) were performed in pepper. A total of 19 pepper MAPK (CaMAPKs) genes and five MAPKK (CaMAPKKs) genes were identified. Phylogenetic analysis indicated that CaMAPKs and CaMAPKKs could be classified into four groups and each group contains similar exon-intron structures. However, significant divergences were also found. Notably, five members of the pepper MAPKK family were much less conserved than those found in Arabidopsis, and 9 Arabidopsis MAPKs did not have orthologs in pepper. Additionally, 7 MAPKs in Arabidopsis had either two or three orthologs in the pepper genome, and six pepper MAPKs and one MAPKK differing in sequence were found in three pepper varieties. Quantitative real-time RT-PCR analysis showed that the majority of MAPK and MAPKK genes were ubiquitously expressed and transcriptionally modified in pepper leaves after treatments with heat, salt, and Ralstonia solanacearum inoculation as well as exogenously applied salicylic acid, methyl jasmonate, ethephon, and abscisic acid. The MAPKK-MAPK interactome was tested by yeast two-hybrid assay, the results showed that one MAPKK might interact with multiple MAPKs, one MAPK might also interact with more than one MAPKKs, constituting MAPK signaling networks which may collaborate in transmitting upstream signals into appropriate downstream cellular responses and processes. These results will facilitate future functional characterization of MAPK cascades in pepper. PMID- 26442089 TI - Mitochondrial pleomorphy in plant cells is driven by contiguous ER dynamics. AB - Mitochondria are pleomorphic, double membrane-bound organelles involved in cellular energetics in all eukaryotes. Mitochondria in animal and yeast cells are typically tubular-reticulate structures and several micro-meters long but in green plants they are predominantly observed as 0.2-1.5 MUm punctae. While fission and fusion, through the coordinated activity of several conserved proteins, shapes mitochondria, the endoplasmic reticulum (ER) has recently been identified as an additional player in this process in yeast and mammalian cells. The mitochondria-ER relationship in plant cells remains largely uncharacterized. Here, through live-imaging of the entire range of mitochondria pleomorphy we uncover the underlying basis for the predominantly punctate mitochondrial form in plants. We demonstrate that mitochondrial morphology changes in response to light and cytosolic sugar levels in an ER mediated manner. Whereas, large ER polygons and low dynamics under dark conditions favor mitochondrial fusion and elongation, small ER polygons result in increased fission and predominantly small mitochondria. Hypoxia also reduces ER dynamics and increases mitochondrial fusion to produce giant mitochondria. By observing elongated mitochondria in normal plants and fission-impaired Arabidopsis nmt1-2 and drp3a mutants we also establish that thin extensions called matrixules and a beads-on-a-string mitochondrial phenotype are direct consequences of mitochondria-ER interactions. PMID- 26442090 TI - Mining the phytomicrobiome to understand how bacterial coinoculations enhance plant growth. AB - In previous work, we showed that coinoculating Rhizobium leguminosarum bv. viciae 128C53 and Bacillus simplex 30N-5 onto Pisum sativum L. roots resulted in better nodulation and increased plant growth. We now expand this research to include another alpha-rhizobial species as well as a beta-rhizobium, Burkholderia tuberum STM678. We first determined whether the rhizobia were compatible with B. simplex 30N-5 by cross-streaking experiments, and then Medicago truncatula and Melilotus alba were coinoculated with B. simplex 30N-5 and Sinorhizobium (Ensifer) meliloti to determine the effects on plant growth. Similarly, B. simplex 30N-5 and Bu. tuberum STM678 were coinoculated onto Macroptilium atropurpureum. The exact mechanisms whereby coinoculation results in increased plant growth are incompletely understood, but the synthesis of phytohormones and siderophores, the improved solubilization of inorganic nutrients, and the production of antimicrobial compounds are likely possibilities. Because B. simplex 30N-5 is not widely recognized as a Plant Growth Promoting Bacterial (PGPB) species, after sequencing its genome, we searched for genes proposed to promote plant growth, and then compared these sequences with those from several well studied PGPB species. In addition to genes involved in phytohormone synthesis, we detected genes important for the production of volatiles, polyamines, and antimicrobial peptides as well as genes for such plant growth-promoting traits as phosphate solubilization and siderophore production. Experimental evidence is presented to show that some of these traits, such as polyamine synthesis, are functional in B. simplex 30N-5, whereas others, e.g., auxin production, are not. PMID- 26442091 TI - Enhanced tomato disease resistance primed by arbuscular mycorrhizal fungus. AB - Roots of most terrestrial plants form symbiotic associations (mycorrhiza) with soil- borne arbuscular mycorrhizal fungi (AMF). Many studies show that mycorrhizal colonization enhances plant resistance against pathogenic fungi. However, the mechanism of mycorrhiza-induced disease resistance remains equivocal. In this study, we found that mycorrhizal inoculation with AMF Funneliformis mosseae significantly alleviated tomato (Solanum lycopersicum Mill.) early blight disease caused by Alternaria solani Sorauer. AMF pre inoculation led to significant increases in activities of beta-1,3-glucanase, chitinase, phenylalanine ammonia-lyase (PAL) and lipoxygenase (LOX) in tomato leaves upon pathogen inoculation. Mycorrhizal inoculation alone did not influence the transcripts of most genes tested. However, pathogen attack on AMF-inoculated plants provoked strong defense responses of three genes encoding pathogenesis related proteins, PR1, PR2, and PR3, as well as defense-related genes LOX, AOC, and PAL, in tomato leaves. The induction of defense responses in AMF pre inoculated plants was much higher and more rapid than that in un-inoculated plants in present of pathogen infection. Three tomato genotypes: a Castlemart wild-type (WT) plant, a jasmonate (JA) biosynthesis mutant (spr2), and a prosystemin-overexpressing 35S::PS plant were used to examine the role of the JA signaling pathway in AMF-primed disease defense. Pathogen infection on mycorrhizal 35S::PS plants led to higher induction of defense-related genes and enzymes relative to WT plants. However, pathogen infection did not induce these genes and enzymes in mycorrhizal spr2 mutant plants. Bioassays showed that 35S::PS plants were more resistant and spr2 plants were more susceptible to early blight compared with WT plants. Our finding indicates that mycorrhizal colonization enhances tomato resistance to early blight by priming systemic defense response, and the JA signaling pathway is essential for mycorrhiza-primed disease resistance. PMID- 26442092 TI - Recent advances in understanding carotenoid-derived signaling molecules in regulating plant growth and development. AB - Carotenoids (C40) are synthesized in plastids and perform numerous important functions in these organelles. In addition, carotenoids can be processed into smaller signaling molecules that regulate various phases of the plant's life cycle. Besides the relatively well-studied phytohormones abscisic acid (ABA) and strigolactones (SLs), additional carotenoid-derived signaling molecules have been discovered and shown to regulate plant growth and development. As a few excellent reviews summarized recent research on ABA and SLs, this mini review will focus on progress made on identification and characterization of the emerging carotenoid derived signals. Overall, a better understanding of carotenoid-derived signaling molecules has immediate applications in improving plant biomass production which in turn will have far reaching impacts on providing food, feed, and fuel for the growing world population. PMID- 26442094 TI - How spatio-temporal habitat connectivity affects amphibian genetic structure. AB - Heterogeneous landscapes and fluctuating environmental conditions can affect species dispersal, population genetics, and genetic structure, yet understanding how biotic and abiotic factors affect population dynamics in a fluctuating environment is critical for species management. We evaluated how spatio-temporal habitat connectivity influences dispersal and genetic structure in a population of boreal chorus frogs (Pseudacris maculata) using a landscape genetics approach. We developed gravity models to assess the contribution of various factors to the observed genetic distance as a measure of functional connectivity. We selected (a) wetland (within-site) and (b) landscape matrix (between-site) characteristics; and (c) wetland connectivity metrics using a unique methodology. Specifically, we developed three networks that quantify wetland connectivity based on: (i) P. maculata dispersal ability, (ii) temporal variation in wetland quality, and (iii) contribution of wetland stepping-stones to frog dispersal. We examined 18 wetlands in Colorado, and quantified 12 microsatellite loci from 322 individual frogs. We found that genetic connectivity was related to topographic complexity, within- and between-wetland differences in moisture, and wetland functional connectivity as contributed by stepping-stone wetlands. Our results highlight the role that dynamic environmental factors have on dispersal-limited species and illustrate how complex asynchronous interactions contribute to the structure of spatially-explicit metapopulations. PMID- 26442093 TI - Cyclic electron flow provides acclimatory plasticity for the photosynthetic machinery under various environmental conditions and developmental stages. AB - Photosynthetic electron flow operates in two modes, linear and cyclic. In cyclic electron flow (CEF), electrons are recycled around photosystem I. As a result, a transthylakoid proton gradient (DeltapH) is generated, leading to the production of ATP without concomitant production of NADPH, thus increasing the ATP/NADPH ratio within the chloroplast. At least two routes for CEF exist: a PROTON GRADIENT REGULATION5-PGRL1-and a chloroplast NDH-like complex mediated pathway. This review focuses on recent findings concerning the characteristics of both CEF routes in higher plants, with special emphasis paid on the crucial role of CEF in under challenging environmental conditions and developmental stages. PMID- 26442095 TI - An introductory review of parallel independent component analysis (p-ICA) and a guide to applying p-ICA to genetic data and imaging phenotypes to identify disease-associated biological pathways and systems in common complex disorders. AB - Complex inherited phenotypes, including those for many common medical and psychiatric diseases, are most likely underpinned by multiple genes contributing to interlocking molecular biological processes, along with environmental factors (Owen et al., 2010). Despite this, genotyping strategies for complex, inherited, disease-related phenotypes mostly employ univariate analyses, e.g., genome wide association. Such procedures most often identify isolated risk-related SNPs or loci, not the underlying biological pathways necessary to help guide the development of novel treatment approaches. This article focuses on the multivariate analysis strategy of parallel (i.e., simultaneous combination of SNP and neuroimage information) independent component analysis (p-ICA), which typically yields large clusters of functionally related SNPs statistically correlated with phenotype components, whose overall molecular biologic relevance is inferred subsequently using annotation software suites. Because this is a novel approach, whose details are relatively new to the field we summarize its underlying principles and address conceptual questions regarding interpretation of resulting data and provide practical illustrations of the method. PMID- 26442096 TI - Evolution of TERT-interacting lncRNAs: expanding the regulatory landscape of telomerase. AB - Long non-coding RNAs (lncRNAs) evolve rapidly and are functionally diverse. The emergence of new lncRNAs is driven by genome disturbance events, including whole genome duplication, and transposition. One of the few lncRNAs with a conserved role throughout eukaryotes is the telomerase RNA, TER. TER works in concert with the telomerase reverse transcriptase (TERT) to maintain telomeres. Here we discuss recent findings from Arabidopsis thaliana and its relatives illustrating the remarkable evolutionary flexibility within TER and the potential for non canonical TERT-lncRNA interactions. We highlight the two TERs in A. thaliana. One is a conventional telomerase template. The other lncRNA negatively regulates telomerase activity in response to DNA damage, a function mediated by co-option of a transposable element. In addition, we discuss evidence for multiple independent TER loci throughout the plant family Brassicaceae, and how these loci not only reflect rapid convergent evolution, but also the flexibility of having a lncRNA at the core of telomerase. Lastly, we discuss the propensity for TERT to bind a suite of non-templating lncRNAs, and how such RNAs may facilitate telomerase regulation and off-telomere functions. PMID- 26442098 TI - Changing values of farm animal genomic resources. from historical breeds to the Nagoya Protocol. AB - The paper reviews the history of Animal genetic resources (AnGRs) and claims that over the course of history they have been conceptually transformed from economic, ecologic and scientific life forms into political objects, reflecting in the way in which any valuation of AnGRs is today inherently imbued with national politics and its values enacted by legally binding global conventions. Historically, the first calls to conservation were based on the economic, ecological and scientific values of the AnGR. While the historical arguments are valid and still commonly proposed values for conservation, the AnGR have become highly politicized since the adoption of the Convention of Biological Diversity (CBD), the subsequent Interlaken Declaration, the Global Plan for Action (GPA) and the Nagoya Protocol. The scientific and political definitions of the AnGRs were creatively reshuffled within these documents and the key criteria by which they are now identified and valued today were essentially redefined. The criteria of "in situ condition" has become the necessary starting point for all valuation efforts of AnGRs, effectively transforming their previous nature as natural property and global genetic commons into objects of national concern pertaining to territorially discrete national genetic landscapes, regulated by the sovereign powers of the parties to the global conventions. PMID- 26442097 TI - Polymorphisms in Toll-like receptor genes are associated with vitiligo. AB - BACKGROUND: The members of Toll-like receptor (TLR) family are responsible for recognizing various molecular patterns associated with pathogens. Their expression is not confined to immune cells and have been detected in skin cells such as keratinocytes and melanocytes. As part of a generated response to pathogens, TLRs are involved in inducing inflammatory mediators to combat these threats. It is therefore not surprising that TLRs have been implicated in inflammatory skin diseases, including atopic dermatitis and psoriasis. Likewise, as key players in autoimmunity, they have been associated with a number of autoimmune diseases. Based on this, the role of TLRs in vitiligo could be suspected, but is yet to be clearly established. METHODS: In order to conduct a genetic association analysis, 30 SNPs were selected from TLR1-TLR8 and TLR10 regions to be genotyped in Estonian case-control cohort consisting of 139 vitiligo patients and 307 healthy control individuals. The patients were further analyzed in subgroups based on sex, age of onset, occurrence of vitiligo among relatives, extent of depigmented areas, vitiligo progression activity, appearance of Kobner's phenomenon, existence of halo naevi, and incidence of spontaneous repigmentation. RESULTS: The most notable finding came with SNP rs179020 situated in TLR7 gene, that was associated in entire vitiligo (Padj = 0.0065) and also several subgroup analyses. Other single marker and haplotype analyses pointed to TLR3, TLR4, and TLR10 genes. CONCLUSIONS: This study investigated the genetic regions of nine TLR genes in relation to vitiligo susceptibility. The main results were the associations of TLR7 SNPs with vitiligo, while several other associations were obtained from the remaining TLR gene regions. This suggests that in addition to other inflammatory skin diseases, TLRs affect the development of vitiligo, thus making them interesting targets for future research. PMID- 26442099 TI - Aging and chronic administration of serotonin-selective reuptake inhibitor citalopram upregulate Sirt4 gene expression in the preoptic area of male mice. AB - Sexual dysfunction and cognitive deficits are markers of the aging process. Mammalian sirtuins (SIRT), encoded by sirt 1-7 genes, are known as aging molecules which are sensitive to serotonin (5-hydroxytryptamine, 5-HT). Whether the 5-HT system regulates SIRT in the preoptic area (POA), which could affect reproduction and cognition has not been examined. Therefore, this study was designed to examine the effects of citalopram (CIT, 10 mg/kg for 4 weeks), a potent selective-serotonin reuptake inhibitor and aging on SIRT expression in the POA of male mice using real-time PCR and immunocytochemistry. Age-related increases of sirt1, sirt4, sirt5, and sirt7 mRNA levels were observed in the POA of 52 weeks old mice. Furthermore, 4 weeks of chronic CIT treatment started at 8 weeks of age also increased sirt2 and sirt4 mRNA expression in the POA. Moreover, the number of SIRT4 immuno-reactive neurons increased with aging in the medial septum area (12 weeks = 1.00 +/- 0.15 vs. 36 weeks = 1.68 +/- 0.14 vs. 52 weeks = 1.54 +/- 0.11, p < 0.05). In contrast, the number of sirt4-immunopositive cells did not show a statistically significant change with CIT treatment, suggesting that the increase in sirt4 mRNA levels may occur in cells in which sirt4 is already being expressed. Taken together, these studies suggest that CIT treatment and the process of aging utilize the serotonergic system to up-regulate SIRT4 in the POA as a common pathway to deregulate social cognitive and reproductive functions. PMID- 26442101 TI - Molecular footprinting of skeletal tissues in the catshark Scyliorhinus canicula and the clawed frog Xenopus tropicalis identifies conserved and derived features of vertebrate calcification. AB - Understanding the evolutionary emergence and subsequent diversification of the vertebrate skeleton requires a comprehensive view of the diverse skeletal cell types found in distinct developmental contexts, tissues, and species. To date, our knowledge of the molecular nature of the shark calcified extracellular matrix, and its relationships with osteichthyan skeletal tissues, remain scarce. Here, based on specific combinations of expression patterns of the Col1a1, Col1a2, and Col2a1 fibrillar collagen genes, we compare the molecular footprint of endoskeletal elements from the chondrichthyan Scyliorhinus canicula and the tetrapod Xenopus tropicalis. We find that, depending on the anatomical location, Scyliorhinus skeletal calcification is associated to cell types expressing different subsets of fibrillar collagen genes, such as high levels of Col1a1 and Col1a2 in the neural arches, high levels of Col2a1 in the tesserae, or associated to a drastic Col2a1 downregulation in the centrum. We detect low Col2a1 levels in Xenopus osteoblasts, thereby revealing that the osteoblastic expression of this gene was significantly reduced in the tetrapod lineage. Finally, we uncover a striking parallel, from a molecular and histological perspective, between the vertebral cartilage calcification of both species and discuss the evolutionary origin of endochondral ossification. PMID- 26442100 TI - Fine-tuning the ubiquitin code at DNA double-strand breaks: deubiquitinating enzymes at work. AB - Ubiquitination is a reversible protein modification broadly implicated in cellular functions. Signaling processes mediated by ubiquitin (ub) are crucial for the cellular response to DNA double-strand breaks (DSBs), one of the most dangerous types of DNA lesions. In particular, the DSB response critically relies on active ubiquitination by the RNF8 and RNF168 ub ligases at the chromatin, which is essential for proper DSB signaling and repair. How this pathway is fine tuned and what the functional consequences are of its deregulation for genome integrity and tissue homeostasis are subject of intense investigation. One important regulatory mechanism is by reversal of substrate ubiquitination through the activity of specific deubiquitinating enzymes (DUBs), as supported by the implication of a growing number of DUBs in DNA damage response processes. Here, we discuss the current knowledge of how ub-mediated signaling at DSBs is controlled by DUBs, with main focus on DUBs targeting histone H2A and on their recent implication in stem cell biology and cancer. PMID- 26442102 TI - From limbs to leaves: common themes in evolutionary diversification of organ form. AB - An open problem in biology is to derive general principles that capture how morphogenesis evolved to generate diverse forms in different organisms. Here we discuss recent work investigating the morphogenetic basis for digit loss in vertebrate limbs and variation in form of marginal outgrowths of angiosperm (flowering plant) leaves. Two pathways underlie digit loss in vertebrate limbs. First, alterations to digit patterning arise through modification of expression of the Patched 1 receptor, which senses the Sonic Hedgehog morphogen and limits its mobility in the limb bud. Second, evolutionary changes to the degree of programmed cell death between digits influence their development after their initiation. Similarly, evolutionary modification of leaf margin outgrowths occurs via two broad pathways. First, species-specific transcription factor expression modulates outgrowth patterning dependent on regulated transport of the hormone auxin. Second, species-specific expression of the newly discovered REDUCED COMPLEXITY homeodomain transcription factor influences growth between individual outgrowths after their initiation. These findings demonstrate that in both plants and animals tinkering with either patterning or post-patterning processes can cause morphological change. They also highlight the considerable flexibility of morphological evolution and indicate that it may be possible to derive broad principles that capture how morphogenesis evolved across complex eukaryotes. PMID- 26442103 TI - A survey about methods dedicated to epistasis detection. AB - During the past decade, findings of genome-wide association studies (GWAS) improved our knowledge and understanding of disease genetics. To date, thousands of SNPs have been associated with diseases and other complex traits. Statistical analysis typically looks for association between a phenotype and a SNP taken individually via single-locus tests. However, geneticists admit this is an oversimplified approach to tackle the complexity of underlying biological mechanisms. Interaction between SNPs, namely epistasis, must be considered. Unfortunately, epistasis detection gives rise to analytic challenges since analyzing every SNP combination is at present impractical at a genome-wide scale. In this review, we will present the main strategies recently proposed to detect epistatic interactions, along with their operating principle. Some of these methods are exhaustive, such as multifactor dimensionality reduction, likelihood ratio-based tests or receiver operating characteristic curve analysis; some are non-exhaustive, such as machine learning techniques (random forests, Bayesian networks) or combinatorial optimization approaches (ant colony optimization, computational evolution system). PMID- 26442104 TI - Establishing the pig as a large animal model for vaccine development against human cancer. AB - Immunotherapy has increased overall survival of metastatic cancer patients, and cancer antigens are promising vaccine targets. To fulfill the promise, appropriate tailoring of the vaccine formulations to mount in vivo cytotoxic T cell (CTL) responses toward co-delivered cancer antigens is essential. Previous development of therapeutic cancer vaccines has largely been based on studies in mice, and the majority of these candidate vaccines failed to induce therapeutic responses in the subsequent human clinical trials. Given that antigen dose and vaccine volume in pigs are translatable to humans and the porcine immunome is closer related to the human counterpart, we here introduce pigs as a supplementary large animal model for human cancer vaccine development. IDO and RhoC, both important in human cancer development and progression, were used as vaccine targets and 12 pigs were immunized with overlapping 20mer peptides spanning the entire porcine IDO and RhoC sequences formulated in CTL-inducing adjuvants: CAF09, CASAC, Montanide ISA 51 VG, or PBS. Taking advantage of recombinant swine MHC class I molecules (SLAs), the peptide-SLA complex stability was measured for 198 IDO- or RhoC-derived 9-11mer peptides predicted to bind to SLA-1(*)04:01, -1(*)07:02, -2(*)04:01, -2(*)05:02, and/or -3(*)04:01. This identified 89 stable (t1/2 >= 0.5 h) peptide-SLA complexes. By IFN-gamma release in PBMC cultures we monitored the vaccine-induced peptide-specific CTL responses, and found responses to both IDO- and RhoC-derived peptides across all groups with no adjuvant being superior. These findings support the further use of pigs as a large animal model for vaccine development against human cancer. PMID- 26442105 TI - Design, measurement and processing of region-specific DNA methylation assays: the mass spectrometry-based method EpiTYPER. AB - EpiTYPER(r) is a mass spectrometry-based bisulfite sequencing method that enables region-specific DNA methylation analysis in a quantitative and high-throughput fashion. The technology targets genomic regions of 100-600 base pairs and results in the quantitative measurement of DNA methylation levels largely at single nucleotide resolution. It is particularly suitable for larger scale efforts to study candidate regions or to validate regions from genome-wide DNA methylation studies. Here, we describe in detail how to design and perform EpiTYPER measurements and preprocess the data, providing details for high quality measurements not provided in the standard EpiTYPER protocol. PMID- 26442107 TI - Quo vadis computational analysis of PPI data or why the future isn't here yet. PMID- 26442106 TI - Exome sequencing of a colorectal cancer family reveals shared mutation pattern and predisposition circuitry along tumor pathways. AB - The molecular basis of cancer and cancer multiple phenotypes are not yet fully understood. Next Generation Sequencing promises new insight into the role of genetic interactions in shaping the complexity of cancer. Aiming to outline the differences in mutation patterns between familial colorectal cancer cases and controls we analyzed whole exomes of cancer tissues and control samples from an extended colorectal cancer pedigree, providing one of the first data sets of exome sequencing of cancer in an African population against a background of large effective size typically with excess of variants. Tumors showed hMSH2 loss of function SNV consistent with Lynch syndrome. Sets of genes harboring insertions deletions in tumor tissues revealed, however, significant GO enrichment, a feature that was not seen in control samples, suggesting that ordered insertions deletions are central to tumorigenesis in this type of cancer. Network analysis identified multiple hub genes of centrality. ELAVL1/HuR showed remarkable centrality, interacting specially with genes harboring non-synonymous SNVs thus reinforcing the proposition of targeted mutagenesis in cancer pathways. A likely explanation to such mutation pattern is DNA/RNA editing, suggested here by nucleotide transition-to-transversion ratio that significantly departed from expected values (p-value 5e-6). NFKB1 also showed significant centrality along with ELAVL1, raising the suspicion of viral etiology given the known interaction between oncogenic viruses and these proteins. PMID- 26442108 TI - Normal vs. Malignant hematopoiesis: the complexity of acute leukemia through systems biology. PMID- 26442109 TI - Efficacy of the porcine species in biomedical research. AB - Since domestication, pigs have been used extensively in agriculture and kept as companion animals. More recently they have been used in biomedical research, given they share many physiological and anatomical similarities with humans. Recent technological advances in assisted reproduction, somatic cell cloning, stem cell culture, genome editing, and transgenesis now enable the creation of unique porcine models of human diseases. Here, we highlight the potential applications and advantages of using pigs, particularly minipigs, as indispensable large animal models in fundamental and clinical research, including the development of therapeutics for inherited and chronic disorders, and cancers. PMID- 26442111 TI - Corrigendum: Historical factors that have shaped the evolution of tropical reef fishes: a review of phylogenies, biogeography, and remaining questions. AB - [This corrects the article on p. 394 in vol. 5, PMID: 25431581.]. PMID- 26442110 TI - Selection and validation of potato candidate genes for maturity corrected resistance to Phytophthora infestans based on differential expression combined with SNP association and linkage mapping. AB - Late blight of potato (Solanum tuberosum L.) caused by the oomycete Phytophthora infestans (Mont.) de Bary, is one of the most important bottlenecks of potato production worldwide. Cultivars with high levels of durable, race unspecific, quantitative resistance are part of a solution to this problem. However, breeding for quantitative resistance is hampered by the correlation between resistance and late plant maturity, which is an undesirable agricultural attribute. The objectives of our research are (i) the identification of genes that condition quantitative resistance to P. infestans not compromised by late plant maturity and (ii) the discovery of diagnostic single nucleotide polymorphism (SNP) markers to be used as molecular tools to increase efficiency and precision of resistance breeding. Twenty two novel candidate genes were selected based on comparative transcript profiling by SuperSAGE (serial analysis of gene expression) in groups of plants with contrasting levels of maturity corrected resistance (MCR). Reproducibility of differential expression was tested by quantitative real time PCR and allele specific pyrosequencing in four new sets of genotype pools with contrasting late blight resistance levels, at three infection time points and in three independent infection experiments. Reproducibility of expression patterns ranged from 28 to 97%. Association mapping in a panel of 184 tetraploid cultivars identified SNPs in five candidate genes that were associated with MCR. These SNPs can be used in marker-assisted resistance breeding. Linkage mapping in two half sib families (n = 111) identified SNPs in three candidate genes that were linked with MCR. The differentially expressed genes that showed association and/or linkage with MCR putatively function in phytosterol synthesis, fatty acid synthesis, asparagine synthesis, chlorophyll synthesis, cell wall modification, and in the response to pathogen elicitors. PMID- 26442112 TI - Mining protein interactomes to improve their reliability and support the advancement of network medicine. AB - High-throughput detection of protein interactions has had a major impact in our understanding of the intricate molecular machinery underlying the living cell, and has permitted the construction of very large protein interactomes. The protein networks that are currently available are incomplete and a significant percentage of their interactions are false positives. Fortunately, the structural properties observed in good quality social or technological networks are also present in biological systems. This has encouraged the development of tools, to improve the reliability of protein networks and predict new interactions based merely on the topological characteristics of their components. Since diseases are rarely caused by the malfunction of a single protein, having a more complete and reliable interactome is crucial in order to identify groups of inter-related proteins involved in disease etiology. These system components can then be targeted with minimal collateral damage. In this article, an important number of network mining tools is reviewed, together with resources from which reliable protein interactomes can be constructed. In addition to the review, a few representative examples of how molecular and clinical data can be integrated to deepen our understanding of pathogenesis are discussed. PMID- 26442114 TI - Identification of single nucleotide polymorphism markers associated with bacterial cold water disease resistance and spleen size in rainbow trout. AB - Bacterial cold water disease (BCWD) is one of the frequent causes of elevated mortality in salmonid aquaculture. Previously, we identified and validated microsatellites on chromosome Omy19 associated with QTL (quantitative trait loci) for BCWD resistance and spleen size in rainbow trout. Recently, SNPs (single nucleotide polymorphism) have become the markers of choice for genetic analyses in rainbow trout as they are highly abundant, cost-effective and are amenable for high throughput genotyping. The objective of this study was to identify SNP markers associated with BCWD resistance and spleen size using both genome-wide association studies (GWAS) and linkage-based QTL mapping approaches. A total of 298 offspring from the two half-sib families used in our previous study to validate the significant BCWD QTL on chromosome Omy19 were genotyped with RAD-seq (restriction-site-associated DNA sequencing), and 7,849 informative SNPs were identified. Based on GWAS, 18 SNPs associated with BCWD resistance and 20 SNPs associated with spleen size were identified. Linkage-based QTL mapping revealed three significant QTL for BCWD resistance. In addition to the previously validated dam-derived QTL on chromosome Omy19, two significant BCWD QTL derived from the sires were identified on chromosomes Omy8 and Omy25, respectively. A sire-derived significant QTL for spleen size on chromosome Omy2 was detected. The SNP markers reported in this study will facilitate fine mapping to identify positional candidate genes for BCWD resistance in rainbow trout. PMID- 26442113 TI - On the evolutionary relationship between chondrocytes and osteoblasts. AB - Vertebrates are the only animals that produce bone, but the molecular genetic basis for this evolutionary novelty remains obscure. Here, we synthesize information from traditional evolutionary and modern molecular genetic studies in order to generate a working hypothesis on the evolution of the gene regulatory network (GRN) underlying bone formation. Since transcription factors are often core components of GRNs (i.e., kernels), we focus our analyses on Sox9 and Runx2. Our argument centers on three skeletal tissues that comprise the majority of the vertebrate skeleton: immature cartilage, mature cartilage, and bone. Immature cartilage is produced during early stages of cartilage differentiation and can persist into adulthood, whereas mature cartilage undergoes additional stages of differentiation, including hypertrophy and mineralization. Functionally, histologically, and embryologically, these three skeletal tissues are very similar, yet unique, suggesting that one might have evolved from another. Traditional studies of the fossil record, comparative anatomy and embryology demonstrate clearly that immature cartilage evolved before mature cartilage or bone. Modern molecular approaches show that the GRNs regulating differentiation of these three skeletal cell fates are similar, yet unique, just like the functional and histological features of the tissues themselves. Intriguingly, the Sox9 GRN driving cartilage formation appears to be dominant to the Runx2 GRN of bone. Emphasizing an embryological and evolutionary transcriptomic view, we hypothesize that the Runx2 GRN underlying bone formation was co-opted from mature cartilage. We discuss how modern molecular genetic experiments, such as comparative transcriptomics, can test this hypothesis directly, meanwhile permitting levels of constraint and adaptation to be evaluated quantitatively. Therefore, comparative transcriptomics may revolutionize understanding of not only the clade-specific evolution of skeletal cells, but also the generation of evolutionary novelties, providing a modern paradigm for the evolutionary process. PMID- 26442115 TI - A new age in functional genomics using CRISPR/Cas9 in arrayed library screening. AB - CRISPR technology has rapidly changed the face of biological research, such that precise genome editing has now become routine for many labs within several years of its initial development. What makes CRISPR/Cas9 so revolutionary is the ability to target a protein (Cas9) to an exact genomic locus, through designing a specific short complementary nucleotide sequence, that together with a common scaffold sequence, constitute the guide RNA bridging the protein and the DNA. Wild-type Cas9 cleaves both DNA strands at its target sequence, but this protein can also be modified to exert many other functions. For instance, by attaching an activation domain to catalytically inactive Cas9 and targeting a promoter region, it is possible to stimulate the expression of a specific endogenous gene. In principle, any genomic region can be targeted, and recent efforts have successfully generated pooled guide RNA libraries for coding and regulatory regions of human, mouse and Drosophila genomes with high coverage, thus facilitating functional phenotypic screening. In this review, we will highlight recent developments in the area of CRISPR-based functional genomics and discuss potential future directions, with a special focus on mammalian cell systems and arrayed library screening. PMID- 26442117 TI - Past, present, and future of epigenetics applied to livestock breeding. AB - This article reviews the concept of Lamarckian inheritance and the use of the term epigenetics in the field of animal genetics. Epigenetics was first coined by Conrad Hal Waddington (1905-1975), who derived the term from the Aristotelian word epigenesis. There exists some controversy around the word epigenetics and its broad definition. It includes any modification of the expression of genes due to factors other than mutation in the DNA sequence. This involves DNA methylation, post-translational modification of histones, but also linked to regulation of gene expression by non-coding RNAs, genome instabilities or any other force that could modify a phenotype. There is little evidence of the existence of transgenerational epigenetic inheritance in mammals, which may commonly be confounded with environmental forces acting simultaneously on an individual, her developing fetus and the germ cell lines of the latter, although it could have an important role in the cellular energetic status of cells. Finally, we review some of the scarce literature on the use of epigenetics in animal breeding programs. PMID- 26442116 TI - Epigenetic marks: regulators of livestock phenotypes and conceivable sources of missing variation in livestock improvement programs. AB - Improvement in animal productivity has been achieved over the years through careful breeding and selection programs. Today, variations in the genome are gaining increasing importance in livestock improvement strategies. Genomic information alone, however, explains only a part of the phenotypic variance in traits. It is likely that a portion of the unaccounted variance is embedded in the epigenome. The epigenome encompasses epigenetic marks such as DNA methylation, histone tail modifications, chromatin remodeling, and other molecules that can transmit epigenetic information such as non-coding RNA species. Epigenetic factors respond to external or internal environmental cues such as nutrition, pathogens, and climate, and have the ability to change gene expression leading to emergence of specific phenotypes. Accumulating evidence shows that epigenetic marks influence gene expression and phenotypic outcome in livestock species. This review examines available evidence of the influence of epigenetic marks on livestock (cattle, sheep, goat, and pig) traits and discusses the potential for consideration of epigenetic markers in livestock improvement programs. However, epigenetic research activities on farm animal species are currently limited partly due to lack of recognition, funding and a global network of researchers. Therefore, considerable less attention has been given to epigenetic research in livestock species in comparison to extensive work in humans and model organisms. Elucidating therefore the epigenetic determinants of animal diseases and complex traits may represent one of the principal challenges to use epigenetic markers for further improvement of animal productivity. PMID- 26442118 TI - A Comparative Study Examining the Management of Bowen's Disease in the United Kingdom and Australia. AB - Background and Aim. The optimum management of Bowen's Disease (BD) is undefined. A review of current practice is required to allow the development of best practice guidelines. Methods. All BD cases, diagnosed in one UK centre and one Australian centre over a year (1 July 2012-30 June 2013), were analysed retrospectively. Patients with BD were identified from histopathology reports and their medical records were analysed to collect demographic data, site of lesion, and treatment used. Results. The treatment of 155 lesions from the UK centre and 151 lesions from the Australian centre was analysed. At both centres BD was most frequently observed on the face: UK had 70 (45%) lesions and Australia had 83 (55%) lesions (P = 0.08). The greatest number of lesions was managed by the plastic surgery department in the UK centre, 72 (46%), and the dermatology department in the Australian centre, 121 (80%). The most common therapy was surgical excision at both centres. Conclusions. In both UK and Australia, BD arises on sun-exposed sites and was most commonly treated with surgical excision despite a lack of robust evidence-based guidelines. PMID- 26442120 TI - The Age-Specific Association of Waist Circumference and Risk of Chronic Kidney Disease in Patients with Type 2 Diabetes Mellitus in Shandong, China. AB - Objective. To examine the association of three most common obesity measures including body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) with chronic kidney disease (CKD) risk in patients with type 2 diabetes mellitus (T2D). Design. Cross-sectional evaluation of the effect of anthropometric measures on CKD risk. Setting. Outpatient Department. Subjects. T2D patients who were treated between October 2012 and May 2013. Intervention. None. Main Outcome Measure. CKD risk. Results. On average, the patients had a mean age of 60.2 years, and 40% were males. CKD was present in 46% of all the patients. In multivariate logistic regression using the imputed data, higher WC was associated with greater odds of CKD (OR = 1.019, 95% CI = 1.002-1.006, P = 0.030), but not BMI and WHR. Interestingly, we found that patients with very small WC seemed to have greater odds of CKD. We observed age-specific effect of WC such that the effect of WC on CKD risk is significant only in middle-aged T2D patients. Conclusion. Our study provides evidence for the association of WC with CKD in Chinese patients with T2D. T2D patients, especially middle-aged T2D patients, should reduce their WC to decrease CKD risk. PMID- 26442119 TI - Therapeutic Potential of Dietary Phenolic Acids. AB - Although modern lifestyle has eased the quality of human life, this lifestyle's related patterns have imparted negative effects on health to acquire multiple diseases. Many synthetic drugs are invented during the last millennium but most if not all of them possess several side effects and proved to be costly. Convincing evidences have established the premise that the phytotherapeutic potential of natural compounds and need of search for novel drugs from natural sources are of high priority. Phenolic acids (PAs) are a class of secondary metabolites spread throughout the plant kingdom and generally involved in plethora of cellular processes involved in plant growth and reproduction and also produced as defense mechanism to sustain various environmental stresses. Extensive research on PAs strongly suggests that consumption of these compounds hold promise to offer protection against various ailments in humans. This paper focuses on the naturally derived PAs and summarizes the action mechanisms of these compounds during disease conditions. Based on the available information in the literature, it is suggested that use of PAs as drugs is very promising; however more research and clinical trials are necessary before these bioactive molecules can be made for treatment. Finally this review provides greater awareness of the promise that natural PAs hold for use in the disease prevention and therapy. PMID- 26442121 TI - The Intervention Effects of Acupuncture on Fatigue Induced by Exhaustive Physical Exercises: A Metabolomics Investigation. AB - In this study, the antifatigue effects of acupuncture had been investigated at the metabolic level on the young male athletes with exhaustive physical exercises. After a series of exhaustive physical exercises and a short-term rest, the athletes either were treated with needling acupuncture on selected acupoints (TA group) or enjoyed an extended rest (TR group). NMR-based metabolomics analysis was then applied to depict the metabolic profiles of urine samples, which were collected from the athletes at three time points including the time before exercises, the time before and after the treatment of acupuncture, or taking the extended rest. The results from multivariate statistical analysis indicated that the recoveries of disturbed metabolites in the athletes treated with acupuncture were significantly faster than in those only taking rest. After the treatment with acupuncture, the levels of distinguished metabolites, 2 hydroxybutyrate, 3-hydroxyisovalerate, lactate, pyruvate, citrate, dimethylglycine, choline, glycine, hippurate, and hypoxanthine were recovered at an accelerated speed in the TA group in comparison with the TR group. The above mentioned results indicated that the acupuncture treatment ameliorated fatigue by backregulating the perturbed energy metabolism, choline metabolism, and attenuating the ROS-induced stress at an accelerated speed, which demonstrated that acupuncture could serve as an alternative fatigue-relieving approach. PMID- 26442122 TI - The Effect of Monochromatic Infrared Photo Energy on the Irritability of Myofascial Trigger Spot of Rabbit Skeletal Muscle. AB - Objective. To determine whether the vasodilatation effect of monochromatic infrared photo energy (MIRE) had the potential for the treatment of myofascial trigger spot (MTrS) in rabbits. Design. A randomized-controlled animal study. Subjects. Twelve adult New Zealand rabbits. Methods. For each rabbit, a MTrS (equivalent to a myofascial trigger point in humans) in one side of the biceps femoris muscle was randomly selected for MIRE treatment (experimental side), while another MTrS in the other side (control side) received a sham treatment. The intervention consisted of a daily 40 minutes treatment, three times per week for 2 weeks. The prevalence of endplate noise (EPN) loci in the MTrS was assessed before, immediately after, and one week after the completion of the 2-week treatment. Results. MIRE could suppress the prevalence of EPN in the MTrS. The degree of reduction in EPN prevalence in the MTrS between the experimental side and the control side was significantly different immediately after MIRE treatment, but not significantly different one week after MIRE treatment. Conclusion. Our study suggests that MIRE may be a useful therapeutic option for the management of the myofascial trigger point in humans. PMID- 26442124 TI - Use of Tranexamic Acid (TXA) on reducing blood loss during scoliosis surgery in Chinese adolescents. AB - BACKGROUND: Many reports had been received on the application of antifibrinolytic medications on spinal corrective surgery and the surgical outcome evaluations of its efficacy on reducing blood loss. This study aimed to assess the efficacy of tranexamic acid (TXA) in reducing operative blood loss during posterior spinal fusion for the treatment of severe adolescent idiopathic scoliosis (AIS). METHODS: A retrospective cohort study was carried out on 90 (TXA = 55, Control = 35) AIS girls undergoing posterior spinal surgery. Patients in TXA group used TXA as an antifibrinolytic agent to reduce blood loss, while control group did not. Blood loss, haemoglobin change and amount of blood transfused was estimated from intraoperative measurement by anaesthesiologists. Demographics were compared using Student's T-test or Chi-square test where appropriate. Linear regression modelling was carried out between the use of TXA and total blood loss with controlling of confounding factors. RESULTS: Mean age and mean maximum major curve were 15.2 and 73 degrees , and 15.3 and 63 degrees in TXA and control groups respectively. TXA group showed significantly less intra-operative blood loss than the control group from intraoperative measurement (1.8 L vs. 3.9 L, p < 0.01) and volume of cell saver blood transfused back to patients (0.6 L vs. 1.7 L, p < 0.01). TXA group also showed significantly shorter total time taken for surgery (437 min vs. 502 min, p < 0.01), and total blood loss per surgical segment level (0.1 L vs. 0.3 L, p < 0.01). Regression models showed that the use of TXA decreased total blood loss by 794.3 ml after adjusting for maximum major curve, age, number of segments fused, bone graft, clotting capability, and infusion of coagulation factors. CONCLUSIONS: Patients undergoing posterior spinal corrective surgery with the use of TXA showed much reduced total blood loss, reduced use of transfused blood, much less cell saver blood transfused back to the patient. The total blood loss was decreased by after using TXA after controlling for maximum major curve, age, surgical parameters, clotting capability, and infusion of coagulation factors. PMID- 26442125 TI - Role of Microstructure in the Electron-Hole Interaction of Hybrid Lead-Halide Perovskites. AB - Solar cells based on hybrid inorganic-organic halide perovskites have demonstrated high power conversion efficiencies in a range of architectures. The existence and stability of bound electron-hole pairs in these materials, and their role in the exceptional performance of optoelectronic devices, remains a controversial issue. Here we demonstrate, through a combination of optical spectroscopy and multiscale modeling as a function of the degree of polycrystallinity and temperature, that the electron-hole interaction is sensitive to the microstructure of the material. The long-range order is disrupted by polycrystalline disorder and the variations in electrostatic potential found for smaller crystals suppress exciton formation, while larger crystals of the same composition demonstrate an unambiguous excitonic state. We conclude that fabrication procedures and morphology strongly influence perovskite behaviour, with both free carrier and excitonic regimes possible, with strong implications for optoelectronic devices. PMID- 26442123 TI - Optimizing Weight for Maternal and Infant Health - Tenable, or Too Late? AB - Obesity in pregnancy is the leading cause of maternal and fetal morbidity, and gestational weight gain (GWG) is one modifiable risk factor that improves pregnancy outcomes. Most pregnant women gain more than the 2009 Institute of Medicine recommendations, particularly overweight and obese women. GWG even less than the 2009 IOM guidelines in obese women may improve pregnancy outcomes and reduce large-for-gestational-age (LGA) infants, an independent risk factor for childhood obesity, without increasing small-for-gestational-age (SGA) infants. Unfortunately, despite the fact that over 50 interventional trials designed to decrease excess GWG have been conducted, these interventions have been only modestly effective, and interventions designed to facilitate weight postpartum weight loss have also been disappointing. Successful interventions are of paramount importance not only to improve pregnancy outcomes but also for the future metabolic health of the mother and her infant, and may be key in attenuating the trans-generational risk on childhood obesity. PMID- 26442126 TI - The Temporal Dynamics of Childhood Economic Deprivation and Children's Achievement. AB - Economic deprivation during childhood adversely affects achievement in adolescence and early adulthood. Economically disadvantaged children tend to achieve less than their more advantaged peers on a variety of measures of educational and socioeconomic achievement. Researchers recognize that what matters for achievement is not merely exposure to economic deprivation during childhood but also the temporal dynamics of deprivation. Recent studies have found that the effects of childhood economic disadvantage on achievement depend on the timing of deprivation (early childhood versus middle or late childhood), the sequencing of deprivation (whether family income is rising or falling), and the overall duration of exposure to deprivation. In this article, I describe conceptual and methodological advances in understanding the temporal dynamics of childhood economic disadvantage, and address the implications of these improvements for our knowledge of how deprivation affects children's achievement. PMID- 26442127 TI - The predictive role of NLR and PLR for solid non-AIDS defining cancer incidence in HIV-infected subjects: a MASTER cohort study. AB - BACKGROUND: The neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR), two low cost, routinely available inflammatory indices, have been found to be associated with risk of death in patients with solid cancer, in both general population and HIV-positive subjects. However, no study investigated the role of NLR and PLR as predictive of cancer incidence so far. METHODS: The aim of our study was to assess the association of PLR and NLR with risk of developing solid non-AIDS defining cancer (NADC) in HIV-infected subjects. We conducted a multicenter Italian cohort study from 2000 to 2012 including HIV-infected subjects naive at antiretroviral treatment at enrollment. The associations of NLR and PLR with NADC incidence were evaluated by univariate and multivariate analyses using both time independent and time dependent Cox proportional hazard models. RESULTS: Thirteen thousand five hundred fifty-nine patients (73.3 % males) with a mean age of 36.0 years (SD 10.0) were included. The median (inter quartile range) of NLR and PLR at baseline were 1.47 (1.03-2.17) and 109.9 (79.6 155.3), respectively. During a median follow-up of 3.9 years, 337 subjects had a first diagnosis of solid NADC. The crude and age- and gender-standardized incidence rates were 3.57 and 3.91 per 1000 person-years, respectively. No statistically significant association was found between NLR and PLR and NADC incidence, using multivariate models, including also time-dependent Cox models with a cubic-spline for NLR and PLR. CONCLUSION: This study does not sustain the hypothesis that NRL and PLR may be useful for predicting the risk of cancer in HIV positive subjects. PMID- 26442128 TI - Physical activity of elderly patients with rheumatoid arthritis and healthy individuals: an actigraphy study. AB - BACKGROUND: Most people with rheumatoid arthritis (RA) are physically inactive. An accelerometer worn on the waist has been used to evaluate physical activity in people with chronic conditions. It is useful for evaluating moderate to vigorous activity, although it tends to underestimate light or mild activities such as housework or family duties. An accelerometer worn on the wrist (i.e., actigraph) has recently been used to capture daily physical activity in inactive individuals. The purposes of this study were to investigate physical activity measured by an actigraph in patients with RA and in healthy individuals and to investigate the association between actigraphic data and self-reported physical function. METHODS: The subjects were 20 RA patients and 20 healthy individuals. All participants wore an actigraph on their wrist for 6-7 consecutive days. They also completed the Health Assessment Questionnaire disability index (HAQ-DI) and the Medical Outcomes Study (MOS) 36-item short form health survey (SF-36). We extracted three parameters from the actigraphic data: mean activity count (MAC), peak activity count (PAC), and low activity ratio (LAR). These three parameters were compared between the RA patients and healthy individuals and with the self reported questionnaires. RESULTS: The MAC was significantly lower and the LAR was significantly higher in RA patients than in healthy individuals. The PAC was not different between the two groups. The LAR was negatively correlated with the MAC for the RA patients and for the healthy individuals. The decrease ratio of the LAR with the increase of the MAC for the RA patients was twice that of the healthy participants. In the RA patients, the LAR was significantly and moderately correlated with the HAQ-DI score and two dimensions of the SF-36 (i.e., "physical functioning" and "bodily pain"). CONCLUSION: Investigation of the proportion of low activity count using an actigraph may be useful to identify characteristics of the physical function in RA patients. PMID- 26442129 TI - Health service resilience in Yobe state, Nigeria in the context of the Boko Haram insurgency: a systems dynamics analysis using group model building. AB - BACKGROUND: Yobe State has faced severe disruption of its health service as a result of the Boko Haram insurgency. A systems dynamics analysis was conducted to identify key pathways of threat to provision and emerging pathways of response and adaptation. METHODS: Structured interviews were conducted with 39 stakeholders from three local government areas selected to represent the diversity of conflict experience across the state: Damaturu, Fune and Nguru, and with four officers of the PRRINN-MNCH program providing technical assistance for primary care development in the state. A group model building session was convened with 11 senior stakeholders, which used participatory scripts to review thematic analysis of interviews and develop a preliminary systems model linking identified variables. RESULTS: Population migration and transport restrictions have substantially impacted access to health provision. The human resource for health capability of the state has been severely diminished through the outward migration of (especially non-indigenous) health workers and the suspension of programmes providing external technical assistance. The political will of the Yobe State government to strengthen health provision - through lifting a moratorium on recruitment and providing incentives for retention and support of staff - has supported a recovery of health systems functioning. Policies of free drug provision and decentralized drug supply appear to have been protective of the operation of the health system. Community resources and cohesion have been significant assets in combatting the impacts of the insurgency on service utilization and quality. Staff commitment and motivation - particularly amongst staff indigenous to the state - has protected health care quality and enabled flexibility of human resource deployment. CONCLUSIONS: A systems analysis using participatory group model building provided a mechanism to identify key pathways of threat and adaptation with regard to health service functioning. Generalizable systems characteristics supportive of resilience are suggested, and linked to wider discussion of the role of factors such as diversity, self-regulation and integration. PMID- 26442130 TI - The influence of maternal health education on the place of delivery in conflict settings of Darfur, Sudan. AB - BACKGROUND: Armed conflict and socio-demographic characteristics of internally displaced persons (IDPs) are very important factors that influence the provision of reproductive health (RH) in humanitarian settings. Maternal health education plays a crucial role to overcome the barriers of RH care, reduce home births conducted by traditional birth attendants (TBAs), and improve increasing births in a health facility. The objectives of this study were to (1) determine the association between the place of delivery and home visits for maternal health education and (2) describe the socio-demographic characteristics of women who gave birth during the last two years. METHODS: A cross-sectional study among married women aged (15-49 years old) in IDP camps. All women were subjected to intensive maternal health education at their homes for 3 years prior to the survey. A sample of 640 women who gave birth during the last two years was randomly selected. RESULTS: Among all women investigated, 36.9 % (95 % CI: 33.1, 40.8) reported a home-based delivery, while 63.1 % (95 % CI: 59.2, 66.9) reported a facility-based delivery. Receiving visits for maternal health education at home was associated with an estimated 43.0 % reduction in odds of giving birth at home, compared to not receiving home visits (adjusted odds ratio [ aOR] 0.57; 95 % CI: 0.35, 0.93). The level of women's education and camp of residence were important predictors for home birth. CONCLUSION: Maternal health education at home was associated with a reduction in home-based delivery performed by TBAs in the conflict-affected setting of Darfur. Our study proposes that when facility based delivery is made available in camp's clinics, and the targeted women educated at home to refrain from home-based delivery, they will choose to undergo facility-based delivery. PMID- 26442133 TI - NSAUA & QUA Joint Oncology Meeting. PMID- 26442132 TI - Northeastern Section of the American Urological Association 67th Annual Meeting, Quebec City, QC Scientific Program View Abstracts at NSAUA.org. PMID- 26442131 TI - Mental Health Service Use in Schools and Non-School-Based Outpatient Settings: Comparing Predictors of Service Use. AB - Researchers have consistently documented a gap between the large number of US youth meeting criteria for a mental health disorder with significant associated impairment, and the comparatively few youth receiving services. School-based mental health care may address the need-services gap by offering services more equitably to youth in need, irrespective of family economic resources, availability of transportation, and other factors that can impede access to community clinics. However, diagnoses alone do not fully capture the severity of an individual's mental health status and need for services. Studying service use only in relation to diagnoses may restrict our understanding of the degree to which service use is reflective of service need, and inhibit our ability to compare school and non-school-based outpatient settings on their responsiveness to service need. The present study evaluated predictors of mental health service use in school- and community-based settings for youth who had had an active case in one of two public sectors of care, comparing empirically-derived dimensional measurements of youth mental health service need and impairment ratings against non-need variables (e.g., ethnicity, income). Three dimensions of youth mental health service need were identified. Mental health service need and non-need variables each played a significant predictive role. Parent-rated impairment was the strongest need-based predictor of service use across settings. The impact of non-need variables varied by service setting, with parental income having a particularly noticeable effect on school-based services. Across time, preceding service use and impairment each significantly predicted future service use. PMID- 26442134 TI - Developing Your Evaluation Plans: A Critical Component of Public Health Program Infrastructure. AB - A program's infrastructure is often cited as critical to public health success. The Component Model of Infrastructure (CMI) identifies evaluation as essential under the core component of engaged data. An evaluation plan is a written document that describes how to monitor and evaluate a program, as well as how to use evaluation results for program improvement and decision making. The evaluation plan clarifies how to describe what the program did, how it worked, and why outcomes matter. We use the Centers for Disease Control and Prevention's (CDC) "Framework for Program Evaluation in Public Health" as a guide for developing an evaluation plan. Just as using a roadmap facilitates progress on a long journey, a well-written evaluation plan can clarify the direction your evaluation takes and facilitate achievement of the evaluation's objectives. PMID- 26442135 TI - Comparison of normalization methods for differential gene expression analysis in RNA-Seq experiments: A matter of relative size of studied transcriptomes. AB - In recent years, RNA-Seq technologies became a powerful tool for transcriptome studies. However, computational methods dedicated to the analysis of high throughput sequencing data are yet to be standardized. In particular, it is known that the choice of a normalization procedure leads to a great variability in results of differential gene expression analysis. The present study compares the most widespread normalization procedures and proposes a novel one aiming at removing an inherent bias of studied transcriptomes related to their relative size. Comparisons of the normalization procedures are performed on real and simulated data sets. Real RNA-Seq data sets analyses, performed with all the different normalization methods, show that only 50% of significantly differentially expressed genes are common. This result highlights the influence of the normalization step on the differential expression analysis. Real and simulated data sets analyses give similar results showing 3 different groups of procedures having the same behavior. The group including the novel method named "Median Ratio Normalization" (MRN) gives the lower number of false discoveries. Within this group the MRN method is less sensitive to the modification of parameters related to the relative size of transcriptomes such as the number of down- and upregulated genes and the gene expression levels. The newly proposed MRN method efficiently deals with intrinsic bias resulting from relative size of studied transcriptomes. Validation with real and simulated data sets confirmed that MRN is more consistent and robust than existing methods. PMID- 26442136 TI - Complete genome sequence of Geobacillus thermoglucosidasius C56-YS93, a novel biomass degrader isolated from obsidian hot spring in Yellowstone National Park. AB - Geobacillus thermoglucosidasius C56-YS93 was one of several thermophilic organisms isolated from Obsidian Hot Spring, Yellowstone National Park, Montana, USA under permit from the National Park Service. Comparison of 16 S rRNA sequences confirmed the classification of the strain as a G. thermoglucosidasius species. The genome was sequenced, assembled, and annotated by the DOE Joint Genome Institute and deposited at the NCBI in December 2011 (CP002835). The genome of G. thermoglucosidasius C56-YS93 consists of one circular chromosome of 3,893,306 bp and two circular plasmids of 80,849 and 19,638 bp and an average G + C content of 43.93 %. G. thermoglucosidasius C56-YS93 possesses a xylan degradation cluster not found in the other G. thermoglucosidasius sequenced strains. This cluster appears to be related to the xylan degradation cluster found in G. stearothermophilus. G. thermoglucosidasius C56-YS93 possesses two plasmids not found in the other two strains. One plasmid contains a novel gene cluster coding for proteins involved in proline degradation and metabolism, the other contains a collection of mostly hypothetical proteins. PMID- 26442137 TI - Magnetic targeting of microbubbles against physiologically relevant flow conditions. AB - The localization of microbubbles to a treatment site has been shown to be essential to their effectiveness in therapeutic applications such as targeted drug delivery and gene therapy. A variety of different strategies for achieving localization has been investigated, including biochemical targeting, acoustic radiation force, and the incorporation of superparamagnetic nanoparticles into microbubbles to enable their manipulation using an externally applied magnetic field. The third of these strategies has the advantage of concentrating microbubbles in a target region without exposing them to ultrasound, and can be used in conjunction with biochemical targeting to achieve greater specificity. Magnetic microbubbles have been shown to be effective for therapeutic delivery in vitro and in vivo. Whether this technique can be successfully applied in humans however remains an open question. The aim of this study was to determine the range of flow conditions under which targeting could be achieved. In vitro results indicate that magnetic microbubbles can be retained using clinically acceptable magnetic fields, for both the high shear rates (approx. 10(4) s(-1)) found in human arterioles and capillaries, and the high flow rates (approx. 3.5 ml s(-1)) of human arteries. The potential for human in vivo microbubble retention was further demonstrated using a perfused porcine liver model. PMID- 26442138 TI - Cavitation inception from bubble nuclei. AB - The tensile strength of ordinary water such as tap water or seawater is typically well below 1 bar. It is governed by cavitation nuclei in the water, not by the tensile strength of the water itself, which is extremely high. Different models of the nuclei have been suggested over the years, and experimental investigations of bubbles and cavitation inception have been presented. These results suggest that cavitation nuclei in equilibrium are gaseous voids in the water, stabilized by a skin which allows diffusion balance between gas inside the void and gas in solution in the surrounding liquid. The cavitation nuclei may be free gas bubbles in the bulk of water, or interfacial gaseous voids located on the surface of particles in the water, or on bounding walls. The tensile strength of these nuclei depends not only on the water quality but also on the pressure-time history of the water. A recent model and associated experiments throw new light on the effects of transient pressures on the tensile strength of water, which may be notably reduced or increased by such pressure changes. PMID- 26442139 TI - Towards numerical prediction of cavitation erosion. AB - This paper is intended to provide a potential basis for a numerical prediction of cavitation erosion damage. The proposed method can be divided into two steps. The first step consists in determining the loading conditions due to cavitation bubble collapses. It is shown that individual pits observed on highly polished metallic samples exposed to cavitation for a relatively small time can be considered as the signature of bubble collapse. By combining pitting tests with an inverse finite-element modelling (FEM) of the material response to a representative impact load, loading conditions can be derived for each individual bubble collapse in terms of stress amplitude (in gigapascals) and radial extent (in micrometres). This step requires characterizing as accurately as possible the properties of the material exposed to cavitation. This characterization should include the effect of strain rate, which is known to be high in cavitation erosion (typically of the order of several thousands s(-1)). Nanoindentation techniques as well as compressive tests at high strain rate using, for example, a split Hopkinson pressure bar test system may be used. The second step consists in developing an FEM approach to simulate the material response to the repetitive impact loads determined in step 1. This includes a detailed analysis of the hardening process (isotropic versus kinematic) in order to properly account for fatigue as well as the development of a suitable model of material damage and failure to account for mass loss. Although the whole method is not yet fully operational, promising results are presented that show that such a numerical method might be, in the long term, an alternative to correlative techniques used so far for cavitation erosion prediction. PMID- 26442140 TI - Modelling cavitation erosion using fluid-material interaction simulations. AB - Material deformation and pitting from cavitation bubble collapse is investigated using fluid and material dynamics and their interaction. In the fluid, a novel hybrid approach, which links a boundary element method and a compressible finite difference method, is used to capture non-spherical bubble dynamics and resulting liquid pressures efficiently and accurately. The bubble dynamics is intimately coupled with a finite-element structure model to enable fluid/structure interaction simulations. Bubble collapse loads the material with high impulsive pressures, which result from shock waves and bubble re-entrant jet direct impact on the material surface. The shock wave loading can be from the re-entrant jet impact on the opposite side of the bubble, the fast primary collapse of the bubble, and/or the collapse of the remaining bubble ring. This produces high stress waves, which propagate inside the material, cause deformation, and eventually failure. A permanent deformation or pit is formed when the local equivalent stresses exceed the material yield stress. The pressure loading depends on bubble dynamics parameters such as the size of the bubble at its maximum volume, the bubble standoff distance from the material wall and the pressure driving the bubble collapse. The effects of standoff and material type on the pressure loading and resulting pit formation are highlighted and the effects of bubble interaction on pressure loading and material deformation are preliminarily discussed. PMID- 26442141 TI - Cavitation and bubble dynamics: the Kelvin impulse and its applications. AB - Cavitation and bubble dynamics have a wide range of practical applications in a range of disciplines, including hydraulic, mechanical and naval engineering, oil exploration, clinical medicine and sonochemistry. However, this paper focuses on how a fundamental concept, the Kelvin impulse, can provide practical insights into engineering and industrial design problems. The pathway is provided through physical insight, idealized experiments and enhancing the accuracy and interpretation of the computation. In 1966, Benjamin and Ellis made a number of important statements relating to the use of the Kelvin impulse in cavitation and bubble dynamics, one of these being 'One should always reason in terms of the Kelvin impulse, not in terms of the fluid momentum...'. We revisit part of this paper, developing the Kelvin impulse from first principles, using it, not only as a check on advanced computations (for which it was first used!), but also to provide greater physical insights into cavitation bubble dynamics near boundaries (rigid, potential free surface, two-fluid interface, flexible surface and axisymmetric stagnation point flow) and to provide predictions on different types of bubble collapse behaviour, later compared against experiments. The paper concludes with two recent studies involving (i) the direction of the jet formation in a cavitation bubble close to a rigid boundary in the presence of high-intensity ultrasound propagated parallel to the surface and (ii) the study of a 'paradigm bubble model' for the collapse of a translating spherical bubble, sometimes leading to a constant velocity high-speed jet, known as the Longuet Higgins jet. PMID- 26442142 TI - Cell mechanics in biomedical cavitation. AB - Studies on the deformation behaviours of cellular entities, such as coated microbubbles and liposomes subject to a cavitation flow, become increasingly important for the advancement of ultrasonic imaging and drug delivery. Numerical simulations for bubble dynamics of ultrasound contrast agents based on the boundary integral method are presented in this work. The effects of the encapsulating shell are estimated by adapting Hoff's model used for thin-shell contrast agents. The viscosity effects are estimated by including the normal viscous stress in the boundary condition. In parallel, mechanical models of cell membranes and liposomes as well as state-of-the-art techniques for quantitative measurement of viscoelasticity for a single cell or coated microbubbles are reviewed. The future developments regarding modelling and measurement of the material properties of the cellular entities for cutting-edge biomedical applications are also discussed. PMID- 26442143 TI - Bubbles with shock waves and ultrasound: a review. AB - The study of the interaction of bubbles with shock waves and ultrasound is sometimes termed 'acoustic cavitation'. It is of importance in many biomedical applications where sound waves are applied. The use of shock waves and ultrasound in medical treatments is appealing because of their non-invasiveness. In this review, we present a variety of acoustics-bubble interactions, with a focus on shock wave-bubble interaction and bubble cloud phenomena. The dynamics of a single spherically oscillating bubble is rather well understood. However, when there is a nearby surface, the bubble often collapses non-spherically with a high speed jet. The direction of the jet depends on the 'resistance' of the boundary: the bubble jets towards a rigid boundary, splits up near an elastic boundary, and jets away from a free surface. The presence of a shock wave complicates the bubble dynamics further. We shall discuss both experimental studies using high speed photography and numerical simulations involving shock wave-bubble interaction. In biomedical applications, instead of a single bubble, often clouds of bubbles appear (consisting of many individual bubbles). The dynamics of such a bubble cloud is even more complex. We shall show some of the phenomena observed in a high-intensity focused ultrasound (HIFU) field. The nonlinear nature of the sound field and the complex inter-bubble interaction in a cloud present challenges to a comprehensive understanding of the physics of the bubble cloud in HIFU. We conclude the article with some comments on the challenges ahead. PMID- 26442144 TI - Tiny bubbles challenge giant turbines: Three Gorges puzzle. AB - Since the birth of the first prototype of the modern reaction turbine, cavitation as conjectured by Euler in 1754 always presents as a challenge. Following his theory, the evolution of modern reaction (Francis and Kaplan) turbines has been completed by adding the final piece of the element 'draft-tube' that enables turbines to explore water energy at efficiencies of almost 100%. However, during the last two and a half centuries, with increasing unit capacity and specific speed, the problem of cavitation has been manifested and complicated by the draft tube surges rather than being solved. Particularly, during the last 20 years, the fierce competition in the international market for extremely large turbines with compact design has encouraged the development of giant Francis turbines of 700 1000 MW. The first group (24 units) of such giant turbines of 700 MW each was installed in the Three Gorges project. Immediately after commission, a strange erosion phenomenon appeared on the guide vane of the machines that has puzzled professionals. From a multi-disciplinary analysis, this Three Gorges puzzle could reflect an unknown type of cavitation inception presumably triggered by turbulence production from the boundary-layer streak transitional process. It thus presents a fresh challenge not only to this old turbine industry, but also to the fundamental sciences. PMID- 26442145 TI - Cavitation in medicine. AB - We generally think of bubbles as benign and harmless and yet they can manifest the most remarkable range of physical effects. Some of those effects are the stuff of our everyday experience as in the tinkling of a brook or the sounds of breaking waves at the beach. But even these mundane effects are examples of the ability of bubbles to gather, focus and radiate energy (acoustic energy in the above examples). In other contexts that focusing of energy can lead to serious technological problems as when cavitation bubbles eat great holes through ships' propeller blades or cause a threat to the integrity of the spillways at the Hoover Dam. In liquid-propelled rocket engines, bubbles pose a danger to the stability of the propulsion system, and in artificial heart valves they can cause serious damage to the red blood cells. In perhaps the most extraordinary example of energy focusing, collapsing cavitation bubbles can emit not only sound, but also light with black body radiation temperatures equal to that of the sun (Brennen 1995 Cavitation and bubble dynamics). But, harnessed carefully, this almost unique ability to focus energy can also be put to remarkably constructive use. Cavitation bubbles are now used in a remarkable range of surgical and medical procedures, for example to emulsify tissue (most commonly in cataract surgery or in lithotripsy procedures for the reduction of kidney and gall stones) or to manipulate the DNA in individual cells. By creating cavitation bubbles non invasively thereby depositing and focusing energy non-intrusively, one can generate minute incisions or target cancer cells. This paper will begin by briefly reviewing the history of cavitation phenomena and will end with a vision of the new horizons for the amazing cavitation bubble. PMID- 26442146 TI - The speed of sound in a gas-vapour bubbly liquid. AB - In addition to the vapour of the liquid, bubbles in cavitating flows usually contain also a certain amount of permanent gas that diffuses out of the liquid as they grow. This paper presents a simplified linear model for the propagation of monochromatic pressure waves in a bubbly liquid with these characteristics. Phase change effects are included in detail, while the gas is assumed to follow a polytropic law. It is shown that even a small amount of permanent gas can have a major effect on the behaviour of the system. Particular attention is paid to the low-frequency range, which is of special concern in flow cavitation. Numerical results for water and liquid oxygen illustrate the implications of the model. PMID- 26442147 TI - The singing vortex. AB - Marine propellers display several forms of cavitation. Of these, propeller-tip vortex cavitation is one of the important factors in propeller design. The dynamic behaviour of the tip vortex is responsible for hull vibration and noise. Thus, cavitation in the vortices trailing from tips of propeller blades has been studied extensively. Under certain circumstances cavitating vortices have been observed to have wave-like disturbances on the surfaces of vapour cores. Intense sound at discrete frequencies can result from a coupling between tip vortex disturbances and oscillating sheet cavitation on the surfaces of the propeller blades. This research article focuses on the dynamics of vortex cavitation and more in particular on the energy and frequency content of the radiated pressures. PMID- 26442148 TI - Bubble dynamics in a compressible liquid in contact with a rigid boundary. AB - A bubble initiated near a rigid boundary may be almost in contact with the boundary because of its expansion and migration to the boundary, where a thin layer of water forms between the bubble and the boundary thereafter. This phenomenon is modelled using the weakly compressible theory coupled with the boundary integral method. The wall effects are modelled using the imaging method. The numerical instabilities caused by the near contact of the bubble surface with the boundary are handled by removing a thin layer of water between them and joining the bubble surface with its image to the boundary. Our computations correlate well with experiments for both the first and second cycles of oscillation. The time history of the energy of a bubble system follows a step function, reducing rapidly and significantly because of emission of shock waves at inception of a bubble and at the end of collapse but remaining approximately constant for the rest of the time. The bubble starts being in near contact with the boundary during the first cycle of oscillation when the dimensionless stand off distance gamma = s/R m < 1, where s is the distance of the initial bubble centre from the boundary and R m is the maximum bubble radius. This leads to (i) the direct impact of a high-speed liquid jet on the boundary once it penetrates through the bubble, (ii) the direct contact of the bubble at high temperature and high pressure with the boundary, and (iii) the direct impingement of shock waves on the boundary once emitted. These phenomena have clear potential to damage the boundary, which are believed to be part of the mechanisms of cavitation damage. PMID- 26442150 TI - Rapid identification of carbapenemase-producing Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii using a modified Carba NP test. AB - Biochemical tests have been previously developed to identify carbapenemase producing Enterobacteriaceae, Pseudomonas spp. (Carba NP test) and Acinetobacter spp. (CarbAcineto NP test). We evaluated a modified Carba NP test to detect carbapenemase production in Enterobacteriaceae, Pseudomonas and Acinetobacter species using a single protocol with rapid results and found good reliability and speed. PMID- 26442151 TI - First fatal case of CNS infection caused by Enterovirus A in Brazil. AB - We describe what is to our knowledge the first fatal case of central nervous system Enterovirus infection in Brazil. Molecular and phylogenetic characterization revealed that Enterovirus A was the aetiologic agent of this case. PMID- 26442149 TI - The bacterial pangenome as a new tool for analysing pathogenic bacteria. AB - The bacterial pangenome was introduced in 2005 and, in recent years, has been the subject of many studies. Thanks to progress in next-generation sequencing methods, the pangenome can be divided into two parts, the core (common to the studied strains) and the accessory genome, offering a large panel of uses. In this review, we have presented the analysis methods, the pangenome composition and its application as a study of lifestyle. We have also shown that the pangenome may be used as a new tool for redefining the pathogenic species. We applied this to the Escherichia coli and Shigella species, which have been a subject of controversy regarding their taxonomic and pathogenic position. PMID- 26442152 TI - Novel strain of Shigella dysenteriae serotype 7 from India. AB - We describe a strain of Shigella dysenteriae serotype 7 which had novel biochemical and genetic characters. Unlike other S. dysenteriae, it produced gas, fermented mannitol, was a late-lactose fermenter and harboured the set 1A and set 1B genes. The significance of such atypical strains is that they are difficult to identify. If such strains are missed, they could prove to be a serious public health problem because the infectious dose is very low and they may harbour integrons contributing to drug resistance. PMID- 26442153 TI - Epidemiology of community-onset bloodstream infections in Bouake, central Cote d'Ivoire. AB - Bacterial bloodstream infections (BSI) account for considerable morbidity worldwide, but epidemiological data from resource-constrained tropical settings are scarce. We analysed 293 blood cultures from patients presenting to a regional referral hospital in Bouake, central Cote d'Ivoire, to determine the aetiology of community-onset BSI. The prevalence of bacteraemia was 22.5%, with children being most commonly affected. Enterobacteriaceae (predominantly Klebsiella pneumoniae and Salmonella enterica) accounted for 94% of BSI. Staphylococcus aureus was the only relevant Gram-positive pathogen. Clinical signs and symptoms were not significantly associated with blood culture positivity after controlling for malaria. PMID- 26442154 TI - Excessive adiposity, metabolic health, and risks for genital human papillomavirus infection in adult women: a population-based cross-sectional study. AB - BACKGROUND: The role of excessive adiposity or its metabolic consequences in persistent HPV infection among general adult women remains unknown. METHODS: Using data from the National Health and Nutrition Examination Survey (NHANES) in 2003-2010, we compared adult women's likelihood for any- or high-risk (HR) type HPV infection by degrees of excessive adiposity and metabolic health status. RESULTS: Any-type (41.1 % vs. 44.9 %, P = 0.045) or HR-type HPV prevalence (21.9 % vs. 25.4 %, P = 0.055) was comparable in women aged 20-59 years with or without central obesity. After adjusting for age, socioeconomic indicators, and lifetime sexual risks, centrally-obese women barely showed a different likelihood for any type (aPR [adjusted prevalence ratio] = 0.91, P = 0.03) or HR-HPV infection (aPR = 0.92, P = 0.279). However, obesity (aPR = 0.76, P = 0.017) or centrally-obesity (aPR = 0.72, P = 0.003) was negatively correlated with HR-HPV infection in women reporting an early sex debut (<16 years; P for interaction <0.05). In the fasting subpopulation, obesity (aPR = 0.77, P = 0.016) or metabolically unhealthy obesity (aPR = 0.69, P = 0.018) was significantly correlated with a 23 % or 31 % reduced prevalence of HR-HPV infection. DISCUSSION: In contrary to findings for the general population, HR-HPV prevalence was decreased in a subgroup of women with obesity or central obesity. Possible explanations for such heterogeneity included less risky sexual behaviors, an altered immune milieu that promoted viral clearance, and increased access to healthcare resources due to other obesity related co-morbidities in this subpopulation. CONCLUSIONS: Obesity or central obesity was not significantly associated with prevalent any-type or HR-type HPV infection among adult women in general. However, in certain subpopulations, excessive adiposity or its relevant metabolic dysfunction was negatively associated with HR-HPV infection. PMID- 26442155 TI - Assessment of growth performance and meat quality of finishing pigs raised on the low plane of nutrition. AB - This study was performed to investigate the effects of the low plane of nutrition on growth and meat quality of finishing pigs. A total of 136 crossbred barrows and gilts weighing approximately 55 kg were allotted to 8 pens, with 17 animals housed per pen, in a 2 (sex) * 2 (nutrition) factorial arrangement of treatments. The animals allotted to a medium plane of nutrition (MPN) received a finisher phase 1 (P1) diet containing 3.47 Mcal DE/kg and 0.92 % lysine and a P2 diet containing 3.40 Mcal DE/kg and 0.78 % lysine for 35 d and 36/43 d, respectively; the animals allotted to the low plane of nutrition (LPN) received only a P2 diet containing 3.00 Mcal DE/kg and 0.68 % lysine 7 d longer than MPN. The animals were slaughtered following the feeding trial, after which the loin, ham, Boston butt, and belly were taken from a total of 24 animals, with the average live weight being 120 kg, and their physicochemical and sensory quality traits were analyzed. Average daily gain did not differ between MPN and LPN during either P1 or P2. Average daily feed intake was greater (P < 0.05) in LPN vs. MPN during both phases whereas the opposite was true for the gain:feed ratio. Backfat thickness (BFT) was less in LPN vs. MPN (21.7 vs. 24.1 mm at 115 kg). The plane of nutrition influenced no effect on any of the physicochemical characteristics of fresh loin, ham, or Boston butt analyzed in the present study. Fresh hams from LPN exhibited superior aroma and odor scores than those from MPN; however, sensory quality traits were not influenced by the plane of nutrition in other fresh primal cuts or cooked meat. Instead, fresh primal cuts and cooked meat from gilts rendered superior physicochemical characteristics and sensory scores, respectively, than those from barrows. Results suggest that the low plane of nutrition may be useful to increase the slaughter weight of finishing pigs with a moderately high BFT by virtue of its BFT-lowering effect with or without exerting a slightly positive influence on pork quality. PMID- 26442156 TI - Social Support and Self-Reported Stress Levels in a Predominantly African American Sample of Women with Systemic Lupus Erythematosus. AB - Lupus patients should avoid stress because physical or emotional stress can affect overall physical health. It has been suggested that social support has a positive influence on health status, but there is a lack of information in the literature on the association between the two among lupus patients. The current study investigated the association between social support and self-reported stress and coping status among African American women with lupus using data collected from two linked cross-sectional surveys. No social support differences in groups of high and low stress/coping were revealed; a duplicate study with a larger sample size is required. PMID- 26442157 TI - Association of IFN-gamma : IL-10 Cytokine Ratio with Nonsegmental Vitiligo Pathogenesis. AB - Background and Objectives. Cytokines regulate immune response and inflammation and play a crucial role in depigmentation process of vitiligo. The present study aimed to estimate the serum levels of pro- and anti-inflammatory cytokines, IFN gamma and IL-10, and their ratios in nonsegmental vitiligo patients and healthy individuals from India. Methods. Blood samples were collected from 280 subjects and serum IFN-gamma and IL-10 levels were measured using standard ELISA. Results. Nonsegmental vitiligo patients showed increased levels of IFN-gamma (12.4 +/- 3.2 versus 9.9 +/- 4.4 pg/mL) and decreased levels of IL-10 (9.3 +/- 1.7 versus 11.5 +/- 5 pg/mL) compared to controls. Ratio of IFN-gamma : IL-10 differed significantly from patients to controls (p < 0.05). IFN-gamma concentrations and IFN-gamma : IL-10 ratio varied significantly with respect to clinical variants, disease stability, and social habits (smoking and alcohol consumption) and showed a positive correlation with disease duration. Family history of vitiligo was significantly associated with IFN-gamma : IL-10 ratio but not with their individual levels. Conclusion. The ratio of IFN-gamma : IL-10 serum levels may be considered as one of the promising immunological markers in nonsegmental vitiligo. This is the first study considering multiple aspects in relation to ratio of cytokine levels. Similar studies with large samples are warranted to confirm our observations. PMID- 26442158 TI - Gender Differences in the Appetite Response to a Satiating Diet. AB - We examined gender differences in appetite sensations when exposed to Mediterranean diet (MedDiet) meals and determined whether there are gender differences in the change in the satiating properties of the MedDiet over time. Thirty-eight men and 32 premenopausal women consumed a 4-week isoenergetic MedDiet under controlled conditions. Visual analogue scales were used to measure perceived appetite sensations before and immediately after each meal consumed over the course of one day (Wednesday) of the first and the fourth week of intervention. Women reported greater decreases for desire to eat, hunger, and appetite score than men in response to the consumption of the MedDiet meals (gender-by-meal interactions, resp., P = 0.04, P = 0.048, and P = 0.03). Fullness and prospective food consumption responses did not significantly differ between men and women. Between the first and the fourth week of intervention, premeal prospective food consumption increased with time in men (P = 0.0007) but not in women (P = 0.84; P for gender-by-time interaction = 0.04). These results indicate gender differences in appetite sensations when exposed to the MedDiet. These results may be useful in order to have a better understanding of gender issues for body weight management. PMID- 26442159 TI - Anatomical Study of Chiari Network and the Remnant of Left Venous Valve in the Interior of Right Atrium. AB - Chiari network occurs due to incomplete resorption of right valve of sinus venosus. It is often noticed as fenestrated membranous structure or reticular network like structure in the valve of inferior vena cava and coronary sinus. The remnant of left venous valve is observed as trabeculae over the fossa ovalis. The incidence of Chiari network and the remnant of left venous valve were studied in 80 cadaveric hearts utilized for teaching the undergraduates. The right atrium was opened anterior to sulcus terminalis and the interior was examined for the presence of these embryological remnants. The incidence of Chiari network and left venous valve in the present study is 3.75% and 7.5%, respectively. Chiari network was observed as a fenestrated membranous structure in 2 specimens and a reticular network in 1 specimen, with variable extension to coronary sinus opening and right atrial wall. The remnant of left venous valve was observed as multiple fine strands in 3 specimens and trabecular structure in 3 specimens. These structures may create diagnostic confusion, difficulty in interventional procedures, and complications like thromboembolic events. Hence, the knowledge about the incidence, morphology, and clinical manifestations of these rare embryological remnants is mandatory. PMID- 26442160 TI - The "Endothelialized Muscularis Mucosae": A Case Report Describing a Large Cavernous Hemangioma at the Terminal Ileum and a New Histologic Clue for Preoperative Diagnosis from Endoscopic Biopsy. AB - Cavernous hemangiomas of the gastrointestinal tract are quite rare and, until now, have been difficult to diagnose preoperatively due their nonspecific presentations and imaging features, as well as a lack of histologic description pertaining to small superficial biopsies such as those obtained endoscopically. We report a unique case of a 4 cm transmural cavernous hemangioma in the terminal ileum with literature review and describe a new histologic finding-the "endothelialized muscularis mucosae," which was discovered upon review of the endoscopic biopsy and could potentially facilitate preoperative diagnosis of these lesions from endoscopic biopsies in the future. These lesions have classically required surgical resection in order to make a definitive diagnosis and rule out malignancy, with which they share many historical and radiographic features. Due to their potential to cause bowel obstruction, intussusception, perforation, and hemorrhage, these lesions may ultimately require surgical resection to relieve symptoms or prevent or treat complications-however, surgical planning and patient counseling could be greatly improved by a preoperative diagnosis. Therefore, gastroenterologists, pathologists, and surgeons should be aware of the "endothelialized muscularis mucosae" which can be very helpful in diagnosing GI cavernous hemangiomas from endoscopic biopsies. PMID- 26442161 TI - Systemic Sarcoidosis Mimicking a Behavioural Variant of Frontotemporal Dementia. AB - Among rare neurological manifestations, a progressive dementia may exceptionally be the revealing clinical feature of a sarcoidosis. Diagnosis may then be difficult, especially when systemic signs are missing or latent, with a risk of therapeutic delay. We report the first case of sarcoidosis mimicking a frontotemporal dementia. A 53-year-old man presented with a dementia clinically suggestive of frontotemporal dementia, progressing slowly for about 2 years. However, MRI revealed unusual aspects, mainly large areas of T2/FLAIR hypersignal within temporal regions and cerebellum, with nodular leptomeningeal and juxtacortical Gadolinium enhancement. The patient was finally diagnosed with a systemic sarcoidosis. We discuss the differential diagnosis based on MRI aspects and review the literature on the clinical, biological, and imaging features of sarcoidosis presenting with dementia. This case demonstrates that brain imaging remains mandatory in the exploration process of a patient with dementia. Although the patient presented with rather typical features of a behavioural variant of frontotemporal dementia, the MRI aspect was the key exploration that leaded to the diagnosis. PMID- 26442162 TI - An Unusual Presentation of Adult Tethered Cord Syndrome Associated with Severe Chest and Upper Back Pain. AB - Adult tethered cord syndrome (ATCS) is a rare entity that usually presents with multiple neurological symptoms, including lower extremity pain, backache, lower extremity muscle weakness, and bowel/bladder disturbances. Prompt surgical treatment is often necessary to avoid permanent sequelae. We report a 63-year-old man with sudden-onset severe right chest and upper back pain, followed by urinary retention. His initial workup included computed tomography of the abdomen and pelvis, which showed a presacral mass. His symptom-driven neurological workup focused on the cervical and thoracic spine, the results of which were normal. Pelvic radiographs and magnetic resonance imaging of the lumbosacral spine showed spina bifida occulta, meningocele, and presacral masses consistent with a teratomatous tumor. His symptoms, except for urinary retention, improved dramatically with surgical treatment. The excised specimen contained a teratomatous lesion plus an organized hematoma. Hematoma formation was suspected as the trigger of his sudden-onset right chest and upper back pain. PMID- 26442163 TI - Noncholesteatomatous Cyst of the Tympanic Membrane: A Nonpublished Entity? AB - Introduction. The presence of a serous cyst in the tympanic membrane implies the description of a new or unpublished entity based on our knowledge whose origin may be very unlikely explained on actual embryologic and anatomic background. Clinical Case. We present a case of a 45-year-old woman with progressing right hearing loss. Physical examination revealed a whitish, round-shaped malformation in the posterior-inferior quadrant of the right tympanic membrane. The cyst was removed with a transcanal tympanoplasty. Discussion. A thorough PubMed search that involved the terms tympanic membrane gland, epithelial inclusion cysts, mucous-secreting cyst, and tympanic cyst has shown no positive results. The first description of an unknown entity, such as a tympanic membrane serous cyst, may be the key for clinicians to start paying attention to patients who suffer from similar pathologies and may pass unnoticed because of their rarity or peculiarity. PMID- 26442164 TI - A Pleural Solitary Fibrous Tumor, Multiple Gastrointestinal Stromal Tumors, Moyamoya Disease, and Hyperparathyroidism in a Patient Associated with NF1. AB - Neurofibromatosis type 1 (NF1), also called von Recklinghausen's disease, is a multisystemic disease caused by an alteration of the NF1 gene, a tumor suppressor located on the long arm of chromosome 17 (17q11.2). Loss of the gene function, due to a point mutation, leads to an increase in cell proliferation and the development of several tumors. We report a 60-year-old female patient manifesting hypercalcemia due to hyperparathyroidism, a solitary fibrous tumor (SFT) of the pleura, multiple gastrointestinal stromal tumors (GISTs), and moyamoya disease associated with NF1. The SFT and GISTs were removed by staged operations. Then, hypercalcemia was successfully controlled after resection of the parathyroid adenoma. Based on a literature review, these combinations have never been reported, and the relevant literature is briefly discussed. PMID- 26442165 TI - Asymptomatic Glomus Tumor of the Mediastinum. AB - Glomus tumors are rare benign neoplasms that predominate in limbs. Infrequently, they can occur in a wide anatomic distribution, to include sites not known to contain glomus cells. Although glomus tumors are usually small, pain and tenderness are common clinical symptoms. We report the case of a 69-year-old man with an asymptomatic large mediastinal glomus tumor, who underwent surgical resection. PMID- 26442166 TI - Stereotactic Body Radiotherapy for Localized Ureter Transitional Cell Carcinoma: Three Case Reports. AB - The gold standard management for ureter transitional cell carcinoma (UTCC) is radical nephroureterectomy with excision of the bladder cuff. However, some patients cannot undergo this procedure for several reasons. In the case reports described herein, we performed stereotactic body radiotherapy (SBRT) on three patients with inoperable or surgery-rejected localized UTCC. Two out of the three patients did not develop local recurrence or distant metastasis during the observation period. However, recurrence was detected in the bladder of one patient 22 months after the treatment. No acute or late adverse events occurred in any of the three patients. SBRT may become one of the treatment options for inoperable or surgery-rejected UTCC patients. PMID- 26442167 TI - Bioaccumulation of Antimony and Arsenic in Vegetables and Health Risk Assessment in the Superlarge Antimony-Mining Area, China. AB - Heavy metal pollution in soils caused by mining and smelting has attracted worldwide attention for its potential health risks to residents. This paper studies the concentrations and accumulations of Sb and As in both soils and vegetables and the human health risks of Sb and As in vegetables from Xikuangshan (XKS) Sb mine, Hunan, China. Results showed that the soils were severely polluted by Sb and As; Sb and As have significant positive correlation. Sb and As concentrations in vegetables were quite different: Coriandrum sativum L. was the highest in Sb, Allium fistulosum L. was the highest in As, and Brassica pekinensis L. was the lowest in both Sb and As; Daucus carota L. and Coriandrum sativum L. showed advantage in accumulating Sb and As; Coriandrum sativum L. had higher capacity of redistributing Sb and As within the plant. Health risk assessment results showed that the hazard quotient (HQ) values of Sb and As in vegetables were in the ranges of 1.61-3.33 and 0.09-0.39, respectively; the chronic daily intake (CDI) and hazard quotient (HQ) values of Sb were over the safe limit recommended by FAO and WHO, indicating that long-term consumption of vegetables from the surrounding soils of XKS mine may bring health risks to residents. PMID- 26442168 TI - Postoperative Autologous Reinfusion in Total Knee Replacement. AB - Surgeries for total knee replacement (TKR) are increasing and in this context there is a need to develop new protocols for management and use of blood transfusion therapy. Autologous blood reduces the need for allogeneic blood transfusion and the aim of the present study was to verify the safety and the clinical efficacy. An observational retrospective study has been conducted on 124 patients, undergoing cemented total knee prosthesis replacement. Observed population was stratified into two groups: the first group received reinfusion of autologous blood collected in the postoperative surgery and the second group did not receive autologous blood reinfusion. Analysis of data shows that patients undergoing autologous blood reinfusion received less homologous blood bags (10.6% versus 30%; p = 0.08) and reduced days of hospitalization (7.88 +/- 0.7 days versus 8.96 +/- 2.47 days for the control group; p = 0.03). Microbiological tests were negative in all postoperatively salvaged and reinfused units. Our results emphasize the effectiveness of this procedure and have the characteristics of simplicity, low cost (?97.53 versus ?103.79; p < 0.01), and easy reproducibility. Use of autologous drainage system postoperatively is a procedure that allows reducing transfusion of homologous blood bags in patients undergoing TKR. PMID- 26442169 TI - Mining hidden polymorphic sequence motifs from divergent plant helitrons. AB - As a major driving force of genome evolution, transposons have been deviating from their original connotation as "junk" DNA ever since their important roles were revealed. The recently discovered Helitron transposons have been investigated in diverse eukaryotic genomes because of their remarkable gene capture ability and other features that are crucial to our current understanding of genome dynamics. Helitrons are not canonical transposons in that they do not end in inverted repeats or create target site duplications, which makes them difficult to identify. Previous methods mainly rely on sequence alignment of conserved Helitron termini or manual curation. The abundance of Helitrons in genomes is still underestimated. We developed an automated and generalized tool, HelitronScanner, that identified a plethora of divergent Helitrons in many plant genomes. A local combinational variable approach as the key component of HelitronScanner offers a more granular representation of conserved nucleotide combinations and therefore is more sensitive in finding divergent Helitrons. This commentary provides an in-depth view of the local combinational variable approach and its association with Helitron sequence patterns. Analysis of Helitron terminal sequences shows that the local combinational variable approach is an efficacious representation of nucleotide patterns imperceptible at a full sequence level. PMID- 26442170 TI - Assembly and characterization of novel Alu inserts detected from next-generation sequencing data. AB - Repetitive elements generally, and Alu inserts specifically are a large contributor to the recent evolution of the human genome. By assembling the sequences of novel Alu inserts using their respective subfamily consensus sequences as references, we found an exponential decay in the Alu subfamily call enrichment with increased number of sequence variants (Pearson correlation [Formula: see text], [Formula: see text]). By mapping the sequences of these inserts to a human reference genome, we infer the reference Alu sources of a subset of the novel Alus, of which 85% were previously shown to be active. We also evaluate relationships between the loci of the novel inserts and their inferred sources. PMID- 26442171 TI - An assay to monitor the activity of DNA transposition complexes yields a general quality control measure for transpositional recombination reactions. AB - Transposon-based technologies have many applications in molecular biology and can be used for gene delivery into prokaryotic and eukaryotic cells. Common transpositional activity measurement assays suitable for many types of transposons would be beneficial, as diverse transposon systems could be compared for their performance attributes. Therefore, we developed a general-purpose assay to enable and standardize the activity measurement for DNA transposition complexes (transpososomes), using phage Mu transposition as a test platform. This assay quantifies transpositional recombination efficiency and is based on an in vitro transposition reaction with a target plasmid carrying a lethal ccdB gene. If transposition targets ccdB, this gene becomes inactivated, enabling plasmid receiving Escherichia coli cells to survive and to be scored as colonies on selection plates. The assay was validated with 3 mini-Mu transposons varying in size and differing in their marker gene constitution. Tests with different amounts of transposon DNA provided a linear response and yielded a 10-fold operational range for the assay. The colony formation capacity was linearly correlated with the competence status of the E.coli cells, enabling normalization of experimental data obtained with different batches of recipient cells. The developed assay can now be used to directly compare transpososome activities with all types of mini-Mu transposons, regardless of their aimed use. Furthermore, the assay should be directly applicable to other transposition-based systems with a functional in vitro reaction, and it provides a dependable quality control measure that previously has been lacking but is highly important for the evaluation of current and emerging transposon-based applications. PMID- 26442172 TI - Rebooting the genome: The role of negative feedback in horizontal gene transfer. AB - Horizontal Gene Transfer (HGT) is one of the key mechanisms driving bacterial evolution. Conjugative plasmids are fundamental vehicles for HGT in bacteria, playing an essential role in the spread of antibiotic resistances. Although the classical view has stressed the instrumental role of these mobile genetic elements in the dissemination of antibiotic resistance genes, plasmids contain a rich physiology devoted to horizontal and vertical reproduction. This particular lifestyle imposes specific constrains and trade-offs on plasmid physiology, and plasmids have evolved dedicated circuits to balance the opposing demands of vertical and horizontal reproduction. Recent studies on the transcriptional networks of IncW plasmids and other incompatibility groups have unveiled common architectures in the regulatory networks of different plasmid groups. Comparative studies show that negative feedback loops (NFLs) with strong gains are preferred, opening the question of a possible convergent evolution dictated by certain adaptive properties of this particular network motif. System analysis of NFLs with strong feedback gains indicate that this architecture exhibits transient overshooting after horizontal gene transfer. Since plasmid burden is dependent on the expression of plasmid functions, transcriptional overshooting results in a transient increase of the burden immediately after conjugation. We discuss the possible implications of this phenomenon on plasmid propagation, and the regulatory networks that plasmids have evolved to counteract the detrimental side effects of transient overshooting. PMID- 26442173 TI - Applications of DNA integrating elements: Facing the bias bully. AB - Retroviruses and DNA transposons are an important part of molecular biologists' toolbox. The applications of these elements range from functional genomics to oncogene discovery and gene therapy. However, these elements do not integrate uniformly across the genome, which is an important limitation to their use. A number of genetic and epigenetic factors have been shown to shape the integration preference of these elements. Insight into integration bias can significantly enhance the analysis and interpretation of results obtained using these elements. For three different applications, we outline how bias can affect results, and can potentially be addressed. PMID- 26442174 TI - Autonomous and non-autonomous Tn3-family transposons and their role in the evolution of mobile genetic elements. AB - The Tn3 family of transposons includes diverse elements that encode homologous transposases and contain conserved terminal inverted repeat sequences (IRs). The recent identification of non-autonomous elements, named TIMEs (Tn3-derived Inverted-repeat Miniature Elements), has shed new light on the diversity and evolution of this transposon family. A common feature of TIMEs and other members of this family is their ability to mobilize genomic DNA for transposition as part of composite transposons. These elements significantly influence the structure and properties of plasmids and other mobile genetic elements (MGEs). They may contain and move by transposition (i) plasmid replication systems, (ii) toxin antitoxin systems and (iii) site-specific recombination modules that can resolve plasmid multimers. Some Tn3 family elements may also transfer large segments of chromosomal DNA into plasmids, which increases the pool of mobile DNA that can take part in horizontal gene transfer. PMID- 26442175 TI - Endogenous retrovirus-mediated genomic variations in chimpanzees. AB - Transposable elements (TEs) have played a significant role in the evolution of host genome by triggering genomic rearrangements. TEs have been studied in various research fields, ranging from population genomics to personalized medicines. Human-specific TEs and TEs existing in the human genome have been well studied. Unlike them, non-human primate-specific TEs remain shrouded in mystery. However, the study of TE-mediated genomic or genetic variations through comparative genomics is essential to understand mechanisms which TEs utilize to modify species-specific genome architecture and to cause species-specific diseases, Therefore, we have studied chimpanzee-specific TEs as well as human specific TEs. At first, we identified human-specific HERV-K integrated into the human genome after the divergence of human and chimpanzee. Then, for a comparative study of HERV-Ks and non-human ERVs, we extracted chimpanzee-specific endogenous retroviruses (PtERVs) from the chimpanzee genome. We identified 256 chimpanzee-specific PtERVs and characterized them, focusing on their estimated evolutionary age, polymorphism level in chimpanzee populations, and potential impact on the difference between the human and chimpanzee genomes. PMID- 26442176 TI - Drawing a fine line on endogenous retroelement activity. AB - Endogenous retroelements (EREs) are essential motors of evolution yet require careful control to prevent genomic catastrophes, notably during the vulnerable phases of epigenetic reprogramming that occur immediately after fertilization and in germ cells. Accordingly, a variety of mechanisms restrict these mobile genetic units. Previous studies have revealed the importance of KRAB-containing zinc finger proteins (KRAB-ZFPs) and their cofactor, KAP1, in the early embryonic silencing of endogenous retroviruses and so-called SVAs, but the implication of this transcriptional repression system in the control of LINE-1, the only known active autonomous retrotransposon in the human genome, was thought to be marginal. Two recent studies straighten the record by revealing that the KRAB/KAP system is key to the control of L1 in embryonic stem (ES) cells, and go further in demonstrating that DNA methylation and KRAB/KAP1-induced repression contribute to this process in an evolutionally dynamic fashion. These results shed light on the delicate equilibrium between higher vertebrates and endogenous retroelements, which are not just genetic invaders calling for strict control but rather a constantly renewed and nicely exploitable source of evolutionary potential. PMID- 26442177 TI - Integration of erm(B)-containing elements through large chromosome fragment exchange in Clostridium difficile. AB - In Clostridium difficile, erm(B) genes are located on mobile elements like Tn5398 and Tn6215. In previous studies, some of these elements were transferred by conjugation-like mechanisms, mobilized in trans by helper conjugative systems. In this study, we analyzed the genomes of several recipient strains that acquired either Tn5398 or Tn6215-like elements. We demonstrated that the integration of the transposons in the genome of the recipient cell was always due to homologous recombination events, involving exchange of large chromosomal segments. We did not observed transposon transfer to a C. difficile strain in presence of DNAse, suggesting that a possible transformation-like mechanism occurred in this recipient. PMID- 26442179 TI - The "complex" RNA post-transcriptional element of a "simple" retrovirus. AB - Replication of retroviruses and transposition of endogenous retroelements exploits a unique mechanism of post-transcriptional regulation as a means of exporting their incompletely-spliced mRNAs (which serve as both the genomic RNA and the template for protein synthesis). Following discovery of the Rev response element (RRE) that mediates nucleocytoplasmic export of the full-length and singly-spliced human immunodeficiency virus type 1 (HIV-1) genome, equivalent cis acting regulatory elements have been characterized for both complex and simple retroviruses and retroelements, together with the obligate viral and host proteins with which they interact. The exception to this is the gammaretrovirus family of simple retroviruses, exemplified by reticuloendotheliosis virus (REV), murine leukemia virus (MLV) and xenotropic MLV-related retrovirus (XMRV). In this commentary, we discuss our recent data that reported structural and functional data on the MLV/XMRV post-transcriptional regulatory element (designated the PTE). The PTE was characterized by a highly-structured region of multiple stem loops (SL1 - SL7) overlapping the pro and 5' portion of the pol open reading frames, comprising a bipartite export signal whose structures are separated by ~1400 nt. In addition, structural probing suggested that SL3 nucleotides were involved in pseudoknot formation. These data, when compared with RNA transport elements of complex retroviruses (HIV) and simple murine retrotransposons (musD), collectively present an emerging picture that long-range tertiary interactions are critical mediators of their biological function. PMID- 26442178 TI - Stable persistence of the yeast plasmid by hitchhiking on chromosomes during vegetative and germ-line divisions of host cells. AB - The chromosome-like stability of the Saccharomyces cerevisiae plasmid 2 micron circle likely stems from its ability to tether to chromosomes and segregate by a hitchhiking mechanism. The plasmid partitioning system, responsible for chromosome-coupled segregation, is comprised of 2 plasmid coded proteins Rep1 and Rep2 and a partitioning locus STB. The evidence for the hitchhiking model for mitotic plasmid segregation, although compelling, is almost entirely circumstantial. Direct tests for plasmid-chromosome association are hampered by the limited resolving power of current cell biological tools for analyzing yeast chromosomes. Recent investigations, exploiting the improved resolution of yeast meiotic chromosomes, have revealed the plasmid's propensity to be present at or near chromosome tips. This localization is consistent with the rapid plasmid movements during meiosis I prophase, closely resembling telomere dynamics driven by a meiosis-specific nuclear envelope motor. Current evidence is consistent with the plasmid utilizing the motor as a platform for gaining access to telomeres. Episomes of viruses of the papilloma family and the gammaherpes subfamily persist in latently infected cells by tethering to chromosomes. Selfish genetic elements from fungi to mammals appear to have, by convergent evolution, arrived at the common strategy of chromosome association as a means for stable propagation. PMID- 26442180 TI - Evaluating the effect of horizontal transmission on the stability of plasmids under different selection regimes. AB - In theory, plasmids can only be maintained in a population when the rate of horizontal gene transfer is larger than the combined effect of segregational loss and the decrease of fitness associated with plasmid carriage. Recent advances in genome sequencing have shown, however, that a large fraction of plasmids do not carry the genes necessary for conjugation or mobilization. So, how are so-called non-transmissible plasmids able to persist? In order to address this question, we examined a previously published evolutionary model based on the interaction between P. aeruginosa and the non-transmissible plasmid pNUK73. Both our in silico and in vitro results demonstrated that, although compensatory adaptation can decrease the rate of plasmid decay, the conditions for the maintenance of a non-transmissible plasmid are very stringent if the genes it carries are not beneficial to the bacterial host. This result suggests that apparently non transmissible plasmids may still experience episodes of horizontal gene transfer occurring at very low frequencies, and that these scattered transmission events are sufficient to stabilize these plasmids. We conclude by discussing different genomic and microbiological approaches that could allow for the detection of these rare transmission events and thus to obtain a reliable estimate of the rate of horizontal gene transfer. PMID- 26442181 TI - Repetitive elements regulate circular RNA biogenesis. AB - It was long assumed that eukaryotic precursor mRNAs (pre-mRNAs) are almost always spliced to generate a linear mRNA that is subsequently translated to produce a protein. However, it is now clear that thousands of protein-coding genes can be non-canonically spliced to produce circular noncoding RNAs, some of which are expressed at much higher levels than their associated linear mRNAs. How then does the splicing machinery decide whether to generate a linear mRNA or a circular RNA? Recent work has revealed that intronic repetitive elements, including sequences derived from transposons, are critical regulators of this decision. In most cases, circular RNA biogenesis appears to be initiated when complementary sequences from 2 different introns base pair to one another. This brings the splice sites from the intervening exon(s) into close proximity and facilitates the backsplicing event that generates the circular RNA. As many pre-mRNAs contain multiple intronic repeats, distinct circular transcripts can be produced depending on which repeats base pair to one another. Intronic repeats are thus critical regulatory sequences that control the functional output of their host genes, and potentially cause the functions of protein-coding genes to be highly divergent across species. PMID- 26442182 TI - LINE-1 activity as molecular basis for genomic instability associated with light exposure at night. AB - The original hypothesis that exposure to light at night increases risk of breast cancer via suppression of nocturnal melatonin production was proposed over 2 decades ago. In 2007, shift work that involves circadian disruption has been recognized by the World Health Organization as a probable human carcinogen. Our discovery of melatonin-dependent regulation of LINE-1 retrotransposon expression and mobilization is the latest addition to the list of cellular genes and processes that are affected by light exposure at night. This finding establishes an unexpected health relevant connection between this endogenous DNA damaging agent and environmental light exposure. It also offers an appealing hypothesis pertaining to the origin of genomic instability in the genomes of individuals with light at night- or age-associated disruption of melatonin signaling. PMID- 26442183 TI - Unraveling the regulatory network of IncA/C plasmid mobilization: When genomic islands hijack conjugative elements. AB - Conjugative plasmids of the A/C incompatibility group (IncA/C) have become substantial players in the dissemination of multidrug resistance. These large conjugative plasmids are characterized by their broad host-range, extended spectrum of antimicrobials resistance, and prevalence in enteric bacteria recovered from both environmental and clinical settings. Until recently, relatively little was known about the basic biology of IncA/C plasmids, mostly because of the hindrance of multidrug resistance for molecular biology experiments. To circumvent this issue, we previously developed pVCR94DeltaX, a convenient prototype that codes for a reduced set of antibiotic resistances. Using pVCR94DeltaX, we then characterized the regulatory pathway governing IncA/C plasmid dissemination. We found that the expression of roughly 2 thirds of the genes encoded by this plasmid, including large operons involved in the conjugation process, depends on an FlhCD-like master activator called AcaCD. Beyond the mobility of IncA/C plasmids, AcaCD was also shown to play a key role in the mobilization of different classes of genomic islands (GIs) identified in various pathogenic bacteria. By doing so, IncA/C plasmids can have a considerable impact on bacterial genomes plasticity and evolution. PMID- 26442184 TI - Get the jump - Do 3'UTRs protect transposable elements from silencing? AB - Eukaryotic genomes contain large numbers of transposable elements and repetitive sequences that are subjected to silencing through epigenetic mechanisms. These involve primarily DNA methylation, chromatin modifications and small RNA. It is known that these transposable elements can affect the expression of neighboring genes; however, little is known about how transposable element silencing depends on the general chromosomal environment at the insertion site. Taking advantage of the vast genomic resources available in Arabidopsis thaliana, a recent report begins to unravel these interactions by identifying insertion sites of one specific MULE element, AtMu1c across the A. thaliana lineage. Among over 30 insertion sites analyzed, a correlation between the loss of epigenetic silencing and the insertion into the 3'end of protein coding genes was found. Here, we discuss details, implications and potential mechanisms of these findings that may be applicable to a much wider set of transposable elements and across diverse species. PMID- 26442185 TI - The coelacanth: Can a "living fossil" have active transposable elements in its genome? AB - The coelacanth has long been regarded as a "living fossil," with extant specimens looking very similar to fossils dating back to the Cretaceous period. The hypothesis of a slowly or even not evolving genome has been proposed to account for this apparent morphological stasis. While this assumption seems to be sustained by different evolutionary analyses on protein-coding genes, recent studies on transposable elements have provided more conflicting results. Indeed, the coelacanth genome contains many transposable elements and has been shaped by several major bursts of transposition during evolution. In addition, comparison of orthologous genomic regions from the genomes of the 2 extant coelacanth species L. chalumnae and L. menadoensis revealed multiple species-specific insertions, indicating transposable element recent activity and contribution to post-speciation genome divergence. These observations, which do not support the genome stasis hypothesis, challenge either the impact of transposable elements on organismal evolution or the status of the coelacanth as a "living fossil." Closer inspection of fossil and molecular data indicate that, even if coelacanths might evolve more slowly than some other lineages due to demographic and/or ecological factors, this variation is still in the range of a "non-fossil" vertebrate species. PMID- 26442186 TI - Comparison of methods for the determination of the transposition rate of mobile elements. AB - There is wide-spread interest in understanding the rate of transposable element movement within populations and between species. A recent study using interprecific crosses between D. buzzatii and D. koepferae indicated that transposition rates in hybrids may be quite high. However, we suggest caution should be taken in this interpretation since AFLP methods to detect transposition events may lead to overestimated rate estimates. Comparative analyses of genome instability received by different methods suggest that transposition rates can be higher in intraspecific crosses compared to interspecific crosses. PMID- 26442187 TI - The lambda - P22 problem. AB - Lambda and P22 are members of 2 families of tailed phages and have limited genomic relationships. Both form hybrids with many phages. P22 appears as a hybrid of mixed ancestry. Despite their similarities, lambda and P22 and their relatives form 2 distinct lineages and must be classified separately. PMID- 26442188 TI - Phage therapy of pulmonary infections. AB - It is generally agreed that a bacteriophage-associated phenomenon was first unambiguously observed one-hundred years ago with the findings of Twort in 1915. This was independently followed by complementary observations by d'Herelle in 1917. D'Herelle's appreciation of the bacteriophage phenomenon appears to have directly led to the development of phages as antibacterial agents within a variety of contexts, including medical and agricultural. Phage use to combat nuisance bacteria appears to be especially useful where targets are sufficiently problematic, suitably bactericidal phages exist, and alternative approaches are lacking in effectiveness, availability, safety, or cost effectiveness, etc. Phage development as antibacterial agents has been strongest particularly when antibiotics have been less available or useful, e.g., such as in the treatment of chronic infections by antibiotic-resistant bacteria. One relatively under explored or at least not highly reported use of phages as therapeutic agents has been to combat bacterial infections of the lungs and associated tissues. These infections are diverse in terms of their etiologies, manifestations, and also in terms of potential strategies of phage delivery. Here I review the literature considering the phage therapy of pulmonary and pulmonary-related infections, with emphasis on reports of clinical treatment along with experimental treatment of pulmonary infections using animal models. PMID- 26442189 TI - Life In Science. PMID- 26442190 TI - My life with Mu. PMID- 26442191 TI - Giuseppe Bertani (1923-2015). PMID- 26442192 TI - Life in science. PMID- 26442193 TI - Serendipity and the times. PMID- 26442194 TI - Bioinformatics as a first-line approach for understanding bacteriophage transcription. AB - Current approach to understanding bacteriophage transcription strategies during infection includes a combination of experimental and bioinformatics approaches, which is often time and resource consuming. Given the exponentially growing number of sequenced bacteriophage genomes, it becomes sensible asking to what extent one can understand bacteriophage transcription by using bioinformatics methods alone. We here argue that a suitable choice of computational methods may provide a highly efficient first-line approach for underst-anding bacteriophage transcription. PMID- 26442195 TI - Phage on the stage. AB - The resurgence of interest in bacteriophages for use in combating antibiotic resistant bacteria is coincident with an urgent call for more effective science education practices, including hands-on learning opportunities. To address this issue, a number of solutions have been proposed, including a large educational experiment, begun in 2007 by the Howard Hughes Medical Institute and currently involving over 85 colleges and universities, which has students discovering unique phages, obtaining images, and purifying phage DNA. A subset of these phage genomes is sequenced and analyzed using bioinformatics tools. Papers describing individual phage discoveries and comparative genomic studies are being published regularly. The vast majority of students in the program are in their first year of college, a critical time in capturing their interest and retaining them as science majors. This viral discovery model is being adopted and modified by a wide variety of educational institutions using a number of different bacterial hosts. In the opinion of the authors, this program and others like it represent a model accessible to virtually any undergraduate setting. And because of these programs, bacteriophage enthusiasts (academics, health professionals, biotechnology companies) can look forward to more well prepared students entering their ranks and should anticipate many more potentially useful phages discovered and characterized. PMID- 26442197 TI - C. elegans sirtuin SIR-2.4 and its mammalian homolog SIRT6 in stress response. AB - Stress is a significant life event. The immediate response to stress is critical for survival. In organisms ranging from the unicellular Saccharomyces cerevisiae to protozoa (Trypanosoma brucei) and metazoan (such as Caenorhabditis elegans, Homo sapiens) stress response leads to the formation of cytoplasmic RNA-protein complexes referred to as stress granules (SGs). SGs regulate cell survival during stress by the sequestration of the signaling molecules implicated in apoptosis. They are a transient place of messenger ribonucleoproteins (mRNPs) remodeling for storage, degradation, or reinitiation of translation during stress and recovery from stress. Recently, we have identified chromatin factor, the sirtuin C. elegans SIR-2.4 variant and its mammalian homolog SIRT6 as a regulator of SGs formation. SIRT6 is highly conserved NAD(+)-dependent lysine deacetylase and ADP ribosyltransferase impacting longevity, metabolism, and cancer. We observed that the cellular formation of SGs by SIRT6 or SIR-2.4 was linked with the cell viability or C. elegans survival and was dependent on SIRT6 enzymatic activity. Here, we discuss how SIR-2.4/SIRT6 influences SGs formation and stress response. We suggest possible mechanisms for such an unanticipated function of a chromatin regulatory factor SIRT6 in assembly of stress granules and cellular stress resistance. PMID- 26442196 TI - Antimicrobial bacteriophage-derived proteins and therapeutic applications. AB - Antibiotics have the remarkable power to control bacterial infections. Unfortunately, widespread use, whether regarded as prudent or not, has favored the emergence and persistence of antibiotic resistant strains of human pathogenic bacteria, resulting in a global health threat. Bacteriophages (phages) are parasites that invade the cells of virtually all known bacteria. Phages reproduce by utilizing the host cell's machinery to replicate viral proteins and genomic material, generally damaging and killing the cell in the process. Thus, phage can be exploited therapeutically as bacteriolytic agents against bacteria. Furthermore, understanding of the molecular processes involved in the viral life cycle, particularly the entry and cell lysis steps, has led to the development of viral proteins as antibacterial agents. Here we review the current preclinical state of using phage-derived endolysins, virion-associated peptidoglycan hydrolases, polysaccharide depolymerases, and holins for the treatment of bacterial infection. The scope of this review is a focus on the viral proteins that have been assessed for protective effects against human pathogenic bacteria in animal models of infection and disease. PMID- 26442199 TI - Rare disease diagnosis: A review of web search, social media and large-scale data mining approaches. AB - Physicians and the general public are increasingly using web-based tools to find answers to medical questions. The field of rare diseases is especially challenging and important as shown by the long delay and many mistakes associated with diagnoses. In this paper we review recent initiatives on the use of web search, social media and data mining in data repositories for medical diagnosis. We compare the retrieval accuracy on 56 rare disease cases with known diagnosis for the web search tools google.com, pubmed.gov, omim.org and our own search tool findzebra.com. We give a detailed description of IBM's Watson system and make a rough comparison between findzebra.com and Watson on subsets of the Doctor's dilemma dataset. The recall@10 and recall@20 (fraction of cases where the correct result appears in top 10 and top 20) for the 56 cases are found to be be 29%, 16%, 27% and 59% and 32%, 18%, 34% and 64%, respectively. Thus, FindZebra has a significantly (p < 0.01) higher recall than the other 3 search engines. When tested under the same conditions, Watson and FindZebra showed similar recall@10 accuracy. However, the tests were performed on different subsets of Doctors dilemma questions. Advances in technology and access to high quality data have opened new possibilities for aiding the diagnostic process. Specialized search engines, data mining tools and social media are some of the areas that hold promise. PMID- 26442198 TI - Ribosomopathies: Global process, tissue specific defects. AB - Disruptions in ribosomal biogenesis would be expected to have global and in fact lethal effects on a developing organism. However, mutations in ribosomal protein genes have been shown in to exhibit tissue specific defects. This seemingly contradictory finding - that globally expressed genes thought to play fundamental housekeeping functions can in fact exhibit tissue and cell type specific functions - provides new insight into roles for ribosomes, the protein translational machinery of the cell, in regulating normal development and disease. Furthermore it illustrates the surprisingly dynamic nature of processes regulating cell type specific protein translation. In this review, we discuss our current knowledge of a variety of ribosomal protein mutations associated with human disease, and models to better understand the molecular mechanisms associated with each. We use specific examples to emphasize both the similarities and differences between the effects of various human ribosomal protein mutations. Finally, we discuss areas of future study that are needed to further our understanding of the role of ribosome biogenesis in normal development, and possible approaches that can be used to treat debilitating ribosomopathy diseases. PMID- 26442200 TI - A Perspective on Prostate Carcinogenesis and Chemoprevention. AB - In this perspective, modifiable carcinogenic factors for the prostate are summarized. This is followed by a discussion of how current knowledge about causation of prostate cancer and chemoprevention of prostate cancer can be used to develop preventive strategies. Prostate cancer is a slowly developing cancer which offers opportunities for preventive interventions. Only a few randomized clinical trials of prostate cancer prevention have been completed. The SELECT study with selenium and vitamin E did not find protective effects, but in two trials with 5alpha-reductase inhibitors risk was reduced about 25%, showing that chemoprevention is possible and indicating that the androgen receptor is a suitable target. Besides smoking cessation and reduction of obesity, there are no known dietary or life style interventions that will have a major impact on prostate cancer risk. Inflammation of the prostate is an attractive target and aspirin may be a promising candidate agent, but has not been addressed yet in preclinical and clinical studies. Antioxidants other than selenium and vitamin E are unlikely to be very effective and data on several dietary supplements are not encouraging. More candidate agents need to be identified and tested in relevant and adequate preclinical models and Phase II trials that have predictive value for outcome of Phase III randomized studies. Doing this will require a systematic approach comparing preclinical and clinical study outcomes to determine their predictive value of preventive efficacy. PMID- 26442202 TI - Targeting the COX-2 Pathway to Improve Therapeutic Response in the Obese Breast Cancer Patient Population. AB - Multiple studies have demonstrated that obesity is associated with a worse outcome for all breast cancer subtypes and that obese breast cancer patients do not respond as well as normal weight patients to aromatase inhibitor treatment and chemotherapy. While a number of mechanisms have been proposed to explain this link, recent studies have provided evidence that elevated local cyclooxygenase-2 (COX-2) expression and the resulting increase in prostaglandin E2 (PGE2) production may play an important role. COX-2 upregulation in breast tumors is associated with a poor prognosis, a connection generally attributed to PGE2's direct effects on apoptosis and invasion as well as its stimulation of pre adipocyte aromatase expression and subsequent estrogen production. Research in this area has provided a strong foundation for the hypothesis that COX-2 signaling is involved in the obesity-breast cancer link, and further study regarding the role of COX-2 in this link is warranted. PMID- 26442201 TI - Targeting HER2 Positive Breast Cancer with Chemopreventive Agents. AB - Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is a subtype of breast cancer that is exhibited in approximately 20-30% of breast cancer cases. The overexpression of HER2 is typically associated with a more aggressive disease and poor prognosis. Currently, the therapeutic drugs trastuzumab and lapatinib are the most commonly used to combat HER2+ breast cancer. However, tumors can develop resistance to these drugs. A better understanding of the mechanism of how HER2+ breast cancer works will help aid the development for new therapeutic approaches which more closely target the source of the signaling dysfunction. This review summarizes four major points in the context of HER2 over-expressing breast cancer (i) HER2 as a molecular target in breast cancer therapy, (ii) current treatment options as well as ongoing clinical studies, (iii) animal and cellular models for the study of HER2 over-expressing breast cancer, and (iv) future therapies and chemopreventive agents used to target HER2+ breast cancer. PMID- 26442204 TI - Letter From the Chair. PMID- 26442203 TI - The AQP2 mutation V71M causes nephrogenic diabetes insipidus in humans but does not impair the function of a bacterial homolog. AB - Several point mutations have been identified in human aquaporins, but their effects on the function of the respective aquaporins are mostly enigmatic. We analyzed the impact of the aquaporin 2 mutation V71M, which causes nephrogenic diabetes insipidus in humans, on aquaporin structure and activity, using the bacterial aquaglyceroporin GlpF as a model. Importantly, the sequence and structure around the V71M mutation is highly conserved between aquaporin 2 and GlpF. The V71M mutation neither impairs substrate flux nor oligomerization of the aquaglyceroporin. Therefore, the human aquaporin 2 mutant V71M is most likely active, but cellular trafficking is probably impaired. PMID- 26442205 TI - The Use of a Pure Native Collagen Dressing for Wound Bed Preparation Prior to Use of a Living Bi-layered Skin Substitute. AB - Management of chronic wounds in the outpatient setting is quite challenging. The extensive co-morbid medical problems of the chronically ill patient along with the complexities of the wound bed and its biochemical environment has led to a plethora of patients with poor wound healing. This ever increasing population is a challenge for the wound care practitioner and cost to the health care system and patient. Increased wound chronicity has promulgated the use of advanced wound care products, including Living Skin Substitutes (LSS), in an attempt to obtain wound closure, and ultimately both physiological and functional healing.(1-3) In the outpatient setting, it is evident that the efficacy of the LSS varies widely depending on the patient type with some patients responding quite favorably while others who do not achieve healing despite repeated applications of LSS. This case series demonstrates that a systematic method of wound bed preparation prior to the application of LSS improved healing outcomes. The entire wound bed preparation protocol included autolytic, non-selective, and sharp-selective debridement, if deemed appropriate, followed by the weekly application of a pure native collagen. The wound bed preparation protocol was completed prior to LSS application. This case series presents evidence supporting the application of a 100% native collagen dressing to wound bed prior to the final step of LSS utilization. PMID- 26442206 TI - Clinical Effectiveness of Hyperbaric Oxygen Therapy in Complex Wounds. AB - Hyperbaric Oxygen (HBO, HBO2) Therapy is a non-invasive therapy. It has been applied as adjuvant treatment in many medical conditions over the past 50 years. Different treatment protocols have been proven effective for specifically indicated conditions. To evaluate the clinical effectiveness of Hyperbaric Oxygen (HBO) Therapy as an adjunctive treatment for patients with complex wounds. In this prospective cohort study, 40 patients with complex wounds were included. All patients received HBO. HBO was delivered with 100% oxygen for 90 min at 2.0-2.4 ATA. Wound sizes were assessed by one wound surgeon before, during, and every 2 weeks for a total of 12 months after HBO. An analysis of demographic data, wound size and wound photography was performed. Over the 22-month period ending October 31, 2013, 40 patients (21 men and 19 women) with a mean age of 59.73 (range, 29 88) with complex wounds were included. All complex wounds studied were at least 6 months old. The mean wound size was 16.72 cm(2) in diameter. Thirty-one patients with complex wounds healed after the completion of a series of HBO treatments (77.5%). Two orocutaneous fistulas were completely closed without further surgery. After 5 HBO treatments, the wound size reduced by 29.7% on average (p = 1.24 * 10(-6)). After 10 HBO treatments, the wound size statistically significantly reduced by an additional 16.9% (p = 0.0002). There were no complications in this study. Wound healing process was accelerated by HBO. Significant wound size reduction was noted after 5 HBO treatments. Because the biggest reduction in wound size occurred within the first 10 HBO treatments, it is important to conduct these first treatments without interruption. HBO is an effective and safe treatment modality for complex wounds. PMID- 26442207 TI - Optimizing Wound Bed Preparation With Collagenase Enzymatic Debridement. AB - Difficult-to-heal and chronic wounds affect tens of millions of people worldwide. In the U.S. alone, the direct cost for their treatment exceeds $25 billion. Yet despite advances in wound research and treatment that have markedly improved patient care, wound healing is often delayed for weeks or months. For venous and diabetic ulcers, complete wound closure is achieved in as few as 25%-50% of chronic or hard-to-heal wounds. Wound bed preparation and the consistent application of appropriate and effective debridement techniques are recommended for the optimized treatment of chronic wounds. The TIME paradigm (Tissue, Inflammation/infection, Moisture balance and Edge of wound) provides a model to remove barriers to healing and optimize the healing process. While we often think of debridement as an episodic event that occurs in specific care giver/patient interface. There is the possibility of a maintenance debridement in which the chronic application of a medication can assist in both the macroscopic and microscopic debridement of a wound. We review the various debridement therapies available to clinicians in the United States, and explore the characteristics and capabilities of clostridial collagenase ointment (CCO), a type of enzymatic debridement, that potentially allows for epithelialization while debriding. It appears that in the case of CCO it may exert this influences by removal of the necrotic plug while promoting granulation and sustaining epithelialization. It is also easily combined with other methods of debridement, is selective to necrotic tissue, and has been safely used in various populations. We review the body of evidence has indicated that this concept of maintenance debridement, especially when combined episodic debridement may add a cost an efficacious, safe and cost effective choice for debridement of cutaneous ulcers and burn wounds and it will likely play an expanding role in all phases of wound bed preparation. PMID- 26442208 TI - Calciphylaxis in Patients With Preserved Kidney Function. AB - Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is a devastating disease typically seen in patients with end stage renal disease. It manifests as extremely painful symmetrical wounds resistant to surgical and medical interventions. The prevalence of CUA among hemodialysis dependent patients was found to be as high as 4.1%. The management of patients with CUA requires a multidisciplinary approach by the medical team, yet often results in a low rate of successful outcomes. Recently, non-uremic calciphylaxis (NUC) has been described in the absence of kidney disease. Limited knowledge exists on the management of NUC and the outcomes of this condition. Herein we describe three clinical scenarios of patients diagnosed with NUC in the absence of permanent or prolonged acute renal pathology. The reporting of successful and fruitless therapeutic interventions for wound management in NUC is important for compiling the evidence of effective therapeutic strategies. PMID- 26442210 TI - Editorial: Advances in Combination Tumor Immunotherapy. PMID- 26442209 TI - Mechanical Stress as the Common Denominator between Chronic Inflammation, Cancer, and Alzheimer's Disease. AB - The pathogenesis of common diseases, such as Alzheimer's disease (AD) and cancer, are currently poorly understood. Inflammation is a common risk factor for cancer and AD. Recent data, provided by our group and from others, demonstrate that increased pressure and inflammation are synonymous. There is a continuous increase in pressure from inflammation to fibrosis and then cancer. This is in line with the numerous papers reporting high interstitial pressure in cancer. But most authors focus on the role of pressure in the lack of delivery of chemotherapy in the center of the tumor. Pressure may also be a key factor in carcinogenesis. Increased pressure is responsible for oncogene activation and cytokine secretion. Accumulation of mechanical stress plays a key role in the development of diseases of old age, such as cardiomyopathy, atherosclerosis, and osteoarthritis. Growing evidence suggest also a possible link between mechanical stress in the pathogenesis of AD. The aim of this review is to describe environmental and endogenous mechanical factors possibly playing a pivotal role in the mechanism of chronic inflammation, AD, and cancer. PMID- 26442211 TI - Dosimetric Effects of the Interfraction Variations during Whole Breast Radiotherapy: A Prospective Study. AB - INTRODUCTION: The aim of this work was to assess the dosimetric impact of the interfraction variations during breast radiotherapy. MATERIALS AND METHODS: Daily portal imaging measurements were prospectively performed in 10 patients treated with adjuvant whole breast irradiation (50 Gy/25 fractions). Margins between the clinical target volume and the planning target volume (PTV) were 5 mm in the three dimensions. Parameters of interest were the central lung distance (CLD) and the inferior central margin (ICM). Daily movements were applied to the baseline treatment planning (TP1) to design a further TP (TP2). The PTV coverage and organ at risk exposure were measured on both TP1 and TP2, before being compared. RESULTS: A total of 241 portal images were analyzed. The random and systematic errors were 2.6 and 3.7 mm for the CLD, 4.3 and 6.9 mm for the ICM, respectively. No significant consequence on the PTV treatments was observed (mean variations: +0.1%, p = 0.56 and -1.8%, p = 0.08 for the breast and the tumor bed, respectively). The ipsilateral lung and heart exposure was not significantly modified. CONCLUSION: In our series, the daily interfraction variations had no significant effect on the PTV coverage or healthy tissue exposure during breast radiotherapy. PMID- 26442213 TI - Use of a Flexible Inflatable Multi-Channel Applicator for Vaginal Brachytherapy in the Management of Gynecologic Cancer. AB - INTRODUCTION: Evaluate use of novel multi-channel applicator (MC) CapriTM to improve vaginal disease coverage achievable by single-channel applicator (SC) and comparable to Syed plan simulation. MATERIALS AND METHODS: Twenty-eight plans were evaluated from four patients with primary or recurrent gynecologic cancer in the vagina. Each received whole pelvis radiation, followed by three weekly treatments using HDR brachytherapy with a 13-channel MC. Upper vagina was treated to 5 mm depth to 1500 cGy/3 fractions with a simultaneous integrated boost totaling 2100 cGy/3 fractions to tumor. Modeling of SC and Syed plans was performed using MC scans for each patient. Dosimetry for MC and SC plans was evaluated for PTV700 cGy coverage, maximum dose to 2 cm(3) to bladder, rectum, as well as mucosal surface points. Dosimetry for Syed plans was calculated for PTV700 cGy coverage. Patients were followed for treatment response and toxicity. RESULTS: Dosimetric analysis between MC and SC plans demonstrated increased tumor coverage (PTV700 cGy), with decreased rectal, bladder, and contralateral vaginal mucosa dose in favor of MC. These differences were significant (p < 0.05). Comparison of MC and Syed plans demonstrated increased tumor coverage in favor of Syed plans which were not significant (p = 0.71). Patients treated with MC had no cancer recurrence or >=grade 3 toxicity. CONCLUSION: Use of MC was efficacious and safe, providing superior coverage of tumor volumes <=1 cm depth compared to SC and comparable to Syed implant. MC avoids excess dose to surrounding organs compared to SC, and potentially less morbidity than Syed implants. For tumors extending <=1 cm depth, use of MC represents an alternative to an interstitial implant. PMID- 26442212 TI - Potential Gene Interactions in the Cell Cycles of Gametes, Zygotes, Embryonic Stem Cells and the Development of Cancer. AB - OBJECTIVES: This review is to explore whether potential gene interactions in the cell cycles of gametes, zygotes, and embryonic stem (ES) cells are associated with the development of cancer. METHODS: MEDPILOT at the Central Library of the University of Cologne, Germany (Zentralbibliothek Koln) that covers 5,800 international medical journals and 4,300 E-journals was used to collect data. The initial searches were done in December 2012 and additional searches in October 2013-May 2015. The search terms included "cancer development," "gene interaction," and "ES cells," and the time period was between 1998 and 2015. A total of 147 articles in English language only were included in this review. RESULTS: Transgenerational gene translation is implemented in the zygote through interactions of epigenetic isoforms of transcription factors (TFs) from parental gametes, predominantly during the first two zygote cleavages. Pluripotent transcription factors may provide interacting links with mutated genes during zygote-to-ES cell switches. Translation of post-transcriptional carcinogenic genes is implemented by abnormally spliced, tumor-specific isoforms of gene encoded mRNA/non-coding RNA variants of TFs employing de novo gene synthesis and neofunctionalization. Post-translationally, mutated genes are preserved in pre neoplastic ES cell subpopulations that can give rise to overt cancer stem cells. Thus, TFs operate as cell/disease-specific epigenetic messengers triggering clinical expression of neoplasms. CONCLUSION: Potential gene interactions in the cell cycle of gametes, zygotes, and ES cells may play some roles in the development of cancer. PMID- 26442214 TI - Inhibition of Immune Checkpoints and Vascular Endothelial Growth Factor as Combination Therapy for Metastatic Melanoma: An Overview of Rationale, Preclinical Evidence, and Initial Clinical Data. AB - The role of angiogenesis as a mediator of immune regulation in the tumor microenvironment has recently come into focus. Furthermore, emerging evidence indicates that immunotherapy can lead to immune-mediated vasculopathy in the tumor, suggesting that the tumor vasculature may be an important interface between the tumor-directed immune response and the cancer itself. The advent of immune checkpoint inhibition as an effective immunotherapeutic strategy for many cancers has led to a better understanding of this interface. While the inhibition of angiogenesis through targeting of vascular endothelial growth factor (VEGF) has been used successfully for the treatment of cancer for many years, the mechanisms of its anti-tumor activity remain poorly understood. Initial studies of the complex relationship between angiogenesis, VEGF signaling and the immune system suggest that the combination of immune checkpoint blockade with angiogenesis inhibition has potential. While the majority of this work has been performed in metastatic melanoma, immunotherapy is rapidly showing promise in a broad range of malignancies and efforts to enhance immunotherapy will broadly impact the future of oncology. Here, we review the preclinical rationale and clinical investigations of combined angiogenesis inhibition and immunotherapy/immune checkpoint inhibition as a potentially promising combinatorial approach for cancer treatment. PMID- 26442215 TI - Screening for Psychological Distress in Adult Primary Brain Tumor Patients and Caregivers: Considerations for Cancer Care Coordination. AB - INTRODUCTION: This study aimed to assess psychological distress (PD) as scored by the Distress Thermometer (DT) in adult primary brain tumor patients and caregivers (CGs) in a clinic setting and ascertain if any high-risk subgroups for PD exist. MATERIAL AND METHODS: From May 2012 to August 2013, n = 96 patients and n = 32 CG underwent DT screening at diagnosis, and a differing cohort of n = 12 patients and n = 14 CGs at first recurrence. Groups were described by diagnosis (high grade, low grade, and benign) and English versus non English speaking. Those with DT score >=4 met caseness criteria for referral to psycho-oncology services. One-way ANOVA tests were conducted to test for between-group differences where appropriate. RESULTS: At diagnosis and first recurrence, 37.5 and 75.0% (respectively) of patients had DT scores above the cutoff for distress. At diagnosis, 78.1% of CGs met caseness criteria for distress. All CGs at recurrence met distress criterion. Patients with high-grade glioma had significantly higher scores than those with a benign tumor. For patients at diagnosis, non English speaking participants did not report significantly higher DT scores than English speaking participants. DISCUSSION: Psychological distress is particularly elevated in CGs and in patients with high-grade glioma at diagnosis. Effective PD screening, triage, and referral by skilled care coordinators are vital to enable timely needs assessment, psychological support, and effective intervention. PMID- 26442216 TI - Preclinical Evaluation of Intraoperative Low-Energy Photon Radiotherapy Using Spherical Applicators in Locally Advanced Prostate Cancer. AB - BACKGROUND: Surgery plus adjuvant radiotherapy is standard care for locally advanced prostate cancer (stage pT3R1). Intraoperative low-energy photon radiotherapy offers several advantages over external beam radiotherapy, and several systems are now available for its delivery, using spherical applicators, which require only limited shielding. The aim of this study was to evaluate the feasibility of this technique for the prostate bed. MATERIALS AND METHODS: Applicators were assessed using MRI image data and cadaveric dissection. In cadavers, targeted tissues, defined as a urethral section, both neurovascular bundle sections, the bladder neck and the beds of the seminal vesicles, were marked with metallic surgical clips. Distances between clips and applicator were measured using CT. A dosimetric study of the application of 12 Gy at 5 mm depth was performed using CT images of prostatectomized cadavers. RESULTS: Using MRI images from 34 prostate cancer patients, we showed that the ideal applicator diameter ranges from 45 to 70 mm. Using applicators of different sizes to encompass the prostate bed in nine cadavers, we showed that the distance between target tissues and applicator was <2 mm for all target tissues except the upper extremity of the seminal vesicles (19 mm). Dosimetric study showed a good dose distribution in all target tissues in contact with the applicator, with a low probability of rectum and bladder complication. CONCLUSION: Intraoperative radiotherapy of the prostate bed is feasible, with good coverage of targeted tissues. Clinical study of safety and efficacy is now required. PMID- 26442217 TI - Editorial: Advances in Epithelial Ovarian Cancer: Model Systems, Microenvironmental Influences, Therapy, and Origins. PMID- 26442218 TI - Resection Followed by Involved-Field Fractionated Radiotherapy in the Management of Single Brain Metastasis. AB - INTRODUCTION: We expanded upon our previous experience using involved-field fractionated radiotherapy (IFRT) as an alternative to whole brain radiotherapy or stereotactic radiosurgery for patients with surgically resected brain metastases (BM). MATERIALS AND METHODS: All patients with single BM who underwent surgical resection followed by IFRT at our institution from 2006 to 2013 were evaluated. Local recurrence (LR)-free survival, distant failure (DF)-free survival, and overall survival (OS) were determined. Analyses were performed associating clinical variables with LR and DF. Salvage approaches and toxicity of treatment for each patient were also assessed. RESULTS: Median follow-up was 19.1 months. Fifty-six patients were treated with a median dose of 40.05 Gy/15 fractions with IFRT to the resection cavity. LR-free survival was 91.4%, DF-free survival was 68.4%, and OS was 77.7% at 12 months. No variables were associated with increased LR; however, melanoma histopathology and infratentorial location were associated with DF on multivariate analysis. LRs were salvaged in 5/8 patients, and DFs were salvaged in 24/29 patients. Two patients developed radionecrosis. CONCLUSION: Adjuvant IFRT is feasible and safe for well-selected patients with surgically resected single BM. Acceptable rates of local control and salvage of distal intracranial recurrences continue to be achieved with continued follow-up. PMID- 26442219 TI - Detection of Circulating Tumor Cells in Non-Small Cell Lung Cancer. AB - Lung cancer is the most common cause of cancer-related deaths that frequently metastasizes prior to disease diagnosis. Circulating tumor cells (CTCs) are found in many different types of epithelial tumors and are of great clinical interest in terms of prognosis and therapy intervention. Here, we present and discuss epithelial cell adhesion molecule-dependent and -independent capture of CTCs in non-small cell lung cancer (NSCLC) and the clinical relevance of CTC detection and characterization. Taking blood samples and analyzing CTCs as "liquid biopsy" might be a far less invasive diagnostic strategy than biopsies of lung tumors or metastases. Moreover, sequential blood sampling allows to study the dynamic changes of tumor cells during therapy, in particular the development of resistant tumor cell clones. PMID- 26442220 TI - Commentary: The unliganded glucocorticoid receptor positively regulates the tumor suppressor gene BRCA1 through GABP beta. PMID- 26442222 TI - Diabetes care among elderly medicare beneficiaries with Parkinson's disease and diabetes. AB - BACKGROUND: Elderly individuals with type 2 diabetes mellitus (T2DM) suffer from several comorbidities, which affect their health outcomes, as well as process of care. This study assessed process and intermediate clinical outcomes of diabetes care among elderly individuals with T2DM and co-occurring Parkinson's disease(PD). METHODS: This study used a retrospective cohort design with propensity score matching using Humana Medicare Advantage Part D claims database (2007-2011) and included elderly (age >= 65 years) Medicare beneficiaries with T2DM (identified by ICD-9-CM code of 250.x0 or 250.x2). PD was identified using ICD-9-CM code of 332.xx. After propensity score matching there were 2,703 individuals with T2DM and PD and 8,109 with T2DM and no PD. The three processes of care measures used in this study included: (i) HbA1c test; (ii) Lipid test; (iii) and Nephropathy screening. Intermediate clinical outcomes consisted of glycemic and lipid control. RESULTS: Multivariable conditional logistic regressions revealed that elderly individuals with T2DM and PD were 12 % (AOR: 0.88, 95 %CI: 0.79-0.97) and 18 % (AOR: 0.82, 95 %CI: 0.72-0.94) less likely to meet the annual American Diabetes Association (ADA) recommended HbA1c and lipid testing goals respectively compared to individuals with T2DM and no PD. Multinomial conditional logistic regressions showed that elderly individuals with T2DM and PD were more likely to have HbA1c and lipid (HbA1c < 8 %; LDL-C <100 mg/dl; HDL-C >= 50 mg/dl; triglyceride <150 mg/dl; and total cholesterol <200 mg/dl) control. CONCLUSIONS: Among elderly individuals with T2DM, those with PD were less likely to achieve ADA recommended annual HbA1c and lipid testing compared to those without PD. However, PD individuals were more likely to achieve intermediate glycemic and lipid control. PMID- 26442221 TI - The trans-Golgi SNARE syntaxin 10 is required for optimal development of Chlamydia trachomatis. AB - Chlamydia trachomatis, an obligate intracellular pathogen, grows inside of a vacuole, termed the inclusion. Within the inclusion, the organisms differentiate from the infectious elementary body (EB) into the reticulate body (RB). The RB communicates with the host cell through the inclusion membrane to obtain the nutrients necessary to divide, thus expanding the chlamydial population. At late time points within the developmental cycle, the RBs respond to unknown molecular signals to redifferentiate into infectious EBs to perpetuate the infection cycle. One strategy for Chlamydia to obtain necessary nutrients and metabolites from the host is to intercept host vesicular trafficking pathways. In this study we demonstrate that a trans-Golgi soluble N-ethylmaleimide-sensitive factor attachment protein (SNARE), syntaxin 10, and/or syntaxin 10-associated Golgi elements colocalize with the chlamydial inclusion. We hypothesized that Chlamydia utilizes the molecular machinery of syntaxin 10 at the inclusion membrane to intercept specific vesicular trafficking pathways in order to create and maintain an optimal intra-inclusion environment. To test this hypothesis, we used siRNA knockdown of syntaxin 10 to examine the impact of the loss of syntaxin 10 on chlamydial growth and development. Our results demonstrate that loss of syntaxin 10 leads to defects in normal chlamydial maturation including: variable inclusion size with fewer chlamydial organisms per inclusion, fewer infectious progeny, and delayed or halted RB-EB differentiation. These defects in chlamydial development correlate with an overabundance of NBD-lipid retained by inclusions cultured in syntaxin 10 knockdown cells. Overall, loss of syntaxin 10 at the inclusion membrane negatively affects Chlamydia. Understanding host machinery involved in maintaining an optimal inclusion environment to support chlamydial growth and development is critical toward understanding the molecular signals involved in successful progression through the chlamydial developmental cycle. PMID- 26442223 TI - Assessment of the feasibility of using sunlight exposure to obtain the recommended level of vitamin D in Canada. AB - BACKGROUND: Endogenous vitamin D synthesis can be affected by a number of variables, including skin colour, amount of skin exposed and levels of ultraviolet radiation. The objective of this study was to assess the feasibility of using only sunlight exposure in Canada to meet the daily recommended level of vitamin D, given differences in these variables and adherence to guidelines for sun protection. METHODS: Ultraviolet index data for 13 Canadian sites were obtained from Environment Canada. The sun exposure times required to synthesize 1000 IU of vitamin D in fair- and dark-skinned people who exposed either 1/4 or 1/8 of their body surface area to the sun were calculated for each hour of the year. These times were then classified according to whether the ultraviolet index was 3 or more (when sun protection is advised) or less than 3. RESULTS: During the fall and winter months and in the more northern sites, ultraviolet radiation levels were too low for all skin types to use sun exposure alone to obtain enough vitamin D within one time period. The required exposure time became longer when a smaller surface area was exposed. For people with darker skin, it can be difficult even in the summer to find opportunities outside of when sun protection is advised to use sunlight to obtain the recommended dose of vitamin D. INTERPRETATION: Although sun exposure is an important source of vitamin D, Canadians should look to other safe sources to meet the body's vitamin D requirements throughout the year. PMID- 26442224 TI - Prevalence and management of osteoarthritis in primary care: an epidemiologic cohort study from the Canadian Primary Care Sentinel Surveillance Network. AB - BACKGROUND: Osteoarthritis is a common chronic condition that affects many older Canadians and is a considerable cause of disability. Our objective was to describe the epidemiology of osteoarthritis in patients aged 30 years and older using electronic medical records (EMRs) in a Canadian primary care population. METHODS: In this retrospective cohort study, we analyzed the EMRs of 207 610 patients over 30 years of age (extracted on December 31, 2012) who had at least one clinic visit during the preceding 2 years. We calculated the age-sex standardized prevalence of diagnosed osteoarthritis and its association with comorbidities and covariates available in the Canadian Primary Care Sentinel Surveillance Network database. RESULTS: The estimated prevalence of diagnosed osteoarthritis was 14.2% (15.6% among women, 12.4% among men). The diagnosis of osteoarthritis was associated with several comorbidities: hypertension (prevalence ratio [PR] 1.17, 95% confidence interval [CI] 1.15-1.18), depression (PR 1.26, 95% CI 1.22-1.3), chronic obstructive pulmonary disease (COPD) (PR 1.16, 95% CI 1.11-1.21) and epilepsy (PR 1.27, 95% CI 1.13-1.43). In addition, 56.6% of patients had received a prescription for a range of nonsteroidal anti inflammatory drugs, 45% of which were topical. Opioid medications were prescribed to 33% of patients for pain management. CONCLUSION: Osteoarthritis is a common disease in middle-aged and older Canadians. It is more common in women than in men and is associated with comorbid conditions. Most patients with osteoarthritis received pharmacotherapy for inflammation and pain management. As the Canadian population ages, osteoarthritis will become an increasing burden for individuals and the health care system. PMID- 26442225 TI - Incidence and cohort prevalence for autism spectrum disorders in the Avalon Peninsula, Newfoundland and Labrador. AB - BACKGROUND: Recent studies have reported increased prevalence for autism spectrum disorders in a number of geographical locations. Our objective was to determine the incidence and 1-year cohort prevalence for autism spectrum disorders in children less than 15 years of age and living in the Avalon Peninsula at the time of diagnosis. METHODS: Retrospective and prospective data were obtained from the Janeway Children's Health and Rehabilitation Centre (St. John's), including the identification and specific diagnosis for all children assessed for autism spectrum disorder from 2006 to 2010. Additional clinic data were reviewed to update the data until the end of 2013. RESULTS: From 2006 to 2010, 272 children had a diagnosis of autism spectrum disorder, averaging 54 new cases per year. The incidence of new cases increased from 10.1 to 16.7 cases per 10 000 per year from 2006 to 2010. At the end of 2013, the prevalence among children born in 2006 was 1 case of autism spectrum disorder per 46 children or 215.77 per 10 000. INTERPRETATION: We found higher rates of autism spectrum disorder than previously reported for this population. The prevalence in this region is also high when compared with other global populations. The high rate of diagnosis supports the need for a provincial autism spectrum disorder registry and further research on autism spectrum disorder within this population. PMID- 26442226 TI - A review of specialties performing temporal artery biopsies in Ontario: a retrospective cohort study. AB - BACKGROUND: Temporal artery biopsy is the gold standard for the diagnosis of giant cell arteritis, but the numbers and types of surgical specialists performing temporal artery biopsies are unknown. The goal of this study was to determine which surgical specialists performed temporal artery biopsies and how geographic location influenced this trend over a period of 10 years. METHODS: This retrospective cohort study included all physicians practising in Ontario from 2002 to 2013. Using comprehensive physician services data from the IntelliHEALTH Medical Services database, physicians performing temporal artery biopsies were identified by the Ontario Health Insurance Plan billing code submitted for remuneration. Physicians were categorized by specialty and geographic Local Health Integration Unit. RESULTS: A total of 9958 patients underwent a temporal artery biopsy during the study period: the biopsies were performed by 11 different subspecialties. The number of patients undergoing a temporal artery biopsy declined over the 10-year study period. Most procedures were performed by general surgeons (38.1%), followed by ophthalmologists (31.0%) and plastic surgeons (23.6%). Ophthalmologists performed more temporal artery biopsies per person compared with general surgeons, but significantly more general surgeons performed at least 1 biopsy. There was significant variation based on geographic location: plastic surgeons performed the most biopsies in regions with a population of more than 1 million people, and general surgeons performed most of the biopsies in rural areas. INTERPRETATION: Geographic location heavily influenced which specialty was most likely to perform temporal artery biopsies. General surgery, ophthalmology and plastic surgery emerged as leaders in this area, and their residency programs should include formal training in this procedure in their curricula. PMID- 26442227 TI - Postmarket safety of drugs approved by Health Canada on the basis of clinical and surrogate outcomes: a cohort study. AB - BACKGROUND: Health Canada approves drugs on the basis of evidence from clinical trials using clinical or surrogate outcomes. This study compares the postmarket safety of these 2 groups of drugs. METHODS: Information about whether clinical or surrogate outcomes were used and the date of market approval were obtained from Health Canada's Summary Basis of Decision documents issued from Jan. 1, 2005, to Dec. 31, 2014. Safety warnings and the dates they were issued were identified through advisories on the MedEffect Canada website. Kaplan-Meier survival curves were calculated to determine the likelihood that drugs in the clinical and surrogate outcome groups would receive a serious safety warning. The time from market authorization to first serious safety warning was compared for the 2 groups of drugs. RESULTS: A total of 124 drugs were approved by Health Canada using clinical outcomes and 114 using surrogate outcomes. Kaplan-Meier curves did not differ between the 2 groups (p < 0.9). The median time from market authorization to first serious safety warning was 722 days in the clinical outcome group and 818 days in the surrogate outcome group (difference 96 days, 95% confidence interval -295 to 425). INTERPRETATION: We found no statistically significant difference in postmarket safety between drugs approved using clinical outcomes and those approved using surrogate outcomes. Because drugs in the surrogate outcome group are approved before their benefit:harm ratio is fully established, these drugs should be used with caution until their clinical benefits are better understood. PMID- 26442229 TI - The experience of nursing women with breastfeeding support: a qualitative inquiry. AB - BACKGROUND: Breastfeeding difficulties are a common occurrence, are highly personal and can vary from one infant to the next for any mother. Multiple sources of support, help and advice for breastfeeding are available to nursing mothers. Evidence suggests that the experience of the quality of breastfeeding supports may play an important role in maternal mental health and well-being in the postpartum period. We sought to explore the experiences of nursing mothers with support they received for breastfeeding in order to better inform and optimize existing breastfeeding supports and interventions. METHODS: We conducted a qualitative inquiry of nursing mothers' experiences with help, advice and support for breastfeeding. Participants were asked to provide open-ended, written accounts of their experiences with all sources of breastfeeding support received in the 6 months following the delivery of a healthy full-term infant in Calgary. We conducted qualitative thematic analysis, using constant comparison techniques. RESULTS: The sample included 86 mothers. Our analyses uncovered 4 emergent themes that contributed to the perceived quality of breastfeeding support: knowledge, effectiveness, sensitivity/emotional support and accessible when sought. INTERPRETATION: Our study provides a greater understanding of how mothers perceive the quality of the breastfeeding support that they receive, as well as what qualities of breastfeeding support are seen as beneficial or negative. The qualities contributing to the perception of breastfeeding support are important to inform and optimize perinatal care, and potentially reduce the risk of negative mental health outcomes for mothers. PMID- 26442228 TI - Identification of the physician workforce providing palliative care in Ontario using administrative claims data. AB - BACKGROUND: Little is known about the physician workforce providing palliative care in Canada, and in Ontario specifically. We developed an algorithm to identify palliative care physicians using administrative claims data and validated it against a reference sample. We then applied the algorithm to all general practitioners/family physicians (GP/FPs) in the province of Ontario to describe and quantify those identified by the algorithm. METHODS: W e reviewed Ontario Health Insurance Plan claims from Jan. 1, 2008, to Dec. 31, 2011, to determine each physician's proportion of claims that were for palliative care. We empirically selected a data-driven cut-off, whereby physicians whose proportion of palliative care claims was above the threshold were defined as palliative care physicians. We validated the cut-off against a reference sample of physicians who self-identified as providing mostly palliative care in a study-specific survey. We then applied this algorithm to all GP/FPs in the province. RESULTS: We empirically selected 10% as the cut-off for the proportion of palliative care claims. This threshold had exceptional specificity and positive predictive value (97.8% and 90.5%, respectively) and adequate sensitivity (76.0%) when compared with the reference sample (n = 118). When applied to all GP/FPs in the province, the algorithm identified 276 practising mostly palliative care. Of these, 135 (48.9%) were women, 265 (96.0%) practised in urban locations, and 145 (52.5%) worked part time. INTERPRETATION: Our algorithm readily identified and quantified the workforce of palliative care physicians in Ontario. Such a tool has numerous applications for both health service planners and researchers. PMID- 26442230 TI - Regional variation in the use of surgery in Ontario. AB - BACKGROUND: Regional variation in the use of surgery implies that there is uncertainty regarding appropriate use. The objectives of this study were to identify which surgical procedures are most commonly performed in the province of Ontario and measure the extent of variation in the use of surgical procedures across Ontario counties. METHODS: We used the Canadian Institute for Health Information Discharge Abstract Database, Same Day Surgery Database and National Ambulatory Care Reporting System to retrieve information on all inpatient and day surgery visits in Ontario between Apr. 1, 2002, and Mar. 31, 2011. We identified the 84 most common procedures according to Canadian Classification of Interventions codes. We calculated rates of use for each procedure throughout the 49 Ontario counties and then calculated measures of variation (quartile ratio and systematic component of variation) in use between the counties. RESULTS: Colonoscopy was the most commonly performed procedure during the study period, with an average adjusted rate of 2012 per 100 000 population. The procedure with the highest measure of variation was iridectomy, with a quartile ratio of 6.7, followed by colposcopy (5.2), cervical biopsy (4.2) and femoral arteriography (4.1). These procedures were less commonly performed. Common procedures such as colonoscopy, cataract extraction and vaginal delivery had lower quartile ratios. Analysis using the systematic component of variation as the measure of variation gave similar results. INTERPRETATION: Colonoscopy was the most commonly performed procedure in Ontario, and cataract extraction was the most common surgical procedure. Procedures with the highest measures of variation between counties tended to be those that occurred less commonly in Ontario, and common procedures were associated with less regional variation. PMID- 26442231 TI - Characteristics of patients receiving long-term opioid therapy for chronic noncancer pain: a cross-sectional survey of patients attending the Pain Management Centre at Hamilton General Hospital, Hamilton, Ontario. AB - BACKGROUND: Characteristics of patients receiving long-term opioid therapy (>= 6 months) for chronic noncancer pain are poorly understood. We conducted a cross sectional survey of this patient population to explore demographic variables, pain relief, functional improvement, adverse effects and impressions of an educational pamphlet on long-term opioid therapy. METHODS: We invited 260 adult patients presenting to the Pain Management Centre at the Hamilton General Hospital, Hamilton, Ontario, with chronic noncancer pain to complete a 20-item survey. Patients who presented for procedures were not eligible for our study. We used adjusted logistic regression models to explore the association between higher morphine equivalent dose and pain relief, functional improvement, adverse events and employment. RESULTS: The survey was completed by 170 patients (a response rate of 65.4%). Most respondents (87.6%; 149 out of 170) were receiving long-term opioid therapy, and the median morphine equivalent dose was 180 mg daily (interquartile range 60-501). Most respondents reported at least modest (> 40%) opioid-specific pain relief (74.1%; 106 out of 143) and functional improvement (67.6%; 96 out of 142), and 46.5% (66 out of 142) reported troublesome adverse effects that they attributed to their opioid use. Most patients were receiving disability benefits (68.3%; 99 out of 145) and, among those respondents who were less than 65 years of age (90.3%; 131 out of 145), 10 (7.6%) were working full-time and 14 (10.7%) part-time. In our adjusted analyses, higher morphine equivalent dose was associated with greater self-reported functional improvement (odds ratio [OR] 1.45, 95% confidence interval [CI] 1.07 1.96) but not with pain relief (OR 1.38, 95% CI 1.00-1.89), troublesome adverse effects (OR 0.92, 95% CI 0.70-1.20) or employment (OR 0.80, 95% CI 0.56-1.15). INTERPRETATION: Most outpatients receiving long-term opioid therapy for chronic noncancer pain at a tertiary care chronic pain clinic reported at least moderate pain relief and functional improvement; however, adverse effects were common and few patients were engaged in competitive employment. PMID- 26442232 TI - Patient and operational factors affecting wait times in a bariatric surgery program in Toronto: a retrospective cohort study. AB - BACKGROUND: Increasing rates of obesity have led to growing demand for bariatric surgery. This has implications for wait times, particularly in publicly funded programs. This study examined the impact of patient and operational factors on wait times in a multidisciplinary bariatric surgery program. METHODS: A retrospective study was conducted involving patients who were referred to a tertiary care centre (University Health Network, Toronto Western Hospital, Toronto) for bariatric surgery between June 2008 and July 2011. Patient characteristics, dates of clinical assessments and records describing operational changes were collected. Univariable analysis and multivariable log-linear and parametric time-to-event regressions were performed to determine whether patient and operational covariates were associated with the wait time for bariatric surgery (i.e., length of preoperative evaluation). RESULTS: Of the 1664 patients included in the analysis, 724 underwent surgery with a mean wait time of 440 (standard deviation 198) days and a median wait time of 445 (interquartile range 298-533) days. Wait times ranged from 3 months to 4 years. Univariable and multivariable analyses showed that patients with active substance use (beta = 0.3482, p = 0.02) and individuals who entered the program in more recent operational periods (beta = 0.2028, p < 0.001) had longer wait times. Additionally, the median time-to-surgery increased over 3 discrete operational periods (characterized by specific program changes related to scheduling and staffing levels, and varying referral rates and defined surgical targets; p < 0.001). INTERPRETATION: Some patients could be identified at referral as being at risk for longer wait times. We also found that previous operational decisions significantly increased the wait time in the program since its inception. Therefore, careful consideration must be devoted to process-level decision-making for multistage bariatric surgical programs, because managerial and procedural changes can affect timely access to treatment. PMID- 26442233 TI - In utero Head Circumference is Associated with Childhood Allergy. AB - BACKGROUND: Altered fetal growth is known to be associated with allergic disease. Specifically, increased head circumference at birth has been linked to asthma and elevated IgE. However, few studies have examined a link between early fetal anthropometry and allergic disease. The aim of this study was to examine head circumference at mid-gestation in children diagnosed with allergy. METHODS: This was a retrospective cohort study, comprising pregnancies delivered between 10/2006 and 9/2010 at Nepean Hospital, Australia. Exclusion criteria were illegal drug use, alcohol consumption, gestation <35 weeks, and gestational hypertension. Pregnancy data were sourced from the Nepean Obstetric Database. Atopic diseases (asthma, atopic dermatitis, and IgE-mediated food allergy) were assessed by questionnaire at age 1-5 years. Infants from pregnancies with completed questionnaires, who also had a mid-gestation ultrasound scan, were included (N = 121). Multiple logistic regression techniques were used to model head circumference against the development of allergies. RESULTS: Smaller head circumference at mid-gestation was associated with increased odds of allergic disease in children aged 1-5 years. A 1 mm smaller head circumference was associated with a 7% increased chance of allergies being later diagnosed, adjusted for gestation (95% CI: 1-14%, p = 0.036). Head circumference at mid gestation was also inversely correlated with the presence of multiple atopic disease. CONCLUSION: Smaller mid-gestational head circumference is associated with early childhood allergic disease, which suggests that fetal programing of allergic disease occurs before mid-gestation. This suggests that mediators such as brain-derived neurotrophic factor may be dysregulated early in utero in a milieu, which also predisposes to atopic disease. PMID- 26442234 TI - Myofascial Structural Integration Therapy on Gross Motor Function and Gait of Young Children with Spastic Cerebral Palsy: A Randomized Controlled Trial. AB - Though the cause of motor abnormalities in cerebral palsy is injury to the brain, structural changes in muscle and fascia may add to stiffness and reduced function. This study examined whether myofascial structural integration therapy, a complementary treatment that manipulates muscle and fascia, would improve gross motor function and gait in children <4 years with cerebral palsy. Participants (N = 29) were enrolled in a randomized controlled trial (NCT01815814, https://goo.gl/TGxvwd) or Open Label Extension. The main outcome was the Gross Motor Function Measure-66 assessed at 3-month intervals. Gait (n = 8) was assessed using the GAITRite((r)) electronic walkway. Parents completed a survey at study conclusion. Comparing Treatment (n = 15) and Waitlist-Control groups (n = 9), we found a significant main effect of time but no effect of group or time * group interaction. The pooled sample (n = 27) showed a main effect of time, but no significantly greater change after treatment than between other assessments. Foot length on the affected side increased significantly after treatment, likely indicating improvement in the children's ability to approach a heel strike. Parent surveys indicated satisfaction and improvements in the children's quality of movement. MSI did not increase the rate of motor skill development, but was associated with improvement in gait quality. PMID- 26442235 TI - Editorial: Univentricular Heart. PMID- 26442236 TI - Work-Life Balance is an Illusion: Replace Guilt with Acceptance. PMID- 26442237 TI - Sarcoidosis with Arteriovenous Malformation in a 15-Year-Old Girl - The Rarest of the Rare. AB - INTRODUCTION: Sarcoidosis is an uncommon multi-system disorder with many possible complications. Arteriovenous malformations (AVMs) are a rare vascular complication of sarcoidosis. CASE DESCRIPTION: A 15-year-old girl presented to the Pediatric Clinic at AKUH with pulmonary, hepatic, joint, and skin manifestations. Physical examination and investigations pointed toward sarcoidosis, including raised erythrocyte sedimentation rate, angiotensin converting enzyme (ACE), and alanine transaminase (ALT). An incidental finding of pulmonary arteriovenous malformation (PAVM) was noticed on echocardiography. She responded to oral corticosteroids, her ACE and ALT levels improved. There was lack of indication for pulmonary angio-embolization for her PAVM. On a 3-year follow-up, her condition improved and she is clinically well. DISCUSSION: Pulmonary arteriovenous malformation is an extremely rare complication of sarcoidosis, especially among the pediatric population. Hence, this is the first reported case of its kind. The relation between sarcoidosis and PAVM is difficult to establish; however, there are some theories. This condition may be treated depending on the symptoms. Since our patient did not have any significant symptoms of PAVM, she was treated for the underlying disease, i.e., sarcoidosis. CONCLUSION: While dealing with patients having multi-system disorders like sarcoidosis, one must be very vigilant so as not to miss out on any complication. Regular follow-up visits should be scheduled to rule out new complications and to monitor the past ones. PMID- 26442238 TI - The Evidence-Based Approach to Adult-Onset Idiopathic Nephrotic Syndrome. AB - Adult-onset nephrotic syndrome (NS) differs from its pediatric counterpart in several important ways. Most importantly, NS in adults is more etiologically heterogeneous compared to children, and thus treatment approaches rely heavily on the histological diagnosis provided by renal biopsy. The evidence-based approach to treatment of adult NS has been critically examined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines in glomerulonephritis, published in 2012. Here, we examine the strengths and limits of those guidelines and review recent work that expands the evidence-based approach. PMID- 26442239 TI - Agenda Setting and Evidence in Maternal Health: Connecting Research and Policy in Timor-Leste. AB - The evidence-based policy (EBP) movement has received significant attention in the scientific literature; however, there is still very little empirical research to provide insight into how policy decisions are made and how evidence is used. The lack of research on this topic in low- and middle-income countries is of particular note. We examine the maternity waiting home policy in Timor-Leste to understand the role of context, policy characteristics, individual actors, and how evidence is used to influence the policy agenda. The research tracked the maternity waiting home policy from 2005 to 2009 and is based on in-depth interviews with 31 senior policy-makers, department managers, non-government organization representatives, and United Nations advisors. It is also informed by direct observation, attendance at meetings and workshops, and analysis of policy documents. The findings from this ethnographic case study demonstrate that although the post-conflict context opened up space for new policy ideas senior Ministry of Health officials rather than donors had the most power in setting the policy agenda. Maternity waiting homes were appealing because they were a visible, non-controversial, and logical solution to the problem of accessing maternal health services. Evidence was used in a variety of ways, from supporting pre-determined agendas to informing new policy directions. In the pursuit of EBP, we conclude that the power of research to inform policy lies in its timeliness and relevance, and is facilitated by the connection between researchers and policy-makers. PMID- 26442240 TI - Budget Impact of Publicly Reimbursed Prescription Medicines in the Republic of Srpska. PMID- 26442241 TI - Review of Current International Decision-Making Processes for Newborn Screening: Lessons for Australia. AB - Newborn bloodspot screening has been operating successfully in Australia for almost 50 years. Recently, the development of new technologies and treatments has led to calls for the addition of new conditions to the screening programs. Internationally, it is recognized by governments that national policies for newborn screening should support transparent and evidence-based decision making, and promote consistency between states within a country. Australia is lagging behind the international community, and currently has no national policies or decision-making processes, agreed by government, to support its newborn screening programs. In contrast, New Zealand (NZ), the United Kingdom (UK), and the United States of America (US) have robust and transparent processes to assess conditions for screening, which have been developed by, and have pathways to, government. This review provides detail on the current policy environment for newborn screening in Australia, highlighting that there are a number of risks to the programs resulting from the lack of a decision-making process. It also describes the processes used to assess conditions for newborn screening in the US, UK, and NZ. These examples highlight the benefits of developing a national decision making process, including ensuring that screening is evidence based and effective. These examples also provide models that might be considered for Australia, as well as other countries currently seeking to introduce or expand newborn bloodspot screening. PMID- 26442242 TI - Disruptive Innovation Can Prevent the Next Pandemic. AB - Public health surveillance (PHS) is at a tipping point, where the application of novel processes, technologies, and tools promise to vastly improve efficiency and effectiveness. Yet twentieth century, entrenched ideology and lack of training results in slow uptake and resistance to change. The term disruptive innovation - used to describe advances in technology and processes that change existing markets - is useful to describe the transformation of PHS. Past disruptive innovations used in PHS, such as distance learning, the smart phone, and field based laboratory testing have outpaced older services, practices, and technologies used in the traditional classroom, governmental offices, and personal communication, respectively. Arguably, the greatest of these is the Internet - an infrastructural innovation that continues to enable exponential benefits in seemingly limitless ways. Considering the Global Health Security Agenda and facing emerging and reemerging infectious disease threats, evolving environmental and behavioral risks, and ever changing epidemiologic trends, PHS must transform. Embracing disruptive innovation in the structures and processes of PHS can be unpredictable. However, it is necessary to strengthen and unlock the potential to prevent, detect, and respond. PMID- 26442243 TI - Anxiety in the Elderly Can be a Vestibular Problem. PMID- 26442244 TI - Relationship between the Quality of Service Provided through Store-and-Forward Telemedicine Consultations and the Difficulty of the Cases - Implications for Long-Term Quality Assurance. AB - We examined the difficulty of telemedicine cases and the quality of the resultant consultation in a mature store-and-forward telemedicine network. A random sample of 10 telemedicine cases was selected from those occurring over a 3-month period (5% of the workload) and they were scored by three experienced observers. Inter observer agreement on the difficulty scores was poor (Fleiss's kappa = 0.18) and it was also poor on the consultation quality scores (Fleiss's kappa = 0.11). Differences between observers were minimized by consensus scoring, and the cases were re-assessed jointly by two observers. Based on the consensus scores, there was a weak negative relation between output quality and case difficulty, i.e., the more difficult cases tended to result in lower quality consultations. However, the effect was non-significant (P = 0.59) and a larger study might be helpful. In the meantime, routine monitoring of telemedicine service quality will continue in the interests of quality assurance. As yet, there is no evidence on which to base a correction for case difficulty. PMID- 26442245 TI - Improving Speaker Recognition by Biometric Voice Deconstruction. AB - Person identification, especially in critical environments, has always been a subject of great interest. However, it has gained a new dimension in a world threatened by a new kind of terrorism that uses social networks (e.g., YouTube) to broadcast its message. In this new scenario, classical identification methods (such as fingerprints or face recognition) have been forcedly replaced by alternative biometric characteristics such as voice, as sometimes this is the only feature available. The present study benefits from the advances achieved during last years in understanding and modeling voice production. The paper hypothesizes that a gender-dependent characterization of speakers combined with the use of a set of features derived from the components, resulting from the deconstruction of the voice into its glottal source and vocal tract estimates, will enhance recognition rates when compared to classical approaches. A general description about the main hypothesis and the methodology followed to extract the gender-dependent extended biometric parameters is given. Experimental validation is carried out both on a highly controlled acoustic condition database, and on a mobile phone network recorded under non-controlled acoustic conditions. PMID- 26442246 TI - Joint Analysis of Dependent Features within Compound Spectra Can Improve Detection of Differential Features. AB - Mass spectrometry is an important analytical technology in metabolomics. After the initial feature detection and alignment steps, the raw data processing results in a high-dimensional data matrix of mass spectral features, which is then subjected to further statistical analysis. Univariate tests like Student's t test and Analysis of Variances (ANOVA) are hypothesis tests, which aim to detect differences between two or more sample classes, e.g., wildtype-mutant or between different doses of treatments. In both cases, one of the underlying assumptions is the independence between metabolic features. However, in mass spectrometry, a single metabolite usually gives rise to several mass spectral features, which are observed together and show a common behavior. This paper suggests to group the related features of metabolites with CAMERA into compound spectra, and then to use a multivariate statistical method to test whether a compound spectrum (and thus the actual metabolite) is differential between two sample classes. The multivariate method is first demonstrated with an analysis between wild-type and an over-expression line of the model plant Arabidopsis thaliana. For a quantitative evaluation data sets with a simulated known effect between two sample classes were analyzed. The spectra-wise analysis showed better detection results for all simulated effects. PMID- 26442247 TI - Approximating Attractors of Boolean Networks by Iterative CTL Model Checking. AB - This paper introduces the notion of approximating asynchronous attractors of Boolean networks by minimal trap spaces. We define three criteria for determining the quality of an approximation: "faithfulness" which requires that the oscillating variables of all attractors in a trap space correspond to their dimensions, "univocality" which requires that there is a unique attractor in each trap space, and "completeness" which requires that there are no attractors outside of a given set of trap spaces. Each is a reachability property for which we give equivalent model checking queries. Whereas faithfulness and univocality can be decided by model checking the corresponding subnetworks, the naive query for completeness must be evaluated on the full state space. Our main result is an alternative approach which is based on the iterative refinement of an initially poor approximation. The algorithm detects so-called autonomous sets in the interaction graph, variables that contain all their regulators, and considers their intersection and extension in order to perform model checking on the smallest possible state spaces. A benchmark, in which we apply the algorithm to 18 published Boolean networks, is given. In each case, the minimal trap spaces are faithful, univocal, and complete, which suggests that they are in general good approximations for the asymptotics of Boolean networks. PMID- 26442248 TI - High-Resolution X-Ray Techniques as New Tool to Investigate the 3D Vascularization of Engineered-Bone Tissue. AB - The understanding of structure-function relationships in normal and pathologic mammalian tissues is at the basis of a tissue engineering (TE) approach for the development of biological substitutes to restore or improve tissue function. In this framework, it is interesting to investigate engineered bone tissue, formed when porous ceramic constructs are loaded with bone marrow stromal cells (BMSC) and implanted in vivo. To monitor the relation between bone formation and vascularization, it is important to achieve a detailed imaging and a quantitative description of the complete three-dimensional vascular network in such constructs. Here, we used synchrotron X-ray phase-contrast micro-tomography to visualize and analyze the three-dimensional micro-vascular networks in bone engineered constructs, in an ectopic bone formation mouse-model. We compared samples seeded and not seeded with BMSC, as well as samples differently stained or unstained. Thanks to the high quality of the images, we investigated the 3D distribution of both vessels and collagen matrix and we obtained quantitative information for all different samples. We propose our approach as a tool for quantitative studies of angiogenesis in TE and for any pre-clinical investigation where a quantitative analysis of the vascular network is required. PMID- 26442250 TI - Underpinning Starch Biology with in vitro Studies on Carbohydrate-Active Enzymes and Biosynthetic Glycomaterials. AB - Starch makes up more than half of the calories in the human diet and is also a valuable bulk commodity that is used across the food, brewing and distilling, medicines and renewable materials sectors. Despite its importance, our understanding of how plants make starch, and what controls the deposition of this insoluble, polymeric, liquid crystalline material, remains rather limited. Advances are hampered by the challenges inherent in analyzing enzymes that operate across the solid-liquid interface. Glyconanotechnology, in the form of glucan-coated sensor chips and metal nanoparticles, present novel opportunities to address this problem. Herein, we review recent developments aimed at the bottom-up generation and self-assembly of starch-like materials, in order to better understand which enzymes are required for starch granule biogenesis and metabolism. PMID- 26442249 TI - Analytics for Metabolic Engineering. AB - Realizing the promise of metabolic engineering has been slowed by challenges related to moving beyond proof-of-concept examples to robust and economically viable systems. Key to advancing metabolic engineering beyond trial-and-error research is access to parts with well-defined performance metrics that can be readily applied in vastly different contexts with predictable effects. As the field now stands, research depends greatly on analytical tools that assay target molecules, transcripts, proteins, and metabolites across different hosts and pathways. Screening technologies yield specific information for many thousands of strain variants, while deep omics analysis provides a systems-level view of the cell factory. Efforts focused on a combination of these analyses yield quantitative information of dynamic processes between parts and the host chassis that drive the next engineering steps. Overall, the data generated from these types of assays aid better decision-making at the design and strain construction stages to speed progress in metabolic engineering research. PMID- 26442251 TI - Biomechanics of Pediatric Manual Wheelchair Mobility. AB - Currently, there is limited research of the biomechanics of pediatric manual wheelchair mobility. Specifically, the biomechanics of functional tasks and their relationship to joint pain and health is not well understood. To contribute to this knowledge gap, a quantitative rehabilitation approach was applied for characterizing upper extremity biomechanics of manual wheelchair mobility in children and adolescents during propulsion, starting, and stopping tasks. A Vicon motion analysis system captured movement, while a SmartWheel simultaneously collected three-dimensional forces and moments occurring at the handrim. A custom pediatric inverse dynamics model was used to evaluate three-dimensional upper extremity joint motions, forces, and moments of 14 children with spinal cord injury (SCI) during the functional tasks. Additionally, pain and health-related quality of life outcomes were assessed. This research found that joint demands are significantly different amongst functional tasks, with greatest demands placed on the shoulder during the starting task. Propulsion was significantly different from starting and stopping at all joints. We identified multiple stroke patterns used by the children, some of which are not standard in adults. One subject reported average daily pain, which was minimal. Lower than normal physical health and higher than normal mental health was found in this population. It can be concluded that functional tasks should be considered in addition to propulsion for rehabilitation and SCI treatment planning. This research provides wheelchair users and clinicians with a comprehensive, biomechanical, mobility assessment approach for wheelchair prescription, training, and long-term care of children with SCI. PMID- 26442252 TI - Correcting Inconsistencies and Errors in Bacterial Genome Metadata Using an Automated Curation Tool in Excel (AutoCurE). AB - Whole-genome data are invaluable for large-scale comparative genomic studies. Current sequencing technologies have made it feasible to sequence entire bacterial genomes with relative ease and time with a substantially reduced cost per nucleotide, hence cost per genome. More than 3,000 bacterial genomes have been sequenced and are available at the finished status. Publically available genomes can be readily downloaded; however, there are challenges to verify the specific supporting data contained within the download and to identify errors and inconsistencies that may be present within the organizational data content and metadata. AutoCurE, an automated tool for bacterial genome database curation in Excel, was developed to facilitate local database curation of supporting data that accompany downloaded genomes from the National Center for Biotechnology Information. AutoCurE provides an automated approach to curate local genomic databases by flagging inconsistencies or errors by comparing the downloaded supporting data to the genome reports to verify genome name, RefSeq accession numbers, the presence of archaea, BioProject/UIDs, and sequence file descriptions. Flags are generated for nine metadata fields if there are inconsistencies between the downloaded genomes and genomes reports and if erroneous or missing data are evident. AutoCurE is an easy-to-use tool for local database curation for large-scale genome data prior to downstream analyses. PMID- 26442253 TI - Car Transfer and Wheelchair Loading Techniques in Independent Drivers with Paraplegia. AB - Car transfers and wheelchair (WC) loading are crucial for independent community participation in persons with complete paraplegia from spinal cord injury, but are complex, physically demanding, and known to provoke shoulder pain. This study aimed to describe techniques and factors influencing car transfer and WC loading for individuals with paraplegia driving their own vehicles and using their personal WCs. Sedans were the most common vehicle driven (59%). Just over half (52%) of drivers place their right leg only into the vehicle prior to transfer. Overall, the leading hand was most frequently placed on the driver's seat (66%) prior to transfer and the trailing hand was most often place on the WC seat (48%). Vehicle height influenced leading hand placement but not leg placement such that drivers of higher profile vehicles were more likely to place their hand on the driver's seat than those who drove sedans. Body lift time was negatively correlated with level of injury and age and positively correlated with vehicle height and shoulder abduction strength. Drivers who transferred with their leading hand on the steering wheel had significantly higher levels of shoulder pain than those who placed their hand on the driver's seat or overhead. The majority of participants used both hands (62%) to load their WC frame, and overall, most loaded their frame into the back (62%) vs. the front seat. Sedan drivers were more likely to load their frame into the front seat than drivers of higher profile vehicles (53 vs. 17%). Average time to load the WC frame (10.7 s) was 20% of the total WC loading time and was not related to shoulder strength, frame weight, or demographic characteristics. Those who loaded their WC frame into the back seat had significantly weaker right shoulder internal rotators. Understanding car transfers and WC loading in independent drivers is crucial to prevent shoulder pain and injury and preserve community participation. PMID- 26442254 TI - A New MRI-Based Model of Heart Function with Coupled Hemodynamics and Application to Normal and Diseased Canine Left Ventricles. AB - A methodology for the simulation of heart function that combines an MRI-based model of cardiac electromechanics (CE) with a Navier-Stokes-based hemodynamics model is presented. The CE model consists of two coupled components that simulate the electrical and the mechanical functions of the heart. Accurate representations of ventricular geometry and fiber orientations are constructed from the structural magnetic resonance and the diffusion tensor MR images, respectively. The deformation of the ventricle obtained from the electromechanical model serves as input to the hemodynamics model in this one-way coupled approach via imposed kinematic wall velocity boundary conditions and at the same time, governs the blood flow into and out of the ventricular volume. The time-dependent endocardial surfaces are registered using a diffeomorphic mapping algorithm, while the intraventricular blood flow patterns are simulated using a sharp-interface immersed boundary method-based flow solver. The utility of the combined heart-function model is demonstrated by comparing the hemodynamic characteristics of a normal canine heart beating in sinus rhythm against that of the dyssynchronously beating failing heart. We also discuss the potential of coupled CE and hemodynamics models for various clinical applications. PMID- 26442255 TI - Fragmentation and Coverage Variation in Viral Metagenome Assemblies, and Their Effect in Diversity Calculations. AB - Metagenomic libraries consist of DNA fragments from diverse species, with varying genome size and abundance. High-throughput sequencing platforms produce large volumes of reads from these libraries, which may be assembled into contigs, ideally resembling the original larger genomic sequences. The uneven species distribution, along with the stochasticity in sample processing and sequencing bias, impacts the success of accurate sequence assembly. Several assemblers enable the processing of viral metagenomic data de novo, generally using overlap layout consensus or de Bruijn graph approaches for contig assembly. The success of viral genomic reconstruction in these datasets is limited by the degree of fragmentation of each genome in the sample, which is dependent on the sequencing effort and the genome length. Depending on ecological, biological, or procedural biases, some fragments have a higher prevalence, or coverage, in the assembly. However, assemblers must face challenges, such as the formation of chimerical structures and intra-species variability. Diversity calculation relies on the classification of the sequences that comprise a metagenomic dataset. Whenever the corresponding genomic and taxonomic information is available, contigs matching the same species can be classified accordingly and the coverage of its genome can be calculated for that species. This may be used to compare populations by estimating abundance and assessing species distribution from this data. Nevertheless, the coverage does not take into account the degree of fragmentation, or else genome completeness, and is not necessarily representative of actual species distribution in the samples. Furthermore, undetermined sequences are abundant in viral metagenomic datasets, resulting in several independent contigs that cannot be assigned by homology or genomic information. These may only be classified as different operational taxonomic units (OTUs), sometimes remaining inadvisably unrelated. Thus, calculations using contigs as different OTUs ultimately overestimate diversity when compared to diversity calculated from species coverage. In order to compare the effect of coverage and fragmentation, we generated three sets of simulated Illumina paired-end reads with different sequencing depths. We compared different assemblies performed with RayMeta, CLC Assembly Cell, MEGAHIT, SPAdes, Meta-IDBA, SOAPdenovo, Velvet, Metavelvet, and MIRA with the best attainable assemblies for each dataset (formed by arranging data using known genome coordinates) by calculating different assembly statistics. A new fragmentation score was included to estimate the degree of genome fragmentation of each taxon and adjust the coverage accordingly. The abundance in the metagenome was compared by bootstrapping the assembly data and hierarchically clustering them with the best possible assembly. Additionally, richness and diversity indexes were calculated for all the resulting assemblies and were assessed under two distributions: contigs as independent OTUs and sequences classified by species. Finally, we search for the strongest correlations between the diversity indexes and the different assembly statistics. Although fragmentation was dependent of genome coverage, it was not as heavily influenced by the assembler. The sequencing depth was the predominant attractor that influenced the success of the assemblies. The coverage increased notoriously in larger datasets, whereas fragmentation values remained lower and unsaturated. While still far from obtaining the ideal assemblies, the RayMeta, SPAdes, and the CLC assemblers managed to build the most accurate contigs with larger datasets while Meta-IDBA showed a good performance with the medium-sized dataset, even after the adjusted coverage was calculated. Their resulting assemblies showed the highest coverage scores and the lowest fragmentation values. Alpha diversity calculated from contigs as OTUs resulted in significantly higher values for all assemblies when compared with actual species distribution, showing an overestimation due to the increased predicted abundance. Conversely, using PHACCS resulted in lower values for all assemblers. Different association methods (random-forest, generalized linear models, and the Spearman correlation index) support the number of contigs, the coverage, and fragmentation as the assembly parameters that most affect the estimation of the alpha diversity. Coverage calculations may provide an insight into relative completeness of a genome but they overlook missing fragments or overly separated sequences in a genome. The assembly of a highly fragmented genomes with high coverage may still lead to the clustering of different OTUs that are actually different fragments of a genome. Thus, it proves useful to penalize coverage with a fragmentation score. Using contigs for calculating alpha diversity result in overestimation but it is usually the only approach available. Still, it is enough for sample comparison. The best approach may be determined by choosing the assembler that better fits the sequencing depth and adjusting the parameters for longer accurate contigs whenever possible whereas diversity may be calculated considering taxonomical and genomic information if available. PMID- 26442256 TI - The Golden Age in Cancer Nanobiotechnology: Quo Vadis? PMID- 26442258 TI - On Accounting for Sequence-Specific Bias in Genome-Wide Chromatin Accessibility Experiments: Recent Advances and Contradictions. PMID- 26442257 TI - Tandem Repeats in Proteins: Prediction Algorithms and Biological Role. AB - Tandem repetitions in protein sequence and structure is a fascinating subject of research which has been a focus of study since the late 1990s. In this survey, we give an overview on the multi-faceted aspects of research on protein tandem repeats (PTR for short), including prediction algorithms, databases, early classification efforts, mechanisms of PTR formation and evolution, and synthetic PTR design. We also touch on the rather open issue of the relationship between PTR and flexibility (or disorder) in proteins. Detection of PTR either from protein sequence or structure data is challenging due to inherent high (biological) signal-to-noise ratio that is a key feature of this problem. As early in silico analytic tools have been key enablers for starting this field of study, we expect that current and future algorithmic and statistical breakthroughs will have a high impact on the investigations of the biological role of PTR. PMID- 26442259 TI - Shikimic Acid Production in Escherichia coli: From Classical Metabolic Engineering Strategies to Omics Applied to Improve Its Production. AB - Shikimic acid (SA) is an intermediate of the SA pathway that is present in bacteria and plants. SA has gained great interest because it is a precursor in the synthesis of the drug oseltamivir phosphate (OSF), an efficient inhibitor of the neuraminidase enzyme of diverse seasonal influenza viruses, the avian influenza virus H5N1, and the human influenza virus H1N1. For the purposes of OSF production, SA is extracted from the pods of Chinese star anise plants (Illicium spp.), yielding up to 17% of SA (dry basis content). The high demand for OSF necessary to manage a major influenza outbreak is not adequately met by industrial production using SA from plants sources. As the SA pathway is present in the model bacteria Escherichia coli, several "intuitive" metabolically engineered strains have been applied for its successful overproduction by biotechnological processes, resulting in strains producing up to 71 g/L of SA, with high conversion yields of up to 0.42 (mol SA/mol Glc), in both batch and fed batch cultures using complex fermentation broths, including glucose as a carbon source and yeast extract. Global transcriptomic analyses have been performed in SA-producing strains, resulting in the identification of possible key target genes for the design of a rational strain improvement strategy. Because possible target genes are involved in the transport, catabolism, and interconversion of different carbon sources and metabolic intermediates outside the central carbon metabolism and SA pathways, as genes involved in diverse cellular stress responses, the development of rational cellular strain improvement strategies based on omics data constitutes a challenging task to improve SA production in currently overproducing engineered strains. In this review, we discuss the main metabolic engineering strategies that have been applied for the development of efficient SA-producing strains, as the perspective of omics analysis has focused on further strain improvement for the production of this valuable aromatic intermediate. PMID- 26442260 TI - Optimization of Alkaline and Dilute Acid Pretreatment of Agave Bagasse by Response Surface Methodology. AB - Utilization of lignocellulosic materials for the production of value-added chemicals or biofuels generally requires a pretreatment process to overcome the recalcitrance of the plant biomass for further enzymatic hydrolysis and fermentation stages. Two of the most employed pretreatment processes are the ones that used dilute acid (DA) and alkaline (AL) catalyst providing specific effects on the physicochemical structure of the biomass, such as high xylan and lignin removal for DA and AL, respectively. Another important effect that need to be studied is the use of a high solids pretreatment (>=15%) since offers many advantaged over lower solids loadings, including increased sugar and ethanol concentrations (in combination with a high solids saccharification), which will be reflected in lower capital costs; however, this data is currently limited. In this study, several variables, such as catalyst loading, retention time, and solids loading, were studied using response surface methodology (RSM) based on a factorial central composite design of DA and AL pretreatment on agave bagasse using a range of solids from 3 to 30% (w/w) to obtain optimal process conditions for each pretreatment. Subsequently enzymatic hydrolysis was performed using Novozymes Cellic CTec2 and HTec2 presented as total reducing sugar (TRS) yield. Pretreated biomass was characterized by wet-chemistry techniques and selected samples were analyzed by calorimetric techniques, and scanning electron/confocal fluorescent microscopy. RSM was also used to optimize the pretreatment conditions for maximum TRS yield. The optimum conditions were determined for AL pretreatment: 1.87% NaOH concentration, 50.3 min and 13.1% solids loading, whereas DA pretreatment: 2.1% acid concentration, 33.8 min and 8.5% solids loading. PMID- 26442261 TI - Fluorescent Reporter Libraries as Useful Tools for Optimizing Microbial Cell Factories: A Review of the Current Methods and Applications. AB - The use of genetically encoded fluorescent reporters allows speeding up the initial optimization steps of microbial bioprocesses. These reporters can be used for determining the expression level of a particular promoter, not only the synthesis of a specific protein but also the content of intracellular metabolites. The level of protein/metabolite is thus proportional to a fluorescence signal. By this way, mean expression profiles of protein/metabolites can be determined non-invasively at a high-throughput rate, allowing the rapid identification of the best producers. Actually, different kinds of reporter systems are available, as well as specific cultivation devices allowing the on line recording of the fluorescent signal. Cell-to-cell variability is another important phenomenon that can be integrated into the screening procedures for the selection of more efficient microbial cell factories. PMID- 26442262 TI - Clueless with fewer cues from endothelin. Commentary: Venous endothelin guides sympathetic innervation of the developing mouse heart. PMID- 26442264 TI - Slow conduction in mixed cultured strands of primary ventricular cells and stem cell-derived cardiomyocytes. AB - Modern concepts for the treatment of myocardial diseases focus on novel cell therapeutic strategies involving stem cell-derived cardiomyocytes (SCMs). However, functional integration of SCMs requires similar electrophysiological properties as primary cardiomyocytes (PCMs) and the ability to establish intercellular connections with host myocytes in order to contribute to the electrical and mechanical activity of the heart. The aim of this project was to investigate the properties of cardiac conduction in a co-culture approach using SCMs and PCMs in cultured cell strands. Murine embryonic SCMs were pooled with fetal ventricular cells and seeded in predefined proportions on microelectrode arrays to form patterned strands of mixed cells. Conduction velocity (CV) was measured during steady state pacing. SCM excitability was estimated from action potentials measured in single cells using the patch clamp technique. Experiments were complemented with computer simulations of conduction using a detailed model of cellular architecture in mixed cell strands. CV was significantly lower in strands composed purely of SCMs (5.5 +/- 1.5 cm/s, n = 11) as compared to PCMs (34.9 +/- 2.9 cm/s, n = 21) at similar refractoriness (100% SCMs: 122 +/- 25 ms, n = 9; 100% PCMs: 139 +/- 67 ms, n = 14). In mixed strands combining both cell types, CV was higher than in pure SCMs strands, but always lower than in 100% PCM strands. Computer simulations demonstrated that both intercellular coupling and electrical excitability limit CV. These data provide evidence that in cultures of murine ventricular cardiomyocytes, SCMs cannot restore CV to control levels resulting in slow conduction, which may lead to reentry circuits and arrhythmias. PMID- 26442265 TI - Viscoelastic Methods of Blood Clotting Assessment - A Multidisciplinary Review. AB - Viscoelastic methods (VEM) made available the bedside assessment of blood clotting. Unlike standard laboratory tests, the results are based on the whole blood coagulation and are available in real time at a much faster turnaround time. In combination with our new knowledge about pathophysiology of the trauma induced coagulopathy, the goal-oriented treatment protocols have been recently proposed for the initial management of bleeding in trauma victims. Additionally, the utility of viscoelastic monitoring devices has been proved even outside this setting in cardiosurgical patients or those undergoing liver transplantation. Many other situations were described in literature showing the potential use of bedside analysis of coagulation for the management of bleeding or critically ill patients. In the near future, we may expect further improvement in current bedside diagnostic tools enabling not only the assessment of secondary hemostasis but also the platelet aggregation. More sensitive assays for new anticoagulants are underway. Aim of this review is to offer the reader a multidisciplinary overview of VEM and their potential use in anesthesiology and critical care. PMID- 26442266 TI - Insights into Regulation of the miR-17-92 Cluster of miRNAs in Cancer. AB - Overexpression of the miR-17-92 cluster is a key oncogenic event in various cancer types. The oncogenic effect of the miR-17-92 cluster is enhanced by cooperation between its members in targeting tumor-suppressive proteins and pathways such as PTEN and TGFbeta signaling. However, in the case of miR-19a and miR-19b, these have been shown to have a preponderant role in the cluster's oncogenicity. Important studies have revealed the influence of the Myc proto oncogene family in the transcriptional regulation of miR-17-92. Recent findings show that other oncogenic signaling pathways, such as those of Notch and Sonic Hedgehog, activate miR-17-92 in cancer. Notwithstanding, another layer of complexity has been added by the influence of the relevant primary miR-17-92 tertiary structure during processing to mature miRNA. In this review, we attempt to integrate current transcriptional and post-transcriptional knowledge to enhance our global understanding of the coordinated up-regulation of miR-17-92 in cancer. PMID- 26442263 TI - The different facets of organelle interplay-an overview of organelle interactions. AB - Membrane-bound organelles such as mitochondria, peroxisomes, or the endoplasmic reticulum (ER) create distinct environments to promote specific cellular tasks such as ATP production, lipid breakdown, or protein export. During recent years, it has become evident that organelles are integrated into cellular networks regulating metabolism, intracellular signaling, cellular maintenance, cell fate decision, and pathogen defence. In order to facilitate such signaling events, specialized membrane regions between apposing organelles bear distinct sets of proteins to enable tethering and exchange of metabolites and signaling molecules. Such membrane associations between the mitochondria and a specialized site of the ER, the mitochondria associated-membrane (MAM), as well as between the ER and the plasma membrane (PAM) have been partially characterized at the molecular level. However, historical and recent observations imply that other organelles like peroxisomes, lysosomes, and lipid droplets might also be involved in the formation of such apposing membrane contact sites. Alternatively, reports on so called mitochondria derived-vesicles (MDV) suggest alternative mechanisms of organelle interaction. Moreover, maintenance of cellular homeostasis requires the precise removal of aged organelles by autophagy-a process which involves the detection of ubiquitinated organelle proteins by the autophagosome membrane, representing another site of membrane associated-signaling. This review will summarize the available data on the existence and composition of organelle contact sites and the molecular specializations each site uses in order to provide a timely overview on the potential functions of organelle interaction. PMID- 26442267 TI - Story of Rubidium-82 and Advantages for Myocardial Perfusion PET Imaging. AB - Rubidium-82 has a long story, starting in 1954. After preclinical studies in dogs showing that myocardial uptake of this radionuclide was directly proportional to myocardial blood flow (MBF), clinical studies were performed in the 80s leading to an approval in the USA in 1989. From that time, thousands of patients have been tested and their results have been reported in three meta-analyses. Pooled patient-based sensitivity and specificity were, respectively, 0.91 and 0.90. By comparison with (99m)Tc-SPECT, (82)Rb PET had a much better diagnostic accuracy, especially in obese patients with body mass index >=30 kg/m(2) (85 versus 67% with SPECT) and in women with large breasts. A great advantage of (82)Rb PET is its capacity to accurately quantify MBF. Quite importantly, it has been recently shown that coronary flow reserve is associated with adverse cardiovascular events independently of luminal angiographic severity. Moreover, coronary flow reserve is a functional parameter particularly useful in the estimate of microvascular dysfunction, such as in diabetes mellitus. Due to the very short half-life of rubidium-82, the effective dose calculated for a rest/stress test is roughly equivalent to the annual natural exposure and even less when stress-only is performed with a low activity compatible with a good image quality with the last generation 3D PET scanners. There is still some debate on the relative advantages of (82)Rb PET with regard to (99m)Tc-SPECT. For the last 10 years, great technological advances substantially improved performances of SPECT with its accuracy getting closer to this of (82)Rb/PET. Currently, the main advantages of PET are its capacity to accurately quantify MBF and to deliver a low radiation exposure. PMID- 26442268 TI - Corrigendum: Escherichia coli Isolated from Urinary Tract Infections of Lebanese Patients between 2005 and 2012: Epidemiology and Profiles of Resistance. AB - [This corrects the article on p. 26 in vol. 2, PMID: 4415468.]. PMID- 26442269 TI - Assessment of Lymph Nodes and Prostate Status Using Early Dynamic Curves with (18)F-Choline PET/CT in Prostate Cancer. AB - INTRODUCTION: Dynamic image acquisition with (18)F-Choline [fluorocholine (FCH)] PET/CT in prostate cancer is mostly used to overcome the bladder repletion, which could obstruct the loco-regional analysis. The aim of our study was to analyze early dynamic FCH acquisitions to define pelvic lymph node or prostate pathological status. MATERIAL AND METHODS: Retrospective analysis was performed on 39 patients for initial staging (n = 18), or after initial treatment (n = 21). Patients underwent 10-min dynamic acquisitions centered on the pelvis, after injection of 3-4 MBq/kg of FCH. Whole-body images were acquired about 1 h after injection using a PET/CT GE Discovery LS (GE-LS) or Siemens Biograph mCT (mCT). Maximum and mean SUV according to time were measured on nodal and prostatic lesions. SUVmean was corrected for partial volume effect (PVEC) with suitable recovery coefficients. The status of each lesion was based on histological results or patient follow-up (>6 months). A Mann-Whitney test and ANOVA were used to compare mean and receiver operating characteristic (ROC) curve analysis. RESULTS: The median PSA was 8.46 ng/mL and the median Gleason score was 3 + 4. Ninety-two lesions (43 lymph nodes and 49 prostate lesions) were analyzed, including 63 malignant lesions. In early dynamic acquisitions, the maximum and mean SUV were significantly higher, respectively, on mCT and GE-LS, in malignant versus benign lesions (p < 0.001, p < 0.001). Mean SUV without PVEC, allowed better discrimination of benign from malignant lesions, in comparison with maximum and mean SUV (with PVEC), for both early and late acquisitions. For patients acquired on mCT, area under the ROC curve showed a trend to better sensitivity and specificity for early acquisitions, compared with late acquisitions (SUVmax AUC 0.92 versus 0.85, respectively). CONCLUSION: Assessment of lymph nodes and prostate pathological status with early dynamic imaging using PET/CT FCH allowed prostate cancer detection in situations where proof of malignancy is difficult to obtain. PMID- 26442270 TI - Pseudogenes in Human Cancer. AB - Recent advances in the analysis of RNA sequencing data have shown that pseudogenes are highly specific markers of cell identity and can be used as diagnostic and prognostic markers. Furthermore, genetically engineered mouse models have recently provided compelling support for a causal link between altered pseudogene expression and cancer. In this review, we discuss the most recent milestones reached in the pseudogene field and the use of pseudogenes as cancer classifiers. PMID- 26442271 TI - Interleukin(IL)-36alpha and IL-36gamma Induce Proinflammatory Mediators from Human Colonic Subepithelial Myofibroblasts. AB - BACKGROUND: Interleukin (IL)-36 cytokines are recently reported member of the IL 1 cytokine family. However, there is little information regarding the association between IL-36 cytokines and gut inflammation. In the present study, we investigated the biological activity of IL-36alpha and IL-36gamma using human colonic subepithelial myofibroblasts (SEMFs). METHODS: The mRNA expression and the protein expression of target molecules in SEMFs were evaluated using real time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The intracellular signaling of IL-36 cytokines was analyzed using Western blot analysis and small interfering RNAs (siRNAs) specific for MyD88 adaptor proteins (MyD88 and IRAK1) and NF-kappaB p65. RESULTS: IL-36alpha and IL 36gamma significantly enhanced the secretion of IL-6 and CXC chemokines (CXCL1, CXCL2, and CXCL8) by SEMFs. The combination of IL-36alpha/gamma and IL-17A or of IL-36alpha/gamma and tumor necrosis factor-alpha showed a synergistic effect on the induction of IL-6 and CXC chemokines. The mRNA expression of proinflammatory mediators induced by IL-36alpha and/or IL-36gamma was significantly suppressed by transfection of siRNA for MyD88 or IRAK1. Both inhibitors of mitogen activated protein kinases and siRNAs specific for NF-kappaBp65 significantly reduced the expression of IL-6 and CXC chemokines induced by IL-36alpha and/or IL-36gamma. CONCLUSION: These results suggest that IL-36alpha and IL-36gamma contribute to gut inflammation through the induction of proinflammatory mediators. PMID- 26442273 TI - Post-Exercise Skeletal Muscle Glycogen Related to Plasma Cytokines and Muscle IL 6 Protein Content, but not Muscle Cytokine mRNA Expression. AB - OBJECTIVES: The purpose of this study was to correlate post-exercise muscle glycogen levels with changes in plasma cytokine, and muscle mRNA cytokine expression and protein content. METHODS: Twenty-four male runners (age 36.5 +/- 1.8 years, VO2max 60.0 +/- 1.5 mL?kg(-1) ? min(-1)) ran twice (separated by 4 weeks) on treadmills to exhaustion at 70% VO2max (average time and distance of 2.24 +/- 0.09 h and 24.9 +/- 1.1 km). Muscle biopsies from the vastus lateralis and blood samples were collected before and after each run, with IL-6, IL-8, and MCP-1 measured in muscle (mRNA and protein) and plasma. Data from the two runs were averaged. RESULTS: Participants experienced a 35.3 +/- 4.2% decrease (P < 0.001) in skeletal muscle glycogen content (67.5 +/- 2.8 to 44.3 +/- 3.7 mmol?kg( 1) wet weight). Muscle mRNA expression for IL-6, IL-8, and MCP-1 increased 7.34 +/- 0.90-, 13.9 +/- 2.3-, and 4.10 +/- 0.60-fold, respectively (all, P < 0.001). Skeletal muscle IL-6, IL-8, and MCP-1 protein content increased 35.8 +/- 10.6, 80.6 +/- 12.1, and 105 +/- 17.9%, respectively (all, P <= 0.005). Plasma IL-6, IL 8, and MCP-1 increased 47.1 +/- 10.0-, 2.6 +/- 0.3-, and 1.6 +/- 0.1-fold, respectively (all, P < 0.001). Post-exercise muscle glycogen concentrations were negatively correlated with run time to exhaustion (r = -0.70, P < 0.001), and changes in muscle IL-6 protein content (r = -0.44, P = 0.049), plasma IL-6 (r = 0.72, P < 0.001), IL-8 (r = -0.60, P = 0.002), and MCP-1 (r = -0.589, P = 0.002), but not with changes in muscle IL-8 and MCP-1 protein content, or muscle mRNA expression for IL-6, IL-8, and MCP-1. CONCLUSION: Prolonged and intensive running increased muscle mRNA expression, muscle protein content, and plasma levels for IL-6, IL-8, and MCP-1, and post-run muscle glycogen levels were most strongly related to plasma cytokine levels. PMID- 26442272 TI - Goals in Nutrition Science 2015-2020. PMID- 26442275 TI - Integrating Environmental Sustainability Considerations into Food and Nutrition Policies: Insights from Australia's National Food Plan. AB - The environmental sustainability (ES) of food systems is a critical challenge for policy makers. This is a highly contested policy area with differing views among stakeholders. The aim of the study was to develop a better understanding of how ES considerations are addressed in Australian food and nutrition policies and the way that consultation processes affect final policy outcomes. A mixed-methods study design combined a detailed chronology of key policy developments (2009 2015), a content analysis of written submissions obtained during the NFP's consultation period (2011-2013) and a frame analysis of the sustainability perspectives - efficiency, demand restraint, and system transformation - in the NFP's Issues, Green, and White Papers. There were 555 written submissions responding to two consultation papers. Stakeholders represented all sectors of Australia's food system including government, non-government organizations, the food supply chain, research and academic institutions, and members of the general public. Around 74% of submissions referred to ES considerations and ~65% supported their inclusion into the final policy. Efficiency frames were most dominant; emphasizing a production-oriented approach that regards the environment as a natural resource base for food production but overlooks consumption and equity concerns. Despite strong support for the inclusion of ES considerations in the NFP, the influence of Australia's socio-political context, powerful, industry dominated stakeholders, and a reliance on traditional production-oriented perspectives delivered a business-as-usual approach to food policy making. It has since been replaced by an agricultural strategy that provides only cursory attention to ES. Our findings indicate that Australia's political environment is not sufficiently mature for ES considerations to be integrated into food and nutrition policies. We propose reforms to the current consultation process in Australia to better support this integration by promoting greater transparency and participation in the development of food and nutrition policy making. PMID- 26442274 TI - Biogas Cook Stoves for Healthy and Sustainable Diets? A Case Study in Southern India. AB - Alternative cook stoves that replace solid fuels with cleaner energy sources, such as biogas, are gaining popularity in low-income settings across Asia, Africa, and South America. Published research on these technologies focuses on their potential to reduce indoor air pollution and improve respiratory health. Effects on other cooking-related aspects, such as diets and women's time management, are less understood. In this study, in southern India, we investigate if using biogas cook stoves alters household diets and women's time management. We compare treatment households who are supplied with a biogas cook stove with comparison households who do not have access to these stoves, while controlling for several socio-economic factors. We find that diets of treatment households are more diverse than diets of comparison households. In addition, women from treatment households spend on average 40 min less cooking and 70 min less collecting firewood per day than women in comparison households. This study illustrates that alongside known benefits for respiratory health, using alternative cook stoves may benefit household diets and free up women's time. To inform development investments and ensure these co-benefits, we argue that multiple dimensions of sustainability should be considered in evaluating the impact of alternative cook stoves. PMID- 26442276 TI - Can the Hydroxyapatite-Coated Skin-Penetrating Abutment for Bone Conduction Hearing Implants Integrate with the Surrounding Skin? AB - INTRODUCTION: Percutaneous implants, such as bone conduction hearing implants, suffer from complications that include inflammation of the surrounding skin. A sealed skin-abutment interface can prevent the ingress of bacteria, which should reduce the occurrence of peri-abutment dermatitis. It was hypothesized that a hydroxyapatite (HA)-coated abutment in conjunction with soft tissue preservation surgery should enable integration with the adjacent skin. Previous research has confirmed that integration is never achieved with as-machined titanium abutments. Here, we investigate, in vivo, if skin integration is achievable in patients using a HA-coated abutment. MATERIALS AND METHODS: One titanium abutment (control) and one HA-coated abutment (case) together with the surrounding skin were surgically retrieved from two patients who had a medical indication for this procedure. Histological sections of the skin were investigated using light microscopy. The abutment was qualitatively analyzed using scanning electron microscopy. RESULTS: The titanium abutment only had a partial and thin layer of attached amorphous biological material. The HA-coated abutment was almost fully covered by a pronounced thick layer of organized skin, composed of different interconnected structural layers. CONCLUSION: Proof-of-principle evidence that the HA-coated abutment can achieve integration with the surrounding skin was presented for the first time. PMID- 26442277 TI - Hearts Not Dead after Circulatory Death. PMID- 26442278 TI - Rigid Posterior Lumbopelvic Fixation without Formal Debridement for Pyogenic Vertebral Diskitis and Osteomyelitis Involving the Lumbosacral Junction: Technical Report. AB - BACKGROUND: Pelvic fixation with S2-alar-iliac (S2AI) screws can increase the rigidity of a lumbosacral construct, which may promote bone healing, improve antibiotic delivery to infected tissues, and avoid L5-S1 pseudarthrosis. PURPOSE: To describe the use of single-stage posterior fixation without debridement for the treatment of pyogenic vertebral diskitis and osteomyelitis (PVDO) at the lumbosacral junction. STUDY DESIGN: Technical report. METHODS: We describe the management of PVDO at the lumbosacral junction in which the infection invaded the endplates, disk space, vertebrae, prevertebral soft tissues, and epidural space. Pedicle involvement precluded screw fixation at L5. Surgical management consisted of a single-stage posterior operation with rigid lumbopelvic fixation augmented with S2-alar-iliac screws and without formal debridement of the infected area, followed by long-term antibiotic treatment. RESULTS: At 2-year follow-up, successful fusion and eradication of the infection were achieved. CONCLUSION: PVDO at the lumbosacral junction may be treated successfully using rigid posterior-only fixation without formal debridement combined with antibiotic therapy. PMID- 26442279 TI - Biological Meshes for Inguinal Hernia Repair - Review of the Literature. AB - INTRODUCTION: Biological meshes are a potential alternative to the synthetic meshes to avoid complications and are used in a contaminated field for incarcerated inguinal hernias. The clinical experiences gained with biological meshes for repair of inguinal hernias are presented in this review. MATERIALS AND METHODS: In a literature search of the Medline database using the key word "Biological mesh," 2,277 citations were found. There remained 14 studies in which biological meshes had been used to repair inguinal hernias. RESULTS: In prospective randomized trials, the use of polypropylene vs. biological meshes was compared in open inguinal hernia repair. There was no difference in the recurrence rate, but differences were observed in the postsurgical pain incidence in favor of the biological mesh. In the remaining retrospective studies, the recurrence rates were also acceptable. The biological mesh was used successfully in a potentially contaminated setting. CONCLUSION: Inguinal hernias can be repaired with biological meshes with reasonable recurrence rate, also as an alternative in a potentially contaminated field. PMID- 26442280 TI - Commentary: How Long Do We Need to Follow-Up Our Hernia Patients to Find the Real Recurrence Rate? PMID- 26442281 TI - Physicochemical characteristics of structurally determined metabolite-protein and drug-protein binding events with respect to binding specificity. AB - To better understand and ultimately predict both the metabolic activities as well as the signaling functions of metabolites, a detailed understanding of the physical interactions of metabolites with proteins is highly desirable. Focusing in particular on protein binding specificity vs. promiscuity, we performed a comprehensive analysis of the physicochemical properties of compound-protein binding events as reported in the Protein Data Bank (PDB). We compared the molecular and structural characteristics obtained for metabolites to those of the well-studied interactions of drug compounds with proteins. Promiscuously binding metabolites and drugs are characterized by low molecular weight and high structural flexibility. Unlike reported for drug compounds, low rather than high hydrophobicity appears associated, albeit weakly, with promiscuous binding for the metabolite set investigated in this study. Across several physicochemical properties, drug compounds exhibit characteristic binding propensities that are distinguishable from those associated with metabolites. Prediction of target diversity and compound promiscuity using physicochemical properties was possible at modest accuracy levels only, but was consistently better for drugs than for metabolites. Compound properties capturing structural flexibility and hydrogen bond formation descriptors proved most informative in PLS-based prediction models. With regard to diversity of enzymatic activities of the respective metabolite target enzymes, the metabolites benzylsuccinate, hypoxanthine, trimethylamine N-oxide, oleoylglycerol, and resorcinol showed very narrow process involvement, while glycine, imidazole, tryptophan, succinate, and glutathione were identified to possess broad enzymatic reaction scopes. Promiscuous metabolites were found to mainly serve as general energy currency compounds, but were identified to also be involved in signaling processes and to appear in diverse organismal systems (digestive and nervous system) suggesting specific molecular and physiological roles of promiscuous metabolites. PMID- 26442282 TI - Ion-pumping microbial rhodopsins. AB - Rhodopsins are light-sensing proteins used in optogenetics. The word "rhodopsin" originates from the Greek words "rhodo" and "opsis," indicating rose and sight, respectively. Although the classical meaning of rhodopsin is the red-colored pigment in our eyes, the modern meaning of rhodopsin encompasses photoactive proteins containing a retinal chromophore in animals and microbes. Animal and microbial rhodopsins possess 11-cis and all-trans retinal, respectively, to capture light in seven transmembrane alpha-helices, and photoisomerizations into all-trans and 13-cis forms, respectively, initiate each function. Ion transporting proteins can be found in microbial rhodopsins, such as light-gated channels and light-driven pumps, which are the main tools in optogenetics. Light driven pumps, such as archaeal H(+) pump bacteriorhodopsin (BR) and Cl(-) pump halorhodopsin (HR), were discovered in the 1970s, and their mechanism has been extensively studied. On the other hand, different kinds of H(+) and Cl(-) pumps have been found in marine bacteria, such as proteorhodopsin (PR) and Fulvimarina pelagi rhodopsin (FR), respectively. In addition, a light-driven Na(+) pump was found, Krokinobacter eikastus rhodopsin 2 (KR2). These light-driven ion-pumping microbial rhodopsins are classified as DTD, TSA, DTE, NTQ, and NDQ rhodopsins for BR, HR, PR, FR, and KR2, respectively. Recent understanding of ion-pumping microbial rhodopsins is reviewed in this paper. PMID- 26442283 TI - Molecular diagnostics of neurodegenerative disorders. AB - Molecular diagnostics provide a powerful method to detect and diagnose various neurological diseases such as Alzheimer's and Parkinson's disease. The confirmation of such diagnosis allows early detection and subsequent medical counseling that help specific patients to undergo clinically important drug trials. This provides a medical pathway to have better insight of neurogenesis and eventual cure of the neurodegenerative diseases. In this short review, we present recent advances in molecular diagnostics especially biomarkers and imaging spectroscopy for neurological diseases. We describe advances made in Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), and finally present a perspective on the future directions to provide a framework for further developments and refinements of molecular diagnostics to combat neurodegenerative disorders. PMID- 26442285 TI - Data in support of genome-wide identification of lineage-specific genes within Caenorhabditis elegans. AB - Two sets of LSGs were identified using BLAST: Caenorhabditis elegans species specific genes (SSGs, 1423), and Caenorhabditis genus-specific genes (GSGs, 4539). The data contained in this article show SSGs and GSGs have significant differences in evolution and that most of them were formed by gene duplication and integration of transposable elements (TEs). Subsequent observation of temporal expression and protein function presents that many SSGs and GSGs are expressed and that genes involved with sex determination, specific stress, immune response, and morphogenesis are most represented. The data are related to research article "Genome-wide identification of lineage-specific genes within Caenorhabditis elegans" in Journal of Genomics [1]. PMID- 26442284 TI - Diabetic Nephropathy Induced by Increased Ace Gene Dosage Is Associated with High Renal Levels of Angiotensin (1-7) and Bradykinin. AB - Population studies have shown an association between diabetic nephropathy (DN) and insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene (ACE in humans, Ace in mice). The aim was to evaluate the modulation of Ace copies number and diabetes mellitus (DM) on renal RAS and correlate it with indicators of kidney function. Increased number of copies of the Ace gene, associated with DM, induces renal dysfunction. The susceptibility to the development of DN in 3 copies of animals is associated with an imbalance in activity of RAS enzymes leading to increased synthesis of Ang II and Ang-(1-7). Increased concentration of renal Ang-(1-7) appears to potentiate the deleterious effects triggered by Ang II on kidney structure and function. Results also show increased bradykinin concentration in 3 copies diabetic group. Taken together, results indicate that the deleterious effects described in 3 copies diabetic group are, at least in part, due to a combination of factors not usually described in the literature. Thus, the data presented here show up innovative and contribute to understanding the complex mechanisms involved in the development of DN, in order to optimize the treatment of patients with this complication. PMID- 26442286 TI - Data on pigments and long-chain fatty compounds identified in Dietzia sp. A14101 grown on simple and complex hydrocarbons. AB - This data article provides: 1.An overview of tentatively identified long chain compounds in Dietzia sp. A14101 grown on simple and complex hydrocarbons;2.Preliminary Identification of pigments in bacterial material obtained from incubation with a hydrocarbon (dodecane, n-C12) as the only carbon and energy source;3.Some pictures to illustrate the cell surface charge test. PMID- 26442287 TI - An enzyme-free colorimetric assay using hybridization chain reaction amplification and split aptamers. AB - A novel unmodified gold nanoparticle (AuNP)-based colorimetric assay was demonstrated using split aptamers and the hybridization chain reaction (HCR) amplification strategy. Here, the aptamer was divided into a structure-switching hairpin probe (DNA probe H1 (or H1')) and a single-stranded probe (DNA probe H2 (or H2')). In the presence of the target, DNA probe H1 (or H1') could specifically capture the target with the assistance of DNA probe H2 (or H2') to form a stable complex. Subsequently, the hairpin structure of DNA probe H1 (or H1') was changed, and then a chain reaction of hybridization events between two other hairpin probes (H3 and H4) propagated, resulting in the formation of nicked double-helices. Since it was difficult for such nicked double-helices to inhibit salt-induced AuNP aggregation, a red-to-blue color change was observed. With the elegant amplification effect of HCR, this assay showed a low detection limit (15 nM for Hg(2+) and 1 MUM for adenosine), which was lower than or at least comparable to previous AuNP-based methods. The novel strategy not only eliminated the requirements of enzymatic reactions, separation processes, chemical modifications, and sophisticated instruments, but also could be used for other targets only by simply changing the DNA probe sequences. PMID- 26442288 TI - Response to Dr. Carbone's Letter to the Editor. PMID- 26442289 TI - Surgical Correction of Rectal Prolapse in Laboratory Mice (Mus musculus). AB - Rectal prolapse is a common clinical problem in laboratory mice. This condition may occur spontaneously, develop after genetic manipulations, result from infections with pathogens such as Citrobacter species, or arise secondary to experimental design such as colitis models. The current standard of care at our institution is limited to monitoring mice until tissue becomes ulcerated or necrotic; this strategy often leads to premature euthanasia of valuable animals prior to the study endpoint. Surgical correction of rectal prolapse is performed routinely and with minimal complications in larger species by using manual reduction with placement of a pursestring suture. In this report, we investigated whether the use of a pursestring suture was an effective treatment for mice with rectal prolapse. The procedure includes anesthetizing mice with isoflurane, manually reducing prolapsed tissue, and placing a pursestring suture of 4-0 polydioxanone. We have performed this procedure successfully in 12 mice. Complications included self-trauma, fecal impaction due to lack of defecation, and mutilation of the surgical site by cage mates. Singly housing mice for 7 d postoperatively, applying multimodal analgesia, and releasing the pursestring when indicated eliminated these complications. The surgical repair of rectal prolapses in mice is a minimally invasive procedure that resolves the clinical symptoms of affected animals and reduces the number of mice that are euthanized prematurely prior to the study endpoint. PMID- 26442290 TI - DIESEL AND GASOLINE ENGINE EXHAUSTS AND SOME NITROARENES. IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC RISKS TO HUMANS. PMID- 26442291 TI - [Related factors of sperm DNA damage: Advances in studies]. AB - The detection of sperm DNA damage, as an important supplement to semen routine examination strategies, has been applied in some clinical andrology laboratories. What factors may lead to sperm DNA damage remains one of the concerns among many andrologists. Present studies show a variety of factors of sperm DNA damage, including age, environmental pollutants such as organophosphorus and organochloride pesticides, plasticizer, heavy metals such as lead, carcinogens such as polycyclic aromatic hydrocarbons (c-PAHs) and zearalenone (ZEA), male reproductive system diseases or systemic diseases such as varicocele, infection, tumor, spermatogenesis and maturation dysfunction, spinal cord injury and endocrine disorders, seasons and temperature, lifestyle, abstinence time, semen refrigeration, semen handling in vitro, and certain medications. Among them, spermatogenesis and sperm maturation dysfunction may be the most secretive factors, which are involved in the molecular mechanisms of sperm chromatin packaging and restructuring, such as the transformation of histone to protamine, single nucleotide polymorphism of genes, and the role of telomere, which may be one of the hotspots in the future studies of sperm DNA damage. Relevant researches in the future are expected to focus on the prevention of sperm DNA damage and clarification of its specific pathogenic mechanisms so as to provide some evidence for its treatment. PMID- 26442292 TI - [Prostatic inflammation-induced chronic pelvic pain: Roles of substance P and c fos in the spinal cord]. AB - OBJECTIVE: To explore the possible pain mechanism of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: The models of CP/CPPS were established in male Wistar rats by the autoimmune method. The paw withdrawal threshold (PWT) was detected using Von Frey filament. The expressions of the substance P and c fos in the prostate and spinal L5-S2 segments were determined by immunohistochemistry followed by analysis of their correlation with CP/CPPS. RESULTS: Compared with the control rats, the CP/CPPS models showed significantly decreased PWT (P < 0.05), remarkable prostatic inflammation, enlarged scope of lesions, and obvious interstitial lymphocytic infiltration (P < 0.05). Both the expressions of substance P and c-fos were markedly elevated in the prostate and spinal dorsal horn (L5-S2) of the rat models (P < 0.05), but the expression of substance P in the prostate exhibited no correlation with that in the spinal cord (r = 0.099, P = 0.338), nor did that of c-fos (r = 0.027, P = 0.454). CONCLUSION: The upregulated expressions of substance P and c-fos in the spinal cord L5-S2 sections may be associated with the pain mechanism of CP/CPPS. PMID- 26442293 TI - [Baicalein enhances the gap junction in the TM4 Sertoli cells of mice]. AB - OBJECTIVE: To investigate the effect of baicalein on the gap junction intercellular communication (GJIC) in the TM4 Sertoli cells of the mouse testis and its related mechanism. METHODS: We measured the cytotoxicity of different concentrations of baicalein on the TM4 Sertoli cells in the mouse testis by MTT, detected the fluorescence transfer of the TM4 Sertoli cells by parachute assay, and determined the expression of the protein connexin 43 ( Cx43) in the baicalein treated cells by Western blot and immunofluorescence assay. RESULTS: Baicalein produced no obvious cytotoxicity on the TM4 Sertoli cells at the concentration below 60 umol/L but significantly increased their GJIC at 0-20 umol/L (P < 0.01). Western blot and immunofluorescence assay showed that 0-20 umol/L baicalein remarkably elevated the expression of Cx43 in the TM4 cells (P < 0.01) and on the membrane of the TM4 cells. CONCLUSION: Baicalein at the concentration of 0-20 umol/L can significantly enhance GJIC in mouse TM4 Sertoli cells by increasing the expression of the Cx43 protein. PMID- 26442294 TI - [Bone marrow mesenchymal stem cells to repair the reproductive system of male azoospermia rats]. AB - OBJECTIVE: To study the ability of bone marrow mesenchymal stem cells (BMSCs) to repair the internal environment of the testis in male azoospermia rats. METHODS: We established azoospermia models in 22 six-week-old male SD rats by intraperitoneal injection of busulfan at 20 mg per kg body weight. We transplanted allogeneic rat BMSCs (rBMSCs) into the testicular seminiferous tubules of the model rats and, 30 days after transplantation, observed the composition and structure of the seminiferous tubular cells by HE staining and detected the expressions of CD44, CD106, and c-kit in the rBMSCs by immunohistochemistry. RESULTS: The number of epididymal sperm was significantly reduced in the model rats as compared with the normal controls (P < 0.01). CD44 and CD106, but not c-kit, were expressed in the isolated rBMSCs. At 30 days after transplantation of rBMSCs, lots of new cells were observed in the seminiferous tubules, some expressing CD106 and some expressing the germ cell surface marker c kit. CONCLUSION: BMSCs can transdifferentiate into germ cells and repair the damaged seminiferous tubules of sterile rats. PMID- 26442295 TI - [An optimal method for cryopreservation of microamount round spermatids of the mouse]. AB - OBJECTIVE: To search for an optimal protocol and freezing conditions for the cryopreservation of microamount round spermatids of the mouse. METHODS: We compared the survival rates of frozen-thawed microamount round spermatids of the mouse achieved by vitrification or standard slow freezing with different concentrations of glycerol (5, 7, or 9%) and different lengths of equilibrium time (0, 15, 30, 45, or 60 min). RESULTS: Under the conditions of 7% glycerol and 30 min equilibrium, both vitrification and standard slow freezing achieved high survival rates of spermatids, and the former obtained an even higher rate than the latter ([72.9 +/- 15.4]% vs [58.2 +/- 17.7]%, P < 0.05). CONCLUSION: A high rate of frozen-thawed microamount round spermatids of the mouse can be achieved by vitrification under the conditions of 7% glycerol and 30 min equilibrium. PMID- 26442296 TI - [Tea polyphenols reduces the apoptosis of spermatogenic cells in rats with experimental varicocele]. AB - OBJECTIVE: To study the effect of tea polyphenols (TP) on the apoptosis of germ cells in rats with experimental varicocele. METHODS: Thirty-two adolescent male Wistar rats were randomly and equally divided into groups A (sham-operation), B (high-dose TP), C (low-dose TP), and D (experimental left varicocele). Experimental varicocele was induced by partial ligation of the left renal vein in the latter three groups of rats. The animals in groups A and D were fed with normal saline, while those in B and C with TP at 40 and 10 mg per kg per d, respectively, all for 4 weeks. Then, all the rats were sacrificed and the left testes harvested for determination of the expression of HIF-1, Bcl-2, Bax, CytC, and caspase-3 by immunohistochemistry and measurement of the apoptosis index (AI) of spermatogenic cells. RESULTS: The expression of Bcl-2 was higher in groups B and C than in D but lower than in A (P < 0.05), and lower in C than in B (P < 0.05). However, the expressions of HIF-1, Bax, CytC, and caspase-3 were lower in groups B and C than in D but higher than in A (P < 0.05), and higher in C than in B (P < 0.05). The AI of spermatogenic cells was the lowest in group A, higher in D than in the other groups but lower in B than in C (P < 0.05). CONCLUSION: TP can reduce the apoptosis of spermatogenic cells in a dose-dependent manner in varicocele rats. PMID- 26442297 TI - [Correlation of TLR2 and TLR4 gene polymorphisms with the susceptibility and recurrence of condyloma acuminatum]. AB - OBJECTIVE: To explore the correlation of the gene polymorphisms of Toll-like receptor 2 ( TLR2) and TLR4 with the susceptibility and recurrence of condyloma acuminatum (CA). METHODS: Using Snapshot, we detected the gene polymorphisms of TLR2 597(T/C), 1350(T/C), 15607(A/G), and 2258(G/A) and TLR4 896(A/G) and 1196(C/T) in the peripheral blood of 140 CA patients and 105 HPV-negative controls. We made comparisons between the CA patients and controls as well as between the cases of recurrent CA and those of non-recurrence at 6 months after treatment. RESULTS: There were 72, 48, and 20 cases of genotype TT, TC, and CC of TLR2 597 (T/C), respectively, in the CA patients, as compared with 71, 31, and 3 cases in the controls. The gene frequency of mutant C was 31. 43% in the patients, significantly higher than 17.62% in the controls (chi2 = 12.04, P < 0.01), and it was 38.68% in the recurrent cases, remarkably higher than 27.01% in the non-recurrent cases (chi2 = 4.16, P < 0.05). There were 74, 49, and 17 cases of genotype TT, TC, and CC of TLR2 1350( T/C), respectively, in the CA patients, as compared with 73, 29, and 3 cases in the controls. The gene frequency of mutant C was 29. 64% in the patients, significantly higher than 16. 67% in the controls (chi2 =11.05, P < 0.01), and it was 36.79% in the recurrent cases, markedly higher than 25. 29% in the non-recurrent cases (chi2 = 4.18, P < 0.05). There were 44, 66, and 30 cases of genotype AA, AG, and GG of TLR2 15607(A/G), respectively, in the CA patients, as compared with 26, 58, and 21 cases in the controls. There was no significant difference in the gene frequencies of mutant G between the two groups (chi2 = 0.33, P > 0.05). No mutant genes of TLR2 2508 (G/A) or TLR4 896(A/G) and 1196(C/ T) were detected in either the CA patients or the controls. Linkage disequilibrium analysis showed a tight linkage between TLR2 597 (T/C) and 1350(T/C) (D' = 1, r2 = 0.93). CONCLUSION: TLR2 597(T/C) is tightly linked to 1350(T/C), which is correlated with both the susceptibility and the recurrence of condyloma acuminatum. PMID- 26442298 TI - [A260G and A386G single nucleotide polymorphisms of the DAZL gene are not correlated with male infertility in the Chinese population of Zhejiang Province]. AB - OBJECTIVE: To assess the association of the A260G and A386G single nucleotide polymorphisms (SNP) of the DAZL gene with male infertility in the Chinese population of Zhejiang Province. METHODS: We collected the peripheral blood samples from 317 idiopathic infertile males with azoospermia or oligozoospermia and 246 normal fertile men, and genotyped the polymorphic loci of the A260G and A386G polymorphisms of the DAZL gene using the SNaPshot technique. RESULTS: The DAZL gene A260G was found genetically polymorphic in the Chinese population of Zhejiang Province, with the gene frequencies and their distribution consistent to the Hardy-Weinberg equilibrium. The frequencies of the AA, AG and GG genotypes of the A260G polymorphism were 92.3%, 7.3%, and 0.4% respectively in the normal controls and 94.3%, 5.7%, and 0% in the infertile patients, with no statistically significant differences between the two groups (P = 0.43, OR = 0.78, 95% CI 0.413 1.46). Heterozygosis (AG) of A386G was found in 1 of the control males but not in the infertile patients, while homozygosis (GG) of A386G was not observed in either group (P = 0.259, OR = 0.698, 59% CI: 0.374-1.306). CONCLUSION: A260G and A386G SNPs of the DAZL gene are not associated with spermatogenic failure and neither represents a molecular marker for the genetic diagnosis of male infertility in the Chinese population of Zhejiang Province. PMID- 26442299 TI - [Dynamic changes of the epididymal size after vasectomy: An ultrasonographic observation]. AB - OBJECTIVE: To investigate the dynamic changes of the epididymal size 1 year after vasectomy. METHODS: Fifty male volunteers received vasoligation. Before and at 1, 2, 3, 6, and 12 months after operation, we measured the size and detected the internal echoes of the epididymis using color Doppler ultrasonography. RESULTS: The bilateral epididymides were both thickened post-operatively in all the 50 cases, with statistically significant differences between the baseline and the 1st month, the 1st and the 2nd month, the 2nd and the 3rd month, or the 3rd and the 6th month after surgery (all P < 0.01), but not between the 6th and the 12th month (P > 0.05). CONCLUSION: Within 6 months after vasectomy, the bilateral epididymides manifested a progressive thickening, but basically restored their balance of secretion-absorption after 6 months. PMID- 26442300 TI - [Different scoring systems to evaluate the prognosis of Fournier's gangrene: A comparative study]. AB - OBJECTIVE: To sum up the experience in diagnosis and treatment of Fournier's gangrene and find an optimal evaluation tool for its prognosis by comparing currently used prognostic scoring systems. METHODS: We retrospectively analyzed 16 cases of Fournier's gangrene diagnosed and surgically treated in our hospital between 2004 and 2012. Using Fournier's Gangrene Severity Index (FGSI), Uludag Fournier's Gangrene Severity Index (UFGSI), Age-Adjusted Charlson Comorbidity Index (ACCI), and Surgical Apgar Score (sAPGAR) , we obtained the prognostic scores of the patients and made comparisons among different scoring systems. RESULTS: FGSI, UFGSI, ACCI, and sAPGAR were all clinically used scoring systems. Statistically significant differences were found in the scores of ACCI and UFGSI but not in those of FGSI and sAPGAR between the death and survival groups, with the maximum area under the ROC curve and minimum standard error for the ACCI score. CONCLUSION: Both ACCI and UFGSI are useful for evaluating the prognosis of Fournier's gangrene. However, ACCI is even better for its higher sensitivity and specificity and easier clinical collection. PMID- 26442302 TI - [The volume of residual urine correlates with bladder outlet obstruction and detrusor contractility in patients with benign prostatic hyperplasia]. AB - OBJECTIVE: To identify the correlation of the volume of residual urine (VRU) with the severity of bladder outlet obstruction (BOO) and detrusor contractility in patients with benign prostatic hyperplasia (BPH). METHODS: A total of 152 patients with clinically diagnosed BPH underwent ultrasonography for measurement of the prostate volume and RVU, free uroflowmetry, and urodynamic examination for the severity of BOO and detrusor contractility. Using the software SPSS20. 0, we analyzed the correlation between the ultrasonographic results and urodynamic parameters and compared the two sample means by the t-test. RESULTS: The prostate volume was correlated positively with BOO severity (r = 0.432, P < 0.01) and detrusor contractility (r = 0.343 , P < 0.01) while Qmax negatively with BOO severity (r = 0.327, P < 0.01) but not significantly with detrusor contractility (r = 0.123, P > 0.05). VRU showed a significantly negative correlation with detrusor contractility when > 150 ml (r = -0.490, P < 0.01), even more significantly when > 300 ml (r = -0.717, P < 0.01), but exhibited no significant correlation with it when <= 150 ml (r = 0.041, P > 0.05). CONCLUSION: VRU can somehow predict the detrusor function. For patients with VRU > 150 ml, especially for those with VRU > 300 ml, the detrusor function should be evaluated and urodynamic examination is recommended for exact assessment of BOO severity and detrusor contractility. PMID- 26442301 TI - [Early diagnosis of prostate cancer by combined use of Trp-p8 expression and PSA density of the transition zone]. AB - OBJECTIVE: To study the expression of the Trp-p8 protein in the prostate tissue of the PSA "grey zone" with different PSA density of the transition zone (PSADTZ) and explore the value of determining Trp-p8 expression and PSADTZ in the early diagnosis of prostate cancer (PCa). METHODS: This study involved 30 cases of benign prostatic hyperplasia (BPH) and another 30 cases of PCa with different PSADTZ values. Using a data imaging and analysis system, we determined the expression levels of Trp-p8 in BPH and PCa tissues and analyzed their correlation with PSADTZ. RESULTS: The expression of Trp-p8 was weak or negative in the BPH but strong in the PCa tissue and even stronger in the PCa tissue with high PSADTZ (F = 34. 05, P < 0.05). CONCLUSION: The Trp-p8 protein is expressed differently in BPH and PCa tissues of the PSA " grey zone" and its expression is positively correlated with PSADTZ. Determination of the Trp-p8 expression and PSADTZ contributes to the early diagnosis of prostate cancer. PMID- 26442303 TI - [Decreases of progressive motility, total motility, and acrosin activity of sperm from oligoasthenoteratospermia males at different time points after sperm activation]. AB - OBJECTIVE: To investigate the progressive motility, (PR), total motility (progressive + non-progressive motility, PR + NP), and acrosin activity of sperm from normal and infertile men at different time points after sperm activation. METHODS: Based on the 5th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen and the results of modified Papanicolaou staining, we divided the semen samples into groups A (normal, n = 28), B (oligoasthenoteratospermia, n = 30), and C (asthenoteratospermia, n = 32). At 1, 24, and 48 hours after sperm activation, we detected sperm PR and PR + NP by CASA and chemical colorimetry, and determined sperm acrosin activity using the modified Kennedy method. RESULTS: Sperm PR and PR + NP were significantly decreased in all the three groups at 1-24 hours and even more significantly at 24 48 hours after sperm activation as compared with the baseline (P < 0.05). Sperm acrosin activity showed remarkable reduction in group A (P = 0. 013) , even more significant at 1-24 hours than at 24-48 hours after sperm activation, but not in groups B and C (P = 0.519 and 0.979). CONCLUSION: Sperm PR, PR + NP, and acrosin activity are all decreased with the extension of time after sperm activation, each in a specific manner. Examination of sperm acrosin activity should be applied as a routine tool in the assessment of male fertility. PMID- 26442305 TI - [Vasectomy does not increase the risk of prostate cancer in Chinese men: A meta analysis]. AB - OBJECTIVE: To investigate the correlation of vasectomy with the risk of prostate cancer in Chinese men. METHODS: We systematically searched the databases CNKI, VIP, Wanfang, PubMed, Embase, and Cochrane Library for the literature relating the relationship between vasectomy and the risk of prostate cancer in Chinese males up to December 2014. According to the inclusion and exclusion criteria, two investigators independently selected the eligible publications, evaluated their quality, and extracted relevant information, followed by a meta-analysis with the software STATA 12.0. RESULTS: Nine studies were included in the analysis involving 1 202 cases of prostate cancer and 4,496 controls. Random-effect model analysis revealed no statistically significant correlation between vasectomy and the risk of prostate cancer (OR = 1.05; 95% CI 0.62-1.79), with an obvious heterogeneity (P < 0.001, I2 = 85.7%). No significant publication bias was found among the included studies (Egger, P = 0.824; Begg, P = 0.348). CONCLUSION: The results of our meta-analysis do not support the association of vasectomy with the increased risk of prostate cancer in Chinese population. PMID- 26442306 TI - [Hepatocyte growth factor and male reproduction]. AB - The hepatocyte growth factor ( HGF) is a multifunctional growth factor, which produces multiple biological effects by binding to the c-Met acceptor. This article reviews the biological properties of HGF, particularly those correlated with male reproduction, including its abilities to promote testis embryonic development, spermatogenesis, and testosterone synthesis of Leydig cells. HGF may provide a new insight into the treatment of male hypogonadism and infertility. PMID- 26442304 TI - [Protective effect of Liuweidihuang Pills against cellphone electromagnetic radiation-induced histomorphological abnormality, oxidative injury, and cell apoptosis in rat testes]. AB - OBJECTIVE: To observe the effect of Liuweidihuang Pills in relieving cellphone electromagnetic radiation-induced histomorphological abnormality, oxidative injury, and cell apoptosis in the rat testis. METHODS: Thirty adult male SD rats were equally randomized into a normal, a radiated, and a Liuweidihuang group, the animals in the latter two groups exposed to electromagnetic radiation of 900 MHz cellphone frequency 4 hours a day for 18 days. Meanwhile, the rats in the Liuweidihuang group were treated with the suspension of Liuweidihuang Pills at 1 ml/100 g body weight and the other rats intragastrically with the equal volume of purified water. Then all the rats were killed for observation of testicular histomorphology by routine HE staining, measurement of testicular malondialdehyde (MDA) and glutathione (GSH) levels by colorimetry, and determination of the expressions of bax and bcl-2 proteins in the testis tissue by immunohistochemistry. RESULTS: Compared with the normal controls, the radiated rats showed obviously loose structure, reduced layers of spermatocytes, and cavitation in the seminiferous tubules. Significant increases were observed in the MDA level (P < 0.01) and bax expression (P < 0.01) but decreases in the GSH level (P < 0.01) and bcl-2 expression (P < 0.01) in the testis issue of the radiated rats. In comparison with the radiated rats, those of the Liuweidihuang group exhibited nearly normal testicular structure, significantly lower MDA level (P < 0.05), bax expression (P < 0.01), and bcl-2 expression (P < 0.01). CONCLUSION: Liuweidihuang Pills can improve cellphone electromagnetic radiation induced histomorphological abnormality of the testis tissue and reduce its oxidative damage and cell apoptosis. PMID- 26442307 TI - [Induced differentiation of stem cells into androgen-secreting cells]. AB - Leydig cells are the major source of androgens in males. Stem cells can be induced to differentiate into androgen-secreting Leydig like cells, whose functions are regulated by the hypothalamus and pituitary, so that they precisely secret the necessary hormones to maintain physiological function. Therefore, the establishment of an effective protocol to induce the differentiation of stem cells into androgen-secreting cells is very helpful for the treatment of hypogonadism caused by abnormalities of Leydig cells. This review outlines the recent findings concerning the differentiation of stem cells into androgen secreting cells. PMID- 26442308 TI - [Medical and technical means for united circle of evacuation measures in military medical organisations of the Ministry of Defence]. AB - Experts of the medical service of the Armed Forces carried out an analysis of capabilities of modern Russian enterprises and their innovative projects regarding creation of unified means of evacuation of wounded and providing to them necessary types of emergency care with the use of existing and future special and regular means of transport for medical evacuation. As a result of the work of industrial enterprises of the OAO Kazan "Vertoletniy Zavod", "Zarechie", "Vysota" was created a device for the medical evacuation of severe wounded patients. The device is designed for medical evacuation of severe wounded patients from the military medical unit to the site providing comprehensive medical care with maintenance of vital functions and monitoring of his condition. Testing was conducted on the products of regular vehicles medical company of one of the brigades of the Western Military District. The device was presented at the special tactical exercises the Armed Forces Medical Service "Frontier-2014", "Innovation Day" of the Defence Ministry in 2014. PMID- 26442309 TI - [Approaches to development and implementation of the medical information system for military-medical commission of the multidisciplinary military-medical organisation]. AB - The current task of the implementation of medical information systems in the military and medical organizations is an automation of the military-medical expertise as one of the most important activities. In this regard, noteworthy experience of the 9th Medical Diagnostic Centre (9th MDC), where on the basis of medical information system "Interi PROMIS" for the first time was implemented the automation of the work of military medical commission. The given paper presents an algorithm for constructing of the information system for the military-medical examination; detailed description of its elements is given. According to military servicemen the implementation of the Military Medical Commission (MMC) subsystem of the medical information system implemented into the 9th MDC has reduced the time required for the MMC and paperwork, greatly facilitate the work of physicians and medical specialists on military servicemen examination. This software can be widely applied in ambulatory and hospital practice, especially in case of mass military-medical examinations. PMID- 26442310 TI - [Organisational peculiarities and principles of medical-psychological rehabilitation of military personnel of special units of the Ministry of Defence]. AB - The authors presented information about current state of organization of medical and psychological rehabilitation at sanatorium stage of military servicemen of special units of the Russian Defense Ministry, information about rehabilitation treatment techniques, and physical and psychological rehabilitation, natural and premature medicinal factors. PMID- 26442311 TI - [Modern methods of inhalation therapy of respiratory diseases]. AB - In pulmonary practice the effectiveness of the therapy depends on a method of drug delivery. In case of different forms of medications, which can be used for the treatment of patients with obstructive pulmonary diseases physicians usually choose inhalants. In this publication authors examines the main aspects of the use of nebulizers in the treatment of obstructive pulmonary diseases: types of nebulizers, their capabilities and limitations, indications for inhalation therapy and drug policy. PMID- 26442313 TI - [The role of the vaccine prophylaxis of cervical cancer among female military personnel]. AB - The authors presented results of the study concerning human papillomavirus infecting of military students of higher military educational institutions of the Ministry of Defence of the Russian Federation. In the Center for Obstetrics and Gynaecology of the Kirov Military-Medical Academy was performed a dynamic examination of 478 female cadets aged 17-25. The high level of high-risk HPV viruses was revealed during the examination what proves the necessity of prophylaxis enhancing with the aim to prevent gynecological diseases and reproductive health promotion. The main ways of cervical cancer prophylaxis are health education, in-depth medical examination of women with the aim to reveal and treat gynecological diseases (this medical examination should be carried out twice a year), primary prevention of cervical cancer by vaccination. PMID- 26442312 TI - [Treatment of patients with bronchial asthma associated with obesity in a health resort "Okeanskiy"]. AB - In this paper we assess the efficiency of sanatorium treatment of patients with bronchial asthma of two different weigh groups: with normal body weight and obesity. According to the results of clinical examination it was found that in patients with bronchial asthma and obesity of I-II degree efficiency of sanatorium treatment is lower in comparison with patients with bronchial asthma and normal body weight. The use of a standard set of procedures is not enough to correct the symptoms of asthma in obese patients. Comparative analysis of clinical symptoms in patients with bronchial asthma with normal body weight and obesity were differences of up to 50%. The conclusion about the need to develop a set of techniques to optimize the effectiveness of rehabilitation is given. PMID- 26442314 TI - [Combined mechanical-cold and mechanical-burn injuries in patients injured in maritime disasters]. AB - On the basis of analysis of 372 medical histories and total amount of victims (2691 people) of marine accidents it was revealed that 303 (83.1%) survivors suffered from combined mechanical-cold injuries, combined two-factor mechanical burn injuries were diagnosed in 115 of wounded (15.7%), combined three-factor mechanical-cold-burn injuries were diagnosed in 162 of wounded (22.5%). It was established that in case of capsizing and shipwrecking chest and abdomen injuries prevail in wounded (22.4%). Pelvic fractures, injuries of the lower extremities and spine traumas prevail in wounded evacuated from the crash area after explosion and fire on the ships (43.3%). The above-mentioned injuries prevail due to mine-blast nature of injuries. Typical injuries in wounded survived in maritime disasters are in non-severe combined mechanical-cold, mechanical-burn, and mechanical-cold-burn injuries, minor and moderate hypothermia, mild burn injuries and mild carbon monoxide poisoning. PMID- 26442315 TI - [The set of wearable medical equipment for medical and nursing teams]. AB - The kit is designed in accordance with the list of the first medical aid procedures and syndromic standards of emergency medical care providing. The kit contains modern local hemostatic agents, vent tubes, cricothyrotomy, needles to eliminate pneumothorax, portable oxygen machine, sets for intravenous and intraosseous infusion therapy, collapsible plastic tires, anti-shock pelvic girdle, and other medical products and pharmaceuticals. As containers used backpack and trolley bag on wheels camouflage colours. For the convenience and safety of the personnel of the vest is designed discharge to be converted in the body armour. PMID- 26442316 TI - [The main ways in performing analysis of the activities of medical supply organizations of the Armed Forces]. AB - Without a complex comprehensive analysis of the activities of medical supply organizations is impossible to effectively manage the processes of provision of medical equipment and property, and provide a quality control of finished products and magistral formulas, technical and metrological provision of medical services and to render better decisions. In this regard, the article provides a list of pharmaceutical services (works) provided by medical supply organizations of the Armed Forces of the Russian Federation and proposes indicators in assessing their effectiveness. Examples of analysis and assessment of the main indicators of provided services (works) in absolute values are given. At the same time, the authors give the ways of solutions aimed at increasing the motivation of various specialists to improve the quality of performance indicators in the medical equipment and property support centres of the Ministry of Defense of the Russian Federation. PMID- 26442317 TI - [Legal regulation of clinical drug trials for the use in military-medical organisations]. AB - The authors identified problematic issues of legal regulation of clinical drug trials for medical use, and proposed possible solutions. It has been established that the conduction of clinical trials, of medicinal products is based on the norms of various branches of law embodied in the Constitution of the Russian Federation, the norms of international law, the Civil Code of the Russian Federation and federal laws and subordinate legislations regulating health and pharmaceutical activity. According to the authors, the norms of bioethics can be attributed to the sources of legal doctrine. It is proposed to oblige executives of clinical trials to make a report about effectiveness and safety of drugs and pass the results to the customer, in his/her turn the customer is obliged to accept the results of these trials and pay for them. PMID- 26442318 TI - [Medical Service of the Estonian Defense Forces]. AB - The article is a brief description of the current state of the Estonian Defense Forces medical service and is based on the study of the open access foreign sources. At the beginning, the general information about Estonia, its Defense Forces, and their medical service is presented. Then the medical service particular features are described with more detail, namely, the organization of the inpatient and outpatient treatment, medical supply, scientific research, combat medicine, medical staff education and training, medical service personnel income. PMID- 26442320 TI - [To the 80th anniversary of the 637th center of the state sanitary and epidemiological surveillance]. AB - In March 2015 marked the 80th anniversary of the creation of the 637th Center of State Sanitary and Epidemiological Surveillance. The date of establishment of the Centre is rooted in the pre-war period, when sanitary-epidemiological laboratories of the Black Sea Fleet were organized as a scientific and methodological institution. During the Great Patriotic War, as well as during the early postwar period, the staff of the Centre carried out valuable work on provision of sanitary and epidemiological welfare of the Black Sea Fleet. Later, soldiers of the Center participated in the aftermath of the Chernobyl accident, fulfilling their international duty in the Democratic Republic of Afghanistan, on the island of Dahlak, as well as in the Chechen Republic during the anti terrorist operation. During its existence, the Centre repeatedly reorganized and is now an institution that successfully solves the problem of ensuring sanitary and epidemiological welfare of the troops in the area of responsibility. PMID- 26442319 TI - [The contribution of the Archive of the Military Medical Museum in summarizing the experience of the Great Patriotic War]. AB - During 70 years of existence of the Military Medical Museum one of its main goals was to create an archive of military medical documents, the formation of his ideology and collecting funds, saving and promotion of unique materials related to the history of Russia, feat of arms Defenders of the Fatherland in the wars of the XX century. Creating a military medical museum archive was conceived in the beginning of the Great Patriotic War by leading figures of the military medicine- E.I.Smirnov, S.M.Bagdasaryan, V.N.Shevkunenko, A.N.Maksimenkov, who offered to collect all materials about the work of physicians at the front and in the rear, to consider the archive as a base for scientific works on the history of the military health care. Today the archive was removed from the Army Medical Museum and now it is a branch of the Central Archive of the Ministry of Defence of the Russian Federation (military medical records). His staff keeps the traditions established by predecessors and use in their activities a wealth of experience and background research. PMID- 26442321 TI - [Dual-wavelenght optoelectronic sensor for monitoring uric acid concentration in dialysis fluid]. PMID- 26442322 TI - [Optoelectronic device for diagnosis of esophagus dysfunction]. PMID- 26442323 TI - [Scanning probe nanotomograph: peculiarities of technical solutions for analysis of biomedical materials at low temperatures]. PMID- 26442324 TI - [Modern methods for measurement of blood coagulation parameters]. PMID- 26442325 TI - [Laboratory equipment for studying cell reaction to high-voltage pulsed electric field]. PMID- 26442326 TI - [Assessment of mechanical characteristics of biological tissue in cases of surface modification with the linearIy chained carbon]. PMID- 26442327 TI - [Improvement of load capacity of piezoceramic emitters of ultrasonic devices used in traumatology and surgery]. PMID- 26442328 TI - [Calculation of coefficients of anisotropy and symmetry of cornea nerve orientation based on automated recognition of digital confocal images]. PMID- 26442329 TI - [A device for noninvasive measurement of the frequency of action potentials of single motor units]. PMID- 26442330 TI - [Preclinical tests of dioxidine as a decontaminating agent for cardiac valve bioimplants]. PMID- 26442331 TI - [Automation of recognition of cerebral stroke boundaries based on the threshold processing of magnetic resonance images]. PMID- 26442332 TI - [The effect of angular displacement of coils on the efficiency of transcutaneous wireless energy transfer using induction coupling]. PMID- 26442333 TI - [The effect of spectral composition of probing signal on the results of bioimpedance measurement in biological objects]. PMID- 26442334 TI - [Development of an automated device for knee joint mechanotherapy]. PMID- 26442335 TI - [Classification and structure of biomedical computer-aided design systems]. PMID- 26442336 TI - [Simulation of processes of generation of peripheral arterial blood pulsation]. PMID- 26442337 TI - From Sound to Significance: Exploring the Mechanisms Underlying Emotional Reactions to Music. AB - A common approach to studying emotional reactions to music is to attempt to obtain direct links between musical surface features such as tempo and a listener's responses. However, such an analysis ultimately fails to explain why emotions are aroused in the listener. In this article we explore an alternative approach, which aims to account for musical emotions in terms of a set of psychological mechanisms that are activated by different types of information in a musical event. This approach was tested in 4 experiments that manipulated 4 mechanisms (brain stem reflex, contagion, episodic memory, musical expectancy) by selecting existing musical pieces that featured information relevant for each mechanism. The excerpts were played to 60 listeners, who were asked to rate their felt emotions on 15 scales. Skin conductance levels and facial expressions were measured, and listeners reported subjective impressions of relevance to specific mechanisms. Results indicated that the target mechanism conditions evoked emotions largely as predicted by a multimechanism framework and that mostly similar effects occurred across the experiments that included different pieces of music. We conclude that a satisfactory account of musical emotions requires consideration of how musical features and responses are mediated by a range of underlying mechanisms. PMID- 26442338 TI - Emotion in Painting and Art Installations. AB - Paintings are static 2-dimensional images with limited narrative means. On the basis of a critical analysis of the relevant laboratory scaling studies, museum studies, and neuroaesthetic work, the article reaches a negative conclusion about most paintings' ability to engage sufficiently with general viewers' associative memory systems, so as to lead to identification and empathy, and induce fundamental psychobiological emotions. In contrast, designers of art installations can draw on subtle combinations of several classes of stimulus properties with psychological significance subsumable under the classical concept of the sublime (physical grandeur, rarity, an association with beauty and with biologically significant outcomes), so that some installations may induce the peak aesthetic emotional response, aesthetic awe--as defined in Aesthetic Trinity Theory (Konecni, 2005, 2011), along with the states of being moved and physiological thrills. The approach also involves an analytical skepticism about emotivism, defined as a culturological proclivity for unnecessary insertion of emotion into accounts of mental life and behavior, especially in the arts. Implications for the role of emotion theory in empirical aesthetics are examined. PMID- 26442339 TI - The Automatic Activation of Emotion and Emotion-Laden Words: Evidence from a Masked and Unmasked Priming Paradigm. AB - A primed lexical decision task (LDT) was used to determine whether emotion (e.g., love, fear) and emotion-laden (e.g., puppy, hospital) word processing differs, both explicitly and implicitly. Previous experiments have investigated how emotion word processing differs from both abstract and concrete word processing (Altarriba & Bauer, 2004; Altarriba, Bauer, & Benvenuto, 1999). To assess for differences between emotion and emotion-laden word processing, 2 experiments were conducted, the first assessing explicit processing (using an unmasked LDT) and the second assessing automatic processing (using a masked LDT). The prediction that semantic priming would differ between emotion word pairs and emotion-laden word pairs was confirmed in both experiments, with shorter response times for emotion targets and greater priming effects for emotion word pairs than for emotion-laden word pairs. The role of valence is discussed, emphasizing the ways valence affects the speed with which these words are accessed and processed. PMID- 26442340 TI - Interference Resolution in Emotional Working Memory as a Function of Alexithymia. AB - Although alexithymia is recognized as a set of traitlike deficits in emotion processing, research suggests there are concomitant cognitive issues as well, including what appears to be an unusual pattern of enhanced working memory (WM) despite broader executive dysfunction. It is unknown whether this enhancement includes the executive elements of WM and whether executive control of WM in alexithymia differs for emotional and neutral stimuli. This study examined how alexithymia moderates patterns of interference resolution in WM with valenced and nonvalenced stimuli. Participants (N = 93) completed the Toronto Alexithymia Scale and a recency probes WM task containing positive, negative, and neutral stimuli, with some trials containing proactive interference from previous trials. The reaction time difference between interference and noninterference trials indexed degree of interference resolution. Toronto Alexithymia Scale score moderated a within-subject effect such that, when valenced probes were used, there was less proactive interference in the positive relative to negative valence condition; this valence-based interference discrepancy was significant for a subset of highly alexithymic participants. Alexithymia did not moderate proactive interference to negative or neutral stimuli or accuracy of responses. These results suggest that, although alexithymia does not influence executive control in WM for nonemotional items, alexithymic people demonstrate an idiosyncratic response to positive stimuli that might indicate blunted reactivity. PMID- 26442341 TI - Reducing Misanthropic Memory Through Self-Awareness: Reducing Bias. AB - Two experiments investigated the influence of self-awareness on misanthropic recall. Misanthropic recall is the tendency to recall more negative behaviors dispositionally attributed and positive behaviors situationally attributed than negative behaviors situationally attributed and positive behaviors dispositionally attributed. It was hypothesized that when one is self-aware, more systematic information processing would occur, thereby reducing misanthropic memory and influencing attitudinal judgments. The first experiment used a mirror and the second experiment used a live video to induce self-awareness. Participants were asked to form an impression of a group. The results of both experiments replicated the previously found pattern of misanthropic memory for non-self-aware participants (Ybarra & Stephan, 1996), and revealed less misanthropic recall bias in self-aware participants. PMID- 26442342 TI - Callosal Sensitivity to Short-Range Stimulus Orientation and Long-Range Stimulus Context Orientation: Tachistoscopic Evidence. AB - To study local-global relationships in interhemispheric interactions, tachistoscopically presented pairs of lines (1.15 degrees) were compared for their relative orientation by 48 neurotypical adults. Orientations of line stimuli (local aspect of the task) were vertical, horizontal, forward slash or backslash, as were those of the interstimulus axes. The latter created a global context that could influence line discrimination. Stimulus pairs were presented within a field (not requiring callosal participation for line orientation comparison) or one on each side of the visual field meridian (requiring callosal participation). The primary purpose of the design was to determine whether local or global violations of stimulus "homotopy" across the meridian would impose costs of interhemispheric integration. The rationale for this expectation is that the fiber projection of the corpus callosum is highly symmetric across the midsagittal plane (i.e., homotopic). The expected "callosal homotopy" effect was significantly upheld as a whole but broke down or became extravagant in certain specific conditions, with specific costs of interhemispheric integration varying from null to a highly significant 20-ms as a function of interactions of interstimulus and stimulus orientations. The corpus callosum seems to be particularly sensitive to local stimulus orientation in interaction with long range stimulus context orientation. PMID- 26442343 TI - Towards a Mechanistic Understanding of the Effects of Body Posture on Facial Emotion Categorization. AB - This study investigated the causes of the face-body congruence effect (FBCE), which refers to the advantage in performance when participants are asked to categorize emotional faces compounded with emotional matching body postures (congruent) compared with incongruent face-body compound stimuli (body postures mismatching the facial emotions). Experiment 1 showed that manipulations aiming to alter holistic processing significantly reduced the FBCE. In particular, the disruption of holistic processing affected significantly the performance for congruent composites. However, no effect was obtained on the incongruent stimuli. In Experiment 2, the inversion manipulation showed a clear disadvantage for incongruent stimuli brought by the disruption of the single feature orientation information. Thus, we found confirmation of the different processing involved in perceiving congruent and incongruent stimuli. Finally, Experiment 3 confirmed that we are able to reduce entirely the FBCE when the orientation of the units (the face and the body) constituting the incongruent composites is matched. PMID- 26442344 TI - Cognitive Processing of Scrambled Faces: Effects of Instructions and Task. AB - The present study tests Rakover and Cahlon's (2013) face-checking model, which grades 7 regular and scrambled faces on a scale of similarity to an upright regular face, by predicting the results of 2 experiments in upright and inverted orientations: Experiment 1, which uses the interest choice task (to choose from a pair of faces the one most interesting), and Experiment 2, which uses the old/new recognition task. The main results of these 2 experiments show that in comparison to Rakover and Cahlon's (2013) findings, the face-checking model preserves its ability to predict satisfactorily the order of the 7 faces in the 2 experiments especially in the upright orientation; however, the model's success in making accurate point predictions is reduced significantly in both the upright and the inverted orientations. PMID- 26442345 TI - The Evolution of The American Journal of Psychology 1, 1887-1903: A Network Investigation. AB - The American Journal of Psychology (AJP) was the first academic journal in the United States dedicated to the "new" scientific form of the discipline. But where did the journal's founding owner/editor, G. Stanley Hall, find the "psychologists" he needed to fill the pages of such a venture 1887, when he was still virtually the only professor of psychology in the country? To investigate this question we used the substantive vocabularies of every full article published in AJP's first 14 volumes to generate networks of verbally similar articles. These networks reveal the variety of research communities that Hall drew on to launch and support the journal. Three separate networks, corresponding to 3 successive time blocks, show how Hall's constellation of participating research communities changed over AJP's first 17 years. Many of these communities started with rather nebulous boundaries but soon began to differentiate into groups of more distinct specialties. Some topics declined over time, but new ones regularly appeared to replace them. We sketch a quasievolutionary model to describe the intellectual ecology of AJP's early years. PMID- 26442346 TI - It's about the journey. PMID- 26442347 TI - Guitar man. PMID- 26442349 TI - Nontraditional path. PMID- 26442348 TI - Clinical hiatus, then what? PMID- 26442350 TI - New designation, new opportunity. PMID- 26442351 TI - TURNING POINTS. PMID- 26442352 TI - WITH A LITTLE HELP. Why all the studying matters. PMID- 26442353 TI - CLINICAL NOTE: MS. S, 25F. Questioning those giving career advice. PMID- 26442354 TI - Rose. When things don't go as planned. PMID- 26442355 TI - CLEARING THE AIR. Looking back on a public health battle. PMID- 26442356 TI - The A, B, C, Ds of Opioid Prescribing for People Living with Cancer. AB - This articles reviews guidelines for safe and effective opioid prescribing by primary care physicians for people living with cancer-related pain. It also offers tips for community clinicians on initiating, titrating and managing opioids for pain management. PMID- 26442357 TI - Recent Outbreaks of Meningococcal Disease among Men Who Have Sex with Men. AB - Meningococcal disease outbreaks recently have occurred in several U.S. cities among men who are HIV-infected and who have had sex with other men. This article describes the first similar case of meningococcal meningitis serogroup C in Minnesota, which was confirmed this summer. It also offers vaccination guidance for physicians who care for patients who may be at high risk for the disease. PMID- 26442359 TI - SERIOUS GAMES FOR HEALTH: AN INTRODUCTION TO THE SYMPOSIUM. PMID- 26442358 TI - Think Globally, Act Locally: Diagnosis and Management of Latent Tuberculosis in Minnesota's Foreign-Born Population. AB - Although the overall incidence and prevalence of tuberculosis (TB) is relatively low in the United States, the disease remains a significant problem among certain populations. Refugees and immigrants migrating from endemic countries are especially at risk for TB, and in Minnesota the majority of cases are found in this population. Given that the vast majority of these cases are caused by reactivated latent infection rather than primary infection, the key to disease control and prevention is the successful diagnosis and management of latent TB in immigrants and refugees from endemic areas. This article details the appropriate approach to screening, diagnosis and management of latent TB in the hope that all physicians are better equipped to aid our state's foreign-born population and improve public health. PMID- 26442360 TI - CREATING A SERIOUS GAME FOR HEALTH. AB - The prevalence of chronic illnesses continues to increase as does the cost of such care. Teaching self-management skills is more effective than solely providing information and teaching technical skills at improving health outcomes. Serious games for health provide an opportunity to support learning and health related behavior change using messages and experiences in an engaging and entertaining format. We developed eSMART-HD with the intention of improving interactions between patients with chronic disorders and their health care providers. This paper describes the factors that we considered when creating eSMART-HD, a serious game for health. PMID- 26442361 TI - WAIT, WON'T! WANT: BARRIERS TO HEALTH CARE AS PERCEIVED BY MEDICALLY AND SOCIALLY DISENFRANCHISED COMMUNITIES. AB - OBJECTIVES: We explored barriers to healthcare as perceived by members of medically and socially disenfranchised communities. METHODS: We conducted focus groups with 28 women and 32 men from Northeast Ohio who identified themselves as African-American, Hispanic/Latino, lesbian/gay/bisexual/transgendered, and/or Russian immigrant. RESULTS: Participants described their experiences of waiting, things they won't tolerate, when they won't participate, and what they want from providers. They described behaviors, actions and relationship characteristics that they want from their providers and characteristics that they prefer in health systems. CONCLUSIONS: The themes of Wait, Won't, and Want have healthcare practice and policy implications. Patient-provider interactions are known to be significant determinants of healthcare outcomes and these exploratory findings suggest that they might also affect patient self-management strategies. Future efforts should focus on developing and testing patient-centered strategies that address the themes identified to increase engagement to increase self-management of health. PMID- 26442362 TI - BE HEARD: HEALTHCARE PERSPECTIVES FROM MEDICALLY AND SOCIALLY DISENFRANCHISED COMMUNITIES. PMID- 26442363 TI - ENHANCING COMMUNICATION BETWEEN PATIENTS AND HEALTHCARE PROVIDERS: SBAR3. PMID- 26442364 TI - IMPACT OF A SERIOUS GAME FOR HEALTH ON CHRONIC DISEASE SELF-MANAGEMENT: PRELIMINARY EFFICACY AMONG COMMUNITY DWELLING ADULTS WITH HYPERTENSION. AB - Most Americans will acquire a chronic disease during their lifetime. One of the most prevalent chronic diseases that affect Americans is hypertension (HTN). Despite the known comorbidities and increased mortality rate associated with uncontrolled HTN, most community dwelling adults with HTN do not have sufficient blood pressure control Therefore, the aim of this article is to report the preliminary efficacy of a serious game for health to enhance blood pressure control among community dwelling adults with HTN. A nonprobability sample of 116 community dwelling adults with HTN participated in this nonblinded, randomized controlled trial. Participants were randomly assigned to: (1) an intervention arm that consisted of four exposures to a serious game for health known as eSMART-HD; or (2) an attentional control arm that compromised of four exposures to screen based HTN education. The primary outcome measure for this trial was blood pressure reduction over a four month observational period. In this study, baseline characteristics and blood pressure measurements were similar between participants in each study arm. There was no significant between-group difference in blood pressure reduction over time. However, there were significant within group reductions in systolic and diastolic blood pressures across time among favoring participants exposed to eSMART-HD. This study establishes the preliminary efficacy of eSMART-HD that can be easily administered to community dwelling adults and facilitate clinically significant reductions in systolic and diastolic blood pressures. Future studies should assess the influential components of this promising serious game for health (eSMART-HD) combined with medication management in larger and more diverse samples of community dwelling adults with HTN. PMID- 26442365 TI - EMPOWERING PATIENTS TO BECOME BETTER PARTNERS. PMID- 26442366 TI - [Relation between Injury Time and the Expression of COX6C mRNA in Skeletal Muscle of Rats after Contusion]. AB - OBJECTIVE: To investigate the relation between injury time and the expression of cytochrome c oxidase subunit VIc (COX6C) mRNA in skeletal muscle of rat after contusion. METHODS: A total of fifty-four SD rats were divided into the control group and the contusion groups (0.5, 1, 6, 12, 18, 24, 30, and 36 h after contusion), randomly. The contusion model was established by free fall drop of gravity hammer. At corresponding time point after contusion, the regular histology was examined and expression level of COX6C mRNA was tested by real-time PCR after extraction of total RNA from the tissues. RESULTS: The main pathological features of 6 h after injury included edema and hemorrhage in myocytes with no inflammatory cells found. After 6 hours, the findings included myocyte degeneration and necrosis, inflammatory cells infiltration, and fibrous connective tissue proliferation in the contused zone. The expression level of COX6C mRNA was higher than that of the control group within 6 h after contusion. The expression level was lower than that of the control group from 6-36 h after contusion. CONCLUSION: The level of COX6C mRNA expresses in a regular way after contusion. It may be useful for estimating wound age in combination with the results of pathological features. PMID- 26442367 TI - [Changes of Serum IgE and Tryptase in Anaphylactic Shock Rats]. AB - OJECTIVE: To explore the changes of serum IgE and tryptase caused by anaphylactic shock rats and discuss the relation to PMI and preservative environment of corpse and specimen. METHODS: Rats were used for establishing anaphylactic shock models and randomly divided into room temperature group, refrigeration group, frozen group, manual hemolysis group, specimen preservation group. And the control group was also established. The blood samples were collected after rats were sacrificed. The degree of hemolysis was graded according to the color of the upper layer of the serum. The mass concentration of IgE and tryptase in each group was detected by ELISA. RESULTS: The levels of serum IgE and tryptase in anaphylactic shock dead rats were higher than that of the control group. Room temperature and frozen made obviously differences on the levels of serum IgE and tryptase with various PMI. The levels of serum IgE and tryptase in refrigeration group showed relatively stable. The levels of serum tryptase and IgE were elevated with differently increasing hemolysis. The levels of serum IgE and tryptase showed no obvious changes during the specimen kept under different temperature conditions for 25 days. CONCLUSION: Serum IgE and tryptase obviously increased in anaphylactic shock rats. However, the levels were influenced by PMI and environmental temperature, especially under the conditions of room temperature and frozen. PMID- 26442368 TI - [Effect of Heroin on DLG4 Expression in Hippocampus, Amygdala and Frontal Cortex of Rats]. AB - OBJECTIVE: To observe the expression of discs large homolog 4 (DLG4) protein in hippocampus, amygdala and frontal cortex of rats and evaluate postsynaptic density in heroin dependence. METHODS: The rat heroin dependent model was established by increasing intraperitoneal injection of heroin. DLG4 proteins in hippocampus, amygdala and frontal cortex of heroin dependent 9, 18, 36 days rats were detected with immunohistochemical staining and compared with that in the control group. RESULTS: DLG4 proteins in hippocampus, amygdala and frontal cortex were gradually reduced with extension of heroin dependent time. CONCLUSION: Heroin dependence can affect postsynaptic density of hippocampus, amygdala and frontal cortex. The changes become more apparent with extension of heroin dependence time. PMID- 26442369 TI - [Diagnostic Significance of BAT in Anaphylaxis to Non-ionic Contrast Media]. AB - OBJECTIVE: To investigate the diagnostic significance of basophil activation test (BAT) in anaphylaxis to non-ionic contrast media through testing the content of CD63, mast cell-carboxypeptidase A3 (MC-CPA3), and terminal complement complex SC5b-9 of the individuals by testing their levels in the normal immune group and the anaphylaxis groups to beta-lactam drugs and non -ionic contrast media. METHODS: The CD63 expression of basophilic granulocyte in blood was detected by flow cytometry. The levels of MC-CPA3 in blood serum and SC5b-9 in blood plasma were detected by ELISA. RESULTS: The CD63 expression of basophilic granulocyte in blood, the levels of MC-CPA3 and SC5b-9 of anaphylaxis to non-ionic contrast media and beta-lactam drugs were significantly higher than that in normal immune group (P < 0.05). CONCLUSION: There is activation of basophilic granulocytes, mast cells and complement system in anaphylaxis to non-ionic contrast media. BAT can be used to diagnose the anaphylaxis to non-ionic contrast media. PMID- 26442370 TI - [Postmortem MSCT Analysis and Identification of Fall from Height: One Case Report]. AB - OBJECTIVE: To explore the application value of postmortem multi-slice spiral computed tomography (MSCT) in cases of fall from height through observing and analyzing the injury features of the fall and reconstructing the process of the fall based on the the above procedure. METHODS: One real fatal case due to fall from height was fully examined using MSCT and three-dimensional reconstruction technique. Analyzing the manner and cause of death through combination of MSCT and systemic autopsy was also implemented. The differences between autopsy and MSCT in getting information of injuries were compared. RESULTS: Fractures involving multiple body regions and liver rupture were found through MSCT and three-dimensional reconstruction. The autopsy got the same results with imageological examination. The case of death was deduced to be fall leading to systemic polytrauma. CONCLUSION: Application of MSCT can be used as the complimentary for traditional autopsy in the analysis of injury manner of fall from height. PMID- 26442371 TI - [Relation between Body Height and Combined Length of Manubrium and Mesosternum of Sternum Measured by CT-VRT in Southwest Han Population]. AB - OBJECTIVE: To establish the linear regression equation between body height and combined length of manubrium and mesostenum of sternum measured by CT volume rendering technique (CT-VRT) in southwest Han population. METHODS: One hundred and sixty subjects, including 80 males and 80 females were selected from southwest Han population for routine CT-VRT (reconstruction thickness 1 mm) examination. The lengths of both manubrium and mesosternum were recorded, and the combined length of manubrium and mesosternum was equal to the algebraic sum of them. The sex-specific linear regression equations between the combined length of manubrium and mesosternum and the real body height of each subject were deduced. RESULTS: The sex-specific simple linear regression equations between the combined length of manubrium and mesostenum (x3) and body height (y) were established (male: y = 135.000+2.118 x3 and female: y = 120.790+2.808 x3). Both equations showed statistical significance (P < 0.05) with a 100% predictive accuracy. CONCLUSION: CT-VRT is an effective method for measurement of the index of sternum. The combined length of manubrium and mesosternum from CT-VRT can be used for body height estimation in southwest Han population. PMID- 26442372 TI - [Analysis of GHB and Its Precursors in Urine and Their Forensic Application]. AB - OBJECTIVE: To establish the method to analyze gamma-hydroxybutyric acid (GHB) and its precursors 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL) in urine through LC-MS/MS and provide evidence for related cases. METHODS: GHB-d6 and MOR d3 were used as the internal standard. The urine sample was separated by LC after protein precipitation with methanol. The electrospray ion source was for ionization. Each compound was detected through multiple-reaction monitoring (MRM) mode. RESULTS: The limits of detection of GHB and its precursors 1,4-BD and GBL were 0.1, 0.1 and 2 MUg/mL. The accuracy was 87.6%-98.1%. The intra-day and inter day precisions were less than 15% and matrix effects were higher than 80%. CONCLUSION: The method is high sensitive, simple, rapid, specific and with high reliability. This study has provided technical support and basic data for forensic cases involving GHB. PMID- 26442373 TI - [Forensic Analysis of Melamine-tainted Milk Powder Poisoning: Six Fatal Cases]. AB - OBJECTIVE: To analyze the medical records of poisoned children to provide references for the forensic identification of melamine-tainted milk powder poisoning. METHODS: Medical records of six fatal cases of consuming some brand melamine-tainted milk powder were studied, specifically the poisoning symptoms, medical imaging, blood biochemical tests, treatment and prognosis. RESULTS: The major medical problems of these eight-month sick infants were urinary tract obstruction caused by urinary tract calculi. The poisoned infants developed oliguria, anuria and other symptoms, eventually, acute renal failure or other complications leaded to death. The serum BUN and Cr abnormally increased. CONCLUSION: By considering the toxicological effects of melamine, it was concluded that the deaths of these sick infants were related to the melamine poisoning. PMID- 26442374 TI - [Analysis of 59 Anaphylactic Death Cases]. AB - OBJECTIVE: To analyze the cases of anaphylactic death cases and explore the standards of judicial expertise of anaphylactic death for providing evidence for judicial expertise. METHODS: Fifty-nine cases death due to allergic reaction in Shanghai were collected. And details of medical history, clinical manifestation of anaphylactic reaction and postmortem examination findings were reviewed for all cases. RESULTS: In the 59 cases, there were 58 cases died from drug allergy, including 77.6% of them were antibiotics. The rates of treating in standard hospital and illegal clinic were 37.3% and 61.0%, respectively. The allergic symptoms were dyspnea and facial cyanosis. The time from contacting allergens to death ranged from 1 min to 3 d. The concentration of total serum IgE ranged from 50 to 576.92 IU/mL. The results of clinical manifestation and pathological anatomy had obviously changes. CONCLUSION: Based on the exclusion of all other cause of death and synthetically analysis of details of cases, medical history, clinical manifestation and anatomy, the conclusion of anaphylactic death can reached. The details of cases including clinical history, exposure to allergens, and clinical manifestation play an important role in diagnosis of anaphylactic death. PMID- 26442375 TI - [Genetic Polymorphisms of 21 Autosomal STR Loci of Fujian Han Population]. AB - OBJECTIVE: To investigate the genetic polymorphisms of 21 autosomal STR loci of Fujian Han population and evaluate the forensic application value of GlobalFiler Express kit. METHODS: Amplified with GlobalFiler Express kit, DNA samples were obtained from 741 unrelated individuals of Fujian Han population. The population genetics parameters of 21 autosomal STR loci were calculated. RESULTS: The 21 autosomal STR loci were found to be no deviation from Hardy-Weinberg equilibration (P > 0.05) and relatively abundant in high polymorphism. Heterozygosity ranged from 0.589 to 0.914, power of discrimination ranged from 0.754 to 0.992, polymorphic information content ranged from 0.520 to 0.940, and power of exclusion ranged from 0.278 to 0.825. The SE33 locus was the highest degree in polymorphism. CONCLUSION: The 21 STR loci of GlobalFiler Express kit have high value in discrimination power and can be useful in personal identification and paternity test in Fujian Han population. PMID- 26442376 TI - [Research Progress of Event-related Potential in Mild Cognitive Impairment]. AB - Mild cognitive impairment caused by craniocerebral trauma is the key points and difficulties in judicial authentication. This article has comparative analysis of each mode of event-related potential (classical Oddball, Eriksen flanker task and so on), which can provide a more objective method for such craniocerebral trauma cases in clinical forensic judicial authentication. PMID- 26442377 TI - [Development and Application of Metabonomics in Forensic Toxicology]. AB - Metabonomics is an important branch of system biology following the development of genomics, transcriptomics and proteomics. It can perform high-throughput detection and data processing with multiple parameters, potentially enabling the identification and quantification of all small metabolites in a biological system. It can be used to provide comprehensive information on the toxicity effects, toxicological mechanisms and biomarkers, sensitively finding the unusual metabolic changes caused by poison. This article mainly reviews application of metabonomics in toxicological studies of abused drugs, pesticides, poisonous plants and poisonous animals, and also illustrates the new direction of forensic toxicology research. PMID- 26442379 TI - How to Respond to "Inappropriate Invitations". PMID- 26442378 TI - [Research Progress on Forensic Entomotoxicology]. AB - Forensic entomotoxicology is a branch of forensic medicine, which applies entomology, toxicology and other related studies to solve the poisoning cases. It has an obvious advantage in the investigation on poisoning death. Based on the expounding definition and research of entomotoxicology, this paper reviews research progress and application value in some aspects of forensic medicine, such as the effects of drugs/toxins on the growth and development of sarcosaphagous insects and the qualitative and quantitative analysis of the drugs/toxins in the poisoned body tissue. PMID- 26442380 TI - What's Past is Prologue. PMID- 26442381 TI - Dinner with a Nobel Laureate. PMID- 26442382 TI - Fellows of the American Physiological Society Inaugural Class. PMID- 26442383 TI - S&R Foundation 15th Anniversary. PMID- 26442384 TI - Meeting of the Minds: Send Your Stories. PMID- 26442385 TI - Letter to Hiroko Nishimura. PMID- 26442387 TI - COMPLICATIONS FOLLOWING DIFFERENT TECHNIQUES OF ONE-LUNG VENTILATION. PMID- 26442386 TI - Letter to Hiroko Nishimura. PMID- 26442388 TI - ANESTHETIC MANAGEMENT FOR DRUG INDUCED SLEEP ENDOSCOPY. PMID- 26442389 TI - PERIOPERATIVE PAIN CONTROL IN GASTROINTESTINAL SURGERY. AB - Perioperative pain control in the setting of gastrointestinal surgery presents unique challenges for the clinician, including the incidence of ileus and its potential exacerbation by analgesics, large incisions, patient characteristics and a wide variety of other factors. At the same time, optimizing postoperative pain control is of key significance in this patient population and has implications for both medical and surgical outcomes, length of hospital stay and associated costs and risks of developing chronic postsurgical pain. Data from recent clinical trials and other studies have highlighted the impact of specific surgical and anesthetic techniques on post-operative pain for several types of abdominal surgeries, including pancreatoduodenectomy, hepatectomy, gastric bypass, cholecystectomy, colectomy, and appendectomy. The management of pain may be optimized through the multidisciplinary and concerted efforts between clinicians involved in the perioperative care of patients undergoing gastrointestinal surgery. PMID- 26442390 TI - RESIDENT IMPLEMENTATION OF THE 2007 ACC/AHA GUIDELINES ON PREOPERATIVE CARDIAC EVALUATION IN NON-CARDIAC SURGERY PATIENTS: IS CLINICAL EXPERIENCE ENOUGH? AB - BACKGROUND: Preoperative evaluation of surgical patients is important, as perioperative complications are associated with increased mortality. Specialties including anesthesiology, internal medicine, cardiology, and surgery are involved in the evaluation and management of these patients. This institutional study investigated the residents' knowledge of the 2007 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on perioperative evaluation of patients undergoing non-cardiac surgery. METHODS: This pilot study used a web-based survey questionnaire to assess resident's knowledge of the 2007 ACC/AHA guidelines through individual steps and corresponding branch point(s) in twelve clinical scenarios. Additionally, residents were asked if they were aware of, or if they had received lectures on ACC/AHA guidelines. Staff anesthesiologists with training in cardiac and intensive care medicine validated the scenarios. RESULTS: A total of 104 resident participants were surveyed including 35 anesthesiology residents, 41 internal medicine residents, 20 surgery residents, and 8 cardiology fellows. Awareness of the 2007 ACC/AHA guidelines by specialty was: anesthesiology (85%), internal medicine (97.6%), cardiology (100%), and surgery (70%). Only 54.3% of anesthesiology, 31.7% of internal medicine, 100% of cardiology, and 10% of surgery residents stated they received lectures. The overall mean score achieved on the eleven scenarios was 50.4% for anesthesiology, 47.0% for internal medicine, 55.7% for cardiology, and 42.3% for surgery. CONCLUSIONS: Although the majority of residents were aware of the 2007 ACC/AHA guidelines, fewer received lectures and regardless of specialty, implementation of these guidelines was poor. There exists significant room for improvement in the understanding of preoperative assessment of non-cardiac surgery patients. PMID- 26442391 TI - PSEUDOCHOLINESTERASE DEFICIENCY IN A OCTOGENARIAN UNDERGOING TOTAL INTRAVENOUS ANESTHESIA; IMPLICATIONS FOR NEUROMONITORING. AB - Pseudocholinesterase deficiency manifests as prolonged motor blockade after the administration of succinylcholine. A previously unknown homozygous form of the disease, became apparent during a lumbar laminectomy seriously limiting the ability to monitor motor evoked potentials and perform electromyelography (EMG). Moreover, concerns were raised as to how the enzyme deficiency would affect the metabolism of remifentanil and other esters during a total intravenous anesthetic. We present the perioperative management of the patient and a literature review of the syndrome. The patient provided written permission for the authors to publish this report. At our institution, IRB review and approval is not required for a single case report. PMID- 26442392 TI - AN AUDIT OF THE CURRENT PRACTICES OF AIRWAY MANAGEMENT IN PATIENTS UNDERGOING SURGERY FOR ATLANTO-AXIAL DISLOCATION IN A SINGLE INSTITUTION. AB - BACKGROUND: Patients with atlanto axial dislocation (AAD) undergo stabilisation procedures under general anesthesia. Airway management in these patients is difficult as cervical spine movements during laryngoscopy can worsen spinal cord damage. Though multiple airway devices are used to intubate the trachea of these patients, there is no evidence of superiority of one technique over another. This retrospective study was designed to audit the practice of airway management during surgery for AAD over a 5 year period, starting from 2006 till 2011. METHODS: Patients' demographics, airway intervention techniques, types of surgical procedures, postoperative neurological and respiratory deterioration were recorded from the case files. Association between the types of airway interventions and the postoperative neurological and respiratory deterioration were analysed. RESULTS: One hundred and six patients underwent surgery for AAD during the study period. Sixty one percent of the patients were intubated with the help of a fiberoptic bronchoscope (FOB) and among them 15% received general anesthesia to facilitate FOB. Eighteen patients developed neurological deterioration and 15 patients developed respiratory weakness requiring ventilation postoperatively. Congenital AAD patients had higher chances for extubation at the end of surgery when intubated using FOB (p = 0.007). Among the AAD patients, female gender had significantly higher incidence of neurological deterioration compared to males. CONCLUSION: In the current audit, there was no correlation between the perioperative variables and postoperative respiratory and neurological deterioration. Most of the respiratory problems occurred between 2-5 postoperative days stressing the need for extended intensive postoperative monitoring of these patients. PMID- 26442393 TI - ULTRASOUND-GUIDED SCIATIC POLITEAL NERVE BLOCK: A COMPARISON OF SEPARATE TIBIAL AND COMMON PERONEAL NERVE INJECTIONS VERSUS INJECTING PROXIMAL TO THE BIFURCATION. AB - OBJECTIVE: Block of the sciatic nerve at the popliteal fossa can be performed using the ultrasound machine; it may be proximally or distally to the bifurcation of the sciatic nerve using lateral, medial, or posterior approaches. It is frequently used for surgeries below the knee specially the foot and ankle operations. PURPOSE: This study compares one and two injections of the sciatic nerve in the popliteal fossa with ultrasound-guided block in foot or ankle surgeries. METHODS: Forty patients received ultrasound-guided sciatic nerve block with the nerve stimulator, using the posterior approach. The patients were enrolled into two groups (20 patients each), group 1: received one injection at 2 cm cephalad to the bifurcation of the sciatic nerve, and group 2: received two injections caudate to the sciatic bifurcation; one for tibial nerve and the other for common peroneal nerve. All patients received 20 ml of levobupivacaine 0.5%. The block performance time, block efficacy, success rate, complications and patient's satisfaction were evaluated. RESULTS: Block the tibial and common peroneal nerves separately (two injections) distal to the point of bifurcation of the sciatic nerve has a significantly (P < 0.05) faster time to complete sensory block of tibial and common peroneal nerves compared to a pre-bifurcation sciatic nerve block (one injection). The complete motor block, block time performance, success rate and patient's satisfaction were not significantly different between groups (P > 0.05). CONCLUSION: The block of tibial and common peroneal nerves separately distal to the sciatic nerve bifurcation is superior to single injection block of sciatic nerve above the bifurcation in the popliteal fossa as regard complete sensory block time. PMID- 26442394 TI - INTRAVENOUS DEXAMETHASONE IN COMBINATION WITH CAUDAL BLOCK PROLONGS POSTOPERATIVE ANALGESIA IN PEDIATRIC DAYCARE SURGERY. AB - BACKGROUND: This study was conducted to determine if intravenous dexamethasone combined with caudal block was able to prolong post-operative analgesia in pediatric daycare surgeries. METHODS: Sixty four ASA I or II children aged 3 to 10 year old scheduled for daycare open unilateral herniotomy received general anesthesia and caudal block using 0.25% levobupivacaine 0.75 mg.kg(-1) with suppository paracetamol 30 mg.kg(-1). After anesthesia induction, they were randomized to receive either intravenous dexamethasone 0.5 mg.kg(-1) (Group I) or same volume intravenous normal saline (Group II). Postoperatively, pain scores were assessed using Wong- Baker faces scale. At home, their parents assessed and recorded the pain scores, time to first oral paracetamol served and frequency of paracetamol given in two consecutive days post surgery. On the third postoperative day, these information were gathered from the parents via a phone call. RESULTS: There were statistically significant differences between Group I and Group II in the median time to first paracetamol (800 vs 520 min, p = 0.01), mean pain scores postoperative day 1 (1.9 +/- 2.0 vs 3.5 +/- 2.2, p = 0.05), mean pain score-postoperative day 2 (0.8 +/- 1.6 vs 2.3 +/- 2.0, p = 0.03) and mean frequencies of paracetamol given on postoperative day 2 (0.3 +/- 0.8 vs 1.1 +/- 1.0, p = 0.02). CONCLUSION: A single intravenous dexamethasone dose when combined with caudal block reduces postoperative pain, decreases paracetamol requirement and prolongs analgesic duration in children after open herniotomy. PMID- 26442395 TI - COMPARATIVE STUDY BETWEEN ULTRASOUND AND NERVE STIMULATOR GUIDED SCIATIC NERVE BLOCK THROUGH THE ANTERIOR APPROACH. AB - INTRODUCTION: The aim of the current study was to compare block of the sciatic nerve through the anterior approach by two methods, namely, the nerve-stimulator guided and ultrasound-guided, with or without nerve stimulation, with regard to the ease of performance, reliability and safety of this approach. PATIENTS AND METHODS: 36 adult patients were randomly allocated equally into one of 2 main groups: "Nerve Stimulator-Guided Group (NSG)" where the nerve was located by nerve stimulator only and "Ultrasound guided group (USG)" where the sciatic nerves were blocked by a stimulated needle under guidance of the ultrasound. Assessment of performing each technique, sensory and motor blockades, occurrence of acute systemic toxicity and haematoma formation were compared. RESULTS: Only one-third of the sciatic nerves could be visualized by US. This did not affect the block execution time but caused less number of needle passes in a statistically significant value. Sensory and motor block showed significant differences between the 2 groups. Criteria of acute systemic toxicity and occurrence of hematoma were not reported in both groups. CONCLUSION: Results of the current study showed that the addition of ultrasound to nerve stimulator in the anterior approach to the sciatic nerve block added only little to the ease of performance, reliability and safety. This was because only one-third of the nerves could be seen. More practice, better machines and new blocking techniques may be needed to overcome the problem of anisotropy of the nerve. PMID- 26442396 TI - WOUND INSTILLATION OF LOCAL ANESTHETIC BUPIVACAINE FOR POSTOPERATIVE ANALGESIA FOLLOWING LUMBAR LAMINECTOMY. AB - PURPOSE: Lumbar laminectomy is a commonly performed procedure in neurosurgical and orthopedic practice. Postoperative pain reliefhelps in early mobilization, initiation of physiotherapy, provides satisfaction to the patients and plays an important role in reducing the morbidity and mortality. This prospective study investigated the simple technique of instillation of wound with bupivacaine and leaving a contact time of 60 seconds on postoperative pain following lumbar laminectomy. METHODS: 32 ASA I and II patients scheduled for laminectomy were randomly allocated to receive either 20 ml of normal saline (group I) or 0.25% of bupivacaine (group II) into the wound after securing hemostasis. After a dwell time of 60sec the wound was closed in layers without mopping or suctioning. After extubation, the pain scores were evaluated by visual analog scale at every 4 hrs. for 24hrs and also the time for first demand of analgesia, number of analgesic demands and the total amount of analgesia consumed were noted by an independent observer.. RESULTS: The median duration of analgesia in group I was 8.8 [5-11] and in group II 13 [8.5-16] hrs. with a p = 0.04. The number of demands and the amount of analgesia consumed was also statistically significant. CONCLUSION: Wound instillation technique is simple, safe and effective in management of acute pain management after lumbar laminectomy and can be used as one among the multimodal armamentarium in pain management. PMID- 26442397 TI - THE EFFECTS OF INTRATHECAL NEOSTIGMINE ADDED TO BUPIVACAINE ON POSTOPERATIVE ANALGESIC REQUIREMENT IN PATIENTS UNDERGOING LOWER LIMB ORTHOPEDIC SURGERY. AB - BACKGROUND: Several additives have been suggested to enhance analgesic effect of local anesthetic agents to decrease the adverse effects of them and increase the degree of satisfaction. We designed this randomized double-blind controlled study to evaluate the analgesic efficacy of the neostigmine added to bupivacaine using spinal anesthesia in patients undergoing lower limb orthopedic surgery. METHODS: Sixty patients 18-80 yr old American Society of Anesthesiologists (ASA) physical status I or II, scheduled for femur surgery under spinal anesthesia, were recruited in a prospective, double-blinded, randomized way. The patients were randomly allocated to one of two groups of 30 each. The neostigmine group (group N) received bupivacaine 20 mg combined with 25 ug neostigmine, and the placebo group (group C) received bupivacaine 20 mg combined with 0.5ml distilled water (intrathecally) 5 minutes prior to surgery. The time to the first analgesic request, analgesic requirement in the first 12 hours after surgery, the duration of sensory and motor blockade, the incidence of adverse effects such as nausea,vomiting,hypotension, ephedrine requirements, bradycardia, and hypoxemia were recorded. RESULTS: Patients receiving neostigmine had a significantly prolonged duration of motor block (C95% CI 30.27 to 87.65; P < 0.001) and sensory block (C95% CI 101.04 to 224.64; P < 0.001) compared to the control group. The difference of the mean time to the first analgesic request was also significantly longer in neostigmine group (C95% CI 83.139 to 208.526; P < 0.001). The total analgesic consumption during the first 12 hours after surgery was devoid of any significant difference between groups N and C (p = 0.41).The two groups were not significantly different in terms of intraoperative and postoperative side effects. CONCLUSION: Intrathecal neostigmine 25 ug with bupivacaine caused a prolonged time to the first analgesic request and its use was not associated with any side effects. PMID- 26442398 TI - THE BENEFICIAL VALUES OF TRANSOESOPHAGEAL DOPPLER IN INTRAOPERATIVE FLUID GUIDANCE VERSUS STANDARD CLINICAL MONITORING PARAMETERS IN INFANTS UNDERGOING KASAI OPERATION. AB - BACKGROUND: Fluid overload in infants can result from inappropriate volume expansion (VE). The aim of this work was to evaluate the beneficial values of Transoesophageal Doppler TED in intraoperative fluid guidance versus standard clinical monitoring parameters in infants undergoing Kasai operation. METHODS: Forty infants scheduled for Kasai procedure were randomly allocated into two groups (Doppler and clinical group). In Doppler group decided to provide VE (10 30 m1/kg of Hydroxyethyl starches HES) when the index stroke volume decreased by >= 15% from the baseline value, in clinical group, hemodynamic variables triggering colloid administration mean arterial blood pressure (MAP) less than 20% below baseline or central venous pressure (CVP) < 5 cmH2O in both groups: Ringer's acetate was infused at constant rate (6 m 1/kg/h). Standard and TED derived data were recorded before and after VE. Follow up the postoperative outcome and hospital stay. RESULTS: There were significantly lower mean volume of HES (42.85 +/- 3.93 versus 84 +/- 14.29 ml) and percent of infants required it (30% versus 90%) associated with earlier tolerance to oral feeding (2 +/- 0.66 versus 3.4 +/- 0.51), shorter hospital stay (5.30 +/- 0.47 versus 6.7 +/- [symbols: see text] days) and lower rate of chest infection (15% versus 30%) in Doppler group than clinical group. There was no difference between the two studied groups regarding heart rate, MAP. CONCLUSIONS: TED guided intraoperative fluid intake in infants undergoing Kasai operation optimize fluid consumption and improve outcome associated with shorter hospital stay. PMID- 26442399 TI - DESFLURANE COMPARED TO SEVOFLURANE FOR CIRRHOTIC PATIENTS UNDERGOING MAJOR LIVER RESECTION. A RANDOMIZED CONTROL STUDY. AB - BACKGROUND: Major liver resection is associated with haemodynamic, hepatic and renal changes as a result of the procedure. AIM: To compare Desflurane (D) versus Sevoflurane (S) on hepatic, renal functions, haemodynamics and perioperative course for cirrhotic patients undergoing major liver resection. PATIENTS AND METHODS: A prospective randomized control study with 50 patients (Child A) (D, n = 25 and S, n = 25). End tidal D or S adjusted with Entropy (40-60). Haemodynamics monitored with invasive blood pressure and trans-oesophageal Doppler (TED). Liver and kidney function tests, blood Glutathione-S-transferase (GST), urinary microalbuminuria (Microalb) were assayed. Extubation time and anaesthetic consumption were recorded. RESULTS: Systemic vascular resistance (SVR) post-resection and stroke volume of D vs S were 835.04 +/- 12.02 vs 778.16 +/- 11.97 dyn.sec.cm(-5), P < 0.01, and 85.72 +/- 2.95 vs 76.16 +/- 6.52 ml, P < 0.01 respectively. Doppler corrected flow time (FTc) between groups were comparable (P > 0.05). No difference post-operatively regarding hepatic and renal functions, and urine Microalb (14.76 +/- 3.95 vs l4.24 +/- 8.65 ug/ml, P = 0.78), but a statistically difference was found with GST (0.046 +/- [symbols: see text], vs 0.043 +/- [symbols: see text] IU/ml, P < 0.01). Despite a higher D consumption (73 +/- 17 vs 64 +/- 22 ml, P = 0.102), cost in Egyptian pounds (LE) was lower with D (141.14 +/- 32.90 vs 320.60 +/- 114.01, LE, P < 0.01). Extubation time and ICU stay with D vS (4.52 +/- 2 vs 7.72 +/- 2 min, P < 0.01) and (1.40 0.50 vs 1.64 +/- 0.48, days P = 0.09) respectively. CONCLUSION: Neither D nor S were clinically superior to the other with respect to liver and kidneys functions, but D was found to preserve better the haemodynamic parameters and enhance recovery at a lower cost. PMID- 26442400 TI - MYOCARDIAL OXYGENATION DURING ACUTE NORMOVOLEMIC HEMODILUTION: IMPACT OF HYPOCAPNIC ALKALOSIS. AB - BACKGROUND: Increases in myocardial blood flow preserve myocardial oxygenation during moderate acute normovolemic hemodilution. Hypocapnic alkalosis (HA) is known to cause coronary vasoconstriction and increase hemoglobin-oxygen affinity. We evaluated whether these effects would compromise myocardial oxygenation during hemodilution. METHODS: Eighteen anesthetized dogs were studied. Myocardial blood flow (MBF) was measured with radioactive microspheres. Arterial and coronary sinus samples were analyzed for oxygen content and plasma lactate. Myocardial oxygen supply, oxygen uptake, and lactate uptake were calculated. HA (PaCO2, 23 +/- 2 (SD); pHa, 7.56 +/- 0.03) was induced by removal of dead space tubing at baseline (n = 8) and during hemodilution (n = 10), with hematocrit at 43 +/- 4% and 19 +/- 2%, respectively. RESULTS: Hemodilution during normocapnia caused decreases in arterial oxygen content (19.9 +/- 2.4 to 9.3 +/- 1.2 ml/100; P < 0.05) and the coronary arteriovenous 02 difference (13.0 +/- 3.0 to 6.4 +/- 0.9 ml/100ml; P < 0.05). MBF increased (52 +/- 12 to 111 +/- 36 ml/min/100g; P < 0.05) to maintain myocardial oxygen supply and oxygen uptake. Myocardial lactate uptake increased (31 +/- 19 to 68 +/- 35 ueq/min/100g; P < 0.05). At normal hematocrit, HA decreased MBF (57 +/- 18 to 45 +/- 10 ml/min/100; P < 0.05), implying vasoconstriction, accompanied by decreased myocardial oxygen supply. These myocardial effects of HA were not apparent during hemodilution. HA did not alter myocardial lactate uptake during hemodilution. CONCLUSION: When HA was induced during hemodilution, its ability to cause coronary vasoconstriction was lost, and myocardial oxygenation remained well preserved. PMID- 26442401 TI - ASSESSMENT OF PREOPERATIVE AND POSTOPERATIVE ANXIETY AMONG ELECTIVE MAJOR SURGERY PATIENTS IN A TERTIARY HOSPITAL IN NIGERIA. AB - BACKGROUND: Anxiety is an unpleasant emotional experience that involves feelings of tension, apprehension, nervousness and high autonomic activity. Few studies have been conducted in Nigeria on anxiety levels among patient undergoing surgical operation. The aim of this study is to assess preoperative and postoperative anxiety level of patients and identify factors that may influence patient's preoperative anxiety level. METHODS: Fifty one adult patients scheduled for elective surgery in a tertiary public hospital in Nigeria were assessed a day before and after their surgery using a questionnaire with socio-demographic and clinical details. Anxiety was assessed with the state portion of the State-Trait Anxiety Inventory (STAI) and different factors responsible for their anxiety were selected from a list. Statistical analysis was done using SPSS version 17. RESULT: Twenty-six patients (51.0%) had significant preoperative anxiety while 8 (15.7%) had significant postoperative anxiety. The patients preoperative mean anxiety score of STAI (42.72 +/- 9.84) was statistically significantly higher than their postoperative mean anxiety score (37.73 +/- 8.44; p = .001). In 10 items of STAI, there were significant differences between the preoperative and postoperative mean STAI scores. Fear of complications and result of operation were the most common factors responsible for preoperative anxiety while few patients were anxious about nil per mouth, getting stuck with needle and harm from doctor/nurse mistake. CONCLUSION: The prevalence of preoperative anxiety is high in Nigerian surgical patients. Psychological preparation and provision of correct information that addresses identified factors may help in reducing preoperative anxiety. PMID- 26442402 TI - THE EFFECTS OF LISTENING TO THE MOTHER'S HEARTBEAT ON THE DEPTH OF ANAESTHESIA IN CHILDREN. AB - BACKGROUND: The present study aimed to evaluate the effects of listening to the mother's heartbeat and womb sounds on the depth of anaesthesia in children. METHODS: The present study included 40 children scheduled for minor surgery under general anaesthesia, with an American Society of Anaesthesiologists (ASA) status of 1 to 2. Anaesthesia was induced with sevoflurane, and maintained with sevoflurane and oxygen in nitrous oxide. Patients were randomly divided into two groups. The children in Group I were made to listen to recordings of their mothers' heartbeat and womb sounds via earphones during anaesthesia induction, while those in Group II were made to listen to ambient noise via earphones. The music was turned off when the inhalational anaesthetics were discontinued. Intraoperative monitoring included electrocardiogram (ECG) recordings, heart rate (HR), oxygen saturation, non-invasive systolic blood pressure (SBP) and diastolic blood pressure (DBP), bispectral index system (BIS), end-tidal (ET) sevoflurane, ET N2O, ET CO2, and SaO2. RESULTS: In Group I, there was a significant decrease in bispectral index (BIS) values over time (p < 0.05). Although blood pressure and heart rate were lower in Group I, no significant differences between the groups were detected. While the duration of extubation was shorter in Group I, overall, there was no significant difference between the groups. CONCLUSION: We found that children exposed to recordings of their mothers' heartbeat and womb sounds in addition to music had lower BIS values under anaesthesia, which indicates deeper anaesthesia levels. PMID- 26442403 TI - LEARNING BY SIMULATION. AB - The future appears bright for the use of simulation in medical education. Medical, nursing, and allied healthcare students trained through simulation have opportunities to practice hands on techniques, teamwork, and communication through trial and error in a safe environment before working with live patients. The cost of high-fidelity simulation will continue to make its use prohibitive and challenging for some programs though the use of low-fidelity simulation, standardized patients, and role-playing continues to have measureable qualitative value. Cost center sharing is one way for programs on a tight budget who desire high-fidelity simulation to access this valuable skills-building, outcome improving medical education adjunct tool. PMID- 26442404 TI - ULTRASOUND GUIDED DORSAL RAMUS NERVE BLOCK FOR REDUCTION OF POSTOPERATIVE PAIN IN PATIENTS UNDERGOING LUMBAR SPINE SURGERY: A CASE SERIES IMAGING STUDY. AB - In patients undergoing spine surgery postoperative pain management can often be complicated with side effects associated with high dose narcotic such as respiratory depression and those associated with non-steroidal anti-inflammatory drugs such as interference with bone healing process. Local anesthetics can help in both decreasing postoperative pain and minimizing side effects associated with systematically administered analgesics. This report describes the use of preoperative ultrasound guided dorsal ramus nerve block to reduce postoperative pain in six patients undergoing lumbar spine surgery under general anesthesia. PMID- 26442405 TI - A SHARED OPERATIVE FIELD AND THE DISPUTE--IS THERE A WAY OUT? AB - Submental intubation is an alternative to tracheostomy in patients requiring surgical access to both oral and nasal cavities. It is relatively safe, simple, and low morbidity procedure and requires only basic surgical equipment to perform. We successfully performed a submental intubation in a young patient with maxillofacial hypoplasia undergoing Le Fort I maxillary advancement without any intra- and post-operative complications. PMID- 26442406 TI - RESIDUAL NEUROMUSCULAR BLOCKADE (RNMB): ROCURONIUM'S DEFASCICULATING DOSE, NEOSTIGMINE- INDUCED WEAKNESS, AND AWARENESS DURING RECOVERY. PMID- 26442407 TI - [Can We Avoid the War?]. PMID- 26442408 TI - [Measurement of the Minimum Pressure in the Bronchial Cuff during One-lung Ventilation Using a Capnometer]. AB - BACKGROUND: It is recommended to avoid overinflation of the bronchial cuff, leading to ischemic pressure damages to the respiratory mucosa and bronchial rupture. We investigated the minimum bronchial cuff pressure of 35 Fr double lumen tubes (DLTs) during one lung ventilation using a capnometer. METHODS: We studied 50 patients who were scheduled to undergo thoracic surgery. General anesthesia was induced and the patients were intubated with 35 Fr left DLT. With a fiberoptic bronchoscope, the DLT was positioned appropriately. The bronchial cuff was inflated first with air 3-3.5 ml. Lung isolation was confirmed by auscultation. Measurements were performed with the patient in the lateral position. Ventilating one lung isolatedly for 5 minutes, we confirmed non ventilated condition with a capnometer displaying flat line. The bronchial cuff was deflated 0.5-ml steps just before displaying the respiratory pattern by the capnogram. The bronchial cuff pressure and volume were recorded at this point RESULTS: The minimum pressures of bronchial cuff (volume) for one lung ventilation are for male 5.46 +/- 0.6 cmH2O (2.33?0.1 ml) and for female 1.5?0.5 cmH20 (1.09 +/- 0.3 ml). These values are smaller than the recommended value (< 25 cmH2O). There was no case in which the collapse of the operated lung was insufficient. CONCLUSIONS: In this study, the bronchial pressure higher than 12 cmH2O was not necessary for one lung ventilation. If high intracuff pressure is necessary to seal the bronchus, there are possibilities of the incompatibility of the size of DLT and the herniation of the bronchial cuff to the proximal side. The method of confirmation of OLV using a capnometer can display the non ventilated condition on the monitor objectively. We can thus decrease troubles during operations. PMID- 26442409 TI - [Side Effects of Continuous Fentanyl Infusion for Postoperative Pain Relief in Children]. AB - BACKGROUND: There have been many reports on the use of morphine for postoperative pain relief in children, but the use of fentanyl for this purpose has not frequently been described. We clarified the details of side effects exhibited in children who had received continuous fentanyl infusion for postoperative pain relief METHODS: The subjects are 1,166 children aged between 0 and 14 years who underwent continuous fentanyl infusion for postoperative pain relief within the previous 4 years. Fentanyl was administered at a dose of 0.5 or 1.0 MUg x kg(-1) x hr(-1), and with continuous use of pulse oximeter, the pulse rate, SpO2, respiratory rate, BP, sedation score, and presence/absence of nausea/vomiting were recorded every 2 hours. The frequencies of side effects were retrospectively examined. RESULTS: Severe side effects, including respiratory depression, for which mask ventilation or tracheal intubation was required were observed in 0.77% of cases. No subjects died or developed permanent sequelae. Nausea/vomiting occurred in 25.4% of cases. CONCLUSIONS: Using monitoring systems that facilitate the early detection of and intervention in respiratory depression, we can safely administer continuous fentanyl infusion for postoperative pain relief in children. It is necessary to adopt countermeasures against nausea/vomiting. PMID- 26442410 TI - [Examination of the Untoward Removal of the Epidural Catheter Due to Differences in Its Fixation Methods]. AB - BACKGROUND: Epidural anesthesia is a useful tool for postoperative pain control. However, inappropriate fixing of the catheter not only hinders the analgesic effect, but could lead to serious accidents as a result of the untoward removal of the epidural catheter. METHODS: In our hospital, in order to reduce the removal of catheter, we introduced a new method of fixing by Steri-StripTM from fiscal 2011. RESULTS: We compared 2337 cases of epidural use for general anesthesia in one fiscal year of 2010. In fiscal year 2011, 2500 examples were examined backward. CONCLUSIONS: The group using the Steri-Strip, was able to significantly reduce the untoward removal (P = 0.002). PMID- 26442411 TI - [A Case of Brainstem Cavernous Hemangioma Showing False Positive Response to Electromyographic Tracheal Tube]. AB - Brainstem cavernous hemangioma is a complex lesion associated with hemorrhage and neurological deficit. The damage of the vagus nerve is a devastating surgical complication. Therefore, intraoperative anatomical and functional evaluation of this nerve is crucial. We used electromyographic tracheal tube (EMG tube)to monitor electromyogram from the vocal cord. We report a case of brainstem cavernous hemangioma showing false positive response to EMG tube. A 66-year-old woman underwent resection of cavernous hemangioma in the pontine tegmentum. General anesthesia was induced with remifentanl, propofol, and suxamethonium, and was maintained with oxygen, air, remifentanil and propofol. We monitored somatosensory evoked potentials, motor evoked potentials, and electromyogram of the vocal cord, orbicularis oculi, orbicularis oris and lateral rectus. When the manipulation reached brainstem, slight spontaneous respiration (SR) appeared on capnogram. Simultaneously, an alarm rang. Exposed nerves were stimulated electrically. However, there was no electromyographic response on the vocal cord. We concluded that the cause was SR accompanied by vocal cord movement. Remifentanil was increased up to 1 MUg x kg(-1) x min(-1). SR did not disappear. Remifentanil was not increased any more without hindering the operation. Her operative course was uneventful. It is necessary to pay attention to false positive response caused by SR with EMG tube. PMID- 26442412 TI - [Airway Obstruction Caused by Heat and Moisture Exchange Filter Used during General Anesthesia: A Case Report and an In Vitro Study]. AB - BACKGROUND: A previously healthy 54-year-old woman underwent a resection of the acoustic tumor. Following induction of general anesthesia and tracheal intubation, volume-controlled ventilation was started and the patient was placed in the left park bench position. The heat and moisture exchange filter (HMEF) was placed within the ventilatory circuit and positioned below the patient's head to avoid unintentional extubation. Six hours after the start of surgery, peak inspiratory pressure gradually rose, and 2 hours later ventilation of the patient's lung became increasingly difficult. When the HMEF was replaced, normal breathing was promptly restored. METHODS: We reproduced this scenario with a similar HMEF under the same ventilator settings by adding 0-8 g of normal saline into the HMEF housing, and measured the inspiratory pressure and tidal volume across the HMEF. RESULTS: When instilling 4 g of saline, an increase in inspiratory pressure occurred. CONCLUSIONS: This case shows a potential risk of unexpectedly early occurrence of obstruction of the HMEF due to accumulation of condensed water within the device when the HMEF was positioned below the patient's head. We recommend selection of the appropriate HMEF and suitable mounting to avoid this problem. PMID- 26442413 TI - [Intubation Using a Double-lumen Tube with a Combination of Fiberoptic Bronchoscope and the Glidescope in a Patient with Difficult Airway]. AB - A 54-year-old man with lung cancer was scheduled for thoracoscopic upper lobe resection under general anesthesia. About half a year previously, he had undergone surgery for oropharyngeal cancer and tongue cancer. As a result of the surgery, elasticity of the neck skin bending of the neck were restricted (Mallampati classification IV). A narrow-bored tracheostomy tube (speech cannula) was inserted. In the operating room, the tip of a 5.0 mm ID standard tube was inserted from the tracheostomy tube, and connected to a breathing circuit. Anesthesia was induced with inhalation of sevoflurane, followed by intravenous propofol, fentanyl, and rocuronium. Four anesthesiologists were required to intubate the trachea. One person held the tracheal tube placed in the tracheotomy tube. The second person performed jaw thrusting. The third person inserted the Glidescope to shift the transplanted tongue to the side. It was then possible for the forth anesthesiologist to manage to see the glottis using a fiberoptic bronchoscope, and a double-lumen tube (DLT) could be inserted to the trachea orally. Inserting a DLT over the fiberoptic bronchoscope is a blind method, but we felt that combined with a variety of tools such as video laryngoscope, the success rate in intubation will increase. PMID- 26442414 TI - [A Case of Septic Shock Immediately following Cesarean Section]. AB - Here we report a case of severe septic shock immediately following cesarean section. A pregnant woman with dichorionic diamniotic twins was diagnosed with preterm rupture of membranes (PROM). Ritodrine hydrochloride and betamethasone did not sufficiently relieve abdominal extension; emergency cesarean section was scheduled 4 days later, at 31 week 5 day gestation. The patient did not show any symptoms or laboratory data suggesting infection. Spinal anesthesia was initiated with 2.2 ml of 0.5% bupivacaine hydrochloride and fentanyl 10 MUg at L3-4; sensory loss (T3) was confirmed. Epidural anesthesia at L1-2 was performed for postoperative pain control. Surgery proceeded uneventfully, but the first baby did not respond to neonatal CPR. One hour after surgery, the patient showed signs of shock and a fever of 40.9 degrees C. Catecholamine and antibiotics relieved her symptoms. Retrograde infection of Escherichia coli was attributed to fetal distress and septic shock. Early phase septic shock should be considered in pregnant women with PROM. PMID- 26442415 TI - [Anesthetic Induction in a Patient with Giant Ovarian Tumor Who Developed Severe Hemodynamic Instability]. AB - A 45 year-old woman underwent a laparotomy for a giant ovarian tumor under general anesthesia. Preoperative CT scan revealed a 30 cm-diameter tumor compressing IVC. She had slight respiratory discomfort on supine position, but respiratory function test showed no abnormalities. In the operating room, after oxygenation for 3 minutes, general anesthesia was induced with fentanyl 100 MUg, propofol 90 mg and rocuronium 40 mg on supine position. Immediately after the induction, her systolic blood pressure and heart rate fell to 45 mmHg and 40 beats per minute, respectively. We considered that her hemodynamic instability was supine hypotensive syndrome due to giant ovarian tumor. Therefore we placed her 30 degree right side up and pushed her tumor to the left so as not to compress the IVC. We rapidly injected acetated Ringer's solution 500 ml, ephedrine 12 mg and phenylephrine 0.1 mg, and her hemodynamic status soon recovered to normal ranges. The anesthetic induction of a patient with a giant ovarian tumor is challenging. Some reports recommend strategies such as induction on lateral position or suctioning tumor contents before induction. Careful induction of general anesthesia is required for these patients. PMID- 26442416 TI - [Development of Takotsubo Cardiomyopathy during Recovery from General Anesthesia: A Case Report]. AB - Takotsubo cardiomyopathy is a cardiac syndrome characterized by transient left ventricular dysfunction. A 61-year-old woman underwent laparoscopic cholecystectomy under general anesthesia. During recovery from general anesthesia, several arrhythmias occurred without cardiac collapse following desflurane discontinuation and sugammadex sodium administration. She had a chest pain after extubation, with ST segment elevation in leads aV(L) and V2-4. Emergency left ventricular angiogram revealed no significant coronary stenosis, and excessive contraction of the base and severe hypokinesis of the apex suggested Takotsubo cardiomyopathy. Sympathetic hyperactivity during acute recovery from anesthesia with desflurane discontinuation and muscle relaxant reversal with sugammadex sodium was considered the likely cause of Takotsubo cardiomyopathy. PMID- 26442417 TI - [Airway Management Utilizing an air-Q blocker in a Patient with Motor Neuron Disease and Soft Palate Paralysis]. AB - A 67-year-old woman suffering from hoarseness or dysphagia was diagnosed with motor neuron disease. She was scheduled for laparoscopic cholecystectomy under general anesthesia for suspected gallbladder cancer. She was concerned about the exacerbation of her hoarseness or dysphagia from tracheal intubation. We therefore decided to perform airway management by using supraglottic device air-Q blocker, through which a gastric tube could be inserted. We first passed the gastric tube through the outer blocker hole and inserted it into the esophagus using Magill forceps. The air-Q blocker was placed position under the guidance of a McGrath videolaryngoscope. Sealing pressure was over 20 cmH2O and mechanical ventilation was performed uneventfully during artificial pneumoperitoneum. We were able to deflate the stomach and perform tracheal suction via the inner hole of the air-Q. Following the operation, the patient developed neither hoarseness nor pharyngeal pain. PMID- 26442418 TI - [Acute Ventilatory Failure during Prone Thoracoscopic Esophagectomy with Carbon Dioxide Insufflation in a Patient Managed by a Single Lumen Tracheal Tube]. AB - A 67-year-old woman underwent prone thoracoscopic esophagectomy with carbon dioxide (CO2) insufflation. After insertion of an epidural catheter, general anesthesia was induced with propofol, sevoflurane, remifentanil and rocuronium. The trachea was intubated with a single lumen endotracheal tube (SLET). CO2 insufflation at 5 mmHg with the SLET deflated the right lung and provided excellent visualization without respiratory instability. The left side pleura was injured during the inferior mediastinal lymphadenectomy and the patient went into sudden profound hypoventilation with an increase in end-tidal CO2 from 43 to 64 mmHg. We observed the trachea with bronchofiberscope and the SLET was correctly located and not obstructed. We were convinced that bilateral pneumothorax occurred because the left side pleura was injured and auscultation revealed decreased breath sounds over the left hemithorax. We asked the surgeon to discontinue the insufflated CO2 and both lungs were fully expanded. The operation was then carried out successfully without further untoward event. The patient was successfully extubated at the intensive care unit on postoperative day 1. The CO2 insufflation during thoracoscopic esophagectomy can cause bilateral pneumothorax and we recommend to inflate the bilateral lungs regularly for the continuation of the surgery. PMID- 26442419 TI - [General Anesthesia for a Patient with Purulent Spondylitis with Retropharyngeal Abscess and Vocal Cord Dysfunction: A Case Report]. AB - A 43-year-old man was admitted to our hospital for neck pain, and diagnosis was fixed as purulent spondylitis with retropharyngeal abscess and vocal cord dysfunction. Deteriorating paresthesia, paralysis and airway narrowing needed airway management emergency cervical laminoplasty and abscess drainage under general anesthesia. On standby of an otorhinolaryngologist for urgent tracheotomy, nasal tracheal intubation with bronchofiberscope was performed in the patient with semi-awake condition. Postoperative airway narrowing and vocal cord dysfunction improved, and the trachea was extubated on the third day after surgery. PMID- 26442420 TI - [Change in Perioperative Hemostatic Function in Patients Undergoing Hepatic Resection for Primary and Metastatic Liver Cancer]. AB - BACKGROUND: Patients undergoing primary hepatic resection often develop hemostatic dysfunction associated with cirrhosis. METHODS: We retrospectively surveyed pre- and postoperative prothrombin time (PT) and the PT expressed as international normalized ratio (PT-INR) in 39 patients undergoing primary liver resection. We also compared PT changes between primary and metastatic cancer cases (8 cases). RESULTS: Postoperative PT-INR was 1.40 +/- 0.38, which was significantly prolonged compared to preoperative PT-INR of 1.08 +/- 0.07. Preoperative PT was over 70% in all 39 patients undergoing primary liver resection, whereas postoperative PT was less than 60% in 13 of 39 patients. No significant difference was found in preoperative PT-INR between primary and metastatic cancer cases, but postoperative PT-INR was significantly prolonged in primary cancer cases. CONCLUSIONS: Patients undergoing primary liver resection are susceptible to hemostatic dysfunction, even with preoperative PT levels within normal limits. PMID- 26442421 TI - [Perioperative Management of a Patient with Severe Parkinson's Disease with Intravenous Levodopa Administration]. AB - A 70-year-old man with severe Parkinson's disease was scheduled for thoracic aortic aneurysm resection and aortic valve replacement. We administered levodopa intravenously during the perioperative period to avoid the malignant syndrome which is reported to arise with abrupt cessation of anti-Parkinson's drugs. The dose of intravenous administration was tapered with the resumption of oral intake. No manifestation of malignant syndrome was observed. We measured blood concentrations of levodopa several times during the perioperative period. The concentration of levodopa during the surgery was relatively high; however no adverse events of overdose (e.g. dyskinesis) occurred. In the postoperative period, administration of levodopa was changed to the oral route and serum levels of levodopa showed a notable decrease, the cause of which may be poor absorption through the digestive system during the perioperative period. Therefore, in the peri- and post-operative periods, it is necessary to take great care when reducing the infusion dose. PMID- 26442422 TI - [Management of a Patient with Aortic Stenosis Undergoing Lung Cancer Surgery]. AB - A 79-year-old man with aortic stenosis (AS) was scheduled for right middle lobectomy under general anesthesia. AS is a significant risk factor for the development of cardiac complications after noncardiac surgery. Anesthetic management adjusting left ventricular preload and coload, and keeping sinus rhythm was successful with no complications. But after moving back to the intensive care unit after surgery, ECG showed paroxysmal complete atrioventricular blocks and we inserted a temporary transvenous pacemaker catheter. We should be very careful with not only the anesthetic but also perioperative management of AS patient. PMID- 26442423 TI - [Anesthetic Management of Three Patients with Chronic Inflammatory Demyelinating Polyradiculoneuropathy]. AB - Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronically progressing or relapsing disease caused by immune-mediated peripheral neuropathy. We report the anesthetic management of three CIDP patients who underwent elective orthopedic surgeries. Owing to the risk of neuraxial anesthetics triggering demyelination, general anesthesia was selected to avoid epidural or spinal anesthesia or other neuraxial blockade. It was also judged prudent to avoid prolonged perioperative immobilization, which might compress vulnerable peripheral nerves. For Patient 1, general anesthesia was induced with propofol, remifentanil, and sevoflurane, and was maintained with sevoflurane and remifentanil. For Patients 2 and 3, general anesthesia was induced and maintained with propofol and remifentanil. For tracheal intubation, under careful monitoring with peripheral nerve stimulators, minimal doses of rocuronium (0.6-0.7 mg x kg( 1)) were administered. When sugammadex was administered to reverse the effect of rocuronium, all patients rapidly regained muscular strength. Postoperative courses were satisfactory without sequelae. PMID- 26442424 TI - [Anesthetic Management of a Parturient with Eclampsia, Posterior Reversible Encephalopathy Syndrome and Pulmonary Edema due to Pregnancy-induced Hypertension]. AB - A 27-year-old woman with mental retardation was admitted to a nearby hospital for an abrupt onset of seizure. Physical examination revealed remarkable hypertension and pregnancy with estimated gestational age of 28th week. Severe pulmonary edema and hypoxia led to a diagnosis of pregnancy-induced hypertension (PIH) accompanied by eclampsia. She was orotracheally intubated because of refractory seizure and hypoxemia, and transferred to our hospital for further treatment. Besides severe hypoxia and hypercapnea, an enhanced lesion was detected in the left posterior cerebrum by brain MRI. No abnormal findings were detected in the fetus, with heart rate of 150 beats x min. She was diagnosed with posterior reversible encephalopathy syndrome (PRES) caused by PIH and emergency cesarean section under general anesthesia was scheduled. A male newborn was delivered with Apgar score of 1/4 (1/5 min), followed by starting continuous infusion of nicardipine for controlling hypertension. Chest X-P on completion of surgery revealed remarkably alleviated pulmonary edema. She received intensive treatment and continued positive pressure ventilation for four days after delivery. She recovered with no neurological deficits and her child was well without any complications. PMID- 26442425 TI - [Problems with the Structure of a New Pentax-Airwayscope S200]. AB - BACKGROUND: Pentax-Airwayscope (AWS-S100) is useful for tracheal intubation, and a new version S200 has recently been introduced to clinical practice. We felt that S200 was more difficult than the S100 in attaching and detaching a single use Introck blade. METHODS: In a randomized cross-over design, we compared S100 and S200, for the ease of attaching to and detaching from the Introck, fixation of the Introck using the fixation ring of the main body, and insertion time. RESULTS: Compared with S100, it was easier for S200 to fix the Introck using the fixation ring (78% vs 72%) (P < 0.05), but it was more difficult for S200 to attach (the incidence 43% vs 2%) and detach (53% vs 11%) the Introck (both P < 0.001). Insertion time was also significantly longer for S200 than S100 (median 9 [IQR : 6-19] s vs 4 [IQR : 3-6] s) (P < 0.001). The flexible scope of one of two S200s kinked and was broken during attachment. CONCLUSIONS: It is necessary to apply lubricant to the distal part of the scope to prevent damage to the scope. PMID- 26442426 TI - [New Insights into Maternal Cardiopulmonary Resuscitation--Significance of Simulation Research and Training]. AB - Pregnancy-related mortality, estimated to occur in approximately 1: 50,000 deliveries, is rare in developed countries. The 2010 American Heart Association (AHA) Guidelines for Resuscitation emphasize the importance of high-quality chest compression as a key determinant of successful cardiopulmonary resuscitation. During pregnancy, the uterus can compress the inferior vena cava, impeding venous return and thereby reducing stroke volume and cardiac output. To maximize the effectiveness of chest compressions in pregnancy, the AHA guidelines recommend the 27-30 degrees left-lateral tilt (LLT) position. When CPR is performed on parturients in the LLT position, chest compressions will probably be more effective if performed with the operator standing on the left side of the patient. The videolaryngoscope Pentax-AWS Airwayscope (AWS) was found to be an effective tool for airway management during chest compressions in 27 LLT simulations, suggesting that the AWS may be a useful device for airway management during maternal resuscitation. PMID- 26442427 TI - [Evaluation of Knowledge on Cardiopulmonary Resuscitation for Pregnant Woman among G2010 AHA-BLS-HCP Participants]. AB - Cardiac arrest during pregnancy is a rare event but it needs rapid and effective cardiopulmonary resuscitation to prevent loss of two lives. In this questionnaire survey, G2010 AHA-BLS Healthcare Provider Course participants answered four questions about CPR caveats which should be considered during pregnancy. The correct answer ratio is generally low among the four questions. Special situation explanation addition such as left uterine displacement in the AHA-BLS healthcare provider course may be needed for the empowerment of knowledge about cardiopulmonary resuscitation during pregnancy. PMID- 26442428 TI - [Tracheal Intubation Using the Pentax-AWS during Chest Compression: A Meta analysis]. AB - BACKGROUND: The aim of this meta-analysis is to evaluate the efficacy of the Pentax-AWS for tracheal intubation during chest compression, compared with that of the Macintosh laryngoscope. METHODS: The systematic search, data extraction, critical appraisal, and pooled analysis were performed according the PRISMA statement. The relative risk (RR), mean difference (MD), and their corresponding 95% confidence intervals (CIs) were calculated by the Review Manager 5.2 software for dichotomous and continuous outcomes, respectively. RESULTS: Twelve trials included 424 tracheal intubations by Pentax-AWS and 421 tracheal intubations by Macintosh laryngoscope. In studies examining novice laryngoscopists, successful intubation (RR1.4, 95% CI 1.1-1.6, P < 0.0007) and time for instrumentation (MD 7.7 sec, 95% CI -10.1 sec--5.4 sec, P < 0.00001) were improved using the Pentax AWS. With respect to experts' hands there was no difference between the two devices in both of these outcomes. CONCLUSIONS: Compared to the Macintosh laryngoscopy, Pentax-AWS offers advantages for novice laryngoscopists during chest compression, while these benefits are not seen with experts' hands. PMID- 26442429 TI - [Usefulness of ACUSON Freestyle (Siemens), Wireless Ultrasound System]. AB - The ACUSON Freestyle, the world's first wireless ultrasound system, was released in April 2014. We assessed its usefulness, using it for central venous cannulation, spinal anesthesia, brachial plexus or obturator nerve block, and for the surgery of metastatic liver cancer as well as the spine. Generally, we could use it smoothly in all situations. Comparing with the conventional ultrasound system, the machine is big, heavy, with many buttons to operate. The main problem with the conventional ultrasound system is the wire connecting probe and the main system, which can interfere with procedures. With ACUSON Freestyle, we could perform the nerve block and the central venous cannulation more easily with little concern about contamination. PMID- 26442430 TI - [Hospital Doctors Should Receive Lecture for Sedation According to Joint Commission International]. AB - BACKGROUND: At our hospital, intending to obtaining an approval from the Joint Commission International (JCI), we conducted a workshop on sedation for all staff physicians. METHODS: A sedation instructor authorized by the Japanese Association for Medical Simulation gave a lecture using the "practice guidelines for sedation and administration of analgesics for non-anesthesiologists", revised in 2002 by the American Society of Anesthesiologists, following which, a test using 10 true false questions was conducted, while before and after the lecture a questionnaire survey on the sedation lecture was carried out RESULTS: Among 191 physicians attending the lecture, except for one person, 7 or more questions were answered correctly. From the questionnaires, the sedation lectures were also generally accepted favourably. In the test of understanding, the mistakes were mostly in the sections on "sedation evaluation" "intraoperative monitoring" "pharmaceutical knowledge" and "airway management methods". CONCLUSIONS: The sedation lecture in the hospital was effective. PMID- 26442431 TI - Physicians' views on pay-for-performance as a reimbursement model: a quantitative study among Dutch surgical physicians. AB - OBJECTIVES: To assess the views, knowledge, and experience of Dutch physicians with regard to the general objectives and values of the pay-for-performance (P4P) system, as the Dutch healthcare industry might find it useful, in terms of governance, to explore this approach further. METHODS: A quantitative cross sectional survey study was conducted among 48 physicians in surgical specialties in the Netherlands between May 2014 and July 2014. The survey questionnaire was designed to gather information regarding the intensity of feelings, on a 7-point Likert scale, toward statements that address the P4P system. Confidence intervals were calculated using the bootstrap technique with 1000 iterations. RESULTS: Physicians see a positive value in P4P for their organizations rather than for personal attainment (mean = 5.00; 95% CI = 4.62-5.39), even though they feared that P4P might put financial pressure on them (mean = 5.03; 95% CI = 4.50-5.54). They strongly share the view that other colleagues will resist adopting P4P as a business model (mean = 5.74; 95% CI = 5.43-6.04). Respondents stated that they would not leave their current jobs if P4P were to be incorporated in their organization. CONCLUSIONS: Physicians see value in P4P for their organizations, and consider that P4P could provide an incentive for improving medical outcomes. There seems to be potential for the P4P system in the Netherlands as participants expressed positive support for its values. There is an intersection of interests between the value of P4P and the physicians' aim of achieving quality outcomes; however, further studies would be needed to investigate perceptions about specific design features in a larger sample. In addition, prior to implementing P4P, broad education about the system should be provided in order to counteract pre-conceptions and prevent resistance. PMID- 26442432 TI - Chlorine Incorporation for Enhanced Performance of Planar Perovskite Solar Cell Based on Lead Acetate Precursor. AB - We show the effects of chlorine incorporation in the crystallization process of perovskite film based on a lead acetate precursor. We demonstrate a fabrication process for fast grain growth with highly preferred {110} orientation upon only 5 min of annealing at 100 degrees C. By studying the correlation between precursor composition and morphology, the growth dynamic of perovskite film in the current system is discussed. In particular, we found that both lead acetate precursor and Cl incorporation are beneficial to perovskite growth. While lead acetate allows fast crystallization process, Cl improves perovskite crystallinity. Planar perovskite solar cells with optimized parameters deliver a best power conversion efficiency of 15.0% and average efficiency of 14.0% with remarkable reproducibility and good stability. PMID- 26442433 TI - Does climate directly influence NPP globally? AB - The need for rigorous analyses of climate impacts has never been more crucial. Current textbooks state that climate directly influences ecosystem annual net primary productivity (NPP), emphasizing the urgent need to monitor the impacts of climate change. A recent paper challenged this consensus, arguing, based on an analysis of NPP for 1247 woody plant communities across global climate gradients, that temperature and precipitation have negligible direct effects on NPP and only perhaps have indirect effects by constraining total stand biomass (Mtot ) and stand age (a). The authors of that study concluded that the length of the growing season (lgs ) might have a minor influence on NPP, an effect they considered not to be directly related to climate. In this article, we describe flaws that affected that study's conclusions and present novel analyses to disentangle the effects of stand variables and climate in determining NPP. We re-analyzed the same database to partition the direct and indirect effects of climate on NPP, using three approaches: maximum-likelihood model selection, independent-effects analysis, and structural equation modeling. These new analyses showed that about half of the global variation in NPP could be explained by Mtot combined with climate variables and supported strong and direct influences of climate independently of Mtot , both for NPP and for net biomass change averaged across the known lifetime of the stands (ABC = average biomass change). We show that lgs is an important climate variable, intrinsically correlated with, and contributing to mean annual temperature and precipitation (Tann and Pann ), all important climatic drivers of NPP. Our analyses provide guidance for statistical and mechanistic analyses of climate drivers of ecosystem processes for predictive modeling and provide novel evidence supporting the strong, direct role of climate in determining vegetation productivity at the global scale. PMID- 26442434 TI - Impedance matching network for high frequency ultrasonic transducer for cellular applications. AB - An approach for the design of an impedance matching network (IMN) for high frequency ultrasonic transducers with large apertures based on impedance analysis for cellular applications is presented in this paper. The main objectives were to maximize energy transmission from the excitation source to the ultrasonic transducers for cell manipulation and to achieve low input parameters for the safe operation of an ultrasonic transducer because the piezoelectric material in high frequency ultrasonic transducers is prone to breakage due to its being extremely thin. Two ultrasonic transducers, which were made of lithium niobate single crystal with the thickness of 15 MUm, having apertures of 4.3 mm (fnumber=1.23) and 2.6mm (fnumber=0.75) were tested. L-type IMN was selected for high sensitivity and compact design of the ultrasonic transducers. The target center frequency was chosen as the frequency where the electrical admittance (|Y|) and phase angle (thetaz) from impedance analysis was maximal and zero, respectively. The reference center frequency and reference echo magnitude were selected as the center frequency and echo magnitude, measured by pulse-echo testing, of the ultrasonic transducer without IMN. Initial component values and topology of IMN were determined using the Smith chart, and pulse-echo testing was analyzed to verify the performance of the ultrasonic transducers with and without IMN. After several iterations between changing component values and topology of IMN, and pulse-echo measurement of the ultrasonic transducer with IMN, optimized component values and topology of IMN were chosen when the measured center frequency from pulse-echo testing was comparable to the target frequency, and the measured echo magnitude was at least 30% larger than the reference echo magnitude. Performance of an ultrasonic transducer with and without IMN was tested by observing a tangible dent on the surface of a plastic petridish and single cell response after an acoustic pulse was applied on a target cell. PMID- 26442435 TI - Investigation of complete bandgaps in a piezoelectric slab covered with periodically structured coatings. AB - The propagation of elastic waves in a piezoelectric slab covered with periodically structured coatings or the so-called stubbed phononic crystal slab is investigated. Four different models are selected and the effects of distribution forms and geometrical parameters of the structured coatings on complete bandgaps are discussed. The phononic crystal slab with symmetric coatings can generate wider complete bandgaps while that with asymmetric coatings is favorable for the generation of multi-bandgaps. The complete bandgaps, which are induced by locally resonant effects, change significantly as the geometry of the coatings changes. Moreover, the piezoelectric effects benefit the opening of the complete bandgaps. PMID- 26442436 TI - Ionic liquids as an electrolyte for the electro synthesis of organic compounds. AB - The use of ionic liquids (ILs) as a solvent and an electrolyte for electro organic synthesis has been reviewed. To date several ILs exist, however the ILs based on tetraalkylammonium, pyrrolidinium, piperidinium and imidazolium cations with BF4(-), PF6(-), and TFSI anions have been widely used and explored the most. Electro organic synthesis in ionic liquid media leading to the synthesis of a wide range of organic compounds has been discussed. Anodic oxidation or cathodic reduction will generate radical cation or anion intermediates, respectively. These radicals can undergo self coupling or coupling with other molecules yielding organic compounds of interest. The cation of the IL is known to stabilize the radical anion extensively. This stabilization effect has a specific impact on the electrochemical CO2 reduction and coupling to various organics. The relative stability of the intermediates in IL leads to the formation of specific products in higher yields. Electrochemical reduction of imidazolium or thiazolium based ILs generates N-heterocyclic carbenes that have been shown to catalyze a wide range of base or nucleophile catalyzed organic reactions in IL media, an aspect that falls into the category of organocatalysis. Electrochemical fluorination or selective electrochemical fluorination is another fascinating area that delivers selectively fluorinated organic products in Et3N.nHF or Et4NF.nHF adducts (IL) via anodic oxidation. Oxidative polymerization in ILs has been explored the most; although morphological changes were observed compared to the conventional methods, polymers were obtained in good yields and in some cases ILs were used as dopants to improve the desired properties. PMID- 26442437 TI - Enteroendocrine Cells: Chemosensors in the Intestinal Epithelium. AB - The enteroendocrine system orchestrates how the body responds to the ingestion of foods, employing a diversity of hormones to fine-tune a wide range of physiological responses both within and outside the gut. Recent interest in gut hormones has surged with the realization that they modulate glucose tolerance and food intake through a variety of mechanisms, and such hormones are therefore excellent therapeutic candidates for the treatment of diabetes and obesity. Characterizing the roles and functions of different enteroendocrine cells is an essential step in understanding the physiology, pathophysiology, and therapeutics of the gut-brain-pancreas axis. PMID- 26442438 TI - DNA Damage and Repair in Vascular Disease. AB - DNA damage affecting both genomic and mitochondrial DNA is present in a variety of both inherited and acquired vascular diseases. Multiple cell types show persistent DNA damage and a range of lesions. In turn, DNA damage activates a variety of DNA repair mechanisms, many of which are activated in vascular disease. Such DNA repair mechanisms either stall the cell cycle to allow repair to occur or trigger apoptosis or cell senescence to prevent propagation of damaged DNA. Recent evidence has indicated that DNA damage occurs early, is progressive, and is sufficient to impair function of cells composing the vascular wall. The consequences of persistent genomic and mitochondrial DNA damage, including inflammation, cell senescence, and apoptosis, are present in vascular disease. DNA damage can thus directly cause vascular disease, opening up new possibilities for both prevention and treatment. We review the evidence for and the causes, types, and consequences of DNA damage in vascular disease. PMID- 26442439 TI - Mammographic density and histopathologic characteristics of screen-detected tumors in the Norwegian Breast Cancer Screening Program. AB - BACKGROUND: High mammographic density might mask breast tumors, resulting in delayed diagnosis or missed cancers. PURPOSE: To investigate the association between mammographic density and histopathologic tumor characteristics (histologic type, size, grade, and lymph node status) among women screened in the Norwegian Breast Cancer Screening Program. MATERIAL AND METHODS: Information about 1760 screen-detected ductal carcinoma in situ (DCIS) and 7366 invasive breast cancers diagnosed among women aged 50-69 years, 1996-2010, was analyzed. The screening mammograms were classified subjectively according to the amount of fibroglandular tissue into fatty, medium dense, and dense by breast radiologists. Chi-square test was used to compare the distribution of tumor characteristics by mammographic density. Odds ratio (OR) of tumor characteristics by density was estimated by means of logistic regression, adjusting for screening mode (screen film and full-field digital mammography), and age. RESULTS: Mean and median tumor size of invasive breast cancers was 13.8 and 12 mm, respectively, for women with fatty breasts, and 16.2 and 14 mm for those with dense breasts. Lymph node positive tumors were identified among 20.6% of women with fatty breasts compared with 27.2% of those with dense breasts (P < 0.001). The proportion of DCIS was significantly lower for women with fatty (15.8%) compared with dense breasts (22.0%). Women with dense breasts had an increased risk of large (OR, 1.44; 95% CI, 1.18-1.73) and lymph node positive tumors (OR, 1.26; 95% CI, 1.05-1.51) compared with women with fatty and medium dense breasts. CONCLUSION: High mammographic density was positively associated with tumor size and lymph node positive tumors. PMID- 26442440 TI - High-fat diet prevents adaptive peripartum-associated adrenal gland plasticity and anxiolysis. AB - Maternal obesity is associated with lower basal plasma cortisol levels and increased risk of postpartum psychiatric disorders. Given that both obesity and the peripartum period are characterized by an imbalance between adrenocorticotropic hormone (ACTH) and cortisol, we hypothesized that the adrenal glands undergo peripartum-associated plasticity and that such changes would be prevented by a high-fat diet (HFD). Here, we demonstrate substantial peripartum adrenal gland plasticity in the pathways involved in cholesterol supply for steroidogenesis in female rats. In detail, the receptors involved in plasma lipid uptake, low density lipoprotein (LDL) receptor (LDLR) and scavenger receptor class B type 1 (SRB1), are elevated, intra-adrenal cholesterol stores are depleted, and a key enzyme in de novo cholesterol synthesis, hydroxymethylglutaryl coenzyme A reductase (HMGCR), is downregulated; particularly at mid-lactation. HFD prevented the lactation-associated anxiolysis, basal hypercorticism, and exaggerated the corticosterone response to ACTH. Moreover, we show that HFD prevented the downregulation of adrenal cholesterol stores and HMGCR expression, and LDLR upregulation at mid-lactation. These findings show that the adrenal gland is an important regulator of peripartum associated HPA axis plasticity and that HFD has maladaptive consequences for the mother, partly by preventing these neuroendocrine and also behavioural changes. PMID- 26442441 TI - Analysis of Proton NMR in Hydrogen Bonds in Terms of Lone-Pair and Bond Orbital Contributions. AB - NMR spectroscopic parameters of the proton involved in hydrogen bonding are studied theoretically. The set of molecules includes systems with internal resonance-assisted hydrogen bonds, internal hydrogen bonds but no resonance stabilization, the acetic acid dimer (AAD), a DNA base pair, and the hydrogen succinate anion (HSA). Ethanol and guanine represent reference molecules without hydrogen bonding. The calculations are based on zero-point vibrationally averaged molecular structures in order to include anharmonicity effects in the NMR parameters. An analysis of the calculated NMR shielding and J-coupling is performed in terms of "chemist's orbitals", that is, localized molecular orbitals (LMOs) representing lone-pairs, atomic cores, and bonds. The LMO analysis associates some of the strong de-shielding of the protons in resonance-assisted hydrogen bonds with delocalization involving the pi-backbone. Resonance is also shown to be an important factor causing de-shielding of the OH protons for AAD and HSA, but not for the DNA base pair. Nitromalonamide (NMA) and HSA have particularly strong hydrogen bonds exhibiting signs of covalency in the associated J-couplings. The analysis results show how NMR spectroscopic parameters that are characteristic for hydrogen bonded protons are influenced by the geometry and degree of covalency of the hydrogen bond as well as intra- and intermolecular resonance. PMID- 26442442 TI - The management of tibial pilon fractures with the Ilizarov fixator: The role of ankle arthroscopy. AB - BACKGROUND: Pilon fractures usually result from high energy trauma, and are commonly associated with extensive soft tissue damage which prevents the use of open reduction and internal fixation. PURPOSE: This study was designed to evaluate the use of the Ilizarov external fixator in the treatment of pilon fractures of the ankle, and to determine whether arthroscopy of the ankle could improve the outcome. METHODS: From February 2011 to May 2013 a total of 23 patients with unilateral closed pilon fractures were divided into two groups treated with and without arthroscopy during fixation with the Ilizarov external fixator. The fractures were classified according to the AO Rudi and Allgower classification. Follow up ranged from 10 to 37 months with a mean of 18 months. RESULTS: All cases were evaluated at follow up by the AOFAS and the Bone et al. grading system. According to Bone et al. there were 3 cases excellent, 4 cases good, 2 cases fair, and 2 cases poor in Group A (without arthroscopy), whereas there were 4 cases excellent, 6 cases good, 2 cases fair in Group B (with arthroscopy). The AOFAS score for Group A was 77.8+/-5.8, and for Group B was 78.4+/-6.9. CONCLUSION: We concluded that the Ilizarov external fixator is an excellent method in treating pilon fractures as it minimizes the need for extensive surgery. We also conclude that the use of arthroscopy during pilon fracture fixation did not add statistically significant improvement to our results and it needs longer term investigation to assess its advantage - if any - to the final outcome. LEVEL OF EVIDENCE: level 2. PMID- 26442443 TI - Methylation-mediated BMPER expression in fibroblast activation in vitro and lung fibrosis in mice in vivo. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease. Although the pathogenesis is poorly understood, evidence suggests that genetic and epigenetic alterations, such as DNA methylation, may play a key role. Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGF-beta) superfamily and are important regulators in IPF. Here we identified BMP endothelial cell precursor-derived regulator (BMPER) as a key regulator of fibroblast activation. BMPER is a secreted glycoprotein that binds directly to BMPs and may regulate TGF-beta/BMP signaling, but its role in lung fibrosis is not clear. BMPER is highly expressed in human IPF lung fibroblasts compared to normal lung fibroblasts. Demethylation agent 5'-azacytidine decreased BMPER expression in fibroblasts, and attenuated the invasion and migration of IPF lung fibroblasts. Furthermore, siRNA-mediated reduction of BMPER in the human lung fibroblasts impaired cell migration and invasion. 5'-azacytidine treatment additionally regulated BMPER expression and reduced lung fibrosis in mice in vivo. These findings demonstrate that methylation of specific genes in fibroblasts may offer a new therapeutic strategy for IPF by modulating fibroblast activation. PMID- 26442444 TI - Effect of Deletion of Ghrelin-O-Acyltransferase on the Pulsatile Release of Growth Hormone in Mice. AB - Ghrelin, a gut hormone originating from the post-translational cleavage of preproghrelin, is the endogenous ligand of growth hormone secretagogue receptor 1a (GHS-R1a). Within the growth hormone (GH) axis, the biological activity of ghrelin requires octanoylation by ghrelin-O-acyltransferase (GOAT), conferring selective binding to the GHS-R1a receptor via acylated ghrelin. Complete loss of preproghrelin-derived signalling (through deletion of the Ghrl gene) contributes to a decline in peak GH release; however, the selective contribution of endogenous acyl-ghrelin to pulsatile GH release remains to be established. We assessed the pulsatile release of GH in ad lib. fed male germline goat(-/-) mice, extending measures to include mRNA for key hypothalamic regulators of GH release, and peripheral factors that are modulated relative to GH release. The amount of GH released was reduced in young goat(-/-) mice compared to age-matched wild-type mice, whereas pulse frequency and irregularity increased. Altered GH release did not coincide with alterations in hypothalamic Ghrh, Srif, Npy or Ghsr mRNA expression, or pituitary GH content, suggesting that loss of Goat does not compromise canonical mechanisms that contribute to pituitary GH production and release. Although loss of Goat resulted in an irregular pattern of GH release (characterised by an increase in the number of GH pulses observed during extended secretory events), this did not contribute to a change in the expression of sexually dimorphic GH-dependent liver genes. Of interest, circulating levels of insulin-like growth factor (IGF)-1 were elevated in goat(-/-) mice. This rise in circulating levels of IGF-1 was correlated with an increase in GH pulse frequency, suggesting that sustained or increased IGF-1 release in goat(-/-) mice may occur in response to altered GH release patterning. Our observations demonstrate that germline loss of Goat alters GH release and patterning. Although the biological relevance of altered GH secretory patterning remains unclear, we propose that this may contribute to sustained IGF-1 release and growth in goat(-/ ) mice. PMID- 26442445 TI - Functional Outcomes of Isolated Medial Tibial Plateau Fractures. AB - Isolated medial tibial plateau injuries are uncommon and underdescribed in the literature. As such, the range of fracture severity and outcomes in comparison to more frequently described tibial plateau fractures are lacking. To assess outcomes of this rare injury, we compared two cohorts of patients. Overall, 27 patients who sustained 27 isolated medial plateau (Schatzker type IV) fractures and 81 patients with 81 split depression lateral plateau (Schatzker type II) fractures were compared. The outcomes were stratified by injury mechanism energy and assessed with radiographs, clinical and arthroscopic examinations, and functional status with the short musculoskeletal function assessment questionnaire (SMFA). Overall, 52% of Schatzker type IV fractures versus 71% of Schatzker type II were associated with high-energy injuries. Schatzker type IV fractures were more often nondisplaced and amenable to being managed, nonoperatively, 22 versus 6%, with excellent results. Schatzker type II fractures had a corresponding higher proportion of postoperative articular step off greater than 12 mm and poorer 12-month SMFA scores. Schatzker type IV fractures were more often treated with an external fixator than Schatzker type II fractures (22 vs. 1%). Within Schatzker type IV fractures, high- versus low-energy injuries did not differ significantly with regards to initial articular step off (4.2 vs. 5.1 mm), ligamentous and meniscal injury, or SMFA outcomes. Isolated medial plateau fractures had low- and high-energy patterns with differing management and outcomes. Schatzker type IV fractures overall were associated with lower energy mechanisms, less initial articular step off, and better functional outcomes than Schatzker II comparisons in this cohort. The level of evidence is 4. PMID- 26442446 TI - How good are routinely collected primary healthcare data for evaluating the effectiveness of health service provision in a remote Aboriginal community? AB - INTRODUCTION: Evaluation and monitoring of primary health care requires the establishment and maintenance of an appropriate data system. This study reviews the application and effectiveness of the Communicare data management system in the delivery of health services to the Fitzroy Valley in the Kimberley region of Western Australia. METHODS: Key demographic fields (sex, date of birth and Aboriginal status) were examined for completeness (whether the date fields were all completed and correct when compared with the paper file) while the 'conditions' field was examined for accuracy. Three chronic diseases (diabetes, hypertension and chronic kidney disease) in adults and age-specific incidence for four acute diseases (otitis media, gastroenteritis, lower respiratory tract infection and skin infection) in children were included. RESULTS: Completeness of chosen demographic fields was 100% for date of birth and sex and 98% for Aboriginal status. Chronic conditions matched the paper files 100%, while the recording of acute conditions was incomplete. Among older adults (>=55 years) the prevalences of diabetes, chronic kidney disease and hypertension were 43%, 42% and 39% respectively. Age-specific incidence of acute conditions was highest in the 0-4 years age group where 25% had had at least one episode of otitis media and 20% at least one episode of skin infection. CONCLUSIONS: The recording of demographic and chronic disease data was complete, but lower for acute conditions. Routinely collected data have a number of limitations, but nonetheless are a feasible way to establish population health indices, particularly for chronic diseases for this remote health service with minimal expenditure and effort. These rates provide useful baselines for monitoring and evaluating the impact of service delivery on health outcomes. This audit provides an indication of the accuracy of routinely collected data in the electronic system compared to the paper medical records, which have traditionally been considered the gold standard. Data collected on chronic disease information were accurate and clinically useful for health service planning, monitoring and evaluation. Acute disease data were not accurate enough to be clinically useful. PMID- 26442447 TI - Observation of tunable nonlinear effects in an analogue of superconducting composite right/left hand filter. AB - Artificial structures with negative permittivity or permeability have attracted significant attention in the science community because they provide a pathway for obtaining exotic electromagnetic properties not found in natural materials. At the moment, the great challenge of these artificial structures in microwave frequency exhibits a relatively large loss. It is well-known that superconducting thin films have extremely low surface resistance. Hence, it is a good candidate to resolve this constraint. Besides, the reported artificial structures with negative permittivity or permeability are mainly focusing on linear regime of wave propagation. However, any future effort in creating tunable structures would require knowledge of nonlinear properties. In this work, a tunable superconducting filter with composite right/left-hand transmission property is proposed and fabricated. Its nonlinear effects on temperature and power are studied by theoretical analysis and experiments. PMID- 26442448 TI - Isolating Visual and Proprioceptive Components of Motor Sequence Learning in ASD. AB - In addition to defining impairments in social communication skills, individuals with autism spectrum disorder (ASD) also show impairments in more basic sensory and motor skills. Development of new skills involves integrating information from multiple sensory modalities. This input is then used to form internal models of action that can be accessed when both performing skilled movements, as well as understanding those actions performed by others. Learning skilled gestures is particularly reliant on integration of visual and proprioceptive input. We used a modified serial reaction time task (SRTT) to decompose proprioceptive and visual components and examine whether patterns of implicit motor skill learning differ in ASD participants as compared with healthy controls. While both groups learned the implicit motor sequence during training, healthy controls showed robust generalization whereas ASD participants demonstrated little generalization when visual input was constant. In contrast, no group differences in generalization were observed when proprioceptive input was constant, with both groups showing limited degrees of generalization. The findings suggest, when learning a motor sequence, individuals with ASD tend to rely less on visual feedback than do healthy controls. Visuomotor representations are considered to underlie imitative learning and action understanding and are thereby crucial to social skill and cognitive development. Thus, anomalous patterns of implicit motor learning, with a tendency to discount visual feedback, may be an important contributor in core social communication deficits that characterize ASD. Autism Res 2016, 9: 563-569. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26442450 TI - Role of DnaK in HspR-HAIR interaction of Mycobacterium tuberculosis. AB - Heat shock proteins (Hsps) are a highly conserved family of proteins. The regulation of expression of Hsps in Mycobacterium tuberculosis, is regulated both positively and negatively by alternate sigma factors and transcriptional DNA repressors, respectively. HspR is a negative regulator of expression of hsps, DnaK, ClpB, and Acr2 in M. tuberculosis. In this study, we expressed the M. tuberculosis HspR (MtHspR) in E. coli, and functionally characterized it. MtHspR independently bound to its putative cognate DNA, the HAIR element. MtHspR was found to exist in a dynamic mixture of dimeric and monomeric protein and presence of salt led to the formation of trimers which lacked the DNA binding activity. MtHspR was found to be heat stable with a Tm of 66 degrees C. HspR-HAIR binding was stable upto 60 degrees C suggesting that MtHspR is not the heat stress sensor. Mycobacterial DnaK was found to interact directly with MtHspR-HAIR complex in vitro in an ATP independent manner. The DnaK-HspR-HAIR binding pattern altered at high temperatures in the presence of aggregated alpha-casein substrate, suggesting that DnaK may indirectly be responding to heat stress in a feedback loop mechanism. PMID- 26442451 TI - A structural and spectrophotometric study on the complexation of Am(III) with TMOGA in comparison with the extracted complex of DMDOOGA. AB - Complexation of Am(iii) with tetramethyl-3-oxa-glutaramide (TMOGA, L(I)) is studied by spectrophotometric titrations and single crystal X-ray diffraction. Three successive complex species, [AmL(I)](3+), [AmL](3+), and [AmL](3+), have been identified and their stability constants are calculated to be 3.71 +/- 0.012, 5.95 +/- 0.021, and 6.93 +/- 0.034 respectively, from the absorption spectra collected from the titrations of Am(iii) with L(I) at 25 degrees C in 1 M NaNO3. Single crystals of AmL(ClO4)3 have been grown from a HClO4 solution containing Am(3+) and L(I). The crystal structure of AmL(ClO4)3 shows that Am(iii) is coordinated by nine oxygen atoms from three L(I) ligands. The deconvoluted UV-Vis absorption spectrum of [AmL](3+) in aqueous solution is nearly identical to the diffusion reflectance spectrum of AmL(ClO4)3 in the solid state, indicating that the coordination geometry of the complexes is nearly the same. In addition, to provide parallels to solvent exaction, the extracted Am(iii) complex with N,N'-dimethyl-N,N'-dioctyl-3-oxa-glutaramide (DMDOOGA, L(II)) is also prepared and studied using spectrophotometry. The similarity in UV Vis absorption of the extracted complex of Am(iii) with L(II) and [AmL](3+) suggests that the Am(iii) ion is also coordinated by three tridentate L(II) ligands existing as [AmL](3+) in the organic phase of solvent extraction. PMID- 26442449 TI - Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. AB - Mesenchymal stem cells (MSCs) and macrophages are fundamental components of the stem cell niche and function coordinately to regulate haematopoietic stem cell self-renewal and mobilization. Recent studies indicate that mitophagy and healthy mitochondrial function are critical to the survival of stem cells, but how these processes are regulated in MSCs is unknown. Here we show that MSCs manage intracellular oxidative stress by targeting depolarized mitochondria to the plasma membrane via arrestin domain-containing protein 1-mediated microvesicles. The vesicles are then engulfed and re-utilized via a process involving fusion by macrophages, resulting in enhanced bioenergetics. Furthermore, we show that MSCs simultaneously shed micro RNA-containing exosomes that inhibit macrophage activation by suppressing Toll-like receptor signalling, thereby de-sensitizing macrophages to the ingested mitochondria. Collectively, these studies mechanistically link mitophagy and MSC survival with macrophage function, thereby providing a physiologically relevant context for the innate immunomodulatory activity of MSCs. PMID- 26442452 TI - The NINDS Parkinson's disease biomarkers program. AB - BACKGROUND: Neuroprotection for Parkinson's disease (PD) remains elusive. Biomarkers hold the promise of removing roadblocks to therapy development. The National Institute of Neurological Disorders and Stroke has therefore established the Parkinson's Disease Biomarkers Program to promote discovery of PD biomarkers for use in phase II and III clinical trials. METHODS: Using a novel consortium design, the Parkinson's Disease Biomarker Program is focused on the development of clinical and laboratory-based biomarkers for PD diagnosis, progression, and prognosis. Standardized operating procedures and pooled reference samples were created to allow cross-project comparisons and assessment of batch effects. A web based Data Management Resource facilitates rapid sharing of data and biosamples across the research community for additional biomarker projects. RESULTS: Eleven consortium projects are ongoing, seven of which recruit participants and obtain biosamples. As of October 2014, 1,082 participants have enrolled (620 PD, 101 with other causes of parkinsonism, 23 essential tremor, and 338 controls), 1,040 of whom have at least one biosample. Six thousand eight hundred ninety-eight total biosamples are available from baseline, 6-, 12-, and 18-month visits: 1,006 DNA, 1,661 RNA, 1,419 whole blood, 1,382 plasma, 1,200 serum, and 230 cerebrospinal fluid (CSF). Quality control analysis of plasma, serum, and CSF samples indicates that almost all samples are high quality (24 of 2,812 samples exceed acceptable hemoglobin levels). CONCLUSIONS: By making samples and data widely available, using stringent operating procedures based on existing standards, hypothesis testing for biomarker discovery, and providing a resource that complements existing programs, the Parkinson's Disease Biomarker Program will accelerate the pace of PD biomarker research. (c) 2015 International Parkinson and Movement Disorder Society. PMID- 26442453 TI - Generation of Oxtr cDNA(HA)-Ires-Cre Mice for Gene Expression in an Oxytocin Receptor Specific Manner. AB - The neurohypophysial hormone oxytocin (OXT) and its receptor (OXTR) have critical roles in the regulation of pro-social behaviors, including social recognition, pair bonding, parental behavior, and stress-related responses. Supporting this hypothesis, a portion of patients suffering from autism spectrum disorder have mutations, such as single nucleotide polymorphisms, or epigenetic modifications in their OXTR gene. We previously reported that OXTR-deficient mice exhibit pervasive social deficits, indicating the critical role of OXTR in social behaviors. In the present study, we generated Oxtr cDNA(HA)-Ires-Cre knock-in mice, expressing both OXTR and Cre recombinase under the control of the endogenous Oxtr promoter. Knock-in cassette of Oxtr cDNA(HA)-Ires-Cre consisted of Oxtr cDNA tagged with the hemagglutinin epitope at the 3' end (Oxtr cDNA(HA)), internal ribosomal entry site (Ires), and Cre. Cre was expressed in the uterus, mammary gland, kidney, and brain of Oxtr cDNA(HA)-Ires-Cre knock-in mice. Furthermore, the distribution of Cre in the brain was similar to that observed in Oxtr-Venus fluorescent protein expressing mice (Oxtr-Venus), another animal model previously generated by our group. Social behavior of Oxtr cDNA(HA)-Ires-Cre knock-in mice was similar to that of wild-type animals. We demonstrated that this construct is expressed in OXTR-expressing neurons specifically after an infection with the recombinant adeno-associated virus carrying the flip-excision switch vector. Using this system, we showed the transport of the wheat-germ agglutinin tracing molecule from the OXTR-expressing neurons to the innervated neurons in knock-in mice. This study might contribute to the monosynaptic analysis of neuronal circuits and to the optogenetic analysis of neurons expressing OXTR. PMID- 26442454 TI - An Unusual Right Atrial Mass: A Misdiagnosis Identified by Intraoperative Transesophageal Echocardiography. PMID- 26442455 TI - Sequential screening to predict symptomatic pulmonary thromboembolism after gynecologic surgery in Nara, Japan. AB - OBJECTIVE: To evaluate a sequential screening method's efficacy in predicting symptomatic pulmonary thromboembolism (PTE) after gynecologic surgery. METHODS: A prospective study employing a two-stage screening process was conducted among consecutive asymptomatic adults who underwent outpatient evaluation for gynecologic surgery at Nara Medical University Hospital, Japan, between April 1, 2004, and December 31, 2013. Patients with a preoperative plasma D-dimer level greater than or equal to 1.0MUg/mL underwent compression ultrasonography of the lower extremities. The primary outcome measure was postoperative detection of symptomatic PTE. RESULTS: Overall, 1729 patients were included. The mean D-dimer level was 1.7+/-3.3MUg/mL. Compression ultrasonography was conducted among 470 (27.1%) patients with positive D-dimer test results; symptomatic deep vein thrombosis (DVT) was preoperatively detected among 94 (20.0%) of them. Patients with DVT (n=94) had higher D-dimer levels than patients (n=1635) without (7.8+/ 12.8MUg/mL vs 1.1+/-1.8MUg/mL; P<0.001). Despite anticoagulant therapy, symptomatic PTE was detected postoperatively among two of these 94 patients. Symptomatic PTE was also detected among four of 376 patients with positive D dimer test results but no evidence of DVT by ultrasonography. No clinical onset of postoperative PTE was observed among 1259 patients with D-dimer levels below the cut-off value. CONCLUSION: The PROVEN screening strategy (Preoperative surveillance using a sequential strategy) was ineffective at predicting postoperative symptomatic PTE. PMID- 26442456 TI - A strategy to discover decoy chemokine ligands with an anti-inflammatory activity. AB - Excessive signaling by chemokines has been associated with chronic inflammation or cancer, thus attracting substantial attention as promising therapeutic targets. Inspired by chemokine-clearing molecules shaped by pathogens to escape the immune system, we designed a generic screening assay to discover chemokine neutralizing molecules (neutraligands) and unambiguously distinguish them from molecules that block the receptor (receptor antagonists). This assay, called TRIC r, combines time-resolved intracellular calcium recordings with pre-incubation of bioactive compounds either with the chemokine or the receptor-expressing cells. We describe here the identification of high affinity neutraligands of CCL17 and CCL22, two chemokines involved in the Th2-type of lung inflammation. The decoy molecules inhibit in vitro CCL17- or CCL22-induced intracellular calcium responses, CCR4 endocytosis and human T cell migration. In vivo, they inhibit inflammation in a murine model of asthma, in particular the recruitment of eosinophils, dendritic cells and CD4(+)T cells. Altogether, we developed a successful strategy to discover as new class of pharmacological tools to potently control cell chemotaxis in vitro and in vivo. PMID- 26442458 TI - Correlation of the New York Heart Association Classification and the 6-Minute Walk Distance: A Systematic Review. AB - BACKGROUND: Functional status assessment is the cornerstone of heart failure management and trials. The New York Heart Association (NYHA) classification and 6 minute walk distance (6MWD) are commonly used tools; however, the correlation between them is not well understood. HYPOTHESIS: We hypothesised that the relationship between the NYHA classification and 6MWD might vary across studies. METHODS: A systematic literature search was performed to identify all studies reporting both NYHA class and 6MWD. Two reviewers independently assessed study eligibility and extracted data. Thirty-seven studies involving 5678 patients were included. RESULTS: There was significant heterogeneity across studies in 6MWD within all NYHA classes: I (n = 16, Q = 934.2; P < 0.001), II (n = 25, Q = 1658.3; P < 0.001), III (n = 30, Q = 1020.1; P < 0.001), and IV (n = 6, Q = 335.5; P < 0.001). There was no significant difference in average 6MWD between NYHA I and II (420 m vs 393 m; P = 0.416). There was a significant difference in average 6MWD between NYHA II and III (393 m vs 321 m; P = 0.014) and III and IV (321 m vs 224 m; P = 0.027). This remained significant after adjusting for region of study, age, and sex. CONCLUSIONS: Although there is an inverse correlation between NYHA II-IV and 6MWD, there is significant heterogeneity across studies in 6MWD within each NYHA class and overlap in 6MWD between NYHA I and II. The NYHA classification performs well in more symptomatic patients (NYHA III/IV) but less so in asymptomatic/mildly symptomatic patients (NYHA I/II). Nonetheless, the NYHA classification is an easily applied first-line tool in everyday clinical practice, but its potential subjectivity should be considered when performing comparisons across studies. PMID- 26442457 TI - Monocyte enhancers are highly altered in systemic lupus erythematosus. AB - OBJECTIVE: Histone modifications set transcriptional competency and can perpetuate pathologic expression patterns. We defined systemic lupus erythematosus (SLE)-specific changes in H3K4me3 and K3K27me3, histone marks of gene activation and repression, respectively. METHODS: We used ChIP-seq to define histone modifications in monocytes from SLE patients and controls. RESULTS: Both promoters and enhancers exhibited significant changes in histone methylation in SLE. Regions with differential H3K4me3 in SLE were significantly enriched in potential interferon-related transcription factor binding sites and pioneer transcription factor sites. CONCLUSION: Enhancer activation defines the character of the cell and our data support extensive disease effects in monocytes, a particularly plastic lineage. Type I interferons not only drive altered gene expression but may also alter the character of the cell through chromatin modifications. PMID- 26442459 TI - Patient volumes and pre- and postdischarge postpartum infection: A retrospective cohort study. AB - BACKGROUND: To examine the association between hospital and clinician obstetric volume and postpartum infection risk in the pre- and postdischarge periods. METHODS: We used data from the 2011 New York State Inpatient and Emergency Department Databases to fit generalized estimating equation models to examine the effect of hospital and clinician obstetric volume on infection before discharge and in the 30 days after discharge after delivery. RESULTS: Higher clinician volume was associated with lower predischarge infection risk (odds ratio [OR] for first vs third quartile was 0.84; 95% confidence interval [CI], 0.77-0.98). There was an uncertain trend toward higher predischarge infection risk in higher volume hospitals (OR for first vs third quartile was 1.36; 95% CI, 0.79-2.34). We found no associations between patient volumes and postdischarge infections; however, power was insufficient to rule out small associations. The joint association of hospital and clinician volumes with postdischarge infection appeared submultiplicative (product term OR = 0.95; 95% CI, 0.92-0.98). CONCLUSION: This study adds to the evidence that hospital obstetric volume is positively associated with predischarge postpartum infections, whereas clinician volume may be negatively associated with those predischarge infections. The associations between hospital obstetric volume and postdischarge infection appear to differ. These results underscore the importance of including postdischarge follow-up in hospital-based studies of postpartum infection. PMID- 26442460 TI - Poor hand hygiene by college students linked to more occurrences of infectious diseases, medical visits, and absence from classes. AB - BACKGROUND: Proper hand hygiene has been linked to lower susceptibility to infectious diseases in many types of communities, but it has not been well established on college campuses. This study investigated the hand hygiene statuses of college students and their occurrences in relation to infectious diseases, medical visits, and absence from classes or work. It also examined the effects of education on handwashing technique to improve hand hygiene. METHODS: College students enrolled at a university in Northwestern Ohio were recruited as study subjects. Microbial samples were collected 3 times from each of the 220 valid volunteers before washing their hands, after washing with their own procedures, and after washing with a procedure recommended by the Centers for Disease Control and Prevention (CDC). Each volunteer also answered a survey including questions on their health conditions, medical visits, and absence from classes or work. RESULTS: Hands of 57.7% volunteers were colonized by an uncountable number of microbial colonies, which were significantly linked to more occurrences to infectious diseases (P < .05), medical visits (P < .05), and arguably more absence from classes or work (P = .09). The handwashing procedure provided by the CDC significantly improved hand hygiene. CONCLUSION: It is critical to promote education on proper handwashing in colleges, in grade schools, and at home to improve health and learning outcomes. PMID- 26442461 TI - Immunity of nursing students to measles, mumps, rubella, and varicella in Yozgat, Turkey. AB - Measles, mumps, rubella, and varicella (MMRV) are vaccine-preventable diseases. The aim of this study was to determine the vaccination status of first-year nursing students in Turkey. The sample used was 180 students and immunoglobulin G antibodies against MMRV viruses were determined quantitatively by enzyme-linked immunosorbent assay. Immunity rates to MMRV were 82.8%, 83.3%, 98.3%, and 100%, respectively. The results of this study showed that all of the students were immune to varicella and 32.8% of the students were not immune to at least 1 of the viruses covered by the measles, mumps, and rubella vaccine. PMID- 26442462 TI - Infection control strategies that successfully controlled an outbreak of Mycobacterium abscessus at a cystic fibrosis center. AB - BACKGROUND: Mycobacterium abscessus infection in patients with cystic fibrosis (CF) can result in accelerated clinical decline and the potential for direct or indirect transmission between patients has been recently demonstrated. Data on the outcomes of M abscessus outbreaks and the efficacy of specific infection control procedures in patients with CF remain limited. This study provides follow up from an outbreak of pulmonary M abscessus in our center, highlighting outcomes and strategies that appear to have prevented further spread of the organism. METHODS: Data from our adult CF center (1989-2015) were analyzed, including chart reviews of all patients with positive mycobacterial sputum cultures, cultures from environment surfaces, and epidemiologic evaluation of infected patients. Following an M abscessus outbreak in 2009, infection control policies were intensified based on CF guidelines and surveillance data were collected and reviewed. RESULTS: Five cases of M abscessus were involved in the outbreak; 3 patients died during follow-up. An environment search failed to reveal an intermediary source of transmission between patients. After implementation of infection control measures composed of staff/patient education, environment sterilization, and patient isolation, no new cases were detected. CONCLUSIONS: Direct or indirect patient-to-patient transmission of M abscessus is a threat in the CF population. A multifaceted infection control strategy based on CF guidelines was effective in halting transmission in our center. PMID- 26442463 TI - Correction: Stereoselective synthesis of the head group of archaeal phospholipid PGP-Me to investigate bacteriorhodopsin-lipid interactions. AB - Correction for 'Stereoselective synthesis of the head group of archaeal phospholipid PGP-Me to investigate bacteriorhodopsin-lipid interactions' by Jin Cui, et al., Org. Biomol. Chem., 2015, DOI: 10.1039/c5ob01252j. PMID- 26442465 TI - Transient apical pseudohypertophy due to myocardial edema in patients with Takotsubo syndrome. PMID- 26442464 TI - Learning from the other limb's experience: sharing the 'trained' M1 representation of the motor sequence knowledge. AB - KEY POINTS: Participants were scanned during the untrained-hand performance of a motor sequence, intensively trained a day earlier, and also a similarly constructed but novel, untrained sequence. The superior performance levels for the trained, compared to the untrained sequence, were associated with a greater magnitude of activity within the primary motor cortex (M1), bilaterally, for the trained sequence. The differential responses in the 'trained' M1, ipsilateral to the untrained hand, were positively correlated with experience-related differences in the functional connectivity between the 'trained' M1 and (1) its homologue and (2) the dorsal premotor cortex (PMd) within the contralateral hemisphere. No significant correlation was evident between experience-related differences in M1 - M1 and M1 - PMd connectivity measures. These results suggest that the transfer of sequence-specific information between the two primary motor cortices is predominantly mediated by excitatory mechanisms driven by the 'trained' M1 via two independent neural pathways. Following unimanual training on a novel sequence of movements, sequence-specific performance may improve overnight not only in the trained hand, but also in the hand afforded no actual physical experience. It is not clear, however, how transfer to the untrained hand is achieved. In the present study, we examined whether and how interaction between the two primary motor cortices contributes to the performance of a sequence of movements, extensively trained the day before, by the untrained hand. Accordingly, we studied participants during the untrained-hand performance of a finger-to-thumb opposition sequence (FOS), intensively trained a day earlier (T FOS), and a similarly constructed, but novel, untrained FOS (U-FOS). Changes in neural signals driven by task performance were assessed using functional magnetic resonance imaging. To minimize potential differences as a result of the rate of sequence execution per se, participants performed both sequences at an identical paced rate. The analyses showed that the superior fluency in executing the T-FOS compared to the U-FOS was associated with higher activity within the primary motor cortex (M1), bilaterally, for the T-FOS. The differential responses in the 'trained' M1 were positively correlated with experience-related differences in the functional connectivity between the 'trained' M1 and (1) its left homologue and (2) the left dorsal premotor cortex. However, no significant correlation was evident between the changes in connectivity in these two routes. These results suggest that the transfer of sequence-specific information between the two primary motor cortices is predominantly mediated by excitatory mechanisms driven by the 'trained' M1 via at least two independent neural pathways. PMID- 26442466 TI - Metric qualities of the cognitive behavioral assessment for outcome evaluation to estimate psychological treatment effects. AB - BACKGROUND: Cognitive behavioral assessment for outcome evaluation was developed to evaluate psychological treatment interventions, especially for counseling and psychotherapy. It is made up of 80 items and five scales: anxiety, well-being, perception of positive change, depression, and psychological distress. The aim of the study was to present the metric qualities and to show validity and reliability of the five constructs of the questionnaire both in nonclinical and clinical subjects. METHODS: Four steps were completed to assess reliability and factor structure: criterion-related and concurrent validity, responsiveness, and convergent-divergent validity. A nonclinical group of 269 subjects was enrolled, as was a clinical group comprising 168 adults undergoing psychotherapy and psychological counseling provided by the Italian public health service. RESULTS: Cronbach's alphas were between 0.80 and 0.91 for the clinical sample and between 0.74 and 0.91 in the nonclinical one. We observed an excellent structural validity for the five interrelated dimensions. The clinical group showed higher scores in the anxiety, depression, and psychological distress scales, as well as lower scores in well-being and perception of positive change scales than those observed in the nonclinical group. Responsiveness was large for the anxiety, well being, and depression scales; the psychological distress and perception of positive change scales showed a moderate effect. CONCLUSION: The questionnaire showed excellent psychometric properties, thus demonstrating that the questionnaire is a good evaluative instrument, with which to assess pre- and post treatment outcomes. PMID- 26442467 TI - Sargaquinoic acid attenuates inflammatory responses by regulating NF-kappaB and Nrf2 pathways in lipopolysaccharide-stimulated RAW 264.7 cells. AB - Myagropsis myagroides, a brown alga, showed strong anti-inflammatory activities in the previous studies. In this study, we isolated a strong anti-inflammatory compound, sargaquinoic acid (SQA), from M. myagroides and investigated the anti inflammatory action using lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. SQA suppressed the production of inducible nitric oxide synthase and cyclooxygenase-2 in LPS-stimulated cells as well as that of reactive oxygen species. As a result, SQA inhibited the production of NO, prostaglandin E2, and pro-inflammatory cytokines. LPS-induced transcriptional activation of nuclear factor-kappaB (NF-kappaB) was remarkably inhibited by SQA treatment through the prevention of inhibitor kappaB-alpha degradation. The regulation of NF-kappaB activation was also mediated by the phosphorylation of ERK and Akt in LPS stimulated RAW 264.7 cells. Moreover, SQA induced the production of heme oxygenase 1 via activation of transcription factor Nrf2. These results indicate that SQA inhibits the LPS-induced expression of inflammatory mediators via suppression of ERK and Akt-mediated NF-kappaB pathway as well as up-regulation of Nrf2/HO-1 pathway, indicating that SQA has a potential therapeutic and preventive application in various inflammatory diseases. PMID- 26442468 TI - A proteomic glimpse into human ureter proteome. AB - Urine has evolved as one of the most important biofluids in clinical proteomics due to its noninvasive sampling and its stability. Yet, it is used in clinical diagnostics of several disorders by detecting changes in its components including urinary protein/polypeptide profile. Despite the fact that majority of proteins detected in urine are primarily originated from the urogenital (UG) tract, determining its precise source within the UG tract remains elusive. In this article, we performed a comprehensive analysis of ureter proteome to assemble the first unbiased ureter dataset. Next, we compared these data to urine, urinary exosome, and kidney mass spectrometric datasets. Our result concluded that among 2217 nonredundant ureter proteins, 751 protein candidates (33.8%) were detected in urine as urinary protein/polypeptide or exosomal protein. On the other hand, comparing ureter protein hits (48) that are not shown in corresponding databases to urinary bladder and prostate human protein atlas databases pinpointed 21 proteins that might be unique to ureter tissue. In conclusion, this finding offers future perspectives for possible identification of ureter disease associated biomarkers such as ureter carcinoma. In addition, the ureter proteomic dataset published in this article will provide a valuable resource for researchers working in the field of urology and urine biomarker discovery. All MS data have been deposited in the ProteomeXchange with identifier PXD002620 (http://proteomecentral.proteomexchange.org/dataset/PXD002620). PMID- 26442470 TI - Increasing Relationship Between Negative Emotionality and Conduct Problems During Childhood: A Cross-Sectional Behavioral Genetic Analysis. AB - Age difference in the etiology of the relationship between childhood negative emotionality (NE) and conduct problems (CP) has not been previously investigated. Mothers of 662 pairs of twins completed questions on the emotionality (NE) scale of the EAS temperament survey and the CP scale of the Strengths and Difficulties Questionnaires (SDQ) via a telephone interview. Twin data were analyzed separately in younger (ages 3 to 7 years; mostly pre-schoolers) and older children (ages 8 to 13 years; mostly elementary school children). The phenotypic correlation between NE and CP increased from 0.33 among younger twins to 0.43 among older twins. Bivariate model-fitting analysis was performed to determine age difference in the etiology of the relationship between NE and CP. Among younger twins, the correlation between NE and CP was entirely explained by additive genetic factors common to NE and CP. Among older children, however, a small but significant amount of unique environmental correlation emerged to account for about 47% of the phenotypic correlation between NE and CP. The remaining 53% of the phenotypic correlation was due to shared additive genetic factors. We speculate that environmental factors associated with school adjustment may exert influences on the relationship between NE and CP among elementary school children. PMID- 26442469 TI - Rhesus monkey model of liver disease reflecting clinical disease progression and hepatic gene expression analysis. AB - Alcoholic liver disease (ALD) is a significant public health issue with heavy medical and economic burdens. The aetiology of ALD is not yet completely understood. The development of drugs and therapies for ALD is hampered by a lack of suitable animal models that replicate both the histological and metabolic features of human ALD. Here, we characterize a rhesus monkey model of alcohol induced liver steatosis and hepatic fibrosis that is compatible with the clinical progression of the biochemistry and pathology in humans with ALD. Microarray analysis of hepatic gene expression was conducted to identify potential molecular signatures of ALD progression. The up-regulation of expression of hepatic genes related to liver steatosis (CPT1A, FASN, LEPR, RXRA, IGFBP1, PPARGC1A and SLC2A4) was detected in our rhesus model, as was the down-regulation of such genes (CYP7A1, HMGCR, GCK and PNPLA3) and the up-regulation of expression of hepatic genes related to liver cancer (E2F1, OPCML, FZD7, IGFBP1 and LEF1). Our results demonstrate that this ALD model reflects the clinical disease progression and hepatic gene expression observed in humans. These findings will be useful for increasing the understanding of ALD pathogenesis and will benefit the development of new therapeutic procedures and pharmacological reagents for treating ALD. PMID- 26442471 TI - Effect of ocean acidification on growth and otolith condition of juvenile scup, Stenotomus chrysops. AB - Increasing amounts of atmospheric carbon dioxide (CO2) from human industrial activities are causing changes in global ocean carbonate chemistry, resulting in a reduction in pH, a process termed "ocean acidification." It is important to determine which species are sensitive to elevated levels of CO2 because of potential impacts to ecosystems, marine resources, biodiversity, food webs, populations, and effects on economies. Previous studies with marine fish have documented that exposure to elevated levels of CO2 caused increased growth and larger otoliths in some species. This study was conducted to determine whether the elevated partial pressure of CO2 (pCO2) would have an effect on growth, otolith (ear bone) condition, survival, or the skeleton of juvenile scup, Stenotomus chrysops, a species that supports both important commercial and recreational fisheries. Elevated levels of pCO2 (1200-2600 MUatm) had no statistically significant effect on growth, survival, or otolith condition after 8 weeks of rearing. Field data show that in Long Island Sound, where scup spawn, in situ levels of pCO2 are already at levels ranging from 689 to 1828 MUatm due to primary productivity, microbial activity, and anthropogenic inputs. These results demonstrate that ocean acidification is not likely to cause adverse effects on the growth and survivability of every species of marine fish. X-ray analysis of the fish revealed a slightly higher incidence of hyperossification in the vertebrae of a few scup from the highest treatments compared to fish from the control treatments. Our results show that juvenile scup are tolerant to increases in seawater pCO2, possibly due to conditions this species encounters in their naturally variable environment and their well-developed pH control mechanisms. PMID- 26442472 TI - Structural phase transitions and photoluminescence properties of Eu(3+) doped Ca(2-x)BaxLaNbO6 phosphors. AB - Crystal structures of the series of double perovskites Ca(2-x)BaxLaNbO6:Eu(3+) phosphors have been examined by powder X-ray diffraction and Rietveld refinements. Ca2LaNbO6 has a monoclinic (P21/n) and Ba2LaNbO6 has a monoclinic (C2/m) structure. The structural phases of Ca(2-x)BaxLaNbO6:Eu(3+) samples are divided into three sections depending on different Ca/Ba ratios: (1) monoclinic phase (P21/n) as Ca2LaNbO6 in the range of x = 0-0.1, (2) mixed phases containing Ca2LaNbO6 and Ba2LaNbO6 between 0.15 and 1.2, and (3) monoclinic phase (C2/m) as Ba2LaNbO6 for x = 1.4-2. Eu(3+) ions act as the structural probes to study the structural phase transitions, and the evolution of the photoluminescence properties and thermal stability behaviours has been also comparatively investigated depending on different structural symmetries from Ca2LaNbO6 to Ba2LaNbO6 phase. The strong red emission from (5)D0-(7)F2 peaking at 618 nm can be found in Ca2LaNbO6:Eu(3+) phosphors, which is attributed to the low crystal field effect of the activator ions located in the highly distorted [LaO8] polyhedra sites. The composition-optimized phosphors can find applications in white light emitting diodes (LEDs). PMID- 26442473 TI - Postexercise heart rate variability following treadmill and cycle exercise: a comparison study. AB - The purpose of this study was to compare postexercise heart rate variability (HRV) immediately following acute bouts of treadmill (T) and cycle (C) exercise at 65% of mode-specific maximal oxygen consumption reserve (65% VO2 R). Fourteen apparently healthy men participated in this study. On two separate and randomized days, each participant performed 30 min of exercise at 65% VO2 R on T and C. Supine HRV was evaluated as normalized and log-transformed (ln) high-frequency (HF) and low-frequency (LF) spectral power, as well as the LF:HF ratio in 5-min segments immediately before (PRE) and at 10-15 min (POST1) and 25-30 min (POST2) following each exercise bout. There were no significant differences in the HRV values at PRE between the modalities. Following each exercise bout, lnHF was significantly lower at POST2 following C compared to T. In addition, lnLF and LF:HF were significantly higher at POST1 and POST2 following C compared to T. All HRV metrics returned towards baseline 30 min following T but remained significantly different than PRE values after C. These results suggest that following exercise at 65% of mode-specific VO2 R, C is associated with a greater delay of postexercise HRV recovery than T in apparently healthy men. PMID- 26442474 TI - Identifying an optimal antiemetic regimen for patients receiving anthracycline and cyclophosphamide-based chemotherapy for breast cancer--an inspection of the evidence base informing clinical decision-making. AB - BACKGROUND: Despite consensus recommendations for antiemetics in breast cancer patients receiving anthracycline and cyclophosphamide-based chemotherapy, control of chemotherapy-induced nausea and vomiting (CINV) remains sub-optimal. OBJECTIVE: To inspect available evidence from randomized controlled trials (RCT) in this population to establish treatment comparisons that have been studied, outcomes that have been reported, and the extent of study heterogeneity. Review of this data helps identify challenges for a systematic review comparing antiemetic regimens, and to identify potential future trials. METHODS: A search of Ovid MEDLINE(r), Embase and Cochrane CENTRAL was performed. We sought RCTs comparing antiemetic regimens in breast cancer patients receiving anthracycline and cyclophosphamide-based chemotherapy. We extracted information related to study design, patient characteristics and interventions compared. Patterns of outcome reporting were studied. While performing network meta-analysis was also of interest, studies were judged highly heterogeneous and it was felt findings from such work would be of uncertain validity. RESULTS: From 1062 citations, a total of 30 full texts were retained. Overall, 47 antiemetic regimens were evaluated using 15 different CINV endpoints. Treatment comparisons were diverse and many were informed by single small trials. Reporting of key endpoints was varied and all endpoints were not consistently available. Heterogeneity in patients, chemotherapies administered, and intervention doses were noted. CONCLUSIONS: Despite the availability of consensus recommendations for antiemetic use, we identified challenges in synthesizing the evidence base including high diversity in treatment comparisons, varied outcome reporting, and study heterogeneity. These represent challenges to identifying an optimal antiemetic regimen. Future antiemetic trials should incorporate more informed comparator selection, report patient-oriented outcomes in a standard fashion, and provide accessible data for these measures. PMID- 26442475 TI - Mechanisms and latest clinical studies of new NK1 receptor antagonists for chemotherapy-induced nausea and vomiting: Rolapitant and NEPA (netupitant/palonosetron). AB - Many patients undergoing moderately or highly emetogenic chemotherapy experience chemotherapy-induced nausea/vomiting (CINV) and report reduced daily functioning, despite prophylaxis with antiemetic drugs. While modern antiemetics have largely alleviated acute emesis, management of nausea and delayed emesis remains particularly challenging. We briefly review the pathophysiologic mechanisms of CINV and the clinical impact of current antiemetics, i.e., the serotonin subtype 3 (5-HT3) receptor antagonists (RAs) and neurokinin-1 (NK1)RAs, before summarizing recent data from clinical trials of new agents. The new antiemetics reviewed include the two most recently approved drugs, the NK1RA rolapitant and the fixed-dose combination product, NEPA, which is composed of the NK1RA netupitant and the 5-HT3RA palonosetron. Phase 3 studies demonstrate improved control of CINV in the delayed and overall phases when rolapitant is added to a standard 5-HT3RA regimen. Phase 2 and phase 3 clinical trials with NEPA demonstrate improved control of CINV in the acute, delayed, and overall phases vs. 5-HT3RA regimens. These data suggest that delayed emesis can be substantially reduced via combined 5-HT3 and NK1 receptor neurotransmitter pathway inhibition. PMID- 26442476 TI - Lessons learned from two decades of research in nutrition education and obesity prevention: Considerations for alcohol education. AB - OBJECTIVE: Effective health interventions involve an understanding of the specific needs and wants of the population to be served. Lessons from more than two decades of obesity prevention can be applied to understanding how to design and implement other behaviorally-focused health interventions, including those for alcohol education. METHODS: Three obesity prevention campaigns were reviewed and evaluated for elements critical to their success in achieving desired outcomes. RESULTS: Evaluation of the three cases studies revealed six key elements common to successful interventions. These include: specifying the desired outcome at the outset, understanding the target population, identifying a framework for the intervention, creating a campaign "identity", enlisting champions, and evaluating both outcomes and process. CONCLUSION: Successful health interventions should be behaviorally-focused and include multiple components to address the various factors that influence behavior. A clear understanding of how and why desired outcomes were achieved can inform dissemination to a wider audience and improve sustainability. PRACTICE IMPLICATIONS: Lessons learned from obesity prevention provide guidance for development of alcohol education. It must be acknowledged that there is still much to be learned to maximize success in prevention efforts. It is likely that analysis of future efforts in alcohol education can contribute to that understanding. PMID- 26442477 TI - Swollen and tender left nipple. PMID- 26442478 TI - Anthelmintic efficacy of cinnamaldehyde and cinnamic acid from cortex cinnamon essential oil against Dactylogyrus intermedius. AB - Utilization of chemical pesticide to control monogenean diseases is often restricted in many countries due to the development of pesticide resistance and concerns of chemical residues and environmental contamination. Thus, the use of antiparasitic agents from plants has been explored as a possible way for controlling monogenean infections. Extracts from Cinnamomum cassia were investigated under in vivo conditions against Dactylogyrus intermedius in goldfish. The two bioactive compounds, cinnamaldehyde and cinnamic acid, were identified using nuclear magnetic resonance and electrospray ionization mass spectrometry. The 48 h median effective concentrations (EC(50)) for these compounds against D. intermedius were 0.57 and 6.32 mg L(-1), respectively. The LD(50) of cinnamaldehyde and cinnamic acid were 13.34 and 59.66 mg L(-1) to goldfish in 48 h acute toxicity tests, respectively. These data confirm that cinnamaldehyde is effective against D. intermedius, and the cinnamaldehyde exhibits potential for the development of a candidate antiparasitic agent. PMID- 26442480 TI - Hydrogenation of Pt/TiO2{101} nanobelts: a driving force for the improvement of methanol catalysis. AB - Single-crystalline anatase TiO2 nanobelts with a dominant surface of the {101} facet were hydrogenated and used as substrates of platinum for methanol oxidation reaction (MOR). The hydrogenated TiO2 anatase{101} supporting Pt exhibits a 228% increase of current density for methanol oxidation compared with the same system without hydrogenation under dark conditions. The synergetic interactions of hydrogenated anatase{101} with the Pt cluster were investigated through first principles calculations, and found that the hydrogenation shifts the conduction band minimum to the Fermi level of pristine TiO2, and reduces the activation barrier for methanol dissociation considerably. Thus, this work provides an experimental and theoretical basis for developing non-carbon substrates with high electro-catalytic activity toward MOR. PMID- 26442479 TI - System N transporters are critical for glutamine release and modulate metabolic fluxes of glucose and acetate in cultured cortical astrocytes: changes induced by ammonia. AB - Glutamine (Gln) is synthesized in astrocytes from glutamate (Glu) and ammonia, whereupon it can be released to be transferred to neurons. This study evaluated the as yet not definitely established role of the astrocytic Gln transporters SN1 and SN2 (Slc38a3 and Slc38a5 respectively) in Gln release and metabolic fluxes of glucose and acetate, the canonical precursors of Glu. Cultured neocortical astrocytes were grown in the absence or presence of ammonia (5 mM NH4 Cl, 24 h), which deregulates astrocytic metabolism in hyperammonemic encephalopathies. HPLC analyses of cell extracts of SN1/SN2 siRNA-treated (SN1/SN2-) astrocytes revealed a ~ 3.5-fold increase in Gln content and doubling of glutathione, aspartate, alanine and glutamate contents, as compared to SN1/SN2+ astrocytes. Uptake and efflux of preloaded [(3) H]Gln was likewise significantly decreased in SN1/SN2- astrocytes. The atom percent excess (13) C values (given as M + 1) for alanine, aspartate and glutamate were decreased when the SN1/SN2- cells were incubated with [1-(13) C] glucose, while Gln consumption was not changed. No difference was seen in M + 1 values in SN1/SN2- cells incubated with [2-(13) C] acetate, which were not treated with ammonia. In SN1/SN2- astrocytes, the increase in Gln content and the decrease in radiolabeled Gln release upon exposure to ammonia were found abrogated, and glutamate labeling from [2-(13) C]acetate was decreased as compared to SN1/SN2+ astrocytes. The results underscore a profound role of SN1 and/or SN2 in Gln release from astrocytes under physiological conditions, but less so in ammonia-overexposed astrocytes, and appear to manifest dependence of astrocytic glucose metabolism to Glu/Gln on unimpaired SN1/SN2- mediated Gln release from astrocytes. The astrocytic N system transporters SN1 and SN2 show preponderance to mediate glutamine (Gln) efflux. Under hyperammonemic conditions, accumulation of Gln, a direct product of ammonia detoxification, may deregulate astrocytic metabolism and seems to be responsible for astrocytic swelling. This study evaluated not definitely established role of SN1 and SN2 in Gln release and metabolic fluxes of radiolabeled glucose and acetate. Simultaneous silencing of SN1/SN2 transporters increase Gln, glutathione, aspartate, alanine and glutamate contents (Panel B; marked in red) as compare to non-silenced astrocytes (Panel A). The atom percent excess (13) C values (given as M + 1) for alanine, aspartate and glutamate were decreased when the cells with silenced transporters were incubated with [1-(13) C]glucose, whereas no difference was seen in M + 1 values when those cells were incubated with [2-(13) C]acetate. Ammonia abrogated the increase in Gln content and decrease in radiolabeled Gln release in astrocytes with silenced transporters, but caused a decrease in glutamate labeling from [2 (13) C]acetate. PMID- 26442481 TI - Where do all the red blood cells (RBCs) go? Results of a survey of RBC use in England and North Wales in 2014. AB - BACKGROUND: Knowledge of blood utilization can assist clinicians in directing patient blood management (PBM) initiatives and can facilitate demand planning by blood services. We describe a national study of red blood cell (RBC) utilization in England and North Wales in 2014. STUDY DESIGN AND METHODS: All hospitals that are supplied with blood components by NHS Blood and Transplant (NHSBT) were asked to provide data on the age and sex of all recipients of transfusions of RBCs, and the clinical indication for every unit transfused, for two separate weeks in 2014. Clinical indication categories were derived from those used in previous studies in an English region. Completeness of data collection was checked against NHSBT issue and wastage data. RESULTS: Data on 46,111 RBC units were collected, representing 73% of all RBCs issued by NHSBT during the weeks surveyed. A total of 67% of RBC units were transfused for a medical indication, with 27 and 6% being transfused for surgical and obstetric/gynecologic indications, respectively. For comparison, figures from a study in the North of England in 2009, on which this national study was based, showed that 64% of RBCs were transfused to medical patients. All but 20 units could be ascribed to a broad clinical heading, for example, "gastrointestinal bleeding." CONCLUSION: Our findings confirm the previous regional finding that the percentage of RBC units that are transfused to surgical patients in England and North Wales is now much lower than for medical patients and suggest that PBM initiatives should now focus on medical patients. PMID- 26442482 TI - Beta diversity as a tool for determining priority streams for management actions. AB - Beta diversity has become essential for understanding ecosystem functioning and for determining biodiversity-conservation priority areas. However, the beta diversity patterns of invertebrates in tropical aquatic ecosystems are not well known, particularly in streams. Using data from low-order streams located in southern Brazil, we evaluated the beta diversity of Chironomidae. We tested the hypothesis that increased environmental heterogeneity increases beta diversity. The streams were grouped into two categories, rural and urban, according to the percentage of urbanization in their micro-basins. Our results showed that the heterogeneity of environmental variables can determine the beta diversity of Chironomidae, and the increased environmental heterogeneity caused by differences in the intensity of urbanization impacts can increase the beta diversity in urban streams. Therefore, the intensified impacts of anthropogenic activities in aquatic ecosystems can also increase beta diversity. Finally, we suggested that beta diversity can be an effective tool for not only designing measures and determining priority conservation areas, but also accurately identifying potentially degraded and priority sites that require water management plans. PMID- 26442483 TI - About the interest of a zooplankton compartment in pond systems: methodology to study the growth kinetic of Daphnia pulex on Scenedesmus sp. AB - A reliable characterization of cladocerans' growth kinetic on their substrates is crucial for the estimation of their biochemical conversion rate in pond models. Although many studies reported cladocerans' growth inhibitions by high chlorophyceae contents, their growth kinetics had continued to be described in many pond system models by Monod-type kinetic, which describes growth saturation by high substrate contents, but fails to explain the disappearance of cladocerans observed during chlorophyceae's bloom periods. This study aimed to develop a methodology and assess whether growth-inhibition-type models used to describe microbial growth kinetics can be applicable to cladocerans. Experiments were carried out using Daphnia pulex populations and Scenedesmus sp. First, biomass of D. pulex was measured through digital image processing (DIP) during growth experiments. Then, three candidate models (i.e., Andrews, Edward and Haldane models), along with the Monod model, were fitted to the observed data and compared. The results showed that the DIP technique provided reliable results for estimating the biomass of D. pulex. Our findings show that the candidate growth inhibition-type models satisfactorily described D. pulex's growth kinetic (86% variance accounted for). Scenesdemus sp. were not strong inhibitors of the growth of D. pulex (high inhibition constant and low half-saturation constant found). PMID- 26442484 TI - Use of multivariate calibration models based on UV-Vis spectra for seawater quality monitoring in Tianjin Bohai Bay, China. AB - A series of ultraviolet-visible (UV-Vis) spectra from seawater samples collected from sites along the coastline of Tianjin Bohai Bay in China were subjected to multivariate partial least squares (PLS) regression analysis. Calibration models were developed for monitoring chemical oxygen demand (COD) and concentrations of total organic carbon (TOC). Three different PLS models were developed using the spectra from raw samples (Model-1), diluted samples (Model-2), and diluted and raw samples combined (Model-3). Experimental results showed that: (i) possible nonlinearities in the signal concentration relationships were well accounted for by the multivariate PLS model; (ii) the predicted values of COD and TOC fit the analytical values well; the high correlation coefficients and small root mean squared error of cross-validation (RMSECV) showed that this method can be used for seawater quality monitoring; and (iii) compared with Model-1 and Model-2, Model-3 had the highest coefficient of determination (R2) and the lowest number of latent variables. This latter finding suggests that only large data sets that include data representing different combinations of conditions (i.e., various seawater matrices) will produce stable site-specific regressions. The results of this study illustrate the effectiveness of the proposed method and its potential for use as a seawater quality monitoring technique. PMID- 26442485 TI - Summertime conditions of a muddy estuarine environment: the EsCoSed project contribution. AB - As part of the Estuarine Cohesive Sediments (EsCoSed) project, a field experiment was performed in a highly engineered environment, acting as a natural laboratory, to study the physico-chemical properties of estuarine sediments and the associated hydro-morphodynamics during different seasons. The present contribution focuses on the results obtained from the summertime monitoring of the most downstream part of the Misa River (Senigallia, Italy). The measured hydrodynamics suggested a strong interaction between river current, wave forcing and tidal motion; flow velocities, affected by wind waves traveling upstream, changed significantly along the water column in both direction and magnitude. Surficial salinities in the estuary were low in the upper reaches of the estuary and exceeded 10 psu before the river mouth. Montmorillonite dominated the clay mineral assemblage, suggesting that large, low density flocs with high settling velocities (>1 mm s(-1)) may dominate the suspended aggregate materials. PMID- 26442486 TI - Leaching behavior of total organic carbon, nitrogen, and phosphorus from banana peel. AB - The leaching behavior of organic carbon and nutrient compounds from banana peel (BP) was investigated in batch assays with respect to particle size, contact time, pH value, and temperature. The granularity, contact time, pH, and temperature caused no significant effects on the leaching of total phosphorus (TP) from the BP. The maximum leached total nitrogen (TN) content was found at pH 5.0 and 90 minutes, while no significant effects were caused by the granularity and temperature. The maximum leached total organic carbon (TOC) content was found by using a powder of 40 mesh, 150 minutes and at pH 6.0, while the temperature had no effect on the TOC leaching. The proportions of the TN, TP, and TOC contents leached from the dried BP ranged from 33.6% to 40.9%, 60.4% to 72.7%, and 8.2% to 9.9%, respectively, indicating that BP could be a potential pollution source for surface and ground water if discharged as domestic waste or reutilized without pretreatment. PMID- 26442487 TI - An ecological compensation standard based on emergy theory for the Xiao Honghe River Basin. AB - The calculation of an ecological compensation standard is an important, but also difficult aspect of current ecological compensation research. In this paper, the factors affecting the ecological-economic system in the Xiao Honghe River Basin, China, including the flow of energy, materials, and money, were calculated using the emergy analysis method. A consideration of the relationships between the ecological-economic value of water resources and ecological compensation allowed the ecological-economic value to be calculated. On this basis, the amount of water needed for dilution was used to develop a calculation model for the ecological compensation standard of the basin. Using the Xiao Honghe River Basin as an example, the value of water resources and the ecological compensation standard were calculated using this model according to the emission levels of the main pollutant in the basin, chemical oxygen demand. The compensation standards calculated for the research areas in Xipin, Shangcai, Pingyu, and Xincai were 34.91 yuan/m3, 32.97 yuan/m3, 35.99 yuan/m3, and 34.70 yuan/m3, respectively, and such research output would help to generate and support new approaches to the long-term ecological protection of the basin and improvement of the ecological compensation system. PMID- 26442488 TI - Assessment of flood hazard in a combined sewer system in Reykjavik city centre. AB - Short-duration precipitation bursts can cause substantial property damage and pose operational risks for wastewater managers. The objective of this study was to assess the present and possible future flood hazard in the combined sewer system in Reykjavik city centre. The catchment is characterised by two hills separated by a plain. A large portion of the pipes in the aging network are smaller than the current minimum diameter of 250 mm. Runoff and sewer flows were modelled using the MIKE URBAN software package incorporating both historical precipitation and synthetic storms derived from annual maximum rainfall data. Results suggest that 3% of public network manholes were vulnerable to flooding during an 11-year long rainfall sequence. A Chicago Design Storm (CDS) incorporating a 10-minute rainfall burst with a 5-year return period predicted twice as many flooded manholes at similar locations. A 20% increase in CDS intensity increased the number of flooded manholes and surface flood volume by 70% and 80%, respectively. The flood volume tripled if rainfall increase were combined with urban re-development, leading to a 20% increase in the runoff coefficient. Results highlight the need for reducing network vulnerabilities, which include decreased pipe diameters and low or drastically varying pipe grades. PMID- 26442489 TI - Oxidative decomposition properties of cationic exchange resins producing SO4(2-) in power plants. AB - The sulphate content of a system increases when strong-acid cationic exchange resins leak into a system or when sulphonic acid groups on the resin organic chain detach. To solve this problem, a dynamic cycle method was used in dissolution experiments of several resins under H2O2 or residual chlorine conditions. Results show that after performing dynamic cycle experiments for 120 hours under oxidizing environments, the SO4(2-) and total organic carbon (TOC) released by four kinds of resins increased with time, contrary to their release velocity. The quantity of released SO4(2-) increased as the oxidizing ability of oxidants was enhanced. Results showed that the quantity and velocity of released SO4(2-) under residual chlorine condition were larger than those under H2O2 condition. Data analysis of SO4(2-) and TOC released from the four kinds of resins by the dynamic cycle experiment revealed that the strength of oxidation resistance of the four resins were as follows: 650C>1500H>S200>SP112H. PMID- 26442490 TI - Assessment of LID practices for restoring pre-development runoff regime in an urbanized catchment in southern Finland. AB - This study quantifies the effects of common stormwater management techniques on urban runoff generation. Simulated flow rates for different low impact development (LID) scenarios were compared with observed flow rates during different urban construction phases in a catchment (12.3 ha) that was developed from natural forest to a residential area over a monitoring period of 5 years. The Storm Water Management Model (SWMM) was calibrated and validated against the observed flow rates in the fully developed catchment conditions, and it was then applied to parameterize the LID measures and produce scenarios of their hydrological impacts. The results from the LID scenarios were compared with the observed flow rates in the pre-development and the partially developed catchment conditions. The results show that LID controls reduce urban runoff towards the flow conditions in the partially developed catchment, but the reduction effect diminishes during large rainfall events. The hydrographs with LID are still clearly different from the observed pre-development levels. Although the full restoration of pre-development flow conditions was not feasible, a combination of several measures controlling both volumes and retention times of storm runoff appeared to be effective for managing the stormwater runoff and mitigating the negative impacts of urban development. PMID- 26442491 TI - Use of geological mapping tools to improve the hydraulic performance of SuDS. AB - Most cities in Denmark are situated on low permeable clay rich deposits. These sediments are of glacial origin and range among the most heterogeneous, with hydraulic conductivities spanning several orders of magnitude. This heterogeneity has obvious consequences for the sizing of sustainable urban drainage systems (SuDS). We have tested methods to reveal geological heterogeneity at field scale to identify the most suitable sites for the placement of infiltration elements and to minimize their required size. We assessed the geological heterogeneity of a clay till plain in Eastern Jutland, Denmark measuring the shallow subsurface resistivity with a geoelectrical multi-electrode system. To confirm the resistivity data we conducted a spear auger mapping. The exposed sediments ranged from clay tills over sandy clay tills to sandy tills and correspond well to the geoelectrical data. To verify the value of geological information for placement of infiltration elements we carried out a number of infiltration tests on geologically different areas across the field, and we observed infiltration rates two times higher in the sandy till area than in the clay till area, thus demonstrating that the hydraulic performance of SuDS can be increased considerably and oversizing avoided if field geological heterogeneity is revealed before placing SuDS. PMID- 26442492 TI - Understanding the contribution of biofilm in an integrated fixed-film-activated sludge system (IFAS) designed for nitrogen removal. AB - The objective of this study is to improve knowledge on the integrated fixed-film activated sludge (IFAS) system designed for nitrogen removal. Biofilm growth and its contribution to nitrification were monitored under various operating conditions in a semi-industrial pilot-scale plant. Nitrification rates were observed in biofilms developed on free-floating media and in activated sludge operated under a low sludge retention time (4 days) and at an ammonia loading rate of 45-70 gNH4-N/kgMLVSS/d. Operational conditions, i.e. oxygen concentration, redox potential, suspended solids concentration, ammonium and nitrates, were monitored continuously in the reactors. High removal efficiencies were observed for carbon and ammonium at high-loading rate. The contribution of biofilm to nitrification was determined as 40-70% of total NOx-N production under the operating conditions tested. Optimal conditions to optimize process compacity were determined. The tested configuration responds especially well to winter and summer nitrification conditions. These results help provide a deeper understanding of how autotrophic biomass evolves through environmental and operational conditions in IFAS systems. PMID- 26442493 TI - Research on classified real-time flood forecasting framework based on K-means cluster and rough set. AB - This research presents a new classified real-time flood forecasting framework. In this framework, historical floods are classified by a K-means cluster according to the spatial and temporal distribution of precipitation, the time variance of precipitation intensity and other hydrological factors. Based on the classified results, a rough set is used to extract the identification rules for real-time flood forecasting. Then, the parameters of different categories within the conceptual hydrological model are calibrated using a genetic algorithm. In real time forecasting, the corresponding category of parameters is selected for flood forecasting according to the obtained flood information. This research tests the new classified framework on Guanyinge Reservoir and compares the framework with the traditional flood forecasting method. It finds that the performance of the new classified framework is significantly better in terms of accuracy. Furthermore, the framework can be considered in a catchment with fewer historical floods. PMID- 26442494 TI - French vertical-flow constructed wetland design: adaptations for tropical climates. AB - The French Outermost Regions are under tropical climate yet still have to comply with both French and EU regulations. French vertical-flow constructed wetland systems appear well adapted to the technical specifics of these regions but their adaptation to tropical climate requires new design guidelines to be defined (area needed, number of filters, type of plants, material to be used, etc.). A study was started in 2008, with backing from the national water authorities, to implement full-scale experimental sites and assess the impacts of local context on design and performances. This paper reports the monitoring results on three vertical-flow constructed wetlands fed directly with raw wastewater (known as the 'French system') in Mayotte and French Guiana. The plants, now in operation for between 1 and 6 years, range from 160 to 480 population equivalent (p.e.). Monitoring consisted of 28 daily composite flow samples in different seasons (dry season, rainy season) at the inlet and outlet of each filter. Performances are benchmarked against French mainland area standards from Irstea's database. Results show that performances are improved by warmer temperature for chemical oxygen demand (COD), suspended solids (SS) and total Kjeldahl nitrogen (TKN) and satisfy national quality objectives with a single stage of filters. Treatment plant footprint can thus be reduced as only two parallel filters are needed. Indeed, warm temperatures allow faster mineralization of the sludge deposit, making it possible to operate at similar rest and feeding period durations. Systems operated using one twin-filter stage can achieve over 90% COD, SS and TKN removal for a total surface of 0.8 m2/p.e. PMID- 26442495 TI - Impact on sludge inventory and control strategies using the benchmark simulation model no. 1 with the Burger-Diehl settler model. AB - An improved one-dimensional (1-D) model for the secondary clarifier, i.e. the Burger-Diehl model, was recently presented. The decisive difference to traditional layer models is that every detail of the implementation is in accordance with the theory of partial differential equations. The Burger-Diehl model allows accounting for hindered and compressive settling as well as inlet dispersion. In this contribution, the impact of specific features of the Burger Diehl model on settler underflow concentration predictions, plant sludge inventory and mixed liquor suspended solids based control actions are investigated by using the benchmark simulation model no. 1. The numerical results show that the Burger-Diehl model allows for more realistic predictions of the underflow sludge concentration, which is essential for more accurate wet weather modelling and sludge waste predictions. The choice of secondary settler model clearly has a profound impact on the operation and control of the entire treatment plant and it is recommended to use the Burger-Diehl model as of now in any wastewater treatment plant modelling effort. PMID- 26442496 TI - An investigation into the effectiveness of sand media amended with biochar to remove BOD5, suspended solids and coliforms using wetland mesocosms. AB - Constructed wetland ecotechnologies (CWEs) are a promising solution to effectively treat domestic wastewater in developing countries at low cost. This paper reports the findings of the effectiveness of sand media amended with woody biochar and two plants species (Melaleuca quinquenervia and Cymbopogon citratus) in removing biological oxygen demand (BOD5), suspended solids and coliforms. The experimental design consisted of 21 vertical flow (VF) mesocosms. There were seven media treatments using sand amended with varying proportions of biochar. During the first 8 months, the mesocosms were loaded with secondary clarified wastewater (SCW) then septage. The influent had a 4-day hydraulic retention time. Samples were monitored for BOD5, total suspended solids (TSS), total volatile solids (TVS), total coliforms and faecal coliforms. In the first 8 months, there were no significant performance differences between media treatments in the outflow concentrations of BOD5, TSS and TVS. The significant differences occurred during the last 3 months; using septage with biochar additions performed better than pure sand. For coliforms, the significant differences occurred after 6 months. In conclusion, the addition of biochar was not effective for SCW. The VF mesocosms system proved to be more effective in removing BOD5, TSS, TVS and coliforms when septage was loaded into the media. PMID- 26442497 TI - Preparation of cationic starch microspheres and study on their absorption to anionic-type substance. AB - Cationic starch microspheres (CSMs) were prepared from lab-made neutral starch based microspheres using a cationic adsorbent, namely 3-chloro-2 hydroxypropyltrimethyl ammonium chloride, as the cationic etherifying agent. Detection by scanning electron microscopy, Fourier transform infrared spectroscopy (FTIR), and laser diffraction techniques revealed that CSMs had coarse surfaces with good sphericity and dispersibility. Differential thermal analysis showed the lower thermostability of the CSMs' main chains. Furthermore, scores of experiments confirmed that CSMs are capable of absorption to N (phosphonomethyl) iminodiacetic acid (PMIDA), a type of anionic substance, which is the intermediate to the preparation of glyphosate, maximally up to 95.24 mg/g. Compared with the Freundlich isotherm model, the Langmuir isotherm model can better describe the absorption process. The kinetic study showed that the pseudo second-order model demonstrated a better correlation of the experimental data in contrast with the pseudo-first-order model. It can be therefore concluded that the rate-limiting step was the chemical absorption rather than the mass transport. PMID- 26442498 TI - Novel diesel-oil-degrading bacteria and fungi from the Ecuadorian Amazon rainforest. AB - Isolating new diesel-oil-degrading microorganisms from crude-oil contaminated sites and evaluating their degradation capacities are vitally important in the remediation of oil-polluted environments and crude-oil exploitation. In this research, new hydrocarbon-degrading bacteria and fungi were isolated from the crude-oil contaminated soil of the oil-fields in the Amazon rainforest of north east Ecuador by using a soil enrichment technique. Degradation analysis was tracked by gas chromatography and a flame ionization detector. Under laboratory conditions, maximum degradability of the total n-alkanes reached up to 77.34 and 62.62 removal ratios after 30 days of incubation for the evaporated diesel oil by fungi (isolate-1) and bacteria (isolate-1), respectively. The 16S/18S rDNA sequence analysis indicated that the microorganisms were most closely (99-100%) related to Bacillus cereus (isolate-1), Bacillus thuringiensis (isolate-2), Geomyces pannorum (isolate-1), and Geomyces sp. (isolate-2). Therefore, these strains enable the degradation of hydrocarbons as the sole carbon source, and these findings will benefit these strains in the remediation of oil-polluted environments and oil exploitation. PMID- 26442499 TI - Water-saving analysis on an effective water reuse system in biodiesel feedstock production based on Chlorella zofingiensis fed-batch cultivation. AB - The micralgae-based biofuel obtained from dairy wastewater (DWW) is considered a promising source of energy. However, this process consumes water due to the concentration of wastewater being normally too high for some micoralgae cultivation, and dilution is always needed. In this work, the cultivation of microalgae has been examined in non-recirculated water (NR) and recirculated water systems (R). The growth of Chlorella zofingiensis and the nutrient removal of DWW have been recorded. The comparison indicates the R had a little more advantage in biomass and lipid output (1.55, 0.22 g, respectively) than the NR (1.51, 0.20 g, respectively). However, the total chemical oxygen demand (COD), total Kjeldahl nitrogen (TKN), and total phosphorus (TP) removals of the R were lower than those of the NR system during the culture. The highest removal of total COD, TKN, and TP were 85.05%, 93.64%, and 98.45%, respectively. Furthermore, no significant difference has been observed in the higher heating value and lipid content of the biomass of the R and NR. The results show the R can save 30% of the total water input during the culture. All above results indicate the R system has great potential in industry. PMID- 26442500 TI - Electrochemical degradation of perfluoroalkyl and polyfluoroalkyl substances (PFASs) in groundwater. AB - Perfluoroalkyl and polyfluoroalkyl substances (PFASs) represent hazardous pollutants and are frequently detected in the environment, e.g. in contaminated groundwater. PFASs are persistent to biodegradation and conventional oxidation processes such as ozonation. In this study electrochemical degradation of PFASs on boron-doped diamond (BDD) electrodes is demonstrated. Experiments were performed with model solutions and contaminated groundwater with a dissolved organic carbon (DOC) content of 13 mg/L. The perfluorinated carboxylic acids (PFCAs) perfluorobutanoate, perfluoropentanoate, perfluorohexanoate, perfluoroheptanoate and perfluorooctanoate, and the perfluorinated sulfonic acids (PFSAs) perfluorobutane sulfonate, perfluorohexane sulfonate, perfluorooctane sulfonate and 6:2 fluorotelomer sulfonate were detected in the groundwater samples. At PFAS concentrations ranging from 0.26 to 34 mg/L (0.7 to 79 MUM), the degradation of PFASs was achieved despite of the high DOC background. Pseudo first-order kinetic constants of PFSA degradation increased with the increase of carbon chain length. Fluoride formation as well as the generation of PFCAs with shortened chain lengths was observed. Inorganic byproducts such as perchlorate were also formed and have to be considered in further process optimization. PMID- 26442501 TI - Improved light-transmission method for the study of LNAPL migration and distribution rule. AB - In this study, diesel was selected as a pollutant to study the migration and distribution rule of light non-aqueous phase liquid (LNAPL) in the simulated vadose zone. Saturation was regarded as a critical parameter to reflect the LNAPL migration and distribution rule. To get LNAPL saturation distribution figures, an image processing method of saturation was established to improve light transmission technology, which can deal with digital camera images. Results showed that the vadose zone contains three areas from top to bottom, named dry media, transition zone and capillary zone. The system has two interfaces at which moisture content increased significantly. The significant increase in moisture content induced two apparent horizontal LNAPL diffusions in the two interfaces. Furthermore, the highly saturated LNAPL was mostly distributed near the wet interface, which lay between the dry media and the transition zone. Moreover, the downstream expansion of LNAPL in the capillary zone was promoted by groundwater flow, yet cutting off LNAPL supply could stop the downstream expansion after a period of time. The accuracy of this image processing method of saturation was verified by mass balance theory and reported a relative error of 4.38%. PMID- 26442502 TI - Kupffer's vesicle size threshold for robust left-right patterning of the zebrafish embryo. AB - BACKGROUND: Motile cilia in the "organ of asymmetry" create directional fluid flows that are vital for left-right (LR) asymmetric patterning of vertebrate embryos. Organ function often depends on tightly regulated organ size control, but the role of organ of asymmetry size in LR patterning has remained unknown. Observations of the organ of asymmetry in the zebrafish, called Kupffer's vesicle (KV), have suggested significant variations in KV size in wild-type embryos, raising questions about the impact of KV organ size on LR patterning. RESULTS: To understand the relationship between organ of asymmetry size and its function, we characterized variations in KV at several developmental stages and in several different zebrafish strains. We found that the number of KV cilia and the size of the KV lumen were highly variable, whereas the length of KV cilia showed less variation. These variabilities were similar among different genetic backgrounds. By specifically modulating KV size and analyzing individual embryos, we identified a size threshold that is necessary for KV function. CONCLUSIONS: Together these results indicate the KV organ of asymmetry size is not tightly controlled during development, but rather must only exceed a threshold to direct robust LR patterning of the zebrafish embryo. PMID- 26442503 TI - Building a cognitive map by assembling multiple path integration systems. AB - Path integration and cognitive mapping are two of the most important mechanisms for navigation. Path integration is a primitive navigation system which computes a homing vector based on an animal's self-motion estimation, while cognitive map is an advanced spatial representation containing richer spatial information about the environment that is persistent and can be used to guide flexible navigation to multiple locations. Most theories of navigation conceptualize them as two distinctive, independent mechanisms, although the path integration system may provide useful information for the integration of cognitive maps. This paper demonstrates a fundamentally different scenario, where a cognitive map is constructed in three simple steps by assembling multiple path integrators and extending their basic features. The fact that a collection of path integration systems can be turned into a cognitive map suggests the possibility that cognitive maps may have evolved directly from the path integration system. PMID- 26442504 TI - A Novel Public Library-Based Sexually Transmitted Infection Screening Program for Younger High-Risk Groups in Omaha, Nebraska, USA. AB - Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are the two most commonly reported sexually transmitted infections (STIs) in the United States (U.S.) and Douglas County, Nebraska has STI rates consistently above the U.S. average. The Douglas County Health Department (DCHD) developed an outreach CT and NG screening program in public libraries to address the problem beyond the traditional STI clinic setting. This study evaluates the effectiveness of the program and identifies factors predictive of CT and NG infections. A retrospective review of surveys of library patrons and DCHD traditional STI clinic clients who submitted urine tests for CT and NG from June 2010 through April 2014 was done. Chi square, Fisher exact, Student's t tests, univariate and multivariate logistic regression were conducted. A total of 977 library records and 4871 DCHD clinic records were reviewed. The percent positive was lower in the library than in the traditional clinic for CT (9.9 vs. 11.2 %) and NG (2.74 vs. 5.3 %) (p = 0.039 and p < 0.001, respectively). Library clients were more likely to be 19 years and younger (OR 6.14, 95 % CI: 5.0, 7.5), Black (OR 3.4, 95 % CI: 2.8, 4.1), and asymptomatic (OR 12.4, 95 % CI: 9.9, 15.5) compared to traditional clinic clients. The library STI screening program effectively reaches a younger, asymptomatic, and predominantly Black population compared to a traditional health department clinic site. PMID- 26442505 TI - Escherichia coli and the Emergence of Molecular Biology. AB - The creation of the "Phage group" by M. Delbruck, S. E. Luria, and A. D. Hershey in 1940 at Cold Spring Harbor played a crucial role in the development of molecular biology. In the 1940s, working with Escherichia coli and its viruses, Luria and Delbruck discovered the spontaneous nature of bacterial mutations and Hershey described recombination in bacteriophages and demonstrated with M. Chase that the genetic material that infects bacteria is DNA. At the same time, S. Benzer defined the structure of a functional genetic unit and J. Lederberg and E. Tatum discovered sexual recombination between bacteria. Some years later, Lederberg's group discovered extrachromosomal particles, the plasmids, and a novel way of genetic transfer through bacteriophages, called transduction. In 1949, at the Pasteur Institute in Paris, A. Lwoff uncovered the mechanism of lysogeny. Shortly afterwards, F. Jacob and E. Wollman unraveled the mechanism of the sexual process in E. coli and established the circularity of the bacterial chromosome. In the 1960s, J. Monod and F. Jacob, by genetic analysis of the E. coli lactose system, proposed the operon model for gene regulation and introduced the concept of messenger RNA. The elucidation of the double helix structure of DNA in 1953 by F. Crick and J. Watson had major consequences: the establishment of the copying mechanism (Meselson and Stahl), the discovery of the nature of the genetic code (S. Brenner) leading to its deciphering. E. coli and its phages were instrumental in the development of recombinant DNA technology based on the discovery of the restriction-modification system by W. Arber. PMID- 26442507 TI - Stationary-Phase Gene Regulation in Escherichia coli S. AB - In their stressful natural environments, bacteria often are in stationary phase and use their limited resources for maintenance and stress survival. Underlying this activity is the general stress response, which in Escherichia coli depends on the sigmaS (RpoS) subunit of RNA polymerase. sigmaS is closely related to the vegetative sigma factor sigma70 (RpoD), and these two sigmas recognize similar but not identical promoter sequences. During the postexponential phase and entry into stationary phase, sigmaS is induced by a fine-tuned combination of transcriptional, translational, and proteolytic control. In addition, regulatory "short-cuts" to high cellular sigmaS levels, which mainly rely on the rapid inhibition of sigmaS proteolysis, are triggered by sudden starvation for various nutrients and other stressful shift conditons. sigmaS directly or indirectly activates more than 500 genes. Additional signal input is integrated by sigmaS cooperating with various transcription factors in complex cascades and feedforward loops. Target gene products have stress-protective functions, redirect metabolism, affect cell envelope and cell shape, are involved in biofilm formation or pathogenesis, or can increased stationary phase and stress-induced mutagenesis. This review summarizes these diverse functions and the amazingly complex regulation of sigmaS. At the molecular level, these processes are integrated with the partitioning of global transcription space by sigma factor competition for RNA polymerase core enzyme and signaling by nucleotide second messengers that include cAMP, (p)ppGpp, and c-di-GMP. Physiologically, sigmaS is the key player in choosing between a lifestyle associated with postexponential growth based on nutrient scavenging and motility and a lifestyle focused on maintenance, strong stress resistance, and increased adhesiveness. Finally, research with other proteobacteria is beginning to reveal how evolution has further adapted function and regulation of sigmaS to specific environmental niches. PMID- 26442506 TI - Homologous Recombination-Experimental Systems, Analysis, and Significance. AB - Homologous recombination is the most complex of all recombination events that shape genomes and produce material for evolution. Homologous recombination events are exchanges between DNA molecules in the lengthy regions of shared identity, catalyzed by a group of dedicated enzymes. There is a variety of experimental systems in Escherichia coli and Salmonella to detect homologous recombination events of several different kinds. Genetic analysis of homologous recombination reveals three separate phases of this process: pre-synapsis (the early phase), synapsis (homologous strand exchange), and post-synapsis (the late phase). In E. coli, there are at least two independent pathway of the early phase and at least two independent pathways of the late phase. All this complexity is incongruent with the originally ascribed role of homologous recombination as accelerator of genome evolution: there is simply not enough duplication and repetition in enterobacterial genomes for homologous recombination to have a detectable evolutionary role and therefore not enough selection to maintain such a complexity. At the same time, the mechanisms of homologous recombination are uniquely suited for repair of complex DNA lesions called chromosomal lesions. In fact, the two major classes of chromosomal lesions are recognized and processed by the two individual pathways at the early phase of homologous recombination. It follows, therefore, that homologous recombination events are occasional reflections of the continual recombinational repair, made possible in cases of natural or artificial genome redundancy. PMID- 26442510 TI - The Origin of Mutants under Selection: Interactions of Mutation, Growth, and Selection. AB - The classical experiments of Luria and Delbruck showed convincingly that mutations exist before selection and do not contribute to the creation of mutations when selection is lethal. In contrast, when nonlethal selections are used,measuring mutation rates and separating the effects of mutation and selection are difficult and require methods to fully exclude growth after selection has been applied. Although many claims of stress-induced mutagenesis have been made, it is difficult to exclude the influence of growth under nonlethal selection conditions in accounting for the observed increases in mutant frequency. Instead, for many of the studied experimental systems the increase in mutant frequency can be explainedbetter by the ability of selection to detect small differences in growth rate caused by common small effect mutations. A verycommon mutant class,found in response to many different types of selective regimensin which increased gene dosage can resolve the problem, is gene amplification. In the well-studiedlac system of Cairns and Foster, the apparent increase in Lac+revertants can be explained by high-level amplification of the lac operon and the increased probability for a reversion mutation to occur in any one of the amplified copies. The associated increase in general mutation rate observed in revertant cells in that system is an artifact caused by the coincidental co-amplification of the nearby dinB gene (encoding the error-prone DNA polymerase IV) on the particular plasmid used for these experiments. Apart from the lac system, similar gene amplification processes have been described for adaptation to toxic drugs, growth in host cells, and various nutrient limitations. PMID- 26442511 TI - Translation Initiation. AB - Selection of correct start codons on messenger RNAs is a key step required for faithful translation of the genetic message. Such a selection occurs in a complex process, during which a translation-competent ribosome assembles, eventually having in its P site a specialized methionyl-tRNAMet base-paired with the start codon on the mRNA. This chapter summarizes recent advances describing at the molecular level the successive steps involved in the process. Special emphasis is put on the roles of the three initiation factors and of the initiator tRNA, which are crucial for the efficiency and the specificity of the process. In particular, structural analyses concerning complexes containing ribosomal subunits, as well as detailed kinetic studies, have shed new light on the sequence of events leading to faithful initiation of protein synthesis in Bacteria. PMID- 26442508 TI - The DNA Exonucleases of Escherichia coli. AB - DNA exonucleases, enzymes that hydrolyze phosphodiester bonds in DNA from a free end, play important cellular roles in DNA repair, genetic recombination and mutation avoidance in all organisms. This article reviews the structure, biochemistry, and biological functions of the 17 exonucleases currently identified in the bacterium Escherichia coli. These include the exonucleases associated with DNA polymerases I (polA), II (polB), and III (dnaQ/mutD); Exonucleases I (xonA/sbcB), III (xthA), IV, VII (xseAB), IX (xni/xgdG), and X (exoX); the RecBCD, RecJ, and RecE exonucleases; SbcCD endo/exonucleases; the DNA exonuclease activities of RNase T (rnt) and Endonuclease IV (nfo); and TatD. These enzymes are diverse in terms of substrate specificity and biochemical properties and have specialized biological roles. Most of these enzymes fall into structural families with characteristic sequence motifs, and members of many of these families can be found in all domains of life. PMID- 26442509 TI - Assembly of Outer Membrane beta-Barrel Proteins: the Bam Complex. AB - The major class of integral proteins found in the outer membrane (OM) of E. coli and Salmonella adopt a beta-barrel conformation (OMPs). OMPs are synthesized in the cytoplasm with a typical signal sequence at the amino terminus, which directs them to the secretion machinery (SecYEG) located in the inner membrane for translocation to the periplasm. Chaperones such as SurA, or DegP and Skp, escort these proteins across the aqueous periplasm protecting them from aggregation. The chaperones then deliver OMPs to a highly conserved outer membrane assembly site termed the Bam complex. In E. coli, the Bam complex is composed of an essential OMP, BamA, and four associated OM lipoproteins, BamBCDE, one of which, BamD, is also essential. Here we provide an overview of what we know about the process of OMP assembly and outline the various hypotheses that have been proposed to explain how proteins might be integrated into the asymmetric OM lipid bilayer in an environment that lacks obvious energy sources. In addition, we describe the envelope stress responses that ensure the fidelity of OM biogenesis and how factors, such as phage and certain toxins, have coopted this essential machine to gain entry into the cell. PMID- 26442512 TI - Primary stability of rotator cuff repair: can more suture materials yield more strength? AB - INTRODUCTION: It remains unclear if the increased biomechanical stability of the double-row repair is solely a result of the technique itself or due to the greater number of utilized materials. This study analyses the various rotator cuff (RC) repair interfaces and the influence of doubling the number of suture knots, stitch techniques and suture anchors on the primary stability of the RC reconstruction. MATERIALS AND METHODS: Established cyclic testing protocols were used to test the primary stability of the knot interface with a Duncan loop and Roeder knot, the tendon-to-suture interface with a single-stitch and Mason-Allen stitch and the anchor-to-bone interface with OPUS Magnum 2(r) and BioCorkscrew(r) anchors. After doubling the materials, the interfaces were tested again and compared to the yielded solitary values. The maximum failure loads (Fmax), clinical failure (CF), system displacement (SD) and modes of failure were recorded. RESULTS: Doubling the amount of knots, stitches and suture anchors improved almost all interface parameters. For example, Fmax, CF and SD of the Roeder knot could be significantly improved from 142.5 N to 256.7 N, from 82.5 N to 155.0 N and from 0.45 mm to 0.20 mm, respectively. The Mason-Allen stitch's Fmax improved from 196.4 N to 324.9 N, and CF from 94.25 N to 139.8 N, with almost identical SD of 0.81 mm and 0.84 mm. Bio-Corkscrew(r) Fmax improved from 232.5 N to 317.5 N, CF from 182.5 N to 210 N, and SD from 0.85 mm to 0.64 mm. CONCLUSION: Doubling the number of knots, stitches and suture anchors increases the primary stability of the various RC repair interfaces and may result in RC rerupture rate reduction. Furthermore, this study suggests that a suture anchor loaded with two or three sutures may yield the same primary stability as two or three suture anchors loaded with a single suture. This in vitro biomechanical study focuses solely on the rotator cuff interfaces at time zero; the biological healing process was therefore not analysed and requires further investigation. CLINICAL RELEVANCE: Improved primary stability by increased number of suture materials may reduce rate of RC rerupture. PMID- 26442513 TI - Artocarpus altilis CG-901 alters critical nodes in the JH1-kinase domain of Janus kinase 2 affecting upstream JAK/STAT3 signaling. AB - As a key step in achieving low-cost, easily accessible anti-cancer therapy for low- and middle-income countries, we recently established the scientific basis for the folkloric use of Artocarpus altilis for the treatment of cancer by investigating the geranyl dihydrochalcone (CG-901) content and its interference with signal transducer and activator of transcription 3 (STAT3) phosphorylation and blockage of further downstream signaling. In the current study, the CG-901 upstream target was queried by chemical fingerprinting similarity assessment, semi-empirical (PM6ESCF) QMMM and molecular dynamics (MD) simulation. Moderate (~0.4) to high (~0.7) Tanimoto scores were found when the CG-901 scaffold was compared to ligands co-crystallized with Janus kinases (JAK) 1-3. High negative energy values were obtained when the CG-901 was treated semi-empirically (PM6ESCF) within the classical field of JAK (1-3). Multiple nanosecond MD simulations showed that CG-901 did not cause any large structural perturbations in the nucleotide-binding, activation and catalytic loops within the kinase (JH1) domain of JAK (1-3); however, it reduced the energy required to attain metastability along the path to energy minima conformation. In comparison to JAK1 and Apo-state JAK2, JAK2-bound CG-901 exhibited a highly re-organized key intra domain protein network; indicating atomic level interference with inter-residue communication. In conclusion, CG-901 isolated from A. altilis represents a broad spectrum JAK inhibitor, which may underlie the mechanism of STAT3 phosphorylation blockage. Graphical abstract Upper panel Janus kinase 2 upstream signaling pathway. Lower panel Apo-JAK2 (left) and CG-901-bound JAK2 (right). PMID- 26442514 TI - Effect of the association of 1-methyl-DL-tryptophan with paclitaxel on the expression of indoleamine 2,3-dioxygenase in cultured cancer cells from patients with breast cancer. AB - Breast cancer is the most common type of cancer among women and the survival of patients affected by it is increasing, mainly due to several new approaches in early diagnosis and more effective treatments. The enzyme indoleamine 2,3 dioxygenase (IDO) is expressed in many cells, including tumor cells. IDO acts by inhibiting the proliferation of T lymphocytes, thus compromising their cytotoxic activity. 1-Methyl-DL-tryptophan (1MT) is a competitive inhibitor of IDO, which blocks its immunosuppressive effect. Paclitaxel is an antineoplastic drug largely used in breast cancer therapy. Thus, this study aimed to determine the in vitro effect of the association of 1MT and paclitaxel chemotherapy, as an approach to reduce tumor growth. It is believed that this would allow the restoration of T lymphocyte proliferation capability and its cytotoxic response. The supplemented cultures showed that the most significant differences in the expression of IDO were observed in the group treated with paclitaxel associated with 1-MT continuous supplementation, reducing enzyme expression from 12.06 to 3.56 %. This association was more effective in reducing IDO expression and could collaborate in developing a new therapeutic strategy for breast cancer treatment. PMID- 26442516 TI - Nocardioides glacieisoli sp. nov., isolated from a glacier. AB - A Gram-stain-positive, rod-shaped, non-spore-forming bacterium (strain HLT3-15T) was isolated from the ice tongue surface of the Hailuogou glacier in Szechwan Province, PR China. Phylogenetic analysis, based on 16S rRNA gene sequences, revealed that strain HLT3-15T belonged to the genus Nocardioides. The highest levels of sequence similarities were found with Nocardioides hwasunensis CGMCC 4.6881T and Nocardioides ganghwensis CGMCC 4.6875T (98.5 % and 98.3 %, respectively). However, DNA-DNA relatedness demonstrated that strain HLT3-15T was distinct from its closest phylogenetic neighbours. The major cellular fatty acids of strain HLT3-15T were C17 : 1omega8c and iso-C16 : 0. Strain HLT3-15T contained ll-2,6-diaminopimelic acid as the diamino acid in the cell-wall peptidoglycan and MK-8(H4) as the predominant menaquinone. On the basis of a polyphasic approach, a novel species, Nocardioides glacieisoli sp. nov., is proposed with HLT3-15T ( = CGMCC 1.11097T = NBRC 109781T) as the type strain. PMID- 26442517 TI - Biosimilar versions of anti-TNF drugs could save NHS money, drug company claims. PMID- 26442515 TI - Clinicopathologic characteristics of anterior prostate cancer (APC), including correlation with previous biopsy pathology. AB - Anterior-predominant prostate cancer (APC) is an incompletely understood entity which can be difficult to sample via transrectal biopsy. Seemingly favorable biopsy results may belie the potential aggressiveness of these tumors. Here, we attempt to characterize APC by retrospectively examining the clinicopathologic features of APC at radical prostatectomy and comparing our findings with prior biopsy information. We found that 17.4 % of patients in our study had APC. APC demonstrated a significantly lower (P value < 0.05) Gleason score (GS) and pathologic stage than non-APC tumors, including the absence of seminal vesicle invasion by APC. A subset (5.6 %) of APC consisted of high-grade tumors (GS >= 8), and these tumors were more often detected on transperineal saturation biopsy than non-transperineal saturation (i.e., transrectal ultrasound guided) biopsy strategies. Four patients (7 %) without transperineal saturation biopsy exhibited a significantly worse GS at RP than biopsy, compared to five patients (36 %) with transperineal saturation biopsy. Our findings corroborate the difficulty in detecting APC and suggest that APC is not a uniform disease with a wholly indolent phenotype. Dedicated long-term outcome data are needed in these patients. Additionally, alternative pathologic staging parameters may be necessary. PMID- 26442518 TI - Time to invest in developing community mental health services. AB - OBJECTIVES: To report on the evaluation of publicly funded community mental health services in two New South Wales health districts. METHODS: Qualitative and quantitative data from 28 publicly funded adult community mental health teams in two NSW health districts were gathered using structured interviews, benchmarking surveys, focus groups and online questionnaires. RESULTS: The community mental health services studied lacked a coherent strategic and recovery oriented framework or model of care for service delivery. There was evidence of poor role definition at the team level, resulting in duplication and inefficiency. There were inadequate staffing levels for stated objectives, a lack of training and continuing education in evidence based intervention, poor consumer and family participation in service design, and no development and monitoring of meaningful outcome measures. CONCLUSIONS: This review and benchmarking study highlights the need for mental health policy implementation to be further supported with: development of a service delivery framework outlining essential components of a specialist community mental health system; operational guidance to enable effective team specialisation in accordance with research; investment in practitioner training to support the development of evidence based practice; and processes to ensure effective consumer and carer participation in developing recovery oriented services. PMID- 26442519 TI - Transcranial direct current stimulation in the male mouse to promote recovery after stroke. AB - Transcranial direct current stimulation (tDCS) constitutes a promising approach for promoting recovery of function after stroke, although the underlying neurobiological mechanisms are unclear. To conduct translational research in animal models, stimulation parameters should not lead to neuronal lesions. Liebetanz et al. recommend charge densities for cathodal stimulation in rats, but parameters for mice are not established. We established tDCS in the wild-type mouse, enabling studies with genetically-engineered mice (GEM). tDCS equipment was adapted to fit the mouse skull. Using different polarities and charge densities, tDCS was safe to apply in the mouse where the charge density was below 198 kC/m(2) for single or repeated stimulations. These findings are crucial for future investigations of the neurobiological mechanisms underlying tDCS using GEM. PMID- 26442521 TI - Body Mass Index, Outcomes, and Mortality Following Cardiac Surgery in Ontario, Canada. PMID- 26442520 TI - Neoplastic cauda equina syndrome: a neuroimaging-based review. AB - Cauda equina syndrome refers to dysfunction of the cauda equina, the collection of ventral and dorsal lumbar, sacral and coccygeal nerve roots that surround the filum terminale. This most commonly occurs as a result of compression by a herniated lumbosacral disc. However, the syndrome may also complicate metastatic cancer or a primary neoplasm within or infiltrating the spinal canal. An accurate and timely diagnosis is critical to avoid irreversible loss of neurological function. The clinician and radiologist must therefore be aware of the many possible causes to guide timely management. Here we review the diverse neoplastic causes affecting the cauda equina nerve roots from a neuroimaging-based perspective. We divide them by location into intramedullary neoplasms at the conus (such as astrocytoma), intradural-extramedullary neoplasms (such as schwannoma and leptomeningeal metastases) and extradural neoplasms (such as spinal metastases from systemic neoplasms). We also discuss the clinical features associated with cauda equina tumours, with special focus on cauda equina syndrome. PMID- 26442522 TI - Pursuing a Desired Future: Continuity and Change in a Long-Term-Care Community. AB - New ways of planning, assessing, and measuring cultural change are needed in long term care. Much effort is focused on person-centered care; less attention is paid to achieving localized change. Long-term-care communities need innovative approaches for identifying local cultural features to preserve and others to reconfigure. This case study involves applied anthropologists working with four stakeholder groups-residents, staff, family members, and volunteers-to document views of their "culture story" and conceptualize a cultural ideal for their community. Based on strengths and weaknesses from their culture story, specific recommendations were made to maintain their strong relationship focus, expand community outreach, and improve staff relations. Incorporating "insider" views of the past, present, and imagined future and building on current "best practices" of the culture-change movement are two distinctive but complementary approaches for motivating and managing cultural change. PMID- 26442523 TI - Integrated Pharmacokinetic/Pharmacodynamic Analysis for Determining the Minimal Anticipated Biological Effect Level of a Novel Anti-CD28 Receptor Antagonist BMS 931699. AB - BMS-931699 (lulizumab pegol), a domain antibody (dAb) conjugated with 40-kDa branched polyethylene glycol, is a human anti-CD28 receptor antagonist under development for the treatment of inflammatory and autoimmune diseases. In the present work, the minimal anticipated biologic effect level (MABEL) was determined for BMS-931699 by integrating all the available preclinical data. The relevance of the in vitro mixed lymphocyte reaction (MLR) assay to a whole blood CD28 receptor occupancy (RO) assessment, as well as the relationship between the CD28 RO and the inhibition of T-cell-dependent antibody response to keyhole limpet hemocyanin in vivo, was demonstrated through an integrated pharmacokinetic/pharmacodynamic analysis using anti-hCD28 dAb-001 (differing from BMS-931699 by two additional amino acids at the N-terminus) and a mouse surrogate. Based on this analysis, the EC10 value (0.32 nM) from the human MLR assay and the human plasma volume (0.04 l/kg) were employed to calculate the MABEL (0.01 mg) of BMS-931699 in humans, with a CD28 RO predicted to be <=10%. The estimated MABEL dose was threefold higher than the value derived from the binding constant and twofold less than the MABEL converted from animal efficacy studies based on the body surface area. Furthermore, it was 2900-fold lower than the human equivalent dose derived from the no observed adverse effect level in monkeys (15 mg/kg/week for 5 doses, intravenous dosing) with a 10-fold safety factor applied. Therefore, the MABEL dose represented a sound approach to mitigate any potential risk in targeting CD28 and was successfully used as the first-in-human starting dose for BMS-931699. PMID- 26442524 TI - MicroRNA-218 is a prognostic indicator in colorectal cancer and enhances 5 fluorouracil-induced apoptosis by targeting BIRC5. AB - One major reason for the failure of advanced colorectal cancer (CRC) treatment is the occurrence of chemoresistance to fluoropyrimidine (FU)-based chemotherapy. Various reports showed that ectopic expression and function of microRNAs (miRNAs) played key roles to mediate apoptosis at the post-transcriptional level. To further explore the possible mechanisms, we evaluated the prognostic effect of miR-218 in patients with CRC receiving 5-FU-based treatment and investigated the proapoptotic role of miR-218 in vitro. Primary tumour specimens and adjacent non tumour sites were used to determine miR-218 expression distribution and explore its potential prognostic value in response to 5-FU-based treatment in patients with CRC. HCT116 and HT29 cells were transfected with precursor miR-218 or negative control, followed by assays to investigate its influence on apoptosis, cell proliferation and pathways involved in molecular mechanisms of chemoresistance to 5-FU. Results showed that high miR-218 expression was associated with positive response to firstline 5-FU treatment in CRC patients. MiR-218 promoted apoptosis, inhibited cell proliferation and caused cell cycle arrest in CRC cells by suppressing BIRC5 expression. Furthermore, miR-218 enhanced 5-FU cytotoxicity in CRC cells by suppressing the 5-FU targeted enzyme, thymidylate synthase (TS). In conclusion, we demonstrated that high miR-218 expression had a positive prognostic value in 5-FU-based treatments for CRC patients and discovered a novel mechanism mediated by miR-218 to promote apoptosis and to function synergistically with 5-FU to promote chemosensitivity by suppressing BIRC5 and TS in CRC. These suggest the unique potential of miR-218 as a novel candidate for developing miR-218-based therapeutic strategies in CRC. PMID- 26442525 TI - Restoration of paclitaxel resistance by CDK1 intervention in drug-resistant ovarian cancer. AB - Epithelial ovarian cancer (EOC) commonly acquires resistance to chemotherapy, and this is the major obstacle to the better prognosis. Elucidating the molecular targets altered by chemotherapy is critically required to understand and overcome drug resistance. As a drug combination including paclitaxel is a prevalent prescription for treatment of EOC, to uncover gene expression altered in paclitaxel-resistant EOC, we analyzed multidirectional microarray profiles in both EOC cell lines and patients with paclitaxel resistance. Cyclin-dependent kinase 1 (CDK1) was found to be a potential target of transcription factors to regulate paclitaxel resistance. As a result of the subsequent pharmacogenomics analysis, CDK1 inhibitor alsterpaullone was also indicated as a promising chemical that may be used in combinatorial therapies to reverse paclitaxel induced chemoresistance. Although a CDK1 inhibitor has the potential to kill cancer cells, short-term treatment over 2 weeks at sublethal doses effectively induced cell death only upon additional treatment with paclitaxel. A prominent reduction in the tumor growth rate was observed upon paclitaxel subsequent to alsterpaullone treatment in EOC xenograft model. Thus, we suggest that inhibition of CDK1 with alsterpaullone may be a novel therapeutic method to reverse paclitaxel-induced resistance in ovarian cancer cells. PMID- 26442526 TI - Assessment of transthoracic ultrasound diagnosis of ovine pulmonary adenocarcinoma in adult sheep. AB - Ovine pulmonary adenocarcinoma (OPA), caused by Jaagsiekte sheep retrovirus (JSRV), is a disease of increasing concern in the sheep industry. There is no commercial antemortem test for OPA; therefore, an early evaluation phase study was undertaken to examine the accuracy of transthoracic ultrasound examination using a 5-6.5 MHz sector ultrasound machine widely available in veterinary practice in the UK to diagnose OPA. Restraint, preparation and examination time was restricted to five minutes per sheep to represent the cost limitations of commercial sheep farming. One hundred sheep were examined. All 41 cases identified with suspect OPA lesions during transthoracic ultrasound examination had the diagnosis confirmed at postmortem examination, while sheep without ultrasonographic changes characteristic of OPA had no gross lesions of OPA at postmortem examination. This demonstrates the specificity of transthoracic ultrasound for diagnosis of OPA. The authors propose that, in the absence of any other reliable preclinical diagnostic test, the use of transthoracic ultrasound examination should be considered for a second opinion on an initial diagnosis of OPA, for screening purchased adult flock replacements for OPA, or for screening sheep in a known OPA-affected flock. However, the authors emphasise that a negative scan cannot provide a guarantee that the animal is free of JSRV infection nor early OPA. PMID- 26442527 TI - Enucleation in equids with and without the use of an orbital suture meshwork implant: a retrospective study of 37 cases. AB - This retrospective study on 37 horses was conducted to assess long-term complications, scarring, cosmetic appearance and owner satisfaction of horses that underwent transpalpebral enucleation with (n=26) or without (n=11) non absorbable sutured meshwork prosthesis between 2006 and 2013. Postoperative complications related to the surgery were wound infection, discharge and dehiscence, and no significant difference between groups was found. In one horse, the meshwork had to be removed in order to treat a chronic fistula. Horses with infection or inflammation before surgery were more likely to encounter postoperative complications, whether or not a meshwork was used. Most owners were satisfied by the surgical technique for scarring, but contrary to the present hypothesis, most horses with a meshwork implant had a poor sunken-in appearance, and 26 per cent of owners would like to attempt other techniques to improve the cosmetic result. Also, a further 44 per cent of owners would prefer a better cosmetic result if the technique does not increase complication risk or cost. Meshwork implant prosthesis after transpalpebral enucleation was safe. However, in order to achieve a better cosmetic result, further improvements of the technique will be required. PMID- 26442530 TI - The Effect of Levetiracetam on Closure of the Midline in Early Chicken Embryos. AB - AIM: Genetic predisposition and some environmental factors play an important role in the development of neural tube defects. Levetiracetam is a new drug that has been approved in the treatment of partial seizures. We aimed in this study to determine the effect of levetiracetam on chick embryos. MATERIAL AND METHODS: One hundred and sixty fertile non-pathogenic Super Nick eggs were incubated for 24 hours and were divided into four groups of 40 eggs each. Levetiracetam was administered via the sub-blastodermic route. The eggs were incubated for another 24 hours. All eggs were opened at the 48th hour, and the embryos were evaluated morphologically and histopathologically. RESULTS: The effects of levetiracetam on the embryo were correlated with the dose of levetiracetam. In the light of the results, it was determined that the use of increasing doses of levetiracetam led to defects of midline closure in early chicken embryos. CONCLUSION: Levetiracetam, a new antiepileptic drug that is effective especially on calcium ion concentration, leads to defects in midline closure in embryos in a dose dependent manner. Further studies are needed to show the mechanism of embryonic damage and the mechanisms of its teratogenous effects associated with genetic and environmental factors. PMID- 26442531 TI - Lumbar Microdiscectomy Under Spinal and General Anesthesia: A Comparative Study. AB - AIM: To compare the safety and efficacy of spinal anesthesia (SA) in patients undergoing lumbar microdiscectomy (LM). MATERIAL AND METHODS: We evaluated 180 patients who underwent LM between 1 January 2012 and 5 July 2013. Demographic, clinical, laboratory, and pre-, intra-, and postoperative information was determined from the patients' medical records. RESULTS: Total anesthetic times were longer in the general anesthesia (GA) group. There was less bleeding at the surgical site in the SA group. Intraoperative blood pressure was significantly also lower in the SA group. Meanwhile, tachycardia was significantly higher in the GA group. The analgesic requirement in post-anesthesia care unit (PACU) was higher in the general anesthesia group. At PACU admission, analgesic requirement, heart rate, and the mean arterial pressure were higher in the GA group. Postoperative nausea and vomiting was more frequent among patients recovering in general anesthesia group. SA patients had an increased incidence of urinary retention compared with GA patients. Pulmonary complications requiring specific treatment were insignificantly higher among GA patients. CONCLUSION: In patients who undergo lumbar disc surgery, SA is a good alternative for experienced surgeons because of a more comfortable healing process. PMID- 26442532 TI - Clinical Features and Surgical Treatment of Aggressive Meningiomas. AB - AIM: To explore the clinical features and surgical treatment of aggressive meningiomas (AMs). MATERIAL AND METHODS: Samples from 55 patients with AMs were analyzed, and their clinical characteristics, molecular biological mechanism, and surgical treatment were studied in combination with the literature. RESULTS: The main clinical and imaging features of AMs included manifestations of local structures invaded by tumors, frequently irregular or flat tumors in shape, more obvious cerebral edema surrounding the tumors, seldom calcification of tumor, more frequent and typical dural tail sign, often absent white or black ring sign, partial or complete occlusion of venous sinus and hyperplasia and destruction of local skull. Simpson I resection was achieved in 31 cases, II in 13, III-IV in 11. No severe complications and death occurred after operation. CONCLUSION: AMs have prominent clinical features. Appropriate surgery can provide a good therapeutic effect. PMID- 26442528 TI - Genomes to natural products PRediction Informatics for Secondary Metabolomes (PRISM). AB - Microbial natural products are an invaluable source of evolved bioactive small molecules and pharmaceutical agents. Next-generation and metagenomic sequencing indicates untapped genomic potential, yet high rediscovery rates of known metabolites increasingly frustrate conventional natural product screening programs. New methods to connect biosynthetic gene clusters to novel chemical scaffolds are therefore critical to enable the targeted discovery of genetically encoded natural products. Here, we present PRISM, a computational resource for the identification of biosynthetic gene clusters, prediction of genetically encoded nonribosomal peptides and type I and II polyketides, and bio- and cheminformatic dereplication of known natural products. PRISM implements novel algorithms which render it uniquely capable of predicting type II polyketides, deoxygenated sugars, and starter units, making it a comprehensive genome-guided chemical structure prediction engine. A library of 57 tailoring reactions is leveraged for combinatorial scaffold library generation when multiple potential substrates are consistent with biosynthetic logic. We compare the accuracy of PRISM to existing genomic analysis platforms. PRISM is an open-source, user friendly web application available at http://magarveylab.ca/prism/. PMID- 26442529 TI - NCLscan: accurate identification of non-co-linear transcripts (fusion, trans splicing and circular RNA) with a good balance between sensitivity and precision. AB - Analysis of RNA-seq data often detects numerous 'non-co-linear' (NCL) transcripts, which comprised sequence segments that are topologically inconsistent with their corresponding DNA sequences in the reference genome. However, detection of NCL transcripts involves two major challenges: removal of false positives arising from alignment artifacts and discrimination between different types of NCL transcripts (trans-spliced, circular or fusion transcripts). Here, we developed a new NCL-transcript-detecting method ('NCLscan'), which utilized a stepwise alignment strategy to almost completely eliminate false calls (>98% precision) without sacrificing true positives, enabling NCLscan outperform 18 other publicly-available tools (including fusion- and circular-RNA-detecting tools) in terms of sensitivity and precision, regardless of the generation strategy of simulated dataset, type of intragenic or intergenic NCL event, read depth of coverage, read length or expression level of NCL transcript. With the high accuracy, NCLscan was applied to distinguishing between trans-spliced, circular and fusion transcripts on the basis of poly(A)- and nonpoly(A)-selected RNA-seq data. We showed that circular RNAs were expressed more ubiquitously, more abundantly and less cell type-specifically than trans spliced and fusion transcripts. Our study thus describes a robust pipeline for the discovery of NCL transcripts, and sheds light on the fundamental biology of these non-canonical RNA events in human transcriptome. PMID- 26442533 TI - Vena Cava Filters are not Superior to Low Molecular Weight Heparin in Venous Thromboembolism Prophylaxis: A Study on Long-Term Immobilized Neurosurgical Patients. AB - AIM: Deep venous thrombosis (DVT) and pulmonary embolism (PE) are the most frequent surgical problems and associated with high morbidity and mortality. Neurosurgical patients constitute a unique group where prophylaxis with anticoagulant and antiaggregant agents are relatively contraindicated due to the natural course of vascular problems such as aneurysms, hemorrhagic tumors or hematomas or increased vulnerability to complex spinal surgeries and trauma. MATERIAL AND METHODS: We included 67 patients predicted to be immobilized for 2 or more months in this retrospective analysis. A vena cava filter was inserted between the first and seventh postoperative day in 40 patients in a prophylactic manner whereas 27 patients received low dose heparin for the same purpose. The patients were evaluated for symptomatic DVT or PE. RESULTS: Percutaneous insertion was performed for all filters without any complication. DVT occurred in two patients of the filter group and 1 patient of the heparin group. There was no PE recorded in any patient of either group. Patients were followed up for 22 months in the filter and 16 months in the heparin group. CONCLUSION: We conclude that prophylactic filter use in high risk neurosurgical patients is not beneficial and not superior to low-molecular-weight heparin use. Nevertheless, it is reasonable to prevent PE in patients with proven DVT who have no contraindication for anticoagulant drugs. PMID- 26442534 TI - The Role of Wrist Magnetic Resonance Imaging in the Differential Diagnosis of the Carpal Tunnel Syndrome. AB - AIM: The carpal tunnel syndrome (CTS) is the commonest compressive neuropathy. Electromyography (EMG) is accepted as gold standard in diagnosis of CTS. However, pathologies and variations that are associated with a various findings may lead to failure. MATERIAL AND METHODS: Magnetic resonance Imaging (MRI) was applied to 69 wrists of 55 patients, who received a diagnosis of CTS by means of clinical and electrodiagnostic testing (EDT) during the years 2011 and 2013. RESULTS: We detected a total of 71 additional pathologies in MRI analyses: 29 degenerative bone cysts, 28 ganglion cysts, 8 tenosynovitis, and 6 avascular necroses. While the MRI detected 44 (59.5%) additional radiological pathologies in 39 wrists diagnosed with mid-level CTS by means of EMG, the number of detected additional pathologies was 27 (36.5%) in 30 wrists diagnosed with advanced-level CTS. CONCLUSION: Wrist MRI is an effective means to reveal associated pathologies in patients diagnosed with CTS by means of clinical testing and EDT. Additional pathologies may not only change the applicable type of surgery, but also decrease the number of postoperative failures. Wrist MRI is recommended, especially for young cases with unilateral CTS history accompanied by dubious clinical symptoms and lacking any pronounced predisposing factors. PMID- 26442535 TI - Use of SpongostanTM for Prevention of Cranial Subdural Adhesions Following Craniotomy in an Experimental Rabbit Model. AB - AIM: SpongostanTM is a sterile, water-insoluble, porcine gelatin absorbable sponge, which is widely used as a hemostatic material. The aim of this study is to test the anti-fibrotic capacity of SpongostanTM, using a craniotomy model in an experimental rabbit model. MATERIAL AND METHODS: Eighteen rabbits were divided into two groups: Each group consisted of 9 rabbits, duratomy plus SpongostanTM (group 1), and duratomy without SpongostanTM (group 2). Right parietal bone was removed via trephine and low speed drill and dura was opened. On the group 1 rabbits, an appropriate piece of SpongostanTM was meticulously placed under dural layer. On group 2 rabbits, same procedures were repeated without SpongostanTM. Histological sections were taken from each group and evaluated for degree of fibrosis and collagen fibers. RESULTS: There was marked increase in number of fibroblasts and collagen fibers in group 2 rabbits, however most of the rabbits in SpongostanTM group demonstrate scarce histopathological findings for fibrosis. CONCLUSION: We conclude that an appropriately placed subdural SpongostanTM over cerebral tissue may prevent postoperative surgical adhesions after neurosurgical operations. PMID- 26442536 TI - Surgical Management of Moderate Sized Spontaneous Cerebellar Hematomas: Role of Intracranial Pressure Monitoring. AB - AIM: Acute onset spontaneous cerebellar hematoma (SCH) is a neurosurgical emergency with unpredictable natural history and outcome. Specific guidelines are available for management of small ( < 2.5 cm) and large sized (4.0 cm < ) SCH. But, literature is sparse for treatment of moderate sized SCH (2.5-4.0 cm). MATERIAL AND METHODS: In a retrospective analysis of 32 patients, with moderate sized acute SCH, external ventricular drainage (EVD) tube was inserted for evaluation of ICP and evacuation of cerebrospinal fluid. All patients with ICP > 25 mmHg underwent emergency SCH evacuation. Postoperatively, EVD was continued for 48-72 hours for ICP monitoring. Patients showing no improvement or persistent ventriculomegaly underwent ventriculoperitoneal shunt (VPS) insertion for the management of hydrocephalus. RESULTS: 29/32 patients needed operative intervention either in the form of hematoma evacuation or shunt placement. 10 patients improved to GOS 5 and 7 to GOS 4. Overall mortality was 25% (n=8). Despite SCH evacuation, none of the patients with ICP > 40 mmHg experienced good outcome (p < 0.0001). CONCLUSION: 47% of patients with moderate sized SCH need surgical evacuation. EVD insertion not only helps in ICP management but also includes the ability to gradually decompress ventricular system by varying the outflow pressure. Apart from radiologic findings, ICP measurement should be a guideline in management decisions. PMID- 26442537 TI - Deep Brain Stimulation of the Rat Subthalamic Nucleus Induced Inhibition of Median Raphe Serotonergic and Dopaminergic Neurotransmission. AB - AIM: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) relieves motor dysfunction in advanced Parkinson's disease (PD). However, STN DBS treated patients can experience unpleasant and debilitating psychiatric side effects such as depression and impulsivity. The neural basis of these psychiatric effects has been linked to a dysfunction of 5-hydroxytryptamine (5-HT, serotonin) neurotransmission. STN DBS inhibited activity of 5-HT cell bodies in the dorsal raphe nucleus (DRN). Another important 5-HT source is located in the median raphe nucleus (MRN), which also contains a population of dopamine neurons. The effects of STN DBS on the MRN are unknown. Here, we test the hypothesis that STN DBS reduces 5-HT and dopaminergic function in the MRN, which may contribute to the psychiatric side effects of STN stimulation. MATERIAL AND METHODS: Bilateral STN DBS was applied in a freely moving rat model. Following STN DBS, rats were sacrificed and the brains were processed for c-Fos, 5-HT and tyrosine hydroxylase (TH) immunohistochemistry. RESULTS: We found that STN DBS significantly lowered c Fos expression compared to non-stimulated controls indicating reduced neuronal activity. Moreover, the mean optical density values of 5-HT and TH cells in the MRN was significantly lower compared to controls. CONCLUSION: These results show that STN DBS inhibits 5-HT and dopamine neurotransmission in the MRN. PMID- 26442538 TI - Surgical Exposure Gained in an Extended Retrosigmoid Approach to the Cerebellopontine Angle Compared to the Traditional Retrosigmoid Approach. AB - AIM: Retrosigmoid approach to the posterior fossa has been a popular and dependable approach for accessing the cerebellopontine angle (CPA) and petroclival region. Although this approach is commonly used, it requires cerebellar retraction and has limitations when the lesion is located ventral to the brainstem. The aim was to quantify the angle of view provided by extended retrosigmoid approach in comparison to the traditional approach. A secondary objective was to identify a strategic initial burr hole site for craniotomy. MATERIAL AND METHODS: Ten adult human cadaver heads (20 sides) were used. First, traditional retrosigmoid approach was performed and the angle of exposure was measured on cranial computerized tomography (CT). Following, extended retrosigmoid approach was performed with mastoid bone drilling and reflection of venous sinuses. Angle of exposure was measured on CT. Two measurements of both approaches were compared. RESULTS: Mean angle of view for the traditional retrosigmoid approach (31.4 degrees +/- 4.1 degrees ) was significantly smaller than that of the extended approach (46.0 degrees +/- 4.7 degrees ) (p < 0.001). Site of strategic burr hole was 5 mm below and 15 mm lateral to the asterion was defined. CONCLUSION: Extended retrosigmoid approach offers neurosurgeons approximately 50% larger angle of view and shorter working distance than the traditional approach provides. This modification permits better access to the CPA and ventral brain stem without cerebellar retraction. PMID- 26442539 TI - Fusiform Enlargement of the Superficial Temporal Artery in the Cases with Intracranial Aneurysm. AB - AIM: The superficial temporal artery is one of the main terminal branches of the external carotid artery. This artery ascends through the lateralposterior margin of the zygomatic arch to reach the temporal region of the scalp. The superficial temporal artery divides its frontal and parietal branches around the zygomatic arch. MATERIAL AND METHODS: The raw data of the Three-dimensional Computerized Tomography Angiography (3D-CTA) were transferred to computer and recorded in a software program. This software program created the three-dimensional images of the superficial temporal artery using these transferred raw data with volume rendering technique. RESULTS: Fifteen cases (5 female and 10 male, mean age 54.26 +/- 12.35 years) with intracranial aneurysm were evaluated in terms of the type, location and dimensions of the fusiform enlargements. Fusiform enlargement was bilateral in eleven of the cases. Remaining four cases have unilateral fusiform enlargement of the superficial temporal artery. CONCLUSION: Fusiform enlargement of the superficial temporal artery may be seen in the cases with intracranial aneurysms. 3D-CTA should be carefully evaluated in the demonstration of extracranial-intracranial vascular pathologies. PMID- 26442540 TI - Role of Post-Decompressive Hydrocephalus in Patients with Malignant Cerebral Infarction. AB - AIM: The association between post-decompressive hydrocephalus and clinical neurological expression is still unclear. In order to investigate this relationship, the authors analyze series of ventricular morphology and level of consciousness at different clinical stages for patients accepting decompressive craniectomy (DC). MATERIAL AND METHODS: From 2005 to 2011, 13 patients accepting DC under the diagnosis of malignant cerebral infarction were retrospectively evaluated in terms of ventricular frontal horn dilatation and level of consciousness, Glasgow Coma Scale score, at four different clinical stages: 1): pre-DC stage; 2): post-DC stage while stabilization; 3): post-cranioplasty stage; 4): post-shunt stage [for those with permanent cerebrospinal fluid (CSF) diversion]. RESULTS: All 13 patients had ventricular dilatation and two of them had extra-axial CSF collection. Restoration of ventricular dilatation was not observed in all patients after bone flap placement, but extra-axial CSF collection resorbed spontaneously. Four patients accepting permanent CSF diversion had no improvement over neurological expression. Otherwise, two of them complicated with subdural effusion after shunt placement. CONCLUSION: Decompressive craniectomy itself would lead to ventricular dilatation universally. There is no direct association between degree of ventriculomegaly and neurological expression. Permanent CSF diversion surgery as treatment for ventriculomegaly makes no clinical improvement with possible complications of overshunting. PMID- 26442541 TI - Increased Expression of Matrix Metalloproteinase-9 in Patients with Temporal Lobe Epilepsy. AB - AIM: The molecular mechanism of epileptogenesis in temporal lobe epilepsy is still unclear. Experimental studies have suggested that matrix metalloproteinases have important roles in this process, but human studies are limited. The aim of this study was to assess the expression of MMP-9, MMP-2 and their tissue inhibitors (TIMP-1 and TIMP-2) in patients with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). MATERIAL AND METHODS: The tissue samples from temporal neocortex and hippocampus were obtained from patients with temporal lobe epilepsy with hippocampal sclerosis who had undergone anterior temporal lobectomy for recurrent medically resistant seizures. Immunohistochemical methods were used to determine the expression of MMP-9, MMP-2 and their tissue inhibitors. Tissue samples were also analyzed with transmission electron microscopy. RESULTS: The immunoreactivity for MMP-9 both in hippocampal and temporal neocortical neurons was stronger than that of MMP-2. Additionally, there was a mild reaction for its tissue inhibitor TIMP-1 as with TIMP-2. The TEM analysis of the hippocampus revealed that there was apparent ultra-structural damage on the pericarya and neuropil of some neurons. There was obvious damage in the mitochondria and the nuclear membrane. CONCLUSION: The preliminary results of this study revealed that MMP-9 may have a role in patients with drug resistant TLE-HS. PMID- 26442542 TI - Effect of Montelukast on Spinal Cord Ischemia- Reperfusion Injury. AB - AIM: Paraplegia due to ischemia-reperfusion (I/R) injury of the spinal cord is a devastating complication of thoracoabdominal aortic surgery. Cysteinyl leukotrienes are potent mediators of inflammation that are associated with I/R injury. The present study was designed to investigate the role of montelukast, a selective reversible CysLT1 receptor antagonist, on spinal cord I/R injury in an experimental model. MATERIAL AND METHODS: Twenty-one male Sprague-Dawley rats were randomly assigned to three groups (n=7 per group) as G1 (no aortic occlusion and montelukast administration), G2 (45 min. aortic occlusion; no montelukast administration) and G3 (45 min. aortic occlusion, 10 mg/kg montelukast administration). After neurologic evaluation using the Motor Deficit Index (MDI) score at the 48th hour of reperfusion, lumbar spinal cords were removed for histopathological evaluation and immunohistochemical staining for HSP70, interleukin-6 and myeloperoxidase (MPO). RESULTS: All rats in the G1 group had a normal neurological status and their MDI score was 0 (p < 0.05). The MDI score of G3 was significantly lower than G2 group (2.8 vs. 5.5; p < 0.05). Vacuolar congestion was found to be significantly lower in G1 than the other groups (p=0.0001). The interleukin-6 receptor level was found to be significantly lower in G3 group than the control group (p=0.013). There was no statistically significant difference found among the groups in terms of the degree of HSP70 and MPO staining. CONCLUSION: Increased generation of leukotrienes in postischemic organs play an important role in I/R injury. The findings of the current study demonstrated that montelukast improved motor recovery and decreased IL-6 levels in spinal cord I/R injury. PMID- 26442543 TI - Percutaneous Laser Disc Decompression: Retrospective Analysis of 197 Cases and Review of The Literature. AB - AIM: Percutaneous laser disc decompression (PLDD) is a one of the well-known minimal invasive treatment methods of disc herniations. The aim of this study is to present our clinical experience and to show the benefits of this technique. MATERIAL AND METHODS: A total of 197 patients, who met the criteria of PLDD, underwent treatment between 2007 and 2009. The data of the patients was reviewed retrospectively. Among them, 107 (54.3 %) patients were male and 90 were female with a mean age of 46.34 years (ranged between 23 and 86 years). Seventy-two patients underwent one level PLDD, 112 (56.8 %) patients two levels PLDD and 13 patients three levels PLDD procedures. The mean follow-up time was 42 months. RESULTS: Among the 72 patients, the level of PLDD was L3-L4 in 4 patients, L4-L5 in 39 patients and L5-S1 in 29 patients. L4-L5 and L5-S1 levels were the most common 2-level PLDD locations in 71 patients. Twenty-five (12.7 %) patients underwent microsurgical discectomy after PLDD. The procedure was repeated in 3 patients. Discitis secondary to possible thermal injury occurred in 2 (0.1%) patients and this complication was improved with conservative treatment. CONCLUSION: PLDD is a safe and effective procedure in the treatment of discogenic pain if the patient met the selection criteria. However, this technique is not an alternative to open surgery. PMID- 26442544 TI - Posterior Lumbar Stabilization Surgery under Spinal Anesthesia for High-Risk Patients with Degenerative Spondylolisthesis, Spinal Stenosis and Lumbar Compression Fracture. AB - AIM: Spinal anesthesia is an appropriate technique for lumbar spine surgeries of two to three hours duration. The aim of this study is to document our experience on spinal anesthesia administered to the patients with degenerative lumbar spine. MATERIAL AND METHODS: A total of 497 patients underwent spinal stabilization surgery with spinal anesthesia for degenerative lumbar spinal disorders in an 8 year period. Spinal anesthesia was performed at the L3-L4 or L4-L5 level and subarachnoid block was achieved with 15 mg of 0.5% plain bupivacaine with 2 MUg of fentanyl and 0.2 mg of epinephrine. There was no failure of anesthesia. The patients were closely monitored for complications associated with the SA technique and especially hypotension and bradycardia but no gross alterations in cardiovascular stability were noted. RESULTS: Among the 497 patients, 139 were male and 358 were female with a median age of 51 years. The average anesthesia duration was 130 minutes and the average operative time was 85 minutes. In the postoperative period 36 patients has nausea (7.2%) and 18 of them had vomiting (3.6%) that required one dose of antiemetic. No spinal headache was observed and 36 (7.2%) patients complained of urinary retention. All recovered with urinary cannulation within 24 hours. No respiratory complication occurred and no patient died. CONCLUSION: Spinal anesthesia is a safe and effective procedure for the lumbar spinal stabilization surgery, especially in high-riskpatients. Proper precautions should be taken in order to achieve an effective anesthesia for these operations. PMID- 26442545 TI - Successful Transarterial Embolization of a Posttraumatic Fistula Between a Posterior Communicating Artery Aneurysm and the Cavernous Sinus: A Case Report. AB - Posterior communicating artery (PCoA) aneurysm-cavernous sinus fistulae are an extremely rare complication of head injury . The treatment of PCoA aneurysm cavernous sinus fistulae has not been well described. A 27-year-old man was admitted with a retroocular bruit and blurred vision of the left eye seven months after a severe head injury. We report the angiographic appearance of a posterior communicating artery (PCoA) aneurysm with a fistula to the cavernous sinus. This injury had been previously misinterpreted to be a PCoA aneurysm by computerized tomographic angiography (CTA). The patient was successfully treated with coils and Onyx of a fistula between the PCoA aneurysm and cavernous sinus. PMID- 26442546 TI - Intracranial Extracranial Huge Meningioma: Report of a Case. AB - Meningioma accounts for 15% to 20% of all intracranial neoplasms. Intracranial meningioma is a common brain tumor but huge meningiomas with extracranial extensions are extremely rare. Various symptoms, including neurological deficits and epileptic seizures are very frequent in these cases. Surgery still remains the principal form of the treatment and must be preceded by appropriate preoperative diagnostics. We report an unusual case of a huge meningioma of the brain (intracranial-extracranial extension) invading and destroying the skull bone and subcutaneous and cutaneous tissue. A 44-year old man in otherwise good general health was admitted to our University Neurosurgical Clinic. The MRI revealed an intracranial-extracranial lesion invading the skull bone, subcutaneous and cutaneous tissue. The tumour was removed by microsurgery. The bone was found to be predominantly lytic, and dura was infiltrated by the tumor. The bone and the dura were completely removed together with the entire tumor. Such cases are very rarely seen these days because of modern radiology techniques A giant intracranial-extracranial meningioma is therefore very unusual. Radiotherapy is generally recommended for incompletely resected meningioma and malignant meningioma. PMID- 26442547 TI - Lhermitte-Duclos Disease Treated Surgically in an Elderly Patient: Case Report and Literature Review. AB - A 75-year-old man with Lhermitte-Duclos Disease (LDD) manifesting as progressive headache is presented. Magnetic resonance imaging demonstrated a right cerebellar mass lesion with the characteristic "tiger-striped appearance". A mild mass effect was evident at the medulla oblongata, accompanied by inferior displacement of the right cerebellar tonsil. Thus, tonsillar herniation was considered the cause of his headache and he underwent partial resection of the tumor to solve tonsillar herniation. His headache gradually improved. LDD in the elderly is quite rare. Several differences in the nature of the lesion are seen in the elderly, with tendencies toward a male predominance, hypervascularity, and low rates of association with Cowden disease. Moreover, partial resection to reduce mass effect can improve clinical symptoms without recurrence. In symptomatic LDD in the elderly, to avoid surgical complication, we recommend partial resection to reduce mass effect. PMID- 26442548 TI - Hydranencephaly: Considering Prolonged Survival and Treatment by Endoscopic Choroid Plexus Coagulation. AB - Arachnoid collapse is a previously unreported complication of endoscopic choroid plexus coagulation (ECPC) treatment of hydranencephaly and is demonstrated in this case report. The variable anatomy found in hydranencephaly supports the use of ECPC as the preferred treatment option. However, the same anatomical anomalies predispose the procedure to this unique complication. A brief literature review of hydranencephaly has also been performed and is reported through the discussion. Neurosurgeons must be aware of this very dangerous complication and a discussion of preventative measures are made. The use of ECPC and the clinical expectations of treating patients with hydranencephaly is also discussed. PMID- 26442549 TI - The Contribution of Three-Dimensional Computerized Tomographic Angiography in the Head Positioning of the Patients with Middle Cerebral Artery Aneurysms. AB - Surgical intervention is a gold standard technique for ruptured and unruptured middle cerebral artery bifurcation aneurysm. Before surgical intervention it is necessary to know the three-dimensional shape, surgical position, projection and position of the aneurysm and the course of the parent artery. In a demonstrative case with middle cerebral artery aneurysm, using the OsiriX MD image processing software for DICOM images, it was demonstrated the position of the aneurysm neck, the projection of the aneurysm and the course of the M1 segment in relation with dynamic rotation and extension of the head. These dynamic videographic neuroradiological images may enhance the surgical anatomic perspective of the surgeon before the surgical intervention. PMID- 26442550 TI - 5-Aminolevulinic Acid-Induced Fluorescence in Cerebellar Primary Central Nervous System Lymphoma: A Case Report and Literature Review. AB - 5-Aminolevulinic acid (5-ALA)-induced fluorescence-guided resection is a widely used procedure for patients with malignant gliomas. However, the clinical application of 5-ALA for surgery in primary central nervous system lymphoma (PCNSL) is uncommon. Here, we present a case of PCNSL treated using 5-ALA-induced fluorescence-guided resective surgery. A 70-year-old woman presented with cerebellar ataxia, and magnetic resonance imaging revealed an irregularly shaped and homogenously enhanced mass with surrounding brain edema in the vermis that extended to the right hemisphere of the cerebellum. Under the preoperative diagnosis of a malignant glioma in the cerebellum, the patient underwent 5-ALA induced fluorescence-guided surgery. Under blue light illumination, the tumor revealed strong 5-ALA-induced fluorescence. The tumor was identified as a diffuse large B-cell lymphoma. After partial resection, the patient received adjuvant chemotherapy and radiotherapy. Importantly, the neurological deficit of the patient improved, and recurrence of the tumor was not observed 21 months post surgery. Together with previous reports, this case study emphasizes the efficacy of the surgical application of 5-ALA for PCNSL. PMID- 26442551 TI - Solitary Metastasis of Renal Cell Carcinoma to the Third Ventricle Mimicking a Colloid Cyst: Case Report. AB - Colloid cysts are the most common third ventricle lesions and metastasis to this area is rare. We presented a case of solitary metastasis from a renal cell carcinoma to the third ventricle choroid plexus mimicking a colloid cyst. A 53 year-old man, who had a history of renal cell carcinoma 12 years ago, was operated for single third ventricle lesion and hydrocephalus via a transcallosal approach. Total removal could not be performed due to intraoperative massive bleeding. Histological examination revealed a metastatic renal cell carcinoma. The patient died on the postoperative 13th day because of bleeding from the residual tumor. Stereotactic radiosurgery and ventriculoperitoneal shunting might be favorable in such cases in order to avoid serious complications. PMID- 26442552 TI - Massive Hemorrhage from the Posterior Ethmoidal Artery during Transsphenoidal Surgery: Report of 2 Cases. AB - Nasal bleeding is a major complication that can occur during and after transsphenoidal surgery (TSS) for intra- and suprasellar tumors. In most cases, the cause of this bleeding can be attributed to a branch of the maxillary artery called the sphenopalatine artery, injury to which can lead to life-threatening situations. Upon exposure of the suprasellar region and planum sphenoidale during surgery, it is also important to avoid damaging the posterior ethmoidal artery (PEA), a branch of the ophthalmic artery. While recent advancement in endoscopic techniques enables the performance of extended TSS, the chances of PEA injury seem to be increasing. In the current report, we present two cases that showed massive PEA bleeding during regular (not extended) TSS. The total blood loss was 2280 ml and 2150 ml, and endoscopic views disturbed by the massive hemorrhages remarkably delayed accurate stanching of the responsive artery. Therefore, anatomical recognition of the PEA is required to avoid fatal hemorrhaging during even regular TSS, especially for the beginners of this surgery. PMID- 26442553 TI - Bilateral Internal Carotid Artery Occlusion as a Cause of Intraventricular Hemorrhage due to Pial Collateral Vessels. AB - In patients with high-grade atherosclerotic stenosis or occlusion of the extracranial cerebral arteries, subarachnoid hemorrhage (SAH) may occur, potentially due to rupture of fragile dilated pial collateral vessels. This association has been well described in Moyamoya disease. There are only few cases in the literature that reported SAH due to bilateral carotid artery stenosis but intraventricular hemorrhage caused by dilated pial collateral has not been reported yet. We present a case of bilateral carotid artery occlusion presented with intraventricular hemorrhage. Based on the findings in the present case, carotid artery stenosis or occlusion may present with intraventricular hemorrhage due to rupture of the dilated, fragile collateral vessels. PMID- 26442554 TI - Moyamoya Disease Associated with Recurrent Right Thalamic Haemorrhage and Hydrocephalus: A Case Report. AB - Moyamoya disease, a rare chronic, progressive cerebrovascular disease leads to occlusion of intracranial internal carotid arteries and its proximal branches. We report a case of a 51-year-old female who presented with recurrent thalamic bleed and intraventricular haemorrhage nine years apart in the same territory. The first bleed was managed conservatively and second bleed led to development of hydrocephalus. The acute phase of the hydrocephalus was managed by external ventricular drainage and the final CSF diversion was managed by ventriculoperitoneal shunt. The definitive treatment could not be done to denial of consent from the patient. We present the case to highlight the role CSF diversion as a means of palliative treatment for the Moyamoya disease. PMID- 26442555 TI - Bipartite Atlas with Os Odontoideum with Block Cervical Vertebrae: A Case Report with Emphasis on the "Overlooked" C1 Lateral Masses. AB - Though rare, a variety of bipartite atlas has been described. However, little has been mentioned about the hypoplastic C1 lateral masses in these cases. An unusual case of bipartite atlas, with hypoplastic lateral masses, os odontoideum and block vertebrae has been described with the surgical challenges encountered. The emphasis here is to study the C1 lateral masses and attempting C1-2 fusion before resorting to occipito-cervical fusion. A 42-year-old lady presented with progressive spastic quadriparesis. Radiology revealed blocked C2-5 vertebrae with os odontoideum with atlanto-axial dislocation with bifid anterior arch of atlas, hypoplastic C1 lateral masses (ill formed postero-inferior part) and posterior arch. Magnetic resonance imaging showed cervicomedullary compression. Reduction was achieved by opening the C1-2 joints posteriorly. Though bilateral C1-2 lateral mass fusion was attempted, we succeeded only on one side necessitating O C2 fusion on the other. Patient improved neurologically, though neck movements were restricted. Partially formed (peg shaped) lateral mass of C1 suggests its development from more than one sclerotome. With normal superior facets of C1 lateral mass, an attempt should always be made at fusing the C1-2 joint rather than O-C2 in such cases to preserve some neck movements. PMID- 26442556 TI - Locally Aggressive De Novo Spinal Fibromatosis: Case Report and Review of the Literature. AB - Fibromatosis is a benign lesion, which originates from proliferating fibroblasts. Although fibromatosis is a benign tumor, it is locally aggressive and invasive. Spinal presentation of fibromatosis is very rare, and case reports are the only source of the clinical knowledge. Herein, we describe the oldest patient having spinal fibromatosis with de novo occurrence and aggressive nature. A 68-year-old female patient admitted to our outpatient clinic with low back pain and neurological claudication. On lumbar spine magnetic resonance imaging, she had spinal canal stenosis with a concomitant lesion in the left longissimus muscle. We did our best to resect the tumor, entirely. The pathology result was consistent with spindle cell lesion. The lesion recurred 6 months after the primary surgery. In the second surgery, we did en bloc resection. Pathology and immunohistochemical analysis results were consistent with fibromatosis. After the second surgery, she had adjuvant radiotherapy. There was nothing other than radionecrosis in the operation site, still after 2 years. In conclusion, radiological work-up is usually insufficient to make fibromatosis diagnosis and whole pathological specimen should be carefully evaluated to achieve the accurate diagnosis. Spinal fibromatosis is very rare and its treatment methods have not universally been conceptualized. However, adjuvant therapies are necessary after en bloc resection. PMID- 26442557 TI - Lumbar Epidural Varicose Vein: Early Neurological Improvement and Late Radiological Full Recovery with Surgery; The Importance of Magnetic Resonance Imaging in Follow-Up. AB - A lumbar epidural varicose vein is a rare clinical condition that can lead to neurological deficits. 3 types of lumbar epidural varicose veins were described according to the magnetic resonance imaging (MRI) findings: Type 1 is a thrombosed dilated epidural vein, type 2 is a non-thrombosed dilated epidural vein and type 3 is a sub-membraneous epidural hematoma. Enlarged epidural venous plexuses must be decompressed if they have lead to a neurological deficit. Surgical treatment is by excision or disrupting the cyst's integrity. We present a case of lumbar epidural varicose vein that was surgically treated twice and showed no radiological change despite the disruption of integrity with a partial excision. The lesion spontaneously and completely disappeared in the late period. We emphasize the importance of MRI in follow-up. PMID- 26442558 TI - Hemorrhagic Epidermoid Cyst in Cerebellar Vermis. AB - Intracranial epidermoid cysts are usually located in the paramedian regions with characteristic imaging features. Intracystic hemorrhage is rarely reported with most in the cerebellopontine angle area. We described a case of hemorrhagic epidermoid cyst in cerebellar vermis. The patient was a 21-year-old male presenting with a first episode of convulsive seizure attack as the initial and sole symptom. Head computed tomography showed a mass lesion in the cerebellar vermis with high density and nodular low density in the back of the lesion. Magnetic resonance imaging revealed most of the lesion was hypointense to isointense, extremely hypointensity on T1-, T2-weighted imaging respectively. The nodule was hyperintense on both T1- and T2-weighted images. The atypical clinical presentation, location and radiological features of intracranial epidermoid cyst make accurate diagnosis quite challenging. In such cases, scrutinized histopathological examination is necessary to exclude the malignancy that may need radio/chemotherapy. PMID- 26442559 TI - A Right Middle Cerebral Artery Infarct After Frontal Eosinophilic Granuloma Resection in an 8-Year-Old Boy with Factor V Leiden. AB - Stroke in children is relatively uncommon. We describe an 8-year-old boy diagnosed with primary eosinophilic granuloma (EG) of the frontal bone. After excision of the EG, the postoperative course was eventful. The patient had an acute right middle cerebral artery (MCA) infarct and had been comatose with a diminished Glasgow Coma Scale (GCS) score of 5. Urgent decompressive hemicraniectomy with duraplasty was performed. The postoperative course after the second operation was uneventful. Hematological tests revealed a diagnosis of factor V Leiden. The patient was discharged with left hemiparesis and GCS of 15. To the best of our knowledge, no such clinical picture of MCA infarction after EG excision has been described before. Neurosurgeons should be aware of inherited thrombophilias, such as factor V Leiden, if the postoperative clinical course worsens because of cerebral artery thrombosis. Also, decompressive hemicraniectomy could be life saving and should be performed urgently without any hesitation. PMID- 26442560 TI - Spontaneous Resolution of Bilateral Chronic Subdural Hematoma. PMID- 26442561 TI - Climate adversity and resilience: the voice of rural Australia. AB - INTRODUCTION: Over the past decade, Australia has experienced prolonged drought and extensive flooding. It is argued that such events impact more significantly on rural communities than urban. Although there is a body of research investigating the effects of drought on mental and physical health in rural Australia, little research has examined the effects of flood and drought on wellbeing. This article explores the influence of drought and flood on the wellbeing of rural residents in New South Wales (NSW), Australia. METHODS: Forty six individuals living in four rural communities in NSW were recruited and asked their experience of flood and drought using in-depth semi-structured face to face interviews or focus groups. The study used a grounded hermeneutic approach to contextualise participants' experiences within a rural social and cultural construct. RESULTS: Weather was found to be at the core of rural life, with flood and drought contributing to decreased wellbeing from stress, anxiety, loss and fear. Social connectedness was found to promote resilience in rural communities buffering the effects of flood and drought. CONCLUSIONS: Flood and drought have negative impacts on an individual's wellbeing. Although these negative effects were seen to be buffered by individual and community resilience, the long term emotional impact of flood and drought on rural communities needs to be further considered. PMID- 26442562 TI - Does skill retention benefit from retentivity and symbolic rehearsal? - two studies with a simulated process control task. AB - Two experiments were designed to compare two symbolic rehearsal refresher interventions (imaginary practice, a hidden introspective process) and investigate the role of retentivity in skill retention. Retentivity is investigated as the ability to memorise and reproduce information and associations that were learned a short time ago. Both experiments comprised initial training (week 1), a symbolic rehearsal for the experimental group (week 2) and a retention assessment (week 3). In the first study, the experimental group received a symbolic rehearsal, while the control group received no rehearsal. In the second study, the experimental group received the same symbolic rehearsal used in study 1, enhanced with rehearsal tasks addressing human computer interaction. The results showed that both symbolic rehearsal interventions were equally likely to mitigate skill decay. The retentivity showed medium to high correlations with skill retention in both studies, and the results suggest that subjects high in retentivity benefit more from a symbolic rehearsal refresher intervention. Practitioner Summary: Skill decay becomes a problem in situations in which jobs require the correct mastery of non-routine situations. Two experimental studies with simulated process control tasks showed that symbolic rehearsal and retentivity can significantly mitigate skill decay and that subjects higher in retentivity benefit more from refresher interventions. PMID- 26442563 TI - Linking emotional distress to unhealthy sleep duration: analysis of the 2009 National Health Interview Survey. AB - OBJECTIVE: The objective of the study was to examine the independent association of emotional distress with unhealthy sleep duration (defined as <7 or >8 hours). METHODS: Data from the 2009 National Health Interview Survey (NHIS), a cross sectional household survey, were analyzed to investigate the associations of emotional distress with unhealthy sleep durations, adjusting for sociodemographic factors, health risks, and chronic diseases through hierarchical multiple logistic regression analysis. PARTICIPANTS: A total of 27,731 participants (age range 18-85 years) from the NHIS 2009 dataset were interviewed. MEASURES: Unhealthy sleep duration is defined as sleep duration <7 or >8 hours, whereas healthy sleep is defined as sleep duration lasting for 7-8 hours. Emotional distress is based on the Kessler 6 Non-Specific Distress Battery, which assesses the frequency of feeling sad, nervous, restless, hopeless, worthless, and burdened, over a 30-day period. RESULTS: Of the sample, 51.7% were female; 83.1% were white and 16.9% were black. Eleven percent experienced emotional distress and 37.6% reported unhealthy sleep. Adjusted logistic regression analysis revealed that individuals with emotional distress had 55% greater odds of reporting unhealthy sleep (odds ratio [OR] =1.55, 95% confidence interval [CI] =1.42, 1.68, P<0.001). CONCLUSION: Emotional distress, an important proxy for poor psychological health, was a significant predictor of unhealthy sleep, independent of the influences of several factors including demographic (age, education, sex, race/ethnicity, and family income), health risks (alcohol consumption and smoking status), and chronic diseases/conditions (diabetes, obesity, hypertension, heart disease, cancer, and arthritis). PMID- 26442564 TI - Prior stillbirth is a risk factor for stillbirth in a subsequent pregnancy. PMID- 26442565 TI - Routine iron supplementation for non-anaemic pregnant women in developed countries needs evaluation. PMID- 26442566 TI - Risk of new-onset diabetes with statin use should not be overemphasised. PMID- 26442567 TI - Sugar-sweetened beverage consumption is linked to global adult morbidity and mortality through diabetes mellitus, cardiovascular disease and adiposity-related cancers. PMID- 26442568 TI - Nucleotide diversity patterns of three divergent soybean populations: evidences for population-dependent linkage disequilibrium and taxonomic status of Glycine gracilis. AB - The level of linkage disequilibrium (LD) is a major factor to determine DNA polymorphism pattern of a population and to construct high-resolution maps useful in localizing and gene cloning of complicated traits. Here, we investigated LD level of three soybean populations with different genetic backgrounds and taxonomic status of G. gracilis by comparing the DNA polymorphism patterns of four high-diversity single-copy nuclear genes. A total of 152, 22, and 77 accessions of G. soja, G. gracilis, and G. max were observed. The results indicated that G. max retained only 75.3 (pi) and 39% (theta) of the nucleotide polymorphism found in G. soja. Four gene loci evolved according to neutrality in both G. max and G. gracilis populations, and three gene loci evolved according to neutrality in G. soja population by Tajima's and Fu and Li's test. However, one gene locus deviated from neutrality by Fu and Li's test in the G. soja population. Further, medial level of LD (average r (2) = 0.2426) was found in intragene in G. max and G. gracilis populations, but unexpected low level of LD (r (2) <= 0.0539) was found in G. soja population. Significant genetic differentiation was detected between G. max and G. soja populations and also between G. max and G. gracilis populations; however, nonsignificant genetic differentiation was found between G. gracilis and G. soja populations. The results suggest that LD level depends on genetic background of soybean population, and implicit that G. gracilis should be regarded as the variant of G. soja, not as an independent species. PMID- 26442569 TI - Old relief printing applied to the current preparation of multi-color and high resolution colloidal photonic crystal patterns. AB - Monodisperse SiO2 colloids are assembled into colloidal crystals in the mixture of monomer and solvent, which is transformed into a mechanochromic photonic crystal paper by polymerization. Following the relief printing strategy, the printing plates are pressed onto the paper to generate letters or images due to the contrast of structural color between the deformed and the undeformed paper, and the images can be permanently retained through UV curing. The wide tunable range of structural color for the current paper under deformation helps to realize multi-color printing. The localized deformation among or even inside the colloidal microcrystals renders the paper with a precise mechanochromic response to the printing plates and leads to the production of high resolution photonic crystal patterns. PMID- 26442571 TI - Synthesis and crystal structure of a new hexagonal perovskite 7H Ba7Li1.75Mn3.5O15.75 with Mn(4+)/Mn(5+) charge distribution. AB - Ba7Li1.75Mn3.5O15.75 is a new hexagonal perovskite whose crystal structure has elements typical for the layered hexagonal perovskites and quasi-one-dimensional oxides, hence representing a new polytype. It has been synthesized via a solid state microwave route. The crystal structure was solved using a combination of X ray and neutron diffraction data, which show that Ba7Li1.75Mn3.5O15.75 crystallizes in a hexagonal unit cell with parameters a = 5.66274(2) A and c = 16.7467(1) A (V = 465.063(4) A(3)), with one formula unit, and can be described as columns of face-shared octahedra occupied by Mn(4+) and Li(+) cations and vacancies along the c axis separated in the ab plane by barium atoms. Every sixth layer, the coordination of Mn(5+) and Li(+) changes to tetrahedral. Additional local ordering of manganese and lithium atoms among cationic sites leading to the formation of a rhombohedral supercell has been observed by scanning transmission electron microscopy. PMID- 26442572 TI - A triple-amplification colorimetric assay for antibiotics based on magnetic aptamer-enzyme co-immobilized platinum nanoprobes and exonuclease-assisted target recycling. AB - Herein, an ultrasensitive and selective colorimetric assay for antibiotics, using chloramphenicol (CAP) as the model analyte, was developed based on magnetic aptamer-HRP-platinum composite probes and exonuclease-assisted target recycling. The composite probes were prepared through immunoreactions between the double stranded DNA antibody (anti-DNA) labeled on core-shell Fe3O4@Au nanoparticles (AuMNP-anti-DNA) as the capture probe, and the double stranded aptamer (aptamer hybrid with its complementary oligonucleotides) labeled on Pt@HRP nanoparticles as the nanotracer (ds-Apt-HRP-PtNPs). When the CAP samples were incubated with the probes for 30 min at room temperature, they could be captured by the aptamer to form a nanotracer-CAP complex, which was then released into the supernatant after magnetic separation. This is because the anti-DNA on the capture probes cannot recognize the single strand aptamer-CAP complex. The exonuclease I (Exo I) added into the supernatant can further digest the aptamer-CAP from the 3'-end of the aptamer and the CAP in the aptamer-CAP complex can be released again, which can further participate in a new cycling process to react with the probes. Pt and HRP in the nanotracer could both catalyze and dual amplify the absorbance at 650 nm ascribed to the 3,3',5,5'-tetramethylbenzidine (TMB)-H2O2 system. Moreover, Exo I can assist the target recycling, which can further amplify the signal. Thus, the triple amplified signal can be quantified by ultraviolet-visible spectroscopy. The experimental results showed that the CAP detection possessed a linear range of 0.001-10 ng mL(-1) and a detection limit of 0.0003 ng mL(-1) (S/N = 3). The assay was successfully employed to detect CAP in milk, which is much more facile, time saving, and sensitive than the commercial ELISA kits. PMID- 26442573 TI - Spatiotemporal characteristics of organic contaminant concentrations and ecological risk assessment in the Songhua River, China. AB - To control source pollution and improve water quality, an understanding of the spatiotemporal characteristics of organic contaminant concentrations in affected receiving waters is necessary. The Songhua River in northeast China is the country's third-largest domestic river and loadings of organic contaminants along an industrialized section have made it the focal point of a national pollution reduction plan. In addition to water quality issues, management of the Songhua River basin must also address local economic development, aquatic ecosystem sustainability and political relationships with Russia. In three periods spanning 2006 to 2010, eight polycyclic aromatic hydrocarbons (PAHs) and eight phenols were measured in surface waters at ten monitoring sites along the river. A generalized linear model (GLM) was used to characterize water quality at different sites and time periods. Chemical concentrations of the organic compounds showed significant sinusoidal seasonal patterns and the concentrations declined significantly from 2006 to 2010, possibly due to management practices designed to control water pollution. A critical body residue analysis showed that water concentrations measured during the winter of 2007 across all monitoring sites, but especially at S1-Shaokou and S2-Songhuajiangcun, presented a high risk for fish species. The spatiotemporal characteristics of water quality and estimated ecological risks shown here add to the body of knowledge to develop policies on industrial output and pollution management strategies for the Songhua River basin. PMID- 26442574 TI - Metallic nanoparticle shape and size effects on aluminum oxide-induced enhancement of exciton-plasmon coupling and quantum dot emission. AB - We investigate the shape and size effects of gold metallic nanoparticles on the enhancement of exciton-plasmon coupling and emission of semiconductor quantum dots induced via the simultaneous impact of metal-oxide and plasmonic effects. This enhancement occurs when metallic nanoparticle arrays are separated from the quantum dots by a layered thin film consisting of a high index dielectric material (silicon) and aluminum oxide. Our results show that adding the aluminum oxide layer can increase the degree of polarization of quantum dot emission induced by metallic nanorods by nearly two times, when these nanorods have large aspect ratios. We show when the aspect ratio of these nanorods is reduced to half, the aluminum oxide loses its impact, leading to no improvement in the degree of polarization. These results suggest that a silicon/aluminum oxide layer can significantly enhance exciton-plasmon coupling when quantum dots are in the vicinity of metallic nanoantennas with high aspect ratios. PMID- 26442575 TI - Comparative net cost impact of the utilization of panitumumab versus cetuximab for the treatment of patients with metastatic colorectal cancer in Canada. AB - OBJECTIVE: Clinical practice guidelines support the use of the epidermal growth factor receptor (EGFR) inhibitors panitumumab and cetuximab for the treatment of metastatic colorectal cancer (mCRC) after failure of other chemotherapy regimens, based on significant clinical benefits in patients with wild-type KRAS. The purpose of the analysis was to compare provincial hospital costs when using panitumumab vs cetuximab with or without irinotecan in this patient population using a Net Impact Analysis (NIA) approach. METHODS: The NIA determined the total per patient cost of the reimbursed regimens of panitumumab vs cetuximab in British Columbia, Alberta, Manitoba, Ontario, and Quebec. Utilization of healthcare resources related to EGFR inhibitor infusions, follow-up monitoring, and treatment of adverse events (AEs) were also included. Healthcare resource use including drugs, medical supplies, laboratory testing, oncology infusion time, and healthcare professionals' time was obtained through expert consultation and the use was then multiplied by the province-specific cost of each resource. Numerous sensitivity analyses were conducted. RESULTS: Based on the dosing regimens in place in each province, the total annual per patient cost of panitumumab ranged from $22,203-$32,600, while the total annual per patient cost of cetuximab treatment varied from $30,321-$40,908. Treatment with panitumumab resulted in lower costs in all cost categories including drug acquisition, infusion preparation/administration, patient monitoring, and AE management. Per patient savings with panitumumab ranged from a low of $3815 in British Columbia to a high of $10,603 in Ontario. In sensitivity analyses, panitumumab remained cost saving in all scenarios where the savings ranged from $150-$16,006 per patient. CONCLUSIONS: Treating chemorefractory mCRC patients with panitumumab rather than cetuximab reduced healthcare resource costs. Provincial healthcare savings achieved with the use of panitumumab could potentially be re-allocated to other cancer treatments, although further study would be needed to validate this assumption. PMID- 26442576 TI - Chain Length of Free Fatty Acids Influences the Phase Behavior of Stratum Corneum Model Membranes. AB - The skin, the largest organ of the human body, forms a flexible interface between our internal and external environment that protects our organism from exogenous compounds as well as excessive water loss. The stratum corneum (SC), the outermost layer of mammal epidermis, is mainly responsible for the skin impermeability. The SC is formed by corneocytes embedded in a lipid matrix, which is mostly constituted of ceramides (Cer), free fatty acids (FFA), and cholesterol (Chol), organized in two coexisting crystalline lamellar phases. This arrangement of lipids is crucial to skin barrier function. The aim of this paper is to determine the impact of FFA chain length on the phase behavior of SC model lipid membranes using solid-state deuterium NMR and IR spectroscopy. We studied ternary mixtures of N-lignoceroyl-d-erythro-sphingosine (Cer24), cholesterol, and palmitic (FFA16) or lignoceric (FFA24) acid in an equimolar ratio. This proportion replicates the lipid composition found in the SC lipid matrix. Our studies revealed that the phase behavior of Cer24/FFA/Chol ternary mixtures is strongly affected by the length of the FFA. We found the formation of phase separated crystalline lipid domains when using palmitic acid whereas the use of lignoceric acid results in a more homogeneous mixture. In addition, it was observed that mixtures with lignoceric acid form a gel phase, a very unusual feature for SC model mixtures. PMID- 26442577 TI - Computational biomechanics of human brain with and without the inclusion of the body under different blast orientation. AB - Three different human head models in a free space are exposed to blast waves coming from four different directions. The four head-neck-body models composed of model a, with the neck free in space; model b, with neck fixed at the bottom; and model c, with the neck attached to the body. The results show that the effect of the body can be ignored for the first milliseconds of the head-blast wave interactions. Also one can see that although most biomechanical responses of the brain have similar patterns in all models, the shear stresses are heavily increased after a few milliseconds in model b in which the head motion is obstructed by the fixed-neck boundary conditions. The free-floating head model results are closer to the attached-body model. PMID- 26442578 TI - Neuroanatomical correlates of individual differences in social anxiety in a non clinical population. AB - Socially anxious individuals are characterized as those with distorted negative self-beliefs (NSBs), which are thought to enhance reactions of social distress (emotional reactivity) and social avoidance (social functioning). However, it remains unclear whether individual differences in social distress and social avoidance are represented by differences in brain morphometry. To probe into these neural correlates, we analyzed magnetic resonance images of a sample of 130 healthy subjects and used the Connectome Computation System (CCS) to evaluate these factors. The results showed that social distress was correlated with the cortical volume of the right orbitofrontal cortex (OFC) and the subcortical volume of the left amygdala, while social avoidance was correlated with the cortical volume of the right dorsolateral prefrontal cortex (DLPFC). Additionally, loneliness might mediate the relationship between the amygdala volume and the social distress score. Our results demonstrated that social distress and social avoidance were represented by segregated cortical regions in the healthy individuals. These findings might provide a valuable basis for understanding the stable brain structures underlying individual differences in social anxiety. PMID- 26442579 TI - Introducing Journal Sections. PMID- 26442580 TI - A Possible Association Between Thyroid Cancer and Breast Cancer. AB - BACKGROUND: Several lines of evidence suggest that breast cancer (BC) and thyroid cancer (TC) occur together in the same female patients more frequently than would be expected by chance. This study investigated the prevalence and clinicopathological characteristics of second primary BC in TC patients and second primary TC in BC patients. METHODS: A retrospective case-controlled study was performed in 4243 patients with differentiated TC and 6833 patients with BC. Age-matched control groups without second malignancies were selected. RESULTS: Of the 4243 patients with TC, 55 patients developed subsequent BC during a five-year follow-up (range 2-40 years); the standardized incidence ratio (SIR) was 2.45 [confidence interval (CI) 1.83-2.96]. Among the 6833 patients with BC, 81 patients developed subsequent TC during a 6.2-year follow-up (range 2-40 years); the SIR was 2.18 [CI 1.43-2.82]. Subsequent second BC or TC diagnosed within five years of the initial primary malignancy showed more clinical characteristics consistent with early-stage cancer than did control BC or TC patients. Notably, the expression of both the estrogen and progesterone receptors was significantly higher in the tissues of BC patients with coexisting TC compared with those with BC alone. CONCLUSIONS: The overall risk of second primary TC or BC is increased in patients with prior BC or TC, respectively. The early detection of second cancer might have contributed to these findings. However, BC that coexisted with TC had a higher expression of hormone receptors, suggesting an association between the molecular pathogenesis of TC and BC. PMID- 26442581 TI - James Cook University's rurally orientated medical school selection process: quality graduates and positive workforce outcomes. AB - INTRODUCTION: The regionally based James Cook University (JCU) College of Medicine and Dentistry aims to meet its mission to address the health needs of the region by using a selection policy favouring rural origin applicants and providing students with early and repeated exposure to rural experiences during training. This study seeks to determine if the JCU medical school's policy of preferentially selecting rural and remote background students is associated with differing patterns of undergraduate performance or graduate practice location. METHODS: Data at application to medical school and during the undergraduate years was retrieved from administrative databases held by the university and the medical school. Postgraduate location data were obtained either from personal contact via email, telephone or Facebook or electronically from the Australian Health Practitioner Regulation Authority website. Practice location was described across Australian Standard Geographical Classification Remoteness Area (ASGC-RA) categories, with 1 being a major city and 5 being a very remote location. RESULTS: The 856 Australian-based students accepted into the JCU medical program between 2000 and 2008 came from all geographical regions across Australia: 20% metropolitan (ASGC-RA 1), 20% inner regional (ASGC-RA 2), 56% outer regional (ASGC-RA 3), and 5% from remote or very remote locations (ASGC-RA 4 and 5). Having a rural or remote hometown at application (ASGC-RA 3-5) was significantly associated with a lower tertiary entrance score (p<0.001), a lower interview score in the medical school selection process (p<0.001), being less likely to be admitted into the Honours program (p=0.001), being an advanced standing student (p=0.025), being awarded a Medical Rural Bonded Scholarship (p=0.005), taking longer to complete the 6-year course (p=<0.009) and having a lower academic achievement across years 1 to 3 (p=0.002, p=0.005 and p=0.025, respectively). Graduates having either a rural or a remote home town at application were more likely to practise in rural (RA 3-5) towns than graduates from metropolitan/inner regional centre across all postgraduate years. For example, the prevalence odds ratios (POR) for graduates practising in a rural town at postgraduate year 1 (PGY 1) having either a rural or remote hometown were 2.6 and 1.8, respectively, times that of graduates having a metropolitan/inner regional hometown, while at PGY 9 the PORs had increased to 4.2 and 9.5, respectively. Bonded medical place students showed many similar trends to rural students in both their pre-medical school and undergraduate performance indicators but lower engagement in rural practice in the 5 years of data available. CONCLUSIONS: Some significant differences were noted between rural and remote origin students and metropolitan or inner regional origin students in terms of academic achievement in the first 3 years of the course and length of time taken to complete the course. However, this group of rural and remote-origin students seems to do just as well in the exams in the clinical years (years 4-6) and are much more likely to practise in rural and remote areas. These data suggest that JCU's selection process favouring rural origin applicants does not compromise academic standards, but does produce graduates whose patterns of practice accord with the mission of the school. PMID- 26442582 TI - Conspicuous male coloration impairs survival against avian predators in Aegean wall lizards, Podarcis erhardii. AB - Animal coloration is strikingly diverse in nature. Within-species color variation can arise through local adaptation for camouflage, sexual dimorphism and conspicuous sexual signals, which often have conflicting effects on survival. Here, we tested whether color variation between two island populations of Aegean wall lizards (Podarcis erhardii) is due to sexual dimorphism and differential survival of individuals varying in appearance. On both islands, we measured attack rates by wild avian predators on clay models matching the coloration of real male and female P. erhardii from each island population, modeled to avian predator vision. Avian predator attack rates differed among model treatments, although only on one island. Male-colored models, which were more conspicuous against their experimental backgrounds to avian predators, were accordingly detected and attacked more frequently by birds than less conspicuous female colored models. This suggests that female coloration has evolved primarily under selection for camouflage, whereas sexually competing males exhibit costly conspicuous coloration. Unexpectedly, there was no difference in avian attack frequency between local and non-local model types. This may have arisen if the models did not resemble lizard coloration with sufficient precision, or if real lizards behaviorally choose backgrounds that improve camouflage. Overall, these results show that sexually dimorphic coloration can affect the risk of predator attacks, indicating that color variation within a species can be caused by interactions between natural and sexual selection. However, more work is needed to determine how these findings depend on the island environment that each population inhabits. PMID- 26442583 TI - Mitogen-activated Protein Kinase (MAPK) Activated by Prostaglandin E2 Phosphorylates Connexin 43 and Closes Osteocytic Hemichannels in Response to Continuous Flow Shear Stress. AB - Cx43 hemichannels serve as a portal for the release of prostaglandins, a critical process in mediating biological responses of mechanical loading on bone formation and remodeling. We have previously observed that fluid flow shear stress (FFSS) opens hemichannels; however, sustained FFSS results in hemichannel closure, as continuous opening of hemichannels is detrimental to cell viability and bone remodeling. However, the mechanism that regulates the closure of the hemichannels is unknown. Here, we show that activation of p44/42 ERK upon continuous FFSS leads to Cx43 phosphorylation at Ser(279)-Ser(282), sites known to be phosphorylated sites by p44/42 MAPK. Incubation of osteocytic MLO-Y4 cells with conditioned media (CM) collected after continuous FFSS increased MAPK-dependent phosphorylation of Cx43. CM treatment inhibited hemichannel opening and this inhibition was reversed when cells were pretreated with the MAPK pathway inhibitor. We found that prostaglandin E2 (PGE2) accumulates in the CM in a time dependent manner. Treatment with PGE2 increased phospho-p44/42 ERK levels and also Cx43 phosphorylation at Ser(279)-Ser(282) sites. Depletion of PGE2 from CM, and pre-treatment with a p44/42 ERK pathway-specific inhibitor, resulted in a complete inhibition of ERK-dependent Cx43 phosphorylation and attenuated the inhibition of hemichannels by CM and PGE2. Consistently, the opening of hemichannels by FFSS was blocked by PGE2 and CM and this blockage was reversed by U0126 and the CM depleted of PGE2. A similar observation was also obtained in isolated primary osteocytes. Together, results from this study suggest that extracellular PGE2 accumulated after continuous FFSS is responsible for activation of p44/42 ERK signaling and subsequently, direct Cx43 phosphorylation by activated ERK leads to hemichannel closure. PMID- 26442584 TI - Cell Cycle-dependent Changes in Localization and Phosphorylation of the Plasma Membrane Kv2.1 K+ Channel Impact Endoplasmic Reticulum Membrane Contact Sites in COS-1 Cells. AB - The plasma membrane (PM) comprises distinct subcellular domains with diverse functions that need to be dynamically coordinated with intracellular events, one of the most impactful being mitosis. The Kv2.1 voltage-gated potassium channel is conditionally localized to large PM clusters that represent specialized PM:endoplasmic reticulum membrane contact sites (PM:ER MCS), and overexpression of Kv2.1 induces more exuberant PM:ER MCS in neurons and in certain heterologous cell types. Localization of Kv2.1 at these contact sites is dynamically regulated by changes in phosphorylation at one or more sites located on its large cytoplasmic C terminus. Here, we show that Kv2.1 expressed in COS-1 cells undergoes dramatic cell cycle-dependent changes in its PM localization, having diffuse localization in interphase cells, and robust clustering during M phase. The mitosis-specific clusters of Kv2.1 are localized to PM:ER MCS, and M phase clustering of Kv2.1 induces more extensive PM:ER MCS. These cell cycle-dependent changes in Kv2.1 localization and the induction of PM:ER MCS are accompanied by increased mitotic Kv2.1 phosphorylation at several C-terminal phosphorylation sites. Phosphorylation of exogenously expressed Kv2.1 is significantly increased upon metaphase arrest in COS-1 and CHO cells, and in a pancreatic beta cell line that express endogenous Kv2.1. The M phase clustering of Kv2.1 at PM:ER MCS in COS-1 cells requires the same C-terminal targeting motif needed for conditional Kv2.1 clustering in neurons. The cell cycle-dependent changes in localization and phosphorylation of Kv2.1 were not accompanied by changes in the electrophysiological properties of Kv2.1 expressed in CHO cells. Together, these results provide novel insights into the cell cycle-dependent changes in PM protein localization and phosphorylation. PMID- 26442585 TI - A Novel Retinoblastoma Protein (RB) E3 Ubiquitin Ligase (NRBE3) Promotes RB Degradation and Is Transcriptionally Regulated by E2F1 Transcription Factor. AB - Retinoblastoma protein (RB) plays critical roles in tumor suppression and is degraded through the proteasomal pathway. However, E3 ubiquitin ligases responsible for proteasome-mediated degradation of RB are largely unknown. Here we characterize a novel RB E3 ubiquitin ligase (NRBE3) that binds RB and promotes RB degradation. NRBE3 contains an LXCXE motif and bound RB in vitro. NRBE3 interacted with RB in cells when proteasome activity was inhibited. NRBE3 promoted RB ubiquitination and degradation via the ubiquitin-proteasome pathway. Importantly, purified NRBE3 ubiquitinated recombinant RB in vitro, and a U-box was identified as essential for its E3 activity. Surprisingly, NRBE3 was transcriptionally activated by E2F1/DP1. Consequently, NRBE3 affected the cell cycle by promoting G1/S transition. Moreover, NRBE3 was up-regulated in breast cancer tissues. Taken together, we identified NRBE3 as a novel ubiquitin E3 ligase for RB that might play a role as a potential oncoprotein in human cancers. PMID- 26442586 TI - Degradation of Stop Codon Read-through Mutant Proteins via the Ubiquitin Proteasome System Causes Hereditary Disorders. AB - During translation, stop codon read-through occasionally happens when the stop codon is misread, skipped, or mutated, resulting in the production of aberrant proteins with C-terminal extension. These extended proteins are potentially deleterious, but their regulation is poorly understood. Here we show in vitro and in vivo evidence that mouse cFLIP-L with a 46-amino acid extension encoded by a read-through mutant gene is rapidly degraded by the ubiquitin-proteasome system, causing hepatocyte apoptosis during embryogenesis. The extended peptide interacts with an E3 ubiquitin ligase, TRIM21, to induce ubiquitylation of the mutant protein. In humans, 20 read-through mutations are related to hereditary disorders, and extended peptides found in human PNPO and HSD3B2 similarly destabilize these proteins, involving TRIM21 for PNPO degradation. Our findings indicate that degradation of aberrant proteins with C-terminal extension encoded by read-through mutant genes is a mechanism for loss of function resulting in hereditary disorders. PMID- 26442587 TI - The Thermotolerant Yeast Kluyveromyces marxianus Is a Useful Organism for Structural and Biochemical Studies of Autophagy. AB - Autophagy is a conserved degradation process in which autophagosomes are generated by cooperative actions of multiple autophagy-related (Atg) proteins. Previous studies using the model yeast Saccharomyces cerevisiae have provided various insights into the molecular basis of autophagy; however, because of the modest stability of several Atg proteins, structural and biochemical studies have been limited to a subset of Atg proteins, preventing us from understanding how multiple Atg proteins function cooperatively in autophagosome formation. With the goal of expanding the scope of autophagy research, we sought to identify a novel organism with stable Atg proteins that would be advantageous for in vitro analyses. Thus, we focused on a newly isolated thermotolerant yeast strain, Kluyveromyces marxianus DMKU3-1042, to utilize as a novel system elucidating autophagy. We developed experimental methods to monitor autophagy in K. marxianus cells, identified the complete set of K. marxianus Atg homologs, and confirmed that each Atg homolog is engaged in autophagosome formation. Biochemical and bioinformatic analyses revealed that recombinant K. marxianus Atg proteins have superior thermostability and solubility as compared with S. cerevisiae Atg proteins, probably due to the shorter primary sequences of KmAtg proteins. Furthermore, bioinformatic analyses showed that more than half of K. marxianus open reading frames are relatively short in length. These features make K. marxianus proteins broadly applicable as tools for structural and biochemical studies, not only in the autophagy field but also in other fields. PMID- 26442588 TI - Tumor Suppressive Function of p21-activated Kinase 6 in Hepatocellular Carcinoma. AB - Our previous studies identified the oncogenic role of p21-activated kinase 1 (PAK1) in hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Contrarily, PAK6 was found to predict a favorable prognosis in RCC patients. Nevertheless, the ambiguous tumor suppressive function of PAK6 in hepatocarcinogenesis remains obscure. Herein, decreased PAK6 expression was found to be associated with tumor node metastasis stage progression and unfavorable overall survival in HCC patients. Additionally, overexpression and silence of PAK6 experiments showed that PAK6 inhibited xenografted tumor growth in vivo, and restricted cell proliferation, colony formation, migration, and invasion and promoted cell apoptosis and anoikis in vitro. Moreover, overexpression of kinase dead and nuclear localization signal deletion mutants of PAK6 experiments indicated the tumor suppressive function of PAK6 was partially dependent on its kinase activity and nuclear translocation. Furthermore, gain or loss of function in polycomb repressive complex 2 (PRC2) components, including EZH2, SUZ12, and EED, elucidated epigenetic control of H3K27me3-arbitrated PAK6 down-regulation in hepatoma cells. More importantly, negative correlation between PAK6 and EZH2 expression was observed in hepatoma tissues from HCC patients. These data identified the tumor suppressive role and potential underlying mechanism of PAK6 in hepatocarcinogenesis. PMID- 26442589 TI - Assembly of a Tyr122 Hydrophobic Cluster in Sarcoplasmic Reticulum Ca2+-ATPase Synchronizes Ca2+ Affinity Reduction and Release with Phosphoenzyme Isomerization. AB - The mechanism whereby events in and around the catalytic site/head of Ca(2+) ATPase effect Ca(2+) release to the lumen from the transmembrane helices remains elusive. We developed a method to determine deoccluded bound Ca(2+) by taking advantage of its rapid occlusion upon formation of E1PCa2 and of stabilization afforded by a high concentration of Ca(2+). The assay is applicable to minute amounts of Ca(2+)-ATPase expressed in COS-1 cells. It was validated by measuring the Ca(2+) binding properties of unphosphorylated Ca(2+)-ATPase. The method was then applied to the isomerization of the phosphorylated intermediate associated with the Ca(2+) release process E1PCa2 -> E2PCa2 -> E2P + 2Ca(2+). In the wild type, Ca(2+) release occurs concomitantly with EP isomerization fitting with rate limiting isomerization (E1PCa2 -> E2PCa2) followed by very rapid Ca(2+) release. In contrast, with alanine mutants of Leu(119) and Tyr(122) on the cytoplasmic part of the second transmembrane helix (M2) and Ile(179) on the A domain, Ca(2+) release in 10 MUm Ca(2+) lags EP isomerization, indicating the presence of a transient E2P state with bound Ca(2+). The results suggest that these residues function in Ca(2+) affinity reduction in E2P, likely via a structural rearrangement at the cytoplasmic part of M2 and a resulting association with the A and P domains, therefore leading to Ca(2+) release. PMID- 26442591 TI - Recent advances in the application of total scattering methods to functional materials. AB - In this Feature Article we provide a description of some of the most recent results obtained in the field of materials science by means of total scattering methods and PDF analysis. Particular attention is devoted to the application of PDF to functional materials and to examples showing the combination of PDF with other solid state chemistry techniques. PMID- 26442590 TI - Dopamine Transporter Activity Is Modulated by alpha-Synuclein. AB - The duration and strength of the dopaminergic signal are regulated by the dopamine transporter (DAT). Drug addiction and neurodegenerative and neuropsychiatric diseases have all been associated with altered DAT activity. The membrane localization and the activity of DAT are regulated by a number of intracellular proteins. alpha-Synuclein, a protein partner of DAT, is implicated in neurodegenerative disease and drug addiction. Little is known about the regulatory mechanisms of the interaction between DAT and alpha-synuclein, the cellular location of this interaction, and the functional consequences of this interaction on the basal, amphetamine-induced DAT-mediated dopamine efflux, and membrane microdomain distribution of the transporter. Here, we found that the majority of DAT.alpha-synuclein protein complexes are found at the plasma membrane of dopaminergic neurons or mammalian cells and that the amphetamine mediated increase in DAT activity enhances the association of these proteins at the plasma membrane. Further examination of the interaction of DAT and alpha synuclein revealed a transient interaction between these two proteins at the plasma membrane. Additionally, we found DAT-induced membrane depolarization enhances plasma membrane localization of alpha-synuclein, which in turn increases dopamine efflux and enhances DAT localization in cholesterol-rich membrane microdomains. PMID- 26442593 TI - Uncoating Mechanism of Carnation Mottle Virus Revealed by Cryo-EM Single Particle Analysis. AB - Genome uncoating is a prerequisite for the successful infection of plant viruses in host plants. Thus far, little is known about the genome uncoating of the Carnation mottle virus (CarMV). Here, we obtained two reconstructions of CarMV at pH7 in the presence (Ca-pH7) and absence (EDTA-pH7) of calcium ions by Cryo-EM single particle analysis, which achieved 6.4 A and 8 A resolutions respectively. Our results showed that chelation of the calcium ions under EDTA-pH7 resulted in reduced interaction between the subunits near the center of the asymmetric unit but not overall size change of the viral particles, which indicated that the role of the calcium ions in CarMV was not predominantly for the structural preservation. Part of the genomic RNA closest to the capsid was found to be located near the center of the asymmetric unit, which might result from the interaction between genomic RNA and Lys194 residues. Together with the electrostatic potential analysis on the inner surface of the asymmetric unit, the reduced interaction near the center of the asymmetric unit under EDTA-pH7 suggested that the genome release of CarMV might be realized through the center of the asymmetric unit. PMID- 26442594 TI - Ruthenium chalcogenonitrosyl and bridged nitrido complexes containing chelating sulfur and oxygen ligands. AB - Ruthenium thio- and seleno-nitrosyl complexes containing chelating sulfur and oxygen ligands have been synthesised and their de-chalcogenation reactions have been studied. The reaction of mer-[Ru(N)Cl3(AsPh3)2] with elemental sulfur and selenium in tetrahydrofuran at reflux afforded the chalcogenonitrosyl complexes mer-[Ru(NX)Cl3(AsPh3)2] [X = S (1), Se (2)]. Treatment of 1 with KN(R2PS)2 afforded trans-[Ru(NS)Cl{N(R2PS)2}2] [R = Ph (3), Pr(i) (4), Bu(t) (5)]. Alternatively, the thionitrosyl complex 5 was obtained from [Bu(n)4N][Ru(N)Cl4] and KN(Bu(t)2PS)2, presumably via sulfur atom transfer from [N(Bu(t)2PS)2](-) to the nitride. Reactions of 1 and 2 with NaLOEt (LOEt(-) = [Co(eta(5) C5H5){P(O)(LOEt)2}3](-)) gave [Ru(NX)LOEtCl2] (X = S (8), Se (9)). Treatment of [Bu(n)4N][Ru(N)Cl4] with KN(R2PS)2 produced Ru(IV)-Ru(IV)MU-nitrido complexes [Ru2(MU-N){N(R2PS)2}4Cl] [R = Ph (6), Pr(i) (7)]. Reactions of 3 and 9 with PPh3 afforded 6 and [Ru(NPPh3)LOEtCl2], respectively. The desulfurisation of 5 with [Ni(cod)2] (cod = 1,5-cyclooctadiene) gave the mixed valance Ru(III)-Ru(IV)MU nitrido complex [Ru2(MU-N){N(Bu(t)2PS)2}4] (10) that was oxidised by [Cp2Fe](PF6) to give the Ru(IV)-Ru(IV) complex [Ru2(MU-N){N(Bu(t)2PS)2}4](PF6) ([10]PF6). The crystal structures of 1, 2, 3, 7, 9 and 10 have been determined. PMID- 26442595 TI - Diacerein protects against iodoacetate-induced osteoarthritis in the femorotibial joints of rats. AB - The present study was undertaken to investigate the effect of diacerein on the histopathology of articular cartilage and subchondral bone of the femorotibial joint in rats. Osteoarthritis was induced in rats after single intra-articular injection of sodium iodoacetate. Rats were sacrificed 1, 2, 4, and 8 weeks post intra-articular injection to evaluate the progression of histopathogenesis of osteoarthritis. Diacerein was orally administered (15 mg/kg) once daily post 1 and 2 weeks of iodoacetate injection in two groups, respectively, for up to 12 weeks. Articular cartilage and subchondral bone of the rats of both groups were examined after 8 and 12 weeks, respectively. Quantitative histological analyses were performed by scoring these sections as per the OARSI system. Chondroitin sulfate was also estimated in articular cartilage by decrease in absorbance of methylene blue on complexation with chondroitin sulfate using a spectrophotometer. Intra-articular injection of iodoacetate induced loss of articular cartilage with progressive subchondral bone sclerosis and degeneration. Based on histopathological and biochemical findings, diacerein treatment showed chondroprotective effect. Furthermore, the chondroprotective effect of diacerein was found to be more pronounced after 12 weeks as compared to 8 weeks in both cases (i.e., post 1 and 2 weeks of iodoacetate injection). Similar results were observed by investigation of chondroitin sulfate during biochemical study, showing the chondroprotective effect. In conclusion, diacerein exhibits chondroprotective effect in rats with late onset of action. PMID- 26442596 TI - HDAC inhibitor misprocesses bantam oncomiRNA, but stimulates hid induced apoptotic pathway. AB - Apoptosis or programmed cell death is critical for embryogenesis and tissue homeostasis. Uncontrolled apoptosis leads to different human disorders including immunodeficiency, autoimmune disorder and cancer. Several small molecules that control apoptosis have been identified. Here, we have shown the functional role of triazole derivative (DCPTN-PT) that acts as a potent HDAC inhibitor and mis express proto onco microRNA (miRNA) bantam. To further understanding the mechanism of action of the molecule in apoptotic pathway, a series of experiments were also performed in Drosophila, a well known model organism in which the nature of human apoptosis is very analogous. DCPTN-PT mis processes bantam microRNA and alters its down regulatory target hid function and cleavage of Caspase-3 which in turn influence components of the mitochondrial apoptotic pathway in Drosophila. However regulatory microRNAs in other pro-apoptotic genes are not altered. Simultaneously, treatment of same molecule also affects the mitochondrial regulatory pathway in human tumour cell lines suggesting its conservative nature between fly and human. It is reasonable to propose that triazole derivative (DCPTN-PT) controls bantam oncomiRNA and increases hid induced apoptosis and is also able to influence mitochondrial apoptotic pathway. PMID- 26442597 TI - Expansile crosslinked polymersomes for pH sensitive delivery of doxorubicin. AB - We report a new crosslinked polymersome with pH-responsive swelling properties through acidic hydrolysis of hydrophobic contents from the amphiphilic polymer chains. Its unique stability under physiological conditions and large swelling capability under low pH conditions give this polymersome promising potential for anticancer drug delivery. PMID- 26442598 TI - Direct regulation of the natural competence regulator gene tfoX by cyclic AMP (cAMP) and cAMP receptor protein (CRP) in Vibrios. AB - TfoX (Sxy) and CRP are two important competence activators. The link between tfoX and CRP has been shown in H. influenza but lacking evidence of direct interaction. Recently a Sxy-dependent CRP (CRP-S) site autoregulating Sxy was reported in E. coli. Here, we show that the cAMP-CRP complex transcriptionally regulates tfoX expression through multiple canonical CRP (CRP-N) sites in Vibrios. This conclusion is supported by an analysis of the tfoX mRNA levels and tfoX transcriptional reporter fusions. The reduced expression of tfoX(VC) was restored by trans-complementation of crp in ?crp and by exogenous cAMP in ?cya. A promoter deletion analysis and the site-directed mutagenesis of the putative CRP N sites revealed the presence of two functional CRP-N sites. The direct binding of cAMP-CRP to the tfoX(VC)promoter was demonstrated by EMSA assays. Additionally, the transcriptional start site (TSS) of tfoX(VF) in V. fluvialis was determined, and -10/-35 regions were predicted. Further comparison of the tfoX promoter in Vibrios revealed the existence of similar -10 motifs and putative CRP-N sites, indicating the conserved mechanism of CRP regulation on tfoX. Our study demonstrates the direct binding of the cAMP-CRP complex to tfoX promoter, and broadens the understanding of the molecular mechanism regulating tfoX in Vibrios. PMID- 26442599 TI - Lateral Hypothalamus GABAergic Neurons Modulate Consummatory Behaviors Regardless of the Caloric Content or Biological Relevance of the Consumed Stimuli. AB - It was recently reported that activation of a subset of lateral hypothalamus (LH) GABAergic neurons induced both appetitive (food-seeking) and consummatory (eating) behaviors in vGat-ires-cre mice, while inhibition or deletion of GABAergic neurons blunted these behaviors. As food and caloric-dense liquid solutions were used, the data reported suggest that these LH GABAergic neurons may modulate behaviors that function to maintain homeostatic caloric balance. Here we report that chemogenetic activation of this GABAergic population in vGat ires-cre mice increased consummatory behavior directed at any available stimulus, including those entailing calories (food, sucrose, and ethanol), those that do not (saccharin and water), and those lacking biological relevance (wood). Chemogenetic inhibition of these neurons attenuated consummatory behaviors. These data indicate that LH GABAergic neurons modulate consummatory behaviors regardless of the caloric content or biological relevance of the consumed stimuli. PMID- 26442600 TI - Varenicline-Induced Elevation of Dopamine in Smokers: A Preliminary [(11)C]-(+) PHNO PET Study. AB - Varenicline, a nicotinic partial agonist, is the most effective treatment for tobacco use disorder. However, its mechanism of action is still unclear and may involve stimulating dopaminergic transmission. Here we used PET imaging with [(11)C]-(+)-PHNO to explore for the first time the impact of varenicline on dopamine transmission in the D2-rich striatum and D3-rich extra-striatal regions and its relationship with craving, withdrawal and smoking. Eleven treatment seeking smokers underwent two PET scans with [(11)C]-(+)-PHNO, each following 12 h overnight smoking abstinence both prior to receiving varenicline and following 10-11 days of varenicline treatment (ie, at steady-state drug levels). Subjective measures of craving and urges to smoke were also assessed on the days of the PET scans. Varenicline treatment significantly reduced [(11)C]-(+)-PHNO binding in the dorsal caudate (p=0.008) and reduced some craving measures. These findings provide the first evidence that varenicline is able to increase DA levels in the human brain, a factor that may contribute to its therapeutic efficacy. PMID- 26442601 TI - GABAergic Signaling within a Limbic-Hypothalamic Circuit Integrates Social and Anxiety-Like Behavior with Stress Reactivity. AB - The posterior hypothalamic nucleus (PH) stimulates autonomic stress responses. However, the role of the PH in behavioral correlates of psychiatric illness, such as social and anxiety-like behavior, is largely unexplored, as is the neurochemistry of PH connectivity with limbic and neuroendocrine systems. Thus, the current study tested the hypothesis that GABAergic signaling within the PH is a critical link between forebrain behavior-regulatory nuclei and the neuroendocrine hypothalamus, integrating social and anxiety-related behaviors with physiological stress reactivity. To address this hypothesis, GABAA receptor pharmacology was used to locally inhibit or disinhibit the PH immediately before behavioral measures of social and anxiety-like behavior in rats. Limbic connectivity of the PH was then established by simultaneous co-injection of anterograde and retrograde tracers. Further, the role of PH GABAergic signaling in neuroendocrine stress responses was tested via inhibition/disinhibition of the PH. These studies determined a prominent role for the PH in the expression of anxiety-related behaviors and social withdrawal. Histological analyses revealed divergent stress-activated limbic input to the PH, emanating predominantly from the prefrontal cortex, lateral septum, and amygdala. PH projections also targeted both parvicellular and magnocellular peptidergic neurons in the paraventricular and supraoptic hypothalamus. Further, GABAA receptor pharmacology determined an excitatory effect of the PH on neuroendocrine responses to stress. These data indicate that the PH represents an important stress-integrative center, regulating behavioral processes and connecting the limbic forebrain with neuroendocrine systems. Moreover, the PH appears to be uniquely situated to have a role in stress-related pathologies associated with limbic-hypothalamic dysfunction. PMID- 26442603 TI - Raising the barrier for photoinduced DNA charge injection with a cyclohexyl artificial base pair. AB - The effects of an artificial cyclohexyl base pair on the quantum yields of fluorescence and dynamics of charge separation and charge recombination have been investigated for several synthetic DNA hairpins. The hairpins possess stilbenedicarboxamide, perylenediimide, or naphthalenediimide linkers and base paired stems. In the absence of the artificial base pair hole injection into both adenine and guanine purine bases is exergonic and irreversible, except in the case of stilbene with adenine for which it is slightly endergonic and reversible. Insertion of the artificial base pair renders hole injection endergonic or isoergonic except in the case of the powerful naphthalene acceptor for which it remains exergonic. Both hole injection and charge recombination are slower for the naphthalene acceptor in the presence of the artificial base pair than in its absence. The effect of an artificial base pair on charge separation and charge recombination in hairpins possessing stilbene and naphthalene acceptor linkers and a stilbenediether donor capping group has also been investigated. In the case of the stilbene acceptor-stilbene donor capped hairpins photoinduced charge separation across six base pairs is efficient in the absence of the artificial base pair but does not occur in its presence. In the case of the naphthalene acceptor-stilbene donor capped hairpins the artificial base pair slows but does not stop charge separation and charge recombination, leading to the formation of long-lived charge separated states. PMID- 26442602 TI - State-Dependent Partial Occlusion of Cortical LTP-Like Plasticity in Major Depression. AB - The synaptic plasticity hypothesis of major depressive disorder (MDD) posits that alterations in synaptic plasticity represent a final common pathway underlying the clinical symptoms of the disorder. This study tested the hypotheses that patients with MDD show an attenuation of cortical synaptic long-term potentiation (LTP)-like plasticity in comparison with healthy controls, and that this attenuation recovers after remission. Cortical synaptic LTP-like plasticity was measured using a transcranial magnetic stimulation protocol, ie, paired associative stimulation (PAS), in 27 in-patients with MDD according to ICD-10 criteria and 27 sex- and age-matched healthy controls. The amplitude of motor evoked potentials was measured before and after PAS. Patients were assessed during the acute episode and at follow-up to determine the state- or trait character of LTP-like changes. LTP-like plasticity, the PAS-induced increase in motor-evoked potential amplitudes, was significantly attenuated in patients with an acute episode of MDD compared with healthy controls. Patients with remission showed a restoration of synaptic plasticity, whereas the deficits persisted in patients without remission, indicative for a state-character of impaired LTP-like plasticity. The results provide first evidence for a state-dependent partial occlusion of cortical LTP-like plasticity in MDD. This further identifies impaired LTP-like plasticity as a potential pathomechanism and treatment target of the disorder. PMID- 26442604 TI - Differential activation of renal sympathetic burst amplitude and frequency during hypoxia, stress and baroreflexes with chronic angiotensin treatment. AB - NEW FINDINGS: What is the central question of this study? Is the elevated tonic renal nerve activity induced by chronic angiotensin administration mediated by recruitment or increased firing frequency and does this occur via stress, chemoreflex or baroreflex pathways? What is the main finding and its importance? Long-term angiotensin treatment in rabbits elevates renal sympathetic nerve activity by recruitment of previously silent fibres. This was similar to the effect of chemoreflex stimulation, but not to stress or baroreceptor activation, suggesting that presympathetic pathways activated by angiotensin may be common to those activated by chemoreceptors. Modulation of sympathetic nerve activity involves control by the CNS of the amplitude of neural discharges, reflecting recruitment of neurons and their firing frequency. We tested whether elevated tonic renal sympathetic nerve activity (RSNA) induced by chronic angiotensin administration is mediated by recruitment or increased firing frequency and whether this is characteristic of the pattern observed with activation of stress, chemoreflex or baroreflex pathways. Conscious rabbits treated with angiotensin II for 12 weeks to increase blood pressure by 10-30% were subjected to stress (air jet), hypoxia (10% O2 + 3% CO2) and drug-induced changes in blood pressure to produce baroreflexes. Total RSNA and RSNA burst amplitude were scaled to 100 normalized units (n.u.) by the maximal response to smoke. After 12 weeks of treatment, blood pressure was 17% higher than baseline 68 +/- 1 mmHg (P = 0.02). Compared with sham treatment, total RSNA and burst amplitude were +82% (P < 0.001) and 39% (P = 0.04) greater, but burst frequency was similar. Total RSNA increased during hypoxia (+38% from 4.9 +/- 0.7 n.u.), owing to greater amplitude, but not frequency. Air-jet stress increased total RSNA (+44% from 4.3 +/- 0.5 n.u.) and burst frequency (+21% from 5.4 +/- 0.7 bursts s(-1) ), but not amplitude. Angiotensin enhanced total RSNA responses to both air jet (+33%) and hypoxia (+58%), but only increased the amplitude response to air jet. The RSNA baroreflexes reset to the higher blood pressure, but amplitude or frequency was not differentially altered. Chronic angiotensin treatment elevated RSNA by recruitment of neurons, which is similar to chemoreflex stimulation, but not to stress or baroreceptor activation, suggesting that presympathetic pathways activated by angiotensin may be common to those activated by chemoreceptors. PMID- 26442606 TI - Chemiluminometric Immunosensor for High-Sensitivity Cardiac Troponin I Employing a Polymerized Enzyme Conjugate as a Tracer. AB - To detect high-sensitivity cardiac troponin I (hs-cTnI; <0.01 ng/mL) at points of care, we developed a rapid immunosensor by using horseradish peroxidase polymerized in 20 molecules on average (Poly-HRP) as a tracer conjugated with streptavidin (SA-Poly-HRP). As shown in the conventional system, enhanced sensitivity could be achieved by using a sequential binding scheme for the complex formation to contain the huge molecular tracer. We used a 2-dimensional chromatographic technology to carry out the sequential bindings in cross-flow directions. After the complex formation of antigen-antibody with analyte in a vertical direction, SA-Poly-HRP was horizontally supplied across the membrane strip for additional binding via a biotin-SA linkage. The HRP substrate was subsequently supplied along the same direction to produce a chemiluminometric signal, which was measured by a cooled charge-coupled device. Hs-cTnI analysis was completed in this format within 25 min, and the results showed a high correlation with those of the CentaurXP(r) reference system (R(2) > 0.99). The detection limit of the rapid immunosensor was 0.003 +/- 0.001 ng/mL cTnI, corresponding to a 10-fold improvement compared to results using the plain enzyme tracer. This demonstrated the measurement of hs-cTnI in a much more cost effective manner compared to the automated versions currently available. PMID- 26442607 TI - Onset and progression of de novo donor-specific anti-human leukocyte antigen antibodies after BK polyomavirus and preemptive immunosuppression reduction. AB - BACKGROUND: BK polyomavirus (BKPyV) viremia/nephropathy and reduction in immunosuppression following viremia may increase the risk of alloimmune activation and allograft rejection. This study investigates the impact of BKPyV viremia on de novo donor anti-human leukocyte antigen (HLA)-specific antibodies (dnDSA). PATIENTS AND METHODS: All primary renal transplants at East Carolina University from March 1999 to December 2010, with at least 1 post-transplant BKPyV viral load testing, were analyzed. Patients were negative for anti-HLA antibodies to donor antigens (tested via single antigen beads) at transplantation and at first BKPyV testing. RESULTS: Nineteen of 174 patients (11%) tested positive for BKPyV viremia. Within 24 months of BKPyV viremia detection, 79% of BKPyV-viremic patients developed dnDSA. Only 20% of BKPyV viremia-persistent cases, compared to 86% of BKPyV viremia-resolved cases, developed dnDSA (P = 0.03). Poor allograft survival was evident in BKPyV viremia-persistent patients (60% failure by 2 years post BKPyV diagnosis) and in BKPyV viremia-resolved patients with dnDSA (5-year post BKPyV diagnosis allograft survival of 48%). CONCLUSIONS: Post-transplant BKPyV viremia and preemptive immunosuppression reduction is associated with high rates of dnDSA. When preemptively treating BKPyV viremia, dnDSA should be monitored to prevent allograft consequences. PMID- 26442608 TI - Rational Design of a Lanthanide-Based Complex Featuring Different Single-Molecule Magnets. AB - The rational synthesis of the 2-{1-methylpyridine-N-oxide-4,5-[4,5 bis(propylthio)tetrathiafulvalenyl]-1H-benzimidazol-2-yl}pyridine ligand (L) is described. It led to the tetranuclear complex [Dy4(tta)12(L)2] (Dy-Dy2-Dy) after coordination reaction with the precursor Dy(tta)3?2 H2O (tta(-) = 2 thenoyltrifluoroacetonate). The X-ray structure of Dy-Dy2-Dy can be described as two terminal mononuclear units bridged by a central antiferromagnetically coupled dinuclear complex. The terminal N2O6 and central O8 environments are described as distorted square antiprisms. The ac magnetism measurements revealed a strong out of-phase signal of the magnetic susceptibility with two distinct sets of data. The high- and low-frequency components were attributed to the two terminal mononuclear single-molecule magnets (SMMs) and the central dinuclear SMM, respectively. A magnetic hysteresis loop was detected at very low temperature. From both structural and magnetic points of view, the tetranuclear SMM Dy-Dy2-Dy is a self-assembly of two known mononuclear SMMs bridged by a known dinuclear SMM. PMID- 26442609 TI - Metal-to-insulator switching in quantum anomalous Hall states. AB - After decades of searching for the dissipationless transport in the absence of any external magnetic field, quantum anomalous Hall effect (QAHE) was recently achieved in magnetic topological insulator films. However, the universal phase diagram of QAHE and its relation with quantum Hall effect (QHE) remain to be investigated. Here, we report the experimental observation of the giant longitudinal resistance peak and zero Hall conductance plateau at the coercive field in the six quintuple-layer (Cr(0.12)Bi(0.26)Sb(0.62))2Te3 film, and demonstrate the metal-to-insulator switching between two opposite QAHE plateau states up to 0.3 K. Moreover, the universal QAHE phase diagram is confirmed through the angle-dependent measurements. Our results address that the quantum phase transitions in both QAHE and QHE regimes are in the same universality class, yet the microscopic details are different. In addition, the realization of the QAHE insulating state unveils new ways to explore quantum phase-related physics and applications. PMID- 26442610 TI - Bortezomib-thalidomide-dexamethasone (VTD) is superior to bortezomib cyclophosphamide-dexamethasone (VCD) as induction therapy prior to autologous stem cell transplantation in multiple myeloma. PMID- 26442611 TI - Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is frequently complicated by secondary autoimmune cytopenias (AICs). Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase approved for the treatment of relapsed CLL and CLL with del(17p). The effect of ibrutinib treatment on the incidence of AIC is currently unknown. We reviewed medical records of 301 patients treated with ibrutinib, as participants in therapeutic clinical trials at The Ohio State University Comprehensive Cancer Center between July 2010 and July 2014. Subjects were reviewed with respect to past history of AIC, and treatment-emergent AIC cases were identified. Before starting ibrutinib treatment, 26% of patients had experienced AIC. Information was available for a total of 468 patient-years of ibrutinib exposure, during which there were six cases of treatment-emergent AIC. This corresponds to an estimated incidence rate of 13 episodes for every 1000 patient-years of ibrutinib treatment. We further identified 22 patients receiving therapy for AIC at the time ibrutinib was started. Of these 22 patients, 19 were able to discontinue AIC therapy. We found that ibrutinib treatment is associated with a low rate of treatment-emergent AIC. Patients with an existing AIC have been successfully treated with ibrutinib and subsequently discontinued AIC therapy. PMID- 26442613 TI - Familial risk of non-Hodgkin lymphoma by sex, relationship, age at diagnosis and histology: a joint study from five Nordic countries. AB - We aimed to estimate stratified absolute (cumulative) and relative (standardized incidence ratios; SIRs) risks of non-Hodgkin lymphoma (NHL) in relatives of NHL patients. A cohort of 169 830 first-degree relatives of 45 406 NHL patients who were diagnosed between 1955 and 2010 in five European countries was followed for cancer incidence. The lifetime (0-79 year) cumulative risk of NHL in siblings of a patient with NHL was 1.6%, which represents a 1.6-fold increased risk (SIR=1.6, 95% confidence interval (CI)=1.2-1.9) over the general population risk. NHL risk among parent-offspring pairs was increased up to 1.4-fold (95% CI=1.3-1.5; lifetime risk 1.4%). The lifetime risk was higher when NHL was diagnosed in a sister (2.5% in her brothers and 1.9% in her sisters) or a father (1.7% in his son). When there were ?2 NHL patients diagnosed in a family, the lifetime NHL risk for relatives was 2.1%. Depending on sex and age at diagnosis, twins had a 3.1-12.9% lifetime risk of NHL. Family history of most of the histological subtypes of NHL increased the risk of concordant and some discordant subtypes. Familial risk did not significantly change by age at diagnosis of NHL in relatives. Familial risk of NHL was not limited to early onset cases. PMID- 26442612 TI - Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. AB - CC-486, the oral formulation of azacitidine (AZA), is an epigenetic modifier and DNA methyltransferase inhibitor in clinical development for treatment of hematologic malignancies. CC-486 administered for 7 days per 28-day treatment cycle was evaluated in a phase 1 dose-finding study. AZA has a short plasma half life and DNA incorporation is S-phase-restricted; extending CC-486 exposure may increase the number of AZA-affected diseased target cells and maximize therapeutic effects. Patients with lower-risk myelodysplastic syndromes (MDS) received 300 mg CC-486 once daily for 14 days (n=28) or 21 days (n=27) of repeated 28-day cycles. Median patient age was 72 years (range 31-87) and 75% of patients had International Prognostic Scoring System Intermediate-1 risk MDS. Median number of CC-486 treatment cycles was 7 (range 2-24) for the 14-day dosing schedule and 6 (1-24) for the 21-day schedule. Overall response (complete or partial remission, red blood cell (RBC) or platelet transfusion independence (TI), or hematologic improvement) (International Working Group 2006) was attained by 36% of patients receiving 14-day dosing and 41% receiving 21-day dosing. RBC TI rates were similar with both dosing schedules (31% and 38%, respectively). CC 486 was generally well-tolerated. Extended dosing schedules of oral CC-486 may provide effective long-term treatment for patients with lower-risk MDS. PMID- 26442614 TI - Switchable Ultrathin Quarter-wave Plate in Terahertz Using Active Phase-change Metasurface. AB - Metamaterials open up various exotic means to control electromagnetic waves and among them polarization manipulations with metamaterials have attracted intense attention. As of today, static responses of resonators in metamaterials lead to a narrow-band and single-function operation. Extension of the working frequency relies on multilayer metamaterials or different unit cells, which hinder the development of ultra-compact optical systems. In this work, we demonstrate a switchable ultrathin terahertz quarter-wave plate by hybridizing a phase change material, vanadium dioxide (VO2), with a metasurface. Before the phase transition, VO2 behaves as a semiconductor and the metasurface operates as a quarter-wave plate at 0.468 THz. After the transition to metal phase, the quarter wave plate operates at 0.502 THz. At the corresponding operating frequencies, the metasurface converts a linearly polarized light into a circularly polarized light. This work reveals the feasibility to realize tunable/active and extremely low-profile polarization manipulation devices in the terahertz regime through the incorporation of such phase-change metasurfaces, enabling novel applications of ultrathin terahertz meta-devices. PMID- 26442615 TI - Protective Role of Crocin Against Nicotine-induced Damages on Male Mice Liver. AB - BACKGROUND: Nicotine is a major pharmacologically active substance in cigarette smoke. It is mainly metabolized in liver and causes devastating effects. Crocin is the chemical ingredient primarily responsible for the color of saffron. It has different pharmacological effects such as antioxidant and anticancer. This study was designed to evaluate the protective role of crocin against nicotine on the liver of mice. METHODS: Forty-eight mice were equally divided into 8 groups; control (normal saline), nicotine (2.5 mg/kg), crocin (12.5, 25 and 50 mg/kg) and crocin plus nicotine treated groups. Saline, crocin, nicotine and crocin/nicotine (once a day) were intraperitoneally injected for 4 weeks. The liver weight and histology, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and serum nitric oxide levels have been studied. RESULTS: The results indicated that nicotine administration significantly decreased liver weight (48.37%) and increased the mean diameter of hepatocyte (239%), central hepatic vein (28.45%), liver enzymes level (ALP 29.43%, AST 21.81%, ALT 21.55%), and blood serum nitric oxide level (57.18%) compared to saline group (P < 0.05). However, crocin and crocin plus nicotine administration significantly boosted liver weight (49.54%) and decreased the mean diameter of hepatocyte (40.48%), central hepatic vein (15.44%), liver enzymes (ALP 22.02%, AST 19.05%, ALT 23.11%), and nitric oxide levels (35.80%) in all groups compared to nicotine group (percentages represent the maximum dose) (P < 0.05). CONCLUSIONS: Crocin showed its partly protective effect against nicotine-induced liver toxicity. PMID- 26442616 TI - Neonatal brain abnormalities associated with autism spectrum disorder in children born very preterm. AB - Very preterm (VP) survivors are at increased risk of autism spectrum disorder (ASD) compared with term-born children. This study explored whether neonatal magnetic resonance (MR) brain features differed in VP children with and without ASD at 7 years. One hundred and seventy-two VP children (<30 weeks' gestation or <1250 g birth weight) underwent structural brain MR scans at term equivalent age (TEA; 40 weeks' gestation +/-2 weeks) and were assessed for ASD at 7 years of age. The presence and severity of white matter, cortical gray matter, deep nuclear gray matter, and cerebellar abnormalities were assessed, and total and regional brain volumes were measured. ASD was diagnosed using a standardized parent report diagnostic interview and confirmed via an independent assessment. Eight VP children (4.7%) were diagnosed with ASD. Children with ASD had more cystic lesions in the cortical white matter at TEA compared with those without ASD (odds ratio [OR] 8.7, 95% confidence interval [CI] 1.5, 51.3, P = 0.02). There was also some evidence for smaller cerebellar volumes in children with ASD compared with those without ASD (OR = 0.82, CI = 0.66, 1.00, P = 0.06). Overall, the results suggest that VP children with ASD have different brain structure in the neonatal period compared with those who do not have ASD. Autism Res 2016, 9: 543-552. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26442617 TI - Effects of landscape matrix on population connectivity of an arboreal mammal, Petaurus breviceps. AB - Ongoing habitat loss and fragmentation is considered a threat to biodiversity as it can create small, isolated populations that are at increased risk of extinction. Tree-dependent species are predicted to be highly sensitive to forest and woodland loss and fragmentation, but few studies have tested the influence of different types of landscape matrix on gene flow and population structure of arboreal species. Here, we examine the effects of landscape matrix on population structure of the sugar glider (Petaurus breviceps) in a fragmented landscape in southeastern South Australia. We collected 250 individuals across 12 native Eucalyptus forest remnants surrounded by cleared agricultural land or exotic Pinus radiata plantations and a large continuous eucalypt forest. Fifteen microsatellite loci were genotyped and analyzed to infer levels of population differentiation and dispersal. Genetic differentiation among most forest patches was evident. We found evidence for female philopatry and restricted dispersal distances for females relative to males, suggesting there is male-biased dispersal. Among the environmental variables, spatial variables including geographic location, minimum distance to neighboring patch, and degree of isolation were the most important in explaining genetic variation. The permeability of a cleared agricultural matrix to dispersing gliders was significantly higher than that of a pine matrix, with the gliders dispersing shorter distances across the latter. Our results added to previous findings for other species of restricted dispersal and connectivity due to habitat fragmentation in the same region, providing valuable information for the development of strategies to improve the connectivity of populations in the future. PMID- 26442618 TI - Assessment of phytochemicals and antioxidant activities of raw and germinating Ceiba pentandra (kapok) seeds. AB - To determine the significance of germination on phytochemical constituents and non-enzymatic antioxidant activities of Ceiba pentandra seed extracts. Phytochemicals and antioxidant activities of raw and germinating seeds of Ceiba pentandra were estimated by different methods. The levels of phytochemical constituents were influenced by germination and increased except alkaloids and tannins, which were decreased significantly during germination. Among non enzymatic antioxidants like DPPH, FRAP, reducing assay and hydroxyl radical scavenging activity all showed improved activity compared with non-germinating seeds. This may be due to various reactive oxygen species (ROS) that were generated as by-products of metabolism during germination. This group of ROS included superoxide radicals (O2), hydrogen peroxide radicals (H2O2) and hydroxyl radicals (OH). The formation of these oxygen radicals resulted in the accumulation of lipid hydroperoxides by radical chain oxidation via phospholipids peroxy radicals within membranes. Therefore, it was hypothesized that this could be related to the increase of antioxidant activity in large unilamellar vesicles observed in germinated seeds. The implication of this study is that the Ceiba pentandra seeds as natural antioxidant agents and put forward the possibility of employing for therapeutic potential. PMID- 26442619 TI - Differential Rates of Inadvertent Intravascular Injection during Lumbar Transforaminal Epidural Injections Using Blunt-Tip, Pencil-Point, and Catheter Extension Needles. AB - OBJECTIVE: To quantify the incidence of inadvertent vascular penetration during lumbosacral transforaminal epidural injections using blunt-tip, pencil-point, and catheter-extension needles. STUDY DESIGN/SETTING: This is a prospective, observational, consecutive cohort study. SUBJECTS: Two hundred consecutive patients undergoing lumbosacral transforaminal epidural injections at an academic outpatient spine center. METHODS: Four hundred seventy-five fluoroscopically guided lumbosacral transforaminal epidural injections were performed on consecutively consenting patients by one interventional spine physician, using three different needle types. The presence or absence of vascular uptake was determined during contrast injection under live fluoroscopy. RESULTS: Vascular uptake of contrast was observed in 58 of the total 475 injections, for an overall incidence of 12.2%. By needle type, the incidence of inadvertent vascular uptake was 16.6% (26/157) in the pencil-point group, 15.6% (24/154) in the blunt-tip group, and 4.9% (8/164) in the catheter-extension group. The difference in rates is statistically significant between the catheter-extension needle group and both the pencil-point group (P = 0.0009) and blunt-tip group (P = 0.0024). A secondary analysis was performed to quantify the incidence of functional pitfalls between needle groups, with a significantly lower incidence in the pencil-point group compared to both the catheter-extension (P = 0.0148) and blunt-tip needle (P = 0.0288) groups. CONCLUSIONS: Blunt-tip and pencil-point needles have comparable risk of inadvertent vascular injection during lumbosacral transforaminal injections. Catheter-extension needles demonstrated a reduce incidence of vascular uptake, but also result in a significantly higher rate of functional pitfalls that limits their usefulness in routine practice. PMID- 26442620 TI - Management of Rapidly Ascending Driveline Tunnel Infection. AB - We present a case of rapidly ascending left ventricular assist device driveline and tunnel infection in a patient with a long length of driveline buried beyond the distal velour coating. Device salvage with radical debridement, exit site relocation, and local tissue advancement is described. The findings in this case suggest that the interface between nonvelour covered driveline and subcutaneous tissue can become the nidus of a virulent ascending infection because of poor tissue ingrowth. PMID- 26442621 TI - Effect of High-Dose Statin Pretreatment on the Incidence of Periprocedural Myocardial Infarction in Patients Undergoing Percutaneous Coronary Intervention: Grading the Evidence Through a Cumulative Meta-analysis. AB - BACKGROUND: Previous studies have showed that high-dose statin pretreatment could reduce the incidence of periprocedural myocardial infarction (PMI) in patients undergoing percutaneous coronary intervention (PCI). However, previous analyses have not performed reliable grading of evidence. HYPOTHESIS: In previous analyses, it supposed that the high-dose statin pretreatment was effective in reduction of the rate of PMI. In this analysis, we evaluated the effect of high dose statin pretreatment on the reduction of rate of PMI based on a cumulative meta-analysis and grading of evidence. METHODS: We assembled the relevant published randomized controlled trials that compared the efficacy of high-dose statin pretreatment prior to PCI. We evaluated the risk of PMI by a cumulative meta-analysis, with subgroups stratified by clinical classifications and different statin histories, and we conducted explicit grading of evidence. RESULTS: High-dose statin pretreatment caused a 55% reduction in PMI through this cumulative meta-analysis of 23 RCTs (odds ratio [OR]: 0.45, 95% confidence interval [CI]: 0.37-0.54). The effect of high-dose statin pretreatment was significant for the stable angina subgroup (OR: 0.42, 95% CI: 0.32-0.56), ACS subgroup (OR: 0.43, 95% CI: 0.29-0.64), and the mixed presentation subgroup (OR: 0.50, 95% CI: 0.36-0.70). In different statin therapy histories, high-dose statin pretreatment reduced incidence of PMI 55% in the statin-naive subgroup (OR: 0.45, 95% CI: 0.36-0.56) and 54% in the low-dose statin subgroup (OR: 0.46, 95% CI: 0.32-0.66). The GRADE system indicated that the overall evidence quality was moderate. This finding may strengthen the confidence in any recommendations. CONCLUSIONS: High-dose statin pretreatment can reduce the rate of PMI, irrespective of either the clinical presentation or previous statin-treatment history. Importantly, the overall GRADE evidence quality was moderate. PMID- 26442622 TI - Evolutionary conservation of molecular structure and antiviral function of a viral receptor, LGP2, in amphioxus Branchiostoma japonicum. AB - RIG-I-like (where RIG-I is retinoic acid inducible gene I) receptor LGP2 (where LGP2 is laboratory of genetics and physiology) is an important intracellular receptor that recognizes viral RNAs in innate immunity, but its origin and evolution remains unknown. Here we clearly demonstrate the presence of a RIG-I like receptor, BjLGP2, in the basal chordate amphioxus. It is predominantly expressed in the hepatic caecum and hindgut, and is upregulated following challenge with poly(I:C). BjLGP2 is distributed in the cytoplasm of both grouper spleen and flounder gill (FG) cells, and the recombinant BjLGP2 interacts with poly(I:C). BjLGP2 can enhance the expression of IFN and IFN-inducible genes in FG cells upon poly(I:C) challenge. It also significantly induces the expression of the antiviral genes ifn-i and Mx as well as the signal transduction relevant genes MAVS, NF-kappaB, and IRF-3 in FG cells upon lymphocystis disease virus challenge. Moreover, BjLGP2 inhibits the replication of lymphocystis disease virus in FG cells and the gene transcription of Singapore grouper iridovirus in grouper spleen cells. This is the first report showing that a LGP2 protein in invertebrate species (amphioxus) is structurally conserved and plays an antiviral role similar to that of vertebrate LGP2 proteins. PMID- 26442623 TI - The ACGME Self-Study-An Opportunity, Not a Burden. PMID- 26442624 TI - Hydration and ion pair formation in aqueous Y(3+)-salt solutions. AB - Raman spectra of aqueous yttrium perchlorate, triflate (trifluoromethanesulfonate), chloride and nitrate solutions were measured over a broad concentration range (0.198-3.252 mol L(-1)). The spectra range from low wavenumbers to 4200 cm(-1). A very weak mode at 384 cm(-1) with a full width at half height at 50 cm(-1) in the isotropic spectrum suggests that the Y(3+)- octa aqua ion is thermodynamically stable in dilute perchlorate solutions (~0.5 mol L( 1)) while in concentrated perchlorate solutions outer-sphere ion pairs and contact ion pairs are formed. The octa-hydrate, [Y(OH2)8](3+) was also detected in a 1.10 mol L(-1) aqueous Y(CF3SO3)3 solution. Furthermore, very weak and broad depolarized modes could be detected which are assigned to [Y(OH2)8](3+)(aq) at 100, 166, 234 and 320 cm(-1) confirming that a hexa-hydrate is not compatible with the hydrated species in solution. In yttrium chloride solutions contact ion pair formation was detected over the measured concentration range from 0.479 3.212 mol L(-1). The contact ion pairs in YCl3(aq) are fairly weak and disappear with dilution. At a concentration <0.2 mol L(-1) almost all complexes have disappeared. In YCl3 solutions, with additional HCl, chloro-complexes of the type [Y(OH2)8-nCln](+3-n) (n = 1,2) are formed. The Y(NO3)3(aq) spectra were compared with a spectrum of a dilute NaNO3 solution and it was concluded that in Y(NO3)3(aq) over the concentration range from 2.035-0.198 mol L(-1) nitrato complexes [Y(OH2)8-n(NO3)ln](+3-n) (n = 1,2) are formed. The nitrato-complexes are weak and disappear with dilution <0.1 mol L(-1). DFT geometry optimizations and frequency calculations are reported for both the yttrium-water cluster in the gas phase and the cluster within a polarizable continuum model in order to implicitly describe the presence of the bulk solvent. The bond distance and angle for the square antiprismatic cluster geometry of [Y(OH2)8](3+) with the polarizable dielectric continuum is in good agreement with data from recent structural experimental measurements. The DFT frequency of the Y-O stretching mode of the [Y(OH2)8](3+) cluster, in a polarizable continuum, is at 372 cm(-1) in satisfactory agreement with the experimental value. PMID- 26442625 TI - Drosophila chitinous aECM and its cellular interactions during tracheal development. AB - The morphology of organs, and hence their proper physiology, relies to a considerable extent on the extracellular matrix (ECM) secreted by their cells. The ECM is a structure contributed to and commonly shared by many cells in an organism that plays an active role in morphogenesis. Increasing evidence indicates that the ECM not only provides a passive contribution to organ shape but also impinges on cell behaviour and genetic programmes. The ECM is emerging as a direct modulator of many aspects of cell biology, rather than as a mere physical network that supports cells. Here, we review how the apical chitinous ECM is generated in Drosophila trachea and how cells participate in the formation of this supracellular structure. We discuss recent findings on the molecular and cellular events that lead to the formation of this apical ECM (aECM) and how it is influenced and affects tracheal cell biology. PMID- 26442627 TI - Circularly polarised luminescence and circular dichroism of l- and d oligopeptides with multiple pyrenes. AB - Among l- and d-oligopeptides with multiple pyrenes as pendants, the dipeptides with two and three pyrenes showed blue-coloured circularly polarised luminescence as high as |gem|~ (0.86-1.1) * 10(-2) at around 450 nm, reflecting from exciton couplets of twisted pyrenes. PMID- 26442628 TI - Ouabain rescues rat nephrogenesis during intrauterine growth restriction by regulating the complement and coagulation cascades and calcium signaling pathway. AB - Intrauterine growth restriction (IUGR) is associated with a reduction in the numbers of nephrons in neonates, which increases the risk of hypertension. Our previous study showed that ouabain protects the development of the embryonic kidney during IUGR. To explore this molecular mechanism, IUGR rats were induced by protein and calorie restriction throughout pregnancy, and ouabain was delivered using a mini osmotic pump. RNA sequencing technology was used to identify the differentially expressed genes (DEGs) of the embryonic kidneys. DEGs were submitted to the Database for Annotation and Visualization and Integrated Discovery, and gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted. Maternal malnutrition significantly reduced fetal weight, but ouabain treatment had no significant effect on body weight. A total of 322 (177 upregulated and 145 downregulated) DEGs were detected between control and the IUGR group. Meanwhile, 318 DEGs were found to be differentially expressed (180 increased and 138 decreased) between the IUGR group and the ouabain-treated group. KEGG pathway analysis indicated that maternal undernutrition mainly disrupts the complement and coagulation cascades and the calcium signaling pathway, which could be protected by ouabain treatment. Taken together, these two biological pathways may play an important role in nephrogenesis, indicating potential novel therapeutic targets against the unfavorable effects of IUGR. PMID- 26442629 TI - In-situ epitaxial growth of graphene/h-BN van der Waals heterostructures by molecular beam epitaxy. AB - Van der Waals materials have received a great deal of attention for their exceptional layered structures and exotic properties, which can open up various device applications in nanoelectronics. However, in situ epitaxial growth of dissimilar van der Waals materials remains challenging. Here we demonstrate a solution for fabricating van der Waals heterostructures. Graphene/hexagonal boron nitride (h-BN) heterostructures were synthesized on cobalt substrates by using molecular beam epitaxy. Various characterizations were carried out to evaluate the heterostructures. Wafer-scale heterostructures consisting of single layer/bilayer graphene and multilayer h-BN were achieved. The mismatch angle between graphene and h-BN is below 1 degrees . PMID- 26442630 TI - Induction of ROS-independent DNA damage by curcumin leads to G2/M cell cycle arrest and apoptosis in human papillary thyroid carcinoma BCPAP cells. AB - Previously we found that curcumin, the active constituent of dietary spice turmeric, showed potent inhibitory effects on the cell growth of thyroid cancer cells. However, the detailed anti-cancer mechanism of curcumin is still unknown. In this study, we have reported that curcumin induces significant DNA damage in human papillary thyroid carcinoma BCPAP cells in a dose-dependent manner as evidenced by the upregulated phosphorylation of H2A.X at Ser139, which was further confirmed by the long tails in the comet assay and the increase in the number of TUNEL-positive cells. Subsequently, curcumin treatment caused a significant accumulation of cells at the G2/M phase that eventually resulted in a caspase-dependent apoptosis in BCPAP cells. DNA agarose gel electrophoresis revealed that curcumin-induced DNA damage in BCPAP cells was independent of DNA conformational change. Pretreatment with reactive oxygen species (ROS) scavengers failed to block the phosphorylation of H2A.X, suggesting the non-involvement of ROS in curcumin-mediated DNA damage. Interestingly, ATM/ATR activation by curcumin induced phosphorylation of Chk2 (Thr68) followed by that of Cdc25C (Ser216) and Cdc2 (Tyr15), and Cyclin B1 accumulation. In addition, the ATM specific inhibitor KU-55933 reversed curcumin-induced phosphorylation of H2A.X. These results collectively show that curcumin treatment induced the DNA damage response via triggering an ATM-activated Chk2-Cdc25C-Cdc2 signaling pathway. These observations provide novel mechanisms and potential targets for the better understanding of the anti-cancer mechanisms of curcumin. PMID- 26442631 TI - Poly(vinyl alcohol)-Poly(ethylene glycol) Double-Network Hydrogel: A General Approach to Shape Memory and Self-Healing Functionalities. AB - A double-network polymer hydrogel composed of chemically cross-linked poly(ethylene glycol) (PEG) and physically cross-linked poly(vinyl alcohol) (PVA) was prepared. When the hydrogel (70 wt % of water) is subjected to freezing/thawing treatment under strain, the enhanced physical network as a result of crystallization of PVA chains can stabilize the hydrogel deformation after removal of the external force at room temperature. Subsequent disruption of the physical network of PVA by heating allows for the recovery of the initial shape of the hydrogel. Moreover, the double-network hydrogel exhibits self healing capability stemming from the physical network of PVA by virtue of the extensive interchain hydrogen bonding between the hydroxyl side groups. This study thus demonstrates a general approach to imparting both the shape memory and self-healing properties to chemically cross-linked hydrogels that otherwise do not have such functionalities. Moreover, by making use of the fixed hydrogel elongation, the effect of anisotropy arising from chain orientation on the self healing was also observed. PMID- 26442632 TI - New insights on the wooden weapons from the Paleolithic site of Schoningen. AB - The Paleolithic site of Schoningen is famous for the earliest known, completely preserved wooden weapons. Here we present recent results of an ongoing analysis of the nine spears, one lance, a double pointed stick, and a burnt stick dating to the Holsteinian, c. 300 kyr. Macroscopic and microscopic analyses, as well as studies of thin sections, contribute to a better understanding of the manufacture of the wooden weapons. They were deposited in organic sediments at a former lakeshore among numerous bones of butchered horses. In general, the spears are extremely well-preserved and show no or little sign of taphonomic alteration, although some of the weapons are broken and parts were slightly moved, probably by water action. The excellent preservation conditions provide considerable information on the operational sequence of production. The hunters selected thin trunks of spruce or pine and initially stripped off the bark. Traces of cutting, scraping, and smoothing can be observed on the spear surfaces in detail. In the case of spear X, repeated use of the weapon is implied by re-sharpening of the tip. Analyses of wood anatomy provide information on climatic conditions and contribute to the better understanding of the development of the site. PMID- 26442634 TI - Sudomotor and vasomotor activity during the menstrual cycle with global heating. AB - Many studies have reported that there are changes in sympathetic activity throughout the menstrual cycle as there are oestrogen receptor in the hypothalamus and all other parts of the sympathetic nervous system. The purpose of this study was to see whether there were variations in sympathetic activity, skin vasomotor and sweat gland sudomotor rhythms during the menstrual cycle. Eight young female subjects with a regular menstrual cycle participated in the study. Subjects were tested once during the follicular phase and once during the luteal phase. Skin blood flow and sweat rate were significantly higher in the luteal phase compared with the follicular phase (p < .05), but the frequency and magnitude of sudomotor and vasomotor rhythms were significantly greater in the follicular phase (p < .05). In contrast, spectral data showed less sympathetic activity in the luteal phase. A significant finding here is that the sudomotor rhythm of sweat glands is altered by the menstrual cycle. PMID- 26442633 TI - Tolerance and reward equity predict cooperation in ravens (Corvus corax). AB - Cooperative decision rules have so far been shown experimentally mainly in mammal species that have variable and complex social networks. However, these traits should not necessarily be restricted to mammals. Therefore, we tested cooperative problem solving in ravens. We showed that, without training, nine ravens spontaneously cooperated in a loose-string task. Corroborating findings in several species, ravens' cooperative success increased with increasing inter individual tolerance levels. Importantly, we found this in both a forced dyadic setting, and in a group setting where individuals had an open choice to cooperate with whomever. The ravens, moreover, also paid attention to the resulting reward distribution and ceased cooperation when being cheated upon. Nevertheless, the ravens did not seem to pay attention to the behavior of their partners while cooperating, and future research should reveal whether this is task specific or a general pattern. Given their natural propensity to cooperate and the results we present here, we consider ravens as an interesting model species to study the evolution of, and the mechanisms underlying cooperation. PMID- 26442635 TI - Mobility behaviour and driving status of patients with mental disorders - an exploratory study. AB - BACKGROUND: Driving is an important activity of daily life and an integral part of mobility. However, impact of mental illness on road mobility is widely unexplored. METHOD: Driving status in 1497 psychiatric inpatients (PPs) and a clinical control group of 313 neurological inpatients (NPs) was investigated using a brief questionnaire. RESULTS: 67% of PPs (89% NPs) reported to have a valid driver's licence and 77% of them (92% NPs) reported to regularly use their cars. Within driver's license holders, patients with organic mental disorder (32%), substance dependence (37%) and psychotic disorder (40%) had the lowest proportion of current drivers. Higher educational qualification (odds ratio [OR] from 2.978 to 17.036) and being married/partnered (OR 3.049) or divorced (OR 4.840) significantly advanced the probability of possession of a driving license. Predictive factors for driving cessation were being female, an older age, drawing a pension and having an organic mental disease or schizophrenic disorder. CONCLUSION: Mental disease has a negative impact on driving status and this is especially true for illnesses frequently being accompanied by distinct cognitive impairments. Factors predicting road mobility elucidate the strong relationship with psychosocial status indicating that recovery of driving competence should be an integral goal of treatment strategies. PMID- 26442636 TI - Macrophage-Associated Osteoactivin/GPNMB Mediates Mesenchymal Stem Cell Survival, Proliferation, and Migration Via a CD44-Dependent Mechanism. AB - Although MSCs have been widely recognized to have therapeutic potential in the repair of injured or diseased tissues, it remains unclear how functional activities of mesenchymal stem cells (MSCs) are influenced by the surrounding inflammatory milieu at the site of tissue injury. Macrophages constitute an essential component of innate immunity and have been shown to exhibit a phenotypic plasticity in response to various stimuli, which play a central role in both acute inflammation and wound repair. Osteoactivin (OA)/Glycoprotein non metastatic melanoma protein B (GPNMB), a transmembrane glycoprotein that plays a role in cell differentiation, survival, and angiogenesis. The objective of this study was to investigate the potential role of OA/GPNMB in macrophage-induced MSC function. We found that reparative M2 macrophages express significantly greater levels of OA/GPNMB than pro-inflammatory M1 macrophages. Furthermore, using loss of function and rescue studies, we demonstrated that M2 macrophages-secreted OA/GPNMB positively regulates the viability, proliferation, and migration of MSCs. More importantly, we demonstrated that OA/GPNMB acts through ERK and AKT signaling pathways in MSCs via CD44, to induce these effects. Taken together, our results provide pivotal insight into the mechanism by which OA/GPNMB contributes to the tissue reparative phenotype of M2 macrophages and positively regulates functional activities of MSCs. J. Cell. Biochem. 117: 1511-1521, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26442637 TI - Spatial nitrifications of microbial processes during composting of swine, cow and chicken manure. AB - Composting is a widely-used method to recycle the nutrients in livestock manure for agriculture. The spatial stratifications of microbial processes inside the manure particle that determine organic and nitrogen transformation are virtually unclear. Here, we show the evolution of the interior microenvironment of swine, cow and chicken manure by using microelectrodes during forced-aeration composting. Composting has generally been regarded as an aerobic bioprocess, however, the long-existing of a large anoxic zone inside these manures was confirmed during the active phase in this study. The profile of the oxidation reduction potential dramatically decreased first and then gradually increased. The spatial difference in the ammonia concentration was not significant, but nitrate concentration continuously decreased with depth. The anoxic condition within the manure particle was demonstrated to be a primary cause of the severe ammonia emission and the long composting period. These founding provided a new insight toward "aerobic" composting process and a sound foundation for the development of efficient composting technology. PMID- 26442638 TI - Human genetics: Strength in numbers in the low-frequency spectrum. PMID- 26442641 TI - Examining sludge production in bioelectrochemical systems treating domestic wastewater. AB - Sludge production in microbial bioelectrochemical systems (BES) was assessed in conjunction with anaerobic and aerobic control reactors. Effluent after primary settling tank (EAPS) and depleted EAPS spiked with acetate were treated. The reactors were loaded with total suspended solids (TSS) and chemical oxygen demand (COD) at average loading rates of 22 mg TSS d(-1)L(-1) and 86 mg COD d(-1)L(-1), respectively. Carbon cloth anode equipped BES reactors delivered the highest performance. They achieved on average a COD removal of 80%, a Coulomb efficiency of 77% for EAPS, a maximum current density of 39 MUA cm(-)(3)/175 MUA cm(-)(2) for EAPS and a TSS removal of 59%, yielding a sludge production of only 80 mg TSS per g DeltaCOD. This study provides further evidence that BES can improve the economics of wastewater treatment via lower sludge production as well as providing a framework for understanding sludge production in BES. PMID- 26442639 TI - Random monoallelic expression of autosomal genes: stochastic transcription and allele-level regulation. AB - Random monoallelic expression (RME) of genes represents a striking example of how stochastic molecular processes can result in cellular heterogeneity. Recent transcriptome-wide studies have revealed both mitotically stable and cell-to-cell dynamic forms of autosomal RME, with the latter presumably resulting from burst like stochastic transcription. Here, we discuss the distinguishing features of these two forms of RME and revisit literature on their nature, pervasiveness and regulation. Finally, we explore how RME may contribute to phenotypic variation, including the incomplete penetrance and variable expressivity often seen in genetic disease. PMID- 26442640 TI - Genetic variation and the de novo assembly of human genomes. AB - The discovery of genetic variation and the assembly of genome sequences are both inextricably linked to advances in DNA-sequencing technology. Short-read massively parallel sequencing has revolutionized our ability to discover genetic variation but is insufficient to generate high-quality genome assemblies or resolve most structural variation. Full resolution of variation is only guaranteed by complete de novo assembly of a genome. Here, we review approaches to genome assembly, the nature of gaps or missing sequences, and biases in the assembly process. We describe the challenges of generating a complete de novo genome assembly using current technologies and the impact that being able to perfectly sequence the genome would have on understanding human disease and evolution. Finally, we summarize recent technological advances that improve both contiguity and accuracy and emphasize the importance of complete de novo assembly as opposed to read mapping as the primary means to understanding the full range of human genetic variation. PMID- 26442643 TI - Erratum. PMID- 26442642 TI - A fluorescent probe for specific detection of cysteine in the lipid dense region of cells. AB - A new cysteine (Cys) specific chemodosimetric reagent () is used in imaging of endogenous Cys localized in the lipid dense region of the live Hct116 cells and the release of Cys within HepG2 cells from a drug following a biochemical transformation. A silica surface, modified with , could be used for quantitative estimation of Cys present in aqueous solution (pH 7.2) and in a human blood plasma (HBP). PMID- 26442644 TI - Caregiver resilience in palliative care: a research protocol. AB - AIM: To describe a research protocol designed to formulate a conceptual framework of informal caregiver resilience in palliative care. BACKGROUND: Resilience is the ability to adapt or to improve one's own conditions following experiences of adversity. The end-of-life care provided by informal caregivers is a form of adversity because it entails objective difficulties, emotional involvement and deep levels of introspection that have been stimulated by the death event. Resilience has not yet been addressed in association with end-of-life care. DESIGN: This is a multicentre cross-sectional study. METHODS: We will administer a questionnaire to a sample of informal end-of-life caregivers to collect data about the main psychological, behavioural and healthcare factors that impact resilience. Data analysis will include descriptive and correlational statistical techniques, multiple linear regressions and structural equation modelling. Data will be collected in multiple palliative care centres and statistical analysis will be carried out using software: SPSS version 19.0 and MPlus version 7.3. The study is supported by a grant from the Centre of Excellence for Nursing Scholarship in Italy (Research Grant number 2.13.10) that was awarded in March 2013. DISCUSSION: The study seeks to identify the predictive, mediating and moderating roles of select variables: caregivers' self-efficacy, burdens of caregiving, depression and resilience. The results of this analysis will impact the theoretical study of resilience in palliative care and will have practical implications for interventions aimed at supporting caregivers through healthcare teams. PMID- 26442645 TI - Biomedical applications of nano-titania in theranostics and photodynamic therapy. AB - Titanium dioxide (TiO2) is one of the most abundantly used nanomaterials for human life. It is used in sunscreen, photovoltaic devices, biomedical applications and as a food additive and environmental scavenger. Nano-TiO2 in biomedical applications is well documented. It is used in endoprosthetic implants and early theranostics of neoplastic and non-neoplastic maladies as a photodynamic therapeutic agent and as vehicles in nano-drug delivery systems. Herein, we focus on the recent advancements and applications of nano-TiO2 in bio nanotechnology, nanomedicine and photodynamic therapy (PDT). PMID- 26442646 TI - Warming decreased and grazing increased plant uptake of amino acids in an alpine meadow. AB - Organic nitrogen (N) uptake by plants has been recognized as a significant component of terrestrial N cycle. Several studies indicated that plants have the ability to switch their preference between inorganic and organic forms of N in diverse environments; however, research on plant community response in organic nitrogen uptake to warming and grazing is scarce. Here, we demonstrated that organic N uptake by an alpine plant community decreased under warming with (13)C (15)N-enriched glycine addition method. After 6 years of treatment, warming decreased plant organic N uptake by 37% as compared to control treatment. Under the condition of grazing, warming reduced plant organic N uptake by 44%. Grazing alone significantly increased organic N absorption by 15%, whereas under warming condition grazing did not affect organic N uptake by the Kobresia humilis community on Tibetan Plateau. Besides, soil NO 3-N content explained more than 70% of the variability observed in glycine uptake, and C:N ratio in soil dissolved organic matter remarkably increased under warming treatment. These results suggested warming promoted soil microbial activity and dissolved organic N mineralization. Grazing stimulated organic N uptake by plants, which counteracted the effect of warming. PMID- 26442647 TI - Empathy from the client's perspective: A grounded theory analysis. AB - : Although empathy is one of most robust predictors of client outcome, there is little consensus about how best to conceptualize this construct. OBJECTIVE: The aim of the present research was to investigate clients' perceptions and in session experiences of empathy. METHOD: Semi-structured, video-assisted interpersonal process recall interviews were used to collect data from nine clients receiving individual psychotherapy at a university psychology clinic. RESULTS: Grounded theory analysis yielded a model consisting of three clusters: (1) relational context of empathy (i.e., personal relationship and professional relationship), (2) types of empathy (i.e., psychotherapists' cognitive empathy, psychotherapists' emotional empathy, and client attunement to psychotherapist), and (3) utility of empathy (i.e., process-related benefits and client-related benefits). CONCLUSIONS: These results suggest that empathy is a multi dimensional, interactional process that affects-and is affected by-the broader relationship between client and psychotherapist. PMID- 26442648 TI - Incidence of alloantibody formation after ABO-D or extended matched red blood cell transfusions: a randomized trial (MATCH study). AB - BACKGROUND: Most incidentally transfused patients receive only ABO-D-compatible transfusions and antibodies are formed in up to 8%. The effect of extended (c, C, E, K, Fy(a) , Jk(a) , and S antigens) matched (EM) and ABO-D-matched red blood cell (RBC) transfusions on the incidence of new clinically relevant RBC antibody formation after a first elective transfusion event in surgical patients was studied. STUDY DESIGN AND METHODS: A multicenter randomized trial was performed in nontransfused patients who were scheduled to experience a single elective transfusion event of maximal 4 RBC units. The primary outcome was the incidence of newly formed warm reacting clinically relevant RBC alloantibodies measured in three follow-up (FU) samples taken at 7 to 10 days, 4 to 6 weeks, and 4 to 6 months posttransfusion. RESULTS: A total of 853 patients were randomized, and of these, 333 patients were transfused with a total of 1035 RBC units. At least one FU sample was available from 97% of transfused patients. In intention-to-treat analysis, new antibodies were detected in 10 of 155 ABO-D and seven of 178 EM patients, respectively. Per-protocol analysis including 190 patients showed a nonsignificant absolute risk difference (ARD) of 5.3% (95% confidence interval [CI], -1.4% to 12%) in alloimmunization between study arms. In a post hoc analysis of 138 patients who received RBCs but no platelet (PLT) transfusions the ARD increased to significance, 8.0% (95% CI, 0.4-16.0). CONCLUSION: Extended matching for selected antigens reduced the alloimmunization risk by 64% in surgical patients. Extended matching seems successful only if the patient did not receive accompanying nonmatched PLT transfusions. PMID- 26442650 TI - Prostate-specific antigen doubling time and response to cabazitaxel in a hormone resistant metastatic prostate cancer patient. AB - We report a case of metastatic castration-resistant prostate cancer, who received prior treatment with docetaxel and was then given cabazitaxel as salvage therapy. The patient was monitored by prostate-specific antigen doubling time and prostate specific antigen absolute value. The prostate-specific antigen doubling time was found to be a good response predictor in the patient. PMID- 26442649 TI - Increasing interest in rural mental health work: the impact of a short term program to orientate allied health and nursing students to employment and career opportunities in a rural setting. AB - INTRODUCTION: Ongoing workforce shortages affect the provision of mental health services to rural and remote communities. This article examines the immediate impact of a novel recruitment strategy that aims to increase the number of mental health professionals commencing their careers in a rural area of Australia. METHODS: This study utilised a sequential confirmatory mixed methods design which included both online pre- and post-program surveys and semi-structured individual interviews. Statistical analyses compared participants' pre- and post-program survey interest in rural work/career, mental health work/career and rural mental health work/career. Content analysis was undertaken to explore interview transcripts for data that confirmed, contradicted or added depth to the quantitative findings. RESULTS: Comparison of pre- and post-program surveys indicated a significant increase in participants' interest in rural work/career and rural mental health work/career. The qualitative findings provided depth to and supported the change in interest toward working in a rural environment. Despite qualitative evidence that the program has increased participants' knowledge and understanding of the mental health sector as a whole, overt support for the changes in interest toward mental health work was not evident. CONCLUSIONS: The study provides evidence that a short-term program can change allied health and nursing students' interest in rural mental health work. The findings have important implications for the recruitment of mental health practitioners to underserved rural areas. PMID- 26442652 TI - Abstracts of the Joint Annual Conference of the International Society for Pediatric and Adolescent Diabetes and Australasian Paediatric Endocrine Group (ISPAD+APEG 2015), 7-10 October 2015, Brisbane, Australia. PMID- 26442651 TI - The application of terminomics for the identification of protein start sites and proteoforms in bacteria. AB - Protein terminomics, or the study of amino acids sequences at the protein amino or carboxyl terminus has rapidly evolved as a proteomic discipline due to significant methodological improvements in the labelling and recovery of terminal peptides as well as the increased speed and sensitivity of current mass spectrometry instrumentation. The most significant beneficiaries of these developments include an increased awareness and understanding of complex proteolytic cascades that regulate key biological processes and in genome annotation. Most terminomics research to date has focused on gaining insight into important biological processes such as inflammation, wound healing and cancer. The application of terminomics to the study of important biological questions in prokaryotes is gaining traction. Here we review current applications and progress of terminomics in prokaryotes, discuss the significance of protease research in bacterial pathogenesis and protein maturation, and suggest novel applications of terminomics in the study of infectious disease. PMID- 26442653 TI - Electrochemical Fluorographane: Hybrid Electrocatalysis of Biomarkers, Hydrogen Evolution, and Oxygen Reduction. AB - Fluorographane (C1 Hx F1-x+delta )n is a new member of the graphene family that exhibits hydrophobicity and a large band gap that is tunable based on the level of fluorination. Herein, sensing and energy applications of fluorographane are reported. The results reveal that the carbon-to-fluoride ratio of fluorographane has a great impact on the electrochemical performance of the materials. Lowered oxidation potentials for ascorbic and uric acids, in addition to a catalytic effect for hydroquinone and dopamine redox processes, are obtained with a high fluoride content. Moreover, fluorographane, together with residual copper- and nickel-based doping, acted as a hybrid electrocatalyst to promote hydrogen evolution and oxygen reduction reactions with considerably lower onset potentials than those of graphane (starting material), which makes this a promising material for a broad range of applications. PMID- 26442654 TI - Development of a novel recessive genetic male sterility system for hybrid seed production in maize and other cross-pollinating crops. AB - We have developed a novel hybridization platform that utilizes nuclear male sterility to produce hybrids in maize and other cross-pollinating crops. A key component of this platform is a process termed Seed Production Technology (SPT). This process incorporates a transgenic SPT maintainer line capable of propagating nontransgenic nuclear male-sterile lines for use as female parents in hybrid production. The maize SPT maintainer line is a homozygous recessive male sterile transformed with a SPT construct containing (i) a complementary wild-type male fertility gene to restore fertility, (ii) an alpha-amylase gene to disrupt pollination and (iii) a seed colour marker gene. The sporophytic wild-type allele complements the recessive mutation, enabling the development of pollen grains, all of which carry the recessive allele but with only half carrying the SPT transgenes. Pollen grains with the SPT transgenes exhibit starch depletion resulting from expression of alpha-amylase and are unable to germinate. Pollen grains that do not carry the SPT transgenes are nontransgenic and are able to fertilize homozygous mutant plants, resulting in nontransgenic male-sterile progeny for use as female parents. Because transgenic SPT maintainer seeds express a red fluorescent protein, they can be detected and efficiently separated from seeds that do not contain the SPT transgenes by mechanical colour sorting. The SPT process has the potential to replace current approaches to pollen control in commercial maize hybrid seed production. It also has important applications for other cross-pollinating crops where it can unlock the potential for greater hybrid productivity through expanding the parental germplasm pool. PMID- 26442655 TI - Long-term spatiotemporal stability and dynamic changes in helminth infracommunities of bank voles (Myodes glareolus) in NE Poland. AB - Parasites are considered to be an important selective force in host evolution but ecological studies of host-parasite systems are usually short-term providing only snap-shots of what may be dynamic systems. We have conducted four surveys of helminths of bank voles at three ecologically similar woodland sites in NE Poland, spaced over a period of 11 years, to assess the relative importance of temporal and spatial effects on helminth infracommunities. Some measures of infracommunity structure maintained relative stability: the rank order of prevalence and abundance of Heligmosomum mixtum, Heligmosomoides glareoli and Mastophorus muris changed little between the four surveys. Other measures changed markedly: dynamic changes were evident in Syphacia petrusewiczi which declined to local extinction, while the capillariid Aonchotheca annulosa first appeared in 2002 and then increased in prevalence and abundance over the remaining three surveys. Some species are therefore dynamic and both introductions and extinctions can be expected in ecological time. At higher taxonomic levels and for derived measures, year and host-age effects and their interactions with site are important. Our surveys emphasize that the site of capture is the major determinant of the species contributing to helminth community structure, providing some predictability in these systems. PMID- 26442656 TI - [Evolution of the interventional reperfusion strategy and reperfusion times in acute ST-segment elevation myocardial infarction]. AB - BACKGROUND: In patients with acute ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI), the recommended times (first medical contact-to-balloon (M2B) <120 or <90min, and door-to-balloon (D2B) <45min) are reached in less than 50% of patients. PURPOSE: To compare the interventional reperfusion strategy and reperfusion times between two series of consecutive STEMI patients referred for pPCI within 12hours of symptom onset, in 2007 and 2012. METHODS: Retrospective study of 182 patients, 87 admitted from January 2007 to March 2008 (period 1), and 95 admitted from January to December 2012 (period 2). The procedural characteristics and the different times between onset of pain and mechanical reperfusion were gathered and compared by non-parametric tests. RESULTS: Radial access, thromboaspiration, and drug eluting stents were more frequent, and cardiogenic shock was less common during period 2, compared with the period 1. The median time from first medical contact to balloon (M2B) decreased by 26% (135min, [quartiles: 113-183] in 2007 versus 100 [76-137] in 2012, P<0.001), in relation to the reduction in both prehospital times and time in the catheterization laboratory (D2B: 51 [44-65] and 44min [37 55], respectively, P<0.01). CONCLUSIONS: The D2B and M2B times significantly decreased in our centre between 2007 and 2012, and reached the recommended values in >60% of the cases. This may be explained by better coordination between emergency medical units and interventional cardiologists, and by the presence of two paramedics in the catheterization laboratory for 24/24 7/7 pPCI since 2010 in France, in accordance with recent national regulation. PMID- 26442657 TI - MyD88 in donor bone marrow cells is critical for protection from acute intestinal graft-vs.-host disease. AB - To understand the role of myeloid differentiation factor 88 (MyD88) expressed by donor bone marrow (BM) in the pathophysiology of graft-vs.-host disease (GVHD), we investigated the effects of transplantation of MyD88-deficient T cell-depleted BM (MyD88KO TCD-BM) on the severity of GVHD. Transplantation with MyD88KO TCD-BM aggravated GVHD; serious gut damage was evident, with high infiltration of T cells into the intestines of recipients and markedly reduced expansion of CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs). MDSCs from MyD88KO mice were defective in inducing donor T-cell apoptosis and inhibiting T-cell proliferation. Supplementation of transplanted mice with MDSCs from wild-type mice, but not MyD88KO mice, attenuated GVHD severity with reduced intestinal T cell infiltration in MyD88KO TCD-BM recipients. Pretreatment of BM donors with lipopolysaccharide to increase MDSC levels and MyD88 transcription in the TCD-BM transplant alleviated GVHD severity and intestinal T-cell infiltration. The T cell/MDSC ratios were correlated with intestinal GVHD severity in both animal models and human patients. This study indicates that MyD88-dependent MDSC expansion from donor BM is critical for protection against fatal intestinal GVHD. PMID- 26442658 TI - Role of mannose-binding lectin in intestinal homeostasis and fungal elimination. AB - Mannose-binding lectin (MBL) is a soluble lectin of the innate immune system that is produced by the liver and secreted into the circulation where it activates the lectin complement pathway, enhances phagocytosis of microorganisms by leukocytes, and modulates inflammation. MBL can recognize patterns on the surface of different pathogens, including Candida albicans. Our aims were to investigate whether MBL is expressed in the gut epithelium and to examine its effect on the modulation of intestinal inflammation and C. albicans elimination. Using reverse transcriptase-PCR, MBL transcripts were highly expressed in different parts of the mouse gut. MBL expression was also detected by immunoblotting and immunolocalization in response to C. albicans colonization of the gut; the highest expression of MBL was detected in the stomach. Blocking MBL by administering mannans to mice increased C. albicans colonization. MBL-deficient mice had a higher level of colonization than wild-type mice. Dextran sodium sulfate-induced colitis promoted C. albicans dissemination to the kidneys and lungs of MBL-deficient mice. MBL-deficient mice exhibited elevated expression of interleukin (IL)-17, IL-23, dectin-1, and Toll-like receptor-4. This study shows that MBL expression is induced in the gut in response to C. albicans sensing and is required for intestinal homeostasis and host defense against C. albicans. PMID- 26442661 TI - Influence of caffeine on 3,4-methylenedioxymethamphetamine-induced dopaminergic neuron degeneration and neuroinflammation is age-dependent. AB - Previous studies have demonstrated that caffeine administration to adult mice potentiates glial activation induced by 3,4-methylenedioxymethamphetamine (MDMA). As neuroinflammatory response seems to correlate with neurodegeneration, and the young brain is particularly vulnerable to neurotoxicity, we evaluated dopamine neuron degeneration and glial activation in the caudate-putamen (CPu) and substantia nigra pars compacta (SNc) of adolescent and adult mice. Mice were treated with MDMA (4 * 20 mg/kg), alone or with caffeine (10 mg/kg). Interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, neuronal nitric oxide synthase (nNOS) were evaluated in CPu, whereas tyrosine hydroxylase (TH), glial fibrillary acidic protein, and CD11b were evaluated in CPu and SNc by immunohistochemistry. MDMA decreased TH in SNc of both adolescent and adult mice, whereas TH-positive fibers in CPu were only decreased in adults. In CPu of adolescent mice, caffeine potentiated MDMA-induced glial fibrillary acidic protein without altering CD11b, whereas in SNc caffeine did not influence MDMA-induced glial activation. nNOS, IL 1beta, and TNF-alpha were increased by MDMA in CPu of adults, whereas in adolescents, levels were only elevated after combined MDMA plus caffeine. Caffeine alone modified only nNOS. Results suggest that the use of MDMA in association with caffeine during adolescence may exacerbate the neurotoxicity and neuroinflammation elicited by MDMA. Previous studies have demonstrated that caffeine potentiated glial activation induced by 3,4 methylenedioxymethamphetamine (MDMA) in adult mice. In this study, caffeine was shown to potentiate MDMA-induced dopamine neuron degeneration in substantia nigra pars compacta, astrogliosis, and TNF-alpha levels in caudate-putamen of adolescent mice. Results suggest that combined use of MDMA plus caffeine during adolescence may worsen the neurotoxicity and neuroinflammation elicited by MDMA. PMID- 26442659 TI - Cardiovascular and pharmacological implications of haem-deficient NO-unresponsive soluble guanylate cyclase knock-in mice. AB - Oxidative stress, a central mediator of cardiovascular disease, results in loss of the prosthetic haem group of soluble guanylate cyclase (sGC), preventing its activation by nitric oxide (NO). Here we introduce Apo-sGC mice expressing haem free sGC. Apo-sGC mice are viable and develop hypertension. The haemodynamic effects of NO are abolished, but those of the sGC activator cinaciguat are enhanced in apo-sGC mice, suggesting that the effects of NO on smooth muscle relaxation, blood pressure regulation and inhibition of platelet aggregation require sGC activation by NO. Tumour necrosis factor (TNF)-induced hypotension and mortality are preserved in apo-sGC mice, indicating that pathways other than sGC signalling mediate the cardiovascular collapse in shock. Apo-sGC mice allow for differentiation between sGC-dependent and -independent NO effects and between haem-dependent and -independent sGC effects. Apo-sGC mice represent a unique experimental platform to study the in vivo consequences of sGC oxidation and the therapeutic potential of sGC activators. PMID- 26442662 TI - Low expression of IL-6 and TNF-alpha correlates with the presence of the nuclear regulators of NF-kappaB, IkappaBNS and BCL-3, in the uterus of mice. AB - The dynamic regulation of NF-kappaB activity in the uterus maintains a favorable environment of cytokines necessary to prepare for pregnancy throughout the estrous cycle. Recently, the mechanisms that directly regulate the NF-kappaB transcriptional activity in different tissues are of growing interest. IkappaBNS and BCL-3 are negative nuclear regulators of NF-kappaB activity that regulate IL 6 and TNF-alpha transcription, respectively. Both cytokines have been described as important factors in the remodeling of uterus for blastocyst implantation. In this work we analyzed in ICR mice the mRNA expression and protein production profile of IL-6, TNF-alpha, and their correspondent negative transcription regulators IkappaBNS or BCL-3 using real-time PCR, western blot and immunochemistry. We found that the expression of TNF-alpha and IL-6 was oscillatory along the estrous cycle, and its low expression coincided with the presence of BCL-3 and IkappaBNS, and vice versa, when the presence of the regulators was subtle, the expression of TNF-alpha and IL-6 was exacerbated. When we compared the production of TNF-alpha and IL-6 in the different estrous stages relating with diestrus we found that at estrus there is an important increase of the cytokines (p<0.05) decreasing at metestrus to reach the basal expression at diestrus. In the immunochemistry analysis we found that at diestrus BCL-3 is distributed all over the tissue with a barely detected TNF-alpha, but on the contrary, at estrus the expression of BCL-3 is not detected with TNF-alpha clearly observable along the tissue; the same phenomenon occur in the analysis of IkappaBNS and IL-6. With that evidence we suggest that the expression of TNF alpha and IL-6 might be regulated through NF-kappaB nuclear regulators BCL-3 and IkappaBNS in the uterus of mice as has been demonstrated in other systems. PMID- 26442663 TI - Endogenous galectin-3 expression levels modulate immune responses in galectin-3 transgenic mice. AB - Galectin-3 (Gal-3), a beta-galactoside-binding mammalian lectin, is involved in cancer progression and metastasis. However, there is an unmet need to identify the underlying mechanisms of cancer metastasis mediated by endogenous host galectin-3. Galectin-3 is also known to be an important regulator of immune responses. The present study was aimed at analysing how expression of endogenous galectin-3 regulates host immunity and lung metastasis in B16F10 murine melanoma model. Transgenic Gal-3(+/-) (hemizygous) and Gal-3(-/-) (null) mice exhibited decreased levels of Natural Killer (NK) cells and lower NK mediated cytotoxicity against YAC-1 tumor targets, compared to Gal-3(+/+) (wild-type) mice. On stimulation, Gal-3(+/-) and Gal-3(-/-) mice splenocytes showed increased T cell proliferation than Gal-3(+/+) mice. Intracellular calcium flux was found to be lower in activated T cells of Gal-3(-/-) mice as compared to T cells from Gal 3(+/+) and Gal-3(+/-) mice. In Gal-3(-/-) mice, serum Th1, Th2 and Th17 cytokine levels were found to be lowest, exhibiting dysregulation of pro-inflammatory and anti-inflammatory cytokines balance. Marked decrease in serum IFN-gamma levels and splenic IFN-gammaR1 (IFN-gamma Receptor 1) expressing T and NK cell percentages were observed in Gal-3(-/-) mice. On recombinant IFN-gamma treatment of splenocytes in vitro, Suppressor of Cytokine Signaling (SOCS) 1 and SOCS3 protein expression was higher in Gal-3(-/-) mice compared to that in Gal-3(+/+) and Gal-3(+/-) mice; suggesting possible attenuation of Signal Transducer and Activator of Transcription (STAT) 1 mediated IFN-gamma signaling in Gal-3(-/-) mice. The ability of B16F10 melanoma cells to form metastatic colonies in the lungs of Gal-3(+/+) and Gal-3(-/-) mice remained comparable, whereas it was found to be reduced in Gal-3(+/-) mice. Our data indicates that complete absence of endogenous host galectin-3 facilitates lung metastasis of B16F10 cells in mice, which may be contributed by dysregulated immune responses resulting from decreased NK cytotoxicity, disturbed serum Th1, Th2, Th17 cytokine milieu, reduced serum IFN-gamma levels and attenuation of splenic STAT1 mediated IFN gamma signalling in Gal-3(-/-) mice. PMID- 26442664 TI - PLGA (85:15) nanoparticle based delivery of rL7/L12 ribosomal protein in mice protects against Brucella abortus 544 infection: A promising alternate to traditional adjuvants. AB - There is a compelling need for the development of suitable adjuvants for human use to enhance the efficacy of the upcoming vaccines for the prevention of life threatening infections. In the current study, we have tried to explore the immunogenic potential of nanoparticles (NPs) made of PLGA (poly lactic-co glycolic acid), a biodegradable and biocompatible polymer approved by FDA for human use after entrapping rL7/L12 protein, an immunodominant antigen of Brucella. Adjuvant properties were exhibited by the formulation as it elicited high IgG antibody titers just after first immunization which increased significantly after the booster administration. A good elicitation of the Th1 cytokines especially IFN-gamma was recorded. Amongst the IgG antibody subclasses, IgG1 remained the predominant subclass to be elicited in mice serum after immunization; however IgG1/2a ratio showed a mixed profile of Th1/Th2 response. Lymphocyte proliferation assay as a marker of amplification in cellular immunity demonstrated that the splenocytes of the immunized mice had a high proliferation index with reference to the control, revealing that L7/L12 entrapping PLGA nanoparticles are potent inducer of inflammatory cell response indispensable to combat Brucella infection. Enumeration of splenic CFU after 14 days of infection with Brucella abortus 544 showed a significant reduction in log CFU of splenic bacteria in the vaccinated mice as compared to the control group. Therefore it is evident that PLGA nano formulations delivering the entrapped vaccine candidate in mice elicit specific humoral as well as cellular responses specific to the entrapped Brucella antigen. So there is much promise in this approach and this work by highlighting the adjuvant properties of the PLGA nanospheres will accelerate the development of improved vaccines safe for human as well as veterinary use. PMID- 26442665 TI - Spontaneous Facial Mimicry is Modulated by Joint Attention and Autistic Traits. AB - Joint attention (JA) and spontaneous facial mimicry (SFM) are fundamental processes in social interactions, and they are closely related to empathic abilities. When tested independently, both of these processes have been usually observed to be atypical in individuals with autism spectrum conditions (ASC). However, it is not known how these processes interact with each other in relation to autistic traits. This study addresses this question by testing the impact of JA on SFM of happy faces using a truly interactive paradigm. Sixty-two neurotypical participants engaged in gaze-based social interaction with an anthropomorphic, gaze-contingent virtual agent. The agent either established JA by initiating eye contact or looked away, before looking at an object and expressing happiness or disgust. Eye tracking was used to make the agent's gaze behavior and facial actions contingent to the participants' gaze. SFM of happy expressions was measured by Electromyography (EMG) recording over the Zygomaticus Major muscle. Results showed that JA augments SFM in individuals with low compared with high autistic traits. These findings are in line with reports of reduced impact of JA on action imitation in individuals with ASC. Moreover, they suggest that investigating atypical interactions between empathic processes, instead of testing these processes individually, might be crucial to understanding the nature of social deficits in autism. Autism Res 2016, 9: 781 789. (c) 2015 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research. PMID- 26442666 TI - Brain substrates of social decision-making in dual diagnosis: cocaine dependence and personality disorders. AB - Cocaine dependence frequently co-occurs with personality disorders, leading to increased interpersonal problems and greater burden of disease. Personality disorders are characterised by patterns of thinking and feeling that divert from social expectations. However, the comorbidity between cocaine dependence and personality disorders has not been substantiated by measures of brain activation during social decision-making. We applied functional magnetic resonance imaging to compare brain activations evoked by a social decision-making task-the Ultimatum Game-in 24 cocaine dependents with personality disorders (CDPD), 19 cocaine dependents without comorbidities and 19 healthy controls. In the Ultimatum Game participants had to accept or reject bids made by another player to split monetary stakes. Offers varied in fairness (in fair offers the proposer shares ~50 percent of the money; in unfair offers the proposer shares <30 percent of the money), and participants were told that if they accept both players get the money, and if they reject both players lose it. We contrasted brain activations during unfair versus fair offers and accept versus reject choices. During evaluation of unfair offers CDPD displayed lower activation in the insula and the anterior cingulate cortex and higher activation in the lateral orbitofrontal cortex and superior frontal and temporal gyri. Frontal activations negatively correlated with emotion recognition. During rejection of offers CDPD displayed lower activation in the anterior cingulate cortex, striatum and midbrain. Dual diagnosis is linked to hypo-activation of the insula and anterior cingulate cortex and hyper-activation of frontal-temporal regions during social decision-making, which associates with poorer emotion recognition. PMID- 26442667 TI - Causal Inference in Developmental Origins of Health and Disease (DOHaD) Research. AB - Studies of the developmental origins of health and disease (DOHaD) often rely on prospective observational data, from which associations between developmental exposures and outcomes in later life can be identified. Typically, conventional statistical methods are used in an attempt to mitigate problems inherent in observational data, such as confounding and reverse causality, but these have serious limitations. In this review, we discuss a variety of methods that are increasingly being used in observational epidemiological studies to help strengthen causal inference. These methods include negative controls, cross contextual designs, instrumental variables (including Mendelian randomization), family-based studies, and natural experiments. Applications within the DOHaD framework, and in relation to behavioral, psychiatric, and psychological domains, are considered, and the considerable potential for expanding the use of these methods is outlined. PMID- 26442669 TI - Beyond Work-Life "Integration". AB - Research on the work-family interface began in the 1960s and has grown exponentially ever since. This vast amount of research, however, has had relatively little impact on workplace practice, and work-family conflict is at an all-time high. We review the work-family research to date and propose that a shift of attention is required, away from the individual experience of work and family and toward understanding how identity and status are defined at work. Several factors enshrine cherished identities around current workplace norms. The work devotion schema demands that those who are truly committed to their work will make it the central or sole focus of their lives, without family demands to distract them. Importantly, the work devotion schema underwrites valued class and gender identities: Work devotion is a key way of enacting elite class status and functions as the measure of a man--the longer the work hours and higher the demand for his attention, the better. Advocating change in the way work is done and life is lived meets resistance because it places these cherished identities at risk. Resistance to these identity threats keeps current workplace norms in place. This is why even the business case-which shows that current practices are not economically efficient-fails to persuade organizations to enact change. What is needed now is sustained attention to the implicit psychological infrastructure that cements the mismatch between today's workplace and today's workforce. PMID- 26442668 TI - Gene * Environment Determinants of Stress- and Anxiety-Related Disorders. AB - The burgeoning field of gene-by-environment (G*E) interactions has revealed fascinating biological insights, particularly in the realm of stress-, anxiety-, and depression-related disorders. In this review we present an integrated view of the study of G*E interactions in stress and anxiety disorders, including the evolution of genetic association studies from genetic epidemiology to contemporary large-scale genome-wide association studies and G*E studies. We convey the importance of consortia efforts and collaboration to gain the large sample sizes needed to move the field forward. Finally, we discuss several robust and well-reproduced G*E interactions and demonstrate how epidemiological identification of G*E interactions has naturally led to a plethora of basic research elucidating the mechanisms of high-impact genetic variants. PMID- 26442670 TI - Role of JAK-STAT signaling in maturation of phagosomes containing Staphylococcus aureus. AB - Phagocytosis is a required mechanism for the defense against pathogens. Staphylococcus aureus, an important bacterial pathogen, can promptly escape from phagosomes and proliferate within the cytoplasm of host. However, the mechanism of phagocytosis against S. aureus has not been intensively investigated. In this study, the S. aureus was engulfed by macrophages (RAW264.7 cells) but not digested by the cells, suggesting that the phagosomes did not maturate in macrophages. Further investigation revealed that peptidoglycan (PG) induced the phagosome maturation of macrophages, resulting in the eradication of S. aureus. Genome-wide analysis and quantitative real-time PCR indicated that the JAK-STAT pathway was activated by PG during the phagosome maturation of macrophages against S. aureus. This finding presented that the PG-activated JAK-STAT pathway was required for phagosome maturation. Therefore, our study contributed evidence that revealed a novel aspect of PG-triggered JAK-STAT pathway in the phagosome maturation of macrophages. PMID- 26442671 TI - Mapping the H(+) (V)-ATPase interactome: identification of proteins involved in trafficking, folding, assembly and phosphorylation. AB - V-ATPases (H(+) ATPases) are multisubunit, ATP-dependent proton pumps that regulate pH homeostasis in virtually all eukaryotes. They are involved in key cell biological processes including vesicle trafficking, endosomal pH sensing, membrane fusion and intracellular signaling. They also have critical systemic roles in renal acid excretion and blood pH balance, male fertility, bone remodeling, synaptic transmission, olfaction and hearing. Furthermore, V-ATPase dysfunction either results in or aggravates various other diseases, but little is known about the complex protein interactions that regulate these varied V-ATPase functions. Therefore, we performed a proteomic analysis to identify V-ATPase associated proteins and construct a V-ATPase interactome. Our analysis using kidney tissue revealed V-ATPase-associated protein clusters involved in protein quality control, complex assembly and intracellular trafficking. ARHGEF7, DMXL1, EZR, NCOA7, OXR1, RPS6KA3, SNX27 and 9 subunits of the chaperonin containing TCP1 complex (CCT) were found to interact with V-ATPase for the first time in this study. Knockdown of two interacting proteins, DMXL1 and WDR7, inhibited V-ATPase mediated intracellular vesicle acidification in a kidney cell line, providing validation for the utility of our interactome as a screen for functionally important novel V-ATPase-regulating proteins. Our data, therefore, provide new insights and directions for the analysis of V-ATPase cell biology and (patho)physiology. PMID- 26442672 TI - Kv3.3 potassium channels and spinocerebellar ataxia. AB - The voltage-dependent potassium channel subunit Kv3.3 is expressed at high levels in cerebellar Purkinje cells, in auditory brainstem nuclei and in many other neurons capable of firing at high rates. In the cerebellum, it helps to shape the very characteristic complex spike of Purkinje cells. Kv3.3 differs from other closely related channels in that human mutations in the gene encoding Kv3.3 (KCNC3) result in a unique neurodegenerative disease termed spinocerebellar ataxia type 13 (SCA13). This primarily affects the cerebellum, but also results in extracerebellar symptoms. Different mutations produce either early onset SCA13, associated with delayed motor and impaired cognitive skill acquisition, or late onset SCA13, which typically produces cerebellar degeneration in middle age. This review covers the localization and physiological function of Kv3.3 in the central nervous system and how the normal function of the channel is altered by the disease-causing mutations. It also describes experimental approaches that are being used to understand how Kv3.3 mutations are linked to neuronal survival, and to develop strategies for treatment. PMID- 26442673 TI - Conceptual Representation Changes in Indonesian-English Bilinguals. AB - This study investigated conceptual representations changes in bilinguals. Participants were Indonesian-English bilinguals (dominant in Indonesian, with different levels of English proficiency) and a control group composed of English dominant bilinguals. All completed a gender decision task, in which participants decided whether English words referred to a male or female person or animal. In order to explore conceptual representations, we divided the words into gender specific and gender-ambiguous words. Gender-specific words were words in which conceptual representations contained gender as a defining feature, in both English and Indonesian (e.g., uncle). In contrast, gender-ambiguous words were words in which gender was a defining feature in English but not a necessary feature in Indonesian (e.g., nephew and niece are both subsumed under the same word, keponakan, in Indonesian). The experiment was conducted exclusively in English. Indonesian-English bilinguals responded faster to gender-specific words than gender-ambiguous words, but the difference was smaller for the most proficient bilinguals. As expected, English-dominant speakers' response latencies were similar across these two types of words. The results suggest that English concepts are dynamic and that proficiency leads to native-like conceptual representations. PMID- 26442674 TI - Cerebral insulin, insulin signaling pathway, and brain angiogenesis. AB - Insulin performs unique non-metabolic functions within the brain. Broadly speaking, two major areas of these functions are those related to brain endothelial cells and the blood-brain barrier (BBB) function, and those related to behavioral effects, like cognition in disease states (Alzheimer's disease, AD) and in health. Recent studies showed that both these functions are associated with brain angiogenesis. These findings raise interesting questions such as how they are linked to each other and whether modifying brain angiogenesis by targeting certain insulin signaling pathways could be an effective strategy to treat dementia as in AD, or even to help secure healthy longevity. The two canonical downstream pathways involved in mediating the insulin signaling pathway, the phosphoinositide-3 kinase (PI3K), and mitogen-activated protein kinase (MAPK) cascades, in the brain are supposed to be similar to those in the periphery. PI3K and MAPK pathways play important roles in angiogenesis. Both are involved in stimulating hypoxia inducible factor (HIF) in angiogenesis and could be activated by the insulin signaling pathway. This suggests that PI3K and MAPK pathways might act as cross-talk between the insulin signaling pathway and the angiogenesis pathway in brain. But the cerebral insulin, insulin signaling pathway, and the detailed mechanism in the connection of insulin signaling pathway, brain angiogenesis pathway, and healthy aging or dementias are still mostly not clear and need further studies. PMID- 26442675 TI - Faster and economical screening for vancomycin-resistant enterococci by sequential use of chromogenic agar and real-time polymerase chain reaction. AB - BACKGROUND/PURPOSE: Screening for vancomycin-resistant enterococci (VRE) by culture takes days to generate results, while polymerase chain reaction (PCR) testing directly from clinical specimens lacks specificity. The aims of this study were to develop a real-time PCR to detect and identify Enterococcus faecium, Enterococcus faecalis, and vanA and vanB genes, and to evaluate the impact of this PCR on test-reporting times when performing it directly from suspect VRE isolates present on screening chromogenic media. METHODS: The tetraplex PCR primers were designed to amplify E. faecium, E. faecalis, and vanA and vanB genes, with melt-curve analysis of PCR products. Following analytical and clinical validation of the molecular assay, PCR testing was performed for target colonies present on VRE chromogenic media. PCR results were evaluated against conventional phenotypic identification and susceptibility testing, with the time to result being monitored for both modalities. RESULTS: A total of 519 colonies from clinical specimens were tested concurrently by real-time PCR and phenotypic methods. In all, 223 isolates were identified with phenotypic vancomycin resistance (vanA, n = 108; vanB, n = 105; non-vanA/vanB = 10), with complete agreement between PCR and phenotypic testing for vancomycin-resistant E. faecium and E. faecalis. The majority (88.6%) of PCR results were reported, on average, 24.8 hours earlier than those of phenotypic testing, with 68% reduction in total costs. CONCLUSION: The use of culture on selective media, followed by direct colony PCR confirmation allows faster and economical VRE screening. PMID- 26442676 TI - Bloodstream infections in pediatric patients with acute leukemia: Emphasis on gram-negative bacteria infections. AB - BACKGROUND/PURPOSE: Acute leukemia is the most common pediatric hematological malignancy. Bloodstream infections (BSIs) are severe complications in these patients during chemotherapy. This study aims to explore clinical features, laboratory, and microbiological characteristics of BSIs in acute leukemic children. METHODS: Patients aged < 18 years, diagnosed with acute myeloid leukemia or acute lymphocytic leukemia with BSIs from January 2004 to December 2013 were enrolled. BSIs was defined as positive isolate(s) of blood culture and associated with clinical findings. Clinical presentations, demographic features, and microbiological findings were retrospectively reviewed. RESULTS: In total, 126 isolates of 115 episodes of BSIs were identified from 69 patients (acute lymphocytic leukemia 56; acute myeloid leukemia 13). Gram-negative bacteria (GNB), gram-positive cocci, and fungi constituted 56.3%, 42.3%, and 2.4% of the pathogens, respectively. Eighty-three and a half percent of BSIs occurred along with neutropenia, and 73% had severe neutropenia. GNB was the leading pathogen of BSIs. The major GNBs were Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa. White blood cell counts, absolute neutrophil counts, and platelet counts were significantly lower in patients of BSIs caused by GNB than gram positive cocci. Plasma level of C-reactive protein was significant high in patients of GNB BSIs (179.8 mg/L vs. 127.2 mg/L; p = 0.005). Eighty-two percent of patients of E. coli, K. pneumonia, and P. aeruginosa BSIs had sepsis related organ failure or organ dysfunction. P. aeruginosa BSIs had the highest case mortality (40%). CONCLUSION: Neutropenia was the major risk factor of BSIs in pediatric leukemic patients. BSIs of GNB were associated with severe neutropenia, systemic inflammatory responses, and high mortality. PMID- 26442677 TI - Management of Retropharyngeal Node Metastases from Thyroid Carcinoma: Reply. PMID- 26442678 TI - Incidence and predictors of myocardial recovery on long-term left ventricular assist device support: Results from the United Network for Organ Sharing database. AB - BACKGROUND: Mechanical circulatory support (MCS) leads to favorable changes in the failing heart at the molecular, cellular, and structural levels. However, myocardial recovery leading to device explantation is rare. We reasoned that the multicenter United Network for Organ Sharing (UNOS) registry might provide insights into clinical predictors and outcomes of the recovery process. METHODS: The MCS device data set of the UNOS registry was queried for patients with long term continuous-flow left ventricular assist devices (CF-LVADs) that were explanted for heart transplantation or indication of recovery. Analysis was restricted to adult patients (>=18 years old) who were listed for an initial heart transplantation. Patients with CF-LVADs that were explanted because of recovery were compared with patients with CF-LVADs who underwent transplantation. RESULTS: We identified 594 patients with HeartMate II devices and 92 patients with HeartWare devices. Duration of support was on average 500.4 +/- 325.3 days. In 34 (5.0%) patients, devices were explanted secondary to myocardial recovery. Univariate predictors of recovery in patients with long-term LVADs included younger age (40 years vs 53 years), female sex, lower body mass index (25.7 kg/m(2) vs 27.9 kg/m(2)), non-ischemic etiology (91% vs 59%), lack of implantable cardioverter defibrillator at the time of listing (44% vs 79%), and lower serum creatinine (0.97 mg/dl vs 1.28 mg/dl) (all p < 0.05). In the post-explantation period, freedom from death or transplantation was 66% at 1 year. CONCLUSIONS: The incidence of recovery on device support is low in the current MCS era and limited to a select cohort of predominantly young patients with non-ischemic myopathy. Given the high incidence of disease recurrence, patients should be closely followed after device explantation. PMID- 26442679 TI - Unique Aspects of Plant Nonsense-Mediated mRNA Decay. AB - Nonsense-mediated mRNA Decay (NMD) is a eukaryotic quality-control mechanism that governs the stability of both aberrant and normal transcripts. Although plant and mammalian NMD share great similarity, they differ in certain mechanistic and regulatory aspects. Whereas SMG6 (from Caenorhabditis elegans 'suppressor with morphogenetic effect on genitalia')-catalyzed endonucleolytic cleavage is a prominent step in mammalian NMD, plant NMD targets are degraded by an SMG7 induced exonucleolytic pathway. Both mammalian and plant NMD are downregulated by stress, thereby enhancing the expression of defense response genes. However, the target genes and processes affected differ. Several plant and mammalian NMD factors are regulated by negative feedback-loops. However, while the loop regulating UPF3 (up-frameshift 3) expression in not vital for mammalian NMD, the sensitivity of UPF3 to NMD is crucial for the overall regulation of plant NMD. PMID- 26442680 TI - Licensed to Kill: Mitochondria, Chloroplasts, and Cell Death. AB - Programmed cell death (PCD) is crucial in plant organogenesis and survival. In this review the involvement of mitochondria and chloroplasts in PCD execution is critically assessed. Recent findings support a central role for mitochondria in PCD, with newly identified components of the mitochondrial electron transport chain (mETC), FOF1 ATP synthase, cardiolipins, and ATPase AtOM66. While chloroplasts received less attention, their contribution to PCD is well supported, suggesting that they possibly contribute by producing reactive oxygen species (ROS) in the presence of light or even contribute through cytochrome f release. Finally we discuss two working models where mitochondria and chloroplasts could cooperatively execute PCD: mitochondria initiate the commitment steps and recruit chloroplasts for swift execution or, alternatively, mitochondria and chloroplasts could operate in parallel. PMID- 26442681 TI - Senescence: Is It Universal or Not? AB - Both demographic and physiological senescence have been demonstrated to occur in various organisms. However, indeterminate growers, such as some animals and most perennial plants, seem to escape the wear and tear of aging. Indeed, most angiosperms show no signs of senescence, and both negligible and negative senescence (improved physiological performance with aging) have been reported in perennial plants growing in their natural habitat. In this opinion article, I review recent developments in the study of senescence in perennial plants and propose that continuous growth prevents senescence. I also address the question whether senescence is a universal process. PMID- 26442682 TI - Missing Pieces in the Puzzle of Plant MicroRNAs. AB - Plant microRNAs (miRNAs) are important regulatory switches. Recent advances have revealed many regulatory layers between the two essential processes, miRNA biogenesis and function. However, how these multilayered regulatory processes ultimately control miRNA gene regulation and connects miRNAs and plant responses with the surrounding environment is still largely unknown. In this opinion article, we propose that the miRNA pathway is highly dynamic and plastic. The apparent flexibility of the miRNA pathway in plants appears to be controlled by a number recently identified proteins and poorly characterized signaling cascades. We further propose that altered miRNA accumulation can be a direct consequence of the rewiring of interactions between proteins that function in the miRNA pathway, an avenue that remains largely unexplored. PMID- 26442683 TI - Genetic and Biochemical Mechanisms of Pollen Wall Development. AB - The pollen wall is a specialized extracellular cell wall matrix that surrounds male gametophytes and plays an essential role in plant reproduction. Uncovering the mechanisms that control the synthesis and polymerization of the precursors of pollen wall components has been a major research focus in plant biology. We review current knowledge on the genetic and biochemical mechanisms underlying pollen wall development in eudicot model Arabidopsis thaliana and monocot model rice (Oryza sativa), focusing on the genes involved in the biosynthesis, transport, and assembly of various precursors of pollen wall components. The conserved and divergent aspects of the genes involved as well as their regulation are addressed. Current challenges and future perspectives are also highlighted. PMID- 26442684 TI - The introduction of early patient rehabilitation in surgery of soft tissue sarcoma and its impact on post-operative outcome. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) programs are implemented in multiple fields of surgery, but not yet in soft-tissue sarcoma (STS) surgery. We wondered whether its introduction into STS surgery might have impacted postoperative outcome. METHODS: Two hundred and fifty seven adult patients with primary limb or trunk wall STS received ERAS from 2008 to 2012 as a part of the intra-operative management. We evaluated, in retrospect, the intra-operative management, post-operative outcomes, functional and oncological results of these patients and compared them with 459 prior patients treated under a standard recovery after surgery (SRAS) program from 1989 to 2007. RESULTS: The most visible change from SRAS to ERAS in the perioperative management was decrease of wound drainage (72% vs. 15%, p < 0.001) and increase of wound bandaging (16% vs. 66%; p < 0.001), underlining the appliance of the ERAS protocol. Post operatively, hospital stay dropped from nine (0-74) to three (0-22) days (p < 0.001) without affecting major morbidity (8% vs. 5%, NS) or readmission to the hospital (5% vs. 4%, NS). Functional outcome improved (p = 0.009) but whether this change was due to ERAS remains to be proved because complementary treatments changed over time. Tumour control remained unaffected, with an estimated risk of local recurrence at 5 years of 12% in both groups. CONCLUSION: Introducing a rapid recovery program was associated with a shorter hospitalization stay without compromising surgical or oncological outcomes. The program appears to be safe and reliable to use in patients undergoing STS surgery. PMID- 26442685 TI - Drug adherence of patients with epilepsy in Iran: the effects of the international economic sanctions. AB - Drug adherence of patients with epilepsy was investigated to determine the reasons behind poor adherence. In this retrospective chart review study, all patients with a clinical diagnosis of epilepsy were recruited at the outpatient epilepsy clinic at Shiraz University of Medical Sciences. We routinely asked about the patient's drug adherence and reasons behind poor drug adherence in every office visit. We defined drug adherence adequate if the patient reported less than or equal to one missed dose per month. Patients' drug adherences were investigated during two time periods: March 2010-2011 (before intensification of the international economic sanctions against Iran), and September 2012-2013 (during intensified international economic sanctions). One hundred and ninety nine patients were studied. Drug adherence was satisfactory in 139 patients (69.8 %) during the first time period. Drug adherence was satisfactory in 146 patients (73.4 %) during the second time period. The most common reasons for poor drug adherence was carelessness, followed by cost and lack of drug availability (1.5 % in the first time period and 4 % in the second time period; P = 0.07). About one third of patients with epilepsy had poor drug adherence. To overcome the problem, it is important to find the reasons behind poor drug adherence in each patient and try to overcome the cause. Purely from a clinical and patient care perspective, it seems necessary that politicians should facilitate decisions that make the health and well-being of ordinary people more affordable and without hardship. PMID- 26442686 TI - The influence of subthalamic nucleus stimulation on pragmatic language production in Parkinson's disease. AB - While the influence of deep brain stimulation (DBS) of the subthalamic nucleus (STN) on the comprehension of pragmatic language in Parkinson's disease (PD) has been the focus of studies, its impact on production, however, has yet to be elucidated. (1) Investigating the inf luence of DBS STN on pragmatic language production in spontaneous speech by comparing different stimulation conditions and (2) evaluating the effect of asymmetric dopaminergic denervation. This paper included 18 patients with advanced idiopathic PD with STN DBS. [Ten PD patients with predominantly left hemispheric dopamine denervation (PD-left) and eight PD patients with predominantly right-hemispheric dopamine denervation (PD-right).] The pragmatic components 'communicative functions' and 'conversational skills' were evaluated by analysing the spontaneous language production in four stimulation conditions. STN stimulation did not appear to influence the pragmatic production skills. Only when asymmetric dopamine depletion was taken into account the parameter 'giving an explanation' interaction was detectable. STN DBS appears to have some influence on the production of pragmatic language depending on asymmetric dopaminergic denervation. Suggestions are made for further research of pragmatic production in Parkinson's disease. PMID- 26442687 TI - The determinants of depression in a Romanian cohort of multiple sclerosis patients. AB - The aim of the present study was to assess the prevalence of depression in a large multiple sclerosis (MS) patient group and to analyse the physical and psycho-socio-economic factors that influence its frequency and severity. In total, 351 consecutive patients with a diagnosis of MS were included in this study. All the patients completed a survey about their demographic characteristics, marital status, presence of children, employment status, educational level, duration of disease, disease course, duration of treatment and type of disease modifying therapies (DMT). Their disability level was evaluated using the Expanded Disability Status Scale (EDSS). Their depression level was evaluated using the Romanian Version (2012) of the Beck Depression Inventory-II (BDI-II). There was a significant positive correlation between the BDI-II score and the actual age of the patients, their disease duration, EDSS and the number of total relapses. From the EDSS functional scores, only the pyramidal score and the sensitive score presented a significant association with BDI-II in the logistic regression analysis. The BDI-II values decreased significantly with increasing education level. In the case of the retired patients, the BDI-II values were significantly higher. The BDI-II scores were also higher in widowers and divorced patients and in patients with children. There was no significant difference in the BDI-II values between different DMT groups. The main physical and psycho-socio-economic determinants of depression in patients with MS are the physical disability, disease duration, number of relapses, marital status, education level, employment status, and the presence of children, but many unsolved questions remain about the interrelations and relative contributions of these factors, which necessitates further research. The DMTs did not significantly influence the depression level. PMID- 26442688 TI - Morphology of muscular function in chronic tension-type headache: a pilot study. AB - Chronic pain has been thought to induce muscular changes in chronic tension-type headache (CTTH) patients. As the knowledge of muscular responses in CTTH is inconsistent, we decided to introduce new electromyogram signal shape descriptors. We also wanted to compare the discriminatory power of proposed indices with classical measures to establish their potential to act as markers for CTTH. Thirty-eight headache patients with twenty healthy volunteers were recruited. Twenty patients had CTTH, while 18 had migraine without aura. Surface electromyogram data were recorded from right sternocleidomastoid and left temporalis muscles during rest and in a headache-free situation. Besides conventional root mean square (RMS) and median frequency (MDF), two morphological based indices, skewness and kurtosis, were proposed to quantify the shape variations of signal distribution. Results demonstrated that the skewness outperformed RMS and MDF in terms of discriminatory power (p < 0.00). Kurtosis values for both muscles differed considerably among study groups (p < 0.04). RMS for both muscles was noticeably higher in CTTH group (p < 0.00). Regarding MDF, migraineurs revealed highest (p < 0.05), while CTTH patients represented the lowest values. Skewness was the most relevant predictor for headache diagnosis, especially in temporalis muscle (migraine, odds ratio = 21.1, p = 0.01; Ctension type headache, odds ratio = 78.8, p = 0.00). There are detectable distinct muscular responses in chronic headache sufferers. This finding could be due to adaptation to muscle underuse or sustained contraction, leading to impaired recruitment and muscle fiber-type conversion with dominant type I fibers in CTTH. PMID- 26442689 TI - Temporary conduction block in acute motor axonal neuropathy. PMID- 26442690 TI - Is the chronic Tier-1 effect assessment approach for insecticides protective for aquatic ecosystems? AB - We investigated the appropriateness of several methods, including those recommended in the Aquatic Guidance Document of the European Food Safety Authority (EFSA), for the derivation of chronic Tier-1 regulatory acceptable concentrations (RACs) for insecticides and aquatic organisms. The insecticides represented different chemical classes (organophosphates, pyrethroids, benzoylureas, insect growth regulators, biopesticides, carbamates, neonicotinoids, and miscellaneous). Chronic Tier-1 RACs derived using toxicity data for the standard species Daphnia magna, Chironomus spp., and/or Americamysis bahia, were compared with Tier-3 RACs derived from micro- and mesocosm studies on basis of the ecological threshold option (ETO-RACs). ETO-RACs could be derived for 31 insecticides applied to micro- and mesocosms in single or multiple applications, yielding a total number of 36 cases for comparison. The chronic Tier-1 RACs calculated according to the EFSA approach resulted in a sufficient protection level, except for 1 neonicotinoid (slightly underprotective) and for several pyrethroids if toxicity data for A. bahia were not included. This latter observation can be explained by 1) the fact that A. bahia is the most sensitive standard test species for pyrethroids, 2) the hydrophobic properties of pyrethroids, and 3) the fact that long-term effects observed in (epi) benthic arthropods may be better explained by exposure via the sediment than via overlying water. Besides including toxicity data for A. bahia, the protection level for pyrethroids can be improved by selecting both D. magna and Chironomus spp. as standard test species for chronic Tier-1 derivation. Although protective in the majority of cases, the conservativeness of the recommended chronic Tier-1 RACs appears to be less than an order of magnitude for a relatively large proportion of insecticides when compared with their Tier-3 ETO-RACs. This may leave limited options for refinement of the chronic effect assessment using laboratory toxicity data for additional species. Integr Environ Assess Manag 2016;12:747-758. (c) 2015 SETAC. PMID- 26442691 TI - Trends form follows function: new ways to inform and inspire. PMID- 26442692 TI - A learning experience. PMID- 26442693 TI - System consolidation during sleep - a common principle underlying psychological and immunological memory formation. AB - Sleep benefits the consolidation of psychological memory, and there are hints that sleep likewise supports immunological memory formation. Comparing psychological and immunological domains, we make the case for active system consolidation that is similarly established in both domains and partly conveyed by the same sleep-associated processes. In the psychological domain, neuronal reactivation of declarative memory during slow-wave sleep (SWS) promotes the redistribution of representations initially stored in hippocampal circuitry to extra-hippocampal circuitry for long-term storage. In the immunological domain, SWS seems to favor the redistribution of antigenic memories initially held by antigen-presenting cells, to persisting T cells serving as a long-term store. Because storage capacities are limited in both systems, system consolidation presumably reduces information by abstracting 'gist' for long-term storage. PMID- 26442694 TI - The molecular constituents of the blood-brain barrier. AB - The blood-brain barrier (BBB) maintains the optimal microenvironment in the central nervous system (CNS) for proper brain function. The BBB comprises specialized CNS endothelial cells with fundamental molecular properties essential for the function and integrity of the BBB. The restrictive nature of the BBB hinders the delivery of therapeutics for many neurological disorders. In addition, recent evidence shows that BBB dysfunction can precede or hasten the progression of several neurological diseases. Despite the physiological significance of the BBB in health and disease, major discoveries of the molecular regulators of BBB formation and function have occurred only recently. This review highlights recent findings describing the molecular determinants and core cellular pathways that confer BBB properties on CNS endothelial cells. PMID- 26442695 TI - Priming the inflammatory pump of the CNS after traumatic brain injury. AB - Traumatic brain injury (TBI) can lead to secondary neuropsychiatric problems that develop and persist years after injury. Mounting evidence indicates that neuroinflammatory processes progress after the initial head injury and worsen with time. Microglia contribute to this inflammation by maintaining a primed profile long after the acute effects of the injury have dissipated. This may set the stage for glial dysfunction and hyperactivity to challenges including subsequent head injury, stress, or induction of a peripheral immune response. This review discusses the evidence that microglia become primed following TBI and how this corresponds with vulnerability to a 'second hit' and subsequent neuropsychiatric and neurodegenerative complications. PMID- 26442697 TI - Depression as a microglial disease. AB - Despite decades of intensive research, the biological mechanisms that causally underlie depression are still unclear, and therefore the development of novel effective antidepressant treatments is hindered. Recent studies indicate that impairment of the normal structure and function of microglia, caused by either intense inflammatory activation (e.g., following infections, trauma, stroke, short-term stress, autoimmune or neurodegenerative diseases) or by decline and senescence of these cells (e.g., during aging, Alzheimer's disease, or chronic unpredictable stress exposure), can lead to depression and associated impairments in neuroplasticity and neurogenesis. Accordingly, some forms of depression can be considered as a microglial disease (microgliopathy), which should be treated by a personalized medical approach using microglial inhibitors or stimulators depending on the microglial status of the depressed patient. PMID- 26442698 TI - Myeloid cells in Alzheimer's disease: culprits, victims or innocent bystanders? AB - Several recent genome-wide association studies (GWAS) in patients with neurodegenerative disorders have shed new light on the brain immune system, suggesting that it plays a pivotal role in disease pathogenesis. Mononuclear phagocytes are blatantly involved in Alzheimer's disease (AD) of the central nervous system (CNS), but the specific functions of resident microglia, perivascular or meningeal macrophages, and circulating myeloid cells have not yet been fully resolved. Next-generation sequencing, high-throughput immune profiling technologies, and novel genetic tools have recently revolutionized the characterization of innate immune responses during AD. These studies advocate selective and non-redundant roles for myeloid subsets, which could be a target for novel disease-modifying therapies in AD. PMID- 26442696 TI - Microglial malfunction: the third rail in the development of Alzheimer's disease. AB - Studies of Alzheimer's disease (AD) have predominantly focused on two major pathologies: amyloid-beta (Abeta) and hyperphosphorylated tau. These misfolded proteins can accumulate asymptomatically in distinct regions over decades. However, significant Abeta accumulation can be seen in individuals who do not develop dementia, and tau pathology limited to the transentorhinal cortex, which can appear early in adulthood, is usually clinically silent. Thus, an interaction between these pathologies appears to be necessary to initiate and propel disease forward to widespread circuits. Recent multidisciplinary findings strongly suggest that the third factor required for disease progression is an aberrant microglial immune response. This response may initially be beneficial; however, a maladaptive microglial response eventually develops, fueling a feed-forward spread of tau and Abeta pathology. PMID- 26442699 TI - Systemic Juvenile Idiopathic Arthritis with Amyloidosis: An Uncommon Complication with a Favourable Outcome. PMID- 26442700 TI - Interprofessionalism between physicians and nurses: moving forward. PMID- 26442701 TI - K11Cd2Sb5 built of an unprecedented planar CdSb3 triangle. AB - The novel ternary Zintl phase K11Cd2Sb5 (1) with the unusual butterfly-shaped [Cd2Sb5](11-) (1a) cluster anion has been prepared by employing an enhanced stoichiometric proportion of K atoms that act as scissors. 1a is composed of two corner-shared unprecedented planar CdSb3 triangles that represent the first tricoordinated example of Cd unexpected for the octet rule. PMID- 26442702 TI - Natural History and Implantable Cardioverter-Defibrillator Implantation After Revascularization for Stable Coronary Artery Disease With Depressed Ejection Fraction. AB - BACKGROUND: Following revascularization, most payors require 3 months of medical therapy, followed by left ventricular ejection fraction (LVEF) reassessment, before implantable cardioverter-defibrillator (ICD) implantation possibly contributing to incomplete follow-up and suboptimal utilization of ICD therapy. The natural history of these patients, and their fate regarding ICD implantation, is unknown. HYPOTHESIS: We hypothesized that a waiting period after revascularization for stable CAD results in missed opportunities to provide care with regard to ICD implantation. METHODS: We followed patients with LVEF <= 35% and no ICD who underwent revascularization (coronary artery bypass grafting [CABG] or percutaneous coronary intervention [PCI]) for stable CAD. Follow-up used chart review and scripted telephone interviews. RESULTS: Among 3164 revascularized patients (2198 [69%] PCI, 966 [31%] CABG), only 62 (2%; 33 [53%] male, age 67 +/- 12 y, LVEF 28% +/- 6%) had stable CAD, depressed LVEF, and no ICD. Over 35 +/- 19 months, 35 (56%) of these 62 patients were no longer candidates for ICD based on improved LVEF, 14 (23%) received an ICD, 5 (8%) declined ICD despite physician recommendation, 3 (5%) were not offered ICD despite continued eligibility, 2 (3%) died, 1 (2%) was not a candidate due to substance abuse, and 1 (2%) had ICD implantation temporarily deferred. Only 1 (2%) was lost to follow-up. CONCLUSIONS: Following revascularization for stable CAD with depressed LVEF, >=50% of patients' ventricular function improved enough to make ICD implantation unnecessary. A waiting period after revascularization prior to ICD implantation appears appropriate and does not significantly negatively impact follow-up or the rate of appropriate ICD implantation. PMID- 26442703 TI - R248Q mutation--Beyond p53-DNA binding. AB - R248 in the DNA binding domain (DBD) of p53 interacts directly with the minor groove of DNA. Earlier nuclear magnetic resonance (NMR) studies indicated that the R248Q mutation resulted in conformation changes in parts of DBD far from the mutation site. However, how information propagates from the mutation site to the rest of the DBD is still not well understood. We performed a series of all-atom molecular dynamics (MD) simulations to dissect sterics and charge effects of R248 on p53-DBD conformation: (i) wild-type p53 DBD; (ii) p53 DBD with an electrically neutral arginine side-chain; (iii) p53 DBD with R248A; (iv) p53 DBD with R248W; and (v) p53 DBD with R248Q. Our results agree well with experimental observations of global conformational changes induced by the R248Q mutation. Our simulations suggest that both charge- and sterics are important in the dynamics of the loop (L3) where the mutation resides. We show that helix 2 (H2) dynamics is altered as a result of a change in the hydrogen bonding partner of D281. In turn, neighboring L1 dynamics is altered: in mutants, L1 predominantly adopts the recessed conformation and is unable to interact with the major groove of DNA. We focused our attention the R248Q mutant that is commonly found in a wide range of cancer and observed changes at the zinc-binding pocket that might account for the dominant negative effects of R248Q. Furthermore, in our simulations, the S6/S7 turn was more frequently solvent exposed in R248Q, suggesting that there is a greater tendency of R248Q to partially unfold and possibly lead to an increased aggregation propensity. Finally, based on the observations made in our simulations, we propose strategies for the rescue of R248Q mutants. PMID- 26442704 TI - Cardiac outflow morphogenesis depends on effects of retinoic acid signaling on multiple cell lineages. AB - BACKGROUND: Retinoic acid (RA), the bioactive derivative of vitamin A, is essential for vertebrate heart development. Both excess and reduced RA signaling lead to cardiovascular malformations affecting the outflow tract (OFT). To address the cellular mechanisms underlying the effects of RA signaling during OFT morphogenesis, we used transient maternal RA supplementation to rescue the early lethality resulting from inactivation of the murine retinaldehyde dehydrogenase 2 (Raldh2) gene. RESULTS: By embryonic day 13.5, all rescued Raldh2(-/-) hearts exhibit severe, reproducible OFT septation defects, although wild-type and Raldh2(+/-) littermates have normal hearts. Cardiac neural crest cells (cNCC) were present in OFT cushions of Raldh2(-/-) mutant embryos but ectopically located in the periphery of the endocardial cushions, rather than immediately underlying the endocardium. Excess mesenchyme was generated by Raldh2(-/-) mutant endocardium, which displaced cNCC derivatives from their subendocardial, medial position. CONCLUSIONS: RA signaling affects not only cNCC numbers but also their position relative to endocardial mesenchyme during the septation process. Our study shows that inappropriate coordination between the different cell types of the OFT perturbs its morphogenesis and leads to a severe congenital heart defect, persistent truncus arteriosus. PMID- 26442705 TI - Epidemiological analysis of the distribution of cystic and alveolar echinococcosis in Osh Oblast in the Kyrgyz Republic, 2000-2013. AB - Alveolar and cystic echinococcosis are highly endemic in the Kyrgyz Republic. This report documents the numbers of recorded cases of these two diseases that have been reported in the past 14 years. The number of cases of echinococcosis has increased from approximately 550 to 1044 cases in 2013. This is an increase in incidence from 11.3 to 18.3 cases per 100,000 annually. In 2000 no cases of alveolar echinococcosis (AE) were reported in the Kyrgyz Republic. During this period the disease has emerged, with 148 cases reported in 2013 (2.6 cases per 100,000). Osh Oblast is a highly endemic focus for AE, with 60 cases reported in 2013 (6.0 per 100,000). The Alay Valley in the south of Osh Oblast reported the majority of AE cases for this region. In this valley, in 2013, 42 cases of AE were reported, which is a local incidence of 58 per 100,000. PMID- 26442706 TI - Risk factors for Echinococcus coproantigen positivity in dogs from the Alay valley, Kyrgyzstan. AB - Echinococcosis, caused by the zoonotic cestodes Echinococcus granulosus (sensu lato) and Echinococcus multilocularis, is highly endemic in the Central Asian Republic of Kyrgyzstan, and is being identified increasingly as a public health problem, especially amongst pastoral communities. As domestic dogs are considered to be the main source of human infection, the identification of potential transmission pathways is of relevance when considering implementing an echinococcosis control scheme. The current report describes the results of an analytical study of canine Echinococcus coproantigen enzyme-linked immunosorbent assay (ELISA) prevalence in the Alay valley of southern Kyrgyzstan prior to the commencement of regular praziquantel dosing of dogs. A logistic regression model using a form of Bayes modal estimation was used to identify possible risk factors for coproantigen positivity, and the output was interpreted in a Bayesian context (posterior distributions of the coefficients of interest). The study found that sheepdogs had lower odds of coproantigen positivity, as did dogs in households with donkeys, where owners had knowledge of echinococcosis, and households which engaged in home slaughtering. Surprisingly, there was no evidence of an association between free roaming or previous praziquantel dosing and coproantigen positivity, as has been found in previous studies. Possible reasons for these findings are discussed in the context of the epidemiology of echinococcosis and potential intervention approaches. PMID- 26442707 TI - Canine echinococcosis: genetic diversity of Echinococcus granulosus sensu stricto (s.s.) from definitive hosts. AB - Canids, particularly dogs, constitute the major source of cystic echinococcosis (CE) infection to humans, with the majority of cases being caused by Echinococcus granulosus (G1 genotype). Canine echinococcosis is an asymptomatic disease caused by adult tapeworms of E. granulosus sensu lato (s.l.). Information on the population structure and genetic variation of adult E. granulosus is limited. Using sequenced data of the mitochondrial cytochrome c oxidase subunit 1 (cox1) we examined the genetic diversity and population structure of adult tapeworms of E. granulosus (G1 genotype) from canid definitive hosts originating from various geographical regions and compared it to that reported for the larval metacestode stage from sheep and human hosts. Echinococcus granulosus (s.s) was identified from adult tapeworm isolates from Kenya, Libya, Tunisia, Australia, China, Kazakhstan, United Kingdom and Peru, including the first known molecular confirmation from Gaza and the Falkland Islands. Haplotype analysis showed a star shaped network with a centrally positioned common haplotype previously described for the metacestode stage from sheep and humans, and the neutrality indices indicated population expansion. Low Fst values suggested that populations of adult E. granulosus were not genetically differentiated. Haplotype and nucleotide diversities for E. granulosus isolates from sheep and human origin were twice as high as those reported from canid hosts. This may be related to self fertilization of E. granulosus and/or to the longevity of the parasite in the respective intermediate and definitive hosts. Improved nuclear single loci are required to investigate the discrepancies in genetic variation seen in this study. PMID- 26442708 TI - The development of Angiostrongylus vasorum (Baillet, 1866) in the freshwater snail Pomacea canaliculata (Lamarck, 1822). AB - Angiostrongylus vasorum is a parasitic nematode that infects the heart and pulmonary artery and its branches of domestic and wild canids. The parasite can use several species of terrestrial and aquatic molluscs as intermediate hosts, although susceptibility varies. Pomacea canaliculata is a mollusc found in lakes, swamps and rivers in South America. In this study, we evaluated the susceptibility, parasite growth, oviposition and larval development of 282 P. canaliculata infected with 500 A. vasorum first-instar larvae (L1). From day 5 post-infection (pi) to day 30 pi, seven specimens per day were sacrificed to recover the larval instars. We compared 50 egg masses from infected and uninfected molluscs to determine the number of eggs per clutch, the hatching rate and the growth of the molluscs. The percentage of recovered larvae ranged from 39.17% to 67.5%. First-stage larvae (L1) were found until day 19 pi, second-stage larvae (L2) were found from days 11 to 25 pi, and third-stage larvae (L3) were recovered only after day 19 pi. Infected snails exhibited the most eggs during spawning, although the rate of hatching and shell size were lower in the infected snails compared with controls. This is the first report of an experimental infection of P. canaliculata with A. vasorum, and the results confirm the non specificity of the nematode in relation to the intermediate host and indicate the importance of epidemiological surveys of this parasite and mollusc. PMID- 26442709 TI - Regioselective synthesis of 2H-indazoles through Ga/Al- and Al-mediated direct alkylation reactions of indazoles. AB - A procedure has been developed for the regioselective, high yielding synthesis of 2H-indazoles that involves direct alkylation of indazoles with various allyl and benzyl bromides, and alpha-bromocarbonyl compounds. PMID- 26442710 TI - Is It Migralepsy? Still Don't Know. PMID- 26442711 TI - Helicobacter pylori virulence genes in the five largest islands of Indonesia. AB - BACKGROUND: It remains unclear whether the low incidence of gastric cancer in Indonesia is due to low infection rates only or is also related to low Helicobacter pylori pathogenicity. We collected H. pylori strains from the five largest islands in Indonesia and evaluated genetic virulence factors. METHODS: The genotypes of H. pylori virulence factors were determined by polymerase chain reaction (PCR)-based sequencing. Histological severity of the gastric mucosa was classified into 4 grades, according to the updated Sydney system. RESULTS: A total of 44 strains were analyzed. Forty-three (97.7 %) were cagA-positive: 26 (60.5 %) were East-Asian-type-cagA, 9 (20.9 %) were Western-type-cagA, and 8 (18.6 %) were novel ABB-type, most of which were obtained from Papuan. EPIYT sequences were more prevalent than EPIYA sequences (P = 0.01) in the EPIYA-B motif of all types of cagA. The majority of cagA-positive strains (48.8 %, 21/43) had a 6-bp deletion in the first pre-EPIYA region. Subjects infected with East Asian-type-cagA strains with a 6-bp deletion had significantly lower inflammation and atrophy scores in the corpus than those infected with Western-type-cagA strains (both P = 0.02). In total, 70.4 % of strains possessed the vacA s1m1 genotype and 29.5 % were m2. All strains from peptic ulcer patients were of the iceA1 genotype, which occurred at a significantly higher proportion in peptic ulcer patients than that in gastritis patients (55.3 %, P = 0.04). The double positive genotype of jhp0562/beta-(1,3)galT was predominant (28/44, 63.6 %), and subjects infected with this type had significantly higher inflammation scores in the corpus than those with the jhp0562 negative/beta-(1,3)galT positive genotype (mean [median]; 1.43 [1] vs. 0.83 [1], P = 0.04). There were significant differences in cagA and pre-EPIYA cagA type, oipA status, and jhp0562/beta (1,3)galT type among different ethnic groups (P < 0.05). CONCLUSIONS: In addition to a low H. pylori infection rate, the low incidence of gastric cancer in Indonesia might be attributed to less virulent genotypes in predominant strains, which are characterized by the East-Asian-type-cagA with a 6-bp deletion and EPIYT motif, a high proportion of m2, dupA negative or short type dupA, and the jhp0562/beta-(1,3)galT double positive genotype. PMID- 26442713 TI - Fabrication of Thermoresponsive Nanoactinia Tentacles by a Single Particle Nanofabrication Technique. AB - Nanowires that are retractable by external stimulus are the key to fabrication of nanomachines that mimick actinia tentacles in nature. A single particle nanofabrication technique (SPNT) was applied over a large area to the fabrication of retractable nanowires (nanoactinia tentacles) composed of poly(N isopropylacrylamide) (PNIPAM) and poly(vinylpyrrolidone) (PVP), which are thermoresponsive and hydrophilic polymers. The nanowires were transformed with increasing temperature from rod-like- to globule-forms with gyration radii of ~1.5 and ~0.7 MUm, respectively. The transformation of the nanowires was reversible and reproducible under repeated cycles of heating and cooling. The reversible transformation was driven by hydration and dehydration of PNIPAM, the thermoresponsive segments, resulting in coil-to-globule transformation of the segments. The nanoactinia tentacle systems trapped the nanoparticles as a model of living cells under thermal stimulation, and the trapping was controlled by temperature. We present herein a unique nanomachine system which can be applicable to nanoparticle filtering/sensing systems and expandable to large-area functionalization and demonstrate polymer-based nanoactuators via scaling of molecular level coil-to-globule transformation into micron-sizes. PMID- 26442712 TI - Maximizing oyster-reef growth supports green infrastructure with accelerating sea level rise. AB - Within intertidal communities, aerial exposure (emergence during the tidal cycle) generates strong vertical zonation patterns with distinct growth boundaries regulated by physiological and external stressors. Forecasted accelerations in sea-level rise (SLR) will shift the position of these critical boundaries in ways we cannot yet fully predict, but landward migration will be impaired by coastal development, amplifying the importance of foundation species' ability to maintain their position relative to rising sea levels via vertical growth. Here we show the effects of emergence on vertical oyster-reef growth by determining the conditions at which intertidal reefs thrive and the sharp boundaries where reefs fail, which shift with changes in sea level. We found that oyster reef growth is unimodal relative to emergence, with greatest growth rates occurring between 20 40% exposure, and zero-growth boundaries at 10% and 55% exposures. Notably, along the lower growth boundary (10%), increased rates of SLR would outpace reef accretion, thereby reducing the depth range of substrate suitable for reef maintenance and formation, and exacerbating habitat loss along developed shorelines. Our results identify where, within intertidal areas, constructed or natural oyster reefs will persist and function best as green infrastructure to enhance coastal resiliency under conditions of accelerating SLR. PMID- 26442714 TI - Separation and characterization of polyphenolics from underutilized byproducts of fruit production (Choerospondias axillaris peels): inhibitory activity of proanthocyanidins against glycolysis enzymes. AB - Bioactive proanthocyanidins were isolated from the peel of Choerospondias axillaris fruit, which is a waste product of the food processing industry. Compositional analysis indicated that the proanthocyanidins had extension units mainly consisting of epicatechin gallate or epicatechin, and terminal units mainly consisting of catechin. Numerous polymeric forms of the molecules were detected, including monomers, dimers, and trimers. Certain fractions exhibited strong alpha-amylase or alpha-glucosidase inhibition in a dose-dependent manner. Furthermore, their inhibitory activities depended on their degree of polymerization and galloylation. For example, the most bioactive fraction had alpha-amylase and alpha-glucosidase inhibitory activities (IC50 values) of 541 and 3.1 MUg mL(-1), respectively. This study demonstrates that proanthocyanidins from C. axillaris peels can inhibit carbohydrate digestive enzymes in vitro and may therefore serve as antidiabetic ingredients in functional or medical foods. PMID- 26442715 TI - Dental students' perceptions of undergraduate clinical training in oral and maxillofacial surgery in an integrated curriculum in Saudi Arabia. AB - PURPOSE: The aim was to understand dental students' experiences with oral and maxillofacial surgery (OMS) teaching, their confidence levels in performing routine dento-alveolar operations, and the relationship between the students' confidence level and the number of teeth extracted during the clinical practice. METHODS: The survey questionnaire was distributed to 32 students at Aljouf University College of Dentistry, Saudi Arabia during their fourth and fifth year in 2015. Respondents were asked to rate 19 items, which represent a student's confidence in performing routine surgical interventions, using a four-point Likert scale (1=very little confidence, 4=very confident). A multivariate regression was computed between average confidence and the variables: weekly hours devoted to studying oral and maxillofacial surgery, college grade point average, and the total number of teeth extracted. RESULTS: The response rate was 100%. Students revealed the highest level of confidence in giving local anesthesia (96.9%), understanding extraction indications (93.8%), and performing simple extractions (90.6%). Less confidence was shown with handling difficult extractions (50.0%), extracting molars with separation (50.0%) or extracting third molars (56.3%). The average confidence in performing surgical procedures was 2.88 (SD=0.55), ranging from 1.79 to 3.89. A given student's confidence increased with an increase in the total number of teeth extracted (P=0.003). CONCLUSION: It reveals a significant impact of undergraduate clinical training on students' confidence in performing oral and maxillofacial surgery clinical procedures: The more clinical experience the students had, the more confidence they reported. PMID- 26442716 TI - Analysis of the study skills of undergraduate pharmacy students of the University of Zambia School of Medicine. AB - It aimed to compare the study skills of two groups of undergraduate pharmacy students in the School of Medicine, University of Zambia using the Study Skills Assessment Questionnaire (SSAQ), with the goal of analysing students' study skills and identifying factors that affect study skills. A questionnaire was distributed to 67 participants from both programs using stratified random sampling. Completed questionnaires were rated according to participants study skill. The total scores and scores within subscales were analysed and compared quantitatively. Questionnaires were distributed to 37 students in the regular program, and to 30 students in the parallel program. The response rate was 100%. Students had moderate to good study skills: 22 respondents (32.8%) showed good study skills, while 45 respondents (67.2%) were found to have moderate study skills. Students in the parallel program demonstrated significantly better study skills (mean SSAQ score, 185.4+/-14.5), particularly in time management and writing, than the students in the regular program (mean SSAQ score 175+/-25.4; P<0.05). No significant differences were found according to age, gender, residential or marital status, or level of study. The students in the parallel program had better time management and writing skills, probably due to their prior work experience. The more intensive training to students in regular program is needed in improving time management and writing skills. PMID- 26442717 TI - Clinical significance of stem cell marker CD133 expression in colorectal cancer. AB - OBJECTIVE: CD133, a glycoprotein, is expressed in different types of human stem cells and tumor cells. Detection of altered CD133 expression in colorectal cancer tissues could be useful as a marker for the prediction of colorectal tumorigenesis, progression, and prognosis. METHODS: A total of 19 fresh and 145 paraffin-embedded tissue specimens from colorectal cancer patients were obtained for detection of CD133 expression using flow cytometry and immunohistochemistry, respectively. The tumorigenic capacity of tumor cells from 19 patients was assessed in nude mice. Association of CD133 expression was then analyzed for clinical significance. RESULTS: The percentage of CD133-positive (CD133+) tumor cell population ranged between 0.84% and16.75% (mean ratio =7.15%) of tumor cells in the 19 freshly isolated tissue samples. CD133 expression in tumor cells was associated with tumor lymph node metastasis (9.81% vs. 3.22%; p=0.013) and poor tumor differentiation (8.32% vs. 5.07%; p=0.043). In the 145 paraffin-embedded samples, CD133+ colorectal cancer was also associated with local recurrence of tumorigenesis (p=0.035) and distant metastasis (p=0.017), while patients with over 5% CD133+ tumor cells exhibited a decreased survival rate (p=0.001). Multivariate COX analysis showed that the depth of tumor invasion, histology, stagWaes, lymph node metastasis, and CD133 expression were all independent prognosis factors for colorectal cancer (p=0.032, 0.011, 0.001, 0.002, and 0.030, respectively). Furthermore, as few as 5,000 CD133+ colorectal cancer HCT116 cells were sufficient to form tumor xenografts, whereas 1x105 CD133- tumor cells failed to develop tumor xenografts in nude mice. CONCLUSIONS: CD133 expression is a useful biomarker for prediction of colorectal cancer progression and survival of patients. PMID- 26442719 TI - Anthropogenic phosphorus flows under different scenarios for the city of Stockholm, Sweden. AB - Today, concerns prevail about the unsustainable use of phosphorus and worldwide eutrophication, thus requiring efficient management of phosphorus flows. With increasing population and associated urban growth, urban management of phosphorus flows in the perspectives of recycling, eutrophication and total budget becomes increasingly important. This study mapped phosphorus flows for a reference year (2013) and a future year (2030) using different scenarios for the city of Stockholm, Sweden. The results indicated that the Swedish goal of recycling phosphorus from wastewater would cover the majority of the total phosphorus budget for Stockholm. However, in 2013, only 10% of phosphorus was recycled for agricultural use, around half of which was from sewage sludge and the other half from food waste. Almost 50% of total phosphorus was sent to landfill/mining waste capping with sewage sludge, for economic reasons and lack of market. Among the scenarios of upstream and downstream urban management options studied in combination with population growth, recovery of phosphorus from sewage sludge had the greatest potential to increase the fraction recycled to agriculture. However, only upstream measures, e.g. changed diet, were able to reduce the total phosphorus budget. Urban management of phosphorus flows based on the different perspectives of recycling, eutrophication or total budget was shown to potentially result in different preferred management actions and both upstream and downstream measures need to be considered. Moreover, management needs to pay attention to small but environmentally sensitive flows, particularly when setting city goals on phosphorus recycling by percentage in a large budget. PMID- 26442718 TI - Linking pattern recognition and salicylic acid responses in Arabidopsis through ACCELERATED CELL DEATH6 and receptors. AB - The Arabidopsis membrane protein ACCELERATED CELL DEATH 6 (ACD6) and the defense signal salicylic acid (SA) are part of a positive feedback loop that regulates the levels of at least 2 pathogen-associated molecular patterns (PAMP) receptors, including FLAGELLIN SENSING 2 (FLS2) and CHITIN ELICITOR RECEPTOR (LYSM domain receptor-like kinase 1, CERK1). ACD6- and SA-mediated regulation of these receptors results in potentiation of responses to FLS2 and CERK1 ligands (e.g. flg22 and chitin, respectively). ACD6, FLS2 and CERK1 are also important for callose induction in response to an SA agonist even in the absence of PAMPs. Here, we report that another receptor, EF-Tu RECEPTOR (EFR) is also part of the ACD6/SA signaling network, similar to FLS2 and CERK1. PMID- 26442720 TI - Controlling phosphate releasing from poultry litter using stabilized Fe-Mn binary oxide nanoparticles. AB - Animal wastes contain high concentrations of phosphorus (P), most of which is lost into the environment due to uncontrolled release rates. Polysaccharide stabilized Fe-Mn binary oxide nanoparticles were prepared and tested for phosphate adsorption from water and for controlling leachability of P from poultry litter. A water soluble starch and carboxymethyl cellulose (CMC) were used as a stabilizer. Both the Freundlich and Langmuir models were able to adequately interpret the isotherm data. The Langmuir maximum capacity was determined at 252, 298 and 313 mg-P/g for bare, CMC- and starch-stabilized nanoparticles, respectively. The presence of the stabilizers not only enhanced the sorption capacity, but facilitated delivery and dispersion of the nanoparticles in poultry litter (PL) and in soil. High phosphate sorption capacity was observed over a broad pH range of 4-9. FTIR analyses indicated that inner sphere surface complexation (Fe-O-P) was the key mechanism for the enhanced uptake of P. When applied to poultry litter, the stabilized nanoparticles reduced water leachable phosphate by >86% at a dose of 0.2 g/L as Fe, and simultaneously, water leachable arsenic by >87-95%. Under conditions of simulated land application of PL, the nanoparticle amendment of PL reduced the water soluble P from 66% (for untreated PL) to 4.4%, and lowered the peak soluble P concentration from 300 to <20 mg/L. By transferring the peak soluble P to the nanoparticle bound P, the nanoparticles not only greatly reduce the potential runoff loss of P from PL, but also provide a long-term slow-releasing nutrient source. Fortuitously, the nanoparticle treatment was able to immobilize arsenic from PL. With excellent adsorption capacity, easy deliverability, low cost and environmental innocuousness, the stabilized Fe-Mn nanoparticles appear promising for controlling P releases from poultry litter or other animal wastes and for phosphate recovery from water. PMID- 26442721 TI - Time to help. PMID- 26442722 TI - [Norway on the overdose top?]. PMID- 26442723 TI - [Re: All suicides are not due to treatment failure]. PMID- 26442724 TI - [Re: The emergency department needs their own specialists]. PMID- 26442726 TI - [Chronic lymphatic leukemia in Norway-incidence and prognosis at diagnosis time]. PMID- 26442727 TI - [Familial occurrence of chronic lymphatic leukemia in Norway]. PMID- 26442728 TI - [Emergency prevention in overweight--to be trusted?]. PMID- 26442730 TI - [In Process Citation]. PMID- 26442729 TI - [Where is the boundary between diagnostics and research?]. PMID- 26442731 TI - [In Process Citation]. PMID- 26442732 TI - Prevalence and incidence of epilepsy in the Nordic countries. AB - BACKGROUND: Updated knowledge on the prevalence of epilepsy is valuable for planning of health services to this large and complex patient group. Comprehensive epidemiological research on epilepsy has been undertaken, but because of variations in methodology, the results are difficult to compare. The objective of this article is to present evidence-based estimates of the prevalence and incidence of epilepsy in the Nordic countries. METHOD: The article is based on a search in PubMed with the search terms epilepsy and epidemiology, combined with each of the Nordic countries separately. RESULTS: Altogether 38 original articles reported incidence and/or prevalence rates of epilepsy in a Nordic country. Four studies had investigated the prevalence of active epilepsy in all age groups, with results ranging from 3.4 to 7.6 per 1,000 inhabitants. Only two studies had investigated the incidence of epilepsy in a prospective material that included all age groups. The reported incidence amounted to 33 and 34 per 100,000 person-years respectively. A prospective study that only included adults reported an incidence of 56 per 100,000 person-years. INTERPRETATION: We estimate that approximately 0.6% of the population of the Nordic countries have active epilepsy, i.e. approximately 30,000 persons in Norway. Epilepsy is thus one of the most common neurological disorders. The incidence data are more uncertain, but we may reasonably assume that 30-60 new cases occur per 100,000 person-years. PMID- 26442733 TI - Neuroprotective effects of hypothermia. AB - BACKGROUND: The neuroprotective effects of hypothermia have been shown in case reports and animal studies. Therapeutic hypothermia is used to provide neuroprotection during certain types of surgery and after serious events that pose a threat to the brain. The aim of this review is to describe the efficacy of such treatment in adults. METHOD: All articles retrieved from five searches in PubMed were examined. Studies were included if they had a hypothermia protocol and a measurement of neuroprotection. The list of randomised studies was completed using studies identified from five international review articles. In all, 103 of 678 studies fulfilled the inclusion criteria, of which 48 were clinical trials. Ten of the clinical trials were randomised, using a normothermic control group. RESULTS: Several randomised clinical trials have suggested that avoidance of hyperthermia provides the same neuroprotection as therapeutic hypothermia after cardiac arrest and traumatic brain injury, but prognostic factors and inclusion criteria vary markedly between the patient populations, including time to target temperature. Two studies found that cognitive function after prolonged aortic surgery under deep hypothermia was equivalent to that after brief normothermic interventions. Animal studies show a neuroprotective effect of hypothermia, but this is dependent on the extent of anoxic damage as well as the rate of cooling. INTERPRETATION: It remains uncertain how best to implement therapeutic hypothermia to achieve neuroprotection after acute events that pose a threat to the brain. Hypothermia during aortic surgery seems to provide adequate neuroprotection for prolonged interventions. PMID- 26442734 TI - [An itchy souvenir]. PMID- 26442735 TI - [A woman with pareses of the arms and legs]. AB - BACKGROUND: Hypokalemic pareses are caused by low extracellular potassium levels which reduce the resting membrane potential of muscle cells and make them less excitable. It may be caused by an intracellular shift of potassium, renal potassium loss, reduced potassium intake or increased gastrointestinal loss. CASE PRESENTATION: A woman in her 60s presented with rapid-onset tetraparesis and hyporeflexia starting the day before admission. The patient history revealed several months of low food intake, increased alcohol consumption and diarrhoea. Laboratory tests showed severe hypokalemia (1.5 mmol/l) and hypomagnesemia (0.38 mmol/l), and ECG showed atrial fibrillation. She was admitted to the medical intensive care unit and treated with intravenous normal saline with added potassium and magnesium, with good effect on her symptoms. Urine tests showed high potassium-creatinine ratio (4.22 mmol/mmol creatinine) and increased fractional excretion of magnesium (18.6%). Abdominal CT scan revealed colonic wall thickening, and colonic biopsies showed mild inflammation. Faecal calprotectin was moderately elevated (294 mg/kg). INTERPRETATION: The patient had hypokalemic pareses for which there were several contributing factors. The renal causes were augmented excretion of magnesium and potassium, probably due to increased alcohol consumption. The extrarenal causes were increased gastrointestinal loss, with ulcerative colitis being the presumed explanation, and reduced food intake. PMID- 26442736 TI - [Nanomedicine in cancer treatment--small particles brings hope]. PMID- 26442737 TI - International collaboration in postgraduate training. PMID- 26442738 TI - [Discontinuation]. PMID- 26442740 TI - [In Process Citation]. PMID- 26442739 TI - [E. Hem replies]. PMID- 26442742 TI - [Choice of specialty--a choice for life]. PMID- 26442743 TI - [The highest priority]. PMID- 26442749 TI - A simple practical balloon anchoring technique within the guide catheter for chronic total occlusion (CTO) of the coronary artery. PMID- 26442748 TI - DTI and VBM reveal white matter changes without associated gray matter changes in patients with idiopathic restless legs syndrome. AB - BACKGROUND AND PURPOSE: We evaluated cerebral white and gray matter changes in patients with iRLS in order to shed light on the pathophysiology of this disease. METHODS: Twelve patients with iRLS were compared to 12 age- and sex-matched controls using whole-head diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) techniques. Evaluation of the DTI scans included the voxelwise analysis of the fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). RESULTS: Diffusion tensor imaging revealed areas of altered FA in subcortical white matter bilaterally, mainly in temporal regions as well as in the right internal capsule, the pons, and the right cerebellum. These changes overlapped with changes in RD. Voxel-based morphometry did not reveal any gray matter alterations. CONCLUSIONS: We showed altered diffusion properties in several white matter regions in patients with iRLS. White matter changes could mainly be attributed to changes in RD, a parameter thought to reflect altered myelination. Areas with altered white matter microstructure included areas in the internal capsule which include the corticospinal tract to the lower limbs, thereby supporting studies that suggest changes in sensorimotor pathways associated with RLS. PMID- 26442750 TI - Assessment of Different Quit Smoking Methods Selected by Patients in Tobacco Cessation Centers in Iran. AB - BACKGROUND: Health systems play key roles in identifying tobacco users and providing evidence-based care to help them quit. This treatment includes different methods such as simple medical consultation, medication, and telephone counseling. To assess different quit smoking methods selected by patients in tobacco cessation centers in Iran in order to identify those that are most appropriate for the country health system. METHODS: In this cross-sectional and descriptive study, a random sample of all quit centers at the country level was used to obtain a representative sample. Patients completed the self-administered questionnaire which contained 10 questions regarding the quality, cost, effect, side effects and the results of quitting methods using a 5-point Likert-type scale. Percentages, frequencies, mean, T-test, and variance analyses were computed for all study variables. RESULTS: A total of 1063 smokers returned completed survey questionnaires. The most frequently used methods were Nicotine Replacement Therapy (NRT) and combination therapy (NRT and Counseling) with 228 and 163 individuals reporting these respectively. The least used methods were hypnotism (n = 8) and the quit and win (n = 17). The methods which gained the maximum scores were respectively the combined method, personal and Champix with means of 21.4, 20.4 and 18.4. The minimum scores were for e-cigarettes, hypnotism and education with means of 12.8, 11 and 10.8, respectively. There were significant differences in mean scores based on different cities and different methods. CONCLUSIONS: According to smokers' selection the combined therapy, personal methods and Champix are the most effective methods for quit smoking and these methods could be much more considered in the country health system. PMID- 26442752 TI - Lower platelet counts and antiplatelet therapy independently predict better outcomes in patients with head and neck squamous cell carcinoma: a retrospective analysis. AB - The paper by Rachidi et al. suggests that antiplatelet drugs may play a role in ameliorating the clinical outcome in a large series of patients with head and neck cancer managed with either surgery or radiation. Our data, as well as confirming the results observed by the authors, enhance their clinical relevance pointing out the effect of antiplatelet drugs in terms of locoregional control in the setting of patients with advanced head and neck cancer managed with definitive chemo-radiotherapy. PMID- 26442753 TI - The inhibitory effect of Thymus vulgaris extracts on the planktonic form and biofilm structures of six human pathogenic bacteria. AB - OBJECTIVE: Microorganisms are responsible for many problems in industry and medicine because of biofilm formation. Therefore, this study was aimed to examine the effect of Thymus vulgaris (T. vulgaris) extracts on the planktonic form and biofilm structures of six pathogenic bacteria. MATERIALS AND METHODS: Antimicrobial activities of the plant extracts against the planktonic form of the bacteria were determined using the disc diffusion method. MIC and MBC values were evaluated using macrobroth dilution technique. Anti-biofilm effects were assessed by microtiter plate method. RESULTS: According to disc diffusion test (MIC and MBC), the ability of Thymus vulgaris (T. vulgaris ) extracts for inhibition of bacteria in planktonic form was confirmed. In dealing with biofilm structures, the inhibitory effect of the extracts was directly correlated to their concentration. Except for the inhibition of biofilm formation, efficacy of each extract was independent from type of solvent. CONCLUSION: According to the potential of Thymus vulgaris (T. vulgaris) extracts to inhibit the test bacteria in planktonic and biofilm form, it can be suggested that Thymus vulgaris (T. vulgaris) extracts can be applied as antimicrobial agents against the pathogenic bacteria particularly in biofilm forms. PMID- 26442751 TI - Neural basis of motivational approach and withdrawal behaviors in neurodegenerative disease. AB - INTRODUCTION: The Behavioral Inhibition System (BIS) and the Behavioral Activation System (BAS) have been theorized as neural systems that regulate approach/withdrawal behaviors. Behavioral activation/inhibition balance may change in neurodegenerative disease based on underlying alterations in systems supporting motivation and approach/withdrawal behaviors, which may in turn be reflected in neuropsychiatric symptoms. METHOD: A total of 187 participants (31 patients diagnosed with behavioral variant of FTD [bvFTD], 13 semantic variant of primary progressive aphasia [svPPA], 14 right temporal variant FTD [rtFTD], 54 Alzheimer's disease [AD], and 75 older healthy controls [NCs]) were included in this study. Changes in behavioral inhibition/activation were measured using the BIS/BAS scale. We analyzed the correlation between regional atrophy pattern and BIS/BAS score, using voxel-based morphometry (VBM). RESULTS: ADs had significantly higher BIS scores than bvFTDs and NCs. bvFTDs activation-reward response (BAS-RR) was significantly lower than ADs and NCs, though their activation-drive (BAS-D) was significantly higher than in ADs. Both AD and rtFTD patients had abnormally low activation fun-seeking (BAS-FS) scores. BIS score correlated positively with right anterior cingulate and middle frontal gyrus volume, as well as volume in the right precentral gyrus and left insula/operculum. CONCLUSIONS: AD, bvFTD, and rtFTD patients show divergent patterns of change in approach/withdrawal reactivity. High BIS scores correlated with preservation of right-predominant structures involved in task control and self-protective avoidance of potentially negative reinforcers. Damage to these regions in bvFTD may create a punishment insensitivity that underlies patients' lack of self-consciousness in social contexts. PMID- 26442754 TI - Preventive brain radio-chemotherapy alters plasticity associated metabolite profile in the hippocampus but seems to not affect spatial memory in young leukemia patients. AB - BACKGROUND: Neuronal plasticity leading to evolving reorganization of the neuronal network during entire lifespan plays an important role for brain function especially memory performance. Adult neurogenesis occurring in the dentate gyrus of the hippocampus represents the maximal way of network reorganization. Brain radio-chemotherapy strongly inhibits adult hippocampal neurogenesis in mice leading to impaired spatial memory. METHODS: To elucidate the effects of CNS radio-chemotherapy on hippocampal plasticity and function in humans, we performed a longitudinal pilot study using 3T proton magnetic resonance spectroscopy ((1)H-MRS) and virtual water-maze-tests in 10 de-novo patients with acute lymphoblastic leukemia undergoing preventive whole brain radio-chemotherapy. Patients were examined before, during and after treatment. RESULTS: CNS radio-chemotherapy did neither affect recall performance in probe trails nor flexible (reversal) relearning of a new target position over a time frame of 10 weeks measured by longitudinal virtual water-maze-testing, but provoked hippocampus-specific decrease in choline as a metabolite associated with cellular plasticity in (1)H-MRS. CONCLUSION: Albeit this pilot study needs to be followed up to definitely resolve the question about the functional role of adult human neurogenesis, the presented data suggest that (1)H-MRS allows the detection of neurogenesis-associated plasticity in the human brain. PMID- 26442755 TI - Copy number loss upstream of RAI1 uncovers gene expression regulatory region that may impact Potocki-Lupski syndrome diagnosis. AB - The identification of structural variants of uncertain clinical significance is increasing; however, studies delineating the functional consequence of these variants in the pathogenicity of phenotypic features are lacking. Understanding the consequence of structural variants such as copy number alterations and their role in gene expression changes is paramount in order to perform a comprehensive analysis of genetic effects on phenotypic variation and disease. RAI1 is a dosage sensitive essential neurodevelopmental gene. Copy number loss of RAI1 results in Smith-Magenis syndrome while copy number gain results in Potocki-Lupski syndrome. Here, we present a case of a six year old female with a newly identified maternally inherited copy number loss that lies within the Smith-Magenis syndrome common deletion region, but RAI1 copy number is normal. Integration of the Encyclopedia of DNA Elements (ENCODE) data at the affected region suggests that the deletion disrupts several cis-acting regulatory elements upstream of RAI1, such as multiple repressor sites and an insulator region. Gene expression studies revealed that both the proband and the mother have significantly elevated RAI1 mRNA levels suggesting that the structural variant alters gene expression regulation. The proband and the mother both have some features of Potocki-Lupski syndrome, while the child appears to be more affected with autistic-like features. Overall, our work demonstrates that the integration of ENCODE data with structural variants of uncertain significance aids in delineating a functional consequence to a genomic aberration and subsequent diagnosis. PMID- 26442756 TI - An integrative Raman microscopy-based workflow for rapid in situ analysis of microalgal lipid bodies. AB - BACKGROUND: Oils and bioproducts extracted from cultivated algae can be used as sustainable feedstock for fuels, nutritional supplements, and other bio-based products. Discovery and isolation of new algal species and their subsequent optimization are needed to achieve economical feasibility for industrial applications. Here we describe and validate a workflow for in situ analysis of algal lipids through confocal Raman microscopy. We demonstrate its effectiveness to characterize lipid content of algal strains isolated from the environment as well as algal cells screened for increased lipid accumulation through UV mutagenesis combined with Fluorescence Activated Cell Sorting (FACS). RESULTS: To establish and validate our workflow, we refined an existing Raman platform to obtain better discrimination in chain length and saturation of lipids through ratiometric analyses of mixed fatty acid lipid standards. Raman experiments were performed using two different excitation lasers (lambda = 532 and 785 nm), with close agreement observed between values obtained using each laser. Liquid chromatography coupled with mass spectrometry (LC-MS) experiments validated the obtained Raman spectroscopic results. To demonstrate the utility and effectiveness of the improved Raman platform, we carried out bioprospecting for algal species from soil and marine environments in both temperate and subtropical geographies to obtain algal isolates from varied environments. Further, we carried out two rounds of mutagenesis screens on the green algal model species, Chlamydomonas reinhardtii, to obtain cells with increased lipid content. Analyses on both environmental isolates and screened cells were conducted which determined their respective lipids. Different saturation states among the isolates as well as the screened C. reinhardtii strains were observed. The latter indicated the presence of cell-to cell variations among cells grown under identical condition. In contrast, non-mutagenized C. reinhardtii cells showed no significant heterogeneity in lipid content. CONCLUSIONS: We demonstrate the utility of confocal Raman microscopy for lipid analysis on novel aquatic and soil microalgal isolates and for characterization of lipid-expressing cells obtained in a mutagenesis screen. Raman microscopy enables quantitative determination of the unsaturation level and chain lengths of microalgal lipids, which are key parameters in selection and engineering of microalgae for optimal production of biofuels. PMID- 26442757 TI - Clinical significance of locoregional and systemic treatment in operable high risk breast cancer patients with more than four positive axillary lymph nodes. AB - PURPOSE: Breast cancer cases with four or more involved axillary lymph nodes (ALNs) feature an aggressive clinical history despite intensive treatment. However, therapies for improving the prognosis for these high-risk patients and the prognostic role of clinical characteristics have been little investigated. Therefore, we sought to assess potential prognostic factors for these patients in female Chinese patients and identify the treatment modalities they might benefit from, which offers implications for clinical practice. PATIENTS AND METHODS: A total of 518 patients with four or more involved ALNs were retrospectively analyzed. Survival-curve analysis was performed with the Kaplan-Meier method, and Cox proportional hazard regression was applied to identify independent variables for disease-free survival (DFS) and overall survival (OS). RESULTS: The patients were divided into groups depending on the number of ALNs, with 38.22% having four to six positive ALNs and 61.78% having seven or more ALNs. Compared with the seven or more-positive ALN subgroup, patients with four to six positive ALNs tended to have smaller tumors and were more likely to undergo modified radical mastectomy rather than radical mastectomy (both P<0.001). Univariate analysis revealed that a fluorouracil/doxorubicin (epirubicin)/cyclophosphamide (CA[E]F) regimen or a CA(E)F followed by docetaxel (CA[E] F > T) regimen conferred significantly better DFS (P=0.0075) and OS (P<0.0001) than those achieved from a cyclophosphamide/methotrexate/fluorouracil regimen, which was almost completely generated by the seven or more ALN subgroup (P=0.0088 and P=0.0001, respectively). Postoperative radiotherapy was associated with better DFS (P=0.0360), which was also generated by the seven or more ALN subgroup (P=0.0107). Subgroup analysis also clarified that the type of surgery conferred a modest effect on DFS in the seven or more ALN subgroup (P=0.0305). Multivariate survival analysis revealed that ALN status (hazard ratio [HR] 2.00, 95% confidence interval [CI] 1.31-3.05; P=0.001), tumor size (HR 1.48, 95% CI 1.06 2.08; P=0.022), and type of surgery (HR 0.47, 95% CI 0.30-0.74; P=0.001) were independent prognostic factors for DFS. Meanwhile, ALN status (HR 2.96, 95% CI 1.51-5.77; P=0.002), tumor size (HR 2.32, 95% CI 1.38-3.89; P=0.001), type of surgery (HR=0.39, 95% CI 0.20-0.76; P=0.006), and regimen of chemotherapy (HR=0.64, 95% CI 0.50-0.85; P=0.002) were identified as independent prognostic factors for OS. CONCLUSION: Besides the classical prognostic factors and the improvement of prognosis achieved from the anthracycline-based or anthracycline taxane combination chemotherapy compared to cyclophosphamide/methotrexate/fluorouracil chemotherapy, our findings showed benefits on DFS and OS for appropriate local treatments, including radiotherapy and sufficient ALN dissection for high-risk breast cancer patients with four or more ALNs involved, which suggests that much importance should also be attached to local treatment besides adjuvant systemic therapy. PMID- 26442758 TI - Effect of hydro-alcoholic extract of Rosa damascena on cardiovascular responses in normotensive rat. AB - OBJECTIVE: Rosa damascena mill L. (R. damascena) is a well-known plant with fragrant effects. Several therapeutic effects of this plant on respiratory, gastrointestinal and nervous systems have been reported. It is also suggested to have beneficial effect on cardiovascular system especially blood pressure regulation. The present study was carried out to evaluate acute cardiovascular effect of hydro-alcoholic extract of R. damascena. MATERIALS AND METHODS: Thirty two male Wistar rats were randomly divided into four groups (n= 8 for each group). After anesthesia, a catheter was inserted into the femoral artery and blood pressure and heart rate (HR) were continuously recorded by a power lab system. Animals received three doses of hydro-alcoholic extract (250, 500, and 1000 mg/kg) via peritoneal (i.p). After 30 min, systolic blood pressure (SBP), mean arterial pressure (MAP) and HR were recorded and maximal changes were compared to control group. RESULTS: Injection of all doses of the extract did not significantly change HR compare to control group. The SBP, dose dependently, was decreased by all doses of the extract and the maximal response was significant compared to saline group (p<0.01 to p<0.001). Different doses of the extract also dose-dependently decreased maximal changes of MAP responses compared to control group. The effect of higher doses of the extract on SBP and MAP was significant compared to lower doses (p<0.05 to p<0.01). CONCLUSION: This study provides evidence of a hypotensive effect of hydro-alcoholic extract of R. damascena with no significant effect on HR. Therefore, R. damascena is suggested to have beneficial effect to control blood pressure. However, it needs to be more investigated. PMID- 26442760 TI - Interspecific variation in the phenology of advertisement calling in a temperate Australian frog community. AB - Spatial and temporal partitioning of resources underlies the coexistence of species with similar niches. In communities of frogs and toads, the phenology of advertisement calling provides insights into temporal partitioning of reproductive effort and its implications for community dynamics. This study assessed the phenology of advertisement calling in an anuran community from Melbourne, in southern Australia. We collated data from 1432 surveys of 253 sites and used logistic regression to quantify seasonality in the nightly probability of calling and the influence of meteorological variables on this probability for six species of frogs. We found limited overlap in the predicted seasonal peaks of calling among these species. Those shown to have overlapping calling peaks are unlikely to be in direct competition, due to differences in larval ecology (Crinia signifera and Litoria ewingii) or differences in calling behavior and acoustics (Limnodynastes dumerilii and Litoria raniformis). In contrast, closely related and ecologically similar species (Crinia signfera and Crinia parinsignifera;Litoria ewingii and Litoria verreauxii) appear to have staggered seasonal peaks of calling. In combination with interspecific variation in the meteorological correlates of calling, these results may be indicative of temporal partitioning of reproductive activity to facilitate coexistence, as has been reported for tropical and temperate anurans from other parts of the globe. PMID- 26442759 TI - Regional anesthesia for an upper extremity amputation for palliative care in a patient with end-stage osteosarcoma complicated by a large anterior mediastinal mass. AB - Tumor progression during end-of-life care can lead to significant pain, which at times may be refractory to routine analgesic techniques. Although regional anesthesia is commonly used for postoperative pain care, there is limited experience with its use during home hospice care. We present a 24-year-old male with end-stage metastatic osteosarcoma who required anesthetic care for a right sided above-the-elbow amputation. The anesthetic management was complicated by the presence of a large mediastinal mass, limited pulmonary reserve, and severe chronic pain with a high preoperative opioid requirement. Intraoperative anesthesia and postoperative pain management were provided by regional anesthesia using an interscalene catheter. He was discharged home with the interscalene catheter in place with a continuous local anesthetic infusion that allowed weaning of his chronic opioid medications and the provision of effective pain control. The perioperative applications of regional anesthesia in palliative and home hospice care are discussed. PMID- 26442761 TI - Cellulosic ethanol production via consolidated bioprocessing at 75 degrees C by engineered Caldicellulosiruptor bescii. AB - BACKGROUND: The C. bescii genome does not encode an acetaldehyde/alcohol dehydrogenase or an acetaldehyde dehydrogenase and no ethanol production is detected in this strain. The recent introduction of an NADH-dependent AdhE from C. thermocellum (Fig. 1a) in an ldh mutant of this strain resulted in production of ethanol from un-pretreated switchgrass, but the thermolability of the C. thermocellum AdhE at the optimum growth temperature of C. bescii (78 degrees C) meant that ethanol was not produced above 65 degrees C.Fig. 1Proposed scheme for the pyruvate to ethanol pathway in C. thermocellum and T. pseudethanolicus 39E. a The C. thermocellum ethanol pathway. The red colored AdhE (Cthe_0423) is already expressed and tested in C. bescii [26]. b The T. pseudethanolicus 39E ethanol pathway. The green colored AdhE (Teth39_0206) and blue colored AdhB (Teth39_0218) are expressed and tested in C. bescii in this study. RESULTS: The adhB and adhE genes from Thermoanaerobacter pseudethanolicus 39E, an anaerobic thermophile that produces ethanol as a major fermentation product at 70 degrees C, were cloned and expressed in an ldh deletion mutant of C. bescii. The engineered strains produced ethanol at 75 degrees C, near the ethanol boiling point. The AdhB expressing strain produced ethanol (1.4 mM on Avicel, 0.4 mM on switchgrass) as well as acetate (13.0 mM on Avicel, 15.7 mM on switchgrass). The AdhE expressing strain produced more ethanol (2.3 mM on Avicel, 1.6 mM on switchgrass) and reduced levels of acetate (12.3 mM on Avicel, 15.1 mM on switchgrass). These engineered strains produce cellulosic ethanol at the highest temperature of any microorganism to date. In addition, the addition of 40 mM MOPS to the growth medium increased the maximal growth yield of C. bescii by approximately twofold. CONCLUSIONS: The utilization of thermostable enzymes will be critical to achieving high temperature CBP in bacteria such as C. bescii. The ability to produce ethanol at 75 degrees C, near its boiling point, raises the possibility that process optimization could allow in situ product removal of this end product to mitigate ethanol toxicity. PMID- 26442762 TI - Correlation between the green-island phenotype and Wolbachia infections during the evolutionary diversification of Gracillariidae leaf-mining moths. AB - Internally feeding herbivorous insects such as leaf miners have developed the ability to manipulate the physiology of their host plants in a way to best meet their metabolic needs and compensate for variation in food nutritional composition. For instance, some leaf miners can induce green-islands on yellow leaves in autumn, which are characterized by photosynthetically active green patches in otherwise senescing leaves. It has been shown that endosymbionts, and most likely bacteria of the genus Wolbachia, play an important role in green island induction in the apple leaf-mining moth Phyllonorycter blancardella. However, it is currently not known how widespread is this moth-Wolbachia-plant interaction. Here, we studied the co-occurrence between Wolbachia and the green island phenotype in 133 moth specimens belonging to 74 species of Lepidoptera including 60 Gracillariidae leaf miners. Using a combination of molecular phylogenies and ecological data (occurrence of green-islands), we show that the acquisitions of the green-island phenotype and Wolbachia infections have been associated through the evolutionary diversification of Gracillariidae. We also found intraspecific variability in both green-island formation and Wolbachia infection, with some species being able to form green-islands without being infected by Wolbachia. In addition, Wolbachia variants belonging to both A and B supergroups were found to be associated with green-island phenotype suggesting several independent origins of green-island induction. This study opens new prospects and raises new questions about the ecology and evolution of the tripartite association between Wolbachia, leaf miners, and their host plants. PMID- 26442763 TI - Long noncoding RNA CCAT2 promotes breast tumor growth by regulating the Wnt signaling pathway. AB - In addition to protein-coding genes, the human genome makes a large amount of noncoding RNAs, including microRNAs and long noncoding RNAs (lncRNAs). Emerging evidence indicates that lncRNAs could have a critical role in the regulation of cellular processes such as cell growth and apoptosis as well as cancer progression and metastasis. The lncRNA CCAT2 is dysregulated in several cancers such as colon cancer, non-small cell lung cancer, esophageal squamous cell carcinoma, gastric cancer, and breast cancer; however, the contributions of CCAT2 to breast cancer remain largely unknown. In the current paper, we first confirmed the high expression level of CCAT2 in breast cancer tissues and breast cancer cell lines by reverse transcription quantitative polymerase chain reaction (RT qPCR) assay, and we further analyzed the relationship between CCAT2 expression and clinical prognostic factors. Also, the biological function of CCAT2 was explored and the results showed silencing of CCAT2 could suppress cell growth in vitro and tumor formation in vivo. Finally, our results revealed that the abnormal expression of CCAT2 could influence the Wnt signaling pathway. In conclusion, lncRNA CCAT2 might be considered as a novel molecule involved in breast cancer development, which provides a potential therapeutic target for breast cancer. PMID- 26442764 TI - Mitochondrial dysfunction in psychiatric morbidity: current evidence and therapeutic prospects. AB - Cumulating evidence for the involvement of mitochondrial dysfunction in psychiatric disorders leaves little to no doubt regarding the involvement of this pathology in mood disorders. However, mitochondrial abnormalities are also observed in a wide range of disorders spanning from cancer and diabetes to various neurodegenerative and neurodevelopmental disorders such as Parkinson's, Alzheimer's, Huntington's, autism, and amyotrophic lateral sclerosis. The apparent lack of specificity questions the role of mitochondrial dysfunction in psychiatric disorders, in general, and in mood disorders, in particular. Is mitochondrial dysfunction a general phenomenon, simplistically rendering brain cells to be more vulnerable to a variety of disease-specific perturbations? Or is it an epiphenomenon induced by various disease-specific factors? Or possibly, the severity and the anatomical region of the dysfunction are the ones responsible for the distinct features of the disorders. Whichever of the aforementioned ones, if any, is correct, "mitochondrial dysfunction" became more of a cliche than a therapeutic target. In this review, we summarize current studies supporting the involvement of mitochondrial dysfunction in different psychiatric disorders. We address the question of specificity and causality of the different findings and provide an alternative explanation for some of the aforementioned questions. PMID- 26442765 TI - Stage susceptibility of Japanese medaka (Oryzias latipes) to selenomethionine and hypersaline developmental toxicity. AB - Anthropogenic disturbance of seleniferous soils can lead to selenium contamination of waterways. Although selenium is an essential micronutrient, bioaccumulation and maternal transfer of proteinaceous selenomethionine (SeMet) can result in embryo toxicity. Furthermore, as the climate changes, the salinity of spawning grounds in water-restrained estuaries is increasing. Although a small increase in salinity may not directly impact adult fish, it may alter the detoxification strategies of developing organisms. Previous research indicates that hypersalinity may potentiate SeMet embryo toxicity at an early developmental stage. However, embryonic development is a complex, spatiotemporal process with a constantly shifting cellular microenvironment. To generate thresholds and an adverse outcome pathway for the interactions between selenium and salinity, we sought to identify windows of susceptibility for lethality and deformities in the Japanese medaka (Oryzias latipes). Embryos were treated in freshwater or saltwater for 24 h with 0.5 uM, 5 uM, and 50 uM SeMet at 6 different developmental stages (9, 17, 25, 29, 34, and 38). Survival, hatch, deformities (total, type, and severity), and days to hatch were quantified. Selenium embryo tissue measurements were performed. Selenomethionine exposures of 5 uM and 50 uM significantly decreased survival and hatch at all stages. However, SeMet uptake was stage-dependent and increased with stage. Stage 17 (early neurulation) was identified as the most susceptible stage for lethality and deformities. Selenomethionine in saltwater caused significantly greater toxicity than freshwater at stage 25 (early organogenesis), suggesting a role for liver and osmoregulatory organogenesis in toxicity. PMID- 26442766 TI - Is it too cold for Leptospira interrrogans transmission on the Faroese Islands? AB - Leptospira interrogans is a bacterium that can infect most mammal species. Brown rats are considered to be one of the most important reservoirs of Leptospira because they frequently are infected and live in close proximity to humans. Past studies of prevalence of Leptospira in brown rats indicate that temperature--both high and low--may negatively affect the prevalence rate in rats, so that Leptospira is rare or even absent at temperatures below 7-8 degrees C. Here we investigated the prevalence of infection in brown rats on the Faroese Islands (mean temperature of 6.5 degrees C) and did not find any infected animals in a sample of 95 animals. We propose that prevalence rates of Leptospira are very low in rural brown rats in the cooler Scandinavian regions, even though urban/sewer rats might be highly infected in the same regions. PMID- 26442767 TI - Student (dis)engagement and need-supportive teaching behavior: a multi-informant and multilevel approach. AB - Starting from self-determination theory, we explored whether student engagement/disengagement relates to teachers' need support and whether this relationship is moderated by teachers' causality orientations. A sample of 2004 students situated in 127 classes taught by 33 physical education teachers participated in the study. Both teachers and students reported on students' (dis)engagement, allowing investigation of the proposed relationships both at the student and teacher level. Most of the variance in need support was at the student level, but there was also between-teacher and between-class variance in need support. Engagement related to more need support, but only at the student level. In total, few moderation effects were found. Teachers with a relatively low controlled orientation were more need supportive when perceiving their students as emotionally and behaviorally engaged. By making teachers aware of these dynamics, automatic responses to student engagement can be better thought out. Recommendations for future research are discussed. PMID- 26442768 TI - "Mean mugging": an exploration of young Aboriginal women's experiences of bullying in team sports. AB - Bullying among youth is rampant and research suggests that young Aboriginal women may be particularly susceptible to bullying. Sport participation has been identified as a possible mechanism to prevent bullying behaviors, yet few researchers have explored bullying within the context of sport. The purpose of this qualitative description study was to explore young Aboriginal women's experiences of bullying in team sports. Eight young Aboriginal women participated in one-on-one semistructured interviews and follow-up phone interviews. Data were analyzed using a content analysis, and findings were represented by five themes: (1) mean mugging, (2) sport specific, (3) happens all the time, (4) team bonding to address bullying, and (5) prevention through active coaches. The detailed descriptions shared by participants provide insight into a broad range of bullying experiences and serve as a foundation for addressing the bullying that occurs in sport. PMID- 26442769 TI - Dealing with negative stereotypes in sports: the role of cognitive anxiety when multiple identities are activated in sensorimotor tasks. AB - Based on research on stereotype threat and multiple identities, this work explores the beneficial effects of activating a positive social identity when a negative identity is salient on women's performance in sports. Further, in line with research on the effects of anxiety in sports, we investigate whether the activation of a positive social identity buffers performance from cognitive anxiety associated with a negative stereotype. Two experiments tested these predictions in field settings. Experiment 1 (N = 83) shows that the simultaneous activation of a positive (i.e., member of a soccer team) and a negative social identity (i.e., woman) led to better performance than the activation of only a negative social identity for female soccer players. Experiment 2 (N = 46) demonstrates that identity condition moderated the effect of cognitive anxiety on performance for female basketball players. Results are discussed concerning multiple identities' potential for dealing with stressful situations. PMID- 26442770 TI - Changes in task self-efficacy and emotion across competitive performances in golf. AB - This research aimed to investigate (a) the effect of golfers' perceptions of coach motivation efficacy on golfers' precompetition task self-efficacy, (b) the effect of performance on pre-to-postround changes in self-efficacy, (c) the effect of pre-to-postround changes in self-efficacy on pre-to-postround changes in affect and emotion, and (d) whether any effects of performance on pre-to postcompetition changes in affect and emotion were mediated by pre-to postcompetition changes in self-efficacy. In Study 1, a scale measuring golf self efficacy was developed and validated using data from 197 golfers. In Study 2, 200 golfers completed this measure alongside measures of coach motivation efficacy, and positive and negative affect before a golf competition; all measures (except coach motivation efficacy) were again completed following the competition. Structural equation modeling showed that coach motivation efficacy positively predicted precompetition self-efficacy, performance positively predicted pre-to postcompetition changes in self-efficacy, which had positive and negative effects, respectively, on pre-to-postcompetition changes in positive and negative affect; mediation analyses demonstrated that pre-to-postcompetition changes in self-efficacy mediated effects of performance on pre-to-postcompetition changes in positive and negative affect. In Study 3, the Study-2 procedures were replicated with a separate sample of 212 golfers, except measures of excitement, concentration disruption, somatic anxiety, and worry replaced those for positive and negative affect. Structural analyses showed the findings from Study 2 were largely replicated when specific emotions were investigated in place of general indices of affect. This investigation makes novel contributions regarding the potential importance of perceptions of coach efficacy for golfers' own efficacy beliefs, and the role personal efficacy beliefs may play in facilitating the effects of performance on affective outcomes. PMID- 26442771 TI - Bayesian structural equation modeling in sport and exercise psychology. AB - Bayesian statistics is on the rise in mainstream psychology, but applications in sport and exercise psychology research are scarce. In this article, the foundations of Bayesian analysis are introduced, and we will illustrate how to apply Bayesian structural equation modeling in a sport and exercise psychology setting. More specifically, we contrasted a confirmatory factor analysis on the Sport Motivation Scale II estimated with the most commonly used estimator, maximum likelihood, and a Bayesian approach with weakly informative priors for cross-loadings and correlated residuals. The results indicated that the model with Bayesian estimation and weakly informative priors provided a good fit to the data, whereas the model estimated with a maximum likelihood estimator did not produce a well-fitting model. The reasons for this discrepancy between maximum likelihood and Bayesian estimation are discussed as well as potential advantages and caveats with the Bayesian approach. PMID- 26442772 TI - Biological evidence of imagery abilities: intraindividual differences. AB - This study extended motor imagery theories by establishing specificity and verification of expected brain activation patterns during imagery. Eighteen female participants screened with the Movement Imagery Questionnaire-3 (MIQ-3) as having good imagery abilities were scanned to determine the neural networks active during an arm rotation task. Four experimental conditions (i.e., KINESTHETIC, INTERNAL Perspective, EXTERNAL Perspective, and REST) were randomly presented (counterbalanced for condition) during three brain scans. Behaviorally, moderate interscale correlations were found between the MIQ-3 and Vividness of Movement Imagery Questionnaire-2, indicating relatedness between the questionnaires. Partially confirming our hypotheses, common and distinct brain activity provides initial biological validation for imagery abilities delineated in the MIQ-3: kinesthetic imagery activated motor-related areas, internal visual imagery activated inferior parietal lobule, and external visual imagery activated temporal, but no occipital areas. Lastly, inconsistent neuroanatomical intraindividual differences per condition were found. These findings relative to recent biological evidence of imagery abilities are highlighted. PMID- 26442773 TI - Development of burnout perceptions during adolescence among high-level athletes: a developmental and gendered perspective. AB - This study examined (a) the developmental trajectories of athlete burnout perceptions, (b) the gender differences on these trajectories, and (c) the interactions in the developmental trajectories of the three burnout dimensions. A five-wave longitudinal study was conducted with 895 athletes (47.6% female; Mage = .67). Results of multilevel growth models revealed that during adolescence, "reduced sense of accomplishment" linearly decreased and was higher for girls than boys. Moreover, "emotional/physical exhaustion" increased then decreased, and seemed to have been attenuated at time points in which athletes also had higher levels of "sport devaluation." Finally, "sport devaluation" increased over time with higher increases for girls than boys. Results of our study depicted the general and the gendered shape of the trajectory of burnout perceptions during adolescence, and underlined the advantages of considering the multifaceted nature of burnout to enable a deeper examination of the within-person synergies in the development of the three dimensions. PMID- 26442774 TI - Things we still haven't learned (so far). AB - Null hypothesis significance testing (NHST) is like an immortal horse that some researchers have been trying to beat to death for over 50 years but without any success. In this article we discuss the flaws in NHST, the historical background in relation to both Fisher's and Neyman and Pearson's statistical ideas, the common misunderstandings of what p < .05 actually means, and the 2010 APA publication manual's clear, but most often ignored, instructions to report effect sizes and to interpret what they all mean in the real world. In addition, we discuss how Bayesian statistics can be used to overcome some of the problems with NHST. We then analyze quantitative articles published over the past three years (2012-2014) in two top-rated sport and exercise psychology journals to determine whether we have learned what we should have learned decades ago about our use and meaningful interpretations of statistics. PMID- 26442776 TI - Amphiphilic polymeric micelles as microreactors: improving the photocatalytic hydrogen production of the [FeFe]-hydrogenase mimic in water. AB - An amphiphilic polymeric micelle is utilized as a microreactor to load a hydrophobic [FeFe]-hydrogenase mimic in water. The local concentration enhancement and strong interaction between the mimic and the photosensitizer as well as the water-mediated fast proton migration caused by the microreactor improve photocatalytic hydrogen production remarkably in water. PMID- 26442777 TI - Impending airway obstruction after dental extractions. PMID- 26442778 TI - Discovery of wrightiadione as a novel template for the TrkA kinase inhibitors. AB - Enzymatic kinase assays and docking simulation studies have shown that the natural product wrightiadione displays inhibitory activity toward TrkA and PLK3. In this study, the template of wrightiadione served as a starting point for Trk inhibitor development campaigns. Molecular simulation provided structural insights for the design of derivatives that were efficiently generated by our recently developed 3-step tandem synthetic approach, resulting in the discovery of compound 2h with biochemical potency at the single-digit micromolar level. PMID- 26442779 TI - Parametric analysis of the biomechanical response of head subjected to the primary blast loading--a data mining approach. AB - Traumatic brain injury due to primary blast loading has become a signature injury in recent military conflicts and terrorist activities. Extensive experimental and computational investigations have been conducted to study the interrelationships between intracranial pressure response and intrinsic or 'input' parameters such as the head geometry and loading conditions. However, these relationships are very complicated and are usually implicit and 'hidden' in a large amount of simulation/test data. In this study, a data mining method is proposed to explore such underlying information from the numerical simulation results. The heads of different species are described as a highly simplified two-part (skull and brain) finite element model with varying geometric parameters. The parameters considered include peak incident pressure, skull thickness, brain radius and snout length. Their interrelationship and coupling effect are discovered by developing a decision tree based on the large simulation data-set. The results show that the proposed data-driven method is superior to the conventional linear regression method and is comparable to the nonlinear regression method. Considering its capability of exploring implicit information and the relatively simple relationships between response and input variables, the data mining method is considered to be a good tool for an in-depth understanding of the mechanisms of blast-induced brain injury. As a general method, this approach can also be applied to other nonlinear complex biomechanical systems. PMID- 26442780 TI - Eye and pit size are inversely correlated in crotalinae: Implications for selection pressure relaxation. AB - Mate, prey, and predator recognition often depend on the integration of information from multiple sensory modalities including visual, auditory, and/or olfactory inputs. In Crotalinae, the eyes sense visible light while the pit organs detect infrared (IR) radiation. Previous studies indicate that there is significant overlap between the eye and pit sensory fields and that both senses are involved in recognition processes. This study investigated the relationships between eye and pit sizes in this taxonomic group as a function of phylogeny and habitat. In view of the fact that pit orientation depends largely on snout shape, pit vipers were grouped as follows: 1) arboreal, 2) terrestrial with rounded snout, and 3) terrestrial with pointed snout. The pit orientations and habitant patterns were fully independent of the Crotalinae phylogenetic tree. The phylogenetic generalized least squares model showed that both eye and pit areas were not of significantly phylogenetic relatedness, implying alternatively a strong effect of adaptation on eye and pit sizes. Negative correlations between relative eye and pit areas in terrestrial (both pointed and rounded snouts) and arboreal species were statistically significant. Our results suggest that the eyes and pits function in a complementary fashion such that selection for IR perception relaxes selection pressures on the visual system and selection for visual discrimination relaxes selection pressures acting on the IR-system. PMID- 26442782 TI - Label-free detection of pH based on the i-motif using an aggregation-caused quenching strategy. AB - A label-free and biocompatible pH sensor system based on the aggregation-caused quenching (ACQ) probe has been reported herein. The DNA i-motif, a kind of pH triggered structure, affects the aggregation of PTCDI derivatives by structural switch that would provide significant fluorescence signals responding to the different pH values. Our method not only shows sensitive and reversible response to pH changes, but also could expand the detection range by allosteric control of the DNA i-motif. PMID- 26442781 TI - Whole Genome Sequencing demonstrates that Geographic Variation of Escherichia coli O157 Genotypes Dominates Host Association. AB - Genetic variation in an infectious disease pathogen can be driven by ecological niche dissimilarities arising from different host species and different geographical locations. Whole genome sequencing was used to compare E. coli O157 isolates from host reservoirs (cattle and sheep) from Scotland and to compare genetic variation of isolates (human, animal, environmental/food) obtained from Scotland, New Zealand, Netherlands, Canada and the USA. Nei's genetic distance calculated from core genome single nucleotide polymorphisms (SNPs) demonstrated that the animal isolates were from the same population. Investigation of the Shiga toxin bacteriophage and their insertion sites (SBI typing) revealed that cattle and sheep isolates had statistically indistinguishable rarefaction profiles, diversity and genotypes. In contrast, isolates from different countries exhibited significant differences in Nei's genetic distance and SBI typing. Hence, after successful international transmission, which has occurred on multiple occasions, local genetic variation occurs, resulting in a global patchwork of continental and trans-continental phylogeographic clades. These findings are important for three reasons: first, understanding transmission and evolution of infectious diseases associated with multiple host reservoirs and multi-geographic locations; second, highlighting the relevance of the sheep reservoir when considering farm based interventions; and third, improving our understanding of why human disease incidence varies across the world. PMID- 26442783 TI - Light attenuates lipid accumulation while enhancing cell proliferation and starch synthesis in the glucose-fed oleaginous microalga Chlorella zofingiensis. AB - The objective of this study was to investigate the effect of light on lipid and starch accumulation in the oleaginous green algae Chlorella zofingiensis supplemented with glucose. C. zofingiensis, when fed with 30 g/L glucose, synthesized lipids up to 0.531 g/g dry weight; while in the presence of light, the lipid content dropped down to 0.352 g/g dry weight. Lipid yield on glucose was 0.184 g/g glucose, 14% higher than that cultured with light. The light mediated lipid reduction was accompanied by the down-regulation of fatty acid biosynthetic genes at the transcriptional level. Furthermore, light promoted cell proliferation, starch accumulation, and the starch yield based on glucose. Taken together, light may attenuate lipid accumulation, possibly through the inhibition of lipid biosynthetic pathway, leading to more carbon flux from glucose to starch. This study reveals the dual effects of light on the sugar-fed C. zofingiensis and provides valuable insights into the possible optimization of algal biomass and lipid production by manipulation of culture conditions. PMID- 26442785 TI - Expression of proteins in superior and inferior spikelets of rice during grain filling under different irrigation regimes. AB - Poor grain filling of later-flowering inferior spikelets is a serious problem in modern rice cultivars, but the reason and regulation remain unclear. This study investigated post-anthesis protein expression in relation with grain filling and the possibility to use irrigation methods to enhance grain filling through regulating protein expression. One japonica rice cultivar was field-grown under three irrigation treatments imposed during the grain filling period: alternate wetting and moderate soil-drying (WMD), alternate wetting and severe soil-drying (WSD), and conventional irrigation. High resolution 2DE, combined with MALDI/TOF, was used to compare differential protein expression between superior and inferior spikelets. Results showed that the expression of proteins that function in photosynthesis, carbohydrate and energy metabolism, amino acids metabolism and defense responses were largely down-regulated in inferior spikelets compared to those in superior spikelets. The WMD treatment enhanced grain filling rate and the expression of these proteins, whereas the WSD treatment decreased them. Similar results were observed for transcript levels of the genes encoding these proteins. These results suggest that down-regulated expression of the proteins associated with grain filling contribute to the poor grain filling of inferior spikelets, and post-anthesis WMD could improve grain filling through regulating protein expression in the spikelets. PMID- 26442784 TI - Nerves Control Redox Levels in Mature Tissues Through Schwann Cells and Hedgehog Signaling. AB - AIMS: Recent advances in redox biology have emphasized the role of hydrogen peroxide (H2O2) in the modulation of signaling pathways and revealed that H2O2 plays a role in cellular remodeling in adults. Thus, an understanding of the mechanisms that control H2O2 levels in mature tissue would be of great interest. RESULTS: We used a denervation strategy to demonstrate that sensory neurons are responsible for controlling H2O2 levels under normal conditions and after being lesioned. Moreover, we demonstrate that severed nerves respond to appendage amputation via the induction of Hedgehog signaling and that this signaling is responsible for H2O2 production in the wounded epidermis. Finally, we show that H2O2 and nerve growth are regulated via reciprocal action in adults. INNOVATION AND CONCLUSION: These data support a new paradigm for the regulation of tissue homeostasis: H2O2 attracts nerves and nerves control H2O2 levels in a positive feedback loop. This finding suggests that the peripheral nerve redox environment could be a target for manipulating cell plasticity in adults. PMID- 26442786 TI - Evaluation of four portable blood glucose meters in diabetic and non-diabetic dogs and cats. AB - BACKGROUND: Monitoring of an animal's blood glucose concentration is critical for diagnostic and therapeutic decisions. Over the past few decades, portable blood glucose meters (PBGMs) have been used to monitor blood glucose concentrations in animals. Recently, new and improved PBGMs have been made available on the market. OBJECTIVE: The purpose of this study was to evaluate four PBGMs for use in dogs and cats. ANIMALS AND METHODS: A total of 155 venous blood samples of dogs and 85 venous blood samples of cats were tested using four PBGMs. Control solutions from manufacturers were used to determine the precision of each meter. The coefficient of variation was calculated to determine precision during a set of replicates. Pearson's correlation analysis, Passing-Bablok regression, and Bland-Altman analysis were used to determine the accuracy of four PBGMs against the hexokinase reference method. Error grid analysis was used to evaluate clinical relevance. RESULTS: All PBGMs, except CERA-PET(r), were clinically acceptable for monitoring blood glucose concentrations; AlphaTrak(r) and VetMate(r) appeared to be the most accurate ones, demonstrating that to use PBGMs for glucose monitoring, it is important to understand the strengths or limitations of each meter. The difference in results between the PBGMs and the reference method increased at high glucose concentration ranges, which were also affected by the hematocrit. CONCLUSIONS: Although readings of the PBGMs and the reference method varied across glycemic ranges (low, normal, and high glucose concentrations), most PBGMs were clinically acceptable for monitoring blood glucose concentrations in dogs and cats. PMID- 26442787 TI - Platelets made HLA deficient by acid treatment aggregate normally and escape destruction by complement and phagocytes in the presence of HLA antibodies. AB - BACKGROUND: The presence of antibodies against HLA Class I can lead to platelet (PLT) transfusion refractoriness, that is, the repeated failure to achieve adequate posttransfusion PLT count increments. PLT refractoriness can be overcome by transfusion of HLA-matched donor PLTs. A different approach is to remove HLA from the PLT surface using low pH. Previous case studies using HLA-stripped PLTs showed encouraging but inconsistent results and lacked information on the biologic effects of acid treatment on PLT function as well as sensitivity to PLT destruction in the presence of HLA antibodies. STUDY DESIGN AND METHODS: PLTs prepared from buffy coats were stripped from HLA Class I using a brief incubation at pH 2.9. Kinetics of acid stripping, viability, phenotypic alterations, and sensitivity to complement-mediated lysis and phagocytosis were determined by flow cytometry. Functional potential was evaluated using a multiplate analyzer. RESULTS: Acid-treated PLTs were viable, upregulated activation markers normally and aggregated to a similar extent as untreated PLTs in response to stimulation with three natural agonists. Acid treatment removed 70% to 90% of HLA Class I complexes from the PLT surface, which led to complete protection from HLA antibody-mediated complement lysis and reduced monocyte-mediated phagocytosis in the presence of anti-HLA in vitro. CONCLUSION: Our study fills an important knowledge gap in how acid treatment affects PLT function and interactions with immune cells, paving the way for controlled clinical trials to evaluate acid treated PLTs as an alternative to HLA-matched donors in PLT refractoriness. PMID- 26442788 TI - Primary care summits. PMID- 26442790 TI - Multilayer CuO@NiO Hollow Spheres: Microwave-Assisted Metal-Organic-Framework Derivation and Highly Reversible Structure-Matched Stepwise Lithium Storage. AB - A unique CuO@NiO microsphere with three-layer ball-in-ball hollow morphology is successfully synthesized by Cu-Ni bimetallic organic frameworks. The beforehand facile microwave-assisted production of the Ni organic framework sphere is used as the template to induce the morphology control of bimetallic oxides. Designed by the controlled surface cationic exchange reactions between Cu and Ni ions, there is an elemental gradient (decreased amount of CuO but increased amount of NiO) from the shell to the core of the microsphere product. This ternary metal oxide hollow structure is found to be very suitable for solving the critical volume expansion problem, which is critical for all high-capacity metal oxide electrodes for lithium ion batteries. A reversible larger-than-theoretical capacity of 1061 mAh.g(-1) can be retained after a repetitive 200 cycles without capacity fading compared to the initial cycle. These excellent electrochemical properties are ascribed to the step-by-step lithium insertion reactions induced by the matched CuO@NiO composition from the shell to the core and facilitated lithium/electron diffusion and accommodated volume change in the porous bimetallic oxides microsphere with a multiple-layer yolk-shell nanostructure. PMID- 26442789 TI - Secular trends and evaluation of complex interventions: the rising tide phenomenon. AB - Evaluations of service delivery interventions with contemporaneous controls often yield null results, even when the intervention appeared promising in advance. There can be many reasons for null results. In this paper we introduce the concept of a 'rising tide' phenomenon being a possible explanation of null results. We note that evaluations of service delivery interventions often occur when awareness of the problems they intend to address is already heightened, and pressure to tackle them is mounting throughout a health system. An evaluation may therefore take place in a setting where the system as a whole is improving - where there is a pronounced temporal trend or a 'rising tide causing all vessels to rise'. As a consequence, control sites in an intervention study will improve. This reduces the difference between intervention and control sites and predisposes the study to a null result, leading to the conclusion that the intervention has no effect. We discuss how a rising tide may be distinguished from other causes of improvement in both control and intervention groups, and give examples where the rising tide provides a convincing explanation of such a finding. We offer recommendations for interpretation of research findings where improvements in the intervention group are matched by improvements in the control group. Understanding the rising tide phenomenon is important for a more nuanced interpretation of null results arising in the context of system-wide improvement. Recognition that a rising tide may have predisposed to a null result in one health system cautions against generalising the result to another health system where strong secular trends are absent. PMID- 26442791 TI - Shared Medical Decision Making in Lung Cancer Screening: Experienced versus Descriptive Risk Formats. AB - BACKGROUND: Annual lung cancer screening using low-dose computed tomography (LDCT) scans is associated with a survival benefit, but it is also associated with potential harm. Unlike descriptive probability formats, experienced tasks have been shown to decrease perceptions of rare events. The objective of this study was to compare descriptive versus experienced probability formats on patients' knowledge, beliefs, endorsement of screening for heavy smokers, and preference (choice predisposition) to undergo screening. METHODS: A total of 276 patients attending an outpatient pulmonary practice were randomized to learn about screening using 1 of 3 formats: numbers only, numbers + icon arrays, numbers + a set of slides illustrating LDCT scans of 250 people in random order that displayed the number of normal scans, false-positive lung nodules, cancers found leading to a life saved, and cancers found leading to death despite treatment. RESULTS: Knowledge differed between the 3 formats (P= 0.001), with participants randomized to the numbers + icon array format having the highest knowledge score. Beliefs were more favorable among participants randomized to the numbers + experienced format compared with the numbers + icon array format (difference between means [95% confidence interval]= 1.6 [0.4-2.8]). Differences in participants' endorsement of screening (P= 0.4) and choice predisposition (P= 0.6) across probability format mirrored those of beliefs but were not statistically significant. DISCUSSION: Contrary to what we expected, the experienced format increased propensity toward screening compared with the numbers + icon array format, as indicated by more favorable beliefs and nonsignificant trends toward stronger choice predisposition and endorsement. Experienced risk formats may not be a practical approach to improve risk communication for patients deciding whether or not to undergo annual lung cancer screening. PMID- 26442792 TI - Genome distribution of differential homoeologue contributions to leaf gene expression in bread wheat. AB - Using a combination of de novo transcriptome assembly, a newly developed 9495 marker transcriptome SNP genetic linkage map and comparative genomics approaches, we developed an ordered set of nonredundant transcripts for each of the subgenomes of hexaploid wheat: A (47 160 unigenes), B (59 663 unigenes) and D (40 588 unigenes). We used these as reference sequences against which to map Illumina mRNA-Seq reads derived from young leaf tissue. Transcript abundance was quantified for each unigene. Using a three-way reciprocal BLAST approach, 15 527 triplet sets of homoeologues (one from each genome) were identified. Differential expression (P < 0.05) was identified for 5248 unigenes, with 2906 represented at greater abundance than their two homoeologues and 2342 represented at lower abundance than their two homoeologues. Analysis of gene ontology terms revealed no biases between homoeologues. There was no evidence of genomewide dominance effects, rather the more highly transcribed individual genes were distributed throughout all three genomes. Transcriptome display tile plot, a visualization approach based on CMYK colour space, was developed and used to assess the genome for regions of skewed homoeologue transcript abundance. Extensive striation was revealed, indicative of many small regions of genome dominance (transcripts of homoeologues from one genome more abundant than the others) and many larger regions of genome repression (transcripts of homoeologues from one genome less abundant than the others). PMID- 26442793 TI - UV irradiation-induced inflammation, what is the trigger? PMID- 26442794 TI - Diversity and patterns of interaction of an anuran-parasite network in a neotropical wetland. AB - We describe the diversity and structure of a host-parasite network of 11 anuran species and their helminth parasites in the Pantanal wetland, Brazil. Specifically, we investigate how the heterogeneous use of space by hosts changes parasite community diversity, and how the local pool of parasites exploits sympatric host species of different habits. We examined 229 anuran specimens, interacting with 32 helminth parasite taxa. Mixed effect models indicated the influence of anuran body size, but not habit, as a determinant of parasite species richness. Variation in parasite taxonomic diversity, however, was not significantly correlated with host size or habit. Parasite community composition was not correlated with host phylogeny, indicating no strong effect of the evolutionary relationships among anurans on the similarities in their parasite communities. Host-parasite network showed a nested and non-modular pattern of interaction, which is probably a result of the low host specificity observed for most helminths in this study. Overall, we found host body size was important in determining parasite community richness, whereas low parasite specificity was important to network structure. PMID- 26442795 TI - Protective effect of nitric oxide in aristolochic acid-induced toxic acute kidney injury: an old friend with new assets. AB - Aristolochic acid (AA) nephropathy (AAN), a progressive tubulointerstitial injury of toxic origin, is characterized by early and transient acute tubular necrosis. This process has been demonstrated to be associated with reduced nitric oxide (NO) production, which can disrupt the regulation of renal function. In this study, we tested the hypothesis that L-arginine (L-Arg) supplementation could restore renal function and reduce renal injury after AA intoxication. C57BL/6 J male mice were randomly subjected to daily i.p. injection of either sterile saline solution or AA (2.5 mg kg(-1)) for 4 days. To determine whether AA-induced renal injuries were linked to reduced NO production, L-Arg, a substrate for NO synthase, was supplemented (5%) in drinking water. Mice intoxicated with AA exhibited features of rapid-onset acute kidney injury, including polyuria, significantly increased plasma creatinine concentrations, proteinuria and fractional excretion of sodium (P < 0.05), along with severe proximal tubular cell injury and increased NADPH oxidase 2 (Nox2)-derived oxidative stress (P < 0.05). This was associated with a significant reduction in NO bioavailability. L Arg supplementation in AA-treated mice significantly increased NO bioavailability, which in turn improved renal function (creatininaemia, polyuria, proteinuria, fractional excreted sodium and N-acetyl-beta-D-glucosaminidase enzymuria) and renal structure (tubular necrosis and tubular cell apoptosis). These changes were associated with significant reductions in Nox2 expression and in production of reactive oxygen species and with an increase in antioxidant concentrations. Our results demonstrate that preservation of NO bioavailability leads to renal protection in AA-induced acute kidney injury by reducing oxidative stress and maintaining renal function. PMID- 26442796 TI - A three-dimensional spin-diffusion model for micromagnetics. AB - We solve a time-dependent three-dimensional spin-diffusion model coupled to the Landau-Lifshitz-Gilbert equation numerically. The presented model is validated by comparison to two established spin-torque models: The model of Slonzewski that describes spin-torque in multi-layer structures in the presence of a fixed layer and the model of Zhang and Li that describes current driven domain-wall motion. It is shown that both models are incorporated by the spin-diffusion description, i.e., the nonlocal effects of the Slonzewski model are captured as well as the spin-accumulation due to magnetization gradients as described by the model of Zhang and Li. Moreover, the presented method is able to resolve the time dependency of the spin-accumulation. PMID- 26442797 TI - Re(I) derivatives functionalised with thioether crowns containing the 1,10 phenanthroline subunit as a new class of chemosensors. AB - A series of luminescent fac-[Re(CO)3(L)(NN)](+) complexes, where L is a pyridine or an imidazole and NN is the 1,10-phenanthroline subunit of mixed donor pentadentate thioether crowns have been synthesised and their luminescence properties have been analysed. Then, heterometallic Re(i)/Au(i) complexes, with the Au(i) fragment bonded directly to the imidazole ligand, and heterometallic Re(i)/Ag(i) complexes, with the silver fragment coordinating the S-donor thioether linker of the rings have also been prepared. Analysis of their luminescence properties showed a considerable blue shift of the emission maxima for the Re(i)/Ag(i) derivatives, upon coordination of the silver centre to the S donor atoms of the aliphatic chain of the macrocyclic units. PMID- 26442798 TI - In Vivo Contact Characteristics of Distal Radioulnar Joint With Malunited Distal Radius During Wrist Motion. AB - PURPOSE: To determine whether distal radioulnar joint (DRUJ) contact characteristics were altered in patients with malunited distal radius fractures. METHODS: We obtained computed tomography scans at 5 positions of both wrists of 6 patients who had unilateral malunited distal radius fractures with dorsal angulation from 10 degrees to 20 degrees and ulnar variance less than 3 mm. We reconstructed 3-dimensional images and mapped contact regions of DRUJ by calculating the shortest distance between the 2 opposing bones. The contact areas of the DRUJ were measured and the contact region centers were calculated and analyzed. The values of the malunited side were compared with those of the contralateral uninjured side. RESULTS: In the uninjured wrist, the contact areas of the DRUJ increased slightly from wrist flexion to extension and ulnar deviation. In the malunited wrist, we found the contact areas of DRUJ to be progressively reduced from 20 degrees flexion to neutral, 40 degrees extension, and 20 degrees extension, to ulnar deviation. The centroid of this area on the sigmoid notch moved to distal from flexion to extension. Compared with the contralateral uninjured wrist, the contact area significantly decreased during wrist extension and ulnar deviation, and significantly increased during wrist flexion. The centroids of this area on sigmoid notch all moved volarly in all selected wrist positions. CONCLUSIONS: The contact areas of the DRUJ and the centroid of contact area on sigmoid notch are altered in patients with malunited distal radius fractures. The contact area of the DRUJ increases during wrist flexion and decreases during wrist extension and ulnar deviation. The centroids of the contact area on sigmoid notch move volarly during wrist flexion-extension and ulnar deviation. CLINICAL RELEVANCE: The in vivo findings suggest that alterations in joint mechanics may have an important role in the dysfunction associated with these injuries. PMID- 26442799 TI - Gene Therapy for Heart Failure: Back to the Bench. PMID- 26442802 TI - Emerging Roles of tRNA-derived Fragments in Viral Infections: The Case of Respiratory Syncytial Virus. PMID- 26442803 TI - Strain-dependent Lethal Toxicity in NKG2D Ligand-targeted CAR T-cell Therapy. PMID- 26442804 TI - Vertigo with dysautonomia and serious allergy: An unusual case of juvenile Meniere's disease. AB - A 13-year-old boy with frequent episodes of vertigo and otologic symptoms was diagnosed with Meniere's disease (MD) but failed to respond to conventional treatment. Allergy testing revealed serious reactions to many allergens, and autonomic tests showed he was dysautonomic. An allergen-restricted diet and treatment of dysautonomia were effective, the boy being free from vertigo within 2 months. This case provides evidence to promote the understanding of MD in children. The authors hypothesize that the autonomic nerves and the immune system can interact, and that such an interaction of dysautonomia and allergy can lead to a serious vertigo episode. PMID- 26442806 TI - Clogging of granular materials in silos: effect of gravity and outlet size. AB - By means of extensive numerical simulations we disclose the role of the driving force in the clogging of inert particles passing through a constriction. We uncover the effect of gravity and outlet size on the flow rate and kinetic energy within the system, and use these quantities to deepen our understanding of the blocking process. First, we confirm the existence of a finite avalanche size when the driving force tends to zero. The magnitude of this limit avalanche size grows with the outlet size, as expected due to geometrical reasons. In addition, there is an augment of the avalanche size when the driving force is increased, an effect that is enhanced by the outlet size. This phenomenology is explained by assuming that in order to get a stable clog developed, two conditions must be fulfilled: (1) an arch spanning the outlet size should be formed; (2) the arch should resist until the complete dissipation of the kinetic energy within the system. From these assumptions, we are able to obtain the probability that an arch gets destabilized, which is shown to primarily depend on the square root of the kinetic energy. A minor additional dependence of the outlet size is also observed which is explained in the light of recent results of the arch resistance in vibrated silos. PMID- 26442805 TI - Development of Planning in Children with High-Functioning Autism Spectrum Disorders and/or Attention Deficit/Hyperactivity Disorder. AB - Planning impairment is often observed in children with high-functioning autism spectrum disorders (ASD), but attempts to differentiate planning in ASD from children with attention deficit hyperactivity disorder (ADHD) and typically developing children (TD) have yielded inconsistent results. This study examined differences between these groups by focusing on development and analyzing performance in searching ahead several steps ("search depth") in addition to commonly used global performance measures in planning. A cross-sectional consecutive sample of 83 male patients (6-13 years), subgrouped as ASD without (ASD-, n = 18) or with comorbid ADHD (ASD+, n = 23), ADHD only (n = 42) and n = 42 TD children (6-13 years) were tested with the Tower-of-London-task. For global performance, ASD+ showed the lowest accuracy in younger children, but similar performance as TD at older ages, suggesting delayed development. Typically, a prolongation of planning time with increasing problem difficulty is observed in older children as compared to younger children. Here, this was most pronounced in ASD-, but under-expressed in ADHD. In contrast to global performance, effects of search depth were independent of age. ASD-, but not ASD+, showed increased susceptibility to raised demands on mentally searching ahead, along with the longest planning times. Thus, examining both global and search depth performance across ages revealed discernible patterns of planning between groups. Notably, the potentially detrimental impact of two diagnosed disorders does not add up in ASD+ in this task. Rather, our results suggest paradoxical enhancement of performance, ostensibly attributable to disruption of behavioral rigidity through increased impulsivity, which did not take place in ASD-. Autism Res 2016, 9: 739 751. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26442807 TI - Volcanic passive margins: another way to break up continents. AB - Two major types of passive margins are recognized, i.e. volcanic and non volcanic, without proposing distinctive mechanisms for their formation. Volcanic passive margins are associated with the extrusion and intrusion of large volumes of magma, predominantly mafic, and represent distinctive features of Larges Igneous Provinces, in which regional fissural volcanism predates localized syn magmatic break-up of the lithosphere. In contrast with non-volcanic margins, continentward-dipping detachment faults accommodate crustal necking at both conjugate volcanic margins. These faults root on a two-layer deformed ductile crust that appears to be partly of igneous nature. This lower crust is exhumed up to the bottom of the syn-extension extrusives at the outer parts of the margin. Our numerical modelling suggests that strengthening of deep continental crust during early magmatic stages provokes a divergent flow of the ductile lithosphere away from a central continental block, which becomes thinner with time due to the flow-induced mechanical erosion acting at its base. Crustal-scale faults dipping continentward are rooted over this flowing material, thus isolating micro continents within the future oceanic domain. Pure-shear type deformation affects the bulk lithosphere at VPMs until continental breakup, and the geometry of the margin is closely related to the dynamics of an active and melting mantle. PMID- 26442808 TI - Is emotional intelligence relevant to a fighting force? AB - Over the past decade, the expectations of what the fighting force are tasked to deal with has changed significantly. The high-risk, high-tempo operational environments in which personnel have deployed in recent years have been complex and diverse, creating a spectrum of conflict where having EI would be an essential attribute. EI could be beneficial for the organisation and the individuals involved, and historically, there has been a distinct lack of EI. For it to be better used within the military, the entire concept needs to be explored, accepted and integrated into training throughout the rank structure; from the recruitment process to throughout the career development with support from senior commanders. This article discusses the relevance of emotional intelligence (EI) to the British Armed Forces. PMID- 26442809 TI - Proteolytic degradation of neuropeptide Y (NPY) from head to toe: Identification of novel NPY-cleaving peptidases and potential drug interactions in CNS and Periphery. AB - The bioactivity of neuropeptide Y (NPY) is either N-terminally modulated with respect to receptor selectivity by dipeptidyl peptidase 4 (DP4)-like enzymes or proteolytic degraded by neprilysin or meprins, thereby abrogating signal transduction. However, neither the subcellular nor the compartmental differentiation of these regulatory mechanisms is fully understood. Using mass spectrometry, selective inhibitors and histochemistry, studies across various cell types, body fluids, and tissues revealed that most frequently DP4-like enzymes, aminopeptidases P, secreted meprin-A (Mep-A), and cathepsin D (CTSD) rapidly hydrolyze NPY, depending on the cell type and tissue under study. Novel degradation of NPY by cathepsins B, D, L, G, S, and tissue kallikrein could also be identified. The expression of DP4, CTSD, and Mep-A at the median eminence indicates that the bioactivity of NPY is regulated by peptidases at the interphase between the periphery and the CNS. Detailed ex vivo studies on human sera and CSF samples recognized CTSD as the major NPY-cleaving enzyme in the CSF, whereas an additional C-terminal truncation by angiotensin-converting enzyme could be detected in serum. The latter finding hints to potential drug interaction between antidiabetic DP4 inhibitors and anti-hypertensive angiotensin converting enzyme inhibitors, while it ablates suspected hypertensive side effects of only antidiabetic DP4-inhibitors application. The bioactivity of neuropeptide Y (NPY) is either N-terminally modulated with respect to receptor selectivity by dipeptidyl peptidase 4 (DP4)-like enzymes or proteolytic degraded by neprilysin or meprins, thereby abrogating signal transduction. However, neither the subcellular nor the compartmental differentiation of these regulatory mechanisms is fully understood. Using mass spectrometry, selective inhibitors and histochemistry, studies across various cell types, body fluids, and tissues revealed that most frequently DP4-like enzymes, aminopeptidases P, secreted meprin-A (Mep-A), and cathepsin D (CTSD) rapidly hydrolyze NPY, depending on the cell type and tissue under study. Novel degradation of NPY by cathepsins B, D, L, G, S, and tissue kallikrein could also be identified. The expression of DP4, CTSD, and Mep-A at the median eminence indicates that the bioactivity of NPY is regulated by peptidases at the interphase between the periphery and the CNS. Detailed ex vivo studies on human sera and CSF samples recognized CTSD as the major NPY-cleaving enzyme in the CSF, whereas an additional C-terminal truncation by angiotensin-converting enzyme could be detected in serum. The latter finding hints to potential drug interaction between antidiabetic DP4 inhibitors and anti hypertensive angiotensin-converting enzyme inhibitors, while it ablates suspected hypertensive side effects of only antidiabetic DP4-inhibitors application. PMID- 26442810 TI - Interpersonal sensitivity, coping ways and automatic thoughts of nursing students before and after a cognitive-behavioral group counseling program. AB - BACKGROUND: In order to provide optimal professional care to patients, nurses must possess a positive self-image and professional identity. High interpersonal sensitivity, coping problems and dysfunctional automatic thoughts can prevent nursing students to be self-confident and successful nurses. Helping nursing students experiencing interpersonal sensitivity problems via cognitive-behavioral counseling strategies can contribute to shape good nurses. OBJECTIVES: This study aims to evaluate interpersonal sensitivity, ways of coping and automatic thoughts of nursing students before and after a cognitive behavioral group counseling program. DESIGN: An intervention study with 43 nursing students. Measurements were done before the counseling program, at the end of the program and 4.5months after the program. SETTINGS: The students were chosen from a faculty of nursing in Turkey. PARTICIPANTS: 43 second and third year nursing students who were experiencing interpersonal sensitivity problems constituted the sample. METHODS: Brief Symptom Inventory, Ways of Coping Inventory and Automatic Thoughts Questionnaire were used for data collection. RESULTS: The students' scores of "interpersonal sensitivity", "hopeless" and "submissive" copings and "automatic thoughts" were significantly lower at the end of and 4.5months after the program than the scores before the program (Interpersonal sensitivity F=52.903, p=0.001; hopeless approach F=19.213, p=0.001; submissive approach F=4.326, p=0.016; automatic thoughts F=45.471, p=0.001). Scores of "self-confident", "optimistic" and "seeking social support" copings were higher at the end of and 4.5months after the program than the scores before the program (Self confident F=11.640, p=0.001; optimistic F=10.860, p=0.001; seeking social support F=10.411, p=0.001). CONCLUSIONS: This program helped the students to have better results at interpersonal sensitivity, ways of coping and automatic thoughts at the end of and 4.5 months after the program. We have reached the aim of the study. We suggest that such counseling programs should be regular and integrated into the services provided for students. PMID- 26442811 TI - Baton pass hypothesis: successive incorporation of unconserved endogenous retroviral genes for placentation during mammalian evolution. AB - It is well accepted that numerous RNAs derived from endogenous retroviruses (ERVs) are expressed in mammalian reproductive structures, particularly in the uterus, trophoblast, and placenta. Syncytin 1 and syncytin 2 in humans and syncytin A and syncytin B in mice are membrane proteins originating from Env genes of ERVs. These ERVs are involved in the fusion of trophoblast cells, resulting in multinucleated syncytiotrophoblast formation. Evidence accumulated indicates that syncytin-like fusogenic proteins are expressed in the placenta of rabbits, dogs/cats, ruminant ungulates, tenrecs, and opossums. The syncytin genes so far characterized are known to be endogenized to the host genome only within the past 12-80 million years, more recently than the appearance of mammalian placentas, estimated to be 160-180 million years ago. We speculate that ERVs including syncytin-like gene variants integrated into mammalian genomes in a locus-specific manner have replaced the genes previously responsible for cell fusion. We therefore propose the 'baton pass' hypothesis, in which multiple successive ERV variants 'take over' cell-fusion roles, resulting in increased trophoblast cell fusion, morphological variations in placental structures, and enhanced reproductive success in placental mammals. PMID- 26442812 TI - Radiographic osteoradionecrosis of the jaw with intact mucosa: Proposal of clinical guidelines for early identification of this condition. PMID- 26442813 TI - Malignant peripheral nerve sheath tumors of the head and neck: Demographics, clinicopathologic features, management, and treatment outcomes. AB - OBJECTIVES: To determine the epidemiology and prognostic indicators in patients with malignant peripheral nerve sheath tumors (MPNST) of the head and neck. MATERIALS AND METHODS: The surveillance, epidemiology, and end results registry was reviewed for patients with head and neck MPNST from 1973 to 2011. Study variables included age, sex, race, tumor size, stage at presentation, and treatment modality. RESULTS: There were 374 cases of head and neck MPNST identified. Mean age at diagnosis was 50.7 y ears; 60.2% of patients were male and 82.6% were white. After diagnosis, 38.8% of patients underwent surgery and radiation therapy and 48.1% underwent surgery alone. Kaplan-Meier analysis demonstrated overall (OS) and disease-specific survival (DSS) of 51% and 67% at 5 years. Multivariate Cox regression analysis showed that age (p=0.030), stage (p=0.002), surgery (p=0.037), and size (p<0.001) were predictors of OS, while stage (p<0.001) and size (p<0.001) were predictors of DSS. For stage I/II cancers, surgery (p=0.011) and size (p=0.010) were predictors of OS, and size (p=0.001) predicted DSS. For stage III/IV cancers, both radiotherapy (p=0.024, p=0.009) and size (p=0.001, p=0.001) predicted OS and DSS. For tumors ?5 cm, stage (p=0.031) predicted DSS. For tumors >5 cm, male gender (p=0.005), stage (p=0.001), surgery (p=0.003), and radiotherapy (p=0.050) were determinants of OS, and male gender (p=0.022), stage (p<0.001), and radiotherapy (p=0.002) were determinants of DSS. CONCLUSION: Surgical resection confers survival benefit in patients with early stage MPNST, while radiotherapy improves survival in cases with metastatic disease. Surgery and radiotherapy are prognostically important in patients with tumors >5 cm. PMID- 26442815 TI - What Will a Post-Aging World Really Be Like? Finally, A Tool to Help Us Predict. PMID- 26442814 TI - Energetics of proton release on the first oxidation step in the water-oxidizing enzyme. AB - In photosystem II (PSII), the Mn4CaO5 cluster catalyses the water splitting reaction. The crystal structure of PSII shows the presence of a hydrogen-bonded water molecule directly linked to O4. Here we show the detailed properties of the H-bonds associated with the Mn4CaO5 cluster using a quantum mechanical/molecular mechanical approach. When O4 is taken as a MU-hydroxo bridge acting as a hydrogen bond donor to water539 (W539), the S0 redox state best describes the unusually short O4-OW539 distance (2.5 A) seen in the crystal structure. We find that in S1, O4 easily releases the proton into a chain of eight strongly hydrogen-bonded water molecules. The corresponding hydrogen-bond network is absent for O5 in S1. The present study suggests that the O4-water chain could facilitate the initial deprotonation event in PSII. This unexpected insight is likely to be of real relevance to mechanistic models for water oxidation. PMID- 26442816 TI - Determination of emerging contaminants in wastewater utilizing comprehensive two dimensional gas-chromatography coupled with time-of-flight mass spectrometry. AB - An analytical method for identification of emerging contaminants of concern, such as pesticides and organohalogens has been developed and utilized for true discovery-based analysis. In order to achieve the level of sensitivity and selectivity necessary for detecting compounds in complex samples, comprehensive gas chromatography coupled with time-of-flight mass spectrometry (GC*GC-TOFMS) was utilized to analyze wastewater samples obtained from the Pennsylvania State University wastewater treatment facility (WWTF). Determination of emerging contaminants through a process of combining samples which represent "normal background" and comparing this to new samples was developed. Results show the presence of halogenated benzotriazoles in wastewater samples as well as soil samples from Pennsylvania State University agricultural fields. The trace levels of chlorinated benzotriazoles observed in the monitoring wells present on the property indicate likely environmental degradation of the chlorinated benzotriazoles. Preliminary investigation of environmental fate of the substituted benzotriazoles indicates their likely degradation into phenol; an Environmental Protection Agency (USEPA) priority pollutant. PMID- 26442817 TI - Ca(2+) signals mediated by bradykinin type 2 receptors in normal pancreatic stellate cells can be inhibited by specific Ca(2+) channel blockade. AB - KEY POINTS: Bradykinin may play a role in the autodigestive disease acute pancreatitis, but little is known about its pancreatic actions. In this study, we have investigated bradykinin-elicited Ca(2+) signal generation in normal mouse pancreatic lobules. We found complete separation of Ca(2+) signalling between pancreatic acinar (PACs) and stellate cells (PSCs). Pathophysiologically relevant bradykinin concentrations consistently evoked Ca(2+) signals, via B2 receptors, in PSCs but never in neighbouring PACs, whereas cholecystokinin, consistently evoking Ca(2+) signals in PACs, never elicited Ca(2+) signals in PSCs. The bradykinin-elicited Ca(2+) signals were due to initial Ca(2+) release from inositol trisphosphate-sensitive stores followed by Ca(2+) entry through Ca(2+) release-activated channels (CRACs). The Ca(2+) entry phase was effectively inhibited by a CRAC blocker. B2 receptor blockade reduced the extent of PAC necrosis evoked by pancreatitis-promoting agents and we therefore conclude that bradykinin plays a role in acute pancreatitis via specific actions on PSCs. ABSTRACT: Normal pancreatic stellate cells (PSCs) are regarded as quiescent, only to become activated in chronic pancreatitis and pancreatic cancer. However, we now report that these cells in their normal microenvironment are far from quiescent, but are capable of generating substantial Ca(2+) signals. We have compared Ca(2+) signalling in PSCs and their better studied neighbouring acinar cells (PACs) and found complete separation of Ca(2+) signalling in even closely neighbouring PACs and PSCs. Bradykinin (BK), at concentrations corresponding to the slightly elevated plasma BK levels that have been shown to occur in the auto digestive disease acute pancreatitis in vivo, consistently elicited substantial Ca(2+) signals in PSCs, but never in neighbouring PACs, whereas the physiological PAC stimulant cholecystokinin failed to evoke Ca(2+) signals in PSCs. The BK induced Ca(2+) signals were mediated by B2 receptors and B2 receptor blockade protected against PAC necrosis evoked by agents causing acute pancreatitis. The initial Ca(2+) rise in PSCs was due to inositol trisphosphate receptor-mediated release from internal stores, whereas the sustained phase depended on external Ca(2+) entry through Ca(2+) release-activated Ca(2+) (CRAC) channels. CRAC channel inhibitors, which have been shown to protect PACs against damage caused by agents inducing pancreatitis, therefore also inhibit Ca(2+) signal generation in PSCs and this may be helpful in treating acute pancreatitis. PMID- 26442818 TI - Assessing the Pathogenicity of Insertion and Deletion Variants with the Variant Effect Scoring Tool (VEST-Indel). AB - Insertion/deletion variants (indels) alter protein sequence and length, yet are highly prevalent in healthy populations, presenting a challenge to bioinformatics classifiers. Commonly used features--DNA and protein sequence conservation, indel length, and occurrence in repeat regions--are useful for inference of protein damage. However, these features can cause false positives when predicting the impact of indels on disease. Existing methods for indel classification suffer from low specificities, severely limiting clinical utility. Here, we further develop our variant effect scoring tool (VEST) to include the classification of in-frame and frameshift indels (VEST-indel) as pathogenic or benign. We apply 24 features, including a new "PubMed" feature, to estimate a gene's importance in human disease. When compared with four existing indel classifiers, our method achieves a drastically reduced false-positive rate, improving specificity by as much as 90%. This approach of estimating gene importance might be generally applicable to missense and other bioinformatics pathogenicity predictors, which often fail to achieve high specificity. Finally, we tested all possible meta predictors that can be obtained from combining the four different indel classifiers using Boolean conjunctions and disjunctions, and derived a meta predictor with improved performance over any individual method. PMID- 26442819 TI - Management of foveal adhesion of a dexamethasone implant. PMID- 26442820 TI - Coordinating ecological risk assessment with natural resource damage assessment: A panel discussion. AB - Contaminated sites in the United States undergo remediation and restoration through regulatory programs that lead the 2 processes through independent but often parallel pathways with different objectives. The objective of remediation is to reduce risk to human health and the environment, whereas that of restoration is to restore injured resources and compensate the public for lost use of the services that natural resources provide. More complex sites, such as those associated with large river systems and urban waterways, have resulted in increasingly larger-scale ecological risk assessments (ERAs) and natural resource damage assessments (NRDAs) that take many years and involve diverse practitioners including scientists, economists, and engineers. Substantial levels of effort are now frequently required, creating a need for more efficient and cost-effective approaches to data collection, analyses, and assessments. Because there are commonalities in the data needs between ERAs and NRDAs, coordination of the design and implementation of site-specific studies that meet the needs of both programs could result in increased efficiency and lower costs. The Association for Environmental Health and Sciences Foundation convened a panel of environmental practitioners from industry, consulting, and regulatory bodies to examine the benefits and challenges associated with coordinating ERA and NRDA activities in the context of a broad range of regulatory programs. This brief communication presents the opinions and conclusions of the panelists on these issues and reports 2 case studies for which coordinated ERA and NRDA activities produced a positive outcome. Integr Environ Assess Manag 2016;12:616-621. (c) 2015 SETAC. PMID- 26442821 TI - Growing evidence that maternal gestational diabetes increases risk of autism in offspring. PMID- 26442822 TI - Antitumor Activity of Garcinol in Human Prostate Cancer Cells and Xenograft Mice. AB - Garcinol, which is isolated from fruit rinds of Garcinia indica, is a polyisoprenylated benzophenone. It has been studied for its antitumor activity by inducing apoptosis and inhibiting autophagy in human prostate cancer cells. The Bax/Bcl-2 ratio increased when garcinol was applied to PC-3 cells indicating a presence of apoptosis. Meanwhile, procaspases-9 and -3 were suppressed with attenuating PARP and DFF-45. Autophagy was inhibited through activating p-mTOR and p-PI3 Kinase/AKT by garcinol, which as a result induced the cells to apoptosis directly. In addition, the apoptosis effect of garcinol in a xenograft mouse model was also tested, suggesting a consistent result with PC-3 cell model. The tumor size was reduced more than 80 percent after the mouse accepted the garcinol treatment. Garcinol was demonstrated to have a strong antitumor activity through inhibiting autophagy and inducing apoptosis, which was discovered for the first time. Based on these findings, our data suggests that garcinol deserves further investigation as a potent chemopreventive agent. PMID- 26442824 TI - Invasive Salmonellosis in Humans. AB - Human salmonellosis is generally associated with Salmonella enterica from subspecies enterica (subspecies I). Acute infections can present in one of four ways: enteric fever, gastroenteritis, bacteremia, or extraintestinal focal infection. As with other infectious diseases, the course and outcome of the infection depend on a variety of factors, including the infecting organism, the inoculating dose, and the immune status and genetic background of the host. For serovarsTyphi and Paratyphi A there is a clear association between the genetic background of the serovar and systemic infection in humans. For serovars Paratyphi B and Paratyphi C, a good clinical description of the host and detailed population genetics of the pathogen are necessary before more detailed genetic studies of novel virulence factors,or host factors,can be initiated. For the nontyphoidalserovars (NTS) the situation is less clear. Serovars Typhimurium and Enteritidis are the most common within the food chain, and so the large number of invasive infections associated with these serovars is most likely due to exposure rather than to increased virulence of the pathogen. In Africa, however, a closely related group of strains of serovar Typhimurium, associated with HIV infection, may have become host adapted tohumans, suggesting that not all isolates called "Typhimurium" should be considered as a single group. Here we review current knowledge of the salmonellae for which invasive disease in humans is an important aspect of their population biology. PMID- 26442825 TI - Aminoacyl-tRNA Synthetases in the Bacterial World. AB - Aminoacyl-tRNAsynthetases (aaRSs) are modular enzymesglobally conserved in the three kingdoms of life. All catalyze the same two-step reaction, i.e., the attachment of a proteinogenic amino acid on their cognate tRNAs, thereby mediating the correct expression of the genetic code. In addition, some aaRSs acquired other functions beyond this key role in translation.Genomics and X-ray crystallography have revealed great structural diversity in aaRSs (e.g.,in oligomery and modularity, in ranking into two distinct groups each subdivided in 3 subgroups, by additional domains appended on the catalytic modules). AaRSs show hugestructural plasticity related to function andlimited idiosyncrasies that are kingdom or even speciesspecific (e.g.,the presence in many Bacteria of non discriminating aaRSs compensating for the absence of one or two specific aaRSs, notably AsnRS and/or GlnRS).Diversity, as well, occurs in the mechanisms of aaRS gene regulation that are not conserved in evolution, notably betweendistant groups such as Gram-positive and Gram-negative Bacteria.Thereview focuses on bacterial aaRSs (and their paralogs) and covers their structure, function, regulation,and evolution. Structure/function relationships are emphasized, notably the enzymology of tRNA aminoacylation and the editing mechanisms for correction of activation and charging errors. The huge amount of genomic and structural data that accumulatedin last two decades is reviewed,showing how thefield moved from essentially reductionist biologytowards more global and integrated approaches. Likewise, the alternative functions of aaRSs and those of aaRSparalogs (e.g., during cellwall biogenesis and other metabolic processes in or outside protein synthesis) are reviewed. Since aaRS phylogenies present promiscuous bacterial, archaeal, and eukaryal features, similarities and differences in the properties of aaRSs from the three kingdoms of life are pinpointedthroughout the reviewand distinctive characteristics of bacterium-like synthetases from organelles are outlined. PMID- 26442826 TI - Homologous Recombination-Enzymes and Pathways. AB - Homologous recombination is an ubiquitous process that shapes genomes and repairs DNA damage. The reaction is classically divided into three phases: presynaptic, synaptic, and postsynaptic. In Escherichia coli, the presynaptic phase involves either RecBCD or RecFOR proteins, which act on DNA double-stranded ends and DNA single-stranded gaps, respectively; the central synaptic steps are catalyzed by the ubiquitous DNA-binding protein RecA; and the postsynaptic phase involves either RuvABC or RecG proteins, which catalyze branch-migration and, in the case of RuvABC, the cleavage of Holliday junctions. Here, we review the biochemical properties of these molecular machines and analyze how, in light of these properties, the phenotypes of null mutants allow us to define their biological function(s). The consequences of point mutations on the biochemical properties of recombination enzymes and on cell phenotypes help refine the molecular mechanisms of action and the biological roles of recombination proteins. Given the high level of conservation of key proteins like RecA and the conservation of the principles of action of all recombination proteins, the deep knowledge acquired during decades of studies of homologous recombination in bacteria is the foundation of our present understanding of the processes that govern genome stability and evolution in all living organisms. PMID- 26442823 TI - Translesion DNA Synthesis. AB - All living organisms are continually exposed to agents that damage their DNA, which threatens the integrity of their genome. As a consequence, cells are equipped with a plethora of DNA repair enzymes to remove the damaged DNA. Unfortunately, situations nevertheless arise where lesions persist, and these lesions block the progression of the cell's replicase. In these situations, cells are forced to choose between recombination-mediated "damage avoidance" pathways or a specialized DNA polymerase (pol) to traverse the blocking lesion. The latter process is referred to as Translesion DNA Synthesis (TLS). As inferred by its name, TLS not only results in bases being (mis)incorporated opposite DNA lesions but also bases being (mis)incorporated downstream of the replicase-blocking lesion, so as to ensure continued genome duplication and cell survival. Escherichia coli and Salmonella typhimurium possess five DNA polymerases, and while all have been shown to facilitate TLS under certain experimental conditions, it is clear that the LexA-regulated and damage-inducible pols II, IV, and V perform the vast majority of TLS under physiological conditions. Pol V can traverse a wide range of DNA lesions and performs the bulk of mutagenic TLS, whereas pol II and pol IV appear to be more specialized TLS polymerases. PMID- 26442829 TI - Lower tacrolimus trough levels are associated with subsequently higher acute rejection risk during the first 12 months after kidney transplantation. AB - The premise that lower TAC trough levels are associated with subsequently higher first BPAR risk during the first 12 mo post-transplant was recently questioned. Using our prospectively followed cohort of 528 adult, primary kidney transplant recipients (pooled across four randomized trials) who received reduced TAC dosing plus an IMPDH inhibitor, TAC trough levels measured at seven time points, 7, 14 days, 1, 2, 3, 6 and 9 months post-transplant, were utilized along with Cox's model to determine the multivariable significance of TAC level(t) (a continuous time-dependent covariate equaling the most recently measured TAC level prior to time t) on the hazard rate of developing first BPAR during the first 12 months post-transplant. The percentage developing BPAR during the first 12 months post transplant was 10.2% (54/528). In univariable analysis, lower TAC level(t) was associated with a significantly higher BPAR rate (P = 0.00006), and its significance was maintained even after controlling for 2 significant baseline predictors (African-American/Hispanic Recipient and Developed DGF) in Cox's model (multivariable P = 0.0003). Use of a cutpoint, TAC level(t) <4.0 vs. >=4.0 ng/ml, yielded an even greater association with BPAR rate (univariable and multivariable P < 0.000001), with an estimated hazard ratio of 6.33. These results suggest that TAC levels <4.0 ng/ml should be avoided during the first 12 months post transplant when TAC is used in combination with fixed-dose mycophenolate with or without corticosteroids and induction therapy. PMID- 26442827 TI - DNA Mismatch Repair. AB - DNA mismatch repair (MMR) corrects replication errors in newly synthesized DNA. It also has an antirecombination action on heteroduplexes that contain similar but not identical sequences. This review focuses on the genetics and development of MMR and not on the latest biochemical mechanisms. The main focus is on MMR in Escherichia coli, but examples from Streptococcuspneumoniae and Bacillussubtilis have also been included. In most organisms, only MutS (detects mismatches) and MutL (an endonuclease) and a single exonucleaseare present. How this system discriminates between newlysynthesized and parental DNA strands is not clear. In E. coli and its relatives, however, Dam methylation is an integral part of MMR and is the basis for strand discrimination. A dedicated site-specific endonuclease, MutH, is present, andMutL has no endonuclease activity; four exonucleases can participate in MMR. Although it might seem that the accumulated wealth of genetic and biochemical data has given us a detailed picture of the mechanism of MMR in E. coli, the existence of three competing models to explain the initiation phase indicates the complexity of the system. The mechanism of the antirecombination action of MMR is largely unknown, but only MutS and MutL appear to be necessary. A primary site of action appears to be on RecA, although subsequent steps of the recombination process can also be inhibited. In this review, the genetics of Very Short Patch (VSP) repair of T/G mismatches arising from deamination of 5-methylcytosineresidues is also discussed. PMID- 26442830 TI - Simulating photoacoustic waves produced by individual biological particles with spheroidal wave functions. AB - Under the usual approximation of treating a biological particle as a spheroidal droplet, we consider the analysis of its size and shape with the high frequency photoacoustics and develop a numerical method which can simulate its characteristic photoacoustic waves. This numerical method is based on the calculation of spheroidal wave functions, and when comparing to the finite element model (FEM) calculation, can reveal more physical information and can provide results independently at each spatial points. As the demonstration, red blood cells (RBCs) and MCF7 cell nuclei are studied, and their photoacoustic responses including field distribution, spectral amplitude, and pulse forming are calculated. We expect that integrating this numerical method with the high frequency photoacoustic measurement will form a new modality being extra to the light scattering method, for fast assessing the morphology of a biological particle. PMID- 26442831 TI - Interaction mechanism exploration of R-bicalutamide/S-1 with WT/W741L AR using molecular dynamics simulations. AB - R-Bicalutamide is a first generation antiandrogen used to treat prostate cancer, which inhibits androgen action by competitively binding to the androgen receptor (AR). However, R-bicalutamide was discovered to exhibit some agonistic properties in clinical application. According to reports, the W741L AR mutation may lead to resistance towards R-bicalutamide. But the mechanism of the R-bicalutamide switch from an antagonist to an agonist due to the mutation of AR W741L is still not so clear. Another molecule, S-1, owing to a very similar structure to R bicalutamide, is always agonistic to both the wild type and W741L AR. The main difference between these two chemicals is that S-1 has an ether linkage while R bicalutamide has a sulfonyl group. To study the drug-resistant mechanism caused by W741L mutation and the opposite effects arising from subtle structure differences, molecular dynamics (MD) simulations and molecular mechanics generalized Born surface area (MM-GBSA) calculations were employed to explore the interaction mechanisms between R-bicalutamide/S-1 and WT/W741L AR. The calculated binding free energies are in accordance with the reported experimental values. The obtained results indicate that M895 and W741 are vital amino acids in the antagonism of R-bicalutamide. The bulkier substitution of sulfonyl and tryptophan push aside M895, together with helix 12 (H12), to expose the ligand-binding domain resulting in the antagonistic conformation of the AR. If W741 is mutated to L741, the B-ring of these two chemicals would shift toward L741. At the same time, M895 dragging helix H12, would also move closer to L741. So H12 tends to cover the AR ligand-binding domain to a certain degree, changing the androgen receptor from an antagonistic to an agonistic conformation, which may explain the agonism of R-bicalutamide to the mutant W741L AR. PMID- 26442832 TI - Decreased expression of pSTAT, IRF-1 and DAP10 signalling molecules in peripheral blood lymphocytes of patients with metastatic melanoma. AB - AIMS: As numerous signalling molecules regulate effector functions of peripheral blood lymphocytes (PBLs) that have an important anti-tumour activity, the aim of this study was to analyse their level in patients with metastatic melanoma (MM) compared with healthy controls (HCs). METHODS: Peripheral blood mononuclear cells (PBMCs) of 36 MMs and 28 HCs were analysed for the level of perforin, interferon regulating transcription factor-1 (IRF-1), DAP10 and Src homology 2 domain containing tyrosine phosphatase-1 by reverse transcriptase PCR, level of phosphorylated signal transducers and activators of transcription (pSTAT)-1, pSTAT-4, pSTAT-5 by western blot and interferon (IFN)-gamma production by ELISA. The expression of activating NKG2D and inhibitory killer immunoglobulin-like receptors (KIR), CD158a and CD158b, on PBL, CD3-CD56+ natural killer (NK) cells and CD3+CD8+ cytotoxic T lymphocytes (CTLs), as well as the percentage of CD14+HLA-DR- cells in PBMC were estimated by flow cytometry. RESULTS: Patients with MM, compared with HCs, had significantly lower level of cytotoxic molecule perforin and decreased IFN-gamma production, as well as lower level of pSTAT-1, pSTAT-4, pSTAT-5 and IRF-1 signalling molecules in PBMC. Furthermore, MM had decreased expression of activating NKG2D receptor on PBL and NK cells and low level of its DAP10 signalling molecule contrary to no changes in KIR expression on all investigated cells. These results could be associated with increased percentage of immunosuppressive CD14+HLA-DR- myeloid-derived suppressor cells detected in patients with MM. CONCLUSIONS: The altered signalling molecules of PBL could represent biomarkers of impaired cytotoxic and immunoregulatory function of these cells, indicating melanoma-associated immunosuppression that facilitates tumour progression. PMID- 26442828 TI - Stress-Induced Mutagenesis. AB - Early research on the origins and mechanisms of mutation led to the establishment of the dogma that, in the absence of external forces, spontaneous mutation rates are constant. However, recent results from a variety of experimental systems suggest that mutation rates can increase in response to selective pressures. This chapter summarizes data demonstrating that,under stressful conditions, Escherichia coli and Salmonella can increase the likelihood of beneficial mutations by modulating their potential for genetic change.Several experimental systems used to study stress-induced mutagenesis are discussed, with special emphasison the Foster-Cairns system for "adaptive mutation" in E. coli and Salmonella. Examples from other model systems are given to illustrate that stress induced mutagenesis is a natural and general phenomenon that is not confined to enteric bacteria. Finally, some of the controversy in the field of stress-induced mutagenesis is summarized and discussed, and a perspective on the current state of the field is provided. PMID- 26442834 TI - [Ezetimibe in clinical practice: from laboratory investigations to the IMPROVE-IT trial results]. AB - The impact of low density lipoprotein (LDL) cholesterol levels on cardiovascular risk has been extensively studied. Statins have been demonstrated to significantly reduce LDL cholesterol levels, contributing to cardiovascular risk reduction particularly in patients with high cardiovascular risk. However, low adherence to statin therapy, often due to adverse effects, has raised the need for new pharmacological approaches to combine with statin therapy in order to reach the target levels of LDL cholesterol. Ezetimibe is a selective inhibitor of Niemann-Pick C1-like 1 (NPC1L1) protein that regulates the cholesterol uptake from the small intestine into the enterocytes. Ezetimibe has been demonstrated to significantly reduce LDL cholesterol levels in combination with statins and recent trials support its role in reducing the risk of cardiovascular events. PMID- 26442833 TI - Prevention for Pediatric and Adolescent Migraine. AB - Children and adolescents can experience significant disability from frequent migraine. A number of tools have been developed to help quantify the impact of migraine in this population. Many preventative medications used in adults are routinely used to prevent migraines in children, although there has been less rigorous study. This article reviews the indications and evidence for the use of migraine preventatives, such as antidepressants, antihypertensives, anticonvulsants, antihistamines, and botulinum toxin, in this population. PMID- 26442835 TI - Adsorption of Anionic or Cationic Surfactants in Polyanionic Brushes and Its Effect on Brush Swelling and Fouling Resistance during Emulsion Filtration. AB - Atom transfer radical polymerization of ionic monomers from membrane surfaces yields polyelectrolyte brushes that swell in water and repel oil droplets to resist fouling during filtration of oil-in-water emulsions. However, surfactant adsorption to polyelectrolyte brushes may overcome this fouling resistance. This work examines adsorption of cationic and anionic surfactants in polyanionic brushes and the effect of these surfactants on emulsion filtration. In situ ellipsometry with films on flat surfaces shows that brushes composed of poly(3 sulfopropyl methacrylate salts) (pSPMK) swell 280% in water and do not adsorb sodium dodecyl sulfate (SDS). pSPMK-modified microfiltration membranes reject >99.9% of the oil from SDS-stabilized submicron emulsions, and the specific flux through these modified membranes is comparable to that through NF270 nanofiltration membranes. Moreover, the brush-modified membranes show no decline in flux over a 12 h filtration, whereas the flux through NF270 membranes decreases by 98.7%. In contrast, pSPMK brushes adsorb large quantities of cetyltrimethylammonium bromide (CTAB), and at low chain densities the brushes collapse in the presence of this cationic surfactant. Filtration of CTAB stabilized emulsions through pSPMK-modified membranes gives minimal oil rejection, presumably due to the brush collapse. Thus, the fouling resistance of polyelectrolyte brush-modified membranes clearly depends on the surfactant composition in a particular emulsion. PMID- 26442837 TI - The impact of occupational therapy and lifestyle interventions on older persons' health, well-being, and occupational adaptation. AB - AIM: The aim of this study was to investigate whether a four-month occupational based health-promoting programme for older persons living in community dwellings could maintain/improve their general health and well-being. Further, the aim was to explore whether the programme facilitated the older persons' occupational adaptation. METHODS: The study had a quasi-experimental design, with a non equivalent control group combined with semi-structured interviews. The intervention group comprised 22 participants, and the control group 18. Outcomes were measured using the Short Form 36, Life Satisfaction Index-Z and Meaningful Activity Participation Assessment. Content analysis, based on concepts from the Model of Occupational Adaptation, was used to analyse the interviews. RESULTS: The intervention group showed statistically significant improvements in general health variables such as vitality and mental health, and positive trends for psychological well-being. There were no statistically significant differences between the intervention group and the control group, but the groups were not fully matched. The qualitative analysis based on Occupational Adaptation pointed out social aspects as a compliment to the overall results. CONCLUSIONS: Participating in meaningful, challenging activities in different environments stimulates the occupational adaptation process; this is something occupational therapists could use to empower older persons to find their optimal occupational lives. PMID- 26442836 TI - A genetic risk score comprising known venous thromboembolism loci is associated with chronic venous disease in a multi-ethnic cohort. AB - BACKGROUND: Chronic venous disease is common and shares some risk factors with venous thromboembolism (VTE). Several genetic loci have been discovered and well replicated for VTE in European descent populations. We examined associations of a genetic risk score (GRS), comprising known VTE loci, with chronic venous disease. METHODS: The San Diego Population Study (SDPS) is a multi-ethnic cohort that evaluated 2404 men and women aged 29-91 from 1994 to 1998 for chronic venous disease. The current study includes 1447 participants genotyped for 33 variants in 22 established VTE risk loci. Using these variants, unweighted and weighted GRS were constructed. Logistic regression was used to examine associations with venous disease. RESULTS: In non-Hispanic whites, African-Americans, Hispanics, and Asians, each standard deviation increment higher of the unweighted 33-SNP GRS was associated with a 1.45-fold (95% CI (1.26, 1.67)), 1.74-fold (1.18, 2.55), a 1.80-fold (1.30, 2.51), and 1.88-fold (1.30, 2.73) greater odds, respectively, for moderate plus severe disease. The difference in c-statistics was significant between a known venous risk factor model and a model adding the 33-SNP GRS for whites (p=0.008), African-Americans (0.03), and Hispanics (p=0.04), with marginal significance in Asians (p=0.06). CONCLUSIONS: GRS comprising variants primarily from VTE findings in European descent populations were associated with chronic venous disease across all race/ethnic groups, and contributed significantly to prediction, indicating some level of generalizability to other race/ethnic groups. Future work should focus on more in depth examination of racial/ethnic group genetic architecture in relation to chronic venous disease. PMID- 26442838 TI - Relative sensitivities among avian species to individual and mixtures of aryl hydrocarbon receptor-active compounds. AB - Dioxins and dioxin-like compounds (DLCs) are potent toxicants to most vertebrates. Sensitivities to DLCs vary among species. In the present study, the sensitivities of avian species (chicken [Gallus gallus], ring-necked pheasant [Phasianus colchicus], and Japanese quail [Coturnix japonica]) to some polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) were determined by using species-specific, in vitro, transactivation assays based on a luciferase reporter gene under control of species-specific aryl hydrocarbon receptors. In ring-necked pheasant and Japanese quail, 2,3,7,8-tetrachlorodibenzo p-dioxin (TCDD) was not the most potent inducer of toxic effects. Especially for Japanese quail, the relative potency values of most of 9 PCDD/Fs tested were greater than for TCDD. The rank order of avian species sensitivities to DLCs was chicken > ring-necked pheasant > Japanese quail. Effects of binary mixtures of TCDD, 2,3,7,8-tetrachlorodibenzofuran, and 2,3,4,7,8-pentachlorodibenzofuran were strictly additive. Moreover, we also found that the primary DLCs that were responsible for most of the potency of the DLC mixtures can be deduced by using ordination in a multidimensional space defined by the avian species sensitivities. Overall, the relative potency and the species sensitivities of these chemicals could guide risk assessments to wild species when exposure to mixtures of DLCs in the environment. PMID- 26442839 TI - Marinobacter confluentis sp. nov., a lipolytic bacterium isolated from a junction between the ocean and a freshwater lake. AB - A Gram-stain-negative, motile, aerobic and rod-shaped bacterium, designated HJM 18T, was isolated from the place where the ocean and a freshwater lake meet at Hwajinpo, South Korea, and subjected to a taxonomic study using a polyphasic approach. Strain HJM-18T grew optimally at 30 degrees C, at pH 7.0-8.0 and in the presence of 1.0-3.0 % (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences showed that strain HJM-18T belonged to the genus Marinobacter. Strain HJM-18T exhibited 16S rRNA gene sequence similarity values of 97.05-98.22 % to the type strains of Marinobacter algicola, Marinobacter flavimaris, Marinobacter adhaerens, Marinobacter salarius, Marinobacter salsuginis, Marinobacter guineae and Marinobacter gudaonensis and of 93.21-96.98 % to the type strains of the other species of the genus Marinobacter. Strain HJM-18T contained Q-9 as the predominant ubiquinone and summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), C16 : 0 and C18 : 1omega9c as the major fatty acids. The major polar lipids detected in strain HJM-18T were phosphatidylethanolamine, phosphatidylglycerol and one unidentified aminophospholipid. The DNA G+C content was 58 mol% and the mean DNA-DNA relatedness values with the type strains of the seven phylogenetically related species of the genus Marinobacter were 10-27 %. Differential phenotypic properties, together with phylogenetic and genetic distinctiveness, revealed that strain HJM-18T is separated from recognized species of the genus Marinobacter. On the basis of the data presented, strain HJM 18T represents a novel species of the genus Marinobacter, for which the name Marinobacter confluentis sp. nov. is proposed. The type strain is HJM-18T ( = KCTC 42705T = NBRC 111223T). PMID- 26442840 TI - Cyclization of sulfide, ether or tertiary amine-tethered N-sulfonyl-1,2,3 triazoles: a facile synthetic protocol for 3-substituted isoquinolines or dihydroisoquinolines. AB - A facile synthetic method to access 3-substituted isoquinoline or dihydroisoquinoline derivatives has been developed via a novel cyclization reaction of N-sulfonyl-1,2,3-triazole derivatives by thermally induced rearrangement. PMID- 26442842 TI - Response to 'Effect of metabolic components on incident type 2 diabetes mellitus in nonalcoholic fatty liver disease subjects'. PMID- 26442841 TI - Diversity Matters: A Revised Guide to Myelination. AB - The evolutionary success of the vertebrate nervous system is largely due to a unique structural feature--the myelin sheath, a fatty envelope that surrounds the axons of neurons. By increasing the speed by which electrical signals travel along axons, myelin facilitates neuronal communication between distant regions of the nervous system. We review the cellular and molecular mechanisms that regulate the development of myelin as well as its homeostasis in adulthood. We discuss how finely tuned neuron-oligodendrocyte interactions are central to myelin formation during development and in the adult, and how these interactions can have profound implications for the plasticity of the adult brain. We also speculate how the functional diversity of both neurons and oligodendrocytes may impact on the myelination process in both health and disease. PMID- 26442843 TI - The History of Patenting Genetic Material. AB - The US Supreme Court's recent decision in Association for Molecular Pathology v. Myriad Genetics, Inc. declared, for the first time, that isolated human genes cannot be patented. Many have wondered how genes were ever the subjects of patents. The answer lies in a nuanced understanding of both legal and scientific history. Since the early twentieth century, "products of nature" were not eligible to be patented unless they were "isolated and purified" from their surrounding environment. As molecular biology advanced, and the capability to isolate genes both physically and by sequence came to fruition, researchers (and patent offices) began to apply patent-law logic to genes themselves. These patents, along with other biological patents, generated substantial social and political criticism. Myriad Genetics, a company with patents on BRCA1 and BRCA2, two genes critical to assessing early-onset breast and ovarian cancer risk, and with a particularly controversial business approach, became the antagonist in an ultimately successful campaign to overturn gene patents in court. Despite Myriad's defeat, some questions concerning the rights to monopolize genetic information remain. The history leading to that defeat may be relevant to these future issues. PMID- 26442844 TI - General Stress Signaling in the Alphaproteobacteria. AB - The Alphaproteobacteria uniquely integrate features of two-component signal transduction and alternative sigma factor regulation to control transcription of genes that ensure growth and survival across a range of stress conditions. Research over the past decade has led to the discovery of the key molecular players of this general stress response (GSR) system, including the sigma factor sigma(EcfG), its anti-sigma factor NepR, and the anti-anti-sigma factor PhyR. The central molecular event of GSR activation entails aspartyl phosphorylation of PhyR, which promotes its binding to NepR and thereby releases sigma(EcfG) to associate with RNAP and direct transcription. Recent studies are providing a new understanding of complex, multilayered sensory networks that activate and repress this central protein partner switch. This review synthesizes our structural and functional understanding of the core GSR regulatory proteins and highlights emerging data that are defining the systems that regulate GSR transcription in a variety of species. PMID- 26442845 TI - Understanding Language from a Genomic Perspective. AB - Language is a defining characteristic of the human species, but its foundations remain mysterious. Heritable disorders offer a gateway into biological underpinnings, as illustrated by the discovery that FOXP2 disruptions cause a rare form of speech and language impairment. The genetic architecture underlying language-related disorders is complex, and although some progress has been made, it has proved challenging to pinpoint additional relevant genes with confidence. Next-generation sequencing and genome-wide association studies are revolutionizing understanding of the genetic bases of other neurodevelopmental disorders, like autism and schizophrenia, and providing fundamental insights into the molecular networks crucial for typical brain development. We discuss how a similar genomic perspective, brought to the investigation of language-related phenotypes, promises to yield equally informative discoveries. Moreover, we outline how follow-up studies of genetic findings using cellular systems and animal models can help to elucidate the biological mechanisms involved in the development of brain circuits supporting language. PMID- 26442847 TI - The Biology and Evolution of Mammalian Y Chromosomes. AB - Mammals have the oldest sex chromosome system known: the mammalian X and Y chromosomes evolved from ordinary autosomes beginning at least 180 million years ago. Despite their shared ancestry, mammalian Y chromosomes display enormous variation among species in size, gene content, and structural complexity. Several unique features of the Y chromosome--its lack of a homologous partner for crossing over, its functional specialization for spermatogenesis, and its high degree of sequence amplification--contribute to this extreme variation. However, amid this evolutionary turmoil many commonalities have been revealed that have contributed to our understanding of the selective pressures driving the evolution and biology of the Y chromosome. Two biological themes have defined Y-chromosome research over the past six decades: testis determination and spermatogenesis. A third biological theme begins to emerge from recent insights into the Y chromosome's roles beyond the reproductive tract--a theme that promises to broaden the reach of Y-chromosome research by shedding light on fundamental sex differences in human health and disease. PMID- 26442848 TI - Chromothripsis: A New Mechanism for Rapid Karyotype Evolution. AB - Chromosomal rearrangements are generally thought to accumulate gradually over many generations. However, DNA sequencing of cancer and congenital disorders uncovered a new pattern in which multiple rearrangements arise all at once. The most striking example, chromothripsis, is characterized by tens or hundreds of rearrangements confined to a single chromosome or to local regions over a few chromosomes. Genomic analysis of chromothripsis and the search for its biological mechanism have led to new insights on how chromosome segregation errors can generate mutagenesis and changes to the karyotype. Here, we review the genomic features of chromothripsis and summarize recent progress on understanding its mechanism. This includes reviewing new work indicating that one mechanism to generate chromothripsis is through the physical isolation of chromosomes in abnormal nuclear structures (micronuclei). We also discuss connections revealed by recent genomic analysis of cancers between chromothripsis, chromosome bridges, and ring chromosomes. PMID- 26442846 TI - Giving Time Purpose: The Synechococcus elongatus Clock in a Broader Network Context. AB - Early research on the cyanobacterial clock focused on characterizing the genes needed to keep, entrain, and convey time within the cell. As the scope of assays used in molecular genetics has expanded to capture systems-level properties (e.g., RNA-seq, ChIP-seq, metabolomics, high-throughput screening of genetic variants), so has our understanding of how the clock fits within and influences a broader cellular context. Here we review the work that has established a global perspective of the clock, with a focus on (a) an emerging network-centric view of clock architecture, (b) mechanistic insights into how temporal and environmental cues are transmitted and integrated within this network, PMID- 26442849 TI - Asymmetry of the Brain: Development and Implications. AB - Although the left and right hemispheres of our brains develop with a high degree of symmetry at both the anatomical and functional levels, it has become clear that subtle structural differences exist between the two sides and that each is dominant in processing specific cognitive tasks. As the result of evolutionary conservation or convergence, lateralization of the brain is found in both vertebrates and invertebrates, suggesting that it provides significant fitness for animal life. This widespread feature of hemispheric specialization has allowed the emergence of model systems to study its development and, in some cases, to link anatomical asymmetries to brain function and behavior. Here, we present some of what is known about brain asymmetry in humans and model organisms as well as what is known about the impact of environmental and genetic factors on brain asymmetry development. We specifically highlight the progress made in understanding the development of epithalamic asymmetries in zebrafish and how this model provides an exciting opportunity to address brain asymmetry at different levels of complexity. PMID- 26442850 TI - Sarcoid-like reactions (SLRs) or autonomous sarcoidosis (AS)? Differentiation probably important? PMID- 26442851 TI - [Diagnostics and management of food allergies in childhood and adolescence]. AB - Food allergies can result in life-threatening reactions and diminish quality of life. The prevalence of food allergies is increasing with large regional variability. A few food allergens cover the majority of food-related reactions (cow's milk, egg, wheat, soy, fish, crustacean, nuts and peanut). Food reactions can be categorized in IgE-mediated and non-IgE-mediated, the latter of which remaining often a clue in the diagnosis. Treatment of food allergy involves mainly strict avoidance of the trigger food. Medications help to manage symptoms of disease, but currently, there is no cure for food allergy. PMID- 26442852 TI - Glial Fibrillary Acidic Protein-Expressing Glia in the Mouse Lung. AB - Autonomic nerves regulate important functions in visceral organs, including the lung. The postganglionic portion of these nerves is ensheathed by glial cells known as non-myelinating Schwann cells. In the brain, glia play important functional roles in neurotransmission, neuroinflammation, and maintenance of the blood brain barrier. Similarly, enteric glia are now known to have analogous roles in gastrointestinal neurotransmission, inflammatory response, and barrier formation. In contrast to this, very little is known about the function of glia in other visceral organs. Like the gut, the lung forms a barrier between airborne pathogens and the bloodstream, and autonomic lung innervation is known to affect pulmonary inflammation and lung function. Lung glia are described as non myelinating Schwann cells but their function is not known, and indeed no transgenic tools have been validated to study them in vivo. The primary goal of this research was, therefore, to investigate the relationship between non myelinating Schwann cells and pulmonary nerves in the airways and vasculature and to validate existing transgenic mouse tools that would be useful for studying their function. We focused on the glial fibrillary acidic protein promoter, which is a cognate marker of astrocytes that is expressed by enteric glia and non myelinating Schwann cells. We describe the morphology of non-myelinating Schwann cells in the lung and verify that they express glial fibrillary acidic protein and S100, a classic glial marker. Furthermore, we characterize the relationship of non-myelinating Schwann cells to pulmonary nerves. Finally, we report tools for studying their function, including a commercially available transgenic mouse line. PMID- 26442853 TI - Crosstalk Between MAPK/ERK and PI3K/AKT Signal Pathways During Brain Ischemia/Reperfusion. AB - The epidermal growth factor receptor (EGFR) is linked to the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Raf/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK1/2) signaling pathways. During brain ischemia/reperfusion, EGFR could be transactivated, which stimulates these intracellular signaling cascades that either protect cells or potentiate cell injury. In the present study, we investigated the activation of EGFR, PI3K/AKT, and Raf/MAPK/ERK1/2 during ischemia or reperfusion of the brain using the middle cerebral artery occlusion model. We found that EGFR was phosphorylated and transactivated during both ischemia and reperfusion periods. During ischemia, the activity of PI3K/AKT pathway was significantly increased, as judged from the strong phosphorylation of AKT; this activation was suppressed by the inhibitors of EGFR and Zn-dependent metalloproteinase. Ischemia, however, did not induce ERK1/2 phosphorylation, which was dependent on reperfusion. Coimmunoprecipitation of Son of sevenless 1 (SOS1) with EGFR showed increased association between the receptor and SOS1 in ischemia, indicating the inhibitory node downstream of SOS1. The inhibitory phosphorylation site of Raf-1 at Ser259, but not its stimulatory phosphorylation site at Ser338, was phosphorylated during ischemia. Furthermore, ischemia prompted the interaction between Raf-1 and AKT, while both the inhibitors of PI3K and AKT not only abolished AKT phosphorylation but also restored ERK1/2 phosphorylation. All these findings suggest that Raf/MAPK/ERK1/2 signal pathway is inhibited by AKT via direct phosphorylation and inhibition at Raf-1 node during ischemia. During reperfusion, we observed a significant increase of ERK1/2 phosphorylation but no change in AKT phosphorylation. Inhibitors of reactive oxygen species and phosphatase and tensin homolog restored AKT phosphorylation but abolished ERK1/2 phosphorylation, suggesting that the reactive oxygen species-dependent increase in phosphatase and tensin homolog activity in reperfusion period relieves ERK1/2 from inhibition of AKT. PMID- 26442855 TI - Microbiota-Gut-Brain Axis: Yeast Species Isolated from Stool Samples of Children with Suspected or Diagnosed Autism Spectrum Disorders and In Vitro Susceptibility Against Nystatin and Fluconazole. AB - Autism spectrum disorder (ASD) is a general term for a group of complex neurodevelopmental disorders of brain development that limits a person's ability to function normally. Etiology has not been clearly defined up to date. However, gut microbiota and the bidirectional communication between the gastrointestinal tract and brain, the so-called microbiota-gut-brain axis, are hypothesized, which may be involved in the etiology of several mental disorders. Recent reports suggest that Candida, particularly Candida albicans, growth in intestines may cause lower absorption of carbohydrates and minerals and higher toxin levels which are thought to contribute autistic behaviors. The aim of this study was to identify the 3-year deposited yeasts isolated from stool samples of children with diagnosed or suspected ASD and to determine in vitro activity of nystatin and fluconazole against these isolates using Clinical Laboratory Standards Institute M27-A3 guidelines. A 17-year retrospective assessment was also done using our laboratory records. Among the species identified, intrinsically fluconazole resistant Candida krusei (19.8 %) and Candida glabrata (14.8 %) with elevated MICs were remarkable. Overall, C. albicans (57.4 %) was the most commonly isolated species in 17 years. The species identification and/or antifungal susceptibility tests have to be performed using the strain isolated from stool sample, to select the appropriate antifungal agent, if antimycotic therapy is needed. PMID- 26442854 TI - A case of oral mycosis fungoides successfully treated by combination of alemtuzumab and chemotherapy. PMID- 26442856 TI - Epithelial-Mesenchymal Transition Protein Expression in Basal Cell Adenomas and Basal Cell Adenocarcinomas. AB - Basal cell adenomas and basal cell adenocarcinomas show marked histomorphologic similarity and are separated microscopically primarily by the invasive characteristics of the adenocarcinomas. We wished to explore potential differences in the expression of epithelial-mesenchymal transition associated proteins in these two tumor types. A tissue microarray was constructed utilizing 29 basal cell adenomas and 16 basal cell adenocarcinomas. Immunohistochemical expression of E-cadherin, beta-catenin, Twist 1 and vimentin were investigated. Both tumors expressed all proteins in a relatively similar manner. Nuclear beta catenin was essentially limited to the abluminal cell populations in both tumor types. E-cadherin was limited largely to luminal locations but was more prevalent in the adenocarcinomas as compared to the adenomas. Primarily abluminal expression for vimentin was seen, sometimes present in an apical dot-like pattern. Distinct populations of cellular expression of these four markers of epithelial mesenchymal transition were present but were similar in locations in both tumors with no patterns discerned to separate basal cell adenoma from basal cell adenocarcinoma. Given these findings, the mechanisms by which basal cell adenocarcinoma is able to invade while its counterpart, basal cell adenoma can not, may be more complex than in other tumor types. PMID- 26442857 TI - Tolerability of Antihypertensive Medications in Older Adults. AB - Several guidelines for hypertension have recently undergone revisions to incorporate an approach providing choices of medications based on age, race, and specific situations where hypertension may co-exist with disorders such as diabetes, coronary artery disease, heart failure and chronic kidney disease. Initial recommendations include diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers; beta blockers are favored in some guidelines and are a choice in specific settings. Within the classes of drugs, several antihypertensive agents provide options. This review discusses antihypertensive drugs by class, including adverse effects and tolerability, with preferences in older adults and specific settings. Adverse drug events from antihypertensive medications are discussed by class and where applicable for specific agents. Data from select studies pertinent to tolerability and adverse effects are presented in tables for several classes of drugs. The rationale for nonadherence to medication is reviewed, including the roles played by tolerability and adverse drug effects. Antihypertensive therapy in typical settings in older adults is discussed; they include hypertension in association with impaired cognition, depression, diabetes, sexual dysfunction, and falls. The key to successful therapy and tolerability is to promote a healthy lifestyle in conjunction with medications as the approach, thereby also lowering the adverse drug effects. The eventual choice of the specific drug(s) is based on risks, benefits, and patient preferences, and is best tailored for each older adult. PMID- 26442858 TI - Treatment of Exudative Age-related Macular Degeneration: Focus on Aflibercept. AB - A formulation of aflibercept for intravitreal injection (Eylea) is approved for the treatment of patients with exudative age-related macular degeneration (AMD). Aflibercept has a significantly higher affinity for Vascular endothelial growth factor (VEGF)-A compared with other monoclonal anti-VEGF antibodies. In addition to binding all VEGF-A isoforms, aflibercept also blocks other proangiogenic factors such as VEGF-B and placental growth factor. The VIEW 1 and 2 trials showed this drug achieves improved results in patients with exudative AMD similar to those obtained with monthly ranibizumab, using a bimonthly treatment regimen after a loading dose of three intravitreal injections, which translates to less use of healthcare resources. There is a subgroup of patients that present with persistent fluid after the loading dose that could benefit from monthly injections or personalized proactive treatment after the first year. In the second year of treatment, the Treat and Extend patterns can permit even more lengthening of the time between injections. More data are needed to confirm the optimal monitoring and retreatment dosing, to maintain long-term efficacy. Other preliminary data suggest that patients that do not respond to other anti angiogenics and patients with special pathologies such as polypoidal choroidopathy or retinal angiomatous proliferation can improve upon switching to aflibercept. To date, the safety profile of aflibercept is excellent and is comparable to other anti-angiogenic treatments. PMID- 26442860 TI - Immunogenicity and Safety of Intradermal Influenza Vaccine in the Elderly: A Meta Analysis of Randomized Controlled Trials. AB - INTRODUCTION: Immunosenescence makes the elderly more susceptible to influenza complications and less responsive to vaccination. An intradermal formulation (IDflu) is one of several strategies being investigated to increase the immunogenicity of influenza vaccines. OBJECTIVE: The overall goal of the study was to assess the safety and immunogenicity of IDflu compared with the intramuscular route (IMflu) in the elderly. METHODS: A meta-analysis of randomized controlled trials (RCTs) was performed. Included articles met the following criteria: RCTs; primary studies, not re-analyses or reviews; enrolment of elderly people; comparing the immunogenicity and/or safety of IDflu with IMflu; measuring seroprotection and/or seroconversion rate to assess immunogenicity; measuring local reactions and/or general symptoms and/or other mild local reactions that could affect acceptability of vaccine as safety indicators, according to the European Medicines Agency (EMA) criteria; published through January 2015. RESULTS: The results of our meta-analysis on seroprotection showed that IDflu is comparable to IMflu for each strain (A/H1N1: risk ratio [RR] 1.02, 95% confidence interval [CI] 0.98-1.07; A/H3N2: RR 1.01, 95% CI 0.99-1.04; B 1.02, 95% CI 0.98-1.08). The seroconversion rate achieved with IDflu was comparable to that of the control group (A/H1N1: RR 1.08, 95% CI 0.97-1.2; A/H3N2: RR 1.08, 95% CI 0.96-1.21; B: RR 1.21, 95% CI 1-1.45). Systemic reactogenicity appeared similar in the two groups, while local reactions were significantly more frequent in the IDflu group. CONCLUSIONS: The novel IDflu appears to have the adequate balance between immunogenicity and safety in the elderly compared with IMflu, and its utilization may be considered among the possible strategies to enhance the control of seasonal influenza outbreaks according to the existing policy recommendations in the elderly. PMID- 26442859 TI - Novel Therapies for Metastatic Melanoma: An Update on Their Use in Older Patients. AB - Cutaneous melanoma is the most aggressive form of skin cancer. With age as a risk factor, melanoma is projected to become a substantial healthcare burden. The clinical course of melanoma in older patients is different from that in middle aged and younger patients: melanomas are thicker, have higher mitotic rates and are more likely to be ulcerated. Older patients also have a higher mortality rate, yet, paradoxically, have a lower rate of lymph node metastases. After decades of no significant progress in the treatment of this devastating disease, novel insights into the mechanisms underlying the pathophysiology of metastatic melanoma have led to new and remarkably efficient therapeutic opportunities. The discovery that about half of all melanomas carry BRAF mutations led to the introduction of targeted therapy with significant improvements in clinical outcomes. Although these drugs appear to be equally effective in older patients, specific considerations regarding adverse events are required. Besides targeted therapy, immunotherapy has emerged as an alternative therapeutic option. Antibodies that block cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) can induce responses with high durability. Despite an aging immune system, older patients seem to benefit to the same degree from these treatments, apparently without increased toxicity. In this review, we focus on the epidemiology, clinicopathological features, and recent developments of systemic treatment in cutaneous melanoma with regard to older patients. PMID- 26442861 TI - Prevalence of Potential and Clinically Relevant Statin-Drug Interactions in Frail and Robust Older Inpatients. AB - BACKGROUND: A significant proportion of older people are prescribed statins and are also exposed to polypharmacy, placing them at increased risk of statin-drug interactions. OBJECTIVE: To describe the prevalence rates of potential and clinically relevant statin-drug interactions in older inpatients according to frailty status. METHODS: A cross-sectional study of patients aged >=65 years who were prescribed a statin and were admitted to a teaching hospital between 30 July and 10 October 2014 in Sydney, Australia, was conducted. Data on socio demographics, comorbidities and medications were collected using a standardized questionnaire. Potential statin-drug interactions were defined if listed in the Australian Medicines Handbook and three international drug information sources: the British National Formulary, Drug Interaction Facts and Drug-Reax((r)). Clinically relevant statin-drug interactions were defined as interactions with the highest severity rating in at least two of the three international drug information sources. Frailty was assessed using the Reported Edmonton Frail Scale. RESULTS: A total of 180 participants were recruited (median age 78 years, interquartile range 14), 35.0% frail and 65.0% robust. Potential statin-drug interactions were identified in 10% of participants, 12.7% of frail participants and 8.5% of robust participants. Clinically relevant statin-drug interactions were identified in 7.8% of participants, 9.5% of frail participants and 6.8% of robust participants. Depending on the drug information source used, the prevalence rates of potential and clinically relevant statin-drug interactions ranged between 14.4 and 35.6% and between 14.4 and 20.6%, respectively. CONCLUSION: In our study of frail and robust older inpatients taking statins, the overall prevalence of potential statin-drug interactions was low and varied significantly according to the drug information source used. PMID- 26442862 TI - The Association Between Anticholinergic Medication Burden and Health Related Outcomes in the 'Oldest Old': A Systematic Review of the Literature. AB - BACKGROUND: Increased exposure to anticholinergic medication is problematic, particularly in those aged 80 years and older. OBJECTIVE: The aim of this systematic review was to identify tools used to quantify anticholinergic medication burden and determine the most appropriate tool for use in longitudinal research, conducted in those aged 80 years and older. METHODS: A systematic literature search was conducted across six electronic databases to identify existing tools. Data extraction was conducted independently by two researchers; studies describing the development of each tool were also retrieved and relevant data extracted. An assessment of quality was completed for all studies. Tools were assessed in terms of their measurement of the association between anticholinergic medication burden and a defined set of clinical outcomes, their development and their suitability for use in longitudinal research; the latter was evaluated on the basis of criteria defined as the key attributes of an ideal anticholinergic risk tool. RESULTS: In total, 807 papers were retrieved, 13 studies were eligible for inclusion and eight tools were identified. Included studies were classed as 'very good' or 'good' following the quality assessment analysis; one study was unclassified. Anticholinergic medication burden as measured in studies was associated with impaired cognitive and physical function, as well as an increased frequency of falls. The Drug Burden Index (DBI) exhibited most of the key attributes of an ideal anticholinergic risk tool. CONCLUSION: This review identified the DBI as the most appropriate tool for use in longitudinal research focused on older people and their exposure to anticholinergic medication burden. PMID- 26442863 TI - High-Dose Nicotinamide Suppresses ROS Generation and Augments Population Expansion during CD8(+) T Cell Activation. AB - During T cell activation, mitochondrial content increases to meet the high energy demand of rapid cell proliferation. With this increase, the level of reactive oxygen species (ROS) also increases and causes the rapid apoptotic death of activated cells, thereby facilitating T cell homeostasis. Nicotinamide (NAM) has previously been shown to enhance mitochondria quality and extend the replicative life span of human fibroblasts. In this study, we examined the effect of NAM on CD8(+) T cell activation. NAM treatment attenuated the increase of mitochondrial content and ROS in T cells activated by CD3/CD28 antibodies. This was accompanied by an accelerated and higher-level clonal expansion resulting from attenuated apoptotic death but not increased division of the activated cells. Attenuation of ROS-triggered pro-apoptotic events and upregulation of Bcl-2 expression appeared to be involved. Although cells activated in the presence of NAM exhibited compromised cytokine gene expression, our results suggest a means to augment the size of T cell expansion during activation without consuming their limited replicative potential. PMID- 26442864 TI - NRROS Negatively Regulates Osteoclast Differentiation by Inhibiting RANKL Mediated NF-N:B and Reactive Oxygen Species Pathways. AB - Negative regulator of reactive oxygen species (NRROS) is known to repress ROS generation in phagocytes. In this study, we examined the roles of NRROS in both osteoclasts and osteoblasts. Our results demonstrate that NRROS negatively regulates the differentiation of osteoclasts, but not osteoblasts. Further, overexpression of NRROS in osteoclast precursor cells attenuates RANKL-induced osteoclast differentiation. Conversely, osteoclast differentiation is enhanced upon siRNA-mediated knockdown of NRROS. Additionally, NRROS attenuates RANKL induced NF-N:B activation, as well as degradation of the NOX1 and NOX2 proteins, which are required for ROS generation. Based on our observations, we present NRROS as a novel negative regulator of RANKL-induced osteoclastogenesis. PMID- 26442866 TI - Ursodeoxycholic Acid (UDCA) Exerts Anti-Atherogenic Effects by Inhibiting Endoplasmic Reticulum (ER) Stress Induced by Disturbed Flow. AB - Disturbed blood flow with low-oscillatory shear stress (OSS) is a predominant atherogenic factor leading to dysfunctional endothelial cells (ECs). Recently, it was found that disturbed flow can directly induce endoplasmic reticulum (ER) stress in ECs, thereby playing a critical role in the development and progression of atherosclerosis. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid, has long been used to treat chronic cholestatic liver disease and is known to alleviate endoplasmic reticulum (ER) stress at the cellular level. However, its role in atherosclerosis remains unexplored. In this study, we demonstrated the anti-atherogenic activity of UDCA via inhibition of disturbed flow-induced ER stress in atherosclerosis. UDCA effectively reduced ER stress, resulting in a reduction in expression of X-box binding protein-1 (XBP-1) and CEBP-homologous protein (CHOP) in ECs. UDCA also inhibits the disturbed flow-induced inflammatory responses such as increases in adhesion molecules, monocyte adhesion to ECs, and apoptosis of ECs. In a mouse model of disturbed flow-induced atherosclerosis, UDCA inhibits atheromatous plaque formation through the alleviation of ER stress and a decrease in adhesion molecules. Taken together, our results revealed that UDCA exerts anti-atherogenic activity in disturbed flow-induced atherosclerosis by inhibiting ER stress and the inflammatory response. This study suggests that UDCA may be a therapeutic agent for prevention or treatment of atherosclerosis. PMID- 26442865 TI - PGC-Enriched miRNAs Control Germ Cell Development. AB - Non-coding microRNAs (miRNAs) regulate the translation of target messenger RNAs (mRNAs) involved in the growth and development of a variety of cells, including primordial germ cells (PGCs) which play an essential role in germ cell development. However, the target mRNAs and the regulatory networks influenced by miRNAs in PGCs remain unclear. Here, we demonstrate a novel miRNAs control PGC development through targeting mRNAs involved in various cellular pathways. We reveal the PGC-enriched expression patterns of nine miRNAs, including miR-10b, 18a, -93, -106b, -126-3p, -127, -181a, -181b, and -301, using miRNA expression analysis along with mRNA microarray analysis in PGCs, embryonic gonads, and postnatal testes. These miRNAs are highly expressed in PGCs, as demonstrated by Northern blotting, miRNA in situ hybridization assay, and miRNA qPCR analysis. This integrative study utilizing mRNA microarray analysis and miRNA target prediction demonstrates the regulatory networks through which these miRNAs regulate their potential target genes during PGC development. The elucidated networks of miRNAs disclose a coordinated molecular mechanism by which these miRNAs regulate distinct cellular pathways in PGCs that determine germ cell development. PMID- 26442867 TI - Reversibly Switching Silver Hierarchical Structures via Reaction Kinetics. AB - Here we report a study on controllable synthesis of hierarchical silver structures via regulating reaction kinetics. Silver particles with various morphologies are synthesized by a solution-based reduction approach at the addition of amino acids. The amino acid is used to coordinate with silver ions to slow down the reduction of silver ions. With the increase of glycine concentration, the morphologies of silver particles switch from dendrites, to flowers and to compacted spheres, which is attributed to the decrease of reaction rate as a result of the coordination. Three more amino acids are examined and confirms the role of reaction kinetic in shaping silver particles. Furthermore, by increasing the concentration of the reductant, the silver morphologies change from compact spheres to loose flowers as a result of the increase of reaction rate. Therefore the silver hierarchical structure can be reversibly switched by reaction kinetics. The silver particles synthesized are tested for surface enhanced Raman scattering (SERS) property and the dendritic particles present a remarkable SERS activity. This study shows that reaction kinetics is a powerful tool to tune hierarchical structures of silver particles, which is expected to be transferable to other material systems. PMID- 26442868 TI - Australia needs more occupational therapists in rural mental health services. PMID- 26442869 TI - Modernising occupational therapy teaching, research and practice in mental health. PMID- 26442870 TI - Re: Modernising occupational therapy teaching, research and practice in mental health. PMID- 26442871 TI - Occupational therapy intervention in mental health should be individualised, occupation focussed, promote inclusion and occur in the context of an authentic relationship. PMID- 26442872 TI - Cognitive adaptation training demonstrated benefits for individuals living with schizophrenia in terms of community functioning and impact of auditory hallucinations. PMID- 26442873 TI - Occupational Therapy Australia Scope of Practice Framework and Statement resources: update. PMID- 26442874 TI - Assessment of native plant species for phytoremediation of heavy metals growing in the vicinity of NTPC sites, Kahalgaon, India. AB - The present investigation was carried out to screen native plants growing in fly ash (FA) contaminated areas near National Thermal Power Corporation (NTPC), Kahalgaon, Bihar, India with a view to using them for the eco-restoration of the area. A total number of 30 plant species (5 aquatic and 25 terrestrial including 6 ferns) were collected and their diversity status and dominance were also studied. After screening of dominant species at highly polluted site, 8 terrestrial and 5 aquatic plants were analyzed for heavy metals (Fe, Zn, Cu, Ni, Si, Al, Pb, Cr, and Cd). Differential accumulations of various heavy metals by different species of plants were observed. Typha latifolia was found to be most efficient metal accumulator of Fe (927), Cu (58), Zn (87), Ni (57), Al (67), Cd (95), and Pb (69), and Azolla pinnata as Cr (93) hyper-accumulator among aquatic species in ug g(-1). In terrestrial species the maximum levels of Fe (998), Zn (81), Ni (93), Al (121), and Si (156) were found in Croton bonplandium. However, there was high spatial variability in total metal accumulation in different species indicated by coefficient of variation (CV%). These results suggest that various aquatic, some dominant terrestrial plants including fern species may be used in a synergistic way to remediate and restore the FA contaminated wastelands. PMID- 26442878 TI - A cross reactive sensor array to probe divalent metal ions. AB - A simple sensing ensemble was designed to discriminate structurally similar divalent metal chlorides utilizing multivariate data analysis. The system features the binding of four synthesized coumarin-enamine probes to a series of ten metal chlorides. Linear discriminant analysis (LDA) achieves what univariate data analysis alone cannot i.e., full analyte discrimination and differentiation. PMID- 26442875 TI - Homology-directed repair in rodent zygotes using Cas9 and TALEN engineered proteins. AB - The generation of genetically-modified organisms has been revolutionized by the development of new genome editing technologies based on the use of gene-specific nucleases, such as meganucleases, ZFNs, TALENs and CRISPRs-Cas9 systems. The most rapid and cost-effective way to generate genetically-modified animals is by microinjection of the nucleic acids encoding gene-specific nucleases into zygotes. However, the efficiency of the procedure can still be improved. In this work we aim to increase the efficiency of CRISPRs-Cas9 and TALENs homology directed repair by using TALENs and Cas9 proteins, instead of mRNA, microinjected into rat and mouse zygotes along with long or short donor DNAs. We observed that Cas9 protein was more efficient at homology-directed repair than mRNA, while TALEN protein was less efficient than mRNA at inducing homology-directed repair. Our results indicate that the use of Cas9 protein could represent a simple and practical methodological alternative to Cas9 mRNA in the generation of genetically-modified rats and mice as well as probably some other mammals. PMID- 26442879 TI - Enzymatic pretreatment of low-grade oils for biodiesel production. AB - The alkaline process for making biodiesel (fatty acid methyl esters, or FAME) is highly efficient at the transesterification of glycerides. However, its performance is poor when it comes to using oil that contain significant amounts of free fatty acids (FFA). The traditional approach to such feedstocks is to employ acid catalysis, which is slow and requires a large excess of methanol, or to evaporate FFA and convert that in a separate process. An attractive option would be to convert the FFA in oil feedstocks to FAME, before introducing it into the alkaline process. The high selectivity of enzyme catalysis makes it a suitable basis for such a pretreatment process. In this work, we present a characterization of the pretreatment of high-FFA rapeseed oil using immobilized Candida antarctica lipase B (Novozym 435), focused on the impact of initial FFA and methanol concentration. Based on experimental results, we have identified limitations for the process in terms of FFA concentration in the feedstock and make suggestions for process operation. It was found that, using 5% catalyst and 4% methanol at 35 degrees C, the FFA concentration could be reduced to 0.5% within an hour for feedstock containing up to 15% FFA. Further, the reaction was observed to be under kinetic control, in that the biocatalyst converts FFA (and FAME) at a much higher rate than glyceride substrates. There is thus, both a minimum and a maximum reaction time for the process to achieve the desired concentration of FFA. Finally, an assessment of process stability in a continuous packed bed system indicates that as much as 15 m(3) oil could potentially be pretreated by 1 kg of biocatalyst at the given process conditions. PMID- 26442880 TI - Hydrogen sulfide reduces serum triglyceride by activating liver autophagy via the AMPK-mTOR pathway. AB - Autophagy plays an important role in liver triglyceride (TG) metabolism. Inhibition of autophagy could reduce the clearance of TG in the liver. Hydrogen sulfide (H2S) is a potent stimulator of autophagic flux. Recent studies showed H2S is protective against hypertriglyceridemia (HTG) and noalcoholic fatty liver disease (NAFLD), while the mechanism remains to be explored. Here, we tested the hypothesis that H2S reduces serum TG level and ameliorates NAFLD by stimulating liver autophagic flux by the AMPK-mTOR pathway. The level of serum H2S in patients with HTG was lower than that of control subjects. Sodium hydrosulfide (NaHS, H2S donor) markedly reduced serum TG levels of male C57BL/6 mice fed a high-fat diet (HFD), which was abolished by coadministration of chloroquine (CQ), an inhibitor of autophagic flux. In HFD mice, administration of NaSH increased the LC3BII-to-LC3BI ratio and decreased the p62 protein level. Meanwhile, NaSH increased the phosphorylation of AMPK and thus reduced the phosphorylation of mTOR in a Western blot study. In cultured LO2 cells, high-fat treatment reduced the ratio of LC3BII to LC3BI and the phosphorylation of AMPK, which were reversed by the coadministration of NaSH. Knockdown of AMPK by siRNA in LO2 cells blocked the autophagic enhancing effects of NaSH. The same qualitative effect was observed in AMPKalpha2(-/-) mice. These results for the first time demonstrated that H2S could reduce serum TG level and ameliorate NAFLD by activating liver autophagy via the AMPK-mTOR pathway. PMID- 26442882 TI - A Palladium- and Copper-Catalyzed Synthesis of Dihydro[1,2-b]indenoindole-9-ol and Benzofuro[3,2-b]indolines: Metal-Controlled Intramolecular C-C and C-O Bond Forming Reactions. AB - A palladium- and copper-catalyzed synthesis of dihydro[1,2-b]indenoindole-9-ol and benzofuro[3,2-b]indolines has been developed, whereby the same starting material is employed for the synthesis of both heterocyclic scaffolds and the selectivity of the product is controlled by switching the choice of metal. Salient features of these cascade reactions include wide-ranging functional group tolerance, simple reaction conditions, and moderate to high yields. PMID- 26442881 TI - Acute ingestion of citrulline stimulates nitric oxide synthesis but does not increase blood flow in healthy young and older adults with heart failure. AB - To determine if age-associated vascular dysfunction in older adults with heart failure (HF) is due to insufficient synthesis of nitric oxide (NO), we performed two separate studies: 1) a kinetic study with a stable isotope tracer method to determine in vivo kinetics of NO metabolism, and 2) a vascular function study using a plethysmography method to determine reactive hyperemic forearm blood flow (RH-FBF) in older and young adults in the fasted state and in response to citrulline ingestion. In the fasted state, NO synthesis (per kg body wt) was ~ 50% lower in older vs. young adults and was related to a decreased rate of appearance of the NO precursor arginine. Citrulline ingestion (3 g) stimulated de novo arginine synthesis in both older [6.88 +/- 0.83 to 35.40 +/- 4.90 MUmol . kg body wt(-1) . h(-1)] and to a greater extent in young adults (12.02 +/- 1.01 to 66.26 +/- 4.79 MUmol . kg body wt(-1) . h(-1)). NO synthesis rate increased correspondingly in older (0.17 +/- 0.01 to 2.12 +/- 0.36 MUmol . kg body wt(-1) . h(-1)) and to a greater extent in young adults (0.36 +/- 0.04 to 3.57 +/- 0.47 MUmol . kg body wt(-1) . h(-1)). Consistent with the kinetic data, RH-FBF in the fasted state was ~ 40% reduced in older vs. young adults. However, citrulline ingestion (10 g) failed to increase RH-FBF in either older or young adults. In conclusion, citrulline ingestion improved impaired NO synthesis in older HF adults but not RH-FBF, suggesting that factors other than NO synthesis play a role in the impaired RH-FBF in older HF adults, and/or it may require a longer duration of supplementation to be effective in improving RH-FBF. PMID- 26442883 TI - A new agenda for mental health in the Eastern Mediterranean Region. PMID- 26442884 TI - Comprehensive mental health action plan 2013-2020. PMID- 26442885 TI - From plan to framework: the process for developing the regional framework to scale up action on mental health in the Eastern Mediterranean Region. PMID- 26442886 TI - Situational analysis: preliminary regional review of the Mental Health Atlas 2014. AB - The WHO comprehensive Mental Health Action Plan 2013-2020 established goals and objectives that Member States have agreed to meet by 2020. To update the Atlas of Mental Health 2011, specific indicators from the Mental Health Action Plan and additional indicators on service coverage were incorporated into the questionnaire for the Atlas 2014. The data will help facilitate improvement in information gathering and focus efforts towards implementation of the Mental Health Action Plan. The questionnaire was completed by the national mental health focal point of each country. This preliminary review seeks to consolidate data from the initial response to the Atlas 2014 questionnaire by Member States in the Eastern Mediterranean Region. Data for this review were analysed for the whole Region, by health systems groupings and by individual countries. Where possible, data are compared with the Mental Health Atlas 2011 to give a longitudinal perspective. PMID- 26442887 TI - Reorganization of mental health services: from institutional to community-based models of care. AB - Mental health services in the Eastern Mediterranean Region are predominantly centralized and institutionalized, relying on scarce specialist manpower. This creates a major treatment gap for patients with common and disabling mental disorders and places an unnecessary burden on the individual, their family and society. Six steps for reorganization of mental health services in the Region can be outlined: (1) integrate delivery of interventions for priority mental disorders into primary health care and existing priority programmes; (2) systematically strengthen the capacity of non-specialized health personnel for providing mental health care; (3) scale up community-based services (community outreach teams for defined catchment, supported residential facilities, supported employment and family support); (4) establish mental health services in general hospitals for outpatient and acute inpatient care; (5) progressively reduce the number of long-stay beds in mental hospitals through restricting new admissions; and (6) provide transitional/bridge funding over a period of time to scale up community-based services and downsize mental institutions in parallel. PMID- 26442888 TI - Informing mental health policies and services in the EMR: cost-effective deployment of human resources to deliver integrated community-based care. AB - For EMR countries to deliver the expectations of the Global Mental Health Action Plan 2013-2020 & the ongoing move towards universal health coverage, all health & social care providers need to innovate and transform their services to provide evidence-based health care that is accessible, cost-effective & with the best patient outcomes. For the primary and community workforce, this includes general medical practitioners, practice & community nurses, community social workers, housing officers, lay health workers, nongovernmental organizations & civil society, including community spiritual leaders/healers. This paper brings together the current best evidence to support transformation & discusses key approaches to achieve this, including skill mix and/or task shifting and integrated care. The important factors that need to be in place to support skill mix/task shifting and good integrated care are outlined with reference to EMR countries. PMID- 26442889 TI - Integration of mental health into priority health service delivery platforms: maternal and child health services. AB - Maternal and child health (MCH) programmes are the most logical and appropriate platforms for integration of mental health care in an equitable, accessible and holistic manner. Such integration has the potential to improve both mental and physical health synergistically. Key steps to successful integration include a) recognition, at the highest international and national policy forums, that mental health and well-being is a generic component of MCH that does not compete with MCH programmes but instead complements them; b) tailoring the training and supervision of MCH and primary care personnel so they can recognize and assist in the management of common maternal and child mental health problems, recognizing that this, in turn, will enable them to be more effective health-care workers; c) adapting effective interventions to local contexts; and d) investing in implementation research so that these approaches are refined and scaled-up, leading to improved outcomes for all MCH programmes. PMID- 26442890 TI - Mental health and psychosocial support in humanitarian emergencies. AB - Armed conflicts and natural disasters impact negatively on the mental health and well-being of affected populations in the short- and long-term and affect the care of people with pre-existing mental health conditions. This paper outlines specific actions for mental health and psychosocial support by the health sector in the preparedness, response and recovery phases of emergencies. Broad recommendations for ministries of health are to: (1) embed mental health and psychosocial support in national health and emergency preparedness plans; (2) put in place national guidelines, standards and supporting tools for the provision of mental health and psychosocial support during emergencies; (3) strengthen the capacity of health professionals to identify and manage priority mental disorders during emergencies; and (4) utilize opportunities generated by the emergency response to contribute to development of sustainable mental health-care services. PMID- 26442891 TI - Promotion of mental health and prevention of mental disorders: priorities for implementation. AB - There is compelling evidence from high-quality studies that mental health promotion and primary prevention interventions can reduce the risk of mental disorders, enhance protective factors for good mental and physical health, and lead to lasting positive effects on a range of social and economic outcomes. This paper reviews the available evidence in order to guide the implementation of mental health promotion and prevention interventions in the Eastern Mediterranean Region. The paper identifies a number of priority areas that can generate clear health and social gains in the population and be implemented and sustained at a reasonable cost. The interventions cover population groups across the lifespan from infancy to adulthood and include actions delivered across different settings and delivery platforms. "Best practices" were identified as interventions for which there is evidence not only of their effectiveness but also of their feasibility within resource constraints. The implications of the findings for capacity development are considered. PMID- 26442892 TI - Mental health surveillance and information systems. AB - Routine information systems for mental health in many Eastern Mediterranean Region countries are rudimentary or absent, making it difficult to understand the needs of local populations and to plan accordingly. Key components for mental health surveillance and information systems are: national commitment and leadership to ensure that relevant high quality information is collected and reported; a minimum data set of key mental health indicators; intersectoral collaboration with appropriate data sharing; routine data collection supplemented with periodic surveys; quality control and confidentiality; and technology and skills to support data collection, sharing and dissemination. Priority strategic interventions include: (1) periodically assessing and reporting the mental health resources and capacities available using standardized methodologies; (2) routine collection of information and reporting on service availability, coverage and continuity, for priority mental disorders disaggregated by age, sex and diagnosis; and (3) mandatory recording and reporting of suicides at the national level (using relevant ICD codes). PMID- 26442893 TI - Mental health research: developing priorities and promoting its utilization to inform policies and services. AB - Investment in research on the prevention and treatment of mental health disorders is disproportionately low in the WHO Eastern Mediterranean Region (EMR) relative to the disease burden. Scaling-up mental health research in the EMR could generate enormous returns in terms of reducing disability, improving outcomes and preventing premature death, through early diagnosis, better management and community-based rehabilitation. EMR countries must therefore work to identify research priorities, mobilize resources, develop human and infrastructure capacities and institutionalize use of research findings to guide development of policies and service delivery models. Several key strategic interventions for EMR Member States are recommended: adopt a prioritized national mental health research agenda; systematically map national and international research funding to identify and secure resources to support the implementation of the agenda; strengthen national capacity to undertake prioritized research; periodically map research output in mental health; and foster dialogue between researchers and policy-makers/programme managers. PMID- 26442894 TI - Mental health policy and strategic plan. PMID- 26442895 TI - Mental health legislation. PMID- 26442896 TI - Investing in mental health. PMID- 26442898 TI - WHO events addressing public health priorities. PMID- 26442897 TI - Scaling up action for mental health in the Eastern Mediterranean Region: an overview. PMID- 26442899 TI - Comparison of parasitological, immunological and molecular methods for evaluation of fecal samples of immunosuppressed rats experimentally infected with Strongyloides venezuelensis. AB - Definitive diagnosis of strongyloidiasis in humans is typically achieved by detection of larvae in fecal samples. However, limitations on sensitivity of parasitological methods emphasize the need for more robust diagnostic methods. The aim of this study was to compare the diagnostic value of three methods: eggs per gram of feces (EPG), coproantigen detection by enzyme linked immunosorbent assay (ELISA), and DNA detection by conventional polymerase chain reaction (PCR). The assays were performed at 0 and 5, 8, 13, 21 and 39 days post-infection (dpi) using fecal samples from experimentally infected immunocompetent and immunosuppressed rats. In immunocompetent rats, eggs were detected in feces on days 5, 8 and 13 dpi; coproantigen detection and PCR amplification were successful at all post-infection time points (5, 8, 13, 21 and 39 dpi). In immunosuppressed rats, eggs were detected at 5, 8, 13 and 21; coproantigen detection and PCR amplification were successful at all post-infection time points. In conclusion, these results suggest that coproantigen detection and PCR may be more sensitive alternatives to traditional methods such as EPG for diagnosis of Strongyloides venezuelensis infection. PMID- 26442900 TI - Exercise at Different Ages and Appendicular Lean Mass and Strength in Later Life: Results From the Berlin Aging Study II. AB - BACKGROUND: Excessive loss of muscle mass in advanced age is a major risk factor for decreased physical ability and falls. Physical activity and exercise training are typically recommended to maintain muscle mass and prevent weakness. How exercise in different stages of life relates to muscle mass, grip strength, and risk for weakness in later life is not well understood. METHODS: Baseline data on 891 participants at least 60 years old from the Berlin Aging Study II (BASE-II) were analyzed. Linear and logistic regressions of self-reported exercise in early adulthood, old age, or both on appendicular lean mass (ALM), grip strength, and a risk indicator for weakness (ALM/ body mass index cutoff) were calculated. In addition, treatment bounds are analyzed to address potential confounding using a method proposed by Oster. RESULTS: Analyses indicate that for men only, continuous exercise is significantly associated with higher muscle mass (SD = 0.24, p < .001), grip strength (SD = 0.18, p < .05), and lower risk for clinically relevant low muscle mass (odds ratio = 0.36, p < .01). Exercise in early adulthood alone is not significantly associated with muscle mass or strength. No significant associations were observed for women. CONCLUSIONS: The results of the current study underscore the importance of health programs to promote physical activity with a focus on young adults, a group known to be affected from environmentally associated decline of physical activity, and to promote the continuation of physical exercise from early adulthood into later life in general. PMID- 26442901 TI - Rapamycin Increases Mortality in db/db Mice, a Mouse Model of Type 2 Diabetes. AB - We examined the effect of rapamycin on the life span of a mouse model of type 2 diabetes, db/db mice. At 4 months of age, male and female C57BLKSJ-lepr (db/db) mice (db/db) were placed on either a control diet, lacking rapamycin or a diet containing rapamycin and maintained on these diets over their life span. Rapamycin was found to reduce the life span of the db/db mice. The median survival of male db/db mice fed the control and rapamycin diets was 349 and 302 days, respectively, and the median survival of female db/db mice fed the control and rapamycin diets was 487 and 411 days, respectively. Adjusting for gender differences, rapamycin increased the mortality risk 1.7-fold in both male and female db/db mice. End-of-life pathological data showed that suppurative inflammation was the main cause of death in the db/db mice, which is enhanced slightly by rapamycin treatment. PMID- 26442902 TI - Effects of citrate dialysate in chronic dialysis: a multicentre randomized crossover study. AB - BACKGROUND: Although citrate dialysate (CiDi) is regarded to be safe, dialysis modalities using higher dialysate volumes, like haemodiafiltration (HDF), may expose patients to higher citrate load and thus increase the risk of complications. We investigated the residual risk of CiDi compared with standard dialysate (StDi) in patients on different dialysis modalities and its effect on dialysis dose. METHODS: In a multicentre randomized crossover study, 92 dialysis patients (HDF post-dilution: n = 44, HDF pre-dilution: n = 26, haemodialysis: n = 25) were treated for 4 weeks with each dialysate (StDi and CiDi). Hypocalcaemia (ionized calcium <=0.9 mmol/L), alkalosis (pH >=7.55), post-treatment bicarbonate >=32 mmol/L, pre-treatment bicarbonate >=27 mmol/L, intra-dialytic events (IEs) and adverse events (AEs) between dialysis sessions were investigated as primary end points. The secondary objective was dialysis efficacy, i.e. dose and removal ratios of urea, creatinine, phosphate and beta-2-microglobulin. RESULTS: Post dialysis overcorrection of bicarbonate (>32 mmol/L) was less frequent with CiDi (P = 0.008). Other predefined calcium and acid-base disturbances did not vary. There was no significant difference in IE. However, more patients developed AEs such as fatigue, muscle spasms or pain using CiDi (StDi: 41 versus CiDi: 55 patients, P = 0.02), particularly in the first 2 weeks of exposure. Dialysis efficacy was comparable with both dialysates. CONCLUSIONS: It can be confirmed that CiDi is not associated with the development of severe calcium and acid-base disorders, even when dialysis modalities with higher citrate loads are used. However, a refinement of the CiDi composition to minimize AEs is necessary. PMID- 26442904 TI - Should women abstain from alcohol throughout pregnancy? PMID- 26442903 TI - Reduced skeletal muscle function is associated with decreased fiber cross sectional area in the Cy/+ rat model of progressive kidney disease. AB - BACKGROUND: The combination of skeletal muscle wasting and compromised function plays a role in the health decline commonly observed in chronic kidney disease (CKD) patients, but the pathophysiology of muscle mass/strength changes remains unclear. The purpose of this study was to characterize muscle properties in the Cy/+ rat model of spontaneously progressive CKD. METHODS: Leg muscle function and serum biochemistry of male Cy/+ (CKD) rats and their nonaffected littermates (NLs) were assessed in vivo at 25, 30 and 35 weeks of age. Architecture and histology of extensor digitorum longus (EDL) and soleus (SOL) muscles were assessed ex vivo at the conclusion of the experiment. We tested the hypothesis that animals with CKD have progressive loss of muscle function, and that this functional deficit is associated with loss of muscle mass and quality. RESULTS: Thirty-five-week-old CKD rats produced significantly lower maximum torque in ankle dorsiflexion and shorter time to maximum torque, and longer half relaxation time in dorsiflexion and plantarflexion compared with NL rats. Peak dorsiflexion torque (but not plantarflexion torque) in CKD remained steady from 25 to 35 weeks, while in NL rats, peak torque increased. Mass, physiologic cross-sectional area (CSA) and fiber-type (myosin heavy chain isoform) proportions of EDL and SOL were not different between CKD and NL. However, the EDL of CKD rats showed reduced CSAs in all fiber types, while only MyHC-1 fibers were decreased in area in the SOL. CONCLUSIONS: The results of this study demonstrate that muscle function progressively declines in the Cy/+ rat model of CKD. Because whole muscle mass and architecture do not vary between CKD and NL, but CKD muscles show reduction in individual fiber CSA, our data suggest that the functional decline is related to increased muscle fiber atrophy. PMID- 26442905 TI - The experimental teaching reform in biochemistry and molecular biology for undergraduate students in Peking University Health Science Center. AB - Since 2010, second-year undergraduate students of an eight-year training program leading to a Doctor of Medicine degree or Doctor of Philosophy degree in Peking University Health Science Center (PKUHSC) have been required to enter the "Innovative talent training project." During that time, the students joined a research lab and participated in some original research work. There is a critical educational need to prepare these students for the increasing accessibility of research experience. The redesigned experimental curriculum of biochemistry and molecular biology was developed to fulfill such a requirement, which keeps two original biochemistry experiments (Gel filtration and Enzyme kinetics) and adds a new two-experiment component called "Analysis of anti-tumor drug induced apoptosis." The additional component, also known as the "project-oriented experiment" or the "comprehensive experiment," consists of Western blotting and a DNA laddering assay to assess the effects of etoposide (VP16) on the apoptosis signaling pathways. This reformed laboratory teaching system aims to enhance the participating students overall understanding of important biological research techniques and the instrumentation involved, and to foster a better understanding of the research process all within a classroom setting. Student feedback indicated that the updated curriculum helped them improve their operational and self-learning capability, and helped to increase their understanding of theoretical knowledge and actual research processes, which laid the groundwork for their future research work. PMID- 26442907 TI - Ceftriaxone reverses ketamine-induced lasting EEG and astrocyte alterations in juvenile mice. AB - BACKGROUND: Ketamine, an N-methyl-d-aspartate receptor antagonist, is used as a pediatric anesthetic because of its favorable safety profile. It is also being investigated as an antidepressant. Unfortunately, ketamine causes adverse reactions including hallucinations and is associated with a high prevalence of abuse among adolescents. Although chronic ketamine use has been shown to produce cognitive impairments even years following cessation, little is known about its long-term consequences on adolescents. The beta-lactam ceftriaxone has been shown to attenuate alcohol withdrawal, and alleviate early brain injury and memory impairments following subarachnoid hemorrhage. However, its ability to reverse the effects of adolescent ketamine exposure is not known. Previous data indicate that ketamine causes a reduction in the number of Excitatory Amino Acid Transporter Type 2 (EAAT2)-containing astrocytes. Additionally, the beta lactam antibiotic ceftriaxone increased expression of EAAT2. As EAAT2 is a principal mechanism of glutamate clearance from the synapse, the current study tests the hypothesis that ceftriaxone may reverse functional consequences of ketamine exposure. METHODS: We examined the effects of chronic ketamine in juvenile mice as well as reversal by ceftriaxone using electroencephalography (EEG). Subsequently, we assessed the effects of these treatments on markers of astrocyte proliferation, using Glial Fibrillary Acidic Protein (GFAP), and function, as evidenced by EAAT2. RESULTS: Juvenile mice exposed to chronic ketamine showed lasting alterations in EEG measurements as well as markers of astrocyte number and function. These alterations were reversed by ceftriaxone. CONCLUSIONS: Data suggest that ceftriaxone may be able to ameliorate ketamine-induced long-term disturbances in adolescent brains. PMID- 26442909 TI - Ultrasensitive nonlinear absorption response of large-size topological insulator and application in low-threshold bulk pulsed lasers. AB - Dirac-like topological insulators have attracted strong interest in optoelectronic application because of their unusual and startling properties. Here we report for the first time that the pure topological insulator Bi2Te3 exhibited a naturally ultrasensitive nonlinear absorption response to photoexcitation. The Bi2Te3 sheets with lateral size up to a few micrometers showed extremely low saturation absorption intensities of only 1.1 W/cm(2) at 1.0 and 1.3 MUm, respectively. Benefiting from this sensitive response, a Q-switching pulsed laser was achieved in a 1.0 MUm Nd:YVO4 laser where the threshold absorbed pump power was only 31 mW. This is the lowest threshold in Q-switched solid-state bulk lasers to the best of our knowledge. A pulse duration of 97 ns was observed with an average power of 26.1 mW. A Q-switched laser at 1.3 MUm was also realized with a pulse duration as short as 93 ns. Moreover, the mode locking operation was demonstrated. These results strongly exhibit that Bi2Te3 is a promising optical device for constructing broadband, miniature and integrated high-energy pulsed laser systems with low power consumption. Our work clearly points out a significantly potential avenue for the development of two-dimensional-material based broadband ultrasensitive photodetector and other optoelectronic devices. PMID- 26442910 TI - Copper(II) tetrafluoroborate complexes with the N(3),N(4)-bridging coordination of 1-(tert-butyl)-1H-tetrazole: synthesis, crystal structure and magnetic properties. AB - 1-(tert-Butyl)-1H-tetrazole (L) reacts with copper(ii) tetrafluoroborate hexahydrate to give the complexes [Cu2L8(H2O)2](BF4)4 (1) or [Cu3L6(H2O)6](BF4)6 (2) depending on the reaction conditions. These complexes, as well as compound L, were characterized using single crystal X-ray analysis. Complex 1 was found to comprise a dinuclear complex cation [Cu2L8(H2O)2](4+) (the Ci symmetry point group), with six tetrazole ligands L showing monodentate N(4)-coordination, and two ligands L providing two tetrazole ring N(3),N(4) bridges between the copper(ii) cations; water molecules complete the distorted octahedral coordination of the metal ions. Complex 2 includes a linear trinuclear complex cation [Cu3L6(H2O)6](6+) (the S6 symmetry point group), in which neighbouring copper(ii) cations are linked by three ligands L via tetrazole ring N(3),N(4) bridges; central and terminal metal ions show octahedral CuN6 and CuN3O3 coordination cores, respectively. The temperature-dependent magnetic susceptibility measurements of complex 2 revealed that the copper(ii) ions were weakly ferromagnetically coupled showing a coupling constant J of 2.2 cm(-1) {H = -2J(S1S2 + S2S3)}. The quantum-chemical investigation of the electronic structure and basicity of ligand L was carried out. PMID- 26442908 TI - Group 1 mGlu-family proteins promote neuroadaptation to ethanol and withdrawal associated hippocampal damage. AB - BACKGROUND: Group 1 mGlu-family proteins (i.e., mGlu) consist of mGlu1 and mGlu5 and their activity may influence voluntary ethanol intake. The present studies sought to examine the influence of these receptors on the development of ethanol dependence using in vitro and in vivo models of chronic, intermittent ethanol (CIE). METHODS: Rat hippocampal explants were exposed to CIE with or without the addition of mGlu1 antagonist (7-hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt; 0.5, 1, and 3MUM) or mGlu5 antagonist (E)-2-methyl-6-styryl pyridine (SIB-1893; 20, 100, and 200MUM) to assess sparing of withdrawal-induced cytotoxicity. In a separate study, adult male rats were administered CIE with or without the addition of oral administration of group 1 mGlu antagonist 2-methyl-6 (phenylethynyl)-pyridine (MPEP; 3mg/kg). Blood ethanol levels (BELs) were determined at 0930h on Day 2 of Weeks 1, 2, and 3. Withdrawal behavior was monitored during Day 6 of the third consecutive withdrawal. RESULTS: CIE produced significant hippocampal cytotoxicity. These effects were attenuated by co exposure to CPCCOEt (3MUM) with ethanol in the CA3. By contrast, these effects were blocked by SIB-1893 (20MUM) in each primary cell layer. Oral administration of MPEP with ethanol significantly attenuated behavioral effects of subsequent withdrawal and reduced BELs. CONCLUSIONS: These data demonstrate that ethanol activates group 1 mGlu-family proteins to promote withdrawal-associated cytotoxicity in vitro and physical dependence in vivo. These findings suggest that group 1 mGlu-family proteins may be therapeutic targets for treatment of alcohol use disorders. PMID- 26442911 TI - Discovery of Small-Molecule Nonfluorescent Inhibitors of Fluorogen-Fluorogen Activating Protein Binding Pair. AB - A new class of biosensors, fluorogen activating proteins (FAPs), has been successfully used to track receptor trafficking in live cells. Unlike the traditional fluorescent proteins (FPs), FAPs do not fluoresce unless bound to their specific small-molecule fluorogens, and thus FAP-based assays are highly sensitive. Application of the FAP-based assay for protein trafficking in high throughput flow cytometry resulted in the discovery of a new class of compounds that interferes with the binding between fluorogens and FAP, thus blocking the fluorescence signal. These compounds are high-affinity, nonfluorescent analogs of fluorogens with little or no toxicity to the tested cells and no apparent interference with the normal function of FAP-tagged receptors. The most potent compound among these, N,4-dimethyl-N-(2-oxo-2-(4-(pyridin-2-yl)piperazin-1 yl)ethyl)benzenesulfonamide (ML342), has been investigated in detail. X-ray crystallographic analysis revealed that ML342 competes with the fluorogen, sulfonated thiazole orange coupled to diethylene glycol diamine (TO1-2p), for the same binding site on a FAP, AM2.2. Kinetic analysis shows that the FAP-fluorogen interaction is more complex than a homogeneous one-site binding process, with multiple conformational states of the fluorogen and/or the FAP, and possible dimerization of the FAP moiety involved in the process. PMID- 26442912 TI - Understanding ForteBio's Sensors for High-Throughput Kinetic and Epitope Screening for Purified Antibodies and Yeast Culture Supernatant. AB - Real-time and label-free antibody screening systems are becoming more popular because of the increasing output of purified antibodies and antibody supernatant from many antibody discovery platforms. However, the properties of the biosensor can greatly affect the kinetic and epitope binning results generated by these label-free screening systems. ForteBio human-specific ProA, anti-human IgG quantitation (AHQ), anti-human Fc capture (AHC) sensors, and custom biotinylated anti-human Fc capture (b-AHFc) sensors were evaluated in terms of loading ability, regeneration, kinetic characterization, and epitope binning with both purified IgG and IgG supernatant. AHC sensors proved unreliable for kinetic or binning assays at times, whereas AHQ sensors showed poor loading and regeneration abilities. ProA sensors worked well with both purified IgG and IgG supernatant. However, the interaction between ProA sensors and the Fab region of the IgG with VH3 germline limited the application of ProA sensors, especially in the epitope binning experiment. In an attempt to generate a biosensor type that would be compatible with a variety of germlines and sample types, we found that the custom b-AHFc sensors appeared to be robust working with both purified IgG and IgG supernatant, with little evidence of sensor-related artifacts. PMID- 26442913 TI - Polypharmacology of Small-Molecule Modulators of the 5-Lipoxygenase Activating Protein (FLAP) Observed via a High-throughput Lipidomics Platform. AB - Leukotrienes (LTs) and related species are proinflammatory lipid mediators derived from arachidonic acid (AA) that have pathological roles in autoimmune and inflammatory conditions, cardiovascular diseases, and cancer. 5-Lipoxygenase activating protein (FLAP) plays a critical accessory role in the conversion of AA to LTA4, and its subsequent conversion to LTC4 by LTC4 synthase. Pharmacological inhibition of FLAP results in a loss of LT production by preventing the biosynthesis of both LTB4 and LTC4, making it an attractive target for the treatment of inflammatory diseases in which LTs likely play a role. Small molecule (SM) drugs often exhibit polypharmacology through various pathways, which may explain the differential therapeutic efficacies of compounds sharing structural similarity. We have profiled a series of SM FLAP modulators for their selectivity across enzymes of AA cascade in human whole blood (HWB), using a recently developed LC/MS (liquid chromatography-mass spectrometry)-based high throughput lipidomics platform that monitors 122 eicosanoids in multiplex. Highly efficient data acquisition coupled with fast and accurate data analysis allowed facile compound profiling from ex vivo study samples. This platform allowed us to quantitatively map the effects of those SMs on the entire AA cascade, demonstrating its potential to discriminate structurally related compounds. PMID- 26442917 TI - Marital Quality Buffers the Association Between Socioeconomic Status and Ambulatory Blood Pressure. AB - BACKGROUND: Socioeconomic status is robustly associated with rates of death and disease. Psychophysiological stress processes are thought to account for a portion of this association. PURPOSE: Although positive and supportive relationships can buffer psychophysiological stress responses, no studies have examined whether the quality of a primary adult relationship-marriage-may buffer the negative association between socioeconomic status and stress-related disease processes. METHODS: The current study examines the interaction between income and marital quality (supportive vs. ambivalent) on individuals' daily ambulatory blood pressure, a valid and reliable indicator of cardiovascular risk. RESULTS: Results revealed that supportive marital relationships buffered the otherwise higher ambulatory diastolic blood pressure associated with low income. CONCLUSIONS: Results are consistent with the buffering hypothesis of social support and suggest that a supportive spouse may buffer stress-related autonomic processes linking low socioeconomic status to risk for cardiovascular disease. PMID- 26442916 TI - Prevalence of Dietary Supplement Use by Athletes: Systematic Review and Meta Analysis. AB - BACKGROUND: Dietary supplements (DSs) are commercially available products consumed as an addition to the usual diet and are frequently ingested by athletes. OBJECTIVE: Our objective was to examine the prevalence of DS use by athletes. DATA SOURCES: PubMed, Ovid MEDLINE, OVID Healthstar, and Cumulative Index to Nursing and Allied Health were searched for original research articles published up to August 2014. Search terms included specific sports, specific DSs, and other terms. STUDY SELECTION: Studies were selected if they were written in English, involved athletes, and provided a quantitative assessment of the proportion of athletes using specific DSs. Percent of athletes using specific DSs. SYNTHESIS OF DATA: Methodological quality of studies was assessed by three reviewers using an 8-point scale that included evaluations for sampling methods, sampling frame, sample size, measurement tools, bias, response rate, statistical presentation, and description of the participant sample. Where there were at least two investigations, meta-analysis was performed to obtain summary (pooled) prevalence estimates (SPEs) on (1) DS use prevalence by sport and sex, (2) DS use prevalence by elite versus non-elite athletic status, and (3) specific DS prevalence for all athletic groups combined. Meta-analyses included evaluations of homogeneity and publication bias. RESULTS: A total of 159 unique studies met the review criteria. Methodological quality was generally low with an average +/- standard deviation of 43 +/- 16% of available rating points. There was low homogeneity for SPEs when compiled by sport, athletic status, and/or specific DSs. Contributing to the lack of homogeneity were differences in studies' objectives and types of assessments used (e.g., dietary surveys, interviews, questionnaires). Despite these limitations, the data generally indicated that elite athletes used DSs much more than their non-elite counterparts. For most DSs, use prevalence was similar for men and women except that a larger proportion of women used iron while a larger proportion of men used vitamin E, protein, and creatine. No consistent change in use over time was observed because even the earliest investigations showed relatively high use prevalence. CONCLUSION: It was difficult to generalize regarding DS use by athletes because of the lack of homogeneity among studies. Nonetheless, the data suggested that elite athletes used dietary supplements far more than their non-elite counterparts; use was similar for men and women with a few exceptions; use appeared to change little over time; and a larger proportion of athletes used DSs compared with the general US population. Improvements in study methodology should be considered in future studies especially (1) defining DSs for participants; (2) querying for very specific DSs; (3) using a variety of reporting timeframes (e.g., daily, 2-6 times/week, 1 time/week and <1 time/week); (4) reporting the sampling frame, number of individuals solicited, and number responding; (5) reporting characteristics of volunteers (and non-volunteers, if available); and (6) using similar methods on several occasions to examine possible temporal trends among athletes. PMID- 26442918 TI - Investigating sesquiterpene biosynthesis in Ginkgo biloba: molecular cloning and functional characterization of (E,E)-farnesol and alpha-bisabolene synthases. AB - Ginkgo biloba is one of the oldest living tree species and has been extensively investigated as a source of bioactive natural compounds, including bioactive flavonoids, diterpene lactones, terpenoids and polysaccharides which accumulate in foliar tissues. Despite this chemical diversity, relatively few enzymes associated with any biosynthetic pathway from ginkgo have been characterized to date. In the present work, predicted transcripts potentially encoding enzymes associated with the biosynthesis of diterpenoid and terpenoid compounds, including putative terpene synthases, were first identified by mining publicly available G. biloba RNA-seq data sets. Recombinant enzyme studies with two of the TPS-like sequences led to the identification of GbTPS1 and GbTPS2, encoding farnesol and bisabolene synthases, respectively. Additionally, the phylogenetic analysis revealed the two terpene synthase genes as primitive genes that might have evolved from an ancestral diterpene synthase. PMID- 26442919 TI - New Pointers for Surgical Staging of Borderline Ovarian Tumors. AB - BACKGROUND: Surgical management of borderline ovarian tumors (BOTs) is similar to that of ovarian cancer apart from lymphadenectomy. However, the complete procedure including peritoneal washing, infracolic omentectomy and random peritoneal biopsies remains a subject of controversy especially in presumed early stage BOTs. To evaluate the prognostic value of complete surgical staging on recurrence rates, recurrence free (RFS) and overall survival (OS) in a multicentre cohort of BOTs. METHODS: This retrospective multicentre study included 428 patients with BOTs diagnosed from January 1980 to December 2008. Survival estimates were based on Kaplan-Meier calculations and RFS defined as the time from the date of surgery to the date of recurrence. RESULTS: The median time of follow-up was 94.9 months (range: 60.00-207.3). The overall recurrence rate was 23.8 %. There was no difference in 5-year RFS between patients with and without complete surgical staging 78.1 % (95 % CI 68.9-88.6) and 70.9 % (95 % CI 64.6-77.8), (p = 0.0806). In the whole cohort, 5-year OS was higher for patients with complete surgical staging 98.4 % (95 % CI 96.8-1.0) and 93.8 % (95 % CI 88.1 1), (p = 0.0182) but this difference was not significant for patients with FIGO stage I 98.6 % (95 % CI 96.7-1) and 92.7 % (95 % CI 83.4-1.0), p = 0.1275, respectively. CONCLUSIONS: Complete staging surgery should be considered as a cornerstone treatment for patients with advanced stage BOT but not for those with stage I disease. PMID- 26442920 TI - Clinicopathological Features and Outcome of Lung Cancer Patients with Hematological Malignancy. AB - PURPOSE: The aim of this study was to report the incidence of lung cancer in patients with hematological malignancy (HM), as well as patient characteristics and outcome. METHODS: We investigated 1503 consecutive patients treated for HM and 1208 patients who underwent surgical resection for lung cancer. RESULTS: Lung cancer with HM was observed in 12 patients (0.8 % of HM cases and 1.0 % of lung cancer cases), including eight men who were smokers and four women who had never smoked. The average Brinkman index was 1010, which suggested heavy smokers. In synchronous cases, all four patients preceded to HM treatment; however, three patients died from HM. In metachronous cases, during a mean 52.7 months after treatment of lung cancer, three patients had HM. At a mean 41.4 months after HM treatment, five patients had lung cancer and underwent surgery without serious postoperative events. CONCLUSIONS: A second cancer tended to be detected within 5 years after treatment of the first cancer. Men with a history of heavy smoking might be at risk for combined lung cancer and HM. Careful follow-up is recommended within 5 years after treatment of the first cancer. Most lung cancer detected synchronously with HM had poor prognosis. In metachronous cases, surgical resection of lung cancer after treatment of HM was feasible and safe. PMID- 26442921 TI - Predictors of Severe Morbidity After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Patients With Colorectal Peritoneal Carcinomatosis. AB - BACKGROUND: Severe morbidity after cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is, besides the obvious short term consequences, associated with impaired long-term outcomes. The risk factors for severe morbidity in patients with peritoneal carcinomatosis (PC) of colorectal origin are poorly defined. This study aimed to identify risk factors for severe morbidity after CRS + HIPEC in patients with colorectal PC. METHODS: Patients with colorectal PC who underwent CRS + HIPEC between 2007 and 2015 were categorized and compared between those with and those without severe morbidity. Risk factors were identified using logistic regression analysis. Morbidity was graded according to the Clavien-Dindo classification, with grade 3 or higher indicating severe morbidity. RESULTS: This study included 211 patients, of whom 53 patients (25.1%) experienced morbidity of grade 3 or higher. The identified risk factors for severe morbidity were extensive prior surgery [odds ratio (OR) 4.3], a positive recent smoking history (OR 4.0), a poor physical performance status (OR 2.9), and extensive cytoreduction (OR 1.2 per additional resection). Patients with a greater number of risk factors more often had severe morbidity and higher reoperation, readmission, and mortality rates. Furthermore, an internally validated preoperative prediction model for severe morbidity with an area under the curve of 70% was constructed. CONCLUSION: The current study identified risk factors for severe morbidity after CRS + HIPEC in patients with colorectal PC. Patients with a combination of risk factors have a substantial risk of severe morbidity and therefore should be carefully selected for CRS + HIPEC. The preoperative decision model can be a valuable additional tool in this process of patient selection. PMID- 26442922 TI - Acute Kidney Injury After Radical Cystectomy for Bladder Cancer is Associated with Chronic Kidney Disease and Mortality. AB - PURPOSE: The aim of this study was to investigate the prevalence of acute kidney injury (AKI) after radical cystectomy, and evaluate its impact on chronic kidney disease (CKD) and mortality. METHODS: The medical records of 866 patients who underwent radical cystectomy for bladder cancer were reviewed. AKI was assessed within 7 days after surgery according to the Acute Kidney Injury Network criteria. The prevalence of AKI after surgery was examined, and the significance of AKI for CKD and mortality was analyzed. RESULTS: Of 866 patients, 269 (31.1 %) developed AKI in the first week after surgery. Of these, 231 (85.9 %) were at stage 1, 32 (11.9 %) at stage 2, and 6 (2.2 %) at stage 3. Of 722 patients with a preoperative Modification of Diet in Renal Disease estimated glomerular filtration rate (eGFR) of >60 ml/min/1.73 m(2), CKD developed in 23.0 % (118/513) of patients in the non-AKI group and 32.5 % (68/209) of patients in the AKI group. Independent factors predicting new-onset CKD were a preoperative eGFR (p < 0.001), age (p = 0.011), urinary tract complication (p < 0.001) and AKI (p = 0.015). In all, 297 patients died (191 in the non-AKI group and 106 in the AKI group). AKI also correlated significantly with overall survival (p = 0.001). CONCLUSIONS: AKI is not only commonly encountered after radical cystectomy but is also associated with higher CKD rates and mortality. There is a critical need for strategies to increase the identification of patients at risk of postoperative AKI, and to improve the management of patients, with an aim toward preventing AKI and improving the treatment of AKI once it occurs. PMID- 26442923 TI - S-1 Adjuvant Chemotherapy Earlier After Surgery Clinically Correlates with Prognostic Factors for Advanced Gastric Cancer. AB - BACKGROUND: S-1 adjuvant chemotherapy is commonly administered postoperatively for stage II and III advanced gastric cancer. METHODS: This study included 113 patients treated with S-1 adjuvant chemotherapy after surgery for stage II and III advanced gastric cancer. These patients were divided into 4 groups: group A (n = 63), who had a longer duration (>=6 months) and earlier S-1 administration (<=6 weeks) after surgery; group B (n = 16), who had a longer and later S-1 administration (>6 weeks) after surgery; group C (n = 27), who had a shorter duration (<6 months) and earlier S-1 administration after surgery; and group D (n = 7), who had a shorter and later S-1 administration after surgery. RESULTS: The recurrence rates in groups A, B, C, and D were 15.7, 43.8, 44.4, and 57.1 %, respectively (A vs. B, p < 0.05, A vs. C and D, p < 0.01). The survival time of group A was significantly longer than that of other groups (p < 0.005). In addition, the survival time of patients with severe complications was significantly shorter than that of patients with non-severe complications (p < 0.05). An earlier S-1 administration after surgery was the only independent prognostic factor in the multivariate analysis. CONCLUSIONS: The prognosis of advanced gastric cancer was significantly related to the start of S-1 adjuvant treatment within 6 weeks after surgery. PMID- 26442924 TI - Influence of tumour stage at breast cancer detection on survival in modern times: population based study in 173,797 patients. AB - OBJECTIVES: To assess the influence of stage at breast cancer diagnosis, tumour biology, and treatment on survival in contemporary times of better (neo-)adjuvant systemic therapy. DESIGN: Prospective nationwide population based study. SETTING: Nationwide Netherlands Cancer Registry. PARTICIPANTS: Female patients with primary breast cancer diagnosed between 1999 and 2012 (n=173,797), subdivided into two time cohorts on the basis of breast cancer diagnosis: 1999-2005 (n=80,228) and 2006-12 (n=93,569). MAIN OUTCOME MEASURES: Relative survival was compared between the two cohorts. Influence of traditional prognostic factors on overall mortality was analysed with Cox regression for each cohort separately. RESULTS: Compared with 1999-2005, patients from 2006-12 had smaller (<= T1 65% (n=60,570) v 60% (n=48,031); P<0.001), more often lymph node negative (N0 68% (n=63,544) v 65% (n=52,238); P<0.001) tumours, but they received more chemotherapy, hormonal therapy, and targeted therapy (neo-adjuvant/adjuvant systemic therapy 60% (n=56,402) v 53% (n=42,185); P<0.001). Median follow-up was 9.8 years for 1999-2005 and 3.9 years for 2006-12. The relative five year survival rate in 2006-12 was 96%, improved in all tumour and nodal stages compared with 1999-2005, and 100% in tumours <= 1 cm. In multivariable analyses adjusted for age and tumour type, overall mortality was decreased by surgery (especially breast conserving), radiotherapy, and systemic therapies. Mortality increased with progressing tumour size in both cohorts (2006-12 T1c v T1a: hazard ratio 1.54, 95% confidence interval 1.33 to 1.78), but without a significant difference in invasive breast cancers until 1 cm (2006-12 T1b v T1a: hazard ratio 1.04, 0.88 to 1.22), and independently with progressing number of positive lymph nodes (2006-12 N1 v N0: 1.25, 1.17 to 1.32). CONCLUSIONS: Tumour stage at diagnosis of breast cancer still influences overall survival significantly in the current era of effective systemic therapy. Diagnosis of breast cancer at an early tumour stage remains vital. PMID- 26442926 TI - Variations of body composition, physical activity and caloric intake in schoolchildren during national holidays. AB - Scientific literature has described that a significant body weight increase in schoolchildren occurs during some holiday periods (summer, winter, and thanksgiving holidays), harming their health. In this regard, it is thought that this phenomenon is mainly due to changes in eating habits and the variation in levels of physical activity; however, this approach has not yet been explored during national holidays (NAH) in Chile. PURPOSE: To determine any changes in body composition, physical activity and caloric intake during NAH. METHODS: A total of 46 schoolchildren (24 boys, age 10.5 +/- 0.5; BMI 21.7 +/- 4.7) participated. Measurements were performed 2 days before and after the NAH (9 days). Weight was measured and fat percentage was established using the Slaughter formula. Levels of physical activity were measured with accelerometers, validating 3 weekdays and 1 weekend; caloric intake was established through a 24 h recall. RESULTS: Weight, percentage of fat and caloric intake increased significantly (250 g, 2.2 % and 733.3 kcal, respectively; p < 0.05); however, none of the variables of physical activity showed significant changes. CONCLUSION: The change in caloric intake seems to be the main cause of weight and fat gain during the NAH. PMID- 26442925 TI - CD1A-positive cells and HSP60 (HSPD1) levels in keratoacanthoma and squamous cell carcinoma. AB - CD1a is involved in presentation to the immune system of lipid antigen derived from tumor cells with subsequent T cell activation. Hsp60 is a molecular chaperone implicated in carcinogenesis by, for instance, modulating the immune reaction against the tumor. We have previously postulated a synergism between CD1a and Hsp60 as a key factor in the activation of an effective antitumor immune response in squamous epithelia. Keratoacantomas (KAs) are benign tumors that however can transform into squamous cell carcinomas (SCCs), but the reasons for this malignization are unknown. In a previous study, we found that CD1a-positive cells are significantly more numerous in KA than in SCC. In this study, we analyzed a series of KAs and SCCs by immunohistochemistry for CD1a and Hsp60. Our results show that the levels of both are significantly lower in KA than in SCC and support the hypothesis that KA may evolve towards SCC if there is a failure of the local modulation of the antitumor immune response. The data also show that immunohistochemistry for CD1a and Hsp60 can be of help in differential diagnosis between KAs and well-differentiated forms of SCC. PMID- 26442927 TI - Individual and Joint Associations of Methylenetetrahydrofolate Reductase C677T Genotype and Plasma Homocysteine With Dyslipidemia in a Chinese Population With Hypertension. AB - We aimed to examine the cross-sectional associations of plasma total homocysteine (tHcy) concentrations and methylenetetrahydrofolate reductase ( MTHFR) C677T genotype with dyslipidemia. A total of 231 patients with mild-to-moderate essential hypertension were enrolled from the Huoqiu and Yuexi communities in Anhui Province, China. Plasma tHcy levels were measured by high-performance liquid chromatography. Genotyping was performed by TaqMan allelic discrimination technique. Compared with MTHFR 677 CC + CT genotype carriers, TT genotype carriers had higher odds of hypercholesterolemia (adjusted odds ratio [OR] [95% confidence interval (CI)]: 2.7 [1.4-5.2]; P = .004) and higher odds of abnormal low-density lipoprotein cholesterol (adjusted OR [95% CI]: 2.3 [1.1-4.8]; P = .030). The individuals with the TT genotype had higher concentrations of log(tHcy) than those with the 677 CC + CT genotype (adjusted beta [standard error]: .2 [0.03]; P < .001). Patients with tHcy >= 10 MUmol/L had significantly higher odds of hypercholesterolemia (adjusted OR [95% CI]: 2.4 [1.2-4.7]; P = .010). Furthermore, patients with both the TT genotype and the tHcy >= 10 MUmol/L had the highest odds of hypercholesterolemia (adjusted OR [95% CI]: 4.1 [1.8 9.4]; P = .001) and low-density lipoprotein cholesterol (adjusted OR [95% CI]: 2.4 [1.0-6.0]; P = .064). This study suggests that both tHcy and the MTHFR C677T gene polymorphism may be important determinants of the incidence of dyslipidemia in Chinese patients with essential hypertension. Further studies are needed to confirm the role of tHcy and the MTHFR C677T mutation in the development of dyslipidemia in a larger sample. PMID- 26442929 TI - Prevalence of primary headache disorders diagnosed according to ICHD-3 beta in three different social groups. AB - BACKGROUND: The aim of our study was to estimate the one-year prevalence of primary headache disorders in three different social groups using the third edition beta of the International Classification of Headache Disorders (ICHD-3 beta). MATERIAL AND METHODS: The study population included a total of 3124 participants: 1042 students (719 females, 323 males, mean age 20.6, age range 17 40), 1075 workers (146 females, 929 males, mean age 40.4, age range 21-67) and 1007 blood donors (484 females, 523 males, mean age 34.1, age range 18-64). We used a semi-structured, validated face-to-face interview. RESULTS: The age adjusted one-year prevalence of migraine in females was significantly higher (p < 0.001) in students (41.9%) than in workers (19.2%) and blood donors (18.7%). Age adjusted prevalence of migraine among males did not differ among the three groups: 4.5% in students, 4.9% in workers and 4.5% in blood donors. Age-adjusted prevalence of tension-type headache (TTH) among females was almost the same in students and blood donors (68.8% and 66.7%) but female workers had a lower prevalence of TTH (57%). Age-adjusted prevalence of TTH among males did not differ significantly between students and blood donors (55.8% and 58.1%) but male workers had a significantly lower (p < 0.001) prevalence of TTH (30.7%). The prevalence of chronic headache in students (TTH and/or migraine) was 3% and of probable medication-overuse headache 3%, significantly more than in workers and blood donors. CONCLUSION: Headache prevalence was high and differed markedly among the three social groups. It is important that headache epidemiology also focus on socially defined groups in order to target future preventive efforts. PMID- 26442928 TI - Trends in colorectal cancer mortality in Europe: retrospective analysis of the WHO mortality database. AB - OBJECTIVE: To examine changes in colorectal cancer mortality in 34 European countries between 1970 and 2011. DESIGN: Retrospective trend analysis. DATA SOURCE: World Health Organization mortality database. POPULATION: Deaths from colorectal cancer between 1970 and 2011. Profound changes in screening and treatment efficiency took place after 1988; therefore, particular attention was paid to the evolution of colorectal cancer mortality in the subsequent period. MAIN OUTCOMES MEASURES: Time trends in rates of colorectal cancer mortality, using joinpoint regression analysis. Rates were age adjusted using the standard European population. RESULTS: From 1989 to 2011, colorectal cancer mortality increased by a median of 6.0% for men and decreased by a median of 14.7% for women in the 34 European countries. Reductions in colorectal cancer mortality of more than 25% in men and 30% in women occurred in Austria, Switzerland, Germany, the United Kingdom, Belgium, the Czech Republic, Luxembourg, and Ireland. By contrast, mortality rates fell by less than 17% in the Netherlands and Sweden for both sexes. Over the same period, smaller or no declines occurred in most central European countries. Substantial mortality increases occurred in Croatia, the former Yugoslav republic of Macedonia, and Romania for both sexes and in most eastern European countries for men. In countries with decreasing mortality, reductions were more important for women of all ages and men younger than 65 years. In the 27 European Union member states, colorectal cancer mortality fell by 13.0% in men and 27.0% in women, compared with corresponding reductions of 39.8% and 38.8% in the United States. CONCLUSION: Over the past 40 years, there has been considerable disparity in the level of colorectal cancer mortality between European countries, as well as between men and women and age categories. Countries with the largest reductions in colorectal cancer mortality are characterised by better accessibility to screening services, especially endoscopic screening, and specialised care. PMID- 26442930 TI - Lateral inhibition in the somatosensory cortex during and between migraine without aura attacks: Correlations with thalamocortical activity and clinical features. AB - BACKGROUND: We studied lateral inhibition in the somatosensory cortex of migraineurs during and between attacks, and searched for correlations with thalamocortical activity and clinical features. PARTICIPANTS AND METHODS: Somatosensory evoked potentials (SSEP) were obtained by electrical stimulation of the right median (M) or ulnar (U) nerves at the wrist or by simultaneous stimulation of both nerves (MU) in 41 migraine without aura patients, 24 between (MO), 17 during attacks, and in 17 healthy volunteers (HVs). We determined the percentage of lateral inhibition of the N20-P25 component by using the formula [(100)-MU/(M + U)*100]. We also studied high-frequency oscillations (HFOs) reflecting thalamocortical activation. RESULTS: In migraine, both lateral inhibition (MO 27.9% vs HVs 40.2%; p = 0.009) and thalamocortical activity (MO 0.5 vs HVs 0.7; p = 0.02) were reduced between attacks, but not during. In MO patients, the percentage of lateral inhibition negatively correlated with days elapsed since the last migraine attack (r = -0.510, p = 0.01), monthly attack duration (r = -0.469, p = 0.02) and severity (r = -0.443, p = 0.03), but positively with thalamocortical activity (r = -0.463, p = 0.02). CONCLUSIONS: We hypothesize that abnormal migraine cycle-dependent dynamics of connectivity between subcortical and cortical excitation/inhibition networks may contribute to clinical features of MO and recurrence of attacks. PMID- 26442931 TI - Direct DNA Lesion Reversal and Excision Repair in Escherichia coli. AB - Cellular DNA is constantly challenged by various endogenous and exogenous genotoxic factors that inevitably lead to DNA damage: structural and chemical modifications of primary DNA sequence. These DNA lesions are either cytotoxic, because they block DNA replication and transcription, or mutagenic due to the miscoding nature of the DNA modifications, or both, and are believed to contribute to cell lethality and mutagenesis. Studies on DNA repair in Escherichia coli spearheaded formulation of principal strategies to counteract DNA damage and mutagenesis, such as: direct lesion reversal, DNA excision repair, mismatch and recombinational repair and genotoxic stress signalling pathways. These DNA repair pathways are universal among cellular organisms. Mechanistic principles used for each repair strategies are fundamentally different. Direct lesion reversal removes DNA damage without need for excision and de novo DNA synthesis, whereas DNA excision repair that includes pathways such as base excision, nucleotide excision, alternative excision and mismatch repair, proceeds through phosphodiester bond breakage, de novo DNA synthesis and ligation. Cell signalling systems, such as adaptive and oxidative stress responses, although not DNA repair pathways per se, are nevertheless essential to counteract DNA damage and mutagenesis. The present review focuses on the nature of DNA damage, direct lesion reversal, DNA excision repair pathways and adaptive and oxidative stress responses in E. coli. PMID- 26442932 TI - An Introduction to the Structure and Function of the Ribosome. AB - E. coli continues to serve as a key model for the structure and function of the ribosome, structures of ribosome from other organisms and domains of life have also greatly contributed to our knowledge of protein synthesis. Many structural models of the ribosome in a number of steps of the protein synthesis cycle have been solved by cryo-electron microscopy (cryo-EM) and x-ray crystallography. This chapter introduces the structure and dynamics of the ribosome based on these structures and ends with a brief discussion of the many questions that the structures leave unanswered. Protein synthesis is a multistep process, and the structural features of the ribosome along with the large number of cofactors reflect the complexity of translation. Numerous protein factors in addition to the ribosome contribute to translation in bacteria during the steps of initiation, elongation, termination, and recycling. These protein factors make intimate contacts to key regions of the ribosome, and this aspect is discussed in the chapter in light of our present understanding of the structure and function of the ribosome. The intact ribosome contains three binding sites for substrate tRNAs that are termed as the aminoacyl-tRNA site (A site), peptidyl-tRNA site (P site), and exit-tRNA site (E site). These three binding sites span the interface between the 30S and 50S subunits. The central activity of the ribosome is catalysis of peptide bond formation. The region of the ribosome responsible for catalyzing the reaction is called the peptidyl transferase center (PTC). PMID- 26442934 TI - Nus Factors of Escherichia coli. AB - The highly conserved Nus factors of bacteria were discovered as essential host proteins for the growth of temperate phage lambda in Escherichia coli. Later, their essentiality and functions in transcription, translation, and, more recently, in DNA repair have been elucidated. Close involvement of these factors in various gene networks and circuits is also emerging from recent genomic studies. We have described a detailed overview of their biochemistry, structures, and various cellular functions, as well as their interactions with other macromolecules. Towards the end, we have envisaged different uncharted areas of studies with these factors, including their participation in pathogenicity. PMID- 26442933 TI - The EcoCyc Database. AB - EcoCyc is a bioinformatics database available at EcoCyc.org that describes the genome and the biochemical machinery of Escherichia coli K-12 MG1655. The long term goal of the project is to describe the complete molecular catalog of the E. coli cell, as well as the functions of each of its molecular parts, to facilitate a system-level understanding of E. coli. EcoCyc is an electronic reference source for E. coli biologists and for biologists who work with related microorganisms. The database includes information pages on each E. coli gene, metabolite, reaction, operon, and metabolic pathway. The database also includes information on E. coli gene essentiality and on nutrient conditions that do or do not support the growth of E. coli. The website and downloadable software contain tools for analysis of high-throughput data sets. In addition, a steady-state metabolic flux model is generated from each new version of EcoCyc. The model can predict metabolic flux rates, nutrient uptake rates, and growth rates for different gene knockouts and nutrient conditions. This review provides a detailed description of the data content of EcoCyc and of the procedures by which this content is generated. PMID- 26442935 TI - Glycogen: Biosynthesis and Regulation. AB - Glycogen accumulation occurs in Escherichia coli and Salmonella enterica serovar Typhimurium as well as in many other bacteria. Glycogen will be formed when there is an excess of carbon under conditions in which growth is limited because of the lack of a growth nutrient, e.g., a nitrogen source. This review describes the enzymatic reactions involved in glycogen synthesis and the allosteric regulation of the first enzyme, ADP-glucose pyrophosphorylase. The properties of the enzymes involved in glycogen synthesis, ADP-glucose pyrophosphorylase, glycogen synthase, and branching enzyme are also characterized. The data describing the genetic regulation of the glycogen synthesis are also presented. An alternate pathway for glycogen synthesis in mycobacteria is also described. PMID- 26442936 TI - Cell-to-Cell Signaling in Escherichia coli and Salmonella. AB - Bacteria must be able to respond rapidly to changes in the environment to survive. One means of coordinating gene expression relies on tightly regulated and complex signaling systems. One of the first signaling systems that was described in detail is quorum sensing (QS). During QS, a bacterial cell produces and secretes a signaling molecule called an autoinducer (AI). As the density of the bacterial population increases, so does the concentration of secreted AI molecules, thereby allowing a bacterial species to coordinate gene expression based on population density. Subsequent studies have demonstrated that bacteria are also able to detect signal molecules produced by other species of bacteria as well as hormones produced by their mammalian hosts. This type of signaling interaction has been termed cell-to-cell signaling because it does not rely on a threshold concentration of bacterial cells. This review discusses the three main types of cell-to-cell signaling mechanisms used by Escherichia coli and Salmonella: the LuxR process, in which E. coli and Salmonella detect signals produced by other species of bacteria; the LuxS/AI-2 system, in which E. coli and Salmonella participate in intra- and interspecies signaling; and the AI 3/epinephrine/norepinephrine system, in which E. coli and Salmonella recognize self-produced AI, signal produced by other microbes, and/or the human stress hormones epinephrine and/or norepinephrine. PMID- 26442937 TI - Transfer RNA Modification: Presence, Synthesis, and Function. AB - Transfer RNA (tRNA) from all organisms on this planet contains modified nucleosides, which are derivatives of the four major nucleosides. tRNA from Escherichia coli/Salmonella enterica serovar Typhimurium contains 33 different modified nucleosides, which are all, except one (Queuosine [Q]), synthesized on an oligonucleotide precursor, which by specific enzymes later matures into tRNA. The structural genes for these enzymes are found in mono- and polycistronic operons, the latter of which have a complex transcription and translation pattern. The synthesis of the tRNA-modifying enzymes is not regulated similarly, and it is not coordinated to that of their substrate, the tRNA. The synthesis of some of them (e.g., several methylated derivatives) is catalyzed by one enzyme, which is position and base specific, whereas synthesis of some has a very complex biosynthetic pathway involving several enzymes (e.g., 2-thiouridines, N 6 cyclicthreonyladenosine [ct6A], and Q). Several of the modified nucleosides are essential for viability (e.g., lysidin, ct6A, 1-methylguanosine), whereas the deficiency of others induces severe growth defects. However, some have no or only a small effect on growth at laboratory conditions. Modified nucleosides that are present in the anticodon loop or stem have a fundamental influence on the efficiency of charging the tRNA, reading cognate codons, and preventing missense and frameshift errors. Those that are present in the body of the tRNA primarily have a stabilizing effect on the tRNA. Thus, the ubiquitous presence of these modified nucleosides plays a pivotal role in the function of the tRNA by their influence on the stability and activity of the tRNA. PMID- 26442939 TI - Escherich and Escherichia. AB - The purpose of this essay is threefold: to give an outline of the life and the various achievements of Theodor Escherich, to provide a background to his discovery of what he called Bacterium coli commune (now Escherichia coli), and to indicate the enormous impact of studies with this organism, long before it became the cornerstone of research in bacteriology and in molecular biology. PMID- 26442941 TI - The Aerobic and Anaerobic Respiratory Chain of Escherichia coli and Salmonella enterica: Enzymes and Energetics. AB - Escherichia coli contains a versatile respiratory chain that oxidizes 10 different electron donor substrates and transfers the electrons to terminal reductases or oxidases for the reduction of six different electron acceptors. Salmonella is able to use two more electron acceptors. The variation is further increased by the presence of isoenzymes for some substrates. A large number of respiratory pathways can be established by combining different electron donors and acceptors. The respiratory dehydrogenases use quinones as the electron acceptors that are oxidized by the terminal reductase and oxidases. The enzymes vary largely with respect to their composition, architecture, membrane topology, and the mode of energy conservation. Most of the energy-conserving dehydrogenases (FdnGHI, HyaABC, HybCOAB, and others) and the terminal reductases (CydAB, NarGHI, and others) form a proton potential (Deltap) by a redox-loop mechanism. Two enzymes (NuoA-N and CyoABCD) couple the redox energy to proton translocation by proton pumping. A large number of dehydrogenases and terminal reductases do not conserve the redox energy in a proton potential. For most of the respiratory enzymes, the mechanism of proton potential generation is known or can be predicted. The H+/2e- ratios for most respiratory chains are in the range from 2 to 6 H+/2e-. The energetics of the individual redox reactions and the respiratory chains is described and related to the H+/2e- ratios. PMID- 26442938 TI - DNA Methylation. AB - The DNA of Escherichia coli contains 19,120 6-methyladenines and 12,045 5 methylcytosines in addition to the four regular bases, and these are formed by the postreplicative action of three DNA methyltransferases. The majority of the methylated bases are formed by the Dam and Dcm methyltransferases encoded by the dam (DNA adenine methyltransferase) and dcm (DNA cytosine methyltransferase) genes. Although not essential, Dam methylation is important for strand discrimination during the repair of replication errors, controlling the frequency of initiation of chromosome replication at oriC, and the regulation of transcription initiation at promoters containing GATC sequences. In contrast, there is no known function for Dcm methylation, although Dcm recognition sites constitute sequence motifs for Very Short Patch repair of T/G base mismatches. In certain bacteria (e.g., Vibrio cholerae, Caulobacter crescentus) adenine methylation is essential, and, in C. crescentus, it is important for temporal gene expression, which, in turn, is required for coordinating chromosome initiation, replication, and division. In practical terms, Dam and Dcm methylation can inhibit restriction enzyme cleavage, decrease transformation frequency in certain bacteria, and decrease the stability of short direct repeats and are necessary for site-directed mutagenesis and to probe eukaryotic structure and function. PMID- 26442942 TI - Analysis of Altered Micro RNA Expression Profiles in Focal Cortical Dysplasia IIB. AB - Focal cortical dysplasia type IIB is a commonly encountered subtype of developmental malformation of the cerebral cortex and is often associated with pharmacoresistant epilepsy. In this study, to investigate the molecular etiology of focal cortical dysplasia type IIB, the authors performed micro ribonucleic acid (RNA) microarray on surgical specimens from 5 children (2 female and 3 male, mean age was 73.4 months, range 50-112 months) diagnosed of focal cortical dysplasia type IIB and matched normal tissue adjacent to the lesion. In all, 24 micro RNAs were differentially expressed in focal cortical dysplasia type IIB, and the microarray results were validated using quantitative real-time polymerase chain reaction (PCR). Then the putative target genes of the differentially expressed micro RNAs were identified by bioinformatics analysis. Moreover, biological significance of the target genes was evaluated by investigating the pathways in which the genes were enriched, and the Hippo signaling pathway was proposed to be highly related with the pathogenesis of focal cortical dysplasia type IIB. PMID- 26442940 TI - Biotin and Lipoic Acid: Synthesis, Attachment, and Regulation. AB - Two vitamins, biotin and lipoic acid, are essential in all three domains of life. Both coenzymes function only when covalently attached to key metabolic enzymes. There they act as "swinging arms" that shuttle intermediates between two active sites (= covalent substrate channeling) of key metabolic enzymes. Although biotin was discovered over 100 years ago and lipoic acid 60 years ago, it was not known how either coenzyme is made until recently. In Escherichia coli the synthetic pathways for both coenzymes have now been worked out for the first time. The late steps of biotin synthesis, those involved in assembling the fused rings, were well described biochemically years ago, although recent progress has been made on the BioB reaction, the last step of the pathway in which the biotin sulfur moiety is inserted. In contrast, the early steps of biotin synthesis, assembly of the fatty acid-like "arm" of biotin were unknown. It has now been demonstrated that the arm is made by using disguised substrates to gain entry into the fatty acid synthesis pathway followed by removal of the disguise when the proper chain length is attained. The BioC methyltransferase is responsible for introducing the disguise, and the BioH esterase is responsible for its removal. In contrast to biotin, which is attached to its cognate proteins as a finished molecule, lipoic acid is assembled on its cognate proteins. An octanoyl moiety is transferred from the octanoyl acyl carrier protein of fatty acid synthesis to a specific lysine residue of a cognate protein by the LipB octanoyltransferase followed by sulfur insertion at carbons C-6 and C-8 by the LipA lipoyl synthetase. Assembly on the cognate proteins regulates the amount of lipoic acid synthesized, and, thus, there is no transcriptional control of the synthetic genes. In contrast, transcriptional control of the biotin synthetic genes is wielded by a remarkably sophisticated, yet simple, system, exerted through BirA, a dual-function protein that both represses biotin operon transcription and ligates biotin to its cognate proteins. PMID- 26442943 TI - A relationship between spinal new bone formation in ankylosing spondylitis and the sonographically determined Achilles tendon enthesophytes. AB - Spinal new bone formation is a major but incompletely understood manifestation of ankylosing spondylitis (AS). We explored the relationship between spinal new bone formation and ultrasound (US)-determined Achilles enthesophytes to test the hypothesis that spinal new bone formation is part of a generalized enthesis bone forming phenotype. A multicenter, case control study of 225 consecutive AS patients and 95 age/body mass index (BMI) matched healthy controls (HC) was performed. US scans of Achilles tendons and cervical and lumbar spine radiographs were obtained. All images were centrally scored by one investigator for US and one for radiographs, blinded to medical data. The relation between syndesmophytes (by modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) and the number of syndesmophytes) and enthesophytes (with a semi-quantitative scoring of the US findings) was investigated. AS patients had significantly higher US enthesophyte scores than HCs (2.1(1.6) vs. 1.6(1.6); p = 0.004). The difference was significant in males (p = 0.001) but not in females (p = 0.5). The enthesophyte scores significantly correlated with mSASSS scores (rho = 0.274, p < 0.0001) with the association even stronger in males (enthesophyte scores vs. mSASSS rho = 0.337, p < 0.0001). In multiple regression analysis, age, BMI, enthesophyte scores and disease duration were significantly associated with syndesmophytes in males, and keeping all other variables constant, increasing US enthesophyte scores increased the odds of having syndesmophytes by 67%. Male AS patients that have more severe US-determined Achilles enthesophyte also associated spinal syndesmophytes suggesting a bone-forming gender-specific phenotype that could be a useful marker predicting of new bone formation. PMID- 26442945 TI - Erotomania and Recommendations for Treatment. AB - The aim of this paper is to help clinicians better understand how erotomania originates in order to facilitate treatment and make it more effective. Data sources are the narratives of six women who spoke in detail about the beginnings of their delusional beliefs and about the nature of the evidence that convinced them that their beliefs were well-founded. In every case, low self-esteem and emotional arousal preceded the emergence of the delusion. Misperceptions and misattributions appeared responsible for keeping the delusion alive. Despite external disconfirmation, social isolation protected the delusional beliefs from revision and extinction. The erotomanic delusion provided a sense of well-being that probably contributed to its maintenance. As well, a delusion-induced boost in well-being delayed help-seeking. Recommendations for treatment include staged interventions, first establishing a therapeutic alliance with a focus on understanding the psychological factors contributing to the origin and maintenance of the delusion. The next stage is the provision of social support and strategies directed at the restoration of self-esteem. The third stage is the gradual introduction of techniques to correct cognitive biases. Medication and risk management form an integral part of overall management. Objective evidence for the effectiveness of this approach is, however, not yet available. PMID- 26442944 TI - Comorbid Personality Disorders in Obsessive-Compulsive Disorder and Its Symptom Dimensions. AB - The current paper was aimed at: (1) investigating the comorbidity between obsessive-compulsive disorder (OCD) and personality disorders (PDs) using an OCD sample and clinician-administered structured interviews; (2) exploring the associations of different cluster comorbid PDs with the specific symptom dimensions of OCD; (3) analyzing the variables which could play a significant role in the probability of having at least one comorbid PD, controlling for confounding variables. The SCID-II and Y-BOCS, together with a series of self report measures of OCD, depression and anxiety symptoms were administered to a clinical sample of 159 patients with a primary diagnosis of OCD. 20.8 % of the participants suffered from at least one comorbid PD; the most common was obsessive-compulsive PD (9.4 %), followed by narcissistic PD (6.3 %). In OCD patients with comorbid cluster C PDs, the percentage of responsibility for harm, injury, or bad luck symptoms was significantly greater than other OCD symptom dimensions (p < .005). Logistic regression found some evidence supporting the association between severity of OCD symptoms and comorbid PDs. PDs are prevalent among Italian people with OCD and should be routinely assessed, as comorbidity may affect help-seeking behaviour and response to treatment. PMID- 26442946 TI - Structural and Chemical Analysis of the Zirconia-Veneering Ceramic Interface. AB - The interfacial interaction of veneering ceramic with zirconia is still not fully understood. This study aimed to characterize morphologically and chemically the zirconia-veneering ceramic interface. Three zirconia-veneering conditions were investigated: 1) zirconia-veneering ceramic fired on sandblasted zirconia, 2) zirconia-veneering ceramic on as-sintered zirconia, and 3) alumina-veneering ceramic (lower coefficient of thermal expansion [CTE]) on as-sintered zirconia. Polished cross-sectioned ceramic-veneered zirconia specimens were examined using field emission gun scanning electron microscopy (Feg-SEM). In addition, argon-ion thinned zirconia-veneering ceramic interface cross sections were examined using scanning transmission electron microscopy (STEM)-energy dispersive X-ray spectrometry (EDS) at high resolution. Finally, the zirconia-veneering ceramic interface was quantitatively analyzed for tetragonal-to-monoclinic phase transformation and residual stress using micro-Raman spectroscopy (uRaman). Feg SEM revealed tight interfaces for all 3 veneering conditions. High-resolution transmission electron microscopy (HRTEM) disclosed an approximately 1.0-um transformed zone at sandblasted zirconia, in which distinct zirconia grains were no longer observable. Straight grain boundaries and angular grain corners were detected up to the interface of zirconia- and alumina-veneering ceramic with as sintered zirconia. EDS mapping disclosed within the zirconia-veneering ceramic a few nanometers thick calcium/aluminum-rich layer, touching the as-sintered zirconia base, with an equally thick silicon-rich/aluminum-poor layer on top. uRaman revealed t-ZrO2-to-m-ZrO2 phase transformation and residual compressive stress at the sandblasted zirconia surface. The difference in CTE between zirconia- and the alumina-veneering ceramic resulted in residual tensile stress within the zirconia immediately adjacent to its interface with the veneering ceramic. The rather minor chemical elemental shifts recorded in the veneering ceramic did not suffice to draw definitive conclusions regarding potential chemical interaction of the veneering ceramic with zirconia. Sandblasting damaged the zirconia surface and induced phase transformation that also resulted in residual compressive stress. Difference in CTE of zirconia versus that of the veneering ceramic resulted in an unfavorable residual tensile stress at the zirconia-veneering ceramic interface. PMID- 26442947 TI - Effect of Industry Sponsorship on Dental Restorative Trials. AB - Industry sponsorship was found to potentially introduce bias into clinical trials. We assessed the effects of industry sponsorship on the design, comparator choice, and findings of randomized controlled trials on dental restorative materials. A systematic review was performed via MEDLINE, CENTRAL, and EMBASE. Randomized trials on dental restorative and adhesive materials published 2005 to 2015 were included. The design of sponsored and nonsponsored trials was compared statistically (risk of bias, treatment indication, setting, transferability, sample size). Comparator choice and network geometry of sponsored and nonsponsored trials were assessed via network analysis. Material performance rankings in different trial types were estimated via Bayesian network meta analysis. Overall, 114 studies were included (15,321 restorations in 5,232 patients). We found 21 and 41 (18% and 36%) trials being clearly or possibly industry sponsored, respectively. Trial design of sponsored and nonsponsored trials did not significantly differ for most assessed items. Sponsored trials evaluated restorations of load-bearing cavities significantly more often than nonsponsored trials, had longer follow-up periods, and showed significantly increased risk of detection bias. Regardless of sponsorship status, comparisons were mainly performed within material classes. The proportion of trials comparing against gold standard restorative or adhesive materials did not differ between trial types. If ranked for performance according to the need to re-treat (best: least re-treatments), most material combinations were ranked similarly in sponsored and nonsponsored trials. The effect of industry sponsorship on dental restorative trials seems limited. PMID- 26442948 TI - Neutrophil Extracellular Traps in Periodontitis: A Web of Intrigue. AB - Neutrophil extracellular traps (NETs) represent a novel paradigm in neutrophil mediated immunity. NETs are believed to constitute a highly conserved antimicrobial strategy comprising decondensed nuclear DNA and associated histones that are extruded into the extracellular space. Associated with the web-like strands of DNA is an array of antimicrobial peptides (AMPs), which facilitate the extracellular destruction of microorganisms that become entrapped within the NETs. NETs can be released by cells that remain viable or following a unique form of programmed cell death known as NETosis, which is dependent on the production of reactive oxygen species (ROS) and the decondensing of the nuclear DNA catalyzed by peptidyl arginine deiminase-4. NETs are produced in response to a range of pathogens, including bacteria, viruses, fungi, and protozoa, as well as host-derived mediators. NET release is, however, not without cost, as the concomitant release of cytotoxic molecules can also cause host tissue damage. This is evidenced by a number of immune-mediated diseases, in which excess or dysfunctional NET production, bacterial NET evasion, and decreased NET removal are associated with disease pathogenesis. Periodontitis is the most prevalent infectious-inflammatory disease of humans, characterized by a dysregulated neutrophilic response to specific bacterial species within the subgingival plaque biofilm. Neutrophils are the predominant inflammatory cell involved in periodontitis and have previously been found to exhibit hyperactivity and hyperreactivity in terms of ROS production in chronic periodontitis patients. However, the contribution of ROS-dependent NET formation to periodontal health or disease remains unclear. In this focused review, we discuss the mechanisms, stimuli, and requirements for NET production; the ability of NET-DNA and NET associated AMPs to entrap and kill pathogens; and the potential immunogenicity of NETs in disease. We also speculate on the potential role of NETs in the pathogenesis of periodontitis. PMID- 26442949 TI - Root and Eruption Defects in c-Fos Mice Are Driven by Loss of Osteoclasts. AB - c-Fos homozygous mice lack osteoclasts with a failure of the teeth to erupt and with an arrest of root development. Here, we characterize the defects associated with the failure in root development and the loss of the tooth-bone interface, and we investigate the underlying causes. We show that, while homozygous c-Fos mice have no multinucleated osteoclasts, heterozygous mice have a reduction in the number of osteoclasts with a reduction in the tooth-bone interface during development and subtle skeletal defects postnatally. In the homozygous mutants bone is found to penetrate the tooth, particularly at the apical end, physically disrupting the root forming HERS (Hertwig's epithelial root sheath) cells. The cells of the HERS continue to proliferate but cannot extend downward due to the presence of bone, leading to a loss of root formation. Tooth germ culture showed that the developing tooth invaded the static bone in mutant tissue, rather than the bone encroaching on the tooth. Although c-Fos has been shown to be expressed in developing teeth, the defect in maintenance of the tooth-bone interface appears to be driven solely by the lack of osteoclasts, as this defect can be rescued in the presence of donor osteoclasts. The rescue suggests that signals from the tooth recruit osteoclasts to clear the bone from around the tooth, allowing the tooth to grow, form roots, and later erupt. PMID- 26442950 TI - The Microbiome in Populations with a Low and High Prevalence of Caries. AB - The oral microbiota was compared between Romanian adolescents with a high prevalence of caries and no dental care and Swedish caries-active and caries-free adolescents in caries prevention programs and with a low prevalence of caries. Biofilm samples were analyzed by FLX+ pyrosequencing of the V1 to V4 hypervariable regions of the 16S rRNA gene and polymerase chain reaction (PCR)/quantitative PCR (qPCR) for Streptococcus mutans and Streptococcus sobrinus. Sequences obtained blasted to 9 phyla, 66 genera, and 401 human oral taxa (HOT) in the 16S rRNA Human Oral Microbiome Database, of which 295 were represented by >=20 sequences. The Romanian adolescents had more sequences in Firmicutes and fewer in Actinobacteria phyla and more sequences in the genera Bacteroidetes [G-3], Porphyromonas, Abiotrophia, Filifactor, Peptostreptococcaceae [11][G-4], Pseudoramibacter, Streptococcus, and Neisseria and fewer in Actinomyces, Selenomonas, Veillonella, Campylobacter, and TM7 [G-1] than the Swedish groups. Multivariate modeling employing HOT, S. sobrinus and S. mutans (PCR/qPCR), and sugar snacks separated Romanian from Swedish adolescents. The Romanian adolescents' microbiota was characterized by a panel of streptococci, including S. mutans, S. sobrinus, and Streptococcus australis, and Alloprevotella, Leptotrichia, Neisseria, Porphyromonas, and Prevotella. The Swedish adolescents were characterized by sweet snacks, and those with caries activity were also characterized by Prevotella, Actinomyces, and Capnocytophaga species and those free of caries by Actinomyces, Prevotella, Selenomonas, Streptococcus, and Mycoplasma. Eight species including Streptococcus mitis and Streptococcus species HOT070 were prevalent in Romanian and Swedish caries-active subjects but not caries-free subjects. In conclusion, S. mutans and S. sobrinus correlated with Romanian adolescents with caries and with limited access to dental care, whereas S. mutans and S. sobrinus were detected infrequently in Swedish adolescents in dental care programs. Swedish caries-active adolescents were typically colonized by Actinomyces, Selenomonas, Prevotella, and Capnocytophaga. Hence, the role of mutans streptococci as a primary caries pathogen appears less pronounced in populations with prevention programs compared to populations lacking caries treatment and prevention strategies. PMID- 26442952 TI - Predictors of Posttraumatic Stress Symptoms Among Adolescent and Young Adult Survivors of Childhood Cancer: Importance of Monitoring Survivors' Experiences of Family Functioning. AB - The purpose of this study was to identify factors associated with posttraumatic stress symptoms (PTSS) among Japanese long-term childhood cancer survivors (CCSs). Subjects comprised 185 adolescent and young adult (AYA) CCSs who completed anonymous self-report questionnaires. Attending physicians also completed an anonymous disease/treatment data sheet. Mean age of survivors was approximately 8 years at diagnosis and 23 years at participation. Multiple regression analysis showed that family functioning, satisfaction with social support, being female, and interactions between family functioning and gender and age at the time of diagnosis were associated with PTSS among survivors. This study revealed family functioning as the most predictive factor of PTSS among AYA CCSs in Japan. Even when the survivor may have unchangeable risk factors, family functioning can potentially moderate the effects on PTSS. Thus, it is crucial for health professionals to carefully monitor and attend to survivors' experiences of family functioning to mitigate PTSS. PMID- 26442951 TI - Clinical Implications of Additional Pedal Artery Angioplasty in Critical Limb Ischemia Patients With Infrapopliteal and Pedal Artery Disease. AB - PURPOSE: To evaluate the clinical implications of additional pedal artery angioplasty (PAA) for patients with critical limb ischemia (CLI). METHODS: Twenty nine patients (mean age 77.8+/-8.6 years; 21 men) with CLI (32 limbs) presenting with de novo infrapopliteal and pedal artery (Kawarada type 2/3) disease were reviewed. The need for PAA was based on the existence of sufficient wound blush (WB) around the target wounds after conventional above-the-ankle revascularization. Fourteen patients with insufficient WB in 14 limbs received additional PAA, while 15 patients with sufficient WB in 18 limbs did not. The groups were compared for overall survival, limb salvage, and amputation-free survival within 1 year after the procedure. The wound healing rate, time to wound healing, and freedom from reintervention rate were also evaluated. RESULT: The success rate of additional PAA was 93% (13/14). All limbs with successful PAA achieved sufficient WB (13/13). Despite insufficient WB before the additional PAA, overall survival (86% vs 73%, p=0.350), limb salvage (93% vs 83%, p=0.400), amputation-free survival (79% vs 53%, p=0.102), and freedom from reintervention (64% vs 73%, p=0.668) rates were similar in both groups. Furthermore, the wound healing rate (93% vs 60%, p=0.05) was higher and time to wound healing (86.0+/ 18.7 vs 152.0+/-60.2 days, p=0.05) was shorter in the patients who received PAA. CONCLUSION: Additional PAA might improve the WB and clinical outcomes (especially speed and extent of wound healing) in patients with CLI attributed to infrapopliteal and pedal artery disease. PMID- 26442954 TI - Beliefs of Palestinian Women From Israel About the Responsibility and Punishment of Violent Husbands and About Helping Battered Women. AB - This article presents a study that examined beliefs about violent husbands and about helping battered women among Palestinian women living in Israel from the perspective of patriarchal ideology. A convenience sample of 701 married women was obtained, and a self-report questionnaire was administered. The findings reveal that the majority of participants held violent husbands accountable for their behavior; however, the majority of them did not support punishing violent husbands through formal agencies (i.e., the police) or through informal social institutions (i.e., the family). In addition, contrary to expectations, the majority of women perceived wife beating as a social problem rather than as a private one that should be dealt with within the family. Regression and multiple regression analysis revealed that women's endorsement of patriarchal ideology was found to influence all three above-mentioned beliefs about violent husbands and battered women, over and above the amount of variance in each of these beliefs that could be attributed to the women's sociodemographic characteristics. The limitations of the study and its implications for future research are discussed. PMID- 26442953 TI - SPINT2 Deregulation in Prostate Carcinoma. AB - SPINT2 is a tumor suppressor gene that inhibits proteases implicated in cancer progression, like HGFA, hepsin and matriptase. Loss of SPINT2 expression in tumors has been associated with gene promoter hypermethylation; however, little is known about the mechanisms of SPINT2 deregulation in prostate cancer (PCa). We aimed to analyze SPINT2 expression levels and understand the possible regulation by SPINT2 promoter hypermethylation in PCa. In a cohort of 57 cases including non neoplastic and PCa tissues, SPINT2 expression and promoter methylation was analyzed by immunohistochemistry and methylation-specific PCR, respectively. Methylation status of the SPINT2 promoter was also evaluated by bisulfite sequencing and 5-aza-2'-deoxycytidine treatment. Oncomine and TCGA databases were used to perform in silico PCa analysis of SPINT2 mRNA and methylation levels. A reduction in SPINT2 expression levels from non-neoplastic to PCa tissues was observed; however, none of the cases exhibited SPINT2 promoter methylation. Both bisulfite sequencing and 5-aza demonstrated that SPINT2 promoter is not methylated in PCa cells. Bioinformatics approaches did not show downregulation of SPINT2 at the mRNA level and, in corroboration with our results, SPINT2 promoter region is reported to be unmethylated. Our study suggests an involvement of SPINT2 in PCa tumorigenesis, probably in association with a post-translational regulation of SPINT2. PMID- 26442955 TI - Elder Abuse in a Developing Area in Bolivia. AB - In many parts of the world, elder abuse happens almost unnoticed. Until recently, this serious social problem was hidden from public view and was regarded as an essentially private matter. However, there is growing evidence that elder abuse is an important problem of public health and in the society. The objective of this study is to determine the degree of abuse of elder and vulnerable people in the families and communities of Eastern Bolivia. With this end in mind, we conducted a cross-sectional descriptive study with a sample size of 210 60-year old people coming from different health care areas. Elder Abuse Suspicion Index (EASI) and Yaffe's Evaluation Form of Social Work were used. An abuse rate of 39% of the older adults was identified. The most common type of abuse observed was psychological abuse (32.4% of cases), followed by neglect (21.9%). Children were identified as triggers of the abuse in 66.7% of cases of abuse. The prevalence of elder abuse was similar to the prevalence of other types of abuse that exist in Bolivia, such as the gender-based abuse. Also, this prevalence is comparable to other developing countries and European countries. The profile of abused older adult is as follows: woman, widow, 70 years old, incomplete primary education, without an occupation, and an average of 4.59 children. The information obtained shows that dysfunctional families have a higher percentage of elder abuse. PMID- 26442956 TI - Lessons for Health From Insights into Environmental Crises. AB - The health of whole populations within nations and globally and the implications of climate change are two of the most important challenges facing humanity in the 21st century. Both are components of a complex global crisis that must be acknowledged and addressed. Here we draw the attention of health professionals to some emerging threats and insights from key works of environmentalists in the hope that these may catalyze reflection on the broader challenges facing human health at a time of deep planetary malaise. PMID- 26442957 TI - Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin. AB - The 30-item revised Mystical Experience Questionnaire (MEQ30) was previously developed within an online survey of mystical-type experiences occasioned by psilocybin-containing mushrooms. The rated experiences occurred on average eight years before completion of the questionnaire. The current paper validates the MEQ30 using data from experimental studies with controlled doses of psilocybin. Data were pooled and analyzed from five laboratory experiments in which participants (n=184) received a moderate to high oral dose of psilocybin (at least 20 mg/70 kg). Results of confirmatory factor analysis demonstrate the reliability and internal validity of the MEQ30. Structural equation models demonstrate the external and convergent validity of the MEQ30 by showing that latent variable scores on the MEQ30 positively predict persisting change in attitudes, behavior, and well-being attributed to experiences with psilocybin while controlling for the contribution of the participant-rated intensity of drug effects. These findings support the use of the MEQ30 as an efficient measure of individual mystical experiences. A method to score a "complete mystical experience" that was used in previous versions of the mystical experience questionnaire is validated in the MEQ30, and a stand-alone version of the MEQ30 is provided for use in future research. PMID- 26442958 TI - Cognitive Rest: An Integrated Literature Review. AB - Cognitive rest has been suggested as a treatment for school athletes who have sustained a concussion, but the concept has rarely been defined. The purpose of this article is to provide a comprehensive definition of cognitive rest, based on an integrative literature review. The method of synthesis was guided by Avant and Walker's concept analysis format. The importance of rest is discussed as a nursing intervention, and model cases are presented to clarify the concept. Three defining attributes of cognitive rest are established: freedom from physical or mental discomfort, abstinence from mental exertion, and mental and emotional balance. Empirical referents are given as well as a suggested protocol to enable school nurses to form cognitive rest and return-to-classroom protocols that can be adapted to individual school settings. PMID- 26442959 TI - Does nutritional counseling in telemedicine improve treatment outcomes for diabetes? A systematic review and meta-analysis of results from 92 studies. AB - BACKGROUND: A growing number of studies and reviews have documented the impact of telemedicine on diabetes management. However, no meta-analysis has assessed whether including nutritional counseling as part of a telemedicine program has a significant impact on diabetes outcomes or what kind of nutritional counseling is most effective. METHODS: Original research articles examining the effect of telemedicine interventions on HbA1c levels in patients with Type 1 or Type 2 diabetes were included in this study. A literature search was performed and 92 studies were retained for analysis. We examined stratified results by differentiating interventions using no nutritional counseling from those that used nutritional counseling. We further compared between nutritional counseling administered via short message systems (SMS) such as email and text messages, and nutritional counseling administered via telephone or videoconference. RESULTS: Telemedicine programs that include a nutritional component show similar effect in diabetes management as those programs that do not. Furthermore, subgroup analysis reveals that nutritional intervention via SMS such as email and text messages is at least as equally effective in reducing HbA1c when compared to personal nutritional counseling with a practitioner over videoconference or telephone. CONCLUSION: The inclusion of nutritional counseling as part of a telemedicine program does not make a significant difference to diabetes outcomes. Incorporating nutritional counseling into telemedicine programs via SMS is at least as effective as counseling via telephone or videoconference. PMID- 26442960 TI - Understanding catalysis in a multiphasic two-dimensional transition metal dichalcogenide. AB - Establishing processing-structure-property relationships for monolayer materials is crucial for a range of applications spanning optics, catalysis, electronics and energy. Presently, for molybdenum disulfide, a promising catalyst for artificial photosynthesis, considerable debate surrounds the structure/property relationships of its various allotropes. Here we unambiguously solve the structure of molybdenum disulfide monolayers using high-resolution transmission electron microscopy supported by density functional theory and show lithium intercalation to direct a preferential transformation of the basal plane from 2H (trigonal prismatic) to 1T' (clustered Mo). These changes alter the energetics of molybdenum disulfide interactions with hydrogen (DeltaG(H)), and, with respect to catalysis, the 1T' transformation renders the normally inert basal plane amenable towards hydrogen adsorption and hydrogen evolution. Indeed, we show basal plane activation of 1T' molybdenum disulfide and a lowering of DeltaG(H) from +1.6 eV for 2H to +0.18 eV for 1T', comparable to 2H molybdenum disulfide edges on Au(111), one of the most active hydrogen evolution catalysts known. PMID- 26442961 TI - Differential roles of dopamine D1 and D2 receptor-containing neurons of the nucleus accumbens shell in behavioral sensitization. AB - The nucleus accumbens (Nac) mediates the reinforcing and motor stimulating properties of psychostimulants. It receives dopaminergic afferents from the ventral midbrain and is divided into two distinct subregions: shell and core. Each of these contains two subtypes of medium spiny neurons, which express either dopamine D1 (D1R) or D2 (D2R) receptors. However, functional dissociation between the two subtypes in psychostimulant response remains to be elucidated. We performed selective ablation of each subtype in the Nac shell in mice, using immunotoxin-mediated cell targeting, and examined the behavioral sensitization evoked by repeated administration of methamphetamine. The D1R cell-ablated mice exhibited delayed induction of sensitized locomotion compared to control mice, whereas the D2R cell-ablated mice showed a mildly enhanced rate of induction of sensitization. In vivo microdialysis revealed a marked blockade of the increase in extracellular dopamine in the Nac of the D1R cell-ablated animals in response to methamphetamine, indicating that the observed delay in behavioral sensitization in these mice involves an impairment in accumbal dopamine release. Our results reveal differential roles of D1R- and D2R-containing accumbal shell neurons in the development of behavioral sensitization to psychostimulants. Behavioral sensitization, enhanced motility by repetitive psychostimulant administration, is a model of drug addiction. Here, we show that the nucleus accumbens (Nac) shell neurons containing dopamine D1 receptor (D1R) or D2 receptor (D2R) play distinct roles in behavioral sensitization triggered by methamphetamine, and that D1R-containing neurons enhance the induction of behavioral sensitization at the early phase, whereas D2R-containing neurons act to suppress the rate of development of the behavior. PMID- 26442962 TI - Monitoring breast tumor progression by photoacoustic measurements: a xenograft mice model study. AB - The current study reports the photoacoustic spectroscopy-based assessment of breast tumor progression in a nude mice xenograft model. The tumor was induced through subcutaneous injection of MCF-7 cells in female nude mice and was monitored for 20 days until the tumor volume reached 1000 mm3. The tumor tissues were extracted at three different time points (days 10, 15, and 20) after tumor inoculation and subjected to photoacoustic spectral recordings in time domain ex vivo at 281 nm pulsed laser excitations. The spectra were converted into the frequency domain using the fast Fourier transformed tools of MATLAB(r) algorithms and further utilized to extract seven statistical features (mean, median, area under the curve, variance and standard deviation, skewness and kurtosis) from each time point sample to assess the tumor growth with wavelet principal component analysis based logistic regression analysis performed on the data. The prediction accuracies of the analysis for day 10 versus day 15, day 15 versus day 20, and day 10 versus day 20 were found to be 92.31, 87.5, and 95.2%, respectively. Also, receiver operator characteristics area under the curve analysis for day 10 versus day 15, day 15 versus day 20, and day 10 versus day 20 were found to be 0.95, 0.85, and 0.93, respectively. The ability of photoacoustic measurements in the objective assessment of tumor progression has been clearly demonstrated, indicating its clinical potential. PMID- 26442963 TI - Laser line illumination scheme allowing the reduction of background signal and the correction of absorption heterogeneities effects for fluorescence reflectance imaging. AB - Intraoperative fluorescence imaging in reflectance geometry is an attractive imaging modality as it allows to noninvasively monitor the fluorescence targeted tumors located below the tissue surface. Some drawbacks of this technique are the background fluorescence decreasing the contrast and absorption heterogeneities leading to misinterpretations concerning fluorescence concentrations. We propose a correction technique based on a laser line scanning illumination scheme. We scan the medium with the laser line and acquire, at each position of the line, both fluorescence and excitation images. We then use the finding that there is a relationship between the excitation intensity profile and the background fluorescence one to predict the amount of signal to subtract from the fluorescence images to get a better contrast. As the light absorption information is contained both in fluorescence and excitation images, this method also permits us to correct the effects of absorption heterogeneities. This technique has been validated on simulations and experimentally. Fluorescent inclusions are observed in several configurations at depths ranging from 1 mm to 1 cm. Results obtained with this technique are compared with those obtained with a classical wide-field detection scheme for contrast enhancement and with the fluorescence by an excitation ratio approach for absorption correction. PMID- 26442965 TI - Atrial myxomas and different clinical presentations. PMID- 26442964 TI - ScbR- and ScbR2-mediated signal transduction networks coordinate complex physiological responses in Streptomyces coelicolor. AB - In model organism Streptomyces coelicolor, gamma-butyrolactones (GBLs) and antibiotics were recognized as signalling molecules playing fundamental roles in intra- and interspecies communications. To dissect the GBL and antibiotic signalling networks systematically, the in vivo targets of their respective receptors ScbR and ScbR2 were identified on a genome scale by ChIP-seq. These identified targets encompass many that are known to play important roles in diverse cellular processes (e.g. gap1, pyk2, afsK, nagE2, cdaR, cprA, cprB, absA1, actII-orf4, redZ, atrA, rpsL and sigR), and they formed regulatory cascades, sub-networks and feedforward loops to elaborately control key metabolite processes, including primary and secondary metabolism, morphological differentiation and stress response. Moreover, interplay among ScbR, ScbR2 and other regulators revealed intricate cross talks between signalling pathways triggered by GBLs, antibiotics, nutrient availability and stress. Our work provides a global view on the specific responses that could be triggered by GBL and antibiotic signals in S. coelicolor, among which the main echo was the change of production profile of endogenous antibiotics and antibiotic signals manifested a role to enhance bacterial stress tolerance as well, shedding new light on GBL and antibiotic signalling networks widespread among streptomycetes. PMID- 26442966 TI - Social Influence on Adolescent Polysubstance Use: The Escalation to Opioid Use. AB - BACKGROUND: Fewer than 9% of 12-17 year olds in need (~146,000 of 1.7 million) receive inpatient or outpatient substance abuse recovery services or other mental health services (SAMHSA, 2012). The literature on adolescent addiction is sparse, however, as most published addiction recovery efforts involve adult populations often college students. OBJECTIVES: The present study examined social influences on escalating substance use (from tobacco, alcohol, and marijuana use to polysubstance use involving opioids) for students enrolled in recovery high schools. METHODS: A sample of 31 adolescents enrolled in substance use recovery high schools were surveyed on their patterns of substance use leading to their abuse of opioids. RESULTS: Youth who begin their substance use as young as age 8 are often pressured by peer culture to do so and come from substance-using families. Their escalation in polysubstance use to a pattern including opioids was also most often attributed to peer influence over several years. Conclusions/Importance: This paper is one of scant few that address patterns of use in high school students. Perhaps most salient from this study are the tertiary prevention implications: similar to their adult counterparts, students enrolled in recovery high school programs are likely from substance-using families and have combined complex constellations of substances including opioids by dint of their relationships with substance-using peers. PMID- 26442968 TI - Formation of oligopeptides in high yield under simple programmable conditions. AB - Many high-yielding reactions for forming peptide bonds have been developed but these are complex, requiring activated amino-acid precursors and heterogeneous supports. Herein we demonstrate the programmable one-pot dehydration-hydration condensation of amino acids forming oligopeptide chains in around 50% yield. A digital recursive reactor system was developed to investigate this process, performing these reactions with control over parameters such as temperature, number of cycles, cycle duration, initial monomer concentration and initial pH. Glycine oligopeptides up to 20 amino acids long were formed with very high monomer-to-oligomer conversion, and the majority of these products comprised three amino acid residues or more. Having established the formation of glycine homo-oligopeptides, we then demonstrated the co-condensation of glycine with eight other amino acids (Ala, Asp, Glu, His, Lys, Pro, Thr and Val), incorporating a range of side-chain functionality. PMID- 26442967 TI - A PI3K p110beta-Rac signalling loop mediates Pten-loss-induced perturbation of haematopoiesis and leukaemogenesis. AB - The tumour suppressor PTEN, which antagonizes PI3K signalling, is frequently inactivated in haematologic malignancies. In mice, deletion of PTEN in haematopoietic stem cells (HSCs) causes perturbed haematopoiesis, myeloproliferative neoplasia (MPN) and leukaemia. Although the roles of the PI3K isoforms have been studied in PTEN-deficient tumours, their individual roles in PTEN-deficient HSCs are unknown. Here we show that when we delete PTEN in HSCs using the Mx1-Cre system, p110beta ablation prevents MPN, improves HSC function and suppresses leukaemia initiation. Pharmacologic inhibition of p110beta in PTEN deficient mice recapitulates these genetic findings, but suggests involvement of both Akt-dependent and -independent pathways. Further investigation reveals that a p110beta-Rac signalling loop plays a critical role in PTEN-deficient HSCs. Together, these data suggest that myeloid neoplasia driven by PTEN loss is dependent on p110beta via p110beta-Rac-positive-feedback loop, and that disruption of this loop may offer a new and effective therapeutic strategy for PTEN-deficient leukaemia. PMID- 26442969 TI - Oxidative Self-Polymerization of Dopamine in an Acidic Environment. AB - A weak alkaline condition (pH > 8) is a general requirement for oxidative self polymerization of dopamine. Here, we first demonstrated the generation of polydopamine in an acidic environment via a hydrothermal method. The pH scope of self-polymerization of dopamine is extended to pH ~ 1 in a hydrothermal process. Polydopamine generated via a hydrothermal method shows similar chemical features and radical scavenging activity with that generated in a basic environment. PMID- 26442970 TI - A phase II study of nab-paclitaxel plus carboplatin in combination with thoracic radiation in patients with locally advanced non-small-cell lung cancer. AB - We investigated the efficacy and safety of albumin-bound paclitaxel (nab-PTX) and carboplatin (CBDCA) with concurrent radiotherapy for unresectable locally advanced non-small-cell lung cancer (NSCLC). Patients with Stage III NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Concurrent chemoradiotherapy consisted of weekly administration of nab-PTX (40 mg/m(2)) plus CBDCA (area under the plasma concentration time curve (AUC) 2) and thoracic radiotherapy (60 Gy/30 fractions) for a total of 6 weeks. After concurrent chemoradiotherapy, patients received an additional two cycles of consolidation phase chemotherapy that consisted of 4-week cycles of nab-PTX (100 mg/m(2) on Days 1, 8 and 15)/CBDCA (AUC 5 mg/ml/min on Day 1). Response was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors. Progression-free survival and overall survival were estimated using the Kaplan Meier method. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events. A total of 10 patients were enrolled in this trial between September 2013 and January 2014 from three institutes. The overall response rate was 40.0% and the median progression-free survival was 6.7 months. Treatment-related death occurred in two patients. Grade 2 or worse severe radiation pneumonitis was observed in all three patients that had the volume of lung receiving at least 20 Gy (V20) >30%. The results of this study indicate that no further investigation is warranted into nab-PTX and CBDCA with concurrent thoracic radiation for Stage III NSCLC with V20 > 30% due to severe toxicity. PMID- 26442971 TI - Economic and Social Impact of Increasing Uptake of Cardiac Rehabilitation Services--A Cost Benefit Analysis. AB - BACKGROUND: Cardiac rehabilitation can reduce mortality, improve cardiac risk factor profile and reduce readmissions; yet uptake remains low at 30%. This research aims to investigate the social and economic impact of increasing the uptake of cardiac rehabilitation in Victoria, Australia using cost benefit analysis (CBA). METHODS: Cost benefit analysis has been undertaken over a 10-year period to analyse three scenarios: (1) Base Case: 30% uptake; (2) Scenario 1: 50% uptake; and (3) Scenario 2: 65% uptake. Impacts considered include cardiac rehabilitation program costs, direct inpatient costs, other healthcare costs, burden of disease, productivity losses, informal care costs and net deadweight loss. RESULTS: There is a net financial saving of $46.7-$86.7 million under the scenarios. Compared to the Base Case, an additional net benefit of $138.9-$227.2 million is expected. This results in a Benefit Cost Ratio of 5.6 and 6.8 for Scenarios 1 and 2 respectively. Disability Adjusted Life Years were 21,117-37,565 years lower than the Base Case. CONCLUSIONS: Greater uptake of cardiac rehabilitation can reduce the burden of disease, directly translating to benefits for society and the economy. This research supports the need for greater promotion, routine referral to be made standard practice and implementation of reforms to boost uptake. PMID- 26442973 TI - [Choosing the right medications in elderly patients with chronic kidney disease]. AB - With the aging of the population, the prevalence of chronic kidney disease (CKD) is increased. Measurement of glomerular filtration rate as a screening tool may over-diagnose CKD, especially when proteinuria is normal, but it can be very useful when considering drug metabolism. Renal dysfunction is a factor predisposing to potential adverse drug reactions, because drug can accumulate to toxic levels. In addition, some drugs are nephrotoxic and can more easily damage the kidneys in the elderly. Limited data are available on the risks of drugs in the elderly population with CKD. Drugs with no clear evidence-based indication, drugs with higher risks of adverse side effects compared to their benefits, and drugs which are not cost-effective, have been defined "potentially inappropriate medications" (PIMs). Even if criteria to evaluate PIMs and adverse drug reactions are available to clinical management, we strongly support the idea that the issue of PIMs in the elderly affected by CKD should be better studied and defined. The Italian website Slow Medicine, based on the US project "Choosing Wisely", opened a new strategy in this field, taking into consideration both economic issues and patients quality of life. The main goal of this initiative is avoiding wasteful or unnecessary medical tests, treatments and procedures. PMID- 26442974 TI - [Advance directives in Italy: a goal not yet reached but already passed?]. AB - The advance directives (ADs) have been adopted in many countries to defend patients' autonomy. In Italy, in the past, this topic gave rise to a heated debate involving philosophers, theologians, and politicians. In 2009, the government presented a bill of law on ADs firmly criticized from a scientific, moral and juridical point of view because the bill's content is against the principles of Italian Constitution, Italian Code of Medical Ethics, Oviedo Convention, and official statements of many scientific societies. Although the bill has passed the Low Chamber it lies, even since, in the Senate, lacking in regard any agreement among the political parties. The purpose of this article is to highlight that, in our country, patients, relatives and doctors deserve a law not only related to the specific topic of ADs, but - as in other European countries (Germany, Spain, France, UK) - aimed to deal with the complex issue of end of life care as a whole. This law should take into account the sound evidence existing in regard to the four fundamental principles supporting the best scientific and ethical approaches to the end of life issues: shared decision making process between doctors and patients/relatives; rejection of dying process marked by the suffering; withholding/withdrawing futile treatments together with palliative sedation as two crucial contributions to suppress the patient suffering and pain; clear-cut difference between these clinical/ethical options and euthanasia. At the same time, this law should be able to provide physicians with a legal coverage to make all the clinical and ethical decisions more and more complex because of the continuous evolution of medical science on one hand, and the impressive development of biotechnology on the other hand. PMID- 26442975 TI - [Clinical research evolution. In parallel with the current changes in welfare expectations and information technology incorporation, study designs and data collection and analysis are quickly changing as well]. AB - The development of both technology, biological, and clinical knowledge leads to remarkable changes of scientific research methodology, including the clinical research. Major changes deal with the pragmatic approach of trial designs, an explosive diffusion of observational research which is becoming a usual component of clinical practice, and an active modelling of new research design. Moreover, a new healthcare landscape could be generated from the information technology routinely used to collect clinical data in huge databases, the management and the analytic methodology of big data, and the development of biological sensors compatible with the daily life delivering signals remotely forwardable to central databases. Precision medicine and individualized medicine seem to be the big novelties of the coming years, guiding to a shared pattern of patient/physician relationship. In healthcare, a huge business related mainly, but not exclusively, to the implementation of information technology is growing. This development will favor radical changes in the health systems, also reshaping the clinical activity. A new governance of the research strategies is needed and the application of the results should be based on shared ethical foundations. This new evolving profile of medical research and practice is discussed in this paper. PMID- 26442976 TI - [Treatment of acute coronary syndrome in older adults and high-risk patients."When the going gets tough..."]. AB - The increasing life expectancy in older adults and the better survival of patients with multiple pathologies require the capability to treat complex clinical conditions with an increased risk of iatrogenic complications. Nevertheless, recent improvements in the pharmacological and interventional treatment of acute coronary syndrome (ACS) have promoted a shift from therapeutic nihilism to a more active management of complex ACS cases. Despite the paucity of specific randomized clinical trials, observational studies seem to show benefit of an early invasive treatment in these patients. This approach requires close cooperation of clinical intensivists, interventional cardiologists and cardiovascular surgeons either in a specialized heart center or in a network of hospitals. PMID- 26442977 TI - [Well ageing in the XXI century. Political, social and individual strategies]. AB - Population ageing is a triumph, but because to the tendency to the increase of the phenomenon in all countries of the globe, it is also a concern and a challenge for national governments and societies. Starting from the current picture in the States of European Union and the future predictions, it's provides an overview of the relationship between ageing and health, emphasizing some social, political and person-related aspects. In particular, it's examined the theoretical models, strategies and multilevel actions proposed to well-ageing and with dignity, focusing on the model of "active and healthy ageing" promoted in 2012 by the World Health Organization and the European Union. PMID- 26442979 TI - [In Process Citation]. PMID- 26442978 TI - [Direct and indirect costs associated with respiratory allergic diseases in Italy. A probabilistic cost of illness study]. AB - BACKGROUND: The respiratory allergies, including allergic rhinitis and allergic asthma, represent a substantial medical and economic burden worldwide. Despite their dimension and huge economic-social burden, no data are available on the costs associated with the management of respiratory allergic diseases in Italy. The objective of this study was to estimate the average annual cost incurred by the National Health Service (NHS), as well as society, due to respiratory allergies and their main co-morbidities in Italy. METHODS: A probabilistic prevalence-based cost of illness model was developed to estimate an aggregate measure of the economic burden associated with respiratory allergies and their main co-morbidities in terms of direct and indirect costs. A systematic literature review was performed in order to identify both the cost per case (expressed in present value) and the number of affected patients, by applying an incidence-based estimation method. Direct costs were estimated multiplying the hospitalization, drugs and management costs derived by the literature with the Italian epidemiological data. Indirect costs were calculated based on lost productivity according to the human capital approach. Furthermore, a one-way and probabilistic sensitivity analysis with 5,000 Monte Carlo simulations were performed, in order to test the robustness of the results and define the proper 95% Confidence Interval (CI). RESULTS: Overall, the total economic burden associated with respiratory allergies and their main co-morbidities was ? 7.33 billion (95% CI: ? 5.99-? 8.82). A percentage of 27.5% was associated with indirect costs (? 2.02; 95% CI: ? 1.72-? 2.34 billion) and 72.5% with direct costs (? 5.32; 95% CI: ? 4.04-? 6.77 billion). In allergic asthma, allergic rhinitis, combined allergic rhinitis and asthma, turbinate hypertrophy and allergic conjunctivitis, the model estimate an average annual economic burden of ? 1,35 (95% CI: ? 1,14-? 1,58) billion, ? 1,72 (95% CI: ? 1,14-? 2,43) billion, ? 1,62 billion (? 0,91-? 2,53) billion, ? 0,12 (? 0,07-? 0,17) billion, ? 0,46 (? 0,16-? 0,92) billion respectively. CONCLUSIONS: To our knowledge, this is the first study in which direct costs (incurred by NHS) and indirect ones (incurred by the society) were taken into account to estimate the overall burden associated with respiratory allergies and their main co-morbidities in our Country. In conclusion, this work may be considered an efficient tool for public decision makers to correctly understand the economic aspects involved by the management and treatment of respiratory allergies-induced diseases in Italy. PMID- 26442980 TI - [In Process Citation]. PMID- 26442982 TI - Effect of respiratory protector intervention among indium reclaiming workers. PMID- 26442981 TI - Stabilization of SIRT7 deacetylase by viral oncoprotein HBx leads to inhibition of growth restrictive RPS7 gene and facilitates cellular transformation. AB - Sirtuin-7 (SIRT7) deacetylase exhibits a high selectivity for acetylated H3K18 and has been implicated in the maintenance of malignant phenotype. However, it remains unclear if SIRT7 and H3K18ac play a role in the tumorigenic program driven by oncogenic viruses. We show that ectopically expressed HBx oncoprotein of hepatitis B virus promoted intracellular stability of SIRT7 by salvaging it from ubiquitin-mediated proteasomal degradation. HBx-dependent accumulation of SIRT7 favored H3K18 deacetylation and down-regulated the small ribosomal protein gene, RPS7, involved in cell death and DNA damage response. HBx facilitated the recruitment of SIRT7 to RPS7 promoter thus impeding H3K18ac occupancy and hindering RPS7 transcription. The antagonistic relationship between SIRT7 and RPS7 was also observed in the HBx transgenic mice, where elevated levels of SIRT7 protein were coincident with low levels of H3K18ac and RPS7. Strikingly, inhibition of cellular deubiquitinase activity restored RPS7 gene transcription. Further, depletion of endogenous SIRT7 led to decreased cell viability and transformation. The biological relevance of RPS7 suppression by HBx-SIRT7 axis was evident from ectopic expression of RPS7 which attenuated clonogenicity of cells. Thus, our findings suggest that SIRT7 is a critical regulator of HBx driven oncogenic program, through its antagonistic impact on growth restrictive ribosomal protein RPS7. PMID- 26442983 TI - Investigating the adduct formation of organic mercury species with carbonic anhydrase and hemoglobin from human red blood cell hemolysate by means of LC/ESI TOF-MS and LC/ICP-MS. AB - The interaction of mercury species with human erythrocytes is studied to investigate possible high molecular binding partners for mercury species. Human blood hemolysate was spiked with methylmercury and investigated by means of liquid chromatography (LC) coupled to electrospray ionization time of flight mass spectrometry (ESI-ToF-MS) and inductively coupled plasma mass spectrometry (ICP MS). Beside adduct formation of mercury species with hemoglobin, the main compound of the erythrocytes, mercury binding to the enzyme carbonic anhydrase was revealed. Due to an enzymatic digest of the protein-mercury adduct, the binding site at the free thiol group of the protein was identified. These results indicate that carbonic anhydrase might play a role in mercury toxicity. PMID- 26442984 TI - Individualised Versus Standardised Assessment of Quality of Life in Eating Disorders. AB - Individualised measures of quality of life (QoL) refer to instruments that encourage the respondent to actively elicit which areas of their life are most relevant for his/her QoL. The aim of this study is to compare individualised versus standard measures of QoL in a sample of patients with eating disorder (ED). The Schedule for the Evaluation of the Individual Quality of Life (SEIQoL) and a generic measure of QoL [World Health Organization Brief Quality of Life Assessment Scale (WHOQOL-BREF)] were applied on two occasions (one-year follow up) to a sample of 165 patients with ED, 57 recovered patients with ED, and 349 women from the general population. The areas of 'family', 'education/career or job', 'friends', 'leisure', 'romantic partner' and 'health' were identified as the most important for their QoL for all groups, both times. The WHOQOL-BREF was more sensitive than the SEIQoL in detecting changes that occurred over time. Clinical interventions for ED should consider social components as objectives of intervention. PMID- 26442985 TI - Greater support and debriefing may help student midwives to process traumatic birth experiences. PMID- 26442986 TI - Efficient Generation of Gene-Modified Pigs Harboring Precise Orthologous Human Mutation via CRISPR/Cas9-Induced Homology-Directed Repair in Zygotes. AB - Precise genetic mutation of model animals is highly valuable for functional investigation of human mutations. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9)-induced homology-directed repair (HDR) is usually used for precise genetic mutation, being limited by the relatively low efficiency compared with that of non-homologous end joining (NHEJ). Although inhibition of NHEJ was shown to enhance HDR-derived mutation, in this work, without inhibition of NHEJ, we first generated gene-modified pigs harboring precise orthologous human mutation (Sox10 c.A325>T) via CRISPR/Cas9 induced HDR in zygotes using single-strand oligo DNA (ssODN) as template with an efficiency as high as 80%, indicating that pig zygotes exhibited high activities of HDR relative to NHEJ and were highly amendable to genetic mutation via CIRSPR/Cas9-induced HDR. Besides, we found a higher concentration of ssODN remarkably reduced HDR-derived mutation in pig zygotes, suggesting a possible balance for optimal HDR-derived mutation in zygotes between the excessive accessibility to HDR templates and the activities of HDR relative to NHEJ which appeared to be negatively correlated to ssODN concentration. In addition, the HDR derived mutation, as well as those from NHEJ, extensively integrated into various tissues including gonad of founder pig without detected off-targeting, suggesting CRISPR/Cas9-induced HDR in zygotes is a reliable approach for precise genetic mutation in pigs. PMID- 26442987 TI - Asian Indians in America: The influence of values and culture on mental health. AB - Asian Indians represent a significant portion of the largest growing race of Asians in the past decade in the United States. This selective review examines major cultural themes related to first- and second-generation Asian Indians living in the United States as they impact psychological and psychiatric dysfunction in this population. Specifically, we review the impact of Asian Indian culture on mental health, discuss the impact of acculturation and ethnic identity development on the mental health of Indian-Americans, and focus on typical mental health problems of Asian Indian adolescents, women and elderly in America. Finally, we provide a brief overview of empirically-supported treatment approaches and cultural considerations for additional treatments relevant to this population. This review is intended to provide an important foundation for more systematic empirically-driven investigation into better understanding how Asian Indian cultural themes impact mental health for Indian-Americans, and how to develop effective treatments for these issues in this cultural group. PMID- 26442988 TI - Reliability, validity and factor structure of the CES-D in Iranian elderly. AB - OBJECTIVES: In developing countries such as Iran, elder populations are growing. Due to the high prevalence of depressive disorders among elders, reliable screening instruments for this population are required. The main purpose of this study was to determine the reliability and validity of the Farsi version of the Center for Epidemiological Studies-Depression Scale-10 (CES-D) among Iranian elderly persons. METHODS: The investigators created the Farsi version of the CES D-10 by translation and back translation. Two hundred and four cases aged 59 and above completed the questionnaire. The reliability and validity of the translated CES-D-10 was established through comparison with the Composite International Diagnostic Interview (CIDI), a recognized gold standard method for diagnosing major depressive disorder. We used a receiver operating curve (ROC) to determine the optimum cutoff score. RESULTS: The Farsi version of the CED-D-10 displayed acceptable psychometric characteristics, as reflected in internal consistency with Cronbach's alpha, split-half coefficients and test-retest reliability of 0.85, 0.65 and 0.49, respectively. Factor analysis and the varimax rotation resulted in two factors including 'depression' and 'interpersonal relationships'. The Depression factor (introduced as CES-D-8 of the scale) had significant correlation with the 10 items form (r=0.99) with 0.87 alpha coefficient. The ROC showed that the optimum cutoff point is 5 with sensitivity of 82% and specificity of 70%, and positive and negative predictive values of 26% and 98%, respectively, for both of the forms. CONCLUSION: Both the 10 and 8 items form of the Farsi version have desirable characteristics to be useful as a screening instrument for depressive disorders in Iranian elders, especially in urban areas. PMID- 26442989 TI - Reflections on attitudes, experiences, and vulnerability of intimate partner violence among Southeast Asian college women living in United States. AB - To provide culturally sensitive intimate partner violence (IPV) prevention programs for ethnic groups, a basic foundational understanding of Southeast Asian (SEA) women living in the United States is vital. The purpose of this study was to describe SEA college women's perceptions of IPV and how the women recognize their vulnerability to such violent situations. Qualitative methods using focus group discussions were employed to elicit participants' perceptions. Participants included 18 SEA college women, ages 18-34 (Mean=22; SD=7.22). Transcriptions were analyzed using a content analysis approach. Five themes emerged: recognition of IPV; perception of individual vulnerability to IPV; experience and responses to IPV; help seeking and support system; and strategies used for prevention of IPV. Findings yielded an understanding of intertwined issues of cultural norms associated with IPV, social and economic disparities, and challenges for IPV prevention in SEA communities. Culturally sensitive prevention programs will be more effective by reforming cultural values, while at the same time promoting non violent relationships and increasing access to services. PMID- 26442990 TI - Flavisolibacter ginsenosidimutans sp. nov., with ginsenoside-converting activity isolated from soil used for cultivating ginseng. AB - A Gram-reaction-negative, aerobic, non-motile and rod-shaped bacterial strain designated Gsoil 636T was isolated from soil of a ginseng cultivation field in Pocheon Province, South Korea and its taxonomic position was investigated using a polyphasic approach. Gsoil 636T grew at 18-30 degrees C and at pH 6.0-8.0 on R2A medium. Gsoil 636T possessed beta-glucosidase activity, which was responsible for its ability to transform ginsenoside Rb1 (ones of the dominant active components of ginseng) to F2. On the basis of 16S rRNA gene sequence similarity, Gsoil 636T was shown to belong to the family Chitinophagaceae and to be related to Flavisolibacter ginsengiterrae Gsoil 492T (96.7 % sequence similarity), Flavisolibacter ginsengisoli Gsoil 643T (96.6 %) and Flavisolibacter rigui 02SUJ3T (96.6 %). The G+C content of the genomic DNA was 48.9 %. The predominant respiratory quinone was MK-7 and the major fatty acids were iso-C15 : 0, summed feature 3 (comprising C16 : 1omega6c and/or C16 : 1omega7c) and iso-C17 : 0 3-OH. DNA and chemotaxonomic data supported the affiliation of Gsoil 636T to the genus Flavisolibacter. Gsoil 636T could be differentiated genotypically and phenotypically from the species of the genus Flavisolibacter with validly published names. The isolate therefore represents a novel species, for which the name Flavisolibacter ginsenosidimutans sp. nov. is proposed, with the type strain Gsoil 636T (KCTC 22818T = JCM 18197T = KACC 14277T). PMID- 26442991 TI - Severe Headache With Left Nasal Discharge: Is it Always Due to Autonomic Over Activity? PMID- 26442992 TI - Exposure to graphic warning labels on cigarette packages: Effects on implicit and explicit attitudes towards smoking among young adults. AB - OBJECTIVE: To test the effect of exposure to the US Food and Drug Administration's proposed graphic images with text warning statements for cigarette packages on implicit and explicit attitudes towards smoking. DESIGN AND METHODS: A two-session web-based study was conducted with 2192 young adults 18-25 years-old. During session one, demographics, smoking behaviour, and baseline implicit and explicit attitudes were assessed. Session two, completed on average 18 days later, contained random assignment to viewing one of three sets of cigarette packages, graphic images with text warnings, text warnings only, or current US Surgeon General's text warnings. Participants then completed post exposure measures of implicit and explicit attitudes. ANCOVAs tested the effect of condition on the outcomes, controlling for baseline attitudes. RESULTS: Smokers who viewed packages with graphic images plus text warnings demonstrated more negative implicit attitudes compared to smokers in the other conditions (p = .004). For the entire sample, explicit attitudes were more negative for those who viewed graphic images plus text warnings compared to those who viewed current US Surgeon General's text warnings (p = .014), but there was no difference compared to those who viewed text-only warnings. CONCLUSION: Graphic health warnings on cigarette packages can influence young adult smokers' implicit attitudes towards smoking. PMID- 26442993 TI - Reduction in Abeta-induced cell death in the hippocampus of 17beta-estradiol treated female rats is associated with an increase in IGF-I signaling and somatostatinergic tone. AB - Several studies indicate that 17beta-estradiol (E2) protects against amyloid beta peptide (Abeta)-induced cell death and activates factors associated with learning and memory, a function involving the hippocampal somatostatinergic system. As alterations in somatostatin have been demonstrated in Alzheimer's disease, we examined whether E2 prevents changes in the hippocampal somatostatinergic system induced by Abeta25-35 and cell death, as well as the possible involvement of leptin and insulin-like growth factor (IGF)-I signaling. We also measured the levels of Abeta proteases neprilysin and insulin-degrading-enzyme. Co administration of E2 with Abeta25-35 reduced both its levels and cell death, in addition to preventing the Abeta-induced depletion of some somatostatinergic parameters. Activation of leptin and IGF-I pathways increased after E2 co administration, and this correlated with changes in the somatostatinergic system. Changes in some components of this system were inversely related with Abeta levels and cell death. Moreover, neprilysin levels were increased only in Abeta plus E2-treated rats and E2 prevented the Abeta-induced insulin-degrading-enzyme reduction. Our results suggest that the E2-induced reduction in cell death is related to lower Abeta levels, probably because of IGF-I and somatostatin modulation of Abeta proteases. We asked how 17beta-estradiol (E2) protects against beta-amyloid (Abeta)-induced cell death. E2 co-administration prevents Abeta-produced depletion of hippocampal somatostatin (SRIF) by an IGF-I-mediated mechanism, being related this protective effect with an increase in Abeta proteases. Our results suggest that the E2-induced reduction in cell death is related to lower Abeta levels, probably because of SRIF modulation of Abeta proteases. CREB, cAMP response element-binding protein; IGF-I, insulin-like growth factor-I; STAT3, signal transducer and activator of transcription-3. PMID- 26442994 TI - Investigation of the magnetic properties in double perovskite R2CoMnO6 single crystals (R = rare earth: La to Lu). AB - We have successfully synthesized the series of the double-perovskite R2CoMnO6 (R = rare earth: La to Lu) single crystals and have investigated their magnetic properties. The ferromagnetic order of Co(2+)/Mn(4+) spins emerges mainly along the c axis. Upon decreasing the size of rare earth ion, the magnetic transition temperature decreases linearly from 204 K for La2CoMnO6 to 48 K for Lu2CoMnO6, along with the enhancement of monoclinic distortion. The temperature and magnetic field dependences of magnetization reveal the various magnetic characteristics such as the metamagnetic transition in R = Eu, the isotropic nature of rare earth moment in R = Gd, and the reversal of magnetic anisotropy in R = Tb and Dy. Our results offer comprehensive information for understanding the roles of mixed-valent magnetic ions and rare earth magnetic moments on the magnetic properties. PMID- 26442995 TI - Fusion with pep-1, a cell-penetrating peptide, enhances the transmembrane ability of human epidermal growth factor. AB - Administration of macromolecule compositions in medicine and cosmetics always exhibited low bioavailability due to the limitation of transmembrane transport. Here, human epidermal growth factor (hEGF) was fused with glutathione S transferase (GST) and Pep-1, the first commercial cell-penetrating peptide, in Escherichia coli. The fusion protein was firstly purified with the affinity chromatography, and then the GST tag was released by TEV protease. Final purification was achieved by the ion exchange chromatography. The biological activities and the transmembrane ability of the obtained products were determined using scratch wound-healing assay, MTT analysis, and immunofluorescence assay. The results showed that both rhEGF and Pep-1-fused hEGF were soluble expressed in E. coli. The fusion of Pep-1 could markedly increase the transmembrane ability of EGF, whereas it did not interfere with the growth-stimulating and migration promoting functions of hEGF on fibroblasts. This research provided a novel strategy for the transmembrane transport of protein-derived cosmetics or drugs. PMID- 26442997 TI - Curcumin enhances the activity of fluconazole against Cryptococcus gattii-induced cryptococcosis infection in mice. AB - AIM: The aim of this study was to investigate the in vitro and in vivo activities of pure curcumin, as well as its combination with fluconazole, against Cryptococcus gattii. METHODS AND RESULTS: The minimal inhibitory concentrations (MIC) of curcumin and its interactions with fluconazole against C. gattii were assessed in vitro using standard methods. This same combination was used to treat C. gattii-induced cryptococcosis in mice. The behavioural and functional assessment of the mice during treatment was also performed. The average MIC for curcumin was 19.8 MUg ml(-1) . Its combination with fluconazole resulted in FICSigma (fractional inhibitory concentration index) values between 0.79 and 2.29. Curcumin (alone or combined with fluconazole) significantly reduced pulmonary damage and fungal burden in the brain. No colonies were found in the brain following combination treatment, which was also confirmed by the improved behaviour of mice. CONCLUSIONS: The combination therapy with curcumin and fluconazole was the most effective among the treatments tested, as in addition to reducing the fungal burden and damage on lung tissues, it was able to eliminate the fungal burden in the brain, enhancing the survival of mice. SIGNIFICANCE AND IMPACT OF THE STUDY: This study points to the possibility of using curcumin in combination with fluconazole as a clinical treatment of cryptococcosis. PMID- 26442998 TI - Urinary 8-Hydroxy-2'-Deoxyguanosine: A Biomarker for Radiation-Induced Oxidative DNA Damage in Pediatric Cardiac Catheterization. AB - OBJECTIVE: To determine the utility of urinary 8-hydroxy-2'-deoxyguanosine (8 OHdG) as a sensitive biomarker for radiation-induced cellular DNA damage in children undergoing cardiac catheterization. STUDY DESIGN: We enrolled pediatric patients with congenital heart diseases requiring cardiac catheterization in conjunction with healthy children and children under sedation as control. Demographic, clinical, laboratory and invasive hemodynamic data, urinary 8-OHdG levels, and radiation exposure measurements were collected prospectively. RESULTS: Nineteen patients, 10 healthy children and 9 children under sedation, were studied. In 19 patients who underwent cardiac catheterization, the median level of 8-OHdG in urine obtained at 24-48 hours after the procedure was significantly higher than at baseline (44.0 vs 17.3 ng/mg creatinine, P = .0001). Furthermore, the urinary 8-OHdG level after the procedure increased in 18 of the 19 study subjects. In contrast, there was no significant difference in 8-OHdG levels between the 2 spot urine samples obtained at arbitrary intervals of 24-48 hours in 10 healthy children (P = .7213), and at baseline and 24-48 hours following echocardiography in 9 children under sedation (P = .1097). Stepwise multiple regression analysis revealed that the cumulative air kerma during the cardiac catheterization was the variable which was strongly and significantly associated with the ratio of post- to precardiac catheterization urinary 8-OHdG levels among the evaluated variables (R(2) = 0.7179, F = 11.0256, P = .0007). CONCLUSIONS: Urinary 8-OHdG could be a useful biomarker for radiation-induced cellular DNA damage in children undergoing diagnostic cardiac catheterization. PMID- 26443000 TI - Reliable Hydrogel with Mechanical "Fuse Link" in an Aqueous Environment. AB - A robust hydrogel with a reliable deformation region in an aqueous environment is proposed. The gel has a homogeneous network where hydrophilic/hydrophobic components are uniformly distributed. In an aqueous environment, aggregated hydrophobic segments serve as "mechanical fuse links," inhibiting sudden macroscopic fracture. The gel endures threefold stretching for more than 100 cycles in water without mechanical hysteresis. PMID- 26442999 TI - Enzyme-linked DNA dendrimer nanosensors for acetylcholine. AB - It is currently difficult to measure small dynamics of molecules in the brain with high spatial and temporal resolution while connecting them to the bigger picture of brain function. A step towards understanding the underlying neural networks of the brain is the ability to sense discrete changes of acetylcholine within a synapse. Here we show an efficient method for generating acetylcholine detecting nanosensors based on DNA dendrimer scaffolds that incorporate butyrylcholinesterase and fluorescein in a nanoscale arrangement. These nanosensors are selective for acetylcholine and reversibly respond to levels of acetylcholine in the neurophysiological range. This DNA dendrimer architecture has the potential to overcome current obstacles to sensing in the synaptic environment, including the nanoscale size constraints of the synapse and the ability to quantify the spatio-temporal fluctuations of neurotransmitter release. By combining the control of nanosensor architecture with the strategic placement of fluorescent reporters and enzymes, this novel nanosensor platform can facilitate the development of new selective imaging tools for neuroscience. PMID- 26443001 TI - Synthesis, fungicidal activity and structure-activity relationships of 3-benzoyl 4-hydroxylcoumarin derivatives. AB - BACKGROUND: To develop a coumarin-based fungicide, a series of 3-benzoyl-4 hydroxylcoumarin derivatives were synthesised and their fungicidal activities were evaluated against typical fungi occurring in Chinese agroecosystems. RESULTS: Target compounds were characterised through (1) H NMR, (13) C NMR and high-resolution mass spectrometry. The crystal structure of compound III-21 was determined through X-ray diffraction. Bioassay results indicated that most of the target compounds showed good growth inhibition against all of the fungi tested in vitro. EC50 of the target compounds against Physalospora piricola, Rhizoctonia cerealis, Sclerotinia sclerotiorum and Botrytis cinerea indicated that most of the target compounds displayed comparable activity with that of carbindazim and chlorothalonil in vitro. Among these compounds, the analogue 3-(2-bromo-4 chlorobenzoyl)-4-hydroxylcoumarin (III-21) displayed the optimum growth inhibition against R. cerealis (87.5%) and B. cinerea (82.7%) in vivo at 200 ug mL(-1) concentration; thus, this analogue is a potential inhibitor of pathogenic fungi and a new major compound for further optimisation. The results of analysing the structure-activity relationships demonstrated that changes in substituents on benzene ring A of 3-benzoyl-4-hydroxylcoumarin caused different fungicidal activities and provided original information on the preferential conformation to maintain high activities. CONCLUSION: The present work demonstrated that 3 benzoyl-4-hydroxylcoumarin derivatives can be used as possible major compounds to develop novel fungicides. (c) 2015 Society of Chemical Industry. PMID- 26443002 TI - Effect of music care on depression and behavioral problems in elderly people with dementia in Taiwan: a quasi-experimental, longitudinal study. AB - OBJECTIVES: The purpose was to examine the effectiveness of music care on cognitive function, depression, and behavioral problems among elderly people with dementia in long-term care facilities in Taiwan. METHODS: The study had a quasi experimental, longitudinal research design and used two groups of subjects. Subjects were not randomly assigned to experimental group (n = 90) or comparison group (n = 56). Based on Bandura's social cognition theory, subjects in the experimental group received Kagayashiki music care (KMC) twice per week for 24 weeks. Subjects in the comparison group were provided with activities as usual. RESULTS: Results found, using the control score of the Clifton Assessment Procedures for the Elderly Behavior Rating Scale (baseline) and time of attending KMC activities as a covariate, the two groups of subjects had statistically significant differences in the mini-mental state examination (MMSE). Results also showed that, using the control score of the Cornell Scale for Depression in Dementia (baseline) and MMSE (baseline) as a covariate, the two groups of subjects had statistically significant differences in the Clifton Assessment Procedures for the Elderly Behavior Rating Scale. CONCLUSION: These findings provide information for staff caregivers in long-term care facilities to develop a non-invasive care model for elderly people with dementia to deal with depression, anxiety, and behavioral problems. PMID- 26443003 TI - Vesicular trafficking mechanisms in endothelial cells as modulators of the tumor vasculature and targets of antiangiogenic therapies. AB - A common feature of solid tumors is their ability to incite the formation of new blood and lymph vessels trough the processes of angiogenesis and lymphangiogenesis, respectively, to support tumor growth and favor metastatic dissemination. As a result of the lack of feedback regulatory control mechanisms or due to the exacerbated presence of pro-angiogenic signals within the tumor microenvironment, the tumor endothelium receives continuous signals to sprout and develop, generating vessels that are structurally and functionally abnormal. An emerging mechanism playing a central role in shaping the tumor vasculature is the endothelial-vesicular network that regulates trafficking/export and degradation of key signaling proteins and membrane receptors, including the vascular endothelial growth-factor receptor-2/3 and members of the Notch pathway. Here we will discuss recent evidence highlighting how vesicular trafficking mechanisms in endothelial cells contribute to pathological angiogenesis/lymphangiogenesis and can provide novel and exploitable targets in antiangiogenic therapies. PMID- 26443004 TI - Interventions for hidradenitis suppurativa. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterised by recurrent painful boils in flexural sites, such as the axillae and groin, that affects about 1% of the population, with onset in early adulthood. OBJECTIVES: To assess the effects of interventions for HS in people of all ages. SEARCH METHODS: We searched the following databases up to 13 August 2015: the Cochrane Skin Group Specialised Register, CENTRAL in the Cochrane Library (Issue 7, 2015), MEDLINE (from 1946), EMBASE (from 1974), and LILACS (from 1982). We also searched five trials registers and handsearched the conference proceedings of eight dermatology meetings. We checked the reference lists of included and excluded studies for further references to relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) of all interventions for hidradenitis suppurativa. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility and methodological quality and performed data extraction. Our primary outcomes were quality of life, measured by a validated dermatology-specific scale, and adverse effects of the interventions. MAIN RESULTS: Twelve trials, with 615 participants, met our inclusion criteria. The median number of participants in each trial was 27, and median trial duration was 16 weeks. The included studies were conducted over a 32-year time period, from 1983 to 2015. A single RCT that was underpowered to detect clinically meaningful differences investigated most interventions.There were four trials of anti-TNF-alpha (tumour necrosis factor-alpha) therapies, which included etanercept, infliximab, and adalimumab. Adalimumab 40 mg weekly improved the Dermatology Life Quality Index (DLQI) score in participants with moderate to severe HS by 4.0 points relative to placebo (95% confidence interval (CI) -6.5 to -1.5 points), an effect size approximately equal to the DLQI minimal clinically important difference. We reduced the evidence quality to 'moderate' because the effect size was based on the results of only one study. In a meta-analysis of two studies with 124 participants, standard dose adalimumab 40 mg every other week was ineffective compared with placebo (moderate quality evidence). In a smaller study of 38 participants, of whom only 33 provided efficacy data, infliximab 5 mg/kg treatment improved DLQI by 8.4 DLQI points after eight weeks. Etanercept 50 mg twice weekly was well tolerated but ineffective.In a RCT of 200 participants, no difference was found in surgical complications (week one: risk ratio (RR) 0.78, 95% CI 0.58 to 1.05, moderate quality evidence) or risk of recurrence (after three months: RR 0.96, 95% CI 0.68 to 1.34, moderate quality evidence) in those randomised to receive a gentamicin-collagen sponge prior to primary closure compared with primary closure alone.RCTs of other interventions, including topical clindamycin 1% solution; oral tetracycline; oral ethinylestradiol 50 mcg with either cyproterone acetate 50 mg or norgestrel 500 mcg; intense pulsed light; neodymium-doped yttrium aluminium garnet (Nd:YAG) laser; methylene blue gel photodynamic therapy; and staphage lysate, were relatively small studies, preventing firm conclusions due to imprecision. AUTHORS' CONCLUSIONS: Many knowledge gaps exist in RCT evidence for HS. Moderate quality evidence exists for adalimumab, which improves DLQI score when 40 mg is given weekly, twice the standard psoriasis dose. However, the 95% confidence interval includes an effect size of only 1.5 DLQI points, which may not be clinically relevant, and the safety profile of weekly dosing has not been fully established. Infliximab also improves quality of life, based on moderate quality evidence.More RCTs are needed in most areas of HS care, particularly oral treatments and the type and timing of surgical procedures. Outcomes should be validated, ideally, including a minimal clinically important difference for HS. PMID- 26443005 TI - Comparative analyses of fecal microbiota in Tibetan and Chinese Han living at low or high altitude by barcoded 454 pyrosequencing. AB - Knowledge about the impact of altitude and ethnicity on human gut microbiota is currently limited. In this study, fecal microbiota from 12 Tibetans (T group), 11 Chinese Han living in Tibet (HH group) and 12 Chinese Han living in Shaanxi province (LH group) were profiled by 454 pyrosequencing. Analysis of UniFrac principal coordinates showed significant structural changes in fecal microbiota among the three groups. There were significant differences in the composition of fecal microbiota among the three groups at phylum and genus levels. At the phylum level, the fecal samples of HH and T groups had higher relative abundances of Firmicutes, whereas the LH group had a higher relative abundance of Bacteroidetes. These changes at the phylum level reflected different dominant genus compositions. Compared with the LH group, changes of Firmicutes and Bacteroidetes were mainly due to a significant decrease of Prevotella in the HH group and were primarily attributable to significant decreases of Bacteroides and Prevotella as well as a significant increase of Catenibacterium in the T group. In conclusion, our results suggest that high altitude may contribute to shaping human gut microbiota. Genetic and dietary factors may also explain the different microbiota compositions between Tibetan and Chinese Han. PMID- 26443006 TI - Unconventional pairings of spin-orbit coupled attractive degenerate Fermi gas in a one-dimensional optical lattice. AB - Understanding novel pairings in attractive degenerate Fermi gases is crucial for exploring rich superfluid physics. In this report, we reveal unconventional pairings induced by spin-orbit coupling (SOC) in a one-dimensional optical lattice, using a state-of-the-art density-matrix renormalization group method. When both bands are partially occupied, we find a strong competition between the interband Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) and intraband Bardeen-Cooper Schrieffer (BCS) pairings. In particular, for the weak and moderate SOC strengths, these two pairings can coexist, giving rise to a new phase called the FFLO-BCS phase, which exhibits a unique three-peak structure in pairing momentum distribution. For the strong SOC strength, the intraband BCS pairing always dominates in the whole parameter regime, including the half filling. We figure out the whole phase diagrams as functions of filling factor, SOC strength, and Zeeman field. Our results are qualitatively different from recent mean-field predictions. Finally, we address that our predictions could be observed in a weaker trapped potential. PMID- 26443007 TI - Hierarchical Pore Development by Plasma Etching of Zr-Based Metal-Organic Frameworks. AB - The typically stable Zr-based metal-organic frameworks (MOFs) UiO-66 and UiO-66 NH2 were treated with tetrafluoromethane (CF4 ) and hexafluoroethane (C2 F6 ) plasmas. Through interactions between fluoride radicals from the perfluoroalkane plasma and the zirconium-oxygen bonds of the MOF, the resulting materials showed the development of mesoporosity, creating a hierarchical pore structure. It is anticipated that this strategy can be used as a post-synthetic technique for developing hierarchical networks in a variety of MOFs. PMID- 26443008 TI - Differences of eye movement pattern in natural and man-made scenes and image categorization with the help of these patterns. AB - In this paper, we investigated the parameters related to eye movement patterns of individuals while viewing images that consist of natural and man-made scenes. These parameters are as follows: number of fixations and saccades, fixation duration, saccade amplitude and distribution of fixation locations. We explored the way in which individuals look at images of different semantic categories, and used this information for automatic image classification. We showed that the eye movements and the contents of eye fixation locations of observers differ for images of different semantic categories. These differences were used effectively in automatic image categorization. Another goal of this study was to find the answer of this question that "whether the image patches of fixation points have sufficient information for image categorization?" To achieve this goal, a number of patches with different sizes from two different image categories was extracted. These patches, which were selected at the location of eye fixation points, were used to form a feature vector based on K-means clustering algorithm. Then, different statistical classifiers were trained for categorization purpose. The results showed that it is possible to predict the image category by using the feature vectors derived from the image patches. We found significant differences in parameters of eye movement pattern between the two image categories (average across subjects). We could categorize images by using these parameters as features. The results also showed that it is possible to predict the image category by using image patches around the subjects' fixation points. PMID- 26443009 TI - Co-sensitization promoted light harvesting with a new mixed-addenda polyoxometalate [Cu(C12H8N2)2]2[V2W4O19].4H2O in dye-sensitized solar cells. AB - A di-vanadium-substituted Lindqvist-type polyoxometalate [Cu(C12H8N2)2]2[V2W4O19].4H2O (1) was hydrothermally synthesized and characterized structurally by single crystal X-ray diffraction analysis. X-ray photoelectron spectroscopy and energy disperse spectroscopy tests further prove the existence of vanadium. Ultraviolet photoelectron spectroscopy and density functional theoretical studies indicate that the energy level of 1 matches well with the conduction band of the TiO2. Furthermore, considering the semiconductor like nature of 1 and the introduction of transition metal element Cu synchronously extends the absorption to the visible region, which should also be beneficial to the photovoltaic device performance. 1-Doped TiO2 composites (denoted as 1@TiO2) have been successfully fabricated by a simple sol-gel method, and introduced into the dye-sensitized solar cells (DSSCs) as co-sensitizers in N719-sensitized photoanodes by mixing 1@TiO2 with P25 nanoparticles with different weight ratios to enhance the photoelectric conversion efficiency. The investigations show that the DSSC assembled with 1@TiO2/19P25 photoanode has the best performance and the overall improvement of the efficiency is 21.6% compared with pure P25. Furthermore, the electrochemical impedance spectroscopy and open circuit voltage decay investigations show that the cosensitization of 1 and N719 can promote electron transfer and restrain charge recombinations in the DSSCs, resulting in a longer electron lifetime. PMID- 26443010 TI - Identifying causal gateways and mediators in complex spatio-temporal systems. AB - Identifying regions important for spreading and mediating perturbations is crucial to assess the susceptibilities of spatio-temporal complex systems such as the Earth's climate to volcanic eruptions, extreme events or geoengineering. Here a data-driven approach is introduced based on a dimension reduction, causal reconstruction, and novel network measures based on causal effect theory that go beyond standard complex network tools by distinguishing direct from indirect pathways. Applied to a data set of atmospheric dynamics, the method identifies several strongly uplifting regions acting as major gateways of perturbations spreading in the atmosphere. Additionally, the method provides a stricter statistical approach to pathways of atmospheric teleconnections, yielding insights into the Pacific-Indian Ocean interaction relevant for monsoonal dynamics. Also for neuroscience or power grids, the novel causal interaction perspective provides a complementary approach to simulations or experiments for understanding the functioning of complex spatio-temporal systems with potential applications in increasing their resilience to shocks or extreme events. PMID- 26443011 TI - Small-Molecule Allosteric Modulators of the Protein Kinase PDK1 from Structure Based Docking. AB - Finding small molecules that target allosteric sites remains a grand challenge for ligand discovery. In the protein kinase field, only a handful of highly selective allosteric modulators have been found. Thus, more general methods are needed to discover allosteric modulators for additional kinases. Here, we use virtual screening against an ensemble of both crystal structures and comparative models to identify ligands for an allosteric peptide-binding site on the protein kinase PDK1 (the PIF pocket). We optimized these ligands through an analog-by catalog search that yielded compound 4, which binds to PDK1 with 8 MUM affinity. We confirmed the docking poses by determining a crystal structure of PDK1 in complex with 4. Because the PIF pocket appears to be a recurring structural feature of the kinase fold, known generally as the helix alphaC patch, this approach may enable the discovery of allosteric modulators for other kinases. PMID- 26443012 TI - Incorporation of nanostructured hydroxyapatite and poly(N-isopropylacrylamide) in demineralized bone matrix enhances osteoblast and human mesenchymal stem cell activity. AB - Demineralized bone matrix (DBM) is currently used in many clinical applications for bone augmentation and repair. DBM is normally characterized by the presence of bone morphogenetic proteins. In this study, the authors have optimized methods to obtain DBM under good manufacturing practice, resulting in enhanced bioactivity. The processed DBM can be used alone, together with nanostructured hydroxyapatite (nanoHA), or dispersed in a physiological carrier or hydrogel. In this study, osteoblasts (MG-63) and human bone marrow derived mesenchymal stem cells (hMSCs) were cultured on DBM pastes made in phosphate buffered saline solution or poly(N-isopropylacrylamide) (PNIPAAM) hydrogels with or without nanoHA. The authors observed that the presence of PNIPAAM reduced osteoblast adhesion, while the addition of nanoHA increased osteoblast adhesion, proliferation, interleukin-6 (IL-6) production, and reduced lactate dehydrogenase (LDH) production. Increasing concentrations of PNIPAAM in combination with nanoHA further increased osteoblast proliferation, and decreased IL-6 and LDH production. Incorporation of PNIPAAM in DBM enhanced hMSCs proliferation and collagen type-I production. Furthermore, a combination of PNIPAAM and nanoHA further increased alkaline phosphatase and osteocalcin production in hMSCs, independently from the concentration of PNIPAAM. This study shows that combinations of DBM with nanoHA and PNIPAAM seem to offer a promising route to enhance cell activity and induce osteogenic differentiation. PMID- 26443013 TI - Short-Term Buffers, but Long-Term Suffers? Differential Effects of Negative Self Perceptions of Aging Following Serious Health Events. AB - Objectives: Large longitudinal studies show that negative self-perceptions of aging can be detrimental for health outcomes. However, negative self-perceptions of aging (i.e., associating aging with physical losses) might be adaptive because they prepare individuals for serious health events (SHEs), resulting in short term positive effects as opposed to long-term negative effects on well-being and health. Method: Longitudinal data from 309 older adults (aged 65 and older) were analyzed. Short-term (6 months) and long-term (2.5 years) effects after a SHE of negative self-perceptions of aging on functional limitations (FLs) and negative affect (NA) were investigated. Results: Results show that in the case of a SHE, individuals with more negative self-perceptions of aging reported less NA after 6 months but more FLs after 2.5 years. In contrast, individuals with less negative self-perceptions of aging reported more NA in the short-run but less FLs later on. Discussion: People with more negative self-perceptions of aging may be mentally prepared for health events or may have habituated to health declines. Individuals with more positive self-perceptions, in contrast, may invest a lot in coping efforts immediately after the health event. Similarities to research on unrealistic optimism are discussed. PMID- 26443014 TI - The Relation of Ego Integrity and Despair to Personality Traits and Mental Health. AB - Objectives: Existing studies in the Eriksonian tradition found that ego integrity and despair are important indicators of life-span development. The present study relates ego integrity and despair to contemporary theories of personality and mental health. Method: A cross-sectional study of Dutch adults aged between 50 and 95 years (N = 218) was carried out, using the Northwestern Ego Integrity Scale, the subscales for neuroticism, extraversion, and openness to experience of the NEO-FFI, the Mental Health Continuum-Short Form, and the Center for Epidemiological Studies Depression Scale-Short Form. Results: Extraversion and openness to experience have an indirect relation to ego integrity that is mediated by well-being. Neuroticism was related to despair and explained the relationship of depressive symptoms to despair. Chronological age did not moderate these findings. Discussion: Ego integrity appears to be related to fluctuating states of mental health, whereas despair is more an expression of a general trait-like disposition of neuroticism. Implications for further research are discussed. PMID- 26443015 TI - Role of Perceived Maternal Favoritism and Disfavoritism in Adult Children's Psychological Well-Being. AB - Objectives: The detrimental consequences of parents' differential treatment on children's well-being have been documented in earlier stages of the life course; however, little is known about this pattern in midlife. Drawing from theories of equity and social comparison, we tested whether psychological well-being was affected only by adult children's perceptions that their mothers treated some offspring in the family differently or by their perceptions that they were favored or disfavored. Further, we explored the extent to which these patterns differed by race. Method: Multilevel regression modeling was conducted using data collected from 725 adult children nested within 309 later-life families as part of the Within-Family Differences Study-II. Results: Depressive symptoms were higher when offspring perceived that they had the most emotional closeness to mothers or the greatest conflict with mothers. Depressive symptoms were also higher when respondents identified themselves as being the children in whom the mothers were most disappointed. Discussion: The findings shed new light on the role of intergenerational relations in adult children's well-being in midlife by taking into consideration the respondents' direct reports of their perceptions of their mothers' favoritism and disfavoritism. Further, the findings provide evidence that the association between maternal differentiation and psychological well-being in adulthood is stronger in Black than in White families. These patterns suggest that the association between psychological well-being and both favoritism and disfavoritism can be accounted for by processes involving social comparison rather than equity for both Black and White adult children in midlife. PMID- 26443017 TI - Atraumatic splenic rupture cases presenting with hemorrhagic shock and coagulopathy treated by splenic artery occlusion using a microballoon catheter before splenectomy. AB - Atraumatic splenic rupture (ASR) is an uncommon pathologic condition in which bleeding from the spleen occurs for a variety of nontraumatic reasons. While the current trend in traumatic splenic rupture is nonoperative management including transcatheter arterial embolization, the current recommendation for the treatment of most patients with ASR is splenectomy. In this report, we describe two cases of ASR presenting with hemorrhagic shock and complicated by anticoagulation therapy. In patients with severe hemorrhagic shock and coagulopathy, a damage control strategy is recommended. Our successful treatment of these patients included a three-step strategy as a damage control: (i) rapid transient hemostasis by splenic artery occlusion using a microballoon catheter, (ii) damage control resuscitation and (iii) splenectomy as a definitive hemostatic treatment. PMID- 26443016 TI - Nicotine Exposure During Pregnancy Results in Persistent Midline Epithelial Seam With Improper Palatal Fusion. AB - INTRODUCTION: Nonsyndromic cleft palate is a common birth defect (1:700) with a complex etiology involving both genetic and environmental risk factors. Nicotine, a major teratogen present in tobacco products, was shown to cause alterations and delays in the developing fetus. METHODS: To demonstrate the postpartum effects of nicotine on palatal development, we delivered three different doses of nicotine (1.5, 3.0, and 4.5mg/kg/d) and sterile saline (control) into pregnant BALB/c mice throughout their entire pregnancy using subcutaneous micro-osmotic pump. Dams were allowed to deliver (~day 21 of pregnancy) and neonatal assessments (weight, length, nicotine levels) were conducted, and palatal tissues were harvested for morphological and molecular analyses, as well as transcriptional profiling using microarrays. RESULTS: Consistent administration of nicotine caused developmental retardation, still birth, low birth weight, and significant palatal size and shape abnormality and persistent midline epithelial seam in the pups. Through microarray analysis, we detected that 6232 genes were up-regulated and 6310 genes were down-regulated in nicotine-treated groups compared to the control. Moreover, 46% of the cleft palate-causing genes were found to be affected by nicotine exposure. Alterations of a subset of differentially expressed genes were illustrated with hierarchal clustering and a series of formal pathway analyses were performed using the bioinformatics tools. CONCLUSIONS: We concluded that nicotine exposure during pregnancy interferes with normal growth and development of the fetus, as well results in persistent midline epithelial seam with type B and C patterns of palatal fusion. IMPLICATIONS: Although there are several studies analyzing the genetic and environmental causes of palatal deformities, this study primarily shows the morphological and large-scale genomic outcomes of gestational nicotine exposure in neonatal mice palate.The previous version was incorrect. New authors Ali Nawshad, Hasan Otu, Janki Sharma, and Elizabeth Sheldon have been included in this version; the funding and acknowledgement sections have been updated accordingly; the article title, some text, and one supplementary data file have been edited; and the corresponding author has been changed. The original corresponding author regrets these earlier errors. PMID- 26443018 TI - Cough Augmentation in Subjects With Duchenne Muscular Dystrophy: Comparison of Air Stacking via a Resuscitator Bag Versus Mechanical Ventilation. AB - BACKGROUND: Air stacking improves cough effectiveness in people with Duchenne muscular dystrophy (DMD) and respiratory muscle weakness. However, it is not known whether air stacking is more effective via a resuscitator bag or a home ventilator. METHODS: This prospective randomized study investigated the effect of air stacking via a volume-cycled home ventilator versus via a resuscitator bag in participants with DMD. Maximum insufflation capacity and peak expiratory flow during spontaneous (cough peak flow) and air stacking-assisted cough maneuvers (air stacking-assisted cough peak flow) were measured. RESULTS: Fifty-two adult DMD subjects receiving noninvasive ventilation were included in the study: 27 participants performed air stacking via their home ventilator (home-ventilator group; age = 25.3 +/- 5.1 y; forced vital capacity (FVC) = 809 +/- 555 mL), and 25 participants used a resuscitator bag (resuscitator-bag group; age = 24.7 +/- 5.7 y, FVC = 807 +/- 495 mL). Following a single training session, air stacking could be performed successfully by 89% (home ventilator) and 88% (resuscitator bag) of participants. There were comparable maximum insufflation capacities (1,481 mL for the home-ventilator group vs 1,344 mL for the resuscitator-bag group, P = .33) and mean air stacking-assisted cough peak flow values (199 L/min for the home-ventilator group vs 186 L/min for the resuscitator-bag group, P = .33) between techniques. Air stacking-assisted cough peak flow increased significantly compared with baseline in both groups (mean increase: +51% [home ventilator] vs +49% [resuscitator bag], P < .001), with individual air stacking assisted cough peak flow improvements ranging from -20 to 245%. CONCLUSIONS: Cough augmentation is an important component of the respiratory management of people with a neuromuscular disorder. No difference in cough effectiveness as measured by air stacking-assisted cough peak flow was found in air stacking via a ventilator compared with via a resuscitator bag. Both methods achieved mean air stacking-assisted cough peak flow values of >160 L/min. Provision of an inexpensive resuscitator bag can effectively improve cough capacity, and it is simple to use, which may improve access to respiratory care in people with DMD. PMID- 26443019 TI - Zinc Supplementation for One Year Among Children with Cystic Fibrosis Does Not Decrease Pulmonary Infection. AB - BACKGROUND: Children with cystic fibrosis may have a deficiency of micronutrients, including zinc, which may affect their susceptibility to infections. There is a paucity of data on zinc supplementation among children with cystic fibrosis. We hypothesized that a pharmacologic dose of zinc administered daily for 12 months would reduce the need for antibiotics by 50%. METHODS: This double-blind randomized placebo-controlled trial was conducted among children with cystic fibrosis to assess the effect of zinc supplementation on the need for antibiotics and pulmonary function tests. The children, age 5-15 y, of either sex, received either 30-mg zinc tablets or similar looking placebo tablets daily in addition to standard care. They were followed up every month for a period of 12 months and whenever they had pulmonary exacerbations. Their serum zinc was estimated at baseline and at 12 months of enrollment. During each visit, the children underwent a pulmonary function test and sputum culture. RESULTS: Of a total of 43 children screened, 40 were enrolled, and of them, 37 completed the study. The median (interquartile range) number of days of the administration of antibiotics over 12 months of follow-up among the children receiving zinc was 42 (14-97) d. In the placebo group, it was 38 (15-70) d (P = .79). There were no significant differences in the percent-of-predicted FEV1 or change in FEV1 values at 12 months (P = .44). The number of children in whose respiratory specimens Pseudomonas was isolated was similar for the 2 groups at different time intervals. The adverse events reported were similar in the 2 groups. CONCLUSION: We did not find any significant difference in the need for antibiotics, pulmonary function tests, hospitalization, colonization with Pseudomonas, or the need for antibiotics for children with cystic fibrosis receiving zinc supplementation of 30 mg/d. PMID- 26443020 TI - The Risk and Related Factors for Readmission to an ICU Within 7 Days in Mechanically Ventilated Subjects--A Nationwide Population-Based Cohort Study. AB - BACKGROUND: Readmission of mechanically ventilated patients to an ICU within 7 d reflects not only patient safety but also the quality of care of the ICU. This study aimed to investigate the risk and related factors for readmission to an ICU within 7 d in mechanically ventilated subjects. METHODS: A total of 658,452 mechanically ventilated subjects discharged from an ICU whose age was >= 17 y old were obtained from the Taiwan National Health Insurance Research Database for the period from January 1, 2005, to December 31, 2011. The study applied a generalized estimating equation logistic regression model to explore whether the mechanically ventilated subjects were readmitted within 7 d or not and the related factors. RESULTS: A total of 29,657 subjects were readmitted to the ICU within 7 d; the total readmission rate was 4.5%. Also, 64.8% of the subjects with the same diagnosis were returned to the ICU within 7 d. Generalized estimating equation logistic regression model results showed that the factors related to higher risk of readmission were male sex, old age, higher comorbidity score, complications (eg, pneumothorax, subcutaneous emphysema, pneumonia, oxygen toxicity, pulmonary embolism, or pulmonary edema), use of a private hospital ICU, ICU stay >=21 d, transfer to a respiratory care center and respiratory care ward, and subsequent transfer to the regional hospital or district hospital. CONCLUSIONS: The risk and related factors of a mechanically ventilated subject whose age is >= 17 y old being readmitted to the ICU within 7 d include subject characteristics, health status, hospital attributes, and the length of ICU stay. Therefore, higher risk subjects should receive attention and assessment before transfer or discharge from the ICU to prevent readmission. PMID- 26443021 TI - Development of potent in vivo mutagenesis plasmids with broad mutational spectra. AB - Methods to enhance random mutagenesis in cells offer advantages over in vitro mutagenesis, but current in vivo methods suffer from a lack of control, genomic instability, low efficiency and narrow mutational spectra. Using a mechanism driven approach, we created a potent, inducible, broad-spectrum and vector-based mutagenesis system in E. coli that enhances mutation 322,000-fold over basal levels, surpassing the mutational efficiency and spectra of widely used in vivo and in vitro methods. We demonstrate that this system can be used to evolve antibiotic resistance in wild-type E. coli in <24 h, outperforming chemical mutagens, ultraviolet light and the mutator strain XL1-Red under similar conditions. This system also enables the continuous evolution of T7 RNA polymerase variants capable of initiating transcription using the T3 promoter in <10 h. Our findings enable broad-spectrum mutagenesis of chromosomes, episomes and viruses in vivo, and are applicable to both bacterial and bacteriophage mediated laboratory evolution platforms. PMID- 26443022 TI - Filimonas endophytica sp. nov., isolated from surface-sterilized root of Cosmos bipinnatus. AB - A Gram-stain-negative, yellow, motile by gliding, filamentous bacterium, designated SR 2-06T, was isolated from surface-sterilized root of garden cosmos. 16S rRNA gene sequence analysis indicated that SR 2-06T was related most closely to Filimonas lacunae YT21T of the family Chitinophagaceae at a sequence similarity of 96.90 %, while levels of similarity to other related taxa were less than 93.08 %. Strain SR 2-06T exhibited similar features to F. lacunae in that it contained MK-7 as the major respiratory quinone, and iso-C15 : 1 G, iso-C15 : 0 and a summed feature consisting of C16 : 1omega6c and/or C16 : 1omega7c as the major fatty acids. However, strain SR 2-06T was distinguished from F. lacunae using a combination of physiological and biochemical properties. The cellular polar lipids were phosphatidylethanolamine, unknown aminophospholipids, unknown aminolipids, an unknown phospholipid and unidentified polar lipids. The DNA G+C content was 46.0 mol%. The phenotypic and phylogenetic evidence clearly indicates that strain SR 2-06T represents a novel species of the genus Filimonas, for which the name Filimonas endophytica sp. nov. is proposed. The type strain is SR 2-06T ( = KCTC 42060T = JCM 19844T). PMID- 26443024 TI - Rheumatoid arthritis and coronary atherosclerosis: two cousins engaging in a dangerous liaison. PMID- 26443023 TI - Efficacy and safety of ticagrelor for long-term secondary prevention of atherothrombotic events in relation to renal function: insights from the PEGASUS TIMI 54 trial. AB - AIMS: We evaluated the relationship of renal function and ischaemic and bleeding risk as well as the efficacy and safety of ticagrelor in stable patients with prior myocardial infarction (MI). METHODS AND RESULTS: Patients with a history of MI 1-3 years prior from PEGASUS-TIMI 54 were stratified based on estimated glomerular filtration rate (eGFR), with <60 mL/min/1.73 m(2) pre-specified for analysis of the effect of ticagrelor on the primary efficacy composite of cardiovascular death, MI, or stroke (major adverse cardiovascular events, MACE) and the primary safety endpoint of TIMI major bleeding. Of 20 898 patients, those with eGFR <60 (N = 4849, 23.2%) had a greater risk of MACE at 3 years relative to those without, which remained significant after multivariable adjustment (hazard ratio, HRadj 1.54, 95% confidence interval, CI 1.27-1.85, P < 0.001). The relative risk reduction in MACE with ticagrelor was similar in those with eGFR <60 (ticagrelor pooled vs. placebo: HR 0.81; 95% CI 0.68-0.96) vs. >=60 (HR 0.88; 95% CI 0.77-1.00, Pinteraction = 0.44). However, due to the greater absolute risk in the former group, the absolute risk reduction with ticagrelor was higher: 2.7 vs. 0.63%. Bleeding tended to occur more frequently in patients with renal dysfunction. The absolute increase in TIMI major bleeding with ticagrelor was similar in those with and without eGFR <60 (1.19 vs. 1.43%), whereas the excess of minor bleeding tended to be more pronounced (1.93 vs. 0.69%). CONCLUSION: In patients with a history of MI, patients with renal dysfunction are at increased risk of MACE and consequently experience a particularly robust absolute risk reduction with long-term treatment with ticagrelor. PMID- 26443025 TI - Hijacking the Hedgehog Pathway in Cancer Therapy. AB - The hedgehog (Hh) signaling pathway, which is almost completely silenced in normal adult tissues but highly activated in cancer, offers ideal drug targets for small molecule development. During the last few years, several studies have indicated that the Hh pathway plays a role in tumor development and maintenance, and novel drugs inhibiting Hh signaling have been discovered. Although results from clinical trials in patients harboring activating mutations of Hh have been promising, there are many controversies regarding the role of the pathway in tumors that demonstrate ligand over-expression without identified mutations. In this review, we focus on the function and expression of the Hh pathway in different tumors and discuss the targeting approaches tested in preclinical and clinical studies. PMID- 26443026 TI - Anticancer Activity of Organogallium(III) Complexes in Colon Cancer Cells. AB - In vitro antitumor activity of various organogallium(III) complexes (1-8) has been tested against CT26CL25, HCT116, SW480 colon cancer cell lines. CV and MTT assays were used to assess on the antiproliferative effect of investigated organogallium(III) complexes. From the investigated complexes, the most active was found to be tetranuclear compound 8 against CT26CL25 cells. Flow cytometric analysis of the CT26CL25 cells upon the treatment with 8 was performed in order to determine the role of apoptosis, caspase activation, autophagy and proliferation rate on the cell death caused with this compound. Results indicate cytotoxic potential of the tetranuclear complex 8 by inducing caspase independent apoptosis and blocking most of the cells before first division. PMID- 26443027 TI - Design and Synthesis of Novel Schiff Base-Benzothiazole Hybrids as Potential Epidermal Growth Factor Receptor (EGFR) Inhibitors. AB - A series of novel Schiff bases -benzothiazole hybrids was designed, synthesized and evaluated for their anticancer activity by MTT assay and western blot method. Antiproliferative screening indicated that compound containing dihydroxy substituents had potent inhibitory activity with IC50 value 34ug/ml against SKOV3, A2780-S and A2780-CR cell lines. It showed more potent cytotoxicity in combination with cisplatin and paclitaxel than alone in the selected cell lines (SKOV3, A2780 and A2780-CR models). The in vitro cytotoxicity of the compounds on IOSE 364 cell line was evaluated to establish the selectivity. Molecular docking study exhibited good binding against epidermal growth factor receptor, which was further ascertained by immunoblot assay using specific antibody against phosphorylated EGFR, and thus unravelling the targeted anticancer mechanism. PMID- 26443028 TI - Creating a Common Curriculum for the DSM-5: Lessons in Collaboration. PMID- 26443029 TI - Integrated Care Training in Canada: Challenges and Future Directions. PMID- 26443030 TI - The University of Manitoba Psychiatry Toolkit: Development and Evaluation. AB - OBJECTIVE: The authors developed and measured the subsequent utilization of a web based point-of-care information tool and meta-search filter, the University of Manitoba Psychiatry Toolkit, as well as conduct an evaluation of its impact on physicians' information seeking. METHODS: Evaluation entailed analysis of toolkit web page utilization data from user visits to the web-based toolkit, as well as an online survey distributed to psychiatrists and resident trainees to assess information gathering behaviors and attitudes regarding various sources of medical information. RESULTS: Electronic resources and colleagues were the preferred sources for gathering health information, while inadequate time and search skills were ranked as important barriers. Age and physician cadre influenced toolkit use. Majority of respondents used the Psychiatry Toolkit to answer a clinical question, and urgency of the clinical problem influenced their decision to use it. CONCLUSIONS: The Psychiatry Toolkit assists psychiatrists and residents in finding answers to clinical questions arising at point-of-care, helping enhance the ongoing educational needs of physicians. PMID- 26443031 TI - Myocardial and Peripheral Ischemia Causes an Increase in Circulating Pregnancy Associated Plasma Protein-A in Non-atherosclerotic, Non-heparinized Pigs. AB - The usefulness of circulating pregnancy-associated plasma protein-A (PAPP-A) as a biomarker for acute coronary syndrome (ACS) is widely debated. We used the pig as a model to assess PAPP-A dynamics in the setting of myocardial ischemia. Induction of myocardial ischemia by ligation of the left anterior descending (LAD) coronary artery caused a systemic rise in PAPP-A. However, the ischemic myocardium was excluded as the source of PAPP-A. Interestingly, induction of ischemia in peripheral tissues by ligation of the left femoral artery caused a systemic rise in PAPP-A originating from the left hind limb. This is the first study to demonstrate PAPP-A elevations in the absence of atherosclerosis or heparin during myocardial ischemia. Our findings thus add to the current discussion of the usefulness of PAPP-A as a biomarker for ACS. PMID- 26443032 TI - Fungal phytotoxins with potential herbicidal activity: chemical and biological characterization. AB - Covering: 2007 to 2015 Fungal phytotoxins are secondary metabolites playing an important role in the induction of disease symptoms interfering with host plant physiological processes. Although fungal pathogens represent a heavy constraint for agrarian production and for forest and environmental heritage, they can also represent an ecofriendly alternative to manage weeds. Indeed, the phytotoxins produced by weed pathogenic fungi are an efficient tool to design natural, safe bioherbicides. Their use could avoid that of synthetic pesticides causing resistance in the host plants and the long term impact of residues in agricultural products with a risk to human and animal health. The isolation and structural and biological characterization of phytotoxins produced by pathogenic fungi for weeds, including parasitic plants, are described. Structure activity relationships and mode of action studies for some phytotoxins are also reported to elucidate the herbicide potential of these promising fungal metabolites. PMID- 26443034 TI - Delusional Infestation With Black Mold Presenting to the General Hospital. PMID- 26443033 TI - An improved chloride-conducting channelrhodopsin for light-induced inhibition of neuronal activity in vivo. AB - Channelrhodopsins are light-gated cation channels that have been widely used for optogenetic stimulation of electrically excitable cells. Replacement of a glutamic acid in the central gate with a positively charged amino acid residue reverses the ion selectivity and produces chloride-conducting ChRs (ChloCs). Expressed in neurons, published ChloCs produced a strong shunting effect but also a small, yet significant depolarization from the resting potential. Depending on the state of the neuron, the net result of illumination might therefore be inhibitory or excitatory with respect to action potential generation. Here we report two additional amino acid substitutions that significantly shift the reversal potential of improved ChloC (iChloC) to the reversal potential of endogenous GABAA receptors. As a result, light-evoked membrane depolarization was strongly reduced and spike initiation after current injection or synaptic stimulation was reliably inhibited in iChloC-transfected neurons in vitro. In the primary visual cortex of anesthetized mice, activation of iChloC suppressed spiking activity evoked by visual stimulation. Due to its high operational light sensitivity, iChloC makes it possible to inhibit neurons in a large volume of brain tissue from a small, point-like light source. PMID- 26443035 TI - Building Bridges Between Silos: An Outcomes-Logic Model for a Multidisciplinary, Subspecialty Fellowship Education Program. PMID- 26443038 TI - Study of electronic and magnetic properties and related x-ray absorption spectroscopy of ultrathin Co films on BaTiO3. AB - We present a first-principles study of electronic and magnetic properties of thin Co films on a BaTiO3(0 0 1) single crystal. The crystalline structure of 1-3 monolayer thick Co films was determined and served as input for calculations of the electronic and magnetic properties of the films. The estimation of exchange constants indicates that the Co films are ferromagnetic with a high critical temperature, which depends on the film thickness and the interface geometry. In addition, we calculated x-ray absorption spectra, related magnetic circular dichroism (XMCD) and linear dichroism (XLD) of the Co L 2, 3 edges as a function of Co film thickness and ferroelectric polarization of BaTiO3. We found characteristic features, which depend strongly on the magnetic properties and the structure of the film. While there is only a weak dependence of XMCD spectra on the ferroelectric polarization, the XLD of the films is much more sensitive to the polarization switching, which could possibly be observed experimentally. PMID- 26443037 TI - Association of impaired left ventricular twisting-untwisting with vascular dysfunction, neurohumoral activation and impaired exercise capacity in hypertensive heart disease. AB - AIMS: We investigated the association between left ventricular (LV) torsional deformation and vascular dysfunction, fibrosis, neurohumoral activation, and exercise capacity in patients with normal ejection fraction METHODS AND RESULTS: In 320 newly-diagnosed untreated hypertensive patients and 160 controls, we measured: pulse wave velocity (PWV); coronary flow reserve (CFR) by Doppler echocardiography; global longitudinal strain and strain rate, peak twisting, the percentage changes between peak twisting, and untwisting at mitral valve opening (%dpTw - UtwMVO ), at peak (%dpTw - UtwPEF ), and the end of early LV diastolic filling (%dpTw - UtwEDF ) by speckle tracking imaging; transforming growth factor (TGFb-1), metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloptoteinase-1(TIMP-1), markers of collagen synthesis, and N-terminal pro brain natriuretic peptide (NT-proBNP). Oxygen consumption (VO2 ), measured by means of cardiopulmonary exercise test, was assessed in a subset of 80 patients. The PWV, CFR, longitudinal strain and strain rate, %dpTw-UtwMVO , %dpTw-UtwPEF , and %dpTw-UtwEDF were impaired in hypertensive patients compared with controls. In multivariable analysis, CFR, PWV, LV mass, and systolic blood pressure were independent determinants of longitudinal strain, strain rate, and untwisting markers (P < 0.05). Increased TGFb-1 was related with increased collagen synthesis markers, TIMP-1 and MMP-9 and these biomarkers were associated with impaired longitudinal systolic strain rate, untwisting markers, CFR and PWV (P < 0.05). Delayed untwisting as assessed by reduced %dpTw - UtwEDF was related with increased NT-proBNP and reduced VO2 (P < 0.05). CONCLUSIONS: Impaired LV untwisting is associated with increased arterial stiffness and coronary microcirculatory dysfunction, and is linked to reduced exercise capacity and neurohumoral activation in hypertensive heart disease. A fibrotic process may be the common link between vascular dysfunction and abnormal myocardial deformation. PMID- 26443036 TI - Health Care Utilization by Body Mass Index in a Pediatric Population. AB - OBJECTIVE: We tested the hypothesis that the frequency of emergency department (ED) visits, outpatient clinic visits, and hospitalizations were higher among children with higher body mass index (BMI) categories, even after controlling for demographics, socioeconomic status, and presence of other chronic medical conditions. METHODS: We obtained electronic height, weight, and utilization data for all residents of Olmsted County, Minnesota, aged 2 to 18 years on January 1, 2005 (n = 34,335), and calculated baseline BMI (kg/m(2)). At least 1 BMI measurement and permission to use medical record information was available for 19,771 children (58%); 19,528 with follow-up comprised the final cohort. BMIs were categorized into underweight/healthy weight (<85th percentile), overweight (85th to <95th percentile), and obese (>=95th percentile). Negative binomial models were used to compare the rate of utilization across BMI categories. Multivariable models were used to adjust for the effects of age, race, sex, socioeconomic status, and chronic medical conditions. RESULTS: Compared to children with BMI <85th percentile, overweight and obese status were associated with increased ED visits (adjusted incident rate ratio [IRR] 1.16, 95% confidence interval [CI] 1.10, 1.23; and IRR 1.27, 95% CI 1.19, 1.35, respectively; P for trend <.0001), and outpatient clinic visits (IRR 1.05, 95% CI 1.02, 1.08; and IRR 1.07, 95% CI 1.04, 1.11, respectively; P for trend <.0001). No associations were observed between baseline BMI category and hospitalizations in the adjusted analyses. CONCLUSIONS: Children who are overweight or obese utilize the ED and outpatient clinics more frequently than those who are underweight/healthy weight, but are not hospitalized more frequently. PMID- 26443039 TI - Evidence of impaired carbohydrate assimilation in euthyroid patients with Hashimoto's thyroiditis. AB - BACKGROUND/OBJECTIVES: Hashimoto's thyroiditis (HT) represents a wide-spread autoimmune disease. In euthyroid patients with HT, an impaired assimilation of common carbohydrates has been observed. Our objectives were to compare the frequency of (1) fructose (FM), lactose (LM) and sorbitol malassimilation (SM), (2) gastrointestinal symptoms (GS) following carbohydrate ingestion and (3) recurrent GS relevant to the participants' daily lives. SUBJECTS/METHODS: We conducted a prospective case-control study of 45 ambulatory patients with HT and 38 healthy volunteers, matched with regard to age, gender and area of origin. Hydrogen breath tests with fructose, lactose, sorbitol and glucose were performed, the lactose testing additionally comprising measurements of capillary blood glucose (cBG). GS during the tests and recurrent GS concerning the participants' daily lives were assessed. A food-frequency questionnaire was administered. RESULTS: FM was diagnosed in 48.9% of patients compared with 26.3% of the control group (P=0.035). In all, 42.2% of patients with HT and 21.1% of healthy controls showed LM (P=0.04). FM and/or LM was present in 73.3% of the patients and in 42.1% of healthy controls (P=0.004). GS after the ingestion of fructose (P=0.003) or lactose (P=0.025) and recurrent GS were significantly more prevalent in the case group. The consumption of free fructose, lactose or sorbitol did not differ. CONCLUSIONS: Carbohydrate malassimilation and gastrointestinal complaints are frequent in euthyroid patients with HT, leading to novel clinical and pathophysiological considerations and concepts. PMID- 26443040 TI - Adolescents' beverage choice at school and the impact on sugar intake. AB - BACKGROUND/OBJECTIVES: To examine students' beverage choice in school, with reference to its contribution to students' intake of non-milk extrinsic (NME) sugars. SUBJECTS/METHODS: Beverage and food selection data for students aged 11 18 years (n=2461) were collected from two large secondary schools in England, for a continuous period of 145 (school A) and 125 (school B) school days. Descriptive analysis followed by cluster analysis of the beverage data were performed separately for each school. RESULTS: More than a third of all items selected by students were beverages, and juice-based beverages were students' most popular choice (school A, 38.6%; school B, 35.2%). Mean NME sugars derived from beverages alone was high (school A, 16.7 g/student-day; school B, 12.9 g/student-day). Based on beverage purchases, six clusters of students were identified at each school (school A: 'juice-based', 'assorted', 'water', 'cartoned flavoured milk', 'bottled flavoured milk', 'high volume juice-based'; school B: 'assorted', 'water with juice-based', 'sparkling juice/juice-based', 'water', 'high volume water', 'high volume juice-based'). Both schools included 'high volume juice-based' clusters with the highest NME sugar means from beverages (school A, 28.6 g/student-day; school B, 24.4 g/student-day), and 'water' clusters with the lowest. A hierarchy in NME sugars was found according to cluster; students in the 'high volume juice-based' cluster returned significantly higher levels of NME sugars than students in other clusters. CONCLUSIONS: This study reveals the contribution that school beverages combined with students' beverage choice behaviour is making to students' NME sugar intake. These findings inform school food initiatives, and more generally public health policy around adolescents' dietary intake. PMID- 26443041 TI - Transmission of energy-saving efficiency from obese parents to their offspring: the Korean National Health and Nutrition Examination Survey 2007-2011. AB - BACKGROUND/OBJECTIVES: Concerns of a growing obesity epidemic have increased since the association between obesity in parents and that in offspring was reported. However, the evidence regarding whether the energy-saving efficiency of obese parents is conveyed to their offspring and the duration of the expression of such transmitted efficiency is limited. SUBJECTS/METHODS: We included 7647 matching sets of parent-offspring trios from South Korea. Multiple linear regression models were performed to estimate the energy-saving efficiency, as assessed by the associations between energy intake and obesity-related indices (waist-to-height ratio, waist circumference and body mass index z-score), and to compare the energy-saving efficiency of offspring of obese and non-obese parents. All analyses were based on a complex sample design and were stratified by gender and age. RESULTS: We identified a parental influence on obesity, that is, the more obese the parent, the higher the obesity-related indices of their offspring, in both genders and all age groups. The energy-saving efficiency of child offspring was highest when both parents were obese and lowest when both were non obese; this difference was significant (P<0.05) with regard to the energy-saving efficiency of all types of intake studied, except fat. However, the energy-saving efficiency of obese and non-obese parents did not differ when their offspring were adolescents and adults. CONCLUSIONS: The critical window for transmission of energy-saving efficiency is limited to childhood. These findings suggest that children of obese parents should be more emphatically advised to maintain a balanced diet and to engage in regular physical activity. PMID- 26443042 TI - Association between bariatric surgery and quality of life. PMID- 26443043 TI - Update on food allergy. AB - Food allergies are a global health issue with increasing prevalence. Allergic reactions can range from mild local symptoms to severe anaphylactic reactions. Significant progress has been made in diagnostic tools such as component-resolved diagnostics and its impact on risk stratification as well as in therapeutic approaches including biologicals. However, a cure for food allergy has not yet been achieved and patients and their families are forced to alter eating habits and social engagements, impacting their quality of life. New technologies and improved in vitro and in vivo models will advance our knowledge of the pathogenesis of food allergies and multicenter-multinational cohort studies will elucidate interactions between genetic background, lifestyle, and environmental factors. This review focuses on new insights and developments in the field of food allergy and summarizes recently published articles. PMID- 26443044 TI - Using Improvement Methodology to Optimize Echocardiographic Imaging of Coronary Arteries in Children. AB - BACKGROUND: According to the American Society of Echocardiography, coronary artery (CA) imaging is recommended in pediatric examinations to identify CA anomalies. A review of the authors' center's echocardiographic studies revealed that CA images were often nondiagnostic. The aim of this study was to utilize quality improvement methodology to increase the percentage of first-time pediatric studies with definitive CA identification from a baseline of 45% to a goal of at least 75% in 9 months. METHODS: A scoring system was developed to characterize the completeness of CA imaging. One point was scored for demonstration of each of the following: right CA origin by two-dimensional imaging, right CA origin by color flow Doppler imaging, left CA origin by two dimensional imaging, and left CA origin by color flow Doppler imaging. A score of 4 was considered to represent definitive imaging. A baseline was obtained on 100 first-time echocardiograms with normal findings. During the intervention, 10 randomly selected first-time studies with normal findings were scored weekly for assessment of CA imaging. Interventions were focused on the following domains: excellence in image quality, shared ownership, transparency, and effective communication. Key interventions included labeling CA images, requiring two dimensional and color Doppler images, optimization of settings, and elimination of macros for CA reporting. RESULTS: The percentage of definitive CA identification increased from 45% to 82.5% over 4 months and was sustained for 7 months. Accurate reporting of incomplete CA imaging increased from 17% to 77.5%. CONCLUSIONS: Improved pediatric CA imaging and reporting were achieved through the implementation of key interventions. PMID- 26443045 TI - The Application of Intravascular Ultrasound to Evaluate Pulmonary Vascular Properties and Mortality in Patients with Pulmonary Arterial Hypertension. AB - BACKGROUND: The aim of this study was to explore the application of intravascular ultrasound (IVUS) to evaluate pulmonary vascular properties and mortality in patients with pulmonary arterial hypertension (PAH). METHODS: Patients (n = 51) with systolic pulmonary artery pressures >= 40 mm Hg on echocardiography were prospectively enrolled. All patients underwent right-heart catheterization and IVUS and were divided into three groups: PAH associated with connective tissue diseases (group 1, n = 25), PAH due to other causes (group 2, n = 15), and patients with connective tissue diseases without pulmonary hypertension (group 3, n = 11). PAH groups (groups 1 and 2) were divided into distal (n = 22) and proximal (n = 18) remodeling subtypes on the basis of IVUS results. All patients were followed (19 +/- 10 months) to compare the differences among clinical variables, pulmonary vascular properties, and survival rates. RESULTS: A total of 408 segments of pulmonary arteries were studied. The PAH groups demonstrated a greater mean wall thickness than group 3 (P < .01 for all). Pulmonary vascular mechanical properties, including compliance, distensibility, elastic modulus, and stiffness index beta, were found to be worse in the PAH groups than in group 3 (P < .01 for all), but they tended to be better in group 1 than in group 2. An inverse exponential association was found between pulmonary vascular mechanical properties and hemodynamics, with R(2) values ranging from 0.54 to 0.78 (P < .001). In the PAH groups, the mortality in group 1 was similar to that in group 2 (12% vs 13%, P > .05), while the distal remodeling subtype had higher mortality than the proximal remodeling subtype (23% vs 0%, P < .05). CONCLUSIONS: IVUS is useful in PAH assessment by evaluating pulmonary vascular properties and predicting mortality. The classification of the proximal and distal remodeling type of PAH may be proposed to predict mortality and evaluate the prognosis of patients with PAH in clinical practice. PMID- 26443046 TI - Chronic Inflammatory Disease Is an Independent Risk Factor for Coronary Flow Velocity Reserve Impairment Unrelated to the Processes of Coronary Artery Calcium Deposition. AB - BACKGROUND: Chronic inflammatory disease (CID) is a complex multisystem disease characterized by chronic inflammation, which can lead to coronary microvascular dysfunction (CMD) and can also predispose to coronary artery calcium deposition, even in the absence of obstructive coronary artery disease. METHODS: Twenty-one patients with systemic lupus erythematosus (SLE; mean age, 60 +/- 11 years), 21 patients with systemic sclerosis (SSc; mean age, 66 +/- 11 years), 32 patients with rheumatoid arthritis (RA; mean age, 65 +/- 9 years), and 23 control subjects with comparable traditional risk factors for coronary artery disease (mean age, 65 +/- 10 years) were prospectively enrolled in the outpatient clinic. All study participants underwent transthoracic Doppler-derived echocardiography for coronary flow velocity reserve (CFVR) measurement in the left anterior descending coronary artery; CFVR < 2.5 defined CMD. Coronary artery calcium score in the left anterior descending coronary artery was also assessed by computed tomography. RESULTS: None of study participants had obstructive coronary artery disease. The prevalence of CMD was 26% in the control group, 67% in the SLE group, 76% in the SSc group, and 63% in the RA group (P < .05, CID groups vs control group). CFVR was significantly lower in all three CID groups than in the control group (control group, 3.01 +/- 0.72; SLE group, 2.23 +/- 0.71; SSc group, 2.14 +/- 0.54; RA group, 2.33 +/- 0.62; P < .05, CID groups vs control group). In contrast, coronary artery calcium scores were similar in the four groups and had no relation to CMD. The odds ratios for CMD in patients with SLE, SSc, and RA were 16.70, 25.78, and 8.44 (P < .05) after adjusting for age, body mass index, the presence or absence of anemia, and hemoglobin level. Multiple linear regression analysis showed that only the presence of CID was independently associated with reduced CFVR among all study participants. CONCLUSIONS: CID strongly contributes to CMD identified by qualitative evaluation of CFVR independently of traditional coronary risk factors of atherosclerosis but does not predispose to coronary artery calcification. PMID- 26443047 TI - Is this STS work-related? ISO 1999 predictions as an adjunct to clinical judgment. AB - BACKGROUND: Physicians and audiologists are often asked to decide whether standard threshold shifts (STSs) are work-related; epidemiological data can inform these decisions. METHODS: Predictions of ISO (2013) for both age-related and noise-induced threshold shifts, for the 2, 3, and 4 kHz average used in calculating OSHA STSs, are presented, in tables, graphs, and an Excel spreadsheet calculator. Specifically, the ISO 1999 model estimates age-related thresholds based on age and sex; it estimates noise-induced threshold shifts based on noise level and duration. It specifies that to estimate the final hearing thresholds for a person of given percentile, age, sex, and noise exposure, the expected age related threshold is to be added to the expected noise-induced threshold shift. Examples show how these data can predict the relative contributions of aging and occupational noise to an STS. RESULTS: Early-career STSs, especially with high levels of noise exposure, are more likely to be primarily noise-induced. After the first decade of exposure, most STSs will be primarily age-related. CONCLUSION: Given a worker's age, sex, and occupational noise exposure history, ISO 1999 estimates of the expected contributions of aging and noise can supplement clinical judgment. PMID- 26443048 TI - Simvastatin inhibits neural cell apoptosis and promotes locomotor recovery via activation of Wnt/beta-catenin signaling pathway after spinal cord injury. AB - Statins exhibit neuroprotective effects after spinal cord injury (SCI). However, the molecular mechanism underlying these effects remains unknown. This study demonstrates that the hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin (Simv) exhibits neuroprotective effects on neuronal apoptosis and supports functional recovery in a rat SCI model by activating the Wnt/beta catenin signaling pathway. In specific, Simv administration after SCI significantly up-regulated the expression of low density lipoprotein receptor related protein 6 phosphorylation and beta-catenin protein, increased the mRNA expression of lymphoid enhancer factor-1 and T-cell factor-1, and suppressed the expression of beta-catenin phosphorylation in the spinal cord neurons. Simv enhanced motor neuronal survival in the spinal cord anterior horn and decreased the lesion of spinal cord tissues after SCI. Simv administration after SCI also evidently reduced the expression levels of Bax, active caspase-3, and active caspase-9 in the spinal cord neurons and the proportion of transferase UTP nick end labeling (TUNEL)-positive neuron cells, but increased the expression level of Bcl-2 in the spinal cord neurons. However, the anti-apoptotic effects of Simv were reduced in cultured spinal cord nerve cells when the Wnt/beta-catenin signaling pathway was suppressed in the lipopolysaccharide-induced model. Furthermore, the Basso, Beattie, and Bresnahan scores indicated that Simv treatment significantly improved the locomotor functions of rats after SCI. This study is the first to report that Simv exerts neuroprotective effects by reducing neuronal apoptosis, and promoting functional and pathological recovery after SCI by activating the Wnt/beta-catenin signaling pathway. We verified the neuroprotective properties associated with simvastatin following spinal cord injury (SCI). Simvastatin reduced neuronal apoptosis, improved the functional and pathological recovery via activating Wnt/beta-catenin signal pathway, however, the anti-apoptosis effects of simvastatin were reversed following suppressing Wnt/beta-catenin signaling pathway in primary spinal cord neurons. The significant findings may provide clinical therapeutic value of simvastatin for treating SCI. PMID- 26443049 TI - Psychobiology of threat appraisal in the context of psychotic experiences: a selective review. AB - A key factor in the transition to psychosis is the appraisal of anomalous experiences as threatening. Cognitive models of psychosis have identified attentional and interpretative biases underlying threat-based appraisals. While much research has been conducted into these biases within the clinical and cognitive literature, little examination has occurred at the neural level. However, neurobiological research in social cognition employing threatening stimuli mirror cognitive accounts of maladaptive appraisal in psychosis. This review attempted to integrate neuroimaging data regarding social cognition in psychosis with the concepts of attentional and interpretative threat biases. Systematic review methodology was used to identify relevant articles from Medline, PsycINFO and EMBASE, and PubMed databases. The selective review showed that attentional and interpretative threat biases relate to abnormal activation of a range of subcortical and prefrontal structures, including the amygdala, insula, hippocampus, anterior cingulate, and prefrontal cortex, as well as disrupted connectivity between these regions, when processing threatening and neutral or ambiguous stimuli. Notably, neural findings regarding the misattribution of threat to neutral or ambiguous stimuli presented a more consistent picture. Overall, however, the findings for any specific emotion were mixed, both in terms of the specific brain areas involved and the direction of effects (increased/decreased activity), possibly owing to confounds including small sample sizes, varying experimental paradigms, medication, and heterogeneous, in some cases poorly characterised, patient groups. Further neuroimaging research examining these biases by employing experimentally induced anomalous perceptual experiences and well-characterised large samples is needed for greater aetiological specificity. PMID- 26443050 TI - Suicidality in schizophrenia spectrum disorders: the relationship to hallucinations and persecutory delusions. AB - BACKGROUND: Assessment of suicide risk is crucial in schizophrenia and results concerning risk contributed by hallucinations and persecutory delusions are inconsistent. We aimed to determine factors associated with suicidal ideation and plans at the time of acute admission in patients suffering from schizophrenia spectrum disorders. METHODS: One hundred and twenty-four patients older than 18 years admitted to an acute psychiatric ward due to psychosis were consecutively included. Predictors of suicidal ideation and suicide plans at the time of admission were examined with multinominal logistic regression and structural equation modelling (SEM). The study design was pragmatic, thus entailing a clinically relevant representation. RESULTS: Depression Odds Ratio (OR) 12.9, Drug use OR 4.07, Hallucinations OR 2.55 and Negative symptoms OR 0.88 significantly predicted Suicidal ideation. Suspiciousness/ Persecution did not. Only Depression and Hallucinations significantly predicted Suicide plans. In the SEM-model Anxiety, Depression and Hopelessness connected Suspiciousness/Persecution, Hallucinations and Lack of insight with Suicidal ideation and Suicide plans. CONCLUSIONS: The study contributes to an increasing evidence base supporting an association between hallucinations and suicide risk. We want to emphasise the importance of treating depression and hallucinations in psychotic disorders, reducing hopelessness while working with insight and reducing drug abuse in order to lower suicide risk. TRIAL REGISTRATION: ClinicalTrials.gov ID; URL: http://www.clinicaltrials.gov/NCT00932529. PMID- 26443051 TI - The measurement invariance of schizotypy in Europe. AB - The short version of the Oxford-Liverpool Inventory of Feelings and Experiences (sO-LIFE) is a widely used measure assessing schizotypy. There is limited information, however, on how sO-LIFE scores compare across different countries. The main goal of the present study is to test the measurement invariance of the sO-LIFE scores in a large sample of non-clinical adolescents and young adults from four European countries (UK, Switzerland, Italy, and Spain). The scores were obtained from validated versions of the sO-LIFE in their respective languages. The sample comprised 4190 participants (M=20.87 years; SD=3.71 years). The study of the internal structure, using confirmatory factor analysis, revealed that both three (i.e., positive schizotypy, cognitive disorganisation, and introvertive anhedonia) and four-factor (i.e., positive schizotypy, cognitive disorganisation, introvertive anhedonia, and impulsive nonconformity) models fitted the data moderately well. Multi-group confirmatory factor analysis showed that the three factor model had partial strong measurement invariance across countries. Eight items were non-invariant across samples. Significant statistical differences in the mean scores of the s-OLIFE were found by country. Reliability scores, estimated with Ordinal alpha ranged from 0.75 to 0.87. Using the Item Response Theory framework, the sO-LIFE provides more accuracy information at the medium and high end of the latent trait. The current results show further evidence in support of the psychometric proprieties of the sO-LIFE, provide new information about the cross-cultural equivalence of schizotypy and support the use of this measure to screen for psychotic-like features and liability to psychosis in general population samples from different European countries. PMID- 26443052 TI - Religiosity and mental health of pre-adolescents with psychiatric problems and their parents: the TRAILS study. AB - BACKGROUND: This study investigated the association between the religiosity of parents and pre-adolescents, and pre-adolescents' psychiatric problems. METHOD: In a clinic-referred cohort of 543 pre-adolescents at least once referred to a mental health outpatient clinic mental health problems were assessed using self reports (Youth Self-Report; YSR), parent reports (Child Behavior Checklist; CBCL), and teacher reports (Teacher's Report Form; TRF) of child behavioral and emotional problems. Paternal, maternal, and pre-adolescent religiosity were assessed by self-report. MANCOVAs were performed for internalizing and externalizing problems as dependent variables, with maternal religiosity, paternal religiosity, pre-adolescent religiosity, parental religious harmony, and gender as independent variables, and socioeconomic status and divorce as covariates. RESULTS: Internalizing problems. Pre-adolescents of actively religious mothers had more internalizing symptoms than pre-adolescents of nonreligious mothers. Harmony and gender did not significantly affect the association between maternal religiosity and internalizing problems. Externalizing problems. No associations between religiosity of pre-adolescents, religiosity of mothers, religiosity of fathers and/or harmony of parents and externalizing problem behavior have been found. DISCUSSION AND CONCLUSIONS: Overall, associations between mental health and religiosity were modest to absent. Results are discussed in the context of a clinic-referred cohort, the quest phase of internalizing religious beliefs and role modeling of parents. PMID- 26443053 TI - Increased affective reactivity to neutral stimuli and decreased maintenance of affective responses in bipolar disorder. AB - BACKGROUND: Affective dysregulation is a core feature of bipolar disorder (BD) and a significant predictor of clinical and functional outcome. Affective dysregulation can arise from abnormalities in multiple processes. This study addresses the knowledge gap regarding the precise nature of the processes that may be dysregulated in BD and their relationship to the clinical expression of the disorder. METHODS: Patients with BD (n=45) who were either in remission or in a depressive or manic state and healthy individuals (n=101) were compared in terms of the intensity, duration and physiological response (measured using inter beat intervals and skin conductance) to affective and neutral pictures during passive viewing and during experiential suppression. RESULTS: Compared to healthy individuals, patients with BD evidenced increased affective reactivity to neutral pictures and reduced maintenance of subjective affective responses to all pictures. This pattern was present irrespective of clinical state but was more pronounced in symptomatic patients, regardless of polarity. Patients, regardless of symptomatic status, were comparable to healthy individuals in terms of physiological arousal and voluntary control of affective responses. CONCLUSION: Our study demonstrates that increased affective reactivity to neutral stimuli and decreased maintenance of affective responses are key dimensions of affective dysregulation in BD. PMID- 26443054 TI - Effect of DISC1 polymorphisms on the long-term course of neurocognitive deficits in non-affective psychosis. AB - Neurocognitive deficits are core symptoms of schizophrenia that determine a poorer outcome. High variability in the progression of neuropsychological deficits in schizophrenia has been described. It is still unknown whether genetic variations can affect the course of cognitive deficits. Variations in the Disrupted in Schizophrenia 1 (DISC1) gene have previously been associated with neurocognitive deficits. This study investigated the association between 3 DISC1 polymorphisms (rs6675281 (Leu607Phe), rs1000731, and rs821616 (Ser704Cys)) and long-term (3 years) cognitive performance. One-hundred-thirty-three Caucasian drug-naive patients experiencing a first episode of non-affective psychosis were genotyped. Cognitive function was assessed at baseline and after 3 years of initiating treatment. Other clinical and socio-demographic variables were recorded to eliminate potential confounding effects. Patients carrying the A allele of rs1000731 exhibited a significant improvement in Working Memory and Attention domains, and the homozygosity of the A allele of rs821616 showed a significant improvement in Motor Dexterity performance over 3 years of follow-up. In conclusion, DISC1 gene variations may affect the course of cognitive deficits found in patients suffering from the first episode of non-affective psychosis. PMID- 26443055 TI - The Rubber Hand Illusion paradigm as a sensory learning process in patients with schizophrenia. AB - OBJECTIVE: The Rubber Hand Illusion (RHI) has previously been used to depict the hierarchy between visual, tactile and perceptual stimuli. Studies on schizophrenia inpatients (SZs) have found mixed results in the ability to first learn the illusion, and have yet to explain the learning process involved. This study's aim was two-fold: to examine the learning process of the RHI in SZs and healthy controls over time, and to better understand the relationship between psychotic symptoms and the RHI. METHOD: Thirty schizophrenia inpatients and 30 healthy controls underwent five different trials of the RHI over a two-week period. RESULTS: As has been found in previous studies, SZs felt the initial illusion faster than healthy controls did, but their learning process throughout the trials was inconsistent. Furthermore, for SZs, no correlations between psychotic symptoms and the learning of the illusion emerged. CONCLUSION: Healthy individuals show a delayed reaction to first feeling the illusion (due to latent inhibition), but easily learn the illusion over time. For SZs, both strength of the illusion and the ability to learn the illusion over time are inconsistent. The cognitive impairment in SZ impedes the learning process of the RHI, and SZs are unable to utilize the repetition of the process as healthy individuals can. PMID- 26443056 TI - No correlation between rates of suicidal ideation and completed suicides in Europe: analysis of 49,008 participants (55+ years) based on the Survey of Health, Ageing and Retirement in Europe (SHARE). AB - BACKGROUND: Little is known about country-specific variations in suicidal ideation (SID) by sex and how they correspond with completed suicide rate. Therefore, the aim of the present study was to assess variations in SID prevalence rates by sex and its correlation to completed suicide rates across European countries. METHOD: SHARE is a cross-national European survey of individuals over the age of 50 and their spouse of any age. The present study relied on wave 4 conducted in 2010-2012 including 49,008 participants aged 55 to 104years from 16 countries. SID was evaluated using a single item from the Euro D. Data on completed suicide rates were taken from the WHO mortality database. RESULTS: Of the study population (n=49,008, 44.3% men, mean age 68.2+/-9.1years), a total of 4139 (8.5%, 95% CI 8.2-8.7) reported suicidal ideation within the last month. The women:men ratio in SID prevalence ranged from 1.30 in Estonia to 2.25 in Spain and Portugal. Regarding country-specific variation, the SID prevalence patterns of both men and women did not correspond to the completed suicide rates for males and females aged 55+ reported by the WHO (2013). Correlations were rather moderate in men (r=0.45) and especially weak in women (r=0.16). CONCLUSION: The study showed remarkable differences in SID prevalence by sex. The most exciting finding was that SID rates did not correspond with completed suicide rates in each country under investigation. However, the strength of these patterns substantially differs across countries. This unexpected finding need to be further evaluated. PMID- 26443057 TI - Factor structure of the Bern Psychopathology Scale in a sample of patients with schizophrenia spectrum disorders. AB - BACKGROUND: The Bern Psychopathology Scale (BPS) is based on a system-specific approach to classifying the psychopathological symptom pattern of schizophrenia. It consists of subscales for three domains (language, affect and motor behaviour) that are hypothesized to be related to specific brain circuits. The aim of the study was to examine the factor structure of the BPS in patients with schizophrenia spectrum disorders. METHODS: One hundred and forty-nine inpatients with schizophrenia spectrum disorders were recruited at the Department of Psychiatry II, Ulm University, Germany (n=100) and at the University Hospital of Psychiatry, Bern, Switzerland (n=49). Psychopathology was assessed with the BPS. The VARCLUS procedure of SAS((r)) (a type of oblique component analysis) was used for statistical analysis. RESULTS: Six clusters were identified (inhibited language, inhibited motor behaviour, inhibited affect, disinhibited affect, disinhibited language/motor behaviour, inhibited language/motor behaviour) which explained 40.13% of the total variance of the data. A binary division of attributes into an inhibited and disinhibited cluster was appropriate, although an overlap was found between the language and motor behaviour domains. There was a clear distinction between qualitative and quantitative symptoms. CONCLUSIONS: The results argue for the validity of the BPS in identifying subsyndromes of schizophrenia spectrum disorders according to a dimensional approach. Future research should address the longitudinal assessment of dimensional psychopathological symptoms and elucidate the underlying neurobiological processes. PMID- 26443058 TI - Characterization of cross-linked immobilized arylesterase from Gluconobacter oxydans 621H with activity toward cephalosporin C and 7-aminocephalosporanic acid. AB - Cross-linked enzyme aggregates (CLEAs) were prepared from several precipitant agents using glutaraldehyde as a cross-linking agent with and without BSA, finally choosing a 40% saturation of ammonium sulfate and 25 mM of glutaraldehyde. The CLEAs obtained under optimum conditions were biochemically characterized. The immobilized enzyme showed higher thermal activity and a broader range of pH and organic solvent tolerance than the free enzyme. Arylesterase from Gluconobacter oxydans showed activity toward cephalosporin C and 7-aminocephalosporanic acid. The CLEAs had a Kcat/KM of 0.9 M(-1) /S(-1) for 7-ACA (7-aminocephalosporanic acid) and 0.1 M(-1) /S(-1) for CPC (cephalosporin c), whereas free enzyme did not show a typical Michaelis-Menten kinetics. PMID- 26443060 TI - wKinMut-2: Identification and Interpretation of Pathogenic Variants in Human Protein Kinases. AB - Most genomic alterations are tolerated while only a minor fraction disrupts molecular function sufficiently to drive disease. Protein kinases play a central biological function and the functional consequences of their variants are abundantly characterized. However, this heterogeneous information is often scattered across different sources, which makes the integrative analysis complex and laborious. wKinMut-2 constitutes a solution to facilitate the interpretation of the consequences of human protein kinase variation. Nine methods predict their pathogenicity, including a kinase-specific random forest approach. To understand the biological mechanisms causative of human diseases and cancer, information from pertinent reference knowledge bases and the literature is automatically mined, digested, and homogenized. Variants are visualized in their structural contexts and residues affecting catalytic and drug binding are identified. Known protein-protein interactions are reported. Altogether, this information is intended to assist the generation of new working hypothesis to be corroborated with ulterior experimental work. The wKinMut-2 system, along with a user manual and examples, is freely accessible at http://kinmut2.bioinfo.cnio.es, the code for local installations can be downloaded from https://github.com/Rbbt Workflows/KinMut2. PMID- 26443059 TI - Sgf73, a subunit of SAGA complex, is required for the assembly of RITS complex in fission yeast. AB - RNA interference (RNAi) is a widespread gene-silencing mechanism and is required for heterochromatin assembly in a variety of organisms. The RNA-induced transcriptional silencing complex (RITS), composed of Ago1, Tas3 and Chp1, is a key component of RNAi machinery in fission yeast that connects short interference RNA (siRNA) and heterochromatin formation. However, the process by which RITS is assembled is not well understood. Here, we identified Sgf73, a subunit of the SAGA co-transcriptional complex, is required for pericentromeric heterochromatin silencing and the generation of siRNA. This novel role of Sgf73 is independent of enzymatic activities or structural integrity of SAGA. Instead, Sgf73 is physically associated with Ago1 and Chp1. The interactions among the subunits of the RITS, including those between Tas3 and Chp1, between Chp1 and Ago1, between Ago1 and Tas3, were all impaired by the deletion of sgf73(+). Consistently, the recruitment of Ago1 and Chp1 to the pericentromeric region was abolished in sgf73Delta cells. Our study unveils a moonlighting function of a SAGA subunit. It suggests Sgf73 is a novel factor that promotes assembly of RITS and RNAi-mediated heterochromatin formation. PMID- 26443061 TI - Pigeons are resistant to experimental infection with H7N9 avian influenza virus. AB - To determine the susceptibility of pigeons to the newly emerged avian influenza virus subtype H7N9, we experimentally infected three different types of pigeons (meat, town, and racing) with two different doses (2 * 10(4) or 2 * 10(5) EID50) of H7N9 avian influenza virus A/Chicken/China/2013 by either intranasal and intraocular inoculation (IN + IO) or intravenous injection (IV). In addition, the potential transmission of H7N9 to pigeons by direct close contact with experimentally infected pigeons and chickens was assessed. Results showed that none of the experimentally infected pigeons exhibited any clinical signs regardless of the infection route and dose. Of the 12 racing pigeons that were randomly selected and necropsied, none of them had any gross lesions. In agreement with this finding, virus was not isolated from all pigeons. No detectable H7-specific antibodies were found in any pigeon. In contrast, 11 of 31 chickens that were either directly infected with H7N9 by IN + IO inoculation or by contact with IN + IO-infected chickens had conjunctivitis. Virus was isolated from all 31 chickens and H7-specific antibodies were detected in these chickens. However, none of the IV-infected chickens or chickens in direct contact with IV infected chickens had any clinical signs. No virus was isolated from these chickens and no H7-specific antibody was detected. Overall, we conclude that pigeons are less or not susceptible to the H7N9 virus at the doses used and are not likely to serve as a reservoir for the virus. However, the virus does cause conjunctivitis in chickens and can transmit to susceptible hosts by direct contact. PMID- 26443062 TI - Comparison of four molecular assays for the detection of Tembusu virus. AB - Tembusu virus (TMUV) belongs to the genus Flavivirus that may cause severe egg drop in ducks. In order to evaluate the most efficient TMUV detection method, the performances of a conventional RT-PCR (C-RT-PCR), a semi-nested PCR (SN-RT-PCR), a reverse-transcriptase real-time quantitative PCR (Q-RT-PCR), and a reverse transcription loop-mediated isothermal amplification (RT-LAMP) targeting the TMUV virus-specific NS5 gene were examined. In order to compare the sensitivity of these four techniques, two templates were used: (1) plasmid DNA that contained a partial region of the NS5 gene and (2) genomic RNA from TMUV-positive cell culture supernatants. The sensitivities using plasmid DNA detection by C-RT-PCR, SN-RT-PCR, Q-RT-PCR, and RT-LAMP were 2 * 10(4) copies/MUL, 20 copies/MUL, 2 copies/MUL, and 20 copies/MUL, respectively. The sensitivities using genomic RNA for the C-RT-PCR, SN-RT-PCR, Q-RT-PCR, and RT-LAMP were 100 pg/tube, 100, 10, and 100 fg/tube, respectively. All evaluated assays were specific for TMUV detection. The TMUV-specific RNA was detected in cloacal swabs from experimentally infected ducks using these four methods with different rates (52-92%), but not in the control (non-inoculated) samples. The sensitivities of RT-PCR, SN-RT-PCR, Q-RT PCR, and RT-LAMP performed with cloacal swabs collected from suspected TMUV infected ducks within 2 weeks of severe egg-drop were 38/69 (55.1%), 52/69 (75.4%), 57/69 (82.6%), and 55/69 (79.7%), respectively. In conclusion, both RT LAMP and Q-RT-PCR can provide a rapid diagnosis of TMUV infection, but RT-LAMP is more useful in TMUV field situations or poorly equipped laboratories. PMID- 26443063 TI - Immunogenic and protective efficacy of recombinant protein GtxA-N against Gallibacterium anatis challenge in chickens. AB - Gallibacterium anatis is a major cause of reproductive tract infections in chickens. Here, we aimed to evaluate the efficacy of the recombinant protein GtxA N at protecting hens, by addressing three objectives; (i) evaluating the antibody response following immunization (ii) scoring and comparing lesions, following challenge with G. anatis, in immunized and non-immunized hens and (iii) investigating if the anti-GtxA-N antibody titre in individual hens correlated with the observed lesions. Two consecutive experiments were performed in hens. In the first experiment hens were immunized with GtxA-N on day 0 and day 14, infected with G. anatis on day 28 and euthanized on day 56. The GtxA-N antibody response was assessed in pooled serum samples throughout the experiment, using an indirect enzyme-linked immunosorbent assay (ELISA). In the second experiment the GtxA-N antibody titres were assessed in individual hens before and after immunization. Subsequently, the hens were inoculated with G. anatis and finally all hens where euthanized and submitted for post mortem examination 48 h after inoculation. Immunization elicited strong antibody responses that lasted at least 8 weeks (P < .0001). The individual antibody titres observed in response to immunization varied considerably among hens (range: 174,100-281,500). Lesion scores following G. anatis infection were significantly lower in immunized hens compared to non-immunized hens (P = .004). Within the immunized group, no correlation was found between the individual antibody titres and the lesion scores. This study clearly demonstrated GtxA-N as a vaccine antigen able of inducing protective immunity against G. anatis. PMID- 26443064 TI - The contribution of aerobic and anaerobic respiration to intestinal colonization and virulence for Salmonella typhimurium in the chicken. AB - The basic mechanism whereby Salmonella serovars colonize the chicken intestine remains poorly understood. Previous studies have indicated that proton translocating proteins utilizing oxygen as terminal electron acceptor do not appear to be of major importance in the gut of the newly hatched chicken and consequently they would be even less significant during intestinal colonization of more mature chickens where the complex gut microflora would trap most of the oxygen in the lumen. Consequently, alternative electron acceptors may be more significant or, in their absence, substrate-level phosphorylation may also be important to Salmonella serovars in this environment. To investigate this we constructed mutants of Salmonella enterica serovar Typhimurium defective in various aspects of oxidative or substrate-level phosphorylation to assess their role in colonization of the chicken intestine, assessed through faecal shedding, and virulence. Mutations affecting use of oxygen or alternative electron acceptors did not eliminate faecal shedding. By contrast mutations in either pta (phosphotransacetylase) or ackA (acetate kinase) abolished shedding. The pta but not the ackA mutation also abolished systemic virulence for chickens. An additional ldhA (lactate dehydrogenase) mutant also showed poor colonizing ability. We hypothesise that substrate-level phosphorylation may be more important than respiration using oxygen or alternative electron acceptors for colonization of the chicken caeca. PMID- 26443066 TI - Intraoral digital impression for fabricating a replica of an implant-supported interim prosthesis. AB - Even though a customized scannable impression coping is used, the precise replication of the emergent profile developed by an implant-supported interim prosthesis (ISIP) is difficult. This article describes a method for overcoming the limitations of a customized scannable impression coping. With this technique, a customized scannable impression coping is eliminated, and the information from an ISIP is obtained. PMID- 26443067 TI - Effect of gingival displacement cord and cordless systems on the closure, displacement, and inflammation of the gingival crevice. AB - STATEMENT OF PROBLEM: The gingival sulcus should remain open long enough for the impression material to flow into it and completely fill the space provided by the gingival displacement. Impressions with less sulcal width have a higher incidence of voids, tearing of impression materials, and reduction in marginal accuracy. PURPOSE: The purpose of this clinical study was to investigate the closure, gingival displacement, and gingival inflammation of the gingival crevice after the use of medicated gingival displacement cord and cordless systems. MATERIAL AND METHODS: Gingival sulcus closure was studied in 40 participants. They were divided into 4 groups: 2 cord (Ultrapack, SilTrax AS) and 2 cordless (Expasyl, Traxodent Hemodent paste) methods. The labial surfaces of the maxillary right and left central incisors were evaluated. Gingival sulcus was photographed every 20 seconds from 0 to 180 seconds after the removal of the cord or cordless system. The bleeding index (BI) and gingival index (GI) were measured at day 0, day 1, and day 7. The width of the sulcal orifice was measured at the mid-buccal (MB) and transitional line angle (TLA) on a digital image, using computer software (Photoshop version 7.0; Adobe). Data were analyzed with ANOVA, Tukey honest significant difference (HSD), Kruskal-Wallis, and Mann-Whitney U tests (alpha=.05). RESULTS: All groups showed a sulcal width greater than 0.22 mm up to 60 seconds after the removal of the displacement materials at the MB and up to 40 seconds at the TLA. Among all groups, Expasyl showed the fastest closure. Gingival displacement in the MB area for the cord group was greater than for the cordless groups. GI and BI indices were larger for the cord group than for the cordless group at days 0 and 1. CONCLUSIONS: At up to 60 seconds, the cord and cordless techniques were equally effective. The cord group showed a greater amount of displacement than the cordless group. However, the cordless materials showed reduced frequency of changes to the gingival index. PMID- 26443068 TI - Relationship between impact of maxillary anterior fixed prosthodontic rehabilitation on daily living, satisfaction, and personality profiles. AB - STATEMENT OF PROBLEM: Personality profiles may affect the impact of dental treatment on daily living and patient satisfaction. PURPOSE: The purpose of this clinical trial was to evaluate the impact of maxillary anterior fixed prosthodontic rehabilitation on daily living and the satisfaction of patients and to investigate its relationship with personality profiles. MATERIAL AND METHODS: Fifty-nine participants (25 men and 34 women; mean age 32.4 +/- 6.9 years) received maxillary anterior partial fixed dental prostheses. The clinical success of the prostheses was evaluated following specific criteria. The Dental Impact on Daily Living (DIDL) questionnaire was used to measure satisfaction with the prostheses and their impact on daily living. The Neuroticism-Extraversion Openness Five-Factor Inventory (NEO-FFI) was used to measure patients' personality profiles. The paired sample t test was used to compare satisfaction and personality scores before and after treatment (alpha=.05). RESULTS: Participants' total satisfaction and their satisfaction with appearance, pain tolerance, oral comfort, general performance, and eating improved after treatment (P<.05). Before treatment, women were less satisfied with general performance (P=.047) and scored higher on the Neuroticism score (P=.039); however, after treatment, women were more satisfied with appearance (P=.004). Age and sex had no significant correlation with personality profiles after treatment. Before treatment, Neuroticism, Openness, and Conscientiousness scores were associated with dental satisfaction and impact on daily life (P<.05). After treatment, Neuroticism, Openness, and Extraversion scores were associated with dental satisfaction and impact on daily life (P<.05). CONCLUSIONS: Patient satisfaction with their oral condition improved after partial fixed dental prosthetic rehabilitation in the maxillary anterior esthetic zone. Psychological profiles (Neuroticism, Extraversion, Openness, and Conscientiousness) may be involved in and explain the impact on daily living and the degree of patient satisfaction with their prostheses. PMID- 26443069 TI - Self-Relay Gold(I)-Catalyzed Pictet-Spengler/Cyclization Cascade Reaction for the Rapid Elaboration of Pentacyclic Indole Derivatives. AB - Gold-catalyzed cascade reactions allow the rapid elaboration of pentacyclic indolo[2,3-a]quinolizidines from N-allyl tryptamines and ortho alkynylarylaldehydes. The tandem process combines a gold-catalyzed Pictet Spengler reaction and a cyclization occurring concomitantly with an allyl transfer from the nitrogen atom to the stilbene function. Various substituted allyls were successfully transferred, furnishing the products in yields typically ranging from 60-98 % in high diastereoselectivity. Tryptamines bearing a butenol chain undergo an additional cyclization to chiral hemiaminals in high diastereoselectivities. PMID- 26443070 TI - Cytomegalovirus immunodiagnostics: Getting closer to personalized cytomegalovirus prevention? PMID- 26443071 TI - Editorial: Looking back and also into the future of Acta Anaesthesiologica Scandinavica. PMID- 26443072 TI - Erratum. AB - Kim SY, Huh KH, Roh YH, Oh YJ, Park J, Choi YS. Nefopam as an adjunct to intravenous patient-controlled analgesia after renal transplantation: a randomised trial. Acta Anaesthesiologica Scandinavica, 59(8), 1068-1075. DOI: 10.1111/aas.12519. In the article "Nefopam as an adjunct to intravenous patient controlled analgesia after renal transplantation: a randomised trial", the published title of vertical axis B in Figure 2 which is 'Pain at rest' was incorrect. The correct title of the vertical axis B is 'Pain on coughing.' The correct figure 2 has been reproduced here for clarity. We apologize for any inconvenience caused. PMID- 26443073 TI - Regulatory T cells induction by autologous mesenchymal stromal cells infusion in kidney transplant: Does the 'immunosuppression' matter? PMID- 26443074 TI - Arthrobacter sanguinis: an uncommon cause of peritonitis in a peritoneal dialysis patient. PMID- 26443075 TI - Analysis and characterization of anthocyanins and carotenoids in Japanese blue tomato. AB - Tomato (Solanum lycopersicum) is rich in anthocyanins, which are polyphenolic pigments. This study aimed to analyze and characterize the anthocyanin composition in cultivated blue tomato in Japan. The extracts of peel, seed, and pulp of tomatoes were purified following which anthocyanins and lycopene contents were analyzed using high-performance liquid chromatography and electrospray ionization mass spectrometry. Eleven types of anthocyanins were identified, including delphinidin, petunidin, and malvidin. Further, the antioxidant activity of anthocyanins was evaluated using 2,2'-azino-bis-(3-ethylbenzthiazoline-6 sulfonic acid) diammonium salt radical quenching assays and electron spin resonance. "Blue tomato" extracts exert antioxidant activity. Thus, we showed that petunidin was present in the "blue tomato" peel while lycopene was present in the peel and pulp. Additionally, the blue tomato peel extract was found to significantly inhibit H2O2-induced cell death in vitro. This is the first study on cell protective effects of Japanese blue tomato extract and petunidin in murine photoreceptor cells. PMID- 26443077 TI - Synthesis and characterization of a trans-1 hexakis-fullerene linker that forms crystalline polymers with silver salts. AB - A new flexible hexakis-fullerene adduct with two bis(pyridin-4-ylmethyl)malonate groups located at trans-1 positions was synthesized. Via reaction with Ag(PF6) under two different conditions, two new 1D coordination polymers were obtained; under a nitrogen atmosphere, the silver ions are connected by argentophilic interactions but under an ambient atmosphere, the silver ions exhibit no interaction between them but coordination to the (H2PO4)(-) ions. PMID- 26443076 TI - Rational Design of Benzylidenehydrazinyl-Substituted Thiazole Derivatives as Potent Inhibitors of Human Dihydroorotate Dehydrogenase with in Vivo Anti arthritic Activity. AB - Human dihydroorotate dehydrogenase (hDHODH) is an attractive therapeutic target for the treatment of rheumatoid arthritis, transplant rejection and other autoimmune diseases. Based on the X-ray structure of hDHODH in complex with lead compound 7, a series of benzylidenehydrazinyl-substituted thiazole derivatives as potent inhibitors of hDHODH were designed and synthesized, of which 19 and 30 were the most potent with IC50 values in the double-digit nanomolar range. Moreover, compound 19 displayed significant anti-arthritic effects and favorable pharmacokinetic profiles in vivo. Further X-ray structure and SAR analyses revealed that the potencies of the designed inhibitors were partly attributable to additional water-mediated hydrogen bond networks formed by an unexpected buried water between hDHODH and the 2-(2-methylenehydrazinyl)thiazole scaffold. This work not only elucidates promising scaffolds targeting hDHODH for the treatment of rheumatoid arthritis, but also demonstrates that the water-mediated hydrogen bond interaction is an important factor in molecular design and optimization. PMID- 26443078 TI - Discovery of Selective Histone Deacetylase 6 Inhibitors Using the Quinazoline as the Cap for the Treatment of Cancer. AB - Novel selective histone deacetylase 6 (HDAC6) inhibitors using the quinazoline as the cap were designed, synthesized, and evaluated for HDAC enzymatic assays. N Hydroxy-4-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)butanamide, 23bb, was the most potent selective inhibitor for HDAC6 with an IC50 of 17 nM and showed 25-fold and 200-fold selectivity relative to HDAC1 and HDAC8, respectively. In vitro, 23bb presented low nanomolar antiproliferative effects against panel of cancer cell lines. Western blot analysis further confirmed that 23bb increased acetylation level of alpha-tubulin in vitro. 23bb has a good pharmacokinetic profile with oral bioavailability of 47.0% in rats. In in vivo efficacy evaluations of colorectal HCT116, acute myelocytic leukemia MV4-11, and B cell lymphoma Romas xenografts, 23bb more effectively inhibited the tumor growth than SAHA even at a 4-fold reduced dose or ACY-1215 at the same dose. Our results indicated that 23bb is a potent oral anticancer candidate for selective HDAC6 inhibitor and deserves further investigation. PMID- 26443080 TI - The network organization of protein interactions in the spliceosome is reproduced by the simple rules of food-web models. AB - The network structure of biological systems provides information on the underlying processes shaping their organization and dynamics. Here we examined the structure of the network depicting protein interactions within the spliceosome, the macromolecular complex responsible for splicing in eukaryotic cells. We show the interactions of less connected spliceosome proteins are nested subsets of the connections of the highly connected proteins. At the same time, the network has a modular structure with groups of proteins sharing similar interaction patterns. We then investigated the role of affinity and specificity in shaping the spliceosome network by adapting a probabilistic model originally designed to reproduce food webs. This food-web model was as successful in reproducing the structure of protein interactions as it is in reproducing interactions among species. The good performance of the model suggests affinity and specificity, partially determined by protein size and the timing of association to the complex, may be determining network structure. Moreover, because network models allow building ensembles of realistic networks while encompassing uncertainty they can be useful to examine the dynamics and vulnerability of intracelullar processes. Unraveling the mechanisms organizing the spliceosome interactions is important to characterize the role of individual proteins on splicing catalysis and regulation. PMID- 26443081 TI - New insights to lateral rooting: Differential responses to heterogeneous nitrogen availability among maize root types. AB - Historical domestication and the "Green revolution" have both contributed to the evolution of modern, high-performance crops. Together with increased irrigation and application of chemical fertilizers, these efforts have generated sufficient food for the growing global population. Root architecture, and in particular root branching, plays an important role in the acquisition of water and nutrients, plant performance, and crop yield. Better understanding of root growth and responses to the belowground environment could contribute to overcoming the challenges faced by agriculture today. Manipulating the abilities of crop root systems to explore and exploit the soil environment could enable plants to make the most of soil resources, increase stress tolerance and improve grain yields, while simultaneously reducing environmental degradation. In this article it is noted that the control of root branching, and the responses of root architecture to nitrate availability, differ between root types and between plant species. Since the control of root branching depends upon both plant species and root type, further work is urgently required to determine the appropriate genes to manipulate to improve resource acquisition by specific crops. PMID- 26443079 TI - Kinases as druggable targets in trypanosomatid protozoan parasites. PMID- 26443082 TI - Metastable orientational order of colloidal discoids. AB - The interplay between phase separation and kinetic arrest is important in supramolecular self-assembly, but their effects on emergent orientational order are not well understood when anisotropic building blocks are used. Contrary to the typical progression from disorder to order in isotropic systems, here we report that colloidal oblate discoids initially self-assemble into short, metastable strands with orientational order-regardless of the final structure. The model discoids are suspended in a refractive index and density-matched solvent. Then, we use confocal microscopy experiments and Monte Carlo simulations spanning a broad range of volume fractions and attraction strengths to show that disordered clusters form near coexistence boundaries, whereas oriented strands persist with strong attractions. We rationalize this unusual observation in light of the interaction anisotropy imparted by the discoids. These findings may guide self-assembly for anisotropic systems in which orientational order is desired, such as when tailored mechanical properties are sought. PMID- 26443083 TI - Fishing the targets of myeloid malignancies in the era of next generation sequencing. AB - Recent advent in next generation sequencing (NGS) and bioinformatics has generated an unprecedented amount of genetic information in myeloidmalignancies. This information may shed lights to the pathogenesis, diagnosis and prognostication of these diseases and provide potential targets for therapeutic intervention. However, the rapid emergence of genetic information will quickly outpace their functional validation by conventional laboratory platforms. Foundational knowledge about zebrafish hematopoiesis accumulated over the past two decades and novel genomeediting technologies and research strategies in thismodel organismhavemade it a unique and timely research tool for the study of human blood diseases. Recent studies modeling human myeloid malignancies in zebrafish have also highlighted the technical feasibility and clinical relevance of thesemodels. Careful validation of experimental protocols and standardization among laboratorieswill further enhance the application of zebrafish in the scientific communities and provide important insights to the personalized treatment ofmyeloid malignancies. PMID- 26443084 TI - Monitoring communication with patients: analyzing judgments of satisfaction (JOS). AB - Medical students struggle to put into practice communication skills learned in medical school. In order to improve our instructional designs, better insight into the cause of this lack of transfer is foundational. We therefore explored students' cognitions by soliciting self-evaluations of their history-taking skills, coined 'judgments of satisfaction (JOSs)'. Our cognitive-psychological approach was guided by Koriat's cue-utilization framework (J Exp Psychol Gen 126:349-370. doi: 10.1037/0096-3445.126.4.349 , 1997) which rests on the assumption that internal and external cues inform learners' metacognitive judgments, which, in turn, steer their actions. Judgments based on unsuitable cues will cause ineffective behavior. Consequently, students are unable to adequately master these skills or properly apply them in similar situations. For the analysis, we had 524 medical undergraduates select scenes they were satisfied or dissatisfied with from their video-recorded simulated-patient encounters and explain why. Twenty transcripts were sampled for directed content analysis. We found that approximately one-third of students' judgments focused on content (JOS type-a); about half on the quality of the communication skills (JOS-type-b); and about ten percent targeted the appropriateness of the skills harnessed (JOS-type c). This lack of reflection on appropriateness may explain why students experience problems adapting to new situations. It was primarily high-performance students who formed type-c judgments; poor performers tended to give type-a and type-b judgments. Future research would benefit from the use of our modified version of Koriat's framework in order to further explore how high and poor performing medical students differ in the way they form JOSs during communications skills training. PMID- 26443085 TI - Critical review: medical students' motivation after failure. AB - About 10 % of students in each years' entrants to medical school will encounter academic failure at some stage in their programme. The usual approach to supporting these students is to offer them short term remedial study programmes that often enhance approaches to study that are orientated towards avoiding failure. In this critical review I will summarise the current theories about student motivation that are most relevant to this group of students and describe how they are enhanced or not by various contextual factors that medical students experience during their programme. I will conclude by suggesting ways in which support programmes for students who have encountered academic failure might be better designed and researched in the future. PMID- 26443087 TI - The First Published Case Report of an Adult Woman Who Developed Suicidal Ideation as an Adverse Event Related to Methylphenidate Use. PMID- 26443086 TI - Knowingly not wanting to know: Discourses of people diagnosed with mild cognitive impairment. AB - Mild cognitive impairment is a heterogeneous clinical state whereby assessed cognitive changes over time may progress to dementia, remain stable or revert to back to normal. This study aimed to identify, through discourse analysis, how people with a diagnosis of mild cognitive impairment used language in order to reveal the societal views and shared meanings of the diagnosis, and the positions taken by people. Seven people with mild cognitive impairment were interviewed, and three discourses emerged during analysis. One of the discourses revealed was 'Not Knowing' about mild cognitive impairment. Furthermore, in the absence of a coherent discourse related to mild cognitive impairment, participants went on to position themselves between two more familiar discourse; 'Knowing' about ageing and dying and 'Not Wanting to Know' about dementia. Clinicians must consider how information is presented to people about mild cognitive impairment, including where mild cognitive impairment is positioned in respect to normal ageing and dementia. PMID- 26443088 TI - Impact of cancer on the effectiveness of cardiac Troponin I to predict right ventricular dysfunction in acute pulmonary embolism. AB - BACKGROUND: Deep vein thrombosis (DVT) and pulmonary embolism (PE) are connected with a poor outcome in cancer patients. We aimed to investigate the impact of cancer on the effectiveness of cardiac Troponin I (cTnI) to predict right ventricular dysfunction (RVD) in acute PE. METHODS: We retrospectively analyzed the data of 182 patients with confirmed PE. PE patients were subdivided into two groups: (i) with concomitant active cancer disease or history of cancer, and (ii) without known cancer. Receiver operating characteristic (ROC) curves with area under the curve (AUC) was calculated for cTnI predicting RVD and related cut-off levels for both groups. RESULTS: Thirty-seven PE patients (20.3%) had an active cancer disease or a history of cancer. In contrast, 145 (79.7%) of the included PE patients did not have a known cancer disease or a history of cancer. In the PE group with cancer, analysis of the ROC curve showed an AUC of 0.76 for cTnI predicting RVD with an optimal cut-off value of 0.04 ng/mL; the risk of misclassification was 25.0%. In the PE group without cancer, AUC was 0.81 for cTnI predicting RVD with an optimal cut-off value of 0.015 ng/mL; the risk of misclassification was 24.9%. CONCLUSIONS: cTnI is effective for predicting RVD in PE patients with and without cancer. However, the effectiveness of cTnI to predict RVD was higher in PE patients without cancer than in those with cancer or a history of cancer. PMID- 26443089 TI - Helicobacter cinaedi knee infection after arthroscopy in an immunocompetent patient. AB - An otherwise healthy 36-year-old man was hospitalised due to a traumatic tear of the meniscus in the left knee. An arthroscopy was performed and his meniscus was partially resected. Thirty days later, he was rehospitalised with arthritis in the left knee and cellulitis on the left tibia. Helicobacter cinaedi was isolated from the synovial fluid, which was incubated in a BACTEC Paediatric bottle. The patient was treated with oral rifampicin and moxifloxacin for 6 weeks with good clinical response without relapse. The source of the infection was not found. The case emphasises the importance of incubating the synovial fluid in a rich medium such as a BACTEC Peds Plus/F bottle. Physicians and microbiologists should be aware of H. cinaedi as a human pathogen causing a range of disease manifestations, including infective arthritis and cellulitis, particularly if symptoms evolve in the weeks following a surgical procedure. PMID- 26443090 TI - Acute appendicitis presenting as pneumoperitoneum in a teenage boy undergoing chemotherapy. AB - Chemotherapy of paediatric haematological malignancies can induce infectious complications of the gastrointestinal tract, with predilection of the ileocaecal region. Common causes of right lower abdominal pain in the febrile patient with neutropaenia include acute appendicitis, typhlitis, ileus and intussusception. In this case report, we describe a teenage boy with acute appendicitis presenting with pneumoperitoneum during his course of chemotherapy. The incidence, aetiology, diagnosis, investigations and management of this uncommon presentation in a common disease are discussed. The controversial topic of the management of acute appendicitis in a febrile patient with neutropaenia is also reviewed and discussed. PMID- 26443091 TI - Neonatal small left colon syndrome. PMID- 26443092 TI - A 75-year-old woman with acquired haemophilia disguised by warfarin treatment. AB - Acquired haemophilia is a rare coagulation disorder more commonly seen in elderly patients. Diagnosis and effective treatment can be delayed if patients are on warfarin treatment, as the bleeding symptoms may be erroneously attributed to this agent. We present a case report of a 75-year-old woman whose unexplained, severe and persistent bleeding was treated with surgical decompression and plasma transfusions, an appropriate management based on the assumption that warfarin was the cause of the bleeding. It was only when the patient's international normalised ratio returned to normal that a persistent abnormal activated partial thromboplastin time was noted. This delayed the correct diagnosis and treatment. Awareness of acquired haemophilia as a possible cause of sudden bleeding should be encouraged, and the wider dissemination of any relevant experience of similar cases would also be welcome. PMID- 26443093 TI - Paediatric trauma with hyperamylasemia. AB - In this case report, we describe a paediatric case of hyperamylasemia following parotid trauma. A 12-year-old boy was hit by a motorcycle, sustaining only superficial lacerations to the face overlying the parotid. A hyperamylasemia was noted, and further characterised by a fractionated isoamylase test, as being predominantly of the salivary type. Serum lipase levels were low. Based on these investigations, pancreatic injury was judged unlikely with the minor parotid trauma being the probable source of the hyperamylasemia. The patient was spared further unnecessary investigations and managed conservatively. PMID- 26443094 TI - An unusual inguinoscrotal hernia with renal involvement. AB - We present a case of a 74-year-old man who, while in intensive treatment unit for an upper gastrointestinal bleed, decompensated cardiac failure and concurrent pneumonia, was found to have a large right hydronephrotic pelvic kidney and bladder within the hernia. After discharge, he was medically optimised for 7 months before undergoing an elective open mesh repair of his hernia. During the procedure, drainage of a large hydrocoele was performed to facilitate reduction of the hernia. Postoperatively, he underwent ureteric stenting due to a persistent hydronephrosis with impairment of his renal function. He subsequently made a good recovery and was discharged home with outpatient follow-up planned. PMID- 26443096 TI - Severe bone and mineral disease in an adolescent with chronic kidney disease: a case from the 70s? PMID- 26443095 TI - Multiple embolic cerebral infarcts as the first manifestation of metastatic ovarian cancer. AB - A 36-year-old woman presented to the emergency department with a 3-day history of an occipital headache associated with transient visual impairment and short-term memory loss. MRI of the brain showed innumerable focal embolic infarcts of differing ages, for which a cause could not be determined. The patient was discharged and readmitted 7 weeks later with acute aphasia and a right-sided hemiplegia. CT of the abdomen revealed a right-sided ovarian mass and prominent retroperitoneal nodes, which cytology confirmed to be metastatic ovarian cancer. PMID- 26443097 TI - Reversed ocular ischaemic syndrome secondary to carotid cavernous sinus embolisation. AB - Ocular ischaemic syndrome is a progressive and serious vision-threatening condition that is usually associated with carotid artery disease, and poor effective therapeutic options are available. In the present case, a 65-year-old woman was submitted to embolisation of spontaneous carotid-cavernous fistula with complete resolution of initial ophthalmoplaegia and ocular hypertension. Later, ocular ischaemia was detected. Cerebral angiography showed delayed choroidal flush and the patient was admitted for hypervolaemic hypertension therapy and medicated with nimodipine. The ischaemia was reversed and visual function improved. PMID- 26443098 TI - Tuberculous pseudoaneurysm of the ascending aorta. AB - Increase in the incidence of drug resistance and association with HIV has led to a resurgence of tuberculosis. However, tubercular arteritis continues to remain a rare entity with a prelidection for the thoracic aorta. We report a tubercular ascending aortic pseudoaneurysm in a patient already on treatment for disseminated tuberculosis who underwent successful surgical repair and also review literature pertaining to this entity. PMID- 26443099 TI - Iron-induced gastric ulceration with radiological and endoscopic appearance of carcinoma. AB - Erosive injury of the upper gastrointestinal tract resulting from therapeutic oral iron supplements is an uncommon phenomenon. We present a case of a large gastric ulcer with clinical, endoscopic and radiological features suggestive of malignancy, which resolved completely on cessation of iron therapy. PMID- 26443100 TI - Acute myeloid leucaemia with trisomy 14 as a sole cytogenetic abnormality. PMID- 26443101 TI - Short-term outcomes following elective transcatheter arterial embolization for splenic artery aneurysms: data from a nationwide administrative database. AB - BACKGROUND: Splenic artery aneurysm (SAA) rupture is life-threatening. Although elective transcatheter arterial embolization (TAE) suggested low in-hospital death in previous studies, there has been no large multi-center study of elective TAE for SAA. PURPOSE: To examine the short-term outcomes of TAE for splenic artery aneurysm (SAA) and analyze the factors associated with the outcomes, including liver cirrhosis, using a nationwide administrative inpatient database. MATERIAL AND METHODS: We identified patients who received elective TAE with a principal diagnosis of SAA. We assessed the patient background characteristics, comprising age, sex, and specific co-morbidities, including liver cirrhosis. The outcomes included the rate of TAE-related complications (acute pancreatitis, splenic infarction, splenic abscess, or intraperitoneal hematoma), length of stay, and in-hospital mortality. RESULTS: Among 18.3 million inpatients in the database between July 2010 and March 2013, we identified 534 patients who received elective TAE for SAA at 229 participating hospitals. Fifty-four (10.1%) patients had liver cirrhosis. No in-hospital deaths were observed. Thirty-two (6.0%) patients had at least one TAE-related complication. A multivariate linear regression analysis revealed that liver cirrhosis was significantly associated with longer length of stay (9.5 days; 95% confidence interval [CI], 7.0-12.0 days; P < 0.001). A logistic regression analysis showed that liver cirrhosis was not significantly associated with TAE-related complications (odds ratio, 0.99; 95% CI, 0.29-3.39; P = 0.980). CONCLUSION: The results revealed no in-hospital mortality and a low complication rate associated with elective TAE for SAA including liver cirrhosis patients. PMID- 26443102 TI - Surface engineering for an enhanced photoelectrochemical response of TiO2 nanotube arrays by simple surface air plasma treatment. AB - A simple method to improve the photoelectrochemical performance of TiO2 nanotube arrays (NTs) by simple air plasma post-treatment is reported. The air plasma treated sample shows higher photocurrent density and incident photo current efficiency with high stability, about 3-4 times that of the pristine TiO2 NTs even after six months. PMID- 26443103 TI - A DFT study of adsorption of imidazole, triazole, and tetrazole on oxidized copper surfaces: Cu2O(111) and Cu2O(111)-w/o-CuCUS. AB - Azoles and their derivatives are known for their corrosion inhibition ability for copper. For this reason the bonding of imidazole, triazole, and tetrazole-used as archetypal models of azole corrosion inhibitors-to Cu2O(111) and Cu2O(111)-w/o Cu(CUS) was characterized using density functional theory (DFT) calculations. The former surface contains coordinatively-saturated (CSA) and coordinatively unsaturated (CUS) Cu sites, whereas the latter lacks the CUS sites. We find that the molecules preferentially bond with a single unsaturated N atom to a surface Cu ion and concomitantly form a hydrogen bond with the surface O ion. They adsorb rather strongly at CUS sites with an adsorption energy of about -1.6 eV (as calculated with the PBE functional), whereas the bonding at CSA sites is about three times weaker thus being similar as on metallic Cu(111). The impact of van der Waals dispersion interactions on molecular adsorption bonding is also addressed. Depending on specifics of the adsorption structure, they strengthen the adsorption bonding by about 0.2-0.5 eV. Due to this specific bonding enhancement, dispersion interactions alter the relative stability of adsorption modes for tetrazole. An atomistic thermodynamics approach was used to construct two-dimensional phase diagrams for all the three molecules. In the viable range of oxygen chemical potential only three phases appear in the phase-diagrams, two of which are the high coverage (1 * 1) molecular phases (one on Cu2O(111) and the other on Cu2O(111)-w/o-Cu(CUS)) and the third is clean Cu2O(111)-w/o-Cu(CUS). The current results indicate that molecular adsorption at CUS sites is strong enough to compensate the thermodynamic deficiency of stoichiometric Cu2O(111) thus making it more stable than Cu2O(111)-w/o-Cu(CUS), unless the conditions are too oxygen rich and/or for azole lean. This finding may tentatively suggest that the corrosion inhibition capability of azoles stems from their ability to passivate reactive surface sites. PMID- 26443104 TI - Revisiting the chlorophyll biosynthesis pathway using genome scale metabolic model of Oryza sativa japonica. AB - Chlorophyll is one of the most important pigments present in green plants and rice is one of the major food crops consumed worldwide. We curated the existing genome scale metabolic model (GSM) of rice leaf by incorporating new compartment, reactions and transporters. We used this modified GSM to elucidate how the chlorophyll is synthesized in a leaf through a series of bio-chemical reactions spanned over different organelles using inorganic macronutrients and light energy. We predicted the essential reactions and the associated genes of chlorophyll synthesis and validated against the existing experimental evidences. Further, ammonia is known to be the preferred source of nitrogen in rice paddy fields. The ammonia entering into the plant is assimilated in the root and leaf. The focus of the present work is centered on rice leaf metabolism. We studied the relative importance of ammonia transporters through the chloroplast and the cytosol and their interlink with other intracellular transporters. Ammonia assimilation in the leaves takes place by the enzyme glutamine synthetase (GS) which is present in the cytosol (GS1) and chloroplast (GS2). Our results provided possible explanation why GS2 mutants show normal growth under minimum photorespiration and appear chlorotic when exposed to air. PMID- 26443105 TI - The champagne toast position isolates the supraspinatus better than the Jobe test: an electromyographic study of shoulder physical examination tests. AB - BACKGROUND: While Jobe's test is widely used, it does not isolate supraspinatus activity. Our purpose was to examine the electromyographic (EMG) activity within the supraspinatus and deltoid with resisted abduction to determine the shoulder position that best isolates the activity of the supraspinatus. METHODS: We performed EMG analysis of the supraspinatus, anterior head of the deltoid, and middle head of the deltoid in 10 normal volunteers. We measured EMG activity during resisted shoulder abduction in the scapular plane to both manual resistance and a standardized load in varying degrees of abduction and rotation. To determine which position best isolates supraspinatus activity, the ratio of supraspinatus to deltoid activity (S:D) was calculated for each position. Results were analyzed with a repeated-measures analysis of variance with Bonferroni correction. The posterior deltoid was excluded as it serves mostly to extend and externally rotate. RESULTS: Our study confirmed Jobe's findings of maximal supraspinatus activity at 90 degrees of abduction. However, decreasing abduction significantly increased S:D for both resisted manual testing and testing against a standardized load (P = .002 and .001, respectively). The greatest S:D ratio (4.6 +/- 3.4 for standardized load testing) was seen at the "champagne toast" position, i.e., 30 degrees of abduction, mild external rotation, 30 degrees of flexion, and 90 degrees of elbow flexion. The smallest ratio (0.8 +/- 0.6) was seen at Jobe's position. CONCLUSIONS: Testing of abduction strength in the champagne toast position, i.e., 30 degrees of abduction, mild external rotation, and 30 degrees of flexion, better isolates the activity of the supraspinatus from the deltoid than Jobe's "empty can" position. PMID- 26443106 TI - Long-term outcome of tuberoplasty for irreparable massive rotator cuff tears: is tuberoplasty really applicable? AB - BACKGROUND: Tuberoplasty is a therapeutic option for irreparable massive rotator cuff tear (RCT). However, no study has reported long-term outcomes after arthroscopic tuberoplasty. METHODS: We evaluated 16 patients who underwent arthroscopic tuberoplasty for symptomatic irreparable massive RCT without pseudoparalysis. Patients were a mean age of 64 years (range, 43-80 years) at the time of the operation, and the mean duration of follow-up was 98 months (range, 84-126 months). RESULTS: At the last follow-up, the visual analog scale score for pain during motion had decreased to 2.3 from a preoperative mean of 6.9 (P < .001). The mean University of California at Los Angeles and Constant scores improved from 10.3 and 37.9 preoperatively to 27.2 and 59.2, respectively, at the last follow-up (P < .001 for both). The best University of California at Los Angeles (UCLA) and Constant scores during the follow-up duration were 28.3 and 60.3, respectively, at 5 years. The mean acromiohumeral interval changed from 5 mm preoperatively to 4 mm at the last follow-up. The rate of continuity in the inferior scapulohumeral line decreased significantly from 69% (11 shoulders) preoperatively to 19% (3 shoulders) at the last follow-up (P = .011). Only 1 patient underwent revision surgery. CONCLUSIONS: Arthroscopic tuberoplasty yielded satisfactory outcomes during a mean 8-year follow-up period. Although superior migration of the humeral head progressed with time, the clinical outcomes were not affected. Arthroscopic tuberoplasty is a good option for relieving pain and improving functionality in nonpseudoparalytic patients with painful irreparable massive RCT. PMID- 26443107 TI - Response to Jani et al. A prospective, randomized, doubleblind, multicentre, parallel-group, active controlled study to compare efficacy and safety of biosimilar adalimumab (Exemptia; ZRC-3197) and adalimumab (Humira) in patients with rheumatoid arthritis. PMID- 26443108 TI - Next generation sequencing and the next generation: how genomics is revolutionizing reproduction. PMID- 26443109 TI - Polyethyleneimine-associated polycaprolactone-Superparamagnetic iron oxide nanoparticles as a gene delivery vector. AB - This study describes the synthesis of novel gene delivery vector with low toxicity and high transfection efficiency for magnetofection. The rational design of magnetofection vector called PPMag (PEI-associated polycaprolactone (PCL) SPIONs) composed of oleic acid (OA) stabilized superparamagnetic iron oxide nanoparticles (SPPIONs) prepared by thermolysis of iron oleate with a combination of hydrophobic PCL and proton absorbing polymer polyethyleneimine (PEI) (PEI-PCL SPIONs) is described. Encapsulation of amphiphilic PEI with SPIONs not only improves water dispersity of SPIONs, but also allows nucleic acid (NA) condensation and endosomal/lysosomal escape via proton sponge effect after internalization in cells. MTT cytotoxicity assay showed that cell viability was improved compared to conventional PEI-SPIONs. The luciferase activity of magneto polyplexes treated cells significantly improved compared to both controls revealed that transfection efficiency of PPMag- pCIKlux polyplexes group was improved compared to naked pCIKlux group. The application underneath of a rare earth magnet significantly improve the transfection efficiency (i.e., the luciferase activity doubles) compared to cells without magnet, indicating that sedimentation induced by magnetic field plays important role in accumulation of magneto-polyplexes on cell surfaces. The results demonstrate that PPMag can be used as a novel gene transfection vector to improve transfection efficiency. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 145 154, 2017. PMID- 26443110 TI - Pretreating porcine sperm with lipase enhances developmental competence of embryos produced by intracytoplasmic sperm injection. AB - Intracytoplasmic sperm injection (ICSI) has been widely applied in humans, mice, and some domestic animals to cure human infertility, or produce genetically superior or genetically engineered animals. However, the production efficiency of ICSI in pigs remains quite low. In this study, we developed a new sperm pretreatment method to improve production efficiency of ICSI in pigs. Experiment 1 revealed that pretreating porcine sperm with 2.5 mg/ml lipase before ICSI operation, not only can reduce the adhesion between sperm and the injection pipette without adding polyvinylpyrrolidone (PVP) in the operating medium, but also significantly improve male pronuclei (MPN) formation rate (55.56% vs. 40.00% (0 mg/ml), 42.59% (5.0 mg/ml), 40.00% (10.0 mg/ml), P < 0.05) and enhance developmental competence of ICSI embryos (26.03% vs. 10.87% (0 mg/ml), 10.00% (5.0 mg/ml), 10.13% (10.0 mg/ml), P < 0.05). Experiment 2 showed that this method has a higher MPN formation rate (50.47% vs. 30.78%, P < 0.05) and blastocyst rate (18.81% vs. 7.41%, P < 0.05) than the PVP method, and was better than the Triton X-100 treatment method (50.47% vs. 46.23%, 18.81% vs. 12.75%). Therefore, pretreating porcine sperm with 2.5 mg/ml lipase before ICSI operation is highly recommended, instead of adding PVP in the operating medium. PMID- 26443111 TI - Erratum: Nanometre-scale probing of spin waves using single electron spins. PMID- 26443112 TI - [Mechanical ileus in children with no prior history of abdominal surgery]. AB - In children with no prior history of abdominal surgery and no signs of intussusception or incarcerated inguinal hernia, mechanical ileus may have a congenital cause such as malrotation with volvulus or a persistent omphalomesenteric duct. Acquired causes include sigmoid volvulus. We present two cases of mechanical ileus in children. The first case involved a 6-year-old boy who presented with acute abdominal pain and vomiting. An emergency laparotomy was performed, with resection of the omphalomesenteric duct. Recovery was uneventful. The other case concerned a 9-year-old boy who presented with increasing abdominal pain, bilious vomiting and general clinical deterioration. An emergency laparotomy was performed, revealing malrotation with volvulus and intestinal ischaemia. Children with no prior abdominal history who present with symptoms that may be caused by mechanical obstruction should be managed with a view to surgery and without delay, in order to prevent a catastrophic outcome resulting from a congenital or acquired mechanical obstruction. PMID- 26443113 TI - [Unusual causes of hyperprolactinaemia]. AB - Pituitary adenoma is the main cause of hyperprolactinaemia; however, physicians should be aware that the pituitary is not always to blame. There are many other physiological and pathological causes for hyperprolactinaemia, and the contribution of stress, medication and the presence of macroprolactin should not be overlooked. We describe three patients - a 19-year-old female, a 28-year-old female and a 20-year-old male - in whom hyperprolactinaemia was due to medication use, physical stimulation of the nipple and a combination of macroprolactianaemia with a microadenoma, respectively. The first two case reports show that conducting a thorough patient history can prevent unnecessary imaging and laboratory costs. The third case illustrates that macroprolactinaemia and true hyperprolactinaemia may coexist. While early screening for macroprolactinaemia in an asymptomatic patient can save money, finding macroprolactinaemia in a symptomatic patient still warrants further workup. PMID- 26443114 TI - [A pitfall in the treatment of hypothyroidism]. AB - Primary hypothyroidism is a disease commonly encountered by GPs and internal medicine doctors. It is treated with levothyroxine, the synthetic T4 hormone. If a patient with primary hypothyroidism suddenly requires higher dosages the reason for this should be investigated. Common causes are drug-interactions, pregnancy or non-compliance. Nevertheless, if a patient has other symptoms such as oedema or unexpected weight gain, nephrotic syndrome should be considered. Urinalysis can be very helpful in this. Thyroxin binds to plasma albumin, high levels of which are excreted in patients with nephrotic syndrome. This paper presents two patients, a 45-year-old male and a 72-year-old male, with primary hypothyroidism who due to nephrotic syndrome required large amounts of levothyroxine. PMID- 26443115 TI - [Ten tips for optimising your handover]. AB - Patient handover is of major importance for continuity of care and contributes to patient safety. According to Joint Commission International (JCI), an American quality institute, 67% of medical errors result from miscommunication. More than half of these errors appear to be attributable to poor medical handover. JCI and the World Health Organisation recommend standardising handover and training doctors in order to improve the quality of medical handover. Little attention is paid to handover as an essential medical competence during training to become a doctor or medical specialist. Many hospitals lack either training or a standardised format for handover. In this paper we discuss 10 tips for improving the quality of intradisciplinary handover. PMID- 26443116 TI - [Suicidality and alcohol abuse]. AB - This article describes the role played by a patient's mental competency in the assessment and treatment of patients who are under the influence of alcohol and expressing suicidal thoughts. The factors that should be taken into consideration in the assessment of suicidality are not always clear: somatic complications or possible discharge from the emergency room. The treating physician at the emergency department should evaluate the mental competency. The risk of suicide should also be assessed by a psychiatrist. In order to make the right decisions about treatment and mental competency, the key concepts of proportionality, effectiveness and subsidiarity in the assessment of mental competency are crucial. These concepts require a personalized, multidisciplinary approach and result in unique decisions which may differ from case to case. In the assessment and treatment of patients under the influence of alcohol who are suicidal and do not want to have a proper medical evaluation, communication between the emergency physician, internist and psychiatrist is crucial to optimize both evaluation and treatment. In this context, tasks and responsibilities should be clearly defined in order to minimize the risk of errors and complications. PMID- 26443117 TI - [Two travellers returning from the tropics with persistent wounds on their feet]. AB - Two young tropical medicine residents returned from Zanzibar with multiple aching wounds on their toes that did not heal within 6 weeks. The clinical picture fit 'tungiasis', which is caused by Tunga penetrans, also known as jigger or sandflea. The ectoparasites were surgically removed and the status of tetanus vaccination was checked. PMID- 26443118 TI - [Pneumomediastinum: intervention is not always necessary]. AB - Pneumomediastinum is characterized by the presence of free air in the mediastinum. This can be a sign of a severe underlying disorder that requires urgent intervention. However, pneumomediastinum is also associated with other causes that can be treated conservatively. Here, we describe three patients who presented with a primary or spontaneous pneumomediastinum and a secondary pneumomediastinum due to traumatic or iatrogenic perforation. Recognition of the underlying cause of pneumomediastinum is essential for further diagnostic studies and patient management. Unnecessary investigations and interventions, which may cause further harm to and hospitalization of the patient, can thereby be prevented. PMID- 26443119 TI - [A man with a painful hand after punching a wall]. AB - A 23-year-old man had a painful right hand after punching a wall. The base of the second metacarpal was swollen and painful. The base of the second metacarpal is difficult to assess radiologically, due to overlying structures. After a trauma, additional slight oblique X-rays may help to make a diagnosis. PMID- 26443120 TI - [A child with substantially itchy bumps on the back]. AB - A 2-year-old boy showed itchy papules and wheals, which were diagnosed as papular urticaria. Papular urticaria are a hypersensitivity reaction after insect bites. The condition can relapse even without the presence of insects or new bites. Topical steroids or antihistamines diminish the symptoms in some cases. PMID- 26443121 TI - Shifting the light emitting component from core to shell: an effective approach to improve the efficiency of light-emitting diodes based on multi-junction quantum materials. AB - Herein, using the light emitting component as the inner shell, we construct an advanced quantum-dot-quantum-well structure, ZnCdS/CdSe/CdZnSeS/ZnS, and use it for the fabrication of a light-emitting-diode. In comparison with the device containing conventional structured quantum dots, CdSe/CdZnSeS/ZnS, the advanced device possesses a superior performance in aspects of luminance, current efficiency, turn-on voltage and emitting wavelength tunability. Therefore, this paper indicates a promising strategy for the fabrication of light emitting devices based on quantum materials. PMID- 26443122 TI - Spanish Implantable Cardioverter-defibrillator Registry. Eleventh Official Report of the Spanish Society of Cardiology Electrophysiology and Arrhythmias Section (2014). AB - INTRODUCTION AND OBJECTIVES: We present the results of the Spanish Implantable Cardioverter-defibrillator Registry for 2014, as compiled by the Electrophysiology and Arrhythmia Section of the Spanish Society of Cardiology. METHODS: Data collection sheets were voluntarily completed by each implantation team and prospectively sent to the Spanish Society of Cardiology. RESULTS: The number of reported implantations was 4911 (82% of the estimated total number of implantations). The implantation rate was 106 per million population while the estimated rate was 128. First implantations comprised 72.2%. Data were obtained from 162 hospitals (8 more than in 2013). Most implantations (82%) were performed in men. The mean patient age was 61.8+/-13.7 years. Most patients showed severe or moderate-to-severe ventricular dysfunction and were in New York Heart Association functional class II. The most frequent cardiac condition was ischemic heart disease, followed by dilated cardiomyopathy. Implantations for primary prevention indications comprised 58.5%. Electrophysiologists performed 85.6% of the implantations. CONCLUSIONS: The 2014 Spanish Implantable Cardioverter defibrillator Registry received information on 82% of the implantations performed in Spain. The number of implantations has increased from previous years and the percentage of implantations for primary prevention indications has increased from the previous year. PMID- 26443124 TI - Microscopic basis for the band engineering of Mo1-xWxS2-based heterojunction. AB - Transition-metal dichalcogenide layered materials, consisting of a transition metal atomic layer sandwiched by two chalcogen atomic layers, have been attracting considerable attention because of their desirable physical properties for semiconductor devices, and a wide variety of pn junctions, which are essential building blocks for electronic and optoelectronic devices, have been realized using these atomically thin structures. Engineering the electronic/optical properties of semiconductors by using such heterojunctions has been a central concept in semiconductor science and technology. Here, we report the first scanning tunneling microscopy/spectroscopy (STM/STS) study on the electronic structures of a monolayer WS2/Mo1-xWxS2 heterojunction that provides a tunable band alignment. The atomically modulated spatial variation in such electronic structures, i.e., a microscopic basis for the band structure of a WS2/Mo1-xWxS2 heterojunction, was directly observed. The macroscopic band structure of Mo1-xWxS2 alloy was well reproduced by the STS spectra averaged over the surface. An electric field of as high as 80 * 10(6) Vm(-1) was observed at the interface for the alloy with x = 0.3, verifying the efficient separation of photoexcited carriers at the interface. PMID- 26443125 TI - Hyperkalaemia in heart failure: binding the patient to improved treatment? PMID- 26443123 TI - Stem and Progenitor Cell-Derived Astroglia Therapies for Neurological Diseases. AB - Astroglia are a major cellular constituent of the central nervous system (CNS) and play crucial roles in brain development, function, and integrity. Increasing evidence demonstrates that astroglia dysfunction occurs in a variety of neurological disorders ranging from CNS injuries to genetic diseases and chronic degenerative conditions. These new insights herald the concept that transplantation of astroglia could be of therapeutic value in treating the injured or diseased CNS. Recent technological advances in the generation of human astroglia from stem and progenitor cells have been prominent. We propose that a better understanding of the suitability of astroglial cells in transplantation as well as of their therapeutic effects in animal models may lead to the establishment of astroglia-based therapies to treat neurological diseases. PMID- 26443126 TI - Recombinant Mal d 1 facilitates sublingual challenge tests of birch pollen allergic patients with apple allergy. AB - It is still unclear whether allergen-specific immunotherapy (AIT) with birch pollen improves birch pollen-related food allergy. One reason for this may be the lack of standardized tests to assess clinical reactions to birch pollen-related foods, for example apple. We tested the applicability of recombinant (r) Mal d 1, the Bet v 1-homolog in apple, for oral challenge tests. Increasing concentrations of rMal d 1 in 0.9% NaCl were sublingually administered to 72 birch pollen allergic patients with apple allergy. The dose of 1.6 MUg induced oral allergy syndromes in 26.4%, 3.2 MUg in 15.3%, 6.3 MUg in 27.8%, 12.5 MUg in 8.3%, 25 MUg in 11.1%, and 50 MUg in 4.2% of the patients. No severe reactions occurred. None of the patients reacted to 0.9% NaCl alone. Sublingual administration of 50 MUg of rMal d 1 induced no reactions in three nonallergic individuals. Our approach allows straight forward, dose-defined sublingual challenge tests in a high number of birch pollen-allergic patients that inter alia can be applied to evaluate the therapeutic efficacy of birch pollen AIT on birch pollen-related food allergy. PMID- 26443127 TI - Towards understanding resprouting at the global scale. AB - Understanding and predicting plant response to disturbance is of paramount importance in our changing world. Resprouting ability is often considered a simple qualitative trait and used in many ecological studies. Our aim is to show some of the complexities of resprouting while highlighting cautions that need be taken in using resprouting ability to predict vegetation responses across disturbance types and biomes. There are marked differences in resprouting depending on the disturbance type, and fire is often the most severe disturbance because it includes both defoliation and lethal temperatures. In the Mediterranean biome, there are differences in functional strategies to cope with water deficit between resprouters (dehydration avoiders) and nonresprouters (dehydration tolerators); however, there is little research to unambiguously extrapolate these results to other biomes. Furthermore, predictions of vegetation responses to changes in disturbance regimes require consideration not only of resprouting, but also other relevant traits (e.g. seeding, bark thickness) and the different correlations among traits observed in different biomes; models lacking these details would behave poorly at the global scale. Overall, the lessons learned from a given disturbance regime and biome (e.g. crown-fire Mediterranean ecosystems) can guide research in other ecosystems but should not be extrapolated at the global scale. PMID- 26443128 TI - Electrostatic interactions in charged nanoslits within an explicit solvent theory. AB - Within a dipolar Poisson-Boltzmann theory including electrostatic correlations, we consider the effect of explicit solvent structure on solvent and ion partition confined to charged nanopores. We develop a relaxation scheme for the solution of this highly non-linear integro-differential equation for the electrostatic potential. The scheme is an extension of the approach previously introduced for simple planes (Buyukdagli and Blossey 2014 J. Chem. Phys. 140 234903) to nanoslit geometry. We show that the reduced dielectric response of solvent molecules at the membrane walls gives rise to an electric field significantly stronger than the field of the classical Poisson-Boltzmann equation. This peculiarity associated with non-local electrostatic interactions results in turn in an interfacial counterion adsorption layer absent in continuum theories. The observation of this enhanced counterion affinity in the very close vicinity of the interface may have important impacts on nanofluidic transport through charged nanopores. Our results indicate the quantitative inaccuracy of solvent implicit nanofiltration theories in predicting the ionic selectivity of membrane nanopores. PMID- 26443129 TI - Serum concentrations of cholesterol, apolipoprotein A-I and apolipoprotein B in a total of 1694 meat-eaters, fish-eaters, vegetarians and vegans. PMID- 26443131 TI - Revalidation rules must be clear from the start. PMID- 26443130 TI - The use of personal flotation devices in the Northeast lobster fishing industry: An examination of the decision-making process. AB - BACKGROUND: This study explored perspectives of Northeast commercial lobstermen regarding the use of personal flotation devices (PFDs). Researchers sought to identify factors contributing to low PFD use, and motivators that could lead to increased use of PFDs. METHODS: This qualitative research (n = 72) included 25 commercial fishermen who participated in in-depth, semi-structured interviews, and 47 attendees of Lobstermen's meetings who engaged in focus groups. RESULTS: The results showed substantial barriers to PFD use. Fishermen described themselves as being proactive about safety whenever possible, but described a longstanding tradition of not wearing PFDs. Key factors integrally linked with the lack of PFD use were workability, identity/social stigma, and risk diffusion. CONCLUSION: Future safety interventions will need to address significant barriers to PFD use that include issues of comfort and ease of use, as well as social acceptability of PFDs and reorientation of risk perceptions related to falls overboard. PMID- 26443132 TI - One in four nurses say stress and workload are driving them away. PMID- 26443133 TI - Rugby World Cup bar gets people talking. PMID- 26443134 TI - Call for nursing to be added to shortage occupation list. PMID- 26443135 TI - NHS England to transform care for people with learning disabilities. PMID- 26443136 TI - Band 5 and 6 nurses unaware of revalidation. PMID- 26443137 TI - Pride award for Ebola survivors. PMID- 26443138 TI - Stella creasy speaks out on 'crippling' PFIs. PMID- 26443139 TI - QNI launches leadership plan for community nursing. PMID- 26443141 TI - Staff get behind a good night's sleep. PMID- 26443142 TI - NHS 111 could be 'overwhelmed' this winter without more nurses. PMID- 26443143 TI - The ward feedback wall that is 'better than chocolates'. PMID- 26443144 TI - Co-operation replaces competition as NHS shares best practice. PMID- 26443150 TI - Foot health and homelessness. PMID- 26443151 TI - Big lessons in revalidation. AB - A huge revalidation pilot at Aneurin Bevan Health Board in Wales - more than 800 staff embarked on the process in February - has delivered important lessons for other organisations and individual registrants about what to expect when they begin the process. PMID- 26443152 TI - Seeing cancer from a cultural perspective. AB - Black and minority ethnic people are at risk of delayed cancer diagnoses because of language barriers and the social stigma attached to cancer in some communities. Nurses can help by acting as advocates for patients, and by being aware of the risks for different ethnic groups. PMID- 26443165 TI - As nurses we should understand the dilemma over RAF sergeant. PMID- 26443166 TI - Let's communicate better with children who have complex needs. PMID- 26443167 TI - NHS interview panels must do more to encourage would-be BME leaders. PMID- 26443168 TI - No one should miss out on end of life care offered by Marie Curie. PMID- 26443169 TI - How does Jeremy Hunt propose I spend more time with patients? PMID- 26443170 TI - What you're saying on our Facebook page.... PMID- 26443172 TI - Correction. PMID- 26443174 TI - How to remove a chest drain. AB - RATIONALE AND KEY POINTS: This article aims to help nurses to undertake the removal of a chest drain in a safe, effective and patient-centred manner. This procedure requires two practitioners. The chest drain will have been inserted aseptically to remove air, blood, fluid or pus from the pleural cavity. ? Chest drains may be small or wide bore depending on the underlying condition and clinical setting. They may be secured with a mattress suture and/or an anchor suture. ? Chest drains are usually removed under medical instructions when the patient's lung has inflated, the underlying condition has resolved, there is no evidence of respiratory compromise or failure, and their anticoagulation status has been assessed as satisfactory. ? Chest drains secured with a mattress suture should be removed by two practitioners. One practitioner is required to remove the tube and the other to tie the mattress suture (if present) and secure the site. REFLECTIVE ACTIVITY: Clinical skills articles can help update your practice and ensure it remains evidence based. Apply this article to your practice. Reflect on and write a short account of: 1. How reading this article will change your practice. 2. How this article could be used to educate patients with chest drains. Subscribers can upload their reflective accounts at: rcni.com/portfolio . PMID- 26443175 TI - Improving diabetes care at the end of life. AB - The number of people with diabetes in the UK is increasing. Many are aged over 75 years, and this has resulted in rising numbers of patients for whom diabetes exists comorbidly with other disease processes. Those with life-limiting illness require palliative care services. However, end of life care for patients with diabetes is generally poor. The aim of end of life care for these individuals is to maintain comfort, while minimising the risks of osmotic symptoms. The wishes of patients, carers and families should be taken into consideration when agreeing new glucose control targets, adjusting treatment or changing focus on diet. Patients and carers should feel that the condition is being managed with the support of healthcare professionals. These professionals need the knowledge, skills and confidence to recognise the end of life to tailor diabetes care appropriately. PMID- 26443176 TI - Supporting band 5 practitioners in professional and leadership roles. AB - Interest in professionalism and leadership has increased within the nursing and midwifery community. The NHS Lanarkshire Practice Development Centre established a study day on these concepts for band 5 practitioners. This formed part of NHS Lanarkshire's implementation of Scotland's nursing and midwifery leadership development strategy, Leading Better Care. The aims of the study day were to reinforce individual professional responsibility, promote the principles of professionalism and explore the concept of leadership in the band 5 role. This article reports on the development, implementation and evaluation of the study day. PMID- 26443177 TI - Caring for patients with limb amputation. AB - This article provides an overview of the care of patients undergoing limb amputation. Absence of a limb can be congenital or the result of trauma or complications of chronic diseases. While the economic burden of limb amputation is significant, nurses have an important role in limiting other losses attributable to limb loss, such as long-term disability leading to loss of employment and delayed return to work or school. Comprehensive nursing assessments and appropriate interventions, pre and post-operatively, as well as early discharge planning and community reintegration can help avoid some of these losses. Nurses should be aware of the resources available in communities and work in multidisciplinary teams to ensure optimal outcomes for patients following limb amputation and their families. PMID- 26443178 TI - Intramuscular injection. PMID- 26443179 TI - Prepare to succeed. PMID- 26443181 TI - Values light the way to work. PMID- 26443182 TI - Succeed as an agency nurse. PMID- 26443183 TI - Student life - encouraging students to opt for mental health. PMID- 26443184 TI - Mutation Update for COL2A1 Gene Variants Associated with Type II Collagenopathies. AB - Mutations in the COL2A1 gene cause a spectrum of rare autosomal-dominant conditions characterized by skeletal dysplasia, short stature, and sensorial defects. An early diagnosis is critical to providing relevant patient care and follow-up, and genetic counseling to affected families. There are no recent exhaustive descriptions of the causal mutations in the literature. Here, we provide a review of COL2A1 mutations extracted from the Leiden Open Variation Database (LOVD) that we updated with data from PubMed and our own patients. Over 700 patients were recorded, harboring 415 different mutations. One-third of the mutations are dominant-negative mutations that affect the glycine residue in the G-X-Y repeats of the alpha 1 chain. These mutations disrupt the collagen triple helix and are common in achondrogenesis type II and hypochondrogenesis. The mutations resulting in a premature stop codon are found in less severe phenotypes such as Stickler syndrome. The p.(Arg275Cys) substitution is found in all patients with COL2A1-associated Czech dysplasia. LOVD-COL2A1 provides support and potential collaborative material for scientific and clinical projects aimed at elucidating phenotype-genotype correlation and differential diagnosis in patients with type II collagenopathies. PMID- 26443185 TI - Exfoliation of large-area transition metal chalcogenide single layers. AB - Isolating large-areas of atomically thin transition metal chalcogenide crystals is an important but challenging task. The mechanical exfoliation technique can provide single layers of the highest structural quality, enabling to study their pristine properties and ultimate device performance. However, a major drawback of the technique is the low yield and small (typically < 10 MUm) lateral size of the produced single layers. Here, we report a novel mechanical exfoliation technique, based on chemically enhanced adhesion, yielding MoS2 single layers with typical lateral sizes of several hundreds of microns. The idea is to exploit the chemical affinity of the sulfur atoms that can bind more strongly to a gold surface than the neighboring layers of the bulk MoS2 crystal. Moreover, we found that our exfoliation process is not specific to MoS2, but can be generally applied for various layered chalcogenides including selenites and tellurides, providing an easy access to large-area 2D crystals for the whole class of layered transition metal chalcogenides. PMID- 26443187 TI - Smokeless tobacco-associated cancers: A systematic review and meta-analysis of Indian studies. AB - The International Agency for Research on Cancer (IARC) has concluded that there is sufficient evidence in humans for the carcinogenicity of smokeless tobacco (SLT) for mouth, oesophagus and pancreas, based largely on Western studies. We wanted to confirm this by conducting a systematic review using Indian studies because India faces the biggest brunt of SLT-attributable health effects. A systematic search was conducted for published and unpublished studies. Two authors independently reviewed the studies and extracted data. Summary odds ratio (OR) for each cancer type was calculated using fixed and random effects model. The population attributable fraction (PAF) method was used to calculate the attributable burden of incident cases. A significant association was found for oral-5.55 (5.07, 6.07), pharyngeal-2.69 (2.28, 3.17), laryngeal-2.84 (2.18, 3.70), oesophageal-3.17 (2.76, 3.63) and stomach-1.26 (1.00, 1.60) cancers. But in random effects model, laryngeal-1.79 (0.70, 4.54) and stomach-1.31 (0.92, 1.87) cancers became non-significantly associated. Gender-wise analysis revealed that women had a higher risk (OR = 12.0 vs. 5.16) of oral but a lower risk (1.9 vs. 4.5) of oesophageal cancer compared with men. For oral cancer, studies that adjusted for smoking, alcohol and other factors reported a significantly lower OR compared with studies that adjusted for smoking only or smoking and alcohol only (3.9 vs. 8.4). The annual number of attributable cases was calculated as 49,192 (PAF = 60%) for mouth, 14,747 (51%) for pharynx, 11,825 (40%) for larynx, 14,780 (35%) for oesophagus and 3,101 (8%) for stomach. PMID- 26443188 TI - A proposal for a preoperative clinical scoring system for acute cholecystitis. AB - BACKGROUND: Acute cholecystitis is a common diagnosis for which surgery is usually indicated. However, the heterogeneity of clinical presentation makes it difficult to standardize management. The variation in clinical presentation is influenced by both patient-dependent and disease-specific factors. A preoperative clinical scoring system designed to included patient-dependent and clinical factors might be a useful tool in clinical decision making. METHODS: The data of patients undergoing laparoscopic cholecystectomy for acute cholecystitis in a university hospital were retrospectively reviewed. Patient-dependent factors (age, sex, body mass index, and American Society of Anesthesiologists score) and disease-specific factors (history of biliary colics, white blood count, C reactive protein, and gallbladder wall thickness) were used to compute a clinical score between zero and nine for each patient. Cholecystitis was classified as mild (score <= 3), moderate (4 <= score <= 6), or severe (score >= 7). RESULTS: Cholecystitis was mild in 45 cases, moderate in 105 cases, and severe in 27 cases. Among patient-dependent factors, the male gender, age >65 y, and American Society of Anesthesiologists score >2 correlated significantly with high scores, P = 0.001. Equally, high white blood count, elevated C-reactive protein, and gallbladder wall thickness >4 mm correlated significantly with high scores, P = 0.001. These findings were confirmed on multivariate analyses. High scores correlated significantly with the duration of surgery (P = 0.007), the need of intensive care unit management (P = 0.001) and the length of stay (P = 0.001). However, there was no significant association between the preoperative score and the rate of conversion (P = 0.103) or the rate of complication (P = 0.209). CONCLUSIONS: This preoperative clinical scoring system has a potential to select patients with severe cholecystitis and therefore might be a useful tool in clinical decision making. PMID- 26443186 TI - Vinorelbine and epirubicin share common features with polysialic acid and modulate neuronal and glial functions. AB - Polysialic acid (PSA), a large, linear glycan composed of 8 to over 100 alpha2,8 linked sialic acid residues, modulates development of the nervous system by enhancing cell migration, axon pathfinding, and synaptic targeting and by regulating differentiation of progenitor cells. PSA also functions in developing and adult immune systems and is a signature of many cancers. In this study we identified vinorelbine, a semi-synthetic third generation vinca alkaloid, and epirubicin, an anthracycline and 4'-epimer of doxorubicin, as PSA mimetics. Similar to PSA, vinorelbine and epirubicin bind to the PSA-specific monoclonal antibody 735 and compete with the bacterial analog of PSA, colominic acid in binding to monoclonal antibody 735. Vinorelbine and epirubicin stimulate neurite outgrowth of cerebellar neurons via the neural cell adhesion molecule, via myristoylated alanine-rich C kinase substrate, and via fibroblast growth factor receptor, signaling through Erk pathways. Furthermore, the two compounds enhance process formation of Schwann cells and migration of cerebellar neurons in culture, and reduce migration of astrocytes after injury. These novel results show that the structure and function of PSA can be mimicked by the small organic compounds vinorelbine and epirubicin, thus raising the possibility to re-target drugs used in treatment of cancers to nervous system repair. Vinorelbine and epirubicin, identified as PSA mimetics, enhance, like PSA, neuronal migration, neuritogenesis, and formation of Schwann cell processes, and reduce astrocytic migration. Ablating NCAM, inhibiting fibroblast growth factor (FGFR) receptor, or adding the effector domain of myristoylated alanine-rich C kinase substrate (MARCKS) minimize the vinorelbine and epirubicin effects, indicating that they are true PSA mimetics triggering PSA-mediated functions. PMID- 26443189 TI - Normal mast cell numbers in the tissues of AhR-deficient mice. AB - The transcription factor aryl hydrocarbon receptor (AhR) acts as an immunomodulatory molecule in several immune cell lineages. Recently, it has been implicated in development and maintenance of immune cells in barrier tissues such as skin and mucosa. To investigate its role on mast cell development and maintenance in skin, peritoneal exudate cells (PECs) and lymph nodes, we studied in depth their phenotype in AhR-deficient mice. Our findings do not provide any evidence for a suspected role of the AhR in mast cell homeostasis. PMID- 26443190 TI - Translating the genome in time and space: specialized ribosomes, RNA regulons, and RNA-binding proteins. AB - A central question in cell and developmental biology is how the information encoded in the genome is differentially interpreted to generate a diverse array of cell types. A growing body of research on posttranscriptional gene regulation is revealing that both global protein synthesis rates and the translation of specific mRNAs are highly specialized in different cell types. How this exquisite translational regulation is achieved is the focus of this review. Two levels of regulation are discussed: the translation machinery and cis-acting elements within mRNAs. Recent evidence shows that the ribosome itself directs how the genome is translated in time and space and reveals surprising functional specificity in individual components of the core translation machinery. We are also just beginning to appreciate the rich regulatory information embedded in the untranslated regions of mRNAs, which direct the selective translation of transcripts. These hidden RNA regulons may interface with a myriad of RNA-binding proteins and specialized translation machinery to provide an additional layer of regulation to how transcripts are spatiotemporally expressed. Understanding this largely unexplored world of translational codes hardwired in the core translation machinery is an exciting new research frontier fundamental to our understanding of gene regulation, organismal development, and evolution. PMID- 26443191 TI - Placenta: the forgotten organ. AB - The placenta sits at the interface between the maternal and fetal vascular beds where it mediates nutrient and waste exchange to enable in utero existence. Placental cells (trophoblasts) accomplish this via invading and remodeling the uterine vasculature. Amazingly, despite being of fetal origin, trophoblasts do not trigger a significant maternal immune response. Additionally, they maintain a highly reliable hemostasis in this extremely vascular interface. Decades of research into how the placenta differentiates itself from embryonic tissues to accomplish these and other feats have revealed a previously unappreciated level of complexity with respect to the placenta's cellular composition. Additionally, novel insights with respect to roles played by the placenta in guiding fetal development and metabolism have sparked a renewed interest in understanding the interrelationship between fetal and placental well-being. Here, we present an overview of emerging research in placental biology that highlights these themes and the importance of the placenta to fetal and adult health. PMID- 26443192 TI - Motors, anchors, and connectors: orchestrators of organelle inheritance. AB - Organelle inheritance is a process whereby organelles are actively distributed between dividing cells at cytokinesis. Much valuable insight into the molecular mechanisms of organelle inheritance has come from the analysis of asymmetrically dividing cells, which transport a portion of their organelles to the bud while retaining another portion in the mother cell. Common principles apply to the inheritance of all organelles, although individual organelles use specific factors for their partitioning. Inheritance factors can be classified as motors, which are required for organelle transport; anchors, which immobilize organelles at distinct cell structures; or connectors, which mediate the attachment of organelles to motors and anchors. Here, we provide an overview of recent advances in the field of organelle inheritance and highlight how motor, anchor, and connector molecules choreograph the segregation of a multicopy organelle, the peroxisome. We also discuss the role of organelle population control in the generation of cellular diversity. PMID- 26443193 TI - Systematic review: factors contributing to burnout in dentistry. AB - BACKGROUND: Dentists and dental students have been reported to be at high risk of burnout and risk factors have been identified. Despite research into burnout in dentists, only a few papers have identified significantly associated factors. AIMS: To identify the most significant factors associated with burnout in dentists and dental students in published literature. METHODS: We systematically searched MEDLINE, EMBASE and HMIC electronic databases to source literature on the factors associated with burnout in dentists. We critically appraised and themed papers using the Critical Appraisal Skills Programme to find the most significant factors. RESULTS: From 115 studies identified by the search string, we deemed 33 papers to be relevant for review. The most prevalent and significant factors associated with burnout were: younger age, male gender, student status, high job-strain/working hours, those enrolled in clinical degree programmes and certain personality types. However, only a limited amount of literature explored the directional relationship between these factors and burnout. CONCLUSIONS: This review identified several significant factors contributing to burnout in dentists and dental students. Further longitudinal and prospective studies are required to assess causation. Burnout should be considered a multifactorial phenomenon that can develop early in a dental career. Screening programmes and coping strategies might help to identify and prevent it. PMID- 26443195 TI - Heptagons in Aromatics: From Monocyclic to Polycyclic. PMID- 26443194 TI - Can Chinese Herbal Medicine Adjunctive Therapy Improve Outcomes of Senile Vascular Dementia? Systematic Review with Meta-analysis of Clinical Trials. AB - Many publications have reported the growing application of complementary and alternative medicine, particularly the use of Chinese herbal medicine (CHM) in combination with routine pharmacotherapy (RP) for senile vascular dementia (SVD), but its efficacy remains largely unexplored. The purpose of this study is to evaluate the efficacy of CHM adjunctive therapy (CHMAT), which is CHM combined with RP, in the treatment of SVD. Publications in seven electronic databases were searched extensively, and 27 trials with a total of 1961 patients were included for analysis. Compared with RP alone, CHMAT significantly increased the effective rate [odds ratio (OR) 2.98, 95% confidence interval (CI) 2.30, 3.86]. In addition, CHMAT showed benefits in detailed subgroups of the Mini-Mental State Exam (MMSE) score from time of onset to 4 weeks (WMD 3.01, 95% CI 2.15, 3.87), 8 weeks (weighted mean difference (WMD) 2.30, 95% CI 1.28, 3.32), 12 weeks (WMD 2.93, 95% CI 2.17, 3.69), and 24 weeks (WMD 3.25, 95% CI 2.61, 3.88), and in the activity of daily living scale score from time of onset to 4 weeks (WMD -4.64, 95% CI -6.12, -3.17), 8 weeks (WMD -4.30, 95% CI -6.04, -2.56), 12 weeks (WMD 3.89, 95% CI -4.68, -3.09), and 24 weeks (WMD -4.04, 95% CI -6.51, -1.57). Moreover, CHMAT had positive effects on changes in the Hasegawa dementia scale, National Institutes of Health Stroke Scale, Clinical Dementia Rating, and Montreal Cognitive Assessment scores, as well as blood fat levels (total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and apolipoprotein E), platelet aggregation rate (1-min platelet aggregation rate, 5-min platelet aggregation rate, and maximal platelet aggregation rate), and blood rheology (whole-blood viscosity and hematocrit). No serious or frequently occurring adverse effects were reported. Weaknesses of methodological quality in most trials were assessed using the Cochrane risk of bias tool, while the quality level of Grades of Recommendations Assessment Development and Evaluation (GRADE) evidence classification indicated 'very low'. This systematic review suggests that CHM as an adjunctive therapy can improve cognitive impairment and enhance immediate response and quality of life in SVD patients. However, because of limitations of methodological quality in the included studies, further research of rigorous design is needed. PMID- 26443196 TI - Comparison of antiplatelet effect and safety of clopidogrel napadisilate with clopidogrel bisulfate in stroke patients: multicenter, randomized, open-label, phase 4, non-inferiority clinical trial. AB - OBJECTIVE: Clopidogrel napadisilate has better chemical stability than clopidogrel bisulfate. Our trial's objective was to compare the efficacy and safety of clopidogrel napadisilate with clopidogrel bisulfate in participants with ischemic stroke. RESEARCH DESIGN AND METHODS: The study was a phase 4, 4 week, randomized, parallel-group, non-inferiority trial. Patients with ischemic stroke were randomized to receive either clopidogrel napadisilate 75 mg or clopidogrel bisulfate 75 mg. The primary study endpoint was change from baseline in P2Y12 percentage inhibition at week 4. The primary analysis was conducted in the per-protocol population. Non-inferiority was confirmed if the lower limit of the 95% confidence interval (CI) of the treatment difference was greater than or equal to -9.0% points. RESULTS: Sixty-one participants were randomly assigned clopidogrel napadisilate and 60 were randomly assigned clopidogrel bisulfate. Thirty-nine participants in the clopidogrel napadisilate group and 39 in the clopidogrel bisulfate group were analyzed for the primary endpoint. At 4 weeks, mean P2Y12 percentage inhibition had increased in both treatment groups. The estimated mean change from baseline was 22.3% with clopidogrel napadisilate and 21.4% with clopidogrel bisulfate; the estimated treatment difference of 0.9% (95% CI, -8.6 to 10.4) confirmed the non-inferiority of clopidogrel napadisilate to clopidogrel bisulfate. CONCLUSIONS: Clopidogrel napadisilate was non-inferior to clopidogrel bisulfate as assessed by change in P2Y12 percentage inhibition. Rates of adverse events were similar between the two groups. Therefore, clopidogrel napadisilate is a useful alternative option for the dosing of ischemic stroke patient populations. PMID- 26443197 TI - Glycation of human serum albumin alters its binding efficacy towards the dietary polyphenols: a comparative approach. AB - Diabetes is a major problem in the world. The proteins became modified during glycation after reacting with the reducing sugars (e.g. D-glucose) via non enzymatic pathways. The glycated analogue of human serum albumin (HSA) has been characterized with the help of multi-spectroscopic methods. It has been observed that six glucose molecules can bind covalently to HSA under experimental condition. The binding affinity of the modified HSA towards the dietary polyphenols has been estimated using UV-vis and fluorescence spectroscopic techniques. The binding constant values of the ligands were found to decrease after the modification of HSA. PMID- 26443198 TI - Posttranslational modification of E-cadherin by core fucosylation regulates Src activation and induces epithelial-mesenchymal transition-like process in lung cancer cells. AB - E-cadherin is often dysregulated in aggressive lung cancer, the mechanism of which cannot always be explained at the level of transcription. In 66 patients with lung cancer, immunohistochemical staining demonstrated that co-localization of E-cadherin and core fucose by Lens culinaris agglutinin was significantly less extensive in tumor than in nontumor tissue. Through gain and loss of fucosylation experiments in the giant lung carcinoma cell lines 95C and 95D, our results revealed that E-cadherin core fucosylation in 95C cells overexpressing alpha-1, 6 fucosyltransferase (Fut8) inhibited Fut8-95C cell migration, whereas knockdown of Fut8 in 95D cells enhanced migration of short-interfering RNA-targeting Fut8 (siFut8)-95D cells. The level of active Src (phosphorylated Src [Y416]) was significantly reduced in Fut8-95C cells, but elevated in siFut8-95D cells. In protein complexes immunoprecipitated from Fut8-95C cell lysates with anti-E cadherin, less phosphorylated Src (Y416) and more beta-catenin were observed, but immunoprecipitates from siFut8-95D cells, containing less core fucosylated E cadherin, contained an elevated level of phospho-Src Y416. In Fut8-95C cells, phosphorylation of Akt (Y315, Y326) and GSK-3beta (S9) was significantly reduced, but beta-catenin (S37) phosphorylation was enhanced. Expression of N-cadherin and Snail1 was also reduced in Fut8-95C cells, but significantly increased in siFut8 95D cells. Intriguingly, when Src kinase activity was inhibited by treatment of cells with PP2 and SU6656, regulation of N-cadherin, Snail1 and cell migration by E-cadherin core fucosylation was abrogated in both Fut8-95C and siFut8-95D cells. Therefore, posttranslational modification of E-cadherin by less core fucosylation recruited and activated Src, and induced an epithelial-mesenchymal transition like process in lung cancer cells. PMID- 26443199 TI - Aurantivirga profunda gen. nov., sp. nov., isolated from deep-seawater, a novel member of the family Flavobacteriaceae. AB - A Gram-stain-negative, aerobic, proteorhodopsin-containing, orange, rod-shaped bacterium, designated SAORIC-234T, was isolated from deep seawater in the Pacific Ocean. 16S rRNA gene sequence analysis revealed that the strain could be affiliated with the family Flavobacteriaceae of the phylum Bacteroidetes and shared less than 94.6 % similarity with other species of the family with validly published names. The phenotypic characteristics of this novel isolate, such as growth properties and enzyme activities, could be differentiated from those of other species. The strain was non-motile, oxidase-positive and catalase-negative. The G+C content of the genomic DNA was determined to be 34.8 mol% and menaquinone 6 (MK-6) was the predominant isoprenoid quinone. The predominant fatty acids were iso-C15 : 0, iso-C15 : 1 G, iso-C16 : 0 3-OH, iso-C17 : 0 3-OH and iso-C15 : 0 3 OH. The major polar lipids comprised phosphatidylethanolamine, three unknown aminolipids and three unknown lipids. On the basis of the taxonomic data collected in this study, it was concluded that strain SAORIC-234T represents a novel genus and species in the family Flavobacteriaceae, for which the name Aurantivirga profunda gen. nov., sp. nov. is proposed. The type strain of the type species, Aurantivirga profunda sp. nov., is SAORIC-234T ( = NBRC 110606T = KACC 18400T). PMID- 26443200 TI - C-H activation in Ir(III) and N-demethylation in Pt(II) complexes with mesoionic carbene ligands: examples of monometallic, homobimetallic and heterobimetallic complexes. AB - Mononuclear Pt(II) and the first dinuclear Pt(II) complexes along with a cyclometalated heterobimetallic Ir(III)/Pd(II) complex bearing mesoionic carbene donor ligands are presented starting from the same bis-triazolium salt. The mononuclear Pt(II) complex possesses a free triazole moiety which is generated from the corresponding triazolium salt through an N-demethylation reaction, whereas the mononuclear Ir(III) complex features an unreacted triazolium unit. PMID- 26443202 TI - Prenatal vesico-allantoic cyst outcome - a spectrum from patent urachus to bladder exstrophy. AB - OBJECTIVE: The purpose of this study is to assess the prognostic significance of a cystic vesico-allantoic communication discovered on prenatal ultrasound in terms of its effect on the developing urinary tract. METHODS: Multi-institution review of prenatal screening ultrasound was performed between 2004 and 2015 to identify cases of in utero communication between the fetal urinary bladder and a cystic dilatation of the umbilical cord. Gestational age at diagnosis, perinatal evolution, and eventual urinary tract outcome are described and compared with existing literature. RESULTS: Five cases of cystic vesico-allantoic communication were identified on second-trimester screening ultrasound. Serial ultrasounds showed an increase in the size of the umbilical cystic component with gestational age, followed by its eventual rupture prior to delivery. All neonates had urinary leakage through the inferior portion of the umbilicus with bladder prolapse ranging from patent urachus to partial bladder exstrophy. CONCLUSIONS: An isolated prenatal ultrasound finding of an hourglass communication between the fetal bladder and a cyst of the umbilical cord should be considered predictive of a spectrum from patent urachus to bladder exstrophy. Given the significant ramications on the developing urinary tract, the prenatal finding of vesico allantoic cyst warrants referral to a high-risk obstetrical center with urologic consultation. PMID- 26443201 TI - Epigenetic silencing of the XAF1 gene is mediated by the loss of CTCF binding. AB - XAF1 is a tumour suppressor gene that compromises cell viability by modulating different cellular events such as mitosis, cell cycle progression and apoptosis. In cancer, the XAF1 gene is commonly silenced by CpG-dinucleotide hypermethylation of its promoter. DNA demethylating agents induce transcriptional reactivation of XAF1, sensitizing cancer cells to therapy. The molecular mechanisms that mediate promoter CpG methylation have not been previously studied. Here, we demonstrate that CTCF interacts with the XAF1 promoter in vivo in a methylation-sensitive manner. By transgene assays, we demonstrate that CTCF mediates the open-chromatin configuration of the XAF1 promoter, inhibiting both CpG-dinucleotide methylation and repressive histone posttranslational modifications. In addition, the absence of CTCF in the XAF1 promoter inhibits transcriptional activation induced by well-known apoptosis activators. We report for the first time that epigenetic silencing of the XAF1 gene is a consequence of the loss of CTCF binding. PMID- 26443203 TI - [New physical therapy procedures]. PMID- 26443206 TI - Nanoscale Graphene Disk: A Natural Functionally Graded Material-How is Fourier's Law Violated along Radius Direction of 2D Disk. AB - In this Paper, we investigate numerically and analytically the thermal conductivity of nanoscale graphene disks (NGDs), and discussed the possibility to realize functionally graded material (FGM) with only one material, NGDs. Different from previous studies on divergence/non-diffusive of thermal conductivity in nano-structures with different size, we found a novel non homogeneous (graded) thermal conductivity along the radius direction in a single nano-disk structure. We found that, instead of a constant value, the NGD has a graded thermal conductivity along the radius direction. That is, Fourier's law of heat conduction is not valid in two dimensional graphene disk structures Moreover, we show the dependent of NGDs' thermal conductivity on radius and temperature. Our study might inspire experimentalists to develop NGD based versatile FGMs, improve understanding of the heat removal of hot spots on chips, and enhance thermoelectric energy conversion efficiency by two dimensional disk with a graded thermal conductivity. PMID- 26443208 TI - Musculoskeletal complications of haematological disease. AB - Rheumatological manifestations complicate many benign and malignant blood disorders. Significant advances in haematology, with improved diagnostic techniques and newer musculoskeletal imaging, have occurred in the past two decades. This review focuses on the interrelationship between the major haematological diseases (haemochromatosis, haemophilia, sickle cell disease, thalassaemia, leukaemia, lymphoma, myelodysplastic syndromes, multiple myeloma and cryoglobulinaemia) and rheumatic manifestations. PMID- 26443209 TI - Xanthomonas and the TAL Effectors: Nature's Molecular Biologist. AB - Agrobacterium, due to the transfer of T-DNA to the host genome, is known as nature's genetic engineer. Once again, bacteria have led the way to newfound riches in biotechnology. Xanthomonas has emerged as nature's molecular biologist as the functional domains of the sequence-specific DNA transcription factors known as TAL effectors were characterized and associated with the cognate disease susceptibility and resistance genes of plants. PMID- 26443207 TI - NSMCE2 suppresses cancer and aging in mice independently of its SUMO ligase activity. AB - The SMC5/6 complex is the least understood of SMC complexes. In yeast, smc5/6 mutants phenocopy mutations in sgs1, the BLM ortholog that is deficient in Bloom's syndrome (BS). We here show that NSMCE2 (Mms21, in Saccharomyces cerevisiae), an essential SUMO ligase of the SMC5/6 complex, suppresses cancer and aging in mice. Surprisingly, a mutation that compromises NSMCE2-dependent SUMOylation does not have a detectable impact on murine lifespan. In contrast, NSMCE2 deletion in adult mice leads to pathologies resembling those found in patients of BS. Moreover, and whereas NSMCE2 deletion does not have a detectable impact on DNA replication, NSMCE2-deficient cells also present the cellular hallmarks of BS such as increased recombination rates and an accumulation of micronuclei. Despite the similarities, NSMCE2 and BLM foci do not colocalize and concomitant deletion of Blm and Nsmce2 in B lymphocytes further increases recombination rates and is synthetic lethal due to severe chromosome mis segregation. Our work reveals that SUMO- and BLM-independent activities of NSMCE2 limit recombination and facilitate segregation; functions of the SMC5/6 complex that are necessary to prevent cancer and aging in mice. PMID- 26443210 TI - TAL Effector DNA-Binding Principles and Specificity. AB - Transcription activator-like effectors (TALEs) are proteins with a unique DNA binding domain that confers both a predictable and programmable specificity. The DNA-binding domain consists typically of 34-amino acid near-identical repeats. The repeats form a right-handed superhelical structure that wraps around the DNA double helix and exposes the variable amino acids at position 13 of each repeat to the sense strand DNA bases. Each repeat binds one base in a highly specific, non-overlapping, and comma-free fashion. Although TALE specificities are encoded in a simple way, sophisticated rules can be taken into account to build highly efficient DNA-binding modules for biotechnological use. PMID- 26443212 TI - Online Tools for TALEN Design. AB - Transcription activator-like effector nucleases (TALENs) can be exquisitely specific and highly effective genome editing reagents. Specificity and efficacy depend however on good design for minimal off-targeting and strong binding. Several online tools are accessible to aid in this process. Here, we tabulate those tools, noting their functions and key features. PMID- 26443213 TI - Assembly of Customized TAL Effectors Through Advanced ULtiMATE System. AB - Transcription activator-like effectors (TALEs) have been widely applied in gene targeting. Here we describe an advanced ULtiMATE (USER-based Ligation-Mediated Assembly of TAL Effector) system that utilizes USER fusion technique and archive of 512 tetramer templates to achieve highly efficient construction of TALEs, which takes only half a day to accomplish the assembly of any given TALE construct. This system is also suitable for large-scale assembly of TALENs and any other TALE-based constructions. PMID- 26443211 TI - The Development of TALE Nucleases for Biotechnology. AB - The development of a facile genome engineering technology based on transcription activator-like effector nucleases (TALENs) has led to significant advances in diverse areas of science and medicine. In this review, we provide a broad overview of the development of TALENs and the use of this technology in basic science, biotechnology, and biomedical applications. This includes the discovery of DNA recognition by TALEs, engineering new TALE proteins to diverse targets, general advances in nuclease-based editing strategies, and challenges that are specific to various applications of the TALEN technology. We review examples of applying TALENs for studying gene function and regulation, generating disease models, and developing gene therapies. The current status of genome editing and future directions for other uses of these technologies are also discussed. PMID- 26443214 TI - Engineering Customized TALENs Using the Platinum Gate TALEN Kit. AB - Among various strategies for constructing customized transcription activator-like effector nucleases (TALENs), the Golden Gate assembly is the most widely used and most characterized method. The principle of Golden Gate assembly involves cycling reactions of digestion and ligation of multiple plasmids in a single tube, resulting in PCR-, fragmentation-, and purification-free concatemerization of DNA binding repeats. Here, we describe the protocols for Golden Gate assembly-based TALEN construction using the Platinum Gate TALEN Kit, which allows generation of highly active Platinum TALENs. PMID- 26443215 TI - Design, Assembly, and Characterization of TALE-Based Transcriptional Activators and Repressors. AB - Transcription activator-like effectors (TALEs) are modular DNA-binding proteins that can be fused to a variety of effector domains to regulate the epigenome. Nucleotide recognition by TALE monomers follows a simple cipher, making this a powerful and versatile method to activate or repress gene expression. Described here are methods to design, assemble, and test TALE transcription factors (TALE TFs) for control of endogenous gene expression. In this protocol, TALE arrays are constructed by Golden Gate cloning and tested for activity by transfection and quantitative RT-PCR. These methods for engineering TALE-TFs are useful for studies in reverse genetics and genomics, synthetic biology, and gene therapy. PMID- 26443216 TI - A New Approach to Dissect Nuclear Organization: TALE-Mediated Genome Visualization (TGV). AB - Spatiotemporal organization of chromatin within the nucleus has so far remained elusive. Live visualization of nuclear remodeling could be a promising approach to understand its functional relevance in genome functions and mechanisms regulating genome architecture. Recent technological advances in live imaging of chromosomes begun to explore the biological roles of the movement of the chromatin within the nucleus. Here I describe a new technique, called TALE mediated genome visualization (TGV), which allows us to visualize endogenous repetitive sequence including centromeric, pericentromeric, and telomeric repeats in living cells. PMID- 26443217 TI - TALEN-Induced Translocations in Human Cells. AB - Induction of chromosomal translocations in human cells is of a great interest to study tumorigenesis and genome instability. Here, we explain in detail a method to induce translocations using the transcription activator-like effector nucleases (TALENs). We describe how to detect translocation formation by PCR, calculate translocation frequency by 96-well PCR screen, and analyze breakpoint junctions. When inducing cancer translocations, it is also possible to detect the fusion gene by FISH analysis or western blot. PMID- 26443218 TI - Mutagenesis in Newts: Protocol for Iberian Ribbed Newts. AB - Newts have the remarkable capability of organ/tissue regeneration, and have been used as a unique experimental model for regenerative biology. The Iberian ribbed newt (Pleurodeles waltl) is suitable as a model animal. We have established methods for artificial insemination and efficient transgenesis using P. waltl newts. In addition to the transgenic technique, development of TALENs enables targeting mutagenesis in the newts. We have reported that TALENs efficiently disrupted targeted genes in newt embryos. In this chapter, we introduce a protocol for TALEN-mediated gene targeting in Iberian ribbed newts. PMID- 26443219 TI - Targeted Mutagenesis in Bombyx mori Using TALENs. AB - Bombyx mori is a valuable model organism of high economic importance. Its genome sequence is available, as well as basic genetic and molecular genetic tools and markers. The introduction of genome editing methods based on engineered nucleases enables precise manipulations with genomic DNA, including targeted DNA deletions, insertions, or replacements in the genome allowing gene analysis and various applications. We describe here the use of TALENs which have a simple modular design of their DNA-binding domains, are easy to prepare and proved to be efficient in targeting of a wide range of cleavage sites. Our procedure often allows the production of individuals carrying homozygous mutations as early as in the G1 generation. PMID- 26443220 TI - GeneKnockout by Targeted Mutagenesis in a Hemimetabolous Insect, the Two-Spotted Cricket Gryllus bimaculatus, using TALENs. AB - Hemimetabolous, or incompletely metamorphosing, insects are phylogenetically basal. These insects include many deleterious species. The cricket, Gryllus bimaculatus, is an emerging model for hemimetabolous insects, based on the success of RNA interference (RNAi)-based gene-functional analyses and transgenic technology. Taking advantage of genome-editing technologies in this species would greatly promote functional genomics studies. Genome editing using transcription activator-like effector nucleases (TALENs) has proven to be an effective method for site-specific genome manipulation in various species. TALENs are artificial nucleases that are capable of inducing DNA double-strand breaks into specified target sequences. Here, we describe a protocol for TALEN-based gene knockout in G. bimaculatus, including a mutant selection scheme via mutation detection assays, for generating homozygous knockout organisms. PMID- 26443221 TI - Methods for TALEN Evaluation, Use, and Mutation Detection in the Mosquito Aedes aegypti. AB - The generation and study of transgenic Aedes aegypti mosquitoes provides an essential tool for elucidating the complex molecular biology of this important vector. Within the field, genetic manipulation has surpassed the proof of principle stage and is now utilized in both applied and theoretical vector control strategies. The application of new instruments, technologies and techniques allows ever more controlled experiments to be conducted. In this text we describe microinjection of Ae. aegypti embryos in the context of evaluating and performing genomic editing with transcription activator-like effector nucleases (TALENs). PMID- 26443222 TI - Methods for TALEN-Mediated Genomic Manipulations in Drosophila. AB - TALEN (transcription activator-like effector nuclease) is a powerful tool for gene disruption and other genomic modifications. In the past 3 years or so, it has attracted eyes from every corner of the biological world, due to its characteristics of simplicity, high efficiency, low toxicity, and applicability across almost all species. In our lab, we first reported the TALEN-mediated gene disruption in Drosophila, and recently employed this technique in precisely modifying the Drosophila genome, such as in vivo tagging and gene correction. Here, we describe in detail the protocols and experiences in TALEN-mediated genomic modifications to share with the Drosophilists all over the world. PMID- 26443223 TI - Targeted Mutagenesis in Zebrafish by TALENs. AB - Zebrafish is a valuable model organism to study vertebrate development, organ regeneration and to generate human disease models. As an important member of the arsenal of genome editing, TALE nucleases (TALENs) have implicated in broad applications in zebrafish reverse genetic studies. In this chapter, we describe the detailed protocols of TALEN-mediated genome manipulations in zebrafish, including targeted gene disruption by indel mutations, deletion of large genomic regions by using two pairs of TALENs, and precise genome modification by homologous recombination (HR). PMID- 26443224 TI - Mutagenesis in Xenopus and Zebrafish using TALENs. AB - Transcription activator-like effector nucleases (TALENs) have been proven to be effective for gene specific targeting across species. Here we describe the validated protocol for TALEN assembly as well as methods for generating gene knockout animals of Xenopus and zebrafish. This protocol covers selection of TALEN targeting sites, TALEN assembly with a modified Golden Gate method, injection of TALEN mRNAs into Xenopus and zebrafish embryos as well as the detection of somatic and germ-line transmitted mutations. Finally, the establishment of knockout Xenopus and zebrafish lines is also described. This protocol will facilitate broader applications of TALENs in developmental biology. PMID- 26443225 TI - Genome Editing in Mice Using TALE Nucleases. AB - Gene engineering for generating targeted mouse mutants is a key technology for biomedical research. Using TALENs as sequence-specific nucleases to induce targeted double-strand breaks, the mouse genome can be directly modified in zygotes in a single step without the need for embryonic stem cells. By embryo microinjection of TALEN mRNAs and targeting vectors, knockout and knock-in alleles can be generated fast and efficiently. In this chapter we provide protocols for the application of TALENs in mouse zygotes. PMID- 26443226 TI - Genome Editing in Rats Using TALE Nucleases. AB - The rat is an important animal model to understand gene function and model human diseases. Since recent years, the development of gene-specific nucleases has become important for generating new rat models of human diseases, to analyze the role of genes and to generate human antibodies. Transcription activator-like (TALE) nucleases efficiently create gene-specific knockout rats and lead to the possibility of gene targeting by homology-directed recombination (HDR) and generating knock-in rats. We describe a detailed protocol for generating knockout and knock-in rats via microinjection of TALE nucleases into fertilized eggs. This technology is an efficient, cost- and time-effective method for creating new rat models. PMID- 26443227 TI - Designer Nuclease-Mediated Generation of Knockout THP1 Cells. AB - Recent developments in the field of designer nucleases allow the efficient and specific manipulation of genomic architectures in eukaryotic cell lines. To this end, it has become possible to introduce DNA double strand breaks (DSBs) at user defined genomic loci. If located in critical coding regions of genes, thus induced DSBs can lead to insertions or deletions (indels) that result in frameshift mutations and thereby the knockout of the target gene. In this chapter, we describe a step-by-step workflow for establishing knockout cell clones of the difficult-to-transfect suspension cell line THP1. The here described protocol encompasses electroporation, cell cloning, and a deep sequencing-based genotyping step that allows the in-parallel analysis of 96 cell clones per gene of interest. Furthermore, we describe the use of the analysis tool OutKnocker that allows rapid identification of cell clones with all-allelic frameshift mutations. PMID- 26443228 TI - A systematic review of predictors and moderators of improvement in cognitive behavioral therapy for panic disorder and agoraphobia. AB - BACKGROUND: Despite the considerable efficacy of cognitive-behavioral therapy (CBT) for panic disorder (PD) and agoraphobia, a substantial minority of patients fail to improve for reasons that are poorly understood. OBJECTIVE: The aim of this study was to identify consistent predictors and moderators of improvement in CBT for PD and agoraphobia. DATA SOURCES: A systematic review and meta-analysis of articles was conducted using PsycInfo and PubMed. Search terms included panic, agoraphobi*, cognitive behavio*, CBT, cognitive therapy, behavio* therapy, CT, BT, exposure, and cognitive restructuring. STUDY SELECTION: Studies were limited to those employing semi-structured diagnostic interviews and examining change on panic- or agoraphobia-specific measures. DATA EXTRACTION: The first author extracted data on study characteristics, prediction analyses, effect sizes, and indicators of study quality. Interrater reliability was confirmed. SYNTHESIS: 52 papers met inclusion criteria. Agoraphobic avoidance was the most consistent predictor of decreased improvement, followed by low expectancy for change, high levels of functional impairment, and Cluster C personality pathology. Other variables were consistently unrelated to improvement in CBT, understudied, or inconsistently related to improvement. LIMITATIONS: Many studies were underpowered and failed to report effect sizes. Tests of moderation were rare. CONCLUSIONS: Apart from agoraphobic avoidance, few variables consistently predict improvement in CBT for PD and/or agoraphobia across studies. PMID- 26443229 TI - Structure of P3HT crystals, thin films, and solutions by UV/Vis spectral analysis. AB - Optical absorption spectra of poly(3-hexylthiophene) (P3HT) are calculated in solution, spin-coated thin films, and the bulk crystal using a multiscale simulation approach. The structure of the amorphous thin film is obtained from coarse grained molecular dynamics (MD) simulations and subsequent back-mapping onto an atomistic force field representation. The absorption spectra are computed using TDDFT by statistically averaging over an ensemble of molecules taken from the MD simulations. Experimental UV/Vis spectra of spin-coated thin films and solutions are recorded with varying ratios of 'good' versus 'poor' solvent. The theoretical approach is able to faithfully predict the spectral position in the various phases and offers fundamental insight into the cause of any spectral shifts. The position of the main absorption peak is found to be chiefly determined by the level of torsion between the thiophene rings inside each molecule, while intermolecular effects are less important. Hence, optical absorption spectra hold valuable clues about the microscopic structure of disordered P3HT phases. PMID- 26443230 TI - Paraneoplastic fasciitis and polyarthritis syndrome as a manifestation of breast cancer recurrence in a BRCA1 gene-positive patient. PMID- 26443231 TI - Ultra-high-resolution 3D digitalized imaging of the cerebral angioarchitecture in rats using synchrotron radiation. AB - The angioarchitecture is a fundamental aspect of brain development and physiology. However, available imaging tools are unsuited for non-destructive cerebral mapping of the functionally important three-dimensional (3D) vascular microstructures. To address this issue, we developed an ultra-high resolution 3D digitalized angioarchitectural map for rat brain, based on synchrotron radiation phase contrast imaging (SR-PCI) with pixel size of 5.92 MUm. This approach provides a systematic and detailed view of the cerebrovascular anatomy at the micrometer level without any need for contrast agents. From qualitative and quantitative perspectives, the present 3D data provide a considerable insight into the spatial vascular network for whole rodent brain, particularly for functionally important regions of interest, such as the hippocampus, pre-frontal cerebral cortex and the corpus striatum. We extended these results to synchrotron based virtual micro-endoscopy, thus revealing the trajectory of targeted vessels in 3D. The SR-PCI method for systematic visualization of cerebral microvasculature holds considerable promise for wider application in life sciences, including 3D micro-imaging in experimental models of neurodevelopmental and vascular disorders. PMID- 26443232 TI - Dermal Fenestration With Negative Pressure Wound Therapy: A Technique for Managing Soft Tissue Injuries Associated With High-Energy Complex Foot Fractures. AB - Military casualties can sustain complex foot fractures from blast incidents. This frequently involves the calcaneum and is commonly associated with mid-foot fracture dislocations. The foot is at risk of both compartment syndrome and the development of fracture blisters after such injuries. The amount of energy transfer and the environment in which the injury was sustained also predispose patients to potential skin necrosis and deep infection. Decompression of the compartments is a part of accepted practice in civilian trauma to reduce the risk of complications associated with significant soft tissue swelling. The traditional methods of foot fasciotomy, however, are not without significant complications. We report a simple technique of dermal fenestration combined with the use of negative pressure wound therapy, which aims to preserve the skin integrity of the foot without resorting to formal fasciotomy. PMID- 26443233 TI - Characteristics of frozen epididymal spermatozoa from stallions that died 12 to 36 hours after colic surgery. AB - Equine spermatozoa from the cauda epididymis were previously collected and frozen, and the fertility was assessed. Most studies were performed on healthy stallions that had undergone routine castration or on the epididymis collected at the abattoir, but there are no studies on the quality of epididymal semen in subjects which have died from colic or which underwent intensive care. The present study was designed to verify whether a severe illness could affect epididymal semen quality and freezability in the stallion. Therefore, epididymal semen characteristics during the freezing process in stallions which had died from colic and in healthy stallions submitted to elective castration were compared. Five stallions that had died from colic (ill stallions [ISs]) and seven stallions that had undergone elective castration (healthy stallions) were castrated, and cauda epididymis spermatozoa were collected and processed. Sperm quality was tested after collection, after washing procedures, at the end of the equilibration (5 degrees C for 75 minutes), and after freezing/thawing. Sperm quality was measured by objective motility characteristics, membrane and acrosome integrity, and mitochondrial activity. After collection, sperm in ISs showed low kinetic parameters (total motility: 17.3 +/- 3%, progressive motility: 6 +/- 1%, average path velocity: 57.4 +/- 35.4 MUm/s, straightness: 74.2%) compared with healthy stallions (total motility: 90.8 +/- 3.7%, progressive motility: 70 +/- 4%, average path velocity: 118.1 +/- 12.6 MUm/s, straightness: 82.4%) but demonstrated similar membrane and acrosome integrity (85 +/- 2.8% vs. 87.6 +/- 3.1%). Sperm kinetic parameters increased after washing procedures and cooling in ISs, reaching comparable values after equilibration (5 degrees C for 75 minutes) and freezing/thawing. The data reported in this study suggest that the quality of the equine epididymal spermatozoa cryopreserved in stallions that had died from colic was similar to that reported in epididymal sperm after elective castration and was also similar to the data reported in literature for cryopreserved equine semen. PMID- 26443234 TI - A phosphodiesterase type-5 inhibitor, sildenafil, induces sperm capacitation and penetration into porcine oocytes in a chemically defined medium. AB - The present study was undertaken to determine the effect of a phosphodiesterase (PDE) type-5 (cyclic guanosine monophosphate-specific) inhibitor, sildenafil, on capacitation and penetration of boar spermatozoa in a basic chemically defined medium (adenosine- and theophylline-free PGM-tac4). When ejaculated spermatozoa were cultured for 90 minutes in the absence or presence of sildenafil at 2.5 mM, the inhibitor significantly increased the percentage of capacitated/acrosome reacted spermatozoa, as a result of the chlortetracycline assay. When fresh spermatozoa were co-cultured with oocytes in the presence of sildenafil at a different concentration (0, 2.5, 25, or 250 MUM), higher sildenafil concentrations (25 and 250 MUM) significantly resulted in higher sperm penetration rates. When oocytes matured in vitro were co-cultured with spermatozoa in the presence of 25 MUM sildenafil or 25 mM caffeine benzoate for 8 hours, the incidence of penetrated oocytes did not differ between two groups, whereas the incidence of monospermic oocytes in penetrated one was significantly higher in the presence of sildenafil. Immunocytochemical analysis reported the presence of PDE type-5 on the acrosome region of boar spermatozoa. These results report that regulation of cyclic guanosine monophosphate-specific PDE type-5 by sildenafil somehow can increase the penetrability of boar spermatozoa in vitro. PMID- 26443235 TI - Effect of early pregnancy diagnosis by per rectum amniotic sac palpation on pregnancy loss, calving rates, and abnormalities in newborn dairy calves. AB - The objectives of the present study were to evaluate the effect of per rectal amniotic sac palpation (ASP) for pregnancy diagnosis during the late embryonic period on pregnancy loss, calving rates, and abnormalities in newborn calves. A controlled, randomized, blocked, blind experiment containing 680 lactating pregnant dairy cows with a viable embryo diagnosed by transrectal ultrasonography was performed. Two dairy operation sites (farm A and farm B) were selected. At each farm, the cows were randomly divided into control (CON) and ASP groups. The CON group was not subjected to pregnancy diagnosis via per rectum palpation. The ASP examinations were performed by one experienced veterinarian between Days 34 and 45 after breeding. All cows were reevaluated by transrectal ultrasonography only between 2 and 4 weeks later. Two calving rates were calculated: calving rate 1 (cows that calved from the initial number of pregnant cows) and calving rate 2 (cows that calved from cows pregnant at reexamination). In farm A, the percentages of early pregnancy loss were 11.5% (19 of 165) and 13.2% (24 of 182) for the CON and the ASP groups, respectively (P = 0.64). In farm B, the percentage of early pregnancy loss was 11.2% (19 of 170) for the CON group and 8.8% (14 of 159; P = 0.48) for the ASP group. In farm A, the percentage of late pregnancy loss was 7.6% (11 of 145) for the CON group and 5.5% (8 of 155; P = 0.39) for the ASP group. In farm B, the percentage of late pregnancy loss was 3.7% (5 of 137) for the CON group and 6.3% (8 of 127; P = 0.32) for the ASP group. In farm A, early pregnancy loss was higher than late pregnancy loss (12.4% vs. 6.3%; P = 0.01), and in farm B, the same tendency was detected (10.0% vs. 4.9%, for early and late pregnancy loss, respectively; P = 0.02). In farm A, calving rate 1 was 81.2% (134 of 165) for the CON group and 80.8% (147 of 182; P = 0.92) for the ASP group. Calving rate 2 for the same groups was 92.4% (134 of 145) and 94.8% (147 of 155), respectively (P = 0.68). In farm B, calving rate 1 was 77.7% (132 of 170) for the CON group and 74.8% (119 of 159; P = 0.55) for the ASP group. Calving rates 2 for the same groups were 87.4% (132 of 151) and 82.1% (119 of 145), respectively (P = 0.20). Two female calves with atresia coli were diagnosed only in the CON group. It was concluded that ASP during the late embryonic period for pregnancy diagnosis did not increase the pregnancy loss, affect calving rates, or produce abnormalities in calves. PMID- 26443237 TI - A clinical survey of pain in Parkinson's disease in Eastern China. AB - BACKGROUND: This is a case-control study to investigate the prevalence, characteristics, and risk factors of pain in patients with Parkinson's disease (PD). METHODS: A total of 200 PD patients from eastern China were enrolled in our study. Accordingly, 200 healthy elderly adults were recruited as controls. The characteristics of pain were collected by using the Visual Analog Scale, Brief Pain Inventory (BPI), SF-36 Bodily Pain Scale, Unified Parkinson's Disease Rating Scale, Hoehn-Yahr Scale (H-Y), Hamilton Depression Scale, and Leeds Assessment of Neuropathic Symptoms and Signs. RESULTS: Of the 200 PD patients, pain was complained by 106 patients (53%). According to the SF-36 Bodily Pain Scale, pain morbidity in PD patients was significantly higher than in the control group. The average pain during last 24 h measured by the BPI was 2.67. About 76% of PD patients were found to have one pain type, 21.7% were having two pain types, and 1.9% had three pain types. Further, 69.8% of these patients were presented with musculoskeletal pain, 4.7% with dystonic pain, 22.6% with radicular-neuropathic pain, 20.8% with central neuropathic pain, and 9.4% with akathisia pain. The onset age and depression were the most significant predictors of pain in PD patients (p < 0.05). However, there was no significant association between pain and gender, age, disease duration, or severity of the disease. Only 5.7% of PD patients with pain received treatment in this study. CONCLUSIONS: Pain is frequent and disabling, independent of demographic and clinical variables, and is significantly more common in PD patients. PMID- 26443236 TI - Neural Correlates of Self and Its Interaction With Memory in Healthy Adolescents. AB - Adolescence is marked by the development of personal identity and is associated with structural and functional changes in brain regions associated with Self processing. Yet, little is known about the neural correlates of self-reference processing and self-reference effect in adolescents. This functional magnetic resonance imaging study consists of a self-reference paradigm followed by a recognition test proposed to 30 healthy adolescents aged 13-18 years old. Results showed that the rostral anterior cingulate cortex is specifically involved in self-reference processing and that this specialization develops gradually from 13 to 18 years old. The self-reference effect is associated with increased brain activation changes during encoding, suggesting that the beneficial effect of Self on memory may occur at encoding of self-referential information, rather than at retrieval. PMID- 26443238 TI - Modulation of intestinal calcium and phosphate transport in young goats fed a nitrogen- and/or calcium-reduced diet. AB - Feeding ruminants a reduced N diet is a common approach to reduce N output based on rumino-hepatic circulation. However, a reduction in N intake caused massive changes in Ca and inorganic phosphate (Pi) homoeostasis in goats. Although a single dietary Ca reduction stimulated intestinal Ca absorption in a calcitriol dependent manner, a concomitant reduction of Ca and N supply led to a decrease in calcitriol, and therefore a modulation of intestinal Ca and Pi absorption. The aim of this study was to examine the potential effects of dietary N or Ca reduction separately on intestinal Ca and Pi transport in young goats. Animals were allocated to a control, N-reduced, Ca-reduced or combined N- and Ca-reduced diet for about 6-8 weeks, whereby N content was reduced by 25 % compared with recommendations. In Ussing chamber experiments, intestinal Ca flux rates significantly decreased in goats fed a reduced N diet, whereas Pi flux rates were unaffected. In contrast, a dietary Ca reduction stimulated Ca flux rates and decreased Pi flux rates. The combined dietary N and Ca reduction withdrew the stimulating effect of dietary Ca reduction on Ca flux rates. The expression of Ca transporting proteins decreased with a reduced N diet too, whereas Pi transporting proteins were unaffected. In conclusion, a dietary N reduction decreased intestinal Ca transport by diminishing Ca-transporting proteins, which became clear during simultaneous N and Ca reduction. Therefore, N supply in young ruminant nutrition is of special concern for intestinal Ca transport. PMID- 26443239 TI - Mobile in Situ Simulation as a Tool for Evaluation and Improvement of Trauma Treatment in the Emergency Department. AB - BACKGROUND: Medical simulation is an increasingly recognized tool for teaching, coaching, training, and examining practitioners in the medical field. For many years, simulation has been used to improve trauma care and teamwork. Despite technological advances in trauma simulators, including better means of mobilization and control, most reported simulation-based trauma training has been conducted inside simulation centers, and the practice of mobile simulation in hospitals' trauma rooms has not been investigated fully. METHODS: The emergency department personnel from a second-level trauma center in Israel were evaluated. Divided into randomly formed trauma teams, they were reviewed twice using in situ mobile simulation training at the hospital's trauma bay. In all, 4 simulations were held before and 4 simulations were held after a structured learning intervention. The intervention included a 1-day simulation-based training conducted at the Israel Center for Medical Simulation (MSR), which included video based debriefing facilitated by the hospital's 4 trauma team leaders who completed a 2-day simulation-based instructors' course before the start of the study. The instructors were also trained on performance rating and thus were responsible for the assessment of their respective teams in real time as well as through reviewing of the recorded videos; thus enabling a comparison of the performances in the mobile simulation exercise before and after the educational intervention. RESULTS: The internal reliability of the experts' evaluation calculated in the Cronbach alpha model was found to be 0.786. Statistically significant improvement was observed in 4 of 10 parameters, among which were teamwork (29.64%) and communication (24.48%) (p = 0.00005). CONCLUSION: The mobile in situ simulation-based training demonstrated efficacy both as an assessment tool for trauma teams' function and an educational intervention when coupled with in vitro simulation-based training, resulting in a significant improvement of the teams' function in various aspects of treatment. PMID- 26443240 TI - PKA antagonizes CLASP-dependent microtubule stabilization to re-localize Pom1 and buffer cell size upon glucose limitation. AB - Cells couple growth with division and regulate size in response to nutrient availability. In rod-shaped fission yeast, cell-size control occurs at mitotic commitment. An important regulator is the DYRK-family kinase Pom1, which forms gradients from cell poles and inhibits the mitotic activator Cdr2, itself localized at the medial cortex. Where and when Pom1 modulates Cdr2 activity is unclear as Pom1 medial cortical levels remain constant during cell elongation. Here we show that Pom1 re-localizes to cell sides upon environmental glucose limitation, where it strongly delays mitosis. This re-localization is caused by severe microtubule destabilization upon glucose starvation, with microtubules undergoing catastrophe and depositing the Pom1 gradient nucleator Tea4 at cell sides. Microtubule destabilization requires PKA/Pka1 activity, which negatively regulates the microtubule rescue factor CLASP/Cls1/Peg1, reducing CLASP's ability to stabilize microtubules. Thus, PKA signalling tunes CLASP's activity to promote Pom1 cell side localization and buffer cell size upon glucose starvation. PMID- 26443241 TI - Robot-assisted laparoscopic management of duplex renal anomaly: Comparison of surgical outcomes to traditional pure laparoscopic and open surgery. AB - INTRODUCTION: Surgical management of duplex renal anomaly (DRA) is complex because of individual anatomic variation, competing priorities of vesicoureteral reflux (VUR) and ureteral obstruction present in the same child, the varied differential function of the different renal moieties, and the presence of voiding dysfunction and recurrent urinary tract infection (UTI). Robot-assisted laparoscopic (RAL) surgical management has been under-reported in this group of children but is becoming a viable alternative to traditional open surgery. OBJECTIVE: The aim was to report the surgical outcomes of a series of children with DRA who had RAL surgery and compare these outcomes to historical cohorts of open and laparoscopic surgery. STUDY DESIGN: This was a retrospective analysis of a prospective series of children who had RAL surgery for DRA over an 8-year period. Forty-five RAL surgeries were performed in 47 children. RAL heminephrectomy (RAL HN) was performed in 19 children for poorly or non functional renal moiety. One had staged bilateral RAL HN. RAL ureteroureterostomy (RAL UU) was performed in 14 children for upper pole ureteral obstruction. Thirteen RAL common sheath ureteral reimplants (RAL csUN) with or without ureteral tapering were performed in 12 children with VUR and UTI. Diagnosis and demographics, results of preoperative imaging, intraoperative time stamps, perioperative complications, success rate, and renal outcomes were recorded. RESULTS: Low-grade VUR present preoperatively in the RAL UU group all resolved within the follow-up period. Four (25%) children in the RAL HN group developed de novo VUR after surgery, which resolved in two (50%) and required surgery in two (50%). Grade I VUR after RAL csUR that occurred in two (14.3%) children was asymptomatic and observed when off preventative antibiotics. DISCUSSION: Most children with DRA who need surgical treatment can be offered RAL surgery. We report good outcomes and improved operative times for RAL HN and UU that approach historical open and pure laparoscopic cohorts. However, RAL csUR, especially with ureteral tapering, is more complex and inherently susceptible to complications, and has not met the outcomes of the open gold standard. The limits of this study are that selection bias is present, and there is no study control cohort. CONCLUSIONS: This report achieves its aim to report surgical outcomes of children who had RAL surgery for DRA. PMID- 26443242 TI - Contrasting acute and chronic effects of tolvaptan on serum osmolality in the EVEREST trial. AB - AIMS: In the EVEREST trial, tolvaptan improved symptoms and body weight during hospitalization for heart failure (HF), but did not improve post-discharge cardiovascular outcomes. We hypothesized that this disconnect between the short- and long-term effects may be related to changes in serum osmolality. We describe the longitudinal profile of osmolality and its response to tolvaptan during and after hospitalization for HF. METHODS AND RESULTS: EVEREST enrolled 4133 patients hospitalized for HF and reduced EF. Serum osmolality data were available in 3744 (91%). We assessed the effects of tolvaptan on serum osmolality and related these effects to in-hospital changes in body weight and physician-assessed symptoms. Calculated values of osmolality, determined from serum sodium, blood urea nitrogen, and glucose, were 3-4 mOsm/kg higher than concurrently measured serum osmolality at enrolment and discharge in both treatment arms. During hospitalization in the placebo group, serum osmolality slightly increased throughout hospitalization, whereas serum sodium decreased and blood urea nitrogen increased until discharge. Tolvaptan increased osmolality by hospital day 1, but this effect diminished by post-discharge week 4-8 and disappeared by post-discharge week 56. In-hospital changes in osmolality were poorly correlated with in-hospital changes in body weight and physician-assessed dyspnoea. CONCLUSION: Tolvaptan increased serum osmolality during hospitalization for HF, a time frame when the drug also improved signs and symptoms of HF. However, this effect on osmolality declined in the early post-discharge period, when tolvaptan failed to influence clinical outcomes. Serum osmolality, which can be estimated based on readily available laboratory parameters, may be a marker or a target of response to tolvaptan. PMID- 26443243 TI - New reconstruction of the Wiwaxia scleritome, with data from Chengjiang juveniles. AB - Wiwaxiids are a problematic group of scale-covered lophotrochozoans known from Cambrian Stages 3-5. Their imbricating dorsal scleritome of leaf-like scales has prompted comparison with various annelids and molluscs, and has been used as a template to reconstruct the articulation pattern of isolated Small Shelly Fossils. The first articulated specimens of Wiwaxia from the Cambrian Stage 3 Chengjiang Konservat-Lagerstatte show that the Wiwaxia scleritome comprised nine equivalent transverse rows associated with outgrowths of soft tissue, but did not possess a separate zone of anterior sclerites. This serial construction is fundamentally incompatible with the circumferential disposition of sclerites in early molluscs, but does closely resemble the armature of certain annelids. A deep homology with the annelid scleritome must be reconciled with Wiwaxia's mollusc-like mouthparts and foot; together these point to a deep phylogenetic position, close to the common ancestor of annelids and molluscs. PMID- 26443244 TI - Latest developments in allergic rhinitis in Allergy for clinicians and researchers. AB - Research efforts in allergic rhinitis have always been intense. Over the past 3 years, numerous breakthroughs in basic science and clinical research have been made, augmenting our understanding of this condition that afflicts a significant proportion of the global population. New epidemiological findings, novel insights into the molecular and cellular mechanisms of allergy, enhancement of current developmental theories, new concepts of the goals and endpoints of management, and latest therapeutic modalities that includes the harnessing of information technology and big data are some areas where important advances were made. We attempt to bring you a summary of the key research advances made in the field of allergic rhinitis from 2013 to 2015. PMID- 26443245 TI - Equity Chasm in Megacities: Five Leading Causes of Death in Tehran. AB - BACKGROUND: Inequity in megacities is a real concern in public health perspective. Tehran is a megacity with more than 8 million population that is divided into 22 regions (counties) with considerable diversity in socioeconomic status. On the other hand, spatial cluster detection is an important tool in disease surveillance to identify areas of elevated risk and to generate hypotheses about disease or mortality etiology. The present research aims to identify high or low-risk clusters for five non-communicable leading causes of death in 22 regions of Tehran province. METHODS: Cause-specific mortality rates were extracted from Behesht-e-Zahra registry system for Tehran province in 2011. Spatial scan statistic as a most common method in spatial cluster detection was chosen to detect clusters with elevated risk of death. Given the observed and expected number death in each region, a log likelihood ratio (LLR) criterion was used to test whether a cluster is significant. RESULT: Two high-risk and two low risk clusters were detected for each cause of death. All these clusters were statistically significant with P value less than 0.05. Mapping these clusters shows substantial differences between regions in Tehran. For mortality due to ischemic heart diseases, cerebrovascular diseases, hypertensive diseases, respiratory diseases, and stomach cancer, the high-risk clusters concentrated in southern half of Tehran and low-risk clusters were in northern half of Tehran. In the most situations, regions 2, 3 and 5 seemed to have lower rate of death comparing with other regions. On the other hand, regions, 16, 19 and 20 were in the high rate clusters. CONCLUSION: There was substantial disparity between regions of Tehran for five non-communicable causes of death studied in this article. Identifying factors affecting the observed differences is useful to set effective preventive interventions and can be investigated in future researches. PMID- 26443246 TI - Burden of Cancers in Iran from 1990 to 2010: findings from the Global Burden of Disease study 2010. AB - BACKGROUND: Cancer is one of the most common non-communicable diseases in both sexes and a major cause of disability and death around the world, as well as in Iran. The aim of the present manuscript is to report the results of the Global Burden of Disease study 2010 (the GBD 2010) to compare the results with the other similar findings. The paper also discusses the existing deficiencies of the GBD study. Our aim was to describe and criticize the attributed burden of cancers according to the GBD results by sex and age. METHODS: The GBD 2010 has profited from 100 collaborators worldwide and provides a vast network of data on health outcomes, vital registries, and population surveys. The GBD has used various scientific-approved methods to estimate important health statuses like death rates, life expectancy, and healthy adjusted life expectancy, disability-adjusted life years, years of living lost due to premature death and years of life with disabilities. In the present study, we extracted and graphed the GBD results for Iran in order to present a better scheme for readers. RESULTS: The mortality rate of cancers in Iranians has increased by about 8.5%, the disability-adjusted life year rates have declined by about 9%, and years lost due to premature death have also decreased by about 10% from 1990 to 2010 compared to an 85% increase in years of life with disabilities in the same time period. CONCLUSION: The burden of all non-communicable diseases (NCDs) including cancers showed decrease during the past two decades. However, these diseases still remain worldwide health challenge. Prevention should be considered as an important priority and responsibility. The health authorities also need to determine the burden of cancers at the national and sub-national levels for implementation of effective preventive strategies. PMID- 26443247 TI - Identification of Genomic Species of Acinetobacter Isolated from Burns of ICU Patients. AB - BACKGROUND: The worldwide emergence of multi-drug resistant (MDR) bacteria in recent years has caused many problems for hospitals and patients, especially intensive care unit patients. Among these clinically important MDR bacteria are Acinetobacter baumannii complex species (A. baumannii, Acinetobacter genomic species 3 and Acinetobacter genomic species 13TU) that cause a wide range of infections. METHODS: The sequencing and bioinformatics analysis of a part of the Zone 1 of rpoB gene was performed for species identification of Acinetobacter isolates obtained from ICU patients with infected burns hospitalized in a hospital in Isfahan, Iran, over a 9-month period. Antibiotic sensitivity of Acinetobacter isolates was investigated using the disk diffusion method and different classes of antibiotics including amikacin, cefotaxime, ceftriaxone, ciprofloxacin, imipenem and piperacillin. RESULTS: Acinetobacter spp. were isolated from 10 of 80 (12.5%) investigated patients. All of the 10 Acinetobacter isolates were identified as Acinetobacter baumannii and multi-drug resistant according to antibiotic susceptibility tests. CONCLUSION: Of the Acinetobacter baumannii complex members, only A. baumannii species was identified among the isolates obtained from patients with infected burns in an Isfahan hospital over a 9-month period. PMID- 26443248 TI - Carrier Testing in Known Autosomal Recessive Intellectual Disability Genes in an Iranian Healthy Individual Using Exome Sequencing. AB - BACKGROUND: Intellectual Disability (ID) is one of the most common disabling impairments worldwide. Autosomal recessive ID (ARID), a genetically heterogeneous disorder, is more common in countries such as Iran where the rate of consanguineous marriages is high. Considering the social-economic burden of ARID in our country, it is crucial to find out whether couples who are cousins are carriers for disease causing mutations, in order to prevent the birth of an affected child. METHODS: Using exome sequencing, we screened known ARID genes in a normal individual to identify possible mutations in heterozygous form. RESULTS: We identified four protein coding alleles which possibly affect protein function, in different ID genes: PMM2, RBM28, SLC19A3, and VPS13B. CONCLUSION: These findings can be used to prevent the birth of children with ARID by checking the other partner for possible disease causing variants. PMID- 26443249 TI - Exome Sequencing and Linkage Analysis Identified Novel Candidate Genes in Recessive Intellectual Disability Associated with Ataxia. AB - BACKGROUND: Intellectual disability (ID) is a neuro-developmental disorder which causes considerable socio-economic problems. Some ID individuals are also affected by ataxia, and the condition includes different mutations affecting several genes. METHODS: We used whole exome sequencing (WES) in combination with homozygosity mapping (HM) to identify the genetic defects in five consanguineous families among our cohort study, with two affected children with ID and ataxia as major clinical symptoms. RESULTS: We identified three novel candidate genes, RIPPLY1, MRPL10, SNX14, and a new mutation in known gene SURF1. All are autosomal genes, except RIPPLY1, which is located on the X chromosome. Two are housekeeping genes, implicated in transcription and translation regulation and intracellular trafficking, and two encode mitochondrial proteins. The pathogenesis of these variants was evaluated by mutation classification, bioinformatic methods, review of medical and biological relevance, co-segregation studies in the particular family, and a normal population study. CONCLUSIONS: Linkage analysis and exome sequencing of a small number of affected family members is a powerful new technique which can be used to decrease the number of candidate genes in heterogenic disorders such as ID, and may even identify the responsible gene(s). PMID- 26443250 TI - Impact of KIF6 Polymorphism rs20455 on Coronary Heart Disease Risk and Effectiveness of Statin Therapy in 100 Patients from Southern Iran. AB - BACKGROUND: The purpose of this study was to investigate the association between Trp719Arg (rs20455) and Coronary Heart Disease (CHD), and also Coronary Heart Disease reduction in individuals with this SNP during statin therapy in southern Iran. It has been shown that rs20455, which could affect the function of kinesin protein, is associated with Coronary Heart Disease and could be an effective factor for patients who take statin therapy. METHODS: Patients and control individuals were genotyped for rs20455 Single Nucleotide Polymorphism (SNP) using ARMS PCR (Amplification Refractory Mutation System Polymerase Chain Reaction) and RFLP (Restriction Fragment Length Polymorphism) analysis. The effect of kinesin family member 6 (KIF6) on statin therapy was also examined among patients who had a history of one or two heart attacks. RESULTS: It was found that rs20455 had a significant association with Coronary Heart Disease (Odds Ratio [OR] 3.17, 95% Confidence Interval [CI] 1.68 to 5.98). In addition, statin therapy was more effective in rs20455 carriers than non-carriers, with 80% of the carriers showed positive response to this treatment. CONCLUSIONS: Trp 719Arg have an effect on development of Coronary Heart Disease but it is very useful for statin therapy. Overall, individuals with this Single Nucleotide Polymorphism can take statin therapy to prevent the catastrophic consequences of Coronary Heart Disease. PMID- 26443251 TI - Genetic Investigation of an Iranian Supercentenarian by Whole Exome Sequencing. AB - BACKGROUND: The genetic basis of longevity is an important field of study because the majority of supercentenarian cases experience healthy aging and may only show age-related diseases in their last few years of life. It is clear that genetic factors play an important role in survival beyond 90 years of age, but the exact relationship of genetic variants to this phenomenon remains unknown. OBJECTIVE: The aim of this project was to investigate different hypotheses that describe the relationship between genetic variants and human longevity in a living Iranian man by Whole Exome Sequencing. METHODS: Initially, we conducted high quality DNA extraction on a peripheral blood sample. Then, whole exome sequencing was performed on the DNA and different bioinformatic software packages and databases were used to analyze the data. Tertiary analysis was performed on four genetic hypotheses for longevity. RESULTS: Analysis showed that among 27 metabolic variants which are related to longevity, 18 variants encompassed the exceptional longevity allele. In comparison with the NHGRI GWAS catalog, the case had 58 trait-associated variants of which 11 were homozygous for the risk allele. We also discovered 25 novel variants within candidate genes for aging and longevity and we detected seven longevity-associated variants in the sample. CONCLUSION: This study was performed on just one sample and so the results cannot be interpreted as a generalized principle for other elderly societies, but this is the first step towards investigation of the genetic basis of longevity in Iran and provides an insight for further studies in the field of longevity. PMID- 26443252 TI - Analysis of HLA-DQB1*0602 in Multiple Sclerosis Patients in Khuzestan Province, Iran. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic, demyelinating, autoimmune and also complex disease of the central nervous system the etiology of which is not completely defined; but both genetic and environmental factors are regarded as main factors in its susceptibility. HLA-DQB1*0602 is considered as one of the most important genetic factors in MS predisposition but contradictory results have been reported in different populations world-wide. Since there are no data with respect to the correlation of HLA-DQB1*0602 and multiple sclerosis in Khuzestan province, and because of ethnic diversity in Khuzestan province, the aim was to examine the association of this allele with multiple sclerosis in Khuzestan. METHODS: This is a case control study that evaluated 200 MS patients from Khuzestan and 200 healthy individuals from the same geographical region. DNA extraction was performed by salting out method; in addition, HLA typing was carried out by polymerase chain reaction amplification with sequence-specific primers (PCR-SSP) method. The present study also considered probable association among HLA-DQB1*0602 with sex, ethnicity, and type of disease. RESULTS: Results revealed that distribution of mentioned allele was not statistically different among cases and controls (61.5% vs. 64%, P = 0.605); furthermore, no association was shown between this allele and gender, ethnicity or type of disease. CONCLUSION: On the whole, our result is consistent with most of the other studies in Iran; but contrasts with most of the studies in European populations. PMID- 26443253 TI - Comparison of Oral Lichen Planus and Systemic Lupus Erythematosus in Interleukins Level. AB - Lichen planus (LP) is a chronic inflammatory mucocutaneous disorder with unknown etiology. Systemic lupus erythematosus (SLE) is known as a prototypic autoimmune disease. Cytokines play a key role in the pathogenesis of both diseases. Various cytokines, such as interleukin 6 (IL-6), interleukin 10 (IL-10), interferon alpha (INF-a), and Tumor Necrosis Factor-alpha (TNF-a) can serve as biomarkers to predict SLE severity and monitor disease activity. In this review, we compare interleukins in oral lichen planus and lupus erythematosus as an autoimmune disease prototype. So, this review may provide insight for researchers in completing the cytokine network in OLP. Among the etiologic factors, the imbalance between Th-1 and Th-2 cytokine production plays an important role in the development of both diseases. By understanding cytokines and immunoregulatory networks of cytokines in these patients, appropriate treatment can be offered. There are many limitations in cytokine studies, which we have described in this article. PMID- 26443254 TI - Statistical Issues in Estimation of Adjusted Risk Ratio in Prospective Studies. AB - BACKGROUND: Binary outcomes are common in prospective studies such as randomized controlled trials and cohort studies. Logistic regression is the most popular regression model for binary outcomes. Logistic regression yields an odds ratio that approximates the risk ratio when the risk of outcome is low. A consensus has been reached in an extensive argument in much of the literature that the risk ratio is preferred over the odds ratio for prospective studies. To obtain a model based estimate of risk ratios, log-binomial regression has been recommended. However, this model may fail to converge and many methods have been provided as an alternative in these situations. METHODS: In this paper, we discuss the methods to obtain adjusted risk ratios in settings with independent and clustered data and we will review the results of comparisons between these methods based on simulation studies, especially a large simulation study which was conducted by the authors. We use hypothetical examples to show how log-Poisson regression with modified standard errors can be used to estimate risk ratio in practice using popular statistical software. CONCLUSION: The potential misinterpretation of odds ratios should be considered by researchers, especially when the risk of the outcome is high. When researchers want to estimate the effect of exposure or intervention by controlling potential covariates, the misinterpretation of odds ratios can be avoided using regression models that can estimate risk ratios instead of logistic regression. The log-Poisson regression with modified standard errors can be considered to estimate risk ratios in both independent and clustered data settings. PMID- 26443255 TI - Hypercalcemia and Lytic Bone Lesions Masquerading Inflammatory Arthritis Treated as Rheumatoid Arthritis. AB - Hyperparathyroidism is a complex clinical syndrome characterized by dysfunction in the metabolism of bone, calcium and phosphorus. Rheumatologic manifestations are common amongst patients with hyperparathyroidism. We report a 50-year-old woman with hypercalcemia, lytic bone lesions and inflammatory arthritis of both hands that were not resolved after parathyroidectomy. Laboratory evidence of elevated erythrocyte sedimentation rate, positive C-reactive protein (CRP) and high titers of anti-CCP and rheumatoid factor was diagnostic of rheumatoid arthritis (RA) according to European League Against Rheumatism criteria. Eventually, with the concomitant diagnoses of hyperparathyroidism and RA, she was treated with methotrexate and hydroxychloroquin. Hyperparathyroidism may present with rheumatologic manifestations, leading to an initial misdiagnosis. Furthermore, attention to this fact that hypercalcemia is not commonly associated with RA, and rather suggestive of a concomitant disorder, is crucial to the diagnosis of hyperparathyroidism in RA patients with hypercalcemia. PMID- 26443256 TI - Acute Severe Hepatitis and Hemophagocytosis in Adult Onset Still's Disease. AB - We report a 44-year-old male Turkish patient with adult onset Still's disease (AOSD) complicated by acute severe hepatitis and hemophagocytosis. Initial investigations for fever and rapidly progressive elevation of liver function tests were not diagnostic. Routine evaluations of liver and bone marrow biopsies missed the fundamental pathology. Extremely elevated ferritin levels led to a more detailed search, and immunohistochemical staining with CD68 for macrophages revealed extensive hemophagocytosis in both the first and second bone marrow biopsies, as well as in the liver biopsy. Treatment with steroid and cyclosporine A induced complete remission. PMID- 26443257 TI - Professor Kamaleddin Armin (1914-1995); a Superb Mentor with High Morals. PMID- 26443258 TI - The Oldest Recorded Case of Acromegaly and Gigantism in Iran. AB - Here we commemorate the character and academic authority of Prof. Zabiholah Gorban (1903-2006), the founder of Shiraz medical school. No doubt, in the scope of history of contemporary medicine, he has been efficient and effective. With respect to this fact, his article on a rare case described in Acta anatomica published in Iran in 1966, entitled (Observations on a giant skeleton) is browsed and reviewed. A case named Siah Khan with combined acromegaly and gigantism that appears to have letters to say still after nearly half a century. PMID- 26443259 TI - Dr. Nasser Moeinzadeh (1930-2015); A Pioneering Otolaryngologist in Iran. PMID- 26443260 TI - Chest Wall and Spinal Tuberculous Abscess. PMID- 26443261 TI - Unlocking the potential of lignocellulosic biomass through plant science. AB - The aim of producing sustainable liquid biofuels and chemicals from lignocellulosic biomass remains high on the sustainability agenda, but is challenged by the costs of producing fermentable sugars from these materials. Sugars from plant biomass can be fermented to alcohols or even alkanes, creating a liquid fuel in which carbon released on combustion is balanced by its photosynthetic capture. Large amounts of sugar are present in the woody, nonfood parts of crops and could be used for fuel production without compromising global food security. However, the sugar in woody biomass is locked up in the complex and recalcitrant lignocellulosic plant cell wall, making it difficult and expensive to extract. In this paper, we review what is known about the major polymeric components of woody plant biomass, with an emphasis on the molecular interactions that contribute to its recalcitrance to enzymatic digestion. In addition, we review the extensive research that has been carried out in order to understand and reduce lignocellulose recalcitrance and enable more cost-effective production of fuel from woody plant biomass. PMID- 26443262 TI - Differential Many-Body Cooperativity in Electronic Spectra of Oligonuclear Transition-Metal Complexes. AB - In computational chemistry, non-additive and cooperative effects can be defined in terms of a (differential) many-body expansion of the energy or any other physical property of the molecular system of interest. One-body terms describe energies or properties of the subsystems, two-body terms describe non-additive but pairwise contributions and three-body as well as higher-order terms can be interpreted as a measure for cooperativity. In the present article, this concept is applied to the analysis of ultraviolet/visible (UV/Vis) spectra of homotrinuclear transition-metal complexes by means of a many-body expansion of the change in the spectrum induced by replacing each of the three transition metal ions by another transition-metal ion to yield a different homotrinuclear transition-metal complex. Computed spectra for the triangulo-complexes [M3 {Si(mt(Me) )3}2] (M=Pd/Pt, mt(Me) =methimazole) and tritopic triphenylene-based N heterocyclic carbene Rh/Ir complexes illustrate the concept, showing large and small differential three-body cooperativity, respectively. PMID- 26443263 TI - 3D stereolithography printing of graphene oxide reinforced complex architectures. AB - Properties of polymer based nanocomposites reply on distribution, concentration, geometry and property of nanofillers in polymer matrix. Increasing the concentration of carbon based nanomaterials, such as CNTs, in polymer matrix often results in stronger but more brittle material. Here, we demonstrated the first three-dimensional (3D) printed graphene oxide complex structures by stereolithography with good combination of strength and ductility. With only 0.2% GOs, the tensile strength is increased by 62.2% and elongation increased by 12.8%. Transmission electron microscope results show that the GOs were randomly aligned in the cross section of polymer. We investigated the strengthening mechanism of the 3D printed structure in terms of tensile strength and Young's modulus. It is found that an increase in ductility of the 3D printed nanocomposites is related to increase in crystallinity of GOs reinforced polymer. Compression test of 3D GOs structure reveals the metal-like failure model of GOs nanocomposites. PMID- 26443264 TI - Adherence to Antiretroviral Therapy Among Children Living with HIV in South India. AB - Adherence to ART, fundamental to treatment success, has been poorly studied in India. Caregivers of children attending HIV clinics in southern India were interviewed using structured questionnaires. Adherence was assessed using a visual analogue scale representing past-month adherence and treatment interruptions >48 h during the past 3 months. Clinical features, correlates of adherence and HIV-1 viral-load were documented. Based on caregiver reports, 90.9 % of the children were optimally adherent. In multivariable analysis, experiencing ART-related adverse effects was significantly associated with suboptimal adherence (p = 0.01). The proportion of children who experienced virological failure was 16.5 %. Virological failure was not linked to suboptimal adherence. Factors influencing virological failure included running out of medications (p = 0.002) and the child refusing to take medications (p = 0.01). Inclusion of drugs with better safety profiles and improved access to care could further enhance outcomes. PMID- 26443265 TI - Developing an intervention to facilitate family communication about inherited genetic conditions, and training genetic counsellors in its delivery. AB - Many families experience difficulty in talking about an inherited genetic condition that affects one or more of them. There have now been a number of studies identifying the issues in detail, however few have developed interventions to assist families. The SPRinG collaborative have used the UK Medical Research Council's guidance on Developing and Evaluating Complex Interventions, to work with families and genetic counsellors (GCs) to co-design a psycho-educational intervention to facilitate family communication and promote better coping and adaptation to living with an inherited genetic condition for parents and their children (<18 years). The intervention is modelled on multi family discussion groups (MFDGs) used in psychiatric settings. The MFDG was developed and tested over three phases. First focus groups with parents, young people, children and health professionals discussed whether MFDG was acceptable and proposed a suitable design. Using evidence and focus group data, the intervention and a training manual were developed and three GCs were trained in its delivery. Finally, a prototype MFDG was led by a family therapist and co facilitated by the three GCs. Data analysis showed that families attending the focus groups and intervention thought MFDG highly beneficial, and the pilot sessions had a significant impact on their family' functioning. We also demonstrated that it is possible to train GCs to deliver the MFDG intervention. Further studies are now required to test the feasibility of undertaking a definitive randomised controlled trial to evaluate its effectiveness in improving family outcomes before implementing into genetic counselling practice. PMID- 26443266 TI - A recessive form of extreme macrocephaly and mild intellectual disability complements the spectrum of PTEN hamartoma tumour syndrome. AB - PTEN hamartoma tumour syndrome (PHTS) is caused by heterozygous variants in PTEN and is characterised by tumour predisposition, macrocephaly, and cognition impairment. Bi-allelic loss of PTEN activity has not been reported so far and animal models suggest that bi-allelic loss of PTEN activity is embryonically lethal. Here, we report the identification of a novel homozygous variant in PTEN, NM_000314.4; c.545T>C; p.Leu182Ser, in two adolescent siblings with severe macrocephaly and mild intellectual disability. The variant is predicted to be damaging and is associated with significantly increased phospho-S6 downstream of PTEN. The absence of tumours in the two homozygous siblings as well as lack of symptoms of PHTS in the heterozygous carriers of the family suggest that this particular variant is functionally hypomorphic rather than deleterious. PMID- 26443269 TI - Clinical utility gene card for: acrodermatitis enteropathica - update 2015. PMID- 26443268 TI - CUGC for hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP). PMID- 26443267 TI - Imbalance of excitatory/inhibitory synaptic protein expression in iPSC-derived neurons from FOXG1(+/-) patients and in foxg1(+/-) mice. AB - Rett syndrome (RTT) is a severe neurodevelopmental disorder associated with mutations in either MECP2, CDKL5 or FOXG1. The precise molecular mechanisms that lead to the pathogenesis of RTT have yet to be elucidated. We recently reported that expression of GluD1 (orphan glutamate receptor delta-1 subunit) is increased in iPSC-derived neurons obtained from patients with mutations in either MECP2 or CDKL5. GluD1 controls synaptic differentiation and shifts the balance between excitatory and inhibitory synapses toward the latter. Thus, an increase in GluD1 might be a critical factor in the etiology of RTT by affecting the excitatory/inhibitory balance in the developing brain. To test this hypothesis, we generated iPSC-derived neurons from FOXG1(+/-) patients. We analyzed mRNA and protein levels of GluD1 together with key markers of excitatory and inhibitory synapses in these iPSC-derived neurons and in Foxg1(+/-) mouse fetal (E11.5) and adult (P70) brains. We found strong correlation between iPSC-derived neurons and fetal mouse brains, where GluD1 and inhibitory synaptic markers (GAD67 and GABA AR-alpha1) were increased, whereas the levels of a number of excitatory synaptic markers (VGLUT1, GluA1, GluN1 and PSD-95) were decreased. In adult mice, GluD1 was decreased along with all GABAergic and glutamatergic markers. Our findings further the understanding of the etiology of RTT by introducing a new pathological event occurring in the brain of FOXG1(+/-) patients during embryonic development and its time-dependent shift toward a general decrease in brain synapses. PMID- 26443271 TI - The ulnar artery pseudoaneurysm. PMID- 26443270 TI - Schisandrae Fructus Inhibits IL-1beta-Induced Matrix Metalloproteinases and Inflammatory Mediators Production in SW1353 Human Chondrocytes by Suppressing NF kappaB and MAPK Activation. AB - Proinflammatory cytokine interleukin-1 beta (IL-1beta) plays a crucial role in the pathogenesis of osteoarthritis (OA) by stimulating several mediators that contribute to cartilage degradation. Schisandrae Fructus (SF), the dried fruit of Schisandra chinensis (Turcz.) Baill. (Magnoliaceae), is widely used in traditional medicine for the treatment of a number of chronic inflammatory diseases. This study investigated the antiosteoarthritis properties of an ethanol extract of SF on IL-1beta-stimulated SW1353 chondrocytes. SF attenuated IL-1beta induced expression and activity of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 and also reduced the elevated levels of cyclooxygenase-2 and inducible nitric oxide synthase associated with the inhibition of prostaglandin E2 and nitric oxide production in IL-1beta-stimulated SW1353 chondrocytes. In addition, SF markedly suppressed the nuclear translocation of nuclear factor-kappa B (NF kappaB) by blocking inhibitor kappaB-alpha degradation and inhibited the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). These results indicate that the inhibitory effect of SF on IL-1beta-stimulated expression of MMPs and inflammatory mediators production in SW1353 cells were associated with the suppression of the NF-kappaB and JNK/p38 MAPK signaling pathways. The results from this study indicate that SF may have therapeutic potential for the treatment of OA due to its anti-inflammatory and chondroprotective features. PMID- 26443272 TI - Skeletal stability of surgery-first bimaxillary orthognathic surgery for skeletal class III malocclusion, using standardized criteria. AB - The purpose of this study was to compare the postoperative stability following bimaxillary surgery performed either with or without preoperative orthodontic treatment, in class III malocclusion patients. These patients were enrolled using standardized inclusion criteria. Forty patients with a class III malocclusion were included in this retrospective study. Inclusion criteria were class III malocclusion with and without premolar extraction, <3mm midline deviation, and <5mm arch width discordance. Patients were assigned to the conventional bimaxillary surgery group (n=20) or the surgery-first bimaxillary surgery group (n=20). Serial cephalometric radiographs obtained before surgery (T0), at 2 months after surgery (T1), and at 6 months after surgery (T2) were used to assess the variation in surgical change (T0 to T1) and postsurgical change (T1 to T2). Eight linear and three angular parameters were used to evaluate postoperative stability. With respect to postsurgical changes, significant differences were observed in the changes for the vertical reference plane to the posterior nasal spine, horizontal reference plane to B-point, and occlusal plane angle in both groups. No statistically significant differences in the relapse rates were observed between the two groups. No significant differences were observed between the two groups in terms of the postoperative stability. PMID- 26443273 TI - Palatal bone dimensions on cone beam computed tomography. Implications for the palate as autogenous donor site: an observational study. AB - This study analyzed cone beam computed tomography (CBCT) records. Radiographic image analysis included: (1) the width and height of the palatal vault, and diameter and location of the incisive foramen; (2) the potential block graft dimensions and their correlation to arch dimensions; (3) the potential graft size and its variation by sex. CBCT scans of 76 patients were included, 42 from female patients and 34 from male patients (mean age 42.3 years). The mean palatal width was 35.2+/-3.4 mm, while the mean palatal height was 15.2+/-2.9 mm. The mean diameter of the incisive foramen was 3.1+/-1.3. mm. The mean potential osteotomy diameter was 7.8+/-1.5 mm. The mean osteotomy length varied according to site: central incisor region, 5.9+/-2.0 mm; lateral incisor region, 5.2+/-2.1 mm; canine region, 4.7+/-1.9 mm; premolar region, 4.1+/-1.7 mm. A positive correlation was observed between the osteotomy diameter and the palatal width: a greater osteotomy length was obtained from the more anterior teeth position. Males presented significantly greater osteotomy diameter and length compared to females. The palate represents a potential site for the harvest of autogenous bone block grafts for the reconstruction of ridge defects. PMID- 26443274 TI - Neonatal care in low- and middle-income countries. Introduction. PMID- 26443275 TI - Thinking beyond global neonatal mortality rates. PMID- 26443278 TI - Social relationships and social support among post-war youth in Northern Uganda. AB - Although social relationships and social support are salient factors for post-war adolescents' psychosocial coping and adjustment, there is only limited information regarding war-affected adolescents' views on social support and the relationships within which social support is provided. This study therefore explored both elements among a clinical sample of 20 adolescents living in post war Northern Uganda. Following Braun and Clarke's thematic analysis, we found a prominent role of the biological mother and other primary biological family members in the upbringing of our participants. Spiritual and material support were perceived to be the most important type of support, respectively, while the adolescents were growing up and in their current lives. These findings provide support for the perception that caregiving systems are adaptable to particular sociocultural contexts. Further, the importance of particular functions of social support could signify a potentially selective buffering effect of these functions in adverse contexts. Because of the importance of the primary biological family and the salient role of parent-child relationships in the face of adversity, future research needs to focus on this particular kind of social relationship in contexts of prolonged collective violence. PMID- 26443277 TI - Structural basis of Ornithine Decarboxylase inactivation and accelerated degradation by polyamine sensor Antizyme1. AB - Ornithine decarboxylase (ODC) catalyzes the first and rate-limiting step of polyamine biosynthesis in humans. Polyamines are essential for cell proliferation and are implicated in cellular processes, ranging from DNA replication to apoptosis. Excessive accumulation of polyamines has a cytotoxic effect on cells and elevated level of ODC activity is associated with cancer development. To maintain normal cellular proliferation, regulation of polyamine synthesis is imposed by Antizyme1 (AZ1). The expression of AZ1 is induced by a ribosomal frameshifting mechanism in response to increased intracellular polyamines. AZ1 regulates polyamine homeostasis by inactivating ODC activity and enhancing its degradation. Here, we report the structure of human ODC in complex with N terminally truncated AZ1 (cAZ1). The structure shows cAZ1 binding to ODC, which occludes the binding of a second molecule of ODC to form the active homodimer. Consequently, the substrate binding site is disrupted and ODC is inactivated. Structural comparison shows that the binding of cAZ1 to ODC causes a global conformational change of ODC and renders its C-terminal region flexible, therefore exposing this region for degradation by the 26S proteasome. Our structure provides the molecular basis for the inactivation of ODC by AZ1 and sheds light on how AZ1 promotes its degradation. PMID- 26443279 TI - Response evaluation in mesothelioma: Beyond RECIST. AB - Malignant pleural mesothelioma (MPM) typically demonstrates a non-spherical growth pattern, so it is often difficult to accurately categorize change in tumour burden using size-based tumour response criteria (e.g., WHO (World Health Organisation), RECIST (Response Evaluation Criteria in Solid Tumours) and modified RECIST). Functional imaging techniques are applied to derive quantitative measurements of tumours, which reflect particular aspects of the tumour pathophysiology. By quantifying how these measurements change with treatment, it is possible to observe treatment effects. In this review, we survey the existing roles of CT and MRI for the management of MPM, including the currently applied size measurement criteria for the assessment of treatment response. New functional imaging techniques, such as positron emission tomography (PET), diffusion-weighted MRI (DWI) and dynamic contrast-enhanced MRI (DCE-MRI) that may potentially improve the assessment of treatment response will be highlighted and discussed. PMID- 26443280 TI - Cerebellar ataxia with unilateral high frequency vestibulopathy and caloric disinhibition. PMID- 26443281 TI - Continuous duodenal levodopa infusion in a patient with Crohn's disease and small bowel surgery - Case report. PMID- 26443283 TI - Our journal: past, present and future. PMID- 26443282 TI - Differential regulation of matrix metalloproteinases in varicella zoster virus infected human brain vascular adventitial fibroblasts. AB - Upon reactivation, varicella zoster virus (VZV) spreads transaxonally, infects cerebral arteries and causes ischemic or hemorrhagic stroke, as well as aneurysms. The mechanism(s) of VZV-induced aneurysm formation is unknown. However, matrix metalloproteinases (MMPs), which digest extracellular structural proteins in the artery wall, play a role in cerebral and aortic artery aneurysm formation and rupture. Here, we examined the effect of VZV infection on expression of MMP-1, -2, -3, and -9 in primary human brain vascular adventitial fibroblasts (BRAFS). At 6 days post-infection, VZV- and mock-infected BRAFs were analyzed for mRNA levels of MMP-1, -2, -3 and -9 by RT-PCR and for corresponding total intra- and extracellular protein levels by multiplex ELISA. The activity of MMP-1 was also measured in a substrate cleavage assay. Compared to mock-infected BRAFs, MMP-1, MMP-3 and MMP-9 transcripts, cell lysate protein and conditioned supernatant protein were all increased in VZV-infected BRAFs, whereas MMP-2 transcripts, cell lysate protein and conditioned supernatant protein were decreased. MMP-1 from the conditioned supernatant of VZV-infected BRAFs showed increased cleavage activity on an MMP-1-specific substrate compared to mock infected BRAFs. Differential regulation of MMPs in VZV-infected BRAFs may contribute to aneurysm formation in VZV vasculopathy. PMID- 26443284 TI - Diabetes and driving: 2015 Canadian Diabetes Association updated recommendations for private and commercial drivers. PMID- 26443285 TI - The Canadian Diabetes Association names Dr. Barry I. Posner as the 2015 Clinical & Scientific Section Lifetime Achievement Award Recipient. PMID- 26443286 TI - SQUIRE 2.0 (Standards for QUality Improvement Reporting Excellence): revised publication guidelines from a detailed consensus process. AB - Since the publication of Standards for Quality Improvement Reporting Excellence (SQUIRE 1.0) guidelines in 2008, the science of the field has advanced considerably. In this manuscript, we describe the development of SQUIRE 2.0 and its key components. We undertook the revision between 2012 and 2015 using 1) semistructured interviews and focus groups to evaluate SQUIRE 1.0 plus feedback from an international steering group; 2) 2 face-to-face consensus meetings to develop interim drafts and 3) pilot testing with authors and a public comment period. SQUIRE 2.0 emphasizes the reporting of 3 key components of systematic efforts to improve the quality, value and safety of healthcare: the use of formal and informal theory in planning, implementing and evaluating improvement work; the context in which the work is done and the study of the intervention(s). SQUIRE 2.0 is intended for reporting the range of methods used to improve healthcare, recognizing that they can be complex and multidimensional. It provides common ground to share these discoveries in the scholarly literature (www.squire-statement.org). PMID- 26443287 TI - Addendum to policies, guidelines and consensus statements: pharmacologic management of type 2 diabetes: 2015 interim update. PMID- 26443288 TI - Assessment of clonality and serotypes of Streptococcus mutans among children by multilocus sequence typing. AB - Studies using multilocus sequence typing (MLST) have demonstrated that Streptococcus mutans isolates are genetically diverse. Our laboratory previously demonstrated clonality of S. mutans using MLST but could not discount the possibility of sampling bias. In this study, the clonality of randomly selected S. mutans plaque isolates from African-American children was examined using MLST. Serotype and the presence of collagen-binding proteins (CBPs) encoded by cnm/cbm were also assessed. One-hundred S. mutans isolates were randomly selected for MLST analysis. Sequence analysis was performed and phylogenetic trees were generated using start2 and mega. Thirty-four sequence types were identified, of which 27 were unique to this population. Seventy-five per cent of the isolates clustered into 16 clonal groups. The serotypes observed were c (n = 84), e (n = 3), and k (n = 11). The prevalence of S. mutans isolates of serotype k was notably high, at 17.5%. All isolates were cnm/cbm negative. The clonality of S. mutans demonstrated in this study illustrates the importance of localized population studies and are consistent with transmission. The prevalence of serotype k, a recently proposed systemic pathogen, observed in this study, is higher than reported in most populations and is the first report of S. mutans serotype k in a United States population. PMID- 26443289 TI - Young Coconut Juice Supplementation Results in Greater Bone Mass and Bone Formation Indices in Ovariectomized Rats: A Preliminary Study. AB - Young coconut juice (Cocos nucifera Linn.) (YCJ) has traditionally been consumed to alleviate symptoms associated with menopause by women in Southeast Asia. The aim of the present study was to determine the effects of YCJ on bone metabolism in ovariectomized rats. Female 10-week-old Wistar rats were randomly assigned to the following 4 groups: Baseline, Sham, Ovx, and Ovx + YCJ (n = 10 rats per group). Rats in the Baseline group were sacrificed immediately, and those in the other groups were subjected to either sham operation (Sham) or bilateral ovariectomy (Ovx and Ovx + YCJ). The Ovx + YCJ rats were administered 5* concentrated YCJ at a dose of 10 mL/kg body weight per day. Six weeks after surgery, the rats were sacrificed, and indices of bone mass and bone histomorphometry were measured. The bone mineral density of the left femur was significantly higher in the Ovx + YCJ group compared with the Ovx group. In addition, the Ovx + YCJ group showed significantly higher measurements for bone formation rate compared with the Ovx group. These findings suggest that YCJ supplementation has a positive effect on bone metabolism and thus represents a possible intervention to slow the bone loss observed following menopause. PMID- 26443290 TI - IDegLira Improves Both Fasting and Postprandial Glucose Control as Demonstrated Using Continuous Glucose Monitoring and a Standardized Meal Test. AB - OBJECTIVE: IDegLira is a novel, fixed-ratio combination of the long-acting basal insulin, insulin degludec, and the long-acting glucagon-like peptide-1 analog liraglutide. We studied the effect of IDegLira versus its components on postprandial glucose (PPG) in type 2 diabetes. METHODS: In this substudy, 260 (15.6%) of the original 1663 patients with inadequate glycemic control participating in a 26-week, open-label trial (DUAL I) were randomized 2:1:1 to once-daily IDegLira, insulin degludec or liraglutide. Continuous glucose monitoring (CGM) for 72 hours and a meal test were performed. RESULTS: At week 26, IDegLira produced a significantly greater decrease from baseline in mean PPG increment (normalized iAUC0-4h) than insulin degludec (estimated treatment difference [ETD] -12.79 mg/dl [95% CI: -21.08; -4.68], P = .0023) and a similar magnitude of decrease as liraglutide (ETD -1.62 mg/dl [95% CI: -10.09; 6.67], P = .70). CGM indicated a greater reduction in change from baseline in PPG increment (iAUC0-4h) for IDegLira versus insulin degludec over all 3 main meals (ETD -6.13 mg/dl [95% CI: -10.27, -1.98], P = .0047) and similar reductions versus liraglutide (ETD -1.80 mg/dl [95% CI: -2.52, 5.95], P = .4122). Insulin secretion ratio and static index were greater for IDegLira versus insulin degludec (P = .048 and P = .006, respectively) and similar to liraglutide (P = .45 and P = .895, respectively). CONCLUSIONS: Once-daily IDegLira provides significantly better PPG control following a mixed meal test than insulin degludec. The improvement is at least partially explained by higher endogenous insulin secretion and improved beta cell function with IDegLira. The benefits of liraglutide on PPG control are maintained across all main meals in the combination. PMID- 26443291 TI - Classification of Physical Activity: Information to Artificial Pancreas Control Systems in Real Time. AB - Physical activity has a wide range of effects on glucose concentrations in type 1 diabetes (T1D) depending on the type (ie, aerobic, anaerobic, mixed) and duration of activity performed. This variability in glucose responses to physical activity makes the development of artificial pancreas (AP) systems challenging. Automatic detection of exercise type and intensity, and its classification as aerobic or anaerobic would provide valuable information to AP control algorithms. This can be achieved by using a multivariable AP approach where biometric variables are measured and reported to the AP at high frequency. We developed a classification system that identifies, in real time, the exercise intensity and its reliance on aerobic or anaerobic metabolism and tested this approach using clinical data collected from 5 persons with T1D and 3 individuals without T1D in a controlled laboratory setting using a variety of common types of physical activity. The classifier had an average sensitivity of 98.7% for physiological data collected over a range of exercise modalities and intensities in these subjects. The classifier will be added as a new module to the integrated multivariable adaptive AP system to enable the detection of aerobic and anaerobic exercise for enhancing the accuracy of insulin infusion strategies during and after exercise. PMID- 26443292 TI - Cost Burden of Chronic Pain Patients in a Large Integrated Delivery System in the United States. AB - OBJECTIVES: To estimate all-cause healthcare resource utilization and costs among chronic pain patients within an integrated healthcare delivery system in the United States. METHODS: Electronic medical records and health claims data from the Henry Ford Health System were used to determine healthcare resource utilization and costs for patients with 24 chronic pain conditions. Patients were identified by >= 2 ICD-9-CM codes >= 30 days apart from January to December, 2010; the first ICD-9 code was the index event. Continuous coverage for 12 months pre- and postindex was required. All-cause direct medical costs were determined from billing data. RESULTS: A total of 12,165 patients were identified for the analysis. After pharmacy, the most used resource was outpatient visits, with a mean of 18.8 (SD 13.2) visits per patient for the postindex period; specialty visits accounted for 59.0% of outpatient visits. Imaging was utilized with a mean of 5.2 (SD 5.5) discrete tests per patient, and opioids were the most commonly prescribed medication (38.7%). Annual direct total costs for all conditions were $386 million ($31,692 per patient; a 40% increase from the pre-index). Pharmacy costs comprised 14.3% of total costs, and outpatient visits were the primary cost driver. CONCLUSIONS: Chronic pain conditions impose a substantial burden on the healthcare system, with musculoskeletal conditions associated with the highest overall costs. Costs appeared to be primarily related to use of outpatient services. This type of research supports integrated delivery systems as a source for assessing opportunities to improve patient outcomes and lower the costs for chronic pain patients. PMID- 26443293 TI - An observational study of the 'isolated forearm technique' in unparalysed, spontaneously breathing patients. AB - The isolated forearm technique enables a patient, otherwise paralysed by neuromuscular blockade, to communicate by movement if wakeful during surgery. The positive response rate to verbal command is high (~32%). The 5th National Audit Project recommended that this monitoring technique should become more widely taught and considered, so this study was designed to assess its utility as a standard of care in unparalysed patients. A positive response rate as high as in the paralysed would justify local adoption. Therefore, 100 consecutive patients undergoing urology surgery were given verbal commands to move at two-minute intervals from induction of anaesthesia (fentanyl and propofol) to full emergence and extubation of the supraglottic airway. Anaesthesia was maintained with isoflurane in oxygen/nitrous oxide. Although 24 patients moved during surgery (and therefore needed additional anaesthetic), none moved to verbal command. Even at extubation, when patients moved to expel the airway, there was no response to command until after wakening. These results suggest that in contrast to its use in paralysed patients, the isolated forearm technique does not yield useful information about the patient's state of wakefulness in the unparalysed. Another interpretation is that unparalysed patients are less prone to wakefulness than the paralysed. PMID- 26443294 TI - Clustering medication adherence behavior based on beliefs in medicines and illness perceptions in patients taking asthma maintenance medications. AB - OBJECTIVES: The prevalence of medication non-adherence is 50% in chronic disease conditions and varies from 30% to 70% in asthma maintenance medications. A major drawback in addressing medication non-adherence is the short time available for patient consultations, which limits the ability of the clinician in identifying the problem. Thus, this study explores how medication adherence behavior can be clustered and identifies the unique characteristics of each cluster so that clinicians can recognize the cluster characteristics in patients to provide targeted interventions. The study objectives were to: (1) cluster patients' medication adherence behavior with asthma maintenance medications based on their beliefs in medicines and illness perceptions, and (2) describe the characteristics of the patients in each cluster based on psychosocial, clinical, and demographic characteristics. RESEARCH DESIGN AND METHODS: A cross-sectional online survey design on a convenience sample of adult individuals who were taking asthma maintenance medications. MAIN OUTCOME MEASURES: Self-reported medication adherence using Morisky scale, beliefs in medicines using Beliefs in Medicines Questionnaire, and illness perceptions using the Brief Illness Perceptions Questionnaire. RESULTS: The cluster analysis with 392 subjects resulted in five clusters based on patients' beliefs in medicines and their illness perceptions. The clusters formed had distinct characteristics that lend themselves to monitoring or for which targeted interventions can be framed to improve medication adherence. LIMITATIONS: The study only examined asthma maintenance medications limiting the generalizability of the study. Also, all the data collected including medication adherence were self-reported data from an online panel. This can cause selection bias and lack of generalizability. CONCLUSIONS: The study demonstrated how the concept of 'non-adherence' is different for different patients and the need for tailored interventions for each type of non adherence. With the limited consultation time available for clinicians to communicate with the patients, identifying the characteristics of patients in different clusters can assist clinicians in providing appropriate targeted interventions. PMID- 26443295 TI - Substance use, sexual behaviour and prevention strategies of Vancouver gay and bisexual men who recently attended group sex events. AB - Group sex events are an epidemiologically important part of some gay and bisexual men's sexual culture in Canada. Associated with condomless anal intercourse and polysubstance use, such events have been cited as disproportionally contributing to HIV infection rates. We analysed questionnaire data from the Momentum Health Study in Vancouver, Canada, to understand substance use, sexual behaviour, psychosocial variables (Sexual Sensation Seeking, Sexual Escape Motivation, Treatment Optimism) and HIV prevention strategies (sero-sorting, strategic positioning, avoiding anal sex, disclosure, treatment as prevention) of men attending such events, which were defined as group (n >= 4 partners) sex parties, blackout events and darkrooms. Analysis by multivariable logistic regression compared men attending group sex events within the past six months (n = 180) with non-attendees (n = 539). Results showed that attendees reported: (1) significantly higher use of sex drugs and alcohol consumption, (2) higher scores on the Sexual Sensation Scale, more anal sex partners, greater odds of any condomless anal sex with sero-discordant partners and greater odds of reporting fisting and sex toy use and (3) different prevention practices that varied by HIV serostatus. Findings are interpreted in light of the importance of pleasure, sociality and HIV/STI prevention strategies associated with group sex events. Findings contribute to the development of appropriate education and intervention for attendees. PMID- 26443296 TI - Spiritual well-being and quality of life among Icelanders receiving palliative care: data from Icelandic pilot-testing of a provisional measure of spiritual well-being from the European Organisation for Research and Treatment of Cancer. AB - Palliative care focuses on improving quality of life (QoL). This study examined the feasibility of the Icelandic version of a provisional European Organisation for Research and Treatment of Cancer (EORTC) measure of spiritual well-being (SWB), and explored the relationship between SWB and QoL for palliative care patients in Iceland. Instruments from the EORTC were used: the provisional measure of SWB, which was undergoing pilot-testing in Iceland, and the EORTC QLQ C15-PAL. The correlation between scores was examined and descriptive statistics were used. Structured interviews explored feasibility. Thirty persons participated with average age 72 years. Belief in God or a higher power had the mean 3.33 on a 1-4 scale and the mean for overall SWB was 5.73 on a 1-7 scale. The mean score for global health/QoL was 59.4, physical functioning 48.5 and emotional functioning 78.9 on a 0-100 scale. Overall QoL was positively correlated with SWB showing r(30) = 0.386, P = 0.035. The participants found that answering the provisional EORTC QLQ-SWB prompted an emotional response and took the opportunity to discuss the subject. The provisional SWB measure was found relevant for the Icelandic context, and the study indicates that SWB and QoL are closely connected. PMID- 26443297 TI - Mechanical thrombectomy with 'ADAPT' technique by transcervical access in acute ischemic stroke. AB - BACKGROUND: The mechanical thrombectomy (MT) for endovascular clot retrieval has dramatically improved successful revascularization and clinical outcome in selected acute stroke patients. MT is typically performed via a transfemoral approach, but catheterization of the occluded vessel can be problematic in cases of extensive vessel tortuosity. We describe a case of MT with the 'ADAPT' technique by direct carotid access due to an inability to catheterize the ICA by a transfemoral approach for acute cerebral ischemia in the setting of left MCA occlusion. Excellent angiographic and good clinical results were obtained without any complications. CASE REPORT: An 80-year-old woman was admitted with a stroke by occlusion of the left MCA, with an NIHSS: 11, and an ASPECT: 7 in the CT. Under sedation a transfemoral angiography was performed, but after multiple attempts, it was impossible to make a stable catheterization of the left CCA. A transcervical approach was pursued. With ultrasound guidance the CCA was catheterized. Using the 'ADAPT' technique, we performed a successful MT. Post procedure angiography (at 14 minutes) demonstrated recanalization of the entire left MCA (TICI: 3), without complications. The carotid access point was closed with a percutaneous closure. Control TC at 24 h showed a slight hypodensity in the left lenticular nucleus, and loss of gray-white matter differentiation in the adjacent cortex. Neurologically, the patient presented with progressive improvement. At discharge, she had an NIHSS: 0, mRS: 0 and Barthel: 100. CONCLUSIONS: MT by direct carotid access is an effective alternative technique in those cases where it is not accessible by a transfemoral approach. PMID- 26443298 TI - Functional MRI in clinical practice: Assessment of language and motor for pre surgical planning. AB - Functional magnetic resonance imaging (fMRI) has been widely used for pre neurosurgical planning and may eventually become a routine pre-surgical imaging modality. The validity of fMRI for clinical application depends on various factors such as proper task selection, correct statistical analysis and threshold setting with appropriate patient cooperation. This study was performed on 40 patients with different types of brain mass lesions or hippocampal sclerosis to assess the role of appropriate patient selection for achieving a reliable fMRI result. Accurate and reproducible fMRI strongly depends on the patient's cooperation. In this study we observed that a pre-test mock fMRI session held by a radiologist may help to predict which patients are more or less suitable candidates for fMRI. PMID- 26443299 TI - Absent circle of Willis with vascular pollarding in an adult with colpocephaly: A developmental perspective. AB - Absent circle of Willis (COW) has been described in cases of severe forms of cerebral developmental anomalies such as alobar prosencephaly. However, there are no reports of absent COW in patients with a milder form of cerebral abnormality such as colpocephaly. We report a unique case of an adult with colpocephaly and absent COW and discuss their association from a developmental perspective. PMID- 26443300 TI - Extracranial, peritoneal seeding of primary malignant brain tumors through ventriculo-peritoneal shunts in children: Case report and review of the literature. AB - INTRODUCTION: Ventriculoperitoneal shunts (VPS) have been implicated as a source of the extraneural spread of a wide variety of central nervous system tumors. The purpose is to review the literature on peritoneal seeding of central nervous system tumors from VPS in the context of a case report. METHODS: Medline was searched using the phrase 'peritoneal seeding ventriculoperitoneal shunt'. Inclusion criteria included patients (<18 years) with evidence of peritoneal seeding from VPS. RESULTS: Search of the literature revealed a final total of 22 articles and a total of 28 patients. CASE REPORT: A 7-year-old boy presented with intermittent vomiting, headaches, photophobia; a 4.4 cm left thalamic mass (glioblastoma multiforme) was found. Occipital VPS catheters were placed for increasing hydrocephalus and the patient developed increased abdominal distention and pain. Computed tomography revealed diffuse ascites with carcinomatosis and the patient was diagnosed clinically with peritoneal metastases. DISCUSSION: Our case report and literature review revealed 28 cases of central nervous system tumors demonstrating evidence of extraneural spread associated with VPS in children in a wide variety of tumors. Larger studies are required to evaluate VPS as potential risk factors for peritoneal seeding and familiarity with potential VPS-related peritoneal seeding is important for diagnostic consideration. PMID- 26443301 TI - Novel brain MRI abnormalities in Gitelman syndrome. AB - Gitelman syndrome is an autosomal recessive renal tubular disorder characterized by hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. The syndrome is caused by a defective thiazide-sensitive sodium chloride co transporter in the distal convoluted tubules of the kidneys. Gitelman syndrome could be confused with Bartter syndrome; the main differentiating feature is the presence of low urinary calcium excretion in the former. Descriptions of neuroradiological imaging findings associated with Gitelman syndrome are very scarce in the literature and include basal ganglia calcification, idiopathic intracranial hypertension and sclerochoroidal calcification. Cauda equina syndrome-like presentation has been reported, but without any corresponding imaging findings on lumbar spine MRI. We report a 13-year-old male with Gitelman syndrome who presented with altered mental status following a fall and scalp laceration and unremarkable brain CT, followed during hospitalization by somnolence and seizures. Metabolically the patient demonstrated hypokalemia and hypomagnesemia. MRI demonstrated features of encephalopathy including predominantly right-sided cerebral hemispheric signal abnormality and cytotoxic edema, with bilateral symmetric involvement of the thalami, midbrain tegmentum and tectum and cerebellar dentate nuclei. MRI after five months obtained during a later episode of encephalopathy showed resolution of the signal abnormalities with setting in of brain atrophy and also areas of newly developed cytotoxic edema in the left thalamus, bilateral dorsal midbrain and right greater than left dentate nuclei. The described abnormalities, either recurrent or in isolation, have not previously been published in patients with Gitelman syndrome. We believe that the findings are due to alteration of respiratory chain function secondary to the metabolic derangement and hence have a similar imaging appearance as encephalopathy related to mitochondrial cytopathy or metabolic encephalopathy. PMID- 26443303 TI - Experimental and theoretical investigations of four 3d-4f butterfly single molecule magnets. AB - The syntheses, structures, and characterization of four 3d-4f butterfly clusters are described. With different polyhydroxy Schiff-base ligands 2-(((2-hydroxy-3 methoxyphenyl)methylene)amino)-2-(hydroxymethyl)-1,3-propanediol (H4L1) and 2 (2,3-dihydroxpropyliminomethyl)-6-methoxyphenol (H3L2), three heterotetranuclear NiLn complexes (NiDy-L1 (1), NiTb-L2 (2), NiDy-L2 (3)) and one heterohexanuclear CoDy complex (4) were obtained. The three heterotetranuclear NiLn complexes display a central planar butterfly topology. The heterohexanuclear complex was built from butterfly CoDy clusters and two Dy(III) ions by the bridging of pivalate. The vertices of the body positions of the butterfly are occupied by transition metal ions in all four complexes. Magnetic analyses indicate that the complexes exhibit typical single-molecule magnet behaviour with anisotropy barriers of 33.7 cm(-1), 60.3 cm(-1), 39.6 cm(-1), and 18.4 cm(-1) for 1-4, respectively. Ab initio calculations were performed on these complexes, and the low lying electronic structure of each Ln(III) (Ln = Dy, Tb) ion and the magnetic interactions were determined. It was found that the two Ln ions may have much more contribution to the total relaxation barrier through the stronger 3d-4f exchange couplings compared to weak Ln-Ln interactions. PMID- 26443302 TI - Microbial metabolic networks in a complex electrogenic biofilm recovered from a stimulus-induced metatranscriptomics approach. AB - Microorganisms almost always exist as mixed communities in nature. While the significance of microbial community activities is well appreciated, a thorough understanding about how microbial communities respond to environmental perturbations has not yet been achieved. Here we have used a combination of metagenomic, genome binning, and stimulus-induced metatranscriptomic approaches to estimate the metabolic network and stimuli-induced metabolic switches existing in a complex microbial biofilm that was producing electrical current via extracellular electron transfer (EET) to a solid electrode surface. Two stimuli were employed: to increase EET and to stop EET. An analysis of cell activity marker genes after stimuli exposure revealed that only two strains within eleven binned genomes had strong transcriptional responses to increased EET rates, with one responding positively and the other responding negatively. Potential metabolic switches between eleven dominant members were mainly observed for acetate, hydrogen, and ethanol metabolisms. These results have enabled the estimation of a multi-species metabolic network and the associated short-term responses to EET stimuli that induce changes to metabolic flow and cooperative or competitive microbial interactions. This systematic meta-omics approach represents a next step towards understanding complex microbial roles within a community and how community members respond to specific environmental stimuli. PMID- 26443304 TI - A homozygous PAX3 mutation leading to severe presentation of Waardenburg syndrome with a prenatal diagnosis. PMID- 26443305 TI - Clinical features of rheumatoid arthritis-associated interstitial lung disease. AB - Interstitial lung disease (ILD) is the most common extra-articular manifestations of rheumatoid arthritis (RA) in the lung. This study aimed to identify clinical features of RA-associated ILD (RA-ILD). Patients with RA were retrospectively enrolled and sub-classified as RA-ILD or RA without ILD based on high-resolution computed tomography imaging. Pulmonary function testing parameters and levels of RA-related biomarkers, tumour markers, and acute-phase proteins were compared between the two groups. Logistic regression model was used to assess the strength of association between RA-ILD and clinical features of interest. Receiver operating characteristic analysis was performed to assess potential predictive value of clinical features for detecting RA-ILD. Comparison analysis indicated that the percentage of predicted value of total lung capacity, inspiratory capacity, and diffusion capacity of the lung for carbon monoxide (DLCO) were reduced in patients with RA-ILD. Tumour markers CA15-3 and CA125 were increased in patients with RA-ILD. Logistic regression analysis revealed that decreased DLCO was related to the increased likelihood of RA-ILD (OR = 0.94, 95%CI = [0.91, 0.98]). The cut-off point at 52.95 percent of predicted value could sensitively discriminate RA patients with or without ILD. Our study suggested that DLCO value could be a useful tool for detecting ILD in patients with RA. PMID- 26443306 TI - Retrospective analysis of 95 patients with large vessel vasculitis: a single center experience. AB - AIM: Although Takayasu arteritis (TAK) and giant cell arteritis (GCA) have been considered as distinct disease entities, similarities of these diseases have been recently reported. However, little data is available regarding this issue in Japanese patients with TAK and GCA. In addition, the classification criteria for TAK established in 1990 by the American College of Rheumatology (ACR) have been criticized due to the age restriction for disease onset (<= 40 years). Thus, we aimed to compare the clinical characteristics of Japanese patients with TAK and those with GCA and to clarify whether clinical differences existed between patients with early-onset (<= 40 years) and late-onset (> 40 years) TAK. METHODS: We enrolled 86 patients with TAK and nine with GCA who visited our department from 1990 to 2014. The diagnoses of TAK and GCA were based on the criteria of the Japanese Circulation Society and the ACR, respectively. RESULTS: Mean ages at onset for TAK and GCA were 36.4 and 71.0 years, respectively. Patients with TAK had significantly higher incidences of aortic regurgitation and carotid and subclavian arterial involvement, lower frequencies of polymyalgia rheumatica, and better prognoses than those with GCA. In contrast, the clinical characteristics, distribution of arterial lesions, treatments administered, and prognoses of patients with early- and late-onset TAK were comparable. CONCLUSIONS: These results suggested that TAK and GCA differed substantially, and that the age restriction (<= 40 years) may not be necessary for the diagnosis of TAK. PMID- 26443308 TI - Intracellular Zn(2+) detection with quantum dot-based FLIM nanosensors. AB - Fluorescence Lifetime Imaging Microscopy (FLIM) has been employed for the detection of intracellular Zn(2+) levels, implicated in various signalling pathways, using a family of quantum dot (QD) nanosensors. The sensing mechanism was based on photoinduced electron transfer (PET) between an azacycle receptor group and the QD nanoparticles. PMID- 26443307 TI - Biosorption of alpacide blue from aqueous solution by lignocellulosic biomass: Luffa cylindrica fibers. AB - The aim of the present work is to develop an effective and inexpensive pollutant removal technology using lignocellulosic fibers: Luffa cylindrica, for the biosorption of an anionic dye: alpacide blue. The influence of some experimental parameters such as pH, temperature, initial concentration of the polluted solution, and mass of the sorbent L. cylindrica on the biosorption of alpacide blue by L. cylindrica fibers has been investigated. Optimal parameters for maximum quantity of biosorption dye were achieved after 2 h of treatment in a batch system using an initial dye concentration of 20 mg/L, a mass of 1 g of L. cylindrica fibers, and pH 2. In these conditions, the quantity of dye retained is 2 mg/g and the retention rate is 78 %. Finally, a mathematical modeling of kinetics and isotherms has been used for mathematical modeling; the model of pseudo-second order is more appropriate to describe this phenomenon of biosorption. Concerning biosorption isotherms, the Freundlich model is the most appropriate for a biosorption of alpacide blue dye by L. cylindrica fibers. PMID- 26443309 TI - Biopathology of astrocytes in human traumatic and complicated brain injuries. Review and hypothesis. AB - The biopathology of astrocyte cells in severe human brain traumatic injuries complicated with subdural and epidural haematoma and hygroma is reviewed. Clear and dense oedematous and hypertrophic reactive astrocytes are distinguished in severe primary traumatic vasogenic and secondary cytotoxic brain oedema. Swollen perineuronal astrocytes appear compressing and indenting clear and dark degenerated pyramidal and non-pyramidal nerve cells, degenerated myelinated axons and synaptic contacts. Hypertrophic astrocytes display dense cytoplasm and contain numerous rosettes of alpha, beta- and gamma-type glycogen granules, swollen mitochondria, dilated smooth and rough endoplasmic reticulum, oedematous Golgi apparatus, microtubules, gliofilaments, intermediate filaments, lysosomes and liposomes. The perisynaptic astrocyte ensheathment of synaptic contacts, containing beta type-glycogen granules, can be traced in the neuropil, surrounding swollen, bead-shaped dendritic profiles, and degenerated myelinated axons. This perisynaptic glial layer is absent in severe oedematous regions. The glycogen-rich and glycogendepleted perivascular astrocyte end-feet appear attached or dissociated from the capillary basement membrane. Phagocytic astrocytes can be seen engulfing degenerated synaptic contacts, necrotic membranes, degenerated myelinated axons, and myelin ovoids. Lipofuscin-rich astrocytes are also observed. The interastrocytary gap junctions appear either widened, fused or fragmented. The key role of aquaporin in astrocyte swelling and brain oedema is emphasized. The findings are compared with those reported in experimental traumatic animal models, a large variety of pathogenetically related neuropathological conditions, and in vivo and in vitro experimental conditions. The contribution of pathological astrocytes to neurobehavioral disorders, such as loss of consciousness, neurological deficits and seizures is emphasized. Some hypotheses are postulated related to the dissociated or absent perisynaptic layer, neurobiology of glycogen-rich and glycogen-depleted perivascular astrocytes, the glio-basal dissociation process, abnormal astrocyte-neuronal unit, and astrocyte participation in seizures in patients with severe and complicated brain injuries. PMID- 26443310 TI - Quantitative pathological changes in the cerebellum of multiple system atrophy. AB - Multiple system atrophy (MSA) is a rare neurodegenerative disorder associated with parkinsonism, ataxia, and autonomic dysfunction. Its pathology is primarily subcortical comprising vacuolation, neuronal loss, gliosis, and alpha synucleinimmunoreactive glial cytoplasmic inclusions (GCI). To quantify cerebellar pathology in MSA, the density and spatial pattern of the pathological changes were studied in alpha-synuclein-immunolabelled sections of the cerebellar hemisphere in 10 MSA and 10 control cases. In MSA, densities of Purkinje cells (PC) were decreased and vacuoles in the granule cell layer (GL) increased compared with controls. In six MSA cases, GCI were present in cerebellar white matter. In the molecular layer (ML) and GL of MSA, vacuoles were clustered, the clusters exhibiting a regular distribution parallel to the edge of the folia. Purkinje cells were randomly or regularly distributed with large gaps between surviving cells. Densities of glial cells and surviving neurons in the ML and surviving cells and vacuoles in the GL were negatively correlated consistent with gliosis and vacuolation in response to neuronal loss. Principal components analysis (PCA) suggested vacuole densities in the ML and vacuole density and cell losses in the GL were the main source of neuropathological variation among cases. The data suggest that: (1) cell losses and vacuolation of the GCL and loss of PC were the most significant pathological changes in the cases studied, (2) pathological changes were topographically distributed, and (3) cerebellar pathology could influence cerebral function in MSA via the cerebello-dentato thalamic tract. PMID- 26443311 TI - Ganglion cell tumours in the sella turcica in close morphological connection with pituitary adenomas. AB - Ganglion cell tumours in the sellar region are uncommon. They are usually associated with pituitary adenomas, while isolated ganglion cell neoplasms are extremely rare. We report the clinicopathological studies of five cases diagnosed as ganglion cell tumours located in the intrasellar region: four mixed/collision tumours composed of gangliocytoma and pituitary adenoma, and one isolated ganglioglioma unrelated to adenoma. Clinically, two patients presented with acromegaly, while three others were initially diagnosed as non-functioning adenomas. In four cases, the histopathological examination of surgical specimens revealed intermixed lesions composed of pituitary adenoma and ganglion cell elements. The adenomas appeared to secrete growth hormone. Electron microscopy enabled identification of the sparsely granulated somatotroph cells. Neoplastic neuronal lesions were composed of mature ganglion cells, including binucleate or multinucleate cells. In all cases, boundaries between adenomatous and gangliocytic components were not clearly demarcated, and numerous gangliocytic cells were closely intermingled with adenomatous tissue. One case lacked endocrine symptoms, and no pituitary adenoma was identified in the surgically excised material; it was finally diagnosed as low-grade ganglioglioma. The etiopathogenesis of ganglion cell neoplasms in the sellar region is not clearly defined. Our study revealed that if ganglion cell neoplasms were combined with adenoma, both neoplastic components were closely related to each other, and numerous neuronal elements were strictly intermingled with adenoma cells. Such a tissue pattern indicates that these neoplastic changes, including their common respective etiopathogeneses, are closely related. The identification of both components in sellar regions may have some nosological implications. PMID- 26443312 TI - The effect of neurosphere culture conditions on the cellular metabolism of glioma cells. AB - Malignant gliomas, with an average survival time of 16-19 months after initial diagnosis, account for one of the most lethal tumours overall. Current standards in patient care provide only unsatisfying strategies in diagnostic and treatment for high-grade gliomas. Here we describe metabolic phenomena in the choline and glycine network associated with stem cell culture conditions in the classical glioma cell line U87. Using high-resolution proton magnetic resonance spectroscopy of cell culture metabolic extracts we compare the metabolic composition of U87 chronically propagated as adherent culture in medium supplemented with serum to serum-free neurosphere growth. We found that the switch to neurosphere growth, besides the increase of cells expressing the putative glioma stem cell marker CD133, modulated a number of intracellular metabolites including choline, creatine, glycine, and myo-inositol that have been previously reported as potential diagnostic markers in various tumours. These findings highlight the critical influence of culture conditions on glioma cell metabolism, and therefore particular caution should be drawn to the use of in vitro system research in order to investigate cancer metabolism. PMID- 26443313 TI - Ciliary neurotrophic factor protects SH-SY5Y neuroblastoma cells against Abeta1 42-induced neurotoxicity via activating the JAK2/STAT3 axis. AB - The neurotoxicity of aggregated amyloid beta (Abeta) has been implicated as a critical cause in the pathogenesis of Alzheimer's disease (AD), which leads to neuronal cell damage by inducing oxidative stress and consequently triggering cell apoptosis. Recently, Abeta-dependent inactivation of the Janus tyrosine kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway was found to play a critical role in the memory impairment related to AD. Previous research indicated that JAK2/STAT3 axis inactivation might be the result of aberrant reactive oxygen species (ROS) generation induced by Abeta in neurons. As the JAK2/STAT3 axis is a major transducer of ciliary neurotrophic factor (CNTF)-mediated neuroprotective activity, this study extensively evaluated whether activation of the JAK2/STAT3 axis by CNTF was responsible for the neuroprotective effect of this protein against Abeta1-42 induced cytotoxicity, oxidative injury and cell apoptosis in human SH-SY5Y neuroblastoma cells. Our data showed that CNTF could attenuate or restore cell injury induced by Abeta1-42 in human SH-SY5Y neuroblastoma cells through activating the JAK2/STAT3 signaling pathway. Furthermore, CNTF strikingly prevented Abeta1-42-induced mitochondrial dysfunction and activation of mitogen activated protein kinases (MAPKs), an effect that could be potently attenuated by the specific JAK2 inhibitor AG490. In summary, this study confirmed the detailed mechanism accounting for CNTF's protective effect against Abeta1-42-induced cytotoxic events in human SH-SY5Y neuroblastoma cells - information which might significantly contribute to better understanding of the mechanism of action of CNTF as well as providing a novel target in AD therapy. PMID- 26443314 TI - MicroRNA-210 regulates cell proliferation and apoptosis by targeting regulator of differentiation 1 in glioblastoma cells. AB - MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate protein biosynthesis and participate in the pathogenesis of various tumours. Previous studies have shown that miR-210 is highly expressed in different types of human cancers, including glioblastoma multiforme (GBM). However, the role that miR-210 plays in GBM remains unclear. Here, we detected the expression and examined the function of miRNA-210 in GBM cells. Furthermore, we investigated the possible molecular mechanisms by which miRNA-210 mediates cell proliferation and apoptosis. Fifteen GBM and five normal brain tissues, in addition to the U87MG and U251 GBM cell lines, were analysed in this study. We found that miR-210 was upregulated in GBM tissues and cell lines when compared to normal brain tissue. Cell counting and flow cytometric assay results demonstrated that upregulation of miR-210 induced cell proliferation and decreased cell apoptosis, respectively. In addition, downregulation of miR-210 inhibited cell proliferation and induced apoptosis. We also detected a miR-210 target, regulator of differentiation 1 (ROD1), which is involved in GBM progression. Knockdown of ROD1 reversed the growth arrest and apoptosis that were originally induced by miR-210 inhibition. We propose that miR-210 regulates cell proliferation and apoptosis in GBM cells by targeting ROD1. Our findings may provide a new potential therapeutic target for the treatment of GBM. PMID- 26443315 TI - Occurrence of spontaneous and audiogenic seizures following global brain ischaemia due to cardiac arrest. AB - Transient cardiac arrest due to cardiac vessel bundle occlusion was used to produce a rat model of spontaneous and audiogenic seizures. Among the rats, spontaneous seizures were present in 64%, and audiogenic seizures could be evoked in 86%, during two weeks of survival after cardiac arrest, by exposure to a loud sound produced by rattling keys, beginning one day after the post-ischaemic injury. Data from literature suggested a key role for GABA-ergic system widespread dysfunction especially in the hippocampus in post-cardiac arrest onset of audiogenic seizures. Reduced GABA inhibition in the hippocampus seems responsible for audiogenic seizures following cardiac arrest. In summary it may be considered that the occurrence of audiogenic seizures following cardiac arrest is determined not only by a neuronal loss, especially in the hippocampus, but also by a condition of synapse modification by a regenerative phenomenon. Data from our study clearly indicate that global brain ischaemia due to cardiac arrest may induce the susceptibility to spontaneous and audiogenic seizures, but this effect is transient. PMID- 26443316 TI - Rapamycin protects dopaminergic neurons against rotenone-induced cell death in primary mesencephalic cell culture. AB - INTRODUCTION: Parkinson's disease is the most common movement disorder, characterized by a progressive and extensive loss of dopaminergic neurons in the substantia nigra pars compacta and their terminals in the striatum. So far, only symptomatic treatment is available, and no cure or disease-modifying drugs exist. The present study was designed to investigate the neuroprotective effect of rapamycin, an autophagy inducer, on dopaminergic neurons against rotenone-induced cell death in primary mesencephalic cell culture. MATERIAL AND METHODS: Primary mesencephalic cell cultures were prepared from embryonic mouse mesencephala (OFI/SPF, Vienna, Austria) at gestation day 14. Four sets of cultures were treated as follows: one was run as an untreated control, a second one was treated with 20 nM rotenone on the 10th day in vitro (DIV) for 48 h, a third one was co treated with 20 nM rotenone and rapamycin (1, 10, 100, 1000 nM) on the 10th DIV for 48 h, and a fourth one was treated with rapamycin alone (1, 10, 100, 1000 nM) on the 10th DIV for 48 h. On the 12th DIV, cultures were subjected to immunohistochemistry against tyrosine hydroxylase and to fluorescence staining using LysoTracker Deep Red, JC-1 and DAPI stains. RESULTS: Exposure of such cultures to 20 nM rotenone on the 10th DIV for 48 h reduced the number of dopaminergic neurons by 41% and increased the release of lactate dehydrogenase (LDH) by 178% above untreated controls. Rapamycin (1, 10, 100, 1000 nM) added together with rotenone from the 10th to 12th DIV spared dopaminergic neurons by 17% and reduced the release of LDH by 64% at the concentration of 100 nM compared to rotenone-treated cultures. Activation of an autophagic process by rapamycin was demonstrated by LysoTracker Deep Red fluorescent dye, as indicated by a shift to increased red fluorescence. Rapamycin also significantly elevated the mitochondrial membrane potential (Deltapsim), as shown by an increase of the red:green fluorescence ratio of JC-1. Increased apoptotic cell death due to rotenone was lowered by rapamycin, as shown by the blue-fluorescent DAPI nucleic acid stain. CONCLUSIONS: Our study indicates for the first time that rapamycin, known as an autophagy inducer, protected dopaminergic neurons against rotenone induced cell death in primary mesencephalic cell culture. PMID- 26443317 TI - Investigation of iron's neurotoxicity during cerebral maturation in the neonatal rat model of haemolysis. AB - INTRODUCTION: Haemolytic disease of newborns due to rhesus and AB0 incompatibility is encountered frequently in neonatal clinics and may lead to severe haemolysis. In this study, it is suggested that important amounts of iron released with haemolysis may have a toxic effect on the brain parenchymal tissue, and the severity of the toxic effect can be correlated with the maturation of the brain barrier systems. To demonstrate the accumulation and the neuro-toxic effects of free iron (Fe) in the brain an experimental haemolysis model with various maturation phases was performed. MATERIAL AND METHODS: The study was composed of 48 Wistar rats with the following ages: five days old (Group A), 10 days old (Group B), and 19 days old (Group C). Each group was divided into three experimental subgroups and three control groups. Experimental groups were treated with intraperitoneal 75 mg/kg/day phenyl hydrazine hydrochloride for haemolysis. RESULTS: We demonstrated that the blood brain barrier (BBB) is permeable in five day-old newborn rats and is mature in 10- and 19-day-old rats. Iron staining and neuronal damage were detected in group A and group B rats. No damage was detected in the brain tissue of group C animals. The presence of iron staining and neuronal damage in group B with mature BBB may suggest the existence of other incomplete barrier systems different from BBB that lead to iron accumulation in the brain. CONCLUSIONS: Blood brain barrier has a partial role in Fe transport, and the alternative barrier systems may also be involved. It could be supposed that after maturation of all barrier systems, excessive Fe penetration to the brain cannot occur. Our findings showed that the toxic amounts of iron may penetrate into the brain parenchyma of newborns despite the BBB preservation and cause neuronal damage in newborns, but the mature brain is not affected by the same magnitude blood levels. PMID- 26443318 TI - Emery-Dreifuss muscular dystrophy type 2 associated (?) with mild peripheral polyneuropathy. AB - In recent years numerous mutations in the LMNA gene encoding lamin A/C were shown to segregate with a wide spectrum of phenotypes. A recurrent p.R377H mutation in the LMNA gene was reported in patients with Emery-Dreifuss dystrophy (EDMD2) with various ethnic backgrounds. We present a patient with EDMD2 caused by a p.R377H mutation, associated with mild peripheral polyneuropathy. The analysis of peripheral myelin protein 22 (PMP22), ganglioside induced differentiation associated protein 1 (GDAP1), gap junction beta-1 protein (GJB1), and myelin protein zero (MPZ) genes did not reveal mutations; however, we identified a new sequence intronic variant in the mitofusin 2 (MFN2) gene of unknown pathogenic significance. A complex phenotype in the presented patient might depend either on single mutation in the LMNA gene or on bigenic defect; therefore, a wide genetic investigation is needed to elucidate the molecular background of EDMD2/polyneuropathy in this case. PMID- 26443319 TI - Schwannoma of the medial cutaneous nerve of the arm: a rare location with concomitant compression neuropathy of the ulnar nerve. AB - The objective of this paper is to present a case of rare location of schwannoma in the medial cutaneous nerve of the arm at the level of the axilla. Preliminary diagnostic examination of the tumour was carried out in another hospital by means of open biopsy. In the preoperative period symptoms of ulnar nerve dysfunction (paraesthesias, positive Hoffmann-Tinel sign) dominated the clinical picture. After having performed imaging studies and electromyographic (EMG) examination, the patient was scheduled for an operation. The tumour, measuring 3.5 * 3.0 * 1.5 cm, was resected without damage to the fascicular structure. Presence of paraesthesias in the distribution of the medial cutaneous nerve of the arm, which was first noted in the postoperative period, persists in moderate severity until now. As a result of the performed operative treatment, such symptoms as palpable tumour mass, pain, paraesthesias in the ulnar nerve distribution and positive Hoffmann-Tinel sign resolved. On the basis of histopathological examination results the final diagnosis of classical schwannoma was established. PMID- 26443320 TI - Comparison Between Dual-Energy Computed Tomography and Ultrasound in the Diagnosis of Gout of Various Joints. AB - RATIONALE AND OBJECTIVES: Dual-energy computed tomography (DECT) and ultrasound are both used to assess gouty arthritis. The present study was designed to compare the diagnostic accuracy of DECT and ultrasound in detecting monosodium urate (MSU) crystal deposition in various joints. MATERIALS AND METHODS: This study enrolled 40 patients diagnosed with acute gouty arthritis. All affected and contralateral joints were scanned (128 in total) using both DECT and ultrasound to determine the MSU deposition in upper limbs (wrist and elbow) and lower limbs (the first metatarsophalangeal joints, ankles, and knee). The MSU crystal accumulation detected by each method was compared for various joints. RESULTS: The 128 scanned joints included 52 of the upper limbs and 76 of the lower limbs. For the upper limbs, the percentage of MSU crystal accumulation detected by DECT (22/52, 42.3%) was significantly higher than that by ultrasound (10/52, 19.2%; P = .0027). The detection rates of the two methods for the lower limbs were similar (P = .3173). CONCLUSIONS: For detection of MSU crystal deposition in the upper limb joints, DECT was superior to ultrasound, whereas there was no difference between the two methods for the lower limbs. Therefore, ultrasound can be used for primary screening, and DECT afterward. Although the modalities are similar in making the initial diagnosis, DECT is far superior at displaying the anatomic extent of the disease. PMID- 26443321 TI - Scientific evidence for health effects attributed to the consumption of probiotics and prebiotics: an update for current perspectives and future challenges. AB - Probiotics and prebiotics, mainly commercialised as food ingredients and also as supplements, are considered highly profitable niche markets. However, in recent years, the food industry has suffered from a series of health claim restrictions on probiotics and prebiotics in many parts of the world, including those made by the European Food Safety Authority. Therefore, we reviewed the core benefits of probiotic and prebiotic consumption on health. A number of studies have examined the prevention and/or management of intestinal infections, respiratory tract infections, CVD, osteoporosis, urogenital infections, cavities, periodontal disease and halitosis, allergic reactions, inflammatory bowel disease and irritable bowel syndrome and Helicobacter pylori gastric infections. In fact, a deeper understanding of the mechanisms involved in human microbiota and immune system modulation by probiotics and prebiotics relies on continuous efforts to establish suitable biomarkers of health and diseases risk factors for the design of clinical trials required for health claim approval. In spite of the promising results, the performance of large, long-term, well-planned, well-aligned clinical studies is crucial to provide more reliability and a more solid basis for the outcomes achieved and to support the potential use of probiotics and prebiotics in clinical practice. PMID- 26443323 TI - Seismological constraints on the crustal structures generated by continental rejuvenation in northeastern China. AB - Crustal rejuvenation is a key process that has shaped the characteristics of current continental structures and components in tectonic active continental regions. Geological and geochemical observations have provided insights into crustal rejuvenation, although the crustal structural fabrics have not been well constrained. Here, we present a seismic image across the North China Craton (NCC) and Central Asian Orogenic Belt (CAOB) using a velocity structure imaging technique for receiver functions from a dense array. The crustal evolution of the eastern NCC was delineated during the Mesozoic by a dominant low seismic wave velocity with velocity inversion, a relatively shallow Moho discontinuity, and a Moho offset beneath the Tanlu Fault Zone. The imaged structures and geochemical evidence, including changes in the components and ages of continental crusts and significant continental crustal growth during the Mesozoic, provide insight into the rejuvenation processes of the evolving crust in the eastern NCC caused by structural, magmatic and metamorphic processes in an extensional setting. The fossil structural fabric of the convergent boundary in the eastern CAOB indicates that the back-arc action of the Paleo-Pacific Plate subduction did not reach the hinterland of Asia. PMID- 26443322 TI - Sleep-based memory processing facilitates grammatical generalization: Evidence from targeted memory reactivation. AB - Generalization-the ability to abstract regularities from specific examples and apply them to novel instances-is an essential component of language acquisition. Generalization not only depends on exposure to input during wake, but may also improve offline during sleep. Here we examined whether targeted memory reactivation during sleep can influence grammatical generalization. Participants gradually acquired the grammatical rules of an artificial language through an interactive learning procedure. Then, phrases from the language (experimental group) or stimuli from an unrelated task (control group) were covertly presented during an afternoon nap. Compared to control participants, participants re exposed to the language during sleep showed larger gains in grammatical generalization. Sleep cues produced a bias, not necessarily a pure gain, suggesting that the capacity for memory replay during sleep is limited. We conclude that grammatical generalization was biased by auditory cueing during sleep, and by extension, that sleep likely influences grammatical generalization in general. PMID- 26443324 TI - Detoxification of hostplant's chemical defence rather than its anti-predator co option drives beta-glucosidase-mediated lepidopteran counteradaptation. AB - The evolutionary plant-herbivore arms race sometimes gives rise to remarkably unique adaptation strategies. Here we report one such strategy in the lepidopteran herbivore Manduca sexta against its hostplant Nicotiana attenuata's major phytotoxins, 17-hydroxygeranyllinalool diterpene glycoside, lyciumoside IV and its malonylated forms. We show that alkalinity of larval regurgitant non enzymatically demalonylates the malonylated forms to lyciumoside IV. Lyciumoside IV is then detoxified in the midgut by beta-glucosidase 1-catalysed deglycosylation, which is unusual, as typically the deglycosylation of glycosylated phytochemicals by insects results in the opposite: toxin activation. Suppression of deglucosylation by silencing larval beta-glucosidase 1 by plant mediated RNAi causes moulting impairments and mortality. In the native habitat of N. attenuata, beta-glucosidase 1 silencing also increases larval unpalatability to native predatory spiders, suggesting that the defensive co-option of lyciumoside IV may be ecologically advantageous. We infer that M. sexta detoxifies this allelochemical to avoid its deleterious effects, rather than co opting it against predators. PMID- 26443325 TI - Representativeness of the German National Register for Congenital Heart Defects: a clinically oriented analysis. AB - BACKGROUND: Approximately 6000 children are born with CHD in Germany each year. It is increasingly rare that these children die from their chronic illness. In the present study, data recorded in the National Register for Congenital Heart Defects with respect to the prevalence of specific lesions and sex distribution are compared with that recorded in a published German prevalence study (Prevalence Study) and with the meta-analysis by van der Linde et al. METHODS: A descriptive data analysis was performed using a minimal data set. The demographic data included sex and birth year; the medical data comprised the cardiovascular diagnosis according to the short list of the International Paediatric and Congenital Cardiac Code. RESULTS: As the data analysis shows, the National Register is a clinical register including primarily clinical cases/cases relevant to healthcare. The prevalence values and sex ratios recorded in the register are closer to the values given in the literature than those determined by the Prevalence Study. Severe CHD was slightly over-represented in the National Register compared with the van der Linde et al meta-analysis. The deviations with respect to prevalence values are within an acceptable range. CONCLUSION: With its 48,000 patients, the National Register plays a unique and important role for research in the field of CHD. Samples from the National Register can be used as a gold standard for future studies, as the patient population registered in it can be considered representative of CHD in Germany and Europe. PMID- 26443326 TI - A splicing variant of Merlin promotes metastasis in hepatocellular carcinoma. AB - Merlin, which is encoded by the tumour suppressor gene Nf2, plays a crucial role in tumorigenesis and metastasis. However, little is known about the functional importance of Merlin splicing forms. In this study, we show that Merlin is present at low levels in human hepatocellular carcinoma (HCC), particularly in metastatic tumours, where it is associated with a poor prognosis. Surprisingly, a splicing variant of Merlin that lacks exons 2, 3 and 4 ((Delta2-4)Merlin) is amplified in HCC and portal vein tumour thrombus (PVTT) specimens and in the CSQT2 cell line derived from PVTT. Our studies show that (Delta2-4)Merlin interferes with the capacity of wild-type Merlin to bind beta-catenin and ERM, and it is expressed in the cytoplasm rather than at the cell surface. Furthermore, (Delta2-4)Merlin overexpression increases the expression levels of beta-catenin and stemness-related genes, induces the epithelium-mesenchymal transition phenotype promoting cell migration in vitro and the formation of lung metastasis in vivo. Our results indicate that the (Delta2-4)Merlin variant disrupts the normal function of Merlin and promotes tumour metastasis. PMID- 26443327 TI - Barriers to guideline-concordant antibiotic use among inpatient physicians: A case vignette qualitative study. AB - BACKGROUND: Greater adherence to antibiotic-prescribing guidelines may promote more judicious antibiotic use, which could benefit individual patients and society at large. OBJECTIVE: To assess physician knowledge and acceptance of antibiotic-prescribing guidelines through the use of case vignettes. DESIGN: We conducted semistructured interviews with 30 inpatient physicians. Participants were asked to respond to 3 hypothetical case vignettes: (1) a skin and soft tissue infection (SSTI), (2) suspected hospital-acquired pneumonia (HAP), and (3) asymptomatic bacteriuria (ASB). All participants received feedback according to guidelines from the Infectious Diseases Society of America (IDSA) and were asked to discuss their level of comfort with following these guidelines. SETTING: Two acute care teaching hospitals for adult patients. INTERVENTION: None. MEASUREMENTS: Data from transcribed interviews were analyzed using emergent thematic analysis. RESULTS: Participants were receptive to guidelines and believed they were useful. However, participants' responses to the case vignettes demonstrated that IDSA guideline recommendations were not routinely followed for SSTI, HAP, and ASB. We identified 3 barriers to guideline-concordant care: (1) physicians' lack of awareness of specific guideline recommendations; (2) tension between adhering to guidelines and the desire to individualize patient care; and (3) skepticism of certain guideline recommendations. CONCLUSIONS: Case vignettes may be useful tools to assess physician knowledge and acceptance of antibiotic prescribing guidelines. Using case vignettes, we identified 3 barriers to following IDSA guidelines. Efforts to improve guideline-concordant antibiotic prescribing should focus on reducing such barriers at the local level. PMID- 26443328 TI - CD38 Monoclonal Antibody Therapies for Multiple Myeloma. AB - The goal of this review is to provide historical, recent preclinical, and current clinical summaries of efforts to understand the CD38 molecule and to develop monoclonal antibodies that target it. We focus particularly on efforts involving multiple myeloma, a malignancy of terminally differentiated B cells that remains incurable despite many advances. An era of anti-CD38 monoclonal antibody therapy for myeloma is approaching, one that, we hope, will enable patients to live longer and better lives. PMID- 26443330 TI - [Clinical forensic imaging. Detection and documentation of internal injuries in living victims of violence]. AB - External examination of the body surface with documentation of all visible findings can still be regarded as the status quo of clinical forensic injury assessment. It is obvious that internal findings cannot be detected using this technique. For obtaining such findings accessible well-established radiological techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI) should be used. Especially MRI with no damaging radiation exposure for the examined person allows the detection of internal soft tissue and organ damage and offers a great potential regarding new techniques for allowing insights into tissue composition and function. Furthermore, imaging data collected in clinical institutions before the patient was transferred to the department of legal medicine will play a major role in the future. Although these data were obtained based on a different approach, they provide excellent and recent information on injuries in the respective (current) case und can therefore be of high value for the forensic expertise. PMID- 26443329 TI - [SENDS criteria from the diversification of MAST procedures. Implementation of preoperative simulation]. AB - CLINICAL ISSUE: Minimal access spinal technologies (MAST) lead to a diversification of surgical procedures, which requires careful selection of the procedure and outcome monitoring. For a rational selection of the procedure simulation, endoscopy, navigation, decompression and stabilization (SENDS) criteria can be derived from the development of the MAST procedures. Preoperative simulation has diagnostic and therapeutic values. The SENDS criteria can be verified indirectly via outcome control. STANDARD TREATMENT: Biomechanically meaningful diagnostic x-rays of the spinal segment to be surgically treated are currently carried out with the patient in inclination and reclination. TREATMENT INNOVATIONS: Software-related preoperative simulation based on these x-ray images facilitates the selection and implementation of the MAST procedure. DIAGNOSTIC WORK-UP: For preoperative simulation motion shots are needed in inclination, neutral position and reclination and the dimensions can be obtained using an x ray ball or a computed tomography (CT) scan. PERFORMANCE: The SENDS criteria are useful because established procedures based on these criteria reach a comparable outcome. Preoperative simulation appears to be a useful selection criterion. ACHIEVEMENTS: Preoperatively it is necessary to collate patient and segment information in order to provide each patient with individualized treatment. So far there is no evidence for a better outcome after preoperative simulation but a reduction of surgery time and intraoperative radiation exposure could already be demonstrated. PRACTICAL RECOMMENDATIONS: Minimally invasive methods should be preferred if there is a comparable outcome. The establishment of new procedures has to be accompanied by the maintenance of a spine register. Minimally invasive surgical procedures should be individualized for each patient and segment. Mobility X-ray images should be prepared for use with the preoperative simulation as the information content significantly increases with respect to the MAST procedure. PMID- 26443331 TI - Shifts in leaf N:P stoichiometry during rehabilitation in highly alkaline bauxite processing residue sand. AB - Large quantities of sodic and alkaline bauxite residue are produced globally as a by-product from alumina refineries. Ecological stoichiometry of key elements [nitrogen (N) and phosphorus (P)] plays a critical role in establishing vegetation cover in bauxite residue sand (BRS). Here we examined how changes in soil chemical properties over time in rehabilitated sodic and alkaline BRS affected leaf N to P stoichiometry of native species used for rehabilitation. Both Ca and soil pH influenced the shifts in leaf N:P ratios of the study species as supported by consistently significant positive relationships (P < 0.001) between these soil indices and leaf N:P ratios. Shifts from N to P limitation were evident for N-fixing species, while N limitation was consistently experienced by non-N-fixing plant species. In older rehabilitated BRS embankments, soil and plant indices (Ca, Na, pH, EC, ESP and leaf N:P ratios) tended to align with those of the natural ecosystem, suggesting improved rehabilitation performance. These findings highlight that leaf N:P stoichiometry can effectively provide a meaningful assessment on understanding nutrient limitation and productivity of native species used for vegetating highly sodic and alkaline BRS, and is a crucial indicator for assessing ecological rehabilitation performance. PMID- 26443332 TI - Contrasting microbial biogeographical patterns between anthropogenic subalpine grasslands and natural alpine grasslands. AB - The effect of plant species composition on soil microbial communities was studied at the multiregional level. We compared the soil microbial communities of alpine natural grasslands dominated by Carex curvula and anthropogenic subalpine pastures dominated by Nardus stricta. We conducted paired sampling across the Carpathians and the Alps and used Illumina sequencing to reveal the molecular diversity of soil microbes. We found that bacterial and fungal communities exhibited contrasting regional distributions and that the distribution in each grassland is well discriminated. Beta diversity of microbial communities was much higher in C. curvula grasslands due to a marked regional effect. The composition of grassland-type core microbiomes suggest that C. curvula, and N. stricta to a lesser extent, tend to select a cohort of microbes related to antibiosis/exclusion, pathogenesis and endophytism. We discuss these findings in light of the postglacial history of the studied grasslands, the habitat connectivity and the disturbance regimes. Human-induced disturbance in the subalpine belt of European mountains has led to homogeneous soil microbial communities at large biogeographical scales. Our results confirm the overarching role of the dominant grassland plant species in the distribution of microbial communities and highlight the relevance of biogeographical history. PMID- 26443333 TI - Advancing a distributed multi-scale computing framework for large-scale high throughput discovery in materials science. AB - We describe the development of a large-scale high-throughput application for discovery in materials science. Our point of departure is a computational framework for distributed multi-scale computation. We augment the original framework with a specialized module whose role is to route evaluation requests needed by the high-throughput application to a collection of available computational resources. We evaluate the feasibility and performance of the resulting high-throughput computational framework by carrying out a high throughput study of battery solvents. Our results indicate that distributed multi scale computing, by virtue of its adaptive nature, is particularly well-suited for building high-throughput applications. PMID- 26443334 TI - Eye care services for the populations of remote districts in eastern Taiwan: a practical framework using a Mobile Vision Van Unit. AB - INTRODUCTION: To put a blindness prevention program into practice in remote districts of Eastern Taiwan, a Mobile Vision Van Unit (MVVU) was established to work as a community eyecare station. The aim of this study was to describe the operation and challenges encountered with this unit and its efficacy in expanding eyecare services. METHODS: A population-based primary eyecare model was applied to a population in remote regions of eastern Taiwan. An MVVU, equipped with an autorefractometer, a non-contact tonometer, a slit-lamp biomicroscope, a retinoscope, an ophthalmoscope and a mini optician workshop was taken into remote areas of eastern Taiwan to provide comprehensive eyecare services. An integrated vertical referral system for further diagnosis and treatment was also employed. Data including the services provided, spectacles dispensed, health promotion activities conducted and the effectiveness of the model were collected and analysed. The main outcome measures were practicability of a primary eyecare model, prevalence of visual impairment and the major causes in middle-aged and elderly patients. RESULTS: Between 2002 and 2008, a total of 600 primary eyecare services were delivered to 28 indigenous villages and remote townships in eastern Taiwan. The MVVU screened a total of 35 275 inhabitants. The ages of those screened ranged from preschool children to the elderly, and 2073 patients were referred to secondary or tertiary centres in the middle-aged and elderly blindness prevention program. On-site dispensing of low-cost spectacles and the rapid delivery of more complex prescriptions were provided without charge to 1816 participants who could not afford glasses. In addition, 118 eye health educational programs and training courses for paramedical personnel and volunteers were conducted. CONCLUSIONS: An MVVU model for blindness prevention is highly feasible in its efficiency and cost-effectiveness in communities with deficient medical resources. PMID- 26443335 TI - Nanothermometry: From Microscopy to Thermal Treatments. AB - Measuring temperature in cells and tissues remotely, with sufficient sensitivity, and in real time presents a new paradigm in engineering, chemistry and biology. Traditional sensors, such as contact thermometers, thermocouples, and electrodes, are too large to measure the temperature with subcellular resolution and are too invasive to measure the temperature in deep tissue. The new challenge requires novel approaches in designing biocompatible temperature sensors-nanothermometers and innovative techniques for their measurements. In the last two decades, a variety of nanothermometers whose response reflected the thermal environment within a physiological temperature range have been identified as potential sensors. This review covers the principles and aspects of nanothermometer design driven by two emerging areas: single-cell thermogenesis and image guided thermal treatments. The review highlights the current trends in nanothermometry illustrated with recent representative examples. PMID- 26443336 TI - Is consuming yoghurt associated with weight management outcomes? Results from a systematic review. AB - BACKGROUND: Yoghurt is part of the diet of many people worldwide and is commonly recognised as a 'health food'. Epidemiological studies suggest that yoghurt may be useful as part of weight management programs. In the absence of comprehensive systematic reviews, this systematic review investigated the effect of yoghurt consumption by apparently healthy adults on weight-related outcomes. METHODS: An extensive literature search was undertaken, as part of a wider scoping review, to identify yoghurt studies. A total of 13 631 records were assessed for their relevance to weight-related outcomes. RESULTS: Twenty-two publications were eligible according to the review protocol. Cohort studies (n=6) and cross sectional studies (n=7) all showed a correlation between yoghurt and lower or improved body weight/composition. Six randomised controlled trials (RCTs) and one controlled trial had various limitations, including small size and short duration. One RCT showed significant effects of yoghurt on weight loss, but was confounded by differences in calcium intake. One trial showed nonsignificant weight gain and the remaining five trials showed nonsignificant weight losses that were greater in yoghurt consumers. CONCLUSIONS: Yoghurt consumption is associated with lower body mass index, lower body weight/weight gain, smaller waist circumference and lower body fat in epidemiological studies. RCTs suggest weight reduction effects, but do not permit determination of a cause-effect relationship. Well-controlled, adequately powered trials in research and community settings appear likely to identify a modest but beneficial effect of yoghurt consumption for prevention of weight gain and management of obesity. The ready availability of yoghurt (a nutrient-dense food) and its ease of introduction to most diets suggests that educating the public to eat yoghurt as part of a balanced and healthy diet may potentially contribute to improved public health. Future carefully designed RCTs could provide proof of principle and large community-based studies could determine the practical impact of yoghurt on body weight/composition. PMID- 26443337 TI - Interplay of atherogenic factors, protein intake and betatrophin levels in obese metabolic syndrome patients treated with hypocaloric diets. AB - CONTEXT: The understanding of the potential role of betatrophin in human metabolic disorders is a current challenge. OBJECTIVE: The present research evaluated circulating betatrophin levels in obese patients with metabolic syndrome (MetSyn) features under energy-restricted weight-loss programs and in normal weight in order to establish the putative interplay between the levels of this hormone, diet and metabolic risk factors linked to obesity and associated comorbidities. SUBJECTS AND METHODS: One hundred forty-three participants were enrolled in the study (95 obese-MetSyn; age 49.5+/-9.4 years; body mass index (BMI) 35.7+/-4.5 kg m(-2) and 48 normal weight; age 35.71+/-8.8 years; BMI 22.9+/ 2.2 kg m(-2)). A nutritional therapy consisting in two hypocaloric strategies (control diet based on the AHA recommendations and the RESMENA (MEtabolic Syndrome REduction in Navarra) diet, a novel dietary program with changes in the macronutrient distribution) was only prescribed to obese-MetSyn participants who were randomly allocated to the dietary strategies. Dietary records, anthropometrical and biochemical variables as well as betatrophin levels were analyzed before (pre-intervention, week 0), at 8 weeks (post-intervention, week 8) and after 4 additional months of self-control period (follow-up, week 24). RESULTS: Betatrophin levels were higher in obese-MetSyn patients than normal weight subjects (1.24+/-0.43 vs 0.97+/-0.69 ng ml(-1), respectively, P=0.012), and levels were positively associated with body composition, metabolic parameters, leptin and irisin in all participants at baseline. Notably, low pre intervention (week 0) betatrophin levels in obese patients were significantly associated with higher dietary-induced changes in atherogenic risk factors after 8 weeks. Moreover, protein intake, especially proteins from animal sources, was an independent determinant of betatrophin levels after dietary treatment (B= 0.27; P=0.012). CONCLUSIONS: Betatrophin is elevated in obese patients with MetSyn features and is associated with poorer nutritional outcomes of adiposity and dyslipidemia traits after a weight-loss program. Dietary protein intake could be a relevant modulator of betatrophin secretion and activity. PMID- 26443338 TI - Waist-to-height ratio centiles by age and sex for Japanese children based on the 1978-1981 cross-sectional national survey data. AB - OBJECTIVES: To construct waist-to-height ratio (WC/Ht) reference values and centile curves for Japanese children and to compare these references with those from other countries. METHODS: The 1978-1981 national survey data were used for reference and the 1992-1994 national survey data were used for validation. The former included 19 233 children, and the latter included 10 446 children, aged 6 to 18 years. Waist circumferences (WC) were measured at the level of maximum waist narrowing in girls, and at the level of the top of the iliac crest in boys. Age- and sex-specific reference curves were fitted with the LMS method. Cut-off points were arbitrarily set at 85th, 90th, 95th and 97th centiles, and compared with WC/Ht 0.50. RESULTS: The proportion of children in whom WC/Ht exceeded 0.50 was 18.7% of boys and 1.9% of girls, whereas the proportion of children exceeding 90th centile was 42.4% for boys and 17.3% for girls. The reference values decreased with age in girls but varied by age without a clear trend in boys. CONCLUSIONS: The first reference values for WC/Ht are provided for Japanese youth based on the 1978-1981 national survey data. These curves are age- and sex dependent, precluding the use of universal cut-off for WC/Ht of 0.50. PMID- 26443339 TI - Wheat gluten intake increases weight gain and adiposity associated with reduced thermogenesis and energy expenditure in an animal model of obesity. AB - BACKGROUND/OBJECTIVES: The association between gluten and body weight is inconsistent. Previously, we showed that a gluten-free diet reduces weight gain without changing food intake in mice fed high-fat diets. In the present study, we investigated the effects of gluten intake on fat metabolism, thermogenesis and energy expenditure in mice fed a standard or high-fat diet. METHODS: Mice were fed four different experimental diets during 8 weeks: a control-standard diet (CD), a CD added with 4.5% of wheat gluten (CD-G), a high-fat diet (HFD) and a HFD added with 4.5% of wheat gluten (HFD-G). After 8 weeks, the mice received (99m)Tc-radiolabeled gluten orally to study gluten absorption and biodistribution or they underwent indirect calorimetry. After killing, subcutaneous and brown adipose tissues (SAT and BAT) were collected to assess thermogenesis-related protein expression. Lipid metabolism was studied in adipocyte cultures from the four groups. RESULTS: Despite having had the same energy intake, CD-G and HFD-G mice exhibited increased body weight and fat deposits compared with their respective controls. (99m)Tc-GLU or its peptides were detected in the blood, liver and visceral adipose tissue, suggesting that gluten can even reach extraintestinal organs. Uncoupling protein-1 expression was reduced in the BAT of HFD-G and in the SAT of CD-G and HFD-G mice. Indirect calorimetry showed lower oxygen volume consumption in CD-G and HFD-G groups compared with their controls. In HFD mice, daily energy expenditure was reduced with gluten intake. Gluten also reduced adiponectin, peroxisome proliferator-activated receptor (PPAR)-alpha and PPARgamma and hormone-sensitive lipase in cultures of isolated adipocytes from HFD mice, whereas in the CD-G group, gluten intake increased interleukin-6 expression and tended to increase that of tumor necrosis factor. CONCLUSIONS: Wheat gluten promotes weight gain in animals on both HFD and CD, partly by reducing the thermogenic capacity of adipose tissues. PMID- 26443340 TI - Saturation of subcutaneous adipose tissue expansion and accumulation of ectopic fat associated with metabolic dysfunction during late and post-pubertal growth. AB - BACKGROUND/OBJECTIVE: Puberty is a period defined by large changes in adipose tissue accumulation and distribution; however, longitudinal patterns of ectopic fat development have not been shown. We have previously shown significant declines in beta-cell function (BCF) across puberty and hypothesize that accumulation of ectopic fat deposition, particularly hepatic fat, will predict this fall. SUBJECT/METHODS: We conducted a longitudinal study and examined 2-year change in abdominal fat distribution and type 2 diabetes risk markers in 76 Hispanic children and young adults (16.1+/-0.5 years, 66% obese, 52% male, 51% post-pubertal). Subcutaneous abdominal adipose tissue (SAAT), visceral adipose tissue (VAT), hepatic fat fraction (HFF) and pancreatic fat fraction (PFF) were measured by 3-Tesla magnetic resonance imaging, and markers of type 2 diabetes risk were collected at fasting and during an oral glucose tolerance test (OGTT). RESULTS: Baseline pubertal status significantly moderated the 2-year change in ectopic fat deposition, such that VAT, HFF and PFF increased in individuals during late and post-pubertal growth, whereas children earlier in their pubertal development decreased ectopic accumulation and had less VAT accumulation (VAT: pTanner*time=0.044, 0.31+/-0.08 l vs 0.03+/-0.10 l; HFF: pTanner*time=0.007, 1.34+/-0.87% vs -2.61+/-1.11%; PFF: pTanner*time<0.001, 1.61+/-0.39% vs -0.96+/ 0.50%). Independent of pubertal status, the 2-year increase in HFF and VAT significantly associated with a decline in BCF (beta=-1.04, P=0.038; beta=-1.81, P=0.020) and metabolic function, while accumulation of SAAT significantly associated with BCF (beta=1.36, P=0.012) and metabolic improvement. HFF accumulation was the only depot to significantly predict clinical markers of type 2 diabetes risk, fasting glucose and HbA1c, and circulating free fatty acid levels (beta=1.00, P=0.034; beta=1.00, P=0.015; beta=01.01, P=0.024). CONCLUSIONS: The accumulation of SAAT defends against type 2 diabetes risk and potentially ectopic fat accumulation. Intra-abdominal VAT and HFF accumulation both associate with metabolic decline and BCF, while HFF predicts an even greater number of metabolic risk features. PMID- 26443341 TI - Measuring perceived exercise capability and investigating its relationship with childhood obesity: a feasibility study. AB - BACKGROUND/OBJECTIVES: According to the COM-B ('Capability', 'Opportunity', 'Motivation' and 'Behaviour') model of behaviour, three factors are essential for behaviour to occur: capability, opportunity and motivation. Obese children are less likely to feel capable of exercising. The implementation of a new methodological approach to investigate the relationship between perceived exercise capability (PEC) and childhood obesity was conducted, which involved creating a new instrument, and demonstrating how it can be used to measure obesity intervention outcomes. SUBJECTS/METHODS: A questionnaire aiming to measure perceived exercise capability, opportunity and motivation was systematically constructed using the COM-B model and administered to 71 obese children (aged 9-17 years (12.24+/-0.2.01), body mass index (BMI) standard deviation scores (SDS) 2.80+/-0.660) at a weight-management camp in northern England. Scale validity and reliability was assessed. Relationships between PEC, as measured by the questionnaire, and BMI SDS were investigated for the children at the weight-management camp, and for 45 Spanish schoolchildren (aged 9-13 years, (10.52+/-1.23), BMI SDS 0.80+/-0.99). A pilot study, demonstrating how the questionnaire can be used to measure the effectiveness of an intervention aiming to bring about improved PEC for weight-management camp attendees, was conducted. No participants withdrew from these studies. RESULTS: The questionnaire domain (exercise capability, opportunity and motivation) composite scales were found to have adequate internal consistency (a=0.712-0.796) and construct validity (chi(2)/degrees of freedom=1.55, root mean square error of approximation=0.072, comparative fit index=0.92). Linear regression revealed that low PEC was associated with higher baseline BMI SDS for both UK (b=-0.289, P=0.010) and Spanish (b=-0.446, P=0.047) participants. Pilot study findings provide preliminary evidence for PEC improvements through intervention being achievable, and measurable using the questionnaire. CONCLUSIONS: Evidence is presented for reliability and validity of the questionnaire, and for feasibility of its use in the context of a childhood obesity intervention. Future research could investigate the link between PEC and childhood obesity further. PMID- 26443342 TI - Secreted factors derived from obese visceral adipose tissue regulate the expression of breast malignant transformation genes. AB - BACKGROUND/OBJECTIVES: Obese adipose tissue, especially the visceral depot, exhibits altered production of several molecules that could have a role on the initiation/promotion of breast cancer development. The aim of this work was to evaluate the effect of excess adipose tissue and its secreted factors on the expression of genes involved in the early steps of tumor promotion on the mammary gland. SUBJECTS AND METHODS: Carcinogenesis-related gene expression was evaluated in mammary gland tissue from female diet-induced obese (DIO) Sprague-Dawley rats and circulating leukocytes isolated from a group of breast cancer diagnosed and non-diagnosed obese women and compared with their normal weight counterparts. In addition, the human non-tumoral mammary epithelial cell line MCF10A was treated in vitro with the visceral (retroperitoneal adipose tissue (RPAT)) or subcutaneous adipose tissue (SAT) secretome and with rising concentrations of the lipid peroxidation by-product 4-hydroxynonenal (4-HNE). RESULTS: DIO rats were classified as susceptible to DIO (DIO-S) or partially resistant to DIO (DIO-R) according to the maximum fat mass gain of the lean group as a cut-off. As compared with lean and DIO-R, the DIO-S group showed a higher fat mass and lower lean mass. The anatomical characteristic of DIO-S was correlated with differential expression of cellular proliferation (ALDH3A1 and MYC) and antioxidant and DNA protection (GSTM2, SIRT1), and tumor suppression (TP53, PTEN, TGFB1) genes. Remarkably, this carcinogenesis-related gene expression pattern was reproduced in MCF10A treated with the RPAT secretome from DIO-S rats and with the lipid peroxidation by-product 4-HNE. Moreover, this pattern was also detected in leukocytes from obese women compared with normal weight women without evidence of breast cancer. CONCLUSIONS: Lipid peroxides secreted by the obese visceral adipose tissue could be among the relevant factors that promote changes involved in the early steps of tumor development in mammary gland. These changes can be detected even before histological alterations and in circulating leukocytes. PMID- 26443344 TI - Accuracy of abdominal ultrasound for the diagnosis of pneumoperitoneum in patients with acute abdominal pain: a pilot study. AB - BACKGROUND: Pneumoperitoneum is a rare cause of abdominal pain characterized by a high mortality. Ultrasonography (US) can detect free intraperitoneal air; however, its accuracy remains unclear. The aims of this pilot study were to define the diagnostic performance and the reliability of abdominal US for the diagnosis of pneumoperitoneum. METHODS: This was a prospective observational study. Four senior and two junior physicians were shown, in an unpaired randomized order, abdominal US videos from 11 patients with and 11 patients without pneumoperitoneum. Abdominal US videos were obtained from consecutive patients presenting to ED complaining abdominal pain with the diagnosis of pneumoperitoneum established by CT. Abdominal US was performed according to a standardized protocol that included the following scans: epigastrium, right and left hypochondrium, umbilical area and right hypochondrium with the patient lying on the left flank. We evaluated accuracy, intra- and inter-observer agreement of abdominal US when reviewed by senior physicians. Furthermore, we compared the accuracy of a "2 scan-fast exam" (epigastrium and right hypochondrium) vs the full US examination and the accuracy of physicians expert in US vs nonexpert ones. Finally, accuracy of US was compared with abdominal radiography in patients with available images. RESULTS: Considering senior revision, accuracy of abdominal US was 88.6 % (95 % CI 79.4-92.4 %) with a sensitivity of 95.5 % (95 % CI 86.3-99.2 %) and a specificity of 81.8 % (95 % CI 72.6-85.5 %). Inter- and intra-observer agreement (k) were 0.64 and 0.95, respectively. Accuracy of a "2 scan-fast exam" (87.5 %, 95 % CI 77.9-92.4 %) was similar to global exam. Sensitivity of abdominal radiography (72.2 %, 95 % CI 54.8-85.7 %) was lower than that of abdominal US, while specificity (92.5 %, 95 % CI 79.5-98.3 %) was higher. Accuracy (68.2 %, 95 % CI 51.4-80.9 %) of junior reviewers evaluating US was lower than senior reviewers. CONCLUSIONS: Senior physicians can recognize US signs of pneumoperitoneum with a good accuracy and reliability; sensitivity of US could be superior to abdominal radiography and a 2 fast-scan exam seems as accurate as full abdominal examination. US could be a useful bedside screening test for pneumoperitoneum. Trial registry ClinicalTrials.gov; No.: NCT02004925; URL: http://www.clinicaltrials.gov. PMID- 26443343 TI - Body mass index and breast cancer: analysis of a nation-wide population-based prospective cohort study on 1 393 985 Taiwanese women. AB - BACKGROUND: Asian women have a younger age at onset of breast cancer and a lower body mass index (BMI) than Western women. The link between obesity and risk of breast cancer in Asian women is still elusive. We aimed to investigate the effect of BMI on the risk of incident breast cancer in Taiwanese women. METHODS: A total of 1,393,985 women who had been cancer-free before recruitment and attended a nation-wide Taiwanese breast cancer-screening program between 1999 and 2009 were enrolled using a prospective cohort study. Obesity and other relevant variables (such as menopause status and other biochemical markers) were collected through in-person interviews, anthropometric measurements and blood samples at first screen. Incident breast cancers during follow-up were ascertained through the linkage of the cohort with the National Cancer Registry and the National Death Certification System. RESULTS: A total of 6969 and 7039 incident breast cancer cases were identified among women enrolled before and after menopause, respectively. Compared with a BMI range of 18.5-23.9 kg m(-)(2), the incremental level of BMI in the enrolled women before menopause revealed a lack of statistically significant association with the risk of incident breast cancer (adjusted hazard ratio=0.94, 0.98, 1.02, 1.01 and 0.82 for BMI <18.5, 24-26.9, 27 29.9, 30-34.9 and ?35, respectively), but the incremental level of BMI in the enrolled women after menopause led to a statistically significant incremental increase in the risk of breast cancer (adjusted hazard ratio=0.78, 1.19, 1.31, 1.53 and 1.65 for BMI <18.5, 24-26.9, 27-29.9, 30-34.9 and ?35, respectively) after adjusting for other explanatory risk factors. CONCLUSION: Obesity acts mainly as an influential promoter of the development of late-onset breast cancer after menopause in Taiwanese women. PMID- 26443346 TI - The Ecology and Evolution of Microbial Defense Systems in Escherichia coli. AB - Microbes produce an extraordinary array of microbial defense systems. These include broad-spectrum classical antibiotics critical to human health concerns; metabolic by-products, such as the lactic acids produced by lactobacilli; lytic agents, such as lysozymes found in many foods; and numerous types of protein exotoxins and bacteriocins. The abundance and diversity of this biological arsenal are clear. Lactic acid production is a defining trait of lactic acid bacteria. Bacteriocins are found in almost every bacterial species examined to date, and within a species, tens or even hundreds of different kinds of bacteriocins are produced. Halobacteria universally produce their own version of bacteriocins, the halocins. Streptomycetes commonly produce broad-spectrum antibiotics. It is clear that microbes invest considerable energy in the production and elaboration of antimicrobial mechanisms. What is less clear is how such diversity arose and what roles these biological weapons play in microbial communities. One family of microbial defense systems, the bacteriocins, has served as a model for exploring evolutionary and ecological questions. In this review, current knowledge of how the extraordinary range of bacteriocin diversity arose and is maintained in one species of bacteria, Escherichia coli, is assessed and the role these toxins play in mediating microbial dynamics is discussed. PMID- 26443345 TI - Genetics of Glioblastomas in Rare Anatomical Locations: Spinal Cord and Optic Nerve. PMID- 26443347 TI - Type 1 Fimbriae, Curli, and Antigen 43: Adhesion, Colonization, and Biofilm Formation. AB - This review is primarily concerned with the first step in biofilm formation, namely, bacterial attachment to surfaces. It describes three examples of bacterial adhesins, each of which belongs to a different subgroup and follows different strategies for surface presentation and adhesin exposure. These are type 1 fimbriae, very long stiff rodlike organelles; curli, amorphous fluffy coat structures; and finally antigen 43, short outer membrane structures with a simple assembly system. Their role as adhesins, their structure and biosynthesis, and their role in biofilm formation are described in detail in the review. The FimH protein presented by type 1 fimbriae seems to be a highly versatile adhesin fulfilling a diverse spectrum of roles ranging from pellicle and biofilm formation to being a bona fide virulence factor in uropathogenic E. coli (UPEC) strains, where it plays important roles in the manifestation of cystitis. Curli formation promotes two fundamental processes associated with biofilm formation: initial adhesion and cell-to-cell aggregation. A role for curli in the colonization of inert surfaces has been demonstrated. Severe sepsis and septic shock are frequently caused by gram-negative bacteria, and several factors suggest a significant role for curli during E. coli sepsis. The protection provided by Ag43-mediated aggregation was underlined in a series of experiments addressing the role of Ag43 in protection against oxidizing agents. Type 1 fimbriae, curli, and Ag43 are structurally different bacterial surface structures and follow completely different strategies for surface display and assembly. PMID- 26443348 TI - Regulation of Glutamine Synthetase Activity. AB - Detailed studies of the glutamine synthetase (GS) in Escherichia coli and other bacteria have shown that the activity of this enzyme is regulated by at least five different mechanisms: (i) cumulative feedback inhibition by multiple end products of glutamine metabolism, (ii) interconversion between taut and relaxed protein configurations in response to binding and dissociation of divalent cations at one of its two metal binding sites, (iii) dynamic interconversion of the enzyme between covalently modified (adenylylated) and unmodified forms by a novel bicyclic cascade system, (iv) repression and derepression of glutamine synthetase formation by cyclic phosphorylation and dephosphorylation of an RNA factor that governs transcription activities, and (v) regulation of glutamine synthetase turnover by the coupling of site specific metal ion-catalyzed oxidation with proteolytic degradation of the enzyme. Glutamine synthetase activity in E. coli is subject to inhibition by seven different end products of glutamine metabolism, namely, by tryptophan, histidine, carbamyl-phosphate, CTP, AMP, glucose-6-phosphate, and NAD+, and also by serine, alanine, and glycine. The cascade theory predicts that the steady-state level of glutamine synthetase adenylylation and therefore its catalytic activity is determined by the combined effects of all metabolites that affect the kinetic parameters of one or more of the enzymes in the cascade. Furthermore, under conditions where the supplies of ATP and glutamate are not limiting and the production of glutamine exceeds the demand, GS is no longer needed, then it will be converted to the catalytically inactive adenylylated form that is not under protection of ATP and glutamate. PMID- 26443349 TI - The Influence of Ecological Factors on the Distribution and the Genetic Structure of Escherichia coli. AB - This review focuses on recent data concerning the ecological factors that determine the distribution of Escherichia coli and the genetic structures of naturally occurring E. coli populations. It summarizes some of the older literature concerning the dynamics of E. coli populations within a host and poses some questions that arise from our more recently acquired understanding of the factors affecting the genetic structures of E. coli populations. Multilocus enzyme electrophoresis (MLEE) studies indicate that E. coli, relative to other members of the family Enterobacteriaceae, exhibits a moderate degree of genetic diversity. The existence of subspecific structure in E. coli has for the most part been determined by largely neutral in its effects on the fitness of a strain. The consequences for E. coli of the transition between its primary and secondary habitats are of considerable practical significance for water quality assessment and disease transmission. E. coli causes a significant fraction of human bacterial disease and is responsible for two main types of disease in humans and domestic animals: diarrheal disease and extraintestinal infections. The observed distribution of strains from the different E. coli genetic groups indicates that they have different life history tactics and ecological niches. A and B1 strains appear to be generalists, as they can be recovered from any vertebrate group. Group B2 and D strains appear to be more specialized, as they are largely restricted to endothermic vertebrates. PMID- 26443350 TI - Anaerobic Formate and Hydrogen Metabolism. AB - During fermentative growth, Escherichia coli degrades carbohydrates via the glycolytic route into two pyruvate molecules. Pyruvate can be reduced to lactate or nonoxidatively cleaved by pyruvate formate lyase into acetyl-coenzyme A (acetyl-CoA) and formate. Acetyl-CoA can be utilized for energy conservation in the phosphotransacetylase (PTA) and acetate kinase (ACK) reaction sequence or can serve as an acceptor for reducing equivalents gathered during pyruvate formation, through the action of alcohol dehydrogenase (AdhE). Formic acid is strongly acidic and has a redox potential of -420 mV under standard conditions and therefore can be classified as a high-energy compound. Its disproportionation into CO2 and molecular hydrogen (Em,7 -420 mV) via the formate hydrogenlyase (FHL) system is therefore of high selective value. The FHL reaction involves the participation of at least seven proteins, most of which are metalloenzymes, with requirements for iron, molybdenum, nickel, or selenium. Complex auxiliary systems incorporate these metals. Reutilization of the hydrogen evolved required the evolution of H2 oxidation systems, which couple the oxidation process to an appropriate energy-conserving terminal reductase. E. coli has two hydrogen oxidizing enzyme systems. Finally, fermentation is the "last resort" of energy metabolism, since it gives the minimal energy yield when compared with respiratory processes. Consequently, fermentation is used only when external electron acceptors are absent. This has necessitated the establishment of regulatory cascades, which ensure that the metabolic capability is appropriately adjusted to the physiological condition. Here we review the genetics, biochemistry, and regulation of hydrogen metabolism and its hydrogenase maturation system. PMID- 26443351 TI - Exoribonucleases and Endoribonucleases. AB - This review provides a description of the known Escherichia coli ribonucleases (RNases), focusing on their structures, catalytic properties, genes, physiological roles, and possible regulation. Currently, eight E. coli exoribonucleases are known. These are RNases II, R, D, T, PH, BN, polynucleotide phosphorylase (PNPase), and oligoribonuclease (ORNase). Based on sequence analysis and catalytic properties, the eight exoribonucleases have been grouped into four families. These are the RNR family, including RNase II and RNase R; the DEDD family, including RNase D, RNase T, and ORNase; the RBN family, consisting of RNase BN; and the PDX family, including PNPase and RNase PH. Seven well characterized endoribonucleases are known in E. coli. These are RNases I, III, P, E, G, HI, and HII. Homologues to most of these enzymes are also present in Salmonella. Most of the endoribonucleases cleave RNA in the presence of divalent cations, producing fragments with 3'-hydroxyl and 5'-phosphate termini. RNase H selectively hydrolyzes the RNA strand of RNA?DNA hybrids. Members of the RNase H family are widely distributed among prokaryotic and eukaryotic organisms in three distinct lineages, RNases HI, HII, and HIII. It is likely that E. coli contains additional endoribonucleases that have not yet been characterized. First of all, endonucleolytic activities are needed for certain known processes that cannot be attributed to any of the known enzymes. Second, homologues of known endoribonucleases are present in E. coli. Third, endonucleolytic activities have been observed in cell extracts that have different properties from known enzymes. PMID- 26443352 TI - Vaccines against Infections Caused by Salmonella, Shigella, and Pathogenic Escherichia coli. AB - Infectious diseases represent one of the most common causes of death worldwide, with the enteropathogenic bacteria Salmonella and Shigella and pathogenic Escherichia coli being among the most detrimental. Currently, vaccination represents the preferred method of preventing such infections. For stimulating the adaptive immune response, immunizations are frequently based on formulations which include inactivated whole-cell vaccines, live attenuated vaccines, or subunit vaccines. These can be administered via a parenteral or mucosal route, the latter having the advantage that it most closely mimics the actual course of infection. In addition to the type of vaccine and method of application, important consideration needs to be paid to safety, efficacy, and cost, which are often major bottlenecks in the successful implementation of vaccines. In this chapter we take a limited look at the history surrounding vaccinations involving Salmonella, Shigella, and pathogenic E. coli. Salmonella infections, which can lead to typhoid fever, are becoming increasing difficult to treat with antibiotics due to multi-drug-resistant strains. At present, the parenteral Vi based subunit vaccines and the live attenuated oral vaccine Ty21a have proven to be the vaccines of choice, with high levels of protective efficacy and limited side effects. Shigella infections are responsible for the diarrheal disease shigellosis. Various live and nonliving mucosal and parenteral vaccines have been tested, with the most promising candidates evolving around those that stimulate the production of O-antigen-specific antibodies. Pathogenic Escherichia coli infections can lead to severe diseases due to the bacterium's production of several specific toxins. Vaccines against this bacterium target its toxins, as well as surface-exposed antigens, all of which have been found to be effective as immunogens. PMID- 26443353 TI - Selenophosphate Synthetase. AB - Selenophosphate synthetase, the selD gene product from Escherichia coli, is one of the enzymes required for the synthesis and specific insertion of selenocysteine into proteins directed by the TGA codon. Selenophosphate synthetases have been isolated from or are thought to be present in most organisms; however, the best characterized selenophosphate synthetase is from E. coli, in which both in vivo and in vitro studies have been performed. Leinfelder and coworkers showed that an E. coli mutant lacking an intact selD gene fails to incorporate Se into both the selenocysteine-containing enzyme formate dehydrogenase (FDH) and tRNA species that normally contain 2-selenouridine residues at the wobble position. Thus, this study strongly implicated selenophosphate as playing a major role in E. coli selenium metabolic pathways. The selenophosphate synthetase reaction requires some form of reduced selenium such as hydrogen selenide (HSe-) and ATP as substrates to generate a stoichiometric amount of SePO3, AMP, and orthophosphate. Studies of selenophosphate inhibition have provided further insight into the mechanism of selenophosphate synthetase. An assay by which AMP formation is measured in the absence of selenide showed that selenophosphate synthetase catalyzes hydrolysis of ATP to AMP and two orthophosphates in an uncoupled reaction. The sequencing of selenophosphate synthetase genes from various organisms reveals several conserved regions in the gene product. Recent investigations into the mechanism of selenophosphate synthetase have revealed a property of selenophosphate synthetase not previously observed. In samples of purified selenophosphate synthetase, an unusual optical absorption spectrum is seen. PMID- 26443354 TI - The Life of Commensal Escherichia coli in the Mammalian Intestine. AB - In this chapter we review the literature with respect to what is known about how Escherichia coli colonizesthe mammalian intestine. We begin with a brief discussion of the mammalian large intestine, the major site that commensal strains of E. coli colonize. Next, evidence is discussed showing that, in order to colonize, E. coli must be able to penetrate and grow in the mucus layer of the large intestine. This is followed by discussions of colonization resistance, i.e., factors that are involved in the ability of a complete microbiota (microflora) to resist colonization by an invading bacterium, the advantages and disadvantages of the in vivo colonization models used in colonization research, the initiation and maintenance stages of E. coli colonization, and the rate of E. coli growth in the intestine. The next two sections of the chapter discuss the role of motility in colonization and how adhesion to mucosal receptors aids or inhibits penetration of the intestinal mucus layer and thereby either promotes or prevents E. coli colonization. Finally, the contribution of nutrition to the ability of E. coli to colonize is discussed based on the surprising finding that different nutrients are used by E. coli MG1655, a commensal strain, and by E. coli EDL933, an enterohemorrhagic strain, to colonize the intestine. PMID- 26443355 TI - Cytotoxic Necrotizing Factors: Rho-Activating Toxins from Escherichia coli. AB - This article reviews the Escherichia coli toxins called cytotoxic necrotizing factors (CNFs), which cause activation of Rho GTPases. It describes their modes of action, structure-function relationships, and roles in disease. Rho GTPases, the targets of CNFs, belong to the Ras superfamily of low molecular mass GTPases and act as molecular switches in various signaling pathways. Low molecular mass GTPases of the Rho family are known as master regulators of the actin cytoskeleton. Moreover, they are involved in various signal transduction processes, from transcriptional activation, cell cycle progression, and cell transformation to apoptosis. CNFs are cytotoxic for a wide variety of cells, including 3T3 fibroblasts, Chinese hamster ovary cells, Vero cells, HeLa cells, and cell lines of neuronal origin. This implies that a commonly expressed receptor is responsible for the uptake of CNF1. Cultured mammalian cells treated with CNFs are characterized by dramatic changes in actin-containing structures, including stress fibers, lamellipodia, and filopodia. Most striking is the formation of multinucleation in these cells. Rho GTPases are increasingly recognized as essential factors in the development of cancer and metastasis. This fact has initiated a discussion as to whether activation of Rho proteins by CNFs might be involved in tumorigenesis. Moreover, CNF1 increases the expression of the cyclooxygenase 2 (Cox2) gene in fibroblasts. Increased expression of Cox2 is observed in some types of tumors, e.g., colon carcinoma. Lipid-mediators produced by the enzyme are suggested to be responsible for tumor progression. PMID- 26443356 TI - Molecular Epidemiology of Extraintestinal Pathogenic Escherichia coli. AB - Extraintestinal pathogenic Escherichia coli (ExPEC), the specialized E. coli strains that possess the ability to overcome or subvert host defenses and cause extraintestinal disease, are important pathogens in humans and certain animals. Molecular epidemiological analysis has led to an appreciation of ExPEC as being distinct from other E. coli (including intestinal pathogenic and commensal variants) and has offered insights into the ecology, evolution, reservoirs, transmission pathways, host-pathogen interactions, and pathogenetic mechanisms of ExPEC. Molecular epidemiological analysis also provides an essential complement to experimental assessment of virulence mechanisms. This chapter first reviews the basic conceptual and methodological underpinnings of the molecular epidemiological approach and then summarizes the main aspects of ExPEC that have been investigated using this approach. PMID- 26443357 TI - The Cytology of Bacterial Conjugation. AB - This review focuses on the membrane-associated structures present at cell-cell contact sites during bacterial conjugation. These transfer proteins/structures have roles in the formation and stabilization of mating contacts and ultimately the passage of substrate across the cell envelope between two bacterial cells. The review presents evidence for the dynamic interaction between donor and recipient cells, including the assembly of a transmembrane protein complex, and concludes with a refined model for the mechanism of bacterial conjugation. Bacterial conjugation, in addition to being a mechanism for genome evolution, can be considered as a mechanism for macromolecular secretion. In particular, plasmid conjugative transfer is classified as a type IV secretion (T4S) system and represents the only known bacterial system for secretion of DNA. In all known conjugative transfer systems, a multitude of proteins are required for both plasmid transfer and pilus production. The plasmids discussed in the review include the F factor; the P group of plasmids, including RP4 and R751 (rigid); and the H plasmid group, including R27 (also thick flexible). With the LacI GFP/lacO system, the F, P, and H plasmids were observed to reside at well-defined positions located at the mid and quarter-cell positions of Escherichia coli throughout the vegetative cycle. In this review, recent observations based on bacterial cell biology techniques, including visualization of plasmid DNA and proteins at the subcellular level, have been combined with electron and light microscopy studies of mating cells to create an integrated overview of gram negative bacterial conjugation, a concept referred to as the conjugative cycle. PMID- 26443358 TI - Cytokines in Salmonellosis. AB - The recruitment and activation of phagocytic cells in infected tissues and the induction of T-cell- and B-cell-dependent acquired immunity are crucial for the control and resolution of Salmonella infections. These complex processes require the interaction of bacteria with a multitude of cell surface receptors and the controlled production of soluble mediators. The mechanisms of cytokine induction in response to Salmonella and the role of cytokine networks in Salmonella infections are the main foci of this review. Pathogen-associated molecular pattern receptors play an important role in recognition of bacteria by the host. Effective immunity against the bacterium therefore relies on the ability of the host to recruit phagocytes in the tissues and to enhance the antibacterial functions of these inflammatory cells. TNF-a, IFN-?, IL12, IL15, and IL18 are needed for the full expression of innate host resistance to Salmonella. The genes for mammalian cytokines can be cloned into suitable vectors and expressed in Salmonella as functional proteins. The in vivo production of cytokines by Salmonella carriers can have therapeutic applications and can modulate immune functions in the host. The possibility to modulate antigen-specific immune responses by expressing cytokines in Salmonella is illustrated by the increase in Salmonella-specific IgA responses induced by administration of IL-5-expressing bacteria. The same cytokines that are responsible for endotoxic shock are elevated in the late stages of lethal Salmonella infections, indicating that the toxicity of Salmonella lipopolysaccharide (LPS) may actually be contributing to the death of the host. PMID- 26443359 TI - Selenocysteine Lyase. AB - Selenocysteine is a naturally occurring analog of cysteine in which the sulfur atom of the latter is replaced with selenium. This seleno-amino acid occurs as a specific component of various selenoproteins and selenium-dependent enzymes. Incorporation of selenocysteine into these proteins occurs cotranslationally as directed by the UGA codon. For this process, a special tRNA having an anticodon complimentary to UGA, tRNASec, is utilized. In Escherichia coli and related bacteria, this tRNA first is amino acylated with serine, and the seryl-tRNASec is converted to selenocysteyl-tRNASec. The specific incorporation of selenocysteine into proteins directed by the UGA codon depends on the synthesis of selenocysteyl tRNASec. Included in the selenium delivery protein category are rhodaneses that mobilize selenium from inorganic sources and NIFS-like proteins that liberate elemental selenium from selenocysteine. The NIFS protein from Azotobacter vinelandii was found to serve as an efficient catalyst in vitro for delivery of selenium from free selenocysteine to Escherichia coli selenophosphate synthetase for selenophosphate formation. The widespread distribution of selenocysteine lyase in numerous bacterial species was reported and the bacterial enzymes, like the pig liver enzyme, required pyridoxal phosphate as cofactor. Three NIFS-like genes were isolated from E. coli by Esaki and coworkers and the expressed gene products were isolated and characterized. One of these NIFS-like proteins also exhibited a high preference for selenocysteine over cysteine. M. vannielii, an anaerobic methane-producing organism, that grows in a mineral medium containing formate as sole organic carbon source, synthesizes several specific selenoenzymes required for growth and energy production under these conditions. PMID- 26443360 TI - Modified Nucleosides of Escherichia coli Ribosomal RNA. AB - The modified nucleosides of RNA are chemically altered versions of the standard A, G, U, and C nucleosides. This review reviews the nature and location of the modified nucleosides of Escherichia coli rRNA, the enzymes that form them, and their known and/or putative functional role. There are seven Psi (pseudouridines) synthases to make the 11 pseudouridines in rRNA. There is disparity in numbers because RluC and RluD each make 3 pseudouridines. Crystal structures have shown that the Psi synthase domain is a conserved fold found only in all five families of Psi synthases. The conversion of uridine to Psi has no precedent in known metabolic reactions. Other enzymes are known to cleave the glycosyl bond but none carry out rotation of the base and rejoining to the ribose while still enzyme bound. Ten methyltransferases (MTs) are needed to make all the methylated nucleosides in 16S RNA, and 14 are needed for 23S RNA. Biochemical studies indicate that the modes of substrate recognition are idiosyncratic for each Psi synthase since no common mode of recognition has been detected in studies of the seven synthases. Eight of the 24 expected MTs have been identified, and six crystal structures have been determined. Seven of the MTs and five of the structures are class I MTs with the appropriate protein fold plus unique appendages for the Psi synthases. The remaining MT, RlmB, has the class IV trefoil knot fold. PMID- 26443361 TI - Catabolism of Hexuronides, Hexuronates, Aldonates, and Aldarates. AB - Following elucidation of the regulation of the lactose operon in Escherichia coli, studies on the metabolism of many sugars were initiated in the early 1960s. The catabolic pathways of D-gluconate and of the two hexuronates, D-glucuronate and D-galacturonate, were investigated. The post genomic era has renewed interest in the study of these sugar acids and allowed the complete characterization of the D-gluconate pathway and the discovery of the catabolic pathways for L idonate, D-glucarate, galactarate, and ketogluconates. Among the various sugar acids that are utilized as sole carbon and energy sources to support growth of E. coli, galacturonate, glucuronate, and gluconate were shown to play an important role in the colonization of the mammalian large intestine. In the case of sugar acid degradation, the regulators often mediate negative control and are inactivated by interaction with a specific inducer, which is either the substrate or an intermediate of the catabolism. These regulators coordinate the synthesis of all the proteins involved in the same pathway and, in some cases, exert crosspathway control between related catabolic pathways. This is particularly well illustrated in the case of hexuronide and hexuronate catabolism. The structural genes encoding the different steps of hexuronate catabolism were identified by analysis of numerous mutants affected for growth with galacturonate or glucuronate. E. coli is able to use the diacid sugars D-glucarate and galactarate (an achiral compound) as sole carbon source for growth. Pyruvate and 2-phosphoglycerate are the final products of the D-glucarate/galactarate catabolism. PMID- 26443362 TI - Virulence Gene Regulation in Shigella. AB - Shigella species are the causative agents of bacillary dysentery in humans, an invasive disease in which the bacteria enter the cells of the epithelial layer of the large intestine, causing extensive tissue damage and inflammation. They rely on a plasmid-encoded type III secretion system (TTSS) to cause disease; this system and its regulation have been investigated intensively at the molecular level for decades. The lessons learned have not only deepened our knowledge of Shigella biology but also informed in important ways our understanding of the mechanisms used by other pathogenic bacteria to cause disease and to control virulence gene expression. In addition, the Shigella story has played a central role in the development of our appreciation of the contribution of horizontal DNA transfer to pathogen evolution.A 30-kilobase-pair "Entry Region" of the 230-kb virulence plasmid lies at the heart of the Shigella pathogenesis system. Here are located the virB and mxiE regulatory genes and most of the structural genes involved in the expression of the TTSS and its effector proteins. Expression of the virulence genes occurs in response to an array of environmental signals, including temperature, osmolarity, and pH.At the top of the regulatory hierarchy and lying on the plasmid outside the Entry Region isvirF, encoding an AraC-like transcription factor.Virulence gene expression is also controlled by chromosomal genes,such as those encoding the nucleoid-associated proteins H-NS, IHF, and Fis, the two-component regulators OmpR/EnvZ and CpxR/CpxA, the anaerobic regulator Fnr, the iron-responsive regulator Fur, and the topoisomerases of the cell that modulate DNA supercoiling. Small regulatory RNAs,the RNA chaperone Hfq,and translational modulation also affect the expression of the virulence phenotypetranscriptionally and/orposttranscriptionally. PMID- 26443363 TI - Regulation of Serine, Glycine, and One-Carbon Biosynthesis. AB - The biosynthesis of serine, glycine, and one-carbon (C1) units constitutes a major metabolic pathway in Escherichia coli and Salmonella enterica serovar Typhimurium. C1 units derived from serine and glycine are used in the synthesis of purines, histidine, thymine, pantothenate, and methionine and in the formylation of the aminoacylated initiator fMet-TRNAfMet used to start translation in E. coli and serovar Typhimurium. The need for serine, glycine, and C1 units in many cellular functions makes it necessary for the genes encoding enzymes for their synthesis to be carefully regulated to meet the changing demands of the cell for these intermediates. This review discusses the regulation of the following genes: serA, serB, and serC; gly gene; gcvTHP operon; lpdA; gcvA and gcvR; and gcvB genes. Threonine utilization (the Tut cycle) constitutes a secondary pathway for serine and glycine biosynthesis. L-Serine inhibits the growth of E. coli cells in GM medium, and isoleucine releases this growth inhibition. The E. coli glycine transport system (Cyc) has been shown to transport glycine, D-alanine, D-serine, and the antibiotic D-cycloserine. Transport systems often play roles in the regulation of gene expression, by transporting effector molecules into the cell, where they are sensed by soluble or membrane-bound regulatory proteins. PMID- 26443364 TI - Biosynthesis of Glutamate, Aspartate, Asparagine, L-Alanine, and D-Alanine. AB - Glutamate, aspartate, asparagine, L-alanine, and D-alanine are derived from intermediates of central metabolism, mostly the citric acid cycle, in one or two steps. While the pathways are short, the importance and complexity of the functions of these amino acids befit their proximity to central metabolism. Inorganic nitrogen (ammonia) is assimilated into glutamate, which is the major intracellular nitrogen donor. Glutamate is a precursor for arginine, glutamine, proline, and the polyamines. Glutamate degradation is also important for survival in acidic environments, and changes in glutamate concentration accompany changes in osmolarity. Aspartate is a precursor for asparagine, isoleucine, methionine, lysine, threonine, pyrimidines, NAD, and pantothenate; a nitrogen donor for arginine and purine synthesis; and an important metabolic effector controlling the interconversion of C3 and C4 intermediates and the activity of the DcuS-DcuR two-component system. Finally, L- and D-alanine are components of the peptide of peptidoglycan, and L-alanine is an effector of the leucine responsive regulatory protein and an inhibitor of glutamine synthetase (GS). This review summarizes the genes and enzymes of glutamate, aspartate, asparagine, L-alanine, and D-alanine synthesis and the regulators and environmental factors that control the expression of these genes. Glutamate dehydrogenase (GDH) deficient strains of E. coli, K. aerogenes, and S. enterica serovar Typhimurium grow normally in glucose containing (energy-rich) minimal medium but are at a competitive disadvantage in energy limited medium. Glutamate, aspartate, asparagine, L-alanine, and D-alanine have multiple transport systems. PMID- 26443365 TI - Evolution and Ecology of Salmonella. AB - Over the past 120 to 160 million years, the genus Salmonella has evolved into a complex group of more than 2,300 genetically and phenotypically diverse serovars. Members of this genus are able to infect a wide diversity of vertebrate and invertebrate hosts; disease manifestations in humans range from gastroenteritis to typhoid fever. The evolution of the genus Salmonella and the divergence and radiation of particular lineages within this group have resulted from selection acting on new genetic variation generated by events such as the gain, loss, and/or rearrangement of genetic material. These types of genetic events have contributed to the speciation of Salmonella from its ancestral association with cold-blood animals to a pathogen of warm-blooded hosts. Moreover, adaptive radiation due to changes in gene content within S. enterica subspecies I has impacted host specificity and aided in the selection of host-restricted, host adapted, and non-host-adapted serovars. In addition to the genetic diversity important for the wide phenotypic heterogeneity within the genus, a subset of core Salmonella-specific genes present in all Salmonella species and serovars has been identified that may contribute to the conserved aspects of the lifestyle of this microorganism, including the ability to survive in nutrient-poor nonhost environments such as soil and water. Whole-genome comparisons of isolates differing in host range and virulence will continue to elucidate the genetic mechanisms that have contributed to the evolution and diverse ecology of the genus Salmonella. PMID- 26443366 TI - Biosynthesis of Arginine and Polyamines. AB - Early investigations on arginine biosynthesis brought to light basic features of metabolic regulation. The most significant advances of the last 10 to 15 years concern the arginine repressor, its structure and mode of action in both E. coli and Salmonella typhimurium, the sequence analysis of all arg structural genes in E. coli and Salmonella typhimurium, the resulting evolutionary inferences, and the dual regulation of the carAB operon. This review provides an overall picture of the pathways, their interconnections, the regulatory circuits involved, and the resulting interferences between arginine and polyamine biosynthesis. Carbamoylphosphate is a precursor common to arginine and the pyrimidines. In both Escherichia coli and Salmonella enterica serovar Typhimurium, it is produced by a single synthetase, carbamoylphosphate synthetase (CPSase), with glutamine as the physiological amino group donor. This situation contrasts with the existence of separate enzymes specific for arginine and pyrimidine biosynthesis in Bacillus subtilis and fungi. Polyamine biosynthesis has been particularly well studied in E. coli, and the cognate genes have been identified in the Salmonella genome as well, including those involved in transport functions. The review summarizes what is known about the enzymes involved in the arginine pathway of E. coli and S. enterica serovar Typhimurium; homologous genes were identified in both organisms, except argF (encoding a supplementary OTCase), which is lacking in Salmonella. Several examples of putative enzyme recruitment (homologous enzymes performing analogous functions) are also presented. PMID- 26443367 TI - C4-Dicarboxylate Degradation in Aerobic and Anaerobic Growth. AB - C4-dicarboxylates, like succinate, fumarate, L- and D-malate, tartrate, and the C4-dicarboxylic amino acid aspartate, support aerobic and anaerobic growth of Escherichia coli and related bacteria and can serve as carbon and energy sources. In aerobic growth, the C4-dicarboxylates are oxidized in the citric acid cycle. Due to the interruption of the citric acid cycle under anaerobic conditions, anaerobic metabolism of the C4-dicarboxylates depends on fumarate reduction to succinate. In some related bacteria (e.g., Klebsiella), degradation of C4 dicarboxylates, like tartrate, uses a different mechanism and pathway. It requires the functioning of an Na+-dependent and membrane-associated oxaloacetate decarboxylase. Due to the incomplete function of the citric acid cycle in anaerobic growth, succinate supports only aerobic growth of E. coli. This chapter describes the pathways of and differences in aerobic and anaerobic C4 dicarboxylate metabolism and the physiological consequences. The citric acid cycle, fumarate respiration, and fumarate reductase are discussed here only in the context of aerobic and anaerobic C4-dicarboxylate metabolism. Some recent aspects of C4-dicarboxylate metabolism, such as transport and sensing of C4 dicarboxylates, and their relationships are treated in more detail. PMID- 26443368 TI - Fermentative Pyruvate and Acetyl-Coenzyme A Metabolism. AB - Pyruvate and acetyl-CoA form the backbone of central metabolism. The nonoxidative cleavage of pyruvate to acetyl-CoA and formate by the glycyl radical enzyme pyruvate formate lyase is one of the signature reactions of mixed-acid fermentation in enterobacteria. Under these conditions, formic acid accounts for up to one-third of the carbon derived from glucose. The further metabolism of acetyl-CoA to acetate via acetyl-phosphate catalyzed by phosphotransacetylase and acetate kinase is an exemplar of substrate-level phosphorylation. Acetyl-CoA can also be used as an acceptor of the reducing equivalents generated during glycolysis, whereby ethanol is formed by the polymeric acetaldehyde/alcohol dehydrogenase (AdhE) enzyme. The metabolism of acetyl-CoA via either the acetate or the ethanol branches is governed by the cellular demand for ATP and the necessity to reoxidize NADH. Consequently, in the absence of an electron acceptor mutants lacking either branch of acetyl-CoA metabolism fail to cleave pyruvate, despite the presence of PFL, and instead reduce it to D-lactate by the D-lactate dehydrogenase. The conversion of PFL to the active, radical-bearing species is controlled by a radical-SAM enzyme, PFL-activase. All of these reactions are regulated in response to the prevalent cellular NADH:NAD+ ratio. In contrast to Escherichia coli and Salmonella species, some genera of enterobacteria, e.g., Klebsiella and Enterobacter, produce the more neutral product 2,3-butanediol and considerable amounts of CO2 as fermentation products. In these bacteria, two molecules of pyruvate are converted to alpha-acetolactate (AL) by alpha acetolactate synthase (ALS). AL is then decarboxylated and subsequently reduced to the product 2,3-butandiol. PMID- 26443369 TI - Escherichia coli and Salmonella 2000: the View From Here. AB - In 1995, an editorial in Science (267:1575) commented that predictions made some 25 years previously regarding "Biology and the Future of Man" were largely fulfilled but that "the most revolutionary and unexpected findings were not predicted." We would be glad to do as well! As we stated at the beginning, our work as editors of the Escherichia coli and Salmonella book did not endow us with special powers of prophecy but it does permit us to express our excitement for the future. In our opinion, E. coli and S. enterica will continue to play a central role in biological research. This is not because they are intrinsically more interesting than any other bacteria, as we believe that all bacteria are equally interesting. However, knowledge builds on knowledge, and it is here that these two species continue to have a large edge not only over other microorganisms but also, for some time to come, over all other forms of life. It is interesting in this connection that biotechnology, having made detours through other microorganisms, always seems to return to E. coli. PMID- 26443370 TI - Molecular Basis for Bacterial Growth on Citrate or Malonate. AB - Environmental citrate or malonate is degraded by a variety of aerobic or anaerobic bacteria. For selected examples, the genes encoding the specific enzymes of the degradation pathway are described together with the encoded proteins and their catalytic mechanisms. Aerobic bacteria degrade citrate readily by the basic enzyme equipment of the cell if a specific transporter for citrate is available. Anaerobic degradation of citrate in Klebsiella pneumoniae requires the so-called substrate activation module to convert citrate into its thioester with the phosphoribosyl dephospho-CoA prosthetic group of citrate lyase. The citryl thioester is subsequently cleaved into oxaloacetate and the acetyl thioester, from which a new citryl thioester is formed as the turnover continues. The degradation of malonate likewise includes a substrate activation module with a phosphoribosyl dephospho-CoA prosthetic group. The machinery gets ready for turnover after forming the acetyl thioester with the prosthetic group. The acetyl residue is then exchanged by a malonyl residue, which is easily decarboxylated with the regeneration of the acetyl thioester. This equipment suffices for aerobic growth on malonate, since ATP is produced via the oxidation of acetate. Anaerobic growth on citrate or malonate, however, depends on additional enzymes of a so-called energy conservation module. This allows the conversion of decarboxylation energy into an electrochemical gradient of Na+ ions. In citrate fermenting K. pneumoniae, the Na+ gradient is formed by the oxaloacetate decarboxylase and mainly used to drive the active transport of citrate into the cell. To use this energy source for this purpose is possible, since ATP is generated by substrate phosphorylation in the well-known sequence from pyruvate to acetate. In the malonate-fermenting bacterium Malonomonas rubra, however, no reactions for substrate level phosphorylation are available and the Na+ gradient formed in the malonate decarboxylation reaction must therefore be used as the driving force for ATP synthesis. PMID- 26443371 TI - Ammonia Transport. AB - This review reviews the ammonium/methylammonium transport (Amt) proteins of Escherichia coli and Salmonella enterica serovar Typhimurium. The Amt proteins and their homologs, the methylammonium/ammonium permease proteins of Saccharomyces cerevisiae, constitute a distinct class of membrane-associated ammonia transporters. Members of the Amt family are found in archaea, bacteria, fungi, plants, and invertebrate animals. In E. coli and serovar Typhimurium, the Amt proteins are essential to maintain maximal growth at low concentrations of ammonia, the preferred nitrogen source. Soupene and coworkers showed that a mutant of E. coli with only the low-affinity glutamate dehydrogenase pathway for assimilation of ammonia, which therefore grows slowly at low ammonia concentrations, is not relieved of its growth defect by overexpression of AmtB. A recent study on an Amt protein from tomato concluded that it was a specific transporter for NH4+. A trimeric stoichiometry for AmtB is supported by the observation of a direct interaction between AmtB and the trimeric signal transduction protein GlnK. In E. coli, GlnK has been observed to associate with the membrane in an AmtB-dependent fashion. Both GlnK and GlnB are sensors of nitrogen status. Their interaction with AmtB suggests a role for AmtB in nitrogen regulation. In summary, AmtB is a membrane-associated ammonia transporter that is important for growth at external concentrations of the uncharged species (NH3) below about 50 nM. The preponderance of evidence suggests that AmtB specifically transports the charged species (NH4+) and that this transport is passive and, hence, bidirectional. PMID- 26443372 TI - Selenocysteine. AB - About 50 years ago, research on the biological function of the element selenium was initiated by the report of J. Pinsent that generation of formate dehydrogenase activity by Escherichia coli requires the presence of both selenite and molybdate in the growth medium. In nature, selenium is predominantly associated with sulfur minerals, the Se/S ratios of which vary widely depending on the geological formation. Because of the chemical similarity between the two elements, selenium can intrude into the sulfur pathway at high Se/S ratios and can be statistically incorporated into polypeptides. The central macromolecule for the synthesis and incorporation of selenocysteine is a specialized tRNA, designated tRNASec. It is the product of the selC (previously fdhC) gene. tRNASec fulfils a multitude of functions, which are based on its unique structural properties, compared to canonical elongator RNAs. tRNASec possesses the discriminator base G73 and the identity elements of serine-specific tRNA isoacceptors. The conversion of seryl-tRNASec into selenocysteyl-tRNASec is catalyzed by selenocysteine synthase, the product of the selA gene (previously the fdhA locus, which was later shown to harbor two genes, selA and selB). The crucial element for the regulation is a putative secondary structure at the 5' end of the untranslated region of the selAB mRNA. The generation and analysis of transcriptional and translational reporter gene fusions of selA and selB yield an expression pattern identical to that obtained by measuring the actual amounts of SelA and SelB proteins. PMID- 26443373 TI - Different risk factors for bleeding and discontinuation between dabigatran and rivaroxaban. AB - BACKGROUND: It is unclear whether risk factors for bleeding and discontinuation are different between dabigatran and rivaroxaban. METHODS AND RESULTS: We enrolled consecutive patients with atrial fibrillation who received dabigatran or rivaroxaban, had a CHADS2 score >1 and creatinine clearance >30ml/min. During this period, only dabigatran and rivaroxaban were available as non-vitamin K oral anticoagulants (NOACs) in our hospital. We compared the clinical and demographic data and the incidence of bleeding for one year between dabigatran group and rivaroxaban group. As a result, the dabigatran group consisted of 177 patients and the rivaroxaban group consisted of 179 patients. The incidence of discontinuation was significantly higher in the dabigatran group than in the rivaroxaban group (27.7% vs. 13.4%, p<0.001). Multivariate analysis, even after propensity score-matching analysis, revealed that there were no independent risk factors for bleeding in the dabigatran group, while in the rivaroxaban group, use of antiplatelet therapy was an independent factor correlating with bleeding. CONCLUSIONS: The risk factors for bleeding may be different between dabigatran and rivaroxaban. To avoid bleeding, rivaroxaban should be prescribed with caution or avoided in patients using antiplatelet therapy. Upon discontinuation, rivaroxaban may be more favorable than dabigatran. PMID- 26443374 TI - Whole exome sequencing combined with integrated variant annotation prediction identifies a causative myosin essential light chain variant in hypertrophic cardiomyopathy. AB - BACKGROUND: The development of candidate gene approaches to enable molecular diagnosis of hypertrophic cardiomyopathy (HCM) has required extensive and prolonged efforts. Whole exome sequencing (WES) technologies have already accelerated genetic studies of Mendelian disorders, yielding approximately 30% diagnostic success. As a result, there is great interest in extending the use of WES to any of Mendelian diseases. This study investigated the potential of WES for molecular diagnosis of HCM. METHODS: WES was performed on seven relatives from a large HCM family with a clear HCM phenotype (five clinically affected and two unaffected) in the Kanazawa University Hypertrophic Cardiomyopathy Registry. Serial bioinformatics filtering methods as well as using combined annotation dependent depletion (CADD) score and high heart expression (HHE) gene data were applied to detect the causative variant. Moreover, additional carriers of the variant were investigated in the HCM registry, and clinical characteristics harboring the variant were collected and evaluated. RESULTS: WES detected 60020 rare variants in the large HCM family. Of those, 3439 were missense, nonsense, splice-site, or frameshift variants. After genotype-phenotype matching, 13 putative variants remained. Using CADD score and HHE gene data, the number of candidates was reduced to one, a variant in the myosin essential light chain (MYL3, NM_000258.2:c.281G>A, p.Arg94His) that was shared by the five affected subjects. Additional screening of the HCM registry (n=600) identified two more subjects with this variant. Serial assessments of the variant carriers revealed the following phenotypic characteristics: (1) disease-penetrance of 88%; (2) all clinically affected carriers exhibited asymmetric septal hypertrophy with a substantial maximum left ventricular wall thickness of 18+/-3mm without any obstruction. CONCLUSIONS: WES combined with CADD score and HHE gene data may be useful even in HCM. Furthermore, the MYL3 Arg94His variant was associated with high disease penetrance and substantial interventricular septal hypertrophy. PMID- 26443376 TI - Rice ONAC106 Inhibits Leaf Senescence and Increases Salt Tolerance and Tiller Angle. AB - NAM/ATAF1/ATAF2/CUC2 (NAC) is a plant-specific transcription factor (TF) family, and NACs participate in many diverse processes during the plant life cycle. Several Arabidopsis thaliana NACs have important roles in positively or negatively regulating leaf senescence, but in other plant species, including rice, the senescence-associated NACs (senNACs) remain largely unknown. Here we show that the rice senNAC TF ONAC106 negatively regulates leaf senescence. Leaves of onac106-1D (insertion of the 35S enhancer in the promoter region of the ONAC106 gene) mutants retained their green color under natural senescence and dark-induced senescence conditions. Genome-wide transcriptome analysis revealed that key senescence-associated genes (SGR, NYC1, OsNAC5, OsNAP, OsEIN3 and OsS3H) were differentially expressed in onac106-1D during dark-induced senescence. In addition to delayed senescence, onac106-1D also showed a salt stress-tolerant phenotype; key genes that down-regulate salt response signaling (OsNAC5, OsDREB2A, OsLEA3 and OsbZIP23) were rapidly up-regulated in onac106-1D under salt stress. Interestingly, onac106-1D also exhibited a wide tiller angle phenotype throughout development, and the tiller angle-related gene LPA1 was down-regulated in onac106-1D. Using yeast one-hybrid assays, we found that ONAC106 binds to the promoter regions of SGR, NYC1, OsNAC5 and LPA1. Taking these results together, we propose that ONAC106 functions in leaf senescence, salt stress tolerance and plant architecture by modulating the expression of its target genes that function in each signaling pathway. PMID- 26443375 TI - Arabidopsis ABA-Activated Kinase MAPKKK18 is Regulated by Protein Phosphatase 2C ABI1 and the Ubiquitin-Proteasome Pathway. AB - Phosphorylation and dephosphorylation events play an important role in the transmission of the ABA signal. Although SnRK2 [sucrose non-fermenting1-related kinase2] protein kinases and group A protein phosphatase type 2C (PP2C)-type phosphatases constitute the core ABA pathway, mitogen-activated protein kinase (MAPK) pathways are also involved in plant response to ABA. However, little is known about the interplay between MAPKs and PP2Cs or SnRK2 in the regulation of ABA pathways. In this study, an effort was made to elucidate the role of MAP kinase kinase kinase18 (MKKK18) in relation to ABA signaling and response. The MKKK18 knockout lines showed more vigorous root growth, decreased abaxial stomatal index and increased stomatal aperture under normal growth conditions, compared with the control wild-type Columbia line. In addition to transcriptional regulation of the MKKK18 promoter by ABA, we demonstrated using in vitro and in vivo kinase assays that the kinase activity of MKKK18 was regulated by ABA. Analysis of the cellular localization of MKKK18 showed that the active kinase was targeted specifically to the nucleus. Notably, we identified abscisic acid insensitive 1 (ABI1) PP2C as a MKKK18-interacting protein, and demonstrated that ABI1 inhibited its activity. Using a cell-free degradation assay, we also established that MKKK18 was unstable and was degraded by the proteasome pathway. The rate of MKKK18 degradation was delayed in the ABI1 knockout line. Overall, we provide evidence that ABI1 regulates the activity and promotes proteasomal degradation of MKKK18. PMID- 26443377 TI - The Relationships between Development and Low Temperature Tolerance in Barley Near Isogenic Lines Differing for Flowering Behavior. AB - Flowering time, vernalization requirement, photoperiod sensitivity and low temperature tolerance are key traits in the Triticeae. We characterized a set of isogenic genetic stocks-representing single and pairwise substitutions of spring alleles at the VRN-H1, VRN-H2 and VRN-H3 loci in a winter barley background-at the structural, functional and phenotypic levels. High density mapping with reference to the barley genome sequence confirmed that in all cases target VRN alleles were present in the near isogenic lines (NILs) and allowed estimates of introgression size (at the genetic and physical levels) and gene content. Expression data corroborated the structural and phenotypic results. The latter confirmed that substitution of a spring allele at any of the VRN loci is sufficient to eliminate vernalization requirement. There was no significant change in low temperature tolerance with substitution of a spring allele at VRN H2, but there were significant losses in cold tolerance with substitutions at VRN H1 and VRN-H3. Reductions in cold tolerance are ascribed to an accelerated transition from the vegetative to reproductive state. The set of NILs will be a rich resource for understanding the genetics of vernalization, low temperature tolerance and other traits encoded/regulated by genes within the introgressed intervals. PMID- 26443378 TI - A Functional EXXEK Motif is Essential for Proton Coupling and Active Glucosinolate Transport by NPF2.11. AB - The proton-dependent oligopeptide transporter (POT/PTR) family shares a highly conserved E1X1X2E2RFXYY (E1X1X2E2R) motif across all kingdoms of life. This motif is suggested to have a role in proton coupling and active transport in bacterial homologs. For the plant POT/PTR family, also known as the NRT1/PTR family (NPF), little is known about the role of the E1X1X2E2R motif. Moreover, nothing is known about the role of the X1 and X2 residues within the E1X1X2E2R motif. We used NPF2.11-a proton-coupled glucosinolate (GLS) symporter from Arabidopsis thaliana to investigate the role of the E1X1X2E2K motif variant in a plant NPF transporter. Using liquid chromatography-mass spectrometry (LC-MS)-based uptake assays and two-electrode voltage clamp (TEVC) electrophysiology, we demonstrate an essential role for the E1X1X2E2K motif for accumulation of substrate by NPF2.11. Our data suggest that the highly conserved E1, E2 and K residues are involved in translocation of protons, as has been proposed for the E1X1X2E2R motif in bacteria. Furthermore, we show that the two residues X1 and X2 in the E1X1X2E2[K/R] motif are conserved as uncharged amino acids in POT/PTRs from bacteria to mammals and that introducing a positive or negative charge in either position hampers the ability to overaccumulate substrate relative to the assay medium. We hypothesize that introducing a charge at X1 and X2 interferes with the function of the conserved glutamate and lysine residues of the E1X1X2E2K motif and affects the mechanism behind proton coupling. PMID- 26443380 TI - Acculturation and Psychological Adjustment of Vietnamese Refugees: An Ecological Acculturation Framework. AB - Acculturation to the culture of the host society as well as to one's heritage culture have been shown to impact immigrants' adjustment during the years following resettlement. While acculturation has been identified as an important factor in adjustment of Vietnamese immigrants (Birman and Tran in Am J Orthopsychiatr 78(1):109-120. doi: 10.1037/0002-9432.78.1.109 , 2008), no clear pattern of findings has emerged and too few studies have employed an ecological approach. The purpose of this paper is to contextualize the study of acculturation and adjustment by taking an ecological approach to exploring these relationships across several life domains, using a bilinear scale, and examining mediators of these relationships for adult Vietnamese refugees (N = 203) in the United States. We call this approach the Ecological Acculturation Framework (EAF). Results of a structural equation model (SEM) showed that job satisfaction fully mediated the relationship between American acculturation and psychological distress, demonstrating that this relationship was specific to an occupational domain. However, while Vietnamese acculturation predicted co-ethnic social support satisfaction, it did not predict reduced psychological distress. Implications for a life domains approach, including domain specificity, are discussed. PMID- 26443379 TI - Functional analyses of phosphorylation events in human Argonaute 2. AB - Argonaute 2 (Ago2) protein is a central effector of RNA interference (RNAi) pathways and regulates mammalian genes on a global level. The mechanisms of Ago2 mediated silencing are well understood, but less is known about its regulation. Recent reports indicate that phosphorylation significantly affects Ago2 activity. Here, we investigated the effect of mutating all known phospho-residues within Ago2 on its localization and activity. Ago2 associates with two different cytoplasmic RNA granules known as processing bodies (P-bodies) and stress granules, but the nature of this phenomenon is controversial. We report that replacing serine with a phospho-mimetic aspartic acid at position 798 completely abrogates association of Ago2 with P-bodies and stress granules. The effect of this mutation on its activity in gene silencing was modest, which was surprising because association of Ago2 with cytoplasmic RNA granules is thought to be a consequence of its role in RNAi. As such, our data indicate that targeting of Ago2 to P-bodies and stress granules is separable from its role in RNAi and likely requires dynamic phosphorylation of serine 798. PMID- 26443381 TI - Giant photovoltaic effect of ferroelectric domain walls in perovskite single crystals. AB - The photovoltaic (PV) effect in polar materials offers great potential for light energy conversion that generates a voltage beyond the bandgap limit of present semiconductor-based solar cells. Ferroelectrics have received renewed attention because of the ability to deliver a high voltage in the presence of ferroelastic domain walls (DWs). In recent years, there has been considerable debate over the impact of the DWs on the PV effects, owing to lack of information on the bulk PV tensor of host ferroelectrics. In this article, we provide the first direct evidence of an unusually large PV response induced by ferroelastic DWs-termed 'DW'-PV effect. The precise estimation of the bulk PV tensor in single crystals of barium titanate enables us to quantify the giant PV effect driven by 90 degrees DWs. We show that the DW-PV effect arises from an effective electric field consisting of a potential step and a local PV component in the 90 degrees DW region. This work offers a starting point for further investigation into the DW-PV effect of alternative systems and opens a reliable route for enhancing the PV properties in ferroelectrics based on the engineering of domain structures in either bulk or thin-film form. PMID- 26443382 TI - [Long-term efficacy of Fadenoperation associated to conventional surgery in the treatment of esotropia with distance-near incomitance: About 55 cases]. AB - OBJECTIVE: The purpose of this study is to evaluate the short-, medium- and long term efficacy of posterior fixation sutures with conventional surgery in controlling strabismus in the case of esotropia with distance-near incomitance. MATERIALS AND METHODS: This is a retrospective study of consecutive patients with partially accommodative and non-accommodative esotropia associated with distance near incomitance who underwent posterior fixation sutures along with conventional surgery. The preoperative and postoperative distance and near deviation measurements and the distance-near incomitance were evaluated at 1, 6 and 12 years. Surgical success was defined as a postoperative distance angle and a distance-near incomitance less than 10 prism diopters (PD). RESULTS: In total, 55 patients were included. Preoperatively, the mean distance deviation, near deviation and distance-near incomitance were 15.9 (+/- 3.4), 29.7 (+/- 5.8) and 13.8 (+/- 3.1) PD, respectively. Postoperatively, the mean distance deviation was 1.6 (+/- 0.8) PD (P < 0.001) at 1 year, 2.8 (+/- 1.6) PD (P< 0.005) at 6 years and 5.6 (+/- 2.4) PD (P < 0.05) at 12 years. The mean near deviation was 7.8 (+/- 2.3) PD (P < 0.001) at 1 year, 10.5 (+/- 3.7) PD (P < 0.005) at 6 years and 15.2 (+/- 4.4) PD (P < 0.05) at 12 years. The mean distance-near incomitance was 5.2 (+/- 1.8) PD (P < 0.01) at 1 year, 7.7 (+/- 2.8) PD (P < 0.05) at 6 years and 9.6 (+/- 3.2) PD (P > 0.05) at 12 years. The success rate was 91, 78 and 58% at 1, 6 and 12 years, respectively. CONCLUSION: Distance-near incomitance is a source of amblyopia. It needs to be corrected while treating an esotropia. This study seems to confirm the short- and medium-term efficacy of posterior fixation sutures along with conventional surgery in the treatment of this problem. It also seems to show progressive, albeit partial, loss of its long-term efficacy. PMID- 26443383 TI - [Clinical pilot study to evaluate the efficacy of a preservative-free hypertonic ophthalmic solution for patients with symptomatic corneal edema]. AB - This exploratory clinical trial aims to assess the effect on visual acuity and central corneal thickness of an unpreserved hypertonic ophthalmic solution containing sodium chloride (5%) and sodium hyaluronate, in patients with chronic corneal edema caused by endothelial disease reducing their visual acuity. Twenty patients were enrolled and treated with the hypertonic solution (1 to 2 drops per eye, 4 times a day over 28 days). Progression of visual acuity (ETDRS score) and corneal thickness (ultrasonic pachymetry) was measured from baseline (without treatment) through the treatment period (Day 7 and Day 28). The analyses were performed on 18 patients (Full Analysis Set [FAS] population). The causes of corneal edema were Fuchs endothelial dystrophy in 10 cases and post-cataract surgery endothelial decompensation in 8 patients. The mean visual acuity values for the FAS population compared between baseline (Day-7) and one week of treatment (Day+7) show a significant 5-point VA improvement (P<0.001 paired Wilcoxon test). For corneal thickness, there was also a significant decrease (P=0.033 paired Wilcoxon test). Functional improvement was observed at 28 days of instillation. No adverse events were recorded during the clinical study. In conclusion, the unpreserved hyperosmolar solution containing sodium chloride and sodium hyaluronate significantly improved ETDRS visual acuity after one week of use. In this clinical trial, the solution also showed excellent tolerability results. PMID- 26443384 TI - The role of miRNAs in endometrial cancer. AB - miRNAs are small noncoding RNAs that regulate gene expression at the post transcriptional level. Since their discovery, miRNAs have been associated with every cell function including malignant transformation and metastasis. Endometrial cancer is the most common gynecologic malignancy. However, improvement should be made in interobserver agreement on histological typing and individualized therapeutic approaches. This article summarizes the role of miRNAs in endometrial cancer pathogenesis and treatment. PMID- 26443385 TI - Fluctuating asymmetry as a pollution monitor: The Australian estuarine smooth toadfish Tetractenos glaber (Teleostei: Tetraodontidae). AB - The relationship between pollution level in estuarine sediment and fluctuating asymmetry (FA) of resident smooth toadfish Tetractenos glaber was evaluated. A total of 188 fish from Sydney and Hawkesbury River estuaries (5 locations from each) were analysed for 28 bilateral skull bone characters. Sediment pollution was quantified based on analysis of heavy metals (Cd, Cr, Cu, Ni, Pb and Zn) and organochlorine pesticides (DDT, DDD, DDE, chlordane, dieldrin, lindane). Sediment toxicity was characterized using the mean quotient approach (MERMQ) and ranged from low to moderate level for heavy metals and from low to severe for organochlorides. The mean shape and directional asymmetry of fish bones differed among locations, suggesting a response to local environments. FA was positively correlated with organochlorine pesticides across locations, but not with heavy metals. These results suggest that fish FA could be a useful estimator of stress caused by organic toxicity based on the MERMQ approach. PMID- 26443386 TI - Declines in TBT contamination in Irish coastal waters 1987-2011, using the dogwhelk (Nucella lapillus) as a biological indicator. AB - Using the vas deferens sequence index (VDSI) and relative penis size index (RPSI) in dogwhelks (Nucella lapillus), imposex levels were assessed at 63 sites within 11 sea inlets during 2010/2011 and compared these with levels gathered since 1987. Sterile females (VDS>5.0) were found at 14 of the 63 sites and 47 sites (75%) met the EcoQO (VDSI<2.0). The absence of imposex in 'control' areas on the west coast is due to the lack of vessel paint applications or net dips with TBT being used as an active anti-fouling ingredient. A significant decline was observed following 2005 when comparing VDSI levels which is consistent with the decline of TBT usage. Current levels are consistent with an overall improvement towards achieving Good Environmental Status according to the requirements under the Marine Strategy Framework Directive. PMID- 26443387 TI - Impact of deep-water fish farms on benthic macrofauna communities under different hydrodynamic conditions. AB - In this study the environmental impacts of two fish farms located over deep water (180-190 m) were compared. MC-Farm was located at a site with slightly higher water currents (mean current speed 3-5 cms(-1)) than LC-farm (<2 cms(-1)). Macrofauna composition, bioirrigation and benthic fluxes (CO2 and NH4(+)) were quantified at different stages of the production cycle, revealing very different impact of the two farms. Macrofauna abundance and bioirrigation were stimulated compared to a non-impacted reference site at MC-farm, while macrofauna diversity was only moderately reduced. In contrast, macrofauna communities and related parameters were severely impoverished at LC-Farm. This study suggests that deep water fish farms should not be sited in low current areas (<2 cms(-1)), since this will hamper waste dispersal and aggravate environmental impacts. On the other hand, fish farming at slightly more dynamic sites can lead to stimulated benthic macrofauna communities and only moderate environmental impacts. PMID- 26443388 TI - Urinary tract infection-like symptom is associated with worse bladder cancer outcomes in the Medicare population: Implications for sex disparities. AB - OBJECTIVES: To determine the time to bladder cancer diagnosis from initial infection-like symptoms and its impact on cancer outcomes. METHODS: Using Surveillance, Epidemiology and End Results-Medicare, we designed a retrospective cohort study identifying beneficiaries aged >= 66 years diagnosed with bladder cancer from 2007 to 2009. Patients were required to have a hematuria or urinary tract infection claim within 1 year of bladder cancer diagnosis (n = 21 216), and have 2 years of prior Medicare data (n = 18 956) without any precedent hematuria, bladder cancer or urinary tract infection claims (n = 12 195). The number of days to bladder cancer diagnosis was measured, as well as the impact of sex and presenting symptom on time to diagnosis, pathology, and oncological outcomes. RESULTS: The mean time to bladder cancer diagnosis was 72.2 days in women versus 58.9 days in men (P < 0.001). A logistic regression model identified the greatest predictors of >= pT2 pathology were both women (odds ratio 2.08, 95% confidence interval 1.70-2.55) and men (odds ratio 1.71, 95% confidence interval 1.49-1.97) presenting with urinary tract infection. Cox proportional hazards analysis identified an increased risk of mortality from bladder cancer and all causes in women presenting with urinary tract infection (hazard ratio 1.37, 95% confidence interval 1.10-1.71, and hazard ratio 1.47, 95% confidence interval 1.28-1.69) compared with women with hematuria. CONCLUSIONS: Women have a longer interval from urinary tract infection to diagnosis of bladder cancer. Urinary tract infection presentation can adversely affect time to diagnosis, pathology and survival. Time to diagnosis seems not to be an independent predictor of bladder cancer outcomes. PMID- 26443389 TI - Effect of Hyaluronidase Addition to Lidocaine for Trigger Point Injection in Myofascial Pain Syndrome. AB - INTRODUCTION: This randomized, double-blind study compared the efficacy of hyaluronidase co-injection with that of local anesthesia alone on the degree of pain and quality of life in patients with myofascial pain syndrome (MPS). METHODS: Sixty-one adults, aged 25 to 75 years, with MPS affecting both trapezius muscles were randomly assigned to one of the 2 treatment groups: lidocaine (group L: n = 31) or hyaluronidase (group H: n = 30). All patients received Trigger point injection (TPI). Group L received 3.2 mL 0.5% lidocaine alone. Group H received the same solution of lidocaine mixed with hyaluronidase (600 iu/mL). Patients were followed for 14 days (pre- and post-TPI days 0, 1, 4, 7, and 14) with the verbal numerical rating scale (VNRS), and the primary outcome was VNRS on day 7. Also, we evaluated the neck disability index (NDI) and the short form of brief pain inventory (BPI-SF) on pre- and post-TPI day 14. RESULTS: In both groups, VNRS decreased on days 4, 7, and 14 compared to the pre-TPI. However, in group H, VNRS decreased on day 1 also. There were no significant differences of VNRS between the 2 groups during 14 days. NDI and BPI-SF scores also significantly decreased after TPI in both groups. CONCLUSIONS: There were no significant differences between groups in terms of VNRS, NDI, or BPI-SF scores. However, TPI consisting of lidocaine mixed with hyaluronidase worked more effectively than lidocaine alone on post-TPI day 1. Further, hyaluronidase showed a tendency to reduce TPI-related soreness. PMID- 26443390 TI - Application of ion mobility tandem mass spectrometry to compositional and structural analysis of glycopeptides extracted from the urine of a patient diagnosed with Schindler disease. AB - RATIONALE: Schindler disease is caused by the deficient activity of alpha-N acetylgalactosaminidase, which leads to an abnormal accumulation of O glycopeptides in tissues and body fluids. In this work the Schindler condition is for the first time approached by ion mobility (IMS) tandem mass spectrometry (MS/MS), for determining urine glycopeptide fingerprints and discriminate isomeric structures. METHODS: IMS-MS experiments were conducted on a Synapt G2s mass spectrometer operating in negative ion mode. A glycopeptide mixture extracted from the urine of a patient suffering from Schindler disease was dissolved in methanol and infused into the mass spectrometer by electrospray ionization using a syringe-pump system. MS/MS was performed by collision-induced dissociation (CID) at low energies, after mobility separation in the transfer cell. Data acquisition and processing were performed using MassLynx and Waters Driftscope software. RESULTS: IMS-MS data indicated that the attachment of one or two amino acids to the carbohydrate backbone has a minimal influence on the molecule conformation, which limits the discrimination of the free oligosaccharides from the glycosylated amino acids and dipeptides. The structural analysis by CID MS/MS in combination with IMS-MS of species exhibiting the same m/z but different configurations demonstrated for the first time the presence of positional isomers for some of the Schindler disease biomarker candidates. CONCLUSIONS: The IMS-MS and CID MS/MS platform was for the first time optimized and applied to Schindler disease glycourinome. By this approach the separation and characterization of Neu5Ac positional isomers was possible. IMS CID MS/MS showed the ability to determine the type of the glycopeptide isomers from a series of possible candidates. PMID- 26443391 TI - The influence of different referencing methods on the accuracy of delta(13) C value measurement of ethanol fuel by gas chromatography/combustion/isotope ratio mass spectrometry. AB - RATIONALE: Brazil is the largest producer of sugar cane bioethanol in the world. Isotope ratio mass spectrometry (IRMS) is the technique of choice to certify the origin/raw materials for ethanol production, but the lack of certified reference materials (CRMs) for accurate measurements of delta(13) C values traceable to Vienna Pee Dee Belemnite (VPDB), the international zero point for (13) C/(12) C measurements, certified and compatible with gas chromatography (GC)/IRMS instruments may compromise the accuracy of delta(13) C determinations. METHODS: We evaluated the influence of methods for the calibration and normalization of raw delta(13) C values of ethanol samples. Samples were analyzed by GC/C/IRMS using two different GC columns. Different substances were used as isotopic standards for the working gas calibration. The delta(13) C values obtained with the three methods of normalization were statistically compared with those obtained with elemental analyzer (EA)/IRMS, since the delta(13) C results obtained using EA are traceable to VPDB via the NBS 22 reference material. RESULTS: It was observed that both the isotopic reference material for CO2 calibration and the GC column have a major effect on the delta(13) C measurements, leading to a bias of almost 2-3 0/00 in the delta(13) C values. All three methods of normalization were equivalent in performance, enabling an improvement in the GC/C/IRMS accuracy, compared with the EA/IRMS reference values for the samples. CONCLUSIONS: All the methods of CO2 calibration, chromatography and normalization presented in this work demonstrated several sources of traceability and accuracy loss for the determination of delta(13) C values in ethanol fuel samples by GC/C/IRMS. This work has also shown the importance of using proper CRMs traceable to VPBD that should be compatible and certified using GC/C/IRMS, ideally in a wide range of delta(13) C values. This is important not only for bioethanol fuel samples, but also for many analytes commonly analyzed by IRMS. PMID- 26443392 TI - Fast screening of analytes for chemical reactions by reactive low-temperature plasma ionization mass spectrometry. AB - RATIONALE: Approaches for analyte screening have been used to aid in the fine tuning of chemical reactions. Herein, we present a simple and straightforward analyte screening method for chemical reactions via reactive low-temperature plasma ionization mass spectrometry (reactive LTP-MS). METHODS: Solution-phase reagents deposited on sample substrates were desorbed into the vapor phase by action of the LTP and by thermal desorption. Treated with LTP, both reagents reacted through a vapor phase ion/molecule reaction to generate the product. Finally, protonated reagents and products were identified by LTP-MS. RESULTS: Reaction products from imine formation reaction, Eschweiler-Clarke methylation and the Eberlin reaction were detected via reactive LTP-MS. Products from the imine formation reaction with reagents substituted with different functional groups (26 out of 28 trials) were successfully screened in a time of 30 s each. Besides, two short-lived reactive intermediates of Eschweiler-Clarke methylation were also detected. CONCLUSIONS: LTP in this study serves both as an ambient ionization source for analyte identification (including reagents, intermediates and products) and as a means to produce reagent ions to assist gas-phase ion/molecule reactions. The present reactive LTP-MS method enables fast screening for several analytes from several chemical reactions, which possesses good reagent compatibility and the potential to perform high-throughput analyte screening. In addition, with the detection of various reactive intermediates (intermediates I and II of Eschweiler-Clarke methylation), the present method would also contribute to revealing and elucidating reaction mechanisms. PMID- 26443393 TI - Soft Cold EI - approaching molecular ion only with electron ionization. AB - RATIONALE: Cold EI is defined as electron ionization of cold molecules in supersonic molecular beams (SMB). Gas chromatography/mass spectrometry (GC/MS) with Cold EI provides informative mass spectra, which combine the usual library searchable EI fragment ions with enhanced molecular ions for improved library based identification probabilities. However, in some cases, such as in the analysis of complex petrochemical matrices, a soft ionization method that provides only molecular ions is desirable. METHODS: GC/MS with Cold EI was used with a fly-through ion source at selected electron energies, including at low electron energies, in an attempt to observe molecular ions alone. RESULTS: We explored low electron energy Cold EI and found that once the sample compound is cooled by the supersonic expansion it can be reheated via reflected scattered helium atoms near the skimmer. Furthermore, once a labile molecular ion is formed it can undergo undesirable collision-induced dissociation (CID) in the same way as in tandem mass spectrometry (MS/MS), and the magnitude of such CID can be significant for labile molecular ions such as those of hydrocarbons. In order to reduce these adverse effects we reduced the helium pressure at the ion source and MS vacuum chamber by increasing the nozzle-skimmer distance. Cold EI at low electron energies was explored with a squalane isomer (C30 H62 ) and with n-C24 H50 . CONCLUSIONS: It was found that an increased nozzle-skimmer distance resulted in a noticeable increase in the abundance ratio of molecular ions to low mass fragment ions. Consequently, Cold EI at low electron energies and a large nozzle-skimmer distance converts EI into Soft Cold EI while further approaching the ideal of a molecular ion only ionization method. PMID- 26443394 TI - Instrumental improvements and sample preparations that enable reproducible, reliable acquisition of mass spectra from whole bacterial cells. AB - RATIONALE: Rapid sub-species characterization of pathogens is required for timely responses in outbreak situations. Pyrolysis mass spectrometry (PyMS) has the potential to be used for this purpose. METHODS: However, in order to make PyMS practical for traceback applications, certain improvements related to spectrum reproducibility and data acquisition speed were required. The main objectives of this study were to facilitate fast detection (<30 min to analyze 6 samples, including preparation) and sub-species-level bacterial characterization based on pattern recognition of mass spectral fingerprints acquired from whole cells volatilized and ionized at atmospheric pressure. An AccuTOF DART mass spectrometer was re-engineered to permit ionization of low-volatility bacteria by means of Plasma Jet Ionization (PJI), in which an electric discharge, and, by extension, a plasma beam, impinges on sample cells. RESULTS: Instrumental improvements and spectral acquisition methodology are described. Performance of the re-engineered system was assessed using a small challenge set comprised of assorted bacterial isolates differing in identity by varying amounts. In general, the spectral patterns obtained allowed differentiation of all samples tested, including those of the same genus and species but different serotypes. CONCLUSIONS: Fluctuations of +/-15% in bacterial cell concentrations did not substantially compromise replicate spectra reproducibility. PMID- 26443395 TI - Hyphenating size-exclusion chromatography with electrospray mass spectrometry; using on-line liquid-liquid extraction to study the lipid composition of lipoprotein particles. AB - RATIONALE: Lipoproteins belong to the most commonly measured clinical biochemical parameters. Lipidomics is an orthogonal approach and aims to profile the individual lipid molecules that jointly form the lipoprotein particles. However, in the first step of the extraction of lipid molecules from serum, an organic solvent is used leading to dissociation of the lipoproteins. Thus far it has been impossible to combine lipidomics and lipoprotein analysis in one analytical system. METHODS: Human plasma was diluted in phosphate-buffered saline (PBS) and injected onto a Superose 6 PC 3.2 column with PBS as a mobile phase to separate lipoproteins. The eluent was led to a Syrris FLLEX module, which also received CHCl3 /MeOH (3:1). The two phases were mixed and subsequently separated using a Teflon membrane in an especially designed pressurized flow chamber. The organic phase was led to a standard electrospray source of an Orbitrap mass spectrometer. RESULTS: Size-exclusion chromatography (SEC) has been commonly applied to separate lipoproteins and is considered a practical alternative to ultracentrifugation. Through the on-line liquid-liquid extraction method it becomes possible to obtained detailed mass spectra of lipids across different lipoprotein fractions. The extracted ion chromatograms of specific lipid signals showed their distribution against the size of lipoprotein particles. CONCLUSIONS: The application of on-line liquid-liquid extraction allows for the continuous electrospray-based mass spectral analysis of SEC eluent, providing the detailed lipid composition of lipoprotein particles separated by size. This approach provides new possibilities for the study of the biochemistry of lipoproteins. PMID- 26443396 TI - Rapid determination of rivaroxaban in human urine and serum using colloidal palladium surface-assisted laser desorption/ionization mass spectrometry. AB - RATIONALE: Rivaroxaban is a new anticoagulant drug that has recently been introduced for clinical applications. To ensure optimum efficacy while minimizing the risk of toxicity and other adverse effects, a simple and sensitive analytical procedure for monitoring the concentration of rivaroxaban in biological fluids is required. METHODS: Rivaroxaban was extracted from aqueous solutions by dispersive liquid-liquid microextraction (DLLME). Detection of rivaroxaban was achieved through surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS) using colloidal palladium as the SALDI matrix. RESULTS: The calibration curve for rivaroxaban in aqueous solutions was linear over the concentration range from 5 to 500 nM. The limit of detection (LOD) for rivaroxaban at a signal-to-noise ratio of 3 was 2 nM. With a sample-to-extract volume ratio of 200, the enrichment factors were calculated to be 141. This method was successfully applied for the determination of rivaroxaban in human urine and serum samples. The LODs for rivaroxaban in urine and serum were calculated to be 6 nM and 60 nM, respectively. CONCLUSIONS: The analysis speed, together with the ease of operation and high sensitivity, allows SALDI-MS method to be particularly suitable for the high-throughput screening of rivaroxaban levels in human urine and serum samples. PMID- 26443397 TI - Traceability of different apple varieties by multivariate analysis of isotope ratio mass spectrometry data. AB - RATIONALE: The awareness of customers of the origin of foods has become an important issue. The growing demand for foods that are healthy, safe and of high quality has increased the need for traceability and clear labelling. Thus, this study investigates the capability of C and N stable isotope ratios to determine the geographical origin of several apple varieties grown in northern Italy. METHODS: Four apple varieties (Cripps Pink, Gala, Golden Delicious, Granny Smith) have been sampled in orchards located in the Districts of Bolzano, Ferrara, Verona and Udine (northern Italy). Carbon (delta(13) C) and nitrogen (delta(15) N) isotope values of the whole apple fruits and three sub-fractions (peel, pulp and seed) have been determined simultaneously by isotope ratio mass spectrometry. RESULTS: The delta(13) C and delta(15) N values of apples and apple sub fractions, such as peel, seed and pulp, were significantly affected by the geographical origin and the fruit variety. The four varieties could be distinguished to a certain extent only within each district. A 99% correct identification of the samples according to their origin was, however, achieved by cross validation with the 'leave-one-out' method. CONCLUSIONS: This study proves the potential of stable isotopes to discriminate the geographical origin of apples grown in orchards located only a few hundreds of kilometres apart. Stable isotopes were also able to discriminate different apple varieties, although only within small geographical areas. PMID- 26443398 TI - Comparison of methods to determine triple oxygen isotope composition of N2O. AB - RATIONALE: The oxygen isotope anomaly, Delta(17) O, of N2 O and nitrate is useful to elucidate nitrogen oxide dynamics. A comparison of different methods for Delta(17) O measurement was performed. METHODS: For Delta(17) O measurements, N2 O was converted into O2 and N2 using microwave-induced plasma in a quartz or corundum tube reactor, respectively, or conversion was carried out in a gold wire oven. In each case, isotope ratios were measured by isotope ratio mass spectrometry. RESULTS: All the tested methods showed acceptable precision (coefficient of variation <2.4 % at 160 nmol N2 O) with high sample size but the sample size dependence was lowest when using microwave-induced plasma in a corundum tube reactor. CONCLUSIONS: The use of microwave-induced plasma in a corundum tube yields best results for Delta(17) O measurement on N2 O gas samples. PMID- 26443399 TI - Simultaneous analysis of (17) O/(16) O, (18) O/(16) O and (2) H/(1) H of gypsum hydration water by cavity ring-down laser spectroscopy. AB - RATIONALE: The recent development of cavity ring-down laser spectroscopy (CRDS) instruments capable of measuring (17) O-excess in water has created new opportunities for studying the hydrologic cycle. Here we apply this new method to studying the triple oxygen ((17) O/(16) O, (18) O/(16) O) and hydrogen ((2) H/(1) H) isotope ratios of gypsum hydration water (GHW), which can provide information about the conditions under which the mineral formed and subsequent post depositional interaction with other fluids. METHODS: We developed a semi automated procedure for extracting GHW by slowly heating the sample to 400 degrees C in vacuo and cryogenically trapping the evolved water. The isotopic composition (delta(17) O, delta(18) O and delta(2) H values) of the GHW is subsequently measured by CRDS. The extraction apparatus allows the dehydration of five samples and one standard simultaneously, thereby increasing the long-term precision and sample throughput compared with previous methods. The apparatus is also useful for distilling brines prior to isotopic analysis. A direct comparison is made between results of (17) O-excess in GHW obtained by CRDS and fluorination followed by isotope ratio mass spectrometry (IRMS) of O2 . RESULTS: The long-term analytical precision of our method of extraction and isotopic analysis of GHW by CRDS is +/-0.070/00 for delta(17) O values, +/-0.130/00 for delta(18) O values and +/-0.490/00 for delta(2) H values (all +/-1SD), and +/-1.10/00 and +/-8 per meg for the deuterium-excess and (17) O-excess, respectively. Accurate measurement of the (17) O-excess values of GHW, of both synthetic and natural samples, requires the use of a micro-combustion module (MCM). This accessory removes contaminants (VOCs, H2 S, etc.) from the water vapour stream that interfere with the wavelengths used for spectroscopic measurement of water isotopologues. CRDS/MCM and IRMS methods yield similar isotopic results for the analysis of both synthetic and natural gypsum samples within analytical error of the two methods. CONCLUSIONS: We demonstrate that precise and simultaneous isotopic measurements of delta(17) O, delta(18) O and delta(2) H values, and the derived deuterium-excess and (17) O-excess, can be obtained from GHW and brines using a new extraction apparatus and subsequent measurement by CRDS. This method provides new opportunities for the application of water isotope tracers in hydrologic and paleoclimatologic research. PMID- 26443400 TI - Identification of bacteria by fatty acid profiling with direct analysis in real time mass spectrometry. AB - RATIONALE: Bacterial fatty acid profiling is a well-established technique for bacterial identification. Current methods involving esterification and gas chromatography/mass spectrometry (GC/MS) or matrix-assisted laser desorption/ionization (MALDI) analysis are effective, but there are potential benefits to be gained by investigating ambient ionization methods that can provide rapid analysis without derivatization or additional sample handling. METHODS: Lipid extracts from colonies of five Gram-positive and five Gram negative pathogenic bacteria were analyzed by Direct Analysis in Real Time (DART) ionization coupled with a time-of-flight mass spectrometer. Fatty acid profiles were obtained from the negative-ion DART mass spectra without additional derivatization or sample preparation. RESULTS: Fatty acid profiles obtained from the deprotonated molecules [M - H](-) were found to be highly species-specific and reproducible. Leave-one-out cross validation (LOOCV) for principal component analysis (PCA) showed 100% correct classification accuracy. CONCLUSIONS: The results of this preliminary feasibility study show good precision and accuracy, and the fatty acid patterns are clearly distinctive for each of the ten species examined. The speed and ease of analysis and the high classification accuracy for this initial study indicate that DART is an effective method for bacterial fatty acid profiling. PMID- 26443401 TI - Chemical lipid extraction or mathematical isotope correction models: should mathematical models be widely applied to marine species? AB - RATIONALE: Chemical lipid extractions, as means of standardizing sample preparations, have been identified as important for comparability of studies. Unfortunately, these methods are expensive, because of the costly chemicals and the need to analyse two sets of samples, one for delta(13) C values (treated) and another for delta(15) N values (untreated). To avoid this, studies have suggested mathematical solutions to the problem. Our study intends to (i) determine the applicability of the five most common mathematical correction models and (ii) which of the widely applied chemical extraction methods is the most suitable for a variety of marine organisms. METHODS: Muscle, heart and liver samples were collected from eight different species. The tissues were treated with Bligh and Dyer, Folch and Soxhlet extraction methods and analysed in a Europa 20-20 mass spectrometer. Predicted lipid-extracted delta(13) C values were calculated from untreated tissue values using the five most common mathematical models. RESULTS: The results indicated that the mathematical methods could not be accurately applied to any of the eight species used in this study, highlighting current issues with accepted isotope methodologies. The Folch chemical extraction removed the highest amount of lipid, suggesting it is the most suitable delipidation method. CONCLUSIONS: Analysing two samples, one treated one not, remains the best method to obtain accurate delta(13) C isotope values of muscle tissue. By using this approach every study will obtain two datasets, eventually providing a suitable collective dataset for determining how isotopic signatures are affected by delipidation and potentially producing better mathematical correction models in future. PMID- 26443402 TI - Site-specific (13) S/(12) S isotope abundance ratios in dicarboxylic oxyacids as characteristics of their origin. AB - RATIONALE: Recommendations of relevant international organizations controlling the quality of grape wines and beverages specify that only tartaric acids of grape origin can be introduced to achieve the required parameters. The development of methods for determining the origin of tartaric acid in grape wine is of great technological significance. METHODS: Organic dicarboxylic oxyacids were extracted from wines as barium salts. Carbon dioxide, which included all the carbon atoms of the acids, was used to determine the carbon isotope ratios by Isotope Ratio Mass Spectrometry. The alkyl part of the oxyacids was burned at 560 degrees C in the presence of air; BaCO3 containing the carboxyl carbon was left. This carbonate was used to measure the carbon isotope ratios in the carboxyl part of the acid. The carbon isotope ratios of the alkyl part of tartaric acid were found by isotope mass balance. RESULTS: The carbon isotope composition of carboxyl groups (delta(13) S values) in tartaric acid of grape (biogenic origin) had a higher (13) S content than the carbon in the alkyl part of the molecule. Tartaric acid produced by chemical synthesis (abiogenic origin) was noted to have a different (13) S/(12) S distribution: the carboxyl group of tartaric acid produced by chemical synthesis contained a smaller than or equal amount of (13) S to the alkyl part. CONCLUSIONS: This is the first determination of the site specific distribution of the (13) S/(12) S isotopes in tartaric acids as evidence of their biogenic and abiogenic origins. The presented method for determining the origin of tartaric acid can be used for efficient control of the quality of grape wines and beverages. PMID- 26443403 TI - Study of the non-covalent interactions of ginsenosides and lysozyme using electrospray ionization mass spectrometry. AB - RATIONALE: Ginsenosides are an important class of natural products extracted from ginseng that possess various important biological activities. Studies of interactions of ginsenosides with proteins are essential for comprehensive understanding of the biological activities of ginsenosides. In this study, the interactions of ginsenosides with lysozyme were investigated by electrospray ionization mass spectrometry (ESI-MS). METHODS: Both protopanaxadiol-type and protopanaxatriol-type ginsenosides were chosen to explore the interactions of ginsenosides towards lysozyme near the physiological conditions by direct ESI-MS, respectively. Comparative experiments were conducted to confirm the interactions were specific. In addition, the dissociation constants of ginsenoside-lysozyme complexes were determined by a ESI-MS titration strategy. RESULTS: The results showed ginsenosides bound to lysozyme at the stoichiometries of 1:1 and 2:1. The association constants of ginsenosides to lysozyme were in the order of Re>Rd>Rf>Rg2 >Rg3 . According to their structures, the binding affinities associated with the type of aglycone and the type and the number of sugar moieties linked on the aglycone. CONCLUSIONS: It has been demonstrated that ESI MS is a powerful tool to probe the non-covalent interactions between lysozyme and ginsenosides. These results provide insights into the interaction of ginsenosides with lysozyme at the molecular level. The developed strategy could be applied to determine the interactions of proteins with other natural products. PMID- 26443404 TI - Oxygen isotope studies of phosphite oxidation: purification and analysis of reactants and products by high-temperature conversion elemental analyzer/isotope ratio mass spectrometry. AB - RATIONALE: Increased attention has been recently focused on the origin and reactions of reduced-P oxyanions such as phosphite [PO3 (III)] in terrestrial and biological systems. We present new methods for studying O-isotopic reactions between PO3 (III) and other oxygen sources during oxidation of PO3 (III) to PO4 (V). METHODS: Na2 (HPO3 ).5H2 O, used as a PO3 (III) source, contains structural water due to its hygroscopic nature; thus, we developed a method for determining the delta(18) O value of PO3 (III) after the removal of structural water. Next, we tested two techniques for purifying PO4 (V) from aqueous PO3 (III)/PO4 (V) mixtures: (1) precipitation of PO4 (V) as ammonium phosphomolybdate (APM); and (2) precipitation of PO4 (V) as magnesium ammonium phosphate (MAP). The O-isotope compositions, (18) O:(16) O (delta(18) O values), of Na2 (HPO3 ) and Ag3 PO4 were analyzed by TC/EA/IRMS. RESULTS: Structural water was removed from Na2 (HPO3 ).5H2 O after drying at 100 degrees C under vacuum and the delta(18) O value of PO3 (III) was obtained. The delta(18) O values of PO4 (V), which was extracted from (18) O-labeled PO3 (III)/PO4 (V) mixtures by APM and MAP precipitations, were not altered by the precipitation process. This result confirms that PO3 (III) is not converted into PO4 (V) by oxidation or hydrolysis under either strong acidic/oxidizing (APM) or alkaline (MAP) conditions for up to a 24-h period. CONCLUSIONS: We conclude that both APM and MAP precipitation are reliable and effective methods for the separation and purification of PO4 (V) from aqueous PO3 (III)/PO4 (V) mixtures. The methods described here will permit the study of the isotopic evolution of various pathways of geochemical as well as biological PO3 (III) oxidation. PMID- 26443405 TI - Comparative metabolism of four limonoids in human liver microsomes using ultra high-performance liquid chromatography coupled with high-resolution LTQ-Orbitrap mass spectrometry. AB - RATIONALE: Limonoids, characterized by a triterpenoid skeleton with a furan ring, are unique secondary metabolites widely distributed in the families of Rutaceae, particularly in Citrus species and Meliaceae. Studies on health benefits have demonstrated that limonoids have a range of biological activities. Dietary intake of citrus limonoids may provide a protective effect against the onset of various cancers and other xenobiotic related diseases. However, few studies about the metabolic profiles of limonoids have been carried out. METHODS: The objectives of this study were to investigate the metabolic profiles of four limonoids (limonin, obacunone, nominin and gedunin) in human liver microsomes (HLMs) using ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC/HRMS) and to identify the cytochrome P450 (CYP) enzymes involved in the formation of their metabolites by recombinant human CYP enzymes. RESULTS: Based on the accurate HR-MS/MS spectra and the proposed MS/MS fragmentation pathways, four metabolites of limonin (M1-1, M1-2, M1-3 and M1-4), eight metabolites ofobacunone (M2-1, M2-2, M2-3, M2-4, M2-5, M2-6, M2-7 and M2-8), six metabolites of nominin (M3-1, M3-2, M3-3, M3-4, M3-5 and M3-6) and three metabolites of gedunin (M4-1, M4-2 and M4-3) in HLMs were tentatively identified and the involved CYPs were investigated. CONCLUSIONS: The results demonstrated that reduction at C-7 and C-16, hydroxylation and reaction of glycine with reduction limonoids were the major metabolic pathways of limonoids in HLMs. Among them, glycination with reduction was the unique metabolic process of limonoids observed for the first time. CYP2D6 and CYP3A4 played an important role in the isomerization and glycination of limonoids in HLMs, whereas other CYP isoforms were considerably less active. The results might help to understand the metabolic process of limonoids in vitro such as the unidentified metabolites of limonin glucoside observed in the medium of microbes and the biotransformation of limonin in juices. Moreover, it would be beneficial for us to further study the pharmacokinetic behavior of limonoids in vivo systematically. PMID- 26443406 TI - Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to detect monoclonal immunoglobulin light chains in serum and urine. AB - RATIONALE: Use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) to monitor serum and urine samples for endogenous monoclonal immunoglobulins. MALDI-TOFMS is faster, fully automatable, and provides superior specificity compared to protein gel electrophoresis (PEL). METHODS: Samples were enriched for immunoglobulins in 5 min using Melon GelTM followed by reduction with dithiothreitol for 15 min to separate immunoglobulin light chains and heavy chains. Samples were then desalted using C4 ZipTips, mixed with sinapinic acid matrix, and analyzed on a Bruker Biflex III MALDI-TOF mass spectrometer. RESULTS: Monoclonal immunoglobulin light chains were identified in serum and urine samples from patients with a known monoclonal gammopathy using MALDI-TOFMS with minimal sample preparation. CONCLUSIONS: MALDI-TOFMS can identify a monoclonal immunoglobulin in serum and urine samples. The molecular mass of the monoclonal immunoglobulin light chain is obtained providing unprecedented specificity compared to PEL. In addition, the methodology can be automated, making it a practical alternative to PEL. PMID- 26443407 TI - Skin secretion peptides: the molecular facet of the deimatic behavior of the four eyed frog, Physalaemus nattereri (Anura, Leptodactylidae). AB - RATIONALE: Amphibians can produce a large amount of bioactive peptides over the skin. In order to map the precise tissue localization of these compounds and evaluate their functions, mass spectrometry imaging (MSI) and gene expression studies were used to investigate a possible correlation between molecules involved in the antimicrobial defense mechanisms and anti-predatory behavior by Physalaemus nattereri. METHODS: Total skin secretion of P. nattereri was analyzed by classical Protein Chemistry and proteomic techniques. Intact inguinal macroglands were dissected from the rest of the skin and both tissues were analyzed by MSI and real-time polymerase chain reaction (RT-PCR) experiments. Peptides were primarily identified by de novo sequencing, automatic Edman degradation and cDNA data. RESULTS: Fifteen bradykinin (BK)-related peptides and two antimicrobial peptides were sequenced and mapped by MSI on the inguinal macrogland and the rest of P. nattereri skin. RT-PCR results revealed that BK related peptide levels of expression were about 30,000 times higher on the inguinal macroglands than on the any other region of the skin, whilst antimicrobial peptide ions appear to be evenly distributed in both investigated regions. CONCLUSIONS: The presence of antimicrobial peptides in all investigated tissue regions is in accordance with the defensive role against microorganisms thoroughly demonstrated in the literature, whereas BK-related molecules are largely found on the inguinal macroglands suggesting an intriguing link between their noxious activities against potential predators of P. nattereri and the frog's deimatic behavior. PMID- 26443408 TI - Fish tissue lipid-C:N relationships for correcting delta(13) C values and estimating lipid content in aquatic food-web studies. AB - RATIONALE: Normalizing delta(13) C values of animal tissue for lipid content is necessary to accurately interpret food-web relationships from stable isotope analysis. To reduce the effort and expense associated with chemical extraction of lipids, various studies have tested arithmetic mass balance to mathematically normalize delta(13) C values for lipid content; however, the approach assumes that lipid content is related to the tissue C:N ratio. METHODS: We evaluated two commonly used models for estimating tissue lipid content based on C:N ratio (a mass balance model and a stoichiometric model) by comparing model predictions to measure the lipid content of white muscle tissue. We then determined the effect of lipid model choice on delta(13) C values normalized using arithmetic mass balance. To do so, we used a collection of fish from Lake Superior spanning a wide range in lipid content (5% to 73% lipid). RESULTS: We found that the lipid content was positively related to the bulk muscle tissue C:N ratio. The two different lipid models produced similar estimates of lipid content based on tissue C:N, within 6% for tissue C:N values <7. Normalizing delta(13) C values using an arithmetic mass-balance equation based on either model yielded similar results, with a small bias (<10/00) compared with results based on chemical extraction. CONCLUSIONS: Among-species consistency in the relationship between fish muscle tissue C:N ratio and lipid content supports the application of arithmetic mass balance to normalize delta(13) C values for lipid content. The uncertainty associated with both lipid extraction quality and choice of model parameters constrains the achievable precision of normalized delta(13) C values to about +/-1.00/00. PMID- 26443409 TI - A new isotopic reference material for stable hydrogen and oxygen isotope-ratio measurements of water - USGS50 Lake Kyoga Water. AB - RATIONALE: As a result of the need for isotopic reference waters having high delta(2) HVSMOW-SLAP and delta(18) OVSMOW-SLAP values for daily use, especially for tropical and equatorial-zone freshwaters, a new secondary isotopic reference material for international distribution was prepared from water collected from Lake Kyoga, Uganda. METHODS: This isotopic reference lakewater was filtered through a membrane with 0.2-um pore size, homogenized, loaded into glass ampoules that were sealed with a torch and autoclaved to eliminate biological activity, and measured by dual-inlet isotope-ratio mass spectrometry. This reference material is available in a case of 144 glass ampoules each containing 5 mL of water. RESULTS: The delta(2) H and delta(18) O values of this reference material are +32.8 +/- 0.4 and +4.95 +/- 0.02 mUr (milliurey = 0.001 = 1 0/00), respectively, relative to VSMOW, on scales normalized such that the delta(2) H and delta(18) O values of SLAP reference water are, respectively, -428 and -55.5 mUr. Each uncertainty is an estimated expanded uncertainty (U = 2uc ) about the reference value that provides an interval that has about a 95 % probability of encompassing the true value. CONCLUSIONS: This isotopic reference material, designated as USGS50, is intended as one of two reference waters for daily normalization of stable hydrogen and oxygen isotopic analysis of water with an isotope-ratio mass spectrometer or a laser absorption spectrometer, of use especially for isotope-hydrology laboratories analyzing freshwater samples from equatorial and tropical regions. PMID- 26443411 TI - Formation of amino acids from NH3 /NO2, CO2 and H2O: implications for the prebiotic origin of biomolecules. AB - RATIONALE: The search for the conditions which must have prevailed in the long distant past during the conversion of inanimate matter into animate matter is a fascinating area of research and it continues to draw the attention of the scientific community. The initiation of life on this planet must have been preceded by the development of biomolecules, amongst which amino acids have unique importance. Formation of amino acids under a certain set of conditions is shown in the present experiments. METHODS: Solutions of ammonium carboxylates or the mixture of two such salts were prepared in 3:6.9:0.1 (v/v/v) acetonitrile/water/formic acid at a concentration of 50 MUM. The studies were performed using a quadrupole time-of-flight (QqTOF) mass spectrometer. The formation of different amino acids was detected with high-resolution mass spectrometry. RESULTS: Here, we show the formation of amino acids when a solution of ammonium salts was injected into an electrospray ionization (ESI)-QqTOF-MS instrument. The ammonium salts were the source of NH3 and CO2 and H2 O was available in the medium. It seems that the combination of NH3 , CO2 , and H2 O leads to the formation of amino acids. CONCLUSIONS: Further to the literature reports of formation of amino acids under the reduced atmosphere represented by gases such as NH3 , CH4 , H2 and H2 O, here we demonstrate the formation of amino acids by the combination of NH3 /NO2 , CO2 and water vapours in the ESI source of the mass spectrometer. PMID- 26443410 TI - Software-aided structural elucidation in drug discovery. AB - RATIONALE: Structural information on metabolites obtained in relevant biological systems can have considerable impact on the design of new drug candidates. However, with demanding turnaround times, the amount of available structural information may become rate limiting. METHODS: The workflow for metabolite identification used in our laboratory was compared to a workflow using a software tool built for computer-assisted metabolite identification. The present study covered the in vitro metabolism of a diverse set of 65 in-house compounds. The compounds were profiled across three liver-based systems, 17 compounds were tested in human liver microsomes (HLM), 12 in rat hepatocytes (RHEP), and 36 in human hepatocytes (HHEP). RESULTS: For 92% of the metabolites reported, the exact match or Markush representations were in agreement between the two workflows. The major specific biotransformations in hepatocytes which formed the metabolites were aromatic or aliphatic hydroxylations (33%), N-dealkylations (15%) and glucuronidations (12%). CONCLUSIONS: The software was shown to perform well for structural elucidation of metabolites from both phase I and phase II metabolism where the focus was on quickly understanding the rate-limiting metabolic step(s). PMID- 26443412 TI - Mechanistic study on lowering the sensitivity of positive atmospheric pressure photoionization mass spectrometric analyses: size-dependent reactivity of solvent clusters. AB - RATIONALE: Understanding the mechanism of atmospheric pressure photoionization (APPI) is important for studies employing APPI liquid chromatography/mass spectrometry (LC/MS). In this study, the APPI mechanism for polyaromatic hydrocarbon (PAH) compounds dissolved in toluene and methanol or water mixture was investigated by use of MS analysis and quantum mechanical simulation. In particular, four different mechanisms that could contribute to the signal reduction were considered based on a combination of MS data and quantum mechanical calculations. METHODS: The APPI mechanism is clarified by combining MS data and density functional theory (DFT) calculations. To obtain MS data, a positive-mode (+) APPI Q Exactive Orbitrap mass spectrometer was used to analyze each solution. DFT calculations were performed using the general atomic and molecular electronic structure system (GAMESS). RESULTS: The experimental results indicated that methanol significantly reduced the signal in (+) APPI, but no significative signal reduction was observed when water was used as a co-solvent with toluene. The signal reduction is more significant especially for molecular ions than for protonated ions. Therefore, important information about the mechanism of methanol-induced signal reduction in (+) APPI-MS can be gained due its negative impact on APPI efficiency. CONCLUSIONS: The size-dependent reactivity of methanol clusters ((CH3 OH)n , n = 1-8) is an important factor in determining the sensitivity of (+) APPI-MS analyses. Clusters can compete with toluene radical ions for electrons. The reactivity increases as the sizes of the methanol clusters increase and this effect can be caused by the size-dependent ionization energy of the solvent clusters. The resulting increase in cluster reactivity explains the flow rate and temperature-dependent signal reduction observed in the analytes. Based on the results presented here, minimizing the sizes of methanol clusters can improve the sensitivity of LC/(+)-APPI-MS. PMID- 26443413 TI - Effects of different water storage procedures on the dissolved Fe concentration and isotopic composition of chemically contrasted waters from the Amazon River Basin. AB - RATIONALE: Although recent studies have investigated the Fe isotopic composition of dissolved, colloidal and particulate phases from continental and oceanic natural waters, few efforts have been made to evaluate whether water sample storage and the separation of different pore-size fractions through filtration can cause any change to the Fe isotopic compositions. The present study investigates the possible biases introduced by different water storage conditions on the dissolved Fe concentration and isotopic composition of chemically different waters. METHODS: Water samples were collected from an organic-rich river and from mineral particulate-rich rivers. Filtered and unfiltered water samples were stored either at room temperature or frozen at -18 degrees C in order to assess possible biases due to (i) different water storage temperature, and (ii) storage of bulk (unfiltered) vs filtered water. Iron isotope measurements were performed by Multicollector Inductively Coupled Plasma Mass Spectrometry with a Thermo Electron Neptune instrument, after Fe purification using anion-exchange resins. RESULTS: Our data reveal that bulk water storage at room temperature without filtration produces minor changes in the dissolved Fe isotopic composition of mineral particulate-rich waters, but significant isotopic composition changes in organic-rich waters. In both cases, however, the impact of the different procedures on the Fe concentrations was strong. On the other hand, the bulk water stored frozen without filtration produced more limited changes in the dissolved Fe concentrations, and also on isotopic compositions, relative to the samples filtered in the field. The largest effect was again observed for the organic-rich waters. CONCLUSIONS: These findings suggest that a time lag between water collection and filtration may cause isotopic exchanges between the dissolved and particulate Fe fractions. When it is not possible to filter the samples in the field immediately after collection, the less detrimental approach is to freeze the bulk water sample until filtration, to reduce isotopic artifacts. PMID- 26443414 TI - Long-term storability of water samples in vials used with laser absorption isotope analyzers. PMID- 26443415 TI - A Novel In Vitro Technique for Assessing Dental Implant Osseointegration. AB - By definition, osseointegration means close contact between bone and implant. Bone response is related to implant surface properties. Various surfaces have been studied and applied to improve the biological properties of the implant and thereby favor the mechanism of osseointegration. This strategy aims to promote osseointegration by means of a faster and stronger bone formation, improving stability during the healing process, and thus allowing for earlier loading of the implant. Dental implant osseointegration has so far been studied in various animal models. The development of a method based on tissue engineering for assessing the osseointegration process in vitro could prove a valid biomimetic alternative to sacrificing animals. In this study, flat cylindrical dental implants with moderately rough surfaces and machined implants were set in bovine bone blocks. Then, adipose-derived stem cells (ADSCs) were three dimensionally cultured onto these blocks in osteo-endothelial medium for up to 30 days to mimic the osseointegration process in vitro. Scanning electron microscopy (SEM) and gene expression were used to examine stem cell commitment. Mechanical pull-out tests were also performed. SEM analysis identified cells with an osteoblast morphology adhering to the surface of the implants after their removal. Gene expression analysis showed that ADSCs seeded onto the bone blocks were able to express osteoblast and endothelial markers. The implants with the moderately rough surface generated higher pull-out strengths when compared with the machined implants. Nevertheless, the pull-out test values were higher for implants placed in bone blocks with ADSCs than for those set in scaffolds without stem cells. Our results demonstrate the validity of the method adopted and its potential for use in the in vitro assessment of the biological behavior of dental implant surfaces. PMID- 26443416 TI - RNA approaches the B-form in stacked single strand dinucleotide contexts. AB - Duplex RNA adopts an A-form structure, while duplex DNA interconverts between the A- and B-forms depending on the environment. The C2'-endo sugar pucker seen in B form DNA can occur infrequently in ribose sugars as well, but RNA is not understood to assume B-form conformations. Through analysis of over 45,000 stacked single strand dinucleotide (SSD) crystal structure conformations, this study demonstrates that RNA is capable of adopting a wide conformational range between the canonical A- and B-forms at the localized SSD level, including many B form-like conformations. It does so through C2'-endo ribose conformations in one or both nucleotides, and B-form-like neighboring base stacking patterns. As chemical reactions on nucleic acids involve localized changes in chemical bonds, the understanding of how enzymes distinguish between DNA and RNA nucleotides is altered by the energetic accessibility of these rare B-form-like RNA SSD conformations. The existence of these conformations also has direct implications in parametrization of molecular mechanics energy functions used extensively to model nucleic acid behavior., 2016. (c) 2015 Wiley Periodicals, Inc. Biopolymers 105: 65-82, 2016. PMID- 26443417 TI - Childhood wheezing, asthma, allergy, atopy, and lung function: different socioeconomic patterns for different phenotypes. AB - Identifying preventable exposures that lead to asthma and associated allergies has proved challenging, partly because of the difficulty in differentiating phenotypes that define homogeneous disease groups. Understanding the socioeconomic patterns of disease phenotypes can help distinguish which exposures are preventable. In the present study, we identified disease phenotypes that are susceptible to socioeconomic variation, and we determined which life-course exposures were associated with these inequalities in a contemporary birth cohort. Participants included children from the Avon Longitudinal Study of Parents and Children, a population-based birth cohort in England, who were born in 1991 and 1992 and attended the clinic at 7-8 years of age (n = 6,378). Disease phenotypes included asthma, atopy, wheezing, altered lung function, and bronchial reactivity phenotypes. Combining atopy with a diagnosis of asthma from a doctor captured the greatest socioeconomic variation, including opposing patterns between phenotype groups: Children with a low socioeconomic position (SEP) had more asthma alone (adjusted multinomial odds ratio = 1.50, 95% confidence interval: 1.21, 1.87) but less atopy alone (adjusted multinomial odds ratio = 0.80, 95% confidence interval: 0.66, 0.98) than did children with high SEP. Adjustment for maternal exposure to tobacco smoke during pregnancy and childhood exposure to tobacco smoke reduced the odds of asthma alone in children with a low SEP. Current inequalities among children who have asthma but not atopy can be prevented by eliminating exposure to tobacco smoke. Other disease phenotypes were not socially patterned or had SEP patterns that were not related to smoke exposure. PMID- 26443418 TI - Childhood body weight in relation to morbidity from cardiovascular disease and cancer in older adulthood: 67-year follow-up of participants in the 1947 Scottish Mental Survey. AB - Although it has been well documented that elevated body weight in middle- and older-aged populations is associated with multiple morbidities, the influence of childhood body weight on health endpoints other than coronary heart disease is not well understood. Accordingly, using a subsample of 4,620 participants (2,288 women) from the Scottish Mental Survey of 1947, we examined the association between body mass index measured at 11 years of age and future risk of 9 independent health endpoints as ascertained from national hospital admissions and cancer registers until 2014 (up to age 77 years). Although there was some evidence of a relationship between elevated childhood body mass index and higher rates of peripheral vascular disease (per each 1-standard deviation increase in body mass index, hazard ratio = 1.21, 95% confidence interval: 1.07, 1.37) and smoking-related cancers (per each 1-standard deviation increase in body mass index, hazard ratio = 1.09, 95% confidence interval: 1.01, 1.17), there was no apparent association with coronary heart disease, stroke (including ischemic stroke), heart failure, or carcinomas of the colorectum, stomach, lung, prostate, or breast. In conclusion, a relationship between childhood body weight and later morbidity was largely lacking in the present study. PMID- 26443419 TI - From Smallpox to Big Data: The Next 100 Years of Epidemiologic Methods. AB - For more than a century, epidemiology has seen major shifts in both focus and methodology. Taking into consideration the explosion of "big data," the advent of more sophisticated data collection and analytical tools, and the increased interest in evidence-based solutions, we present a framework that summarizes 3 fundamental domains of epidemiologic methods that are relevant for the understanding of both historical contributions and future directions in public health. First, the manner in which populations and their follow-up are defined is expanding, with greater interest in online populations whose definition does not fit the usual classification by person, place, and time. Second, traditional data collection methods, such as population-based surveillance and individual interviews, have been supplemented with advances in measurement. From biomarkers to mobile health, innovations in the measurement of exposures and diseases enable refined accuracy of data collection. Lastly, the comparison of populations is at the heart of epidemiologic methodology. Risk factor epidemiology, prediction methods, and causal inference strategies are areas in which the field is continuing to make significant contributions to public health. The framework presented herein articulates the multifaceted ways in which epidemiologic methods make such contributions and can continue to do so as we embark upon the next 100 years. PMID- 26443420 TI - Optimal use of available claims to identify a Medicare population free of coronary heart disease. AB - We examined claims-based approaches for identifying a study population free of coronary heart disease (CHD) using data from 8,937 US blacks and whites enrolled during 2003-2007 in a prospective cohort study linked to Medicare claims. Our goal was to minimize the percentage of persons at study entry with self-reported CHD (previous myocardial infarction or coronary revascularization). We assembled 6 cohorts without CHD claims by requiring 6 months, 1 year, or 2 years of continuous Medicare fee-for-service insurance coverage prior to study entry and using either a fixed-window or all-available look-back period. We examined adding CHD-related claims to our "base algorithm," which included claims for myocardial infarction and coronary revascularization. Using a 6-month fixed-window look-back period, 17.8% of participants without claims in the base algorithm reported having CHD. This was reduced to 3.6% using an all-available look-back period and adding other CHD claims to the base algorithm. Among cohorts using all-available look-back periods, increasing the length of continuous coverage from 6 months to 1 or 2 years reduced the sample size available without lowering the percentage of persons with self-reported CHD. This analysis demonstrates approaches for developing a CHD-free cohort using Medicare claims. PMID- 26443422 TI - Terahertz meets sculptural and architectural art: Evaluation and conservation of stone objects with T-ray technology. AB - Conservation of cultural heritage is an area where novel scientific techniques are having enormous impact. Given the value and uniqueness of art pieces, non invasive diagnostic methods are highly appreciated by conservators. Terahertz radiation has shown enormous potential as non-contact probe that can be used for the three-dimensional reconstruction of internal structure of stone-made objects. In this article we report the evaluation of the internal damage state of two art pieces, a medallion from the Castle of Celle and a window sill from the St. Peter of Trier Cathedral. We also used terahertz radiation to follow and assess the restoration process of the window sill. We found that terahertz spectroscopy is an excellent non-destructive evaluation method for stone artwork that shows enormous potential as a tool for conservation. PMID- 26443421 TI - Risk of thyroid follicular adenoma among children and adolescents in Belarus exposed to iodine-131 after the Chornobyl accident. AB - Several studies reported an increased risk of thyroid cancer in children and adolescents exposed to radioactive iodines, chiefly iodine-131 ((131)I), after the 1986 Chornobyl (Ukrainian spelling) nuclear power plant accident. The risk of benign thyroid tumors following such radiation exposure is much less well known. We have previously reported a novel finding of significantly increased risk of thyroid follicular adenoma in a screening study of children and adolescents exposed to the Chornobyl fallout in Ukraine. To verify this finding, we analyzed baseline screening data from a cohort of 11,613 individuals aged <=18 years at the time of the accident in Belarus (mean age at screening = 21 years). All participants had individual (131)I doses estimated from thyroid radioactivity measurements and were screened according to a standardized protocol. We found a significant linear dose response for 38 pathologically confirmed follicular adenoma cases. The excess odds ratio per gray of 2.22 (95% confidence interval: 0.41, 13.1) was similar in males and females but decreased significantly with increasing age at exposure (P < 0.01), with the highest radiation risks estimated for those exposed at <2 years of age. Follicular adenoma radiation risks were not significantly modified by most indicators of past and current iodine deficiency. The present study confirms the (131)I-associated increases in risk of follicular adenoma in the Ukrainian population and adds new evidence on the risk increasing with decreasing age at exposure. PMID- 26443423 TI - Insights into Mechanistic Models for Evaporation of Organic Liquids in the Environment Obtained by Position-Specific Carbon Isotope Analysis. AB - Position-specific isotope effects (PSIEs) have been measured by isotope ratio monitoring (13)C nuclear magnetic resonance spectrometry during the evaporation of 10 liquids of different polarities under 4 evaporation modes (passive evaporation, air-vented evaporation, low pressure evaporation, distillation). The observed effects are used to assess the validity of the Craig-Gordon isotope model for organic liquids. For seven liquids the overall isotope effect (IE) includes a vapor-liquid contribution that is strongly position-specific in polar compounds but less so in apolar compounds and a diffusive IE that is not position specific, except in the alcohols, ethanol and propan-1-ol. The diffusive IE is diminished under forced evaporation. The position-specific isotope pattern created by liquid-vapor IEs is manifest in five liquids, which have an air-side limitation for volatilization. For the alcohols, undefined processes in the liquid phase create additional PSIEs. Three other liquids with limitations on the liquid side have a lower, highly position-specific, bulk diffusive IE. It is concluded that evaporation of organic pollutants creates unique position-specific isotope patterns that may be used to assess the progress of remediation or natural attenuation of pollution and that the Craig-Gordon isotope model is valid for the volatilization of nonpolar organic liquids with air-side limitation of the volatilization rate. PMID- 26443424 TI - Contingent non-invasive prenatal testing: an opportunity to improve non-genetic aspects of fetal aneuploidy screening. AB - BACKGROUND: Several countries today struggle with suboptimal performances in many aspects of the fetal aneuploidy screening process and consider introducing non invasive prenatal screening (NIPT) as a solution. In this study, costs and benefits of different scenarios for contingent NIPT screening in Belgium are evaluated with respect to partial redistribution of the national screening budget into quality improving measures for those screening activities that will be maintained when full NIPT screening is implemented. METHODS: Data from the Belgian National Institute for Health and Disability Insurance and the Study Centre for Perinatal Epidemiology were used in modeled calculations of medical and economic impact of NIPT after prior conventional screening (1) at thresholds 1:300 and 1:600, and (2) at current and improved screening sensitivity. RESULTS: Contingent NIPT screening under current screening conditions would maintain today's 7.9(0)/000 live birth prevalence of Down syndrome (LBPD) at an 11% reduction of overall short-term costs. Lowering the screening threshold to 1:600 or increasing sensitivity by 10% would reduce LBPD to 7(0)/000 at a maximum 3% increase of overall short-term costs. CONCLUSION: Today, in Belgium and in many other countries, full NIPT screening is considered too expensive for immediate introduction into the national fetal aneuploidy screening program. Contingent NIPT screening is both clinically and economically beneficial. A temporary contingent NIPT protocol allows for reinvesting economic savings into optimization of those screening aspects, which are to be maintained in parallel to full NIPT screening. PMID- 26443425 TI - Is left ventricular diastolic function impaired in patients with ankylosing spondylitis? PMID- 26443426 TI - Household physical activity and cancer risk: a systematic review and dose response meta-analysis of epidemiological studies. AB - Controversial results of the association between household physical activity and cancer risk were reported among previous epidemiological studies. We conducted a meta-analysis to investigate the relationship of household physical activity and cancer risk quantitatively, especially in dose-response manner. PubMed, Embase, Web of science and the Cochrane Library were searched for cohort or case-control studies that examined the association between household physical activity and cancer risks. Random-effect models were conducted to estimate the summary relative risks (RRs), nonlinear or linear dose-response meta-analyses were performed to estimate the trend from the correlated log RR estimates across levels of household physical activity quantitatively. Totally, 30 studies including 41 comparisons met the inclusion criteria. Total cancer risks were reduced 16% among the people with highest household physical activity compared to those with lowest household physical activity (RR = 0.84, 95% CI = 0.76-0.93). The dose-response analyses indicated an inverse linear association between household physical activity and cancer risk. The relative risk was 0.98 (95% CI = 0.97-1.00) for per additional 10 MET-hours/week and it was 0.99 (95% CI = 0.98 0.99) for per 1 hour/week increase. These findings provide quantitative data supporting household physical activity is associated with decreased cancer risk in dose-response effect. PMID- 26443427 TI - Direct electron transfer from photosystem II to hematite in a hybrid photoelectrochemical cell. AB - A hybrid photoanode integrating the cyanobacterial photosystem II (PSII) with a hematite film for water oxidation is constructed. Direct electron transfer from PSII to the excited Ti/Fe2O3 electrode occurs under light irradiation, resulting in a significant improvement of the photocurrent. PMID- 26443428 TI - Reply from Authors re: Julia Verne, Luke Hounsome, Roger Kockelbergh, Jem Rashbass. Improving Outcomes from Prostate Cancer: Unlocking the Treasure Trove of Information in Cancer Registries. Eur Urol 2016;69:1013-4. PMID- 26443429 TI - Urology Tag Ontology Project: Standardizing Social Media Communication Descriptors. AB - Standardizing social media hashtag descriptors is likely to facilitate communication and promote collaboration in both health care provider and patient communities. PMID- 26443430 TI - Reply from Authors re: Ronald C. Chen. Decisions Regarding Whether to Use Androgen Deprivation Therapy with Radiotherapy in Prostate Cancer: Is Cardiovascular Mortality the Most Relevant Outcome? Eur Urol 2016;69:211-2: Outcomes for Favorable and Unfavorable Intermediate Risk Prostate Cancer Patients Receiving Radiation Therapy With or Without Short-term Androgen Deprivation Therapy. PMID- 26443431 TI - Detailed Quantification of High-grade Cancer Allows Precise Prediction of Prostate Cancer Prognosis. PMID- 26443432 TI - Racial Variations in Prostate Cancer Molecular Subtypes and Androgen Receptor Signaling Reflect Anatomic Tumor Location. AB - Prostate cancer (PCa) subtypes based on ETS gene expression have been described. Recent studies suggest there are racial differences in tumor location, with PCa located anteriorly more often among African-American (AA) compared to Caucasian American (CA) men. In this retrospective analysis of a multi-institutional cohort treated by radical prostatectomy (179 CA, 121 AA), we evaluated associations among molecular subtype, race, anatomic tumor location, and androgen receptor (AR) signaling. Subtype (m-ERG(+), m-ETS(+), m-SPINK1(+), or triple-negative) was determined using distribution-based outlier analysis. AR signaling was investigated using gene expression profiling of canonical AR targets. m-ERG(+) was more common in CA than AA men (47% vs 22%, p<0.001). AA men were more likely to be m-SPINK1(+) (13% vs 7%; p=0.069) and triple-negative (50% vs 37%; p=0.043). Racial differences in molecular subtypes did not persist when tumors were analyzed by location, suggesting a biologically important relationship between tumor location and subtype. Accordingly, anterior tumor location was associated with higher Decipher scores and lower global AR signaling. PATIENT SUMMARY: This study demonstrates associations among patient race, prostate cancer molecular subtypes, and tumor location. Location-specific differences in androgen regulation may further underlie these relationships. PMID- 26443433 TI - Molecular dynamics simulations for designing biomimetic pores based on internally functionalized self-assembling alpha,gamma-peptide nanotubes. AB - A molecular dynamics study on internally functionalized peptide nanotubes composed of alpha- and gamma-amino acids self-assembled in lipid bilayers is presented. One of the main advantages of peptide nanotubes composed of gamma amino acids is that the properties of their inner cavities can be tuned by introducing different functions on beta-carbon of the gamma-amino acid. In the work described here we studied the effect of the presence of different numbers of hydroxyl groups in different positions in the lumen of these channels when they are inserted into a lipid bilayer and assessed how they affect the structural and dynamic behavior of the modified peptide nanotubes as well as the transmembrane transport of different ions. The results provided atomic information about the effect of polar groups on the dynamic, structural and transport properties of this type of peptidic channel upon insertion into lipid bilayers, projecting a promising future for their use as biomimetic channels when properly inner derivatized. Furthermore, the chemical versatility of the hydroxyl groups in the lumen of the peptide nanotubes would enable appealing applications for these channels, such as a controlled method for the activation/inactivation of the transmembrane transport along the nanopore. PMID- 26443434 TI - Identification of cross-reactivity between buckwheat and coconut. PMID- 26443435 TI - Effect modification by race-ethnicity of environmental tobacco smoke exposure on airway inflammation in US children. AB - BACKGROUND: Asthma mortality and morbidity are higher in black than in white children. Fractional exhaled nitric oxide (FeNO) is a noninvasive biomarker of eosinophilic airway inflammation. Identification of differences in the effect of environmental tobacco smoke (ETS) on airway inflammation by race and ethnicity from a large sample is needed. OBJECTIVE: To estimate a racial difference in association with ETS and FeNO. METHODS: Data from the 2007 to 2012 National Health and Nutrition Examination Survey were analyzed to compare associations of ETS and FeNO levels in US black and other children. No ETS exposure was defined as a serum cotinine level lower than 0.05 ng/mL and ETS exposure was defined as a serum cotinine level of at least 0.05 ng/mL. FeNO was measured using a device that relies on an electrochemical sensor. Analyses took the complex survey design into account. RESULTS: The analytic sample was formed by 5,473 participants (6-11 years old, n = 2,385; 12-19 years old, n = 3,088) with complete data on demographics, serum cotinine levels, and 2 reproducible FeNO measurements. In weighted linear regression analyses at 6 to 11 years, the interaction term for ETS and black race was not significant (P = .15). At 12 to 19 years, the interaction term was significant (P = .03) in an analysis of all racial groups. In race-specific models, the coefficient for ETS exposure in blacks was -0.033 and that in others was -0.175, ie, ETS exposure was associated with a greater decrease in FeNO in non-blacks than in blacks. CONCLUSION: There was no evidence at 6 to 11 years of age for an effect modification by race of the association between ETS and FeNO. At 12 to 19 years, the data suggested an effect modification. PMID- 26443436 TI - Spontaneous regression of laryngeal squamous cell carcinoma. AB - BACKGROUND: Spontaneous regression of solid malignancy is extremely rare. It is virtually unheard of in the last half century in the published literature. The overwhelming majority of medical professionals do not know that this phenomenon exists. CASE REPORT: This paper reports such a case involving a patient with proven laryngeal squamous cell carcinoma in New Zealand. Whilst waiting for definitive treatment, he was afflicted with prolonged septicaemia secondary to peritonitis from percutaneous endoscopic gastrostomy tube insertion. Following a total laryngectomy, histology of the specimen did not contain any evidence of neoplasia. CONCLUSION: Based predominantly on work established by Dr William Coley, we believe that a period of prolonged pyrexia preceding definitive surgery contributed to this apparent 'miracle'. The time may be ripe to further debate on whether the medical profession should consider pyrexia therapy as a last resort treatment for patients deemed incurable by conventional methods. PMID- 26443437 TI - Individual Vaccination as Nash Equilibrium in a SIR Model with Application to the 2009-2010 Influenza A (H1N1) Epidemic in France. AB - The vaccination against ongoing epidemics is seldom compulsory but remains one of the most classical means to fight epidemic propagation. However, recent debates concerning the innocuity of vaccines and their risk with respect to the risk of the epidemic itself lead to severe vaccination campaign failures, and new mass behaviors appeared driven by individual self-interest. Prompted by this context, we analyze, in a Susceptible-Infected-Recovered model, whether egocentric individuals can reach an equilibrium with the rest of the society. Using techniques from the "Mean Field Games" theory, we extend previous results and show that an equilibrium exists and characterizes completely the individual best vaccination strategy (with or without discounting). We also compare with a strategy based only on overall societal optimization and exhibit a situation with nonnegative price of anarchy. Finally, we apply the theory to the 2009-2010 Influenza A (H1N1) vaccination campaign in France and hint that a group of individuals stopped vaccinating at levels that indicated a pessimistic perception of the risk of the vaccine. PMID- 26443438 TI - Negotiability of Second Mesiobuccal Canals in Maxillary Molars Using a Reciprocating System. AB - The aim of this prospective case series report was to assess the frequency in which the Reciproc R25 instrument (VDW, Munich, Germany) is able to scout and reach the full working length (WL) in second mesiobuccal (MB2) canals from maxillary molars. Conventional hand file negotiation was used as the reference technique for comparison. Maxillary molars (270 first molars and 71 second molars) were included in this study. After local anesthesia, the tooth was isolated with a rubber dam, and traditional straight-line access was made. After locating both first mesiobuccal and MB2 canals, patients were randomly assigned to one of the experimental groups (conventional hand filing preparation or R25 Reciproc preparation). All cases in which the hand files (G1) and R25 instrument (G2) were able to reach the fully electronically determined WL were classified as "reaching full WL" (RFWL). All cases in which the hand files (G1) and R25 instrument (G2) were unable to negotiate the full-length canal were classified as "not reaching full WL" (NRFWL). The number of root canals classified as RFWL and NRFWL from both groups were recorded and tabulated on an Excel data sheet (Microsoft, Redmond, WA). The frequency distributions (%) of root canals classified as RFWL and NRFWL were compared with overall-treated canals and for each treatment approach (hand file and R25 instrument) using a Pearson chi-square test. In group 1, the hand file approach reached the full WL in 57.48% of cases, whereas in group 2 the R25 instrument reached the full WL in 85.63% of cases. Three file separations occurred in each group while negotiating the MB2 canal. According to this study, the R25 instrument was 32% more effective when compared with hand files in scouting and negotiating MB2 canals in maxillary first and second molars. There was no difference with regard to file separation when comparing both preparation techniques. PMID- 26443439 TI - Fermi states and anisotropy of Brillouin zone scattering in the decagonal Al-Ni Co quasicrystal. AB - Quasicrystals (QCs) are intermetallic alloys that have excellent long-range order but lack translational symmetry in at least one dimension. The valence band electronic structure near the Fermi energy EF in such materials is of special interest since it has a direct relation to their unusual physical properties. However, the Fermi surface (FS) topology as well as the mechanism of QC structure stabilization are still under debate. Here we report the first observation of the three-dimensional FS and valence band dispersions near EF in decagonal Al70Ni20Co10 (d-AlNiCo) QCs using soft X-ray angle-resolved photoemission spectroscopy. We show that the FS, formed by dispersive Al sp-states, has a multicomponent character due to a large contribution from high-order bands. Moreover, we discover that the magnitude of the gap at the FS related to the interaction with Brillouin zone boundary (Hume-Rothery gap) critically differs for the periodic and quasiperiodic directions. PMID- 26443440 TI - Density-gradient centrifugation enables the purification of cultured corneal endothelial cells for cell therapy by eliminating senescent cells. AB - The corneal endothelium is essential for maintaining corneal transparency; therefore, corneal endothelial dysfunction causes serious vision loss. Tissue engineering-based therapy is potentially a less invasive and more effective therapeutic modality. We recently started a first-in-man clinical trial of cell based therapy for treating corneal endothelial dysfunction in Japan. However, the senescence of corneal endothelial cells (CECs) during the serial passage culture needed to obtain massive quantities of cells for clinical use is a serious technical obstacle preventing the push of this regenerative therapy to clinical settings. Here, we show evidence from an animal model confirming that senescent cells are less effective in cell therapy. In addition, we propose that density gradient centrifugation can eliminate the senescent cells and purify high potency CECs for clinical use. This simple technique might be applicable for other types of cells in the settings of regenerative medicine. PMID- 26443441 TI - Dynamic Expression Patterns of Progenitor and Neuron Layer Markers in the Developing Human Dentate Gyrus and Fimbria. AB - The molecular mechanisms that orchestrate the development of the human dentate gyrus are not known. In this study, we characterized the formation of human dentate and fimbrial progenitors and postmitotic neurons from 9 gestational weeks (GW9) to GW25. PAX6+ progenitor cells remained proliferative until GW16 in the dentate ventricular zone. By GW11, the secondary dentate matrix had developed in the intermediate zone, surrounding the dentate anlage and streaming toward the subpial layer. This secondary matrix contained proliferating PAX6+ and/or TBR2+ progenitors. In parallel, SOX2+ and PAX6+ fimbrial cells were detected approaching the dentate anlage, representing a possible source of extra-dentate progenitors. By GW16, when the granule cell layer could be delineated, a hilar matrix containing PAX6+ and some TBR2+ progenitors had become identifiable. By GW25, when the 2 limbs of the granule cell layer had formed, the secondary dentate matrix was reduced to a pool of progenitors at the fimbrio-dentate junction. Although human dentate development recapitulates key steps previously described in rodents, differences seemed to emerge in neuron layer markers expression. Further studies are necessary to better elucidate their role in dentate formation and connectivity. PMID- 26443442 TI - Dopamine D1 Receptor-Mediated Transmission Maintains Information Flow Through the Cortico-Striato-Entopeduncular Direct Pathway to Release Movements. AB - In the basal ganglia (BG), dopamine plays a pivotal role in motor control, and dopamine deficiency results in severe motor dysfunctions as seen in Parkinson's disease. According to the well-accepted model of the BG, dopamine activates striatal direct pathway neurons that directly project to the output nuclei of the BG through D1 receptors (D1Rs), whereas dopamine inhibits striatal indirect pathway neurons that project to the external pallidum (GPe) through D2 receptors. To clarify the exact role of dopaminergic transmission via D1Rs in vivo, we developed novel D1R knockdown mice in which D1Rs can be conditionally and reversibly regulated. Suppression of D1R expression by doxycycline treatment decreased spontaneous motor activity and impaired motor ability in the mice. Neuronal activity in the entopeduncular nucleus (EPN), one of the output nuclei of the rodent BG, was recorded in awake conditions to examine the mechanism of motor deficits. Cortically evoked inhibition in the EPN mediated by the cortico striato-EPN direct pathway was mostly lost during suppression of D1R expression, whereas spontaneous firing rates and patterns remained unchanged. On the other hand, GPe activity changed little. These results suggest that D1R-mediated dopaminergic transmission maintains the information flow through the direct pathway to appropriately release motor actions. PMID- 26443443 TI - Substantial differences in initiation of oral anticoagulant therapy and clinical outcome among non-valvular atrial fibrillation patients treated in inpatient and outpatient settings. AB - AIMS: Patients with atrial fibrillation (AF) are encountered and treated in different healthcare settings, which may affect the quality of care. We investigated the use of oral anticoagulant (OAC) therapy and the risk of thrombo embolism (TE) and bleeding, according to the healthcare setting. METHODS AND RESULTS: Using national Danish registers, we categorized non-valvular AF patients (2002-11) according to the setting of their first-time AF contact: hospitalization (inpatients), ambulatory (outpatients), or emergency department (ED). Event rates and hazard ratios (HRs), calculated using Cox regression analysis, were estimated for outcomes of TE and bleeding. We included 116 051 non valvular AF patients [mean age 71.9 years (standard deviation 14.1), 51.3% males], of whom 55.2% were inpatients, 41.9% outpatients, and 2.9% ED patients. OAC therapy 180 days after AF diagnosis among patients with a CHADS2 >= 2 was 42.1, 63.0, and 32.4%, respectively. Initiation of OAC therapy was only modestly influenced by CHADS2 and HAS-BLED scores, regardless of the healthcare setting. The rate of TE was 4.30 [95% confidence interval (CI) 4.21-4.40] per 100 person years for inpatients, 2.28 (95% CI 2.22-2.36) for outpatients, and 2.30 (95% CI 2.05-2.59) for ED patients. The adjusted HR of TE, with inpatients as reference, was 0.74 (95% CI 0.71-0.77) for outpatients and 0.89 (95% CI 0.79-1.01) for ED patients. CONCLUSION: In a nationwide cohort of non-valvular AF patients, outpatients were much more likely to receive OAC therapy and had a significantly lower risk of stroke/TE compared with inpatients and ED patients. However, across all settings investigated, OAC therapy was far from optimal. PMID- 26443444 TI - The risk of atrial fibrillation during right ventricular pacing. AB - AIMS: Right ventricular pacing adversely affects left atrial (LA) structure and function that may trigger atrial fibrillation (AF). This study compares the occurrence of persistent/permanent AF during long-term Hisian area (HA), right ventricular septal (RVS), and right ventricular apex (RVA) pacing in patients with complete/advanced atrioventricular block (AVB). METHODS AND RESULTS: We collected retrospective data from 477 consecutive patients who underwent pacemaker implantation for complete/advanced AVB. Ventricular pacing leads were located in the HA, RVS, and RVA in 148, 140, and 189 patients, respectively. The occurrence of persistent/permanent AF was observed in 114 (23.9%) patients (follow-up 58.5 +/- 26.5 months). Hisian area groups presented a lower rate of AF occurrence (16.9%) compared with RVS and RVA groups (25.7 and 28.0%, respectively), P = 0.049. Cox's proportional hazard model was used to estimate HR. The risk of persistent/permanent AF was significantly lower in the patients paced from HA compared with those paced from RVA, HR = 0.28 (95% CI 0.16-0.48, P = 0.0001). The RVS and RVA pacing groups showed a similar AF risk: HR 1.04 (95% CI 0.66-1.64, P = 0.856). Other independent predictors of persistent/permanent AF occurrence included previous (before device implantation) paroxysmal AF (HR = 4.08; 95% CI 3.15-7.31, P = 0.0001), LA diameter, and age, whereas baseline bundle-branch block was associated with a lower risk of AF occurrence (HR = 0.56; 95% CI 0.35-0.81, P = 0.003). CONCLUSIONS: HA pacing compared with RVA or RVS pacing seems to be associated with a lower risk of persistent/permanent AF occurrence. The risk of persistent/permanent AF was similar in the RVA vs. RVS groups. PMID- 26443445 TI - Effect of caffeine on ventricular arrhythmia: a systematic review and meta analysis of experimental and clinical studies. AB - AIMS: The relationship between caffeine consumption and the occurrence of arrhythmias remains controversial. Despite this lack of scientific evidence, counselling to reduce caffeine consumption is still widely advised in clinical practice. We conducted a systematical review and meta-analysis of interventional studies of the caffeine effects on ventricular arrhythmias. METHODS AND RESULTS: The search was performed on Pubmed, Embase, and Cochrane database, and terms related to coffee, caffeine, and cardiac arrhythmias were used. Methodological quality was assessed based on The Cochrane Collaboration recommendations and the ARRIVE guidelines. There were 2016 citations retrieved on the initial research. After full-text assessment, seven human and two animal studies were included in the meta-analysis. In animal studies, the main outcome reported was the ventricular fibrillation threshold. We observed a significant mean difference of 2.15 mA (95% CI -3.43 to -0.87; I(2) 0.0%, P for heterogeneity = 0.37). The main outcome evaluated in human studies was the rate of ventricular premature beats (VPBs). The overall relative risk for occurrence of VPBs in 24 h attributed to caffeine exposure was 1.00 (95% CI 0.94-1.06; I(2) 13.5%, P for heterogeneity = 0.32). Sensitivity analysis for caffeine dose, different designs, and subject profile was performed and no major differences were observed. CONCLUSION: Our meta-analysis demonstrates that data from human interventional studies do not show a significant effect of caffeine consumption on the occurrence of VBPs. The effects observed in animal studies are most probably the result of very high caffeine doses that are not regularly consumed in a daily basis by humans. PMID- 26443446 TI - Tilt testing results are influenced by tilt protocol. AB - AIMS: It is unknown how the return to supine position influences duration of loss of consciousness (LOC) and cardioinhibition during tilt test. METHODS AND RESULTS: Retrospective analysis of two datasets containing records of patients who underwent tilt testing for unexplained syncope in two centres was performed. Patients, totalling 1232, were included in the study: 262 in a Swedish centre and 970 patients in a Polish centre. In Sweden, tilt table with tilt-down time (TDT) of 18 s was used (Group II). In Poland, two different tilt tables were used, one of them with TDT of 10 s (Group I, n = 325), and the other with TDT of 47 s (Group III, n = 645). Cardioinhibitory reflex occurred most frequently in Group III, whereas number of pauses >3 s, frequency of very long asystole >=30 s, and the total duration of pauses >3 s demonstrated a trend to increase from Group I to III. Duration of LOC in Groups II and III was significantly longer compared with Group I (32.0 and 33.7 s vs. 16.4 s). In the multivariate-adjusted regression model, cardioinhibitory reflex was predicted by tilt-table model (odds ratio per model with increasing TDT: 1.40; 95% confidence interval, 1.19-1.64; P < 0.0001), whereas LOC duration was longer with increasing TDT (P < 0.0001) and age (P < 0.0001). CONCLUSION: Longer TDT during induced vasovagal syncope increases the prevalence of cardioinhibitory reflex and prolongs the duration of LOC. Tilt-down time does not affect asystolic pause duration but delay may lead to occurrence of multiple pauses, higher frequency of very long asystole, and longer total asystole duration. PMID- 26443447 TI - Active fixation of a thin transvenous left-ventricular lead by a side helix facilitates targeted and stable placement in cardiac resynchronization therapy. AB - AIMS: Suboptimal placement, phrenic nerve stimulation, and dislodgements of left ventricular (LV) leads are main challenges in cardiac resynchronization therapy. We investigated the handling, performance, safety, and stability for a novel 4Fr LV lead with a small side helix located proximal to the ring electrode for active fixation of the LV lead. METHODS AND RESULTS: The novel LV lead was successfully implanted in 103 of 106 patients. Patients with dislodged LV leads and with demanding coronary vein anatomies were included. The lead body was rotated clockwise to engage the active fixation side helix in the vein wall. The stimulating electrode was located in basal LV segment and middle LV segment in 54 and 46% of the patients, respectively. The lead was targeted to a vein concordant to the LV segment with latest mechanical activation. Concordant LV lead placement was achieved in 73% of the patients and in adjacent segment in 24%. The average pacing capture threshold (PCT) at implantation was 1.04 +/- 0.6 V (n = 103) and at an average follow-up at 7 months, the PCT remained low and no dislodgements have been observed. During follow-up, four leads have been explanted without complications. CONCLUSION: Active fixation of this 4Fr LV lead by using a side helix, offers flexibility to place the lead precisely in targeted vein segments over a wide range of vein anatomies. The average LV pacing threshold was low at implantation and follow-ups. The lead seems to be extractable and no late dislodgements have been observed. PMID- 26443448 TI - [Not Available]. PMID- 26443450 TI - Constriction of the ductus arteriosus, severe right ventricular hypertension, and a right ventricular aneurysm in a fetus after maternal use of a topical treatment for striae gravidarum. AB - Fetal constriction of the ductus arteriosus is a complication of maternal non steroidal anti-inflammatory drug use and polyphenol-rich food intake. It is unclear as to whether polyphenol-containing topical treatments have similar effects. We present a case of fetal constriction of the ductus arteriosus, severe right ventricular hypertension, and a right ventricular aneurysm associated with maternal use of a topical treatment for striae gravidarum. PMID- 26443449 TI - Large-scale association analysis in Asians identifies new susceptibility loci for prostate cancer. AB - Genome-wide association studies (GWAS) have identified ~100 genetic loci associated with prostate cancer risk. Less than a dozen of these loci were initially identified from GWAS in two Asian populations, likely because of smaller sample sizes of these individual GWAS in Asians. Here, we conduct a large scale meta-analysis of two GWAS from the Japanese population (1,583 cases and 3,386 controls) and the Chinese population (1,417 cases and 1,008 controls), followed by replication in three independent sample sets. We identify two independent susceptibility loci for prostate cancer at 11p15.4 (rs12791447, P=3.59 * 10(-8); PPFIBP2) and 14q23.2 (rs58262369, P=6.05 * 10(-10); ESR2). The mRNA levels of PPFIBP2 and ESR2 are differentially expressed in prostate tumours and paired normal tissues. Our study adds two new loci to the limited number of prostate cancer risk-associated variants in Asians and provides important insight into potential biological mechanisms of prostate cancer. PMID- 26443451 TI - The imaging conundrum of hepatic lymphoma revisited. AB - The imaging manifestations of hepatic lymphoma, both in its primary and secondary form, are extremely variable and overlap with a number of other more common hepatic diseases. However, in the appropriate clinical context, combining the imaging and laboratory features can aid in making the correct diagnosis. Since the management and prognosis of lymphomas are significantly different from other malignancies, early diagnosis and prompt commencement of therapy is of paramount importance. The various morphological appearances of hepatic lymphoma on imaging have been described here along with their possible differentials. TEACHING POINTS: * Primary hepatic lymphoma is extremely rare. * Secondary liver involvement occurs in 50 % of patients with non-Hodgkin lymphoma. * The imaging manifestations of hepatic lymphoma are largely non-specific. * Some imaging features may be helpful in the appropriate clinical setting. * Management and prognosis of lymphoma is significantly different from other malignancies. PMID- 26443452 TI - Cancer therapy related complications in the liver, pancreas, and biliary system: an imaging perspective. AB - Awareness of cancer therapy-induced toxicities is important for all clinicians treating patients with cancer. Cancer therapy has evolved to include classic cytotoxic agents in addition to newer options such as targeted agents and catheter-directed chemoembolisation. Several adverse affects can result from the wide array of treatments including effects on the liver, pancreas, and biliary system that can be visualised on imaging. These complications include sinusoidal obstruction syndrome, fatty liver, pseudocirrhosis, acute hepatitis, pancreatitis, pancreatic atrophy, cholecystitis, biliary sclerosis, and biliary stasis. Many of these toxicities are manageable and reversible with supportive therapies and/or cessation of cancer therapy. The objective of this review is to discuss the imaging findings associated with cancer therapy-induced toxicity of the liver, biliary system, and pancreas. TEACHING POINTS: * Cancer therapy can have adverse effects on the hepatobiliary system and pancreas. * Cancer therapy induced toxicities can be visualised on imaging. * Knowledge of imaging changes associated with cancer therapy complications can improve treatment. PMID- 26443453 TI - Enhanced Trapping of HIV-1 by Human Cervicovaginal Mucus Is Associated with Lactobacillus crispatus-Dominant Microbiota. AB - Cervicovaginal mucus (CVM) can provide a barrier that precludes HIV and other sexually transmitted virions from reaching target cells in the vaginal epithelium, thereby preventing or reducing infections. However, the barrier properties of CVM differ from woman to woman, and the causes of these variations are not yet well understood. Using high-resolution particle tracking of fluorescent HIV-1 pseudoviruses, we found that neither pH nor Nugent scores nor total lactic acid levels correlated significantly with virus trapping in unmodified CVM from diverse donors. Surprisingly, HIV-1 was generally trapped in CVM with relatively high concentrations of d-lactic acid and a Lactobacillus crispatus-dominant microbiota. In contrast, a substantial fraction of HIV-1 virions diffused rapidly through CVM with low concentrations of d-lactic acid that had a Lactobacillus iners-dominant microbiota or significant amounts of Gardnerella vaginalis, a bacterium associated with bacterial vaginosis. Our results demonstrate that the vaginal microbiota, including specific species of Lactobacillus, can alter the diffusional barrier properties of CVM against HIV and likely other sexually transmitted viruses and that these microbiota associated changes may account in part for the elevated risks of HIV acquisition linked to bacterial vaginosis or intermediate vaginal microbiota. IMPORTANCE: Variations in the vaginal microbiota, especially shifts away from Lactobacillus dominant microbiota, are associated with differential risks of acquiring HIV or other sexually transmitted infections. However, emerging evidence suggests that Lactobacillus iners frequently colonizes women with recurring bacterial vaginosis, raising the possibility that L. iners may not be as protective as other Lactobacillus species. Our study was designed to improve understanding of how the cervicovaginal mucus barrier against HIV may vary between women along with the vaginal microbiota and led to the finding that the vaginal microbiota, including specific species of Lactobacillus, can directly alter the diffusional barrier properties of cervicovaginal mucus. This work advances our understanding of the complex barrier properties of mucus and highlights the differential protective ability of different species of Lactobacillus, with Lactobacillus crispatus and possibly other species playing a key role in protection against HIV and other sexually transmitted infections. These findings could lead to the development of novel strategies to protect women against HIV. PMID- 26443454 TI - Identification of a Natural Viral RNA Motif That Optimizes Sensing of Viral RNA by RIG-I. AB - Stimulation of the antiviral response depends on the sensing of viral pathogen associated molecular patterns (PAMPs) by specialized cellular proteins. During infection with RNA viruses, 5'-di- or -triphosphates accompanying specific single or double-stranded RNA motifs trigger signaling of intracellular RIG-I-like receptors (RLRs) and initiate the antiviral response. Although these molecular signatures are present during the replication of many viruses, it is unknown whether they are sufficient for strong activation of RLRs during infection. Immunostimulatory defective viral genomes (iDVGs) from Sendai virus (SeV) are among the most potent natural viral triggers of antiviral immunity. Here we describe an RNA motif (DVG(70-114)) that is essential for the potent immunostimulatory activity of 5'-triphosphate-containing SeV iDVGs. DVG(70-114) enhances viral sensing by the host cell independently of the long stretches of complementary RNA flanking the iDVGs, and it retains its stimulatory potential when transferred to otherwise inert viral RNA. In vitro analysis showed that DVG(70-114) augments the binding of RIG-I to viral RNA and promotes enhanced RIG I polymerization, thereby facilitating the onset of the antiviral response. Together, our results define a new natural viral PAMP enhancer motif that promotes viral recognition by RLRs and confers potent immunostimulatory activity to viral RNA. IMPORTANCE: A discrete group of molecular motifs, including 5' triphosphates associated with double-stranded RNA, have been identified as essential for the triggering of antiviral immunity. Most RNA viruses expose these motifs during their replication; however, successful viruses normally evade immune recognition and replicate to high levels before detection, indicating that unknown factors drive antiviral immunity. DVGs from SeV are among the most potent natural viral stimuli of the antiviral response known to date. These studies define a new natural viral motif present in DVGs that maximizes viral recognition by the intracellular sensor RIG-I, allowing fast and strong antiviral responses even in the presence of viral-encoded immune antagonists. This motif can be harnessed to increase the immunostimulatory potential of otherwise inert viral RNAs and represents a novel immunostimulatory enhancer that could be used in the development of vaccine adjuvants and antivirals. PMID- 26443455 TI - Sphingosine Kinase Regulates Microtubule Dynamics and Organelle Positioning Necessary for Proper G1/S Cell Cycle Transition in Trypanosoma brucei. AB - Sphingolipids are important constituents of cell membranes and also serve as mediators of cell signaling and cell recognition. Sphingolipid metabolites such as sphingosine-1-phosphate and ceramide regulate signaling cascades involved in cell proliferation and differentiation, autophagy, inflammation, and apoptosis. Little is known about how sphingolipids and their metabolites function in single celled eukaryotes. In the present study, we investigated the role of sphingosine kinase (SPHK) in the biology of the protozoan parasite Trypanosoma brucei, the agent of African sleeping sickness. T. brucei SPHK (TbSPHK) is constitutively but differentially expressed during the life cycle of T. brucei. Depletion of TbSPHK in procyclic-form T. brucei causes impaired growth and attenuation in the G1/S phase of the cell cycle. TbSPHK-depleted cells also develop organelle positioning defects and an accumulation of tyrosinated alpha-tubulin at the elongated posterior end of the cell, known as the "nozzle" phenotype, caused by other molecular perturbations in this organism. Our studies indicate that TbSPHK is involved in G1-to-S cell cycle progression, organelle positioning, and maintenance of cell morphology. Cytotoxicity assays using TbSPHK inhibitors revealed a favorable therapeutic index between T. brucei and human cells, suggesting TbSPHK to be a novel drug target. IMPORTANCE: Trypanosoma brucei is a single-celled parasite that is transmitted between humans and other animals by the tsetse fly. T. brucei is endemic in sub-Saharan Africa, where over 70 million people and countless livestock are at risk of developing T. brucei infection, called African sleeping sickness, resulting in economic losses of ~$35 million from the loss of cattle alone. New drugs for this infection are sorely needed and scientists are trying to identify essential enzymes in the parasite that can be targets for new therapies. One possible enzyme target is sphingosine kinase, an enzyme involved in the synthesis of lipids important for cell surface integrity and regulation of cell functions. In this study, we found that sphingosine kinase is essential for normal growth and structure of the parasite, raising the possibility that it could be a good target for new chemotherapy for sleeping sickness. PMID- 26443456 TI - What's in a Name? ISSwi1 Corresponds to Transposons Related to Tn2 and Tn3. PMID- 26443457 TI - Trading Capsule for Increased Cytotoxin Production: Contribution to Virulence of a Newly Emerged Clade of emm89 Streptococcus pyogenes. AB - Strains of emm89 Streptococcus pyogenes have become one of the major causes of invasive infections worldwide in the last 10 years. We recently sequenced the genome of 1,125 emm89 strains and identified three major phylogenetic groups, designated clade 1, clade 2, and the epidemic clade 3. Epidemic clade 3 strains, which now cause the great majority of infections, have two distinct genetic features compared to clade 1 and clade 2 strains. First, all clade 3 organisms have a variant 3 nga promoter region pattern, which is associated with increased production of secreted cytolytic toxins SPN (S. pyogenes NADase) and SLO (streptolysin O). Second, all clade 3 strains lack the hasABC locus mediating hyaluronic acid capsule synthesis, whereas this locus is intact in clade 1 and clade 2 strains. We constructed isogenic mutant strains that produce different levels of SPN and SLO toxins and capsule (none, low, or high). Here we report that emm89 strains with elevated toxin production are significantly more virulent than low-toxin producers. Importantly, we also show that capsule production is dispensable for virulence in strains that already produce high levels of SPN and SLO. Our results provide new understanding about the molecular mechanisms contributing to the rapid emergence and molecular pathogenesis of epidemic clade 3 emm89 S. pyogenes. IMPORTANCE: S. pyogenes (group A streptococcus [GAS]) causes pharyngitis ("strep throat"), necrotizing fasciitis, and other human infections. Serious infections caused by emm89 S. pyogenes strains have recently increased in frequency in many countries. Based on whole-genome sequence analysis of 1,125 strains recovered from patients on two continents, we discovered that a new emm89 clone, termed clade 3, has two distinct genetic features compared to its predecessors: (i) absence of the genes encoding antiphagocytic hyaluronic acid capsule virulence factor and (ii) increased production of the secreted cytolytic toxins SPN and SLO. emm89 S. pyogenes strains with the clade 3 phenotype (absence of capsule and high expression of SPN and SLO) are highly virulent in mice. These findings provide new understanding of how new virulent clones emerge and cause severe infections worldwide. This newfound knowledge of S. pyogenes virulence can be used to help understand future epidemics and conduct new translational research. PMID- 26443459 TI - A comment on the AAM track. PMID- 26443458 TI - Development of protective inflammation and cell-mediated immunity against Cryptococcus neoformans after exposure to hyphal mutants. AB - Morphological switch is tightly coupled with the pathogenesis of many dimorphic fungal pathogens. Cryptococcus neoformans, the major causative agent of cryptococcal meningitis, mostly presents as the yeast form but is capable of switching to the hyphal form. The filamentous form has long been associated with attenuated virulence, yet the underlying mechanism remains elusive. We previously identified the master regulator Znf2 that controls the yeast-to-hypha transition in Cryptococcus. Activation of Znf2 promotes hyphal formation and abolishes fungal virulence in vivo. Here we demonstrated that the cryptococcal strain overexpressing ZNF2 elicited strong and yet temporally confined proinflammatory responses in the early stage of infection. In contrast, exacerbated inflammation in mice infected with the wild-type (WT) strain showed that they were unable to control the infection. Animals inoculated with this filamentous Cryptococcus strain had fewer pulmonary eosinophils and CD11c(+) CD11b(+) cells than animals inoculated with WT yeast. Moreover, mice infected with this strain developed protective Th1- or Th17-type T cell responses. These findings suggest that the virulence attenuation of the filamentous form is likely due to its elicitation of protective host responses. The antivirulence effect of Znf2 was independent of two previously identified factors downstream of Znf2. Interestingly, mucosal immunizations with high doses of ZNF2-overexpressing cells, either in the live or heat-killed form, offered 100% protection to the host from a subsequent challenge with the otherwise lethal clinical strain H99. Our results demonstrate that heat resistant cellular components presented in cryptococcal cells with activated ZNF2 elicit protective host immune responses. These findings could facilitate future research on novel immunological therapies. IMPORTANCE: Cryptococcal meningitis is one of the leading causes of death among AIDS patients. This disease presents a severe threat to public health. The current antifungal regimens are unsatisfactory in controlling or clearing the pathogen Cryptococcus neoformans. Immunotherapies and/or vaccines could be a promising approach to prevent or manage this deadly disease. However, the lack of understanding of host-pathogen interactions during cryptococcal infection greatly hampers the development of effective immunotherapies. In this study, we discovered that inoculation of cryptococcal cells with activated Znf2, a morphogenesis regulator and an antivirulence factor, could shift the host pathological Th2 responses to the protective Th1 or Th17 responses. Importantly, we discovered that vaccination with either the viable or heat-killed form of ZNF2-overexpressing cells protected animals from the otherwise lethal infection by the highly virulent clinical strain. Our study suggests that the fungal cellular component(s) of the ZNF2 overexpressing strain may provide potential vaccine candidate(s) for controlling the fatal disease. PMID- 26443460 TI - Plasmodium falciparum-infected erythrocyte knob density is linked to the PfEMP1 variant expressed. AB - Members of the clonally variant Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family mediate adhesion of infected erythrocytes (IEs) to vascular receptors. PfEMP1 expression is normally confined to nanoscale knob protrusions on the IE surface membrane. To investigate the relationship between the densities of these IE surface knobs and the PfEMP1 variant expressed, we used specific antibody panning to generate three sublines of the P. falciparum clone IT4, which expresses the PfEMP1 variants IT4VAR04, IT4VAR32b, and IT4VAR60. The knob density in each subline was then determined by atomic force microscopy (AFM) and scanning electron microscopy (SEM) and compared to PfEMP1 and knob-associated histidine-rich protein (KAHRP) expression. Selection for uniform expression of IT4VAR04 produced little change in knob density, compared to unselected IEs. In contrast, selection for IT4VAR32b expression increased knob density approximately 3-fold, whereas IEs selected for IT4VAR60 expression were essentially knobless. When IT4VAR60(+) IEs were subsequently selected to express IT4VAR04 or IT4VAR32b, they again displayed low and high knob densities, respectively. All sublines expressed KAHRP regardless of the PfEMP1 expressed. Our study documents for the first time that knob density is related to the PfEMP1 variant expressed. This may reflect topological requirements to ensure optimal adhesive properties of the IEs. IMPORTANCE: Infections with Plasmodium falciparum malaria parasites are still responsible for many deaths, especially among children and pregnant women. New interventions are needed to reduce severe illness and deaths caused by this malaria parasite. Thus, a better understanding of the mechanisms behind the pathogenesis is essential. A main reason why Plasmodium falciparum malaria is more severe than disease caused by other malaria species is its ability to express variant antigens on the infected erythrocyte surface. These antigens are presented on membrane protrusions known as knobs. This study set out to investigate the interplay between different variant antigens on the surface of P. falciparum-infected erythrocytes and the density of the knobs on which the antigens are expressed. Such a direct analysis of this relationship has not been reported before but adds to the important understanding of the complexity of malaria antigen presentation. PMID- 26443461 TI - HIV inhibition by lactobacilli: easier in a test tube than in real life. AB - A lactobacillus-dominant vaginal microbiota has been shown to decrease heterosexual HIV transmission. Nunn et al. now report that a vaginal microbiota dominated by Lactobacillus crispatus is associated with a relative inability of HIV pseudoviral particles to transverse cervicovaginal mucus (CVM) in vitro [mBio 6(5):e01084-15, 2015, doi:10.1128/mBio.01084-15]. The purported inhibitory mechanism is the interaction between carboxyl groups present on HIV and in CVM that occurred only under acidic conditions when carboxyl groups were protonated. L. crispatus produces high levels of lactic acid and results in the lowest vaginal pH when it is the dominant vaginal bacterium. In addition, high levels of lactic acid inhibit the proliferation of other bacteria that might negatively affect CVM structure. The utility of enhancing L. crispatus dominance to inhibit HIV transmission awaits assessment of the influence of ejaculated semen on this property and investigations on the role of Lactobacillus products such as d lactic acid in this property. PMID- 26443462 TI - Erratum for Boudry et al., function of the CRISPR-Cas system of the human pathogen Clostridium difficile. PMID- 26443463 TI - Subassemblies and asymmetry in assembly of herpes simplex virus procapsid. AB - The herpes simplex virus 1 (HSV-1) capsid is a massive particle (~200 MDa; 1,250 A diameter) with T=16 icosahedral symmetry. It initially assembles as a procapsid with ~4,000 protein subunits of 11 different kinds. The procapsid undergoes major changes in structure and composition as it matures, a process driven by proteolysis and expulsion of the internal scaffolding protein. Assembly also relies on an external scaffolding protein, the triplex, an alpha2beta heterotrimer that coordinates neighboring capsomers in the procapsid and becomes a stabilizing clamp in the mature capsid. To investigate the mechanisms that regulate its assembly, we developed a novel isolation procedure for the metastable procapsid and collected a large set of cryo-electron microscopy data. In addition to procapsids, these preparations contain maturation intermediates, which were distinguished by classifying the images and calculating a three dimensional reconstruction for each class. Appraisal of the procapsid structure led to a new model for assembly; in it, the protomer (assembly unit) consists of one triplex, surrounded by three major capsid protein (MCP) subunits. The model exploits the triplexes' departure from 3-fold symmetry to explain the highly skewed MCP hexamers, the triplex orientations at each 3-fold site, and the T=16 architecture. These observations also yielded new insights into maturation. IMPORTANCE: This paper addresses the molecular mechanisms that govern the self assembly of large, structurally complex, macromolecular particles, such as the capsids of double-stranded DNA viruses. Although they may consist of thousands of protein subunits of many different kinds, their assembly is precise, ranking them among the largest entities in the biosphere whose structures are uniquely defined to the atomic level. Assembly proceeds in two stages: formation of a precursor particle (procapsid) and maturation, during which major changes in structure and composition take place. Our analysis of the HSV procapsid by cryo-electron microscopy suggests a hierarchical pathway in which multisubunit "protomers" are the building blocks of the procapsid but their subunits are redistributed into different subcomplexes upon being incorporated into a nascent procapsid and are redistributed again in maturation. Assembly is a highly virus-specific process, making it a potential target for antiviral intervention. PMID- 26443464 TI - Is it possible? A different approach to creating a universal influenza vaccine. AB - The best way to combat influenza virus infection is to prevent it. However, the continual evolution of circulating influenza virus strains and the constant threat of newly emerging viruses forces the public health community to annually update seasonal influenza vaccines while stockpiling potential pandemic virus vaccines. Thus, there is an urgent need to develop a "universal" influenza vaccine that affords protection against all strains. In their recent article, L. M. Schwartzman et al. (mBio 6:e01044-15, 2015, doi:10.1128/mBio.01044-15) demonstrated that intranasal immunization of mice with a cocktail of viral-like particles (VLPs) expressing distinct influenza virus hemagglutinin (HA) proteins can broadly protect against infection not only with the same viral strains but also with unrelated strains. These findings suggest a promising strategy for developing a broadly protective "universal" influenza vaccine. PMID- 26443465 TI - Three-dimensional analysis of palatal shape in patients treated with SARME using traditional and geometric morphometrics. AB - OBJECTIVES: To demonstrate the advantages of dense surface models in the evaluation of surgical-assisted rapid maxillary expansion's effect (SARME) on palatal morphology. Furthermore, we compared the palatal surface before (T1) and after (T2) therapy with controls. SETTING AND SAMPLE POPULATION: Surgical assisted rapid maxillary expansion's effect group of 15 adult patients (Le Fort I and midpalatal sagittal osteotomy, hyrax screw) and 50 adult individuals. Patients were treated in General Faculty Hospital, Prague. MATERIALS AND METHODS: Eighty plaster casts were digitized using a three-dimensional laser scanner and evaluated using traditional and geometric morphometrics. RESULTS: An unpaired Student's t-test on the controls and the SARME T1 group revealed significant differences in all width measurements. Between the controls and the SARME T2 group, significant differences were only related to the interdental angle between the first molars and particularly to the palatal height. The most remarkable differences between the pre- and post-treatment palatal morphology were a widening of the dental arch and buccal shift of the lateral teeth associated with apparent flattening of the alveolar crest. CONCLUSIONS: Dense surface model provided descriptive visualization of the treatment effect and was helpful in the evaluation of palatal shape variability including detection of the most difficult patients. Correction of the dental arch width discrepancy by SARME was successfully achieved. After therapy, palatal shape variability of most of the patients was comparable to the variability of the control group. PMID- 26443466 TI - Comparative analyses of ion release, pH and multispecies biofilm formation between conventional and bioactive gutta-percha. AB - AIM: To analyse the effect of commercial and experimental gutta-percha with the addition of niobium phosphate glass on biofilm formation by oral bacteria from human dental plaque. Additional pH and elemental release of the materials were analysed. METHODOLOGY: The multispecies biofilm was grown anaerobically from plaque bacteria on standardized discs of each material: hydroxyapatite (HA), gutta-percha pellets (OBT) (Obtura pellets, Shoreline, CT, USA), ProTaper gutta percha (PTP) (ProTaper Universal Gutta-Percha Points, Dentsply Maillefer, Ballaigues, Switzerland), EndoSequence BC gutta-percha (GBC) (Brasseler USA, Savannah, GA, USA), experimental gutta-percha associated with niobium phosphate glass (GNB) and niobium phosphate glass (NPG). Specimens (n = 5 per group and per incubation period) were incubated in brain-heart infusion broth for 3, 14 and 30 days, at 37 degrees C, and stained using live/dead viability assay. Images were analysed by confocal laser scanning microscopy (CLSM) and the total biovolume (mm3 ), viable bacteria biovolume (mm3 ), and live percentage (%) were quantified. For pH measurement, specimens of each material (n = 3) were immersed in phosphate-buffered saline at 37 degrees C, and pH was monitored in multiple intervals, up to 30 days. For elemental analysis, additional specimens (n = 3) were immersed in deionized water and elemental release was analysed by ICP-OES (inductively coupled plasma - optical emission spectrometry) at time intervals of 3, 14 and 30 days. Differences between groups were evaluated by the two-way analysis of variation (anova) with Tukey's post hoc test (P < 0.05). RESULTS: The lowest total biovolume at 30 days was found in GNB, GBC and NPG. GNB had the lowest viable bacteria biovolume (mean value) at 30 days (P < 0.05), and the lowest live percentage of bacteria at 3 and 30 days (P < 0.05), whilst NPG had the lowest live percentage at 14 days (P < 0.05). GNB had the highest pH (8.45) after 30 days (P < 0.05), and the greatest Zn and Na release at all time intervals (P < 0.05). Both GBC and GNB had significantly higher Ca release at 14 and 30 days. CONCLUSION: GNB and GBC reduced biofilm formation, GNB had the lowest amount of viable bacteria in biofilms with the highest pH, and high Zn and Na release values after 30 days. PMID- 26443467 TI - A highly efficient Mukaiyama-Mannich reaction of N-Boc isatin ketimines and other active cyclic ketimines using difluoroenol silyl ethers catalyzed by Ph3PAuOTf. AB - Ph3PAuOTf is identified as a powerful catalyst for the addition of difluoroenol silyl ethers to N-Boc isatin ketimines and other two kinds of active cyclic ketimines. This represents the first Au(i)-catalyzed Mukaiyama-Mannich reaction, and the corresponding non-fluorinated enol silyl ether proves to be even much more reactive under the same conditions. This method paves the way to the total synthesis of difluoromethylated analogues of AG-041R, a gastrin/CCK-B receptor antagonist. PMID- 26443468 TI - Differences in environmental exposure assignment due to residential mobility among children with a central nervous system tumor: Texas, 1995-2009. AB - In epidemiologic studies of childhood cancer, environmental exposures are often assigned based on either residence at birth or diagnosis without considering the impact of residential mobility. Therefore, we evaluated residential mobility and exposure assignment differences to hazardous air pollutants between birth and diagnosis in children with a central nervous system (CNS) tumor. Children diagnosed with CNS tumors during 1995-2009 (N=1,196) were identified from the Texas Cancer Registry. Census tract-level estimates of 1,3-butadiene and benzene were used to assign quartiles of exposure based on the maternal residence at birth and the child's residence at diagnosis. Overall, 64% of younger (0-4 years) children and 79% of older (5-14 years) children moved between birth and diagnosis. Using mixed-effects ordinal logistic regression, residence at diagnosis compared to birth did not result in a significant change in exposure assignment for younger children; however, older children were more likely to be placed in a lower 1,3-butadiene or benzene exposure quartile based on residence at diagnosis compared to birth (odds ratio (OR)=0.58, 95% confidence interval (CI)=0.45-0.76; OR=0.57, 95% CI=0.44-0.75, respectively). In conclusion, while the majority of children moved between birth and CNS tumor diagnosis, mobility did not significantly impact 1,3-butadiene and benzene exposure assessment in younger children. PMID- 26443469 TI - Soil ingestion rates for children under 3 years old in Taiwan. AB - Soil and dust ingestion rates by children are among the most critical exposure factors in determining risks to children from exposures to environmental contaminants in soil and dust. We believe this is the first published soil ingestion study for children in Taiwan using tracer element methodology. In this study, 66 children under 3 years of age were enrolled from Taiwan. Three days of fecal samples and a 24-h duplicate food sample were collected. The soil and household dust samples were also collected from children's homes. Soil ingestion rates were estimated based on silicon (Si) and titanium (Ti). The average soil ingestion rates were 9.6+/-19.2 mg/day based on Si as a tracer. The estimated soil ingestion rates based on Si did not have statistically significant differences by children's age and gender, although the average soil ingestion rates clearly increased as a function of children's age category. The estimated soil ingestion rates based on Si was significantly and positively correlated with the sum of indoor and outdoor hand-to-mouth frequency rates. The average soil ingestion rates based on Si were generally lower than the results from previous studies for the US children. Ti may not be a suitable tracer for estimating soil ingestion rates in Taiwan because the Ti dioxide is a common additive in food. To the best of our knowledge, this is the first study that investigated the correlations between soil ingestion rates and mouthing behaviors in Taiwan or other parts of Asia. It is also the first study that could compare available soil ingestion data from different countries and/or different cultures. The hand-to mouth frequency and health habits are important to estimate the soil ingestion exposure for children. The results in this study are particularly important when assessing children's exposure and potential health risk from nearby contaminated soils in Taiwan. PMID- 26443470 TI - Third Molars on the Internet: A Guide for Assessing Information Quality and Readability. AB - BACKGROUND: Directing patients suffering from third molars (TMs) problems to high quality online information is not only medically important, but also could enable better engagement in shared decision making. OBJECTIVES: This study aimed to develop a scale that measures the scientific information quality (SIQ) for online information concerning wisdom tooth problems and to conduct a quality evaluation for online TMs resources. In addition, the study evaluated whether a specific piece of readability software (Readability Studio Professional 2012) might be reliable in measuring information comprehension, and explored predictors for the SIQ Scale. METHODS: A cross-sectional sample of websites was retrieved using certain keywords and phrases such as "impacted wisdom tooth problems" using 3 popular search engines. The retrieved websites (n=150) were filtered. The retained 50 websites were evaluated to assess their characteristics, usability, accessibility, trust, readability, SIQ, and their credibility using DISCERN and Health on the Net Code (HoNCode). RESULTS: Websites' mean scale scores varied significantly across website affiliation groups such as governmental, commercial, and treatment provider bodies. The SIQ Scale had a good internal consistency (alpha=.85) and was significantly correlated with DISCERN (r=.82, P<.01) and HoNCode (r=.38, P<.01). Less than 25% of websites had SIQ scores above 75%. The mean readability grade (10.3, SD 1.9) was above the recommended level, and was significantly correlated with the Scientific Information Comprehension Scale (r=.45. P<.01), which provides evidence for convergent validity. Website affiliation and DISCERN were significantly associated with SIQ (P<.01) and explained 76% of the SIQ variance. CONCLUSION: The developed SIQ Scale was found to demonstrate reliability and initial validity. Website affiliation, DISCERN, and HoNCode were significant predictors for the quality of scientific information. The Readability Studio software estimates were associated with scientific information comprehensiveness measures. PMID- 26443471 TI - Potential for community pharmacies to promote rational drug use in Pakistan. PMID- 26443473 TI - Gliotoxin--bane or boon? AB - Gliotoxin (GT) is the most important epidithiodioxopiperazine (ETP)-type fungal toxin. GT was originally isolated from Trichoderma species as an antibiotic substance involved in biological control of plant pathogenic fungi. A few isolates of GT-producing Trichoderma virens are commercially marketed for biological control and widely used in agriculture. Furthermore, GT is long known as an immunosuppressive agent and also reported to have anti-tumour properties. However, recent publications suggest that GT is a virulence determinant of the human pathogen Aspergillus fumigatus. This compound is thus important on several counts - it has medicinal properties, is a pathogenicity determinant, is a potential diagnostic marker and is important in biological crop protection. The present article addresses this paradox and the ecological role of GT. We discuss the function of GT as defence molecule, the role in aspergillosis and suggest solutions for safe application of Trichoderma-based biofungicides. PMID- 26443472 TI - Medical marijuana patient counseling points for health care professionals based on trends in the medical uses, efficacy, and adverse effects of cannabis-based pharmaceutical drugs. AB - The purpose of this report is to present a review of the medical uses, efficacy, and adverse effects of the three approved cannabis-based medications and ingested marijuana. A literature review was conducted utilizing key search terms: dronabinol, nabilone, nabiximols, cannabis, marijuana, smoke, efficacy, toxicity, cancer, multiple sclerosis, nausea, vomiting, appetite, pain, glaucoma, and side effects. Abstracts of the included literature were reviewed, analyzed, and organized to identify the strength of evidence in medical use, efficacy, and adverse effects of the approved cannabis-based medications and medical marijuana. A total of 68 abstracts were included for review. Dronabinol's (Marinol) most common medical uses include weight gain, chemotherapy-induced nausea and vomiting (CINV), and neuropathic pain. Nabiximol's (Sativex) most common medical uses include spasticity in multiple sclerosis (MS) and neuropathic pain. Nabilone's (Cesamet) most common medical uses include CINV and neuropathic pain. Smoked marijuana's most common medical uses include neuropathic pain and glaucoma. Orally ingested marijuana's most common medical uses include improving sleep, reducing neuropathic pain, and seizure control in MS. In general, all of these agents share similar medical uses. The reported adverse effects of the three cannabis-based medications and marijuana show a major trend in central nervous system (CNS)-related adverse effects along with cardiovascular and respiratory related adverse effects. Marijuana shares similar medical uses with the approved cannabis-based medications dronabinol (Marinol), nabiximols (Sativex), and nabilone (Cesamet), but the efficacy of marijuana for these medical uses has not been fully determined due to limited and conflicting literature. Medical marijuana also has similar adverse effects as the FDA-approved cannabis-based medications mainly consisting of CNS related adverse effects but also including cardiovascular and respiratory related adverse effects. Finally, insufficient higher-order evidence to support the widespread use of medical marijuana was found, but a limited amount of moderate-level evidence supports its use in pain and seizure management. PMID- 26443474 TI - Virus-resembling nano-structures for near infrared fluorescence imaging of ovarian cancer HER2 receptors. AB - Ovarian cancer remains the dominant cause of death due to malignancies of the female reproductive system. The capability to identify and remove all tumors during intraoperative procedures may ultimately reduce cancer recurrence, and lead to increased patient survival. The objective of this study is to investigate the effectiveness of an optical nano-structured system for targeted near infrared (NIR) imaging of ovarian cancer cells that over-express the human epidermal growth factor receptor 2 (HER2), an important biomarker associated with ovarian cancer. The nano-structured system is comprised of genome-depleted plant infecting brome mosaic virus doped with NIR chromophore, indocyanine green, and functionalized at the surface by covalent attachment of monoclonal antibodies against the HER2 receptor. We use absorption and fluorescence spectroscopy, and dynamic light scattering to characterize the physical properties of the constructs. Using fluorescence imaging and flow cytometry, we demonstrate the effectiveness of these nano-structures for targeted NIR imaging of HER2 receptors in vitro. These functionalized nano-materials may provide a platform for NIR imaging of ovarian cancer. PMID- 26443475 TI - Cannabinoids in paediatric neurology. PMID- 26443476 TI - Audiometric Outcomes in Pediatric Temporal Bone Trauma. AB - OBJECTIVE: To characterize pediatric temporal bone trauma, focusing on audiometric outcomes. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care children's hospital. SUBJECTS AND METHODS: Cases were reviewed of children (<18 years) presenting over a 3-year period with computed tomography proven temporal bone fracture and audiology examination. All scans were read by a neuroradiologist and reviewed by a pediatric otolaryngologist. Demographics, fracture pattern, and audiometric data were recorded. RESULTS: Fifty-eight patients (60 fractures) met inclusion criteria. The majority (93%) were otic capsule-sparing fractures. The types and severity of hearing loss were significantly different between the 2 fracture patterns. Based on pure-tone average, all otic capsule-violating fractures had abnormal initial audiograms; 75% of these losses were severe. Approximately half (54%) of otic capsule-sparing fractures had abnormal initial audiograms; a majority were mild losses (85%). All classifiable losses in otic capsule-violating cases were of mixed type, whereas the majority (75%) of losses in otic capsule-sparing cases were conductive. Regardless of classification, 72% of patients with otic capsule-sparing fractures and initially abnormal audiograms improved to normal levels at a mean of 48 days posttrauma; this increased to 83% when only conductive losses were considered. CONCLUSIONS: Hearing loss type and severity differ in otic capsule-sparing and otic capsule-violating temporal bone fractures. A majority of children with otic capsule-sparing fractures and associated hearing loss improve to normal levels in about 6 weeks, especially if the original loss is classified as solely conductive. Children who do not improve within this time frame may warrant early investigation into surgically correctable causes. PMID- 26443477 TI - Office Insertion of Tympanostomy Tubes without Anesthesia in Young Children. PMID- 26443478 TI - Impact of Diabetes Mellitus on Head and Neck Cancer Patients Undergoing Surgery. AB - OBJECTIVE: The impact of diabetes mellitus (DM) on surgical outcomes and cost of care for patients undergoing surgery for head and neck cancer (HNCA) is not well established. We used the Nationwide Inpatient Sample to analyze the postoperative impact of DM on HNCA patients. STUDY DESIGN: Population-based inpatient registry analysis. SETTING: Academic medical center. SUBJECTS AND METHODS: Discharge data from the Nationwide Inpatient Sample were analyzed for patients undergoing HNCA surgery from 2002 to 2010. Patient demographics, comorbidities, length of stay, hospital charges, and postoperative complications were compared between HNCA patients with and without DM. RESULTS: Of 31,075 patients, 4029 patients (13.0%) had a DM diagnosis. DM patients were older (65.7 +/- 10.8 vs 61.1 +/- 14.1 years old; P < .001), had more preexisting comorbidities, had longer hospitalizations, and incurred greater hospital charges. Compared with the non-DM cohort, DM patients experienced significantly higher rates of postoperative infections (2.6% vs 2.1%, P = .025), cardiac events (9.0% vs 4.3%, P < .001), pulmonary edema/failure (6.6% vs 5.7%, P = .023), acute renal failure (3.3% vs 1.5%, P < .001), and urinary tract infections (2.8 % vs 2.1%, P = .005). No differences in surgical wound healing rates were observed (0.1 vs 0.1, P = .794). On multivariate logistic regression corrected for age and race, DM patients had greater odds of postoperative infections (1.382, P = .007), cardiac events (1.893, P < .001), and acute renal failure (2.023, P < .001). CONCLUSIONS: DM is associated with greater length of stay and hospital charges among HNCA patients. DM patients have significantly greater rates of postoperative complications, including postoperative infections, cardiac events, and acute renal failure. PMID- 26443479 TI - Who Wrote This Clinical Practice Guideline? AB - The American Academy of Otolaryngology-Head and Neck Surgery Foundation clinical practice guidelines address a variety of otolaryngologic diseases and/or procedures. It may seem reasonable to create these guidelines by assembling a team of expert clinicians familiar with the pertinent clinical issues and the available evidence, with debate and eventual agreement leading to recommendations. However, trustworthy clinical practice guidelines are in fact created via a defined process to assemble a guideline development group composed of diverse stakeholders: clinician generalists and specialists, content experts, methodologists, physicians and nonphysicians, patients, and advocates. Such a guideline development group can create a valuable and trusted guideline for clinicians and affected patients. PMID- 26443480 TI - Genetic Alterations in Gliosarcoma and Giant Cell Glioblastoma. AB - The majority of glioblastomas develop rapidly with a short clinical history (primary glioblastoma IDH wild-type), whereas secondary glioblastomas progress from diffuse astrocytoma or anaplastic astrocytoma. IDH mutations are the genetic hallmark of secondary glioblastomas. Gliosarcomas and giant cell glioblastomas are rare histological glioblastoma variants, which usually develop rapidly. We determined the genetic patterns of 36 gliosarcomas and 19 giant cell glioblastomas. IDH1 and IDH2 mutations were absent in all 36 gliosarcomas and in 18 of 19 giant cell glioblastomas analyzed, indicating that they are histological variants of primary glioblastoma. Furthermore, LOH 10q (88%) and TERT promoter mutations (83%) were frequent in gliosarcomas. Copy number profiling using the 450k methylome array in 5 gliosarcomas revealed CDKN2A homozygous deletion (3 cases), trisomy chromosome 7 (2 cases), and monosomy chromosome 10 (2 cases). Giant cell glioblastomas had LOH 10q in 50% and LOH 19q in 42% of cases. ATRX loss was detected immunohistochemically in 19% of giant cell glioblastomas, but absent in 17 gliosarcomas. These and previous results suggest that gliosarcomas are a variant of, and genetically similar to, primary glioblastomas, except for a lack of EGFR amplification, while giant cell glioblastoma occupies a hybrid position between primary and secondary glioblastomas. PMID- 26443481 TI - Validation of a five-factor model of a Chinese Mandarin version of the Positive and Negative Syndrome Scale (CMV-PANSS) in a sample of 813 schizophrenia patients. AB - OBJECTIVES: The Positive and Negative Syndrome Scale (PANSS) is one of the most widely used instruments for measuring the severity of schizophrenia. However, until now, there has not been a published, validated Chinese Mandarin version of the five-factor model PANSS with confirmatory factor analysis (CFA) for schizophrenic patients in Taiwan. METHODS: A total of 813 subjects were recruited. Internal consistency was evaluated with Cronbach's alpha coefficient. For test re-test reliability, 57 patients were reassessed and intra-class correlation coefficients were calculated. For validity, exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) using a Structured Equation Model were implemented to identify the factor model. RESULTS: The Cronbach's alpha coefficient was 0.928. The intra-class coefficient was 0.878 (95% CI: 0.79 0.92). The final model was composed of five factors. EFA explained a total of 64.2% of the variance. CFA indicated a good fitting model. Except for the PANSS items G7 (motor retardation), G8 (uncooperativeness), N5 (abstract thinking), and G10 (disorientation), this study found that the items loaded on these factors were similar to the consensus items published in prior studies. CONCLUSIONS: In summary, these findings support the Chinese Mandarin version of the PANSS as a reliable and valid instrument for the assessment of the severity of psychopathology in hospitalized, stable patients with schizophrenia. More effective and specific treatment models targeting sub-culture differences are expected to be developed in future studies. PMID- 26443482 TI - Primary and secondary alterations of white matter connectivity in schizophrenia: A study on first-episode and chronic patients using whole-brain tractography based analysis. AB - Schizophrenia is a debilitating mental disorder that is associated with an impaired connection of cerebral white matter. Studies on patients with chronic and first-episode schizophrenia have found widespread white matter abnormalities. However, it is unclear whether the altered connections are inherent in or secondary to the disease. Here, we sought to identify white matter tracts with altered connections and to distinguish primary or secondary alterations among 74 fiber tracts across the whole brain using an automatic tractography-based analysis method. Thirty-one chronic, 25 first-episode patients with schizophrenia and 31 healthy controls were recruited to receive diffusion spectrum magnetic resonance imaging at 3T. Seven tracts were found to exhibit significant differences between the groups; they included the right arcuate fasciculus, bilateral fornices, left superior longitudinal fasciculus I, and fibers of the corpus callosum to the bilateral dorsolateral prefrontal cortices (DLPFC), bilateral temporal poles, and bilateral hippocampi. Post-hoc between-group analyses revealed that the connection of the callosal fibers to the bilateral DLPFC was significantly decreased in chronic patients but not in first-episode patients. In a stepwise regression analysis, the decline of the tract connection was significantly predicted by the duration of illness. In contrast, the remaining six tracts showed significant alterations in both first-episode and chronic patients and did not associate with clinical variables. In conclusion, reduced white matter connectivity of the callosal fibers to the bilateral DLPFC may be a secondary change that degrades progressively in the chronic stage, whereas alterations in the other six tracts may be inherent in the disease. PMID- 26443483 TI - Volatile Organic Metabolites Identify Patients with Mesangial Proliferative Glomerulonephritis, IgA Nephropathy and Normal Controls. AB - Urinary volatile organic compounds (VOCs) analysis for kidney diseases has attracted a large amount of scientific interest recently, and urinary metabolite analysis has already been applied to many diseases. Urine was collected from 15 mesangial proliferative glomerulonephritis (MsPGN) patients, 21 IgA nephropathy (IgAN) patients and 15 healthy controls. Solid phase microextraction chromatography- mass spectrometry (SPME-GC-MS) was used to analyse the urinary metabolites. The statistical methods principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLSDA) were performed to process the final data. Five metabolites were significantly greater in the group of MsPGN patients than in the normal control group (P < 0.05) while three metabolites were found at increased levels in the group of IgAN patients compared with the normal controls (P < 0.05). In addition, five metabolites were significantly increased in the group of IgAN patients compared with the MsPGN patients (P < 0.05). These five metabolites may be specific biomarkers for distinguishing between MsPGN and IgAN. The analysis of urinary VOCs appears to have potential clinical applications as a diagnostic tool. PMID- 26443484 TI - Reduced occurrence of ventilator-associated pneumonia after cardiac surgery using preoperative 0.2% chlorhexidine oral rinse: results from a single-centre single blinded randomized trial. AB - Since mechanical ventilation after cardiac surgery increases the risk of ventilator-associated pneumonia (VAP), we conducted a prospective randomized controlled trial to investigate the effect of preoperative 0.2% chlorhexidine on postoperative VAP. Ninety-four patients scheduled for heart surgery were randomized to a chlorhexidine group (N = 47) or control (saline) group (N = 47). On the day before surgery, patients gargled three times with 0.2% chlorhexidine or saline 30 min after each meal and 5 min after teeth brushing at bedtime. VAP occurred in 8.5% of the chlorhexidine group and in 23.4% of the controls. Preoperative chlorhexidine mouthwash reduced the incidence of postoperative VAP significantly. PMID- 26443485 TI - Effectiveness of meticillin-resistant Staphylococcus aureus decolonization in long-term haemodialysis patients: a systematic review and meta-analysis. AB - BACKGROUND: Chronic haemodialysis patients are a high-risk population for meticillin-resistant Staphylococcus aureus (MRSA) colonization, which is a precursor of infection. AIM: To summarize the effect of nasal (+/- whole-body wash) MRSA decolonization in haemodialysis patients by means of a systematic review and meta-analysis. METHODS: We identified eligible studies using Medline, Embase, the Cochrane database, clinicaltrials.org, and conference abstracts investigating the success of MRSA decolonization in haemodialysis patients. For the statistical analysis, we used Stata 13 to express study-specific proportions with 95% confidence intervals. A likelihood ratio test was used to assess inter study heterogeneity. FINDINGS: Six published prospective cohort studies and one study described in a conference abstract met our inclusion criteria. From 1150 haemodialysis patients enrolled in these studies, MRSA was isolated from nasal swabs of 147 (12.8%) patients. Six of the trials used mupirocin nasal ointment and combined it with chlorhexidine body washes for decolonization. The most widely used protocol was a five-day course of mupirocin nasal ointment application three times a day, and chlorhexidine body wash once daily. The pooled success rate of decolonization was 0.88 (95% confidence interval: 0.75-0.95). A likelihood ratio test of the fixed versus the random-effects model showed significant inter-study heterogeneity (P = 0.047). Four of seven studies determined subsequent MRSA infections in 94 carriers overall, two (2%) of which experienced infection. CONCLUSION: The use of mupirocin together with whole-body decolonization is highly effective in eradicating MRSA carriage in haemodialysis patients. The current literature, however, is characterized by a lack of comparative effectiveness studies for this intervention. PMID- 26443486 TI - Development and evaluation of the Turkish matrix sentence test. AB - OBJECTIVES: The Turkish matrix sentence test, TURMatrix, was developed for precise, internationally comparable speech intelligibility testing. DESIGN: The TURMatrix comprises a base matrix of ten well-known Turkish names, numbers, adjectives, objects, verbs, from which syntactically fixed sentences were randomly composed. Test conduction may be in an open-set (standard), or closed set response format. Homogeneity in intelligibility of the test material was optimized by applying level adaptations (maximal +/- 3 dB) based on word-specific speech reception thresholds (SRTs). Test list equivalence was verified and reference values were determined. STUDY SAMPLE: Thirty-eight native listeners of Turkish with normal hearing. RESULTS: After training, mean SRT and slope of the final test lists were -8.3 +/- 0.2 dB SNR and 14.1 +/- 1.0%/dB, respectively (fixed SNR measurements; inter-list variability). For adaptive measurements, average across listeners was -7.2 +/- 0.7 dB SNR in the open-set and -7.9 +/- 0.7 dB SNR in the closed-set response format. Mean SRT for adaptive measurements in the open-set response format in quiet was 20.3 +/- 4.1 dB. Individual SRTs in quiet correlated more closely with audiograms than with SRTs in noise. CONCLUSIONS: The TURMatrix was developed according to European standards and provides reliable speech intelligibility measurements in noise and quiet. PMID- 26443488 TI - Management of Children with Unilateral Hearing Loss. AB - Children with impaired hearing in one ear (unilateral hearing loss [UHL]) and normal hearing in the other ear experience challenges in understanding speech in noisy backgrounds and localizing the source of sounds in 3-dimensional space. They are at a high risk for speech and language delay and need educational help in school. However, definitive evidence of benefit from amplification is currently lacking to recommend placement of hearing aids or cochlear implants in all young children with UHL. Management of UHL in children should be guided by the child's development, performance in school, and personal/family values and preferences. PMID- 26443487 TI - Genetics of Hearing Loss: Syndromic. AB - Hearing loss (HL) is one of the most common birth defects in developed countries and is a diverse pathologic condition with different classifications. One of these is based on the association with other clinical features, defined as syndromic hearing loss (SHL). Determining the cause of the HL in these patients is extremely beneficial as it enables a personalized approach to caring for the individual. Early screening can further aid in optimal rehabilitation for a child's development and growth. The advancement of high-throughput sequencing technology is facilitating rapid and low-cost diagnostics for patients with SHL. PMID- 26443489 TI - Communication Assessment and Intervention: Implications for Pediatric Hearing Loss. AB - Historically, children with hearing loss have fallen well behind their hearing peers in the areas of speech and language development, which has often limited their participation in a range of social, educational, and vocational activities. However, with early identification and appropriate intervention coupled with current hearing technology, children with hearing loss can achieve speech and language milestones at rates commensurate with hearing peers. To attain the best outcomes for these children, an early intervention system that provides thorough and unbiased information to families and allows for the efficient and coordinated efforts of qualified professionals must be present. PMID- 26443491 TI - Prospective gait changes as a function of shifting perceptions of slipperiness: effects of visual and somatosensory cues. AB - Forty participants, ages 18-45 years, rated perceived slipperiness before and after walking on five different floors under three different surface conditions. The before-ratings were taken as a proxy for visual cues to slipperiness, while after-ratings were taken as a proxy for somatosensory feedback received while walking on the surface. Before and after ratings of slipperiness were used to predict gait parameters, as a function of trial, during repeated walking. Effects of after-ratings of slipperiness were observed beginning on the second trial, and continued through the fifth trial, while effects of before-ratings of slipperiness were most apparent on the first trial. When perceived slipperiness increased (or decreased) from before to after walking on the surface, gait became more (or less) protective across trials. It is concluded that both visual cues, as well as somatosensory feedback, are used in the prospective control of gait. Practitioner Summary: Effects of visual and somatosensory cues to slipperiness on gait were disentangled using floor surfaces varying in the slipperiness suggested by those cues. Visually based ratings of slipperiness predicted gait parameters on earlier trials, while somatosensory-based ratings predicted gait parameters on subsequent trials. Flooring design should provide reliable information regarding slipperiness. PMID- 26443490 TI - On the Horizon: Cochlear Implant Technology. AB - Cochlear implantation and cochlear implants (CIs) have a long history filled with innovations that have resulted in the high-performing device's currently available. Several promising technologies have been reviewed in this article, which hold the promise to drive performance even higher. Remote CI programming, totally implanted devices, improved neural health and survival through targeted drug therapy and delivery, intraneural electrode placement, electroacoustical stimulation and hybrid CIs, and methods to enhance the neural-prosthesis interface are evolving areas of innovation reviewed in this article. PMID- 26443492 TI - On the self-damping nature of densification in photonic sintering of nanoparticles. AB - Sintering of nanoparticle inks over large area-substrates is a key enabler for scalable fabrication of patterned and continuous films, with multiple emerging applications. The high speed and ambient condition operation of photonic sintering has elicited significant interest for this purpose. In this work, we experimentally characterize the temperature evolution and densification in photonic sintering of silver nanoparticle inks, as a function of nanoparticle size. It is shown that smaller nanoparticles result in faster densification, with lower temperatures during sintering, as compared to larger nanoparticles. Further, high densification can be achieved even without nanoparticle melting. Electromagnetic Finite Element Analysis of photonic heating is coupled to an analytical sintering model, to examine the role of interparticle neck growth in photonic sintering. It is shown that photonic sintering is an inherently self damping process, i.e., the progress of densification reduces the magnitude of subsequent photonic heating even before full density is reached. By accounting for this phenomenon, the developed coupled model better captures the experimentally observed sintering temperature and densification as compared to conventional photonic sintering models. Further, this model is used to uncover the reason behind the experimentally observed increase in densification with increasing weight ratio of smaller to larger nanoparticles. PMID- 26443494 TI - Editorial Comment to Urinary tract infection-like symptom is associated with worse bladder cancer outcomes in the Medicare population: Implications for sex disparities. PMID- 26443493 TI - Stepped care versus standard trauma-focused cognitive behavioral therapy for young children. AB - BACKGROUND: To compare the effectiveness and cost of stepped care trauma-focused cognitive behavioral therapy (SC-TF-CBT), a new service delivery method designed to address treatment barriers, to standard TF-CBT among young children who were experiencing posttraumatic stress symptoms (PTSS). METHODS: A total of 53 children (ages 3-7 years) who were experiencing PTSS were randomly assigned (2:1) to receive SC-TF-CBT or TF-CBT. Assessments by a blinded evaluator occurred at screening/baseline, after Step One for SC-TF-CBT, posttreatment, and 3-month follow-up. TRIAL REGISTRATION: ClinicalTrials.gov: https://www.clinicaltrials.gov/ct2/show/NCT01603563. RESULTS: There were comparable improvements over time in PTSS and secondary outcomes in both conditions. Noninferiority of SC-TF-CBT compared to TF-CBT was supported for the primary outcome of PTSS, and the secondary outcomes of severity and internalizing symptoms, but not for externalizing symptoms. There were no statistical differences in comparisons of changes over time from pre- to posttreatment and pre- to 3-month follow-up for posttraumatic stress disorder diagnostic status, treatment response, or remission. Parent satisfaction was high for both conditions. Costs were 51.3% lower for children in SC-TF-CBT compared to TF-CBT. CONCLUSIONS: Although future research is needed, preliminary evidence suggests that SC-TF-CBT is comparable to TF-CBT, and delivery costs are significantly less than standard care. SC-TF-CBT may be a viable service delivery system to address treatment barriers. PMID- 26443495 TI - Evaluating Guideline-recommended Pain Medication Use Among Patients with Newly Diagnosed Fibromyalgia. AB - OBJECTIVES: To compare pain medication treatment changes across cohorts of newly diagnosed patients with fibromyalgia (FM) treated with guideline-recommended medications or opioids. METHODS AND DESIGN: Retrospective claims data analysis examined adult commercial health plan members newly diagnosed with FM (initial diagnosis = index date) from January 2008 to February 2012. Patients had 6-month pre-index and 12-month postindex periods and received pain medication within 6 months postindex; cohorts were based on the first postindex medication. Guideline recommended medication cohorts were anti-epileptic drug (AED), serotonin norepinephrine reuptake inhibitor (SNRI), selective serotonin reuptake inhibitor (SSRI), and tricyclic antidepressant (TCA). Short-acting and long-acting opioid (SAO, LAO) cohorts were also identified. Pairwise comparisons with the SAO cohort were conducted. Cox proportional hazards regressions modeled the likelihood of receiving guideline-recommended therapy. RESULTS: The final sample was 96,175 patients (mean age 47.3 years; 72.5% female), distributed into SAO (57%), SSRI (22%), AED (10%), SNRI (6%), TCA (3%), and LAO (2%) cohorts. The SAO cohort had the most discontinuation (49% vs. 6% to 22%, P < 0.01) and the least augmentation (29% vs. 35% to 50%, P < 0.01). Regression analyses indicated that patients with (vs. without) pre-index guideline-recommended medications were 2 to 4 times more likely to receive them postindex. Patients in the opioid cohorts were about half as likely to receive subsequent guideline-recommended medications. CONCLUSIONS: Opioid use was widespread among patients with FM. Once patients received opioids postdiagnosis, the likelihood of receiving guideline-recommended medications was small. These real-world results indicate an opportunity may exist for improved FM management using recommended therapies in clinical practice. PMID- 26443496 TI - The AbgT family: A novel class of antimetabolite transporters. AB - The AbgT family of transporters was thought to contribute to bacterial folate biosynthesis by importing the catabolite p-aminobenzoyl-glutamate for producing this essential vitamin. Approximately 13,000 putative transporters of the family have been identified. However, before our work, no structural information was available and even functional data were minimal for this family of membrane proteins. To elucidate the structure and function of the AbgT family of transporters, we recently determined the X-ray structures of the full-length Alcanivorax borkumensis YdaH and Neisseria gonorrhoeae MtrF membrane proteins. The structures reveal that these two transporters assemble as dimers with architectures distinct from all other families of transporters. Both YdaH and MtrF are bowl-shaped dimers with a solvent-filled basin extending from the cytoplasm halfway across the membrane bilayer. The protomers of YdaH and MtrF contain nine transmembrane helices and two hairpins. These structures directly suggest a plausible pathway for substrate transport. A combination of the crystal structure, genetic analysis and substrate accumulation assay indicates that both YdaH and MtrF behave as exporters, capable of removing the folate metabolite p aminobenzoic acid from bacterial cells. Further experimental data based on drug susceptibility and radioactive transport assay suggest that both YdaH and MtrF participate as antibiotic efflux pumps, importantly mediating bacterial resistance to sulfonamide antimetabolite drugs. It is possible that many of these AbgT-family transporters act as exporters, thereby conferring bacterial resistance to sulfonamides. The AbgT-family transporters may be important targets for the rational design of novel antibiotics to combat bacterial infections. PMID- 26443497 TI - Heat shock protein 20 (HSP20) is a novel substrate for protein kinase D1 (PKD1). AB - Heat shock protein 20 (HSP20) has cardioprotective qualities, which are triggered by PKA phosphorylation. PKD1 is also a binding partner for HSP20, and this prompted us to investigate whether the chaperone was a substrate for PKD1. We delineate the PKD1 binding sites on HSP20 and show for the first time HSP20 is a substrate for PKD1. Phosphorylation of HSP20 by PKD1 is diminished by pharmacological or siRNA reduction of PKD1 activity and is enhanced following PKD1 activation. Our results suggest that both PKA and PKD1 can both phosphorylate HSP20 on serine 16 but that PKA is the most dominant. PMID- 26443498 TI - 2014 CODEPEH recommendations: Early detection of late onset deafness, audiological diagnosis, hearing aid fitting and early intervention. AB - The latest scientific literature considers early diagnosis of deafness as the key element to define the educational and inclusive prognosis of the deaf child, because it allows taking advantage of the critical period of development (0-4 years). Highly significant differences exist between deaf people who have been stimulated early and those who have received late or improper intervention. Early identification of late-onset disorders requires special attention and knowledge on the part of every childcare professional. Programs and additional actions beyond neonatal screening should be designed and planed to ensure that every child with a significant hearing loss is detected early. For this purpose, the CODEPEH would like to highlight the need for continuous monitoring of children's auditory health. Consequently, CODEPEH has drafted the recommendations included in the present document. PMID- 26443499 TI - Diversity-oriented synthesis of tetrathia[8]circulenes by sequential C-H borylation and annulation. AB - We have succeeded in the diversity-oriented synthesis of tetrathia[8]circulenes by sequential C-H borylation and annulation from cyclic tetrathiophene, and time resolved microwave conductivity studies have proved that the intrinsic hole mobilities of tetrathia[8]circulenes are dependent on the chain length of the alkyl substituents at the peripheral positions. PMID- 26443500 TI - One-Pot Aminoethylation of Indoles/Pyrroles with Alkynes and Sulfonyl Azides. AB - A general and efficient one-pot aminoethylation of substituted indoles/pyrroles was accomplished for the synthesis of various tryptamine derivatives employing a combination of alkynes and sulfonyl azides as readily accessible aminoethylating agents. The reaction features a successful integration of copper-catalyzed alkyne and azide cycloaddition to N-sulfonyl-1,2,3-triazole, rhodium-catalyzed selective insertion of alpha-iminocarbenes onto the C3-H bond of indoles, and reduction of the resultant enamides to tryptamine derivatives employing either NaCNBH3 or palladium catalyst, in one-pot. The reaction also showed excellent functional group tolerance and allowed the synthesis of various substituted tryptamines in good to excellent yield. This transformation constitutes a one-pot formal regioselective functionalization of terminal alkynes. Utility of the synthesized tryptamine was further demonstrated in the synthesis of dihydro-beta-carboline and tryptoline. PMID- 26443501 TI - Finding cannabinoids in hair does not prove cannabis consumption. AB - Hair analysis for cannabinoids is extensively applied in workplace drug testing and in child protection cases, although valid data on incorporation of the main analytical targets, ?9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-THC (THC COOH), into human hair is widely missing. Furthermore, ?9-tetrahydrocannabinolic acid A (THCA-A), the biogenetic precursor of THC, is found in the hair of persons who solely handled cannabis material. In the light of the serious consequences of positive test results the mechanisms of drug incorporation into hair urgently need scientific evaluation. Here we show that neither THC nor THCA-A are incorporated into human hair in relevant amounts after systemic uptake. THC-COOH, which is considered an incontestable proof of THC uptake according to the current scientific doctrine, was found in hair, but was also present in older hair segments, which already grew before the oral THC intake and in sebum/sweat samples. Our studies show that all three cannabinoids can be present in hair of non-consuming individuals because of transfer through cannabis consumers, via their hands, their sebum/sweat, or cannabis smoke. This is of concern for e.g. child-custody cases as cannabinoid findings in a child's hair may be caused by close contact to cannabis consumers rather than by inhalation of side-stream smoke. PMID- 26443502 TI - The mechanism of water/ion exchange at a protein surface: a weakly bound chloride in Helicobacter pylori apoflavodoxin. AB - Binding/unbinding of small ligands, such as ions, to/from proteins influences biochemical processes such as protein folding, enzyme catalysis or protein/ligand recognition. We have investigated the mechanism of chloride/water exchange at a protein surface (that of the apoflavodoxin from Helicobacter pylori) using classical all-atom molecular dynamics simulations. They reveal a variety of chloride exit routes and residence times; the latter is related to specific coordination modes of the anion. The role of solvent molecules in the mechanism of chloride unbinding has been studied in detail. We see no temporary increase in chloride coordination along the release process. Instead, the coordination of new water molecules takes place in most cases after the chloride/protein atom release event has begun. Moreover, the distribution function of water entrance events into the first chloride solvation shell peaks after chloride protein atom dissociation events. All these observations together seem to indicate that water molecules simply fill the vacancies left by the previously coordinating protein residues. We thus propose a step-by-step dissociation pathway in which protein/chloride interactions gradually break down before new water molecules progressively fill the vacant positions left by protein atoms. As observed for other systems, water molecules associated with bound chloride or with protein atoms have longer residence times than those bound to the free anion. The implications of the exchange mechanism proposed for the binding of the FMN (Flavin Mononucleotide) protein cofactor are discussed. PMID- 26443504 TI - The Escherichia coli Hemolysin. AB - The Escherichia coli hemolysin, earlier referred to as the hemolysin, is the best characterized repeats in toxin (RTX) secreted by a type I exoprotein secretion system. The E. coli hemolysin is a significant virulence factor in murine models of peritonitis and ascending urinary tract infection, which suggests it is likely to be an important cytotoxin in human, extraintestinal E. coli diseases. Among E. coli or Salmonella strains there are no known examples of strict RTX leukotoxins in which lytic activity is limited to white blood cells. The general gene organization of the Vibrio cholerae RTX locus is similar to that seen with either of the E. coli hly and ehx loci with C, B, and D RTX homologs, clearly indicating it is a member of the RTX family. The hemolysin occurs less frequently in cystitis strains and only rarely among normal fecal strains. Among the extraintestinal E. coli isolates, the hlyCABDgenes were among the first virulence factors localized to unique, tRNA-associated segments of E. coli chromosomes. The hemolysin genes were eventually linked to P-type pilin and cytotoxic necrotizing factor-1 genes. Recent progress with its study has slowed down because of the difficulty in deriving the physical structure of the hemolysin protein or other RTX toxins and establishing its precise cytotoxic mechanism and role in pathogenesis of extraintestinal E. coli disease. Genomic sequencing has revealed that there are additional RTX-like genes found among many different pathogens; perhaps new efforts to discover their functions will aid progress in the RTX toxin field. PMID- 26443503 TI - Implicit Theories Relate to Youth Psychopathology, But How? A Longitudinal Test of Two Predictive Models. AB - Research shows relations between entity theories-i.e., beliefs that traits and abilities are unchangeable-and youth psychopathology. A common interpretation has been that entity theories lead to psychopathology, but another possibility is that psychopathology predicts entity theories. The two models carry different implications for developmental psychopathology and intervention design. We tested each model's plausibility, examining longitudinal associations between entity theories of thoughts, feelings, and behavior and psychopathology in early adolescents across one school year (N = 59, 52 % female, ages 11-14, 0 % attrition). Baseline entity theories did not predict increases in psychopathology; instead, baseline psychopathology predicted increased entity theories over time. When symptom clusters were assessed individually, greater youth internalizing (but not externalizing) problems predicted subsequent increases in entity theories. Findings suggest that the commonly proposed predictive model may not be the only one warranting attention. They suggest that youth psychopathology may contribute to the development of certain kinds of entity theories. PMID- 26443505 TI - Glycolysis and Flux Control. AB - Central metabolism of carbohydrates uses the Embden-Meyerhof-Parnas (EMP), pentose phosphate (PP), and Entner-Doudoroff (ED) pathways. This review reviews the biological roles of the enzymes and genes of these three pathways of E. coli. Glucose, pentoses, and gluconate are primarily discussed as the initial substrates of the three pathways, respectively. The genetic and allosteric regulatory mechanisms of glycolysis and the factors that affect metabolic flux through the pathways are considered here. Despite the fact that a lot of information on each of the reaction steps has been accumulated over the years for E. coli, surprisingly little quantitative information has been integrated to analyze glycolysis as a system. Therefore, the review presents a detailed description of each of the catalytic steps by a systemic approach. It considers both structural and kinetic aspects. Models that include kinetic information of the reaction steps will always contain the reaction stoichiometry and therefore follow the structural constraints, but in addition to these also kinetic rate laws must be fulfilled. The kinetic information obtained on isolated enzymes can be integrated using computer models to simulate behavior of the reaction network formed by these enzymes. Successful examples of such approaches are the modeling of glycolysis in S. cerevisiae, the parasite Trypanosoma brucei, and the red blood cell. With the rapid developments in the field of Systems Biology many new methods have been and will be developed, for experimental and theoretical approaches, and the authors expect that these will be applied to E. coli glycolysis in the near future. PMID- 26443506 TI - Glycerol and Methylglyoxal Metabolism. AB - The metabolic connection between glycerol and methylglyoxal (MG) is principally that DHAP, which is an intermediate in the aerobic breakdown of glycerol, is also the major precursor of MG, being the substrate for methylglyoxal synthase (MGS). The synthesis of MG is a consequence of unbalanced metabolism related either to a limitation for phosphate or to excessive carbon flux through the pathways that have the capacity to generate significant pools of DHAP. Cells producing MG produce a poison as an intermediate strategy for survival of metabolic imbalance. Indeed the panoply of metabolic regulation in this sector of catabolism can be seen as a strategy to avoid death by self-poisoning. Glycerol entry into Escherichia coli and Salmonella enterica serovar Typhimurium is facilitated by the aquaglyceroporin, GlpF. A homologous protein in serovar Typhimurium, PduF, facilitates the entry of 1,2-propanediol (Ppd) and is part of the Ppd metabolic pathway. MGS catalyzes the elimination of phosphate from DHAP, forming an enzyme bound enediol(ate) intermediate that is released from the enzyme, followed by release of inorganic phosphate. The enzyme is highly specific for DHAP. Multiple MG detoxification pathways are found in both E. coli and serovar Typhimurium, but the dominant pathway is the GSH-dependent glyoxalase III system. The KefB and KefC systems have evolved to provide protection during detoxification of electrophiles. KefB and KefC are GSH-gated K+ efflux systems that are activated by the formation and binding of glutathione adducts that are generated during detoxification. PMID- 26443507 TI - Catabolism of Amino Acids and Related Compounds. AB - This review considers the pathways for the degradation of amino acids and a few related compounds (agmatine, putrescine, ornithine, and aminobutyrate), along with their functions and regulation. Nitrogen limitation and an acidic environment are two physiological cues that regulate expression of several amino acid catabolic genes. The review considers Escherichia coli, Salmonella enterica serovar Typhimurium, and Klebsiella species. The latter is included because the pathways in Klebsiella species have often been thoroughly characterized and also because of interesting differences in pathway regulation. These organisms can essentially degrade all the protein amino acids, except for the three branched chain amino acids. E. coli, Salmonella enterica serovar Typhimurium, and Klebsiella aerogenes can assimilate nitrogen from D- and L-alanine, arginine, asparagine, aspartate, glutamate, glutamine, glycine, proline, and D- and L serine. There are species differences in the utilization of agmatine, citrulline, cysteine, histidine, the aromatic amino acids, and polyamines (putrescine and spermidine). Regardless of the pathway of glutamate synthesis, nitrogen source catabolism must generate ammonia for glutamine synthesis. Loss of glutamate synthase (glutamineoxoglutarate amidotransferase, or GOGAT) prevents utilization of many organic nitrogen sources. Mutations that create or increase a requirement for ammonia also prevent utilization of most organic nitrogen sources. PMID- 26443508 TI - Transfer RNA Modification. AB - Transfer RNA (tRNA) from all organisms on this planet contains modified nucleosides, which are derivatives of the four major nucleosides. tRNA from Escherichia coli/Salmonella enterica contains 31 different modified nucleosides, which are all, except for one (Queuosine[Q]), synthesized on an oligonucleotide precursor, which through specific enzymes later matures into tRNA. The corresponding structural genes for these enzymes are found in mono- and polycistronic operons, the latter of which have a complex transcription and translation pattern. The syntheses of some of them (e.g.,several methylated derivatives) are catalyzed by one enzyme, which is position and base specific, but synthesis of some have a very complex biosynthetic pathway involving several enzymes (e.g., 2-thiouridines, N6-threonyladenosine [t6A],and Q). Several of the modified nucleosides are essential for viability (e.g.,lysidin, t6A, 1 methylguanosine), whereas deficiency in others induces severe growth defects. However, some have no or only a small effect on growth at laboratory conditions. Modified nucleosides that are present in the anticodon loop or stem have a fundamental influence on the efficiency of charging the tRNA, reading cognate codons, and preventing missense and frameshift errors. Those, which are present in the body of the tRNA, have a primarily stabilizing effect on the tRNA. Thus, the ubiquitouspresence of these modified nucleosides plays a pivotal role in the function of the tRNA by their influence on the stability and activity of the tRNA. PMID- 26443509 TI - Two-Carbon Compounds and Fatty Acids as Carbon Sources. AB - This review concerns the uptake and degradation of those molecules that are wholly or largely converted to acetyl-coenzyme A (CoA) in the first stage of metabolism in Escherichia coli and Salmonella enterica. These include acetate, acetoacetate, butyrate and longer fatty acids in wild type cells plus ethanol and some longer alcohols in certain mutant strains. Entering metabolism as acetyl-CoA has two important general consequences. First, generation of energy from acetyl CoA requires operation of both the citric acid cycle and the respiratory chain to oxidize the NADH produced. Hence, acetyl-CoA serves as an energy source only during aerobic growth or during anaerobic respiration with such alternative electron acceptors as nitrate or trimethylamine oxide. In the absence of a suitable oxidant, acetyl-CoA is converted to a mixture of acetic acid and ethanol by the pathways of anaerobic fermentation. Catabolism of acetyl-CoA via the citric acid cycle releases both carbon atoms of the acetyl moiety as carbon dioxide and growth on these substrates as sole carbon source therefore requires the operation of the glyoxylate bypass to generate cell material. The pair of related two-carbon compounds, glycolate and glyoxylate are also discussed. However, despite having two carbons, these are metabolized via malate and glycerate, not via acetyl-CoA. In addition, mutants of E. coli capable of growth on ethylene glycol metabolize it via the glycolate pathway, rather than via acetyl- CoA. Propionate metabolism is also discussed because in many respects its pathway is analogous to that of acetate. The transcriptional regulation of these pathways is discussed in detail. PMID- 26443510 TI - Adhesins of Enterotoxigenic Escherichia coli Strains That Infect Animals. AB - The first described adhesive antigen of Escherichia coli strains isolated from animals was the K88 antigen, expressed by strains from diarrheic pigs. The K88 antigen was visible by electron microscopy as a surface-exposed filament that was thin and flexible and had hemagglutinating properties. Many different fimbriae have been identified in animal enterotoxigenic E. coli (ETEC) and have been discussed in this article. The role of these fimbriae in the pathogenesis of ETEC has been best studied with K88, K99, 987P, and F41. Each fimbrial type carries at least one adhesive moiety that is specific for a certain host receptor, determining host species, age, and tissue specificities. ETEC are the most frequently diagnosed pathogens among neonatal and post-weaning piglets that die of diarrhea. Immune electron microscopy of animal ETEC fimbriae usually shows that the minor subunits are located at the fimbrial tips and at discrete sites along the fimbrial threads. Since fimbriae most frequently act like lectins by binding to the carbohydrate moieties of glycoproteins or glycolipids, fimbrial receptors have frequently been studied with red blood cells of various animal species. Identification and characterization of the binding moieties of ETEC fimbrial adhesins should be useful for the design of new prophylactic or therapeutic strategies. Some studies describing potential receptor or adhesin analogues that interfere with fimbria-mediated colonization have been described in the article. PMID- 26443511 TI - Outer Membrane Vesicles. AB - Outer membrane vesicles (blebs) are produced by Escherichia coli, Salmonella, and all other gram-negative bacteria both in vitro and in vivo. Most of the research in the field has focused on the properties of vesicles derived from pathogenic bacteria and their interactions with eukaryotic cells. These data indicate that vesicles are able to contribute to pathogenesis. Thus, it appears that pathogenic gram-negative bacteria have co-opted vesicles for the dissemination of virulence determinants. However, the role of vesicle production by nonpathogenic bacteria is less obvious. This section reviews the data demonstrating the mechanistic and physiological basis of outer membrane vesicle production by bacteria. Vesiculation can be seen as a mechanism for cells to react to conditions in the surrounding environment by carrying away unnecessary components and allowing rapid modification of the outer membrane composition. In addition, vesicles can transmit biological activities distant from the originating cell. Vesicles could act to bind and deplete host immune factors at the site of infection that would otherwise attack the bacteria. Vesicles in the area surrounding the cell may also provide the cell protection inside a human or animal host. The concept of vesicles as virulence factors has received considerable attention, and they are likely to play a significant role in the pathogenesis of gram-negative bacteria. By analysis of their composition, mechanism of formation, regulation, and physiological function, progress is being made in understanding the ubiquitous nature of outer membrane vesicles produced by gram-negative bacteria. PMID- 26443512 TI - Adhesins of Diffusely Adherent and Enteroaggregative Escherichia coli. AB - Epidemiological studies have implicated enteroaggregative Escherichia coli (EAEC) strains in acute and persistent diarrhea in children, in food-borne diarrhea outbreaks, and in traveler's diarrhea, and this group is recognized as an emerging pathotype of enteric disease. Diffusely adherent E. coli (DAEC) have been implicated as a cause of diarrhea, especially in children more than 2 years old, in both developing and developed countries. Although EAEC and DAEC strains appear to have different molecular equipment for attachment to host cell surfaces, identification and characterization of the gene clusters encoding adherence evidenced close relatedness between those determinants most frequently detected in isolates belonging to these two pathotypes of diarrheagenic E. coli. DAEC strains are a heterogeneous group of E. coli isolates, many of which express the related so-called Dr adhesins. The single designation is based on the identification of one similar cellular receptor for all these proteins. Although structurally different, they all recognize the Dr human blood group antigen on the decay-accelerating factor (DAF or CD55). These adhesins are encoded by a family of closely related operons, the first characterized and sequenced being the afa operon. Consequently, it has been suggested that this group of DAEC strains producing such adhesins be named the Afa/Dr DAEC family. Three distinct but closely related gene clusters coding for phenotypically and morphologically distinct aggregative adherence fimbriae (AAF) have been characterized. In each case, electron microscopy revealed that bacterial surfaces were surrounded by long, relatively flexible fimbrial structures. PMID- 26443513 TI - Nitric Oxide in Salmonella and Escherichia coli Infections. AB - This review discusses the role that nitric oxide (NO) and its congeners play on various stages in the pathophysiology of Escherichia coli and Salmonella infections, with special emphasis on the regulatory pathways that lead to high NO synthesis, the role of reactive nitrogen species (RNS) in host resistance, and the bacterial molecular targets and defense mechanisms that protect enteric bacteria against the nitrosative stress encountered in diverse host anatomical sites. In general, NO can react directly with prosthetic groups containing transition metal centers, with other radicals, or with sulfhydryl groups in the presence of an electron acceptor. Binding to iron complexes is probably the best characterized direct reaction of NO in biological systems. The targets of RNS are numerous. RNS can facilitate oxidative modifications including lipid peroxidation, hydroxylation, and DNA base and protein oxidation. In addition, RNS can inflict nitrosative stress through the nitrosation of amines and sulfhydryls. Numerous vital bacterial molecules can be targeted by NO. It is therefore not surprising that enteropathogenic bacteria are armed with a number of sensors to coordinate the protective response to nitrosative stress, along with an assortment of antinitrosative defenses that detoxify, repair, or avoid the deleterious effects of RNS encountered within the host. NO and NO-derived RNS play important roles in innate immunity to Salmonella and E. coli. Enzymatic NO production by NO synthases can be enhanced by microbial and other inflammatory stimuli and it exerts direct antimicrobial actions as well as immunomodulatory and vasoregulatory effects. PMID- 26443514 TI - Shiga Toxins: Potent Poisons, Pathogenicity Determinants, and Pharmacological Agents. AB - The Shiga toxins (Stxs), also known as Vero toxins and previously called Shiga like toxins, are a family of potent protein synthesis inhibitors made by Shigella dysenteriae type 1 and some serogroups of Escherichia coli that cause bloody diarrhea in humans. Stxs act as virulence factors for both S. dysenteriae and E. coli and contribute to the disease process initiated by those organisms both directly and indirectly. A handful of methods exist for toxin purification, and the toxins can now even be purchased commercially. However, the Stxs are now classified as select agents, and specific rules govern the distribution of both the toxin and clones of the toxin. Toxin delivery into the host in S. dysenteriae type 1 is most likely aided by the invasiveness of that organism. Although the Stxs are made and produced by bacteria, they do not appear to act against either their host organism or other bacteria under normal circumstances, most likely because the A subunit is secreted from the cytoplasm as soon as it is synthesized and because the holotoxin cannot enter intact bacterial cells. The effectiveness of antibiotic therapy in patients infected with Stx-producing E. coli (STEC) such as O157:H7 as well as the potential risks of such treatment are areas of controversy. Several studies indicate that the course of the diarrhea stage of the disease is unaltered by antibiotic treatment. Several groups anticipate that a therapy that targets the Stxs is an important component of trying to alleviate disease caused by Stx-producing bacteria. PMID- 26443515 TI - Adhesins of Enterohemorrhagic Escherichia coli. AB - Enterohemorrhagic Escherichia coli (EHEC) was first recognized as a cause of human disease in 1983 and is associated with diarrhea and hemorrhagic colitis, which may be complicated by life-threatening renal and neurological sequelae. EHEC are defined by their ability to produce one or more Shiga-like toxins (Stx), which mediate the systemic complications of EHEC infections, and to induce characteristic attaching and effacing lesions on intestinal epithelia, a phenotype that depends on the locus of enterocyte effacement. Acquisition of Stx encoding bacteriophages by enteropathogenic E. coli is believed to have contributed to the evolution of EHEC, and consequently some virulence factors are conserved in both pathotypes. A key requirement for E. coli to colonize the intestines and produce disease is the ability to adhere to epithelial cells lining the gastrointestinal tract. Here, we review knowledge of the adhesins produced by EHEC and other Stx-producing E. coli, with emphasis on genetic, structural, and mechanistic aspects and their contribution to pathogenesis. PMID- 26443516 TI - Hexose/Pentose and Hexitol/Pentitol Metabolism. AB - Escherichia coli and Salmonella enterica serovar Typhimurium exhibit a remarkable versatility in the usage of different sugars as the sole source of carbon and energy, reflecting their ability to make use of the digested meals of mammalia and of the ample offerings in the wild. Degradation of sugars starts with their energy-dependent uptake through the cytoplasmic membrane and is carried on further by specific enzymes in the cytoplasm, destined finally for degradation in central metabolic pathways. As variant as the different sugars are, the biochemical strategies to act on them are few. They include phosphorylation, keto enol isomerization, oxido/reductions, and aldol cleavage. The catabolic repertoire for using carbohydrate sources is largely the same in E. coli and in serovar Typhimurium. Nonetheless, significant differences are found, even among the strains and substrains of each species. We have grouped the sugars to be discussed according to their first step in metabolism, which is their active transport, and follow their path to glycolysis, catalyzed by the sugar-specific enzymes. We will first discuss the phosphotransferase system (PTS) sugars, then the sugars transported by ATP-binding cassette (ABC) transporters, followed by those that are taken up via proton motive force (PMF)-dependent transporters. We have focused on the catabolism and pathway regulation of hexose and pentose monosaccharides as well as the corresponding sugar alcohols but have also included disaccharides and simple glycosides while excluding polysaccharide catabolism, except for maltodextrins. PMID- 26443517 TI - Autotransporter Proteins. AB - This review focuses on the function of the Escherichia coli and Salmonella autotransporters for which a considerable amount of literature is available. Members of the serine protease autotransporters of the Enterobacteriaceae (SPATEs) family are proteins from E. coli and Shigella spp., which, like the Neisseria and Haemophilus influenzae IgA1 proteases and Hap, possess a consensus serine protease motif. The largest subfamily of autotransporters is defined by the AidA conserved domain COG3468 and consists of members from a diverse range of animal and plant pathogens including E. coli, S. enterica, Yersinia pestis. This subfamily, which is composed of more than 55 proteins, possesses some of the best characterized autotransporter proteins including the S. flexneri mediator of motility IcsA, the major phase-variable E. coli outer membrane protein antigen 43 (Ag43) and the diffuse adhering E. coli (DAEC) adhesin AIDA-I, from which this subfamily derives its name. Another member of the AIDA-I family, and one of the most studied autotransporter proteins, is IcsA. The autotransporter pathway is emerging as the most common mechanism of protein translocation across the gram negative outer membrane. PMID- 26443518 TI - Colonization of Abiotic Surfaces. AB - E. coli is a relevant model organism for the study of the molecular mechanisms underlying surface colonization. This process requires two essential steps: adhesion to a surface, followed by cell-cell adhesion counteracting the shear forces of the environment, with both steps contributing to the formation of a biofilm. This review provides an overview of the current knowledge of the genetic analyses aiming at identifying factors involved in both of these two highly related biological processes, with a particular emphasis on studies performed in Escherichia coli K-12. Bacterial adhesion to abiotic surfaces is likely to be highly dependent on the physicochemical and electrostatic interactions between the bacterial envelope and the substrate, which is itself often conditioned by the fluids to which it is exposed. Genetic analyses have revealed the diversity of genetic factors in E. coli that participate in colonization and biofilm formation on abiotic surfaces. The study of surface colonization and biofilm formation represents a rapidly expanding field of investigation. The use of E. coli K-12 to investigate the genetic basis of bacterial interactions with surfaces has led to the identification of a large repertoire of adhesins whose expression is subject to a complex interplay between regulatory networks. Understanding how E. coli K-12 behaves in complex biofilm communities will certainly contribute to an understanding of how natural commensal and pathogenic E. coli isolates develop. PMID- 26443519 TI - Imaging Techniques for the Study of Escherichia coli and Salmonella Infections. AB - Infectious diseases are among the leading causes of mortality worldwide, and numerous bacterial species are included in the vast array of causative agents. This review describes microscopy-based techniques that can be used to study interactions between bacteria and infected host cells, bacterial gene expression in the infected animal, and bacteria-induced cell signaling in eukaryotic cells. As infectious model systems, urinary tract infections caused by uropathogenic Escherichia coli (UPEC) and a mouse model of typhoid fever caused by Salmonella enterica serovar Typhimurium are used. To study the interaction mechanism between bacteria and eukaryotic cells, one commonly uses cell lines, primary cells, and animal models. Within the host, bacteria can be located in various organs where they are exposed to different cell types, ranging from epithelial cells at the mucosal linings to phagocytic white blood cells. In each site, bacteria are exposed to specific sets of innate immune defense mechanisms, and to survive these threats, bacteria must rapidly adapt their gene expression profile to maximize their chance of survival in any situation. The rapid development of fluorescent reporter proteins and advances in microscopy-based techniques have provided new and promising approaches not only to locate bacteria in tissues, but also to analyze expression of virulence factors in individual bacteria and host cells during the progression of disease. These techniques enable, for the first time, studies of the complex microenvironments within infected organs and will reveal the alterations of bacterial physiology that occur during bacterial growth within a host. PMID- 26443520 TI - Tricarboxylic Acid Cycle and Glyoxylate Bypass. AB - The tricarboxylic acid (TCA) cycle plays two essential roles in metabolism. First, under aerobic conditions the cycle is responsible for the total oxidation of acetyl-CoA that is derived mainly from the pyruvate produced by glycolysis. Second, TCA cycle intermediates are required in the biosynthesis of several amino acids. Although the TCA cycle has long been considered a "housekeeping" pathway in Escherichia coli and Salmonella enterica, the pathway is highly regulated at the transcriptional level. Much of this control is exerted in response to respiratory conditions. The TCA cycle gene-protein relationship and mutant phenotypes have been well studied, although a few loose ends remain. The realization that a "shadow" TCA cycle exists that proceeds through methylcitrate has cleared up prior ambiguities. The glyoxylate bypass has long been known to be essential for growth on carbon sources such as acetate or fatty acids because this pathway allowsnet conversion of acetyl-CoA to metabolic intermediates. Strains lacking this pathway fail to grow on these carbon sources, since acetate carbon entering the TCA cycle is quantitatively lost as CO2 resulting in the lack of a means to replenish the dicarboxylic acids consumed in amino acid biosynthesis. The TCA cycle gene-protein relationship and mutant phenotypes have been well studied, although the identity of the small molecule ligand that modulates transcriptional control of the glyoxylate cycle genes by binding to the IclR repressor remains unknown. The activity of the cycle is also exerted at the enzyme level by the reversible phosphorylation of the TCA cycle enzyme isocitrate dehydrogenase catalyzed by a specific kinase/phosphatase to allow isocitratelyase to compete for isocitrate and cleave this intermediate to glyoxylate and succinate. PMID- 26443521 TI - Salmonella Epidemiology and Pathogenesis in Food-Producing Animals. AB - This review reviews the pathogenesis of different phases of Salmonella infections. The nature of Salmonella infections in several domesticated animal species is described to highlight differences in the epidemiology and pathogenesis of salmonellosis in different hosts. The biology of Salmonella serovar host specificity is discussed in the context of our current understanding of the molecular basis of pathogenesis and the potential impact of different virulence determinants on Salmonella natural history. The ability to colonize the intestine, as evidenced by the shedding of relatively large numbers of bacteria in the feces over a long period, is shared unequally by Salmonella serovars. Studies probing the molecular basis of Salmonella intestinal colonization have been carried out by screening random transposon mutant banks of serovar Typhimurium in a range of avian and mammalian species. It is becoming increasingly clear that Salmonella pathogenicity island 2 (SPI2) is a major virulence factor during infection of food-producing animals, including cattle and poultry. The prevalence of Salmonella serovars in domestic fowl varies in different countries and with time. Although chickens are the natural hosts of serovars Gallinarum and Pullorum, natural outbreaks caused by these serovars in turkeys, guinea fowl, and other avian species have been described. There are two possible explanations to account for the apparent host specificity of certain Salmonella serovars. Environmental factors may increase exposure of particular animal species to certain serovars. Alternatively, there are genetic differences between these serovars, which allow them to survive and/or grow in specific niches only found within ruminants or pigs. PMID- 26443522 TI - Intracellular Voyeurism: Examining the Modulation of Host Cell Activities bySalmonella enterica Serovar Typhimurium. AB - Salmonella spp. can infect host cells by gaining entry through phagocytosis or by inducing host cell membrane ruffling that facilitates bacterial uptake. With its wide host range, Salmonella enterica serovar Typhimurium has proven to be an important model organism for studying intracellular bacterial pathogenesis. Upon entry into host cells, serovar Typhimurium typically resides within a membrane bound compartment termed the Salmonella-containing vacuole (SCV). From the SCV, serovar Typhimurium can inject several effector proteins that subvert many normal host cell systems, including endocytic trafficking, cytoskeletal rearrangements, lipid signaling and distribution, and innate and adaptive host defenses. The study of these intracellular events has been made possible through the use of various imaging techniques, ranging from classic methods of transmission electron microscopy to advanced livecell fluorescence confocal microscopy. In addition, DNA microarrays have now been used to provide a "snapshot" of global gene expression in serovar Typhimurium residing within the infected host cell. This review describes key aspects of Salmonella-induced subversion of host cell activities, providing examples of imaging that have been used to elucidate these events. Serovar Typhimurium engages specific host cell machinery from initial contact with the host cell to replication within the SCV. This continuous interaction with the host cell has likely contributed to the extensive arsenal that serovar Typhimurium now possesses, including two type III secretion systems, a range of ammunition in the form of TTSS effectors, and a complex genetic regulatory network that coordinates the expression of hundreds of virulence factors. PMID- 26443523 TI - Changes in the transcriptome of bovine ovarian cortex during follicle activation in vitro. AB - The signals that regulate activation, a key transition in ovarian follicular development, are still not well understood, especially in nonrodent species. To gain insight into the regulation of this transition in cattle, we combined a microarray approach with an in vitro system in which ovarian cortical pieces cultured in control medium are enriched for primordial follicles, whereas pieces cultured with insulin are enriched for primary follicles. Total RNA was extracted from cultured cortical pieces, and then transcripts were identified and analyzed using the Affymetrix Bovine Genome GeneChip array. Around 65% of the transcripts in the bovine GeneChip were detected in cultured cortical pieces. Comparison between pieces cultured with or without insulin generated 158 differentially expressed transcripts. Compared with controls, 90 transcripts were upregulated and 68 were downregulated by insulin. These transcripts are involved in many biological processes and functions, but most are associated with cellular growth or cell cycle/cell death. The transcript encoding ubiquitin-conjugating enzyme E2C (UBE2C) was significantly upregulated during follicle activation, and Ingenuity Pathways Analysis revealed that UBE2C can interact with the tumor suppressor phosphatase and tensin homolog (PTEN). Both PTEN mRNA and protein were lower in cortical pieces cultured with insulin than in controls. In addition, FOXO3a, a downstream effector of PTEN signaling, underwent nuclear-cytoplasmic shuttling during primordial to primary follicle development in bovine fetal ovaries, further suggesting the involvement of the PTEN pathway in follicle activation in cattle. Genes and pathways identified in this study provide interesting candidates for further investigation of mechanisms underlying follicle activation. PMID- 26443525 TI - Patched bimetallic surfaces are active catalysts for ammonia decomposition. AB - Ammonia decomposition is often used as an archetypical reaction for predicting new catalytic materials and understanding the very reason of why some reactions are sensitive on material's structure. Core-shell or surface-segregated bimetallic nanoparticles expose outstanding activity for many heterogeneously catalysed reactions but the reasons remain elusive owing to the difficulties in experimentally characterizing active sites. Here by performing multiscale simulations in ammonia decomposition on various nickel loadings on platinum (111), we show that the very high activity of core-shell structures requires patches of the guest metal to create and sustain dual active sites: nickel terraces catalyse N-H bond breaking and nickel edge sites drive atomic nitrogen association. The structure sensitivity on these active catalysts depends profoundly on reaction conditions due to kinetically competing relevant elementary reaction steps. We expose a remarkable difference in active sites between transient and steady-state studies and provide insights into optimal material design. PMID- 26443524 TI - Crosstalk between purinergic receptors and canonical signaling pathways in the mouse salivary gland. AB - Isolated clusters of mouse parotid acinar cells in combination with live cell imaging were used to explore the crosstalk in molecular signaling between purinergic, cholinergic and adrenergic pathways that integrate to control fluid and protein secretion. This crosstalk was manifested by (1) beta-adrenergic receptor activation and amplification of P2X4R evoked Ca(2+) signals, (2) beta adrenergic-induced amplification of P2X7R-evoked Ca(2+) signals and (3) muscarinic receptor induced activation of P2X7Rs via exocytotic activity. The findings from our study reveal that purinoceptor-mediated Ca(2+) signaling is modulated by crosstalk with canonical signaling pathways in parotid acinar cells. Integration of these signals are likely important for dynamic control of saliva secretion to match physiological demand in the parotid gland. PMID- 26443526 TI - Whispering-gallery nanocavity plasmon-enhanced Raman spectroscopy. AB - The synergy effect in nature could enable fantastic improvement of functional properties and associated effects. The detection performance of surface-enhanced Raman scattering (SERS) can be highly strengthened under the cooperation with other factors. Here, greatly-enhanced SERS detection is realized based on rolled up tubular nano-resonators decorated with silver nanoparticles. The synergy effect between whispering-gallery-mode (WGM) and surface plasmon leads to an extra enhancement at the order of 10(5) compared to non-resonant flat SERS substrates, which can be well tuned by altering the diameter of micron- and nanotubes and the excitation laser wavelengths. Such synchronous and coherent coupling between plasmonics and photonics could lead to new principle and design for various sub-wavelength optical devices, e.g. plasmonic waveguides and hyperbolic metamaterials. PMID- 26443527 TI - Prophylactic Laparoscopic Total Gastrectomy with Jejunal Pouch Reconstruction in Patients Carrying a CDH1 Germline Mutation. AB - BACKGROUND: For patients with an identified germline E-cadherin-1 (CDH1) mutation, prophylactic gastrectomy is the treatment of choice to eliminate the high risk of developing diffuse gastric cancer. Laparoscopic total gastrectomy with jejunal pouch reconstruction is a novel approach that may be especially suitable in these patients. METHODS: Patients with a germline CDH1 mutation who underwent prophylactic laparoscopic total gastrectomy with jejunal pouch were included in our prospective database. RESULTS: A total of 11 patients with a median age of 40 (22-61) years were included. The average operative time was 4:26 +/- 0:49 h and the average blood loss was 219 +/- 155 ml. Median length of hospital stay was 10 (7-27) days. In two patients, an esophagojejunal anastomotic leakage occurred (grade 4). The leakages were seen in patient numbers 2 and 3, which may be a result of a learning curve. The latter eight patients did not develop anastomotic leakage. Pulmonary complications occurred in one patient with atelectasis and in one patient with pneumonia (grade 2). The 60-day mortality rate was 0 %. Multiple foci of intramucosal diffuse gastric signet ring cell carcinoma were found in the resection specimen of 9/11 (82 %) patients. All 11/11 (100 %) resections were microscopically radical. CONCLUSIONS: Prophylactic laparoscopic total gastrectomy with jejunal pouch reconstruction in patients with a CDH1 germline mutation is feasible and safe. In 82 % of patients, foci of intramucosal diffuse gastric signet ring cell carcinoma in the resection specimen were found. PMID- 26443528 TI - The Neutrophil-to-Lymphocyte Ratio Predicts Malignant Potential in Intraductal Papillary Mucinous Neoplasms. AB - BACKGROUND: Accurately identifying malignant components in patients with pancreatic intraductal papillary mucinous neoplasms (IPMN) remains challenging. Preoperative neutrophil-to-lymphocyte ratio (NLR) is a marker of poor prognosis in patients with several types of malignancy. This study assessed whether NLR was predictive of intraductal papillary mucinous carcinoma (IPMC) in patients with IPMN. METHOD: This study retrospectively assessed 76 patients who underwent curative resection for IPMN from 1995 to 2015. The correlation between the presence of malignant components and preoperative NLR was analyzed. RESULTS: Preoperative NLR in IPMC was significantly higher in patients with in IPMC (2.51 +/- 0.84) than in patients with intraductal papillary mucinous adenoma (2.01 +/- 0.71, P = 0.0079) and healthy volunteers (1.37 +/- 0.33, P < 0.0001). NLR was significantly reduced after curative tumor resection. The main duct type (P = 0.0231) and NLR >2.074 (P = 0.0329) were independent predictors of IPMC in all patients. Combined criteria including international consensus guidelines, CA19-9 >37 IU/ml, and NLR >2.074 shows a high positive predictive value of 78 % and high specificity of 96 %. CONCLUSIONS: Preoperative NLR is a useful supportive marker to predict IPMC in patients with IPMN. PMID- 26443529 TI - Is Abdominal Fat Distribution Measured by Axial CT Imaging an Indicator of Complications and Mortality in Acute Pancreatitis? AB - BACKGROUND: Obesity is an important risk-stratifying co-morbidity for many pathological conditions. Controversy exists about its influence in outcomes after acute pancreatitis (AP). This study assessed abdominal fat distribution (subcutaneous, retroperitoneal and intra-abdominal) measured using computer tomography (CT) images and related it to outcomes in patients with AP. METHODS: The case notes of patients admitted with AP were identified from computerised records from 2008 to the 2013. Image analysis software was used to assess the individual abdominal fat distributions from CT images. RESULTS: A total of 79 patients were included. There was no relationship between fat distribution and either severity of, or mortality from, AP. Fat distribution was not found to be an independent risk factor on multivariate analysis. There was, however, a positive correlation between retroperitoneal and intra-abdominal fat with APACHE II scores, Ranson and Glasgow score and Multiple Organ Dysfunction score (MODS) on various days following admission (r = 0.421, p = 0.0008; r = 0.469, p < 0.0001; r = 0.398, p = 0.007; r = 0.336, p = 0.011, respectively). On multiple logistical regression analysis, the only variables associated with mortality were Balthazar Severity Index, MODS and EWS with a p value of <0.0001, 0.0019 and 0.0481, respectively. CONCLUSIONS: Obese patients have worse predicted outcomes as measured by the EWS, MODS and Ranson scores. Abdominal fat distribution, however, was not shown to be directly related to AP severity or mortality. The addition of fat parameters may be of use in prognostic CT severity index models, but from this data, it does not appear to be an independent risk factor of adverse outcome. PMID- 26443531 TI - The 2015 Karl Meyer Lectureship Award and the Rosalind Kornfeld Award for Lifetime Achievement in Glycobiology, from the Society for Glycobiology. PMID- 26443532 TI - Remembering J. A. Cifonelli (1916-2005) An Early Leader in Glycosaminoglycan Biochemistry. PMID- 26443533 TI - Using political science to progress public health nutrition: a systematic review. AB - OBJECTIVE: Poor dietary intake is the most important behavioural risk factor affecting health globally. Despite this, there has been little investment in public health nutrition policy actions. Policy process theories from the field of political science can aid understanding why policy decisions have occurred and identify how to influence ongoing or future initiatives. The present review aims to examine public health nutrition policy literature and identify whether a policy process theory has been used to analyse the process. DESIGN: Electronic databases were searched systematically for studies examining policy making in public health nutrition in high-income, democratic countries. SETTING: International, national, state and local government jurisdictions within high income, democratic countries. SUBJECTS: Individuals and organisations involved in the nutrition policy-making process. RESULTS: Sixty-three studies met the eligibility criteria, most were conducted in the USA and a majority focused on obesity. The analysis demonstrates an accelerating trend in the number of nutrition policy papers published annually and an increase in the diversity of nutrition topics examined. The use of policy process theory was observed from 2003; however, it was utilised by only 14 % of the reviewed papers. CONCLUSIONS: There is limited research into the nutrition policy process in high-income countries. While there has been a small increase in the use of policy process theory from 2003, an opportunity to expand its use is evident. We suggest that nutrition policy making would benefit from a pragmatic approach that ensures those trying to influence or understand the policy-making process are equipped with basic knowledge around these theories. PMID- 26443534 TI - Pseudoxanthomonas humi sp. nov., a bacterium isolated from rhizospheric soil of Fraxinus chinensis in Gyeonggi Province, South Korea. AB - A novel bacterial strain THG-MM13(T) was isolated from rhizospheric soil sample and was characterized by using a polyphasic approach. Cells were Gram-reaction negative, non-motile and rod-shaped. The strain was aerobic, catalase and oxidase positive, and optimum growth temperature and pH were 28 degrees C and 7.0, respectively. On the basis of 16S rRNA gene sequence analysis, strain THG-MM13(T) (KM598260) belongs to the genus Pseudoxanthomonas and is most closely related to Pseudoxanthomonas wuyuanensis KCTC 23877(T) (97.4 %) (JN247803), followed by Pseudoxanthomonas koreensis KCTC 12208(T) (96.7 %) (AY550263) and Pseudoxanthomonas yeongjuensis KACC 11580(T) (96.7 %) (DQ438977). The DNA G + C content was 63.7 mol%, and the predominant respiratory quinone was ubiquinone-8. The major polar lipids were diphosphatidylglycerol and phosphatidylethanolamine. The major fatty acids were iso-C15:0 (31.3 %) and iso-C16:0 (19.3 %). The DNA-DNA relatedness value between strain THG-MM13(T) and P. wuyuanensis KCTC 23877(T) was below 50 %. The DNA-DNA hybridization result and results of the genotypic analysis in combination with chemotaxonomic and physiological data demonstrated that strain THG-MM13(T) represented a novel species within the genus Pseudoxanthomonas, for which the name Pseudoxanthomonas humi is proposed. The type strain is THG-MM13(T) (=KACC 18280(T) = CCTCC AB 2015122(T)). PMID- 26443535 TI - Posterior Humeral Avulsion of the Glenohumeral Ligament and Associated Injuries: Assessment Using Magnetic Resonance Imaging. AB - BACKGROUND: Lesions associated with posterior humeral avulsion of the glenohumeral ligament (HAGL) can lead to persistent symptoms related to posterior shoulder instability and can be commonly missed or delayed in diagnosis. PURPOSE: To identify and characterize the MRI findings in patients with a posterior HAGL lesion. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: This retrospective case series included 27 patients (28 shoulders) identified by search through the senior authors' databases, with cross-reference to their institutional radiologic communication system for MRI review. Baseline patient demographic data were collected, including age and sex. All posterior HAGL lesions were identified on MRI and characterized as partial, complete, or floating lesions. All acute glenohumeral pathologic changes concurrent with the posterior HAGL were documented. Chondrolabral retroversion of the injured shoulder was measured on axial MRI. RESULTS: The average age of the identified cohort was 33.6 years (range, 15-81 years), and 23 patients were male (86%). Posterior HAGL injuries were found to be complete tears (71%), partial tears (25%), and floating lesions (4%); concomitant bony HAGL avulsion was found in 7% of injuries. Additional traumatic glenohumeral disorders occurred in 93% of cases. The most common concurrent injuries were reverse Hill-Sachs lesions (36%), anterior Bankart lesions (29%), and posterosuperior rotator cuff tears (25%). Notably, concomitant anterior labral or capsular injury was found in 50% of patients, signifying bidirectional disruption of the capsule. In addition, increased chondrolabral version was found in this cohort (10.2 degrees +/- 3.7 degrees retroversion). CONCLUSION: This study depicts the high association of combined injury with posterior HAGL lesions and increased chondrolabral retroversion. Findings on MRI related to a posterior HAGL injury could potentially be masked by additional injury and may occur with mechanisms that also lead to anterior glenohumeral disorders. PMID- 26443536 TI - Radiographic Identification of the Deltoid Ligament Complex of the Medial Ankle. AB - BACKGROUND: An injury to the deltoid ligament complex of the ankle can require surgical intervention in cases of chronic instability. There is an absence of data describing medial ankle ligament anatomy on standard radiographic views. PURPOSE: To quantitatively describe the anatomic origins and insertions of the individual ligamentous bands of the superficial and deep deltoid on standard lateral and mortise radiographic views with reference to osseous landmarks and anatomic axes. STUDY DESIGN: Descriptive laboratory study. METHODS: Twelve nonpaired, fresh-frozen cadaveric foot and ankle specimens were utilized. Specimens were dissected free of all overlying soft tissue to identify individual ligamentous bands of the superficial and deep deltoid ligaments and to isolate their distinct origins and insertions. Footprint centers were identified on standard lateral and mortise radiographs by 2-mm stainless steel spheres embedded at the level of the cortical bone. Distances to osseous landmarks were measured independently by 2 blinded reviewers to calculate mean distances and evaluate reliability and repeatability measures using intraclass correlation coefficients. RESULTS: Varying subsets of the 4 superficial deltoid bands including the tibionavicular (12/12), tibiospring (12/12), tibiocalcaneal (9/12), and superficial posterior tibiotalar (9/12) ligaments were found across specimens. On the lateral view, the tibionavicular ligament was the most anterior and attached 7.6 +/- 1.9 mm superior and anterior to the inferior tip of the medial malleolus. The tibiospring ligament attached 12.1 +/- 2.2 mm superior and anterior to the inferior tip of the medial malleolus and attached to the spring ligament, which coursed from its origin 12.3 +/- 1.6 mm anterior and slightly inferior to the posterior point of the sustentaculum tali to its insertion on the navicular tuberosity. The tibiocalcaneal ligament and superficial posterior tibiotalar ligament were found posteriorly in the majority of specimens. Two constituents of the deep deltoid, including the deep anterior tibiotalar (11/12) and deep posterior tibiotalar (12/12) ligaments, were found in the majority of specimens. The deep posterior was larger and coursed from the tibia, 8.1 +/- 2.2 mm posterior and superior to the inferior tip of the medial malleolus, to its attachment on the talus, 15.5 +/- 2.4 mm superior and anterior to the posterior inferior point of the talus on the lateral view. CONCLUSION: Quantitative radiographic relationships describing the anatomic origins and insertions of the individual superficial and deep deltoid constituents were defined with excellent reliability and reproducibility. CLINICAL RELEVANCE: Radiographic parameters will augment current anatomic data by assisting with preoperative planning, intraoperative guidance, and postoperative assessment. These radiographic guidelines will facilitate the development of novel anatomic reconstructions and allow surgeons to plan the locations of reconstruction tunnels. PMID- 26443538 TI - Ambulance Dispatches From Unaffected Areas After the Great East Japan Earthquake: Impact on Emergency Care in the Unaffected Areas. AB - OBJECTIVE: Although dispatching ambulance crews from unaffected areas to a disaster zone is inevitable when a major disaster occurs, the effect on emergency care in the unaffected areas has not been studied. We evaluated whether dispatching ambulance crews from unaffected prefectures to those damaged by the Great East Japan Earthquake was associated with reduced resuscitation outcomes in out-of-hospital cardiac arrest (OHCA) cases in the unaffected areas. METHODS: We used the Box-Jenkins transfer function model to assess the relationship between ambulance crew dispatches and return of spontaneous circulation (ROSC) before hospital arrival or 1-month survival after the cardiac event. RESULTS: In a model whose output was the rate of ROSC before hospital arrival, dispatching 1000 ambulance crews was associated with a 0.474% decrease in the rate of ROSC after the dispatch in the prefectures (p=0.023). In a model whose output was the rate of 1-month survival, dispatching 1000 ambulance crews was associated with a 0.502% decrease in the rate of 1-month survival after the dispatch in the prefectures (p=0.011). CONCLUSIONS: The dispatch of ambulances from unaffected prefectures to earthquake-stricken areas was associated with a subsequent decrease in the ROSC and 1-month survival rates in OHCA cases in the unaffected prefectures. PMID- 26443539 TI - Overexpression of Rab5a promotes hepatocellular carcinoma cell proliferation and invasion via FAK signaling pathway. AB - Rab5a was reported to be overexpressed in human malignancy and associated with the malignant phenotype. To data, its expression pattern and biological function in hepatocellular carcinoma (HCC) have not been studied. We analyzed Rab5a protein expression in 98 cases of HCC tissues and four HCC cell lines. We found that Rab5a expression was upregulated in HCC tissues and cell lines. Rab5a overexpression correlated with TNM stage and nodal metastasis (p < 0.05). To confirm the biological function of Rab5a in HCC cell lines, Rab5a siRNA was employed in SK-Hep-1 cell line and plasmid transfection was performed in Huh7 cell line. CCK-8 assay showed that Rab5a depletion blocked cell growth rate while Rab5a overexpression facilitated proliferation. Transwell and migration assay showed that Rab5a positively regulated cell invasion and migration. To explore the molecular mechanism underlying the biological effects of Rab5a, we checked several signaling pathways and found that Rab5a overexpression upregulated cyclin D1, cyclin E expression, FAK (Tyr397), and AKT (Ser473) phosphorylation. Blockage of FAK using inhibitor PF573228 abolished the role of Rab5a on cyclin D1. In conclusion, Rab5a is overexpressed in human HCC and contributes to cancer cell proliferation and invasion through regulation of FAK and AKT signaling. PMID- 26443540 TI - Overexpression of acylglycerol kinase is associated with poorer prognosis and lymph node metastasis in nasopharyngeal carcinoma. AB - Acylglycerol kinase (AGK) has been reported to promote a malignant phenotype and enhance the development of cancer stem cells. However, the clinical value of AGK in cancer remains unclear. This study aimed to investigate the expression and clinicopathological significance of AGK in nasopharyngeal carcinoma (NPC). AGK was significantly upregulated in NPC cell lines and clinical specimens as indicated by real-time PCR and Western blotting. Among the AGK-positive cases, 52/114 (45.6 %) of the archived human NPC specimens expressed high levels of AGK. High expression of AGK was associated with significantly shorter overall and disease-free survival (P < 0.001 and P = 0.002; log-rank test) and was an independent prognostic factor for overall survival (P = 0.041; multivariate Cox analysis). High AGK expression was associated with lymph node metastasis (P < 0.001; chi-squared test) and was an independent predicted factor for lymph node metastasis in NPC (P = 0.032; multivariate logistic analysis). AGK is overexpressed and associated with disease progression and lymph node metastasis in NPC. AGK has potential as a novel prognostic factor for overall survival in NPC. PMID- 26443541 TI - Engaging youth in communities: a framework for promoting adolescent and community health. AB - Health researchers and practitioners increasingly recognise the important role communities play in shaping individual health. Health researchers recognise the role of community factors as causes or determinants of health problems; use community-based methods for understanding complex health issues; and design community-level health solutions. In this commentary, we propose a fourth way to think about the role of communities in individual health by arguing that the community engagement process itself has implications for individual health and strong communities. This topic is especially important during adolescence, a developmental window of opportunity during which individuals need meaningful opportunities to contribute to the world around them. PMID- 26443542 TI - Surgical repair of complete atrioventricular defect (Nunn technique). AB - Two procedures have been traditionally used for the surgical repair of complete atrioventricular canal. The single-patch technique includes the division of valve leaflets, and the use of one patch to close the ventricular and the atrial septal defects, whereas the double-patch technique uses two separate patches, without the division of the bridging leaflets. Between 1997 and 2007, another technique emerged, the modified single-patch technique, or the 'Australian' technique, whereby the ventricular septal defect (VSD) is closed by the direct apposition of the bridging leaflets against the crest of the defect. Because of the absence of the ventricular septal patch, concerns have been raised about the possible left ventricular outflow tract obstruction (LVOTO), or atrioventricular valve (AVV) distortion, especially in case of a deep VSD, or if the defect extends superiorly. The results of the modified single-patch technique in terms of mortality, immediate and long-term AVV function and LVOTO have been similar to the standard techniques in most reports. This article will describe in detail the operative technique and review the relevant literature. PMID- 26443543 TI - ERK5/HDAC5-mediated, resveratrol-, and pterostilbene-induced expression of MnSOD in human endothelial cells. AB - SCOPE: Mitochondrial oxidative stress is closely correlated with numerous cardiovascular diseases. Manganese superoxide dismutase (MnSOD) is an important antioxidant enzyme in mitochondria. Although polyphenols can induce the expression of MnSOD, their corresponding mechanisms remains unclear. In this study, we tested the hypothesis that resveratrol and pterostilbene can activate the expression of MnSOD through an AMPK-ERK5/HDAC5-KLF2 pathway. METHODS AND RESULTS: Our results revealed that two stilbenes reduced mitochondrial superoxide free radicals, and endothelial cell senescence, and increased the mRNA expression of several genes related to mitochondrial function, including MnSOD. Moreover, two stilbenes upregulated the activation of human MnSOD promoter luciferase reporter gene and protein level in human umbilical vein endothelial cells. Similarly, two stilbenes also stimulated LKB1, AMPKalpha, extracellular-signal related kinase 5 (ERK5) phosphorylation, and histone acetylase 5 (HDAC5) and Kruppel-like factor 2 (KLF2) expression. The knockdown of AMP-activated protein kinase (AMPK), ERK5, and HDAC5 by using short-hairpin RNA blocked pterostilbene induced phosphorylation of their downstream signaling proteins and the expression of KLF2. Furthermore, using a chromatin immunoprecipitation-PCR detection method, we found that resveratrol and pterostilbene promoted KLF2 binding to CACCC sites of the human MnSOD promoter. CONCLUSION: Resveratrol and pterostilbene can activate MnSOD expression through ERK5/HDAC5 pathway, thus alleviating mitochondrial oxidative stress in endothelial cells that relates to cardiovascular disease. PMID- 26443544 TI - A STUDY ON THE UNCERTAINTY FOR THE ROUTINE DOSIMETRY SERVICE AT THE LEBANESE ATOMIC ENERGY COMMISSION USING HARSHAW 8814 DOSEMETERS. AB - The personal dosimetry service at the Lebanese Atomic Energy Commission uses Harshaw 8814 cards with LiF:Mg,Ti detectors. The dosemeters are read in a Harshaw 6600 TLD reader. In the process of accreditation for the ISO 17025 standard((1)), different influence factors are investigated and the uncertainty has been determined. The Individual Monitoring Service Laboratory-LAEC reads the dosemeters once it receives them from the customer, and new cards are immediately given for the next wearing period. The wearing period is 2 months. The dosemeter results are reported to the customers without background subtraction. Both Hp(10) and Hp(0.07) are reported. For this paper, only the uncertainty on Hp(10) will be focussed. The following factors are taken into account for the uncertainty: calibration factor, dosemeter homogeneity and repeatability, energy and angular dependence, non-linearity, temperature dependence, etc. Also the detection limit was determined. One of the important factors is the correction for fading. This fading correction depends on the procedure used such as storage temperatures, the time-temperature profile of the read-out, pre-heat and annealing conditions. Pre- and post-irradiation fading curves were measured for a storage period up to 182 d at room temperature (15-25 degrees C). The resulting final combined standard uncertainty on the reported doses is of the order of 24 % for doses of ~1 mSv. PMID- 26443545 TI - EVOLUTION OF THE IEC AND EN STANDARDS FOR INDIVIDUAL MONITORING OF IONISING RADIATION. AB - This article presents the evolution of the International Electrotechnical Commission (IEC) and the European standards for individual monitoring of ionising radiation issued, respectively, from the committees IEC/Sub Committee 45B and European Committee for Electro-technical Standardization/Technical Committee 45B 'Radiation protection instrumentation'. Standards for passive individual photon and beta dosimetry systems as well as those for active individual monitors are discussed. A neutron ambient dose equivalent (rate) meter standard and a technical report concerning the determination of uncertainty in measurement are also covered. PMID- 26443546 TI - COMPARISON OF DIFFERENT PADC MATERIALS AND ETCHING CONDITIONS FOR FAST NEUTRON DOSIMETRY. AB - Etched-track polyallyl diglycol carbonate (PADC) dosemeters have been in use at the Paul Scherrer Institute since 1998 in neutron dosimetry for individual monitoring. In the last years, the availability of PADC materials from different manufacturers has grown, and different etching conditions were proposed, with the intention to improve the quality and overall performance of PADC in individual neutron monitoring. The goal of the present study was to compare the performance of different PADC materials and to investigate the influence of different etching conditions on sensitivity to fast neutrons and lower detection limit. The comparison covers six different PADC materials and eight different etching conditions. PMID- 26443547 TI - MONTE CARLO SIMULATION OF THE BREMSSTRAHLUNG RADIATION FOR THE MEASUREMENT OF AN INTERNAL CONTAMINATION WITH PURE-BETA EMITTERS IN VIVO. AB - Rapid measurement techniques are required for a large-scale emergency monitoring of people. In vivo measurement of the bremsstrahlung radiation produced by incorporated pure-beta emitters can offer a rapid technique for the determination of such radionuclides in the human body. This work presents a method for the calibration of spectrometers, based on the use of UPh-02T (so-called IGOR) phantom and specific (90)Sr/(90)Y sources, which can account for recent as well as previous contaminations. The process of the whole- and partial-body counter calibration in combination with application of a Monte Carlo code offers readily extension also to other pure-beta emitters and various exposure scenarios. PMID- 26443548 TI - Promoting health and reducing costs: a role for reform of self-monitoring of blood glucose provision within the National Health Service. AB - AIM: To determine the cost-effectiveness of all options for the self-monitoring of blood glucose funded by the National Health Service, providing guidance for disinvestment and testing the hypothesis that advanced meter features may justify higher prices. METHODS: Using data from the Health and Social Care Information Centre concerning all 8 340 700 self-monitoring of blood glucose-related prescriptions during 2013/2014, we conducted a cost-minimization analysis, considering both strip and lancet costs, including all clinically equivalent technologies for self-monitoring of blood glucose, as determined by the ability to meet ISO-15197:2013 guidelines for meter accuracy. RESULTS: A total of 56 glucose monitor, test strip and lancet combinations were identified, of which 38 met the required accuracy standards. Of these, the mean (range) net ingredient costs for test strips and lancets were L0.27 (L0.14-L0.32) and L0.04 (L0.02 L0.05), respectively, resulting in a weighted average of L0.28 (L0.18-L0.37) per test. Systems providing four or more advanced features were priced equal to those providing just one feature. A total of L12 m was invested in providing 42 million self-monitoring of blood glucose tests with systems that fail to meet acceptable accuracy standards, and efficiency savings of L23.2 m per annum are achievable if the National Health Service were to disinvest from technologies providing lesser functionality than available alternatives, but at a much higher price. CONCLUSION: The study uncovered considerable variation in the price paid by the National Health Service for self-monitoring of blood glucose, which could not be explained by the availability of advanced meter features. A standardized approach to self-monitoring of blood glucose prescribing could achieve significant efficiency savings for the National Health Service, whilst increasing overall utilisation and improving safety for those currently using systems that fail to meet acceptable standards for measurement accuracy. PMID- 26443550 TI - Toward the discovery of dual HCMV-VZV inhibitors: Synthesis, structure activity relationship analysis, and cytotoxicity studies of long chained 2-uracil-3-yl-N (4-phenoxyphenyl)acetamides. AB - The need for novel therapeutic options to fight herpesvirus infections still persists. Herein we report the design, synthesis and antiviral evaluation of a new family of non-nucleoside antivirals, derived from 1-[omega-(4 bromophenoxy)alkyl]uracil derivatives--previously reported inhibitors of human cytomegalovirus (HCMV). Introduction of the N-(4-phenoxyphenyl)acetamide side chain at N(3) increased their potency and widened activity spectrum. The most active compounds in the series exhibit submicromolar activity against different viral strains of HCMV and varicella zoster virus (VZV) replication in HEL cell cultures. Inactivity against other DNA and RNA viruses, including herpes simplex virus 1/2, points to a novel mechanism of antiviral action. PMID- 26443549 TI - Antiviral activity of benzotriazole derivatives. 5-[4-(Benzotriazol-2-yl)phenoxy] 2,2-dimethylpentanoic acids potently and selectively inhibit Coxsackie Virus B5. AB - A library of 64 benzotriazole derivatives (17 of which were [4-(benzotriazol-2 yl)phenoxy]alkanoic acids) were screened for antiviral activity against a panel of twelve DNA and RNA viruses. Twenty-six compounds (12 of which were [4 (benzotriazol-2-yl)phenoxy]alkanoic acids) displayed activity against one or more viruses. CVB-5, RSV, BVDV, Sb-1 and YFV were, in decreasing order, the more frequently and effectively affected viruses; DENV-2, WNV, HIV-1 and Reo-1 were only occasionally and modestly affected, while the remaining viruses were not affected by any of the tested compounds. Worth of note were compounds 33 and 35; the former for the activity against Sb-1 (EC50=7 MUM) and the latter for the large spectrum of activity including six viruses with a mean EC50=12 MUM. Even more interesting were the alkanoic acids 45-48 and 50-57 for their activity against RSV and/or CVB-5. In particular, compound 56 displayed a potent and selective activity against CVB-5 with EC50=0.15 MUM and SI=100, thus representing a valuable hit compound for the development of antiviral agents for the treatment of human pathologies related to this virus. PMID- 26443552 TI - Growth parameter design for homogeneous material composition in ternary Ga(x)In(1 x)P nanowires. AB - Ternary nanowires (NWs) often exhibit varying material composition along the NW growth axis because of different diffusion properties of the precursor molecules. This constitutes a problem for optoelectronic devices for which a homogeneous material composition is most often of importance. Especially, ternary GaInP NWs grown under a constant Ga-In precursor ratio typically show inhomogeneous material composition along the length of the NW due to the complexity of low temperature precursor pyrolysis and relative rates of growth species from gas phase diffusion and surface diffusion that contribute to synthesis of particle assisted growth. Here, we present the results of a method to overcome this challenge by in situ tuning of the trimethylindium molar fraction during growth of ternary Zn-doped GaInP NWs. The NW material compositions were determined by use of x-ray diffraction, scanning transmission electron microscopy and energy dispersive x-ray spectroscopy and the optical properties by photoluminescence spectroscopy. PMID- 26443551 TI - Ethanol inhibits gamma-secretase proteolytic activity in vascular smooth muscle cells. AB - BACKGROUND: Ethanol (EtOH) inhibits Notch-mediated vascular smooth muscle cell (SMC) proliferation, an event that is key in vessel remodeling and atherogenesis. The object of this study was to determine whether EtOH inhibits Notch signaling in SMC at the level of gamma-secretase, a protease that in concert with alpha secretase catalyzes the release of the intracellular domain of the Notch receptor necessary for signaling. METHODS: Human coronary artery SMCs (HCASMCs) were treated with a recombinant soluble Notch ligand, Delta-like ligand 4 (DLL4) (2 MUg/ml), or transfected with a constitutively active Notch 1 intracellular domain (N1ICD), in the absence or presence of EtOH. EtOH (25 mM) treatment inhibited DLL4-stimulated CBF-1/RBP-Jk-dependent promoter activity (determined by luciferase assay) and downstream target gene HRT-3 mRNA levels. In contrast, EtOH had no effect on N1ICD-driven CBF-1/RBP-Jk-dependent promoter activity or HRT-3 expression. RESULTS: These data suggest that EtOH inhibits Notch signaling at, or prior to, Notch intracellular domain (NICD) generation. gamma-Secretase activity was determined in solubilized membrane preparations from HCASMC treated with/without EtOH (25 mM) or the gamma-secretase inhibitor DAPT (20 MUM) using (i) a fluorometric assay and (ii) Western blot detection of cleavage products using a Flag-tagged Notch-based substrate, N100Flag. EtOH inhibited basal and DLL4-stimulated gamma-secretase activity, and SMC growth to a similar extent as DAPT, whereas it had no effect on alpha-secretase (TACE/ADAM17) activity also determined by fluorometric assay. Moreover, EtOH treatment inhibited the expression of caveolin-1, a lipid raft protein implicated in regulating gamma secretase activity, and altered its cellular distribution in HCASMC. CONCLUSIONS: EtOH inhibits Notch signaling in vascular SMCs at the level of gamma-secretase activity, possibly by affecting lipid raft function. Such a response might be expected to result in attenuation of pathologic vessel remodeling and thus may contribute to moderate alcohols' cardioprotective effects. PMID- 26443553 TI - Synthesis of novel polymerizable molecules bearing bisphosphonate. AB - In recent years, bisphosphonate chemistry has undergone an exponential growth due to the potential applications of these compounds in medicine and nanobiomaterial research. In this paper we describe the synthesis methods of different families of methacrylic monomers bearing a bisphosphonate with varying lengths of the chain, PEG linkers and more or less hydrolysable functions such as ester, carbamate or amide. PMID- 26443554 TI - Managing Suicidal Patients in the Emergency Department. PMID- 26443555 TI - Development of a Hospital Standardized Mortality Ratio for Emergency Department Care. AB - STUDY OBJECTIVE: Experts have recommended including measures of mortality in emergency department (ED) performance evaluation frameworks. This study aims to develop a hospital standardized mortality ratio (HSMR) for patients admitted to the hospital with conditions for which ED care may reduce mortality (emergency sensitive conditions). METHODS: Data were extracted from Canadian hospital discharge databases from April 1, 2009, to March 31, 2012. The ED HSMR is the ratio of the observed deaths among patients with emergency-sensitive conditions in a hospital during a year to the expected deaths for the same patients during the reference year (2009-2010). The expected deaths were estimated with predictive models fitted for different hospital peer groups (teaching hospitals and large, medium, and small community hospitals). RESULTS: The data set included 1,770,809 admissions (9.2% deaths). The ED HSMR was calculated for 47% (294/629) of all Canadian hospitals. The majority of exclusions (98%) were for small community hospitals with fewer than 20 expected deaths. Predictive models had good calibration and discrimination, with areas under the curve ranging from 0.80 to 0.81. In comparisons of 2010-2011 and 2011-2012, the classification of hospitals by ED HSMR quartile was stable, with the majority remaining within the same quartile (43.5%) or moving up or down a single quartile (40.2%). Peer-group level comparisons between ED HSMR measured at different points after admission (2, 7, and 30 days, and hospital discharge) did not demonstrate any significant differences. CONCLUSION: The ED HSMR appears to be a reliable measure with high discrimination, calibration, and forecasting properties that can be used to guide assessment of ED performance. PMID- 26443556 TI - Response to Letter to the Editor re: 'Movement-based subgrouping in low back pain: synergy and divergence in approaches'. PMID- 26443557 TI - Parent Engagement With a Telehealth-Based Parent-Mediated Intervention Program for Children With Autism Spectrum Disorders: Predictors of Program Use and Parent Outcomes. AB - BACKGROUND: There has been growing interest in using telehealth to increase access to parent-mediated interventions for children with ASD. However, little is known about how parents engage with such programs. OBJECTIVE: This paper presents program engagement data from a pilot study comparing self-directed and therapist assisted versions of a novel telehealth-based parent-mediated intervention for young children with autism spectrum disorders (ASD). METHODS: Parents of young children with ASD were randomly assigned to receive a self-directed or therapist assisted version of ImPACT Online. Parent engagement and satisfaction with the different components of the program website were examined using the program's automated data collection and a post-treatment evaluation survey. We examined the relationship between program engagement and changes in parent knowledge and implementation and participant characteristics associated with program engagement. RESULTS: Of the 27 parent participants, the majority were female (26/27, 96%), married (22/27, 81%), with a college degree or higher (18/27, 66%), and less than half were employed outside of the home (10/27, 37%). The mean chronological age of the child participants was 43.26 months, and the majority were male (19/27, 70%) and white (21/27, 78%). Most of the families (19/27, 70%) resided in a rural or medically underserved area. Parents logged into the website an average of 46.85 times, spent an average of 964.70 minutes on the site, and completed an average of 90.17% of the lesson learning activities. Participants in the therapist-assisted group were more likely to engage with the website than those in the self-directed group: F2,24=17.65, P<.001. In total, 85% of participants completed the program, with a significantly greater completion rate in the therapist-assisted group (N=27): chi(2) 1=5.06, P=.03. Lesson learning activities were visited significantly more often than the supplemental activities (all Ps<.05). Multiple regression controlling for pretreatment performance indicated that program completion (beta=.51, P=.02) predicted post-treatment intervention knowledge, and program completion (beta=.43, P=.03) and group assignment (beta=-.37, P=.045) predicted post-treatment intervention fidelity. Partial correlations indicated that parent depressive symptoms at pretreatment were negatively associated with program completion (r=-.40, P=.04), but other key parent and child demographic factors were not. Post-treatment measures of website usability (r=.65, P<.001), treatment acceptability (r=.58, P=.002), and overall satisfaction (r=.58, P=.002) were all related to program completion. CONCLUSIONS: Parent engagement and satisfaction with ImPACT Online was high for both self directed and therapist-assisted versions of the program, although therapist assistance increased engagement. Program completion was associated with parent outcomes, providing support for the role of the website in parent learning. This program has the potential to increase access to parent-mediated intervention for families of children with ASD. PMID- 26443559 TI - Ten-year retrospective review of transfusion practices in beating-heart organ donors. AB - BACKGROUND: Recent studies suggest that restrictive transfusion strategies are equivocal or noninferior to liberal strategies in various patient populations; however, evidence for the optimal transfusion threshold or current transfusion practice in beating-heart organ donors is lacking. A 10-year retrospective analysis of blood product utilization in beating-heart organ donors was performed to determine current transfusion practice. STUDY DESIGN AND METHODS: An institutional review board-approved retrospective review of 439 beating-heart organ donors from January 1, 2004, to October 1, 2014, was performed. For each donor, hemoglobin (Hb), platelet (PLT), prothrombin time/international normalized ratio (PT/INR), and fibrinogen levels as well as all transfusion reaction reports were recorded from the time of declaration of brain death to organ procurement. RESULTS: Red blood cell transfusion occurred in 304 donors (69.2%), with a trough Hb level of more than 8 g/dL in 63.2% and more than 10 g/dL in 15.8%; final Hb was more than 10 g/dL in 44.1% of transfused donors. PLT transfusion occurred in 165 donors (37.6%), with a trough PLT count of more than 50 * 10(9) /L in 113 (68.5%) and more than 100 * 10(9) /L in 15 (9.1%). Plasma transfusion occurred in 217 donors (49.4%), with a peak INR of less than 1.5 in 75 donors (34.6%) and a peak INR of 1.6 to 2.0 in 112 donors (51.6%). Only 17.4% of donors who received cryoprecipitate had fibrinogen levels measured, and results were all more than 200 mg/dL. Transfusion reactions were underreported (p = 0.0001). CONCLUSIONS: This study suggests potential suboptimal use of limited biologic resources in beating-heart organ donors, as well as significant underreporting of suspected transfusion reactions. Additional studies are indicated to determine optimal transfusion thresholds in this population. PMID- 26443558 TI - Epidemiologic trends in medically-attended tree stand fall injuries among Wisconsin deer hunters. AB - BACKGROUND: Tree stand falls are the most common injury to hunters in the USA, but there is limited research on the topic. This study examined the 5-year trends in incident tree stand fall injuries in rural north-central Wisconsin and described patient demographics and injury features. METHODS: A retrospective analysis was conducted on five prior hunting seasons, 2009-2013. Cases were ascertained from electronic health records via natural language processing that identified patients from the Marshfield Epidemiologic Study Area who received medical attention for a tree stand fall. Annual incidence rates were calculated using the number of hunting license holders in the target population, per administrative data from the Wisconsin Department of Natural Resources. RESULTS: There were 16,556-16,902 deer hunters in any given year, with 39 (92% male) confirmed medically-attended tree stand fall injuries in 2009-2013. Injuries mainly occurred in the lower extremities (n=23), and included two fatalities and one paralysis case. The risk of tree stand fall injuries went from 6.0 (95% CI: 3.2, 11.1) per 10,000 hunters in 2009 to 3.6 (95% CI: 1.6, 7.9) per 10,000 hunters in 2013, which was not a significant change over 5 years (p=0.79). Most falls occurred among archery hunters, in the evening and when descending from a tree stand. Cases were demographically similar to the general population of Wisconsin deer hunters. CONCLUSIONS: The current seasonal incidence rate of tree stand fall injuries is relatively low in rural Wisconsin, but with limited signs of improvement. Continued efforts are needed to promote the long-term safety of the hunting public. PMID- 26443560 TI - Clinical Features and outcomes in adults with cardiogenic shock supported by extracorporeal membrane oxygenation. AB - Extracorporeal membrane oxygenation (ECMO) is an increasingly used supportive measure for patients with refractory cardiogenic shock (CS). Despite its increasing use, there remain minimal data regarding which patients with refractory CS are most likely to benefit from ECMO. We retrospectively studied all patients (n = 123) who underwent initiation of ECMO for CS from February 2009 to September 2014 at a single center. Baseline patient characteristics, including demographics, co-morbid illness, cause of CS, available laboratory values, and patient outcomes were analyzed. Overall, 69 patients (56%) were weaned from ECMO, with 48 patients (39%) surviving to discharge. Survivors were younger (50 vs 60 years; p <=0.0001), had a lower rate of previous smoking (27 vs 56%; p = 0.01) and chronic kidney disease (2% vs 13%; p = 0.03), and had lower lactate measured soon after ECMO initiation (3.1 vs 10.2 mmol/l; p = 0.01). Patients with pulmonary embolism (odds ratio 8.0, 95% confidence interval 2.00 to 31.99; p = 0.01) and acute cardiomyopathy (odds ratio 7.5, 95% confidence interval 1.69 to 33.27; p = 0.01) had a higher rate of survival than acute myocardial infarction, chronic cardiomyopathy, and miscellaneous etiologies compared to postcardiotomy CS as a referent. In conclusion, survival after ECMO initiation differs based on underlying cause of CS. Survival may be lower in older patients and those with early evidence of persistent hypoperfusion after initiation of ECMO for CS. PMID- 26443561 TI - Comparison of Estimations Versus Measured Oxygen Consumption at Rest in Patients With Heart Failure and Reduced Ejection Fraction Who Underwent Right-Sided Heart Catheterization. AB - Cardiac output during right-sided heart catheterization is an important variable for patient selection of advanced therapies (cardiac transplantation and left ventricular assist device implantation). The Fick method to determine cardiac output is commonly used and typically uses estimated oxygen consumption (VO2) from 1 of 3 published empirical formulas. However, these estimation equations have not been validated in patients with heart failure and reduced ejection fraction (HFrEF). The objectives of the present study were to determine the accuracy of 3 equations for estimating VO2 compared with direct measurement of VO2 and determine the extent clinically significant error occurred in calculating cardiac output of patients with HFrEF. Breath-by-breath measurements of VO2 from 44 patients who underwent cardiac catheterization (66% men; age, 65 +/- 11 years, left ventricular ejection fraction, 22 +/- 6%) were compared with the derived estimations of LaFarge and Miettinen, Dehmer et al, and Bergstra et al. Single sample t tests found only the mean difference between the estimation of LaFarge and Miettinen and the measured VO2 to be nonsignificant (-10.3 ml/min +/- 6.2 SE, p = 0.053). Bland-Altman plots demonstrated unacceptably large limits of agreement for all equations. The rate of >=25% error in the equations by LaFarge and Miettinen, Dehmer et al, and Bergstra et al occurred in 11%, 23%, and 45% of patients, respectively. Misclassification of cardiac index derived from each equation for 2 clinically important classifications: cardiogenic shock-21%, 23%, and 32% and hypoperfusion-16%, 16%, and 25%; respectively. In conclusion, these findings do not support the use of these empiric formulas to estimate the VO2 at rest in patients with HFrEF who underwent right-sided heart catheterization. PMID- 26443562 TI - Interdisciplinary Discrepancies Between Parenteral Nutrition Macronutrient Prescribing and Recommendations: Is Body Mass Index a Factor? AB - BACKGROUND: Formal nutrition training in medical schools and residencies is lacking and needed. Registered dietitians (RDs) are formally trained in nutrition support and considered experts in the nutrition field. Our purpose was to examine prescribing and recommending discrepancies of parenteral nutrition macronutrients between medical residents (MRs) and RDs and compare results with the ASPEN clinical care guidelines. We also looked at discrepancies among obese patients, due to their increased risk of mortality. MATERIALS AND METHODS: The primary end point of this retrospective review was discrepancies in nonprotein calories (NPCs) and grams of protein (PRO) between MRs and RDs. The secondary end point was discrepancies in NPCs and PRO between MRs and RDs among patients stratified by body mass index category. RESULTS: MRs prescribed 300 NPCs more versus RDs ( P < .001). When compared with RDs, MRs prescribed fewer NPCs for underweight patients and more for obese patients ( P < .001). The same analysis found that the PRO discrepancies significantly varied by body mass index classification as well ( P = .022). When these results were compared with the ASPEN clinical care guidelines, RDs adhered closer to the guidelines than did MRs in terms of permissive underfeeding of obese patients. CONCLUSION: It is widely accepted that MRs are in need of increased formal training, and the results of our study confirm this need and suggest a short-term solution of increasing order-writing privileges for the RD. RDs with this privilege may adhere more closely to clinical care guidelines and therefore increase patient safety. PMID- 26443563 TI - The significance of lymphatic space invasion and its association with vascular endothelial growth factor-C expression in ovarian cancer. AB - The aim of this study is to investigate the significance of lymphatic space invasion (LSI) and tumor VEGF-C expression in the lymphatic spread of ovarian cancer. By performing immunostaining using human ovarian cancer specimens, we first investigated the association between the extent of LSI and tumor VEGF-C expression, tumor lymphangiogenesis, or the lymphatic metastasis. Moreover, by performing in vitro and in vivo experiments, we elucidated the role of VEGF-C in tumor lymphangiogenesis and lymph node metastasis as well as its role as a therapeutic target in ovarian cancer. The presence of LSI was associated with lymph node metastasis in patients with ovarian cancer. VEGF-C overexpression was significantly associated with the increased LSI and LVD in ovarian cancer. VEGF-C stimulated the lymphangiogenesis in vitro, induced the new lymph vessel formation, and increased the lymph node metastasis in mice models of ovarian cancer. The attenuation of VEGF-C expression by the treatment with mTORC1 inhibitor significantly inhibited lymphangiogenesis, and decreased lymph node metastasis in mice models of ovarian cancer. The presence of LSI is an indicator of nodal metastasis and is associated with higher tumor VEGF-C expression and worse clinical outcome of ovarian cancer patients. VEGF-C plays a crucial role in tumor lymphangiogenesis and lymph node metastasis of ovarian cancer. PMID- 26443564 TI - Supramolecular Adducts of Cucurbit[7]uril and Amino Acids in the Gas Phase. AB - The complexation of the macrocyclic cavitand cucurbit[7]uril (Q7) with a series of amino acids (AA) with different side chains (Asp, Asn, Gln, Ser, Ala, Val, and Ile) is investigated by ESI-MS techniques. The 1:1 [Q7 + AA + 2H](2+) adducts are observed as the base peak when equimolar Q7:AA solutions are electrosprayed, whereas the 1:2 [Q7 + 2AA + 2H](2+) dications are dominant when an excess of the amino acid is used. A combination of ion mobility mass spectrometry (IM-MS) and DFT calculations of the 1:1 [Q7 + AA + 2H](2+) (AA = Tyr, Val, and Ser) adducts is also reported and proven to be unsuccessful at discriminating between exclusion or inclusion-type conformations in the gas phase. Collision induced dissociation (CID) revealed that the preferred dissociation pathways of the 1:1 [Q7 + AA + 2H](2+) dications are strongly influenced by the identity of the amino acid side chain, whereas ion molecule reactions towards N-butylmethylamine displayed a common reactivity pattern comprising AA displacement. Special emphasis is given on the differences between the gas-phase behavior of the supramolecular adducts with amino acids (AA = Asp, Asn, Gln, Ser, Ala, Val, and Ile) and those featuring basic (Lys and Arg) and aromatic (Tyr and Phe) side chains. PMID- 26443565 TI - Multiple strokes associated with herpes simplex virus type-2 infection: case report. AB - Herpes simplex virus (HSV) type-2 is known to cause meningitis and usually runs a benign course. Association of such infection with vasculitis of the central nervous system is not well known. Presented here is a case initially diagnosed as aseptic meningitis that subsequently evolved as stroke and exhibited angiographic evidence of widespread vasculitis of the intracranial vessels in association with a positive polymerase chain reaction (PCR) for HSV-2 in the cerebrospinal fluid (CSF). PMID- 26443566 TI - With better adjuvant therapy, does breast cancer stage still matter? PMID- 26443567 TI - Methionine. AB - This review focuses on the steps unique to methionine biosynthesis, namely the conversion of homoserine to methionine. The past decade has provided a wealth of information concerning the details of methionine metabolism and the review focuses on providing a comprehensive overview of the field, emphasizing more recent findings. Details of methionine biosynthesis are addressed along with key cellular aspects, including regulation, uptake, utilization, AdoMet, the methyl cycle, and growing evidence that inhibition of methionine biosynthesis occurs under stressful cellular conditions. The first unique step in methionine biosynthesis is catalyzed by the metA gene product, homoserine transsuccinylase (HTS, or homoserine O-succinyltransferase). Recent experiments suggest that transcription of these genes is indeed regulated by MetJ, although the repressor binding sites have not yet been verified. Methionine also serves as the precursor of S-adenosylmethionine, which is an essential molecule employed in numerous biological processes. S-adenosylhomocysteine is produced as a consequence of the numerous AdoMet-dependent methyl transfer reactions that occur within the cell. In E. coli and Salmonella, this molecule is recycled in two discrete steps to complete the methyl cycle. Cultures challenged by oxidative stress appear to experience a growth limitation that depends on methionine levels. E. coli that are deficient for the manganese and iron superoxide dismutases (the sodA and sodB gene products, respectively) require the addition of methionine or cysteine for aerobic growth. Modulation of methionine levels in response to stressful conditions further increases the complexity of its regulation. PMID- 26443568 TI - Mucosal Immune Responses to Escherichia coli and Salmonella Infections. AB - The best-characterized mucosa-associated lymphoid tissue (MALT), and also the most relevant for this review, is the gastrointestinal-associated lymphoid tissue (GALT). The review reviews our understanding of the importance of mucosal immune responses in resisting infections caused by E. coli and Salmonella spp. It focuses on the major human E. coli infections and discusses whether antigen specific mucosal immune responses are important for resistance against primary infection or reinfection by pathogenic E. coli. It analyzes human data on mucosal immunity against E. coli, a growing body of data of mucosal responses in food production animals and other natural hosts of E. coli, and more recent experimental studies in mice carrying defined deletions in genes encoding specific immunological effectors, to show that there may be considerable conservation of the effective host mucosal immune response against this pathogen. The species Salmonella enterica contains a number of serovars that include pathogens of both humans and animals; these bacteria are frequently host specific and may cause different diseases in different hosts. Ingestion of various Salmonella serovars, such as Typhimurium, results in localized infections of the small intestine leading to gastroenteritis in humans, whereas ingestion of serovar Typhi results in systemic infection and enteric fever. Serovar Typhi infects only humans, and the review discusses the mucosal immune responses against serovar Typhi, focusing on the responses in humans and in the mouse typhoid fever model. PMID- 26443569 TI - Meningitis-Associated Escherichia coli. AB - Escherichia coliis the most common Gram-negative organism causing neonatal meningitis. Neonatal E. colimeningitis continues to be an important cause of mortality and morbidity throughout the world. Our incomplete knowledge of its pathogenesis and pathophysiology contributes to such mortality and morbidity. Recent reports of neonatal meningitis caused by E. coli strains producing CTX-M type or TEM-type extended-spectrum beta-lactamases create a challenge. E. colipenetration into the brain, the essential step in the development of E. coli meningitis, requires a high-degree of bacteremia and penetration of the blood brain barrier as live bacteria, but the underlying mechanisms remain incompletely understood. Recent functional genomic approaches of meningitis-causing E. coli in both in vitro and in vivo models of the blood-brain barrier (e.g., human brain microvascular endothelial cells and animal models of experimental hematogenousE. colimeningitis, respectively) have identified several E. coli factors contributing to a high-degree of bacteremia, as well as specific microbial factors contributing to E. coli invasion of the blood-brain barrier. In addition, E. coli penetration of the blood-brain barrier involves specific host factors as well as microbe- and host-specific signaling molecules. Blockade of such microbial and host factors and host cell signaling molecules is efficient in preventing E. coli penetration into the brain. Continued investigation of the microbial and host factors contributing to E. colibacteremia andinvasion of the blood-brain barrier is likely to identify new targets for prevention and therapy of E. coli meningitis, thereby limiting the exposure to emerging antimicrobial resistant E. coli. PMID- 26443570 TI - Heat-Labile Enterotoxins. AB - Heat-labile enterotoxins (LTs) of Escherichia coli are closely related to cholera toxin (CT), which was originally discovered in 1959 in culture filtrates of the gram-negative bacterium Vibrio cholerae. Several other gram-negative bacteria also produce enterotoxins related to CT and LTs, and together these toxins form the V. cholerae-E. coli family of LTs. Strains of E. coli causing a cholera-like disease were designated enterotoxigenic E. coli (ETEC) strains. The majority of LTI genes (elt) are located on large, self-transmissible or mobilizable plasmids, although there are instances of LTI genes being located on chromosomes or carried by a lysogenic phage. The stoichiometry of A and B subunits in holotoxin requires the production of five B monomers for every A subunit. One proposed mechanism is a more efficient ribosome binding site for the B gene than for the A gene, increasing the rate of initiation of translation of the B gene independently from A gene translation. The three-dimensional crystal structures of representative members of the LT family (CT, LTpI, and LTIIb) have all been determined by X-ray crystallography and found to be highly similar. Site-directed mutagenesis has identified many residues in the CT and LT A subunits, including His44, Val53, Ser63, Val97, Glu110, and Glu112, that are critical for the structures and enzymatic activities of these enterotoxins. For the enzymatically active A1 fragment to reach its substrate, receptor-bound holotoxin must gain access to the cytosol of target cells. PMID- 26443571 TI - Virulence Gene Regulation in Escherichia coli. AB - Escherichia colicauses three types of illnesses in humans: diarrhea, urinary tract infections, and meningitis in newborns. The acquisition of virulence associated genes and the ability to properly regulate these, often horizontally transferred, loci distinguishes pathogens from the normally harmless commensal E. coli found within the human intestine. This review addresses our current understanding of virulence gene regulation in several important diarrhea-causing pathotypes, including enteropathogenic, enterohemorrhagic,enterotoxigenic, and enteroaggregativeE. coli-EPEC, EHEC, ETEC and EAEC, respectively. The intensely studied regulatory circuitry controlling virulence of uropathogenicE. coli, or UPEC, is also reviewed, as is that of MNEC, a common cause of meningitis in neonates. Specific topics covered include the regulation of initial attachment events necessary for infection, environmental cues affecting virulence gene expression, control of attaching and effacing lesionformation, and control of effector molecule expression and secretion via the type III secretion systems by EPEC and EHEC. How phage control virulence and the expression of the Stx toxins of EHEC, phase variation, quorum sensing, and posttranscriptional regulation of virulence determinants are also addressed. A number of important virulence regulators are described, including the AraC-like molecules PerA of EPEC, CfaR and Rns of ETEC, and AggR of EAEC;the Ler protein of EPEC and EHEC;RfaH of UPEC;and the H-NS molecule that acts to silence gene expression. The regulatory circuitry controlling virulence of these greatly varied E. colipathotypes is complex, but common themes offerinsight into the signals and regulators necessary forE. coli disease progression. PMID- 26443572 TI - Salmonella and Enteropathogenic Escherichia coli Interactions with Host Cells: Signaling Pathways. AB - The host-pathogen interaction involves a myriad of initiations and responses from both sides. Bacterial pathogens such as enteropathogenic Escherichia coli (EPEC) and Salmonella enterica have numerous virulence factors that interact with and alter signaling components of the host cell to initiate responses that are beneficial to pathogen survival and persistence. The study of Salmonella and EPEC infection reveals intricate connections between host signal transduction, cytoskeletal architecture, membrane trafficking, and cytokine gene expression. The emerging picture includes elements of molecular mimicry by bacterial effectors and bacterial subversion of typical host events, with the result that EPEC is able to survive and persist in an extracellular milieu, while Salmonella establishes an intracellular niche and is able to spread systemically throughout the host. This review focuses on recent advances in our understanding of the signaling events stemming from the host-pathogen interactions specific to Salmonella and EPEC. PMID- 26443573 TI - Modulation of Iron Availability at the Host-Pathogen Interface in Phagocytic Cells. AB - This review summarizes recent data on iron metabolism in macrophages, with a special emphasis on possible bacteriostatic and bactericidal consequences for intracellular pathogens. It includes the role of biological chelators and transporters in normal macrophage physiology and antimicrobial defense. Iron is an essential metal cofactor for many biochemical pathways in mammals. However, excess iron promotes the formation of cytotoxic oxygen derivatives so that systemic iron levels must be tightly regulated. The mechanism of iron recycling by macrophages including iron efflux from erythrocyte-containing phagosomes, iron release from macrophages, and entry into the transferrin (Tf) cycle remain poorly understood. Ferroportin expression in the liver, spleen, and bone marrow cells appears to be restricted to macrophages. Mutant mice bearing a conditional deletion of the ferroportin gene in macrophages show retention of iron by hepatic Kupffer cells and splenic macrophages. Hepcidin is induced by lipopolysaccharide (LPS) in mouse spleens and splenic macrophage in vitro and appears to mediate the LPS-induced down-regulation of ferroportin in the intestine and in splenic macrophages, suggesting that inflammatory agents may regulate iron metabolism through modulation of ferroportin expression. The host transporter Nramp1 may compete directly with bacterial divalent-metal transport systems for the acquisition of divalent metals within the phagosomal space. The ultimate outcome of these competing interactions influences the ability of pathogens to survive and replicate intracellularly. This seems particularly relevant to the Salmonella, Leishmania, and Mycobacterium spp., in which inactivating mutations in Nramp1 abrogate the natural resistance of macrophages to these pathogens. PMID- 26443574 TI - Biosynthesis and Regulation of the Branched-Chain Amino Acids?. AB - This review focuses on more recent studies concerning the systems biology of branched-chain amino acid biosynthesis, that is, the pathway-specific and global metabolic and genetic regulatory networks that enable the cell to adjust branched chain amino acid synthesis rates to changing nutritional and environmental conditions. It begins with an overview of the enzymatic steps and metabolic regulatory mechanisms of the pathways and descriptions of the genetic regulatory mechanisms of the individual operons of the isoleucine-leucine-valine (ilv) regulon. This is followed by more-detailed discussions of recent evidence that global control mechanisms that coordinate the expression of the operons of this regulon with one another and the growth conditions of the cell are mediated by changes in DNA supercoiling that occur in response to changes in cellular energy charge levels that, in turn, are modulated by nutrient and environmental signals. Since the parallel pathways for isoleucine and valine biosynthesis are catalyzed by a single set of enzymes, and because the AHAS-catalyzed reaction is the first step specific for valine biosynthesis but the second step of isoleucine biosynthesis, valine inhibition of a single enzyme for this enzymatic step might compromise the cell for isoleucine or result in the accumulation of toxic intermediates. The operon-specific regulatory mechanisms of the operons of the ilv regulon are discussed in the review followed by a consideration and brief review of global regulatory proteins such as integration host factor (IHF), Lrp, and CAP (CRP) that affect the expression of these operons. PMID- 26443575 TI - Cytokines and Escherichia coli Sepsis. AB - This review reviews the critical role played by cytokines in the pathogenesis of Escherichia coli sepsis. It focuses on prototypic pro-inflammatory and anti inflammatory cytokines and their influence on mortality in experimental animal models of E. coli endotoxemia and of live E. coli sepsis. The review reviews the results of clinical trials on anticytokine therapy in patients with severe sepsis or septic shock. The recognition of the critical role played by tumor necrosis factor (TNF), a secreted 17kDa cytokine, in endotoxic and gram-negative shock has been a major step forward in our understanding of the pathogenesis of sepsis. The review describes the role of TNF, IL1, and IL6 in animal models of E. coli endotoxemia and sepsis. Given the pivotal role played by TNF in experimental sepsis and the fact that elevated concentrations of TNF were detected in the circulation of patients with sepsis, anti-TNF treatment strategies were investigated as adjunctive therapy for severe sepsis and septic shock. Several studies demonstrated that high levels of interleukin-6 (IL-6) are associated with an increased risk for fatal outcome. Gamma interferon (IFN-gamma), IL-12, and IL 18 are functionally related cytokines. A recent study has indicated that transgenic mice overexpressing IL-15 are resistant to an otherwise lethal intraperitoneal E. coli challenge. IL4, IL10, and IL13are prototypic anti inflammatory cytokines. Their classification as anti-inflammatory cytokines is based on the observation that these molecules inhibit the production of proinflammatory cytokines (primarily TNF and IL1) and toxic oxygen and reactive nitrogen species by myeloid cells. PMID- 26443576 TI - Adhesins of Enteropathogenic Escherichia coli. AB - Enteropathogenic Escherichia coli (EPEC) strains induce morphological changes in infected epithelial cells. The resulting attaching and effacing (A/E) lesion is characterized by intimate bacterial adherence to epithelial cells, with microvillus destruction, cytoskeletal rearrangement, and aggregation of host cytoskeletal proteins. This review presents an overview of the adhesion mechanisms used for the colonization of the human gastrointestinal tract by EPEC. The mechanisms underlying EPEC adhesion, prior to and during the formation of the A/E lesion, and the host cytosolic responses to bacterial infection leading to diarrheal disease are discussed. PMID- 26443577 TI - Detection of Delirium in Hospitalized Older General Medicine Patients: A Comparison of the 3D-CAM and CAM-ICU. AB - BACKGROUND: Delirium is common in older hospitalized patients and is associated with poor outcomes, yet most cases go undetected. The best approach for systematic delirium identification outside the intensive care unit remains unknown. OBJECTIVE: To conduct a comparative effectiveness study of the Confusion Assessment Method for the ICU (CAM-ICU) and the newly developed 3-minute diagnostic assessment for delirium using the Confusion Assessment Method (3D-CAM) in general medicine inpatients. DESIGN: Cross-sectional comparative effectiveness study. SETTING: Two non-intensive care general medicine units at a single academic medical center. PARTICIPANTS: Hospitalized general medicine patients aged >=75 years. MEASUREMENTS: Clinicians performed a reference standard assessment for delirium that included patient interviews, family interviews, and review of the medical record. An expert panel determined the presence or absence of delirium using DSM-IV criteria. Two blinded research assistants administered the CAM-ICU and the 3D-CAM in random order, and we determined their diagnostic test characteristics compared to the reference standard. RESULTS: Among the 101 participants (mean age 84 +/- 5.5 years, 61 % women, 25 % with dementia), 19 % were classified as delirious based on the reference standard. Evaluation times for the 3D-CAM and CAM-ICU were similar. The sensitivity [95 % confidence interval (CI)] of delirium detection for the 3D-CAM was 95 % [74 %, 100 %] and for the CAM-ICU was 53 % [29 %, 76 %], while specificity was >90 % for both instruments. Subgroup analyses showed that the CAM-ICU had sensitivity of 30 % in patients with mild delirium vs. 100 % for the 3D-CAM. CONCLUSIONS: In this comparative effectiveness study, we found that the 3D-CAM had substantially higher sensitivity than the CAM-ICU in hospitalized older general medicine patients, and similar administration time. Therefore, the 3D-CAM may be a superior screening tool for delirium in this patient population. PMID- 26443579 TI - NADH as Donor. AB - The number of NADH dehydrogenases and their role in energy transduction in Escherchia coli have been under debate for a long time. Now it is evident that E. coli possesses two respiratory NADH dehydrogenases, or NADH:ubiquinone oxidoreductases, that have traditionally been called NDH-I and NDH-II. This review describes the properties of these two NADH dehydrogenases, focusing on the mechanism of the energy converting NADH dehydrogenase as derived from the high resolution structure of the soluble part of the enzyme. In E. coli, complex I operates in aerobic and anaerobic respiration, while NDH-II is repressed under anaerobic growth conditions. The insufficient recycling of NADH most likely resulted in excess NADH inhibiting tricarboxylic acid cycle enzymes and the glyoxylate shunt. Salmonella enterica serovar Typhimurium complex I mutants are unable to activate ATP-dependent proteolysis under starvation conditions. NDH-II is a single subunit enzyme with a molecular mass of 47 kDa facing the cytosol. Despite the absence of any predicted transmembrane segment it has to be purified in the presence of detergents, and the activity of the preparation is stimulated by an addition of lipids. PMID- 26443578 TI - Peroxisome Proliferator Activated Receptor-alpha Association With Silent Information Regulator 1 Suppresses Cardiac Fatty Acid Metabolism in the Failing Heart. AB - BACKGROUND: Heart failure is accompanied by changes in cardiac metabolism characterized by reduced fatty acid (FA) utilization. However, the underlying mechanism and its causative involvement in the progression of heart failure are poorly understood. The peroxisome proliferator activated receptor-alpha (PPARalpha)/retinoid X receptor (RXR) heterodimer promotes transcription of genes involved in FA metabolism through binding to the PPAR response element, called direct repeat 1 (DR1). Silent information regulator 1 (Sirt1) is a histone deacetylase, which interacts with PPARalpha. METHODS AND RESULTS: To investigate the role of PPARalpha in the impaired FA utilization observed during heart failure, genetically altered mice were subjected to pressure overload. The DNA binding of PPARalpha, RXRalpha, and Sirt1 to DR1 was evaluated with oligonucleotide pull-down and chromatin immunoprecipitation assays. Although the binding of PPARalpha to DR1 was enhanced in response to pressure overload, that of RXRalpha was attenuated. Sirt1 competes with RXRalpha to dimerize with PPARalpha, thereby suppressing FA utilization in the failing heart. DR1 sequence analysis indicated that the typical DR1 sequence favors PPARalpha/RXRalpha heterodimerization, whereas the switch from RXRalpha to Sirt1 takes place on degenerate DR1s. Sirt1 bound to PPARalpha through a region homologous to the PPARalpha binding domain in RXRalpha. A short peptide corresponding to the RXRalpha domain not only inhibited the interaction between PPARalpha and Sirt1 but also improved FA metabolism and ameliorated cardiac dysfunction. CONCLUSIONS: A change in the heterodimeric partner of PPARalpha from RXRalpha to Sirt1 is responsible for the impaired FA metabolism and cardiac dysfunction in the failing heart. PMID- 26443580 TI - Biosynthesis of Hemes. AB - This review is concerned specifically with the structures and biosynthesis of hemes in E. coli and serovar Typhimurium. However, inasmuch as all tetrapyrroles share a common biosynthetic pathway, much of the material covered here is applicable to tetrapyrrole biosynthesis in other organisms. Conversely, much of the available information about tetrapyrrole biosynthesis has been gained from studies of other organisms, such as plants, algae, cyanobacteria, and anoxygenic phototrophs, which synthesize large quantities of these compounds. This information is applicable to E. coli and serovar Typhimurium. Hemes play important roles as enzyme prosthetic groups in mineral nutrition, redox metabolism, and gas-and redox-modulated signal transduction. The biosynthetic steps from the earliest universal precursor, 5-aminolevulinic acid (ALA), to protoporphyrin IX-based hemes constitute the major, common portion of the pathway, and other steps leading to specific groups of products can be considered branches off the main axis. Porphobilinogen (PBG) synthase (PBGS; also known as ALA dehydratase) catalyzes the asymmetric condensation of two ALA molecules to form PBG, with the release of two molecules of H2O. Protoporphyrinogen IX oxidase (PPX) catalyzes the removal of six electrons from the tetrapyrrole macrocycle to form protoporphyrin IX in the last biosynthetic step that is common to hemes and chlorophylls. Several lines of evidence converge to support a regulatory model in which the cellular level of available or free protoheme controls the rate of heme synthesis at the level of the first step unique to heme synthesis, the formation of GSA by the action of GTR. PMID- 26443581 TI - Regulation of Fimbrial Expression. AB - Fimbria-mediated interaction with the host elicits both innate and adaptive immune responses, and thus their expression may not always be beneficial in vivo. Furthermore, the metabolic drain of producing fimbriae is significant. It is not surprising, therefore, to find that fimbrial production in Escherichia coli and Salmonella enterica is under extensive environmental regulation. In many instances, fimbrial expression is regulated by phase variation, in which individual cells are capable of switching between fimbriate and afimbriate states to produce a mixed population. Mechanisms of phase variation vary considerably between different fimbriae and involve both genetic and epigenetic processes. Notwithstanding this, fimbrial expression is also sometimes controlled at the posttranscriptional level. In this chapter, we review key features of the regulation of fimbrial gene expression in E. coli and Salmonella. The occurrence and distribution of fimbrial operons vary significantly among E. coli pathovars and even among the many Salmonella serovars. Therefore, general principles are presented on the basis of detailed discussion of paradigms that have been extensively studied, including Pap, type 1 fimbriae, and curli. The roles of operon specific regulators like FimB or CsgD and of global regulatory proteins like Lrp, CpxR, and the histone-like proteins H-NS and IHF are reviewed as are the roles of sRNAs and of signalling nucleotide cyclic-di-GMP. Individual examples are discussed in detail to illustrate how the regulatory factors cooperate to allow tight control of expression of single operons. Molecular networks that allow coordinated expression between multiple fimbrial operons and with flagella in a single isolate are also presented. This chapter illustrates how adhesin expression is controlled, and the model systems also illustrate general regulatory principles germane to our overall understanding of bacterial gene regulation. PMID- 26443582 TI - Copper Homeostasis in Escherichia coli and Other Enterobacteriaceae. AB - An interesting model for studying environmental influences shaping microbial evolution is provided by a multitude of copper resistance and copper homeostasis determinants in enteric bacteria. This review describes these determinants and tries to relate their presence to the habitat of the respective organism, as a current hypothesis predicts that the environment should determine an organism's genetic makeup. In Escherichia coli there are four regulons that are induced in the presence of copper. Two, the CueR and the CusR regulons, are described in detail. A central component regulating intracellular copper levels, present in all free-living enteric bacteria whose genomes have so far been sequenced, is a Cu(I)translocating P-type ATPase. The P-type ATPase superfamily is a ubiquitous group of proteins involved in the transport of charged substrates across biological membranes. Whereas some components involved in copper homeostasis can be found in both anaerobes and aerobes, multi-copper oxidases (MCOs) implicated in copper tolerance in E. coli, such as CueO and the plasmid-based PcoA, can be found only in aerobic organisms. Several features indicate that CueO, PcoA, and other related MCOs are specifically adapted to combat copper-mediated oxidative damage. In addition to these well-characterized resistance operons, there are numerous other genes that appear to be involved in copper binding and trafficking that have not been studied in great detail. SilE and its homologue PcoE, for example, are thought to effect the periplasmic binding and sequestration of silver and copper, respectively. PMID- 26443583 TI - ATP Synthesis by Oxidative Phosphorylation. AB - The F1F0-ATP synthase (EC 3.6.1.34) is a remarkable enzyme that functions as a rotary motor. It is found in the inner membranes of Escherichia coli and is responsible for the synthesis of ATP in response to an electrochemical proton gradient. Under some conditions, the enzyme functions reversibly and uses the energy of ATP hydrolysis to generate the gradient. The ATP synthase is composed of eight different polypeptide subunits in a stoichiometry of alpha3beta3gammadeltaepsilonab2c10. Traditionally they were divided into two physically separable units: an F1 that catalyzes ATP hydrolysis (alpha3beta3gammadeltaepsilon) and a membrane-bound F0 sector that transports protons (ab2c10). In terms of rotary function, the subunits can be divided into rotor subunits (gammaepsilonc10) and stator subunits (alpha3beta3deltaab2). The stator subunits include six nucleotide binding sites, three catalytic and three noncatalytic, formed primarily by the beta and alpha subunits, respectively. The stator also includes a peripheral stalk composed of delta and b subunits, and part of the proton channel in subunit a. Among the rotor subunits, the c subunits form a ring in the membrane, and interact with subunit a to form the proton channel. Subunits gamma and epsilon bind to the c-ring subunits, and also communicate with the catalytic sites through interactions with alpha and beta subunits. The eight subunits are expressed from a single operon, and posttranscriptional processing and translational regulation ensure that the polypeptides are made at the proper stoichiometry. Recent studies, including those of other species, have elucidated many structural and rotary properties of this enzyme. PMID- 26443584 TI - Messenger RNA Decay. AB - This chapter discusses several topics relating to the mechanisms of mRNA decay. These topics include the following: important physical properties of mRNA molecules that can alter their stability; methods for determining mRNA half lives; the genetics and biochemistry of proteins and enzymes involved in mRNA decay; posttranscriptional modification of mRNAs; the cellular location of the mRNA decay apparatus; regulation of mRNA decay; the relationships among mRNA decay, tRNA maturation, and ribosomal RNA processing; and biochemical models for mRNA decay. Escherichia coli has multiple pathways for ensuring the effective decay of mRNAs and mRNA decay is closely linked to the cell's overall RNA metabolism. Finally, the chapter highlights important unanswered questions regarding both the mechanism and importance of mRNA decay. PMID- 26443585 TI - S- and N-Oxide Reductases. AB - Escherichia coli is a versatile facultative anaerobe that can respire on a number of terminal electron acceptors, including oxygen, fumarate, nitrate, and S- and N oxides. Anaerobic respiration using S- and N-oxides is accomplished by enzymatic reduction of these substrates by dimethyl sulfoxide reductase (DmsABC) and trimethylamine N-oxide reductase (TorCA). Both DmsABC and TorCA are membrane associated redox enzymes that couple the oxidation of menaquinol to the reduction of S- and N-oxides in the periplasm. DmsABC is membrane bound and is composed of a membrane-extrinsic dimer with a 90.4-kDa catalytic subunit (DmsA) and a 23.1 kDa electron transfer subunit (DmsB). These subunits face the periplasm and are held to the membrane by a 30.8-kDa membrane anchor subunit (DmsC). The enzyme provides the scaffold for an electron transfer relay composed of a quinol binding site, five [4Fe-4S] clusters, and a molybdo-bis(molybdopterin guanine dinucleotide) (present nomenclature: Mo-bis-pyranopterin) (Mo-bisMGD) cofactor. TorCA is composed of a soluble periplasmic subunit (TorA, 92.5 kDa) containing a Mo-bis-MGD. TorA is coupled to the quinone pool via a pentaheme c subunit (TorC, 40.4 kDa) in the membrane. Both DmsABC and TorCA require system-specific chaperones (DmsD or TorD) for assembly, cofactor insertion, and/or targeting to the Tat translocon. In this chapter, we discuss the complex regulation of the dmsABC and torCAD operons, the poorly understood paralogues, and what is known about the assembly and translocation to the periplasmic space by the Tat translocon. PMID- 26443586 TI - Salmonella as an Inducer of Autoimmunity. AB - A clear etiological link has been established between infection with several gram negative enteric pathogens, including Salmonella spp., and the incidence of reactive arthritis (ReA), an autoimmune disease that largely affects the joints. ReA is sometimes referred to as Reiter's syndrome, particularly when accompanied by uveitis and urethritis. This review reviews the evidence etiologically linking Salmonella infection with autoimmune disease and addresses the roles that bacterial and host elements play in controlling disease outcome. ReA is an autoimmune disease that largely consists of painful joint inflammation but also can include inflammation of the eye, gastrointestinal tract, and skin. ReA is a member of a broad spectrum of chronic inflammatory disorders termed the seronegative spondyloarthropathies (SNSpAs) that includes ankylosing spondylitis (AS), psoriatic arthritis, and enteropathic arthritis. Salmonella species, as well as other enteric pathogens associated with postgastroenteritis ReA, are facultative intracellular gram-negative bacteria. Many studies have analyzed the association of the HLA class I molecule, HLA-B27, with SNSpAs. Whereas B27 has been shown to be present in 90 to 95% of cases of AS, the association of the B27 haplotype with other SNSpAs is more tenuous. The clear association between ReA and infection with Salmonella or other gram-negative enteric pathogens has led to the suggestion that the adaptive immune response to infection has an autoimmune component. In addition to various Salmonella species, other gram-negative enteric pathogens have been linked to the development of ReA. Given their close relationship to Salmonella, this review considers the involvement of Shigella species in ReA. PMID- 26443587 TI - Fimbriae: Classification and Biochemistry. AB - Proteinaceous, nonflagellar surface appendages constitute a variety of structures, including those known variably as fimbriae or pili. Constructed by distinct assembly pathways resulting in diverse morphologies, fimbriae have been described to mediate functions including adhesion, motility, and DNA transfer. As these structures can represent major diversifying elements among Escherichia and Salmonella isolates, multiple fimbrial classification schemes have been proposed and a number of mechanistic insights into fimbrial assembly and function have been made. Herein we describe the classifications and biochemistry of fimbriae assembled by the chaperone/usher, curli, and type IV pathways. PMID- 26443588 TI - Folate Biosynthesis, Reduction, and Polyglutamylation and the Interconversion of Folate Derivatives. AB - Many microorganisms and plants possess the ability to synthesize folic acid derivatives de novo, initially forming dihydrofolate. All the folic acid derivatives that serve as recipients and donors of one-carbon units are derivatives of tetrahydrofolate, which is formed from dihydrofolate by an NADPH dependent reduction catalyzed by dihydrofolate reductase (FolA). This review discusses the biosynthesis of dihydrofolate monoglutamate, its reduction to tetrahydrofolate monoglutamate, and the addition of glutamyl residues to form folylpolyglutamates. Escherichia coli and Salmonella, like many microorganisms that can synthesize folate de novo, appear to lack the ability to transport folate into the cell and are thus highly susceptible to inhibitors of folate biosynthesis. The review includes a brief discussion of the inhibition of folate biosynthesis by sulfa drugs. The folate biosynthetic pathway can be divided into two sections. First, the aromatic precursor chorismate is converted to paminobenzoic acid (PABA) by the action of three proteins. Second, the pteridine portion of folate is made from GTP and coupled to PABA to generate dihydropteroate, and the bifunctional protein specified by folC, dihydrofolate synthetase, or folylpolyglutamate synthetase, adds the initial glutamate molecule to form dihydrofolate (H2PteGlu1, or dihydropteroylmonoglutamate). Bacteriophage T4 infection of E. coli has been shown to cause alterations in the metabolism of folate derivatives. Infection is associated with an increase in the chain lengths in folylpolyglutamates and particularly the accumulation of hexaglutamate derivatives. PMID- 26443590 TI - Introduction and Perspectives. AB - Classically, metabolism was investigated by studying molecular characteristics of enzymes and their regulators in isolation. This reductionistic approach successfully established mechanistic relationships with the immediate interacting neighbors and allowed reconstruction of network structures. Severely underdeveloped was the ability to make precise predictions about the integrated operation of pathways and networks that emerged from the typically nonlinear and complex interactions of proteins and metabolites. The burden of metabolic engineering is a consequence of this fact-one cannot yet predict with any certainty precisely what needs to be engineered to produce more complex phenotypes. What was and still is missing are concepts, methods, and algorithms to integrate data and information into a quantitatively coherent whole, as well as theoretical concepts to reliably predict the consequence of environmental stimuli or genetic interventions. This introduction and perspective to Domain 3, Metabolism and Metabolic Fluxes, starts with a brief overview of the panoply of global measurement technologies that herald the dawning of systems biology and whose impact on metabolic research is apparent throughout the Domain 3. In the middle section, applications to Escherichia coli are used to illustrate general concepts and successes of computational methods that approach metabolism as a network of interacting elements, and thus have potential to fill the gap in quantitative data and information integration. The final section highlights prospective focus areas for future metabolic research, including functional genomics, eludication of evolutionary principles, and the integration of metabolism with regulatory networks. PMID- 26443591 TI - Biosynthesis of Proline. AB - Proline was among the last biosynthetic precursors to have its biosynthetic pathway unraveled. This review recapitulates the findings on the biosynthesis and transport of proline. Glutamyl kinase (GK) catalyzes the ATP-dependent phosphorylation of L-glutamic acid. Purification of gamma-GK from Escherichia coli was facilitated by the expression of the proB and proA genes from a high copy-number plasmid and the development of a specific coupled assay based on the NADPH-dependent reduction of GP by gamma-glutamyl phosphate reductase (GPR). GPR catalyzes the NADPH-dependent reduction of GP to GSA. Site directed mutagenesis was used to identify residues that constitute the active site of E. coli GK. This analysis indicated that there is an overlap between the binding sites for glutamate and the allosteric inhibitor proline, suggesting that proline competes with the binding of glutamate. The review also summarizes the genes involved in the metabolism of proline in E. coli and Salmonella. Among the completed genomic sequences of Enterobacteriaceae, genes specifying all three proline biosynthetic enzymes can be discerned in E. coli, Shigella, Salmonella enterica, Serratia marcescens, Erwinia carotovora, Yersinia, Photorhabdus luminescens, and Sodalis glossinidius strain morsitans. The intracellular proline concentration increases with increasing external osmolality in proline-overproducing mutants. This apparent osmotic regulation of proline accumulation in the overproducing strains may be the result of increased retention or recapture of proline, achieved by osmotic stimulation of the ProP or ProU proline transport systems. A number of proline analogs can be incorporated into proteins in vivo or in vitro. PMID- 26443592 TI - How We Got to Where We Are: the Ribosome in the 21st Century. AB - This article is a short, informal history of the ribosome field that begins with the emergence of the field in the 1930s and ends with a description of its state in 2007, the year this essay was written. The growth in our understanding of both the role of the ribosome in protein synthesis and its structure is emphasized. Starting in 2000, the field experienced a massive upheaval as a result of the publication of the first atomic-resolution crystal structures for ribosomes. However, by 2007, the field had recovered sufficiently so that one could begin to understand how it was likely to evolve in its "poststructural" era. For that reason, this essay is about as useful as a short history of the ribosome field today as it was several years ago, when it was written. PMID- 26443589 TI - Biosynthesis of Pantothenic Acid and Coenzyme A. AB - Pantothenate is vitamin B5 and is the key precursor for the biosynthesis of coenzyme A (CoA), a universal and essential cofactor involved in a myriad of metabolic reactions, including the synthesis of phospholipids, the synthesis and degradation of fatty acids, and the operation of the tricarboxylic acid cycle. CoA is also the only source of the phosphopantetheine prosthetic group for enzymes that shuttle intermediates between the active sites of enzymes involved in fatty acid, nonribosomal peptide, and polyketide synthesis. Pantothenate can be synthesized de novo and/or transported into the cell through a pantothenatepermease. Pantothenate uptake is essential for those organisms that lack the genes to synthesize this vitamin. The intracellular levels of CoA are controlled by the balance between synthesis and degradation. In particular, CoA is assembled in five enzymatic steps, starting from the phosphorylation of pantothenate to phosphopantothenatecatalyzed by pantothenate kinase, the product of the coaA gene. In some bacteria, the production of phosphopantothenate by pantothenate kinase is the rate limiting and most regulated step in the biosynthetic pathway. CoA synthesis additionally networks with other vitamin associated pathways, such as thiamine and folic acid. PMID- 26443593 TI - Succinate as Donor; Fumarate as Acceptor. AB - Succinate and fumarate are four-carbon dicarboxylates that differ in the identity of their central bond (single or double). The oxidoreduction of these small molecules plays a central role in both aerobic and anaerobic respiration. During aerobic respiration, succinate is oxidized, donating two reducing equivalents, while in anaerobic respiration, fumarate is reduced, accepting two reducing equivalents. Two related integral membrane Complex II superfamily members catalyze these reactions, succinate:ubiquinone oxidoreductase (SQR) and fumarate:menaquinol oxidoreductase (QFR). The structure, function, and regulation of these integral-membrane enzymes are summarized here. The overall architecture of these Complex II enzymes has been found to consist of four subunits: two integral membrane subunits, and a soluble domain consisting of an iron-sulfur protein subunit, and a flavoprotein subunit. This architecture provides a scaffold that houses one active site in the membrane and another in the soluble milieu, making a linear electron transfer chain that facilities shuttling of reducing equivalents between the two active sites. A combination of kinetic measurements, mutagenesis, electron paramagnetic resonance spectroscopy, UV/Vis spectroscopy, and x-ray crystallography have suggested mechanisms for succinate:fumarate interconversion, electron transfer, and quinone:quinol interconversion. Of particular interest are the structural details that control directionality and make SQR and QFR primed for preferential catalysis each in different favored directions. PMID- 26443595 TI - Progress toward improved therapies for inborn errors of metabolism. AB - Because of their prevalence, severity and lack of effective treatments, inborn errors of metabolism need novel and more effective therapeutic approaches. The opportunity for an early treatment coming from expanded newborn screening has made this need even more urgent. To meet this demand, a growing number of novel treatments are entering in the phase of clinical development. Strategies to overcome the detrimental consequences of the enzyme deficiencies responsible for inborn errors of metabolism have been focused on multiple fronts at the levels of the gene, RNA, protein and whole cell. These strategies have been accomplished using a wide spectrum of approaches ranging from small molecules to enzyme replacement therapy, cell and gene therapy. The applications of new technologies in the field of inborn errors of metabolism, such as genome editing, RNA interference and cell reprogramming, along with progress in pre-existing strategies, such as gene therapy or cell transplantation, have tremendous potential for clinical translation. PMID- 26443596 TI - Advances in treatment of achondroplasia and osteoarthritis. AB - Achondroplasia (ACH) is the prototype and most common of the human chondrodysplasias. It results from gain-of-function mutations that exaggerate the signal output of the fibroblast growth factor receptor 3 (FGFR3), a receptor tyrosine kinase that negatively regulates growth plate activity and linear bone growth. Several approaches to reduce FGFR3 signaling by blocking receptor activation or inhibiting downstream signals have been proposed. Five show promise in preclinical mouse studies. Two candidate therapies target the extracellular domain of FGFR3. The first is a decoy receptor that competes for activating ligands. The second is a synthetic blocking peptide that prevents ligands from binding and activating FGFR3. Two established drugs, statins and meclozine, improve growth of ACH mice. The strongest candidate therapy employs an analog of C-type natriuretic peptide (CNP), which antagonizes the mitogen-activated-protein (MAP) kinase pathway downstream of the FGFR3 receptor and may also act independently in the growth plate. Only the CNP analog has reached clinical trials. Preliminary results of Phase 2 studies show a substantial increase in growth rate of ACH children after six months of therapy with no serious adverse effects. A challenge for drug therapy in ACH is targeting agents to the avascular growth plate. The application of gene therapy in osteoarthritis offers insights because it faces similar technical obstacles. Major advances in gene therapy include the emergence of recombinant adeno-associated virus as the vector of choice, capsid engineering to target vectors to specific tissues, and development of methods to direct vectors to articular chondrocytes. PMID- 26443594 TI - Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems. AB - Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected individuals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected individuals. We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular. PMID- 26443597 TI - Prevention of abdominal aortic aneurysm progression by targeted inhibition of matrix metalloproteinase activity with batimastat-loaded nanoparticles. AB - RATIONALE: Matrix metalloproteinases (MMPs)-mediated extracellular matrix destruction is the major cause of development and progression of abdominal aortic aneurysms. Systemic treatments of MMP inhibitors have shown effectiveness in animal models, but it did not translate to clinical success either because of low doses used or systemic side effects of MMP inhibitors. We propose a targeted nanoparticle (NP)-based delivery of MMP inhibitor at low doses to the abdominal aortic aneurysms site. Such therapy will be an attractive option for preventing expansion of aneurysms in patients without systemic side effects. OBJECTIVE: Our previous study showed that poly(d,l-lactide) NPs conjugated with an antielastin antibody could be targeted to the site of an aneurysm in a rat model of abdominal aortic aneurysms. In the study reported here, we tested whether such targeted NPs could deliver the MMP inhibitor batimastat (BB-94) to the site of an aneurysm and prevent aneurysmal growth. METHODS AND RESULTS: Poly(d,l-lactide) NPs were loaded with BB-94 and conjugated with an elastin antibody. Intravenous injections of elastin antibody-conjugated BB-94-loaded NPs targeted the site of aneurysms and delivered BB-94 in a calcium chloride injury-induced abdominal aortic aneurysms in rats. Such targeted delivery inhibited MMP activity, elastin degradation, calcification, and aneurysmal development in the aorta (269% expansion in control versus 40% elastin antibody-conjugated BB-94-loaded NPs) at a low dose of BB-94. The systemic administration of BB-94 alone at the same dose was ineffective in producing MMP inhibition. CONCLUSIONS: Targeted delivery of MMP inhibitors using NPs may be an attractive strategy to inhibit aneurysmal progression. PMID- 26443598 TI - Soluble CD14: An Independent Biomarker for the Risk of Mother-to-Child Transmission of HIV in a Setting of Preexposure and Postexposure Antiretroviral Prophylaxis. AB - Elevated soluble CD14 (sCD14) concentrations, a marker of monocyte activation, predicts adverse outcomes in human immunodeficiency virus (HIV)-infected adults. To examine the association of sCD14 concentrations with the risk of mother-to child transmission (MTCT) of HIV, we nested a case-control study (49 pairs of infants and their HIV-infected mothers) within the Six-Week Extended-Dose Nevirapine trial. Median peripartum maternal log2 sCD14 concentration was higher among transmitters (defined as pairs in which maternally transmitted HIV infection occurred by 12 months of age) than nontransmitters (20.29 pg/mL vs 19.41 pg/mL; P = .005). There was an increased odds of MTCT for every log2 increase in maternal sCD14 concentration, after adjustment for maternal HIV load, CD4 count and cART exposure (adjusted odds ratio, 3.51; 95% confidence interval, 1.21-10.21). Maternal monocyte activation may adversely influence the risk of MTCT of HIV. PMID- 26443599 TI - Delay and death-thought accessibility: a meta-analysis. AB - The dual-process component of Terror Management Theory (TMT) proposes that different types of threats lead to increases in death-thought accessibility (DTA) after different delay intervals. Experimental studies of terror management threats' effect on DTA were collected and coded for their use of explicitly death related (vs. not explicitly death-related) threats, and for their use of delay and task-switching during the delay. Results reveal that studies using death related threats achieved larger DTA effect-sizes when they included more task switching or a longer delay between the threat and the DTA measurement. In contrast, studies using threats that were not explicitly death-related achieved smaller DTA effect-sizes when they included more task-switching between the threat and the DTA measurement. These findings provide partial support for the dual-process component's predictions regarding delay and DTA. Limitations and future directions are discussed. PMID- 26443600 TI - Prospective Comparison between two different magnetic resonance defecography techniques for evaluating pelvic floor disorders: air-balloon versus gel for rectal filling. AB - PURPOSE: to prospectively compare two rectal filling techniques for dynamic MRI of pelvic floor disorders (PFD). METHODS AND MATERIALS: Twenty-six patients with PFD underwent the two techniques during the same procedure, one based on rectal placement of a balloon-catheter filled with saline and air insufflation (air balloon technique or AB); another based on rectal filling with 180 cc of gel (gel filling technique or GF). The examinations were compared for assessment and staging of PFD, including rectal-descent, rectocele, cystocele, colpocele, enterocele, rectal invagination. Surgery and clinical examinations were the gold standard. RESULTS: AB showed sensitivity of 96 % for rectal descent, 100 % for both rectocele and colpocele, 86 % for rectal invagination and 100 % for enterocele; understaged 11 % of rectal descents and 19 % of rectoceles. GF showed sensitivity of 100 % for rectal descent, 91 % for rectocele, 83 % for colpocele, 100 % for rectal invagination and 73 % for enterocele; understaged 3.8 % of rectal descent and 11.5 % of rectoceles. Both techniques showed 100 % of specificity. Agreement between air-balloon and gel filling was 84 % for rectal descent, 69 % for rectocele, 88 % for rectal invagination, 84 % for enterocele, 88 % for cystocele and 92 % for colpocele. CONCLUSION: Both techniques allowed a satisfactory evaluation of PFD. The gel filling was superior for rectal invagination, the air-balloon for rectocele and anterior/middle compartment disorders. KEY POINTS: * A standardized MRI technique for assessing pelvic floor disorders is not yet established. * This study compares two MRI techniques based on different rectal filling: air-balloon versus gel. * Both MRI techniques proved to be valuable in assessing PFD, with good agreement. * Air-balloon technique is more hygienic and better tolerated than the gel-filling technique. * Gel was superior for rectal invagination, air-balloon for rectocele and uro-genital prolapses. PMID- 26443601 TI - Computer-aided detection of pulmonary nodules: a comparative study using the public LIDC/IDRI database. AB - OBJECTIVES: To benchmark the performance of state-of-the-art computer-aided detection (CAD) of pulmonary nodules using the largest publicly available annotated CT database (LIDC/IDRI), and to show that CAD finds lesions not identified by the LIDC's four-fold double reading process. METHODS: The LIDC/IDRI database contains 888 thoracic CT scans with a section thickness of 2.5 mm or lower. We report performance of two commercial and one academic CAD system. The influence of presence of contrast, section thickness, and reconstruction kernel on CAD performance was assessed. Four radiologists independently analyzed the false positive CAD marks of the best CAD system. RESULTS: The updated commercial CAD system showed the best performance with a sensitivity of 82 % at an average of 3.1 false positive detections per scan. Forty-five false positive CAD marks were scored as nodules by all four radiologists in our study. CONCLUSIONS: On the largest publicly available reference database for lung nodule detection in chest CT, the updated commercial CAD system locates the vast majority of pulmonary nodules at a low false positive rate. Potential for CAD is substantiated by the fact that it identifies pulmonary nodules that were not marked during the extensive four-fold LIDC annotation process. KEY POINTS: * CAD systems should be validated on public, heterogeneous databases. * The LIDC/IDRI database is an excellent database for benchmarking nodule CAD. * CAD can identify the majority of pulmonary nodules at a low false positive rate. * CAD can identify nodules missed by an extensive two-stage annotation process. PMID- 26443602 TI - Diffusion-tensor-based method for robust and practical estimation of axial and radial diffusional kurtosis. AB - OBJECTIVES: A new method that can estimate diffusional kurtosis image (DKI), estimated DKI (eDKI), parallel and perpendicular to neuronal fibres from greatly limited image data was designed to enable quick and practical assessment of DKI in clinics. The purpose of this study was to discuss the potential of this method for clinical use. METHODS: Fourteen healthy volunteers were examined with a 3 Tesla MRI. The diffusion-weighting parameters included five different b-values (0, 500, 1,500, 2,000 and 2,500 s/mm(2)) with 64 different encoding directions for each of the b-values. K values were calculated by both conventional DKI (convDKI) and eDKI from these complete data, and also from the data that the encoding directions were abstracted to 32, 21, 15, 12 and 6. Error-pixel ratio and the root mean square error (RMSE) compared with the standard were compared between the methods (Wilcoxon signed-rank test: P < 0.05 was considered significant). RESULTS: Error-pixel ratio was smaller in eDKI than in convDKI and the difference was significant. In addition, RMSE was significantly smaller in eDKI than in convDKI, or otherwise the differences were not significant when they were obtained from the same data set. CONCLUSION: eDKI might be useful for assessing DKI in clinical settings. KEY POINTS: * A method to practically estimate axial/radial DKI from limited data was developed. * The high robustness of the proposed method can greatly improve map images. * The accuracy of the proposed method was high. * Axial/radial K maps can be calculated from limited diffusion-encoding directions. * The proposed method might be useful for assessing DKI in clinical settings. PMID- 26443603 TI - Quantitative 3D analysis of bone in hip osteoarthritis using clinical computed tomography. AB - OBJECTIVE: To assess the relationship between proximal femoral cortical bone thickness and radiological hip osteoarthritis using quantitative 3D analysis of clinical computed tomography (CT) data. METHODS: Image analysis was performed on clinical CT imaging data from 203 female volunteers with a technique called cortical bone mapping (CBM). Colour thickness maps were created for each proximal femur. Statistical parametric mapping was performed to identify statistically significant differences in cortical bone thickness that corresponded with the severity of radiological hip osteoarthritis. Kellgren and Lawrence (K&L) grade, minimum joint space width (JSW) and a novel CT-based osteophyte score were also blindly assessed from the CT data. RESULTS: For each increase in K&L grade, cortical thickness increased by up to 25 % in distinct areas of the superolateral femoral head-neck junction and superior subchondral bone plate. For increasing severity of CT osteophytes, the increase in cortical thickness was more circumferential, involving a wider portion of the head-neck junction, with up to a 7 % increase in cortical thickness per increment in score. Results were not significant for minimum JSW. CONCLUSIONS: These findings indicate that quantitative 3D analysis of the proximal femur can identify changes in cortical bone thickness relevant to structural hip osteoarthritis. KEY POINTS: * CT is being increasingly used to assess bony involvement in osteoarthritis * CBM provides accurate and reliable quantitative analysis of cortical bone thickness * Cortical bone is thicker at the superior femoral head-neck with worse osteoarthritis * Regions of increased thickness co-locate with impingement and osteophyte formation * Quantitative 3D bone analysis could enable clinical disease prediction and therapy development. PMID- 26443604 TI - Is there a systematic bias of apparent diffusion coefficient (ADC) measurements of the breast if measured on different workstations? An inter- and intra-reader agreement study. AB - OBJECTIVES: To evaluate the influence of post-processing systems, intra- and inter-reader agreement on the variability of apparent diffusion coefficient (ADC) measurements in breast lesions. METHODS: Forty-one patients with 41 biopsy-proven breast lesions gave their informed consent and were included in this prospective IRB-approved study. Magnetic resonance imaging (MRI) examinations were performed at 1.5 T using an EPI-DWI sequence, with b-values of 0 and 1000 s/mm(2). Two radiologists (R1, R2) reviewed the images in separate sessions and measured the ADC for lesion, using MRI-workstation (S-WS), PACS-workstation (P-WS) and a commercial DICOM viewer (O-SW). Agreement was evaluated using the intraclass correlation coefficient (ICC), Bland-Altman plots and coefficient of variation (CV). RESULTS: Thirty-one malignant, two high-risk and eight benign mass-like lesions were analysed. Intra-reader agreement was almost perfect (ICC-R1 = 0.974; ICC-R2 = 0.990) while inter-reader agreement was substantial (ICC from 0.615 to 0.682). Bland-Altman plots revealed a significant bias in ADC values measured between O-SW and S-WS (P = 0.025), no further systematic differences were identified. CV varied from 6.8 % to 7.9 %. CONCLUSION: Post-processing systems may have a significant, although minor, impact on ADC measurements in breast lesions. While intra-reader agreement is high, the main source of ADC variability seems to be caused by inter-reader variation. KEY POINTS: * ADC provides quantitative information on breast lesions independent from the system used. * ADC measurement using different workstations and software systems is generally reliable. * Systematic, but minor, differences may occur between different post processing systems. * Inter-reader agreement of ADC measurements exceeded intra reader agreement. PMID- 26443605 TI - Outcomes of transplantations of cryopreserved ovarian tissue to 41 women in Denmark. AB - STUDY QUESTION: What are the results of transplanting cryopreserved ovarian tissue? SUMMARY ANSWER: The transplanted ovarian tissue can last up to 10 years, with no relapses following the 53 transplantations, and the chance of a successful pregnancy is currently around one in three for those with a pregnancy wish. WHAT IS KNOWN ALREADY: Cryopreservation of ovarian tissue is now gaining ground as a valid method for fertility preservation. More than 36 children worldwide have now been born following this procedure. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study of 41 women who had thawed ovarian tissue transplanted 53 times over a period of 10 years, including 1 patient who was lost to follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 41 Danish women, who had in total 53 transplantations, were followed for ovarian function and fertility outcome. Safety was assessed by monitoring relapse in cancer survivors. MAIN RESULTS, AND THE ROLE OF CHANCE: Among 32 women with a pregnancy wish, 10 (31%) had a child/children (14 children in total); this included 1 woman with a third trimester on-going pregnancy. In addition, two legal abortions and one second trimester miscarriage occurred. A total of 24 clinical pregnancies were established in the 32 women with a pregnancy-wish. The tissue remained functional for close to 10 years in some cases and lasted only a short period in others. Three relapses occurred but were unlikely to be due to the transplanted tissue. LIMITATIONS, REASONS FOR CAUTION: Self-report through questionnaires with only in-one hospital formalised follow-up of transplanted patients could result in unreported miscarriages. The longevity of the tissue may vary by few months compared with those reported because some patients simply could not remember the date when the tissue became non-functional. WIDER IMPLICATIONS OF THE FINDINGS: Cryopreservation of ovarian tissue is likely to become integrated into the treatment of young women, with cancer, who run a risk of losing their fertility. The full functional lifespan of grafts is still being evaluated, because many of the transplanted women have continued to maintain ovarian activity. Some of our first cases have had tissue functioning for ~ 10 years. PMID- 26443606 TI - David Oliver: Why shouldn't hospitals challenge inspections? PMID- 26443607 TI - Genetic variants in ANCA-associated vasculitis: a meta-analysis. AB - BACKGROUND: Genetic factors may influence the pathogenic pathways leading to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We performed a meta-analysis to determine the genetic variants most likely associated with AAV and investigated whether diagnostic and serological subtypes within AAV have distinct genetic backgrounds. METHODS: Studies investigating the association between genetic variants and AAV in humans were searched in PubMed, EMBASE and Web of Science. All variants investigated in at least two studies were selected. Subsequently, all studies assessing these variants were included in this meta-analysis. Additionally, data on these variants from the largest genome wide association studies in AAV were included to increase the validity of this meta-analysis. RESULTS: The literature search yielded 5180 articles. 62 articles investigating 140 genetic variants were included, 33 of which were associated with AAV in a meta-analysis. These genetic variants were in or near the following genes: CD226, CTLA-4, FCGR2A, HLA-B, HLA-DP, HLA-DQ, HLA-DR, HSD17B8, IRF5, PTPN22, RING1/RXRB, RXRB, STAT4, SERPINA1 and TLR9. Moreover, we identified genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis and between proteinase 3 ANCA vasculitis and myeloperoxidase ANCA vasculitis. In 76% of the genetic variants, subdivision based on ANCA serotype resulted in higher ORs than subdivision based on clinical diagnosis. CONCLUSIONS: This meta-analysis identified 33 genetic variants associated with AAV, supporting a role for alpha-1-antitrypsin, the major histocompatibility complex system, and several distinct inflammatory processes in AAV pathogenesis. Our results indicate that subdivision of AAV based on ANCA serotype has a stronger genetic basis than subdivision based on clinical diagnosis. PMID- 26443608 TI - Anticarbamylated protein antibodies are associated with long-term disability and increased disease activity in patients with early inflammatory arthritis: results from the Norfolk Arthritis Register. AB - OBJECTIVES: Anticarbamylated protein (anti-CarP) antibodies are a novel family of autoantibodies recently identified in patients with inflammatory arthritis. The aim of this study was to investigate their association with long-term outcomes of disability and disease activity over 20 years' follow-up in a cohort of patients with inflammatory polyarthritis (IP). METHODS: Norfolk Arthritis Register recruited adults with recent-onset swelling of >=2 joints for >=4 weeks from 1990 to 2009. At baseline, Health Assessment Questionnaire (HAQ) and 28 joint disease activity scores (DAS28) were obtained, and C reactive protein, rheumatoid factor (RF), anticitrullinated protein antibodies (ACPA) and anti-CarP antibodies were measured. Further HAQ scores and DAS28 were obtained at regular intervals over 20 years. Generalised estimating equations were used to test the association between anti-CarP antibody status and longitudinal HAQ and DAS28 scores; adjusting for age, gender, smoking status, year of inclusion and ACPA status. Analyses were repeated in subgroups stratified by ACPA status. The relative association of RF, ACPA and anti-CarP antibodies with HAQ and DAS28 scores was investigated using a random effects model. RESULTS: 1995 patients were included; 1310 (66%) were female. Anti-CarP antibodies were significantly associated with more disability and higher disease activity, HAQ multivariate beta-coefficient (95% CI) 0.12 (0.02 to 0.21), and these associations remained significant in the ACPA-negative subgroups. The associations of RF, ACPA and anti-CarP antibodies were found to be additive in the random effects model. CONCLUSIONS: Anti-CarP antibodies are associated with increased disability and higher disease activity in patients with IP. Our results suggest that measurement of anti-CarP antibodies may be useful in identifying ACPA-negative patients with worse long-term outcomes. Further, anti CarP antibody status provided additional information about RF and ACPA. PMID- 26443609 TI - Immunogenicity, drug trough levels and therapeutic response in patients with rheumatoid arthritis or ankylosing spondylitis after 24-week golimumab treatment. PMID- 26443610 TI - Cardiac Arrest in Pregnancy: A Scientific Statement From the American Heart Association. AB - This is the first scientific statement from the American Heart Association on maternal resuscitation. This document will provide readers with up-to-date and comprehensive information, guidelines, and recommendations for all aspects of maternal resuscitation. Maternal resuscitation is an acute event that involves many subspecialties and allied health providers; this document will be relevant to all healthcare providers who are involved in resuscitation and specifically maternal resuscitation. PMID- 26443612 TI - Yeast: a microbe with macro-implications to antimicrobial drug discovery. AB - Paramount to any rational discovery of new antibiotics displaying novel mechanisms of action is a deep knowledge of the genetic basis of microbial growth, division and virulence. The bakers' yeast,Saccharomyces cerevisiae, illustrates the highest understanding of the genetic underpinnings of microbial life, and from this framework, a systems biology paradigm has evolved, begging to be emulated in antibacterial discovery. Here, we review landmark events in the history of yeast genomics that provide this new foundation for antibacterial drug discovery. PMID- 26443611 TI - Influence of Sex on Long-Term Outcomes After Implantation of Bare-Metal Stent: A Multicenter Report From the Coronary Revascularization Demonstrating Outcome Study-Kyoto (CREDO-Kyoto) Registry Cohort-1. AB - BACKGROUND: Female sex was reported to be associated with lower risk for midterm restenosis and repeat revascularization after bare-metal stent implantation. However, the influence of sex on very long-term outcomes after bare-metal stent implantation has not been yet reported. METHODS AND RESULTS: Among the 9877 patients in the multicenter Coronary Revascularization Demonstrating Outcome study in Kyoto (CREDO-Kyoto) registry cohort-1, bare-metal stent implantation was performed in 5313 patients (men, n=3742 and women, n=1571). Follow-up was completed in 4515 patients (85.0%) at 10 years (duration, 10.3 +/- 3.1 [0.0-14.1] years). The cumulative incidence of target-lesion revascularization (TLR) was 27% at 1 year and 34% at 10 years (0.8%/y beyond 1 year). Non-target-lesion revascularization (non-TLR) was the dominant coronary revascularization beyond 1 year (13% at 1 year and 31% at 10 years [2.0%/y beyond 1 year]). Cumulative incidence of stent thrombosis was low (1.2% at 1 year and 1.9% at 10 years). Women were older and had greater prevalence of cardiovascular risk factors than men. The cumulative 10-year incidences of and adjusted risk for TLR were significantly higher in men than in women (36% versus 30%, P<0.001; adjusted hazard ratio, 1.29; 95% confidence interval, 1.15-1.46; P<0.001). The higher risk of men relative to women for TLR was consistent regardless of age (<75 years and >= 75 years). Men in comparison with women were also associated with significantly higher adjusted risks for all-cause death, myocardial infarction, stroke, coronary artery bypass grafting, TLR, and non-TLR. CONCLUSIONS: TLR and stent thrombosis continued to occur without attenuation up to 10 years after bare metal stent implantation. Men in comparison with women were associated with higher adjusted 10-year risks for all-cause death, myocardial infarction, stroke, coronary artery bypass grafting, TLR, and non-TLR. PMID- 26443613 TI - Quality control, imputation and analysis of genome-wide genotyping data from the Illumina HumanCoreExome microarray. AB - The decreasing cost of performing genome-wide association studies has made genomics widely accessible. However, there is a paucity of guidance for best practice in conducting such analyses. For the results of a study to be valid and replicable, multiple biases must be addressed in the course of data preparation and analysis. In addition, standardizing methods across small, independent studies would increase comparability and the potential for effective meta analysis. This article provides a discussion of important aspects of quality control, imputation and analysis of genome-wide data from a low-coverage microarray, as well as a straight-forward guide to performing a genome-wide association study. A detailed protocol is provided online, with example scripts available at https://github.com/JoniColeman/gwas_scripts. PMID- 26443614 TI - A Comparison of Base-calling Algorithms for Illumina Sequencing Technology. AB - Recent advances in next-generation sequencing technology have yielded increasing cost-effectiveness and higher throughput produced per run, in turn, greatly influencing the analysis of DNA sequences. Among the various sequencing technologies, Illumina is by far the most widely used platform. However, the Illumina sequencing platform suffers from several imperfections that can be attributed to the chemical processes inherent to the sequencing-by-synthesis technology. With the enormous amounts of reads produced, statistical methodologies and computationally efficient algorithms are required to improve the accuracy and speed of base-calling. Over the past few years, several papers have proposed methods to model the various imperfections, giving rise to accurate and/or efficient base-calling algorithms. In this article, we provide a comprehensive comparison of the performance of recently developed base-callers and we present a general statistical model that unifies a large majority of these base-callers. PMID- 26443616 TI - Nobel awarded to discoverers of ivermectin and artemisinin. PMID- 26443615 TI - MST2-RASSF protein-protein interactions through SARAH domains. AB - The detailed, atomistic-level understanding of molecular signaling along the tumor-suppressive Hippo signaling pathway that controls tissue homeostasis by balancing cell proliferation and death through apoptosis is a promising avenue for the discovery of novel anticancer drug targets. The activation of kinases such as Mammalian STE20-Like Protein Kinases 1 and 2 (MST1 and MST2)-modulated through both homo- and heterodimerization (e.g. interactions with Ras association domain family, RASSF, enzymes)-is a key upstream event in this pathway and remains poorly understood. On the other hand, RASSFs (such as RASSF1A or RASSF5) act as important apoptosis activators and tumor suppressors, although their exact regulatory roles are also unclear. We present recent molecular studies of signaling along the Ras-RASSF-MST pathway, which controls growth and apoptosis in eukaryotic cells, including a variety of modern molecular modeling and simulation techniques. Using recently available structural information, we discuss the complex regulatory scenario according to which RASSFs perform dual signaling functions, either preventing or promoting MST2 activation, and thus control cell apoptosis. Here, we focus on recent studies highlighting the special role being played by the specific interactions between the helical Salvador/RASSF/Hippo (SARAH) domains of MST2 and RASSF1a or RASSF5 enzymes. These studies are crucial for integrating atomistic-level mechanistic information about the structures and conformational dynamics of interacting proteins, with information available on their system-level functions in cellular signaling. PMID- 26443617 TI - Junior doctors' dispute goes beyond pay, Tory MP says. PMID- 26443618 TI - Trade pact disappoints biotechnology companies and campaigners for better access to drugs. PMID- 26443619 TI - Longitudinal study of very low birth weight infants until 9years of age; attention deficit hyperactivity and autistic features are correlated with their cognitive functions. AB - BACKGROUND: Increasing attention has been given to neuro-developmental problems of very low birth weight infants (VLBWIs) at school age. However, it remains unknown whether their neuro-cognitive function and psychiatric symptoms are mutually associated. AIM: The aim of this study was to investigate the characteristics of neuro-cognitive functions in VLBWIs and their relationship with psychiatric symptoms. METHODS: A total of 160 VLBWIs who were born at our institute between 2001 and 2005 were recruited consecutively and followed up until nine years of age. The developmental profiles were obtained from 77 children (45 males and 32 females) at six to nine years of age using the ADHD Rating Scale-Fourth edition (ADHD-RS), Autism Screening Questionnaire-Japanese version (ASQ-J) and the Wechsler Intelligence Scale for Children-Third edition (WISC-III). RESULTS: The full-scale intelligence quotient did not significantly differ between the male and female VLBWIs (median: 91 vs. 99, p=0.17). The males had higher total scores (median: 13 vs. 4, p<0.01) and higher scores on the subscales of Inattention (8 vs. 2, p<0.01) and Hyperactivity-Impulsivity (5 vs. 1, p<0.01) of the ADHD-RS compared with the females. The Verbal Comprehension Index (VCI) of the WISC-III was inversely correlated with the total scores of the ASQ-J for all VLBWIs (n=77, rc: -0.32, 95% CI: -0.19 to -0.01, p=0.04). We also observed that the Freedom from Distractibility Index (FDI) of the WISC-III was significantly correlated with the Inattentive scores of the ADHD-RS (n=45, rc: 0.18, 95% CI: -0.35 to -0.02, p=0.03) in male, but not female VLBWIs. CONCLUSIONS: We herein report that the VCI and FDI of the WISC-III were correlated with the autism spectrum disorder and attention deficit hyperactivity disorder symptoms, respectively, in male VLBWIs. PMID- 26443620 TI - Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation: 20-year experience. PMID- 26443621 TI - slan-defined subsets of CD16-positive monocytes: impact of granulomatous inflammation and M-CSF receptor mutation. AB - Human monocytes are subdivided into classical, intermediate, and nonclassical subsets, but there is no unequivocal strategy to dissect the latter 2 cell types. We show herein that the cell surface marker 6-sulfo LacNAc (slan) can define slan positive CD14(+)CD16(++) nonclassical monocytes and slan-negative CD14(++)CD16(+) intermediate monocytes. Gene expression profiling confirms that slan-negative intermediate monocytes show highest expression levels of major histocompatibility complex class II genes, whereas a differential ubiquitin signature is a novel feature of the slan approach. In unsupervised hierarchical clustering, the slan positive nonclassical monocytes cluster with monocytes and are clearly distinct from CD1c(+) dendritic cells. In clinical studies, we show a selective increase of the slan-negative intermediate monocytes to >100 cells per microliter in patients with sarcoidosis and a fivefold depletion of the slan-positive monocytes in patients with hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), which is caused by macrophage colony-stimulating factor (M-CSF) receptor mutations. These data demonstrate that the slan-based definition of CD16-positive monocyte subsets is informative in molecular studies and in clinical settings. PMID- 26443622 TI - Intravenous immune globulin and thromboembolic adverse events in patients with hematologic malignancy. AB - In patients with hypogammaglobulinemia secondary to chronic lymphocytic leukemia (CLL) or multiple myeloma (MM), intravenous immune globulin (IVIg) may be administered to reduce the risk of infection. Since 2013, IVIg products have carried a boxed safety warning about the risk of thromboembolic events (TEEs), with TEEs reported in 0.5% to 15% of patients treated with IVIg. In this retrospective cohort study of older patients with CLL or MM identified from the Surveillance, Epidemiology, and End Results-Medicare Linked Database, we assessed rates of clinically serious TEEs in 2724 new users of IVIg and a propensity matched comparison group of 8035 nonusers. For the primary end point, arterial TEE, we observed a transient increased risk of TEE during the day of an IVIg infusion and the day afterward (hazard ration = 3.40; 95% confidence interval [CI]: 1.25, 9.25); this risk declined over the remainder of the 30-day treatment cycle. When considered in terms of absolute risk averaged over a 1-year treatment period, the increase in risk attributable to IVIg was estimated to be 0.7% (95% CI: -0.2%, 2.0%) compared with a baseline risk of 1.8% for the arterial TEE end point. A statistically nonsignificant risk increase of 0.3% (95% CI: -0.4%, 1.5%) compared with a baseline risk of 1.1% was observed for the venous TEE end point. Further research is needed to establish the generalizability of these results to patients receiving higher doses of IVIg for other indications. PMID- 26443623 TI - NADPH oxidase controls neutrophilic response to sterile inflammation in mice by regulating the IL-1alpha/G-CSF axis. AB - The leukocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase generates reactive oxygen species essential in microbial killing and regulation of inflammation. Inactivating mutations in this enzyme lead to chronic granulomatous disease (CGD), associated with increased susceptibility to both pyogenic infections and to inflammatory disorders. The role of the NADPH oxidase in regulating inflammation driven by nonmicrobial stimuli is poorly understood. Here, we show that NADPH oxidase deficiency enhances the early local release of interleukin-1alpha (IL-1alpha) in response to damaged cells, promoting an excessive granulocyte colony-stimulating factor (G-CSF)-regulated neutrophilic response and prolonged inflammation. In peritoneal inflammation elicited by tissue injury, X-linked Cybb-null (X-CGD) mice exhibited increased release of IL 1alpha and IL-1 receptor -mediated G-CSF production. In turn, higher levels of systemic G-CSF increased peripheral neutrophilia, which amplified neutrophilic peritoneal inflammation in X-CGD mice. Dampening early neutrophil recruitment by neutralization of IL-1alpha, G-CSF, or neutrophil depletion itself promoted resolution of otherwise prolonged inflammation in X-CGD. IL-1beta played little role. Thus, we identified an excessive IL-1alpha/G-CSF response as a major driver of enhanced sterile inflammation in CGD in the response to damaged cells. More broadly, these results provide new insights into the regulation of sterile inflammation, and identify the NADPH oxidase in regulating the amplitude of the early neutrophilic response. PMID- 26443625 TI - Effectiveness of glucose-methanol extender for cryopreservation of Huso huso spermatozoa. AB - The present approach was designed to evaluate the methanol-glucose extender effects on sperm cryopreservation in beluga sturgeon, Huso huso. Sperm quality was examined by measuring post-thaw sperm motility and fertilizing rate at hatching stage. We first tested the effect of glucose concentration (0, 0.10, 0.15, 0.20 and 0.30M) in a methanol extender on post-thaw sperm motility. The optimal cryopreservation conditions were found to be 0.2M glucose in the extender. Then, motility and fertilization rates of sperm cryopreserved with 0.2M glucose and 10% methanol (GM) were compared to Tris-sucrose-KCl in 10% methanol extender (TSKM). Additionally, sperm motility and fertilizing ability in relation to 15 and 30min equilibration in GM extender before and after cryopreservation were measured. Higher post-thaw sperm motility duration and percentage as well as fertilization rate were obtained with the GM extender when compared to TSKM extender. Equilibration of sperm in extender did not affect the motility quality of either fresh-diluted or frozen/thawed sperm, while fertilization rate showed a significant decline alone after 30min of post-thaw storage. Our results indicated that the use of a simple extender consisting of 0.2M glucose in 10% methanol can be an alternative cryopreservation method to those previously described for sturgeons. PMID- 26443624 TI - Tumor-specific HSP90 inhibition as a therapeutic approach in JAK-mutant acute lymphoblastic leukemias. AB - The development of the dual Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib for the treatment of myeloproliferative neoplasms (MPNs) has led to studies of ruxolitinib in other clinical contexts, including JAK-mutated acute lymphoblastic leukemia (ALL). However, the limited ability of JAK inhibition to induce molecular or clinicopathological responses in MPNs suggests a need for development of better therapies for JAK kinase-dependent malignancies. Here, we demonstrate that heat shock protein 90 (HSP90) inhibition using a purine-scaffold HSP90 inhibitor in early clinical development is an effective therapeutic approach in JAK-dependent ALL and can overcome persistence to JAK-inhibitor therapy in ALL cells. PMID- 26443626 TI - Multidimensional staging system for pediatric acquired cholesteatoma: A 30-year verification data. AB - OBJECTIVE: This article presents a points-based prognostic prediction model for pediatric acquired cholesteatoma, incorporating the multidimensional factors that contribute to surgical failure. METHODS: This study included 132 ears with acquired cholesteatoma from 128 children (<=18 years) identified between 1982 and 2012. Each case was scored for the extent of the cholesteatoma, history of grommet insertion, age of the patient, ossicular destruction, and otorrhea. The patients were classified as stage I, II, or III. We compared differences between stages regarding the cumulative rates of recidivism and linear trends in these rates. RESULTS: Among stage I cases, the rate of cumulative recidivism was 0%; however, among stage 2 cases, this increased with time, eventually leveling off at 15.7% after 18 years of follow-up. The same was observed among stage III cases, which leveled off at 34.1% after 17 years of follow-up. In the second half of the cohort and the entire cohort, differences in the cumulative recidivism curves reached statistical significance, as did the linear trends (all p<0.05). CONCLUSIONS: Our findings demonstrate the efficacy of the proposed multidimensional staging system in linking the severity of cholesteatoma to outcomes, thereby enabling the stratification of patients according to prognosis in order to identify children at risk of recidivism. PMID- 26443627 TI - Older patients with HIV should be offered cancer screening, study recommends. PMID- 26443628 TI - Misdiagnosis of gastroesophageal reflux disease as epileptic seizures in children. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) can mimic epileptic seizure, and may be misdiagnosed as epilepsy. On the other hand, GERD can be more commonly seen in children with neurological disorders such as cerebral palsy (CP); this co incidence may complicate the management of patients by mimicking refractory seizures. OBJECTIVE: The purpose of our study was to evaluate the clinical features, definite diagnoses and treatment approaches of the patients with clinically suspected GERD who were referred to the division of pediatric neurology with a suspected diagnosis of epileptic seizure. We also aimed to investigate the occurrence of GERD in children with epilepsy and/or CP. METHODS: Fifty-seven children who had a final diagnosis of GERD but were initially suspected of having epileptic seizures were assessed prospectively. RESULTS: All patients were assigned to 3 groups according to definite diagnoses as follows: patients with only GERD who were misdiagnosed as having epileptic seizure (group 1: n=16; 28.1%), those with comorbidity of epilepsy and GERD (group 2: n=21; 36.8%), and those with the coexistence of GERD with epilepsy and CP (group 3: n=20; 35.1%). Five patients (8.8%) did not respond to anti-reflux treatment and laparoscopic reflux surgery was performed. The positive effect of GERD therapy on paroxysmal nonepileptic events was observed in 51/57 (89.5%) patients. CONCLUSIONS: GERD is one of the important causes of paroxysmal nonepileptic events. In addition, GERD must be kept in mind at the initial diagnosis and also in the long-term management of patients with neurological disorders such as epilepsy and CP. PMID- 26443629 TI - Novel missense mutation in CLN8 in late infantile neuronal ceroid lipofuscinosis: The first report of a CLN8 mutation in Japan. AB - Neuronal ceroid lipofuscinoses (NCLs) are clinically and genetically heterogeneous neurodegenerative lysosomal diseases. Fourteen distinct NCL subtypes (CLN1-CLN14) are known, and they are caused by mutations in different genes. CLN8 was first identified in Finnish patients, and the phenotype was subsequently found in Turkish, Italian, and Pakistani patients. We report a 6 year-old Japanese boy with NCL with a novel missense mutation in CLN8. At the age of 3years, he manifested frequent drop seizures, and then progressively developed motor difficulties with an ataxic gait, myoclonus, left conjugate deviation, and rotational nystagmus. At age 5, he developed profound visual difficulty and dysphagia, and he has now lost his mobility. A bone marrow examination at age 5 showed sea-blue histiocytes. An electroretinogram was non-recordable. No giant somatosensory evoked potentials were found. Brain magnetic resonance imaging revealed bilateral diffuse hyperintensities in the white matter around the lateral ventricles and cerebellar and pontine atrophy on T2-weighted images. In a lysosomal enzyme study, the palmitoyl-protein-thioesterase and pepinase activity was within normal limits. Whole-exome sequencing revealed a homozygous CLN8 mutation: c.620T>G (p.L207R). His parents were both heterozygous for this mutation. To our knowledge, this is the first report of a CLN8 mutation in late infantile NCL in Japan. PMID- 26443630 TI - Spreading the word: non-autonomous effects of apoptosis during development, regeneration and disease. AB - Apoptosis, in contrast to other forms of cell death such as necrosis, was originally regarded as a 'silent' mechanism of cell elimination designed to degrade the contents of doomed cells. However, during the past decade it has become clear that apoptotic cells can produce diverse signals that have a profound impact on neighboring cells and tissues. For example, apoptotic cells can release factors that influence the proliferation and survival of adjacent tissues. Apoptosis can also affect tissue movement and morphogenesis by modifying tissue tension in surrounding cells. As we review here, these findings reveal unexpected roles for apoptosis in tissue remodeling during development, as well as in regeneration and cancer. PMID- 26443632 TI - A developmental framework for induced pluripotency. AB - During development, cells transition from a pluripotent to a differentiated state, generating all the different types of cells in the body. Development is generally considered an irreversible process, meaning that a differentiated cell is thought to be unable to return to the pluripotent state. However, it is now possible to reprogram mature cells to pluripotency. It is generally thought that reprogramming is accomplished by reversing the natural developmental differentiation process, suggesting that the two mechanisms are closely related. Therefore, a detailed study of cell reprogramming has the potential to shed light on unexplained developmental mechanisms and, conversely, a better understanding of developmental differentiation can help improve cell reprogramming. However, fundamental differences between reprogramming processes and multi-lineage specification during early embryonic development have also been uncovered. In addition, there are multiple routes by which differentiated cells can re-enter the pluripotent state. In this Review, we discuss the connections and disparities between differentiation and reprogramming, and assess the degree to which reprogramming can be considered as a simple reversal of development. PMID- 26443631 TI - Photoreceptor cell fate specification in vertebrates. AB - Photoreceptors--the light-sensitive cells in the vertebrate retina--have been extremely well-characterized with regards to their biochemistry, cell biology and physiology. They therefore provide an excellent model for exploring the factors and mechanisms that drive neural progenitors into a differentiated cell fate in the nervous system. As a result, great progress in understanding the transcriptional network that controls photoreceptor specification and differentiation has been made over the last 20 years. This progress has also enabled the production of photoreceptors from pluripotent stem cells, thereby aiding the development of regenerative medical approaches to eye disease. In this Review, we outline the signaling and transcription factors that drive vertebrate photoreceptor development and discuss how these function together in gene regulatory networks to control photoreceptor cell fate specification. PMID- 26443633 TI - Differentiation of human embryonic stem cells into cone photoreceptors through simultaneous inhibition of BMP, TGFbeta and Wnt signaling. AB - Cone photoreceptors are required for color discrimination and high-resolution central vision and are lost in macular degenerations, cone and cone/rod dystrophies. Cone transplantation could represent a therapeutic solution. However, an abundant source of human cones remains difficult to obtain. Work performed in model organisms suggests that anterior neural cell fate is induced 'by default' if BMP, TGFbeta and Wnt activities are blocked, and that photoreceptor genesis operates through an S-cone default pathway. We report here that Coco (Dand5), a member of the Cerberus gene family, is expressed in the developing and adult mouse retina. Upon exposure to recombinant COCO, human embryonic stem cells (hESCs) differentiated into S-cone photoreceptors, developed an inner segment-like protrusion, and could degrade cGMP when exposed to light. Addition of thyroid hormone resulted in a transition from a unique S-cone population toward a mixed M/S-cone population. When cultured at confluence for a prolonged period of time, COCO-exposed hESCs spontaneously developed into a cellular sheet composed of polarized cone photoreceptors. COCO showed dose dependent and synergistic activity with IGF1 at blocking BMP/TGFbeta/Wnt signaling, while its cone-inducing activity was blocked in a dose-dependent manner by exposure to BMP, TGFbeta or Wnt-related proteins. Our work thus provides a unique platform to produce human cones for developmental, biochemical and therapeutic studies and supports the hypothesis that photoreceptor differentiation operates through an S-cone default pathway during human retinal development. PMID- 26443634 TI - Regulation of Nematostella neural progenitors by SoxB, Notch and bHLH genes. AB - Notch signalling, SoxB and Group A bHLH 'proneural' genes are conserved regulators of the neurogenic program in many bilaterians. However, the ancestry of their functions and interactions is not well understood. We address this question in the sea anemone Nematostella vectensis, a representative of the Cnidaria, the sister clade to the Bilateria. It has previously been found that the SoxB orthologue NvSoxB(2) is expressed in neural progenitor cells (NPCs) in Nematostella and promotes the development of both neurons and nematocytes, whereas Notch signalling has been implicated in the negative regulation of neurons and the positive regulation of nematocytes. Here, we clarify the role of Notch by reporting that inhibition of Notch signalling increases the numbers of both neurons and nematocytes, as well as increasing the number of NvSoxB(2) expressing cells. This suggests that Notch restricts neurogenesis by limiting the generation of NPCs. We then characterise NvAth-like (Atonal/Neurogenin family) as a positive regulator of neurogenesis that is co-expressed with NvSoxB(2) in a subset of dividing NPCs, while we find that NvAshA (Achaete-scute family) and NvSoxB(2) are co-expressed in non-dividing cells only. Reciprocal knockdown experiments reveal a mutual requirement for NvSoxB(2) and NvAth-like in neural differentiation; however, the primary expression of each gene is independent of the other. Together, these data demonstrate that Notch signalling and NvSoxB(2) regulate Nematostella neural progenitors via parallel yet interacting mechanisms; with different aspects of these interactions being shared with Drosophila and/or vertebrate neurogenesis. PMID- 26443635 TI - The small leucine-rich repeat secreted protein Asporin induces eyes in Xenopus embryos through the IGF signalling pathway. AB - Small leucine-rich repeat proteoglycan (SLRP) family proteins play important roles in a number of biological events. Here, we demonstrate that the SLRP family member Asporin (ASPN) plays a crucial role in the early stages of eye development in Xenopus embryos. During embryogenesis, ASPN is broadly expressed in the neuroectoderm of the embryo. Overexpression of ASPN causes the induction of ectopic eyes. By contrast, blocking ASPN function with a morpholino oligonucleotide (ASPN-MO) inhibits eye formation, indicating that ASPN is an essential factor for eye development. Detailed molecular analyses revealed that ASPN interacts with insulin growth factor receptor (IGFR) and is essential for activating the IGF receptor-mediated intracellular signalling pathway. Moreover, ASPN perturbed the Wnt, BMP and Activin signalling pathways, suggesting that ASPN thereby creates a favourable environment in which the IGF signal can dominate. ASPN is thus a novel secreted molecule essential for eye induction through the coordination of multiple signalling pathways. PMID- 26443636 TI - Wnt/beta-catenin signaling modulates corneal epithelium stratification via inhibition of Bmp4 during mouse development. AB - The development of organs with an epithelial parenchyma relies on reciprocal mesenchymal-epithelial communication. Mouse corneal epithelium stratification is the consequence of a coordinated developmental process based on mesenchymal epithelial interactions. The molecular mechanism underlying these interactions remains unclear. The Wnt/beta-catenin signaling pathway is involved in fundamental aspects of development through the regulation of various growth factors. Here, we show that conditional ablation of either beta-catenin (Ctnnb1(cKO)) or co-receptors Lrp5/6 (Lrp5/6(cKO)) in corneal stromal cells results in precocious stratification of the corneal epithelium. By contrast, ectopic expression of a murine Ctnnb1 gain-of-function mutant (Ctnnb1(cGOF)) retards corneal epithelium stratification. We also discovered that Bmp4 is upregulated in the absence of beta-catenin in keratocytes, which further triggers ERK1/2 (Mapk3/1) and Smad1/5 phosphorylation and enhances transcription factor p63 (Trp63) expression in mouse corneal basal epithelial cells and in a human corneal epithelial cell line (HTCE). Interestingly, mouse neonates given a subconjunctival BMP4 injection displayed a phenotype resembling that of Ctnnb1(cKO). Conditional ablation of Bmp4 eradicates the phenotype produced in Ctnnb1(cKO) mice. Furthermore, ChIP and promoter-luciferase assays show that beta catenin binds to and suppresses Bmp4 promoter activity. These data support the concept that cross-talk between the Wnt/beta-catenin/Bmp4 axis (in the stromal mesenchyme) and Bmp4/p63 signaling (in the epithelium) plays a pivotal role in epithelial stratification during corneal morphogenesis. PMID- 26443637 TI - Cell type-specific translational repression of Cyclin B during meiosis in males. AB - The unique cell cycle dynamics of meiosis are controlled by layers of regulation imposed on core mitotic cell cycle machinery components by the program of germ cell development. Although the mechanisms that regulate Cdk1/Cyclin B activity in meiosis in oocytes have been well studied, little is known about the trans-acting factors responsible for developmental control of these factors in male gametogenesis. During meiotic prophase in Drosophila males, transcript for the core cell cycle protein Cyclin B1 (CycB) is expressed in spermatocytes, but the protein does not accumulate in spermatocytes until just before the meiotic divisions. Here, we show that two interacting proteins, Rbp4 and Fest, expressed at the onset of spermatocyte differentiation under control of the developmental program of male gametogenesis, function to direct cell type- and stage-specific repression of translation of the core G2/M cell cycle component cycB during the specialized cell cycle of male meiosis. Binding of Fest to Rbp4 requires a 31 amino acid region within Rbp4. Rbp4 and Fest are required for translational repression of cycB in immature spermatocytes, with Rbp4 binding sequences in a cell type-specific shortened form of the cycB 3' UTR. Finally, we show that Fest is required for proper execution of meiosis I. PMID- 26443639 TI - Dynamic measurement of patello-femoral joint alignment using weight-bearing magnetic resonance imaging (WB-MRI). AB - OBJECTIVE: Aim of our work was to compare standard and weight-bearing WB-MRI to define their contribution in unmasking patello-femoral (PF) maltracking and to define what measurement of patellar alignment is the most reliable. METHODS: We prospectively collected 95 non consecutive patients, clinically divided into 2 groups: group A (the control group), including 20 patients (negative for patellar maltracking), and group B including 75 patients (positive for patellar maltracking). The patients underwent a dedicated 0.25 T MRI, in supine and WB position, with knee flexion of 12-15 degrees . The following measurements were performed: Insall-Salvati index (IS), lateral patellar displacement (LPD), lateral patello-femoral angle (LPA) and lateral patellar tilt (LPT). Quantitative and qualitative statistical analyses were performed to compare the results obtained before and after WB-MRI. Measurements were subsequently performed on both groups. RESULTS: Group A patients showed no statistically significant variations at all measurements both on standard and WB-MRI. On the basis of measurements made on standard MRI, group B patients were divided into group B1 (23 patients) (negative or positive at 1 measurement) and group B2 (52 patients) (positive at 2 or more measurements). After WB-MRI, group B1 patients were divided into group B1a (6 patients), in case they remained positive at 0/1 measurement, and group B1b (17 patients), in case they became positive at 2 or more measurements. All group B2 patients confirmed to be positive at 2 or more measurements at WB-MRI. Quantitative statistical analysis showed that LPT and LPA were the most reproducible and clinically useful measurements. Qualitative statistical analysis performed on standard and WB-MRI demonstrated that LPT was the best predictive measurement. CONCLUSIONS: This study demonstrates both the high diagnostic value of WB-MRI in unmasking PF-maltracking and the best predictive value of LPT measurement. PMID- 26443640 TI - Expiratory air trapping during asthma exacerbation: Relationships with clinical indices and proximal airway morphology. AB - OBJECTIVES: To semi-quantitatively assess expiratory air trapping (AT(exp)) and structural changes in the proximal airways in asthma during asthma exacerbation (AE) and to explore the relationships among AT(exp), clinical indices, and proximal airway changes. METHODS: Paired inspiratory-dynamic forced expiratory CT scans of 36 asthmatics (30 women, 6 men; mean age, 49.2+/-18.9 years) performed during AE were retrospectively reviewed for the total AT(exp) score (summed scores [extent grading (0-4)*pattern grading (1-4)] of the twelve lung zones), morphologic parameters and expiratory bronchial collapse (BC(exp)) of the proximal airways. The relationships of the score with clinical indices and proximal airway morphology (normalized by body surface area [BSA]) were analyzed. A p value of <0.05 was considered statistically significant. RESULTS: The mean total AT(exp) score was 110.1+/-43.4 (range, 8-166). It was higher in the lower zones and in patients older than 60 years, having BMI of <27.5 kg/m(2), and peak expiratory flow rate (PEFR) of <60% predicted. Correlation existed between the score and age (r=0.331), BMI (r=-0.375), BSA (r=-0.442), % predicted PEFR (r= 0.332), right upper lobe apical segmental bronchus (RB1)-wall area (WA)/BSA (r=0.467), %RB1-WA (r=0.395), and RB1-bronchial wall thickness (BWT)/BSA (r=0.378). The score showed no correlation with BC(exp) and other morphologic bronchial parameters. Area under receiver-operating-characteristic curve 0.724 (95% CI) showed that the score of 110 could discriminate patients with PEFR of <60% predicted from those with PEFR of >=60% predicted. CONCLUSION: During AE, there was a high prevalence of extensive AT(exp) which was correlated with patient's age, BMI, BSA, AE severity and RB1 morphology but not correlated with BC(exp). PMID- 26443638 TI - Prdm12 specifies V1 interneurons through cross-repressive interactions with Dbx1 and Nkx6 genes in Xenopus. AB - V1 interneurons are inhibitory neurons that play an essential role in vertebrate locomotion. The molecular mechanisms underlying their genesis remain, however, largely undefined. Here, we show that the transcription factor Prdm12 is selectively expressed in p1 progenitors of the hindbrain and spinal cord in the frog embryo, and that a similar restricted expression profile is observed in the nerve cord of other vertebrates as well as of the cephalochordate amphioxus. Using frog, chick and mice, we analyzed the regulation of Prdm12 and found that its expression in the caudal neural tube is dependent on retinoic acid and Pax6, and that it is restricted to p1 progenitors, due to the repressive action of Dbx1 and Nkx6-1/2 expressed in the adjacent p0 and p2 domains. Functional studies in the frog, including genome-wide identification of its targets by RNA-seq and ChIP Seq, reveal that vertebrate Prdm12 proteins act as a general determinant of V1 cell fate, at least in part, by directly repressing Dbx1 and Nkx6 genes. This probably occurs by recruiting the methyltransferase G9a, an activity that is not displayed by the amphioxus Prdm12 protein. Together, these findings indicate that Prdm12 promotes V1 interneurons through cross-repressive interactions with Dbx1 and Nkx6 genes, and suggest that this function might have only been acquired after the split of the vertebrate and cephalochordate lineages. PMID- 26443641 TI - Factors Associated with Hospitalization among Emergency Department Patients Referred for Quick Investigation of Iron-Deficiency Anemia. AB - BACKGROUND: Although patients with anemia are frequently seen in emergency departments (EDs), studies on patients presenting there with symptomatic chronic anemia--usually iron-deficiency anemia (IDA) caused by occult gastrointestinal bleeding--are lacking. Awareness of predictors of hospitalization could direct the ED triage to the appropriate diagnostic setting. OBJECTIVE: Based on initial observations that some patients with IDA were hospitalized after ED referral and initial evaluation at a quick diagnosis unit (QDU), a new cost-effective alternative to hospitalization for diagnostic workup, this study aimed to determine the patient factors associated with hospitalization after the first QDU visit. METHODS: An 8-year prospective cohort study of patients with IDA referred from the ED to the QDU of a third-level university hospital was conducted. Patients with a baseline hemoglobin level of <9 g/dL in the ED, proven iron deficiency, and no overt bleeding were included. The primary outcome was hospitalization after the initial QDU assessment. RESULTS: Two hundred eighty four (7.7%) of 3692 patients were hospitalized. Inter-rater agreement of appropriateness of admissions was 90.6% (kappa = 0.82). Overall, 90% of study patients presented to the ED with symptomatic anemia, and 87% were transfused there. On multivariate analysis, age >= 65 years, living alone, a post transfusion hemoglobin level of <9 g/dL, higher age-adjusted overall comorbidity, heart failure, and poor physical health-related quality of life at first QDU visit independently predicted hospitalization. CONCLUSION: While these predictors do not necessarily reflect the need for hospitalization, they are easily evaluated during the initial ED visit and can guide the triage of similar IDA patients to the suitable setting for timely investigation. PMID- 26443642 TI - Young Man with Sore Throat, Headache, and Rash. PMID- 26443643 TI - Septic Pulmonary Emboli Associated with Klebsiella Pneumoniae Epididymitis. PMID- 26443644 TI - Assessment of Emergency Department Eye Examinations in Patients Presenting with Mid-Face Injury. AB - BACKGROUND: One-fifth of patients with severe facial trauma suffer ophthalmic injury. Currently, patients presenting with mid-face injury to the emergency department (ED) undergo visual examination and then further assessment by ophthalmologists and with computed tomography (CT) scanning. The utility of the initial visual examination in the ED, performed by nonophthalmologists, remains unclear. OBJECTIVE: We aimed to objectively identify whether a more thorough initial visual assessment, performed by nonophthalmologists in the ED, was associated with improved ophthalmic outcomes. METHODS: Patients (n = 100) were retrospectively recruited from a tertiary craniomaxillofacial center. Visual examinations performed in the ED were scored objectively and measured against defined management and prognostic outcomes. RESULTS: There was no significant difference between more thorough initial visual examination and reduced time to ophthalmology assessment or reduced visual complications. There was no correlation between more comprehensive examination and incidence of CT scanning. CONCLUSIONS: We identified no significant difference between a comprehensive visual examination performed by nonophthalmologists in the ED, and improved ophthalmic outcomes. Physicians assessing patients with mid-face trauma in the ED should rule out eye emergencies, including retrobulbar hemorrhage and penetrating globe injury, and initiate expeditious CT scan and assessment by specialist ophthalmologists. PMID- 26443645 TI - Development of an International Elective in an Emergency Medicine Residency. AB - BACKGROUND: There is a continued interest in global emergency medicine (EM) training, research, and clinical program development. There are many opportunities for "voluntourism" in medicine, but many of these experiences do not have standard goals and objectives. OBJECTIVE: This article describes a rotation for EM residents from the United States to have a structured learning experience focusing on emergency medical settings in the prehospital phase (something often lacking in U.S. programs). DISCUSSION: The authors discuss the structure of the training program, including goals, objectives, and core competencies. First-hand accounts of the training experience are also presented. CONCLUSIONS: Global training experiences can have clear benefits. Students go to places to "learn," but can also "teach" at the same time. Setting goals and objectives helps to assure that students are gaining specific core competencies as part of the experience. Other global rotations would benefit from having a defined structure. PMID- 26443646 TI - The Joys and Pains of Major Medical Journals. PMID- 26443647 TI - Simultaneous imaging of blood flow dynamics and vascular remodelling during development. AB - Normal vascular development requires blood flow. Time-lapse imaging techniques have revolutionised our understanding of developmental biology, but measuring changes in blood flow dynamics has met with limited success. Ultrasound biomicroscopy and optical coherence tomography can concurrently image vascular structure and blood flow velocity, but these techniques lack the resolution to accurately calculate fluid forces such as shear stress. This is important because hemodynamic forces are biologically active and induce changes in the expression of genes important for vascular development. Regional variations in shear stress, rather than the overall level, control processes such as vessel enlargement and regression during vascular remodelling. We present a technique to concurrently visualise vascular remodelling and blood flow dynamics. We use an avian embryonic model and inject an endothelial-specific dye and fluorescent microspheres. The motion of the microspheres is captured with a high-speed camera and the velocity of the blood flow in and out of the region of interest is quantified by micro particle image velocitymetry (uPIV). The vessel geometry and flow are used to numerically solve the flow physics with computational fluid dynamics (CFD). Using this technique, we can analyse changes in shear stress, pressure drops and blood flow velocities over a period of 10 to 16 h. We apply this to study the relationship between shear stress and chronic changes in vessel diameter during embryonic development, both in normal development and after TGFbeta stimulation. This technique allows us to study the interaction of biomolecular and biomechanical signals during vascular remodelling using an in vivo developmental model. PMID- 26443648 TI - The Nonspecific Binding of Tyrosine Kinase Inhibitors to Human Liver Microsomes. AB - Drugs and other chemicals frequently bind nonspecifically to the constituents of an in vitro incubation mixture, particularly the enzyme source [e.g., human liver microsomes (HLM)]. Correction for nonspecific binding (NSB) is essential for the accurate calculation of the kinetic parameters Km, Clint, and Ki. Many tyrosine kinase inhibitors (TKIs) are lipophilic organic bases that are nonionized at physiologic pH. Attempts to measure the NSB of several TKIs to HLM by equilibrium dialysis proved unsuccessful, presumably due to the limited aqueous solubility of these compounds. Thus, the addition of detergents to equilibrium dialysis samples was investigated as an approach to measure the NSB of TKIs. The binding of six validation set nonionized lipophilic bases (felodipine, isradipine, loratidine, midazolam, nifedipine, and pazopanib) to HLM (0.25 mg/ml) was shown to be unaffected by the addition of CHAPS (6 mM) to the dialysis medium. This approach was subsequently applied to measurement of the binding of axitinib, dabrafenib, erlotinib, gefitinib, ibrutinib, lapatinib, nilotinib, nintedanib, regorafenib, sorafenib, and trametinib to HLM (0.25 mg/ml). As with the validation set drugs, attainment of equilibrium was demonstrated in HLM-HLM and buffer-buffer control dialysis experiments. Values of the fraction unbound to HLM ranged from 0.14 (regorafenib and sorafenib) to 0.93 (nintedanib), and were generally consistent with the known physicochemical determinants of drug NSB. The extensive NSB of many TKIs to HLM underscores the importance of correction for TKI binding to HLM and, presumably, other enzyme sources present in in vitro incubation mixtures. PMID- 26443649 TI - Musculoskeletal pain and limitations in work ability in Swedish marines: a cross sectional survey of prevalence and associated factors. AB - OBJECTIVES: To estimate the prevalence of self-rated musculoskeletal pain and pain limiting work ability in Swedish Armed Forces (SAF) marines, and to study factors potentially associated with pain limiting work ability for the most prevalent pain regions reported. DESIGN: Population-based, cross-sectional survey. PARTICIPANTS: There were 272 SAF marines from the main marine battalion in Sweden included in the study. OUTCOMES: Self-assessed musculoskeletal pain and pain limiting the marines' work ability within a 6-month period, as obtained from structured questionnaires. The association of individual, health and work-related factors with musculoskeletal pain limiting work ability was systematically regressed with multiple logistic models, estimating OR and 95% CI. RESULTS: Musculoskeletal pain and pain limiting work ability were most common in the back, at 46% and 20%, and lower extremities at 51% and 29%, respectively. Physical training <=1 day/week (OR 5.3, 95% CI 1.7 to 16.8); body height <=1.80 m (OR 5.0, 95% CI 1.6 to 15.1) and >=1.86 m (OR 4.4, 95% CI 1.4 to 14.1); computer work 1/4 of the working day (OR 3.2, 95% CI 1.0 to 10.0) and >=1/2 (OR 3.3, 95% CI 1.1 to 10.1) of the working day were independently associated with back pain limiting work ability. None of the studied variables emerged significantly associated with such pain for the lower extremities. CONCLUSIONS: Our findings show that musculoskeletal pain and resultant limitations in work ability are common in SAF marines. Low frequency of physical training emerged independently associated with back pain limiting work ability. This suggests that marines performing physical training 1 day per week or less are suitable candidates for further medical evaluation and secondary preventive actions. While also associated, body height and computer work need further exploration as underlying mechanisms for back pain limiting work ability. Further prospective studies are necessary to clarify the direction of causality. PMID- 26443650 TI - Accuracy and readability of cardiovascular entries on Wikipedia: are they reliable learning resources for medical students? AB - OBJECTIVE: To evaluate accuracy of content and readability level of English Wikipedia articles on cardiovascular diseases, using quality and readability tools. METHODS: Wikipedia was searched on the 6 October 2013 for articles on cardiovascular diseases. Using a modified DISCERN (DISCERN is an instrument widely used in assessing online resources), articles were independently scored by three assessors. The readability was calculated using Flesch-Kincaid Grade Level. The inter-rater agreement between evaluators was calculated using the Fleiss kappa scale. RESULTS: This study was based on 47 English Wikipedia entries on cardiovascular diseases. The DISCERN scores had a median=33 (IQR=6). Four articles (8.5%) were of good quality (DISCERN score 40-50), 39 (83%) moderate (DISCERN 30-39) and 4 (8.5%) were poor (DISCERN 10-29). Although the entries covered the aetiology and the clinical picture, there were deficiencies in the pathophysiology of diseases, signs and symptoms, diagnostic approaches and treatment. The number of references varied from 1 to 127 references; 25.9+/-29.4 (mean+/-SD). Several problems were identified in the list of references and citations made in the articles. The readability of articles was 14.3+/-1.7 (mean+/-SD); consistent with the readability level for college students. In comparison, Harrison's Principles of Internal Medicine 18th edition had more tables, less references and no significant difference in number of graphs, images, illustrations or readability level. The overall agreement between the evaluators was good (Fleiss kappa 0.718 (95% CI 0.57 to 0.83). CONCLUSIONS: The Wikipedia entries are not aimed at a medical audience and should not be used as a substitute to recommended medical resources. Course designers and students should be aware that Wikipedia entries on cardiovascular diseases lack accuracy, predominantly due to errors of omission. Further improvement of the Wikipedia content of cardiovascular entries would be needed before they could be considered a supplementary resource. PMID- 26443651 TI - Pregnancy-related venous thrombosis: comparison between spontaneous and ART conception in an Italian cohort. AB - OBJECTIVE: To evaluate in an Italian cohort the incidence of venous thromboembolic events (VTE) in pregnancies after assisted reproductive technologies (ART). SETTING: Thrombosis and Haemostasis Unit at I.R.C.C.S. 'Casa Sollievo della Sofferenza', S. Giovanni Rotondo. PARTICIPANTS: A prospective cohort of 998 women advised to undergo ART was referred by local fertility clinics from April 2002 to July 2011. Follow-up information was obtained during the check-up and/or by phone interviews. In a cohort of women who consecutively gave birth (n=3339) after spontaneous conception in our Institution, information on the diagnoses of pregnancy-related venous thromboses was obtained by linkage to a patient administrative register. PRIMARY AND SECONDARY OUTCOME MEASURES: We calculated the incidence of VTE and superficial venous thrombosis in successful ART cycles and compared it with that of the general population conceiving spontaneously. RESULTS: Overall, 684 ART cycles were carried out by 234 women, who achieved a clinical pregnancy; in case of more than one successful cycle, only the first pregnancy was considered. Three vein thromboses (two VTE and one superficial vein thrombosis) were recorded. An antithrombotic prophylaxis with LMWH alone or combined with low-dose aspirin was prescribed in 23/234 (9.8%) women. In the reference cohort of 3339 women, a total of 11 vein thromboses were observed: six VTE and five SVT. The two-tailed Fisher exact test showed a trend towards statistical significance (p: 0.06, OR: 3.9, 95% CI 0.87 to 15.3). After the exclusion of superficial thromboses in both the groups, we found that the incidence of VTE in our population of women who had undergone ART was 2/234 pregnancies (8.5 0/00), whereas that in our reference population was 6/3339 (1.8 0/00) (p: 0.09). CONCLUSIONS: Our data show a slightly higher incidence of vein thromboses in pregnancies after ART than in those after natural conception. PMID- 26443652 TI - Patient-physician mistrust and violence against physicians in Guangdong Province, China: a qualitative study. AB - OBJECTIVE: To better understand the origins, manifestations and current policy responses to patient-physician mistrust in China. DESIGN: Qualitative study using in-depth interviews focused on personal experiences of patient-physician mistrust and trust. SETTING: Guangdong Province, China. PARTICIPANTS: One hundred and sixty patients, patient family members, physicians, nurses and hospital administrators at seven hospitals varying in type, geography and stages of achieving goals of health reform. These interviews included purposive selection of individuals who had experienced both trustful and mistrustful patient physician relationships. RESULTS: One of the most prominent forces driving patient-physician mistrust was a patient perception of injustice within the medical sphere, related to profit mongering, knowledge imbalances and physician conflicts of interest. Individual physicians, departments and hospitals were explicitly incentivised to generate revenue without evaluation of caregiving. Physicians did not receive training in negotiating medical disputes or humanistic principles that underpin caregiving. Patient-physician mistrust precipitated medical disputes leading to the following outcomes: non-resolution with patient resentment towards physicians; violent resolution such as physical and verbal attacks against physicians; and non-violent resolution such as hospital-mediated dispute resolution. Policy responses to violence included increased hospital security forces, which inadvertently fuelled mistrust. Instead of encouraging communication that facilitated resolution, medical disputes sometimes ignited a vicious cycle leading to mob violence. However, patient-physician interactions at one hospital that has implemented a primary care model embodying health reform goals showed improved patient-physician trust. CONCLUSIONS: The blind pursuit of financial profits at a systems level has eroded patient-physician trust in China. Restructuring incentives, reforming medical education and promoting caregiving are pathways towards restoring trust. Assessing and valuing the quality of caregiving is essential for transitioning away from entrenched profit-focused models. Moral, in addition to regulatory and legal, responses are urgently needed to restore trust. PMID- 26443653 TI - Study protocol for a controlled trial of Strengths Model Case Management in mental health services in Hong Kong. AB - INTRODUCTION: Although strengths-based models are popular within recovery oriented approaches, there is still a lack of conclusive research to guide how they should be implemented. A recent meta-analysis confirmed the lack of clarity in how this perspective is operationalised and that fidelity monitoring during the implementation process is lacking. Hence, there is a clear need to evaluate the feasibility of delivering and evaluating a clearly operationalised strengths based intervention that incorporates fidelity checks to inform more definitive research. This protocol therefore describes a controlled trial of Strengths Model Case Management (SMCM), a complex intervention, for people with severe mental illnesses in Hong Kong. This trial follows the guidelines of the Medical Research Council as a phase 2 trial. Hence, it is a pilot study that tests the feasibility and effectiveness of the model. METHODS AND ANALYSIS: This is a 9-month controlled trial that uses the Kansas Model. Participants and a matched control group are recruited on a voluntary basis, after screening for eligibility. Effectiveness of the SMCM will be measured through outcome measures taken at baseline, the mid-point and at the end of the trial. Outcomes for service users include personal recovery, hope, subjective well-being, psychiatric symptoms, perceived level of recovery features within the organisation, therapeutic alliance and achievement of recovery goals. Outcomes for care workers will include job burnout, organisational features of recovery and perceived supervisory support. With a 2*3 analysis of variance design and a moderate intervention effect (Cohen's d=0.50), a total of 86 participants will be needed for a statistical power of 0.80. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Human Research Ethics Committee for Non-Clinical Faculties at The University of Hong Kong (HRECNCF: EA140913). TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trial Registry (ACTRN)12613001120763. PMID- 26443654 TI - Simulation-based multiprofessional obstetric anaesthesia training conducted in situ versus off-site leads to similar individual and team outcomes: a randomised educational trial. AB - OBJECTIVE: To investigate the effect of in situ simulation (ISS) versus off-site simulation (OSS) on knowledge, patient safety attitude, stress, motivation, perceptions of simulation, team performance and organisational impact. DESIGN: Investigator-initiated single-centre randomised superiority educational trial. SETTING: Obstetrics and anaesthesiology departments, Rigshospitalet, University of Copenhagen, Denmark. PARTICIPANTS: 100 participants in teams of 10, comprising midwives, specialised midwives, auxiliary nurses, nurse anaesthetists, operating theatre nurses, and consultant doctors and trainees in obstetrics and anaesthesiology. INTERVENTIONS: Two multiprofessional simulations (clinical management of an emergency caesarean section and a postpartum haemorrhage scenario) were conducted in teams of 10 in the ISS versus the OSS setting. PRIMARY OUTCOME: Knowledge assessed by a multiple choice question test. EXPLORATORY OUTCOMES: Individual outcomes: scores on the Safety Attitudes Questionnaire, stress measurements (State-Trait Anxiety Inventory, cognitive appraisal and salivary cortisol), Intrinsic Motivation Inventory and perceptions of simulations. Team outcome: video assessment of team performance. Organisational impact: suggestions for organisational changes. RESULTS: The trial was conducted from April to June 2013. No differences between the two groups were found for the multiple choice question test, patient safety attitude, stress measurements, motivation or the evaluation of the simulations. The participants in the ISS group scored the authenticity of the simulation significantly higher than did the participants in the OSS group. Expert video assessment of team performance showed no differences between the ISS versus the OSS group. The ISS group provided more ideas and suggestions for changes at the organisational level. CONCLUSIONS: In this randomised trial, no significant differences were found regarding knowledge, patient safety attitude, motivation or stress measurements when comparing ISS versus OSS. Although participant perception of the authenticity of ISS versus OSS differed significantly, there were no differences in other outcomes between the groups except that the ISS group generated more suggestions for organisational changes. TRIAL REGISTRATION NUMBER: NCT01792674. PMID- 26443655 TI - Clarifying the learning experiences of healthcare professionals with in situ and off-site simulation-based medical education: a qualitative study. AB - OBJECTIVE: To examine how the setting in in situ simulation (ISS) and off-site simulation (OSS) in simulation-based medical education affects the perceptions and learning experience of healthcare professionals. DESIGN: Qualitative study using focus groups and content analysis. PARTICIPANTS: Twenty-five healthcare professionals (obstetricians, midwives, auxiliary nurses, anaesthesiologists, a nurse anaesthetist and operating theatre nurse) participated in four focus groups and were recruited due to their exposure to either ISS or OSS in multidisciplinary obstetric emergencies in a randomised trial. SETTING: Departments of obstetrics and anaesthesia, Rigshospitalet, Copenhagen, Denmark. RESULTS: Initially participants preferred ISS, but this changed after the training when the simulation site became of less importance. There was a strong preference for simulation in authentic roles. These perceptions were independent of the ISS or OSS setting. Several positive and negative factors in simulation were identified, but these had no relation to the simulation setting. Participants from ISS and OSS generated a better understanding of and collaboration with the various health professionals. They also provided individual and team reflections on learning. ISS participants described more experiences that would involve organisational changes than the OSS participants did. CONCLUSIONS: Many psychological and sociological aspects related to the authenticity of the learning experience are important in simulation, but the physical setting of the simulation as an ISS and OSS is the least important. Based on these focus groups OSS can be used provided that all other authenticity elements are taken into consideration and respected. The only difference was that ISS had an organisational impact and ISS participants talked more about issues that would involve practical organisational changes. ISS and OSS participants did, however, go through similar individual and team learning experiences. PMID- 26443656 TI - Pattern of cardiac surveillance among patients with lymphoma receiving anthracycline-based chemotherapy. AB - OBJECTIVE: Anthracyclines are potent antineoplastic agents in the treatment of lymphoid malignancies, but their therapeutic benefit is limited by cardiotoxicity. The American Heart Association (AHA) recommends routine surveillance, early diagnosis and treatment of anthracycline-based chemotherapy (AC) induced cardiomyopathy (AC-CMP). We aimed to assess the prevalence of AC-CMP in patients with lymphoma, surveillance patterns of left ventricular ejection fraction (LVEF) in those receiving AC and management of patients with AC-CMP at an academic medical centre prior to the development of a comprehensive cardio oncology programme. METHODS: We performed a retrospective cohort study examining 218 patients with aggressive B cell non-Hodgkin's lymphomas (B-NHL) who received AC 1992-2012 and had serial follow-up. AC-CMP was defined as LVEF decrease >=10% with final LVEF<=50% or LVEF reduction >=15% regardless of final LVEF. RESULTS: Of 218 patients treated with AC, 73 (34%) had LVEF assessment both prior to and after receiving AC. Of these 73 patients, 24 developed AC-CMP and had higher cumulative all-cause mortality than those without AC-CMP (HR 2.35, p=0.03). Coronary artery disease (CAD) was an independent predictor of AC-CMP (p=0.048). Mean post-AC LVEF was lower in patients with CAD compared with those without CAD when their baseline LVEF was 45% (p=0.0009) or 55% (p=0.001) but was similar at 65% (p=0.33). Less than half of patients with AC-CMP received recommended heart failure medication therapy. CONCLUSIONS: Historically, one-third of patients with B-NHL treated with AC underwent surveillance according to AHA guidelines. There is substantial opportunity for collaboration between oncologists and cardiologists to improve the care of patients with lymphoma receiving AC. PMID- 26443657 TI - Trends in complementary feeding indicators in Nigeria, 2003-2013. AB - OBJECTIVE: The study aimed to examine secular trends and determinants of changes in complementary feeding indicators in Nigeria. DESIGN, SETTING AND PARTICIPANTS: Data on 79 953 children aged 6-23 months were obtained from the Nigeria Demographic and Health Surveys (NDHS) for the period spanning 2003-2013. The surveys used a stratified two-stage cluster sample of eligible mothers aged 15-49 years from the six geopolitical zones of Nigeria. Trends in complementary feeding indicators and socioeconomic, health service and individual characteristics including factors associated with complementary feeding indicators were examined using multilevel logistic regression analyses. RESULTS: Minimum dietary diversity for children aged 6-23 months worsened from 26% in 2003 to 16% in 2013. Minimum meal frequency improved from 43% in 2003 to 56% in 2013 and minimum acceptable diet worsened from 11% to 9%. Among educated mothers, there was a decreasing prevalence of the introduction of solid, semisolid and soft foods in infants aged 6-8 months (67% in 2003 to 57% in 2013); minimum dietary diversity (33% in 2003 to 24% in 2013) and minimum acceptable diet (13% in 2003 to 8% in 2013). Mothers with a higher education level and mothers who reported more health service contacts were more likely to meet the minimum dietary diversity. Similarly, the odds for minimum acceptable diet were higher among mothers from higher socioeconomic status groups and mothers who reported frequent health services use. CONCLUSIONS: Complementary feeding practices in Nigeria declined over the study period and are below the expected levels required to ensure adequate growth and development of Nigerian children. National policies and programmes that ensure sustainability of projects post-MDGs and higher health service coverage for mothers, including community-based education initiatives, are proposed to improve complementary feeding practices among Nigerian mothers. PMID- 26443658 TI - Comparative efficacy and acceptability of psychotherapies for acute anxiety disorders in children and adolescents: study protocol for a network meta analysis. AB - INTRODUCTION: Anxiety disorders are associated with significant public health burden in young individuals. Cognitive-behavioural therapy (CBT) is the most commonly used psychotherapy for anxiety disorders in children and adolescents, but previous reviews were hindered by a limited number of trials with direct comparisons between different psychotherapies and their deliveries. Consequently, the main aim of this research was to investigate the comparative efficacy and acceptability of various types and deliveries of psychotherapies for anxiety disorders in children and adolescents. METHODS AND ANALYSIS: We will systematically search PubMed, EMBASE, Cochrane, Web of Science, PsycINFO, CINAHL, ProQuest Dissertations and LiLACS for randomised controlled trials, regardless of whether participants received blinding or not, published from 1 January 1966 to 30 January 2015 (updated to 1 July 2015), that compared any psychotherapy with either a control condition or an active comparator with different types and/or different delivery formats for the acute treatment of anxiety disorders in children and adolescents. Data extraction, risk of bias and quality assessments will be independently extracted by two reviewers. The primary outcome for efficacy will be mean overall change scores in anxiety symptoms (self-rated or assessor-rated) from baseline to post-treatment between two groups. The acceptability of treatment will be measured as the proportion of patients who discontinued treatment during the acute phase of treatment. We will assess efficacy, based on the standardised mean difference (SMD), and acceptability, based on the OR, using a random-effects network meta-analysis within a Bayesian framework. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. ETHICS AND DISSEMINATION: No ethical issues are foreseen. The results will be published in a peer-reviewed journal and will be disseminated electronically and in print. The meta-analysis may be updated to inform and guide management of anxiety in children and adolescents. TRIAL REGISTRATION NUMBER: PROSPERO CRD42015016283. PMID- 26443659 TI - Assessing the feasibility of screening and providing brief advice for alcohol misuse in general dental practice: a clustered randomised control trial protocol for the DART study. AB - INTRODUCTION: Alcohol misuse is a significant public health problem with major health, social and economic consequences. Systematic reviews have reported that brief advice interventions delivered in various health service settings can reduce harmful drinking. Although the links between alcohol and oral health are well established and dentists come into contact with large numbers of otherwise healthy patients regularly, no studies have been conducted in the UK to test the feasibility of delivering brief advice about alcohol in general dental settings. METHODS AND ANALYSIS: The Dental Alcohol Reduction Trial (DART) aims to assess the feasibility and acceptability of screening for alcohol misuse and delivering brief advice in patients attending National Health Service (NHS) general dental practices in North London. DART is a cluster randomised control feasibility trial and uses a mixed methods approach throughout the development, design, delivery and evaluation of the intervention. It will be conducted in 12 NHS general dental practices across North London and will include dental patients who drink above the recommended guidance, as measured by the Alcohol Use Disorders Identification Test (AUDIT-C) screening tool. The intervention involves 5 min of tailored brief advice delivered by dental practitioners during the patient's appointment. Feasibility and acceptability measures as well as suitability of proposed primary outcomes of alcohol consumption will be assessed. Initial economic evaluation will be undertaken. Recruitment and retention rates as well as acceptability of the study procedures from screening to follow-up will be measured. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Camden and Islington Research Ethics Committee. Study outputs will be disseminated via scientific publications, newsletters, reports and conference presentations to a range of professional and patient groups and stakeholders. Based on the results of the trial, recommendations will be made on the conduct of a definitive randomised controlled trial. TRIAL REGISTRATION NUMBER: ISRCTN81193263. PMID- 26443660 TI - Longitudinal qualitative exploration of cancer information-seeking experiences across the disease trajectory: the INFO-SEEK protocol. AB - INTRODUCTION: Alpha substantial corpus of literature has sought to describe the information-seeking behaviour of patients with cancer. Yet, available evidence comes mainly from cross-sectional studies, which provide 'snapshots' of patients' information needs and information-seeking styles at a single time point. Only a few longitudinal studies currently exist; however, these are quantitative in nature and, despite successfully documenting changes in patients' information needs throughout the clinical course of cancer, they have failed to provide an evidence-based interpretation of the causes and consequences of change. The goal of this study is threefold: First, we wish to provide a holistic understanding of how cancer information-seeking behaviour may evolve across different stages of the patient journey. Second, we will seek to elucidate the contextual and intervening conditions that may affect possible changes in information seeking. Third, we will attempt to identify what the consequences of these changes are, while heightening their implications for clinical practice and policy. METHODS AND ANALYSIS: We will carry out a longitudinal qualitative study, based on face to-face, in-depth interviews with approximately 25 individuals diagnosed with cancer. Patients will be recruited from 2 oncology hospitals located in Ticino, Switzerland, and will be interviewed at 3 different time points: (1) within 2 weeks after receiving the cancer diagnosis; (2) within 2 weeks after their initial treatment; and (3) 6 months after their initial treatment. All interviews will be recorded and transcribed verbatim. A grounded theory approach will be used for the analysis of the data. ETHICS AND DISSEMINATION: The study protocol has been approved by the Ethics Committee of Canton Ticino (CE 2813). Participation in the study will be voluntary, and confidentiality and anonymity ensured. Prior to study participation, patients will be asked to provide signed informed consent. Findings will be disseminated in international peer-reviewed journals and presented in relevant conferences. PMID- 26443661 TI - Longitudinal cohort study describing persistent frequent attenders in Australian primary healthcare. AB - OBJECTIVES: To describe patterns of frequent attendance in Australian primary care, and identify the prospective risk factors for persistent frequent attendance. DESIGN, SETTING AND PARTICIPANTS: This study draws on data from the Personality and Total Health (PATH) Through Life Project, a representative community cohort study of residents from the Canberra region of Australia. Participants were assessed on 3 occasions over 8 years. The survey assessed respondents' experience of chronic physical conditions, self-reported health, symptoms of common mental disorders, personality, life events, sociodemographic characteristics and self-reported medication use. A balanced sample was used in analysis, comprising 1734 respondents with 3 waves of data. The survey data for each respondent were individually linked to their administrative health service use data which were used to generate an objective measure of general practitioner (GP) consultations in the 12 months surrounding their interview date. MAIN OUTCOME MEASURES: Respondents in the (approximate) highest decile of attenders on number of GP consultations over a 12-month period at each time point were defined as frequent attenders (FAs). RESULTS: Baseline FAs (8.4%) were responsible for 33.4% of baseline consultations, while persistent FAs (3.6%) for 15.5% of all consultations over the 3 occasions. While there was considerable movement between FA status over time, consistency was greater than expected by chance alone. While there were many factors that differentiated non-FAs from FAs in general, persistent frequent attendance was specifically associated with gender, baseline reports of depression, self-reported physical conditions and disability, and medication use. CONCLUSIONS: The degree of persistence in GP consultations was limited. The findings of this study contribute to our understanding of the risk factors that predict subsequent persistent frequent attendance in primary care. However, further detailed investigation of longitudinal patterns of frequent attendance and consideration of time-varying determinants of frequent attendance is required. PMID- 26443662 TI - Development of the Serious Illness Care Program: a randomised controlled trial of a palliative care communication intervention. AB - INTRODUCTION: Ensuring that patients receive care that is consistent with their goals and values is a critical component of high-quality care. This article describes the protocol for a cluster randomised controlled trial of a multicomponent, structured communication intervention. METHODS AND ANALYSIS: Patients with advanced, incurable cancer and life expectancy of <12 months will participate together with their surrogate. Clinicians are enrolled and randomised either to usual care or the intervention. The Serious Illness Care Program is a multicomponent, structured communication intervention designed to identify patients, train clinicians to use a structured guide for advanced care planning discussion with patients, 'trigger' clinicians to have conversations, prepare patients and families for the conversation, and document outcomes of the discussion in a structured format in the electronic medical record. Clinician satisfaction with the intervention, confidence and attitudes will be assessed before and after the intervention. Self-report data will be collected from patients and surrogates approximately every 2 months up to 2 years or until the patient's death; patient medical records will be examined at the close of the study. Analyses will examine the impact of the intervention on the patient receipt of goal-concordant care, and peacefulness at the end of life. Secondary outcomes include patient anxiety, depression, quality of life, therapeutic alliance, quality of communication, and quality of dying and death. Key process measures include frequency, timing and quality of documented conversations. ETHICS AND DISSEMINATION: This study was approved by the Dana-Farber Cancer Institute Institutional Review Board. Results will be reported in peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: Protocol identifier NCT01786811; Pre-results. PMID- 26443664 TI - Correction: Therapeutic Peptide Vaccine-Induced CD8 T Cells Strongly Modulate Intratumoral Macrophages Required for Tumor Regression. PMID- 26443663 TI - The EARN-Health Trial: protocol for a randomised controlled trial to identify health effects of a financial savings programme among low-income US adults. AB - INTRODUCTION: A theory within the social epidemiology field is that financial stress related to having inadequate financial savings may contribute to psychological stress, poor mental health and poor health-related behaviours among low-income US adults. Our objective is to test whether an intervention that encourages financial savings among low-income US adults improves health behaviours and mental health. METHODS AND ANALYSIS: A parallel group two-arm controlled superiority trial will be performed in which 700 participants will be randomised to the intervention or a wait list. The intervention arm will be provided an online Individual Development Account (IDA) for 6 months, during which participants receive a $5 incentive (L3.2, ?4.5) for every month they save $20 in their account (L12.8, ?18), and an additional $5 if they save $20 for two consecutive months. Both groups will be provided links to standard online financial counselling materials. Online surveys in months 0 (prior to randomisation), 6 and 12 (6 months postintervention) will assess self-reported health behaviours and mental health among participants in both arms. The surveys items were tested previously in the US Centers for Disease Control and Prevention national health interviews and related health studies, including self-reported overall health, health-related quality of life, alcohol and tobacco use, depression symptoms, financial stress, optimism and locus of control, and spending and savings behaviours. Trial data will be analysed on an intent-to treat basis. ETHICS AND DISSEMINATION: This protocol was approved by the Institutional Review Board of Stanford University (Protocol ID: 30641). The findings of the trial will be disseminated through peer-reviewed publication. TRIAL REGISTRATION NUMBER: Identifier NCT02185612; Pre-results. PMID- 26443665 TI - Influence of provider mix and regulation on primary care services supplied to US patients. AB - Access to medical care and how it differs for various patients remain key policy issues. While existing work has examined clinic structure's influence on productivity, less research has explored the link between provider mix and access for different patient types - which also correspond to different service prices. We exploit experimental data from a large field study spanning 10 US states where trained audit callers were randomly assigned an insurance status and then contacted primary care physician practices seeking new patient appointments. We find clinics with more non-physician clinicians are associated with better access for Medicaid patients and lower prices for office visits; however, these relationships are only found in states granting full practice autonomy to these providers. Substituting more non-physician labor in primary care settings may facilitate greater appointment availability for Medicaid patients, but this likely rests on a favorable policy environment. Relaxing regulations for non physicians may be an important initiative as US health reforms continue and also relevant to other countries coping with greater demands for medical care and related financial strain. PMID- 26443666 TI - The Impact of Age on 5-Year Outcomes After Atrial Fibrillation Catheter Ablation. AB - BACKGROUND: Catheter ablation of atrial fibrillation (AF) is an established therapeutic rhythm approach in symptomatic patients. Many studies have shown that age has little to no impact on outcomes during the first year after ablation. However, AF is a disease of aging and age-based substrate for arrhythmia is likely to progress. To this regard, we examined patients with 5-year outcome data following an index AF ablation procedure to define the impact of age on long-term outcomes. METHODS: A total of 923 patients that underwent their index AF ablation and had 5 years of follow-up were studied. Patients were followed up for atrial flutter/AF recurrence, heart failure, stroke, death, and cardiac function. Patients were separated and compared in 5 age-based groups (<50, 51-60, 61-70, 71 80, >80). RESULTS: The average age of the population was 66 +/- 11 years and 59% were male. The AF was paroxysmal in 55%, persistent in 27%, and longstanding persistent in 18%. Older patients were more likely female and had higher rates of cardiovascular diseases. For every 10-year increase in age there was a higher multivariate-adjusted risk of atrial flutter/AF recurrence (HR: 1.13, P = 0.01), death (HR:1.91, P < 0.0001), and major adverse cardiac events (HR: 1.09, P = 0.07). Although atrial flutter/AF recurrence rates by age were similar at 1 year, at 5 years, younger patients had significantly lower rates of recurrences. CONCLUSION: Age significantly impacts outcomes after AF ablation when analyzed with long-term follow-up. These data highlight the progressive nature of AF and the need to consider interventions early. PMID- 26443668 TI - A Sleep Like Death: Identification of Genes Related to Seed Longevity in Medicago truncatula and Arabidopsis. PMID- 26443667 TI - CELLULOSE SYNTHASE INTERACTIVE1 Is Required for Fast Recycling of Cellulose Synthase Complexes to the Plasma Membrane in Arabidopsis. AB - Plants are constantly subjected to various biotic and abiotic stresses and have evolved complex strategies to cope with these stresses. For example, plant cells endocytose plasma membrane material under stress and subsequently recycle it back when the stress conditions are relieved. Cellulose biosynthesis is a tightly regulated process that is performed by plasma membrane-localized cellulose synthase (CESA) complexes (CSCs). However, the regulatory mechanism of cellulose biosynthesis under abiotic stress has not been well explored. In this study, we show that small CESA compartments (SmaCCs) or microtubule-associated cellulose synthase compartments (MASCs) are critical for fast recovery of CSCs to the plasma membrane after stress is relieved in Arabidopsis thaliana. This SmaCC/MASC mediated fast recovery of CSCs is dependent on CELLULOSE SYNTHASE INTERACTIVE1 (CSI1), a protein previously known to represent the link between CSCs and cortical microtubules. Independently, AP2M, a core component in clathrin-mediated endocytosis, plays a role in the formation of SmaCCs/MASCs. Together, our study establishes a model in which CSI1-dependent SmaCCs/MASCs are formed through a process that involves endocytosis, which represents an important mechanism for plants to quickly regulate cellulose synthesis under abiotic stress. PMID- 26443669 TI - Lipomatous metaplasia of superficial dermis. AB - Lipomatous metaplasia is an uncommon phenomenon. After identifying the presence of a band of adipocytes in the superficial reticular dermis underlying two excisions for basal cell carcinoma, we prospectively reviewed all skin specimens accessioned in our laboratory over a 6-month period and identified eight additional cases. In each example there was a band of adipocytes in the upper dermis, at the level of solar elastosis that was widely separated from the subcutaneous fat by a normal appearing reticular dermis. The cells were positive for S100 and negative for CD163. No connection between the superficial band of adipocytes and the subcutaneous or periappendageal fat was seen. The alterations were flat in configuration without polypoid changes. Eyerich et al. reported lipomatous metaplasia in the dermis of a patient with acute generalized exanthematic pustulosis and psoriasis, and postulated this to be a postinflammatory phenomenon. Fatty metaplasia occurs within a variety of cutaneous neoplasms including nevi, adnexal tumors and peripheral nerve sheath tumors. However, superficial dermal fatty metaplasia beneath cutaneous neoplasms is a newly described phenomenon and we suspect this process represents fatty metaplasia within solar elastosis and that it may occur more frequently than recognized. PMID- 26443670 TI - Promoting psychosocial adaptation of youths in residential care through animal assisted psychotherapy. AB - The goal of this study was to examine the influence of animal-assisted psychotherapy (AAP) on the psychosocial adaptation of a group of adolescents in residential care who had suffered traumatic childhood experiences and who presented with mental health problems. This study recruited 63 youths (mean age=15.27, SD=1.63) who were divided into two groups: a treatment group of 39 youths (19 female and 20 male; mean age=15.03, SD=0.51) and a control group of 24 (five female and 19 male; mean age=15.67, SD=1.63). The youths who underwent the AAP program had higher school adjustment in comparison to their peers who did not receive treatment. Their hyperactive behavior decreased, and they showed better social skills, more leadership, and fewer attention problems. They also showed a more positive attitude toward their teachers in comparison to controls. No differences were observed in other variables associated with clinical symptoms or personal adjustment. These results suggest that AAP can be effective with teenagers who have suffered childhood traumas and who present with problems of psychosocial adaptation. PMID- 26443671 TI - Health Literacy Among People with Serious Mental Illness. AB - People diagnosed with a mental illness are at higher risk of developing preventable chronic diseases; thus, health literacy improvements may have great potential to impact health outcomes for this typically underserved population. However, there is a dearth of research on health literacy of persons with severe mental illness. The purpose of this research was to investigate aspects of health literacy and identify factors associated with low literacy among adults with severe mental illness using three literacy assessment tools. Seventy-one adults with serious mental illness were assessed and a high proportion had limited literacy levels: 42% with the Single Item Literacy Screener, 50% with the Rapid Estimate of Adult Literacy in Medicine-Short Form, and 67% with the Newest Vital Sign. Findings suggest that individuals with certain mental illnesses and lower functioning may have more difficulty understanding health information and have limited numerical literacy. PMID- 26443672 TI - Novel environmental species isolated from the plaster wall surface of mural paintings in the Takamatsuzuka tumulus: Bordetella muralis sp. nov., Bordetella tumulicola sp. nov. and Bordetella tumbae sp. nov. AB - Ten strains of Gram-stain-negative, non-spore-forming, non-motile coccobacilli were isolated from the plaster wall surface of 1300-year-old mural paintings inside the stone chamber of the Takamatsuzuka tumulus in Asuka village (Asuka mura), Nara Prefecture, Japan. Based on 16S rRNA gene sequence analysis of the isolates, they belonged to the proteobacterial genus Bordetella (class Betaproteobacteria) and could be separated into three groups representing novel lineages within the genus Bordetella. Three isolates were selected, one from each group, and identified carefully using a polyphasic approach. The isolates were characterized by the presence of Q-8 as their major ubiquinone system and C16 : 0 (30.0-41.8 %), summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c; 10.1-27.0 %) and C17 : 0 cyclo (10.8-23.8 %) as the predominant fatty acids. The major hydroxy fatty acids were C12 : 0 2-OH and C14 : 0 2-OH. The DNA G+C content was 59.6-60.0 mol%. DNA-DNA hybridization tests confirmed that the isolates represented three separate novel species, for which the names Bordetella muralis sp. nov. (type strain T6220-3-2bT = JCM 30931T = NCIMB 15006T), Bordetella tumulicola sp. nov. (type strain T6517-1-4bT = JCM 30935T = NCIMB 15007T) and Bordetella tumbae sp. nov. (type strain T6713-1-3bT = JCM 30934T = NCIMB 15008T) are proposed. These results support previous evidence that members of the genus Bordetella exist in the environment and may be ubiquitous in soil and/or water. PMID- 26443673 TI - Neofunctionalization of a Duplicate dachshund Gene Underlies the Evolution of a Novel Leg Segment in Arachnids. AB - The acquisition of a novel function, or neofunctionalization, protects duplicated genes from redundancy and subsequent loss, and is a major force that drives adaptive evolution. Neofunctionalization has been inferred for many duplicated genes based on differences in regulation between the parental gene and its duplicate. However, only few studies actually link the new function of a duplicated gene to a novel morphological or physiological character of the organism. Here we show that the duplication of dachshund (dac) in arachnids (spiders and allies) is linked with the evolution of a novel leg segment, the patella. We have studied dac genes in two distantly related spider species, the entelegyne spider Parasteatoda tepidariorum and the haplogyne spider Pholcus phalangioides. Both species possess two paralogous dac genes that duplicated before the split between entelegyne and haplogyne spiders. In contrast to the evolutionarily highly conserved dac1, its duplicate dac2 is strongly expressed in the patella leg segment during embryogenesis in both species. Using parental RNA interference in P. tepidariorum we show that dac2 is required for the development of the patella segment. If dac2 function is impaired, then the patella is fused with the tibia into a single leg segment. Thus, removing the function of dac2 experimentally reverts P. tepidariorum leg morphology into a stage before the duplication of dac and the evolution of the patella segment. Our results indicate that the origin of the patella is the result of the duplication and subsequent neofunctionalization of dac in the arachnid lineage. PMID- 26443674 TI - Life in standby: hemodialysis patients' experiences of waiting for kidney transplantation. AB - AIM AND OBJECTIVES: Our aim was to explore the experiences of hemodialysis patients who are waiting for a kidney transplant. BACKGROUND: Currently, more than 100,000 persons are waiting for kidney transplantation in the United States. In Sweden, the number is exceeding 600. The waiting period for a deceased donor can be one to three years or even longer in Sweden. This can be challenging, since the patients' situation, with chronic treatment and illness, is burdensome and requires advanced self-care. DESIGN: This study included a purposeful sample of eight patients (33-53 years old) who had been undergoing hemodialysis treatment for at least six months and were waiting for kidney transplantation. METHODS: The patients were interviewed, and descriptive content analysis was performed. RESULTS: Four categories emerged: (1) 'The waiting process,' what thoughts and expectations occur and what to do and how to be prepared for the transplant. (2) 'Awareness that time is running out,' patients felt tied up by treatment and by needing to be available for transplantation, and they had concerns about health. (3) 'Need for communication,' patients described needing support from others and continuous information from the staff. (4) 'Having relief and hope for the future,' patients described how to preserve the hope of being able to participate fully in life once again. CONCLUSIONS: This study reveals the need for extra attention paid to patients waiting for kidney transplantation. Patients' experiences during the waiting period indicate that pretransplant patients have an increased need to be prepared for the transition and for life post-transplantation. RELEVANCE TO CLINICAL PRACTICE: Dialysis patients on waiting lists must be prepared for the upcoming life change. This includes preserving hope during the waiting period and being mentally prepared for transplantation and a dialysis-free life. A pretransplant education program to prevent medical and psychosocial issues is highly recommended. PMID- 26443675 TI - Pharmacological Modulation of GABA Function in Autism Spectrum Disorders: A Systematic Review of Human Studies. AB - Autism spectrum disorders are an emerging health problem worldwide, but little is known about their pathogenesis. It has been hypothesized that autism may result from an imbalance between excitatory glutamatergic and inhibitory GABAergic pathways. Commonly used medications such as valproate, acamprosate, and arbaclofen may act on the GABAergic system and be a potential treatment for people with ASD. The present systematic review aimed at evaluating the state-of the-art of clinical trials of GABA modulators in autism. To date there is insufficient evidence to suggest the use of these drugs in autistic subjects, even if data are promising. Of note, short-term use of all the reviewed medications appears to be safe. Future well designed trials are needed to elucidate these preliminary findings. PMID- 26443676 TI - The Tomato MIXTA-Like Transcription Factor Coordinates Fruit Epidermis Conical Cell Development and Cuticular Lipid Biosynthesis and Assembly. AB - The epidermis of aerial plant organs is the primary source of building blocks forming the outer surface cuticular layer. To examine the relationship between epidermal cell development and cuticle assembly in the context of fruit surface, we investigated the tomato (Solanum lycopersicum) MIXTA-like gene. MIXTA/MIXTA like proteins, initially described in snapdragon (Antirrhinum majus) petals, are known regulators of epidermal cell differentiation. Fruit of transgenically silenced SlMIXTA-like tomato plants displayed defects in patterning of conical epidermal cells. They also showed altered postharvest water loss and resistance to pathogens. Transcriptome and cuticular lipids profiling coupled with comprehensive microscopy revealed significant modifications to cuticle assembly and suggested SlMIXTA-like to regulate cutin biosynthesis. Candidate genes likely acting downstream of SlMIXTA-like included cytochrome P450s (CYPs) of the CYP77A and CYP86A subfamilies, LONG-CHAIN ACYL-COA SYNTHETASE2, GLYCEROL-3-PHOSPHATE SN 2-ACYLTRANSFERASE4, and the ATP-BINDING CASSETTE11 cuticular lipids transporter. As part of a larger regulatory network of epidermal cell patterning and L1-layer identity, we found that SlMIXTA-like acts downstream of SlSHINE3 and possibly cooperates with homeodomain Leu zipper IV transcription factors. Hence, SlMIXTA like is a positive regulator of both cuticle and conical epidermal cell formation in tomato fruit, acting as a mediator of the tight association between fruit cutin polymer formation, cuticle assembly, and epidermal cell patterning. PMID- 26443677 TI - RNA Silencing of Exocyst Genes in the Stigma Impairs the Acceptance of Compatible Pollen in Arabidopsis. AB - Initial pollen-pistil interactions in the Brassicaceae are regulated by rapid communication between pollen grains and stigmatic papillae and are fundamentally important, as they are the first step toward successful fertilization. The goal of this study was to examine the requirement of exocyst subunits, which function in docking secretory vesicles to sites of polarized secretion, in the context of pollen-pistil interactions. One of the exocyst subunit genes, EXO70A1, was previously identified as an essential factor in the stigma for the acceptance of compatible pollen in Arabidopsis (Arabidopsis thaliana) and Brassica napus. We hypothesized that EXO70A1, along with other exocyst subunits, functions in the Brassicaceae dry stigma to deliver cargo-bearing secretory vesicles to the stigmatic papillar plasma membrane, under the pollen attachment site, for pollen hydration and pollen tube entry. Here, we investigated the functions of exocyst complex genes encoding the remaining seven subunits, SECRETORY3 (SEC3), SEC5, SEC6, SEC8, SEC10, SEC15, and EXO84, in Arabidopsis stigmas following compatible pollinations. Stigma-specific RNA-silencing constructs were used to suppress the expression of each exocyst subunit individually. The early postpollination stages of pollen grain adhesion, pollen hydration, pollen tube penetration, seed set, and overall fertility were analyzed in the transgenic lines to evaluate the requirement of each exocyst subunit. Our findings provide comprehensive evidence that all eight exocyst subunits are necessary in the stigma for the acceptance of compatible pollen. Thus, this work implicates a fully functional exocyst complex as a component of the compatible pollen response pathway to promote pollen acceptance. PMID- 26443678 TI - Roseomonas oryzicola sp. nov., isolated from the rhizosphere of rice (Oryza sativa L.). AB - A Gram-stain-negative, coccobacilli-shaped bacterium, designated YC6724T, was isolated from the rhizosphere of rice in Jinju, Korea. The taxonomy of strain YC6724T was studied using a polyphasic approach. Strain YC6724T grew optimally at 30 degrees C and pH 7.0-8.0. Comparative 16S rRNA gene sequence analyses showed that the strain was most closely related to Roseomonas soli 5N26T (98.4 % 16S rRNA gene sequence similarity), Roseomonas lacus THG33T(97.3 %) and Roseomonas terrae DS-48T (97.3 %). Sequence similarities with other species of the genus Roseomonas with validly published names were lower than 94.0 %. Phylogenetic analysis based on the 16S rRNA gene sequence showed that strain YC6724T formed a distinct phyletic lineage within the genus Roseomonas. Strain YC6724T had DNA-DNA relatedness values of 16.6 %, 44.0 % and 33.2 % with R. soli KACC 16376T, R. terrae KACC 12677T and R. lacus KACC 11678T, respectively. The predominant fatty acids of strain YC6724T were C18 : 1omega7c and/or C18 : 1omega6c, C16 : 0 and C18 : 1 2-OH. The polar lipid profile contained phosphatidylethanolamine, phosphatidylcholine, phosphatidylglycerol,diphosphatidylglycerol, an unknown aminolipid and two unknown lipids. The G+C content of the genomic DNA was 70.5 mol% and the major quinone was Q-10. Strain YC6724T contained spermidine as the major polyamine. On the basis of phenotypic, chemotaxonomic and molecular data, it is clear that strain YC6724T represents a novel species of the genus Roseomonas, for which the name Roseomonas oryzicola sp. nov. is proposed. The type strain is YC6724T (=KCTC 22478T=NBRC 109439T). PMID- 26443679 TI - Cumulative stress in childhood is associated with blunted reward-related brain activity in adulthood. AB - Early life stress (ELS) is strongly associated with negative outcomes in adulthood, including reduced motivation and increased negative mood. The mechanisms mediating these relations, however, are poorly understood. We examined the relation between exposure to ELS and reward-related brain activity, which is known to predict motivation and mood, at age 26, in a sample followed since kindergarten with annual assessments. Using functional neuroimaging, we assayed individual differences in the activity of the ventral striatum (VS) during the processing of monetary rewards associated with a simple card-guessing task, in a sample of 72 male participants. We examined associations between a cumulative measure of ELS exposure and VS activity in adulthood. We found that greater levels of cumulative stress during childhood and adolescence predicted lower reward-related VS activity in adulthood. Extending this general developmental pattern, we found that exposure to stress early in development (between kindergarten and grade 3) was significantly associated with variability in adult VS activity. Our results provide an important demonstration that cumulative life stress, especially during this childhood period, is associated with blunted reward-related VS activity in adulthood. These differences suggest neurobiological pathways through which a history of ELS may contribute to reduced motivation and increased negative mood. PMID- 26443680 TI - [Current aspects on the management of normal tension glaucoma]. AB - In a considerable proportion of glaucoma patients (25-50 %) the intraocular pressure (IOP) is not elevated higher than 22 mmHg at first diagnosis and during subsequent follow-up controls. Although the IOP level remains in the low range < 22 mmHg, progression of glaucoma can still occur. A multitude of different factors are assumed to be involved in glaucoma progression, such as very low nocturnal diastolic blood pressure values, a low mean ocular perfusion pressure, extensive fluctuations in perfusion (e.g. in cases of vascular dysregulation), an increased vulnerability of the optic nerve support structures, an increased translaminar pressure gradient and various underlying systemic diseases. The most important evidence-based aspect of treatment in normal tension glaucoma is pharmaceutical or surgical reduction of the IOP by 30 % or more in comparison to the initial pressure level. Vascular and neuroprotective concepts of treatment for normal tension glaucoma have been strongly advocated and the object of experimental and clinical studies. As yet a clear clinical benefit has not been proven by large prospective randomized studies. PMID- 26443681 TI - Nocardioides ungokensis sp. nov., isolated from lake sediment. AB - A Gram-reaction-positive, aerobic, coccus- to rod-shaped, non-motile, non-spore forming bacterium (strain UKS-03T) was isolated from a sediment sample of Ungok Lake in Gochang, Republic of Korea. The taxonomic position of this bacterium was determined in an investigation based on a polyphasic approach. On the basis of 16S rRNA gene sequence analysis, strain UKS-03T was shown to belong to the family Nocardioidaceae and to be related most closely to Nocardioides ginsengisegetis Gsoil 485T (98.5 % similarity), Nocardioides koreensis MSL-09T (98.4 %) and 'Nocardioides panaciterrulae' Gsoil 958 (97.3 %). Strain UKS-03T was characterized chemotaxonomically as having ll-2,6-diaminopimelic acid in its cell wall peptidoglycan, MK-8(H4) as the predominant menaquinone, diphosphatidylglycerol and phosphatidylglycerol as the main polar lipids, and iso C16 : 0, C17 : 1omega8c and C17 : 0 10-methyl as its major fatty acids. The G+C content of the genomic DNA was 71.9 mol%. Mean DNA-DNA relatedness values between strain UKS-03T and N. ginsengisegetis Gsoil 485T, N. koreensis KCTC 19272T and 'N. panaciterrulae' Gsoil 958 were 37.5 +/- 7.2, 6.8 +/- 0.9 and 3.1 +/- 0.7 %, respectively. On the basis of the data from this polyphasic taxonomic study, strain UKS-03T represents a novel species of the genus Nocardioides, for which the name Nocardioides ungokensis sp. nov. is proposed. The type strain is UKS-03T ( = KACC 18304T = LMG 28591T). PMID- 26443682 TI - Reward memory relieves anxiety-related behavior through synaptic strengthening and protein kinase C in dentate gyrus. AB - Anxiety disorders are presumably associated with negative memory. Psychological therapies are widely used to treat this mental deficit in human beings based on the view that positive memory competes with negative memory and relieves anxiety status. Cellular and molecular processes underlying psychological therapies remain elusive. Therefore, we have investigated its mechanisms based on a mouse model in which food reward at one open-arm of the elevated plus-maze was used for training mice to form reward memory and challenge the open arms. Mice with the reward training showed increased entries and stay time in reward open-arm versus neutral open-arm as well as in open-arms versus closed-arms. Accompanying with reward memory formation and anxiety relief, glutamatergic synaptic transmission in dentate gyrus in vivo and dendritic spines in granule cells became upregulated. This synaptic up-regulation was accompanied by the expression of more protein kinase C (PKC) in the dendritic spines. The inhibition of PKC by chelerythrine impaired the formation of reward memory, the relief of anxiety related behavior and the up-regulation of glutamate synapses. Our results suggest that reward-induced positive memory relieves mouse anxiety-related behavior by strengthening synaptic efficacy and PKC in the hippocampus, which imply the underlying cellular and molecular processes involved in the beneficial effects of psychological therapies treating anxiety disorders. PMID- 26443683 TI - Writing throughout the biochemistry curriculum: Synergistic inquiry-based writing projects for biochemistry students. AB - This article describes a synergistic two-semester writing sequence for biochemistry courses. In the first semester, students select a putative protein and are tasked with researching their protein largely through bioinformatics resources. In the second semester, students develop original ideas and present them in the form of a research grant proposal. Both projects involve multiple drafts and peer review. The complementarity of the projects increases student exposure to bioinformatics and literature resources, fosters higher-order thinking skills, and develops teamwork and communication skills. Student feedback and responses on perception surveys demonstrated that the students viewed both projects as favorable learning experiences. PMID- 26443684 TI - Where are the sensory organs of Nybelinia surmenicola (Trypanorhyncha)? A comparative analysis with Parachristianella sp. and other trypanorhynchean cestodes. AB - The sensory organs in tegument of two trypanorhynchean species--Nybelinia surmenicola (plerocercoid) and adult Parachristianella sp. (Cestoda, Trypanorhyncha)--were studied with the aim of ultrastructural description and a comparative analysis. The Nybelinia surmenicola plerocercoid lacks papillae with sensory cilia on the bothria adhesive surface. We found an unciliated sensory organ within the median bothria fold. This unciliated free nerve ending contains the central electron-dense disc, three dense supporting rings, and broad root. The nerve ending locates in the basal matrix under the tegument. The tegument of N. surmenicola has a number of ultrastructural features which make it significantly different from other Trypanorhyncha: (i) the tegumental cytoplasm has a plicated constitution in a form of high apical and deep basal folds, (ii) numerous layers of the basal matrix are presented in the subtegument, and (iii) the squamiform and bristlelike microtriches N. surmenicola lack the base and the basal plate. In contrast, numerous ciliated and unciliated receptors were found in Parachristianella sp.: six types on the bothria and one type in the strobila tegument. Ultrastructural constitution of sensory organs in the form of ciliated free nerve endings as well as unciliated basal nerve endings of Parachristianella sp. has many common features inside Eucestoda. In comparison with other Trypanorhyncha, all Nybelinia species studied have less quantity of the bothrial sensory organs. This fact may reflect behavioral patterns of Nybelinia as well as phylogenetic position into Trypanorhyncha. Our observations of living animals conventionally demonstrate the ability of N. surmenicola plerocercoids to locomote in forward direction on the Petri dish surface. The participation of the bothrial microtriches in a parasite movement has been discussed. PMID- 26443685 TI - The diversity and prevalence of hard ticks attacking human hosts in Eastern Siberia (Russian Federation) with first description of invasion of non-endemic tick species. AB - Hard ticks are the vectors of many pathogens including tick-borne encephalitis virus and the Lyme disease agent Borrelia burgdorferi sensu lato. In Eastern Siberia, Ixodes persulcatus, Dermacentor nuttalli, Dermacentor silvarum and Haemaphysalis concinna are regarded as aggressive to humans. Recently, significant changes in world tick fauna have been reported and this affects the spread of tick-borne pathogens. We studied the current species diversity, population structure and prevalence of tick-borne pathogens of hard ticks (Acari: Ixodidae) that attacked humans in Eastern Siberia (Irkutsk region, Russia). In total, 31,892 individual ticks were identified and analysed during the years 2007 2014. The majority (85.4%) of victims was bitten by I. persulcatus, 14.55% of attacks on humans were caused by D. nuttalli and D. silvarum, whereas H. concinna was documented only in 15 cases (0.05%). The seasonal activity and the age/gender structure of the tick population were studied as well. Among all the studied ticks, three unconventional species, i.e. Rhipicephalus sanguineus, Dermacentor reticulatus and Amblyomma americanum, were identified. Analysis of tick bite histories indicates at least three events of invasion of non-endemic ticks into the ecosystems of northern Eurasia with harsh continental climates. Invading ticks are able to reach the adult life stage and are aggressive to the local human population. Phylogenetic analysis of mt 16S rRNA gene fragments suggests multiple independent routes of tick migration to Eastern Siberia. Possible implications to human health and epidemiology of tick-borne infections are discussed. PMID- 26443686 TI - A molecular perspective on rituximab: A monoclonal antibody for B cell non Hodgkin lymphoma and other affections. AB - Rituximab (a chimeric anti-CD20 monoclonal antibody) is the first Food and Drug Administration approved anti-tumor antibody. Immunotherapy by rituximab, especially in combination-therapy, is a mainstay for a vast variety of B-cell malignancies therapy. Its therapeutic value is unquestionable, yet the mechanisms of action responsible for anti-tumor activity of rituximab and rituximab resistance mechanisms are not completely understood. Investigation of the mechanisms of action that contribute to the rituximab activity have eventually directed to a suite of novel combinations and novel treatment schedules, and also have resulted new generations of antibodies with more desired effects. Although, further investigations are needed to define the mechanisms of rituximab resistance and prominent effector activity of the altered next generation anti CD20 to improve their efficacies and develop new anti-CD20 monoclonal antibodies in NHL treatment. This article focuses on the properties of CD20 which led scientists to select it as an effective therapeutic target and the molecular details of mechanisms of rituximab action and resistance. We also discuss about the impact of rituximab in monotherapy and in combination with chemotherapy regimens. Finally, we comparatively summarize the next generations of anti CD20 monoclonal antibodies to highlight their advantages relative to their ancestor: Rituximab. PMID- 26443687 TI - A simple assessment model to quantifying the dynamic hippocampal neurogenic process in the adult mammalian brain. AB - Adult hippocampal neurogenesis is a highly dynamic process in which new cells are born, but only some of which survive. Of late it has become clear that these surviving newborn neurons have functional roles, most notably in certain forms of memory. Conventional methods to look at adult neurogenesis are based on the quantification of the number of newly born neurons using a simple cell counting methodology. However, this type of approach fails to capture the dynamic aspects of the neurogenic process, where neural proliferation, death and differentiation take place continuously and simultaneously. In this paper, we propose a simple mathematical approach to better understand the adult neurogenic process in the hippocampus which in turn will allow for a better analysis of this process in disease states and following drug therapies. PMID- 26443688 TI - Dietary fatty acids and risk of hepatocellular carcinoma in the Singapore Chinese health study. AB - BACKGROUND & AIM: Lipidomic signature of lipid metabolism suggests that omega-6 polyunsaturated fatty acids (PUFA) may play a role in oncogenesis of hepatocellular carcinoma (HCC). Hence, we examined the association between dietary fatty acids and risk of HCC. METHODS: We used data from the Singapore Chinese Health Study, a population-based prospective cohort of 63 257 Chinese men and women aged 45-74 years enrolled between 1993 and 1998. Information on current diet assessed via a validated semi-quantitative food frequency questionnaire, medical history and lifestyle factors were obtained through in-person interview, and incidence of HCC recorded through 31 Dec 2010. We also examined the association between dietary fatty acids and HCC risk using a case-control set of 92 cases and 274 controls with available serological biomarkers of chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) nested within this cohort. RESULTS: Among the dietary fat components examined, which included saturated, monounsaturated, omega-3 and omega-6 PUFA, only omega-6 PUFA intake displayed a dose-dependent, positive association with HCC risk (p for trend = 0.02). Compared to the lowest quartile, the hazard ratio for the highest quartile intake was 1.49 [(95% confidence interval (CI):1.08-2.07)]. In the nested case control study, only among individuals negative for serology markers of chronic infection with HBV or HCV, those who consumed above median levels of dietary omega-6 PUFA had increased HCC risk (odds ratio = 4.36, 95% CI = 1.59-11.94) compared to those with lower intake. CONCLUSION: Dietary omega-6 PUFA may be implicated in the risk of non-viral hepatitis related HCC. PMID- 26443689 TI - Purification of a recombinant glutathione transferase from the causative agent of hydatidosis, Echinococcus granulosus. AB - This practical class activity was designed to introduce students to recombinant protein expression and purification. The principal goal is to shed light on basic aspects concerning recombinant protein production, in particular protein expression, chromatography methods for protein purification, and enzyme activity as a tool to evaluate purity and conformation of the recombinant product. Herein, we describe the purification of a glutathione transferase from the human parasite Echinococcus granulosus (EgGST1), the causative agent of hydatidosis. EgGST1 is expressed fused to a histidine tag and is purified by immobilized metal affinity chromatography. Protein quantification based on direct (UV absorbance) and indirect (colorimetric) methods are used and discussed. A simple colorimetric assay is used to measure GST activity and special emphasis is put on how to use these measurements to follow protein purification yields, its enrichment and its correct folding along the purification process. EgGST1 is easily expressed with high yields, purified in absence of protease inhibitors and proved to be robust concerning enzyme activity and protein integrity on a 1 week practical activity. PMID- 26443690 TI - Prognostic significance of transaminases after acute ST-elevation myocardial infarction: insights from a cardiac magnetic resonance study. AB - BACKGROUND: In patients with ST-elevation myocardial infarction (STEMI), the relationship between transaminases and myocardial damage detected by cardiac magnetic resonance (CMR) imaging is unknown and the prognostic value incompletely investigated. MATERIALS AND METHODS: CMR imaging was performed in 167 STEMI patients 2.3 [1.6-3.9] days after primary percutaneous coronary intervention (PPCI). Blood samples for transaminase measurement (aspartate transaminase (AST) and alanine transaminase (ALT)) were obtained serially from day 1 to day 4 after PPCI. Patients were followed for major adverse cardiac events (MACE) for 2.7 [1.1 3.3] years. RESULTS: Admission and peak concentrations of AST and ALT were significantly associated with ejection fraction (p < 0.001), infarct size (p < 0.001), and the presence of microvascular obstruction (p < 0.01). Peak values of both transaminases showed a stronger correlation with CMR parameters than admission values (all p < 0.05). In Kaplan-Meier analysis, a high peak AST or high peak ALT was associated with reduced MACE-free survival (both p < 0.01), whereas admission values were not (both p > 0.05). Peak AST (hazard ratio (HR): 4.93 [1.70-14.32], p = 0.003) and peak ALT (HR: 5.67 [1.94-16.56], p = 0.002) were independent predictors of MACE after adjusting for clinical risk factors. CONCLUSIONS: Transaminases measured in the acute phase after PPCI for STEMI are associated with systolic dysfunction, more extensive myocardial necrosis and microvascular injury with subsequent prognostic information on MACE at long-term follow-up. PMID- 26443691 TI - Towards scene adaptive image correspondence for placental vasculature mosaic in computer assisted fetoscopic procedures. AB - BACKGROUND: Visualization of the vast placental vasculature is crucial in fetoscopic laser photocoagulation for twin-to-twin transfusion syndrome treatment. However, vasculature mosaic is challenging due to the fluctuating imaging conditions during fetoscopic surgery. METHOD: A scene adaptive feature based approach for image correspondence in free-hand endoscopic placental video is proposed. It contributes towards existing techniques by introducing a failure detection method based on statistical attributes of the feature distribution, and an updating mechanism that self-tunes parameters to recover from registration failures. RESULTS: Validations on endoscopic image sequences of a phantom and a monkey placenta are carried out to demonstrate mismatch recovery. In two 100 frame sequences, automatic self-tuned results improved by 8% compared with manual experience-based tuning and a slight 2.5% deterioration against exhaustive tuning (gold standard). CONCLUSION: This scene-adaptive image correspondence approach, which is not restricted to a set of generalized parameters, is suitable for applications associated with dynamically changing imaging conditions. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26443693 TI - Examination of the Synthetic Control Method for Evaluating Health Policies with Multiple Treated Units. AB - This paper examines the synthetic control method in contrast to commonly used difference-in-differences (DiD) estimation, in the context of a re-evaluation of a pay-for-performance (P4P) initiative, the Advancing Quality scheme. The synthetic control method aims to estimate treatment effects by constructing a weighted combination of control units, which represents what the treated group would have experienced in the absence of receiving the treatment. While DiD estimation assumes that the effects of unobserved confounders are constant over time, the synthetic control method allows for these effects to change over time, by re-weighting the control group so that it has similar pre-intervention characteristics to the treated group. We extend the synthetic control approach to a setting of evaluation of a health policy where there are multiple treated units. We re-analyse a recent study evaluating the effects of a hospital P4P scheme on risk-adjusted hospital mortality. In contrast to the original DiD analysis, the synthetic control method reports that, for the incentivised conditions, the P4P scheme did not significantly reduce mortality and that there is a statistically significant increase in mortality for non-incentivised conditions. This result was robust to alternative specifications of the synthetic control method. (c) 2015 The Authors. Health Economics published by John Wiley & Sons Ltd. PMID- 26443692 TI - Effects of 2-year calorie restriction on circulating levels of IGF-1, IGF-binding proteins and cortisol in nonobese men and women: a randomized clinical trial. AB - Young-onset calorie restriction (CR) in rodents decreases serum IGF-1 concentration and increases serum corticosterone levels, which have been hypothesized to play major roles in mediating its anticancer and anti-aging effects. However, little is known on the effects of CR on the IGF-1 system and cortisol in humans. To test the sustained effects of CR on these key hormonal adaptations, we performed a multicenter randomized trial of a 2-year 25% CR intervention in 218 nonobese (body mass index between 22 and 27.8 kg m(-2) ) young and middle-aged (20-50 years age range) men and women. Average CR during the first 6 months was 19.5 +/- 0.8% and 9.1 +/- 0.7% over the next 18 months of the study. Weight loss averaged 7.6 +/- 0.3 kg over the 2-years period of which 71% was fat mass loss (P < 0.0001). Average CR during the CR caused a significant 21% increase in serum IGFBP-1 and a 42% reduction in IGF-1:IGFBP-1 ratio at 2 years (P < 0.008), but did not change IGF-1 and IGF-1:IGFBP-3 ratio levels. Serum cortisol concentrations were slightly but significantly increased by CR at 1 year only (P = 0.003). Calorie restriction had no effect on serum concentrations of PDGF-AB and TGFbeta-1. We conclude, on the basis of the present and previous findings, that, in contrast to rodents, humans do not respond to CR with a decrease in serum IGF-1 concentration or with a sustained and biological relevant increase in serum cortisol. However, long-term CR in humans significantly and persistently increases serum IGFBP-1 concentration. PMID- 26443694 TI - Robot-assisted laparoscopic resection of large retroperitoneal paraganglioma - initial experience from China. AB - BACKGROUND: There have been only four cases of robot-assisted laparoscopic resection of retroperitoneal paraganglioma (PGL) in the literature. Here we present our experience on robot-assisted laparoscopic resection of large PGL in four patients to further evaluate its safety and efficacy. METHODS: From March 2013 to January 2015, four patients with large PGL underwent robot-assisted laparoscopic resection. The tumors were located on the left side and adjacent to the aorta. Patients' demographics, intraoperative and postoperative data were collected, including intraoperative hemodynamic outcomes. RESULTS: In all cases, the PGLs were successfully removed robotically without conversion to open surgery and no intraoperative or postoperative complication occurred. The operative time ranged from 58-113 min, and estimated blood loss ranged from 50-350 mL. There were no significant intraoperative hemodynamic instabilities. The postoperative hospital stay ranged from 4-6 days. CONCLUSIONS: With the advantages of robotic system, robot-assisted resection of large retroperitoneal PGL is feasible, safe and efficient. The robotic system has the potential to expand surgical treatment modalities for complex PGL. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26443695 TI - Complication rate in adult deformity surgical treatment: safety of the posterior osteotomies. AB - PURPOSE: The treatment of adult scoliosis is a challenge especially in patients over 50 years old with severe, rigid curves in whom the use of vertebral osteotomies may be necessary to correct the deformity. The aim the study was to analyse the perioperative complications related to vertebral osteotomies in elderly treated for spinal deformity. METHODS: We analysed 72 consecutive cases of kyphoscoliosis, we classify them according to Berjano-Lamartina classification. We divided patients into two groups: we only practised SPO and/or PO in patients that composed group A; we practised also PSO in patients that composed group B. We retrospectively analysed the perioperative complications and radiographical results. Average follow-up was 30 months. RESULTS: We had 50 cases of degenerative segment diseases (DSD) Type III, 13 Type IVa DSD and 9 Type IVb DSD. Mean age was 60.7 years old. Overall complication rate was 22.2 %. In group A, the complication rate was 16.9 % while in group B it was 46.2 %. Mean Cobb primary curve angle was 41.75 degrees with average C7 plumb line (C7PL) of 4.49 cm, residual scoliosis after surgery was 15.41 degrees and average C7PL of 2.08 cm, with statistically significant differences. CONCLUSIONS: Previous studies have shown increased complication rates with vertebral osteotomies in elderly patients, our experience support this evidence. Our study demonstrates a high incidence of intraoperative complication rate in elderly patients underwent a PSO. PSO is a demanding technique to be considered in very selected and motivated patients who must be carefully informed about the risks of the procedure. PMID- 26443696 TI - Effect of strength training with blood flow restriction on muscle power and submaximal strength in eumenorrheic women. AB - Blood flow restriction (BFR) training stimulates muscle size and strength by increasing muscle activation, accumulation of metabolites and muscle swelling. This method has been used in different populations, but no studies have evaluated the effects of training on muscle power and submaximal strength (SS) in accounted for the menstrual cycle. The aim of this study was to analyse the effect of strength training (ST) with BFR on the muscle power and SS of upper and lower limbs in eumenorrheic women. Forty untrained women (18-40 years) were divided randomly and proportionally into four groups: (i) high-intensity ST at 80% of 1RM (HI), (ii) low-intensity ST at 20% of 1RM combined with partial blood flow restriction (LI + BFR), (iii) low-intensity ST at 20% of 1RM (LI) and d) control group (CG). Each training group performed eight training sessions. Tests with a medicine ball (MB), horizontal jump (HJ), vertical jump (VJ), biceps curls (BC) and knee extension (KE) were performed during the 1st day follicular phase (FP), 14th day (ovulatory phase) and 26-28th days (luteal phase) of the menstrual cycle. There was no significant difference among groups in terms of the MB, HJ, VJ or BC results at any time point (P>0.05). SS in the KE exercise was significantly greater in the LI + BFR group compared to the CG group (P = 0.014) during the LP. Therefore, ST with BFR does not appear to improve the power of upper and lower limbs and may be an alternative to improve the SS of lower limbs of eumenorrheic women. PMID- 26443697 TI - Operative Treatment of the Insertional Achilles Tendinopathy Through a Transtendinous Approach. AB - BACKGROUND: Different operative techniques have been proposed for the treatment of insertional Achilles tendinopathy (IAT), with often disappointing results. The aim of this study was to evaluate the outcome of the transtendinous approach in IAT. METHODS: Forty patients operated with an IAT between 2010 and 2011 were included in this retrospective study. The mean follow-up was 15.6 (+/-3.7, 12-27) months. Indication for surgery was IAT with failed conservative therapy. Using a transtendinous approach, the Achilles tendon (AT) was partially detached and all pathologic tissues were debrided. The AT was reinserted using different anchor techniques. Clinical data were recorded using examination and clinical scores (American Orthopaedic Foot & Ankle Society [AOFAS], Foot and Ankle Outcome Score [FAOS], Numerical Rating Scale [NRS], and Short Form-36 [SF-36]). RESULTS: The mean AOFAS hindfoot score improved from 59.4 preoperatively to 86.5 postoperatively (P < .05). All FAOS subscales, NRS pain scores, and pain and function subscales of SF-36 improved significantly. The median time of return to work and sports was 14.5 (+/-17.6; 2-82) and 22.7 (+/-13.4; 7-58) weeks. Three patients had superficial wound healing difficulties but required no revision. One patient had to be revised due to a hematoma. Patients treated with 2 suture anchors or double-row fixation technique improved significantly (P < .05) compared to those with single anchor fixation, regarding AOFAS score (79.6 and 90.2) and FAOS subscale scores. Eighty-three percent of the patients showed good to excellent results. CONCLUSION: The transtendinous approach allowed access to all associated pathologies in IAT. It had relatively few complications and lead to good clinical results. LEVEL OF CLINICAL EVIDENCE: Level IV, retrospective case series. PMID- 26443699 TI - Using motion parallax for laparoscopic surgery. AB - BACKGROUND: In typical stereo display systems, the reproduced 3D scene is distorted when the observer moves. Motion parallax is an important depth cue that has the ability to correct this distortion. More importantly, motion parallax enables the observer to look around objects to provide a better view. METHODS: A robotically assisted laparoscope prototype was designed to provide motion parallax. A study to adjust the camera-head mapping ratio (gain of motion parallax) was performed. A series of phantom tests was conducted to test the effectiveness of motion parallax. RESULTS: The experimental results showed that the motion parallax was effective, and the gain of motion parallax was subjective. For a regular laparoscope view distance, larger image zooming rates required smaller gain; for the same equivalent image size, further observer distance decreased the optimal gain. CONCLUSIONS: Motion parallax could be used for improved visualization in laparoscopic surgery. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26443698 TI - Posterior Talar Shifting in Mobile-Bearing Total Ankle Replacement. AB - BACKGROUND: End-stage ankle osteoarthritis frequently involves multiplanar malalignment in both the coronal and the sagittal planes. Sagittal malalignment often includes anterior translation of the talus relative to the tibia. Restoration of the correct tibial and talar alignment is essential for the long term survival of total ankle replacement. METHODS: This study includes 66 consecutive patients who underwent total ankle arthroplasty with the Hintegra prosthesis from May 2011 to April 2014. There were 28 females (42.4%) and 38 males (57.6%) with a mean age of about 57 years (25-82 years). Patients were clinically and radiologically assessed preoperatively and at 2, 6, and 12 months postoperatively. RESULTS: At 12 months postoperatively, there was a statistically significant increase in American Orthopaedic Foot & Ankle Society scores from 31.9 to 72.3. Range of motion significantly increased from 9.5 to 25.4 degrees. In addition, there was a statistically significant decrease in visual analog scale (VAS) pain score from 8.9 to 2.2. Furthermore, there was a significant increase in the Tibio-Talar ratio from 2 to 6 months postoperatively (34.6% 37.2%). CONCLUSIONS: This study demonstrated significant improvements in clinical and radiologic outcomes after Hintegra total ankle arthroplasty. Significant movement of the talus occurs within the first 6 months postoperatively. This may be the result of rebalancing of muscle and ligament forces after surgery. LEVEL OF EVIDENCE: Level IV, case series. PMID- 26443700 TI - Fixed ratio or lower limit of normal for the FEV1 /VC ratio: relation to symptoms and extended lung function tests. AB - There is no general agreement on the spirometric definition of chronic obstructive pulmonary disease (COPD). The global initiative for obstructive lung disease recommends a fixed ratio between forced expiratory volume in one-second (FEV1 ) and forced vital capacity (FVC) of <0.7 (FR) for the diagnosis of COPD. European Respiratory Society and American Thoracic Society favour the use of the fifth percentile of the age-related FEV1 /FVC ratio (the lower limit of normal, LLN). The purpose of this study was to analyse extensive lung function tests in groups of subjects fulfilling none, either or both of the spirometric criteria for COPD. From a previous population-based study, 450 subjects were examined with spirometry, body pletysmography diffusing capacity for CO (DL,CO ), Impulse Oscillometry System (IOS) and answered a questionnaire on respiratory symptoms and diseases. Seventy subjects fulfilled both spirometric COPD criteria (FR+LLN+), 62 subjects the fixed ratio criterion (FR+) only. Of the remaining 318 subjects, 236 were ever smokers (N-ES). Significant differences between all groups were seen for FEV1 and DL,CO . Significant differences between groups were also seen for residual volume (RV) and RV/total lung capacity. For IOS, variables and symptoms increasingly abnormal values were seen from never smokers to FR+LLN+. This study shows that subjects meeting both spirometric COPD criteria frequently have symptoms and findings at extended lung function tests compatible with the diagnosis. Also subjects meeting the fixed ratio criterion only tend to have more symptoms and lung function findings compatible with COPD than ever smoking subjects with FEV1 /VC > 0.7. PMID- 26443701 TI - The rationale for deep brain stimulation in Alzheimer's disease. AB - Alzheimer's disease is a major worldwide health problem with no effective therapy. Deep brain stimulation (DBS) has emerged as a useful therapy for certain movement disorders and is increasingly being investigated for treatment of other neural circuit disorders. Here we review the rationale for investigating DBS as a therapy for Alzheimer's disease. Phase I clinical trials of DBS targeting memory circuits in Alzheimer's disease patients have shown promising results in clinical assessments of cognitive function, neurophysiological tests of cortical glucose metabolism, and neuroanatomical volumetric measurements showing reduced rates of atrophy. These findings have been supported by animal studies, where electrical stimulation of multiple nodes within the memory circuit have shown neuroplasticity through stimulation-enhanced hippocampal neurogenesis and improved performance in memory tasks. The precise mechanisms by which DBS may enhance memory and cognitive functions in Alzheimer's disease patients and the degree of its clinical efficacy continue to be examined in ongoing clinical trials. PMID- 26443702 TI - Putting it all on pigmentation: Heuristics of a bold and stochastic cell fate decision. AB - Gradients of transmembrane potential coordinate cell-fate decisions and patterning during embryogenesis and wound-healing. Bioelectrical signaling may also be more important for adult pathologies than currently recognized. In this issue of Science Signaling, Lobikin et al. describe a role for bioelectric signals during the development of Xenopus leavis embryos to instruct an organism level response reminiscent of neoplastic progression in melanoma. PMID- 26443703 TI - Proteostasis trumps YAP in colon cancer. AB - In this issue of Science Signaling, Zhang et al. find a new role for verteporfin in the control of colorectal cancer progression through the selective induction of proteotoxicity rather than through inhibition of the transcription cofactor YAP. The study further documents the potential strategy of targeting proteostasis to kill cancer cells. PMID- 26443704 TI - The kinases NDR1/2 act downstream of the Hippo homolog MST1 to mediate both egress of thymocytes from the thymus and lymphocyte motility. AB - The serine and threonine kinase MST1 is the mammalian homolog of Hippo. MST1 is a critical mediator of the migration, adhesion, and survival of T cells; however, these functions of MST1 are independent of signaling by its typical effectors, the kinase LATS and the transcriptional coactivator YAP. The kinase NDR1, a member of the same family of kinases as LATS, functions as a tumor suppressor by preventing T cell lymphomagenesis, which suggests that it may play a role in T cell homeostasis. We generated and characterized mice with a T cell-specific double knockout of Ndr1 and Ndr2 (Ndr DKO). Compared with control mice, Ndr DKO mice exhibited a substantial reduction in the number of naive T cells in their secondary lymphoid organs. Mature single-positive thymocytes accumulated in the thymus in Ndr DKO mice. We also found that NDRs acted downstream of MST1 to mediate the egress of mature thymocytes from the thymus, as well as the interstitial migration of naive T cells within popliteal lymph nodes. Together, our findings indicate that the kinases NDR1 and NDR2 function as downstream effectors of MST1 to mediate thymocyte egress and T cell migration. PMID- 26443706 TI - Serotonergic regulation of melanocyte conversion: A bioelectrically regulated network for stochastic all-or-none hyperpigmentation. AB - Experimentally induced depolarization of resting membrane potential in "instructor cells" in Xenopus laevis embryos causes hyperpigmentation in an all or-none fashion in some tadpoles due to excess proliferation and migration of melanocytes. We showed that this stochastic process involved serotonin signaling, adenosine 3',5'-monophosphate (cAMP), and the transcription factors cAMP response element-binding protein (CREB), Sox10, and Slug. Transcriptional microarray analysis of embryos taken at stage 15 (early neurula) and stage 45 (free-swimming tadpole) revealed changes in the abundance of 45 and 517 transcripts, respectively, between control embryos and embryos exposed to the instructor cell depolarizing agent ivermectin. Bioinformatic analysis revealed that the human homologs of some of the differentially regulated genes were associated with cancer, consistent with the induced arborization and invasive behavior of converted melanocytes. We identified a physiological circuit that uses serotonergic signaling between instructor cells, melanotrope cells of the pituitary, and melanocytes to control the proliferation, cell shape, and migration properties of the pigment cell pool. To understand the stochasticity and properties of this multiscale signaling system, we applied a computational machine-learning method that iteratively explored network models to reverse engineer a stochastic dynamic model that recapitulated the frequency of the all or-none hyperpigmentation phenotype produced in response to various pharmacological and molecular genetic manipulations. This computational approach may provide insight into stochastic cellular decision-making that occurs during normal development and pathological conditions, such as cancer. PMID- 26443707 TI - A programme based on repeated hypoxia-hyperoxia exposure and light exercise enhances performance in athletes with overtraining syndrome: a pilot study. AB - Overtraining syndrome (OTS) is a major concern among endurance athletes and is a leading cause in preventing them to perform for long periods. Intermittent exposure to hypoxia has been shown to be an effective way of improving performance without exercising. Aim of this pilot study was to evaluate intermittent hypoxia-hyperoxia training combined with light exercise as an intervention to facilitate athletes with OTS to restore their usual performance level. Thirty-four track and field athletes were recruited: 15 athletes with OTS volunteered to participate and undertook a conditioning programme consisting of repeated exposures to hypoxia (O2 at 10%) and hyperoxia (O2 at 30%) (6-8 cycles, total time 45 min-1 h), three times a week, delivered 1.5-2 h after a low intensity exercise session (2 bouts of 30 min, running at 50% of VO2max with 10 min rest between bouts) over 4 weeks. Nineteen healthy track and field athletes volunteered to participate as a control group and followed their usual training schedule. Measurements before and after the intervention included exercise capacity, analysis of heart rate variability and hematological parameters. In athletes with OTS, a 4-week light exercise combined with intermittent hypoxia hyperoxia training improved exercise performance (191.9 +/- 26.9 W versus 170.8 +/- 44.8 W in exercise capacity test, P = 0.01). Heart rate variability analysis revealed an improved sympatho-parasympathetic index (low frequency/high frequency ratio, 8.01 +/- 7.51 before and 1.45 +/- 1.71 after, P = 0.007). Hematological parameters were unchanged. Our pilot study showed that intermittent hypoxia hyperoxia training and low-intensity exercise can facilitate functional recovery among athletes with OTS in a relatively short time. PMID- 26443705 TI - Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of YAP1. AB - Yes-associated protein 1 (YAP1) is a transcriptional coactivator in the Hippo signaling pathway. Increased YAP1 activity promotes the growth of tumors, including that of colorectal cancer (CRC). Verteporfin, a drug that enhances phototherapy to treat neovascular macular degeneration, is an inhibitor of YAP1. We found that verteporfin inhibited tumor growth independently of its effects on YAP1 or the related protein TAZ in genetically or chemically induced mouse models of CRC, in patient-derived xenografts, and in enteroid models of CRC. Instead, verteporfin exhibited in vivo selectivity for killing tumor cells in part by impairing the global clearance of high-molecular weight oligomerized proteins, particularly p62 (a sequestrome involved in autophagy) and STAT3 (signal transducer and activator of transcription 3; a transcription factor). Verteporfin inhibited cytokine-induced STAT3 activity and cell proliferation and reduced the viability of cultured CRC cells. Although verteporfin accumulated to a greater extent in normal cells than in tumor cells in vivo, experiments with cultured cells indicated that the normal cells efficiently cleared verteporfin-induced protein oligomers through autophagic and proteasomal pathways. Culturing CRC cells under hypoxic or nutrient-deprived conditions (modeling a typical CRC microenvironment) impaired the clearance of protein oligomers and resulted in cell death, whereas culturing cells under normoxic or glucose-replete conditions protected cell viability and proliferation in the presence of verteporfin. Furthermore, verteporfin suppressed the proliferation of other cancer cell lines even in the absence of YAP1, suggesting that verteporfin may be effective against multiple types of solid cancers. PMID- 26443708 TI - Robot-assisted laparoscopic (RAL) procedures in general surgery. AB - BACKGROUND: Robotics was introduced in clinical practice more than two decades ago, and it has gained remarkable popularity for a wide variety of laparoscopic procedures. We report our results of robot-assisted laparoscopic surgery (RALS) in the most commonly applied general surgical procedures. METHOD: Ninety seven patients underwent RALS from 2009 to 2012. Indications for RALS were cholelithiasis, gastric carcinoma, splenic tumors, colorectal carcinoma, benign colorectal diseases, non-toxic nodular goiter and incisional hernia. Records of patients were analyzed for demographic features, intraoperative and postoperative complications and conversion to open surgery. RESULTS: Forty six female and 51 male patients were operated and mean age was 58,4 (range: 25-88). Ninety three out of 97 procedures (96%) were completed robotically, 4 were converted to open surgery and there were 15 postoperative complications. There was no mortality. CONCLUSION: Wide variety of procedures of general surgery can be managed safely and effectively by RALS. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26443710 TI - Ninety-six hours ordeal of priapism induced by paroxetine--A case report and literature review. AB - Priapism is a rare but severe medical condition of sustained and painful erection of penis in the absence of any sexual stimulation, in which the penis does not return to a flaccid state. It is considered to be a medical emergency because without treatment it can lead to permanent damage and fibrosis of penis and in the long run to impotency. Albeit that there is no uniform consensus regarding the duration of sustained erection, an erection lasting more than 4 h is generally considered as an emergency which needs immediate medical attention and care. Priapism is commonly associated with iatrogenic, pharmacologic, underlying medical, or traumatic causes. In this report, we present the case of a 42-year old African American man who developed priapism after three weeks of therapy with paroxetine which lasted for more than 96 h before coming to the attention of his health-care providers. This case is unique in that there are no reports in literature of an erection lasting for such a long duration following therapy with paroxetine. The objective of this report is to highlight the importance of recognizing the possibility of priapism with selective serotonin reuptake inhibitors in general and paroxetine in particular since this condition is not commonly seen in clinical practice to be associated with selective serotonin reuptake inhibitors and may go unrecognized. Also, potential biological mechanisms involved in the development of paroxetine-induced priapism are presented. PMID- 26443709 TI - Efficacy of four preventive measures against enamel demineralization at the bracket periphery-comparison of microhardness and confocal laser microscopy analysis. AB - OBJECTIVES: The aim of this in-vitro study was to investigate the efficacy of four preventive measures against enamel demineralization and to compare the suitability of microhardness (MH) measurements and confocal laser microscopy (CLSM). MATERIALS AND METHODS: A total of 80 teeth were randomly allocated into four groups. The effect against demineralization of two coating materials (group 1: resin-modified glass ionomer (RMGI) cement varnish (ClinproXT); group 2: composite sealant (ProSeal)) and that of two types of bracket-bonding material (group 3: amorphous calcium phosphate (ACP) composite (AegisOrtho); group 4: RMGI (FujiOrthoLC)) was compared after pH-cycling by MH and CLSM. Measurements were made at the edge of the coating/bracket as well as at 50, 100, 200, and 400 MUm distance. The data were converted into values of mineralization (Vol%) and analyzed by parametric (ANOVA and Tukey's post hoc) or non-parametric (Kruskal Wallis and Games-Howell post hoc) tests. RESULTS: ClinproXT and ProSeal were proved to protect the bracket periphery. However, the area next to them showed demineralizations. The mean area of lesion (CLSM-data) was significantly different between the groups (p < 0.0001). The smallest lesions were revealed for the RMGI-based materials. MH identified only for group 4 a significant difference between the area next to the bracket base and that at 200 and 400 um distance. CONCLUSION: There was nearly no lesion under both coatings. A stagnation of demineralization was identified particularly for the RMGI. ProSeal showed an inferior protection of the untreated enamel. MH and CLSM analysis were suitable to detect subsurface lesions. CLINICAL RELEVANCE: A diverse efficacy of materials against enamel demineralization at bracket periphery has to be noticed. PMID- 26443711 TI - Effectiveness of long-acting risperidone in a patient with comorbid intellectual disability, catatonic schizophrenia, and oneiroid syndrome. AB - A patient with comorbid intellectual disability, catatonic schizophrenia, and recurrent oneiroid state of consciousness improved on long-acting risperidone and remains well at the three-year follow-up. We report a case treated with 50 mg long-acting risperidone administered every 14 days, who has been followed-up for three years. We studied his regional cerebral blood flow through technetium-99 m hexamethylpropyleneamine oxime single-photon emission computed tomography after two years of treatment. Symptoms of catatonic schizophrenia improved after two months of treatment, followed suit by oneiroid syndrome remission. Two years later, his brain perfusion was normal. No side effect has occurred since the patient was started on long-acting risperidone. Long-acting risperidone proved to be safe and effective in treating symptoms of catatonia and oneiroid syndrome. PMID- 26443712 TI - Joint kinematics of surgeons during lumbar pedicle screw placement. AB - BACKGROUND: A surgical robot for spine surgery has recently been developed. The objective is to assess the joint kinematics of the surgeon during spine surgery. METHODS: We enrolled 18 spine surgeons, who each performed pedicle screw placement, and used an optoelectronic motion analysis system. Using three dimensional (3D) motion images, distance changes in five joints and angle changes in six joints were calculated during surgery. RESULTS: Distance fluctuations increased gradually from the proximal to the distal joint. Angle fluctuations were largest at the distal point but did not gradually increase, and the elbow showed the second largest fluctuation. Changes along the X axis were larger than those of the Y and Z axes. CONCLUSION: The distances gradually increased from proximal portions of the body to the hand. In angle changes, the elbow was most dynamic during pedicle screw placement. The surgeons' whole joints carry out a harmonic role during lumbar pedicle screw placement. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26443713 TI - Superior vena cava syndrome due to isolated intrapulmonary Castleman's disease. PMID- 26443714 TI - Intrauterine exposure to bisphenol A promotes different effects in both neonatal and adult prostate of male and female gerbils (Meriones unguiculatus). AB - Substances that mimic endogenous hormones may alter the cell signaling that govern prostate development and predispose it to developing lesions in adult and senile life. Bisphenol A is able to mimic estrogens, and studies have demonstrated that low levels of exposure to this compound have caused alterations during prostate development. The aim of this study was to describe the prostate development in both male and female neonatal gerbils in normal conditions and under exposure to BPA during intrauterine life, and also to analyze whether the effects of intrauterine exposure to BPA remain in adulthood. Morphological, stereological, three-dimensional reconstruction, and immunohistochemical methods were employed. The results demonstrated that in 1-day-old normal gerbils, the female paraurethral glands and the male ventral lobe are morphologically similar, although its tissue components-epithelial buds (EB), periurethral mesenchyme (PeM), paraurethral mesenchyme (PaM) or ventral mesenchymal pad (VMP), and smooth muscle (SM)-have presented different immunolabeling pattern for androgen receptor (AR), and for proliferating cell nuclear antigen (PCNA). Moreover, we observed a differential response of male and female prostate to intrauterine BPA exposure. In 1-day-old males, the intrauterine exposure to BPA caused a decrease of AR positive cells in the PeM and SM, and a decrease of the proliferative status in the EB. In contrast, no morphological alterations were observed in ventral prostate of adult males. In 1-day-old females, BPA exposure promoted an increase of estrogen receptor alpha (ERalpha) positive cells in PeM and PaM, a decrease of AR-positive cells in EB and PeM, besides a reduction of cell proliferation in EB. Additionally, the adult female prostate of BPA-exposed animals presented an increase of AR- and PCNA-positive cells. These results suggest that the prostate of female gerbils were more susceptible to the intrauterine BPA effects, since they became more proliferative in adult life. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1740-1750, 2016. PMID- 26443715 TI - Epigenetics in Legg-Calve-Perthes disease: A study of global DNA methylation. AB - OBJECTIVE: To examine the global methylation status of DNA in blood cells of children with Legg-Calve-Perthes disease (LCPD), since the aetiopathogenesis of LCPD remains unclear, and many factors closely associated with DNA methylation may be linked to the occurrence of LCPD. METHODS: Children with LCPD and age-, sex- and body mass index-matched controls were evaluated. Methylation levels of the long interspersed nuclear element 1 (LINE-1), a biomarker of global DNA methylation, were quantified by methylation-specific polymerase chain reaction. RESULTS: Of 82 children with LCPD (68 male/14 female) and 120 matched controls (98 male/22 female), methylation of the LINE-1 promoter was significantly lower in patients with LCPD compared with controls. Subgroup analyses showed that methylation of the LINE-1 promoter was significantly lower in male patients with LCPD compared with male controls. No significant between-group differences were observed in female participants. CONCLUSIONS: Reduced global DNA methylation may be associated with increased risk of LCPD in male children. Further research is required to understand whether detection of global DNA methylation may provide a basis for clinical diagnosis and early intervention of LCPD. PMID- 26443716 TI - Antenatal depression in coastal South India: Prevalence and risk factors in the community. AB - BACKGROUND: Antenatal depression is a highly prevalent disorder with serious implications on maternal and child outcomes. There are few studies examining this in low-middle-income community settings. AIMS: To determine the prevalence of antenatal depression in women from a coastal rural background in Kerala and Tamil Nadu and to determine its associated factors. MATERIALS AND METHODS: In this cross-sectional community-based study, in 202 antenatal women, standard interview and diagnostic criteria (Clinical Interview Schedule-Revised (CIS-R)) were employed for identifying depression and examining a wide range of putative clinical and sociocultural risk factors including domestic violence. RESULTS: There was a 16.3% prevalence of depression among the 202 women sampled. The possible risk factors after stepwise backward regression were pressure to have a male child, 11.48 (2.36-55.78); financial difficulties, 8.23 (2.49-27.22); non arranged marriage, 6.05 (1.72-21.23); history of miscarriage-still birth, 5.77 (1.55-21.43) and marital conflict, 9.55 (2.34-38.98). CONCLUSION: There is a need to develop strategies for recognition and appropriate intervention for antenatal depression, in the context of locally relevant risk factors, so as to improve both maternal and child outcomes. PMID- 26443717 TI - How Do Hospital Palliative Care Teams Use the WHO Guidelines to Manage Unrelieved Cancer Pain? A 1-Year, Multicenter Audit in Japan. AB - It has been reported that pain relief for patients with cancer is suboptimal in Japan. This has been mainly attributed to inadequate dissemination of the World Health Organization (WHO) guidelines for cancer pain management. To better understand this problem, we reviewed how 6 hospital palliative care teams (HPCTs) used the WHO guidelines for unrelieved pain in a 1-year audit that included 534 patients. The HPCT interventions were classified according to the contents of the WHO guidelines. In our study, HPCT interventions involved opioid prescriptions in >80% of referred patients, and "For the Individual" and "Attention to Detail" were the 2 most important principles. Our study indicates which parts of the WHO guidelines should be most heavily emphasized, when disseminating them in Japan. PMID- 26443718 TI - Pediatrician Ambiguity in Understanding Palliative Sedation at the End of Life. AB - CONTEXT: Palliative sedation is a means of relieving intractable symptoms at the end of life, however, guidelines about its use lack consistency. In addition, ethical concerns persist around the practice. There are reports of palliative sedation in the pediatric literature, which highlight various institutional perspectives. OBJECTIVES: This survey of 4786 pediatric providers sought to describe their knowledge of and current practices around pediatric palliative sedation. METHODS: Our survey was administered to pediatricians who care for children at the end of life. The survey assessed agreement with a definition of palliative sedation, as well as thoughts about its alignment with aggressive symptom management. Bivariate analyses using chi2 and analysis of variance were calculated to determine the relationship between responses to closed-ended questions. Open-ended responses were thematically coded by the investigators and reviewed for agreement. RESULTS: Nearly half (48.6%) of the respondents indicated that the stated definition of palliative sedation "completely" reflected their own views. Respondents were split when asked if they viewed any difference between palliative sedation and aggressive symptom management: Yes (46%) versus No (54%). Open-ended responses revealed specifics about the nature of variation in interpretation. CONCLUSIONS: Responses point to ambiguity surrounding the concept of palliative sedation. Pediatricians were concerned with a decreased level of consciousness as the goal of palliative sedation. Respondents were split on whether they view palliative sedation as a distinct entity or as one broad continuum of care, equivalent to aggressive symptom management. Institutional based policies are essential to clarify acceptable practice, enable open communication, and promote further research. PMID- 26443719 TI - Prevalence and Gender Differences of ODD, Anxiety, and Depression in a Sample of Children With ADHD. AB - OBJECTIVE: Studies on comorbidity in children diagnosed with ADHD have relied more on parent/teacher reports instead of self-reported data and have focused on the frequency of comorbid symptoms instead of scores above clinical cutoffs. The purpose of this study was to examine the prevalence of oppositional defiant disorder (ODD), anxiety, and depression in children with ADHD, using self-report measures for internalizing symptoms and parent-reported measures for externalizing symptoms for increased accuracy. Gender differences were also assessed. METHOD: Parents of 197 children diagnosed with ADHD answered the Disruptive Behavior Rating Scale, and 112 of the children filled out the Multidimensional Anxiety Scale for Children and the Children's Depression Inventory. RESULTS: Results revealed that 19.28% of the children met cut-off criteria for ODD, 41.96% for anxiety, and 21.43% for depression. CONCLUSION: Our findings indicate a relatively lower prevalence of ODD and a slightly higher prevalence of anxiety symptoms than previously reported. Possible explanations and future directions are discussed. PMID- 26443720 TI - Radiation-Induced Thyroid Cancer: Gender-Related Disease Characteristics and Survival. AB - BACKGROUND: Radiation exposure is a well-known risk factor for well differentiated thyroid cancer (WDTC). However, gender disparity in disease characteristics is not completely understood. The purpose of this study was to determine the behavior of radiation-induced thyroid cancer according to gender. METHODS: Charts of all patients diagnosed with WDTC after radiation exposure between the years 1985 and 2013 in a tertiary referral center were retrieved. RESULTS: Forty-three patients were reviewed, 29 females and 14 males. Mean age of exposure for women and men were 17.1 +/- 19.5 and 15.5 +/- 12.5 years, respectively (P = .78). Age at diagnosis were 47.5 +/- 15.5 and 41.5 +/- 15 years for women and men, respectively (P = .18). Mean disease-specific survival was 44.1 and 43.7 years for women and men, respectively (P = .50). CONCLUSIONS: Similar disease characteristics, tumor pathology, disease-free survival, and overall survival in both genders. In sporadic well-differentiated thyroid carcinoma, female gender is associated with better tumor behavior and prognosis. However, our results suggest that women are more affected by radiation than men and therefore have the same prognosis as men. PMID- 26443721 TI - The P2RY2 Receptor Induces Carcinoma Cell Migration and EMT Through Cross-Talk With Epidermal Growth Factor Receptor. AB - Extracellular nucleotides are signaling elements present in the tumor microenvironment; however, their role in tumor growth is not completely understood. In the present study, we asked whether nucleotides regulate cell migration in ovarian carcinoma-derived cells. We observed that 100 MUM UTP induced migration in SKOV-3 cells (1.57 +/- 0.08 fold over basal), and RT-PCR showed expression of transcripts for the P2RY2 and P2RY4 receptors. Knockdown of P2RY2 expression in SKOV-3 cells (P2RY2-KD) abolished the UTP-induced migration. The mechanism activated by UTP to induce migration involves transactivation of the epidermal growth factor receptor (EGFR) since we observed that the EGFR kinase inhibitor AG1478 and the PI3K inhibitor Wortmannin inhibit this response (to 0.76 +/- 0.23 and 0.46 +/- 0.14 relative to the control, respectively). In agreement with these observations, UTP was able to modify the phosphorylation state of the EGFR; likewise, the induction of ERK1/2 phosphorylation promoted by UTP was abolished by a 30-60 min treatment with AG1478. Our data also suggested that the enhanced cell migration involves the epithelium to mesenchymal transition (EMT) process, since a 12 h stimulation of SKOV-3 cells with 100 MUM UTP showed an increase in vimentin and SNAIL protein levels (459.8 +/- 132.4% over basal for SNAIL). Interestingly, treatment with apyrase (10 U/mL) reduces the migration of control cells and induces a considerable enrichment of E cadherin in the cell-cell contacts, favoring an epithelial phenotype and strongly suggesting that the nucleotides released by tumor cells and acting through the P2RY2 receptor are potential regulators of invasiveness. PMID- 26443723 TI - Magnesium Transport and Magnesium Homeostasis. AB - This review reviews the properties and regulation of the Salmonella enterica serovar Typhimurium and Escherichia coli transporters that mediate Mg2+ influx: CorA and the Mgt P-type ATPases. In addition, potential Mg2+ regulation of transcription and translation, largely via the PhoPQ two component system, is discussed. CorA proteins are a unique class of transporters and are widespread in the Bacteria and Archaea, with rather distant but functional homologs in eukaryotes. The Mgt transporters are highly homologous to other P-type ATPases but are more closely related to the eukaryotic H+ and Ca2+ ATPases than to most prokaryotic ATPases. Hundreds of homologs of CorA are currently known from genomic sequencing. In contrast, only when extracellular and possibly intracellular Mg2+ levels fall significantly is the expression of mgtA and mgtB induced. Topology studies using blaM and lacZ fusions initially indicated that the Salmonella serovar Typhimurium CorA contained three transmembrane (TM) segments; however, subsequent data obtained using a variety of approaches showed that the CorA superfamily of proteins have only two TMs at the extreme C terminus. PhoP-PhoQ is a two-component system consisting of PhoQ, the sensor/receptor histidine kinase, and PhoP, the response regulator/transcriptional activator. The expression of both mgtA and mgtCB in either E. coli or Salmonella serovar Typhimurium is markedly induced in a PhoPQ dependent manner by low concentrations of Mg2+ in the medium. phoP and phoQ form an operon with two promoters in both E. coli and Salmonella serovar Typhimurium. PMID- 26443724 TI - Undecaprenyl Phosphate Synthesis. AB - Undecaprenyl phosphate (C55-P) is an essential 55-carbon long-chain isoprene lipidinvolved in the biogenesis of bacterial cell wall carbohydrate polymers: peptidoglycan, O antigen, teichoic acids, and other cell surface polymers. It functions as a lipid carrier that allows the traffic of sugar intermediates across the plasma membrane, towards the periplasm,where the polymerization of the different cellwall components occurs. At the end of these processes, the lipid is released in a pyrophosphate form (C55-PP). C55-P arises from the dephosphorylation of C55-PP, which itself originates from either a recycling event or a de novo synthesis. In Escherichia coli, the formation of C55-PP is catalyzed by the essential UppS synthase, a soluble cis-prenyltransferase, whichadds eight isoprene units ontofarnesyl pyrophosphate. Severalapo- and halo UppSthree-dimensional structures have provided a high level of understanding of this enzymatic step. The following dephosphorylationstep is required before the lipid carrier can accept a sugar unit at the cytoplasmic face of the membrane. Four integralmembrane proteins have been shown to catalyzethis reaction in E. coli:BacA and three members of the PAP2 super-family:YbjG, LpxT, and PgpB. None of these enzymes is essential,but the simultaneous inactivation of bacA, ybjG, and pgpB genes gave rise to a lethal phenotype, raising the question of the relevance of such a redundancy of activity. It was alsorecently shown that LpxTcatalyzes the specific transfer of the phosphate group arising from C55-PP to the lipidA moiety of lipopolysaccharides, leading to a lipid-A 1-diphosphate form whichaccounts for one-third of the total lipidA in wild-type E. coli cells. The active sites of LpxT, PgpB,andYbjG were shown to face the periplasm, suggesting that PAP2 enzymes arerather involved in C55-PP recycling. These recent discoveries have opened the way to the elucidation of the functional and structural characterization of these different phosphatases. PMID- 26443725 TI - Antibiotic Resistance Mechanisms, with an Emphasis on Those Related to the Ribosome. AB - Antibiotic resistance is a fundamental aspect of microbiology, but it is also a phenomenon of vital importance in the treatment of diseases caused by pathogenic microorganisms. A resistance mechanism can involve an inherent trait or the acquisition of a new characteristic through either mutation or horizontal gene transfer. The natural susceptibilities of bacteria to a certain drug vary significantly from one species of bacteria to another and even from one strain to another. Once inside the cell, most antibiotics affect all bacteria similarly. The ribosome is a major site of antibiotic action and is targeted by a large and chemically diverse group of antibiotics. A number of these antibiotics have important applications in human and veterinary medicine in the treatment of bacterial infections. The antibiotic binding sites are clustered at functional centers of the ribosome, such as the decoding center, the peptidyl transferase center, the GTPase center, the peptide exit tunnel, and the subunit interface spanning both subunits on the ribosome. Upon binding, the drugs interfere with the positioning and movement of substrates, products, and ribosomal components that are essential for protein synthesis. Ribosomal antibiotic resistance is due to the alteration of the antibiotic binding sites through either mutation or methylation. Our knowledge of antibiotic resistance mechanisms has increased, in particular due to the elucidation of the detailed structures of antibiotic ribosome complexes and the components of the efflux systems. A number of mutations and methyltransferases conferring antibiotic resistance have been characterized. These developments are important for understanding and approaching the problems associated with antibiotic resistance, including design of antimicrobials that are impervious to known bacterial resistance mechanisms. PMID- 26443726 TI - Peptidoglycan Recycling. AB - Peptidoglycan (PG) recycling allows Escherichia coli to reuse the massive amounts of sacculus components that are released during elongation. Goodell and Schwarz, in 1985, labeled E. coli cells with 3H-diaminopimelic acid (DAP) and chased. During the chase, the DAP pool dropped dramatically, whereas the precursor pool dropped only slightly. This could only occur if DAP from the sacculi was being used to produce more precursor. They calculated that the cells were recycling about 45% of their wall DAP (actually, 60% of the side walls, since the poles are stable). Thus, recycling was discovered. Goodell went on to show that the tripeptide, L-Ala-D-Glu-DAP, could be taken up via opp and used directly to form PG. It was subsequently shown that uptake was predominantly via a permease, AmpG, that was specific for GlcNAc-anhMurNAc with attached peptides. Eleven genes have been identified which appear to have as their sole function the recovery of degradation products from PG. PG represents only 2.5% of the cell mass, so the reason for this investment in recycling is obscure. Recycling enzymes exist that are specific for every bond in the principal product taken up by AmpG, namely, GlcNAc-anh-MurNAc-tetrapeptide. However, most of the tripeptide, L-Ala-D-Glu-DAP, is used by murein peptide ligase (Mpl) to form the precursor intermediate UDP MurNAc-tripeptide. anh-MurNAc can be converted to GlcNAc by a two-step process and thus is available for use. Surprisingly, in the absence of AmpD, an enzyme that cleaves the anh-MurNAc-L-Ala bond, anh-MurNAc-tripeptide accumulates, resulting in induction of beta-lactamase. However, this has nothing to do with the induction of beta-lactamase by beta-lactam antibiotics. Uehara, Suefuji, and Park (unpublished data) have some evidence suggesting that murein pentapeptide may be involved. The presence of orthologs suggests that recycling also exists in many Gram-negative bacteria. Surprisingly, the ortholog search also revealed that all mammals may have an AmpG ortholog! Hence, mammalian AmpG may be involved in the process of innate immunity. PMID- 26443722 TI - Protein and small non-coding RNA-enriched extracellular vesicles are released by the pathogenic blood fluke Schistosoma mansoni. AB - BACKGROUND: Penetration of skin, migration through tissues and establishment of long-lived intravascular partners require Schistosoma parasites to successfully manipulate definitive host defences. While previous studies of larval schistosomula have postulated a function for excreted/secreted (E/S) products in initiating these host-modulatory events, the role of extracellular vesicles (EVs) has yet to be considered. Here, using preparatory ultracentrifugation as well as methodologies to globally analyse both proteins and small non-coding RNAs (sncRNAs), we conducted the first characterization of Schistosoma mansoni schistosomula EVs and their potential host-regulatory cargos. RESULTS: Transmission electron microscopy analysis of EVs isolated from schistosomula in vitro cultures revealed the presence of numerous, 30-100 nm sized exosome-like vesicles. Proteomic analysis of these vesicles revealed a core set of 109 proteins, including homologs to those previously found enriched in other eukaryotic EVs, as well as hypothetical proteins of high abundance and currently unknown function. Characterization of E/S sncRNAs found within and outside of schistosomula EVs additionally identified the presence of potential gene regulatory miRNAs (35 known and 170 potentially novel miRNAs) and tRNA-derived small RNAs (tsRNAs; nineteen 5' tsRNAs and fourteen 3' tsRNAs). CONCLUSIONS: The identification of S. mansoni EVs and the combinatorial protein/sncRNA characterization of their cargo signifies that an important new participant in the complex biology underpinning schistosome/host interactions has now been discovered. Further work defining the role of these schistosomula EVs and the function/stability of intra- and extra-vesicular sncRNA components presents tremendous opportunities for developing novel schistosomiasis diagnostics or interventions. PMID- 26443727 TI - Modification of the Ribosome and the Translational Machinery during Reduced Growth Due to Environmental Stress. AB - Escherichia coli strains normally used under laboratory conditions have been selected for maximum growth rates and require maximum translation efficiency. Recent studies have shed light on the structural and functional changes undergone by the translational machinery in E. coli during heat and cold shock and upon entry into stationary phase. In these situations both the composition and the partitioning of this machinery into the different pools of cellular ribosomes are modified. As a result, the translational capacity of the cell is dramatically altered. This review provides a comprehensive account of these modifications, regardless of whether or not their underlying mechanisms and their effects on cellular physiology are known. Not only is the composition of the ribosome modified upon entry into stationary phase, but the modification of other components of the translational machinery, such as elongation factor Tu (EFTu) and tRNAs, has also been observed. Hibernation-promoting factor (HPF), paralog protein Y (PY), and ribosome modulation factor (RMF) may also be related to the general protection against environmental stress observed in stationary-phase E. coli cells, a role that would not be revealed necessarily by the viability assays. Even for the best-characterized ribosome-associated factors induced under stress (RMF, PY, and initiation factors), we are far from a complete understanding of their modes of action. PMID- 26443728 TI - Biosynthesis and Use of Cobalamin (B12). AB - This review summarizes research performed over the last 23 years on the genetics, enzyme structures and functions, and regulation of the expression of the genes encoding functions involved in adenosylcobalamin (AdoCbl, or coenzyme B12) biosynthesis. It also discusses the role of coenzyme B12 in the physiology of Salmonella enterica serovar Typhimurium LT2 and Escherichia coli. John Roth's seminal contributions to the field of coenzyme B12 biosynthesis research brought the power of classical and molecular genetic, biochemical, and structural approaches to bear on the extremely challenging problem of dissecting the steps of what has turned out to be one of the most complex biosynthetic pathways known. In E. coli and serovar Typhimurium, uro'gen III represents the first branch point in the pathway, where the routes for cobalamin and siroheme synthesis diverge from that for heme synthesis. The cobalamin biosynthetic pathway in P. denitrificans was the first to be elucidated, but it was soon realized that there are at least two routes for cobalamin biosynthesis, representing aerobic and anaerobic variations. The expression of the AdoCbl biosynthetic operon is complex and is modulated at different levels. At the transcriptional level, a sensor response regulator protein activates the transcription of the operon in response to 1,2-Pdl in the environment. Serovar Typhimurium and E. coli use ethanolamine as a source of carbon, nitrogen, and energy. In addition, and unlike E. coli, serovar Typhimurium can also grow on 1,2-Pdl as the sole source of carbon and energy. PMID- 26443729 TI - Amino Acid Metabolism and Fluxes. AB - By the mid1960s, the pioneering work of Umbarger and Gerhart and Pardee had shown us that carbon flow through a biosynthetic pathway was controlled by allosteric inhibition of the first enzyme of the pathway by its end product; and, studies of the lac operon by Jacob and Monod had established that genes were controlled by an operator-repressor mechanism. During the intervening forty-plus years, knowledge and technologies have continued to explode in unanticipated ways. Today, we understand in great detail the molecular mechanisms of the many levels of metabolic and genetic regulation that control carbon flow through the amino acid biosynthetic pathways. Traditional experimental approaches are not sufficient for the integration and reconstruction of complex biological systems using data mostly generated by high-throughput experiments. Only with computational methods and adequate modeling tools will we be able to reconstruct and query these large and complicated systems. Due to complicated enzyme reaction mechanisms and the frequent lack of rate constant measurements needed for solving differential equations, most investigators have turned their attention to the development of abstract, top-down modeling tools. For example, Palsson and colleagues have used metabolic flux balance analysis (FBA) methods to simulate steady-state metabolite flux through E. coli pathways representing hundreds of enzyme steps. Recently, Yang et al. have developed a bottom-up, enzyme mechanism modeling language, kMech (kinetic mechanism), for the mathematical simulation of metabolic pathways. PMID- 26443730 TI - Nus Factors of Escherichia coli. AB - The Nus factors-NusA, NusB, NusE, and NusG-area set of well-conserved proteins in bacteria and are involved in transcription elongation, termination, antitermination, and translation processes. Originally, Escherichia coli host mutations defective for supporting bacteriophage lambda N-mediated antitermination were mapped to the nusA (nusA1), nusB (nusB5, nusB101), and nusE (nusE71) genes, and hence, these genes were named nus for Nutilization substances (Nus). Subsequently,the Nus factors were purified and their roles in different host functions were elucidated. Except for NusB, deletion of which is conditionally lethal, all the other Nus factors are essential for E. coli. Among the Nus factors, NusA has the most varied functions. It specifically binds to RNA polymerase (RNAP), nascent RNA, and antiterminator proteins like N and Q and hence takes part in modulating transcription elongation, termination, and antitermination. It is also involved in DNA repair pathways. NusG interacts with RNAP and the transcription termination factor Rho and therefore is involved in both factor-dependent termination and transcription elongation processes. NusB and NusE are mostly important in antitermination at the ribosomal operon transcription. NusE is a component of ribosome and may take part in facilitating the coupling between transcription and translation. This chapter emphasizes the structure-function relationship of these factors and their involvement in different fundamental cellular processes from a mechanistic angle. PMID- 26443731 TI - Respiration of Nitrate and Nitrite. AB - Nitrate reduction to ammonia via nitrite occurs widely as an anabolic process through which bacteria, archaea, and plants can assimilate nitrate into cellular biomass. Escherichia coli and related enteric bacteria can couple the eight electron reduction of nitrate to ammonium to growth by coupling the nitrate and nitrite reductases involved to energy-conserving respiratory electron transport systems. In global terms, the respiratory reduction of nitrate to ammonium dominates nitrate and nitrite reduction in many electron-rich environments such as anoxic marine sediments and sulfide-rich thermal vents, the human gastrointestinal tract, and the bodies of warm-blooded animals. This review reviews the regulation and enzymology of this process in E. coli and, where relevant detail is available, also in Salmonella and draws comparisons with and implications for the process in other bacteria where it is pertinent to do so. Fatty acids may be present in high levels in many of the natural environments of E. coli and Salmonella in which oxygen is limited but nitrate is available to support respiration. In E. coli, nitrate reduction in the periplasm involves the products of two seven-gene operons, napFDAGHBC, encoding the periplasmic nitrate reductase, and nrfABCDEFG, encoding the periplasmic nitrite reductase. No bacterium has yet been shown to couple a periplasmic nitrate reductase solely to the cytoplasmic nitrite reductase NirB. The cytoplasmic pathway for nitrate reduction to ammonia is restricted almost exclusively to a few groups of facultative anaerobic bacteria that encounter high concentrations of environmental nitrate. PMID- 26443732 TI - Assembly of the 30S Ribosomal Subunit. AB - Protein synthesis involves nearly a third of the total molecules in a typical bacterial cell. Within the cell, protein synthesis is performed by the ribosomes, and research over several decades has investigated ribosomal formation, structure, and function. This review provides an overview of the current understanding of the assembly of the Escherichia coli 30S ribosomal subunit. The E. coli 30S subunit contains one rRNA molecule (16S) and 21 ribosomal proteins (r proteins; S1 to S21). The formation of functional subunits can occur as a self assembly process in vitro; i.e., all the information required for the formation of active ribosomes resides in the primary sequences of the r-proteins and rRNAs. In vitro reconstitution of functional 30S subunits is carried out by using a mixture of TP30, individually purified natural or recombinant r-proteins, and natural 16S rRNA. Chemical probing and primer extension analysis have been used extensively to monitor changes in the reactivities of nucleotides in 16S rRNA during the in vitro reconstitution of 30S subunits. The potential roles for r proteins in 30S subunit assembly were determined by omitting single proteins in reconstitution experiments. The RNPs resulting from single protein omissions were examined in terms of their composition and function to determine the roles of the absent proteins. Recent developments in understanding the structure of the 30S subunit have led to speculation about roles for some of the r-proteins in assembly. The crystal structures of the 30S subunit (1, 2) and the 70S ribosome (3) reveal details of the r-protein and rRNA interactions. PMID- 26443733 TI - The Cold Shock Response. AB - This review focuses on the cold shock response of Escherichia coli. Change in temperature is one of the most common stresses that an organism encounters in nature. Temperature downshift affects the cell on various levels: (i) decrease in the membrane fluidity; (ii) stabilization of the secondary structures of RNA and DNA; (iii) slow or inefficient protein folding; (iv) reduced ribosome function, affecting translation of non-cold shock proteins; (v) increased negative supercoiling of DNA; and (vi) accumulation of various sugars. Cold shock proteins and certain sugars play a key role in dealing with the initial detrimental effect of cold shock and maintaining the continued growth of the organism at low temperature. CspA is the major cold shock protein of E. coli, and its homologues are found to be widespread among bacteria, including psychrophilic, psychrotrophic, mesophilic, and thermophilic bacteria, but are not found in archaea or cyanobacteria. Significant, albeit transient, stabilization of the cspA mRNA immediately following temperature downshift is mainly responsible for its cold shock induction. Various approaches were used in studies to detect cold shock induction of cspA mRNA. Sugars are shown to confer protection to cells undergoing cold shock. The study of the cold shock response has implications in basic and health-related research as well as in commercial applications. The cold shock response is elicited by all types of bacteria and affects these bacteria at various levels, such as cell membrane, transcription, translation, and metabolism. PMID- 26443734 TI - Nucleotides, Nucleosides, and Nucleobases. AB - We review literature on the metabolism of ribo- and deoxyribonucleotides, nucleosides, and nucleobases in Escherichia coli and Salmonella,including biosynthesis, degradation, interconversion, and transport. Emphasis is placed on enzymology and regulation of the pathways, at both the level of gene expression and the control of enzyme activity. The paper begins with an overview of the reactions that form and break the N-glycosyl bond, which binds the nucleobase to the ribosyl moiety in nucleotides and nucleosides, and the enzymes involved in the interconversion of the different phosphorylated states of the nucleotides. Next, the de novo pathways for purine and pyrimidine nucleotide biosynthesis are discussed in detail.Finally, the conversion of nucleosides and nucleobases to nucleotides, i.e.,the salvage reactions, are described. The formation of deoxyribonucleotides is discussed, with emphasis on ribonucleotidereductase and pathways involved in fomation of dUMP. At the end, we discuss transport systems for nucleosides and nucleobases and also pathways for breakdown of the nucleobases. PMID- 26443735 TI - From Iron and Cysteine to Iron-Sulfur Clusters: the Biogenesis Protein Machineries. AB - This review describes the two main systems, namely the Isc (iron-sulfur cluster) and Suf (sulfur assimilation) systems, utilized by Escherichia coli and Salmonella for the biosynthesis of iron-sulfur (Fe-S) clusters, as well as other proteins presumably participating in this process. In the case of Fe-S cluster biosynthesis, it is assumed that the sulfur atoms from the cysteine desulfurase end up at cysteine residues of the scaffold protein, presumably waiting for iron atoms for cluster assembly. The review discusses the various potential iron donor proteins. For in vitro experiments, in general, ferrous salts are used during the assembly of Fe-S clusters, even though this approach is unlikely to reflect the physiological conditions. The fact that sulfur atoms can be directly transferred from cysteine desulfurases to scaffold proteins supports a mechanism in which the latter bind sulfur atoms first and iron atoms afterwards. In E. coli, fdx gene inactivation results in a reduced growth rate and reduced Fe-S enzyme activities. Interestingly, the SufE structure resembles that of IscU, strengthening the notion that the two proteins share the property of acting as acceptors of sulfur atoms provided by cysteine desulfurases. Several other factors have been suggested to participate in cluster assembly and repair in E. coli and Salmonella. Most of them were identified by their abilities to act as extragenic and/or multicopy suppressors of mutations in Fe-S cluster metabolism, while others possess biochemical properties that are consistent with a role in Fe-S cluster biogenesis. PMID- 26443736 TI - The Aerobic and Anaerobic Respiratory Chain of Escherichia coli and Salmonella enterica: Enzymes and Energetics. AB - Escherichia coli contains a versatile respiratory chain which oxidizes ten different electron donor substrates and transfers the electrons to terminal reductases or oxidases for the reduction of six different electron acceptors. Salmonella is able to use even two more electron acceptors. The variation is further increased by the presence of isoenzymes for some substrates. Various respiratory pathways can be established by combining the oxidation of different electron donors and acceptors which are linked by respiratory quinones. The enzymes vary largely with respect to architecture, membrane topology, and mode of energy conservation. Most of the energy-conserving dehydrogenases (e.g., FdnGHI, HyaABC, and HybCOAB) and of the terminal reductases (CydAB, NarGHI, and others) form a proton potential (Deltap) by a redox loop mechanism. Only two enzymes (NuoA-N and CyoABCD) couple the redox energy to proton translocation by proton pumping. A large number of dehydrogenases (e.g., Ndh, SdhABCD, and GlpD) and of terminal reductases (e.g., FrdABCD and DmsABC) do not conserve the redox energy in a proton potential. For most of the respiratory enzymes, the mechanism of proton potential generation is known from structural and biochemical studies or can be predicted from sequence information. The H+/2e- ratios of proton translocation for most respiratory chains are in the range from 2 to 6 H+/2e-. The energetics of the individual redox reactions and of the respiratory chains is described. In contrast to the knowledge on enzyme function are physiological aspects of respiration such as organization and coordination of the electron transport and the use of alternative respiratory enzymes, not well characterized. PMID- 26443737 TI - Biotin and Lipoic Acid: Synthesis, Attachment, and Regulation. AB - Two vitamins, biotin and lipoic acid, are essential in all three domains of life. Both coenzymes function only when covalently attached to key metabolic enzymes. There they act as "swinging arms" that shuttle intermediates between two active sites (= covalent substrate channeling) of key metabolic enzymes. Although biotin was discovered over 100 years ago and lipoic acid was discovered 60 years ago, it was not known how either coenzyme is made until recently. In Escherichia coli the synthetic pathways for both coenzymes have now been worked out for the first time. The late steps of biotin synthesis, those involved in assembling the fused rings, were well described biochemically years ago, although recent progress has been made on the BioB reaction, the last step of the pathway, in which the biotin sulfur moiety is inserted. In contrast, the early steps of biotin synthesis, assembly of the fatty acid-like "arm" of biotin, were unknown. It has now been demonstrated that the arm is made by using disguised substrates to gain entry into the fatty acid synthesis pathway followed by removal of the disguise when the proper chain length is attained. The BioC methyltransferase is responsible for introducing the disguise and the BioH esterase for its removal. In contrast to biotin, which is attached to its cognate proteins as a finished molecule, lipoic acid is assembled on its cognate proteins. An octanoyl moiety is transferred from the octanoyl-ACP of fatty acid synthesis to a specific lysine residue of a cognate protein by the LipB octanoyl transferase, followed by sulfur insertion at carbons C6 and C8 by the LipA lipoyl synthetase. Assembly on the cognate proteins regulates the amount of lipoic acid synthesized, and thus there is no transcriptional control of the synthetic genes. In contrast, transcriptional control of the biotin synthetic genes is wielded by a remarkably sophisticated, yet simple, system exerted through BirA, a dual-function protein that both represses biotin operon transcription and ligates biotin to its cognate protein. PMID- 26443738 TI - The SOS Regulatory Network. AB - All organisms possess a diverse set of genetic programs that are used to alter cellular physiology in response to environmental cues. The gram-negative bacterium Escherichia coli induces a gene regulatory network known as the "SOS response" following exposure to DNA damage, replication fork arrest, and a myriad of other environmental stresses. For over 50 years, E. coli has served as the paradigm for our understanding of the transcriptional and physiological changes that occur after DNA damage. In this chapter, we summarize the current view of the SOS response and discuss how this genetic circuit is regulated. In addition to examining the E. coli SOS response, we include a discussion of the SOS regulatory networks found in other bacteria to provide a broad perspective on the mechanism and diverse physiological responses that ensueto protect cells and maintain genome integrity. PMID- 26443739 TI - Biosynthesis and Insertion of the Molybdenum Cofactor. AB - The transition element molybdenum (Mo) is of primordial importance for biological systems as it is required by enzymes catalyzing key reactions in global carbon, sulfur, and nitrogen metabolism. In order to gain biological activity, Mo has to be complexed by a special cofactor. With the exception of bacterial nitrogenase, all Mo-dependent enzymes contain a unique pyranopterin-based cofactor coordinating a Mo atom at their catalytic site. Various types of reactions are catalyzed by Mo enzymes in prokaryotes, including oxygen atom transfer, sulfur or proton transfer, hydroxylation, or even nonredox ones. Mo enzymes are widespread in prokaryotes, and many of them were likely present in LUCA. To date, more than 50-mostly bacterial-Mo enzymes are described in nature. In a few eubacteria and in many archaea, Mo is replaced by tungsten bound to the same unique pyranopterin. How Moco is synthesized in bacteria is reviewed as well as the way until its insertion into apo-Mo-enzymes. PMID- 26443740 TI - Modulation of Chemical Composition and Other Parameters of the Cell at Different Exponential Growth Rates. AB - This review begins by briefly presenting the history of research on the chemical composition and other parameters of cells of E. coli and S. enterica at different exponential growth rates. Studies have allowed us to determine the in vivo strength of promoters and have allowed us to distinguish between factor-dependent transcriptional control of the promoter and changes in promoter activity due to changes in the concentration of free functional RNA polymerase associated with different growth conditions. The total, or bulk, amounts of RNA and protein are linked to the growth rate, because most bacterial RNA is ribosomal RNA (rRNA). Since ribosomes are required for protein synthesis, their number and their rate of function determine the rate of protein synthesis and cytoplasmic mass accumulation. Many mRNAs made in the presence of amino acids have strong ribosome binding sites whose presence reduces the expression of all other active genes. This implies that there can be profound differences in the spectrum of gene activities in cultures grown in different media that produce the same growth rate. Five classes of growth-related parameters that are generally useful in describing or establishing the macromolecular composition of bacterial cultures are described in detail in this review. A number of equations have been reported that describe the macromolecular composition of an average cell in an exponential culture as a function of the culture doubling time and five additional parameters: the C- and D-periods, protein per origin (PO), ribosome activity, and peptide chain elongation rate. PMID- 26443741 TI - Biosynthesis of the Aromatic Amino Acids. AB - This chapter describes in detail the genes and proteins of Escherichia coli involved in the biosynthesis and transport of the three aromatic amino acids tyrosine, phenylalanine, and tryptophan. It provides a historical perspective on the elaboration of the various reactions of the common pathway converting erythrose-4-phosphate and phosphoenolpyruvate to chorismate and those of the three terminal pathways converting chorismate to phenylalanine, tyrosine, and tryptophan. The regulation of key reactions by feedback inhibition, attenuation, repression, and activation are also discussed. Two regulatory proteins, TrpR (108 amino acids) and TyrR (513 amino acids), play a major role in transcriptional regulation. The TrpR protein functions only as a dimer which, in the presence of tryptophan, represses the expression of trp operon plus four other genes (the TrpR regulon). The TyrR protein, which can function both as a dimer and as a hexamer, regulates the expression of nine genes constituting the TyrR regulon. TyrR can bind each of the three aromatic amino acids and ATP and under their influence can act as a repressor or activator of gene expression. The various domains of this protein involved in binding the aromatic amino acids and ATP, recognizing DNA binding sites, interacting with the alpha subunit of RNA polymerase, and changing from a monomer to a dimer or a hexamer are all described. There is also an analysis of the various strategies which allow TyrR in conjunction with particular amino acids to differentially affect the expression of individual genes of the TyrR regulon. PMID- 26443742 TI - Biosynthesis of Cysteine. AB - The synthesis of L-cysteine from inorganic sulfur is the predominant mechanism by which reduced sulfur is incorporated into organic compounds. L-cysteineis used for protein and glutathione synthesis and serves as the primary source of reduced sulfur in L-methionine, lipoic acid, thiamin, coenzyme A (CoA), molybdopterin, and other organic molecules. Sulfate and thiosulfate uptake in E. coli and serovar Typhimurium are achieved through a single periplasmic transport system that utilizes two different but similar periplasmic binding proteins. Kinetic studies indicate that selenate and selenite share a single transporter with sulfate, but molybdate also has a separate transport system. During aerobic growth, the reduction of sulfite to sulfide is catalyzed by NADPH-sulfite reductase (SiR), and serovar Typhimurium mutants lacking this enzyme accumulate sulfite from sulfate, implying that sulfite is a normal intermediate in assimilatory sulfate reduction. L-Cysteine biosynthesis in serovar Typhimurium and E. coli ceases almost entirely when cells are grown on L-cysteine or L cystine, owing to a combination of end product inhibition of serine transacetylase by L-cysteine and a gene regulatory system known as the cysteine regulon, wherein genes for sulfate assimilation and alkanesulfonate utilization are expressed only when sulfur is limiting. In vitro studies with the cysJIH, cysK, and cysP promoters have confirmed that they are inefficient at forming transcription initiation complexes without CysB and N-acetyl-L-serine. Activation of the tauA and ssuE promoters requires Cbl. It has been proposed that the three serovar Typhimurium anaerobic reductases for sulfite, thiosulfate, and tetrathionate may function primarily in anaerobic respiration. PMID- 26443743 TI - Cytochrome c Biogenesis. AB - Escherichia coli employs several c-type cytochromes, which are found in the periplasm or on the periplasmic side of the cytoplasmic membrane; they are used for respiration under different growth conditions. All E. colic-type cytochromes are multiheme cytochromes; E. coli does not have a monoheme cytochrome c of the kind found in mitochondria. The attachment of heme to cytochromes c occurs in the periplasm, and so the apoprotein must be transported across the cytoplasmic membrane; this step is mediated by the Sec system, which transports unfolded proteins across the membrane. The protein CcmE has been found to bind heme covalently via a single bond and then transfer the heme to apocytochromes. It should be mentioned that far less complex systems for cytochrome c biogenesis exist in other organisms and that enterobacteria do not function as a representative model system for the process in general, although plant mitochondria use the Ccm system found in E. coli. The variety and distribution of cytochromes and their biogenesis systems reflect their significance and centrality in cellular bioenergetics, though the necessity for and origin of the diverse biogenesis systems are enigmatic. PMID- 26443744 TI - Biosynthesis of Membrane Lipids. AB - The pathways in Escherichia coli and (largely by analogy) S. enterica remain the paradigm of bacterial lipid synthetic pathways, although recently considerable diversity among bacteria in the specific areas of lipid synthesis has been demonstrated. The structural biology of the fatty acid synthetic proteins is essentially complete. However, the membrane-bound enzymes of phospholipid synthesis remain recalcitrant to structural analyses. Recent advances in genetic technology have allowed the essentialgenes of lipid synthesis to be tested with rigor, and as expected most genes are essential under standard growth conditions. Conditionally lethal mutants are available in numerous genes, which facilitates physiological analyses. The array of genetic constructs facilitates analysis of the functions of genes from other organisms. Advances in mass spectroscopy have allowed very accurate and detailed analyses of lipid compositions as well as detection of the interactions of lipid biosynthetic proteins with one another and with proteins outside the lipid pathway. The combination of these advances has resulted in use of E. coli and S. enterica for discovery of new antimicrobials targeted to lipid synthesis and in deciphering the molecular actions of known antimicrobials. Finally,roles for bacterial fatty acids other than as membrane lipid structural components have been uncovered. For example, fatty acid synthesis plays major roles in the synthesis of the essential enzyme cofactors, biotin and lipoic acid. Although other roles for bacterial fatty acids, such as synthesis of acyl-homoserine quorum-sensing molecules, are not native to E. coli introduction of the relevant gene(s) synthesis of these foreign molecules readily proceeds and the sophisticated tools available can used to decipher the mechanisms of synthesis of these molecules. PMID- 26443745 TI - Promoter Escape by Escherichia coli RNA Polymerase. AB - Promoter escape is the process that an initiated RNA polymerase (RNAP) molecule undergoes to achieve the initiation-elongation transition. Having made this transition, an RNAP molecule would be relinquished from its promoter hold to perform productive (full-length) transcription. Prior to the transition, this process is accompanied by abortive RNA formation-the amount and pattern of which is controlled by the promoter sequence information. Qualitative and quantitative analysis of abortive/productive transcription from several Escherichia coli promoters and their sequence variants led to the understanding that a strong (RNAP-binding) promoter is more likely to be rate limited (during transcription initiation) at the escape step and produce abortive transcripts. Of the two subelements in a promoter, the PRR (the core Promoter Recognition Region) was found to set the initiation frequency and the rate-limiting step, while the ITS (the Initial Transcribed Sequence region) modulated the ratio of abortive versus productive transcription. The highly abortive behavior of E. coli RNAP could be ameliorated by the presence of Gre (transcript cleavage stimulatory) factor(s), linking the first step in abortive RNA formation by the initial transcribing complexes (ITC) to RNAP backtracking. The discovery that translocation during the initiation stage occurs via DNA scrunching provided the source of energy that converts each ITC into a highly unstable "stressed intermediate." Mapping all of the biochemical information onto an X-ray crystallographic structural model of an open complex gave rise to a plausible mechanism of transcription initiation. The chapter concludes with contemplations of the kinetics and thermodynamics of abortive initiation-promoter escape. PMID- 26443746 TI - Generalisability of pharmacoepidemiological studies using restricted prescription data. AB - BACKGROUND: Linking medication databases to disease registries enables population based pharmacoepidemiology research. In Ireland, country-wide dispensing data is available only from the means-tested government-medical cards scheme. This restriction may impact generalisability of analyses based on these data. AIM: Gender was previously identified as predictor of card status so we aimed to compare women with and without medical cards at the time of ovarian cancer diagnosis. METHODS: Ovarian cancers diagnosed 2001-2010 were identified from the National Cancer Registry Ireland. Age, region, deprivation, smoking, employment and marital status were evaluated using logistic regression for associations with card status. Cumulative incidence of de novo card receipt post-diagnosis was assessed. RESULTS: 1778 (52 %) of 3396 women with incident ovarian cancer had a card at diagnosis (<70:33 %; 70+:87 %). Within those <70, all variables were significantly associated with card status at diagnosis. 52 % of those without a card at diagnosis received one post-diagnosis. CONCLUSIONS: Although medical card coverage within ovarian cancer patients is similar to the general population, various factors predict card status. Particularly within those under 70, external validity needs to be considered when interpreting pharamcoepidemiological analyses using these data. PMID- 26443747 TI - Characteristics of coronary artery lesion in patients with and without diabetes mellitus. AB - PURPOSE: The goal of this study was to compare the coronary atherosclerotic burden in patients with and without type-2 diabetes by using CT coronary angiography (CTCA). METHODS: A total of 206 diabetic (mean age 67 +/- 11 years; male: 136) and 523 non-diabetic patients (mean age 62 +/- 13 years; male: 323) without history of coronary artery disease (CAD) underwent CTCA. The per-patient number of diseased coronary segments was determined, and each diseased segment was classified as showing obstructive lesion (luminal narrowing >50 %) or not. Coronary angiography was then performed to confirm diagnosis. RESULTS: Diabetics showed a higher rate of abnormal CAD (76 vs. 53 % of patients; p < 0.0001) and fewer normal coronary arteries (24 vs. 47 %; p < 0.0001) compared with non diabetics. Multi-vessel disease was seen more frequently in patients with diabetes than in patients without diabetes [15 % (n = 22) vs. 7 % (n = 62), respectively; p = 0.0004]. The per-patient number of segments with plaque (4.5 vs. 2.0, respectively; p < 0.0001) and the number of segments with obstructive disease (0.9 vs. 0.5, respectively; p = 0.0001) were higher for diabetic patients than for non-diabetic patients. CONCLUSION: Diabetes was associated with higher coronary plaque burden. PMID- 26443748 TI - Stability and accuracy of total and free PSA values in samples stored at room temperature. AB - INTRODUCTION: In 2010, an estimated 476,076 total PSA tests were performed in Ireland, at a cost of ?3.6 million with the majority ordered by general practitioners. We aimed to replicate storage conditions at room temperature and see if prolonged storage affected total and free PSA values. METHODS: Blood samples were taken from 20 male patients in four VACUETTE(r) Serum Separator tubes (Greiner-Bio-One, Austria) and stored at room temperature (22 degrees C) for different time intervals (4, 8, 24, 48 h) before being centrifuged and analyzed. Total PSA (tPSA) and free PSA (fPSA) values were determined using the Tosoh AIA 1800 assay (Tokyo, Japan). RESULTS: Mean tPSA values were measured at 4, 8, 24 and 48 h with values of 7.9, 8.1, 7.8 and 8.0 MUg/L, respectively. Values ranged from -1.26 to +2.53 % compared to the initial 4 h interval reading, indicating tPSA remained consistent at room temperature. The tPSA showed no significance between groups (ANOVA, p = 0.283). Mean fPSA values at 4, 8, 24 and 48 h were 2.05, 2.04, 1.83, 1.82 MUg/L, respectively. At 24 and 48 h there was 10.73 and 11.22 % reduction, respectively, in fPSA compared to the 4-h time interval, indicating prolonged storage resulted in reduced fPSA values. After 24 h, there was an 8.8 % reduction in the free/total PSA %. The fPSA showed significant differences between groups (ANOVA, p = 0.024). CONCLUSIONS: Our recommendation is that samples that have been stored for prolonged amounts of time (greater than 24 h) should not be used for free PSA testing. PMID- 26443749 TI - Outcomes for patients with Guillain-Barre syndrome requiring mechanical ventilation: a literature review. AB - BACKGROUND: This is a literature review of outcomes for patients with Guillain Barre Syndrome (GBS) who require admission to the intensive care unit for mechanical ventilation. Respiratory distress is the leading cause of death in the acute phase, and occurs in about 25 % of patients. AIMS: The aim of this review is to compile, analyse, and summarise the most relevant literature looking at outcomes for Guillain-Barre (GB) patients requiring admission to the intensive care unit and mechanical ventilation. METHODS: A PubMed and Google-Scholar literature search was performed using the key words 'Guillain-Barre, Outcomes, Mechanical Ventilation, Prognosis, Mortality, ICU. All 7 papers from the years 2000-2014 which assessed outcomes for GBS patients requiring mechanical ventilation were included, and critically analysed. RESULTS: The parameters recorded by these studies looked at mortality, disability, length of hospitalisation, and complications. The mortality of GB patients requiring mechanical ventilation varied from 8.3 to 20 %, Disability was primarily measured by the GBS disability scale. One study deemed that a score of 0-1 was a positive outcome, and found that slightly over half 53.8 % of the patients fulfilled that criteria. Over half of the mechanically ventilated patients were required to be admitted for over 3 weeks. Complications during ICU admission are common, with bed-sores (40 %), pneumonia (30.2 %) and sepsis (17.4) being the most frequently encountered in one study. CONCLUSION: Accurate data are limited by the fact that these studies are retrospective, often covering long periods in the past. Larger, more recent, prospective, multi-centre studies will be required. PMID- 26443750 TI - Comparison of DNA Methylation and Expression Pattern of S100 and Other Epidermal Differentiation Complex Genes in Differentiating Keratinocytes. AB - Epidermal Differentiation Complex (EDC) is a gene cluster on human chromosome 1 q21, which comprises genes encoding four protein families: S100, S100 fused (SFTP), small proline-rich region (SPRR) and late cornified envelope (LCE) proteins. Contrary to the latter three families, which group proteins important for skin barrier formation, the role of S100 proteins has not been well defined and there are no systematic comparative data concerning their expression in the epidermis. Furthermore, little is known about epigenetic mechanisms controlling changes in S100 and other EDC genes expression in differentiating epidermis. In our study, using real-time PCR, we followed the expression of nine S100 genes at subsequent stages of differentiation of primary human keratinocytes and found that they exhibited different expression patterns. Then, we confronted the expression level in undifferentiated and differentiated keratinocytes with the extent of DNA methylation within their promoter or intragenic regions assessed by bisulfite sequencing. Methylation analysis was also performed for three other EDC genes of known expression pattern (involucrin, loricrin, and NICE-1) and a recently identified evolutionary conserved region with defined enhancer properties. The results indicate that altered EDC genes expression is not accompanied by major changes in DNA methylation. PMID- 26443751 TI - Factor analysis of the hospital anxiety and depression scale among a Huntington's disease population. AB - INTRODUCTION: Depression and anxiety are common in Huntington's disease, a genetic neurodegenerative disorder. There is a need for measurement tools of mood to be validated within a Huntington's disease population. The current study aimed to analyze the factor structure of the Hospital Anxiety and Depression Scale in Huntington's disease. METHODS: Data from the European Huntington's Disease Network study REGISTRY 3 were used to undertake a factor analysis of the scale among a sample of 492 Huntington's disease mutation carriers. The sample was randomly divided into two equal subsamples and an exploratory factor analysis conducted on the first subsample suggested a two-factor interpretation, using eight of the items. A confirmatory factor analysis was then performed to test six possible models for goodness of fit. RESULTS: A bifactor model, with all items loading onto a general distress factor, with two group factors, comprising four depression and four anxiety items, provided the best fit of the data. The salience of loadings on the bifactor model suggested that loadings were high on the general factor (accounting for 64% of the variance) and low on the group factors (21% for anxiety and 15% for depression). CONCLUSIONS: The findings suggest that eight items from the scale perform well among the sample. Consistent with recent developments in modeling the Hospital Anxiety and Depression Scale, a bifactor interpretation for an eight-item version outperformed other extant models. Our findings provide support for an eight-item version of the scale to be used as a measure of general distress within Huntington's disease populations. PMID- 26443753 TI - Glycogen: Biosynthesis and Regulation. AB - The accumulation of glycogen occurs in Escherichia coli and Salmonella enterica serovar Typhimurium as well as in many other bacteria. Glycogen will be formed when there is an excess of carbon under conditions in which growth is limited due to the lack of a growth nutrient, e.g., a nitrogen source. The structural genes of the glycogen biosynthetic enzymes of E. coli and S. serovar Typhimurium have been cloned previously, and that has provided insights in the genetic regulation of glycogen synthesis. An important aspect of the regulation of glycogen synthesis is the allosteric regulation of the ADP-Glc PPase. The current information, views, and concepts regarding the regulation of enzyme activity and the expression of the glycogen biosynthetic enzymes are presented in this review. The recent information on the amino acid residues critical for the activity of both glycogen synthase and branching enzyme (BE) is also presented. The residue involved in catalysis in the E. coli ADP-Glc PPase was determined by comparing a predicted structure of the enzyme with the known three-dimensional structures of sugar-nucleotide PPase domains. The molecular cloning of the E. coliglg K-12 structural genes greatly facilitated the subsequent study of the genetic regulation of bacterial glycogen biosynthesis. Results from studies of glycogen excess E. coli B mutants SG3 and AC70R1, which exhibit enhanced levels of the enzymes in the glycogen synthesis pathway (i.e., they are derepressed mutants), suggested that glycogen synthesis is under negative genetic regulation. PMID- 26443754 TI - Oxygen as Acceptor. AB - Like most bacteria, Escherichia coli has a flexible and branched respiratory chain that enables the prokaryote to live under a variety of environmental conditions, from highly aerobic to completely anaerobic. In general, the bacterial respiratory chain is composed of dehydrogenases, a quinone pool, and reductases. Substrate specific dehydrogenases transfer reducing equivalents from various donor substrates (NADH, succinate, glycerophoshate, formate, hydrogen, pyruvate, and lactate) to a quinone pool (menaquinone, ubiquinone, and demethylmenoquinone). Then electrons from reduced quinones (quinols) are transferred by terminal reductases to different electron acceptors. Under aerobic growth conditions, the terminal electron acceptor is molecular oxygen. A transfer of electrons from quinol to O2 is served by two major oxidoreductases (oxidases), cytochrome bo3 and cytochrome bd. Terminal oxidases of aerobic respiratory chains of bacteria, which use O2 as the final electron acceptor, can oxidize one of two alternative electron donors, either cytochrome c or quinol. This review compares the effects of different inhibitors on the respiratory activities of cytochrome bo3 and cytochrome bd in E. coli. It also presents a discussion on the genetics and the prosthetic groups of cytochrome bo3 and cytochrome bd. The E. coli membrane contains three types of quinones which all have an octaprenyl side chain (C40). It has been proposed that the bo3 oxidase can have two ubiquinone-binding sites with different affinities. The spectral properties of cytochrome bd-II closely resemble those of cydAB-encoded cytochrome bd. PMID- 26443756 TI - Structure and Assembly of Escherichia coli Capsules. AB - The capsule is a cell surface structure composed of long-chain polysaccharides that envelops many isolates of Escherichia coli. It protects the cell against host defenses or physical environmental stresses, such as desiccation. The component capsular polysaccharides (CPSs) are major surface antigens in E. coli. They are named K antigens (after the German word Kapsel). Due to variations in CPS structures, more than 80 serologically unique K antigens exist in E. coli. Despite the hypervariability in CPS structures, only two capsule-assembly strategies exist in E. coli. These have led to the assignment of group 1 and group 2 capsules, and many of the key elements of the corresponding assembly pathways have been resolved. Structural features, as well as genetic and regulatory variations, give rise to additional groups 3 and 4. These employ the same biosynthesis processes described in groups 2 and 1, respectively. Each isolate possesses a distinctive set of cytosolic and inner-membrane enzymes, which generate a precise CPS structure, defining a given K serotype. Once synthesized, a multiprotein complex is needed to translocate the nascent CPS across the Gram-negative cell envelope to the outer surface of the outer membrane, where the capsule structure is assembled. While the translocation machineries for group 1 and group 2 CPSs are fundamentally different from one another, they possess no specificity for a given CPS structure. Each is conserved in all isolates producing capsules belonging to a particular group. PMID- 26443752 TI - Late initiation of combination antiretroviral therapy in Canada: a call for a national public health strategy to improve engagement in HIV care. AB - INTRODUCTION: Combination antiretroviral therapy (ART) significantly decreases morbidity, mortality and HIV transmission. We aimed to characterize the timing of ART initiation based on CD4 cell count from 2000 to 2012 and identify factors associated with late initiation of treatment. METHODS: Participants from the Canadian Observational Cohort (CANOC), a multi-site cohort of HIV-positive adults initiating ART naively after 1 January 2000, in three Canadian provinces (British Columbia, Ontario and Quebec) were included. Late initiation was defined as a CD4 count <200 cells/mm(3) or an AIDS-defining illness before ART initiation (baseline). Temporal trends were assessed using the Cochran-Armitage test, and independent correlates of late initiation were identified using logistic regression. RESULTS: In total, 8942 participants (18% female) of median age 40 years (Q1-Q3 33-47) were included. The median baseline CD4 count increased from 190 cells/mm(3) (Q1-Q3 80-320) in 2000 to 360 cells/mm(3) (Q1-Q3 220-490) in 2012 (p<0.001). Overall, 4274 participants (48%) initiated ART with a CD4 count <200 cells/mm(3) or AIDS-defining illness. Late initiation was more common among women, non-MSM, older individuals, participants from Ontario and BC (vs. Quebec), persons with injection drug use (IDU) history and individuals starting ART in earlier calendar years. In sub-analysis exploring recent (2008 to 2012) predictors using an updated CD4 criterion (<350 cells/mm(3)), IDU and residence in BC (vs. Quebec) were no longer significant correlates of late initiation. CONCLUSIONS: This analysis documents increasing baseline CD4 counts over time among Canadians initiating ART. However, CD4 counts at ART initiation remain below contemporary treatment guidelines, highlighting the need for strategies to improve earlier engagement in HIV care. PMID- 26443755 TI - Biosynthesis of Thiamin Pyrophosphate. AB - The biosynthesis of thiamin pyrophosphate (TPP) in prokaryotes, as represented by the Escherichia coli and the Bacillus subtilis pathways, is summarized in this review. The thiazole heterocycle is formed by the convergence of three separate pathways. First, the condensation of glyceraldehyde 3-phosphate and pyruvate, catalyzed by 1-deoxy-D-xylulose 5-phosphate synthase (Dxs), gives 1-deoxy-D xylulose 5-phosphate (DXP). Next, the sulfur carrier protein ThiS-COO- is converted to its carboxyterminal thiocarboxylate in reactions catalyzed by ThiF, ThiI, and NifS (ThiF and IscS in B. subtilis). Finally, tyrosine (glycine in B. subtilis) is converted to dehydroglycine by ThiH (ThiO in B. subtilis). Thiazole synthase (ThiG) catalyzes the complex condensation of ThiS-COSH, dehydroglycine, and DXP to give a thiazole tautomer, which is then aromatized to carboxythiazole phosphate by TenI (B. subtilis). Hydroxymethyl pyrimidine phosphate (HMP-P) is formed by a complicated rearrangement reaction of 5-aminoimidazole ribotide (AIR) catalyzed by ThiC. ThiD then generates hydroxymethyl pyrimidine pyrophosphate. The coupling of the two heterocycles and decarboxylation, catalyzed by thiamin phosphate synthase (ThiE), gives thiamin phosphate. A final phosphorylation, catalyzed by ThiL, completes the biosynthesis of TPP, the biologically active form of the cofactor. This review reviews the current status of mechanistic and structural studies on the enzymes involved in this pathway. The availability of multiple orthologs of the thiamin biosynthetic enzymes has also greatly facilitated structural studies, and most of the thiamin biosynthetic and salvage enzymes have now been structurally characterized. PMID- 26443757 TI - NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins. AB - Eukaryotes have evolved strategies to detect microbial intrusion and instruct immune responses to limit damage from infection. Recognition of microbes and cellular damage relies on the detection of microbe-associated molecular patterns (MAMPs, also called PAMPS, or pathogen-associated molecular patterns) and so called "danger signals" by various families of host pattern recognition receptors (PRRs). Members of the recently identified protein family of nucleotide-binding domain andleucine-rich-repeat-containing proteins (NLR), including Nod1, Nod2, NLRP3, and NLRC4, have been shown to detect specific microbial motifs and danger signals for regulating host inflammatory responses. Moreover, with the discovery that polymorphisms in NOD1, NOD2, NLRP1, and NLRP3 are associated with susceptibility to chronic inflammatory disorders, the view has emerged that NLRs act not only as sensors butalso can serve as signaling platforms for instructing and balancing host immune responses. In this chapter, we explore the functions of these intracellular innate immune receptors and examine their implication in inflammatory diseases. PMID- 26443759 TI - Envelope Stress Responses. AB - The gram-negative bacterial envelope is a complex extracytoplasmic compartment responsible for numerous cellular processes. Among its most important functions is its service as the protective layer separating the cytoplasmic space from the ever-changing external environment. To adapt to the diverse conditions encountered both in the environment and within the mammalian host, Escherichia coli and Salmonella species have evolved six independent envelope stress response systems . This review reviews the sE response, the CpxAR and BaeSR two-component systems (TCS) , the phage shock protein response, and the Rcs phosphorelay system. These five signal transduction pathways represent the most studied of the six known stress responses. The signal for adhesion to abiotic surfaces enters the pathway through the novel outer membrane lipoprotein NlpE, and activation on entry into the exponential phase of growth occurs independently of CpxA . Adhesion could disrupt NlpE causing unfolding of its unstable N-terminal domain, leading to activation of the Cpx response. The most recent class of genes added to the Cpx regulon includes those involved in copper homeostasis. Two separate microarray experiments revealed that exposure of E. coli cells to high levels of external copper leads to upregulation of several Cpx regulon members. The BaeSR TCS has also been shown to mediate drug resistance in Salmonella. Similar to E. coli, the Bae pathway of Salmonella enterica mediates resistance to oxacillin, novobiocin, deoxycholate, beta-lactams, and indole. PMID- 26443760 TI - The Nucleoid: an Overview. AB - This review provides a brief review of the current understanding of the structure function relationship of the Escherichia coli nucleoid developed after the overview by Pettijohn focusing on the physical properties of nucleoids. Isolation of nucleoids requires suppression of DNA expansion by various procedures. The ability to control the expansion of nucleoids in vitro has led to purification of nucleoids for chemical and physical analyses and for high-resolution imaging. Isolated E. coli genomes display a number of individually intertwined supercoiled loops emanating from a central core. Metabolic processes of the DNA double helix lead to three types of topological constraints that all cells must resolve to survive: linking number, catenates, and knots. The major species of nucleoid core protein share functional properties with eukaryotic histones forming chromatin; even the structures are different from histones. Eukaryotic histones play dynamic roles in the remodeling of eukaryotic chromatin, thereby controlling the access of RNA polymerase and transcription factors to promoters. The E. coli genome is tightly packed into the nucleoid, but, at each cell division, the genome must be faithfully replicated, divided, and segregated. Nucleoid activities such as transcription, replication, recombination, and repair are all affected by the structural properties and the special conformations of nucleoid. While it is apparent that much has been learned about the nucleoid, it is also evident that the fundamental interactions organizing the structure of DNA in the nucleoid still need to be clearly defined. PMID- 26443761 TI - DNA Topoisomerases. AB - DNA topoisomerases are enzymes that control the topological state of DNA in all cells; they have central roles in DNA replication and transcription. They are classified into two types, I and II, depending on whether they catalyze reactions involving the breakage of one or both strands of DNA. Structural and mechanistic distinctions have led to further classifications: IA, IB, IC, IIA, and IIB. The essence of the topoisomerase reaction is the ability of the enzymes to stabilize transient breaks in DNA, via the formation of tyrosyl-phosphate covalent intermediates. The essential nature of topoisomerases and their ability to stabilize DNA breaks has led to them being key targets for antibacterial and anticancer agents. This chapter reviews the basic features of topoisomerases focussing mainly on the prokaryotic enzymes. We highlight recent structural advances that have given new insight into topoisomerase mechanisms and into the molecular basis of the action of topoisomerase-specific drugs. PMID- 26443762 TI - Cell-to-Cell Signaling in Escherichia coli and Salmonella. AB - Bacteria must be able to respond rapidly to changes in the environment in order to survive. One means of coordinating gene expression relies on tightly regulated and complex signaling systems. One of the first signaling systems that was described in detail is quorum sensing (QS). During QS, a bacterial cell produces and secretes a signaling molecule called an autoinducer (AI). As the density of the bacterial population increases, so does the concentration of secreted AI molecules, thereby allowing a bacterial species to coordinate gene expression based on population density. Subsequent studies have demonstrated that bacteria are also able to detect signal molecules produced by other species of bacteria as well as hormones produced by their mammalian hosts. These types of signaling interactions have been termed cell-to-cell signaling because the interaction does not rely on a threshold concentration of bacterial cells. This review discusses the three main types of cell-to-cell signaling mechanisms used by E. coli and Salmonella, including the LuxR process, in which E. coli and Salmonella detect signals produced by other species of bacteria; the LuxS/AI-2 system, in which E. coli and Salmonella participate in intra- and interspecies signaling; and the AI 3/ epinephrine/norepinephrine system, in which E. coli and Salmonella recognize self-produced AI, signal produced by other microbes, and/or the human stress hormones epinephrine or norepinephrine. PMID- 26443758 TI - Biogenesis and Homeostasis of Nicotinamide Adenine Dinucleotide Cofactor. AB - Universal and ubiquitous redox cofactors, nicotinamide adenine dinucleotide (NAD) and its phosphorylated analog (NADP), collectively contribute to approximately 12% of all biochemical reactions included in the metabolic model of Escherichia coli K-12. A homeostasis of the NAD pool faithfully maintained by the cells results from a dynamic balance in a network of NAD biosynthesis, utilization, decomposition, and recycling pathways that is subject to tight regulation at various levels. A brief overview of NAD utilization processes is provided in this review, including some examples of nonredox utilization. The review focuses mostly on those aspects of NAD biogenesis and utilization in E. coli and Salmonella that emerged within the past 12 years. The first pyridine nucleotide cycle (PNC) originally identified in mammalian systems and termed the Preiss Handler pathway includes a single-step conversion of niacin (Na) to NaMN by nicotinic acid phosphoribosyltransferase (PncB). In E. coli and many other prokaryotes, this enzyme, together with nicotinamide deamidase (PncA), compose the major pathway for utilization of the pyridine ring in the form of amidated (Nm) or deamidated (Na) precursors. The existence of various regulatory mechanisms and checkpoints that control the NAD biosynthetic machinery reflects the importance of maintaining NAD homeostasis in a variety of growth conditions. Among the most important regulatory mechanisms at the level of individual enzymes are a classic feedback inhibition of NadB, the first enzyme of NAD de novo biosynthesis, by NAD and a metabolic regulation of NadK by reduced cofactors. PMID- 26443763 TI - Uropathogenic Escherichia coli. AB - The urinary tract is among the most common sites of bacterial infection, and Escherichia coli is by far the most common species infecting this site. Individuals at high risk for symptomatic urinary tract infection (UTI) include neonates, preschool girls, sexually active women, and elderly women and men. E. coli that cause the majority of UTIs are thought to represent only a subset of the strains that colonize the colon. E. coli strains that cause UTIs are termed uropathogenic E. coli (UPEC). In general, UPEC strains differ from commensal E. coli strains in that the former possess extragenetic material, often on pathogenicity-associated islands (PAIs), which code for gene products that may contribute to bacterial pathogenesis. Some of these genes allow UPEC to express determinants that are proposed to play roles in disease. These factors include hemolysins, secreted proteins, specific lipopolysaccharide and capsule types, iron acquisition systems, and fimbrial adhesions. The current dogma of bacterial pathogenesis identifies adherence, colonization, avoidance of host defenses, and damage to host tissues as events vital for achieving bacterial virulence. These considerations, along with analysis of the E. coli CFT073, UTI89, and 536 genomes and efforts to identify novel virulence genes should advance the field significantly and allow for the development of a comprehensive model of pathogenesis for uropathogenic E. coli.Further study of the adaptive immune response to UTI will be especially critical to refine our understanding and treatment of recurrent infections and to develop vaccines. PMID- 26443764 TI - Osmotic Stress. AB - Escherichia coli and Salmonella encounter osmotic pressure variations in natural environments that include host tissues, food, soil, and water. Osmotic stress causes water to flow into or out of cells, changing their structure, physics, and chemistry in ways that perturb cell functions. E. coli and Salmonella limit osmotically induced water fluxes by accumulating and releasing electrolytes and small organic solutes, some denoted compatible solutes because they accumulate to high levels without disturbing cell functions. Osmotic upshifts inhibit membrane based energy transduction and macromolecule synthesis while activating existing osmoregulatory systems and specifically inducing osmoregulatory genes. The osmoregulatory response depends on the availability of osmoprotectants (exogenous organic compounds that can be taken up to become compatible solutes). Without osmoprotectants, K+ accumulates with counterion glutamate, and compatible solute trehalose is synthesized. Available osmoprotectants are taken up via transporters ProP, ProU, BetT, and BetU. The resulting compatible solute accumulation attenuates the K+ glutamate response and more effectively restores cell hydration and growth. Osmotic downshifts abruptly increase turgor pressure and strain the cytoplasmic membrane. Mechanosensitive channels like MscS and MscL open to allow nonspecific solute efflux and forestall cell lysis. Research frontiers include (i) the osmoadaptive remodeling of cell structure, (ii) the mechanisms by which osmotic stress alters gene expression, (iii) the mechanisms by which transporters and channels detect and respond to osmotic pressure changes, (iv) the coordination of osmoregulatory programs and selection of available osmoprotectants, and (v) the roles played by osmoregulatory mechanisms as E. coli and Salmonella survive or thrive in their natural environments. PMID- 26443766 TI - Structural Basis for the Decoding Mechanism. AB - The bacterial ribosome is a complex macromolecular machine that deciphers the genetic code with remarkable fidelity. During the elongation phase of protein synthesis, the ribosome selects aminoacyl-tRNAs as dictated by the canonical base pairing between the anticodon of the tRNA and the codon of the messenger RNA. The ribosome's participation in tRNA selection is active rather than passive, using conformational changes of conserved bases of 16S rRNA to directly monitor the geometry of codon-anticodon base pairing. The tRNA selection process is divided into an initial selection step and a subsequent proofreading step, with the utilization of two sequential steps increasing the discriminating power of the ribosome far beyond that which could be achieved based on the thermodynamics of codon-anticodon base pairing stability. The accuracy of decoding is impaired by a number of antibiotics and can be either increased or decreased by various mutations in either subunit of the ribosome, in elongation factor Tu, and in tRNA. In this chapter we will review our current understanding of various forces that determine the accuracy of decoding by the bacterial ribosome. PMID- 26443765 TI - Biosynthesis of Menaquinone (Vitamin K2) and Ubiquinone (Coenzyme Q). AB - Escherichia coli and Salmonella contain the naphthoquinones menaquinone (MK; vitamin K2) and demethylmenaquinone and the benzoquinone ubiquinone (coenzyme Q; Q). Both quinones are derived from the shikimate pathway, which has been called a "metabolic tree with many branches." There are two different pathways for the biosynthesis of the naphthoquinones. The vast majority of prokaryotes, including E. coli and Salmonella, and the plants use the o-succinylbenzoate pathway, while a minority uses the futalosine pathway. The quinone nucleus of Q is derived directly from chorismate, while that of MK is derived from chorismate via isochorismate. The prenyl side chains of both quinones are from isopentenyl diphosphate formed by the 2-C-methyl-D-erythritol 4-phosphate (non-mevalonate) pathway and the methyl groups are from S-adenosylmethionine. In addition, MK biosynthesis requires 2-ketoglutarate and cofactors ATP, coenzyme A, and thiamine pyrophosphate. Despite the fact that both quinones originate from the shikimate pathway, there are important differences in their biosyntheses. The prenyl side chain in MK biosynthesis is introduced at the penultimate step, accompanied by decarboxylation, whereas in Q biosynthesis it is introduced at the second step, with retention of the carboxyl group. In MK biosynthesis, all the reactions of the pathway up to prenylation are carried out by soluble enzymes, whereas all the enzymes involved in Q biosynthesis except the first are membrane bound. In MK biosynthesis, the last step is a C-methylation; in Q biosynthesis, the last step is an O-methylation. In Q biosynthesis a second C-methylation and O-methylation take place in the middle part of the pathway. Despite the fact that Q and MK biosyntheses diverge at chorismate, the C-methylations in both pathways are carried out by the same methyltransferase. PMID- 26443769 TI - DNA Methylation. AB - The DNA of Escherichia coli contains 19,120 6-methyladenines and 12,045 5 methylcytosines in addition to the four regular bases, and these are formed by the postreplicative action of three DNA methyltransferases. The majority of the methylated bases are formed by the Dam and Dcmmethyltransferases encoded by the dam (DNA adenine methyltransferase) and dcm (DNA cytosine methyltransferase) genes. Although not essential, Dam methylation is important for strand discrimination during repair of replication errors, controlling the frequency of initiation of chromosome replication at oriC, and regulation of transcription initiation at promoters containing GATC sequences. In contrast, there is no known function for Dcm methylation, although Dcm recognition sites constitute sequence motifs for Very Short Patch repair of T/G base mismatches. In certain bacteria (e.g., Vibrio cholera and Caulobactercrescentus) adenine methylation is essential, and in C.crescentus it is important for temporal gene expression which, in turn, is required for coordination of chromosome initiation, replication, and division. In practical terms, Dam and Dcm methylation can inhibit restriction enzyme cleavage,decrease transformation frequency in certain bacteria,and decrease the stability of short direct repeats andare necessary for site-directed mutagenesis and to probe eukaryotic structure and function. PMID- 26443770 TI - Adaptive Immune Responses during Salmonella Infection. AB - The interaction betweenSalmonella and its host is complex and dynamic: the host mounts an immune defense against the pathogen, which in turn acts to reduce, evade, or exploit these responses to successfully colonize the host. Although the exact mechanisms mediating protective immunity are poorly understood, it is known that T cells are a critical component of immunity to Salmonella infection, and a robust T-cell response is required for both clearance of primary infection and resistance to subsequent challenge. B-cell functions, including but not limited to antibody production, are also required for generation of protective immunity. Additionally, interactions among host cells are essential. For example, antigen presenting cells (including B cells) express cytokines that participate in CD4+ T cell activation and differentiation. Differentiated CD4+ T cells secrete cytokines that have both autocrine and paracrine functions, including recruitment and activation of phagocytes, and stimulation of B cell isotype class switching and affinity maturation. Multiple bacterium-directed mechanisms, including altered antigen expression and bioavailability and interference with antigen presenting cell activation and function, combine to modify Salmonella's "pathogenic signature" in order to minimize its susceptibility to host immune surveillance. Therefore, a more complete understanding of adaptive immune responses may provide insights into pathogenic bacterial functions. Continued identification of adaptive immune targets will guide rational vaccine development, provide insights into host functions required to resist Salmonella infection, and correspondingly provide valuable reagents for defining the critical pathogenic capabilities of Salmonella that contribute to their success in causing acute and chronic infections. PMID- 26443767 TI - Replisome Dynamics during Chromosome Duplication. AB - This review describes the components of the Escherichia coli replisome and the dynamic process in which they function and interact under normal conditions. It also briefly describes the behavior of the replisome during situations in which normal replication fork movement is disturbed, such as when the replication fork collides with sites of DNA damage. E. coli DNA Pol III was isolated first from a polA mutant E. coli strain that lacked the relatively abundant DNA Pol I activity. Further biochemical studies, and the use of double mutant strains, revealed Pol III to be the replicative DNA polymerase essential to cell viability. In a replisome, DnaG primase must interact with DnaB for activity, and this constraint ensures that new RNA primers localize to the replication fork. The leading strand polymerase continually synthesizes DNA in the direction of the replication fork, whereas the lagging-strand polymerase synthesizes short, discontinuous Okazaki fragments in the opposite direction. Discontinuous lagging strand synthesis requires that the polymerase rapidly dissociate from each new completed Okazaki fragment in order to begin the extension of a new RNA primer. Lesion bypass can be thought of as a two-step reaction that starts with the incorporation of a nucleotide opposite the lesion, followed by the extension of the resulting distorted primer terminus. A remarkable property of E. coli, and many other eubacterial organisms, is the speed at which it propagates. Rapid cell division requires the presence of an extremely efficient replication machinery for the rapid and faithful duplication of the genome. PMID- 26443771 TI - Oxidative Stress. AB - The ancestors of Escherichia coli and Salmonella ultimately evolved to thrive in air-saturated liquids, in which oxygen levels reach 210 MUM at 37 degrees C. However, in 1976 Brown and colleagues reported that some sensitivity persists: growth defects still become apparent when hyperoxia is imposed on cultures of E. coli. This residual vulnerability was important in that it raised the prospect that normal levels of oxygen might also injure bacteria, albeit at reduced rates that are not overtly toxic. The intent of this article is both to describe the threat that molecular oxygen poses for bacteria and to detail what we currently understand about the strategies by which E. coli and Salmonella defend themselves against it. E. coli mutants that lack either superoxide dismutases or catalases and peroxidases exhibit a variety of growth defects. These phenotypes constitute the best evidence that aerobic cells continually generate intracellular superoxide and hydrogen peroxide at potentially lethal doses. Superoxide has reduction potentials that allow it to serve in vitro as either a weak univalent reductant or a stronger univalent oxidant. The addition of micromolar hydrogen peroxide to lab media will immediately block the growth of most cells, and protracted exposure will result in the loss of viability. The need for inducible antioxidant systems seems especially obvious for enteric bacteria, which move quickly from the anaerobic gut to fully aerobic surface waters or even to ROS perfused phagolysosomes. E. coli and Salmonella have provided two paradigmatic models of oxidative-stress responses: the SoxRS and OxyR systems. PMID- 26443772 TI - Transition Metal Homeostasis. AB - This chapter focuses on transition metals. All transition metal cations are toxic those that are essential for Escherichia coli and belong to the first transition period of the periodic system of the element and also the "toxic-only" metals with higher atomic numbers. Common themes are visible in the metabolism of these ions. First, there is transport. High-rate but low-affinity uptake systems provide a variety of cations and anions to the cells. Control of the respective systems seems to be mainly through regulation of transport activity (flux control), with control of gene expression playing only a minor role. If these systems do not provide sufficient amounts of a needed ion to the cell, genes for ATP-hydrolyzing high-affinity but low-rate uptake systems are induced, e.g., ABC transport systems or P-type ATPases. On the other hand, if the amount of an ion is in surplus, genes for efflux systems are induced. By combining different kinds of uptake and efflux systems with regulation at the levels of gene expression and transport activity, the concentration of a single ion in the cytoplasm and the composition of the cellular ion "bouquet" can be rapidly adjusted and carefully controlled. The toxicity threshold of an ion is defined by its ability to produce radicals (copper, iron, chromate), to bind to sulfide and thiol groups (copper, zinc, all cations of the second and third transition period), or to interfere with the metabolism of other ions. Iron poses an exceptional metabolic problem due its metabolic importance and the low solubility of Fe(III) compounds, combined with the ability to cause dangerous Fenton reactions. This dilemma for the cells led to the evolution of sophisticated multi-channel iron uptake and storage pathways to prevent the occurrence of unbound iron in the cytoplasm. Toxic metals like Cd2+ bind to thiols and sulfide, preventing assembly of iron complexes and releasing the metal from iron-sulfur clusters. In the unique case of mercury, the cation can be reduced to the volatile metallic form. Interference of nickel and cobalt with iron is prevented by the low abundance of these metals in the cytoplasm and their sequestration by metal chaperones, in the case of nickel, or by B12 and its derivatives, in the case of cobalt. The most dangerous metal, copper, catalyzes Fenton-like reactions, binds to thiol groups, and interferes with iron metabolism. E. coli solves this problem probably by preventing copper uptake, combined with rapid efflux if the metal happens to enter the cytoplasm. PMID- 26443773 TI - Not the last word: arthrostasis. PMID- 26443768 TI - Biosynthesis of Histidine. AB - The biosynthesis of histidine in Escherichia coli and Salmonella typhimurium has been an important model system for the study of relationships between the flow of intermediates through a biosynthetic pathway and the control of the genes encoding the enzymes that catalyze the steps in a pathway. This article provides a comprehensive review of the histidine biosynthetic pathway and enzymes, including regulation of the flow of intermediates through the pathway and mechanisms that regulate the amounts of the histidine biosynthetic enzymes. In addition, this article reviews the structure and regulation of the histidine (his) biosynthetic operon, including transcript processing, Rho-factor-dependent "classical" polarity, and the current model of his operon attenuation control. Emphasis is placed on areas of recent progress. Notably, most of the enzymes that catalyze histidine biosynthesis have recently been crystallized, and their structures have been determined. Many of the histidine biosynthetic intermediates are unstable, and the histidine biosynthetic enzymes catalyze some chemically unusual reactions. Therefore, these studies have led to considerable mechanistic insight into the pathway itself and have provided deep biochemical understanding of several fundamental processes, such as feedback control, allosteric interactions, and metabolite channeling. Considerable recent progress has also been made on aspects of his operon regulation, including the mechanism of pp(p)Gpp stimulation of his operon transcription, the molecular basis for transcriptional pausing by RNA polymerase, and pathway evolution. The progress in these areas will continue as sophisticated new genomic, metabolomic, proteomic, and structural approaches converge in studies of the histidine biosynthetic pathway and mechanisms of control of his biosynthetic genes in other bacterial species. PMID- 26443774 TI - Is there an association between whole-body pain with osteoarthritis-related knee pain, pain catastrophizing, and mental health? AB - BACKGROUND: Greater levels of self-reported pain, pain catastrophizing, and depression have been shown to be associated with persistent pain and functional limitation after surgeries such as TKA. It would be useful for clinicians to be able to measure these factors efficiently. QUESTIONS/PURPOSES: We asked: (1) What is the association of whole-body pain with osteoarthritis (OA)-related knee pain, function, pain catastrophizing, and mental health? (2) What is the sensitivity and specificity for different cutoffs for body pain diagram region categories in relation to pain catastrophizing? METHODS: Patients (n = 267) with knee OA undergoing elective TKA at one academic center and two community orthopaedic centers were enrolled before surgery in a prospective cohort study. Questionnaires included the WOMAC Pain and Function Scales, Pain Catastrophizing Scale (PCS), Mental Health Inventory-5 (MHI-5), and a pain body diagram. The diagram documents pain in 19 anatomic areas. Based on the distribution of the anatomic areas, we established six different body regions. Our analyses excluded the index (surgically treated) knee. Linear regression was used to evaluate the association between the total number of nonindex painful sites on the whole-body pain diagram and measures of OA-related pain and function, mental health, and pain catastrophizing. Generalized linear regression was used to evaluate the association between the number of painful nonindex body regions (categorized as 0; 1-2; or 3-6) with our measures of interest. All models were adjusted for age, sex, and number of comorbid conditions. The cohort included 63% females and the mean age was 66 years (SD, 9 years). With removal of the index knee, the median pain diagram score was 2 (25(th), 75(th) percentiles, 1, 4) with a range of 0 to 15. The median number of painful body regions was 2 (25(th), 75(th) percentiles, 1, 3). RESULTS: After adjusting for age, sex, and number of comorbid conditions, we found modest associations between painful body region categories and mean scores for WOMAC physical function (r = 0.22, p < 0.001), WOMAC pain (r = 0.20, p = 0.001), MHI-5 (r = -0.31, p < 0.001), and PCS (r = 0.27, p < 0.001). A nonindex body pain region score greater than 0 had 100% (95% CI, 75%-100%) sensitivity for a pain catastrophizing score greater than 30 but a specificity of just 23% (95% CI, 18%-29%) . A score of 3 or greater had greater specificity (73%; 95% CI, 66% 79%) but lower sensitivity (53%; 95% CI, 27%-78%). CONCLUSIONS: We found modest associations between the number of painful sites on a whole-body pain diagram and the number of painful body regions and measures of OA-related pain, function, pain catastrophizing, and mental health. Patients with higher self-reported body pain region scores might benefit from further evaluation for depression and pain catastrophizing. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26443776 TI - Efficacy of Plectranthus glandulosus (Lamiaceae) and Callistemon rigidus (Myrtaceae) Leaf Extract Fractions to Callosobruchus maculatus (Coleoptera: Bruchidae). AB - As part of on-going efforts to use eco-friendly alternatives to chemical pesticides, methanol crude extracts of Plectranthus glandulosus and Callistemon rigidus leaves were sequentially fractionated in hexane, chloroform, ethyl acetate, and methanol to establish the most active fraction(s) against Callosobruchus maculatus in cowpea. Cowpea seeds (25 g) were treated with 0.5, 1, 2, and 4 g/kg of extract to evaluate the contact toxicity and F1 progeny production of the beetles in the laboratory. Mortality was recorded 1, 3, and 7 d postexposure. P. glandulosus hexane fraction was more toxic than the other fractions recording 100% mortality at 4 g/kg, within 7 d with LC50 of 0.39 g/kg. Hexane fraction of C. rigidus showed superior toxicity, causing 100% mortality at 4 g/kg within only 1 d of exposure with LC50 of 1.02 g/kg. All the fractions greatly reduced progeny emergence, with C. rigidus hexane fraction being the best progeny inhibitor. Fractions of P. glandulosus and C. rigidus leaves had sufficient efficacy to be a component of storage pest management package for C. maculatus. PMID- 26443775 TI - Patients With Thumb Carpometacarpal Arthritis Have Quantifiable Characteristic Expectations That Can Be Measured With a Survey. AB - BACKGROUND: Although patient expectations associated with major orthopaedic conditions have shown clinically relevant and variable effects on outcomes, expectations associated with thumb carpometacarpal (CMC) arthritis have not been identified, described, or analyzed before, to our knowledge. QUESTIONS/PURPOSES: We asked: (1) Do patients with thumb CMC arthritis express characteristic expectations that are quantifiable and have measurable frequency? (2) Can a survey on expectations developed from patient-derived data quantitate expectations in patients with thumb CMC arthritis? METHODS: The study was a prospective cohort study. The first phase was a 12-month-period involving interviews of 42 patients with thumb CMC arthritis to define their expectations of treatment. The interview process used techniques and principles of qualitative methodology including open-ended interview questions, unrestricted time, and study size determined by data saturation. Verbatim responses provided content for the draft survey. The second phase was a 12-month period assessing the survey for test-retest reliability with the recruitment of 36 participants who completed the survey twice. The survey was finalized from clinically relevant content, frequency of endorsement, weighted kappa values for concordance of responses, and intraclass coefficient and Cronbach's alpha for interrater reliability and internal consistency. RESULTS: Thirty-two patients volunteered 256 characteristic expectations, which consisted of 21 discrete categories. Expectations with similar concepts were combined by eliminating redundancy while maintaining original terminology. These were reduced to 19 items that comprised a one-page survey. This survey showed high concordance, interrater reliability, and internal consistency, with weighted kappa values between 0.58 and 0.78 (95% CI, 0.39-0.78; p < 0.001); intraclass correlation coefficient of 0.94 (95% CI, 0.94-0.98; p < 0.001), and Cronbach's alpha values of 0.94 and 0.95 (95% CI, 0.91-0.96; p < 0.001). The thumb CMC arthritis expectations survey score is convertible to an overall score between 0 to 100 points calculated on the basis of the number of expectations and the degree of improvement expected, with higher scores indicating higher expectations. CONCLUSIONS: Patients with thumb CMC arthritis volunteer a characteristic and quantifiable set of expectations. Using responses recorded verbatim from patient interviews, a clinically relevant, valid, and reliable expectations survey was developed that measures the physical and psychosocial expectations of patients seeking treatment for CMC arthritis. The survey provides a calculable score that can record patients' expectations. Clinical application of this survey includes identification of factors that influence fulfilment of these expectations. LEVEL OF EVIDENCE: Level II, prospective study. PMID- 26443778 TI - Reconstruction and Use of Microbial Metabolic Networks: the Core Escherichia coli Metabolic Model as an Educational Guide. AB - Biochemical network reconstructions have become popular tools in systems biology. Metabolicnetwork reconstructions are biochemically, genetically, and genomically (BiGG) structured databases of biochemical reactions and metabolites. They contain information such as exact reaction stoichiometry, reaction reversibility, and the relationships between genes, proteins, and reactions. Network reconstructions have been used extensively to study the phenotypic behavior of wild-type and mutant stains under a variety of conditions, linking genotypes with phenotypes. Such phenotypic simulations have allowed for the prediction of growth after genetic manipulations, prediction of growth phenotypes after adaptive evolution, and prediction of essential genes. Additionally, because network reconstructions are organism specific, they can be used to understand differences between organisms of species in a functional context.There are different types of reconstructions representing various types of biological networks (metabolic, regulatory, transcription/translation). This chapter serves as an introduction to metabolic and regulatory network reconstructions and models and gives a complete description of the core Escherichia coli metabolic model. This model can be analyzed in any computational format (such as MATLAB or Mathematica) based on the information given in this chapter. The core E. coli model is a small-scale model that can be used for educational purposes. It is meant to be used by senior undergraduate and first-year graduate students learning about constraint-based modeling and systems biology. This model has enough reactions and pathways to enable interesting and insightful calculations, but it is also simple enough that the results of such calculations can be understoodeasily. PMID- 26443777 TI - The Efficacy of Some Commercially Available Insect Repellents for Aedes aegypti (Diptera: Culicidae) and Aedes albopictus (Diptera: Culicidae). AB - Reducing the number of host-vector interactions is an effective way to reduce the spread of vector-borne diseases. Repellents are widely used to protect humans from a variety of protozoans, viruses, and nematodes. DEET (N,N-Diethyl-meta toluamide), a safe and effective repellent, was developed during World War II. Fear of possible side effects of DEET has created a large market for "natural" DEET-free repellents with a variety of active ingredients. We present a comparative study on the efficacy of eight commercially available products, two fragrances, and a vitamin B patch. The products were tested using a human hand as attractant in a Y-tube olfactometer setup with Aedes aegypti (Linnaeus) and Aedes albopictus (Skuse), both major human disease vectors. We found that Ae. albopictus were generally less attracted to the test subject's hand compared with Ae, aegypti. Repellents with DEET as active ingredient had a prominent repellency effect over longer times and on both species. Repellents containing p-menthane 3,8-diol produced comparable results but for shorter time periods. Some of the DEET-free products containing citronella or geraniol did not have any significant repellency effect. Interestingly, the perfume we tested had a modest repellency effect early after application, and the vitamin B patch had no effect on either species. This study shows that the different active ingredients in commercially available mosquito repellent products are not equivalent in terms of duration and strength of repellency. Our results suggest that products containing DEET or p menthane-3,8-diol have long-lasting repellent effects and therefore provide good protection from mosquito-borne diseases. PMID- 26443779 TI - Biogenesis and Membrane Targeting of Lipoproteins. AB - Bacterial lipoproteins represent a unique class of membrane proteins, which are anchored to membranes through triacyl chains attached to the amino-terminal cysteine. They are involved in various functions localized in cell envelope. Escherichia coli possesses more than 90 species of lipoproteins, most of which are localized in the outer membrane, with others being in the inner membrane. All lipoproteins are synthesized in the cytoplasm with an N-terminal signal peptide, translocated across the inner membrane by the Sec translocon to the periplasmic surface of the inner membrane, and converted to mature lipoproteins through sequential reactions catalyzed by three lipoprotein-processing enzymes: Lgt, LspA, and Lnt. The sorting of lipoproteins to the outer membrane requires a system comprising five Lol proteins. An ATP-binding cassette transporter, LolCDE, initiates the sorting by mediating the detachment of lipoproteins from the inner membrane. Formation of the LolA-lipoprotein complex is coupled to this LolCDE dependent release reaction. LolA accommodates the amino-terminal acyl chain of lipoproteins in its hydrophobic cavity, thereby generating a hydrophilic complex that can traverse the periplasmic space by diffusion. Lipoproteins are then transferred to LolB on the outer membrane and anchored to the inner leaflet of the outer membrane by the action of LolB. In contrast, since LolCDE does not recognize lipoproteins possessing Asp at position +2, these lipoproteins remain anchored to the inner membrane. Genes for Lol proteins are widely conserved among gram-negative bacteria, and Lol-mediated outer membrane targeting of lipoproteins is considered to be the general lipoprotein localization mechanism. PMID- 26443780 TI - Solute and Ion Transport: Outer Membrane Pores and Receptors. AB - Two membranes enclose Gram-negative bacteria-an inner membrane consisting of phospholipid and an outer membrane having an asymmetric structure in which the inner leaflet contains phospholipid and the outer leaflet consists primarily of lipopolysaccharide. The impermeable nature of the outer membrane imposes a need for numerous outer membrane pores and transporters to ferry substances in and out of the cell. These outer membrane proteins have structures distinct from their inner membrane counterparts and most often function without any discernable energy source. In this chapter, we review the structures and functions of four classes of outer membrane protein: general and specific porins, specific transporters, TonB-dependent transporters, and export channels. While not an exhaustive list, these classes exemplify small-molecule transport across the outer membrane and illustrate the diversity of structures and functions found in Gram-negative bacteria. PMID- 26443781 TI - Biosynthesis of Riboflavin. AB - The biosynthesis of riboflavin requires 1 equivalent of GTP and 2 equivalents of ribulose phosphate. The first committed reactions of the convergent pathway are catalyzed by GTP hydrolase II and 3,4-dihydroxy-2-butanone 4-phosphate synthase. The initial reaction steps afford 5-amino-6-ribitylaminopyrimidine 5'-phosphate, which needs to be dephosphorylated by a hitherto elusive hydrolase. The dephosphorylated pyrimidine is condensed with the carbohydrate precursor, 3,4 dihydroxy-2-butanone 4-phosphate. The resulting 6,7-dimethyl-8-ribityllumazine affords riboflavin by a mechanistically unique dismutation, i.e., by formation of a pentacyclic dimer that is subsequently fragmented. PMID- 26443782 TI - Type II Secretion in Escherichia coli. AB - The type II secretion system (T2SS) is used by Escherichia coli and other gram negative bacteria to translocate many proteins, including toxins and proteases, across the outer membrane of the cell and into the extracellular space. Depending on the bacterial species, between 12 and 15 genes have been identified that make up a T2SS operon. T2SSs are widespread among gram-negative bacteria, and most E. coli appear to possess one or two complete T2SS operons. Once expressed, the multiple protein components that form the T2S system are localized in both the inner and outer membranes, where they assemble into an apparatus that spans the cell envelope. This apparatus supports the secretion of numerous virulence factors; and therefore secretion via this pathway is regarded in many organisms as a major virulence mechanism. Here, we review several of the known E. coli T2S substrates that have proven to be critical for the survival and pathogenicity of these bacteria. Recent structural and biochemical information is also reviewed that has improved our current understanding of how the T2S apparatus functions; also reviewed is the role that individual proteins play in this complex system. PMID- 26443783 TI - DNA Helicases. AB - DNA and RNA helicases are organized into six superfamilies of enzymes on the basis of sequence alignments, biochemical data, and available crystal structures. DNA helicases, members of which are found in each of the superfamilies, are an essential group of motor proteins that unwind DNA duplexes into their component single strands in a process that is coupled to the hydrolysis of nucleoside 5' triphosphates. The purpose of this DNA unwinding is to provide nascent, single stranded DNA (ssDNA) for the processes of DNA repair, replication, and recombination. Not surprisingly, DNA helicases share common biochemical properties that include the binding of single- and double-stranded DNA, nucleoside 5'-triphosphate binding and hydrolysis, and nucleoside 5'-triphosphate hydrolysis-coupled, polar unwinding of duplex DNA. These enzymes participate in every aspect of DNA metabolism due to the requirement for transient separation of small regions of the duplex genome into its component strands so that replication, recombination, and repair can occur. In Escherichia coli, there are currently twelve DNA helicases that perform a variety of tasks ranging from simple strand separation at the replication fork to more sophisticated processes in DNA repair and genetic recombination. In this chapter, the superfamily classification, role(s) in DNA metabolism, effects of mutations, biochemical analysis, oligomeric nature, and interacting partner proteins of each of the twelve DNA helicases are discussed. PMID- 26443784 TI - Escherichia coli and the French School of Molecular Biology. AB - Andre Lwoff, Jacques Monod, and Francois Jacob, the leaders of the French school of molecular biology, greatly contributed between 1937 and 1965 to its development and triumph. The main discovery of Lwoff was the elucidation of the mechanism of bacteriophage induction, the phenomenon of lysogeny, that led to the model of genetic regulation uncovered later by Jacob and Monod. Working on bacterial growth, Monod discovered in 1941 the phenomenon of diauxy and uncovered the nature of enzyme induction. By combining genetic and biochemical approaches, Monod brought to light the structure and functions of the Escherichia coli lactose system, comprising the genes necessary for lactose metabolism, i.e., beta galactosidase and lactose permease, a pump responsible for accumulation of galactosides into the cells. An additional genetic factor (the i gene) determines the inducibility and constitutivity of enzyme synthesis. Around the same time, Francois Jacob and Elie Wollman dissected the main events of bacterial conjugation that enabled them to construct a map of the E. coli chromosome and to demonstrate its circularity. The genetic analysis of the lactose system led Monod and Jacob to elucidate the mechanism of the regulation of gene expression and to propose the operon model: a unit of coordinate transcription. One of the new concepts that emerged from the operon model was messenger RNA. In 1963, Monod developed one of the most elegant concepts of molecular biology, the theory of allostery. In 1965, Lwoff, Monod and Jacob were awarded the Nobel Prize in Physiology or Medicine. PMID- 26443785 TI - Binding Protein-Dependent Uptake of Maltose into Cells via an ATP-Binding Cassette Transporter. AB - Maltose and maltodextrins are actively transported across the cytoplasmic membrane of Escherichia coli and Salmonella by a periplasmic binding protein (BP) dependent transport system. Since 1996, there have been many advances in the understanding of the structure and mechanism of the maltose transporter, in the assembly of the membrane-associated transporter complex, and in the mechanism of regulation of transport both at the DNA and the protein level. The transporter has been studied in detergent and reconstituted in liposome vesicles, and while many features, including the ability of maltose-binding protein (MBP) to stimulate ATPase activity, are retained in detergent, it has been noted that the basal ATPase activity of the transporter is elevated in detergent compared with liposomes. This review focuses on these recent developments, which have culminated in a high resolution structure of MBP in a complex with the MalFGK2 transporter. While this review focuses on the maltose system, complementary work has been carried out on many different ATP binding cassette (ABC) transporters, all of which has contributed in important ways to the understanding of the maltose transport system. The regulation of the maltose transport system, at the DNA level, is implemented by the synergistic action of MalT and cAMP/CAP complex and, at the protein level, by interactions of MalK with unphosphorylated EIIAglc, a signal-transducing component of the phosphoenolpyruvate-glucose phosphotransferase system. PMID- 26443788 TI - The Tat Protein Export Pathway. AB - Proteins that reside partially or completely outside the bacterial cytoplasm require specialized pathways to facilitate their localization. Globular proteins that function in the periplasm must be translocated across the hydrophobic barrier of the inner membrane. While the Sec pathway transports proteins in a predominantly unfolded conformation, the Tat pathway exports folded protein substrates. Protein transport by the Tat machinery is powered solely by the transmembrane proton gradient, and there is no requirement for nucleotide triphosphate hydrolysis. Proteins are targeted to the Tat machinery by N-terminal signal peptides that contain a consensus twin arginine motif. In Escherichia coli and Salmonella there are approximately thirty proteins with twin arginine signal peptides that are transported by the Tat pathway. The majority of these bind complex redox cofactors such as iron sulfur clusters or the molybdopterin cofactor. Here we describe what is known about Tat substrates in E. coli and Salmonella, the function and mechanism of Tat protein export, and how the cofactor insertion step is coordinated to ensure that only correctly assembled substrates are targeted to the Tat machinery. PMID- 26443789 TI - Bacterial Ion Channels. AB - Bacterial ion channels were known, but only in special cases, such as outer membrane porins in Escherichia coli and bacterial toxins that form pores in their target (bacterial or mammalian) membranes. The exhaustive coverage provided by a decade of bacterial genome sequencing has revealed that ion channels are actually widespread in bacteria, with homologs of a broad range of mammalian channel proteins coded throughout the bacterial and archaeal kingdoms. This review discusses four groups of bacterial channels: porins, mechano-sensitive (MS) channels, channel-forming toxins, and bacterial homologs of mammalian channels. The outer membrane (OM) of gram-negative bacteria blocks access of essential nutrients; to survive, the cell needs to provide a mechanism for nutrients to penetrate the OM. Porin channels provide this access by forming large, nonspecific aqueous pores in the OM that allow ions and vital nutrients to cross it and enter the periplasm. MS channels act as emergency release valves, allowing solutes to rapidly exit the cytoplasm and to dissipate the large osmotic disparity between the internal and external environments. MS channels are remarkable in that they do this by responding to forces exerted by the membrane itself. Some bacteria produce toxic proteins that form pores in trans, attacking and killing other organisms by virtue of their pore formation. The review focuses on those bacterial toxins that kill other bacteria, specifically the class of proteins called colicins. Colicins reveal the dangers of channel formation in the plasma membrane, since they kill their targets with exactly that approach. PMID- 26443787 TI - Type V Secretion: the Autotransporter and Two-Partner Secretion Pathways. AB - The autotransporter and two-partner secretion (TPS) pathways are used by E. coli and many other Gram-negative bacteria to delivervirulence factors into the extracellular milieu.Autotransporters arecomprised of an N-terminal extracellular ("passenger") domain and a C-terminal beta barrel domain ("beta domain") that anchors the protein to the outer membrane and facilitates passenger domain secretion. In the TPS pathway, a secreted polypeptide ("exoprotein") is coordinately expressed with an outer membrane protein that serves as a dedicated transporter. Bothpathways are often grouped together under the heading "type V secretion" because they have many features in common and are used for the secretion of structurally related polypeptides, but it is likely that theyhave distinct evolutionary origins. Although it was proposed many years ago that autotransporterpassenger domains are transported across the outer membrane through a channel formed by the covalently linked beta domain, there is increasing evidence that additional factors are involved in the translocation reaction. Furthermore, details of the mechanism of protein secretion through the TPS pathway are only beginning to emerge. In this chapter I discussour current understanding ofboth early and late steps in the biogenesis of polypeptides secreted through type V pathways and current modelsofthe mechanism of secretion. PMID- 26443790 TI - The Legacy of 20th Century Phage Research. AB - The Golden Age of Phage Research, where phage was the favored material for attacking many basic questions in molecular biology, lasted from about 1940 to 1970. The era was initiated by Ellis and Delbruck, whose analysis defined the relevant parameters to measure in studying phage growth, and depended on the fact that the contents of a plaque can comprise descendants of a single infecting particle. It ended around 1970 because definitive methods had then become available for answering the same questions in other systems. Some of the accomplishments of phage research were the demonstration by Hershey and Chase that the genetic material of phage T2 is largely composed of DNA, the construction of linkage maps of T2 and T4 by Hershey and Rotman and their extension to very short molecular distances by Benzer, and the isolation of conditionally lethal mutants in T4 by Epstein et al. and in lambda by Campbell. The dissection of the phage life cycle into causal chains was explored by Edgar and Wood for T4 assembly and later in the regulation of lysogeny by Kaiser, extended to the molecular level by Ptashne and others. Restriction/modification was discovered in lambda by Bertani and Weigle, and the biochemical mechanism was elucidated by Arber and by Smith. PMID- 26443786 TI - Initiation of DNA Replication. AB - In recent years it has become clear that complex regulatory circuits control the initiation step of DNA replication by directing the assembly of a multicomponent molecular machine (the orisome) that separates DNA strands and loads replicative helicase at oriC, the unique chromosomal origin of replication. This chapter discusses recent efforts to understand the regulated protein-DNA interactions that are responsible for properly timed initiation of chromosome replication. It reviews information about newly identified nucleotide sequence features within Escherichia coli oriC and the new structural and biochemical attributes of the bacterial initiator protein DnaA. It also discusses the coordinated mechanisms that prevent improperly timed DNA replication. Identification of the genes that encoded the initiators came from studies on temperature-sensitive, conditional lethal mutants of E. coli, in which two DNA replication-defective phenotypes, "immediate stop" mutants and "delayed stop" mutants, were identified. The kinetics of the delayed stop mutants suggested that the defective gene products were required specifically for the initiation step of DNA synthesis, and subsequently, two genes, dnaA and dnaC, were identified. The DnaA protein is the bacterial initiator, and in E. coli, the DnaC protein is required to load replicative helicase. Regulation of DnaA accessibility to oriC, the ordered assembly and disassembly of a multi-DnaA complex at oriC, and the means by which DnaA unwinds oriC remain important questions to be answered and the chapter discusses the current state of knowledge on these topics. PMID- 26443791 TI - How are arrhythmias detected by implanted cardiac devices managed in Europe? Results of the European Heart Rhythm Association Survey. AB - The management of arrhythmias detected by implantable cardiac devices can be challenging. There are no formal international guidelines to inform decision making. The purpose of this European Heart Rhythm Association (EHRA) survey was to assess the management of various clinical scenarios among members of the EHRA electrophysiology research network. There were 49 responses to the questionnaire. The survey responses were mainly (81%) from medium-high volume device implanting centres, performing more than 200 total device implants per year. Clinical scenarios were described focusing on four key areas: the implantation of pacemakers for bradyarrhythmia detected on an implantable loop recorder (ILR), the management of patients with ventricular arrhythmia detected by an ILR or pacemaker, the management of atrial fibrillation in patients with pacemakers and cardiac resynchronization therapy devices and the management of ventricular tachycardia in patients with implantable cardioverter-defibrillators. PMID- 26443792 TI - Brugada Syndrome with Early Repolarization masked by Complete Right Bundle-Branch Block. PMID- 26443793 TI - Authors' reply to Ozeke et al. PMID- 26443795 TI - Healthicization and Lay Knowledge About Eating Practices in Two African American Communities. AB - In this manuscript, we expand upon sociological research in lay knowledge about health and healthicization by examining socially mediated ways in which 40 African American adults in two communities acquired information about eating practices. Participants employed a variety of socially informed information seeking strategies. Many, but not all, used socially prescribed sources exhorting them to maximize their own health and reported an amalgam of experiences concerning their interpretation of healthist messages. Participants variously accepted messages about healthy eating or engaged in strategies of micro resistance that decentered and/or reinterpreted health promotion discourse. Furthermore, participants used emic community-based resources including those that prioritized familial engagement over individual responsibility in eating practices or that drew upon alternative health practices. We discuss the implications our work has for further research on healthicization and lay knowledge about eating practices, in which community members are actively engaged in meaning-making within local socio-structural contexts. PMID- 26443796 TI - What Parents and Their Gay and Bisexual Sons Say About HIV Prevention. AB - Despite ongoing prevention efforts, young gay and bisexual men (YGBM) accounted for more than three fourths of all recent HIV infections. Furthermore, they continue to engage in high-risk sexual behaviors at alarming rates. Nowadays, families are beginning to emerge as important resources for these youth. However, the viewpoints of YGBM and their families are largely missing from HIV prevention research and intervention development. To address this gap, we solicited the opinions of YGBM and their parents as to why YGBM engage in unsafe sex and what might be done to help them avoid HIV. Participants discussed youth's sense of invulnerability, sexual arousal, parental disapproval, and lack of societal acceptance as contributors to unsafe sex. Participants called for gay-sensitive sex education and community programming as well as increased societal acceptance. Overall, respondents recommended interpersonal and structural-level interventions that emphasized the importance of reducing stigma as a key component of HIV prevention. PMID- 26443794 TI - Recent insights into the biological functions of liver fatty acid binding protein 1. AB - Over four decades have passed since liver fatty acid binding protein (FABP)1 was first isolated. There are few protein families for which most of the complete tertiary structures, binding properties, and tissue occurrences are described in such detail and yet new functions are being uncovered for this protein. FABP1 is known to be critical for fatty acid uptake and intracellular transport and also has an important role in regulating lipid metabolism and cellular signaling pathways. FABP1 is an important endogenous cytoprotectant, minimizing hepatocyte oxidative damage and interfering with ischemia-reperfusion and other hepatic injuries. The protein may be targeted for metabolic activation through the cross talk among many transcriptional factors and their activating ligands. Deficiency or malfunction of FABP1 has been reported in several diseases. FABP1 also influences cell proliferation during liver regeneration and may be considered as a prognostic factor for hepatic surgery. FABP1 binds and modulates the action of many molecules such as fatty acids, heme, and other metalloporphyrins. The ability to bind heme is another cytoprotective property and one that deserves closer investigation. The role of FABP1 in substrate availability and in protection from oxidative stress suggests that FABP1 plays a pivotal role during intracellular bacterial/viral infections by reducing inflammation and the adverse effects of starvation (energy deficiency). PMID- 26443797 TI - Challenges in Exploratory Methods for Tuberculosis Research in South Africa. AB - Haunted by a legacy of apartheid governance that left millions in material poverty, South Africa has among the highest tuberculosis (TB) morbidity and mortality rates in the world. Our Social Markers of TB research project shared a vision of working with ethnographic research methods to understand TB-infected persons, their families, care providers, and social networks. We argue that felt and enacted TB stigma and the related HIV-TB stigma impaired our ability to collect the necessary data for a full portrait of TB-infected persons and their lived conditions. To circumvent this limitation, each researcher improvised and augmented conventional anthropological methods with more creative, directed, and at times destabilizing methods. We present three case studies as useful illustrations of the complexities and challenges we encountered in our attempts to conduct ethically sound TB research. We discuss the implications of our call for "improvisation" for the politics of research and ethical oversight. PMID- 26443798 TI - Childbearing Experiences Following an HIV Diagnosis in Iringa, Tanzania. AB - People living with HIV (PLHIV) continue to have children after being diagnosed with HIV, yet little research attention has been paid to actual lived childbearing experiences of PLHIV post-HIV diagnosis. We interviewed 10 HIV positive women and 11 HIV-positive men in Iringa, Tanzania, about their experiences of conceiving and having children after being diagnosed with HIV. We adopted an approach to data analysis based on grounded theory and phenomenology. Participants' experiences were shaped by social and institutional factors. Some participants reported pressures to bear children by partners and relatives, whereas others reported negative reactions from others concerning their pregnancies. Most participants had not discussed having children with a provider before attempting to conceive. Some reported being reprimanded by health providers for getting pregnant without seeking their advice. Consideration of support systems and challenges surrounding the childbearing experiences of PLHIV can help inform reproductive health interventions for those who desire children. PMID- 26443800 TI - Feasibility of a Modified Biopsy Needle for Irreversible Electroporation Ablation and Periprocedural Tissue Sampling. AB - OBJECTIVES: To test the feasibility of modified biopsy needles as probes for irreversible electroporation ablation and periprocedural biopsy. METHODS: Core biopsy needles of 16-G/9-cm were customized to serve as experimental ablation probes. Computed tomography-guided percutaneous irreversible electroporation was performed in in vivo porcine kidneys with pairs of experimental (n = 10) or standard probes (n = 10) using a single parameter set (1667 V/cm, ninety 100 us pulses). Two biopsy samples were taken immediately following ablation using the experimental probes (n = 20). Ablation outcomes were compared using computed tomography, simulation, and histology. Biopsy and necropsy histology were compared. RESULTS: Simulation-suggested ablations with experimental probes were smaller than that with standard electrodes (455.23 vs 543.16 mm2), although both exhibited similar shape. Computed tomography (standard: 556 +/- 61 mm2, experimental: 515 +/- 67 mm2; P = .25) and histology (standard: 313 +/- 77 mm2, experimental: 275 +/- 75 mm2; P = .29) indicated ablations with experimental probes were not significantly different from the standard. Histopathology indicated similar morphological changes in both groups. Biopsies from the ablation zone yielded at least 1 core with sufficient tissue for analysis (11 of the 20). CONCLUSIONS: A combined probe for irreversible electroporation ablation and periprocedural tissue sampling from the ablation zone is feasible. Ablation outcomes are comparable to those of standard electrodes. PMID- 26443801 TI - Lupeol Induces Apoptosis and Cell Cycle Arrest of Human Osteosarcoma Cells Through PI3K/AKT/mTOR Pathway. AB - Lupeol, a dietary triterpene present in many fruits and medicinal plants, has been reported to possess many pharmacological properties including anticancer effect in vitro and in vivo However, the activity of lupeol against osteosarcoma remains unclear. The present study is conducted to investigate the anticancer activity and the underlying mechanisms of lupeol on human osteosarcoma cells (MNNG/HOS and MG-63) in vitro and in vivo MNNG/HOS and MG-63 cells were treated by lupeol and subjected to methyl thiazolyl tetrazolium analysis, Hoechst staining, annexin V/propidium iodide double staining, cell cycle analysis, and Western blot analysis. In addition, MNNG/HOS xenograft tumors were established in female nude BALB/c mice, and lupeol was intravenously administered to evaluate the anticancer capacity in vivo Our results showed that lupeol induced apoptosis as well as cell cycle arrest in G0/G1 phase of MNNG/HOS and MG-63 cells in a dose dependent manner in vitro Furthermore, the protein expression levels of phospho phosphatidylinositol 3-kinase (p-PI3K), phospho-protein kinase B (p-AKT), p p70S6K, and cyclin D1 were significantly downregulated, whereas the expression levels of p21 and p27 were upregulated. These protein interactions may play a pivotal role in the regulation of apoptosis and cell cycle arrest. More importantly, our in vivo studies showed that administration of lupeol decreased tumor growth in a dose-dependent manner and has no significant effect on the function of liver and kidney. Taken together, our findings indicated that lupeol can induce apoptosis as well as cell cycle arrest of human osteosarcoma cells through phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway and might offer a promising new approach in the effective treatment of osteosarcoma. PMID- 26443802 TI - Images in Vascular Medicine. A new or overlooked finding of varicose veins: Ecchymosis. PMID- 26443803 TI - Chronic cough revealing a giant thoraco-abdominal aortic aneurysm. PMID- 26443804 TI - Recombinant Immunotoxin with T-cell Epitope Mutations That Greatly Reduce Immunogenicity for Treatment of Mesothelin-Expressing Tumors. AB - SS1P is a recombinant immunotoxin (RIT) that targets mesothelin. It consists of an antimesothelin Fv fused to a portion of Pseudomonas exotoxin A. In clinical studies, it has produced dramatic responses in patients with advanced mesothelioma, when combined with immunosuppressive therapy so that several treatment cycles could be given. Otherwise its activity is limited by its immunogenicity. In this work, we describe the development and characterization of LMB-T20, a highly potent RIT targeted at mesothelin-expressing cancers with low immunogenicity due to removal of its eight T-cell epitopes. LMB-T20 was more active than SS1P when tested on four different mesothelin-expressing cell lines as well as on cells obtained from patients with mesothelioma. It also has potent antitumor activity in mice, and has reduced immunogenicity as measured by cytokine secretion assays. In conclusion, LMB-T20 is a favorable candidate for evaluation in clinical trials due to its reduced immunogenicity and excellent activity. PMID- 26443805 TI - Genome-Wide Identification of a Methylation Gene Panel as a Prognostic Biomarker in Nasopharyngeal Carcinoma. AB - DNA methylation, the best known epigenetic marker, can be used as a prognostic biomarker in many cancers. We examined DNA methylation status and survival in nasopharyngeal carcinoma (NPC) patients. Aberrant DNA-methylated genes in 24 NPC tissues and 24 noncancer nasopharyngitis biopsy tissues (NCNBT) were identified using Illumina 450K BeadChip. Correlations between DNA methylation and clinical outcomes were evaluated using bisulfite pyrosequencing in 454 NPC patients. Genome-wide methylation analysis demonstrated that NPC tissues had distinct DNA methylation patterns compared with NCNBT. Among all significant CpG sites, 2,173 CpG sites with beta change >= 0.2 (1,880 hypermethylated, 293 hypomethylated) were identified (P < 0.05). A methylation gene panel comprising six hypermethylated genes was constructed with the average Z-score method. Patients in the training cohort with high methylation had poorer disease-free survival [DFS, HR, 2.26; 95% confidence interval (CI), 1.28-4.01; P, 0.005] and overall survival (OS, HR, 2.47; 95% CI, 1.30-4.71; P, 0.006) than those with low methylation. There were similar results in the validation (DFS, HR, 2.07; 95% CI, 1.17-3.67; P, 0.013; OS, HR, 1.83; 95% CI, 1.01-3.31; P, 0.046) and independent cohorts (DFS, HR, 1.94; 95% CI, 1.08-3.47; P, 0.026; OS, HR, 2.09; 95% CI, 1.10 3.98; P, 0.022). Analysis indicated that the methylation gene panel was an independent prognostic factor. Furthermore, patients with low methylation had a favorable response to concurrent chemotherapy with an improved DFS (P = 0.045) and OS (P = 0.031), whereas patients with high methylation did not benefit from concurrent chemotherapy. The six-hypermethylated gene panel was associated with poor survival in patients with NPC, demonstrating its potential usefulness as a prognostic biomarker to clinicians in NPC management. PMID- 26443806 TI - Antitumor Activity of KW-2450 against Triple-Negative Breast Cancer by Inhibiting Aurora A and B Kinases. AB - Currently, no targeted drug is available for triple-negative breast cancer (TNBC), an aggressive breast cancer that does not express estrogen receptor, progesterone receptor, or HER2. TNBC has high mitotic activity, and, because Aurora A and B mitotic kinases drive cell division and are overexpressed in tumors with a high mitotic index, we hypothesized that inhibiting Aurora A and B produces a significant antitumor effect in TNBC. We tested this hypothesis by determining the antitumor effects of KW-2450, a multikinase inhibitor of both Aurora A and B kinases. We observed significant inhibitory activities of KW-2450 on cell viability, apoptosis, colony formation in agar, and mammosphere formation in TNBC cells. The growth of TNBC xenografts was significantly inhibited with KW 2450. In cell-cycle analysis, KW-2450 induced tetraploid accumulation followed by apoptosis or surviving octaploid (8N) cells, depending on dose. These phenotypes resembled those of Aurora B knockdown and complete pharmaceutical inhibition of Aurora A. We demonstrated that 8N cells resulting from KW-2450 treatment depended on the activation of mitogen-activated protein kinase kinase (MEK) for their survival. When treated with the MEK inhibitor selumetinib combined with KW-2450, compared with KW-2450 alone, the 8N cell population was significantly reduced and apoptosis was increased. Indeed, this combination showed synergistic antitumor effect in SUM149 TNBC xenografts. Collectively, Aurora A and B inhibition had a significant antitumor effect against TNBC, and this antitumor effect was maximized by the combination of selumetinib with Aurora A and B inhibition. PMID- 26443807 TI - The impact of oxaliplatin on the gonads: from bedside to the bench. AB - STUDY HYPOTHESIS: What is the impact of oxaliplatin on gonadal function? STUDY FINDING: Our results in both the clinical and pre-clinical settings indicate that oxaliplatin exerts moderate transient gonadal toxicity. WHAT IS KNOWN ALREADY: Recent studies have indicated a significant increase in survivorship of colorectal cancer patients of reproductive age, who may then face fertility concerns. The impact of oxaliplatin on gonadal function is yet to be discovered. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Eleven female (<43 years) and eight male (<45 years) patients recently diagnosed with colorectal cancer, who were candidates for oxaliplatin-based protocol, were enrolled into the study. FSH, estradiol, anti-Mullerian hormone (AMH) and menstrual pattern were measured in female patients, whereas FSH, inhibin-B, testosterone, and steroid-hormone binding globulin were measured in male patients. Hormones were measured at baseline and 6 months post-treatment (last chemotherapy administration) in men and women. In the animal model, pubertal mice were injected with oxaliplatin and sacrificed 1 week, 1 month and 3 months later. Ovarian reserve was estimated by serum AMH measurements. Testicular function was evaluated by serum inhibin-B and sperm evaluation. Gonadal apoptosis (TUNEL), proliferation (Ki-67), repair (PCNA), ovarian reserve (AMH) and testicular reserve (DAZL) were measured by immunohistochemistry. MAIN RESULTS AND THE ROLE OF CHANCE: In all women, AMH decreased post-treatment, but remained above the detection limit in 9/11 patients (P < 0.05). FSH was elevated, but did not exceed the premenopausal range in 9/11 patients. All patients remain menstruating or resumed menstruation post treatment. In female mice oxaliplatin induced transient apoptosis at 1-month post treatment. In men Inhibin-B was slightly reduced post-treatment. In male mice oxaliplatin did not affect spermatozoa concentration, but was associated with transient, moderate reductions of spermatocytes-spermatogonia numbers and spermatozoa motility. LIMITATIONS, REASONS FOR CAUTION: Future prospective large scale studies are warranted in order to affirm these outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Due to high survival rates of colorectal cancer patients of reproductive age that were diagnosed at early stages of the disease, the issue of treatment-induced gonadotoxicity gains significance. Since at the individual level there might be a risk of infertility, a detailed discussion and referral to fertility preservation prior to initiation of treatment is recommended. Nevertheless, oxaliplatin-based protocols appear to be less gonadotoxic than other chemotherapeutic protocols. LARGE SCALE DATA: None. STUDY FUNDING AND COMPETING INTERESTS: This study was supported by the Israeli Science Foundation (ISF) grant 13-1816 (I.B.-A.). There is no conflict of interest. PMID- 26443808 TI - Brown-Vialetto-Van Laere syndrome: a 28-year follow-up. PMID- 26443809 TI - 3'-Deoxyadenosine (Cordycepin) Produces a Rapid and Robust Antidepressant Effect via Enhancing Prefrontal AMPA Receptor Signaling Pathway. AB - BACKGROUND: The development of rapid and safe antidepressants for the treatment of major depression is in urgent demand. Converging evidence suggests that glutamatergic signaling seems to play important roles in the pathophysiology of depression. METHODS: We studied the antidepressant effects of 3(')-deoxyadenosine (3'-dA, Cordycepin) and the critical role of the alpha-amino-3-hydroxy-5-methyl-4 isoxazole propionic acid (AMPA) receptor in male CD-1 mice via behavioral and biochemical experiments. After 3'-dA treatment, the phosphorylation and synaptic localization of the AMPA receptors GluR1 and GluR2 were determined in the prefrontal cortex (PFC) and hippocampus (HIP). The traditional antidepressant imipramine was applied as a positive control. RESULTS: We found that an injection of 3'-dA led to a rapid and robust antidepressant effect, which was significantly faster and stronger than imipramine, after 45min in tail suspension and forced swim tests. This antidepressant effect remained after 5 days of treatment with 3' dA. Unlike the psycho-stimulants, 3'-dA did not show a hyperactive effect in the open field test. After 45min or 5 days of treatment, 3'-dA enhanced GluR1 S845 phosphorylation in both the PFC and HIP. In addition, after 45min of treatment, 3'-dA significantly up-regulated GluR1 S845 phosphorylation and GluR1, but not GluR2 levels, at the synapses in the PFC. After 5 days of treatment, 3'-dA significantly enhanced GluR1 S845 phosphorylation and GluR1, but not GluR2, at the synapses in the PFC and HIP. Moreover, the AMPA-specific antagonist GYKI 52466 was able to block the rapid antidepressant effects of 3'-dA. CONCLUSION: This study identified 3'-dA as a novel rapid antidepressant with clinical potential and multiple beneficial mechanisms, particularly in regulating the prefrontal AMPA receptor signaling pathway. PMID- 26443810 TI - Oxidative Stress and Response to Thymidylate Synthase-Targeted Antimetabolites. AB - Thymidylate synthase (TYMS; EC 2.1.1.15) catalyzes the reductive methylation of 2'-deoxyuridine-5'-monophosphate (dUMP) by N(5),N(10)-methyhlenetetrahydrofolate, forming dTMP for the maintenance of DNA replication and repair. Inhibitors of TYMS have been widely used in the treatment of neoplastic disease. A number of fluoropyrimidine and folate analogs have been developed that lead to inhibition of the enzyme, resulting in dTMP deficiency and cell death. In the current study, we have examined the role of oxidative stress in response to TYMS inhibitors. We observed that intracellular reactive oxygen species (ROS) concentrations are induced by these inhibitors and promote apoptosis. Activation of the enzyme NADPH oxidase (NOX), which catalyzes one-electron reduction of O2 to generate superoxide (O2 (?-)), is a significant source of increased ROS levels in drug treated cells. However, gene expression profiling revealed a number of other redox-related genes that may contribute to ROS generation. TYMS inhibitors also induce a protective response, including activation of the transcription factor nuclear factor E2-related factor 2 (NRF2), a critical mediator of defense against oxidative and electrophilic stress. Our results show that exposure to TYMS inhibitors induces oxidative stress that leads to cell death, while simultaneously generating a protective response that may underlie resistance against such death. PMID- 26443811 TI - A Green's function method for simulation of time-dependent solute transport and reaction in realistic microvascular geometries. AB - A novel theoretical method is presented for simulating the spatially resolved convective and diffusive transport of reacting solutes between microvascular networks and the surrounding tissues. The method allows for efficient computational solution of problems involving convection and non-linear binding of solutes in blood flowing through microvascular networks with realistic 3D geometries, coupled with transvascular exchange and diffusion and reaction in the surrounding tissue space. The method is based on a Green's function approach, in which the solute concentration distribution in the tissue is expressed as a sum of fields generated by time-varying distributions of discrete sources and sinks. As an example of the application of the method, the washout of an inert diffusible tracer substance from a tissue region perfused by a network of microvessels is simulated, showing its dependence on the solute's transvascular permeability and tissue diffusivity. Exponential decay of the washout concentration is predicted, with rate constants that are about 10-30% lower than the rate constants for a tissue cylinder model with the same vessel length, vessel surface area and blood flow rate per tissue volume. PMID- 26443812 TI - The usage of a three-compartment model to investigate the metabolic differences between hepatic reductase null and wild-type mice. AB - 278: The Cytochrome P450 (CYP) system is involved in 90% of the human body's interactions with xenobiotics and due to this, it has become an area of avid research including the creation of transgenic mice. This paper proposes a three compartment model which is used to explain the drug metabolism in the Hepatic Reductase Null (HRN) mouse developed by the University of Dundee (Henderson, C. J., Otto, D. M. E., Carrie, D., Magnuson, M. A., McLaren, A. W., Rosewell, I. and Wolf, C. R. (2003) Inactivation of the hepatic cytochrome p450 system by conditional deletion of hepatic cytochrome p450 reductase. J. Biol. Chem. , 13480 13486). The model is compared with a two-compartment model using experimental data from studies using wild-type and HRN mice. This comparison allowed for metabolic differences between the two types of mice to be isolated. The three sets of drug data (Gefitinib, Midazolam and Thalidomide) showed that the transgenic mouse has a decreased rate of metabolism. PMID- 26443813 TI - Quality management and perceptions of teamwork and safety climate in European hospitals. AB - OBJECTIVE: This study aimed to investigate the associations of quality management systems with teamwork and safety climate, and to describe and compare differences in perceptions of teamwork climate and safety climate among clinical leaders and frontline clinicians. METHOD: We used a multi-method, cross-sectional approach to collect survey data of quality management systems and perceived teamwork and safety climate. Our data analyses included descriptive and multilevel regression methods. SETTING AND PARTICIPANTS: Data on implementation of quality management system from seven European countries were evaluated including patient safety culture surveys from 3622 clinical leaders and 4903 frontline clinicians. MAIN OUTCOME MEASURES: Perceived teamwork and safety climate. RESULTS: Teamwork climate was reported as positive by 67% of clinical leaders and 43% of frontline clinicians. Safety climate was perceived as positive by 54% of clinical leaders and 32% of frontline clinicians. We found positive associations between implementation of quality management systems and teamwork and safety climate. CONCLUSIONS: Our findings, which should be placed in a broader clinical quality improvement context, point to the importance of quality management systems as a supportive structural feature for promoting teamwork and safety climate. To gain a deeper understanding of this association, further qualitative and quantitative studies using longitudinally collected data are recommended. The study also confirms that more clinical leaders than frontline clinicians have a positive perception of teamwork and safety climate. Such differences should be accounted for in daily clinical practice and when tailoring initiatives to improve teamwork and safety climate. PMID- 26443814 TI - Quality improvement and accountability in the Danish health care system. AB - Denmark has unique opportunities for quality measurement and benchmarking since Denmark has well-developed health registries and unique patient identifier that allow all registries to include patient-level data and combine data into sophisticated quality performance monitoring. Over decades, Denmark has developed and implemented national quality and patient safety initiatives in the healthcare system in terms of national clinical guidelines, performance and outcome measurement integrated in clinical databases for important diseases and clinical conditions, measurement of patient experiences, reporting of adverse events, national handling of patient complaints, national accreditation and public disclosure of all data on the quality of care. Over the years, Denmark has worked up a progressive and transparent just culture in quality management; the different actors at the different levels of the healthcare system are mutually attentive and responsive in a coordinated effort for quality of the healthcare services. At national, regional, local and hospital level, it is mandatory to participate in the quality initiatives and to use data and results for quality management, quality improvement, transparency in health care and accountability. To further develop the Danish governance model, it is important to expand the model to the primary care sector. Furthermore, a national quality health programme 2015-18 recently launched by the government supports a new development in health care focusing upon delivering high-quality health care-high quality is defined by results of value to the patients. PMID- 26443815 TI - Population experiences of primary care in 11 Organization for Economic Cooperation and Development countries. AB - OBJECTIVE: To develop a measure of individual user assessments of primary care and test its association with health system performance and quality indicators. DESIGN: Cross-sectional analysis of secondary survey data collected in 2013. SETTING: Australia, Canada, France, Germany, Netherlands, New Zealand, Norway, Sweden, Switzerland, the UK and the USA. STUDY PARTICIPANTS: 20 045 respondents. MAIN OUTCOME MEASURES: Individual report of financial protection (out of pocket expenses over USD 1000), lack of receipt of appropriate/timely care (use of the emergency room in the past 2 years, having consulted three of more doctors in the past year) and clinical prevention (blood pressure check in past year, cholesterol checked in the past 5 years, receipt of influenza vaccination in past year and report of any medical error). METHODS: A score of users' primary care experiences was constructed from 14 individual survey questions. Multivariable Poisson and augmented inverse-probability weighted regression assess the relationship between the primary care experience score and outcomes. RESULTS: Countries differed regarding the proportion of the population experiencing problems with primary care. In analyses controlling for age, sex, health status, chronic disease, income level and health insurance, users experiencing poorer primary care were significantly more likely to report significant out of pocket expenses, emergency room use in the past 2 years, having consulted more than three doctors in the past year, lower likelihood of blood pressure or cholesterol screening, an annual flu shot and higher reports of medical error. CONCLUSIONS: The measure of individual primary care experience can be used to differentiate among different country's primary care approaches and is strongly associated with overall health system performance and quality indicators. PMID- 26443816 TI - Missense mutations of PBP2a are associated with reduced susceptibility to ceftaroline and ceftobiprole in African MRSA. AB - OBJECTIVES: Ceftaroline and ceftobiprole are new cephalosporins, which are active against MRSA by inhibiting PBP2a. Recently, high rates of resistance to ceftaroline were reported from Ghana. The objective of this study was to assess rates of resistance to ceftaroline and ceftobiprole in MRSA from Africa and to describe potential missense mutations of PBP2a. METHODS: MRSA isolates derived from Staphylococcus aureus colonization (n = 37) and infection (n = 23) and were collected in Cote d'Ivoire (n = 17), DR Congo (n = 6), Gabon (n = 21) and Nigeria (n = 16). The MICs were determined by the broth microdilution method. The mecA gene was sequenced and missense mutations were associated with the corresponding MLST ST. RESULTS: In total, 16.7% (n = 10) and 15% (n = 9) of isolates were resistant to ceftaroline and ceftobiprole, respectively. The corresponding MICs of ceftaroline and ceftobiprole correlated significantly (r = 0.92). Isolates belonging to ST241 harboured a triple mutation of PBP2a (N146K-N204K-G246E), which was associated with high rates of resistance to ceftaroline (90.9%) and ceftobiprole (81.8%). CONCLUSIONS: Resistances to ceftaroline and ceftobiprole were only detected in Nigeria and were associated with ST241 and a triple mutation of PBP2a. PMID- 26443817 TI - Chaperome screening leads to identification of Grp94/Gp96 and FKBP4/52 as modulators of the alpha-synuclein-elicited immune response. AB - We have investigated the potential role of molecular chaperones as modulators of the immune response by using alpha-synuclein (alphaSyn) as an aggregation-prone model protein. We first performed an in vitro immunoscreening with 21 preselected candidate chaperones and selected 2 from this set as displaying immunological activity with differential profiles, Grp94/Gp96 and FKBP4/52. We then immunized mice with both chaperone/alpha-synuclein combinations using monomeric or oligomeric alpha-synuclein (MalphaSyn or OalphaSyn, respectively), and we characterized the immune response generated in each case. We found that Grp94 promoted alphaSyn-specific T-helper (Th)1/Th17 and IgG1 antibody responses (up to a 3-fold increase) with MalphaSyn and OalphaSyn, respectively, coupled to a Th2 type general phenotype (generating 2.5-fold higher IgG1/IgG2 levels). In addition, we observed that FKBP4 favored a Th1-skewed phenotype with MalphaSyn but strongly supported a Th2-type phenotype with OalphaSyn (with a 3-fold higher IL-10/IFN-gamma serum levels). Importantly, results from adoptive transfer of splenocytes from immunized animals in a Parkinson's disease mouse model indicates that these effects are robust, stable in time, and physiologically relevant. Taken together, Grp94 and FKBP4 are able to generate differential immune responses to alpha-synuclein-based immunizations, depending both on the nature of the chaperone and on the aggregation state of alpha-synuclein. Our work reveals that several chaperones are potential modulators of the immune response and suggests that different chaperones could be exploited to redirect the amyloid elicited immunity both for basic studies of the immunological processes associated with neurodegeneration and for immunotherapy of pathologies associated with protein misfolding and aggregation. PMID- 26443818 TI - Biomedical science postdocs: an end to the era of expansion. AB - After >3 decades of steady growth, the number of biological and medical science postdoctorates at doctoral degree-granting institutions recently began to decline. From 2010 through 2013, the most recent survey years, the postdoctoral population decreased from 40,970 to 38,719, a loss of 5.5%. This decline represents a notable departure from the previous long-standing increases in the number of postdoctorates in the biomedical workforce. The rate of contraction appears to be accelerating in the most recent survey years, and this has important implications for the biomedical workforce. PMID- 26443819 TI - Scleraxis is required for the development of a functional tendon enthesis. AB - The attachment of dissimilar materials is a major engineering challenge, yet this challenge is seemingly overcome in biology. This study aimed to determine how the transcription factor Scleraxis (Scx) influences the development and maturation of the tendon-to-bone attachment (enthesis). Mice with conditional knockout (cKO) for Scx (Scx(flx/-), Prx1Cre(+)) and wild-type [(WT) Scx(flx/+) or Scx(flx/flx)] littermates were killed at postnatal days 7-56 (P7-P56). Enthesis morphometry, histology, and collagen alignment were investigated throughout postnatal growth. Enthesis tensile mechanical properties were also assessed. Laser microdissection of distinct musculoskeletal tissues was performed at P7 for WT, cKO, and muscle unloaded (botulinum toxin A treated) attachments for quantitative PCR. cKO mice were smaller, with altered bone shape and impaired enthesis morphology, morphometry, and organization. Structural alterations led to altered mechanical properties; cKO entheses demonstrated reduced strength and stiffness. In P7 attachments, cKO mice had reduced expression of transforming growth factor (TGF) superfamily genes in fibrocartilage compared with WT mice. In conclusion, deletion of Scx led to impairments in enthesis structure, which translated into impaired functional (i.e., mechanical) outcomes. These changes may be driven by transient signaling cues from mechanical loading and growth factors. PMID- 26443821 TI - Site-specific recombination in the chicken genome using Flipase recombinase mediated cassette exchange. AB - Targeted genome recombination has been applied in diverse research fields and has a wide range of possible applications. In particular, the discovery of specific loci in the genome that support robust and ubiquitous expression of integrated genes and the development of genome-editing technology have facilitated rapid advances in various scientific areas. In this study, we produced transgenic (TG) chickens that can induce recombinase-mediated gene cassette exchange (RMCE), one of the site-specific recombination technologies, and confirmed RMCE in TG chicken derived cells. As a result, we established TG chicken lines that have, Flipase (Flp) recognition target (FRT) pairs in the chicken genome, mediated by piggyBac transposition. The transgene integration patterns were diverse in each TG chicken line, and the integration diversity resulted in diverse levels of expression of exogenous genes in each tissue of the TG chickens. In addition, the replaced gene cassette was expressed successfully and maintained by RMCE in the FRT predominant loci of TG chicken-derived cells. These results indicate that targeted genome recombination technology with RMCE could be adaptable to TG chicken models and that the technology would be applicable to specific gene regulation by cis element insertion and customized expression of functional proteins at predicted levels without epigenetic influence. PMID- 26443820 TI - Basement membrane stiffening promotes retinal endothelial activation associated with diabetes. AB - Endothelial activation is a hallmark of the high-glucose (HG)-induced retinal inflammation associated with diabetic retinopathy (DR). However, precisely how HG induces retinal endothelial activation is not fully understood. We hypothesized that HG-induced up-regulation of lysyl oxidase (LOX), a collagen-cross-linking enzyme, in retinal capillary endothelial cells (ECs) enhances subendothelial basement membrane (BM) stiffness, which, in turn, promotes retinal EC activation. Diabetic C57BL/6 mice exhibiting a 70 and 50% increase in retinal intercellular adhesion molecule (ICAM)-1 expression and leukocyte accumulation, respectively, demonstrated a 2-fold increase in the levels of BM collagen IV and LOX, key determinants of capillary BM stiffness. Using atomic force microscopy, we confirmed that HG significantly enhances LOX-dependent subendothelial matrix stiffness in vitro, which correlated with an ~2.5-fold increase in endothelial ICAM-1 expression, a 4-fold greater monocyte-EC adhesion, and an ~2-fold alteration in endothelial NO (decrease) and NF-kappaB activation (increase). Inhibition of LOX-dependent subendothelial matrix stiffening alone suppressed HG induced retinal EC activation. Finally, using synthetic matrices of tunable stiffness, we demonstrated that subendothelial matrix stiffening is necessary and sufficient to promote EC activation. These findings implicate BM stiffening as a critical determinant of HG-induced retinal EC activation and provide a rationale for examining BM stiffness and underlying mechanotransduction pathways as therapeutic targets for diabetic retinopathy. PMID- 26443822 TI - Stretch regulates expression and binding of chymotrypsin-like elastase 1 in the postnatal lung. AB - Lung stretch is critical for normal lung development and for compensatory lung growth after pneumonectomy (PNX), but the mechanisms by which strain induces matrix remodeling are unclear. Our prior work demonstrated an association of chymotrypsin-like elastase 1 (Cela1) with lung elastin remodeling, and that strain triggered a near-instantaneous elastin-remodeling response. We sought to determine whether stretch regulates Cela1 expression and Cela1 binding to lung elastin. In C57BL/6J mice, Cela1 protein increased 176-fold during lung morphogenesis. Cela1 was covalently bound to serpin peptidase inhibitor, clade A, member 1, resulting in a higher molecular mass in lung homogenate compared to pancreas homogenate. Post-PNX, Cela1 mRNA increased 6-fold, protein 3-fold, and Cela1-positive cells 2-fold. Cela1 was expressed predominantly in alveolar type II cells in the embryonic lung and predominantly in CD90-positive lung fibroblasts postnatally. During compensatory lung growth, Cela1 expression was induced in nonproliferative mesenchymal cells. In ex vivo mouse lung sections, stretch increased Cela1 binding to lung tissue by 46%. Competitive inhibition with soluble elastin completely abrogated this increase. Areas of stretch-induced elastase activity and Cela1 binding colocalized. The stretch-dependent expression and binding kinetics of Cela1 indicate an important role in stretch-dependent remodeling of the peripheral lung during development and regeneration. PMID- 26443823 TI - Imaging rhodopsin degeneration in vivo in a new model of ocular ischemia in living mice. AB - Delivery of antibodies to monitor key biomarkers of retinopathy in vivo represents a significant challenge because living cells do not take up immunoglobulins to cellular antigens. We met this challenge by developing novel contrast agents for retinopathy, which we used with magnetic resonance imaging (MRI). Biotinylated rabbit polyclonal to chick IgY (rIgPxcIgY) and phosphorylthioate-modified oligoDNA (sODN) with random sequence (bio-sODN-Ran) were conjugated with NeutrAvidin-activated superparamagnetic iron oxide nanoparticles (SPION). The resulting Ran-SPION-rIgPxcIgY carries chick polyclonal to microtubule-associated protein 2 (MAP2) as Ran-SPION-rIgP/cIgY-MAP2, or to rhodopsin (Rho) as anti-Rho-SPION-Ran. We examined the uptake of Ran-SPION rIgP/cIgY-MAP2 or SPION-rIgP/cIgY-MAP2 in normal C57black6 mice (n = 3 each, 40 MUg/kg, i.c.v.); we found retention of Ran-SPION-rIgP/cIgY-MAP2 using molecular contrast-enhanced MRI in vivo and validated neuronal uptake using Cy5-goat IgPxcIgY ex vivo. Applying this novel method to monitor retinopathy in a bilateral carotid artery occlusion-induced ocular ischemia, we observed pericytes (at d 2, using Gd-nestin, by eyedrop solution), significant photoreceptor degeneration (at d 20, using anti-Rho-SPION-Ran, eyedrops, P = 0.03, Student's t test), and gliosis in Muller cells (at 6 mo, using SPION-glial fibrillary acidic protein administered by intraperitoneal injection) in surviving mice (n >= 5). Molecular contrast-enhanced MRI results were confirmed by optical and electron microscopy. We conclude that chimera and molecular contrast-enhanced MRI provide sufficient sensitivity for monitoring retinopathy and for theranostic applications. PMID- 26443824 TI - CX3CR1 deficiency delays acute skeletal muscle injury repair by impairing macrophage functions. AB - Adequate inflammatory response predominated by macrophage infiltration is essential to acute skeletal muscle injury repair. The majority of intramuscular macrophages express the chemokine receptor CX3CR1. We studied the role of CX3CR1 in regulating intramuscular macrophage number and function in acute injury repair by using a loss-of-function approach. Muscle injury repair was delayed in CX3CR1(GFP/GFP) mice as compared with wild-type (WT) controls. CX3CR1 was predominantly expressed by macrophages but not by myogenic cells or capillary endothelia cells in injured muscles. Intramuscular macrophage number and subset composition were not altered by CX3CR1 deficiency. Intramuscular macrophage phagocytosis function was impaired by CX3CR1 deficiency as demonstrated by increased number of necrotic fibers (+115%) and percentage of necrotic area (+204%) at 7 d, increased number of intramuscular neutrophils at 3 (+89%) but not 1 d, reduced number of phagocytosing macrophages (-12%) and phagocytosed beads within macrophages (-15%) in CX3CR1(GFP/GFP) mice as compared with WT controls. The mRNA expression of CD36 (-50%), CD14 (-43%), IGF-1 (-53%), and IL-6 (-40%) was reduced in CX3CR1-deficient macrophages as compared with WT controls. We conclude that CX3CR1 is important to acute skeletal muscle injury repair by regulating macrophage phagocytosis function and trophic growth factor production. PMID- 26443825 TI - Plasmodium actin is incompletely folded by heterologous protein-folding machinery and likely requires the native Plasmodium chaperonin complex to enter a mature functional state. AB - Actin filament turnover underpins several processes in the life cycle of the malaria parasite, Plasmodium falciparum. Polymerization and depolymerization are especially important for gliding motility, a substrate-dependent form of cell movement that underpins the protozoan parasite's ability to disseminate and invade host cells. To date, given difficulties in extraction of native actins directly from parasites, much of our biochemical understanding of malarial actin has instead relied on recombinant protein extracted and purified from heterologous protein expression systems. Here, using in vitro transcription translation methodologies and quantitative protein-binding assays, we explored the folding state of heterologously expressed P. falciparum actin 1 (PfACTI) with the aim of assessing the reliability of current recombinant-protein-based data. We demonstrate that PfACTI, when expressed in non-native systems, is capable of binding to and release from bacterial, yeast, and mammalian chaperonin complexes but appears to be incompletely folded. Characterization of the native Plasmodium folding machinery in silico, the chaperonin containing t-complex protein-1 complex, highlights key divergences between the different chaperonin systems that likely underpins this incomplete folded state. These results highlight the importance of characterizing actin's folded state and raise concerns about the interpretation of actin polymerization kinetics based solely on protein derived from heterologous expression systems. PMID- 26443827 TI - Letter by Woodworth and Simard Regarding Article, "Outcome Following Decompressive Hemicraniectomy for Malignant Cerebral Infarction: Ethical Considerations". PMID- 26443826 TI - Hydrogel biophysical properties instruct coculture-mediated osteogenic potential. AB - Cell-based approaches for bone formation require instructional cues from the surrounding environment. As an alternative to pharmacological strategies or transplanting single cell populations, one approach is to coimplant populations that can establish a new vasculature and differentiate to bone-forming osteoblasts. Mesenchymal stem/stromal cells (MSCs) possess osteogenic potential and produce numerous angiogenic growth factors. Endothelial colony-forming cells (ECFCs) are a subpopulation of endothelial progenitor cells capable of vasculogenesis in vivo and may provide endogenous cues to support MSC function. We investigated the contribution of the carrier biophysical properties to instruct entrapped human MSCs and ECFCs to simultaneously promote their osteogenic and proangiogenic potential. Compared with gels containing MSCs alone, fibrin gels engineered with increased compressive stiffness simultaneously increased the osteogenic and proangiogenic potential of entrapped cocultured cells. ECFCs produced bone morphogenetic protein-2 (BMP-2), a potent osteoinductive molecule, and increases in BMP-2 secretion correlated with gel stiffness. Coculture of MSCs with ECFCs transduced to knockdown BMP-2 production abrogated the osteogenic response to levels observed with MSCs alone. These results demonstrate that physical properties of engineered hydrogels modulate the function of cocultured cells in the absence of inductive cues, thus increasing the translational potential of coimplantation to speed bone formation and repair. PMID- 26443830 TI - Letter by Avasarala Regarding Article, "2015 AHA/ASA Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association". PMID- 26443828 TI - Differences in Common Genetic Predisposition to Ischemic Stroke by Age and Sex. AB - BACKGROUND AND PURPOSE: Evidence from epidemiological studies points to differences in factors predisposing to stroke by age and sex. Whether these arise because of different genetic influences remained untested. Here, we use data from 4 genome-wide association data sets to study the relationship between genetic influence on stroke with both age and sex. METHODS: Using genomic-relatedness matrix restricted maximum likelihood methods, we performed 4 analyses: (1) we calculated the genetic correlation between groups divided by age and (2) by sex, (3) we calculated the heritability of age-at-stroke-onset, and (4) we evaluated the evidence that heritability of stroke is greater in women than in men. RESULTS: We found that genetic factors influence age at stroke onset (h2 [SE]=18.0 [6.8]; P=0.0038), with a trend toward a stronger influence in women (women: h2 [SE]=21.6 [3.5]; Men: h2 [SE]=13.9 [2.8]). Although a moderate proportion of genetic factors was shared between sexes (rG [SE]=0.68 [0.16]) and between younger and older cases (rG [SE]=0.70 [0.17]), there was evidence to suggest that there are genetic susceptibility factors that are specific to sex (P=0.037) and to younger or older groups (P=0.056), particularly for women (P=0.0068). Finally, we found a trend toward higher heritability of stroke in women although this was not significantly greater than in men (P=0.084). CONCLUSIONS: Our results indicate that there are genetic factors that are either unique to or have a different effect between younger and older age groups and between women and men. Performing large, well-powered genome-wide association study analyses in these groups is likely to uncover further associations. PMID- 26443831 TI - Response to Letter Regarding Article, "Outcome Following Decompressive Hemicraniectomy for Malignant Cerebral Infarction: Ethical Considerations". PMID- 26443829 TI - Effects of Induced Hypertension on Cerebral Perfusion in Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: A Randomized Clinical Trial. AB - BACKGROUND AND PURPOSE: The presumed effectiveness of induced hypertension for treating delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage is based on uncontrolled case-series only. We assessed the effect of induced hypertension on cerebral blood flow (CBF) in aneurysmal subarachnoid hemorrhage patients with delayed cerebral ischemia in a randomized clinical trial. METHODS: Aneurysmal subarachnoid hemorrhage patients were randomized to induced or no induced hypertension (control group) at delayed cerebral ischemia onset. CBF was assessed, blinded for treatment allocation, with computed tomographic perfusion in standardized predefined regions at delayed cerebral ischemia onset and after 24 to 36 hours of study treatment. Mean arterial blood pressure was compared between groups (linear mixed model). The primary outcome measure was the difference in change in overall CBF (Mann-Whitney U test). RESULTS: Mean arterial blood pressure was, on average, 12 mm Hg (95% confidence interval, 8.6-14.5) higher in the hypertension group (n=12) than in the control group (n=13). Change in overall CBF (mL/100g per s) was -8.5 (range, -42 to 30) in the control group and 0.1 (range, -31-43) in the hypertension group (P=0.25). CONCLUSIONS: Change in overall CBF did not differ to a statistically significant extent between the groups. Based on our results, 225 to 250 patients per group are needed to find a statistically significant difference in change in overall CBF between induced hypertension and no hypertension. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT0161323. PMID- 26443832 TI - Alteplase Reduces Downstream Microvascular Thrombosis and Improves the Benefit of Large Artery Recanalization in Stroke. AB - BACKGROUND AND PURPOSE: Downstream microvascular thrombosis (DMT) is known to be a contributing factor to incomplete reperfusion in acute ischemic stroke. The aim of this study was to determine the timing of DMT with intravital imaging and to test the hypothesis that intravenous alteplase infusion could reduce DMT in a transient middle cerebral artery occlusion (MCAO) rat stroke model. METHODS: Rats were subjected to 60-minute transient MCAO. Alteplase (10 mg/kg) was administered 30 minutes after the beginning of MCAO. Real-time intravital fluorescence microscopy through a dura-sparing craniotomy was used to visualize circulating blood cells and fibrinogen. Cerebral microvessel patency was quantitatively evaluated by fluorescein isothiocyanate-dextran perfusion. RESULTS: Immediately after MCAO, platelet and leukocyte accumulation were observed mostly in the venous compartment. Within 30 minutes after MCAO, microthrombi and parietal fibrin deposits were detected in postcapillary microvessels. Alteplase treatment significantly (P=0.006) reduced infarct volume and increased the percentage of perfused vessels during MCAO (P=0.02) compared with saline. Plasma levels of fibrinogen from alteplase-treated rats showed a rapid and profound hypofibrinogenemia. In vitro platelet aggregation demonstrated that alteplase reduced platelet aggregation (P=0.0001) and facilitated platelet disaggregation (P=0.001). These effects were reversible in the presence of exogenous fibrinogen. CONCLUSIONS: Our data demonstrate that DMT is an early phenomenon initiated before recanalization. We further show that alteplase-dependent maintenance of downstream perfusion during MCAO improves acute ischemic stroke outcome through a fibrinogen-dependent platelet aggregation reduction. Our results indicate that early targeting of DMT represents a therapeutic strategy to improve the benefit of large artery recanalization in acute ischemic stroke. PMID- 26443833 TI - Quantifying the Benefit of Prehospital Rapid Treatment in Acute Stroke: Benchmark for Future Innovative Clinical Trials. AB - BACKGROUND AND PURPOSE: In acute ischemic stroke, time from onset to tissue-type plasminogen activator treatment (OTT) is a major determinant of outcome. To reduce OTT, clinical trials have been undertaken evaluating prehospital cerebral imaging with mobile computed tomographic scanners. Furthermore, blood biomarkers may allow rapid differentiation between ischemic stroke and intracerebral hemorrhage before hospital admission. How such treatment strategies translate into clinical benefit has not been specifically evaluated. METHODS: We constructed decision models to estimate the net clinical benefit yielded by shorter OTT. In different scenarios, we estimated the proportion of patients with favorable outcome and the average quality of life. RESULTS: An OTT reduction of 60 minutes increases the probability of favorable outcome by 6.6% in a mixed stroke population. For comparison, the average effect of tissue-type plasminogen activator itself is 7.0%. Prehospital mobile computed tomography gaining 25 to 40 minutes increases the probability of favorable outcome by 3.0% to 4.6%. The additional benefit of prehospital computed tomography to deliver patients with large vessel occlusion directly to endovascular treatment centers increases the probability of favorable outcome by another 0.2% to 1.0%. A blood test discriminating ischemic stroke and intracerebral hemorrhage may beneficially substitute brain scan before tissue-type plasminogen activator if >32 to 40 minutes are gained and if sensitivity for intracerebral hemorrhage is >75% to 80%. CONCLUSIONS: Reducing the OTT has robust beneficial effects for acute stroke patients. Prehospital tissue-type plasminogen activator treatment without brain imaging may become conceivable under several preconditions, including a point-of care test with >75% to 80% sensitivity to detect intracerebral hemorrhage and a time gain of >32 to 40 minutes. Ethical implications remain to be addressed. PMID- 26443834 TI - Genetic analysis of environmental strains of the plant pathogen Phytophthora capsici reveals heterogeneous repertoire of effectors and possible effector evolution via genomic island. AB - Phytophthora capsici is a virulent oomycete pathogen of many vegetable crops. Recently, it has been demonstrated that the recognition of the RXLR effector AVR3a1 of P. capsici (PcAVR3a1) triggers a hypersensitive response and plays a critical role in mediating non-host resistance. Here, we analyzed the occurrence of PcAVR3a1 in 57 isolates of P. capsici derived from globe squash, eggplant, tomato and bell pepper cocultivated in a small geographical area. The occurrence of PcAVR3a1 in environmental strains of P. capsici was confirmed by PCR in only 21 of these pathogen isolates. To understand the presence-absence pattern of PcAVR3a1 in environmental strains, the flanking region of this gene was sequenced. PcAVR3a1 was found within a genetic element that we named PcAVR3a1-GI (PcAVR3a1 genomic island). PcAVR3a1-GI was flanked by a 22-bp direct repeat, which is related to its site-specific recombination site. In addition to the PcAVR3a1 gene, PcAVR3a1-GI also encoded a phage integrase probably associated with the excision and integration of this mobile element. Exposure to plant induced the presence of an episomal circular intermediate of PcAVR3a1-GI, indicating that this mobile element is functional. Collectively, these findings provide evidence of PcAVR3a1 evolution via mobile elements in environmental strains of Phytophthora. PMID- 26443835 TI - Rationale design of quorum-quenching peptides that target the VirSR system of Clostridium perfringens. AB - In Clostridium perfringens, a 5-membered thiolactone peptide acts as an autoinducing peptide (AIPCp) to activate the VirSR two-component signal transduction system, which in turn controls the expression of genes encoding multiple toxins, including alpha, theta and kappa. To develop anti-pathogenic agents against virulent C. perfringens, quorum-quenching peptides were rationally designed based on the structure-activity relationship (SAR) data on AIPCp. Alanine scanning study of AIPCp suggested that Trp(3) and Phe(4) are involved in receptor binding and activation, respectively. On the basis of the SAR, we designed two quorum-quenching peptides with different modes of action: Z-AIPCp L2A/T5A (partial agonist) and Z-AIPCp-F4A/T5S (partial antagonist). Both peptides significantly attenuated transcription of theta toxin gene (pfoA) in a virulent strain of C. perfringens with IC50 = 0.32 and 0.72 MUM, respectively. PMID- 26443836 TI - Different roles of the C-terminal end of Stx1A and Stx2A for AB5 complex integrity and retrograde transport of Stx in HeLa cells. AB - Shiga toxin 1 (Stx1) and Shiga toxin 2 (Stx2) differ regarding receptor affinity, cellular toxicity and clinical outcome. To this date, it is not clarified in detail why the subtypes display these differences. Even though the crystal structures of Stx1 and Stx2 share overall similarities, significant differences were found in the C-terminal end of the A-subunits. The aim of this study was to investigate the role of the C-terminal end of the A-subunit in complex stability and retrograde transport by generating truncated mutants where 2, 4, 6 and 8 amino acids were removed from the C-terminal end of Stx1A and Stx2A. The results obtained show that removal of 6 or 8 amino acids from the Stx1A C-terminus abolishes the AB5 complex integrity, while removing up to 8 amino acids from Stx2A does not affect the complex in vivo (in the bacteria). We also present results showing different levels of A1-subunit in HeLa cells after exposure to Stx1, Stx2 and their truncated mutants. PMID- 26443837 TI - Social Media Use Among Physicians and Trainees: Results of a National Medical Oncology Physician Survey. AB - PURPOSE: Cancer management requires coordinated care from many health care providers, and its complexity requires physicians be up to date on current research. Web-based social media support physician collaboration and information sharing, but the extent to which physicians use social media for these purposes remains unknown. The complex field of oncology will benefit from increased use of online social media to enhance physician communication, education, and mentorship. To facilitate this, patterns of social media use among oncologists must be better understood. METHODS: A nine-item survey investigating physician social media use, designed using online survey software, was distributed via e mail to 680 oncology physicians and physicians in training in Canada. Responses were analyzed using descriptive statistics. RESULTS: A total of 207 responses (30%) were received; 72% of respondents reported using social media. Social media use was highest, at 93%, in respondents age 25 to 34 years and lowest, at 39%, in those age 45 to 54 years. This demonstrates a significant gap in social media use between younger users and mid- to late-career users. The main barrier to use was lack of free time. CONCLUSION: The identified gap in social media use between age cohorts may have negative implications for communication in oncology. Despite advancements in social media and efforts to integrate social media into medical education, most oncologists and trainees use social media rarely, which, along with the age-related gap in use, may have consequences for collaboration and education in oncology. Investigations to further understand barriers to social media use should be undertaken to enhance physician collaboration and knowledge sharing through social media. PMID- 26443838 TI - Extended RAS Gene Mutation Testing in Metastatic Colorectal Carcinoma to Predict Response to Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update 2015 Summary. PMID- 26443839 TI - Reducing Oncology Unit Central Line-Associated Bloodstream Infections: Initial Results of a Simulation-Based Educational Intervention. AB - PURPOSE: Patients with cancer may be more vulnerable to infection because of impaired immune competence as a result of their disease or chemotherapy-induced neutropenia. In these patients, central line-associated bloodstream infections (CLABSIs) can result in significant morbidity and mortality, prolonged hospitalization, and increased costs. METHODS: We developed a staff educational series to identify knowledge deficits and standardize the use, care, and maintenance of central lines, with the goal of reducing the rate of CLABSIs. The methodology used for this study employed a simulated central line care model, focused on the re-education of nursing staff from January 2012 to June 2012, and included a pretest, an educational blitz, and a post-test. The educational blitz content was tailored to specifically address the significant practice and knowledge deficits identified from the results of the pretest. RESULTS: On completion of the education program, the post-test demonstrated a 16.9% increase in nursing staff competence related to the care and maintenance of central lines. Six months before the educational series (June 2011 to January 2012), the CLABSI rate was 5.86 per 1,000 patient line-days. Throughout the educational series (February 2012 to May 2012), the CLABSI rate was 3.45. The data revealed a CLABSI rate of 3.43 for the 6-month period after the educational series (June 2012 to January 2013). CONCLUSION: A targeted educational intervention using a simulated central line care model improved competence in central line care and resulted in decreased CLABSI rates for inpatient oncology patients. PMID- 26443840 TI - The Synthetic Triterpenoid RTA 405 (CDDO-EA) Halts Progression of Liver Fibrosis and Reduces Hepatocellular Carcinoma Size Resulting in Increased Survival in an Experimental Model of Chronic Liver Injury. AB - Patients with cirrhosis have an increased risk of developing liver cancer and a higher rate of mortality. Cirrhosis currently has no known cure, and patients may benefit from new agents aimed at alleviating their complications and slowing down the rate of disease progression. Therefore, the effects of the orally bioavailable synthetic triterpenoid 2-cyano-3,12-dioxooleana- 1,9(11)-dien-28 oate-ethyl amide (CDDO-EA, RTA 405), which has potent antioxidative and antiinflammatory properties, was evaluated in a chronic carbon tetrachloride (CCl(4))-induced model of liver cirrhosis and hepatocellular carcinoma (HCC). Mice were injected with CCl(4) (to induce fibrosis and cirrhosis) or placebo biweekly for 12 weeks followed by CDDO-EA in the diet for 18 weeks with continued biweekly injections of CCl(4). Chronic CCl(4) administration resulted in cirrhosis, ascites, and HCC formation, associated with increased serum transforming growth factor-beta1, hepatic hydroxyproline content, and increased serum bilirubin. CDDO-EA, whose administration commenced after establishment of liver fibrosis, decreased liver fibrosis progression, serum bilirubin, ascites, and HCC formation and markedly increased overall survival. CDDO-EA also attenuated -TNFalpha (tumor necrosis factor-alpha), alpha-SMA (alpha smooth muscle actin), augmented -IL-10 levels, and improved histologic and serologic markers of fibrosis. CONCLUSIONS: CDDO-EA mitigates the progression of liver fibrosis induced by chronic CCl(4) administration, which is associated with the induction of antifibrogenic genes and suppression of profibrogenic genes. PMID- 26443841 TI - Environmentally Relevant Concentrations of Arsenite Induce Dose-Dependent Differential Genotoxicity Through Poly(ADP-Ribose) Polymerase Inhibition and Oxidative Stress in Mouse Thymus Cells. AB - Inhibition of DNA repair and oxidative stress are 2 common mechanisms associated with arsenic-induced genotoxicity. The purpose of this study was to examine mechanisms of genotoxicity induced by environmentally relevant doses of arsenite (As(+3)) in mouse thymus cells. An increase in DNA damage and a decrease in poly(ADP-ribose) polymerase (PARP) activity were seen in vitro following exposure to 50 nM As(+3) in primary mouse thymus cells and a murine thymus pre-T cell line, D1. 3,4-Dihydro-5[4-(1-piperindinyl) butoxyl]-1(2H)-isoquinoline, a well characterized PARP inhibitor, also produced DNA damage in D1 cells, confirming the correlation between PARP inhibition and DNA damage increase. As(+3) at 500 nM induced double strand breaks (DSBs) in DNA and oxidative stress at 4 h in D1 cells, which was reversed at 18 h. No apoptosis or decrease of viability was observed in these exposures. 4-Hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl, a widely-used antioxidant, was utilized to confirm that oxidative stress is partially responsible for the increase of strand breaks in 500 nM As(+3) exposure at 4 h. Expression of As(+3) exporters, Mdr1 and Mrp1, were found to be induced by 500 nM As(+3) in D1 cells, suggesting a possible mechanism for reversal of oxidative stress and DSBs at the 18-h timepoint. Finally, we showed that DNA damage and PARP inhibition by As(+3) were reversed by zinc (Zn(+2)) at approximate equimolar doses. Collectively, these results demonstrate that As(+3) at doses within the nanomolar range induce genotoxicity by inhibiting PARP, and produces oxidative stress at higher concentrations, which can be reversed by a Zn(+2) treatment. PMID- 26443842 TI - Correlation of In Vivo Versus In Vitro Benchmark Doses (BMDs) Derived From Micronucleus Test Data: A Proof of Concept Study. AB - In this study, we explored the applicability of using in vitro micronucleus (MN) data from human lymphoblastoid TK6 cells to derive in vivo genotoxicity potency information. Nineteen chemicals covering a broad spectrum of genotoxic modes of action were tested in an in vitro MN test using TK6 cells using the same study protocol. Several of these chemicals were considered to need metabolic activation, and these were administered in the presence of S9. The Benchmark dose (BMD) approach was applied using the dose-response modeling program PROAST to estimate the genotoxic potency from the in vitro data. The resulting in vitro BMDs were compared with previously derived BMDs from in vivo MN and carcinogenicity studies. A proportional correlation was observed between the BMDs from the in vitro MN and the BMDs from the in vivo MN assays. Further, a clear correlation was found between the BMDs from in vitro MN and the associated BMDs for malignant tumors. Although these results are based on only 19 compounds, they show that genotoxicity potencies estimated from in vitro tests may result in useful information regarding in vivo genotoxic potency, as well as expected cancer potency. Extension of the number of compounds and further investigation of metabolic activation (S9) and of other toxicokinetic factors would be needed to validate our initial conclusions. However, this initial work suggests that this approach could be used for in vitro to in vivo extrapolations which would support the reduction of animals used in research (3Rs: replacement, reduction, and refinement). PMID- 26443843 TI - N-(2-Aminoethyl) Ethanolamine-Induced Morphological, Biochemical, and Biophysical Alterations in Vascular Matrix Associated With Dissecting Aortic Aneurysm. AB - Dissecting aortic aneurysm (DAA) is an extended tear in the wall of the aorta along the plane of the vascular media. Our previous studies indicated in a developmental animal model, that DAA was related to pathological alteration in collagen, especially collagen type III. Accordingly, in the present studies, neonatal aortic vascular smooth muscle cells (VSMC) and timed pregnant Sprague Dawley rat dams were treated with N-(2-aminoethyl) ethanolamine (AEEA), which, as shown previously, causes DAA in offspring. Morphological changes in extracellular matrix (ECM) produced by VSMC in vitro were detailed with scanning electron microscopy (SEM), and biochemical changes in cells and ECM produced by VSMCs were defined by Western blotting. Biophysical changes of the collagen extracted from both the ECM produced by VSMC and extracted from fetal rat aortas were studied with atomic force microscopy (AFM). ECM disruption and irregularities were observed in VSMCs treated with AEEA by SEM. Western blotting showed that collagen type I was much more extractable, accompanied by a decrease of the pellet size after urea buffer extraction in the AEEA-treated VSMC when compared with the control. AFM found that collagen samples extracted from the fetal rat aortas of the AEEA-treated dam, and in the in vitro formed ECM prepared by decellularization, became stiffer, or more brittle, indicating that the 3D organization associated with elasticity was altered by AEEA exposure. Our results show that AEEA causes significant morphological, biochemical, and biomechanical alterations in the ECM. These in vitro and in vivo strategies are advantageous in elucidating the underlying mechanisms of DAA. PMID- 26443844 TI - Mitochondrial biogenesis and dynamics in the developing and diseased heart. AB - The mitochondrion is a complex organelle that serves essential roles in energy transduction, ATP production, and a myriad of cellular signaling events. A finely tuned regulatory network orchestrates the biogenesis, maintenance, and turnover of mitochondria. The high-capacity mitochondrial system in the heart is regulated in a dynamic way to generate and consume enormous amounts of ATP in order to support the constant pumping function in the context of changing energy demands. This review describes the regulatory circuitry and downstream events involved in mitochondrial biogenesis and its coordination with mitochondrial dynamics in developing and diseased hearts. PMID- 26443845 TI - Dynamic enhancer-gene body contacts during transcription elongation. AB - Enhancers govern transcription through multiple mechanisms, including the regulation of elongation by RNA polymerase II (RNAPII). We characterized the dynamics of looped enhancer contacts during synchronous transcription elongation. We found that many distal enhancers form stable contacts with their target promoters during the entire interval of elongation. Notably, we detected additional dynamic enhancer contacts throughout the gene bodies that track with elongating RNAPII and the leading edge of RNA synthesis. These results support a model in which the gene body changes its position relative to a stable enhancer promoter complex, which has broad ramifications for enhancer function and architectural models of transcriptional elongation. PMID- 26443846 TI - The Y3** ncRNA promotes the 3' end processing of histone mRNAs. AB - We demonstrate that the Y3/Y3** noncoding RNAs (ncRNAs) bind to the CPSF (cleavage and polyadenylation specificity factor) and that Y3** associates with the 3' untranslated region (UTR) of histone pre-mRNAs. The depletion of Y3** impairs the 3' end processing of histone pre-mRNAs as well as the formation and protein dynamics of histone locus bodies (HLBs), the site of histone mRNA synthesis and processing. HLB morphology is also disturbed by knockdown of the CPSF but not the U7-snRNP components. In conclusion, we propose that the Y3** ncRNA promotes the 3' end processing of histone pre-mRNAs by enhancing the recruitment of the CPSF to histone pre-mRNAs at HLBs. PMID- 26443847 TI - Role of the small subunit processome in the maintenance of pluripotent stem cells. AB - RNA-binding proteins (RBPs) play integral roles in gene regulation, yet only a small fraction of RBPs has been studied in the context of stem cells. Here we applied an RNAi screen for RBPs in mouse embryonic stem cells (ESCs) and identified 16 RBPs involved in pluripotency maintenance. Interestingly, six identified RBPs, including Krr1 and Ddx47, are part of a complex called small subunit processome (SSUP) that mediates 18S rRNA biogenesis. The SSUP components are preferentially expressed in stem cells and enhance the global translational rate, which is critical to sustain the protein levels of labile pluripotency factors such as Nanog and Esrrb. Furthermore, the SSUP proteins are required for efficient reprogramming of induced pluripotent stem cells. Our study uncovers the role of the SSUP and the importance of translational control in stem cell fate decision. PMID- 26443848 TI - Proliferation of progeria cells is enhanced by lamina-associated polypeptide 2alpha (LAP2alpha) through expression of extracellular matrix proteins. AB - Lamina-associated polypeptide 2alpha (LAP2alpha) localizes throughout the nucleoplasm and interacts with the fraction of lamins A/C that is not associated with the peripheral nuclear lamina. The LAP2alpha-lamin A/C complex negatively affects cell proliferation. Lamins A/C are encoded by LMNA, a single heterozygous mutation of which causes Hutchinson-Gilford progeria syndrome (HGPS). This mutation generates the lamin A variant progerin, which we show here leads to loss of LAP2alpha and nucleoplasmic lamins A/C, impaired proliferation, and down regulation of extracellular matrix components. Surprisingly, contrary to wild type cells, ectopic expression of LAP2alpha in cells expressing progerin restores proliferation and extracellular matrix expression but not the levels of nucleoplasmic lamins A/C. We conclude that, in addition to its cell cycle inhibiting function with lamins A/C, LAP2alpha can also regulate extracellular matrix components independently of lamins A/C, which may help explain the proliferation-promoting function of LAP2alpha in cells expressing progerin. PMID- 26443849 TI - Widespread JNK-dependent alternative splicing induces a positive feedback loop through CELF2-mediated regulation of MKK7 during T-cell activation. AB - Alternative splicing is prevalent among genes encoding signaling molecules; however, the functional consequence of differential isoform expression remains largely unknown. Here we demonstrate that, in response to T-cell activation, the Jun kinase (JNK) kinase MAP kinase kinase 7 (MKK7) is alternatively spliced to favor an isoform that lacks exon 2. This isoform restores a JNK-docking site within MKK7 that is disrupted in the larger isoform. Consistently, we show that skipping of MKK7 exon 2 enhances JNK pathway activity, as indicated by c-Jun phosphorylation and up-regulation of TNF-alpha. Moreover, this splicing event is itself dependent on JNK signaling. Thus, MKK7 alternative splicing represents a positive feedback loop through which JNK promotes its own signaling. We further show that repression of MKK7 exon 2 is dependent on the presence of flanking sequences and the JNK-induced expression of the RNA-binding protein CELF2, which binds to these regulatory elements. Finally, we found that ~25% of T-cell receptor-mediated alternative splicing events are dependent on JNK signaling. Strikingly, these JNK-dependent events are also significantly enriched for responsiveness to CELF2. Together, our data demonstrate a widespread role for the JNK-CELF2 axis in controlling splicing during T-cell activation, including a specific role in propagating JNK signaling. PMID- 26443850 TI - Local regulation of the Srs2 helicase by the SUMO-like domain protein Esc2 promotes recombination at sites of stalled replication. AB - Accurate completion of replication relies on the ability of cells to activate error-free recombination-mediated DNA damage bypass at sites of perturbed replication. However, as anti-recombinase activities are also recruited to replication forks, how recombination-mediated damage bypass is enabled at replication stress sites remained puzzling. Here we uncovered that the conserved SUMO-like domain-containing Saccharomyces cerevisiae protein Esc2 facilitates recombination-mediated DNA damage tolerance by allowing optimal recruitment of the Rad51 recombinase specifically at sites of perturbed replication. Mechanistically, Esc2 binds stalled replication forks and counteracts the anti recombinase Srs2 helicase via a two-faceted mechanism involving chromatin recruitment and turnover of Srs2. Importantly, point mutations in the SUMO-like domains of Esc2 that reduce its interaction with Srs2 cause suboptimal levels of Rad51 recruitment at damaged replication forks. In conclusion, our results reveal how recombination-mediated DNA damage tolerance is locally enabled at sites of replication stress and globally prevented at undamaged replicating chromosomes. PMID- 26443851 TI - Genotoxicity of flubendazole and its metabolites in vitro and the impact of a new formulation on in vivo aneugenicity. AB - The anti-parasitic benzimidazole flubendazole has been used for many years to treat intestinal infections in humans and animals. Previous genotoxicity studies have shown that the compound is not a bacterial mutagen and a bone marrow micronucleus test, using a formulation that limited systemic absorption, was negative. The purpose of this study is to explore the genotoxicity of flubendazole and its main metabolites in in vitro micronucleus studies and to test a new oral formulation that improves systemic absorption in an in vivo micronucleus test. The isolated metabolites were also screened using the Ames test for bacterial mutagenicity. It was found that flubendazole, like other chemically related benzimidazoles used in anti-parasitic therapies, is a potent aneugen in vitro The hydrolysed metabolite of flubendazole is negative in these tests, but the reduced metabolite (R- and S-forms) shows both aneugenic and clastogenic activity. However, in vitro micronucleus tests of flubendazole in the presence of rat liver S9 gave almost identical signals for aneugenicity as they did in the absence of S9, suggesting that any clastogenicity from the reduced metabolite is not sufficient to change the overall profile. Like flubendazole itself, both metabolites are negative in the Ames test. Analysis of dose-response curves from the in vitro tests, using recently developed point of departure approaches, demonstrate that the aneugenic potency of flubendazole is very similar to related anti-parasitic benzimidazoles, including albendazole, which is used in mass drug administration programmes to combat endemic filarial diseases. The in vivo micronucleus test of the new formulation of flubendazole also showed evidence of induced aneugenicity. Analysis of the in vivo data allowed a reference dose for aneugenicity to be established which can be compared with therapeutic exposures of flubendazole when this has been established. Analysis of the plasma from the animals used in the in vivo micronucleus test showed that there is increased exposure to flubendazole compared with previously tested formulations, as well as significant formation of the non-genotoxic hydrolysed metabolite of flubendazole and small levels of the reduced metabolite. In conclusion, this study shows that flubendazole is a potent aneugen in vitro with similar potency to chemically related benzimidazoles currently used as anti parasitic therapies. The reduced metabolite also has aneugenic properties as well as clastogenic properties. Treatment with a new formulation of flubendazole that allows increased systemic exposure, compared with previously used formulations, also results in detectable aneugenicity in vivo. Based on the lack of carcinogenicity of this class of benzimidazoles and the intended short-term dosing, it is unlikely that flubendazole treatment will pose a carcinogenic risk to patients. PMID- 26443853 TI - News Feature: Reionizing the universe. PMID- 26443852 TI - The genome as a record of environmental exposure. AB - Whole genome sequencing of human tumours has revealed distinct patterns of mutation that hint at the causative origins of cancer. Experimental investigations of the mutations and mutation spectra induced by environmental mutagens have traditionally focused on single genes. With the advent of faster cheaper sequencing platforms, it is now possible to assess mutation spectra in experimental models across the whole genome. As a proof of principle, we have examined the whole genome mutation profiles of mouse embryo fibroblasts immortalised following exposure to benzo[a]pyrene (BaP), ultraviolet light (UV) and aristolochic acid (AA). The results reveal that each mutagen induces a characteristic mutation signature: predominantly G->T mutations for BaP, C->T and CC->TT for UV and A->T for AA. The data are not only consistent with existing knowledge but also provide additional information at higher levels of genomic organisation. The approach holds promise for identifying agents responsible for mutations in human tumours and for shedding light on the aetiology of human cancer. PMID- 26443854 TI - Core Concept: Atom interferometry. PMID- 26443856 TI - Drosophila TRPA1 isoforms detect UV light via photochemical production of H2O2. AB - The transient receptor potential A1 (TRPA1) channel is an evolutionarily conserved detector of temperature and irritant chemicals. Here, we show that two specific isoforms of TRPA1 in Drosophila are H2O2 sensitive and that they can detect strong UV light via sensing light-induced production of H2O2. We found that ectopic expression of these H2O2-sensitive Drosophila TRPA1 (dTRPA1) isoforms conferred UV sensitivity to light-insensitive HEK293 cells and Drosophila neurons, whereas expressing the H2O2-insensitive isoform did not. Curiously, when expressed in one specific group of motor neurons in adult flies, the H2O2-sensitive dTRPA1 isoforms were as competent as the blue light-gated channelrhodopsin-2 in triggering motor output in response to light. We found that the corpus cardiacum (CC) cells, a group of neuroendocrine cells that produce the adipokinetic hormone (AKH) in the larval ring gland endogenously express these H2O2-sensitive dTRPA1 isoforms and that they are UV sensitive. Sensitivity of CC cells required dTRPA1 and H2O2 production but not conventional phototransduction molecules. Our results suggest that specific isoforms of dTRPA1 can sense UV light via photochemical production of H2O2. We speculate that UV sensitivity conferred by these isoforms in CC cells may allow young larvae to activate stress response--a function of CC cells--when they encounter strong UV, an aversive stimulus for young larvae. PMID- 26443857 TI - An invertebrate smooth muscle with striated muscle myosin filaments. AB - Muscle tissues are classically divided into two major types, depending on the presence or absence of striations. In striated muscles, the actin filaments are anchored at Z-lines and the myosin and actin filaments are in register, whereas in smooth muscles, the actin filaments are attached to dense bodies and the myosin and actin filaments are out of register. The structure of the filaments in smooth muscles is also different from that in striated muscles. Here we have studied the structure of myosin filaments from the smooth muscles of the human parasite Schistosoma mansoni. We find, surprisingly, that they are indistinguishable from those in an arthropod striated muscle. This structural similarity is supported by sequence comparison between the schistosome myosin II heavy chain and known striated muscle myosins. In contrast, the actin filaments of schistosomes are similar to those of smooth muscles, lacking troponin dependent regulation. We conclude that schistosome muscles are hybrids, containing striated muscle-like myosin filaments and smooth muscle-like actin filaments in a smooth muscle architecture. This surprising finding has broad significance for understanding how muscles are built and how they evolved, and challenges the paradigm that smooth and striated muscles always have distinctly different components. PMID- 26443858 TI - Selective optogenetic activation of arcuate kisspeptin neurons generates pulsatile luteinizing hormone secretion. AB - Normal reproductive functioning in mammals depends upon gonadotropin-releasing hormone (GnRH) neurons generating a pulsatile pattern of gonadotropin secretion. The neural mechanism underlying the episodic release of GnRH is not known, although recent studies have suggested that the kisspeptin neurons located in the arcuate nucleus (ARN) may be involved. In the present experiments we expressed channelrhodopsin (ChR2) in the ARN kisspeptin population to test directly whether synchronous activation of these neurons would generate pulsatile luteinizing hormone (LH) secretion in vivo. Characterization studies showed that this strategy targeted ChR2 to 70% of all ARN kisspeptin neurons and that, in vitro, these neurons were activated by 473-nm blue light with high fidelity up to 30 Hz. In vivo, the optogenetic activation of ARN kisspeptin neurons at 10 and 20 Hz evoked high amplitude, pulse-like increments in LH secretion in anesthetized male mice. Stimulation at 10 Hz for 2 min was sufficient to generate repetitive LH pulses. In diestrous female mice, only 20-Hz activation generated significant increments in LH secretion. In ovariectomized mice, 5-, 10-, and 20-Hz activation of ARN kisspeptin neurons were all found to evoke LH pulses. Part of the sex difference, but not the gonadal steroid dependence, resulted from differential pituitary sensitivity to GnRH. Experiments in kisspeptin receptor-null mice, showed that kisspeptin was the critical neuropeptide underlying the ability of ARN kisspeptin neurons to generate LH pulses. Together these data demonstrate that synchronized activation of the ARN kisspeptin neuronal population generates pulses of LH. PMID- 26443859 TI - A complexity classification of spin systems with an external field. AB - We study the computational complexity of approximating the partition function of a q-state spin system with an external field. There are just three possible levels of computational difficulty, depending on the interaction strengths between adjacent spins: (i) efficiently exactly computable, (ii) equivalent to the ferromagnetic Ising model, and (iii) equivalent to the antiferromagnetic Ising model. Thus, every nontrivial q-state spin system, irrespective of the number q of spins, is computationally equivalent to one of two fundamental two state spin systems. PMID- 26443860 TI - Resting state of the human proton channel dimer in a lipid bilayer. AB - The voltage-gated proton channel Hv1 plays a critical role in the fast proton translocation that underlies a wide range of physiological functions, including the phagocytic respiratory burst, sperm motility, apoptosis, and metastatic cancer. Both voltage activation and proton conduction are carried out by a voltage-sensing domain (VSD) with strong similarity to canonical VSDs in voltage dependent cation channels and enzymes. We set out to determine the structural properties of membrane-reconstituted human proton channel (hHv1) in its resting conformation using electron paramagnetic resonance spectroscopy together with biochemical and computational methods. We evaluated existing structural templates and generated a spectroscopically constrained model of the hHv1 dimer based on the Ci-VSD structure at resting state. Mapped accessibility data revealed deep water penetration through hHv1, suggesting a highly focused electric field, comprising two turns of helix along the fourth transmembrane segment. This region likely contains the H(+) selectivity filter and the conduction pore. Our 3D model offers plausible explanations for existing electrophysiological and biochemical data, offering an explicit mechanism for voltage activation based on a one-click sliding helix conformational rearrangement. PMID- 26443861 TI - Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis. AB - Homeostatic synaptic plasticity is a form of non-Hebbian plasticity that maintains stability of the network and fidelity for information processing in response to prolonged perturbation of network and synaptic activity. Prolonged blockade of synaptic activity decreases resting Ca(2+) levels in neurons, thereby inducing retinoic acid (RA) synthesis and RA-dependent homeostatic synaptic plasticity; however, the signal transduction pathway that links reduced Ca(2+) levels to RA synthesis remains unknown. Here we identify the Ca(2+)-dependent protein phosphatase calcineurin (CaN) as a key regulator for RA synthesis and homeostatic synaptic plasticity. Prolonged inhibition of CaN activity promotes RA synthesis in neurons, and leads to increased excitatory and decreased inhibitory synaptic transmission. These effects of CaN inhibitors on synaptic transmission are blocked by pharmacological inhibitors of RA synthesis or acute genetic deletion of the RA receptor RARalpha. Thus, CaN, acting upstream of RA, plays a critical role in gating RA signaling pathway in response to synaptic activity. Moreover, activity blockade-induced homeostatic synaptic plasticity is absent in CaN knockout neurons, demonstrating the essential role of CaN in RA-dependent homeostatic synaptic plasticity. Interestingly, in GluA1 S831A and S845A knockin mice, CaN inhibitor- and RA-induced regulation of synaptic transmission is intact, suggesting that phosphorylation of GluA1 C-terminal serine residues S831 and S845 is not required for CaN inhibitor- or RA-induced homeostatic synaptic plasticity. Thus, our study uncovers an unforeseen role of CaN in postsynaptic signaling, and defines CaN as the Ca(2+)-sensing signaling molecule that mediates RA-dependent homeostatic synaptic plasticity. PMID- 26443862 TI - A novel peroxisome proliferator response element modulates hepatic low-density lipoprotein receptor gene transcription in response to PPARdelta activation. AB - The hepatic expression of low-density lipoprotein (LDL) receptor (LDLR) gene is regulated primarily at the transcriptional level by a sterol-regulatory element (SRE) in its proximal promoter region which is the site of action of SRE-binding protein 2 (SREBP2). However whether additional cis-regulatory elements contribute to LDLR transcription has not been fully explored. We investigated the function of a putative peroxisome proliferator-activated receptor (PPAR)-response element (PPRE) sequence motif located at -768 to -752 bases upstream of the transcription start site of human LDLR gene in response to PPARdelta activation. Promoter luciferase reporter analyses showed that treating HepG2 cells with PPARdelta agonist L165041 markedly increased the activity of a full-length LDLR promoter construct (pLDLR-1192) without any effects on the shorter promoter reporter pLDLR 234 that contains only the core regulatory elements SRE-1 and SP1 sites. Importantly, mutation of the PPRE sequence greatly attenuated the induction of the full-length LDLR promoter activity by L165041 without affecting rosuvastatin (RSV)-mediated transactivation. EMSA and ChIP assay further confirmed the binding of PPARdelta to the LDLR-PPRE site. Treating HepG2 cells with L165041 elevated the mRNA and protein expressions of LDLR without affecting the LDLR mRNA decay rate. The induction of LDLR expression by PPARdelta agonist was further observed in liver tissue of mice and hamsters treated with L165041. Altogether, our studies identify a novel PPRE-mediated regulatory mechanism for LDLR transcription and suggest that combined treatment of statin with PPARdelta agonists may have advantageous effects on LDLR expression. PMID- 26443863 TI - VID22 is required for transcriptional activation of the PSD2 gene in the yeast Saccharomyces cerevisiae. AB - Phosphatidylethanolamine (PE) in the yeast Saccharomyces cerevisiae is synthesized through decarboxylation of phosphatidylserine (PS), catalysed by PS decarboxylase 1 (Psd1p) and 2 (Psd2p) and the cytidine 5'-diphosphate (CDP) ethanolamine (CDP-Etn) pathway. PSD1 null (psd1Delta) and PSD2 null (psd2Delta) mutants are viable in a synthetic minimal medium, but a psd1Delta psd2Delta double mutant exhibits Etn auxotrophy, which is incorporated into PE through the CDP-Etn pathway. We have previously shown that psd1Delta is synthetic lethal with deletion of VID22 (vid22Delta) [Kuroda et al. (2011) Mol. Microbiol. 80: , 248 265]. In the present study, we found that vid22Delta mutant exhibits Etn auxotrophy under PSD1-depressed conditions. Deletion of VID22 in wild-type and PSD1-depressed cells caused partial defects in PE formation through decarboxylation of PS. The enzyme activity of PS decarboxylase in an extract of vid22Delta cells was ~70% of that in wild-type cells and similar to that in psd2Delta cells and the PS decarboxylase activity remaining in the PSD1-depressed cells became almost negligible with deletion of VID22. Thus, the vid22Delta mutation was suggested to cause a defect in the Psd2p activity. Furthermore, vid22Delta cells were shown to be defective in expression of the PSD2 gene tagged with 6*HA, the defect being ameliorated by replacement of the native promoter of the PSD2 gene with a CYC1 promoter. In addition, an alpha-galactosidase reporter assay revealed that the activity of the promoter of the PSD2 gene in vid22Delta cells was ~5% of that in wild-type cells. These results showed that VID22 is required for transcriptional activation of the PSD2 gene. PMID- 26443864 TI - Nuclear protein kinase CLK1 uses a non-traditional docking mechanism to select physiological substrates. AB - Phosphorylation-dependent cell communication requires enzymes that specifically recognize key proteins in a sea of similar, competing substrates. The protein kinases achieve this goal by utilizing docking grooves in the kinase domain or heterologous protein adaptors to reduce 'off pathway' targeting. We now provide evidence that the nuclear protein kinase CLK1 (cell division cycle2-like kinase 1) important for splicing regulation departs from these classic paradigms by using a novel self-association mechanism. The disordered N-terminus of CLK1 induces oligomerization, a necessary event for targeting its physiological substrates the SR protein (splicing factor containing a C-terminal RS domain) family of splicing factors. Increasing the CLK1 concentration enhances phosphorylation of the splicing regulator SRSF1 (SR protein splicing factor 1) compared with the general substrate myelin basic protein (MBP). In contrast, removal of the N-terminus or dilution of CLK1 induces monomer formation and reverses this specificity. CLK1 self-association also occurs in the nucleus, is induced by the N-terminus and is important for localization of the kinase in sub nuclear compartments known as speckles. These findings present a new picture of substrate recognition for a protein kinase in which an intrinsically disordered domain is used to capture physiological targets with similar disordered domains in a large oligomeric complex while discriminating against non-physiological targets. PMID- 26443865 TI - Phosphoregulation of the C. elegans cadherin-catenin complex. AB - Adherens junctions play key roles in mediating cell-cell contacts during tissue development. In Caenorhabditis elegans embryos, the cadherin-catenin complex (CCC), composed of the classical cadherin HMR-1 and members of three catenin families, HMP-1, HMP-2 and JAC-1, is necessary for normal blastomere adhesion, gastrulation, ventral enclosure of the epidermis and embryo elongation. Disruption of CCC assembly or function results in embryonic lethality. Previous work suggests that components of the CCC are subject to phosphorylation. However, the identity of phosphorylated residues in CCC components and their contributions to CCC stability and function in a living organism remain speculative. Using mass spectrometry, we systematically identify phosphorylated residues in the essential CCC subunits HMR-1, HMP-1 and HMP-2 in vivo. We demonstrate that HMR-1/cadherin phosphorylation occurs on three sites within its beta-catenin binding domain that each contributes to CCC assembly on lipid bilayers. In contrast, phosphorylation of HMP-2/beta-catenin inhibits its association with HMR-1/cadherin in vitro, suggesting a role in CCC disassembly. Although HMP-1/alpha-catenin is also phosphorylated in vivo, phosphomimetic mutations do not affect its ability to associate with other CCC components or interact with actin in vitro. Collectively, our findings support a model in which distinct phosphorylation events contribute to rapid CCC assembly and disassembly, both of which are essential for morphogenetic rearrangements during development. PMID- 26443867 TI - Response to the Letter to the Editor. PMID- 26443866 TI - Improvement of skin wound healing in diabetic mice by kinin B2 receptor blockade. AB - Impaired skin wound healing is a major medical problem in diabetic subjects. Kinins exert a number of vascular and other actions limiting organ damage in ischaemia or diabetes, but their role in skin injury is unknown. We investigated, through pharmacological manipulation of bradykinin B1 and B2 receptors (B1R and B2R respectively), the role of kinins in wound healing in non-diabetic and diabetic mice. Using two mouse models of diabetes (streptozotocin-induced and db/db mice) and non-diabetic mice, we assessed the effect of kinin receptor activation or inhibition by subtype-selective pharmacological agonists (B1R and B2R) and antagonist (B2R) on healing of experimental skin wounds. We also studied effects of agonists and antagonist on keratinocytes and fibroblasts in vitro. Levels of Bdkrb1 (encoding B1R) and Bdkrb2 (encoding B2R) mRNAs increased 1-2 fold in healthy and wounded diabetic skin compared with in non-diabetic skin. Diabetes delayed wound healing. The B1R agonist had no effect on wound healing. In contrast, the B2R agonist impaired wound repair in both non-diabetic and diabetic mice, inducing skin disorganization and epidermis thickening. In vitro, B2R activation unbalanced fibroblast/keratinocyte proliferation and increased keratinocyte migration. These effects were abolished by co-administration of B2R antagonist. Interestingly, in the two mouse models of diabetes, the B2R antagonist administered alone normalized wound healing. This effect was associated with the induction of Ccl2 (encoding monocyte chemoattractant protein 1)/Tnf (encoding tumour necrosis factor alpha) mRNAs. Thus stimulation of kinin B2 receptor impairs skin wound healing in mice. B2R activation occurs in the diabetic skin and delays wound healing. B2R blockade improves skin wound healing in diabetic mice and is a potential therapeutic approach to diabetic ulcers. PMID- 26443868 TI - More iconoclasts than icons? PMID- 26443869 TI - Genetics: Fluent in DNA. PMID- 26443871 TI - The Prevalence of Individual Histopathologic Features Varies according to Autoantibody Status in Muscle Biopsies from Patients with Dermatomyositis. AB - OBJECTIVE: Individual dermatomyositis (DM)-associated autoantibodies are associated with distinct clinical phenotypes. This study was undertaken to explore the association of these autoantibodies with specific muscle biopsy features. METHODS: DM subjects with a muscle biopsy reviewed at Johns Hopkins had sera screened for autoantibodies recognizing Mi-2, transcriptional intermediary factor 1-gamma (TIF1-gamma), NXP2, MDA5, Ro52, PM-Scl, and Jo1. We also included anti-Jo1-positive patients with polymyositis (PM) who had a biopsy read at Johns Hopkins. Analyzed histological features included perifascicular atrophy, perivascular inflammation, mitochondrial dysfunction, primary inflammation, and myofiber necrosis. Duration of disease, biopsy location, and treatment at biopsy were also analyzed. RESULTS: We studied 91 DM and 7 anti-Jo1-positive patients with PM. In univariate analyses, TIF1-gamma+ patients had more mitochondrial dysfunction (47% vs 18%; p = 0.05), NXP2+ patients had less primary inflammation (0% vs 28%; p = 0.01), Mi-2+ patients had more primary inflammation (50% vs 19%; p = 0.03), and PM-Scl+ patients had more primary inflammation (67% vs 18%; p = 0.004) than those who were negative for each autoantibody. Although reliability was limited because of small sample numbers, multivariate analysis confirmed that TIF1-gamma+ patients had more mitochondrial dysfunction [prevalence ratio (PR) 2.6, 95% CI 1.0-6.5, p = 0.05] and PM-Scl+ patients had more primary inflammation (PR 5.2, 95% CI 2.0-13.4; p = 0.001) independent of disease duration at biopsy, biopsy site, and treatment at biopsy. No differences in muscle biopsy features were noted between anti-Jo1-positive patients diagnosed with DM and PM. CONCLUSION: The prevalence of different histological features varies according to autoantibody status in DM. Muscle biopsy features are similar in anti-Jo1 patients with and without a rash. PMID- 26443872 TI - Systems Biology of Alzheimer's Disease. Preface. PMID- 26443873 TI - Synergistic inhibition of PARP-1 and NF-kappaB signaling downregulates immune response against recombinant AAV2 vectors during hepatic gene therapy. AB - Host immune response remains a key obstacle to widespread application of adeno associated virus (AAV) based gene therapy. Thus, targeted inhibition of the signaling pathways that trigger such immune responses will be beneficial. Previous studies have reported that DNA damage response proteins such as poly(ADP ribose) polymerase-1 (PARP-1) negatively affect the integration of AAV in the host genome. However, the role of PARP-1 in regulating AAV transduction and the immune response against these vectors has not been elucidated. In this study, we demonstrate that repression of PARP-1 improves the transduction of single stranded AAV vectors both in vitro (~174%) and in vivo (two- to 3.4-fold). Inhibition of PARP-1, also significantly downregulated the expression of several proinflammatory and cytokine markers such as TLRs, ILs, NF-kappaB subunit proteins associated with the host innate response against self-complementary AAV2 vectors. The suppression of the inflammatory response targeted against these vectors was more effective upon combined inhibition of PARP-1 and NF-kappaB signaling. This strategy also effectively attenuated the AAV capsid-specific cytotoxic T-cell response, with minimal effect on vector transduction, as demonstrated in normal C57BL/6 and hemophilia B mice. These data suggest that targeting specific host cellular proteins could be useful to attenuate the immune barriers to AAV-mediated gene therapy. PMID- 26443874 TI - Radiology on Board the PLA(N) Peace Ark Hospital Ship During a Humanitarian Medical Relief Mission to the Philippines. AB - OBJECTIVE: From November 24 to December 10, 2013, the Chinese People's Liberation Army Navy [PLA(N)] hospital ship Peace Ark was deployed to the Leyte Gulf in the Philippines to provide humanitarian medical relief in Tacloban after Typhoon Haiyan. The purpose of this study was to assess the radiological services aboard the ship to provide guidance for future missions. METHODS: A retrospective review was performed on a cohort of 109 patients who underwent digital radiography (DR) and 59 patients who underwent computed tomography (CT) scans during a 16-day period during a humanitarian medical relief mission to the Philippines. Patient demographics, DR findings, and CT findings were analyzed. RESULTS: The mean age of the 109 DR patients was 39.7 years for the 64 males and 43.7 years for the 45 females. A total of 148 DR examinations were performed of the chest (n=109), extremities (n=35), and spine (n=4). The mean age of the 59 CT patients was 43.8 years for the 32 males and 49.1 years for the 27 females. A total of 72 CT scans were performed of the head and neck (n=36), thorax (n=24), abdomen (n=5), spine (n=4), and extremities (n=3). The imaging findings mainly included disaster related and non-disaster-related fractures, pulmonary tuberculosis, pulmonary infection, acute brain infarction, intracranial hematoma, and occupying lesions. CONCLUSION: Analysis of radiological services during a humanitarian medical relief mission to the Philippines provided meaningful information for future humanitarian medical relief missions. PMID- 26443875 TI - GRIN1 polymorphisms do not affect susceptibility or phenotype in NMDA receptor encephalitis. AB - OBJECTIVE: To determine whether distinct single nucleotide polymorphisms (SNPs) within the glutamate receptor ionotropic NMDA 1 gene (GRIN1) are associated with NMDA receptor (NMDAR) encephalitis and whether these same variants are associated with variability in the clinical presentation and course of affected patients. METHODS: We performed clinical follow-up on 48 patients with NMDAR encephalitis and NMDAR autoantibodies detected in serum or CSF. All RefSeq GRIN1 coding exons were sequenced in 39 Caucasian-European patients, and the frequencies of SNPs were compared with those of an ethnically similar population using a case-control study design. Predetermined clinical variables were compared between patients with and without identified SNPs. RESULTS: Two SNPs were identified in GRIN1: 24 (62%) Caucasian-European patients with NMDAR encephalitis had alternate alleles at both rs6293 (exon 6) and rs1126442 (exon 7; exon numbering according to NM_001185090). The SNPs were in complete linkage disequilibrium. The frequency of these variants did not differ between patients with NMDAR encephalitis and ethnically matched individuals in the general population. No differences in clinical presentation, measures of disease severity, clinical course, or outcomes were observed between patients with different genotypes at these SNPs. CONCLUSION: Disease susceptibility or course in patients with NMDAR encephalitis was not strongly affected by SNPs in GRIN1. This study provides an estimate of the frequency of SNPs in GRIN1 in patients with NMDAR encephalitis and emphasizes the need for multisite collaborative studies enrolling larger numbers of patients to identify the genetic contributions to NMDAR encephalitis. PMID- 26443876 TI - Grounding after moderate eccentric contractions reduces muscle damage. AB - Grounding a human to the earth has resulted in changes in the physiology of the body. A pilot study on grounding and eccentric contractions demonstrated shortened duration of pain, reduced creatine kinase (CK), and differences in blood parameters. This follow-up study was conducted to investigate the effects of grounding after moderate eccentric contractions on pain, CK, and complete blood counts. Thirty-two healthy young men were randomly divided into grounded (n=16) and sham-grounded (n=16) groups. On days 1 through 4, visual analog scale for pain evaluations and blood draws were accomplished. On day 1, the participants performed eccentric contractions of 200 half-knee bends. They were then grounded or sham-grounded to the earth for 4 hours on days 1 and 2. Both groups experienced pain on all posttest days. On day 2, the sham-grounded group experienced significant CK increase (P<0.01) while the CK of the grounded group did not increase significantly; the between-group difference was significant (P=0.04). There was also an increase in the neutrophils of the grounded group on day 3 (P=0.05) compared to the sham-grounded group. There was a significant increase in platelets in the grounded group on days 2 through 4. Grounding produced changes in CK and complete blood counts that were not shared by the sham grounded group. Grounding significantly reduced the loss of CK from the injured muscles indicating reduced muscle damage. These results warrant further study on the effects of earthing on delayed onset muscle damage. PMID- 26443877 TI - High-Dose-Rate Monotherapy for Localized Prostate Cancer: 10-Year Results. AB - PURPOSE: High-dose-rate (HDR) brachytherapy was originally used with external beam radiation therapy (EBRT) to increase the dose to the prostate without injuring the bladder or rectum. Numerous studies have reported HDR brachytherapy is safe and effective. We adapted it for use without EBRT for cases not requiring lymph node treatment. PATIENTS AND METHODS: We entered the patient demographics, disease characteristics, and treatment parameters into a prospective registry and serially added follow-up data for 448 men with low-risk (n=288) and intermediate risk (n=160) prostate cancer treated from 1996 to 2009. Their median age was 64 years (range 42-90). The median prostate-specific antigen (PSA) level was 6.0 ng/mL (range 0.2-18.2). The Gleason score was <=6 in 76% and 7 in 24%. The median dose was 43.5 Gy in 6 fractions. The clinical and biochemical disease control and survival rates were calculated. Adverse events were graded according to the Common Toxicity Criteria of Adverse Events. RESULTS: The median follow-up period was 6.5 years (range 0.3-15.3). The actuarial 6- and 10-year PSA progression-free survival was 98.6% (95% confidence interval [CI] 96.9%-99.4%) and 97.8% (95% CI 95.5%-98.9%). Overall survival at 10 years was 76.7% (95% CI 69.9%-82.2%). The local control, distant metastasis-free survival, and cause-specific survival were 99.7% (95% CI 97.9%-99.9%), 98.9% (95% CI 96.3%-99.7%), and 99.1% (95% CI 95.8% 99.8%). T stage, initial PSA level, Gleason score, National Comprehensive Cancer Network risk group, patient age, and androgen deprivation therapy did not significantly correlate with disease control or survival. No late grade 3 to 4 rectal toxicities developed. Late grade 3 to 4 genitourinary toxicity occurred in 4.9% (grade 3 in 4.7%). CONCLUSIONS: HDR monotherapy is a safe and highly effective treatment of low- and intermediate-risk prostate cancer. PMID- 26443878 TI - The influence of communication and information sources upon decision-making around complementary and alternative medicine use for back pain among Australian women aged 60-65 years. AB - This study examined factors influencing decision-making on complementary and alternative medicine (CAM) use for back pain and back pain sufferers' communication about CAM use. A cross-sectional postal survey was conducted in 2011/2012 as a sub-study of the Australian Longitudinal Study on Women's Health (ALSWH). The sample contained 1620 women from the 1945-1951 cohort of the ALSWH, aged 60-65 years who were eligible for the sub-study, as they had experienced back pain during 12 months prior to the survey. Of these, 1310 (80.9%) returned completed questionnaires. A significant proportion of women consulted a CAM practitioner (76%, n = 1001) and/or had self-prescribed CAM treatment (75%, n = 985). Of the women who used CAM for their back pain, 20% consulted their general practitioner (GP) prior to using CAM and 34% always informed their GP following CAM use. Forty-three per cent of the women were influenced by their doctors, 39% by friends/colleagues, 36% by family/relatives, 33% by their partner, 30% by a CAM practitioner, 20% by a pharmacist, 16% by a book/magazine, 11% by mass media, 10% by an allied health worker and 6% by the Internet. Our results show that information sources used by women for their decision-making on CAM use differed according to the symptoms. While non-professional information sources (e.g. family/relatives) positively influenced women in their decision to use CAM for a range of back pain-related symptoms (e.g. headaches/migraines), doctors and allied health workers (e.g. nurses) negatively influenced women in their decision to consult a CAM practitioner for a range of back pain-related symptoms (e.g. headaches/migraines, neck pain). Women seek information from a wide range of professional and non-professional sources with regard to their decision-making around CAM use for back pain. Back pain care providers need to ensure effective communication with their back pain patients regarding safe, effective and co ordinated back pain care options. PMID- 26443879 TI - Bleeding, Transfusion, and Mortality on Extracorporeal Life Support: ECLS Working Group on Thrombosis and Hemostasis. AB - BACKGROUND: Bleeding may occur frequently during adult extracorporeal life support; however, there are no detailed investigations of bleeding events, red blood cell transfusion, and their impact on mortality. The purpose of our study was to characterize the incidence of bleeding and red blood cell transfusion during adult extracorporeal life support and examine the impact on mortality. METHODS: We performed a retrospective analysis of adult extracorporeal life support patients over approximately a 3-year period. The incidence of bleeding events and transfusions were recorded. Unadjusted and adjusted multivariate logistic regression analyses were performed to estimate the odds of inhospital mortality among patients with bleeding and for each red blood cell unit transfused. Ninety-day survival was compared between patients who bled and those who did not. RESULTS: Serious bleeding events occurred in 74 of 132 patients (56.1%), and the rate of bleeding was 10 events per 100 days. The crude odds ratio for inhospital mortality in patients who bled was 2.22 (95% confidence interval [CI]: 1.00 to 4.94, p = 0.05); and for each unit of red blood cells transfused, it was 1.03 (95% CI: 1.01 to 1.04, p = 0.005). The adjusted odds ratios for bleeding and red blood cell transfusions were 0.90 (95% CI: 0.37 to 2.19, p = 0.82) and 1.03 (95% CI: 1.00 to 1.06, p = 0.04). There was a trend toward decreased 90-day survival among patients who bled compared with patients who did not (46.7% versus 64.9%, p = 0.08). CONCLUSIONS: Bleeding and red blood cell transfusion occur frequently during adult extracorporeal life support, but only the amount of red blood cell transfusion is associated with inhospital mortality after controlling for confounding variables. PMID- 26443880 TI - A European Multicenter Study of 616 Patients Receiving the Freedom Solo Stentless Bioprosthesis. AB - BACKGROUND: The purpose of this study was to evaluate the safety and performance of the Freedom Solo valve in aortic valve replacement by clinical and hemodynamic outcomes. METHODS: Six hundred sixteen patients underwent aortic valve replacement in 18 European centers; mean age was 74.5 +/- 5.9 years, 54.1% of the patients were male, and concomitant procedures were performed in 43.2% of the patients. The majority (69%) of the implanted sizes were 23 mm and 25 mm. RESULTS: At 1 year, overall survival was 94.0%, whereas freedom from valve related death was 98.6%. There were 9 (1.5%) early (<= 30 days) and 27 (4.4%) late (>30 days) deaths. Early and late valve-related mortality was 0.3% (n = 2) and 1.1% (n = 7), respectively. Freedom from explant was 97.6%; 10 valves were explanted for endocarditis and 4 for paravalvular leak. There were 10 (1.6%) early and 5 (0.8%) late strokes. Atrioventricular block requiring pacemaker implant occurred in 8 (1.3%) and 1 (0.2%) patients in the early and late postoperative period, respectively. Thrombocytopenia was seen in 27 cases (4.4%) in the early postoperative period. Preoperatively, 93.8% of patients were in New York Heart Association functional classes II through IV, whereas at 1 year 96.9% of patients were in New York Heart Association functional classes I and II. At 1 year follow-up, mean and peak pressure gradients were 7.2 and 14.6 mm Hg, respectively. Indexed left ventricular mass decreased by 12% from 138 g/m(2) at discharge to 122 g/m(2) at 1 year. CONCLUSIONS: At 1-year follow-up after Freedom Solo implantation, we found acceptable clinical results with low mortality and morbidity and good hemodynamic performance, confirming safety and effectiveness in this multicenter experience. PMID- 26443881 TI - Long-Term Effect of an Interdisciplinary Supportive Care Intervention for Lung Cancer Survivors After Surgical Procedures. AB - BACKGROUND: Surgical procedures provide the best chance for cure and long-term survival in non-small cell cancer (NSCLC). Persistent symptoms after surgical procedures are common, and they can negatively affect health-related quality of life (HRQOL). The purpose of this study was to examine the long-term effect of an interdisciplinary supportive care intervention to improve HRQOL, psychological distress, and symptoms in lung cancer survivors who were treated surgically. METHODS: Patients undergoing curative intent resection for NSCLC were enrolled in a prospective sequential design whereby the control group was accrued first, followed by the intervention group. Patients in the intervention group were assessed and presented by nurses at weekly interdisciplinary care meetings before surgical procedures, and received four educational sessions (physical, psychological, social, and spiritual well-being) after surgical procedures. Appropriate symptom management, social work, rehabilitation, and spiritual support interventions were coordinated by the study nurse. In both groups, HRQOL, psychological distress, and symptom severity were assessed at baseline and at 6, 12, 24, 36, and 52 weeks with the use of surveys that included the validated Functional Assessment of Cancer Therapy-Lung (FACT-L), Lung Cancer Subscale (LCS), and Distress Thermometer. Mean survey scores were analyzed with factorial analysis of covariance at 12 months. RESULTS: A total of 71 survivors (control = 33; intervention = 38) were accrued. No difference was found in age, baseline performance status, or stage of disease between groups. Patients in the intervention group had significantly less distress (mean, 1.0 versus 4.0; range, 0 to 10; p < 0.001) and more favorable mean FACT-L scores (126.1 versus 98.7; range, 0 to 140; p < 0.001) and LCS scores (29.4 versus 23.6; range, 0 to 32; p < 0.001) at 12 months. The mean scores of all categories of questions in FACT-L (physical, social/family, emotional, and functional well-being) were considerably more favorable in the intervention group at 12 months. CONCLUSIONS: An interdisciplinary supportive care intervention improves psychological distress and HRQOL at 12 months after lung cancer surgical procedures. This study has important implications in improving HRQOL of lung cancer survivors after surgical procedures. Further study is warranted on incorporating the interdisciplinary personalized interventions used in this study into clinical practice for lung cancer survivors. PMID- 26443882 TI - Extra-articular step osteotomy of the olecranon: A biomechanical assessment. AB - BACKGROUND: Trans-olecranon chevron osteotomies (COs) remain the gold standard surgical approach to type C fractures of the distal humerus. This technique is associated with a high complication rate and development of an extra-articular olecranon osteotomy may be advantageous. The aim of this study was to compare the load to failure of COs with extra-articular oblique osteotomies (OOs) as well as modified, extra-articular step osteotomies (SOs). METHODS: These three osteotomies and their subsequent fixation utilizing a standardized tension band wiring technique were tested in 42 composite analog ulnae models at 20 degrees and 70 degrees of flexion. Triceps loading was simulated with a servo hydraulic testing machine. All specimens were isometrically loaded until failure. Kinematic and force data, as well as interfragmentary motion were recorded. RESULTS: At 70 degrees , CO failed at a mean load of 963 N (SD 104 N), the OO at 1512 N (SD 208 N) and the SO at 1484 N (SD 153 N), (P<0.001). At 20 degrees , CO failed at a mean load of 707 N (SD 104 N) and OO at 1009 N (SD 85 N) (P=0.006). The highest load to failure was observed for the SO, which was 1277 N (SD 172 N). The load to failure of the SO was significantly higher than the CO as well as the OO. CONCLUSION: Extra-articular osteotomies showed a significantly higher load to failure in comparison to traditional CO. At near full extension (20 degrees of flexion), this biomechanical advantage was further enhanced by a step-cut modification of the extra-articular oblique osteotomy. PMID- 26443883 TI - California's Early Coverage Expansion under the Affordable Care Act: A County Level Analysis. AB - OBJECTIVE: To assess the coverage effects of California's 2011 Low-Income Health Program (LIHP), enacted as an "early expansion" under the Affordable Care Act (ACA), and to demonstrate the feasibility of using Census data to measure county level coverage changes. DATA SOURCES/STUDY SETTING: 2008-2012 American Community Survey (ACS). The sample contained California adults ages 19-64 years (n = 237,876) and children 0-18 years (n = 113,159) with incomes below 200 percent of the federal poverty level. STUDY DESIGN: Differences-in-differences analysis comparing public coverage, private insurance, and the uninsured rate in counties that expanded the LIHP in 2011 versus California counties not expanding during this time. Additional analyses tested for heterogeneous impacts of the LIHP and spillover effects on children. PRINCIPAL FINDINGS: Compared to nonexpansion counties, public coverage for adults increased by 1.8 percentage points (p = .02) in expanding counties, while the uninsured rate declined by 2.1 percentage points (p = .01). There was no significant change in private coverage. Public coverage gains were largest for Latinos and those with limited English proficiency. The expansion produced a positive spillover effect on children's Medicaid enrollment. CONCLUSIONS: California's 2011 expansion produced significant increases in public coverage for low-income individuals, particularly Latinos. Substate coverage analyses with the ACS can add valuable detail to future assessments of the ACA. PMID- 26443884 TI - Progression after spontaneous regression in lung large cell neuroendocrine carcinoma: Report of a curative resection. AB - We present the first reported case of lung large cell neuroendocrine carcinoma (LCNEC) with spontaneous regression followed by progression. An 85-year-old woman presented with a 2.8-cm nodule in the right upper lung lobe on chest computed tomography. After four months, the tumor decreased to 1.8 cm and remained unchanged in size for the next three months, but it grew to 8.6 cm and invaded the mediastinal fat tissue after approximately one year. Ultrasound echo-guided percutaneous biopsy revealed the tumor to be LCNEC. The patient underwent a right upper lobectomy with lymph node dissection. She had a good postoperative course with no complications. Physicians and surgeons should be aware that radiographic regression of a pulmonary nodule does not necessarily exclude the possibility of lung cancer. PMID- 26443886 TI - Design of isolated iron species for Fenton reactions: lyophilization beats calcination treatment. AB - Lyophilization is used to prepare a Fenton catalyst containing a predominant amount of isolated Fe(3+) species with an 8.90% iron content. This catalyst shows a higher catalytic rate and H2O2 utilization efficiency but lower iron leaching in phenol degradation, compared with the calcination sample. PMID- 26443885 TI - Membrane stiffening by STOML3 facilitates mechanosensation in sensory neurons. AB - Sensing force is crucial to maintain the viability of all living cells. Despite its fundamental importance, how force is sensed at the molecular level remains largely unknown. Here we show that stomatin-like protein-3 (STOML3) controls membrane mechanics by binding cholesterol and thus facilitates force transfer and tunes the sensitivity of mechano-gated channels, including Piezo channels. STOML3 is detected in cholesterol-rich lipid rafts. In mouse sensory neurons, depletion of cholesterol and deficiency of STOML3 similarly and interdependently attenuate mechanosensitivity while modulating membrane mechanics. In heterologous systems, intact STOML3 is required to maintain membrane mechanics to sensitize Piezo1 and Piezo2 channels. In C57BL/6N, but not STOML3(-/-) mice, tactile allodynia is attenuated by cholesterol depletion, suggesting that membrane stiffening by STOML3 is essential for mechanical sensitivity. Targeting the STOML3-cholesterol association might offer an alternative strategy for control of chronic pain. PMID- 26443887 TI - Editorial Comment for Wiener et al. PMID- 26443888 TI - Comparison of carbon-sulfur and carbon-amine bond in therapeutic drug: 4beta-S aromatic heterocyclic podophyllum derivatives display antitumor activity. AB - Herein is a first effort to systematically study the significance of carbon sulfur (C-S) and carbon-amine (C-NH) bonds on the antitumor proliferation activity of podophyllum derivatives and their precise mechanism of apoptosis. Compared with the derivative modified by a C-NH bond, the derivative modified by a C-S bond exhibited superior antitumor activity, the inhibition activity of target proteins tubulin or Topo II, cell cycle arrest, and apoptosis induction. Antitumor mechanistic studies showed that the death receptor and the mitochondrial apoptotic pathways were simultaneously activated by the C-S bond modified aromatic heterocyclic podophyllum derivatives with a higher cellular uptake percentage of 60-90% and induction of a higher level of reactive oxygen species (ROS). Only the mitochondrial apoptotic pathway was activated by the C-NH bond modified aromatic heterocyclic podophyllum derivatives, with a lower cellular uptake percentage of 40-50%. This study provided insight into effects of the C-S and C-NH bond modification on the improvement of the antitumor activity of Podophyllum derivatives. PMID- 26443890 TI - The EMG activity-acceleration relationship to quantify the optimal vibration load when applying synchronous whole-body vibration. AB - PURPOSE: To date are lacking methodological approaches to individualizing whole body vibration (WBV) intensity. The aim of this study was: (1) to determine the surface-electromyography-root-mean-square (sEMG(RMS))-acceleration load relationship in the vastus lateralis (VL), vastus medialis (VM), rectus femoris (RF), lateral gastrocnemius (LG) muscles during synchronous WBV, and (2) to assess the reliability of the acceleration corresponding to the maximal sEMG(RMS). METHODS: Twenty-five sportsman voluntarily took part in this study with a single-group, repeated-measures design. All subjects postured themselves in an isometric half-squat during nine trials in the following conditions: no vibrations and random vibrations of different acceleration loads (from 0.12 to 5.72 g). RESULTS: The sEMG(RMS) were dependent on the acceleration loads in the VL (p = 0.0001), LG (p = 0.0001) and VM (p = 0.011) muscles; while RF was not affected by the acceleration loads (p = 0.508). The comparisons among the sEMG(RMS)-accelerations relationships revealed a significant difference between the LG and the others muscles (p = 0.001). No significant difference was found between the different thigh muscles (p > 0.05). The intra-class correlation coefficient ranged from 0.87 to 0.99 for the measurements performed on the LG, VL and VM. CONCLUSIONS: The sEMG(RMS)-acceleration relationship in the VL, VM and LG is a reliable test to individualize the WBV intervention. PMID- 26443892 TI - Dehydrodipeptide Hydrogelators Containing Naproxen N-Capped Tryptophan: Self Assembly, Hydrogel Characterization, and Evaluation as Potential Drug Nanocarriers. AB - In this work, we introduce dipeptides containing tryptophan N-capped with the nonsteroidal anti-inflammatory drug naproxen and C-terminal dehydroamino acids, dehydrophenylalanine (DeltaPhe), dehydroaminobutyric acid (DeltaAbu), and dehydroalanine (DeltaAla) as efficacious protease resistant hydrogelators. Optimized conditions for gel formation are reported. Transmission electron microscopy experiments revealed that the hydrogels consist of networks of micro/nanosized fibers formed by peptide self-assembly. Fluorescence and circular dichroism spectroscopy indicate that the self-assembly process is driven by stacking interactions of the aromatic groups. The naphthalene groups of the naproxen moieties are highly organized in the fibers through chiral stacking. Rheological experiments demonstrated that the most hydrophobic peptide (containing C-terminal DeltaPhe) formed more elastic gels at lower critical gelation concentrations. This gel revealed irreversible breakup, while the C terminal DeltaAbu and DeltaAla gels, although less elastic, exhibited structural recovery and partial healing of the elastic properties. A potential antitumor thieno[3,2-b]pyridine derivative was incorporated (noncovalently) into the gel formed by the hydrogelator containing C-terminal DeltaPhe residue. Fluorescence and Forster resonance energy transfer measurements indicate that the drug is located in a hydrophobic environment, near/associated with the peptide fibers, establishing this type of hydrogel as a good drug-nanocarrier candidate. PMID- 26443893 TI - Low prevalence of long-term breastfeeding among women with type 2 diabetes. AB - OBJECTIVE: To investigate the prevalence of long-term breastfeeding among women with type 2 diabetes compared to women with type 1 diabetes and to identify predictors of long-term breastfeeding for women with pre-gestational diabetes. METHODS: In total, 149 women with diabetes were interviewed about long-term breastfeeding, defined as any breastfeeding 4 months postpartum. RESULTS: Ninety eight percent of the women aimed to breastfeed. At time of discharge, any breastfeeding was frequent for both groups of women (86% versus 93%, p = 0.17). However, 4 months postpartum, the 44 women with type 2 diabetes showed significantly lower prevalence of breastfeeding than the 105 women with type 1 diabetes (34% versus 61%, p < 0.01). Number of feedings in the first 24 h was an independent positive predictor, whereas pre-pregnancy body mass index (BMI) and smoking were independent negative predictors of long-term breastfeeding. CONCLUSION: The prevalence of long-term breastfeeding among women with type 2 diabetes was considerably lower than in women with type 1 diabetes. Number of feedings in the first 24 h was positive and BMI and smoking were negative predictors of long-term breastfeeding in women with pre-gestational diabetes. PMID- 26443891 TI - Changes in lower extremity peak angles, moments and muscle activations during stair climbing at different speeds. AB - Stair climbing is a common daily activity, yet there is no basic knowledge on how lower extremity joint angles, moments or muscle activations are affected by stair climbing speed. This information will determine whether speed matching is necessary for stair climbing studies. Moreover, changes in lower extremity biomechanics during stair climbing at different speeds will aid in the clinical interpretation of a patient's maximal stair climbing speed. Thirty healthy participants provided consent. Kinematics, kinetics, and muscle activations were collected on a three step staircase. Subjects climbed the staircase at normal, slow and fast self-selected speeds. Linear mixed models for repeated measures were used to study the associations between speed and the lower extremity peak joint angles and moments, and muscle activations. The peak hip flexion and extension moments increased with increasing speed, while peak knee flexion moment did not vary consistently with speed. The peak muscle activations varied consistently with respect to the sagittal plane kinetics. These results suggest that in healthy subjects, the hip is the greatest contributor when modulating stair climbing speed, while additional knee contributions do not appear necessary to increase speed. Further stair studies should consider speed matching in order to accurately assess biomechanical differences. PMID- 26443894 TI - Perceptual assessment of dysarthria: Comparison of a general and a detailed assessment protocol. AB - OBJECTIVE: The present, preliminary study was designed to investigate whether the results of the use of a detailed assessment protocol ad modum the Mayo Clinic rating of dysarthria and that of a more general assessment protocol, corresponding to ratings of deviances of the different speech production processes, differed primarily in terms of reliability. PATIENTS AND METHODS: Recordings of text readings of 20 patients with various degrees and types of dysarthria were assessed using both protocols by five clinicians with extensive experience in assessment of neurogenic communication disorders, and results from both assessments were compared. RESULTS: The general assessment protocol was carried out with higher intra- and inter-rater reliability compared with the detailed assessment protocol. Perceptual deviations were identified in the same domains using both protocols, although only the more detailed protocol could be used to specify particular audible symptoms. Monotony, imprecise consonants, and harsh voice were the most prominent deviations identified with the detailed protocol. CONCLUSION: It is concluded that a general assessment protocol is sufficient to identify problem areas reliably and indicate severity of dysarthria but needs to be complemented with a short description of the most prominent audible symptoms and an assessment of intelligibility. PMID- 26443889 TI - Peste des petits ruminants. AB - Peste des petits ruminants virus causes a highly infectious disease of small ruminants that is endemic across Africa, the Middle East and large regions of Asia. The virus is considered to be a major obstacle to the development of sustainable agriculture across the developing world and has recently been targeted by the World Organisation for Animal Health (OIE) and the Food and Agriculture Organisation (FAO) for eradication with the aim of global elimination of the disease by 2030. Fundamentally, the vaccines required to successfully achieve this goal are currently available, but the availability of novel vaccine preparations to also fulfill the requisite for differentiation between infected and vaccinated animals (DIVA) may reduce the time taken and the financial costs of serological surveillance in the later stages of any eradication campaign. Here, we overview what is currently known about the virus, with reference to its origin, updated global circulation, molecular evolution, diagnostic tools and vaccines currently available to combat the disease. Further, we comment on recent developments in our knowledge of various recombinant vaccines and on the potential for the development of novel multivalent vaccines for small ruminants. PMID- 26443896 TI - ? PMID- 26443895 TI - The effects of direction similarity in visual working memory: Behavioural and event-related potential studies. AB - Object similarity can improve visual working memory (VWM) performance in the change-detection task, but impair the recognition performance when it occurs at retrieval of VWM in the recognition task. The effect of direction similarity is an issue that has not been well resolved. Furthermore, electrophysiological evidence in support of the mechanisms that underlie the effects of similarity is still scarce. In the current study, we conducted three behavioural experiments to examine the effects of direction similarity on memory performance with regard to both the encoding and retrieval phases of VWM and one event-related potential (ERP) experiment to explore the neural signatures of direction similarity in VWM. Our behavioural studies indicated that direction similarity improved performance when it occurred at the encoding phase but impaired performance when it occurred at the retrieval phase. Moreover, the ERP experiment showed that the amplitude of the contralateral delay activity (CDA) increased with the increasing set size for similar but not dissimilar directions. In addition, the CDA amplitude for similar directions was lower than that for dissimilar directions at set size 2. Taken together, these findings suggest that direction similarity at encoding has a positive effect on VWM performance and at retrieval has a negative effect. Given that VWM capacity depends on information load and the number of objects, the positive effect of similarity may be attributed to reduced information load of memory objects. PMID- 26443897 TI - ? PMID- 26443898 TI - ? PMID- 26443899 TI - ? PMID- 26443900 TI - Cell-free production of VDAC directly into liposomes for integration with biomimetic membrane systems. AB - The mitochondrial voltage-dependent anion channel (VDAC) is a pivotal protein since it provides the major transport pathway between the cytosol and the mitochondrial intermembrane space and it is implicated in cell apoptosis by functioning as a gatekeeper for the trafficking of mitochondrial death molecules. VDAC is a beta-barrel channel with a large conductance, and we use it as a model transport protein for the design of biomimetic systems. To overcome the limitations of classical overexpression methods for producing and purifying membrane proteins (MPs) we describe here the use of an optimized cell-free system. In a one-step reaction VDAC is obtained directly integrated into liposomes and purified by ultracentrifugation. We then combine proteoliposomes with different bilayers models in order to validate VDAC insertion and functionality. This VDAC biomimetic model is the first example validating the use of a cell-free expression system for production of MPs into liposomes and tethered bilayers as a toolbox to build a wide range of biomimetic devices. PMID- 26443901 TI - A Virtual Reality. PMID- 26443904 TI - Ten Questions With . . . PMID- 26443906 TI - Ask George. PMID- 26443907 TI - The Rise of Telehealth: 'Triple Aim,' Innovative Technology, and Popular Demand Are Spearheading New Models of Health and Wellness Care. PMID- 26443908 TI - A Roundtable Discussion: Combination Products: Twice the Challenge? AB - Combination products are therapeutic or diagnostic medical products that combine drugs, devices, and/or biological products with one another. FDA developed a regulation (final rule) on Current Good Manufacturing Practices (CGMP) for combination products that became effective July 22, 2013 (21 CFR Part 4). AAMI recently developed a technical information report (TIR) that provides information on how to effectively implement FDA's regulation. The overall goal of the TIR is to aid informed, risk-based decisions in establishing CGMP operating systems that support development, manufacture, premarket regulatory evaluation, and ultimately commercialization of combination products. This article, a result of an discussion with industry and FDA representatives, explores the landscape of combination products, highlights important considerations in developing and seeking marketing clearance for these innovative products, and provides insight on trends in the area. PMID- 26443909 TI - Special Series: A Clinical Engineer's Approach To CMS Compliance. PMID- 26443910 TI - Shuren Says Patients Are 'The Heart' of CDRH Focus. PMID- 26443911 TI - Two-Man Biomed Team Adds Bed/Stretcher Maintenance to Arsenal. PMID- 26443912 TI - Repairing Surgical Table Requires Extreme Caution. PMID- 26443914 TI - Why Every Manager Should Take the CHTM Examination. PMID- 26443916 TI - Lessons in Leadership. PMID- 26443915 TI - Evaluating Device Design and Cleanability of Orthopedic Device Models Contaminated with a Clinically Relevant Bone Test Soil. AB - Reusable medical devices need to be cleaned prior to disinfection or sterilization and subsequent use to prevent infections. The cleanability of medical devices depends in part on the design of the device. This study examined how models of orthopedic medical devices of increasing complexity retain calcium phosphate bone cement, a relevant test soil for these devices. METHODS: The dye Alizarin Red S and micro-computed tomography (MUCT) were used to assess the amount and location of bone cement debris in a series of model orthopedic devices. Testing was performed after soiling and cleaning once, and soiling and cleaning 10 times. RESULTS: The color change of the dye after reacting with the bone cement was useful for indicating the presence of bone cement in these models. High-resolution MUCT analysis provided the volume and location of the bone cement. Models that were more complex retained significantly more bone debris than simpler designs. Model devices repeatedly soiled and cleaned 10 times retained significantly more bone debris than those soiled and cleaned once. CONCLUSION: Significantly more bone cement was retained in the more complex lumen structures. This information may be useful in designing reusable orthopedic devices, and other complex medical devices with lumens. PMID- 26443918 TI - Magneto-Structural Correlations in a Series of Pseudotetrahedral [Co(II)(XR)4](2 ) Single Molecule Magnets: An ab Initio Ligand Field Study. AB - Over the past several decades, tremendous efforts have been invested in finding molecules that display slow relaxation of magnetization and hence act as single molecule magnets (SMMs). While initial research was strongly focused on polynuclear transition metal complexes, it has become increasingly evident that SMM behavior can also be displayed in relatively simple mononuclear transition metal complexes. One of the first examples of a mononuclear SMM that shows a slow relaxation of the magnetization in the absence of an external magnetic field is the cobalt(II) tetra-thiolate [Co(SPh)4](2-). Fascinatingly, substitution of the donor ligand atom by oxygen or selenium dramatically changes zero-field splitting (ZFS) and relaxation time. Clearly, these large variations call for an in-depth electronic structure investigation in order to develop a qualitative understanding of the observed phenomena. In this work, we present a systematic theoretical study of a whole series of complexes (PPh4)2[Co(XPh)4] (X = O, S, Se) using multireference ab initio methods. To this end, we employ the recently proposed ab initio ligand field theory, which allows us to translate the ab initio results into the framework of ligand field theory. Magneto-structural correlations are then developed that take into account the nature of metal-ligand covalent bonding, ligand spin-orbit coupling, and geometric distortions away from pure tetrahedral symmetry. The absolute value of zero-field splitting increases when the ligand field strength decreases across the series from O to Te. The zero field splitting of the ground state of the hypothetical [Co(TePh)4](2-) complex is computed to be about twice as large as for the well-known (PPh4)2[Co(SPh)4] compound. It is shown that due to the pi-anisotropy of the ligand donor atoms (S, Se) magneto-structural correlations in [Co(OPh)4](2-) complex differ from [Co(S/SePh)4](2-). In the case of almost isotropic OPh ligand, only variations in the first coordination sphere affect magnetic properties, but in the case of S/SePh ligand, variations in the first and second coordination sphere become equally important for magnetic properties. PMID- 26443919 TI - UV-Light-Induced Improvement of Fluorescence Quantum Yield of DNA-Templated Gold Nanoclusters: Application to Ratiometric Fluorescent Sensing of Nucleic Acids. AB - The use of DNA as a template has been demonstrated as an effective method for synthesizing different-sized silver nanoclusters. Although DNA-templated silver nanoclusters show outstanding performance as fluorescent probes for chemical sensing and cellular imaging, the synthesis of DNA-stabilized gold nanoclusters (AuNCs) with high fluorescence intensity remains a challenge. Here a facile, reproducible, scalable, NaBH4-free, UV-light-assisted method was developed to prepare AuNCs using repeats of 30 adenosine nucleotides (A30). The maximal fluorescence of A30-stabilized AuNCs appeared at 475 nm with moderate quantum yield, two fluorescence lifetimes, and a small amount of Au(+) on the surface of the Au core. Results of size-exclusion chromatography revealed that A30 stabilized AuNCs were more compact than A30. A series of control experiments showed that UV light played a dual role in the reduction of gold-ion precursors and the decomposition of citrate ions. A30 also acted as a stabilizer to prevent the aggregation of AuNCs. In addition, single-stranded DNA (ssDNA) consisting of an AuNC-nucleation sequence and a hybridization sequence was utilized to develop a AuNC-based ratiometric fluorescent probe in the presence of the double-strand chelating dye SYBR Green I (SG). Under conditions of single-wavelength excitation, the combination of AuNC/SG-bearing ssDNA and perfectly matched DNA emitted fluorescence at 475 and 525 nm, respectively. The formed AuNC/SG-bearing ssDNA enabled the sensitive, selective, and ratiometric detection of specific nucleic acid targets. Finally, the AuNC-based ratiometric probes were successfully applied to determine specific nucleic acid targets in human serum. PMID- 26443920 TI - Structure and Absolute Configuration of Jurassic Polyketide-Derived Spiroborate Pigments Obtained from Microgram Quantities. AB - Complete structural elucidation of natural products is often challenging due to structural complexity and limited availability. This is true for present-day secondary metabolites, but even more for exceptionally preserved secondary metabolites of ancient organisms that potentially provide insights into the evolutionary history of natural products. Here, we report the full structure and absolute configuration of the borolithochromes, enigmatic boron-containing pigments from a Jurassic putative red alga, from samples of less than 50 MUg using microcryoprobe NMR, circular dichroism spectroscopy, and density functional theory calculations and reveal their polyketide origin. The pigments are identified as spiroborates with two pentacyclic sec-butyl-trihydroxy-methyl benzo[gh]tetraphen-one ligands and less-substituted derivatives. The configuration of the sec-butyl group is found to be (S). Because the exceptional benzo[gh]tetraphene scaffold is otherwise only observed in the recently discovered polyketide clostrubin from a present-day Clostridium bacterium, the Jurassic borolithochromes now can be unambiguously linked to the modern polyketide, providing evidence that the fossil pigments are almost originally preserved secondary metabolites and suggesting that the pigments in fact may have been produced by an ancient bacterium. The borolithochromes differ fundamentally from previously described boronated polyketides and represent the first boronated aromatic polyketides found so far. Our results demonstrate the potential of microcryoprobe NMR in the analysis of previously little-explored secondary metabolites from ancient organisms and reveal the evolutionary significance of clostrubin-type polyketides. PMID- 26443921 TI - Investigations of the effect of nonmagnetic Ca substitution for magnetic Dy on spin-freezing in Dy2Ti2O7. AB - Physical properties of partially Ca substituted hole-doped Dy2Ti2O7 have been investigated by ac magnetic susceptibility chi(ac)(T), dc magnetic susceptibility chi(T), isothermal magnetization M(H) and heat capacity C(p)(T) measurements on Dy1.8Ca0.2Ti2O7. The spin-ice system Dy2Ti2O7 exhibits a spin-glass type freezing behavior near 16 K. Our frequency dependent chi(ac)(T) data of Dy1.8Ca0.2Ti2O7 show that the spin-freezing behavior is significantly influenced by Ca substitution. The effect of partial nonmagnetic Ca(2+) substitution for magnetic Dy(3+) is similar to the previous study on nonmagnetic isovalent Y(3+) substituted Dy(2-x)Y(x) Ti2O7 (for low levels of dilution), however the suppression of spin-freezing behavior is substantially stronger for Ca than Y. The Cole-Cole plot analysis reveals semicircular character and a single relaxation mode in Dy1.8Ca0.2Ti2O7 as for Dy2Ti2O7. No noticeable change in the insulating behavior of Dy2Ti2O7 results from the holes produced by 10% Ca(2+) substitution for Dy(3+) ions. PMID- 26443923 TI - Functional evaluation of gene silencing on macrophages derived from U937 cells using interference RNA (shRNA) in a model of macrophages infected with Leishmania (Viannia) braziliensis. AB - Leishmaniasis development is multifactorial; nonetheless, the establishment of the infection, which occurs by the survival and replication of the parasite inside its main host cell, the macrophage, is mandatory. Thus, the importance of studying the molecular mechanisms involved in the Leishmania-macrophage interaction is highlighted. The aim of this study was to characterize a cellular model of macrophages derived from U937 cells that would allow for the identification of infection phenotypes induced by genetic silencing with interference RNA in the context of macrophages infected with Leishmania (Viannia) braziliensis. The model was standardized by silencing an exogenous gene (gfp), an endogenous gene (lmna) and a differentially expressed gene between infected and non-infected macrophages (gro-beta). The silencing process was successful for the three genes studied, obtaining reductions of 88.9% in the GFP levels, 87.5% in LMNA levels and 74.4% for Gro-beta with respect to the corresponding control cell lines. The cell model revealed changes in the infection phenotype of the macrophages in terms of number of amastigotes per infected macrophage, number of amastigotes per sampled macrophage and percentage of infected macrophages as a result of gene silencing. Thus, this cell model constitutes a research platform for the study of parasite-host interactions and for the identification of potentially therapeutic targets. PMID- 26443922 TI - Design, Synthesis and Structure-Activity Relationship Optimization of Lycorine Derivatives for HCV Inhibition. AB - Lycorine is reported to be a multifunctional compound. We previously showed that lycorine is an HCV inhibitor with strong activity. Further research on the antivirus mechanism indicated that lycorine does not affect the enzymes that are indispensable to HCV replication but suppresses the expression of Hsc70 in the host cell to limit HCV replication. However, due to the cytotoxicity and apoptosis induction of lycorine, lycorine is unsafe to be a anti-HCV agent for clinical application. As a result of increasing interest, its structure was optimized for the first time and a novel series of lycorine derivatives was synthesized, all of which lost their cytotoxicity to different degrees. Structure activity analysis of these compounds revealed that disubstitution on the free hydroxyl groups at C1 and C2 and/or degradation of the benzodioxole group would markedly reduce the cytotoxicity. Furthermore, an alpha, beta-unsaturated ketone would improve the HCV inhibitory activity of lycorine. The C3-C4 double bond is crucial to the anti-HCV activity because hydrogenation of this double bond clearly weakened HCV inhibition. PMID- 26443924 TI - "I'm scared of being like mum": The Experience of Adolescents Living in Families with Huntington Disease. AB - BACKGROUND: The debilitating and very visible motor effects of the incurable, progressive, and fatal neurodegenerative condition Huntington disease (HD) are accompanied by more insidious cognitive, behavioural and personality disturbance. The usual age of HD onset exposes children and adolescents to the natural history of the condition as it affects a parent. This group of young people has been largely overlooked in most research, which has concentrated upon the experiences of affected individuals and their partners. OBJECTIVE: This study explores the psychosocial context of young people living in families affected by HD, to better understand their experiences and the specific challenges they face. METHOD: Ten young people from five unrelated families affected by HD separately participated in semi-structured individual interviews. At the time of interview, nine were less than 18 years of age, and none had requested a predictive genetic test. RESULTS: The young people demonstrated a depth of insight in their descriptions of complex and often painful family circumstances. In addition to the tasks and challenges associated with typical adolescent development, young people from families affected by Huntington disease recognize that they face greater responsibilities and stresses. CONCLUSION: This study highlights areas of unmet needs for young people living in families affected by HD. Best practice HD care should include consideration of the needs of young people in the family, and offer developmentally appropriate HD education, prospective orientation to genetic services, and psychological and social support. PMID- 26443925 TI - Abnormal Weight and Body Mass Index in Children with Juvenile Huntington's Disease. AB - BACKGROUND AND OBJECTIVES: The hallmark clinical manifestation of Huntington's disease (HD), namely lower weight and BMI has been reported in prodromal HD (PreHD) adults and also in PreHD children. Here, we aim to evaluate anthropometric measures of growth and development (height, weight, body mass index (BMI)) in a group of children, adolescents, and young adults diagnosed with Juvenile Onset Huntington's Disease (JHD). METHODS: Growth measures for 18 JHD patients, documented prior to or shortly after diagnosis, were obtained through medical records. JHD growth measures were compared to a large sample (n = 274) of healthy children, as well as the Center for Disease Control (CDC) growth norms. RESULTS: After controlling for sex and age, the JHD subjects had no significant differences in height. However, they were an average of 10% lower than controls in weight and BMI. Using CDC norms, the JHD subjects had the same pattern of normal height but decrement in weight. Length of cytosine-adenine-guanine (CAG) repeat in the huntingtin gene was significantly correlated to measures of weight with longer CAG repeats being associated with more severe weight reduction. A subset of 4 subjects had measures that pre-dated onset of any symptom and were therefore prodromal JHD (preJHD). These subjects also had a significant decrement in BMI compared to CDC norms. CONCLUSIONS: Children with JHD have normal height, but significantly reduced weight and BMI, indicative of a specific deficit in body weight. As the preJHD subjects were also low in BMI, this suggests that these changes are directly due to the effect of the mutated gene on development, rather than symptom manifestation of the disease itself. Potential mechanisms of the weight decrement include energy deficiency due to mitochondrial dysfunction during development. PMID- 26443927 TI - Stereoselective Construction of 2,7-Disubstituted fused-Bis Tetrahydrofuran Skeletons: Biomimetic-Type Synthesis and Biological Evaluation of (+/-)- and (-) Aplysiallene and Their Derivatives. AB - A series of trans/trans and cis/cis fused-bis tetrahydrofuran compounds have been obtained stereoselectively in high yields via a one-pot operation involving the intramolecular haloetherification of (Z,Z)-diene diol 19a and (E,E)-diene disilylether 19d, respectively. This method was subsequently applied to the biomimetic-type synthesis of (+/-)- and (-)-aplysiallene. The inhibitory activities of these compounds and their bromodiene isomers toward Na(+)/K(+) ATPase were determined in vitro, and gave IC50 values of approximately 15 MUM in all cases. PMID- 26443928 TI - The role of working memory and verbal fluency in autobiographical memory in early Alzheimer's disease and matched controls. AB - Retrieval of autobiographical memories (AMs) is important for "sense of self". Previous research and theoretical accounts suggest that working memory (WM) and semantic and phonemic fluency abilities facilitate the hierarchical search for, and reliving of past, personal events in the mind's eye. However, there remains a lack of consensus as to the nature of the relationships between these cognitive functions and the truly episodic aspects of AM. The present study therefore aimed to explore the associations between these variables in a sample with a wide range of cognitive abilities. The study incorporated a between-groups component, and a correlational component with multiple regression. Participants with Alzheimer's disease (n=10) and matched healthy controls (n=10) were assessed on measures of semantic and episodic AM search and retrieval, auditory and spatial WM, and semantic and phonemic fluency. The AD group produced less episodic AM content compared to controls. Semantic fluency predicted episodic AM retrieval independent of age effects but there were no significant relationships between measures of phonemic fluency, WM and episodic AM. The results suggest that the ability to maintain hierarchical search of the semantic knowledge-base is important for truly episodic reliving, and interventions for people with AM impairment might therefore benefit from incorporating structured, individualised external memory-aids to facilitate AM search and retrieval. PMID- 26443929 TI - Reply to beta blockers in epithelial ovarian cancer and beta-blockers and improved survival from ovarian cancer: New miracle treatment or another case of immortal person-time bias? PMID- 26443926 TI - Neuropsychiatry and White Matter Microstructure in Huntington's Disease. AB - BACKGROUND: Neuropsychiatric symptoms in Huntington's disease (HD) are often evident prior to clinical diagnosis. Apathy is highly correlated with disease progression, while depression and irritability occur at different stages of the disease, both before and after clinical onset. Little is understood about the neural bases of these neuropsychiatric symptoms and to what extent those neural bases are analogous to neuropsychiatric disorders in the general population. OBJECTIVE: We used Diffusion Tensor Imaging (DTI) to investigate structural connectivity between brain regions and any putative microstructural changes associated with depression, apathy and irritability in HD. METHODS: DTI data were collected from 39 premanifest and 45 early-HD participants in the Track-HD study and analysed using whole-brain Tract-Based Spatial Statistics. We used regression analyses to identify white matter tracts whose structural integrity (as measured by fractional anisotropy, FA) was correlated with HADS-depression, PBA-apathy or PBA-irritability scores in gene-carriers and related to cumulative probability to onset (CPO). RESULTS: For those with the highest CPO, we found significant correlations between depression scores and reduced FA in the splenium of the corpus callosum. In contrast, those with lowest CPO demonstrated significant correlations between irritability scores and widespread FA reductions. There was no significant relationship between apathy and FA throughout the whole brain. CONCLUSIONS: We demonstrate that white matter changes associated with both depression and irritability in HD occur at different stages of disease progression concomitant with their clinical presentation. PMID- 26443932 TI - Exploring Safe Sleep and SIDS Risk Perception in an African-American Community: Focused Ethnography. AB - OBJECTIVES: Explore the cultural influences of safe sleep practices by African American caregivers of children under 2 years old. Explore the role of health care professionals in promoting safe sleep. DESIGN AND SAMPLE: A focused ethnography was used to understand the contextual cultural meaning and experiences of safe sleep practices of African-American caregivers of children under 2 years. Nineteen African-Americans participated in this study. MEASURES: Demographic data were collected and semi-structured interviews were conducted with individuals and small groups. Saturation of the data occurred after 17 interviews. Data were analyzed using Leininger's four Phases of qualitative data analysis. RESULTS: (Themes): (1) The informants expressed both accurate and inaccurate knowledge of Sudden Infant Death Syndrome (SIDS) and safe sleep practices influenced by personal experiences, hospital education, family, extended family and television; (2) Sleeping with infants and children was viewed as a cultural caring behavior promoting comfort, closeness and protection for infants, children, parents and caregivers; (3) The informants want and are seeking collaboration with nurses and health care professionals who are viewed as important in promoting accurate information about SIDS and safe sleep practices. CONCLUSION: The role of the nurse can impact accurate outcomes about SIDS and safe sleep practices. PMID- 26443930 TI - Stem cell therapy for cardiac regeneration: hits and misses. AB - Cardiac injury and loss of cardiomyocytes is a causative as well as a resultant condition of cardiovascular disorders, which are the leading cause of death throughout the world. This loss of cardiomyocytes cannot be completely addressed through the currently available drugs being administered, which mainly function only in relieving the symptoms. There is a huge potential being investigated for regenerative and cell replacement therapies through recruiting stem cells of various origins namely embryonic, reprogramming/induction, and adult tissue. These sources are being actively studied for translation to clinical scenarios. In this review, we attempt to discuss some of these promising scenarios, including the clinical trials and the obstacles that need to be overcome, and hope to address the direction in which stem cell therapy is heading. PMID- 26443933 TI - Effects of lip-closing training on maximum voluntary lip-closing force during lip pursing in healthy young adults. AB - To investigate the effect of lip-closing training, the time-course of multidirectional lip-closing forces during training was evaluated. The subjects were healthy young adults with no systemic disease. Ten subjects each were allocated to the training and non-training (control) groups. The subjects were instructed to use a lip muscle strength fixation device (M Patakara) for lip closing training. Regarding closing the upper and lower lips against this force for 3 min as one task, the subjects were instructed to perform three tasks a day for 4 weeks. The multidirectional lip-closing forces were measured before, during and after training every week. In the control group, the forces were measured under the same schedule without training. After the initiation of training, the total lip-closing force significantly increased at 3 and 4 weeks in the training group compared with that in the control group (P = 0.003 at 3 weeks, P < 0.001 at 4 weeks). After the completion of training, the force decreased from 1 week and no significant difference from the control group was noted. When the lip-closing force was evaluated by direction, significant increases in the upward and downward directions were noted in the training group compared with those in the control group (P = 0.034 at 3 weeks for upwards; P = 0.027 at 4 weeks for downwards). Quantitative analysis confirmed that lip-closing training enhanced the lip-closing force regionally. PMID- 26443934 TI - Mediation Analysis of Hepatitis B and C in Relation to Hepatocellular Carcinoma Risk. AB - BACKGROUND: Hepatitis B and C viruses are well-established risk factors for hepatocellular carcinoma (HCC) but their coordinated etiologic mechanism remains unclear. We aimed to assess the mediation effect of the two viruses on HCC risk. METHODS: We conducted a prospective cohort study in Taiwan (R.E.V.E.A.L. Hepatitis B Virus study), which included 3,851 participants seropositive for hepatitis B surface antigen and 278 incident HCC cases. Serum samples at enrollment or follow-up were tested for seromarkers and viral load of hepatitis B (HBV) and C (HCV). Mediation analyses for HCC risk were performed using Cox proportional hazards and linear regression models. RESULTS: Among participants with chronic hepatitis B, the direct effect of anti-HCV serostatus (positive vs. negative) independent of HBV viral load was associated with increased risk of HCC with a hazard ratio (HR) of 2.5 (95% confidence interval [CI] = 1.7, 3.6), and the indirect effect mediated through suppressing HBV viral load decreased the HCC risk with an HR of 0.75 (95% CI = 0.67, 0.84). Opposite effects led to an attenuated marginal effect with an HR of 1.7 (95% CI = 1.2, 2.5). For an increase in HCV viral load from 800 to 404,000 IU/ml (minimum to median viral level), the HRs were 1.6 (95% CI = 1.2, 2.0) for the direct effect, 0.78 (95% CI = 0.72, 0.85) for the indirect effect, and 1.1 (95% CI = 0.89, 1.5) for the marginal effect. CONCLUSION: The results support a suppressive effect of HCV on HCC risk mediated through HBV viral load and an adverse direct effect. PMID- 26443935 TI - The Transition of Medical Students Through Residency: Effects on Physical Activity and Other Lifestyle-Related Behaviors. AB - BACKGROUND: Little is known about lifestyle choices and preventive healthcare seeking behaviors during the transition from medical school graduation to residency training, a period characterized by increased rates of stress and lack of free time due to demanding working conditions. All of these issues are likely to affect physical activity (PA) level. This study explored the evolution of PA and other lifestyle behaviors during this transition. METHODS: A cross-sectional study and a cohort study were conducted with medical students (2010) and physicians before and after the first year of residency (2013 and 2014). A self administered questionnaire assessed PA, health and lifestyle behaviors. RESULTS: From a sample of 420 medical students and 478 residents, 74% comply with current PA guidelines. PA decreased by 16% during residency. Low levels of PA were found among (i) females and in respondents who reported (ii) poor self-perceived health and (iii) unhealthy body weight (P < .05). Low PA level was also significantly associated with poor mental health in first-year residents. CONCLUSIONS: The transition has a negative effect on physicians' PA level that may affect physicians' own health and patient care. Medical programs should encourage residents to engage in PA to assure physicians' personal and mental health. PMID- 26443936 TI - Frequency of Surgery Cancellations Associated With Myocardial Infarction or Death 6 Months After Coronary Stent Placement. PMID- 26443937 TI - The perilipin 2 (PLIN2) gene Ser251Pro missense mutation is associated with reduced insulin secretion and increased insulin sensitivity in Italian obese subjects. AB - BACKGROUND: Perilipin 2 (PLIN2), a member of the family of perilipin lipid droplets coating proteins, is very widely expressed. The Ser251Pro (rs35568725) missense mutation in exon 6 of PLIN2 gene was previously associated with increased lipid accumulation, decreased lipolysis and increased number of small lipid droplets per cell. Furthermore, the Pro251 mutation was associated with decreased plasma triglyceride and very low density lipoprotein concentrations in population studies. The aim of this study was to evaluate the effect of the Ser251Pro mutation of PLIN2 gene in a cohort with a higher predisposition to obesity-associated metabolic alterations, such as insulin resistance, decreased insulin-secretion, hyperglycaemia, and dyslipidaemia. METHODS: A large cohort (N = 1692) of Italian obese subjects (mean body mass index = 41 kg/m(2) ) was genotyped for the Ser251Pro mutation. All participants underwent oral glucose tolerance tests (OGTT), with measurement of glucose and insulin levels. Indices of insulin resistance and of insulin secretion were also calculated. Clinical and biochemical parameters were collected for all participants. RESULTS: We observed that insulin concentration was significantly reduced at 120 min after the administration of glucose in Pro251 allele carriers, whereas glucose levels were similar in Pro251 allele carriers and non-carriers throughout the OGTT. Furthermore, the CIR120 index of insulin secretion was significantly lower (P < 0.035) and the ISI index of insulin-sensitivity was significantly higher (P < 0.031) in carriers of the Pro251 allele. When we analysed men and women separately to test for gender-specific associations, we observed that in women insulin levels were significantly lower in Pro251 allele carriers compared with wild-type subjects throughout the whole OGTT. In men, we confirmed a significant reduction in insulin concentration only at 120 min after the OGTT. No significant differences between genotype groups regarding triglyceride levels and anyother clinical and metabolic parameters were observed. CONCLUSION: We observed a strong significant association between the PLIN2 Pro251 mutation and lower insulin secretion associated with an increased insulin sensitivity. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26443938 TI - Effects of passive and active movement on vibrotactile detection thresholds of the Pacinian channel and forward masking. AB - We investigated the gating effect of passive and active movement on the vibrotactile detection thresholds of the Pacinian (P) psychophysical channel and forward masking. Previous work on gating mostly used electrocutaneous stimulation and did not allow focusing on tactile submodalities. Ten healthy adults participated in our study. Passive movement was achieved by swinging a platform, on which the participant's stimulated hand was attached, manually by a trained operator. The root-mean-square value of the movement speed was kept in a narrow range (slow: 10-20 cm/s, fast: 50-60 cm/s). Active movement was performed by the participant him-/herself using the same apparatus. The tactile stimuli consisted of 250-Hz sinusoidal mechanical vibrations, which were generated by a shaker mounted on the movement platform and applied to the middle fingertip. In the forward-masking experiments, a high-level masking stimulus preceded the test stimulus. Each movement condition was tested separately in a two-interval forced choice detection task. Both passive and active movement caused a robust gating effect, that is, elevation of thresholds, in the fast speed range. Statistically significant change of thresholds was not found in slow movement conditions. Passive movement yielded higher thresholds than those measured during active movement, but this could not be confirmed statistically. On the other hand, the effect of forward masking was approximately constant as the movement condition varied. These results imply that gating depends on both peripheral and central factors in the P channel. Active movement may have some facilitatory role and produce less gating. Additionally, the results support the hypothesis regarding a critical speed for gating, which may be relevant for daily situations involving vibrations transmitted through grasped objects and for manual exploration. PMID- 26443939 TI - Structural heart interventions training in Europe. AB - BACKGROUND: Structural heart interventions have made major strides over the last years with the introduction of TAVR, percutaneous mitral valve repair and adult congenital heart disease procedures. METHODS: As part of the SCAI SHD Early Career Task Force committee, we complied a survey of 17 questions using a Survey Monkey website. We sent invitations twice by email to 183 European program directors of interventional cardiology fellowship programs in Europe. RESULTS: The most commonly performed procedures performed by the fellows were transseptal punctures, TAVR, BAV, PFO and BMV. For the rest of the structural procedures, each fellow performed <10 procedures during their training. CONCLUSION: Structural heart interventions training will keep expanding over the next years with the introduction of newer devices and techniques and accumulation of experience. Given the small number of the more rare structural procedures, it becomes apparent that we need to design national or international training networks to provide adequate training experience to all trainees. PMID- 26443940 TI - [Editor's Comment]. PMID- 26443941 TI - [Core needle biopsy]. PMID- 26443942 TI - [Not Available]. PMID- 26443943 TI - [Not Available]. PMID- 26443944 TI - [Postoperative care]. PMID- 26443945 TI - Clinical roles and applications of progesterone in reproductive medicine: an overview. AB - The physiologic and clinical value of progesterone is undisputed and a cornerstone of human reproduction. Better understanding of the exact dynamics and effects of endogenous progesterone secretion, as well as its therapeutic actions, is critical to ensure optimal clinical results in artificial reproduction technology, and to enhance chances of successfully completing pregnancy. Novel progesterone-based drugs and administration regimens will provide clinicians with greater options to make the management and treatment of infertile couples less burdensome and more successful. PMID- 26443946 TI - Biological pretreatment of rice straw with Streptomyces griseorubens JSD-1 and its optimized production of cellulase and xylanase for improved enzymatic saccharification efficiency. AB - Biological pretreatment of rice straw and production of reducing sugars by hydrolysis of bio-pretreated material with Streptomyces griseorubens JSD-1 was investigated. After 10 days of incubation, various chemical compositions of inoculated rice straw were degraded and used for further enzymatic hydrolysis studies. The production of cellulolytic enzyme by S. griseorubens JSD-1 favored the conversion of cellulose to reducing sugars. The culture medium for cellulolytic enzyme production by using agro-industrial wastes was optimized through response surface methodology. According to the response surface analysis, the concentrations of 11.13, 20.34, 4.61, and 2.85 g L(-1) for rice straw, wheat bran, peptone, and CaCO3, respectively, were found to be optimum for cellulase and xylanase production. Then the hydrolyzed spent Streptomyces cells were used as a nitrogen source and the maximum filter paper cellulase, carboxymethylcellulase, and xylanase activities of 25.79, 78.91, and 269.53 U mL( 1) were achieved. The crude cellulase produced by S. griseorubens JSD-1 was subsequently used for the hydrolysis of bio-pretreated rice straw, and the optimum saccharification efficiency of 88.13% was obtained, indicating that the crude enzyme might be used instead of commercial cellulase during a saccharification process. These results give a basis for further study of bioethanol production from agricultural cellulosic waste. PMID- 26443947 TI - RUPTURES IN THE ANALYTIC SETTING AND DISTURBANCES IN THE TRANSFORMATIONAL FIELD OF DREAMS. AB - This paper explores some implications of Bleger's (1967, 2013) concept of the analytic situation, which he views as comprising the analytic setting and the analytic process. The author discusses Bleger's idea of the analytic setting as the depositary for projected painful aspects in either the analyst or patient or both-affects that are then rendered as nonprocess. In contrast, the contents of the analytic process are subject to an incessant process of transformation (Green 2005). The author goes on to enumerate various components of the analytic setting: the nonhuman, object relational, and the analyst's "person" (including mental functioning). An extended clinical vignette is offered as an illustration. PMID- 26443948 TI - "I HEAR MY VOICE, BUT WHO IS TALKING?": UNDERSTANDING DEPERSONALIZATION. AB - Depersonalization is the frightening experience of being a shut-inside, ghostlike, "true" self that observes another part of the self interacting in the outside world. The "true" self hides safely within, while the "participating" self holds all affects and impulses. This split in the ego is created via internal projective identification in the face of overwhelming affect, unavailability of adequate identifications, and insufficient support for psychic cohesion. As the transference develops, the powerful entrapping cocoon of depersonalization can be projected onto the now-entrapping analyst, where it can be addressed. A clinical vignette illustrates these points. PMID- 26443949 TI - HANSEL AND GRETEL: A TALE OF TERROR. AB - In the analysis of a woman with multiple childhood traumas, the fairy tale "Hansel and Gretel" figured prominently. The author discusses the use of the fairy tale in this case at various levels. He suggests an interplay between a national myth, the fairy tale, and a personal myth-the patient's psychodynamics. The fairy tale can be used to illuminate personal meanings derived from it. In the experience of childhood trauma, the repeated reading of a fairy tale can help organize and defend against terrifying anxiety. PMID- 26443950 TI - ATTACKS ON LINKING OR A DRIVE TO COMMUNICATE? TOLERATING THE PARADOX. AB - The notion of attacks on linking, as described by Bion, may depict a patient's drive to communicate the internalization of a destructive relationship between a primary object and an infant. This may be enacted between patient and analyst in the here and now of the analysis, whereby fragmentation and numbing of thinking may point to a primitive catastrophe relived in the psychoanalytic setting. The patient's material may seem incoherent, but incoherence might be the communication the patient is unconsciously trying to convey. Thus, the notion of attacks on linking depicts a paradoxical, caesural experience in which the attack on linking is itself a link. PMID- 26443951 TI - MOTILITY, AGGRESSION, AND THE BODILY I: AN INTERPRETATION OF WINNICOTT. AB - Among the central ideas associated with the name of Winnicott, scant mention is made of motility. This is largely attributable to Winnicott himself, who never thematized motility and never wrote a paper specifically devoted to the topic. This paper suggests both that the idea of motility is nonetheless of central significance in Winnicott's thought, and that motility is of central importance in the development and constitution of the bodily I. In elaborating both these suggestions, the paper gives particular attention to the connections between motility, continuity, aggression, and creativity in Winnicott's work. PMID- 26443952 TI - "AFTER THE EVENT": FREUD'S UNCANNY AND THE ANXIETY OF ORIGINS. AB - This essay aims to revise Freud's theory of the uncanny by rereading his own essay of that name along with the key material Freud drew on in formulating his theory: E. T. A. Hoffmann's short story "The Sandman" (1816a) and Ernst Jentsch's essay "On the Psychology of the Uncanny" (1906a). While arguing, initially, both that Jentsch's work is fundamentally misconstrued by Freud and that it offers a better account of what happens in Hoffmann's story, the essay moves beyond Jentsch's account to offer a more philosophically oriented theory of the uncanny, one more in line with Freud's ideas in Beyond the Pleasure Principle (1920a). PMID- 26443963 TI - Effects of Combined High Hydrostatic Pressure and Dense Phase Carbon Dioxide on the Activity, Structure and Size of Polyphenoloxidase. AB - High hydrostatic pressure (HHP) may activate undesirable enzymes such as polyphenoloxidase (PPO). Carbon dioxide (CO2 ) addition to HHP could increase enzyme inactivation. We investigated the inactivation of combined HHP and dense phase carbon dioxide process on activity, secondary conformation and size of pure PPO from mushroom. Solutions (2.35MUM, in phosphate buffer pH 6.8) were treated with HHP alone (HHP), or 3.6% w/w of CO2 was injected into the package (HHP+CO2). Treatment conditions were 600 MPa, 20 degrees C, for 1, 3, 5, 7, and 9 min. HHP+CO2 treatment significantly decreased residual enzyme activity (REA) to 30% to 12% after 1 to 9 min, respectively, whereas only HHP had no significant effect. Both HHP and HHP+CO2 treatments caused changes in secondary conformations, however HHP+CO2 changes were more extensive. Alpha-helix fractions were reduced by 32% and 41%, while beta sheet, turn and unordered increased by 63% and 213%, 100% and 71%, and 118% and 82% for HHP and HHP+CO2, respectively after 9 min. The protein size in HHP+CO2 samples was 5- to 6-fold larger than that of Control and HHP treatment, and this increase was inversely correlated with REA. The best inactivation kinetics of HHP+CO2 model was the 2-fractional model with 2 simultaneous 1st-order steps, contributing 70% and 30% to original enzyme activity, with k(labile) = 12.15 min(-1) and k(stable) = 0.07 min(-1), respectively. No recovery in activity, secondary conformation and size in all samples were observed after 1-mo storage. Addition of CO2 in HHP treatment can improve enzyme inactivation, and therefore product shelf-life and quality. PRACTICAL APPLICATION: High hydrostatic pressure (HHP) achieves the safety of foods as a nonthermal method, but it may activate undesirable enzymes resulting in short shelf life due to, for example flavor and color changes. Our study determined that addition of CO2 to HHP has significant effects on enzyme inactivation, secondary conformational and molecular size changes of mushroom PPO. No recovery in activity, secondary conformation and size in all samples were observed after 1 mo storage at 4 degrees C. This combined process increases product shelf life, in addition to safety and nutrient preservation. PMID- 26443964 TI - Anatomy and development of the cardiac lymphatic vasculature: Its role in injury and disease. AB - Lymphatic vessels are present throughout the entire body in all mammals and function to regulate tissue fluid balance, lipid transport and survey the immune system. Despite the presence of an extensive lymphatic plexus within the heart, until recently the importance of the cardiac lymphatic vasculature and its origins were unknown. Several studies have described the basic anatomy of the developing cardiac lymphatic vasculature and more recently the detailed development of the murine cardiac lymphatics has been documented, with important insight into their cellular sources during embryogenesis. In this review we initially describe the development of systemic lymphatic vasculature, to provide the background for a comparative description of the spatiotemporal development of the cardiac lymphatic vessels, including detail of both canonical, typically venous, and noncanonical (hemogenic endothelium) cellular sources. Subsequently, we address the response of the cardiac lymphatic network to myocardial infarction (heart attack) and the therapeutic potential of targeting cardiac lymphangiogenesis. PMID- 26443965 TI - Coincidence of late-onset cytomegalovirus-induced myositis and gastritis in a pediatric renal transplant recipient. AB - An 8-year-old girl with a renal transplant was admitted for myalgia and muscle weakness in both legs over the previous 2 weeks. She also had fever and intermittent epigastric pain. Based on these clinical manifestations, and laboratory and histopathological findings, the diagnosis was coincidence of late onset cytomegalovirus (CMV)-induced myositis and gastritis in an immunocompromised child with a renal transplant. After administration of intravenous ganciclovir for 3 weeks, her symptoms resolved, with normalization of abnormal muscle enzymes, including lactate dehydrogenase, creatine kinase, aspartate aminotransferase, and the disappearance of CMV viremia. PMID- 26443966 TI - Ultrasensitive self-powered cytosensors based on exogenous redox-free enzyme biofuel cells as point-of-care tools for early cancer diagnosis. AB - An exogenous redox-free, membrane-less enzyme biofuel cell-based ultrasensitive self-powered cytosensing platform was fabricated. With the ultrahigh sensitivity and the merits of not requiring external power sources or exogenous reagents, the device has great potential as a point-of-care tool for early diagnosis of cancer in vivo. PMID- 26443967 TI - Visualization of Patients' Skin Lesions on Their Smartphones: A New Step During Dermatology Visits. PMID- 26443969 TI - Successful treatment with intravenous high-dose immunoglobulin for cardiomyopathy in dermatomyositis complicated with rapid progressive interstitial pneumonia. AB - Cardiomyopathy and rapid progressive interstitial pneumonia (IP) are potentially fatal complications in polymyositis/dermatomyositis. We experienced a dermatomyositis patient with multiple adverse prognostic factors, complicating rapid progressive IP, macrophage activation syndrome (MAS), and cardiomyopathy. IP and MAS improved with strong immunosuppressive therapy, despite which cardiomyopathy developed. Therefore, we applied intravenous high-dose immunoglobulin therapy (IVIg), and cardiac function improved dramatically. This is the first report to present the effectiveness of IVIg for cardiomyopathy in dermatomyositis. PMID- 26443970 TI - The Diaza[5.5.6.6]fenestrane Skeleton-Synthesis of Leuconoxine Alkaloids. AB - Among the Aspidosperma-derived monoterpene indole alkaloids, the leuconoxine subgroup has drawn significant attention from the synthetic community during the past few years. This Minireview summarizes the hitherto six completed total syntheses of leuconoxines emphasizing the different strategies for assembling the key structural motif, an unprecedented diaza[5.5.6.6]fenestrane skeleton. In addition, the proposed biogenetic relationships within the group of these alkaloids are described. PMID- 26443971 TI - The role of sensitization in musculoskeletal shoulder pain. AB - INTRODUCTION: Peripheral and central sensitization are neurophysiological processes that can prolong painful conditions. Painful shoulder conditions are often persistent, perhaps due to the presence of sensitization. METHOD: This manuscript summarizes six studies that have evaluated those with musculoskeletal shoulder pain for the presence of sensitization. RESULTS: All six manuscripts report evidence of peripheral sensitization, while central sensitization was described in five of the studies. The chronicity of symptoms in subjects who were included in the studies is probably influencing this finding. The primary somatosensory test used to assess sensitization in these studies was Pressure Pain Threshold, a test for lowered nociceptive thresholds. DISCUSSION: It appears that peripheral sensitization manifests consistently in those with musculoskeletal shoulder pathology, probably due to the inflammatory processes related to tissue injury. Central sensitization, while not universally present, was reported in a majority of the manuscripts. Because central sensitization is thought to be a key step on the pathway to chronic pain, evidence for its presence in those with shoulder pain is significant. Clinicians should expect the presence of sensitization with shoulder pathology and make appropriate choices about interventions so as not to exacerbate pain. PMID- 26443972 TI - Interval and continuous exercise enhances aerobic capacity and hemodynamic function in CHF rats. AB - OBJECTIVE: The aim of the present study was to compare the effects of continuous versus interval aerobic exercise training on hemodynamic parameters, cardiac remodeling, and maximal exercise capacity (MEC) in chronic heart failure (CHF) rats. METHOD: Twenty-four male Wistar rats were subjected to myocardial infarction (MI) surgery. Five weeks post MI, the animals were assigned to one of three groups: sedentary group (CHF-Sed, n=8), aerobic continuous training group (CHF-ACT, n=8), and aerobic interval training group (CHF-AIT, n=8). Treadmill training was performed five times a week for 8 weeks (ACT: 50 min/day at 15 m/min and AIT: 40 min/day with 8 min of warm-up at 10 m/min and exercise at 15 m/min 4*4 min interspersed with 4*4 min at 23 m/min). MEC was evaluated pre and post exercise program. RESULTS: Left ventricular end-diastolic pressure (LVEDP), left ventricular mass/body mass ratio (LVM:BM), and total collagen volume fraction were lower in the trained groups compared with the sedentary group, but no difference was found between the trained groups. Systolic ventricular pressure (SVP) and maximum positive derivative of LV pressure (+dP/dtmax) were higher in the trained groups, but CHF-ACT showed higher +dP/dt(max) compared to CHF-AIT. Both training regimens were able to increase MEC. However, the aerobic interval training was superior for improving MEC. CONCLUSION: Aerobic training is an important intervention to improve cardiac function and remodeling and physical capacity in CHF rats. Interval training is a potential strategy to maximize the results, but exercise type and intensity are still topics to be explored. PMID- 26443973 TI - Effects of nephrectomy on respiratory function and quality of life of living donors: a longitudinal study. AB - BACKGROUND: A living donor transplant improves the survival and quality of life of a transplant patient. However, the impact of transplantation on postoperative lung function and respiratory muscular strength in kidney donors remains unknown. OBJECTIVE: To evaluate pulmonary function, respiratory muscle strength, quality of life and the incidence of postoperative pulmonary complications (PPCs) in kidney donors undergoing nephrectomy. METHOD: This prospective cohort enrolled 110 consecutive kidney donors undergoing nephrectomy. Subjects underwent pulmonary function (using spirometry) and respiratory muscular strength (using manovacuometry) assessments on the day prior to surgery and 1, 2, 3 and 5 days postoperatively. Quality of life (measured by the SF-36) was evaluated preoperatively and 30 days postoperatively. PPCs were assessed daily by a blinded assessor. RESULTS: Donors exhibited a decrease of 27% in forced vital capacity, 58% in maximum inspiratory capacity and 51% in maximum expiratory pressure on the 1stpostoperative day (p<0.001) but this improved over days 2, 3 and 5 but had not returned to preoperative levels. Patient quality of life was still impaired at 30 days with regards to functional capacity, physical role, pain, vitality and social functioning (p<0.05) but these parameters improved slowly. None of the patients developed PPCs. CONCLUSION: Kidney donors submitted to nephrectomy exhibited a reduction in pulmonary function, respiratory muscular strength and quality of life, most of which were improving toward pre-surgical levels. PMID- 26443974 TI - Influence of obstructive sleep apnea syndrome in the fluctuation of the submaximal isometric torque of knee extensors in patients with early-grade osteoarthritis. AB - OBJECTIVE: The aim of this study was to investigate whether obstructive sleep apnea (OSA) alters the fluctuation of submaximal isometric torque of the knee extensors in patients with early-grade osteoarthritis (OA). METHOD: The study included 60 male volunteers, aged 40 to 70 years, divided into four groups: Group 1 (G1) - Control (n=15): without OA and without OSA; Group 2 (G2) (n=15): with OA and without OSA; Group 3 (G3) (n=15): without OA and with OSA; and Group 4 (G4) (n=15) with OA and with OSA. Five patients underwent maximal isometric contractions of 10 seconds duration each, with the knee at 60 degrees of flexion to determine peak torque at 60 degrees . To evaluate the fluctuation of torque, 5 submaximal isometric contractions (50% of maximum peak torque) of 10 seconds each, which were calculated from the standard deviation of torque and coefficient of variation, were performed. RESULTS: Significant differences were observed between groups for maximum peak torque, while G4 showed a lower value compared with G1 (p=0.005). Additionally, for the average torque exerted, G4 showed a lower value compared to the G1 (p=0.036). However, no differences were found between the groups for the standard deviation (p=0.844) and the coefficient of variation (p=0.143). CONCLUSION: The authors concluded that OSA did not change the parameters of the fluctuation of isometric submaximal torque of knee extensors in patients with early-grade OA. PMID- 26443975 TI - Reliability of new software in measuring cervical multifidus diameters and shoulder muscle strength in a synchronized way; an ultrasonographic study. AB - OBJECTIVES: This study was conducted with the purpose of evaluating the inter session reliability of new software to measure the diameters of the cervical multifidus muscle (CMM), both at rest and during isometric contractions of the shoulder abductors in subjects with neck pain and in healthy individuals. METHOD: In the present study, the reliability of measuring the diameters of the CMM with the Sonosynch software was evaluated by using 24 participants, including 12 subjects with chronic neck pain and 12 healthy individuals. The anterior posterior diameter (APD) and the lateral diameter (LD) of the CMM were measured in a resting state and then repeated during isometric contraction of the shoulder abductors. Measurements were taken on separate occasions 3 to 7 days apart in order to determine inter-session reliability. Intraclass correlation coefficient (ICC), standard error of measurement (SEM), and smallest detectable difference (SDD) were used to evaluate the relative and absolute reliability, respectively. RESULTS: The Sonosynch software has shown to be highly reliable in measuring the diameters of the CMM both in healthy subjects and in those with neck pain. The ICCs 95% CI for APD ranged from 0.84 to 0.94 in subjects with neck pain and from 0.86 to 0.94 in healthy subjects. For LD, the ICC 95% CI ranged from 0.64 to 0.95 in subjects with neck pain and from 0.82 to 0.92 in healthy subjects. CONCLUSIONS: Ultrasonographic measurement of the diameters of the CMM using Sonosynch has proved to be reliable especially for APD in healthy subjects as well as subjects with neck pain. PMID- 26443976 TI - Physiotherapy: a historical analysis of the transformation from an occupation to a profession in Brazil. AB - ABSTRACTBackground:Analyzing the historical and social path of an occupation using the sociology of professions and the perspective of scientific knowledge promotes an understanding of the origin of physical therapy in Brazil and of discussions of the profession in its contemporary context. OBJECTIVE: The aim of this paper was to discuss the professionalization process of physical therapy in Sao Paulo. The authors tried to analyze bath therapy, massage therapy, and physical therapy as occupations involving distinct expertise and as part of the group of occupations that evolved into the profession of physiotherapy in the first half of the twentieth century. METHOD: The analysis undertaken was a qualitative study based on an analysis of historical documents. Eighty-six professional records from the Service of Inspection of Professional Practice in the state of Sao Paulo and healthcare legislation from the 1930s and 1940s were analyzed. RESULTS: The distinction between physical therapy practitioner and profession of physiotherapy can be seen by examining registration requirements for rank-and-file nurses with expertise in interactions; this distinction suggests the emergence of specialized expertise that was clearly a part of neither medicine nor nursing and contributed to expertise in physical therapy since the 1950s. CONCLUSION: The regulation of physiotherapy practices, the recognition of expertise, the accreditation of practical nurses by the State, and the institutionalization of a course for physical therapy practitioners in 1951 are key elements of the professionalization process for the physical therapy profession in Brazil. PMID- 26443977 TI - Evidence-Based Practice: a survey regarding behavior, knowledge, skills, resources, opinions and perceived barriers of Brazilian physical therapists from Sao Paulo state. AB - BACKGROUND: Evidence-Based Practice (EBP) has been widely used by health professionals. However, no study in Brazil has investigated the data regarding the knowledge and difficulties related to EBP from a representative sample of physical therapists. OBJECTIVE: To identify behavior, knowledge, skills, resources, opinions and perceived barriers of Brazilian physical therapists from the state of Sao Paulo regarding EBP. METHOD: A customized questionnaire about behavior, knowledge, skills, resources, opinions and perceived barriers regarding EBP was sent by email to a sample of 490 physical therapists registered by the Registration Board of Sao Paulo, Brazil. Physical therapists who did not respond to the questionnaire were contacted by telephone and/or letter. The data were analyzed descriptively. RESULTS: The final response rate was 64.4% (316/490). Because 60 physical therapists were no longer practicing, 256 answers were analyzed. The physical therapists reported that they routinely read scientific papers (89.5%) as a resource for professional development, followed by continuing education courses (88.3%) and books (86.3%). Approximately 35% of the respondents reported a clear understanding of the implementation of research findings in their practice; approximately 37% reported no difficulties in critically appraising scientific papers; and 67.2% strongly agreed that EBP is important for their practice. The most commonly reported barriers were related to difficulties in obtaining full-text papers (80.1%), using EBP may represent higher cost (80.1%) and the language of publication of the papers (70.3%). CONCLUSION: Physical therapists from Sao Paulo state believe that they have knowledge and skills to use EBP. Although they have favorable opinions regarding its implementation, they still encounter difficulties in implementing EBP successfully. PMID- 26443978 TI - Joint positioning sense, perceived force level and two-point discrimination tests of young and active elderly adults. AB - BACKGROUND: Changes in the proprioceptive system are associated with aging. Proprioception is important to maintaining and/or recovering balance and to reducing the risk of falls. OBJECTIVE: To compare the performance of young and active elderly adults in three proprioceptive tests. METHOD: Twenty-one active elderly participants (66.9 +/- 5.5 years) and 21 healthy young participants (24.6 +/- 3.9 years) were evaluated in the following tests: perception of position of the ankle and hip joints, perceived force level of the ankle joint, and two-point discrimination of the sole of the foot. RESULTS: No differences (p>0.05) were found between groups for the joint position and perceived force level. On the other hand, the elderly participants showed lower sensitivity in the two-point discrimination (higher threshold) when compared to the young participants (p < 0.01). CONCLUSION: Except for the cutaneous plantar sensitivity, the active elderly participants had maintained proprioception. Their physical activity status may explain similarities between groups for the joint position sense and perceived force level, however it may not be sufficient to prevent sensory degeneration with aging. PMID- 26443979 TI - Moderating effect of the environment in the relationship between mobility and school participation in children and adolescents with cerebral palsy. AB - BACKGROUND: The literature demonstrates that the social participation of children with disabilities is influenced by both their functional skills repertoire and environmental factors. However, it is not yet known whether the effect of functional limitations on social participation is minimized or enhanced by the environmental facilitators and barriers. This study aimed to test this hypothesis. OBJECTIVE: To investigate the moderating effect of environmental factors in the relationship between mobility and school participation of children and adolescents with cerebral palsy (CP). METHOD: Participants were 102 elementary school children and adolescents with CP, aged 6 to 17 years, classified as levels I, II, and III according to the Gross Motor Classification System, along with their parents or caregivers and teachers. School participation and parents' perceptions of barriers were evaluated using the School Function Assessment and the Craig Hospital Inventory of Environmental Factors (CHIEF), respectively. RESULTS: The regression model failed to reveal a moderating effect of environmental factors in the relationship between mobility and school participation. While mobility was a strong predictor of participation, environmental factors demonstrated a weak predictive effect on the latter. The CHIEF subscale school/work showed the factors which were greatest barrier to children's participation, while the subscale attitude/support had the least impact. CONCLUSION: The absence of moderation on the tested relationship suggests that, when investigated under the negative perspective of environmental barriers, the contextual factors do not modify the relationship between mobility and school participation. Factors specific to the school environment might add to the present study's results regarding the effect of school participation in this population. PMID- 26443980 TI - Usage evaluation of the Physiotherapy Evidence Database (PEDro) among Brazilian physical therapists. AB - BACKGROUND: It is unclear whether the Physiotherapy Evidence Database (PEDro) is widely and equally used by physical therapists in Brazil. As PEDro is considered a key resource to support evidence-based physical therapy, analyses of PEDro usage could reflect the extent of dissemination of evidence-based practice. OBJECTIVE: To describe the usage of PEDro among the five regions of the World Confederation for Physical Therapy (WCPT) and, in more detail, in the South American region and Brazil over a 5-year period. METHOD: PEDro home-page sessions and the number of searches performed were logged for a 5-year period (2010-2014). Absolute usage and relative usage were calculated for each region of the WCPT, each country in the South American region of WCPT, and each Regional Council (CREFITO) in Brazil. RESULTS: Europe had the highest absolute and relative usage among the five regions of the WCPT (971 searches per million-population per year), with the South American region ranked 4th in absolute terms and 3rd in relative terms (486). Within the South American region, Brazil accounted for nearly 60% of searches (755). Analysis at a national level revealed that usage per physical therapist in Brazil is very low across all CREFITOs. The highest usage occurred in CREFITO 6 with 1.3 searches per physical therapist per year. CONCLUSIONS: PEDro is not widely and equally used throughout Brazil. Strategies to promote PEDro and to make PEDro more accessible to physical therapists speaking Portuguese are needed. PMID- 26443981 TI - A novel, self-shielded modular radiosynthesis system for fully automated preparation of PET and therapeutic radiopharmaceuticals. AB - OBJECTIVE: With the vast development of theranostics and, recently, (68)Ga radiolabeled molecules, there is also a need for novel, smaller, flexible, safe, and efficient modular automated synthesis systems in different clinical settings. The aim of our study was to determine the shielding properties of the modular self-shielded automated radiosynthesis box and determine its suitability for routine preparation of different radiopharmaceuticals to be used for diagnosis and therapy. METHODS: To evaluate shielding properties, shielding factors were determined using two different radiation sources: (137)Cs and (68)Ga. The dose rates were measured at critical points at the surface and 1 m distance from the surface. Three different methods were used to concentrate and purify (68)Ga generator eluate. Performance of the system was tested by evaluating several radiolabeling applications using (68)Ga, (177)Lu, and (90)Y. RESULTS: Dose rates measured at the surface did not exceed 9 MUSv/h for (68)Ga and 20 MUSv/h when using (137)Cs. On average, dose rates at the surface were reduced for factors of 1665 and 906, respectively. Different DOTA peptides were labeled successfully with (68)Ga with radiochemical purities more than 94% using three different radiolabeling methods. (177)Lu-DOTATATE and (90)Y-DOTATATE were synthesized reproducibly with a radiochemical purity of more than 99% and more than 97%, respectively. CONCLUSION: A self-shielded radiosynthesis box is a unique solution for nuclear medicine departments that lack space for installation of standard automated synthesis systems set in large and heavy dedicated PET synthesis boxes. Shielding properties are sufficient for safe clinical use for both PET and beta( ) radioisotopes. Because of its modular design and the simple adaptability of system parameters, the system can be used for the preparation of different clinically used radiopharmaceuticals and is also useful for research purposes. PMID- 26443982 TI - Differential Links Between Leisure Activities and Depressive Symptoms in Unemployed Individuals. AB - OBJECTIVE: Unemployment has consistently been linked to an elevated risk for depression. Exercise, specifically leisure-based physical activities, has received increasing attention as alternative treatment options. However, because leisure activities are pursued during discretionary time, it is unclear if the mental health benefits of physical and leisure activities apply during times of unemployment as well. METHOD: Depressive symptoms and participation in recreational activities were assessed in 142 employed and 158 unemployed participants (age = 34 +/- 11 years; male = 150). RESULTS: Independent of employment status, all recreational activities were inversely associated with depressive symptoms. However, social (employed: etap (2) = .21; unemployed: etap (2) = .11) and self-focused (employed: etap (2) = .19; unemployed: etap (2) = .10) recreational activities were more strongly related to depressive symptoms than exercise (employed: etap (2) = .12; unemployed: etap (2) > .05). CONCLUSION: These findings highlight the strong mental health associations of recreational activities and suggest that, particularly for unemployed individuals, promoting recreational activities, rather than exercise, may leverage the stronger negative relationship with risk of depression. PMID- 26443983 TI - Maternal Mortality versus Researcher's Responsibility to Contribute to Its Reduction. PMID- 26443984 TI - The Importance of Null Findings: Preterm Delivery and Cardiovascular Disease. PMID- 26443985 TI - Air Pollution, Neighbourhood Socioeconomic Factors, and Neural Tube Defects in the San Joaquin Valley of California. AB - BACKGROUND: Environmental pollutants and neighbourhood socioeconomic factors have been associated with neural tube defects, but the potential impact of interaction between ambient air pollution and neighbourhood socioeconomic factors on the risks of neural tube defects is not well understood. METHODS: We used data from the California Center of the National Birth Defects Study and the Children's Health and Air Pollution Study to investigate whether associations between air pollutant exposure in early gestation and neural tube defects were modified by neighbourhood socioeconomic factors in the San Joaquin Valley of California, 1997 2006. There were 5 pollutant exposures, 3 outcomes, and 9 neighbourhood socioeconomic factors included for a total of 135 investigated associations. Estimates were adjusted for maternal race-ethnicity, education, and multivitamin use. RESULTS: We present below odds ratios (ORs) that exclude 1 and a chi-square test of homogeneity P-value of <0.05. We observed increased odds of spina bifida comparing the highest to lowest quartile of particulate matter <10 MUm (PM10 ) among those living in a neighbourhood with: (i) median household income of less than $30 000 per year [OR 5.1, 95% confidence interval (CI) 1.7, 15.3]; (ii) more than 20% living below the federal poverty level (OR 2.6, 95% CI 1.1, 6.0); and (iii) more than 30% with less than or equal to a high school education (OR 3.2, 95% CI 1.4, 7.4). The ORs were not statistically significant among those higher socioeconomic status (SES) neighbourhoods. CONCLUSIONS: Our results demonstrate effect modification by neighbourhood socioeconomic factors in the association of particulate matter and neural tube defects in California. PMID- 26443986 TI - Social Environments, Genetics, and Black-White Disparities in Infant Mortality. AB - BACKGROUND: Genes and environments often interplay to produce population health. However, in some instances, the scientific literature has favoured one explanation, underplaying the other, even in the absence of rigorous support. We examine parental race disparity on the risk of infant mortality to see if such an analysis might provide clues to understanding the extent to which genes and environment may shape perinatal risks. METHODS: We assessed parental racial disparities in infant mortality among singletons by analysing the risk of infant mortality among racially consonant vs. dissonant couples over time between 1989 1997 and 1998-2006 in the state of Michigan (n = 1 428 199). We calculated the degree of modification of the relation between maternal race and infant mortality by paternal race dynamically across the two time periods. RESULTS: Infant mortality among interracial couples decreased with time relative to white-white couples, while infant mortality among black-black couples increased with time after adjusting for socio-economic, demographic, and prenatal care differences. The degree to which paternal black race strengthened the relation between maternal black race and higher infant mortality risk relative to white mothers increased with time throughout our study. CONCLUSIONS: Evidence from these data suggests that environmental factors likely play the greater role in explaining the parental race disparity and risk of infant mortality. PMID- 26443988 TI - Erratum. PMID- 26443987 TI - Maternal Recall Error in Retrospectively Reported Time-to-Pregnancy: an Assessment and Bias Analysis. AB - BACKGROUND: Epidemiologic studies of fecundability often use retrospectively measured time-to-pregnancy (TTP), thereby introducing potential for recall error. Little is known about how recall error affects the bias and precision of the fecundability odds ratio (FOR) in such studies. METHODS: Using data from the Danish Snart-Gravid Study (2007-12), we quantified error for TTP recalled in the first trimester of pregnancy relative to prospectively measured TTP among 421 women who enrolled at the start of their pregnancy attempt and became pregnant within 12 months. We defined recall error as retrospectively measured TTP minus prospectively measured TTP. Using linear regression, we assessed mean differences in recall error by maternal characteristics. We evaluated the resulting bias in the FOR and 95% confidence interval (CI) using simulation analyses that compared corrected and uncorrected retrospectively measured TTP values. RESULTS: Recall error (mean = -0.11 months, 95% CI -0.25, 0.04) was not appreciably associated with maternal age, gravidity, or recent oral contraceptive use. Women with TTP > 2 months were more likely to underestimate their TTP than women with TTP <= 2 months (unadjusted mean difference in error: -0.40 months, 95% CI -0.71, -0.09). FORs of recent oral contraceptive use calculated from prospectively measured, retrospectively measured, and corrected TTPs were 0.82 (95% CI 0.67, 0.99), 0.74 (95% CI 0.61, 0.90), and 0.77 (95% CI 0.62, 0.96), respectively. CONCLUSIONS: Recall error was small on average among pregnancy planners who became pregnant within 12 months. Recall error biased the FOR of recent oral contraceptive use away from the null by 10%. Quantitative bias analysis of the FOR can help researchers quantify the bias from recall error. PMID- 26443989 TI - The Association Between Obstructive Sleep Apnea and Nonarteritic Anterior Ischemic Optic Neuropathy: A Systematic Review and Meta-Analysis. AB - PURPOSE: Nonarteritic anterior ischemic optic neuropathy (NAION) is a multifactorial disease, and recently epidemiologic studies have investigated the association between obstructive sleep apnea (OSA) and NAION. A systematic review of the association of OSA and NAION has not been performed. Therefore, the current meta-analysis was performed to assess such potential association between OSA and risk of NAION. METHODS: A systematic search of PubMed and EMBASE databases was performed for published studies evaluating the association between OSA and NAION. The summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for categorical risk estimates. Sensitivity analyses and subgroup analyses were also performed to assess the robustness of pooled outcomes. RESULTS: A total of four prospective cohort studies and one case-control study met our inclusion criteria. The pooled OR of developing NAION in the subjects with OSA was 6.18 (95% CI, 2.00-19.11) versus non-OSA controls. Sensitivity analyses showed that no matter one study excluded, the pooled OR did not change significantly, which indicated that the evidence was robust. In subgroup analyses, a significant association was seen in studies matched systemic risk factors (OR, 5.00; 95% CI, 2.22-11.25), but not in those non-matched. The magnitude and direction of effects were also affected by methodological variability, including study design, and diagnosis of OSA. CONCLUSIONS: The findings from this meta-analysis supported the robust evidence that OSA was a strong independent risk factor of NAION. Relative to non-OSA controls, the subjects with OSA were found to have a more than sixfold risk of NAION. In future, more well-designed studies are needed to confirm these findings. PMID- 26443991 TI - Prediction of hyperdynamic circulation by arterial diastolic reflected waveform analysis in patients undergoing liver transplantation. AB - OBJECTIVES: In cirrhotic patients with hyperdynamic circulation characterized by a decrease in systemic vascular resistance (SVR) and an increase in cardiac output, cardiac and vascular properties are expressed in peripheral arterial pressure waveforms. We attempted to assess whether the variables derived from the radial artery waveform can predict hyperdynamic circulation in liver transplant recipients. MATERIALS AND METHODS: Before surgical incision, we obtained the simultaneous cardiac index (CI) and SVR determined by a pulmonary artery catheter in 30 liver transplant recipients. We analyzed the diastolic reflected waveform characteristics by calculating the diastolic augmentation index (DAIx, %), which was defined as 100*[peak pressure of diastolic reflected wave-diastolic arterial pressure]/pulse pressure. The time from diastolic arterial pressure to the peak of the diastolic reflected wave, corrected by RR intervals (tDA), was also determined. RESULTS: CI and SVR were correlated with DAIx (r=-0.553, P=0.002 and r=0.617, P<0.001) and tDA (r=0.504, P=0.004 and r=-0.692, P<0.001). The areas under the receiver operating characteristic curves were 0.900 [95% confidence interval: 0.713-0.978 for both DAIx and tDA to predict hyperdynamic circulation (CI>4.0 l/min/m and SVR<800 dynes.s/cm, n=13)]. DAIx less than 35% and tDA more than 484 ms were the best cutoff values for differentiation of hyperdynamic circulation (sensitivity/specificity 92.3%/76.5% and 100%/70.6%, respectively). CONCLUSION: Diastolic reflected waveform characteristics can be used to predict high CI and low SVR in liver transplant recipients. This study suggests that these minimally invasive indicators may also be valuable when pulmonary artery catheterization is not available in patients with a hyperdynamic condition. PMID- 26443990 TI - Fully automatic analysis of the knee articular cartilage T1rho relaxation time using voxel-based relaxometry. AB - PURPOSE: To develop and compare with the classical region of interest (ROI)-based approach a fully automatic, local, and unbiased way of studying the knee T1rho relaxation time by creating an atlas and using voxel-based relaxometry (VBR) in osteoarthritis (OA) and anterior cruciate ligament (ACL) subjects. MATERIALS AND METHODS: In this study 110 subjects from two cohorts: 1) Mild OA 40 patients with mild-OA Kellgren-Lawrence (KL) <= 2 and 15 controls KL <= 1; 2) ACL cohort (a model for early OA): 40 ACL-injured patients imaged prior to ACL reconstruction and 1-year postsurgery and 15 controls are analyzed. All the subjects were acquired at 3T with a protocol that includes: 3D-FSE (CUBE) and 3D-T1rho . A nonrigid registration technique was applied to align all the images on a single template. This allows for performing VBR to assess local statistical differences of T1rho values using z-score analysis. VBR results were compared with those obtained with classical ROI-based technique. RESULTS: ROI-based results from atlas-based segmentation were consistent with classical ROI-based method (coefficient of variation [CV] = 3.83%). Voxel-based group analysis revealed local patterns that were overlooked by the ROI-based approach; eg, VBR showed posterior lateral femur and posterior lateral tibia significant T1rho elevations in ACL-injured patients (sample mean z-score=9.7 and 10.3). Those elevations were overlooked by the classical ROI-based approach (sample mean z-score=1.87 and 1.73) CONCLUSION: VBR is a feasible and accurate tool for the local evaluation of the biochemical composition of knee articular cartilage. VBR is capable of detecting specific local patterns on T1rho maps in OA and ACL subjects. PMID- 26443992 TI - Super enhanced permeability and retention (SUPR) effects in tumors following near infrared photoimmunotherapy. AB - To date, the delivery of nano-sized therapeutic agents to cancers largely relies on enhanced permeability and retention (EPR) effects that are caused by the leaky nature of cancer vasculature. However, nano-sized agents delivered in this way have demonstrated limited success in oncology due to the relatively small magnitude of the EPR effect. For achieving superior delivery of nano-sized agents, super-enhanced permeability and retention (SUPR) effects are needed. Near infrared photo-immunotherapy (NIR-PIT) is a recently reported therapy that treats tumors with light therapy and subsequently causes an increase in nano-drug delivery up to 24-fold compared with untreated tumors in which only the EPR effect is present. SUPR effects could enhance delivery into tumor beds of a wide variety of nano-sized agents including particles, antibodies, and protein binding small molecular agents. Therefore, taking advantage of the SUPR effects after NIR PIT may be a promising avenue to utilize a wide variety of nano-drugs in a highly effective manner. PMID- 26443993 TI - Frequency of cancer events with saxagliptin in the SAVOR-TIMI 53 trial. AB - The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial randomized trial of 16,492 patients (placebo, n = 8212; saxagliptin, n = 8280) treated and followed for a median of 2.1 years afforded an opportunity to explore whether there was any association with cancer reported as a serious adverse event. At least one cancer event was reported by 688 patients (4.1%): 362 (4.3%) and 326 (3.8%) in the placebo and saxagliptin arms, respectively (p = 0.13). There were 59 (0.6%) deaths adjudicated as malignancy deaths with placebo and 53 (0.6%) with saxagliptin. Stratification by gender, age, race and ethnicity, diabetes duration, baseline glycated haemoglobin and pharmacotherapy did not show any clinically meaningful differences between the two study arms. The overall number of cancer events and malignancy-associated mortality rates were generally balanced between the placebo and saxagliptin groups, suggesting a null relationship with saxagliptin use over the median follow-up of 2.1 years. Multivariable modelling showed that male gender, dyslipidaemia and current smoking were independent predictors of cancer. These randomized data with adequate numbers of cancer cases are reassuring but limited, by the short follow up in a trial not designed to test this hypothesis. PMID- 26443995 TI - High-Intensity Induction Chemotherapy Is Feasible for Elderly Patients with Acute Myeloid Leukemia. AB - BACKGROUND: The prognosis of elderly patients with acute myeloid leukemia (AML) is poor, and the best treatment is controversial. Since the majority of AML patients are older than 60 years, identification of those who might benefit from intensive treatment is essential. METHODS: Data from electronic charts of consecutive AML patients treated in our center were analyzed. Eligibility criteria included newly diagnosed de novo or secondary AML, an age of 60 years or older, and intensive induction treatment. RESULTS: Sixty-two patients were included in the analysis. Forty-six patients (74%) achieved complete remission (CR) after 1-2 intensive induction courses. Twenty of them received consolidation with conventional chemotherapy, 20 proceeded to allogeneic hematopoietic cell transplantation (allo-HCT), and 6 were ineligible for further treatment. The projected overall survival (OS) at 2 and 3 years was 28 and 23%, respectively. A normal karyotype, CR achievement, and allo-HCT were associated with improved OS, while an Eastern Cooperative Oncology Group performance status of 0-1 was borderline associated. The median survival and disease-free survival at 2 years was 18.7 months and 49%, respectively, for patients who underwent allo-HCT in CR1, compared to 12.8 months and 25%, respectively, for those who did not. CONCLUSION: Based on our data, selected eligible elderly AML patients might benefit from intensive treatment. PMID- 26443994 TI - Cooperative and independent functions of FGF and Wnt signaling during early inner ear development. AB - BACKGROUND: In multiple vertebrate organisms, including chick, Xenopus, and zebrafish, Fibroblast Growth Factor (FGF) and Wnt signaling cooperate during formation of the otic placode. However, in the mouse, although FGF signaling induces Wnt8a expression during induction of the otic placode, it is unclear whether these two signaling pathways functionally cooperate. Sprouty (Spry) genes encode intracellular antagonists of receptor tyrosine kinase signaling, including FGF signaling. We previously demonstrated that the Sprouty1 (Spry1) and Sprouty2 (Spry2) genes antagonize FGF signaling during induction of the otic placode. Here, we investigate cross talk between FGF/SPRY and Wnt signaling during otic placode induction and assess whether these two signaling pathways functionally cooperate during early inner ear development in the mouse. METHODS: Embryos were generated carrying combinations of a Spry1 null allele, Spry2 null allele, beta catenin null allele, or a Wnt reporter transgene. Otic phenotypes were assessed by in situ hybridization, semi-quantitative reverse transcriptase PCR, immunohistochemistry, and morphometric analysis of sectioned tissue. RESULTS: Comparison of Spry1, Spry2, and Wnt reporter expression in pre-otic and otic placode cells indicates that FGF signaling precedes and is active in more cells than Wnt signaling. We provide in vivo evidence that FGF signaling activates the Wnt signaling pathway upstream of TCF/Lef transcriptional activation. FGF regulation of Wnt signaling is functional, since early inner ear defects in Spry1 and Spry2 compound mutant embryos can be genetically rescued by reducing the activity of the Wnt signaling pathway. Interestingly, we find that although the entire otic placode increases in size in Spry1 and Spry2 compound mutant embryos, the size of the Wnt-reporter-positive domain does not increase to the same extent as the Wnt-reporter-negative domain. CONCLUSIONS: This study provides genetic evidence that FGF and Wnt signaling cooperate during early inner ear development in the mouse. Furthermore, our data suggest that although specification of the otic placode may be globally regulated by FGF signaling, otic specification of cells in which both FGF and Wnt signaling are active may be more tightly regulated. PMID- 26443996 TI - Influence of supplemental parenteral nutrition approach on nosocomial infection in pediatric intensive care unit of Emergency Department: a retrospective study. AB - BACKGROUND & AIMS: Nutritional support for patients in the intensive-care unit (ICU) is a part of standard care which promotes medical quality and decreases nosocomial infection. Supplemental parenteral nutrition (SPN) approach (enteral nutrition (EN) combined with parenteral nutrition (PN) when EN alone is insufficient) has become one major concern in nutrition research field. This research aims to explore the following relationships: (i) the relationship between SPN and nosocomial infection, (ii) the relationship between early and late SPN initiation and the development of nosocomial infection. METHODS: A retrospective study was conducted in patients who met the inclusion criteria from February 2012 to February 2015 in Pediatric ICU (PICU). Patients were classified into two groups according to nutrition delivery approach-SPN group and EN alone group. Then SPN group were further divided into two subgroups by initiation timing, which were defined as early-initiation SPN and late-initiation SPN group respectively. Age, gender, serum albumin at admission, severity of disease, length of stay in PICU, nutrition delivery approach, amounts of delivered caloric intake and occurence of nosocomial infection were recorded. Univariate analysis and binary logistic regression analysis were performed to identify the risk factors and assess the independent effect of SPN approach on nosocomial infection in PICU of Emergency Department. RESULTS: 204 patients were included in our study. Compared with EN alone group, patients delivered by SPN approach had a higher nosocomial infection rate (34.0 vs.10.9%, p < 0.001). The late-initiation subgroup of SPN approach was found to be an independent predictor of nosocomial infection in the logistic regression analysis model (OR = 3.40; 95% CI, 1.13 ~ 10.19; p = 0.029). Serum albumin at admission (OR = 0.91; 95% CI, 0.84 ~ 0.97; p = 0.008), mechanical ventilation (OR = 3.85; 95% CI, 1.43 ~ 10.39; p = 0.008), severity of disease (OR = 3.79; 95% CI, 1.03 ~ 13.99; p = 0.045) and PICU length of stay (OR = 1.23; 95% CI, 1.11 ~ 1.35; p < 0.001) were also identified as significant risk factors for nosocomial infection. CONCLUSIONS: Our study shows late-initiation SPN approach increases the incidence of nosocomial infection compared with early-initiation approach in critically ill children in PICU of Emergency Department. Compared with EN alone group, patients delivered by SPN approach had a higher nosocomial infection rate. PMID- 26443997 TI - Effects of melatonin on the nitric oxide system and protein nitration in the hypobaric hypoxic rat hippocampus. AB - BACKGROUND: It is well documented that the nitric oxide (NO) might be directly involved in brain response to hypobaric hypoxia, and could contribute to memory deficiencies. Recent studies have shown that melatonin could attenuate hypoxia or ischemia-induced nerve injuries by decreasing the production of free radicals. The present study, using immunohistochemical and immunoblot methods, aimed to explore whether melatonin treatment may affect the expression of nitric oxide system and protein nitration, and provide neuroprotection in the rat hippocampus injured by hypobaric hypoxia. Prior to hypoxic treatment, adult rats were pretreated with melatonin (100 mg/kg, i.p.) before they were exposed to the altitude chamber with 48 Torr of the partial oxygen concentration (pO2) for 7 h to mimic the ambience of being at 9000 m in height. They were then sacrificed after 0 h, 1, and 3 days of reoxygenation. RESULTS: The results obtained from the immunohistochemical and immunoblotting analyses showed that the expressions of neuronal nitric oxide synthase (nNOS), endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), nitrotyrosine (Ntyr) and Caspase 3 in the hypoxic hippocampus were increased from 0 h to 3 days of reoxygenation. Interestingly, the hypoxia-induced increase of nNOS, eNOS, iNOS, Ntyr and Caspase 3 protein expression was significantly depressed in the hypoxic rats treated with melatonin. CONCLUSIONS: Activation of the nitric oxide system and protein nitration constitutes a hippocampal response to hypobaric hypoxia and administration of melatonin could provide new therapeutic avenues to prevent and/or treat the symptoms produced by hypobaric hypoxia. PMID- 26443998 TI - Predicting Falls in Parkinson Disease: What Is the Value of Instrumented Testing in OFF Medication State? AB - BACKGROUND: Falls are a common complication of advancing Parkinson's disease (PD). Although numerous risk factors are known, reliable predictors of future falls are still lacking. The objective of this prospective study was to investigate clinical and instrumented tests of balance and gait in both OFF and ON medication states and to verify their utility in the prediction of future falls in PD patients. METHODS: Forty-five patients with idiopathic PD were examined in defined OFF and ON medication states within one examination day including PD-specific clinical tests, instrumented Timed Up and Go test (iTUG) and computerized dynamic posturography. The same gait and balance tests were performed in 22 control subjects of comparable age and sex. Participants were then followed-up for 6 months using monthly fall diaries and phone calls. RESULTS: During the follow-up period, 27/45 PD patients and 4/22 control subjects fell one or more times. Previous falls, fear of falling, more severe motor impairment in the OFF state, higher PD stage, more pronounced depressive symptoms, higher daily levodopa dose and stride time variability in the OFF state were significant risk factors for future falls in PD patients. Increased stride time variability in the OFF state in combination with faster walking cadence appears to be the most significant predictor of future falls, superior to clinical predictors. CONCLUSION: Incorporating instrumented gait measures into the baseline assessment battery as well as accounting for both OFF and ON medication states might improve future fall prediction in PD patients. However, instrumented testing in the OFF state is not routinely performed in clinical practice and has not been used in the development of fall prevention programs in PD. New assessment methods for daylong monitoring of gait, balance and falls are thus required to more effectively address the risk of falling in PD patients. PMID- 26443999 TI - Why (we think) facilitation works: insights from organizational learning theory. AB - BACKGROUND: Facilitation is a guided interactional process that has been popularized in health care. Its popularity arises from its potential to support uptake and application of scientific knowledge that stands to improve clinical and managerial decision-making, practice, and ultimately patient outcomes and organizational performance. While this popular concept has garnered attention in health services research, we know that both the content of facilitation and its impact on knowledge implementation vary. The basis of this variation is poorly understood, and understanding is hampered by a lack of conceptual clarity. DISCUSSION: In this paper, we argue that our understanding of facilitation and its effects is limited in part by a lack of clear theoretical grounding. We propose a theoretical home for facilitation in organizational learning theory. Referring to extant literature on facilitation and drawing on theoretical literature, we discuss the features of facilitation that suggest its role in contributing to learning capacity. We describe how facilitation may contribute to generating knowledge about the application of new scientific knowledge in health care organizations. Facilitation's promise, we suggest, lies in its potential to stimulate higher-order learning in organizations through experimenting with, generating learning about, and sustaining small-scale adaptations to organizational processes and work routines. The varied effectiveness of facilitation observed in the literature is associated with the presence or absence of factors known to influence organizational learning, since facilitation itself appears to act as a learning mechanism. We offer propositions regarding the relationships between facilitation processes and key organizational learning concepts that have the potential to guide future work to further our understanding of the role that facilitation plays in learning and knowledge generation. PMID- 26444000 TI - Heightened Delta Power during Slow-Wave-Sleep in Patients with Rett Syndrome Associated with Poor Sleep Efficiency. AB - Sleep problems are commonly reported in Rett syndrome (RTT); however the electroencephalographic (EEG) biomarkers underlying sleep dysfunction are poorly understood. The aim of this study was to analyze the temporal evolution of quantitative EEG (qEEG) biomarkers in overnight EEGs recorded from girls (2-9 yrs. old) diagnosed with RTT using a non-traditional automated protocol. In this study, EEG spectral analysis identified high delta power cycles representing slow wave sleep (SWS) in 8-9h overnight sleep EEGs from the frontal, central and occipital leads (AP axis), comparing age-matched girls with and without RTT. Automated algorithms quantitated the area under the curve (AUC) within identified SWS cycles for each spectral frequency wave form. Both age-matched RTT and control EEGs showed similar increasing trends for recorded delta wave power in the EEG leads along the antero-posterior (AP). RTT EEGs had significantly fewer numbers of SWS sleep cycles; therefore, the overall time spent in SWS was also significantly lower in RTT. In contrast, the AUC for delta power within each SWS cycle was significantly heightened in RTT and remained heightened over consecutive cycles unlike control EEGs that showed an overnight decrement of delta power in consecutive cycles. Gamma wave power associated with these SWS cycles was similar to controls. However, the negative correlation of gamma power with age (r = -.59; p<0.01) detected in controls (2-5 yrs. vs. 6-9 yrs.) was lost in RTT. Poor % SWS (i.e., time spent in SWS overnight) in RTT was also driven by the younger age-group. Incidence of seizures in RTT was associated with significantly lower number of SWS cycles. Therefore, qEEG biomarkers of SWS in RTT evolved temporally and correlated significantly with clinical severity. PMID- 26444002 TI - Sporangium Exposure and Spore Release in the Peruvian Maidenhair Fern (Adiantum peruvianum, Pteridaceae). AB - We investigated the different processes involved in spore liberation in the polypod fern Adiantum peruvianum (Pteridaceae). Sporangia are being produced on the undersides of so-called false indusia, which are situated at the abaxial surface of the pinnule margins, and become exposed by a desiccation-induced movement of these pinnule flaps. The complex folding kinematics and functional morphology of false indusia are being described, and we discuss scenarios of movement initiation and passive hydraulic actuation of these structures. High speed cinematography allowed for analyses of fast sporangium motion and for tracking ejected spores. Separation and liberation of spores from the sporangia are induced by relaxation of the annulus (the 'throwing arm' of the sporangium catapult) and conservation of momentum generated during this process, which leads to sporangium bouncing. The ultra-lightweight spores travel through air with a maximum velocity of ~5 m s(-1), and a launch acceleration of ~6300 g is measured. In some cases, the whole sporangium, or parts of it, together with contained spores break away from the false indusium and are shed as a whole. Also, spores can stick together and form spore clumps. Both findings are discussed in the context of wind dispersal. PMID- 26444001 TI - Use of and short-term impacts of new cycling infrastructure in inner-Sydney, Australia: a quasi-experimental design. AB - BACKGROUND: Given increasing investment in new cycling infrastructure, it is important to understand its impacts. The Sydney Transport and Health Study evaluates a new 2.4 km bi-directional separated bicycle path in inner-Sydney. This paper describes the users of the new bicycle path, and examines its short term impacts upon cycling behaviour and perceptions of the local environment. METHODS: Data were collected from two bike counts at two intersections on the new bicycle path in the intervention area in 2013 and 2014. On-line surveys collected individual participant data in the intervention area and a similar comparison area before the bicycle path was built (2013), and 12 months later (four months after completion) (n = 512). The data included self-reported cycling behaviour, use of the new bicycle path and perceptions of changes in the local environment. RESULTS: Bike counts at two sites on the new bicycle path reported an increase of 23% and 97% respectively at 12 months. However, among the participants in the cohort, there was no change in the self-reported weekly frequency of cycling. One in six (approximately 15%) participants reported using the new bicycle path, with most users (76%) living in the intervention area. Bicycle path users were most likely to be frequent riders (at least weekly) [adjusted odds ratio (AOR) = 7.50, 95 % CI 3.93-14.31], be a high intensity recreational rider (AOR = 4.38, 95 % CI 1.53-12.54) or a low intensity transport rider (AOR = 2.42, 95 % CI 1.17-5.04) and live closer to the bicycle path (AOR = 1.24, 1.13-1.37). Perceptions that the neighbourhood was more pleasant, that there were more people walking and cycling were significantly higher in the intervention area at 12 months (both P values <0.05). CONCLUSIONS: Existing cycling behaviour and proximity to the bicycle path were associated with the use of the new bicycle path. Increased use of the new bicycle path as reported by the participants in the intervention area and increased cycling recorded by the bike counts may be due to existing cyclists changing routes to use the new path, and more cyclists from outside the study area using the new path, as study participants did not increase their frequency of cycling. Increases in cycling frequency in the intervention neighbourhood may require a longer lead time, additional promotional activities and further maturation of the Sydney bicycle path network. KEY MESSAGE: Understanding how new cycling infrastructure impacts communities can influence the promotion of such infrastructure. PMID- 26444003 TI - Hemodialysis versus Peritoneal Dialysis: A Comparison of Survival Outcomes in South-East Asian Patients with End-Stage Renal Disease. AB - BACKGROUND: Studies comparing patient survival of hemodialysis (HD) and peritoneal dialysis (PD) have yielded conflicting results and no such study was from South-East Asia. This study aimed to compare the survival outcomes of patients with end-stage renal disease (ESRD) who started dialysis with HD and PD in Singapore. METHODS: Survival data for a maximum of 5 years from a single center cohort of 871 ESRD patients starting dialysis with HD (n = 641) or PD (n = 230) from 2005-2010 was analyzed using the flexible Royston-Parmar (RP) model. The model was also applied to a subsample of 225 propensity-score-matched patient pairs and subgroups defined by age, diabetes mellitus, and cardiovascular disease. RESULTS: After adjusting for the effect of socio-demographic and clinical characteristics, the risk of death was higher in patients initiating dialysis with PD than those initiating dialysis with HD (hazard ratio [HR]: 2.08; 95% confidence interval [CI]: 1.67-2.59; p<0.001), although there was no significant difference in mortality between the two modalities in the first 12 months of treatment. Consistently, in the matched subsample, patients starting PD had a higher risk of death than those starting HD (HR: 1.73, 95% CI: 1.30-2.28, p<0.001). Subgroup analysis showed that PD may be similar to or better than HD in survival outcomes among young patients (<=65 years old) without diabetes or cardiovascular disease. CONCLUSION: ESRD patients who initiated dialysis with HD experienced better survival outcomes than those who initiated dialysis with PD in Singapore, although survival outcomes may not differ between the two dialysis modalities in young and healthier patients. These findings are potentially confounded by selection bias, as patients were not randomized to the two dialysis modalities in this cohort study. PMID- 26444004 TI - Steroid Treatment Reduces Allergic Airway Inflammation and Does Not Alter the Increased Numbers of Dendritic Cells and Calcitonin Gene-Related Peptide Expressing Neurons in Airway Sensory Ganglia. AB - OBJECTIVES: Our previous data demonstrated that allergic airway inflammation induces migration of dendritic cells (DC) into airway sensory jugular and nodose ganglia (jugular-nodose ganglion complex; JNC). Here we investigated the effects of steroid treatment regarding the expression and migration of DC and calcitonin gene-related peptide (CGRP)-immunoreactive neurons of vagal sensory ganglia during allergic airway inflammation. METHODS: A house dust mite (HDM) model for allergic airway inflammation was used. The mice received 0.3 mg fluticasone propionate per kilogram of body weight in the last 9 days. JNC slices were analyzed on MHC II, the neuronal marker PGP9.5, and the neuropeptide CGRP. RESULTS: Allergic airway inflammation increased the numbers of DC and CGRP expressing neurons in the JNC significantly in comparison to the controls (DC/neurons: HDM 44.58 +/- 1.6% vs. saline 33.29 +/- 1.6%, p < 0.05; CGRP positive neurons/total neurons: HDM 30.65 +/- 1.9% vs. saline 19.49 +/- 2.3%, p < 0.05). Steroid treatment did not have any effect on the numbers of DC and CGRP expressing neurons in the JNC compared to HDM-treated mice. CONCLUSIONS: The present findings indicate an important role of DC and CGRP-containing neurons in the pathogenesis of allergic airway inflammation. However, steroid treatment did not have an effect on the population of DC and neurons displaying CGRP in the JNC, whereas steroid treatment was found to suppress allergic airway inflammation. PMID- 26444005 TI - Functional characterization of biodegradable nanoparticles as antigen delivery system. AB - BACKGROUND: Peptide based vaccines may suffer from limited stability and inefficient delivery to professional antigen-presenting cells (APCs), such as dendritic cells (DCs). In order to overcome such limitations, several types of biodegradable nanoparticles (NPs) have been developed as carrier system for antigens. The present study describes for the first time the extensive biological characterization of cationic NPs made of poly (D,L-lactide-co-glycolide) (PLGA) and polyethylenimine (PLGA/PEI) as delivery system for protein/peptide antigens, with potential in therapeutic cancer vaccine development. RESULTS: Flow cytometry as well as confocal laser scanning microscopy (CLSM) showed that PLGA/PEI NPs are more readily taken up than PLGA NPs by both human CD14(+) monocytes and mouse Hepa 1-6 hepatoma cell line. No signs of toxicity were observed in either cellular setting. Sequential image acquisition by TEM showed an intracellular apical localization for PLGA NPs and a perinuclear localization for PLGA/PEI NPs. Both NPs showed a clathrin-dependent as well as a caveolin-dependent internalization pathway and, once in the cells, they formed multivesicular endosomes (MVE). Finally, an ex vivo priming experiment showed that PLGA/PEI NPs are comparable to PLGA NPs in delivering a non-self antigen (i.e., ovalbumin - OVA) to immature dendritic cells (imDCs), which matured and induced autologous naive CD4(+) T cells to differentiate to memory (i.e., central memory and effector memory) cells. Such a differentiation was associated with a Th1 phenotype suggesting a downstream activation and amplification of a CD8(+) T cell cytotoxic response. The same OVA antigen in a soluble form was unable to induce maturation of DCs, indicating that both NP formulations provided an intrinsic adjuvanting effect combined to efficient antigen delivery. CONCLUSIONS: Our study represents the first report on side-by-side comparison of PLGA and PLGA/PEI NPs as strategy for protein antigen delivery. PLGA/PEI NPs are superior for cellular uptake and antigen delivery as compared to PLGA NPs. Such an evidence suggests their great potential value for vaccine development, including therapeutic cancer vaccines. PMID- 26444006 TI - Placental Aromatase Is Deficient in Placental Ischemia and Preeclampsia. AB - INTRODUCTION: Preeclampsia is a maternal hypertensive disorder with uncertain etiology and a leading cause of maternal and fetal mortality worldwide, causing nearly 40% of premature births delivered before 35 weeks of gestation. The first stage of preeclampsia is characterized by reduction of utero-placental blood flow which is reflected in high blood pressure and proteinuria during the second half of pregnancy. In human placenta androgens derived from the maternal and fetal adrenal glands are converted into estrogens by the enzymatic action of placental aromatase. This implies that alterations in placental steroidogenesis and, subsequently, in the functionality or bioavailability of placental aromatase may be mechanistically involved in the pathophysiology of PE. METHODS: Serum samples were collected at 32-36 weeks of gestation and placenta biopsies were collected at time of delivery from PE patients (n = 16) and pregnant controls (n = 32). The effect of oxygen tension on placental cells was assessed by incubation JEG-3 cells under 1% and 8% O2 for different time periods, Timed-mated, pregnant New Zealand white rabbits (n = 6) were used to establish an in vivo model of placental ischemia (achieved by ligature of uteroplacental vessels). Aromatase content and estrogens and androgens concentrations were measured. RESULTS: The protein and mRNA content of placental aromatase significantly diminished in placentae obtained from preeclamptic patients compared to controls. Similarly, the circulating concentrations of 17-beta-estradiol/testosterone and estrone/androstenedione were reduced in preeclamptic patients vs. controls. These data are consistent with a concomitant decrease in aromatase activity. Aromatase content was reduced in response to low oxygen tension in the choriocarcinoma JEG 3 cell line and in rabbit placentae in response to partial ligation of uterine spiral arteries, suggesting that reduced placental aromatase activity in preeclamptic patients may be associated with chronic placental ischemia and hypoxia later in gestation. CONCLUSIONS: Placental aromatase expression and functionality are diminished in pregnancies complicated by preeclampsia in comparison with healthy pregnant controls. PMID- 26444007 TI - Synchronous mucosal Schwann-cell hamartomas in a young adult suggestive of mucosal Schwann-cell harmatomatosis: a case report. AB - BACKGROUND: Mucosal Schwann-cell hamartoma is a rare mesenchymal polyp that presents in the intestine. Despite lacking ganglion cells, it resembles a gastrointestinal ganglioneuroma. CASE PRESENTATION: We report a case of synchronous mucosal Schwann-cell hamartomas in a young male patient, who presented with a single discrete polyp in the mid-rectum and multiple polypoid mucosal lesions in the distal rectum. CONCLUSION: To the best of our knowledge, this is the first report of a case of multiple mucosal Schwann-cell hamartomas. PMID- 26444008 TI - CD24 Overexpression Is Associated with Poor Prognosis in Luminal A and Triple Negative Breast Cancer. AB - CD24 is associated with unfavourable prognoses in various cancers, but the prevalence of CD24 expression and its influence on clinical outcome in subtypes of breast cancers remain unclear. CD24 expression was analyzed by immunohistochemistry in 747 breast cancer tissues, and DNA methylation and histone modification status in the promoter region of CD24 were assessed using bisulfite sequencing and chromatin immunoprecipitation assay. 213 (28.5%) samples exhibited high CD24 expression in the membrane and/or cytoplasm of breast cancer cells, and CD24 overexpression was significantly correlated with the presence of lymph node metastasis and more advanced pathological stage. Patients with CD24 high tumours had significantly shorter patient survival than those with CD24-low tumours. Importantly, multivariate analysis that included tumour size, lymph node metastasis and chemotherapy demonstrated that high CD24 expression is independently associated with poorer survival in luminal A and triple-negative breast cancer (TNBC) subtypes. Furthermore, CD24 gene expression was associated with histone acetylation independent of DNA methylation, suggesting its epigenetic regulation in breast cancer. Our results suggest that CD24 overexpression is an independent unfavourable prognostic factor in breast cancer, especially for luminal A and TNBC subtypes, and CD24 may be a promising therapeutic target for specific subtypes of breast cancer. PMID- 26444009 TI - Boundaries and conditions of interpretation in multilingual and multicultural elderly healthcare. AB - BACKGROUND: Elderly migrants who do not speak the official language of their host country have increased due to extensive international migration, and will further increase in the future. This entails major challenges to ensure good communication and avoid communication barriers that can be overcome by the use of adequate interpreter services. To our knowledge, there are no previous investigations on interpreting practices in multilingual elderly healthcare from different healthcare professionals' perspectives. This study examines issues concerning communication and healthcare through a particular focus on interpretation between health professionals and patients of different ethnic and linguistic backgrounds. The central aim of the project is to explore interpretation practices in multilingual elderly healthcare. METHODS: A purposive sample of 33 healthcare professionals with experience of using interpreters in community multilingual elderly healthcare. Data were collected between October 2013 and March 2014 by 18 individual and four focus group interviews and analysed with qualitative content analysis. RESULTS: The main results showed that interpreting practice in multilingual elderly healthcare was closely linked to institutional, interpersonal and individual levels. On the organizational level, however, guidelines for arranging the use of interpreters at workplaces were lacking. Professional interpreters were used on predictable occasions planned long in advance, and bilingual healthcare staff and family members acting as interpreters were used at short notice in everyday caring situations on unpredictable occasions. The professional interpreter was perceived as a person who should interpret spoken language word-for-word and who should translate written information. Furthermore, the use of a professional interpreter was not adapted to the context of multilingual elderly healthcare. CONCLUSION: This study found that interpreter practice in multilingual elderly healthcare is embedded in the organizational environment and closely related to the individual's language skills, cultural beliefs and socio-economic factors. In order to formulate interpreter practice in the context of multilingual elderly healthcare it is important to consider organizational framework and cultural competence, cultural health knowledge, beliefs and customs. PMID- 26444010 TI - Seeing More by Showing Less: Orientation-Dependent Transparency Rendering for Fiber Tractography Visualization. AB - Fiber tractography plays an important role in exploring the architectural organization of fiber trajectories, both in fundamental neuroscience and in clinical applications. With the advent of diffusion MRI (dMRI) approaches that can also model "crossing fibers", the complexity of the fiber network as reconstructed with tractography has increased tremendously. Many pathways interdigitate and overlap, which hampers an unequivocal 3D visualization of the network and impedes an efficient study of its organization. We propose a novel fiber tractography visualization approach that interactively and selectively adapts the transparency rendering of fiber trajectories as a function of their orientation to enhance the visibility of the spatial context. More specifically, pathways that are oriented (locally or globally) along a user-specified opacity axis can be made more transparent or opaque. This substantially improves the 3D visualization of the fiber network and the exploration of tissue configurations that would otherwise be largely covered by other pathways. We present examples of fiber bundle extraction and neurosurgical planning cases where the added benefit of our new visualization scheme is demonstrated over conventional fiber visualization approaches. PMID- 26444011 TI - Sex Differences in Object Manipulation in Wild Immature Chimpanzees (Pan troglodytes schweinfurthii) and Bonobos (Pan paniscus): Preparation for Tool Use? AB - Sex differences in immatures predict behavioural differences in adulthood in many mammal species. Because most studies have focused on sex differences in social interactions, little is known about possible sex differences in 'preparation' for adult life with regards to tool use skills. We investigated sex and age differences in object manipulation in immature apes. Chimpanzees use a variety of tools across numerous contexts, whereas bonobos use few tools and none in foraging. In both species, a female bias in adult tool use has been reported. We studied object manipulation in immature chimpanzees at Kalinzu (Uganda) and bonobos at Wamba (Democratic Republic of Congo). We tested predictions of the 'preparation for tool use' hypothesis. We confirmed that chimpanzees showed higher rates and more diverse types of object manipulation than bonobos. Against expectation, male chimpanzees showed higher object manipulation rates than females, whereas in bonobos no sex difference was found. However, object manipulation by male chimpanzees was play-dominated, whereas manipulation types of female chimpanzees were more diverse (e.g., bite, break, carry). Manipulation by young immatures of both species was similarly dominated by play, but only in chimpanzees did it become more diverse with age. Moreover, in chimpanzees, object types became more tool-like (i.e., sticks) with age, further suggesting preparation for tool use in adulthood. The male bias in object manipulation in immature chimpanzees, along with the late onset of tool-like object manipulation, indicates that not all (early) object manipulation (i.e., object play) in immatures prepares for subsistence tool use. Instead, given the similarity with gender differences in human children, object play may also function in motor skill practice for male-specific behaviours (e.g., dominance displays). In conclusion, even though immature behaviours almost certainly reflect preparation for adult roles, more detailed future work is needed to disentangle possible functions of object manipulation during development. PMID- 26444012 TI - Using height-for-age differences (HAD) instead of height-for-age z-scores (HAZ) for the meaningful measurement of population-level catch-up in linear growth in children less than 5 years of age. AB - BACKGROUND: Evidence from studies conducted in nutritionally deprived children in low- and middle-income countries (LIMC) in past decades showed little or no population-level catch-up in linear growth (mostly defined as reductions in the absolute height deficit) after 2 years of age. Recent studies, however, have reported population-level catch-up growth in children, defined as positive changes in mean height-for-age z-scores (HAZ). The aim of this paper was to assess whether population-level catch-up in linear growth is found when height for-age difference (HAD: child's height compared to standard, expressed in centimeters) is used instead of HAZ. Our premise is that HAZ is inappropriate to measure changes in linear growth over time because they are constructed using standard deviations from cross-sectional data. METHODS: We compare changes in growth in populations of children between 2 and 5 years using HAD vs. HAZ using cross-sectional data from 6 Demographic and Health Surveys (DHS) and longitudinal data from the Young Lives and the Consortium on Health-Orientated Research in Transitional Societies (COHORTS) studies. RESULTS: Using HAD, we find not only an absence of population-level catch-up in linear growth, but a continued deterioration reflected in a decrease in mean HAD between 2 and 5 years; by contrast, HAZ shows either no change (DHS surveys) or an improvement in mean HAZ (some of the longitudinal data). Population-level growth velocity was also lower than expected (based on standards) in all four Young Lives data sets, confirming the absence of catch-up growth in height. DISCUSSION: We show no evidence of population-level catch-up in linear growth in children between 2 to 5 years of age when using HAD (a measure more appropriate than HAZ to document changes as populations of children age), but a continued deterioration reflected in a decrease in mean HAD. CONCLUSIONS: The continued widening of the absolute height deficit after 2 years of age does not challenge the critical importance of investing in improving nutrition during the first 1000 days (i.e., from conception to 2 years of age), but raises a number of research questions including how to prevent continued deterioration and what is the potential of children to benefit from nutrition interventions after 2 years of age. Preventing, rather than reversing linear growth retardation remains the priority for reducing the global burden of malnutritionworldwide. PMID- 26444013 TI - Effect of Antiepileptic Drugs for Acute and Chronic Seizures in Children with Encephalitis. AB - BACKGROUND: Encephalitis presents with seizures in the acute phase and increases the risk of late unprovoked seizures and epilepsy. This study aimed to evaluate the effect of antiepileptic drugs in pediatric patients with acute seizures due to encephalitis and epilepsy. PATIENTS AND METHODS: Cases of acute pediatric encephalitis between January 2000 and December 2010 were reviewed. Clinical data, including onset at age, seizure type, seizure frequency, effects of antiepileptic drugs, and prognosis were analyzed. RESULTS: During the study period, 1038 patients (450 girls, 588 boys) were enrolled. Among them, 44.6% (463) had seizures in the acute phase, 33% had status epilepticus, and 26% (251) developed postencephalitic epilepsy. At one year of follow-up, 205 of the 251 patients with postencephalitic epilepsy were receiving antiepileptic drugs while 18% were seizure free even after discontinuing the antiepileptic drugs. Among those with postencephalitic epilepsy, 67% had favorable outcomes and were using <2 anti epileptic drugs while 15% had intractable seizures and were using >= 2 antiepileptic drugs. After benzodiazepines, intravenous phenobarbital was preferred over phenytoin as treatment of postencephalitic seizures in the acute phase. For refractory status epilepticus, high-dose topiramate combined with intravenous high-dose phenobarbital or high-dose lidocaine had less side effects. CONCLUSIONS: Children with encephalitis have a high rate of postencephalitic epilepsy. Phenobarbital and clonazepam are the most common drugs used, alone or in combination, for postencephalitic epilepsy. PMID- 26444014 TI - KCl -Permeabilized Pancreatic Islets: An Experimental Model to Explore the Messenger Role of ATP in the Mechanism of Insulin Secretion. AB - Our previous work has demonstrated that islet depolarization with KCl opens connexin36 hemichannels in beta-cells of mouse pancreatic islets allowing the exchange of small metabolites with the extracellular medium. In this study, the opening of these hemichannels has been further characterized in rat islets and INS-1 cells. Taking advantage of hemicannels'opening, the uptake of extracellular ATP and its effect on insulin release were investigated. 70 mM KCl stimulated light emission by luciferin in dispersed rat islets cells transduced with the fire-fly luciferase gene: it was suppressed by 20 mM glucose and 50 MUM mefloquine, a specific connexin36 inhibitor. Extracellular ATP was taken up or released by islets depolarized with 70 mM KCl at 5 mM glucose, depending on the external ATP concentration. 1 mM ATP restored the loss of ATP induced by the depolarization itself. ATP concentrations above 5 mM increased islet ATP content and the ATP/ADP ratio. No ATP uptake occurred in non-depolarized or KCl depolarized islets simultaneously incubated with 50 MUM mefloquine or 20 mM glucose. Extracellular ATP potentiated the secretory response induced by 70 mM KCl at 5 mM glucose in perifused rat islets: 5 mM ATP triggered a second phase of insulin release after the initial peak triggered by KCl-depolarization itself; at 10 mM, it increased both the initial, KCl-dependent, peak and stimulated a greater second phase of secretion than at 5 mM. These stimulatory effects of extracellular ATP were almost completely suppressed by 50 MUM mefloquine. The magnitude of the second phase of insulin release due to 5 mM extracellular ATP was decreased by addition of 5 mM ADP (extracellular ATP/ADP ratio = 1). ATP acts independently of KATP channels closure and its intracellular concentration and its ATP/ADP ratio seems to regulate the magnitude of both the first (triggering) and second (amplifying) phases of glucose-induced insulin secretion. PMID- 26444015 TI - The Significance of Myriophyllum elatinoides for Swine Wastewater Treatment: Abundance and Community Structure of Ammonia-Oxidizing Microorganisms in Sediments. AB - Myriophyllum elatinoides was reported to effectively treat wastewater by removing nitrogen (N) and phosphorus (P). However, little is known about the abundance and community structure of ammonia-oxidizing microorganisms associated with M. elatinoides purification systems. The objective of this research was to characterize the abundance and community structure of ammonia-oxidizing microorganisms in swine wastewater and determine the main nitrogen removal pathways. In this study, five different waters were treated by M. elatinoides in microcosms for one month. The five waters included tap water (Control), swine wastewater (SW), 50% diluted swine wastewater (50% SW), and two synthetic wastewaters: 200 mg NH4+-N L(-1) (200 NH4+-N) and 400 mg NH4+-N L(-1) (400 NH4+ N). The most dramatic changes were in NH4+-N and total N (TN) concentrations, with average removal rates of 84% and 90%, respectively, in the treatments containing swine wastewater. On days 7, 14, and 28, the dissolved oxygen (DO) increased by 81.8%, 210.4% and 136.5%, respectively, compared with on day 0, in the swine wastewater. The results also showed that the bacterial amoA (AOB) copy numbers in the sediments of the treatments were significantly higher than those of archaeal amoA (AOA) copy numbers (p = 0.015). In addition, the high DO concentrations in swine wastewater responded well to the high abundance of AOB. The AOA and AOB community distributions were positively related with NO3-N and were negatively related with DO in swine wastewater treatments. In summary, our experimental results suggested that the M. elatinoides purification system could improve the activity of ammonia-oxidizing microorganisms and consequently might contribute to the significant N removal from the swine wastewater. PMID- 26444016 TI - Polymorphism of the Oxytocin Receptor Gene Modulates Behavioral and Attitudinal Trust among Men but Not Women. AB - A relationship between the oxytocin receptor gene (OXTR) and behavioral and attitudinal trust has been suggested, but the nature of this relationship has not yet been established. We obtained behavioral trust data from 470 Japanese participants (242 women) aged 20-59 years, together with their levels of general trust and personality traits (NEO-FFI). Saliva buccal swabs were collected from 411 of these 470 participants and used for genotyping of OXTR rs53576. Our participants were found to have more AA alleles (40%) than GG alleles (12%). The GG men were more trusting and also rated higher on attitudinal trust than AA men, and this difference did not diminish when personality traits were controlled for. However, this pattern was not observed among women. In addition, controlling for attitudinal trust reduced the difference in behavioral trust among men to a non significant level, but the difference in attitudinal trust remained significant when behavioral trust was controlled. These results indicate that the OXTR genotype affects attitudinal trust as part of an individual's relatively stable disposition, and further affects behavioral trust through changes in attitudinal trust. PMID- 26444018 TI - Hyaluronic acid increases tendon derived cell viability and collagen type I expression in vitro: Comparative study of four different Hyaluronic acid preparations by molecular weight. AB - BACKGROUND: Hyaluronic Acid (HA) has been already approved by Food and Drug Administration (FDA) for osteoarthritis (OA), while its use in the treatment of tendinopathy is still debated. The aim of this study was to evaluate in human rotator cuff tendon derived cells the effects of four different HA on cell viability, proliferation, apoptosis and the expression of collagen type I and collagen type III. METHODS: An in vitro model was developed on human tendon derived cells from rotator cuff tears to study the effects of four different HA preparations (Ps) (sodium hyaluronate MW: 500-730 KDa - Hyalgan(r), 1000 kDa Artrosulfur HA(r), 1600 KDa Hyalubrix(r) and 2200 KDa Synolis-VA(r)) at various concentrations. Tendon derived cells morphology were evaluated after 0, 7 and 14 d of culture. Viability, proliferation, apoptosis were evaluated after 0, 24 and 48 h of culture. The expression and deposition of collagen type I and collagen type III were evaluated after 1, 7 and 14 d of culture. RESULTS: All HAPs tested increased viability and proliferation, in dose dependent manner. HAPs already reduce apoptosis at 24 h compared to control cells (without HAPs). Furthermore, HAPs stimulated the synthesis of collagen type I in a dose dependent fashion over 14 d, without increase in collagen type III; moreover, in the presence of Synolis VA(r) the expression and deposition of collagen type I was significantly higher as compare with the other HAPs. CONCLUSIONS: HAPs enhanced viability, proliferation and expression of collagen type I in tendon derived cells. PMID- 26444017 TI - Endoplasmic Reticulum Stress-Induced Autophagy Provides Cytoprotection from Chemical Hypoxia and Oxidant Injury and Ameliorates Renal Ischemia-Reperfusion Injury. AB - We examined whether endoplasmic reticulum (ER) stress-induced autophagy provides cytoprotection from renal tubular epithelial cell injury due to oxidants and chemical hypoxia in vitro, as well as from ischemia-reperfusion (IR) injury in vivo. We demonstrate that the ER stress inducer tunicamycin triggers an unfolded protein response, upregulates ER chaperone Grp78, and activates the autophagy pathway in renal tubular epithelial cells in culture. Inhibition of ER stress induced autophagy accelerated caspase-3 activation and cell death suggesting a pro-survival role of ER stress-induced autophagy. Compared to wild-type cells, autophagy-deficient MEFs subjected to ER stress had enhanced caspase-3 activation and cell death, a finding that further supports the cytoprotective role of ER stress-induced autophagy. Induction of autophagy by ER stress markedly afforded cytoprotection from oxidants H2O2 and tert-Butyl hydroperoxide and from chemical hypoxia induced by antimycin A. In contrast, inhibition of ER stress-induced autophagy or autophagy-deficient cells markedly enhanced cell death in response to oxidant injury and chemical hypoxia. In mouse kidney, similarly to renal epithelial cells in culture, tunicamycin triggered ER stress, markedly upregulated Grp78, and activated autophagy without impairing the autophagic flux. In addition, ER stress-induced autophagy markedly ameliorated renal IR injury as evident from significant improvement in renal function and histology. Inhibition of autophagy by chloroquine markedly increased renal IR injury. These studies highlight beneficial impact of ER stress-induced autophagy in renal ischemia reperfusion injury both in vitro and in vivo. PMID- 26444019 TI - Strategies for engaging with future radiation protection professionals: a public outreach case study. AB - It is evident that there is a nuclear skills shortage within the UK, and logically it can be assumed that the shortfall extends to the radiation protection arena. Plans for nuclear new-build and the decommissioning of existing nuclear sites will require many more people with radiological knowledge and practical competencies. This converts to a nuclear industry requirement in the order of 1000 new recruits per year over at least the next ten years, mainly as new apprentices and graduates. At the same time, the strong demand for persons with radiation protection know-how in the non-nuclear and health care sectors is unlikely to diminish. The task of filling this skills gap is a significant one and it will require a determined effort from many UK stakeholders. The Society for Radiological Protection (SRP) has adopted a strategy in recent years to help address this skills gap. The aim is to engage the interest of secondary school students in the science of radiation and inspire them to follow a career in radiation protection. This paper presents the reasoning behind this strategy and, in an 'outreach case study', describes the establishment of the annual SRP Schools Event. This event is becoming an important addition to the national efforts aimed at increasing the numbers of skilled UK radiation protection professionals over the forthcoming decades. PMID- 26444020 TI - Huntington's Disease in Arab Countries. AB - Huntington's disease (HD) is an inherited neurodegenerative disorder. Involuntary choreaform movements are the main symptom. The prevalence of HD in Arab countries is not fully understood, as there are only a few reports indicating disease incidence. Therefore, there is an urgent need for an investigation to determine the frequency of HD in the Middle East, especially within Arab countries, and at the same time enhance people's awareness of the disease. PMID- 26444022 TI - Practice Effects and Stability of Neuropsychological and UHDRS Tests Over Short Retest Intervals in Huntington Disease. AB - BACKGROUND: In Huntington disease (HD), cognitive changes due to disease progression or treatment are potentially confounded by "practice effects" (PE)- performance improvement from prior exposure to test materials. OBJECTIVE: A practice run-in ("dual baseline") was used in an HD cognitive trial to determine if PE could be minimized and evaluate performance trajectories over multiple visits. METHODS: Non-depressed adults (N = 36) with mild to moderate HD-related cognitive deficits participated in a clinical trial to examine the efficacy of citalopram to enhance cognition. Cognitive tests were administered at three visits (2 weeks separating each visit), before active treatment randomization. Some tests were also administered at screening. Therefore 3-4 pre-treatment repetitions were available. We examined test improvement using repeated-measures ANOVAs with planned pairwise comparisons. RESULTS: Despite the practice run-in and use of alternate test forms, results indicated ongoing improvements over at least three test sessions on all three UHDRS cognitive tests. Trails A and B showed improvements between the third and fourth session, which suggests that one pre-baseline visit may not be effective in reducing practice on this important and commonly used test. CONCLUSIONS: Overall, 7 out of 13 variables showed some degree of short-term PE, even after multiple sessions and alternate forms. Tests assessing processing speed and memory may be particularly confounded by ongoing PE across at least 2-3 sessions. Practice run-in periods and alternate forms may help minimize the impact of such effects in HD clinical trials but awareness of which tests are most susceptible to PE is important in clinical trial design. PMID- 26444021 TI - Safety of Striatal Infusion of siRNA in a Transgenic Huntington's Disease Mouse Model. AB - BACKGROUND: The immune system In Huntington's disease (HD) is activated and may overreact to some therapies. RNA interference using siRNA lowers mutant huntingtin (mHTT) protein but could increase immune responses. OBJECTIVE: To examine the innate immune response following siRNA infusion into the striatum of wild-type (WT) and HD transgenic (YAC128) mice. METHODS: siRNAs (2'-O-methyl phosphorothioated) were infused unilaterally into striatum of four month-old WT and YAC128 mice for 28 days. Microglia number and morphology (resting (normal), activated, dystrophic), cytokine levels, and DARPP32-positive neurons were measured in striatum immediately or 14 days post-infusion. Controls included contralateral untreated striatum, and PBS and sham treated striata. RESULTS: The striata of untreated YAC128 mice had significantly fewer resting microglia and more dystrophic microglia than WT mice, but no difference from WT in the proportion of activated microglia or total number of microglia. siRNA infusion increased the total number of microglia in YAC128 mice compared to PBS treated and untreated striata and increased the proportion of activated microglia in WT and YAC128 mice compared to untreated striata and sham treated groups. Cytokine levels were low and siRNA infusion resulted in only modest changes in those levels. siRNA infusion did not change the number of DARPP32-positive neurons. CONCLUSION: Findings suggest that siRNA infusion may be a safe method for lowering mHTT levels in the striatum in young animals, since treatment does not produce a robust cytokine response or cause neurotoxicity. The potential long term effects of a sustained increase in total and activated microglia after siRNA infusion in HD mice need to be explored. PMID- 26444023 TI - A Concept Map of What Helps People with HD Live with their Condition. AB - BACKGROUND: The complex effects of Huntington's disease (HD) negatively impact on every area of independent living. The perspectives of people impacted by HD on how to best manage the disease are not clearly understood. OBJECTIVE: To identify what is most helpful for living with HD from the perspectives of people with HD, family caregivers and health professionals. METHODS: A cross-sectional, mixed methods concept mapping methodology was used. Participants generated statements during brainstorming in response to the question 'what helps people with HD live with their condition'. Participants then prioritised statements for importance and they grouped together statements that were related into clusters. Concept mapping software ('Ariadne' (r)) used multi-dimensional scaling and hierarchical cluster analysis to produce a conceptual framework of participants views about what is helpful for people living with HD. RESULTS: Thirty nine people at various stages of HD disease progression, 48 family caregivers and 39 health professionals with experience of HD care (n = 126) participated. The most helpful factors for living with HD were identified as access to expert assessment and treatment for co-morbid mental health problems, integrated specialist multi disciplinary HD expertise, and the provision of flexible care. CONCLUSIONS: HD requires specialist, expert, multidisciplinary care teams to manage it well. Specialists need to focus on the mental health aspects, and the provision must be flexible and responsive to current needs. Patients may have impaired insight into their abilities (e.g. driving) or the need for interventions, so carers' opinions should also be respected. PMID- 26444024 TI - Informativeness of Early Huntington Disease Signs about Gene Status. AB - BACKGROUND: The cohort-level risk of Huntington disease (HD) is related to the age and symptom level of the cohort, but this relationship has not been made precise. OBJECTIVE: To predict the evolving likelihood of carrying the Huntington disease (HD) gene for at-risk adults using age and sign level. METHODS: Using data from adults with early signs and symptoms of HD linked to information on genetic status, we use Bayes' theorem to calculate the probability that an undiagnosed individual of a certain age and sign level has an expanded CAG repeat. RESULTS: Both age and sign levels have substantial influence on the likelihood of HD onset, and the probability of eventual diagnosis changes as those at risk age and exhibit (or fail to exhibit) symptoms. For example, our data suggest that in a cohort of individuals age 26 with a Unified Huntington's Disease Rating Scale (UHDRS) motor score of 7-10 70% of them will carry the HD mutation. For individuals age 56, the same motor score suggests only a 40% chance of carrying the mutation. Early motor signs of HD, overall and the chorea subscore, were highly predictive of disease onset at any age. However, body mass index (BMI) and cognitive performance scores were not as highly predictive. CONCLUSIONS: These results suggest that if researchers or clinicians are looking for early clues of HD, it may be more foretelling to look at motor rather than cognitive signs. Application of similar approaches could be used with other adult onset genetic conditions. PMID- 26444025 TI - The Genetic Modifiers of Motor OnsetAge (GeM MOA) Website: Genome-wide Association Analysis for Genetic Modifiers of Huntington's Disease. AB - BACKGROUND: Huntington's disease (HD) is a dominantly inherited disease caused by a CAG expansion mutation in HTT. The age at onset of clinical symptoms is determined primarily by the length of this CAG expansion but is also influenced by other genetic and/or environmental factors. OBJECTIVE: Recently, through genome-wide association studies (GWAS) aimed at discovering genetic modifiers, we identified loci associated with age at onset of motor signs that are significant at the genome-wide level. However, many additional HD modifiers may exist but may not have achieved statistical significance due to limited power. METHODS: In order to disseminate broadly the entire GWAS results and make them available to complement alternative approaches, we have developed the internet website "GeM MOA" where genetic association results can be searched by gene name, SNP ID, or genomic coordinates of a region of interest. RESULTS: Users of the Genetic Modifiers of Motor Onset Age (GeM MOA) site can therefore examine support for association between any gene region and age at onset of HD motor signs. GeM MOA's interactive interface also allows users to navigate the surrounding region and to obtain association p-values for individual SNPs. CONCLUSIONS: Our website conveys a comprehensive view of the genetic landscape of modifiers of HD from the existing GWAS, and will provide the means to evaluate the potential influence of genes of interest on the onset of HD. GeM MOA is freely available at https://www.hdinhd.org/. PMID- 26444027 TI - Subclinical pulmonary congestion is prevalent in nephrotic syndrome. AB - In patients with nephrotic syndrome (NS), the lung is considered an organ protected from the risk of edema. However, data on objectively measured lung water in NS patients is lacking. Here we measured lung water by an ultrasound (US) technique as well as by transthoracic impedance in 42 asymptomatic patients with active NS, in 14 stage G5D CKD patients on chronic hemodialysis, and in 21 healthy individuals. In patients with active NS, the median number of US-B lines (a metric of lung water) after 5 min in a supine position was significantly higher (12; interquartile range: 7-25) compared with that in healthy individuals (4; 2-9) but similar to that in hemodialysis patients (23; 10-39). The difference between NS patients and healthy individuals was significantly amplified (16; 10 35 vs. 4; 2-9) after 60 min of supine resting and significantly attenuated after 5 min of standing (10; 7-25 vs. 3; 1-6). Posture-dependent changes in lung water in patients with active NS were significantly accentuated compared with both hemodialysis patients and healthy individuals. After NS remission, the number of US-B lines was significantly reduced to 5 (4-18) at 5 min and to 6 (5-22) at 60 min approaching the normal range. Lung congestion in patients with active NS was confirmed by transthoracic impedance. Thus, asymptomatic pulmonary congestion is pervasive in patients with NS. A clinical trial is needed to assess the utility of lung US for the management of patients with NS. PMID- 26444028 TI - Src inhibition blocks renal interstitial fibroblast activation and ameliorates renal fibrosis. AB - Increased Src activity has been associated with the pathogenesis of renal tumors and some glomerular diseases, but its role in renal interstitial fibrosis remains elusive. To evaluate this, cultured renal interstitial fibroblasts (NRK-49F) were treated with PP1, a selective inhibitor of Src. This resulted in decreased expression of alpha-smooth muscle actin, fibronectin, and collagen I in response to serum, angiotension II, or transforming growth factor-beta1 (TGF-beta1). Silencing Src with siRNA also inhibited expression of those proteins. Furthermore, inhibition of Src activity blocked renal fibroblast proliferation. In a murine model of renal interstitial fibrosis induced by unilateral ureteral obstruction, the active form of Src (phopsho-Src Tyr416) was upregulated in both renal interstitial fibroblasts and renal tubular cells of the fibrotic kidney. Its inactivation reduced renal fibroblast activation and attenuated extracellular matrix protein deposition. Src inhibition also suppressed activation of TGF-beta1 signaling, activation of the epidermal growth factor receptor and STAT3, and reduced the number of renal epithelial cells arrested at the G2/M phase of the cell cycle after ureteral obstruction. Thus, Src is an important mediator of renal interstitial fibroblast activation and renal fibrosis, and we suggest that Src is a potential therapeutic target for treatment of chronic renal fibrosis. PMID- 26444030 TI - Perioperative dexmedetomidine reduces the incidence and severity of acute kidney injury following valvular heart surgery. AB - Acute kidney injury (AKI) following cardiac surgery is closely interrelated with hemodynamic instability and sympathetic activity, and adversely influences prognosis. Here, we investigated in a randomized placebo-controlled trial whether dexmedetomidine, an alpha2 adrenoreceptor agonist, could prevent AKI after valvular heart surgery. Two hundred patients undergoing valvular heart surgery were randomly assigned to equal placebo or treatment groups. Dexmedetomidine was infused at a rate of 0.4 MUg/kg/h starting immediately after anesthetic induction and continuing for 24 h after surgery. We then assessed the incidence of AKI during the first 48 postoperative hours, hemodynamic variables, and a composite of major morbidity end points. The incidence of AKI, based on Acute Kidney Injury Network criteria, was significantly lower in the treatment group compared with the control group (14 vs. 33%). The dexmedetomidine group exhibited a significantly lower incidence of a composite of major morbidity end points (21 vs. 38%) and a significantly shorter length of intensive care unit stay (3 [2, 3] days vs. 3 [2, 4] days) compared with the control group. Thus, perioperative infusion of dexmedetomidine effectively reduced both the incidence and severity of AKI, and improved outcome in patients undergoing valvular heart surgery without untoward hemodynamic side effects. PMID- 26444029 TI - Molecular mechanisms of insulin resistance in chronic kidney disease. AB - Insulin resistance refers to reduced sensitivity of organs to insulin-initiated biologic processes that result in metabolic defects. Insulin resistance is common in patients with end-stage renal disease but also occurs in patients with chronic kidney disease (CKD), even when the serum creatinine is minimally increased. Following insulin binding to its receptor, auto-phosphorylation of the insulin receptor is followed by kinase reactions that phosphorylate insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), and Akt. In fact, low levels of Akt phosphorylation (p-Akt) identify the presence of the insulin resistance that leads to metabolic defects in insulin-initiated metabolism of glucose, lipids, and muscle proteins. Besides CKD, other complex conditions (e.g., inflammation, oxidative stress, metabolic acidosis, aging, and excess angiotensin II) reduce p-Akt resulting in insulin resistance. Insulin resistance in each of these conditions is due to the activation of different E3 ubiquitin ligases, which specifically conjugate ubiquitin to IRS-1 marking it for degradation in the ubiquitin-proteasome system (UPS). Consequently, IRS-1 degradation suppresses insulin-induced intracellular signaling, causing insulin resistance. Understanding mechanisms of insulin resistance could lead to therapeutic strategies that improve the metabolism of patients with CKD. PMID- 26444031 TI - Inhibition of H3K9 histone methyltransferase G9a attenuates renal fibrosis and retains klotho expression. AB - H3K9 methyltransferase G9a is reportedly induced by transforming growth factor beta1 (TGF-beta1) and has an important role in the development of epithelial mesenchymal transposition in cancer cells. Since the transcriptional activity of the Klotho gene is regulated by H3K9 modification, we investigated the effects of G9a on renal fibrosis and klotho expression. G9a levels were significantly upregulated by day 7 in the kidneys of unilateral ureteral-obstructed mice, but this was inhibited by TGF-beta1-neutralizing antibody. Administration of G9a small interfering RNA not only decreased alpha-smooth muscle actin and fibronectin but also increased klotho expression in the ureteral-obstructed mice. Similarly, intraperitoneal injection of BIX01294, a specific inhibitor of G9a, showed beneficial effects on renal fibrosis and klotho expression with decreased monomethylation of H3K9 (me1). In in vitro experiments, BIX01294 also inhibited TGF-beta1-induced fibrotic changes and klotho downregulation along with suppressed H3K9me1. In human kidney biopsy specimens, areas of G9a immunostaining correlated positively with H3K9me1 levels, as well as fibrotic markers, but correlated negatively with klotho expression. Thus, TGF-beta1-induced G9a has an important role in the progression of renal fibrosis and reduced klotho expression through H3K9me1. PMID- 26444032 TI - Super-resolution stimulated emission depletion imaging of slit diaphragm proteins in optically cleared kidney tissue. AB - The glomerular filtration barrier, consisting of podocyte foot processes with bridging slit diaphragm, glomerular basement membrane, and endothelium, is a key component for renal function. Previously, the subtlest elements of the filtration barrier have only been visualized using electron microscopy. However, electron microscopy is mostly restricted to ultrathin two-dimensional samples, and the possibility to simultaneously visualize multiple different proteins is limited. Therefore, we sought to implement a super-resolution immunofluorescence microscopy protocol for the study of the filtration barrier in the kidney. Recently, several optical clearing methods have been developed making it possible to image through large volumes of tissue and even whole organs using light microscopy. Here we found that hydrogel-based optical clearing is a beneficial tool to study intact renal tissue at the nanometer scale. When imaging samples using super-resolution STED microscopy, the staining quality was critical in order to assess correct nanoscale information. The signal-to-noise ratio and immunosignal homogeneity were both improved in optically cleared tissue. Thus, STED of slit diaphragms in fluorescently labeled, optically cleared, intact kidney samples is a new tool for studying the glomerular filtration barrier in health and disease. PMID- 26444033 TI - The Effect of Increasing Autonomy Through Choice on Young Children's Physical Activity Behavior. AB - BACKGROUND: Increasing autonomy by manipulating the choice of available physical activity options in a laboratory setting can increase physical activity in older children and adults. However, the effect of manipulating the number of physically active choices has yet to be examined in young children in a gymnasium environment. METHODS: Twenty children (n = 10 girls, 6.1 +/- 1.4 years old) individually participated in 2 [low choice (LC), high choice (HC)] free-choice activity conditions for 30 minutes in a 4360 square foot gymnasium. Children had access to 2 or 8 physical activity options in the LC and HC conditions, respectively. Physical activity behavior was measured via accelerometry. RESULTS: Children's 30-minute accelerometer counts increased (P < .03) from the LC (2675 +/- 294 counts.min-1) to the HC (3224 +/- 280 counts.min-1) condition. CONCLUSIONS: Providing greater autonomy through choice of a greater number of physically active options increased young children's physical activity participation by 20.5%. PMID- 26444034 TI - Wurtzite-Phased InP Micropillars Grown on Silicon with Low Surface Recombination Velocity. AB - The direct growth of III-V nanostructures on silicon has shown great promise in the integration of optoelectronics with silicon-based technologies. Our previous work showed that scaling up nanostructures to microsize while maintaining high quality heterogeneous integration opens a pathway toward a complete photonic integrated circuit and high-efficiency cost-effective solar cells. In this paper, we present a thorough material study of novel metastable InP micropillars monolithically grown on silicon, focusing on two enabling aspects of this technology-the stress relaxation mechanism at the heterogeneous interface and the microstructure surface quality. Aberration-corrected transmission electron microscopy studies show that InP grows directly on silicon without any amorphous layer in between. A set of periodic dislocations was found at the heterointerface, relaxing the 8% lattice mismatch between InP and Si. Single crystalline InP therefore can grow on top of the fully relaxed template, yielding high-quality micropillars with diameters expanding beyond 1 MUm. An interesting power-dependence trend of carrier recombination lifetimes was captured for these InP micropillars at room temperature, for the first time for micro/nanostructures. By simply combining internal quantum efficiency with carrier lifetime, we revealed the recombination dynamics of nonradiative and radiative portions separately. A very low surface recombination velocity of 1.1 * 10(3) cm/sec was obtained. In addition, we experimentally estimated the radiative recombination B coefficient of 2.0 * 10(-10) cm(3)/sec for pure wurtzite-phased InP. These values are comparable with those obtained from InP bulk. Exceeding the limits of conventional nanowires, our InP micropillars combine the strengths of both nanostructures and bulk materials and will provide an avenue in heterogeneous integration of III-V semiconductor materials onto silicon platforms. PMID- 26444036 TI - Efficient Electrochemical and Photoelectrochemical H2 Production from Water by a Cobalt Dithiolene One-Dimensional Metal-Organic Surface. AB - Solar-driven hydrogen evolution from water has emerged as an important methodology for the storage of renewable energy in chemical bonds. Efficient and practical clean-energy devices for electrochemical or photoelectrochemical splitting of water require the immobilization of stable and active hydrogen evolving catalysts onto electrode or photocathode materials, which remains a significant challenge. Here we show that cobalt(II) reacts with benzene-1,2,4,5 tetrathiol in the presence of base to form a cobalt dithiolene polymer 1. The generated polymer is immobilized onto glassy carbon electrodes (GCE) to generate a metal-organic surface (MOS 1|GCE), which displays efficient H2-evolving activity and stability in acidic aqueous solutions. Moreover, the generated polymer is integrated with planar p-type Si to generate very efficient photocathode materials (MOS 1|Si) for solar-driven hydrogen production from water. Photocurrents up to 3.8 mA/cm(2) at 0 V vs RHE were achieved under simulated 1 Sun illumination. MOS 1|Si photocathodes operate at potentials 550 mV more positive than MOS 1|GCE cathodes to reach the same activity for H2 evolution from water (1 mA/cm(2)). PMID- 26444037 TI - Stabilizing and Improving Solar H2 Generation from Zn(0.5)Cd(0.5)S Nanorods@MoS2/RGO Hybrids via Dual Charge Transfer Pathway. AB - The incorporated Zn(0.5)Cd(0.5)S (ZCS) nanorods with MoS2/RGO cocatalysts by a simultaneous reduction reaction was reported. The preparation of RGO and formation of MoS2 with intimate interfacial contact with ZCS were achieved. Through the optimizing of each component proportion, the ZCS@MoS2/RGO hybrid with 1.5 wt % MoS2 and 3 wt % RGO showed the highest photocatalytic H2 production activity (2.31 mmol/h) with long time stability (50 h). The relative mechanism has been investigated. It is believed that the stabilizing and improving solar H2 generation is originating from dual charge transfer pathway from excited ZCS to RGO, then to MoS2 due to intimate interfacial structure. PMID- 26444035 TI - Synthesis and Biological Evaluation of (S)-Amino-2-methyl-4-[(76)Br]bromo-3-(E) butenoic Acid (BrVAIB) for Brain Tumor Imaging. AB - The novel compound, (S)-amino-2-methyl-4-[(76)Br]bromo-3-(E)-butenoic acid (BrVAIB, [(76)Br]5), was characterized against the known system A tracer, IVAIB ([(123)I]8). [(76)Br]5 was prepared in a 51% +/- 19% radiochemical yield with high radiochemical purity (>=98%). The biological properties of [(76)Br]5 were compared with those of [(123)I]8. Results showed that [(76)Br]5 undergoes mixed amino acid transport by system A and system L transport, while [(123)I]8 had less uptake by system L. [(76)Br]5 demonstrated higher uptake than [(123)I]8 in DBT tumors 1 h after injection (3.7 +/- 0.4% ID/g vs 1.5 +/- 0.3% ID/g) and also showed higher uptake vs [(123)I]8 in normal brain. Small animal PET studies with [(76)Br]5 demonstrated good tumor visualization of intracranial DBTs up to 24 h with clearance from normal tissues. These results indicate that [(76)Br]5 is a promising PET tracer for brain tumor imaging and lead compound for a mixed system A and system L transport substrate. PMID- 26444038 TI - Correction to Measurements of Methane Emissions from Natural Gas Gathering Facilities and Processing Plants: Measurement Results. PMID- 26444040 TI - ? PMID- 26444039 TI - Differential Diagnosis of Cerebellar Atrophy in Childhood: An Update. AB - Cerebellar atrophy (CA) is a relatively common, but nonspecific finding in pediatric neurology and neuroradiology. Here, we provide an update of checklists for postnatally acquired CA, unilateral CA, and hereditary CA. In addition, we include a list of disorders with ataxia as a symptom, but without CA. These checklists may help the evaluation of differential diagnosis and planning of additional investigations. For diseases associated with hereditary CA, we provide an updated version of our neuroimaging-based pattern-recognition approach that classify CA as isolated ("pure") or associated ("plus") with other neuroimaging findings including hypomyelination, progressive white matter abnormalities, signal changes of the dentate nucleus, cerebellar cortex T2-hyperintensity, and basal ganglia involvement. Finally, we discuss some rules with their exceptions related to pediatric CA, discrepancies between clinical and neuroimaging course, and the difficulties to differentiate CA from cerebellar hypoplasia. PMID- 26444042 TI - ? PMID- 26444041 TI - ? PMID- 26444043 TI - Effects of self-generated versus experimenter-provided cues on the representation of future events. AB - Most experimental studies of prospection focused on episodic forms of future events prompted by means of verbal cues. However, there is evidence suggesting that future events differ considerably according to whether they are produced in response to external, experimenter-provided verbal cues or they are self generated. In the present study, we compared the quality, the phenomenal characteristics, the temporal distribution, and the content of imagined events prompted by experimenter-provided cues (i.e., cue-words and short verbal sentences) or elicited by means of verbal cues that were self-generated in an autobiographical fluency task. The results showed that future events prompted by means of self-generated cues contained fewer event-specific details than future events prompted by experimenter-provided cues. However, future events elicited by means of self-generated and by experimenter-provided cues did not differ with respect to their phenomenal characteristics. The temporal distribution and the thematic content of future representations were also affected by the type of cue used to elicit prospection. These results offer a holistic view of the properties of future thinking and suggest that the content and the characteristics of envisioned future events may be affected by the method used to elicit prospection. PMID- 26444044 TI - A Roundtable Discussion: Working Toward Safer, Easier-to-Use Infusion Systems. PMID- 26444045 TI - IV Smart Pumps: The Impact of a Simplified User Interface on Clinical Use. PMID- 26444046 TI - Eliminating Clinical Workarounds through Improved Smart Pump Drug Library Use. PMID- 26444047 TI - Reducing Intermittent Infusion Syringe Pump Errors via Weight-Based Safety Parameters. AB - Historically, smart infusion pumps with dose error reduction software were implemented to improve safety associated with programming of continuous infusion modes on large-volume infusion pumps. Much of the published literature related to smart infusion pumps and safety alerts is focused on continuous medication infusions, with little available information related to their use with intermittent infusions. As a result of the focus on continuous infusions, an impression exists that intermittent infusions are less prone to programming errors and/or do not require comparably rigorous safety parameters, such as use of weight-based medication programming. METHODS: A retrospective study was conducted with data from 10 pediatric inpatient hospitals, all of which used syringe infusion pumps for intermittent medications, to describe the impact of weight-based safety parameters on the occurrence of potential programming errors. The data were analyzed based on recorded safety alerts and alert triggers for weight-based (dose/kilogram/time) and non-weight-based (volume-over-time [VOT]) intermittent infusions. RESULTS: Data from a total of 4,162 pumps, 943,448 total infusions, and 810,359 intermittent infusions between January 1 and December 31, 2013, were reviewed. Weight-based infusions had a greater percentage of safety alerts (83.3%) compared with VOT infusions (16.7%). CONCLUSION: Weight-based intermittent infusion modes can prevent programming errors and, compared with non weight-based intermittent infusion modes, can be used to improve safety in the pediatric population. Additional research should be conducted to confirm a decrease in adverse drug events resulting from implementation of weight-based safety parameters. PMID- 26444048 TI - Ensuring Optimal Smart Pump Use Through Augmented User Interface. PMID- 26444049 TI - Implementing Smart Infusion Pumps at Kaiser Permanente. PMID- 26444051 TI - Umbilical blood gas analysis in preeclamptic versus healthy pregnancies with preterm birth. AB - OBJECTIVE: Comparing the value of umbilical cord arterial blood gas (UC-ABG) analysis in the prediction of neonatal mortality and morbidity in the preeclamptic versus healthy pregnancies with preterm birth. METHODS: Eight hundred sixteen preterm (born at <37 gestational weeks) neonates with no other morbidities who were born by cesarean section were evaluated. Immediately after delivery, UC-ABG analysis was performed and the neonates were followed. RESULTS: Preeclamptic women had lower umbilical cord blood (UCB) pH (7.2 4 +/- 0.1 versus 7.2 7 +/- 0.08, p = 0.008) and higher UCB base deficit (BD) (3.5 +/- 3.7 versus 2.2 +/- 3.4, p = 0.005) compared with controls. In the preeclamptic group, UCB metabolic acidosis (pH < 7.15 and B.D > 8) was not independently associated with neonatal morbidity or mortality, while in the control group UCB metabolic acidosis was independently associated with low 10-min Apgar (OR, 4.9; 95%CI 1.37 18.03), respiratory distress syndrome (OR, 2.37; 95%CI 1.05-6.17), intraventricular hemorrhage (OR, 3.01; 95%CI 1.13-7.99), and neonatal mortality (OR, 17.33; 95%CI 4.51-66.53). CONCLUSIONS: The preterm neonates born to preeclamptic mothers have lower UCB pH and higher BD. In these neonates, UCB acidosis is not independently associated with any adverse neonatal outcomes. In contrast, in the preterm neonates born to healthy mothers, UCB metabolic acidosis is independently associated with neonatal mortality and morbidity. PMID- 26444052 TI - Statistical media design for efficient polyhydroxyalkanoate production in Pseudomonas sp. MNNG-S. AB - Polyhydroxyalkanoate (PHA) is a promising polymer for various biomedical applications. There is a high need to improve the production rate to achieve end use. When a cost-effective production was carried out with cheaper agricultural residues like molasses, traces of toxins were incorporated into the polymer, which makes it unfit for biomedical applications. On the other hand, there is an increase in the popularity of using chemically defined media for the production of compounds with biomedical applications. However, these media do not exhibit favorable characteristics such as efficient utilization at large scale compared to complex media. This article aims to determine the specific nutritional requirement of Pseudomonas sp. MNNG-S for efficient production of polyhydroxyalkanoate. Response surface methodology (RSM) was used in this study to statistically design for PHA production based on the interactive effect of five significant variables (sucrose; potassium dihydrogen phosphate; ammonium sulfate; magnesium sulfate; trace elements). The interactive effects of sucrose with ammonium sulfate, ammonium sulfate with combined potassium phosphate, and trace element with magnesium sulfate were found to be significant (p < .001). The optimization approach adapted in this study increased the PHA production more than fourfold (from 0.85 g L(-1) to 4.56 g L(-1)). PMID- 26444053 TI - Exoskeletons for industrial application and their potential effects on physical work load. AB - The aim of this review was to provide an overview of assistive exoskeletons that have specifically been developed for industrial purposes and to assess the potential effect of these exoskeletons on reduction of physical loading on the body. The search resulted in 40 papers describing 26 different industrial exoskeletons, of which 19 were active (actuated) and 7 were passive (non actuated). For 13 exoskeletons, the effect on physical loading has been evaluated, mainly in terms of muscle activity. All passive exoskeletons retrieved were aimed to support the low back. Ten-forty per cent reductions in back muscle activity during dynamic lifting and static holding have been reported. Both lower body, trunk and upper body regions could benefit from active exoskeletons. Muscle activity reductions up to 80% have been reported as an effect of active exoskeletons. Exoskeletons have the potential to considerably reduce the underlying factors associated with work-related musculoskeletal injury. Practitioner Summary: Worldwide, a significant interest in industrial exoskeletons does exist, but a lack of specific safety standards and several technical issues hinder mainstay practical use of exoskeletons in industry. Specific issues include discomfort (for passive and active exoskeletons), weight of device, alignment with human anatomy and kinematics, and detection of human intention to enable smooth movement (for active exoskeletons). PMID- 26444054 TI - Predictors of Recent Marijuana Use and Past Year Marijuana Use Among a National Sample of Hispanic Youth. AB - BACKGROUND: Marijuana use rates remain higher among Hispanic youth compared to youth from other ethnic groups. OBJECTIVES: The purpose of the study was to examine if sex, age, authoritarian parenting, perceived school experiences, lifetime depression, legal involvement, and perceived social norms of marijuana use predicted recent marijuana use and past year marijuana use among Hispanic youth. METHODS: The participants of this study were a nationwide sample of Hispanic youth (n = 3,457) in the United States. A secondary data analysis of the 2012 National Survey on Drug Use and Health was performed. Unadjusted odds ratios were computed via univariate logistic regression analyses and all statistically significant variables were retained and included in the final multiple logistic regression analyses. Recent marijuana use was operationally defined as use within the past 30 days, and marijuana use in the past year was defined as use within the past year. RESULTS: Results indicated that 7.5% of Hispanic youth used within the past month and 14.5% of Hispanic youth used within the past year. Results revealed that significant predictors for recent use were age, authoritarian parenting, perceived school experiences, legal involvement, and perceived social norms of youth marijuana use. Predictors for past year were age, perceived school experiences, legal involvement, and perceived social norms of youth marijuana use. CONCLUSIONS/IMPORTANCE: Findings from this study can be used to address the public health problem of marijuana use among Hispanic youth that is ultimately contributing to health disparities among this ethnic group nationwide. Recommendations for future studies are included. PMID- 26444055 TI - Getting Warmer on Critical Care for Head Injury. PMID- 26444056 TI - Cardioprotection and arrhythmias, Part I. PMID- 26444057 TI - Cryptosporidium infections in birds--a review. AB - Cryptosporidiosis is one of the main protozoan infections in birds. It manifests as either a respiratory or a digestive illness, and it affects a very large number of avian species across several continents. The aim of this review is to report on the main results of studies on cryptosporidiosis among birds and the importance of these results to veterinary medicine and public health. PMID- 26444058 TI - Anthelmintic activity of Cymbopogon citratus against Haemonchus contortus. AB - Parasitic nematodes are of major economic importance in livestock. An alternative for the control of parasites is phytotherapy. This study evaluated the efficacy of Cymbopogon citratus decoction (CcD), C. citratus essential oil (CcEo) and citral against Haemonchus contortus using in vitro egg hatch test (EHT) and larval development test (LDT) and an in vivo test using a Meriones unguiculatus (gerbil) model. The effect of 800 mg/kg CcEo was evaluated in gerbils that had been artificially infected with 5,000 third-stage H. contortus larvae. The effective concentrations required to inhibit 50% (EC50) of egg hatching were 0.46, 0.14 and 0.13 mg/mL for CcD, CcEo and citral, respectively. The EC50 values in the LDT were 5.04, 1.92 and 1.37 mg/mL for CcD, CcEo and citral, respectively. H. contortus population in the group treated with C. citratus essential oil was reduced by 38.5% (P< 0.05) in comparison to the control group. These results suggest that it may be possible to use C. citratus essential oil to control of H. contortus parasite of small ruminant. PMID- 26444059 TI - Gastrointestinal and external parasites of the white-crested elaenia Elaenia albiceps chilensis (Aves, Tyrannidae) in Chile. AB - The objective of this study is to evaluate the ectoparasites and helminths of the white-crested elaenia, Elaenia albiceps chilensis. Feather mites Anisophyllodes elaeniae, Trouessartia elaeniae, and Analges sp. were detected in 51% of birds (n=106), whereas 24% were infected with lice (Tyranniphilopterus delicatulus, Menacanthus cfr. distinctus, and Ricinus cfr. invadens). Helminths Viguiera sp. and Capillaria sp. were found in five of the birds that were necropsied (n=20). With the exception of A. elaeniae, T. elaeniae, and T. delicatulus, all parasites represented new records found for the white-crested elaenia, and therefore for the Chilean repertoire of biodiversity. PMID- 26444060 TI - Ectocommensal and ectoparasites in goldfish Carassius auratus (Linnaeus, 1758) in farmed in the State of Sao Paulo. AB - Concomitant infections by several parasitic genera are rare, very debilitating and often lethal to fish reared under commercial breeding conditions. Were describe a multiple and concurrent parasite infestation in cultured goldfish Carassius auratus with skin damage (nodules and/or ulceration). Fish with skin lesions underwent necropsy, and the skin and gills were scraped and examined. Histopathological examination with Hematoxylin-Eosin and Giemsa stain, and an ultrastructure study using transmission and scanning electron microscopy were conducted. In the skin, we identified multiple-parasite infestations by Gyrodactylidae, Epistylis sp., Trichodina sp., Ichthyophthirius multifiliis, Tetrahymena sp. and Ichthyobodo necator,associated with epithelial cell hyperplasia and epidermal sloughing. Although no gross lesions were observed, were identified a large number of parasites in the gills (Epistylis sp., Piscinoodinium sp., Ichthyophthirius multifiliis, Trichodina sp., Apiosoma sp., Hexamitasp. and cysts of a trematode digenean). The observed trematodes were not identified. The associated microscopic lesions were epithelial hypertrophic and hyperplasic and exhibited fusion of secondary lamellae and epithelial cell detachment. This is the first description of a protozoan Vorticella sp. parasitizing goldfish in Brazil. Multiple ectoparasitism by protozoa and Platyhelminthes, with or without apparent tissue damage, can be fatal for goldfish raised on farms with poor management. PMID- 26444061 TI - Expression of a recombinant protein, A2 family, from Leishmania infantum (Jaboticabal strain) and its evaluation in Canine Visceral Leishmaniasis serological test. AB - This study aimed to express a recombinant A2 family protein of Leishmania chagasi, Jaboticabal strain; test this protein as an antigen in serological assays; and investigate its antigenicity and immunogenicity. A protein coded by an allele of the A2 gene isolated from L. chagasi was expressed in three different strains of Escherichia coli. We used 29 sera samples from Leishmune vaccinated dogs, 482 sera samples from dogs from endemic areas (positive controls), and 170 sera samples from dogs from non-endemic areas (negative controls) in ELISA tests using soluble Leishmaniaantigen (SLA) and His-A2 as antigen. Expressed proteins showed, by western blotting, the expression of an 11 KDa protein. Sixty-three percent (303/482) of the samples from endemic areas were positive by ELISA His-A2, whereas 93.1% (27/29) of Leishmune(r)-vaccinated animals were negative by His-A2-ELISA. Anti-A2 antibodies from mice inoculated with the A2 protein were detected in slides containing amastigote forms, but not in slides containing promastigote forms. The A2 recombinant protein from L. chagasi may be a useful tool in the diagnosis of CVL, and further tests regarding the infection stage and the specie of parasite at which the dogs are sampled should provide a better understanding of our results. PMID- 26444063 TI - New records of three species of nematodes in Cerdocyon thous from the Brazilian Pantanal wetlands. AB - We report the occurrence of nematodes collected from the gut of roadkilled crab eating foxes (two adult males and one juvenile female), Cerdocyon thous (Linnaeus, 1766), found on the BR 262 highway in Mato Grosso do Sul state, Brazil in 2011. Three helminth species were identified: Ancylostoma buckleyi, Pterygodermatites (Multipectines) pluripectinata, and Ascaridia galli. These nematodes are reported for the first time to infect C. thous from the Brazilian Pantanal wetlands, thereby expanding their geographical distribution. PMID- 26444062 TI - Galectins and collectinis expression are increased in Haemonchus contortus infected corriedale sheep. AB - Galectins and collectins are proteins classified in the lectin family that have the ability to recognize molecular patterns associated with pathogens. Studies on cattle have demonstrated high expression of these proteins during infection with gastrointestinal nematodes. The aim of this study was to investigate whether the level of Haemonchus contortus infection would alter the expression of galectins (Gal11 and Gal14) and collectins (SPA and CGN) in sheep. Twelve Corriedale sheep exposed to natural infection with nematodes were divided into two groups: group 1 (G1, n = 7) and group 2 (G2, n = 5), with low and high parasite burdens, respectively, based on fecal egg counts and abomasal parasite counts. The fecal egg counts and abomasal parasite counts were significantly different (p < 0.05) between the groups. Galectin and collectin gene expression was observed in all sheep abomasal samples. However, animals with lower infection levels showed lower expression of the genes Gal14, SPA and CGN (p < 0.05). Expression of lectins was associated with the abomasal H. contortus burden, thus suggesting that these proteins may have a role in controlling of this infection. PMID- 26444064 TI - Antimicrobial activity of Stomoxys calcitrans against Beauveria bassiana sensu lato isolates. AB - This study had the aims of evaluating the antimicrobial characteristics of Stomoxys calcitrans (Diptera: Muscidae) larvae against the fungal isolates CG138, CG228 and ESALQ986 of Beauveria bassiana sensu lato (Balsamo-Crivelli) Vuillemin, 1912 (Hypocreales: Cordycipitaceae). S. calcitrans eggs, larvae and pupae were exposed to these same isolates. Statistical analysis showed that the immature stages of S. calcitrans were not susceptible to the fungal isolates used, regardless of the exposure method. Diffusion test on solid culture medium reveled that macerated S. calcitrans larvae exposed to isolate CG138 reduced CG138 fungal development. The analysis of the chromatographic profiles indicated that the macerate or mucus of larvae of the control group and the groups exposed to the isolate CG138 presented different profiles. Reduced development of the isolate CG138 on the larvae cuticle was observed by means of scanning electron microscopy. PMID- 26444065 TI - Brazilian donkeys (Equus asinus) have a low exposure to Neospora spp. AB - Donkeys (Equus asinus) are closely related to horses and are known to be infected by several equine pathogens. Neospora caninum and Neospora hughesi are protozoan parasites that infect horses, but they were not confirmed in donkeys up to this date. The aim of this study was to evaluate the exposure of donkeys (Equus asinus) to Neospora spp. using tachyzoites of N. caninum as antigen and employing two common serologic methods, IFAT and immunoblot. Sera from 500 donkeys were obtained from 30 municipalities in Bahia state and tested by IFAT. Two of 500 sera were positive for Neospora spp. by IFAT with antibody titers of 100, and recognized a 37kDa antigen in immunoblot. Approximately 22% of the samples showed strong apical reactions and/or incomplete fluorescence, what may cause confusion in the interpretation of IFAT. We concluded that Neospora spp. are possibly of minor importance for Brazilian donkeys. Future studies are necessary to prove that Neospora spp. can naturally infect donkeys. PMID- 26444066 TI - Pathological and parasitological characterization of infection by trematodes (Paramphistomatidae) in the large intestine of capybaras. AB - Gross and histological lesions caused by an intestinal parasite were described in three capybaras. The parasites presented a mean length of 14 mm and width of 7 mm, were round to oval or piriform, reddish and pedunculated, and adhered strongly to the mucosa of the large intestine. The intestinal mucosa at the parasite attachment site presented loss of surface epithelium and most glands, with replacement by fibrovascular proliferation that protruded from the mucosa and was involuted by the ventral sucker of the parasite. The lamina propria presented cellular debris, eosinophils, macrophages and plasma cells. The morphological characteristics, observed using serial histological sections, made it possible to classify the parasite as a trematode (Paramphistomatidae), compatible with Taxorchis schistocotyle. One capybara also harbored many ciliated protozoa in the large intestine (at the site of attachment of the parasite) and inside the caeca of the trematodes. In conclusion, this study described a multifocal necrotizing colitis associated with T. schistocotyle parasitism in capybaras. PMID- 26444067 TI - Development and health status of Centropomus undecimalisparasitized by Rhabdosynochus rhabdosynochus (Monogenea) under different salinity and temperature conditions. AB - This study evaluated the correlation of hematological parameters with the mean abundance of the monogenean helminth Rhabdosynochus rhabdosynochus in Centropomus undecimalis reared at different temperatures and salinities. The experimental conditions were: 28 degrees C/0 ppt (parts per thousand); 28 degrees C/15 ppt; 28 degrees C/32 ppt; 25 degrees C/0 ppt; 25 degrees C/15 ppt; and 25 degrees C/32 ppt. The prevalence was 100.0% in fish at 28 degrees C/15 ppt, 28 degrees C/32 ppt and 25 degrees C/15 ppt, which was significantly different (p < 0.05) from those at 25 degrees C/32 ppt. The red blood cell (RBC) count, hematocrit and total leukocyte (WBC) count were significantly higher in fish at 28 degrees C/15 ppt and 28 degrees C/32 ppt. The mean abundance of R. rhabdosynochus, hematocrit and RBC showed positive correlations (P < 0.05) with temperature (rho= 0.3908; rho= 0.4771 and rho = 0.2812). Mean abundance showed negative correlations with hemoglobin (rho= -0.3567) and mean corpuscular hemoglobin concentration (MCHC) (rho = -0.2684). No correlation between abundance and salinity was detected among the experimental conditions (rho = -0.0204). The low numbers of monogeneans recorded (min -1 and max -33) explain the few changes to fish health. This suggests that these experimental conditions may be recommended for development of rearing of C. undecimalis in Brazil, without any influence or economic losses from R. rhabdosynochus. PMID- 26444068 TI - Toxoplasma gondii antibodies in wild rodents and marsupials from the Atlantic Forest, state of Sao Paulo, Brazil. AB - Toxoplasma gondii is a protozoan parasite that infects a large spectrum of warm blooded animals, including humans. Small rodents and marsupials play an important role in the epidemiology of T. gondii because they are sources of infection for domestic and feral cats. Serum samples from 151 rodents and 48 marsupials, captured in the Atlantic Forest, Sao Paulo State, southeastern Brazil, were analyzed for the presence of T. gondii antibodies. Antibodies detected by the modified agglutination test (MAT >= 25) were found in 8.6% (13/151) of the rodents and 10.4% (5/48) of the marsupials, with titers ranging from 25 to 6400 and from 25 to 3200, respectively for the rodents and marsupials. Three of the eight species of rodents (Akodon spp., Oligoryzomys nigripesand Rattus norvegicus), and one from the four marsupial species (Didelphis aurita) presented positive animals. T. gondii was described for the first time in the rodent Oligoryzomys nigripes. PMID- 26444070 TI - The Scholarship of Practice Within the Academic Clinical Enterprise. PMID- 26444069 TI - Effect of growth factors on oocyte maturation and allocations of inner cell mass and trophectoderm cells of cloned bovine embryos. AB - This study was conducted to determine the additive effects of exogenous growth factors during in vitro oocyte maturation (IVM) and the sequential culture of nuclear transfer (NT) embryos. Oocyte maturation and culture of reconstructed embryos derived from bovine granulosa cells were performed in culture medium supplemented with either epidermal growth factor (EGF) alone or a combination of EGF with insulin-like growth factor-I (IGF-I). The maturation rates of oocytes matured in the presence of EGF or the EGF + IGF-I combination were significantly higher than those of oocytes matured in the presence of only fetal calf serum (FCS) (P 0.05). IGF-I alone or in combination with EGF in sequential embryo culture medium significantly increased the ratio of inner cell mass (ICM) to total blastocyst cells (P < 0.05). Our results showed that the addition of growth factors to IVM and sequential culture media of cloned bovine embryos increased the ICM without changing the total cell number. These unknown and uncontrolled effects of growth factors can alter the allocation of ICM and trophectoderm cells (TE) in NT embryos. A decrease in TE cell numbers could be a reason for developmental abnormalities in embryos in the cloning system. PMID- 26444071 TI - Target-Driven Evolution of Scorpion Toxins. AB - It is long known that peptide neurotoxins derived from a diversity of venomous animals evolve by positive selection following gene duplication, yet a force that drives their adaptive evolution remains a mystery. By using maximum-likelihood models of codon substitution, we analyzed molecular adaptation in scorpion sodium channel toxins from a specific species and found ten positively selected sites, six of which are located at the core-domain of scorpion alpha-toxins, a region known to interact with two adjacent loops in the voltage-sensor domain (DIV) of sodium channels, as validated by our newly constructed computational model of toxin-channel complex. Despite the lack of positive selection signals in these two loops, they accumulated extensive sequence variations by relaxed purifying selection in prey and predators of scorpions. The evolutionary variability in the toxin-bound regions of sodium channels indicates that accelerated substitutions in the multigene family of scorpion toxins is a consequence of dealing with the target diversity. This work presents an example of atypical co-evolution between animal toxins and their molecular targets, in which toxins suffered from more prominent selective pressure from the channels of their competitors. Our discovery helps explain the evolutionary rationality of gene duplication of toxins in a specific venomous species. PMID- 26444072 TI - ITI-007 for the Treatment of Schizophrenia: A 4-Week Randomized, Double-Blind, Controlled Trial. AB - BACKGROUND: An urgent need exists for new treatments of schizophrenia that are effective against a broad range of symptoms and free of limiting safety issues. ITI-007 is a new molecular entity with a pharmacologic profile that combines dose related monoamine modulation with phosphorylation of intracellular signaling proteins. METHODS: A phase II randomized, double-blind, placebo-controlled, and active-controlled trial was conducted at eight sites in the United States with randomization of 335 acutely psychotic adults with schizophrenia. ITI-007 (60 mg and 120 mg), placebo, and risperidone, included for assay sensitivity, were evaluated as monotherapy for 4 weeks. The primary outcome measure was the Positive and Negative Syndrome Scale total score, with secondary analyses conducted on symptom subscales. RESULTS: ITI-007 60 mg (p = .017, effect size = .4) and risperidone (p = .013, effect size = .4) demonstrated antipsychotic efficacy superiority over placebo on the primary end point. The results of secondary analyses reflected improvements in negative and depressive symptoms by ITI-007 60 mg. ITI-007 120 mg did not separate from placebo. However, both doses of ITI-007 were well tolerated in this patient population, as evidenced by low discontinuation and adverse event rates, and were associated with a benign metabolic profile as evidenced by significantly lower levels of prolactin, fasting glucose, total cholesterol, and triglycerides than risperidone. CONCLUSIONS: The mechanistically novel investigational drug ITI-007 was effective for the treatment of schizophrenia and comparable with placebo on safety measures in this trial. Secondary analyses indicated that ITI-007 improved negative and depression symptoms and might have expanded therapeutic efficacy in comparison with current antipsychotic drugs. PMID- 26444073 TI - A Meta-Analysis of Mismatch Negativity in Schizophrenia: From Clinical Risk to Disease Specificity and Progression. AB - BACKGROUND: The observation that mismatch negativity (MMN) is consistently impaired in schizophrenia has generated considerable interest in the use of this biomarker as an index of disease risk and progression. Despite such enthusiasm, a number of issues remain unresolved regarding the nature of MMN impairment. The present study expands upon an earlier meta-analysis of MMN impairment in schizophrenia by examining impairment across a range of clinical presentations, as well as across experimental parameters. METHODS: One hundred one samples of schizophrenia patients were included in the present study, including first episode (n = 13), chronic (n = 13), and mixed-stage (n = 75) samples. Additionally, MMN was examined in three related conditions: bipolar disorder (n = 9), unaffected first-degree relatives (n = 8), and clinical high risk (n = 16). RESULTS: We found that MMN impairment 1) likely reflects a vulnerability to disease progression in clinical high-risk populations rather than a genetic risk for the condition; 2) is largely unrelated to duration of illness after the first few years of illness, indicating that impairment is not progressive throughout the life span; 3) is present in bipolar disorder, albeit to a lesser degree than in schizophrenia; and 4) is not modulated by experimental parameters such as magnitude of change between standard and deviant tones or frequency of deviant tones but may be modulated by attentional demands. CONCLUSIONS: Such findings lay the foundation for a better understanding of the nature of MMN impairment in schizophrenia, as well as its potential as a clinically useful biomarker. PMID- 26444074 TI - Prenatal Caffeine Exposure and Child IQ at Age 5.5 Years: The EDEN Mother-Child Cohort. AB - BACKGROUND: Evidence from animal studies suggests maternal caffeine intake during pregnancy has detrimental effects on subsequent brain development in offspring. However, human data in this area are limited. The aim of this study was to assess whether caffeine intake by women during pregnancy is associated with impaired cognitive development in offspring at age 5.5 years. METHODS: Multivariate modeling was conducted using data of 1083 mother-child pairs from a population based birth cohort in France followed from pregnancy to age 5.5 years of the children. Measures included an estimate of maternal caffeine intake during pregnancy, children's IQ at age 5.5, and individual and family characteristics. RESULTS: Prenatal caffeine exposure was common in the sample (91%) with 12% displaying an intake >=200 mg/day (high). Multivariable modeling showed a significant negative relationship between caffeine intake and children's IQ at 5.5 years (-.94 [95% confidence interval = -1.70, -.17] full IQ unit per 100 mg daily caffeine intake). In particular, children of mothers consuming >=200 mg/day were more likely to have borderline or lower IQ compared with children of mothers consuming <100 mg/day (13.5% vs. 7.3%; odds ratio = 2.30, 95% confidence interval = 1.13, 4.69). CONCLUSIONS: We found an association between caffeine intake during pregnancy and impaired cognitive development in offspring, a result in line with animal data. More epidemiologic and biologically grounded research is needed to determine whether this association is causal. This finding suggests that conservative guidelines regarding the maximum caffeine intake recommended in pregnancy (i.e., 200 mg/day) should be maintained. PMID- 26444075 TI - Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort. AB - BACKGROUND: Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations. METHODS: We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues. RESULTS: In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 * 10(-4); odds ratio = 1.9; 95% confidence interval = 1.33 2.71). Furthermore, RNA in situ hybridization and reverse transcription polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology. CONCLUSIONS: AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS. PMID- 26444077 TI - Motor intensive anti-gravity training improves performance in dynamic balance related tasks in persons with Parkinson's disease. AB - Recent studies indicate that the effect of training on motor performance in persons with Parkinson's disease (PDP) is dependent on motor intensity. However, training of high motor intensity can be hard to apply in PDP due to e.g. bradykinesia, rigidity, tremor and postural instability. Therefore, the aim was to study the effect of motor intensive training performed in a safe anti-gravity environment using lower-body positive pressure (LBPP) technology on performance during dynamic balance related tasks. Thirteen male PDP went through an 8-week control period followed by 8 weeks of motor intensive antigravity training. Seventeen healthy males constituted a control group (CON). Performance during a five repetition sit-to-stand test (STS; sagittal plane) and a dynamic postural balance test (DPB; transversal plane) was evaluated. Effect measures were completion time, functional rates of force development, directional changes and force variance. STS completion time improved by 24% to the level of CON which was explained by shorter sitting-time and standing-time and larger numeric rate of force change during lowering to the chair, indicating faster vertical directional change and improved relaxation. DPB completion time tended to improve and was accompanied by improvements of functional medial and lateral rates of force development and higher vertical force variance during DPB. Our results suggest that the performance improvements may relate to improved inter-limb coordination. It is concluded that 8 weeks of motor intensive training in a safe LBPP environment improved performance during dynamic balance related tasks in PDP. PMID- 26444078 TI - Changes in serotonin (5-HT) and brain-derived neurotrophic factor (BDFN) expression in frontal cortex and hippocampus of aged rat treated with high tryptophan diet. AB - Age-related cognitive decline is accompanied by an alteration in neurotransmitter synthesis and a dysregulation of neuroplasticity-related molecules such as serotonin (5-HT) and brain-derived neurotrophic factor (BDFN). It has been previously demonstrated that hyperserotonemia induced by l-Tryptophan (TrP) enriched diet protect against memory deficits during physiological aging. Since 5 HT is closely associated to BDNF, we aimed to investigate the effect of high TrP diet on 5-HT levels and BDNF expression in Frontal Cortex (FC) and Hippocampus (Hp) of aged rats. We found that the raising of systemic 5-HT levels by chronic diet (1 month) containing high TrP significantly prevents age-related decline of BDNF protein expression in both brain areas as indicated by ELISA and Western Blot analyses. Interestingly, immunohistochemical analyses confirmed that high TrP diet significantly elevates the number of 5-HT immunoreactive fibers in both brain areas tested and this correlated with BDNF increase in the FC and hippocampal regions CA1, CA2, CA3 and a strikingly down-regulation of neurotrophin levels in the dentate gyrus (DG) of aged rats. Altogether, these finding provide evidence that enhanced TrP intake and the consequent increase in 5-HT neurotransmission may act as a modulator of BDNF system suggesting a possible mechanism for the protective role of serotonergic system on memory impairment occurring along normal aging process. PMID- 26444076 TI - Maternal Exposure to Childhood Trauma Is Associated During Pregnancy With Placental-Fetal Stress Physiology. AB - BACKGROUND: The effects of exposure to childhood trauma (CT) may be transmitted across generations; however, the time period(s) and mechanism(s) have yet to be clarified. We address the hypothesis that intergenerational transmission may begin during intrauterine life via the effect of maternal CT exposure on placental-fetal stress physiology, specifically placental corticotropin-releasing hormone (pCRH). METHODS: The study was conducted in a sociodemographically diverse cohort of 295 pregnant women. CT exposure was assessed using the Childhood Trauma Questionnaire. Placental CRH concentrations were quantified in maternal blood collected serially over the course of gestation. Linear mixed effects and Bayesian piece-wise linear models were employed to test hypothesized relationships. RESULTS: Maternal CT exposure (CT+) was significantly associated with pCRH production. Compared with nonexposed women, CT+ was associated with an almost 25% increase in pCRH toward the end of gestation, and the pCRH trajectory of CT+ women exhibited an approximately twofold steeper increase after the pCRH inflection point at 19 weeks gestation. CONCLUSIONS: To the best of our knowledge, this finding represents the first report linking maternal CT exposure with placental-fetal stress physiology, thus identifying a potential novel biological pathway of intergenerational transmission that may operate as early as during intrauterine life. PMID- 26444079 TI - Possible neural network mediating jaw opening during prey-catching behavior of the frog. AB - The prey-catching behavior of the frog is a complex, well-timed sequence of stimulus response chain of movements. After visual analysis of the prey, a size dependent program is selected in the motor pattern generator of the brainstem. Besides this predetermined feeding program, various direct and indirect sensory inputs provide flexible adjustment for the optimal contraction of the executive muscles. The aim of the present study was to investigate whether trigeminal primary afferents establish direct contacts with the jaw opening motoneurons innervated by the facial nerve. The experiments were carried out on Rana esculenta (Pelophylax esculentus), where the trigeminal and facial nerves were labeled simultaneously with different fluorescent dyes. Using a confocal laser scanning microscope, close appositions were detected between trigeminal afferent fibers and somatodendritic components of the facial motoneurons. Quantitative analysis revealed that the majority of close contacts were encountered on the dendrites of facial motoneurons and approximately 10% of them were located on the perikarya. We suggest that the identified contacts between the trigeminal afferents and facial motoneurons presented here may be one of the morphological substrate in the feedback and feedforward modulation of the rapidly changing activity of the jaw opening muscle during the prey-catching behavior. PMID- 26444080 TI - Effects of loading misalignment and tapering angle on the measured mechanical properties of nanowires. AB - Loading misalignment and tapering of nanowires are usually unavoidable factors in compression and tensile mechanical property testing of nanowires. Herein, we report quantitative finite element analyses and experimental measurements on how these two factors affect the measured compression and tensile mechanical properties if they are not included in the data analysis. The results obtained show that ignoring these two factors leads to different degrees of underestimation of the critical load, Young's modulus and tensile fracture strength. PMID- 26444081 TI - Silent IL2RG Gene Editing in Human Pluripotent Stem Cells. AB - Many applications of pluripotent stem cells (PSCs) require efficient editing of silent chromosomal genes. Here, we show that a major limitation in isolating edited clones is silencing of the selectable marker cassette after homologous recombination and that this can be overcome by using a ubiquitous chromatin opening element (UCOE) promoter-driven transgene. We use this strategy to edit the silent IL2RG locus in human PSCs with a recombinant adeno-associated virus (rAAV)-targeting vector in the absence of potentially genotoxic, site-specific nucleases and show that IL2RG is required for natural killer and T-cell differentiation of human PSCs. Insertion of an active UCOE promoter into a silent locus altered the histone modification and cytosine methylation pattern of surrounding chromatin, but these changes resolved when the UCOE promoter was removed. This same approach could be used to correct IL2RG mutations in X-linked severe combined immunodeficiency patient-derived induced PSCs (iPSCs), to prevent graft versus host disease in regenerative medicine applications, or to edit other silent genes. PMID- 26444082 TI - Grapefruit-derived Nanovectors Delivering Therapeutic miR17 Through an Intranasal Route Inhibit Brain Tumor Progression. AB - The lack of access to the brain is a major obstacle for central nervous system drug development. In this study, we demonstrate the capability of a grapefruit derived nanovector (GNV) to carry miR17 for therapeutic treatment of mouse brain tumor. We show that GNVs coated with folic acid (FA-GNVs) are enhanced for targeting the GNVs to a folate receptor-positive GL-26 brain tumor. Additionally, FA-GNV-coated polyethylenimine (FA-pGNVs) not only enhance the capacity to carry RNA, but the toxicity of the polyethylenimine is eliminated by the GNVs. Intranasal administration of miR17 carried by FA-pGNVs led to rapid delivery of miR17 to the brain that was selectively taken up by GL-26 tumor cells. Mice treated intranasally with FA-pGNV/miR17 had delayed brain tumor growth. Our results demonstrate that this strategy may provide a noninvasive therapeutic approach for treating brain-related disease through intranasal delivery. PMID- 26444084 TI - Global Materials Structure Search with Chemically Motivated Coordinates. AB - Identification of relevant reaction pathways in ever more complex composite materials and nanostructures poses a central challenge to computational materials discovery. Efficient global structure search, tailored to identify chemically relevant intermediates, could provide the necessary first-principles atomistic insight to enable a rational process design. In this work we modify a common feature of global geometry optimization schemes by employing automatically generated collective curvilinear coordinates. The similarity of these coordinates to molecular vibrations enhances the generation of chemically meaningful trial structures for covalently bound systems. In the application to hydrogenated Si clusters, we concomitantly observe a significantly increased efficiency in identifying low-energy structures and exploit it for an extensive sampling of potential products of silicon-cluster soft landing on Si(001) surfaces. PMID- 26444083 TI - Host Anti-antibody Responses Following Adeno-associated Virus-mediated Delivery of Antibodies Against HIV and SIV in Rhesus Monkeys. AB - Long-term delivery of antibodies against the human immunodeficiency virus (HIV) using adeno-associated virus (AAV) vectors is a promising approach for the prevention or treatment of HIV infection. However, host antibody responses to the delivered antibody are a serious concern that could significantly limit the applicability of this approach. Here, we describe the dynamics and characteristics of the anti-antibody responses in monkeys that received either rhesus anti-simian immunodeficiency virus (SIV) antibodies (4L6 or 5L7) in prevention trials or a combination of rhesusized human anti-HIV antibodies (1NC9/8ANC195/3BNC117 or 10-1074/10E8/3BNC117) in therapy trials, all employing AAV1 delivery of IgG1. Eight out of eight monkeys that received the anti-HIV antibodies made persisting antibody responses to all three antibodies in the mix. Six out of six uninfected monkeys that received the anti-SIV antibody 4L6 and three out of six of those receiving anti-SIV antibody 5L7 also generated anti antibodies. Both heavy and light chains were targeted, predominantly or exclusively to variable regions, and reactivity to complementarity-determining region (CDR)-H3 peptide could be demonstrated. There was a highly significant correlation of the magnitude of anti-antibody responses with the degree of sequence divergence of the delivered antibody from germline. Our results suggest the need for effective strategies to counteract the problem of antibody responses to AAV-delivered antibodies. PMID- 26444085 TI - Objectively Measured School Day Physical Activity Among Elementary Students in the United States and Finland. AB - BACKGROUND: Schools are in a unique position to ensure that all students meet the current physical activity (PA) recommendations. This study aimed to examine 1st to 3rd grade elementary students' accelerometer measured school day PA in the United States (U.S.) and Finland. METHODS: The sample consisted of 200 students (107 girls, 93 boys; ages 6 to 8) and their school day PA was monitored with hip worn ActiGraph GT3X+ accelerometers across a 5-day school week and the thresholds 100 and 2296 count per minute were used to separate sedentary time, light PA, and moderate-to-vigorous PA (MVPA). RESULTS: On an average school day, students were engaged in MVPA for 20.0 min in the U.S. and 24.1 min in Finland. Students' school-day MVPA was 9 to 16 minutes higher during physical education (PE) days compared with non-PE days (U.S: 25.8 vs. 16.6 min/day; Finland: 36.3 vs. 20.1 min/day). Girls had less MVPA and more sedentary time compared with boys in both samples. CONCLUSION: This study highlights both the role of PE and other school day physical activities in meeting PA guidelines. Policy measures are needed to change the structure of the school day and enhance PA to ensure that students meet the PA recommendations. PMID- 26444086 TI - String Vessel Formation is Increased in the Brain of Parkinson Disease. AB - BACKGROUND: String vessels are collapsed basement membrane without endothelium and have no function in circulation. String vessel formation contributes to vascular degeneration in Alzheimer disease. By comparing to age-matched control cases we have recently reported endothelial degeneration in brain capillaries of human Parkinson disease (PD). OBJECTIVE: Current study evaluated changes of basement membrane of capillaries, string vessel formation and their association with astrocytes, blood-brain-barrier integrity and neuronal degeneration in PD. METHODS: Brain tissue from human cases of PD and age-matched controls was used. Immunohistochemical staining for collagen IV, GFAP, NeuN, tyrosine hydroxylase, fibrinogen and Factor VIII was evaluated by image analysis in the substantia nigra, caudate nucleus and middle frontal gyrus. RESULTS: While the basement membrane-associated vessel density was similar between the two groups, the density of string vessels was significantly increased in the PD cases, particularly in the substantia nigra. Neuronal degeneration was found in all brain regions. Astrocytes and fibrinogen were increased in the caudate nuclei of PD cases compared with control cases. CONCLUSIONS: Endothelial degeneration and preservation of basement membrane result in an increase of string vessel formation in PD. The data may suggest a possible role for cerebral hypoperfusion in the neuronal degeneration characteristic of PD, which needs further investigation. Elevated astrocytosis in the caudate nucleus of PD cases could be associated with disruption of the blood-brain barrier in this brain region. PMID- 26444087 TI - Risk of Disabling Response Fluctuations and Dyskinesias for Dopamine Agonists Versus Levodopa in Parkinson's Disease. AB - BACKGROUND: Response fluctuations and dyskinesias develop during the use of both levodopa (LD) and dopamine agonists (DA), but may not be equally disabling. OBJECTIVE: To compare the risk and time of onset of disabling response fluctuations and dyskinesias (DRFD) among patients with Parkinson's disease (PD) who were initially treated with either LD or DA. METHODS: Open cohort study of all consecutive de-novo PD patients in routine clinical practice, included over a period of 15 years (median follow-up: 8.1 years, range 1.1-17.7), since embarking on LD or DA. Older patients and patients with more severe PD were started on LD (n = 77), younger patients on a DA (n = 50). Therapy was adjusted according to generally accepted guidelines. The primary endpoints were: the onset of response fluctuations, dyskinesias, and the moment when these complications became disabling (DRFD). RESULTS: LD-starters developed response fluctuations 0.8 years earlier than DA-starters (p = 0.07), while dyskinesias appeared around 2.5 years earlier (p = 0.003). However, the risk and time of onset of DRFD did not differ statistically between the groups (LD-starters: 60% , median interval 7.3 years, DA-starters: 52% , 6.1 years, p = 0.63). DA-starters displayed a 0.19 points lower adjusted mean improvement in motor scores than LD-starters (p = 0.002). Adjustments for age and severity of PD at start of dopaminergic therapy did not change these results. CONCLUSIONS: In routine clinical practice, the risk and time of onset of DRFD is comparable for LD-starters versus DA-starters, but motor functioning is worse in DA-starters. These results support the use of LD as initial therapy for PD. PMID- 26444088 TI - Freezing of Gait and its Associations in the Early and Advanced Clinical Motor Stages of Parkinson's Disease: A Cross-Sectional Study. AB - BACKGROUND: Freezing of gait is a common disabling symptom of Parkinson's disease (PD) with limited treatment options. The pathophysiological mechanisms of freezing behaviour are still contentious. OBJECTIVE: To investigate the prevalence of freezing of gait and its associations with increasing disease severity to gain a better understanding of the underlying pathophysiology. METHODS: This exploratory study included 389 idiopathic PD patients, divided into four groups; early and advanced PD with freezing of gait, and early and advanced PD without freezing of gait. Motor, cognitive and affective symptoms, REM sleep behaviour disorder and autonomic function were assessed. RESULTS: Regardless of disease stage, patients with freezing of gait had more severe motor symptoms and a predominant non-tremor phenotype. In the early stages, freezers had a selective impairment in executive function and had more marked REM sleep behaviour disorder. Autonomic disturbances were not associated with freezing of gait across early or advanced disease stages. CONCLUSION: These findings support the notion that impairments across the frontostriatal pathways are intricately linked to the pathophysiology underlying freezing of gait across all stages of PD. Features of REM sleep behaviour disorder suggest a contribution to freezing from brainstem pathology but this does not extend to more general autonomic dysfunction. PMID- 26444089 TI - Knowledge of Parkinson's Disease in a Multiethnic Urban Asian Setting. AB - BACKGROUND: Public knowledge regarding Parkinson's disease (PD) is important to facilitate good health-seeking behavior, but the literature on this topic is scarce. OBJECTIVE: We aimed to explore the level of public knowledge regarding PD in a large multiethnic urban Asian cohort, and (as a secondary aim) in a smaller cohort of PD patients and caregivers. METHODS: A Knowledge of PD Questionnaire (KPDQ) was developed and administered to members of the Malaysian general public, and to PD patients and caregivers. The KPDQ tests recognition of PD symptoms and general knowledge regarding PD. RESULTS: 1,258 members of the general public completed the KPDQ. Tremor was the most widely recognized symptom (recognized by 79.0% of respondents); however, 83.7% incorrectly believed that all PD patients experience tremor. Memory problem was the most widely recognized NMS. Overall, motor symptoms were better recognized than NMS. Common misperceptions were that there is a cure for PD (49.8%) and that PD is usually familial (41.4%). Female gender, Chinese ethnicity, tertiary education, healthcare-related work, and knowing someone with PD were independently associated with higher KPDQ scores. PD patients (n = 116) and caregivers (n = 135) demonstrated superior knowledge compared with the general public group, but one-third of them believed that PD is currently curable. CONCLUSIONS: This is the only study on public knowledge regarding PD in Asia. Important gaps in knowledge were evident, which could present a barrier to early diagnosis and appropriate treatment of PD. This highlights the need for targeted education campaigns and further research in this area. PMID- 26444090 TI - Conversion to IPX066 from Standard Levodopa Formulations in Advanced Parkinson's Disease: Experience in Clinical Trials. AB - BACKGROUND: Due to the short half-life of levodopa, immediate-release carbidopa levodopa (IR CD-LD) produces fluctuating LD concentrations, contributing to a risk of eventual motor complications. IPX066 was designed to rapidly attain therapeutic LD concentrations and maintain them to allow a dosing interval of ~6 hours. OBJECTIVE: To extensively analyze the dosing data collected in IPX066 studies during open-label conversions from IR CD-LD alone or with entacapone (CLE) and identify patterns relevant for managing conversion in the clinical setting. METHODS: Patients had >=2.5 hours/day of "off" time despite a stable IR or CLE regimen. Suggested initial dosing conversion tables based on prior LD daily dosage were provided. RESULTS: Of 450 patients previously treated with IR CD-LD and 110 with CLE, 87.3% and 82.7% completed conversion to IPX066, respectively. At the end of conversion, average IPX066 LD daily dosages were higher than pre-conversion dosages, with a mean conversion ratio of 2.1+/-0.6 for IR CD-LD and 2.8+/-0.8 for CLE; >90% of patients took IPX066 3 or 4 times/day, compared with a median of 5 times/day at baseline in both studies. After conversion, daily "off" time significantly decreased, with no significant increase in troublesome dyskinesia. The most common adverse event reported during conversion was nausea, with an incidence of 5.3% for conversion from IR and 7.3% from CLE. CONCLUSIONS: Among PD patients with substantial "off" time, a majority were safely converted to IPX066. The sustained LD profile from the IPX066 formulation allowed an increase in LD dose accompanied by improved motor functions, without increased troublesome dyskinesia. PMID- 26444091 TI - Occupational Characteristics and Patterns as Risk Factors for Parkinson's Disease: A Case Control Study. AB - BACKGROUND: Associations have been reported between the risk of Parkinson's disease (PD) and employment in certain fields. Most studies have focused on toxic exposures as potential causal explanations. However, PD also has been associated with personality characteristics that may influence occupational choices and patterns. OBJECTIVE: This study evaluates the role of personality as indicated by occupational choices and employment patterns in the risk for PD. METHODS: In person interviews were conducted to assess occupational histories and early-adult personality indicators among 89 PD patients and 99 controls. RESULTS: PD cases had fewer lifetime jobs than controls (mean for cases = 4.38 +/- 2.20; mean for controls = 5.00 +/- 2.26; p = 0.03). Among women, PD was positively associated with more complex work with people (OR = 1.45, 95% CI 1.12-1.89), representing a 95% increased risk for PD comparing women with the greatest complexity of work with those requiring the least complexity of work with people. Women PD cases also performed less complex work with things compared with controls (OR = 0.69 (95% CI 0.53-0.90)), translating into a 13-fold increased risk for PD among women whose work involved the least complex work with things compared with the most. The numbers of jobs and job types were associated with taking more activity risks as a young-adult (r = 0.19, p = 0.02; r = 0.26, p = 0.001, respectively). CONCLUSIONS: Cases with PD held fewer lifetime jobs compared with controls. Occupational complexity was associated with the risk for PD among women, but not men. Further consideration of the possible influence of personality on occupational choices is warranted. PMID- 26444092 TI - A Positive 'Pointing Test' in a Parkinson's Disease Patient. PMID- 26444093 TI - Disability is an Independent Predictor of Falls and Recurrent Falls in People with Parkinson's Disease Without a History of Falls: A One-Year Prospective Study. AB - BACKGROUND: Predictors of falls in people with Parkinson's disease (PD) who have not previously fallen are yet to be identified. OBJECTIVES: We aimed to identify predictors of all falls and recurrent falls in people with PD who had not fallen in the previous year and to explore the timing of falls in a 12-month follow-up period. METHODS: Participants with PD (n = 130) were assessed by disease specific, self-report and balance measures. Falls were recorded prospectively for 12 months. Univariate and multivariate analyses were performed. Kaplan-Meier survival analysis was used to investigate time to falling. RESULTS: Forty participants (31%) had >=1 fall during follow-up and 21 (16%) had >=2 falls. Disability, reduced balance confidence and greater concern about falling were associated with >=1 fall in univariate analyses. Additionally, PD duration and severity, freezing of gait and impaired balance were associated with >=2 falls (p < 0.05). Disability (Schwab and England scale, Odds Ratio [OR] = 0.56 per 10 points increase; 95% confidence interval [CI] 0.39-0.80; p = 0.002) was associated with >=1 fall in the final multivariate model (area under the receiver operating characteristic curve [AUC] = 0.65; 95% CI 0.55-0.76; p = 0.005). Disability (Unified Parkinson's Disease Rating Scale activities of daily living, OR = 1.20; 95% CI 1.07-1.34; p = 0.001) and levodopa equivalent dose (OR = 1.11 per 100 mg increase; 95% CI 0.95-1.30; p = 0.19) were associated with >=2 falls in the final multivariate model (AUC = 0.72; 95% CI 0.60-0.84; p = 0.001). Recurrent fallers experienced their first fall earlier than single fallers (p < 0.05). CONCLUSIONS: Self-reported disability was the strongest single predictor of all falls and recurrent falls. PMID- 26444094 TI - Anticholinergic Load: Is there a Cognitive Cost in Early Parkinson's Disease? AB - We evaluated the effect of anticholinergic burden on 219 participants with incident Parkinson's disease (PD) and 99 controls at study baseline and 18 months. Anticholinergic burden for each individual was calculated and summed according to the Anticholinergic Drug Scale (ADS). Medication with anticholinergic activity was more commonly prescribed in PD compared to controls, although mean ADS scores were not significantly different. Cognitive scores did not differ in PD participants taking medications with anticholinergic activity compared to those who were not. Low overall ADS scores due to increased awareness of adverse effects of medications and brevity of follow-up are potential explanations. PMID- 26444096 TI - Multidisciplinary Collaboration in Professional Networks for PD A Mixed-Method Analysis. AB - BACKGROUND: ParkinsonNet, a nationwide organization with regionally oriented professional health networks in TheNetherlands, aims to improve the quality of Parkinson care. Facilitation of multidisciplinary collaboration is a key objective of ParkinsonNet. OBJECTIVES: This study examined whether the concept enhances multidisciplinary collaboration between healthcare professionals involved in Parkinson care. METHODS: A regional network involving 101 healthcare professionals was newly established. Participants received two questionnaires. One aimed at documenting direct working relationships ('connections') between professionals and the other aimed at evaluating multidisciplinary team performance. Additionally, thirteen healthcare professionals were interviewed to identify barriers and facilitators for multidisciplinary collaboration. 'Social network analysis' focused on sub-networks around three community hospitals at baseline and one year after the implementation. RESULTS: The number of 'knowing each other' connections increased from 1431 to 2175 (52% , p < 0.001) and 'professional contact' connections increased from 664 to 891 (34% , p < 0.001). Large differences between sub-networks were found, positive changes being associated with a central role of neurologists and nurse specialists committed to multidisciplinary care. The perceived team performance did not change. Participants experienced problems with information exchange and interdisciplinary communication. Generally, participants were unaware of other healthcare professionals involved in individual patients and what treatments they provide simultaneously. CONCLUSIONS: ParkinsonNet partially enhanced multidisciplinary collaboration between healthcare professionals involved in Parkinson care. Crucial facilitators of this were a central role of nurse specialists and the commitment to collaborate with and refer to expert therapists among neurologists. Additional measures are needed to further improve multidisciplinary care across different institutions and around individual patients. PMID- 26444097 TI - Unravelling the Proton Conduction Mechanism from Room Temperature to 553 K in a 3D Inorganic Coordination Framework. AB - The preparation of proton-conducting materials that are functional and stable at intermediate temperatures (393-573 K) is a focal point of fuel cell development. The purely inorganic material, HNd(IO3)4, which possesses a dense 3D framework structure, can reach a maximum of 4.6 * 10(-4) S.cm(-1) at 353 K and 95% relative humidity and exhibit a high conductivity of 8.0 * 10(-5) S.cm(-1) from 373 to 553 K under the flow of wet N2. HNd(IO3)4 exhibits a variety of improvements including high thermal stability, low solubility in water, and resistance to reducing atmosphere. The proton conductivity in such a wide temperature range originates from the intrinsic liberated protons in the structure and the resulting 1D hydrogen-bonding network confirmed by bond valence sum calculation and solid-state NMR analysis. Moreover, two different activation energies are observed in different temperature regions (0.23 eV below 373 K and 0.026 eV from 373 to 553 K), indicating that two types of proton motion are responsible for proton diffusion, as further domenstrated by temperature-dependent open-circuit voltage hysteresis in a tested fuel cell assembly as well as variable-temperature and double quantum filtered solid-state NMR measurements. PMID- 26444095 TI - Peripheral Biomarkers of Parkinson's Disease Progression and Pioglitazone Effects. AB - Pioglitazone, an oral hypoglycemic agent, recently failed to show promise as a disease-modifying agent in a 44-week phase 2 placebo-controlled study in 210 Parkinson's disease (PD) subjects. We analyzed peripheral biomarkers, including leukocyte PGC-1alpha and target gene expression, plasma interleukin 6 (IL-6) as a marker of inflammation, and urine 8-hydroxydeoxyguanosine (8OHdG) as a marker of oxidative DNA damage. Baseline or changes from baseline in biomarker levels were not associated with the rate of progression of PD. Pioglitazone did not significantly alter biomarker levels. Other agents that more effectively target these mechanisms remain of potential interest as disease modifying therapies in PD. PMID- 26444098 TI - Anti-inflammatory Inositol Derivatives from the Whole Plant of Inula cappa. AB - Twelve new inositol derivatives, classified into myoinositol (1-6) and l-inositol (10-15) types, along with five known analogues were isolated from the whole plant of Inula cappa. The structures of the new compounds were established by extensive analysis of mass spectrometric and 1D and 2D NMR spectroscopic data. All the tested compounds showed anti-inflammatory activities against the production of NO in RAW264.7 macrophages stimulated by lipopolysaccharide, with IC50 values ranging from 7 to 23 MUM. PMID- 26444100 TI - Catalytic Role of Multinuclear Palladium-Oxygen Intermediates in Aerobic Oxidation Followed by Hydrogen Peroxide Disproportionation. AB - Aerobic oxidation of alcohols are catalyzed by the Pd-acetate compound [LPd(OAc)]2(OTf)2 (L = neocuproine = 2,9-dimethyl-1,10-phenanthroline) to form ketones and the release of hydrogen peroxide, but the latter rapidly undergoes disproportionation. We employ a series of kinetic and isotope labeling studies made largely possible by electrospray ionization mass spectrometry to determine the role of intermediates in causing this complex chemical transformation. The data suggested that multiple catalytic paths for H2O2 disproportionation occur, which involve formation and consumption of multinuclear Pd species. We find that the trinuclear compound [(LPd)3(MU(3)-O)2](2+), which we have identified in a previous study, is a product of dioxygen activation that is formed during aerobic oxidations of alcohols catalyzed by [LPd(OAc)]2(OTf)2. It is also a product of hydrogen peroxide activation during disproportionation reactions catalyzed by [LPd(OAc)]2(OTf)2. The results suggest that this trinuclear Pd compound is involved in one of the simultaneous mechanisms for the reduction of oxygen and/or the disproportionation of hydrogen peroxide during oxidation catalysis. Electrospray ionization mass spectrometry of hydrogen peroxide disproportionation reactions suggested the presence of other multinuclear Pd-O2 species in solution. Theoretical calculations of these compounds yield some insight into their structure and potential chemistry. PMID- 26444099 TI - Chlorabietols A-C, Phloroglucinol-Diterpene Adducts from the Chloranthaceae Plant Chloranthus oldhamii. AB - Three unprecedented phloroglucinol-diterpene adducts, chlorabietols A-C (1-3), were isolated from the roots of the rare Chloranthaceae plant Chloranthus oldhamii. They represent a new class of compounds, featuring an abietane-type diterpenoid coupled with different alkenyl phloroglucinol units by forming a 2,3 dihydrofuran ring. Their structures were elucidated by detailed spectroscopic analysis, molecular modeling studies, and electronic circular dichroism calculations. Compounds 1-3 showed inhibitory activity against protein tyrosine phosphatase 1B (PTP1B) with IC50 values of 12.6, 5.3, and 4.9 MUM, respectively. PMID- 26444101 TI - Dissociative Photoionization of Diethyl Ether. AB - The dissociative photoionization of internal energy selected diethyl ether ions was investigated by imaging photoelectron photoion coincidence spectroscopy. In a large, 5 eV energy range Et2O(+) cations decay by two parallel and three sequential dissociative photoionization channels, which can be modeled well using statistical theory. The 0 K appearance energies of the CH3CHOCH2CH3(+) (H-loss, m/z = 73) and CH3CH2O?CH2(+) (methyl-loss, m/z = 59) fragment ions were determined to be 10.419 +/- 0.015 and 10.484 +/- 0.008 eV, respectively. The reemergence of the hydrogen-loss ion above 11 eV is attributed to transition state (TS) switching, in which the second, outer TS is rate-determining at high internal energies. At 11.81 +/- 0.05 eV, a secondary fragment of the CH3CHOCH2CH3(+) (m/z = 73) ion, protonated acetaldehyde, CH3CH?OH(+) (m/z = 45) appears. On the basis of the known thermochemical onset of this fragment, a reverse barrier of 325 meV was found. Two more sequential dissociation reactions were examined, namely, ethylene and formaldehyde losses from the methyl-loss daughter ion. The 0 K appearance energies of 11.85 +/- 0.07 and 12.20 +/- 0.08 eV, respectively, indicate no reverse barrier in these processes. The statistical model of the dissociative photoionization can also be used to predict the fractional ion abundances in threshold photoionization at large temperatures, which could be of use in, for example, combustion diagnostics. PMID- 26444102 TI - Tuning Phase Composition of TiO2 by Sn(4+) Doping for Efficient Photocatalytic Hydrogen Generation. AB - The anatase-rutile mixed-phase photocatalysts have attracted extensive research interest because of the superior activity compared to their single phase counterparts. In this study, doping of Sn(4+) ions into the lattice of TiO2 facilitates the phase transformation from anatase to rutile at a lower temperature while maintaining the same crystal sizes compared to the conventional annealling approach. The mass ratios between anatase and rutile phases can be easily manipulated by varying the Sn-dopant content. Characterization results reveal that the Sn(4+) ions entered into the lattice of TiO2 by substituting some of the Ti(4+) ions and distributed evenly in the matrix of TiO2. The substitution induced the distortion of the lattice structure, which realized the phase transformation from anatase to rutile at a lower temperature and the close contact phase junctions were consequently formed between anatase and rutile, accounting for the efficient charge separations. The mixed-phase catalysts prepared by doping Sn(4+) ions into the TiO2 exhibit superior activity for photocatalytic hydrogen generation in the presence of Au nanoparticles, relatively to their counterparts prepared by the conventional annealling at higher temperatures. The band allignment between anatase and rutile phases is established based on the valence band X-ray photoelectron spectra and diffuse reflectance spectra to understand the spatial charge separation process at the heterojunction between the two phases. The study provides a new route for the synthesis of mixed-phase TiO2 catalysts for photocatalytic applications and advances the understanding on the enhanced photocatalytic properties of anatase rutile mixtures. PMID- 26444103 TI - Use of Immunomodulators and Biologics Before, During, and After Pregnancy. AB - Immunomodulators and biologic medications, alone or in combination, form the core therapeutic strategy for managing moderate-to-severe inflammatory bowel disease (IBD). IBD incidence peaks during the prime reproductive years, raising concerns about the impact of disease and its treatment on fertility, maternal and fetal health during pregnancy, breastfeeding safety, and childhood development. Although IBD increases risk of pregnancy complications independent of disease activity, adverse pregnancy outcomes are more common when disease is active. To mitigate fetal risk, women should conceive while disease is quiescent. Aside from methotrexate, immunomodulators and biologics may be used during pregnancy to achieve and maintain disease control. Based on available safety data, there is no increased risk of congenital anomalies among infants exposed to these medications. Active thiopurine metabolites and most monoclonal antibodies cross the placenta and are detectable in neonates. They are detectable in breast milk in minute levels as well. The impact of this exposure on neonatal outcomes is discussed. Adjusted dosing schedules during gestation may reduce fetal drug exposure, though the maternal risks of such manipulation require careful consideration. Ongoing prospective studies will further inform risk assessment, including for newer medications such as the anti-integrin agents. PMID- 26444104 TI - Genome-based Definition of an Inflammatory Bowel Disease-associated Adherent Invasive Escherichia coli Pathovar. AB - BACKGROUND: Mucosal-associated Escherichia coli are commonly found in inflamed tissues during inflammatory bowel disease (IBD). These bacteria often possess an adherent and invasive phenotype but lack virulence-associated features of well described intestinal E. coli pathogens, and are of diverse serology and phylotypes, making it difficult to correlate strain characteristics with exacerbations of disease. METHODS: The genome sequences of 14 phenotypically assigned adherent-invasive Escherichia coli (AIEC) isolates obtained from intestinal biopsies of patients with IBD were compared with the genome sequences of 37 other pathogenic and commensal E. coli available from public databases. RESULTS: Core genome-based phylogenetic analyses and genome-wide comparison of genetic content established the existence of a closely related cluster of AIEC strains with 3 distinct genetic insertions differentiating them from commensal E. coli. These strains are of the B2 phylotype have a variant type VI secretion system (T6SS-1), and are highly related to extraintestinal pathogenic E. coli, suggesting that these 2 clinically distinct pathovars have common virulence strategies. Four other mucosally adherent E. coli strains from patients with IBD were of diverse phylogenetic origins and lacked the 3 genetic features, suggesting that they are not related to the B2 AIEC cluster. Although AIEC are often considered as having a unique association with Crohn's disease, isolates from Crohn's disease and ulcerative colitis were genetically indistinguishable. CONCLUSIONS: B2 AIEC thus represent a closely related cluster of IBD-associated E. coli strains that are distinct from normal commensal isolates, and which should be considered separately from the phenotypically similar but genetically distinct non-B2 AIEC strains when considering their association with intestinal pathogenesis. PMID- 26444105 TI - Rapid Stereocomplexation between Enantiomeric Comb-Shaped Cellulose-g-poly(L lactide) Nanohybrids and Poly(D-lactide) from the Melt. AB - In this work we report the in situ preparation of fully biobased stereocomplex poly(lactide) (SC-PLA) nanocomposites grafted onto nanocrystalline cellulose (NCC). The stereocomplexation rate by compounding high-molar-mass poly(D-lactide) (PDLA) with comb-like NCC grafted poly(L-lactide) is rather high in comparison with mixtures of PDLA and PLLA. The rapid stereocomplexation was evidenced by a high stereocomplexation temperature (Tc-sc = 145 degrees C) and a high SC crystallinity (Xc-sc = 38%) upon fast cooling (50 degrees C/min) from the melt (250 degrees C for 2 min), which are higher than currently reported values. Moreover, the half-life crystallization time (175-190 degrees C) of the SC-PLA was shortened by 84-92% in comparison with the PDLA/PLLA blends. The high(er) stereocomplexation rate and the melt stability of the SC in the nanocomposites were ascribed to the nucleation effect of the chemically bonded NCC and the "memory effect" of molecular pairs in the stereocomplex melt because of the confined freedom of the grafted PLLA chains. PMID- 26444106 TI - Maternal Influenza Vaccination and Risk for Congenital Malformations: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To systematically summarize the literature on maternal influenza vaccination and the risk for congenital malformations using the methodology of meta-analysis. DATA SOURCES: PubMed, Scopus, and Embase databases (up to December 2014) as well as ClinicalTrials.gov (May 2015) and references of relevant articles were searched. The search strategy included combinations of the terms "influenza," "vaccin*," "pregnan*," "safe*," "adverse," "congenital," "malformation," "defect," and "anomal*." METHODS OF STUDY SELECTION: Eligible studies examined the association between antepartum or preconceptional maternal immunization with inactivated influenza vaccines (seasonal trivalent or monovalent H1N1) and the risk for congenital malformations. Studies with no or inappropriate control group (comparison with population background rates or other vaccine types) were excluded. TABULATION, INTEGRATION, AND RESULTS: The risk for congenital anomalies after influenza vaccination was examined in 15 studies: 14 cohorts (events per vaccinated compared with unvaccinated: 859/32,774 [2.6%] compared with 7,644/245,314 [3.1%]) and one case-control study (vaccinated per cases compared with controls: 1,351/3,618 [37.3%] compared with 511/1,225 [41.7%]). Eight studies reported on first-trimester immunization (events per vaccinated compared with unvaccinated: 258/4,733 [5.4%] compared with 6,470/196,054 [3.3%]). No association was found between congenital defects and influenza vaccination at any trimester of pregnancy (odds ratio [OR] 0.96, 95% confidence interval 0.86-1.07; 15 studies; I2=36) or at the first trimester (OR 1.03, 0.91-1.18; eight studies; I2=0). When assessing only major malformations, no increased risk was detected after immunization at any trimester (OR 0.99, 0.88 1.11; 12 studies; I2=31.5) or at the first trimester (OR 0.98, 0.83-1.16; seven studies; I2=0). Neither adjuvanted (OR 1.06, 0.95-1.20; five studies; I2=18.8) nor unadjuvanted vaccines (OR 0.89, 0.75-1.04; seven studies; I2=22.6) were associated with an increased risk for congenital defects. CONCLUSION: This systematic review did not indicate an increased risk for congenital anomalies after maternal influenza immunization adding to the evidence base on the safety of influenza vaccination in pregnancy. PMID- 26444108 TI - Current Status of Testing for Microdeletion Syndromes and Rare Autosomal Trisomies Using Cell-Free DNA Technology. AB - Noninvasive prenatal testing using cell-free DNA in maternal blood for trisomy 21 was introduced in 2011. This technology has continuously evolved with the addition of screening for trisomy 18 and trisomy 13 followed by the inclusion of sex chromosome aneuploidies. Expanded noninvasive prenatal test panels have recently become available, which enable screening for microdeletion syndromes such as the 22q11.2 deletion (associated with the velocardiofacial syndrome) and others. However, the performance data for these microdeletion syndromes are derived from a small number of samples, mostly generated in vitro. Rigorous performance evaluation, as was done at least for trisomy 21 testing using cell free DNA analysis, is difficult to perform given the rarity of each condition. In addition, detection rates may vary considerably depending on deletion size. Importantly, positive predictive values (PPVs), strongly influenced by the low prevalence, are expected to be significantly lower than 10% for most conditions. Thus, screening in an average-risk population is likely to have many more false positives than affected cases detected. Conversely, testing in a high-risk population such as fetuses with cardiac anomalies may have higher PPVs, but a negative result needs to be considered carefully as a result of uncertain information about detection rates and a significant residual risk for other copy number variants and single gene disorders. This article integrates current knowledge on cell-free DNA testing for microdeletions with the aim to assist clinicians and policymakers in designing optimal programs for screening in pregnancy. PMID- 26444107 TI - Predicting Cesarean Delivery After Induction of Labor Among Nulliparous Women at Term. AB - OBJECTIVE: To identify independent risk factors for cesarean delivery after induction of labor and to develop a nomogram for predicting cesarean delivery among nulliparous women undergoing induction of labor at term. METHODS: This is a retrospective cohort study including nulliparous women with singleton, term (37 0/7 weeks of gestation or greater), cephalic pregnancies undergoing induction of labor from July 1, 2006, through May 31, 2012, at a tertiary care academic center. Inductions were identified using International Classification of Diseases, 9th Revision codes. Demographic, delivery, and outcome data were abstracted manually from the medical record. Women with a contraindication to vaginal delivery (malpresentation, abnormal placentation, prior myomectomy) were excluded. Independent risk factors for cesarean delivery were identified using logistic regression. RESULTS: During the study period, there were 785 nulliparous inductions that met study criteria; 231 (29.4%) underwent cesarean delivery. Independent risk factors associated with an increased risk of cesarean delivery included older maternal age, shorter maternal height, greater body mass index, greater weight gain during pregnancy, older gestational age, hypertension, diabetes mellitus, and initial cervical dilation less than 3 cm. A nomogram was constructed based on the final model with a bias-corrected c-index of 0.709 (95% confidence interval 0.671-0.750). CONCLUSION: We identified independent risk factors that can be used to predict cesarean delivery among nulliparous women undergoing induction of labor at term. If validated in other populations, the nomogram could be useful for individualized counseling of women with a combination of identifiable antepartum risk factors. LEVEL OF EVIDENCE: II. PMID- 26444109 TI - Safety of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis and Influenza Vaccinations in Pregnancy. AB - OBJECTIVE: To evaluate the safety of coadministering tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) and influenza vaccines during pregnancy by comparing adverse events after concomitant and sequential vaccination. METHODS: We conducted a retrospective cohort study of pregnant women aged 14-49 years in the Vaccine Safety Datalink from January 1, 2007, to November 15, 2013. We compared medically attended acute events (fever, any acute reaction) and adverse birth outcomes (preterm delivery, low birth weight, small for gestational age) in women receiving concomitant Tdap and influenza vaccination and women receiving sequential vaccination. RESULTS: Among 36,844 pregnancies in which Tdap and influenza vaccines were administered, the vaccines were administered concomitantly in 8,464 (23%) pregnancies and sequentially in 28,380 (77%) pregnancies. Acute adverse events after vaccination were rare. We found no statistically significant increased risk of fever or any medically attended acute adverse event in pregnant women vaccinated concomitantly compared with sequentially. When analyzing women at 20 weeks of gestation or greater during periods of influenza vaccine administration, there were no differences in preterm delivery, low-birth-weight, or small-for-gestational-age neonates between women vaccinated concomitantly compared with sequentially in pregnancy. CONCLUSION: Concomitant administration of Tdap and influenza vaccines during pregnancy was not associated with a higher risk of medically attended adverse acute outcomes or birth outcomes compared with sequential vaccination. LEVEL OF EVIDENCE: II. PMID- 26444110 TI - Changes in Use of Long-Acting Reversible Contraceptive Methods Among U.S. Women, 2009-2012. AB - OBJECTIVE: To examine current levels, current correlates of, and changes in long acting reversible contraceptive (LARC) use, including intrauterine devices and implants, among females aged 15-44 years using contraception between 2008-2010 and 2011-2013 with specific attention to associations between race, income, and age and their LARC use. METHODS: We analyzed data from two rounds of the National Survey of Family Growth, nationally representative samples of females aged 15-44 years, consisting of 6,428 females in 2008-2010 and 5,601 females in 2011-2013. We conducted simple and multivariable logistic regression analyses with adjustments for the sampling design to identify demographic characteristics predictive of LARC use and changes in these patterns between the two time periods. In this cross-sectional, descriptive study, our primary outcome of interest was current prevalence of LARC use among all contraceptive users at the time of the interview. RESULTS: The prevalence of LARC use among contracepting U.S. females increased from 8.5% in 2009 to 11.6% in 2012 (P<.01). The most significant increases occurred among Hispanic females (from 8.5% to 15.1%), those with private insurance (7.1-11.1%), those with fewer than two sexual partners in the previous year (9.2-12.4%), and those who were nulliparous (2.1-5.9%) (all P<.01). In multivariable analyses adjusting for key demographic characteristics, the strongest associations with LARC use in 2012 were parity (adjusted odds ratios [ORs] 4.3-5.5) and having a history of stopping non-LARC hormonal use (adjusted OR 1.9). Women aged 35-44 years (adjusted OR 0.3) were less likely to be LARC users than their counterparts (all P<.001). Poverty status was not associated with LARC use. There were no differences in discontinuation of LARC methods resulting from dissatisfaction between minority women and non-Hispanic white women. CONCLUSION: During the most recent time period surveyed, use of LARC methods, particularly intrauterine devices, increased almost uniformly across the population of users. LEVEL OF EVIDENCE: III. PMID- 26444111 TI - Prior Ultrasound-Indicated Cerclage: Comparison of Cervical Length Screening or History-Indicated Cerclage in the Next Pregnancy. AB - OBJECTIVE: To evaluate outcomes of women with prior ultrasound-indicated cerclage, who in their subsequent pregnancy were either followed by transvaginal ultrasound cervical length screening or received a planned history-indicated cerclage. METHODS: Multicenter cohort study of singleton gestations with a prior ultrasound-indicated cerclage performed from 1994 to 2014. We evaluated three pregnancies in the study participants: first pregnancy with prior spontaneous preterm birth at less than 37 weeks of gestation; second pregnancy with ultrasound-indicated cerclage for cervical length 25 mm or less; and the third index pregnancy managed with either transvaginal ultrasound cervical length screening with ultrasound-indicated cerclage for cervical length 25 mm or less or planned history-indicated cerclage. The primary outcome was incidence of spontaneous preterm birth at less than 37 weeks of gestation. We planned a subgroup analysis for women who delivered at less than 32 weeks of gestation compared with 32 weeks of gestation or greater in their prior ultrasound indicated cerclage pregnancy. RESULTS: Of 102 singleton gestations included, 38 (37.3%) were followed with transvaginal ultrasound cervical length screening and 64 (62.7%) underwent history-indicated cerclage. Of 38 women in the transvaginal ultrasound group, 18 (47.4%) underwent ultrasound-indicated cerclage for cervical length 25 mm or less. After adjusting for confounders, the rate of spontaneous preterm birth at less than 37 weeks of gestation was similar between transvaginal ultrasound cervical length screening and history-indicated cerclage groups (36.8% compared with 43.8%; adjusted odds ratio 0.77, 95% confidence interval 0.47 1.45). Secondary outcomes were also similar in both groups. All women (n=7) who delivered at less than 32 weeks of gestation in their prior pregnancy and subsequently had transvaginal ultrasound screening received ultrasound-indicated cerclage in the index pregnancy compared with only 35.5% of women who delivered at 32 weeks of gestation or greater in their prior pregnancy. CONCLUSION: Women with prior ultrasound-indicated cerclage have similar outcomes if they receive either transvaginal ultrasound cervical length screening with ultrasound indicated cerclage for cervical length 25 mm or less or planned history-indicated cerclage in the subsequent pregnancy. Less than 50% of the transvaginal ultrasound cervical length screening group require a repeat ultrasound-indicated cerclage in the subsequent pregnancy. LEVEL OF EVIDENCE: II. PMID- 26444112 TI - Health Care Disparities in Hysterectomy for Gynecologic Cancers: Data From the 2012 National Inpatient Sample. AB - OBJECTIVE: To examine hysterectomies in the United States performed for gynecologic malignancies and identify factors associated with the use of minimally invasive techniques. METHODS: This is a cross-sectional analysis of the 2012 National Inpatient Sample, the largest national all-payer database of hospital discharges. International Classification of Diseases, 9th Revision, Clinical Modification codes for any type of hysterectomy performed for gynecologic malignancy were used to abstract pertinent observations. Weighted multivariable logistic regression models were used to examine the associations between demographic and clinical factors and mode of hysterectomy by cancer diagnosis. RESULTS: In 2012, there were an estimated 46,450 hysterectomies for gynecologic malignancy in the United States. Of these, 28,285 (61%) were performed for uterine, 4,275 (9%) for cervical, 12,370 (27%) for ovarian cancer, and 1,520 (3%) for other gynecologic malignancies. Minimally invasive hysterectomy was used in 50% of uterine, 43% of cervical, and 8.5% of ovarian cancer cases. Black women had decreased odds of undergoing minimally invasive hysterectomy for uterine (adjusted odds ratio [OR] 0.50, 95% confidence interval [CI] 0.40-0.0.63, P<.001) and cervical (adjusted OR 0.56, 95% CI 0.33-0.96, P=.03) cancers. Those without insurance or with Medicaid had decreased odds of undergoing minimally invasive hysterectomy (P<.001) for uterine cancer. As compared with the Northeast, patients in the South (adjusted OR 0.72, 95% CI 0.53 0.98, P=.04) were less likely to undergo minimally invasive hysterectomy for uterine cancer, whereas those in the West more likely (adjusted OR 1.48, 95% CI 1.10-1.99, P=.009). CONCLUSION: Minimally invasive hysterectomy for gynecologic malignancies remained underused in 2012; there were striking racial disparities associated with use of minimally invasive hysterectomy for uterine and cervical cancers. LEVEL OF EVIDENCE: III. PMID- 26444113 TI - Heterogeneity in Blood Product Acceptance Among Antenatal Patients of the Jehovah's Witness Faith. AB - OBJECTIVE: To understand the antepartum attitudes toward blood product transfusion among members of the Jehovah's Witness faith. METHODS: We performed a retrospective study using antenatal consultation notes of Jehovah's Witness patients from the bloodless medicine program at a regional tertiary care maternity hospital over a 4-year period to determine their blood transfusion preferences. RESULTS: Eighty-seven consultations were performed. The median age of women undergoing consultation was 27 years (range 14-39 years), and most were either African American (48/87 [55.2%]; 95% confidence interval [CI] 44.8-65.7) or Caucasian (35/87 [40.2%]; 95% CI 29.9-50.5). The mean+/-standard deviation antenatal hemoglobin concentration was 11.9+/-1.4 g/dL (n=57). Although all 87 women stated that they would not accept conventional blood products such as red blood cells, plasma, or platelets, 55 of 87 (63.2%; 95% CI 53.1-73.3) stated that they would accept all of the recombinant or fractionated blood products including cryoprecipitate. Stated acceptance of fractionated or recombinant products did not vary by parity, race, or age. A further 23 of 87 (26.4%; 95% CI 17.1-35.7) women stated they would accept some but not all of the fractionated or recombinant blood products, whereas 9 of 87 (10.3%; 95% CI 3.9-16.7) stated they would not accept any of these products. CONCLUSION: In the antenatal period, Jehovah's Witness women have variable attitudes toward receipt of blood products. A discussion with each patient is essential to understand whether and which blood products may be used when indicated. PMID- 26444114 TI - A Proactive Approach to Neonates Born at 23 Weeks of Gestation. AB - OBJECTIVE: To evaluate in-hospital survival, survival without major morbidity, and neurodevelopmental impairment for neonates born at 23 weeks of gestation provided proactive, coordinated, and comprehensive perinatal and neonatal management. METHODS: This was a retrospective cohort study conducted at a single, tertiary care center between 2004 and 2013. Enrollment was limited to mother neonate dyads at 23 weeks of gestation who were provided a proactive approach defined as documented evidence of antenatal corticosteroid administration, willingness to provide cesarean delivery for fetal distress, and neonatal resuscitation and intensive care. Among survivors, major morbidities (predischarge) and neurodevelopmental assessments at corrected ages of 18-22 months were examined. RESULTS: Among 152 live births identified, 101 neonates received proactive care, of whom 60 (59%) survived to hospital discharge. Preterm premature rupture of membranes (adjusted odds ratio [OR] 0.29, 95% confidence interval [CI] 0.09-0.94), fetal growth restriction (OR 0.16, 95% CI 0.03-0.89), delivery room cardiopulmonary resuscitation (OR 0.07, 95% CI 0.02-0.32), and prolonged intubation sequence (OR 0.15, 95% CI 0.05-0.45) were associated with lower neonatal survival. Among neonatal intensive care unit survivors, 62% had at least one major morbidity. Among 50 survivors with assessment at 18-22 months, six (12%) were unimpaired, 20 (40%) had mild impairment, and 24 (48%) had moderate or severe neurodevelopmental impairment. CONCLUSION: Proactive, interdisciplinary care enabled more than half of the neonates born at 23 weeks of gestation to survive, and approximately half of children evaluated at 18 months exhibited no or mild impairment. This information should be considered when providing prognostic advice to families with threatened preterm birth at 23 weeks of gestation. LEVEL OF EVIDENCE: II. PMID- 26444115 TI - Tocolysis for Women With Early Spontaneous Preterm Labor and Advanced Cervical Dilation. AB - OBJECTIVE: To characterize tocolytic use and examine perinatal outcomes among women presenting very preterm with spontaneous labor and cervical dilation 4 cm or greater. METHODS: This was a retrospective cohort study. Data from January 2000 to June 2011 in a single health care system were reviewed. Women with singleton, nonanomalous fetuses and preterm labor with intact membranes between 23 and 32 weeks of gestation who had cervical dilation 4 cm or greater and less than 8 cm at admission were included. Women receiving one or more tocolytics (magnesium sulfate, indomethacin, or nifedipine) were compared with those who did not receive tocolysis. The primary outcome was composite major neonatal morbidity. RESULTS: Two hundred ninety-seven women were included; 233 (78.5%) received at least one tocolytic. Women receiving tocolysis were slightly less dilated (median 5 compared with 6 cm, P<.001) at presentation and were more likely to receive at least a partial course of corticosteroids (88.4% compared with 56.3%, P<.001). Initial composite severe neonatal morbidity rates were similar (41.6% compared with 43.8%, P=.761) regardless of tocolytic administration. Those receiving tocolysis were significantly more likely to be pregnant at least 48 hours after admission (23.6% compared with 7.8%, P=.005), but a similar proportion delivered within 7 days of admission (94.8% compared with 95.3%, P>.99), and delivery gestational ages were similar (28.9 compared with 29.2 weeks, P=.408). The incidence of chorioamnionitis and postpartum endometritis was similar between groups. CONCLUSION: The majority of women presenting very preterm with advanced cervical dilation received tocolysis. Although tocolysis administration increased the likelihood of achieving at least 48 hours of latency, initial neonatal outcomes were similar. LEVEL OF EVIDENCE: II. PMID- 26444116 TI - The Relationship Between Intertwin Membrane Separation and Pregnancy Outcome. AB - OBJECTIVE: To evaluate the association of intertwin membrane separation and pregnancy outcome. METHODS: This is a retrospective cohort study of women with dichorionic twins who were diagnosed with spontaneous intertwin membrane separation between 2004 and 2013 at a large tertiary care maternity hospital. Control participants were selected as the next two sets of dichorionic twins that delivered at the study institution after a case participant delivered and that did not have an intrauterine procedure. Maternal, fetal, and delivery characteristics were compared using Wilcoxon rank-sum tests. Logistic regressions were used to assess the association of membrane separation and preterm delivery. RESULTS: Among the 27 cases of spontaneous intertwin membrane separation, the median gestational age at diagnosis was 28 weeks (interquartile range 25.5-28.8) and the median gestational age at delivery was 37 weeks (interquartile range 35.3 37.0). The rate of preterm delivery, our primary outcome, was 48% for the case group and 76% for the control group (odds ratio [OR] 0.29, P=.01). The rate of spontaneous preterm delivery was also lower for the case group (19% compared with 44%; OR 0.25, P=.26) as was the rate of neonatal intensive care unit admission (37% compared with 61%; OR 0.37, P=.04). CONCLUSION: Our retrospective cohort study demonstrates that intertwin membrane separation is not associated with adverse outcomes in dichorionic twin pregnancies. Thus, it is reasonable to manage these pregnancies expectantly. LEVEL OF EVIDENCE: II. PMID- 26444117 TI - Cross-Cultural Obstetric and Gynecologic Care of Muslim Patients. AB - With the growing number of Muslim patients in the United States, there is a greater need for obstetrician-gynecologists (ob-gyns) to understand the health care needs and values of this population to optimize patient rapport, provide high-quality reproductive care, and minimize health care disparities. The few studies that have explored Muslim women's health needs in the United States show that among the barriers Muslim women face in accessing health care services is the failure of health care providers to understand and accommodate their beliefs and customs. This article outlines health care practices and cultural competency tools relevant to modern obstetric and gynecologic care of Muslim patients, incorporating emerging data. There is an exploration of the diversity of opinion, practice, and cultural traditions among Muslims, which can be challenging for the ob-gyn who seeks to provide culturally competent care while attempting to avoid relying on cultural or religious stereotypes. This commentary also focuses on issues that might arise in the obstetric and gynecologic care of Muslim women, including the patient-physician relationship, modesty and interactions with male health care providers, sexual health, contraception, abortion, infertility, and intrapartum and postpartum care. Understanding the health care needs and values of Muslims in the United States may give physicians the tools necessary to better deliver high-quality care to this minority population. PMID- 26444118 TI - Physician Needs Help Stat in Room 3. PMID- 26444119 TI - Beyond Coercion: Let Us Grapple With Bias. PMID- 26444120 TI - Connect the Dots.... PMID- 26444121 TI - What Is New in Pelvic Organ Prolapse?: Best Articles From the Past Year. AB - This month we focus on current research in pelvic organ prolapse. Dr. Kenton discusses five recent publications, which are concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 26444122 TI - Disseminated Intravascular Coagulation Syndromes in Obstetrics. AB - Disseminated intravascular coagulation (DIC) is a syndrome that can be initiated by a myriad of medical, surgical, and obstetric disorders. Also known as consumptive coagulopathy, DIC is a common contributor to maternal morbidity and mortality and is associated with up to 25% of maternal deaths. The etiopathogenesis of DIC is complex and currently thought to be initiated by tissue factor or thromboplastin, which is released from trophoblastic or fetal tissue, or maternal decidua or endothelium. Tissue factor activates the coagulation sequence to cause fibrin clotting and its dissolution by the fibrinolysin system. The result of this process can range from mild, clinically insignificant laboratory derangements to marked coagulopathy with bleeding at sites of minimal trauma. Although clinical recognition varies by disease severity, several organizations have attempted to standardize the diagnosis through development of scoring systems. Several important--albeit not necessarily common--obstetric disorders associated with DIC include placental abruption, amniotic fluid embolism, sepsis syndrome, and acute fatty liver of pregnancy. More common disorders include severe preeclampsia, hemolysis, elevated liver enzymes, and low platelet count syndrome, and massive obstetric hemorrhage. Importantly, many of these disorders either cause or are associated with substantive obstetric hemorrhage. Treatment of DIC is centered on two principles. The first is identification and treatment of the underlying disorder. Because many women with consumptive coagulopathy also have massive hemorrhage, the second tenet of treatment is that obstetric complications such as uterine atony or lacerations must be controlled simultaneously with prompt blood and component replacement for a salutary outcome. PMID- 26444124 TI - Removal of a Nonpalpable Etonogestrel Implant With Preprocedure Ultrasonography and Modified Vasectomy Clamp. AB - BACKGROUND: Deep etonogestrel contraceptive implant placements still occur despite design modifications to the implant inserter. We present a method for outpatient removal of a nonpalpable etonogestrel implant using preprocedure ultrasonography for implant localization followed by removal with a modified vasectomy clamp, a modification of the "U" technique for six-capsule levonorgestrel implant removal. TECHNIQUE: In women with a nonpalpable etonogestrel implant containing barium sulfate, we obtain a radiographic examination to confirm the implant's presence in the upper extremity. Using an 18 MHz linear ultrasound transducer, we identify and mark the implant location on the patient's arm, noting the depth. We remove the implant with local anesthesia in the office using a modified vasectomy clamp through a 5-mm or less skin incision directly over the implant. EXPERIENCE: All three patients referred to our office with nonpalpable etonogestrel implants had successful removal using this technique. CONCLUSION: Nonpalpable contraceptive implants can be removed in the office using a modified vasectomy clamp after localization with high frequency ultrasonography. Given the relative infrequency of nonpalpable implant removals, regional expert sites with health care providers experienced in difficult removals should be created for patient referrals. PMID- 26444123 TI - Pregnancy Outcomes Among Obese Women and Their Offspring by Attempted Mode of Delivery. AB - OBJECTIVE: To compare maternal and neonatal morbidities among obese women and their offspring by attempted delivery approach. METHODS: We performed a retrospective cohort study of 47,372 obese women at delivery (body mass index 30 or greater) eligible for vaginal delivery who were carrying singleton vertex fetuses at 37 weeks of gestation or greater. Prior cesarean delivery, congenital anomalies, and antepartum stillbirth were exclusion criteria. We analyzed outcomes by attempted delivery route and stratified by parity. The composite maternal outcome included intensive care admission, death, hemorrhage, transfusion, or thromboembolism. The neonatal composite included intensive care unit admission, death, seizure, ventilator use, birth injury, or asphyxia. Adjusted relative risks (RRs) and 95% confidence intervals (CIs) were calculated using Poisson regression. RESULTS: Among nulliparous women attempting vaginal delivery (n=15,268), the success rate was 72.6% and among parous women (n=23,426), it was 93.7%. The maternal composite outcome rate was not statistically higher among nulliparous women (7.7% compared with 4.2% [adjusted RR 1.58, 95% CI 0.96-2.59]) but it was among parous women (7.6% compared with 2.5% [adjusted RR 2.45, 95% CI 1.23-4.90]) attempting vaginal delivery related to hemorrhage, blood transfusion, or both. In contrast, the neonatal composite outcome rate was lower in parous women (6.0% compared with 11.6% [adjusted RR 0.65, 95% CI 0.51-0.83]) but not in nulliparous women (10.2% compared with 12.4% [adjusted RR 0.91, 95% CI 0.74-1.12]) parous. CONCLUSION: In obese nulliparous women, attempted vaginal delivery was not associated with increased composite maternal or neonatal morbidity. In obese parous women, attempted vaginal delivery was associated with increased composite maternal morbidity and lower composite neonatal morbidity. LEVEL OF EVIDENCE: II. PMID- 26444125 TI - Short-Term and Long-Term Postnatal Outcomes of Expectant Management After Previable Preterm Premature Rupture of Membranes With and Without Persistent Oligohydramnios. AB - OBJECTIVE: To compare postnatal outcomes in pregnancies managed expectantly after previable preterm premature rupture of membranes (PROM) in relation to amniotic fluid volume. METHODS: A retrospective cohort study was performed in 92 women with amniotic fluid leakage for more than a week after previable preterm PROM (gestational age 14 1/7-24 0/7 weeks) who delivered a liveborn neonate at or after 24 1/7 weeks of gestation from 2002 to 2014. Short-term (sepsis, intracerebral hemorrhage, retinopathy of prematurity, respiratory distress syndrome, bronchopulmonary dysplasia) and long-term (cerebral palsy and developmental delay) outcomes were compared between women with (n=58) and without persistent oligohydramnios (n=34), defined as maximal vertical pocket less than 2 cm or amniotic fluid index less than 5 cm. We analyzed discrete data using the chi2 or Fisher's exact test and continuous variables using Student's t test or Mann-Whitney U test. We also performed multivariable analyses. RESULTS: There was a significant difference in survival rate at discharge (44/58 [75.9%] compared with 34/34 [100%], P=.001) and developmental delay at a median age of 4 years after performing multiple regression analysis (adjusted odds ratio [OR] 70.3, 95% confidence interval [CI] 2.9-1,719.9, P=.009) between participants with persistent oligohydramnios and participants with normal amniotic fluid volume. A multiple regression analysis, performed to control for confounders, revealed that gestational age at delivery (adjusted OR 0.3, 95% CI 0.1-0.7, P=.008) and breech presentation (adjusted OR 90.8, 95% CI 2.2-3,778.1, P=.018) were significant factors affecting survival of children with persistent oligohydramnios. CONCLUSION: The postnatal survival rate after previable preterm PROM was lower and developmental delay more frequent in participants with persistent oligohydramnios than in participants with normal amniotic fluid volume. Even so, most neonates born alive after previable preterm PROM and persistent oligohydramnios survived to discharge and were developmentally normal. The overall survival rate was higher than in previous studies. LEVEL OF EVIDENCE: II. PMID- 26444126 TI - Racial and Ethnic Disparities in Hospital Readmissions After Delivery. AB - OBJECTIVE: To examine 30-day readmission rates after vaginal and cesarean delivery by race-ethnicity and insurance status. METHODS: We analyzed hospital discharge data contained in a statewide database maintained by the Connecticut Department of Public Health. Discharge data for patients admitted for vaginal delivery without complication (n=167,857) and cesarean delivery without complication (n=75,552) from 2005 to 2012 were analyzed using marginal logistic models for clustered data with generalized estimating equations. RESULTS: Results from logistic models indicated that 30-day readmission rates per 1,000 patients were significantly higher among black (28.9/1,000; confidence interval [CI] 25.5 32.7) and Hispanic women (21.4/1,000; CI 18.9-24.2) than among white women (12.9/1,000; CI 11.9-14.0) after cesarean delivery. Similarly higher rates of readmission were observed for black (14.6/1,000; CI 13.0-16.5) and Hispanic women (10.7/1,000; CI 9.6-12.0) relative to white women (7.5/1,000; CI 7.0-8.1) after vaginal delivery. Rates of 30-day readmission were significantly higher (odds ratio 1.27-1.30) among those covered by Medicaid. Controlling for patient socioeconomic status, comorbidities, and payer did not substantially reduce race and ethic differences in the odds of readmission. CONCLUSION: Significant racial and ethnic disparities in readmissions were observed for procedures related to childbirth using a statewide database capturing all payers across all acute care hospital settings. Compared with white women, black women were twice as likely and Hispanic women 40-50% more likely to be readmitted within 30 days of vaginal or cesarean delivery. LEVEL OF EVIDENCE: II. PMID- 26444127 TI - Intrauterine Contraception Among Women Living With Human Immunodeficiency Virus: A Randomized Controlled Trial. AB - OBJECTIVE: To compare discontinuation rates of the levonorgestrel and copper intrauterine devices (IUDs) among women with human immunodeficiency virus. METHODS: A double-masked randomized trial was conducted at Mulago Hospital, Uganda. Women received either a copper or levonorgestrel IUD. The primary outcome was discontinuation of intrauterine contraception within 1 year of placement. The secondary outcomes were incidence of side effects and severe adverse events. To discern a difference of 10% from a copper IUD discontinuation rate of 18%, power of 80%, and 95% confidence interval (CI), a sample size of 351 per arm was estimated. Analysis of the primary outcome was by intension-to-treat principle. RESULTS: From September 2013 to December 2014, 979 were screened and 703 randomized as follows: 349 to the copper group and 354 to the levonorgestrel group. In total, 8.6% (29/338) women in the copper group compared with 8.1% (27/334) in the levonorgestrel group discontinued intrauterine conception within 1 year of placement (incidence rate ratio 1.1 [95% CI 0.64-1.96]). Overall, the incidence of heavy bleeding was higher in the copper group (37% [125/338]) than in the levonorgestrel group (19.5% [65/334]). However, the incidence of amenorrhea, which occurred in 3.3% (11/338) of women, was lower in the copper group than the 19.8% (66/334) of women who reported amenorrhea in the levonorgestrel group. CONCLUSION: There was no difference in discontinuation rates between the copper and levonorgestrel devices. Women in the levonorgestrel group had reduced incidence of heavy bleeding and a higher incidence of amenorrhea compared with those in the copper group. CLINICAL TRIAL REGISTRATION: Pan African Clinical Trial Registry, www.pactr.org, PACTR 201308000561212. LEVEL OF EVIDENCE: I. PMID- 26444128 TI - Precesarean Prophylactic Balloon Catheters for Suspected Placenta Accreta: A Randomized Controlled Trial. AB - OBJECTIVE: To examine the effect of prophylactic balloon catheters on bleeding morbidity among women with a prenatal diagnosis of placenta accreta. METHODS: In a randomized trial, women with a prenatal diagnosis of placenta accreta were randomized to either preoperative prophylactic balloon catheters (intervention group) or to a control group. Other than placement of the prophylactic balloon catheters in the anterior division of the internal iliac arteries, the same multidisciplinary approach was used in both groups. The primary study outcome was the number of packed red blood cell (RBC) units transfused. To detect a mean reduction of three packed RBC units with the prophylactic balloon catheters, 12 women in each group were needed. RESULTS: Between January 2009 and March 2015, 27 women were randomized: 13 in the intervention group and 14 in the control group. Demographic and obstetric characteristics were similar between the groups. Six (46.2%) women in the intervention and seven (50.0%) in the control group underwent cesarean hysterectomy (P=.84). There were no significant differences between the intervention and control groups in the mean number of packed RBC units transfused, 5.2 (+/-6.2) and 4.1 (+/-3.8), respectively (P=.90), or in the calculated blood loss, 4,950 (+/-5,051) and 4,709 (+/-3,434) mL (P=.72). The number of women with blood loss greater than 2,500 mL, number of plasma products transfused, duration of surgery, peripartum complications, and hospitalization length did not differ significantly between the groups. Reversible adverse effects related probably to prophylactic balloon catheter insertion were noted in 2 of 13 (15.4%) women. CONCLUSION: In women with preoperative suspicion of placenta accreta, preoperative placement of prophylactic balloon catheters did not affect the number of packed RBC units transfused. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01373255. LEVEL OF EVIDENCE: I. PMID- 26444129 TI - Large-for-Gestational-Age Ultrasound Diagnosis and Risk for Cesarean Delivery in Women With Gestational Diabetes Mellitus. AB - OBJECTIVE: To assess the accuracy of a large-for-gestational-age (LGA) ultrasound diagnosis and the subsequent risk for cesarean delivery associated with ultrasound diagnosis of LGA among women with gestational diabetes mellitus. METHODS: This was a retrospective cohort study of 903 women with GDM who delivered after 36 weeks of gestation with an ultrasound-estimated fetal weight within 31 days of delivery. Delivery outcomes were compared between women with an ultrasound diagnosis of LGA and a non-LGA ultrasound diagnosis. RESULTS: Based on ultrasound assessments, we identified 248 women with an LGA fetus and 655 women with a non-LGA fetus. Among women with an LGA ultrasound diagnosis, 56 of 248 (22.6%) delivered an LGA neonate, whereas, of women with a non-LGA ultrasound diagnosis, 18 of 655 (2.8%) delivered an LGA neonate. Ultrasound diagnosis of LGA was associated with increased risk for cesarean delivery (adjusted odds ratio [OR] 3.13, 95% confidence interval [CI] 2.10-4.67, P<.001) after adjusting for relevant covariates. Stratified analyses demonstrated that ultrasound diagnosis of LGA was associated with an increased risk for cesarean delivery whether the birth weight was between 2,500 and 3,499 g (OR 2.82, 95% CI 1.62-4.84, P<.001) or between 3,500 and 4,500 g (OR 3.47, 95% CI 2.06-5.88, P<.001). CONCLUSION: Ultrasonography significantly overestimates the prevalence of LGA in women with gestational diabetes mellitus, and an ultrasound diagnosis of LGA is associated with an increased risk for cesarean delivery independent of birth weight. LEVEL OF EVIDENCE: II. PMID- 26444130 TI - Enhancing Participation in Depression Care in Outpatient Perinatal Care Settings: A Systematic Review. AB - OBJECTIVE: To examine a wide range of study designs and outcomes to estimate the extent to which interventions in outpatient perinatal care settings are associated with an increase in the uptake of depression care. DATA SOURCES: PubMed, CINAHL, PsycINFO, ClinicalTrials.gov, and Scopus (EMBASE) were searched for studies published between 1999 and 2014 that evaluated mental health care use after screening for depression in perinatal care settings. METHODS OF STUDY SELECTION: Inclusion criteria were: 1) English language; 2) pregnant and postpartum women who screened positive for depression; 3) exposure (validated depression screening in outpatient perinatal care setting); and, 4) outcome (mental health care use). Searches yielded 392 articles, 42 met criteria for full text review, and 17 met inclusion criteria. Study quality was assessed using a modified Downs and Black scale. TABULATION, INTEGRATION, AND RESULTS: Articles were independently reviewed by two abstractors and consensus reached. Study design, intervention components, and mental health care use were defined and categorized. Seventeen articles representing a range of study designs, including one randomized controlled trial and one cluster randomized controlled trial, were included. The average quality rating was 61% (31.0-90.0%). When no intervention was in place, an average of 22% (13.8-33.0%) of women who screened positive for depression had at least one mental health visit. The average rate of mental health care use was associated with a doubling of this rate with patient engagement strategies (44%, 29.0-90.0%), on-site assessments (49%, 25.2-90.0%), and perinatal care provider training (54%, 1.0-90.0%). High rates of mental health care use (81%, 72.0-90.0%) were associated with implementation of additional interventions, including resource provision to women, perinatal care provider training, on-site assessment, and access to mental health consultation for perinatal care providers. CONCLUSION: Screening alone was associated with 22% mental health care use among women who screened positive for depression; however, implementation of additional interventions was associated with a two to fourfold increased use of mental health care. Although definitive studies are still needed, screening done in conjunction with interventions that target patient, health care provider, and practice-level barriers is associated with increased improved rates of depression detection, assessment, referral, and treatment in perinatal care settings. PMID- 26444131 TI - Quantification of Heteroaggregation between Citrate-Stabilized Gold Nanoparticles and Hematite Colloids. AB - Collisions with and attachment to natural colloids (heteroaggregation) is likely to influence significantly the fate, transport, and toxicity of engineered nanoparticles (ENPs). This study investigated heteroaggregation between hematite (alpha-Fe2O3) colloids and citrate-capped gold nanoparticles (Cit-AuNPs) using a novel approach involving time-resolved dynamic light scattering and parallel experiments designed to quantify nanoparticle attachment and heteroaggregate surface charge. Experiments were performed in low ionic strength synthetic water at environmentally relevant pH in the presence and absence of Suwannee River Natural Organic Matter (SRNOM). In the absence of SRNOM at pH values where Cit AuNPs and hematite are oppositely charged, attachment efficiencies are high and Cit-AuNPs are capable of destabilizing hematite following an "electrostatic patch" mechanism. Furthermore, maximum observed surface coverages were far below those predicted by geometry alone, a fact predicted by the random sequential adsorption (RSA) model that has significant implications for the estimation of heteroaggregate attachment efficiencies. At pH values where both particles are negative or in the presence of small amounts of SRNOM, attachment was minimal. Calculated attachment efficiencies using the measured surface coverages corroborate these findings. The calculation of attachment efficiencies and the identification of mechanisms governing heteroaggregation represents an important step toward predicting the transport, fate, and toxicity of ENPs in the environment. PMID- 26444132 TI - Disowning the self: The cultural value of modesty can attenuate self-positivity. AB - Western participants endorse a higher number of positive traits as self descriptive, but endorse a lower number of negative traits as self-descriptive. They also respond quicker to categorize positive traits as self-descriptive, but respond slower to categorize negative traits as self-descriptive. Is this self positivity bias qualified by the cultural value of modesty? We induced modesty (vs. punctuality) and assessed self-descriptiveness judgments and response times among Chinese participants. We replicated the self-positivity bias in regards to both self-descriptiveness judgments and response times. In the case of self descriptiveness judgments, however, the bias was partially qualified by modesty. Relative to control participants, those in the modesty condition endorsed fewer positive traits as self-descriptive and manifested a tendency toward endorsing more negative traits as self-descriptive. In the case of response times, the self positivity bias was unqualified by modesty. Within both conditions, participants were quicker to categorize positive traits as self-descriptive and were slower to categorize negative traits as self-descriptive. The results speak to the relation between the self-positivity bias and the self-reference effect and illustrate the malleability of self-processing. PMID- 26444133 TI - The role of emotions in the reduction of HIV/AIDS stigma among physicians in training. AB - Scientific literature has systematically documented the negative effects of social stigma for people living with HIV/AIDS (PLWHA). HIV/AIDS stigma has the potential to negatively impact self-care strategies for those already affected, and simultaneously hinder prevention efforts to deter the emergence of new infections. When health professionals manifest these negative attitudes access to quality health-care and prevention strategies can be seriously affected. Scientifically tested interventions to reduce HIV/AIDS stigma among health professionals are still scarce. Although the number of tested interventions has increased over the past decade, few of them target Latino health professionals or Spanish-speaking populations. Furthermore, although some of those interventions have been reported as effective for stigma reduction, more work is needed to better understand the underlying variables that account for the reduction of stigma attitudes in those efforts. The SPACES intervention has been documented as an effective HIV/AIDS stigma-reduction intervention focusing on health-care professionals in training. The intervention, which is delivered in Spanish, has been previously tested with medical students in Puerto Rico and shown significant results in addressing negative attitudes toward PLWHA. The main objective of this study was to document the underlying variables that fostered reduction of HIV/AIDS stigma due to participation in the SPACES intervention. Results evidence that health professionals in training who participated in the intervention (n = 507) had less stigmatizing attitudes toward PLWHA due to an increase in their positive emotions toward this population. In light of these results, we discuss the importance of engaging health professionals in HIV/AIDS stigma-reduction interventions that go beyond the provision of information and skills for interacting with PLWHA, and address the emotional component of HIV/AIDS stigma. PMID- 26444134 TI - [What is Important for Diagnosis and Therapy Follow-up in Chronic Cough?]. AB - Within the last years there has been significant progress in the field of chronic cough. So far, the analysis and evaluation of chronic cough was done mainly on the basis of subjective methods such as manual counts of cough events, questionnaires and diaries. Testing cough hypersensitivity and monitoring 24 h cough represent objective criteria. Validated questionnaires on cough frequency and quality of life represent the impact of chronic cough. Cough frequency monitoring, the preferred tool to objectively assess cough, should be used as primary end-point in clinical trials. It will also be possible to discriminate between productive and non-productive cough. The relationship with subjective measures of cough is weak. In the future, cough and its therapy should therefore be assessed with a combination of subjective and objective tools. PMID- 26444136 TI - [Idiopathic Pulmonary Fibrosis]. AB - Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia and a disease of the elderly. Cigarette smoking and longterm exposure to substances harming alveolar epithelial cells are risk factors for the development of IPF. There is also evidence for a genetic susceptibility. IPF is defined as the idiopathic variant of Usual Interstitial Pneumonitis (UIP). Diagnosis of IPF is complex and based on the exclusion of other diseases associated with an UIP pattern. The only cure is lung transplantation. In the last years there was a breakthrough in the treatment of IPF. With pirfenidone and nintedanib there are now two compounds approved for the treatment of IPF. PMID- 26444135 TI - S2k-Guideline "Prolonged Weaning". AB - All mechanically ventilated patients must be weaned from the ventilator at some stage. According to an International Consensus Conference the criteria for "prolonged weaning" are fulfilled if patients fail at least 3 weaning attempts (i. e. spontaneous breathing trial, SBT) or require more than 7 days of weaning after the first SBT. This occurs in about 15 - 20 % of patients.Because of the growing number of patients requiring prolonged weaning a German guideline on prolonged weaning has been developed. It is an initiative of the German Respiratory Society (Deutsche Gesellschaft fur Pneumologie und Beatmungsmedizin e. V., DGP) in cooperation with other societies (see acknowledgement) engaged in the field chaired by the Association of Scientific and Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF).This guideline deals with the definition, epidemiology, weaning categories, underlying pathophysiology, therapeutic strategies, the weaning unit, transition to out-of-hospital ventilation and therapeutic recommendations for end of life care. This short version summarises recommendations on prolonged weaning from the German guideline. PMID- 26444137 TI - The role of respiratory measures to assess mental load in pilot selection. AB - While cardiovascular measures have a long tradition of being used to determine operator load, responsiveness of the respiratory system to mental load has rarely been investigated. In this study, we assessed basic and variability measures of respiration rate (RR), partial pressure of end-tidal carbon dioxide (petCO2) as well as performance measures in 63 male pilot candidates during completion of a complex cognitive task and subsequent recovery. Mental load was associated with an increase in RR and a decrease in respiratory variability. A significant decrease was also found for petCO2. RR and respiratory variability showed partial and complete effects of recovery, respectively, whereas petCO2 did not return to baseline level. Overall, a good performance was related to a stronger reactivity in RR. Our findings suggest that respiratory parameters would be a useful supplement to common measures for the assessment of mental load in pilot selection. Practitioner Summary: Respiratory measures are a promising yet poorly investigated approach to monitor operator load. For pilot selection, we assessed respiration in response to multitasking in 63 candidates. Task-related changes as well as covariation with performance strongly support the consideration of respiratory parameters when evaluating reactivity to mental load. PMID- 26444138 TI - ? PMID- 26444139 TI - ? PMID- 26444140 TI - ? PMID- 26444141 TI - ? PMID- 26444142 TI - Slowed atrial and atrioventricular conduction and depressed HRV in a murine model of hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is a common heritable cardiac disorder with diverse clinical outcomes including sudden death, heart failure, and stroke. Depressed heart rate variability (HRV), a measure of cardiac autonomic regulation, has been shown to predict mortality in patients with cardiovascular disease. Cardiac autonomic remodelling in animal models of HCM are not well characterised. This study analysed Gly203Ser cardiac troponin-I transgenic (TG) male mice previously demonstrated to develop hallmarks of HCM by age 21 weeks. 33 mice aged 30 and 50 weeks underwent continuous electrocardiogram (ECG) recording for 30 min under anaesthesia. TG mice demonstrated prolonged P-wave duration (P < 0.001) and PR intervals (P < 0.001) compared to controls. Additionally, TG mice demonstrated depressed standard deviation of RR intervals (SDRR; P < 0.01), coefficient of variation of RR intervals (CVRR; P < 0.001) and standard deviation of heart rate (SDHR; P < 0.001) compared to controls. Additionally, total power was significantly reduced in TG mice (P < 0.05). No significant age-related difference in either strain was observed in ECG or HRV parameters. Mice with HCM developed slowed atrial and atrioventricular conduction and depressed HRV. These changes were conserved with increasing age. This finding may be indicative of atrial and ventricular hypertrophy or dysfunction, and perhaps an indication of worse clinical outcome in heart failure progression in HCM patients. PMID- 26444143 TI - Introduction of a closed-system cell processor for red blood cell washing: postimplementation monitoring of safety and efficacy. AB - BACKGROUND: After introduction of a closed-system cell processor, the effect of this product change on safety, efficacy, and utilization of washed red blood cells (RBCs) was assessed. STUDY DESIGN AND METHODS: This study was a pre /postimplementation observational study. Efficacy data were collected from sequentially transfused washed RBCs received as prophylactic therapy by beta thalassemia patients during a 3-month period before and after implementation of the Haemonetics ACP 215 closed-system processor. Before implementation, an open system (TerumoBCT COBE 2991) was used to wash RBCs. The primary endpoint for efficacy was a change in hemoglobin (Hb) concentration corrected for the duration between transfusions. The primary endpoint for safety was the frequency of adverse transfusion reactions (ATRs) in all washed RBCs provided by Canadian Blood Services to the transfusion service for 12 months before and after implementation. RESULTS: Data were analyzed from more than 300 RBCs transfused to 31 recipients before implementation and 29 recipients after implementation. The number of units transfused per episode reduced significantly after implementation, from a mean of 3.5 units to a mean of 3.1 units (p < 0.005). The corrected change in Hb concentration was not significantly different before and after implementation. ATRs occurred in 0.15% of transfusions both before and after implementation. CONCLUSION: Safety and efficacy of washed RBCs were not affected after introduction of a closed-system cell processor. The ACP 215 allowed for an extended expiry time, improving inventory management and overall utilization of washed RBCs. Transfusion of fewer RBCs per episode reduced exposure of recipients to allogeneic blood products while maintaining efficacy. PMID- 26444144 TI - Combined use of cyclofructans and an amino acid ester-based ionic liquid for the enantioseparation of huperzine A and coumarin derivatives in CE. AB - Cyclofructans (CFs) and their derivatives have recently been proven to be efficient chiral selectors (CSs) for the enantioseparation of several analytes in CE, HPLC, and GC. In this study, the chiral separation ability of a number of native and derivatized CFs was examined in CE. Particularly, six different CFs, with different derivatization groups and cavity sizes [native CF-6 and CF-7, isopropyl cyclofructan-6 (IPCF-6), IPCF-7, sulfated cyclofructan-6 (SCF-6), and SCF-7] were used as CSs for the enantioseparation of huperzine A, warfarin, and coumachlor. Almost all of the examined CFs, except from SCF-6 & -7, demonstrated relatively low and sometimes no chiral separation ability for huperzine A. In an effort to improve both resolution and efficiency, the chiral ionic liquid D Alanine tert butyl ester lactate (D-AlaC4Lac) was added into the BGE. In most of the cases, the combination of CF with D-AlaC4Lac resulted in an improvement in peak efficiency and/or resolution. When CF-6 was utilized with D-AlaC4Lac, a resolution of 1.4 was obtained, while the use of IPCF-6/D-AlaC4Lac provided a baseline enantioseparation. Although the combination of SCF-7 and 40 mM D AlaC4Lac did not affect resolution, it dramatically increased peak efficiency from 24,000 to 117,000. In the case of warfarin and coumachlor, IPCF-6 and IPCF-7 proved to be the most effective CSs. It is, therefore, concluded that the size of the cavity and the CF derivatization are the key parameters for the chiral separation capability. It is also clear from this study that D-AlaC4Lac is necessary for improved peak efficiencies and resolutions. PMID- 26444146 TI - Copper-catalyzed arylation of biguanide derivatives via C-N cross-coupling reactions. AB - An efficient copper-catalyzed cross-coupling reaction of biguanide hydrochloride derivatives with both aryl iodides and bromides under mild conditions has been developed. The reaction occurred in good yields and tolerated aryl halides containing functionalities such as nitriles, sulfonamides, ethers, and halogens. Alkyl and cyclic substituted biguanidines were also well tolerated. PMID- 26444145 TI - Left ventricular outflow tract gradient is associated with reduced capillary density in hypertrophic cardiomyopathy irrespective of genotype. AB - BACKGROUND: Coronary microvascular dysfunction (CMD) is an important feature of hypertrophic cardiomyopathy (HCM), which contributes negatively to symptoms and long-term outcome. Previous in vivo imaging studies in HCM suggest that left ventricular outflow tract (LVOT) gradient and genetic status are important contributors to CMD. CMD may be caused by reduced capillary density. Here, we investigated whether a reduction in capillary density is related to genetic status or LVOT gradient severity in an in vitro study of HCM cardiac samples. METHODS: Using immunofluorescence microscopy, we analysed capillaries (Cap) and cardiomyocytes (CM) in myectomy specimens from 18 HCM patients with maximum left ventricular (LV) wall thickness >=15 mm. All subjects exhibited significant LVOT obstruction, necessitating septal myectomy. In addition, control myocardium from the LV septal wall was collected at autopsy of 6 individuals that suffered a noncardiac death. RESULTS: CM area was higher in patients with HCM compared to controls. Capillary density was significantly lower in patients with HCM compared with controls (1425 +/- 262 vs. 2543 +/- 509 Cap/mm(2) , P < 0.001), as was the number of Cap per CM corrected for CM area (2.2 +/- 0.5 vs. 4.2 +/- 0.9 Cap/CM area, P < 0.001). Capillary density did not differ between genotype-negative and genotype-positive HCM patients at similar resting LVOT gradients. A significant correlation was present between resting LVOT gradient and CM area (r = 0.73, P < 0.001), capillary density (r = -0.74, P < 0.001) and the number of Cap per CM corrected for CM area (r = -0.82, P < 0.001). CONCLUSIONS: Our data indicate that LVOT gradient, rather than genetic status, is associated with reduced capillary density in HCM. PMID- 26444147 TI - Volatilization of elemental mercury from fresh blast furnace sludge mixed with basic oxygen furnace sludge under different temperatures. AB - Blast furnace sludge (BFS) is a waste with elevated mercury (Hg) content due to enrichment during the production process of pig iron. To investigate the volatilization potential of Hg, fresh samples of BFS mixed with basic oxygen furnace sludge (BOFS; a residue of gas purification from steel making, processed simultaneously in the cleaning devices of BFS and hence mixed with BFS) were studied in sealed column experiments at different temperatures (15, 25, and 35 degrees C) for four weeks (total Hg: 0.178 mg kg(-1)). The systems were regularly flushed with ambient air (every 24 h for the first 100 h, followed by every 72 h) for 20 min at a flow rate of 0.25 +/- 0.03 L min(-1) and elemental Hg vapor was trapped on gold coated sand. Volatilization was 0.276 +/- 0.065 ng (x m: 0.284 ng) at 15 degrees C, 5.55 +/- 2.83 ng (x m: 5.09 ng) at 25 degrees C, and 2.37 +/- 0.514 ng (x m: 2.34 ng) at 35 degrees C. Surprisingly, Hg fluxes were lower at 35 than 25 degrees C. For all temperature variants, an elevated Hg flux was observed within the first 100 h followed by a decrease of volatilization thereafter. However, the background level of ambient air was not achieved at the end of the experiments indicating that BFS mixed with BOFS still possessed Hg volatilization potential. PMID- 26444149 TI - A comparison of single dose dexmedetomidine with propofol for the prevention of emergence delirium after desflurane anaesthesia in children. AB - Emergence delirium is a common problem in children recovering from general anaesthesia. We performed a study comparing emergence characteristics in 100 patients who were randomly allocated to receive either 0.3 MUg.kg(-1) dexmedetomidine, 1 mg.kg(-1) propofol or saline 0.9% and undergoing infra umbilical surgery. The Pediatric Anesthesia Emergence Delirium scale was used to grade emergence delirium. Emergence delirium occurred in 9.4% of children in the dexmedetomidine group compared with 13.9% in the propofol group and 40.6% in the control group (p = 0.004). In the dexmedetomidine group, sedation occurred in 62.5% of children at 10 min after transfer to the recovery area, compared with 44.4% in the propofol group and 12.5% in the control group (p = 0.010). We conclude that dexmedetomidine significantly reduced the incidence of emergence delirium but this was at the expense of a greater incidence of sedation in the recovery period. PMID- 26444150 TI - Lignan enhancement in hairy root cultures of Linum album using coniferaldehyde and methylenedioxycinnamic acid. AB - Feeding experiments with hairy root cultures of Linum album have established that the extracellular coniferaldehyde is a good precursor for production of two lignans: lariciresinol (LARI) and pinoresinol (PINO). The accumulation of the LARI, PINO, and podophyllotoxin (PTOX) in hairy roots were enhanced about 14.8-, 8.7-, and 1.5-fold (107.61, 8.7 and 6.42 ug g(-1) Fresh Wight), respectively, by the addition of coniferaldehyde (2 mM) to the culture media (after 24 hr). This result was correlated with an increase pinoresinol/lariciresinol reductase (PLR) expression gene and cinnamyl alcohol dehydrogenase (CAD) activity in the fed hairy roots. Adding 3,4-(methylendioxy)cinnamic acid (MDCA) precursor did not influence on the lignans accumulation, but the lignin content of the hairy roots was increased. Moreover, the expression genes of phenylalanine ammonialyase (PAL), CAD, and cinnamoyl-CoA reductase (CCR) were influenced after feeding hairy roots with MDCA. PMID- 26444151 TI - CRISPR-Based Technologies and the Future of Food Science. AB - The on-going CRISPR craze is focused on the use of Cas9-based technologies for genome editing applications in eukaryotes, with high potential for translational medicine and next-generation gene therapy. Nevertheless, CRISPR-Cas systems actually provide adaptive immunity in bacteria, and have much promise for various applications in food bacteria that include high-resolution typing of pathogens, vaccination of starter cultures against phages, and the genesis of programmable and specific antibiotics that can selectively modulate bacterial population composition. Indeed, the molecular machinery from these DNA-encoded, RNA mediated, DNA-targeting systems can be harnessed in native hosts, or repurposed in engineered systems for a plethora of applications that can be implemented in all organisms relevant to the food chain, including agricultural crops trait enhancement, livestock breeding, and fermentation-based manufacturing, and for the genesis of next-generation food products with enhanced quality and health promoting functionalities. CRISPR-based applications are now poised to revolutionize many fields within food science, from farm to fork. In this review, we describe CRISPR-Cas systems and highlight their potential for the development of enhanced foods. PMID- 26444153 TI - Federal Funding for Food Science--A Tail of Discovery and Careers. PMID- 26444156 TI - My wish for a global research agenda in nursing. PMID- 26444157 TI - A study of the Unna Boot compared with the elastic bandage in venous ulcers: a randomized clinical trial. AB - OBJECTIVE: to analyze the process of tissue repair in patients with venous ulcers using inelastic compression therapy (the Unna Boot), in comparison with the use of the elastic bandage. METHOD: a controlled randomized clinical trial in which the patients (n=18) were allocated to two groups, those who used the Unna Boot (group B) and those who used the elastic bandage (group A). The study's follow-up period was 13 weeks. RESULTS: a significant reduction took place, at the level of 5%, in the area, in square centimeters, of the ulcers of group B (p<0.0001) throughout the treatment, and there was a tendency of group A for reduction in the area of the ulcer, in centimeters squared (p=0.06), only after the fifth week. CONCLUSION: the treatment with the Unna Boot presented better results in venous ulcers with areas over 10cm2, and the elastic bandage with Petrolatum(r) gauze in venous ulcers below 10cm2. Brazilian Clinical Trials Register: Trial (req: 195) and WHO UTN U1111-1122-5489. PMID- 26444155 TI - Collective dynamics of processive cytoskeletal motors. AB - Major cellular processes are supported by various biomolecular motors that usually operate together as teams. We present an overview of the collective dynamics of processive cytokeletal motor proteins based on recent experimental and theoretical investigations. Experimental studies show that multiple motors function with different degrees of cooperativity, ranging from negative to positive. This effect depends on the mechanical properties of individual motors, the geometry of their connections, and the surrounding cellular environment. Theoretical models based on stochastic approaches underline the importance of intermolecular interactions, the properties of single motors, and couplings with cellular medium in predicting the collective dynamics. We discuss several features that specify the cooperativity in motor proteins. Based on this approach a general picture of collective dynamics of motor proteins is formulated, and the future directions and challenges are discussed. PMID- 26444158 TI - Self-care in heart failure patients. AB - OBJECTIVE: to describe self-care behavior and its associated factors in a sample of heart failure Brazilian patients. METHOD: descriptive cross-sectional study with non-probabilistic sample of 116 ambulatory patients undergoing heart failure treatment. Self-care was evaluated using the Self-Care of Heart Failure Index, (scores >=70 points=appropriate self-care). Association tests were applied, considering a descriptive level of 0.05. RESULTS: the mean age of participants was 57.7 (SD =11.3) years; 54.3% were male; the mean schooling was 5.5 (SD = 4.0) years; and 74.1% had functional class II-III. The mean scores on the subscales of the Self-Care of Heart Failure Index indicated inappropriate self-care (self-care maintenance: 53.2 (SD =14.3), selfcare management: 50.0 (SD = 20.3) and self-care confidence: 52.6 (SD=22.7)) and it was found low frequencies of participants with appropriate self-care (self-care maintenance, 6.9%), self-care management (14.7%) and self-care confidence (19%). Higher scores of the Self-Care of Heart Failure Index were associated with: reduced left ventricular ejection fraction (p=0.001), longer time of experience with the disease (p=0.05) and joint monitoring by physician and nurse (p=0.007). CONCLUSION: investments are needed to improve the self-care behavior and the nursing can play a relevant role in this improvement. PMID- 26444159 TI - Relationship between complaints presented by emergency patients and the final outcome. AB - OBJECTIVE: to relate complaints presented by emergency room patients, classified using the Manchester Triage System, with the final outcome (discharge/death/transfer). METHODS: prospective cohort study, involving 509 patients who were admitted to the emergency room and remained there for more than 24 hours after admission, being monitored to the final outcome. Data were analyzed with a statistical program using descriptive and analytical statistics. RESULTS: the mean age of the patients was 59.1 years and 59.3% were male. The main complaints were unwell adult (130 - 22.5%), shortness of breath in adults (81 - 14.0%), abdominal pain in adults (58 - 10.0%) and behaving strangely (34 - 5.9%), with 87% of the patients being discharged. More deaths were found in the patients classified in the severe colors, with 42.8% classified as red, 17.0% as orange and 8.9% as yellow. Among the patients classified as green, 9.6% died. CONCLUSION: in the various colors of the Manchester Triage System, death prevailed in patients that presented the complaints of unwell adult, shortness of breath, head injury, major trauma, diarrhea and vomiting. The higher the clinical priority the greater the prevalence of death. PMID- 26444160 TI - Factors associated with knowledge of the nursing staff at a teaching hospital on blood transfusion. AB - OBJECTIVE: to determine whether there is an association between knowledge of the nursing professionals about blood transfusion and the variables related to the professional aspects. METHOD: this is an observational, cross-sectional and quantitative study, carried out at a large general teaching hospital. The sample consisted of 209 nursing professionals, obtained by simple random sampling. For data collection, a checklist was used. In the univariate analysis, descriptive statistics and central trend and dispersion measures were used. In the bivariate analysis, Student's t-Test, analysis of variance and Pearson's correlation were used. To determine the predictors, multiple linear regression was applied. The Institutional Review Board (Opinion number 2434) approved the study. RESULTS: the overall average knowledge score was 52.66%; in the Pre-transfusion Step, it corresponded to 53.38%; in the Transfusion Step 51.25% and, in the Post transfusion Step, 62.68%. The factors related to knowledge were professional category and received training and/or guidance to accomplish the transfusion process (p<0.01). CONCLUSION: this study showed the influence of training and guidance on the knowledge and provided a diagnosis to identify the professionals' difficulties regarding the transfusion process. PMID- 26444161 TI - Foot reflexology in feet impairment of people with type 2 diabetes mellitus: randomized trial. AB - OBJECTIVE: to evaluate the effect of foot reflexology on feet impairment of people with type 2 diabetes mellitus. METHOD: this is a randomized, controlled and blind clinical trial. The sample was comprised by people with type 2 diabetes mellitus who, after being randomized into Treated group (n = 21) and Control group (n = 24), received guidelines on foot self-care. To the Treated Group it was also provided 12 sessions of foot reflexology. The scores of impairment indicators related to skin and hair, blood circulation, tissue sensitivity and temperature were measured by means of the instrument for assessing tissue integrity of the feet of people with diabetes mellitus. Chi-square test, Fisher exact test, Mann-Whitney test and regression analyzes were applied to the data, considering a significance level of 5% (P value <0.05). RESULTS: participants who received the therapy showed better scores in some impairment indicators related to skin and hair (hair growth, elasticity/turgor, hydration, perspiration, texture and integrity of the skin/ skin peeling). CONCLUSION: the foot reflexology had a beneficial effect on feet impairment of people with type 2 diabetes mellitus, which makes it a viable therapy, deserving investment. This study was registered in the Brazilian Registry of Clinical Trials - RBR-8zk8sz. PMID- 26444162 TI - Hospitalizations for cardiovascular diseases and the coverage by the family health strategy. AB - OBJECTIVE: to verify the correlation between the rates of hospitalization for primary care-sensitive cardiovascular diseases and the coverage by the Family Health Strategy of residents of the State of Parana, by regional health divisions, from 2000 to 2011. METHOD: ecological study developed from data of the Hospital Information System of the Brazilian Unified Health System (SUS) and the Department of Primary Care of the Ministry of Health. The rates of hospitalization for cardiovascular diseases were correlated with the annual coverage by the Family Health Strategy using Pearson's and Spearman's correlation coefficients. RESULT: there was a strong and negative correlation in the State of Parana (r=-0.91; p <0.001) and in most regional health divisions, with the highest correlations observed in the Metropolitan and Toledo (r =-0.93; p<0.001) and Paranagua (r=-0.92, p<0.001) regional health divisions. CONCLUSION: the results suggest that the increase in the coverage by the Family Health Strategy was an important factor for decrease in the hospitalizations for cardiovascular conditions among residents of the State of Parana and in most regional health divisions. Other studies should be performed to analyze the factors and causes in regional health divisions where there was no correlation with increase in the Family Health Strategy. PMID- 26444163 TI - Meaning of leprosy for people who have experienced treatment during the sulfonic and multidrug therapy periods. AB - OBJECTIVE: to analyze the meanings of leprosy for people treated during the sulfonic and multidrug therapy periods. METHOD: qualitative nature study based on the Vigotski's historical-cultural approach, which guided the production and analysis of data. It included eight respondents who have had leprosy and were submitted to sulfonic and multidrug therapy treatments. The participants are also members of the Movement for Reintegration of People Affected by Leprosy. RESULTS: the meanings were organized into three meaning cores: spots on the body: something is out of order; leprosy or hanseniasis? and leprosy from the inclusion in the Movement for Reintegration of People Affected by Leprosy. CONCLUSION: the meanings of leprosy for people submitted to both regimens point to a complex construction thereof, indicating differences and similarities in both treatments. Health professionals may contribute to the change of the meanings, since these are socially constructed and the changes are continuous. PMID- 26444164 TI - Risk behaviors for sexually transmitted diseases among crack users. AB - OBJECTIVES: to investigate the prevalence and risk behaviors by means of reporting of sexually transmitted diseases among crack users. METHOD: cross sectional study carried out with 588 crack users in a referral care unit for the treatment of chemical dependency. Data were collected by means of face-to-face interview and analyzed using Stata statistical software, version 8.0. RESULTS: of the total participants, 154 (26.2%; 95% CI: 22.8-29.9) reported antecedents of sexually transmitted diseases. Ages between 25 and 30 years (RP: 2.1; 95% CI: 1.0 4.0) and over 30 years (RP: 3.8; 95% CI: 2.1-6.8), alcohol consumption (RP: 1.9; 95% CI: 1.1-3.3), antecedents of prostitution (RP: 1.9; 95% CI: 1.3-2.9) and sexual intercourse with person living with human immunodeficiency virus/AIDS (RP: 2.7; 95% CI: 1.8-4.2) were independently associated with reporting of sexually transmitted diseases. CONCLUSION: the results of this study suggest high risk and vulnerability of crack users for sexually transmitted diseases. PMID- 26444165 TI - Validation of the content of the prevention protocol for early sepsis caused by Streptococcus agalactiaein newborns. AB - OBJECTIVE: to validate the content of the prevention protocol for early sepsis caused by Streptococcus agalactiaein newborns. METHOD: a transversal, descriptive and methodological study, with a quantitative approach. The sample was composed of 15 judges, 8 obstetricians and 7 pediatricians. The validation occurred through the assessment of the content of the protocol by the judges that received the instrument for data collection - checklist - which contained 7 items that represent the requisites to be met by the protocol. The validation of the content was achieved by applying the Content Validity Index. RESULT: in the judging process, all the items that represented requirements considered by the protocol obtained concordance within the established level (Content Validity Index > 0.75). Of 7 items, 6 have obtained full concordance (Content Validity Index 1.0) and the feasibility item obtained a Content Validity Index of 0.93. The global assessment of the instruments obtained a Content Validity Index of 0.99. CONCLUSION: the validation of content that was done was an efficient tool for the adjustment of the protocol, according to the judgment of experienced professionals, which demonstrates the importance of conducting a previous validation of the instruments. It is expected that this study will serve as an incentive for the adoption of universal tracking by other institutions through validated protocols. PMID- 26444166 TI - Instrument to assess the nursing care product: development and content validation. AB - OBJECTIVES: develop and validate the content of a tool about nursing care production. METHOD: the data were collected between 2011 and 2013, based on focus groups, the application of semistructured questionnaires (prototype test) and the Delphi technique. The focus groups were used to produce the instrument items and held at three hospitals in the interior of the State of Sao Paulo, involving 20 nurses. A panel of 10 experts evaluated the instrument. RESULTS: after two phases of the Delphi technique, the tool consisted of eight items. The content validity index of the scale corresponded to >=0.9 and the content validity of the items ranged between 0.8 and 1.0, indicating the maintenance of the structure and content. The assertion on the applicability in daily nursing practice showed a content validity index of the scale equal to 0.8. CONCLUSION: this study permitted the development and content validation of scale on nursing care production, equipping the nurses in their management practice. PMID- 26444167 TI - Cultural adaptation to Brazilian Portuguese of the Face, Legs, Activity, Cry, Consolability revised (FLACCr) scale of pain assessment. AB - OBJECTIVE: to perform the translation into Brazilian Portuguese and cultural adaptation of the Face, Legs, Activity, Cry, Consolability revised (FLACCr) scale, with children under 18 years old, affected by cerebral palsy, presenting or not cognitive impairment and unable to report their pain. METHOD: methodological development study of translation into Portuguese and cultural adaptation of the FLACCr. After approval by the ethics committee, the process aimed at translation and back-translation, evaluation of translation and back translation using the Delphi technique and assessment of cultural equivalence. The process included the five categories of the scale and the four application instructions, considering levels of agreement equal to or greater than 80%. RESULTS: it was necessary three rounds of the Delphi technique to achieve consensus among experts. The agreement achieved for the five categories was: Face 95.5%, Legs 90%, Activity 94.4%, Cry 94.4% and Consolability 99.4%. The four instructions achieved the following consensus levels: 1st 99.1%, 2nd 99.2%, 3rd 99.1% and 4th 98.3%. CONCLUSION: the method enabled the translation and cultural adaptation of the FLACCr. This is a study able to expand the knowledge of Brazilian professionals on pain assessment in children with CP. PMID- 26444168 TI - Validation of the Comfort scale for relatives of people in critical states of health. AB - OBJECTIVE: this methodological study aims to present the construct validity of the Comfort scale for family members of people in a critical state of health (ECONF). METHOD: this is a methodological study. The sample was made up of 274 family members of adults receiving inpatient treatment in six Intensive Care Units (ICU) in the State of Bahia responded to 62 items distributed in 7 dimensions. The validation procedures adopted were based on the techniques of the Classical Test Theory. RESULTS: the analysis of dimensionality was undertaken through principal components analysis, a scale being obtained with 55 items distributed in four factors: Safety, Support, Family member-relative interaction and Integration with oneself and the everyday. The analysis of the items' , discriminative power, undertaken by the item-total correlation-coefficient showed a good relationship of the items with their respective factors. From the ECONF's reliability test, from the analysis of internal consistency, a raised Alpha Cronbach coefficient was obtained for the 4 factors and the general measurement. CONCLUSION: the comfort scale presented satisfactory psychometric parameters, thus constituting the first valid instrument for evaluating the comfort of family members of people in a critical state of health. The advance made by the study lies in its theoretical framework on comfort, and provides the health team with a scale based on empirical evidence. PMID- 26444169 TI - Cross-cultural adaptation and validation of the Protective Nursing Advocacy Scale for Brazilian nurses. AB - OBJECTIVE: to adapt culturally and validate the Protective Nursing Advocacy Scale for Brazilian nurses. METHOD: methodological study carried out with 153 nurses from two hospitals in the South region of Brazil, one public and the other philanthropic. The cross-cultural adaptation of the Protective Nursing Advocacy Scale was performed according to international standards, and its validation was carried out for use in the Brazilian context, by means of factor analysis and Cronbach's alpha as measure of internal consistency. RESULTS: by means of evaluation by a committee of experts and application of pre-test, face validity and content validity of the instrument were considered satisfactory. From the factor analysis, five constructs were identified: negative implications of the advocacy practice, advocacy actions, facilitators of the advocacy practice, perceptions that favor practice advocacy and barriers to advocacy practice. The instrument showed satisfactory internal consistency, with Cronbach's alpha values ranging from 0.70 to 0.87. CONCLUSION: it was concluded that the Protective Nursing Advocacy Scale - Brazilian version, is a valid and reliable instrument for use in the evaluation of beliefs and actions of health advocacy, performed by Brazilian nurses in their professional practice environment. PMID- 26444170 TI - Risk factor for phlebitis: a questionnaire study of nurses' perception. AB - OBJECTIVES: to assess nurses' perceptions of risk factors for the development of phlebitis, with a special focus on the perception of phlebitic potentials of some infusion medications and solutions. METHOD: a cross-sectional questionnaire study, which included a sample of 102 nurses. RESULTS: Nurses recognized some factors that may reduce the incidence of phlebitis; however, more than half of the nurses were unaware that the material and diameter of the cannula can affect the incidence rate of phlebitis. Furthermore,underlying disease and high pH of medications or solutions were identified as potential risk factors, whereas low pH and low osmolality were not. Nurses identified Vancomycin and Benzylpenicillin antibiotics with the strongest phlebitic potential. Among other medications and intravenous fluids, Aminophylline, Amiodaronehydrochloride and Potassium chloride 7.4% were identified as potentially causing phlebitis. CONCLUSION: predisposing factors for phlebitis relating to patients and administered therapy were identified by nurses, while some cannula related risk factors, in particular its physicochemical properties and the time for cannula replacement, were not fully perceived. PMID- 26444171 TI - The pain of existing and religion from the perspective of Catholics. AB - OBJECTIVE: to characterize the understanding of leaders and members of the Catholic religion on pain of existing. METHOD: 80 Catholics participated in the study. Data collection was carried out using the Religious Content Assessment Tool. The content analysis was carried out and arithmetic mean and standard deviation were calculated. RESULTS: the following categories emerged: length of affiliation, beginning of the religious practice and affiliation changes, responsibility for the actions and relationship with death, description of God, awareness of the existence of profound experiences, possibility of reward, increased faith in proximity to death, religion as an attempt to explain human limitations, relationship between religion and science and religion of the past and present in relation to science. On the instrument, the highest assigning items were: I believe that nature should be respected (9.96+/-0.19); I believe that all living beings deserve respect (9.70+/-0.67); make life worth living (9.70+/-0.78); my life is a transformation process (9.63+/-1.04) and I respect the diversity of people (9.56+/-0.91). CONCLUSION: it was observed associations between the participants' perceptions and religious constructs, highlighting the need to approach the religious phenomenon as part of the human being and potential resource for management and modulation of the pain of existing. PMID- 26444172 TI - Readmissions due to traffic accidents at a general hospital. AB - OBJECTIVE: to verify the occurrence and the causes of hospital readmissions within a year after discharge from hospitalizations due to traffic accidents. METHODS: victims of multiple traumas due to traffic accidents were included, who were admitted to an Intensive Care Unit. Sociodemographic data, accident circumstances, body regions affected and cause of readmission were collected from the patient histories. RESULTS: among the 109 victims of traffic accidents, the majority were young and adult men. Most hospitalizations due to accidents involved motorcycle drivers (56.9%). The causes of the return to the hospital were: need to continue the surgical treatment (63.2%), surgical site infection (26.3%) and fall related to the physical sequelae of the trauma (10.5%). The rehospitalization rate corresponded to 174/1,000 people/year. CONCLUSION: the hospital readmission rate in the study population is similar to the rates found in other studies. Victims of severe limb traumas need multiple surgical procedures, lengthier hospitalizations and extended rehabilitation. PMID- 26444173 TI - Evaluation of the quality of the teaching-learning process in undergraduate courses in Nursing. AB - OBJECTIVE: to identify aspects of improvement of the quality of the teaching learning process through the analysis of tools that evaluated the acquisition of skills by undergraduate students of Nursing. METHOD: prospective longitudinal study conducted in a population of 60 secondyear Nursing students based on registration data, from which quality indicators that evaluate the acquisition of skills were obtained, with descriptive and inferential analysis. RESULTS: nine items were identified and nine learning activities included in the assessment tools that did not reach the established quality indicators (p<0.05). There are statistically significant differences depending on the hospital and clinical practices unit (p<0.05). CONCLUSION: the analysis of the evaluation tools used in the article "Nursing Care in Welfare Processes" of the analyzed university undergraduate course enabled the detection of the areas for improvement in the teachinglearning process. The challenge of education in nursing is to reach the best clinical research and educational results, in order to provide improvements to the quality of education and health care. PMID- 26444175 TI - Domestic violence against women: representations of health professionals. AB - OBJECTIVE: to analyze the representations about domestic violence against women, among health professionals of Family Health Units. METHOD: qualitative study based on the Theory of Social Representations. Data were collected by means of evocations and interviews, treating them in the Ensemble de Programmes Pemettant L'Analyse des Evocations software - EVOC and content analysis. RESULTS: nurses, physicians, nursing technicians and community health agents participated. The evocations were answered by 201 professionals and, of these, 64 were interviewed. The central core of this representation, comprised by the terms "aggression", "physical-aggression", "cowardice" and "lack of respect", which have negative connotations and were cited by interviewees. In the contrast zone, comprised by the terms "abuse", "abuse-power", "pain", "humiliation", "impunity", "suffering", "sadness" and "violence", two subgroups were identified. The first periphery contains the terms "fear", evoked most often, followed by "revolt", "low self esteem" and "submission", and in the second periphery "acceptance" and "professional support". CONCLUSION: this is a structured representation since it contains conceptual, imagetic and attitudinal elements. The subgroups were comprised by professionals working in the rural area and by those who had completed their professional training course in or after 2004. These presented a representation of violence different from the representation of the general group, although all demonstrated a negative connotation of this phenomenon. PMID- 26444174 TI - Hand hygiene technique quality evaluation in nursing and medicine students of two academic courses. AB - OBJECTIVE: because they are health professionals, nursing and medical students' hands during internships can function as a transmission vehicle for hospital acquired infections. METHOD: a descriptive study with nursing and medical degree students on the quality of the hand hygiene technique, which was assessed via a visual test using a hydroalcoholic solution marked with fluorescence and an ultraviolet lamp. RESULTS: 546 students were assessed, 73.8% from medicine and 26.2% from nursing. The area of the hand with a proper antiseptic distribution was the palm (92.9%); areas not properly scrubbed were the thumbs (55.1%). 24.7% was very good in both hands, 29.8% was good, 25.1% was fair, and 20.3% was poor. The worst assessed were the male, nursing and first year students. There were no significant differences in the age groups. CONCLUSIONS: hand hygiene technique is not applied efficiently. Education plays a key role in setting a good practice base in hand hygiene, theoretical knowledge, and in skill development, as well as good practice reinforcement. PMID- 26444176 TI - An experimental study of an educational intervention to promote maternal self efficacy in breastfeeding. AB - OBJECTIVE: to build, validate and assess an educational intervention using the flip chart titled "I Can Breastfeed My Child." METHOD: an experimental study using a pretest, intervention and posttest, as well as a control group. A total of 201 women, who had been hospitalized immediately, for at least 6 hours, postpartum. The mothers were allocated to the intervention (100 women) or control groups (101 women) according to the length of their hospital stay. The effectiveness of the flip chart was assessed by applying the Breastfeeding Self Efficacy Scale - Short-Form at admission, discharge and by telephone in the second month postpartum. The intervention and control groups were similar in their socio-demographic, obstetric and gynecological variables. RESULTS: the intervention was beneficial because mothers in the intervention group had higher self-efficacy scores, more mothers continued breastfeeding and mothers had a longer duration of exclusive breastfeeding, both at the time of hospital discharge and at the second month postpartum, with statistically significant associations. CONCLUSIONS: this experimental study assessed the educational strategy mediated via the flip chart titled "I Can Breastfeed My Child" as being effective both in increasing self-efficacy and increasing the duration of breastfeeding. PMID- 26444177 TI - Association between depression and work stress in nursing professionals with technical education level. AB - OBJECTIVE: to analize the relationship between depression and work stress in nursing professionals with technical education level of a teaching hospital in a city of the state of Sao Paulo. METHODS: a cross-sectional study was carried out with 310 nursing technicians and nursing assistants, randomly selected. The outcome analyzed was the report of depression and its relationship with high levels of work stress, measured using the Job Stress Scale. Descriptive statistics and logistic regression were performed. RESULTS: the prevalence of depression in this study was 20%, and it was more expressive in females, aged over 40 years, living without a partner and in smokers. The chance of depression was twice as high among professionals showing high levels of work stress, even after multiple regression adjusting. CONCLUSION: depressive symptoms were strongly associated with high stress levels among nursing assistants and nursing technicians, evidencing a problem to be considered along with the planning of specific intervention programs for this population, as well as the need for better cases management by the supervisors. PMID- 26444178 TI - Efficacy and effectiveness of alcohol in the disinfection of semi-critical materials: a systematic review. AB - OBJECTIVE: to assess the efficacy and the effectiveness of 60-80% alcohol (v/v) in the disinfection of semi-critical materials which were either previously cleaned or not. METHOD: studies obtained from BIREME, IBECS, MEDLINE, ScIELO, PubMed, Ask Medline web portals, and references from other studies. Criteria were created to assess the methodological quality of articles. Out of the 906 studies found, 14 have been included. RESULTS: after materials were disinfected with alcohol, microorganisms were detected in 104/282 (36.9%) effectiveness tests and in 23/92 (25.0%) efficacy tests that were conducted. In the field studies, disinfection was not achieved for 74/218 (33.9%) of the products that were submitted to previous cleaning and for 30/64 (46.9%) of the ones which were not submitted to previous cleaning. In the experimental studies, alcohol disinfection was not efficacy in 11/30 (36.7%) and 12/62 (19.4%) of products, respectively. The studies were not found to have followed standardized methods. CONCLUSION: disinfection of semi-critical products with alcohol 70% - or in an approximate concentration - cannot be recommended to all health care products in an unrestricted way. However, according to the type of semi-critical product, disinfection can be attained with or without previous cleaning. PMID- 26444179 TI - An integrative literature review on nursing interventions aimed at increasing self-care among heart failure patients. AB - OBJECTIVE: to analyze and summarize knowledge concerning critical components of interventions that have been proposed and implemented by nurses with the aim of optimizing self-care by heart failure patients. METHODS: PubMed and CINAHL were the electronic databases used to search full peer-reviewed papers, presenting descriptions of nursing interventions directed to patients or to patients and their families and designed to optimize self-care. Forty-two studies were included in the final sample (n=4,799 patients). RESULTS: this review pointed to a variety and complexity of nursing interventions. As self-care encompasses several behaviors, interventions targeted an average of 3.6 behaviors. Educational/counselling activities were combined or not with cognitive behavioral strategies, but only about half of the studies used a theoretical background to guide interventions. Clinical assessment and management were frequently associated with self-care interventions, which varied in number of sessions (1 to 30); length of follow-up (2 weeks to 12 months) and endpoints. CONCLUSIONS: these findings may be useful to inform nurses about further research in self-care interventions in order to propose the comparison of different modalities of intervention, the use of theoretical background and the establishment of endpoints to evaluate their effectiveness. PMID- 26444180 TI - Burden and quality of life of mothers of children and adolescents with chronic illnesses: an integrative review. AB - OBJECTIVE: to identify and analyze the evidence available regarding evaluation of burden and quality of life of mothers who are caregivers for children and adolescents with chronic illnesses. METHOD: an integrative review, undertaken in the electronic sources MEDLINE; Academic Search Premier; CINAHL; LILACS; SciELO and PubMed, between 2010 and 2014. RESULTS: among the 22 documents selected, there was a predominance of convenience samples and non-experimental transversal designs, at the levels IV and III2. The caregiver burden scales used were the Zarit Burden Interview and Montgomery-Borgatta Caregiver Burden Scale-Revised along with the following instruments for evaluating quality of life: The World Health Organization Quality of Life-BREF Scale; Self-report questionnaires; The Ulm Quality of Life Inventory for Parents of chronically ill children; Asthma Caregiver Quality of Life Questionnaire; and the Nottingham Health Profile. Quality-of-life appears to be influenced in a complex and interrelated way by the physical and mental health of the mothers who are caregivers, in accordance with their level of independence, social relationships, environment, and the extent to which they see themselves as burdened. CONCLUSION: the revealing of the results for the evaluation of burden and quality of life of mothers who are caregivers has implications for the planning and implementation of effective interventions, by the multidisciplinary team, if they are to relieve the burden. PMID- 26444181 TI - Major Effect of the Syndrome of Rapid-Onset End-Stage Renal Disease on the Use of Arteriovenous Fistulas: High Rates of Initiation of Hemodialysis With Hemodialysis Catheter in the United States. PMID- 26444182 TI - Two equivalent methyl internal rotations in 2,5-dimethylthiophene investigated by microwave spectroscopy. AB - The microwave spectrum of 2,5-dimethylthiophene, a sulfur-containing five membered ring with two conjugated double bonds, was recorded in the frequency range from 2 to 40 GHz using molecular beam Fourier transform technique. Highly accurate molecular parameters were determined. A labeling scheme for the group G36 written as the semi-direct product (C(I)(3) * C(I)(3)) ? C(2v) was introduced. PMID- 26444184 TI - Controlling Electrical Conductance through a pi-Conjugated Cruciform Molecule by Selective Anchoring to Gold Electrodes. AB - Tuning charge transport at the single-molecule level plays a crucial role in the construction of molecular electronic devices. Introduced herein is a promising and operationally simple approach to tune two distinct charge-transport pathways through a cruciform molecule. Upon in situ cleavage of triisopropylsilyl groups, complete conversion from one junction type to another is achieved with a conductance increase by more than one order of magnitude, and it is consistent with predictions from ab initio transport calculations. Although molecules are well known to conduct through different orbitals (either HOMO or LUMO), the present study represents the first experimental realization of switching between HOMO- and LUMO-dominated transport within the same molecule. PMID- 26444183 TI - Hormonal contraceptive use before hCG remission does not increase the risk of gestational trophoblastic neoplasia following complete hydatidiform mole: a historical database review. AB - OBJECTIVE: To re-evaluate the safety of hormonal contraceptives (HC) after uterine evacuation of complete hydatidiform mole (CHM). DESIGN: Historical database review. SETTING: Charing Cross Hospital Gestational Trophoblastic Disease Centre, London, United Kingdom. POPULATION: Two thousand four hundred and twenty-three women with CHM of whom 154 commenced HC while their human chorionic gonadotropin (hCG) was still elevated, followed between 2003 and 2012. METHODS: We compared time to hCG remission between HC users and nonusers. The relationship between HC use and gestational trophoblastic neoplasia (GTN) development was assessed. The relationship between HC use and a high International Federation of Gynecology and Obstetrics (FIGO) risk score was determined. MAIN OUTCOME MEASURES: Time to hCG remission, risk of developing postmolar GTN and proportion of women with high FIGO risk score. RESULTS: No relationship was observed between HC use with mean time to hCG remission (HC users versus non-users: 12 weeks in both, P = 0.19), GTN development (HC users versus non-users: 20.1 and 16.7%, P = 0.26) or high-risk FIGO score (HC users versus nonusers: 0% and 8%, P = 0.15). Moreover, no association between HC and GTN development was found, even when an age-adjusted model was used (OR = 1.37, 95% CI 0.91-2.08, P = 0.13). CONCLUSIONS: The use of current HC is not associated with development of postmolar GTN or delayed time to hCG remission. Therefore, HC can be safely used to prevent a new conception following CHM regardless of hCG level. TWEETABLE ABSTRACT: Non concurrent cohort study to re-evaluate the safety of low dose HCs after uterine evacuation of CHM. PMID- 26444186 TI - Targeted Droplet-Digital PCR as a Tool for Novel Deletion Discovery at the DFNB1 Locus. AB - Pathogenic variants at the DFNB1 locus encompassing the GJB2 and GJB6 genes account for 50% of autosomal-recessive, congenital nonsyndromic hearing loss in the United States. Most cases are caused by sequence variants within the GJB2 gene, but a significant number of DFNB1 patients carry a large deletion (GJB6 D13S1830) in trans with a GJB2 variant. This deletion lies upstream of GJB2 and was shown to reduce GJB2 expression by disrupting unidentified regulatory elements. First-tier genetic testing for hearing loss includes GJB2 sequence and GJB6-D13S1830 deletion analysis; however, several other deletions in this locus, each with distinct breakpoints, have been reported in DFNB1 patients and are missed by current panels. Here, we report the development of a targeted droplet digital polymerase chain reaction-based assay for comprehensive copy-number analysis at the DFNB1 locus that detects all deletions reported to date. This assay increased detection rates in a multiethnic cohort of 87 hearing loss patients with only one identified pathogenic GJB2 variant. We identify two deletions, one of which is novel, in two patients (2/87 or 2.3%), suggesting that other pathogenic deletions at the DFNB1 locus may be missed. Mapping the assayed DFNB1 deletions also revealed a ~ 95 kb critical region, which may harbor the GJB2 regulatory element(s). PMID- 26444185 TI - Polydrug Use and HIV Risk Among People Who Inject Heroin in Tijuana, Mexico: A Latent Class Analysis. AB - BACKGROUND: Although most people who inject drugs (PWID) in Tijuana, Mexico, primarily inject heroin, injection and non-injection use of methamphetamine and cocaine is common. We examined patterns of polydrug use among heroin injectors to inform prevention and treatment of drug use and its health and social consequences. METHODS: Participants were PWID residing in Tijuana, aged >=18 years who reported heroin injection in the past six months and were recruited through respondent-driven sampling (n = 1,025). Latent class analysis was conducted to assign individuals to classes on a probabilistic basis, using four indicators of past six-month polydrug and polyroute use: cocaine injecting, cocaine smoking or snorting, methamphetamine injecting, and methamphetamine smoking or snorting. Latent class membership was regressed onto covariates in a multinomial logistic regression. RESULTS: Latent class analyses testing 1, 2, 3, and 4 classes were fit, with the 3-class solution fitting best. Class 1 was defined by predominantly heroin use (50.2%, n = 515); class 2 by methamphetamine and heroin use (43.7%, n = 448), and class 3 by methamphetamine, cocaine, and heroin use (6.0%, n = 62). Bivariate and multivariate analyses indicated a group of methamphetamine and cocaine users that exhibited higher-risk sexual practices and lower heroin injecting frequency, and a group of methamphetamine users who were younger and more likely to be female. CONCLUSIONS: Discrete subtypes of heroin PWID were identified based on methamphetamine and cocaine use patterns. These findings have identified subtypes of heroin injectors who require more tailored interventions to reduce the health and social harms of injecting drug use. PMID- 26444187 TI - Modification of solid lipid nanoparticles loaded with nebivolol hydrochloride for improvement of oral bioavailability in treatment of hypertension: polyethylene glycol versus chitosan oligosaccharide lactate. AB - Nebivolol (NB)-loaded solid lipid nanoparticles (SLNs) were prepared and modified with chitosan oligosaccharide lactate (COL) and polyethylene glycol (PEG) stearate for improvement of its oral bioavailability. Compritol, poloxamer and lecithin were used for the preparation of SLNs by homogenisation method. After in vitro characterisation effect of lipase, pepsin, or pancreatin on degradation and release rate were investigated. Cytotoxicity and permeation were studied on Caco 2 cells. As COL concentration increased in SLNs, size and zeta potential increased. PEG concentration was reversely proportional to particle size with no change in zeta potential. Encapsulation efficiencies (EEs) were determined as 84 98%. DSC confirmed solubilisation of NB in lipid matrix. A sustained release with no burst effect was determined. The presence of enzymes affected the release. SLNs did not reveal cytotoxicity and highest permeability was obtained with PEG modification. PEG-modified SLNs could be offered as a promising strategy for oral delivery of NB. PMID- 26444188 TI - Electromagnetic fields: activities in the European Commission with a focus on research projects and the Scientific Committee of Emerging and Newly Identified Health Risks (SCENIHR). AB - The article summarizes the main activities of the European Commission concerning electromagnetic fields. It explains also the regulatory context, with a special focus on past and current research projects funded by the European Union and the role of the SCENIHR in assessing risks related to EMF. Main conclusions of the SCENIHR opinion adopted in 2015 on EMF are reported. PMID- 26444189 TI - A need to provide explanations for observed biological effects of radiofrequency exposure. AB - Although there is scientific consensus that radiofrequency (RF) exposure at high intensity can cause thermal effects, including well-established adverse health effects, there is still considerable controversy on whether low-intensity RF exposure can cause biological effects, especially adverse health effects. The objective of this paper is to describe several reported "non-thermal" effects that were later shown to be due to a weak thermal effect or an experimental artifact by properly conducted and thorough follow-on scientific research. First, the multiple factors that can cause different RF energy absorption in biological tissues are reviewed and second, several examples of experimental artifacts in published papers are described to demonstrate the importance of paying attention to dosimetry and temperature control. For example, isolated nerve response studies show that when temperature of the RF-exposed tissues is controlled, effects disappeared. During RF exposure, conductive electrodes routinely used in physiological studies have been shown to cause field intensification at the tips or contacts of the electrodes with biological tissue; thus, the RF exposure at the site of measurement could be much higher than the incident field. In some in vitro studies, a lack of temperature uniformity in RF-exposed cell cultures and rate of heating explain changes originally reported to be due to low-level RF exposure. In other studies, detailed dosimetry studies have identified artifacts that explain the reasons why so-called "non-thermal" effects were mistakenly reported. Researchers should look for explanations for their own findings, and not expect others to figure out what was the reason for their observed effects. PMID- 26444190 TI - Near-field radiofrequency electromagnetic exposure assessment. AB - Personal wireless telecommunication devices, such as radiofrequency (RF) electromagnetic field (EMF) sources operated in vicinity of human body, have possible adverse health effects. Therefore, the correct EMF assessment is necessary in their near field. According to international near-field measurement criteria, the specific absorption rate (SAR) is used for absorbed energy distribution assessment in tissue simulating liquid phantoms. The aim of this investigation is to validate the relationship between the H-field of incident EMF and absorbed energy in phantoms. Three typical wireless telecommunication system frequencies are considered (900, 1800 and 2450 MHz). The EMF source at each frequency is an appropriate half-wave dipole antenna and the absorbing medium is a flat phantom filled with the suitable tissue simulating liquid. Two methods for SAR estimation have been used: standard procedure based on E-field measured in tissue simulating medium and a proposed evaluation by measuring the incident H field. Compared SAR estimations were performed for various distances between sources and phantom. Also, these research data were compared with simulation results, obtained by using finite-difference time-domain method. The acquired data help to determine the source near-field space characterized by the smallest deviation between SAR estimation methods. So, this region near the RF source is suitable for correct RF energy absorption assessment using the magnetic component of the RF fields. PMID- 26444191 TI - An historical overview of the activities in the field of exposure and risk assessment of non-ionizing radiation in Bulgaria. AB - The exposure and risk evaluation process in Bulgaria concerning non-ionizing radiation health and safety started in the early 1970s. Then, the first research laboratory "Electromagnetic fields in the working environment" was founded in the framework of the Centre of Hygiene, belonging to the Medical Academy, Sofia. The main activities were connected with developing legislation, new equipment for measurement of electromagnetic fields, new methods for measurement and exposure assessment, in vivo and human studies for developing methods, studying the effect of non-ionizing radiation on human body, developing exposure limits. Most of the occupations as metal industry, plastic welding, energetics, physiotherapy, broadcasting, telephone stations, computer industry, etc., have been covered by epidemiological investigations and risk evaluation. In 1986, the ANSI standard for safe use of lasers has been implemented as national legislation that gave the start for studies in the field of risk assessment concerning the use of lasers in industry and medicine. The environmental exposure studies started in 1991 following the very fast implementation of the telecommunication technologies. Now, funds for research are very insignificant, and studies in the field of risk assessment are very few. Nevertheless, Bulgaria has been an active member of the WHO International EMF Project, since 1997, and that gives good opportunity for collaboration with other Member states, and for implementation of new approach in the EMF policy for workers and people's protection against non-ionizing radiation exposure. PMID- 26444192 TI - XXIst century magnetotherapy. AB - This paper discusses the state of the art therapeutic application of magnetic and electromagnetic fields (EMF) in treatment of various medical problems - from pain relief to musculoskeletal trauma, to vascular and endocrine disorders. The paper describes problems related to physical parameters of used fields, biophysical dosimetry, clinical protocols, and safety of the device operators. Clinical benefits and mechanisms of action are also discussed. PMID- 26444193 TI - The role of cell hydration in realization of biological effects of non-ionizing radiation (NIR). AB - The weak knowledge on the nature of cellular and molecular mechanisms of biological effects of NIR such as static magnetic field, infrasound frequency of mechanical vibration, extremely low frequency of electromagnetic fields and microwave serves as a main barrier for adequate dosimetry from the point of Public Health. The difficulty lies in the fact that the biological effects of NIR depend not only on their thermodynamic characteristics but also on their frequency and intensity "windows", chemical and physical composition of the surrounding medium, as well as on the initial metabolic state of the organism. Therefore, only biomarker can be used for adequate estimation of biological effect of NIR on organisms. Because of the absence of such biomarker(s), organizations having the mission to monitor hazardous effects of NIR traditionally base their instruction on thermodynamic characteristics of NIR. Based on the high sensitivity to NIR of both aqua medium structure and cell hydration, it is suggested that cell bathing medium is one of the primary targets and cell hydration is a biomarker for NIR effects on cells and organisms. The purpose of this article is to present a short review of literature and our own experimental data on the effects of NIR on plants' seeds germination, microbe growth and development, snail neurons and heart muscle, rat's brain and heart tissues. PMID- 26444194 TI - Change of growth pattern, metabolism, and quality and quantity of maize plants after irrigation with magnetically treated water. AB - Water molecules can be affected by magnetic fields (MF) due to their bipolar characteristics. In the present study maize plants, from sowing to the end period of generative stage, were irrigated with magnetically treated water (MTW).Tap water was treated with MF by passing through a locally designed alternative magnetic field generating apparatus (110 mT). Irrigation with MTW increased the ear length and fresh weight, 100-grain fresh and dry weights, and water productivity (119.5%, 119.1%, 114.2%, 116.6% and 122.3%, respectively), compared with the control groups. Levels of photosynthetic pigments i.e. chlorophyll a and b, and the contents of anthocyanin and flavonoids of the leaves were increased compared to those of non-treated ones. Increase of the activity of superoxide dismutase (SOD) and ascorbate peroxidase (APX) in leaves of the treated plants efficiently scavenged active oxygen species and resulted in the maintenance of photosynthetic membranes and reduction of malondealdehyde. Total ferritin, sugar, iron and calcium contents of kernels of MTW-irrigated plants were respectively 122.9%, 167.4%, 235% and 185% of the control ones. From the results presented here it can be concluded that the influence of MF on living plant cells, at least in part, is mediated by water. The results also suggest that irrigation of maize plant with MTW can be applied as a useful method for improvement of quantity and quality of it. PMID- 26444195 TI - Investigation on the effect of static magnetic field up to 30 mT on viability percent, proliferation rate and IC50 of HeLa and fibroblast cells. AB - We have investigated the effects of static magnetic field (SMF) on the viability of the human cervical cancer (HeLa) cell line and fibroblast cells. The cells were cultured in DMEM medium and treated several times (24, 48,72 and 96 h) and at several intensities (5, 10, 20 and 30 mT) of magnetic field (MF). The cytotoxicity and cell viability percent in treated cells were performed using MTT assay by evaluating mitochondrial dehydrogenase activity. The MF ability on inducing cell death or inhibiting biochemical function was reported as cell death percent. The results showed that the increase of MF intensity and the time that cells were exposed to this treatment increased sharply cell death percent and proliferation rate in HeLa cell compare to fibroblast cells. Our data suggest that SMF biological effects on cell death were different in our selected targets. Cell type and time of exposure have been therefore found to be significant factors. These findings could be used to improve new effective method using SMF in conjunction with the common therapeutic approaches. PMID- 26444196 TI - Occupational exposure of personnel operating military radio equipment: measurements and simulation. AB - Technical literature provides numerous studies concerning radiofrequency exposure measurements for various radio communication devices, but there are few studies related to exposure of personnel operating military radio equipment. In order to evaluate exposure and identify cases when safety requirements are not entirely met, both measurements and simulations are needed for accurate results. Moreover, given the technical characteristics of the radio devices used in the military, personnel mainly operate in the near-field region so both measurements and simulation becomes more complex. Measurements were made in situ using a broadband personal exposimeter equipped with two isotropic probes for both electric and magnetic components of the field. The experiment was designed for three different operating frequencies of the same radio equipment, while simulations were made in FEKO software using hybrid numerical methods to solve complex electromagnetic field problems. The paper aims to discuss the comparative results of the measurements and simulation, as well as comparing them to reference levels specified in military or civilian radiofrequency exposure standards. PMID- 26444197 TI - Thermo-induced modifications and selective accumulation of glucose-conjugated magnetic nanoparticles in vivo in rats - increasing the effectiveness of magnetic assisted therapy - pilot study. AB - Ferro-Magnetic nanoparticles (Fe-MNP) have gained a lot of attention in biomedical and industrial applications due to their biocompatibility, ease of surface modification and paramagnetic properties. The basic idea of our study is whether it is possible to use glucose-conjugate Fe-MNP (Glc-Fe-MNP) for targeting and more accurate focusing in order to increase the effect of high-frequency electromagnetic fields induced hyperthermia in solid tumors. Tumors demonstrate high metabolic activity for glucose in comparison with other somatic cells.Increasing of accumulation of glucose conjugated (Glc)-Fe-MNP on tumor site and precision of radio frequency electro-magnetic field (RF-EMF) energy absorption in solid tumors, precede RF-EMF induced hyperthermia. Rat model for monitoring the early development of breast cancer. Twenty female Wistar rats (MU line-6171) were divided into two groups of 10 rats that were either treated with N-methyl-N-nitrosourea to induce breast cancer and 10 with carrageenan to induce inflammation (control). Glc-Fe-MNP can offer a solution to increase hyperthermia effect to the desired areas in the body by accumulation and increasing local concentration due to high tissue metabolic assimilation. In this condition, it is considered that the magnetization of the nanoparticles is a single-giant magnetic moment, the sum of all the individual magnetic moments and is proportional to the concentration of Glc-Fe-MNP. PMID- 26444198 TI - The treatment of tendon injury with electromagnetic fields evidenced by advanced ultrasound image processing. AB - This article presents a novel modality for accelerating the repair of tendon and ligament lesions by means of a specifically designed electromagnetic field in an equine model. This novel therapeutic approach employs a delivery system that induces a specific electrical signal from an external magnetic field derived from Superconductive QUantum Interference Device (SQUID) measurements of injured vs. healthy tissue. Evaluation of this therapy technique is enabled by a proposed new technology described as Predictive Analytical Imagery (PAITM). This technique examines an ultrasound grayscale image and seeks to evaluate it by means of look ahead predictive algorithms and digital signal processing. The net result is a significant reduction in background noise and the production of a high-resolution grayscale or digital image. PMID- 26444199 TI - Body mass index as a risk prediction and prevention factor for professional mixed low-intensity EMF burden. AB - The exposure conditions in the physiotherapy are characterized with various sources emitting electromagnetic fields (EMF) in different frequency ranges. Very little is known about the exposure modalities' influence on the operators. In this article, we present the effects of EMF on personnel morbidity profile dependent on the body mass index (BMI) increase. By cross-tabulation, the role of higher BMI on enhancing the EMF vulnerability potential is confirmed. The correlation of the higher BMI with some serious diseases and conditions' development has been evidenced statistically significant. Vy the whole-studied group, a general tendency for allergy, cardiovascular diseases, sleep disruption and age-shortened menopause, as well as allergy and leiomyoma in the expositional criteria subgroups (ESG), formed for the purposes of this study, is evidenced. The three ESGs are formed on work residence duration in the electrolight therapy section. The first - up to four working hour daily, the second - the entire working day (7 h) and the third group is not residenced in the electrolight therapy section. We hypothesize two signaling ways of interaction of the chronically low-intensity EMF and the higher BMI as the most likely: hormonal - by melatonin levels decrease due to estrogen levels increasing and endocrine - mast-cells auto replication and degranulation stimulation. Based on the results of the study, the BMI increase as an observed control factor in the prediction of the professional risk can be recommended. PMID- 26444200 TI - Extremely low frequency (ELF) stray magnetic fields of laboratory equipment: a possible co-exposure conducting experiments on cell cultures. AB - Measurements of extremely low frequency (ELF) magnetic fields were conducted in the environment of commercial laboratory equipment in order to evaluate the possible co-exposure during the experimental processes on cell cultures. Three types of device were evaluated: a cell culture CO2 incubator, a thermostatic water bath and a laboratory shaker table. These devices usually have electric motors, heating wires and electronic control systems, therefore may expose the cell cultures to undesirable ELF stray magnetic fields. Spatial distributions of magnetic field time domain signal waveform and frequency spectral analysis (FFT) were processed. Long- and short-term variation of stray magnetic field was also evaluated under normal use of investigated laboratory devices. The results show that the equipment under test may add a considerable ELF magnetic field to the ambient environmental magnetic field or to the intentional exposure to ELF, RF or other physical/chemical agents. The maximum stray magnetic fields were higher than 3 uT, 20 uT and 75 uT in the CO2 incubator, in water bath and on the laboratory shaker table, respectively, with high variation of spatial distribution and time domain. Our investigation emphasizes possible confounding factors conducting cell culture studies related to low-level ELF-EMF exposure due to the existing stray magnetic fields in the ambient environment of laboratory equipment. PMID- 26444201 TI - Protect children from EMF. AB - The twenty-first century is marked with aggressive development of the wireless communications (satellite, mobile phones, Internet, Wi-Fi). In addition to thousand of satellites that deliver radio and TV signals, large satellite and base station networks secure intensive instant delivery of audio and video information. It is fair to say that that the entire civilization, both biosphere and mankind are exposed to continuous exposure of multitude of radiofrequency (RF) signals. It should be taken into account that the entire world population is exposed to exponentially increasing RF radiation from base stations and satellite antennas. While several years ago the potential hazard was connected with placement of mobile phones close to human head, today "smart phones" represent small, but powerful computers continuously receiving audio and video data. The largest group of users is the children and teenagers who "need" to communicate nearly 24 h a day. This is even more important because cell phones and tablets may be seen in the hands of children as little as two years in age. There is no way to assess and predict the potential damages of children brain, vision and hearing under exposure to RF radiation. The WHO precautionary principle and IARC classification must be applied in discussing the potential hazard of the use of today's and tomorrow's communication devices. PMID- 26444202 TI - Electromagnetic fields from mobile phone base station - variability analysis. AB - The article describes the character of electromagnetic field (EMF) in mobile phone base station (BS) surroundings and its variability in time with an emphasis on the measurement difficulties related to its pulse and multi-frequency nature. Work also presents long-term monitoring measurements performed recently in different locations in Poland - small city with dispersed building development and in major polish city - dense urban area. Authors tried to determine the trends in changing of EMF spectrum analyzing daily changes of measured EMF levels in those locations. Research was performed using selective electromagnetic meters and also EMF meter with spectrum analysis. PMID- 26444203 TI - Subjective symptoms and their evolution in a small group of magnetic resonance imaging (MRI) operators recently engaged. AB - Using a specific questionnaire, we examined subjective symptoms in a group of 17 physicians (9 males and 8 females, mean age 32.9 +/- 3.71), attending a Postgraduate Medical School in Radiology and engaged in MRI for less than 1 year. Sixteen subjects (94%) reported the presence of at least one of the investigated symptoms during the period of MRI activity. The main symptoms were: unusual drowsiness/tiredness (88%), concentration problems (82%), headaches (76%), sleep disorders (47%), nausea (47%), illusion of movement (47%) and dizziness/vertigo (35%); the former two were subjectively related to MRI by the majority of the operators. These symptoms appeared (or worsened) in more than 15 min and, in the vast majority disappeared 30 min, or more, after the end of exposure. In 13 subjects (81%), the symptom (or some symptoms) appeared at least weekly. In this small group of health care workers recently exposed to MRI, the prevalence of subjective symptoms was higher than reported in other similar studies but, notably, the majority of subjects (77%) reported a regression within 4-8 weeks, suggesting some form of adaptation. PMID- 26444204 TI - Radiofrequency electromagnetic radiation exposure inside the metro tube infrastructure in Warszawa. AB - Antennas from various wireless communications systems [e.g. mobile phones base transceiver stations (BTS) and handsets used by passengers, public Internet access, staff radiophone transmitters used between engine-drivers and traffic operators] emitting radiofrequency electromagnetic radiation (RF-EMR) are used inside underground metro public transportation. Frequency-selective exposimetric investigations of RF-EMR exposure inside the metro infrastructure in Warsaw (inside metro cars passing between stations and on platforms) were performed. The statistical parameters of exposure to the E-field were analyzed for each frequency range and for a total value (representing the wide-band result of measurements of complex exposure). The recorded exposimetric profiles showed the dominant RF-EMR sources: handsets and BTS of mobile communication systems (GSM 900 and UMTS 2100) and local wireless Internet access (WiFi 2G). Investigations showed that the GSM 900 system is the dominant source of exposure - BTS (incessantly active) on platforms, and handsets - used by passengers present nearby during the tube drive. The recorded E-field varies between sources (for BTS were: medians - 0.22 V/m and 75th percentile - 0.37 V/m; and for handsets: medians - 0.28 V/m and 75th percentile - 0.47 V/m). Maximum levels (peaks) of exposure recorded from mobile handsets exceeded 10 V/m (upper limit of used exposimeters). Broadband measurements of E-field, including the dominant signal emitted by staff radiophones (151 MHz), showed that the level of this exposure of engine-drivers does not exceed 2.5 V/m. PMID- 26444205 TI - Dynamics of the public concern and risk communication program implementation. AB - The public concern about electromagnetic field (EMF) exposure varies due to different reasons. A part of them are connected with the better and higher quality of information that people receive from science, media, Internet, social networks, industry, but others are based on good communication programs performed by the responsible institutions, administration and persons. Especially, in Bulgaria, public concern follows interesting changes, some of them in correlation with the European processes of concern, but others following the economic and political processes in the country. Here, we analyze the dynamics of the public concern over the last 10 years. Our explanation of the decrease of the people's complaints against EMF exposure from base stations for mobile communication is as a result of our risk communication program that is in implementation for >10 years. PMID- 26444206 TI - Risk Factors for Stillbirth: Findings from a Population-Based Case-Control Study, Haryana, India. AB - BACKGROUND: Stillbirth is a prevalent adverse outcome of pregnancy in India despite efforts to improve care of women during pregnancy. Risk factors for stillbirths include sociodemographic factors, medical complications during pregnancy, intake of harmful drugs, and complications during delivery. The objective of the study was to examine the risk factors for stillbirth with a focus on sex selection drugs (SSDs). METHODS: A population-based case-control study was undertaken in Haryana. Cases of stillbirths were identified from the Maternal Infant Death Review System portal of Haryana state for the months of August-September 2014. A consecutive birth from the same geographical area as the case was selected as the control. The sample size was 325 per group. Mothers were interviewed using a validated tool. Bivariate analyses and logistic regression were conducted to examine the association between risk factors and stillbirth. Attributable risk proportions (ARP) and population attributable risk proportions (PARP) were estimated. RESULTS: The sociodemographic profiles of the cases and controls were similar. History of intake of SSDs [adjusted odds ratio (OR) 2.6, 95% confidence interval (CI) 1.5, 4.5] emerged as a risk factor. Other significant factors were preterm <37 weeks (OR 3.5, 95% CI 2.1, 6.0), history of previous stillbirths (OR 4.0, 95% CI 2.1, 7.8), and complications during labour (OR 3.3, 95% CI 2.1, 5.3). Estimates of the ARP and PARP for intake of SSDs were 0.60 (95% CI 0.32, 0.77) and 0.1 (95% CI -0.13, 0.28), respectively. CONCLUSIONS: SSDs could be attributed as a risk factor in a fifth of the cases of stillbirths. The number needed to harm for the use of SSDs in causing adverse effect of stillbirths was 5, suggesting thereby that for every five mothers exposed to SSDs, one would have stillbirth. Greater efforts are required to inform people about the harmful effects of SSD consumption during pregnancy. PMID- 26444207 TI - Cardioprotection and arrhythmias, Part 2. PMID- 26444208 TI - [The MATRIX study]. PMID- 26444209 TI - [The PEGASUS-TIMI 54 study]. PMID- 26444210 TI - [Endomyocardial biopsy should be performed in every patient with suspected myocarditis]. AB - The diagnosis of myocarditis is difficult because there is no pathognomonic clinical presentation and the disease may mimic other non-inflammatory diseases. Thus, current classifications on cardiomyopathies (e.g., the World Health Organization and the International Society and Federation of Cardiology [WHO/ISFC], the European Society of Cardiology [ESC], and the 2013 Expert Myocarditis ESC Task Force) define myocarditis as an inflammatory disease of the myocardium, which is diagnosed on endomyocardial biopsy (EMB) based upon histological, immunological, immunohistochemical and molecular tools. This will identify etiology, and differentiate between infectious, mainly viral, and non infectious, immune-mediated forms. The term "inflammatory cardiomyopathy" may be applied in biopsy-proven myocarditis with associated left, right or biventricular dysfunction. Myocarditis may resolve spontaneously, relapse or become chronic progressing to dilated cardiomyopathy, death or heart transplantation. The 2013 Myocarditis ESC Task Force consensus document recommends consideration of EMB and selective coronary angiography in all patients with clinically suspected myocarditis according to the Task Force criteria. It is recommended that EMB analysis includes not only histology (Dallas criteria), but also immunohistology and detection of the genome of infectious agents by molecular tools. EMB should be performed by expert teams. The rationale for this diagnostic effort is the availability of a wide range of immunosuppressive or immunomodulatory agents that, as shown in systemic extracardiac autoimmune disease and in many clinical studies, can be used in infection-negative myocarditis patients to stop or at least stabilize chronic cardiac tissue damage mediated by the immune system, and thus prevent fibrosis and progression to irreversible end-stage dilated cardiomyopathy. PMID- 26444211 TI - [Endomyocardial biopsy should be performed in selected patients with suspected myocarditis]. AB - Endomyocardial biopsy (EMB) is the gold standard for the diagnosis of myocarditis. Patients with clinical presentation consistent with myocarditis and acute heart failure should undergo EMB, in particular to exclude giant-cell myocarditis or necrotizing eosinophilic myocarditis that are life-threatening conditions. The indication for EMB is debatable in case of suspected myocarditis with infarct-like presentation and preserved left ventricular ejection fraction. In fact, in this group of patients the prognosis is fairly good, and the clinical advantage to reach a histological diagnosis by means of an invasive procedure with potential complications such as EMB is limited. In this article we discuss the indication for EMB in the light of current guidelines based on existing consensus documents. PMID- 26444212 TI - [Controversies on the role of mitochondria in coronary reperfusion damage as potential therapeutic target]. AB - Reperfusion of an occluded coronary artery is the most effective intervention in reducing cardiac injury which occurs as a consequence of an acute myocardial infarction. However, reperfusion per se may exacerbate the extent of myocardial injury which started at the onset of ischemia, thus leading to the so-called "reperfusion injury". The published studies in the last few years provide new hopes on the mitochondrion and its role in ischemia/reperfusion injury, through the modulation of the mitochondrial permeability pore. After very encouraging experimental data, two clinical trials are presented, CIRCUS and CYCLE, which should help addressing the still outstanding question: may an intervention targeted to decrease the permeability of the mitochondrial pore during reperfusion reduce infarct size and improve clinical outcomes of patients with myocardial infarction undergoing primary percutaneous coronary intervention? PMID- 26444213 TI - [The emerging role of three-dimensional transesophageal echocardiography in guiding the MitraClip procedure]. AB - Percutaneous edge-to-edge mitral valve repair with the MitraClip device has been shown to be a safe and effective procedure in selected patients with moderate-to severe mitral regurgitation. Two-dimensional transesophageal echocardiography (2D TEE) is the primary imaging modality for guidance of the procedure. Real-time three-dimensional (3D) TEE has recently been used as additional imaging modality during the MitraClip procedure. In comparison with 2D TEE, 3D TEE provides additional information in several steps of the procedure, including precise positioning of the clip delivery system into the left atrium, correct alignment of the clip arms perpendicular to the coaptation line and confirmation of the correct grasping location. This review describes the relevant role of 3D TEE imaging during the procedure, but also its limitations. PMID- 26444214 TI - [Percutaneous treatment of chronic total occlusions: state of the art and future perspectives]. AB - Coronary chronic total occlusions (CTO) are a frequent finding in patients undergoing coronary angiography. However, a low percentage of patients is still referred for percutaneous coronary intervention. The main reasons lie in the skepticism concerning the real benefit and high technical complexity of these interventions. In recent years, thanks to the growing operators' experience and the introduction of new techniques and materials, the procedural success has increased with relatively low complication rates. There is growing evidence in recent literature that percutaneous recanalization improves symptoms and quality of life, increases ejection fraction and prolongs survival. Appropriate patient selection alone may involve a real clinical benefit in case of percutaneous CTO treatment. The key to procedural success is to use the right method and the knowledge of dedicated techniques and devices: CTO recanalization should be performed by experienced operators, and non-CTO interventionalists should approach these procedures only after specific training. PMID- 26444215 TI - [A novel standard protocol of long-term follow-up shared with general practitioners after percutaneous coronary intervention: appropriateness and economic impact]. AB - BACKGROUND: Follow-up modalities for patients undergoing percutaneous coronary intervention (PCI) are not well defined and standard protocols have been not established. The purpose of this study was to assess: a) the frequency and patterns of cardiology visits, echocardiographic examinations and stress tests after PCI in clinical practice; b) the impact of a multidisciplinary protocol of long-term follow-up after PCI shared with general practitioners on the appropriateness and reduction in healthcare costs. METHODS: A total of 780 patients who underwent PCI in 2010 in two Italian hospitals were analyzed. The number of cardiological examinations (total, routine and clinically driven) performed during 2 years of follow-up were recorded and stratified according to the patient's risk profile. The latter was defined according to the multidisciplinary protocol. In addition, a simulation of the spread between provided and necessary tests (according to the multidisciplinary protocol) was carried out. RESULTS: The mean number of cardiological examinations per patient provided during follow-up was 5, of which 4.4 were routine tests in asymptomatic patients. Routine tests were performed more frequently in patients at low risk compared to those at higher risk. By applying the multidisciplinary protocol to the case mix and by merging clinical visit and stress test or echocardiographic examination, a reduction of 0.87 tests per patient/year would be expected. This reduction would result in a 39% decrease in follow-up examinations in this specific clinical setting. CONCLUSIONS: This observational study demonstrates that unnecessary cardiological clinical and functional tests are often performed in long-term follow-up of patients submitted to PCI. The application of a standard protocol of follow-up shared with general practitioners may help avoiding unnecessary consultations, thus reducing healthcare costs. PMID- 26444216 TI - [An unexpected culprit lesion: subclavian artery stenosis]. AB - After non-ST-elevation myocardial infarction, a 61-year-old woman underwent coronary artery bypass grafting with left internal mammary artery (LIMA) to left anterior descending artery combined with saphenous vein grafts to the second obtuse marginal branch and the right coronary artery. At age 79, she was admitted for anterior non-ST-elevation myocardial infarction. Echocardiography showed hypokinesia of the left anterior descending territory. From the left radial approach the LIMA graft was patent, but a critical stenosis of the proximal subclavian artery was diagnosed and treated with stenting. The coronary subclavian steal syndrome usually presents with effort angina but has rarely been reported as a cause of myocardial infarction. A coronary steal syndrome should be suspected in patients with internal mammary artery bypass with recurrence of angina but also in case of acute coronary syndrome. When stable angina is present, a computed tomography scan of the bypass and subclavian artery may allow diagnosis before coronary angiography. In case of urgent coronary angiography and undetectable culprit lesions, selective angiography of the subclavian artery may confirm the suspicion of the coronary steal syndrome. PMID- 26444217 TI - [The radial access approach in complex coronary anatomy: case report and literature review]. AB - The radial artery approach has been accepted as an alternative to the traditional femoral approach in both diagnostic and interventional procedures, including treatment of complex coronary lesions such as chronic total occlusions. Catheterization of the left internal mammary artery (LIMA) graft is frequently performed through this route in order to limit catheter manipulation and avoid dissection of the subclavian and mammary artery, a dramatic event rarely reported in the literature. Nonetheless, indication for this approach should be carefully evaluated, especially if an unfavorable angle of origin of the mammary artery is present. We report the case of a patient who, following iatrogenic dissection of the LIMA during catheterization through the left radial artery, was electively treated with percutaneous coronary angioplasty on a complex anatomy, rather than with high-risk redo coronary artery bypass surgery. Using a combined radial and femoral approach, retrograde disobstruction of the left anterior descending artery, followed by plaque debulking with rotational atherectomy through the struts of a previously implanted stent in the left main-left circumflex artery, was performed. Although the radial approach might be considered even for the treatment of complex coronary anatomy subsets, appropriate use in diagnostic and interventional settings should always be carefully evaluated. PMID- 26444218 TI - [Position paper of the Italian Society of Invasive Cardiology (SICI-GISE) on indications for coronary angiography in patients with stable angina]. AB - Available data suggest a steep increase in stable coronary artery disease with age. Its prevalence reaches a peak of almost 12-14% in men aged 65-84 years with an annual mortality ranging from 1.2% to 2.4%. The diagnosis of stable angina is primarily based on history and therefore relies on clinical judgment. In addition, its diagnosis can be extremely challenging because of the frequent transition from unstable to stable angina. Current European guidelines on the management of stable coronary artery disease give increased importance to the pre test probability, which strongly affects the diagnostic algorithms. Imaging techniques play a greater role in the diagnosis of stable angina than in the past. Conversely, despite recent advances in technology and in the physiological assessment of coronary stenosis, an ever decreasing relevance is conferred to coronary angiography. Another difficult and controversial issue relates to the prognostic benefit of myocardial revascularization. The aim of this position paper is to review the most relevant clinical aspects of the European guidelines on the management of stable coronary artery disease. PMID- 26444219 TI - [SICI-GISE position paper on standards and guidelines for diagnostic and catheterization laboratories]. AB - In the last few years, the activity of cath labs has undergone some notable changes, at present largely focusing on diagnosis and invasive therapy of a broad spectrum of cardiovascular diseases. Technological and pharmacological advances have allowed for procedures to be performed in patients who are increasingly complex, and cath labs have become the preferred venue for endovascular treatment of coronary artery disease, in particular acute coronary syndrome, as well as the treatment of structural heart disease and peripheral vascular disease. This position paper is an update of the 1996 and 2008 versions, given the present level of experience and the situation in Italy. It aims to provide the quality standards required to maintain adequate conditions of know-how and safety, as well as the structural and organizational requirements that are fundamental to obtain the best possible use of human and technological resources. Position papers should be a stimulus and guide for operators in the field as well as for those who govern health policies. This should allow for an improved and more rational allocation of cath labs in Italy, based on the real need for procedures and an optimal distribution and organization of the cardiovascular emergency networks while respecting the minimum standards of care. PMID- 26444220 TI - Online Advertising for Cancer Prevention: Google Ads and Tanning Beds. PMID- 26444222 TI - Timing of elective cesarean section and neonatal morbidity: a population-based study. AB - PURPOSE: To assess the incidence of neonatal complications related to gestational age at elective cesarean section near term. METHODS: We used a population-based dataset to compare neonatal outcomes by gestational age in uncomplicated singleton pregnancies delivered by elective cesarean section >=37 weeks. RESULTS: A total of 7364 mothers had an elective cesarean during 2002-2012; 343 (4.7%) at 37, 21 753 (3.8%) at 38, 3140 (2.6%) at 39, 1718 (23.3%) at 40 and 410 (5.6%) at >=41 weeks. Infants born at a lower gestational age had a higher rate of Apgar scores <7 (2%, 0.4%, 0.6%, 0,3%, 0.2% at 37, 38, 39, 40 and >=41 week, p = 0.013), hypoglycemia (1.5%, 1.0%, 0.8%, 0.4%, 0.5% at 37, 38, 39, 40 and >= 41 week, p = 0.012), hyperbilirubinemia (12.2%, 9.5%, 6.4%, 4.8%, 4.1% at 37, 38, 39, 40 and >= 41 week, p < 0.001), respiratory distress syndrome (5.5%, 2.2%, 1.6%, 0.5%, 0.7% at 37, 38, 39, 40 and >= 41 week, p < 0.001), and neonatal intensive care admissions (8.7%, 2.3%, 1.9%, 1.0%, 1.7% at 37, 38, 39, 40 and >= 41 week, p < 0.001). CONCLUSIONS: Elective cesarean section at >= 39 weeks gestation would significantly reduce neonatal complications. PMID- 26444223 TI - Comparative analysis of redox and inflammatory properties of pristine nanomaterials and commonly used semiconductor manufacturing nano-abrasives. AB - Continued expansion of the nanotechnology industry has necessitated the self assessment of manufacturing processes, specifically in regards to understanding the health related aspects following exposure to nanomaterials. There exists a growing concern over potential occupational exposure in the semiconductor industry where Al2O3, CeO2 and SiO2 nanoparticles are commonly featured as part of the chemical mechanical planarization (CMP) process. Chronic exposure to toxicants can result not only in acute cytotoxicity but also initiation of a chronic inflammatory state associated with diverse pathologies. In the current investigation, pristine nanoparticles and CMP slurry formulations of Al2O3, SiO2 and CeO2 were employed to assess their ability to induce cytotoxicity, inflammatory responses and reactive oxygen species in a mouse alveolar macrophage cell model. The pristine nanoparticles and slurries were not intrinsically cytotoxic and did not generate free radicals but were found to act as scavengers in the presence of an oxidant stimulant. Al2O3 and SiO2 nanoparticles increased levels of pro-inflammatory cytokines while pristine SiO2 nanoparticles induced generation of F2-Isoprostanes. In co-treatment studies, the pristine nanomaterials modulated the response to the inflammatory stimulant lipopolysaccharide. The studies have established that pristine nanoparticles and slurries do not impact the cells in a similar way indicating that they should not be used as slurry substitutes in toxicity evaluations. Further, we have defined how an alveolar cell line, which would likely be the first challenged upon nanomaterial aerosolization, responds to diverse mixtures of nanomaterials. Moreover, our findings reinforce the importance of using multiple analytic methods to define the redox state of the cell following exposure to commonly used industrial nanomaterials and toxicants. PMID- 26444224 TI - Histological and biomechanical changes in a mouse model of venous thrombus remodeling. AB - BACKGROUND: Deep vein thrombosis and the risk of pulmonary embolism are significant causes of morbidity and mortality. Much remains unclear, however, about the mechanisms by which a venous thrombus initiates, progresses, or resolves. In particular, there is a pressing need to characterize the evolving mechanical properties of a venous thrombus for its mechanical integrity is fundamental to many disease sequelae. OBJECTIVE: The primary goal of the present study was to initiate a correlation between evolving histological changes and biomechanical properties of venous thrombus. METHODS: We employed an inferior vena cava ligation model in mice to obtain cylindrical samples of thrombus that were well suited for mechanical testing and that could be explanted at multiple times following surgery. Using uniaxial micro-mechanical testing, we collected stress-stretch data that were then fit with a microstructurally-inspired material model before submitting the samples to immunohistological examination. RESULTS: We found that venous thrombus underwent a radially inward directed replacement of fibrin with collagen between 2 weeks and 4 weeks of development, which was accompanied by the infiltration of inflammatory and mesenchymal cells. These histological changes correlated with a marked increase in material stiffness. CONCLUSIONS: We demonstrated that 2 to 4 week old venous thrombus undergoes drastic remodeling from a fibrin-dominated mesh to a collagen-dominated microstructure and that these changes are accompanied by dramatic changes in biomechanical behavior. PMID- 26444221 TI - Hypothermia for Intracranial Hypertension after Traumatic Brain Injury. AB - BACKGROUND: In patients with traumatic brain injury, hypothermia can reduce intracranial hypertension. The benefit of hypothermia on functional outcome is unclear. METHODS: We randomly assigned adults with an intracranial pressure of more than 20 mm Hg despite stage 1 treatments (including mechanical ventilation and sedation management) to standard care (control group) or hypothermia (32 to 35 degrees C) plus standard care. In the control group, stage 2 treatments (e.g., osmotherapy) were added as needed to control intracranial pressure. In the hypothermia group, stage 2 treatments were added only if hypothermia failed to control intracranial pressure. In both groups, stage 3 treatments (barbiturates and decompressive craniectomy) were used if all stage 2 treatments failed to control intracranial pressure. The primary outcome was the score on the Extended Glasgow Outcome Scale (GOS-E; range, 1 to 8, with lower scores indicating a worse functional outcome) at 6 months. The treatment effect was estimated with ordinal logistic regression adjusted for prespecified prognostic factors and expressed as a common odds ratio (with an odds ratio <1.0 favoring hypothermia). RESULTS: We enrolled 387 patients at 47 centers in 18 countries from November 2009 through October 2014, at which time recruitment was suspended owing to safety concerns. Stage 3 treatments were required to control intracranial pressure in 54% of the patients in the control group and in 44% of the patients in the hypothermia group. The adjusted common odds ratio for the GOS-E score was 1.53 (95% confidence interval, 1.02 to 2.30; P=0.04), indicating a worse outcome in the hypothermia group than in the control group. A favorable outcome (GOS-E score of 5 to 8, indicating moderate disability or good recovery) occurred in 26% of the patients in the hypothermia group and in 37% of the patients in the control group (P=0.03). CONCLUSIONS: In patients with an intracranial pressure of more than 20 mm Hg after traumatic brain injury, therapeutic hypothermia plus standard care to reduce intracranial pressure did not result in outcomes better than those with standard care alone. (Funded by the National Institute for Health Research Health Technology Assessment program; Current Controlled Trials number, ISRCTN34555414.). PMID- 26444225 TI - Storage and source of polycyclic aromatic hydrocarbons in sediments downstream of a major coal district in France. AB - During the 20th century, the local economy of the Upper Loire Basin (ULB) was essentially based on industrial coal mining extraction. One of the major French coal districts with associated urban/industrial activities and numerous coking/gas plants were developed in the Ondaine-Furan subbasins, two tributaries of the upper Loire main stream. To determine the compositional assemblage, the level and the potential sources of contamination, the historical sedimentary chronicle of the 16 US EPA priority polycyclic aromatic hydrocarbons (PAHs) has been investigated. PAH concentrations were determined using gas chromatography/mass spectrometry (GC/MS) in a dated core, sampled in the Villerest flood-control reservoir located downstream of the Ondaine-Furan corridor (OFC). The most contaminated sediments were deposited prior to 1983 (Sigma16PAHs ca. 4429-13,348 ng/g) and during flood events (Sigma16PAHs ca. 6380 ng/g - 1996 flood; 5360 ng/g - 2003 flood; 6075 ng/g - 2008 flood), especially in medium and high molecular weight PAHs. Among them, typical pyrogenic PAHs such as FLT, PYR, BbF and BaP were prevalent in most of the core samples. In addition, some PAHs last decade data is available from the Loire Bretagne Water Agency and were analyzed using high-performance liquid chromatography with postcolumn fluorescence derivatization (HPLC/FLD). These results confirm that the most highly contaminated sediments were found downstream of OFC (Sigma16PAHs ca. 2264 7460 ng/g). According to the observed molecular distribution, PAHs are originated largely from high-temperature pyrolytic processes. Major sources of pyrogenic PAHs have been emphasized by calculation of specific ratios and by comparison to reported data. Atmospheric deposition of urban and industrial areas, wood combustion and degraded coal tar derived from former factories of coking/gas plants seem to be the major pyrogenic sources. Specifically, particular solid transport conditions that can occur during major flood events lead us to emphasize weathering of former contamination sources, such as more preserved coal tar. PMID- 26444226 TI - Constitutive stable DNA replication in Escherichia coli cells lacking type 1A topoisomerase activity. AB - Type 1A topoisomerases (topos) are ubiquitous enzymes involved in supercoiling regulation and in the maintenance of genome stability. Escherichia coli possesses two type 1A enzymes, topo I (topA) and topo III (topB). Cells lacking both enzymes form very long filaments and have severe chromosome segregation and growth defects. We previously found that RNase HI overproduction or a dnaT::aph mutation could significantly correct these phenotypes. This leads us to hypothesize that they were related to unregulated replication originating from R loops, i.e. constitutive stable DNA replication (cSDR). cSDR, first observed in rnhA (RNase HI) mutants, is characterized by its persistence for several hours following protein synthesis inhibition and by its requirement for primosome components, including DnaT. Here, to visualize and measure cSDR, the incorporation of the nucleotide analog ethynyl deoxyuridine (EdU) during replication in E. coli cells pre-treated with protein synthesis inhibitors, was revealed by "click" labeling with Alexa Fluor((r)) 488 in fixed cells, and flow cytometry analysis. cSDR was detected in rnhA mutants, but not in wild-type strains, and the number of cells undergoing cSDR was significantly reduced by the introduction of the dnaT::aph mutation. cSDR was also found in topA, double topA topB but not in topB null cells. This result is consistent with the established function of topo I in the inhibition of R-loop formation. Moreover, our finding that topB rnhA mutants are perfectly viable demonstrates that topo III is not uniquely required during cSDR. Thus, either topo I or III can provide the type 1A topo activity that is specifically required during cSDR to allow chromosome segregation. PMID- 26444227 TI - Syn-Selective Synthesis of beta-Branched alpha-Amino Acids by Alkylation of Glycine-Derived Imines with Secondary Sulfonates. AB - A syn-selective synthesis of beta-branched alpha-amino acids has been developed based on the alkylation of glycine imine esters with secondary sulfonates. The potassium counterion for the enolate, the solvent, and the leaving group on the electrophile were key levers to maximize the diasteroselectivity of the alkylation. The optimized conditions enabled a straightforward preparation of a number of beta-branched alpha-amino acids that can be challenging to obtain. PMID- 26444228 TI - [Will there be new drugs for patients in Iceland 2016?[Editorial]]. PMID- 26444229 TI - [Meeting refugees[Editorial]]. PMID- 26444230 TI - [Prevalence of sport injuries, sport participation and drop out due to injury in young adults]. AB - INTRODUCTION: Sport participation has increased during the past few decades, with accompanying rise in sport injuries. The purpose of this study was to assess the prevalence of sport injuries, and drop-out due to them along with possible risk factors (hours of sports participation, sex, age, aerobic fitness and body composition). MATERIAL AND METHODS: A retrospective, cross-sectional design was used and the 457 participants were 17 and 23 years old. Height, weight, body fat, lean soft tissue, bone mass, and aerobic fitness (W/kg) were measured. Participation in sports and physical training, and the prevalence of sport injuries and drop-out were estimated using questionnaires. RESULTS: Four hundred and forty participants (96%) had at some time point participated in organized sports, but 277 (63%) were no longer practicing, more commonly (p=0.058) among girls (67.6%) than boys (58.8%). Thirty-seven (8.4%) dropped-out due to sport injuries. Of those participating in organized sports for the past 12 months, 51% required medical assistance at least once because of sport injuries. Multiple regression analysis revealed 5-fold increased risk for requiring medical assistance among those practicing more than 6 hours per week compared to those who practiced 6 hours or less (OR=5.30, 95% CI: 3.00 to 9.42). CONCLUSION: Youth sport injuries are a significant problem that can cause drop-out from participation in sport. More research is needed to better understand the impact of risk factors in order to promote prevention and ensure evidence-based training. PMID- 26444231 TI - [Case of the month. An elderly woman with dyspnea and stridor]. PMID- 26444232 TI - [Human Primordial Germ Cell Specification--Breakthrough In Culture and Hopes for Therapeutic Utilization]. AB - Germ cells are the precursors to the gametes that carry genetic and epigenetic information between human generations and generate a new individual. Because germ cells are specified early during embryogenesis, at the time of embryo implantation, they are inaccessible for research. Our understanding of their biology has therefore developed slowly since their identification over one hundred years ago. As a result of research into the properties of human and mouse embryonic stem cells and primordial germ cells, scientists have now succeeded in efficiently generating human primordial germ cells in culture by embryonic stem cell and induced pluripotent stem cell culture. In this review we will discuss the state of our knowledge of human primordial germ cells and how research into the pluripotent properties of human and mouse embryonic germ cells has led to this breakthrough. In addition we will discuss the possible utilization of a cell culture system of human primordial germ cells for research into and treatment of germ cell related abnormalities. PMID- 26444233 TI - Evolution: An avian explosion. PMID- 26444234 TI - Erratum: Arithmetic and local circuitry underlying dopamine prediction errors. PMID- 26444235 TI - Biological techniques: Kidney tissue grown from induced stem cells. PMID- 26444236 TI - Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. AB - The human kidney contains up to 2 million epithelial nephrons responsible for blood filtration. Regenerating the kidney requires the induction of the more than 20 distinct cell types required for excretion and the regulation of pH, and electrolyte and fluid balance. We have previously described the simultaneous induction of progenitors for both collecting duct and nephrons via the directed differentiation of human pluripotent stem cells. Paradoxically, although both are of intermediate mesoderm in origin, collecting duct and nephrons have distinct temporospatial origins. Here we identify the developmental mechanism regulating the preferential induction of collecting duct versus kidney mesenchyme progenitors. Using this knowledge, we have generated kidney organoids that contain nephrons associated with a collecting duct network surrounded by renal interstitium and endothelial cells. Within these organoids, individual nephrons segment into distal and proximal tubules, early loops of Henle, and glomeruli containing podocytes elaborating foot processes and undergoing vascularization. When transcription profiles of kidney organoids were compared to human fetal tissues, they showed highest congruence with first trimester human kidney. Furthermore, the proximal tubules endocytose dextran and differentially apoptose in response to cisplatin, a nephrotoxicant. Such kidney organoids represent powerful models of the human organ for future applications, including nephrotoxicity screening, disease modelling and as a source of cells for therapy. PMID- 26444237 TI - A comprehensive phylogeny of birds (Aves) using targeted next-generation DNA sequencing. AB - Although reconstruction of the phylogeny of living birds has progressed tremendously in the last decade, the evolutionary history of Neoaves--a clade that encompasses nearly all living bird species--remains the greatest unresolved challenge in dinosaur systematics. Here we investigate avian phylogeny with an unprecedented scale of data: >390,000 bases of genomic sequence data from each of 198 species of living birds, representing all major avian lineages, and two crocodilian outgroups. Sequence data were collected using anchored hybrid enrichment, yielding 259 nuclear loci with an average length of 1,523 bases for a total data set of over 7.8 * 10(7) bases. Bayesian and maximum likelihood analyses yielded highly supported and nearly identical phylogenetic trees for all major avian lineages. Five major clades form successive sister groups to the rest of Neoaves: (1) a clade including nightjars, other caprimulgiforms, swifts, and hummingbirds; (2) a clade uniting cuckoos, bustards, and turacos with pigeons, mesites, and sandgrouse; (3) cranes and their relatives; (4) a comprehensive waterbird clade, including all diving, wading, and shorebirds; and (5) a comprehensive landbird clade with the enigmatic hoatzin (Opisthocomus hoazin) as the sister group to the rest. Neither of the two main, recently proposed Neoavian clades--Columbea and Passerea--were supported as monophyletic. The results of our divergence time analyses are congruent with the palaeontological record, supporting a major radiation of crown birds in the wake of the Cretaceous Palaeogene (K-Pg) mass extinction. PMID- 26444238 TI - Control of REM sleep by ventral medulla GABAergic neurons. AB - Rapid eye movement (REM) sleep is a distinct brain state characterized by activated electroencephalogram and complete skeletal muscle paralysis, and is associated with vivid dreams. Transection studies by Jouvet first demonstrated that the brainstem is both necessary and sufficient for REM sleep generation, and the neural circuits in the pons have since been studied extensively. The medulla also contains neurons that are active during REM sleep, but whether they play a causal role in REM sleep generation remains unclear. Here we show that a GABAergic (gamma-aminobutyric-acid-releasing) pathway originating from the ventral medulla powerfully promotes REM sleep in mice. Optogenetic activation of ventral medulla GABAergic neurons rapidly and reliably initiated REM sleep episodes and prolonged their durations, whereas inactivating these neurons had the opposite effects. Optrode recordings from channelrhodopsin-2-tagged ventral medulla GABAergic neurons showed that they were most active during REM sleep (REMmax), and during wakefulness they were preferentially active during eating and grooming. Furthermore, dual retrograde tracing showed that the rostral projections to the pons and midbrain and caudal projections to the spinal cord originate from separate ventral medulla neuron populations. Activating the rostral GABAergic projections was sufficient for both the induction and maintenance of REM sleep, which are probably mediated in part by inhibition of REM-suppressing GABAergic neurons in the ventrolateral periaqueductal grey. These results identify a key component of the pontomedullary network controlling REM sleep. The capability to induce REM sleep on command may offer a powerful tool for investigating its functions. PMID- 26444239 TI - The genetic sex-determination system predicts adult sex ratios in tetrapods. AB - The adult sex ratio (ASR) has critical effects on behaviour, ecology and population dynamics, but the causes of variation in ASRs are unclear. Here we assess whether the type of genetic sex determination influences the ASR using data from 344 species in 117 families of tetrapods. We show that taxa with female heterogamety have a significantly more male-biased ASR (proportion of males: 0.55 +/- 0.01 (mean +/- s.e.m.)) than taxa with male heterogamety (0.43 +/- 0.01). The genetic sex-determination system explains 24% of interspecific variation in ASRs in amphibians and 36% in reptiles. We consider several genetic factors that could contribute to this pattern, including meiotic drive and sex-linked deleterious mutations, but further work is needed to quantify their effects. Regardless of the mechanism, the effects of the genetic sex-determination system on the adult sex ratio are likely to have profound effects on the demography and social behaviour of tetrapods. PMID- 26444241 TI - Peptoid nanosheets exhibit a new secondary-structure motif. AB - A promising route to the synthesis of protein-mimetic materials that are capable of complex functions, such as molecular recognition and catalysis, is provided by sequence-defined peptoid polymers--structural relatives of biologically occurring polypeptides. Peptoids, which are relatively non-toxic and resistant to degradation, can fold into defined structures through a combination of sequence dependent interactions. However, the range of possible structures that are accessible to peptoids and other biological mimetics is unknown, and our ability to design protein-like architectures from these polymer classes is limited. Here we use molecular-dynamics simulations, together with scattering and microscopy data, to determine the atomic-resolution structure of the recently discovered peptoid nanosheet, an ordered supramolecular assembly that extends macroscopically in only two dimensions. Our simulations show that nanosheets are structurally and dynamically heterogeneous, can be formed only from peptoids of certain lengths, and are potentially porous to water and ions. Moreover, their formation is enabled by the peptoids' adoption of a secondary structure that is not seen in the natural world. This structure, a zigzag pattern that we call a Sigma('sigma')-strand, results from the ability of adjacent backbone monomers to adopt opposed rotational states, thereby allowing the backbone to remain linear and untwisted. Linear backbones tiled in a brick-like way form an extended two dimensional nanostructure, the Sigma-sheet. The binary rotational-state motif of the Sigma-strand is not seen in regular protein structures, which are usually built from one type of rotational state. We also show that the concept of building regular structures from multiple rotational states can be generalized beyond the peptoid nanosheet system. PMID- 26444242 TI - Erratum: A positional Toll receptor code directs convergent extension in Drosophila. PMID- 26444243 TI - Prevalence of Obesity and Overweight in an Indigenous Population in Central Brazil: A Population-Based Cross-Sectional Study. AB - OBJECTIVE: To estimate the prevalence of obesity and overweight and associated factors in indigenous people of the Jaguapiru village in Central Brazil. METHODS: We conducted a population-based cross-sectional study between January 2009 and July 2011 in the adult native population of the Jaguapiru village, Central Brazil. Sociodemographic and lifestyle data were obtained; anthropometric measures, arterial blood pressure, and blood glucose were measured. The independent variables were tested by Poisson regression, and the interactions between them were analyzed. RESULTS: 1,608 indigenous people (982 females, mean age 37.7 +/- 15.1 years) were included. The prevalence of obesity was 23.2% (95% CI 20.9-25.1%). Obesity was more prevalent among 40- to 49-year-old and overweight among 50- to 59-year-old persons. Obesity was positively associated with female sex, higher income, and hypertension. Among indigenous people, interactions were found with hypertension and sedentary lifestyle - hypertension in males and sedentary lifestyle in females. CONCLUSIONS: The prevalence of obesity and overweight in indigenous people of the Jaguapiru village is high. Males as well as hypertensive and higher family income individuals have higher rates. Sedentary lifestyle and hypertension leverage the rates of obesity. Prevention and adequate public health policies can be critical for the control of excess weight and its comorbidities among Brazilian indigenous people. PMID- 26444240 TI - Alternative transcription initiation leads to expression of a novel ALK isoform in cancer. AB - Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in ~11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novel ALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALK(ATI). In ALK(ATI)-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK(ATI) is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK(ATI) transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALK(ATI) stimulates multiple oncogenic signalling pathways, drives growth-factor independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK(ATI), suggesting that patients with ALK(ATI)-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation. PMID- 26444244 TI - High-Intensity Induction in the Elderly. PMID- 26444245 TI - Supramolecular Macrocyclic Pd(II) and Pt(II) Squares and Rectangles with Aryldithiolate Ligands and their Excellent Catalytic Activity in Suzuki C-C Coupling Reaction. AB - Addition of 1,4-benezenedithiol and 4,4'-biphenyldithiol to M(OTf)2 (M = cis [Pt(PEt3)2](2+) or cis-[Pd(dppe)](2+)) (dppe = 1,2-bis(diphenylphosphino)ethane) gave self-assembled tetranuclear complexes [M2{S(C6H4)nS}]2(OTf)4 (n = 1, 2). The same reaction with 1,4-benezenedimethanethiol yielded octanuclear supramolecular coordination complexes (SCC) [M2{SCH2C6H4CH2S}]4(OTf)8. These complexes were characterized by NMR, mass, and UV-vis spectroscopies, cyclic voltammetry, as well as density functional theory studies and represent the first examples of SCCs constructed by thiolate groups and square-planar metal ions. The rectangular shape of tetranuclear complexes and square shape of octanuclear complex are confirmed by single-crystal structures and computational studies. The palladium complexes showed excellent catalytic activity in Suzuki C-C cross-coupling reactions with high turnover numbers (2 * 10(7)), even with low catalyst loading. PMID- 26444246 TI - Anchoring High-Concentration Oxygen Vacancies at Interfaces of CeO(2-x)/Cu toward Enhanced Activity for Preferential CO Oxidation. AB - Catalysts are urgently needed to remove the residual CO in hydrogen feeds through selective oxidation for large-scale applications of hydrogen proton exchange membrane fuel cells. We herein propose a new methodology that anchors high concentration oxygen vacancies at interface by designing a CeO2-x/Cu hybrid catalyst with enhanced preferential CO oxidation activity. This hybrid catalyst, with more than 6.1% oxygen vacancies fixed at the favorable interfacial sites, displays nearly 100% CO conversion efficiency in H2-rich streams over a broad temperature window from 120 to 210 degrees C, strikingly 5-fold wider than that of conventional CeO2/Cu (i.e., CeO2 supported on Cu) catalyst. Moreover, the catalyst exhibits a highest cycling stability ever reported, showing no deterioration after five cycling tests, and a super long-time stability beyond 100 h in the simulated operation environment that involves CO2 and H2O. On the basis of an arsenal of characterization techniques, we clearly show that the anchored oxygen vacancies are generated as a consequence of electron donation from metal copper atoms to CeO2 acceptor and the subsequent reverse spillover of oxygen induced by electron transfer in well controlled nanoheterojunction. The anchored oxygen vacancies play a bridging role in electron capture or transfer and drive molecule oxygen into active oxygen species to interact with the CO molecules adsorbed at interfaces, thus leading to an excellent preferential CO oxidation performance. This study opens a window to design a vast number of high performance metal-oxide hybrid catalysts via the concept of anchoring oxygen vacancies at interfaces. PMID- 26444247 TI - Development of an Optical Nanosensor Incorporating a pH-Sensitive Quencher Dye for Potassium Imaging. AB - One of the key challenges in the design of a sensor for measuring extracellular changes in potassium concentration is selectivity against the competing cation, sodium. Here, we present an optode-based nanosensor selective to potassium ions, owing to the addition of a pH-sensitive quencher molecule paired with a static fluorophore. The nanosensor was fabricated using emulsification and characterized in solution by absorbance and fluorescence spectroscopy. The resulting nanosensor detected potassium with nearly 1 order of magnitude higher selectivity compared to our chromoionophore-based optode nanosensors. In addition to the improved selectivity, the nanosensor has the following properties required for measurements in a biological environment: (1) a physiologically relevant dynamic range, (2) response to potassium ions at a physiological ionic strength, and (3) response to serum potassium in the presence of fouling biological components. The potassium nanosensor described in this study is envisioned to have application in cellular imaging and drug screening. PMID- 26444248 TI - Labdane and Clerodane Diterpenoids from Colophospermum mopane. AB - Five labdane (1-5), an isolabdane (6), and five clerodane diterpenoids (7-11), were isolated from seeds, husks, and leaves of Colophospermum mopane. Compounds 1 3 and 6-9 are new, and their structures were elucidated by means of physical data analysis (1D and 2D NMR, HRESIMS). The absolute configurations of 1, 7, and 10 were determined by single-crystal X-ray diffraction with Cu Kalpha radiation. For compounds 2 and 6, the absolute configurations were established by the modified Mosher's method and corroborated by comparison of experimental and calculated electronic circular dichroism spectra of their 3-p-bromobenzoate derivatives. The crude extracts and compounds were evaluated for antimicrobial activity. The leaf extract was the most active against Staphylococcus aureus (125 MUg/mL). Compound 11 showed the best inhibitory activity, with minimum inhibitory values of 15.6 MUg/mL against Escherichia coli and Staphylococcus aureus and 31.3 MUg/mL against Enterococcus faecalis. PMID- 26444249 TI - Synthesis of N-Aryl beta-Amino Alcohols by Trifluoroacetic Acid Promoted Multicomponent Coupling of Aziridines, Arynes, and Water. AB - A transition-metal-free, three-component coupling involving N-substituted aziridines, arynes, and water promoted by trifluoroacetic acid (TFA) has been reported. The reaction furnished medicinally important N-aryl beta-amino alcohol derivatives in moderate to good yields. In addition, the use of azetidines in this reaction afforded N-aryl gamma-amino alcohol derivatives. PMID- 26444250 TI - Designing a "Flatter" ExBox(4+) Analogue. AB - Analogues of ExBox(4+) 1 are proposed that possess triaryl fragments that are nearly flat. These two new hosts are predicted by density functional theory (omegaB97X-D/6-311G(d,p)) to bind five small linear acenes more tightly than does 1. The "flatter" triaryl fragments provide a less congested interior along with improved pi-pi-stacking between these hosts and guests. PMID- 26444251 TI - Morphologic Features Suggestive of Endometriosis in Nondiagnostic Peritoneal Biopsies. AB - Endometriosis is a common disorder that causes significant morbidity from dysmenorrhea, pelvic pain, and subfertility. Establishment of a definitive diagnosis has important therapeutic implications; however, only approximately 50% of biopsies of laparoscopically suspicious areas provide a diagnosis of endometriosis. Histologic criteria for diagnosis require the presence of endometrial glands or endometrial-type stroma. We hypothesize that other frequently present, but nondiagnostic, histologic features of endometriosis suggest its presence in patients with nondiagnostic peritoneal biopsies. We performed a retrospective clinicopathologic study of morphologic and immunohistochemical features that may improve the histologic diagnosis of endometriosis on laparoscopic peritoneal biopsies. We compared diagnostic (n=88) and nondiagnostic (n=54) peritoneal biopsies from pathologically confirmed endometriosis cases with negative peritoneal biopsies (n=84) from early-stage gynecologic cancer cases. Statistical analysis utilized the Fisher exact test. Multiple morphologic features were significantly increased in nondiagnostic biopsies from patients with endometriosis in comparison with those from negative controls, including foamy macrophages (P=0.0001) and submesothelial stromal clusters (SSCs) (P=0.0008). SSCs ranged from subtle aggregates of spindle cells to nodules of whorled spindle cells with small vessels and extravasated red blood cells resembling stromal endometriosis. Immunohistochemical studies confirmed that ER and CD10-positive SSCs were present in a greater proportion of both nondiagnostic and diagnostic peritoneal biopsies and at a greater number of lesions per biopsy. The overall histologic detection rate of peritoneal biopsies for endometriosis was 62.0%, and inclusion of SSCs with or without foamy macrophages in the diagnostic criteria appreciably increased this rate to between 72.5% and 76.8%. We describe SSCs, which appear to be an early or less developed form of stromal endometriosis, and, when included in the diagnostic criteria, improve the histologic detection rate of endometriosis in peritoneal biopsies. PMID- 26444252 TI - Coexistence of Microcystic Stromal Tumor of the Ovary With Mutation of beta Catenin and Contralateral Mucinous Cystadenoma. PMID- 26444253 TI - Analysis of MDM2 Amplification in 43 Endometrial Stromal Tumors: A Potential Diagnostic Pitfall. AB - MDM2 amplification is known to occur in a variety of neoplasms and its detection by fluorescence in situ hybridization is helpful in distinguishing well differentiated and dedifferentated liposarcoma from classic lipoma. We recently evaluated a mesenteric mass initially diagnosed as dedifferentiated liposarcoma, largely due to the neoplasm's myxoid morphology and MDM2 expression by immunohistochemistry, from a 46-yr-old woman with a history of uterine low-grade endometrial stromal sarcoma (LG-ESS) with a JAZF1 rearrangement. Our workup of the mesenteric mass revealed a JAZF1 rearrangement and a revised diagnosis of metastatic LG-ESS with myxoid change was rendered. Retrospective testing of the mesenteric mass was negative for MDM2 amplification, an uncommon, but known diagnostic pitfall in MDM2 expression by immunohistochemistry. As MDM2 amplification is not specific for the diagnosis of liposarcoma, we investigated its occurrence in 43 cases of endometrial stromal tumors: 14 uterine LG-ESS, 11 metastatic or recurrent uterine LG-ESS, 8 undifferentiated uterine sarcomas, 5 endometrial stromal nodules, and 4 high-grade ESS with YHWAE rearrangement. In addition, 40 of the 43 cases had previously undergone fluorescence in situ hybridization analysis of JAZF1, PHF1, and YHWAE. Two of the 43 cases (5%) had MDM2 amplification: one was a uterine LG-ESS (JAZF1 rearrangement) and the other was a undifferentiated uterine sarcoma (polysomy intact JAZF1, PHF1, and YHWAE), both metastatic to the lung. Both cases positive for MDM2 amplification showed MDM2 expression by immunohistochemistry. At last follow-up, both patients had died of disease (19 and 60 mo). Our study is the first to demonstrate MDM2 amplification in endometrial stromal tumor. Awareness of MDM2 amplification in endometrial stromal tumor is critical; particularly in locations more common to liposarcoma, to avoid diagnostic errors. PMID- 26444254 TI - The relationship between serum levels of total bilirubin and coronary plaque vulnerability. AB - OBJECTIVES: Previous studies have reported that serum total bilirubin provides some protection against coronary artery disease (CAD); however, the relationship between serum levels of total bilirubin and culprit/target plaque vulnerability in patients with CAD remains unclear. In this study, we investigated the association between total bilirubin and tissue characterization of coronary plaque in patients with CAD. METHODS: We enrolled 85 consecutive patients with CAD who underwent coronary angiography and intravascular ultrasound analyses [45 with acute coronary syndrome (ACS); 40 with stable angina pectoris (SAP)], and 45 age-matched participants served as the control group. Serum levels of total bilirubin in all participants were measured. The stability of the coronary plaque was compared between the ACS group and the SAP group, and the relationship between serum levels of total bilirubin and the features of coronary plaque was analyzed. RESULTS: Serum levels of total bilirubin in the ACS group were significantly lower than those in the SAP and control groups (P<0.01). Serum levels of total bilirubin were positively associated with fibrous plaques (r=0.386, P<0.001), whereas they were negatively associated with plaque burden (r=-0.413, P<0.001), lipid plaque (r=-0.419, P<0.001), and remodeling index (r= 0.275, P<0.05). Furthermore, an independent association between serum levels of total bilirubin and lipid-rich plaques (odds ratio, 0.78; 95% confidence interval, 0.64-0.95) was observed. CONCLUSION: Serum total bilirubin levels were found to be inversely associated with coronary plaque vulnerability, and decreased serum levels of total bilirubin may be an important factor for coronary lipid plaque formation, which contributes to the pathogenesis of CAD. PMID- 26444255 TI - Transition strategies from cangrelor to oral platelet P2Y12 receptor antagonists. AB - Cangrelor is the first parenteral antagonist of the platelet P2Y12 receptor. This direct-acting antagonist of the platelet P2Y12 receptor should be considered an adjunct to a percutaneous coronary intervention in patients who have not been adequately pretreated with platelet P2Y12 receptor antagonists at the time of the procedure. The use of cangrelor requires transition to an oral platelet P2Y12 receptor antagonist. Transition strategies have been developed on the basis of pharmacologic characteristics of platelet P2Y12 receptor antagonists, results of pharmacodynamic studies, and results from clinical trials. Cangrelor blocks the binding to the platelet P2Y12 receptor of the active metabolite of the thienopyridines, clopidogrel and prasugrel. The active metabolite of thienopyridines is present in blood for a short interval after administration. For this reason, clopidogrel should be administered after cangrelor is stopped. Prasugrel can be administered at the end of the cangrelor infusion or up to 30 min before cangrelor is stopped. Ticagrelor is also a reversible direct-acting antagonist of the platelet P2Y12 receptor. Because there is no interaction between ticagrelor and cangrelor, ticagrelor can be administered before or during the infusion of cangrelor. PMID- 26444256 TI - Impacts of Silver Nanoparticles on a Natural Estuarine Plankton Community. AB - Potential effects of metal nanoparticles on aquatic organisms and food webs are hard to predict from the results of single-species tests under controlled laboratory conditions, and more realistic exposure experiments are rarely conducted. We tested whether silver nanoparticles (Ag NPs) had an impact on zooplankton grazing on their prey, specifically phytoplankton and bacterioplankton populations. If Ag NPs directly reduced the abundance of prey, thereby causing the overall rate of grazing by their predators to decrease, a cascading effect on a planktonic estuarine food web would be seen. Our results show that the growth rates of both phytoplankton and bacterioplankton populations were significantly reduced by Ag NPs at concentrations of >=500 MUg L(-1). At the same time, grazing rates on these populations tended to decline with exposure to Ag NPs. Therefore, Ag NPs did not cause a cascade of effects through the food web but impacted a specific trophic level. Photosynthetic efficiency of the phytoplankton was significantly reduced at Ag NPs concentrations of >=500 MUg L( 1). These effects did not occur at relatively low concentrations of Ag that are often toxic to single species of bacteria and other organisms, suggesting that the impacts of Ag NP exposure may not be apparent at environmentally relevant concentrations due to compensatory processes at the community level. PMID- 26444257 TI - Genetic diversity of variants involved in drug response and metabolism in Sri Lankan populations: implications for clinical implementation of pharmacogenomics. AB - BACKGROUND: Interpopulation differences in drug responses are well documented, and in some cases they correspond to differences in the frequency of associated genetic markers. Understanding the diversity of genetic markers associated with drug response across different global populations is essential to infer population rates of drug response or risk for adverse drug reactions, and to guide implementation of pharmacogenomic testing. Sri Lanka is a culturally and linguistically diverse nation, but little is known about the population genetics of the major Sri Lankan ethnic groups. The objective of this study was to investigate the diversity of pharmacogenomic variants in the major Sri Lankan ethnic groups. METHODS: We examined the allelic diversity of more than 7000 variants in genes involved in drug biotransformation and response in the three major ethnic populations of Sri Lanka (Sinhalese, Sri Lankan Tamils, and Moors), and compared them with other South Asian, South East Asian, and European populations using Wright's Fixation Index, principal component analysis, and STRUCTURE analysis. RESULTS: We observed overall high levels of similarity within the Sri Lankan populations (median FST=0.0034), and between Sri Lankan and other South Asian populations (median FST=0.0064). Notably, we observed substantial differentiation between Sri Lankan and European populations for important pharmacogenomic variants related to warfarin (VKORC1 rs9923231) and clopidogrel (CYP2C19 rs4986893) response. CONCLUSION: These data expand our understanding of the population structure of Sri Lanka, provide a resource for pharmacogenomic research, and have implications for the clinical use of genetic testing of pharmacogenomic variants in these populations. PMID- 26444259 TI - Early group bias in the Faroe Islands: Cultural variation in children's group based reasoning. AB - Recent developmental research demonstrates that group bias emerges early in childhood. However, little is known about the extent to which bias in minimal (i.e., arbitrarily assigned) groups varies with children's environment and experience, and whether such bias is universal across cultures. In this study, the development of group bias was investigated using a minimal groups paradigm with 46 four- to six-year-olds from the Faroe Islands. Children observed in-group and out-group members exhibiting varying degrees of prosocial behaviour (egalitarian or stingy sharing). Children did not prefer their in-group in the pretest, but a pro-in-group and anti-out-group sentiment emerged in both conditions in the posttest. Faroese children's response patterns differ from those of American children [Schug, M. G., Shusterman, A., Barth, H., & Patalano, A. L. (2013). Minimal-group membership influences children's responses to novel experience with group members. Developmental Science, 16(1), 47-55], suggesting that intergroup bias shows cultural variation even in a minimal groups context. PMID- 26444258 TI - Wheat WCBP1 encodes a putative copper-binding protein involved in stripe rust resistance and inhibition of leaf senescence. AB - BACKGROUND: Stripe rust, a highly destructive foliar disease of wheat (Triticum aestivum), causes severe losses, which may be accompanied by reduced photosynthetic activity and accelerated leaf senescence. METHODS: We used suppression subtractive hybridization (SSH) to examine the mechanisms of resistance in the resistant wheat line L693 (Reg. No. GP-972, PI 672538), which was derived from a lineage that includes a wide cross between common and Thinopyrum intermedium. Sequencing of an SSH cDNA library identified 112 expressed sequence tags. RESULTS: In silico mapping placed one of these tags [GenBank: JK972238] on chromosome 1A. Primers based on [GenBank: JK972238] amplified a polymorphic band, which co-segregated with YrL693. We cloned a candidate gene encoding wheat copper-binding protein (WCBP1) by amplifying the polymorphic region, and we mapped WCBP1 to a 0.64 cM genetic interval. Brachypodium, rice, and sorghum have genes and genomic regions syntenic to this region. DISCUSSION: Sequence analysis suggested that the resistant WCBP1 allele might have resulted from a deletion of 36-bp sequence of the wheat genomic sequence, rather than direct transfer from Th. intermedium. qRT-PCR confirmed that WCBP1 expression changes in response to pathogen infection. CONCLUSIONS: The unique chromosomal location and expression mode of WCBP1 suggested that WCBP1 is the putative candidate gene of YrL693, which was involved in leaf senescence and photosynthesis related to plant responses to stripe rust infection during the grain-filling stage. PMID- 26444260 TI - Effects of smoking and alcohol use on neurocognitive functioning in heavy drinking, HIV-positive men who have sex with men. AB - High rates of cognitive impairment persist in human immunodeficiency virus (HIV) infection, despite improved health outcomes and reduced mortality through widespread use of antiretroviral therapy (ART). Heavy alcohol use and cigarette smoking are potential contributors to neurocognitive impairment in people living with HIV (PLWH), yet few studies have examined their influence concurrently. Here we investigated the effects of self-reported alcohol use and smoking on learning, memory, processing speed, verbal fluency, and executive function in 124 HIV positive men who have sex with men [age (mean +/- SD) = 42.8 +/- 10.4 years], engaged with medical care. All participants were heavy drinkers. Duration of HIV infection averaged 9.9 +/- 7.6 years, and 92.7% were on a stable ART regimen. Participants completed a neuropsychological battery and assessment of past 30-day substance use. Average number of drinks per drinking day (DPDD) was 5.6 +/- 3.5, and 33.1% of participants were daily smokers. Rates of neurocognitive impairment were the highest in learning (50.8%), executive function (41.9%), and memory (38.0%). Multiple regression models tested DPDD and smoking status as predictors of neurocognitive performance, controlling for age and premorbid intelligence. Smoking was significantly, negatively related to verbal learning (p = .046) and processing speed (p = .001). DPDD was a significant predictor of learning (p = .047) in a model that accounted for the interaction of DPDD and smoking status. As expected, premorbid intelligence significantly predicted all neurocognitive scores (ps < .01), and older age was associated with slower processing speed (ps < .01). In conclusion, smoking appears to be associated with neurocognitive functioning deficits in PLWH beyond the effects of heavy drinking, aging, and premorbid intelligence. Smoking cessation interventions have the potential to be an important target for improving functional outcomes in heavy drinking PLWH. PMID- 26444261 TI - Cultural competency training of GP Registrars-exploring the views of GP Supervisors. AB - INTRODUCTION: An equitable multicultural society requires General Practitioners (GPs) to be proficient in providing health care to patients from diverse backgrounds. This requires a certain set of attitudes, knowledge and skills known as cultural competence. While training in cultural competence is an important part of the Australian GP Registrar training curriculum, it is unclear who provides this training apart from in Aboriginal and Torres Strait Islander training posts. The majority of Australian GP Registrar training takes place in a workplace setting facilitated by the GP Supervisor. In view of the central role of GP Supervisors, their views on culturally competent practice, and their role in its development in Registrars, are important to ascertain. METHODS: We conducted 14 semi-structured interviews with GP Supervisors. These were audiotaped, transcribed verbatim and thematically analyzed using an iterative approach. RESULTS: The Supervisors interviewed frequently viewed cultural competence as adequately covered by using patient-centered approaches. The Supervisor role in promoting cultural competence of Registrars was affirmed, though training was noted to occur opportunistically and focused largely on patient-centered care rather than health disparities. CONCLUSION: Formal training for both Registrars and Supervisors may be beneficial not only to develop a deeper understanding of cultural competence and its relevance to practice but also to promote more consistency in training from Supervisors in the area, particularly with respect to self-reflection, non-conscious bias and utilizing appropriate cultural knowledge without stereotyping and assumption-making. PMID- 26444262 TI - Conservation analysis of sequences flanking the testis-determining gene Sry in 17 mammalian species. AB - BACKGROUND: Sex determination in mammals requires expression of the Y-linked gene Sry in the bipotential genital ridges of the XY embryo. Even minor delay of the onset of Sry expression can result in XY sex reversal, highlighting the need for accurate gene regulation during sex determination. However, the location of critical regulatory elements remains unknown. Here, we analysed Sry flanking sequences across many species, using newly available genome sequences and computational tools, to better understand Sry's genomic context and to identify conserved regions predictive of functional roles. METHODS: Flanking sequences from 17 species were analysed using both global and local sequence alignment methods. Multiple motif searches were employed to characterise common motifs in otherwise unconserved sequence. RESULTS: We identified position-specific conservation of binding motifs for multiple transcription factor families, including GATA binding factors and Oct/Sox dimers. In contrast with the landscape of extremely low sequence conservation around the Sry coding region, our analysis highlighted a strongly conserved interval of ~106 bp within the Sry promoter (which we term the Sry Proximal Conserved Interval, SPCI). We further report that inverted repeats flanking murine Sry are much larger than previously recognised. CONCLUSIONS: The unusually fast pace of sequence drift on the Y chromosome sharpens the likely functional significance of both the SPCI and the identified binding motifs, providing a basis for future studies of the role(s) of these elements in Sry regulation. PMID- 26444263 TI - PIPEQ-OS--an instrument for on-site measurements of the experiences of inpatients at psychiatric institutions. AB - BACKGROUND: The Psychiatric Inpatient Patient Experience Questionnaire (PIPEQ) was developed for post-discharge measurements of experiences, but the low response rates associated with post-discharge surveys restrict their usefulness. A new questionnaire was developed based on the PIPEQ for on-site measurements of patient experiences: the PIPEQ-OS. The aim of this study was to psychometrically test the PIPEQ-OS using data from a nationally representative survey conducted in Norway in 2014. METHODS: Data were collected using a nationally representative patient-experience survey; 25% of the institutions in each of the 4 health regions in Norway were randomly selected, yielding a total of 26 institutions. The PIPEQ-OS questionnaire was completed by patients on-site on an agreed day in week 37 of 2014. Item missing and ceiling effects were assessed, and factor analysis was used to assess the structure of the items included in the PIPEQ-OS. The scales were tested for internal consistency reliability, test-retest reliability and construct validity. RESULTS: The initial sample comprised 857 patients. Of these, 60 were excluded for ethical reasons and 57 were excluded because they were absent on the day of the survey. Of the remaining 740 patients, 552 (74.6% of the included population) returned the questionnaire. Low levels of missing or "not applicable" responses were found for 18 of the 21 items (<20%), and 20 of 21 items were below the ceiling-effect criterion. Psychometric testing identified three scales: structure and facilities (six items), patient-centred interaction (six items) and outcomes (five items). All scales met the criterion of 0.7 for Cronbach's alpha (range: 0.79-0.91) and test-retest reliability (range: 0.83-0.84). The construct validity of the scales was supported by 14 of 15 significant associations with variables known to be related to psychiatric inpatient experiences. CONCLUSIONS: The PIPEQ-OS comprises three scales with satisfactory internal consistency reliability and construct validity. This instrument can be used for on-site assessments of psychiatric inpatient patient experiences, but further research is needed to evaluate its usefulness as basis for external quality indicators. PMID- 26444264 TI - Development and field evaluation of the sentinel mosquito arbovirus capture kit (SMACK). AB - BACKGROUND: Although sentinel animals are used successfully throughout the world to monitor arbovirus activity, ethical considerations and cross-reactions in serological assays highlight the importance of developing viable alternatives. Here we outline the development of a passive sentinel mosquito arbovirus capture kit (SMACK) that allows for the detection of arboviruses on honey-baited nucleic acid preservation cards (Flinders Technology Associates; FTA(r)) and has a similar trap efficacy as standard light traps in our trials. METHODS: The trap efficacy of the SMACK was assessed against Centers for Disease Control and Prevention (CDC) miniature light traps (standard and ultraviolet) and the Encephalitis Vector Survey (EVS) trap in a series of Latin square field trials conducted in North Queensland, Australia. The ability of the SMACK to serve as a sentinel arbovirus surveillance tool was assessed in comparison to Passive Box Traps (PBT) during the 2014 wet season in the Cairns, Australia region and individually in the remote Northern Peninsula Area (NPA) of Australia during the 2015 wet season. RESULTS: The SMACK caught comparable numbers of mosquitoes to both CDC light traps (mean capture ratio 0.86: 1) and consistently outperformed the EVS trap (mean capture ratio 2.28: 1) when CO2 was supplied by either a gas cylinder (500 ml/min) or dry ice (1 kg). During the 2014 arbovirus survey, the SMACK captured significantly (t 6 = 2.1, P = 0.04) more mosquitoes than the PBT, and 2 and 1 FTA(r) cards were positive for Ross River virus and Barmah Forest virus, respectively, while no arboviruses were detected from PBTs. Arbovirus activity was detected at all three surveillance sites during the NPA survey in 2015 and ca. 27 % of FTA(r) cards tested positive for either Murray Valley encephalitis virus (2 detections), West Nile virus (Kunjin subtype; 13 detections), or both viruses on two occasions. CONCLUSIONS: These results demonstrate that the SMACK is a versatile, simple, and effective passive arbovirus surveillance tool that may also be used as a traditional overnight mosquito trap and has the potential to become a practical substitute for sentinel animal programs. PMID- 26444266 TI - [Funding for Health Care Innovation in Germany - New Chances for Optimized Care for Severely Mentally Ill?]. PMID- 26444265 TI - Trends in upper gastrointestinal diagnosis over four decades in Lusaka, Zambia: a retrospective analysis of endoscopic findings. AB - BACKGROUND AND AIMS: There a shortage of robust information about profiles of gastrointestinal disease in sub-Saharan Africa. The endoscopy unit of the University Teaching Hospital in Lusaka has been running without interruption since 1977 and this 38-year record is largely intact. We report an analysis of endoscopic findings over this period. METHODS: Written endoscopy records from 29th September 1977 to 16th December 2014 were recovered, computerised, coded by two experienced endoscopists and analysed. Temporal trends were analysed using tables, graphs, and unconditional logistic regression, with age, sex of patient, decade, and endoscopist as independent variables to adjust for inter-observer variation. RESULTS: Sixteen thousand nine hundred fifty-three records were identified and analysed. Diagnosis of gastric ulcer rose by 22 %, and that of duodenal ulcer fell by 14 % per decade. Endoscopically diagnosed oesophageal cancer increased by 32 % per decade, but gastric cancer rose only in patients under 60 years of age (21 % per decade). Oesophageal varices were the commonest finding in patients presenting with haematemesis, increasing by 14 % per decade in that patient group. Two HIV-related diagnoses, oesophageal candidiasis and Kaposi's sarcoma, rose from almost zero to very high levels in the 1990s but fell substantially after 2005 when anti-retroviral therapy became widely available. CONCLUSIONS: This useful dataset suggests that there are important trends in some endoscopic findings over four decades. These trends are not explained by inter observer variation. Reasons for the divergent trends in incidence of peptic ulceration and apparent trends in diagnosis of upper gastrointestinal cancers merit further exploration. PMID- 26444267 TI - [Discharge on the Day After Admission Following Announcement of Suicide - Pro]. PMID- 26444268 TI - [Discharge on the Day After Admission Following Announcement of Suicide - Contra]. PMID- 26444269 TI - [News releases from the Federal Directors' Conference]. PMID- 26444270 TI - Inhibition of oleandrin on the proliferation show and invasion of osteosarcoma cells in vitro by suppressing Wnt/beta-catenin signaling pathway. AB - BACKGROUND: Osteosarcoma (OS) is a high-grade bone sarcoma with early metastasis potential, and the clinical chemotherapy drugs that are currently used for its treatment have some limitations. Recently, several studies have reported the selective antitumor effect of oleandrin on various tumor cells. In this study, we aimed to evaluate the effects and underlying mechanisms of oleandrin on OS cells. METHODS: The effect of oleandrin on the proliferation, morphology, and apoptosis of U2OS and SaOS-2 cells were analyzed in vitro. The activity of the Wnt/beta catenin signaling pathway was determined using a dual luciferase assay. Semi quantitative RT-PCR and western blot assays were performed to evaluate the mRNA and total protein expression of the downstream target genes. Changes of beta catenin in intracellular localization were also explored using a western blot after separating the nucleus and cytoplasm proteins. The MMP-2 and MMP-9 enzymatic activities were determined using gelatin zymography. RESULTS: Oleandrin significantly inhibited the proliferation and invasion of OS cells in vitro, and induced their apoptosis. After treatment with oleandrin, the TOP/FOP flash ratio in OS cells was noticeably decreased, which indicated that the Wnt/beta-catenin signaling pathway was repressed. The expression of related Wnt target genes and total beta-catenin was downregulated, and a reduced nuclear beta-catenin level by oleandrin was observed as well. In addition, oleandrin suppressed the activities of MMP-2 and MMP-9. CONCLUSIONS: Oleandrin, in vitro, exerted a strong antitumor effect on human OS cells by suppressing the Wnt/beta-catenin signaling pathway, which interfered with the proliferation and invasion of OS cells, as well as induced cells apoptosis. Moreover, the expression and activities of MMP-2 and MMP 9 were downregulated by oleandrin, which contributed to the cells' lower invasiveness. PMID- 26444271 TI - Reduced cortical thickness in patients with acute-on-chronic liver failure due to non-alcoholic etiology. AB - BACKGROUND: Acute-on-chronic liver failure (ACLF) is a form of liver disease with high short-term mortality. ACLF offers considerable potential to affect the cortical areas by significant tissue injury due to loss of neurons and other supporting cells. We measured changes in cortical thickness and metabolites profile in ACLF patients following treatment, and compared it with those of age matched healthy volunteers. METHODS: For the cortical thickness analysis we performed whole brain high resolution T1-weighted magnetic resonance imaging (MRI) on 15 ACLF and 10 healthy volunteers at 3T clinical MR scanner. Proton MR Spectroscopy ((1)H MRS) was also performed to measure level of altered metabolites. Out of 15 ACLF patients 10 survived and underwent follow-up study after clinical recovery at 3 weeks. FreeSurfer program was used to quantify cortical thickness and LC- Model software was used to quantify absolute metabolites concentrations. Neuropsychological (NP) test was performed to assess the cognitive performance in follow-up ACLF patients compared to controls. RESULTS: Significantly reduced cortical thicknesses in multiple brain sites, and significantly decreased N-acetyl aspartate (NAA), myo-inositol (mI) and significantly increased glutamate/glutamine (glx) metabolites were observed in ACLF compared to those of controls at baseline study. Follow-up patients showed significant recovery in cortical thickness and Glx level, while NAA and mI were partially recovered compared to baseline study. When compared to controls, follow up patients still showed reduced cortical thickness and altered metabolites level. Follow-up patients had abnormal neuropsychological (NP) scores compared to controls. CONCLUSIONS: Neuronal loss as suggested by the reduced NAA, decreased cellular density due to increased cerebral hyperammonemia as supported by the increased glx level, and increased proinflammatory cytokines and free radicals may account for the reduced cortical thickness in ACLF patients. Presence of reduced cortical thickness, altered metabolites and abnormal NP test scores in post recovery subjects as compared to those of controls is associated with incomplete clinical recovery. The current imaging protocol can be easily implemented in clinical settings to evaluate and monitor brain tissue changes in patients with ACLF during the course of treatment. PMID- 26444272 TI - Availability of emergency neonatal care in eight districts of Karnataka state, southern India: a cross-sectional study. AB - BACKGROUND: Emergency Neonatal Care (EmNC) is an important service for the health and survival of newborns. The objective of our study was to assess the availability of emergency neonatal care services in the north-eastern region of Karnataka state in India. METHODS: We undertook a cross-sectional epidemiologic study in the year 2010. We assessed the provision of eight life-saving 'signal functions' (Comprehensive EmNC) or at least five 'signal functions' (Basic EmNC) by self-reporting through a structured questionnaire, coupled with verification by direct observation for presence of drugs and equipment in the prior three months. The assessment was undertaken in 443 government and 422 private healthcare facilities of eight districts of Karnataka. RESULTS: There was an average of 3.6 EmNC facilities available per 500,000 population for the entire region. Only three out of eight districts and 10 of 42 sub-districts in the region had the recommended [greater than or equal to 5] EmNC facilities per 500,000. Further, over 95 % of CEmNC facilities and 88 % of BEmNC facilities were within the private sector. About 80 % of government hospitals at district and sub district levels did not have EmNC capability. CONCLUSIONS: This study demonstrates the feasibility of using a simple assessment tool to measure health facility availability of life-saving services for newborn care. EmNC availability was seen to be suboptimal at the regional, district and sub-district levels within the northern part of Karnataka state. There is a need to improve availability of emergency newborn care in health facilities, with special emphasis on equity at population level. PMID- 26444273 TI - Battery electric vehicles - implications for the driver interface. AB - The current study examines the human-machine interface of a battery electric vehicle (BEV) from a user-perspective, focussing on the evaluation of BEV specific displays, the relevance of provided information and challenges for drivers due to the concept of electricity in a road vehicle. A sample of 40 users drove a BEV for 6 months. Data were gathered at three points of data collection. Participants perceived the BEV-specific displays as only moderately reliable and helpful for estimating the displayed parameters. This was even less the case after driving the BEV for 3 months. A taxonomy of user requirements was compiled revealing the need for improved and additional information, especially regarding energy consumption and efficiency. Drivers had difficulty understanding electrical units and the energy consumption of the BEV. On the background of general principles for display design, results provide implications how to display relevant information and how to facilitate drivers' understanding of energy consumption in BEVs. Practitioner Summary: Battery electric vehicle (BEV) displays need to incorporate new information. A taxonomy of user requirements was compiled revealing the need for improved and additional information in the BEV interface. Furthermore, drivers had trouble understanding electrical units and energy consumption; therefore, appropriate assistance is required. Design principles which are specifically important in the BEV context are discussed. PMID- 26444274 TI - The degree of local inflammatory response after colonic resection depends on the surgical approach: an observational study in 61 patients. AB - BACKGROUND: Clinical data indicate that laparoscopic surgery reduces postoperative inflammatory response and benefits patient recovery. Little is known about the mechanisms involved in reduced systemic and local inflammation and the contribution of reduced trauma to the abdominal wall and the parietal peritoneum. METHODS: Included were 61 patients, who underwent elective colorectal resection without intraabdominal complications; 17 received a completely laparoscopic, 13 a laparoscopically- assisted procedure and 31 open surgery. Local inflammatory response was quantified by measurement of intraperitoneal leukocytes and IL-6 levels during the first 4 days after surgery. RESULTS: There was no statistical difference between the groups in systemic inflammatory parameters and intraperitoneal leukocytes. Intraperitoneal interleukin-6 was significantly lower in the laparoscopic group than in the laparoscopically assisted and open group on postoperative day 1 (26.16 versus 43.25 versus 40.83 ng/ml; p = 0.001). No difference between the groups was recorded on POD 2-4. Intraperitoneal interleukin-6 showed a correlation with duration of hospital stay on POD 1 (0.233, p = 0.036), but not on POD 2-4. Patients who developed a surgical wound infection showed higher levels of intraperitoneal interleukin-6 on postoperative day 2-4 (POD 2: 42.56 versus 30.02 ng/ml, p = 0.03), POD 3: 36.52 versus 23.62 ng/ml, p = 0.06 and POD 4: 34.43 versus 19.99 ng/ml, p = 0.046). Extraabdominal infections had no impact. CONCLUSION: The analysis shows an attenuated intraperitoneal inflammatory response on POD 1 in completely laparoscopically-operated patients, associated with a quicker recovery. This effect cannot be observed in patients, who underwent a laparoscopically-assisted or open procedure. Factors inflicting additional trauma to the abdominal wall and parietal peritoneum promote the intraperitoneal inflammation process. PMID- 26444275 TI - The transcatheter aortic valve implementation (TAVI)--a qualitative approach to the implementation and diffusion of a minimally invasive surgical procedure. AB - BACKGROUND: The transcatheter aortic valve implantation (TAVI), a minimally invasive surgical procedure to treat patients with severe symptomatic aortic stenosis, showed a rapid diffusion in Germany compared to the international level. The aim of this study is to identify and analyze factors affecting the implementation and diffusion of the procedure in hospitals using a qualitative application of the diffusion of innovations theory. METHODS: We conducted problem centered interviews with cardiologists and cardiac surgeons working in German hospitals. The multi-level model "diffusion of innovations in health services organizations" developed by Greenhalgh et al. was used to guide the research. Data was analyzed using content and a thematic analysis. RESULTS: Among the ten participants who were interviewed, we found both barriers and facilitators related to the innovation itself, system readiness and antecedents, communication and influence, and the outer context. Key issues were the collaboration between cardiologists and cardiac surgeons, reimbursement policies, requirements needed to conduct the procedure, and medical advantages of the method. CONCLUSIONS: The findings show that there are multiple factors influencing the diffusion of TAVI that go beyond the reimbursement and cost issues. The diffusion of innovations model proved to be helpful in understanding the different aspects of the uptake of the procedure. A central theme that affected the implementation of TAVI was the collaboration and competition between involved medical departments: cardiology and cardiac surgery. Against this background, it seems especially important to moderate and coordinate the cooperation of the different medical disciplines. PMID- 26444276 TI - ? PMID- 26444277 TI - ? PMID- 26444278 TI - ? PMID- 26444279 TI - Increased ratio of neutrophil elastase to alpha1-antitrypsin is closely associated with liver inflammation in patients with nonalcoholic steatohepatitis. AB - An imbalance between neutrophil elastase (NE) and its inhibitor alpha1 antitrypsin (A1 AT) is known to contribute to the development of obesity-related inflammation. This study aimed to investigate the role of the NE-A1 AT system in the histological progression of non-alcoholic fatty liver disease (NAFLD), and to evaluate the ability of it to predict nonalcoholic steatohepatitis (NASH). A total of 252 adults (NAFLD group, n = 202; healthy group, n = 50) were recruited. Clinical biochemical characteristics, NE and A1 AT concentrations were measured in all subjects. Among the NAFLD group, 86 patients had previously undergone liver biopsy and information on histological characteristics was consequently available. The area under the receiver operating characteristic curve (AUC) was used to determine the predictive accuracy of the NE-A1 AT system for NASH. NAFLD patients had an elevated serum NE concentration and a reduced A1 AT level with consequent NE/A1 AT imbalance. NE increased in the early stage of steatosis, preceding the decline in A1 AT, dating from the onset of NASH (NAS 3-4), and subsequently NE/A1 AT increased in the presence of NASH. Nonetheless, this increase began to resolve as the disease state progressed to advanced fibrosis. A1 AT had a sensitivity (SEN) of 83.8% and a specificity (SP) of 83.3% with the optimal cut-off of -1459.43, NE/A1 AT had a SEN of 88.8% and a SP of 83.3% with cut-off of 0.363 to predict NASH. An increased NE: A1 AT ratio is closely associated with liver Inflammation in patients with NASH and could serve as a novel marker to predict NASH in humans. PMID- 26444280 TI - Spatial Niche Segregation of Sympatric Stone Marten and Pine Marten--Avoidance of Competition or Selection of Optimal Habitat? AB - Coexistence of ecologically similar species relies on differences in one or more dimensions of their ecological niches, such as space, time and resources in diel and/or seasonal scales. However, niche differentiation may result from other mechanisms such as avoidance of high predation pressure, different adaptations or requirements of ecologically similar species. Stone marten (Martes foina) and pine marten (Martes martes) occur sympatrically over a large area in Central Europe and utilize similar habitats and food, therefore it is expected that their coexistence requires differentiation in at least one of their niche dimensions or the mechanisms through which these dimensions are used. To test this hypothesis, we used differences in the species activity patterns and habitat selection, estimated with a resource selection function (RSF), to predict the relative probability of occurrence of the two species within a large forest complex in the northern geographic range of the stone marten. Stone martens were significantly heavier, have a longer body and a better body condition than pine martens. We found weak evidence for temporal niche segregation between the species. Stone and pine martens were both primarily nocturnal, but pine martens were active more frequently during the day and significantly reduced the duration of activity during autumn-winter. Stone and pine martens utilized different habitats and almost completely separated their habitat niches. Stone marten strongly preferred developed areas and avoided meadows and coniferous or deciduous forests. Pine marten preferred deciduous forest and small patches covered by trees, and avoided developed areas and meadows. We conclude that complete habitat segregation of the two marten species facilitates sympatric coexistence in this area. However, spatial niche segregation between these species was more likely due to differences in adaptation to cold climate, avoidance of high predator pressure and/or food preferences by both species than competitive interaction between them. PMID- 26444281 TI - Effect of Chronic Psychological Stress on Liver Metastasis of Colon Cancer in Mice. AB - Metastasis to the liver is a main factor in colorectal cancer mortality. Previous studies suggest that chronic psychological stress is important in cancer progression, but its effect on liver metastasis has not been investigated. To address this, we established a liver metastasis model in BALB/c nude mice to investigate the role of chronic stress in liver metastasis. Our data suggest that chronic stress elevates catecholamine levels and promotes liver metastasis. Chronic stress was also associated with increased tumor associated macrophages infiltration into the primary tumor and increased the expression of metastatic genes. Interestingly, beta-blocker treatment reversed the effects of chronic stress on liver metastasis. Our results suggest the beta-adrenergic signaling pathway is involved in regulating colorectal cancer progression and liver metastasis. Additionally, we submit that adjunctive therapy with a beta-blocker may complement existing colorectal cancer therapies. PMID- 26444283 TI - Complete Mitochondrial Genomes of New Zealand's First Dogs. AB - Dogs accompanied people in their migrations across the Pacific Ocean and ultimately reached New Zealand, which is the southern-most point of their oceanic distribution, around the beginning of the fourteenth century AD. Previous ancient DNA analyses of mitochondrial control region sequences indicated the New Zealand dog population included two lineages. We sequenced complete mitochondrial genomes of fourteen dogs from the colonisation era archaeological site of Wairau Bar and found five closely-related haplotypes. The limited number of mitochondrial lineages present at Wairau Bar suggests that the founding population may have comprised only a few dogs; or that the arriving dogs were closely related. For populations such as that at Wairau Bar, which stemmed from relatively recent migration events, control region sequences have insufficient power to address questions about population structure and founding events. Sequencing mitogenomes provided the opportunity to observe sufficient diversity to discriminate between individuals that would otherwise be assigned the same haplotype and to clarify their relationships with each other. Our results also support the proposition that at least one dispersal of dogs into the Pacific was via a south-western route through Indonesia. PMID- 26444284 TI - Temporal Patterns in Seawater Quality from Dredging in Tropical Environments. AB - Maintenance and capital dredging represents a potential risk to tropical environments, especially in turbidity-sensitive environments such as coral reefs. There is little detailed, published observational time-series data that quantifies how dredging affects seawater quality conditions temporally and spatially. This information is needed to test realistic exposure scenarios to better understand the seawater-quality implications of dredging and ultimately to better predict and manage impacts of future projects. Using data from three recent major capital dredging programs in North Western Australia, the extent and duration of natural (baseline) and dredging-related turbidity events are described over periods ranging from hours to weeks. Very close to dredging i.e. <500 m distance, a characteristic features of these particular case studies was high temporal variability. Over several hours suspended sediment concentrations (SSCs) can range from 100-500 mg L-1. Less turbid conditions (10-80 mg L-1) can persist over several days but over longer periods (weeks to months) averages were <10 mg L-1. During turbidity events all benthic light was sometimes extinguished, even in the shallow reefal environment, however a much more common feature was very low light 'caliginous' or daytime twilight periods. Compared to pre-dredging conditions, dredging increased the intensity, duration and frequency of the turbidity events by 10-, 5- and 3-fold respectively (at sites <500 m from dredging). However, when averaged across the entire dredging period of 80-180 weeks, turbidity values only increased by 2-3 fold above pre-dredging levels. Similarly, the upper percentile values (e.g., P99, P95) of seawater quality parameters can be highly elevated over short periods, but converge to values only marginally above baseline states over longer periods. Dredging in these studies altered the overall probability density distribution, increasing the frequency of extreme values. As such, attempts to understand the potential biological impacts must consider impacts across telescoping-time frames and changes to extreme conditions in addition to comparing central tendency (mean/median). An analysis technique to capture the entire range of likely conditions over time-frames from hours to weeks is described using a running means/percentile approach. PMID- 26444282 TI - Interleukin-1 Antagonist Anakinra in Amyotrophic Lateral Sclerosis--A Pilot Study. AB - Preclinical studies show that blocking Interleukin-1 (IL-1) retards the progression of Amyotrophic Lateral Sclerosis (ALS). We assessed the safety of Anakinra (ANA), an IL-1 receptor antagonist, in ALS patients. In a single arm pilot study we treated 17 ALS patients with ANA (100 mg) daily for one year. We selected patients with dominant or exclusive lower motor neuron degeneration (LMND) presentation, as peripheral nerves may be more accessible to the drug. Our primary endpoint was safety and tolerability. Secondary endpoints included measuring disease progression with the revised ALS functional rating scale (ALSFRSr). We also quantified serum inflammatory markers. For comparison, we generated a historical cohort of 47 patients that fit the criteria for enrollment, disease characteristics and rate of progression of the study group. Only mild adverse events occurred in ALS patients treated with ANA. Notably, we observed lower levels of cytokines and the inflammatory marker fibrinogen during the first 24 weeks of treatment. Despite of this, we could not detect a significant reduction in disease progression during the same period in patients treated with ANA compared to controls as measured by the ALSFRSr. In the second part of the treatment period we observed an increase in serum inflammatory markers. Sixteen out of the 17 patients (94%) developed antibodies against ANA. This study showed that blocking IL-1 is safe in patients with ALS. Further trials should test whether targeting IL-1 more efficiently can help treating this devastating disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT01277315. PMID- 26444285 TI - Long Noncoding RNA MEG3 Interacts with p53 Protein and Regulates Partial p53 Target Genes in Hepatoma Cells. AB - Maternally Expressed Gene 3 (MEG3) encodes a lncRNA which is suggested to function as a tumor suppressor. Previous studies suggested that MEG3 functioned through activation of p53, however, the functional properties of MEG3 remain obscure and their relevance to human diseases is under continuous investigation. Here, we try to illuminate the relationship of MEG3 and p53, and the consequence in hepatoma cells. We find that transfection of expression construct of MEG3 enhances stability and transcriptional activity of p53. Deletion analysis of MEG3 confirms that full length and intact structure of MEG3 are critical for it to activate p53-mediated transactivation. Interestingly, our results demonstrate for the first time that MEG3 can interact with p53 DNA binding domain and various p53 target genes are deregulated after overexpression of MEG3 in hepatoma cells. Furthermore, results of qRT-PCR have shown that MEG3 RNA is lost or reduced in the majority of HCC samples compared with adjacent non-tumorous samples. Ectopic expression of MEG3 in hepatoma cells significantly inhibits proliferation and induces apoptosis. In conclusion, our data demonstrates that MEG3 functions as a tumor suppressor in hepatoma cells through interacting with p53 protein to activate p53-mediated transcriptional activity and influence the expression of partial p53 target genes. PMID- 26444286 TI - Kefir Grains Change Fatty Acid Profile of Milk during Fermentation and Storage. AB - Several studies have reported that lactic acid bacteria may increase the production of free fatty acids by lipolysis of milk fat, though no studies have been found in the literature showing the effect of kefir grains on the composition of fatty acids in milk. In this study the influence of kefir grains from different origins [Rio de Janeiro (AR), Vicosa (AV) e Lavras (AD)], different time of storage, and different fat content on the fatty acid content of cow milk after fermentation was investigated. Fatty acid composition was determined by gas chromatography. Values were considered significantly different when p<0.05. The highest palmitic acid content, which is antimutagenic compost, was seen in AV grain (36.6g/100g fatty acids), which may have contributed to increasing the antimutagenic potential in fermented milk. Higher monounsaturated fatty acid (25.8 g/100g fatty acids) and lower saturated fatty acid (72.7 g/100g fatty acids) contents were observed in AV, when compared to other grains, due to higher Delta9-desaturase activity (0.31) that improves the nutritional quality of lipids. Higher oleic acid (25.0 g/100g fatty acids) and monounsaturated fatty acid (28.2g/100g fatty acids) and lower saturated fatty acid (67.2g/100g fatty acids) contents were found in stored kefir relatively to fermented kefir leading to possible increase of antimutagenic and anticarcinogenic potential and improvement of nutritional quality of lipids in storage milk. Only high-lipidic matrix displayed increase polyunsaturated fatty acids after fermentation. These findings open up new areas of study related to optimizing desaturase activity during fermentation in order to obtaining a fermented product with higher nutritional lipid quality. PMID- 26444287 TI - Economic Evaluation of Immunisation Programme of 23-Valent Pneumococcal Polysaccharide Vaccine and the Inclusion of 13-Valent Pneumococcal Conjugate Vaccine in the List for Single-Dose Subsidy to the Elderly in Japan. AB - BACKGROUND: Currently in Japan, both 23-valent pneumococcal polysaccharide vaccine (PPSV-23) and 13-valent pneumococcal conjugate vaccine (PCV-13) are available for the elderly for the prevention of S. pneumoniae-related diseases. PPSV-23 was approved in 1988, while the extended use of PCV-13 was approved for adults aged 65 and older in June 2014. Despite these two vaccines being available, the recently launched national immunisation programme for the elderly only subsidised PPSV-23. The framework of the current immunisation programme lasts for five years. The elderly population eligible for the subsidised PPSV-23 shot for the 1st year are those aged 65, 70, 75, 80, 85, 90, 95 and >= 100. While from the 2nd year to the 5th year, those who will age 65, 70, 75, 80, 85, 90, 95 and 100 will receive the same subsidised shot. METHODS: We performed economic evaluations to (1) evaluate the efficiency of alternative strategies of PPSV-23 single-dose immunisation programme, and (2) investigate the efficiency of PCV-13 inclusion in the list for single-dose pneumococcal vaccine immunisation programme. Three alternative strategies were created in this study, namely: (1) current PPSV-23 strategy, (2) 65 to 80 (as "65-80 PPSV-23 strategy"), and (3) 65 and older (as ">= 65 PPSV-23 strategy"). We constructed a Markov model depicting the S. pneumoniae-related disease course pathways. The transition probabilities, utility weights to estimate quality adjusted life year (QALY) and disease treatment costs were either calculated or cited from literature. Cost of per shot of vaccine was Y 8,116 (US$74; US$1 = Y 110) for PPSV-23 and Y 10,776 (US$98) for PCV-13. The model runs for 15 years with one year cycle after immunisation. Discounting was at 3%. RESULTS: Compared to current PPSV-23 strategy, 65-80 PPSV 23 strategy cost less but gained less, while the incremental cost-effectiveness ratios (ICERs) of >= 65 PPSV-23 strategy was Y 5,025,000 (US$45,682) per QALY gained. PCV-13 inclusion into the list for single-dose subsidy has an ICER of Y 377,000 (US$3,427) per QALY gained regardless of the PCV-13 diffusion level. These ICERs were found to be cost-effective since they are lower than the suggested criterion by WHO of three times GDP (Y 11,000,000 or US$113,636 per QALY gained), which is the benchmark used in judging the cost-effectiveness of an immunisation programmne. CONCLUSIONS: The results suggest that switching current PPSV-23 strategy to >= 65 PPSV-23 strategy or including PCV-13 into the list for single-dose subsidy to the elderly in Japan has value for money. PMID- 26444288 TI - Multiplex Assay for Protein Profiling and Potency Measurement of German Cockroach Allergen Extracts. AB - BACKGROUND: German cockroach (GCr) allergens induce IgE responses and may cause asthma. Commercial GCr allergen extracts are variable and existing assays may not be appropriate for determining extract composition and potency. OBJECTIVE: Our aim was to develop a multiplex antibody/bead-based assay for assessment of GCr allergen extracts. METHODS: Single chain fragment variable (scFv) antibodies against GCr were obtained by screening libraries derived from naive human lymphocytes and hyperimmunized chicken splenocytes and bone marrow. Selected clones were sequenced and characterized by immunoblotting. Eighteen scFv antibodies (17 chicken, 1 human) coupled to polystyrene beads were used in this suspension assay; binding of targeted GCr allergens to antibody-coated beads was detected using rabbit antisera against GCr, and against specific allergens rBla g 1, rBla g 2, and rBla g 4. The assay was tested for specificity, accuracy, and precision. Extracts were also compared by IgE competition ELISA. RESULTS: Chicken scFv's generated eight different binding patterns to GCr proteins from 14 to 150 kDa molecular weight. Human scFv's recognized a 100 kDa GCr protein. The multiplex assay was found to be specific and reproducible with intra-assay coefficient of variation (CV) of 2.64% and inter-assay CV of 10.0%. Overall potencies of various GCr extracts were calculated using mean logEC50s for eight selected scFvs. Overall potency measures were also analyzed by assessing the contributions to potency of each target. CONCLUSIONS: An scFv antibody-based multiplex assay has been developed capable of simultaneously measuring different proteins in a complex mixture, and to determine the potencies and compositions of allergen extracts. PMID- 26444290 TI - Intravitreal Injection of a Rho-Kinase Inhibitor (Fasudil) for Recent-Onset Nonarteritic Anterior Ischemic Optic Neuropathy. AB - This study evaluated the effects of intravitreal injection of fasudil (IVF), a Rho-kinase inhibitor, in cases of recent-onset nonarteritic anterior ischemic optic neuropathy (NAION). In this interventional case series, 13 eyes of 13 patients diagnosed with NAION within 14 days of onset were included. The affected eyes received a 0.025 mg/0.05 mL IVF. Functional and structural outcomes were assessed 1 and 3 months following treatment. Best corrected visual acuity (BCVA) was the main outcome measured, with mean deviation (MD) index of the VF test and peripapillary retinal nerve fiber layer thickness as secondary measures. There was a statistically significant improvement in the patients' BCVA 1 and 3 months following IVF; BCVA improved from 1.69 +/- 0.55 logMAR at baseline to 0.98 +/- 0.47 and 0.93 +/- 0.51 logMAR at 1 and 3 months, respectively (P = .004). The change in BCVA was not significant between month 1 and month 3 (P = .22). Peripapillary retinal nerve fiber layer thickness decreased from 173.5 +/- 29.28 um in the baseline evaluation to 85.8 +/- 8.8 um at 1 month, and 62.9 +/- 5.97 um at 3 months (P = .003). MD values changed from 24.60 +/- 3.80 to 21.0 +/- 6.10 and 20.5 +/- 6.50 at 1 and 3 months, respectively (P = .007 and .005, respectively). This pilot study suggests that IVF may be an effective treatment for patients with recent-onset NAION. Larger studies are required to establish the therapeutic role of fasudil for NAION. PMID- 26444289 TI - Defense of Elevated Body Weight Setpoint in Diet-Induced Obese Rats on Low Energy Diet Is Mediated by Loss of Melanocortin Sensitivity in the Paraventricular Hypothalamic Nucleus. AB - Some animals and humans fed a high-energy diet (HED) are diet-resistant (DR), remaining as lean as individuals who were naive to HED. Other individuals become obese during HED exposure and subsequently defend the obese weight (Diet-Induced Obesity- Defenders, DIO-D) even when subsequently maintained on a low-energy diet. We hypothesized that the body weight setpoint of the DIO-D phenotype resides in the hypothalamic paraventricular nucleus (PVN), where anorexigenic melanocortins, including melanotan II (MTII), increase presynaptic GABA release, and the orexigenic neuropeptide Y (NPY) inhibits it. After prolonged return to low-energy diet, GABA inputs to PVN neurons from DIO-D rats exhibited highly attenuated responses to MTII compared with those from DR and HED-naive rats. In DIO-D rats, melanocortin-4 receptor expression was significantly reduced in dorsomedial hypothalamus, a major source of GABA input to PVN. Unlike melanocortin responses, NPY actions in PVN of DIO-D rats were unchanged, but were reduced in neurons of the ventromedial hypothalamic nucleus; in PVN of DR rats, NPY responses were paradoxically increased. MTII-sensitivity was restored in DIO D rats by several weeks' refeeding with HED. The loss of melanocortin sensitivity restricted to PVN of DIO-D animals, and its restoration upon prolonged refeeding with HED suggest that their melanocortin systems retain the ability to up- and downregulate around their elevated body weight setpoint in response to longer term changes in dietary energy density. These properties are consistent with a mechanism of body weight setpoint. PMID- 26444291 TI - Do Interventions that Promote Awareness of Rights Increase Use of Maternity Care Services? A Systematic Review. AB - Twenty years after the rights of women to go through pregnancy and childbirth safely were recognized by governments, we assessed the effects of interventions that promote awareness of these rights to increase use of maternity care services. Using inclusion and exclusion criteria defined in a peer-reviewed protocol, we searched published and grey literature from one database of studies on maternal health, two search engines, an internet search and contact with experts. From the 707 unique documents found, 219 made reference to rights, with 22 detailing interventions promoting awareness of rights for maternal and newborn health. Only four of these evaluated effects on health outcomes. While all four interventions promoted awareness of rights, they did so in different ways. Interventions included highly-scripted dissemination meetings with educational materials and other visual aids, participatory approaches that combined raising awareness of rights with improving accountability of services, and broader multi stakeholder efforts to improve maternal health. Study quality ranged from weak to strong. Measured health outcomes included increased antenatal care and facility birth. Improvements in human rights outcomes such as availability, acceptability, accessibility, quality of care, as well as the capacity of rights holders and duty bearers were also reported to varying extents. Very little information on costs and almost no information on harms or risks were described. Despite searching multiple sources of information, while some studies did report on activities to raise awareness of rights, few detailed how they did so and very few measured effects on health outcomes. Promoting awareness of rights is one element of increasing demand for and use of quality maternity care services for women during pregnancy, birth and after birth. To date efforts have not been well documented in the literature and the program theories, processes and costs, let alone health effects have not been well evaluated. PMID- 26444292 TI - An Organocatalytic Regiospecific Synthesis of 1,5-Disubstituted 4-Thio-1,2,3 triazoles and 1,5-Disubstituted 1,2,3-Triazoles. AB - Organocatalytic azide-ketone [3+2] cycloaddition (OrgAKC) of a variety of 1-aryl 2-(arylthio)ethanones and 1-alkyl-2-(alkylthio)ethanones with different aryl or alkyl azides is reported in dimethyl sulfoxide or solvent-free under ambient conditions to furnish 1,5-disubstituted 4-thio-1,2,3-triazoles in a regiospecific manner, which are further converted into useful 1,5-disubstituted 1,2,3-triazoles by treatment with Raney Ni at 25 degrees C for 1-3 h. Notable features of the OrgAKC reaction include high rate and selectivity, solvent-free conditions, easily available substrates and catalysts, a wide range of synthetic and medicinal applications, and excellent yields generating a vast library of triazoles. PMID- 26444293 TI - Determining the Optimum Power Load in Jump Squat Using the Mean Propulsive Velocity. AB - The jump squat is one of the exercises most frequently used to improve lower body power production, which influences sports performance. However, the traditional determination of the specific workload at which power production is maximized (i.e., optimum power load) is time-consuming and requires one-repetition maximum tests. Therefore, the aim of this study was to verify whether elite athletes from different sports would produce maximum mean propulsive power values at a narrow range of mean propulsive velocities, resulting in similar jump heights. One hundred and nine elite athletes from several individual/team sport disciplines underwent repetitions at maximal velocity with progressive loads, starting at 40% of their body mass with increments of 10% to determine the individual optimum power zone. Results indicated that regardless of sport discipline, the athletes' optimum mean propulsive power was achieved at a mean propulsive velocity close to 1.0 m.s(-1) (1.01 +/- 0.07 m.s(-1)) and at a jump height close to 20 cm (20.47 +/ 1.42 cm). Data were narrowly scattered around these values. Therefore, jump squat optimum power load can be determined simply by means of mean propulsive velocity or jump height determination in training/testing settings, allowing it to be implemented quickly in strength/power training. PMID- 26444294 TI - A new rescue regimen with plasma exchange and rituximab in high-risk membranous glomerulonephritis. AB - BACKGROUND: Even though current treatment guidelines for idiopathic membranous glomerulonephritis (iMGN) exist, many questions regarding an optimal therapy remain unanswered. Complete remission cannot be achieved in all patients; relapses occur, in some cases frequently, and side effects from the immunosuppressive therapy are common. Therapeutic options in high-risk patients not responding to standard immunosuppressive therapies are limited. Recent research reveals that the human M-type phospholipase A2 receptor (PLA2 R) is a causative factor in iMGN that parallels clinical disease activity. However, in some patients, this correlation is not evident and additional undetermined factors seem to play a role. DESIGN: We evaluated a new rescue protocol including plasma exchanges (PE) against albumin, intravenous immunoglobulins (IVIGs) and rituximab for 10 patients with a biopsy-proven diagnosis of iMGN who were therapy resistant to all conventional regimens and had a urinary protein to creatinine ratio of more than 10 000 mg/g Crea. We compared this protocol with standard immunosuppressive protocols including monthly alternating prednisolone plus cyclophosphamide (18 patients), cyclosporine plus prednisolone (23 patients) and rituximab alone (eight patients) in a retrospective design. RESULTS: Our rescue regimen with PE, IVIGs and rituximab achieved partial remission in 90% of patients who had been otherwise refractory to therapy. The mean time to partial remission was 2.1 months. Furthermore, two anti-PLA2 R-antibody negative patients were also treated with this rescue regimen, achieving partial remission after 1 and 4 months. CONCLUSION: A combination of PE, IVIGs and rituximab is a treatment option to consider for high-risk patients with iMGN who are refractory to conventional therapy. PMID- 26444295 TI - Callus Formation and Mineralization after Fracture with Different Fixation Techniques: Minimally Invasive Plate Osteosynthesis versus Open Reduction Internal Fixation. AB - Minimally invasive plate osteosynthesis(MIPO) has been considered as an alternative for fracture treatment. Previous study has demonstrated that MIPO technique has the advantage of less soft tissue injury compared with open reduction internal fixation (ORIF). However, the comparison of callus formation and mineralization between two plate osteosynthesis methods remains unknown. In this experiment, ulna fracture model was established in 42 beagle dogs. The fractures underwent reduction and internal fixation with MIPO or ORIF. Sequential fluorescent labeling and radiographs were applied to determine new callus formation and mineralization in two groups after operation. At 4, 8 and 12 weeks postoperatively, the animals were selected to be sacrificed and the ulna specimens were analyzed by Micro-CT. The sections were also treated with Masson staining for histological evaluation. More callus formation was observed in MIPO group in early stage of fracture healing. The fracture union rate has no significant difference between two groups. The results indicate that excessive soft tissue stripping may impact early callus formation. As MIPO technique can effectively reduce soft tissue injury with little incision, it is considered to be a promising alternative for fracture fixation. PMID- 26444296 TI - Novel process and catalytic materials for converting CO2 and H2 containing mixtures to liquid fuels and chemicals. AB - Carbon dioxide and water are renewable and the most abundant feedstocks for the production of chemicals and fungible fuels. However, the current technologies for production of hydrogen from water are not competitive. Therefore, reacting carbon dioxide with hydrogen is not economically viable in the near future. Other alternatives include natural gas, biogas or biomass for the production of carbon dioxide, hydrogen and carbon monoxide mixtures that react to yield chemicals and fungible fuels. The latter process requires a high performance catalyst that enhances the reverse water-gas-shift (RWGS) reaction and Fischer-Tropsch synthesis (FTS) to higher hydrocarbons combined with an optimal reactor system. Important aspects of a novel catalyst, based on a Fe spinel and three-reactor system developed for this purpose published in our recent paper and patent, were investigated in this study. Potassium was found to be a key promoter that improves the reaction rates of the RWGS and FTS and increases the selectivity of higher hydrocarbons while producing mostly olefins. It changed the texture of the catalyst, stabilized the Fe-Al-O spinel, thus preventing decomposition into Fe3O4 and Al2O3. Potassium also increased the content of Fe5C2 while shifting Fe in the oxide and carbide phases to a more reduced state. In addition, it increased the relative exposure of carbide iron on the catalysts surface, the CO2 adsorption and the adsorption strength. A detailed kinetic model of the RWGS, FTS and methanation reactions was developed for the Fe spinel catalyst based on extensive experimental data measured over a range of operating conditions. Significant oligomerization activity of the catalyst was found. Testing the pelletized catalyst with CO2, CO and H2 mixtures over a range of operating conditions demonstrated its high productivity to higher hydrocarbons. The composition of the liquid (C5+) was found to be a function of the potassium content and the composition of the feedstock. PMID- 26444297 TI - Flexible behavioral capture-recapture modeling. AB - We develop alternative strategies for building and fitting parametric capture recapture models for closed populations which can be used to address a better understanding of behavioral patterns. In the perspective of transition models, we first rely on a conditional probability parameterization. A large subset of standard capture-recapture models can be regarded as a suitable partitioning in equivalence classes of the full set of conditional probability parameters. We exploit a regression approach combined with the use of new suitable summaries of the conditioning binary partial capture histories as a device for enlarging the scope of behavioral models and also exploring the range of all possible partitions. We show how one can easily find unconditional MLE of such models within a generalized linear model framework. We illustrate the potential of our approach with the analysis of some known datasets and a simulation study. PMID- 26444300 TI - A method for estimating spatial resolution of real image in the Fourier domain. AB - Spatial resolution is a fundamental parameter in structural sciences. In crystallography, the resolution is determined from the detection limit of high angle diffraction in reciprocal space. In electron microscopy, correlation in the Fourier domain is used for estimating the resolution. In this paper, we report a method for estimating the spatial resolution of real images from a logarithmic intensity plot in the Fourier domain. The logarithmic intensity plots of test images indicated that the full width at half maximum of a Gaussian point spread function can be estimated from the images. The spatial resolution of imaging X ray microtomography using Fresnel zone-plate optics was also estimated with this method. A cross section of a test object visualized with the imaging microtomography indicated that square-wave patterns up to 120-nm pitch were resolved. The logarithmic intensity plot was calculated from a tomographic cross section of brain tissue. The full width at half maximum of the point spread function estimated from the plot coincided with the resolution determined from the test object. These results indicated that the logarithmic intensity plot in the Fourier domain provides an alternative measure of the spatial resolution without explicitly defining a noise criterion. PMID- 26444299 TI - Purification and characterization of a highly active chromate reductase from endophytic Bacillus sp. DGV19 of Albizzia lebbeck (L.) Benth. actively involved in phytoremediation of tannery effluent-contaminated sites. AB - Phytoremediation using timber-yielding tree species is considered to be the most efficient method for chromium/tannery effluent-contaminated sites. In this study, we have chosen Albizzia lebbeck, a chromium hyperaccumulator plant, and studied one of its chromium detoxification processes operated by its endophytic bacterial assemblage. Out of the four different groups of endophytic bacteria comprising Pseudomonas, Rhizobium, Bacillus, and Salinicoccus identified from A. lebbeck employed in phytoremediation of tannery effluent-contaminated soil, Bacillus predominated with three species, which exhibited not only remarkable chromium accumulation ability but also high chromium reductase activity. A chromate reductase was purified to homogeneity from the most efficient chromium accumulator, Bacillus sp. DGV 019, and the purified 34.2-kD enzyme was observed to be stable at temperatures from 20 degrees C to 60 degrees C. The enzyme was active over a wide range of pH values (4.0-9.0). Furthermore, the enzyme activity was enhanced with the electron donors NADH, followed by NADPH, not affected by glutathione and ascorbic acid. Cu(2+) enhanced the activity of the purified enzyme but was inhibited by Zn(2+) and etheylenediamine tetraacetic acid (EDTA). In conclusion, due to its versatile adaptability the chromate reductase can be used for chromium remediation. PMID- 26444301 TI - Impact of pH and Total Soluble Solids on Enzyme Inactivation Kinetics during High Pressure Processing of Mango (Mangifera indica) Pulp. AB - This study was undertaken with an aim to enhance the enzyme inactivation during high pressure processing (HPP) with pH and total soluble solids (TSS) as additional hurdles. Impact of mango pulp pH (3.5, 4.0, 4.5) and TSS (15, 20, 25 degrees Brix) variations on the inactivation of pectin methylesterase (PME), polyphenol oxidase (PPO), and peroxidase (POD) enzymes were studied during HPP at 400 to 600 MPa pressure (P), 40 to 70 degrees C temperature (T), and 6- to 20 min pressure-hold time (t). The enzyme inactivation (%) was modeled using second order polynomial equations with a good fit that revealed that all the enzymes were significantly affected by HPP. Response surface and contour models predicted the kinetic behavior of mango pulp enzymes adequately as indicated by the small error between predicted and experimental data. The predicted kinetics indicated that for a fixed P and T, higher pulse pressure effect and increased isobaric inactivation rates were possible at lower levels of pH and TSS. In contrast, at a fixed pH or TSS level, an increase in P or T led to enhanced inactivation rates, irrespective of the type of enzyme. PPO and POD were found to have similar barosensitivity, whereas PME was found to be most resistant to HPP. Furthermore, simultaneous variation in pH and TSS levels of mango pulp resulted in higher enzyme inactivation at lower pH and TSS during HPP, where the effect of pH was found to be predominant than TSS within the experimental domain. PRACTICAL APPLICATION: Exploration of additional hurdles such as pH, TSS, and temperature for enzyme inactivation during high pressure processing of fruits is useful from industrial point of view, as these parameters play key role in preservation process design. PMID- 26444302 TI - Effect of Airway Pressure Release Ventilation on Dynamic Alveolar Heterogeneity. AB - IMPORTANCE: Ventilator-induced lung injury may arise from heterogeneous lung microanatomy, whereby some alveoli remain collapsed throughout the breath cycle while their more compliant or surfactant-replete neighbors become overdistended, and this is called dynamic alveolar heterogeneity. OBJECTIVE: To determine how dynamic alveolar heterogeneity is influenced by 2 modes of mechanical ventilation: low tidal-volume ventilation (LTVV) and airway pressure release ventilation (APRV), using in vivo microscopy to directly measure alveolar size distributions. DESIGN, SETTING, AND PARTICIPANTS: In a randomized, nonblinded laboratory animal study conducted between January 2013 and December 2014, 14 rats (450-500 g in size) were randomized to a control group with uninjured lungs (n = 4) and 2 experimental groups with surfactant deactivation induced by polysorbate lavage: the LTVV group (n = 5) and the APRV group (n = 5). For all groups, a thoracotomy and in vivo microscopy were performed. Following lung injury induced by polysorbate lavage, the LTVV group was ventilated with a tidal volume of 6 mL/kg and progressively higher positive end-expiratory pressure (PEEP) (5, 10, 16, 20, and 24 cm H2O). Following lung injury induced by polysorbate lavage, the APRV group was ventilated with a progressively shorter time at low pressure, which increased the ratio of the end-expiratory flow rate (EEFR) to the peak expiratory flow rate (PEFR; from 10% to 25% to 50% to 75%). MAIN OUTCOMES AND MEASURES: Alveolar areas were quantified (using PEEP and EEFR to PEFR ratio) to determine dynamic heterogeneity. RESULTS: Following lung injury induced by polysorbate lavage, a higher PEEP (20-24 cm H2O) with LTVV resulted in alveolar occupancy (reported as percentage of total frame area) at inspiration (39.9% 42.2%) and expiration (35.9%-38.7%) similar to that in the control group (inspiration 53.3%; expiration 50.3%; P > .01). Likewise, APRV with an increased EEFR to PEFR ratio (50%-75%) resulted in alveolar occupancy at inspiration (46.7% 47.9%) and expiration (40.2%-46.6%) similar to that in the control group (P > .01). At inspiration, the distribution of the alveolar area of the control group was similar to that of the APRV group (P > .01) (but not to that of the LTVV group [P < .01]). A lower PEEP (5-10 cm H2O) and a decreased EEFR to PEFR ratio (<=50%) demonstrated dynamic heterogeneity between inspiration and expiration (P < .01 for both) with a greater percentage of large alveoli at expiration. Dynamic alveolar homogeneity between inspiration and expiration occurred with higher PEEP (16-24 cm H2O) (P > .01) and an increased EEFR to PEFR ratio (75%) (P > .01). CONCLUSIONS AND RELEVANCE: Increasing PEEP during LTVV increased alveolar recruitment and dynamic homogeneity but had a significantly different alveolar size distribution compared with the control group. By comparison, reducing the time at low pressure (EEFR to PEFR ratio of 75%) in the APRV group provided dynamic homogeneity and a closer approximation of the dynamics observed in the control group. PMID- 26444303 TI - Nitrogen content and morphology dependent field emission properties of nitrogen doped SiC nanowires and density functional calculations. AB - Nitrogen-doped SiC nanowires (N-doped SiC NWs) with a nitrogen content from 0.975 wt% to 2.265 wt% have been synthesized via a one-step chemical vapor reaction (CVR), where melamine served as both the carbon and nitrogen source. Interestingly, the morphology of the products changed from slightly curled to very curled with crowding together with the increase of N dopants, which was interpreted reasonably by the proposed N-doping growth model of SiC NWs. In addition, according to the electronic structure calculation results, the band gap is narrowed progressively with the increase of N content, which greatly enhances the field emission (FE) properties. However, the experimental results of the FE measurements substantiate that only when the N content takes an optimal value can the N-doped SiC NWs act as candidates for field emitters with very low turn-on fields (E(to)) of 1.5 V MUm(-1) and threshold fields (E(thr)) of 4 V MUm(-1). On the basis of the aforementioned phenomenon, a universal cooperativity mechanism was put forward to explain the effect of the N content and morphology on the FE properties of the N-doped SiC NWs. PMID- 26444310 TI - Driven by Ambitions: The Nurse Practitioner's Role Transition in Dutch Hospital Care. AB - INTRODUCTION: Insight into nurse practitioners' (NPs') role transition can help NP students and new graduates in taking on new responsibilities in a changing and demanding healthcare context. The aim of the research was to explore the role transition from nurse to NP using the components of Meleis's Framework of Transitions. METHOD: A qualitative descriptive design was used. Individual interviews (n = 9) and two focus group discussions (n = 12) were held with NPs. Data were analyzed with the directed content analysis method. FINDINGS: The Framework component transitions' nature was characterized by changes in the healthcare system, combined with professional and educational role changes. Transition conditions showed that the respondents felt distressed after they became accountable for a patient's care and well-being. Although the respondents were authorized to do medical procedures, they initially lacked nursing role models and NP protocols. Process indicators showed ongoing transition; the respondents were still developing clinical competencies and confidence in patient care while relying on earlier acquired nursing competencies. Outcome indicators showed that the respondents found themselves successful in the medical extension of two different nursing roles: continuity of medical care for hospitalized patients in acute and intensive care settings, and being responsible for continuity of care for chronic patients in outpatient clinics. CONCLUSIONS: Role transition was characterized by coping with feelings of distress at the cost of time and effort. The respondents' strategies to adapt to new expectations, combined with organizational support, determined the outcomes as well as the start of new transitions. CLINICAL RELEVANCE: NPs' role transition in hospital care implies a dynamic ongoing process that needs to be supported, with the ultimate goal to improve patient outcomes. PMID- 26444311 TI - Association of general and abdominal obesity with age, endocrine and metabolic factors in Asian men. AB - OBJECTIVE: This study made use of the percent abdominal fat to define abdominal obesity (AbO) and examined the differential associations of general obesity (GOb) and AbO with age, metabolic and endocrine factors. METHODS: Metabolic, endocrine and anthropometric factors and body composition were measured in 481 Asian men. RESULTS: A DEXA-derived >=25% abdominal fat (PAbdF) was used to define men with AbO. Age was directly associated with PAbdF and percent total body fat (PBF). Exercise intensity was negatively associated with PBF. Both PBF and PAbdF were associated with HDL and LDL, but have opposite correlation with triglyceride. Furthermore, both PBF and PAbdF were associated with the number of metabolic syndrome (MetS) risk factors. Men with GOb had lower levels of percent lean mass (PLM), testosterone and bioavailable testosterone, and higher insulin and glucose levels. Men with AbO had lower arm and leg fat, higher insulin levels and triglycerides. CONCLUSIONS: Men with GOb and AbO had different pattern of body composition. Age may be a contributory factor in AbO and a sedentary lifestyle may contribute to GOb. Both GOb and AbO are associated with an increased risk of MetS, with GOb more predispose to risk of diabetes, while AbO more at risk for cardiovascular diseases. PMID- 26444312 TI - Revealing and tuning the core, structure, properties and function of polymer micelles with lanthanide-coordination complexes. AB - Controlling self-assembly processes is of great interest in various fields where multifunctional and tunable materials are designed. We here present the versatility of lanthanide-complex-based micelles (Ln-C3Ms) with tunable coordination structures and corresponding functions (e.g. luminescence and magnetic relaxation enhancement). Micelles are prepared by charge-driven self assembly of a polycationic-neutral diblock copolymer and anionic coordination complexes formed by Ln(III) ions and the bis-ligand L2EO4, which contains two dipicolinic acid (DPA) ligand groups (L) connected by a tetra-ethylene oxide spacer (EO4). By varying the DPA/Ln ratio, micelles are obtained with similar size but with different stability, different aggregation numbers and different oligomeric and polymeric lanthanide(III) coordination structures in the core. Electron microscopy, light scattering, luminescence spectroscopy and magnetic resonance relaxation experiments provide an unprecedented detailed insight into the core structures of such micelles. Concomitantly, the self-assembly is controlled such that tunable luminescence or magnetic relaxation with Eu-C3Ms, respectively, Gd-C3Ms is achieved, showing potential for applications, e.g. as contrast agents in (pre)clinical imaging. Considering the various lanthanide(III) ions have unique electron configurations with specific physical chemical properties, yet very similar coordination chemistry, the generality of the current coordination-structure based micellar design shows great promise for development of new materials such as, e.g., hypermodal agents. PMID- 26444313 TI - Assessing the Role of Capping Molecules in Controlling Aggregative Growth of Gold Nanoparticles in Heated Solution. AB - This report describes findings of an investigation of the role of capping molecules in the size growth in the aggregative growth of pre-formed small-sized gold nanoparticles capped with alkanethiolate monolayers toward monodispersed larger sizes. The size controllability depends on the thiolate chain length and concentration in the thermal solution. The size evolution in solution at different concentrations of alkanethiols is analyzed in relation to adsorption isotherms and cohesive energy. The size dependence on thiolate chain length is also analyzed by considering the cohesive energy of the capping molecules, revealing the importance of cohesive energy in the capping structure. Theoretical and experimental comparisons of the surface plasmonic resonance optical properties have also provided new insights into the mechanism, thus enabling the exploitation of size-dependent nanoscale properties. PMID- 26444314 TI - Evaluation of antibacterial activity of caffeic acid encapsulated by beta cyclodextrins. AB - CONTEXT: Caffeic acid is described as antibacterial, but this bioactive molecule has some issues regarding solubility and stability to environmental stress. Thus, encapsulation devices are required. OBJECTIVE: The aim of this work was to study the effect of the caffeic acid encapsulation by cyclodextrins on its antibacterial activity. MATERIALS AND METHODS: The interactions between the caffeic acid and three cyclodextrins (beta-cyclodextrin (betaCD), 2-hydroxypropyl beta-cyclodextrin (HPbetaCD) and methyl-beta-cyclodextrin were study. RESULTS AND DISCUSSION: The formation of an aqueous soluble inclusion complex was confirmed for betaCD and HPbetaCD with a 1:1 stoichiometry. The betaCD/caffeic acid complex showed higher stability than HPbetaCD/caffeic acid. Caffeic acid antibacterial activity was similar at pH 3 and pH 5 against the three bacteria (K. pneumoniae, S. epidermidis and S. aureus). CONCLUSIONS: The antibacterial activity of the inclusion complexes was described here for the first time and it was shown that the caffeic acid activity was remarkably enhanced by the cyclodextrins encapsulation. PMID- 26444315 TI - Low-temperature dynamic nuclear polarization of gases in Frozen mixtures. AB - PURPOSE: To present a new cryogenic technique for preparing gaseous compounds in solid mixtures for polarization using dynamic nuclear polarization (DNP). METHODS: (129) Xe and (15) N2 O samples were prepared using the presented method. Samples were hyperpolarized at 1.42K at 5 Tesla. (129) Xe was polarized at 1.65K and 1.42K to compare enhancement. Polarization levels for both samples and T1 relaxation times for the (129) Xe sample were measured. Sample pulverization for the (129) Xe and controlled annealing for both samples were introduced as additional steps in sample preparation. RESULTS: Enhancement increased by 15% due to a temperature drop from 1.65K to 1.42K for the (129) Xe sample. A polarization level of 20 +/- 3% for the (129) Xe sample was achieved, a two-fold increase from 10 +/- 1% after pulverization of the sample at 1.42K. T1 of the (129) Xe sample was increased by more than three-fold by means of annealing. In the case of (15) N2 O, annealing led to a ~two-fold increase in the signal level after DNP. CONCLUSION: The presented technique for producing and manipulating solid gas/glassing agent/radical mixtures for DNP led to high polarization levels in (129) Xe and (15) N2 O samples. These methods show potential for polarizing other gases using DNP technology. Magn Reson Med 76:1007-1014, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26444316 TI - Inhibition of soluble epoxide hydrolase activity by compounds isolated from the aerial parts of Glycosmis stenocarpa. AB - The aim of this study is to search for soluble epoxide hydrolase (sEH) inhibitors from natural plants, bioassay-guided fractionation of lipophilic n-hexane and chloroform layers of an extract of the aerial parts of Glycosmis stenocarpa led to the isolation of 12 compounds (1-12) including murrayafoline-A (1), isomahanine (2), bisisomahanine (3), saropeptate (4), (24 S)-ergost-4-en-3,6 dione (5), stigmasta-4-en-3,6-dion (6), stigmast-4-en-3-one (7), beta-sitosterol (8), 24-methylpollinastanol (9), trans-phytol (10), neosarmentol III (11) and (+) epiloliolide (12). Their structures were elucidated on the basis of spectroscopic data. Among them, neosarmentol III (11) was isolated from nature for the first time. All the isolated compounds were evaluated for their inhibitory activity against sEH. Among isolated carbazole-type compounds, isomahanine (2) and bisisomahanine (3) were identified as a potent inhibitor of sEH, with IC50 values of 22.5 +/- 1.7 and 7.7 +/- 1.2 uM, respectively. Moreover, the inhibitory action of 2 and 3 represented mixed-type enzyme inhibition. PMID- 26444317 TI - Childhood Bereavement and Type 1 Diabetes: a Danish National Register Study. AB - BACKGROUND: Death of a close family member such as a parent or a sibling can cause prolonged stress and changes in the family structure that may have extensive social and health effects on a young child. The aim of this paper is to examine the rate of type 1 diabetes following bereavement due to death of a first degree family member in early life. METHODS: We used data from the Danish Civil Registration System (CRS) to identify singleton births in Denmark born 1 January 1980 through 31 December 2005, n = 1 740 245 and their next of kin. We categorised children as exposed to bereavement if they lost a mother, father or sibling from age 5 years onwards, the remaining children were considered unexposed. Children were followed until first diagnosis of diabetes, death, emigration, or 31 December 2010. We estimated incidence rate ratios (IRRs) from birth using log-linear Poisson regression models with person-years as an offset variable. Exposed children were followed up for an average of 9.1 years [standard deviation (SD) 6.7] and unexposed children were followed up for an average of 12.3 years (SD 7.3). RESULTS: In our sample 94 943 children were exposed to bereavement, and 6110 cases of type 1 diabetes were identified. Bereavement was associated with an increased rate of type 1 diabetes when exposure onset began after 11 years of age (adjusted IRR 1.28, 95% confidence interval 1.08, 1.51). CONCLUSION: We found some evidence to indicate an increase in the rate of type 1 diabetes among children exposed to bereavement when exposure occurred after 11 years of age. PMID- 26444318 TI - Columellar-Frenulum Angle - A Significant Clinical Parameter in Assessing the Degree of Severity in Unilateral Cleft Lip. AB - OBJECTIVES: The study was carried out to learn if the columellar-frenulum angle could be used as one of the most important anthropometric measurements to predict the clinical severity in unilateral cleft lip patients. SETTINGS AND DESIGN: This is a prospective case series conducted at Banaras Hindu University, Varanasi, India. METHODS AND MATERIAL: The study was based on the Thomson and Reinders criteria (1995), and various anthropometric measurements, including the columellar-frenulum angle, were measured. A total of 30 patients (21 boys and 9 girls) were included in the study. The ages of the children varied from 4 months to 15 years. The left side was affected in 18 patients, and 2 gave a significant positive family history. All the patients were subjected uniformly to Tennison's cleft lip repair. Patients with strictly unilateral complete cleft lip and palate were included in the study. Microform clefts, incomplete cleft lips, and bilateral clefts were excluded from the study. STATISTICAL ANALYSIS: The data was analyzed using Pearson's correlation coefficient. RESULTS: The CF angle correlated negatively with the soft tissue defect of the cleft, cutaneous lip length, and vermilion lip length discrepancies from normal and soft tissue width just behind the alveolus. CONCLUSIONS: CF angle promises to offer a method by which prognosis of clefts can be predicted in terms of its severity in patients with unilateral cleft lip. PMID- 26444319 TI - Assessing the Interdental Septal Thickness in Alveolar Bone Grafting Using Cone Beam Computed Tomography. AB - OBJECTIVE: To assess the interdental septal thickness of grafted bone bridges using cone beam computed tomography (CBCT). PATIENTS: Of 71 patients with cleft lip and/or palate having undergone alveolar bone grafting for the first time at least 6 months previously, 52 patients with 57 grafted sites rated type I or II based on the Bergland scale using occlusal radiographs were selected. INTERVENTIONS: CBCT was performed for each bone-grafted alveolar cleft within 1 week after the occlusal radiographs were taken. MAIN OUTCOME MEASURES: The thickness of the grafted bone bridge was evaluated using CBCT according to the relationship between crest thickness and the root width of cleft-adjacent teeth, and the results were classified into four categories, with scores of 1 to 4 indicating that the thickness of the bony bridge was >=100%, >=75%, >=50%, and <50% of the root width of the cleft-adjacent teeth, respectively. RESULTS: Of the 34 grafted sites rated type I on the Bergland scale, 15 (44.12%), 10 (29.41%), 4 (11.76%), and 5 (14.71%) clefts were scored 1 to 4 on interdental septal thickness using CBCT, respectively. Of the 23 cases of type II, 3 (13.04%), 9 (39.13%), 1 (3.45%), and 10 (43.48%) clefts were scored 1 to 4, respectively. CONCLUSIONS: The interdental septal thickness of grafted bone bridges with clinically successful heights based on the Bergland scale (type I or II) using occlusal radiographs varied significantly in the evaluation using CBCT. PMID- 26444320 TI - Subacute Cutaneous Lupus Erythematosus Induced by Mitotane. PMID- 26444321 TI - Intrapartum sonographic signs: new diagnostic tools in malposition and malrotation. AB - In the past years, numerous studies have been published on the use of ultrasound during labor, showing this is an effective, accurate and objective tool for the assessment of the fetal head position and station. Literature affirmed that traditional transvaginal digital examination is highly subjective and dependent on the operator's experience. On the contrary, the use of intrapartum suprapubic transabdominal ultrasound can improve accuracy in determination of fetal head position and the precise knowledge of the location of specific fetal head landmarks in relationship to maternal pelvis. Intrapartum ultrasound will assist obstetricians in the diagnosis of normal labor progression, suggesting when medical and or operative intervention should be taken in case of complications. During each fetal head movement, there is a very specific relationship between fetal head landmarks and well-identified maternal structures, so the ultrasound diagnosis is performed step by step. In this review, we summarized the clinical situation of the fetal head in the pelvis and the relative ultrasonographic signs. Moreover, we collected all the ultrasonographic measures to diagnose the fetal head progression and rotations in the birth canal. PMID- 26444322 TI - Patient-Reported Health in Young People With Congenital Heart Disease Transitioning to Adulthood. AB - PURPOSE: Because life expectancy of patients with congenital heart disease (CHD) has increased substantially, assessment of patient-reported health is seen as an important component in the follow-up. Therefore, we (1) examined patient-reported health status of young people with CHD from a longitudinal perspective; (2) compared patient-reported health of patients with that of controls from the general population; and (3) investigated longitudinal interrelationships among various domains of patient-reported health. METHODS: We included 429 patients with CHD (aged 14-18 years) in a longitudinal study with four measurement points. Patient-reported health status was measured using a linear analog scale for self rated health and the Pediatric Quality of Life Inventory (PedsQL). RESULTS: Self rated health was good, with mean scores that slightly decreased from 81.78 to 78.90 from Time 1 to Time 4. PedsQL scores were also good, with the highest scores obtained for physical functioning. Patients with mild heart defects consistently reported higher scores on self-rated health and PedsQL than the general population. The scores of patients with complex heart defects were generally lower than those of the general population. Cross-lagged path analyses demonstrated that symptoms, cognitive functioning, and communication problems constituted the most consistent predictors of perceived health domains over time. CONCLUSIONS: Patient-reported health was considerably good. Domains of patient reported health that deserve specific attention are symptoms, cognitive functioning, and communication problems. Intervening in these three domains may yield indirect benefits on other health status domains and may improve the overall perceived health status of young people with CHD. PMID- 26444323 TI - Reducing LDL with PCSK9 Inhibitors--The Clinical Benefit of Lipid Drugs. PMID- 26444324 TI - Nonmedical Uses of Antibiotics: Time to Restrict Their Use? AB - The global crisis of antibiotic resistance has reached a point where, if action is not taken, human medicine will enter a postantibiotic world and simple injuries could once again be life threatening. New antibiotics are needed urgently, but better use of existing agents is just as important. More appropriate use of antibiotics in medicine is vital, but the extensive use of antibiotics outside medical settings is often overlooked. Antibiotics are commonly used in animal husbandry, bee-keeping, fish farming and other forms of aquaculture, ethanol production, horticulture, antifouling paints, food preservation, and domestically. This provides multiple opportunities for the selection and spread of antibiotic-resistant bacteria. Given the current crisis, it is vital that the nonmedical use of antibiotics is critically examined and that any nonessential use halted. PMID- 26444325 TI - Eldecalcitol (ED-71), an analog of 1alpha,25-dihydroxyvitamin D3 as a potential anti-cancer agent for oral squamous cell carcinomas. AB - We have previously reported that 1,25(OH)2D3 inhibits NF-kappaB activity and thus inhibits growth of OSCC cells in serum-free culture and down-regulates HBp17/FGFBP-1 expression, which is important for cancer cell growth and angiogenesis. Here, we have investigated the effects of ED-71, an analog of vitamin D3 (VD) on OSCC cell lines in serum-free culture. It is known that ED-71 has a stronger inhibitory effect on bone resorption compared to VD and other VD analogs. To the best of our knowledge, there was no report examining the potential of ED-71 as an anti-cancer agent for OSCC. We found that ED-71 is able to inhibit the growth of cancer cell lines at a concentration of hundred times lower than calcitriol. As Cyp24A1 was reportedly induced in cancer cells, we measured the expression of CYP24A1 in OSCC cell lines (NA and UE), A431 epidermoid carcinoma and normal fibroblast cell (gfi) in serum-free culture. As a result, CYP24A1 mRNA and the protein expression in the OSCC cells treated with ED 71 increased in a dose-dependent manner. However, in vivo experiment, in which the A431 cells were implanted in mice, tumor formation was reduced by the ED-71 treatment with no significant difference between Cyp24A1 expression in the tumors of ED-71-treated and control group, as analyzed by western blotting and immunohistochemistry. These results suggest that ED-71 is a potential anti-cancer agent for OSCC. PMID- 26444326 TI - Factors associated with surgical management in an underinsured, safety net population. AB - BACKGROUND: Few studies include significant numbers of racial and ethnic minority patients. The current study was performed to examine factors that affect breast cancer operations in an underinsured population. METHODS: We performed a retrospective review of all breast cancer patients from January 2010 to May 2012. Patients with American Joint Committee on Cancer clinical stage 0-IIIA breast cancer underwent evaluation for type of operation: breast conservation, mastectomy alone, and reconstruction after mastectomy. RESULTS: The population included 403 patients with mean age 53 years. Twelve of the 50 patients (24%) diagnosed at stage IIIB presented with synchronous metastatic disease. Of the remaining patients, only 2 presented with metastatic disease (0.6%). The initial operation was 65% breast conservation, 26% mastectomy alone, and 10% reconstruction after mastectomy. Multivariate analysis revealed that Hispanic ethnicity (odds ratio [OR], 0.38; 95% CI, 0.19-0.73; P = .004), presentation with palpable mass (OR, 0.34; 95% CI, 0.13-0.90; P = .03), preoperative chemotherapy (OR, 0.25; 95% CI, 0.10-0.62; P = .003) were associated with a lesser likelihood of mastectomy. Multivariate analysis of factors associated with reconstruction after mastectomy showed that operation with Breast surgical oncologist (OR, 18.4; 95% CI, 2.18-155.14; P < .001) and adequate health literacy (OR, 3.13; 95% CI, 0.95-10.30; P = .06) were associated with reconstruction. CONCLUSION: The majority of safety net patients can undergo breast conservation despite delayed presentation and poor use of screening mammography. Preoperative chemotherapy increased the likelihood of breast conservation. Routine systemic workup in patients with operable breast cancer is not indicated. PMID- 26444327 TI - Diaphragm pacing system implanted in a patient with ALS. AB - The diaphragm pacing system (DPS) is a life quality improving operation in amyotrophic lateral sclerosis (ALS) patients who need mechanical ventilation or have chronic respiratory insufficiency. This procedure is gaining in popularity, and the number of centers implanting diaphragm pacing systems (DPS) is increasing. DPS delays the need for a ventilation machine in the early stages of Amyotrophic lateral sclerosis (ALS) disease. In this case study, we present a young female ALS patient. A DPS was implanted after respiratory insufficiency began. In the one-year follow-up period following her operation, her need for ventilatory support disappeared. PMID- 26444328 TI - The effects of neuromuscular electrical stimulation at different frequencies on the activations of deep abdominal stabilizing muscles. AB - BACKGROUD: Low back pain is associated with transversus abdominis (TrA) dysfunction. Recently, it was proposed that Neuromuscular Electrical Stimulation (NMES) could be used to stimulate deep abdominal muscle contractions and improve lumbopelvic stability. OBJECTIVE: The purpose of this study was to determine the optimal stimulation frequency required during NMES for the activation of deep abdominal muscles. METHODS: Twenty healthy volunteers between the ages of 24 and 32 were included. The portable research-stimulator was applied using a 10 second contraction time, and a 10 second resting time at 20 Hz, 50 Hz, and 80 Hz. Changes in muscle thicknesses were determined for the TrA, obliquus internus (OI), and obliquus externus (OE) by real time ultrasound imaging. RESULTS: Significant thickness increases in the TrA, OI, and OE were observed during NMES versus the resting state (p < 0.05). Of the frequencies examined, 50 Hz NMES produced the greatest increase in TrA thickness (1.33 fold as compared with 1.22 fold at 20 Hz and 1.21 fold at 80 Hz) (p < 0.05). CONCLUSIONS: Our results indicate that NMES can preferentially stimulate contractions in deep abdominal stabilizing muscles. Most importantly, 50 Hz NMES produced greater muscle thickness increases than 20 or 80 Hz. PMID- 26444329 TI - Measurement of lumbar spine intervertebral motion in the sagittal plane using videofluoroscopy. AB - BACKGROUND: Static radiographic techniques are unable to capture the wealth of kinematic information available from lumbar spine sagittal plane motion. OBJECTIVE: Demonstration of a viable non-invasive technique for acquiring and quantifying intervertebral motion of the lumbar spine in the sagittal plane. METHODS: Videofluoroscopic footage of sagittal plane lumbar spine flexion extension in seven symptomatic volunteers (mean age = 48 yrs) and one asymptomatic volunteer (age = 54 yrs) was recorded. Vertebral bodies were digitised using customised software employing a novel vertebral digitisation scheme that was minimally affected by out-of-plane motion. RESULTS: Measurement errors in intervertebral rotation (+/- 1 degrees ) and intervertebral displacement (+/- 0.5 mm) compare favourably with the work of others. Some subjects presenting with an identical condition (disc prolapse) exhibited a similar column vertebral flexion-extension relative to S1 (L3: max. 5.9 degrees , min. 5.6 degrees ), while in others (degenerative disc disease) there was paradoxically a significant variation in this measurement (L3: max. 28.1 degrees , min. 0.7 degrees ). CONCLUSIONS: By means of a novel vertebral digitisation scheme and customised digitisation/analysis software, sagittal plane intervertebral motion data of the lumbar spine data has been successfully extracted from videofluoroscopic image sequences. Whilst the intervertebral motion signatures of subjects in this study differed significantly, the available sample size precluded the inference of any clinical trends. PMID- 26444330 TI - Efficacy of low-level laser therapy associated to orthoses for patients with carpal tunnel syndrome: A randomized single-blinded controlled trial. AB - OBJECTIVE: Compare the efficacy of orthoses and patient education with and without the addition to Low-Level Laser Therapy (LLLT - 660 nm, 30 mW, a continuous regime and bean area of 0.06 cm2). The laser irradiation was delivered with the fluency of 10J/cm2 in patients with mild and moderate Carpal Tunnel Syndrome (CTS). METHODS: 48 patients were randomized and 30 finished the protocol (a sample loss of 37.5%), 90% female and 10% males. Randomization was applied to allocate the patients in each one of the groups, with association or not to LLLT (group orthoses or LLLT and orthoses). All of them were submitted to ergonomic home orientations. The short-term symptoms and function outcome were assessed through: Boston Carpal Tunnel Questionnaire (BCTQ) - Severity of Symptoms (SS) Functional Score (FS). Pain (VAS), Semmes-Weinstein monofilaments, 2PD and pinch strength was used for characterization of the sample. Most of the participants were women, over 4th decade enrolled on heavy hand duties occupations, right handed, 66.7% affected on dominant hand, without alterations in sensory median nerve thresholds or pinch strength. RESULTS: Both groups showed a reduction of total BCTQ score and its subdomains after six weeks, with significant difference (p< 0.05), comparing to baseline. No significant difference was found between groups. A Minimal clinical change was observed after the intervention in 92.3% of participants for BCTQ subdomain severity of symptoms at individual comparison for LLLT and orthoses group and 76.5% for the orthoses group, demonstrating clinical relevance. Effect size Cohen's index was moderate for the severity of symptoms. CONCLUSION: LLLT in association to orthoses and ergonomic orientation seems to be effective in short-term symptoms relieve for patients with mild and moderate CTS. PMID- 26444331 TI - Associations between phenotypes of preeclampsia and thrombophilia. AB - OBJECTIVES: Preeclampsia complicates 2-8% of all pregnancies. Studies on the association of preeclampsia with thrombophilia are conflicting. Clinical heterogeneity of the disease may be one of the explanations. The present study addresses the question whether different phenotypes of preeclampsia are associated with thrombophilia factors. Study design We planned a retrospective cohort study. From 1985 until 2010 women with preeclampsia were offered postpartum screening for the following thrombophilia factors: anti-phospholipid antibodies, APC-resistance, protein C deficiency and protein S deficiency, hyperhomocysteineamia, factor V Leiden and Prothrombin gene mutation. Hospital records were used to obtain information on phenotypes of the preeclampsia and placental histology. RESULTS: We identified 844 women with singleton pregnancies who were screened for thrombophilia factors. HELLP complicated 49% of pregnancies; Fetal growth restriction complicated 61% of pregnancies. Early delivery (<34th week) occurred in 71% of pregnancies. Any thrombophilia factor was present in 29% of the women. Severe preeclampsia was associated with protein S deficiency (p=0.01). Fetal growth restriction was associated with anti phospholipid antibodies (p<0.01). Early onset preeclampsia was associated with anti-phospholipid antibodies (p=0.01). Extensive placental infarction (>10%) was associated with anti-phospholipid antibodies (p<0.01). Low placental weight (<5th percentile) was associated with hyperhomocysteineamia (p=0.03). No other associations were observed. CONCLUSIONS: Early onset preeclampsia, especially if complicated by fetal growth restriction, are associated with anti-phospholipid antibodies. Other phenotypes of preeclampsia, especially HELLP syndrome, were not associated with thrombophilia. We advise only to test for anti-phospholipid antibodies after early onset preeclampsia, especially if complicated by fetal growth restriction. We suggest enough evidence is presented to justify no further studies are needed. PMID- 26444332 TI - Mouse preantral follicle development in two-dimensional and three-dimensional culture systems after ovarian tissue vitrification. AB - OBJECTIVES: This work on follicle culture and evaluation of expression of oocyte maturation genes helps to better understand the complicated processes of folliculogenesis and to develop new approaches for infertility treatment. STUDY DESIGN: Ovaries of 12-day-old female NMRI mice were divided into control and vitrification groups. After vitrification and warming procedures, ovarian tissue morphologies were histologically evaluated and compared to those of the control group. In the second stage, preantral follicles were mechanically isolated from non-vitrified and vitrified ovaries and cultured for 12 days in two-dimensional (2D) and three-dimensional (3D) systems. Finally, the survival and growth rate of follicles and quantitative expression of oocyte maturation genes (Gdf9, Bmp15 and Bmp6) were studied. RESULT: Morphological integrity of ovarian tissue in vitrification group was well preserved. Survival rates of cultured preantral follicles in control group during 2D and 3D systems were somewhat similar, but were significantly different between 2D and 3D systems in vitrification group. Although the growth rate of follicles was similar in the 3D system in both groups, substantially higher growth rate was observed for the control group in the 2D system. Expressions of oocyte maturation genes were, to some extent, similar between control and vitrification groups. There was a remarkable reduction in expression pattern of genes in 3D compared to 2D system in both experimental groups, during the 12th day of culture period. CONCLUSIONS: 3D in vitro culture system could be appeared more appropriate than 2D culture system for preservation of follicles in terms of spatial morphology, growth rate and expression reduction of maturation genes. PMID- 26444333 TI - Capillary electrophoresis coupled with 1,1'-thiocarbonyldiimidazole derivatization for the rapid detection of total homocysteine and cysteine in human plasma. AB - A simple and rapid approach is described for the determination of total plasma cysteine and homocysteine using capillary electrophoresis. Human plasma samples were reduced with dithiothreitol and then processed with 1,1' thiocarbonyldiimidazole in acetonitrile. After centrifugation, the sample supernatant was injected directly into a capillary by applying negative voltage and analytes were stacked after alkaline post-injection. Using a 50MUm i.d. silica capillary of 35cm total length, filled with 0.1M triethanolamine, 0.15M formic acid, and 50MUM hexadecyltrimethylammonium bromide (pH 3.9), we reached a limit of quantification of 2.5MUM for homocysteine. Accuracy was 94.7-105.1%, intra- and inter-day imprecisions were <2.5 and <3%, respectively. The total analysis time was 6min. Furthermore, liquid-phase extraction with isopropanol led to a fourfold increase in sensitivity. PMID- 26444334 TI - Development and validation of an improved HPLC-MS/MS method for comparative pharmacokinetics of penehyclidine hydrochloride following a single intravenous or intramuscular injection. AB - Penehyclidine hydrochloride (PHC) is an anticholinergic drug with both antimuscarinic and antinicotinic activity. In order to compare the pharmacokinetics of two administration routes (intravenous injection (i.v.) and intramuscular injection (i.m.)) of PHC, an improved High Performance Liquid Chromatography Tandem Mass Spectrometry (HPLC-MS/MS) bioanalytical method was developed for the quantification of PHC in plasma and urine using verapamil as the internal standard (I.S.). Chromatography was performed using a Thermo Hypersil GOLD column (30mm*2.1mm, 3MUm), with a gradient elution of 10/00 formic acid-10mmol/L ammonium acetate and acetonitrile at 0.3mL/min. Detection and quantitation were performed by electrospray ionization (ESI) and multiple reaction monitoring (MRM) in the positive ion mode. The most intense [M+H](+) MRM transition of PHC at m/z 316.2->128.3 was used for PHC quantitation, and the transition at m/z 454.6->303.2 was used to monitor I.S. The lower limit of quantification (LLOQ) was 0.05 ng/mL. The intraday precision was <6.71% and the interday precision was <11.69%. The pharmacokinetic parameters of i.v. and i.m. administration routes were as follows (i.v. vs i.m.): t1/2 15.73 vs 17.24h, Tmax 0.06 vs 0.26h, AUC0-t 69.35 vs 67.90hng/mL, AUC0-inf 78.24 vs 79.67hng/mL, Cmax 37.5 vs 9.1ng/mL, Ae0-24h 22.7 vs 25.21MUg. There were no significant differences between parameters t1/2 and AUC (P>0.05), but significant differences were observed in Cmax, Tmax and Ae0-24h between the two administration routes (P<0.05). The mean absolute bioavailability of the i.m. administration route was 98.4% (95% confidence interval, 93.4-103.6%). Safety results showed that PHC appeared to be well tolerated in both i.v. and i.m. administration routes and pharmacokinetic results showed that PHC was nearly completely absorbed via i.m. administration route. PMID- 26444335 TI - Method development for quantification of the environmental neurotoxin annonacin in Rat plasma by UPLC-MS/MS and application to a pharmacokinetic study. AB - Annonacin is an environmental neurotoxin identified in the pulp of several fruits of the Annonaceae family (for example in Annona muricata, Asimina triloba), whose consumption was linked with the occurrence of sporadic atypical Parkinsonism with dementia. Pharmacokinetic parameters of this molecule are unknown. A method for its quantification in Rat plasma was developed, using its analogue annonacinone as an internal standard. Extraction from plasma was performed using ethylacetate with a good recovery. Quantification was performed by UPLC-MS/MS in SRM mode, based on the loss of the gamma-methyl-gamma-lactone (-112amu) from the sodium cationized species [M+Na](+) of both annonacin and internal standard. The limit of quantification was 0.25ng/mL. Despite strong matrix effects, a good linearity was obtained over two distinct ranges 0.25-10ng/mL and 10-100ng/mL. The intra- and inter-day precisions (RSD) were lower than 10%, while accuracy was within +/ 10%. This method was applied to a pharmacokinetic study in the Rat. After oral administration of 10mg/kg annonacin, a Cmax of 7.9+/-1.5ng/mL was reached at Tmax 0.25h; T1/2 was 4.8+/-0.7h and apparent distribution volume was 387.9+/-64.6L. The bioavailability of annonacin was estimated to be 3.2+/-0.3% of the ingested dose. PMID- 26444337 TI - Phenyliodine(III) Diacetate Mediated Oxidative Cyclization of 1-Alkenoyl-1 carbamoyl Cycloalkanes: Access to Spiro-Fused Dihydrofuran-3(2H)-ones. AB - Facile and efficient synthesis of spiro-fused dihydrofuran-3(2H)-ones was developed via phenyliodine(III) diacetate (PIDA) mediated oxidative cyclization of 1-alkenoyl-1-carbamoyl cycloalkanes under very mild conditions. PMID- 26444336 TI - Graphitic carbon nitrides modified hollow fiber solid phase microextraction for extraction and determination of uric acid in urine and serum coupled with gas chromatography-mass spectrometry. AB - An elevated uric acid (UA) in urine or serum can affect renal function and blood pressure, which is an indicator of gout, cardiovascular and renal diseases, hypertension, etc. In this work, a new type of mixed matrix membrane (MMM), based on graphitic carbon nitrides (g-CNs) and hollow fiber (HF), was prepared and combined with solid phase microextraction (SPME) mode to determine UA in urine and serum followed by gas chromatography-mass spectrometry (GC/MS). The porous g CNs were dispersed in ammonia, and then the exfoliated g-CNs nanosheets were held in the pores of HF by capillary forces and sonification. The prepared g-CNs modified HF (g-CNs-HF) was immersed in biofluid directly to extract UA with SPME mode and the solvent-free mode is convenient for further derivatization and analysis. To achieve the highest extraction efficiency (EF), main extraction and derivatization parameters, such as g-CNs-HF immobilizing time, sonification power and time of extraction, derivatization and desorption time, were optimized. Under the optimum extraction conditions, a favorable linearity of UA was obtained in the range 0.1-200MUgmL(-1) with correlation coefficients higher than 0.9990, and the average recoveries at three spiked levels of UA in urine and serum ranged from 80.7% to 121.6%, from 84.7% to 101.1%, respectively. The obtained results demonstrated the developed g-CNs-HF-SPME is a simple, rapid, cost-effective, solvent-free method for the analysis of UA in biofluid. PMID- 26444338 TI - In vitro cytotoxicity evaluation of different pulp capping materials: a comparative study. AB - Direct pulp capping covers the exposed surface of the pulp to maintain its vitality and preserve its functional and biologic activity. The aim of the present study was to compare the biocompatibility effects of seven different pulp capping materials in vitro: Dycal(r), Calcicur(r), Calcimol LC(r), TheraCal LC(r), ProRoot MTA(r), MTA-Angelus(r), and Biodentine(r). Using the Transwell insert methodology by Alamar blue test, we evaluated the cytocompatibility of the above mentioned materials towards murine odontoblasts cells (MDPC-23) at three different times (24, 48, and 72 h). For additional control, the cell viability at 72 hours was also assessed by MTT assay. Morphological analysis of murine odontoblasts was assessed by Confocal Laser Scanning Microscope. The results indicate significantly different biocompatibility among materials with different composition. Biodentine(r) and mineral trioxide aggregate (MTA)-based products showed lower cytotoxicity, varying from calcium hydroxide-based materials, which exhibited higher cytotoxicity. Although our findings are limited to in vitro conditions, the observation that Biodentine(r) caused a cytotoxic effect similar to MTA suggests that it may be considered an alternative in pulp-capping treatment, as calcium hydroxide-based materials present higher cytotoxic effects. PMID- 26444339 TI - Acute toxicity of maneb in the tadpoles of common and green toad. AB - Pesticides used in agriculture can have hazardous effects on aquatic organisms, and amphibians are even more threatened than other aquatic vertebrates. Maneb is widely used to control fungal diseases on crops, fruits, and vegetables. The aim of this study was to investigate the acute toxic effects of maneb on the common (Bufo bufo) and green toad (Pseudepidalea viridis) tadpoles. Tadpoles at the development stage 21 were exposed to maneb (0-5 mg L(-1)) for 120 h. Maneb LC50 values at hour 120 were 1.966 mg L(-1) for B. bufo and 0.332 mg L-1 for P. viridis. To the best of our knowledge, these are the first published LC50 findings for the two species. Visceral oedema and tail deformations were observed in both species. We also observed liver necrosis, pronephric tubule deformations, somite deteriorations, and visceral oedema at maneb concentrations>=0.1 mg L(-1) for B. bufo and >=0.05 mg L(-1) for P. viridis. Our results show that B. bufo tadpoles have a much higher resilience to maneb than P. viridis tadpoles. This resilience seems to be related to the larger size of the B. bufo tadpoles and their ability to metamorphose faster in adverse conditions. Future research should look into the mechanisms of toxic action of maneb in anurans. PMID- 26444340 TI - Quantitative analysis of arbutin and hydroquinone in strawberry tree (Arbutus unedo L., Ericaceae) leaves by gas chromatography-mass spectrometry. AB - The phenolic glycoside arbutin and its metabolite with uroantiseptic activity hydroquinone occur naturally in the leaves of various medicinal plants and spices. In this study, an extraction procedure coupled with gas chromatography mass spectrometry (GC-MS) was developed to determine arbutin and hydroquinone content in strawberry tree (Arbutus unedo L., Ericaceae) leaves. The method showed good linearity (R2>0.9987) in the tested concentration range (0.5-200 MUg mL(-1)), as well as good precision (RSD<5%), analytical recovery (96.2-98.0%), and sensitivity (limit of detection=0.009 and 0.004 MUg mL(-1) for arbutin and hydroquinone, respectively). The results obtained by the validated GC-MS method corresponded well to those obtained by high performance liquid chromatography (HPLC) method. The proposed method was then applied for determining arbutin and hydroquinone content in methanolic leaf extracts. The amount of arbutin in the leaves collected on the island of Kolocep (6.82 mg g(-1) dry weight) was found to be higher (tpaired=43.57, tc=2.92) in comparison to the amount of arbutin in the leaves collected on the island of Mali Losinj (2.75 mg g(-1) dry weight). Hydroquinone was not detected in any of the samples. The analytical features of the proposed GC-MS method demonstrated that arbutin and hydroquinone could be determined alternatively by gas chromatography. Due to its wide concentration range, the method could also be suitable for arbutin and hydroquinone analysis in leaves of other plant families (Rosaceae, Lamiaceae, etc.). PMID- 26444341 TI - Assessment of exposure to the Penicillium glabrum complex in cork industry using complementing methods. AB - Cork oak is the second most dominant forest species in Portugal and makes this country the world leader in cork export. Occupational exposure to Chrysonilia sitophila and the Penicillium glabrum complex in cork industry is common, and the latter fungus is associated with suberosis. However, as conventional methods seem to underestimate its presence in occupational environments, the aim of our study was to see whether information obtained by polymerase chain reaction (PCR), a molecular-based method, can complement conventional findings and give a better insight into occupational exposure of cork industry workers. We assessed fungal contamination with the P. glabrum complex in three cork manufacturing plants in the outskirts of Lisbon using both conventional and molecular methods. Conventional culturing failed to detect the fungus at six sampling sites in which PCR did detect it. This confirms our assumption that the use of complementing methods can provide information for a more accurate assessment of occupational exposure to the P. glabrum complex in cork industry. PMID- 26444342 TI - Levels of house dust mite allergen in cars. AB - This small study investigated house dust mite (HDM) allergen levels in cars and their owners' homes in north-east Scotland. Dust samples from twelve households and cars were collected in a standardised manner. The dust samples were extracted and measured for the Dermatophagoides group 2 allergens (Der p 2 and Der f 2) and total soluble protein. Allergen levels at homes tended to be higher than in the cars, but not significantly. However, they significantly correlated with paired car dust samples expressed either per unit weight of dust or soluble protein (rho=0.657; p=0.02 and 0.769; p=0.003, respectively). This points to house-to-car allergen transfer, with the car allergen levels largely reflecting levels in the owner's home. Car HDM allergen levels were lower than those reported in Brazil and the USA. Twenty-five percent of the houses and none of the cars had allergen levels in dust greater than 2000 ng g(-1). This value is often quoted as a threshold for the risk of sensitisation, although a number of studies report increased risk of sensitisation at lower levels. This small study does not allow for characterisation of the distribution of HDM allergen in vehicles in this geographic area, or of the likely levels in other warmer and more humid areas of the UK. Cars and other vehicles are an under-investigated micro-environment for exposure to allergenic material. PMID- 26444343 TI - Accidental discovery of asbestos-related occupational pleural disease in unemployed carpenter: a healthcare safety net that needs mending. AB - Unemployed persons are often on the margins of the healthcare system and under the radar of safety and health organisations, as no systematic records are kept of occupational diseases caused by exposure at previous work place. Law in Slovenia requires that asbestos-related occupational diseases are verified by establishing the causal relationship between exposure at work and its effect on the worker. This report describes a case of verifying occupational pleural disease in an unemployed carpenter who was referred for consultation with occupational health specialist as part of the regular procedure for the unemployed registered at the Employment Service of Slovenia. At the consultation it turned out that the carpenter had been exposed to asbestos when he worked as a teenage apprentice. The diagnosis of the bilateral pleural disease and asbestosis was confirmed by X-ray and high-resolution computed tomography. Because he had no record of exposure in that period, we analysed his past working environment for minerals and found chrysotile in all asbestos board samples. The case was presented to an interdisciplinary committee, which verified his disease as occupational. This case points to the need of adopting guidelines for occupational health specialists providing counsel to the national employment service so that the number of unrecorded occupational diseases is minimised and their treatment is covered by the state. PMID- 26444344 TI - Hydroxyethyl starch should not be used to manage severe aluminium phosphide poisoning. PMID- 26444345 TI - Response to Professor Rumboldt's reaction to our letter on hydroxyethyl starch use in managing aluminium phosphide poisoning. PMID- 26444346 TI - The 2nd Croatian Symposium on Membrane Transporters (2. hrvatski simpozij o transporterima): Membrane Transporters in Toxicological and Pharmacological Research. PMID- 26444347 TI - Brown-Vialetto-Van Laere syndrome: two siblings with a new mutation and dramatic therapeutic effect of high-dose riboflavin. AB - Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare and severe neurometabolic disease. We present two siblings with BVVLS with a novel homozygous mutation in SLC52A3 (formerly C20orf54) gene. The first sibling was admitted with respiratory insufficiency and required mechanical ventilation. After administration of a high dose of riboflavin, all his clinical symptoms were resolved, which also strongly suggested the diagnosis of BVVLS. The second sibling was also found to have the same genetic mutation as her brother. Although she was symptom-free, riboflavin was initiated empirically. On follow-up, she developed no neurologic or metabolic problems with entirely normal growth and development. BVVLS should be considered in the differential diagnosis of unexplained neurologic symptoms such as polyneuropathy and respiratory insufficiency, as BVVLS and multiple acyl-CoA dehydrogenation defect have broadly overlapping symptoms. Furthermore, our cases once again suggest that with proper diagnosis and early high-dose riboflavin treatment, complete reversal of neurologic deficits in BVVLS is possible. PMID- 26444348 TI - Entorhinal cortex: a good biomarker of mild cognitive impairment and mild Alzheimer's disease. AB - Entorhinal cortex (EC), thought to be the location of the earliest lesions in Alzheimer's disease (AD), has been widely studied in recent years. With the irreversible pathological changes of AD, there is an urgent need to find biomarkers that can be used to predict the presence of the disease before it is clinically expressed. The aim of this review is to summarize and analyze recent findings that are relevant to the important role of EC in the diagnosis of mild cognitive impairment (MCI) and mild AD and to describe a range of neuroimaging techniques used to define the EC boundary. A comprehensive literature search for articles published up to May 2015 was performed. Our research highlights the finding that atrophy in EC reflects the early pathological changes of AD and can be a strong predictor of prodromal AD. The early changes in EC are a good imaging biomarker that can be used to discriminate individuals with MCI from normal control subjects. A larger degree of atrophy in EC predicts increased disease severity, and the right EC in patients with mild AD exhibited greater changes than the left side. In addition, the EC seems to have an obvious advantage over the hippocampus as a biomarker when predicting future conversion to AD in individuals with MCI, and it may be of help in following the course of disease progression. In this review, we also summarize the main differences observed between the hippocampus and the EC when differentiating diseases. These findings will hopefully provide an opportunity for the effective prevention and early treatment of AD. PMID- 26444349 TI - The bridge between two worlds: psychoanalysis and fMRI. AB - In recent years, a connection between psychoanalysis and neuroscience has been sought. The meeting point between these two branches is represented by neuropsychoanalysis. The goal of the relationship between psychoanalysis and neuroscience is to test psychoanalytic hypotheses in the human brain, using a scientific method. A literature search was conducted on May 2015. PubMed and Scopus databases were used to find studies for the inclusion in the systematic review. Common results of the studies investigated are represented by a reduction, a modulation, or a normalization of the activation patterns found after the psychoanalytic therapy. New findings in the possible and useful relationship between psychoanalysis and neuroscience could change the modalities of relating to patients for psychoanalysts and the way in which neuroscientists plan their research. Researchers should keep in mind that in any scientific research that has to do with people, neuroscience and a scientific method cannot avoid subjective interpretation. PMID- 26444350 TI - Selective nematocidal effects of essential oils from two cultivated Artemisia absinthium populations. AB - Essential oils (EOs) obtained from two crops and populations of thujone-free cultivated Artemisia absinthium were tested against two nematode models, the mammalian parasite Trichinella spiralis, and the plant parasitic root knot nematode Meloidogyne javanica. The EOs were characterized by the presence of (Z) epoxyocimene and chrysanthenol as major components and showed time and population dependent quantitative and qualitative variations in composition. The EOs showed a strong ex vivo activity against the L1 larvae of the nematode Trichinella spiralis with a reduction of infectivity between 72 and 100% at a dose range of 0.5-1 mg/ml in absence of cytotoxicity against mammalian cells. Moreover, the in vivo activity of the EO against T. spiralis showed a 66% reduction of intestinal adults. However, these oils were not effective against M. javanica. PMID- 26444351 TI - Salivary alpha-Amylase And Chromogranin A In Anxiety-Related Research. AB - Salivary alpha-amylase (sAA) and chromogranin A (sCgA) are at the forefront of current biochemical research on anxiety. Their use is being driven by the sudden surge of interest in "salivaomics," a new field in medicine studying saliva's genetic code, proteome and methabolom. Interestingly, it is not the primary functions of the enzyme and the protein, but the ingenious capture of their secondary ones (maintenance of the acid-alkaline balance and bactericidal / antifungal action) that allows for a swift, precise and pain-free measurement under physical and mental duress. Upon stimulation, sAA and sCgA are almost simultaneously released. Studying them allows a closer look at the autonomic nervous system (ANS) as opposed to the hypothalamic-pituitary-adrenal axis (HPA), which involves a long cascade of complex, hard to measure and interpret bio chemical reactions. PMID- 26444352 TI - Bone And Soft Tissue Changes In Patients With Spinal Cord Injury And Multiple Sclerosis. AB - In patients with spinal cord injury and multiple sclerosis, deterioration of body composition (changes in bone, fat and muscle mass) is associated with increased risk for diseases such as coronary artery heart disease, non-insulin dependent diabetes mellitus, lipid metabolism abnormalities, and osteoporotic fractures in these patients. Immobility leads to a changing pattern of loading in the paralyzed areas, and secondary alteration in structure. However, bone and soft tissue changes in these patients are usually neglected. The purpose of this article is to update on the pathophysiological mechanisms leading to bone and soft tissue changes, and to increase the awareness of the treating physicians with respect to bone, muscle and fat loss and their consequences aiming to obtain measures to prevent bone and soft tissue loss in these patients. PMID- 26444353 TI - Clinical And Morphological Improvement Of Lupus Nephritis Treated With Rituximab. AB - AIM: TO assess the effects of rituximab (RTM) therapy on clinical and morphologic activity of lupus nephritis (LN). MATERIAL AND METHODS: The study included 45 patients with confirmed diagnosis of systemic lupus erythematosus (SLE), unaffected by previously received standard therapy with glucocorticoids (GCs) and cytostatics. The disease activity was assessed using Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K); to assess the LN activity we used the SLICC RA/RE index. Forty-five patients with LN were given puncture renal biopsy prior to prescribing RTM; 16 patients had repeated renal biopsy 1 year and more after beginning the anti-B-cell therapy. LN was graded histologically in accordance with the WHO classification (2003) with indices of activity (AI) and chronicity (CI). RESULTS: The predominant number of patients had class III - IV of LN. The repeated renal biopsies demonstrated that LN had undergone a transition into a more favourable morphologic class, which was associated, in most of these cases, with a positive therapeutic effect. The follow-up dynamics showed a statistically significant reduction of AI (p=0.006), and no statistically significant changes in the CI (p = 0.14). CONCLUSION: The long-term follow-up in the study has showed that repeated courses of anti-B-cell therapy with RTM have a positive effect both on SLE activity and generally on the renal process. The reduction of the morphologic class of LN as assessed in the repeated renal biopsies is a convincing proof for this. Eleven out of 16 patients experienced transition of the morphologic class into a more favourable type, which in most cases was combined with lower AI (p = 0.006). We found no evidence of increase in the CI (p = 0.14). PMID- 26444354 TI - Medical And Surgical Management Of Orbital Cellulitis In Children. AB - OBJECTIVE: The purpose of this study was to identify features of orbital cellulitis that predict response to conservative treatment without surgical intervention and factors associated with a decision for surgery. PATIENTS AND METHODS: The medical files of patients diagnosed with orbital cellulitis at a tertiary medical center in central Israel between 1995 and 2010 were reviewed for clinical data, diagnosis, complications, and type of treatment. Comparison was made between patients treated with antibiotics and patients treated with antibiotics and surgery. RESULTS: Fifty-one patients (35 male) with a mean age of 6.1 years were identified. Main clinical signs included fever (mean 38.5 degrees C), proptosis (82.3%), extraocular motility restriction (74.5%), and ocular pain (41.1%). Forty-one patients were successfully treated with antibiotics and 10 required endoscopic sinus surgery. On between-group comparison, the surgery group had severe eye pain (p = 0.009), severe proptosis (P = 0.02), longer intravenous antibiotic treatment (13.2 vs. 9.2 days, p = 0.04), and several imaging findings. Additional factors associated with surgical intervention included older children, subperiorbital abscess, larger dimension of the abscess (mean 15 mm), involvement of frontal sinuses and findings of intraorbital air bubbles. There was no visual deterioration in either group and no late sequelae. CONCLUSION: Factors associated with surgery included age older than 9 years, severe ocular pain, severe proptosis, and subperiorbital large abscess. These may be used for early identification of patients at risk of failure of only medical management. PMID- 26444356 TI - Behaviour Evaluation Scales For Pediatric Dental Patients - Review And Clinical Experience. AB - The present article makes a review of the relevant literature on the scales used in the assessment of behaviour of pediatric dental patients as well as presents the results we have had of using a modified Kurosu Behaviour Evaluation Scale to assess a study sample. The review makes a critical analysis of current evaluation methods and the design of assessment scales. The assessment tools most commonly used in pediatric dentistry are presented in a chronological order from the past to the present. The clinical study we conducted used a modified Behaviour Evaluation Scale developed by Kurosu for the assessment of the behaviour of children. The study showed that during dental treatment of children in the age range of 6 to 12 years the prevailing objective behaviour characteristics in accordance with Kurosu's behaviour evaluation scale are related to the eyes and the facial expression. The findings from the literature review and the results of our study warrant further studies to develop easy-to-use assessment tools that would enhance the objective assessment of behaviour. PMID- 26444355 TI - Surgical Site Infection In Orthopaedic Surgery: Correlation Between Age, Diabetes, Smoke And Surgical Risk. AB - INTRODUCTION: Surgical site infection is a common complication after orthopaedic surgery. It can be associated with increased morbidity rate and social cost. The accurate identification of risk factors is essential so that strategies to prevent these potentially devastating infections can be developed. We have conducted this study to determine the possible risk factors for the surgical site infections. OBJECTIVES: We aimed at finding exhaustive evidence concerning the potential risk factors for infections in orthopaedic surgery. PATIENTS AND METHODS: Between October 2009 and December 2011, we identified 84 patients with a superficial and/or deep surgical site infection and compared them with 203 uninfected patients (control group), taken out from a series of 486 patients. We considered the following risk factors: diabetes, BMI >30, ASA Score of 3 or 4, smoking and age. RESULTS: The most frequently performed operations of the 287 examined patients were the knee and hip arthroplasties (n = 32, 11.14%) and open fracture reductions (n = 178, 62.02%). Staphylococcus Aureus was the most common identified pathogen (n = 63, 75%). The analyses (preoperative and postoperative) of the infected patients showed them to have significantly high serum glucose levels in comparison with the control group (odds ratio = 8.7). We found a significant high rate of infection in patients smoking for more than 20 years (67 patients, 79.7%). The remaining variables (BMI, OR = 2.21; ASA score, OR = 1.3) showed no significant differences between the study group and controls. We also found a correlation between > 65-year-old patients and infections at the surgical site (61 patients, 72.6%). CONCLUSION: We found that there was correlation between diabetes, smoking and age as risk factors with the development of infection at the surgical site; other variables such as the ASA score and BMI are not relevant here (contrary to what is reported in literature). We believe that postoperative results can be improved considerably with a properly conducted antibiotic treatment, stringent glycemic control (achievable only with careful multidisciplinary management) and good compliance of patients. PMID- 26444357 TI - Clear Cell Sarcoma Of Metatarsus. AB - We report a case of clear cell sarcoma in the third metatarsus of the right foot. This type of tumor is very rare and scantily reported in literature. A 42-year old Caucasian male presented with a nodular ulcerated mass on the dorsal side of the left foot. X-rays demonstrated a nodular solid lesion which dislodged the third metatarsus. A biopsy revealed a neoplastic proliferation with a sarcoma clear cell profile; because of the aggressive nature of this type of neoplasm, we performed a trans-tibial amputation according to Bugess to achieve a better functionality for the patient. The present study underlines clinical, morphological, as well as imaging and therapeutic aspects of a rare neoplasm such as clear cell sarcoma. The location site is also quite unusual - the metatarsus of the foot. The histological and immunohistochemical data were suggestive of the diagnosis of clear cell sarcoma of metatarsus. After MRI and a bone scan, the surgical treatment suggested the extension over the forefoot and the ankle and therefore a trans-tibial amputation was made. PMID- 26444358 TI - Investigation Of Chromium-Cobalt Coated Scaffolds On Cell Cultures In Vitro. AB - INTRODUCTION: The use of diverse materials for medical purposes is continuously expanding. The modification of materials which are routinely applied in medical practice as well as the development and introduction of new materials require studies on their biological activity. The first steps in this process are the preliminary short-term screening tests for cytotoxicity and biocompatibility performed on cell cultures. METHODS: Coating of stainless steel (316 L) scaffolds with chromium-cobalt was performed by electroplating using the non-standard electrolyte Chromispel. The process was carried through at different cathode current densities and deposition times. The modified surface of the metal scaffolds was studied for cytoxicity and cell vitality on the serum-free McCoy Plovdiv and the immortalized PDL cell cultures. RESULTS: Our results indicate no cytotoxic effect of the coated metal scaffolds. Even more, three of the samples stimulated the proliferation and growth of McCoy-Plovdiv cells. CONCLUSION: We have strong reasons to believe that chromium-cobalt coatings are promising for future studies and reliable for medical purposes. PMID- 26444359 TI - Latent Bipolarity In Unipolar Depression: Experimental Findings, Conceptual Analysis And Implications For Treatment Strategies. AB - INTRODUCTION: Previous studies have suggested that the two opposite poles of psychomotor disturbances in unipolar depression (UD) - retardation and agitation require different treatment strategies as the psychomotor overactivation requires an augmentation of the antidepressant therapy with mood stabilizers and/or atypical antipsychotics. OBJECTIVE: The aim of the present study was to objectively identify and measure the psycho-motor disturbances in UD using differentiation between activity and reactivity. MATERIAL AND METHODS: An equilibriometric movement pattern analysis system that allows differentiation between psychomotor activity and reactivity was applied in 58 unipolar depressive patients and 76 healthy controls. RESULTS: Compared to controls, the patients as a group were significantly slower in their psychomotor reactivity. However, the subsequent subgrouping according to the direction of deviation of their objective psychomotor parameters revealed a disinhibition of psychomotor activity and/or reactivity in about one half of them. Such a contradictory combination of clinically manifested depressive mood and subclinically detected manic-like psychomotor overactivation might be regarded as belonging to the bipolar spectrum, since it was admitted that manic psychomotor disinhibition in unipolar depressive patients uncovers a latent bipolarity. CONCLUSION: Not only prototypical depressive inhibition, but also prototypical manic-like disinhibition may underlie clinically manifested UD. Since the combination between depressive mood and psychomotor overactivation multiplies the suicidal risk, we may presume that the timely detection of this combination at a subclinical level would contribute to an earlier and more effective suicidal prevention by an objectively-guided optimization of pharmacological treatment. PMID- 26444360 TI - Emergence Of Consciousness And Qualia From A Complex Brain. AB - Qualia are private conscious experiences of which the associated feelings can be reported to other people. Whether qualia are amenable to scientific exploration has often been questioned, which is challenged by the present article. The following arguments are given: 1. the configuration of the brain changes continuously and irreversibly, because of genetic and environmental influences and interhuman communication; 2. qualia and consciousness are processes, rather than states; 3. private feelings, including those associated with qualia, should be positioned in the context of a personal brain as being developed during life; 4. consciousness and qualia should be understood in the context of general system theory, thus concluding that isolated, in vitro, properties of neurons and other brain constituents might marginally contribute to the understanding of higher brain functions, mind or qualia; 5. current in vivo approaches have too little resolution power - in terms of space and time - to delineate individual and subjective brain processes. When subtle personalized properties of the nervous system can be assessed in vivo or in vitro, qualia can scientifically be investigated. We discuss some approaches to overcome these barriers. PMID- 26444361 TI - World, Time And Anxiety. Heidegger's Existential Analytic And Psychiatry. AB - Martin Heidegger was one of the most influential but also criticized philosophers of the XX century. With Being and Time 1927 he sets apart his existential analytic from psychology as well as from anthropology and from the other human sciences that deny the ontological foundation, overcoming the Cartesian dualism in search of the ontological unit of an articulated multiplicity, as human being is. Heidegger's Dasein Analytic defines the fundamental structures of human being such as being-in-the-world, a unitary structure that discloses the worldhood of the world; the modes of being (Seinsweisen), such as fear (Furcht) and anxiety (Angst); and the relationship between existence and time. In his existential analytic, anxiety is one of the fundamental moods (Grundbefindlichkeit) and it plays a pivotal role in the relationship of Dasein with time and world. The paper firstly focuses on the modes of being, underlining the importance of anxiety for the constitution of human being; secondly, it shows the relationship between anxiety and the world, and anxiety and time: rejecting both the Aristotelian description of time, as a sequence of moments that informs our common understanding of time, and the Augustine's mental account of inner time, Heidegger considers temporality under a transcendental point of view. Temporality is ek-static, it is a process through which human being comes toward and back to itself, letting itself encounter the world and the entities. The transcendental interpretation of time provided by Heidegger may give its important contribution to psychopathology. PMID- 26444362 TI - Mental Illness And Brain Disease. AB - It has become common to say psychiatric illnesses are brain diseases. This reflects a conception of the mental as being biologically based, though it is also thought that thinking of psychiatric illness this way will reduce the stigma attached to psychiatric illness. If psychiatric illnesses are brain diseases, however, it is not clear why psychiatry should not collapse into neurology, and some argue for this course. Others try to maintain a distinction by saying that neurology deals with abnormalities of neural structure while psychiatry deals with specific abnormalities of neural functioning. It is not clear that neurologists would accept this division, nor that they should. I argue that if we take seriously the notion that psychiatric illnesses are mental illnesses we can draw a more defensible boundary between psychiatry and neurology. As mental illnesses, psychiatric illnesses must have symptoms that affect our mental capacities and that the sufferer is capable of being aware of, even if they are not always self-consciously aware of them. Neurological illnesses, such as stroke or multiple sclerosis, may be diagnosed even if they are silent, just as the person may not be aware of having high blood pressure or may suffer a silent myocardial infarction. It does not make sense to speak of panic disorder if the person has never had a panic attack, however, or of bipolar disorder in the absence of mood swings. This does not mean psychiatric illnesses are not biologically based. Mental illnesses are illnesses of persons, whereas other illnesses are illnesses of biological individuals. PMID- 26444363 TI - Clinical examinations after the Fukushima disaster: a case report of Soma General Hospital. PMID- 26444364 TI - The side effects of translational omics: overtesting, overdiagnosis, overtreatment. AB - High-throughput technologies such as next-generation genomics, transcriptomics and proteomics are capable of generating massive amounts of data quickly, and at relatively low costs. It is tempting to use this data for various medical applications including preclinical disease detection and for prediction of disease predisposition. Pilot projects, initiated by various research groups and Google, are currently underway, but results with not be available for a few years. We here summarize some possible difficulties with these approaches, by using examples from already tried cancer and other screening programs. Population screening, especially with multiparametric algorithms, will identify at least some false positive parameters and screening programs will identify abnormal results in otherwise healthy individuals. Whole genome sequencing will identify genetic changes of unknown significance and may not predict accurately future disease predisposition if the disease is also influenced by environmental factors. In screening programs, if the disease is rare, the positive predictive value of the test will be low, even if the test has excellent sensitivity and specificity. False positive results may require invasive procedures to delineate. Furthermore, screening programs are not effective if the cancer grows quickly, and will identify indolent forms of the disease with slow-growing tumors. It has also been recently shown that for some cancers, more intensive and radical treatments do not usually lead to better clinical outcomes. We conclude that new omics testing technologies should avoid overdiagnosis and overtreatment and need to be evaluated for overall clinical benefit before introduction to the clinic. PMID- 26444365 TI - ABCG2/BCRP interaction with the sea grass Thalassia testudinum. AB - BACKGROUND: The aqueous ethanolic extract from leaves of the marine plant Thalassia testudinum has shown antioxidant, cytoprotective, and neuroprotective properties. The chemical composition of this extract, rich in polyphenols, could interfere with active transport of drugs out of the cell and circumvent the phenomenon of multidrug resistance (MDR). The extract can act as an MDR modulator through its interaction with efflux transporters. The ABCG2/BCRP has been shown to confer MDR acting in tumor cells. METHODS: To evaluate the interaction of ABCG2/BCRP with the extract, studies in cells overexpressing human BCRP transporter and its murine ortholog Bcrp1 were performed. RESULTS AND CONCLUSIONS: T. testudinum extract could be included as MDR modulator, as interaction with ABCG2/BCRP has been shown through flow cytometry and MTT assays. The cells overexpressing ABCG2/BCRP in the presence of the extract (25-150 MUg/mL) decreased the survival rates of the anti-tumoral mitoxantrone. Our results support its inclusion as a possible MDR modulator against tumor cells that overexpress ABCG2/BCRP. PMID- 26444366 TI - Beauty. PMID- 26444367 TI - Q&A: Karl Grammer. Innate attractions. PMID- 26444368 TI - Masculinity: Men's makeover. PMID- 26444369 TI - Mental health: Monsters in the mirror. PMID- 26444370 TI - Q&A: David Deutsch. Objective beauty. PMID- 26444371 TI - Beauty: 4 big questions. PMID- 26444372 TI - Neuroscience: The aesthetic brain. PMID- 26444373 TI - Cosmetics: Molecular beauty. PMID- 26444374 TI - Surgery: Diverse interventions. PMID- 26444375 TI - Animal behaviour: Come mate with me. PMID- 26444376 TI - Delayed administration of recombinant human erythropoietin reduces apoptosis and inflammation and promotes myelin repair and functional recovery following spinal cord compressive injury in rats. AB - PURPOSE: A previous study showed that a 1-h delay in treatment of thoracic spinal cord injury (SCI) with recombinant human erythropoietin (rhEPO) lacked neuroprotective efficacy. The aim of the present study was to reassess delayed administration of different doses of rhEPO on acute spinal cord compressive injury in rats. METHODS: The experiment was divided into first and second stages, which SCI rats were observed for 4 and 28 days, respectively. All rats were randomly divided into four groups at both stages: control group, and rhEPO-3,000U (Unit), rhEPO-4,000U and rhEPO-5,000U groups. SCI rats received rhEPO treatment at different time points. The primary indicators were locomotor recovery, histopathology, apoptotic index, inflammatory index, ultrastructural scoring system and volume of areas of demyelination. RESULTS: The most significant locomotor functional and histopathological improvements and the best myelin protection were observed after administration of 5,000 U/kg rhEPO. rhEPO at 3,000, 4,000 and 5,000 U/kg showed similar ultrastructural neuroprotection, as well as similar inhibition of apoptosis and regulation of inflammation. CONCLUSION: Delayed administration of rhEPO can reduce apoptosis and inflammation, and promote myelin repair and functional recovery following spinal cord compressive injury in rats. PMID- 26444377 TI - CXCR4 antagonist AMD3100 reverses the neurogenesis and behavioral recovery promoted by forced limb-use in stroke rats. AB - PURPOSE: Forced limb-use can enhance neurogenesis and behavioral recovery as well as increasing the level of stromal cell-derived factor-1 (SDF-1) in stroke rats. We examined whether the SDF-1/CXCR4 pathway is involved in the enhanced neurogenesis and promoted behavioral recovery induced by forced limb-use in the chronic phase of stroke. METHODS: The CXCR4 antagonist, AMD3100, was used to block the SDF-1/CXCR4 pathway in the ischemic rats. Brain ischemia was induced by endothelin-1. One week after ischemia, the unimpaired forelimb of rats was immobilized for 3 weeks. The proliferation, migration, and survival of DCX positive cells in the subventricular zone (SVZ), and the dendritic complexity of DCX-positive cells in the dentate gyrus (DG), as well as the inflammatory response in the infarcted striatum were analyzed by immunohistochemistry. Functional recovery was assessed in beam-walking and water maze tests. RESULTS: Forced limb-use enhanced the proliferation, migration, dendritic complexity and the survival of newborn neurons. Furthermore, forced limb-use suppressed the inflammatory response and improved both motor and cognitive functions after stroke. AMD3100 significantly abrogated the enhanced neurogenesis and behavioral recovery induced by forced limb-use without influencing the inflammatory response. CONCLUSIONS: SDF-1/CXCR4 pathway seems to be involved in the enhancement of neurogenesis and behavioral recovery induced by post-stroke forced limb-use. PMID- 26444378 TI - Determination of Neutral Monosaccharides as Per-O-methylated Derivatives Directly from a Drop of Whole Blood by Gas Chromatography-Mass Spectrometry. AB - A new analytical procedure was developed for the simultaneous quantification of neutral monosaccharides from a drop of whole blood using gas chromatography-mass spectrometry analysis (GC-MS) of their per-O-methylated derivatives. The per-O methylation reaction with methyl iodide and solid sodium hydroxide in methyl sulfoxide was used for the first time for analysis of blood monosaccharides. A blood drop volume of 0.6 MUL was used without special purification. The elimination of the undesirable components was carried out during methylation in the presence of a strong base and by liquid extraction of the per-O-methylated monosaccharides. The neutral monosaccharides with an anomeric center gave four per-O-methylated isomers, which were well-separated using a capillary column. Identification was done by electron impact mass spectrometry fragmentation, retention times, and library searching. The limits of detection were determined for standards and varied from 2.0 to 2.3 ng mL(-1). Recoveries for human blood samples varied from 99.22% to 99.65%. The RSD values ranged from 1.92 to 2.37. The method is fast, sensitive, reproducible, and an alternative to current methods for quantitative analysis of blood monosaccharides. PMID- 26444379 TI - Synthesis and Antiproliferative Activity Evaluation of the Disulfide-Containing Cyclic Peptide Thiochondrilline C and Derivatives. AB - Thiochondrilline C (4) was previously isolated from Verrucisispora sp. and reported to have moderate cytotoxicity against human lung adenocarcinoma cells. Herein, we report the synthesis of thiochondrilline C by N-terminal peptide extension, oxidative disulfide bond formation, and heterocycle installation as key steps. Antiproliferative activities for the prepared natural product and several derivatives against the NCI 60 cancer cell line panel are also described. Derivative 22 was identified as a moderately potent antiproliferative agent (50% growth inhibition (GI50) = 0.2-12.2 MUM) with leukemia (average GI50 = 1.8 +/- 0.1 MUM) and colon (average GI50 = 2.4 +/- 0.3 MUM) cells being most sensitive. PMID- 26444380 TI - Accounting for Diradical Character through DFT. The Case of Vinyl Allene Oxide Rearrangement. AB - The transformation of vinyl allene oxides into cyclopentenones is key to the biosynthesis of a number of hormone-like molecules in plants. Two competitive paths are generally accepted for this transformation: a concerted SN2-like mechanism and a stepwise path with a diradical oxyallyl intermediate. Recently, a new stepwise closed-shell path has been proposed that circumvents the key oxyallyl intermediate. In this work, we conduct a thorough computational investigation, including dynamic effects, to identify the most likely mechanism for this transformation. PMID- 26444381 TI - Molecular Heterogeneity of Thalassemia among Pregnant Laotian Women. AB - BACKGROUND AND AIMS: A pilot screening program for thalassemia was initiated in the Lao People's Democratic Republic. This study aimed to describe the genotype diversity and hematologic features of thalassemia among the participating pregnant women. METHODS: Blood samples of 411 pregnant Laotian women were collected. Hemoglobin (Hb) profiles were determined using a capillary zone electrophoresis system. Mutations of alpha- and beta-globin genes were investigated using a polymerase chain reaction and related techniques. RESULTS: As many as 26 different thalassemia genotypes including non-transfusion-dependent thalassemia, i.e. Hb E-beta-thalassemia, Hb H, and EA Bart's diseases, were identified. A variety of phenotypic expressions of hematologic features and Hb profiles were observed, including an unusual phenotype of Hb E-beta0 thalassemia with 89.1% Hb E, 1.6% Hb F, and 9.3% Hb A2. CONCLUSIONS: The remarkable genotype phenotype diversity indicates a need for careful laboratory interpretation in order to provide appropriate genetic counseling and care to the Laotian population. PMID- 26444382 TI - Weight Loss Expectations and Attrition in Treatment-Seeking Obese Women. AB - OBJECTIVE: The analysis of the relation between weight loss goals and attrition in the treatment of obesity has produced conflicting results. The aim of the present study was to investigate the role of weight loss goals on attrition in a cohort of obese women seeking treatment at 8 Italian medical centres. METHODS: 634 women with obesity, consecutively enrolled in weight loss programmes, were included in the study. Weight loss goals were evaluated with the Goals and Relative Weights Questionnaire (GRWQ), reporting a sequence of unrealistic ('dream' and 'happy') and more realistic ('acceptable' and 'disappointing') weight loss goals. Attrition was assessed at 12 months on the basis of patients' medical records. RESULTS: At 12 months, 205/634 patients (32.3%) had interrupted their programme and were lost to follow-up. After adjustment for age, baseline weight, education and employment status, attrition was significantly associated with higher percent acceptable and disappointing weight loss targets, not with dream and happy weight loss. CONCLUSION: In 'real world' clinical settings, only realistic expectations might favour attrition whenever too challenging, whereas unrealistic weight loss goals have no effect. Future studies should assess the effect of interventions aimed at coping with too challenging weight goals on attrition. PMID- 26444383 TI - Role of Quantum Vibrations on the Structural, Electronic, and Optical Properties of 9-Methylguanine. AB - In this work, we report theoretical predictions of the UV-absorption spectra of 9 methylguanine using time dependent density functional theory (TDDFT). Molecular dynamics simulations of the hydrated DNA base are peformed using an empirical force field, Born-Oppenheimer ab initio molecular dynamics (AIMD), and finally path-integral AIMD to understand the role of the underlying electronic potential, solvation, and nuclear quantum vibrations on the absorption spectra. It is shown that the conformational distributions, including hydrogen bonding interactions, are perturbed by the inclusion of nuclear quantum effects, leading to significant changes in the total charge and dipole fluctuations of the DNA base. The calculated absorption spectra using the different sampling protocols shows that the inclusion of nuclear quantum effects causes a significant broadening and red shift of the spectra bringing it into closer agreement with experiments. PMID- 26444384 TI - Deoxynyboquinones as NQO1-Activated Cancer Therapeutics. AB - One of the major goals of cancer therapy is the selective targeting of cancer cells over normal cells. Unfortunately, even with recent advances, the majority of chemotherapeutics still indiscriminately kill all rapidly dividing cells. Although these drugs are effective in certain settings, their inability to specifically target cancer results in significant dose-limiting toxicities. One way to avoid such toxicities is to target an aspect of the cancer cell that is not shared by normal cells. A potential cancer-specific target is the enzyme NAD(P)H quinone oxidoreductase 1 (NQO1). NQO1 is a 2-electron reductase responsible for the detoxification of quinones. Its expression is typically quite low in normal tissue, but it has been found to be greatly overexpressed in many types of solid tumors, including lung, breast, pancreatic, and colon cancers. This overexpression is thought to be in response to the higher oxidative stress of the cancer cell, and it is possible that NQO1 contributes to tumor progression. The overexpression of NQO1 and its correlation with poor patient outcome make it an intriguing target. Although some have explored inhibiting NQO1 as an anticancer strategy, this has generally been unsuccessful. A more promising strategy is to utilize NQO1 substrates that are activated upon reduction by NQO1. For example, in principle, reduction of a quinone can result in a hydroquinone that is a DNA alkylator, protein inhibitor, or reduction-oxidation cycler. Although there are many proposed NQO1 substrates, head-to-head assays reveal only two classes of compounds that convincingly induce cancer cell death through NQO1 mediated activation. In this Account, we describe the discovery and development of one of these compounds, the natural product deoxynyboquinone (DNQ), an excellent NQO1 substrate and anticancer agent. A modular synthesis of DNQ was developed that enabled access to the large compound quantities needed to conduct extensive mechanistic evaluations and animal experiments. During these evaluations, we found that DNQ is an outstanding NQO1 substrate that is processed much more efficiently than other putative NQO1 substrates. Importantly, its anticancer activity is strictly dependent on the overexpression of active NQO1. Using previous crystal structures of NQO1, novel DNQ derivatives were designed that are also excellent NQO1 substrates and possess properties that make them more attractive than the parent natural product for translational development. Given their selectivity, potency, outstanding pharmacokinetic properties, and the ready availability of diagnostics to assess NQO1 in patients, DNQ and its derivatives have considerable potential as personalized medicines for the treatment of cancer. PMID- 26444385 TI - Designing of Biodegradable and Biocompatible Release and Delivery Systems of Selected Antioxidants Used in Cosmetology. AB - Conjugates of antioxidants p-anisic (p-AA) and vanillic (VA) acids with nontoxic, biocompatible, and biodegradedable oligo-(R,S)-(3-hydoxybutyrate) carrier were synthesized, and their structural and biological characterization was performed. The molecular structure of the bioconjugates, in which antioxidants are covalently bonded with oligo(3-hydroxybutyrate) (OHB) chains, has been proven by mass spectrometry supported by NMR. The bioconjugate hydrolytic degradation studies allowed gaining thorough insight into the hydrolysis process and confirmed the release of p-AA and VA. In vitro studies demonstrated that all of the conjugates studied were well tolerated by KB and HaCaT cell lines, as they had no marked cytotoxicity, while conjugates with a relatively short OHB carrier are optimal to support keratinocyte function. The preliminary study of the biological activity confirmed the protective effect of VA-OHB conjugates against H2O2-induced lipid peroxidation in human keratinocytes (HaCaT). It was also demonstrated that the selected bioconjugates can penetrate all layers of the skin, which shows their functionality and opens up their potential application in cosmetology. PMID- 26444386 TI - Predicting Honeybee Colony Failure: Using the BEEHAVE Model to Simulate Colony Responses to Pesticides. AB - To simulate effects of pesticides on different honeybee (Apis mellifera L.) life stages, we used the BEEHAVE model to explore how increased mortalities of larvae, in-hive workers, and foragers, as well as reduced egg-laying rate, could impact colony dynamics over multiple years. Stresses were applied for 30 days, both as multiples of the modeled control mortality and as set percentage daily mortalities to assess the sensitivity of the modeled colony both to small fluctuations in mortality and periods of low to very high daily mortality. These stresses simulate stylized exposure of the different life stages to nectar and pollen contaminated with pesticide for 30 days. Increasing adult bee mortality had a much greater impact on colony survival than mortality of bee larvae or reduction in egg laying rate. Importantly, the seasonal timing of the imposed mortality affected the magnitude of the impact at colony level. In line with the LD50, we propose a new index of "lethal imposed stress": the LIS50 which indicates the level of stress on individuals that results in 50% colony mortality. This (or any LISx) is a comparative index for exploring the effects of different stressors at colony level in model simulations. While colony failure is not an acceptable protection goal, this index could be used to inform the setting of future regulatory protection goals. PMID- 26444387 TI - Atopic Diseases and Subsequent Ischemic Stroke Among Patients With Schizophrenia: A Nationwide Longitudinal Study. AB - BACKGROUND: Chronic inflammation plays an important role in schizophrenia and atopic diseases, and studies have suggested that chronic inflammation is associated with an increased risk of stroke. The role of atopic diseases in the development of stroke among patients with schizophrenia is still unknown. METHODS: A total of 63,913 patients with schizophrenia without a stroke history between 2002 and 2008 and 63,913 age- and sex-matched controls were included and followed up to the end of 2011. Patients with schizophrenia and the reference group were divided into subgroups based on the presence or absence of atopic diseases. Individuals who developed stroke during follow-up were identified. RESULTS: Patients with schizophrenia had an increased risk of developing ischemic stroke (no atopic disease: hazard ratio [HR] = 2.18, 95% confidence interval [CI] = 1.88-2.53; with atopic disease: HR = 3.11, 95% CI = 2.63-3.69) compared with the reference group without atopic diseases. Among patients with schizophrenia, the presence of atopic diseases increased the risk of developing ischemic stroke (HR = 1.44, 95% CI = 1.24-1.66), with a cumulative relationship between greater numbers of atopic comorbidities and a greater risk of ischemic stroke (one atopic disease: HR = 1.39, 95% CI = 1.19-1.63; two atopic comorbidities: HR = 1.48, 95% CI = 1.10-2.00; at least 3 atopic comorbidities: HR = 2.81, 95% CI = 1.55-5.12). CONCLUSIONS: The combined presence of schizophrenia and atopic diseases is associated with an increased risk of ischemic stroke in later life compared with individuals without these conditions. PMID- 26444388 TI - Dissociating biases towards the self and positive emotion. AB - We examined whether self-biases in perceptual matching reflect the positive valence of self-related stimuli. Participants associated geometric shapes with either personal labels (e.g., you, friend, stranger) or faces with different emotional expressions (e.g., happy, neutral, sad). They then judged whether shape label or shape-face pairs were as originally shown or re-paired. Match times were faster to self-associated stimuli and to stimuli associated with the most positive valence. In addition, both the self-bias and the positive emotion bias were reliable across individuals in different test sessions. In contrast there was no sign of a correlation between the self-bias and the emotion-bias effects. We argue that self-bias and the bias to stimuli linked to positive emotion are separate and may reflect different underlying processes. PMID- 26444390 TI - Sexual risk behaviors among apps-using young men who have sex with men in Hong Kong. AB - This study is among the first to examine the sexual risk behaviors and attendant factors of young men who have sex with men (YMSM) in Hong Kong using location aware gay social networking mobile applications ("gay apps"). Among the 213 YMSM (Mage = 21.52, SD = 2.29 years, range 17-25) who reported their recent (past six months) sexual history with male partners and gay apps use, inconsistent condom use (ICU) during anal sex was fairly common (60.2% regular partners, 45.8% non regular partners). One-fifth of the sample reported condomless internal ejaculation (CIE) during anal sex (19.3% insertive, 19.8% receptive). Frequent "Grindr" and "Jack'd" users were less likely to report anal sex, and hence ICU, with regular [adjusted odds ratio (AOR) = 0.72] and non-regular (AOR = 0.62) partners, respectively. Sexual partnering via apps doubled the odds of ICU with both regular (AOR = 1.99) and non-regular (AOR = 2.17) partners. The odds of ICU with regular partners also increased with relationship status (AOR = 2.86 exclusive, AOR = 3.23 non-exclusive) but reduced for those who never had STI/HIV testing (AOR = 0.27). With non-regular partners, YMSM's likelihood of ICU increased with more recent partners (AOR = 3.25) and drug use (AOR = 3.79), but reduced with group sex (AOR = 0.15). The odds of receptive CIE increased with alcohol consumption (AOR = 4.04), non-exclusive relationship (AOR = 4.10), and more recent partners (AOR = 2.47), but reduced with group sex (AOR = 0.15) and older age (AOR = 0.84). For insertive CIE, the odds increased with bisexual YMSM (AOR = 2.89), exclusive relationship (AOR = 3.97), and longtime apps-use (AOR = 1.81). The findings identify meaningful differences among YMSM app-users that inform sexual health intervention and suggest attention on alcohol or drug use during sex and condomless sex with non-exclusive regular partners. PMID- 26444391 TI - Beau B. Bruce, MD, PhD. PMID- 26444389 TI - In vitro analyses of mitochondrial ATP/phosphate carriers from Arabidopsis thaliana revealed unexpected Ca(2+)-effects. AB - BACKGROUND: Adenine nucleotide/phosphate carriers (APCs) from mammals and yeast are commonly known to adapt the mitochondrial adenine nucleotide pool in accordance to cellular demands. They catalyze adenine nucleotide--particularly ATP-Mg--and phosphate exchange and their activity is regulated by calcium. Our current knowledge about corresponding proteins from plants is comparably limited. Recently, the three putative APCs from Arabidopsis thaliana were shown to restore the specific growth phenotype of APC yeast loss-of-function mutants and to interact with calcium via their N-terminal EF--hand motifs in vitro. In this study, we performed biochemical characterization of all three APC isoforms from A. thaliana to gain further insights into their functional properties. RESULTS: Recombinant plant APCs were functionally reconstituted into liposomes and their biochemical characteristics were determined by transport measurements using radiolabeled substrates. All three plant APCs were capable of ATP, ADP and phosphate exchange, however, high preference for ATP-Mg, as shown for orthologous carriers, was not detectable. By contrast, the obtained data suggest that in the liposomal system the plant APCs rather favor ATP-Ca as substrate. Moreover, investigation of a representative mutant APC protein revealed that the observed calcium effects on ATP transport did not primarily/essentially involve Ca(2+) binding to the EF-hand motifs in the N-terminal domain of the carrier. CONCLUSION: Biochemical characteristics suggest that plant APCs can mediate net transport of adenine nucleotides and hence, like their pendants from animals and yeast, might be involved in the alteration of the mitochondrial adenine nucleotide pool. Although, ATP-Ca was identified as an apparent import substrate of plant APCs in vitro it is arguable whether ATP-Ca formation and thus the corresponding transport can take place in vivo. PMID- 26444392 TI - What's Hot in Neuro-Ophthalmology. PMID- 26444393 TI - Ocular Fundus Photography as a Tool to Study Stroke and Dementia. AB - Although cerebral small vessel disease has been linked to stroke and dementia, due to limitations of current neuroimaging technology, direct in vivo visualization of changes in the cerebral small vessels (e.g., cerebral arteriolar narrowing, tortuous microvessels, blood-brain barrier damage, capillary microaneurysms) is difficult to achieve. As the retina and the brain share similar embryological origin, anatomical features, and physiologic properties with the cerebral small vessels, the retinal vessels offer a unique and easily accessible "window" to study the correlates and consequences of cerebral small vessel diseases in vivo. The retinal microvasculature can be visualized, quantified and monitored noninvasively using ocular fundus photography. Recent clinic- and population-based studies have demonstrated a close link between retinal vascular changes seen on fundus photography and stroke and dementia, suggesting that ocular fundus photography may provide insights to the contribution of microvascular disease to stroke and dementia. In this review, we summarize current knowledge on retinal vascular changes, such as retinopathy and changes in retinal vascular measures with stroke and dementia as well as subclinical makers of cerebral small vessel disease, and discuss the possible clinical implications of these findings in neurology. Studying pathologic changes of retinal blood vessels may be useful for understanding the etiology of various cerebrovascular conditions; hence, ocular fundus photography can be potentially translated into clinical practice. PMID- 26444394 TI - Nonmydriatic Ocular Fundus Photography in the Emergency Department: How It Can Benefit Neurologists. AB - Examination of the ocular fundus is a critical aspect of the neurologic examination. For example, in patients with headache the ocular fundus examination is needed to uncover "red flags" suggestive of secondary etiologies. However, ocular fundus examination is infrequently and poorly performed in clinical practice. Nonmydriatic ocular fundus photography provides an alternative to direct ophthalmoscopy that has been studied as part of the Fundus Photography versus Ophthalmoscopy Trial Outcomes in the Emergency Department (FOTO-ED) Study. Herein, the results of the FOTO-ED study are reviewed with a particular focus on the study's implications for the acute care of patients presenting with headache and focal neurologic deficits. In headache patients, not only optic disc edema and optic disc pallor were observed as would be expected, but also a large number of abnormalities associated with hypertension. Based upon subjects with focal neurologic deficits, the FOTO-ED study suggests that the ocular fundus examination may assist with the triage of patients presenting with suspected transient ischemic attack. Continued advances in the ease and portability of nonmydriatic fundus photography will hopefully help to restore ocular fundus examination as a routinely performed component of all neurologic examinations. PMID- 26444395 TI - Ocular Fundus Photography as an Educational Tool. AB - The proficiency of nonophthalmologists with direct ophthalmoscopy is poor, which has prompted a search for alternative technologies to examine the ocular fundus. Although ocular fundus photography has existed for decades, its use has been traditionally restricted to ophthalmology clinical care settings and textbooks. Recent research has shown a role for nonmydriatic fundus photography in nonophthalmic settings, encouraging more widespread adoption of fundus photography technology. Recent studies have also affirmed the role of fundus photography as an adjunct or alternative to direct ophthalmoscopy in undergraduate medical education. In this review, the authors examine the use of ocular fundus photography as an educational tool and suggest future applications for this important technology. Novel applications of fundus photography as an educational tool have the potential to resurrect the dying art of funduscopy. PMID- 26444396 TI - Diagnosing Stroke in Acute Vertigo: The HINTS Family of Eye Movement Tests and the Future of the "Eye ECG". AB - Patients who present to the emergency department with symptoms of acute vertigo or dizziness are frequently misdiagnosed. Missed opportunities to promptly treat dangerous strokes can result in poor clinical outcomes. Inappropriate testing and incorrect treatments for those with benign peripheral vestibular disorders leads to patient harm and unnecessary costs. Over the past decade, novel bedside approaches to diagnose patients with the acute vestibular syndrome have been developed and refined. A battery of three bedside tests of ocular motor physiology known as "HINTS" (head impulse, nystagmus, test of skew) has been shown to identify acute strokes more accurately than even magnetic resonance imaging with diffusion-weighted imaging (MRI-DWI) when applied in the early acute period by eye-movement specialists. Recent advances in lightweight, high-speed video-oculography (VOG) technology have made possible a future in which HINTS might be applied by nonspecialists in frontline care settings using portable VOG. Use of technology to measure eye movements (VOG-HINTS) to diagnose stroke in the acute vestibular syndrome is analogous to the use of electrocardiography (ECG) to diagnose myocardial infarction in acute chest pain. This "eye ECG" approach could transform care for patients with acute vertigo and dizziness around the world. In the United States alone, successful implementation would likely result in improved quality of emergency care for hundreds of thousands of peripheral vestibular patients and tens of thousands of stroke patients, as well as an estimated national health care savings of roughly $1 billion per year. In this article, the authors review the origins of the HINTS approach, empiric evidence and pathophysiologic principles supporting its use, and possible uses for the eye ECG in teleconsultation, teaching, and triage. PMID- 26444397 TI - Treatment of Nystagmus. AB - Acquired and congenital forms of nystagmus are commonly encountered in the course of clinical practice. Although some patients are asymptomatic, many others describe disabling oscillopsia that impairs visual function, social function, and quality of life. Such patients may present to the neurologist to request treatment. Numerous treatment approaches for nystagmus have been proposed, including medical, surgical, and optical treatments. Some of the treatments aim to reduce nystagmus slow-phase speed, whereas others aim to negate the visual consequences of the nystagmus. The approach must be tailored depending on the type of nystagmus, its characteristics, and in some cases, its cause. In this review, the treatment approach for acquired and congenital forms of nystagmus is summarized with an emphasis on treatments that have been evaluated in well designed clinical trials. Novel approaches that have not yet been evaluated in clinical trials are also discussed. PMID- 26444398 TI - Update on the Diagnosis and Treatment of Idiopathic Intracranial Hypertension. AB - Idiopathic intracranial hypertension (IIH) is a rare disorder occurring more frequently in obese women of childbearing age, resulting in increased intracranial pressure (ICP) from an unknown cause. Recent advances in epidemiology, imaging, and treatment have provided a better understanding of IIH in recent years, with better identification of visual risk factors and atypical forms of IIH, including fulminant IIH and spontaneous cerebrospinal fluid leaks, and a randomized clinical trial providing the rationale for the use of acetazolamide. In addition, a revised version of the modified Dandy criteria for the diagnosis of IIH was suggested in 2013, with better definition of IIH in adults and children; however, controversy regarding nomenclature has precluded its acceptance among IIH experts. Finally, questions regarding the best surgical strategy, the indications for venous sinus stenting, and the diagnostic role of the radiologic findings commonly seen in IIH have remained unanswered. PMID- 26444399 TI - Isolated Ocular Motor Nerve Palsies. AB - An isolated ocular motor nerve palsy is defined as dysfunction of a single ocular motor nerve (oculomotor, trochlear, or abducens) with no associated or localizing neurologic signs or symptoms. When occurring in patients aged 50 or older, the most common cause is microvascular ischemia, but serious etiologies such as aneurysm, malignancy, and giant cell arteritis should always be considered. In this article, the authors review the clinical approach, anatomy, and differential diagnosis of each isolated ocular motor nerve palsy and discuss the clinical characteristics, pathophysiology, and treatment of microvascular ischemia. PMID- 26444400 TI - Prognosis and Treatment of Visual Field Defects. AB - Visual field deficits are common in neurologic disease conditions such as cerebrovascular disease, traumatic brain injury, and brain tumors. Loss of visual fields may lead to impairment of reading skills (hemianopic dyslexia) and limitations of daily activities such as driving, which can have a significant impact on an individual's socioeconomic status and quality of life. Moreover, patients with motor deficits from neurologic diseases have a 20% decreased likelihood of achieving independence in ambulation and self-care activities with coexisting hemianopia. Studies on the natural history of homonymous hemianopia have shown that spontaneous improvement of visual fields may occur in less than 40% of individuals early in the disease process. Improvement is usually incomplete, which implies that a significant number of individuals will be left with a disabling visual deficit. Although several methods of rehabilitation (optical, compensatory, and restitution therapy) are used in practice, none, unfortunately, have shown consistent and significant benefits. In this review, the authors focus on the natural history, impact, prognosis, and treatment modalities for neurologic field defects. PMID- 26444401 TI - Functional Vision Disorder. AB - Functional vision disorder (FVD) is a common problem seen in many neurologic and ophthalmologic practitioners' offices and may occur in isolation or in the presence of medical illness. This disorder presents with visual or oculomotor symptoms and manifests as vision loss in one or both eyes, visual field loss, double vision, oscillopsia, anisocoria, blepharospasm, or ptosis. Manual perimetry is the most effective method for determining functional visual loss, and the presence of a central scotoma in a functional visual field signifies that a neuropathophysiologic process is almost certainly present. The exact neuropathophysiologic mechanism of this disorder is unknown; however, information can be drawn from the small studies of FVD samples and studies examining neuropsychiatric factors in other conversion disorder semiologies. Psychological and psychiatric interventions can be useful in treating these patients. PMID- 26444402 TI - Optical Coherence Tomography for the Neurologist. AB - Optical coherence tomography (OCT) is a relatively new technology that is now routinely and very widely used by ophthalmologists for structural documentation of the optic nerve and retina. In neuro-ophthalmology and neurology, the value of OCT is ever expanding; its role in an increasing number of conditions is being reported in parallel with the advances of the technology. Currently, as a clinical tool, OCT is particularly useful for the structural measurement of peripapillary retinal nerve fiber layer thickness, optic nerve head volumetric analysis, and macular anatomy. Optic neuropathies of varied etiology (particularly from multiple sclerosis) may be the most common clinical indications for neurologists to obtain OCT imaging. Documentation and follow-up of disc edema of varied etiology (papilledema and idiopathic intracranial hypertension), discriminating true disc swelling from pseudopapilledema, and differentiating optic neuropathy from maculopathy are some other examples from clinical practice. PMID- 26444403 TI - Therapeutic Approaches to Inherited Optic Neuropathies. AB - As a group, inherited optic neuropathies represent an important cause of severe irreversible visual loss among children and young adults. Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA) are the two most common forms encountered in clinical practice and several shared disease pathways have emerged that contribute to retinal ganglion cell loss, and eventually visual failure. In this review, the author critically appraises the evidence base for the various therapeutic strategies that have been put forward to treat these two mitochondrially determined optic neuropathies, including future developments. Innovative in vitro fertilization techniques to prevent female carriers of childbearing age from transmitting pathogenic mitochondrial DNA mutations to their biological children will also be discussed. PMID- 26444404 TI - The Effects of Primary Brain Tumors on Vision and Quality of Life in Pediatric Patients. AB - Brain tumors are the leading cause of death from childhood cancer. Overall survival has improved due to earlier detection, better therapies, and improved posttreatment surveillance. Permanent sequelae of the tumor and its treatment may cause severe impairment and decreased quality of life (QoL). Pediatric primary brain tumor patients' vision can be severely affected, even when the tumor location does not primarily involve the visual pathway. Visual dysfunction and impaired vision-related QoL may not be detected or screened for in children with primary brain tumors for many reasons, including examination difficulty and lack of awareness. The authors review the ophthalmic presenting symptoms, effects on vision, and quality of life in pediatric patients with primary brain tumors. They also describe and emphasize the importance of systematic neuro-ophthalmologic examinations in this population, which may improve long-term visual and QoL outcomes through earlier interventions. PMID- 26444405 TI - The Concussion Toolbox: The Role of Vision in the Assessment of Concussion. AB - Concussion may lead to subtle changes in brain function, and tests involving the visual system probe higher cortical functioning and increase our sensitivity in detecting these changes. Concussions are acutely and sometimes more persistently associated with abnormalities in balance, cognition, and vision. The visual system involves roughly half of the brain's circuits, including many regions susceptible to head impacts. After a concussion, the neuro-ophthalmologic exam commonly detects abnormalities in convergence, accommodation, the vestibulo ocular reflex, ocular muscle balance, saccades, and pursuit. The King-Devick (K D) test is a visual performance measure that may increase the sensitivity of detecting concussions on the sideline when used in combination with tests of cognition and balance that are part of the Sports Concussion Assessment Tool (3rd ed.; SCAT3). Portable eye movement trackers and pupillometry may in the future improve our neuro-ophthalmic assessment after concussions. Combining visual tasks with neuroimaging and neurophysiology has allowed subtle changes to be detected, may refine our ability to make appropriate return-to-play decisions, and could potentially determine susceptibility to long-term sequelae of concussion. PMID- 26444406 TI - Emergency team calls for critically ill non-trauma patients in the emergency department: an observational study. AB - BACKGROUND: Handling critically ill patients is a complex task for Emergency Department (ED) personnel. Initial treatment is of major importance and requires adequately experienced ED doctors to initiate and decide for the right medical or surgical treatment. Our aim was, with regard to clinical presentation, management and mortality to describe adult non-trauma patients that upon ED arrival elicited emergency team calls. METHODS: An observational study of adult patients (>= 18 years) admitted to a regional ED with conditions that elicited acute team activation and additional emergency team consultation calls for non-ED specialist physicians. Emergency team calls were two-tiered with 'orange' and 'red' calls. Additionally, intensive care unit (ICU) admission charts were reviewed to identify the total number of adult non-trauma and non-cardiac arrest patients admitted to the ICU from the ED during the study period. RESULTS: A total of 109 emergency team calls were triggered (79 orange and 30 red), comprising 66 (60.6 %) men and 43 women, with a median age of 64 years. Patients presented with: 4 Airway, 27 Breathing, 41 Circulation, 31 Disability, 2 Exposure and 4 Other problems. Overall, 58/109 (53.2 %) patients were admitted to the ICU, while 20/109 (18.3 %) patients were deemed ineligible for ICU admission. 30-day mortality was 34/109 (31.2 %), and circulatory problems were the most frequent cause of death (61.8 %, p = 0.02). Patients who died were significantly older than those who survived (p = 0.004). Additionally, 115 adult patients were admitted to the ICU directly from the ED without eliciting an emergency team call during the study period. These patients mainly comprised patients who were intoxicated, were unconscious or had respiratory failure. CONCLUSION: The majority of emergency team call patients presented with circulatory, disability and breathing problems. Half of the patients were admitted to the ICU, although a high rate of patients was deemed ineligible for ICU admission. 30-day mortality was considerable and circulatory related illnesses were associated with increased short-term mortality. PMID- 26444408 TI - ? PMID- 26444407 TI - Air toxics and the risk of autism spectrum disorder: the results of a population based case-control study in southwestern Pennsylvania. AB - BACKGROUND: Autism spectrum disorders (ASD) constitute a major public health problem affecting one in 68 children. There is little understanding of the causes of ASD despite its serious social impact. Air pollution contains many toxicants known to have adverse effects on the fetus. We conducted a population based case control study in southwestern Pennsylvania to estimate the association between ASD and 2005 US EPA modeled NATA (National Air Toxics Assessment) levels for 30 neurotoxicants. METHODS: A total of 217 ASD cases born between 2005 and 2009 were recruited from local ASD diagnostic and treatment centers. There were two different control groups: 1) interviewed controls (N = 224) frequency matched by child's year of birth, sex and race with complete residential histories from prior to pregnancy through the child's second birthday, and 2) 5,007 controls generated from a random sample of birth certificates (BC controls) using residence at birth. We used logistic regression analysis comparing higher to first quartile of exposure to estimate odds ratios (ORs) and 95% confidence intervals (CI), adjusting for mother's age, education, race, smoking status, child's year of birth and sex. RESULTS: Comparing fourth to first quartile exposures for all births, the adjusted OR for styrene was 2.04 (95% CI = 1.17 3.58, p = 0.013) for the interviewed case-control analysis and 1.61 (95% CI = 1.08-2.40, p = 0.018) for the BC analysis. In the BC comparison, chromium also exhibited an elevated OR of 1.60 (95% CI = 1.08-2.38, p = 0.020), which was similarly elevated in the interviewed analysis (OR = 1.52, 95% CI = 0.87-2.66). There were borderline significant ORs for the BC comparison for methylene chloride (OR = 1.41, 95% CI = 0.96-2.07, p = 0.082) and PAHs (OR = 1.44, 95% CI = 0.98-2.11, p = 0.064). CONCLUSIONS: Living in areas with higher levels of styrene and chromium during pregnancy was associated with increased risk of ASD, with borderline effects for PAHs and methylene chloride. These results are consistent with other studies. It is unclear, however, whether these chemicals are risk factors themselves or if they reflect the effect of a mixture of pollutants. Future work should include improved spatiotemporal estimates of exposure to air toxics, taking into account the dynamic movement of individuals during daily life. PMID- 26444409 TI - ? PMID- 26444410 TI - ? PMID- 26444411 TI - ? PMID- 26444412 TI - Integration of molecular cytogenetics, dated molecular phylogeny, and model-based predictions to understand the extreme chromosome reorganization in the Neotropical genus Tonatia (Chiroptera: Phyllostomidae). AB - BACKGROUND: Defining factors that contributed to the fixation of a high number of underdominant chromosomal rearrangements is a complex task because not only molecular mechanisms must be considered, but also the uniqueness of natural history attributes of each taxon. Ideally, detailed investigation of the chromosome architecture of an organism and related groups, placed within a phylogenetic context, is required. We used multiple approaches to investigate the dynamics of chromosomal evolution in lineages of bats with considerable karyotypic variation, focusing on the different facets contributing to fixation of the exceptional chromosomal changes in Tonatia saurophila. Integration of empirical data with proposed models of chromosome evolution was performed to understand the probable conditions for Tonatia's karyotypic evolution. RESULTS: The trajectory of reorganization of chromosome blocks since the common ancestor of Glossophaginae and Phyllostominae subfamilies suggests that multiple tandem fusions, as well as disruption and fusions of conserved phyllostomid chromosomes were major drivers of karyotypic reshuffling in Tonatia. Considerable variation in the rates of chromosomal evolution between phyllostomid lineages was observed. Thirty-nine unique fusions and fission events reached fixation in Tonatia over a short period of time, followed by ~12 million years of chromosomal stasis. Physical mapping of repetitive DNA revealed an unusual accumulation of LINE-1 sequences on centromeric regions, probably associated with the chromosomal dynamics of this genus. CONCLUSIONS: Multiple rearrangements have reached fixation in a wave-like fashion in phyllostomid bats. Different biological features of Tonatia support distinct models of rearrangement fixation, and it is unlikely that the fixations were a result of solely stochastic processes in small ancient populations. Increased recombination rates were probably facilitated by expansion of repetitive DNA, reinforced by aspects of taxon reproduction and ecology. PMID- 26444414 TI - Rare cause of severe anemia due to pyogenic granuloma in the jejunum. AB - BACKGROUND: Pyogenic granuloma (PG) is a polypoid lobular capillary hemangioma rarely observed in the gastrointestinal tract. Only a few cases in the small bowel have been described in the literature. CASE PRESENTATION: A 58-year-old man had been suffering from general fatigue and severe anemia. Esophagogastroduodenoscopy and colonoscopy did not reveal any significant bleeding. Abdominal computer tomography revealed a hypervascular tumor in the small intestine. Oral double-balloon endoscopy (DBE) detected a polypoid lesion (2 cm in diameter) in the jejunum. We performed laparoscopic-assisted partial resection of the jejunum. The histological features of the tumor were consistent with PG. The patient's anemia gradually improved without the need for oral iron after surgery. CONCLUSION: In this case report, we present a case of pyogenic granuloma in in the jejunum that was detected by DBE. PMID- 26444413 TI - SLC39A6: a potential target for diagnosis and therapy of esophageal carcinoma. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a highly lethal cancer, and its underlying molecular mechanisms are poorly understood. Recent large-scale genome-wide association studies in Chinese Han populations have identified an ESCC susceptibility locus within the SLC39A6 gene. Here, we sought to explore the expression and biological function of SLC39A6 in ESCC. METHODS: Multiethnic validation of SLC39A6 protein expression was performed in different cohorts of patients from Chinese Han and Kazakh populations in the Xinjiang region by immunohistochemistry. The associations among SLC39A6 expression, clinicopathological parameters, and prognosis outcomes of ESCC were analyzed. And the effects of SLC39A6 silencing by siRNA on cell proliferation, apoptosis, and invasiveness, as well as the proteins involved in epithelial-to-mesenchymal transition (EMT) of esophageal cancer cells, were studied. RESULTS: SLC39A6 protein expression increased progressively from normal esophageal epithelium (NEE) to low-grade intraepithelial neoplasia to ESCC, and finally reached the highest in high-grade intraepithelial neoplasia from Han ethnic. Similarly, SLC39A6 protein was significantly overexpressed in Kazakh ethnic ESCC compared with that in NEE. Increased expression of SLC39A6 was found to be closely correlated with histological grade and early Tumor-Node-Metastasis stage I/II. High tumorous SLC39A6 expression was significantly correlated with shorter overall survival (OS). Cox regression analysis confirmed that SLC39A6 expression was an independent prognostic factor for poor OS in ESCC. Experimentally, the suppression of SLC39A6 expression promoted ESCC cell apoptosis but abrogated proliferation and invasion, and induced an EMT phenotype that included enhanced expression of E-cadherin, loss of vimentin, and morphological changes in ESCC cells in vitro. CONCLUSIONS: Combined, our findings highlight a tumor-promoting role for SLC39A6 in ESCC, suggesting that SLC39A6 could serve as an early detector of high-risk subjects and prognostic biomarker. The targeting of SLC39A6 might be a potential therapeutic strategy for blocking ESCC. PMID- 26444415 TI - Do users desire symmetrical lumbar supports in task seating? AB - This research was designed to objectively investigate the desired low back (lumbar) support in a task chair; specifically by allowing a user to self-select the magnitude and location of support. An experimental chair built specifically for this study allowed the users to remotely adjust 35 diodes to achieve their desired level of support. Pressure mapping was used to measure the interface pressure at the user-seat back interface. It was determined that 73.8% of the 201 participants in this study, self-selected asymmetrical lower back support that was at least 20% greater on one side vs. the other. Additionally, 16.9% of the participants self-selected support on one side which was at least twice that of the other side. Contrary to popular practice, participants were found to prefer asymmetric support in the lower back region. It is anticipated that the culmination of this research will aid chair manufacturers in designing adaptable back rests. Practitioner Summary: Most current lumbar supports are designed to move vertically and to symmetrically increase or decrease in firmness as per a user's adjustment. This investigation highlights that participants tended to select asymmetrical lumbar support, and as such, designers should consider providing lumbar supports that provide the desired support at appropriate locations. PMID- 26444416 TI - The role of domestic animals in the epidemiology of human African trypanosomiasis in Ngorongoro conservation area, Tanzania. AB - BACKGROUND: Trypanosomiasis is a neglected tropical disease caused by the trypanosome parasite and transmitted by the tsetse fly vector. In Sub-saharan Africa, both the human and animal variants of the disease are a great obstacle towards agriculture, development, and health. In order to better understand and therefore combat Trypanosomiasis, characterizing disease hotspots across species is critical. METHODS: In this study, 193 samples from cattle, sheep, and goats were collected from eight sites. Samples were taken from animals belonging mostly to Maasai herdsmen in the Ngorongoro Crater Conservation Area (NCA) and analysed for the presence of trypanosomiasis infection using PCR techniques. Those that tested positive for T. brucei parasite were further tested using SRA LAMP technique to check for T. brucei rhodesiense, the human infective subspecies of parasite. RESULTS: Our study found a high incidence of Trypanosoma brucei infections across species. Of animals tested, 47 % of cattle, 91.7 % of sheep, and 60.8 % of goats were infected. Most of the infections were of the T. brucei species. We also identified sheep and goats as carriers of the T. brucei rhodesiense subspecies, which causes acute human trypanosomiasis. CONCLUSIONS: Together, these results point toward the need for stricter control strategies in the area to prevent disease outbreak. PMID- 26444417 TI - Comparison of characteristics and mortality in multidrug resistant (MDR) and non MDR tuberculosis patients in China. AB - BACKGROUND: We conducted a cohort study to compare the characteristics of MDR-TB with non-MDR-TB patients and to measure long term (9-year) mortality rate and determine factors associated with death in China. METHODS: We reviewed the medical records of 250 TB cases from a 2001 survey to compare 100 MDR-TB patients with 150 non-MDR-TB patients who were treated in 2001-2002. Baseline attributes extracted from the records were compared between the two cohorts and long-term mortality and risk factors were determined at nine-year follow-up in 2010. RESULTS: Among the 234 patients successfully followed up, 63 (26.9%) were female and 171 (73.1 %) were male. MDR-TB patients had poorer socioeconomic status compared to non-MDRTB. Nine years after the diagnosis of TB, 69 or 29.5 % of the 234 patients had died (32 or 21.6 % of non-MDR-TB versus 37 or 43.0 % of MDR-TB) and the overall mortality rate was 39/1000 per year (PY) (27/1000 PY among non MDR versus 63/1000 PY among MDR-TB). Factors associated with death included: MDR status (hazard ratio (HR): 1.86; CI: 1.09-3.13), limited education of primary school or lower (HR: 2.51; CI 1.34-4.70) and received TB treatment during the nine-year period (HR 1.82; 95 % CI 1.02-3.26). CONCLUSIONS: MDR-TB was a strong predictor for poor long-term outcome. High quality diagnosis and treatment must be ensured. Greater reimbursement or free treatment may be needed to provide access for the poor and vulnerable populations, and to increase treatment compliance. PMID- 26444418 TI - Role of cyclooxygenase-1 and -2 in endothelium-dependent contraction of atherosclerotic mouse abdominal aortas. AB - The objective of this study was to determine the role of cyclooxygenase (COX)-1 or -2 in endothelium-dependent contraction under atherosclerotic conditions. Atherosclerosis was induced in apoE knockout (apoE(-/-)) mice and those with COX 1(-/-) (apoE(-/-)-COX-1(-/-)) by feeding with high fat and cholesterol food. Aortas (abdominal or the whole section) were isolated for functional and/or biochemical analyses. As in non-atherosclerotic conditions, the muscarinic receptor agonist acetylcholine (ACh) evoked an endothelium-dependent, COX mediated contraction following NO synthase (NOS) inhibition in abdominal aortic rings from atherosclerotic apoE(-/-) mice. Interestingly, COX-1 inhibition not only abolished such a contraction in rings showing normal appearance, but also diminished that in rings with plaques. Accordingly, only a minor contraction (<30% that of apoE(-/-) counterparts) was evoked by ACh (following NOS inhibition) in abdominal aortic rings of atherosclerotic apoE(-/-)-COX-1(-/-) mice with plaques, and none was evoked in those showing normal appearance. Also, the contraction evoked by ACh in apoE(-/-)-COX-1(-/-) abdominal aortic rings with plaques was abolished by non-selective COX inhibition, thromboxane-prostanoid (TP) receptor antagonism, or endothelial denudation. Moreover, it was noted that ACh evoked a predominant production of the prostacyclin (PGI2, which mediates abdominal aortic contraction via TP receptors in mice) metabolite 6-keto PGF1alpha, which was again sensitive to COX-1 inhibition or COX-1(-/-). Therefore, in atherosclerotic mouse abdominal aortas, COX-1 can still be the major isoform mediating endothelium-dependent contraction, which probably results largely from PGI2 synthesis as in non-atherosclerotic conditions. In contrast, COX-2 may have only a minor role in such response limited to areas of plaques under the same pathological condition. PMID- 26444419 TI - Enhanced expression of TWIK-related arachidonic acid-activated K+ channel in the spinal cord of detrusor overactivity rats after partial bladder outlet obstruction. AB - BACKGROUND: Detrusor overactivity (DO) secondary to partial bladder outlet obstruction (PBOO) is closely associated with alteration of ion channels. The objective of this study is to investigate the expression of the TWIK-related arachidonic acid-activated K(+) channel (TRAAK) in the L6-S1 spinal cord of DO rats after PBOO. METHODS: Female Sprague-Dawley rats undergoing PBOO surgery were screened for DO by cystometry. Sham-operated rats served as controls. The expression of TRAAK in the L6-S1 spinal cord was detected by real-time polymerase chain reaction, western blotting and immunohistochemistry. RESULTS: DO was successfully induced after chronic PBOO in rats, with an incidence rate of 62.5 %. Compared with sham-operated rats, the expression of TRAAK in the L6-S1 spinal cord of DO rats was significantly increased at the mRNA (1.886 +/- 0.710 versus 0.790 +/- 0.679, P < 0.05) and protein level (0.510 +/- 0.087 versus 0.255 +/- 0.107, P < 0.05). Immunohistochemical staining showed increased expression of TRAAK in the dorsal horn and ventral horn of the spinal cord. CONCLUSIONS: Upregulation of TRAAK was observed in the spinal cord of DO rats after chronic PBOO, which may exert a protective effect against DO by suppressing the excitability of neurons. PMID- 26444421 TI - Risk Factors for Multidrug-Resistant Tuberculosis among Patients with Pulmonary Tuberculosis at the Central Chest Institute of Thailand. AB - There are limited data available on the risk factors for multidrug-resistant tuberculosis (MDR-TB). Therefore, we here conducted a retrospective matched case control study among adults with pulmonary TB who received treatment at the Central Chest Institute of Thailand (CCIT) between January 2007 and December 2013, in order to determine the risk factors associated with MDR-TB among patients with pulmonary TB. We identified 145 patients with pulmonary MDR-TB (cases) and 145 patients with drug-sensitive pulmonary TB (controls). Multivariate analysis identified the independent risk factors for MDR-TB as follows: (1) >= 2 episodes of prior pulmonary TB (odds ratio [OR] 39.72, 95% confidence interval (95% CI) 7.86-200.66), (2) duration of illness > 60 days (OR 3.08, 95% CI 1.52-6.22), (3) sputum acid fast bacilli smear 3+ (OR 13.09, 95% CI 4.64-36.91), (4) presence of lung cavities (OR 3.82, 95% CI 1.89-7.73), and (5) presence of pleural effusion (OR 2.75, 95% CI 1.06-7.16). Prior pulmonary TB management with a non-category I regimen (P = 0.012) and having treatment failure or default as treatment outcomes (P = 0.036) were observed in a higher proportion among patients with MDR-TB. Particular characteristics of lung cavities, including the maximum diameter >= 30 mm (P < 0.001), the number of cavities >= 3 (P = 0.001), bilateral involvement (P < 0.001), and >= 2 lung zones involved (P = 0.001) were more commonly observed in patients with MDR-TB. In conclusion, these clinical factors and chest radiographic findings associated with MDR-TB among patients with pulmonary TB may help physicians to provide proper management of cases for prevention of the development and spread of MDR-TB in future. PMID- 26444420 TI - Leukotriene B4 Enhances NOD2-Dependent Innate Response against Influenza Virus Infection. AB - Leukotriene B4 (LTB4), a central mediator of inflammation, is well known for its chemoattractant properties on effectors cells of the immune system. LTB4 also has the ability to control microbial infection by improving host innate defenses through the release of antimicrobial peptides and modulation of intracellular Toll-like receptors (TLRs) expression in response to agonist challenge. In this report, we provide evidences that LTB4 acts on nucleotide-binging oligomerization domain 2 (NOD2) pathway to enhance immune response against influenza A infection. Infected mice receiving LTB4 show improved survival, lung architecture and reduced lung viral loads as compared to placebo-treated animals. NOD2 and its downstream adaptor protein IPS-1 have been found to be essential for LTB4 mediated effects against IAV infection, as absence of NOD2 or IPS-1 diminished its capacity to control viral infection. Treatment of IAV-infected mice with LTB4 induces an increased activation of IPS-1-IRF3 axis leading to an enhanced production of IFNbeta in lungs of infected mice. LTB4 also has the ability to act on the RICK-NF-kappaB axis since administration of LTB4 to mice challenged with MDP markedly increases the secretion of IL-6 and TNFalpha in lungs of mice. TAK1 appears to be essential to the action of LTB4 on NOD2 pathway since pretreatment of MEFs with TAK1 inhibitor prior stimulation with IAV or MDP strongly abrogated the potentiating effects of LTB4 on both IFNbeta and cytokine secretion. Together, our results demonstrate that LTB4, through its ability to activate TAK1, potentiates both IPS-1 and RICK axis of the NOD2 pathway to improve host innate responses. PMID- 26444422 TI - CD98 Heavy Chain Is a Potent Positive Regulator of CD4+ T Cell Proliferation and Interferon-gamma Production In Vivo. AB - Upon their recognition of antigens presented by the MHC, T cell proliferation is vital for clonal expansion and the acquisition of effector functions, which are essential for mounting adaptive immune responses. The CD98 heavy chain (CD98hc, Slc3a2) plays a crucial role in the proliferation of both CD4+ and CD8+ T cells, although it is unclear if CD98hc directly regulates the T cell effector functions that are not linked with T cell proliferation in vivo. Here, we demonstrate that CD98hc is required for both CD4+ T cell proliferation and Th1 functional differentiation. T cell-specific deletion of CD98hc did not affect T cell development in the thymus. CD98hc-deficient CD4+ T cells proliferated in vivo more slowly as compared with control T cells. C57BL/6 mice lacking CD98hc in their CD4+ T cells could not control Leishmania major infections due to lowered IFN-gamma production, even with massive CD4+ T cell proliferation. CD98hc deficient CD4+ T cells exhibited lower IFN-gamma production compared with wild type T cells, even when comparing IFN-gamma expression in cells that underwent the same number of cell divisions. Therefore, these data indicate that CD98hc is required for CD4+ T cell expansion and functional Th1 differentiation in vivo, and suggest that CD98hc might be a good target for treating Th1-mediated immune disorders. PMID- 26444424 TI - Efficacy and Safety of Metronidazole Monotherapy versus Vancomycin Monotherapy or Combination Therapy in Patients with Clostridium difficile Infection: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Clostridium difficile infection (CDI) has become a global epidemiological problem for both hospitalized patients and outpatients. The most commonly used drugs to treat CDI are metronidazole and vancomycin. The aim of this study was to compare the efficacy and safety of metronidazole monotherapy with vancomycin monotherapy and combination therapy in CDI patients. METHODS: A comprehensive search without publication status or other restrictions was conducted. Studies comparing metronidazole monotherapy with vancomycin monotherapy or combination therapy in patients with CDI were considered eligible. Meta-analysis was performed using the Mantel-Haenszel fixed-effects model, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated and reported. RESULTS: Of the 1910 records identified, seventeen studies from thirteen articles (n = 2501 patients) were included. No statistically significant difference in the rate of clinical cure was found between metronidazole and vancomycin for mild CDI (OR = 0.67, 95% CI (0.45, 1.00), p = 0.05) or between either monotherapy and combination therapy for CDI (OR = 1.07, 95% CI (0.58, 1.96), p = 0.83); however, the rate of clinical cure was lower for metronidazole than for vancomycin for severe CDI (OR = 0.46, 95% CI (0.26, 0.80), p = 0.006). No statistically significant difference in the rate of CDI recurrence was found between metronidazole and vancomycin for mild CDI (OR = 0.99, 95% CI (0.40, 2.45), p = 0.98) or severe CDI (OR = 0.98, 95% CI (0.63, 1.53), p = 0.94) or between either monotherapy and combination therapy for CDI (OR = 0.91, 95% CI (0.66, 1.26), p = 0.56). In addition, there was no significant difference in the rate of adverse events (AEs) between metronidazole and vancomycin (OR = 1.18, 95% CI (0.80, 1.74), p = 0.41). In contrast, the rate of AEs was significantly lower for either monotherapy than for combination therapy (OR = 0.30, 95% CI (0.17, 0.51), p < 0.0001). CONCLUSIONS: Metronidazole and vancomycin are equally effective for the treatment of mild CDI, but vancomycin is superior for the treatment of severe CDI. Combination therapy is not superior to monotherapy because it appears to be associated with an increase in the rate of AEs. PMID- 26444423 TI - An Oriental Medicine, Hyungbangpaedok-San Attenuates Motor Paralysis in an Experimental Model of Multiple Sclerosis by Regulating the T Cell Response. AB - The preventive and therapeutic mechanisms in multiple sclerosis are not clearly understood. We investigated whether Hyungbangpaedok-san (HBPDS), a traditional herbal medicine, has a beneficial effect in experimental autoimmune encephalomyelitis (EAE) mice immunized with myelin oligodendrocyte glycoprotein peptide (MOG 35-55). Onset-treatment with 4 types of HBPDS (extracted using distilled water and 30%/70%/100% ethanol as the solvent) alleviated neurological signs, and HBPDS extracted within 30% ethanol (henceforth called HBPDS) was more effective. Onset-treatment with HBPDS reduced demyelination and the recruitment/infiltration and activation of microglia/macrophages in the spinal cord of EAE mice, which corresponded to the reduced mRNA expression of pro inflammatory cytokines (TNF-alpha, IL-6, and IL-1beta), iNOS, and chemokines (MCP 1, MIP-1alpha, and RANTES) in the spinal cord. Onset-treatment with HBPDS inhibited changes in the components of the blood-brain barrier such as astrocytes, adhesion molecules (ICAM-1 and VCAM-1), and junctional molecules (claudin-3, claudin-5, and zona occludens-1) in the spinal cord of EAE mice. Onset-treatment with HBPDS reduced the elevated population of CD4+, CD4+/IFN gamma+, and CD4+/IL-17+ T cells in the spinal cord of EAE mice but it further increased the elevated population of CD4+/CD25+/Foxp3+ and CD4+/Foxp3+/Helios+ T cells. Pre-, onset-, post-, but not peak-treatment, with HBPDS had a beneficial effect on behavioral impairment in EAE mice. Taken together, HBPDS could alleviate the development/progression of EAE by regulating the recruitment/infiltration and activation of microglia and peripheral immune cells (macrophages, Th1, Th17, and Treg cells) in the spinal cord. These findings could help to develop protective strategies using HBPDS in the treatment of autoimmune disorders including multiple sclerosis. PMID- 26444425 TI - Molecular Characterization and Expression Profiling of NAC Transcription Factors in Brachypodium distachyon L. AB - NAC (NAM, ATAF1/2, CUC2) transcription factors are involved in regulating plant developmental processes and response to environmental stresses. Brachypodium distachyon is an emerging model system for cereals, temperate grasses and biofuel crops. In this study, a comprehensive investigation of the molecular characterizations, phylogenetics and expression profiles under various abiotic stresses of the NAC gene family in Brachypodium distachyon was performed. In total, 118 BNAC genes in B. distachyon were identified, of which 22 (18.64%) were tandemly duplicated and segmentally duplicated, respectively. The Bayesian phylogenetic inference using Markov Chain Monte Carlo (MCMC) algorithms showed that they were divided into two clades and fourteen subfamilies, supported by similar motif compositions within one subfamily. Some critical amino acids detected using DIVERGE v3.0 might contribute to functional divergence among subfamilies. The different exon-intron organizations among subfamilies revealed structural differentiation. Promoter sequence predictions showed that the BNAC genes were involved in various developmental processes and diverse stress responses. Three NAC domain-encoding genes (BNAC012, BNAC078 and BNAC108), orthologous of NAC1, were targeted by five miRNA164 (Bdi-miR164a-c, e, f), suggesting that they might function in lateral organ enlargement, floral development and the responses to abiotic stress. Eleven (~9.32%) BNAC proteins containing alpha-helical transmembrane motifs were identified. 23 representative BNAC genes were analyzed by quantitative real-time PCR, showing different expression patterns under various abiotic stresses, of which 18, 17 and 11 genes were up-regulated significantly under drought, H2O2 and salt stresses, respectively. Only four and two genes were up-regulated under cold and cadmium stresses, respectively. Dynamic transcriptional expression analysis revealed that six genes showed constitutive expression and period-specific expression. The current results provide novel insights into the structure and function of the plant NAC gene family. PMID- 26444427 TI - Schleyer hyperconjugative aromaticity and Diels-Alder reactivity of 5-substituted cyclopentadienes. AB - Schleyer's discovery of hyperconjugative aromaticity and antiaromaticity in 5 substituted cyclopentadienes further expanded our understanding of the pervasive influence of aromaticity. Acceptors induce antiaromatic character by Schleyer's negative hyperconjugative aromaticity, and donors have the opposite effect. We computationally explored the Diels-Alder reactivity of 5-substituted cyclopentadienes with ethylene and maleic anhydride. The predicted billionfold difference in the computed gas phase rate constants at room temperature for the Diels-Alder reactions of 5-substituted cyclopentadienes with ethylene or maleic anhydride results from differences in the transition state distortion energies, which are directly related to the hyperconjugative aromaticity of these molecules. PMID- 26444426 TI - Gait Biomechanics and Patient-Reported Function as Predictors of Response to a Hip Strengthening Exercise Intervention in Patients with Knee Osteoarthritis. AB - OBJECTIVE: Muscle strengthening exercises have been shown to improve pain and function in adults with mild-to-moderate knee osteoarthritis, but individual response rates can vary greatly. Predicting individuals who respond and those who do not is important in developing a more efficient and effective model of care for knee osteoarthritis (OA). Therefore, the purpose of this study was to use pre intervention gait kinematics and patient-reported outcome measures to predict post-intervention response to a 6-week hip strengthening exercise intervention in patients with mild-to-moderate knee OA. METHODS: Thirty-nine patients with mild to-moderate knee osteoarthritis completed a 6-week hip-strengthening program and were subgrouped as Non-Responders, Low-Responders, or High-Responders following the intervention based on their change in Knee injury Osteoarthritis Outcome Score (KOOS). Predictors of responder subgroups were retrospectively determined from baseline patient-reported outcome measures and kinematic gait parameters in a discriminant analysis of principal components. A 3-4 year follow-up on 16 of the patients with knee OA was also done to examine long-term changes in these parameters. RESULTS: A unique combination of patient-reported outcome measures and kinematic factors was able to successfully subgroup patients with knee osteoarthritis with a cross-validated classification accuracy of 85.4%. Lower patient-reported function in daily living (ADL) scores and hip frontal plane kinematics during the loading response were most important in classifying High Responders from other sub-groups, while a combination of hip, knee, ankle kinematics were used to classify Non-Responders from Low-Responders. CONCLUSION: Patient-reported outcome measures and objective biomechanical gait data can be an effective method of predicting individual treatment success to an exercise intervention. Measuring gait kinematics, along with patient-reported outcome measures in a clinical setting can be useful in helping make evidence-based decisions regarding optimal treatment for patients with knee OA. PMID- 26444428 TI - Comparing the Rates of Early Childhood Victimization across Sexual Orientations: Heterosexual, Lesbian, Gay, Bisexual, and Mostly Heterosexual. AB - Few studies have examined the rates of childhood victimization among individuals who identify as "mostly heterosexual" (MH) in comparison to other sexual orientation groups. For the present study, we utilized a more comprehensive assessment of adverse childhood experiences to extend prior literature by examining if MH individuals' experience of victimization more closely mirrors that of sexual minority individuals or heterosexuals. Heterosexual (n = 422) and LGB (n = 561) and MH (n = 120) participants were recruited online. Respondents completed surveys about their adverse childhood experiences, both maltreatment by adults (e.g., childhood physical, emotional, and sexual abuse and childhood household dysfunction) and peer victimization (i.e., verbal and physical bullying). Specifically, MH individuals were 1.47 times more likely than heterosexuals to report childhood victimization experiences perpetrated by adults. These elevated rates were similar to LGB individuals. Results suggest that rates of victimization of MH groups are more similar to the rates found among LGBs, and are significantly higher than heterosexual groups. Our results support prior research that indicates that an MH identity falls within the umbrella of a sexual minority, yet little is known about unique challenges that this group may face in comparison to other sexual minority groups. PMID- 26444429 TI - Clinical effect of cardiac shock wave therapy on patients with ischaemic heart disease: a systematic review and meta-analysis. AB - BACKGROUND: After several years of study, CSWT has been initially applied to IHD treatment, but the actual effectiveness has never been well evaluated with a meta analysis. METHODS: MEDLINE, EMBASE, Science Direct, Cochrane Controlled Trials Register database and Chinese database were searched. The randomized controlled trials, and single-arm and cohort study related to in patients with IHD undergoing CSWT were included and 14 articles were finally analysed. The data related to the study design, patient characteristics and outcomes were extracted. All the selected data were calculated with random-effects models in weighted mean differences, and heterogeneity was carefully evaluated as well. RESULTS: (i) Cardiac shock wave therapy improves the angina pectoris symptom (including the decrease of Canadian Cardiovascular Society class [-0.86 (-1.12, -0.65), P < 0.00001], nitroglycerin dosage (times/weeks) [-0.71 (-1.08, -0.33), P = 0.0002] and a increase of Seattle Angina Questionnaire score [5.64 (3.12, 8.15), P < 0.0001)]); (ii) CSWT leads to a reduce in heart failure (including a reduction of New York Heart Association functional class [-0.49 (-0.62, -0.37), P < 0.00001], a stable rise in 6-min walking distance [68.38 (39.70, 97.05), P < 0.00001] and a growth in left ventricular ejection fraction with echocardiography screening [6.73 (4.67,8.80), P < 0.00001]); (iii) CSWT improves myocardial viability within improving in total score of perfusion imaging [-5.19 (-8.08, -2.30), P = 0.0004] and total score of metabolism imaging [-5.33 (-7.77, -2.90), P < 0.0001]. CONCLUSIONS: The meta-analysis suggests that CSWT may offer beneficial effects to patients with IHD, although there was significant heterogeneity across the studies. PMID- 26444430 TI - Inflammation Induces TDP-43 Mislocalization and Aggregation. AB - TAR DNA-binding protein 43 (TDP-43) is a major component in aggregates of ubiquitinated proteins in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we report that lipopolysaccharide (LPS)-induced inflammation can promote TDP-43 mislocalization and aggregation. In culture, microglia and astrocytes exhibited TDP-43 mislocalization after exposure to LPS. Likewise, treatment of the motoneuron-like NSC-34 cells with TNF-alpha (TNF alpha) increased the cytoplasmic levels of TDP-43. In addition, the chronic intraperitoneal injection of LPS at a dose of 1mg/kg in TDP-43(A315T) transgenic mice exacerbated the pathological TDP-43 accumulation in the cytoplasm of spinal motor neurons and it enhanced the levels of TDP-43 aggregation. These results suggest that inflammation may contribute to development or exacerbation of TDP-43 proteinopathies in neurodegenerative disorders. PMID- 26444431 TI - New Insights into Butyrylcholinesterase Activity Assay: Serum Dilution Factor as a Crucial Parameter. AB - Butyrylcholinesterase (BChE) activity assay and inhibitor phenotyping can help to identify patients at risk of prolonged paralysis following the administration of neuromuscular blocking agents. The assay plays an important role in clinical chemistry as a good diagnostic marker for intoxication with pesticides and nerve agents. Furthermore, the assay is also commonly used for in vitro characterization of cholinesterases, their toxins and drugs. There is still lack of standardized procedure for measurement of BChE activity and many laboratories use different substrates at various concentrations. The purpose of this study was to validate the BChE activity assay to determine the best dilution of human serum and the most optimal concentration of substrates and inhibitors. Serum BChE activity was measured using modified Ellman's method applicable for a microplate reader. We present our experience and new insights into the protocol for high throughput routine assays of human plasma cholinesterase activities adapted to a microplate reader. During our routine assays used for the determination of BChE activity, we have observed that serum dilution factor influences the results obtained. We show that a 400-fold dilution of serum and 5mM S-butyrylthiocholine iodide can be successfully used for the accurate measurement of BChE activity in human serum. We also discuss usage of various concentrations of dibucaine and fluoride in BChE phenotyping. This study indicates that some factors of such a multicomponent clinical material like serum can influence kinetic parameters of the BChE. The observed inhibitory effect is dependent on serum dilution factor used in the assay. PMID- 26444433 TI - Supramolecular bimetallic assemblies for photocatalytic hydrogen generation from water. AB - A series of supramolecular assemblies of the type [Ru(L-L)2(L'-L)MX2)](n+) are reported where L-L is 2,2'-bipyridine (bipy), 4,4'-di-tetra-butyl-bipyridine (tbbipy) or 4,4'-diethoxycarbonyl-2,2'-bipyridine (dceb), L-L' is tetrapyrido[3,2 a:2',3'-c:3'',2''-h:2''',3'''-j]phenazine (tpphz), 2,2':5',2''-terpyridine (2,5 bpp), 2,2':6',2''-terpyridine, (2,6-bpp), 2,5-di(pyridine-2-yl)pyrazine (2,5-dpp) or 2,3-di(pyridine-2-yl)pyrazine (2,3-dpp), and MX2 is PdCl2, PtCl2 or PtI2. The photocatalytic behaviour with respect to hydrogen generation of these compounds and their ultrafast photophysical properties are discussed as a function of the nature of the peripheral ligands, the bridging ligands and the catalytic centre. The results obtained show how differences in the chemical composition of the photocatalysts can affect intramolecular photoinduced electron transfer processes and the overall photocatalytic efficiency. PMID- 26444432 TI - Effects of Pyriproxyfen on Female Reproduction in the Common Cutworm, Spodoptera litura (F.) (Lepidoptera: Noctuidae). AB - The common cutworm, Spodoptera litura, is a rapidly reproducing pest of numerous agricultural ecosystems worldwide. The use of pesticides remains the primary means for controlling S. litura, despite their negative ecological impact and potential threat to human health. The use of exogenous hormone analogs may represent an alternative to insecticides. Juvenile hormones (JHs) play an important role in the reproductive systems of female insects, but the effects of pyriproxyfen, a JH analog, on reproduction in S. litura were poorly understood. In this paper, we topically treated the newly emerged females with 20, 60, or 100 MUg of pyriproxyfen to determine its effects on reproduction. Then, we examined the expression of vitellogenin (Vg) and three hormone receptors, USP, HR3, and EcR, using quantitative reverse transcription and real-time polymerase chain reaction (qRT-PCR), and found that pyriproxyfen up-regulated the expression of Vg, USP, and HR3, whereas the expression of EcR was unaffected. An analysis of fecundity showed that the peak oviposition day, lifespan, and oviposition period were progressively shortened as the pyriproxyfen dosage increased. We also found that pyriproxyfen decreased egg laying amount, whereas the number of mature eggs that remained in the ovarioles of dead females increased as the pyriproxyfen dosage increased. We examined oocytes using transmission electron microscopy and found that treatment with 100 MUg of pyriproxyfen increased the metabolism by increasing the amount of rough endoplasmic reticulum and mitochondria in the primary oocytes. Our results suggest that the topical application of pyriproxyfen on newly emerged females can efficiently reduce reproduction in S. litura and may represent an alternative to the use of insecticides for controlling the agricultural pest. PMID- 26444435 TI - A flexible AFT model for misclassified clustered interval-censored data. AB - Motivated by a longitudinal oral health study, we propose a flexible modeling approach for clustered time-to-event data, when the response of interest can only be determined to lie in an interval obtained from a sequence of examination times (interval-censored data) and on top of that, the determination of the occurrence of the event is subject to misclassification. The clustered time-to-event data are modeled using an accelerated failure time model with random effects and by assuming a penalized Gaussian mixture model for the random effects terms to avoid restrictive distributional assumptions concerning the event times. A general misclassification model is discussed in detail, considering the possibility that different examiners were involved in the assessment of the occurrence of the events for a given subject across time. A Bayesian implementation of the proposed model is described in a detailed manner. We additionally provide empirical evidence showing that the model can be used to estimate the underlying time-to event distribution and the misclassification parameters without any external information about the latter parameters. We also provide results of a simulation study to evaluate the effect of neglecting the presence of misclassification in the analysis of clustered time-to-event data. PMID- 26444434 TI - Importance of the Side Chain at Position 296 of Antibody Fc in Interactions with FcgammaRIIIa and Other Fcgamma Receptors. AB - Antibody-dependent cellular cytotoxicity (ADCC) is an important effector function determining the clinical efficacy of therapeutic antibodies. Core fucose removal from N-glycans on the Fc portion of immunoglobulin G (IgG) improves the binding affinity for Fcgamma receptor IIIa (FcgammaRIIIa) and dramatically enhances ADCC. Our previous structural analyses revealed that Tyr-296 of IgG1-Fc plays a critical role in the interaction with FcgammaRIIIa, particularly in the enhanced FcgammaRIIIa binding of nonfucosylated IgG1. However, the importance of the Tyr 296 residue in the antibody in the interaction with various Fcgamma receptors has not yet been elucidated. To further clarify the biological importance of this residue, we established comprehensive Tyr-296 mutants as fucosylated and nonfucosylated anti-CD20 IgG1s rituximab variants and examined their binding to recombinant soluble human Fcgamma receptors: shFcgammaRI, shFcgammaRIIa, shFcgammaRIIIa, and shFcgammaRIIIb. Some of the mutations affected the binding of antibody to not only shFcgammaRIIIa but also shFcgammaRIIa and shFcgammaRIIIb, suggesting that the Tyr-296 residue in the antibody was also involved in interactions with FcgammaRIIa and FcgammaRIIIb. For FcgammaRIIIa binding, almost all Tyr-296 variants showed lower binding affinities than the wild-type antibody, irrespective of their core fucosylation, particularly in Y296K and Y296P. Notably, only the Y296W mutant showed improved binding to FcgammaRIIIa. The 3.00 A-resolution crystal structure of the nonfucosylated Y296W mutant in complex with shFcgammaRIIIa harboring two N-glycans revealed that the Tyr-to-Trp substitution increased the number of potential contact atoms in the complex, thus improving the binding of the antibody to shFcgammaRIIIa. The nonfucosylated Y296W mutant retained high ADCC activity, relative to the nonfucosylated wild-type IgG1, and showed greater binding affinity for FcgammaRIIa. Our data may improve our understanding of the biological importance of human IgG1-Fc Tyr-296 in interactions with various Fcgamma receptors, and have applications in the modulation of the IgG1-Fc function of therapeutic antibodies. PMID- 26444436 TI - Flexible thin-film battery based on graphene-oxide embedded in solid polymer electrolyte. AB - Enhanced safety of flexible batteries is an imperative objective due to the intimate interaction of such devices with human organs such as flexible batteries that are integrated with touch-screens or embedded in clothing or space suits. In this study, the fabrication and testing of a high performance thin-film Li-ion battery (LIB) is reported that is both flexible and relatively safer compared to the conventional electrolyte based batteries. The concept is facilitated by the use of solid polymer nanocomposite electrolyte, specifically, composed of polyethylene oxide (PEO) matrix and 1 wt% graphene oxide (GO) nanosheets. The flexible LIB exhibits a high maximum operating voltage of 4.9 V, high capacity of 0.13 mA h cm(-2) and an energy density of 4.8 mW h cm(-3). The battery is encapsulated using a simple lamination method that is economical and scalable. The laminated battery shows robust mechanical flexibility over 6000 bending cycles and excellent electrochemical performance in both flat and bent configurations. Finite element analysis (FEA) of the LIB provides critical insights into the evolution of mechanical stresses during lamination and bending. PMID- 26444437 TI - Improving the productivity of 19,20-epoxy-cytochalasin Q in Xylaria sp. sof11 with culture condition optimization. AB - 19,20-Epoxy-cytochalasin Q (B5A) is a cytochalasin with a wide range of biological activities, which can be produced by Xylaria sp. sof11, a strain isolated from the seafloor of the northern South China Sea. Since the low titer of B5A has greatly limited its further studies, we have systematically conducted the fermentative optimization for B5A production in this article. The effects of major medium components, including the carbon and organic nitrogen sources, as well as of the concentration of sea salt, were respectively investigated through single-factor experiments. As a result, sucrose and fish meal were determined to be the key factors affecting the production of B5A. Then three important variables, sucrose, fish meal, and filling volume, were screened out by the Plackett-Burman (PB) design. The optimal level of these variables was further confirmed by response surface analysis. The final formulated medium was set as 35.2 g/L sucrose and 18.0 g/L fish meal, with filling volume of 34.6 mL, which could afford 440.3 mg/L production of B5A, approximately 4.4-fold higher than that in the original medium. The significantly improved productivity of B5A will facilitate the subsequent mechanistic and clinical studies of B5A. PMID- 26444438 TI - Cryptococcal meningitis due to Cryptococcus neoformans genotype AFLP1/VNI in Iran: a review of the literature. AB - Cryptococcal meningitis is the most important opportunistic fungal infection with a high mortality in HIV-patients in less developed regions. Here, we report a case of cryptococcal meningitis in a 49-year-old HIV-positive female due to Cryptococcus neoformans (serotype A, mating-type alpha, genotype AFLP1/VNI) in Sari, Iran. In vitro antifungal susceptibility tests showed MICs of isavuconazole (0.016 MUg ml(-1) ), voriconazole (0.031 MUg ml(-1) ), posaconazole (0.031 MUg ml(-1) ), itraconazole (0.063 MUg ml(-1) ), amphotericin B (0.125 MUg ml(-1) ) and fluconazole (8 MUg ml(-1) ). Despite immediate antifungal therapy, the patient died 4 days later due to respiratory failure. Cryptococcal infections have been infrequently reported from Iran and therefore we analysed all published cases of cryptococcosis in Iran since the first reported case from 1969. PMID- 26444439 TI - Important factors determining the nanoscale tracking precision of dynamic microtubule ends. AB - Tracking dynamic microtubule ends in fluorescence microscopy movies provides insight into the statistical properties of microtubule dynamics and is vital for further analysis that requires knowledge of the trajectories of the microtubule ends. Here we analyse the performance of a previously developed automated microtubule end tracking routine; this has been optimized for comparatively low signal-to-noise image sequences that are characteristic of microscopy movies of dynamic microtubules growing in vitro. Sequences of simulated microtubule images were generated assuming a variety of different experimental conditions. The simulated movies were then tracked and the tracking errors were characterized. We found that the growth characteristics of the microtubules within realistic ranges had a negligible effect on the tracking precision. The fluorophore labelling density, the pixel size of the images, and the exposure times were found to be important parameters limiting the tracking precision which could be explained using concepts of single molecule localization microscopy. The signal-to-noise ratio was found to be a good single predictor of the tracking precision: typical experimental signal-to-noise ratios lead to tracking precisions in the range of tens of nanometres, making the tracking program described here a useful tool for dynamic microtubule end tracking with close to molecular precision. PMID- 26444440 TI - Changes in Volatile Compounds of Chinese Luzhou-Flavor Liquor during the Fermentation and Distillation Process. AB - The aim of this study was to investigate the dynamic of volatile compounds in the Zaopei during the fermentation and distillation process by headspace solid-phase microextraction-gas chromatography mass spectrometry (HS-SPME-GCMS). Physicochemical properties analysis of Zaopei (fermented grains [FG], fermented grains mixed with sorghum [FGS], streamed grains [SG], and streamed grains mixed with Daqu [SGD]) showed distinct changes. A total number of 66 volatile compounds in the Zaopei were identified, in which butanoic acid, hexanoic acid, ethyl hexanoate, ethyl lactate, ethyl octanoate, hexyl hexanoate, ethyl hydrocinnamate, ethyl oleate, ethyl hexadecanoate, and ethyl linoleate were considered to be the dominant compounds due to their high concentrations. FG had the highest volatile compounds (112.43 mg/kg), which significantly decreased by 17.05% in the FGS, 67.12% in the SG, and 73.75% in the SGD. Furthermore, about 61.49% of volatile compounds of FGS were evaporated into raw liquor, whereas head, heart, and tail liquor accounted for 29.84%, 39.49%, and 30.67%, respectively. Each volatile class generally presented a decreasing trend, except for furans. Especially, the percentage of esters was 55.51% to 67.41% in the Zaopei, and reached 92.60% to 97.67% in the raw liquor. Principal component analysis based ordination of volatile compounds data segregated FGS and SGD samples. In addition, radar diagrams of the odor activity values suggested that intense flavor of fruit was weakened most from FG to SGD. PRACTICAL APPLICATION: The dynamic of volatile compounds in the Zaopei during the fermentation and distillation process was tested by SPME-GCMS. The result of this study demonstrated that both volatile compounds of Zaopei and thermal reaction during distillation simply determined the unique feature of raw liquor. This study was conducted based on the real products from liquor manufactory, so it is practicable that the method can be used in an industry setting. PMID- 26444442 TI - Assessing Toxicity of Intravenous Crystalloids in Critically Ill Patients. PMID- 26444441 TI - The Epidemiology of Alcohol Use and Alcohol Use Disorders among Young People in Northern Tanzania. AB - INTRODUCTION: Alcohol use is a global public health problem, including as a risk factor for HIV infection, but few data are available on the epidemiology of alcohol use and alcohol use disorders (AUD) among young people in sub-Saharan Africa. METHODS: We conducted a cross-sectional survey among 4 groups of young people aged 15-24 years old (secondary school students, college/university students, employees of local industries and casual labourers) in two regions (Kilimanjaro and Mwanza) of northern Tanzania. Using a multistage stratified random sampling strategy, we collected information on demographics, alcohol use, and behavioural factors. We screened severity of alcohol use using the Alcohol Use Disorder Identification Test (AUDIT) and estimated the quantity and frequency of alcohol consumption using the timeline-follow-back-calendar (TLFB) method. RESULTS: A total of 1954 young people were surveyed. The prevalence of reported alcohol use was higher among males (47-70% ever users and 20-45% current users) than females (24-54% ever users and 12-47% current users). Prevalence of use was substantially higher in Kilimanjaro than Mwanza region. In both regions, participants reported high exposure to alcohol advertisements, and wide alcohol availability. College students reported the highest prevalence of current alcohol use (45% among males; 26% among females) and of heavy episodic drinking (71% among males; 27% among females) followed by casual labourers. Males were more likely to have AUD (an AUDIT score >=8) than females, with 11-28% of males screening positive for AUD. Alcohol use was associated with male gender, being in a relationship, greater disposable income, non-Muslim religion and a higher number of sexual partners. CONCLUSIONS: Alcohol use is a significant problem among young people in northern Tanzania. There is an urgent need to develop, pilot and deliver interventions to help young people delay initiation and reduce levels of harmful drinking, particularly among college students and casual labourers. PMID- 26444443 TI - The effect of various electrolyte cations on electrochemical performance of polypyrrole/RGO based supercapacitors. AB - In this work, polypyrrole/graphene doped by p-toluenesulfonic is prepared as an active material for supercapacitors, and its capacitance performance is investigated in various aqueous electrolytes including HCl, LiCl, NaCl, and KCl with a concentration of 3 M, respectively. A rising trend of capacitance is observed according to the cationic mobility (Li(+) < Na(+) < K(+) < H(+)), which is due to its effect on the ionic conductivity, efficient ion/charge diffusion/exchange and relaxation time. On the other hand, long-term cycling stability is in the following order: KCl < NaCl < LiCl < HCl, corresponding to the decreasing tendency of cation size (K(+) > Na(+) > Li(+) > H(+)). The reason can be attributed to the fact that the insertion/de-insertion of large size cation brings a significant doping level decrease and an over-oxidation increase during the charging-discharging cycles. Hence, we not only obtain good capacitance performance (280.3 F g(-1) at 5 mV s(-1)), superior rate capability (225.8 F g(-1) at 500 mV s(-1)) and high cycling stability (92.0% capacitance retention after 10,000 cycles at 1 A g(-1)) by employing 3 M HCl as an electrolyte, but also reveal that the electrolyte cations have a significant effect on the supercapacitors' electrochemical performance. PMID- 26444444 TI - Self-harm Emergencies After Bariatric Surgery: A Population-Based Cohort Study. AB - IMPORTANCE: Self-harm behaviors, including suicidal ideation and past suicide attempts, are frequent in bariatric surgery candidates. It is unclear, however, whether these behaviors are mitigated or aggravated by surgery. OBJECTIVE: To compare the risk of self-harm behaviors before and after bariatric surgery. DESIGN, SETTING, AND PARTICIPANTS: In this population-based, self-matched, longitudinal cohort analysis, we studied 8815 adults from Ontario, Canada, who underwent bariatric surgery between April 1, 2006, and March 31, 2011. Follow-up for each patient was 3 years prior to surgery and 3 years after surgery. MAIN OUTCOMES AND MEASURES: Self-harm emergencies 3 years before and after surgery. RESULTS: The cohort included 8815 patients of whom 7176 (81.4%) were women, 7063 (80.1%) were 35 years or older, and 8681 (98.5%) were treated with gastric bypass. A total of 111 patients had 158 self-harm emergencies during follow-up. Overall, self-harm emergencies significantly increased after surgery (3.63 per 1000 patient-years) compared with before surgery (2.33 per 1000 patient-years), equaling a rate ratio (RR) of 1.54 (95% CI, 1.03-2.30; P = .007). Self-harm emergencies after surgery were higher than before surgery among patients older than 35 years (RR, 1.76; 95% CI, 1.05-2.94; P = .03), those with a low-income status (RR, 2.09; 95% CI, 1.20-3.65; P = .01), and those living in rural areas (RR, 6.49; 95% CI, 1.42-29.63; P = .02). The most common self-harm mechanism was an intentional overdose (115 [72.8%]). A total of 147 events (93.0%) occurred in patients diagnosed as having a mental health disorder during the 5 years before the surgery. CONCLUSIONS AND RELEVANCE: In this study, the risk of self-harm emergencies increased after bariatric surgery, underscoring the need for screening for suicide risk during follow-up. PMID- 26444445 TI - Guided inquiry activities for learning about the macro- and micronutrients in introductory nutrition courses. AB - Most students enroll in general education introductory nutrition classes because they want to improve their diets in order to lose weight or enhance athletic performance. These nonscience majors are often less interested in learning about the fundamental biochemical principles underlying nutrition or are surprised that this foundational knowledge of biochemistry is essential for appropriate diet planning. Furthermore, nonscience majors sometimes find traditional, lecture oriented science classes that encourage competition rather than collaboration to be uninviting and unappealing. For these reasons, we have developed a set of guided inquiry activities about macronutrients (carbohydrates, lipids, and proteins) and micronutrients (vitamins and minerals) for use in introductory nutrition courses for nonscience majors. In our first study (Spring 2012), we divided students into two groups with two different approaches for learning about the macronutrients: (1) a traditional, lecture-based approach and (2) an active learning approach with guided inquiry activities. We showed through the use of embedded common exam questions that students mastered concepts related to the macronutrients equally well using either approach. Due to positive student and faculty feedback from the first study, we decided to have all students use the guided inquiry approach in a subsequent study the following year (Spring 2013). In our second study we used pre/post survey data to evaluate both students' concept mastery and confidence in answering questions about the macro- and micronutrients. We found that (1) students showed gains in both concept mastery and confidence and (2) as students' confidence increased, post-test concept scores also increased. PMID- 26444446 TI - Corticosteroids as co-analgesics with opioids for cancer pain: a survey of Australian and New Zealand palliative care clinicians. AB - Corticosteroids are commonly used as co-analgesics with opioids for cancer pain; however limited quality data exist supporting their efficacy for this purpose. Further, little is known about individual prescribing practices. The current study surveyed members of the Australian New Zealand Society of Palliative Medicine about their use of corticosteroids as adjuvant analgesics in cancer pain. It confirmed high rates of utilisation and found variability in starting doses and associated decision-making. Further research is required to determine the efficacy and safety of corticosteroids as co-analgesics in cancer pain management. PMID- 26444447 TI - Cultural Competence Among Italian Nurses: A Multicentric Survey. AB - PURPOSE: To assess Italian nurses' cultural competence, as they are increasingly called upon to care for people of foreign origins. DESIGN: A cross-sectional, multicentric study. METHODS: From September 2013 to May 2014, a survey was carried out among Italian nurses. Cultural competence was assessed by the Cultural Competence Assessment tool, translated and adapted to the Italian context. FINDINGS: Nurses who completed the survey numbered 1,432; 70.6% were female; 42.6% ranged in age from 41 to 50 years; and 50.0% were bachelor's prepared. More than 50% had participated in some kind of cultural diversity training. Overall, cultural competence was moderate, showing a moderately high level of cultural awareness and sensitivity (mean = 5.41; SD = 0.66) and a moderate level of culturally competent behaviors (mean = 4.33; SD = 1.10). CONCLUSIONS: Although Italian nurses' cultural competence was acceptable, given the growing diversity of the patient population, nurses should be better prepared to face the changing health requests. CLINICAL RELEVANCE: Providing culturally competent care has been associated with improved provider-client communication, higher satisfaction with care, and health status improvement, as full comprehension of health status, adherence to medications and lifestyle recommendations, and appropriate utilization of the health system. Healthcare providers need to be adequately trained to provide culturally competent care. This research provides, for the first time, a report on Italian nurses' levels of cultural competence, and strengthens the current literature underlining the need for continuous education to enhance cultural competence among nurses. PMID- 26444448 TI - Hormonal determinants of erectile dysfunction and lower urinary tract symptoms in middle-aged and elderly men with prediabetes. AB - OBJECTIVES: Erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) are common in diabetic men. The aim of this study was to investigate hormonal determinants, the prevalence and severity of ED and LUTS in middle-aged and elderly men with prediabetes (PD). METHODS: We investigated 176 men with PD and 184 healthy peers. PD was defined according American Diabetes Association. ED according IIEF scale and LUTS according IPSS scale were assessed. Total testosterone (TT), calculated free testosterone (cFT), dehydroepiandrosterone sulfate (DHEAS) and insulin-like growth factor 1 (IGF-1) were measured. RESULTS: The prevalence of ED in patients with PD was higher than in control group (30 versus 24%) as well as the prevalence and severity of ED and LUTS in elderly (60 80 years) and middle-aged (40-59 years) men with PD was higher than in healthy peers. In middle-aged pre-diabetic men, the more severe LUTS symptoms were associated with low TT and DHEAS, while in elderly men with low cFT and DHEAS. The higher prevalence of ED in middle-aged men with PD was associated with cFT and DHEAS, while in elderly pre-diabetic men with TT and IGF-1. CONCLUSIONS: The prevalence and severity of LUTS and ED symptoms were higher in pre-diabetic men than in healthy peers. Hormonal determinants of these symptoms are different in middle-aged and elderly patients with PD. PMID- 26444450 TI - Disease activity score in 28 joints at 3 months after the initiation of biologic agent can be a predictive target for switching to the second biologic agent in patients with polyarticular juvenile idiopathic arthritis. AB - OBJECTIVE: To clarify polyarticular juvenile idiopathic arthritis (pJIA) patients who failed to maintain prolonged remission with the first biologic agent. METHODS: Fourteen pJIA patients were observed for 47.5 months (median) after initiating the first biologic agent. RESULTS: Eight maintained sustained clinical remission (median 47 months) with the first biologic agents, while the six switched to the second one due to lack of efficacy, thereafter. Receiver operating characteristic (ROC) analysis revealed that disease activity score in 28 joints (DAS28) of 2.37 at 3 months could distinguish between the two patient groups (p = 0.001). CONCLUSION: pJIA patients with DAS28 >2.37 at 3 months of the initial biologic therapy may be considered to switch to the second biologics. PMID- 26444452 TI - Assessment of the Helical Ventricular Myocardial Band Using Standard Echocardiography. PMID- 26444453 TI - Reply: To PMID 24814570. PMID- 26444454 TI - Reply: To PMID 24814570. PMID- 26444456 TI - Epithelial sodium channel is involved in H2S-induced acute pulmonary edema. AB - Acute pulmonary edema is one of the major outcomes of exposure to high levels of hydrogen sulfide (H2S). However, the mechanisms involved in H2S-induced acute pulmonary edema are still poorly understood. Therefore, the present study is designed to evaluate the role of epithelial sodium channel (ENaC) in H2S-induced acute pulmonary edema. The Sprague-Dawley rats were exposed to sublethal concentrations of inhaled H2S, then the pulmonary histological and lung epithelial cell injury were evaluated by hematoxylin-eosin staining and electron microscopy, respectively. In addition to morphological investigation, our results also revealed that H2S exposure significantly decreased the alveolar fluid clearance and increased the lung tissue wet-dry ratio. These changes were demonstrated to be associated with decreased ENaC expression. Furthermore, the extracellular-regulated protein kinases 1/2 pathway was demonstrated to be implicated in H2S-mediated ENaC expression, because PD98059, an ERK1/2 antagonist, significantly mitigated H2S-mediated ENaC down-regulation. Therefore, our results show that ENaC might represent a novel pharmacological target for the treatment of acute pulmonary edema induced by H2S and other hazardous gases. PMID- 26444457 TI - The influence of prostatic anatomy and neurotrophins on basal prostate epithelial progenitor cells. AB - BACKGROUND: Based on findings of surface marker, protein screens as well as the postulated near-urethral location of the prostate stem cell niche, we were interested whether androgen ablation, distinct anatomic regions within the prostate or neurotrophins have an influence on basal prostate epithelial progenitor cells (PESCs). METHODS: Microdissection of the prostate, enzymatic digestion, and preparation of single cells was performed from murine and human prostates. Adult PESC marker expressions were compared between a group of C57BL/6 mice and a separate group of castrated C57BL/6 mice. Surface markers CD13/CD271 on human prostate epithelial progenitor cells were evaluated by FACS analyses in cells cultured under novel stem cell conditions. The effect of neurotrophins NGF, NT3, and BDNF were evaluated with respect to their influence on proliferation and activation of human basal PESCs in vitro. RESULTS: We demonstrate the highest percentage of CD49f+ and Trop2+ expressing cells in the urethra near prostatic regions of WT mice (Trop2+ proximal: 10% vs. distal to the urethra: 3%, P < 0.001). While a marked increase of Trop2 expressing cells can be measured both in the proximal and distal prostatic regions after castration, the most prominent increase in Trop2+ cells can be measured in the prostatic tissue distant to the urethra. Furthermore, we demonstrate that the proportion of syndecan-1 expressing cells greatly increases in the regions proximal to the urethra after castration (WT: 5% vs. castrated: 40%). We identified heterogeneous CD13 and nerve growth factor receptor (p75(NGFR), CD271) expression on CD49f(+)/TROP2(high) human basal PESCs. Addition of the neurotrophins NT3, BDNF, and NGF to the stem cell media led to a marked temporary increase in the proliferation of human basal PESCs. CONCLUSIONS: Our results in mice support the model, in which the proximal urethral region contains the prostate stem cell niche while a stronger androgen dependent regulation of adult prostate stem cells can be found in the peripheral prostatic tissue. Neutrophin signaling via nerve growth factor receptor is possibly involved in human prostate stem cell homeostasis. PMID- 26444458 TI - The Cutaneous, Net Clinical, and Health Economic Benefits of Advanced Pneumatic Compression Devices in Patients With Lymphedema. AB - IMPORTANCE: The prevalence and clinical burden of lymphedema is known to be increasing. Nevertheless, evidence-based comparative effectiveness data regarding lymphedema therapeutic interventions have been poor. OBJECTIVE: To examine the impact of an advanced pneumatic compression device (APCD) on cutaneous and other clinical outcomes and health economic costs in a representative privately insured population of lymphedema patients. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of a deidentified private insurance database from 2007 through 2013, and multivariate regression analysis comparing outcomes for the 12 months before and after APCD purchase, adjusting for baseline patient characteristics. Patients with lymphedema who received an APCD who were commercially insured and Medicare managed care enrollees from a large, national US managed care health insurer. The study population was evaluated as cancer related and non-cancer-related lymphedema cohorts. INTERVENTION: Receipt of an APCD. MAIN OUTCOMES AND MEASURES: Rates of cellulitis, use of lymphedema-related manual therapy, outpatient hospital visits, and inpatient hospitalizations. Lymphedema-related direct costs were measured for home health care, hospital outpatient care, office visits, emergency department use, and inpatient care. RESULTS: The study sample included 718 patients (374 in the cancer cohort and 344 in the noncancer cohort). In both cohorts, use of an APCD was associated with similar reductions in adjusted rates of cellulitis episodes (from 21.1% to 4.5% in the cancer cohort and 28.8% to 7.3% in the noncancer cohort; P < .001 for both), lymphedema-related manual therapy (from 35.6% to 24.9%in the cancer cohort and 32.3% to 21.2% in the noncancer cohort; P < .001 for both), and outpatient visits (from 58.6% to 41.4% in the cancer cohort and 52.6% to 31.4% in the noncancer cohort; P < .001 for both). Among the cancer cohort, total lymphedema related costs per patient, excluding medical equipment costs, were reduced by 37% (from $2597 to $1642, P = .002). The corresponding decline in costs for the noncancer cohort was 36% (from $2937 to $1883, P = .007). CONCLUSIONS AND RELEVANCE: The study found an association between significant reductions in episodes of cellulitis (cancer vs noncancer cohorts) and outpatient care and costs of APCD acquisition within a 1-year time frame in patients with both cancer related and non-cancer-related lymphedema. PMID- 26444459 TI - A Review of HIV in Baltimore, Maryland, USA. PMID- 26444460 TI - Specialty Pharmaceuticals for Hyperlipidemia--Impact on Insurance Premiums. PMID- 26444461 TI - Post-Vietnam Dioxin Exposure in Agent Orange-Contaminated C-123 Aircraft. PMID- 26444462 TI - The Interwar Period: Is There a Plan for Sustainment of Essential Skills? PMID- 26444463 TI - Palliative Care in the U.S. Military Health System. PMID- 26444464 TI - Veterans Health Administration's MOVE! Weight Management Program: Primary Care Clinicians' Perceptions of Program Implementation. AB - The Veterans Health Administration's MOVE! Program is the largest health care delivered weight loss intervention in the United States. As a referring clinician's perceptions and knowledge of health programs may impact implementation, examining perceptions of MOVE! may inform improvements to this and other programs. This study investigated primary care clinician perceptions of MOVE! (n = 754, 50% nurses). Perceived effectiveness ratings were highest for groups with 11 to 25 group members (p < 0.01) and for a combined lecture and support group format (p = 0.026), though session length and several other aspects of delivery were not associated with perceptions of effectiveness. MOVE! staff also rated the program as more effective than did other clinicians (p < 0.01). Many respondents lacked knowledge about program specifics, especially those not involved with MOVE! delivery (vs. those directly involved; p < 0.01). These findings indicate that variety in group size and format is related to perceptions of MOVE! effectiveness. Also, clinicians not involved with MOVE! may lack knowledge about the program and underestimate its effectiveness, which could negatively affect referral likelihood or enthusiasm expressed to referred patients. Findings highlight opportunities for clarifying perceptions of a weight control program among clinicians in a large health care system. PMID- 26444465 TI - Health and Health Care Service Utilization Among U.S. Veterans Denied VA Service Connected Disability Compensation: A Review of the Literature. AB - The general consensus in studies of individuals seeking federal disability compensation is that individuals "denied" disability compensation are healthier than those "awarded." In contrast, studies of military veterans seeking U.S. Department of Veterans Affairs (VA) disability compensation suggest that those "denied" ("denied applicants") may be as impaired as those "awarded" ("awarded applicants"), and likely have critical, albeit unmet health care needs. Moreover, although social isolation among U.S. Veterans has received some attention, its broad influence on health and health care consumption among veterans "denied" VA disability compensation is not well understood. OBJECTIVES: To provide a more thorough understanding of "denied" applicants' health, health care utilization, and social conditions. METHODS: We reviewed published reports of health, health care utilization, and social isolation "relevant" to U.S. Veterans "denied" VA disability compensation. Among 122 research items initially reviewed, a total of 47 met our inclusion criteria and are summarized herein. RESULTS: Compared to veterans "awarded" VA disability compensation, those "denied" have poorer health, use less VA health care, and may experience social isolation. CONCLUSIONS: Veterans "denied" VA disability compensation may comprise a vulnerable subgroup of veterans in need of supportive services. Such needs may be addressed through evidence-based targeted outreach programs. PMID- 26444467 TI - Army Active Duty Members' Linkage to Veterans Health Administration Services After Deployments to Iraq or Afghanistan and Following Separation. AB - This study described the rate and predictors of Operation Enduring Freedom/Operation Iraqi Freedom active duty Army members' enrollment in and use of Veterans Health Administration (VHA) services (linkage), as well as variation in linkage rates by VHA facility. We used a multivariate mixed effect regression model to predict linkage to VHA, and also calculated linkage rates in the catchment areas of each facility (n = 158). The sample included 151,122 active duty members who deployed to Iraq or Afghanistan and then separated from the Army between fiscal years 2008 and 2012. Approximately 48% of the active duty members separating utilized VHA as an enrollee within one year. There was significant variation in linkage rates by VHA facilities (31-72%). The most notable variables associated with greater linkage included probable serious injury during index deployment (odds ratio = 1.81), separation because of disability (odds ratio = 2.86), and various measures of receipt of VHA care before and after separation. Information about the individual characteristics that predict greater or lesser linkage to VHA services can be used to improve delivery of health care services at VHA as well as outreach efforts to active duty Army members. PMID- 26444466 TI - Mental Health Treatment Among Soldiers With Current Mental Disorders in the Army Study to Assess Risk and Resilience in Service Members (Army STARRS). AB - A representative sample of 5,428 nondeployed Regular Army soldiers completed a self-administered questionnaire (SAQ) and consented to linking SAQ data with administrative records as part of the Army Study to Assess Risk and Resilience in Service members. The SAQ included information about prevalence and treatment of mental disorders among respondents with current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) internalizing (anxiety, mood) and externalizing (disruptive behavior, substance) disorders. 21.3% of soldiers with any current disorder reported current treatment. Seven significant predictors of being in treatment were identified. Four of these 7 were indicators of psychopathology (bipolar disorder, panic disorder, post-traumatic stress disorder, 8+ months duration of disorder). Two were sociodemographics (history of marriage, not being non-Hispanic Black). The final predictor was history of deployment. Treatment rates varied between 4.7 and 71.5% depending on how many positive predictors the soldier had. The vast majority of soldiers had a low number of these predictors. These results document that most nondeployed soldiers with mental disorders are not in treatment and that untreated soldiers are not concentrated in a particular segment of the population that might be targeted for special outreach efforts. Analysis of modifiable barriers to treatment is needed to help strengthen outreach efforts. PMID- 26444468 TI - A Health Assessment Survey of Veteran Students: Utilizing a Community College Veterans Affairs Medical Center Partnership. AB - OBJECTIVE: To assess health status among student veterans at a community college utilizing a partnership between a Veterans Affairs Medical Center and a community college. PARTICIPANTS: Student veterans at Cuyahoga Community College in Cleveland, Ohio, in January to April 2013. METHODS: A health assessment survey was sent to 978 veteran students. Descriptive analyses to assess prevalence of clinical diagnoses and health behaviors were performed. Logistic regression analyses were performed to assess for independent predictors of functional limitations. RESULTS: 204 students participated in the survey (21% response rate). Self-reported depression and unhealthy behaviors were high. Physical and emotional limitations (45% and 35%, respectively), and pain interfering with work (42%) were reported. Logistic regression analyses confirmed the independent association of self-reported depression with functional limitation (odds ratio [OR] = 3.3, 95% confidence interval [CI] 1.4-7.8, p < 0.05, and C statistic 0.72) and of post-traumatic stress disorder with pain interfering with work (OR 3.9, CI 1.1-13.6, p < 0.05, and C statistic 0.75). CONCLUSION: A health assessment survey identified priority areas to inform targeted health promotion for student veterans at a community college. A partnership between a Veterans Affairs Medical Center and a community college can be utilized to help understand the health needs of veteran students. PMID- 26444469 TI - Impact of Childhood Abuse on Physical and Mental Health Status and Health Care Utilization Among Female Veterans. AB - OBJECTIVE: To determine whether childhood abuse predicts health symptoms and health care use among female veterans. METHODS: Participants were 369 female patients at Veterans Affairs hospitals in New England who completed a mail survey. Multiple regression analyses were conducted to determine the differential impact of childhood physical abuse and childhood sexual abuse on health symptoms and health care use, while accounting for age, race, military branch, and military sexual trauma (MST). RESULTS: In our sample, 109 (29%) female veterans reported experiencing childhood abuse. After adjusting for age, race, military branch, childhood sexual abuse, and MST, childhood physical abuse was predictive of poorer physical health, and greater depressive and post-traumatic stress disorder symptoms. No significant association was found between childhood sexual abuse and poor physical or mental health status. After adjusting for other factors, childhood physical abuse was associated with more frequent use of medical health care. Childhood sexual abuse was not a predictor for health care use. CONCLUSIONS: Childhood physical abuse remains an important contributor to physical health and mental health, even after adjusting for the more proximate experience of MST. Screening for adverse childhood experiences may facilitate access to appropriate physical and mental health treatment among female veterans. PMID- 26444470 TI - Humanitarian Surgical Care Provided by a French Forward Surgical Team: Ten Years of Providing Medical Support to the Population of the Ivory Coast. AB - INTRODUCTION: The aims of this study were as follows: first to quantify and review the types of surgical procedures performed by military surgeons assigned to a Forward Surgical Team (FST) providing medical support to the population (MSP) in the Ivory Coast (IC), and second to analyze how this MSP was achieved. METHODS: Between 2002 and 2012, all of the local nationals operated on by the different FSTs deployed in the IC were included in the study. The surgical activity was analyzed and divided into surgical specialties, war wounds, nonwar emergency trauma, nontrauma emergencies, and elective surgery. Demographics, circumstances of health care management, wounded organs, and types of surgical procedures were described. RESULTS: Over this period, surgeons operated on 2,315 patients and performed 2,556 procedures. Elective surgery accounted for 78.7% of the surgical activity, nontrauma emergencies accounted for 12.7%, nonwar emergency trauma accounted for 8%, and war wounds accounted for 0.6%. The main surgical activities were visceral (43.8%) and orthopedic (including soft tissues) surgeries (38.5%). CONCLUSION: The FSTs contributed widely to MSP in the IC. This MSP required limited resources, standardization of the procedures and specific skills beyond the original surgical specialties of military surgeons to fulfill the needs of the local population. PMID- 26444471 TI - Falls in a Young Active Amputee Population: A Frequent Cause of Rehospitalization? AB - Falls occur in up to 50% of amputees within a single year of their operation and up to 40% of these falls result in injury. However, there is a lack of data evaluating falls in a young, active amputee population despite an estimated 58% of persons living with an amputation being under the age of 65. The authors evaluated an amputee population (n = 393) with a mean age of 25.53 years. Overall incidence, prevalence, fall characteristics, and risk factors were calculated for falls resulting in rehospitalization. An incidence of 1.92 per 1,000 person years with a prevalence of 2.04% was found with 87.5% occurring within the first 6 months following definitive amputation. Of the patients rehospitalized, 75% required at least 1 surgical procedure. Infectious complications had the most significant morbidity requiring a mean of 5 operative procedures. Those that delayed evaluation (mean = 13 days) vs. those that presented 0 to 1 day from a fall were significantly more at risk of an infectious complication (p = 0.03). This study is the first to report such a relationship, and emphasizes the need for at-risk patients to seek early medical attention as this may minimize the risk of infection and obviate the need for surgical intervention. PMID- 26444472 TI - The Use of Intravenous Tranexamic Acid in Patients Undergoing Total Hip or Knee Arthroplasty: A Retrospective Analysis at a Single Military Institution. AB - OBJECTIVE: To describe a single institution's experience after initiation of a protocol in which all primary total hip arthroplasty (THA) and total knee arthroplasty (TKA) patients were administered intravenous tranexamic acid (TXA) intraoperatively to decrease perioperative blood loss. METHODS: A retrospective review of medical records at a single institution from February 2012 to April 2014. The TXA treatment group was compared to a control group. We reviewed intraoperative blood loss, preoperative hemoglobin (Hb) levels, postoperative day 0 to 2 Hb levels, transfusion rates, postoperative venous thromboembolism, and other complication rates. RESULTS: 259 patients underwent either TKA (165) or THA (94). 121 received perioperative intravenous TXA and 138 did not. There was a statistically decreased rate of allogeneic blood transfusion (0 vs. 10, p = 0.003) as well as a higher postoperative day 2 Hb level (10.8 +/- 1.1 vs. 10.2 +/ 2.6 g/dL, p = 0.02) in the treatment group. There was no statistical difference in any variable measured in the THA group, though there was a trend toward higher postoperative Hb levels at all-time points measured. CONCLUSION: Intravenous TXA is a safe and effective drug to decrease perioperative blood loss and allogeneic transfusion in THA and TKA. There was no increased risk of venous thromboembolism or other complications in our review. PMID- 26444473 TI - Impact of a Diabetes Risk Score on Lifestyle Education and Patient Adherence (IDEA) in Prediabetes: A Multisite Randomized Controlled Trial. AB - BACKGROUND: To evaluate whether knowledge of a personalized Diabetes Risk Score (DRS) improved performance in a 12-week lifestyle change program for prediabetes. METHODS: Randomized subjects at four clinics provided samples for a DRS at baseline, 12, and 24 weeks. The intervention group received scores at each point, whereas the control group only received this information at 12 and 24 weeks. Outcomes included attendance and changes in weight, abdominal circumference, blood pressure, fasting glucose, hemoglobin A1c, cholesterol, and risk score. RESULTS: Baseline characteristics were similar in the groups (n = 192) and within risk-stratified subgroups. At 12 weeks, there were no differences in outcomes, with mean weight loss of 4.61 kg in the intervention group and 4.43 kg in the control group (p = 0.79). Both groups were given 12-week risk scores, with previously unseen baseline scores for the control group. The control group continued to lose additional weight (1.21 kg) by 24 weeks, whereas the intervention group regained previously lost weight (0.33 kg) (p = 0.04). CONCLUSIONS: The knowledge of a single baseline personalized DRS did not affect performance in a lifestyle modification program. However, the knowledge of an improvement in risk score, and the timing of this information, may impact further adherence. PMID- 26444474 TI - Effectiveness of a Dental Unit Waterline Treatment Protocol With A-Dec ICX and Citrisil Disinfectants. AB - This study evaluated the effectiveness of a Dental Unit Waterline disinfection protocol utilizing two waterline disinfectant tablets in a dental treatment clinic. The water effluent from 47 dental treatment units was sampled to determine bacterial load. Four dental treatment units were shocked with the multivalent Sterilex Ultra liquid biocide, followed by a 5-week course of routine disinfection using either the A-dec ICX or Citrisil effervescing tablets. Aseptic samples were taken twice weekly, and bacterial load was determined. No significant difference was found when comparing A-dec ICX with Citrisil, but a significant difference was seen between the use of either tablet and no tablet. In addition, a survey was conducted to evaluate the effect of user compliance on infection control. The results indicate that proper training, coupled with the use of appropriate disinfectants and shock treatment, are important aspects of maintaining low bacterial burden in dental water lines. PMID- 26444475 TI - "Angels in Army Drab": The Medical Specialists Corps and COL Emma Vogel. PMID- 26444476 TI - Neurotherapy of Traumatic Brain Injury/Post-Traumatic Stress Symptoms in Vietnam Veterans. AB - Previous report suggested the beneficial effects of an adaptation of the Flexyx Neurotherapy System (FNS) for the amelioration of mixed traumatic brain injury/post-traumatic stress symptoms in veterans of the Afghanistan and Iraq wars. As a novel variant of electroencephalograph biofeedback, FNS falls within the bioenergy domain of complementary and alternative medicine. Rather than learning voluntary control over the production/inhibition of brain wave patterns, FNS involves offsetting stimulation of brain wave activity by means of an external energy source, specifically, the conduction of electromagnetic energy stimulation via the connecting electroencephalograph cables. Essentially, these procedures subliminally induce strategic distortion of ongoing brain wave activity to presumably facilitate resetting of more adaptive patterns of activity. Reported herein are two cases of Vietnam veterans with mixed traumatic brain injury/post-traumatic stress symptoms, each treated with FNS for 25 sessions. Comparisons of pre- and post-treatment questionnaire assessments revealed notable decreases for all symptoms, suggesting improvements across the broad domains of cognition, pain, sleep, fatigue, and mood/emotion, including post-traumatic stress symptoms, as well as for overall activity levels. Findings suggest FNS treatment may be of potential benefit for the partial amelioration of symptoms, even in some individuals for whom symptoms have been present for decades. PMID- 26444477 TI - Surgical Management of Symptomatic Extensor Digitorum Brevis Manus: A Proposed Algorithm for Treatment. AB - First described in 1734, the extensor digitorum brevis manus (EDBM) is an anomalous extensor muscle found in the dorsum of the wrist and hand. Extensor muscle variants of the hand are not uncommon, and EDBM has an estimated reported incidence of approximately 2%. Although few extensor muscle variants become clinically significant, there is a paucity of literature discussing these anatomic variants, with most reports arising from cadaveric studies or isolated case series. Similarly, there are few established indications for surgical treatment of EDBM. In this case report, we describe the successful treatment of a young patient with persistently symptomatic anomalous extensor tendon with surgical excision and propose an algorithm for management after failure of conservative measures. PMID- 26444478 TI - Percutaneous Drainage of a Rapidly Enlarging Simple Ovarian Cyst in the Third Trimester. AB - BACKGROUND: Persistent adnexal masses increase the risk of pregnancy complications including cyst rupture, ovarian torsion, and labor obstruction. Treatment options include observation, surgical excision, and early first or second trimester drainage. Our case represents the most advanced gestational age for intervention with percutaneous drainage. CASE: A 32-year old G3P1102 at 29.2 weeks gestation presented with left lower quadrant pressure, right abdominal fullness, and left uterine displacement. She had a right, simple-appearing ovarian cyst, which had increased in size from previous ultrasounds to 12.8 * 13.4 * 15.7 cm. Ultrasound-guided percutaneous drainage with pigtail catheter placement removed 1.2 L serous green fluid. Fluid culture was negative and cytology showed no evidence of malignancy. The pigtail catheter was removed at 31.2 weeks because of pain at the surgical site and significant cyst regression. The cyst resolved and she delivered via uncomplicated vaginal delivery at term. CONCLUSION: A few case reports describe first and second trimester percutaneous or transvaginal drainage of symptomatic ovarian cysts as a less invasive approach than surgical excision. However, our case suggests drainage of a simple-appearing cyst as an alternative treatment option in the third trimester when the risk of preterm labor and fetal complications with surgical intervention is at its highest. PMID- 26444479 TI - Immunocompetent, Immunized Male With Mumps, Complicated by Orchitis and Meningitis. AB - Mumps is a rare pathology often not encountered in the emergency department setting. It is an especially unusual finding in a fully immunized individual. We present a case of a 26-year-old Army active duty male who was evaluated in the emergency department for mumps over the course of two visits. The military population is presumed fully immunized and immunocompetent, travels widely and often lives in close quarters. This case highlights the importance for providers to consider such a disease that carries a risk of significant morbidity, and rarely, mortality. A literature review was performed evaluating mumps in the vaccinated population. PMID- 26444480 TI - Fluticasone as Treatment for Cluster Headaches in a Navy Aircrew Member. AB - Cluster headaches (CHs) are one of the most debilitating of all the identified headache syndromes. Their pathogenesis is poorly understood, which has made their treatment challenging. Various medicines and modalities have been put forth in an effort to minimize the symptoms, but none have proven to be consistently reliable. For the active duty military aviator with CHs, this is further compounded by the administrative restrictions to use many of those medications secondary to their unwanted and potentially dangerous side effects. We present a case of refractory CH in an active duty air crewman, treated with fluticasone, which resulted in a remarkable reduction in symptoms allowing him to resume his primary flight duties. We propose that fluticasone's effectiveness in improving his CH symptoms stems from its anti-inflammatory properties. PMID- 26444481 TI - A Case of Superior Mesenteric Artery Syndrome in a Healthy Active Duty Marine. AB - Superior mesenteric artery (SMA) syndrome is an uncommon disorder that can lead to small bowel obstructions or perforations. Typical populations include young females with anorexia. However, there have been a few reports of healthy males with acute vomiting reported to have SMA syndrome. Our case report highlights an active duty Marine who developed SMA syndrome and the importance of recognizing this disease given the severity in delay of diagnosis in population of young healthy active duty members. PMID- 26444482 TI - What to Do When the Inhaler Fails: Revisiting the Diagnosis. AB - Paradoxical vocal fold movement is important to consider in the differential for dyspnea on exertion or shortness of breath. It is often confused with asthma and remains undiagnosed because of a paucity of pathognomonic examination and imaging findings. This case serves as a reminder of the specific clinical picture, diagnosis, and treatment of paradoxical vocal fold movement. It also highlights the broader importance of continuity of care and the clinician's ability to revisit the differential diagnosis if an initial workup is unrevealing or the patient is not responding to treatment. PMID- 26444483 TI - Manual Therapy for Chronic Low Back Pain in an F-5 Pilot. AB - INTRODUCTION: Low back pain (LBP) in the aviator can be a significant safety risk because of distraction during flight. Flight Surgeons are tasked with seeking out appropriate medical care that reduces pilot risk while providing squadron specific mission support. CASE: An F-5 pilot presented with chronic LBP seeking nonpharmacological and noninvasive therapy. After 3 days of manual treatment that corrected sacral, pelvic, and lumbar dysfunction, this pilot reported greater than 80% reduction in overall pain and was able to return to flight. DISCUSSION: Although underreported, a radiographic study and multiple case reports, identify LBP as a significant problem among tactical air (tac air) pilots. As such, LBP can become an in-flight distraction increasing the risk of a mishap. Benefits of osteopathic manipulative therapy (OMT) as an adjunct to treatment of LBP in civilian population were recently demonstrated. This case identified a tac air pilot with chronic LBP that responded to three OMT sessions focused at the sacrum, lumbar, and pelvis. CONCLUSION: The use of manual therapy in the form of OMT significantly reduced this pilot's pain in three visits and maintained flight status per aeromedical waiver guidelines. PMID- 26444484 TI - Trichobezoars Detected and Treated Based on Plain Radiography. AB - Bezoars are conglomerations of indigestible material that become trapped in the gastrointestinal tract. We present a case of an 8-year-old female child diagnosed with a gastric bezoar solely on plain radiography and treated with abdominal surgical exploration and removal. In addition, traditional characteristic radiographic findings and treatment options for bezoars found in the current literature are reviewed. PMID- 26444485 TI - Application of platelet/lymphocyte and neutrophil/lymphocyte ratios in early diagnosis and prognostic prediction in patients with resectable gastric cancer. AB - BACKGROUND: Gastric cancer is the fourth most frequent cancer and the second cause of cancer-related deaths worldwide. China has a high incidence of gastric cancer. Inflammation is a critical component of tumor progression. It has been widely accepted that gastric cancer is an inflammation-driven cancer. In this study, we investigated the application value of systemic inflammatory response (SIR) markers, platelet to lymphocyte ratio (PLR) and neutrophil to lymphocyte ratio (NLR), in early diagnosis and prognostic prediction in patients with resectable gastric cancer. MATERIALS AND METHODS: One hundred and sixty-two patients with resectable gastric cancer were included and separated into groups according to median pre-operative PLR or NLR values (PLR low: < 208 or PLR high: >= 208, and NLR low: < 4.02 or NLR high: >= 4.02, respectively). To evaluate the changes in PLR or NLR values after operation, we introduced the concept of postpre-operative PLR or NLR ratios (< 1 indicated PLR or NLR values were decreased after operation, while >= 1 suggested not decreased PLR or NLR values). RESULTS: Pre-operative PLR and NLR levels were significantly higher in gastric cancer patients compared with the healthy subjects. Low pre-operative PLR and NLR levels correlated with better clinicopathological features, including decreased depth of invasion, less lymph node metastasis and early tumor stage. Kaplan-Meier plots illustrated that higher pre-operative NLR and PLR had decreased overall survival (OS) and disease-free survival (DFS). Surgical tumor resection resulted in a significant CONCLUSIONS: PLR and NLR measurements can provide important diagnostic and prognostic results in patients with resectable gastric cancer. PMID- 26444486 TI - Pyrolysis characteristics and pyrolysis products separation for recycling organic materials from waste liquid crystal display panels. AB - Waste liquid crystal display (LCD) panels mainly contain inorganic materials (glass substrate with indium-tin oxide film), and organic materials (polarizing film and liquid crystal). The organic materials should be removed beforehand since the organic matters would hinder the indium recycling process. In the present study, pyrolysis process is used to remove the organic materials and recycle acetic as well as and triphenyl phosphate (TPP) from waste LCD panels in an environmental friendly way. Several highlights of this study are summarized as follows: (i) Pyrolysis characteristics and pyrolysis kinetics analysis are conducted which is significant to get a better understanding of the pyrolysis process. (ii) Optimum design is developed by applying Box-Behnken Design (BBD) under response surface methodology (RSM) for engineering application which is significant to guide the further industrial recycling process. The oil yield could reach 70.53 wt% and the residue rate could reach 14.05 wt% when the pyrolysis temperature is 570 degrees C, nitrogen flow rate is 6 L min(-1) and the particle size is 0.5 mm. (iii) Furthermore, acetic acid and TPP are recycled, and then separated by rotary evaporation, which could reduce the consumption of fossil energy for producing acetic acid, and be reused in electronics manufacturing industry. PMID- 26444487 TI - Defect creation in metal-organic frameworks for rapid and controllable decontamination of roxarsone from aqueous solution. AB - Given the great harm to the human health of organic arsenic compounds (OACs), developing highly efficient adsorbents with both rapid adsorption rate and high saturation capacity is paramount important. Herein, Zr-based metal-organic frameworks (MOFs) of UiO-66 have been successfully exploited for the efficient decontamination of a typical organic arsenic compound of roxarsone (ROX) from aqueous solution. The influences of the most significant parameters such as contact time, adsorbate concentration, pH as well as ionic strength on the adsorption of ROX were investigated. The amount of missing-linker defects in UiO 66 was systematically tuned by changing the concentration of modulator in the reactants. The presence of the defects not only resulted in the dramatically enhanced porosity, but also induced the creation of ZrOH groups which served as the main active adsorption sites for efficient ROX sequestration. As a result, adsorptive capacity of ROX over UiO-66 could be improved to 730 mg/g, which was much higher than those of many reported adsorbents. Meanwhile, the adsorption equilibrium time could be reduced to as short as 30 min. These merits, combined with their excellent stability, prefigure the great potentials of these defect tunable UiO-66 MOFs as adsorbents for the efficient removal of various OACs from the polluted water. PMID- 26444488 TI - Organic acids enhanced decoloration of azo dye in gas phase surface discharge plasma system. AB - A gas phase surface discharge plasma combined with organic acids system was developed to enhance active species mass transfer and dye-containing wastewater treatment efficacy, with Acid Orange II (AO7) as the model pollutant. The effects of discharge voltage and various organic acid additives (acetic acid, lactic acid and nonoic acid) on AO7 decoloration efficiency were evaluated. The experimental results showed that an AO7 decoloration efficiency of approximately 69.0% was obtained within 4 min of discharge plasma treatment without organic acid addition, which was improved to 82.8%, 83.5% and 88.6% within the same treatment time with the addition of acetic acid, lactic acid and nonoic acid, respectively. The enhancement effects on AO7 decoloration efficiency could be attributed to the decrease in aqueous surface tension, improvement in bubble distribution and shape, and increase in ozone equivalent concentration. The AO7 wastewater was biodegradable after discharge plasma treatment with the addition of organic acid. AO7 decomposition intermediates were analyzed by UV-vis spectrometry and GC-MS; 2 naphthol, 1,4-benzoquinone, phthalic anhydride, coumarin, 1,2-naphthoquinone, and 2-formyl-benzoic acid were detected. A possible pathway for AO7 decomposition in this system was proposed. PMID- 26444489 TI - Risk assessment of persistent pharmaceuticals in biosolids: Dealing with uncertainty. AB - A screening-level risk assessment of biosolids-borne PPCPs in agricultural scenarios was developed in this work. While several of these compounds are efficiently removed in sewage treatment plants (STPs), others are recalcitrant to degradation and can be found in sludge at significant levels. As the rate of biosolids reuse for fertilising and/or amendment purposes is increasing, it is necessary to evaluate the fate in soil and possible biotransfer of this type of pollutants in the long-term. The study includes six compounds that were selected considering data availability, presence in sludge and persistence. Due to the scarce data still present in literature, a probabilistic assessment to address uncertainty was developed. A 95th percentile of the hazard index (HI) exceeding 1 was obtained, with main contributions of triclosan and carbamazepine. Although these estimates were obtained under a worst-case approach, and that they can vary depending on scenario characteristics, they change the least-concern classification associated to the presence of PPCPs in biosolids. A sensitivity analysis indicates the high influence of application rate and sludge concentration level on the results. Thus, the importance of developing new strategies of removal in advanced STPs and the establishment of a specific biosolids reuse regulation including this type of compounds acquires an added significance. PMID- 26444490 TI - Ligand Discovery for the Alanine-Serine-Cysteine Transporter (ASCT2, SLC1A5) from Homology Modeling and Virtual Screening. AB - The Alanine-Serine-Cysteine transporter ASCT2 (SLC1A5) is a membrane protein that transports neutral amino acids into cells in exchange for outward movement of intracellular amino acids. ASCT2 is highly expressed in peripheral tissues such as the lung and intestines where it contributes to the homeostasis of intracellular concentrations of neutral amino acids. ASCT2 also plays an important role in the development of a variety of cancers such as melanoma by transporting amino acid nutrients such as glutamine into the proliferating tumors. Therefore, ASCT2 is a key drug target with potentially great pharmacological importance. Here, we identify seven ASCT2 ligands by computational modeling and experimental testing. In particular, we construct homology models based on crystallographic structures of the aspartate transporter GltPh in two different conformations. Optimization of the models' binding sites for protein-ligand complementarity reveals new putative pockets that can be targeted via structure-based drug design. Virtual screening of drugs, metabolites, fragments-like, and lead-like molecules from the ZINC database, followed by experimental testing of 14 top hits with functional measurements using electrophysiological methods reveals seven ligands, including five activators and two inhibitors. For example, aminooxetane-3-carboxylate is a more efficient activator than any other known ASCT2 natural or unnatural substrate. Furthermore, two of the hits inhibited ASCT2 mediated glutamine uptake and proliferation of a melanoma cancer cell line. Our results improve our understanding of how substrate specificity is determined in amino acid transporters, as well as provide novel scaffolds for developing chemical tools targeting ASCT2, an emerging therapeutic target for cancer and neurological disorders. PMID- 26444491 TI - A novel UHPLC method for the rapid and simultaneous determination of daidzein, genistein and equol in human urine. AB - This work reports on a novel method involving reverse-phased ultra-high performance liquid chromatography (UHPLC) plus a spectrophotometric photodiode array/fluorescence (FLR) detection system for determining the concentration of equol and major soy isoflavones (daidzein and genistein) in human urine. The proposed method was validated in terms of its linearity, sensitivity, accuracy (recovery) and precision (intra- and inter-day repeatability). The isoflavone profiles of urine samples from a group of menopausal women following oral soy isoflavone supplementation were determined and compared. Screening for equol producer status was accomplished with high sensitivity (detection limit of the FLR detector 2.93nM). The method involves a short chromatographic run time compared to conventional HPLC methods while allowing for the simultaneous and reliable quantification of daidzein, genistein and equol in human urine. It also allows for the rapid screening of multiple urine samples when testing for equol production status and checking patient adherence to isoflavone treatment regimens. PMID- 26444492 TI - Structure and Biogenesis of Roussoellatide, a Dichlorinated Polyketide from the Marine-Derived Fungus Roussoella sp. DLM33. AB - The structure of the fungal metabolite roussoellatide (1) has been established by spectroscopic and X-ray diffraction analyses. Results from feeding experiments with [1-(13)C]acetate, [2-(13)C]acetate, and [1,2-(13)C]acetate were consistent with a biosynthetic pathway to the unprecedented skeleton of 1 involving Favorskii rearrangements in separate pentaketides, subsequently joined via an intermolecular Diels-Alder reaction. PMID- 26444493 TI - Long-term Cosmetic Alignment Following Surgery for Esotropia Versus Exotropia in Childhood: A Comparison Using Survival Curves. AB - PURPOSE: Although long-term results following repair of esotropia and exotropia in childhood have been reported, the two entities have never been directly compared. METHODS: Records of all children younger than 18 years who underwent horizontal strabismus surgery from 2000 through 2012 were reviewed. Children with structural eye pathology, severe vision loss, neurologic disorders, and incomitant or combined horizontal and vertical deviations were excluded. Failure was defined by a second horizontal surgery or a primary position deviation greater than 20 prism diopters (PD) at any time during follow-up (as long as 10 years). A threshold of 20 PD was chosen because families often consider deviations important enough to warrant a first or second surgery if it is larger but not if it is smaller. RESULTS: Of 317 children, 235 with esotropia had surgery at a mean age of 42 months and 82 with exotropia had surgery at a mean age of 60 months. Overall, surgery was successful in 78% of those with esotropia and 65% of those with exotropia. A second surgery was performed in 29 (12%) of those with esotropia and 15 (18%) of those with exotropia. The mean deviation at last follow-up, using absolute values, was 9 PD for esotropia and 10 PD for exotropia. Survival curve success was better for esotropia (P = .008). CONCLUSION: By survival curve analysis, success was more likely among children with esotropia. Many "failures" slipped beyond the 20 PD threshold only transiently and had deviations that were not noticeable to family or friends. Overall, children did reasonably well long-term following surgery for both esotropia and exotropia. Only 14% of the entire group required a second surgery during an average of 41 months of follow-up. PMID- 26444495 TI - Time evolution within a comoving window: scaling of signal fronts and magnetization plateaus after a local quench in quantum spin chains. AB - We present a modification of Matrix Product State time evolution to simulate the propagation of signal fronts on infinite one-dimensional systems. We restrict the calculation to a window moving along with a signal, which by the Lieb-Robinson bound is contained within a light cone. Signal fronts can be studied unperturbed and with high precision for much longer times than on finite systems. Entanglement inside the window is naturally small, greatly lowering computational effort. We investigate the time evolution of the transverse field Ising (TFI) model and of the S = 1/2 XXZ antiferromagnet in their symmetry broken phases after several different local quantum quenches. In both models, we observe distinct magnetisation plateaus at the signal front for very large times, resembling those previously observed for the particle density of tight binding (TB) fermions. We show that the normalised difference to the magnetisation of the ground state exhibits similar scaling behaviour as the density of TB fermions. In the XXZ model there is an additional internal structure of the signal front due to pairing, and wider plateaus with tight binding scaling exponents for the normalised excess magnetisation. We also observe parameter dependent interaction effects between individual plateaus, resulting in a slight spatial compression of the plateau widths. In the TFI model, we additionally find that for an initial Jordan-Wigner domain wall state, the complete time evolution of the normalised excess longitudinal magnetisation agrees exactly with the particle density of TB fermions. PMID- 26444494 TI - An LSC epigenetic signature is largely mutation independent and implicates the HOXA cluster in AML pathogenesis. AB - Acute myeloid leukaemia (AML) is characterized by subpopulations of leukaemia stem cells (LSCs) that are defined by their ability to engraft in immunodeficient mice. Here we show an LSC DNA methylation signature, derived from xenografts and integration with gene expression that is comprised of 71 genes and identifies a key role for the HOXA cluster. Most of the genes are epigenetically regulated independently of underlying mutations, although several are downstream targets of epigenetic modifier genes mutated in AML. The LSC epigenetic signature is associated with poor prognosis independent of known risk factors such as age and cytogenetics. Analysis of early haematopoietic progenitors from normal individuals reveals two distinct clusters of AML LSC resembling either lymphoid primed multipotent progenitors or granulocyte/macrophage progenitors. These results provide evidence for DNA methylation variation between AML LSCs and their blast progeny, and identify epigenetically distinct subgroups of AML likely reflecting the cell of origin. PMID- 26444496 TI - Rapid, Regioconvergent, Solvent-Free Alkene Hydrosilylation with a Cobalt Catalyst. AB - Alkene hydrosilylation is typically performed with Pt catalysts, but inexpensive base-metal catalysts would be preferred. We report a Co catalyst for anti Markovnikov alkene hydrosilylation that can be used without added solvent at low temperatures with low loadings, and can be generated in situ from an air-stable precursor that is simple to synthesize from low-cost, commercially available materials. In addition, a mixture of Co catalysts performs a tandem catalytic alkene isomerization/hydrosilylation reaction that converts multiple isomers of hexene to the same terminal product. This regioconvergent reaction uses isomerization as a benefit rather than a hindrance. PMID- 26444497 TI - Role of Fluorophore Charge on the In Vivo Optical Imaging Properties of Near Infrared Cyanine Dye/Monoclonal Antibody Conjugates. AB - Near-infrared (NIR) fluorophores have several advantages over visible-light fluorophores, including superior light penetration in tissue and lower autofluorescence. We recently demonstrated that a new class of NIR cyanine dyes containing a novel C4'-O-alkyl linker exhibit greater chemical stability and excellent optical properties relative to existing C4'-O-aryl variants. We synthesized two NIR cyanine dyes with the same core structure but different indolenine substituents: FNIR-774 bearing four sulfonate groups and FNIR-Z-759 bearing a combination of two sulfonates and two quaternary ammonium cations, resulting in an anionic (-3) or monocationic (+1) charge, respectively. In this study, we compare the in vitro and in vivo optical imaging properties of monoclonal antibody (mAb) conjugates of FNIR-774 and FNIR-Z-759 with panitumumab (pan) at antibody-to-dye ratios of 1:2 or 1:5. Conjugates of both dyes demonstrated similar quenching capacity, stability, and brightness in target cells in vitro. However, FNIR-Z-759 conjugates showed significantly lower background in mice, resulting in higher tumor-to-background ratio. Thus, FNIR-Z 759 conjugates appear to have superior in vivo imaging characteristics compared with FNIR-774 conjugates, especially in the abdominal region, regardless of the dye-mAb ratio. These results suggest that zwitterionic cyanine dyes are a promising class of fluorophores for improving in vivo optical imaging with antibody-NIR dye conjugates. PMID- 26444498 TI - Aromatic C-H Bond Functionalization Induced by Electrochemically in Situ Generated Tris(p-bromophenyl)aminium Radical Cation: Cationic Chain Reactions of Electron-Rich Aromatics with Enamides. AB - An effective Friedel-Crafts alkylation reaction of electron-rich aromatics with N vinylamides, induced by electrochemically in situ-generated TBPA radical cation, has been developed; the resulting adducts are produced in good to excellent yields. In the "ex-cell" type electrolysis, TBPA is transformed to its oxidized form in situ and subsequently employed as an electron transfer reagent to initiate a cationic chain reaction. An easily recoverable and reusable polymeric ionic liquid-carbon black (PIL-CB) composite was also utilized as a supporting electrolyte for the electrochemical generation of TBPA cation radical, without sacrificing efficiency or stability after four electrolyses. Cyclic voltammetry analysis and the results of control experiments demonstrate that the reaction of electron-rich aromatics and N-vinylamides occurs via a cationic chain reaction, which takes place though an oxidative activation of a C-H bond of electron-rich aromatics instead of oxidation of the N-vinylamide as previously assumed. PMID- 26444499 TI - Theoretical Investigation of Intramolecular Hydrogen Shift Reactions in 3 Methyltetrahydrofuran (3-MTHF) Oxidation. AB - 3-Methyltetrahydrofuran (3-MTHF) is proposed to be a promising fuel component among the cyclic oxygenated species. To have detailed insight of its combustion kinetics, intramolecular hydrogen shift reactions for the ROO to QOOH reaction class are studied for eight ROO isomers of 3-MTHF. Rate constants of all possible reaction paths that involve formation of cyclic transition states are computed by employing the CBS-QB3 composite method. A Pitzer-Gwinn-like approximation has been applied for the internal rotations in reactants, products, and transition states for the accurate treatment of hindered rotors. Calculated relative barrier heights highlight that the most favorable reaction channel proceeds via a six membered transition state, which is consistent with the computed rate constants. Comparing total rate constants in ROO isomers of 3-MTHF with the corresponding isomers of methylcyclopentane depicts faster kinetics in 3-MTHF than methylcyclopentane reflecting the effect of ring oxygen on the intramolecular hydrogen shift reactions. PMID- 26444501 TI - Newsletter: President's Message. PMID- 26444500 TI - The J-Curve in HIV: Low and Moderate Alcohol Intake Predicts Mortality but Not the Occurrence of Major Cardiovascular Events. AB - OBJECTIVES: In HIV-negative populations, light-to-moderate alcohol consumption is associated with a lower cardiovascular morbidity and mortality than alcohol abstention. Whether the same holds true for HIV-infected individuals has not been evaluated in detail. DESIGN: Cohort study. METHODS: Adults on antiretroviral therapy in the Swiss HIV Cohort Study with follow-up after August 2005 were included. We categorized alcohol consumption into: abstention or very low (<1 g/d), low (1-9 g/d), moderate (10-29 g/d in women and 10-39 g/d in men), and high alcohol intake. Cox proportional hazards models were used to describe the association between alcohol consumption and cardiovascular disease-free survival (combined endpoint), cardiovascular disease events (CADE) and overall survival. Baseline and time-updated risk factors for CADE were included in the models. RESULTS: Among 9741 individuals included, there were 788 events of major CADE or death during 46,719 patient-years of follow-up, corresponding to an incidence of 1.69 events/100 person-years. Follow-up according to alcohol consumption level was 51% no or very low, 20% low, 23% moderate, and 6% high intake. As compared with no or very low alcohol intake, low (hazard ratio 0.79, 95% confidence interval 0.63 to 0.98) and moderate alcohol intakes (0.78, 0.64 to 0.95) were associated with a lower incidence of the combined endpoint. There was no significant association between alcohol consumption and CADE. CONCLUSIONS: Compared with no or very low alcohol consumption, low and moderate intake associated with a better CADE-free survival. However, this result was mainly driven by mortality and the specific impact of drinking patterns and type of alcoholic beverage on this outcome remains to be determined. PMID- 26444502 TI - Publish and Perish? PMID- 26444503 TI - Letter to the Editor. PMID- 26444504 TI - Letter to the Editor. PMID- 26444505 TI - Point of Care Testing: Ensuring Accuracy. PMID- 26444506 TI - A Critique of the Short Test of Functional Health Literacy in Adults. AB - Effective healthcare relies on the ability to communicate with patients. Ninety eight million Americans are estimated to have limited health literacy that can impair their ability to read and interpret health-related education and information. Low health literacy is associated with higher mortality and 30-day hospital readmissions. Clinical nurse specialists and other advanced practice nurses must be able to evaluate and select a health literacy assessment instrument that is both reliable and produces valid data for the populations they serve. To assist with this important decision-making process, the psychometric properties of the Short Test of Functional Health Literacy in Adults are critiqued in the following article. PMID- 26444507 TI - Prescribing Sunshine: Evidence for Vitamin D Supplements. PMID- 26444508 TI - beta-Adrenergic Blockers for Perioperative Cardiac Risk Reduction in People Undergoing Vascular Surgery (Review). PMID- 26444509 TI - Setting Motivation Into Motion. PMID- 26444510 TI - Restraint Reduction, Restraint Elimination, and Best Practice: Role of the Clinical Nurse Specialist in Patient Safety. AB - PURPOSE: Baseline restraint prevalence for surgical step-down unit was 5.08%, and for surgical intensive care unit, it was 25.93%, greater than the National Database of Nursing Quality Indicators (NDNQI) mean. Project goal was sustained restraint reduction below the NDNQI mean and maintaining patient safety. BACKGROUND/RATIONALE: Soft wrist restraints are utilized for falls reduction and preventing device removal but are not universally effective and may put patients at risk of injury. Decreasing use of restrictive devices enhances patient safety and decreases risk of injury. DESCRIPTION: Phase 1 consisted of advanced practice nurse-facilitated restraint rounds on each restrained patient including multidisciplinary assessment and critical thinking with bedside clinicians including reevaluation for treatable causes of agitation and restraint indications. Phase 2 evaluated less restrictive mitts, padded belts, and elbow splint devices. Following a 4-month trial, phase 3 expanded the restraint initiative including critical care requiring education and collaboration among advanced practice nurses, physician team members, and nurse champions. EVALUATION AND OUTCOMES: Phase 1 decreased surgical step-down unit restraint prevalence from 5.08% to 3.57%. Phase 2 decreased restraint prevalence from 3.57% to 1.67%, less than the NDNQI mean. Phase 3 expansion in surgical intensive care units resulted in wrist restraint prevalence from 18.19% to 7.12% within the first year, maintained less than the NDNQI benchmarks while preserving patient safety. INTERPRETATION/CONCLUSION: The initiative produced sustained reduction in acute/critical care well below the NDNQI mean without corresponding increase in patient medical device removal. IMPLICATIONS: By managing causes of agitation, need for restraints is decreased, protecting patients from injury and increasing patient satisfaction. Follow-up research may explore patient experiences with and without restrictive device use. PMID- 26444511 TI - Building a Unit-Level Mentored Program to Sustain a Culture of Inquiry for Evidence-Based Practice. AB - PURPOSE: This study tested the effectiveness of a dynamic educational and mentoring program, facilitated by unit-level mentors, to introduce, promote, and sustain an evidence-based practice (EBP) culture among nurses in a military healthcare setting. BACKGROUND: The need to identify gaps in practice, apply principles of EBP, and advance scientific applications in the pursuit of quality nursing care is as important to military healthcare as it is in the civilian sector. DESCRIPTION: The Advancing Research through Close Collaboration Model guided the intervention and study. Three instruments were used: the Organizational Readiness for System-wide Integration of Evidence-Based Practice, EBP Beliefs, and EBP Implementation scales. The study took place in 3 military hospitals simultaneously undergoing facility and staff integration. Data were collected from staff nurses in the inpatient nursing units before and after a facilitated education and mentoring intervention. OUTCOME: Three hundred sixty nurses (38%) completed baseline, and 325 (31%) completed follow-up surveys. Scores improved on all 3 measures following implementation of the program; however, the differences were statistically significant only for the Organizational Readiness for System-wide Integration of Evidence-Based Practice scale (70.96 vs 77.63, t = -3.95, P < .01). In the paired individual pretest/posttest subsample (n = 56), scores improved significantly on all 3 instruments. CONCLUSIONS: Despite typically high turnover rates of military personnel and restructuring of 3 facilities during the study period, the readiness for, beliefs about, and implementation of EBP improved. This study suggests that a commitment to an EBP culture may diffuse among individuals in an organization, even while experiencing significant change. It also demonstrates that a unit-level mentored EBP program is sustainable despite changes in organizational structure and workforce composition. PMID- 26444512 TI - A Business Case Framework for Planning Clinical Nurse Specialist-Led Interventions. AB - PURPOSE: The purpose of this article is to describe a business case framework that can guide clinical nurse specialists (CNS) in clinical intervention development. BACKGROUND: Increased emphasis on cost-effective interventions in healthcare requires skills in analyzing the need to make the business case, especially for resource-intensive interventions. This framework assists the CNS to anticipate resource use and then consider if the intervention makes good business sense. BUSINESS CASE FRAMEWORK: We describe a business case framework that can assist the CNS to fully explore the problem and determine if developing an intervention is a good investment. We describe several analyses that facilitate making the business case to include the following: problem identification and alignment with strategic priorities, needs assessment, stakeholder analysis, market analysis, intervention implementation planning, financial analysis, and outcome evaluation. The findings from these analyses can be used to develop a formal proposal to present to hospital leaders in a position to make decisions. By aligning intervention planning with organizational priorities and engaging patients in the process, interventions will be more likely to be implemented in practice and produce robust outcomes. CONCLUSION: The business case framework can be used to justify to organization decision makers the need to invest resources in new interventions that will make a difference for quality outcomes as well as the financial bottom line. This framework can be used to plan interventions that align with organizational strategic priorities, plan for associated costs and benefits, and outcome evaluation. IMPLICATIONS FOR CNS PRACTICE: Clinical nurse specialists are well positioned to lead clinical intervention projects that will improve the quality of patient care and be cost effective. To do so requires skill development in making the business case. PMID- 26444513 TI - Michael Verde's Memory Bridge: A Beacon of Hope for People Living With Dementia and Those Who Care for Them. PMID- 26444514 TI - Outcomes of Clinical Nurse Specialist Role Transformation to Population-Focused Model. AB - PURPOSE/OBJECTIVES: In 2010, our comprehensive cancer center developed a professional practice model where the clinical nurse specialist role was transformed to proactively plan and facilitate evidence-based best practices in collaboration with a transdisciplinary, population-focused team that manages the patient across the cancer care continuum. BACKGROUND: Prior to this transition, practice was unit based, focused on nursing staff education, skills, and competencies, and practice varied widely based on the needs of the unit. This lack of role consistency resulted in decreased autonomy and collaboration and frustration with not consistently impacting positive outcomes. DESCRIPTION: Nursing leadership worked with the clinical nurse specialists to develop and transition to a population-focused model. Some responsibilities in the unit-based model were retained, whereas others were transitioned to different roles. The reporting structure was centralized, and the role was realigned to focus on a specific patient population encompassing care from diagnosis throughout survivorship. OUTCOME: Baseline job satisfaction data were collected prior to the transition and repeated at 6 and 12 months, then 2, 3, and 4 years after implementation. Over time, there was significant improvement in participation in decision making, support of leadership, and positive contributions to patients and staff, resulting in improved nursing-sensitive patient outcomes, an increase in evidence-based practice initiatives and nursing research projects, and substantial professional growth of clinical staff. CONCLUSION: With this practice model, clinical nurse specialists consistently and proactively plan and facilitate evidence-based best practice in collaboration with a transdisciplinary team that manages the patient from diagnosis through the cancer trajectory. Results of outcome measurement report job satisfaction at an all-time high. Significant impact is demonstrated for patients and families, the nursing staff, and the organization. IMPLICATIONS: Healthcare organizations should evaluate current roles and practice models for opportunities to incorporate innovations that will result in improved patient care and satisfaction. PMID- 26444516 TI - The Neutrophil-to-Lymphocyte Ratio Is Valuable at All Stages of Coronary Artery Disease. PMID- 26444517 TI - A Prospective Study of the Intra- and Postoperative Efficacy of Intraoperative Neuromonitoring in Spinal Cord Stimulation. AB - BACKGROUND: Accurate lead placement is critical for spinal cord stimulation (SCS) efficacy. The traditional gold standard of awake placement is often technically difficult. While there is retrospective evidence supporting the use of intraoperative neurophysiological monitoring (IOM) as an alternative, a prospective assessment has not yet been performed. OBJECTIVE: To prospectively evaluate pain and functionality outcomes for IOM-guided SCS, validate two IOM modalities as a means to lateralize lead placement and assess whether IOM can be useful for postoperative programming. METHODS: A total of 73 patients were implanted with SCS using electromyography (EMG) and somatosensory-evoked potential collision studies (SSEP-CS) to verify lead placement. Patient pain and function were assessed through serial administration of several validated questionnaires. Stimulation parameters at 6 months were documented. RESULTS: Statistically significant (p < 0.05) improvements were observed in the McGill Pain Questionnaire, Oswestry Disability Index, Pain Catastrophizing Scale, and Visual Analog Scale. EMG and SSEP-CS appropriately lateralized leads in 65/73 (89.0%) and 40/58 (69.0%) cases, respectively. EMG predicted active contacts in use at follow-up with 82.7% sensitivity. CONCLUSIONS: We provide prospective evidence that IOM can be used to verify SCS placement. Additionally, EMG may help to streamline device programming and thereby improve outcomes by predicting the ideal stimulation contacts in many cases. PMID- 26444518 TI - Supported Lipid Bilayer Platform To Test Inhibitors of the Membrane Attack Complex: Insights into Biomacromolecular Assembly and Regulation. AB - Complement activation plays an important role in innate immune defense by triggering formation of the membrane attack complex (MAC), which is a biomacromolecular assembly that exhibits membrane-lytic activity against foreign invaders including various pathogens and biomaterials. Understanding the details of MAC structure and function has been the subject of extensive work involving bulk liposome and erythrocyte assays. However, it is difficult to characterize the mechanism of action of MAC inhibitor drug candidates using the conventional assays. To address this issue, we employ a biomimetic supported lipid bilayer platform to investigate how two MAC inhibitors, vitronectin and clusterin, interfere with MAC assembly in a sequential addition format, as monitored by the quartz crystal microbalance-dissipation (QCM-D) technique. Two experimental strategies based on modular assembly were selected, precincubation of inhibitor and C5b-7 complex before addition to the lipid bilayer or initial addition of inhibitor followed by the C5b-7 complex. The findings indicate that vitronectin inhibits membrane association of C5b-7 via a direct interaction with C5b-7 and via competitive membrane association onto the supported lipid bilayer. On the other hand, clusterin directly interacts with C5b-7 such that C5b-7 is still able to bind to the lipid bilayer, and clusterin affects the subsequent binding of other complement proteins involved in the MAC assembly. Taken together, the findings in this study outline a biomimetic approach based on supported lipid bilayers to explore the interactions between complement proteins and inhibitors, thereby offering insight into MAC assembly and regulation. PMID- 26444519 TI - Indoor Air Pollutant Exposure for Life Cycle Assessment: Regional Health Impact Factors for Households. AB - Human exposure to indoor pollutant concentrations is receiving increasing interest in Life Cycle Assessment (LCA). We address this issue by incorporating an indoor compartment into the USEtox model, as well as by providing recommended parameter values for households in four different regions of the world differing geographically, economically, and socially. With these parameter values, intake fractions and comparative toxicity potentials for indoor emissions of dwellings for different air tightness levels were calculated. The resulting intake fractions for indoor exposure vary by 2 orders of magnitude, due to the variability of ventilation rate, building occupation, and volume. To compare health impacts as a result of indoor exposure with those from outdoor exposure, the indoor exposure characterization factors determined with the modified USEtox model were applied in a case study on cooking in non-OECD countries. This study demonstrates the appropriateness and significance of integrating indoor environments into LCA, which ensures a more holistic account of all exposure environments and allows for a better accountability of health impacts. The model, intake fractions, and characterization factors are made available for use in standard LCA studies via www.usetox.org and in standard LCA software. PMID- 26444520 TI - DETECTION OF CHOROIDAL FOLDS IN PATIENTS WITH VOGT-KOYANAGI-HARADA DISEASE BY RETROMODE SCANNING LASER OPHTHALMOSCOPY. AB - PURPOSE: To determine whether the choroidal folds in patients with Vogt-Koyanagi Harada disease can be detected by retromode of a scanning laser ophthalmoscopy (SLO) with infrared laser light source. METHODS: The authors examined two patients with Vogt-Koyanagi-Harada disease at the acute stage by retromode imaging scanning laser ophthalmoscopy with an infrared laser before and after steroid treatment. RESULTS: The retromode imaging by scanning laser ophthalmoscopy clearly and noninvasively delineated the choroidal folds in both cases. The folds disappeared after steroid treatment and reappeared with recurrences of uveitis. CONCLUSION: The retromode imaging by scanning laser ophthalmoscopy can detect the choroidal folds and should be useful for detecting and monitoring the choroidal folds in Vogt-Koyanagi-Harada disease. PMID- 26444521 TI - ENDOGENOUS ENDOPHTHALMITIS CAUSED BY BRUCELLA MELITENSIS. AB - PURPOSE: Brucella is an intracellular gram-negative pathogen that acts as a facultative parasite. B. Melitensis endogenous endophthalmitis is quite rare. We herein report an unusual case of B. melitensis endophthalmitis with a good outcome after appropriate management. METHODS: A retrospective interventional case report of an 18-year-old boy who had unexplained interrupted fever and malaise for the past 4 months and was being treated as a case of fever of unknown origin. He presented with a 10-day history of pain and loss of vision in the left eye. Visual acuity in the left eye at time of presentation was counting fingers near face. Extensive anterior chamber reaction and flare, as well as, vitritis were found on examination. All blood and urine investigations and radiological imaging were negative. RESULTS: A diagnostic/therapeutic vitrectomy with antibiotic injection helped in identifying the offending organism and controlling the inflammation. Vitrectomy sample revealed B. melitensis with no sensitive result. Patient recovered vision in his eye to 20/150. Eye examination revealed a quiet eye, with flat retina and some retinal pigment epithelial changes at macula. CONCLUSION: B. melitensis endophthalmitis is a rarely encountered disease entity. High suspicion and prompt management with vitrectomy and appropriate antibiotic injection was successful in salvaging the patient's eye. PMID- 26444522 TI - PSEUDO UVEAL MELANOMA CAUSED BY OPTIC DISK DRUSEN WITH JUXTAPAPILLARY CHOROIDAL NEOVASCULAR MEMBRANE. AB - PURPOSE: To describe two cases of choroidal hemorrhage caused by optic disk drusen-induced choroidal neovascularization simulating uveal melanoma. METHODS: Observational case reports of two patients and brief review of the literature. RESULTS: Two patients were referred with pigmented juxtapapillary lesions concerning for choroidal melanoma. Multimodal imaging revealed the presence of optic disk drusen with overlying choroidal neovascular membranes and peripapillary choroidal hemorrhage. Both patients were treated with antivascular endothelial growth factor and the lesions resolved. CONCLUSION: In the setting of diagnostic uncertainty, careful multimodal imaging can assist in distinguishing between malignant choroidal melanoma and a benign simulating lesion. Optic disk drusen with associated neovascularization and hemorrhage should be included in the list of pseudomelanomas. PMID- 26444523 TI - PIMASERTIB AND SEROUS RETINAL DETACHMENTS. AB - PURPOSE: To report a case of multifocal serous retinal detachments associated with pimasertib. METHODS: The authors report a 26-year-old patient who developed bilateral multifocal serous retinal detachments appearing 2 days after starting pimasertib (as part of a clinical trial investigating its use in low-grade metastatic ovarian cancer) and rapidly resolving 3 days after stopping it. CONCLUSION: The mechanism of MEK inhibitor induced visual toxicity remains unclear. The pathophysiology of multifocal serous retinal detachments as a complication of pimasertib is still poorly understood. PMID- 26444526 TI - 2015 Eberhard F. Mammen Award Announcements: Part I--Most Popular Articles. PMID- 26444525 TI - Suicidal ideation and suicide attempts among human immunodeficiency virus infected adults: differences in risk factors and their implications. AB - Many studies have investigated risk factors for suicidal ideation and suicide attempt; however, most have failed to show differences in risk factors between suicidal ideation and suicide attempt among the human immunodeficiency virus (HIV)-infected population. This study was designed to identify differences in risk factors between suicidal ideation and suicide attempts among HIV-infected adults in Seoul. A face-to-face survey of 457 HIV-infected adults was conducted by the Seoul Metropolitan Government in 2013. Multivariate logistic regression analysis was used to identify factors associated with suicidal ideation and suicide attempt. Among 422 participants, 44% had suicidal ideation, and 11% had suicide attempts. The independent risk factors for suicidal ideation were young and middle age, living with someone, history of AIDS-defining opportunistic disease, history of treatment for depression, lower social support, and psychological status. Beneficiaries of National Medical Aid, economic barriers to treatment, history of treatment for depression, and lower psychological status were independently associated with suicide attempts. Patients with HIV in Korea were treated without cost in some centers. Thus, experiencing an economic barrier to treatment might be due in part to ignorance of HIV care policies. Our findings indicate that suicide attempts are associated with socioeconomic factors and information inequality regarding medical care. In conclusion, suicidal ideation closely associated with the psychosocial factors, whereas suicide attempt demonstrates a stronger association with socioeconomic factors. Suicide prevention measures should be implemented to provide information to help HIV infected patients. PMID- 26444527 TI - Tissue Factor in Arterial and Venous Thrombosis: From Pathophysiology to Clinical Implications. PMID- 26444529 TI - ? PMID- 26444528 TI - Using the combined analysis of transcripts and metabolites to propose key genes for differential terpene accumulation across two regions. AB - BACKGROUND: Terpenes are of great interest to winemakers because of their extremely low perception thresholds and pleasant floral odors. Even for the same variety, terpene profile can be substantially different for grapevine growing environments. Recently a series of genes required for terpene biosynthesis were biochemically characterized in grape berries. However, the genes that dominate the differential terpene accumulation of grape berries between regions have yet to be identified. METHODS: Free and glycosidically-bound terpenes were identified and quantified using gas chromatography-mass spectrometry (GC-MS) technique. The transcription expression profiling of the genes was obtained by RNA sequencing and part of the results were verified by quantitative real time PCR (QPCR). The gene co-expression networks were constructed with the Cytoscape software v 2.8.2 ( www.cytoscape.org). RESULTS: 'Muscat Blanc a Petits Grains' berries were collected from two wine-producing regions with strikingly different climates, Gaotai (GT) in Gansu Province and Changli (CL) in Hebei Province in China, at four developmental stages for two consecutive years. GC-MS analysis demonstrated that both free and glycosidically bound terpenes accumulated primarily after veraison and that mature grape berries from CL contained significantly higher concentrations of free and glycosidically bound terpenes than berries from GT. Transcriptome analysis revealed that some key genes involved in terpene biosynthesis were markedly up-regulated in the CL region. Particularly in the MEP pathway, the expression of VviHDR (1-hydroxy-2-methyl-2-butenyl 4-diphosphate reductase) paralleled with the accumulation of terpenes, which can promote the flow of isopentenyl diphosphate (IPP) into the terpene synthetic pathway. The glycosidically bound monoterpenes accumulated differentially along with maturation in both regions, which is synchronous with the expression of a monoterpene glucosyltransferase gene (VviUGT85A2L4 (VviGT14)). Other genes were also found to be related to the differential accumulation of terpenes and monoterpene glycosides in the grapes between regions. Transcription factors that could regulate terpene synthesis were predicted through gene co-expression network analysis. Additionally, the genes involved in abscisic acid (ABA) and ethylene signal responses were expressed at high levels earlier in GT grapes than in CL grapes. CONCLUSIONS: Differential production of free and glycosidically bound terpenes in grape berries across GT and CL regions should be related at least to the expression of both VviHDR and VviUGT85A2L4 (VviGT14). Considering the expression patterns of both transcription factors and mature-related genes, we infer that less rainfall and stronger sunshine in the GT region could initiate the earlier expression of ripening-related genes and accelerate the berry maturation, eventually limiting the production of terpene volatiles. PMID- 26444531 TI - ? PMID- 26444530 TI - ? AB - Interethnic Analyses of Distributions in Children and Adolescents Mental Disorders in a Health Care Utilization The study examines ethnic differences in mental disorders in a child and adolescent psychiatry population in a major German city from 2007 to 2011 (N = 5,680). Risks of developing specific mental disorders were calculated. African migrant children and adolescents showed higher risk in traumatic stress and adjustment disorders (F 43 in ICD-10), the Asiatic group in dissociative disorders (F 44-45). Compared to other European migrants the German children and adolescents without migration background had a higher risk of affective disorders (F 3). Adolescents (N = 3,556) with Russian and Polish background had a higher risk of disorders induced by psychotropic substances (F 1). Turkish and Arabic adolescents had a 4- to 5-times increasing risk in schizophrenia as well as schizotypal or delusional disorders (F 2). In addition, mental disorders were influenced by gender and nationality. These study results suggest that a different vulnerability to specific mental disorders is associated to ethnicity. PMID- 26444532 TI - ? PMID- 26444533 TI - ? PMID- 26444534 TI - ? PMID- 26444535 TI - The Effect of Physicians' Treatment Recommendations on Their Epistemic Authority: The Medical Expertise Bias. AB - This study examines the hypothesis that patients perceive physicians who recommend more active and major treatment as having greater epistemic authority. The hypothesis is based on the assumption that patients expect that their physicians should advocate for an active treatment rather than abstention from treatment. The sample included 631 participants. Data were collected using a between-subjects design and scenarios that described a person who suffers from a medical problem and visits a physician (surgeon, orthopedist, or dentist). The physician gives a passive or active recommendation regarding treatment. Different levels of passive recommendation (against or wait on treatment) and active recommendation (minor, moderate, or major procedures) were used. The experience of the physician was also manipulated. The dependent measure was the patient's rating of the physician's epistemic authority. Physicians who prescribed an active mode of treatment were perceived as having a higher epistemic authority than physicians who gave a passive recommendation. We named this phenomenon the medical expertise bias, as people might be biased when judging the level of expertise of their physicians such that those physicians who recommend an active treatment are considered to have greater medical epistemic authority in general. PMID- 26444536 TI - Evaluation of 563 children with chronic cough accompanied by a new clinical algorithm. AB - BACKGROUND: This study aims to evaluate the children with chronic cough and to analyze their etiological factors according to the age groups. METHOD: Five hundred sixty-three children with chronic cough were included. The last diagnosis were established and were also emphasized according to the age groups. RESULTS: The mean age was 5.4 +/- 3.8 years (2-months-17-years) and 52 % of them were male. The most common final diagnosis from all the participants were: asthma (24.9 %), asthma-like symptoms (19 %), protracted bacterial bronchitis (PBB) (11.9 %), and upper airway cough syndrome (9.1 %). However, psychogenic cough was the second most common diagnosis in the subjects over 6 years of age. CONCLUSION: Asthma and asthma-like symptoms were the most common diagnosis in children. Different age groups in children may have a different order of frequencies. Psychogenic cough should be thought of in the common causes especially in older children. PMID- 26444538 TI - Erratum to: Single centre experience of the application of self navigated 3D whole heart cardiovascular magnetic resonance for the assessment of cardiac anatomy in congenital heart disease. PMID- 26444537 TI - Evaluation of carbapenem resistance using phenotypic and genotypic techniques in Enterobacteriaceae isolates. AB - BACKGROUND: Bacterial resistance to antibiotics is increasing worldwide. Antibiotic-resistant strains can lead to serious problems regarding treatment of infection. Carbapenem antibiotics are the final treatment option for infections caused by serious and life-threatening multidrug-resistant gram-negative bacteria. Therefore, an understanding of carbapenem resistance is important for infection control. In the study described herein, the phenotypic and genotypic features of carbapenem-resistant Enterobacteriaceae strains isolated in our hospital were evaluated. METHODS: In total, 43 carbapenem-resistant strains were included in this study. Sensitivity to antibiotics was determined using the VITEK((r))2 system. The modified Hodge test (MHT) and metallo-beta-lactamase (MBL) antimicrobial gradient test were performed for phenotypic identification. Resistance genes IMP, VIM, KPC, NDM-1, and OXA-48 were amplified by multiplex PCR. RESULTS: The OXA-48 gene was detected in seven strains, and the NDM-1 gene in one strain. No resistance genes were detected in the remainder of strains. A significant correlation was observed between the MHT test and OXA-48 positivity, and between the MBL antimicrobial gradient test and positivity for resistance genes (p < 0.05). CONCLUSION: The finding of one NDM-1-positive isolate in this study indicates that carbapenem resistance is spreading in Turkey. Carbapenem resistance spreads rapidly and causes challenges in treatment, and results in high mortality/morbidity rates. Therefore, is necessary to determine carbapenem resistance in Enterobacteriaceae isolates and to take essential infection control precautions to avoid spread of this resistance. PMID- 26444540 TI - Inflammatory myofibroblastic tumour of the testis with confirmed anaplastic lymphoma kinase gene rearrangement. PMID- 26444539 TI - De novo transcriptome sequencing and comprehensive analysis of the drought responsive genes in the desert plant Cynanchum komarovii. AB - BACKGROUND: Cynanchum komarovii Al Iljinski is a xerophytic plant species widely distributing in the severely adverse environment of the deserts in northwest China. At present, the detailed transcriptomic and genomic data for C. komarovii are still insufficient in public databases. RESULTS: To investigate changes of drought-responsive genes and explore the mechanisms of drought tolerance in C. komarovii, approximately 27.5 GB sequencing data were obtained using Illumina sequencing technology. After de novo assembly 148,715 unigenes were generated with an average length of 604 bp. Among these unigenes, 85,106 were annotated with gene descriptions, conserved domains, gene ontology terms, and metabolic pathways. The results showed that a great number of unigenes were significantly affected by drought stress. We identified 3134 unigenes as reliable differentially expressed genes (DEGs). During drought stress, the regulatory genes were involved in signaling transduction pathways and in controlling the expression of functional genes. Moreover, C. komarovii activated many functional genes that directly protected against stress and improved tolerance to adapt drought condition. Importantly, the DEGs were involved in biosynthesis, export, and regulation of plant cuticle, suggesting that plant cuticle may play a vital role in response to drought stress and the accumulation of cuticle may allow C. komarovii to improve the tolerance to drought stress. CONCLUSION: This is the first large-scale reference sequence data of C. komarovii, which enlarge the genomic resources of this species. Our comprehensive transcriptome analysis will provide a valuable resource for further investigation into the molecular adaptation of desert plants under drought condition and facilitate the exploration of drought-tolerant candidate genes. PMID- 26444541 TI - Prevalence of fatigue in patients 3 months after stroke and association with early motor activity: a prospective study comparing stroke patients with a matched general population cohort. AB - BACKGROUND: Fatigue is a common complaint after stroke. Reasons for higher prevalence are still unclear. This study aimed to determine if fatigue prevalence in stroke patients is different to that of age and gender matched general population controls, and to explore whether early motor activity was associated with reduced likelihood of fatigue three months after stroke. METHODS: This was a prospective multicenter cohort study of stroke patients admitted to eleven regional Norwegian hospitals, within 14 days after stroke. Stroke patients (n = 257) were age and gender matched to participants in a general population health survey (HUNT3-survey) carried out in a regional county of central Norway. The single-item fatigue questionnaire from the HUNT3-survey was administered to both groups to compare prevalence. The association between early motor activity (time in bed, time sitting out of bed, and time upright) and fatigue at three months after stroke (Fatigue Severity Scale) was tested with logistic regression. Simple models including each activity outcome, with adjustment for stroke severity and pre-stroke function, were tested, as well as a comprehensive model that included additional independent variables of depression, pain, pre-stroke fatigue, age and gender. RESULTS: Prevalence was higher after stroke compared with the general population: 31.1% versus 10.9%. In the simple regression models, none of the early motor activity categories were associated with fatigue three months after stroke. In the comprehensive model, depression, pain and pre-stroke fatigue were significantly associated with post-stroke fatigue. Time in bed through the daytime during hospital stay approached statistical significance (p = 0.058) with an odds ratio for experiencing fatigue of 1.02 (95% CI 1.00-1.04) for each additional 5.4 minutes in bed. CONCLUSIONS: Stroke patients had higher prevalence of fatigue three months after stroke than the age and gender matched general population sample, which may be partly explained by the stroke population being in poorer health overall. The relationship between early motor activity (and inactivity) and fatigue remains unclear. Further research, which may help drive development of new treatments to target this challenging condition, is needed. PMID- 26444542 TI - Production of serine protease inhibitors by mutagenesis and their effects on the mortality of Aedes aegypti L. larvae. AB - BACKGROUND: Dengue, transmitted primarily by the bites of infected Aedes aegypti L., is transmitted to millions of individuals each year in tropical and subtropical areas. Dengue control strategies are primarily based on controlling the vector, using insecticides, but the appearance of resistance poses new challenges. Recently, highly selective protease inhibitors by phage display were obtained for digestive enzymes of the 4th instar larvae (L4) midgut. These mutants were not confirmed as a larvicide due to the low yield of the expression of these inhibitors. In the present study, chimera molecules were constructed based on the mutations at positions P1-P4' selected previously. The T6, T23 and T149 mutants were mixed with another Kunitz inhibitor, domain 1 of the inhibitor boophilin (D1). METHODS: The chimeras T6/D1, T149/D1 and T23/D1 were expressed at high levels in P. pastoris yeast, purified by ionic exchange chromatography and their homogeneity was analyzed by SDS-PAGE. The chimera inhibitors were assayed against larval trypsin, chymotrypsin and elastase using specific chromogenic substrates. The inhibitors were assayed for their larvicide potential against L4. RESULTS: The chimeras exhibited strong inhibitory activities against the larval digestive enzymes in a dose-dependent manner. T6/D1, T149/D1 and T23/D1 exhibited strong larvicidal activity against L4 of Ae. aegypti with inhibitor concentrations in the MUM range. A synergistic increase in mortality was observed when a mixture of the three chimeric inhibitors was tested. CONCLUSIONS: The strategy for constructing the chimeric inhibitors was successful. The chimeras showed strong larvicidal activity against Ae. aegypti. In the future, our findings can be used to design synthetic inhibitors for larvae digestive enzymes as an alternative method to control the dengue vector. PMID- 26444543 TI - Ever dispense of prescribed allergy medication in children growing up close to traffic: a registry-based birth cohort. AB - BACKGROUND: Epidemiologic studies have shown conflicting results regarding the role of traffic pollution in the development of allergic disease. This study investigated the relationship between living close to traffic and ever dispense of prescribed oral antihistamines or nasal anti-allergic medication, among young children. The underlying aim was to investigate if children growing up close to traffic pollution are at higher risk of developing allergy in early childhood. METHODS: We investigated a birth cohort in southern Sweden, consisting of N = 26 128 children (0-6 years) with health outcome and exposure data. Of these children, N = 7898, had additional covariate information. Traffic intensity and yearly averages of dispersion-modeled concentrations of NOX (100 * 100 m grid) at residential addresses, were linked with registry data on dispensed allergy medication (the Swedish Prescribed Drug Register). Individual level covariate information was obtained from questionnaires distributed to parents at Child Health Care-center visits, eight months after birth. Cox proportional hazards regression was used for the statistical analyses. RESULTS: Living in close proximity to a road with equal to or greater than 8640 cars/day (compared to 0 8639 cars/day), was not associated with higher incidence of ever dispensed oral antihistamine or nasal anti-allergic medication, with or without adjustment for confounders (sex, breastfeeding, parental allergy, parental origin, season, and year of birth). Similar results were found in relation to NOX. CONCLUSIONS: Traffic-related exposure was not associated with higher incidence of ever dispensed medication against allergy, in children 0-6 years in southern Sweden. These results indicates that traffic-related exposure may not be a risk factor for early onset allergy in children in southern Sweden. However, children with dispense of prescribed allergy medication may be a selected subgroup, and the results for this group may not be generalizable to all children with allergy. PMID- 26444544 TI - A new high-throughput screening-compatible gap junctional intercellular communication assay. AB - BACKGROUND: Gap junctions (GJs) are intercellular channels through which molecules smaller than 1 kDa can diffuse, and they have been suggested as drug targets. To develop chemical drugs acting on this target, a high-throughput screening (HTS) system for GJ modulators is necessary. RESULTS: We designed a new, high-throughput GJ intercellular communication (GJIC) assay. This assay system consisted of donor and acceptor cells from LN215 glioma cells that expressed SLC26A4 and yellow fluorescent protein-H148Q/I152L (YFP(QL)), respectively. The fluorescence of LN215-YFP(QL) acceptor cells, when cultured alone, was not quenched by iodide. However when donor and acceptor cells, or LN215-YFP(QL) and LN215-I(-) cells, were mixed and plated, they formed GJs. When iodide was added, it was transported into donor cells by SLC26A4, diffused through the GJs to acceptor cells, and quenched the YFP(QL) fluorescence. The quenching rate was optimal at a 2:1 mixture of donor and acceptor cells. The assay quality parameter, Z' factor, was calculated from data collected with vehicle and carbenoxolone. For each assay, the Z' factor increased with time. The Z' factor of a 10-s assay was 0.72 indicating that the assay quality was high enough for use in HTS. This assay system also worked well in HOS osteosarcoma cells with a Z' factor at 10 s of 0.70. CONCLUSIONS: We developed a new HTS system for GJ modulators. The system had a high assay quality with a Z' factor >= 0.70, was rapid and required only 10 s per well, was inexpensive in requiring no additional reagents, and was predicted to have a low rate of false-positive hits. PMID- 26444545 TI - Erratum to: Establishing medical plausibility in the context of orphan medicines designation in the European Union. PMID- 26444546 TI - Forebrain-Specific Loss of BMPRII in Mice Reduces Anxiety and Increases Object Exploration. AB - To investigate the role of Bone Morphogenic Protein Receptor Type II (BMPRII) in learning, memory, and exploratory behavior in mice, a tissue-specific knockout of BMPRII in the post-natal hippocampus and forebrain was generated. We found that BMPRII mutant mice had normal spatial learning and memory in the Morris water maze, but showed significantly reduced swimming speeds with increased floating behavior. Further analysis using the Porsolt Swim Test to investigate behavioral despair did not reveal any differences in immobility between mutants and controls. In the Elevated Plus Maze, BMPRII mutants and Smad4 mutants showed reduced anxiety, while in exploratory tests, BMPRII mutants showed more interest in object exploration. These results suggest that loss of BMPRII in the mouse hippocampus and forebrain does not disrupt spatial learning and memory encoding, but instead impacts exploratory and anxiety-related behaviors. PMID- 26444547 TI - Endothelium Expression of Bcl-2 Is Essential for Normal and Pathological Ocular Vascularization. AB - Bcl-2 is an anti-apoptotic protein with important roles in vascular homeostasis and angiogenesis. Mice globally lacking Bcl-2 (Bcl-2 -/-) are small in stature and succumb to renal failure shortly after weaning as a result of renal hypoplasia/cystic dysplasia. We have shown that Bcl-2 -/- mice displayed attenuated retinal vascular development and neovascularization. In vitro studies indicated that in addition to modulating apoptosis, Bcl-2 expression also impacts endothelial and epithelial cell adhesion, migration and extracellular matrix production. However, studies delineating the cell autonomous role Bcl-2 expression plays in the endothelium during vascular development, pruning and remodeling, and neovascularization are lacking. Here we generated mice carrying a conditional Bcl-2 allele (Bcl-2Flox/Flox) and VE-cadherin-cre (Bcl-2EC mice). Bcl 2EC mice were of normal stature and lifespan and displayed some but not all of the retinal vascular defects previously observed in global Bcl-2 deficient mice. Bcl-2EC mice had decreased numbers of endothelial cells, decreased retinal arteries and premature primary branching of the retinal vasculature, but unlike the global knockout mice, spreading of the retinal superficial vascular layer proceeded normally. Choroidal neovascularization was attenuated in Bcl-2EC mice, although retinal neovascularization accompanying oxygen-induced ischemic retinopathy was not. Thus, Bcl-2 expression in the endothelium plays a significant role during postnatal retinal vascularization, and pathological choroidal but not retinal neovascularization, suggesting vascular bed specific Bcl-2 function in the endothelium. PMID- 26444548 TI - Predicting Pathological Features at Radical Prostatectomy in Patients with Prostate Cancer Eligible for Active Surveillance by Multiparametric Magnetic Resonance Imaging. AB - PURPOSE: The aim of this study was to investigate the prognostic performance of multiparametric magnetic resonance imaging (mpMRI) and Prostate Imaging Reporting and Data System (PIRADS) score in predicting pathologic features in a cohort of patients eligible for active surveillance who underwent radical prostatectomy. METHODS: A total of 223 patients who fulfilled the criteria for "Prostate Cancer Research International: Active Surveillance", were included. Mp-1.5 Tesla MRI examination staging with endorectal coil was performed at least 6-8 weeks after TRUS-guided biopsy. In all patients, the likelihood of the presence of cancer was assigned using PIRADS score between 1 and 5. Outcomes of interest were: Gleason score upgrading, extra capsular extension (ECE), unfavorable prognosis (occurrence of both upgrading and ECE), large tumor volume (>= 0.5 ml), and seminal vesicle invasion (SVI). Receiver Operating Characteristic (ROC) curves and Decision Curve Analyses (DCA) were performed for models with and without inclusion of PIRADS score. RESULTS: Multivariate analysis demonstrated the association of PIRADS score with upgrading (P < 0.0001), ECE (P < 0.0001), unfavorable prognosis (P < 0.0001), and large tumor volume (P = 0.002). ROC curves and DCA showed that models including PIRADS score resulted in greater net benefit for almost all the outcomes of interest, with the only exception of SVI. CONCLUSIONS: mpMRI and PIRADS scoring are feasible tools in clinical setting and could be used as decision-support systems for a more accurate selection of patients eligible for AS. PMID- 26444550 TI - Sensory and instrumental characterization of fast inverting oil-in-water emulsions for cosmetic application. AB - OBJECTIVE: The aim of this study was to perform short-term sensory testing and instrumental (conductivity and rheological) characterization of a fast inverted oil-in-water (o/w) emulsion base, also known as a SWOP (Switch-Oil-Phase) emulsion, and reference o/w and water-in-oil (w/o) emulsion bases under various testing conditions: in the presence of ions and at different temperatures. SWOP emulsions are known as metastable o/w emulsions, which invert into w/o emulsions on application of mechanical energy, while rubbing it onto the skin and due to their properties SWOP emulsion are especially suitable as a cosmetic vehicle in, for example, sun-protection products. METHODS: Sensory testing, which included the evaluation of twenty attributes of the investigated emulsion bases, was performed by a panel of 20 healthy assessors experienced in the evaluation of cosmetic products. Rheological characterization of the investigated emulsion bases included continuous flow testing and oscillatory measurements under various testing conditions. Additionally, conductivity measurements were combined with rheological characterization to monitor stability changes of investigated emulsions. The instrumental and sensory results were analysed statistically and compared. RESULTS: The obtained results indicated that the investigated emulsions behaved differently in the presence of ions (originating from artificial sweat solution) and at different temperatures (under storage and application conditions). Namely, the SWOP emulsion showed similar behaviour to the reference o/w emulsion under storage conditions, but in the presence of ions and at skin temperature, the SWOP emulsion was followed by re-establishment of a stable w/o system, whereas reference o/w emulsion was irreversibly destroyed. The statistical analysis of chosen sensorial attributes indicated that the reference w/o emulsion was significantly different in comparison with the reference o/w and SWOP emulsions, mainly, standing in good agreement with the results of rheological characterization. CONCLUSION: The study showed that rheological measurements potentially could be related to certain sensory attributes and used for faster development of SWOP emulsions in the future. Finally, SWOP emulsions should be considered for further investigation as suitable vehicles in cosmetic products due to their favourable physicochemical and sensory characteristics which could be partially predicted with instrumental characterization. PMID- 26444549 TI - Immune dysregulation in the functional gastrointestinal disorders. AB - Gastrointestinal conditions may be broadly classified into two: organic and functional disease, with functional disorders accounting for the majority of patients with chronic gastrointestinal symptoms. Functional gastrointestinal disorders (FGIDs) present with no obvious pathology or well-accepted biochemical mechanism and, as such, treatment strategies are limited and focus on symptoms rather than cure. Irritable bowel syndrome and functional dyspepsia are the most widely recognised FGIDs, and there is a growing body of evidence to suggest an underlying inflammatory phenotype in subsets with these conditions. Here, we discuss the current knowledge of immune involvement in FGIDs and the commonalities between the different manifestations of FGIDs and propose a new hypothesis, potentially defining an underlying immunopathological basis of these conditions. PMID- 26444551 TI - Substituent effects on the optical properties of naphthalenediimides: A frontier orbital analysis across the periodic table. AB - A comprehensive theoretical treatment is presented for the electronic excitation spectra of ca. 50 different mono-, di-, and tetrasubstituted naphthalenediimides (NDI) using time-dependent density functional theory (TDDFT) at ZORA-CAM B3LYP/TZ2P//ZORA-BP86/TZ2P with COSMO for simulating the effect of dichloromethane (DCM) solution. The substituents -XHn are from groups 14-17 and rows 2-5 of the periodic table. The lowest dipole-allowed singlet excitation (S0 S1 ) of the monosubstituted NDIs can be tuned from 3.39 eV for -F to 2.42 eV for TeH, while the S0 -S2 transition is less sensitive to substitution with energies ranging between 3.67 eV for -CH3 and 3.44 eV for -SbH2 . In the case of NDIs with group-15 and -16 substituents, the optical transitions strongly depend on the extent to which -XHn is planar or pyramidal as well as on the possible formation of intramolecular hydrogen bonds. The accumulative effect of double and quadruple substitution leads in general to increasing bathochromic shifts, but the increased steric hindrance in tetrasubstituted NDIs can lead to deformations that diminish the effectiveness of the substituents. Detailed analyses of the Kohn Sham orbital electronic structure in monosubstituted NDIs reveal the mesomeric destabilization of the HOMO as the primary cause of the bathochromic shift of the S0-S1 transition. PMID- 26444552 TI - A Zebrafish Drug-Repurposing Screen Reveals sGC-Dependent and sGC-Independent Pro Inflammatory Activities of Nitric Oxide. AB - Tissue injury and infection trigger innate immune responses. However, dysregulation may result in chronic inflammation and is commonly treated with corticosteroids and non-steroidal anti-inflammatory drugs. Unfortunately, long term administration of both therapeutic classes can cause unwanted side effects. To identify alternative immune-modulatory compounds we have previously established a novel screening method using zebrafish larvae. Using this method we here present results of an in vivo high-content drug-repurposing screen, identifying 63 potent anti-inflammatory drugs that are in clinical use for other indications. Our approach reveals a novel pro-inflammatory role of nitric oxide. Nitric oxide affects leukocyte recruitment upon peripheral sensory nervous system or epithelial injury in zebrafish larvae both via soluble guanylate cyclase and in a soluble guanylate cyclase -independent manner through protein S nitrosylation. Together, we show that our screening method can help to identify novel immune-modulatory activities and provide new mechanistic insights into the regulation of inflammatory processes. PMID- 26444553 TI - On-chip assessment of human primary cardiac fibroblasts proliferative responses to uniaxial cyclic mechanical strain. AB - Cardiac cell function is substantially influenced by the nature and intensity of the mechanical loads the cells experience. Cardiac fibroblasts (CFs) are primarily involved in myocardial tissue remodeling: at the onset of specific pathological conditions, CFs activate, proliferate, differentiate, and critically alter the amount of myocardial extra-cellular matrix with important consequences for myocardial functioning. While cyclic mechanical strain has been shown to increase matrix synthesis of CFs in vitro, the role of mechanical cues in CFs proliferation is unclear. We here developed a multi-chamber cell straining microdevice for cell cultures under uniform, uniaxial cyclic strain. After careful characterization of the strain field, we extracted human heart-derived CFs and performed cyclic strain experiments. We subjected cells to 2% or 8% cyclic strain for 24 h or 72 h, using immunofluorescence to investigate markers of cell morphology, cell proliferation (Ki67, EdU, phospho-Histone-H3) and subcellular localization of the mechanotransduction-associated transcription factor YAP. Cell morphology was affected by cyclic strain in terms of cell area, cell and nuclear shape and cellular alignment. We additionally observed a strain intensity-dependent control of cell growth: a significant proliferation increase occurred at 2% cyclic strain, while time-dependent effects took place upon 8% cyclic strain. The YAP-dependent mechano-transduction pathway was similarly activated in both strain conditions. These results demonstrate a differential effect of cyclic strain intensity on human CFs proliferation control and provide insights into the YAP-dependent mechano-sensing machinery of human CFs. PMID- 26444554 TI - Novel Use of the Nintendo Wii Board for Measuring Isometric Lower Limb Strength: A Reproducible and Valid Method in Older Adults. AB - BACKGROUND: Portable, low-cost, objective and reproducible assessment of muscle strength in the lower limbs is important as it allows clinicians to precisly track progression of patients undergoing rehabilitation. The Nintendo Wii Balance Board (WBB) is portable, inexpensive, durable, available worldwide, and may serve the above function. OBJECTIVE: The purpose of the study was to evaluate (1) reproducibility and (2) concurrent validity of the WBB for measuring isometric muscle strength in the lower limb. METHODS: A custom hardware and software was developed to utilize the WBB for assessment of isometric muscle strength. Thirty older adults (69.0 +/- 4.2 years of age) were studied on two separate occasions on both the WBB and a stationary isometric dynamometer (SID). On each occasion, three recordings were obtained from each device. For the first recording, means and maximum values were used for further analysis. The test-retest reproducibility was examined using intraclass correlation coefficients (ICC), Standard Error of Measurement (SEM), and limits of agreement (LOA). Bland-Altman plots (BAP) and ICC's were used to explore concurrent validity. RESULTS: No systematic difference between test-retest was detected for the WBB. ICC within device were between 0.90 and 0.96 and between-devices were from 0.80 to 0.84. SEM ranged for the WBB from 9.7 to 13.9%, and for the SID from 11.9 to 13.1%. LOA ranged for the WBB from 20.3 to 28.7% and for the SID from 24.2 to 26.6%. The BAP showed no relationship between the difference and the mean. CONCLUSIONS: A high relative and an acceptable absolute reproducibility combined with a good validity was found for the novel method using the WBB for measuring isometric lower limb strength in older adults. Further research using the WBB for assessing lower limb strength should be conducted in different study-populations. PMID- 26444555 TI - Bisphosphonate Use and Risk of Implant Revision after Total Hip/Knee Arthroplasty: A Meta-Analysis of Observational Studies. AB - OBJECTIVE: Several studies investigated the association between bisphosphonate use and the risk of implant revision after total hip or knee arthroplasty (THA or TKA); However, the findings were inconsistent. We performed this meta-analysis to evaluate the overall relative risk of such an event. METHODS: We searched the PubMed, EMBASE and Cochrane library databases to identify relevant publications on April 22, 2015. To calculate the pooled risk ratios (RRs) with 95% confidential intervals (CIs), a fixed- or random-effects model was applied based on the heterogeneity across studies. RESULTS: Three cohort studies and one case control study were included in this meta-analysis. Compared with the bisphosphonate nonusers, the patients who used bisphosphonates for a long period of time had a significantly decreased risk of implant revision after THA/TKA (summary adjusted RR = 0.48, 95% CI: 0.38-0.61), and the summary adjusted RRs for the users who underwent THA and those who underwent TKA were 0.47 (95% CI: 0.36 0.61) and 0.45 (95% CI: 0.21-0.95), respectively. CONCLUSIONS: Long-term use of bisphosphonates is correlated with a significantly decreased risk of implant revision after THA/TKA. However, due to limited number of the included studies, the findings of the present study should be treated with caution. More well designed studies are required to further confirm our findings. PMID- 26444556 TI - Surface-enhanced Raman scattering from AgNP-graphene-AgNP sandwiched nanostructures. AB - We developed a facile approach toward hybrid AgNP-graphene-AgNP sandwiched structures using self-organized monolayered AgNPs from wet chemical synthesis for the optimized enhancement of the Raman response of monolayer graphene. We demonstrate that the Raman scattering of graphene can be enhanced 530 fold in the hybrid structure. The Raman enhancement is sensitively dependent on the hybrid structure, incident angle, and excitation wavelength. A systematic simulation is performed, which well explains the enhancement mechanism. Our study indicates that the enhancement resulted from the plasmonic coupling between the AgNPs on the opposite sides of graphene. Our approach towards ideal substrates offers great potential to produce a "hot surface" for enhancing the Raman response of two-dimensional materials. PMID- 26444557 TI - Markers for Routine Assessment of Fatigue and Recovery in Male and Female Team Sport Athletes during High-Intensity Interval Training. AB - AIM: Our study aimed to investigate changes of different markers for routine assessment of fatigue and recovery in response to high-intensity interval training (HIIT). METHODS: 22 well-trained male and female team sport athletes (age, 23.0 +/- 2.7 years; VO2 max, 57.6 +/- 8.6 mL . min . kg(-1)) participated in a six-day running-based HIIT-microcycle with a total of eleven HIIT sessions. Repeated sprint ability (RSA; criterion measure of fatigue and recovery), countermovement jump (CMJ) height, jump efficiency in a multiple rebound jump test (MRJ), 20-m sprint performance, muscle contractile properties, serum concentrations of creatinkinase (CK), c-reactive protein (CRP) and urea as well as perceived muscle soreness (DOMS) were measured pre and post the training program as well as after 72 h of recovery. RESULTS: Following the microcycle significant changes (p < 0.05) in RSA as well as in CMJ and MRJ performance could be observed, showing a decline (%Delta +/- 90% confidence limits, ES = effect size; RSA: -3.8 +/- 1.0, ES = -1.51; CMJ: 8.4 +/- 2.9, ES = -1.35; MRJ: 17.4 +/- 4.5, ES = -1.60) and a return to baseline level (RSA: 2.8 +/- 2.6, ES = 0.53; CMJ: 4.1 +/- 2.9, ES = 0.68; MRJ: 6.5 +/- 4.5, ES = 0.63) after 72 h of recovery. Athletes also demonstrated significant changes (p < 0.05) in muscle contractile properties, CK, and DOMS following the training program and after the recovery period. In contrast, CRP and urea remained unchanged throughout the study. Further analysis revealed that the accuracy of markers for assessment of fatigue and recovery in comparison to RSA derived from a contingency table was insufficient. Multiple regression analysis also showed no correlations between changes in RSA and any of the markers. CONCLUSIONS: Mean changes in measures of neuromuscular function, CK and DOMS are related to HIIT induced fatigue and subsequent recovery. However, low accuracy of a single or combined use of these markers requires the verification of their applicability on an individual basis. PMID- 26444559 TI - Substance P and Chronic Pain in Patients with Chronic Inflammation of Connective Tissue. AB - OBJECTIVE: Evidence suggests that substance P (SP) is involved in chronic joint inflammation, such as the pathogenesis of rheumatoid arthritis and osteoarthritis. The goal of the research was to evaluate the correlation between chronic pain and changes in the SP level in patients with chronic inflammation of the connective tissue. METHODS: Patients with osteoarthritis and rheumatoid arthritis were enrolled in this study. The relationship between chronic pain intensity and the serum SP concentration was evaluated in these groups of patients with osteoarthritis and rheumatoid arthritis. RESULTS: The results showed a positive correlation between the serum SP concentrations and chronic pain intensity. CONCLUSIONS: 1. The SP serum concentration was significantly different between the groups of patients with OA and RA. 2. There was a positive correlation between the serum SP concentration and chronic pain intensity in OA and RA patients. PMID- 26444558 TI - Genetic Transformation of Artemisia carvifolia Buch with rol Genes Enhances Artemisinin Accumulation. AB - The potent antimalarial drug artemisinin has a high cost, since its only viable source to date is Artemisia annua (0.01-0.8% DW). There is therefore an urgent need to design new strategies to increase its production or to find alternative sources. In the current study, Artemisia carvifolia Buch was selected with the aim of detecting artemisinin and then enhancing the production of the target compound and its derivatives. These metabolites were determined by LC-MS in the shoots of A. carvifolia wild type plants at the following concentrations: artemisinin (8MUg/g), artesunate (2.24MUg/g), dihydroartemisinin (13.6MUg/g) and artemether (12.8MUg/g). Genetic transformation of A. carvifolia was carried out with Agrobacterium tumefaciens GV3101 harboring the rol B and rol C genes. Artemisinin content increased 3-7-fold in transgenics bearing the rol B gene, and 2.3-6-fold in those with the rol C gene. A similar pattern was observed for artemisinin analogues. The dynamics of artemisinin content in transgenics and wild type A.carvifolia was also correlated with the expression of genes involved in its biosynthesis. Real time qPCR analysis revealed the differential expression of genes involved in artemisinin biosynthesis, i.e. those encoding amorpha-4, 11 diene synthase (ADS), cytochrome P450 (CYP71AV1), and aldehyde dehydrogenase 1 (ALDH1), with a relatively higher transcript level found in transgenics than in the wild type plant. Also, the gene related to trichome development and sesquiterpenoid biosynthesis (TFAR1) showed an altered expression in the transgenics compared to wild type A.carvifolia, which was in accordance with the trichome density of the respective plants. The trichome index was significantly higher in the rol B and rol C gene-expressing transgenics with an increased production of artemisinin, thereby demonstrating that the rol genes are effective inducers of plant secondary metabolism. PMID- 26444560 TI - Biomass and lipid enhancement in Ankistrodesmus sp. cultured with reused and minimal nutrients media. AB - Microalgae are a promising feedstock for biofuel production. Lipid content in microalgae could be enhanced under nutrient depletion. This work investigated the effect of the nutrient on lipid accumulation in Ankistrodesmus sp. culture. Batch cultures were carried out using fresh BG11 medium, and after the harvest, the medium was reused for the next culture; this method was repeated two times. The maximum lipid productivity of 29.75 mg L(-1) day(-1) was obtained from the culture with the second reuse medium. In continuous cultures, Ankistrodesmus sp. was cultured in both fresh and modified BG11 mediums. The modified BG11 medium was adjusted to resemble the content of the first reuse medium. As a comparison between batch and continuous cultures, it was proven that the productivity in the continuous culture was better than in the batch, where the achievable maximum biomass and lipid were 188.30 and 38.32 mg L(-1) day(-1). The maximum lipid content of 34.22% was obtained from the continuous culture at a dilution rate of 0.08 day(-1), whereas the maximum saturated and unsaturated fatty acid productivities of 79.96 and 104.54 mg L(-1) day(-1) were obtained at a dilution rate of 0.16 day(-1.) PMID- 26444561 TI - Cells on biomaterials--some aspects of elemental analysis by means of electron probes. AB - Electron probe X-ray microanalysis enables concomitant observation of specimens and analysis of their elemental composition. The method is attractive for engineers developing tissue-compatible biomaterials. Either changes in element composition of cells or biomaterial can be defined according to well-established preparation and quantification procedures. However, the qualitative and quantitative elemental analysis appears more complicated when cells or thin tissue sections are deposited on biomaterials. X-ray spectra generated at the cell/tissue-biomaterial interface are modelled using a Monte Carlo simulation of a cell deposited on borosilicate glass. Enhanced electron backscattering from borosilicate glass was noted until the thickness of the biological layer deposited on the substrate reached 1.25 MUm. It resulted in significant increase in X-ray intensities typical for the elements present in the cellular part. In this case, the mean atomic number value of the biomaterial determines the strength of this effect. When elements are present in the cells only, the positive linear relationship appears between X-ray intensities and cell thickness. Then, spatial dimensions of X-ray emission for the particular elements are exclusively in the range of the biological part and the intensities of X-rays become constant. When the elements are present in both the cell and the biomaterial, X-ray intensities are registered for the biological part and the substrate simultaneously leading to a negative linear relationship of X-ray intensities in the function of cell thickness. In the case of the analysis of an element typical for the biomaterial, strong decrease in X-ray emission is observed in the function of cell thickness as the effect of X-ray absorption and the limited excitation range to biological part rather than to the substrate. Correction procedures for calculations of element concentrations in thin films and coatings deposited on substrates are well established in materials science, but little is known about factors that have to be taken into account to accurately quantify bioelements in thin and semi-thick biological samples. Thus thorough tests of currently available quantification procedures are required to verify their applicability to cells or tissues deposited on the biomaterials. PMID- 26444562 TI - High-Performance Lead-Free Piezoceramics with High Curie Temperatures. AB - A bismuth ferrite and barium titanate solid solution compound can achieve good piezoelectric properties with a high Curie temperature when fabricated with low temperature sintering followed by a water-quenching process, with no complicated grain alignment processes performed. By adding the super-tetragonal bismuth gallium oxide to the compound, the piezoelectric properties are as good as those of lead zirconate titanate ceramics. PMID- 26444563 TI - Relationship between Objective and Subjective Atmospheric Visibility and Its Influence on Willingness to Accept or Pay in China. AB - This study is to distinguish the objective and subjective measures of atmospheric visibility, and investigate the relationship between the two measures as well as the effect on the people's behavioral intentions on air pollution in China. A mixed method was adopted in this study combining both lab experiments to measure objective atmospheric visibility and a questionnaire survey to measure subjective atmospheric visibility. The regression results show that: (a) The people's perception of atmospheric visibility is based on objective information about the ambient air (Relative Humidity, PM2.5, Atmospheric Visibility) and there are some turning points that could enable people to distinguish good and poor air quality; (b) The people's perception of visibility has a significant effect on either their willingness-to-accept (WTA) the visibility or on their willingness-to-pay (WTP) for improving the air quality; PMID- 26444564 TI - Factors Affecting Growth of Tengmalm's Owl (Aegolius funereus) Nestlings: Prey Abundance, Sex and Hatching Order. AB - In altricial birds, energy supply during growth is a major predictor of the physical condition and survival prospects of fledglings. A number of experimental studies have shown that nestling body mass and wing length can vary with particular extrinsic factors, but between-year observational data on this topic are scarce. Based on a seven-year observational study in a central European Tengmalm's owl population we examine the effect of year, brood size, hatching order, and sex on nestling body mass and wing length, as well as the effect of prey abundance on parameters of growth curve. We found that nestling body mass varied among years, and parameters of growth curve, i.e. growth rate and inflection point in particular, increased with increasing abundance of the owl's main prey (Apodemus mice, Microtus voles), and pooled prey abundance (Apodemus mice, Microtus voles, and Sorex shrews). Furthermore, nestling body mass varied with hatching order and between sexes being larger for females and for the first hatched brood mates. Brood size had no effect on nestling body mass. Simultaneously, we found no effect of year, brood size, hatching order, or sex on the wing length of nestlings. Our findings suggest that in this temperate owl population, nestling body mass is more sensitive to prey abundance than is wing length. The latter is probably more limited by the physiology of the species. PMID- 26444565 TI - Development of Active Films From Pectin and Fruit Extracts: Light Protection, Antioxidant Capacity, and Compounds Stability. AB - Pectin films containing fruit extracts were developed and tested in relation to ultraviolet light transmission, phytochemical contents, and antioxidant capacity during 90 d shelf life storage. Aqueous and alcoholic extracts from 5 different fruits (acerola, cashew apple, papaya, pequi, and strawberry) were obtained. Because the alcoholic extracts from acerola, cashew apple, and strawberry presented the highest phytochemical content and antioxidant capacity, they were incorporated into pectin films individually or as a mixture. Incorporation of these extracts into pectin films provided antioxidant capacity while retaining the physical properties. The pectin films containing fruit extract acted as adequate light barrier and prevented photooxidation. Among the prepared films, the pectin film containing acerola extract afforded the highest antioxidant capacity, with a half-life of 99 d. Overall, the results revealed that incorporation of fruit extracts into pectin films potentially produces antioxidant films and coatings for different food applications. PRACTICAL APPLICATION: The production of pectin films incorporated with fruit extract is based on combination of the antioxidant activity, natural color, and optical barrier properties from fruit phytochemical components to the active film. This film could be potentially used as active packing on food products in order to protect their nutrients against free radicals action and photooxidation and, hence, preserve the quality, integrity, and safety of food during the storage period. PMID- 26444567 TI - The Changing Landscape of Noninvasive Ventilation in the Intensive Care Unit. PMID- 26444566 TI - Genetic Polymorphisms in Inflammasome-Dependent Innate Immunity among Pediatric Patients with Severe Renal Parenchymal Infections. AB - BACKGROUND: Inflammasome innate immune response activation has been demonstrated in various inflammatory diseases and microbial infections. However, to our knowledge, no study has examined the inflammasome-dependent pathways in patients with urinary tract infection. Defective or variant genes associated with innate immunity are believed to alter the host's susceptibility to microbial infection. This study investigated genetic polymorphisms in genes encoding inflammasomes and the subsequent released cytokines in pediatric patients with severe renal parenchymal infections. METHODOLOGY: This study included patients diagnosed with acute pyelonephritis (APN) and acute lobar nephronia (ALN) who had no underlying disease or structural anomalies other than vesicoureteral reflux (VUR). Single nucleotide polymorphism (SNP) genotyping was performed in the genes associated with inflammasome formation and activation (NLRP3, CARD8) and subsequent IL-1beta cytokine generation (IL-1beta). PRINCIPAL FINDINGS: A total of 40 SNPs were selected for initial genotyping. Analysis of samples from 48 patients each and 96 controls revealed that only nine SNPs (five SNPs in NLRP3; three SNPs in CARD8; one SNP in IL-1beta) had heterozygosity rates >0.01. Hardy-Weinberg equilibrium was satisfied for the observed genotype frequencies of these SNPs. Analysis excluding patients with VUR, a well-known risk factor for severe UTIs, revealed a lower frequency of the CC genotype in NLRP3 (rs4612666) in patients with APN and ALN than in controls. Correction for multiple-SNP testing showed that the non-VUR subgroup of the APN+ALN combined patient groups remained significantly different from the control group (P < 0.0055). CONCLUSIONS: This study is the first to suggest that the inflammasome-dependent innate immunity pathway is associated with the pathogenesis of pediatric severe renal parenchymal infections. Further investigation is warranted to clarify its pathogenic mechanism. PMID- 26444568 TI - Is C50 a superaromat? Evidence from electronic structure and ring current calculations. AB - The fullerene-50 is a 'magic number' cage according to the 2(N + 1)(2) rule. For the three lowest isomers of C50 with trigonal and pentagonal symmetries, we calculate the sphericity index, the spherical parentage of the occupied pi orbitals, and the current density in an applied magnetic field. The minimal energy isomer, with D3 symmetry, comes closest to a spherical aromat or a superaromat. In the D5h bond-stretch isomers the electronic structure shows larger deviations from the ideal spherical shells, with hybridisation or even reversal of spherical parentages. It is shown that relative stabilities of fullerene cages do not correlate well with aromaticity, unlike the magnetic properties which are very sensitive indicators of spherical aromaticity. Superaromatic diamagnetism in the D3 cage is characterized by global diatropic currents, which encircle the whole cage. The breakdown of sphericity in the D5h cages gives rise to local paratropic countercurrents. PMID- 26444569 TI - Blood Transfusion and 30-Day Mortality in Patients With Coronary Artery Disease and Anemia Following Noncardiac Surgery. AB - IMPORTANCE: Although liberal blood transfusion thresholds have not been beneficial following noncardiac surgery, it is unclear whether higher thresholds are appropriate for patients who develop postoperative myocardial infarction (MI). OBJECTIVE: To evaluate the association between postoperative blood transfusion and mortality in patients with coronary artery disease and postoperative MI following noncardiac surgery. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study involving Veterans Affairs facilities from January 1, 2000, to December 31, 2012. A total of 7361 patients with coronary artery disease who underwent inpatient noncardiac surgery and had a nadir postoperative hematocrit between 20% and 30%. Patients with significant bleeding, including any preoperative blood transfusion or transfusion of greater than 4 units during the intraoperative or postoperative setting, were excluded. Mortality rates were compared using both logistic regression and propensity score matching. Patients were stratified by postoperative nadir hematocrit and the presence of postoperative MI. EXPOSURE: Initial postoperative blood transfusion. MAIN OUTCOMES AND MEASURES: The 30-day postoperative mortality rate. RESULTS: Of the 7361 patients, 2027 patients (27.5%) received at least 1 postoperative blood transfusion. Postoperative mortality occurred in 267 (3.6%), and MI occurred in 271 (3.7%). Among the 5334 patients without postoperative blood transfusion, lower nadir hematocrit was associated with an increased risk for mortality (hematocrit of 20% to <24%: 7.3%; 24% to <27%: 3.7%; and 27% to 30%: 1.6%; P < .01). In patients with postoperative MI, blood transfusion was associated with lower mortality, for those with hematocrit of 20% to 24% (odds ratio, 0.28; 95% CI, 0.13-0.64). In patients without postoperative MI, transfusion was associated with significantly higher mortality for those with hematocrit of 27% to 30% (odds ratio, 3.21; 95% CI, 1.85-5.60). CONCLUSIONS AND RELEVANCE: These findings support a restrictive postoperative transfusion strategy in patients with stable coronary artery disease following noncardiac surgery. However, interventional studies are needed to evaluate the use of a more liberal transfusion strategy in patients who develop postoperative MI. PMID- 26444570 TI - Bullying and Its Prevention Among Intensive Care Nurses. AB - PURPOSE: International studies report that nurse bullying is a common occurrence. The intensive care unit (ICU) is known for its high stress levels, one factor thought to increase bullying. No studies were found that investigated bullying in this population. The purpose of this study was to describe the prevalence of ICU nurse bullying and what measures were taken to prevent bullying. DESIGN: This was a descriptive study of a convenience sample of 156 ICU nurses from five medical centers in Israel. Data collection was conducted over a 10-month period in 2012 and 2013. METHODS: After ethical approval, three questionnaires (background characteristics, Negative Acts Questionnaire-Revised, and Prevention of Bullying Questionnaire) were administered according to unit preference. Descriptive statistics were calculated for all responses and a Pearson product moment correlation was calculated to determine the relationship between bullying and its prevention. FINDINGS: Most of the nurses in the study were married, female staff nurses with a baccalaureate in nursing. No participant responded that they had been bullied daily, but 29% reported that they were a victim of bullying. The mean bullying score was 1.6 +/- 1.4 out of 5. The mean prevention score was 2.4 +/- 0.3 out of 4. Significant differences were found between hospitals on bullying, F (4,155) = 2.7, p = .039, and between hospitals, F (4,155) = 2.9, p = .026, and units, F (5,143) = 3.4, p = .006, on prevention. The Prevention Scale significantly correlated with the bullying scale (r = .58, p < .001). No other variables were found to be associated with either bullying or prevention scores. CONCLUSIONS: An alarming percentage of nurses were victims of bullying. Levels of bullying were low to moderate. Level of prevention was weak or moderate. The higher the level of bullying, the lower the level of prevention. The work environment as opposed to individual characteristics seems to have an impact on bullying and its prevention. CLINICAL RELEVANCE: More measures must be taken to prevent bullying. Nurses must be educated to accept only a zero tolerance to bullying and to report bullying when confronted by bullying. PMID- 26444571 TI - Local outbreak of hepatitis E: a rare cause of viral hepatitis in Australia. AB - Hepatitis E is a not uncommon cause of viral hepatitis globally but is relatively rare in Australia. Here, we report a case of acute hepatitis E that was acquired in Sydney and was part of a cluster believed to be infected locally. This is to our knowledge the first known outbreak of locally acquired hepatitis E in Australia. We discuss pathogenesis, clinical features and means by which further spread of infection can be limited. PMID- 26444572 TI - Reward related neurotransmitter changes in a model of depression: An in vivo microdialysis study. AB - OBJECTIVES: The self-medication hypothesis assumes that symptoms related to potential monoaminergic deficits in depression may be relieved by drug abuse. The aim of this study was to elucidate the neurotransmitter changes in a rat model of depression by measuring their levels in the nucleus accumbens shell, which is typically involved in the drug of abuse acquisition mechanism. METHODS: Depression was modelled by the olfactory bulbectomy (OBX) in Wistar male rats. In vivo microdialysis was performed, starting from the baseline and following after a single methamphetamine injection and behaviour was monitored. The determination of neurotransmitters and their metabolites was performed by high-performance liquid chromatography combined with mass spectrometry. RESULTS: OBX animals had lower basal levels of dopamine and serotonin and their metabolites. However, gamma-aminobutyric acid (GABA) and glutamate levels were increased. The methamphetamine injection induced stronger dopamine and serotonin release in the OBX rats and lower release of glutamate in comparison with sham-operated rats; GABA levels did not differ significantly. CONCLUSIONS: This study provides an evidence of mesolimbic neurotransmitter changes in the rat model of depression which may elucidate mechanisms underlying intravenous self-administration studies in which OBX rats were demonstrated to have higher drug intake in comparison to intact controls. PMID- 26444573 TI - Transcriptome Analysis of CD4+ T Cells in Coeliac Disease Reveals Imprint of BACH2 and IFNgamma Regulation. AB - Genetic studies have to date identified 43 genome wide significant coeliac disease susceptibility (CD) loci comprising over 70 candidate genes. However, how altered regulation of such disease associated genes contributes to CD pathogenesis remains to be elucidated. Recently there has been considerable emphasis on characterising cell type specific and stimulus dependent genetic variants. Therefore in this study we used RNA sequencing to profile over 70 transcriptomes of CD4+ T cells, a cell type crucial for CD pathogenesis, in both stimulated and resting samples from individuals with CD and unaffected controls. We identified extensive transcriptional changes across all conditions, with the previously established CD gene IFNy the most strongly up-regulated gene (log2 fold change 4.6; P(adjusted) = 2.40x10(-11)) in CD4+ T cells from CD patients compared to controls. We show a significant correlation of differentially expressed genes with genetic studies of the disease to date (P(adjusted) = 0.002), and 21 CD candidate susceptibility genes are differentially expressed under one or more of the conditions used in this study. Pathway analysis revealed significant enrichment of immune related processes. Co-expression network analysis identified several modules of coordinately expressed CD genes. Two modules were particularly highly enriched for differentially expressed genes (P<2.2x10(-16)) and highlighted IFNy and the genetically associated transcription factor BACH2 which showed significantly reduced expression in coeliac samples (log2FC -1.75; P(adjusted) = 3.6x10(-3)) as key regulatory genes in CD. Genes regulated by BACH2 were very significantly over-represented among our differentially expressed genes (P<2.2x10(-16)) indicating that reduced expression of this master regulator of T cell differentiation promotes a pro-inflammatory response and strongly corroborates genetic evidence that BACH2 plays an important role in CD pathogenesis. PMID- 26444575 TI - FTIR microscopy reveals distinct biomolecular profile of crustacean digestive glands upon subtoxic exposure to ZnO nanoparticles. AB - Biomolecular profiling with Fourier-Transform InfraRed Microscopy was performed to distinguish the Zn(2+)-mediated effects on the crustacean (Porcellio scaber) digestive glands from the ones elicited by the ZnO nanoparticles (NPs). The exposure to ZnO NPs or ZnCl2 (1500 and 4000 ug Zn/g of dry food) activated different types of metabolic pathways: some were found in the case of both substances, some only in the case of ZnCl2, and some only upon exposure to ZnO NPs. Both the ZnO NPs and the ZnCl2 increased the protein (~1312 cm(-1); 1720 1485 cm(-1)/3000-2830 cm(-1)) and RNA concentration (~1115 cm(-1)). At the highest exposure concentration of ZnCl2, where the effects occurred also at the organismal level, some additional changes were found that were not detected upon the ZnO NP exposure. These included changed carbohydrate (most likely glycogen) concentrations (~1043 cm(-1)) and the desaturation of cell membrane lipids (~3014 cm(-1)). The activation of novel metabolic pathways, as evidenced by changed proteins' structure (at 1274 cm(-1)), was found only in the case of ZnO NPs. This proves that Zn(2+) are not the only inducers of the response to ZnO NPs. Low bioavailable fraction of Zn(2+) in the digestive glands exposed to ZnO NPs further supports the role of particles in the ZnO NP-generated effects. This study provides the evidence that ZnO NPs induce their own metabolic responses in the subtoxic range. PMID- 26444576 TI - Response to Carlsson et al.: Prevalence and incidence of diabetes mellitus: a nationwide population-based pharmaco-epidemiological study in Sweden. PMID- 26444577 TI - Asthma-like symptoms, diagnostic tests, and asthma medication use in children and adolescents: a population-based nationwide survey. AB - OBJECTIVE: This study aimed to estimate the prevalence of asthma-like symptoms, current asthma (CA), asthma diagnostic tests, and inhaled medication use in a nationwide pediatric population (<18 years). METHODS: Pediatric-specific data from a cross-sectional, population-based telephone survey (INAsma study) in Portugal were analyzed. CA was defined as lifetime asthma and (1) wheezing, (2) waking with breathlessness, or (3) asthma attack in the previous 12 months, and/or (4) taking asthma medication at the time of the interview. RESULTS: In total, 716 children were included. The prevalence of asthma-like symptoms was 39.4% [95% confidence interval (95% CI): 35.7-43.3]. The most common symptoms were waking with cough (30.9%) and wheezing (19.1%). The prevalence of CA was 8.4% (95% CI: 6.6-10.7). Among children with CA, 79.9% and 52.9% reported prior allergy testing and pulmonary function testing (PFT), respectively. Inhaled medication use in the previous 12 months was reported by 67.6% (reliever inhalers, 40.1%; controller inhalers, 41.5%). Those who only used inhaled reliever medications experienced more asthma attacks [odds ratio (OR): 2.69]. Significantly fewer children with CA living in rural areas than those living in urban areas had undergone PFT or used inhaled medication (OR: 0.06 for PFT, 0.20 for medication]. CONCLUSIONS: The prevalence of CA in the Portuguese pediatric population was 8.4%. Only half of children with CA had ever undergone PFT; more than half did not use controller inhalers, and those who only used reliever inhalers reported more asthma attacks. These findings suggest that asthma management has been substandard, mainly in rural areas. PMID- 26444578 TI - Purification of intact chloroplasts from marine plant Posidonia oceanica suitable for organelle proteomics. AB - Posidonia oceanica is a marine angiosperm, or seagrass, adapted to grow to the underwater life from shallow waters to 50 m depth. This raises questions of how their photosynthesis adapted to the attenuation of light through the water column and leads to the assumption that biochemistry and metabolism of the chloroplast are the basis of adaptive capacity. In the present study, we described a protocol that was adapted from those optimized for terrestrial plants, to extract chloroplasts from as minimal tissue as possible. We obtained the best balance between tissue amount/intact chloroplasts yield using one leaf from one plant. After isopynic separations, the chloroplasts purity and integrity were evaluated by biochemical assay and using a proteomic approach. Chloroplast proteins were extracted from highly purified organelles and resolved by 1DE SDS-PAGE. Proteins were sequenced by nLC-ESI-IT-MS/MS of 1DE gel bands and identified against NCBInr green plant databases, Dr. Zompo database for seagrasses in a local customized dataset. The curated localization of proteins in sub-plastidial compartments (i.e. envelope, stroma and thylakoids) was retrieved in the AT_CHLORO database. This purification protocol and the validation of compartment markers may serve as basis for sub-cellular proteomics in P. oceanica and other seagrasses. PMID- 26444579 TI - Resolving power for the diffusion orientation distribution function. AB - PURPOSE: The diffusion orientation distribution function (dODF) is primarily used for white matter fiber tractography. Here the resolving power of the dODF is investigated for a simple diffusion model of two intersecting axonal fiber bundles. METHODS: The resolving power for the dODF is evaluated using the Sparrow criterion. This is determined for the exact dODF and also for q-space imaging (QSI), q-ball, and kurtosis approximations. RESULTS: Based on theoretical and numerical calculations, the resolving power is found to depend on the eigenvalues of the diffusion model and on the degree of radial weighting for the dODF. The resolving powers of the QSI and q-ball dODFs improve with increased b-value. The kurtosis dODF has a resolving power similar to that of the exact dODF. CONCLUSION: The dODFs, whether exact or approximate, have finite resolving powers that limit their sensitivity to fiber crossings. The resolving powers for the different dODFs considered here provide convenient benchmarks for assessing and comparing their performance. Magn Reson Med 76:679-688, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26444580 TI - Association of Skin Cancer and Indoor Tanning in Sexual Minority Men and Women. AB - Importance: Skin cancer, the most common cancer in the United States, is highly associated with outdoor and indoor tanning behaviors. Although indoor tanning has been suggested to be more common among sexual minority (self-reported as homosexual, gay, or bisexual) men compared with heterosexual men, whether rates of skin cancer vary by sexual orientation is unknown. Objective: To investigate whether skin cancer prevalence and indoor tanning behaviors vary by sexual orientation in the general population. Design, Setting, and Participants: We performed a cross-sectional study using data from the 2001, 2003, 2005, and 2009 California Health Interview Surveys (CHISs) and the 2013 National Health Interview Survey (NHIS) of population-based samples of the California and US noninstitutionalized civilian population. Participants included 192 575 men and women 18 years or older who identified as heterosexual or a sexual minority. Main Outcomes and Measures: Self-reported lifetime history of skin cancer and 12-month history of indoor tanning. Results: The study included 78 487 heterosexual men, 3083 sexual minority men, 107 976 heterosexual women, and 3029 sexual minority women. Sexual minority men were more likely than heterosexual men to report having skin cancer (2001-2005 CHISs: adjusted odds ratio [aOR], 1.56; 95% CI, 1.18-2.06, P < .001; 2013 NHIS: aOR, 2.13; 95% CI, 1.14-3.96, P = .02) and having tanned indoors (2009 CHIS: aOR, 5.80; 95% CI, 2.90-11.60, P < .001; 2013 NHIS: aOR, 3.16; 95% CI, 1.77-5.64, P < .001). Sexual minority women were less likely than heterosexual women to report having had nonmelanoma skin cancer (2001-2005 CHIS: aOR, 0.56; 95% CI, 0.37-0.86, P = .008) and having tanned indoors (2009 CHIS: aOR, 0.43; 95% CI, 0.20-0.92, P = .03; 2013 NHIS: aOR, 0.46; 95% CI, 0.26 0.81, P = .007). Conclusions and Relevance: Sexual minority men indoor tan more frequently and report higher rates of skin cancer than heterosexual men. Primary and secondary prevention efforts targeted at sexual minority men might reduce risk factors for, and consequences of, skin cancer. PMID- 26444581 TI - Ischemic placental syndrome--prediction and new disease monitoring. AB - The last decade has seen an improved understanding of the cause of the development of pathologies such as gestational hypertension, preeclampsia, intrauterine growth restriction, intrauterine fetal death or placental abruption. Nowadays, we know that most conditions within this group share the same pathogenesis, the cause of which is placental ischemia. The following review is an attempt to propose a new method for prediction, diagnosis and--above all- appropriate monitoring of pregnant women and fetuses developing the ischemic placental syndrome with the use of tests that are new but yet widely available in clinical diagnosis. They are closely related to the condition's pathogenesis, therefore their elevated levels may predate clinical symptoms, and--most importantly--they correlate with syndrome aggravation and the occurrence of complications. Perhaps, the new look will allow us to improve perinatal results by reducing mortality and severe complications in pregnant women and fetal deaths resulting from sudden intrauterine fetal death or placental abruption. PMID- 26444582 TI - Serious Neurologic Events after Epidural Glucocorticoid Injection--The FDA's Risk Assessment. PMID- 26444583 TI - Genotyping of Mycobacterium leprae strains from a region of high endemic leprosy prevalence in India. AB - Leprosy is still a major health problem in India which has the highest number of cases. Multiple locus variable number of tandem repeat analysis (MLVA) and single nucleotide polymorphism (SNP) have been proposed as tools of strain typing for tracking the transmission of leprosy. However, empirical data for a defined population from scale and duration were lacking for studying the transmission chain of leprosy. Seventy slit skin scrapings were collected from Purulia (West Bengal), Miraj (Maharashtra), Shahdara (Delhi), and Naini (UP) hospitals of The Leprosy Mission (TLM). SNP subtyping and MLVA on 10 VNTR loci were applied for the strain typing of Mycobacterium leprae. Along with the strain typing conventional epidemiological investigation was also performed to trace the transmission chain. In addition, phylogenetic analysis was done on variable number of tandem repeat (VNTR) data sets using sequence type analysis and recombinational tests (START) software. START software performs analyses to aid in the investigation of bacterial population structure using multilocus sequence data. These analyses include data summary, lineage assignment, and tests for recombination and selection. Diversity was observed in the cross-sectional survey of isolates obtained from 70 patients. Similarity in fingerprinting profiles observed in specimens of cases from the same family or neighborhood locations indicated a possible common source of infection. The data suggest that these VNTRs including subtyping of SNPs can be used to study the sources and transmission chain in leprosy, which could be very important in monitoring of the disease dynamics in high endemic foci. The present study strongly indicates that multi-case families might constitute epidemic foci and the main source of M. leprae in villages, causing the predominant strain or cluster infection leading to the spread of leprosy in the community. PMID- 26444584 TI - Phylogenetic analysis of a circulating hepatitis C virus recombinant strain 1b/1a isolated in a French hospital centre. AB - Genetic recombination is now a well-established feature of the hepatitis C virus (HCV) variability and evolution, with the recent identification of circulating recombinant forms. In Amiens University Hospital Centre (France), a discrepancy of genotyping results was observed for 9 samples, between their 5' untranslated region assigned to genotype 1b and their NS5B region assigned to genotype 1a, suggesting the existence of a recombinant strain. In the present study, clinical and phylogenetic analyses of these isolates were conducted and a putative relationship with previously identified HCV 1b/1a recombinants was investigated. The results revealed that all 9 strains displayed a breakpoint within the beginning of the core protein, were closely related between each other and with the H23 strain identified in Uruguay (Moreno et al., 2009). Then, the clinical characteristics of the 9 unlinked individuals infected with this 1b/1a genotype were analysed. This is the first report on the circulation, in a French population, of a HCV recombinant strain 1b/1a. The identification of this genotype in other patients and in other geographical zones would allow to further investigate its prevalence in the population and to better understand its molecular epidemiology. PMID- 26444585 TI - The role of Neuropeptide Y in fear conditioning and extinction. AB - While anxiety disorders are the brain disorders with the highest prevalence and constitute a major burden for society, a considerable number of affected people are still treated insufficiently. Thus, in an attempt to identify potential new anxiolytic drug targets, neuropeptides have gained considerable attention in recent years. Compared to classical neurotransmitters they often have a regionally restricted distribution and may bind to several distinct receptor subtypes. Neuropeptide Y (NPY) is a highly conserved neuropeptide that is specifically concentrated in limbic brain areas and signals via at least 5 different G-protein-coupled receptors. It is involved in a variety of physiological processes including the modulation of emotional-affective behaviors. An anxiolytic and stress-reducing property of NPY is supported by many preclinical studies. Whether NPY may also interact with processing of learned fear and fear extinction is comparatively unknown. However, this has considerable relevance since pathological, inappropriate and generalized fear expression and impaired fear extinction are hallmarks of human post-traumatic stress disorder and a major reason for its treatment-resistance. Recent evidence from different laboratories emphasizes a fear-reducing role of NPY, predominantly mediated by exogenous NPY acting on Y1 receptors. Since a reduction of fear expression was also observed in Y1 receptor knockout mice, other Y receptors may be equally important. By acting on Y2 receptors, NPY promotes fear extinction and generates a long-term suppression of fear, two important preconditions that could support cognitive behavioral therapies in human patients. A similar effect has been demonstrated for the closely related pancreatic polypeptide (PP) when acting on Y4 receptors. Preliminary evidence suggests that NPY modulates fear in particular by activation of Y1 and Y2 receptors in the basolateral and central amygdala, respectively. In the basolateral amygdala, NPY signaling activates inhibitory G protein-coupled inwardly-rectifying potassium channels or suppresses hyperpolarization-induced I(h) currents in a Y1 receptor-dependent fashion, favoring a general suppression of neuronal activity. A more complex situation has been described for the central extended amygdala, where NPY reduces the frequency of inhibitory and excitatory postsynaptic currents. In particular the inhibition of long-range central amygdala output neurons may result in a Y2 receptor dependent suppression of fear. The role of NPY in processes of learned fear and fear extinction is, however, only beginning to emerge, and multiple questions regarding the relevance of endogenous NPY and different receptor subtypes remain elusive. Y2 receptors may be of particular interest for future studies, since they are the most prominent Y receptor subtype in the human brain and thus among the most promising therapeutic drug targets when translating preclinical evidence to potential new therapies for human anxiety disorders. PMID- 26444586 TI - Y2 receptor signalling in NPY neurons controls bone formation and fasting induced feeding but not spontaneous feeding. AB - Y2 receptors have been implicated in the development of obesity and are a potential target for obesity treatment due to their known role of inhibiting neuropeptide Y (NPY) induced feeding responses. However, the precise neuronal population on which Y2 receptors act to fulfil this role is less clear. Here we utilise a novel inducible, postnatal onset NPY neurons specific deletion model to investigate the functional consequences of loss of Y2 signalling in this population of neurons on feeding and energy homeostasis regulation. While the consequences of lack of Y2 signalling in NPY neurons are confirmed in terms of the uncoupling of suppression/increasing of NPY and pro-opiomelanocortin (POMC) mRNA expression in the arcuate nuclei (Arc), respectively, this lack of Y2 signalling surprisingly does not have any significant effect on spontaneous food intake. Fasting induced food intake, however, is strongly increased but only in the first 1h after re-feeding. Consequently no significant changes in body weight are being observed although body weight gain is increased in male mice after postnatal onset Y2 deletion. Importantly, another known function of central Y2 receptor signalling, the suppression of bone formation is conserved in this conditional model with whole body bone mineral content being decreased. Taken together this model confirms the critical role of Y2 signalling to control NPY and associated POMC expression in the Arc, but also highlights the possibility that others, non-NPY neuronal Y2 receptors, are also involved in controlling feeding and energy homeostasis regulation. PMID- 26444587 TI - Decreased maternal hypothalamic-pituitary-adrenal axis activity in very severely obese pregnancy: Associations with birthweight and gestation at delivery. AB - BACKGROUND: The maternal hypothalamic-pituitary-adrenal-axis (HPAA) undergoes dramatic activation during pregnancy. Increased cortisol and corticotrophin releasing-hormone (CRH) associate with low birthweight and preterm labor. In non pregnant obesity, the HPAA is activated but circulating cortisol levels are normal or lower than in lean women. We hypothesized that maternal cortisol levels would be lower in obese pregnancy, and would associate with increased fetal size and length of gestation. METHOD: Fasting serum cortisol was measured at 16, 28 and 36 weeks gestation and at 3-6 months postpartum in 276 severely obese and 135 lean women. In a subset of obese (n=20) and lean (n=20) we measured CRH, hormones that regulate bioavailable cortisol (corticosteroid-binding-globulin, estradiol, estriol, and progesterone). Urinary glucocorticoid metabolites were measured in pregnant (obese n=6, lean n=5) and non-pregnant (obese n=7, lean n=7) subjects. RESULTS: Maternal cortisol and HPAA hormones were lower in obese pregnancy. Total urinary glucocorticoid metabolites increased significantly in lean pregnancy, but not in obese. Lower maternal cortisol in obese tended to be associated with increased birthweight (r=-0.13, p=0.066). In obese, CRH at 28 weeks correlated inversely with gestational length (r=-0.49, p=0.04), and independently predicted gestational length after adjustment for confounding factors (mean decrease in CRH of -0.25 pmol/L (95% CI -0.45 to -0.043 pmol/L) per/day increase in gestation). CONCLUSION: In obese pregnancy, lower maternal cortisol without an increase in urinary glucocorticoid clearance may indicate a lesser activation of the HPAA than in lean pregnancy. This may offer a novel mechanism underlying increased birthweight and longer gestation in obese pregnancy. PMID- 26444588 TI - Are leptin levels increased among people with schizophrenia versus controls? A systematic review and comparative meta-analysis. AB - OBJECTIVE: Leptin may play a role in the pathophysiology of schizophrenia and it remains unclear if levels are raised compared to controls. Therefore, we performed a systematic review and meta-analysis comparing leptin levels among people with schizophrenia and controls. METHOD: Two authors independently searched major electronic databases from inception until June 2015 for studies measuring blood leptin levels among people with schizophrenia and controls. Random effects meta-analysis calculating hedges g and 95% confidence intervals (CI) and meta-regression analyses were conducted. RESULTS: Twenty-seven articles representing 1674 individuals with schizophrenia (34.6 +/- 6.8 years, 55% male (0 100%), BMI 25.2 +/- 3.1) and 2033 controls (33.9 +/- 7.0 years, 51% male (0 100%), BMI=24.1 +/- 2.1) were included. Across all studies, leptin levels may be marginally higher in schizophrenia (g=0.164, 95% CI -0.014-0.341, p=0.07, Q=217, p<0.01), particularly when one outlier was removed (g=0.196, 95% CI 0.210-0.370, p=0.02) and when we included the smallest effect size from studies with multiple comparisons (g=0.318, 95% CI 0.125-0.510, p=0.001). Leptin levels were higher in multi-episode schizophrenia (g=0.245, 95% CI 0.058-0.433, p=0.01) and females (g=0.557 95% CI 0.16-0.954, p=0.006). Subgroup analyses revealed leptin levels may be higher in participants taking second-generation antipsychotics compared to controls. Multivariate meta-regression demonstrated a lower percentage of males (beta=-0.0064, 95% CI -0.0129 to -0.0002, p=0.05), but not BMI, moderated the results. CONCLUSION: Our results suggest that schizophrenia is associated with increased blood leptin levels compared to controls, which may not be entirely attributable to antipsychotic medication or BMI. Other illness related and lifestyle choices may play a pivotal role. PMID- 26444589 TI - Controlled immobilization of His-tagged proteins for protein-ligand interaction experiments using Ni2+-NTA layer on glass surfaces. AB - Gold surfaces functionalized with nickel-nitrilotriacetic acid (Ni2+-NTA) as self assembled monolayers (SAM) to immobilize histidine (His)-tagged biomolecules are broadly reported in the literature. However, the increasing demand of using microfluidic systems and biosensors takes more and more advantage on silicon technology which provides dedicated glass surfaces and substantially allows cost and resource savings. Here we present a novel method for the controlled oriented immobilization of His-tagged proteins on glass surfaces functionalized with a Ni2+-NTA layer. Exemplarily, the protein pattern morphology after immobilization on the Ni2+-NTA layer of His6-tagged soluble receptor for advanced glycation endproducts (sRAGE) was investigated and compared to non-oriented immobilization of sRAGE on amino SAM by using scanning electron microscopy (SEM). Moreover, we demonstrated interaction of immobilized sRAGE with three structurally different ligands, S100A12, S100A4, and glycated low density lipoproteins (glycLDL), by means of peak-force tapping atomic force microscopy (PF-AFM). We showed a clear discrimination of different protein-ligand orientations by differential height measurements. PMID- 26444590 TI - Analysis of microcirculation measurements by novice users trained by a standardized interactive tutorial: An inter-observer variability study. AB - Excessive time for analysis may impede microcirculatory studies with large amounts of video data. Engaging more personnel in the analyses seems to be a rational approach in that scenario and could shorten the time-interval between capturing images and obtaining results. Our hypothesis was that novice users would be able to determine standard microcirculatory parameters using a semi automated software with an acceptable degree of variability after participating in a standardized interactive training session. 14 volunteers were included in the study. All volunteers analyzed separately the same sample video after the training. The kappa statistic was calculated for the primary outcome parameter microvascular flow index (MFI) within small and large vessels and indicated a fair level of agreement in the results of the novice users. A standardized interactive tutorial can be useful to teach microcirculatory analysis in previously untrained subjects. PMID- 26444591 TI - Influence of blood pressure variability on the life of arteriovenous fistulae in maintenance hemodialysis patients. AB - BACKGROUND: Although numerous risk factors for arteriovenous fistulae (AVF) dysfunction have been identified, these risk factors do not explain all cases of AVF dysfunction. Because of the importance of blood pressure variability (BPV) in vascular injury, the predictive value of BPV for AVF dysfunction, was evaluated in this prospective cohort study. METHODS: Twenty-four-hour BP monitoring at the intervals of dialysis was recorded every 3 months in 137 patients. The expression of smooth muscle actin (SMA) and the infiltration of mononuclear cells and T lymphocytes were determined by immunohistochemistry on the specimens of fistula vessels. RESULTS: Eighteen patients developed AVF dysfunction. Cox proportional hazards multivariate analysis revealed a significant relationship between fistula dysfunction and daytime systolic-BPV (d-SBPV), nighttime systolic-BPV (n-SBPV), diabetes mellitus, and initial venous diameter. Patients with AVF dysfunction were observed to have increased SMA expression and more infiltration of inflammatory cells in venous walls compared with the controls. A significant correlation between SBPV and the infiltration of CD68-positive cells was observed. CONCLUSIONS: Our study showed that the degrees of SBPV were significantly associated with the risk of AVF dysfunction. Potentially, the increase of SBPV will aggravate venous wall inflammation and may play a role in AVF dysfunction. PMID- 26444593 TI - Measurement of platelet aggregation functions using whole blood migration ratio in a microfluidic chip. AB - Platelets play a major role in maintaining endothelial integrity and hemostasis. Of the various soluble agonists, ADP is an important in vivo stimulus for inducing platelet aggregation. In this study, a simple, rapid, and affordable method was designed for testing bleeding time (BT) and platelet aggregation with a two-channel microfluidic chip. Whole blood migration ratio (MR) from a microchip system was evaluated in comparison to the closure time (CT) from PFA 100 assays (Siemens, Germany) and CD62P expression on platelets. To induce platelet aggregation, a combination of collagen (1.84 mg/ml) and ADP (37.5 mg/ml) were used as agonists. After adding the agonists to samples, whole blood MR from the microchip system was measured. The outcome of the assessment depended on reaction time and agonist concentration. MR of whole blood from the microchip system was significantly correlated with CT from PFA-100 (r = 0.61, p < 0.05, n = 60). In addition, MR was negatively correlated with CD62P expression (r =-0.95, p < 0.05, n = 60). These results suggest that the measurement of MR using agonists is an easy, simple and efficient method for monitoring platelet aggregation in normal and ADP-receptors defective samples, along with the BT test. Thus, usage of the current microfluidic method could expand to diverse applications, including efficacy assessments in platelet therapy. PMID- 26444594 TI - Perfusion quantification of vascular malformations using contrast-enhanced ultrasound (CEUS) with time intensity curve analysis before and after treatment: First results. AB - AIM: Aim of this pilot-study was to quantify perfusion changes of vascular malformations before and after the first interventional treatment using contrast enhanced ultrasound (CEUS). MATERIAL AND METHODS: 29 patients (10 male, 19 female) between 6 and 63 years (mean 28.1 years) with 12 arterio-venous (AVM) and 17 venous malformations (VM) were examined before and after their first percutaneous interventional treatment. CEUS was performed with a 2.4 ml bolus injection of sulfur-hexafluorid microbubbles, and a 6-9 MHz mulitfrequency transducer. A 60 sec cine sequence was recorded and regions of interest (10 mm*30 mm) were defined in the centre, and the margins of the vascular malformation as well as in the surrounding healthy tissue. Time Intensity Curves (TIC) were analysed, and Time to Peak (TTP) as well as Area under the Curve (AUC) were calculated. RESULTS: For VM there was a significant perfusion difference (p < 0.05) in AUC between centre and the surrounding tissue before (323.1 vs. 130.4 rU) and after treatment (331.0 vs. 106.9 rU). There was no significant difference for TTP in ROIs of VM (19.1 vs. 26.5 sec). After the treatment there was a significant decrease in AUC for all three regions in AVMs, and an increase in TTP for AVM. However TTP for AVM in the centre ROI still remained shorter than in the surrounding tissue even after therapy (20.9 vs. 25.4 sec). CONCLUSION: CEUS with TIC analysis is a promising imaging method for the evaluation of perfusion before and after percutaneous treatment of vascular malformations. AUC decrease indicates therapy-induced changes in perfusion of VM whereas an increase in TTP shows therapy-related changes in AVM. PMID- 26444595 TI - Imaging of idle breast implants with ultrasound-strain elastography- A first experimental study to establish criteria for accurate imaging of idle implants via ultrasound-strain elastography. AB - AIM: To investigate whether there are fundamental sonographic and elastographic criteria to precisely assess different surfaces and fillings of idle breast implants and to determine their most distinctive parameters. This was a comparative study of different unused breast implant materials, neighter in animals nor in humans. This knowledge should be transferred in vivo to develop an objective measurement tool. METHODS: Nine idle breast implants-silicone and polyurethane (PU)-were examined in an experimental study by using ultrasound B mode with tissue harmonic imaging (THI), speckle reduction imaging (SRI, level 0 4), cross-beam (CB, low, medium, high), photopic and the colour coded ultrasound strain elastography with a multifrequency probe (9-15 MHz).Using a standardised protocol the implants' centre as well as the edge were analysed by one experienced examiner. Two independent readers performed analysis and evaluation. For image interpretation a score was created (score 0:inadequate image, score 5:best image quality). RESULTS: The highest score result for the centre was achieved by using ultrasound with B-mode in addition with CB level medium, SRI level 2, THI and photopic (mean:3.22+/-SD:1.56), but without any statistic significant difference (t-value = 0.71). With elastography the implants' edge in general was represented without disruptive artefacts (3.89+/-0.60) with statistic significant difference (t-value = 5.29). Implants filled with inner cohesive silicone gel II degrees showed best imaging conditions for their centre via ultrasound (5+/-0) as well as for their edge via elastography (4.50+/-0.71). CONCLUSION: Ultrasound-strain elastography and high resolution ultrasound represent a valuable measurement tool to evaluate different properties of idle breast implants. These modified ultrasound examinations could be an additional help for clinical investigations and be correlated with Baker's Classification. PMID- 26444592 TI - Impaired blood rheology is associated with endothelial dysfunction in patients with coronary risk factors. AB - To investigate the relationship between blood rheology and endothelial function in patients with coronary risk factors, brachial arterial flow-mediated vasodilatation (FMD), an index of endothelial function and blood passage time (BPT), an index of blood rheology, and fasting blood cell count, glucose metabolism, and plasma fibrinogen, lipid, C-reactive protein, and whole blood viscosity levels were measured in 95 patients with coronary risk factors and 37 healthy controls. Brachial arterial FMD after reactive hyperemia was assessed by ultrasonography. BPT was assessed using the microchannel method. In healthy controls, BPT significantly correlated with FMD (r = - 0.325, p < 0.05), HDL cholesterol (r = - 0.393, p < 0.05), body mass index (BMI; r = 0.530, p < 0.01), and plasma fibrinogen concentration (r = 0.335, p < 0.05). In a multivariate regression analysis adjusted for all clinical variables, BPT remained significantly associated with BMI and fibrinogen, but not with FMD, in healthy controls. In patients with coronary risk factors, BPT significantly correlated with FMD (r = - 0.331, p < 0.01), HDL cholesterol (r = - 0.241, p < 0.05), BMI (r = 0.290, p < 0.01), hematocrit (r = 0.422, p < 0.001), white blood cell count (r = 0.295, p < 0.01), platelet count (r = 0.204, p < 0.05), and insulin (r = 0.210, p < 0.05). In a multivariate regression analysis adjusted for all clinical variables, BPT remained strongly associated with FMD and hematocrit in patients with coronary risk factors. These data indicate that BPT is closely associated with FMD in patients with coronary risk factors and suggest that the measurement of blood rheology using the microchannel method may be useful in evaluating brachial arterial endothelial function as a marker of atherosclerosis in these patients. PMID- 26444596 TI - Contrast enhanced ultrasound (CEUS) - an unique monitoring technique to assess microvascularization after buried flap transplantation. AB - OBJECTIVE: Incidence of patients requiring complex soft tissue or osseous reconstruction has dramatically increased. However most of the monitoring systems have limitations in tissue penetration and are not able to detect microvascular complications after transplantation of so-called buried-flaps, that have no contact to the surface.Aim of the study was to assess contrast enhanced ultrasound (CEUS) as monitoring tool after buried flap transplantations. METHODS: 20 patients were examined after buried flap transplantation using CEUS. Quantitative perfusion analysis (TIC) was performed with an integrated perfusion software using stored cine-loops. Two perfusion-parameters, time to PEAK (TtoPk) and area under the curve (Area), were evaluated using TIC analysis. RESULTS: Minor complications were observed in 3 patients. In these patients a delayed contrast agent wash-in and wash-out was observed. Additionally the perfusion values TtoPk (sec.) and Area (relative Units) were clearly different in the patients with minor complications: TtoPk: 32.0 sec; Area 425.5 rU (without complication), TtoPk: 38.6 sec.; Area: 18.3 rU (wound healing disturbance) and TtoPk: 14.4 sec.; Area: 105.9 rU (hematoma). CONCLUSION: As CEUS can assess microvascularization almost depth-independent, CEUS is an unique method to assess global flap perfusion after buried flap transplantation. PMID- 26444597 TI - The effect of centrifugation at various g force levels on rheological properties of rat, dog, pig and human red blood cells. AB - Laboratory investigations often require centrifugation of blood samples for various erythrocyte tests. Although there is a lack of data about the effect of centrifugation at various g force levels on erythrocyte rheological properties. We aimed to investigate the effect of a 10-minute centrifugation at 500, 1000 or 1500 g at 15 degrees C of rat, dog, pig and human venous (K3-EDTA, 1.5 mg/ml) blood samples. Hematological parameters, erythrocyte deformability, cell membrane stability, osmotic gradient ektacytometry (osmoscan) and erythrocyte aggregation were determined. Hematological and erythrocyte deformability parameters showed interspecies differences, centrifugation caused no significant alterations. Cell membrane stability for human erythrocytes centrifuged at higher g level showed less decrease in deformability. Osmoscan O min parameter showed slight elevation in dog centrifuged aliquots. Erythrocyte aggregation parameters changed unexpectedly. Rat and dog erythrocyte aggregation indices significantly dropped in centrifuged aliquots. Pig erythrocyte aggregation indices increased significantly after centrifugation. Human erythrocyte aggregation was the most stable one among the investigated species. The used centrifugation protocols caused the largest alterations in erythrocyte aggregation in a controversial way among the investigated species. On the other hand, erythrocyte deformability parameters were stable, cell membrane stability and osmoscan data show minor shifts. PMID- 26444598 TI - Assessment of renal perfusion with contrast-enhanced ultrasound: Preliminary results in early diabetic nephropathies. AB - OBJECTIVE: We performed a prospective study to evaluate the value of contrast enhanced ultrasound (CEUS) in quantitative evaluation of renal cortex perfusion in patients suspected of early diabetic nephropathies (DN), with the estimated GFR (MDRD equation) as the gold standard. METHODS: The study protocol was approved by the hospital review board; each patient gave written informed consent. Our study included 46 cases (21 males and 25 females, mean age 55.6 +/- 4.14 years) of clinical confirmed early DN patients. After intravenous bolus injection of 1 ml sulfur hexafluoride microbubbles of ultrasound contrast agent, real time CEUS of renal cortex was performed successively using a 2-5 MHz convex probe. Time-intensity curves (TICs) and quantitative indexes were created with Qlab software. Receiver operating characteristic (ROC) curves were used to predict the diagnostic criteria of CEUS quantitative indexes, and their diagnostic efficiencies were compared with resistance index (RI) and peak systolic velocity (PSV) of renal segmental arteries by chi square test. Our control group included forty-five healthy volunteers. Difference was considered statistically significant with P < 0.05. RESULTS: Changes of area under curve (AUC), derived peak intensity (DPI) were statistically significant (P < 0.05). DPI less than 12 and AUC greater than 1400 had high utility in DN, with 71.7% and 67.3% sensitivity, 77.8% and 80.0% specificity. These results were significantly better than those obtained with RI and PSV which had no significant difference in early stage of DN (P > 0.05). CONCLUSIONS: CEUS might be helpful to improve early diagnosis of DN by quantitative analyses. AUC and DPI might be valuable quantitative indexes. PMID- 26444599 TI - Behaviour of the neutrophil to lymphocyte ratio in young subjects with acute myocardial infarction. AB - In the last years the neutrophil to lymphocyte ratio (NLR) has been examined in cardiovascular disorders and in particular in coronary artery disease and acute myocardial infarction (AMI). Now we examined this parameter in subjects with juvenile myocardial infarction at the initial stage and after 3 and 12 months. We enrolled 123 young subjects (112 men and 11 women, mean age 39.4 +/- 5.8 yrs) with AMI. The time interval between the AMI onset and the investigation was 13 +/ 7 days. The mean value of NLR observed in young AMI subjects was significantly increased compared to normal controls (N = 1.817 +/- 0.711; young AMI subjects = 2.376 +/- 0.873, p < 0.0001). NLR does not discriminate STEMI (2.427 +/- 0.878) and non STEMI (2.392 +/- 0.868) or diabetics (2.604 +/- 1.000) and non diabetics (2.324 +/- 0.853), but it differentiates smokers (2.276 +/- 0.853) and non smokers (2.837 +/- 1.072). NLR at the initial stage is not correlated with the number of cardiovascular risk factors or with the extent of the coronary disease. In this study we found a significant decrease of neutrophil count at 3 and 12 months later AMI without any significant variation of lymphocyte and consequently we observed a decrease in NLR at these two intervals of time in comparison with the initial stage. Despite some limitations present in this study, it is interesting to underline that also in juvenile myocardial infarction this low cost haematological marker may be considered together with other inflammatory indicators. PMID- 26444600 TI - Influence of shear stress on erythrocyte aggregation. AB - Shear stress is known to induce platelet activation and aggregation. The red blood cell (RBC) aggregation test requires the application of shear stress for the cells to disaggregate for initialization. We tested the hypothesis that applying shear stress may activate platelets, which can influence RBC aggregation. The present study used a commercial microchip-based aggregometer (RheoSCan-AnD300) with a rotating stirrer for RBC disaggregation. Whole blood samples were exposed to different magnitudes of shear stress with various shearing times. As the rotational speed was increased up to 2800 rpm, the RBC aggregation index (AI) of the whole blood increased by up to 30% (p < 0.05), whereas that of the platelet-excluded blood samples did not show any apparent alteration. The AI also increased in proportion with the stirring time. The data suggest that high shear stress affects RBC aggregation through shear-induced platelet aggregation. PMID- 26444601 TI - Elevated whole blood viscosity in patients with lumbar disc herniation. AB - BACKGROUND: Various vascular risk factors such as smoking, obesity, and diabetes mellitus are associated with hyperviscosity and lumbar disc herniation (LDH). However, the changes of viscosity in LDH have not been examined. AIMS: The present study was to elucidate 1) the rheological parameter levels in patients with LDH, 2) the risk factors that were related to rheological parameters. METHODS: Our study evaluated the rheological parameters in 307 cases with LDH and in 307 control subjects. Multiple linear regression analysis was conducted to assess the significant factors for whole blood viscosity (WBV) at low shear rate. RESULTS: LDH patients had markedly lower physical activity and significantly higher WBV 3 s-1 compared with non-LDH subjects (p < 0.001). Moreover, WBV (3 s 1) tended to increase as physical activity decreased. Multiple linear regression analysis revealed that reduced physical activity was a significant factor contributing to elevated WBV (3 s-1). CONCLUSIONS: WBV (3 s-1) is elevated in patients with LDH. In addition, reduced physical activity is a significant factor for WBV (3 s-1). Further studies are warranted to determine the role of WBV (3 s 1) in LDH. PMID- 26444602 TI - Vascular phases in imaging and their role in focal liver lesions assessment. AB - The incidental finding of a liver lesion with basic ultrasound is one of the most common clinical issues. Some of the liver lesions which present typical morphological B-mode features (e.g. cysts, typically localized focal fatty sparing/accumulations, hyperechoic hemangiomas) can be easily diagnosed by conventional ultrasound without the need of further diagnostic procedures. Others frequently necessitate further investigation with contrast-enhanced imaging techniques or biopsy in order to differentiate benign from malignant lesions and obtain a final diagnosis. This paper will discuss differences between vascular phases of different cross-sectional contrast-enhanced methods, as well as their subsequent benefits for focal liver lesions (FLLs) assessment, adding also a particular emphasis on small FLLs detection and characterization. PMID- 26444603 TI - Pfaffia paniculata extract improves red blood cell deformability in sickle cell patients. AB - The aim of the present study was to test the effects of Pfaffia paniculata (PP) extract on the red blood cell (RBC) rheological properties of patients with sickle cell disease (SCD) and healthy (AA) individuals. Blood from 7 SCD and 4 AA individuals were collected in EDTA tubes. Washed RBCs were incubated with various concentration of PP extract: 0.0, 0.2 or 0.5 mg/ml of PP solution for 5 hrs at 37 degrees C. RBC deformability was measured by ektacytometry at 9 shear stresses ranging from 0.3 to 30 Pa, and RBC aggregation properties were determined by laser-backscattered techniques. Because RBCs from SCD patients are fragile, a stability test was also performed to test for the fragility of RBC exposed to a constant shear stress (70 Pa) for 10 min. While RBC deformability was not improved by the use of PP extract in AA, we noted an improvement of this parameter in patients with SCD between the 0.0 and 0.5 mg/ml conditions. In contrast to AA RBCs, the fragility of SCD RBCs was not affected by PP extract. In conclusion, this study demonstrates the beneficial effects, in-vitro, of PP extract on the RBC deformability of SCD patients, notably at high shear stress (a shear stress condition usually found in capillaries). PMID- 26444604 TI - Chronic intermittent hypoxia versus continuous hypoxia: Same effects on hemorheology? AB - Although both chronic intermittent hypoxia (CIH) and chronic continuous hypoxia (CCH) have effects on hemorheology, we do not know whether their roles are the same. In this study, we explored the effect of simulated-apnea CIH on hemorheology in experimental rats and compared with the effect of CCH. 45 adult SD rats were randomly divided into the normoxic control group, CCH and CIH groups. CIH rats were given nitrogen and air alternately for 8 hours per day and the experiment lasted for 5 weeks. The control group were placed in the normoxia animal chambers, and the CCH rats were housed in the same chambers which were continuously given normobaric hypoxia (FiO2 = 10%). After the preparations, the blood samples were taken and the hemorheology were determined. Compared with control group, the whole blood apparent viscosity, plasma viscosity, hematocrit, erythrocyte aggregation index and electrophoresis index, platelet aggregation rate and fibrinogen significantly increased in CIH group and CCH group. The whole blood viscosity, plasma viscosity, hematocrit and fibrinogen values were much higher in CCH group than in CIH group. However, there was not significantly difference in RBC deformation index or rigidity index among the three groups and no significantly differences were found in the effects on RBC rheological property between CIH and CCH. Our results suggest that intermittent hypoxia and continuous hypoxia increase whole blood viscosity, impair the functions of red blood cells and promote the platelet aggregation in model rats. Moreover, CCH had a greater effect on blood rheology than CIH. PMID- 26444605 TI - Association of whole blood viscosity with non-alcoholic fatty liver disease. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is an independent risk factor for increased cardiovascular disease. Altered hemorheological parameters have also been shown to play a crucial role in atherogenesis. Moreover, increased viscosity is observed in insulin resistance, metabolic syndrome, hypertension, diabetes, ischemic heart disease, and stroke. A recent study confirmed that whole blood viscosity (WBV) is a predictor of cardiovascular events. AIMS: This study aimed to investigate the association of WBV with NAFLD. METHODS: In this cross sectional study, we investigated the relationship between WBV and NAFLD in 1329 subjects (962 men and 367 women) in a general health examination. RESULTS: WBV at low shear stress was elevated in patients with NAFLD. In addition, the prevalence of metabolic syndrome and NAFLD increased as WBV quartiles increased both in men and in women. Multiple regression analysis further identified WBV as an independent and significant determinant for NAFLD. CONCLUSIONS: The findings showed that WBV at low shear stress is increased in NAFLD. Moreover, WBV at low shear stress is independently associated with NAFLD even after adjusting other cardiovascular risk factors. PMID- 26444606 TI - Serial assessments of microvascular obstruction by contrast-enhanced magnetic resonance predict contractile recovery and clinical outcome after reperfused acute myocardial infarction. AB - AIMS: The purpose of the study was to investigate, using cardiac magnetic resonance (CMR), the presence and time course of microvascular obstruction (MO) in patients with acute myocardial infarction (AMI), and to test its relationship with cardiac remodeling and clinical outcomes. METHODS AND RESULTS: 53 patients with AMI and successful percutaneous reperfusion underwent CMR examination at four separate timepoints: within the first 48 hours, at 10 days, at six and twelve months after infarction. MO was quantified immediately (early imaging) and 10 minutes (late imaging) after contrast administration in each session. The extent of MO decreased from early to late imaging at both the first and the second CMR exam (p<=0.001). Early MO was absent in 18(36%) patients both at 48 hours and 10 days after AMI. At 1 year follow-up, LVEF in these patients improved to normal (median = 62% (53-70)). Early MO was present in the first but not in the second CMR in 13 (26%) patients; LVEF at one year in these patients reached a median = 52% (47-61). Finally, Early MO was present in both exams in 19 (38%) patients, who at 1 year after infarction had a LVEF of median = 49% (42-54, P<=0.001 across groups). The time course of MO was a predictor of prognosis upon Kaplan-Meier analysis (P = 0.035). The presence of MO at 10 days after AMI was associated with a higher risk of MACE during a 5-years follow-up. CONCLUSIONS: The presence of MO within 48 hours after AMI, and its time course in the following ten days, provides complementary information on both functional myocardial recovery and long-term outcome. PMID- 26444607 TI - Wall shear stress in the human eye microcirculation in vivo, segmental heterogeneity and performance of in vitro cerebrovascular models. AB - Wall shear stress (WSS) is a very important hemodynamic parameter implicated in many physiological and pathological phenomena. In order to study these phenomena, it is more convenient to use in vitro models before testing on animals and humans. Dynamic in vitro cerebrovascular models are considered capable of simulating the in vivo hemodynamic conditions, but only few of them seem to meet the criteria for this task. It is now clear that in the human eye microcirculation a significant pulsation exists at the pre-capillary arterioles with average WSS values more than twice those in the venular side, for the same diameters. WSS heterogeneity is in support of segmental heterogeneity i.e. the endothelial phenotypic and functional difference among arterioles, capillaries and venules. In this review paper, the importance of WSS is described in detail and two more microvascular segments are proposed: a pre-capillary arteriolar and a post-capillary venular segment. The accurate hemodynamic simulation in all microvascular segments seems to be a prerequisite step in the development of dynamic in vitro blood brain barrier (BBB) models and microfluidic platforms on chip. Endothelial cells in the cardiovascular system seem to have sophisticated role acting like cardiovascular processing sensors (CPSs). PMID- 26444608 TI - Conjunctival microvascular hemodynamics following vaso-occlusive crisis in sickle cell disease. AB - Painful vaso-occlusive crisis (VOC) is the clinical hallmark of sickle cell disease (SCD). Microcirculatory hemodynamic changes following painful VOC may be indicative of future development of VOC events in subjects with SCD. The purpose of the present study was to determine alterations in conjunctival microvascular hemodynamics during non-crisis state in SCD subjects with a history of VOC. Conjunctival microcirculation imaging was performed to measure conjunctival diameter (D) and axial blood velocity (V) in 10 control and 30 SCD subjects. SCD subjects were categorized into two groups based on their history of VOC within a 2-year period before imaging (with or without VOC-H) and also based on whether there was progression in the rate of VOCs during a 2-year period following imaging as compared to before imaging (with or without VOC-P). Conjunctival V was significantly higher in SCD subjects with VOC-H than in both control subjects and SCD subjects without VOC-H (P<=0.03). Conjunctival V was also significantly higher in SCD subjects with VOC-P compared with control subjects and SCD subjects without VOC-P (P<=0.03). Assessment of the conjunctival microcirculation may be useful for understanding hemodynamic changes that lead to VOC events in SCD subjects. PMID- 26444609 TI - High red blood cell distribution width is associated with the metabolic syndrome. AB - OBJECTIVES: High values of Red Blood Cell Distribution Width (RDW) have been associated with adverse outcome in various clinical settings. The mechanism behind this association is not clear. The Metabolic Syndrome (MetS) is a chronic inflammatory disorder that increases the risk for cardiovascular disease and death. The aim of our study was to evaluate the association between high RDW and the MetS in a relatively large cohort of patients. METHODS: A cohort of 3,529 consecutive patients undergoing coronary angiography was used to evaluate the association between RDW and the MetS. The association was assessed by using a logistic regression. Cox's regression analysis was used to evaluate the impact of RDW on long term mortality. RESULTS: The mean age was 65 years (range 24-97), with 27% women. Overall, 30% were diagnosed with metabolic syndrome. The prevalence of MetS was 29% in patients with RDW <14% and 34% in patients with RDW >=14% (P = 0.003).Using multivariate analysis, RDW values above 14% were independently associated with MetS (odds ratio 1.2 [95% CI 1.0-1.4], P = 0.043). Among all the criteria of the metabolic syndrome, hypertension, elevated glucose levels and abdominal obesity were associated with high RDW, with hypertension being the strongest criteria, with an increased risk of 1.8 fold ([95% CI 1.5 2.1]; P = 0.001). During follow up (1614 +/- 709 days, 2-2763 days), long term mortality was 8% in the low RDW group and 28% in the high RDW group (p < 0.001). CONCLUSION: RDW >=14% is independently associated with higher rates of metabolic syndrome and long-term all-cause mortality. PMID- 26444610 TI - Importance of methodological standardization for the ektacytometric measures of red blood cell deformability in sickle cell anemia. AB - Red blood cell (RBC) deformability is severely decreased in patients with sickle cell anemia (SCA), which plays a role in the pathophysiology of the disease. However, investigation of RBC deformability from SCA patients demands careful methodological considerations. We assessed RBC deformability by ektacytometry (LORRCA MaxSis, Mechatronics, The Netherlands) in 6 healthy individuals and 49 SCA patients and tested the effects of different heights of the RBC diffraction patterns, obtained by altering the camera gain of the LORRCA, on the result of RBC deformability measurements, expressed as Elongation Index (EI). Results indicate that the pattern of RBCs from control subjects adopts an elliptical shape under shear stress, whereas the pattern of RBCs from individuals with SCA adopts a diamond shape arising from the superposition of elliptical and circular patterns. The latter represent rigid RBCs. While the EI measures did not change with the variations of the RBC diffraction pattern heights in the control subjects, we observed a decrease of EI when the RBC diffraction pattern height is increased in the SCA group. The differences in SCA EI values measured at 5 Pa between the different diffraction pattern heights correlated with the percent of hemoglobin S and the percent of sickled RBC observed by microscopy. Our study confirms that the camera gain or aperture of the ektacytometer should be used to standardize the size of the RBC diffraction pattern height when measuring RBC deformability in sickle cell patients and underscores the potential clinical utility of this technique. PMID- 26444611 TI - Quantifying local characteristics of velocity, aggregation and hematocrit of human erythrocytes in a microchannel flow. AB - The effect of erythrocyte aggregation on blood viscosity and microcirculatory flow is a poorly understood area of haemodynamics, especially with relevance to serious pathological conditions. Advances in microfluidics have made it possible to study the details of blood flow in the microscale, however, important issues such as the relationship between the local microstructure and local flow characteristics have not been investigated extensively. In the present study an experimental system involving simple brightfield microscopy has been successfully developed for simultaneous, time-resolved quantification of velocity fields and local aggregation of human red blood cells (RBC) in microchannels. RBCs were suspended in Dextran and phosphate buffer saline solutions for the control of aggregation. Local aggregation characteristics were investigated at bulk and local levels using statistical and edge-detection image processing techniques. A special case of aggregating flow in a microchannel, in which hematocrit gradients were present, was studied as a function of flowrate and time. The level of aggregation was found to strongly correlate with local variations in velocity in both the bulk flow and wall regions. The edge detection based analysis showed that near the side wall large aggregates are associated with regions corresponding to high local velocities and low local shear. On the contrary, in the bulk flow region large aggregates occurred in regions of low velocity and high erythrocyte concentration suggesting a combined effect of hematocrit and velocity distributions on local aggregation characteristics. The results of this study showed that using multiple methods for aggregation quantification, albeit empirical, could help towards a robust characterisation of the structural properties of the fluid. PMID- 26444612 TI - MicroRNA-761 inhibits Angiotensin II-induced vascular smooth muscle cell proliferation and migration by targeting mammalian target of rapamycin. AB - Aberrant vascular smooth muscle cell (VSMC) proliferation and migration are a major pathological phenomenon in vascular disease characterized by intimal thickening. The important role of the mammalian target of rapamycin (mTOR) signaling in VSMC proliferation has been previously reported. Consequently, down regulation of mTOR pathway may be an effective way of controlling excessive VSMC proliferation. Since microRNAs (miRNA) are newly emerging regulators of virtually all the biological processes including cellular proliferation, miRNAs targeting mTOR pathway may be utilized to suppress aberrant VSMC proliferation during pathologic conditions. Thus, in the present study, we screened miRNAs targeting mTOR, and we identified miR-761 as a new mTOR targeting miRNA. Luciferase assay using luciferase vector containing 3'UTR of mTOR indicated that miR-761 directly targets mTOR mRNA leading to suppression of mTOR protein expression. Our data also indicate that miR-761 expression decreases during angiotensin II (AngII) induced proliferation of VSMCs, and exogenous miR-761 delivery effectively inhibit the AngII-induced VSMC proliferation. Additionally, the results of migration tests demonstrate that down-regulation of mTOR using exogenous miR-761 suppresses AngII-induced migration of VSMCs as well. Taken together, the present study provided evidence that miR-761 can be a potent anti-proliferative agent for vascular diseases such as atherosclerosis and restenosis, and warrants further studies to validate the effectiveness of miR-761 in vivo. PMID- 26444613 TI - The interaction of human macrophage subsets with silicone as a biomaterial. AB - Silicones are widely used as biomaterials for medical devices such as extracorporeal equipments. However, there is often conflicting evidence about their supposed cell- and histocompatibility. Macrophages could mediate silicone induced adverse responses such as foreign body reaction and fibrous encapsulation. The polarization behaviour of macrophages could determine the clinical outcome after implantation of biomaterials. Induction of classically activated macrophages (CAM) may induce and support uncontrolled inflammatory responses and undesired material degradation. In contrast, polarization into alternatively activated macrophages (AAM) is assumed to support healing processes and implant integration.This study compared the interaction of non-polarized macrophages (M0), CAM, and AAM with commercially available tissue culture polystyrene (TCP) and a medical grade silicone-based biomaterial, regarding the secretion of inflammatory mediators such as cytokines and chemokines. Firstly, by using the Limulus amoebocyte lysate (LAL) test the silicone films were shown to be free of soluble endotoxins, which is the prerequisite to investigate their interaction with primary immune cells. Primary human monocyte-derived macrophages (M0) were polarized into CAM and AAM by addition of suitable differentiation factors. These macrophage subsets were incubated on the materials for 24 hours and their viability and cytokine secretion was assessed. In comparison to TCP, cell adhesion was lower on silicone after 24 hours for all three macrophage subsets. However, compared to TCP, silicone induced higher levels of certain inflammatory and chemotactic cytokines in M0, CAM, and AAM macrophage subsets.Conclusively, it was shown that silicone has the ability to induce a pro inflammatory state to different magnitudes dependent on the macrophage subsets. This priming of the macrophage phenotype by silicone could explain the incidence of severe foreign body complications observed in vivo. PMID- 26444614 TI - Human microvascular endothelial cells displaying reduced angiogenesis and increased uptake of lipids during in vitro culture. AB - Human microvascular ECs from the neonatal foreskin of two donors purchased from one distributor were used in an angiogenesis assay under the same culture conditions. Different angiogenic potency was apparent in these two batches (ECang and ECnon-ang). During the cultivation period of three weeks, ECang ran through all stages of angiogenesis starting from proliferation to migration up to the formation of three-dimensional capillary-like structures. Despite of expression of endothelial markers, ECnon-ang showed excessive intracellular storage of lipids in form of multilamellar bodies and decreased angiogenic potency in contrast to its counterpart, ECang. Results indicate that lipid metabolism differs in ECang versus ECnon-ang. This study points up that these differences are based on the different donors and presents a novel and valuable model for the study of mechanisms of atherosclerosis in endothelial cells in vitro. PMID- 26444615 TI - Evaluation of the diagnostic accuracy of CEUS in children with benign and malignant liver lesions and portal vein anomalies. AB - OBJECTIVE: Comparison of the diagnostic findings of MRI, CT and CEUS in children with benign and malignant and portal venous anomalies of the liver. MATERIALS/METHODS: Retrospective analysis of the diagnostic findings of CEUS, MRI and CT scans in 56 children (age 0-17 years) with a total of 60 benign and malignant liver lesions and anomalies of the portal vein/perfusion. All patients underwent CEUS using sulphur hexafluoride microbubbles and a multi-frequency probe (1-5 MHz, 6-9 MHz). Cine-loops were stored up to 3 minutes. MRI was performed in 38 lesions. CT was performed in 8 lesions. RESULTS: Out of the 56 patients 49 liver lesions (48 benign, 1 malignant), 9 anomalies of the portal vein/perfusion and 2 of the biliary system were detected. 16/49 lesions were analyzed histopathologically. Using CEUS, the characterization of the lesions was possible in 45 out of 49 cases. In 32 cases, CEUS provided the exact diagnosis. Only two benign lesions were falsely categorized as malignant.Findings of MRI and CEUS were concordant in 84% of cases (n = 32/38). CEUS considered 1 benign lesion to be malignant. 2 lesions were not detectable and in 3 lesions no definite diagnosis was established using MRI.Findings of CT and CEUS were concordant in 5 of 8 cases. In 21 lesions CEUS as the only imaging modality was found to be sufficient for diagnostics. CONCLUSION: Despite the restricted indications for using CEUS in children, it offers a high diagnostic detection rate (93%) for characterization of liver lesions and portal vein anomalies. PMID- 26444616 TI - Polymeric inserts differing in their chemical composition as substrates for dendritic cell cultivation. AB - Dendritic cells (DC) contribute to immunity by presenting antigens to T cells and shape the immune response by the secretion of cytokines. Due to their immune stimulatory potential DC-based therapies are promising approaches to overcome tolerance e.g. against tumors. In order to enforce the immunogenicity of DCs, they have to be matured and activated in vitro, which requires an appropriate cell culture substrate, supporting their survival expansion and activation.Since most cell culture devices are not optimized for DC growth, it is hypothesized that polymers with certain physicochemical properties can positively influence the DC cultures. With the aim to evaluate the effects that polymers with different chemical compositions have on the survival, the activation status, and the cytokine/chemokine secretion profile of DC, their interaction with polystyrene (PS), polycarbonate (PC), poly(ether imide) (PEI), and poly(styrene co-acrylonitrile) (PSAN)-based cell culture inserts was investigated. By using this insert system, which fits exactly into 24 well cell culture plates, effects induced from the culture dish material can be excluded. The viability of untreated DC after incubation with the different inserts was not influenced by the different inserts, whereas LPS-activated DC showed an increased survival after cultivation on PC, PS, and PSAN compared to tissue culture polystyrene (TCP). The activation status of DC estimated by the expression of CD40, CD80, CD83, CD86 and HLA-DR expression was not altered by the different inserts in untreated DC but slightly reduced when LPS-activated DC were cultivated on PC, PS, PSAN, and PEI compared to TCP. For each polymeric cell culture insert a distinct cytokine profile could be observed.Since inserts with different chemical compositions of the inserts did not substantially alter the behavior of DC all insert systems could be considered as alternative substrate. The observed increased survival on some polymers, which showed in contrast to TCP a hydrophobic surface, could be beneficial for certain applications such as T cell expansion and activation. PMID- 26444617 TI - Recommendations for contrast enhanced ultrasound (CEUS) in free tissue transplant monitoring. AB - Complications rates after free flap transplantation still amount up to 5% . Consequently a reliable monitoring system is of high importance in plastic and reconstructive surgery. The following guidelines provide an overview of the current opportunities for free flap planning and monitoring with ultrasound and in particular with contrast enhanced ultrasound. PMID- 26444618 TI - The asymmetric facial skin perfusion distribution of Bell's palsy discovered by laser speckle imaging technology. AB - Bell's palsy is a kind of peripheral neural disease that cause abrupt onset of unilateral facial weakness. In the pathologic study, it was evidenced that ischemia of facial nerve at the affected side of face existed in Bell's palsy patients. Since the direction of facial nerve blood flow is primarily proximal to distal, facial skin microcirculation would also be affected after the onset of Bell's palsy. Therefore, monitoring the full area of facial skin microcirculation would help to identify the condition of Bell's palsy patients. In this study, a non-invasive, real time and full field imaging technology - laser speckle imaging (LSI) technology was applied for measuring facial skin blood perfusion distribution of Bell's palsy patients. 85 participants with different stage of Bell's palsy were included. Results showed that Bell's palsy patients' facial skin perfusion of affected side was lower than that of the normal side at the region of eyelid, and that the asymmetric distribution of the facial skin perfusion between two sides of eyelid is positively related to the stage of the disease (P < 0.001). During the recovery, the perfusion of affected side of eyelid was increasing to nearly the same with the normal side. This study was a novel application of LSI in evaluating the facial skin perfusion of Bell's palsy patients, and we discovered that the facial skin blood perfusion could reflect the stage of Bell's palsy, which suggested that microcirculation should be investigated in patients with this neurological deficit. It was also suggested LSI as potential diagnostic tool for Bell's palsy. PMID- 26444619 TI - Whole blood viscosity of preterm infants - differences to term neonates. AB - Determination of shear stresses at given shear rates with the LS 300 allows approximation of flow curves by mathematical models and to calculate viscosities of non-Newtonian fluids across the entire physiological shear range. Particular in preterm neonates, which in comparison to term neonates and adults have a substantially lower mean arterial blood pressure (MAP), rheological blood properties play a decisive role to maintain the perfusion. Whole blood viscosity was measured in umbilical cord blood taken from 34 preterm neonates using the LS 300 viscometer. In addition aggregation index, plasma viscosity, hematocrit and red blood cell (RBC) deformability was determined. The highest quality of approximation of the flow curve of whole blood was achieved by the method of Ostwald. Shear stresses of whole blood of preterm neonates were significantly lower compared to term neonates at similar shear rates (velocity range 6.16 s-1 50 s-1). With hematocrit calculated to 0.40 the related exponent (n) of the viscosity of preterm neonates (by Ostwald) showed a significant lower exponent (n) (0.71 +/- 0.07) than term neonates (0.76 +/- 0.06). The highest quality of approximation of the flow curve of plasma was achieved with the model of Ostwald in preterm neonates as well as in term neonates. The viscosity of plasma determined by Newton was lower for preterm neonates (0.89 +/- 0.19) than for term neonates (1.04 +/- 0.16). Concurrent to term neonates the whole blood of preterm neonates showed a very low aggregation index (term neonates 2.97 +/- 2.10; preterm neonates 2.37 +/- 1.32) and preterm neonates showed higher RBC deformability than term neonates. Because of the physiologically lower MAP and the particular viscous properties of neonatal blood special attention should be given when treating neonates with conventional blood products derived from adult donors. PMID- 26444620 TI - Determination of whole blood and plasma viscosity in term neonates by flow curve analysis with the LS300 viscometer1. AB - Determination of shear stresses at given shear rates allow approximation of flow curves by mathematical models and to calculate viscosities of non-Newtonian fluids. In term neonates, the mean arterial blood pressure (MAP) is markedly below that of adults, therefore rheological properties of blood play an important role in maintaining perfusion. Whole blood viscosity was measured in umbilical cord blood taken from 62 term neonates using the LS 300 viscometer. Individual parameters that influence the viscosity of whole blood were measured: red blood cell (RBC) aggregation, plasma viscosity, hematocrit, and RBC deformability. The flow curve of whole blood of neonates was approximated by the method of Ostwald with the highest quality whereas in adults the best approximation was found by the method of Casson. With hematocrits of 0.40, the viscosity of whole blood in newborns approximated by Ostwald (9.84 +/- 5.12 mPa.s) was significantly lower than that of adults (15.34 +/- 3.01 mPa.s). The aggregation index of the blood of newborns was markedly lower (2.98 +/- 2.12) than in adults (14.63 +/- 3.50) whereas RBC deformability was higher in neonates. The viscosity of plasma determined by Ostwald revealed a lower exponent (n) in neonates (0.94 +/- 022) compared to adults (1.01 +/- 0.12) and the viscosity determined by Newton was lower in neonates (1.04 +/- 0.16 mPa.s) than in adults (1.19 +/- 0.07 mPa.s). The flow curve of neonatal blood which is best approximated by the model of Ostwald emphasizes its important viscous properties necessary for conditions with physiologically low blood pressure. PMID- 26444621 TI - Harvesting Nanocatalytic Heat Localized in Nanoalloy Catalyst as a Heat Source in a Nanocomposite Thin Film Thermoelectric Device. AB - This report describes findings of an investigation of harvesting nanocatalytic heat localized in a nanoalloy catalyst layer as a heat source in a nanocomposite thin film thermoelectric device for thermoelectric energy conversion. This device couples a heterostructured copper-zinc sulfide nanocomposite for thermoelectrics and low-temperature combustion of methanol fuels over a platinum-cobalt nanoalloy catalyst for producing heat localized in the nanocatalyst layer. The possibility of tuning nanocatalytic heat in the nanocatalyst and thin film thermoelectric properties by compositions points to a promising pathway in thermoelectric energy conversion. PMID- 26444622 TI - Higher Retail Prices of Sugar-Sweetened Beverages 3 Months After Implementation of an Excise Tax in Berkeley, California. AB - OBJECTIVES: We assessed the short-term ability to increase retail prices of the first US 1-cent-per-ounce excise tax on the distribution of sugar-sweetened beverages (SSBs), which was implemented in March 2015 by Berkeley, California. METHODS: In 2014 and 2015, we examined pre- to posttax price changes of SSBs and non-SSBs in a variety of retailers in Berkeley and in the comparison cities Oakland and San Francisco, California. We examined price changes by beverage, brand, size, and retailer type. RESULTS: For smaller beverages (<= 33.8 oz), price increases (cents/oz) in Berkeley relative to those in comparison cities were 0.69 (95% confidence interval [CI] = 0.36, 1.03) for soda, 0.47 (95% CI = 0.08, 0.87) for fruit-flavored beverages, and 0.47 (95% CI = 0.25, 0.69) for SSBs overall. For 2-liter bottles and multipacks of soda, relative price increases were 0.46 (95% CI = 0.03, 0.89) and 0.49 (95% CI = 0.21, 0.77). We observed no relative price increases for nontaxed beverages overall. CONCLUSIONS: Approximately 3 months after the tax was implemented, SSB retail prices increased more in Berkeley than in nearby cities, marking a step in the causal pathway between the tax and reduced SSB consumption. PMID- 26444623 TI - A closer look at the 21(st) Century Cures Act. PMID- 26444624 TI - A dormant danger: New therapies target a ubiquitous pathogen known as cytomegalovirus. PMID- 26444625 TI - MERS vaccines advance, but will humans or camels get the jab? PMID- 26444626 TI - Chikungunya is moving fast, but so are researchers in the field. PMID- 26444627 TI - Bugging out over Chagas: Bioluminescent protozoans and old drugs might help unravel kissing-bug disease. PMID- 26444628 TI - The Canadian MD/PhD training program needs reinstated support. PMID- 26444630 TI - Characterization of extracellular DDX4- or Ddx4-positive ovarian cells. PMID- 26444631 TI - Adult human and mouse ovaries lack DDX4-expressing functional oogonial stem cells. PMID- 26444632 TI - Woods and Tilly reply. PMID- 26444633 TI - CD47 blockade as another immune checkpoint therapy for cancer. PMID- 26444634 TI - Antigen-presenting cells look within during influenza infection. PMID- 26444635 TI - Remodeling the susceptibility to stress-induced depression. PMID- 26444636 TI - A detour in the quest for oogonial stem cells: methods matter. PMID- 26444638 TI - Radiation-assisted magnetotransport in two-dimensional electron gas systems: appearance of zero resistance states. AB - Zero-resistance states (ZRS) are normally associated with superconducting and quantum Hall phases. Experimental detection of ZRS in two-dimensional electron gas (2DEG) systems irridiated by microwave(MW) radiation in a magnetic field has been quite a surprise. We develop a semiclassical transport formalism to explain the phenomena. We find a sequence of Zero-Resistance States (ZRS) inherited from the suppression of Shubnikov-de Haas (SdH) oscillations under the influence of high-frequency and large amplitude microwave radiation. Furthermore, the ZRS are well pronounced and persist up to broad intervals of magnetic field as observed in experiments on microwave illuminated 2DEG systems. PMID- 26444637 TI - Natural and therapy-induced immunosurveillance in breast cancer. AB - The immunosurveillance theory postulates that tumors evolve and progress in an uncontrolled fashion only when anticancer immune responses fail. Natural immunosurveillance clearly influences human breast cancer (BC) progression because the prognosis of BC patients is dictated by the density, composition and activity of the tumor immune infiltrate at diagnosis. Moreover, chemotherapeutic and radiotherapeutic regimens commonly employed for the treatment of BC affect the tumor immune infiltrate, and accumulating data suggest that the clinical efficacy of these treatments is largely determined by T cell-dependent tumor specific immune responses. In addition, the mechanism of action of targeted anticancer therapeutics, such as the erb-b2 receptor tyrosine kinase 2 (ERBB2) targeting agent trastuzumab, involves the innate and adaptive arms of the immune system. In this Review, we discuss these findings as well as preliminary evidence indicating that immunotherapy constitutes a promising option for the treatment of BC. Moreover, we point out that the successful implementation of immunotherapy to BC management requires the optimization of current immunotherapeutic regimens and the identification of immunological biomarkers that enable improved risk stratification and the design of personalized, dynamic treatment plans. PMID- 26444639 TI - Depressive symptoms influence use of feedback for motor learning and recovery in chronic stroke. AB - PURPOSE: Sensorimotor impairments and depressive symptoms (PSD) influence arm motor recovery post-stroke. Feedback provision improves upper limb motor learning in patients with chronic stroke but factors including PSD may affect ability to use feedback. We evaluated the influence of PSD on the ability to use auditory feedback for upper limb recovery and motor learning in patients with chronic stroke. METHODS: Participants (n = 24) practiced 72 pointing movements/session (6 targets, 12 sessions, randomized) with auditory feedback on movement speed and trunk displacement. The presence of PSD (Beck's Depression Inventory; BDI-II) was assessed at pre-intervention (PRE). Arm motor impairment (Fugl-Meyer Assessment, shoulder horizontal adduction, shoulder flexion, elbow extension ranges, trunk displacement) and arm use (Motor Activity Log) were assessed at PRE, immediately after (POST) and retention (3 mos; RET). Participants were divided into two groups based on BDI-II scores: >= 14/63 (DEP group; n = 8; score: 20.5 +/- 7.5) and <= 13/63 (no PSD (ND) group; n = 16; score: 5.0 +/- 3.8). Changes in impairment and arm use levels were assessed (mixed-model ANOVAs). RESULTS: All participants improved arm use. DEP had lower Fugl-Meyer scores, used more compensatory trunk displacement and had lower shoulder horizontal adduction range compared to ND. CONCLUSION: The presence of PSD diminished the ability to use auditory feedback for arm motor recovery and motor learning. PMID- 26444640 TI - Neuroprotective effects of Aceglutamide on motor function in a rat model of cerebral ischemia and reperfusion. AB - PURPOSE: To investigate the effect and underlying mechanism of Aceglutamide on motor dysfunction in rats after cerebral ischemia-reperfusion. METHODS: Adult male Sprague-Dawley rats were subjected to 2 h transient middle cerebral artery occlusion (MCAO). Aceglutamide or vehicle was intraperitoneally given to rats at 24 h after reperfusion and lasted for 14 days. Subsequently functional recovery was assessed and number of tyrosine hydroxylase (TH)-positive neurons in substantia nigra (SN) was analyzed. Tumor necrosis factor receptor-associated factor 1(TRAF1), P-Akt and Bcl-2/Bax were determined in mesencephalic tissue by Western blot method. PC12 cells and primary cultured mesencephalic neurons were employed to further investigate the mechanism of Aceglutamide. RESULTS: Aceglutamide treatment improved behavioral functions, reduced the infarction volume, and elevated the number of TH-positive neurons in the SN. Moreover, Aceglutamide significantly attenuated neuronal apoptosis in the SN. Meanwhile Aceglutamide treatment significantly inhibited the expression of TRAF1 and up regulated the expression of P-Akt and Bcl-2/Bax ratio both in vitro and in vivo. CONCLUSIONS: Aceglutamide ameliorated motor dysfunction and delayed neuronal death in the SN after ischemia, which involved the inhibition of pro-apoptotic factor TRAF1 and activation of Akt/Bcl-2 signaling pathway. These data provided experimental information for applying Aceglutamide to ischemic stroke treatment. PMID- 26444641 TI - Electrodeposited MnO(x)/PEDOT Composite Thin Films for the Oxygen Reduction Reaction. AB - Manganese oxide (MnOx) was anodically coelectrodeposited with poly(3,4 ethylenedioxythiophene) (PEDOT) from an aqueous solution of Mn(OAc)2, 3,4 ethylenedioxythiophene, LiClO4 and sodium dodecyl sulfate to yield a MnOx/PEDOT composite thin film. The MnOx/PEDOT film showed significant improvement over the MnOx only and PEDOT only films for the oxygen reduction reaction, with a >0.2 V decrease in onset and half-wave overpotential and >1.5 times increase in current density. Furthermore, the MnOx/PEDOT films were competitive with commercial benchmark 20% Pt/C, outperforming it in the half-wave ORR region and exhibiting better electrocatalytic selectivity for the oxygen reduction reaction upon methanol exposure. The high activity of the MnOx/PEDOT composite is attributed to synergistic charge transfer capabilities, attained by coelectrodepositing MnOx with a conductive polymer while simultaneously achieving intimate substrate contact. PMID- 26444642 TI - Correction: Fine Mapping of Dominant X-Linked Incompatibility Alleles in Drosophila Hybrids. PMID- 26444643 TI - On the Construction of Property Based Diabatizations: Diabolical Singular Points. AB - Diabatizations achieved by diagonalization of a property operator or as the extremum of a molecular property are numerous and widely used, although for a particular system a given property method may have limited accuracy or even fail catastrophically. These failures are usually analyzed in terms of limitations of the chosen property or method. Here we introduce an alternative perspective, failure attributable to singularities in the defining equations. The singular subspace is analogous to the conical intersection seam in potential energy surfaces. Using the archetypical NH3 nonadiabatic photodissociation, it is shown that for two states the diabatization condition has singularities on a subspace of dimension N - 2, where N = 3N(atom) - 6, is the number of internal coordinates. This singular subspace is distinct from the N - 2-dimensional seam of conical intersections of the electronic Hamiltonian and results incorrectly, in singular derivative couplings between diabatic states in unexpected regions of nuclear coordinate space. Simple indicators are developed that provide ways to anticipate and avoid these singularities. PMID- 26444645 TI - The Incidence of Gastric Adenocarcinoma Among Patients With Gastric Intestinal Metaplasia: A Long-term Cohort Study. AB - BACKGROUND AND AIMS: Gastric intestinal metaplasia (IM) has been known as a premalignant condition, but estimates of its cancer risk vary widely. We aimed to analyze cancer risk of gastric IM by a long-term cohort study. METHODS: We conducted a hospital-based study that included all patients with gastric IM between 1992 and 2010, and the development of gastric adenocarcinoma was evaluated until July 2011. Patients developing gastric cancer <=180 days after the index diagnosis of IM were excluded. The incidence rate, the cumulative incidence, and the standardized incidence ratio (SIR) of gastric cancer were determined, and hazard ratios (HRs) of risk factors were calculated. RESULTS: We identified 7059 patients with a median follow-up duration of 5.1 years, and 81 patients developed gastric adenocarcinoma during the study period. The 5-, 10-, and 15-year cumulative incidences of gastric cancer were 0.9% [95% confidence interval (CI), 0.6-1.1), 2.0% (95% CI, 1.5-2.6), and 3.0% (95% CI, 2.0-4.0), respectively. On multivariate analysis, older age (eg, 75 y and above; HR=7.4; 95% CI, 2.8-19.6), low-grade dysplasia (HR=4.0; 95% CI, 2.1-7.9), and high-grade dysplasia (HR=18.8; 95% CI, 9.0-39.5) were independent risk factors. As compared with the risk in the general population, the SIR of gastric cancer among patients with gastric IM was 2.5 (95% CI, 2.0-3.1). However, the SIR was only 2.0 (95% CI, 1.5-2.6) in the nondysplasia subgroup, but was up to 35.2 (95% CI, 15.2-69.4) in the high-grade dysplasia subgroup. CONCLUSIONS: Gastric IM is an important risk factor for gastric cancer, but surveillance should be arranged only for those at an especially high risk. PMID- 26444644 TI - Label-Free Nanoplasmonic-Based Short Noncoding RNA Sensing at Attomolar Concentrations Allows for Quantitative and Highly Specific Assay of MicroRNA-10b in Biological Fluids and Circulating Exosomes. AB - MicroRNAs are short noncoding RNAs consisting of 18-25 nucleotides that target specific mRNA moieties for translational repression or degradation, thereby modulating numerous biological processes. Although microRNAs have the ability to behave like oncogenes or tumor suppressors in a cell-autonomous manner, their exact roles following release into the circulation are only now being unraveled and it is important to establish sensitive assays to measure their levels in different compartments in the circulation. Here, an ultrasensitive localized surface plasmon resonance (LSPR)-based microRNA sensor with single nucleotide specificity was developed using chemically synthesized gold nanoprisms attached onto a solid substrate with unprecedented long-term stability and reversibility. The sensor was used to specifically detect microRNA-10b at the attomolar (10(-18) M) concentration in pancreatic cancer cell lines, derived tissue culture media, human plasma, and media and plasma exosomes. In addition, for the first time, our label-free and nondestructive sensing technique was used to quantify microRNA-10b in highly purified exosomes isolated from patients with pancreatic cancer or chronic pancreatitis, and from normal controls. We show that microRNA-10b levels were significantly higher in plasma-derived exosomes from pancreatic ductal adenocarcinoma patients when compared with patients with chronic pancreatitis or normal controls. Our findings suggest that this unique technique can be used to design novel diagnostic strategies for pancreatic and other cancers based on the direct quantitative measurement of plasma and exosome microRNAs, and can be readily extended to other diseases with identifiable microRNA signatures. PMID- 26444646 TI - Obesity and Cardiovascular Risk in Adults With Celiac Disease. AB - BACKGROUND: Patients with celiac disease (CD) may be at an increased risk of cardiovascular disease (CVD), yet CVD risk factors are not well defined in CD. The validated Framingham Heart Study 10-year general CVD risk score (FRS) that incorporates traditional CVD risk factors including body mass index (BMI) has not been previously studied in CD patients. AIMS: To compare BMI and FRS in CD patients with population-based controls. METHODS: Biopsy-proven CD patients were ascertained retrospectively and data on BMI, systolic blood pressure, hypertension, smoking status, and diabetes were obtained at initial and follow-up visits. FRS was calculated and compared with 4 matched general population non-CD controls from the 2009 to 2010 National Health and Nutrition Examination Survey (NHANES). RESULTS: Of 258 total CD patients, 38.3% were overweight or obese compared with 69.8% of controls (P<0.001). In total, 174 CD patients met the inclusion criteria for FRS calculation. Of these, the median FRS was lower in CD patients compared with controls (3.9 vs. 4.2; P=0.011). In CD patients, tobacco use was significantly lower (P<0.001), whereas systolic blood pressure was significantly higher (P<0.01) than controls. CONCLUSIONS: Global CVD risk is lower among patients with CD compared with population controls. Lower BMI and tobacco use among CD patients could account for this difference. These results suggest that factors other than those measured by FRS could contribute to the increased risk of CVD in CD observed in some studies. PMID- 26444647 TI - Identifying Minimal Changes in Nonerosive Reflux Disease: Is the Pay Worth the Labor? AB - Gastroesophageal reflux disease has a variable presentation on upper endoscopy. Gastroesophageal reflux disease can be divided into 3 endoscopic categories: Barrett's esophagus, erosive esophagitis, and normal mucosa/nonerosive reflux disease (NERD). Each of these phenotypes behave in a distinct manner, in regards to symptom response to treatment, and risk of development of complications such as esophageal adenocarcinoma. Recently, it has been proposed to further differentiate NERD into 2 categories: those with and those without "minimal changes." These minimal changes include endoscopic abnormalities, such as villous mucosal surface, mucosal islands, microerosions, and increased vascularity at the squamocolumnar junction. Although some studies have shown that patients with minimal changes may have higher rates of esophageal acid exposure compared with those without minimal changes, it is currently unclear if these patients behave differently than those currently categorized as having NERD. The clinical utility of identifying these lesions should be weighed against the cost of the requisite equipment and the additional time required for diagnosis, compared with conventional white light endoscopy. PMID- 26444648 TI - Quality and Safety in Health Care, Part IV: Quality and Cancer Care. AB - The 1999 Institute of Medicine report Ensuring Quality Cancer Care discussed the difference between the actual cancer care received in the United States and the care that the patients should get, as well as some points to consider in delivering optimum care. In 2012, a follow-up review article in the journal Cancer entitled "Ensuring quality cancer care" indicated that there had been some interval progress, but more are needed to be done. The 2013 Institute of Medicine report Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis indicated that there are continuing major problems with cancer care and that they advocated a national system of quality reporting and a major information technology system to capture and help assess the data. PMID- 26444649 TI - Visualization of Lymph Nodal and Hepatic Metastases of Medullary Thyroid Carcinoma on 18F-Fluoride PET/CT. AB - F-fluoride uptake in soft tissue metastases has been previously described. Herein, we report a case of F-fluoride uptake in lymph nodal and hepatic metastases of medullary thyroid carcinoma. Simultaneous CT showed calcified lesions in these regions. PMID- 26444650 TI - 18F-NaF PET/CT Findings in Fibrous Dysplasia. AB - A 43-year-old woman with breast cancer underwent Tc-hydroxymethylene diphosphonate bone scintigraphy for preoperative workup. An abnormal lesion with increased uptake was found in the right humeral shaft, and F-NaF bone PET/CT was performed for clarification. There was high uptake of F-NaF without cortical bone disruption in the right humeral shaft, corresponding to the site on bone scintigraphy. Upper arm MRI was performed subsequently, and metastasis was suggested as a differential diagnosis. However, this lesion was pathologically diagnosed as fibrous dysplasia after curettage surgery. PMID- 26444651 TI - Pulmonary Artery Sarcoma Detected on 18F-FDG PET/CT With Unusual Findings. AB - A 32-year-old woman, who presented with "sharp pain" in the right chest for more than 1 month and worsening dyspnea and fever for 10 days, was initially thought to have a pulmonary embolism. Cardiac ultrasound showed an ill-defined echogenic mass within the pulmonary trunk. F-FDG PET/CT was performed for further evaluation. PET/CT showed an intense hypermetabolism in the main, bilateral proximal, and the right main pulmonary arteries, suggesting the presence of a malignant lesion. Biopsy confirmed the lesion as a primary pulmonary artery sarcoma. PMID- 26444652 TI - Light-Driven Heterogeneous Reduction of Carbon Dioxide: Photocatalysts and Photoelectrodes. PMID- 26444653 TI - Freezing-Enhanced Dissolution of Iron Oxides: Effects of Inorganic Acid Anions. AB - Dissolution of iron from mineral dust particles greatly depends upon the type and amount of copresent inorganic anions. In this study, we investigated the roles of sulfate, chloride, nitrate, and perchlorate on the dissolution of maghemite and lepidocrocite in ice under both dark and UV irradiation and compared the results with those of their aqueous counterparts. After 96 h of reaction, the total dissolved iron in ice (pH 3 before freezing) was higher than that in the aqueous phase (pH 3) by 6-28 times and 10-20 times under dark and UV irradiation, respectively. Sulfuric acid was the most efficient in producing labile iron under dark condition, whereas hydrochloric acid induced the most dissolution of the total and ferrous iron in the presence of light. This ice-induced dissolution result was also confirmed with Arizona Test Dust (AZTD). In the freeze-thaw cycling test, the iron oxide samples containing chloride, nitrate, or perchlorate showed a similar extent of total dissolved iron after each cycling while the sulfate-containing sample rapidly lost its dissolution activity with repeating the cycle. This unique phenomenon observed in ice might be related to the freeze concentration of protons, iron oxides, and inorganic anions in the liquid-like ice grain boundary region. These results suggest that the ice-enhanced dissolution of iron oxides can be a potential source of bioavailable iron, and the acid anions critically influence this process. PMID- 26444654 TI - The drawing effect: Evidence for reliable and robust memory benefits in free recall. AB - In 7 free-recall experiments, the benefit of creating drawings of to-be remembered information relative to writing was examined as a mnemonic strategy. In Experiments 1 and 2, participants were presented with a list of words and were asked to either draw or write out each. Drawn words were better recalled than written. Experiments 3-5 showed that the memory boost provided by drawing could not be explained by elaborative encoding (deep level of processing, LoP), visual imagery, or picture superiority, respectively. In Experiment 6, we explored potential limitations of the drawing effect, by reducing encoding time and increasing list length. Drawing, relative to writing, still benefited memory despite these constraints. In Experiment 7, the drawing effect was significant even when encoding trial types were compared in pure lists between participants, inconsistent with a distinctiveness account. Together these experiments indicate that drawing enhances memory relative to writing, across settings, instructions, and alternate encoding strategies, both within- and between-participants, and that a deep LoP, visual imagery, or picture superiority, alone or collectively, are not sufficient to explain the observed effect. We propose that drawing improves memory by encouraging a seamless integration of semantic, visual, and motor aspects of a memory trace. PMID- 26444655 TI - T-Cell Cytokines as Predictive Markers of the Risk of Allograft Rejection. AB - Over the last decade, several biomarkers and surrogate markers have surfaced as promising predictive markers of risk of rejection in solid organ transplantation. The monitoring of these markers can help to improve graft and recipient care by personalizing immunomodulatory therapies. The complex immune system response against an implanted graft can change during long-term follow-up, and the dynamic balance between effector and regulatory T-cell populations is a crucial factor in antidonor response, risk of rejection, and immunosuppression requirements. Therefore, at any time before and after transplantation, T-effector activity, which is associated with increased production and release of proinflammatory cytokines, can be a surrogate marker of the risk of rejection and need for immunosuppression. In addition, immunosuppressive drugs may have a different effect in each individual patient. The pharmacokinetics and pharmacodynamics of these drugs show high interpatient variability, and pharmacodynamic markers, strongly associated with the specific mechanism of action, can potentially be used to measure individual susceptibility to a specific immunosuppressive agent. The monitoring of a panel of valid biomarkers can improve patient stratification and the selection of immunosuppressive drugs. After transplantation, therapy can be adjusted based on the prediction of rejection episodes (maintained alloreactivity), the prognosis of allograft damage, and the individual's response to the drugs. This review will focus on current data indicating that changes in the T-cell production of the intracellular cytokines interferon-gamma and interleukin-2 could be used to predict the risk of rejection and to guide immunosuppressive therapy in transplant recipients. PMID- 26444656 TI - Intimate relationships in young adults with perinatally acquired HIV: a qualitative study of strategies used to manage HIV disclosure. AB - An increasing number of children born with perinatally acquired HIV (PAH) are surviving into late adolescence and early adulthood. At this developmental stage, forming and sustaining intimate relationships is important. Young adults with PAH face both normative challenges and additional, HIV-related, relationship stressors. One key issue is the decision about whether and how to share their HIV status with others. Being able to disclose one's HIV status to sexual partners may reduce the risk of onward HIV transmission but is associated with the fear of rejection. There has been little research on how young people with PAH manage such disclosure-related stressors in intimate relationships. This study examined how disclosure challenges are managed by young adults with PAH in the UK within their intimate relationships. Seven participants (five females and two males) currently or previously in an intimate relationship, aged 18-23 years, were recruited from a UK hospital clinic. The majority of participants were of sub Saharan African origins. They took part in in-depth interviews, with data analysed according to the principles of interpretative phenomenological analysis. Four themes were elicited: (1) decisions about starting, continuing or resuming relationships shaped by disclosure, (2) disclosing early to avoid the pain of future rejection, (3) using condoms to avoid disclosure and (4) testing likely partner reactions to disclosure. The study revealed the significant extent to which HIV disclosure affected the experience of relationships in this population. Interventions to support adolescents and young adults with PAH to disclose to their partners should be developed alongside guidance for professionals. Future research should include older samples of adults with PAH and studies in sub Saharan African settings. PMID- 26444657 TI - Editor's Commentary. PMID- 26444658 TI - Biological versus Mechanical Heart Valve Prostheses. Has the Paradigm Shifted Definitively? PMID- 26444659 TI - Trends in Surgical Aortic Valve Replacement in More Than 3,000 Consecutive Cases in the Era of Transcatheter Aortic Valve Implantations. AB - Objectives Biological prostheses for surgical aortic valve replacement (sAVR) are increasingly being considered in patients < 60 years of age. Likely, preserving the option of performing a transcatheter valve-in-valve (ViV) procedure in cases of structural valve deterioration has contributed to this development. We assessed the use pattern in sAVR over an 11-year period. Methods From 2002 through 2012, a total of 3,172 patients underwent sAVR at our center. Results Mean age was 70.4 +/- 10.6 years and mortality was 1.9%. From 2002 to 2012, mean manufacturer given valve size increased from 22.8 +/- 1.7 to 23.9 +/- 2.0 mm (p < 0.001). Mean true internal diameter and effective orifice area increased from 19.6 to 20.3 mm (p = 0.027) and 1.41 to 1.56 cm(2) (p < 0.001), respectively. Use of mechanical valves decreased from 10.9 to 1.8% (p < 0.001), and patients were younger in 2012 than in 2002 (52.8 +/- 16.5 vs. 41.0 +/- 14.3 years; p = 0.028). Conclusion Profound change of use pattern in sAVR was observed as indication for biological prostheses became more liberal. Larger prostheses were implanted during the observational period. Especially in younger patients, optimal sizing is essential to preserve the option for subsequent ViV procedures. PMID- 26444660 TI - Authors' Reply. PMID- 26444661 TI - Anterior Temporal Sulcus: A Reliable Intraoperative Landmark for Accurately Delineating the Superior Limit of Amygdala Resection during Anterior Temporal Lobectomy. AB - BACKGROUND: Reliable anatomical landmarks are essential to avoiding injuries to the optic tract, anterior choroidal artery and basal ganglia during anterior temporal lobectomy (ATL). We describe an anatomic landmark, specifically the anterior temporal sulcus (ATS), as a reliable method to define the anterior portion of the endorhinal sulcus and the superior limit of amygdala resection. METHODS: A total of 25 consecutive patients undergoing ATL at Rush University Medical Center (RUMC) were identified, and their preoperative brain magnetic resonance imaging (MRI) studies were analyzed. RESULTS: All patients underwent successful ATL without any complication. There was no injury to the optic tract, anterior choroidal artery or basal ganglia using ATS as the landmark for the superior limit of amygdala resection. The ATS was clearly identifiable on coronal preoperative MRI in 48 out of 50 temporal lobes (96%). The ATS was present in all 25 left temporal lobes (100%); 2 of the 25 right temporal lobes had absent ATS (8%). Following the ATS posteriorly on coronal MRI, it led to the endorhinal sulcus and accurately predicted the superior extent of amygdala resection in all 25 patients (48 temporal lobes). CONCLUSION: The ATS is a reliable anatomical landmark that accurately delineates the superior border of the amygdala during ATL. PMID- 26444662 TI - Diagnostic Performance of Transluminal Attenuation Gradient and Noninvasive Fractional Flow Reserve Derived from 320-Detector Row CT Angiography to Diagnose Hemodynamically Significant Coronary Stenosis: An NXT Substudy. AB - PURPOSE: To compare the diagnostic performance of 320-detector row computed tomography (CT) coronary angiography-derived computed fractional flow reserve (FFR; FFRCT), transluminal attenuation gradient (TAG; TAG320), and CT coronary angiography alone to diagnose hemodynamically significant stenosis as determined by invasive FFR. MATERIALS AND METHODS: This substudy of the prospective NXT study (no. NCT01757678) was approved by each participating institution's review board, and informed consent was obtained from all participants. Fifty-one consecutive patients who underwent 320-detector row CT coronary angiographic examination and invasive coronary angiography with FFR measurement were included. Independent core laboratories determined coronary artery disease severity by using CT coronary angiography, TAG320, FFRCT, and FFR. TAG320 is defined as the linear regression coefficient between luminal attenuation and axial distance from the coronary ostium. FFRCT was computed from CT coronary angiography data by using computational fluid dynamics technology. Diagnostic performance was evaluated and compared on a per-vessel basis by the area under the receiver operating characteristic (ROC) curve (AUC). RESULTS: Among 82 vessels, 24 lesions (29%) had ischemia by FFR (FFR <= 0.80). FFRCT exhibited a stronger correlation with invasive FFR compared with TAG320 (Spearman rho, 0.78 vs 0.47, respectively). Overall per-vessel accuracy, sensitivity, specificity, and positive and negative predictive values for TAG320 (<15.37) were 78%, 58%, 86%, 64%, and 83%, respectively; and those of FFRCT were 83%, 92%, 79%, 65%, and 96%, respectively. ROC curve analysis showed a significantly larger AUC for FFRCT (0.93) compared with that for TAG320 (0.72; P = .003) and CT coronary angiography alone (0.68; P = .008). CONCLUSION: FFRCT computed from 320-detector row CT coronary angiography provides better diagnostic performance for the diagnosis of hemodynamically significant coronary stenoses compared with CT coronary angiography and TAG320. PMID- 26444663 TI - Quantitative Assessment of Foot Blood Flow by Using Dynamic Volume Perfusion CT Technique: A Feasibility Study. AB - PURPOSE: To demonstrate the feasibility of foot blood flow measurement by using dynamic volume perfusion computed tomographic (CT) technique with the upslope method in an animal experiment and a human study. MATERIALS AND METHODS: The human study was approved by the institutional review board, and written informed consent was obtained from all patients. The animal study was approved by the research animal care and use committee. A perfusion CT experiment was first performed by using rabbits. A color-coded perfusion map was reconstructed by using in-house perfusion analysis software based on the upslope method, and the measured blood flow on the map was compared with the reference standard microsphere method by using correlation analysis. A total of 17 perfusion CT sessions were then performed (a) once in five human patients and (b) twice (before and after endovascular revascularization) in six human patients. Perfusion maps of blood flow were reconstructed and analyzed. The Wilcoxon signed rank test was used to prove significant differences in blood flow before and after treatment. RESULTS: The animal experiment demonstrated a strong correlation (R(2) = 0.965) in blood flow between perfusion CT and the microsphere method. Perfusion maps were obtained successfully in 16 human clinical sessions (94%) with the use of 32 mL of contrast medium and an effective radiation dose of 0.31 mSv (k factor for the ankle, 0.0002). The plantar dermis showed the highest blood flow among all anatomic structures of the foot, including muscle, subcutaneous tissue, tendon, and bone. After a successful revascularization procedure, the blood flow of the plantar dermis increased by 153% (P = .031). The interpretations of the color-coded perfusion map correlated well with the clinical and angiographic findings. CONCLUSION: Perfusion CT could be used to measure foot blood flow in both animals and humans. It can be a useful modality for the diagnosis of peripheral arterial disease by providing quantitative information on foot perfusion status. PMID- 26444664 TI - Heart Disease and Colon Cancer Prevention Beliefs and Their Association With Information Seeking and Scanning. AB - Despite their understanding of the links between (a) information seeking and scanning and (b) health outcomes, researchers still know relatively little about the impact of information behaviors on people's disease-related beliefs and attitudes. The goal of this study was to validate findings linking information and health behaviors and to assess whether information seeking and scanning are associated with beliefs about the effectiveness of heart disease and colon cancer risk prevention behaviors (in regard to exercise, controlling one's diet to prevent overweight/obesity, and daily fruit and vegetable intake), as well as determine whether the effects of seeking versus scanning on these beliefs differ. Data from the Annenberg National Health Communication Survey were analyzed (N = 3,212). For colon cancer, significant main effects were detected for information scanning for each of the 3 beliefs assessed (p < .05). For heart disease, both information scanning and heart disease media exposure (p < .05) were associated with stronger beliefs. Information seeking was not associated with beliefs for either disease (p > .05). Our results suggest that disease-related cognitions and beliefs, which ultimately impact decisions to engage in prevention behaviors, may be influenced most by less purposeful forms of information acquisition. PMID- 26444666 TI - Congenital esophageal stenosis diagnosed in an infant at 9 month of age. AB - Esophageal stenosis is a relatively uncommon condition in pediatrics and requires an accurate diagnostic approach. Here we report the case of a 9-month old female infant who presented intermittent vomiting, dysphagia and refusal of solid foods starting after weaning. She was treated for gastroesophageal reflux. At first, radiological investigation suggested achalasia, while esophagoscopy revelaed a severe congenital esophageal stenosis at the distal third of the esophagus. She underwent four endoscopic balloon dilatations that then allowed her to swallow solid food with intermittent mild dysphagia. After 17 months of esomeprazole treatment off therapy impedance-pH monitoring was normal. At 29 months of follow up the child is asymptomatic and eats without problems.Infants with dysphagia and refusal of solid foods may have undiagnosed medical conditions that need treatment. Many disorders can cause esophageal luminal stricture; in the pediatric age the most common are peptic or congenital. Careful assessment with endoscopy is needed to diagnose these conditions early and referral to a pediatric gastroenterologic unit may be necessary. PMID- 26444665 TI - Global analysis of uncapped mRNA changes under drought stress and microRNA dependent endonucleolytic cleavages in foxtail millet. AB - BACKGROUND: mRNA degradation plays an important role in the determination of mRNA abundance and can quickly regulate gene expression. The production of uncapped mRNAs, an important mechanism of mRNA degradation, can be initiated by decapping enzymes, endonucleases or small RNAs such as microRNAs (miRNAs). Little is known, however, about the role of uncapped mRNAs in plants under environmental stress. RESULTS: Using a novel approach called parallel analysis of RNA ends (PARE), we performed a global study of uncapped mRNAs under drought stress in foxtail millet (Setaria italica [L.] P. Beauv.). When both gene degradation (PARE) and gene transcription (RNA-sequencing) data were considered, four types of mRNA decay patterns were identified under drought stress. In addition, 385 miRNA-target interactions were identified in the PARE data using PAREsnip. The PARE analysis also suggested that two miRNA hairpin processing mechanisms--loop-last and loop first processing--operate in foxtail millet, with both miR319 and miR156 gene families undergoing precise processing via the unusual loop-first mechanism. Finally, we found 11 C4 photosynthesis-related enzymes encoded by drought responsive genes. CONCLUSIONS: We performed a global analysis of mRNA degradation under drought stress and uncovered diverse drought-response mechanisms in foxtail millet. This information will deepen our understanding of mRNA expression under stressful environmental conditions in gramineous plants. In addition, PARE analysis identified many miRNA targets and revealed miRNA-precursor processing modes in foxtail millet. PMID- 26444667 TI - Negative impact of low body mass index on liver cirrhosis patients with hepatocellular carcinoma. AB - BACKGROUND: The impact of obesity on the prognosis of hepatocellular carcinoma (HCC) has not been well characterized in a Chinese population. Therefore, the aim of this study was to examine the influence of BMI on the clinicopathological characteristics and mortality of patients with HCC. METHODS: The study cohort consisted of 379 patients who were diagnosed with HCC at the First Affiliated Hospital of Harbin Medical University between June 2012 and August 2014. Study subjects were divided into two body mass index (BMI) categories: normal weight (BMI <23 kg/m(2)) and overweight (BMI >=23 kg/m(2)). RESULTS: Of the 379 patients, 44 (11.6%) were underweight (<18.5 kg/m(2)), 172 (45.4%) had a normal weight (18.5 <= BMI < 23.0), 133 (35.1 %) were overweight (23.0 <= BMI < 27.5), and 30 (7.9%) were obese (BMI >=27.5). After a median follow-up time of 296 (range, 15-720) days, 168 (44.3%) patients died with median survival time of 159 (range, 15-690) days. Patients with lower BMIs also exhibited a higher liver related mortality rate (60.6 vs. 22.7%; p = 1.8 * 10(-13)) and a shorter survival time (353 days vs. 571 days; p = 6.2 * 10(-6)) than patients with higher BMIs. In multivariate analysis, the BMI class was also found to be a significant independent impact factor for overall survival (p = 2.2 * 10(-8)), age, alpha fetoprotein level, Child-Pugh score, treatment strategy, antiviral treatment, extrahepatic metastasis, and tumor infiltration of the portal vein. CONCLUSIONS: Our data suggest that lower BMI has a significant impact regarding poor outcomes in patients with HCC. To better understand the impact of BMI on the prognosis of HCC patients, more large-scale cohort studies will be necessary. PMID- 26444668 TI - Combined clinical and genomic signatures for the prognosis of early stage non small cell lung cancer based on gene copy number alterations. AB - BACKGROUND: The development of a more refined prognostic methodology for early non-small cell lung cancer (NSCLC) is an unmet clinical need. An accurate prognostic tool might help to select patients at early stages for adjuvant therapies. RESULTS: A new integrated bioinformatics searching strategy, that combines gene copy number alterations and expression, together with clinical parameters was applied to derive two prognostic genomic signatures. The proposed methodology combines data from patients with and without clinical data with a priori information on the ability of a gene to be a prognostic marker. Two initial candidate sets of 513 and 150 genes for lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), respectively, were generated by identifying genes which have both: a) significant correlation between copy number and gene expression, and b) significant prognostic value at the gene expression level in external databases. From these candidates, two panels of 7 (ADC) and 5 (SCC) genes were further identified via semi-supervised learning. These panels, together with clinical data (stage, age and sex), were used to construct the ADC and SCC hazard scores combining clinical and genomic data. The signatures were validated in two independent datasets (n = 73 for ADC, n = 97 for SCC), confirming that the prognostic value of both clinical-genomic models is robust, statistically significant (P = 0.008 for ADC and P = 0.019 for SCC) and outperforms both the clinical models (P = 0.060 for ADC and P = 0.121 for SCC) and the genomic models applied separately (P = 0.350 for ADC and P = 0.269 for SCC). CONCLUSION: The present work provides a methodology to generate a robust signature using copy number data that can be potentially used to any cancer. Using it, we found new prognostic scores based on tumor DNA that, jointly with clinical information, are able to predict overall survival (OS) in patients with early-stage ADC and SCC. PMID- 26444669 TI - When flexibility is not necessarily a virtue: a review of hypermobility syndromes and chronic or recurrent musculoskeletal pain in children. AB - Chronic or recurrent musculoskeletal pain is a common complaint in children. Among the most common causes for this problem are different conditions associated with hypermobility. Pediatricians and allied professionals should be well aware of the characteristics of the different syndromes associated with hypermobility and facilitate early recognition and appropriate management. In this review we provide information on Benign Joint Hypermobility Syndrome, Ehlers-Danlos Syndrome, Marfan Syndrome, Loeys-Dietz syndrome and Stickler syndrome, and discuss their characteristics and clinical management. PMID- 26444670 TI - Incidence, causes and phenotypes of acute seizures in Kenyan children post the malaria-decline period. AB - BACKGROUND: Acute seizures are a common cause of paediatric admissions to hospitals in Africa, and malaria is an important cause of seizures in endemic areas. Malaria has declined in the past decade whilst neonatal admissions have increased, both which may affect the incidence and phenotypes of acute seizures in African children. METHODS: We examined the effect of recent decline in malaria and the increasing burden of neonatal admissions on the incidence, causes and phenotypes of acute seizures admitted to hospital from 2009-2013. We used logistic regression to measure associations and Poisson regression to calculate the incidence and rate ratios. RESULTS: The overall incidence of acute seizures over the 5-year period was 312 per 100,000/year (95% CI, 295-329): 116 per 100,000/year (95% CI, 106-127) for complex seizures and 443 per 100,000 live births (95% CI, 383-512) for neonatal seizures. Over the period, there was an increase in incidence of seizures-attributable to malaria (SAM) (incidence rate ratio (IRR) = 1.25; p < 0.001), but neither non-SAM (IRR = 1.03; p = 0.569) nor neonatal seizures (IRR = 0.99; p = 0.905). Important causes of acute seizures were malaria (33%) and respiratory tract infections (19%); and for neonatal seizures were neonatal sepsis (51%), hypoglycemia (41%) and hypoxic-ischemic encephalopathy (21%). Mortality occurred in 6% of all acute seizures, being more common in complex seizures (8%) and neonatal seizures (10 %) than other seizures (p < 0.001 for both comparisons). CONCLUSIONS: Acute seizures remain common in children despite a decline in the incidence of malaria; suggesting that causes for these seizures need to be prevented in the community. PMID- 26444671 TI - Early treatment with hydroxychloroquine prevents the development of endothelial dysfunction in a murine model of systemic lupus erythematosus. AB - INTRODUCTION: Accelerated atherosclerosis is one of the major causes of morbidity in patients with systemic lupus erythematosus (SLE). Endothelial dysfunction (ED) is considered an early marker of atherosclerosis. It is a reversible alteration, thus representing an attractive target for prevention strategies against cardiovascular disease. Studies have shown that ED occurs in patients with SLE even in the absence of severe, active disease. Hydroxychloroquine (HCQ) is widely used in SLE to control disease activity, but its use is also associated with an improvement in long-term prognosis. Beyond the beneficial effect in well established disease, our hypothesis is that treatment with HCQ might have a beneficial impact on ED prevention in SLE. The aim of this study was to assess the impact of early treatment with HCQ on ED in a murine model of SLE. METHODS: Twelve-week-old NZB/W F1 (NZ) and C57BL/6 J mice (controls) were allocated to receive HCQ or vehicle for 6, 12, or 18 weeks. Proteinuria and anti-double stranded DNA autoantibodies were determined. ED was assessed in mesenteric arteries (pressurized myography). Nitric oxide (NO) availability and reactive oxygen species (ROS) production were evaluated. Vascular ROS production was measured with dihydroethidium (DHE) fluorescent dye. RESULTS: Starting from 18 weeks of age, NZ mice showed a progressive reduction in NO availability, which was normalized by ascorbic acid and apocynin in the up to 24-week-old group, and partly ameliorated in older animals. HCQ administration normalized the NO availability in the up to 24-week-old group, with a partial amelioration in the 30-week-old group. DHE analysis revealed a progressive increment of vascular ROS generation among NZ groups, which was prevented by apocynin. Similarly, in the NZ HCQ-treated group, vascular ROS production was abrogated. CONCLUSIONS: The ED that characterizes this mouse model of SLE is caused by the nicotinamide adenine dinucleotide phosphate oxidase-driven ROS excess. Very early treatment with HCQ is able to exert vascular protection via an antioxidant effect. PMID- 26444672 TI - Quantifying the contribution of changes in healthcare expenditures and smoking to the reversal of the trend in life expectancy in the Netherlands. AB - BACKGROUND: Since 2001 the Netherlands has shown a sharp upturn in life expectancy (LE) after a longer period of slower improvement. This study assessed whether changes in healthcare expenditure (HCE) explain this reversal in trends in LE. As an alternative explanation, the impact of changes in smoking behavior was also evaluated. METHODS: To quantify the contribution of changes in HCE to changes in LE, we estimated a health-production function using a dynamic panel regression approach with data on 19 OECD countries (1980-2009), accounting for temporal and spatial correlation. Smoking-attributable mortality was estimated using the indirect Peto-Lopez method. RESULTS: As compared to 1990-1999, during 2000-2009 LE in the Netherlands increased by 1.8 years in females and by 1.5 years in males. Whereas changes in the impact of smoking between the two periods made almost no contribution to the acceleration of the increase in LE, changes in the trend of HCE added 0.9 years to the LE increase between 2000 and 2009. The exceptional reversal in the trend of LE and HCE was not found among the other OECD countries. CONCLUSION: This study suggests that changes in Dutch HCE, and not in smoking, made an important contribution to the reversal of the trend in LE; these findings support the view that investments in healthcare are increasingly important for further progress in life expectancy. PMID- 26444673 TI - Repeat HIV-testing is associated with an increase in behavioral risk among men who have sex with men: a cohort study. AB - BACKGROUND: The Center for Disease Control and Prevention recommends that high risk groups, like sexually active men who have sex with men (MSM), receive HIV testing and counseling at least annually. The objective of this study was to investigate the relationship between voluntary repeat HIV testing and sexual risk behavior in MSM receiving rapid serologic and nucleic acid amplification testing. METHODS: We performed a cohort study to analyze reported risk behavior among MSM receiving the "Early Test", a community-based, confidential acute and early HIV infection screening program in San Diego, California, between April 2008 and July 2014. The study included 8,935 MSM receiving 17,333 "Early Tests". A previously published risk behavior score for HIV acquisition in MSM (i.e. Menza score) was chosen as an outcome to assess associations between risk behaviors and number of repeated tests. RESULTS: At baseline, repeat-testers (n = 3,202) reported more male partners and more condomless receptive anal intercourse (CRAI) when compared to single-testers (n = 5,405, all P <0.001). In 2,457 repeat testers there was a strong association observed between repeated HIV tests obtained and increased risk behavior, with number of male partners, CRAI with high risk persons, non injection stimulant drug use, and sexually transmitted infections all increasing between the first and last test. There was also a linear increase of risk (i.e. high Menza scores) with number of tests up to the 17th test. In the multivariable mixed effects model, more HIV tests (OR = 1.18 for each doubling of the number of tests, P <0.001) and younger age (OR = 0.95 per 5-year increase, P = 0.006) had significant associations with high Menza scores. CONCLUSIONS: This study found that the highest risk individuals for acquiring HIV (e.g. candidates for antiretroviral pre-exposure prophylaxis) can be identified by their testing patterns. Future studies should delineate causation versus association to improve prevention messages delivered to repeat testers during HIV testing and counseling sessions. PMID- 26444674 TI - Determinants of ventricular arrhythmias in human explanted hearts with dilated cardiomyopathy. AB - BACKGROUND: The molecular and cellular determinants of ventricular tachycardia (VT) in patients with nonischaemic dilated cardiomyopathy (NIDCM) remain poorly defined. MATERIALS AND METHODS: We examined 20 NIDCM hearts where VT was reported in 10 cases and VT was absent in 10 cases, using a double-blinded case-control study design, and assessed the molecular and cellular features of the adverse myocardial remodelling. RESULTS: Explanted hearts from patients with VT showed greater hypertrophic changes based on cardiomyocyte cross-sectional area and expression of disease markers, and increased myocardial fibrosis which extended into the left ventricular and right ventricular outflow tract regions. The VT group also showed increased oxidative stress with reduction in reduced glutathione levels. Connexin 43 levels in the intercalated discs showed increased levels in the VT group with reduced phosphorylation. Microarray mRNA analysis of gene expression in the left ventricle (LV) free wall revealed several families of genes which were differentially upregulated or downregulated in hearts with documented VT compared to hearts without VT. Notably, we identified reduced expression of the Ca(2+) -activated K(+) channel (KCNN2) and increased expression of the transient receptor potential cation channel 7 (TRPM7) and intracellular chloride channel 3. Western blot analysis on LV membrane fractions showed reduced KCNN2 and increased TRPM7 levels in hearts with VT. CONCLUSIONS: In explanted human hearts with NIDCM, VT is associated with greater hypertrophy, oxidative stress and myocardial fibrosis, differential gene expression, and altered ion channel levels indicative of a distinctive adverse myocardial remodelling process associated with clinically significant VT. PMID- 26444675 TI - Prospective study of the primary evaluation of 1016 horses with clinical signs of abdominal pain by veterinary practitioners, and the differentiation of critical and non-critical cases. AB - BACKGROUND: The majority of research on the evaluation of horses with colic is focused on referral hospital populations. Early identification of critical cases is important to optimise outcome and welfare. The aim of this prospective study was to survey the primary evaluation of horses with clinical signs of abdominal pain by veterinary practitioners, and compare the initial presentation of critical and non-critical cases. RESULTS: Data from 1016 primary evaluations of horses presenting with clinical signs of colic were submitted by 167 veterinary practitioners across the United Kingdom over a 13 month period. The mean age of the study population was 13.5 years (median 12.0, range 0-42). Mean heart rate on primary presentation was 47 beats/min (median 44, range 18-125), mean respiratory rate was 20 breaths/min (median 16, range 6-100), and median gastrointestinal auscultation score (0-12, minimum-maximum) was 5 (range 0-12). Clinical signs assessed using a behavioural severity score (0-17, minimum-maximum), were between 0 and 6 in 70.4 % of cases, and 7-12 for 29.6 % of cases. Rectal examination was performed in 73.8 % of cases. Cases that responded positively to simple medical treatment were categorised retrospectively as 'non-critical'; cases that required intensive medical treatment, surgical intervention, died or were euthanased were categorised as 'critical'. Eight-hundred-and-twenty-two cases met these criteria; 76.4 % were 'non-critical' and 23.6 % were 'critical'. Multivariable logistic regression was used to identify features of the clinical presentation associated with critical cases. Five variables were retained in the final multivariable model: combined pain score: (OR 1.19, P < 0.001, 95 % CI 1.09-1.30), heart rate (OR 1.06, P < 0.001, 95 % CI 1.04-1.08), capillary refill time >2.5 s (OR 3.21, P = 0.046, 95 % CI 1.023-10.09), weak pulse character (OR 2.90, P = 0.004, 95 % CI 1.39-5.99) and absence of gut sounds in >=1 quadrant (OR 3.65, P < 0.001, 95 % CI 2.08-6.41). CONCLUSIONS: This is the first study comparing the primary presentation of critical and non-critical cases of abdominal pain. Pain, heart rate, gastrointestinal borborygmi and simple indicators of hypovolaemia were significant indicators of critical cases, even at the primary veterinary examination, and should be considered essential components of the initial assessment and triage of horses presenting with colic. PMID- 26444676 TI - Brief analysis of causes of sensitive skin and advances in evaluation of anti allergic activity of cosmetic products. AB - This review focuses on the causes of sensitive skin and elaborates on the relationship between skin sensitivity and skin irritations and allergies, which has puzzled cosmetologists. Here, an overview is presented of the research on active ingredients in cosmetic products for sensitive skin (anti-sensitive ingredients), which is followed by a discussion of their experimental efficacy. Moreover, several evaluation methods for the efficacy of anti-sensitive ingredients are classified and summarized. Through this review, we aim to provide the cosmetic industry with a better understanding of sensitive skin, which could in turn provide some theoretical guidance to the research on targeted cosmetic products. PMID- 26444677 TI - Validation of 10-Minute Delayed Hepatocyte Phase Imaging with 30 degrees Flip Angle in Gadoxetic Acid-Enhanced MRI for the Detection of Liver Metastasis. AB - OBJECTIVES: To compare 10-minute delayed hepatocyte phase imaging using a 30 degrees flip angle (10 min-FA30) and 20-minute hepatocyte phase imaging using a 10 degrees FA (20 min-FA10) in gadoxetic acid-enhanced MRI of patients with possible liver metastases, regarding lesion-to-liver contrast-to-noise ratio (CNR) and focal hepatic lesion (FHL) detection to evaluate whether 10 min-FA30 would be superior to 20 min-FA10. MATERIALS AND METHODS: Eighty-three patients with 248 liver metastases and 78 benign FHLs who underwent gadoxetic acid enhanced MRI with 10 min-FA30 and 20 min-FA10 were enrolled. Lesion-to-liver CNRs were compared between the two image groups. Two radiologists independently assessed the presence of FHLs using a four-point scale and detection sensitivity was calculated. RESULTS: The mean CNR for liver metastases on the 10 min-FA30 (248.5 +/- 101.6) were significantly higher than that of the 20 min-FA10 (187.4 +/- 77.4) (p < 0.001). The mean CNR difference between the two image groups was 61.2 +/- 56.8. There was no significant difference in detection sensitivity of FHLs for two readers between 10 min-FA30 (mean 97.7%) and 20 min-FA10 (mean 97.9%), irrespective of the lesion size or malignancy. CONCLUSION: 10 min-FA30 yielded higher CNR with similar sensitivity compared to 20 min-FA10. This finding indicates that 10 min-FA30 can potentially replace 20 min-FA10 with higher diagnostic performance and save 10 minutes of time. PMID- 26444678 TI - Catalytic enantioselective addition of isocyanoacetate to 3-methyl-4-nitro-5 styrylisoxazoles under phase transfer catalysis conditions. AB - The reaction between 3-methyl-4-nitro-5-styrylisoxazoles and ethyl isocyanoacetate proceeded under phase transfer catalysis to give enantioenriched monoadducts in high enantiomeric excess (up to 99% ee). The resulting adducts were subsequently cyclised to give 2,3-dihydropyrroles and substituted pyrrolidines in identical high ees and as a single diastereoisomer. PMID- 26444679 TI - Ab initio spectroscopic characterization of borane, BH, in its X1Sigma+ electronic state. AB - The accurate potential energy and electric dipole moment functions of borane, BH, in its X1Sigma+ electronic state have been determined from ab initio calculations using the multireference averaged coupled-pair functional method in conjunction with the correlation-consistent core-valence basis sets up to septuple-zeta quality. The higher-order electron correlation, scalar relativistic, adiabatic, and nonadiabatic effects were discussed. Vibration-rotation energy levels of the (11)BH, (11)BD, (10)BH, and (10)BD isotopologues were predicted to near "spectroscopic" accuracy. For the main isotopologue (11)BH, the adiabatic dissociation energy D0 and the effective equilibrium internuclear distance r(e) were predicted to be 28,469 +/- 10 cm(-1) and 1.23214 +/- 0.0001 A, respectively. PMID- 26444680 TI - Differential Metabolic Profiles during the Albescent Stages of 'Anji Baicha' (Camellia sinensis). AB - 'Anji Baicha' is an albino tea cultivar with white shoots at low air temperature and green shoots at high air temperature in early spring. The metabolite contents in the shoots dynamically vary with the color changes and with shoot development. To investigate the metabolomic variation during the albescent and re-greening stages, gas chromatography-mass spectrometry combined with multivariate analysis were applied to analyze the metabolite profiles in the different color stages during the development of 'Anji Baicha' leaves. The metabolite profiles of three albescent stages, including the yellow-green stage, the early albescent stage, and the late albescent stage, as well as the re-greening stage were distinguished using principal component analysis, revealing that the distinct developmental stages were likely responsible for the observed metabolic differences. Furthermore, a group classification and pairwise discrimination was revealed among the three albescent stages and re-greening stage by partial least squares discriminant analysis. A total of 65 differential metabolites were identified with a variable influence on projection greater than 1. The main differential metabolic pathways of the albescent stages compared with the re-greening stage included carbon fixation in photosynthetic organisms and the phenylpropanoid and flavonoid biosynthesis pathways. Compared with the re-greening stage, the carbohydrate and amino acid metabolic pathways were disturbed during the albescent stages. During the albescent stages, the sugar (fructofuranose), sugar derivative (glucose-1-phosphate) and epicatechin concentrations decreased, whereas the amino acid (mainly glycine, serine, tryptophan, citrulline, glutamine, proline, and valine) concentrations increased. These results reveal the changes in metabolic profiling that occur during the color changes associated with the development of the albino tea plant leaves. PMID- 26444681 TI - Otx2 Requires Lmx1b to Control the Development of Mesodiencephalic Dopaminergic Neurons. AB - Studying the development of mesodiencephalic dopaminergic (mdDA) neurons provides an important basis for better understanding dopamine-associated brain functions and disorders and is critical for establishing cell replacement therapy for Parkinson's disease. The transcription factors Otx2 and Lmx1b play a key role in the development of mdDA neurons. However, little is known about the genes downstream of Otx2 and Lmx1b in the pathways controlling the formation of mdDA neurons in vivo. Here we report on our investigation of Lmx1b as downstream target of Otx2 in the formation of mdDA neurons. Mouse mutants expressing Otx2 under the control of the En1 promoter (En1+/Otx2) showed increased Otx2 expression in the mid-hindbrain region, resulting in upregulation of Lmx1b and expansion of mdDA neurons there. In contrast, Lmx1b-/- mice showed decreased expression of Otx2 and impairments in several aspects of mdDA neuronal formation. To study the functional interaction between Otx2 and Lmx1b, we generated compound mutants in which Otx2 expression was restored in mice lacking Lmx1b (En1+/Otx2;Lmx1b-/-). In these animals Otx2 was not sufficient to rescue any of the aberrations in the formation of mdDA neurons caused by the loss of Lmx1b, but rescued the loss of ocular motor neurons. Gene expression studies in Lmx1b-/- embryos indicated that in these mutants Wnt1, En1 and Fgf8 expression are induced but subsequently lost in the mdDA precursor domain and the mid-hindbrain organizer in a specific, spatio-temporal manner. In summary, we demonstrate that Otx2 critically depends on Lmx1b for the formation of mdDA neurons, but not for the generation of ocular motor neurons. Moreover, our data suggest that Lmx1b precisely maintains the expression pattern of Wnt1, Fgf8 and En1, which are essential for mid-hindbrain organizer function and the formation of mdDA neurons. PMID- 26444682 TI - Enhanced stem cell-derived cardiomyocyte differentiation in suspension culture by delivery of nitric oxide using S-nitrosocysteine. AB - The development of cell-based treatments for heart disease relies on the creation of functionally mature stem cell-derived cardiomyocytes employing in vitro culture suspension systems, a process which remains a formidable and expensive endeavor. The use of nitric oxide as a signaling molecule during differentiation has demonstrated the potential for creating increased numbers of spontaneously contracting embryoid bodies in culture; however, the effects of nitric oxide signaling on the function and maturation of stem cell-derived cardiomyocytes is not well understood. In this study, the effects of nitric oxide on mouse embryonic stem cell-derived cardiomyocyte contractile activity, protein, and gene expression, and calcium handling were quantified. Embryoid bodies (EBs) formed using the hanging drop method, were treated with the soluble nitric oxide donor S nitrosocysteine (CysNO) over a period of 18 days in suspension culture and spontaneous contractile activity was assessed. On day 8, selected EBs were dissociated to form monolayers for electrophysiological characterization using calcium transient mapping. Nitric oxide treatment led to increased numbers of stem cell-derived cardiomyocytes (SC-CMs) relative to non-treated EBs after 8 days in suspension culture. Increased incidence of spontaneous contraction and frequency of contraction were observed from days 8-14 in EBs receiving nitric oxide treatment in comparison to control. Expression of cardiac markers and functional proteins was visualized using immunocytochemistry and gene expression was assessed using qPCR. Cardiac-specific proteins were present in both CysNO treated and control SC-CMs; however, CysNO treatment during differentiation significantly increased betaMHC gene expression in SC-CMs relative to control SC CMs. Furthermore, increased calcium transient velocity and decreased calcium transient duration was observed for CysNO-treated SC-CMs in comparison to control SC-CMs. Soluble nitric oxide donors, including S-nitrosocysteine, have advantages over other bioactive molecules for use in scalable culture systems in driving cardiac differentiation, since they are inexpensive and the diffusivity of nitric oxide is relatively high. By enabling maintenance of spontaneous contraction in suspension culture and progressing electrophysiological function of resulting SC CMs toward a more mature phenotype, long-term application of S-nitrosocysteine was shown to be beneficial during cardiac differentiation. Taken together, these results demonstrate the efficiency of nitric oxide as a signaling compound, with implications in the improvement of pluripotent stem cell-derived cardiomyocyte maturation in large-scale culture systems. PMID- 26444683 TI - Time Course of Cell Sheet Adhesion to Porcine Heart Tissue after Transplantation. AB - Multilayered cell sheets have been produced from bone marrow-derived mesenchymal stem cells (MSCs) for investigating their adhesion properties onto native porcine heart tissue. Once MSCs reached confluence after a 7-day culture on a temperature responsive culture dish, a MSCs monolayer spontaneously detached itself from the dish, when the culture temperature was reduced from 37 to 20 degrees C. The basal extracellular matrix (ECM) proteins of the single cell sheet are preserved, because this technique requires no proteolytic enzymes for harvesting cell sheet, which become a basic building block for assembling a multilayer cell sheet. The thickness of multilayered cell sheets made from three MSC sheets was found to be approximately 60 MUm. For investigating the adhesion properties of the basal and apical sides, the multilayered cell sheets were transplanted onto the surface of the heart's left ventricle. Multilayered cell sheets were histological investigated at 15, 30, 45 and 60 minutes after transplantation by hematoxylin eosin (HE) and azan dyes to determine required time for the adhesion of the multilayered sheets following cell-sheet transplantation. The results showed that only the basal side of multilayered cell sheets significantly enhanced the sheets adhesion onto the surface of heart 30 minutes after transplantation. This study concluded that (1) cell sheets had to be transplanted with its basal side onto the surface of heart tissue and (2) at least 30 minutes were necessary for obtaining the histological adhesion of the sheets to the heart tissue. This study provided clinical evidence and parameters for the successful application of MSC sheets to the myocardium and allowed cell sheet technology to be adapted clinical cell-therapy for myocardial diseases. PMID- 26444684 TI - SAD-B kinase regulates pre-synaptic vesicular dynamics at hippocampal Schaffer collateral synapses and affects contextual fear memory. AB - Synapses of amphids defective (SAD)-A/B kinases control various steps in neuronal development and differentiation, such as axon specifications and maturation in central and peripheral nervous systems. At mature pre-synaptic terminals, SAD-B is associated with synaptic vesicles and the active zone cytomatrix; however, how SAD-B regulates neurotransmission and synaptic plasticity in vivo remains unclear. Thus, we used SAD-B knockout (KO) mice to study the function of this pre synaptic kinase in the brain. We found that the paired-pulse ratio was significantly enhanced at Shaffer collateral synapses in the hippocampal CA1 region in SAD-B KO mice compared with wild-type littermates. We also found that the frequency of the miniature excitatory post-synaptic current was decreased in SAD-B KO mice. Moreover, synaptic depression following prolonged low-frequency synaptic stimulation was significantly enhanced in SAD-B KO mice. These results suggest that SAD-B kinase regulates vesicular release probability at pre-synaptic terminals and is involved in vesicular trafficking and/or regulation of the readily releasable pool size. Finally, we found that hippocampus-dependent contextual fear learning was significantly impaired in SAD-B KO mice. These observations suggest that SAD-B kinase plays pivotal roles in controlling vesicular release properties and regulating hippocampal function in the mature brain. Synapses of amphids defective (SAD)-A/B kinases control various steps in neuronal development and differentiation, but their roles in mature brains were only partially known. Here, we demonstrated, at mature pre-synaptic terminals, that SAD-B regulates vesicular release probability and synaptic plasticity. Moreover, hippocampus-dependent contextual fear learning was significantly impaired in SAD-B KO mice, suggesting that SAD-B kinase plays pivotal roles in controlling vesicular release properties and regulating hippocampal function in the mature brain. PMID- 26444685 TI - Evaluation of cotton stalk hydrolysate for xylitol production. AB - Cotton stalk is a widely distributed and abundant lignocellulosic waste found in Turkey. Because of its rich xylose content, it can be a promising source for the production of xylitol. Xylitol can be produced by chemical or biotechnological methods. Because the biotechnological method is a simple process with great substrate specificity and low energy requirements, it is more of an economic alternative for the xylitol production. This study aimed to use cotton stalk for the production of xylitol with Candida tropicalis Kuen 1022. For this purpose, the combined effects of different oxygen concentration, inoculum level and substrate concentration were investigated to obtain high xylitol yield and volumetric xylitol production rate. Candida tropicalis Kuen 1022 afforded different concentrations of xylitol depending on xylose concentration, inoculum level, and oxygen concentration. The optimum xylose, yeast concentration, and airflow rate for cotton stalk hydrolysate were found as 10.41 g L(-1), 0.99 g L( 1), and 1.02 vvm, respectively, and under these conditions, xylitol yield and volumetric xylitol production rate were obtained as 36% and 0.06 g L(-1) hr(-1), respectively. The results of this study show that cotton stalk can serve as a potential renewable source for the production of xylitol. PMID- 26444686 TI - Planar Heterojunction Perovskite Solar Cells Incorporating Metal-Organic Framework Nanocrystals. AB - Zr-based porphyrin metal-organic framework (MOF-525) nanocrystals with a crystal size of about 140 nm are synthesized and incorporated into perovskite solar cells. The morphology and crystallinity of the perovskite thin film are enhanced since the micropores of MOF-525 allow the crystallization of perovskite to occur inside; this observation results in a higher cell efficiency of the obtained MOF/perovskite solar cell. PMID- 26444687 TI - Thermal Modelling Analysis of Spiral Wound Supercapacitor under Constant-Current Cycling. AB - A three-dimensional modelling approach is used to study the effects of operating and ambient conditions on the thermal behaviour of the spiral wound supercapacitor. The transient temperature distribution during cycling is obtained by using the finite element method with an implicit predictor-multicorrector algorithm. At the constant current of 2A, the results show that the maximum temperature appears in core area. After 5 cycles, the maximum temperature is 34.5 degrees C, while in steady state, it's up to 42.5 degrees C. This paper further studies the relationship between the maximum temperature and charge-discharge current. The maximum temperature will be more than 60 degrees C after 5 cycles at the current of 4A, and cooling measurements should be taken at that time. It can provide thoughts on inner temperature field distribution and structure design of the spiral wound supercapacitor in working process. PMID- 26444688 TI - Preparation and Characterization of Composites Based on Polylactic Acid and Beeswax with Improved Water Vapor Barrier Properties. AB - Beeswax and a plasticizer (ATBC) were added to polylactic acid (PLA) films in order to enhance the water vapor barrier properties of the films. Beeswax improved the barrier properties; the water vapor permeability in the composite containing 1% beeswax was 58% lower than that of the neat PLA. Fourier transform infrared spectroscopy and X-ray diffraction analysis revealed that the incorporation of beeswax and ATBC had so little effect on the PLA structure. In addition, the structure of PLA did not vary substantially with the additions. The surfaces of the composites were examined by using field emission scanning electron microscopy. Differential scanning calorimetry results showed that the degree of crystallinity of the PLA films increased with the addition of beeswax and ATBC. However, the tensile strength and elongation at break of the composites containing beeswax were up to approximately 50% lower than those of the neat PLA. Although further study is needed to improve the mechanical properties, the aforementioned results showed that the PLA barrier properties can be improved by the incorporation of a small amount of beeswax and ATBC. PRACTICAL APPLICATION: The results of this study can be applied for the preparation of PLA composite films with improved barrier properties. Such biodegradable films are extremely useful for applications in the food packaging industry. PMID- 26444689 TI - Abacus Training Affects Math and Task Switching Abilities and Modulates Their Relationships in Chinese Children. AB - Our previous work demonstrated that abacus-based mental calculation (AMC), a traditional Chinese calculation method, could help children improve their math abilities (e.g. basic arithmetical ability) and executive function (e.g. working memory). This study further examined the effects of long-term AMC training on math ability in visual-spatial domain and the task switching component of executive function. More importantly, this study investigated whether AMC training modulated the relationship between math abilities and task switching. The participants were seventy 7-year-old children who were randomly assigned into AMC and control groups at primary school entry. Children in AMC group received 2 hour AMC training every week since primary school entry. On the contrary, children in the control group had never received any AMC training. Math and task switching abilities were measured one year and three years respectively after AMC training began. The results showed that AMC children performed better than their peers on math abilities in arithmetical and visual-spatial domains. In addition, AMC group responded faster than control group in the switching task, while no group difference was found in switch cost. Most interestingly, group difference was present in the relationships between math abilities and switch cost. These results implied the effect of AMC training on math abilities as well as its relationship with executive function. PMID- 26444690 TI - Structure Identification of Uncertain Complex Networks Based on Anticipatory Projective Synchronization. AB - This paper investigates a method to identify uncertain system parameters and unknown topological structure in general complex networks with or without time delay. A complex network, which has uncertain topology and unknown parameters, is designed as a drive network, and a known response complex network with an input controller is designed to identify the drive network. Under the proposed input controller, the drive network and the response network can achieve anticipatory projective synchronization when the system is steady. Lyapunov theorem and Barbalat's lemma guarantee the stability of synchronization manifold between two networks. When the synchronization is achieved, the system parameters and topology in response network can be changed to equal with the parameters and topology in drive network. A numerical example is given to show the effectiveness of the proposed method. PMID- 26444691 TI - Correction: KORRIGAN1 Interacts Specifically with Integral Components of the Cellulose Synthase Machinery. PMID- 26444693 TI - Applications of Nanotechnology in the Management of Cancer: Miniature Technology, Great Potential. PMID- 26444692 TI - Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial. AB - IMPORTANCE: Saline (0.9% sodium chloride) is the most commonly administered intravenous fluid; however, its use may be associated with acute kidney injury (AKI) and increased mortality. OBJECTIVE: To determine the effect of a buffered crystalloid compared with saline on renal complications in patients admitted to the intensive care unit (ICU). DESIGN AND SETTING: Double-blind, cluster randomized, double-crossover trial conducted in 4 ICUs in New Zealand from April 2014 through October 2014. Three ICUs were general medical and surgical ICUs; 1 ICU had a predominance of cardiothoracic and vascular surgical patients. PARTICIPANTS: All patients admitted to the ICU requiring crystalloid fluid therapy were eligible for inclusion. Patients with established AKI requiring renal replacement therapy (RRT) were excluded. All 2278 eligible patients were enrolled; 1152 of 1162 patients (99.1%) receiving buffered crystalloid and 1110 of 1116 patients (99.5%) receiving saline were analyzed. INTERVENTIONS: Participating ICUs were assigned a masked study fluid, either saline or a buffered crystalloid, for alternating 7-week treatment blocks. Two ICUs commenced using 1 fluid and the other 2 commenced using the alternative fluid. Two crossovers occurred so that each ICU used each fluid twice over the 28 weeks of the study. The treating clinician determined the rate and frequency of fluid administration. MAIN OUTCOMES AND MEASURES: The primary outcome was proportion of patients with AKI (defined as a rise in serum creatinine level of at least 2-fold or a serum creatinine level of >=3.96 mg/dL with an increase of >=0.5 mg/dL); main secondary outcomes were incidence of RRT use and in-hospital mortality. RESULTS: In the buffered crystalloid group, 102 of 1067 patients (9.6%) developed AKI within 90 days after enrollment compared with 94 of 1025 patients (9.2%) in the saline group (absolute difference, 0.4% [95% CI, -2.1% to 2.9%]; relative risk [RR], 1.04 [95% CI, 0.80 to 1.36]; P = .77). In the buffered crystalloid group, RRT was used in 38 of 1152 patients (3.3%) compared with 38 of 1110 patients (3.4%) in the saline group (absolute difference, -0.1% [95% CI, -1.6% to 1.4%]; RR, 0.96 [95% CI, 0.62 to 1.50]; P = .91). Overall, 87 of 1152 patients (7.6%) in the buffered crystalloid group and 95 of 1110 patients (8.6%) in the saline group died in the hospital (absolute difference, -1.0% [95% CI, -3.3% to 1.2%]; RR, 0.88 [95% CI, 0.67 to 1.17]; P = .40). CONCLUSIONS AND RELEVANCE: Among patients receiving crystalloid fluid therapy in the ICU, use of a buffered crystalloid compared with saline did not reduce the risk of AKI. Further large randomized clinical trials are needed to assess efficacy in higher-risk populations and to measure clinical outcomes such as mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier: ACTRN12613001370796.